PMID- 25813071 TI - Consumption of black and green teas as a dietary source of polyphenols in Polish inhabitants of the Mazovian region. AB - BACKGROUND: Tea is a very popular drink throughout many parts of the world, that includes Poland. The tea infusion (cup of tea) itself contains phenolic compounds with anti-oxidant properties that constitute 30% of the dry mass of tea leaves responsible for a health promoting effect on the human body. OBJECTIVES: To estimate the determinants and amounts of black and green tea consumed by a selected population group, along with their polyphenols intake from tea. MATERIAL AND METHODS: A survey was conducted of 281 subjects in 2012 from the Mazovian region of Poland, recruited from social-networking sites which had been sent a web application questionnaire (Mini-ankiety.pl). RESULTS: Subjects were aged 18 56 years, of whom the majority (73%) were aged 21-30 years. City dwellers constituted 86%, whilst those remaining were from small towns (14%). Black tea was drunk by 80% of whom 39% did so daily, whilst green tea was drunk by 72% of whom 17% did so daily. Determinants affecting the amounts of tea drinking were principally gender, education, place of residence and number of household members. Women significantly drank more than one cup of green tea daily compared to men. Those with a higher education significantly drank more than one cup of black tea daily compared to those with lower education levels. Homeowning subjects with 2 household members significantly drank more than one cup of green tea daily than the others. The average daily intakes of polyphenols from black tea in those who drank so regularly was 503 mg and that for green tea was 361 mg. CONCLUSIONS: The main source of tea polyphenols was found to be black tea as this was drunk more often than green tea. There is a need for promoting more green tea to be drunk as a source of polyphenols. PMID- 25813072 TI - Studies to determine whether underground waters in Wielkopolska Region (Poland) containing humus substances are suitable for practical purposes. AB - BACKGROUND: Water derived from Miocene aquifer in Wielkopolska region (Poland) has a 'brown-black' colouration resulting from humus substances. Because this colour is difficult to remove, such water is considered unfit for human consumption. The presence of naturally occurring humus acids with known biochemical properties may however lend such water for use in medicine, cosmetics or agriculture. OBJECTIVES: To determine and evaluate the properties of 'brown black' Miocene waters from analysing their physico-chemistry properties, mineral content and the presence and structures of humus acids. MATERIAL AND METHODS: The test material was 4 samples of intensely coloured 'brown-black' underground waters from Miocene aquifer taken from the Greater Poland region at different locations; Obrzycko and Braczewo (both by Szamotuly), Sepno (by Koscian) and in Poznan (Szkolna Street). RESULTS: The water type was HCO3-Cl-Na with dissolved minerals ranging at concentrations of 828.5 mg/dm3 (Poznan) to 1600.5 mg/dm3 (Obrzycko). Fluorides were present at 0.71 mg/dm3 (Poznan) to 1.41 mg/dm3 (Braczewo) whilst iron (II) (ferrous ion) ranged from >10 mg/dm3 (Obrzycko) to 22.7 mg/dm3 (Sepno). Levels of humus acids varied between 188.6 mg/dm3 (Sepno) to 1501.8 mg/dm3 (Obrzycko) with predomination humic acids over hymatomelanic acids by factors from 1.3 to 10.6. CONCLUSIONS: Due to the test water's mineral content, which includes significant levels of iron II, fluoride and humus acids (>50 mg/dm3), it is suggested that it has therapeutic value and is suitable for medicinal bath treatments and in manufacturing medical products or cosmetics. PMID- 25813073 TI - Profiles of selected nutrients affecting skin condition in children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammation of the skin recognised to be one of the first clinical signs of allergy. In the first years of life, epidemiological evidence has demonstrated that common causative foods of a child's diet are: cow's milk, hen's eggs, wheat and soya. Children with AD being treated with elimination diets are at risk of nutritional deficiencies that include those nutrients required for ensuring proper skin structure and function. OBJECTIVES: The aim of the study was to assess dietary intake of nutrients which affect skin condition in children with AD being treated with a milk-free diet. MATERIAL AND METHODS: Subjects were 25 children aged 4-6 years with AD undergoing the milk exclusion diet and 25 age-matched healthy controls. The energy and nutritional value of diets were evaluated that included those components affecting skin condition; ie. vitamins A, D, E, B2 and C; minerals iron (Fe) and zinc (Zn); polyunsaturated fatty acids (PUFAs). The Dieta 5.0 programme was used for dietary assessment and outcomes were then related to dietary recommendations. RESULTS: There were no significant differences between groups in mean energy values and mean intakes of protein, fats and carbohydrates (p>0.05). The percentage of subjects with low energy value were 44% and 36% in respectively Groups I and II. Deficiencies of fat intake were observed in 60% in Group I and 44% in Group II. There were however no risks in the dietary intakes of protein, carbohydrate, vitamins A, B2 and C nor of Fe and Zn. Deficiencies of dietary intakes were observed in respectively Groups I and II in the following; vitamin E (24% vs 64%), vitamin D (36% vs 92%), linoleic acid (36% vs 72%), alpha-linolenic acid (36% vs 40%) and long chain PUFAs (96% in both groups). CONCLUSIONS: Ensuring recommended dietary supply of those nutrients affecting skin condition is required for both groups of children. Children with AD had better balanced diets in respect of the studied nutrients that may reflect the influence of continuous healthcare received from physicians and dieticians. PMID- 25813074 TI - Dietary sources of lutein in adults suffering eye disease (AMD/cataracts). AB - BACKGROUND: Epidemiological studies indicate that by consuming 6-14 mg lutein daily, the risk of acquiring eye diseases like age-related macular degeneration (AMD) or cataracts becomes reduced. Their symptoms can also by such means be alleviated and treatment improved. OBJECTIVES: To estimate dietary intakes of lutein obtained from foodstuffs and supplements along with determining its main sources in selected groups of adults suffering from eye disease and healthy controls. MATERIAL AND METHODS: The study was performed in Warsaw and its neighbourhoods during 2008-12. Subjects were 375 adults aged 50-97 years, of whom half had been diagnosed with AMD and/or cataracts; constituting the test group. Dietary intakes of lutein were assessed by Food Frequency Questionnaire Method whilst interview questionnaires assessed the intake of supplements. RESULTS: Overall, the average dietary intake of lutein from foodstuffs was 2.5 mg daily, with the test group being significantly higher than healthy controls (2.9 vs 2.1 mg daily). Women's intakes were also higher than in men (2.9 vs 2.1 mg daily), as were those possessing higher or secondary education compared to the others with primary or vocational education (2.7 vs 2.3 mg daily). Fresh vegetables were found to be the main dietary sources of lutein that included green leafy vegetables and frozen vegetables, constituting respectively 63% and 13% of the dietary intake. Dietary supplements containing lutein were taken by 109 subjects of whom most had eye disease (over 80%); where the average daily consumption of lutein from this source was 6.5 mg. CONCLUSIONS: For older people, the dietary intake of lutein from foodstuffs may be insufficient to prevent eye disease. Taking daily dietary supplements would thus be indicated to make up such deficiencies of lutein. PMID- 25813075 TI - Evaluation of mineral status in hypertensive patients undergoing pharmacotherapy. AB - BACKGROUND: The widespread and increasing occurrence of obesity, hypertension and associated disease has necessitated serial testing in order that risks of contracting such conditions become minimised through appropriate therapy and prevention. Many studies report that nutritional factors significantly affect the aetiology of hypertension and obesity that include mineral uptake. There are only a few studies however which are focused on the body's changing mineral content during pharmaco-therapeutic treatment. OBJECTIVES: To determine concentrations of minerals in the hair and urine of hypertensive patients in conjunction with assessing their nutrition. MATERIAL AND METHODS: Subjects were 17 patients presenting with essential hypertension and 18 healthy controls. Atomic absorption spectrometry (AAS) was used to measure Mg, Ca, Fe, Zn and Cu in the hair and urine on a Zeiss AAS-3 instrument. Dietary mineral intakes were assessed by interview over 24 hours prior to the analysis. RESULTS: The hypertensive group had significantly lower urine concentrations of Ca and Mg as well as Mg and Zn in hair. Urinary zinc excretion was significantly increased in this group compared to controls, but dietary intakes of Cu were reduced. The dietary mineral intakes were found to be unrelated to the concentrations of such minerals in the hair and urine. CONCLUSIONS: Compared to controls, excretion of Ca and Mg were reduced in hypertensive subjects, whereas Zn excretion was higher, and Mg and Zn were relatively low in the hair. Daily dietary intakes of Cu were also reduced in the hypertensive. PMID- 25813076 TI - The effect of girls attitudes towards the health benefits of food on selected dietary characteristics. The GEBahealth Project. AB - BACKGROUND: Dietary habits are formed at an early age and to a large extent they affect such nutritional behaviour in adulthood. Mothers in particular, influence family nutrition. In this respect, their knowledge, attitudes and behaviour about nutrition are responsible for the schooling of future generations. Many aspects of the link between food and health with nutritional behaviour in girls remain, however, unknown. OBJECTIVES: To determine the effect of girls attitudes towards the health benefits of food on selected dietary characteristics. MATERIAL AND METHODS: Study included 186 girls aged 13-21 years. Using a food frequency method the three dietary characteristics were obtained; food intake variety, fibre intake and fat intake, all of them expressed by a graded scale. Three validated questionnaires were used; FIVeQ, BSQFVF and BSQF. The girls attitudes towards the health benefits of food were rated from one of the survey's six parts, comprising of 8 statements from the Health and Taste Attitude Scale (HTAS) accordingly graded. Statistical analyses used logistic regression. RESULTS: The mean index of food intake variety was 28.7 foods/week (ranging 0-60), whilst the mean dietary intakes of fibre and fat were 16.7 points (0-36 range) and 18.2 points (0-52 range), respectively. Girls from the upper tertile with favourable attitudes on food health benefits had an odds ratio (OR) for adequate fat intake (<22 points) of 3.1 (95% CI: 1.28, 7.52; p<0.05), as compared to those from the middle-neutral attitudes tertile, with an OR = 1.00. The ORs for the relatively high food intake variety and acceptable fibre intake were 1.05 in girls from the positive-upper tertiles, which were not significant. CONCLUSIONS: The positive attitudes of girls towards the health benefits of food are conducive for making more favourable food choices and lowered dietary fat intake, however this did not significantly affect fibre intake nor food intake variety. PMID- 25813077 TI - Anthropometric assessment of the nutritional status of children and adolescents residing in selected Polish orphanages based on their energy intake and physical activity level. AB - BACKGROUND: Actions to the prevention of overweight and obesity should be first addressed to the youngest population and their parents, guardians as well as teachers. The major objectives of prevention and treatment of overweight and obesity programme should be focused on modification of nutritional habits and promotion of physical activity. OBJECTIVES: The aim of this study was to evaluate the nutritional status, intake of energy and macronutrients as well as the physical activity of students from orphanages in Krakow. MATERIAL AND METHODS: Study was performed in 5 orphanages located in Krakow (Poland), which were under control of Social Welfare Centre in Krakow. The study involved 153 students, 67 girls and 86 boys, aged from 7 to 20 years. Nutritional status was assessed by anthropometric measurements. The protein and total fat content in diets was measured by chemical analyses and carbohydrates were calculated by difference. Physical activity level of children and adolescents was assessed by questionnaire. RESULTS: Over 80% of boys and about 90% of girls had a normal body mass. Students have spent their free time on additional physical activity from 1h 34 min/day to 5 h 12 min/day. They also have spent their free time on sedentary activities on average 4 h/day. Daily diets of students did not met recommendations for energy, carbohydrates and fats. Intake of protein was too high and exceeded the estimated average requirement even over three times. CONCLUSIONS: Despite the insufficient intake of fat and carbohydrates, students generally showed a proper BMI value. This suggests that excess intake of protein was used for maturation process and was additional source of energy. Reported additional physical activity was satisfactory. PMID- 25813078 TI - Influence of non-dietary factors on the prevalence of abdominal obesity as a major component of the metabolic syndrome among 17-18-year-old youth. AB - BACKGROUND: Youth nutrition and their nutritional status are conditioned by many factors, some of the main ones being: economic, social, climatic, cultural, and psychological factors as well as nutritional knowledge. With the growing problem of overweight and obesity among children and young people, the incidence of the metabolic syndrome is also increasing. OBJECTIVES: The aim of the study was to assess the impact of demographic, sociological and psychological factors on the incidence of obesity among 17-18-year-old adolescents from Wroclaw and vicinity as a major risk factor for the development of the metabolic syndrome. MATERIAL AND METHODS: The study was conducted in three upper-secondary schools in Wroclaw, Poland. In the surveyed group (17-18 years old, n = 269) girls accounted for 59.5% and boys constituted 40.5%. Majority of young people were Wroclaw citizens (72.9%). Centile charts elaborated by the Children's Memorial Health Institute were adopted for the evaluation of anthropometric parameters. Evaluation of the impact of non-dietary factors on the manner of nutrition was carried out using own questionnaire. RESULTS: Based on the tests, abdominal obesity was determined among 34.5% of adolescents aged 17 years and among 65.5% of these aged 18 years. Obesity was more common in girls carrying genetic burden of the disease. Youth with the largest waist circumference most often declared to use slimming diets - 6.7%, and the lowest hunger sensation in stress - 3.4%. In addition, 30.5% of the adolescents with the smallest waist circumference and 11.5% with the largest waist circumference declared to be non-smoking. Occasional alcohol consumption was declared by 30.1% of young people with the smallest waist circumference, and 13.4% with the largest waist circumference. CONCLUSIONS: Youth with abdominal obesity significantly more likely than those with normal waist circumference applied slimming diets. Significant impact on the formation of abdominal obesity among girls had inherited disease burden. PMID- 25813079 TI - NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. PMID- 25813081 TI - Kinematic, kinetic and EMG analysis of four front crawl flip turn techniques. AB - This study aimed to analyse the kinematic, kinetic and electromyographic characteristics of four front crawl flip turn technique variants. The variants distinguished from each other by differences in body position (i.e., dorsal, lateral, ventral) during rolling, wall support, pushing and gliding phases. Seventeen highly trained swimmers (17.9 +/- 3.2 years old) participated in interventional sessions and performed three trials of each variant, being monitored with a 3-D video system, a force platform and an electromyography (EMG) system. Studied variables: rolling time and distance, wall support time, push-off time, peak force and horizontal impulse at wall support and push-off, centre of mass horizontal velocity at the end of the push-off, gliding time, centre of mass depth, distance, average and final velocity during gliding, total turn time and electrical activity of Gastrocnemius Medialis, Tibialis Anterior, Biceps Femoris and Vastus Lateralis muscles. Depending on the variant, total turn time ranged from 2.37 +/- 0.32 to 2.43 +/- 0.33 s, push-off force from 1.86 +/- 0.33 to 1.92 +/- 0.26 BW and centre of mass velocity during gliding from 1.78 +/- 0.21 to 1.94 +/- 0.22 m . s(-1). The variants were not distinguishable in terms of kinematical, kinetic and EMG parameters during the rolling, wall support, pushing and gliding phases. PMID- 25813080 TI - Etiology, clinical course and outcome of healthcare-associated bloodstream infections in patients with hematological malignancies: a retrospective study of 350 patients in a Finnish tertiary care hospital. AB - This retrospectively collected laboratory-based surveillance data includes 575 healthcare-associated bloodstream infections (BSIs) in 350 patients with hematological malignancy in Tampere University Hospital, Finland, during 1999 2001 and 2005-2010. The most common underlying diseases were acute myelogenous leukemia (n=283, 49%), followed by myeloma (n=87, 15%) and acute lymphocytic leukemia (n=76, 13%). The overall rate was 9.1 BSIs per 1000 patient-days. Gram positive BSIs predominated and the most common pathogens were coagulase-negative staphylococci (23%), viridans streptococci (11%), enterococci (9%) and Escherichia coli (9%). Fungi caused 2% of BSIs. The 7-day and 28-day case fatalities were 5% and 10% and were highest in BSIs caused by P. aeruginosa (19% and 34%, respectively). The median age of patients with BSI has increased; it was 55.0 years during 1999-2001, compared to 59.0 years in 2005-2007 and 59.0 years in 2008-2010 (p<0.0001). Gram-positive bacteria predominated in this material. Case fatalities were low as compared to previous reports although the median age of patients increased. PMID- 25813082 TI - Phytochemical screening and antimicrobial activities of the constituents isolated from Koelreuteria paniculata leaves. AB - Methanolic extract of Golden rain leaves was fractionated by column chromatography on silica gel and 18 fractions were obtained. Antimicrobial activities of fractions were investigated against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa as quality control bacteria and fungus Pyricularia grisea which causes Blast disease in rice. Fractions showed more antibacterial activity at 0.04 g/mL concentration only on B. subtilis and S. aureus as gram positive bacteria. Also, three fractions indicated excellent antifungal effect on fungus P. grisea. Moreover, in the present study, fractions that showed very good effect on microorganisms were used for gas chromatography-mass spectrometry analysis to identify different phytochemicals. PMID- 25813083 TI - Hyperbaric oxygen for idiopathic sudden hearing loss: is the routine application helpful? AB - CONCLUSION: We recommend the routine application of hyperbaric oxygen (HBO) in conjunction with intravenous steroid (IVS) for all patients with idiopathic sudden sensorineural hearing loss (ISSNHL). For best results, this therapy must be started within 14 days. OBJECTIVE: To investigate the necessity of routine application of HBO therapy for ISSNHL. METHODS: This was a retrospective cohort study. A total of 300 patients (300 diseased ears) were divided into 3 groups according to the therapy received: IVS (group A), HBO (group B), or IVS + HBO (group C). Patients in each treatment group were subdivided into subgroups according to the time of therapy initiation. The outcomes of their hearing recovery were classified into three recovery grades: good, fair, and poor. RESULTS: The proportion of patients responding to therapy and those with complete recovery was the highest in the combined treatment group, 84% and 58%, respectively, regardless of the initial hearing levels. In all the groups, mean gains of cases in whom therapy was started in the first 2 weeks were significantly higher (p < 0.05) and hypercholesterolemia (>240 mg/dl) caused significantly worse responses (p < 0.05). PMID- 25813084 TI - Magnetoelectric quasi-(0-3) nanocomposite heterostructures. AB - Magnetoelectric composite thin films hold substantial promise for applications in novel multifunctional devices. However, there are presently shortcomings for both the extensively studied bilayer epitaxial (2-2) and vertically architectured nanocomposite (1-3) film systems, restricting their applications. Here we design a novel growth strategy to fabricate an architectured nanocomposite heterostructure with magnetic quasiparticles (0) embedded in a ferroelectric film matrix (3) by alternately growing (2-2) and (1-3) layers within the film. The new heteroepitaxial films not only overcome the clamping effect from substrate, but also significantly suppress the leakage current paths through the ferromagnetic phase. We demonstrate, by focusing on switching characteristics of the piezoresponse, that the heterostructure shows magnetic field dependence of piezoelectricity due to the improved coupling enabled by good connectivity amongst the piezoelectric and magnetostrictive phases. This new architectured magnetoelectric heterostructures may open a new avenue for applications of magnetoelectric films in micro-devices. PMID- 25813086 TI - Mandibular trauma: a two-centre study. AB - The aims of this study were to assess and compare epidemiological data on mandibular fractures from two European centres and to perform a review of the literature. Between 2001 and 2010, a total of 752 patients with a total of 1167 mandibular fractures were admitted to a hospital in Turin, and 245 patients with a total of 434 mandibular fractures were admitted to a hospital in Amsterdam. The mean age in Turin was 34.8 years and in Amsterdam was 32 years. The age group 20 29 years showed the highest incidence of mandibular fractures in both centres. The fractures were mainly the result of assaults, in agreement with several articles in the recent literature, followed by falls. The continuous long-term and multicentre collection of data on the epidemiology of maxillofacial trauma is important because it provides the information necessary for the development of preventative measures aimed at reducing the incidence of facial injuries. PMID- 25813087 TI - Raloxifene enhances peri-implant bone healing in osteoporotic rats. AB - The aim of this study was to evaluate bone healing at the bone-implant interface in rats with induced osteoporosis. The rats underwent a bilateral ovariectomy (OVX) and were fed a low calcium and phosphate diet. The OVX rats were divided into three groups: one was treated with raloxifene (OVX-RAL), one with alendronate (OVX-ALE), and one received no medication (OVX-NT). The control group rats (SHAM-DN) underwent sham surgery and were fed a normal diet. Each animal received one implant in each tibia: a machined surface implant in the right tibia and an implant with surface etching in the left tibia. All animals were euthanized after 42 days. Analysis of variance (ANOVA) and Tukey post hoc tests were applied to the biomechanics (reverse torque) and bone-implant contact (BIC) data (P<0.05). The RAL and ALE groups showed improved peri-implant bone healing. However, the ALE group showed no significant difference from the OVX-NT group. Surface treatment promoted higher corticalization at the bone-implant interface, but showed the same characteristics of mature bone and bone neoformation in concentric laminations as the machined implant. There were no statistically significant differences in reverse torque (P=0.861) or BIC (P=0.745) between the OVX-RAL and SHAM-DN groups. Therefore, the use of raloxifene resulted in good biomechanical, BIC, and histological findings in the treatment of induced osteoporosis in rats. PMID- 25813085 TI - Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. AB - Here we show that iNOS-deficient mice display enhanced classically activated M1 macrophage polarization without major effects on alternatively activated M2 macrophages. eNOS and nNOS mutant mice show comparable M1 macrophage polarization compared with wild-type control mice. Addition of N6-(1-iminoethyl)-L-lysine dihydrochloride, an iNOS inhibitor, significantly enhances M1 macrophage polarization while S-nitroso-N-acetylpenicillamine, a NO donor, suppresses M1 macrophage polarization. NO derived from iNOS mediates nitration of tyrosine residues in IRF5 protein, leading to the suppression of IRF5-targeted M1 macrophage signature gene activation. Computational analyses corroborate a circuit that fine-tunes the expression of IL-12 by iNOS in macrophages, potentially enabling versatile responses based on changing microenvironments. Finally, studies of an experimental model of endotoxin shock show that iNOS deficiency results in more severe inflammation with an enhanced M1 macrophage activation phenotype. These results suggest that NO derived from iNOS in activated macrophages suppresses M1 macrophage polarization. PMID- 25813088 TI - Microsurgical free flap reconstructions of the head and neck region: Shanghai experience of 34 years and 4640 flaps. AB - This study represents the surgical experience of 4481 microvascular free flap cases performed at the authors' institution in China, between 1979 and 2013. Four thousand four hundred and eighty-one patients underwent reconstruction with 4640 flaps: 56% radial forearm flaps, 8% iliac crest flaps, 13% fibula flaps, 10% anterolateral thigh flaps, and other flaps. In the overwhelming majority of cases, the flap transfer was required following tumour resection (97.5%). Three hundred and twenty minor complications (6.9%) occurred. One hundred and eighteen major complications (2.5%) were encountered: 114 cases of failure (2.4%) and four deaths. Among the 118 cases with major complications, 26 - 22.0% - had received radiotherapy; this proportion was higher than the 6.9% in the minor complications group and 8.1% in the non-intervention group. Venous thrombosis was the most common complication at the recipient site and was the main cause of flap failure. When a compromised flap is identified, surgical re-exploration should not be delayed. This study confirms that free flaps are reliable in achieving successful reconstruction in the head and neck region; however this technique requires extensive clinical experience. Owing to the large number of flap options, microsurgeons should always pay attention to the details of the different surgical defects and choose the most appropriate flap. PMID- 25813089 TI - Regenerating the cell resistance of micromolded PEG hydrogels. AB - Polydimethylsiloxane stamp materials used during soft lithography undermine the non-fouling behaviour of bio-inert PEG-based hydrogels, resulting in increased protein adsorption and cell adhesion and migration on the gel. This previously unreported phenomenon undermines the function of lab-on-a-chip devices that require the device to be bio-inert, and slows the implementation of promising micromolding and imprinting methods for 3D culture and commercial cell culture systems. We illustrate that the degree of cell adhesion and protein adsorption to the gels correlates with the amount of residual stamp material remaining at the hydrogel interface after fabrication. After identifying this previously unreported phenomenon, we screened multiple polymer cleaning/fabrication techniques in order to maintain/restore the non-fouling properties of the gels including PDMS curing and extraction, use of other common soft lithography stamp materials, post-fabrication cleaning of the hydrogels, and changing the composition of the hydrogel. The optimal solution was determined to be incorporation of reactive sites into the hydrogel during micromolding followed by grafting of PEG macromers to these sites post-fabrication. This treatment resulted in micromolded hydrogels with robust cell resistant properties. Broadly, this work identifies and solves a previously unreported problem in hydrogel micromolding, and specifically reports the development of a cell culture platform that when combined with video microscopy enables high-resolution in situ study of single cell behaviour during in vitro culture. PMID- 25813090 TI - Impact of TiO2 nanoparticles on freshwater bacteria from three Swedish lakes. AB - Due to the rapidly rising production and usage of nano-enabled products, aquatic environments are increasingly exposed to engineered nanoparticles (ENPs), causing concerns about their potential negative effects. In this study we assessed the effects of uncoated titanium dioxide nanoparticles (TiO2NPs) on the growth and activity of bacterial communities of three Swedish lakes featuring different chemical characteristics such as dissolved organic carbon (DOC) concentration, pH and elemental composition. TiO2NP exposure concentrations were 15, 100, and 1000 MUg L(-1), and experiments were performed in situ under three light regimes: darkness, photosynthetically active radiation (PAR), and ambient sunlight including UV radiation (UVR). The nanoparticles were most stable in lake water with high DOC and low chemical element concentrations. At the highest exposure concentration (1000 MUg L(-1) TiO2NP) the bacterial abundance was significantly reduced in all lake waters. In the medium and high DOC lake waters, exposure concentrations of 100 MUg L(-1) TiO2NP caused significant reductions in bacterial abundance. The cell-specific bacterial activity was significantly enhanced at high TiO2NP exposure concentrations, indicating the loss of nanoparticle sensitive bacteria and a subsequent increased activity by tolerant ones. No UV induced phototoxic effect of TiO2NP was found in this study. We conclude that in freshwater lakes with high DOC and low chemical element concentrations, uncoated TiO2NPs show an enhanced stability and can significantly reduce bacterial abundance at relatively low exposure concentrations. PMID- 25813091 TI - The emerging role of miRNAs in combined cancer therapy. AB - MicroRNAs (miRNAs) control physiological and fundamental processes in cellular development and differentiation by modulating the expression of their target genes. They have been found to participate in cell transformation and multiplication by functioning as oncomiRs and tumor suppressors in diverse cancers. Introduction of antisense miRNAs (antagomiRs) into primary cells such as immune cells by lipofection, viral vectors or electroporation can achieve the specific silencing of individual miRNAs. Therefore, harnessing miRNAs may lead to promising cancer therapeutics. There is emerging evidence demonstrating the involvement of miRNAs in combined cancer therapies, including chemotherapy, radiotherapy and immunotherapy combining with miRNA therapy. PMID- 25813092 TI - Dawn simulation light: a potential cardiac events protector. AB - OBJECTIVE/BACKGROUND: Major cardiovascular events frequently increase in the morning due to abrupt changes in the sympatho-vagal cardiac control during the transition from sleep to wakefulness. These neural changes are translated into stepwise increases in cardiac functions, resulting in a potential cardiovascular stress. Here, we explored whether light can "optimize" heart rate and its neural control, by actively promoting a less steep transition from sleep to wakefulness, thus minimizing morning cardiovascular vulnerability. METHODS: Seventeen healthy young men were awakened 2-hours before their habitual wake-time. In a counterbalanced within-subject design, we applied a control condition (darkness during sleep and dim light during wakefulness) or dawn-simulation-light (DSL) starting 30-minutes before and ending 30-minutes after scheduled wake-up time. RESULTS: Our data reveal a significantly gradient reduction in heart rate during the transition from sleep to wakefulness, when applying DSL as compared to a control condition. Likewise, cardiac sympatho-vagal control smoothly increased throughout the 30-min sleep episode preceding scheduled wake-up under DSL and remained stable for the first 30-min of wakefulness. Interestingly, these effects were mostly driven by changes in the parasympathetic cardiac control. CONCLUSIONS: Our data demonstrate for the first time that a non-invasive strategy, as light exposure surrounding the wake-up process, can significantly reduce the deleterious sleep-to-wake evoked cardiac modulation in healthy young men awakened under conditions of increased sleep pressure. A translational approach of this light exposure, which closely resembles natural lighting conditions in the morning, may therefore act as a potential protector for cardiac vulnerability in the critical morning hours. PMID- 25813093 TI - Recent Developments in the Preparation and Chemistry of Metallacycles and Metallacages via Coordination. PMID- 25813094 TI - Demethoxycurcumin induces the apoptosis of human lung cancer NCI-H460 cells through the mitochondrial-dependent pathway. AB - Lung cancer is the most common cause of cancer-related mortality in the US as well as other regions of the world. Curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the major components of Curcuma longa L. It has been reported that curcumin inhibits the growth of various types of cancer cells in vitro and in vivo. However, the mechanisms involved in the inhibition of cell growth and induced apoptosis by DMC in human lung cancer cells remain unclear. In the present study, we investigated the effect of DMC on cell death via the induction of apoptosis in NCI-H460 human lung cancer cells. Flow cytometric assay was used to examine the total percentage of viable cells, the population of cells in the sub-G1 phase of the cell cycle, the level of reactive oxygen species (ROS), Ca2+ production, mitochondrial membrane potential (DeltaPsim) and caspase activity. Western blotting was used to examine the changes in the expression of cell cycle- and apoptosis-associated proteins. Confocal microscopy was used to examine the translocation of apoptosis-associated proteins. The results indicated that DMC significantly induced cell morphological changes and decreased the percentage of viable NCI-H460 cells and DMC induced apoptosis based on the cell distribution in the sub-G1 phase. Moreover, DMC promoted ROS and Ca2+ production and decreased the level of DeltaPsim and promoted the activities of caspase-3, -8 and -9. The Western blotting results showed that DMC promoted the expression of AIF, Endo G and PARP. The levels of Fas ligand (Fas L) and Fas were also upregulated. Furthermore, DMC promoted expression of ER stress-associated proteins such as GRP78, GADD153, IRE1beta, ATF-6alpha, ATF-6beta and caspase-4. Based on the findings, we suggest that DMC may be used as a novel anticancer agent for the treatment of lung cancer in the future. PMID- 25813095 TI - [Psychiatric comorbidities and quality of life in adult individuals with high potential: Relationships with self-esteem]. AB - OBJECTIVE: The objectives of this study were: 1) to describe the psychiatric comorbidities in adult individuals with high potential; 2) to assess self-esteem and quality of life in comparison with general population; 3) to study the relationships between intelligent quotient (IQ), self-esteem, psychiatric comorbidities and quality of life. METHODS: This cross-sectional study was conducted in the psychiatric department of a public university hospital (Marseille, France). An outpatient hospital service has been specifically opened to test intelligence since 2012. During a period of six months, it was proposed to all the major individuals with high intellectual potential to receive a psychiatric evaluation using the Mini International Neuropsychiatric Interview (MINI) and to complete self-report questionnaires assessing depression (Beck scale), anxiety (STAI), self-esteem (Rosenberg scale) and quality of life (SF 36). Relationships between IQ, self-esteem, psychiatric comorbidities and quality of life were analyzed using a Bayesian path analysis. RESULTS: Twenty-eight subjects were included, 8 had an IQ between 115 and 130, and 20 had an IQ>130. Fifty-seven percent of individuals had generalized anxiety, 21.4% a current major depressive episode, and 75% a past major depressive episode. Subjects had a low self-esteem and quality of life levels significantly lower than those in the French general population. Subjects with higher self-esteem levels had more depressive (beta=0.726, P<0.001) and anxiety (beta=0.335, P<0.001) disorders, associated with lower quality of life levels (beta=-0.447, P<0.001 and beta= 0.276, P=0.012), suggesting that self-esteem was defensive and inadequate. CONCLUSION: Our study found a high frequency of psychiatric disorders associated with low levels of self-esteem and quality of life. A psychological treatment focusing on self-esteem may have a beneficial effect on anxiety, depression and quality of life. PMID- 25813096 TI - [Management of symptoms and pain at the end of life]. PMID- 25813097 TI - [Is there a place of multiantigenes immunodot determination in systemic sclerosis patients without anti-centromeres or anti-Scl70 antibodies?]. PMID- 25813098 TI - [The Smallpox case]. PMID- 25813099 TI - Update on clinically isolated syndrome. AB - Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple sclerosis (MS) in young adults. They are called "clinically isolated syndrome" (CIS) and correspond to the typical first multiple sclerosis (MS) episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of differential diagnosis. After a CIS, the delay of apparition of a relapse, which corresponds to the conversion to clinically definite MS (CDMS), varies from several months to more than 10 years (10-15% of cases, generally called benign RRMS). This delay is generally associated with the number and location of demyelinating lesions of the brain and spinal cord and the results of CSF analysis. Several studies comparing different MRI criteria for dissemination in space and dissemination in time of demyelinating lesions, two hallmarks of MS, provided enough substantial data to update diagnostic criteria for MS after a CIS. In the last revision of the McDonald's criteria in 2010, diagnostic criteria were simplified and now the diagnosis can be made by a single initial scan that proves the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions. However, time to conversion remains highly unpredictable for a given patient and CIS can remain isolated, especially for idiopathic unilateral optic neuritis or myelitis. Univariate analyses of clinical, radiological, biological or electrophysiological characteristics of CIS patients in small series identified numerous risk factors of rapid conversion to MS. However, large series of CIS patients analyzing several characteristics of CIS patients and the influence of disease modifying therapies brought important information about the risk of CDMS or RRMS over up to 20 years of follow-up. They confirmed the importance of the initial MRI pattern of demyelinating lesions and of CSF oligoclonal bands. Available treatments of MS (immunomodulators or immunosuppressants) have also shown unequivocal efficacy to slow the conversion to RRMS after a CIS, but they could be unnecessary for patients with benign RRMS. Beyond diagnostic criteria, knowledge of established and potential risk factors of conversion to MS and of disability progression is essential for CIS patients' follow-up and initiation of disease modifying therapies. PMID- 25813100 TI - [Evolution of patients' rights at the end of life]. AB - Since the early 1999, palliative cares were legally allowed in France. The rights of end of life'patients have been reinforced by the Kouchner law in 2002 and by the Leonetti law in 2005. During the last decade, several critical conditions of end of life showed the weaknesses of the Leonetti law however different assessments of this law recently carried out by officials, revealed that healthcare providers and general population were unfamiliar with this law. Before adopting new legislation, there is a huge need to promote palliative care and to train healthcare providers and general population to manage the last moments of end of life. PMID- 25813101 TI - The autoimmune concept of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). With growing evidence for environmental and genetic factors, MS is now accepted as an autoimmune disease. This complex disease seems to implicate various cell types in both innate and adaptive compartments. Here, we discuss recent advances in the immunological field of MS research. PMID- 25813102 TI - Update on treatments in multiple sclerosis. AB - While there is no cure for multiple sclerosis (MS), numerous disease-modifying drugs are now available to treat MS patients. In fact, the therapeutic strategies are now more and more complex, directly impacting the management of patients. Despite the good safety profile of the first-line immunomodulatory drugs, the clinical response is often suboptimal. Important questions remain about the right timing to switch for a second-line agent and whether escalation therapy is an appropriate therapeutic strategy. In this review, we conducted a systematic search by PubMed using the terms: treatment, multiple sclerosis, therapeutic, DMT and treatment response. Randomized trials and reviews addressing MS, DMTs and management strategies were selected and included in this review. Herein, we present the currently approved and emerging drugs used for the treatment of MS with their relative benefit/risk profiles, and their respective positions in the therapeutic arsenal. We then focused on the different therapeutic strategies and criteria available to evaluate the response to disease-modifying therapies (DMTs). PMID- 25813103 TI - Soluble uric acid increases NALP3 inflammasome and interleukin-1beta expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway. AB - Urate crystals activate innate immunity through Toll like receptor 4 (TLR4) activation, leading to the formation of the NACHT, LRR and PYD domains-containing protein 3 [NALP3; also known as NOD-like receptor family, pyrin domain containing 3 (NALP3) and cryopyrin] inflammasome, caspase-1 activation and interleukin (IL) 1beta expression in gout. However, whether elevated serum uric acid (UA) levels are associated with the development and progression of renal diseases without renal urate crystal deposition remains unknown. In the present study, human primary renal proximal tubule epithelial cells were incubated with soluble UA (100 ug/ml) with or without the TLR4 inhibitor, TAK242 (1 uM). The gene expression and protein synthesis of TLR4, NALP3, caspase-1, IL-1beta and intercellular adhesion molecule-1 (ICAM-1) were detected by real-time PCR, ELISA, western blot analysis and fluorescence-activated cell sorting (FACS), respectively. Soluble UA significantly enhanced TLR4, NALP3, caspase-1, IL-1beta and ICAM-1 expression in the human primary renal proximal tubule epithelial cells. The TLR4 inhibitor, TAK242 effectively blocked the soluble UA-induced upregulation of TLR4, NALP3, caspase-1, IL-1beta and ICAM-1 expression in the human primary renal proximal tubule epithelial cells. Our findings indicate that soluble UA enhances NALP3 expression, caspase-1 activation, IL-1beta and ICAM-1 production in renal proximal tubule epithelial cells in a TLR4-dependent manner, suggesting the activation of innate immunity in human primary renal proximal tubule epithelial cells by soluble UA. PMID- 25813104 TI - Improved Outcomes for Women on the Heart Transplant Wait List in the Modern Era. AB - BACKGROUND: Whether the routine use of continuous-flow left ventricular assist devices (LVAD) has affected gender differences in outcomes for patients listed for heart transplantation (HT) is unclear. METHODS AND RESULTS: We identified 20,468 adults (25% women) listed as status 1A or 1B for HT from 2000 to 2014. Sex differences in removal from the wait list during the first 365 days due to death or deterioration was assessed with the use of Kaplan-Meier survival analysis. Patients were stratified according to listing before (era 1) or after (era 2) Food and Drug Administration approval of the Heartmate II LVAD on April 22, 2008. Freedom from death or deterioration on the wait list was higher for men than for women (70% vs 64%; P < .001). After adjusting for risk factors, women had a higher risk of removal from the wait list at 365 days during both era 1 (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.10-1.36; P < .001) and era 2 (HR 1.15, 95% CI 1.01-1.31; P = .029). Further adjustment for LVAD use eliminated the higher risk for women in era 2 (HR 1.14, 95% CI 0.99-1.29; P = .053) and not in era 1 (HR 1.22, 95% CI 1.10-1.36; P < .001). CONCLUSIONS: The higher risk for death or deterioration in women waiting for HT has improved in the modern era. PMID- 25813105 TI - [Evaluation of the feasibility of ultrasound in a community care outpatient pregnancy assessment clinic for high-risk pregnancies]. AB - OBJECTIVES: To assess the clinical, legal, and technical roles of ultrasound in an outpatient pregnancy assessment clinic, while evaluating the feasibility for these consultations to be performed at home. MATERIALS AND METHODS: We prospectively assessed all consultations from April 3 to May 31, 2013, at the outpatient pregnancy assessment clinic of La Pitie-Salpetriere, Paris, France. We recorded all procedures and the number and type of ultrasound examination performed, according to their indication. For each consultation, we evaluated whether the routine protocols were sufficient or if the attending obstetrician was asked for advice. Finally, we asked the patients if they would prefer having this consultation in a home-care setting. RESULTS: We recorded 429 consultations (n) for 234 patients (Np). Indications were diabetes (n=106/Np=59), assessment of fetal growth (n=90/Np=43), another single indication (n=106/Np=59), multiple indications (n=46/Np=12), term pregnancies (n=39/Np=30), and a history of abnormal pregnancy (n=27/Np=10). CTG was performed for 91 % of consultations, blood samples for 10 %, and ultrasound for 88 %, which included amniotic fluid evaluation (79 %), umbilical Doppler (69 %), fetal biometries (36 %), uterine artery Doppler (0.7 %), cervical length (2 %), suspicion of breech presentation (4 %) and placenta position (0.7 %). Most of these ultrasound examinations could not be financially value if performed by a midwife. Routine protocols were sufficient for the management of 68 % of these consultations, 26 % required the attending obstetrician, and 6 % were finally low-risk. Performing these consultations in a home-care setting was medically possible and requested by the patient for 16 % of consultations (6 % of patients). CONCLUSION: These are encouraging results to experiment the outpatient pregnancy assessment clinic in a home-care setting, although the financial valorization system in France is poorly adapted. PMID- 25813106 TI - Vision of the korean association of medical colleges. AB - The Korean Association of Medical Colleges (KAMC) has launched as a corporate aggregate in August 2008, since the inauguration meeting as "Korean Association of Medical School Deans" 24 years before. The mission of KAMC is to be the representing agency of medical education in Korea, producing policies and strategies, suggesting and influencing government agencies related to medical education. The KAMC will consolidate its basic role and continue to expand its role as well; evaluation of basic medical education, representative of graduate medical education, policy making of medical manpower education system. PMID- 25813107 TI - Application of computerized adaptive testing in medical education. AB - Application of computerized adaptive testing (CAT) in medical education is still spare in the high stakes examination or in the school-based examination. In the medical school in Belgium, CAT was used for an assessment tool in general practice as pilot test was reported. In Hallym University, CAT has been introduced in the evaluation of the students' performance as in-course general evaluation test and parasitology test. Another examples of application of CAT for high stakes examination are Medical Council of Canada Qualifying Examination - Part 1 in Canada and National Council Licensure EXamination - Registered Nurse in USA. CAT has some merits such as accurate estimation of the ability parameters of the examinees and the shorter period of examination. To apply the CAT in medical education more actively, medical teachers should have an interest in the modern measurement theories such as item response theory and technologies. It is still uncertain if CAT may be prosperous in the medical education as a tool for the measurement of the examinees' ability. However, we should prepare the era of application of CAT in high stakes examination such as medical licensing examination. PMID- 25813108 TI - Multiple mini-interview in selecting medical students. AB - PURPOSE: Selecting medical students through interviews seems difficult and the reliability of the results is one of the major concerns. The purpose of this study was to investigate the reliability and acceptability of the Multiple Mini Interview (MMI) in selecting medical students of Kangwon National University. METHODS: Eighty-four applicants participated in the MMI which consists of 3 8 minute stations that have 9 checklist items and 3 global items. The 3 domains that we chose were motivation to become a doctor, communication and interpersonal skills, and ethical decision-making. We placed 2 interviewers in each room. The interviewers were chosen from our faculty. We analyzed the reliability of the MMI with urGENOVA for PC. We conducted a survey of these applicants and interviewers. RESULTS: The reliability was 0.791. Students answered that the interview was impressive and enjoyable. Students were also satisfied with the level and quality of the MMI cases. They described that they were evaluated objectively. Interviewers also responded positively. They stated that more stations and more efforts to develop the cases were needed to improve the reliability and validity. CONCLUSION: The MMI was acceptable to our applicants and faculty. It is reliable for assessing medical school applicants in Korea. We should develop more stations and better cases to increase the reliability and validity of the MMI. PMID- 25813109 TI - The Relationship between Empathy and Medical Education System, Grades, and Personality in Medical College Students and Medical School Students. AB - PURPOSE: This study investigated the relationship between empathy and medical education system, grades, and personality in medical college (MC) students and medical school (MS) students. METHODS: One hundred fifty-five MC students and 137 MS students participated in this study, completing questionnaires on sociodemographic data, Jefferson Scale of Empathy, S-version, Korean edition (JSE S-K), and Temperament and Character Inventory (TCI). RESULTS: Reward Dependence (RD), Cooperativeness (C), and Self-directedness+ Cooperativeness (SC), which are subscales of the TCI, correlated significantly with JSE-S-K score. Third-year students had significantly higher scores on the JSE-S-K than first-year students. MS students had significantly higher scores on the JSE-S-K and the SC subscale of the TCI than MC students. However, there were no significant differences in empathy with regard to age, sex, motivation toward medical science, club activity, and applied specialty. CONCLUSION: These results suggest that empathy is associated with personality traits, such as RD, C, and SC, and medical education curriculum contributes incrementally to empathy for students. The difference in test scores for empathy between MC students and MS students might be due to differences in personality traits, such as SC. PMID- 25813110 TI - Comparison of Learning Styles between Medical College Students and Professional Graduate Medical School Students. AB - PURPOSE: The Professional Graduate Medical School (PGMS) was established in 2003 in South Korea to train doctors that had better humanities and various educational backgrounds. By comparing the learning styles between students of the Medical College (MC) and PGMS, we investigated the characteristics of these students. METHODS: The Kolb Learning Style Inventory (LSI) is used to determine learning preferences. It is composed of 12 statements on concrete experience, reflective observation, abstract conceptualization, and active experimentation. Six hundred nine students from all years of the 2 medical schools completed the Kolb LSI between June 1st and June 30th, 2008 (response rate: 91.4%). RESULTS: MC students preferred Kolb's 'assimilator (56.3%)' and 'diverger (25.6%)', and PGMS students preferred Kolb's 'assimilator (61.2%)' and 'converger (19.3%)'. PGMS students showed a higher preference for abstract conceptualization compared with MC students (adjusted Odds Ratio=2.191; 95% Confidence Interval=1.115~4.306). CONCLUSION: This study showed that the learning styles of PGMS and MC students differed. We can use this result not only in developing curricula and teaching strategies, but also in providing support to students. PMID- 25813111 TI - Comparison of Patient-centeredness Changes between Medical School Graduates and Medical Students after Psychiatric Clerkship. AB - PURPOSE: The aim of this study was to compare patient-centeredness changes between medical school graduates and medical students after a psychiatric clinical clerkship. METHODS: We focused on 40 medical school graduates. We received permission to use data from a 2006 study on patient-centeredness of 94 medical students. The following was repeated before and after clerkship: Minnesota Multiphasic Personality Inventory (MMPI), Meyers-Briggs type indicator (MBTI), Patient-practitioner Orientation Scale (PPOS) and Authoritarian Personality (AP) scale. RESULTS: In the 2006 study on patient-centeredness of medical students, the AP scores were significantly lower than before clerkship and the PPOS scores were significantly higher than before clerkship. AP score changes were related to MBTI, correlated with MMPI subscales, but inversely correlated with PPOS changes. In this study, the change in PPOS scores was not significant after clerkship in case of medical school graduates. AP score changes inversely correlated with PPOS changes, but neither correlated with MMPI subscales or MBTI. CONCLUSION: Considering previous findings, medical school graduates tend to be more patient-centered than medical students, but medical students can adopt a more patient-centered attitude than graduates through a psychiatric clinical clerkship. PMID- 25813112 TI - Predictors of failure in medical students. AB - PURPOSE: This study aimed to identify the predictors of failure in medical students. METHODS: We conducted a 10-year follow-up survey of 231 medical students. The students' general characteristics, study-related factors, health related behavior, and self-perceived health were examined using questionnaires that were given late in the first year of a premedical course. We evaluated the failure incidence of students using school records from the second year of a premedical course to the fourth year of medical school. The statistical analyses that were used were chi2-test, student t-test, and multiple logistic regression analysis. RESULTS: Sixty-five students experienced failure. Thirty-seven (56.9%) had 1 failure, 11 (16.9%) had 2 failures, 8 (12.3%) had 3 failures, 4 (6.2%) had 4 failures, and 5 (7.7%) had 5 failures. From the results of multiple logistic regression, the rates of failure were significantly higher for those whose grade point average (GPA) in the first year of a premedical course was below 2.5 (Relative Risk [RR]=6.52, 95% Confidence Interval [CI]: 1.42~29.8), who smoked more than 1 pack of cigarettes per day (RR=7.37, 95% CI: 1.23~44.07), who drank more (RR=1.16, 95% CI: 1.02~1.33), and exercised less (RR=0.997, 95% CI: 0.995~0.999). CONCLUSION: It was demonstrated that the incidence of failure in medical students was reflected in their academic records in the first year of a premedical course and by unhealthy lifestyles. This study suggests that students who have poor academic marks and unhealthy lifestyles in the first year of a premedical course should be properly guided to reduce the incidence of failure. PMID- 25813113 TI - Changes of Epistemological Beliefs and Self-regulated Learning in Problem-based Learning. AB - PURPOSE: Epistemological beliefs (EBs) are fundamental assumptions about the nature of knowledge and learning. Self-regulation (SR) is the ability and willingness to effectively use and monitor cognitive strategies. Problem-based learning (PBL) emphasizes meaningful learning through solving ill-structured problems. PBL, as a constructivist learning environment, affects students' epistemological beliefs (EBs) and self-regulation learning (SRL). The purpose of this study was to investigate the change in EBs and SRL between pre- and post PBL. METHODS: The subjects were 123 third-year medical students who attended Chonnam National University Medical School (CNUMS), Korea. Participants had to fill out a questionnaire concerning epistemological beliefs and self-regulated learning before and after PBL. RESULTS: Students' EBs about rigid learning was positively changed; however, certainty of knowledge and speed of knowledge acquisition were negatively changed after PBL. Students' SRL related to self efficacy and self-regulation was significantly improved in PBL. There was no significant change with regard to internal value, cognitive strategy, and anxiety. CONCLUSION: EBs on certainty of knowledge and speed of knowledge acquisition were negatively changed after PBL. This result may be due to other leaning environments besides PBL i.e., the lecture-based objective learning environment of medical school. It is suggested that partial PBL cannot fully change students' EBs to higher levels. Students' SR about self-efficacy and self regulation was significantly improved in PBL. The characteristics of PBL: small group discussion and co-operative team activity, as well as students-centered learning environments, facilitate self-efficacy, and self-regulation. PMID- 25813114 TI - What Do the Patients Want to be Called during Medical Encounters? AB - PURPOSE: The aims of this study were to explore the terms that patients preferred to be called during medical encounters and to provide a guideline about the proper use of appellations about patients in teaching medical students. METHODS: Patients were asked to select items from given examples to indicate how they wanted to be addressed by their doctors and how their doctors tended to address them. These terms were categorized into 3 groups; 1) terms that includes name, 2) "patient+honorific suffix, boon (hwanja- boon)", and 3) other general terms. The survey also included questions on patient's perception of the importance of terms of address in building a good doctor-patient relationship. The questionnaire was distributed to 440 out-patients of the three university affiliated hospitals in Seoul and Gyeonggi province from August to September 2007. RESULTS: Three hundred ninety-two respondents were analyzed after excluding 58 respondents who did not meet the study criteria. The ages of the respondents ranged from 18 to 80 years, and 56% of them were male. Most patients preferred to be called by the terms that includes their name (284, 72.4%) and the most preferred term was "family name (FN)+given name (GN)+honorific suffix, nim" (156, 39.8%), while doctors used the terms "patient+honorific suffix, boon" (188, 48.0%) most frequently. About 59% of respondents were addressed as they preferred. Patients in their 30s and 40s showed significantly higher perceptions of the importance of terms of address than other age groups (p= 0.0007). CONCLUSION: Patients preferred to be called by their full name with an honorific suffix; however, patients' preferences and doctors' usage were not in agreement in many cases. The results of this study suggest that doctors should pay more attention to the proper use of appellation during medical encounters. Furthermore, these results can be used to teach undergraduate medical students and guide physicians on how to address patients in practice. PMID- 25813115 TI - Results of a survey of residents who experience pregnancy and delivery. AB - PURPOSE: A growing number of residents bear children during residency training. This study was conducted to examine the pregnancy and maternity leave experiences of women who delivered infants during their residency training. METHODS: From March 2007 through June 2007, we surveyed 94 women who had given birth during their residency training during the past 5 years from the survey date. Participants were recruited using snowball sampling. RESULTS: Most of the respondents (70.2%) delivered in the 3rd and 4th year of residency. The average length of leave was 68.9 days, and more than half (54.3%) of the women expressed that a maternity leave policy was not formally established in the department. In general, participants believed that having a child during residency was difficult (mean=4.18 in 5-point Likert scale), and this perception was inversely related with systematic departmental support. CONCLUSION: Pregnancy is a special challenge for residents, with regard to not only physical overexertion but also psychosocial impacts on pregnant residents and their colleagues. However, most current residency programs do not have written policies on pregnancy. A formal policy and more flexible curriculum can help both the training program and the pregnant resident. PMID- 25813116 TI - Medical professionalism development of oliver R. Avison. AB - PURPOSE: How does professionalism develop while becoming a great doctor? This study based on the life of Avison, a great doctor, aims to identify the developmental features of an excellence and professionally ethical doctor. METHODS: We chose Oliver R. Avison, who founded the first modern hospital and medical school in Korea, now known as Severance Hospital and Yonsei University College of Medicine. Sixteen pivotal events in Avison's life were extracted, based on 2 standards: self-memory and strong feeling. Further we analyzed Avison' life using a professional development analysis model. RESULTS: Oliver Avison's medical professionalism development was divided into 4 periods: 'Motivating in Medicine period', 'Medical Training period', 'Medical Doctor period', and 'Medical Educating period'. A hallmark of Oliver Avison's medical professionalism development was the growth of motivation and social responsibility, medical knowledge, medical creativity, intra-personal intelligence, and relationship forming abilities. CONCLUSION: To excel in medicine, a medical student should be encouraged to understand his unique intellectual potentials and interest as a medical worker, and try to understand problems in the established domain and field of medicine, to develop new medical symbol systems, and climates. PMID- 25813117 TI - Twelve tips for successful use of "clickers" in the classroom. PMID- 25813118 TI - Apprenticeship in thinking: cognitive development in social context (barbara rogoff). PMID- 25813120 TI - Specimens as primary data: museums and 'open science'. PMID- 25813121 TI - Autonomic and prefrontal events during moral elevation. AB - Moral elevation, or elevation, is a specific emotional state triggered by witnessing displays of profound virtue and moral beauty. This study set out to characterize the physiology underlying elevation with measurements of heart rate (HR), respiratory sinus arrhythmia (RSA), and medial prefrontal cortex (mPFC) activity. During elevation, HR and RSA increased. These findings illustrate that elevation involves an uncommon combination of both sympathetic and parasympathetic activation, which is present in circumstances where arousal and social engagement are both required. In addition, we show evidence of content dependent alterations of mPFC activity during elevation peaks. Altogether, this study shows that the induction of moral elevation recruits an uncommon autonomic and neural pattern that is consistent with previous understanding of socioemotional-induced allostasis. PMID- 25813123 TI - Testosterone and cortisol jointly modulate risk-taking. AB - Recent theories propose that testosterone should be positively related to risk taking, but empirical support is mixed. Building on the dual-hormone hypothesis, the present research tested whether testosterone's role in risk-taking depends on cortisol. Study 1 (N=115) tested this hypothesis in a mixed-sex sample with self and informant reports of risk-taking. Study 2 (N=165) tested this hypothesis in a male-only sample with the Balloon Analog Risk Task, a behavioral measure of risk taking. Across both studies, there was a positive association between basal testosterone and risk-taking among individuals low in basal cortisol but not individuals high in basal cortisol. This pattern emerged in both males and females and across multiple measures of risk-taking (self reports, informant reports, behavior). These studies provide novel empirical support for the claim that testosterone and cortisol jointly regulate risk-taking. Discussion focuses on putative mechanisms as well as implications for real-world risk-taking behaviors. PMID- 25813122 TI - Electrophysiological evidence for an attentional bias in processing body stimuli in bulimia nervosa. AB - Empirical evidence suggests abnormalities in the processing of body stimuli in bulimia nervosa (BN). This study investigated central markers of processing body stimuli by means of event-related potentials in BN. EEG was recorded from 20 women with BN and 20 matched healthy controls while watching and evaluating underweight, normal and overweight female body pictures. Bulimics evaluated underweight bodies as less unpleasant and overweight bodies as bigger and more arousing. A higher P2 to overweight stimuli occurred in BN only. In contrast to controls, no N2 increase to underweight bodies was observed in BN. P3 was modulated by stimulus category only in healthy controls; late slow waves to underweight bodies were more pronounced in both groups. P2 amplitudes to overweight stimuli were correlated with drive for thinness and body dissatisfaction. We present novel support for altered perceptual and cognitive affective processing of body images in BN on the subjective and electrophysiological level. PMID- 25813124 TI - Twin pregnancy in an accessory cavitated non-communicating uterus. AB - BACKGROUND: A uterine malformation is a type of female genital malformation resulting from abnormal development of the Mullerian duct(s) during embryogenesis. The type and degree of uterine malformation depends on the level at which the fusion process of the two Mullerian ducts stops; thus, there is a wide variety of malformations. A newly described deformity called accessory cavitated uterine mass (ACUM) has been increasingly reported. THE CASE: We report this deformity (in a 20-year-old married woman) which appears to be an additional incompletely developed, cavitated and presumably non-communicating uterus in addition to a normally shaped and developed uterus. The former uterus became impregnated with twins that died in a missed abortion at 13 weeks of gestation. Before discovering the presence of the deformity, three attempts were made to evacuate the dead fetuses by cervical dilatation and curettage of the normal empty uterus. These attempts resulted in perforation of its fundus, a laparotomy was performed to repair the uterus. During the laparotomy, the pregnant accessory uterus was discovered and was excised with the dead twins. DISCUSSION: The lack of good medical history was a cause of the mismanagement of this patient. Most probably, the origin of ACUM is a growth from the right Mullerian duct. The ovum has entered the ACUM through the rudimentary tube and has been fertilized by a sperm travelled either through the normal vaginal and uterine cavities or through the lymphatics. CONCLUSIONS: (1) A detailed case history is important. (2) An ACUM can be impregnated. PMID- 25813125 TI - Ureteroscopy-assisted retrograde nephrostomy (UARN) without ureteral access sheath (UAS). AB - INTRODUCTION: We previously described ureteroscopy assisted retrograde nephrostomy (UARN). In UARN, it is possible to continuously visualize the dilation of the ureter from puncture to insertion of the nephroaccess sheath with minimal complication. But in the course of making nephrostomy, UARN requires ureteral access sheath (UAS). UAS has a potential risk of ureteral stricture. Herein, we report the first case of UARN without the use of UAS. PRESENTATION OF CASE: A 53-year-old female was referred to our hospital for treatment of her right renal stone. Because her stone burden was 27mm, we planned to perform percutaneous nephrolithotomy (PCNL) using UARN without UAS. DISCUSSION: UAS facilitates a decrease in the intrarenal pressure due to irrigation, and it makes controlling the URS easier. However, in terms of the risk of ureteral stricture, unnecessary insertion of a UAS should be avoided. CONCLUSION: We describe the first case of a renal stone successfully treated by PCNL using the UARN method without the use of a UAS. PMID- 25813127 TI - Survival games at medical schools. PMID- 25813126 TI - Effect of REG Ialpha protein on angiogenesis in gastric cancer tissues. AB - Regenerating gene (REG) Ialpha is not only overexpressed in a subset of gastric cancers, but also involved in tumor progression. However, the mechanism by which (REG) Ialpha promotes tumor growth is not fully understood. In the present study, we investigated whether REG Ialpha plays a role in angiogenesis during the progression of gastric cancers. Expression of REG Ialpha and its receptor (EXTL3; exostoses like-3) was examined using immunohistochemistry in specimens of human gastric cancer. Microvessel density (MVD) in gastric cancer tissues was evaluated using an image analysis system after CD34 immunostaining. Relationships among clinicopathological features, REG Ialpha expression and MVD in gastric cancer tissues were analyzed. Effects of REG Ialpha protein on HUVEC cells in terms of proliferation and anti-apoptosis were assessed by WST-1 assay and FACS, respectively. Furthermore, the intracellular signaling by which REG Ialpha exerts its biological roles was examined in vitro. REG Ialpha expression was significantly related to lymph node metastasis and its receptor EXTL3 was ubiquitously expressed in not only the tumor cells, but also the tumor vessel cells in the gastric cancer tissues. MVD was significantly higher in gastric cancers that were REG Ialpha-positive than in those that were negative. Treatment with REG Ialpha protein promoted growth and anti-apoptosis through activation of the ERK and Akt signaling pathways in HUVEC cells, whereas these effects were attenuated by treatment with anti-REG Ialpha -antibody. REG Ialpha protein may play a role in angiogenesis during progression of gastric cancer. PMID- 25813128 TI - Application of 'writing for healing' in premedical humanities education. AB - There has been a recent tendency to attach special importance to writing education. Books on 'writing to heal' are being written in or translated into Korean. According to these texts, writing is a valuable tool for internal healing, depending on the mode of application. Writing can have positive effects and give hope to an individual or group, but it can also be a source of frustration and despair. Based on the distinct effects of writing, we cannot overemphasize the significance of writing education. Writing is generally taught during a premedical course that targets students who will eventually practice medicine. Many reports have examined immorality in medical students and health care providers, which is a reason that writing education is important for medical systems. 'Writing for Healing' is open to freshmen at Yonsei University Wonju College of Medicine. The aim of this subject is to help students identify and acknowledge internal diseases to lead a healthier life and eventually become positive and responsible health care providers. However, in addition to the vague definition of what 'healing' is, the concept of 'writing for healing' has not been defined. This paper attempts to define the concept of 'writing for healing' and considers what influences it can have on a humanities curriculum in medical colleges. PMID- 25813129 TI - Medical students' perception and satisfaction with medical communication teaching using electronic modules. AB - PURPOSE: To teach communication skills to medical students, a variety of instructional text and video materials are used. The purpose of this study was to investigate medical students' perception and satisfaction with medical communication teaching using electronic modules. METHODS: Medical communication subjects were developed for freshmen of the medical department. Each lesson was configured for the use of educational electronic modules. The modules were composed of a database of instructional materials and a program file that could link the materials. After the 2nd and 12th week of classes, the 8th and 14th practice interviews with simulated patients, and the end of the course, medical students' perception and satisfaction were assessed. RESULTS: Forty-five students participated in the survey. Students' satisfaction after the 2nd and 12th week of class was 16.2 (standard deviation [SD], 2.0) and 16.2 (SD, 2.1), respectively. The correlation between class satisfaction and awareness of the usefulness of the electronic modules was significant (p<0.05). After the end of the course, the students' average satisfaction score was 6.7 of 10 points (SD, 1.4). Satisfaction with the practice interview and evaluation using simulated patients was 7.5 (SD, 2.3). For the practice interview, empathy, building a relationship, effective questioning, and active listening could be applied. CONCLUSION: Medical student satisfaction with medical communication teaching using electronic modules was high. Students who were aware of the usefulness of the electronic modules had higher satisfaction with their classes. Many interview skills of the initial and middle phase of interviewing could be applied for the practice interview. PMID- 25813130 TI - Experiences with establishing and implementing learning management system and computer-based test system in medical college. AB - PURPOSE: The purpose of this study was to establish an e-learning system to support learning in medical education and identify solutions for improving the system. METHODS: A learning management system (LMS) and computer-based test (CBT) system were established to support e-learning for medical students. A survey of 219 first- and second-grade medical students was administered. The questionnaire included 9 forced choice questions about the usability of system and 2 open-ended questions about necessary improvements to the system. RESULTS: The LMS consisted of a class management, class evaluation, and class attendance system. CBT consisted of a test management, item bank, and authoring tool system. The results of the survey showed a high level of satisfaction in all system usability items except for stability. Further, the advantages of the e-learning system were ensuring information accessibility, providing constant feedback, and designing an intuitive interface. Necessary improvements to the system were stability, user control, readability, and diverse device usage. CONCLUSION: Based on the findings, suggestions for developing an e-learning system to improve usability by medical students and support learning effectively are recommended. PMID- 25813131 TI - Impact of critical thinking disposition, general self-efficacy, and leadership on clinical competence in nursing students. AB - PURPOSE: The purpose of this study was to evaluate the relationships among critical thinking disposition, general self-efficacy, leadership and clinical competence, and identify the factors influencing clinical competence in nursing students. METHODS: In this descriptive study, 153 nursing students (from 2nd to 4th school year) of a university in South Korea were enrolled in December 2010. The instruments for this study were the Korean versions of the Critical Thinking Disposition Scale, General Self-Efficacy Scale, Leadership Inventory, and Clinical Competence Scale. Data were analyzed by descriptive statistics, t-test, MANOVA, Pearson correlation, and multiple linear regression with PASW 18.0 software. RESULTS: The mean scores (ranging from 1 to 5) in nursing students for critical thinking disposition, general self-efficacy, leadership, and clinical competence were 3.44, 3.51, 3.55, and 3.42, respectively. Positive correlations were found for clinical competence with critical thinking disposition, general self-efficacy, and leadership. The strongest predictor of clinical competence was leadership. In addition, leadership, nursing school year, and subjective academic achievement accounted for 34.5% of variance in clinical competence. CONCLUSION: This study revealed that developing leadership, critical thinking disposition, and self-efficacy in undergraduate nursing education is important to improve clinical competence of nursing students. PMID- 25813132 TI - Medical students' failure experiences and their related factors. AB - PURPOSE: A considerable number of medical students drop out due to low academic achievement, and these students have a high probability of repeated failure experiences. This study investigated the personal and academic problems of these students to help develop student support systems. METHODS: First-year (n=146) and second-year (n=119) medical students were asked to complete questionnaires. The questionnaires consisted of personality traits and the students' management of/satisfaction with school life. RESULTS: Students who had already dropped out accounted for 17.4% of the study subjects. The most common reason for dropping out was low academic achievement, and the most difficult part of taking a leave of absence from school was psychological anxiety. The group who dropped out had significantly lower levels of emotional stability, sociability, responsibility, dominance, masculinity, and superiority and more vulnerable mental states compared with those who did not drop out. They also expressed less motivation with regard to medical science and less satisfaction with school life than did the group that did not drop out. Those who dropped out tended not to prepare for exams, and they managed their time ineffectively. They also tried to resolve their difficulties alone and rarely sought help from teachers. CONCLUSION: More intimate student-teacher relationships should be established, and teachers should be encouraged to meet and interact with their students on a regular basis. Additionally, personality inventories should be used to assist in efforts to understand students, especially to identify hidden social and emotional problems. PMID- 25813133 TI - Transfer students' personality types and their academic performance in a graduate entry dental school. AB - PURPOSE: The study was designed to identify how different types of transfer student personality would be constituted in Seoul National University School of Dentistry (SNU SD) and delve into what personal types were often observed more competent in academic performance. METHODS: Among 40 students who transferred to SNU SD in 2004, 15 students voluntarily participated in completing the Myers Briggs type indicator (MBTI; GS form); then, it was tested whether or not their MBTI types would be dependent upon their final grades. In addition, another 32 out of the 50 students who were enrolled through a traditional pre-den system served as a control group. RESULTS: It was mainly found that ISTJ type was the most typical one for those transfer dental students as well as for other native dental students who excelled in their academic performance. The noticeable majority of transfer students were Introverted (67%), Sensing (80%), Thinking (86%), and Judging (80%), with S-J pattern being statistically significant. CONCLUSION: SNU SD has been in a rebuilding process in terms of student/outcome centered dental education to have it up to the global standards. For this reason, it is ultimately a crucial part of that process to understand what personality types of the dental students with different backgrounds in major are observed and thus recognize how to support their learning according to different patterns of individual personality. PMID- 25813134 TI - Comparing Attitudes toward Disclosing Medical Errors between Medical Students and Interns. AB - PURPOSE: The purpose of this study was to compare attitudes toward disclosing medical errors between medical students and interns. METHODS: The questionnaires were administrated to 164 medical students and interns. The questionnaires consist of 3 major concepts: knowledge, attitudes toward disclosure of medical error, barriers to the disclosure of medical error. RESULTS: Interns (56.1%) took medical errors less seriously than medical students (74.8%). Medical students (75.6%) believed that patients would want to be informed of any kind of medical errors while Interns (46.3%) thought so. Medical students (83.1%) considered that serious medical errors should be disclosed to patients. On the contrary, only 46.3% of interns believed so. Medical students (16.3%) and interns (19.5%) believed disclosing medical error would increase patients trust in doctors. Both medical students and interns pointed out worries about malpractice suits as the biggest barrier to disclosing medical error. CONCLUSION: The attitudes toward disclosing medical error between medical students and interns were significantly different in many aspects. Interns show more negative attitudes about disclosing medical errors than medical students. And they also take medical errors less seriously than medical students. In particular, the attitudes of the subjects in this study were greatly different from the results of a previous patients' attitudes study. These perspectives differences could work against achieving patient-centered care which is the upmost priority in the current trends in health care. The efforts to bridge these perspective gaps between patients and doctors should start from medical school by teaching medical students the importance of the disclosing medical errors. PMID- 25813135 TI - Seven strategies for effective questioning. PMID- 25813136 TI - Medical education of north Korea. PMID- 25813137 TI - Facile synthesis of metal/metal oxide nanoparticles inside a nanoporous carbon matrix (M/MO@C) through the morphology-preserved transformation of metal-organic framework. AB - A facile method to transform metal-organic frameworks (MOFs) into metal/metal oxide@carbon (M/MO@C) composites with well-defined shapes is reported. The porosity of carbon and the particle sizes of M/MO are readily controlled by a simple two-step process that includes impregnation of the polymer precursors and a thermolysis reaction. PMID- 25813138 TI - Long-term assessment of contaminated articles from the Chernobyl reactor. AB - The Chernobyl accident caused a release of radioactive materials from the reactor into the environment. This event contaminated people, their surroundings and their personal property, especially in the zone around the reactor. Among the affected individuals were British students who were studying in Minsk and Kiev at the time of the Chernobyl accident. These students were exposed to external and internal radiation, and the individuals' articles of clothing were contaminated. The primary objective of this study was to analyze a sample of this contaminated clothing 20 years after the accident using three different detectors, namely, a BP4/4C scintillation detector, a Min-Con Geiger-Muller tube detector and a high purity germanium (HPGe) detector. The clothing articles were initially assessed and found not to be significantly contaminated. However, there were several hot spots of contamination in various regions of the articles. The net count rates for these hot spots were in the range of 10.00 +/- 3.16 c/s to 41.00 +/- 6.40 c/s when the BP4/4C scintillation detector was used. The HPGe detector was used to identify the radionuclides present in the clothing, and the results indicated that the only active radionuclide was (137)Cs because of this isotope's long half life. PMID- 25813139 TI - Interplay of vitamin D and metabolic syndrome: A review. AB - Vitamin D deficiency is a worldwide public health problem. Vitamin D deficiency plays key role in the pathophysiology of risk factors of metabolic syndrome which affect cardiovascular system, increase insulin resistance and obesity, stimulate rennin-angiotensin-aldosterone system that cause hypertension. The discovery of vitamin D receptor expressed ubiquitously in almost all body cells such as immune, vascular and myocardial cells, pancreatic beta cells, neurons and osteoblasts suggests an involvement of vitamin D mediated effects on metabolic syndrome. Moreover vitamin D deficiency as well as cardiovascular diseases and related risk factors frequently co-occur. This underlines the importance of understanding the role of vitamin D in the context of metabolic syndrome. The paper provides an insight into the physiology of vitamin D and relationship of vitamin D deficiency with risk factors of metabolic syndrome through observational and supplementation studies. PMID- 25813140 TI - Balance and ankle muscle strength predict spatiotemporal gait parameters in individuals with diabetic peripheral neuropathy. AB - AIMS: The aims of this study were to evaluate aspects of balance, ankle muscle strength and spatiotemporal gait parameters in individuals with diabetic peripheral neuropathy (DPN) and verify whether deficits in spatiotemporal gait parameters were associated with ankle muscle strength and balance performance. MATERIALS AND METHODS: Thirty individuals with DPN and 30 control individuals have participated. Spatiotemporal gait parameters were evaluated by measuring the time to walk a set distance during self-selected and maximal walking speeds. Functional mobility and balance performance were assessed using the Functional Reach and the Time Up and Go tests. Ankle isometric muscle strength was assessed with a handheld digital dynamometer. Analyses of variance were employed to verify possible differences between groups and conditions. Multiple linear regression analysis was employed to uncover possible predictors of gait deficits. RESULTS: Gait spatiotemporal, functional mobility, balance performance and ankle muscle strength were affected in individuals with DPN. The Time Up and Go test performance and ankle muscle isometric strength were associated to spatiotemporal gait changes, especially during maximal walking speed condition. CONCLUSION: Functional mobility and balance performance are damaged in DPN and balance performance and ankle muscle strength can be used to predict spatiotemporal gait parameters in individuals with DPN. PMID- 25813141 TI - An inconvenient truth: urgent care is not primary care. PMID- 25813142 TI - Preoperative ejection fraction determines early recovery of left ventricular end diastolic dimension after aortic valve replacement for chronic severe aortic regurgitation. AB - BACKGROUND: In patients with chronic severe aortic regurgitation (AR), aortic valve replacement (AVR) has been proved to promote left ventricular (LV) remodeling, especially LV end-diastolic dimension (LVEDD) reduction. However, there is little research whether postoperative LVEDD could return to normal parameter after AVR. The objective of this study was to determine predictors for the recovery of dilated LVEDD early after AVR. METHODS: The echocardiographic data of 105 patients, who underwent AVR for chronic pure AR between January 2005 and December 2011, were analyzed at the preoperative (3-7 d), early (6-8 mo), and late (2-y) postoperative stages, retrospectively. According to the baseline level, LVEDD >70 mm or LV end-systolic dimension (LVESD) >50 mm or LVESD index >25 mm/m(2) were defined as severe LV dilation. Patients were then categorized into two groups (group 1: severe LV dilation; group 2: nonsevere LV dilation). RESULTS: In all patients, four-fifth of the reduction in LV dimension occurred at early (6-8 mo) postoperative stage. The patients in both groups had significant decreases in the LVEDD and LVESD early after AVR, with an additional but insignificant reduction at late postoperative stage. The ejection fraction (EF) in both groups significantly increased at either early or late stage. However, the LVEDD and LVESD in group 1 were larger than those in group 2, and the EF in group 1 was lower than that in group 2 at early postoperative stage. By multivariate analysis, we found that the preoperative EF was a good predictor for the recovery of dilated LVEDD early after AVR (P = 0.009). Receiver-operating characteristics analysis showed that EF >52% was the best cut-off value for the recovery of LVEDD. CONCLUSIONS: In patients with chronic pure AR, preoperative EF may be a good predictor for successful recovery of dilated LVEDD early after AVR. PMID- 25813143 TI - Measures of survival benefit in cancer drug development and their limitations. AB - BACKGROUND: A variety of measures of survival benefit are available to an investigator comparing outcomes across the various arms of a drug development trial. In this article, we systematically review the most common measures of comparative survival used in published studies. MATERIALS: We distinguish between relative and absolute survival differences, and measures of instantaneous and cumulative risk. We consider settings in which the end point is overall survival as well as those in which disease-specific end points are of primary interest. RESULTS: We note that different measures capture different aspects of benefit, and some may be more reliable than others or more representative of clinically relevant benefit. CONCLUSIONS: Rather than simply using procedures that have become standard, analyses should identify the most clinically relevant measures of effect and apply procedures that reliably estimate these. PMID- 25813144 TI - BCG-refractory vs. BCG-relapsing non-muscle-invasive bladder cancer: a prospective cohort outcomes study. AB - PURPOSE: Patients with recurrent or persistent high-grade non-muscle-invasive bladder cancer after bacille Calmette-Guerin (BCG) therapy are termed "BCG failures." We hypothesize that BCG-refractory patients who fail to respond to BCG have worse outcomes after bladder-sparing treatments compared with BCG-relapsing patients whose tumors recur after at least a 6-month disease-free interval. MATERIALS AND METHODS: We screened 32 patients who had failed BCG therapy for eligibility in a multicenter investigational trial. BCG-refractory patients received instillations of a mycobacterial cell wall-DNA complex extract. BCG relapsing patients were treated with additional BCG or other intravesical agents. Both groups of patients were followed prospectively with transurethral biopsy after 6 months, and cystoscopy every 3 to 6 months for more than 2 years. Median follow-up time for all patients was 53 months (range: 24-72 mo). RESULTS: Seventeen patients were classified as BCG refractory and 15 patients defined BCG relapsing. Recurrence-free median survival time was 10 months for BCG-refractory patients receiving mycobacterial cell wall-DNA complex vs. 23 months for BCG relapsing patients who received another induction course of BCG therapy (P = 0.002). Progression-free survival time was 18 months for BCG-refractory vs. 52 months for BCG-relapsing patients (P = 0.001). Of the 17 BCG-refractory patients, 8 (47%) have died vs. 3 (20%) of the 15 BCG-relapsing patients. CONCLUSIONS: BCG refractory and BCG-relapsing categories differentiate BCG-failed patients into high-and lower-risk prognostic groups that may be useful in guiding treatment strategies. PMID- 25813145 TI - The transcription factor nuclear factor interleukin 6 mediates pro- and anti inflammatory responses during LPS-induced systemic inflammation in mice. AB - The transcription factor nuclear factor interleukin 6 (NF-IL6) plays a pivotal role in neuroinflammation and, as we previously suggested, hypothalamus-pituitary adrenal-axis-activation. Here, we investigated its contribution to immune-to brain communication and brain controlled sickness symptoms during lipopolysaccharide (LPS)-induced (50 or 2500 MUg/kg i.p.) systemic inflammation in NF-IL6-deficient (KO) or wildtype mice (WT). In WT LPS induced a dose dependent febrile response and reduction of locomotor activity. While KO developed a normal fever after low-dose LPS-injection the febrile response was almost abolished 3-7 h after a high LPS-dose. High-dose LPS-stimulation was accompanied by decreased (8 h) followed by enhanced (24 h) inflammation in KO compared to WT e.g. hypothalamic mRNA-expression including microsomal prostaglandin E synthase, inducible nitric oxide synthase and further inflammatory mediators, neutrophil recruitment to the brain as well as plasma levels of inflammatory markers such as IL-6 and IL-10. Interestingly, KO showed reduced locomotor activity even under basal conditions, but enhanced locomotor activity to novel environment stress. Hypothalamic-pituitary-adrenal-axis activity of KO was intact, but tryptophan-metabolizing enzymes were shifted to enhanced serotonin production and reuptake. Overall, we showed for the first time that NF-IL6 plays a dual role for sickness response and immune-to-brain communication: acting pro-inflammatory at 8h but anti-inflammatory at 24 h after onset of the inflammatory response reflecting active natural programming of inflammation. Moreover, reduced locomotor activity observed in KO might be due to altered tryptophan metabolism and serotonin reuptake suggesting some role for NF IL6 as therapeutic target for depressive disorders. PMID- 25813146 TI - [Condylar remodelling after temporomandibular joint reconstruction with fibula free flap]. AB - AIM: Mandibular reconstructions with fibula free flap are commonly used in maxillo-facial surgery; termino-lateral mandibulectomy with reconstruction of the ramus and condylar unit is seldom used. Consequences on the temporomandibular joint remain unclear, and the type of reconstruction is still subject to controversy. METHODS: Six patients were followed after terminal mandibulectomy, reconstructed with fibular free flap. Evaluations of the results were made on functional and radiological criteria. RESULTS: No patient presented functional disturbances due to reconstruction. Remodeling of the neocondyle extremity was weak in adults but important in children, with modification of morphology and architecture of the condyle in children. DISCUSSION: Preservation of the disc is recommended. Many techniques are described to improve congruence, preservation and remodeling of the free extremity of the fibula flap. All give similar results. It seems that the real determinant factors on the quality of the result are age, presence of the disc or not, previous surgery performed, with or without radiotherapy. PMID- 25813147 TI - Evaluation of the co-existence of the red fluorescent plaque bacteria P. gingivalis with S. gordonii and S. mutans in white spot lesion formation during orthodontic treatment. AB - BACKGROUND: Early detection of white spot lesions (WSLs) around brackets during orthodontic treatment is important for treatment and prevention. But it is unclear whether red fluorescent plaque (RFP) bacteria Porphyromonas gingivalis and its co-existence with Streptococcus mutans and Streptococcus gordonii has any significant influence on this. Therefore the role of this bacterial co existence and WSLs formation during one year of fixed orthodontic therapy was evaluated. METHODS: Fourteen 12 to 22 year old (mean 15 +/- 3 years) consecutive patients attending the University of Liverpool dental hospital were recruited for this study. Quantitative Light-induced Fluorescence (QLF) was used to identify RFP and enamel demineralisation, respectively, on anterior labial surfaces before and after placement of fixed orthodontic appliances. Bacterial composition was determined by denaturing gradient gel electrophoresis (DGGE) following nested PCR amplification of the 16S rRNA V2-V3 hypervariable region. RESULTS: WSLs were recorded on 4.2% of tooth surfaces and WSL development was not associated with RFP bacteria P. gingivalis presence. Differences in RFP bacteria P. gingivalis presence with S. mutans and S. gordonii, were observed before and after appliance placement. Intra subject changes in plaque flora between visits were not significantly associated with WSL development (p > 0.05). However, DGGE profiles indicated that apart from S. mutans, S. gordonii might also have a role in human enamel demineralisation. CONCLUSIONS: Fixed orthodontic brackets in adolescents may play a role in altering bacterial composition around brackets during orthodontic treatment and it is plausible that S. gordonii also have a role in human enamel demineralisation. Combinatorial approach of QLF technology and DGGE may be useful in determining bacterial composition during orthodontic therapy which could inform clinical interventions. PMID- 25813148 TI - Polymorphisms in Tumor Necrosis Factor-alpha Are Associated With Higher Anxiety Levels in Women After Breast Cancer Surgery. AB - INTRODUCTION: Before and after breast cancer surgery, women have reported varying anxiety levels. Recent evidence has suggested that anxiety has a genetic basis and is associated with inflammation. The purposes of the present study were to identify the subgroups of women with distinct anxiety trajectories; to evaluate for differences in the phenotypic characteristics between these subgroups; and to evaluate for associations between polymorphisms in cytokine genes and subgroup membership. PATIENTS AND METHODS: Patients with breast cancer (n = 398) were recruited before surgery and followed up for 6 months. The patients completed the Spielberger State Anxiety Inventory and provided a blood sample for genomic analyses. Growth mixture modeling was used to identify the subgroups of patients with distinct anxiety trajectories. RESULTS: Two distinct anxiety subgroups were identified. The women in the higher anxiety subgroup were younger and had a lower functional status score. Two single nucleotide polymorphisms in tumor necrosis factor-alpha (rs1799964, rs3093662) were associated with the higher anxiety subgroup. CONCLUSION: The results of the present exploratory study suggest that polymorphisms in cytokine genes could partially explain the interindividual variability in anxiety. The determination of phenotypic and molecular markers associated with greater levels of anxiety can assist clinicians to identify high risk patients and initiate appropriate interventions. PMID- 25813149 TI - Zebrafish Nk-lysins: First insights about their cellular and functional diversification. AB - Nk-lysins are antimicrobial proteins produced by cytotoxic T lymphocytes and natural killer cells with a broad antimicrobial spectrum (including bacteria, fungi and parasites). Nevertheless, the implication of these proteins in the protection against viral infections is still poorly understood. In this work, four different Nk-lysin genes (nkla, nklb, nklc and nkld) were identified in the zebrafish genome. That means that zebrafish is the species with the higher repertoire of Nk-lysin genes described so far. The differential expression pattern of the Nk-lysins in several tissues, during ontogeny, among the different kidney cell populations, as well as between Rag1(-/-) and Rag1(+/+) individuals, could suggest a certain specialization of different cell types in the production of different Nk-lysin. Moreover, only two of these genes (nkla and nkld) were significantly up-regulated after viral infection, and this observation could be also a consequence of a functional diversification of the zebrafish Nk-lysins. PMID- 25813150 TI - Development of a gLCR-based KRAS mutation detection approach and its comparison with other screening methods. AB - A gapped ligase chain reaction (gLCR)-based technique was developed and tested on clinical formalin-fixed, paraffin-embedded (FFPE) tissues from colorectal cancer patients. The technique was designed to detect low-level KRAS codon 12 or 13 mutations or confirming doubtful results gained by less sensitive KRAS screening techniques. The gLCR approach was compared with mutation screening techniques commonly used in routine diagnostics regarding sensitivity and specificity. The herein described monoplex gLCR technique is a useful and powerful tool for detecting low-level KRAS codon 12 and 13 mutations in a vast majority of wild type DNA. The gLCR has the capacity to detect one mutated allele in an excess of at least one million wild type alleles (0.0001 %) and is therefore an ideal technique for confirming doubtful KRAS mutation screening results obtained by other techniques. The variance of the gLCRs signal amplitude was very low and is showing a high reproducibility with constant sensitivity even at higher dilutions. The financial effort and the handling time for this technique are low and comparable to a standard cycle sequencing reaction. Additionally, the gLCR technique is easy extendable for the detection of many other clinical relevant mutation hotspots. PMID- 25813151 TI - The clinicopathological significance of ALK rearrangements and KRAS and EGFR mutations in primary pulmonary mucinous adenocarcinoma. AB - Primary pulmonary mucinous adenocarcinoma (PPMA) is one of the important subtypes of lung adenocarcinoma. Detection of anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements and of KRAS and epidermal growth factor receptor (EGFR) mutations will help in diagnosing and predicting treatment outcome. The aim of this study was to investigate the clinicopathological significance of ALK rearrangements, KRAS and EGFR mutations in PPMA. ALK expression was detected immunohistochemically. KRAS and EGFR mutations were determined by the amplification refractory mutation system. Seventy-three patients of PPMA were enrolled. ALK rearrangements were detected in 34.2 % of patients and were more frequent in upper/middle lobe, stage III-IV, lymphatic permeation-positive patients and non-smokers. ALK rearrangements were significantly increased in the solid tumor predominant with mucin production subtype, and in special tissue structures, including signet ring cells, cribriform, and micropapillary patterns. KRAS mutations were observed in 23.3 % of patients and were more prevalent in invasive mucinous adenocarcinoma and lower lobe tumors. Only one case of ALK rearrangements harbored KRAS mutation, and no cases manifested with the coexistence of ALK rearrangements and EGFR mutations. KRAS and EGFR co-mutation was detected in one case. PPMA patients with ALK rearrangements or KRAS mutation represent a unique subtype in NSCLC. The results provide basis data for target therapy screening of PPMA patients. PMID- 25813152 TI - Impact of TGF-beta1 -509C/T and 869T/C polymorphisms on glioma risk and patient prognosis. AB - Transforming growth factor beta (TGF-beta) plays an important role in carcinogenesis. Two polymorphisms in the TGF-beta1 gene (-509C/T and 869T/C) were described to influence susceptibility to gastric and breast cancers. The 869T/C polymorphism was also associated with overall survival in breast cancer patients. In the present study, we investigated the relevance of these TGF-beta1 polymorphism in glioma risk and prognosis. A case-control study that included 114 glioma patients and 138 cancer-free controls was performed. Single nucleotide polymorphisms (SNPs) were evaluated by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). Univariate and multivariate logistic regression analyses were used to calculate odds ratio (OR) and 95 % confidence intervals (95 % CI). The influence of TGF-beta1 -509C/T and 869T/C polymorphisms on glioma patient survival was evaluated by a Cox regression model adjusted for patients' age and sex and represented in Kaplan-Meier curves. Our results demonstrated that TGF-beta1 gene polymorphisms -509C/T and 869T/C are not significantly associated with glioma risk. Survival analyses showed that the homozygous -509TT genotype associates with longer overall survival of glioblastoma (GBM) patients when compared with patients carrying CC + CT genotypes (OR, 2.41; 95 % CI, 1.06-5.50; p = 0.036). In addition, the homozygous 869CC genotype is associated with increased overall survival of GBM patients when compared with 869TT + TC genotypes (OR, 2.62; 95 % CI, 1.11-6.17; p = 0.027). In conclusion, this study suggests that TGF-beta1 -509C/T and 869T/C polymorphisms are not significantly associated with risk for developing gliomas but may be relevant prognostic biomarkers in GBM patients. PMID- 25813154 TI - Rare case of subcarinal thymic carcinoma in the middle mediastinum. AB - We report an extremely rare case of a thymic carcinoma occurring in the subcarinal location of the middle mediastinum, masquerading as subcarinal adenopathy. A 6.2 * 5 cm mass was detected on computed tomography scan and found to be hypermetabolic on positron emission tomography scan. Transbronchial biopsy was performed and the mass was found to be suspicious for malignancy. A thoracoscopic resection of the mass was performed and found to be thymic carcinoma. The patient underwent a course of adjuvant radiation. To the best of our knowledge, this is the first reported case of a thymic carcinoma resected from the middle mediastinum. PMID- 25813153 TI - Tumor suppressive microRNA-200a inhibits renal cell carcinoma development by directly targeting TGFB2. AB - A large body of evidence indicates that microRNAs play a critical role in tumor initiation and progression by negatively regulating oncogenes or tumor suppressor genes. Here, we report that the expression of miR-200a was notably downregulated in 45 renal cell carcinoma (RCC) samples. Restoration of miR-200a suppressed cell proliferation, migration, and invasion in two RCC cell lines. Furthermore, we used an epithelial-to-mesenchymal transition PCR array to explore the putative target genes of miR-200a. By performing quantitative real-time PCR, ELISA, and luciferase reporter assays, transforming growth factor beta2 (TGFB2) was validated as a direct target gene of miR-200a. Moreover, siRNA-mediated knockdown of TGFB2 partially phenocopied the effect of miR-200a overexpression. These results suggest that miR-200a suppresses RCC development via directly targeting TGFB2, indicating that miR-200a may present a novel target for diagnostic and therapeutic strategies in RCC. PMID- 25813155 TI - Cystic multiglandular maternal hyperparathyroidism diagnosed by neonatal hypocalcemic seizures. AB - A 7-day-old male infant born to a healthy 33-year-old female at 37 weeks of gestation was brought to the local emergency department (ED) with sudden-onset tonic-clonic seizures. Laboratory testing revealed extreme hypocalcemia (ionized calcium of 3.2 mg/dl) and undetectable parathyroid hormone (PTH <10 pg/ml). Concomitant evaluation of the mother revealed both elevated ionized calcium (5.9 mg/dl) and PTH (116 pg/ml). The mother underwent preoperative ultrasound localization and sestamibi scan, followed promptly by parathyroidectomy. Given the cystic appearance and presence of multiglandular disease, evaluation for familial cystic parathyroid adenomatosis (hyperparathyroidism-jaw bone-tumor syndrome) and MEN 1 were undertaken. The infant was stabilized and discharged home. He returned to the ED with seizures at 1 month of age. After increasing calcium supplementation appropriately, he was monitored with weekly office visits. This represents a unique case of undiagnosed maternal primary hyperparathyroidism manifesting with intrauterine parathyroid suppression and hypocalcemic seizures in the newborn. PMID- 25813157 TI - Laser treatment of onychomycosis: beware of ring block anesthesia! PMID- 25813156 TI - Treatment of periodontal disease with an Er,Cr:YSGG laser in rats exposed to cigarette smoke inhalation. AB - The purpose of this study was to evaluate the erbium, chromium:yttrium scandiumgallium-garnet (Er,Cr:YSGG) laser irradiation in the treatment of periodontitis in rats exposed to cigarette smoke inhalation (CSI). Ligatures were placed in the maxillary second molars. After a 15-day period, the ligatures were removed and 180 animals were randomly divided into six groups: (1) CSRP group- CSI and manual scaling and root planing (SRP) treatment; (2) CL group--CSI and Er,Cr:YSGG laser irradiation; (3) CSRP + L group-CSI, SRP, and Er,Cr:YSGG irradiation; (4) SRP group-manual SRP; (5) L group--Er,Cr:YSGG irradiation; (6) SRP + L group--SRP and Er,Cr:YSGG irradiation. At 7, 15, and 30 days after treatments, animals were euthanized and histologic, histometric, immunohistochemistry, and real-time PCR analyses were performed. Histometrically, no differences were observed in the SRP, L, and SRP + L groups exposed to CSI. The CSRP group showed more bone formation at 30 days than at 15 days (p < 0.01) but less bone at 30 days than the CL group at 30 days (p < 0.05). Immunohistochemical staining was positive for osteoblasts, fibroblasts, and osteoclasts. Real-time PCR showed more (vascular endothelial growth factor) VEGF expression in the L (p < 0.05) and SRP + L (p < 0.01) groups at 30 days than at 15 days and less VEGF expression in the CSRP group at 30 days than at 15 days (p < 0.05). There was no difference in fibroblast growth factor (FGF) expression. The Er,Cr:YSGG laser irradiation promotes favorable conditions for tissue repair even in animals exposed to CSI, with similar results as those achieved from manual scaling and root planing. PMID- 25813158 TI - Small cyclic agonists of iron regulatory hormone hepcidin. AB - Minihepcidins are in vitro and in vivo active mimetics of iron-regulatory hormone hepcidin. They contain various unusual amino acids including: N-substituted, beta homo-, and d-amino acids with their combination depending on particular minihepcidin. In the current study, we sought to limit the use of unusual/more expensive amino acids derivatives by peptide cyclization. Novel cyclic mimetics of hepcidin were synthesized and tested in vitro and showed activity at low nanomolar concentration. Nonetheless, the most active cyclic compound (mHS17) is approximately ten times less active than the parental minihepcidin PR73. Collectively, our findings suggest that cyclization is viable approach in the synthesis of hepcidin mimetics. PMID- 25813159 TI - New septanoside and 20-hydroxyecdysone septanoside derivative from Atriplex portulacoides roots with preliminary biological activities. AB - The phytochemical investigation of a Tunisian plant Atriplex portulacoides (Chenopodiaceae) led to the isolation of two new compounds designated as portulasoid (2) and septanoecdysone (3) along with the known 20-hydroxyecdysone (20HE) (1). Their chemical structures were elucidated on the basis of extensive spectroscopic methods including ES-HRMS, 1D and 2D-NMR. The isolated compounds were finally tested for their antioxidant activity by using DPPH, ABTS(+), Fe(3+) and catalase assays and also for their antibacterial and anticholinesterase activities. PMID- 25813160 TI - Substituted piperazines as nootropic agents: 2- or 3-phenyl derivatives structurally related to the cognition-enhancer DM235. AB - A series of 2-phenyl- or 3-phenyl piperazines, structurally related to DM235 and DM232, two potent nootropic agents, have been prepared and tested in the mouse passive-avoidance test, to assess their ability to revert scopolamine-induced amnesia. Although the newly synthesized molecules were less potent than the parent compounds, some useful information has been obtained from structure activity relationships. A small but significant enantioselectivity has been found for the most potent compound 5a. PMID- 25813161 TI - Evaluation of the relationship between cardiovascular risk factors and periaortic fat thickness in children with type 1 diabetes mellitus. PMID- 25813162 TI - Synthesis, structural and computational characterization of 2-amino-3,5 diiodobenzoic acid and 2-amino-3,5-dibromobenzoic acid. AB - The benzoic acid compounds 2-amino-3,5-dibromobenzoic acid (2A35Br) and 2-amino 3,5-diiodobenzoic (2A35I) acid have been synthesized and characterized by single crystal X-ray diffraction, FT-IR spectroscopy, UV-Vis spectroscopy and computational methods. Molecular geometry, intra- and inter-molecular interactions have been investigated by using X-ray diffraction technique. Fundamental vibrational bands of the title compounds were founded by FT-IR and UV Vis method was used to obtain electronic bands. Geometry optimizations and the calculation of IR frequencies were performed both Gaussian type orbitals at Gaussian 09W and Slater type orbitals at ADF2009.01 software. The calculations are compatible with the experiment results. In addition, geometrical parameters, energies, HOMO-LUMO gaps and electrophilicity indexes have been calculated for thirty possible positional isomers of 2A35Br and 2A35I. Calculations show that 2A35Br and 2A35I isomers have the lowest energy, the narrowest HOMO-LUMO gap and the highest electrophilicity index values. Molecular electrostatic potential maps, Fukui indices, natural bond orbital analysis, thermodynamic parameters and non-linear optical properties of the 2A35Br and 2A35I were also investigated by theoretical calculations. PMID- 25813163 TI - Effect of pH in the photoluminescence of a ruthenium complex featuring a derivative of the ligand pyrazine[2,3-f][1,10]-phenanthroline. AB - A new ruthenium complex, [Ru(bpy)2(dbe-ppl)](PF6)2 (bpy=2,2'-bipyridine and dbe ppl=dimethyl 4,4'-(pyrazino[2,3-f][1,10]phenanthroline-2,3-diyl)dibenzoate, has been synthesized and characterized by (1)H NMR spectroscopy, UV-Vis, IR, and cyclic voltammetry. Irradiation on the MLCT band results in photoluminescence in both protic and aprotic solvents. The photoluminescence in water is pH dependent, it shows a behavior which can be described by the Henderson-Hasselbalch assuming the protonation/deprotonation of the excited state with a pKa of 2.40+/-0.01. PMID- 25813164 TI - Assessment of long-range corrected and conventional DFT functional for the prediction of second--order NLO properties and other molecular properties of N-(2 cyanoethyl)-N-butylaniline--a vibrational spectroscopy study. AB - Vibrational spectral analysis and quantum chemical computations based on density functional theory have been performed on the N-(2-cyanoethyl)-N-butylaniline. The geometry, structural properties, intermolecular hydrogen bond, and harmonic vibrational frequencies of the title molecule have been investigated with the help of DFT (B3LYP) and LC-DFT (CAM-B3LYP) method. Molecular electrostatic potential (MEP) have been performed. The various intramolecular interactions have been exposed by natural bond orbital analysis. The distribution of atomic charges and bending of natural hybrid orbitals also reflect the presence of intramolecular hydrogen bonding. Global reactivity and local reactivity descriptors of the title molecule have been calculated. The analysis of the electron density of HOMO and LUMO gives an idea of the delocalization and low value of energy gap indicated the electron transport in the molecule and thereby NLO activity. The effect of solvent on second-order NLO properties has been studied using polarized continuum model (PCM) in the tetrahydrofuran (THF) solution. The solvent leads to a slight enhancement of the NLO responses for the studied complexes relevant to their NLO responses in gas phase. The electronic absorption spectra were investigated by the TDDFT methods. The frequency dependent first hyperpolarizabilities of the N-(2-cyanoethyl)-N-butylaniline were also evaluated. The (1)H and (13)C NMR chemical shifts have been calculated by gauge-indepedent atomic orbital (GIAO) method with B3LYP/6-311++G(d, p) approach. PMID- 25813165 TI - Synthesis and spectroscopic study of highly fluorescent beta-enaminone based boron complexes. AB - The newly synthesized 1, 1, 2-trimethyl-1H benzo[e]indoline based beta-enaminone boron complexes exhibited the intense fluorescence (Fmax=522-547 nm) in solution as well as in solid state (F max=570-586 nm). These complexes exhibited large stoke shift, excellent thermal and photo stability when compared to the boron dipyrromethene (BODIPY) colorants. Optimized geometry and orbital distribution in ground states were computed by employing density functional theory (DFT). The cyclic voltammetry study revealed the better electron transport ability of these molecules than current electroluminescent materials like tris(8-hydroxyquinoli nato)-aluminium (Alq3) and BODIPY, which can find application in electroluminescent devices. PMID- 25813166 TI - An investigations on the molecular structure, FT-IR, FT-Raman and NMR spectra of 1-(p-tolylsulfonyl) pyrrole by theoretical and experimental approach. AB - Fourier-Transform-Infrared, Fourier-Transform-Raman and Nuclear Magnetic Rezonans spectra of 1-(p-tolylsulfonyl) pyrrole molecule have been recorded. In the powder form, vibrational spectra of 1-(p-tolylsulfonyl) pyrrol molecule were investigated in the region 4000-400 cm(-1) and 3500-50 cm(-1), respectively. The conformational analysis, geometrical structure, molecular electrostatic potential map, HOMO-LUMO and vibrational spectroscopic properties of the isolated 1-(p tolylsulfonyl) pyrrole molecule have also been carried out at the Molecular Mechanic and Density Functional Theory approaches. Density Functional Theory results have been associated with Scaled Quantum Mechanics Force Field for fitting between the theoretical and the experimental frequencies. PMID- 25813167 TI - Vibrational spectroscopic study of dehydroacetic acid and its cinnamoyl pyrone derivatives. AB - The infrared and Raman spectra of dehydroacetic acid and some of its derivatives were measured. The assignments of the vibrational bands were based on quantum chemical calculations and normal coordinate analysis. The optimized structures, atomic net charges and dipole moments of the investigated molecules were also results of our quantum chemical calculations. The analysis of the last properties made possible a deeper insight into the structure and substituent effect on the investigated molecules. One of them is presented in the graphical abstract. PMID- 25813168 TI - High calcination of ferroelectric BaTiO3 doped Fe nanoceramics prepared by a solid-state sintering method. AB - This study examined the effects of the combination of starting materials on the properties of solid-state reacted BaTiO3 using two different types of BaCO3 and TiO2. In addition, the effect of mechanochemical activation by high energy milling and the Ba/Ti molar ratio on the reaction temperature, particle size and tetragonality were investigated. The TiO2 phase and size plays a major role in increasing the reaction temperature and particle size. With the optimum selection of starting materials and processing conditions, BaTiO3 with a particle size <200 nm (Scherrer's formula) and a tetragonality c/a of approximately 1.007 was obtained. Broadband dielectric spectroscopy is applied to investigate the electrical properties of disordered perovskite-like ceramics in a wide temperature range. From the X-ray diffraction analysis it was found that the newly obtained BaTi0.5Fe0.5O3 ceramics consist of two chemically different phases. The electric modulus M* formalism used in the analysis enabled us to distinguish and separate the relaxation processes, dominated by marked conductivity in the epsilon*(omega) representation. Interfacial effects on the dielectric properties of the samples have been understood by Cole-Cole plots in complex impedance and modulus formalism. Modulus formalism has identified the effects of both grain and grain boundary microstructure on the dielectric properties, particularly in solid state routed samples. PMID- 25813169 TI - Studies on the weak interactions and CT complex formations between chloranilic acid, 2,3-dichloro-5,6-dicyano-p-benzoquinone, tetracyanoethylene and papaverine in acetonitrile and their thermodynamic properties, theoretically, spectrophotometrically aided by FTIR. AB - Spectrophotometric, FTIR and theoretical studies of the charge-transfer complexes between mild narcotic drug papaverine and the acceptors chloranilic acid (Cl-A), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tetracyanoethylene (TCNE) in acetonitrile, their association constants, thermodynamic (DeltaG(0), DeltaH(0) and DeltaS(0)) and other related properties had been described. Papaverine was found to form colored charge-transfer complexes with Cl-A, DDQ and TCNE in acetonitrile. The absorption maxima of the complexes were 518.5, 584.0 and 464.0 nm for Cl-A complex, DDQ complex, and TCNE complex respectively. The compositions of the papaverine complexes were determined to be 1:1 from Job's method of continuous variation. Solid complexes formed between papaverine and the acceptors were isolated. Comparison of the FTIR spectra of the solid complexes between papaverine and the acceptors and their constituents showed considerable shift in absorption peaks, changes in intensities of the peaks and formation of the new bands on complexation. However, no attempt has been made to purify the complexes and study the detailed spectra both theoretically and experimentally. The energies hnu(CT) of the charge-transfer complexes were compared with the theoretical values of hnu(CT) of the complexes obtained from HOMO and LUMO of the donor and the acceptors. The reasons for the differences in hnuCT values were explained. Density function theory was used for calculation. hnu(CT) (experimental) values of the transition energies of the complexes in acetonitrile differed from hnu(CT) (theoretical) values. ID(V) value of papaverine was calculated. Charge-transfer complexes were assumed to be partial electrovalent compounds with organic dative ions D(+) and A(-) (in the excited state) and attempts had been made to correlate the energy changes for the formation of the complexes with the energy changes for the formation of electrovalent compounds between M(+) and X(-) ions. PMID- 25813170 TI - Study on molecular structure, spectroscopic behavior, NBO, and NLO analysis of 3 methylbezothiazole-2-thione. AB - Experimentally observed spectral data (FT-TR and FT-Raman) of 3 methylbezothiazole-2-thione (3MBT2T) were compared with the spectral data obtained by DFT/B3LYP method using 6-311++G(d,p) basis set. UV-Vis spectrum of the title compound was recorded and the electronic properties, such as frontier molecular orbitals and band gap energies were calculated by TD-DFT approach. The molecular properties like dipole moment, polarizability, first static hyperpolarizability, molecular electrostatic potential surface (MEPs), and contour map were calculated to get a better comprehension of the properties of the title molecule. Natural bond orbital (NBO) analysis was applied to investigate the stability of the molecule arising from charge delocalization. Global and local reactivity descriptors were also computed to predict reactivity and reactive sites on the molecule. PMID- 25813171 TI - Three novel input logic gates supported by fluorescence studies: organic nanoparticles (ONPs) as chemo-sensor for detection of Zn2+ and Al3+ in aqueous medium. AB - Organic nanoparticles (ONPs) of N,N'-ethylenebis(salicylimine) (salen) were synthesized and applied for specific recognition of Zn(2+) and Al(3+) ions in an aqueous medium. The results show that fluorescence intensity rises with the increasing concentration of Zn(2+) in salen solution, proving that salen-ONPs detect Zn(2+) efficiently in the aqueous medium as chemo-sensor. Furthermore, the salen-ONPs/Zn(2+) system performs as an ON-OFF switch between pH 6.0 and 4.0. Amusingly, although salen-ONPs/Al(3+) does not show any significant effect in the fluorescence spectra, highest fluorescence intensity was observed when Al(3+) ion was added to salen-ONPs/Zn(2+) in a sequential order (addition of Zn(2+) to salen ONPs, followed by Al(3+)). This system can be applied as a novel three inputs logic gate supported by the fluorescence for the detection of Zn(2+) and Al(3+) in biological and environmental samples. It appears that photo induced electron transfer (PET) occurs in the salen-ONPs when the fluorophore is excited. For salen/Zn(2+) system, the PET is being inhibited considerably by lowering the receptor HOMO energy due to the formation of a bond between the metal ion and ligand, enhancing the fluorescence emission. This is consistent with the theoretical study that the energy of HOMO of the ligand is lower than that of Zn(salen)(2+) complex. PMID- 25813172 TI - Synthesis and investigation of the properties of novel azocalix[4]arenes. AB - The azocalix[4]arenes molecules such as methylphenylazocalix[4]aren (MPcalix[4]) and methoxyphenylazocalix[4]aren (MOPcalix[4]) have been synthesized and characterized by experimental FT-IR and (1)H NMR spectral analyses. The fundamental vibrational transitions have been addressed by experimental FT-IR (4000-400 cm(-1)) technique and density functional theory (DFT) employing B3LYP level with the 6-31G(d) and 6-311G(d,p) basis sets. The (1)H NMR spectra of the studied compounds have been recorded in chloroform, and compared with computed data obtained by using gauge including atomic orbital (GIAO) method. Furthermore, thermodynamic properties (heat capacity, entropy, and enthalpy changes) and frontier molecular orbitals of the molecules in the ground state have been calculated by using the same method and basis sets. The non-linear optical properties such as the first order hyperpolarizability (beta0), related properties (alpha0 and Deltaalpha) are also computed. Information about the charge density distribution of the molecules and its chemical reactivity has been studied by mapping molecular electrostatic potential surface (MEPs). The scaled vibrational frequency values have been compared with experimental FT-IR spectroscopic data. The correlations between the observed and calculated frequencies are in good agreement with each other as well as the correlation of NMR data. The linear polarizability and first hyperpolarizability of the studied molecules indicate that the compounds are a good candidate of nonlinear optical materials. PMID- 25813173 TI - Synthesis, spectral characterization, computational calculations and biological activity of complexes designed from NNO donor Schiff-base ligand. AB - A new series of Co(II), Ni(II) and Cu(II) complexes of (Z)-2-oxo-2-(phenylamino) N'-(1-(pyridin-2-yl)ethylidene)acetohydrazide (H2OPPAH) have been prepared and characterized by conventional techniques. The spectral data indicated that the ligand acts as neutral or mononegative NNO tridentate. On the basis of magnetic and electronic spectral data an octahedral geometry for Ni(II) and Cu(II) complexes and a tetrahedral geometry for Co(II) complex have been proposed. The molecular modeling using DFT method are drawn showing the bond length, bond angle, chemical reactivity, energy components (kcal/mol) and binding energy (kcal/mol) for all title compounds. The Kinetic parameters were determined for each thermal degradation stages of the ligand and its complexes using Coats Redfern and Horowitz-Metzger methods. Also, the compounds were screened for antioxidant activity using ABTS free radical, anti-hemolytic, and in vitro cytotoxic assay. H2OPPAH showed the potent antioxidant activity followed by Co(II) and Cu(II) complexes. On the other hand Ni(II) complex exhibited weak antioxidant activity using ABTS free radical and Erlich and strong erythrocyte hemolysis activity. PMID- 25813174 TI - Spectroscopic investigation (FTIR spectrum), NBO, HOMO-LUMO energies, NLO and thermodynamic properties of 8-Methyl-N-vanillyl-6-nonenamideby DFT methods. AB - Capsicum a hill grown vegetable is also known as red pepper or chili pepper. Capsaicin(8-Methyl-N-vanillyl-6-nonenamide) is the active component in chili peppers, which is currently used in the treatment of osteoarthritis, psoriasis and cancer. Fourier transform infrared (FT-IR) spectrum of Capsaicin in the solid phase were recorded in the region 4000-400 cm(-1) and analyzed. The vibrational frequencies of the title compound were obtained theoretically by DFT/B3LYP calculations employing the standard 6-311++G(d,p) basis set and were compared with Fourier transform infrared spectrum. Complete vibrational assignment analysis and correlation of the fundamental modes for the title compound were carried out. The vibrational harmonic frequencies were scaled using scale factor, yielding a good agreement between the experimentally recorded and the theoretically calculated values. Stability of the molecule arising from hyper conjugative interactions, charge delocalization and intra molecular hydrogen bond like weak interaction has been analyzed using Natural bond orbital (NBO) analysis by using B3LYP/6-311++G(d,p) method. The results show that electron density (ED) in the sigma* and pi* antibonding orbitals and second-order delocalization energies E (2) confirm the occurrence of intra molecular charge transfer (ICT) within the molecule. The dipole moment (MU), polarizability (alpha) and the hyperpolarizability (beta) values of the molecule has been computed. Thermodynamic properties (heat capacity, entropy and enthalpy) of the title compound at different temperatures were calculated. PMID- 25813175 TI - Second-order susceptibility spectra for delta-BiB3O6 polymer nanocomposites deposited on the chalcogenide crystals. AB - The optimized conditions for the enhancement of the second harmonic generation in the composites of the orthorhombic delta-BiB3O6:Pr(3+) nanoparticles embedded in polyvinyl alcohol films and deposited on the AgGaGe2Se6, AgGaGe2.7Si0.3Se8 (90 mol.% AgGaGe3Se8 - 10 mol.% AgGaSi3Se8), and AgGaGe3Se8:Cu substrates were established. The highest second-order susceptibility was achieved during the Ag Ga-Ge-Se crystalline substrates photo-illumination by nanosecond laser pulses of about 2900 nm wavelength. The effect was found to be completely reversible after the interruption of the photo-inducing stimulation. Complementary studies of Atomic Force Microscopy, AFM, X-ray Diffraction, XRD, and Fourier-Transform Infrared Spectroscopy, and DFT simulations of spectral dependences of the corresponding second-order nonlinear optical susceptibilities, were performed. PMID- 25813176 TI - Surface enhanced Raman scattering, natural bond orbitals and Mulliken atomic charge distribution in the normal modes of diethyldithiocarbamate cadmium (II) complex, [Cd(DDTC)2]. AB - Theoretical and experimental bands have been assigned to the Fourier Transform Infrared (FT-IR) and FT-Raman spectra of the bis(diethyldithiocarbamate)Cd(II) complex, abbreviated as ([Cd(DDTC)2]). The calculations and spectral interpretation have been based on the DFT/B3LYP method, infrared and Raman second derivative spectra, and band deconvolution analysis to assist in the assignment of observed fundamentals. This study validated the unusual pseudo tetrahedral molecular structure formed around the Cd(II) cation. Surface-enhanced Raman scattering (SERS) was used to determine the interactions of the normal-modes of the diethyldithiocarbamate cadmium (II) complex on nano-structured silver surfaces. Natural bond orbital (NBO) analysis was also carried out to study the Cd(II) hybridization causing the pseudo tetrahedral geometry of the framework of the [Cd(DDTC)2] complex, and to confirm the charge transfer mechanisms through second order perturbation theory analysis of the Fox Matrix. In order to find out the electronic dispersion of the Mulliken atomic charges (MAC) in the normal modes, we calculated the MAC for each normal mode and correlated these values with the SERS effect. Experimental UV-Vis spectra were obtained and charge transfer bands were assigned. Good agreement between the calculated and experimental values for the vibrational and UV-Vis spectra was obtained. PMID- 25813177 TI - XRD, vibrational spectra and quantum chemical studies of an anticancer drug: 6 Mercaptopurine. AB - The single crystal of the hydrated anticancer drug, 6-Mercaptopurine (6-MP), has been grown by slow evaporation technique under room temperature. The structure was determined by single crystal X-ray diffraction. The vibrational spectral analysis was carried out using Laser Raman and FT-IR spectroscopy in the range of 3300-100 and 4000-400 cm(-1). The single crystal X-ray studies shows that the crystal packing is dominated by N-H?O and O-H?N classical hydrogen bonds leading to a hydrogen bonded ensemble. This classical hydrogen bonds were further connected through O-H?S hydrogen bond to form two primary ring R4(4)(16) and R4(4)(12) motifs. These two primary ring motifs are interlinked with each other to build a ladder like structure. These ladders are connected through N-H?N hydrogen bond along c-axis of the unit cell through chain C(5) motifs. Further, the strength of the hydrogen bonds is studied through vibrational spectral measurements. The shifting of bands due to the intermolecular interactions was also analyzed in the solid crystalline state. Geometrical optimizations of the drug molecule were done by Density Functional Theory (DFT) using the B3LYP function and Hartree-Fock (HF) level with 6-311++G(d,p) basis set. The optimized molecular geometry and computed vibrational spectra are compared with experimental results which show significant agreement. The natural bond orbital (NBO) analysis was carried out to interpret hyperconjugative interaction and intramolecular charge transfer (ICT). The chemical hardness, electro-negativity and chemical potential of the molecule are carried out by HOMO-LUMO plot. In which, the frontier orbitals has lower band gap value indicating the possible pharmaceutical activity of the molecule. PMID- 25813178 TI - beta-Alaninium tetrafluoroborate: a new salt with di-beta-alaninium dimeric cation. AB - beta-Alaninium tetrafluoroborate crystallizes in the monoclinic system (space group P21/n, Z=4). The asymmetric unit contains one beta-alaninium cation and one tetrafluoroborate anion, in which the fluorine atoms are disordered. All beta alaninium cations are connected with the symmetry related cations via an inversion center, thus forming dimeric centrosymmetric beta-Ala(+)...beta-Ala(+) cations. The O...O distance (2.698(2)A) in the dimeric cation is relatively long compared to known distances of previously reported salts with A(+)...A(+) type dimeric cations. The infrared and Raman spectra are studied. PMID- 25813179 TI - New tetradentate Schiff bases of 2-amino-3,5-dibromobenzaldehyde with aliphatic diamines and their metal complexes: synthesis, characterization and thermal stability. AB - The tetradentate Schiff base ligands (L(1)-L(4)), were synthesized by reaction between 2-amino-3,5-dibromobenzaldehyde and aliphatic diamines. Then, nickel and oxovanadium(IV) complexes of these ligands were synthesized and characterized by (1)H NMR, Mass, IR, UV-Vis spectroscopy and thermogravimetry. The kinetic parameters of oxovanadium(IV) complexes were calculated from thermal studies. According to the results of thermogravimetric data, the thermal stability of oxovanadium(IV) complexes is as follow: [Formula: see text]. PMID- 25813180 TI - Structural, spectral, thermal and biological studies on (Z)-N-benzoyl-N'-(2-oxo-2 (phenylamino)acetyl)carbamohydrazonothioic acid (H2PABT) and its Cd(II), Hg(II), Zn(II) and U(VI)O22+ complexes. AB - A new metal complexes formed by the reaction of (Z)-N-benzoyl-N'-(2-oxo-2 (phenylamino)acetyl)carbamohydrazonothioic acid (H2PABT) and Cd(II), Hg(II), Zn(II) and U(VI)O2(2+) ions. The isolated complexes were prepared and characterized by conventional techniques. The IR data revealed that the ligand behaves as mononegative tridentate in Zn(II) and U(VI)O2(2+) complexes also, binegative tetradentate on Cd(II) and Hg(II) complexes. On the basis of magnetic and electronic spectral data an octahedral geometry for the U(VI)O2(2+) complex, a tetrahedral structure for the Cd(II), Zn(II) and Hg(II) complexes have been proposed. The IR spectrum of ligand which determined experimentally is compared with those obtained theoretically from DFT calculations. Also, the bond lengths, bond angles, HOMO, LUMO and dipole moments have been calculated. The calculated HOMO-LUMO energy gap reveals that charge transfer occurs within the ligand molecules. The calculated values of binding energies indicates the stability of complexes is higher that of ligand. Also, the kinetic and thermodynamic parameters for the different thermal degradation steps of the complexes were determined by Coats-Redfern and Horowitz-Metzger methods. Moreover, the ligand and its complexes were screened against Bacillus subtilis as Gram positive bacteria and Escherichia coli Gram negative bacteria using the inhibitory zone diameter. Also the antitumor activities of the ligand and its complexes have been evaluated against liver (HePG2) and breast (MCF-7) cancer cells. Out of all the synthesized compounds, [Hg2(PABT)Cl2(H2O)2] and [(UO2)(HPABT)(OAc)(H2O)] complexes showed high antibacterial activity with 55.5% while H2PABT showed the best cytotoxic effect on liver and breast cancer cells with IC50 2.10 and 5.91 of cytotoxicity respectively. PMID- 25813181 TI - Synthesis, and spectroscopic studies of charge transfer complex of 1,2 dimethylimidazole as an electron donor with pi-acceptor 2,4-dinitro-1-naphthol in different polar solvents. AB - The charge transfer (CT) complex of 1,2-dimethylimidazole (DMI) as an electron donor with pi acceptor 2,4-dinitro-1-naphthol (DNN) has been studied spectrophotometrically in different solvents like chloroform, acetonitrile, methanol, methylene chloride, etc. at room temperature. The CT complex which is formed through the transfer of lone pair electrons from DMI to DNN exhibits well resolved CT bands and the regions of these bands were remarkably different from those of the donor and acceptor. The stoichiometry of the CT complex was found to be 1:1 by a straight-line method between donor and acceptor with maximum absorption bands. The novel CT complex has been characterized by FTIR, TGA-DTA, powder XRD, (1)H NMR and (13)C NMR spectroscopic techniques. The Benesi Hildebrand equation has been used to determine the formation constant (K(CT)), molar extinction coefficient (epsilon(CT)), standard gibbs free energy (DeltaG degrees ) and other physical parameters of the CT complex. The formation constant recorded higher values and molar extinction coefficient recorded lower values in chloroform compared with methylene chloride, methanol and acetonitrile, confirming the strong interaction between the molecular orbital's of donor and acceptor in the ground state in less polar solvent. This CT complex has been studied by absorption spectra of donor 1,2-dimethylimidazole (DMI) and acceptor 2,4-dinitro-1-naphthol (DNN) by using the spectrophotometric technique in various solvents at room temperature. PMID- 25813182 TI - [Alopecia areata occurring during anti-TNF-alpha therapy: A French prospective multicentre study]. PMID- 25813183 TI - [Palmoplantar keratoderma syndromes: new findings]. PMID- 25813184 TI - [Burow's advancement flap after excision of lentigo maligna from the cheek]. PMID- 25813185 TI - [Virilizing ovarian tumor: a rare cause of androgenetic alopecia]. PMID- 25813186 TI - [Diagnostic pitfalls of solar urticaria]. PMID- 25813187 TI - [Male genital lichen planus]. PMID- 25813188 TI - [Facial inflammatory cutaneous leishmaniasis or "erysipeloid"]. PMID- 25813189 TI - [Infantile xanthelasmoid mastocytosis]. PMID- 25813190 TI - The roles of thermal transient receptor potential channels in thermotactic behavior and in thermal acclimation in the red flour beetle, Tribolium castaneum. AB - To survive in variable or fluctuating temperature, organisms should show appropriate behavioral and physiological responses which must be mediated through properly attuned thermal sensory mechanisms. Transient receptor potential channels (TRPs) are a family of cation channels a number of which, called thermo TRPs, are known to function as thermosensors. We investigated the potential role of thermo-TPRs that have been previously identified in the fruit fly, Drosophila melanogaster, in thermotaxis and thermal acclimation in the red flour beetle, Tribolium castaneum. Phylogenetic analysis of the trp genes showed generally one to-one orthology between those in D. melanogaster and in T. castaneum, although there are putative gene-losses in two TRP subfamilies of D. melanogaster. With RNA interference (RNAi) of T. castaneum thermo-TRP candidates painless, pyrexia and trpA1, we measured thermal avoidance behavior. RNAi of trpA1 resulted in reduced avoidance of high temperatures, 39 and 42 degrees C. We also measured the effects of RNAi on heat-induced knockout and death under a short exposure to high temperature (1min at 52 degrees C) either with or without a 10-min acclimation period at 42 degrees C. Relatively short exposure to high temperature was enough to induce high temperature thermal acclimation. RNAi of trpA1 led to faster knockout at 52 degrees C. RNAi of painless showed lower recovery rates from heat-induced knockout after thermal acclimation, and RNAi of pyrexia showed lower long-term survivorship without thermal acclimation. Therefore, we concluded that trpA1 is important in high temperature sensing and also in enhanced tolerance to high-temperature induced knockout; painless plays a role in rapid acclimation to high temperature; and pyrexia functions in protecting beetles from acute heat stress without acclimation. PMID- 25813191 TI - Poststroke angiogenesis: blood, bloom, or brood? PMID- 25813192 TI - Classification of subtypes of ischemic stroke: history of the trial of org 10172 in acute stroke treatment classification. PMID- 25813193 TI - Four-year follow-up of transient ischemic attacks, strokes, and mimics: a retrospective transient ischemic attack clinic cohort study. AB - BACKGROUND AND PURPOSE: There is limited information on outcomes from rapid access transient ischemic attack (TIA) clinics. We present 4-year outcomes of TIAs, strokes, and mimics from a UK TIA clinic database. METHODS: All patients referred between April 2010 and May 2012 were retrospectively identified and outcomes determined. End points were stroke, myocardial infarction, any vascular event (TIA, stroke, or myocardial infarction), and all-cause death. Data were analyzed by survival analysis. RESULTS: Of 1067 patients, 31.6% were TIAs, 18% strokes, and 50.4% mimics. Median assessment time was 4.5 days from onset and follow-up was for 34.9 months. Subsequent strokes occurred in 7.1% of patients with TIA, 10.9% of patients with stroke, and 2.0% of mimics at the end of follow up. Stroke risk at 90 days was 1.3% for patients diagnosed as TIA or stroke. Compared with mimics, hazard ratios for subsequent stroke were 3.88 (1.90-7.91) for TIA and 5.84 (2.81-12.11) for stroke. Hazard ratio for any subsequent vascular event was 2.91 (1.97-4.30) for TIA and 2.83 (1.81-4.41) for stroke. Hazard ratio for death was 1.68 (1.10-2.56) for TIA and 2.19 (1.38-3.46) for stroke. CONCLUSIONS: Our results show a lower 90-day stroke incidence after TIA or minor stroke than in earlier studies, suggesting that rapid access daily TIA clinics may be having a significant effect on reducing strokes. PMID- 25813194 TI - Lower serum calcium level is associated with hemorrhagic transformation after thrombolysis. AB - BACKGROUND AND PURPOSE: We aim to investigate whether lower admission serum calcium levels are associated with hemorrhagic transformation (HT) after intravenous thrombolysis (IVT). METHODS: A total of 362 patients treated with IVT was divided into 4 quartiles based on admission serum calcium levels (Q1[<2.16], Q2[2.16, 2.23], Q3[2.24, 2.31], and Q4[>2.31] mmol/L). HT was classified as hemorrhagic infarction and parenchymal hemorrhage. Logistic regression was applied to assess the association between serum calcium levels and the incidence of HT. RESULTS: Compared with Q4, HT was more common in Q1 (odds ratio, 2.580; 95% CI, [1.258-5.292]; P=0.010), Q2 (odds ratio, 2.382; 95% CI, [1.163-4.877]; P=0.018), and Q3 (odds ratio, 2.293; 95% CI, [1.133-4.637]; P=0.021). Hemorrhagic infarction was more common in Q1 (P=0.037), and Q2 (P=0.018), compared with Q4, and parenchymal hemorrhage was more common in Q1 (P=0.029) than Q4. CONCLUSIONS: Lower admission serum calcium level is independently associated with HT after IVT, and this hypothesis needs larger confirmatory trials. PMID- 25813195 TI - Poststroke angiogenesis, con: dark side of angiogenesis. PMID- 25813196 TI - Poststroke angiogenesis, pro: making the desert bloom. PMID- 25813197 TI - Changes in wall shear stress of cerebral arteriovenous malformation feeder arteries after embolization and surgery. AB - BACKGROUND AND PURPOSE: Wall shear stress (WSS) has been implicated as an important stimulus for vascular remodeling. The purpose of this study is to measure WSS in AVM arterial feeders using quantitative magnetic resonance angiography pre- and post-embolization/surgery. METHODS: Records of patients who underwent AVM embolization and surgical resection at our institution between 2007 and 2013 and had WSS, flow rate, and vessel diameter obtained pre- and post treatment using quantitative magnetic resonance angiography were retrospectively reviewed. WSS was compared between the feeder and contralateral artery pre- and post-embolization/surgery. RESULTS: Twenty-one patients were included (mean age 34 years, 19% hemorrhagic presentation), with Spetzler-Martin grades 1 to 4. WSS, blood flow, and vessel diameter were assessed in a total of 51 feeder arteries. At baseline, mean WSS was significantly higher compared with the contralateral vessel (29.7+/-12.0 dynes/cm(2) versus 23.3+/-11.0 dynes/cm(2); P=0.007). After embolization (23.0 dynes/cm(2) versus 22.5 dynes/cm(2); P=0.78) and surgery (17.9 dynes/cm(2) versus 23.2 dynes/cm(2); P=0.09), WSS was not significantly different than in the contralateral vessel. Reduced WSS post-embolization corresponded to significantly decreased flow (338.1 mL/min versus 170.3 mL/min; P<0.001) and smaller vessel diameter (3.7 mm versus 3.5 mm; P=0.01). CONCLUSIONS: Enlargement of cerebral AVM arterial feeders is insufficient to compensate for increased blood flow, creating high WSS. After treatment, flow diminishes and so WSS and vessel diameter concomitantly decrease. Thus, WSS plays a pivotal role in vascular remodeling that may be exploited to monitor AVM response to treatment or understand other high-flow vascular pathologies. PMID- 25813198 TI - The role of sensory-motor modality compatibility in language processing. AB - Language processing requires the combination of compatible (auditory-vocal and visual-manual) or incompatible (auditory-manual and visual-vocal) sensory-motor modalities, and switching between these sensory-motor modality combinations is very common in every-day life. Sensory-motor modality compatibility is defined as the similarity of stimulus modality and the modality of response-related sensory consequences. We investigated the influence of sensory-motor modality compatibility during performing language-related cognitive operations on different linguistic levels. More specifically, we used a variant of the task switching paradigm, in which participants had to switch between compatible or between incompatible sensory-motor modality combinations during a verbal semantic categorization (Experiment 1) or during a word-form decision (Experiment 2). The data show higher switch costs (i.e., higher reaction times and error rates in switch trials compared to repetition trials) in incompatible sensory-motor modality combinations than in compatible sensory-motor modality combinations. This was true for every language-related cognitive operation, regardless of the individual linguistic level. Taken together, the present study demonstrates that sensory-motor modality compatibility plays an important role in modality switching during language processing. PMID- 25813199 TI - Precursor directed biosynthesis of odd-numbered fatty acids by different yeasts. AB - Precursor-directed biosynthesis was used for directed preparation of positional isomers of heptadecanoic acid (17:1), which have convenient pharmacological properties. Cultivation of Candida sp., Kluyveromyces polysporus, Rhodotorula glutinis, Saccharomyces cerevisiae, Torulaspora delbrueckii, Trichosporon cutaneum, and Yarrowia lipolytica on 20 g/L glucose, 4 g/L acetic, or 4 g/L propionic acids yielded different proportions of 17:1. Cultivation on carbon sources with even numbers of carbon atoms (glucose and acetic acid) produced preferentially 8Z- and 10Z-heptadecenoic acids in about equal amounts, in agreement with the proposed biosynthesis of fatty acids, whereas cultivation on propionic acid as the only carbon source produced over 90 % of total fatty acids of 9-17:1 out of all possible positional isomers. The structures of positional isomers of 17:1 acid were determined using dimethyl disulfides of fatty acid methyl esters. In cultivation of Candida sp. on propionic acid, the yield of heptadecenoic acid reached 111 mg/L cultivation medium. Principal component analysis was used for identifying the effect of cultivation conditions on the production of the 17:1 acid by individual yeast strains. PMID- 25813200 TI - Alternative nutrient sources for biotechnological use of Sporosarcina pasteurii. AB - The potential use of Sporosarcina pasteurii in possible biotechnological applications on a large scale (ground improvement, consolidation of building structures and ornamental stone, or in developing bio-materials for the building industry), is based on its ability to produce high amounts of carbonate in a short period of time via urea hydrolysis. Industrial biomass production would have a low environmental impact and would be most economical if the standard growth media could be replaced with alternative nutrient sources, such as byproducts or wastes from other industries, or other low cost ingredients. The use of cost effective ingredients must guarantee ureolytic activities and growth conditions that are comparable to those resulting from the standard nutrient medium. In this work, three types of alternative media were tested for growing the ureolytic active bacteria S. pasteurii: (1) alternative nutrient sources such as industrial wastes resulting from the dairy and brewery industries, (2) fertilizer urea as an alternative urea substitute, and (3) different types of poultry manure based fertilizers as nutrient and urea substitutes. The comparison between the standard media, the nutrient alternatives and urea substitutes was possible by taking the protein concentration and nitrogen content into account. Bacterial activity was evaluated in terms of biomass changes over time (CFU, optical density, ATP measurements) and indirect estimation of the enzyme production (Nessler assay, conductivity measurement). The results revealed that some of the dairy wastes tested, such as whey and buttermilk, are potential alternative nutrients for bacterial development, while the urea fertilizer is perfectly suitable as an economical substitute for pure laboratory grade urea. PMID- 25813201 TI - Weighting of Acoustic Cues to a Manner Distinction by Children With and Without Hearing Loss. AB - PURPOSE: Children must develop optimal perceptual weighting strategies for processing speech in their first language. Hearing loss can interfere with that development, especially if cochlear implants are required. The three goals of this study were to measure, for children with and without hearing loss: (a) cue weighting for a manner distinction, (b) sensitivity to those cues, and (c) real world communication functions. METHOD: One hundred and seven children (43 with normal hearing [NH], 17 with hearing aids [HAs], and 47 with cochlear implants [CIs]) performed several tasks: labeling of stimuli from /balpha/-to-/walpha/ continua varying in formant and amplitude rise time (FRT and ART), discrimination of ART, word recognition, and phonemic awareness. RESULTS: Children with hearing loss were less attentive overall to acoustic structure than children with NH. Children with CIs, but not those with HAs, weighted FRT less and ART more than children with NH. Sensitivity could not explain cue weighting. FRT cue weighting explained significant amounts of variability in word recognition and phonemic awareness; ART cue weighting did not. CONCLUSION: Signal degradation inhibits access to spectral structure for children with CIs, but cannot explain their delayed development of optimal weighting strategies. Auditory training could strengthen the weighting of spectral cues for children with CIs, thus aiding spoken language acquisition. PMID- 25813203 TI - The expression levels of JunB, JunD and p-c-Jun are positively correlated with tumor cell proliferation in diffuse large B-cell lymphomas. AB - We analyzed the expression of Jun family in relation to CD30 expression, cell proliferation and B-cell differentiation immunophenotypes [Germinal Center and non-Germinal Center] in diffuse large B-cell lymphomas (DLBCL). Expression and high expression of phosphorylated-c-Jun (p-c-Jun), JunB, JunD and CD30 (cut-off scores 20% and 50%, respectively) was found in 18/103, 49/103, 72/101 and 26/102 cases, respectively, and in 6/103, 27/103, 60/101 and 21/102 cases, respectively. The following significant positive correlations were observed: (a) JunB with cyclin A (p = 0.046), cyclin B1 (p = 0.033), cyclin E (p = 0.003), MUM-1 (p = 0.002) and CD30 (p < 0.001), (b) JunD with Ki67 (p = 0.002) and cyclin E (p = 0.014), (c) p-c-Jun with CD30 (p = 0.015), and (d) high p-c-Jun with cyclin A (p = 0.034). The positive correlation between expression of JunB, JunD and p-c-Jun and tumor cell proliferation in DLBCL, suggests that increased JunB, JunD and p-c Jun expression may be involved in the pathogenesis of DLBCL by increasing tumor cell proliferation. PMID- 25813204 TI - Histopathological analysis of B-cell non-Hodgkin lymphomas without light chain restriction by using flow cytometry. AB - Detection of immunoglobulin light chain restriction (LCR) by flow cytometry (FCM) is a useful tool for B-cell non-Hodgkin lymphoma (B-NHL) diagnosis. Here, we identified B-NHLs without LCR by FCM and investigated the pathological causes for lack of LCR. A total of 89/471 cases (19%) of B-NHL were LCR-negative. The incidence of lack of LCR was 30% both in diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), and was 6% in follicular lymphoma (FL). In DLBCL cases, low expression of surface membrane light chain (33%), low proportion of lymphoma cells (11%), CD45 negativity (9%), and destruction or sampling error were suggested as reasons for lack of LCR. In MZL cases, the low proportion of lymphoma cells owing to admixture of many reactive germinal centres, and non detection of plasmacytoid lymphoma cells by CD45 gating might be the reasons. Based on pathological subtypes, the frequency and reasons for lack of LCR by FCM varied. PMID- 25813206 TI - Clinical features of life-threatening complications following autologous stem cell transplantation in patients with lymphoma. AB - Toxic effects of high dose therapy (HDT) combined with autologous stem cell transplantation (ASCT) can lead to life-threatening conditions that may require intensive care unit (ICU) admission. We conducted a retrospective observational study over a 10-year period of all patients admitted to the ICU within 3 months after HDT/ASCT for lymphoma. Among the 532 patients treated by HDT/ASCT at our hospital, 27 (5%) were admitted to the ICU. Infections accounted for 88% (n = 24) of diagnoses, in whom 50% were microbiologically documented. Primary sources of infections were neutropenic enterocolitis (n = 9, 33%) and pneumonia (n = 9, 33%). Bacteria were identified in 83% of documented infections. ICU mortality was 18.5% (n = 5), representing 0.9% of the 532 patients. Among the 22 ICU survivors, 72.7% (n = 16) were alive and in complete remission 6 months after ICU discharge. In our experience, maximal intensive care support is justified for HDT/ASCT recipients with severe complications. PMID- 25813205 TI - Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD 0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. AB - This phase 1/2 study was the first to evaluate the safety and efficacy of the cyclin-dependent kinase (CDK) 4/6-specific inhibitor palbociclib (PD-0332991) in sequential combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. The recommended phase 2 dose was palbociclib 100 mg orally once daily on days 1-12 of a 21-day cycle with bortezomib 1.0 mg/m2 (intravenous) and dexamethasone 20 mg (orally 30 min pre-bortezomib dosing) on days 8 and 11 (early G1 arrest) and days 15 and 18 (cell cycle resumed). Dose-limiting toxicities were primarily cytopenias; most other treatment-related adverse events were grade<=3. At a bortezomib dose lower than that in other combination therapy studies, antitumor activity was observed (phase 1). In phase 2, objective responses were achieved in 5 (20%) patients; 11 (44%) achieved stable disease. Biomarker and pharmacodynamic assessments demonstrated that palbociclib inhibited CDK4/6 and the cell cycle initially in most patients. PMID- 25813207 TI - The addition of a spin column step in the telomeric repeat application protocol removes telomerase inhibitors. AB - Telomerase activity in cancer cells is commonly analyzed by a polymerase chain reaction (PCR)-based assay termed the telomeric repeat amplification protocol (TRAP). However, nonspecific inhibition of Taq polymerase during the PCR step is frequently observed in inhibitor analysis or drug screening. Thus, the removal of excess inhibitors prior to PCR is an essential step for the proper evaluation of telomerase inhibitory effects. Here, a size exclusion spin column was applied to remove small molecular weight inhibitors from the telomerase extension products. The spin column-added protocol, termed sTRAP, provides a more reliable estimation of the inhibitory effects of telomerase activity. PMID- 25813208 TI - Automated capillary Western dot blot method for the identity of a 15-valent pneumococcal conjugate vaccine. AB - Simple Western is a new technology that allows for the separation, blotting, and detection of proteins similar to a traditional Western except in a capillary format. Traditionally, identity assays for biological products are performed using either an enzyme-linked immunosorbent assay (ELISA) or a manual dot blot Western. Both techniques are usually very tedious, labor-intensive, and complicated for multivalent vaccines, and they can be difficult to transfer to other laboratories. An advantage this capillary Western technique has over the traditional manual dot blot Western method is the speed and the automation of electrophoresis separation, blotting, and detection steps performed in 96 capillaries. This article describes details of the development of an automated identity assay for a 15-valent pneumococcal conjugate vaccine, PCV15-CRM197, using capillary Western technology. PMID- 25813209 TI - Attenuation of cellular toxicity by calpain inhibitor induced by bacterial endotoxin: a mechanistic study using muscle precursor cells as a model system. AB - This investigation was under taken to explore probable mechanisms and signal pathways involved in cytotoxicity induced by bacterial endotoxin lipopolysaccharide (LPS). Herein, we selected muscle precursor C2C12 myoblasts as representative cells to test effect of calpain inhibitor 3-(4-iodophenyl)-2 mercapto-(Z)-2-propenoic acid (PD150606) on LPS induced inflammation and apoptosis. In order to rule out the toxicity of endotoxin, mouse myoblasts were exposed to various concentrations of LPS and viability of cells and morphology were assessed using CCK-8 assay and simple microscopy respectively. Apoptotic cell death was examined by fluorescence microscope at regular time intervals. Additionally, LPS induced apoptosis in C2C12 cells were determined by mRNA expression of u-calpain, caspase-3 and tumor necrosis factor alpha (TNF-alpha) and were quantified by qRT-PCR. Our results point out that LPS stimulation produced dose dependent toxicity in muscle precursor cells. Pre-treatment with a calpain inhibitor can significantly attenuate LPS-induced inflammation/apoptosis. Results of present research determined that mRNA expression of aforesaid genes was amplified (p<0.05) in LPS stimulated C2C12 cells, whereas a noticeable drop off in mRNA expression of these genes was observed when pre-exposed with calpain inhibitor PD150606. Our study has outlined the current understanding regarding the connection between u-calpain and caspase-3 in skeletal muscle wasting and as a result provides suitable choice for designing promising chemotherapeutic system for muscle illness and atrophy. PMID- 25813211 TI - Effect of orthorhombic-tetragonal phase transition on structure and piezoelectric properties of KNN-based lead-free ceramics. AB - (1 - x)(K0.5Na0.5)0.95Li0.05Nb0.93Sb0.07O3-xSrZrO3 ((1 - x)KNLNS-xSZ) lead free piezoelectric ceramics have been prepared by the conventional solid state reaction method, via adjusting the orthorhombic-tetragonal phase transition temperature to near room temperature with doping SrZrO3, and the effects of SrZrO3 content on polymorphic phase transition have been investigated. These results show that the phase structure of the ceramics was changed from orthorhombic to tetragonal at x >= 0.02 mol, and the orthorhombic-tetragonal phase transition temperature was modified to around room temperature with increasing SrZrO3. Remarkable piezoelectric and ferroelectric properties has been obtained in (1 - x)KNLNS-xSZ system with x = 0.02, which showed a piezoelectric parameter of d33 = 256 pC N(-1), Curie temperature Tc = 270 degrees C, strain levels of 0.16% at 50 kV cm(-1), remnant polarization Pr = 24.9 MUC cm(-2) and coercive field Ec = 10.6 kV cm(-1). PMID- 25813210 TI - GPX2 underexpression indicates poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder. AB - PURPOSE: Oxidative stress is believed to be one of the important etiologies in carcinogenesis that has not been systemically investigated in urothelial carcinoma (UC). Through data mining from a published transcriptomic database of UC of urinary bladders (UBUCs) (GSE31684), glutathione peroxidase 2 (GPX2) was identified as the most significant downregulated gene among those response to oxidative stress (GO:0006979). We therefore analyze GPX2 transcript and protein expressions and its clinicopathological significance. METHODS: Real-time RT-PCR assay was used to detect GPX2 mRNA level in 20 fresh UBUC specimens. Immunohistochemistry was used to determine GPX2 protein expression in 340 urothelial carcinomas of upper tracts (UTUCs) and 295 UBUCs with mean/median follow-up of 44.7/38.9 and 30.8/23.1 months, respectively. Its expression status was further correlated with clinicopathological features and evaluated for its impact on disease-specific survival and metastasis-free survival (MeFS). RESULTS: Decrease in GPX2 transcript level was associated with both higher pT and positive nodal status in 20 UBUCs (all p < 0.05). GPX2 protein underexpression was also significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses in both groups of UCs (all p < 0.05). GPX2 underexpression not only predicted dismal DDS and MeFS at univariate analysis, but also implicated worse DDS (UTUC, p = 0.002; UBUC, p = 0.029) and MeFS (UTUC, p = 0.001; UBUC, p = 0.032) in multivariate analysis. CONCLUSIONS: GPX2 underexpression is associated with advanced tumor status and implicated unfavorable clinical outcome of UCs, suggesting its role in tumor progression and may serve as a theranostic biomarker of UCs. PMID- 25813212 TI - Eliminating the use of allogeneic blood products in adolescent idiopathic scoliosis surgery. AB - PURPOSE: The aim of this study was to compare transfusion requirements in patients before and after the introduction of tranexamic acid as standard in patients undergoing spinal surgery for idiopathic scoliosis in a national orthopaedic hospital. METHODS: A retrospective chart review of 56 idiopathic scoliosis patients who underwent posterior spinal instrumentation and fusion between 2009 and 2013 at our institution. Preoperative, intraoperative, and postoperative data were measured. RESULTS: Patients who received tranexamic acid as standard (n = 31) showed a trend towards a decrease in transfusion requirements compared with those who received no tranexamic acid (n = 25). These patients had a statistically significant decrease in operative time (223 vs 188 min, p = 0.005), and estimated intraoperative blood loss was reduced by nearly 50% in the tranexamic acid group. They also had an associated reduced decrease in haemoglobin between preoperative and postoperative levels (4 vs 5 g/dL, p = 0.01). CONCLUSIONS: Since February 2012, no patient has required intraoperative or postoperative allogeneic blood product transfusion in this hospital. The routine use of antifibrinolytic medications in patients undergoing surgery for adolescent idiopathic scoliosis has effectively eliminated the need for allogeneic blood products. PMID- 25813214 TI - Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. AB - AIMS/HYPOTHESIS: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces HbA1c, body weight and systolic BP (SBP) in patients with type 2 diabetes. As weight loss is known to reduce both HbA1c and SBP, these analyses were performed to evaluate the contribution of weight loss resulting from treatment with canagliflozin to HbA1c and SBP reductions in patients with type 2 diabetes. METHODS: Pooled data from four placebo-controlled Phase 3 studies (N = 2,250) in patients with type 2 diabetes were used in the analyses. In each study, patients were treated with placebo, canagliflozin 100 mg or canagliflozin 300 mg, once daily for 26 weeks. Changes from baseline in body weight, HbA1c and SBP were measured at week 26, and the contribution of weight loss to the lowering of HbA1c and SBP was obtained using ANCOVA. RESULTS: Canagliflozin 100 and 300 mg reduced mean body weight, HbA1c and SBP compared with placebo (p < 0.001 for each), and more patients had body-weight reductions >0%, >=5% and >=10% with canagliflozin treatment than with placebo. Weight-loss-independent and weight-loss-associated mechanisms contributed to HbA1c and SBP lowering with canagliflozin: ~85% of HbA1c lowering and ~60% of SBP lowering was independent of weight loss. CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, canagliflozin provided clinically meaningful body-weight reductions, and the weight loss contributed to reductions in HbA1c and SBP. PMID- 25813215 TI - Orexin A regulates plasma insulin and leptin levels in a time-dependent manner following a glucose load in mice. AB - AIMS/HYPOTHESIS: Orexin A (OXA) is a neuropeptide implicated in the regulation of arousal status and energy metabolism. Orexin receptors are expressed not only in the central nervous system but also in the pancreas and adipose tissue. However, little is known about the physiological function of orexins. This study investigated the role of exogenous OXA in blood glucose control after glucose load in mice. In addition, the effect of OXA on insulin secretion was also identified in mouse pancreatic beta cells. METHODS: Insulin secretion and intracellular Ca(2+) levels were measured in perifused mouse islets. To investigate the effects of exogenous OXA on blood glucose levels in vivo, intraperitoneal glucose tolerance tests were performed after a subcutaneous injection of OXA in normal and high-fat diet-induced diabetic mice. RESULTS: OXA significantly potentiated glucose-stimulated insulin secretion in vitro, which increased intracellular Ca(2+) levels, mainly through adenylate cyclase and ryanodine receptor activation. This Ca(2+)-dependent insulinotropic effect of OXA was blocked in Epac2 (Rapgef4)-deficient beta cells. After a glucose load in mice, exogenous OXA decreased blood glucose levels, compared with the control, by enhancing plasma insulin and decreasing plasma glucagon levels. Additionally, OXA caused a delayed increase in plasma leptin levels, resulting in lower plasma insulin levels when blood glucose levels fell to baseline. CONCLUSIONS/INTERPRETATION: These results suggest that OXA might be a critical regulator of insulin, glucagon and leptin secretion in response to glucose. Thus, exogenous OXA might have therapeutic potential in improving blood glucose control in patients with type 2 diabetes. PMID- 25813216 TI - Dose proportionality of a hydrocodone extended-release tablet formulated with abuse-deterrence technology. AB - BACKGROUND AND OBJECTIVE: This open-label, crossover study evaluated the dose proportionality of a hydrocodone extended-release (ER) tablet employing the CIMA((r)) Abuse-Deterrence Technology platform. METHODS: Healthy volunteers were randomized to receive single doses of hydrocodone ER 15, 30, 45, 60, and 90 mg separated by a minimum 14-day washout. Subjects received naltrexone to minimize opioid-related adverse events (AEs). Blood samples were collected for 72 h after each hydrocodone administration. Pharmacokinetic measures included maximum observed plasma hydrocodone concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUCinfinity). Dose proportionality was concluded if the confidence interval (CI) of the slope of the regression line for C max and AUCinfinity versus dose fell within 0.875-1.125. RESULTS: In total, 60 subjects were evaluable for pharmacokinetics. The mean C max was 12.6, 20.7, 30.3, 41.2, and 62.5 ng/mL and the mean AUCinfinity was 199, 382, 592, 766, and 1189 ng.h/mL for hydrocodone ER 15, 30, 45, 60, and 90 mg, respectively. C max and AUCinfinity increased linearly with increasing dose. The 90 % CIs of the slope of the regression line for C max (0.880-0.922) and AUCinfinity (0.984-1.026) indicated systemic exposure to hydrocodone increased in a dose-proportional manner. In these naltrexone-blocked subjects, no increased incidence of AEs was apparent with increasing dose. CONCLUSION: Hydrocodone exposure increased in a dose-proportional manner after administration of hydrocodone ER 15-90 mg tablets in healthy, naltrexone-blocked subjects. PMID- 25813213 TI - Fibroblast growth factor signaling in the vasculature. AB - Despite their discovery as angiogenic factors and mitogens for endothelial cells more than 30 years ago, much remains to be determined about the role of fibroblast growth factors (FGFs) and their receptors in vascular development, homeostasis, and disease. In vitro studies show that members of the FGF family stimulate growth, migration, and sprouting of endothelial cells, and growth, migration, and phenotypic plasticity of vascular smooth muscle cells. Recent studies have revealed important roles for FGFs and their receptors in the regulation of endothelial cell sprouting and vascular homeostasis in vivo. Furthermore, recent work has revealed roles for FGFs in atherosclerosis, vascular calcification, and vascular dysfunction. The large number of FGFs and their receptors expressed in endothelial and vascular smooth muscle cells complicates these studies. In this review, we summarize recent studies in which new and unanticipated roles for FGFs and their receptors in the vasculature have been revealed. PMID- 25813217 TI - Safety and pharmacokinetics of single and multiple ascending doses of avibactam alone and in combination with ceftazidime in healthy male volunteers: results of two randomized, placebo-controlled studies. AB - BACKGROUND AND OBJECTIVE: Avibactam is a novel non-beta-lactam beta-lactamase inhibitor effective against Ambler class A, C and some class D beta-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of beta-lactams, including ceftazidime, against extended-spectrum beta lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. METHODS: The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104 1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000-500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg). RESULTS: No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam's safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion. CONCLUSION: Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime. PMID- 25813218 TI - Epigenetic Mechanisms Involved in Huntington's Disease Pathogenesis. AB - Transcriptional dysregulation is an early event and may be an important pathological mechanism in Huntington's disease (HD). However, the exact process that leads to alterations in gene expression in HD is not clear. One potential mechanism underlying transcriptional abnormalities in HD may be epigenetic alterations which regulate gene expression without changing the DNA sequence. Previous work has demonstrated that epigenetic marks, such as DNA methylation and post-translational modifications of histone proteins, are significantly altered in HD cellular and animal models as well as HD patients. Furthermore, studies have shown a therapeutic role for histone deacetylase (HDAC) inhibitors in numerous HD ...models. Here, we review a range of studies describing epigenetic changes in HD as well as several potential therapeutics that target aberrant epigenetic alterations in HD. PMID- 25813219 TI - Estimation of dynamic time activity curves from dynamic cardiac SPECT imaging. AB - Whole-heart coronary flow reserve (CFR) may be useful as an early predictor of cardiovascular disease or heart failure. Here we propose a simple method to extract the time-activity curve, an essential component needed for estimating the CFR, for a small number of compartments in the body, such as normal myocardium, blood pool, and ischemic myocardial regions, from SPECT data acquired with conventional cameras using slow rotation. We evaluated the method using a realistic simulation of (99m)Tc-teboroxime imaging. Uptake of (99m)Tc-teboroxime based on data from the literature were modeled. Data were simulated using the anatomically-realistic 3D NCAT phantom and an analytic projection code that realistically models attenuation, scatter, and the collimator-detector response. The proposed method was then applied to estimate time activity curves (TACs) for a set of 3D volumes of interest (VOIs) directly from the projections. We evaluated the accuracy and precision of estimated TACs and studied the effects of the presence of perfusion defects that were and were not modeled in the estimation procedure.The method produced good estimates of the myocardial and blood-pool TACS organ VOIs, with average weighted absolute biases of less than 5% for the myocardium and 10% for the blood pool when the true organ boundaries were known and the activity distributions in the organs were uniform. In the presence of unknown perfusion defects, the myocardial TAC was still estimated well (average weighted absolute bias <10%) when the total reduction in myocardial uptake (product of defect extent and severity) was <= 5%. This indicates that the method was robust to modest model mismatch such as the presence of moderate perfusion defects and uptake nonuniformities. With larger defects where the defect VOI was included in the estimation procedure, the estimated normal myocardial and defect TACs were accurate (average weighted absolute bias ~ 5% for a defect with 25% extent and 100% severity). PMID- 25813220 TI - The "Siamese twins" polyps. PMID- 25813221 TI - Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha synuclein aggregation. AB - Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes beta-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When alpha synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of alpha synuclein aggregates. PMID- 25813223 TI - Anesthetic Management of Thoracoscopic Lobectomy in a Patient with Severe Biventricular Dysfunction: Thoracic Anesthesia Perspectives. PMID- 25813222 TI - Analyses of the TCR repertoire of MHC class II-restricted innate CD4+ T cells. AB - Analysis of the T-cell receptor (TCR) repertoire of innate CD4(+) T cells selected by major histocompatibility complex (MHC) class II-dependent thymocyte thymocyte (T-T) interaction (T-T CD4(+) T cells) is essential for predicting the characteristics of the antigens that bind to these T cells and for distinguishing T-T CD4(+) T cells from other types of innate T cells. Using the TCR(mini) Tg mouse model, we show that the repertoire of TCRalpha chains in T-T CD4(+) T cells was extremely diverse, in contrast to the repertoires previously described for other types of innate T cells. The TCRalpha chain sequences significantly overlapped between T-T CD4(+) T cells and conventional CD4(+) T cells in the thymus and spleen. However, the diversity of the TCRalpha repertoire of T-T CD4(+) T cells seemed to be restricted compared with that of conventional CD4(+) T cells. Interestingly, the frequency of the parental OT-II TCRalpha chains was significantly reduced in the process of T-T interaction. This diverse and shifted repertoire in T-T CD4(+) T cells has biological relevance in terms of defense against diverse pathogens and a possible regulatory role during peripheral T-T interaction. PMID- 25813224 TI - Prolonged Hypotension Following Innominate and Left Common Carotid Artery Bypass. PMID- 25813225 TI - Intraoperative Right Ventricular Fractional Area Change Is a Good Indicator of Right Ventricular Contractility: A Retrospective Comparison Using Two- and Three Dimensional Echocardiography. AB - OBJECTIVE: Intraoperative two-dimensional echocardiography is technically challenging, given the unique geometry of the right ventricle (RV). It was hypothesized that the RV fractional area change (RVFAC) could be used as a simple method to evaluate RV function during surgery. Therefore, the correlation between the intraoperative RVFAC and the true right ventricular ejection fraction (RVEF), as measured using newly developed three-dimensional (3D) analysis software, was evaluated. DESIGN: Retrospective study. SETTING: University hospital. PARTICIPANTS: Patients who underwent cardiac surgery with transesophageal echocardiography monitoring between March 2014 and June 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-two patients were included in this study. After the exclusion of poor imaging data and patients with arrhythmias, 54 data sets were analyzed. RVFAC was measured by one anesthesiologist during surgery, and full-volume 3D echocardiographic data were recorded simultaneously. The 3D data were analyzed postoperatively using off-line 3D analysis software by a second anesthesiologist, who was blinded to the RVFAC results. The mean RVFAC was 38.8% +/- 8.7%, the mean RVEF was 41.4% +/- 8.3%, and there was a good correlation between the RVFAC and the RVEF (r(2) = 0.638; p<0.0001). CONCLUSIONS: The RVFAC was well-correlated with the RVEF calculated using 3D echocardiography; therefore, RVFAC provides a simple and useful method for anesthesiologists to evaluate intraoperative RV function. PMID- 25813226 TI - Reversal of heparin after cardiac surgery: protamine titration using a statistical model. AB - OBJECTIVE: To establish a statistical model for determination of protamine dose in conjunction with cardiopulmonary bypass. DESIGN: Prospective. SETTING: University hospital. PARTICIPANTS: Ninety consecutive cardiac surgical patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A series of clinically oriented variables were introduced into a statistical model for projection of the protamine dose after cardiopulmonary bypass. The following significant predictors were identified using multivariable regression analysis: The patient's body surface area, the administered dose of heparin, heparin clearance, and the preoperative platelet count. The statistical model projected the protamine dose within 3+/-23 mg of the point-of-care test used as reference. CONCLUSION: Protamine dosing based on statistical modeling represents an alternative to point of-care tests. PMID- 25813227 TI - Acute Takotsubo Cardiomyopathy During Elective Hernia Repair in a Patient With Previously Resected Pheochromocytoma. PMID- 25813228 TI - Germline mutations predisposing to non-small cell lung cancer. AB - Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well. PMID- 25813229 TI - Fabrication of graphene/Fe3O4@polythiophene nanocomposite and its application in the magnetic solid-phase extraction of polycyclic aromatic hydrocarbons from environmental water samples. AB - Polythiophene (PT) was used as a surface modifier of graphene/Fe3O4 (G/Fe3O4) composite to increase merit of it, and also overcome some limitations and disadvantages of using G/Fe3O4 alone as solid phase extraction (SPE) sorbent. An in-situ chemical polymerization method was employed to prepare G/Fe3O4@PT nanocomposites. Application of this newly designed material in the magnetic SPE (MSPE) of polycyclic aromatic hydrocarbons (PAHs), as model analytes, in the environmental water samples was investigated. The characterization of the hybrid material was performed using transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray analysis, Fourier transform-infrared (FT-IR) spectroscopy and vibrating sample magnetometry. Seven important parameters, affecting the extraction efficiency of PAHs, including: amount of adsorbent, adsorption and desorption times, type and volume of the eluent solvent, initial sample volume and salt content of the sample were evaluated. The optimum extraction conditions were obtained as: 4 min for extraction time, 20 mg for sorbent amount, 100mL for initial sample volume, toluene as desorption solvent, 0.6 mL for desorption solvent volume, 6 min for desorption time and 30% (w/v) for NaCl concentration. Good performance data were obtained at the optimized conditions. Detection limits were in the range of 0.009-0.020 MUg L(-1) in the real matrix. The calibration curves were linear over the concentration ranges from 0.03 to 80 MUg L(-1) with correlation coefficients (R(2)) between 0.995 and 0.998 for all the analytes. Relative standard deviations were ranged from 4.3 to 6.3%. Appropriate recovery values, in the range of 83-107%, were also obtained for the real sample analysis. PMID- 25813230 TI - Practical guidelines for reporting results in single- and multi-component analytical calibration: a tutorial. AB - Practical guidelines for reporting analytical calibration results are provided. General topics, such as the number of reported significant figures and the optimization of analytical procedures, affect all calibration scenarios. In the specific case of single-component or univariate calibration, relevant issues discussed in the present Tutorial include: (1) how linearity can be assessed, (2) how to correctly estimate the limits of detection and quantitation, (2) when and how standard addition should be employed, (3) how to apply recovery studies for evaluating accuracy and precision, and (4) how average prediction errors can be compared for different analytical methodologies. For multi-component calibration procedures based on multivariate data, pertinent subjects here included are the choice of algorithms, the estimation of analytical figures of merit (detection capabilities, sensitivity, selectivity), the use of non-linear models, the consideration of the model regression coefficients for variable selection, and the application of certain mathematical pre-processing procedures such as smoothing. PMID- 25813231 TI - Development of models for prediction of the antioxidant activity of derivatives of natural compounds. AB - Antioxidants are important for maintaining the appropriate balance between oxidizing and reducing species in the body and thus preventing oxidative stress. Many natural compounds are being screened for their possible antioxidant activity. It was found that a mushroom pigment Norbadione A, which is a pulvinic acid derivative, shows an antioxidant activity; the same was found for other pulvinic acid derivatives and structurally related coumarines. Based on the results of in vitro studies performed on these compounds as a part of this study quantitative structure-activity relationship (QSAR) predictive models were constructed using multiple linear regression, counter-propagation artificial neural networks and support vector regression (SVR). The models have been developed in accordance with current QSAR guidelines, including the assessment of the models applicability domains. A new approach for the graphical evaluation of the applicability domain for SVR models is suggested. The developed models show sufficient predictive abilities for the screening of virtual libraries for new potential antioxidants. PMID- 25813232 TI - Synthesis of magnetic framework composites for the discrimination of Escherichia coli at the strain level. AB - Rapid and efficient characterization and identification of pathogens at the strain level is of key importance for epidemiologic investigations, which still remains a challenge. In this work, solvothermically Fe3O4-COOH@MIL-101 composites were fabricated by in situ crystallization approach. The composites combine the excellent properties of both chromium (III) terephthalate (MIL-101) and carboxylic-functionalized magnetite (Fe3O4-COOH) particles and possess the efficient peptides/proteins enrichment properties and magnetic responsiveness. Fe3O4-COOH@MIL-101 composites as magnetic solid phase extraction materials were used to increase the discriminatory power of MALDI-TOF MS profiles. BSA tryptic peptides at a low concentration of 0.25 fmol MUL(-1) could be detected by MALDI TOF MS. In addition, Fe3O4-COOH@MIL-101 composites were successfully applied in the selective enrichment of the protein biomarkers from bacterial cell lysates and discrimination of Escherichia coli at the strain level. This work provides the possibility for wide applications of magnetic MOFs to discriminate pathogens below the species level. PMID- 25813233 TI - Ultrasensitive and rapid screening of mercury(II) ions by dual labeling colorimetric method in aqueous samples and applications in mercury-poisoned animal tissues. AB - Rapid and ultrasensitive detection of trace heavy metal mercury(II) ions (Hg(2+)) are of significant importance due to the induced serious risks for environment and human health. This presented article reports the gold nanoparticle-based dual labeling colorimetric method (Dual-COLO) for ultrasensitive and rapid detection of Hg(2+) using the specific thymine-Hg(2+)-thymine (T-Hg(2+)-T) as recognition system and the dual labeling strategy for signal amplification. Both qualitative and quantitative detections of Hg(2+) are achieved successfully in aqueous samples. More importantly, the achieved detection limit of 0.005 ng mL(-1) (0.025 nM) without any instruments is very competitive to other rapid detection methods even ICP-MS based methods. This Dual-COLO method is also applied directly for real water sample monitoring and, more importantly, applied in analysis of mercury poisoned animal tissues and body fluidic samples, indicating a potentially powerful and promising tool for environmental monitoring and food safety control. PMID- 25813234 TI - Solvent-dependent turn-on probe for dual monitoring of Ag(+) and Zn(2+) in living biological samples. AB - A novel, solvent-dependent "off-on" probe with benzoylthiourea moiety as the functional receptor and fluorescein as the fluorophore was designed for monitoring of Ag(+) in EtOH-H2O (2:8, v/v) solution and Zn(2+) in CH3CN-H2O (2:8, v/v) solution at physiological range with sufficient selectivity and sensitivity. The Ag(+) promoted desulfurization of thiosemicarbazide functionality in formation of the 1,3,4-oxadiazole and the coordination of Zn(2+) to the O atom and N atom of the spoirolactam moiety and the S atom of the benzoylthiourea moiety were investigated to be the power that promoted the fluorescent enhancement. This probe was tested highly suitable for mapping Ag(+) and Zn(2+) in living human osteosarcoma MG-63 cells and microbial cell-EPS-mineral aggregates, thus, providing a wonderful candidate for tracking Ag(+) and Zn(2+) in biological organisms and processes. PMID- 25813235 TI - Detection of iprobenfos and edifenphos using a new multi-aptasensor. AB - The sensitive detection of iprobenfos (IBF) and edifenphos (EDI) was successfully conducted by using a new aptamer-based colorimetric multi-aptasensor. The dissociation constants of this multi-target aptamer to both iprobenfos and edifenphos were found to be 1.67 MUM and 38 nM, respectively, according to the isothermal calorimetry assay. The aptamer EIA2 was selective to only IBF and EDI, confirmed by AuNP assays. By using this multi-aptasensor, both pesticides IBF and EDI can be eventually detected in a range from 10 nM to 5 nM, respectively. This multi-aptasensor was successfully implemented in spiked rice samples and the accuracies of this AuNP-based multi-aptasensor were around 80 and 90% in spiked paddy and polished rice samples, respectively. This aptamer EIA2 could be applied not only for the detection of pesticides from real samples in agriculture field as POC, but also can be used as a bioreceptor for other types of aptasensors. PMID- 25813237 TI - Methoxypropylamino beta-cyclodextrin clicked AC regioisomer for enantioseparations in capillary electrophoresis. AB - In this work, a novel methoxypropylamino beta-cyclodextrin (beta-CD) clicked AC regioisomer, 6(A)-4-hydroxyethyl-1,2,3-triazolyl-6(C)-3-methoxypropylamino beta cyclodextrin (HETz-MPrAMCD), was synthesized via nucleophilic addition and click chemistry. The chiral separation ability of this AC regioisomer cationic CD was evaluated toward 7 ampholytic and 13 acidic racemates by capillary electrophoresis. Dependence of enantioselectivity and resolution on buffer pH (5.5-8.0) and chiral selector concentration (0.5-7.5 mM) was investigated. Enantioselectivities (alpha>=1.05) could be achieved for most analytes under optimal conditions except dansyl-DL-noreleucine and dansyl-DL-serine. The highest resolutions for 2-chloromandelic acid p-hydroxymandelic acid were 15.6 and 9.7 respectively. The inclusion complexation between HETz-MPrAMCD and each 3 phenyllactic acid enantiomer was also revealed with nuclear magnetic resonance study. PMID- 25813236 TI - Determination of methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteria in blood by capillary zone electrophoresis. AB - Serious bloodstream infections are a significant complication in critically ill patients. The treatment of these infections has become more difficult because of the increasing prevalence of multiresistant strains, especially methicillin resistant Staphylococcus aureus (MRSA). Rapid differentiation of low number of MRSA from methicillin-susceptible S. aureus (MSSA) cells (10(1)-10(2) cells mL( 1)) in blood is necessary for fast effective antibiotic therapy. Currently, three groups of techniques, phenotyping, genotyping, and mass spectrometry, are used for MRSA and MSSA strains differentiation. Most of these techniques are time consuming. PCR and other molecular techniques allow the detection and differentiation between MSSA and MRSA directly from blood cultures. These methods alone are rapid and they have good reproducibility and repeatability. Potential disadvantages of the genotyping methods include their discrimination ability, technical complexity, financial costs, and difficult interpretation of the results. Recently, capillary electrophoresis (CZE) was successfully used to differentiate between the agar-cultivated MRSA and MSSA strains in fused silica capillaries etched with supercritical water and modified with (3 glycidyloxypropyl)trimethoxysilane. The possible use of CZE as a fast and low cost method for distinguishing between the blood-incubated MRSA or MSSA cells has been tested in this manuscript. Our goal was to test low amounts of bacteria (~10(2) cell mL(-1)) similar to those in clinical samples. The migration times of the purified blood-incubated cells and the agar-cultivated cells were different from each other. However, their isoelectric point was the same for all strains. PMID- 25813238 TI - The SickKids Genome Clinic: developing and evaluating a pediatric model for individualized genomic medicine. AB - Our increasing knowledge of how genomic variants affect human health and the falling costs of whole-genome sequencing are driving the development of individualized genomic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to anticipate, diagnose and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific and clinical paradigms. The potential benefits of pre-symptomatic identification of at-risk individuals, improved diagnostics, individualized therapy, accurate prognosis and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models and increased health care costs. Here we review the challenges, opportunities and limits of integrating genomic analysis into pediatric clinical practice and describe a model for implementing individualized genomic medicine. Our multidisciplinary team of bioinformaticians, health economists, health services and policy researchers, ethicists, geneticists, genetic counselors and clinicians has designed a 'Genome Clinic' research project that addresses multiple challenges in pediatric genomic medicine--ranging from development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference and the ethics of consent. PMID- 25813239 TI - Physico-chemical properties of Tecoma stans Linn. seed oil: a new crop for vegetable oil. AB - Tecoma stans Linn. is known to have various medicinal and therapeutic properties. However, to our knowledge, no information is available regarding their seed oils. In this study, the fatty acid (FA) compositions, physico-chemical properties and antioxidant capacities of T. stans seed oils (TSOs) were investigated. The oil content of the seeds was 15%. The FAs of the TSOs were analysed by GC-MS. alpha Linolenic (45.47%), oleic (23.56%), linoleic (11.48%), palmitic (6.09%) and stearic (4.12%) acids were the major detected FAs. gamma-Linolenic acid and stearidonic acid, unusually FAs, were also present (1.04% and 6.65%, respectively). The total tocol content in the TSOs was found to be 266.06 mg/100 g. The main component was gamma-tocopherol (78.93%). The total phenolic content (168.69 mg GAE/100 g oil) and total flavonoid content (5.54 mg CE/g oil) were also determined in the TSOs. PMID- 25813240 TI - Lactobacillus rhamnosus GG in adenoid tissue: Double-blind, placebo-controlled, randomized clinical trial. AB - CONCLUSION: Lactobacillus rhamnosus GG (L.GG) was present in all adenoids of children receiving the L. GG product. However, since L.GG was also found from the placebo group, one cannot confirm its effect on the occurrence of rhinovirus (RV) or enterovirus (EV). OBJECTIVES: The present study was conducted to determine whether a 3-week oral consumption of L.GG would lead to presence of the probiotic in adenoid tissue. Furthermore, nasopharyngeal RV and EV findings and symptom data were investigated. METHOD: The tissue samples were collected from 40 children aged 1-5 years about to undergo adenotomy due to recurrent acute/secretory otitis media, chronic rhinitis, or recurrent sinusitis after a 3 week daily consumption of L.GG (n = 20) or placebo (n = 20). Strain-specific real time PCR was used to detect RV, EV, and L.GG in adenoid tissue. RESULTS: L.GG was recovered in the adenoid sample in 100% of children in the L.GG group and in 76% in the placebo group (p = 0.07). Both RV and EV were found in 31% of children in the L.GG group and in 18% of children in the placebo group (p = 0.67). The majority of the positive samples were positive for both RV and EV. Study diaries showed no differences in symptoms between the groups. PMID- 25813243 TI - Neurorehabilitation: motor recovery after stroke as an example. AB - The field of neurorehabilitation aims to translate neuroscience research toward the goal of maximizing functional recovery after neurological injury. A growing body of research indicates that the fundamental principles of neurological rehabilitation are applicable to a broad range of congenital, degenerative, and acquired neurological disorders. In this perspective, we will focus on motor recovery after acquired brain injuries such as stroke. Over the past few decades, a large body of basic and clinical research has created an experimental and theoretical foundation for approaches to neurorehabilitation. Recent randomized clinical trials all emphasize the requirement for intense progressive rehabilitation programs to optimally enhance recovery. Moreover, advances in multimodal assessment of patients with neuroimaging and neurophysiological tools suggest the possibility of individualized treatment plans based on recovery potential. There are also promising indications for medical as well as noninvasive brain stimulation paradigms to facilitate recovery. Ongoing or planned clinical studies should provide more definitive evidence. We also highlight unmet needs and potential areas of research. Continued research built upon a robust experimental and theoretical foundation should help to develop novel treatments to improve recovery after neurological injury. PMID- 25813241 TI - Physiology of the Renal Interstitium. AB - Long overlooked as the virtual compartment and then strictly characterized through descriptive morphologic analysis, the renal interstitium has finally been associated with function. With identification of interstitial renin- and erythropoietin-producing cells, the most prominent endocrine functions of the kidney have now been attributed to the renal interstitium. This article reviews the functional role of renal interstitium. PMID- 25813244 TI - First unusual case of keratitis in Europe due to the rare fungus Metarhizium anisopliae. AB - Metarhizium anisopliae is a fungus utilized worldwide for insect-pest biocontrol. Few M. anisopliae infections have been reported previously. Here, M. anisopliae was isolated from a corneal ulcer in a healthy man. It is the first ocular case in France and Europe of this extremely rare fungus in humans. PMID- 25813242 TI - Non-canonical active site architecture of the radical SAM thiamin pyrimidine synthase. AB - Radical S-adenosylmethionine (SAM) enzymes use a [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical. Canonical radical SAM enzymes are characterized by a beta-barrel-like fold and SAM anchors to the differentiated iron of the cluster, which is located near the amino terminus and within the beta-barrel, through its amino and carboxylate groups. Here we show that ThiC, the thiamin pyrimidine synthase in plants and bacteria, contains a tethered cluster-binding domain at its carboxy terminus that moves in and out of the active site during catalysis. In contrast to canonical radical SAM enzymes, we predict that SAM anchors to an additional active site metal through its amino and carboxylate groups. Superimposition of the catalytic domains of ThiC and glutamate mutase shows that these two enzymes share similar active site architectures, thus providing strong evidence for an evolutionary link between the radical SAM and adenosylcobalamin dependent enzyme superfamilies. PMID- 25813245 TI - Traits allowing some ant species to nest syntopically with the fire ant Solenopsis saevissima in its native range. AB - Supercolonies of the red fire ant Solenopsis saevissima (Smith) develop in disturbed environments and likely alter the ant community in the native range of the species. For example, in French Guiana only 8 ant species were repeatedly noted as nesting in close vicinity to its mounds. Here, we verified if a shared set of biological, ecological, and behavioral traits might explain how these 8 species are able to nest in the presence of S. saevissima. We did not find this to be the case. We did find, however, that all of them are able to live in disturbed habitats. It is likely that over the course of evolution each of these species acquired the capacity to live syntopically with S. saevissima through its own set of traits, where colony size (4 species develop large colonies), cuticular compounds which do not trigger aggressiveness (6 species) and submissive behaviors (4 species) complement each other. PMID- 25813246 TI - HDAC inhibitors induce epithelial-mesenchymal transition in colon carcinoma cells. AB - The effects of histone deacetylase (HDAC) inhibitors on epithelial-mesenchymal transition (EMT) differ in various types of cancers. We investigated the EMT phenotype in four colon cancer cell lines when challenged with HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) with or without transforming growth factor-beta1 (TGF-beta1) treatment. Four colon cancer cell lines with different phenotypes in regards to tumorigenicity, microsatellite stability and DNA mutation were used. EMT phenotypes were assessed by the expression of E-cadherin and vimentin using western blot analysis, immunofluorescence, quantitative real time RT-PCR following treatment with TSA (100 or 200 nM) or VPA (0.5 mM) with or without TGF-beta1 (5 ng/ml) for 24 h. Biological EMT phenotypes were also evaluated by cell morphology, migration and invasion assays. TSA or VPA induced mesenchymal features in the colon carcinoma cells by a decrease in E-cadherin and an increase in vimentin expression at the mRNA and protein levels. Confocal microscopy revealed membranous attenuation or nuclear translocation of E-cadherin and enhanced expression of vimentin. These responses occurred after 6 h and increased until 24 h. Colon cancer cells changed from a round or rectangular shape to a spindle shape with increased migration and invasion ability following TSA or VPA treatment. The susceptibility to EMT changes induced by TSA or VPA was comparable in microsatellite stable (SW480 and HT29) and microsatellite unstable cells (DLD1 and HCT116). TSA or VPA induced a mesenchymal phenotype in the colon carcinoma cells and these effects were augmented in the presence of TGF-beta1. HDAC inhibitors require careful caution before their application as new anticancer drugs for colon cancers. PMID- 25813247 TI - Rational design of capillary-driven flows for paper-based microfluidics. AB - The design of paper-based assays that integrate passive pumping requires a precise programming of the fluid transport, which has to be encoded in the geometrical shape of the substrate. This requirement becomes critical in multiple step processes, where fluid handling must be accurate and reproducible for each operation. The present work theoretically investigates the capillary imbibition in paper-like substrates to better understand fluid transport in terms of the macroscopic geometry of the flow domain. A fluid dynamic model was derived for homogeneous porous substrates with arbitrary cross-sectional shapes, which allows one to determine the cross-sectional profile required for a prescribed fluid velocity or mass transport rate. An extension of the model to slit microchannels is also demonstrated. Calculations were validated by experiments with prototypes fabricated in our lab. The proposed method constitutes a valuable tool for the rational design of paper-based assays. PMID- 25813248 TI - Clinical perspectives and murine models of lichenoid tissue reaction/interface dermatitis. AB - A set of histopathological elements, that is death of epidermal basal cell layer keratinocytes and inflammatory cell infiltration, distinguishes lichenoid tissue reaction (LTR)/interface dermatitis (IFD) from other inflammatory mucocutaneous diseases with histological findings of superficial perivascular dermatitis. The LTR/IFD is observed in inflammatory mucocutaneous diseases such as lichen planus, Stevens-Johnson syndrome/toxic epidermal necrolysis, acute graft-versus-host disease, lupus erythematosus and dermatomyositis. Clinical and basic researches have suggested that keratinocytes are antigen-presenting cells and mediate LTR/IFD reaction via production of cytokines/chemokines and inhibitory molecules such as programmed cell death (PD)-L1, and that cytotoxic CD8(+) T cells producing cytotoxic granules, perforin, granzyme B and granulysin are final effector cells to cause keratinocyte death. Because interferon-gamma and FasL, which are produced by not only CD8(+) but also CD4(+) T cells, are candidates of the pathogenic molecules in LTR/IFD, CD4(+) T cells may also play a role to develop LTR/IFD. On the other hand, CD4(+) Treg cells accelerate the remission of LTR/IFD. Some murine models of LTR/IFD have been established. For example, LTR/IFD reactions were induced in keratinocyte-specific membrane-binding ovalbumin-transgenic (mOVA Tg) mice by adoptive transfer of CD8(+) T cells with OVA-specific T-cell-receptor. It has also been shown that human CD8(+) T cells are pathogenic immune cells in human skin-xenografted mice. Various immunosuppressants are used to treat patients with mucocutaneous diseases with LTR/IFD. By analysis of the mOVA Tg mice, a JAK inhibitor was suggested to be a new candidate drug to inhibit not only pathogenic T cells but also keratinocyte death in LTR/IFD. More specific treatments for patients with LTR/IFD will be developed in future. PMID- 25813249 TI - Genome-wide analysis of 5-hmC in the peripheral blood of systemic lupus erythematosus patients using an hMeDIP-chip. AB - Systemic lupus erythematosus (SLE) is a chronic, potentially fatal systemic autoimmune disease characterized by the production of autoantibodies against a wide range of self-antigens. To investigate the role of the 5-hmC DNA modification with regard to the onset of SLE, we compared the levels 5-hmC between SLE patients and normal controls. Whole blood was obtained from patients, and genomic DNA was extracted. Using the hMeDIP-chip analysis and validation by quantitative RT-PCR (RT-qPCR), we identified the differentially hydroxymethylated regions that are associated with SLE. There were 1,701 genes with significantly different 5-hmC levels at the promoter region in the SLE patients compared with the normal controls. The CpG islands of 3,826 genes showed significantly different 5-hmC levels in the SLE patients compared with the normal controls. Out of the differentially hydroxymethylated genes, three were selected for validation, including TREX1, CDKN1A and CDKN1B. The hydroxymethylation levels of the three genes were confirmed by RT-qPCR. The results suggested that there were significant alterations of 5-hmC in SLE patients. Thus, these differentially hydroxymethylated genes may contribute to the pathogenesis of SLE. These findings show the significance of 5-hmC as a potential biomarker or promising target for epigenetic-based SLE therapies. PMID- 25813250 TI - miR-141 confers docetaxel chemoresistance of breast cancer cells via regulation of EIF4E expression. AB - Resistance to docetaxel, a chemotherapy drug for breast cancer (BC) treatment, occurs in ~50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through miR-141 has been proven to play an important role in cancer drug resistance. The present study investigated the role of miR-141 expression in BC cells of acquired docetaxel resistance. Inhibition of miR-141 enhanced the response to docetaxel in docetaxel resistant cells (MCF-7/DTX and MDA-MB-231/DTX, respectively), whereas overexpression of miR-141 confered resistance in docetaxel-sensitive cells (MCF-7 and MDA-MB-231, respectively). By directly targeting the eukaryotic translation initiation factor 4E (EIF4E) mRNA, miR-141 acts on genes that are necessary for drug induced apoptosis rendering the cells drug resistant. Modulation of miR-141 expression was correlated with EIF4E expression changes and a direct interaction of miR-141 with EIF4E was shown by a luciferase assay. Thus, the present study is the first to show an increased expression of miR-141 in an acquired model of docetaxel resistance in BC. This serves as a mechanism of acquired docetaxel resistance in BC cells, possibly through direct interactions with EIF4E, therefore presenting a potential therapeutic target for the treatment of docetaxel resistant BC. PMID- 25813251 TI - [Has the pregnancy outcome of women with pregestational diabetes mellitus improved in ten years?]. AB - INTRODUCTION: In spite of progress in medicine, studies from a number of countries indicate steadily increased risk of perinatal morbidity and mortality in the offspring of diabetic mothers. No data regarding the pregnancy outcome in women with diabetes mellitus type 1 and 2 (pregestational DM) have been published in the Czech Republic. The aim of the study was to evaluate the pregnancy course of women with pregestational DM and outcome of their offspring and to assess whether it has improved in ten years. METHODS: A retrospective evaluation of pregnancy outcome of pregestational DM women followed up in the University Hospital Pilsen in years 2000-2009 (Group A, n = 107) and comparison with the period 1990-1997 (Group B, n = 39) were performed. Wilcoxon non-paired test, contingency tables, step-wise logistic regression and step-wise linear multiple regression methods were used for statistical analyses. RESULTS: Data is presented as median (interquartile range). Women from the Group A were older 28 (25, 31) vs 25 (22, 27) years, p = 0.01. Otherwise, the groups did not statistically significantly differ in diabetes duration, BMI, and representation of women with type 2 diabetes. A better glycemic control (HbA1c, mmol/mol) was achieved in the Group A in all trimesters - 1st trimester: 59 (47, 67) vs 66 (56, 76), 2nd trimester: 46 (40, 52) vs 54 (48, 59) and 3rd trimester: 46 (40, 51) vs 53 (47, 60), p = 0.01. The caesarean section rate decreased (65.2 % vs 87.5 %, p < 0.05). The incidence of the respiratory distress syndrome after adjustment for age and diabetes duration also decreased (8.9 % vs 18.2 %, p < 0.05). A decreasing trend in the rate of premature delivery before 34th week of gestation (1.1 % vs 6.3 %) and neonatal mortality (1.1 % vs 2.9 %) was observed, however, the differences were not statistically significant. CONCLUSION: The achieved improved glycemic control led to only a partial improvement in the course of pregnancy and outcome of the offspring of diabetic mothers. PMID- 25813252 TI - [The importance of transcutaneous oxygen tension monitoring in diabetic patient with complications]. AB - Monitoring of transcutaneous perfusion pressure of tissue oxygen (tcpO2) is a simple, non-invasive method performed in diagnostic process of chronic diabetic complications. Primary, tcpO2is used as an indicator of microcirculatory function. Properly placed and fixed Clark electrode is able to detect with high accuracy partial oxygen pressure on the skin surface by polarographic system of dissolved oxygen from capillary bed through tissues to upper layers of the skin. The microcirculation function is influenced by macrocirculation, thus, tcpO2is a suitable parameter in diagnosis of peripheral arterial obliterative disease or other vascular pathologies. Combination of tcpO2monitoring and skin perfusion pressure by laser Doppler technique gives us information not only about nutritive capillary flow, but also about vessels which precede capillary bed. The article discusses current guidelines for measurement of tcpO2and evaluation of the results. Also reviews the results of recent studies which are interested in the use of tcpO2in diabetic patients. PMID- 25813253 TI - [Autoimmune pancreatitis - diagnostic consensus]. AB - The autoimmune type of pancreatitis represents the specific disease of pancreas, with significant contribution of autoimmune processes in its etiopathogenesis. Currently, there are two proved subtypes of this particular pancreatopathy, which are defined clinically, histomorphologically and serologically. They have many histomorphological signs in common, but differ in the presence of so-called granulocytic epithelial lesions (GEL), which are absent in subtype 1. The subtype 1 is characterized by the presence of gammaglobulines, esp. immunoglobuline G4 and IgG4 positive extrapancreatic lesions. The subtype 2 is typically associated with the inflammatory bowel diseases, esp. ulcerative colitis. But the common characteristic of both subtypes is the fact response to applied steroid treatment. Due to diverse diagnostic criteria in the past, in 2011 the consensus for the diagnosis of autoimmune pancreatitis was announced. It is based on clinical symptoms, biochemical results, the results got by using of imaging methods, histomorphology and positive response to steroid treatment. The matter to be solved is the question of early differential diagnosis between focal autoimmune pancreatitis and adenocarcinoma of pancreatic head. From imaging methods are MRI/CT, MRCP (in Asia ERCP), EUS with targeted biopsy of the gland (under EUS control), are recommended as the methods of choice. PMID- 25813254 TI - [Interstitial lung diseases and granulomatoses associated common variable immunodeficiency]. AB - Common variable immunodeficiency disorder belongs to the most common primary human immunodeficiencies and it is characterized by primary defective immunoglobulin production. Hypogammaglobulinemia manifests in every age, usually in adult people. There is no gender predisposition. The prevalence is 1 : 25 000 1 : 50 000. The ethiopathogenesis of the majority of CVIDs is unknown. The main clinical respiratory symptoms include recurrent respiratory infects, especially bacterial etiology, sinusitis, bronchitis, pneumonia, leading to bronchiectasis and lung fibrosis. Interstitial lung fibrosis and granulomatosis often manifest at diagnosis of CVID and they are negative prognostic factors of the disease. PMID- 25813255 TI - [The examination of the small intestine by magnetic resonance imaging]. AB - Diagnostic imaging of the abdominal cavity and the gastrointestinal tract is increasingly performed by new-emerged fast MR imaging sequences and it is moving to the centers of magnetic resonance. Our work is devoted to the examination of the small intestine by magnetic resonance, so-called MR enterography. Review discusses general description - from preparation of patient to basic pathological findings, with special focus on currently most investigated small intestine disease - Crohns disease. PMID- 25813256 TI - [The new drug is much more effective than ACE inhibitors in chronic heart failure]. AB - PARADIGM-HF study observed clinical outcomes after treatment by new drug LCZ696 or enalapril in patients with systolic chronic heart failure. It was randomized double-blind trial with LCZ696 (200 mg twice a day) and enalapril (10 mg twice a day). 8442 patients were enrolled with NYHA class II or III and left ventricular ejection fiction of 40% or less. Study drugs were added to other recommended medication. The trial was prematurely terminated after median follow-up of 27 months. The primary endpoint of the study was a combination of cardiovascular mortality and the first hospitalization for heart failure. LCZ696 drug, an inhibitor of angiotensin receptor and neprilysin (Arnie), has led to a reduction in the primary composite target by 20% (p <0.001). The treatment has decreased cardiovascular mortality by 20%, p <0.001 and hospitalization for worsening heart failure by 21%, p <0.001. LCZ696 has also decreased total mortality by 16%, p <0.001. The use of LCZ696 has been accompanied by frequent symptomatic hypotension and hypotension with a decrease in systolic blood pressure below 90 mm Hg, however, LCZ696 was less often associated with an increase in serum creatinine and serum potassium than enalapril. In addition, cough has occurred less frequently after LCZ696 than after enalapril. Discontinuation of therapy occurred in 746 patients (17.8%) treated with LCZ696 and in 833 patients (19.8%) treated with enalapril (19.8%) (p = 0.02). PARADIGM-HF study has also shown superiority of LCZ696 compared to ACE inhibitors in stable outpatients with chronic systolic heart failure NYHA stages II and III. Therefore, LCZ696 is more effective than ACE inhibitors (and angiotensin receptor blockers). Moreover, it is well tolerated. LCZ696 seems to replace the ACE inhibitors in mentioned patients. The authors also discuss the results of the first randomized study PARAMOUNT investigating LCZ696 efficacy in patients with chronic heart failure and good left ventricular ejection fraction. PMID- 25813257 TI - [Spontaneous bacterial peritonitis]. AB - Spontaneous bacterial peritonitis (SBP) represents a frequent and serious complication in patients with ascites in liver cirrhosis. Hospital mortality in patients with SBP reaches 10-20 %, so it is necessary to consider this diagnosis in every clinical decompensation of a cirrhotic patient, diagnose it early and treat it effectively. The clinical manifestation is nonspecific and variable, up to one third of patients might be asymptomatic. The diagnosis of SBP is based on the ascitic neutrophils count greater than 250 per mm3. Bacteriological examination of ascites fluid detects causative agents at less than half of the cases and the result is available after a few days. However, treatment should be initiated without delay. SBP is generally treated with antibiotics, the first choice therapy are the third generation cephalosporins, mostly cefotaxime, alternatively fluoroquinolones. Long-term prognosis of patients with the history of SBP is poor owing to its high recurrence rate, one-year survival after an episode of SBP is 30-40 %, 20 % at two years. Therefore, these patients should receive long-term antibiotic prophylaxis and should be evaluated for liver transplantation. PMID- 25813258 TI - [What are biosimilars and what do they bring to us?]. AB - Biosimilar medicines are a new category of medicinal products that substantially differ from generic preparations through the necessary submission of conclusive evidence of their therapeutic efficacy and therefore it is not sufficient to merely state their biological equivalence. Apart from the proven efficacy, also their safety is evaluated of course, with an emphasis on immunogenicity regarding biological nature of these substances. As a result, requirements for registration are much stricter. With regard to the current boom of the preparations labelled in a simplified way as biological or specifically targeted drugs, we can certainly expect a growing number of newly registered medicinal products in this category in the near future. Last year, a biosimilar insulin analogue of glargine was approved for administration at the level of the European Medicines Agency (EMA) in accordance with the aforementioned procedures; its efficacy and safety profile have been found within the registration studies practically identical, or non-inferior, to the original insulin analogue. PMID- 25813259 TI - [Insulin analogues of patients with diabetes and renal impairment]. AB - The main cause of renal failure is diabetic nephropathy which affects 20-40 % of diabetic patients. Diabetics with altered renal function have restricted therapeutic options due to the risk of accumulation of oral antidiabetic drugs and of their metabolites at a reduced glomerular filtration rate. Good metabolic control is very important during the early phases of nephropathy for reducing the risk of progression and in the stage of renal failure reduces the risk of progression of atherosclerosis and improves life prognosis. Metabolism of insulin is changed during renal failure, clearance of insulin is prolonged, the risk of hypoglycemia increases. Short-acting insulin analogues have faster absorption and long-acting analogues have a lower risk of hypoglycemia. Thus they can positively affect glycemic control of patients with diabetes and impaired renal function. PMID- 25813260 TI - [Present and future in the management of venous vascular diseases]. AB - The prevalence and the incidence of chronic and acute venous vascular disease has been shown to be globally very high, in both industrialized and developing countries. Chronic venous diseases of lower extremities are being an integral part of the third millennium's deadly angiopandemy, at the present time. The rate of the most severe cases with advanced stage of venous failure is approximately twice as high in the population (2.1 %) as has been assumed so far. Among venoactive drugs (VAD), micronized purified flavonoid fraction (MPFF) of diosmin hesperidin remains the agent with the highest degree of recommendation and it also indicated to pharmacotherapeutical support of leg ulcer healing, along with sulodexide and pentoxifylline. Compressive sclerotherapy, liquid or foam, is a safe and effective invasive method to treat telangiectasias, reticular varicose veins and subcutaneous varicose veins. Direct oral anticoagulants (DOAC) represent one of the therapeutic and preventive options of deep venous thrombosis (DVT) and of venous thromboembolism (VTE) with a limitation in patients with malignant conditions and in pregnancy. The most effective is triple simultaneous pharmaco-kinezio-mechano-phlebothromboemboloprophylaxis. Superficial vein thromboses longer than 5 cm are indicated to anticoagulant therapy too. PMID- 25813261 TI - [Akromegaly and pharmacotherapy]. AB - Acromegaly is a rare and serious disease. A successful and rational therapy of acromegaly ought to combine surgery, radiotherapy and pharmacotherapy. The submitted article presents a case of acromegaly that was only diagnosed at the stage when total pituitary adenoma removal was impossible. Even so, the long-term stabilisation of the disease was reached by way of repeated surgery through transfenoidal and transcranial approach, by linear accelerator radiation therapy and Leksell Gamma Knife radiotherapy and by pharmacotherapy with somatostatin analogon octreotide and growth hormone receptor antagonist pegvisomant. The octreotide and pegvisomant dosage has been repeatedly changed according to IGF1 levels. The contemporary somatostatin analogon Sandostatin LAR 30 mg is given once every 3 weeks and the growth hormone receptor antagonist Somavert 20 mg is applied daily. Despite this serious disease, the patient has already been living contentedly for 10 years. From the ethical point of view, the financials costingness of the therapy should be considered as reasonable. PMID- 25813262 TI - [A rare case of multiple myeloma: multiple solitary plasmacytomas of distal extremities]. AB - This article describes a case of 68-years-old male with very atypic variation of multiple myeloma occuring as multifocal osteolysis limited to tibiae, cuboid bone, radius and ulna, in the absence of diffuse bone marrow infiltration. The main goal of this article is to point out the importance of permanent awareness during diagnostics and treatment of this insidious disease. PMID- 25813263 TI - [Calcific uremic arteriolopathy - treatment with sodium thiosulfate]. AB - Calcific uremic arteriolopathy or calciphylaxis is a rare disorder characterized by systemic medial calcification of arterioles that leads to ischemia and subcutaneous necrosis. It most commonly occurs in patients with end-stage renal disease who are on haemodialysis or who have received a renal transplant. Calciphylaxis is dangerous by its fast progression into tissue necrosis, difficult healing process and a great risk of secondary infection which is the most common cause of death in this condition. The reported mortality rates are as high as 60-80 % in a couple of months once it is diagnosed. The key to successful treatment of calciphylaxis is fast diagnosing of the disease and appropriate treatment management. On the examples of three patients from our haemodialysis centre we demonstrate typical clinical manifestation of calciphylaxis and its treatment, which requires close patient-medical staff cooperation. The basic principle of treatment of all our patients was normalization of calcium-phosphate metabolism and secondary hyperparathyroidism. Sodium thiosulfate had been administered to all patients at the end of haemodialysis session. The wound care played another major role with gentle debridement and intensive local care. After five to six months the skin defects resolved in the first patient, partially resolved in the second patient and deteriorated in the third patient. We have observed no side effects of sodium thiosulfate application. PMID- 25813264 TI - [Empagliflozin - the new representative of SGLT2 transporter inhibitors for the treatment of patients with diabetes 2 type]. AB - Empagliflozin is a new medicine used to reduce hyperglycemia in patients with type 2 diabetes. It belongs to the most advanced class of antidiabetic drugs, known as gliflozins, which prevent reabsorption of glucose through inhibiting SGLT2 sodium-glucose cotransporter. Thereby they cause therapeutic glycosuria, thanks to which a loss of approximately 70 g of glucose per day occurs. This not only effects the decrease in glycemia, but also the loss of body mass, since this excreted glucose cannot be used as an energetic substrate. The studies within phase 3 have proven the therapeutic efficacy of empagliflozin in monotherapy, in combination with the other oral antidiabec drugs and insulin. Another favourable effect of empagliflozin is a slight decrease in blood pressure. In May 2014, empagliflozin was approved for the treatment of patients with type 2 diabetes within the European Union 2014, since October 2014 it has been available in the Czech Republic and since 1 February 2015 empagliflozin (under the trade name Jardiance(r)) has been partially covered by the health insurance for the treatment of patients with type 2 diabetes either in combination with metformin or in combination with insulin (with or without metformin). PMID- 25813265 TI - Giant oscillating thermopower at oxide interfaces. AB - Understanding the nature of charge carriers at the LaAlO3/SrTiO3 interface is one of the major open issues in the full comprehension of the charge confinement phenomenon in oxide heterostructures. Here, we investigate thermopower to study the electronic structure in LaAlO3/SrTiO3 at low temperature as a function of gate field. In particular, under large negative gate voltage, corresponding to the strongly depleted charge density regime, thermopower displays high negative values of the order of 10(4)-10(5) MUVK(-1), oscillating at regular intervals as a function of the gate voltage. The huge thermopower magnitude can be attributed to the phonon-drag contribution, while the oscillations map the progressive depletion and the Fermi level descent across a dense array of localized states lying at the bottom of the Ti 3d conduction band. This study provides direct evidence of a localized Anderson tail in the two-dimensional electron liquid at the LaAlO3/SrTiO3 interface. PMID- 25813266 TI - The subcellular compartmentalization of TGFbeta-RII and the dynamics of endosomal formation during the signaling events: An in vivo study on rat mesothelial cells. AB - We previously showed that intraperitoneal administration of Freund's adjuvant treatment resulted in acute peritonitis and TGF-beta was found to be one of the main organizers of the subsequent EMT in mesothelial cells. In the present study, we investigated whether TGF-beta signaling molecules are present in mesothelial cells and how their compartmentalization pattern changes with the dynamics of inflammatory events in vivo. In addition, we tried to evaluate the turnover of endosomal compartments concomitant with the internalization of signaling molecules and examine whether caveola-mediated internalization might play a role in the termination of TGF-beta signaling. Using immunocytochemical approach, we could detect TbetaRII in EEA1 positive compartments and as the inflammation progressed, at D3, the receptor appeared in caveolin-1 positive intracellular structures as well. The latter event was accompanied by the appearance of negative regulatory protein, Smad7 in caveolae. We also found EEA1 and caveolin-1 double positive vesicular structures that were corresponded to forming MVBs affirmed by our immuno-electron microscopical results. Fine structural, morphometric and immunoblot analysis proved that Cd63 positive multivesicular body (MVB) formation was significantly increased by D3 and the IP results confirmed that TbetaRII as well as caveolin-1 were strongly associated with these endosomal compartments at this time. In contrast, by the termination of inflammation, by D5, caveolin-1 was found to be associated with late endosomal marker, Rab7 and entirely degraded from the system. Despite the limitations of an in vivo system, our results provide both morphological and biochemical data about the endosomal compartments involved in the internalization of TbetaRII upon inflammatory stimuli. Furthermore, our study implies the possible role of caveola mediated endocytosis in the attenuation of TGF-beta signaling and highlight the significance of endosomal compartments via which caveolae might meet the classical endocytic pathway under in vivo inflammatory conditions. PMID- 25813267 TI - Risk factors for alcoholism in the Oklahoma Family Health Patterns project: impact of early life adversity and family history on affect regulation and personality. AB - AIM: This study examined the impact of early lifetime adversity (ELA) on affect regulation and personality in persons with family history (FH+) and without (FH-) a family history of alcoholism. We examined the impact of early life adversity in healthy young adults, 18-30 years of age enrolled in a long-term study on risk for alcohol and other substance abuse. METHODS: ELA was assessed by a composite score of low socioeconomic status and personal experience of physical or sexual abuse and/or separation from parents before age 16, resulting in a score of 0, 1 2, or >3 adverse events. Unstable affect regulation and personality variables were obtained via self-report measures. RESULTS: Higher ELA scores were seen in FH+ (chi(2)=109.2, p<0.0001) and in women (chi(2)=17.82, p=0.0019). Although higher ELA predicted less emotional stability and more behavioral undercontrol, further analysis including both FH and ELA showed that FH+ persons are prone to poor affect regulation, negative moods, and have risky drinking and drug abuse tendencies independent of ELA level. ELA predicts reduced stress reactivity and poorer cognitive control over impulsive behaviors as shown elsewhere. CONCLUSIONS: The present work shows that FH+ have poor mood regulation and antisocial characteristics. The greater prevalence of ELA in FH+ persons indicates that life experience and FH+ work in tandem to result in risky patterns of alcohol and drug experimentation to elevate risk for alcoholism. Further studies of genetic and environmental contributions to alcoholism are called for. PMID- 25813268 TI - Mechanisms of change associated with technology-based interventions for substance use. AB - BACKGROUND: Technology-based interventions (TBIs) for substance use disorders have been increasing steadily. The mechanisms by which TBIs produce change in substance use outcomes have not been reviewed. This article is the first review of the conceptual and empirical underpinnings of the mechanisms associated with TBIs for substance use disorders. METHODS: We review the literature on potential mechanisms associated with TBIs targeting tobacco, alcohol, and poly-substance use. We did not identify TBIs targeting other drug classes and that assessed mechanisms. RESULTS: Research suggests that TBIs impact outcomes via similar potential mechanisms as in non-TBIs (e.g., in-person treatment), with the exception of substance use outcomes being associated with changes in the quality of coping skills. The most frequent potential mechanisms detected were self efficacy for tobacco abstinence and perceived peer drinking for alcohol abstinence. CONCLUSIONS: Research on mechanisms associated with TBIs is still in a nascent stage. We provide several recommendations for future work, including broadening the range of mechanisms assessed and increasing the frequency of assessment to detect temporal relations between mechanisms and outcomes. We also discuss unique challenges and opportunities afforded by technology that can advance theory, method, and clinical practice. PMID- 25813270 TI - sRNA profiling in Aspergillus flavus reveals differentially expressed miRNA-like RNAs response to water activity and temperature. AB - Small non-coding RNA (sRNA) in various organisms remains a mysterious subject. Although microRNAs (miRNAs) have been intensively investigated in plants and animals, the study of miRNAs in fungi has been limited. Only microRNA-like RNAs (milRNAs) have been reported in several filamentous fungi. In this study, Illumina deep sequencing was performed to characterize the sRNA in Aspergillus flavus and to evaluate their responses to water activity and temperature. Global expression analysis showed an extensively differential expression of sRNA loci in A. flavus under different temperature or water activities. In addition, a total of 135 milRNAs were identified in A. flavus. The milRNA profiles obtained in deep sequencing were further validated by RT-qPCR assay. The presence and differential expression of milRNAs under different temperature or water activities in A. flavus imply that milRNAs might play important roles in the mycotoxin biosynthesis and mycelium growth in fungi A. flavus. PMID- 25813269 TI - Pilot Study of a Computer-Based Parental Questionnaire and Visual Profile of Obesity Risk in Healthy Preschoolers. AB - PURPOSE: This group field-tested a computer-based, parental questionnaire entitled the Childhood Obesity Risk Questionnaire 2-5 (CORQ 2-5) designed to assess obesity risk in healthy preschoolers. COR 2-5 generates a profile of seven obesity risk factors. RESULTS: Field studies provided good internal reliability data and evidence of discriminant validity for the CORQ 2-5. Pediatric nurse clinicians found the CORQ 2-5 profile to be clinically relevant. CONCLUSION: The CORQ 2-5 is a promising measure of obesity risk in preschoolers who attend community-based health centers for their wellchild visits and who are not yet obese. CORQ 2-5 is intended to guide provider-parental obesity risk discussions. PMID- 25813271 TI - Task and barrier self-efficacy among treatment-seeking smokers with current, past or no psychiatric diagnosis. AB - OBJECTIVE: Individuals with a lifetime diagnosis of mental illness smoke at rates greater than the general population, and have more difficulty quitting. Cessation self-efficacy has been linked with positive cessation outcomes and can be assessed as either task (confidence to quit) or barrier self-efficacy (confidence to quit in the face of obstacles). We investigated differences in self-efficacy among smokers with a current, past or no lifetime diagnosis of psychiatric illness. METHODS: 737 treatment-seeking smokers provided demographic info and smoking history, and were assessed for nicotine dependence, motivation to quit, and task and barrier self-efficacy (Smoking Self-Efficacy Questionnaire; SEQ-12) for smoking cessation. Current and past psychiatric diagnoses were assessed with the Mini International Psychiatric Interview (M.I.N.I. 6.0). ANOVA, chi-square and correlations were calculated for the smoking-related variables across the psychiatric categories. RESULTS: Those with a current diagnosis smoked more cigarettes and were highly nicotine dependent. These individuals had lower barrier self-efficacy compared to those with past or no diagnosis; no differences between groups were observed on task self-efficacy. Motivation to quit was significantly correlated with task self-efficacy in all 3 groups, but with barrier-self efficacy only among those with no lifetime diagnosis of psychiatric illness. CONCLUSION: Our results highlight the differences in task and barrier cessation self-efficacy in treatment-seeking smokers. Those with a current psychiatric diagnosis have less confidence in their ability to quit when confronting barriers, especially those reflecting internal states. These results highlight the need for targeted interventions to improve cessation self-efficacy, an important determinant of health behavior change. PMID- 25813272 TI - TiO2 embedded in carbon submicron-tablets: synthesis from a metal-organic framework precursor and application as a superior anode in lithium-ion batteries. AB - Rutile TiO2 embedded in carbon submicron-tablets (TiO2/C) with a "blueberry muffin" morphology was fabricated via a two-step pyrolysis from a metal-organic framework precursor. Such a unique structure of the TiO2/C submicron-tablets provides the ideal anode characteristics (high reversible capacity, superior rate capability and excellent long-term cycling stability) for fast rechargeable lithium ion batteries. PMID- 25813273 TI - Congenital mirror movements: phenotypes associated with DCC and RAD51 mutations. AB - Congenital mirror movements (CMM) is a disorder characterized by unintentional mirroring in homologous motor systems of voluntary movements on the opposite side, usually affecting the distal upper extremities. Genetic analyses have revealed involvement of three genes (DCC, RAD51, and DNAL4). We sought to distinguish whether different phenotypes of CMM exist, and if so, whether they might map to different causative genes. We studied 14 individuals across five families with dominantly-inherited CMM. We used accelerometer gloves to analyse the fine detail of index finger tapping movements, and applied standard genetic methodology to analyse DNA samples. Two forms of mirroring were distinguished: 'actual' in which the mirroring followed precisely the movements of the voluntary hand, and 'fractionated' in which the mirroring was saccadic. We found that actual mirroring was characteristic of individuals in a family with a RAD51 mutation, and fractionated more characteristic of a family with a DCC mutation. These findings are suggestive of specific genotype-phenotype correlations in CMM. Three heterozygous individuals (one RAD51; two DCC) showed no apparent mirroring on visual inspection, although mirroring was detectable with the accelerometer gloves. Thus, subclinical mirroring may be present even when undetectable on clinical observation. PMID- 25813274 TI - Analyzing hospitalization data: potential limitations of Poisson regression. AB - BACKGROUND: Poisson regression is commonly used to analyze hospitalization data when outcomes are expressed as counts (e.g. number of days in hospital). However, data often violate the assumptions on which Poisson regression is based. More appropriate extensions of this model, while available, are rarely used. METHODS: We compared hospitalization data between 206 patients treated with hemodialysis (HD) and 107 treated with peritoneal dialysis (PD) using Poisson regression and compared results from standard Poisson regression with those obtained using three other approaches for modeling count data: negative binomial (NB) regression, zero inflated Poisson (ZIP) regression and zero-inflated negative binomial (ZINB) regression. We examined the appropriateness of each model and compared the results obtained with each approach. RESULTS: During a mean 1.9 years of follow up, 183 of 313 patients (58%) were never hospitalized (indicating an excess of 'zeros'). The data also displayed overdispersion (variance greater than mean), violating another assumption of the Poisson model. Using four criteria, we determined that the NB and ZINB models performed best. According to these two models, patients treated with HD experienced similar hospitalization rates as those receiving PD {NB rate ratio (RR): 1.04 [bootstrapped 95% confidence interval (CI): 0.49-2.20]; ZINB summary RR: 1.21 (bootstrapped 95% CI 0.60 2.46)}. Poisson and ZIP models fit the data poorly and had much larger point estimates than the NB and ZINB models [Poisson RR: 1.93 (bootstrapped 95% CI 0.88 4.23); ZIP summary RR: 1.84 (bootstrapped 95% CI 0.88-3.84)]. CONCLUSIONS: We found substantially different results when modeling hospitalization data, depending on the approach used. Our results argue strongly for a sound model selection process and improved reporting around statistical methods used for modeling count data. PMID- 25813275 TI - Interstitial eosinophilic aggregates in diabetic nephropathy: allergy or not? AB - BACKGROUND: Interstitial eosinophilic aggregates (IEA) in renal biopsies often suggest allergic tubulointerstitial nephritis, yet clear associations with drug reactions are often difficult to establish. IEA are also encountered in diabetic nephropathy (DN) and thought to be attributed to medication exposure. METHODS: Native medical kidney biopsies performed at the University of Washington Medical Center were reviewed, including DN (n = 64), IgA nephropathy (IgAN, n = 28), membranous nephropathy (MN, n = 14), focal and segmental glomerulosclerosis (FSGS, n = 27) and membranoproliferative glomerulonephritis (MPGN, n = 28). IEA were defined as >=5 eosinophils per high power field. The severity of interstitial fibrosis and tubular atrophy (IFTA) was scored semi-quantitatively as minimal, mild, moderate or severe. RESULTS: IEA were remarkably more prevalent in DN (41%), when compared with IgAN (7%, P = 0.001), MN (8%, P = 0.017) or MPGN (14%, P = 0.013), but not FSGS (26%, P = 0.18). In DN cases, univariate analysis revealed that IEA were associated with greater IFTA severity, but not with the percentage of glomerulosclerosis, mesangial expansion, history of drug allergy, number of prescribed medications or particular class of medications (antibiotics, NSAIDs, aspirin, thiazide, loop diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, insulin, sulfonylurea, metformin or allopurinol). Multivariate analysis showed that the severity of IFTA was the only significant predictor for IEA (P < 0.01) after stepwise adjustment for age, number of medications, drug allergy, diabetes type, % global glomerulosclerosis and mesangial expansion. CONCLUSIONS: Our study shows that IEA are more common in DN, when compared with other types of glomerulopathy. In DN, IEA are associated with the severity of IFTA but not with prescribed medications or clinical history of allergy. This suggests that in DN IEA are often associated with chronic tubulointerstitial injury and are not diagnostic of an allergic interstitial nephritis. PMID- 25813277 TI - Adverse pregnancy and birth outcomes associated with underlying diagnosis with and without assisted reproductive technology treatment. AB - OBJECTIVE: To compare the risks for adverse pregnancy and birth outcomes by diagnoses with and without assisted reproductive technology (ART) treatment to non-ART pregnancies in fertile women. DESIGN: Historical cohort of Massachusetts vital records linked to ART clinic data from Society for Assisted Reproductive Technology Clinic Outcome Reporting System. SETTING: Not applicable. PATIENT(S): Diagnoses included male factor (ART only), endometriosis, ovulation disorders, tubal (ART only), and reproductive inflammatory disorders (non-ART only). Pregnancies resulting in singleton and twin live births from 2004 to 2008 were linked to hospital discharges in women who had ART treatment (n = 3,689), women with no ART treatment in the current pregnancy (n = 4,098), and non-ART pregnancies in fertile women (n = 297,987). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Risks of gestational diabetes, prenatal hospitalizations, prematurity, low birth weight, and small for gestational age were modeled using multivariate logistic regression with fertile deliveries as the reference group adjusted for maternal age, race/ethnicity, education, chronic hypertension, diabetes mellitus, and plurality (adjusted odds ratios [AORs] and 95% confidence intervals [CIs]). RESULT(S): Risk of prenatal hospital admissions was increased for endometriosis (ART: 1.97, 1.38-2.80; non-ART: 3.34, 2.59-4.31), ovulation disorders (ART: 2.31, 1.81-2.96; non-ART: 2.56, 2.05-3.21), tubal factor (ART: 1.51, 1.14-2.01), and reproductive inflammation (non-ART: 2.79, 2.47-3.15). Gestational diabetes was increased for women with ovulation disorders (ART: 2.17, 1.72-2.73; non-ART: 1.94, 1.52-2.48). Preterm delivery (AORs, 1.24-1.93) and low birth weight (AORs, 1.27-1.60) were increased in all groups except in endometriosis with ART. CONCLUSION(S): The findings indicate substantial excess perinatal morbidities associated with underlying infertility-related diagnoses in both ART-treated and non-ART-treated women. PMID- 25813278 TI - Effect of vitamin D supplementation during pregnancy on maternal and neonatal outcomes: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To assess the effects of vitamin D supplementation during pregnancy on obstetric outcomes and birth variables. DESIGN: Systematic review and meta analysis of randomized controlled trials (RCTs). SETTING: Not applicable. PATIENT(S): Pregnant women and neonates. INTERVENTION(S): PubMed and 5 other research databases were searched through March 2014 for RCTs evaluating vitamin D supplementation +/- calcium/vitamins/ferrous sulfate vs. a control (placebo or active) during pregnancy. MAIN OUTCOME MEASURE(S): Measures were: circulating 25 hydroxyvitamin D [25(OH)D] levels, preeclampsia, gestational diabetes mellitus (GDM), small for gestational age (SGA), low birth weight, preterm birth, birth weight, birth length, cesarean section. Mantel-Haenszel fixed-effects models were used, owing to expected scarcity of outcomes. Effects were reported as relative risks and their 95% confidence intervals (CIs). RESULT(S): Thirteen RCTs (n = 2,299) were selected. Circulating 25(OH)D levels were significantly higher at term, compared with the control group (mean difference: 66.5 nmol/L, 95% CI 66.2 66.7). Birth weight and birth length were significantly greater for neonates in the vitamin D group; mean difference: 107.6 g (95% CI 59.9-155.3 g) and 0.3 cm (95% CI 0.10-0.41 cm), respectively. Incidence of preeclampsia, GDM, SGA, low birth weight, preterm birth, and cesarean section were not influenced by vitamin D supplementation. Across RCTs, the doses and types of vitamin D supplements, gestational age at first administration, and outcomes were heterogeneous. CONCLUSION(S): Vitamin D supplementation during pregnancy was associated with increased circulating 25(OH)D levels, birth weight, and birth length, and was not associated with other maternal and neonatal outcomes. Larger, better-designed RCTs evaluating clinically relevant outcomes are necessary to reach a definitive conclusion. PMID- 25813279 TI - Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis. AB - OBJECTIVE: To assess genetic mutations and associated somatic anomalies in a series of patients with 46,XY gonadal dysgenesis (GD). DESIGN: Single center retrospective study. SETTING: University pediatric hospital. PATIENT(S): Fourteen patients with 46,XY GD. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotype phenotype relationship. RESULT(S): The presenting symptom was disorders of sex development (6 patients), primary amenorrhea (2 patients), discordance between 46,XY karyotype and female external genitalia (3 patients), discovery of Mullerian structures at surgery (2 patients), or diagnosed in the evaluation of a gonadal tumor (1 patient). Mullerian structures were shown by ultrasound evaluation in 7 of 13 patients, genitography in 3 of 6 patients and/or surgery in 8 of 10 patients (3 not seen at imaging), or only by histologic examination (1 patient). Three patients had gonadoblastoma and/or seminoma. A mutation was found in 7 patients of whom 2 had family history of reproductive problems and 5 had associated somatic anomalies. The mutations were FOG2/ZFPM2 (1 patient), SRY (2 patients), WT1 (1 patient), or deletions of distal chromosome 9p (3 patients). Among the three other patients with associated anomalies and no mutation, two had ectodermal dysplasia and one had leukemia. CONCLUSION(S): Mutations were observed in half of the patients with 46,XY GD with Mullerian structures. We also describe for the first time the association between GD and ectodermal dysplasia. Mullerian structures can be found in some cases only by histologic examination, which should be coupled to preventive gonadectomy because of the risk of tumor formation. PMID- 25813276 TI - Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease. AB - BACKGROUND: Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3-5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. METHODS: Circulating ACE2 activity was measured in human ethylenediamine tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. RESULTS: In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. CONCLUSIONS: Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event. PMID- 25813280 TI - Comparison of live-birth defects after luteal-phase ovarian stimulation vs. conventional ovarian stimulation for in vitro fertilization and vitrified embryo transfer cycles. AB - OBJECTIVE: To assess live-birth defects after a luteal-phase ovarian-stimulation regimen (LPS) for in vitro fertilization (IVF) and vitrified embryo transfer (ET) cycles. DESIGN: Retrospective cohort study. SETTING: Tertiary-care academic medical center. PATIENT(S): Infants who were born between January 1, 2013 and May 1, 2014 from IVF with intracytoplasmic sperm injection (ICSI) treatments (n = 2,060) after either LPS (n = 587), the standard gonadotropin-releasing hormone agonist (GnRH-a) short protocol (n = 1,257), or mild ovarian stimulation (n = 216). INTERVENTION(S): The three ovarian-stimulation protocols described and assisted reproductive technology (ART) treatment (IVF or ICSI, and vitrified ET) in ordinary practice. MAIN OUTCOME MEASURE(S): The main measures were: gestational age, birth weight and length, multiple delivery, early neonatal mortality, and birth defects. Associations were assessed using logistic regression by adjusting for confounding factors. RESULT(S): The final sample included 2,060 live-born infants, corresponding to 1,622 frozen-thawed (FET) cycles, which led to: 587 live-born infants from LPS (458 FET cycles); 1,257 live born infants from the short protocol (984 FET cycles); and 216 live-born infants from mild ovarian stimulation (180 FET cycles). Birth characteristics regarding gestational age, birth weight and length, multiple delivery, and early neonatal death were comparable in all groups. The incidence of live-birth defects among the LPS group (1.02%) and the short GnRH-a protocol group (0.64%) was slightly higher than in the mild ovarian-stimulation group (0.46%). However, none of these differences reached statistical significance. For congenital malformations, the risk significantly increased for the infertility-duration factor and multiple births; the adjusted odds ratios were 1.161 (95% confidence interval [CI]: 1.009 1.335) and 3.899 (95% CI: 1.179-12.896), respectively. No associations were found between congenital birth defects and various ovarian-stimulation regimens, maternal age, body mass index, parity, insemination method, or infant gender. CONCLUSION(S): To date, the data do not indicate an elevated rate of abnormality at birth after LPS, but further study with larger populations is needed to confirm these results. However, infertility itself poses a risk factor for congenital malformation. A higher likelihood of birth defects in multiple births may lead couples to favor elective, single ET; couples undertaking ART should be made aware of the known increased birth defects associated with a twin birth. PMID- 25813281 TI - Baby budgeting: oocyte cryopreservation in women delaying reproduction can reduce cost per live birth. AB - OBJECTIVE: To determine whether oocyte cryopreservation for deferred reproduction is cost effective per live birth using a model constructed from observed clinical practice. DESIGN: Decision-tree mathematical model with sensitivity analyses. SETTING: Not applicable. PATIENT(S): A simulated cohort of women wishing to delay childbearing until age 40 years. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Cost per live birth. RESULT(S): Our primary model predicted that oocyte cryopreservation at age 35 years by women planning to defer pregnancy attempts until age 40 years would decrease cost per live birth from $55,060 to $39,946 (and increase the odds of live birth from 42% to 62% by the end of the model), indicating that oocyte cryopreservation is a cost-effective strategy relative to forgoing it. If fresh autologous assisted reproductive technology (ART) was added at age 40 years, before thawing oocytes, 74% obtained a live birth, and cost per live birth increased to $61,887. Separate sensitivity analyses demonstrated that oocyte cryopreservation remained cost effective as long as performed before age 38 years, and more than 49% of those women not obtaining a spontaneously conceived live birth returned to thaw oocytes. CONCLUSION(S): In women who plan to delay childbearing until age 40 years, oocyte cryopreservation before 38 years of age reduces the cost to obtain a live birth. PMID- 25813282 TI - Variations in RBM8A and TBX6 are associated with disorders of the mullerian ducts. AB - OBJECTIVE: To identify genetic causes of malformations of the mullerian ducts. DESIGN: Retrospective laboratory study. SETTING: University hospital. PATIENT(S): A total of 167 patients with disorders of the mullerian ducts: 116 patients with Mayer-Rokitansky-Kuster-Hauser syndrome and 51 patients with fusion disorders of the mullerian ducts. The control group was composed of 94 fertile women with at least one child. INTERVENTION(S): Sequential analysis of RBM8A and TBX6 in a group of 167 clinically well-defined patients with disorders of the mullerian ducts. MAIN OUTCOME MEASURE(S): Identification of rare variants in RBM8A and TBX6. RESULT(S): In total, we detected four RBM8A variants in 13 patients with disorders of the mullerian ducts and two heterozygous TBX6 variants in 5 of 167 patients. CONCLUSION(S): Mutations of RBM8A and TBX6 are associated with disorders of the mullerian ducts. PMID- 25813283 TI - Single vitrified blastocyst transfer maximizes liveborn children per embryo while minimizing preterm birth. AB - OBJECTIVE: To compare live-birth rates, blastocyst to live-birth efficiency, gestational age, and birth weights in a large cohort of patients undergoing single versus double thawed blastocyst transfer. DESIGN: Retrospective cohort study. SETTING: Assisted reproduction technology (ART) practice. PATIENT(S): All autologous frozen blastocyst transfers (FBT) of one or two vitrified-warmed blastocysts from January 2009 through April 2012. INTERVENTION(S): Single or double FBT. MAIN OUTCOME MEASURE(S): Live birth, blastocyst to live-birth efficiency, preterm birth, low birth weight. RESULT(S): Only supernumerary blastocysts with good morphology (grade BB or better) were vitrified, and 1,696 FBTs were analyzed. No differences were observed in patient age, rate of embryo progression, or postthaw blastomere survival. Double FBT yielded a higher live birth per transfer, but 33% of births from double FBT were twins versus only 0.6% of single FBT. Double FBT was associated with statistically significant increases in preterm birth and low birth weight, the latter of which was statistically significant even when the analysis was limited to singletons. Of the blastocysts transferred via single FBT, 38% resulted in a liveborn child versus only 34% with double FBT. This suggests that two single FBTs would result in more liveborn children with significantly fewer preterm births when compared with double FBT. CONCLUSION(S): Single FBT greatly decreased multiple and preterm birth risk while providing excellent live-birth rates. Patients should be counseled that a greater overall number of live born children per couple can be expected when thawed blastocysts are transferred one at a time. PMID- 25813284 TI - Contribution of different bone marrow-derived cell types in endometrial regeneration using an irradiated murine model. AB - OBJECTIVE: To study the involvement of seven types of bone marrow-derived cells (BMDCs) in the endometrial regeneration in mice after total body irradiation. DESIGN: Prospective experimental animal study. SETTING: University research laboratories. ANIMAL(S): beta-Actin-green fluorescent protein (GFP) transgenic C57BL/6-Tg (CAG-EGFP) and C57BL/6J female mice. INTERVENTION(S): The BMDCs were isolated from CAG-EGFP mice: unfractionated bone marrow cells, hematopoietic progenitor cells, endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). In addition three murine GFP(+) cell lines were used: mouse Oct4 negative BMDC multipotent adult progenitor cells (mOct4(-)BM-MAPCs), BMDC hypoblast-like stem cells (mOct4(+) BM-HypoSCs), and MSCs. All cell types were injected through the tail vein of 9 Gy-irradiated C57BL/6J female mice. MAIN OUTCOME MEASURE(S): Flow cytometry, cell culture, bone marrow transplantation assays, histologic evaluation, immunohistochemistry, proliferation, apoptosis, and statistical analysis. RESULT(S): After 12 weeks, histologic analysis revealed that uteri of mice with mOct4(-)BM-MAPCs and MSC line were significantly smaller than uteri of mice with uncultured BMDCs or mOct4(+) BM-HypoSCs. The percentage of engrafted GFP(+) cells ranged from 0.13%-4.78%. Expression of Ki-67 was lower in all uteri from BMDCs treated mice than in the control, whereas TUNEL(+) cells were increased in the EPCs and mOct4(+)BM-HypoSCs groups. CONCLUSION(S): Low number of some BMDCs can be found in regenerating endometrium, including stromal, endotelial, and epithelial compartments. Freshly isolated MSCs and EPCs together with mOct4(+) BM-HypoSCs induced the greatest degree of regeneration, whereas culture isolated MSCs and mOct4(-)BM-MAPCs transplantation may have an inhibitory effect on endometrial regeneration. PMID- 25813285 TI - Heparin modulates chemokines in human endometrial stromal cells by interaction with tumor necrosis factor alpha and thrombin. AB - OBJECTIVE: To study the impact of heparins on chemokines in decidualized human endometrial stromal cells (ESCs) in vitro. DESIGN: In vitro experiment. SETTING: Research laboratory. PATIENT(S): Premenopausal women undergoing hysterectomy for benign reasons. INTERVENTION(S): ESCs were isolated from hysterectomy specimens, decidualized in vitro and incubated with unfractionated heparin and low-molecular weight heparins (LMWHs) as well as tumor necrosis factor (TNF) alpha or thrombin with or without heparins. MAIN OUTCOME MEASURE(S): Chemokines CXCL1, CXCL5, CXCL8, CCL2, and CCL5 were measured with the use of ELISA, and CXCL5, CXCL8, CCL2, and CCL5 were detected with the use of real-time reverse-transcription polymerase chain reaction. Cell viability was determined with the use of a fluorometric assay. RESULT(S): TNF-alpha and thrombin stimulated distinct patterns of chemokines in ESCs. Unfractionated heparin and LMWHs attenuated the TNF-alpha-mediated induction of CXCL8 and enhanced CXCL5, CCL2, and CCL5. The stimulating effect of thrombin on CXCL8 could be inhibited by heparin, whereas heparin had no impact on thrombin-induced CXCL1 and CCL2. Nuclear factor of transcription kappaB signaling mediated the effects of TNF-alpha. The effects of thrombin were mediated via extracellular signal-regulated protein kinases 1/2. CONCLUSION(S): Heparins have modulating effects on TNF-alpha- and thrombin induced endometrial chemokines, which might have implications in the regulation of endometrial receptivity and early implantation. PMID- 25813286 TI - Neonatal outcomes after early rescue intracytoplasmic sperm injection: an analysis of a 5-year period. AB - OBJECTIVE: To evaluate the safety and efficacy of early rescue intracytoplasmic sperm injection (ICSI). DESIGN: Retrospective cohort study. SETTING: Teaching hospital. PATIENT(S): There were 13,232 ovarian stimulation cycles (IVF, n = 9,631; ICSI, n = 2,871; early rescue ICSI, n = 730) that resulted in the delivery of 5,001 babies (IVF, n = 3,670; ICSI, n = 1,095; early rescue ICSI, n = 246) from August 2008 to August 2013. INTERVENTION(S): Early rescue ICSI. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates, neonatal outcomes, and congenital birth defects were analyzed. RESULT(S): The early rescue ICSI cycles did not seem to have a negative effect on the clinical pregnancy rate (43.42%) when IVF cycles (45.33%) were compared with ICSI cycles (44.39%). In the early rescue ICSI group, a total of 254 clinical pregnancies were achieved: 197 (33.67%) live births, 38 (6.49%) miscarriages, 2 (0.79%) induced abortions, 3 (1.18%) fetal deaths, and 4 pregnancies (1.57%) without completion at follow-up. Overall, the multiple gestations, the delivery method, mean gestational age, preterm deliveries, mean birth weight, and rate of congenital birth defects of the early rescue ICSI group were similar to those in the conventional IVF and ICSI groups. CONCLUSION(S): Early rescue ICSI had similar clinical pregnancy rates when compared with conventional IVF and ICSI, in addition to the delivery of healthy children. The clinical evidence from the early rescue ICSI group did not show an elevated rate of malformations. Early rescue ICSI seems to be a safe alternative method for individuals with total fertilization failure or near total fertilization failure when compared with conventional IVF treatment. PMID- 25813287 TI - Use of assisted reproductive technology treatment as reported by mothers in comparison with registry data: the Upstate KIDS Study. AB - OBJECTIVE: To assess the validity of maternally reported assisted reproductive technologies (ART) use and to identify predictors of reporting errors. DESIGN: Linkage study. SETTING: Not applicable. PATIENT(S): A total of 5,034 (27%) mothers enrolled, from whom 4,886 (97%) self-reported information about use of infertility treatment, including ART, for the index birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Four measures of validity (sensitivity, specificity, positive and negative predictive values) and use of net reclassification improvement (NRI) methods to identify predictors associated with concordant/discordant maternal reporting. RESULT(S): The Upstate New York Infant Development Screening Program (Update KIDS Study) was linked with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) using a defined algorithm for 2008-2010. The sensitivity, specificity, positive and negative predictive values were high (0.93, 0.99, 0.80, and 1.00, respectively). The validity of maternal report was high, reflecting few differences by participant characteristics except for maternal age dichotomized at 29 years as identified with NRI methods. CONCLUSION(S): Maternally reported ART is valid, with little variation across various characteristics. No strong predictors of discordant reporting were found, supporting the utility of population-based research with SART CORS linkage. PMID- 25813288 TI - Antioxidant properties of high-density lipoproteins are impaired in women with polycystic ovary syndrome. AB - OBJECTIVE: To determine the relationships among the inflammatory index, intrinsic oxidation levels, lipid and apolipoprotein (apo)A-I concentrations of high density lipoprotein (HDL), and polycystic ovary syndrome (PCOS). DESIGN: Cross sectional study. SETTING: University hospital. PATIENT(S): A total of 425 patients with PCOS and 441 control women were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The HDL inflammatory index (HII) was determined using a cell-free fluorometric assay. Intrinsic HDL oxidation levels, HDL-free cholesterol, HDL-cholesterol ester, HDL-triglyceride, serum apoA-I, and malondialdehyde levels were also measured. RESULT(S): The mean HII value and the frequency of HII >=1 were significantly higher in the PCOS group (0.77 +/- 0.54, 27.1%) than in the control group (0.53 +/- 0.37, 8.4%). These values were also higher in each of the 4 PCOS phenotypes based on the Rotterdam criteria than in the controls, and higher in patients with hyperandrogenism (HA) + oligo- and/or anovulation (OA) phenotype than in those with OA + polycystic ovary (PCO) phenotype. Furthermore, patients with PCOS with OA + PCO had lower malondialdehyde and intrinsic HDL oxidation levels compared with those with HA. Multivariate regression analysis demonstrated that PCOS, HDL-cholesterol ester, and E2 levels were the main predictors of HII value. CONCLUSION(S): The impairment of HDL antioxidant/anti-inflammatory function in PCOS is related to HA status, increased oxidative stress, and abnormalities in HDL components and thus may contribute to PCOS pathogenesis and increase the risks of future cardiovascular diseases. PMID- 25813289 TI - Sildenafil stimulates human trophoblast invasion through nitric oxide and guanosine 3',5'-cyclic monophosphate signaling. AB - OBJECTIVE: To determine the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on trophoblast invasiveness. DESIGN: Laboratory investigation. SETTING: Academic medical center. PATIENT(S): Placental tissues discarded after first-trimester terminations were obtained from patients with informed consent. INTERVENTION(S): A cell line, HTR-8/SVneo, established from first-trimester cytotrophoblast, and villous explants, was treated with or without sildenafil, guanosine 3',5'-cyclic monophosphate (cGMP) analog, cGMP inhibitor, or L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride) and cultured on fibronectin or Matrigel. Integrins alpha6beta4 and alpha1beta1 were detected by immunocytochemistry. MAIN OUTCOME MEASURE(S): Trophoblast outgrowth from villous tips, cytotrophoblast cell invasion, and integrin immunostaining were assessed in cytotrophoblast and explant cultures. RESULT(S): Integrin expression in trophoblast cells ex vivo switched from alpha6 to alpha1, and invasiveness increased, when exposed to sildenafil or cGMP agonist. Either cGMP antagonist or L-NAME blocked integrin switching and invasion induced by sildenafil. Elevation of nitric oxide pharmacologically induced invasion, but not when cGMP antagonist was present. CONCLUSION(S): Sildenafil altered trophoblast phenotype through a process dependent on nitric oxide availability and cGMP accumulation. In addition to its vasoactivity, sildenafil directly stimulates trophoblast extravillous differentiation, which would be favorable for implantation and reduce risk for adverse pregnancy outcomes. PMID- 25813290 TI - Are we facing a potential effective treatment for endometriosis? PMID- 25813291 TI - Rejuvenating effect of pregnancy on the mother. AB - Aging is associated with reduced tissue regenerative capacity. In recent years, studies in mice have shown that transfusion of blood from young animals to old ones can reverse some aging effects and increase regenerative potential similar to that seen in young animals. Because pregnancy is a unique biological model of a partially shared blood system, we have speculated that pregnancy would have a rejuvenating effect on the mother. Recent studies support this idea. In this review, we will summarize the current knowledge of the rejuvenating effect of pregnancy on the mother. PMID- 25813292 TI - Evaluating the potential effect on fetal tissue after exposure to granisetron during pregnancy. AB - The objective of this study was to elucidate the possible toxic effects on the fetal tissues after exposure to two clinically relevant concentrations of granisetron. Primary cells were isolated from human fetal organs of 16-19 weeks gestational age and treated with 3 ng/mL or 30 ng/mL of granisetron. Cell cycle progression was evaluated by flow cytometry. ELISA was used to detect alterations in major apoptotic proteins. Up to 10% apoptosis in cardiac tissue was observed following treatment with 30 ng/mL granisetron. Neither concentration of granisetron caused alteration in cell cycle progression or alterations in apoptotic proteins in any of the other tissues. At 30 ng/mL granisetron concentration had the potential to induce up to 10% apoptosis in cardiac tissue; clinical significance needs further evaluation. At granisetron 3 ng/mL there was no detectable toxicity or on any fetal tissue in this study. Further research is needed to confirm these preliminary findings and determine if clinically significant. PMID- 25813293 TI - Predatory publishers: what the nursing community needs to know. PMID- 25813294 TI - Predatory publishers. PMID- 25813295 TI - Transferring patient care: patterns of synchronous bidisciplinary communication between physicians and nurses during handoffs in a critical care unit. AB - PURPOSE: The transfer of patient care from one health care worker to another involves communication in high-pressure contexts that are often vulnerable to error. This research project captured current practices for handoffs during the critical care stage of surgical recovery in a hospital setting. The objective was to characterize information flow during transfer and identify patterns of communication between nurses and physicians. DESIGN AND METHODS: Observations were used to document communication exchanges. The data were analyzed qualitatively according to the types of information exchanged and verbal behavior types. FINDINGS: Reporting and questions were the most common verbal behaviors, and retrospective medical information was the focus of information exchange. The communication was highly interactive when discussing patient status and future care plans. Nurses proactively asked questions to capture a large proportion of the information they needed. CONCLUSIONS: Findings reflect positive and constructive patterns of communication during handoffs in the observed hospital unit. PMID- 25813296 TI - An observational study of postoperative handover in anesthetic clinics; the content of verbal information and factors influencing receiver memory. AB - PURPOSE: The aim was to examine the handover process in the postanesthesia care unit, how much the receiver remembered, and what factors influenced memory. DESIGN: An observational study with a descriptive and correlational design. METHODS: A total of 73 handovers were investigated, and data were collected using observation, audiotape recordings of the handovers, and the patient's anesthetic record. FINDING: Interruptions occurred at 56 (77%) handovers and the sender expressed unclear information at 51 (70%) handovers. The mean of the verbally given information remembered by the receivers was 47%; the items mostly likely not to be remembered were the drugs used during anesthesia. A linear generalized estimating equation was used and identified variables that were significantly associated with receivers' retention of information were structure and handover duration. CONCLUSION: Lack of structure and long duration of the verbal handover decrease how much the receiver will remember. PMID- 25813297 TI - Decreasing the length of stay in phase I postanesthesia care unit: an evidence based approach. AB - Patient length of stay (LOS) in the postanesthesia care unit (PACU) Phase I and Phase II influences patient throughput, staff nurse satisfaction, and financial expenditure. The purpose of this project was to determine if re-education of nursing staff would decrease the LOS in Phase I PACU. The goals of the leadership team were to implement a plan that would result in a decreased LOS, decreased financial expenditure, increased patient throughput, and a change in culture of the work environment. Methods included re-education of nursing staff on American Society of Perianesthesia Nursing (ASPAN) Standards for patient care in Phase I and Phase II PACU. In addition, a pre-survey of the nurses was completed to determine their knowledge of the ASPAN Standards and how they perceived their work environment. Data were collected on the LOS in Phase I for two groups of patients who underwent cystoscopy with stent implantation and hernia repair. The LOS data were collected before and after the staff education. Results of this re education initiative revealed improved patient throughput, decreased operating room hold time, reduced perioperative expenditure, and an increase in staff nurse satisfaction. An unanticipated result was increased scores on patient satisfaction surveys after the educational initiative. PMID- 25813298 TI - Fast-tracking ambulatory surgery patients following anesthesia. AB - PURPOSE: The purpose of this process improvement project was to introduce and evaluate the efficacy of fast-tracking ambulatory surgical patients in a community hospital. DESIGN: An observational pre-post design was used, in which patient data from a reference period (pre-fast-tracking) was compared with patient data collected during an implementation period (post-fast-tracking). METHODS: Anesthesia providers were trained to use a tool to assess patients for eligibility to bypass the postanesthesia care unit (PACU). Fifty-nine patients met the fast-track criteria during the implementation period and were transferred directly to the ambulatory care unit from the operating room. FINDING: During the fast-track implementation period, a PACU-bypass rate of 79% was achieved, and a significant decrease in the total number of patients held in the operating room and in total length of stay was noted. CONCLUSIONS: Results suggest that fast tracking is a suitable intervention to increase work flow efficiency and decrease both patient and hospital costs while promoting a more rapid discharge from the facility. PMID- 25813299 TI - Contract anesthesia: the good news and the challenge. AB - The dramatic pace of change in health care is intimidating, and results can be unpredictable and often negative. The practice of contract anesthesia delivery is an excellent example of how a clinical microsystem interacts with the constant change common in today's health care environment. This article identifies many of the issues of concern in contract anesthesia. Awareness of issues will afford nurses, nurse anesthetists, and managers a structure for a smooth, safe, and effective transition of contracting providers. PMID- 25813300 TI - Effects of P6 stimulation on postoperative nausea and vomiting in laparoscopic cholecystectomy patients. AB - PURPOSE: Postoperative nausea and vomiting (PONV) remains one of the most common postsurgical complications after anesthesia and surgery. Pericardium 6 (P6) stimulation is believed to prevent PONV and is a potential adjunctive treatment with pharmacologic agents. The purpose of this study was to compare the effects of P6 stimulation on PONV occurrence to a control group not receiving the P6 stimulation in sequential female patients undergoing laparoscopic cholecystecomy at a community hospital in central Florida between November 2010 and March 2013. DESIGN: This study is a double-blinded randomized controlled trial. METHODS: PONV was measured on admission to the postanesthesia care unit (PACU), at 30 and 60 minutes, at discharge from the PACU to home and at two points at home up to 6 hours and between 6 and 24 hours. FINDINGS: Of the 56 total patients, those in the P6 group (n = 26) had statistically significant lower incidence of PONV, 0%, vs 14.3% in the control group (n = 27; P < .05) on admission to the PACU, but at all other time points, there was no significant difference in PONV. Thirty-one percent of the patients in the P6 group had PONV in PACU or at home compared with 51.9% in the control group. CONCLUSIONS: The results of the study demonstrate that the use of P6 stimulation in the perioperative arena is clinically meaningful; however, more research is needed with a larger sample size. PMID- 25813301 TI - Rethinking mobility and intensive care patients. PMID- 25813302 TI - The leadership relationship. Part I: understanding trust. PMID- 25813303 TI - Assessing the whole person to improve outcomes. PMID- 25813304 TI - Finding joy, gratitude, and meaning in routine PACU tasks. PMID- 25813305 TI - Preoperative screening for MRSA/MSSA. PMID- 25813306 TI - Retirement--letting go is hard to do! PMID- 25813307 TI - Single-incision laparoscopic cholecystectomy for acute cholecystitis: A retrospective cohort study of 52 consecutive patients. AB - BACKGROUND: Single-incision laparoscopic cholecystectomy (SILC) has become increasingly popular but its role in acute cholecystitis remains controversial. METHODS: We compared the clinical features and outcomes of SILC procedures between 52 patients with acute cholecystitis (the AC group) and 308 patients without acute cholecystitis (the NAC group). We also analyzed clinical variables to identify factors affecting difficulties associated with SILC for acute cholecystitis. RESULTS: The patients in the AC group were significantly older than those in the NAC group (72 vs. 61 years, median, P = 0.0005). The preoperative levels of white blood cell counts were significantly higher in the AC group than in the NAC group (6600 vs. 5500/MUL, P = 0.0004). The operative time was significantly longer in the AC group than in the NAC group (188 vs. 135 min, P < 0.0001). The volume of intraoperative blood loss was significantly larger in the AC group than in the NAC group (20 vs. 5 mL, P < 0.001). Furthermore, additional trocar insertion was required in 12% in the NAC group, whereas it was required in 60% in the AC group (P < 0.0001). Regarding the difficulties of SILC for acute cholecystitis, delayed operation (after 72 h from the onset) was significantly associated with a prolonged operative time, while a higher grade of acute cholecystitis (grade II or III) was significantly associated with an increased blood loss during surgery. CONCLUSIONS: These findings suggest that when compared to SILC for gallbladder diseases without acute inflammation, SILC for acute cholecystitis was associated with a longer operative time, increased blood loss, higher rate of additional trocar requirement, higher rate of postoperative complications, and longer hospital stay. The difficulties associated with SILC for acute cholecystitis were affected by the timing of surgery and the grade of inflammation. PMID- 25813308 TI - Targeting dynamic interplay among disordered domains or endophenotypes to understand complex neuropsychiatric disorders: Translational lessons from preclinical models. AB - Contemporary biological psychiatry uses clinical and experimental (animal) models to increase our understanding of brain pathogenesis. Modeling psychiatric disorders is currently performed by targeting various key neurobehavioral clusters of phenotypic traits (domains), including affective, cognitive, social, motor and reward. Analyses of such domains and their 'smaller units' - individual endophenotypes - are critical for the study of complex brain disorders and their neural underpinnings. The spectrum nature of brain disorders and the importance of pathogenetic linkage among various disordered domains or endophenotypes have also been recognized as an important strategic direction of translational research. Here, we discuss cross-domain analyses of animal models, and focus on their value for mimicking the clinical overlap between disordered neurobehavioral domains in humans. Based on recent experimental evidence, we argue that understanding of brain pathogenesis requires modeling the clinically relevant inter-relationships between various individual endophenotypes (or their domains). PMID- 25813309 TI - How to succeed in carrying out the first trial of the clinical skills examination in the korean medical licensing examination. PMID- 25813310 TI - Adoption of clinical skills examination: the challenge of national health personnel licensing examination board. PMID- 25813311 TI - Patient safety curriculum in medical education. AB - Since release of the Institute of Medicine (IOM) report, To Err Is Human: Building a Safer System, patient safety has emerged as a global concern in the provision of quality health care. In response to growing recognition of the importance of patient safety, some medical schools in other countries have created and/or implemented patient safety curricula. In Korea, however, patient safety medical curriculum has not been actively discussed by medical educators. The purpose of this article is to introduce patient safety concepts and the global efforts on patient safety medical education. Specifically, this article describes; 1) current concepts in patient safety, 2) global trends of patient safety movement and education, 3) contents, instructional and assessment methods of patient safety education for both undergraduate medical education and graduate medical education, suggested in the previous studies, 4) WHO Patient Safety Guide for Medical Curriculum developed by the Medical Education Team within the World Alliance for Patient Safety and 5) known barriers against patient safety education. Patient safety is a major priority for all healthcare providers. In reality, however, teaching and learning about patient safety in medical curriculum offers a challenge to all medical schools, especially, the health care environment is not favorable to physicians such as Korea. More attention and recognition about patient safety by all health personnel and medical educators is needed. In addition, the national conversation about medical errors and patient safety and how best to incorporate it to the existing curriculum should be discussed. PMID- 25813312 TI - Comparative Analysis of the Role of Beliefs in the Causes of Illness and Attitudes toward Medical Services in University Students from Disparate Specialties. AB - PURPOSE: This study aims to compare and investigate the differences in beliefs with regard to the cause of illnesses, medial skepticism, and attitudes toward medical care between medical, Oriental medical, and nonmedical students. METHODS: To this end, we used a structured questionnaire and collected self-reported data from a sample of 667 respondents. RESULTS: First, their beliefs on the causes of illness were markedly different, depending on their specialty. Compared with students from other specialties, Oriental medical students ranked host factors, environmental factors, and natural factors as the highest causes of illness. -the former group regarded supernatural factors as a more influential cause of illnesses compared with the latter. Among Oriental medical students and nonmedical students-who were also subdivided into the aforementioned groups-the upper-grade group regarded host factors as a higher cause of illness than the lower-grade group. Second, Medical skepticism also differed depending on specialty. Compared with the medical students, Oriental medical students were more likely to have high confidence in "overcoming illnesses", "home remedies", "self-decision in treatments", and "understanding their own health". In subdividing medical and Oriental medical students according to grade we observed that the senior group had more confidence in home remedies than the junior group. Third, In an analysis of the students attitudes toward medical care, we found that nonmedical students had the highest score in the "care-oriented" and "cure oriented" attitude categories. In the overall results, the care-oriented category ranked highest for the nonmedical students, followed by Oriental medical students and medical students; the cure-oriented category ranked highest for nonmedical students, followed by medical students and then Oriental medical students. CONCLUSION: Based on our results, we conclude that these differences between specialties should be reflected in medical curricula to bridge the gap between patients and doctors in medical education with regard to the causes of illness and attitudes toward medical care. PMID- 25813313 TI - Student satisfaction and self-assessment after small group discussion in a medical ethics education program. AB - PURPOSE: Small group discussions are useful tools in medical ethics education. We aimed to assess student satisfaction with specific components of a small group discussion and to evaluate student self-assessment of the objectives of education. METHODS: A structured questionnaire was developed after a literature review and a focus group interview. Components of the small group discussion were categorized by discussion case (self, other), individual activities (self-study, making materials, presentation experience), and group activities (preclass/in class/postclass/plenary discussion, instructor's comments). The items for student self-assessment were: "To specify ethical issue in actual practice", "To get new knowledge", "To consider doctor's entity", "Empathy to others", "To get multidimensional viewpoint", "Viewpoint change", "To deliver my thought clearly", and "Ability to confront the medical ethics dilemma in the future". After the survey, an in-depth interview was performed to determine the reason behind the students' answers. RESULTS: A total of 121 students responded, for whom overall satisfaction and self-assessment were high. Students reported greater satisfaction with self-case, presentation experience, in-class discussion, and instructor's comments but less satisfaction with self-study before class and postclass discussion. Student self-assessment was highest in the ability to specify an ethical issue and lowest for viewpoint change and self-confidence. After multivariate analysis, higher student self-assessment was associated with greater satisfaction with the small group discussion. CONCLUSION: To improve the quality of medical ethics education, close investigation and monitoring of each component of the small group discussion and student achievement are essential, as is continuous feedback. PMID- 25813314 TI - Development and validation of a questionnaire to evaluate medical students' evidence-based medicine competencies. AB - PURPOSE: The purpose of the study was to develop and validate a questionnaire to evaluate medical students' knowledge of, attitude towards and practice of evidence-based medicine (EBM). METHODS: The participants of the study were 418 medical students enrolled in the Kyung Hee University School of Medicine in Seoul, Korea. To examine construct validity of the questionnaire, an exploratory factor analysis (EFA) was performed with 118 participants; a confirmatory factor analysis (CFA) was conducted with the remaining 281 participants. We developed 41 items with a 4-point Likert scale. An EFA was performed to verify the emergence of four dimensions of EBM competencies. The principal axis factoring method and the direct oblimin rotation method were used. To confirm construct validity, a CFA was conducted with the remaining 281 participants. To evaluate model fitness, root mean square error of approximation (RMSEA) and comparative fit index (CFI) were used as fit indices. We conducted ANOVA with Scheffe as discriminant validation, and calculated Cronbach's alpha of 4 subscales as reliability checkup. RESULTS: After refinement procedure, factor analysis of the 32 items in therevised questionnaire yielded 4 factors. The Scree plot supported a 4 factor solution explaining 53.5% of the variance. The 4 components derived were: factor 1_knowledge on EBM (11 items; Cronbach's alpha=0.92); factor 2_ pursuit towards EBM (10; 0.88); factor 3_reluctance on EBM (7; 0.78); factor 4_practice of EBM (4; 0.75). The questionnaire could discriminate competence differences among 1-3 yr students. Satisfactory Cronbach's alpha scores were noted for each factor as well. CONCLUSION: The EBM competency questionnaire was validated. PMID- 25813315 TI - Relationship between the Clinical Performance Examination and Associated Variables. AB - PURPOSE: The purpose of this study was to identify the causal relationship between the following variables: basic science score, written examination score (Internal medicine and Pediatrics), clinical clerkship score (Internal medicine and Pediatrics), and affective factors (self-efficacy, anxiety, and perception of preparedness). METHODS: Forty-two medical students took the clinical performance examination (CPX) at the end of the first semester. One day before the CPX, the students completed a brief survey, which included 11 items that sampled their self-efficacy, preparedness and anxiety with regard to the CPX. The responses from the 38 identifiable surveys (90%), out of 42, were analyzed for this study. Structural equation modeling techniques were used to test the relationships between the variables. The students' basic science scores, clinical clerkship scores, and written examination scores were considered for this study. RESULTS: We found that self-efficacy influenced students' CPX scores indirectly through their preparedness and anxiety. Preparedness influenced students' CPX scores indirectly through their anxiety. Anxiety was predicated on self-efficacy directly or indirectly and it predicted CPX scores. The clinical clerkship scores affected the students' CPX scores indirectly. The written examination scores and basic science scores, however, did not impact the students' CPX scores directly or indirectly. The basic science scores, clinical clerkship scores, and written examination scores were not associated with self-efficacy. CONCLUSION: Our findings highlight the importance of clinical clerkship education and reasonable medical teaching methods in improving the student self-efficacy for the CPX. PMID- 25813316 TI - Differences between Scores Assessed by Examiners and Examinees on Objective Structured Clinical Examination. AB - PURPOSE: Self-assessment is important for learning. But, the reliability of self assessment has long been questioned. We investigated this problem in an objective structured clinical examination (OSCE) setting. METHODS: Forty third-year nursing students who participated in the OSCE were given the same checklist that was used for assessment by the examiners after they finished the OSCE. Then, the scores that were calculated by the examiners and examinees were compared, measuring the average, correlation, difference in score between examinee and examiner, difference in score according to the examinee's level, and Z-score. RESULTS: Scores that were made by the examinees were significantly higher than those of the examiners (average 72.34 vs. 64.03), between which there was a loose positive correlation (r=0.34). The correlation coefficient increased (r=0.62) when a difference in score (examinee-examiner) was compared with the examiner score. When examinees were divided into 3 groups according to their scores, the difference tended to become less as the scores of examinee rose. When the Z-score was compared with the level of the examinee, examinees who had higher scores evaluated themselves lower than the examiners, and examinees with lower scores assessed themselves higher than the examiners. CONCLUSION: According to comparison of averages or correlation analysis, self-assessment by the examinee appeared to be less reliable. But when data were analyzed using difference in score, examinee levels, and Z-score, a certain tendency developed. This pattern may be due to the heterogeneity of the examinee group. Selection of appropriate analysis methods might be important to estabilish the reliability of self assessment skills. PMID- 25813317 TI - Faculty observer and standardized patient accuracy in recording examinees' behaviors using checklists in the clinical performance examination. AB - PURPOSE: The purpose of the study was to examine the recording accuracy of faculty observers and standardized patients (SPs) on a clinical performance examination (CPX). METHODS: This was a cross-sectional study of a fourth-year medical students' CPX that was held at a medical school in Seoul, Korea. The CPX consisted of 4 cases and was administered to 118 examinees, with the participation of 52 SP and 45 faculty observers. For the study we chose 15 examinees per case, and analyzed 60 student-SP encounters in total. To determine the recording accuracy level, 2 SP trainers developed an answer key for each encounter. First, we computed agreement rates (P) and kappa coefficient (K) values between the answer key-SPs and the answer key-faculty observers. Secondly, we analyzed variance (ANOVA) with repeated measures to determine whether the mean percentage of the correct checklist score differed as a function of the rater, the case, or the interaction between both factors. RESULTS: Mean P rates ranged from 0.72 to 0.86, while mean K values varied from 0.39 to 0.59. The SP checklist accuracy was higher than that of faculty observersat the level of item comparison. Results from ANOVA showed that there was no significant difference between the percentage of correct scores by the answer key, faculty observers and SPs. There was no significant interaction between rater and case factors. CONCLUSION: Acceptable levels of recording accuracy were obtained in both rater groups. SP raters can replace faculty raters in a large-scale CPX with thorough preparation. PMID- 25813318 TI - Estimation of optimal educational cost per medical student. AB - PURPOSE: This study aims to estimate the optimal educational cost per medical student. METHODS: A private medical college in Seoul was targeted by the study, and its 2006 learning environment and data from the 2003~2006 budget and settlement were carefully analyzed. Through interviews with 3 medical professors and 2 experts in the economics of education, the study attempted to establish the educational cost estimation model, which yields an empirically computed estimate of the optimal cost per student in medical college. RESULTS: The estimation model was based primarily upon the educational cost which consisted of direct educational costs (47.25%), support costs (36.44%), fixed asset purchases (11.18%) and costs for student affairs (5.14%). These results indicate that the optimal cost per student is approximately 20,367,000 won each semester; thus, training a doctor costs 162,936,000 won over 4 years. Consequently, we inferred that the tuition levels of a local medical college or professional medical graduate school cover one quarter or one-half of the per- student cost. CONCLUSION: The findings of this study do not necessarily imply an increase in medical college tuition; the estimation of the per-student cost for training to be a doctor is one matter, and the issue of who should bear this burden is another. For further study, we should consider the college type and its location for general application of the estimation method, in addition to living expenses and opportunity costs. PMID- 25813319 TI - A trend study of student' consistent responses to course evaluation. AB - PURPOSE: Most students choose the same option to questions in course evaluation surveys. Identical answers to each question render the results unreliable. The purpose of this study was to analyze the trend of medical student' consistent responses to course evaluations. METHODS: The data of this study were the results of a course evaluation over 3 years (from 2006 to 2008) at the School of Medicine at A University. RESULTS: The proportion of students who replied with the same answers to each question was below 20%. This result was consistent in freshmen, sophomores, and junior students. Using a 5-point Likert scale, more than 40% of the students gave 5 points consistently. CONCLUSION: We conclude that student' responses to evaluations do not have a significant impact on the reliability of course evaluations at Medical School at A University. These results differ significantly from those of previous research. Hence, future studies are required to analyze course evaluations in medical schools using diverse aspects. PMID- 25813320 TI - Twelve tips for computer-based assessment in medical education. PMID- 25813322 TI - Mistyped references in the issues of volume 20, 2008. PMID- 25813321 TI - Professionalism in medicine. PMID- 25813323 TI - Student centered medical education. PMID- 25813324 TI - Outcome-based medical education: implications, opportunities, and challenges. AB - Outcome-based education (OBE) is a major reframing of how medical educators think about teaching, learning, and assessment. There are many alternative versions of OBE and the implications of this framework are not always well-understood. A review of the literature on OBE and an analysis of the educational implications suggest seven areas of contrast with traditional educational frameworks. Key contrasts center around how educational outcomes are defined, the emphasis of learning over teaching, the centrality of rigorous assessment, the need for flexibility and individualization in the curriculum, and shifting roles and responsibilities of teachers and learners. OBE has the potential for dramatic and even revolutionary changes in medical education. However, it carries with it significant challenges that include the expenses of additional assessment, uncertainty among students and faculty about their responsibilities, and complexities in planning and organizing the educational process. Instead, of whole-hearted adoption of the OBE model, most medical schools and residency programsare exploring OBE in small-scale "experiments" that will inform the field about the best ways to incorporate the critical features of OBE into medical education. Such experiments are invaluable for helping us better understand the promise and possibilities of OBE. PMID- 25813325 TI - Trends analysis on research articles in the korean journal of medical education. AB - The purpose of this study was to examine the chronological changes and progress in medical education research in Korea and to identify the less investigated topics that need further study and improvement with regard to methodological quality. Of the 590 articles that were published from 1989 to 2010 in the Korean Journal of Medical Education, 386 original research papers were extracted for the analysis. The extracted papers were systematically reviewed using 2 analysis schemes that we developed: one scheme was designed to classify research topics, and the other determined the methodology that was used. The main results were as follows: The most popular research areas were curriculum, educational method, and evaluation in basic medical education; in contrast, studies that addressed postgraduate education, continuous professional development, and educational administration were less frequent; The most frequently studied topics were clinical performance/skills evaluation, clerkship, curriculum development, and problem-based learning, Quantitative studies predominated over qualitative studies and mixed methods (265 vs. 95 vs. 26). Two hundred forty papers were descriptive, cross-sectional studies, and 17 were experimental studies. Most qualitative studies were non-participation observational studies. In conclusion, there has been dramatic growth in the extent of medical education research in Korea in the past two decades. However, more studies that investigate the graduate medical education and the continuous professional development should be performed. Moreover, robust experimental designs and methods should be applied to provide stronger evidence that can practice best-evidence medical education. PMID- 25813326 TI - Development of learning consultation program for medical students. AB - PURPOSE: The purpose of this report was to develop a learning consultation program to help medical students adjust to studying. Also, it investigated students with learning difficulties and determined their learning needs. METHODS: Four hundred forty-two medical students from 2 medical schools in Korea were surveyed with regard to learning difficulties and learning consultation needs. Of the respondents, 202 students were male and 206 were female; the remained was unidentified. We used frequency and crosstab analysis to analyze the data from the survey. RESULTS: The needs analysis showed that first-year students had the most serious academic difficulties of those who were surveyed, possessing a lack of learning skills and medical adaptation to clinical situations. In response, these students wished to receive learning consultation from the medical faculty and senior students. Thus, we developed a learning consultation program for medical students, based on learning consultation cases in domestic and foreign universities. CONCLUSION: This study indicates that medical students have learning difficulties and need learning consultations, especially first-year students. Therefore, we developed a learning consultation program that consists of problem screening, problem specifications, and choosing strategies. After implementing the program, it can help medical students adjust to the medical environment. Furthermore, these findings have implications for studies on learning consultation programs for medical students. PMID- 25813327 TI - Vocational interest types of medical students and its usage in student career counseling program. AB - PURPOSE: It is very important to consider student's personality, aptitudes, and interest to choose an appropriate major or career. This study explored three overarching topics: Are there difference in vocational interest types by gender? Do students' vocational interest type concur with type related to medicine? Are the results of Strong Interest Inventory useful in student career counseling? METHODS: The subjects were 124 freshmen in Konyang University College of Medicine. The Strong Interest Inventory (Korean version) was used. This were divided into three scales: general occupational themes (GOT), basic interest scales (BIS), and personal style scales (PSS). The data were analyzed by the frequency analysis, chi-square test and t-test. RESULTS: From GOT six interest types, male and female showed significant differences in realistic (t=2.71, p=0.008), artist (t=-3.33, p=0.001), and social (t=-2.08, p=0.039) types. From PSS, the score of work style was below 50 points, it is mean they prefer to work alone, with the ideas, materials rather than work with people. Investigative type was the most frequent type (63.7%) and social type was the least (8.1%). The interest test results were very useful in student career counseling with professors (n=53). The satisfaction survey results showed 58.5% of professors were very satisfied as the data was "helpful in understanding the students," "useful in leading natural conversation (41.5%)," and "helpful in creating rapport (39.6%)." CONCLUSION: Strong vocational interest types explains an individual's career interests, and reflect the characteristics of medical students are. The finding of the study can be used to provide student counseling and developing a tailored student career guidance program. PMID- 25813328 TI - International collaborative faculty development program on simulation-based healthcare education: a report on its successes and challenges. AB - PURPOSE: Countries that are less experienced with simulation-based healthcare education (SBHE) often import Western programs to initiate their efforts to deliver effective simulation training. Acknowledging cultural differences, we sought to determine whether faculty development program on SBHE in the United States could be transported successfully to train faculty members in Korea. METHODS: An international, collaborative, multi-professional program from a pre existing Western model was adapted. The process focused on prioritization of curricular elements based on local needs, translation of course materials, and delivery of the program in small group facilitation exercises. Three types of evaluation data were collected: participants' simulation experience; participants' ratings of the course; and participant's self-assessment of the impact of the course on their knowledge, skills, and attitudes (KSA) toward simulation teaching. RESULTS: Thirty faculty teachers participated in the course. Eighty percent of the participants answered that they spent less than 25% of their time as simulation instructors. Time spent on planning, scenario development, delivering training, research, and administrative work ranged from 10% to 30%. Twenty-eight of 30 participants agreed or strongly agreed that the course was excellent and relevant to their needs. The participants' assessment of the impact of the course on their KSA toward simulation teaching improved significantly. CONCLUSION: Although there were many challenges to overcome, a systematic approach in the adaptation of a Western simulation faculty development course model was successfully implemented in Korea, and the program improves self confidence and learning in participants. PMID- 25813329 TI - Improvement in Clinical Performance of Interns and Residents through Clinical Skills Assessment of the Korean Medical Licensing Examination. AB - PURPOSE: To evaluate the clinical performance through the Korean Medical Licensing Examination clinical skills assessment (KMLE CSA) this survey was done. METHODS: A survey of 130 interns and residents (46 applicants and 84 non applicants for the KMLE CSA) at a university hospital in Seoul was conducted in January and February 2012. The data were gathered using a structured and self administered questionnaire. For the items that assessed the clinical performance of these subjects, we selected 15 items that are mostly frequently used by Delphi's technique, and difficult procedural skills based on the results of medical students' performance. We also used subcomponents of the clinical problems test of the KMLE CSA. RESULTS: The total score on the KMLE CSA improved by 1.33 points (a perfect score is 10), 1.49 points for procedural skills, and 0.84 points for clinical problems by multiple regression analysis. The variables that influenced clinical skills were sex (females had 0.86 more points than males), experience in military or public services (1.04 points higher than persons without experience), and type of school (graduates of medical school had 1.41 more points than graduates of professional graduate school). CONCLUSION: Implementation of the KMLE CSA improved the clinical performance of medical graduates. PMID- 25813330 TI - Exploratory and confirmatory factor analysis of medical professionalism core attributes scale. AB - PURPOSE: Evaluating the professional attributes of medical students is critical, because medical professionalism is an essential quality of a good doctor. But, few studies have examined the tools for assessing such attributes. This study analyzed factors of medical professionalism in medical students to develop standards that can assess medical professional attributes. METHODS: A total of 1,508 medical students in Korean medical schools or colleges answered a self assessment survey of medical professionalism elements from 2005 to 2012 that we developed. The survey consisted of core 31 attributes on a 5-point Likert scale. Factor analysis was performed using SPSS version 20.0 and AMOS version 20.0. RESULTS: Exploratory factor analysis revealed six factors with total variance of 59.56%. The factors were termed 'empathy and accountability,' 'self-development skills,' 'academic competence,' 'interpersonal skills,' 'high intelligence,' and 'attitude towards oneself and life.' These factors showed statistically significant correlation (0.310~0.663). From the confirmatory factor analysis a six-factor model were appropriate (CFI=0.873, TLI=0.853, RMSEA=0.065). Cronbach alpha of six factors ranged from 0.718 to 0.864. CONCLUSION: Good doctors need to have not only appropriate standards of medical knowledge but also skills to understand and communicate well with patients, as well as self-management skills, which should not be overlooked in the medical education curriculum. By optimizing the results of this study, a more refined assessment tool of professionalism can be exploited. PMID- 25813331 TI - Effects of problem-based learning by learning style in medical education. AB - PURPOSE: Although problem-based learning (PBL) has been popularized in many colleges, few studies have analyzed the relationship between individual differences and PBL. The purpose of this study was to analyze the relationship between learning style and the perception on the effects of PBL. METHODS: Grasha Riechmann Student Learning Style Scales was used to assess the learning styles of 38 students at Ajou University School of Medicine who were enrolled in a respiratory system course in 2011. The data were analyzed by regression analysis and Spearman correlation analysis. RESULTS: By regression analysis, dependent beta=0.478) and avoidant styles (beta=-0.815) influenced the learner's satisfaction with PBL. By Spearman correlation analysis, there was significant link between independent, dependent, and avoidant styles and the perception of the effect of PBL. CONCLUSION: There are few significant relationships between learning style and the perception of the effects of PBL. We must determine how to teach students with different learning styles and the factors that influence PBL. PMID- 25813332 TI - Quality of Life of Medical Students during Clinical Clerkship. AB - PURPOSE: This study examined the stress, resilience, social support, and quality of life (QOL) of medical students during a clinical clerkship and identified the factors that affected their QOL. METHODS: The subjects were 53 medical college students and 43 postgraduate medical school students of D medical school in Korea. They completed a demographic questionnaire and self-rated questionnaires on stress, resilience, social support, and QOL. Frequency and descriptive analysis, correlation analysis, and regression analysis were performed. RESULTS: The level of students' QOL was moderate. QOL correlated negatively with stress and positively with resilience and social support. Stress correlated negatively with resilience and social support. By regression analysis, stress and resilience affected the QOL of medical students. CONCLUSION: The results of this study indicate that stress negatively affects the QOL of medical students during clinical clerkship, which can be mitigated by resilience. Therefore, it is advisable to develop measures to ease stress and enhance resilience. PMID- 25813333 TI - How to administer the peer evaluation in team-based learning. PMID- 25813336 TI - Global, regional, and national consumption levels of dietary fats and oils in 1990 and 2010: a systematic analysis including 266 country-specific nutrition surveys. PMID- 25813334 TI - The good doctor: what patients want. PMID- 25813337 TI - The use of a lighted stent as a method for identifying the urethra in male patients undergoing transanal total mesorectal excision: a video demonstration. PMID- 25813338 TI - Skin features in myotonic dystrophy type 1: an observational study. AB - Poor data regarding skin involvement in Myotonic Dystrophy, also named Dystrophia Myotonica type 1, have been reported. This study aimed to investigate the prevalence and types of skin disorders in adult patients with Myotonic Dystrophy type 1. Fifty-five patients and one hundred age- and sex-matched healthy subjects were referred to a trained dermatologist for a complete skin examination to check for potential cutaneous hallmarks of disease. No difference in prevalence of preneoplastic, neoplastic, and cutaneous lesions was detected between the two groups. Among morphofunctional, proliferative and inflammatory lesions, focal hyperhidrosis (p < 0.0001), follicular hyperkeratosis (p = 0.0003), early androgenic alopecia (p = 0.01), nail pitting (p = 0.003), pedunculus fibromas (p = 0. 01), twisted hair (p = 0.01), seborrheic dermatitis (p = 0.02), macules of hyperpigmentation (p = 0.03) were significantly more frequent in patients compared with controls. In patients with Myotonic Dystrophy type 1 significant differences according to sex were found for: early androgenic alopecia, twisted hair and seborrheic dermatitis, whose prevalence was higher in males (p < 0.0001). Our preliminary results seem to rule out an increased prevalence of pre neoplastic, and neoplastic skin lesions in Myotonic Dystrophy type 1. On the other hand, an increased prevalence of morphofunctional, inflammatory, and proliferative diseases involving adnexal structures seems to characterize adult patients with Myotonic Dystrophy type 1. PMID- 25813339 TI - Muscular dystrophy in a family of Labrador Retrievers with no muscle dystrophin and a mild phenotype. AB - Animal models of dystrophin deficient muscular dystrophy, most notably canine X linked muscular dystrophy, play an important role in developing new therapies for human Duchenne muscular dystrophy. Although the canine disease is a model of the human disease, the variable severity of clinical presentations in the canine may be problematic for pre-clinical trials, but also informative. Here we describe a family of Labrador Retrievers with three generations of male dogs having markedly increased serum creatine kinase activity, absence of membrane dystrophin, but with undetectable clinical signs of muscle weakness. Clinically normal young male Labrador Retriever puppies were evaluated prior to surgical neuter by screening laboratory blood work, including serum creatine kinase activity. Serum creatine kinase activities were markedly increased in the absence of clinical signs of muscle weakness. Evaluation of muscle biopsies confirmed a dystrophic phenotype with both degeneration and regeneration. Further evaluations by immunofluorescence and western blot analysis confirmed the absence of muscle dystrophin. Although dystrophin was not identified in the muscles, we did not find any detectable deletions or duplications in the dystrophin gene. Sequencing is now ongoing to search for point mutations. Our findings in this family of Labrador Retriever dogs lend support to the hypothesis that, in exceptional situations, muscle with no dystrophin may be functional. Unlocking the secrets that protect these dogs from a severe clinical myopathy is a great challenge which may have important implications for future treatment of human muscular dystrophies. PMID- 25813341 TI - The natural theology of Victorian industry. AB - As clergymen in Britain celebrated the Great Exhibition in the summer of 1851 and drew appropriate moral lessons, there was widespread agreement that the triumphs of industry on display represented the fulfilment of God's will. The basic assumption was that overcoming God's curse on Adam had been possible only through sustained hard work - industry in the early Victorian sense - and that this imperative work ethic had always been God's intention for mankind. In elaborating the details, preachers combined the British tradition of natural theology with the Scottish Enlightenment's progressive science of man to paint a picture of the slow recovery of man from the Fall through his own industry. This was the very story of civilization itself, with God the driving force. The celebrants were quite clear that it was divine providence that had ordained the greatness of Great Britain. PMID- 25813342 TI - Treatment Efficacy of Integrative Family and Systems Treatment (I-FAST) With and Without Consultation: The Role of Model Training in the Sustainability of Evidence-Based Family Treatments. AB - This study examined the efficacy of the Integrative Family and Systems Treatment (I-FAST) training model that seeks to support development of model expertise within the agency in the context of facilitating the sustainability of evidence based family treatment within community mental health settings. A quasi experimental design was used to examine treatment outcomes of I-FAST among agencies that received ongoing Consultation and agencies that received No Consultation upon completion of I-FAST training. chi (2) analyses and independent samples t test analyses showed that there were no significant differences between the two groups on clients who had achieved reliable change on Problem Severity and Functioning based on parents' assessments. Significance of this study is discussed in the context of the role of evidence-based family therapy (EBFT) training in facilitating its sustainability in community mental health settings. PMID- 25813343 TI - Autochthonous arbuscular mycorrhizal fungi and Bacillus thuringiensis from a degraded Mediterranean area can be used to improve physiological traits and performance of a plant of agronomic interest under drought conditions. AB - Studies have shown that some microorganisms autochthonous from stressful environments are beneficial when used with autochthonous plants, but these microorganisms rarely have been tested with allochthonous plants of agronomic interest. This study investigates the effectiveness of drought-adapted autochthonous microorganisms [Bacillus thuringiensis (Bt) and a consortium of arbuscular mycorrhizal (AM) fungi] from a degraded Mediterranean area to improve plant growth and physiology in Zea mays under drought stress. Maize plants were inoculated or not with B. thuringiensis, a consortium of AM fungi or a combination of both microorganisms. Plants were cultivated under well-watered conditions or subjected to drought stress. Several physiological parameters were measured, including among others, plant growth, photosynthetic efficiency, nutrients content, oxidative damage to lipids, accumulation of proline and antioxidant compounds, root hydraulic conductivity and the expression of plant aquaporin genes. Under drought conditions, the inoculation of Bt increased significantly the accumulation of nutrients. The combined inoculation of both microorganisms decreased the oxidative damage to lipids and accumulation of proline induced by drought. Several maize aquaporins able to transport water, CO2 and other compounds were regulated by the microbial inoculants. The impact of these microorganisms on plant drought tolerance was complementary, since Bt increased mainly plant nutrition and AM fungi were more active improving stress tolerance/homeostatic mechanisms, including regulation of plant aquaporins with several putative physiological functions. Thus, the use of autochthonous beneficial microorganisms from a degraded Mediterranean area is useful to protect not only native plants against drought, but also an agronomically important plant such as maize. PMID- 25813345 TI - Tracking word frequency effects through 130 years of sound change. AB - Contemporary New Zealand English has distinctive pronunciations of three characteristic vowels. Did the evolution of these distinctive pronunciations occur in all words at the same time or were different words affected differently? We analyze the changing pronunciation of New Zealand English in a large set of recordings of speakers born over a 130 year period. We show that low frequency words were at the forefront of these changes and higher frequency words lagged behind. A long-standing debate exists between authors claiming that high frequency words lead regular sound change and others claiming that there are no frequency effects. The leading role of low frequency words is surprising in this context. It can be elucidated in models of lexical processing that include detailed word-specific memories. PMID- 25813344 TI - The pentameric nucleoplasmin fold is present in Drosophila FKBP39 and a large number of chromatin-related proteins. AB - Nucleoplasmin is a histone chaperone that consists of a pentameric N-terminal domain and an unstructured C-terminal tail. The pentameric core domain, a doughnut-like structure with a central pore, is only found in the nucleoplasmin family. Here, we report the first structure of a nucleoplasmin-like domain (NPL) from the unrelated Drosophila protein, FKBP39, and we present evidence that this protein associates with chromatin. Furthermore, we show that two other chromatin proteins, Arabidopsis thaliana histone deacetylase type 2 (HD2) and Saccharomyces cerevisiae Fpr4, share the NPL fold and form pentamers, or a dimer of pentamers in the case of HD2. Thus, we propose a new family of proteins that share the pentameric nucleoplasmin-like NPL domain and are found in protists, fungi, plants and animals. PMID- 25813346 TI - A Bayesian framework for knowledge attribution: evidence from semantic integration. AB - We propose a Bayesian framework for the attribution of knowledge, and apply this framework to generate novel predictions about knowledge attribution for different types of "Gettier cases", in which an agent is led to a justified true belief yet has made erroneous assumptions. We tested these predictions using a paradigm based on semantic integration. We coded the frequencies with which participants falsely recalled the word "thought" as "knew" (or a near synonym), yielding an implicit measure of conceptual activation. Our experiments confirmed the predictions of our Bayesian account of knowledge attribution across three experiments. We found that Gettier cases due to counterfeit objects were not treated as knowledge (Experiment 1), but those due to intentionally-replaced evidence were (Experiment 2). Our findings are not well explained by an alternative account focused only on luck, because accidentally-replaced evidence activated the knowledge concept more strongly than did similar false belief cases (Experiment 3). We observed a consistent pattern of results across a number of different vignettes that varied the quality and type of evidence available to agents, the relative stakes involved, and surface details of content. Accordingly, the present findings establish basic phenomena surrounding people's knowledge attributions in Gettier cases, and provide explanations of these phenomena within a Bayesian framework. PMID- 25813347 TI - Smoothened mutations underlie Basal cell carcinoma resistance. PMID- 25813349 TI - In silico analysis of tumors identifies cancer treatment strategies. PMID- 25813350 TI - Super-enhancers facilitate gene regulation by signaling pathways. PMID- 25813351 TI - MEK Inhibition Enhances Preclinical Activity of BRAF Inhibition and Immunotherapy. PMID- 25813353 TI - Experts endorse 21 as legal smoking age. PMID- 25813352 TI - The p53 Target Gene SIVA Enables Non-Small Cell Lung Cancer Development. AB - Although p53 transcriptional activation potential is critical for its ability to suppress cancer, the specific target genes involved in tumor suppression remain unclear. SIVA is a p53 target gene essential for p53-dependent apoptosis, although it can also promote proliferation through inhibition of p53 in some settings. Thus, the role of SIVA in tumorigenesis remains unclear. Here, we seek to define the contribution of SIVA to tumorigenesis by generating Siva conditional knockout mice. Surprisingly, we find that SIVA loss inhibits non small cell lung cancer (NSCLC) development, suggesting that SIVA facilitates tumorigenesis. Similarly, SIVA knockdown in mouse and human NSCLC cell lines decreases proliferation and transformation. Consistent with this protumorigenic role for SIVA, high-level SIVA expression correlates with reduced NSCLC patient survival. SIVA acts independently of p53 and, instead, stimulates mTOR signaling and metabolism in NSCLC cells. Thus, SIVA enables tumorigenesis in a p53 independent manner, revealing a potential new cancer therapy target. SIGNIFICANCE: These findings collectively reveal a novel role for the p53 target gene SIVA both in regulating metabolism and in enabling tumorigenesis, independently of p53. Importantly, these studies further identify SIVA as a new prognostic marker and as a potential target for NSCLC cancer therapy. PMID- 25813355 TI - A Meta-Analysis of Cross Sectional Studies Investigating Language in Maltreated Children. AB - Purpose: In this review article, meta-analysis was used to summarize research investigating language skills in maltreated children. Method: A systematic search of published studies was undertaken. Studies were included in the meta-analysis if they investigated language skills in groups comprising maltreated and nonmaltreated children. Studies were selected if these 2 groups of children were of comparable age and from a similar socioeconomic background. Results: A total of 26 studies were identified that met the inclusion criteria. Results from the meta-analysis showed that maltreated children demonstrated consistently poorer language skills with respect to receptive vocabulary (k = 19; standardized mean difference [SMD] = .463; 95% confidence interval [CI; .293, .634]; p < .001), expressive language (k = 4; SMD =.860; 95% CI [.557, 1.163]; p < .001), and receptive language (k = 9; SMD =.528; 95% CI [.220, .837]; p < .001). Conclusion: Together, these results indicate a reliable association between child maltreatment and poor language skills. PMID- 25813354 TI - Identification of imaging biomarkers for the assessment of tumour response to different treatments in a preclinical glioma model. AB - PURPOSE: Hypoxia-inducible factor 1alpha (HIF-1alpha) activity is one of the major players in hypoxia-mediated glioma progression and resistance to therapies, and therefore the focus of this study was the evaluation of HIF-1alpha modulation in relation to tumour response with the purpose of identifying imaging biomarkers able to document tumour response to treatment in a murine glioma model. METHODS: U251-HRE-mCherry cells expressing Luciferase under the control of a hypoxia responsive element (HRE) and mCherry under the control of a constitutive promoter were used to assess HIF-1alpha activity and cell survival after treatment, both in vitro and in vivo, by optical, MRI and positron emission tomography imaging. RESULTS: This cell model can be used to monitor HIF-1alpha activity after treatment with different drugs modulating transduction pathways involved in its regulation. After temozolomide (TMZ) treatment, HIF-1alpha activity is early reduced, preceding cell cytotoxicity. Optical imaging allowed monitoring of this process in vivo, and carbonic anhydrase IX (CAIX) expression was identified as a translatable non-invasive biomarker with potential clinical significance. A preliminary in vitro evaluation showed that reduction of HIF-1alpha activity after TMZ treatment was comparable to the effect of an Hsp90 inhibitor, opening the way for further elucidation of its mechanism of action. CONCLUSION: The results of this study suggest that the U251-HRE-mCherry cell model can be used for the monitoring of HIF-1alpha activity through luciferase and CAIX expression. These cells can become a useful tool for the assessment and improvement of new targeted tracers for potential theranostic procedures. PMID- 25813357 TI - Promoting health and well-being at the end of life through client-centered care. AB - BACKGROUND: Client-centered care is the cornerstone of the hospice and includes family members and significant others as the client unit. There needs to be a conceptual shift away from "medicalizing" patients at the end of life to promoting their health and considering their well-being a shared responsibility. Using the hospice philosophy of client-centered care can inform and expand health promotion occupational therapy practice, particularly for people at the end of life. OBJECTIVES: This paper examines client-centered care at the end of life as that which enables engagement in meaningful occupation and promotes health and well-being until one dies. METHODS: Constant comparison and thematic analysis is used for 12 interviews of hospice professionals. One of the themes, client centered care, is discussed relative to the promotion of health and well-being at the end of life. RESULTS: Client-centered care is deemed to be an important approach at the end of life. CONCLUSIONS/SIGNIFICANCE: It is determined that client-centered care at the end of life is vital to promote quality of life, health, and well-being. Further research is indicated. PMID- 25813356 TI - Home-use servo-ventilation therapy in chronic pain patients with central sleep apnea: initial and 3-month follow-up. AB - PURPOSE: Opioid treatment of non-malignant chronic pain can result in hypoxemia, hypercarbia, and central sleep apnea. The aim of this study was to determine the initial efficacy of auto servo-ventilation (ASV) and after 3 months of home use. METHODS: This prospective multicenter interventional study recruited chronic pain patients prescribed >=100 morphine equivalents for at least 4 months. PARTICIPANTS: Following full-night polysomnography (PSG) to confirm the presence of sleep-disordered breathing, patients were randomized to three additional full night-attended PSGs with continuous positive airway pressure (CPAP), ASV, and servo-ventilation with an initial mandatory pressure support of 6 cm H2O (ASV manual PSmin 6). Following the PSGs, patients were sent home with EncoreAnywhere and ASV with or without mandatory pressure support. RESULTS: Based on the initial PSG studies, CPAP improved but did not normalize the apnea-hypopnea index (AHI), central apnea index (CAI), or hypopnea index (HI), as all remained elevated. Clinically significant reductions were noted after just one night of ASV and ASV manual (PSmin 6). After 3 months of ASV home use, the AHI, CAI, and obstructive apnea index (OAI) were significantly reduced when compared to baseline diagnostic levels and even when compared to respiratory disturbance indices with CPAP treatment. CONCLUSIONS: Initial and home use of ASV for 3 months resulted in significantly lower AHI, CAI, and OAI. This reduction attests to the efficacy of ASV treatment in chronic pain patients on high doses of opioids. PMID- 25813358 TI - On the Robustness to Gene Tree Estimation Error (or lack thereof) of Coalescent Based Species Tree Methods. AB - The estimation of species trees using multiple loci has become increasingly common. Because different loci can have different phylogenetic histories (reflected in different gene tree topologies) for multiple biological causes, new approaches to species tree estimation have been developed that take gene tree heterogeneity into account. Among these multiple causes, incomplete lineage sorting (ILS), modeled by the multi-species coalescent, is potentially the most common cause of gene tree heterogeneity, and much of the focus of the recent literature has been on how to estimate species trees in the presence of ILS. Despite progress in developing statistically consistent techniques for estimating species trees when gene trees can differ due to ILS, there is substantial controversy in the systematics community as to whether to use the new coalescent based methods or the traditional concatenation methods. One of the key issues that has been raised is understanding the impact of gene tree estimation error on coalescent-based methods that operate by combining gene trees. Here we explore the mathematical guarantees of coalescent-based methods when analyzing estimated rather than true gene trees. Our results provide some insight into the differences between promise of coalescent-based methods in theory and their performance in practice. PMID- 25813359 TI - Adsorption of proteins at the aqueous solution/alkane interface: Co-adsorption of protein and alkane. AB - The equations of state, adsorption isotherms and functions of the distribution of protein molecules in liquid interfacial layers with respect to molar area and the equations for their viscoelastic behavior are presented. This theory was used to determine the adsorption characteristics of beta-casein and beta-lactoglobulin at water/oil interfaces. The experimental results are shown to be describable quite adequately by the proposed theory with consistent model parameters. The data analysis demonstrated that the beta-casein molecule adsorbed at equilibrium conditions is more unfolded as compared with dynamic conditions, and this fact causes the significant increase of the adsorption equilibrium constant. The theory assumes the adsorption of protein molecules from the aqueous solution and a competitive adsorption of alkane molecules from the alkane phase. The comparison of the experimental equilibrium interfacial tension isotherms for beta lactoglobulin at the solution/hexane interface with data calculated using the proposed theoretical model demonstrates that the assumption of a competitive adsorption is essential, and the influence of the hexane molecules on the shape of the adsorption isotherm does in fact exist. PMID- 25813360 TI - Calcium desensitizer catechin reverses diastolic dysfunction in mice with restrictive cardiomyopathy. AB - Diastolic dysfunction refers to an impaired relaxation and an abnormality in ventricular blood filling during diastole while systolic function is preserved. Cardiac myofibril hypersensitivity to Ca(2+) is a major factor that causes impaired relaxation of myocardial cells. The present study investigates the effect of the green tea extract catechins on myofibril calcium desensitization and restoration of diastolic function in a restrictive cardiomyopathy (RCM) mouse model with cardiac troponin mutations. Wild type (WT) and RCM mice were treated daily with catechin (epigallocatechin-3-gallate, EGCg, 50 mg/kg body weight) for 3 months. Echocardiography and cell based assays were performed to measure cardiac structure and flow-related variables including chamber dimensions, fraction shortening, trans-mitral flow patterns in the experimental mice. In addition, myocyte contractility and calcium dynamics were measured in WT and RCM cardiomyocytes treated in vitro with 5 MUM EGCg. Our data indicated that RCM mice treated with EGCg showed an improved diastolic function while systolic function remained unchanged. At the cellular level, sarcomere relaxation and calcium decay were accelerated in RCM myocardial cells treated with EGCg. These results suggest that catechin is effective in reversing the impaired relaxation in RCM myocardial cells and rescuing the RCM mice with diastolic dysfunction. PMID- 25813362 TI - The effect of plasma-derived activated protein C on leukocyte cell-death and vascular endothelial damage. AB - INTRODUCTION: The role of leukocyte and its death in the progression in inflammation attracts attention nowadays. The purpose of this study is to examine the effects of activated protein C (APC) on leucocyte cell death and vascular endothelial damage in sepsis. METHODS: Wistar rats were infused with lipopolysaccharide (8.0mg/kg) concomitantly with either a low dose (0.5mg/kg), a high dose (5.0mg/kg) of plasma-derived APC or albumin. One and 3hours after the injections, the mesenteric microcirculation was observed by intravital microscopy. The serum levels of nucleosome and High Mobility Group Box 1 (HMGB1) were measured in each group. In another series, cultured leukocyte cell-death in the medium supplemented with serum obtained from each group was examined in vitro. RESULTS: Microcirculatory disturbance was significantly suppressed in both the high-dose and low-dose groups compared to the control group (P<0.01, 0.05, respectively). The bleeding area was significantly increased in the control and high-dose groups (P<0.05, 0.01, respectively). Serum levels of cell death markers such as nucleosome and HMGB1 were significantly decreased in the treatment groups (P<0.01), and the protective effect was more pronounced in high-dose group. Cell death suppression was most prominent in high-dose group and the formation of neutrophil extracellular traps (NETs) was significantly suppressed in the treatment groups. CONCLUSION: Low-dose plasma-derived APC exerted protective effects on the microcirculation without increasing the risk of bleeding. The protective effect against leukocyte cell death and the suppressive effect on NETs formation of APC might be related to its beneficial effects. PMID- 25813363 TI - Bacillus rigiliprofundi sp. nov., an endospore-forming, Mn-oxidizing, moderately halophilic bacterium isolated from deep subseafloor basaltic crust. AB - A facultatively anaerobic bacterium, designated strain 1MBB1T, was isolated from basaltic breccia collected from 341 m below the seafloor by seafloor drilling of Rigil Guyot during Integrated Ocean Drilling Program Expedition 330. The cells were straight rods, 0.5 MUm wide and 1-3 MUm long, that occurred singly and in chains. Strain 1MBB1T stained Gram-positive. Catalase and oxidase were produced. The isolate grew optimally at 30 degrees C and pH 7.5, and could grow with up to 12 % (w/v) NaCl. The DNA G+C content was 40.5 mol%. The major cellular fatty acids were C16:1omega11c (26.5 %), anteiso-C15:0 (19.5 %), C16:0 (18.7 %) and iso C15:0 (10.4 %), and the cell-wall diamino acid was meso-diaminopimelic acid. Endospores of strain 1MBB1T oxidized Mn(II) to Mn(IV), and siderophore production by vegetative cells was positive. Phylogenetic analysis of the 16S rRNA gene indicated that strain 1MBB1T was a member of the family Bacillaceae, with Bacillus foraminis CV53T and Bacillus novalis LMG 21837T being the closest phylogenetic neighbours (96.5 and 96.2 % similarity, respectively). This is the first novel species described from deep subseafloor basaltic crust. On the basis of our polyphasic analysis, we conclude that strain 1MBB1T represents a novel species of the genus Bacillus, for which we propose the name Bacillus rigiliprofundi sp. nov. The type strain is 1MBB1T ( = NCMA B78T = LMG 28275T). PMID- 25813364 TI - Aneurinibacillus tyrosinisolvens sp. nov., a tyrosine-dissolving bacterium isolated from organics- and methane-rich seafloor sediment. AB - A novel Gram-positive-staining, strictly aerobic and heterotrophic bacterium, designated strain LL-002T, was isolated from organics- and methane-rich seafloor sediment at a depth of 100 m in Kagoshima Bay, Kagoshima, Japan. Colonies were lustreless and translucent white in colour. The temperature, pH and salt concentration ranges for growth were 10-30 degrees C, pH 6.0-6.5 and 0-1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that strain LL-002T belongs to the genus Aneurinibacillus of the family Paenibacillaceae. 16S rRNA gene sequence similarities between strain LL-002T and the type strains of species of the genus Aneurinibacillus were 92.8-95.7 %; the highest sequence identity was with the type strain of Aneurinibacillus migulanus. The DNA G+C content of strain LL-002T was 46.2 mol%. MK-7 was the predominant menaquinone. The predominant cellular fatty acids were iso-C15 : 0 and anteiso C15 : 0, and the cell-wall peptidoglycan contained meso-diaminopimelic acid and glutamic acid, glycine and alanine in addition to muramic acid and glucosamine. The peptidoglycan type was A1gamma. In DNA-DNA hybridization assays between strain LL-002T and the type strains of the other species of the genus Aneurinibacillus, the level of hybridization was 6.3-30.1 %. On the basis of its biological features and the 16S rRNA gene sequence comparison presented here, strain LL-002T is considered to represent a novel species of the genus Aneurinibacillus, for which the name Aneurinibacillus tyrosinisolvens sp. nov. is proposed; the type strain is LL-002T ( = NBRC 110097T = CECT 8536T). PMID- 25813365 TI - Autoantigenicity of human C1q is associated with increased hydrophobicity due to conformational transitions in the globular heads. AB - We analyzed the structural features of C1q that underlie its autoantigenicity by means of a model system using the amphiphilic polyzwitterion (PZ), poly(ethylene oxide-b-N,N-dimethyl(methacryloyloxyethyl) ammonium propanesulfonate) in the process of C1q immobilization. The source of anti-C1q autoantibodies was human sera from patients with Lupus Nephritis (LN). Both analyzed concentrations of PZ, 25 mM and 50 mM, were found to be applicable for inducing conformational transitions which resulted in increased recognition of C1q and the globular domain of its B polypeptide chain, designated ghB, by the LN autoantibodies. The registered conformational transitions displayed a hydrophobic enhancement of the protein microenvironment due to the presence of hydrophobic binding sites in ghB which consequently affected the autoantigenicity of the whole C1q molecule. PMID- 25813361 TI - Polymeric nanoparticle drug delivery technologies for oral delivery applications. AB - INTRODUCTION: Many therapeutics are limited to parenteral administration. Oral administration is a desirable alternative because of the convenience and increased compliance by patients, especially for chronic diseases that require frequent administration. Polymeric nanoparticles (NPs) are one technology being developed to enable clinically feasible oral delivery. AREAS COVERED: This review discusses the challenges associated with oral delivery. Strategies used to overcome gastrointestinal (GI) barriers using polymeric NPs will be considered, including mucoadhesive biomaterials and targeting of NPs to transcytosis pathways associated with M cells and enterocytes. Applications of oral delivery technologies will also be discussed, such as oral chemotherapies, oral insulin, treatment of inflammatory bowel disease, and mucosal vaccinations. EXPERT OPINION: There have been many approaches used to overcome the transport barriers presented by the GI tract, but most have been limited by low bioavailability. Recent strategies targeting NPs to transcytosis pathways present in the intestines have demonstrated that it is feasible to efficiently transport both therapeutics and NPs across the intestines and into systemic circulation after oral administration. Further understanding of the physiology and pathophysiology of the intestines could lead to additional improvements in oral polymeric NP technologies and enable the translation of these technologies to clinical practice. PMID- 25813366 TI - A1c value for diabetes diagnosis in subjects with established cardiovascular disease. PMID- 25813367 TI - Clinical factors that predict remission of diabetes after different bariatric surgical procedures: interdisciplinary group of bariatric surgery of Verona (G.I.C.O.V.). AB - AIMS: The aims of the study were to investigate weight loss and glycemic control parameters after different bariatric surgical procedures in type 2 diabetes (T2D) obese patients and identify patients' factors that predict diabetes remission. METHODS: The study included 105 obese T2D patients (66 women and 39 men) who underwent laparoscopic gastric banding (LAGB, 11 subjects, age 47 +/- 10 years, BMI 42.3 +/- 8.3 kg/m(2)), or laparoscopic Roux-en-Y gastric bypass (RYBP, 77 subjects, age 50 +/- 8 years, BMI 45.7 +/- 6.8 kg/m(2)), or sleeve gastrectomy (SG, 17 subjects, age 49 +/- 11 years, BMI 50.2 +/- 8.8 kg/m(2)) during 2005-2012 period. RESULTS: The average percentage of weight loss at 12 months after surgery was 26.4 +/- 9.8 %, and it was maintained at 24 and 36 months of follow-up. Diabetes remission occurred in 68.6 % of study participants (4/11 of LAGB, 54/77 of RYBP and 14/17 of SG). In multivariate Cox analysis, age, duration of diabetes, surgical procedure and glycated hemoglobin <53 mmol/mol (7 %) resulted significant predictors of diabetes remission (age RR = 0.97, 95 %CI 0.94-1.0, p = 0.05; diabetes duration RR = 0.93, 95 % CI 0.86-0.99, p = 0.036; rif LAGB, RYBP RR = 3.9, 95 % CI 1.31-11.57, p = 0.014; SG RR = 5.6, 95 % CI 1.67-18.64, p = 0.005; glycated hemoglobin RR = 0.54, 95 % CI 0.32-0.92, p = 0.024). CONCLUSIONS: Bariatric surgical procedures that modify the upper gastrointestinal tract anatomy (RYBP and SG) are more successful in producing weight loss and remission of T2D than those that simply restrict stomach capacity (LAGB). Younger age, short duration of diabetes and better glucose control confer higher probability of achieving remission of diabetes. PMID- 25813368 TI - Sympathovagal balance and 1-h postload plasma glucose in normoglucose tolerant hypertensive patients. AB - AIMS: Normoglucose tolerant (NGT) subjects with a 1-h postload plasma glucose (PLPG) value >=155 mg/dL have an increased risk of type-2 diabetes and subclinical organ damage. Heart rate variability (HRV) reflects cardiac autonomic balance, frequently impaired in course of diabetes. At this time, no data support the association between 1-h PLPG and HRV; thus, we investigated the possible association between 1-h PLPG and HRV. METHODS: We enrolled 92 never-treated hypertensive subjects (56 women, 36 men), aged 55 +/- 9.8 years. During OGTT, the patients underwent electrocardiographic recordings to evaluate HRV in the time domain (SDNN). Insulin sensitivity was assessed by Matsuda index. RESULTS: Among participants, 56 were NGT, 20 had impaired glucose tolerance (IGT), and 16 had type-2 diabetes. According to the 1-h PLPG cutoff point of 155 mg/dL, we divided NGT subjects into: NGT < 155 (n = 38) and NGT >= 155 (n = 18). Glucose tolerance status was associated with a significant (P < 0.0001) increase in PLPG and insulin and the reduction in Matsuda index. In all groups, the SDNN values significantly (P < 0.0001) decreased during the first hour of OGTT. A complete recovery in NGT groups was observed at the end of the second hour; in IGT and type-2 diabetes, SDNN remained significantly lower with respect to baseline values. At multiple regression analysis, Matsuda index resulted in the only determinant of SDNN modification, explaining the 12.3 % of its variability. CONCLUSIONS: Our data demonstrate that during OGTT, sympathovagal balance is acutely affected by both glucose and insulin modifications. Particularly, NGT >= 155 subjects behave in the same way of IGT and type-2 diabetes patients. PMID- 25813369 TI - Nitrogen loading and nitrous oxide emissions from a river with multiple hydroelectric reservoirs. AB - River networks receive a large fraction of the anthropogenic nitrogen applied to river catchments. The different impacts of the stream nitrogen (N) loading on nitrous oxide (N2O) emissions from various of aquatic ecosystems are still unknown. In this study, direct measurements of water-air interface N2O exchange in different water bodies were conducted. Results showed that the water-air interface N2O exchange from tributaries, hydropower station reservoirs, a main stream, and its estuary were 10.14 +/- 13.51, 15.64 +/- 10.72, 27.59 +/- 20.99, and 15.98 +/- 12.26 ug N2O-N m(-2) h(-1), respectively, indicating the strong impacts of human activities on N2O emission rates. The water NO2 (-)-N values predicted the dissolved N2O concentrations better than did the NO3 (-)-N and NH4 (+)-N values, indicating strong denitrification and nitrification processes. The dissolved inorganic N explained 36 % of the variations in the N2O emissions for the whole river network. PMID- 25813370 TI - Experimental validation of beam quality correction factors for proton beams. AB - This paper presents a method to experimentally validate the beam quality correction factors (kQ) tabulated in IAEA TRS-398 for proton beams and to determine the kQ of non-tabulated ionization chambers (based on the already tabulated values). The method is based exclusively on ionometry and it consists in comparing the reading of two ionization chambers under the same reference conditions in a proton beam quality Q and a reference beam quality (60)Co. This allows one to experimentally determine the ratio between the kQ of the two ionization chambers. In this work, 7 different ionization chamber models were irradiated under the IAEA TRS-398 reference conditions for (60)Co beams and proton beams. For the latter, the reference conditions for both modulated beams (spread-out Bragg peak field) and monoenergetic beams (pseudo-monoenergetic field) were studied. For monoenergetic beams, it was found that the experimental kQ values obtained for plane-parallel chambers are consistent with the values tabulated in IAEA TRS-398; whereas the kQ values obtained for cylindrical chambers are not consistent--being higher than the tabulated values. These results support the suggestion (of previous publications) that the IAEA TRS-398 reference conditions for monoenergetic proton beams should be revised so that the effective point of measurement of cylindrical ionization chambers is taken into account when positioning the reference point of the chamber at the reference depth. For modulated proton beams, the tabulated kQ values of all the ionization chambers studied in this work were found to be consistent with each other--except for the IBA FC65-G, whose experimental kQ value was found to be 0.6% lower than the tabulated one. The kQ of the PTW Advanced Markus chamber, which is not tabulated in IAEA TRS-398, was found to be 0.997 +/- 0.042 (k = 2), based on the tabulated value of the PTW Markus chamber. PMID- 25813371 TI - Preclinical model of transcorneal alternating current stimulation in freely moving rats. AB - PURPOSE: Transcorneal alternating current stimulation (tACS) has become a promising tool to modulate brain functions and treat visual diseases. To understand the mechanisms of action a suitable animal model is required. However, because existing animal models employ narcosis, which interferes with brain oscillations and stimulation effects, we developed an experimental setup where current stimulation via the eye and flicker light stimulation can be applied while simultaneously recording local field potentials in awake rats. METHOD: tACS was applied in freely-moving rats (N = 24) which had wires implanted under their upper eye lids. Field potential recordings were made in visual cortex and superior colliculus. To measure visual evoked responses, rats were exposed to flicker-light using LEDs positioned in headset spectacles. RESULTS: Corneal electrodes and recording assemblies were reliably operating and well tolerated for at least 4 weeks. Transcorneal stimulation without narcosis did not induce any adverse reactions. Stable head stages allowed repetitive and long-lasting recordings of visual and electrically evoked potentials in freely moving animals. Shape and latencies of electrically evoked responses measured in the superior colliculus and visual cortex indicate that specific physiological responses could be recorded after tACS. CONCLUSIONS: Our setup allows the stimulation of the visual system in unanaesthetised rodents with flicker light and transcorneally applied current travelling along the physiological signalling pathway. This methodology provides the experimental basis for further studies of recovery and restoration of vision. PMID- 25813372 TI - An examination of survival by sex and race in the HeartWare Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) Bridge to Transplant (BTT) and continued access protocol trials. AB - BACKGROUND: The Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) Bridge to Transplant (BTT) trial was a multicenter, prospective trial of the HeartWare Ventricular Assist Device (HVAD). The performance of the HVAD in various demographic sub-groups was evaluated. METHODS: Baseline characteristics, adverse events, and survival were compared for men vs. women and whites vs. non-whites in the combined ADVANCE BTT and continued access protocol trial. Of 332 patients enrolled in these trials, 236 were men and 96 women, with 228 whites and 104 non-whites. RESULTS: At baseline, women had a smaller body surface area (1.8 +/- 0.2 vs. 2.1 +/- 0.3 m2, p < 0.0001), less hypertension (50.0% vs. 61.9%, p = 0.05), and less ischemic cardiomyopathy (15.6% vs. 45.3%, p < 0.0001). Differences in Kaplan-Meier survival were not significant at 180 days (men, 91.8%; women, 91.7%) and 1 year (men, 85.3%; women, 85.1%) despite adjustment for baseline differences. Men had a lower incidence of early right heart failure and renal and respiratory dysfunction, and a shorter length of stay. In the analysis by race, non-whites were younger than whites and had less ischemic heart failure, more hypertension, and lower creatinine levels at baseline. Non-whites had lower rates of arrhythmia, bleeding requiring rehospitalization, and device malfunctions than whites. Survival was high in non whites and whites, at 94.1% vs. 90.4% at 180 days and 89.2% vs. 82.8% at 1 year, respectively, despite adjustment for baseline differences. CONCLUSIONS: Although heart failure etiology differed between men and women and between whites and non whites, sex and race were not factors that affected survival in patients receiving the HVAD as BTT, which was high in all sub-groups. PMID- 25813373 TI - It takes two: noninvasive brain stimulation combined with neurorehabilitation. AB - The goal of postacute neurorehabilitation is to maximize patient function, ideally by using surviving brain and central nervous system tissue when possible. However, the structures incorporated into neurorehabilitative approaches often differ from this target, which may explain why the efficacy of conventional clinical treatments targeting neurologic impairment varies widely. Noninvasive brain stimulation (eg, transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS]) offers the possibility of directly targeting brain structures to facilitate or inhibit their activity to steer neural plasticity in recovery and measure neuronal output and interactions for evaluating progress. The latest advances as stereotactic navigation and electric field modeling are enabling more precise targeting of patient's residual structures in diagnosis and therapy. Given its promise, this supplement illustrates the wide-ranging significance of TMS and tDCS in neurorehabilitation, including in stroke, pediatrics, traumatic brain injury, focal hand dystonia, neuropathic pain, and spinal cord injury. TMS and tDCS are still not widely used and remain poorly understood in neurorehabilitation. Therefore, the present supplement includes articles that highlight ready clinical application of these technologies, including their comparative diagnostic capabilities relative to neuroimaging, their therapeutic benefit, their optimal delivery, the stratification of likely responders, and the variable benefits associated with their clinical use because of interactions between pathophysiology and the innate reorganization of the patient's brain. Overall, the supplement concludes that whether provided in isolation or in combination, noninvasive brain stimulation and neurorehabilitation are synergistic in the potential to transform clinical practice. PMID- 25813374 TI - Modified technique of levator plication for the correction of Marcus Gunn jaw winking ptosis: a case series. AB - To conduct a study on ptotic eyelids with Marcus Gunn jaw-winking ptosis operated via a technique of modified levator plication, prospective interventional case series. Ten ptotic eyelids with Marcus Gunn jaw-winking phenomenon (MGJWP) underwent modified levator plication surgery. Postoperatively, all cases were followed up for at least 6 months. Outcome parameters included amount of ptosis correction, amount of MGJWP correction, palpebral aperture height, lid lag, and lagophthalmos. The mean amount of ptosis was 4.25 +/- 0.79 mm (range of 3-6 mm), mean amount of MGJWP was 5.10 +/- 2.27 mm (range 2-9 mm), and the mean levator function was 8.3 +/- 2.27 mm (range of 4-12 mm). At 6 months follow-up, good correction of ptosis was seen in nine out of ten patients. Resolution of MGJWP (<=1 mm of excursion of upper eyelid with synkinetic mouth movement) was seen in three patients. Improvement in MGJWP (>1 mm of excursion of upper eyelid with synkinetic mouth movement) was seen in seven patients. The mean post-operative lagophthalmos was 0.80 +/- 0.88 mm. The modified levator plication technique was effective in the treatment of MGJWP. This modified technique of levator plication is anatomically less destructive and hence more acceptable, with the added advantages of less post-operative lagophthalmos and no lid contour defects. PMID- 25813375 TI - Spectral domain optical coherence tomography imaging of tubercular chorioretinitis and intraretinal granuloma. Intraretinal tuberculosis: a case report. AB - The aim of this study is to report the clinical and spectral domain optical coherence tomography (SD-OCT) findings in a patient suffering from ulcerative colitis with bilateral tubercular chorioretinitis and intraretinal granuloma regressed with systemic antitubercular therapy (ATT). This study is a case report of a 33-year-old Bangladeshi male with ulcerative colitis treated with oral corticosteroids and azathioprine who was referred to our department with a diagnosis of central serous chorioretinopathy. Serological tests, the Mantoux skin test, complete ophthalmologic examination, ocular fundus photography, fundus fluorescein angiography, and SD-OCT scans were performed. The ophthalmological inflammatory pattern and serological investigations provided an early diagnosis of ocular tuberculosis. Systemic ATT led to significant improvement and resolution of the ocular inflammation. SD-OCT was a useful non-contact imaging technique in the follow-up of tubercular choroiditis. The excellent response to systemic ATT confirmed the clinical diagnosis. This is an unusual case of tubercular chorioretinitis with intraretinal granuloma and is the first such SD OCT description reported in the ophthalmological literature. PMID- 25813376 TI - Comparison of the current and a new RTVue OCT software version for detection of ganglion cell complex changes due to cataract surgery. AB - The purpose was to compare the current (6.3) and a novel software version (6.12) of the RTVue-100 optical coherence tomograph (RTVue OCT) for ganglion cell complex (GCC) and retinal nerve fibre layer thickness (RNFLT) changes after phacoemulsification in healthy cataract eyes, and to investigate whether version 6.12, in which image segmentation is improved, provides benefits over version 6.3 for RNFLT and GCC imaging via mild cataract. One eye of 22 consecutive healthy cataract patients were imaged before and 1 month after uncomplicated cataract surgery using RTVue-100 OCT software version 6.3. The images were analysed with both software versions. Signal strength index increased significantly after surgery for both RNFLT and the GCC measurements (p <= 0.0015). No difference was seen for any RNFLT parameter between the software versions and time points (p >= 0.0140). The GCC values did not differ between the versions either before or after surgery (p >= 0.4471), but all increased significantly after surgery with software version 6.12 (p < 0.0001). Neither focal loss volume (FLV) nor global loss volume (GLV) differed between the software versions before and after surgery, respectively, but GLV decreased (improved) significantly after surgery (p = 0.010 and <0.001 for versions 6.3 and 6.12, respectively). Cataract surgery induced similar changes with both software versions, but version 6.12 identified the increase of GCC thickness and the decrease of GLV better than the current version. Although no significant difference between software versions was seen before surgery, our results suggest that version 6.12 may be more precise in measuring GCC parameters than the currently available version. PMID- 25813377 TI - Long-term heavy silicone oil intraocular tamponade. AB - Heavy silicone oil tamponade is intended to be temporary, but may occasionally be indefinite in patients who refuse, or are deemed unsuitable for, further surgery. The aim of this study is to compare the outcomes of patients with temporary versus indefinite heavy silicone oil intraocular tamponade. This retrospective, comparative case series identified 75 patients who underwent heavy silicone oil instillation (Oxane HD) over a 6 year period (2006-2012) in one institution. Thirty-nine patients had temporary heavy oil tamponade and 36 patients had indefinite tamponade. The majority (68 %) of patients had a history of previous vitreoretinal surgery prior to oil instillation and 66.7 % had pre-existing proliferative vitreoretinopathy (PVR). The mean final logMAR best corrected visual acuity (BCVA) was significantly better in the temporary tamponade group (1.34 +/- 0.66) than the indefinite tamponade group 1.82 +/- 0.64 (p = 0.003). Ambulatory BCVA (>= 4/200) was retained in 76.3 % of temporary tamponade patients versus 54.3 % of indefinite tamponade patients (p = 0.093). Successful retinal reattachment was significantly more likely in temporary tamponade patients (92.3 %) than indefinite tamponade patients (75 %; p = 0.04). Complications in the patients with indefinite heavy silicone oil tamponade included redetachment (38.9 %), corneal pathology (13.8 %), secondary glaucoma (11.1 %) and anterior segment emulsification (8.3 %).While temporary tamponade patients had better outcomes than those with indefinite tamponade, the majority of indefinite tamponade patients still retained ambulatory vision in the affected eye. Indefinite heavy silicone oil tamponade remains a viable option for those who cannot undergo removal of oil surgery. PMID- 25813378 TI - Label-free Quantitative Proteomics Reveals a Role for the Mycobacterium tuberculosis SecA2 Pathway in Exporting Solute Binding Proteins and Mce Transporters to the Cell Wall. AB - Mycobacterium tuberculosis is an example of a bacterial pathogen with a specialized SecA2-dependent protein export system that contributes to its virulence. Our understanding of the mechanistic basis of SecA2-dependent export and the role(s) of the SecA2 pathway in M. tuberculosis pathogenesis has been hindered by our limited knowledge of the proteins exported by the pathway. Here, we set out to identify M. tuberculosis proteins that use the SecA2 pathway for their export from the bacterial cytoplasm to the cell wall. Using label-free quantitative proteomics involving spectral counting, we compared the cell wall and cytoplasmic proteomes of wild type M. tuberculosis to that of a DeltasecA2 mutant. This work revealed a role for the M. tuberculosis SecA2 pathway in the cell wall localization of solute binding proteins that work with ABC transporters to import solutes. Another discovery was a profound effect of SecA2 on the cell wall localization of the Mce1 and Mce4 lipid transporters, which contribute to M. tuberculosis virulence. In addition to the effects on solute binding proteins and Mce transporter export, our label-free quantitative analysis revealed an unexpected relationship between SecA2 and the hypoxia-induced DosR regulon, which is associated with M. tuberculosis latency. Nearly half of the transcriptionally controlled DosR regulon of cytoplasmic proteins were detected at higher levels in the DeltasecA2 mutant versus wild type M. tuberculosis. By increasing the list of M. tuberculosis proteins known to be affected by the SecA2 pathway, this study expands our appreciation of the types of proteins exported by this pathway and guides our understanding of the mechanism of SecA2-dependent protein export in mycobacteria. At the same time, the newly identified SecA2-dependent proteins are helpful for understanding the significance of this pathway to M. tuberculosis virulence and physiology. PMID- 25813379 TI - Immunocapture-Selected Reaction Monitoring Screening Facilitates the Development of ELISA for the Measurement of Native TEX101 in Biological Fluids. AB - Monoclonal antibodies that bind the native conformation of proteins are indispensable reagents for the development of immunoassays, production of therapeutic antibodies and delineating protein interaction networks by affinity purification-mass spectrometry. Antibodies generated against short peptides, protein fragments, or even full length recombinant proteins may not bind the native protein form in biological fluids, thus limiting their utility. Here, we report the application of immunocapture coupled with selected reaction monitoring measurements (immunocapture-SRM), in the rapid screening of hybridoma culture supernatants for monoclonal antibodies that bind the native protein conformation. We produced mouse monoclonal antibodies, which detect in human serum or seminal plasma the native form of the human testis-expressed sequence 101 (TEX101) protein-a recently proposed biomarker of male infertility. Pairing of two monoclonal antibodies against unique TEX101 epitopes led to the development of an ELISA for the measurement of TEX101 in seminal plasma (limit of detection: 20 pg/ml) and serum (limit of detection: 40 pg/ml). Measurements of matched seminal plasma samples, obtained from men pre- and post-vasectomy, confirmed the absolute diagnostic specificity and sensitivity of TEX101 for noninvasive identification of physical obstructions in the male reproductive tract. Measurement of male and female serum samples revealed undetectable levels of TEX101 in the systemic circulation of healthy individuals. Immunocapture-SRM screening may facilitate development of monoclonal antibodies and immunoassays against native forms of challenging protein targets. PMID- 25813381 TI - Solvent-based extraction optimisation for efficient ultrasonication-assisted ginsenoside recovery from Panax quinquefolius and P. sikkimensis cell suspension lines. AB - The present study aims at developing an extraction protocol for efficient ginsenoside recovery from cell suspensions of Panax quinquefolius and P. sikkimensis. Methanol (100%, 70% and 30%), water (40 degrees C, 90 degrees C), water-saturated butanol and butanol-saturated water were compared for their ultrasonication-assisted ginsenoside retrieval efficacy. HPLC and HP-TLC analysis revealed 100% methanol as the best solvent for maximum retrieval of Rb (diol) and Rg (triol) ginsenosides (P. quinquefolius: Rb: 0.189, Rg: 3.163 mg/g DW; P. sikkimensis: Rb: 0.245, Rg: 4.073 mg/g DW), followed by water (90 degrees C). Methanolic solutions, especially 70%, proved to be significant retrievers of Rg1 (1.812 and 1.327 mg/g DW in P. quinquefolius and P. sikkimensis), with poor Re recovery (0.328 and 0.342 mg/g DW). Water-saturated butanol also led to significant ginsenoside extraction (72.4% of content extracted by methanol), selectively in P. quinquefolius, with a less than 50% of total content extracted by methanol, in P. sikkimensis. PMID- 25813382 TI - The Male Genital Examination: Overcoming Barriers to Prevent Missed Diagnoses. PMID- 25813380 TI - Probing the O-glycoproteome of gastric cancer cell lines for biomarker discovery. AB - Circulating O-glycoproteins shed from cancer cells represent important serum biomarkers for diagnostic and prognostic purposes. We have recently shown that selective detection of cancer-associated aberrant glycoforms of circulating O glycoprotein biomarkers can increase specificity of cancer biomarker assays. However, the current knowledge of secreted and circulating O-glycoproteins is limited. Here, we used the COSMC KO "SimpleCell" (SC) strategy to characterize the O-glycoproteome of two gastric cancer SimpleCell lines (AGS, MKN45) as well as a gastric cell line (KATO III) which naturally expresses at least partially truncated O-glycans. Overall, we identified 499 O-glycoproteins and 1236 O glycosites in gastric cancer SimpleCells, and a total 47 O-glycoproteins and 73 O glycosites in the KATO III cell line. We next modified the glycoproteomic strategy to apply it to pools of sera from gastric cancer and healthy individuals to identify circulating O-glycoproteins with the STn glycoform. We identified 37 O-glycoproteins in the pool of cancer sera, and only nine of these were also found in sera from healthy individuals. Two identified candidate O-glycoprotein biomarkers (CD44 and GalNAc-T5) circulating with the STn glycoform were further validated as being expressed in gastric cancer tissue. A proximity ligation assay was used to show that CD44 was expressed with the STn glycoform in gastric cancer tissues. The study provides a discovery strategy for aberrantly glycosylated O glycoproteins and a set of O-glycoprotein candidates with biomarker potential in gastric cancer. PMID- 25813383 TI - Physicians' Lack of Adherence to National Heart, Lung, and Blood Institute Guidelines for Pediatric Lipid Screening. AB - OBJECTIVES: To determine adherence to the 2011 National Heart, Lung, and Blood Institute lipid screening guidelines and identify patient factors promoting screening. METHODS: Records of children who received well-child care at age 11 years and turned 12 in 2013 were reviewed. Subjects were stratified by guideline defined dyslipidemia risk based on documented medical or family history risk factors. We defined adherence as the order of a lipid profile when age 11 years or completed lipid screening at 9 to 10 years. RESULTS: Of 298 subjects, 42% were assigned to the dyslipidemia high-risk subgroup. Records of 27.2% demonstrated adherence. Fifty-six percent of high-risk subjects versus 6% of their non-high risk counterparts received lipid screening by age 12 (P < .001). Among screened subjects, history of obesity and parental history of dyslipidemia were significantly associated with lipid testing. CONCLUSIONS: Lipid screening rates were low. Strategies to increase lipid screening in the primary care setting are needed. PMID- 25813384 TI - Russian Adoption: A Case Study With Mixed Clinical Presentation. PMID- 25813385 TI - Asymptomatic Mycoplasma Infection Causing Acute Demyelinating Encephalomyelitis: Case Report and Review of Literature. PMID- 25813387 TI - Acoustic analysis of overnight consecutive snoring sounds by sound pressure levels. AB - CONCLUSION: The sound pressure level (SPL) parameters, especially the A-weighted equivalent sound level (LAeq) and accumulative percentile sound level 10 (L10), were significantly different between simple snoring (SS) and obstructive sleep apnea-hypopnea syndrome (OSAHS). The apnea-hypopnea index (AHI) was the most significant factor to affect the SPLs of snoring sounds. LAeq and L10 were valuable acoustic characters of snoring which could reflect the severity of sleep disordered breathing in clinic. OBJECTIVES: Due to the limitation of acoustic analysis of single snoring sound for snorers, this study analyzed characteristics of consecutive snoring sounds overnight by the SPLs in patients of SS and OSAHS. METHOD: Ninety-four patients who underwent simultaneous SPL recording and polysomnography (PSG) were included in this study. Parameters of SPL such as LAeq, peak sound level (Lpeak), L10, L50, and L90 were analyzed. The correlation between these parameters and PSG results was also analyzed. RESULTS: The LAeq and L10 in OSAHS patients were significantly different from patients with SS. The body mass index (BMI) was positively correlated to LAeq and L10. Among various factors of PSG data and demographic factors, the SPLs were mostly affected by the AHI and the lowest oxygen saturation (LSaO2). PMID- 25813386 TI - In Vitro Repair of Meniscal Radial Tear Using Aligned Electrospun Nanofibrous Scaffold. AB - Radial tears of the meniscus represent one of the most common injuries of the knee, and result in loss of biomechanical meniscal function. However, there have been no established, effective treatments for radial meniscal tears. Nanofibrous materials produced by electrospinning have shown high promise in the engineering of soft musculoskeletal tissues. The goal of our study is to apply these technologies to develop a functional cell-seeded scaffold as a potential, new surgical method to enhance meniscal radial repair. Cylinder-shaped explants were excised from the inner avascular region of bovine meniscus and a radial tear was created in the center of the explant. The torn site was wrapped with either nanofibrous scaffold alone or scaffold seeded with meniscal fibrochondrocytes (MFC). A control group was prepared as explants without scaffolds or cells. The composite constructs in each group were cultured in vitro for 4 and 8 weeks, and these were then assessed histologically and mechanically. Histological analysis showed partial repair of the radial tear was observed with adherence between scaffold and native meniscal tissue in either the scaffold alone or cell-seeded scaffold group. Only the cell-seeded scaffold exhibited significant positive Picrosirius red staining and Safranin O staining. Mechanical testing of the repaired meniscus showed that the load-to-failure and stiffness values were significantly improved in the cell-seeded group. These results demonstrated the applicability of the MFC-seeded nanofibrous scaffold for meniscal radial tear repair based on both histological and mechanical analyses. In particular, the highly adhesive property of the cell-seeded scaffold to the meniscal tissue should be beneficial in helping to preserve the meniscal function by stabilizing meniscal fibers. PMID- 25813388 TI - Alternative splicing modulates Kv channel clustering through a molecular ball and chain mechanism. AB - Ion channel clustering at the post-synaptic density serves a fundamental role in action potential generation and transmission. Here, we show that interaction between the Shaker Kv channel and the PSD-95 scaffold protein underlying channel clustering is modulated by the length of the intrinsically disordered C terminal channel tail. We further show that this tail functions as an entropic clock that times PSD-95 binding. We thus propose a 'ball and chain' mechanism to explain Kv channel binding to scaffold proteins, analogous to the mechanism describing channel fast inactivation. The physiological relevance of this mechanism is demonstrated in that alternative splicing of the Shaker channel gene to produce variants of distinct tail lengths resulted in differential channel cell surface expression levels and clustering metrics that correlate with differences in affinity of the variants for PSD-95. We suggest that modulating channel clustering by specific spatial-temporal spliced variant targeting serves a fundamental role in nervous system development and tuning. PMID- 25813389 TI - Therapeutic prospects for migraine: can paradise be regained? AB - Migraine is a common, complex brain disorder whose biology is becoming better understood. Despite being the most disabling of the neurological disorders on a worldwide basis, headache disorders broadly, and migraine in particular, have poor research funding and a limited academic base. Given a modicum of investment, new targets, such as calcitonin gene-related peptide-based mechanisms, and entirely novel neuromodulation approaches illustrate that much can be done to improve patient care. Genetics and neuroimaging combined with excellent clinical phenotyping and translational neuroscience approaches are set to transform life for a cohort of patients with these common brain disorders. PMID- 25813390 TI - Peripheral Cardiopulmonary Bypass under Local Anaesthesia for Tracheal Tumour Resection. AB - A 63 year-old female was diagnosed with an adenoid cystic carcinoma causing near total tracheal lumen obstruction. The tumour was successfully resected using cardiopulmonary bypass via femoral vessels under local anaesthetic before induction to secure the airway and facilitate the operation. PMID- 25813391 TI - Abamectin resistance in strains of vegetable leafminer, Liriomyza sativae (Diptera: Agromyzidae) is linked to elevated glutathione S-transferase activity. AB - Abamectin resistance was selected in the vegetable leafminer, Liriomyza sativae (Blanchard) (Diptera: Agromyzidae) under laboratory conditions, and cross resistance patterns and possible resistance mechanisms in the abamectin-resistant strains (AL-R, AF-R) were investigated. Compared with the susceptible strain (SS), strain AL-R displayed 39-fold resistance to abamectin after 20 selection cycles during 25 generations, and strain AF-R exhibited 59-fold resistance to abamectin after 16 selection cycles during 22 generations. No cross-resistance to cyromazine was found in both abamectin-resistant strains. However, we failed to select for cyromazine resistance in L. sativae under laboratory conditions by conducting 17 selection cycles during 22 generations. However, moderate levels of cross-resistance to abamectin (6-9 fold) were observed in strains which received cyromazine treatments. Biochemical analysis showed that glutathione S-transferase (GST) activity in both abamectin-resistant strains (AL-R, AF-R) was significantly higher than in the susceptible strain (SS), suggesting metabolically driven resistance to abamectinin L. sativae. Recommendations of mixtures or rotation of cyromazine and abamectin should be considered carefully, as consecutive cyromazine treatments may select for low-level cross-resistance to abamectin. PMID- 25813392 TI - Different profiles of notch signaling in cigarette smoke-induced pulmonary emphysema and bleomycin-induced pulmonary fibrosis. AB - OBJECTIVE: Different profiles of Notch signaling mediate naive T cell differentiation which might be involved in pulmonary emphysema and fibrosis. METHODS: C57BL/6 mice were randomized into cigarette smoke (CS) exposure, bleomycin (BLM) exposure, and two separate groups of control for sham exposure to CS or BLM. The paratracheal lymph nodes of the animals were analyzed by real-time PCR and immunohistochemistry. Morphometry of the lung parenchyma, measurement of the cytokines, and cytometry of the bronchoalveolar lavage fluid (BALF) were also done accordingly. RESULTS: In comparison with controls, all Notch receptors and ligands were upregulated by chronic CS exposure, especially Notch3 and DLL1 (P < 0.01), and this was in line with emphysema-like morphology and Th1-biased inflammation. While Notch3 and DLL1 were downregulated by BLM exposure (P < 0.01), those was in line with fibrotic lung remodeling and Th2 polarization. CONCLUSIONS: This founding implies that the CS exposure but not the BLM exposure is capable of initiating Notch signaling in lymphoid tissue of the lung, which is likely relevant to the pathogenesis of pulmonary emphysema. Unable to initiate the Th1 response or inhibit it may lead to Th2 polarization and aberrant repair. PMID- 25813393 TI - The aerobic activity of metronidazole against anaerobic bacteria. AB - Recently, the aerobic growth of strictly anaerobic bacteria was demonstrated using antioxidants. Metronidazole is frequently used to treat infections caused by anaerobic bacteria; however, to date its antibacterial activity was only tested in anaerobic conditions. Here we aerobically tested using antioxidants the in vitro activities of metronidazole, gentamicin, doxycycline and imipenem against 10 common anaerobic and aerobic bacteria. In vitro susceptibility testing was performed by the disk diffusion method, and minimum inhibitory concentrations (MICs) were determined by Etest. Aerobic culture of the bacteria was performed at 37 degrees C using Schaedler agar medium supplemented with 1mg/mL ascorbic acid and 0.1mg/mL glutathione; the pH was adjusted to 7.2 by 10M KOH. Growth of anaerobic bacteria cultured aerobically using antioxidants was inhibited by metronidazole after 72h of incubation at 37 degrees C, with a mean inhibition diameter of 37.76mm and an MIC of 1MUg/mL; however, strains remained non sensitive to gentamicin. No growth inhibition of aerobic bacteria was observed after 24h of incubation at 37 degrees C with metronidazole; however, inhibition was observed with doxycycline and imipenem used as controls. These results indicate that bacterial sensitivity to metronidazole is not related to the oxygen tension but is a result of the sensitivity of the micro-organism. In future, both culture and antibiotic susceptibility testing of strictly anaerobic bacteria will be performed in an aerobic atmosphere using antioxidants in clinical microbiology laboratories. PMID- 25813394 TI - Use of Monte Carlo simulation to evaluate the development of vancomycin resistance in meticillin-resistant Staphylococcus aureus. AB - Monte Carlo simulations were performed for various vancomycin dosage regimens to evaluate the potential for development of vancomycin resistance in meticillin resistant Staphylococcus aureus (MRSA). When the target of free AUC(24)/MIC>=200 was considered (where AUC(24) is the area under the drug concentration-time curve in a 24-h interval and MIC is the minimum inhibitory concentration), a standard dose regimen (1000 mg every 12 h) yielded unacceptable simulated outcomes in patients with normal renal function; in particular, the probability of target attainment (PTA) was only 30.5% at an MIC of 1mg/L. For the same dosage regimens and the mutant prevention concentration (MPC)-based pharmacokinetic target (total AUC(24)/MPC>15), the cumulative fraction of response exceeded 80% for all renal function strata; low values of PTA (<80%) were obtained only for isolates with MPCs of >=22.4 mg/L, which consisted of all 21 strains of heterogeneous vancomycin-intermediate S. aureus (hVISA) and a handful of non-hVISA strains with MICs of 2mg/L (32%; 16/50). Based on the current status of vancomycin resistance, we conclude that total AUC(24)/MPC>15, derived from in vivo experiments, is more suitable to predict the development of vancomycin resistance. In clinical practice, individualised vancomycin therapy should be considered to minimise selection of resistance mutations. PMID- 25813395 TI - Effect of dexamethasone on the efficacy of daptomycin in the therapy of experimental pneumococcal meningitis. AB - This study aimed to determine the effect of dexamethasone in combination with low dose or high-dose daptomycin for the treatment of penicillin- and cephalosporin resistant pneumococcal meningitis. Efficacy (DeltaCFU/mL) and cerebrospinal fluid (CSF) levels of daptomycin at 15mg/kg and 25mg/kg were studied in a rabbit model of pneumococcal meningitis, comparing them with the same doses in combination with dexamethasone at 0.125mg/kg every 12h over a 26-h period against two different Streptococcus pneumoniae strains, HUB 2349 and ATCC 51916 with daptomycin minimum inhibitory concentrations (MICs) of 0.09mg/L and 0.19mg/L, respectively. Daptomycin levels in CSF were lower when dexamethasone was given concurrently. Against strain HUB 2349, therapeutic failure occurred with daptomycin 15mg/kg+dexamethasone; daptomycin 25mg/kg+dexamethasone was better at reducing bacterial counts than the lower dose throughout treatment. Against the highly cephalosporin-resistant ATCC 51916 strain, daptomycin 15mg/kg+dexamethasone achieved a lower bacterial decrease than daptomycin 15mg/kg alone, and therapeutic failure at 24h occurred in the daptomycin 15mg/kg+dexamethasone group. Addition of dexamethasone to a 25mg/kg daptomycin dose did not affect the efficacy of daptomycin: it remained bactericidal throughout treatment. In conclusion, against the studied strains, low-dose (15mg/kg/day) daptomycin is affected by concomitant use of dexamethasone: CSF levels are reduced and its bacterial efficacy is affected. At a higher daptomycin dose (25mg/kg/day), however, the use of dexamethasone does not alter efficacy; the combination appears to be a good choice for the treatment of pneumococcal meningitis. PMID- 25813396 TI - Predictive of the quantum capacitance effect on the excitation of plasma waves in graphene transistors with scaling limit. AB - Plasma waves in graphene field-effect transistors (FETs) and nano-patterned graphene sheets have emerged as very promising candidates for potential terahertz and infrared applications in myriad areas including remote sensing, biomedical science, military, and many other fields with their electrical tunability and strong interaction with light. In this work, we study the excitations and propagation properties of plasma waves in nanometric graphene FETs down to the scaling limit. Due to the quantum-capacitance effect, the plasma wave exhibits strong correlation with the distribution of density of states (DOS). It is indicated that the electrically tunable plasma resonance has a power-dependent V0.8 TG relation on the gate voltage, which originates from the linear dependence of density of states (DOS) on the energy in pristine graphene, in striking difference to those dominated by classical capacitance with only V0.5 TG dependence. The results of different transistor sizes indicate the potential application of nanometric graphene FETs in highly-efficient electro-optic modulation or detection of terahertz or infrared radiation. In addition, we highlight the perspectives of plasma resonance excitation in probing the many body interaction and quantum matter state in strong correlation electron systems. This study reveals the key feature of plasma waves in decorated/nanometric graphene FETs, and paves the way to tailor plasma band-engineering and expand its application in both terahertz and mid-infrared regions. PMID- 25813397 TI - Vitamin D/VDR signaling pathway ameliorates 2,4,6-trinitrobenzene sulfonic acid induced colitis by inhibiting intestinal epithelial apoptosis. AB - Increasing epidemiological data have suggested a link between vitamin D deficiency and the incidence of inflammatory bowel disease (IBD). In the present study, we confirmed that vitamin D deficiency, as well as the decreased local expression of vitamin D receptor (VDR), was prevalent in an IBD cohort. The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD. Based on the established inhibitory effects of the vitamin D/VDR pathway on IEC apoptosis, we treated mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with paricalcitol, a vitamin D analog, in order to investigate the mechanisms responsible for the inhibitory effects of the vitamin D/VDR pathway. We observed that following treatment with vitamin D, the mice presented with only minor bodyweight loss, and the mice also showed improved histological scores and decreased intestinal epithelial permeability compared with the vehicle-treated group. The colonic mRNA expression of inflammatory cytokines and chemokines was markedly suppressed, indicating less severe colitis in the vitamin D-treated mice. Subsequently, we investigated p53 upregulated modulator of apoptosis (PUMA) and p53, two major independent pathways of apoptosis, as well as caspase-3. We found that the vitamin D-treated mice had lower expression levels of caspase-3 than the vehicle-treated mice. PUMA expression showed the same tendency; however, the p53 protein level was not altered. The present study indicates that vitamin D attenuates the development of TNBS-induced colitis by inhibiting the apoptosis of IECs. The mechanisms involved include the downregulation of PUMA expression. Our data provide experimental support for the clinical trials of vitamin D intervention in patients with IBD. PMID- 25813398 TI - Oncogene ATAD2 promotes cell proliferation, invasion and migration in cervical cancer. AB - The ATPase family AAA domain-containing protein 2 (ATAD2) is associated with many cellular processes, such as cell proliferation, invasion and migration. However, the molecular biological function of the ATAD2 gene in cervical cancer is unclear. The purpose of this study was to explore ATAD2 expression in cervical cancer, evaluate the relationship between the development of cervical cancer, metastasis and clinicopathological characteristics, and discuss the implications for its use in clinical treatment. Protein and mRNA expression of ATAD2 was examined in tissues and cell lines. Tumor tissues from 135 cases of cervical cancer were collected for evaluation of ATAD2 expression by immunohistochemistry and western blotting. Prognostic significance was evaluated by the Cox hazards model and Kaplan-Meier survival method. HeLa and SiHa cells were transfected with two siRNAs targeting ATAD2. ATAD2 knockdown was used to analyze cell proliferation, invasion and migration. Cell viability was evaluated with the Cell Counting Kappait-8 (CCK-8) assay, cell invasion by a Transwell assay and cell migration by a wound healing/scratch migration assay. ATAD2 was shown to be highly expressed in cervical cancer tissues, both at the transcriptional and protein levels, and was correlated with poor patient survival (P<0.05). Knockdown of ATAD2 in the HeLa and SiHa cells was found to reduce the capacity for invasion and migration (P<0.05), and inhibited the growth and clonogenic potential of the HeLa and SiHa cell lines. Our results suggest that cervical cancer tissues may have highly expressed ATAD2, which is associated with tumor stage and lymph node status (P<0.05). Oncogene ATAD2 may play an important role in cervical cancer proliferation, invasion and migration. It could serve as a prognostic marker and a therapeutic target for cervical cancer. PMID- 25813400 TI - Feline idiopathic cystitis. AB - While FIC remains a diagnosis of exclusion, studies over the last two decades suggest that it results from complex interactions between the urinary bladder, neuroendocrine system and environmental factors, and stress appears to play a role in the pathogenesis. The self-limiting nature of FIC and importance of environmental factors on recurrence of clinical signs emphasize the need for controlled, prospective, double-blinded clinical studies to determine the best management options. Current best evidence for initial management of acute, non obstructive FIC supports a specific nutritional recommendation for a therapeutic urinary food proven to reduce recurrent episodes, environmental enrichment and feeding moist food. PMID- 25813401 TI - Diagnostic imaging of lower urinary tract disease. AB - Diagnostic imaging is routinely performed in small animals with lower urinary tract disease. Survey radiographs allow identification of radiopaque calculi, gas within the urinary tract, and lymph node or bone metastases. Cystography and urethrography remain useful in the evaluation of bladder or urethral rupture, abnormal communication with other organs, and lesions of the pelvic or penile urethra. Ultrasonography is the modality of choice for the diagnosis of most disorders. Computed tomography and magnetic resonance imaging are useful in evaluating the ureterovesical junction and intrapelvic lesions, monitoring the size of lesions, and evaluating lymph nodes and osseous structures for metastases. PMID- 25813402 TI - Avoiding readmissions-support systems required after discharge to continue rapid recovery? AB - Increasing participation in alternative payment models such as episode-of-care has become a driving force to improve outcomes while decreasing cost. Reducing the hospital length of stay and discharging patients to home have been shown to decrease readmissions, thereby achieving these goals. The purpose of this study was to determine if utilization of a patient management support system, TAVHealthTM in our clinical pathway would reduce our readmission rates during the episode-of-care. We retrospectively reviewed 1874 total joint arthroplasties, 1281 TJAs in the pre-TAVHealthTM group (2009-2012) and 593 TJRs in the post TAVHealthTM group (2013-2014). Despite a low length of stay (1.2days) there was a significant reduction in readmissions from 205 (16.0%) to 54 (9.2%) with incorporation of this patient management support system into our clinical pathway. PMID- 25813403 TI - Wnt/beta-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion. AB - Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR 183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients. PMID- 25813404 TI - Novel ALK fusion partners in lung cancer. AB - Detection of ALK rearrangements in patients with non-small cell lung cancer (NSCLC) presents a significant technical challenge due to the existence of multiple translocation partners and break-points. To improve the performance of PCR-based tests, we utilized the combination of 2 assays, i.e. the variant specific PCR for the 5 most common ALK rearrangements and the test for unbalanced 5'/3'-end ALK expression. Overall, convincing evidence for the presence of ALK translocation was obtained for 34/400 (8.5%) cases, including 14 EML4ex13/ALKex20, 12 EML4ex6/ALKex20, 3 EML4ex18/ALKex20, 2 EML4ex20/ALKex20 variants and 3 tumors with novel translocation partners. 386 (96.5%) out of 400 EGFR mutation-negative NSCLCs were concordant for both tests, being either positive (n = 26) or negative (n = 360) for ALK translocation; 49 of these samples (6 ALK+, 43 ALK-) were further evaluated by FISH, and there were no instances of disagreement. Among the 14 (3.5%) "discordant" tumors, 5 demonstrated ALK translocation by the first but not by the second PCR assay, and 9 had unbalanced ALK expression in the absence of known ALK fusion variants. 5 samples from the latter group were subjected to FISH, and the presence of translocation was confirmed in 2 cases. Next generation sequencing analysis of these 2 samples identified novel translocation partners, DCTN1 and SQSTM1; furthermore, the DCTN1/ALK fusion was also found in another NSCLC sample with unbalanced 5'/3'-end ALK expression, indicating a recurrent nature of this translocation. We conclude that the combination of 2 different PCR tests is a viable approach for the diagnostics of ALK rearrangements. Systematic typing of ALK fusions is likely to reveal new NSCLC-specific ALK partners. PMID- 25813405 TI - CRNDE, a long-noncoding RNA, promotes glioma cell growth and invasion through mTOR signaling. AB - The transcripts of the gene Colorectal Neoplasia Differentially Expressed (CRNDE) are recognized as long-noncoding RNAs (lncRNAs), which are expressed in specific regions within the human brain, and are the most upregulated lncRNA in gliomas. However, the underlying regulation and function of CRNDE in gliomas are largely unknown. In this study, the upregulation of CRNDE was confirmed in both primary specimens from glioma patients and in vitro with cell lines. Overexpression of specific CRNDE transcript promotes cell growth and migration in vitro while knockdown of CRNDE expression manifests a repressive function during these cellular processes. The growth promoting effect of CRNDE was also demonstrated in a xenograft mouse model. Mechanistic studies further revealed that histone acetylation in the promoter region might account for the upregulation of CRNDE, and the level of CRNDE expression could be modulated by mammalian Target of Rapamycin (mTOR) signaling in glioma. Thus, our results shed a light on utilizing CRNDE as a potential novel therapeutic target for the treatment of glioma. PMID- 25813399 TI - Global migration of influenza A viruses in swine. AB - The complex and unresolved evolutionary origins of the 2009 H1N1 influenza pandemic exposed major gaps in our knowledge of the global spatial ecology and evolution of influenza A viruses in swine (swIAVs). Here we undertake an expansive phylogenetic analysis of swIAV sequence data and demonstrate that the global live swine trade strongly predicts the spatial dissemination of swIAVs, with Europe and North America acting as sources of viruses in Asian countries. In contrast, China has the world's largest swine population but is not a major exporter of live swine, and is not an important source of swIAVs in neighbouring Asian countries or globally. A meta-population simulation model incorporating trade data predicts that the global ecology of swIAVs is more complex than previously thought, and the United States and China's large swine populations are unlikely to be representative of swIAV diversity in their respective geographic regions, requiring independent surveillance efforts throughout Latin America and Asia. PMID- 25813406 TI - 17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation. AB - Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the stability of many client proteins, including androgen receptor (AR) and survivin, making Hsp90 an attractive molecular therapeutic target for prostate cancer. Several Hsp90 inhibitors have shown antitumor activity in various preclinical models and in clinical trials. Geldanamycin is a well-known inhibitor of Hsp90, but its associated liver toxicity limited its clinical development. Here, we report a highly effective and low-hepatotoxic geldanamycin derivative that exhibits antitumor activity against human prostate cancer cells. Treatment of cells with 17-DMCHAG (17-(6-(3,4-dimethoxycinnamamido)hexylamino)-17-demethoxy-geldanamycin) dose-dependently suppressed the proliferation, reduced colony formation and induced apoptosis of human prostate cancer cell lines. 17-DMCHAG exhibits anti invasive and anti-migratory activities in prostate cancer cells through down regulating of transcription factors Zeb1, Snail1, Slug, and mesenchymal marker Vimentin, while up-regulating the epithelial marker of E-cadherin. Furthermore, 17-DMCHAG treatment damaged the Hsp90/AR and Hsp90/survivin complexes and induced the proteasome-dependent degradation of AR and survivin, then inhibited the activity of these two proteins. In vivo, we observed that 17-DMCHAG showed strong antitumor effects in LNCaP and DU-145 cell-xenografted nude mice. Thus, 17-DMCHAG is a potential treatment for prostate cancer. PMID- 25813408 TI - Preparation of anion-exchangeable polymer vesicles through the self-assembly of hyperbranched polymeric ionic liquids. AB - This work reports the self-assembly of anion-exchangeable vesicles from an amphiphilic hyperbranched polymeric ionic liquid (HBPIL). By a simple one-step anion exchange with methyl orange, the obtained HBPILs could self-assemble into pH-indicative and colorful vesicles in water with color changes directly visible to the naked eye in response to solution pH. In addition, by another step of anion exchange with bovine serum albumin (BSA), the BSA-coated vesicles could also be readily prepared. PMID- 25813407 TI - Vascular actions of 20-HETE. AB - 20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid that exhibits a myriad of biological effects in the vascular system. This review discusses the current knowledge related to the effects of 20-HETE on vascular reactivity, activation, and remodeling, as well as its role in vascular inflammation and angiogenesis. The information explaining how 20-HETE and the renin-angiotensin system interact to promote hypertension, vasoconstriction, and vascular dysfunction is summarized in this article. 20-HETE enhances vascular inflammation and injury in models of diabetes, ischemia/reperfusion, and cerebrovascular oxidative stress. Recent studies also established a role for 20 HETE in normal and pathological angiogenesis conditions. This review will also discuss the molecular mechanisms through which 20-HETE induces these vascular actions. Potential additional studies are suggested to address shortcomings in the current knowledge of 20-HETE in the vascular system. PMID- 25813409 TI - How Well Is CHIP Addressing Oral Health Care Needs and Access for Children? AB - OBJECTIVE: We examine how access to and use of oral and dental care under the Children's Health Insurance Program (CHIP) compared to private coverage and being uninsured in 10 states. METHODS: We report on findings drawn from a 2012 survey of CHIP enrollees in 10 states. We examined a range of parent-reported dental care access and use measures among CHIP enrollees. Comparisons of the experiences of established CHIP enrollees to the experiences of newly enrolling children who had been uninsured or privately insured were used to estimate the impacts of CHIP on children's oral health and dental care. RESULTS: Most children enrolled in CHIP had a usual source of dental care and had received a dental checkup or cleaning in the past year, and most over age 6 had had sealants placed on their molars. In addition, parents of most CHIP enrollees were aware that CHIP covered dental benefits, and most reported not having trouble finding a dentist to see their child. Even so, 12% of CHIP enrollees had unmet dental care needs. Compared to being uninsured, CHIP enrollees did better across nearly all oral health measures. Compared to being privately insured, CHIP enrollees were more likely to have dental benefits, to have a usual source of dental care, and to have had a dental checkup/cleaning, but they were more likely to have trouble finding a dentist and less likely to say that their child's teeth were in excellent/very good condition. CONCLUSIONS: Enrolling eligible uninsured children in CHIP led to improvements in their access to preventive dental care, as well as reductions in their unmet dental care needs, yet the CHIP program has more work to do to address the oral health problems of children. PMID- 25813410 TI - Characterization of microRNA transcriptome in tumor, adjacent, and normal tissues of lung squamous cell carcinoma. AB - OBJECTIVES: MicroRNAs are a class of regulatory molecules involved in a wide variety of biological processes, including growth, development, and apoptosis. Given the widespread roles of microRNAs in biological processes, understanding their different expression profiles in normal, adjacent, and tumor tissues will provide insights into the consequences of aberrant expression. METHODS: With the use of next-generation deep sequencing technology, microRNA profiles in 3 pooled samples from normal, adjacent, and tumor tissues of 19 patients with lung squamous cell carcinoma were characterized comprehensively. Quantitative polymerase chain reaction was used to verify the primary findings in another 38 lung squamous cell carcinoma tumor samples. In situ hybridization also was performed for validation. RESULTS: A total of 368, 306, and 231 known microRNAs were identified from tumor, adjacent, and normal pooled samples, respectively, of which 40, 44, and 26 microRNAs displayed dysregulation with 2-fold or greater change in 3 compared groups of tumor versus normal, tumor versus adjacent, and adjacent versus normal, respectively. Sequencing data also showed that some coexpressed microRNAs displayed a pattern of progressive dysregulation. Some of the microRNAs exhibited consistent changes; among them, miR-425-5p and miR-218-5p were confirmed by quantitative polymerase chain reaction and in situ hybridization, and proved that the microRNA expression levels were closely related to tumor stages and sizes. It is suggested that some microRNAs, such as miR-425 and miR-183, might be a driver for tumor formation, growth, and progression to higher staging, whereas others, such as miR-218, might behave as a tumor suppressor in lung cancer. Functional annotation analysis indicated that the proteoglycan pathway in cancer and mitogen-activated protein kinase, Wnt, PI3K-Akt, and transforming growth factor-beta signaling pathways might be involved in the pathogenesis of lung squamous cell carcinoma. CONCLUSIONS: This study describes the use of deep sequencing for comprehensive profiling of microRNAs in lung squamous cell carcinoma. The identified microRNA signatures may provide biomarkers for early detection, subclassification, and potential therapeutic targets of lung squamous cell carcinoma. This study also provides some insights into the molecular mechanism underlying the development and progression of lung squamous cell carcinoma, which may prove helpful for early diagnosis and treatment of the disease. PMID- 25813411 TI - TWO TREATMENT APPROACHES FOR HUMAN REGULAR U-500 INSULIN IN PATIENTS WITH TYPE 2 DIABETES NOT ACHIEVING ADEQUATE GLYCEMIC CONTROL ON HIGH-DOSE U-100 INSULIN THERAPY WITH OR WITHOUT ORAL AGENTS: A RANDOMIZED, TITRATION-TO-TARGET CLINICAL TRIAL. AB - OBJECTIVE: To compare the efficacy and safety of 2 dosing regimens for human regular U-500 insulin (U-500R, 500 units/mL) replacing high-dose U-100 insulins with or without oral antihyperglycemic drugs in patients with inadequately controlled type 2 diabetes (T2D). METHODS: We conducted a 24-week, open-label, parallel trial in 325 patients (demographics [means]: age, 55.4 years; diabetes duration, 15.2 years; body mass index, 41.9 kg/m(2); glycated hemoglobin [HbA1c], 8.7%; U-100 insulin dose, 287.5 units administered in 5 injections/day [median; range, 2 to 10]). Patients were randomized to thrice-daily (TID, n = 162) or twice-daily (BID, n = 163) U-500R after a 4-week lead-in period. The primary outcome was HbA1c change from baseline. RESULTS: After 24 weeks, both treatments demonstrated significant HbA1c reductions (TID, -1.12%; BID, -1.22%; both, P<.001) and clinical equivalence (difference, -0.10%; 95% confidence interval, 0.33 to 0.12%; noninferiority margin, 0.4%). Comparable increases in total daily U-500R dose (TID, 242.7 to 343.1 units; BID, 249.0 to 335.0 units) were observed. Incidence and rate of documented symptomatic hypoglycemia (<=70 mg/dL) were lower for TID versus BID (P = .003 and P = .02, respectively); severe hypoglycemia was similar between treatments. Weight gain was similar in both groups (TID, 5.4 kg; BID, 4.9 kg). CONCLUSION: Initiation and titration of U-500R using either algorithm (TID or BID) improves glycemic control effectively and safely with fewer injections in patients with T2D treated with high-dose/high-volume U-100 insulin. These results provide clinicians with a practical framework for using U 500R in severely insulin-resistant patients with suboptimally controlled T2D. PMID- 25813412 TI - Palliative care: from medicine to surgery, from adults to children, and from calls to action to community approaches to advanced care planning. PMID- 25813413 TI - Integrating palliative care and oncology: towards a common understanding. PMID- 25813414 TI - Surgery, palliative care, and the American College of Surgeons. AB - Since the late 1990s, the American College of Surgeons (ACS) has increasingly recognized and advocated palliative care for patients and their families with serious, critical, and terminal illness under surgical care. The college has been the primary catalyst for the recognition of palliative care in the field of surgery in the U.S. and abroad, primarily through educational efforts directed at practicing surgeons and surgeons in training. Roughly 15 years ago a group of surgeons from the fellowship of the college coalesced and then spearheaded these initiatives with invaluable support and advice from leading non-surgeon pioneers of palliative care. This group is now titled, the Committee on Surgical Palliative Care (CSPC). The CSPC's mission is to incorporate the precepts and techniques of palliative care into surgical clinical practice, education, research, and advocacy. This report chronicles the contributions the ACS has made to the evolution of surgical palliative care and details the formation of its CSPC and its role in shaping surgical palliative care today. PMID- 25813415 TI - Lessons learned from New York's community approach to advance care planning and MOLAT. AB - This article reviews the lessons learned from the development and implementation of New York's community approach to advance care planning (ACP) as a wellness initiative and the key components of the complementary programs: Community Conversations on Compassionate Care (CCCC) and Medical Orders for Life-Sustaining Treatment (MOLST). Shared, informed medical decision-making is a patient-centered process that is critical to ensuring patient preferences for care are honored at the end of life. Providers must be trained, qualified, and comfortable with the discussions needed for effective shared, informed medical decision-making. Development, implementation, outcomes, lessons learned and sustainability of the CCCC and MOLST programs highlight the success of a healthcare and community collaborative initiative focused on improving care at the end of life. Community data support the value of implementing the CCCC and New York's MOLST throughout the country. PMID- 25813416 TI - Quality of care and relationships as reported by children with cancer and their parents. AB - Between 2010 and 2011, a non-probability convenience sample of 85 children and adolescents between the ages of 7 to 18 years, who were receiving treatments at the inpatient or outpatient facilities of a tertiary pediatric cancer center in Lebanon, were enrolled in the study. A total of 85 parents or significant others directly involved in the care of these children were also included. The Needs at End of Life Screening Tool (NEST) questionnaire was used to evaluate the quality of palliative care (PC) provided to the children. Parents, adolescents, and children reported high quality medical care. Children reported least satisfaction with participation in decision making, while parents were least satisfied in securing a hospital bed. Spirituality was high among all participants. Parents reported not preparing those around them for the possibility of the child's death. The study has shown that parents have moderate financial problems and encounter difficulties in getting insurance to cover expenses of child's illness. PMID- 25813417 TI - Efficacy of granisetron and aprepitant in a patient who failed ondansetron in the prophylaxis of radiation induced nausea and vomiting: a case report. AB - BACKGROUND: Radiotherapy-induced nausea and vomiting (RINV) is a toxicity that can occur in 40-80% of individuals who receive radiation treatment. Current guidelines recommend 5-hydroxytryptamine3 receptor antagonists (5-HT3 RAs) for prophylaxis of RINV for moderate and highly emetogenic radiotherapy; however, certain patients may suffer from RINV despite prophylaxis. CASE PRESENTATION: This report details the case of a 47-year-old female with extensive bony involvement to the spine from breast cancer presenting with lower back pain. CASE MANAGEMENT: To palliate her symptoms, the patient underwent a course of irradiation to the lumbar spine and was prescribed ondansetron as an antiemetic. However, the patient experienced severe nausea and emesis and was subsequently switched to granisetron and aprepitant. CASE OUTCOME: The patient completed the remainder of the radiation treatment with no further emesis and minimal nausea, representing the first documented success of granisetron and aprepitant for RINV after failure on ondansetron. CONCLUSIONS: In chemotherapy, switching 5-HT3 RAs after failure on the first is successful in preventing chemotherapy-induced nausea and vomiting (CINV), yet this has not been previously reported in radiation. In this patient, granisetron and aprepitant were successful in substantially reducing nausea and preventing further emesis, and may represent an alternative antiemetic regimen for RINV prophylaxis and salvage. PMID- 25813418 TI - A radiotherapy technique for palliative total scalp irradiation. AB - A scalp irradiation technique for palliative treatment of a squamous cell carcinoma was discussed. A patient with multiple cutaneous scalp lesions resulting in bleeding and pain was treated with a 3D conformal radiotherapy technique was performed with five 6 MV electron beams without shifting the field borders during the course of the treatment, due to the finality of the treatment (palliative intent). A reduction of planning and delivery complexity has been obtained not considering the junctioning problems. Nevertheless, the 90% of gross tumor volume (GTV) was covered by the 85% of prescription dose with a significant reduction of patient's symptoms (pain and bleeding). Our patient achieved a significant pain response and resolution of bleeding with this technique. Our study revealed that the scalp irradiation by means of electron beam without considering the junction problem is easy and effective for the palliative intent in elderly patients with squamous cell carcinoma. PMID- 25813420 TI - Heart rate variability measurement: is there a role in predicting the admission outcome of palliative cancer patients? PMID- 25813419 TI - Commentary on Masel et al. Predicting discharge of palliative care inpatients by measuring their heart rate variability. AB - The accurate determination of prognosis is a challenging and important aspect of end of life care. A more accurate prognosis provides patients and their families' time to plan and prepare for the end of life, and prioritize care based on individual goals and values. While a number of prognostic tools and indices provide insight into a patient's general prognosis, the use of heart rate variability (HRV) as a predictor of live discharge from a palliative care unit (PCU) is a unique approach to exploring non-invasive ways for more accurate prognostication. PMID- 25813421 TI - Stephen T. Lutz: palliative radiotherapy, a growing subspecialty. Interview by Nancy Q. Zhong. PMID- 25813423 TI - Homo erectus in Salkhit, Mongolia? AB - In 2006, a skullcap was discovered in Salkhit, Mongolia. The Salkhit skullcap has a mostly complete frontal, two partially complete parietals, and nasals. No chronometric dating has been published yet, and suggested dates range from early Middle Pleistocene to terminal Late Pleistocene. While no chronometric date has been published, the presence of archaic features has led to a potential affiliation with archaic hominin species. If it is indeed Homo erectus or archaic Homo sapiens, Salkhit implies a much earlier spread of hominins farther north and inland Asia than previously thought. In this paper, the nature of the archaic features in Salkhit is investigated. The Salkhit skullcap morphology and metrics were compared with Middle and Late Pleistocene hominin fossils from northeast Asia: Zhoukoudian Locality 1, Dali, and Zhoukoudian Upper Cave. Results show an interesting pattern: on one hand, the archaic features that Salkhit shares with the Zhoukoudian Locality 1 sample also are shared with other later hominins; on the other hand, Salkhit is different from the Middle Pleistocene materials in the same way later hominins differ from the Middle Pleistocene sample, in having a broader frontal and thinner supraorbital region. This may reflect encephalization and gracilization, a modernization trend found in many places. It is concluded that the archaic features observed in Salkhit are regionally predominant features rather than diagnostic features of an archaic species. PMID- 25813422 TI - Abiotic stressors and stress responses: What commonalities appear between species across biological organization levels? AB - Organisms are regularly subjected to abiotic stressors related to increasing anthropogenic activities, including chemicals and climatic changes that induce major stresses. Based on various key taxa involved in ecosystem functioning (photosynthetic microorganisms, plants, invertebrates), we review how organisms respond and adapt to chemical- and temperature-induced stresses from molecular to population level. Using field-realistic studies, our integrative analysis aims to compare i) how molecular and physiological mechanisms related to protection, repair and energy allocation can impact life history traits of stressed organisms, and ii) to what extent trait responses influence individual and population responses. Common response mechanisms are evident at molecular and cellular scales but become rather difficult to define at higher levels due to evolutionary distance and environmental complexity. We provide new insights into the understanding of the impact of molecular and cellular responses on individual and population dynamics and assess the potential related effects on communities and ecosystem functioning. PMID- 25813424 TI - Foot polydactyly and bipartite medial cuneiform: A case of co-occurrence in a Celtic skeleton from Verona (Italy). AB - We report a case of bilateral foot polydactyly and bipartite medial cuneiform in a male individual buried in a Celtic/Roman necropolis (3rd to 1st century BCE) in the city of Verona (Italy). During the construction of an underground garage in the main courtyard of the Bishop's Seminary at Verona between 2005 and 2010, archaeologists uncovered the remains of 174 individuals (108 non-adults and 66 adults). It is thought that these graves could belong to some of the first inhabitants of the urban area of Verona. The individual presented here (US 2807) is a middle-aged male (40-50 years) in a good state of preservation. His estimated stature is 1756 mm (+/- 32.1 mm). This male presents congenital anomalies in the feet and dental agenesis. We believe this to be the only known archaeological case of bilateral postaxial polydactyly with forked (Y) shape, in which both fifth metatarsals are associated with complete bipartition of the left medial cuneiform and partial bipartition of the right one. Polydactyly is fairly common in modern clinical cases but bipartite medial cuneiform is relatively rare; neither of these congenital conditions is well documented archaeologically. PMID- 25813425 TI - Evidence for prostaglandin E2 receptor expression in the intramural ganglia of the guinea pig urinary bladder. AB - Intramural ganglia are present in the bladder wall of several species including human, pig, and guinea-pig. It has been suggested that there is a network of intramural ganglia in the bladder of these species that may be part of a motor sensory system and receive afferent input. Prostaglandins (PG) have been suggested to play a role in this afferent signalling mechanism. To investigate the distribution of the prostaglandin E2 receptors EP1 and EP2 in and around intramural ganglia of the guinea pig, bladders of 6 guinea pigs were dissected, and processed for immunohistochemistry. Sections were examined for prostaglandin E2 receptor EP1- and EP2-immuno-reactivity and co-stained for vimentin, a marker for interstitial cells (IC) and cyclo-oxygenase 1 (COX I), the enzyme responsible for PG synthesis. Immunoreactivities for EP1 and EP2 were found in intramural ganglion cells. These cells were observed in between muscle bundles and on, or close to the serosal surface of the bladder. Furthermore, COX I was present in interstitial cells close to ganglion cells, indicating the possibility of a local synthesis of prostaglandins near the ganglia. The co-staining of EP1 or EP2 with vimentin showed that processes of interstitial cells run through the ganglia, often encircling or ensheathing cells. Therefore, it can be concluded that there is a close relationship between the intramural ganglia and the network of interstitial cells in the muscular layers of the bladder. EP1 and EP2 receptors are expressed on the ganglia and this arrangement suggests that intramural ganglia are involved in (pre)processing afferent information. PMID- 25813426 TI - Building bio-assays with magnetic particles on a digital microfluidic platform. AB - Digital microfluidics (DMF) has emerged as a promising liquid handling technology for a variety of applications, demonstrating great potential both in terms of miniaturization and automation. DMF is based on the manipulation of discrete, independently controllable liquid droplets, which makes it highly reconfigurable and reprogrammable. One of its most exclusive advantages, compared to microchannel-based microfluidics, is its ability to precisely handle solid nano- and microsized objects, such as magnetic particles. Magnetic particles have become very popular in the last decade, since their high surface-to-volume ratio and the possibility to magnetically separate them from the matrix make them perfect suitable as a solid support for bio-assay development. The potential of magnetic particles in DMF-based bio-assays has been demonstrated for various applications. In this review we discuss the latest developments of magnetic particle-based DMF bio-assays with the aim to present, identify and analyze the trends in the field. We also discuss the state-of-the art of device integration, current status of commercialization and issues that still need to be addressed. With this paper we intend to stimulate researchers to exploit and unveil the potential of these exciting tools, which will shape the future of modern biochemistry, microbiology and biomedical diagnostics. PMID- 25813427 TI - Assessing fibrinogen extravasation into Alzheimer's disease brain using high content screening of brain tissue microarrays. AB - BACKGROUND: Tissue microarrays are commonly used to evaluate disease pathology however methods to automate and quantify pathological changes are limited. NEW METHOD: This article demonstrates the utility of the VSlide scanner (MetaSystems) for automated image acquisition from immunolabelled tissue microarray slides, and subsequent automated image analysis with MetaXpress (Molecular Devices) software to obtain objective, efficient and reproducible data from immunolabelled tissue microarray sections. RESULTS: Significant increases in fibrinogen immunolabelling were observed in 29 Alzheimer's disease cases compared to 28 control cases analysed from a single tissue microarray slide. Western blot analysis also demonstrated significant increases in fibrinogen immunolabelling in 6 Alzheimer's cases compared to 6 control cases. The observed changes were also validated with gold standard blinded manual H-scoring. COMPARISON WITH EXISTING METHOD: VSlide Metafer software offers a 'tissue microarray acquisition' plugin for easy mapping of tissue cores with their original position on the tissue microarray map. High resolution VSlide images are compatible with MetaXpress image analysis software. This article details the coupling of these two technologies to accurately and reproducibly analyse immunolabelled tissue microarrays within minutes, compared to the gold standard method of manual counting using H-scores which is significantly slower and prone to inter-observer variation. CONCLUSIONS: Here, we couple brain tissue microarray technology with high-content screening and automated image analysis as a powerful way to address bottle necks in data generation and improve throughput, as well as sensitivity to study biological/pathological changes in brain disease. PMID- 25813428 TI - Usefulness of vessel-sealing devices for peripartum hysterectomy: a retrospective cohort study. AB - To evaluate the feasibility to perform peripartum hysterectomy (PH) with the introduction of LigaSureTM vessels-sealing device (LVSD) and how it influenced the surgical outcomes. We retrospectively evaluated procedures and outcome of women undergoing PH during the period between January 2001 and October 2013. Perioperative surgical results of patients undergoing PH using LVSD were compared to patients undergoing PH without LVSD. Forty-nine subjects had PH during the study period. Twenty (41%) hysterectomies were performed for placenta accreta, 8 (16%) for placenta previa, 21 (43%) for atony. Twenty-three subjects had PH using LVSD and 26 subjects had hysterectomy without the use of this device. We observe significant differences in estimated blood loss (p = 0.001), massive blood transfusions (>10 units RBC) (p = 0.025), operative time (p = 0.06). No difference in term of hospital stay and complications were observed (p = 0.78 and p = 0.35). One patient for each group had intraoperative complication (p = 0.9). The use of LVSD during PH does not increase operative complications, blood loss, and operative time in comparison to standard procedure. PMID- 25813430 TI - Tuning of SFOAEs Evoked by Low-Frequency Tones Is Not Compatible with Localized Emission Generation. AB - Stimulus-frequency otoacoustic emissions (SFOAEs) appear to be well suited for assessing frequency selectivity because, at least on theoretical grounds, they originate over a restricted region of the cochlea near the characteristic place of the evoking tone. In support of this view, we previously found good agreement between SFOAE suppression tuning curves (SF-STCs) and a control measure of frequency selectivity (compound action potential suppression tuning curves (CAP STC)) for frequencies above 3 kHz in chinchillas. For lower frequencies, however, SF-STCs and were over five times broader than the CAP-STCs and demonstrated more high-pass rather than narrow band-pass filter characteristics. Here, we test the hypothesis that the broad tuning of low-frequency SF-STCs is because emissions originate over a broad region of the cochlea extending basal to the characteristic place of the evoking tone. We removed contributions of the hypothesized basally located SFOAE sources by either pre-suppressing them with a high-frequency interference tone (IT; 4.2, 6.2, or 9.2 kHz at 75 dB sound pressure level (SPL)) or by inducing acoustic trauma at high frequencies (exposures to 8, 5, and lastly 3-kHz tones at 110-115 dB SPL). The 1-kHz SF-STCs and CAP-STCs were measured for baseline, IT present and following the acoustic trauma conditions in anesthetized chinchillas. The IT and acoustic trauma affected SF-STCs in an almost indistinguishable way. The SF-STCs changed progressively from a broad high-pass to narrow band-pass shape as the frequency of the IT was lowered and for subsequent exposures to lower-frequency tones. Both results were in agreement with the "basal sources" hypothesis. In contrast, CAP STCs were not changed by either manipulation, indicating that neither the IT nor acoustic trauma affected the 1-kHz characteristic place. Thus, unlike CAPs, SFOAEs cannot be considered as a place-specific measure of cochlear function at low frequencies, at least in chinchillas. PMID- 25813431 TI - [Lipofilling in breast reconstruction: is there any population with higher risk of local recurrence? Literature systematic review]. AB - Safety of the autologous fat grafting (AFG) in the breast parenchyma remains a debated topic, particularly in reconstruction following breast cancer. This procedure still raises many questions, especially considering recent in vitro studies warning about the fact that lipofilling could promote tumor recurrence through increased neoangiogenesis, or facilitate metastasis. Through a systematic literature review on oncological risk and radiological follow-up, conducted from January 2010 to August 2014, we tried to identify populations at risk of recurrence after AFG. The study selection process was adapted from the Prisma statement. Out of the seven analysed patients cohorts, i.e. approximately 1500 AFG procedures, results on the risk of local recurrence appear reassuring after an average follow-up of 42 months. These results should be cautiously interpreted because of the heterogeneity of the studies. However, recurrences have been analysed based on the characteristics of the original tumor and many of them warn about population that seem more at risk of recurrence. Studies on radiological modifications after AFG emphasize the need for the radiologists to know the importance of radiological images induced by this procedure, however, AFG does not seem to interfere with radiological screening of local recurrence. In order to deliver clear information to patients receiving breast reconstruction by lipofilling, prospective studies focused on populations that seem to be most at risk of recurrence are required. PMID- 25813432 TI - [Performance of prenatal diagnosis and postnatal development of congenital lung malformations]. AB - OBJECTIVES: For many diseases, the comparison of prenatal diagnosis with a histopathological reality is not always possible. Fetal lung pathology, with its high rate of surgery in postnatal, allows this assessment. This study proposes an approach to the reliability of prenatal diagnosis and analysis of the postnatal development of all children in care for congenital pulmonary malformation (CPM). METHODS: This is a retrospective study of all cases of CPM diagnosed in Poitiers University Hospital from 1995 to 2011. Cases diagnosed prenatally were identified and the diagnostic accuracy was studied by histology when cases had surgery. The postnatal development of prenatally diagnosed cases is described and compared to children who did not receive prenatal diagnosis. RESULTS: Among the 45 cases of CPM supported at the Poitiers University Hospital, 30 had received prenatal diagnosis of isolated CPM. The diagnostic concordance between antenatal ultrasound and the final diagnosis is kappa=0.67 (CI95% [0.38 to 0.94]). The sensitivity of ultrasound was 90% (CI95% [55-99.7]) in our series for the diagnosis of CAMP (cystic adenomatoid malformation pulmonary). We found a sonographic disappearance of lesions in 4 children, 1 child in regression, stable lesions in 21 cases. Four children showed an increase in volume of the malformation, with signs of poor tolerance in 3 cases. After birth, children who received a prenatal diagnosis were no more symptomatic than those whose diagnosis was made postnatal: 21 (70%) versus 11 (73%; P=1) respectively. Similarly, they often received prophylactic surgery: 18 (60%) versus 2 (13%) respectively (P<0.01) and less often suffered post-surgery complication: 3 (10%) versus 10 (67%) respectively (P<0.01). The number of children monitored was not significantly different in the two groups. CONCLUSION: Prenatal diagnosis allows for the precise nature of the lesion in 90% of cases in 2013 and had no impact on symptomatology at birth. When prenatal diagnosis is possible, preventive surgery probably reduces the occurrence of emergency surgery. PMID- 25813433 TI - [New approach of learning curve for robotic-assisted gynecologic oncology surgery]. AB - OBJECTIVES: Define the phases composing the learning curve of total hysterectomy (TH) and radical hysterectomy with pelvic lymphadenectomy (RHPL) robot-assisted performed by a single surgeon with no prior experience in laparoscopic surgery. METHODS: We retrospectively analyzed 72 procedures (TH, n=34 and RHPL, n=38) conducted between 2002 and 2011. The surgeon console time (CT) was used to determine the learning curve of TH and RHPL using CUSUM analysis. Epidemiological data, perioperative and postoperative complications were compared from the different phases of the learning curve. RESULTS: CUSUM analysis of surgeon console time (CUSUMCT) identified two learning phases for the TH group (phase 1: initial learning, phase 2: surgical skill increase). For the RHPL group, three learning phases were identified (phase 1: initial learning, phase 2: extending surgical indications, phase 3: control of surgical skills). Perioperative and postoperative complication rates did not differ significantly between the learning phases. Surgeon CT decreased from the 9th case (P=0.01) for the TH group and from the 13th case (P=0.04) for the RHPL group. DISCUSSION: CUSUM analysis of the learning curve in robotic-assisted gynecologic oncology surgery identified two phases of learning curve for simple procedures such as total hysterectomy and three phases for more complex procedures as radical hysterectomy with pelvic lymphadenectomy. PMID- 25813434 TI - [Robotic assisted laparoscopy: comparison of segmentary colorectal resection and shaving for colorectal endometriosis]. AB - OBJECTIVES: To compare perioperative complications of two surgical methods for digestive endometriosis management: "shaving" and colorectal resection in robotic assisted laparoscopy. METHODS: Twenty-eight women underwent robotic-assisted laparoscopy for digestive endometriosis, confirmed histologically. Six women had a digestive resection and twenty-one women had a shaving procedure. Short-term and long-term results and complications were compared between the two groups. RESULTS: Operative time was significantly shorter (P=0.0002) and estimated blood loss was significantly lower (200 ml vs 560 ml, P=0.04) in the shaving procedure group in comparison with the resection group. We observed one conversion to laparotomy in the resection group and one case of bladder injury in the shaving group. Length of hospital stay was longer (P=0.0001) in the resection group than in the shaving group. At the two-month re-evaluation, there was no significant difference between the two groups for the number of women in full remission for pelvic pain, urinary or gastrointestinal symptoms or dyspareunia. Two women of the resection group reported functional gastrointestinal signs that persisted 24 months after the intervention. CONCLUSION: Both immediate and delayed operative morbidity are more frequent in case of resection. Surgery for deep infiltrating endometriosis, even if operated with robotic assisted laparoscopy, is associated with significant morbidity. PMID- 25813429 TI - Mechanisms of epithelial wound detection. AB - Efficient wound healing requires the coordinated responses of various cell types within an injured tissue. To react to the presence of a wound, cells have to first detect it. Judging from their initial biochemical and morphological responses, many cells including leukocytes, epithelial cells, and endothelial cells detect wounds from over hundreds of micrometers within seconds-to-minutes. Wound detection involves the conversion of an injury-induced homeostatic perturbation, such as cell lysis, an unconstrained epithelial edge, or permeability barrier breakdown, into a chemical or physical signal. The signal is spatially propagated through the tissue to synchronize protective responses of cells near the wound site and at a distance. This review summarizes the triggers and mechanisms of wound detection in animals. PMID- 25813436 TI - Citation style guides for korean journal of medical education. PMID- 25813435 TI - [Birth of a child with Down syndrome: parental choice or failure of screening policy?]. AB - OBJECTIVES: Birth of a child with Down syndrome (DS) can follow parental choice or failure of screening. The objective of this work is to describe the circumstances of births of children with DS in a French perinatal health network. METHODS: Retrospective multicentric study, with prospective trial registration of all children born alive with DS, between 2010 and 2013. RESULTS: Sixty-three children were born with DS. Complete screening was performed by 61 % of patients, incomplete screening by 29 % of patients and no screening test by 10 %. Among these births, 50 % occurred following parental choice, 40 % following failure of screening and for 10 %, parental choice concerning screening was unknown. False negative had often calculating risk close to 1/1000. CONCLUSION: In this study, the birth of a child with DS occurred following parental choice in half of cases. It's necessary, to optimize the follow-up, to document in medical records the medical information and parental choice concerning DS screening and data of screening when this was done. PMID- 25813437 TI - Vision of the korean institute of medical education and evaluation. PMID- 25813438 TI - Viewing a person through the body: the relevance of philosophical anthropology to medical education. AB - Although the revival of medical humanities in the past three decades has emerged primarily in the US and the UK, continental Europe has a strong tradition in espousing the medical humanities, such as by advancing the anthropological movement in medicine and philosophy. In this paper, we argue that philosophical anthropology deserves a separate focus in medical education from medical ethics and philosophy of science. The focus of the paper is on the philosophical aspects of the human body to view a person 'through the body.' First, a short description of the anthropological movement in medicine is discussed, including its central motive 'to introduce the subject into medicine.' Next, the ontological and moral relationship between the person and his or her body is addressed. Drawing examples from anatomy, a so-called hemicorporectomy, organ donation, and aesthetic surgery, the concept of bodily integrity is expounded. These ideas can encourage medical students to discuss their own moral experiences during medical training and should be taught to enhance their philosophical understanding of medicine and health care. PMID- 25813439 TI - The Correlation between the Scores of Written Examination, the Clinical Clerkship Examination, the Clinical Skill Assessment, and the Graduation Examination of the Medical Students. AB - PURPOSE: The aim of this study was to investigate correlations between medical student scores on 4 examinations: the written examination, clinical clerkship examination, clinical skill assessment, and graduation examination. METHODS: Scores for 51 students who entered Daegu Catholic Medical School in 2005 on the written examination, clinical clerkship examination, clinical skill assessment, and graduation examination were included. Correlations between the scores were analyzed statistically. RESULTS: The scores on the written examination showed a strong correlation with those of the clinical clerkship assessment (0.833) and graduation examination (0.821). The clinical clerkship assessment scores correlated significantly with graduation examination scores (0.907). In addition, clinical skill assessment scores correlated with the written examination (0.579), clinical clerkship examination (0.570), and graduation examination (0.465) scores. CONCLUSION: Overall, the correlation between the scores on the clinical clerkship examination and the written examination was more significant than the correlation between scores on the clinical clerkship examination and clinical skill assessment. Therefore, we need to improve the evaluation method for the clinical clerkship examination and clinical skill assessment. PMID- 25813440 TI - Comparison of medical student responses and course achievement according to different types of patient simulations in an introductory advanced life support course. AB - PURPOSE: The optimal type of patient simulation for different levels of learners has not been extensively studied. The purpose of the study was to compare preclerkship medical student responses and course achievement according to different types of patient simulations in an introductory advanced life support (IALS) course. METHODS: A full-day, simulation-based IALS course was developed for preclerkship medical students who attended a four-week introduction to a clinical medicine program. One hundred eighteen students were trained in three days. Onsite interactive simulation with verbal debriefing (interactive type) was applied on the first day, and full-mission, realistic simulation with video assisted debriefing (realistic type) was applied on the second and third days. At the end of course, students evaluated the course and their simulation experiences and completed a written post-test. RESULTS: Student responses to the course and patient simulations were very positive. Students who experienced the realistic type of patient simulations more highly rated in realistic experiences, such as patient care, than the interactive type group (3.83+/-0.88 vs. 3.41+/-0.84, p=0.018). Values for team communication training were more highly rated by students in the interactive type group than the realistic type (4.69+/-0.52 vs. 4.39+/-0.86, p=0.022). There was no significant difference in post-test scores between the two groups (realistic, 67.63+/-10.80; interactive, 66.73+/-9.93, p=0.654). CONCLUSION: Both types of patient simulation provide valuable learning experiences to preclerkship medical students, with their own advantages in an IALS course. Onsite interactive simulation with verbal debriefing may be more cost-effective tool for preclerkship medical students. PMID- 25813441 TI - Evaluation of a complementary cyber education program for a pathophysiology class. AB - PURPOSE: The goal of this study was to develop and evaluate a complementary cyber education program for a required pathophysiology class for nursing students. METHODS: The cyber education program comprised electronic bulletin boards, correspondence material storage, an announcement section, a report submission section, reference sites, and statistics on learning rates. Twelve online lectures complemented five lectures in the classroom. To evaluate the course's educational effectiveness, we performed an online objective questionnaire and an open questionnaire survey anonymously, and compared the complementary cyber education program with traditional classroom education. RESULTS: The complementary cyber education program effected significant improvements in scores for importance with regard to major, clarity of goals and education plans for courses, professor readiness, preciseness and description of lectures, amount and efficiency of assignments, and fairness in appraisal standards compared with the traditional classroom education group. CONCLUSION: This study indicates that a complementary cyber education program provides nursing students with the flexibility of time and space, the newest information through updated lectures, efficient motivational aids through intimacy between the lecturer and students, and concrete and meaningful tasks. The complementary cyber education course also increased student effort toward studying and student satisfaction with the class. PMID- 25813442 TI - The present conditions of clinical clerkship management in Korea. AB - PURPOSE: This study investigated the present conditions of clinical clerkship management in Korea to make recommendations for it. METHODS: The data were collected between April 15 and May 30 in 2009 using questionnaires that were sent to the clerkship directors of 41 colleges of medicine and medical graduate schools. RESULTS: The elective course system was established in 78% of the institutions; the 6 core specialties were found in all medical schools. The duration of clerkship was longest in internal medicine, followed by surgery, pediatrics, obstetrics and gynecology, psychiatry, and emergency medicine. There were differences between the planning and monitoring agencies. Preclinical courses existed in 92.7% of the institutions. However, much more remains to be done ie, with regard to the issues of student assessment in clinical clerkship, faculty development programs for the faculty and residents, incentive systems for educational involvement, provisions for yearly systematic clerkships, integration of basic-clinical science-medical humanities, and community-based education. CONCLUSION: Because clinical clerkship education is very important as a core curriculum, curriculum planning and its management must be given adequate attention. The following measures are suggested: elective systems that allow students to choose by career planning; concerns over faculty development programs for residents as a teacher; consensus on the concept, objectives, duration, content, evaluation tools of pre-clinical clerkship and clinical clerkship, and student well-being; and emphasis on community-based education. PMID- 25813443 TI - Integrating problem-based learning into clinical clerkship: a pilot study. AB - PURPOSE: This study aims to evaluate the effectiveness of a new teaching segment, named "problem-based clinical teaching," for the clinical clerkship in the undergraduate medical curriculum. METHODS: Students were given a problem weekly on a case that they had seen during their rotation. The problem was provided by the instructor from a case that had already been diagnosed but came up with an additional problem that called for further investigation by the attending physician. The task for the students was to conduct the investigation and discuss the problem with the attending physician. A survey was conducted of a class of 3rd year medical students (n=43) who completed clerkships in internal medicine to measure the level of student engagement in the problem-based clinical teaching segment and the students' overall perceptions of this new teaching method. RESULTS: Students generally agreed with the statements that they were actively engaged in the learning during the problem-based clinical teaching session. The students also perceived that this teaching session helped them acquire a deeper understanding of the knowledge and that it enhanced their problem solving skills and motivation. CONCLUSION: Problem-based clinical teaching is a useful educational method to apply problem-based learning in clinical clerkship settings. PMID- 25813444 TI - Differences in Factors Affecting Medical Specialty Choices between Medical College Students and Graduate Medical School Students. AB - PURPOSE: This study was conducted to compare the specialty preference and factors that affect choices of medical specialties between medical college students and graduate medical school students. METHODS: A self-administered questionnaire was conducted in 563 medical students, and 482 (graduates: 199, undergraduates: 283) responded (response rate, 85.61%). The students completed a brief survey, which included 39 items that sampled their demographic data, career choice, and factors that influenced their choice. RESULTS: Most students in medical college and graduate medical school preferred clinical medicine. Graduate medical school students preferred internal medicine, pediatrics, and family medicine. In contrast, medical college students preferred neurology, family medicine, and psychiatry. Important factors that affected the selection of specialties were seniors' advice, advice of other students, clerkship experiences, and specialty experiences. CONCLUSION: This result shows that there are differences in the factors that affect the selection of medical specialties between medical college students and graduate medical school students. But, the opportunity to explore future careers and to consult their choice of specialty, in accordance with the needs and characteristics of individual students, must be provided for all medical students. PMID- 25813445 TI - Twelve tips for excellent physical examination teaching. PMID- 25813447 TI - A Phase II Study of Pazopanib in Patients with Localized Renal Cell Carcinoma to Optimize Preservation of Renal Parenchyma. AB - PURPOSE: Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy. MATERIALS AND METHODS: Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m(2), or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery. RESULTS: A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization. CONCLUSIONS: Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy in a select subset of patients who would otherwise require radical nephrectomy. PMID- 25813448 TI - Vesicoureteral Reflux Index: 2-Institution Analysis and Validation. AB - PURPOSE: The vesicoureteral reflux index is a novel tool designed to predict spontaneous reflux resolution in infants younger than 2 years. We performed a multi-institutional validation study to confirm the discriminatory power of the vesicoureteral reflux index to predict the vesicoureteral reflux resolution rate in young children. MATERIALS AND METHODS: We identified patients diagnosed with primary vesicoureteral reflux before age 24 months who had 2 or more voiding cystourethrograms available. Demographics, vesicoureteral reflux grade and timing, ureteral anomalies and radiographic outcomes were evaluated. The C-index was estimated for time to event model assessment. RESULTS: A total of 219 girls and 150 boys met study inclusion criteria. Mean +/- SD age at diagnosis was 4.7 +/- 4.9 months. Of the patients 101 (27.4%) had early to mid filling, 214 (58%) had late filling and 54 (14.6%) had voiding only vesicoureteral reflux. High grade reflux was present in 87 patients (23.6%) and ureteral anomalies were observed in 50 (13.6%). A vesicoureteral reflux index of 1, 2, 3, 4 and 5 or greater showed an improvement/resolution rate of 88.2%, 77.3%, 62.3%, 32.1% and 14.3%, respectively. On time to event analysis children with filling phase vesicoureteral reflux (p <0.001), grade 4-5 reflux (p <0.001) and ureteral anomalies (p = 0.003) had significantly longer median time to resolution. Median time to spontaneous resolution was 12.6, 12.7, 15.1, 25.6 and 31 months or greater for a vesicoureteral reflux index of 1, 2, 3, 4 and 5 or greater, respectively (C-index 0.305, 95% CI 0.252-0.357). During the study period 65 patients (17.6%) underwent surgical intervention. CONCLUSIONS: The vesicoureteral reflux index is a simple tool that reliably predicts significant improvement and spontaneous resolution of primary reflux in patients diagnosed at younger than 2 years. The index provides valuable prognostic information, facilitating individualized patient care. PMID- 25813449 TI - Active Surveillance is Superior to Radical Nephrectomy and Equivalent to Partial Nephrectomy for Preserving Renal Function in Patients with Small Renal Masses: Results from the DISSRM Registry. AB - PURPOSE: We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry. MATERIALS AND METHODS: Patients were grouped into chronic kidney disease stages by estimated glomerular filtration rate range. Cases were considered up staged if a more advanced chronic kidney disease stage was entered during followup. Chronic kidney disease up staging-free survival was compared among groups using Kaplan-Meier analysis and paired comparisons log rank tests. Multivariate Cox regression identified independent predictors of chronic kidney disease up staging-free survival. RESULTS: A total of 162 patients met the study inclusion criteria, with 68 in the surveillance arm, 65 undergoing partial nephrectomy, 15 undergoing radical nephrectomy and 14 undergoing cryoablation. Median tumor size was 2.2 cm. Mean estimated glomerular filtration rate change was significantly larger for radical nephrectomy vs surveillance (-9.2 vs -0.5 ml/minute/1.73 m(2)) and for radical vs partial nephrectomy (-9.2 vs -1.9 ml/minute/1.73 m(2)) (p=0.001). No other groups differed significantly. On Kaplan-Meier analysis patients undergoing radical nephrectomy had significantly worse chronic kidney disease up staging-free survival vs those treated with partial nephrectomy (p=0.029), surveillance (p=0.007) and cryoablation (p=0.019). No other groups differed significantly. On multivariate analysis radical nephrectomy independently predicted poor chronic kidney disease up staging-free survival (odds ratio vs surveillance 30.6, p=0.001). Neither partial nephrectomy (p=0.985) nor cryoablation (p=0.976) predicted poor chronic kidney disease up staging-free survival relative to surveillance. CONCLUSIONS: Patients in the surveillance arm had superior estimated glomerular filtration rate preservation compared to those in the radical nephrectomy but not the partial nephrectomy arm. In certain patients with small renal masses surveillance and partial nephrectomy may offer comparable renal functional outcomes. This could be partly attributable to a modest estimated glomerular filtration rate decrease associated with surveillance itself. A thorough understanding of the renal functional impacts of treatment modalities is critical in the management of small renal masses. PMID- 25813450 TI - The Comparison of R.E.N.A.L., PADUA and Centrality Index Score in Predicting Perioperative Outcomes and Complications after Laparoscopic Radio Frequency Ablation of Renal Tumors. AB - PURPOSE: We assessed the association between the R.E.N.A.L., PADUA and centrality index scores and perioperative outcomes, and determined the efficacy of each scoring system over the simple parameter of tumor size. MATERIALS AND METHODS: We conducted a retrospective review of the records of patients who underwent laparoscopic radio frequency ablation of renal tumors from February 2006 to April 2014 at our institution. Tumors were categorized using the R.E.N.A.L., PADUA and centrality index score, which were determined by analyzing preoperative imaging. The relationships between each variable and change in glomerular filtration rate, estimated blood loss, operative time and postoperative complications were examined. RESULTS: Laparoscopic radio frequency ablation was performed in 215 selected patients with preoperative imaging available. The interclass correlations coefficient of the 3 observers was 0.87, 0.84 and 0.82 for the C Index, the R.E.N.A.L. and the PADUA scoring system, respectively. R.E.N.A.L. score, PADUA score and PADUA complexity were significantly associated with postoperative complications (p=0.040, 0.015 and 0.006, respectively). However, major complications were only associated with high PADUA complexity (chi-square 23.851, p <0.05). Each scoring system had a significant association with operative time and estimated blood loss (p <0.05), except that the C-index score had no relationship with estimated blood loss (p=0.083). The accuracy of each scoring system in predicting perioperative outcomes and postoperative complications was superior to that of tumor size. CONCLUSIONS: Each scoring system has an advantage over tumor size in describing tumor complexity and may help with surgical decision making. Further studies are required to validate their efficacy in evaluating the intraoperative and postoperative results after renal laparoscopic radio frequency ablation. PMID- 25813451 TI - Propyl gallate inhibits adipogenesis by stimulating extracellular signal-related kinases in human adipose tissue-derived mesenchymal stem cells. AB - Propyl gallate (PG) used as an additive in various foods has antioxidant and anti inflammatory effects. Although the functional roles of PG in various cell types are well characterized, it is unknown whether PG has effect on stem cell differentiation. In this study, we demonstrated that PG could inhibit adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells (hAMSCs) by decreasing the accumulation of intracellular lipid droplets. In addition, PG significantly reduced the expression of adipocyte-specific markers including peroxisome proliferator-activated receptor-gamma (PPAR-gamma), CCAAT enhancer binding protein-alpha (C/EBP-alpha), lipoprotein lipase (LPL), and adipocyte fatty acid-binding protein 2 (aP2). PG inhibited adipogenesis in hAMSCs through extracellular regulated kinase (ERK) pathway. Decreased adipogenesis following PG treatment was recovered in response to ERK blocking. Taken together, these results suggest a novel effect of PG on adipocyte differentiation in hAMSCs, supporting a negative role of ERK1/2 pathway in adipogenic differentiation. PMID- 25813452 TI - American Joint Committee on Cancer Classification of Uveal Melanoma (Anatomic Stage) Predicts Prognosis in 7,731 Patients: The 2013 Zimmerman Lecture. AB - PURPOSE: To analyze the clinical features and prognosis of posterior uveal melanoma based on the American Joint Committee on Cancer (AJCC) (7th edition) tumor staging. DESIGN: Retrospective interventional case series. PARTICIPANTS: A total of 7731 patients. METHODS: Uveal melanoma management. MAIN OUTCOME MEASURES: Melanoma-related metastasis and death. RESULTS: Of 7731 patients with posterior uveal (ciliary body and choroidal) melanoma, the AJCC tumor staging was stage I in 2767 (36%), stage II in 3735 (48%), stage III in 1220 (16%), and stage IV in 9 (<1%). Based on tumor staging (I, II, III, and IV), features that showed significant increase with tumor staging included age at presentation (57, 58, 60, 60 years) (P < 0.001), tumor base (8, 12, 17, 17 mm) (P < 0.001), tumor thickness (2.9, 6.0, 10.1, 10.2 mm) (P < 0.001), distance to optic disc (3, 5, 5, 5 mm) (P < 0.001), distance to foveola (3, 5, 5, 5 mm) (P < 0.001), mushroom configuration (6%, 24%, 34%, 33%) (P < 0.001), plateau configuration (3%, 4%, 7%, 11%) (P < 0.001), tumor pigmentation (48%, 53%, 69%, 78%) (P < 0.001), and extraocular extension (0%, 1%, 11%, 22%) (P < 0.001). After therapy, Kaplan-Meier estimates of metastasis at 1, 5, 10, and 20 years were <1%, 5%, 12%, and 20% for stage I, 2%; 17%, 29%, and 44% for stage II; 6%, 44%, 61%, and 73% for stage III, and 100% by 1 year for stage IV. Kaplan-Meier estimates of death at 1, 5, 10, and 20 years were <1%, 3%, 6%, and 8% for stage I; <1%, 9%, 15%, and 24% for stage II; 3%, 27%, 39%, and 53% for stage III, and 100% by 1 year for stage IV. Compared with stage I, the hazard ratio for metastasis/death was 3.1/3.1 for stage II and 9.3/10.1 for stage III. CONCLUSIONS: Compared with uveal melanoma classified as AJCC stage I, the rate of metastasis/death was 3 times greater for stage II, 9 to 10 times greater for stage III, and further greater for stage IV. Early detection of posterior uveal melanoma, at a point when the tumor is small, can be lifesaving. PMID- 25813454 TI - Wombats acquired scabies from humans and/or dogs from outside Australia. AB - According to previous studies, Sarcoptes mites of wombats were relatively recently introduced into Australia by colonizers and/or their dogs. However, that affirmation has been called into question due to apparent flaws in the design of the phylogenetic studies. With the aim of providing a definitive answer to this question, a part of the mitochondrial gene coding for 12S rRNA of S. scabiei mites from 23 humans and one dog collected in France was sequenced and a phylogenetic analysis including the sequences previously deposited in Genbank was performed. Phylogenetic analysis did not show host segregation or geographical isolation of the mites. Conversely, the present work suggested that mange in wombats is indeed due to the introduction of S. scabiei into Australia by immigrating individuals and/or their companion animals. PMID- 25813455 TI - Potaspora aequidens n. sp. (Microsporidia, Tetramicridae), a parasite infecting the freshwater fish Aequidens plagiozonatus (Teleostei, Cichlidae) from Brazil. AB - Morphological and molecular procedures were used to describe a new species of microsporidian that infects the muscles of the sub-opercular region and the caudal fins of the freshwater Aequidens plagiozonatus in Brazil. This microsporidian forms whitish xenomas containing variable number of spores, reaching up to ~0.4 mm in diameter. The mature spores, pyriformin shape, with slightly round ends, measured 3.4 +/- 0.5 MUm long and 1.9 +/- 0.3 MUm wide (n = 50) and showed characteristics typical of Microsporidia. The average thickness of the spore wall was 100 (96-108) nm (n = 50), and the spore wall was composed of two layers, a thin, electron-dense exospore and a thick electron-transparent endospore. The exospore was surrounded by a thin, irregular layer of granular material. The anchoring disc was mushroom-like, located in the apical region of the spore in an eccentric position relative to the spore axis, rendering bilateral asymmetry to the spore. The anterior part of the polar filament (PF) (manubrium) measured approximately 125 (122-128) nm thick (n = 30), and the angle of tilt between the anterior PF and the spore axis was ~45 degrees ; the posterior part was packed in 8-9 coils. Phylogenetic analysis showed a strongly supported clade containing family Spragueidae Weissenberg, 1976, family Tetramicridae Matthews and Matthews, 1980, Microsporidium sp. RBS1, and Kabatana spp. In conclusion, the available morphological, ultrastructural, and molecular data shows that this microsporidian is a new species belonging to group 4, classified as Potaspora aequidens n. sp. This is the second species described in the genus Potaspora. PMID- 25813453 TI - Comparing the Impact of Refractive and Nonrefractive Vision Loss on Functioning and Disability: The Salisbury Eye Evaluation. AB - PURPOSE: To compare the effects of uncorrected refractive error (URE) and nonrefractive visual impairment (VI) on performance and disability measures. DESIGN: Cross-sectional, population-based study. PARTICIPANTS: A total of 2469 individuals with binocular presenting visual acuity (PVA) of >= 20/80 who participated in the first round of the Salisbury Eye Evaluation study. METHODS: The URE was defined as binocular PVA of <= 20/30, improving to >20/30 with subjective refraction. The VI was defined as post-refraction binocular best corrected visual acuity (BCVA) of <= 20/30. The visual acuity decrement due to VI was calculated as the difference between BCVA and 20/30, whereas visual acuity due to URE was taken as the difference between PVA and BCVA. Multivariable regression analyses were used to assess the disability impact of (1) vision status (VI, URE, or normal vision) using the group with normal vision as reference and (2) a 1-line decrement in acuity due to VI or URE. MAIN OUTCOME MEASURES: Objective measures of visual function were obtained from timed performance of mobility and near vision tasks, self-reported driving cessation, and self-reported visual difficulty measured by the Activities of Daily Vision (ADV) scale. The ADV responses were analyzed using Rasch analysis to determine visual ability. RESULTS: Compared with individuals with normal vision, subjects with VI (n = 191) had significantly poorer objective and subjective visual functioning in all metrics examined (P < 0.05), whereas subjects with URE (n = 132) demonstrated slower walking speeds, slower near task performance, more frequent driving cessation, and lower ADV scores (P < 0.05), but did not demonstrate slower stair climbing or descent speed. For all functional metrics evaluated, the impact of VI was greater than the impact of URE. The impact of a 1 line VA decrement due to VI was associated with greater deficits in mobility measures and driving cessation when compared with a 1-line VA decrement due to URE. CONCLUSIONS: Visual impairment is associated with greater disability than URE across a wide variety of functional measures, even in analyses adjusting for the severity of vision loss. Refractive and nonrefractive vision loss should be distinguished in studies evaluating visual disability and be understood to have differing consequences. PMID- 25813456 TI - Urban-rural differences in psychological distress in nine countries of the former Soviet Union. AB - BACKGROUND: Studies have shown that the prevalence of mental illness can vary between urban and rural locations. This study extended research to the countries of the former Soviet Union (fSU) by assessing the association between settlement type and psychological distress and whether factors associated with psychological distress vary by settlement type. METHODS: Data on 18,000 adults aged >=18 years from the Health in Times of Transition (HITT) survey undertaken in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russia, and Ukraine in 2010/11 were analyzed. Settlement types were country capitals, regional capitals, cities/other urban settlements, and villages. Psychological distress was defined as the country-specific highest quintile of a composite score based on 11 questions. Logistic regression analysis with random effects was used to examine associations. RESULTS: In a pooled country analysis, living in a smaller urban settlement or village was associated with significantly higher odds for psychological distress compared to living in the country capital. Lower social support was a strong correlate of psychological distress in all locations except capital cities. LIMITATIONS: The psychological distress measure has not been formally validated in the study countries. CONCLUSIONS: Lower levels of urbanicity are associated with greater psychological distress in the fSU countries. As many Western studies have linked greater urbanization to poorer mental health, this highlights the need for caution in extrapolating findings from one part of the world to others and the importance of undertaking research on the geographical correlates of mental health in different world regions. PMID- 25813457 TI - Comparative efficacy and acceptability of atomoxetine, lisdexamfetamine, bupropion and methylphenidate in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis with focus on bupropion. AB - OBJECTIVES: There is a lack of comparative effectiveness research among attention deficit hyperactivity disorder (ADHD) drugs in terms of efficacy and acceptability, where bupropion is compared with atomoxetine, lisdexamfetamine and methylphenidate. The main aim of this work was to compare the efficacy and acceptability of these drugs in children and adolescents using a metaanalysis. METHODS: A literature search was conducted to identify double-blind, placebo controlled, noncrossover studies of ADHD. PubMed/Medline and Clinicaltrials.gov were searched. Comparative drug efficacy to placebo was calculated based on the standardized mean difference (SMD), while the comparative drug acceptability (all cause discontinuation) to placebo was estimated on the odds ratio (OR). RESULTS: In total 28 trials were included in the meta-analysis. Efficacy in reducing ADHD symptoms compared to placebo was small for bupropion (SMD=-0.32, 95% CI; -0.69, 0.05), while modest efficacy was shown for atomoxetine (SMD=-0.68, 95% CI; -0.76, -0.59) and methylphenidate (SMD=-0.75, 95% CI; -0.98, -0.52) and high efficacy was observed for lisdexamfetamine (SMD=-1.28, 95% CI; -1.84, -0.71). Compared to placebo treatment discontinuation was statistically significantly lower for methylphenidate (OR=0.35, 95% CI; 0.24, 0.52), while it was not significantly different for atomoxetine (OR=0.91, 95% CI; 0.66, 1.24), lisdexamfetamine (OR=0.60, 95% CI, 0.22, 1.65), and bupropion (OR=1.64, 95% CI; 0.5, 5.43). LIMITATIONS: The heterogeneity was high, except in atomoxetine trials. The crossover studies were excluded. The effect sizes at specific time points were not computed. Studies with comorbid conditions, except those reporting on oppositional defiant disorder, were also excluded. All studies involving MPH were combined. CONCLUSIONS: The results suggest that lisdexamfetamine has the best benefit risk balance and has promising potential for treating children and adolescents with ADHD. More research is needed for a better clinical evaluation of bupropion. PMID- 25813458 TI - Incidence and predisposing factors of periprosthetic proximal femoral fractures: a literature review. AB - PURPOSE: The purpose of this review article was to investigate the incidence and predisposing factors for periprosthetic proximal femoral fractures (PFF) following total hip arthroplasty. METHODS: We performed a comprehensive search of the medical literature in MEDLINE and EMBASE databases to review articles related to PFF, their incidence and risk factors. RESULTS AND CONCLUSIONS: The incidence of PPF after primary THA was, in general, lower than after revision THA both for intra- and postoperative PFF. The rate of intraoperative PFF ranged from 0.1% to 27.8% and of postoperative PFF from 0.07% to 18%. Predisposing factors for intraoperative PFF are osteoporosis, rheumatoid arthritis, femoral preparation and surgical technique used to insert the rasp or femoral component, the use of press-fit cementless stems, and revision THA. In case of postoperative PFF, the following seem to be significant risk factors: advanced age, female gender, post traumatic osteoarthritis, osteoporosis and rheumatoid arthritis, proximal femoral deformities, previous surgery of the affected hip, implant type (especially cementless stems and press-fit implantation), technical errors such as cortical perforation, cortical stress risers, low-energy trauma, osteolysis, loosening and revision THA. PMID- 25813459 TI - Calcitonin gene-related peptide can be selected as a predictive biomarker on progression and prognosis of knee osteoarthritis. AB - PURPOSE: The purpose of this study was to examine calcitonin gene-related peptide (CGRP) concentrations in serum and synovial fluid of patients with primary knee osteoarthritis (OA) and healthy controls and to explore their relationship with clinical and radiographic severity of OA. METHODS: Sixty-five patients with primary knee OA and 21 healthy controls were recruited. CGRP concentrations in the serum and synovial fluid were measured using enzyme-linked immunosorbent assays. The radiographic severity of OA was evaluated using the Kellgren and Lawrence (KL) classification. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess pain, stiffness and physical function. RESULTS: Serum and synovial fluid CGRP concentrations tended to be higher with the increase in KL grades (r = 0.565 and r = 0.441, P < 0.001, respectively), and were significantly positively correlated with KL grades, total WOMAC score and each subscale (pain, stiffness and physical function). CONCLUSIONS: The result demonstrated that CGRP in serum and synovial fluid was related to progressive joint damage in knee OA. CGRP can be selected as a biomarker for monitoring disease severity and could be a predictive role on prognosis and progression of knee OA. PMID- 25813460 TI - Plate osteosynthesis of humeral diaphyseal fractures associated with radial palsy: twenty cases. AB - BACKGROUND: Surgical management of humeral fractures associated with radial nerve palsy remains controversial. Some advocate surgical treatment in emergency while others recommend nonoperative treatment. PURPOSE: The aim of the study was to assess nerve recovery in a series of patients treated with open reduction and internal fixation (ORIF) with plate for humeral fracture associated with radial nerve palsy. We hypothesised that surgical treatment with ORIF in emergency allows good nerve recovery. METHODS: We conducted a retrospective study on 20 patients out of 225 humeral shaft fractures operated between 1995 and 2012. There were 11 women and nine men, with a mean age of 51 +/- 22 years (23-93). The fractures were located in mid third of the shaft in 15 cases (75 %), distal third in four (20 %) and superior third in one (5 %). Mean delay for surgical treatment was three days (zero to 15). The plate was positioned at the medial face in 16 cases (80 %) and posterior face in four (20 %). In six cases, the radial nerve was not seen (30 %). In the 14 cases where it was seen (70 %), it was continuous. Neurolysis was performed in seven cases (35 %). RESULTS: Fifteen patients (75 %) had a good nerve palsy recovery, with a mean delay of ten months (six to 12). Statistically significant correlation was observed between delay of surgical treatment and delay of radial recovery (p = 0.0166 ; Rho = - 0.53). Early osteosynthesis was correlated with better nerve recovery. One patient required complementary nerve surgery and another tendon transfer. Bone healing was obtained in all cases. Concerning functional outcomes, mean QuickDASH, a shortened version of the Disabilities of the Arm, Shoulder and Hand (DASH) score, was 9 +/- 17 (0-59), and 85 % of patients were able to recover their previous physical activities. CONCLUSION: ORIF by plate of humeral shaft fracture with radial nerve palsy in emergency allows good palsy recovery (75 %) with a short delay (about three days). LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25813461 TI - Item Response Theory Modeling of the Philadelphia Naming Test. AB - Purpose: In this study, we investigated the fit of the Philadelphia Naming Test (PNT; Roach, Schwartz, Martin, Grewal, & Brecher, 1996) to an item-response theory measurement model, estimated the precision of the resulting scores and item parameters, and provided a theoretical rationale for the interpretation of PNT overall scores by relating explanatory variables to item difficulty. This article describes the statistical model underlying the computer adaptive PNT presented in a companion article (Hula, Kellough, & Fergadiotis, 2015). Method: Using archival data, we evaluated the fit of the PNT to 1- and 2-parameter logistic models and examined the precision of the resulting parameter estimates. We regressed the item difficulty estimates on three predictor variables: word length, age of acquisition, and contextual diversity. Results: The 2-parameter logistic model demonstrated marginally better fit, but the fit of the 1-parameter logistic model was adequate. Precision was excellent for both person ability and item difficulty estimates. Word length, age of acquisition, and contextual diversity all independently contributed to variance in item difficulty. Conclusions: Item-response-theory methods can be productively used to analyze and quantify anomia severity in aphasia. Regression of item difficulty on lexical variables supported the validity of the PNT and interpretation of anomia severity scores in the context of current word-finding models. PMID- 25813462 TI - "Mission Indradhanush" targets India's unvaccinated children. PMID- 25813463 TI - Quantifying Adventitious Error in a Covariance Structure as a Random Effect. AB - We present an approach to quantifying errors in covariance structures in which adventitious error, identified as the process underlying the discrepancy between the population and the structured model, is explicitly modeled as a random effect with a distribution, and the dispersion parameter of this distribution to be estimated gives a measure of misspecification. Analytical properties of the resultant procedure are investigated and the measure of misspecification is found to be related to the root mean square error of approximation. An algorithm is developed for numerical implementation of the procedure. The consistency and asymptotic sampling distributions of the estimators are established under a new asymptotic paradigm and an assumption weaker than the standard Pitman drift assumption. Simulations validate the asymptotic sampling distributions and demonstrate the importance of accounting for the variations in the parameter estimates due to adventitious error. Two examples are also given as illustrations. PMID- 25813464 TI - Advances in Modeling Model Discrepancy: Comment on Wu and Browne (2015). AB - Wu and Browne (Psychometrika, 79, 2015) have proposed an innovative approach to modeling discrepancy between a covariance structure model and the population that the model is intended to represent. Their contribution is related to ongoing developments in the field of Uncertainty Quantification (UQ) on modeling and quantifying effects of model discrepancy. We provide an overview of basic principles of UQ and some relevant developments and we examine the Wu-Browne work in that context. We view the Wu-Browne contribution as a seminal development providing a foundation for further work on the critical problem of model discrepancy in statistical modeling in psychological research. PMID- 25813465 TI - Some Comments on Wu and Browne. PMID- 25813466 TI - Comments on "Quantifying Adventitious Error in a Covariance Structure as a Random Effect" by Hao Wu and Michael Browne. PMID- 25813467 TI - A Comment on a Paper by H. Wu and M. W. Browne (2014). PMID- 25813468 TI - Random Model Discrepancy: Interpretations and Technicalities (A Rejoinder). AB - In this rejoinder we discuss the following aspects of our approach to model discrepancy: the interpretations of the two populations and adventitious error, the choice of inverse Wishart distribution, the perceived danger of justifying a model with bad fit, the relationship among our new approach, Chen's (J R Stat Soc Ser B, 41:235-248, 1979) approach and the existing RMSEA-based approach, and the Pitman drift assumption. PMID- 25813470 TI - Phosphohistone H3: implications for clinical practice and risk assessment in meningioma. PMID- 25813469 TI - Seizure outcome after radiotherapy and chemotherapy in low-grade glioma patients: a systematic review. AB - There is growing evidence that antitumor treatment contributes to better seizure control in low-grade glioma patients. We performed a systematic review of the current literature on seizure outcome after radiotherapy and chemotherapy and evaluated the association between seizure outcome and radiological response. Twenty-four studies were available, of which 10 described seizure outcome after radiotherapy and 14 after chemotherapy. All studies demonstrated improvements in seizure outcome after antitumor treatment. Eight studies reporting on imaging response in relation to seizure outcome showed a seizure reduction in a substantial part of patients with stable disease on MRI. Seizure reduction may therefore be the only noticeable effect of antitumor treatment. Our findings demonstrate the clinical relevance of monitoring seizure outcome after radiotherapy and chemotherapy, as well as the potential role of seizure reduction as a complementary marker of tumor response in low-grade glioma patients. PMID- 25813471 TI - Long-term results of a prospective phase II trial of medically inoperable stage I NSCLC treated with SBRT - the Nordic experience. AB - BACKGROUND: Presentation of long term results of a phase II multicenter Nordic trial of medically inoperable stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: We report the extended outcome, focusing on long-term effects, of a prospective cohort of 57 evaluable patients with peripherally located T1N0M0 (72%) and T2N0M0 (28%) NSCLC, treated with SBRT 15 Gy * 3, prescribed to the 67% isodose line encompassing the PTV. The patients were inoperable due to chronic obstructive pulmonary disease (65%), cardiovascular disease (25%) or other illnesses (3%) or refused surgery (7%). Median Karnofsky score pre-treatment was 80% (70-100%). Late effects were defined as occurring > 36 months. RESULTS: Thirty-eight patients (67%) were relapse free during their entire follow-up. Local control rate at four and five years were 79% (CI 95% 64-95%) and local relapses occurred at 10-76 months post treatment. Seven local failures were noted, four occurring <= 36 months (all T2a tumors; two isolated and two in combination with out-of-field relapses) and three occurring > 36 months (T1b-tumors n = 3). Thirteen patients had out-of-field failure only as first presentation of recurrence. Overall survival rate and lung cancer-specific survival rate at five years were 30% and 74%, respectively. Toxicity throughout the entire observation period was acceptable without any grade 5 toxicities. Seventeen grade 3-4 toxicities were noted, three presenting > 36 months (rib fracture, dyspnea and ventricle tachycardia). Median follow-up was 41.5 months (3.4-113.0) for the entire cohort and 59.3 months (36.4-113.0) for the 34 patients (60%) with a follow-up of > 36 months. CONCLUSION: Throughout the observation period local control was excellent and toxicity limited with no increase in late presenting local relapses or late treatment-related morbidity. This further supports SBRT as an efficient local treatment modality even in a medically impaired patient cohort. PMID- 25813472 TI - The amount of injected 177Lu-octreotate strongly influences biodistribution and dosimetry in C57BL/6N mice. AB - BACKGROUND: (177)Lu-octreotate therapy has proven to give favorable results after treatment of patients with neuroendocrine tumors. Much focus has been on the binding and uptake of (177)Lu-octreotate in tumor tissue, but biodistribution properties in normal tissues is still not fully understood, and the effect of receptor saturation may be important. The aim of this study was to investigate the influence of the amount of (177)Lu-octreotate on the biodistribution of (177)Lu-octreotate in normal tissues in mice. MATERIAL AND METHODS: C57BL/6N female mice were intravenously injected with 0.1-150 MBq (177)Lu-octreotate (0.039 MUg peptide/MBq). The mice were killed 0.25 h to 14 days after injection by cardiac puncture under anesthesia. Activity concentration was determined in blood, bone marrow, kidneys, liver, lungs, pancreas, and spleen, and mean absorbed doses were calculated. RESULTS: The activity concentration varied with time and amount of injected activity. At 4-8 h after injection, a local maximum in activity concentration was found for liver, lungs, pancreas, and spleen. With the exception for the lower injected activities (0.1-1 MBq), the overall highest uptake was found in the kidneys (%IA/g). Large variations were found and the activity concentration in kidneys was 11-23%IA/g at 4 h, and 0.22-1.9%IA/g at 7 days after injection. Furthermore, a clear reduction in activity concentration with increased injected activity was observed for lungs, pancreas and spleen. CONCLUSION: The activity concentration in all tissues investigated was strongly influenced by the amount of (177)Lu-octreotate injected. Large differences in mean absorbed dose per unit injected activity were found between low (0.1-1 MBq, 0.0039-0.039 MUg) and moderate amounts (5-45 MBq, 0.2-1.8 MUg). Furthermore, the results clearly showed the need for better ways to estimate absorbed dose to bone marrow other than methods based on a single blood sample analysis. Since the absorbed dose to critical organs will limit the amount of (177)Lu-octreotate administered, these findings must be taken into consideration when optimizing this type of therapy. PMID- 25813473 TI - Childhood cancer survivor cohorts in Europe. AB - With the advent of multimodality therapy, the overall five-year survival rate from childhood cancer has improved considerably now exceeding 80% in developed European countries. This growing cohort of survivors, with many years of life ahead of them, has raised the necessity for knowledge concerning the risks of adverse long-term sequelae of the life-saving treatments in order to provide optimal screening and care and to identify and provide adequate interventions. Childhood cancer survivor cohorts in Europe. Considerable advantages exist to study late effects in individuals treated for childhood cancer in a European context, including the complementary advantages of large population-based cancer registries and the unrivalled opportunities to study lifetime risks, together with rich and detailed hospital-based cohorts which fill many of the gaps left by the large-scale population-based studies, such as sparse treatment information. Several large national cohorts have been established within Europe to study late effects in individuals treated for childhood cancer including the Nordic Adult Life after Childhood Cancer in Scandinavia study (ALiCCS), the British Childhood Cancer Survivor Study (BCCSS), the Dutch Childhood Oncology Group (DCOG) LATER study, and the Swiss Childhood Cancer Survivor Study (SCCSS). Furthermore, there are other large cohorts, which may eventually become national in scope including the French Childhood Cancer Survivor Study (FCCSS), the French Childhood Cancer Survivor Study for Leukaemia (LEA), and the Italian Study on off-therapy Childhood Cancer Survivors (OTR). In recent years significant steps have been taken to extend these national studies into a larger pan-European context through the establishment of two large consortia - PanCareSurFup and PanCareLIFE. The purpose of this paper is to present an overview of the current large, national and pan-European studies of late effects after childhood cancer. This overview will highlight the strong cooperation across Europe, in particular the EU-funded collaborative research projects PanCareSurFup and PanCareLIFE. Overall goal. The overall goal of these large cohort studies is to provide every European childhood cancer survivor with better care and better long-term health so that they reach their full potential, and to the degree possible, enjoy the same quality of life and opportunities as their peers. PMID- 25813474 TI - Effective, clinically feasible and sustainable: Key design features of psycho educational and supportive care interventions to promote individualised self management in cancer care. AB - As the global burden of cancer increases healthcare services will face increasing challenges in meet the complex needs of these patients, their families and the communities in which they live. This raises the question of how to meet patient need where direct clinical contact may be constrained or not readily available. Patients and families require resources and skills to manage their illness outside of the hospital setting within their own communities. AIM: To propose a framework for the development and delivery of psycho-educational and supportive care interventions drawing on theoretical principles of behaviour change and evidence-based interventions, and based on extensive experience in developing and testing complex interventions in oncology. APPROACH: At the core of this intervention framework are considerations of efficiency: interventions are designed to cater for individuals' unique needs; to place minimal demands on the health system infrastructure and to be rapidly disseminated into usual care if successful. There are seven key features: 1) Targeting cancer type and stage; 2) Tailoring to unique individual needs; 3) Promotion of patient self-management of their disease and treatment side effects; 4) Efficient delivery of the intervention; 5) Training and adherence to protocol; 6) Ensuring the intervention is evidence-based; 7) Confirming stakeholder acceptability of the intervention. APPLICATION: A case study of a randomised controlled trial which tested psycho educational oncology interventions using this framework is presented. These interventions were designed to cater for individuals' unique needs and promote self-management while placing minimal demands on the acute health care setting. DISCUSSION: Innovative ways to realise the potentially major impact that psycho educational and supportive care interventions can have on psychological morbidity, coping, symptoms and quality of life in serious and chronic illness are needed. This framework, which is driven by theory, evidence, and experience, is designed to ensure that interventions are effective, clinically feasible and sustainable. PMID- 25813475 TI - LRIG1 is a prognostic biomarker in non-small cell lung cancer. AB - BACKGROUND: The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins are involved in the regulation of cellular signal transduction. LRIG1 is an endogenous inhibitor of receptor tyrosine kinases (RTKs) and an emerging tumor suppressor. In the lung epithelium, the expression of LRIG1 is downregulated by tobacco smoking, and further downregulated in lung squamous cell carcinoma. MATERIAL AND METHODS: The expression of LRIG proteins were analyzed in 347 cases of non-small cell lung cancer (NSCLC) by immunohistochemistry, and LRIG1 mRNA expression was evaluated in 807 lung cancer samples in silico in the Oncomine database. Potential associations between the expression data and the clinical parameters, including patient survival, were investigated. RESULTS: Expression of the LRIG1 protein was found to be an independent prognostic factor in NSCLC, whereas expression of LRIG2 or LRIG3 did not correlate with patient survival. The levels of LRIG1 mRNA also correlated with the survival of NSCLC patients. CONCLUSION: These findings demonstrate that LRIG1 is an independent prognostic factor in patients with NSCLC that could be important in future decision-making algorithms for adjuvant lung cancer treatment. PMID- 25813476 TI - Are male immigrants in Denmark at lower or higher risk of tobacco-related cancers? A Danish nationwide cohort study. AB - BACKGROUND: Tobacco-related cancers (TRC) represent approximately a third of the cancer incidence in Denmark. However, tobacco consumption levels in immigrants may differ to the native population. We compared incidence rates of nine TRCs among male immigrants of first and second generation in Denmark with those among males of the native population. MATERIAL AND METHODS: We used an established cohort of all Danish men (1978-2010) and calculated standardized incidence ratios (SIR) with 95% confidence intervals (CI) to compare incidence by immigration status and region of birth for nine TRCs. RESULTS: We identified 131,317 incident cases of TRCs among 3,508,204 men (280,526 first generation and 129,056 second generation immigrants). Overall, immigrants of both generations experienced approximately 15% lower incidence of TRC than natives, however, with large variations by country of birth and type of TRC. Compared to natives, lung cancer incidence in first and second generation immigrants was 10% and 27% lower, respectively. However, lung cancer incidence increased in first generation immigrants reaching the level of native Danes in the late 2000s. First generation immigrants experienced approximately 50% lower incidence of lower urinary tract cancer than natives. However, only liver and stomach cancer had higher SIRs in immigrants. CONCLUSION: Overall TRC incidence was lower among immigrants than in native Danes. Lower urinary tract cancer among first generation immigrants warrants further investigation. PMID- 25813477 TI - Radiation shielding for diagnostic radiology. AB - Scattered radiation makes up the majority of the stray radiation field around an X-ray unit. The scatter is linked to the amount of radiation incident on the patient. It can be estimated from quantities used to assess patient dose such as the kerma-area product, and factors have been established linking this to levels of scattered radiation for radiography and fluoroscopy. In radiography shielding against primary radiation is also needed, but in other modalities this is negligible, as the beam is intercepted by the image receptor. In the same way scatter from CT can be quantified in terms of dose-length product, but because of higher radiation levels, exposure to tertiary scatter from ceilings needs to be considered. Transmission requirements are determined from comparisons between calculated radiation levels and agreed dose criteria, taking into account the occupancy of adjacent areas. Thicknesses of shielding material required can then be calculated from simple equations. PMID- 25813478 TI - IAEA experience in communicating radiation risks through the RPOP website. AB - The authors report here their successful experience of communicating information to health professionals, patients and the public on benefits and risks of ionising radiation in medical applications. The approaches used have been based on giving importance to clinical benefits against risks, as well as safety in use against risk of use. Communicating brief messages against catchy questions with positive and pragmatic approach resulted in making website on radiation protection of patients (RPOP) as the top website of the world in this area. Credibility of information has been maintained. The results show immense outreach in 213 countries/territories. PMID- 25813479 TI - Analysis of factors correlating with medical radiological examination frequencies. AB - The European Commission (EC) funded project Dose Datamed 2 (DDM2) had two objectives: to collect available data on patient doses from the radiodiagnostic procedures (X-ray and nuclear medicine) in Europe, and to facilitate the implementation of the Radiation Protection 154 Guidelines (RP154). Besides the collection of frequency and dose data, two questionnaires were issued to gather information about medical radiological imaging. This article analyses a possible correlation between the collected frequency data, selected variables from the results of the detailed questionnaire and national economic data. Based on a 35 countries dataset, there is no correlation between the gross domestic product (GDP) and the total number of X-ray examinations in a country. However, there is a significant correlation (p < 0.01) between the GDP and the overall CT examination frequency. High income countries perform more CT examinations per inhabitant. That suggests that planar X-ray examinations are replaced by CT examinations. PMID- 25813480 TI - Dose tracking and radiology department management. AB - The purpose of this work was to review the reasonable measures that should be implemented as part of a routine practice in the process of managing CT radiation risks in a typical average radiology department. Based on 6 y of experience in the management of a general radiology department and the newly implemented supportive software for dose tracking, analysing and reporting, the approach towards radiation risk reduction is presented. Thanks to this approach, some problems have been resolved, and reasonable measures have been introduced into daily practice. PMID- 25813481 TI - Eye dose assessment and management: overview. AB - Some publications have shown that Hp(0.07) or even Hp(10) can be used as good operational quantities for X-rays in view of difficulties with Hp(3). With increasing awareness, there is tendency to use whatever dosimeter is available with correction factor to estimate eye lens dose. The best position for an eye lens dosimeter has been reported to be at the side of the head nearest to the radiation source, close to the eye. Recent studies have reported eye doses with cone beam CT (CBCT) both for patients and staff, and there are many papers reporting eye lens doses to staff in nuclear medicine. To minimise the dose to eyes, the user can take advantage of a feature of CBCT of projections acquired over an angular span of 180 degrees plus cone angle of the X-ray tube and with tube under scan arcs. PMID- 25813482 TI - Preliminary testing of GaN-based dosimeters for electron beam radiotherapy. AB - The response of an implantable in vivo dosimetric system based on gallium nitride radioluminescence was investigated for electron beam radiotherapy using ELEKTA SLi and VARIAN Clinac 2100 CD Linear Accelerators. A bi-channel method has been implemented for fibre background rejection. The percentage depth dose (PDD) profiles were measured in polymethyl methacrylate for 6, 12 and 18 MeV electron beams. The PDD results were in excellent agreement with those measured with reference to ionisation chambers. PMID- 25813483 TI - Assessment of patient dose reduction by bismuth shielding in CT using measurements, GEANT4 and MCNPX simulations. AB - This work reports on the use of two different Monte Carlo codes (GEANT4 and MCNPX) for assessing the dose reduction using bismuth shields in computer tomography (CT) procedures in order to protect radiosensitive organs such as eye lens, thyroid and breast. Measurements were performed using head and body PMMA phantoms and an ionisation chamber placed in five different positions of the phantom. Simulations were performed to estimate Computed Tomography Dose Index values using GEANT4 and MCNPX. The relative differences between measurements and simulations were <10 %. The dose reduction arising from the use of bismuth shielding ranges from 2 to 45 %, depending on the position of the bismuth shield. The percentage of dose reduction was more significant for the area covered by the bismuth shielding (36 % for eye lens, 39 % for thyroid and 45 % for breast shields). PMID- 25813484 TI - Inspection of cardiology departments in Norway: are they making it great in radiation protection? AB - Staff involved in interventional cardiology receive the highest occupational doses in Norway, and skin burns of patients have been reported. To identify the level of radiation protection (RP) for patients and staff, and compliance with the RP regulation, the Norwegian Radiation Protection Authority carried out inspections. The inspections were conducted (2013-14) as quality system reviews, based on document reviews, interviews, on-site inspections and observations of interventional procedures. The inspections revealed that most of the hospitals had non-compliances according to the RP regulation. Most deviations were associated with education in RP and follow-up of patients who had received high radiation doses. Lack of systematic optimisation of procedures and estimation of eye lens doses to evaluate the risk for cataracts were also common. Inspections turned out to increase the awareness of RP in cardiology and are identified as an effective tool for improving RP. PMID- 25813485 TI - Stress of endoplasmic reticulum modulates differentiation and lipogenesis of human adipocytes. AB - BACKGROUND: Adipocytes are cells specialized for storage of neutral lipids. This storage capacity is dependent on lipogenesis and is diminished in obesity. The reason for the decline in lipogenic activity of adipocytes in obesity remains unknown. Recent data show that lipogenesis in liver is regulated by pathways initiated by endoplasmic reticulum stress (ERS). Thus, we aimed at investigating the effect of ERS on lipogenesis in adipose cells. METHODS: Preadipocytes were isolated from subcutaneous abdominal adipose tissue from obese volunteers and in vitro differentiated into adipocytes. ERS was induced pharmacologically by thapsigargin (TG) or tunicamycin (TM). Activation of Unfolded Protein Response pathway (UPR) was monitored on the level of eIF2alpha phosphorylation and mRNA expression of downstream targets of UPR sensors. Adipogenic and lipogenic capacity was evaluated by Oil Red O staining, measurement of incorporation of radio-labelled glucose or acetic acid into lipids and mRNA analysis of adipogenic/lipogenic markers. RESULTS: Exposition of adipocytes to high doses of TG (100 nM) and TM (1 MUg/ml) for 1-24 h enhanced expression of several UPR markers (HSPA5, EDEM1, ATF4, XBP1s) and phosphorylation of eIF2alpha. This acute ERS substantially inhibited expression of lipogenic genes (DGAT2, FASN, SCD1) and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to low dose of TG (2.5 nM) during the early phases of adipogenic conversion of preadipocytes impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in mature adipocytes. CONCLUSIONS: Acute ERS weakened a capacity of mature adipocytes to store lipids and chronic ERS diminished adipogenic potential of preadipocytes. PMID- 25813486 TI - Thrombin generation in abdominal sepsis is Rho-kinase-dependent. AB - Sepsis causes severe derangements of the coagulation system. However, the signaling mechanisms regulating sepsis-induced thrombin generation remain elusive. Herein, we hypothesized that Rho-kinase might be an important regulator of thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57Bl/6 mice. Thrombin generation, coagulation factors, lung histology and myeloperoxidase (MPO) activity were determined 6 h and 24 h after induction of CLP. Induction of CLP triggered a systemic inflammatory response characterized by neutrophil accumulation and tissue injury in the lung as well as thrombocytopenia and leukocytopenia. Administration of Y 27632, a Rho-kinase inhibitor, attenuated these markers of systemic inflammation in CLP animals. Moreover, peak thrombin formation was decreased by 77% and 81% in plasma from mice 6 h and 24 h after induction of CLP. Total thrombin generation was reduced by 64% and 67% 6 h and 24 h after CLP induction, respectively. Notably, administration of Y-27632 increased peak formation by 99% and total thrombin generation by 66% in plasma from septic animals. In addition, CLP markedly decreased plasma levels of prothrombin, factor V and factor X at 6 h and 24 h. Interestingly, Rho-kinase inhibition significantly enhanced levels of prothrombin, factor V and factor X in plasma from septic mice. In addition, inhibition of Rho-kinase decreased CLP-induced elevations of CXCL2 by 36% and interleukin-6 by 38%. These novel findings suggest that sepsis-induced thrombin generation is regulated by Rho-kinase. Moreover, inhibition of Rho-kinase reverses sepsis-evoked consumption of coagulation factors. Thus, our results show that targeting Rho-kinase signaling might protect against coagulation dysfunction in abdominal sepsis. PMID- 25813487 TI - Safely treating hepatitis C in patients with HIV or hepatitis B virus coinfection. AB - INTRODUCTION: There are several clinical trials and prospective studies which support the use of direct-acting antiviral agents (DAAs) in hepatitis C virus (HCV)-coinfected patients. In this review, the safety of DAAs in HCV patients coinfected with hepatitis B virus (HBV) or HIV has been evaluated. AREAS COVERED: All available prospective studies, clinical trials and congress abstracts in the English language that assessed the safety and efficacy of DAAs in HCV coinfections have been considered. EXPERT OPINION: The newer DAAs in the treatment of HCV/HIV-coinfected patients resolved major limitations of the first generation protease inhibitors including complex dosing, poor tolerability and interactions with antiretroviral drugs. There are not yet enough data regarding the safety and efficacy of DAAs in some coinfected patients with comorbidities, nor for pregnant, lactating or pediatric patients. Evaluating the safety and efficacy of these agents in these subgroups with HCV coinfection is recommended for future studies. The role of new direct-acting antiviral-based therapy for the treatment of patients with HCV/HBV coinfection remains to be evaluated. PMID- 25813488 TI - Chlorination of the beta-triketone herbicides tembotrione and sulcotrione: Kinetic and mechanistic study, transformation products identification and toxicity. AB - The fate of tembotrione (TBT) and sulcotrione (SCT) during chlorination was investigated in this work. Chlorination kinetics of TBT and SCT were studied by using a continuous-flow reactor in the pH range 2-12 with an excess of total chlorine. Second-order reaction was observed and rate constants of 9.69 (+/-0.15) * 10(3) M(-1)s(-1) for TBT and 9.48 (+/-0.62) * 10(3) M(-1)s(-1) for SCT were obtained at pH 7. Intrinsic rate constants for the elementary reactions of chlorine species with neutral and deprotonated forms of TBT and SCT were also calculated, leading to the conclusion that the reaction between hypochlorous acid and the deprotonated form of the pesticide is predominant at neutral pH. Several degradation products during chlorination of TBT and SCT were identified by LC MS/MS and a reaction pathway was proposed. Chlorine initially reacted on the alpha-carbon of the three carbonyl functional groups. This reaction initiated the well-known haloform reaction and produced chloroform as end-product. Molar yields of 0.99 mol CHCl3/mol and 0.91 mol CHCl3/mol were obtained for TBT and SCT, respectively at pH 7. Moreover, a toxicity evaluation using Vibrio fischeri was carried out to study the toxicity pattern during TBT and SCT chlorination. An increase in toxicity was observed but it could not be clearly assigned to the identified byproducts. PMID- 25813489 TI - Predictive statistical models linking antecedent meteorological conditions and waterway bacterial contamination in urban waterways. AB - Although the relationships between meteorological conditions and waterway bacterial contamination are being better understood, statistical models capable of fully leveraging these links have not been developed for highly urbanized settings. We present a hierarchical Bayesian regression model for predicting transient fecal indicator bacteria contamination episodes in urban waterways. Canals, creeks, and rivers of the New York City harbor system are used to examine the model. The model configuration facilitates the hierarchical structure of the underlying system with weekly observations nested within sampling sites, which in turn were nested inside of the harbor network. Models are compared using cross validation and a variety of Bayesian and classical model fit statistics. The uncertainty of predicted enterococci concentration values is reflected by sampling from the posterior predictive distribution. Issuing predictions with the uncertainty reasonably reflected allows a water manager or a monitoring agency to issue warnings that better reflect the underlying risk of exposure. A model using only antecedent meteorological conditions is shown to correctly classify safe and unsafe levels of enterococci with good accuracy. The hierarchical Bayesian regression approach is most valuable where transient fecal indicator bacteria contamination is problematic and drainage network data are scarce. PMID- 25813490 TI - Simultaneous phenol removal, nitrification and denitrification using microbial fuel cell technology. AB - Here we show that concomitant removal of phenol and nitrogen can be accomplished in a single dual-chamber microbial fuel cell (MFC) reactor, in which the two chambers are separated with an anion-exchange membrane. A series of experiments were performed with ammonium (230 NH4(+)-N mg L(-1)) and phenol (with concentrations varying from 0 to 1400 mg L(-1)) fed to the aerobic cathode chamber of the MFC. Experimental results demonstrated that no apparent inhibitory effect of phenol on the nitrifying reaction was noted even at the phenol concentration up to 600 mg L(-1). For all the experiments, simultaneous nitrification and denitrification was achieved in the MFC. In comparison to the traditional aerobic bioreactor (ABR) and the same MFC run under the open-circuit condition, the MFC reactor allowed less inhibition of nitrification to phenol exposure and higher rate of nitrogen removal. The data of bacterial analysis revealed that electrochemically active bacteria and denitrifiers in the anaerobic chamber play a significant role in electricity generation and anaerobic denitrification, respectively, while phenol-degrading bacteria, nitrifiers, and denitrifiers in the aerobic cathode chamber are responsible for phenol oxidation, aerobic nitrification and aerobic denitrification, respectively. These results imply that the MFC holds potential for simultaneous removal of phenolic compounds and nitrogen contained in some particular industrial wastewaters. PMID- 25813491 TI - Distribution of perfluorooctane sulfonate isomers and predicted risk of thyroid hormonal perturbation in drinking water. AB - We documented the distribution of seven perfluorooctane sulfonate (PFOS) isomers in drinking water in Jiangsu Province, China. Compared to the 30% proportion of branched PFOS in technical PFOS, the levels of branched PFOS in drinking water increased to 31.8%-44.6% of total PFOS. Because of previous risk assessment without considering the PFOS isomer profile and the toxicity of individual PFOS isomers, here we performed a new health risk assessment of PFOS for thyroid hormonal perturbation in drinking water with the contribution from individual PFOS isomers. The risk quotients (RQs) of individual PFOS isomers indicated that linear PFOS contributed most to the risk among all the target PFOS isomers (83.0% 90.2% of the total PFOS RQ), and that risk from 6m-PFOS (5.2%-11.9% of the total PFOS RQ) was higher than that from other branched PFOS isomers. We found that the risks associated with PFOS in drinking water would be overestimated by 10.0% 91.7% if contributions from individual PFOS isomers were not considered. The results revealed that the PFOS isomer profile and the toxicity of individual PFOS isomers were important factors in health risk assessment of PFOS and should be considered in the future risk assessments. PMID- 25813492 TI - NAD+ treatment can prevent rotenone-induced increases in DNA damage, Bax levels and nuclear translocation of apoptosis-inducing factor in differentiated PC12 cells. AB - Nicotinamide adenine dinucleotide (NAD(+)) plays critical roles in energy metabolism, mitochondrial functions, calcium homeostasis and immunological functions. Our previous studies have found that NAD(+) administration can profoundly decrease ischemic brain injury and traumatic brain injury. Our recent study has also provided first direct evidence indicating that NAD(+) treatment can decrease cellular apoptosis, while the mechanisms underlying this protective effect remain unclear. In our current study, we determined the effects of NAD(+) treatment on several major factors in apoptosis and necrosis, including levels of Bax and nuclear translocation of apoptosis-inducing factor (AIF), as well as levels of DNA double-strand breaks (DSBs) and intracellular ATP in rotenone treated differentiated PC12 cells. We found that NAD(+) treatment can markedly attenuate the rotenone-induced increases in the levels of Bax and nuclear translocation of AIF in the cells. We further found that NAD(+) treatment can significantly attenuate the rotenone-induced increase in the levels of DSBs and decrease in the intracellular ATP levels. Collectively, our study has suggested mechanisms underlying the preventive effects of NAD(+) on apoptosis, which has highlighted the therapeutic potential of NAD(+) for decreasing apoptotic changes in multiple major diseases. PMID- 25813493 TI - Egocentric and geocentric navigation during extremely long foraging paths of desert ants. AB - Desert ants, Cataglyphis fortis, navigate individually in the salt pans of Tunisia by means of path integration. However, as path integration is error prone, the ants in addition use visual and olfactory cues to pinpoint their nest entrance. It has been shown that the accuracy of the path integrator as well as the ants' confidence in that egocentric navigational tool decreases with increasing foraging distance. Here, we show that despite the accumulating errors, even after far-reaching foraging runs path integration provides the ants with surprisingly accurate information regarding the nest position. However, in addition, the ants take into account distant visual cues that are most probably provided by the patterns along the horizon line behind the nest entrance. PMID- 25813494 TI - Selective interfacial synthesis of metal-organic frameworks on a polybenzimidazole hollow fiber membrane for gas separation. AB - Metal-organic frameworks (MOFs) have gained immense attention as new age materials due to their tuneable properties and diverse applicability. However, efforts on developing promising materials for membrane based gas separation, and control over the crystal growth positions on polymeric hollow fiber membranes still remain key challenges. In this investigation, a new, convenient and scalable room temperature interfacial method for growing MOFs (ZIF-8 and CuBTC) on either the outer or inner side of a polybenzimidazole based hollow fiber (PBI BuI-HF) membrane surface has been achieved in a controlled manner. This was made possible by the appropriate selection of an immiscible solvent pair and the synthetic conditions. The growth of MOFs on the PBI-BuI-HF membrane by the interfacial method was continuous and showed an appreciable gas separation performance, conveying promise for their applicability. PMID- 25813495 TI - Guiding fluid resuscitation in critically ill patients: how to evaluate the available tools? PMID- 25813496 TI - Cranioplasty after decompressive craniectomy: about bone flap preservation. PMID- 25813497 TI - Development of a radiation track structure clustering algorithm for the prediction of DNA DSB yields and radiation induced cell death in Eukaryotic cells. AB - The preliminary framework of a combined radiobiological model is developed and calibrated in the current work. The model simulates the production of individual cells forming a tumour, the spatial distribution of individual ionization events (using Geant4-DNA) and the stochastic biochemical repair of DNA double strand breaks (DSBs) leading to the prediction of survival or death of individual cells. In the current work, we expand upon a previously developed tumour generation and irradiation model to include a stochastic ionization damage clustering and DNA lesion repair model. The Geant4 code enabled the positions of each ionization event in the cells to be simulated and recorded for analysis. An algorithm was developed to cluster the ionization events in each cell into simple and complex double strand breaks. The two lesion kinetic (TLK) model was then adapted to predict DSB repair kinetics and the resultant cell survival curve. The parameters in the cell survival model were then calibrated using experimental cell survival data of V79 cells after low energy proton irradiation. A monolayer of V79 cells was simulated using the tumour generation code developed previously. The cells were then irradiated by protons with mean energies of 0.76 MeV and 1.9 MeV using a customized version of Geant4. By replicating the experimental parameters of a low energy proton irradiation experiment and calibrating the model with two sets of data, the model is now capable of predicting V79 cell survival after low energy (<2 MeV) proton irradiation for a custom set of input parameters. The novelty of this model is the realistic cellular geometry which can be irradiated using Geant4-DNA and the method in which the double strand breaks are predicted from clustering the spatial distribution of ionisation events. Unlike the original TLK model which calculates a tumour average cell survival probability, the cell survival probability is calculated for each cell in the geometric tumour model developed in the current work. This model uses fundamental measurable microscopic quantities such as genome length rather than macroscopic radiobiological quantities such as alpha/beta ratios. This means that the model can be theoretically used under a wide range of conditions with a single set of input parameters once calibrated for a given cell line. PMID- 25813499 TI - Expansion and retrenchment of the Swedish welfare state: a long-term approach. AB - In this article, we will undertake a long-term analysis of the evolution of the Swedish welfare state, seeking to explain that evolution through the use of a systemic approach. That is, our approach will consider the interrelations between economic growth (EG), the sociopolitical institutional framework (IF), and the welfare state (WS)-understood as a set of institutions embracing the labor market and its regulation, the tax system, and the so-called social wage-in order to find the main variables that elucidate its evolution. We will show that the expansive phase of the Swedish welfare state can be explained by the symbiotic relationships developed in the WS-EG-IF interaction, whereas the period of welfare state retrenchment is one result of changes operating within the sociopolitical IF and EG bases. PMID- 25813498 TI - Antibody-mediated rejection in pediatric kidney transplantation: pathophysiology, diagnosis, and management. AB - Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR. PMID- 25813500 TI - Three decades of neoliberalism in Mexico: the destruction of society. AB - Neoliberalism has been implemented in Latin America for about three decades. This article reviews Mexico's neoliberal trajectory to illustrate the political, economic, and social alterations that have resulted from this process. It finds that representative democracy has been perverted through fear, putting central political decisions in the hands of power groups with special interests. The border between the state of law and the state of exception is blurred. Economic structural adjustment with liberalization and privatization has provoked recurrent crisis, but has been maintained, leading to the destruction of the national productive structure in favor of supranational corporations, particularly financial capital. The association between criminal economy and economic criminality is also discussed. The privatization of social benefits and services requires state subsidies and allows the privatization of profits and the socialization of losses. The social impact of this process has been devastating, with a polarized income distribution, falling wages, increased precarious jobs, rising inequality, and extreme violence. Health conditions have also deteriorated and disorders associated with violence, chronic stress, and a changing nutritional culture have become dominating. However, in Latin America, massive, organized political and social mobilization has broken the vicious neoliberal circle and elected progressive governments that are struggling to reverse social and economic devastation. PMID- 25813501 TI - Social class and mental health: testing exploitation as a relational determinant of depression. AB - This study tests whether social class exploitation operates as a relational mechanism that generates mental health inequalities in the nursing home industry. We ask, does social class exploitation (i.e., the acquisition of economic benefits from the labor of those who are dominated) have a systematic and predictable impact on depression among nursing assistants? Using cross-sectional data from 868 nursing assistants employed in 50 nursing homes in three U.S. states, we measure social class exploitation as "ownership type" (private for profit, private not-for-profit, and public) and "managerial domination" (labor relations violations, perceptions of labor-management conflict). Depression is assessed using the original and revised versions of the Center for Epidemiologic Studies Depression Scale (CES-D and CESD-R). Using two-level logistic regressions, we find that private for-profit ownership and higher managerial domination are predictive of depression among nursing assistants even after adjustment for potential confounders and mediators. Our findings confirm the theoretical and empirical value of applying a social class approach to understanding how mental health inequalities are generated through exploitative mechanisms. Ownership type and managerial domination appear to affect depression through social relations that generate mental health inequalities through the process of acquiring profits, controlling production, supervising and monitoring labor, and enforcing disciplinary sanctions. PMID- 25813502 TI - The role of ethnic and rural discrimination in the relationship between income inequality and health in Guatemala. AB - This article seeks to understand in the ways in which income inequality can affect children's health (z-score of stunting) in Guatemala. We postulate that there are several transmission channels through which income inequality can affect health and that the children's ethnic and rural origins influence the size and direction of this effect. The methodology employed is systems of simultaneous equations (three-stage least squares and generalized method of moments). Our results highlight the importance of rural and indigenous characteristics in the relationship between income inequality and child health and indicate that the most important transmission channels are household income levels and maternal education. PMID- 25813503 TI - International recruitment of health workers: British lessons for Europe? Emerging concerns and future research recommendations. AB - Immigration as a solution to staff and skill shortages in the health system is increasingly on the agenda in the European Union. This article highlights the related social and policy dilemmas by comparing a new destination country with an old destination country: Spain and the United Kingdom. After describing the challenges met by the United Kingdom, we ask how well-prepared Spain is to face the same issues. In particular, attention is paid to the occupational mobility of health workers after entry and to how immigration as a staffing solution poses new political and social challenges. Through a review of background information regarding the immigration of health workers in the two countries and the preliminary analysis of 15 exploratory interviews, we aim to identify the primary trends and key concerns for future analysis. Although our interviews only allow us to draw tentative conclusions, they do highlight emerging issues to be explored in the near future. Our conclusions show that many of the problems traditionally encountered in the United Kingdom are now emerging in Spain, suggesting scope for further collaboration among government, employers, and other stakeholders across the European Union. PMID- 25813504 TI - "The Major Forces that Need to Back Medical Tourism Were ... in Alignment": Championing Development of Barbados's Medical Tourism Sector. AB - Governments around the world have expressed interest in developing local medical tourism sectors, framing the industry as an opportunity for economic growth and health system improvement. This article addresses questions about how the desire to develop a medical tourism sector in a country emerges and which stakeholders are involved in both creating momentum and informing its progress. Presenting a thematic analysis of 19 key informant interviews conducted with domestic and international stakeholders in Barbados's medical tourism sector in 2011, we examine the roles that "actors" and "champions" at home and abroad have played in the sector's development. Physicians and the Barbadian government, along with international investors, the Medical Tourism Association, and development agencies, have promoted the industry, while actors such as medical tourists and international hospital accreditation companies are passively framing the terms of how medical tourism is unfolding in Barbados. Within this context, we seek to better understand the roles and relationships of various actors and champions implicated in the development of medical tourism in order to provide a more nuanced understanding of how the sector is emerging in Barbados and elsewhere and how its development might impact equitable health system development. PMID- 25813505 TI - Sociopolitical determinants of international health policy. AB - For decades, two opposing logics have dominated the health policy debate: a comprehensive health care approach, with the 1978 Alma Ata Declaration as its cornerstone, and a private competition logic, emphasizing the role of the private sector. We present this debate and its influence on international health policies in the context of changing global economic and sociopolitical power relations in the second half of the last century. The neoliberal approach is illustrated with Chile's health sector reform in the 1980s and the Colombian reform since 1993. The comprehensive "public logic" is shown through the social insurance models in Costa Rica and in Brazil and through the national public health systems in Cuba since 1959 and in Nicaragua during the 1980s. These experiences emphasize that health care systems do not naturally gravitate toward greater fairness and efficiency, but require deliberate policy decisions. PMID- 25813506 TI - An empirical evaluation of devolving administrative control to Costa Rican hospital and clinic directors. AB - In the early 2000s, Costa Rica implemented comprehensive reforms of its health care system, including devolving administrative power from the central government to some providers that remain part of the national system. In this article, we evaluate how this aspect of the reform affected clinic efficiency and population health by analyzing administrative data on regional providers and mortality rates in local areas. We compare changes in outcomes across time between areas that signed performance contracts with the central government and received limited budgetary control to those that continued to be managed directly by the central government. We believe the reform created opportunities for providers to become more efficient and effective. Our results suggest that the reform significantly decreased costs without adversely affecting quality of care or population health. PMID- 25813507 TI - Liquid culture production of microsclerotia and submerged conidia by Trichoderma harzianum active against damping-off disease caused by Rhizoctonia solani. AB - Media and culturing protocols were identified that supported the formation of submerged conidia and microsclerotia (MS) by Trichoderma harzianum Rifai strain T 22 using liquid culture fermentation. Liquid media with a higher carbon concentration (36 g L(-1)) promoted MS formation at all C:N ratios tested. Hyphae aggregated to form MS after 2 d growth and after 7 d MS were fully melanized. This is the first report of MS formation by T. harzianum or any species of Trichoderma. Furthermore, submerged conidia formation was induced by liquid culture media, but yields, desiccation tolerance, and storage stability varied with C:N ratio and carbon rate. Air-dried MS granules (<4% moisture) retained excellent shelf life under cool and unrefrigerated storage conditions with no loss in conidial production. A low-cost complex nitrogen source based on cottonseed flour effectively supported high MS yields. Amending potting mix with dried MS formulations reduced or eliminated damping-off of melon seedlings caused by Rhizoctonia solani. Together, the results provide insights into the liquid culture production, stabilization process, and bioefficacy of the hitherto unreported MS of T. harzianum as a potential biofungicide for use in integrated management programs against soilborne diseases. PMID- 25813508 TI - Aflatoxin-producing fungi in maize field soils from sea level to over 2000 masl: a three year study in Sonora, Mexico. AB - Aflatoxins, highly toxic carcinogens produced by several members of Aspergillus section Flavi, contaminate crops in temperate zones. In the state of Sonora, Mexico, maize is cultivated from 0 to 2100 masl with diverse cultivation practices. This is typical of the nation. In order to design better sampling strategies across Mexico, aflatoxin-producing fungal communities associated with maize production during 2006, 2007, and 2008 in Sonora were investigated in four agro-ecological zones (AEZ) at varying elevation. Fungal communities were dominated by the Aspergillus flavus L strain morphotype (46%), but variation occurred between years and among AEZ. Several atoxigenic isolates with potential to be used as biocontrol agents for aflatoxin mitigation were detected in all AEZ. The characteristics of each AEZ had minimal influences on fungal community structure and should not be a major consideration for future sampling designs for Mexico. Insights into the dynamics and stability of aflatoxin-producing fungal communities across AEZ are discussed. PMID- 25813510 TI - New insights into the characterization of Colletotrichum species associated with apple diseases in southern Brazil and Uruguay. AB - Colletotrichum species are associated with Apple bitter rot (ABR) and Glomerella leaf spot (GLS). Whereas both apple diseases occur frequently in Brazil, only the former has been reported in Uruguay. This work was aimed at identifying and comparing morpho-cultural characteristics and pathogenic variability of thirty nine Colletotrichum isolates from both countries. Sequencing of the internal transcribed spacer (ITS) rDNA, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and beta-tubulin (TUB2) allowed the identification of three species causing ABR and GLS in Brazil, i.e., Colletotrichum fructicola, Colletotrichum karstii, and Colletotrichum nymphaeae; and three species causing ABR in Uruguay, i.e., C. fructicola, Colletotrichum theobromicola, and Colletotrichum melonis. Six groups of colony colours were recorded with group 1 (mycelium white to pink and in reverse pinkish) and group 2 (mycelium white to grey and in reverse pinkish) the most frequent. Isolates of C. fructicola and C. theobromicola were sensitive to benomyl, while C. karstii, C. nymphaeae, and C. melonis were resistant. Conidia were predominantly cylindrical for C. fructicola and C. karstii, fusiform for C. nymphaeae and C. melonis, and obclavate for C. theobromicola. Brazilian isolates caused ABR in wounded fruits, but only five in non-wounded ones. Uruguayan isolates produced symptoms in fruits with or without previous wounding. All Brazilian isolates from GLS and twelve from ABR were able to cause GLS symptoms, while a sole Uruguayan ABR-isolate caused leaf spot symptoms. This study gives a better insight on the new species causing apple disease in both countries and discusses their pathogenic potential. PMID- 25813509 TI - Cryptic diversity in the sequestrate genus Stephanospora (Stephanosporaceae: Agaricales) in Australasia. AB - Historically a single name, Stephanospora flava, was applied to all collections of Stephanospora in Australasia. We used morphological characters with molecular support to differentiate and describe nine novel cryptic species, and refine the circumscription of S. flava. Stephanospora flava is herein restricted to bispored collections from Tasmania, and the quadrisporic Stephanospora tetraspora is raised to species level. Six species (four new) are endemic to Australia, S. flava s.s, S. tetraspora comb. nov., Stephanospora sheoak, Stephanospora cribbae, Stephanospora hystrispora, and Stephanospora occidentiaustralis. Three species Stephanospora poropingao, Stephanospora pounamu, and Stephanospora kanuka are endemic to New Zealand; and one species, Stephanospora aorangi occurs in both Australia and New Zealand. Two other new species, Stephanospora novae-caledoniae and Stephanospora papua, are endemic to New Caledonia or Papua New Guinea, respectively. Analyses of three nuclear gene regions (ITS, ef-1, and LSU) are consistent with current classifications of the family Stephanosporaceae. Athelidium aurantiacum is an outlier, with a strongly supported core of Cristinia (Clade I), Lindtneria (Clade II), Stephanospora, Mayamontana, and Lindtneria trachyspora (Clade III), and a novel lineage of environmental and sporocarp sequences (Clade IV). Taxonomic and nomenclatural issues raised by the presence of both type species of Stephanospora (Stephanospora caroticolor) and Lindtneria (L. trachyspora) in the same clade are discussed. PMID- 25813511 TI - Long-distance dispersal and recolonization of a fire-destroyed niche by a mite associated fungus. AB - The Fynbos Biome in the Core Cape Subregion of South Africa is prone to recurrent fires that can clear vast areas of vegetation. Between periods of fire, ophiostomatoid fungi colonize the fruiting structures of serotinous Protea species through arthropod-mediated dispersal. Using microsatellite markers, this study considered the process whereby a Protea-associated ophiostomatoid fungus, Knoxdaviesia proteae, recolonizes a burnt area. The genetic diversity, composition and structure of fungal populations from young P. repens plants in a recently burnt area were compared to populations from the adjacent, unburnt Protea population. The only difference between K. proteae populations from the two areas was found in the number of private alleles, which was significantly higher in the unburnt population. The population structure, although weak, indicated that most K. proteae individuals from recently burnt areas originated from the unburnt population. However, individuals from unsampled source populations were also detected. This, together with the lack of isolation-by distance across the landscape, suggested that long-distance dispersal is important for K. proteae to recolonize burnt areas. Similarly, the high level of gene flow and low differentiation observed between two distantly separated K. proteae populations also supported the existence of long-distance dispersal. The genetic cohesiveness of populations over long distances and the genetic diversity within populations could be attributed to frequent multiple fungal migration events mediated primarily by arthropods but, potentially, also by birds. PMID- 25813512 TI - Variations in oxygen concentration cause differential antioxidant response and expression of related genes in Beauveria bassiana. AB - The entomopathogenic fungus Beauveria bassiana is widely used in pest biocontrol strategies. We evaluated both the antioxidant response mediated by compatible solutes, trehalose or mannitol, and the expression of related genes using oxygen pulses at three oxygen concentrations in solid state culture (SSC): normal atmosphere (21% O2), low oxygen (16% O2) and enriched oxygen (26% O2). Trehalose concentration decreased 75% after atmospheric modifications in the cultures, whereas mannitol synthesis was three-fold higher under the 16% O2 pulses relative to normal atmosphere (100 and 30 MUg mannitol mg(-1) biomass, respectively). Confirming this result, expression of the mpd gene, coding for mannitol-1-P dehydrogenase (MPD), increased up to 1.4 times after O2 pulses. The expression of the bbrgs1 gene, encoding a regulatory G protein related to conidiation, was analysed to explain previously reported differences in conidial production. Surprisingly, expression of bbrgs1 decreased after atmospheric modification. Finally, principal component analysis (PCA) indicated that 83.39% of the variability in the data could be explained by two components. This analysis corroborated the positive correlation between mannitol concentration and mpd gene expression, as well as the negative correlation between conidial production and bbrgs1 gene expression. This study contributes to understanding of antioxidant and molecular response of B. bassiana induced under oxidant conditions. PMID- 25813513 TI - Changes in Trichoderma asperellum enzyme expression during parasitism of the cotton root rot pathogen Phymatotrichopsis omnivora. AB - The present study determined the activity of hydrolytic enzymes and the gene expression during direct interaction of the novelTrichoderma asperellumstrains TC74 (high antagonistic capacity) and Th1 (low antagonistic capacity) with the plant pathogenic fungusPhymatotrichopsis omnivora. TheT. asperellumstrains produced the lytic enzymes endochitinase, N-acetylglucosaminidase and beta-1,3 glucanase when grown on two different carbon sources. The response of strain TC74 was more rapid than that of strain Th1. When directly exposed toP. omnivora, theT. asperellumstrains expressed one endochitinase and one N acetylglucosaminidase, as shown by RT-PCR experiments. The strains also expressed two beta-1,3-exoglucanases (designated as exg290 and exg343). TC74 and Th1 were able to express their chitinases and beta-1,3-exoglucanase activities when grown on the different carbon sources tested. When theT. asperellumstrains were grown in the presence ofP. omnivora, qRT-PCR experiments revealed that mycoparasitism related genes were first expressed prior to contact between the antagonist and the pathogen's mycelium. As a general response, the transcription level of these genes was increased at the post-contact stage. Although TC74 and Th1 both express the assayed genes when grown in direct contact withP. omnivora, significant differences in the time, intensity and kinetics of the response were observed. PMID- 25813514 TI - Production of hydrocarbons by Aspergillus carbonarius ITEM 5010. AB - The filamentous fungus, Asperigillus carbonarius, is able to produce a series of hydrocarbons in liquid culture using lignocellulosic biomasses, such as corn stover and switch grass as carbon source. The hydrocarbons produced by the fungus show similarity to jet fuel composition and might have industrial application. The production of hydrocarbons was found to be dependent on type of media used. Therefore, ten different carbon sources (oat meal, wheat bran, glucose, carboxymethyl cellulose, avicel, xylan, corn stover, switch grass, pretreated corn stover, and pretreated switch grass) were tested to identify the maximum number and quantity of hydrocarbons produced. Several hydrocarbons were produced include undecane, dodecane, tetradecane, hexadecane 2,4-dimethylhexane, 4 methylheptane, 3-methyl-1-butanol, ethyl benzene, o-xylene. Oatmeal was found to be the carbon source resulting in the largest amounts of hydrocarbon products. The production of fungal hydrocarbons, especially from lignocellulosic biomasses, holds a great potential for future biofuel production whenever our knowledge on regulators and pathways increases. PMID- 25813515 TI - Dissecting the formation, structure and barrier function of the stratum corneum. AB - The skin is the largest organ of the mammalian body. The outermost layer of mammalian skin, the stratum corneum (SC) of the epidermis, consists of piles of dead corneocytes that are the end-products of terminal differentiation of epidermal keratinocytes. The SC performs a crucial barrier function of epidermis. Langerhans cells, when activated, extend their dendrites through tight junctions just beneath the SC to capture external antigens. Recently, knowledge of the biology of corneocytes ('corneobiology') has progressed rapidly and many key factors that modulate its barrier function have been identified and characterized. In this review article on the SC, we summarize its evolution, formation, structure and function. Cornification is an important step of SC formation at the conversion of living epithelial cells to dead corneocytes, and consists of three major steps: formation of the intracellular keratin network, cornified envelopes and intercellular lipids. After cornification, the SC undergoes chemical reactions to form the mature SC with different functional layers. Finally, the SC is shed off at the surface ('desquamation'), mediated by a cascade of several proteases. This review will be helpful to understand our expanding knowledge of the biology of the SC, where immunity meets external antigens. PMID- 25813516 TI - Innovation of a syringe needle auto-detaching device for clinicians. AB - BACKGROUND: Needle-stick injuries accounts for a great proportion of all medical accidents in developing and undeveloped countries. The main cause of needle-stick accident injuries is the medical personnel's ''recovering'' the needle action after injection. OBJECTIVE: This study applies an electronic technique to the needling instrument for the purpose of automatically detaching the needle. The proposed method can effectively avoid needle-stick accident injury when ''recovering'' the needle. METHODS: The syringe needle auto-detaching device includes an abutment on which there is a turntable mechanism composed of a pedestal, a turn-table and a driving unit. A photo interrupter on the pedestal detects the rotational angle of the turntable and controls the stepping motor through a control circuit. An optical sensor is located on the upper end of the sensing mechanism. When the syringe is inserted into the syringe plughole the exposed portion of the needle will be detected by the optical sensor. After the syringe is placed into the plughole, its needle will be detected by the sensor. At this time the needle will be detached from the syringe and automatically fall down into the needle collection box. RESULTS: The syringe needle auto-detaching device was fatigue tested for an extensive period of time (A group: 1000 times/day for 3 ml, B group: 1000 times/day for 5 ml, C group: 1000 times/day for 3 ml and 5 ml staggered, D group: 1000 times/day for 3 ml and 5 ml randomized). The needle and syringe detachment rates were 100% in all test groups. CONCLUSIONS: The syringe needle auto-detaching device developed in this study, in that the clinician performs only one step to dispose a needle. Six syringe needle sets can be managed sequence second by second. The proposed device without all of the risk factors of the traditional syringe needle detachment device. PMID- 25813517 TI - Psychometric Properties of the Brief Autism Mealtime Behaviors Inventory. AB - The purpose of this study was to explore the psychometric properties of the Brief Autism Mealtime Behaviors Inventory (BAMBI). In a sample of 273 well characterized children with ASD, we explored the factor structure of the BAMBI, determined the internal consistency of a newly derived factor structure and provide an empirically derived cut-off for the BAMBI total score. The new psychometrically identified structure consists of 4 factors: (1) Food Selectivity, (2) Disruptive Mealtime Behaviors, (3) Food Refusal and (4) Mealtime Rigidity. Internal consistency was acceptable. A cut off score of 34 is suggested based on our results. The new 15-item BAMB with an alternative 4-factor structure with clinical utility is promising in assessing feeding and mealtime problems in children with ASD. PMID- 25813518 TI - [Editorial]. PMID- 25813519 TI - Phytochemical profile and therapeutic potential of Viscum album L. AB - Viscum album L., the European mistletoe, is a common species from the Viscaceae family. This evergreen hemiparasitic shrub grows on various trees and contains diverse, biologically active substances. Its chemical composition may vary depending on the time of harvest, species of the host tree and the manufacturing process. Among well-described and most active phytochemicals identified in V. album are lectins and viscotoxins, which play substantial role in cancer treatment because of their apoptotic and cytotoxic effects. Another group of compounds found in mistletoe are phenolic acids, phenylpropanoids and flavonoids with antioxidant and anti-inflammatory activities, which decrease blood pressure. Other mistletoe components include, among others, triterpenes with cytotoxic and apoptotic properties, and phytosterols, oligo- and polysaccharides. Extracts from the plant, especially aqueous, are applied in traditional and official medicine, among others in treating hypertension or arthritis. Potentially, it can also be used as a hepatoprotective or a sedative drug. PMID- 25813521 TI - Do patients with chronic rhinosinusitis benefit from consultation with an ENT doctor? AB - CONCLUSION: By consulting an ENT-doctor, patients with chronic rhinosinusitis (CRS), in the general population, receive disease information and adjustment of treatment which can improve disease-specific Quality-of-Life and may improve objective measurements. OBJECTIVES: This study aims to follow persons with clinical diagnosed CRS from the general population, to evaluate their benefit from consultation with an ENT-doctor in terms of severity of symptoms and Quality of-Life. METHODS: As part of a trans-European study, selected respondents to a survey questionnaire were invited for a clinical visit. Based on the European Position Paper on Rhinosinusitis and Nasal Polyps, persons were diagnosed with CRS and followed for 2 years. Quality-of-Life was measured using the Sino Nasal Outcome Test 22 and European Quality-of-Life - 5 Dimensions. Clinical examination included rhinoscopy, acoustic rhinometry, peak nasal inspiratory flow, smell test, and skin prick test. RESULTS: Out of 91 persons with CRS, only 42% had previously consulted an ENT-doctor, and 51% were in current treatment for CRS. Most patients were advised medical treatment and 20% underwent surgery. Disease specific Quality-of-Life, peak nasal inspiratory flow, olfactory function, and the nasal volume significantly increased over the 2-year period. PMID- 25813520 TI - Salicylic Acid-Based Polymers for Guided Bone Regeneration Using Bone Morphogenetic Protein-2. AB - Bone morphogenetic protein-2 (BMP-2) is used clinically to promote spinal fusion, treat complex tibia fractures, and to promote bone formation in craniomaxillofacial surgery. Excessive bone formation at sites where BMP-2 has been applied is an established complication and one that could be corrected by guided tissue regeneration methods. In this study, anti-inflammatory polymers containing salicylic acid [salicylic acid-based poly(anhydride-ester), SAPAE] were electrospun with polycaprolactone (PCL) to create thin flexible matrices for use as guided bone regeneration membranes. SAPAE polymers hydrolyze to release salicylic acid, which is a nonsteroidal anti-inflammatory drug. PCL was used to enhance the mechanical integrity of the matrices. Two different SAPAE-containing membranes were produced and compared: fast-degrading (FD-SAPAE) and slow degrading (SD-SAPAE) membranes that release salicylic acid at a faster and slower rate, respectively. Rat femur defects were treated with BMP-2 and wrapped with FD SAPAE, SD-SAPAE, or PCL membrane or were left unwrapped. The effects of different membranes on bone formation within and outside of the femur defects were measured by histomorphometry and microcomputed tomography. Bone formation within the defect was not affected by membrane wrapping at BMP-2 doses of 12 MUg or more. In contrast, the FD-SAPAE membrane significantly reduced bone formation outside the defect compared with all other treatments. The rapid release of salicylic acid from the FD-SAPAE membrane suggests that localized salicylic acid treatment during the first few days of BMP-2 treatment can limit ectopic bone formation. The data support development of SAPAE polymer membranes for guided bone regeneration applications as well as barriers to excessive bone formation. PMID- 25813523 TI - Importance and hurdles to drug discovery for neurological disease. AB - This is a critical time in neurotherapeutics. The prevalence of neurological disease, such as dementia, stroke, and peripheral neuropathy, is large and growing consequent to the aging population. The personal and societal impact of these disorders is enormous, and the number of novel therapies in the pipeline for these disorders has been contracting. Support for the development of neurotherapies must continue from the bench to their ultimate place at the bedside. Academic medicine must continue to play a critical role, in league with industry and government, in the development of novel neurotherapies desperately needed by an ever-expanding population. Critical steps include the identification and adoption of reliable, valid, and reproducible biomarkers to serve as primary endpoints in clinical trials of neurological disease. PMID- 25813522 TI - Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA. AB - p53 binds enhancers to regulate key target genes. Here, we globally mapped p53 regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer. PMID- 25813524 TI - Cucurbitacin B Alters the Expression of Tumor-Related Genes by Epigenetic Modifications in NSCLC and Inhibits NNK-Induced Lung Tumorigenesis. AB - Non-small cell lung cancer (NSCLC) represents almost 85% of total diagnosed lung cancer. Studies have shown that combination of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors is effective against various cancers, including lung cancer. However, optimizing the synergistic dose regime is very difficult and involves adverse side effects. Therefore, in this study, we have shown that cucurbitacin B (CuB), a single bioactive triterpenoid compound, inhibits both DNMTs and HDACs starting at a very low dose of 60 nmol/L in NSCLC H1299 cells. The CuB-mediated inhibition of DNMTs and HDACs in H1299 cells leads to the reactivation of key tumor suppressor genes (TSG) such as CDKN1A and CDKN2A, as well as downregulation of oncogenes c-MYC and K-RAS and key tumor promoter gene (TPG), human telomerase reverse transcriptase (hTERT). The upregulation of TSGs and downregulation of TPG were consistently correlated with the alterations in their promoter methylation and histone modifications. This altered expression of TPG and TSGs is, at least in part, responsible for the inhibition of cellular proliferation and induction of cellular apoptosis in NSCLC. Furthermore, CuB treatment significantly inhibited the tumor incidence and multiplicity in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, which was associated with the induction of apoptosis and inhibition of hyperproliferation in the lung tissues. Together, our study provides new insight into the CuB-mediated epigenetic alterations and its chemotherapeutic effects on lung cancer. PMID- 25813525 TI - Circulating Vitamin D Levels and Risk of Colorectal Cancer in Women. AB - Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case-control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles. Mean plasma 25(OH)D was lower in cases versus controls (21.9 vs. 23.9 ng/mL, P = 0.01). In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs. quartile 1 [Q1]: OR, 0.45; 95% CI, 0.25-0.81; Ptrend 0.02). In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 0.40; 95% CI, 0.17-0.97; Ptrend 0.05). In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer related mortality. These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women. PMID- 25813526 TI - Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis. AB - Loss of parietal cells initiates the development of spasmolytic polypeptide expressing metaplasia (SPEM), a precancerous lesion in stomach. CD44 variant (CD44v) that enhances the ability to defend against reactive oxygen species (ROS) in epithelial cells is expressed de novo in SPEM of K19-Wnt1/C2mE mice, a transgenic model of gastric tumorigenesis, and is required for the efficient development of SPEM and gastric tumor in these animals. The role of ROS and its downstream signaling in CD44-dependent gastric tumorigenesis has remained unknown, however. With the use of the K19-Wnt1/C2mE mouse, we now show that parietal cells in the inflamed stomach are highly sensitive to oxidative stress and manifest activation of p38(MAPK) signaling by ROS. Oral treatment with the antioxidant ascorbic acid or genetic ablation of the Ink4a/Arf locus, a major downstream target of ROS-p38(MAPK) signaling, inhibited parietal cell loss and the subsequent gastric tumorigenesis. Our results indicate that signaling activated by oxidative stress in parietal cells plays a key role in CD44 dependent gastric tumorigenesis. . PMID- 25813527 TI - Auditory Pathway Features Determined by DTI in Subjects with Unilateral Acoustic Neuroma. AB - PURPOSE: In the studies concerning the pathology of the auditory pathway in the vestibulocochlear system, few use advanced neuroimaging applications of magnetic resonance imaging (MRI) such as diffusion tensor imaging (DTI). Those who did use reported DTI changes only at the lateral lemniscus and inferior colliculus level. The aim of our study was to determine diffusion changes in the bilateral auditory pathways of subjects with unilateral acoustic neuroma (AN) and compare them with healthy controls. MATERIAL AND METHODS: A total of 15 subjects with unilateral AN along with 11 controls underwent routine MRI and DTI. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values obtained from the lateral lemniscus, inferior colliculus, corpus geniculatum mediale, and Heschl's gyrus of the auditory pathway were then compared. RESULTS: The subjects' ADC values measured from the contralateral side were significantly higher at the lateral lemniscus, inferior colliculus, and corpus geniculatum mediale compared with those of the controls. Also, decreased FA values were noted at the inferior colliculus for both the contralateral and ipsilateral sides. The highest ADC values were detected in the inferior colliculus of the auditory pathway. CONCLUSIONS: In the auditory pathway of subjects with AN, the contralateral side is more affected than the ipsilateral side, the most affected region being the inferior colliculus. DTI is an advanced neuroimaging technique that can be used to determine the presence of microstructural damage to the auditory pathway in subjects with AN, whereas conventional MRI is not sensitive enough to detect damage. PMID- 25813528 TI - Tebufenozide resistance is associated with sex-linked inheritance in Plutella xylostella. AB - The diamondback moth (DBM), Plutella xylostella (L.), is a major pest of cruciferous crops. Tebufenozide, a novel nonsteroidal ecdysone agonist, exhibits good efficacy and has played an increasingly important role in the control of Lepidopteran pests in China. For its resistance management, the genetic basis of tebufenozide resistance was studied using a laboratory selected resistant strain of DBM (resistant ratio, RR = 268). A series of crosses with laboratory susceptible and resistant strains revealed that tebufenozide resistance in this pest was partially biased toward female heredity, with a large difference in RR for F1 (RR = 29) and rF1 progeny (RR = 147). The dominance calculated for these 2 cross progeny was -0.788 and 0.09, respectively. Further analysis showed that the susceptible male and female larvae were similar in their sensitivity to tebufenozide, but the resistant female larvae showed significantly higher resistance than the resistant male larvae. The heredity of tebufenozide resistance in DBM might be linked with the W sex chromosome, which suggested that DBM has the ability to develop high levels of resistance to tebufenozide. This is the first report of sex-linked inheritance of tebufenozide resistance in P. xylostella (L.). PMID- 25813529 TI - Feasibility of an interactive ICT-platform for early assessment and management of patient-reported symptoms during radiotherapy for prostate cancer. AB - PURPOSE: The aim of this study was to test the feasibility and acceptability of an Information and Communication Technology platform for assessing and managing patient reported symptoms during radiotherapy for prostate cancer. METHODS: In cooperation with a health management company, using a patient experience co design, we developed the platform operated by an interactive application for reporting and managing symptoms in real time. Nine patients diagnosed with prostate cancer and receiving radiotherapy were recruited from two university hospitals in Sweden. Evidence-based symptoms and related self-care advice specific to prostate cancer were implemented in the application based on a literature review and interviews with patients and health care professionals. In the test of the platform the patients reported symptoms, via a mobile phone, daily for two weeks and were afterwards interviewed about their experiences. RESULTS: Overall, the patients found the symptom questionnaire and the self-care advice relevant and the application user friendly. The alert system was activated on several occasions when the symptoms were severe leading to a nurse contact and support so the patients felt safe and well cared for. CONCLUSIONS: The platform enabled increased patient involvement and facilitated symptom assessment and communication between the patient and the health care provider. The study's results support further development of the platform, as well as tests in full scale studies and in other populations. PMID- 25813530 TI - Validation of the Chinese version of the low anterior resection syndrome score for measuring bowel dysfunction after sphincter-preserving surgery among rectal cancer patients. AB - PURPOSE: The low anterior resection syndrome (LARS) score is a simple and valid instrument for measuring bowel dysfunction after sphincter-preserving surgery (SPS) among rectal cancer patients. We aimed to translate the LARS score into Chinese, and to test its reliability and validity among Chinese rectal cancer patients. METHODS: The LARS score was translated into Chinese by using internationally recognized forward- and back-translation procedures. In total, 102 patients completed the questionnaire; a subgroup of 20 patients answered the survey twice. The reliability was estimated through the test-retest reliability method. The convergent and discriminant validities were confirmed by measuring the relation of the LARS score with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29 domains, respectively, and testing its ability to differentiate among patients with different clinical characteristics. RESULTS: The Spearman correlation coefficient of the LARS-scores at the two surveys was 0.86 (p < .001), and the linear-weighted kappa values of the five items of the LARS score were 0.38, 0.76, 0.79, 0.77, and 0.78, respectively. The LARS score showed significant correlations with all the assumptive domains of QLQ-C30 and QLQ-CR29, especially flatulence, fecal incontinence, and stool frequency (all p < .05). It could also detect differences between female and male patient groups (p = .033), patients who had/had not undergone radiation therapy (p = .007), those who had undergone surgery in the last <12.0 or >=12.0 months (p = .002), and those with low or high tumor edge level (p = .017). CONCLUSIONS: The Chinese version of the LARS score had good psychometric properties and can be used in clinical and research settings in the Chinese population. PMID- 25813531 TI - Being a haematopoietic stem cell donor for a sick sibling: Adult donors' experiences prior to donation. AB - BACKGROUND: There is a lack of knowledge about sibling stem cell donors' experiences pre-donation and the waiting period before the donation might have been long. The donors and their corresponding sibling recipients were simultaneously included in two different interview studies. The results from the recipient study have been presented in a separate paper. PURPOSE: The aim was to explore the experiences of being a stem cell donor for a sibling, prior to donation. METHOD: Ten adult sibling donors were interviewed prior to stem cell donation. The interviews were digitally recorded, transcribed verbatim and subjected to qualitative content analysis. RESULTS: The main theme Being a cog in a big wheel describes the complex process of being a sibling donor prior to donation, covering a mixture of emotions and thoughts. The four subthemes Being available, Being anxious, Being concerned and Being obliged cover the various experiences. The sibling donors' experiences are influenced by the quality of the relationship with the sick sibling. CONCLUSIONS: Sibling stem cell donors go through a complex process once they have accidentally got involved in. They have been asked to become a donor; it was not a voluntary choice. In caring for sibling stem cell donors the nurses should be aware of the complexity of the process they experience and take into consideration their personal situation and needs. Providing optimal care for both sibling donors and their corresponding recipients is a challenge, and further improvement and exploration are needed. PMID- 25813532 TI - Mechanical high-intensity focused ultrasound destruction of soft tissue: working mechanisms and physiologic effects. AB - The best known method of high-intensity focused ultrasound is thermal ablation, but interest in non-thermal, mechanical destruction is increasing. The advantages of mechanical ablation are that thermal protein denaturation remains limited and less damage is created to the surrounding tissue by thermal diffusion. The two main techniques for mechanical fragmentation of tissue are histotripsy and boiling histotripsy. These techniques can be used for complete liquefaction of tumor tissue into submicron fragments, after which the fragmented tissue can be easily removed by natural (immunologic) responses. Interestingly it seems that there is a correlation between the degree of destruction and tissue specific characteristics based on the treatment settings used. In this review article, the technical aspects of these two techniques are described, and an overview of the in vivo pathologic and immunologic responses is provided. PMID- 25813533 TI - Role of contrast-enhanced ultrasound arterial mapping in surgical planning for patients with critical limb ischemia. AB - The goal of the study described here was to evaluate the role of contrast enhanced ultrasound (CEUS) arterial mapping in surgical planning in cases of critical limb ischemia. From March 2007 to December 2012, 565 consecutive patients with critical limb ischemia of the lower limbs were treated and initially examined with only ultrasound (US) arterial mapping. For 479 of the 565 patients, basic US examination results were deemed sufficient for surgical planning (group A). That is, US examination provided sufficient information to decide a surgical plan to treat those patients. In the remaining 86 patients, basic US examination was insufficient for revascularization planning, and CEUS examination was performed (group B). In 5 cases, CEUS results were also insufficient for surgical planning, as a suitable outflow vessel was not visualized. In these cases, a pre-operative arteriogram was performed. To assess the usefulness of CEUS, we compared results of examinations with and without contrast administration, surgical findings and angiographic findings when available. Data were collected prospectively. Examinations were compared by establishing the degree of agreement between results of paired examinations and degree of agreement between CEUS results and surgical findings. Clinical, hemodynamic (ankle-brachial index) and duplex follow-up was performed at 1 and 3 mo to evaluate cumulative patency of the procedures in each group. Within group B, degree of agreement between basic US and CEUS was 46.5%. CEUS resulted in a change in the surgical plan in 46 of 86 patients. Among all 565 patients, degree of agreement between surgical decision based on basic ultrasound arterial mapping and final decision based on surgical findings was 87.1%, and improved to 95.2% with CEUS (p = 0.00001, kappa index = 0.823). Degree of agreement between the ultrasound-based decision and surgical findings was 97.5% in group A (kappa index = 0.818) and 94.2% in group B (kappa = 0.848). There was no significant difference between groups (p = 0.784). Within group B, of the five arteriograms performed, results of only one matched well the US mapping findings. Vessel patency at 1 and 3 mo did not significantly differ between patients whose surgical planning was based on basic US and patients whose planning was based on CEUS (p = 0.418 and p = 0.489, respectively). US arterial mapping is an excellent tool for surgical planning in critical limb ischemia. CEUS arterial mapping improves the accuracy of ultrasound examination in patients with critical limb ischemia, especially in patients with inconclusive non-enhanced exams. PMID- 25813534 TI - Association of genetic variants with hypertension in a longitudinal population based genetic epidemiological study. AB - We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for Japanese patients with myocardial infarction, ischemic stroke, or chronic kidney disease by genome-wide or candidate gene association studies. In the present study, we investigated the possible association of 13 single nucleotide polymorphisms (SNPs) at these 10 loci with the prevalence of hypertension or their association with blood pressure (BP) in community-dwelling individuals in Japan. The study subjects comprised 6,027 individuals (2,250 subjects with essential hypertension, 3,777 controls) who were recruited into the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study on atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center of Inabe General Hospital for an annual health checkup, and they are followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for age, gender, body mass index and smoking status revealed that rs2116519 of family with sequence similarity 78, member B (FAM78B; P=0.0266), rs6929846 of butyrophilin, subfamily 2, member A1 (BTN2A1; P=0.0013), rs146021107 of pancreatic and duodenal homeobox 1 (PDX1; P=0.0031) and rs1671021 of lethal giant larvae homolog 2 (Drosophila) (LLGL2; P=0.0372) were significantly (P<0.05) associated with the prevalence of hypertension. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for age, gender, body mass index and smoking status among individuals not taking anti-hypertensive medication revealed that rs6929846 of BTN2A1 was significantly associated with systolic (P=0.0017), diastolic (P=0.0008) and mean (P=0.0005) BP, and that rs2116519 of FAM78B, rs146021107 of PDX1 and rs1671021 of LLGL2 were significantly associated with diastolic (P=0.0495), systolic (P=0.0132), and both diastolic (P=0.0468) and mean (0.0471) BP, respectively. BTN2A1 may thus be a susceptibility gene for hypertension. PMID- 25813535 TI - A New Measure of Tibial Sesamoid Position in Hallux Valgus in Relation to the Coronal Rotation of the First Metatarsal in CT Scans. AB - BACKGROUND: We aimed to find a new radiographic measurement for evaluating first metatarsal pronation and sesamoid position in hallux valgus (HV) deformity. METHODS: Data from a clinical study of 19 control patients (19 feet) with no HV deformity were compared with preoperative data of 138 patients (166 feet) with HV deformities. Using a weightbearing plain radiograph in anteroposterior (AP) view, the intermetatarsal angles (IMAs) and the hallux valgus angles (HVAs) of the control and study groups were measured. Using a semi-weightbearing coronal computed tomography (CT) axial view, the alpha angle was measured in the control and study groups. In addition, the tibial sesamoid grades in plain radiograph tangential view and the CT axial view were measured. The tibial sesamoid position in an AP view was checked preoperatively. Based on these measurements, 4 types of HV deformities were defined. RESULTS: The mean values of the alpha angle in the control and HV deformity groups (control group u = 13.8 degrees, study group u = 21.9 degrees) was significantly different. Among 166 HV feet, 145 feet (87.3%) had an alpha angle of more than 15.8 degrees, which is the upper value of the 95% confidence interval of the control group, indicating the existence of abnormal first metatarsal pronation in HV deformity. Four types of HV deformities were defined based on their alpha angles and tibial sesamoid grades in CT axial view (CT 4 position). Among 25.9% (43/166) of the study group, abnormal first metatarsal pronation with an absence of sesamoid deviation from its articular facet was observed. The prominent characteristic of this group was that they had high grades in the AP 7 position (>=5); however, in the CT 4 position, their grade was 0. This group was defined as the "pseudo-sesamoid subluxation" group. CONCLUSIONS: Patients with HV deformities had a more pronated first metatarsal than the control group, with a greater alpha angle. Pseudo-subluxation of the sesamoids existed in 25.9% of our study group. From our results, we suggest that the use of the CT axial view in assessments of HV deformity may benefit surgeons when they make operative choices to correct these deformities. With regard to the pseudo-sesamoid subluxation group, the use of the distal soft tissue procedure is not surgically recommended. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25813536 TI - Preclinical assessment of early tumor response after irradiation by positron emission tomography with 2-amino-[3-11C]isobutyric acid. AB - The positron emission tomography (PET) probe, 2-amino-[3-11C]isobutyric acid ([3 11C]AIB), is reported to accumulate less in inflammatory lesions than 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) and has the potential for evaluation of the efficacy of radiotherapy. To determine whether [3-11C]AIB is useful to monitor early metabolic change in tumors after radiotherapy, we evaluated the temporal change in [3-11C]AIB tumor uptake, tumor volume, histological features and expression of amino acid transporters early after radiotherapy in a mouse tumor model. PET with [3-11C]AIB was conducted in mice bearing a subcutaneous tumor (SY, derived from small cell lung cancer) in two schedules: schedule 1, before (day -1) and after (days 1 and 3) 15 Gy of radiation and schedule 2, days -1, 1 and 5. [3-11C]AIB tumor uptake tended to increase on day 1 after irradiation and decreased thereafter. Tumor uptake was not correlated with tumor volume in schedule 1. Although tumor uptake was correlated with tumor volume in schedule 2, this correlation was lost when the day 5 data of greatly reduced tumor volumes were excluded. In a separate group of tumor-bearing mice, excised tumor sections were stained with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) or anti-Ki-67 antibody. There was no correlation between tumor uptake and percentages of TUNEL- or Ki-67-positive cells. Expression of amino acid transporters, SLC38A1, SLC38A2 and SLC38A4, was determined by real-time RT-PCR. SLC38A1 and SLC38A2 were expressed in SY tumors, and a significant correlation was observed between [3-11C]AIB tumor uptake and SLC38A1 expression. In conclusion, early change in [3-11C]AIB tumor uptake after irradiation reflected the temporal change in amino acid transporter expression, while it was independent of change in tumor volume, apoptosis and cell proliferation. PET with [3-11C]AIB has the potential for use in non-invasive evaluation of early metabolic change after irradiation before morphological change of tumors. PMID- 25813537 TI - Molecular protein adaptor with genetically encoded interaction sites guiding the hierarchical assembly of plasmonically active nanoparticle architectures. AB - The control over the defined assembly of nano-objects with nm-precision is important to create systems and materials with enhanced properties, for example, metamaterials. In nature, the precise assembly of inorganic nano-objects with unique features, for example, magnetosomes, is accomplished by efficient and reliable recognition schemes involving protein effectors. Here we present a molecular approach using protein-based 'adaptors/connectors' with genetically encoded interaction sites to guide the assembly and functionality of different plasmonically active gold nanoparticle architectures (AuNP). The interaction of the defined geometricaly shaped protein adaptors with the AuNP induces the self assembly of nanoarchitectures ranging from AuNP encapsulation to one-dimensional chain-like structures, complex networks and stars. Synthetic biology and bionanotechnology are applied to co-translationally encode unnatural amino acids as additional site-specific modification sites to generate functionalized biohybrid nanoarchitectures. This protein adaptor-based nano-object assembly approach might be expanded to other inorganic nano-objects creating biohybrid materials with unique electronic, photonic, plasmonic and magnetic properties. PMID- 25813539 TI - Brg1 modulates enhancer activation in mesoderm lineage commitment. AB - The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also required to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. These findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions. PMID- 25813540 TI - Slit cleavage is essential for producing an active, stable, non-diffusible short range signal that guides muscle migration. AB - During organogenesis, secreted signaling proteins direct cell migration towards their target tissue. In Drosophila embryos, developing muscles are guided by signals produced by tendons to promote the proper attachment of muscles to tendons, essential for proper locomotion. Previously, the repulsive protein Slit, secreted by tendon cells, has been proposed to be an attractant for muscle migration. However, our findings demonstrate that through tight control of its distribution, Slit repulsion is used for both directing and arresting muscle migration. We show that Slit cleavage restricts its distribution to tendon cells, allowing it to function as a short-range repellent that directs muscle migration and patterning, and promotes their halt upon reaching the target site. Mechanistically, we show that Slit processing produces a rapidly degraded C terminal fragment and an active, stable N-terminal polypeptide that is tethered to the tendon cell membrane, which further protects it from degradation. Consistently, the requirement for Slit processing can be bypassed by providing an uncleavable, membrane-bound form of Slit that is stable and is retained on expressing tendon cells. Moreover, muscle elongation appears to be extremely sensitive to Slit levels, as replacing the entire full-length Slit with the stable Slit-N-polypeptide results in excessive repulsion, which leads to a defective muscle pattern. These findings reveal a novel cleavage-dependent regulatory mechanism controlling Slit spatial distribution, which may operate in other Slit-dependent processes. PMID- 25813538 TI - Wnt5a and Wnt11 regulate mammalian anterior-posterior axis elongation. AB - Mesoderm formation and subsequent anterior-posterior (A-P) axis elongation are fundamental aspects of gastrulation, which is initiated by formation of the primitive streak (PS). Convergent extension (CE) movements and epithelial mesenchymal transition (EMT) are important for A-P axis elongation in vertebrate embryos. The evolutionarily conserved planar cell polarity (PCP) pathway regulates CE, and Wnts regulate many aspects of gastrulation including CE and EMT. However, the Wnt ligands that regulate A-P axis elongation in mammalian development remain unknown. Wnt11 and Wnt5a regulate axis elongation in lower vertebrates, but only Wnt5a, not Wnt11, regulates mammalian PCP signaling and A-P axis elongation in development. Here, by generating Wnt5a; Wnt11 compound mutants, we show that Wnt11 and Wnt5a play redundant roles during mouse A-P axis elongation. Both genes regulate trunk notochord extension through PCP-controlled CE of notochord cells, establishing a role for Wnt11 in mammalian PCP. We show that Wnt5a and Wnt11 are required for proper patterning of the neural tube and somites by regulating notochord formation, and provide evidence that both genes are required for the generation and migration of axial and paraxial mesodermal precursor cells by regulating EMT. Axial and paraxial mesodermal precursors ectopically accumulate in the PS at late gastrula stages in Wnt5a(-/-); Wnt11(-/ ) embryos and these cells ectopically express epithelial cell adhesion molecules. Our data suggest that Wnt5a and Wnt11 regulate EMT by inducing p38 (Mapk14) phosphorylation. Our findings provide new insights into the role of Wnt5a and Wnt11 in mouse early development and also in cancer metastasis, during which EMT plays a crucial role. PMID- 25813541 TI - Robust derivation of epicardium and its differentiated smooth muscle cell progeny from human pluripotent stem cells. AB - The epicardium has emerged as a multipotent cardiovascular progenitor source with therapeutic potential for coronary smooth muscle cell, cardiac fibroblast (CF) and cardiomyocyte regeneration, owing to its fundamental role in heart development and its potential ability to initiate myocardial repair in injured adult tissues. Here, we describe a chemically defined method for generating epicardium and epicardium-derived smooth muscle cells (EPI-SMCs) and CFs from human pluripotent stem cells (HPSCs) through an intermediate lateral plate mesoderm (LM) stage. HPSCs were initially differentiated to LM in the presence of FGF2 and high levels of BMP4. The LM was robustly differentiated to an epicardial lineage by activation of WNT, BMP and retinoic acid signalling pathways. HPSC derived epicardium displayed enhanced expression of epithelial- and epicardium specific markers, exhibited morphological features comparable with human foetal epicardial explants and engrafted in the subepicardial space in vivo. The in vitro-derived epicardial cells underwent an epithelial-to-mesenchymal transition when treated with PDGF-BB and TGFbeta1, resulting in vascular SMCs that displayed contractile ability in response to vasoconstrictors. Furthermore, the EPI-SMCs displayed low density lipoprotein uptake and effective lowering of lipoprotein levels upon treatment with statins, similar to primary human coronary artery SMCs. Cumulatively, these findings suggest that HPSC-derived epicardium and EPI SMCs could serve as important tools for studying human cardiogenesis, and as a platform for vascular disease modelling and drug screening. PMID- 25813542 TI - SNPfisher: tools for probing genetic variation in laboratory-reared zebrafish. AB - Single nucleotide polymorphisms (SNPs) are the benchmark molecular markers for modern genomics. Until recently, relatively few SNPs were known in the zebrafish genome. The use of next-generation sequencing for the positional cloning of zebrafish mutations has increased the number of known SNP positions dramatically. Still, the identified SNP variants remain under-utilized, owing to scant annotation of strain specificity and allele frequency. To address these limitations, we surveyed SNP variation in three common laboratory zebrafish strains using whole-genome sequencing. This survey identified an average of 5.04 million SNPs per strain compared with the Zv9 reference genome sequence. By comparing the three strains, 2.7 million variants were found to be strain specific, whereas the remaining variants were shared among all (2.3 million) or some of the strains. We also demonstrate the broad usefulness of our identified variants by validating most in independent populations of the same laboratory strains. We have made all of the identified SNPs accessible through 'SNPfisher', a searchable online database (snpfisher.nichd.nih.gov). The SNPfisher website includes the SNPfisher Variant Reporter tool, which provides the genomic position, alternate allele read frequency, strain specificity, restriction enzyme recognition site changes and flanking primers for all SNPs and Indels in a user defined gene or region of the zebrafish genome. The SNPfisher site also contains links to display our SNP data in the UCSC genome browser. The SNPfisher tools will facilitate the use of SNP variation in zebrafish research as well as vertebrate genome evolution. PMID- 25813543 TI - The vav oncogene antagonises EGFR signalling and regulates adherens junction dynamics during Drosophila eye development. AB - Organ shaping and patterning depends on the coordinated regulation of multiple processes. The Drosophila compound eye provides an excellent model to study the coordination of cell fate and cell positioning during morphogenesis. Here, we find that loss of vav oncogene function during eye development is associated with a disorganised retina characterised by the presence of additional cells of all types. We demonstrate that these defects result from two distinct roles of Vav. First, and in contrast to its well-established role as a positive effector of the EGF receptor (EGFR), we show that readouts of the EGFR pathway are upregulated in vav mutant larval eye disc and pupal retina, indicating that Vav antagonises EGFR signalling during eye development. Accordingly, decreasing EGFR signalling in vav mutant eyes restores retinal organisation and rescues most vav mutant phenotypes. Second, using live imaging in the pupal retina, we observe that vav mutant cells do not form stable adherens junctions, causing various defects, such as recruitment of extra primary pigment cells. In agreement with this role in junction dynamics, we observe that these phenotypes can be exacerbated by lowering DE-Cadherin or Cindr levels. Taken together, our findings establish that Vav acts at multiple times during eye development to prevent excessive cell recruitment by limiting EGFR signalling and by regulating junction dynamics to ensure the correct patterning and morphogenesis of the Drosophila eye. PMID- 25813544 TI - Primary root protophloem differentiation requires balanced phosphatidylinositol 4,5-biphosphate levels and systemically affects root branching. AB - Protophloem is a specialized vascular tissue in growing plant organs, such as root meristems. In Arabidopsis mutants with impaired primary root protophloem differentiation, brevis radix (brx) and octopus (ops), meristematic activity and consequently overall root growth are strongly reduced. Second site mutation in the protophloem-specific presumed phosphoinositide 5-phosphatase cotyledon vascular pattern 2 (CVP2), but not in its homolog CVP2-like 1 (CVL1), partially rescues brx defects. Consistent with this finding, CVP2 hyperactivity in a wild type background recreates a brx phenotype. Paradoxically, however, while cvp2 or cvl1 single mutants display no apparent root defects, the root phenotype of cvp2 cvl1 double mutants is similar to brx or ops, although, as expected, cvp2 cvl1 seedlings contain more phosphatidylinositol-4,5-biphosphate. Thus, tightly balanced phosphatidylinositol-4,5-biphosphate levels appear essential for proper protophloem differentiation. Genetically, OPS acts downstream of phosphatidylinositol-4,5-biphosphate levels, as cvp2 mutation cannot rescue ops defects, whereas increased OPS dose rescues cvp2 cvl1 defects. Finally, all three mutants display higher density and accelerated emergence of lateral roots, which correlates with increased auxin response in the root differentiation zone. This phenotype is also created by application of peptides that suppress protophloem differentiation, clavata3/embryo surrounding region 26 (CLE26) and CLE45. Thus, local changes in the primary root protophloem systemically shape overall root system architecture. PMID- 25813545 TI - Overexpression of the vesicular acetylcholine transporter enhances dendritic complexity of adult-born hippocampal neurons and improves acquisition of spatial memory during aging. AB - Aging is marked by progressive impairments in the process of adult neurogenesis and spatial memory performance. The underlying mechanisms for these impairments have not been fully established; however, they may coincide with decline of cholinergic signaling in the hippocampus. This study investigates whether augmenting cholinergic neurotransmission, by enhancing the expression of the vesicular acetylcholine transporter (VAChT), influences the age-related decline in the development of newborn hippocampal cells and spatial memory. We found that enhanced VAChT expression in the hippocampus of mice contributes to lifelong increases in the dendritic complexity of newborn neurons. Furthermore, enhanced VAChT expression improved memory acquisition through an increased use of spatially precise search strategies in the Morris water maze through the course of the aging process. These data suggest that VAChT overexpression contributes to increases in dendritic complexity and improved spatial memory during aging. PMID- 25813546 TI - A naturally occurring prfA truncation in a Listeria monocytogenes field strain contributes to reduced replication and cell-to-cell spread. AB - Listeria (L.) monocytogenes is an environmental bacterium that may become an intracellular pathogen upon ingestion to cause gastroenteritis, septicaemia, abortions, and/or fatal infections of the central nervous system. We here describe a L. monocytogenes field strain (JF5171) isolated from a bovine placenta in the context of abortion, which exhibited attenuation in bovine brain-slice cultures. The whole genome of strain JF5171 was sequenced, and the invasion, replication, and intercellular spread of JF5171 were further analyzed by quantification of colony forming units and immunofluorescence studies. Phospholipase and hemolysis activity of JF5171 were also quantified along with transcription levels of actA, hly and prfA. The data obtained were compared to those of the widely used L. monocytogenes reference strain, EGD-e. JF5171 exhibited reduced replication and lower levels of phospholipase and hemolysis activity. Invasion and cell-to-cell spread was strongly decreased compared to EGD e, and actin polymerization was absent. A frame shift deletion was identified in the JF5171 coding region of the major regulator for virulence, prfA. This resulted in a truncated C-terminus sequence (WEN* vs. WGKLN*). In addition, a point mutation resulted in a lysine to arginine substitution at amino acid position 197. Complementation with prfA from EGD-e and with (EGD-e) prfA-K197N increased the replication and spread efficiency of JF5171. In contrast, complementation with the truncated version of prfA had no effect. Taken together, these results suggest that the truncated C-terminus of prfA considerably contributes to the strongly attenuated phenotype observed in vitro. PMID- 25813547 TI - Renin-angiotensin system blockers in cardiac surgery. AB - Major complications associated with cardiac surgery are still common and carry great prognostic significance. beta-Blockers, statins, antiplatelets, and renin angiotensin system (RAS) blockers are current medical interventions to prevent cardiovascular complications in cardiac surgery. Renin-angiotensin system blockers include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and antialdosterones. Several lines of evidence support the cardioprotective effects of RAS blockers: they reduce ischemic events and improve outcome in heart failure independently of their effect on heart function and blood pressure. Moreover, early RAS blocker administration has remarkable survival and heart function benefits in patients with acute myocardial infarction. Nevertheless, perioperative studies on the effects of RAS blockers remain few and inconclusive. Results from clinical trials and observational studies are conflicting, and they raise more questions than answers. Further studies are needed to examine whether RAS blockers reduce mortality and major complications in patients undergoing cardiac surgery. In this review, we discuss the use of RAS blockers in the setting of cardiac surgery, underlying the potential benefits in reducing postoperative complications. PMID- 25813548 TI - Prehospital tidal volume influences hospital tidal volume: A cohort study. AB - PURPOSE: The purposes of the study are to describe current practice of ventilation in a modern air medical system and to measure the association of ventilation strategy with subsequent ventilator care and acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: Retrospective observational cohort study of intubated adult patients (n = 235) transported by a university affiliated air medical transport service to a 711-bed tertiary academic center between July 2011 and May 2013. Low tidal volume ventilation was defined as tidal volumes less than or equal to 8 mL/kg predicted body weight. Multivariable regression was used to measure the association between prehospital tidal volume, hospital ventilation strategy, and ARDS. RESULTS: Most patients (57%) were ventilated solely with bag valve ventilation during transport. Mean tidal volume of mechanically ventilated patients was 8.6 mL/kg predicted body weight (SD, 0.2 mL/kg). Low tidal volume ventilation was used in 13% of patients. Patients receiving low tidal volume ventilation during air medical transport were more likely to receive low tidal volume ventilation in the emergency department (P < .001) and intensive care unit (P = .015). Acute respiratory distress syndrome was not associated with prehospital tidal volume (P = .840). CONCLUSIONS: Low tidal volume ventilation was rare during air medical transport. Air transport ventilation strategy influenced subsequent ventilation but was not associated with ARDS. PMID- 25813549 TI - Prospective observation of physical activity in critically ill patients who were intubated for more than 48 hours. AB - PURPOSE: Critical illness can result in impaired physical function. Increased physical activity, additional to rehabilitation, has demonstrated improved functional independence at hospital discharge. The purpose of this study was to measure patterns of physical activity in a group of critically ill patients. METHODS: This was a single-center, open, observational behavioral mapping study performed in a quaternary intensive care unit (ICU) in Melbourne, Australia. Observations were collected every 10 minutes for 8 hours between 8:00 am and 5:00 pm with the highest level of physical activity, patient location, and persons present at the bedside recorded. RESULTS: Two thousand fifty observations were collected across 8 days. Patients spent more than 7 hours in bed (median [interquartile range] of 100% [69%-100%]) participating in little or no activity for approximately 7 hours of the day (median [interquartile range] 96% [76% 96%]). Outside rehabilitation, no activities associated with ambulation were undertaken. Patients who were ventilated at the time of observation compared with those who were not were less likely to be out of bed (98% reduction in odds). Patients spent up to 30% of their time alone. CONCLUSION: Outside rehabilitation, patients in ICU are inactive and spend approximately one-third of the 8-hour day alone. Strategies to increase physical activity levels in ICU are required. PMID- 25813550 TI - Development and validation of a clinical prediction rule for candidemia in hospitalized patients with severe sepsis and septic shock. AB - OBJECTIVE: To develop and internally validate a prediction rule for the presence of candidemia in patients with severe sepsis and septic shock (candidemia rule) that will fill the gap left by previous rules. To compare the accuracy of the available Candida prediction models. DESIGN: Retrospective cohort study. SETTING: Barnes-Jewish Hospital, St. Louis, Missouri. PATIENTS/SUBJECTS: Two thousand five hundred ninety-seven consecutive patients with a positive blood culture and severe sepsis or septic shock. INTERVENTIONS: Logistic regression and a bootstrap resampling procedure were employed for model development and internal validation. MEASUREMENTS AND MAIN RESULTS: Two hundred sixty-six (10.2%) had blood cultures positive for Candida spp. Mortality was significantly higher in patients with candidemia than in patients with bacteremia (47.0% versus 28.4%; P<.001). Administration of total parenteral nutrition, prior antibiotic exposure, transfer from an outside hospital or admission from a nursing home, mechanical ventilation and presence of a central vein catheter were independent predictors of candidemia while the lung as a source for infection was protective. The prediction rule had an area under the receiver operating characteristic curve of 0.798 (95% CI 0.77 0.82). Internal validation using bootstrapping technique with 1000 repetitions produced a similar area under the receiver operating characteristic curve of 0.797 (bias, -0.037; root mean square error 0.039). Our prediction rule outperformed previous rules with a better calibration slope of 0.96 and Brier score of 0.08. CONCLUSIONS: We developed and internally validated a prediction rule for candidemia in hospitalized patients with severe sepsis and septic shock that outperformed previous prediction rules. Our study suggests that locally derived prediction models may be superior by accounting for local case mix and risk factor distribution. PMID- 25813551 TI - The imbalance of redox homeostasis in arthropod-induced plant galls: Mechanisms of stress generation and dissipation. AB - BACKGROUND: Galls have specialized tissues for the protection and nutrition of the inducers, and these tissues have been studied from the developmental and histochemical perspectives. Recently, the role of oxidative stress in galls has been tested histochemically through detection of H2O2 in gall tissues. SCOPE OF REVIEW: Developmental processes and cytological events are revisited from the perspective of the redox-potential balance in both the apoplast and symplast, especially concerning the accumulation of reactive oxygen species (ROS). MAJOR CONCLUSIONS: The redox potential is imbalanced differently in the apoplast and symplast at gall sites, with the apoplast having lower antioxidant-buffering capacity than the symplast. The strategies to recover redox-potential homeostasis involve the dissipation of ROS by scavenging molecules, such as phenolics, flavonoid derivatives, tocopherol, and enzyme systems. GENERAL SIGNIFICANCE: Insect galls are good models to test developmental hypotheses. Although the exact mechanisms of gall induction and development have not been elucidated at the biochemical and biophysical levels, modulation of the redox potential is involved in the crucial steps of gall initiation and establishment. This article is part of a Special Issue entitled Redox regulation of differentiation and de differentiation. PMID- 25813552 TI - ADAMTS13 deficiency in mice does not affect adipose tissue development. AB - BACKGROUND: BMI and ADAMTS13 levels are positively correlated in man. Development of obesity is associated with angiogenesis and inflammation, and increased ADAMTS13 synthesis in the liver. METHODS: Male wild-type (WT) and ADAMTS13 deficient (Adamts13-/-) mice were kept on normal chow (SFD) or high fat diet (HFD) for 15 weeks. RESULTS: HFD feeding of WT mice resulted in significantly enhanced levels of ADAMTS13 antigen and activity as compared to SFD feeding. ADAMTS13 deficiency had no significant effect on body weight gain, subcutaneous (SC) or gonadal (GN) adipose tissue mass, or on adipocyte size. In GN fat of obese (HFD) Adamts13-/- mice, adipocyte density was higher and blood vessel density lower as compared to obese WT mice. No marked effects of genotype were observed on mRNA expression of adipogenic, endothelial, inflammatory or oxidative stress markers in adipose tissue. Analysis of metabolic parameters and of glucose and insulin tolerance did not reveal significant differences between both obese genotypes, except for higher adiponectin and cholesterol levels in obese Adamts13 /- as compared to WT mice. CONCLUSION: Our data do not support a functional role of ADAMTS13 in adiposity nor in associated angiogenesis or inflammation in mice. GENERAL SIGNIFICANCE: ADAMTS13 deficiency may cause thrombotic thrombocytopenic purpura (TTP). Obesity, which is associated with enhanced ADAMTS13 levels is nevertheless considered to be an independent risk factor for TTP. To resolve this apparent contradiction, we show that ADAMTS13 does not directly promote development of adipose tissue in a mouse model. PMID- 25813553 TI - The epidemiology and aetiology of diarrhoeal disease in infancy in southern Vietnam: a birth cohort study. AB - OBJECTIVES: Previous studies indicate a high burden of diarrhoeal disease in Vietnamese children, however longitudinal community-based data on burden and aetiology are limited. The findings from a large, prospective cohort study of diarrhoeal disease in infants in southern Vietnam are presented herein. METHODS: Infants were enrolled at birth in urban Ho Chi Minh City and a semi-rural district in southern Vietnam, and followed for 12 months (n=6706). Diarrhoeal illness episodes were identified through clinic-based passive surveillance, hospital admissions, and self-reports. RESULTS: The minimum incidence of diarrhoeal illness in the first year of life was 271/1000 infant-years of observation for the whole cohort. Rotavirus was the most commonly detected pathogen (50% of positive samples), followed by norovirus (24%), Campylobacter (20%), Salmonella (18%), and Shigella (16%). Repeat infections were identified in 9% of infants infected with rotavirus, norovirus, Shigella, or Campylobacter, and 13% of those with Salmonella infections. CONCLUSIONS: The minimum incidence of diarrhoeal disease in infants in both urban and semi-rural settings in southern Vietnam was quantified prospectively. A large proportion of laboratory-diagnosed disease was caused by rotavirus and norovirus. These data highlight the unmet need for a rotavirus vaccine in Vietnam and provide evidence of the previously unrecognized burden of norovirus in infants. PMID- 25813554 TI - Improvement in clinical and economic outcomes with empiric antibiotic therapy covering atypical pathogens for community-acquired pneumonia patients: a multicenter cohort study. AB - OBJECTIVE: To determine the effectiveness of empiric antibiotic regimens covering atypical pathogens with respect to detailed clinical and economic outcomes in community-acquired pneumonia (CAP). METHODS: A population-based, multicenter, retrospective cohort study was conducted from June 2010 to May 2011. Patients with a diagnosis of CAP were enrolled and categorized into two groups according to the initial antibiotic strategy used - covering or not covering atypical pathogens. Regression analysis was performed to assess their clinical outcomes (all-cause mortality, clinical improvement rate after 72 h of antimicrobial therapy, and clinical cure rate) and economic outcomes (length of stay, hospitalization costs, and antibiotic expenditure). RESULTS: A total of 827 patients met the criteria for CAP; 561 (67.8%) received antibiotics with atypical pathogen coverage (APC group), while 266 (32.2%) did not (non-APC group). Regression analysis revealed that the all-cause mortality was much lower in the APC group than in the non-APC group (0.9% vs. 4.9%, respectively), with an odds ratio (OR) of 0.18 (95% confidence interval (CI) 0.06-0.49). Clinical improvement at 72 h (87.7% vs. 85.0%, p=0.274) and the clinical cure rate (91.1% vs. 88.3%, p=0.213) were more favorable in the APC group, but with no significant difference compared to the non-APC group. Moreover, the APC group had a shorter mean length of stay (APC 10.2 days vs. non-APC 11.6 days, p<0.001). In addition, the mean total hospitalization costs for the APC group were markedly lower compared with the non-APC group (US$ 1172.7 vs. US$ 1510.7; p<0.001). CONCLUSION: Antimicrobial treatment covering atypical pathogens for hospitalized CAP patients is associated with reduced mortality and economic burden. PMID- 25813555 TI - Thiophene synthesis via 1,1-carboboration. AB - Reaction of bis(tert-butylethynyl)sulfide with the boron Lewis acid reagents X B(C6F5)2 (X = CH3, Cl, C6F5) in pentane at r.t. gave the respective borylated thiophenes in a sequence of 1,1-carboboration reactions. In contrast, bis(phenylethynyl)sulfide reacted with B(C6F5)3 only in a 2 : 1 molar ratio to give a benzothiophene derivative. PMID- 25813556 TI - Prematurity, smallness-for-gestational age and later hospital admissions: a nation-wide registry study. AB - INTRODUCTION: Being born premature or small for gestational age (SGA) is known to be associated with diseases later in life, such as gestational diabetes, hypertension and pre-eclampsia. In this study we examined the association between being born premature or SGA and all diseases diagnosed during hospital admissions later in life. METHODS: Using Danish nation-wide registries we created a cohort of 1,348,106 persons born 1974-1996 and assessed all unique diagnoses registered in the Danish Patient Registry (DPR) for hospital admissions in the period 1994 2007 (n=27,910,558). We determined the odds ratios for persons born premature or SGA using multivariate logistic regression. RESULTS: A total of 15,059 unique ICD 10 diagnosis codes were represented in the period. Only diagnoses used at least 100 times were included in the analysis (n=4175). Of these 838 showed an odds ratio that was statistically significantly different from unity for people born premature or SGA. After correcting for multiple testing, 250 remained significant. The diagnoses covered diseases in most organ systems, including cardiovascular, endocrinological, infectious, neurological/neurosurgical, obstetric, orthopedic, psychiatric, lung & urological diseases, and occurred throughout childhood and early adulthood. Novel findings included increased risks for delayed puberty, neurofibromatosis type 1 and ileus and decreased risks of mononucleosis, peritonsillar abscesses, chronic hypothyroidism and several types of fractures and contusions later in life. CONCLUSION: Being born premature or SGA was associated with significantly altered risks of being admitted to a hospital with a wide range of diseases later in life, affecting almost all organ systems throughout childhood and early adulthood. Our findings may motivate testing in other cohorts and search for novel mechanisms of pathogenesis. PMID- 25813557 TI - Diagnostic value of the GNRB (r) in relation to pressure load for complete ACL tears: A prospective case-control study of 118 subjects. AB - INTRODUCTION: The GNRB((r)) is a reliable, validated arthrometer. A pressure pad exerts 0 to 250 Newtons of pressure on the upper calf. The goal of this study was to compare the diagnostic value of the different pressure loads that are usually applied for the diagnosis of complete anterior cruciate ligament (ACL) tears. Our hypothesis was that a load of 200N would be sufficient to diagnose these tears. PATIENTS AND METHODS: A prospective comparative case-control study was performed in 2012. One group included all the male athletes aged 15 to 21 who presented with a complete ACL tear confirmed by arthroscopy (the study group). The control group included male soccer players in a training center aged 15 to 19 with no history of knee injuries (the control group). Anterior laxity was measured in both knees by the same experienced operator using the GNRB((r)) system. The main judgment criteria were the diagnostic values of each pressure load evaluated by the area under the curve (AUC), from "Null" (AUC < 0.5) to "Perfect" (AUC = 1). RESULTS: This study included 118 men: 64 in the study group, mean age 18.1 +/- 2.3-years-old, who were mainly soccer players (39/64) or rugby men (16/64) and 54 control subjects, mean age 17.3 +/- 1.5-years-old. Three hyperalgesic patients could not receive a pressure load of 250N. The mean differential laxity was significantly higher in the control group, whatever the pressure load (P < 10( 5)). The test was "highly informative" for all loads (0.9 <= AUC < 1). Analysis of the AUC revealed a diagnostic value in descending order of: 200N(0.97[0.94-1]) > 134N(0.97[0.93-0.99]) > 250N(0.96[0.93-0.99]) > 89N(0.95[0.90-0.99]). CONCLUSION: The GNRB((r)) at 200N was shown to be sufficient to diagnose complete ACL tears. Applying a pressure load of 250N does not appear to be useful. PMID- 25813558 TI - Enhanced osteoblastic differentiation and bone formation in co-culture of human bone marrow mesenchymal stromal cells and peripheral blood mononuclear cells with exogenous VEGF. AB - BACKGROUND: Despite recent advances in bone tissue engineering, efficient bone formation and vascularization remains a challenge for clinical applications. HYPOTHESIS: The aim of this study was to investigate if the osteoblastic differentiation of human mesenchymal stromal cells (MSCs) can be enhanced by co culturing them with peripheral blood (PB) mononuclear cells (MNCs), with and without vascular endothelial growth factor (VEGF), a coupling factor of bone formation and angiogenesis. MATERIALS AND METHODS: Human bone marrow (BM) derived MSCs were co-cultured with PB-MNCs in osteogenic medium with or without VEGF. Osteoblastic differentiation and mineral deposition were studied by staining for alkaline phosphatase (ALP), and von Kossa, respectively, and measurements for ALP activity and calcium concentration (Ca). Cell proliferation was assayed with Alamar blue. The mechanism(s) were further studied by Transwell((r)) cell culture experiments. RESULTS: Both ALP and mineralization (von Kossa and Ca) were significantly higher in the MSC-MNC co-cultures compared to plain MSC cultures. VEGF alone had no effect on osteoblastic differentiation of MSCs, but further enhanced differentiation in co-culture settings. The mechanism was shown to require cell-cell contact between MSCs and MNCs and the factors contributing to further differentiation appear to be soluble. No differences were observed in cell proliferation. CONCLUSION: Our study demonstrates that the in vitro ALP activity and mineralization of human BM-MSCs is more efficient in the presence of PB-MNCs, and exogenously added VEGF further enhances the stimulatory effect. This indicates that PB-MNCs could be a potential cell source in development of co culture systems for novel tissue engineering applications for enhanced bone healing. PMID- 25813559 TI - Bone density and functional results after femoral revision with a cementless press-fit stem. AB - INTRODUCTION: The influence of radiographic bone density changes in the area surrounding a total hip arthroplasty (THA) revision with a cementless press-fit stem is unknown, notably in terms of functional results. We have therefore conducted a study aiming to (1) propose a radiographic method to assess bone density, (2) measure the functional effects of reduced bone density, and (3) determine the factors contributing to these modifications. HYPOTHESIS: A reduction in radiographic bone density has a negative influence on the functional result after revision using a cementless press-fit stem. MATERIAL AND METHODS: We retrospectively assessed 150 THA revisions at a mean follow-up of 6.3 +/- 3.2 years (range, 2-15 years). The clinical assessment was based on the Harris Hip Score. Bone density modifications were measured radiographically and the method was evaluated. The change in bone density was classified into two groups: (1) bone density not reduced or < 2 Gruen zones (118 cases [79%]); (2) bone density reduced >= 2 zones (32 cases [21%]). The variables showing a potential influence were the Cortical Index (CI), the type of primary stability with the press-fit system, and the femoral implant length. RESULTS: Inter- and intraobserver reliability of radiographic bone density measurement was evaluated as moderate or good (Kappa, 0.58; 0.60 and 0.67, respectively). For the Harris Hip Score at follow-up, there was a borderline statistical relation between stages 1 and 2: for the 118 stage 1 patients, this score was 83.62 +/- 11.54 (range, 27-99) versus 78.34 +/- 15.98 (range, 62-91) for stage 2 patients (P = 0.09). A CI <= 0.44 showed mediocre bone quality contributing to decreased bone density (P < 0.02). On the other hand, there was no statistically significant relation with the type of primary fixation (P = 0.34) or the length of the implant (P = 0.23). CONCLUSIONS: A cementless revision femoral stem can induce a reduction in bone density with possible functional effects. The negative role played by bone scarcity on the functional score is confirmed, and even though the difference is not statistically significant, we suggest using a short stem when this is possible. PMID- 25813560 TI - Risk factors for febrile urinary tract infection in children with prenatal hydronephrosis: a prospective study. AB - PURPOSE: We prospectively investigated the impact of risk factors for febrile urinary tract infection in infants with postnatally confirmed prenatal hydronephrosis. MATERIALS AND METHODS: Patients seen for prenatal hydronephrosis from 2010 to 2013 were prospectively followed. Those with ectopic ureters and ureteroceles, posterior urethral valves and neuropathic bladders were excluded. The primary outcome was febrile catheter specimen urinary tract infection. We performed univariate analysis of 7 a priori risk factors, including age, hydronephrosis grade (low-I or II vs high-III or IV), type (isolated hydronephrosis vs hydroureteronephrosis), continuous antibiotic prophylaxis, vesicoureteral reflux grade, gender and circumcision status. Time to febrile urinary tract infection curves analyzed by Cox proportional regression were generated to adjust for confounders. RESULTS: We collected data on 334 patients, of whom 78% were male. A febrile urinary tract infection developed in 65 patients (19%) at a median of 4 months (range 1 to 31). High grade hydronephrosis was present in 192 infants (57%). Continuous antibiotic prophylaxis was prescribed in 96 cases (29%). Of patients on continuous antibiotic prophylaxis 69% had high grade hydronephrosis. Vesicoureteral reflux was identified in 57 of 238 patients in whom voiding cystourethrogram was done. Reflux was grade I to III in 14 cases and grade IV or V in 43. Two-thirds of the patients with reflux were on continuous antibiotic prophylaxis. Circumcision was performed in 95 males (36%). Cox proportional regression identified female gender (HR 3.3, p = 0.02), uncircumcised males (HR 3.2, p = 0.02), hydroureteronephrosis (HR 10.9, p <0.01), vesicoureteral reflux (HR 20.8, p <0.01) and lack of continuous antibiotic prophylaxis (HR 5.2, p <0.01) as risk factors for febrile urinary tract infection. Subgroup analysis excluding vesicoureteral reflux showed that high grade prenatal hydronephrosis was also a significant risk factor (HR 3.0, p = 0.04). CONCLUSIONS: After patients with vesicoureteral reflux were excluded from the study, females and uncircumcised males with high grade hydroureteronephrosis had significantly higher febrile urinary tract infection rates. Therefore, those patients may benefit from continuous antibiotic prophylaxis. PMID- 25813561 TI - Does intracytoplasmic sperm injection pose an increased risk of genitourinary congenital malformations in offspring compared to in vitro fertilization? A systematic review and meta-analysis. AB - PURPOSE: We systematically reviewed and performed a meta-analysis of the genitourinary congenital malformation rate after conception by intracytoplasmic sperm injection compared to in vitro fertilization. MATERIALS AND METHODS: We systematically reviewed studies to compare perinatal outcomes between children conceived by intracytoplasmic sperm injection vs in vitro fertilization. Studies showing genitourinary congenital malformation rates were included. We assessed the risk of bias, focusing on the quality of genitourinary congenital malformation reporting and analysis targeted at singletons. Meta-analysis was done using a random effects model for 3 outcomes, including overall genitourinary congenital malformation, hypospadias and cryptorchidism. Sensitivity analysis was also performed in only studies at low risk for bias. RESULTS: The initial search yielded 1,482 articles. We performed a full text review of 111 of these studies, of which 22 met inclusion criteria for systematic review. Meta-analysis of intracytoplasmic sperm injection and in vitro fertilization in 12,270 and 24,240 cases, respectively, revealed that intracytoplasmic sperm injection was associated with a significantly higher rate of overall genitourinary congenital malformation compared to in vitro fertilization (OR 1.27, 95% CI 1.02-1.59, p = 0.04). However, when including only 4 studies at low risk for bias with a total of 7,727 and 14,308 intracytoplasmic sperm injection and in vitro fertilization cases, respectively, the difference was not significant (OR 1.28, 95% CI 1.00 1.64, p = 0.05). There was no statistically significant difference in the rate of hypospadias (OR 1.21, 95% CI 0.87-1.69) or cryptorchidism (OR 1.39, 95% CI 0.97 2.00) between males conceived by intracytoplasmic sperm injection vs in vitro fertilization. On all analyses there was no significant statistical heterogeneity between studies (I(2) = 0). CONCLUSIONS: Intracytoplasmic sperm injection is associated with a slightly higher risk of genitourinary malformation in offspring than in vitro fertilization. However, when only higher quality studies were analyzed, the difference was not significant. The hypospadias and cryptorchidism rates in offspring are similar for the 2 conception methods. PMID- 25813562 TI - An initial report of a novel multi-institutional bladder exstrophy consortium: a collaboration focused on primary surgery and subsequent care. AB - PURPOSE: For bladder exstrophy repair it is universally accepted that successful initial surgery is paramount to achieve the optimal outcome. Gaining the necessary surgical experience is challenging due to the rarity of bladder exstrophy. We report preliminary findings of a multi-institutional collaboration created to increase experience and proficiency with the care of bladder exstrophy. MATERIALS AND METHODS: Our 3 institutions alternatively served as the host site for scheduled surgeries with observation, commentary and critique by visitors from the other sites. The technique was complete primary repair with bilateral iliac osteotomy. The timing of complete primary repair at age 1 to 3 months facilitated collaboration. We recorded patient demographics and outcomes, and the impact of this collaboration on our technique and experience. Video recording was used for real-time observation and teaching, and future analysis, editing and review. RESULTS: A total of 16 site visits occurred from February 2013 through May 2014. Complete primary repair was performed in 9 males and 7 females with bladder exstrophy. Median age at complete primary repair was 2 months (range 0.1 to 28.8). Median followup was 8.9 months (range 2.8 to 18.2). All closures were successful with no dehiscence. Complications included urethrocutaneous fistula in 2 patients, 1 episode of pyelonephritis in 3 each and urethral obstruction in 2 females, of whom 1 required clean intermittent catheterization. CONCLUSIONS: We report a multi-institutional collaboration to standardize the surgical management of bladder exstrophy. This effort increased the annual experience of each institution involved from threefold to ninefold and it has accelerated the physician knowledge base to ultimately benefit patient care. PMID- 25813563 TI - Transcutaneous parasacral electrical stimulation vs oxybutynin for the treatment of overactive bladder in children: a randomized clinical trial. AB - PURPOSE: We determined the effectiveness of 2 methods to treat overactive bladder in children using intragroup and intergroup comparisons in a randomized clinical trial. MATERIALS AND METHODS: Nine boys and 19 girls with a mean +/- SD age of 6.4 +/- 2.18 years were randomly divided into group 1-parasacral transcutaneous electrical stimulation with placebo drug and group 2-oxybutynin with sham scapular electrical therapy. Success was assessed by 1) the rate of complete symptom resolution, 2) a visual analog scale of 0 to 10, 3) the dysfunctional voiding score system, 4) voiding diary records, 5) Rome III criteria and 6) side effect frequency in each group. RESULTS: A total of 13 and 15 patients were randomized to groups 1 and 2, respectively. Symptoms completely resolved in 6 patients in group 1 (46%) and 3 in group 2 (20%) (p = 0.204). A statistically significant improvement was found in the 2 groups in the dysfunctional voiding score system and voiding diary records. However, no statistically significant difference was found between the groups in the visual analog scale score, voiding frequency, and maximum and mean voided volume (p = 0.295, 0.098, 0.538 and 0.650, respectively). Constipation improved in 100% of group 1 patients but in only 55% in group 2 (p = 0.031 vs 0.073). Group 1 showed no side effects while dry mouth, hyperthermia and hyperemia developed in 58%, 25% and 50% of group 2 patients (p = 0.002, 0.096 and 0.005, respectively). Treatment was discontinued by 13.3% of patients in group 2. CONCLUSIONS: Parasacral transcutaneous electrical stimulation was as effective as oxybutynin to treat overactive bladder in children. However, transcutaneous parasacral electrical stimulation was more effective against constipation and showed no detectable side effects. Oxybutynin was more effective for decreasing voiding frequency. PMID- 25813564 TI - Semen parameters in adolescents with varicocele: association with testis volume differential and total testis volume. AB - PURPOSE: We evaluated the relationship between testicular volume differential, total testis volume and total motile sperm count in adolescents with varicocele. Prior reports have been inconclusive regarding the association of testis volume with semen analysis parameters. MATERIALS AND METHODS: We retrospectively reviewed a single institution database of Tanner 5 adolescents with nonoperated left varicocele with at least 1 semen analysis available. Patients were included in analysis if they had clinical left varicocele, ultrasound measurement of testis volume and no prior inguinal or scrotal surgery. RESULTS: We analyzed the records of 100 patients. Mean +/- SD age at presentation was 15.2 +/- 3.5 years. The mean testicular volume differential was 8% +/- 23% and 31 patients (31%) had a greater than 20% testicular volume differential. Mean total testis volume was 30.4 +/- 13.3 cc. Varicocele was grade 3 in 39 patients, grade 2 in 50, grade 1 in 8 and ungraded in 3. Median total motile sperm count in the cohort was 42.0 (IQR 9.2, 105.8). ROC analysis with the Youden index indicated an optimal total testis volume cutoff of 30 cc to predict the total motile sperm count. In a multivariable logistic model accounting for age and varicocele grade a testicular volume differential of greater than 20% was associated with twice the odds of a total motile sperm count of less than 20 million per cc (OR 2.1, 95% CI 1.02 4.12, p = 0.04). Total testis volume less than 30 cc more than quadrupled the odds of a total motile sperm count of less than 20 million per cc (OR 4.2, 95% CI 1.8-9.7, p <0.001). CONCLUSIONS: Total testis volume and the testicular volume differential are associated with semen analysis outcomes in adolescents with varicocele. A testicular volume differential of greater than 20% doubles the odds of a low total motile sperm count. A total testis volume of less than 30 cc quadruples the odds of a low total motile sperm count. PMID- 25813565 TI - Cell type specific changes in BMP-7 expression contribute to the progression of kidney disease in patients with obstructive uropathy. AB - PURPOSE: Congenital urinary tract obstruction is a leading cause of renal maldevelopment and pediatric kidney disease. Nonetheless, few groups have examined its molecular pathogenesis in humans. We evaluated the role of BMP-7, a protein required for renal injury repair and nephrogenesis, in disease progression in patients with obstructive uropathy. MATERIALS AND METHODS: Whole kidney and cell specific BMP-7 expression was examined in a murine model of unilateral ureteral obstruction and in patients with congenital ureteropelvic junction obstruction. Findings were correlated with molecular markers of renal injury and clinical parameters. RESULTS: Unilateral ureteral obstruction led to a dramatic decrease in BMP-7 expression in the proximal and distal tubules before the onset of significant loss of renal architecture and fibrosis, suggesting that this is a critical molecular event that drives early stage disease progression. Loss of BMP-7 expression then extended to the collecting ducts and glomeruli in end stage kidney disease. When translating these findings to patients with ureteropelvic junction obstruction, global loss of BMP-7 expression correlated with a decreased number of nephrons, loss of renal architecture, severe renal fibrosis and loss of kidney function. CONCLUSIONS: Given that BMP-7 has a critical role in renal injury repair and nephrogenesis, these findings show that cell specific changes in BMP-7 expression contribute to the onset of irreversible renal injury and impaired kidney development secondary to congenital urinary tract obstruction. Accordingly therapies that target these cell populations to restore BMP-7 activity may limit disease progression in patients with obstructive uropathy. PMID- 25813566 TI - Formulation, characterization, and evaluation of ligand-conjugated biodegradable quercetin nanoparticles for active targeting. AB - The aim of this study was to design a targeted drug delivery system carrying a natural anticancer drug Quercetin (Qu), specifically for skin cancer. A central composite design was applied separately for each ligand, and the quadratic model was used for the process. The surface morphology was confirmed by transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR), and in vitro release studies were also performed. The MTT assay was performed against two different cell lines, to measure their anticancer potentials and their targeting ability. The study thus reveals that MA-Qu-PLGA and FA-Qu-PLGA nanoparticles (NPs) can be used as effective drug delivery systems for skin cancer treatment encompassing natural drugs. PMID- 25813567 TI - Preparation and evaluation of a non-viral gene vector for SiRNA: Multifunctional envelope-type nano device (.). AB - We prepared and evaluated a multifunctional envelope-type nano device (MEND) as a liver-targeting and long-circulation carrier for SiRNA. The polymer GA-PEG-Pp DOPE was synthesized by modifying polyethylene glycol (PEG) with glycyrrhetinic acid (GA), peptide (Pp), and dioleoyl phosphoethanolamine (DOPE). The Pp is a substrate of matrix metalloproteinase 2. MEND was prepared with GA-PEG-Pp-DOPE and cationic phospholipids by the filming-rehydration method, and the orthogonal test was applied to optimize the prescription. The results of the biological evaluation results suggest that MEND is a promising delivery system for SiRNA. PMID- 25813568 TI - Development and in vitro characterization of a multiparticulate delivery system for acyclovir-resinate complex. AB - CONTEXT: Herpes viruses cause threatening infections in humans and stand second as causative agents for most human viral diseases, after influenza and cold viruses. OBJECTIVE: A novel multiparticulate delivery system for acyclovir (ACV), based on ion-exchange resin, was developed to achieve a gastro-mucoadhesive effect in order to effectively combat the herpes simplex virus. MATERIALS AND METHODS: A combination of ACV and cholestyramine resin was optimized and further entrapped within sodium alginate and Carbopol microbeads. The developed systems were evaluated for drug entrapment efficiency (DEE), percentage of mucoadhesion, and in vitro release characteristics in simulated gastric fluid (SGF, pH 1.2). RESULTS: With the aid of scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR), the interaction of the resinate and polycations with alginate has been revealed, which consequently supports the formation of the membrane by the polyelectrolyte complex. The in vitro drug release studies demonstrate that formulations without the drug-resin complex (DRC) released the drug more rapidly than formulations containing DRC, which released the drug in a controlled manner, due the formation of a complex between drug and resin. DISCUSSION AND CONCLUSION: Preliminary results from this study suggest that these DRC-entrapped microbeads may be used to incorporate other antiviral drugs and could be effective against infections caused by herpes viruses. Such formulations developed could be subjected to in vivo studies in future, in order to prove complete clearance of herpes infections. PMID- 25813569 TI - [Shadowy existence of nursing research in hospice nursing and palliative care]. PMID- 25813570 TI - [Transition from childhood to adolescence-a qualitative study on experiences of adolescents with type 1 diabetes mellitus and their mothers]. AB - BACKGROUND: In Germany every year approximately 2.200 children under the age of 14 come down with type 1 diabetes mellitus (T1DM). While parents manage diabetes for infants, children take over some tasks over time. During the transition from childhood to adolescence, between 8 - 13 years of age, children become more independent. Children with T1DM experience an additional transition in diabetes management. So far, however, research focused on the transition from adolescence to adulthood. AIM: With the study, experiences of adolescents with T1DM and their mothers with the transition from childhood to adolescence and the meaning of independence were explored. METHOD: This interpretive phenomenological study was conducted in two diabetes walk-in clinics in the south of Germany. Six adolescents and their mothers participated in interviews with open-ended questions. Data were evaluated using case and thematic analysis. RESULTS: Taking over diabetes tasks for longer periods and the increased independence was perceived as liberating by young people. Mothers learned to have confidence in their children. Their biggest concern was a possible hypoglycemia. Family members as well as teachers were involved in the diabetes management differently. The continuous care by the same physicians was experienced as supportive. CONCLUSION: A continuous care by the same professional persons can positively influence the transition from childhood to adolescence for children with T1DM. PMID- 25813571 TI - [Being cared for and caring: living with multiple chronic diseases (Leila)-a qualitative study about APN contributions to integrated care]. AB - BACKGROUND: Living with multiple chronic diseases is complex and leads to enhanced care needs. To foster integrated care a project called "Living with chronic disease" (Leila) was initiated. AIM: The aim was to develop an Advanced Practice Nursing (APN) service in collaboration with medical centers for persons who are living with multiple chronic diseases. The following research questions were addressed: 1. What are patients' experiences, referring physicians and APNs with the Leila-Service? 2. How are referral processes performed? 3. How do the involved groups experience collaboration and APN role development? METHODS: A qualitative approach according grounded theory of Corbin and Strauss was used to explore the experiences with the Leila project and the interaction of the persons involved. 38 interviews were conducted with patients who are living with multiple chronic diseases, their APN's and the referring physicians. RESULTS: The findings revealed "Being cared for and caring" as main category. The data demonstrated how patients responded to their involvement into care and that they were taken as serious partners in the care process. The category "organizing everyday life" describes how patients learned to cope with the consequences of living with multiple chronic diseases. "Using all resources" as another category demonstrates how capabilities and strengths were adopted. CONCLUSIONS: The results of the cooperation- and allocation processes showed that the APN recognition and APN role performance have to be negotiated. Prospective APN-services for this patient population should be integrated along with physician networks and other service providers including community health nursing. PMID- 25813573 TI - [Patient education in the acute hospital]. PMID- 25813572 TI - [Monitoring of nursing service context factors: first descriptive results of a cross-sectional Swiss study prior the introduction of SwissDRG]. AB - BACKGROUND: The adoption of DRG-based payment systems has narrowed hospitals' financial margins, necessitating streamlining and process optimization. The experience of other countries shows that this restructuring can influence context factors essential to the delivery of nursing care. As a result, nursing care quality and patient safety may be impacted. AIM: The Sinergia Project aims to develop a monitoring model and related instruments to continuously monitor the impact of DRG-based reimbursement on central nursing service context factors. METHOD: The descriptive, quantitative results were collected within the framework of a study with a mixed methods design by means of an online survey in which nurses from five hospitals participated. RESULTS: The results show that the nursing service context factors examined (nursing care complexity, quality of the work environment, management, moral distress and job satisfaction), have relevance in all practice areas as regards practice setting and nursing care delivery. Patterns can be recognized that are consistent with those found in the literature and which could be an indication of the relationships between the context factors above, as was hypothesized in the model. CONCLUSIONS: The study has provided the participating hospitals with useful data upon which to base discussions on ensuring quality of nursing care and practice development, in addition to information important to the further development of the model and the instruments employed. PMID- 25813575 TI - [Hurtful words: verbal violence]. PMID- 25813574 TI - [Daily routine of informal caregivers-needs and concerns with regard to the discharge of their elderly family members from the hospital setting-a qualitative study]. AB - BACKGROUND: The care of an elderly frail and ill family member places a great responsibility on informal caregivers. Following discharge of the older person from the hospital setting it can be observed that caregivers are often inadequately informed about aspects such as health status, prognosis, complications, and care interventions. Concerns and needs of caregivers regarding their daily living and routine following hospital discharge has not been investigated and is considered important for an optimized discharge management. AIM: To explore personal needs and concerns of informal caregivers with regard to daily living prior to discharge of their family member. METHOD: Eight narrative interviews were conducted with caregivers and were analysed using Mayring's content analysing method. RESULTS: All caregivers had concerns regarding the maintenance of a functional daily routine. As well as caring and household duties, this functional daily routine included negotiating one's own personal time off duties, the reality of the deteriorating health status of the family member and the associated sense of hope. The intensity of family ties affected the functional daily routine. Caregivers had different expectations with regard to their integration during the hospital period. CONCLUSIONS: To support caregivers in their situation it is advisable to assess the functional daily routine of caregivers. Their need for time off their household and caring duties and their informational and educational needs to pertaining to disease progression, possible sources of support and symptom management should be recognised. Further inquiries into caregiver's involvement and responsibilities in the discharge process are needed. PMID- 25813576 TI - [Psychological hardiness - focus on resilience in nursing science]. PMID- 25813580 TI - New results on delay-range-dependent stability analysis for interval time-varying delay systems with non-linear perturbations. AB - This paper studies the problem of the stability analysis of interval time-varying delay systems with nonlinear perturbations. Based on the Lyapunov-Krasovskii functional (LKF), a sufficient delay-range-dependent criterion for asymptotic stability is derived in terms of linear matrix inequality (LMI) and integral inequality approach (IIA) and delayed decomposition approach (DDA). Further, the delay range is divided into two equal segments for stability analysis. Both theoretical and numerical comparisons have been provided to show the effectiveness and efficiency of the present method. Two well-known examples are given to show less conservatism of our obtained results and the effectiveness of the proposed method. PMID- 25813581 TI - Photoactivation of Dok1/ERK/PPARgamma signaling axis inhibits excessive lipolysis in insulin-resistant adipocytes. AB - Insulin resistance is a hallmark of the metabolic syndrome and type 2 diabetes. Increased plasma FFA level is an important cause of obesity-associated insulin resistance. Over-activated ERK is closely related with FFA release from adipose tissues in patients with type 2 diabetes. Nevertheless, there are no effective strategies to lower plasma FFA level. Low-power laser irradiation (LPLI) has been reported to regulate multiple biological processes. However, whether LPLI could ameliorate metabolic disorders and the molecular mechanisms involved remain unknown. In this study, we first demonstrated that LPLI suppresses excessive lipolysis of insulin-resistant adipocytes by activating tyrosine kinases 1(Dok1)/ERK/PPARgamma pathway. Our data showed that LPLI inhibits ERK phosphorylation through the activation of Dok1, resulting in decreased phospho PPARgamma level. Non-phosphorylated PPARgamma maintains in nucleus to promote the expression of adipogenic genes, reversing excessive lipolysis in insulin resistant adipocytes. In summary, the present research highlights the important roles of Dok1/ERK/PPARgamma pathway in lowering FFA release from adipocytes, and our research extends the knowledge of the biological effects induced by LPLI. PMID- 25813582 TI - Response to Courtney et al. PMID- 25813583 TI - Alteration of the bone tissue material properties in type 1 diabetes mellitus: A Fourier transform infrared microspectroscopy study. AB - Type 1 diabetes mellitus (T1DM) is a severe disorder characterized by hyperglycemia and hypoinsulinemia. A higher occurrence of bone fractures has been reported in T1DM, and although bone mineral density is reduced in this disorder, it is also thought that bone quality may be altered in this chronic pathology. Vibrational microscopies such as Fourier transform infrared microspectroscopy (FTIRM) represent an interesting approach to study bone quality as they allow investigation of the collagen and mineral compartment of the extracellular matrix in a specific bone location. However, as spectral feature arising from the mineral may overlap with those of the organic component, the demineralization of bone sections should be performed for a full investigation of the organic matrix. The aims of the present study were to (i) develop a new approach, based on the demineralization of thin bone tissue section to allow a better characterization of the bone organic component by FTIRM, (ii) to validate collagen glycation and collagen integrity in bone tissue and (iii) to better understand what alterations of tissue material properties in newly forming bone occur in T1DM. The streptozotocin-injected mouse (150 mg/kg body weight, injected at 8 weeks old) was used as T1DM model. Animals were randomly allocated to control (n = 8) or diabetic (n = 10) groups and were sacrificed 4 weeks post-STZ injection. Bones were collected at necropsy, embedded in polymethylmethacrylate and sectioned prior to examination by FTIRM. FTIRM collagen parameters were collagen maturity (area ratio between 1660 and 1690 cm(-1) subbands), collagen glycation (area ratio between the 1032 cm(-1) subband and amide I) and collagen integrity (area ratio between the 1338 cm(-1) subband and amide II). No significant differences in the mineral compartment of the bone matrix could be observed between controls and STZ-injected animals. On the other hand, as compared with controls, STZ injected animals presented with significant higher value for collagen maturity (17%, p = 0.0048) and collagen glycation (99%, p = 0.0121), while collagen integrity was significantly lower by 170% (p = 0.0121). This study demonstrated the profound effect of early T1DM on the organic compartment of the bone matrix in newly forming bone. Further studies in humans are required to ascertain whether T1DM also lead to similar effect on the quality of the bone matrix. PMID- 25813584 TI - Disagreements between medical specialty boards and their diplomates. PMID- 25813585 TI - Opioids for nonmalignant chronic pain. PMID- 25813586 TI - Withholding information from an anxiety-prone patient? PMID- 25813587 TI - Abusive and disruptive behavior in the surgical team. PMID- 25813588 TI - Education to identify and combat racial bias in pain treatment. PMID- 25813589 TI - Perioperative do-not-resuscitate orders. PMID- 25813590 TI - Is informed consent for extracorporeal life support even possible? PMID- 25813591 TI - Ethical tenets of perioperative care: "finding my surgical way home". PMID- 25813592 TI - Quality improvement and patient safety organizations in anesthesiology. PMID- 25813593 TI - The influence of social values on obstetric anesthesia. PMID- 25813594 TI - The history of professionalism in anesthesiology. PMID- 25813595 TI - The importance of good communication in treating patients' pain. PMID- 25813596 TI - High throughput screening of scFv antibodies against viral hemorrhagic septicaemia virus by flow cytometry. AB - Viral hemorrhagic septicaemia (VHS) is an economically important disease that affects salmon and trout worldwide. In this study, a recombinant single chain variable fragment (scFv) antibody library derived from rainbow trout immunized with purified viral hemorrhagic septicaemia virus (VHSV) was constructed. The library was subjected to three rounds of screening by flow cytometry (FCM) against VHSV through a bacteria display technology, resulting in the enrichment of scFv. Four scFv clones with different fluorescence intensity were obtained by colony pick up at random following three rounds of screening. The isolated scFv antibodies were expressed and purified. Relative affinity assay showed the four clones had different sensitivity to VHSV, in accordance with FCM. The potential use of the selected VHSV-specific scFv antibodies was demonstrated by the successful application in Western blotting assay, ELISA and immunofluorescence antibody test (IFAT), and one of the isolated scFv molecular showed excellent in vitro and in vivo blocking activities against VHSV. scFv isolated in this study can be promising diagnostic and/or therapeutic reagents for VHS. This study provides powerful strategies for screening antibodies against new diseases. PMID- 25813597 TI - A novel assay for detecting canine parvovirus using a quartz crystal microbalance biosensor. AB - Rapid and accurate diagnosis is crucial to reduce both the shedding and clinical signs of canine parvovirus (CPV). The quartz crystal microbalance (QCM) is a new tool for measuring frequency changes associated with antigen-antibody interactions. In this study, the QCM biosensor and ProLinkerTM B were used to rapidly diagnosis CPV infection. ProLinkerTM B enables antibodies to be attached to a gold-coated quartz surface in a regular pattern and in the correct orientation for antigen binding. Receiver operating characteristics (ROC) curves were used to set a cut-off value using reference CPVs (two groups: one CPV positive and one CPV-negative). The ROC curves overlapped and the point of intersection was used as the cut-off value. A QCM biosensor with a cut-off value of -205 Hz showed 95.4% (104/109) sensitivity and 98.0% (149/152) specificity when used to test 261 field fecal samples compared to PCR. In conclusion, the QCM biosensor described herein is eminently suitable for the rapid diagnosis of CPV infection with high sensitivity and specificity. Therefore, it is a promising analytical tool that will be useful for clinical diagnosis, which requires rapid and reliable analyses. PMID- 25813598 TI - Concurrent infections of pseudorabies virus and porcine bocavirus in China detected by duplex nanoPCR. AB - Nanoparticle-assisted polymerase chain reaction (nanoPCR) is a novel method for the simple, rapid, and specific amplification of DNA and has been used to detect viruses. A duplex nanoPCR molecular detection system was developed to detect pseudorabies virus (PRV) and porcine bocavirus (PBoV). Primers were selected to target conserved regions within the PRV gE gene and the PBoV NS1 gene. Under optimized nanoPCR reaction conditions, two specific fragments of 316 bp (PRV) and 996 bp (PBoV) were amplified by the duplex nanoPCR with a detection limit of 6 copies for PRV and 95 copies for PBoV; no fragments were amplified when other porcine viruses were used as template. When used to test 550 clinical samples, the duplex nanoPRC assay and a conventional duplex PCR assay provided very similar results (98.1% consistency); single PRV infections, single PBoV infections, and concurrent PRV and PBoV infections were detected in 37%, 15%, and 9% of the samples, respectively. The results indicate that the novel duplex nanoPCR assay is useful for the rapid detection of PRV and PBoV in pigs. PMID- 25813599 TI - A TaqMan-based real-time PCR for detection and quantification of porcine parvovirus 4. AB - Porcine parvovirus 4 (PPV4) is a DNA virus, and a member of the Parvoviridae family within the Bocavirus genera. It was detected recently in swine, but its epidemiology and pathology remain unclear. A TaqMan-based real-time PCR (qPCR) targeting a conserved region of the ORF3 gene of PPV4 was developed. The qPCR detection limit was 9.5 * 10(1) DNA copies/MUL. There was no cross-reaction with porcine parvovirus, torque teno virus 1, torque teno virus 2, porcine circovirus type 1, porcine circovirus type 2, or with pseudorabies virus. Two hundred and seventy-two samples, including serum, semen, lungs, feces, ovarian follicular fluids, ovaries and uterus, were evaluated by qPCR and PPV4 was detected in 36 samples (13.2%). When compared with a conventional PCR (cPCR), the qPCR assay was 10 times more sensitive and the detection of PPV4 DNA in field samples was increased 2.5 times. Partial sequencing of PPV4 ORF3 gene, obtained from two pooled samples of uterus and ovaries, revealed a high nucleotide identity (98 99%) with a reference PPV4 sequence. The qPCR can be used as a fast and accurate assay for the detection and quantification of PPV4 in field samples and for epidemiological studies in swine herds. PMID- 25813600 TI - Development of sheep kidney cells with increased resistance to different subgenotypes of BVDV-1 by RNA interference. AB - Bovine viral diarrhea virus (BVDV) should be a ubiquitous viral pathogen to the cattle and sheep industry. This pathogen is responsible for severe economic losses. We previously showed that plasmid-mediated dual short hairpin RNA (shRNA) efficiently inhibit BVDV replication in bovine kidney epithelial (MDBK) cells. In this study, we delivered the dual shRNA system to sheep fibroblasts and generated transgenic cell colonies. These transgenic fibroblasts were further used for somatic cell nuclear transfer (SCNT). Three lambs were born at full term, but perished soon after birth. Integration of shRNA into the genome of cloned sheep was confirmed by PCR and expression of shRNA in transgenic sheep was confirmed by real-time PCR. Kidney epithelial cells were isolated from transgenic sheep and challenged with multiple BVDV subgenotypes (BVDV-1a, BVDV-1b and BVDV-1c). The dual shRNA expressed in transgenic kidney epithelial cells significantly inhibited BVDV replication in a cross-resistance manner. Our results showed that transgenic RNAi might be a useful tool for preparation of transgenic animals with increased resistance to BVDV. PMID- 25813601 TI - Transplantation of a 2-year-old deceased-donor liver to a 61-year-old male recipient. AB - The suitable size of a graft is a key element in the success of liver transplantation. A small-for-size liver graft is very likely to sustain a significant degree of injury as a result of ischemia, preservation, reperfusion, and rejection. Usually, small-for-size grafts are a concern in living-donor liver transplantation rather than in deceased-donor liver transplantation. Here, we describe the successful transplantation of a liver from a 2-year-old deceased donor to a 61-year-old male recipient who suffered from liver failure related to hepatitis B. No report of successful deceased-donor liver transplantation with discrepancies between donor and recipient age and size to such an extent has been found in the literature. Despite unusually large discrepancies, with effort in minimizing the ischemic time, revised surgical techniques, and strong regenerative power of the "young" graft, the old patient's liver function gradually returned to normal. This again proves that the definition of a "suitable graft" evolves with time and experience. PMID- 25813602 TI - Gastric outlet obstruction secondary to paraesophageal herniation of gastric antrum after laparoscopic fundoplication. AB - The most common causes of acute gastric outlet obstruction (GOO) are duodenal and type 3 gastric ulcers. However, mechanical or functional causes may also lead to this pathology. Acute GOO is characterized by delayed gastric emptying, anorexia, or nausea accompanied by vomiting. Herein we report a 56-year-old man diagnosed with GOO secondary to paraesophageal hiatal herniation of gastric antrum after laparoscopic fundoplication. Because of the rarity of this disease, common gastrointestinal complaints may mislead the emergency physician to diagnose a nonsurgical gastrointestinal disease if a detailed history and physical examinations are not obtained. PMID- 25813603 TI - Inhibition-Based Biomarkers for Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks. PMID- 25813604 TI - Standing postural instability in patients with schizophrenia: Relationships with psychiatric symptoms, anxiety, and the use of neuroleptic medications. AB - The purpose of this study was to assess postural instability in patients with schizophrenia using a pressure-sensitive platform and to examine the effects of anxiety, psychiatric symptoms, and the use of neuroleptic medications on postural sway. Participants were 23 patients with schizophrenia and 23 healthy controls. We found that the patients showed greater overall postural instability than the controls. Furthermore, they demonstrated greater instability when the test was performed with the eyes closed than with the eyes open. However, removal of visual input had less impact on the indices of postural instability in the patients than in the controls, suggesting that schizophrenia is associated with difficulties in integrating visual information and proprioceptive signals. Furthermore, in contrast to the controls, anxiety exacerbated postural instability in the patients. There were significant associations between postural stability and psychiatric symptoms in the patients without extrapyramidal symptoms, whereas medication dose did not significantly correlate with postural stability. PMID- 25813605 TI - Feedback control of flow vorticity at low Reynolds numbers. AB - Our aim is to explore strategies of feedback control to design and stabilize novel dynamic flow patterns in model systems of complex fluids. To introduce the control strategies, we investigate the simple Newtonian fluid at low Reynolds number in a circular geometry. Then, the fluid vorticity satisfies a diffusion equation. We determine the mean vorticity in the sensing area and use two control strategies to feed it back into the system by controlling the angular velocity of the circular boundary. Hysteretic feedback control generates self-regulated stable oscillations in time, the frequency of which can be adjusted over several orders of magnitude by tuning the relevant feedback parameters. Time-delayed feedback control initiates unstable vorticity modes for sufficiently large feedback strength. For increasing delay time, we first observe oscillations with beats and then regular trains of narrow pulses. Close to the transition line between the resting fluid and the unstable modes, these patterns are relatively stable over long times. PMID- 25813606 TI - Bond lifetime and diffusion coefficient in colloids with short-range interactions. AB - We use molecular dynamics simulations to study the influence of short-range structures in the interaction potential between hard-sphere-like colloidal particles. Starting from model potentials and effective potentials in binary mixtures computed from the Ornstein-Zernike equations, we investigate the influence of the range and strength of a possible tail beyond the usual core repulsion or the presence of repulsive barriers. The diffusion coefficient and mean "bond" lifetimes are used as indicators of the effect of this structure on the dynamics. The existence of correlations between the variations of these quantities with the physical parameters is discussed to assess the interpretation of dynamics slowing down in terms of long-lived bonds. We also discuss the question of a universal behaviour determined by the second virial coefficient B ((2)) and the interplay of attraction and repulsion. While the diffusion coefficient follows the B ((2)) law for purely attractive tails, this is no longer true in the presence of repulsive barriers. Furthermore, the bond lifetime shows a dependence on the physical parameters that differs from that of the diffusion coefficient. This raises the question of the precise role of bonds on the dynamics slowing down in colloidal gels. PMID- 25813607 TI - Topological binding and elastic interactions of microspheres and fibres in a nematic liquid crystal. AB - We present a detailed analysis of topological binding and elastic interactions between a long, and micrometer-diameter fiber, and a microsphere in a homogeneously aligned nematic liquid crystal. Both objects are surface treated to produce strong perpendicular anchoring of the nematic liquid crystal. We use the opto-thermal micro-quench of the laser tweezers to produce topological defects with prescribed topological charge, such as pairs of a Saturn ring and an anti ring, hyperbolic and radial hedgehogs on a fiber, as well as zero-charge loops. We study the entanglement and topological charge interaction between the topological defects of the fiber and sphere and we observe a huge variety of different entanglement topologies and defect-mediated elastic bindings. We explain all observed phenomena with simple topological rule: like topological charges repel each other and opposite topological charges attract. These binding mechanisms not only demonstrate the fascinating topology of nematic colloids, but also open a novel route to the assembly of very complex topological networks of fibers, spheres and other objects for applications in liquid crystal photonics. PMID- 25813608 TI - Optimizing antibiotic therapy of bacteremia and endocarditis due to staphylococci and enterococci: new insights and evidence from the literature. AB - Gram-positive cocci are a well-recognised major cause of nosocomial infection worldwide. Bloodstream infections due to methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, and multi-drug resistant enterococci are a cause of concern for physicians due to their related morbidity and mortality rates. Aim of this article is to review the current state of knowledge regarding the management of BSI caused by staphylococci and enterococci, including infective endocarditis, and to identify those factors that may help physicians to manage these infections appropriately. Moreover, we discuss the importance of an appropriate use of antimicrobial drugs, taking in consideration the in vitro activity, clinical efficacy data, pharmacokinetic/pharmacodynamic parameters, and potential side effects. PMID- 25813609 TI - Gender Development in Indonesian Children, Adolescents, and Adults with Disorders of Sex Development. AB - In most Western countries, clinical management of disorders of sex development (DSD), including ambiguous genitalia, begins at diagnosis soon after birth. For many Indonesian patients born with ambiguous genitalia, limited medical treatment is available. Consequently, affected individuals are raised with ambiguous genitalia and atypical secondary sex characteristics. We investigated gender identity and gender role behavior in 118 Indonesian subjects (77 males, 41 females) with different types of DSD in comparison with 118 healthy controls matched for gender, age, and residential setting (rural, suburban, or urban). In Study 1, we report on methodological aspects of the investigation, including scale adaptation, pilot testing, and determining reliability and validity of measures. In Study 2, we report on gender development in 60 children (42 boys, 18 girls), 24 adolescents (15 boys, 9 girls), and 34 adults (19 men, 15 women) with DSD. The majority of participants with DSD never received any medical or surgical treatment prior to this study. We observed a gender change in all age groups, with the greatest incidence in adults. Among patients who changed, most changed from female to male, possessed a 46,XY karyotype, and had experienced significant masculinization during life. Gender identity confusion and cross-gender behavior was more frequently observed in children with DSD raised as girls compared to boys. Puberty and associated masculinization were related to gender problems in individuals with 46,XY DSD raised female. An integrated clinical and psychological follow-up on gender outcome is necessary prior to puberty and adulthood. PMID- 25813610 TI - Heterosexual Men's Ratings of Sexual Attractiveness of Adolescent Girls: A Cross Cultural Analysis. AB - Following an identical procedure to the one we previously reported (O'Donnell, Lowe, Brotherton, & Bennett, 2014), we examined ratings of sexual attraction to photographs of (the same) adolescent girls (Tanner stages 3-4) labelled as either 14-15 years or 16-17 years old, women, and men. Ratings were made by Bulgarian heterosexual men by pressing buttons on a response box which recorded the ratings made and the time in milliseconds taken to respond. Despite the age of sexual consent in Bulgaria being 14 years, the pattern of findings did not differ from those found in the UK, where the age of consent is 16 years. That is, mean ratings of the sexual attractiveness of the girls labelled as younger were lower than those of the (same) girls labelled as older, and those of the women. In addition, correlations revealed significantly longer responding times when younger girls (and men) were rated as more highly sexually attractive. These associations were reversed in response to the photographs of women. We take these findings to indicate an inhibitory effect arising from generalized sexual norms relating to the inappropriateness of sexual attraction to young girls; the greater the attraction, the higher the inhibition. This second replication of our initial findings suggests a robust effect that may be of benefit in exploration of pedophile or sex offender groups. PMID- 25813611 TI - Assessment of Introital Lubrication. AB - Vaginal vasocongestion and lubrication serve to prepare the vaginal lumen for sexual activity. Lubrication is important for sexual functioning and difficulties with lubrication are one of the most commonly reported symptoms of sexual dysfunction. Few studies have empirically examined how vasocongestion and lubrication relate to one another and there are currently no well-established measures of lubrication. In this study, we designed and tested a simple method to assess lubrication at the vaginal introitus in 19 healthy women, using litmus test strips. We examined the relationship between lubrication and vaginal vasocongestion (measured with a photoplethysmograph) when elicited by audiovisual sexual stimuli (male-female sexual interactions). Lubrication was elicited by the sexual stimuli and was strongly correlated with reports of sexual arousal. Unexpectedly, lubrication was not correlated with vasocongestion, even though the latter was also elicited by the sexual stimuli. We discuss the implications of these findings for informing our understanding of the female sexual response and the potential clinical and scientific utility of this new measure. PMID- 25813612 TI - Acid-Sensing Ion Channels in the nervous system. Foreword. PMID- 25813613 TI - The introduction and development of graduate entry programmes in the United kingdom. AB - In the United Kingdom, 4-year graduate-only medical education programmes (Graduate Entry Programme, GEP) started in 2000, and are running in 16 medical schools with over 800 students annually. This study presents the grounds for introduction of the GEP, and explores its benefits in increasing the medical workforce and widening participation in medical education. An increase in medical student numbers was proposed to cope with the pressing shortage of British doctors and the growing demand for doctors, and the GEP was introduced as a flexible and cost-effective way to meet this demand. It has contributed to increasing the diversity of students in medical schools and widening access to students from more varied social and educational backgrounds. In the United Kingdom, the GEP was established as a supplementary means of providing medical education, and it is unlikely to totally replace traditional 5- or 6-year programmes. PMID- 25813614 TI - Relationships between Cognitive and Learning Styles of Premedical Students. AB - PURPOSE: We investigated the relationship between cognitive and learning style by comparing the Cognitive Styles Analysis (CSA) with the Index of Learning Styles (ILS). We assessed whether cognitive styles correlated with learning styles with regard to their corresponding dimensions. METHODS: One hundred two second-year premedical students participated, and data from ninety-four students were analyzed. One student's data file was lost during data collection, and six students were excluded because their correct response rates on the CSA were lower than 50%. Both scales were presented on a computer item by item, and the assessment was conducted in the computer lab as a group. For analysis, responses and reaction times were recorded. RESULTS: Distributions of the styles were generated. We correlated the verbal-imagery dimension of the CSA with the visual verbal dimension of the ILS and found no correlation. There was no correlation between the wholist-analytic dimension of the CSA with the sequential-global dimension of the ILS. Excluding intermediate students in the verbal-imagery dimension of the CSA, however, there appeared to be a marginally significant correlation between the verbal-imagery dimension of the CSA and the visual-verbal dimension of the ILS. CONCLUSION: In the visual (imagery)-verbal dimension, there was some correlation between cognitive and learning styles. PMID- 25813615 TI - Perception of medical students on real-time class evaluation using mobile phone survey system. AB - PURPOSE: The aim of this study is to investigate the advantage of real-time class evaluation over course evaluation in integrated courses and to explore the usefulness and availability of a mobile phone survey system as a real-time class evaluation tool. METHODS: In six integrated courses at the preclinical second year both course and class evaluations were performed. Class evaluations were carried out 206 times right after every class by a mobile phone survey system that depended on mobile phones to send information. A survey was performed to identify students' perception on real-time class evaluation and the mobile phone survey system. RESULTS: The course evaluation score was found to have greater than 95% confidence interval of class evaluations at 5 of 6 courses. Class evaluations yielded more information on educational content and teaching strategy than course evaluations. A higher score was given in class evaluation regarding effectiveness on improving quality of education (3.77 vs. 2.15) and sincerity during evaluation (3.87 vs. 2.49). Of the three major evaluation tools, such as paper, web and mobile phone, majority of students preferred mobile phones especially in terms of accessibility (89%), familiarity (75.3%), and time (74%). CONCLUSION: In integrated courses, real-time class evaluations could yield more information and better sincerity than course evaluations. Real-time class evaluations could be successfully performed through a mobile phone survey system compared with that of paper- or web-based methods. PMID- 25813616 TI - Effects of differences in problem-based learning course length on academic motivation and self-directed learning readiness in medical school students. AB - PURPOSE: Problem-based learning (PBL) is an educational approach in which complex authentic problems serve as the context and stimulus for learning. PBL is designed to encourage active participation during learning. The goal of this study was to study the effects of PBL on academic motivation and self-directed learning readiness in medical school students. METHODS: The subjects of this study were 190 students in the 1st and 2nd grade of medical school. The period of the PBL course was two weeks for Year 1 and five weeks for Year 2 students. Students completed one module over one week. Academic motivation tests and self directed learning readiness tests were performed before and after the PBL course. The differences between the two groups were analyzed using paired t-test and repeated measures MANCOVA. RESULTS: PBL had positive effects on academic self efficacy (self-control efficacy, task-level preference) and academic failure tolerance (behavior, task-difficulty preference) as academic motivation. PBL had a mildly positive effect on self-directed learning readiness. In addition, the five-week PBL course had greater positive effects on academic motivation than the two-week course but not with regard to self-directed learning readiness. CONCLUSION: Medical students engage in academic motivation and self-directed learning readiness during PBL, suggesting that the five-week PBL course has greater positive effects than the two-week course. Future studies are needed to confirm the most effective periods of PBL. PMID- 25813617 TI - Analysis of the perceived effectiveness and learning experience of medical communication skills training in interns. AB - PURPOSE: This study aims to explore the perceived effectiveness, benefits, and learning experiences of interns with regard to their participation in a communication skills workshop program, which can have implications for the development and implementation of future communication skills training. METHODS: One hundred twenty one interns and 12 senior residents and fellows participated in the workshop program as learners and tutors. The participating interns encountered three difficult communication situations, represented by trained standardized patients. During each encounter, each participant had an individual encounter, group discussion, and feedback on his performance. A self-assessment survey, composed of five itemized questions and seven open-ended questions, was administered after the workshop. A mixed methods approach was used to analyze the quantitative and qualitative data. RESULTS: The participants had positive perceptions of the implementation and effects of the workshop, and they responded higher than 4.0 to all itemized questions on their perception of the effectiveness and benefits of the workshop. The analysis of open-ended questions demonstrated specific learning experiences of the participants, such as the hardship of solving ill-structured communication problems and reflection on their current knowledge, skills, attitudes, and practice as physicians. The participants reported that the workshop provided opportunities of improving diverse communication skills and problem-solving skills and identifying further learning needs. CONCLUSION: The results suggest that communication skills training for interns facilitates their reflection and development of communication skills, as well as their competency of situated problem solving. Consequently, communication skills development should be regarded as an important subject of continuing medical education. Several implications of this study can contribute to the design and development of communication skills-related programs. PMID- 25813618 TI - Methods of effective team-based learning administration and expected effects on medical education. AB - PURPOSE: The aim of this study was to analyze the results of quantitative and qualitative student evaluations of team-based learning (TBL) and student achievement evaluations during TBL. METHODS: Questionnaires that evaluated medical student perception and self-assessment of the TBL experience included 38 questions on the TBL process. Also, we used scores from the TBL session to investigate student academic achievement. RESULTS: Our results showed that the more proper the educational environments were, the more focused students were on team learning. According to the distribution period for preliminary assignments, there was a difference in self-directed learning. In addition, team members had the opportunity to learn new knowledge by interacting with each other, and when they had the experience of feedback, they understood the instruction topics through team learning better. With regard to peer evaluation, the students who recognized the importance of assessment studied more sincerely and honestly. By experiencing the TBL process, every team showed a high significance in the group readiness assurance test score compared with the individual readiness assurance test score, and student satisfaction with the TBL and expectation levels about capacity strengthening increased as well. CONCLUSION: TBL is an effective teaching and learning method and has positive impacts on student academic achievement. A study on student academic achievement and perception of TBL is expected to provide medical educators with suggestions on planning teaching strategies for effective TBL administration. PMID- 25813619 TI - Analytical case study of evaluation of curriculum at a medical school. AB - PURPOSE: This study aims at to make intermediate-term evaluations of a curriculum by investigating its development, operation and outcomes 2 years after its revision. METHODS: A survey using 5-point-Lickert scale questionnaires was given to the group of directors who developed the curriculum, instructors who only used it in their classes, and a student group from the first and second grades. Focus group interviews were performed in the professor groups. RESULTS: Curricular reform was evaluated as being systematic, democratic, and positive in general. Both groups answered questions positively about the relevance of the integrated curriculum and introduction of clinical medicine (ICM), graded as 3.4 (professor) and 3.5 (student). As for problem-based learning (PBL) and the patient-doctor society (PDS), the professor group responded more positively than students. The 'web-based learning center' was recognized positively by many more students (4.01) than professors (2.75). With regard to the education outcome, professors gave 3.3 points and students 3.5 to an item that asked 'whether students attained the learning goal or not?' Professors, through interviews, showed their satisfaction with the attempt to reform the curriculum, but they pointed out that long-term evaluations should be performed. CONCLUSION: The interim evaluation of the revised curriculum, from its planning to its effects, affirmed by several suggestions to be successful in the long run through 1) enhancement of systematic participation and communication, 2) further integration, 3) steady evaluation, 4) greater effort on professional development, and 5) active interaction between professors and students. PMID- 25813621 TI - Simple check list for making test item. PMID- 25813620 TI - Are medical students satisfied with their medical professionalism education? AB - PURPOSE: This study aims to examine the satisfaction of undergraduate medical students with their medical professionalism education. METHODS: Two hundred and one premedical students and 1,287 medical students (from year 1 to 4) participated in a five-point Likert scale survey. There were 27 items in the premedical students' survey and 31 items in the medical students' questionnaire. Statistical analysis including one-way ANOVA was performed. RESULTS: Among the 27 items concerning premedical professionalism education, only six topics scored "average" level. In the survey of medical students only nine items out of 31 were rated "average" which did not reach the satisfactory level. Nine items from the medical students' survey showed significant positive improvements in satisfaction as the academic year increased; however, the changes were not large enough for any of the topics to receive a satisfactory score. CONCLUSION: Overall students were dissatisfied with their professionalism education. The reasons for these results and possible approaches for improving students' satisfaction should be considered in future research. PMID- 25813622 TI - If you can love, you will see. When you can see, it will not be the same as before. PMID- 25813623 TI - A genome-wide expression quantitative trait loci analysis of proprotein convertase subtilisin/kexin enzymes identifies a novel regulatory gene variant for FURIN expression and blood pressure. AB - Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome wide significant (p < 5 * 10(-8)) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic (p = 0.012) and systolic (p = 0.035) BP levels, as well as peripheral vascular resistance (p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease. PMID- 25813624 TI - Poly(ADP-ribosyl)ation of p53 contributes to TPEN-induced neuronal apoptosis. AB - Depletion of intracellular zinc by N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) induces p53-mediated protein synthesis-dependent apoptosis of mouse cortical neurons. Here, we examined the requirement for poly(ADP-ribose) polymerase (PARP)-1 as an upstream regulator of p53 in zinc depletion-induced neuronal apoptosis. First, we found that chemical inhibition or genetic deletion of PARP-1 markedly attenuated TPEN-induced apoptosis of cultured mouse cortical neurons. Poly(ADP-ribosyl)ation of p53 occurred starting 1 h after TPEN treatment. Suggesting the critical role of PARP-1, the TPEN-induced increase of stability and activity of p53 as well as poly(ADP-ribosyl)ation of p53 was almost completely blocked by PARP inhibition. Consistent with this, the induction of downstream proapoptotic proteins PUMA and NOXA was noticeably reduced by chemical inhibitors or genetic deletion of PARP-1. TPEN-induced cytochrome C release into the cytosol and caspase-3 activation were also blocked by inhibition of PARP-1. Taken together, these findings indicate that PARP-1 is essential for TPEN-induced neuronal apoptosis. PMID- 25813625 TI - Heme oxygenase-1 determines the differential response of breast cancer and normal cells to piperlongumine. AB - Piperlongumine, a natural alkaloid isolated from the long pepper, selectively increases reactive oxygen species production and apoptotic cell death in cancer cells but not in normal cells. However, the molecular mechanism underlying piperlongumine-induced selective killing of cancer cells remains unclear. In the present study, we observed that human breast cancer MCF-7 cells are sensitive to piperlongumine-induced apoptosis relative to human MCF-10A breast epithelial cells. Interestingly, this opposing effect of piperlongumine appears to be mediated by heme oxygenase-1 (HO-1). Piperlongumine upregulated HO-1 expression through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) signaling in both MCF-7 and MCF-10A cells. However, knockdown of HO-1 expression and pharmacological inhibition of its activity abolished the ability of piperlongumine to induce apoptosis in MCF-7 cells, whereas those promoted apoptosis in MCF-10A cells, indicating that HO-1 has anti-tumor functions in cancer cells but cytoprotective functions in normal cells. Moreover, it was found that piperlongumine-induced Nrf2 activation, HO-1 expression and cancer cell apoptosis are not dependent on the generation of reactive oxygen species. Instead, piperlongumine, which bears electrophilic alpha,beta-unsaturated carbonyl groups, appears to inactivate Kelch-like ECH-associated protein-1 (Keap1) through thiol modification, thereby activating the Nrf2/HO-1 pathway and subsequently upregulating HO-1 expression, which accounts for piperlongumine induced apoptosis in cancer cells. Taken together, these findings suggest that direct interaction of piperlongumine with Keap1 leads to the upregulation of Nrf2 mediated HO-1 expression, and HO-1 determines the differential response of breast normal cells and cancer cells to piperlongumine. PMID- 25813626 TI - A novel pyruvate kinase M2 activator compound that suppresses lung cancer cell viability under hypoxia. AB - Pyruvate kinase M2 isoform (PKM2), a rate-limiting enzyme in the final step of glycolysis, is known to be associated with the metabolic rewiring of cancer cells, and considered an important cancer therapeutic target. Herein, we report a novel PKM2 activator, PA-12, which was identified via the molecular docking-based virtual screening. We demonstrate that PA-12 stimulates the pyruvate kinase activity of recombinant PKM2 in vitro, with a half-maximal activity concentration of 4.92 MUM, and effectively suppresses both anchorage-dependent and -independent growth of lung cancer cells in non-essential amino acid-depleted medium. In addition, PA-12 blocked the nuclear translocalization of PKM2 in lung cancer cells, resulting in the inhibition of hypoxia response element (HRE)-mediated reporter activity as well as hypoxia-inducible factor 1 (HIF-1) target gene expression, eventually leading to the suppression of cell viability under hypoxia. We also verified that the effects of PA-12 were dependent on PKM2 expression in cancer cells, demonstrating the specificity of PA-12 for PKM2 protein. Taken together, our data suggest that PA-12 is a novel and potent PKM2 activator that has therapeutic implications for lung cancer. PMID- 25813627 TI - Importance of farmland in urbanized areas as a landscape component for barn swallows (Hirundo rustica) nesting on concrete buildings. AB - Urbanization is one of the key factors in the population declines of many species. Conversely, some species may favor urbanized areas. The barn swallow Hirundo rustica is well known to breed in urban areas of Japan, and uses both urban and farmland areas as habitat during the breeding season. Specifically, this species often nests on concrete buildings and feeds in surrounding farmland. Therefore, it was hypothesized that H. rustica is not strongly influenced by heavy urbanization and benefits from farmland areas, even if they are not near its nests. In this study, I evaluated the landscape components around H. rustica nests situated on concrete buildings, focusing on both urbanized and farmland areas. In particular, I explored the occurrence of H. rustica nests at train stations in the Kinki region of Japan. Assisted by 124 citizen scientists, I analyzed the landscape components around the train stations at multiple spatial scales. Results showed that the occurrence of H. rustica nests was negatively influenced by both urbanized land area and road density, whereas nest occurrence was positively influenced by farmland area and river density. These results suggest that H. rustica does not prefer urbanized areas overall, but can rather utilize urbanized areas primarily as nesting spots. Therefore, H. rustica cannot breed in heavily urbanized areas without feeding sites such as farmland or riparian areas. PMID- 25813628 TI - Recreational trails reduce the density of ground-dwelling birds in protected areas. AB - Recreational disturbance associated with trails has been identified as one of the major factors causing a decline of native biodiversity within protected areas. However, despite the negative impacts that recreation can have on biodiversity, providing public access to nature is critical for the future of the conservation of biodiversity. As such, many protected area managers are looking for tools to help maintain a balance between public access and biodiversity conservation. The objectives of this study were to examine the impacts of recreational trails on forest-dwelling bird communities in eastern North America, identify functional guilds which are particularly sensitive to recreational trails, and derive guidelines for trail design to assist in managing the impacts of recreational trails on forest-dwelling birds. Trails within 24 publicly owned natural areas were mapped, and breeding bird communities were described with the use of point count surveys. The density of forest birds, particularly of those species which nest or forage on the ground, were significantly positively influenced by the amount of trail-free refuge habitat. Although management options to control trail use in non-staffed protected areas are limited, this study suggests that protected area managers could design and maintain a trail network that would minimize impacts on resident wildlife, while providing recreational opportunities for visitors, by designing their trail network to maximize the area of trail-free habitat. PMID- 25813629 TI - Soil organic carbon beneath croplands and re-established grasslands in the North Dakota Prairie Pothole Region. AB - Grassland ecosystems established under the conservation reserve program (CRP) in the Prairie Pothole Region (PPR) currently provide soil conservation and wildlife habitat services. We aimed to determine if these lands also sequester soil organic carbon (SOC), as compared with neighboring croplands across multiple farms in the North Dakota PPR. We sampled soil from small plots at 17 private farms in the central North Dakota PPR, where long-term (>=15 years) grasslands managed under the CRP were paired with neighboring annual croplands. Cores were collected to 100 cm and split into 0-10, 10-20, 20-30, 30-40, 40-70, and 70-100 cm soil depth layers. We hypothesized the effect of land use on soil organic carbon (SOC), root carbon (C), and bulk density would be greatest near the surface. For 0-10 and 10-20 cm layers, grasslands managed under the CRP were lower in bulk density and higher in SOC. From 0 to 70 cm, grasslands managed under the CRP were higher in root C. Average (+/-standard error) SOC for re established grasslands and croplands was 25.39 (0.91) and 21.90 (1.02), respectively, for the 0-10 cm soil layer and 19.88 (0.86) and 18.31 (0.82), respectively, for the 10-20 soil layer. Compared to croplands, re-established grasslands sampled in the North Dakota PPR were 3-13 % lower in bulk density and 9-16 % higher in SOC from 0 to 20 cm, while root C was 2-6 times greater from 0 to 70 cm. PMID- 25813630 TI - Bioenergy Development Policy and Practice Must Recognize Potential Hydrologic Impacts: Lessons from the Americas. AB - Large-scale bioenergy production will affect the hydrologic cycle in multiple ways, including changes in canopy interception, evapotranspiration, infiltration, and the quantity and quality of surface runoff and groundwater recharge. As such, the water footprints of bioenergy sources vary significantly by type of feedstock, soil characteristics, cultivation practices, and hydro-climatic regime. Furthermore, water management implications of bioenergy production depend on existing land use, relative water availability, and competing water uses at a watershed scale. This paper reviews previous research on the water resource impacts of bioenergy production-from plot-scale hydrologic and nutrient cycling impacts to watershed and regional scale hydro-economic systems relationships. Primary gaps in knowledge that hinder policy development for integrated management of water-bioenergy systems are highlighted. Four case studies in the Americas are analyzed to illustrate relevant spatial and temporal scales for impact assessment, along with unique aspects of biofuel production compared to other agroforestry systems, such as energy-related conflicts and tradeoffs. Based on the case studies, the potential benefits of integrated resource management are assessed, as is the need for further case-specific research. PMID- 25813631 TI - EV71 infection correlates with viral IgG preexisting at pharyngo-laryngeal mucosa in children. AB - Enterovirus 71 (EV71) infection causes severe central nervous system damage, particularly for children under the age of 5 years old, which remains a major public health burden worldwide. Clinical data released that children may be repeatedly infected by different members in enterovirus and get even worsen. Mucosa, especially epithelium of alimentary canal, was considered the primary site of EV71 infection. It has been elusive whether the preexsiting viral antibody in mucosa plays a role in EV71 infection. To answer this question, we respectively measured viral antibody response and EV71 RNA copy number of one hundred throat swab specimens from clinically confirmed EV71-infected children. The results released that low-level of mucosal IgG antibody against EV71 broadly existed in young population. More importantly, it further elucidated that the children with mucosal preexsiting EV71 IgG were prone to be infected, which suggested a former viral IgG mediated enhancement of viral infection in vivo. PMID- 25813632 TI - Development and Simulation Testing of a Computerized Adaptive Version of the Philadelphia Naming Test. AB - Purpose: The purpose of this study was to develop a computerized adaptive test (CAT) version of the Philadelphia Naming Test (PNT; Roach, Schwartz, Martin, Grewal, & Brecher, 1996), to reduce test length while maximizing measurement precision. This article is a direct extension of a companion article (Fergadiotis, Kellough, & Hula, 2015), in which we fitted the PNT to a 1 parameter logistic item-response-theory model and examined the validity and precision of the resulting item parameter and ability score estimates. Method: Using archival data collected from participants with aphasia, we simulated two PNT-CAT versions and two previously published static PNT short forms, and compared the resulting ability score estimates to estimates obtained from the full 175-item PNT. We used a jackknife procedure to maintain independence of the samples used for item estimation and CAT simulation. Results: The PNT-CAT recovered full PNT scores with equal or better accuracy than the static short forms. Measurement precision was also greater for the PNT-CAT than the static short forms, though comparison of adaptive and static nonoverlapping alternate forms showed minimal differences between the two approaches. Conclusion: These results suggest that CAT assessment of naming in aphasia has the potential to reduce test burden while maximizing the accuracy and precision of score estimates. PMID- 25813634 TI - Modeling of the Elk river spill 2014. AB - A dispersion-advection model was used to simulate the Elk river chemical spill 2014. The numerical and analytical solutions were used to predict the concentrations of 4-methylcyclohexane methanol (MCHM) at the water treatment plants located along the Elk and Kanawha rivers. The results are of similar magnitude as measured concentrations although a time-lag was found between modeled and measured plume arrival likely due to accumulation of systematic errors. Considering MCHM guidelines for drinking water, the spill represented a serious health threat through the water up taken by the treatment plant located on the Elk river and it also constituted a risk of contamination for the drinking water produced by treatment plants located on the Kanawha river. PMID- 25813633 TI - Responses and acclimation of Chinese cork oak (Quercus variabilis Bl.) to metal stress: the inducible antimony tolerance in oak trees. AB - Antimony (Sb) pollution has become a pressing environmental problem in recent years. Trees have been proven to have great potential for the feasible phytomanagement; however, little is known about Sb retention and tolerance in trees. The Chinese cork oak (Quercus variabilis Bl.) is known to be capable of growth in soils containing high concentrations of Sb. This study explored in detail the retention and acclimation of Q. variabilis under moderate and high external Sb levels. Results revealed that Q. variabilis could tolerate and accumulate high Sb (1623.39 mg kg(-1) DW) in roots. Dynamics of Sb retention in leaves, stems, and roots of Q. variabilis were different. Leaf Sb remained at a certain level for several weeks, while in roots and stems, Sb concentrations continued to increase. Sb damaged tree's PSII reaction cores but elicited defense mechanism at the donor side of PSII. It affected the electron transport flow after QA (-) more strongly than the oxygen-evolving complex and light-harvesting pigment-protein complex II. Sb also decreased leaf chlorophyll concentrations and therefore inhibited plant growth. During acclimation to Sb toxicity, Sb concentrations in leaves, stems, and roots decreased, with photosynthetic activity and pigments recovering to normal levels by the end of the experiment. These findings suggest that Sb tolerance in Q. variabilis is inducible. Acclimation seems to be related to homeostasis of Sb in plants. Results of this study can provide useful information for trees breeding and selection of Sb phytomanagement strategies, exploiting the established ability of Q. variabilis to transport, delocalize in the leaves, and tolerate Sb pollutions. PMID- 25813635 TI - Purifying fluoride-contaminated water by a novel forward osmosis design with enhanced flux under reduced concentration polarization. AB - For purifying fluoride-contaminated water, a new forward osmosis scheme in horizontal flat-sheet cross flow module was designed and investigated. Effects of pressure, cross flow rate, draw solution and alignment of membrane module on separation and flux were studied. Concentration polarization and reverse salt diffusion got significantly reduced in the new hydrodynamic regime. This resulted in less membrane fouling, better solute separation and higher pure water flux than in a conventional module. The entire scheme was completed in two stages-an upstream forward osmosis for separating pure water from contaminated water and a downstream nanofiltration operation for continuous recovery and recycle of draw solute. Synchronization of these two stages of operation resulted in a continuous, steady-state process. From a set of commercial membranes, two polyamide composite membranes were screened out for the upstream and downstream filtrations. A 0.3-M NaCl solution was found to be the best one for forward osmosis draw solution. Potable water with less than 1% residual fluoride could be produced at a high flux of 60-62 L m(-2) h(-1) whereas more than 99% draw solute could be recovered and recycled in the downstream nanofiltration stage from where flux was 62-65 L m(-2) h(-1). PMID- 25813636 TI - Isolation and characterization of different bacterial strains for bioremediation of n-alkanes and polycyclic aromatic hydrocarbons. AB - Crude oil is a common environmental pollutant composed of a large number of both aromatic and aliphatic hydrocarbons. Biodegradation is carried out by microbial communities that are important in determining the fate of pollutants in the environment. The intrinsic biodegradability of the hydrocarbons and the distribution in the environment of competent degrading microorganisms are crucial information for the implementation of bioremediation processes. In the present study, the biodegradation capacities of various bacteria toward aliphatic and aromatic hydrocarbons were determined. The purpose of the study was to isolate and characterize hydrocarbon-degrading bacteria from contaminated soil of a refinery in Arzew, Algeria. A collection of 150 bacterial strains was obtained; the bacterial isolates were identified by 16S rRNA gene sequencing and their ability to degrade hydrocarbon compounds characterized. The isolated strains were mainly affiliated to the Gamma-Proteobacteria class. Among them, Pseudomonas spp. had the ability to metabolize high molecular weight hydrocarbon compounds such as pristane (C19) at 35.11 % by strain LGM22 and benzo[a] pyrene (C20) at 33.93 % by strain LGM11. Some strains were able to grow on all the hydrocarbons tested including octadecane, squalene, phenanthrene, and pyrene. Some strains were specialized degrading only few substrates. In contrast, the strain LGM2 designated as Pseudomonas sp. was found able to degrade both linear and branched alkanes as well as low and high poly-aromatic hydrocarbons (PAHs). The alkB gene involved in alkane degradation was detected in LGM2 and other Pseudomonas-related isolates. The capabilities of the isolated bacterial strains to degrade alkanes and PAHs should be of great practical significance in bioremediation of oil contaminated environments. PMID- 25813637 TI - Biodegradation of C.I. Acid Red 1 by indigenous bacteria Stenotrophomonas sp. BHUSSp X2 isolated from dye contaminated soil. AB - A significant proportion of xenobiotic recalcitrant azo dyes are being released in environment during carpet dyeing. The bacterial strain Stenotrophomonas sp. BHUSSp X2 was isolated from dye contaminated soil of carpet industry, Bhadohi, India. The isolated bacterial strain was identified morphologically, biochemically, and on the basis of 16S rRNA gene sequence. The isolate decolorized 97 % of C.I. Acid Red 1 (Acid RED G) at the concentration of 200 mg/l within 6 h under optimum static conditions (temperature -35 degrees C, pH 8, and initial cell concentration 7 * 10(7) cell/ml). Drastic reduction in dye degradation rate was observed beyond initial dye concentration from 500 mg/l (90 %), and it reaches to 25 % at 1000 mg/l under same set of conditions. The analysis related to decolorization and degradation was done using UV-Vis spectrophotometer, HPLC, and FTIR, whereas the GC-MS technique was utilized for the identification of degradation products. Phytotoxicity analysis revealed that degradation products are less toxic as compared to the original dye. PMID- 25813638 TI - Influence of substrate water saturation on pesticide dissipation in constructed wetlands. AB - Constructed wetlands are an effective and practical option for removing pesticide pollution from runoff or subsurface drainage water. The objective of this study was to assess the efficiencies of a ditch with a bundle of straw placed in its centre and a vegetated pond installed in grass cover bands at downstream of a drained plot. The dissipation rates of three herbicides and three fungicides were monitored on four substrates commonly found in constructed wetlands (two soils, sediment and straw). The influence of water content was determined in a sequence of three steps (flooded-unsaturated-flooded) over 120 days. The pesticide dissipation rates observed during the 120 days of incubation ranged from 1.4 to 100%. Isoproturon and 2,4-MCPA (MCPA) showed the highest dissipation rates, which ranged from 61.0 to 100% of the applied quantities during the 120 days of incubation. In contrast, boscalid and tebuconazole showed the lowest dissipation rates, which ranged from 1.4 to 43.9% of the applied quantities during the 120 days of incubation. The estimated DT50 values ranged from 20.5 days to more than 1 year and were influenced by the substrate water content. The soil and straw substrates had the lowest DT50 values during the unsaturated conditions, whereas the sediments had the lowest DT50 values during the flooded conditions. These results could be explained by an adaptation of microbial communities to their environmental conditions. Thus, the most favourable conditions of dissipation for soils and straw are observable when the drainage ceases (spring and summer). However, favourable conditions occur all year for the sediments, except when the constructed wetlands are dry. The results suggest that the dissipation of pesticides in constructed wetlands contributes to the long-term effectiveness of these buffer zones for reducing water pollution. PMID- 25813639 TI - Removal of Cu(2+) by biochars derived from green macroalgae. AB - The by-product char of the fast pyrolysis of a green macroalga Enteromorpha compressa was used to remove copper from an aqueous solution. The surface area and the amount of cation exchange capacity (CEC) were increased by steam activation, resulting in enhanced adsorption capacity. Although chemical activation using a KOH solution increased the pore volume and surface area dramatically, it decreased the adsorption capacity because of activating in the KOH solution and washing decreased CEC. Ion exchange between the Cu ions and cations (Na(+), K(+), Ca(2+), and Mg(2+)) as well as adsorption onto the functional groups on the char surface appeared to be important mechanisms for the removal of Cu. A pseudo-second-order kinetic model and Langmuir isotherm model could interpret the kinetics and equilibrium of the Cu adsorption on the E. compressa char. The maximum amount of Cu adsorption on the char was 137 mg g(-1). PMID- 25813640 TI - Prevalence of antibiotic resistance genes in antibiotic-resistant Escherichia coli isolates in surface water of Taihu Lake Basin, China. AB - The rapid development of antibiotic-resistant bacteria (ARB) has been of concern worldwide. In this study, antibiotic resistance genes (ARGs) were investigated in antibiotic-resistant Escherichia coli isolated from surface water samples (rivers, n = 17; Taihu Lake, n = 16) and from human, chicken, swine, and Egretta garzetta sources in the Taihu Basin. E. coli showing resistance to at least five drugs occurred in 31, 67, 58, 27, and 18% of the isolates from surface water (n = 665), chicken (n = 27), swine (n = 29), human (n = 45), and E. garzetta (n = 15) sources, respectively. The mean multi-antibiotic resistance (MAR) index of surface water samples (0.44) was lower than that of chicken (0.64) and swine (0.57) sources but higher than that of human (0.30) and E. garzetta sources (0.15). Ten tetracycline, four sulfonamide, four quinolone, five beta-lactamase, and two streptomycin resistance genes were detected in the corresponding antibiotic-resistant isolates. Most antibiotic-resistant E. coli harbored at least two similar functional ARGs. Int-I was detected in at least 57% of MAR E. coli isolates. The results of multiple correspondence analysis and Spearman correlation analysis suggest that antibiotic-resistant E. coli in water samples were mainly originated from swine, chicken, and/or human sources. Most of the ARGs detected in E. garzetta sources were prevalent in other sources. These data indicated that human activities may have contributed to the spread of ARB in the aquatic environment. PMID- 25813641 TI - Assessment of total bacterial cells in extended aeration activated sludge plants using flow cytometry as a microbial monitoring tool. AB - The extended aeration activated sludge (EAAS) process is one of the most applied biological processes in small towns. Here, we study the abundance and viability of total bacterial cells in two wastewater treatment plants (WWTPs) operating with an EAAS process. We use flow cytometry (FCM) combined with SYTO13 and propidium iodide (PI) dyes as a rapid, easy, reliable and accurate microbial monitoring tool. A disaggregation procedure with an ultrasonic bath was designed to detach total bacterial cells from activated sludge flocs for subsequent FCM analysis. This procedure permitted the recovery of total bacterial cells from sludge flocs without affecting bacterial viability, as indicated by bacterial strain controls. Since FCM is a multi-parameter technique, it was possible to determine total bacterial abundance and their viability in the activated sludge. As a comparative method, epifluorescence microscopy was also used to quantify total bacterial cells; both methods produced similar results. The FCM analysis revealed relative microbial stability in both the WWTPs. The total bacterial abundance quantified by FCM in the two plants studied was 1.02-6.23 * 10(11) cells L(-1) with 70-72% viability, one logarithm less than that reported in the literature for WWTPs using the conventional activated sludge process. This can be explained by the difference in the operational parameters between the conventional plant and EAAS, mainly the organic loading rate. PMID- 25813642 TI - Influence of exogenous lead pollution on enzyme activities and organic matter degradation in the surface of river sediment. AB - As lead is one of the most hazardous heavy metals in river ecosystem, the influence of exogenous lead pollution on enzyme activities and organic matter degradation in the surface of river sediment with high moisture content were studied at laboratory scale. The dynamic changes of urease, catalase, protease activities, organic matter content, and exchangeable or ethylenediaminetetraacetic acid (EDTA)-extractable Pb concentration in sediment were monitored during different levels of exogenous lead infiltrating into sediment. At the early stage of incubation, the activities of catalase and protease were inhibited, whereas the urease activities were enhanced with different levels of exogenous lead. Organic matter content in polluted sediment with exogenous lead was lower than control and correlated with enzyme activities. In addition, the effects of lead on the three enzyme activities were strongly time-dependent and catalase activities showed lower significant difference (P < 0.05) than urease and protease. Correlations between catalase activities and EDTA extractable Pb in the experiment were significantly negative. The present findings will improve the understandings about the ecotoxicological mechanisms in sediment. PMID- 25813643 TI - Membrane bioreactors fed with different COD/N ratio wastewater: impacts on microbial community, microbial products, and membrane fouling. AB - It is known that an increase of COD/N ratio can result in an enhanced removal of nutrients in membrane bioreactors (MBRs); however, impacts of doing so on membrane filtration performance remain unclear. In this work, comparison of membrane filtration performance, microbial community, and microbial products under low temperature was carried out in anoxic/oxic (A/O) MBRs with COD/N ratios of 9.9 and 5.5 g COD/g N in influent. There was no doubt that an improvement of nitrogen removal under high COD/N ratio was observed; however, severer membrane fouling was found compared to the MBR fed with low COD/N ratio wastewater. The increase of COD/N ratio resulted in an elevated production of humic acids in soluble microbial product (SMP) and carbohydrates, proteins, and humic acids in loosely bound extracellular polymeric substance (LB-EPS). Quartz crystal microbalance with dissipation monitoring (QCM-D) analysis showed that the adsorption capability of SMP and LB-EPS was higher in the MBR with higher COD/N ratio. Four hundred fifty four high-throughput pyrosequencing revealed that the higher COD/N ratio led to the enrichment of Bacteroidetes at phylum level and Azospira, Thauera, Zoogloea, etc. at genus level. Bacteroidetes are considered to potentially release EPS, and Azospira, Thauera, and Zoogloea, etc. have denitrification activity. The change in microbial communities is consistent with MBR performance. PMID- 25813644 TI - Spatial modeling of PM2.5 concentrations with a multifactoral radial basis function neural network. AB - Accurate measurements of PM2.5 concentration over time and space are especially critical for reducing adverse health outcomes. However, sparsely stationary monitoring sites considerably hinder the ability to effectively characterize observed concentrations. Utilizing data on meteorological and land-related factors, this study introduces a radial basis function (RBF) neural network method for estimating PM2.5 concentrations based on sparse observed inputs. The state of Texas in the USA was selected as the study area. Performance of the RBF models was evaluated by statistic indices including mean square error, mean absolute error, mean relative deviation, and the correlation coefficient. Results show that the annual PM2.5 concentrations estimated by the RBF models with meteorological factors and/or land-related factors were markedly closer to the observed concentrations. RBF models with combined meteorological and land-related factors achieved best performance relative to ones with either type of these factors only. It can be concluded that meteorological factors and land-related factors are useful for articulating the variation of PM2.5 concentration in a given study area. With these covariate factors, the RBF neural network can effectively estimate PM2.5 concentrations with acceptable accuracy under the condition of sparse monitoring stations. The improved accuracy of air concentration estimation would greatly benefit epidemiological and environmental studies in characterizing local air pollution and in helping reduce population exposures for areas with limited availability of air quality data. PMID- 25813645 TI - The incidence of late prosthetic joint infections: a registry-based study of 112,708 primary hip and knee replacements. AB - BACKGROUND AND PURPOSE: Late prosthetic joint infections (PJIs) are a growing medical challenge as more and more joint replacements are being performed and the expected lifespan of patients is increasing. We analyzed the incidence rate of late PJI and its temporal trends in a nationwide population. PATIENTS AND METHODS: 112,708 primary hip and knee replacements performed due to primary osteoarthritis (OA) between 1998 and 2009 were followed for a median time of 5 (1 13) years, using data from nationwide Finnish health registries. Late PJI was detected > 2 years postoperatively, and very late PJI was detected > 5 years postoperatively. RESULTS: During the follow-up, involving 619,299 prosthesis years, 1,345 PJIs were registered: cumulative incidence 1.20% (95% CI: 1.13-1.26) (for knees, 1.41%; for hips, 0.92%). The incidence rate of late PJI was 0.069% per prosthesis-year (CI: 0.061-0.078), and it was greater after knee replacement than after hip replacement (0.080% vs. 0.057%, p = 0.006). The incidence rate of very late PJI was 0.051% per prosthesis-year (CI: 0.042-0.063), 0.058% for knees and 0.044% for hips (p = 0.2). The incidence rate of late PJI varied between 0.041% and 0.107% during the years of observation without any temporal trend (incidence rate ratio (IRR) = 0.98, 95% CI: 0.93-1.03). Very late PJI increased from 0.026% in 2004 to 0.056% in 2010 (IRR = 1.11, 95% CI: 1.02-1.20). INTERPRETATION: In our nationwide study, the incidence rate of late PJI after hip or knee arthroplasty was approximately 0.07% per prosthesis-year. The incidence of very late PJI appeared to increase. PMID- 25813646 TI - Regression analysis of longitudinal data with irregular and informative observation times. AB - In longitudinal data analyses, the observation times are often assumed to be independent of the outcomes. In applications in which this assumption is violated, the standard inferential approach of using the generalized estimating equations may lead to biased inference. Current methods require the correct specification of either the observation time process or the repeated measure process with a correct covariance structure. In this article, we construct a novel pairwise likelihood method for longitudinal data that allows for dependence between observation times and outcomes. This method investigates the marginal covariate effects on the repeated measure process, while leaving the probability structure of the observation time process unspecified. The novelty of this method is that it yields consistent estimator of the marginal covariate effects without specification of the observation time process or the covariance structure of the repeated measures process. Large sample properties of the regression coefficient estimates and a pairwise likelihood ratio test procedure are established. Simulation studies demonstrate that the proposed method performs well in finite samples. An analysis of weight loss data from a web-based program is presented to illustrate the proposed method. PMID- 25813647 TI - Rank-based testing of equal survivorship based on cross-sectional survival data with or without prospective follow-up. AB - Existing linear rank statistics cannot be applied to cross-sectional survival data without follow-up since all subjects are essentially censored. However, partial survival information are available from backward recurrence times and are frequently collected from health surveys without prospective follow-up. Under length-biased sampling, a class of linear rank statistics is proposed based only on backward recurrence times without any prospective follow-up. When follow-up data are available, the proposed rank statistic and a conventional rank statistic that utilizes follow-up information from the same sample are shown to be asymptotically independent. We discuss four ways to combine these two statistics when follow-up is present. Simulations show that all combined statistics have substantially improved power compared with conventional rank statistics, and a Mantel-Haenszel test performed the best among the proposal statistics. The method is applied to a cross-sectional health survey without follow-up and a study of Alzheimer's disease with prospective follow-up. PMID- 25813648 TI - Allow GPs and consultants to speak to each other again. PMID- 25813649 TI - [Surgery of grown up congenital heart disease. About 540 cases]. AB - INTRODUCTION: With advances in recent decades in the field of congenital heart disease both for imaging in medical therapy, a large number of heart disease is diagnosed before birth. Many of them benefit from surgery and reach adulthood, they do not require further action. Some of them develop later in their lives other problems requiring reoperation in adulthood. This sparked the birth of a subspecialty within the department of congenital heart disease: GUCH Unit "grown up congenital heart disease". In developing countries, little heart are detected in childhood, a minority of them are operated and very few reach adulthood or with minor heart disease or become advanced enough then inoperable. Only part may still take advantage of surgery at this age. The aim of our study is to describe the spectrum and characteristics of congenital heart disease in adulthood in Algiers a center of cardiovascular surgery. POPULATION AND METHODS: A retrospective descriptive study of patients aged 15 and above operated for congenital heart defects between 1995 and 2011. RESULTS: Five hundred and forty patients aged 15 to 76years (29+/-10 years), including 314 women and 226 men are operated congenital heart defects between 1995 and 2011. The left-right shunts represent two thirds of heart disease, represented mainly (50%) by the atrial septal defect. Barriers to the ejection of the left heart represent one forth of cases with a predominance of subvalvular aortic stenosis. We find the native heart whose survival is considered exceptional in adulthood in the absence of surgery, such as tetralogy of Fallot, aortopulmonary windows wide, double outlet right ventricle and atrioventricular canal that take advantage of always surgery. The results are encouraging with low perioperative mortality (2%). CONCLUSION: The approach of congenital heart disease in developing countries is different from that of developed countries. Efforts need to be made in early detection and monitoring of congenital heart disease and improve access to surgery centers in close collaboration with pediatricians, cardiologists and obstetricians. PMID- 25813650 TI - [Relation between the number of Mc Donald((r))'s restaurants and the prevalence of obesity in France]. PMID- 25813651 TI - [Presumption of sleep apnea in a black African hypertensive population: Importance of the Epworth sleepiness scale in the diagnostic approach]. AB - INTRODUCTION: Sleep apnea syndrome (SAS) is very little described in the hypertensive black African. PURPOSE: To screen sleep apnea syndrome using the rating scale of Epworth daytime sleepiness, and to investigate the determinant factors and to infer therapeutic consequences. METHOD: This is a retrospective and prospective study with descriptive and analytical purpose that focused on 200 hypertensive outpatients of the Cardiology Institute of Abidjan. The primary endpoint studied was the SAS. The diagnostic approach of SAS was performed using the rating scale of Epworth daytime sleepiness. RESULTS: The prevalence of sleep apnea was 45%. The average age of sleep apnea carriers was 56.1 years, with a male predominance (60%). The determinant factors of sleep apnea syndrome were male gender (60% versus 40%, P=0.021), obesity (77.8% versus 62.7%, P<0.0001), diabetes (26.7% versus 15.5%, P=0.5) and dyslipidemia (54.4% versus 27.3%, P=0.0009). Life in urban areas, occupation and smoking were not correlated with SAS in our series. The control of hypertension was better in non-apneic patients compared to apneic patients (63.6% versus 38.9%, P=0.04). The visceral impact of hypertension in apneic patients was highly significant (77.8% versus 41.7%, P=0.014). Therapeutically, it was noted the preferential prescription of combination therapy in apneic patients compared to non-apneic patients (82.3% versus 74.4%). PMID- 25813652 TI - [Is PON1 a factor of cardiovascular risk in type 2 diabetes?]. AB - OBJECTIVE: We evaluate the association between the decrease of serum paraxonase 1 activity and the risk of cardiovascular disease in type 2 diabetes. METHODS: One hundred and fourteen patients with type 2 diabetes were included in the present study. Seventy-one of them have significant coronary disease. The control group consisted of 53 healthy adults. RESULTS: PON1 activity was significantly reduced in diabetic patients compared to controls (P=0.021), especially in those with significant coronary disease (P=0.013). No significant variation in PON1 activity according to age was observed both in controls and in patients. When HDLc>=1.03mmol/L, the PON1 activity was significantly higher in patients without significant coronary disease compared to those with significant coronary disease (0.030). In case of significant coronary disease, a decrease of 12.23% in PON1 activity was observed in smokers compared with non-smokers, but without statistical significance. The PON1 activity did not very significantly according to the presence or absence of hypertension in patients with significant coronary disease. CONCLUSION: The implication of diabetes in the decrease of PON1 activity seems highly probable but PON1 activity seems not to be in itself a marker of cardiovascular disease. PMID- 25813653 TI - [Aortic infective endocarditis: Value of surgery. About 48 cases]. AB - INTRODUCTION: Infective endocarditis (IE) is a serious disease whose prognosis depends on early management. Aortic location is characterized by its evolution toward myocardial failure and the high number of complications reasons for early surgery. AIM: To compare the short- and mid-terms results of surgery for aortic infective endocarditis (IE) in the active phase and the healed phase. PATIENTS AND METHODS: We analyzed retrospectively the data of 48 consecutive patients operated for aortic infective endocarditis between January 2000 and January 2012. The data on operative mortality, morbidity and major cardiovascular events (mortality, recurrent endocarditis, reintervention, and stroke) were analyzed. RESULTS: Twenty-three patients (48%) underwent surgery during the active phase (group I), 19 on native and 4 on prosthetic valves, and 25 patients (52%) were operated during healed endocarditis (group II) only on native valve. Mean age was 39 years (12-81) with a male predominance (83%). Rheumatic valvular disease was the main etiology of underlying valvular disease in both groups (85%). The clinical feature was dominated by signs of cardiogenic shock in group I and dyspnea exertion stage III-IV NYHA in group II. Streptococcus and Staphylococcus germs were most frequently encountered. Indication for surgery was heart failure in group I, it was related to the symptoms, the severity of valvular disease and its impact on the left ventricle in group II. An aortic valve replacement with a mechanical prosthesis was performed in the majority of cases (83%). Postoperative mortality concerned only one patient in group I. Twenty-one patients (44%) were followed for a mean of 30 months (1-72). One patient in group II died following cerebral hemorrhagic stroke related to accident with vitamin K antagonist. In both groups, there was an improvement in the functional class. No recurrence of endocarditis was noted in both groups during follow-up. CONCLUSION: The prognosis of infective endocarditis of the aortic valve is severe due to the fast progression to heart failure. Early medical and surgical approach provides good results on morbidity and mortality in the short- and mid-terms. PMID- 25813654 TI - Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs. AB - The monoamine hypothesis has been the prevailing hypothesis of depression over the last several decades. It states that depression is associated with reduced monoamine function. Hence efforts to increase monoamine transmission by inhibiting serotonin (5-HT) and norepinephrine (NE) transporters has been a central theme in depression research since the 1960s. The selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NE reuptake inhibitors (SNRIs) that have emerged from this line of research are currently first line treatment options for major depressive disorder (MDD). One of the recent trends in antidepressant research has been to refine monoaminergic mechanisms by targeting monoaminergic receptors and additional transporters (e.g. with multimodal drugs and triple re-uptake inhibitors) or by adding atypical antipsychotics to SSRI or SNRI treatment. In addition, several other hypotheses of depression have been brought forward in pre clinical and clinical research based on biological hallmarks of the disease and efficacy of pharmacological interventions. A central strategy has been to target glutamate receptors (for example, with intravenous infusions of the N-methyl-d aspartate (NMDA) receptor antagonist ketamine). Other strategies have been based on modulation of cholinergic and gamma-aminobutyric acid (GABA)ergic transmission, neuronal plasticity, stress/hypothalamic pituitary adrenal(HPA) axis, the reward system and neuroinflammation. Here we review the pharmacological profiles of compounds that derived from these strategies and have been recently tested in clinical trials with published results. In addition, we discuss putative treatments for depression that are being investigated at the preclinical level and outline future directions for antidepressant research. PMID- 25813655 TI - Perinephric stranding and bulky psoas mimicking pyelonephritis in a case of non Hodgkin lymphoma of kidney. AB - A 68-year-old male patient presented with fever and right groin pain. He had leukocytosis with azotemia. Computed tomography revealed enlarged right kidney with thickening and enhancement of walls of pelvicalyceal system and perinephric fat stranding, suggestive of pyelonephritis. Multiple enlarged lymph nodes encased right renal vessels and were present in the retrocaval region. The right psoas muscle was bulky. Fine-needle aspiration cytology and biopsy from the lesions showed features of non-Hodgkin lymphoma. Immunohistochemistry confirmed the diagnosis of diffuse, large, B-cell lymphoma. We emphasize lymphoma in differential diagnosis of atypical renal imaging suggestive of pyelonephritis and perinephritis. PMID- 25813656 TI - Effect of Tadalafil Once Daily on Penile Length Loss and Morning Erections in Patients After Bilateral Nerve-sparing Radical Prostatectomy: Results From a Randomized Controlled Trial. AB - OBJECTIVE: To report penile integrity measures, including stretched penile length (SPL), from a randomized, double-blind, double-dummy, placebo-controlled trial evaluating treatment with tadalafil initiated after nerve-sparing radical prostatectomy (nsRP). METHODS: Patients aged <= 68 years were randomized after nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg once daily (OaD), 20-mg tadalafil on-demand ("pro-re-nata"; PRN), or placebo, followed by 6 week drug-free washout and 3-month open-label OaD treatment. Secondary outcome measures included the change in SPL from pre-nsRP to the end of DBT (analysis of covariance adjusting for treatment, country, baseline, age, and nerve-sparing score), responses to Sexual Encounter Profile (SEP) questions 1-3 (mixed models for repeated measures adjusting for treatment, country, visit, visit-treatment interaction, age), and Standardized Morning Erection Question (Cochran-Mantel Haenszel test adjusted for age and country). RESULTS: Four hundred twenty-three patients were randomized to tadalafil OaD (N = 139), tadalafil PRN (N = 143), and placebo (N = 141). Greater retainment of SPL was observed with tadalafil OaD vs placebo at the end of DBT (least-square mean [95% confidence interval] difference OaD vs placebo, 4.1 mm [0.4 to 7.8 mm]; P = .032). No significant effects on SPL were found for tadalafil PRN vs placebo, or for the nerve-sparing score. Penile tumescence (SEP1) and ability for vaginal insertion (SEP2) significantly improved vs placebo at the end of double-blind and open-label treatment for patients randomized to tadalafil OaD only. The ability for successful sexual intercourse (SEP3) significantly improved with tadalafil OaD vs placebo only during DBT. The distribution of Standardized Morning Erection Question responses was different at the end of DBT (P = .045); 34.2% of patients on tadalafil OaD, 50.0% on tadalafil PRN, and 56.5% on placebo reported absence of morning erections. CONCLUSION: These data suggest the early initiation of tadalafil OaD protects from penile length loss and may contribute to protection from structural cavernosal changes after nsRP. PMID- 25813657 TI - The French Contribution to the Evolution of the Procedure and the Instrumentation for Lithotripsy. PMID- 25813658 TI - Systemic oxidative stress could predict assisted reproductive technique outcome. AB - PURPOSE: Previous studies have indicated that OxS (oxidative stress) may appear as a possible reason for poor ART outcome. Our aim was to study OxS levels in both partners of couples seeking Assisted reproduction Technology (ART). METHODS: Altogether 79 couples were recruited. Oxidative DNA damage (8-OHdG) and lipid peroxidation (8-EPI) were measured, and clinical background and ART outcomes were recorded. RESULTS: Both OxS markers accurately reflected clinical conditions with prominent negative effects attributable to genital tract infections, endometriosis, uterine myoma and smoking. Furthermore, the level of OxS was also affected by partner's state of health. The highest 8-EPI levels were detected in both partners when biochemically detectable pregnancies did not develop into clinically detectable pregnancies (in women, 97,8 +/- 16,7 vs 72.9 +/- 22,9, p = 0.007; in men, 89.6 +/- 20,4 vs 72,1 +/- 22,6, p = 0.049). CONCLUSIONS: To conclude, high grade systemix OxS in both partners may negatively affect the maintenance and outcome of pregnancy. Applying the detection of OxS in ART patients may select patients with higher success rate and/or those who require antioxidant therapy. This would lead to improvement of ART outcome as well as natural fertility. PMID- 25813659 TI - Mathematical modeling analysis of intratumoral disposition of anticancer agents and drug delivery systems. AB - INTRODUCTION: Solid tumors are characterized by complex morphology. Numerous factors relating to the composition of the cells and tumor stroma, vascularization and drainage of fluids affect the local microenvironment within a specific location inside the tumor. As a result, the intratumoral drug/drug delivery system (DDS) disposition following systemic or local administration is non-homogeneous and its complexity reflects the differences in the local microenvironment. Mathematical models can be used to analyze the intratumoral drug/DDS disposition and pharmacological effects and to assist in choice of optimal anticancer treatment strategies. AREAS COVERED: The mathematical models that have been applied by different research groups to describe the intratumoral disposition of anticancer drugs/DDSs are summarized in this article. The properties of these models and of their suitability for prediction of the drug/DDS intratumoral disposition and pharmacological effects are reviewed. EXPERT OPINION: Currently available mathematical models appear to neglect some of the major factors that govern the drug/DDS intratumoral disposition, and apparently possess limited prediction capabilities. More sophisticated and detailed mathematical models and their extensive validation are needed for reliable prediction of different treatment scenarios and for optimization of drug treatment in the individual cancer patients. PMID- 25813660 TI - Roles of volunteers and professionals in medical development -- insights from the development of Allo-HSCT. PMID- 25813661 TI - A hypothesis about the origin of biology. AB - It is proposed that processes characteristic of biology today, autocatalysis, selection of molecules for linkage by their electrical shape, and evolution by survival selection were also the processes that initiated biology. A reconnaissance is made of both paradoxes and potential questions. It is argued that the minimal requirement for initiating Darwinian evolution is not a molecule copying process, but a linkage copying process. Survival selection evolution does not require a heterocatalytic polymer and a separate replicase process until there is uncertainty where molecular additions will occur. It is argued that a linkage directing process will be found for a lipid membrane (though this needs to be verified) and may in the right environment result in initial evolution, including initiation of alpha-helices, the development of a single chirality and NTPs. The system has at this point become sufficiently complex that higher precision copying is needed. However it seems likely that this state is able to generate the first miniature ribozymes and their replicases, and so satisfies the prior requirement. With the proposed requirements, it is likely that the development of polymers was within membranes. PMID- 25813662 TI - Emergence of coding and its specificity as a physico-informatic problem. AB - We explore the origin-of-life consequences of the view that biological systems are demarcated from inanimate matter by their possession of referential information, which is processed computationally to control choices of specific physico-chemical events. Cells are cybernetic: they use genetic information in processes of communication and control, subjecting physical events to a system of integrated governance. The genetic code is the most obvious example of how cells use information computationally, but the historical origin of the usefulness of molecular information is not well understood. Genetic coding made information useful because it imposed a modular metric on the evolutionary search and thereby offered a general solution to the problem of finding catalysts of any specificity. We use the term "quasispecies symmetry breaking" to describe the iterated process of self-organisation whereby the alphabets of distinguishable codons and amino acids increased, step by step. PMID- 25813663 TI - In vitro antiviral activity of germacrone against porcine parvovirus. AB - Porcine parvovirus (PPV) infections can lead to significant losses to the swine industry by causing reproductive failure in pigs. Germacrone has been reported to efficiently suppress the replication of influenza virus. In this report, the antiviral activity of germacrone on PPV in swine testis (ST) cells was investigated. Here, we show for the first time that germacrone protects cells from PPV infection and suppresses the synthesis of viral mRNA and protein. Furthermore, we show that germacrone inhibits PPV replication at an early stage in a dose-dependent manner. These findings suggest that germacrone is a potential candidate for anti-PPV therapy. PMID- 25813664 TI - Ergonomics and workplace adaptation to people with disabilities. PMID- 25813665 TI - Mapping the developing human brain in utero using quantitative MR imaging techniques. AB - Magnetic resonance imaging of the human fetal brain has been a clinical tool for many years and provides valuable additional information to compliment more common ultrasound studies. Advances in both MRI acquisition and post processing over the last 10 years have enabled full 3D imaging and the accurate combination of data acquired in different head positions to create improved geometric integrity, tissue contrast, and resolution. This research is now motivating the development of new quantitative MRI-based techniques for clinical imaging that can more accurately characterize brain development and detect abnormalities. In this article, we will review some of the key areas that are driving changes in our understanding of fetal brain growth using quantitative measures derived from in utero MRI and the possible directions for its increased use in improving the evaluation of pregnancies and the accurate characterization of abnormal brain growth. PMID- 25813666 TI - Injury and repair in perinatal brain injury: Insights from non-invasive MR perfusion imaging. AB - Injury to the developing brain remains an important complication in critically ill newborns, placing them at risk for future neurodevelopment impairments. Abnormal brain perfusion is often a key mechanism underlying neonatal brain injury. A better understanding of how alternations in brain perfusion can affect normal brain development will permit the development of therapeutic strategies that prevent and/or minimize brain injury and improve the neurodevelopmental outcome of these high-risk newborns. Recently, non-invasive MR perfusion imaging of the brain has been successfully applied to the neonatal brain, which is known to be smaller and have lower brain perfusion compared to older children and adults. This article will present an overview of the potential role of non invasive perfusion imaging by MRI to study maturation, injury, and repair in perinatal brain injury and demonstrate why this perfusion sequence is an important addition to current neonatal imaging protocols, which already include different sequences to assess the anatomy and metabolism of the neonatal brain. PMID- 25813668 TI - Plasticity following early-life brain injury: Insights from quantitative MRI. AB - Over the last decade, the application of novel advanced neuroimaging techniques to study congenital brain damage has provided invaluable insights into the mechanisms underlying early neuroplasticity. The concept that is clearly emerging, both from human and nun-human studies, is that functional reorganization in the immature brain is substantially different from that of the more mature, developed brain. This applies to the reorganization of language, the sensorimotor system, and the visual system. The rapid implementation and development of higher order imaging methods will offer increased, currently unavailable knowledge about the specific mechanisms of cerebral plasticity in infancy, which is essential to support the development of early therapeutic interventions aimed at supporting and enhancing functional reorganization during a time of greatest potential brain plasticity. PMID- 25813667 TI - Use of resting-state functional MRI to study brain development and injury in neonates. AB - Advances in methodology have led to expanded application of resting-state functional MRI (rs-fMRI) to the study of term and prematurely born infants during the first years of life, providing fresh insight into the earliest forms of functional cerebral development. In this review, we detail our evolving understanding of the use of rs-fMRI for studying neonates. We initially focus on the biological processes of cortical development related to resting-state network development. We then review technical issues principally affecting neonatal investigations, including the effects of subject motion during acquisition and image distortions related to magnetic susceptibility effects. We next summarize the literature in which rs-fMRI is used to study normal brain development during the early postnatal period, the effects of prematurity, and the effects of cerebral injury. Finally, we review potential future directions for the field, such as the use of complementary imaging modalities and advanced analysis techniques. PMID- 25813669 TI - Prokaryotic Expression, Refolding and Purification of High-Purity Mouse Midkine in Escherichia coli. AB - To evaluate the clinic safety of human Midkine as an articular protective agent, recombinant mouse Midkine (rmMK) was prepared in prokaryotic system for the pre clinic long-term studies in mice. The open reading frame of mouse Midkine (mMK) was sub-cloned onto expression vector pET30a (+) and transformed into Escherichia coli BL21 (DE3) strain line. The rmMK protein, with a Met fused at N terminus of native mMK for expression initiating, proved to be expressed in inclusion bodies and turned out to be soluble post-denaturation and renaturation. The soluble rmMK was purified successfully with ion exchange and affinity chromatography and characterised good enough to meet the requirements for animal use. Eventually, 13.2-mg rmMK with high quality and bioactivity was obtained from 1 L LB culture, and the total recovery was 11.4%. The present work laid a good foundation for pilot- or large-scale production of rmMK in prokaryotic system. PMID- 25813670 TI - Noninvasive reconstruction of cardiac transmembrane potentials using a kernelized extreme learning method. AB - Non-invasively reconstructing the cardiac transmembrane potentials (TMPs) from body surface potentials can act as a regression problem. The support vector regression (SVR) method is often used to solve the regression problem, however the computational complexity of the SVR training algorithm is usually intensive. In this paper, another learning algorithm, termed as extreme learning machine (ELM), is proposed to reconstruct the cardiac transmembrane potentials. Moreover, ELM can be extended to single-hidden layer feed forward neural networks with kernel matrix (kernelized ELM), which can achieve a good generalization performance at a fast learning speed. Based on the realistic heart-torso models, a normal and two abnormal ventricular activation cases are applied for training and testing the regression model. The experimental results show that the ELM method can perform a better regression ability than the single SVR method in terms of the TMPs reconstruction accuracy and reconstruction speed. Moreover, compared with the ELM method, the kernelized ELM method features a good approximation and generalization ability when reconstructing the TMPs. PMID- 25813671 TI - Lysosome-controlled efficient ROS overproduction against cancer cells with a high pH-responsive catalytic nanosystem. AB - Excess reactive oxygen species (ROS) have been proved to damage cancer cells efficiently. ROS overproduction is thus greatly desirable for cancer therapy. To date, ROS production is generally uncontrollable and outside cells, which always bring severe side-effects in the vasculature. Since most ROS share a very short half-life and primarily react close to their site of formation, it would be more efficient if excess ROS are controllably produced inside cancer cells. Herein, we report an efficient lysosome-controlled ROS overproduction via a pH-responsive catalytic nanosystem (FeOx-MSNs), which catalyze the decomposition of H2O2 to produce considerable ROS selectively inside the acidic lysosomes (pH 5.0) of cancer cells. After a further incorporation of ROS-sensitive TMB into the nanosystem (FeOx-MSNs-TMB), both a distinct cell labeling and an efficient death of breast carcinoma cells are obtained. This lysosome-controlled efficient ROS overproduction suggests promising applications in cancer treatments. PMID- 25813672 TI - Ainsliadimer A selectively inhibits IKKalpha/beta by covalently binding a conserved cysteine. AB - Aberrant activation of NF-kappaB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-kappaB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-kappaB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKalpha/beta and suppresses their activities through an allosteric effect, leading to the inhibition of both canonical and non-canonical NF-kappaB pathways. Remarkably, ainsliadimer A induces cell death of various cancer cells and represses in vivo tumour growth and endotoxin-mediated inflammatory responses. Ainsliadimer A is thus a natural product targeting the cysteine 46 of IKKalpha/beta to block NF-kappaB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies. PMID- 25813673 TI - Biodegradability of fluorinated fire-fighting foams in water. AB - Fluorinated fire-fighting foams may be released into the environment during fire fighting activities, raising concerns due to the potential environmental and health impacts for some fluorinated organics. The current study investigated (1) the biodegradability of three fluorinated fire-fighting foams, and (2) the applicability of current standard measures used to assess biodegradability of fluorinated fire-fighting foams. The biodegradability of three fluorinated fire fighting foams was evaluated using a 28-day dissolved organic carbon (DOC) Die Away Test. It was found that all three materials, diluted in water, achieved 77 96% biodegradability, meeting the criteria for "ready biodegradability". Defluorination of the fluorinated organics in the foam during biodegradation was measured using ion chromatography. It was found that the fluorine liberated was 1 2 orders of magnitude less than the estimated initial amount, indicating incomplete degradation of fluorinated organics, and incomplete CF bond breakage. Published biodegradability data may utilize biochemical oxygen demand (BOD), chemical oxygen demand (COD), and total organic carbon (TOC) metrics to quantify organics. COD and TOC of four fluorinated compounds were measured and compared to the calculated carbon content or theoretical oxygen demand. It was found that the standard dichromate-based COD test did not provide an accurate measure of fluorinated organic content. Thus published biodegradability data using COD for fluorinated organics quantification must be critically evaluated for validity. The TOC measurements correlated to an average of 91% of carbon content for the four fluorinated test substances, and TOC is recommended for use as an analytical parameter in fluorinated organics biodegradability tests. PMID- 25813674 TI - The relationship between NR2E1 and subclinical inflammation in newly diagnosed type 2 diabetic patients. AB - AIMS: To evaluate the expression level of NR2E1 (nuclear receptor subfamily 2,group E,member 1) and its correlation with type 2 diabetes (T2DM). METHODS: Plasma and peripheral blood mononuclear cells (PBMCs) were collected from 54 T2DM and 88 healthy individuals. The levels of free fatty acids (FFAs), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL-c), low density lipoprotein (LDL-c), fasting insulin (FIN), and fasting blood glucose (FBG) were measured. The insulin resistance index was calculated using the homeostasis model assessment (HOMA). NR2E1 in PBMCs were analyzed using real-time RT-PCR and Western blots. Tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in the plasma were measured by enzyme-linked immunosorbent assay (ELISA). PBMCs isolated from healthy volunteers were treated with glucose or palmitate for 24h, followed by analysis for the expression level of NR2E1.The amount of TNF-alpha and IL-6 secreted into the supernatant were measured by ELISA. RESULTS: FIN, FBG, HOMA and TNF-alpha, IL-6 were significantly higher in diabetic patients, compared to the control group. Levels of NR2E1 were significantly higher in the PBMCs isolated from the diabetic group, compared to the control group. NR2E1 expression was positively correlated with FBG, FIN, HOMA, FFAs, TNF-alpha and IL-6. Glucose and palmitate treatment significantly increased NR2E1 gene expression and inflammatory cytokines production in PBMCs in vitro. CONCLUSIONS: Increased NR2E1 level may be closely associated with inflammation and disorder of lipid and glucose metabolism in diabetic patients. PMID- 25813675 TI - Insulin enhances dendritic cell maturation and scavenger receptor-mediated uptake of oxidised low-density lipoprotein. AB - OBJECTIVES: The prevalence of atherosclerotic cardiovascular disease is increased in patients with type 2 diabetes. The role of hyperinsulinaemia as an independent participant in the atherogenic process is controversial. Therefore, we examined whether insulin regulates the expression of scavenger receptors responsible for oxidised low-density lipoprotein (oxLDL) uptake in dendritic cells (DCs). In addition, we investigated the impact of insulin on DC maturation with regard to changes in phenotype and cytokine secretion. METHODS: Immature DCs were cultured with different concentrations of insulin (1nmol/L, 10nmol/L, 50nmol/L, and 100nmol/L) in the absence or presence of LY294002 or PD98059 for 24h. The expression of the scavenger receptors SR-A and CD36 was determined by real-time PCR and Western blot analysis. Furthermore, DCs were incubated with 1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labelled oxLDL. The DiI-oxLDL-incorporated fraction was investigated by flow cytometry. Finally, flow cytometry was used to investigate immunophenotypic protein expression (CD83, CD86, and CD11a). Supernatant cytokine measurements were used as indicators of immune function. RESULTS: The incubation of DCs with insulin enhanced SR-A and CD36 gene and protein expression in a dose-dependent manner. This effect was partially abolished by PD98059, which is an extracellular signal regulated kinase (ERK) inhibitor. However, LY294002 did not inhibit the effect of insulin on scavenger receptor expression. A high concentration of insulin increased the oxLDL-uptake capacity of DCs. Inhibition of the scavenger receptors SR-A and CD36 significantly reduced oxLDL uptake. Furthermore, a high concentration of insulin induced DC maturation. The pro-atherosclerotic chemokines IL-6 and IL-12 were induced by a high concentration of insulin, whereas the release of anti-atherosclerotic IL-10 was reduced. CONCLUSION: This study suggests that hyperinsulinaemia can promote DC activation and up-regulate the expression of the scavenger receptors SR-A and CD36, which can increase the oxLDL-uptake capacity of DCs. The results of the present study indicate that one of the mechanisms by which insulin promotes atherogenesis is mediated by its effects on DCs. PMID- 25813676 TI - Electromyographic activities of the subscapularis, supraspinatus and infraspinatus muscles during passive shoulder and active elbow exercises. AB - PURPOSE: Postoperative exercises may increase load on repaired tendons. Differences in the activity of the rotator cuff muscles were assessed during several different types of passive shoulder and active elbow exercises. METHODS: In 15 healthy subjects, passive forward flexion of the shoulder was performed using a table, pulley and rope, and a cane, and external rotation was performed using a cane and a wall. The active elbow flexion-extension exercise was also performed while holding the upper arm with the contralateral hand. Activation amplitudes of the supraspinatus, infraspinatus and subscapularis muscles were evaluated using electromyography with fine wires. RESULTS: During passive forward flexion, the supraspinatus and infraspinatus muscles exhibited lower activity when using a table compared with a cane (both P < 0.01) and a pulley and rope (both P < 0.05). Flexion of <90 degrees decreased supraspinatus activation compared with 170 degrees (P = 0.047). During external rotation of the shoulder while using the cane and wall, there was no difference in the activity of any muscles. Electromyographic activity during the active elbow exercise was lower in the supraspinatus while holding the upper arm (P = 0.018). CONCLUSION: The table sliding exercise may reduce stress on the rotator cuff during passive forward flexion more than the other exercises do. Decreasing the range of motion to less than 90 degrees in forward flexion activated the supraspinatus less. Moreover, movement of the elbow can be performed holding the upper arm to activate the rotator cuff to a lesser extent. LEVEL OF EVIDENCE: Prognostic study, Level II. PMID- 25813677 TI - Inhaled nitric oxide in preterm infants with prolonged preterm rupture of the membranes: a case series. AB - The available evidence does not support the routine use of inhaled nitric oxide (iNO) in the care of premature infants. We present a case series of 22 preterm infants born after prolonged preterm premature rupture of membranes and oligohydramnios with respiratory failure. Oxygenation index decreased significantly after commencement of iNO. PMID- 25813678 TI - Marshall-Smith syndrome. PMID- 25813679 TI - Trial of labor after cesarean: attempted operative vaginal delivery versus emergency repeat cesarean, a prospective national cohort study. PMID- 25813680 TI - Multiples and parents of multiples prefer same arm randomization of siblings in neonatal trials. PMID- 25813681 TI - Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease. AB - BACKGROUND AIMS: This study aimed to characterize the immune effectors contained in the grafts from donor mice mobilized by granulocyte colony-stimulating factor (G-CSF) and plerixafor and to evaluate their impact on the development of acute graft-versus-host-disease (aGVHD). METHODS: Mobilization was done with G-CSF alone or G-CSF plus plerixafor (G+P). RESULTS: In grafts collected after G+P mobilization, we observed a significantly higher proportion of c-kit(+)Sca-1(+) hematopoietic stem cells compared with G-CSF. A significant increase in the percentage of plasmacytoid dendritic cells was detected in the G+P graft compared with G-CSF graft. We also studied the ability of stem cell grafts mobilized with G+P to induce GVHD in a mouse model. We observed higher mortality (P < 0.001) associated with increased aGVHD clinical score (P < 0.0001) as well as higher pathology score in the intestine of mice receiving G+P as compared with G-CSF grafts (P < 0.001). Moreover, the exacerbated aGVHD severity was associated with upregulation of CCR6 expression on both CD4(+) and CD8(+) T cells from the G+P grafts, as well as on T cells from mice transplanted with G+P grafts. CONCLUSIONS: In conclusion, we showed that grafts mobilized with G+P exhibited functional features different from those mobilized with G-CSF alone, which increase the severity of aGVHD in the recipients. PMID- 25813683 TI - [Rare tumors: the need for special centers]. PMID- 25813682 TI - Pediatric Assessment of Vancomycin Empiric Dosing (PAVED): a Retrospective Review. AB - BACKGROUND: Pediatric studies and anecdotal experience suggest that current empiric vancomycin dosing does not reach serum trough concentration targets of at least 10 mg/L for uncomplicated infections or 15-20 mg/L for serious or complicated infections. OBJECTIVES: This study reviewed vancomycin dosing and serum concentrations to (i) determine the proportion of patients who reached initial target concentrations; (ii) describe pharmacokinetic parameters; and (iii) compare patient-specific area-under-the-curve (AUC) values to population estimates using the Rodvold equation. METHODS: Following ethics approval, data were extracted from medical records of 200 patients aged 1 month-18 years, who received intravenous (IV) vancomycin and had at least two pharmacokinetically evaluable serum concentrations. RESULTS: Trough vancomycin concentrations of 10 15 and 15-20 mg/L were achieved in 25 (29%) and 2 (2%) patients receiving vancomycin 15 mg/kg IV every 6 h (q6 h) and 22 (20%) and 9 (8%) patients receiving vancomycin 20 mg/kg IV every 8 h (q8 h), respectively. Patients were stratified into four age groups (1 month-1 year, 1-6 years, 6-13 years and 13-18 years). Median (IQR) pharmacokinetic parameters were elimination rate constant 0.25 (0.09), 0.29 (0.07), 0.24 (0.10) and 0.22 (0.07) h(-1); volume of distribution 0.56 (0.20), 0.61 (0.21), 0.47 (0.26) and 0.49 (0.22) L/kg; and half life 2.8 (1.1), 2.4 (0.5), 2.9 (1.1) and 3.2 (1.0) h, respectively. Median (IQR) AUCs were 458 (170), 338 (132), 478 (215) and 513 (179) mg h/L and population estimated AUCs were 67 (44), 108 (70), 299 (102) and 454 (103) mg h/L (p < 0.05 for all groups). CONCLUSIONS: Based on these findings, we recommend vancomycin 70 and 90 mg/kg/day divided q6 h for troughs of 10-15 and 15-20 mg/L, respectively (patients 1 month-6 years) and 60 mg/kg/day divided q8 h and 70 mg/kg/day divided q6 h, respectively (patients >6 years) to undergo further testing as initial dosing regimens. Furthermore, population estimates grossly underestimate vancomycin AUC in patients 1-18 years old and thus patient-specific parameters are required. PMID- 25813684 TI - Repression of wall shear stress inside cerebral aneurysm at bifurcation of anterior cerebral artery by stents. AB - The effect of a simple bare metal stent on repression of wall shear stress inside a model cerebral aneurysm was experimentally investigated by two-dimensional particle image velocimetry in vitro. The flow model simulated a cerebral aneurysm induced at the apex of bifurcation between the anterior cerebral artery and the anterior communicating artery. Wall shear stress was investigated using both stented and non-stented models to assess the simple stent characteristics. The flow behavior inside the stented aneurysm sac was unusual and wall shear stress was much smaller inside the aneurysm sac. Stent placement effectively repressed the temporal and spatial variations and the magnitude of wall shear stress. Hence, there is an effective possibility that would retard the progress of cerebral aneurysms by even simple stent. PMID- 25813686 TI - Plasma complement C3 levels are associated with insulin secretion independently of adiposity measures in non-diabetic individuals. AB - BACKGROUND AND AIMS: To evaluate if complement C3 is associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders including adiposity measures. METHODS AND RESULTS: 1010 nondiabetic subjects were stratified into quartiles according to complement C3 values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT) in the whole study group and from intravenous glucose tolerance test (IVGTT) in a subgroup (n = 110). Significant differences between quartiles of C3 were observed in body mass index (BMI), waist, fat mass, blood pressure, total cholesterol, high density lipoprotein (HDL), triglycerides, fasting and 2-h post-load glucose, fasting insulin, C reactive protein (hsCRP), fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement C4, and insulin sensitivity with C3 quartiles exhibiting graded increases in cardio metabolic risk factors. Differences in insulin secretion indexes between C3 quartiles remained significant after adjustment for age, gender, BMI, insulin sensitivity, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, and complement C4 levels (P < 0.0001). A multivariable regression analysis revealed that complement C3 is a contributor of insulin secretion, explaining 2.4% and 1.9% of variation of the Stumvoll index for first-phase and second-phase insulin secretion, respectively, and 2.1% of variation of the InsAUC30/GluAUC30 index, independently of gender, age, BMI, waist, fat mass, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, AST, ALT. CONCLUSIONS: Complement C3 concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, subclinical inflammation, and insulin sensitivity. PMID- 25813687 TI - Comparison of non-HDL-cholesterol versus triglycerides-to-HDL-cholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: the CARITALY study. AB - BACKGROUND AND AIMS: Lipid ratios to estimate atherosclerotic disease risk in overweight/obese children are receiving great attention. We aimed to compare the performance of non-high-density lipoprotein-cholesterol (HDL-C) versus triglycerides-to-HDL-C ratio (Tg/HDL-C) in identifying cardiometabolic risk factors (CMRFs) or preclinical signs of organ damage in outpatient Italian overweight/obese children. METHODS AND RESULTS: In this retrospective, cross sectional study, 5505 children (age 5-18 years) were recruited from 10 Italian centers for the care of obesity, of which 4417 (78%) showed obesity or morbid obesity. Anthropometric, biochemical, and blood pressure variables were analyzed in all children. Liver ultrasound scan, carotid artery ultrasound, and echocardiography were performed in 1257, 601, and 252 children, respectively. The entire cohort was divided based on the 75th percentile of non-HDL-C (>=130 mg/dl) or Tg/HDL-C ratio (>=2.2). The odds ratio for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increased levels of carotid intima-media thickness (cIMT) and concentric left ventricular hypertrophy (cLVH) was higher in children with high levels of Tg/HDL-C with respect to children with high levels of non-HDL-C. CONCLUSIONS: In an outpatient setting of overweight/obese children, Tg/HDL-C ratio discriminated better than non-HDL-C children with CMRFs or preclinical signs of liver steatosis, and increased cIMT and cLVH. PMID- 25813688 TI - Undertreatment of Men in Their Seventies with High-risk Nonmetastatic Prostate Cancer. AB - BACKGROUND: Many elderly men with high-risk nonmetastatic prostate cancer (HRnMPCa) do not receive radical treatment, despite the high mortality associated with conservative management. OBJECTIVE: To investigate how age and comorbidity affect treatment of men with HRnMPCa. DESIGN, SETTING, AND PARTICIPANTS: This was an observational nationwide register study during 2001-2012. We identified 19 190 men of <80 yr of age diagnosed with HRnMPCa in the National Prostate Cancer Register of Sweden and 95 948 age-matched men without prostate cancer in the register of the total population. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was the proportion of men with HRnMPCa receiving radical treatment (radical prostatectomy or radiotherapy). Vital status and the Charlson comorbidity index (CCI) were obtained from nationwide registers. The 10-yr survival of men without prostate cancer, stratified by age and CCI, was used as a measure of the life expectancy of the men with prostate cancer. RESULTS AND LIMITATIONS: The proportions receiving radical treatment varied with life expectancy among men younger than 70 yr, whereas use of these treatments did not match the long life expectancy of men in their seventies with CCI 0-1. Only 10% of men aged 75-80 yr with CCI 0 received radical treatment despite 52% probability of 10-yr life expectancy, compared with approximately half of the men younger than 70 yr with a similar life expectancy. The use of radical treatment for HRnMPCa increased with time in all Swedish counties, but a threefold difference between counties remained in 2009-2012 for patients aged 70-80 yr with CCI 0-1. Uncertain external validity is a study limitation, and the impact of physician versus patient preferences on treatment selection could not be assessed. CONCLUSIONS: Otherwise healthy men in their seventies with HRnMPCa were less likely to receive radical treatment than younger men with a similar life expectancy, although increasing use of radical treatment was observed during the study period. Our findings highlight the need for improved methods for clinical decision-making, including improved assessment of life expectancy. PATIENT SUMMARY: We performed a nationwide register study that showed that many healthy men in their seventies live for at least another 10 yr. Despite this long life expectancy, men in their seventies with high-risk nonmetastatic prostate cancer were often not treated with radical prostatectomy or radiotherapy, possibly because their life expectancy was underestimated. Our study highlights the need for improved clinical decision-making, which should incorporate an assessment of the patient's life expectancy. PMID- 25813689 TI - Life Expectancy and Treatment Choice for Men with High-risk Prostate Cancer. PMID- 25813690 TI - Toward Optimal Prediction of Prognosis in T1 Urothelial Carcinoma of the Bladder. PMID- 25813691 TI - Maintenance Bacillus Calmette-Guerin Therapy: The Search for the Optimum Treatment Schedule Continues. PMID- 25813692 TI - Does preoperative magnetic resonance imaging reduce the rate of positive surgical margins at radical prostatectomy in a randomised clinical trial? AB - BACKGROUND: Magnetic resonance imaging (MRI) has the potential to help the surgeon tailor radical prostatectomy (RP) more accurately according to the location and extent of the tumour and thereby reduce the rate of positive surgical margins (PSMs). OBJECTIVE: To evaluate the benefit of performing MRI prior to RP. DESIGN, SETTING, AND PARTICIPANTS: This single-institution randomised trial included 438 patients between December 2009 and June 2012 who were scheduled for robot-assisted laparoscopic prostatectomy. The study was registered (ClinicalTrials.gov identifier NCT01347320). INTERVENTION: Patients were preoperatively randomly assigned to non-MRI or MRI groups. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was the difference in the PSM rates between the two groups. Secondary end points were the rates of PSMs in clinical subgroups. Summary statistics were extracted from descriptive analyses, chi-square, or Fisher exact test, and logistic regression was used to analyse the data according to the intention-to-treat principle. RESULTS AND LIMITATIONS: A total of 216 patients were randomised to non-MRI; 222 were randomised to MRI. There were 49 cases (23%) of PSMs in the non-MRI group and 43 cases (19%) in the MRI group (p=0.4). The relative and absolute risk reduction was 15% and 4%, respectively. Patients with cT1 constituted 55% of the cohort, in which the rate of PSMs was 27% in the non-MRI group and 16% in the MRI group (p=0.035). The relative and absolute risk reduction was 41% and 11%, respectively. A limitation was suboptimal communication between the radiologist and urologist. CONCLUSIONS: MRI prior to RP did not reduce the overall risk for PSMs in this patient cohort. However, at subgroup analysis we observed a possible benefit of MRI in patients with cT1. PATIENT SUMMARY: This study could not demonstrate a definite benefit of performing magnetic resonance imaging before surgery for all patients. However, there was a possible improved result in patients in which physical examination could not detect the cancer. PMID- 25813693 TI - Robotic Surgery Revives Radical Perineal Prostatectomy. PMID- 25813695 TI - Association of genetic variants with dyslipidemia and chronic kidney disease in a longitudinal population-based genetic epidemiological study. AB - We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke, or chronic kidney disease (CKD) in Japanese individuals by genome-wide or candidate gene association studies. In the present study, we examined the association of 13 polymorphisms at these 10 loci with the prevalence of hypertriglyceridemia, hyper-low-density lipoprotein (LDL) cholesterolemia, hypo-high-density lipoprotein (HDL) cholesterolemia, or CKD in community-dwelling Japanese individuals. The study subjects comprised 6,027 individuals who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center at Inabe General Hospital for an annual health checkup, and they were followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for covariates revealed that rs6929846 of butyrophilin, subfamily 2, member A1 gene (BTN2A1) was significantly associated with the prevalence of hypertriglyceridemia (P=0.0001), hyper-LDL cholesterolemia (P=0.0004), and CKD (P=0.0007); rs2569512 of interleukin enhancer binding factor 3 (ILF3) was associated with hyper-LDL cholesterolemia (P=0.0029); and rs2074379 (P=0.0019) and rs2074388 (P=0.0029) of alpha-kinase 1 (ALPK1) were associated with CKD. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for covariates among all individuals revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=0.0011), LDL cholesterol (P=3.3 x 10(-5)), and creatinine (P=0.0006), as well as with the estimated glomerular filtration rate (eGFR) (P=0.0004); rs2569512 of ILF3 was shown to be associated with the serum concentration of LDL cholesterol (P=0.0221); and rs2074379 (P=0.0302) and rs2074388 (P=0.0336) of ALPK1 were shown to be associated with the serum concentration of creatinine. Similar analysis among individuals not taking any anti-dyslipidemic medication revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=8.3 x 10-5) and LDL cholesterol (P=0.0004), and that rs2569512 of ILF3 was associated with the serum concentration of LDL cholesterol (P=0.0010). BTN2A1 may thus be a susceptibility gene for hypertriglyceridemia, hyper-LDL cholesterolemia and CKD in Japanese individuals. PMID- 25813696 TI - Sole effect of genioglossus advancement on apnea hypopnea index of patients with obstructive sleep apnea. AB - CONCLUSION: Selected patients might have benefited from genioglossus advancement (GA), even it was applied solely. GA provided significant reduction on the apnea hypopnea index (AHI), with a 53% surgical success. OBJECTIVES: The aim of this study was to evaluate the impact of GA on AHI of patients with obstructive sleep apnea (OSA). METHOD: From January 2008 to April 2014 patients who underwent a genioglossus advancement procedure alone were included into the study and records of these cases were analyzed retrospectively. Pre-operative and post-operative values of body mass index (BMI), Epworth Sleepiness Scale (ESS), nocturnal polysomnographic data including AHI, mean, and minimum oxygen saturation were compared. RESULTS: There were 16 males and one female patient with the mean age of 46 years. The AHI showed a significant reduction from 27.5 +/- 8 pre operatively to 17.3 +/- 12.6 post-operatively. The pre-operative and post operative mean O2 saturation value improved from 92.1 +/- 2.4% to 93.4 +/- 1.7%. Pre-operative ESS scores decreased significantly from 7.7 +/- 1.6 to 4.8 +/- 1.9. There were no significant difference between pre- and post-operative values of BMI and minimum O2 saturation. The success rate was found to be 53%, which was based on success criteria as an AHI of <20 with at least 50% reduction. PMID- 25813694 TI - Regenerative Medicine Strategies for Esophageal Repair. AB - Pathologies that involve the structure and/or function of the esophagus can be life-threatening. The esophagus is a complex organ comprising nonredundant tissue that does not have the ability to regenerate. Currently available interventions for esophageal pathology have limited success and are typically associated with significant morbidity. Hence, there is currently an unmet clinical need for effective methods of esophageal repair. The present article presents a review of esophageal disease along with the anatomic and functional consequences of each pathologic process, the shortcomings associated with currently available therapies, and the latest advancements in the field of regenerative medicine with respect to strategies for esophageal repair from benchtop to bedside. PMID- 25813697 TI - Inhibition of the autophagy flux by gingerol enhances TRAIL-induced tumor cell death. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a primary anticancer agent and a member of the tumor necrosis factor family that selectively induces apoptosis in various tumor cells, but not in normal cells. Gingerol is a major ginger component with anti-inflammatory and anti-tumorigenic activities. Autophagy flux is the complete process of autophagy, in which the autophagosomes are lysed by lysosomes. The role of autophagy in cell death or cell survival is controversial. A549 adenocarcinoma cells are TRAIL-resistant. In the present study, we showed that treatment with TRAIL slightly induced cell death, but gingerol treatment enhanced the TRAIL-induced cell death in human lung cancer cells. The combination of gingerol and TRAIL increased accumulation of microtubule-associated protein light chain 3-II and p62, confirming the inhibited autophagy flux. Collectively, our results suggest that gingerol sensitizes human lung cancer cells to TRAIL-induced apoptosis by inhibiting the autophagy flux. PMID- 25813699 TI - Cracks in Martian boulders exhibit preferred orientations that point to solar induced thermal stress. AB - The origins of fractures in Martian boulders are unknown. Here, using Mars Exploration Rover 3D data products, we obtain orientation measurements for 1,857 cracks visible in 1,573 rocks along the Spirit traverse and find that Mars rock cracks are oriented in statistically preferred directions similar to those compiled herein for Earth rock cracks found in mid-latitude deserts. We suggest that Martian directional cracking occurs due to the preferential propagation of microfractures favourably oriented with respect to repeating geometries of diurnal peaks in sun-induced thermal stresses. A numerical model modified here with Mars parameters supports this hypothesis both with respect to the overall magnitude of stresses as well as to the times of day at which the stresses peak. These data provide the first direct field and numerical evidence that insolation related thermal stress potentially plays a principle role in cracking rocks on portions of the Martian surface. PMID- 25813698 TI - Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study. AB - Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayers and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, the development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here, we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs were superior to a conventional detergent, n-dodecyl-beta D-maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation. PMID- 25813700 TI - Impaired insulin signaling pathway in ovarian follicles of cows with cystic ovarian disease. AB - Cystic ovarian disease (COD) is an important cause of infertility in dairy cattle. Follicular cell steroidogenesis and proliferation in ovulatory follicles is stimulated by hormones such as insulin and its necessary post-receptor response. The aim of this study was to determine the expression of insulin receptor (IR), IR substrate-1 (IRS1) and phosphatidylinositol 3-kinase (PI3K), key intermediates in the insulin pathway, in control cows and cows with spontaneous COD and ACTH-induced COD. IR and IRS1 mRNA levels were greater in granulosa cells and lower in follicular cysts than in control tertiary follicles. PI3K mRNA levels were similar in all follicles evaluated, whereas the expression of IR, IRS1 and PI3K was similar in theca cells. Protein expression of IR was higher in control tertiary follicles than in the same structures in animals with COD and with cysts. IRS1 and PI3K protein expression showed the same pattern in tertiary and cystic follicles. However, the protein expression of subunit alpha p85 of PI3K was greater in theca cells from tertiary follicles than in cystic follicles. These results provide new insights into the insulin response in cows with COD. The lower gene and protein expressions of some insulin downstream effectors at an early stage of the signaling pathway could negatively influence the functionality of ovaries and contribute to follicle persistence. PMID- 25813701 TI - Growth synchrony between leaves and stems during twig development differs among plant functional types of subtropical rainforest woody species. AB - During the development of woody twigs, the growth in leaf may or may not be proportional to the growth in stem. The presence or absence of a synchronicity between these two phenologies may reflect differences in life history adaptive strategies concerning carbon gain. We hypothesized that sun-adapted species are more likely to be less synchronous between growths in total leaf area (TLA) and stem length compared with shade-adapted species, with a bias in growth in stem length, and that shade-adapted species are more likely to be more synchronous between increases in individual leaf area (ILA) (leaf size) and leaf number (LN) during twig development compared with sun-adapted species, giving priority to growth of leaf size. We tested these two hypotheses by recording the phenologies of leaf emergence, leaf expansion and stem elongation during twig development for 19 evergreen woody species (including five shade-adapted understory species, six sun-adapted understory species and eight sun-adapted canopy species) in a subtropical evergreen broad-leaved forest in eastern China. We constructed indices to characterize the synchronicity between TLA and stem length (alphaLS) and between leaf size and leaf number (alphaSN) and we derived the alpha values from logistic functions taking the general form of A = A(max)/[1 + exp(beta - alphaB)] (where A is the TLA or average ILA, B is the corresponding stem length or LN at a specific time, and A(max) is the maximum TLA or the maximum ILA of a twig; the higher the numerical value of alpha, the less synchronous the corresponding phenologies). Consistent with our hypotheses, sun-adapted species were higher both in alpha(LS) and alpha(SN), showing less synchronous patterns in the growths of TLA vs stem length and leaf size vs LN during twig development. Moreover, alpha(LS) and alpha(SN) were significantly positively correlated with relative growth rates of LN and leaf size across species, as indicated by both analyses of ordinary regression and phylogenetic generalized least squares. The across-species synchronies during twig development show that the temporal dynamics of the leaf size-twig size spectrum is of adaptive significance in plants. We suggest that temporal dynamics of plant functional traits should be extensively studied to characterize plant life history. PMID- 25813702 TI - Information resources used by patients with inflammatory bowel disease: Satisfaction, expectations and information gaps. AB - BACKGROUND AND PURPOSE: Information received by IBD patients about their disease is of particular importance. The objective of the study was to determine the information resources these patients used, together with their perceived information gaps and expected preferences. PATIENTS AND METHODS: A prospective, observational, cross-sectional study conducted on IBD patients attending 13 Spanish hospitals during 2008. Patients completed a semi-structured 52-question survey. RESULTS: Survey was adequately completed by 379 of 385 patients (98%), of whom 57% had Crohn's disease and 43% ulcerative colitis. Mean patient age was 37.9 years (range, 16-76 years). Gastroenterologists were the most commonly used resource (98%), followed by the Internet (60%), and general practitioners (50%). More than 90% reported good to excellent satisfaction with gastroenterologists, nurses, and patients' associations. Only 56% considered their information needs to be covered. The Internet was mostly used by young patients and those with a high education level. In the future, 85% of the patients would like to receive information from the gastroenterologists, and 92% by face-to-face interviews. Patients mainly want additional information on treatment (medical and surgical), clinical manifestations, cancer, and mortality risks. They also think that they are poorly informed about their social and work rights, risks of cancer and death, and research trials. CONCLUSIONS: Patients with IBD use and prefer gastroenterologists as the main source of information, but only half of them consider their information needs to be covered. PMID- 25813703 TI - Sphingomyelin derivatives increase the frequency of microvesicle and granule fusion in chromaffin cells. AB - Sphingomyelin derivatives like sphingosine have been shown to enhance secretion in a variety of systems, including neuroendocrine and neuronal cells. By studying the mechanisms underlying this effect, we demonstrate here that sphingomyelin rafts co-localize strongly with synaptosomal-associated protein of 25Kda (SNAP 25) clusters in cultured bovine chromaffin cells and that they appear to be linked in a dynamic manner. In functional terms, when cultured rat chromaffin cells are treated with sphingomyelinase (SMase), producing sphingomyelin derivatives, the secretion elicited by repetitive depolarizations is enhanced. This increase was independent of cell size and it was significant 15min after initiating stimulation. Interestingly, by evaluating the membrane capacitance we found that the events in control untreated cells corresponded to two populations of microvesicles and granules, and the fusion of both these populations is clearly enhanced after treatment with SMase. Furthermore, SMase does not increase the size of chromaffin granules. Together, these results strongly suggest that SNARE-mediated exocytosis is enhanced by the generation of SMase derivatives, reflecting an increase in the frequency of fusion of both microvesicles and chromaffin granules rather than an increase in the size of these vesicles. PMID- 25813704 TI - Evidence for a role for alpha6(*) nAChRs in l-dopa-induced dyskinesias using Parkinsonian alpha6(*) nAChR gain-of-function mice. AB - l-Dopa-induced dyskinesias (LIDs) are a serious side effect of dopamine replacement therapy for Parkinson's disease. The mechanisms that underlie LIDs are currently unclear. However, preclinical studies indicate that nicotinic acetylcholine receptors (nAChRs) play a role, suggesting that drugs targeting these receptors may be of therapeutic benefit. To further understand the involvement of alpha6beta2(*) nAChRs in LIDs, we used gain-of-function alpha6(*) nAChR (alpha6L9S) mice that exhibit a 20-fold enhanced sensitivity to nAChR agonists. Wildtype (WT) and alpha6L9S mice were lesioned by unilateral injection of 6-hydroxydopamine (6-OHDA, 3MUg/ml) into the medial forebrain bundle. Three to 4wk later, they were administered l-dopa (3mg/kg) plus benserazide (15mg/kg) until stably dyskinetic. l-dopa-induced abnormal involuntary movements (AIMs) were similar in alpha6L9S and WT mice. WT mice were then given nicotine in the drinking water in gradually increasing doses to a final 300MUg/ml, which resulted in a 40% decline AIMs. By contrast, there was no decrease in AIMs in alpha6L9S mice at a maximally tolerated nicotine dose of 20MUg/ml. However, the nAChR antagonist mecamylamine (1mg/kg ip 30min before l-dopa) reduced l-dopa-induced AIMs in both alpha6L9S and WT mice. Thus, both a nAChR agonist and antagonist decreased AIMs in WT mice, but only the antagonist was effective in alpha6L9S mice. Since nicotine appears to reduce LIDs via desensitization, hypersensitive alpha6beta2(*) nAChRs may desensitize less readily. The present data show that alpha6beta2(*) nAChRs are key regulators of LIDs, and may be useful therapeutic targets for their management in Parkinson's disease. PMID- 25813705 TI - Nicotine modulates neurogenesis in the central canal during experimental autoimmune encephalomyelitis. AB - Nicotine has been shown to attenuate experimental autoimmune encephalomyelitis (EAE) through inhibiting inflammation in microglial populations during the disease course. In this study, we investigated whether nicotine modified the regenerative process in EAE by examining nestin-expressing neural stem cells (NSCs) in the spinal cord, which is the primary area of demyelination and inflammation in EAE. Our results show that the endogenous neurogenic responses in the spinal cord after EAE are limited and delayed: while nestin expression is increased, the proliferation of ependymal cells is inhibited compared to healthy animals. Nicotine application significantly reduced nestin expression and partially allowed for the proliferation of ependymal cells. We found that reduction of ependymal cell proliferation correlated with inflammation in the same area, which was relieved by the administration of nicotine. Further, increased numbers of oligodendrocytes (OLs) were observed after nicotine treatment. These findings give a new insight into the mechanism of how nicotine functions to attenuate EAE. PMID- 25813706 TI - Olfactory speed - Temporal odor processing of paired stimuli. AB - OBJECTIVES: Compared to other senses, temporal perception of odors seems fairly slow. In addition it has been shown in previous studies that even not consciously perceived odors could influence our behavior. Aim of the current study therefore was to study the interstimulus interval (ISI) length, which is necessary between two repetitive stimuli to be able to perceive them separately. The additional aim focused on observing central odor processing of not perceived odorous stimuli. MATERIALS AND METHODS: The study was divided into three parts. In each part healthy, normosmic volunteers were included. In part I and II stimulus pairs (CO2, H2S, orange and phenyl ethyl alcohol (PEA)) were presented to the subjects via a computer-controlled olfactometer with short ISI of 0.6-9s. The decision whether one or two stimuli were perceived was recorded. In addition the influence of odor valence, trigeminallity and concentrations was observed. In part III olfactory event-related potentials (OERPs) to perceived and not-perceived odors were recorded. RESULTS: The two stimuli of a stimulus pair were perceived separately more often with increasing ISI length. This increase was significant until an ISI between the stimuli of 4s. Odor intensity, pleasantness, trigeminallity and sex had no major influence on this. In addition we were able to observe that OERPs are less often detected in response to not perceived olfactory stimuli. However, the presence of OERP in response to not perceived stimuli in more than half of the cases indicated that even not perceived stimuli are centrally processed. PMID- 25813707 TI - The differential contributions of the parvocellular and the magnocellular subdivisions of the red nucleus to skilled reaching in the rat. AB - During the execution of the skilled reaching task, naive rats bring their elbow to the midline of their body to aim at the food target, perform the arpeggio movement to grasp it and supinate the paw to bring the food to their mouth. Red nucleus lesions in the rat interfere with each of these three movement elements of reaching. On the other hand, lesions to the rubrospinal tract, which originate from the magnocellular subdivision of the red nucleus, only interfere with the arpeggio movement. This latter evidence strongly suggests that impairment in aiming and supinating could be under the control of the parvocellular subdivision of the red nucleus. In order to test this hypothesis, rats were trained on the skilled reaching task and then received either complete lesions of the red nucleus or lesions restricted to its parvo- or magnocellular subdivision. In line with previous data, complete excitotoxic lesions of the red nucleus compromised limb aiming, arpeggio and supination. Lesions restricted to the parvocellular division of the red nucleus abolish supination and interfere with aiming, although the latter result did not reach significance. The results are discussed in terms of the distinct connectivity and functional significance of these two architectonic subdivisions of the red nucleus. PMID- 25813708 TI - D1 receptors in the nucleus accumbens-shell, but not the core, are involved in mediating ethanol-seeking behavior of alcohol-preferring (P) rats. AB - Clinical and preclinical research suggest that activation of the mesolimbic dopamine (DA) system is involved in mediating the rewarding actions of drugs of abuse, as well as promoting drug-seeking behavior. Inhibition of DA D1 receptors in the nucleus accumbens (Acb) can reduce ethanol (EtOH)-seeking behavior of non selective rats triggered by environmental context. However, to date, there has been no research on the effects of D1 receptor agents on EtOH- seeking behavior of high alcohol-preferring (P) rats following prolonged abstinence. The objective of the present study was to examine the effects of microinjecting the D1 antagonist SCH 23390 or the D1 agonist A-77636 into the Acb shell or Acb core on spontaneous recovery of EtOH-seeking behavior. After 10 weeks of concurrent access to EtOH and water, P rats underwent seven extinction sessions (EtOH and water withheld), followed by 2 weeks in their home cages without access to EtOH or operant sessions. In the 2nd week of the home cage phase, rats were bilaterally implanted with guide cannula aimed at the Acb shell or Acb core; rats were allowed 7d ays to recover before EtOH-seeking was assessed by the Pavlovian Spontaneous Recovery (PSR) model. Administration of SCH23390 (1MUg/side) into the Acb shell inhibited responding on the EtOH lever, whereas administration of A 77636 (0.125MUg/side) increased responding on the EtOH lever. Microinfusion of D1 receptor agents into the Acb core did not alter responding on the EtOH lever. Responses on the water lever were not altered by any of the treatments. The results suggest that activation of D1 receptors within the Acb shell, but not Acb core, are involved in mediating PSR of EtOH-seeking behavior of P rats. PMID- 25813709 TI - Comparison of noradrenaline, dopamine and serotonin in mediating the tachycardic and thermogenic effects of methamphetamine in the ventral medial prefrontal cortex. AB - Methamphetamine (METH) is a psychostimulant that disrupts monoaminergic neurotransmission to evoke profound behavioral and physiological effects. Rapidly distributing to forebrain regions to increase synaptic concentrations of three monoamines (dopamine (DA), serotonin (5-HT) and noradrenaline (NA)), the medial prefrontal cortex (mPFC) is important in METH-altered behavioral and psychological profiles. Activation of the ventral mPFC can modify physiological variables, however, METH-evoked autonomic changes from this region are unknown. Therefore, the aim of this study was to characterize the respiratory, metabolic and cardiovascular effects of microinjection of METH, DA, 5-HT and NA into the ventral mPFC in urethane-anesthetized Sprague-Dawley rats. METH and NA microinjection evoked dose-related increases in heart rate, interscapular brown adipose tissue temperature and expired CO2, a pattern of response characteristic of non-shivering thermogenesis. NA and 5-HT microinjection elicited pressor and depressor responses, respectively, with matching baroreflex adjustments in sympathetic nerve activity while METH and DA evoked no change in vasomotor outflow. Low doses of METH and DA may evoke respiratory depression. These data suggest that METH's actions in the ventral mPFC, likely via adrenergic receptors, evoke non-shivering thermogenesis which may contribute to the increased body temperature and tachycardia seen in those that abuse METH. PMID- 25813710 TI - HMGB1 may act via RAGE to promote angiogenesis in the later phase after intracerebral hemorrhage. AB - Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote vascular remodeling. Whether HMGB1 supports angiogenesis after ICH is unclear, as are the receptors and downstream signaling pathway(s) involved. We used the rat model of collagenase-induced ICH to determine whether HMGB1 acts via the receptor for advanced glycation end-products (RAGE) to upregulate vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells and key regulator of normal and abnormal angiogenesis in the late phase of injury. At 3d after ICH induction, rats were treated with saline, ethyl pyruvate (EP) or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). ICH induced the movement of HMGB1 from the nucleus into the cytoplasm. Levels of HMGB1 and RAGE in the ipsilateral striatum increased within a few days of induction and continued to rise for 7-14d afterward. By 14d after induction, levels of VEGF and vessel density were higher than in the Sham group. Administering EP 3 days after ICH induction prevented much of the stroke-induced increases in vessel density and in expression of HMGB1, RAGE, and VEGF. Administering FPS-ZM1 after ICH blocked much of the stroke-induced increases in vessel density and VEGF expression. Our results suggest that after ICH, HMGB1 may upregulate VEGF in the ipsilateral striatum predominantly via RAGE. Hence, targeting the HMGB1/RAGE signaling pathway may help reduce inappropriate angiogenesis after ICH. PMID- 25813711 TI - Brain-derived neurotrophic factor inhibits osmotic swelling of rat retinal glial (Muller) and bipolar cells by activation of basic fibroblast growth factor signaling. AB - Water accumulation in retinal glial (Muller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Intravitreal administration of neurotrophins such as brain derived neurotrophic factor (BDNF) is known to promote survival of retinal neurons. Here, we show that exogenous BDNF inhibits the osmotic swelling of Muller cell somata induced by superfusion of rat retinal slices or freshly isolated cells with a hypoosmotic solution containing barium ions. BDNF also inhibited the osmotic swelling of bipolar cell somata in retinal slices, but failed to inhibit the osmotic soma swelling of freshly isolated bipolar cells. The inhibitory effect of BDNF on Muller cell swelling was mediated by activation of tropomyosin-related kinase B (TrkB) and transactivation of fibroblast growth factor receptors. Exogenous basic fibroblast growth factor (bFGF) fully inhibited the osmotic swelling of Muller cell somata while it partially inhibited the osmotic swelling of bipolar cell somata. Isolated Muller cells displayed immunoreactivity of truncated TrkB, but not full-length TrkB. Isolated rod bipolar cells displayed immunoreactivities of both TrkB isoforms. Data suggest that the neuroprotective effect of exogenous BDNF in the retina is in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. While BDNF directly acts on Muller cells by activation of TrkB, BDNF indirectly acts on bipolar cells by inducing glial release of factors like bFGF that inhibit bipolar cell swelling. PMID- 25813712 TI - Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats. AB - A hallmark of peripheral neuropathic pain (PNP) is chronic spontaneous pain and/or hypersensitivity to normally painful stimuli (hyperalgesia) or normally nonpainful stimuli (allodynia).This pain results partly from abnormal hyperexcitability of dorsal root ganglion (DRG) neurons. We have previously shown, using a modified version of the lumbar 5 (L5)-spinal nerve ligation model of PNP (mSNA model involving L5-spinal nerve axotomy plus loose ligation of the lumbar 4 (L4)-spinal nerve with neuroinflammation-inducing chromic-gut), that L4 DRG neurons exhibit increased spontaneous activity, the key characteristic of neuronal hyperexcitability. The underlying ionic and molecular mechanisms of the hyperexcitability of L4 DRG neurons are incompletely understood, but could result from changes in expression and/or function of ion channels including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are active near the neuron's resting membrane potential, and which produce an excitatory inward current that depolarizes the membrane potential toward the threshold of action potential generation. Therefore, in the present study we used the mSNA model to investigate whether: (a) expression of HCN1-HCN3 channels is altered in L4 DRG neurons which, in the mSNA model, are essential for transmission of the evoked pain, and which contribute to chronic spontaneous pain, and (b) local (intraplantar) blockade of these HCN channels, with a specific blocker, ZD7288, attenuates chronic spontaneous pain and/or evoked pain in mSNA rats. We found 7days after mSNA: (1) a significant increase in HCN2 immunoreactivity in small (<30MUm) DRG neurons (predominantly IB4-negative neurons), and in the proportion of small neurons expressing HCN2 (putative nociceptors); (2) no significant change in HCN1- or HCN3-immunoreactivity in all cell types; and (3) attenuation, with ZD7288 (100MUM intraplantar), of chronic spontaneous pain behavior (spontaneous foot lifting) and mechanical, but not, heat hypersensitivity. The results suggest that peripheral HCN channels contribute to mechanisms of spinal nerve injury-induced PNP, and that HCN channels, possibly HCN2, represent a novel target for PNP treatment. PMID- 25813713 TI - Effects of ampicillin, cefazolin and cefoperazone treatments on GLT-1 expressions in the mesocorticolimbic system and ethanol intake in alcohol-preferring rats. AB - Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate concentrations in subregions of the mesocorticolimbic reward pathway. While beta lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, adult male alcohol-preferring (P) rats exposed chronically to ethanol were treated with other beta-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to the saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these beta-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple beta-lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1. PMID- 25813715 TI - X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors. AB - 1-N-Alkylated-6-sulfamoyl saccharin derivatives were prepared and assayed as carbonic anhydrase inhibitors (CAIs). During X-ray crystallographic experiments an unexpected hydrolysis of the isothiazole ring was evidenced which allowed us to prepare highly potent enzyme inhibitors with selectivity for some isoforms with medical applications. PMID- 25813714 TI - Prelude to oral microbes and chronic diseases: past, present and future. AB - Associations between oral and systemic health are ancient. Oral opportunistic bacteria, particularly, Porphyromonas gingivalis and Fusobacterium nucleatum, have recently been deviated from their traditional roles as periodontal pathogens and arguably ascended to central players based on their participations in complex co-dependent mechanisms of diverse systemic chronic diseases risk and pathogenesis, including cancers, rheumatoid-arthritis, and diabetes. PMID- 25813716 TI - Oil spill experiment using airborne DLR ESAR off the coast of Diu, India. AB - Oil spill experiment results in the coastal waters of Diu, India, with an airborne DLR ESAR sensor are discussed with reference to the SAR frequency, polarization and viewing angle. The SAR data acquired in the quad polarization of the L band and dual polarization of the C band over two spills are studied. A higher oil and water contrast is observed in the L-VV polarization than in the C HH mode. Oil spill discrimination is possible over a wider view angle of the airborne SAR sensor data in L band than in C band. This study has also analyzed the spread and drift of oil in coastal waters. PMID- 25813717 TI - Assessment of oil slick hazard and risk at vulnerable coastal sites. AB - This work gives an assessment of the hazard faced by Sicily coasts regarding potential offshore surface oil spill events and provides a risk assessment for Sites of Community Importance (SCI) and Special Protection Areas (SPA). A lagrangian module, coupled with a high resolution finite element three dimensional hydrodynamic model, was used to track the ensemble of a large number of surface trajectories followed by particles released over 6 selected areas located inside the Sicily Channel. The analysis was carried out under multiple scenarios of meteorological conditions. Oil evaporation, oil weathering, and shore stranding are also considered. Seasonal hazard maps for different stranding times and seasonal risk maps were then produced for the whole Sicilian coastline. The results highlight that depending on the meteo-marine conditions, particles can reach different areas of the Sicily coast, including its northern side, and illustrate how impacts can be greatly reduced through prompt implementation of mitigation strategies. PMID- 25813718 TI - Spatial and temporal analysis of the risks posed by polycyclic aromatic hydrocarbon, polychlorinated biphenyl and metal contaminants in sediments in UK estuaries and coastal waters. AB - The environmental risks of 22 contaminants, comprising 6 metals, 10 PAHs and 6 PCB congeners occurring in UK estuaries and coastal waters were assessed as single substances. Sediment samples were taken within 12 nautical miles of the English and Welsh coastlines between 1999 and 2011. The measured environmental concentrations were compared to quality standards including ERL, ERM and EAC, all of which have been established internationally. Out of a total of 38,031 individual samples analysed, 42.6% and 7.7% exceeded the ERL/EAC and ERM values, respectively. The highest Risk Characterisation Ratios (RCRs) for metals, PAHs and PCBs were observed for copper, fluorene and CB118 (2,3',4,4',5 pentachlorobiphenyl). In general, the highest concentrations of PAHs and PCBs were observed in 2011 in the Lower Medway indicating a potential risk to the aquatic environment. This study suggests that re-suspension of contaminants banned over 20years ago is still an ongoing issue. PMID- 25813719 TI - The use of the Renfrew Bus Story with 5-8-year-old Australian children. AB - PURPOSE: Research into the language sampling practices of Australian speech pathologists suggests the Bus Story Test is a frequently used standardized tool for eliciting story retelling samples for screening, diagnosis, goal-setting, and progress monitoring purposes. Because this task has not been normed on an Australian population, this study investigated the usefulness of the Bus Story for young school-age Australian children. METHOD: In total, 125 Australian primary-school children (aged 5;3-8;9) participated in the Bus Story task. Children attending Year 2 also retold the story Frog Where Are You. Children's performance was analysed for measures of information and sentence length (Bus Story only), story length, MLU, number of different words and clausal density. RESULT: Performance on the Bus Story improved with year-of-schooling for all measures. Between 21-64% of the children performed below expectations on information or length scores when using the published norms. The retell task Frog Where Are You elicited longer samples, containing a higher number of different words. CONCLUSION: Using the published Bus Story norms will potentially result in over- identification of language impairment. The retell task Frog Where Are You may provide a useful alternative for assessing young school-aged children's story retelling ability. PMID- 25813720 TI - Continuous cytogenetic follow-up, over 5 years, of three individuals accidentally irradiated by a cobalt-60 source. AB - A cobalt-60 irradiation accident occurred in Shanxi, China, on April 11, 2008. Five people were exposed to total-body irradiation ranging from 1.7 to 14.5 Gy. Two victims died post-irradiation, due to acute intestinal radiation sickness (at 62 days) and tuberculosis (at 1.5 year). The other three victims received medical follow-ups and were monitored for 5 years with multiple cytogenetic analyses. Unstable chromosome aberrations, including dicentric and centric rings (dic+r) and the micronucleus frequency in binucleated lymphocytes, were monitored. In addition, G-banding karyotype and fluorescence in situ hybridization (FISH) methods were used to analyze translocations, for exploring chromosome stability and for retrospective dosimetry. The results show that unstable chromosome aberrations (dic+r) declined each year, dropping to about 20-40% of initial levels by the 5th year. A similar trend was observed for the micronucleus frequency. Our results show that the translocation frequencies of the three victims, detected by G-banding karyotype, remained stable for the 5 years. Five years after irradiation, the translocation rates of the three victims (G-banding and FISH analyses) were similar. The retrospective estimated doses, reconstructed based on the translocation frequencies, were consistent with the biological doses estimated at the first day post-irradiation using dic+r. The results of this study indicate that chromosome translocation frequencies can be used as a biological dosimeter and are an excellent index for dose reconstruction. PMID- 25813721 TI - DSB repair model for mammalian cells in early S and G1 phases of the cell cycle: application to damage induced by ionizing radiation of different quality. AB - The purpose of this work is to test the hypothesis that kinetics of double strand breaks (DSB) repair is governed by complexity of DSB. To test the hypothesis we used our recent published mechanistic mathematical model of DSB repair for DSB induced by selected protons, deuterons, and helium ions of different energies representing radiations of different qualities. In light of recent advances in experimental and computational techniques, the most appropriate method to study cellular responses in radiation therapy, and exposures to low doses of ionizing radiations is using mechanistic approaches. To this end, we proposed a 'bottom up' approach to study cellular response that starts with the DNA damage. Monte Carlo track structure method was employed to simulate initial damage induced in the genomic DNA by direct and indirect effects. Among the different types of DNA damage, DSB are known to be induced in simple and complex forms. The DSB repair model in G1 and early S phases of the cell cycle was employed to calculate the repair kinetics. The model considers the repair of simple and complex DSB, and the DSB produced in the heterochromatin. The inverse sampling method was used to calculate the repair kinetics for each individual DSB. The overall repair kinetics for 500 DSB induced by single tracks of the radiation under test were compared with experimental results. The results show that the model is capable of predicting the repair kinetics for the DSB induced by radiations of different qualities within an accepted range of uncertainty. PMID- 25813722 TI - Genotoxicity of tungsten carbide-cobalt (WC-Co) nanoparticles in vitro: mechanisms-of-action studies. AB - We showed previously that tungsten carbide-cobalt (WC-Co) nanoparticles (NP) can be used as a nanoparticulate positive control in some in vitro mammalian genotoxicity assays. Here, we investigate the mechanisms of action involved in WC Co NP genotoxicity in L5178Y mouse lymphoma cells and primary human lymphocytes, in vitro. Data from the micronucleus assay coupled with centromere staining and from the chromosome-aberration assay show the involvement of both clastogenic and aneugenic events. Experiments with the formamidopyrimidine DNA glycosylase (FPG) modified comet assay showed a slight (non-significant) increase in FPG-sensitive sites in the L5178Y mouse lymphoma cells but not in the human lymphocytes. Electron paramagnetic resonance spin-trapping results showed the presence of hydroxyl radicals (*OH) in WC-Co NP suspensions, with or without cells, but with time-dependent production in the presence of cells. However, a significant difference in *OH production was observed between human lymphocytes from two different donors. Using H2O2, we showed that WC-Co NP can participate in Fenton like reactions. Thus, *OH might be produced either via intrinsic generation by WC Co NP or through a Fenton-like reaction in the presence of cells. PMID- 25813723 TI - Capsaicin-induced genotoxic stress does not promote apoptosis in A549 human lung and DU145 prostate cancer cells. AB - Capsaicin is the major pungent component of the hot chili peppers of the genus Capsicum, which are consumed worldwide as a food additive. More recently, the selective action of capsaicin against cancer cells has been reported. Capsaicin was found to induce apoptosis and inhibit proliferation of a wide range of cancer cells in vitro, whereas being inactive against normal cells. As data on capsaicin induced genotoxicity are limited and the effects of capsaicin against human lung A549 and DU145 prostate cancer cells were not explored in detail, we were interested in determining whether capsaicin-associated genotoxicity may also provoke A549 and DU145 cell death. Capsaicin-induced decrease in metabolic activity and cell proliferation, and changes in the cell cycle were limited to high concentrations used (>= 100 MUM), whereas, at lower concentrations, capsaicin stimulated both DNA double strand breaks and micronuclei production. Capsaicin was unable to provoke apoptotic cell death when used up to 250 MUM concentrations. Capsaicin induced oxidative stress, but was ineffective in provoking the dissipation of the mitochondrial inner transmembrane potential. A different magnitude of p53 binding protein 1 (53BP1) recruitment contributed to diverse capsaicin-induced genotoxic effects in DU145 and A549 cells. Capsaicin was also found to be a DNA hypermethylating agent in A549 cells. In summary, we have shown that genotoxic effects of capsaicin may contribute to limited susceptibility of DU145 and A549 cancer cells to apoptosis in vitro, which may question the usefulness of capsaicin-based anticancer therapy, at least in a case of lung and prostate cancer. PMID- 25813724 TI - The Syrian hamster embryo cells transformation assay identifies efficiently nongenotoxic carcinogens, and can contribute to alternative, integrated testing strategies. AB - The long-term carcinogenesis bioassays have played a central role in protecting human health, but for ethical and practical reasons their use is dramatically diminishing and the genotoxicity short-term tests have taken the pivotal role in the pre-screening of chemical carcinogenicity. However, this strategy cannot detect nongenotoxic carcinogens. Since up to 25% of IARC human carcinogens are recognized to have nongenotoxic mechanisms of action, the risk they pose to human health cannot be disregarded, and it is urgent to fill the gap in the tools for alternative testing. In this paper, we analyze from different perspectives the ability of Cell Transformation Assays to identify nongenotoxic carcinogens, and we conclude that the Syrian hamster embryo cells test is able to identify nongenotoxic carcinogens with 80-90% efficiency, and thus, can play an important role in integrated, alternative testing strategies. PMID- 25813725 TI - Gene expression and epigenetic profiles of mammary gland tissue: insight into the differential predisposition of four rat strains to mammary gland cancer. AB - Rats are excellent experimental models for studying breast cancer, but rat strains differ in susceptibility. Among the four strains used in this study, Fischer rats are less susceptible to spontaneous breast cancer, yet they are highly prone to extremely severe metastatic and drug-resistant tumors, in those case where they actually develop the disease. In contrast, Sprague Dawley rats are the most susceptible to spontaneous breast cancer among the strains. ACI rats are highly prone to estrogen-induced cancer. Long-Evans rats are commonly used in mammary gland carcinogenesis studies. The molecular mechanisms of differential breast cancer susceptibility among rat strains are not well understood. Here, gene expression analysis was conducted in the mammary gland tissue of four rat strains--August * Copenhagen Irish (ACI), Long Evans, Fischer-344 and Sprague Dawley--to evaluate possible explanations for the differing breast cancer predispositions. According to the DAVID functional annotation analysis, there were at least eleven, five, and one significantly different pathways, respectively, in Fischer-344, Long-Evans and Sprague Dawley rats, in comparison to ACI rats. Two strains, Fischer-344 and Long-Evans, displayed differential expression in the complement and coagulation cascades, chemokine signaling, PPAR signaling, renin-angiotensin system, ECM-receptor interaction, focal adhesion and glutathione metabolism pathways. The only pathway that was significantly different between the Sprague Dawley and the ACI rats was the ribosome pathway. Our data indicate that general cancer susceptibility and predisposition to the development of aggressive and metastatic cancer are independent genetic conditions. Moreover, we have identified several important differences in the basal epigenetic profile of four rat strains with varying degrees of susceptibility to spontaneous and induced mammary carcinogenesis. PMID- 25813726 TI - Gene promoter methylation and DNA repair capacity in monozygotic twins with discordant smoking habits. AB - The influence of DNA repair capacity, plasma nutrients and tobacco smoke exposure on DNA methylation was investigated in blood cells of twenty-one couples of monozygotic twins with discordant smoking habits. All study subjects had previously been characterized for mutagen sensitivity with challenge assays with ionizing radiation in peripheral blood lymphocytes. Plasma levels of folic acid, vitamin B12 and homocysteine were also available from a previous investigation. In this work DNA methylation in the promoter region of a panel of ten genes involved in cell cycle control, differentiation, apoptosis and DNA repair (p16, FHIT, RAR, CDH1, DAPK1, hTERT, RASSF1A, MGMT, BRCA1 and PALB2) was assessed in the same batches of cells isolated for previous studies, using the methylation sensitive high-resolution melting technique. Fairly similar profiles of gene promoter methylation were observed within co-twins compared to unrelated subjects (p= 1.23 * 10(-7)), with no significant difference related to smoking habits (p = 0.23). In a regression analysis the methylation index of study subjects, used as synthetic descriptor of overall promoter methylation, displayed a significant inverse correlation with radiation-induced micronuclei (p = 0.021) and plasma folic acid level (p = 0.007) both in smokers and in non-smokers. The observed association between repair of radiation-induced DNA damage and promoter methylation suggests the involvement of the DNA repair machinery in DNA modification. Data also highlight the possible modulating effect of folate deficiency on DNA methylation and the strong influence of familiarity on the individual epigenetic profile. PMID- 25813727 TI - 'It's time she stopped torturing herself': structural constraints to decision making about life-sustaining treatment by medical trainees. AB - This article explores how structural factors associated with the profession and organization of medicine can constrain internal medicine residents, leading them to sometimes limit or terminate treatment in end-of-life care in ways that do not always embrace patient autonomy. Specifically, it examines the opportunities and motivations that explain why residents sometimes arrogate decision-making for themselves about life-sustaining treatment. Using ethnographic data drawn from over two years at an American community hospital, I contend that unlike previous studies which aggregate junior and senior physicians' perspectives, medical trainees face unique constraints that can lead them to intentionally or unintentionally overlook patient preferences. This is especially salient in cases where they misunderstand their patients' wishes, disagree about what is in their best interest, and/or lack the standing to pursue alternative ethical approaches to resolving these tensions. The study concludes with recommendations that take into account the structural underpinnings of arrogance in decision-making about life-sustaining treatment. PMID- 25813728 TI - Genetically at-risk status and individual agency. A qualitative study on asymptomatic women living with genetic risk of breast/ovarian cancer. AB - For the last 20 years, genetic tests have allowed unaffected women to determine whether they are predisposed to developing breast/ovarian cancer due to BRCA1/2 gene mutations. In the event of adverse results, women receive a specific label associated with a set of medical recommendations: the genetically at-risk status. This qualitative study adopted a life-course perspective to understand the impact of this status on women's agency. Following a grounded theory design, retrospective biographical interviews were conducted in Switzerland between 2011 and 2013 with 32 unaffected women at risk of developing genetic breast/ovarian cancer and aware of their predisposition for at least three years. The results show that the genetically at-risk status conveys an invitation to transform health into a project, i.e., into a set of planned activities realized in collaboration with the medical system in order to reduce the risk of developing cancer. This health project shapes women's agency in three ways: it enhances, constrains and questions it, thus creating a sense of disorientation about what is considered rational and appropriate in terms of genetic risk management. Based on these findings, the paper concludes by stressing the paradoxes of the genetically at-risk status and the limits of the medical system in managing women designated with it. The paper also suggests that because of the disorientation intrinsic to their situation, genetically at-risk women have to reflexively construct their own health project from a range of available options in ways that are coherent and viable for themselves and their significant others. This process of reflexive construction may be called legitimation. PMID- 25813729 TI - A blessing I can't afford: factors underlying the paradox of happiness about unintended pregnancy. AB - An unresolved paradox in the measurement and interpretation of unintended pregnancy is that women frequently report feeling happy about pregnancies they also classify as unintended (i.e. they have incongruent intentions and feelings). This study explores the underlying reasons why women profess such happiness and how these relate to their motivations to avoid pregnancy. Between September 2013 and February 2014, semi-structured in-depth interviews were conducted with 27 women (8 white, 19 Latina) selected from a longitudinal study measuring prospective pregnancy intentions and feelings among 403 women in Austin, Texas. Women were selected for interview on the basis of wanting no more children and consistently professing either happiness (n = 17) or unhappiness (n = 10) at the prospect of pregnancy. Interviews were coded and analyzed following the principles of grounded theory. We found that it is possible for women to express happiness at the idea of pregnancy while simultaneously earnestly trying to prevent conception. Happiness at the idea of an unintended pregnancy was explained as the result of deep and heartfelt feelings about children taking precedence over practical considerations, the perception that the psychosocial stress resulting from another child would be low, and the ability to rationalize an unintended pregnancy as the result of fate or God's plan. The major exception to the sincerity of professed happiness was that conveyed as a result of social pressure despite truly negative feelings, predominantly expressed by foreign-born Latina women. Overall, equating incongruence with ambivalence about avoiding conception may undermine the sincerity of women's intentions and their desires for highly-effective contraception. At the same time, unintended pregnancies that are greeted with happiness may have different implications for maternal and child health outcomes compared to pregnancies that are greeted with unhappiness. Identifying which unintended pregnancies are most likely to result in adverse outcomes is a target for future research. PMID- 25813730 TI - Cream skimming and hospital transfers in a mixed public-private system. AB - The increasing prominence of the private sector in health care provision has generated considerable interest in understanding its implications on quality and cost. This paper investigates the phenomenon of cream skimming in a mixed public private hospital setting using the novel approach of analysing hospital transfers. We analyse hospital administrative data of patients with ischemic heart disease from the state of Victoria, Australia. The data set contains approximately 1.77 million admission episodes in 309 hospitals, of which 132 are public hospitals, and 177 private hospitals. We ask if patients transferred between public and private hospitals differ systematically in the severity and complexity of their medical conditions; and if so, whether utilisation also differs. We find that patients with higher disease severity are more likely to be transferred from private to public hospitals whereas the opposite is true for patients transferred to private hospitals. We also find that patients transferred from private to public hospitals stayed longer and cost more than private-to private transfer patients, after controlling for patients' observed health conditions and personal characteristics. Overall, the evidence is suggestive of the presence of cream skimming in the Victorian hospital system, although we cannot conclusively rule out other mechanisms that might influence hospital transfers. PMID- 25813731 TI - Colonic injury after gunshot wound to the scrotum with accompanying inguinal hernia. PMID- 25813732 TI - Surgical treatment for mono-segmental lumbar tuberculosis by single-stage posterior debridement, compact bone grafting and posterior single-segment fixation. AB - PURPOSE: To evaluate the efficacy and safety of single-stage posterior debridement, compact bone grafting and posterior single-segment fixation for the treatment of mono-segmental lumbar tuberculosis. METHODS: We enrolled 32 patients with mono-segmental lumbar tuberculosis from January 2005 to April 2011. The severity of damage to the vertebral bodies is not more than 2/3 height. All the patients were treated by single-stage posterior debridement, compact bone grafting and posterior single-segment fixation. RESULTS: Patients were followed 21-63 months (43.5+/-9.5 months). The average Cobb angle decreased to 5.3+/-3.0 degrees postoperatively from 22.1+/-6.1 degrees preoperatively. Meanwhile, average 1.8+/-1.0 degrees loss was observed at last visit. Fusion occurred at 3 9 months (mean 5.1 months). All patients with preoperative neurologic deficit recovered in different degree. 1 with grade B recovered to grade D; 2 with grade C recovered to grade E; 18 with grade D recovered to grade E. No mortality occurred. One patient experienced anti-tuberculosis drug-induced liver dysfunction which was managed successfully with modified anti-TB treatment and hepato-protective treatment. The Oswestry Disability Index decreased from 40.1+/ 4.0 preoperatively to 13.7+/-3.1 postoperatively. CONCLUSIONS: Single-stage posterior debridement, compact bone grafting and posterior single-segment fixation is an effective method for the treatment of mono-segmental lumbar tuberculosis. PMID- 25813733 TI - VATS versus intrapleural streptokinase: A prospective, randomized, controlled clinical trial for optimum treatment of post-traumatic Residual Hemothorax. AB - BACKGROUND: Post-traumatic residual haemothorax (RH) is common and carries significant morbidity. However, its optimal treatment is not clear. AIM: The aim of this study was to find the extent of this problem and the choice of treatment between VATS and intra-pleural streptokinase instillation (IPSI). MATERIAL AND METHODS: This RCT, conducted over 18 months period, included all patients of chest trauma between 18 and 70 years of age, admitted with haemothorax or haemopneumothorax requiring inter-costal drain (ICD) insertion. 154 events of haemothorax/haemopneumothorax requiring ICD insertion were enrolled. RH was seen in 48 (31%) patients: 13 patients were excluded from RCT after refusal for treatment. Seventeen (49%) patients of remaining 35 RH cases were randomized to IPSI group and 18 (51%) patients were randomized to VATS group. The outcome parameters were resolution of RH and treatment related complications. RESULTS: RH resolved equally well in VATS and IPSI group [13 patients (72%) versus 12 patients (71%), respectively; continuity-adjusted p=1]. Morbidity wise no difference (p-value 0.529) was seen in the two groups. CONCLUSION: Post-traumatic RH is seen in 1/3rd patients and is equally well treated by VATS and IPSI. PMID- 25813734 TI - Risk factor profiles for early and delayed mortality after hip fracture: Analyses of linked Australian Department of Veterans' Affairs databases. AB - INTRODUCTION: One-year mortality after hip fracture may exceed 30% with a very large number of reported risk factors. Determinants of mortality beyond 1 year are rarely described. This study employs multiple data linkages to examine mortality rates, risk factor profiles and age-specific excess mortality at intervals from 30 days to 4 years. METHODS: Retrospective cohort study of linked administrative datasets describing hospital episodes, residential aged care (RAC) admissions and date of death for 2552 Australian veterans and war widows hospitalised for hip fracture in 2008-09. Associations between time to death and patient age, sex, pre-fracture accommodation, fracture type, treatment options, selected comorbidities and complications were tested in Cox proportional hazards models. RESULTS: In a population with mean age of 86.6 years (range 54-100 years), overall death rate was 11% at 30 days, 34% at 1 year, 47% at 2 years and 67% after 4 years. For males hospitalised from RAC 1-year mortality was 72%, contrasting with 19% for females from the community. Risk of death within 1 year was increased by male sex, increasing age, pre-fracture RAC residency, transfer to intensive care and coexistent cancer, cardiac and renal failure, cerebrovascular disease and pressure ulcers. Patients selected for rehabilitation had lower mortality rates. Patterns of determinants for mortality changed over time. Above-expected age-specific mortality was sustained for 4 years except for males 90 years and older. CONCLUSION: Pre-fracture RAC residence was the strongest determinant factor for mortality. Patients selected for rehabilitation had lower mortality rates. The profiles of explanatory variables for death altered with increasing time from the index fracture event. PMID- 25813735 TI - Comparison of isorhamnetin absorption properties in total flavones of Hippophae rhamnoides L. with its pure form in a Caco-2 cell model mediated by multidrug resistance-associated protein. AB - Total flavones of Hippophae rhamnoides L. (TFH) are extracted from the widely distributed thorny bush Sea buckthorn (Hippophae rhamnoides L.). Isorhamnetin (IS) is one of the representative ingredients in TFH. In this study, the absorption properties of IS in TFH and its pure form were compared through transepithelial transport and cellular uptake experiments in a Caco-2 cell model. Our results show that the absorption properties of IS in TFH and its pure form were remarkably different: (1) Both PappAB and PappBA of IS in TFH were dramatically increased compared with those of IS pure form; consequently, its Pratio was 2.3-fold higher than that of IS; (2) Both the accumulation and efflux of IS in TFH were significantly enhanced compared with the single compound. One likely reason for these differences is that the multiple components in TFH significantly down regulated the mRNA expression level of MRP2, which lead to a decrease in the protein level of MRP2, based on western blotting and RT-PCR assays. This study highlights the significant differences in the absorption properties of flavonoid components in different forms and the potential multi component interactions in TFH. PMID- 25813736 TI - Octuplicate this interval! Axiomatic examination of the ratio properties of duration perception. AB - The relationship between the physical intensity of a stimulus and its perceived magnitude can be described by Stevens' power law (Stevens, American Journal of Psychology, 69(1), 1-15, 1956), i.e., a power function with an exponent depending on the sensory modality studied. Direct scaling methods used to determine the power function exponent are based on the assumption that subjects are capable of processing ratios of magnitudes. The present experiments investigate whether this assumption holds for duration perception by empirically testing (Narens, Journal of Mathematical Psychology, 40(2), 109-129, 1996) fundamental axioms of monotonicity, commutativity, and multiplicativity. To determine whether the exponent can be interpreted in a meaningful way, i.e., whether it is invariant under changes of the reference stimulus, two further axioms, invertibility and weak multiplicativity (Augustin, Acta Psychologica, 128(1), 176-185, 2008) are evaluated. N=25 participants were required to adjust the duration of a comparison tone to specific ratios of different standard durations in two experiments. In accordance with previous findings for other sensory continua, monotonicity held for the duration adjustments of most participants. Significant violations of the commutativity axiom were found in 12.5% of all pertinent tests, whereas multiplicativity was violated in 32% of such tests. The axioms of weak multiplicativity and invertibility, however, were violated in over 50% of the tests. These results indicate that even though a ratio scale for perceived duration exists, the numbers as used by the participants cannot always be taken at face value and that even though power functions fit the data quite well, the exponent depends on the size of the standard and therefore cannot always be interpreted in a meaningful way. PMID- 25813737 TI - Irrelevant reward and selection histories have different influences on task relevant attentional selection. AB - Task-relevant and physically salient features influence visual selective attention. In the present study, we investigated the influence of task-irrelevant and physically nonsalient reward-associated features on visual selective attention. Two hypotheses were tested: One predicts that the effects of target defining task-relevant and task-irrelevant features interact to modulate visual selection; the other predicts that visual selection is determined by the independent combination of relevant and irrelevant feature effects. These alternatives were tested using a visual search task that contained multiple targets, placing a high demand on the need for selectivity, and that was data limited and required unspeeded responses, emphasizing early perceptual selection processes. One week prior to the visual search task, participants completed a training task in which they learned to associate particular colors with a specific reward value. In the search task, the reward-associated colors were presented surrounding targets and distractors, but were neither physically salient nor task-relevant. In two experiments, the irrelevant reward-associated features influenced performance, but only when they were presented in a task relevant location. The costs induced by the irrelevant reward-associated features were greater when they oriented attention to a target than to a distractor. In a third experiment, we examined the effects of selection history in the absence of reward history and found that the interaction between task relevance and selection history differed, relative to when the features had previously been associated with reward. The results indicate that under conditions that demand highly efficient perceptual selection, physically nonsalient task-irrelevant and task-relevant factors interact to influence visual selective attention. PMID- 25813738 TI - Low cognitive load strengthens distractor interference while high load attenuates when cognitive load and distractor possess similar visual characteristics. AB - Studies on visual cognitive load have reported inconsistent effects of distractor interference when distractors have visual characteristic that are similar to the cognitive load. Some studies have shown that the cognitive load enhances distractor interference, while others reported an attenuating effect. We attribute these inconsistencies to the amount of cognitive load that a person is required to maintain. Lower amounts of cognitive load increase distractor interference by orienting attention toward visually similar distractors. Higher amounts of cognitive load attenuate distractor interference by depleting attentional resources needed to process distractors. In the present study, cognitive load consisted of faces (Experiments 1-3) or scenes (Experiment 2). Participants performed a selective attention task in which they ignored face distractors while judging a color of a target dot presented nearby, under differing amounts of load. Across these experiments distractor interference was greater in the low-load condition and smaller in the high-load condition when the content of the cognitive load had similar visual characteristic to the distractors. We also found that when a series of judgments needed to be made, the effect was apparent for the first trial but not for the second. We further tested an involvement of working memory capacity (WMC) in the load effect (Experiment 3). Interestingly, both high and low WMC groups received an equivalent effect of the cognitive load in the first distractor, suggesting these effects are fairly automatic. PMID- 25813739 TI - Converging evidence that common timing processes underlie temporal-order and simultaneity judgments: a model-based analysis. AB - Perception of simultaneity and temporal order is studied with simultaneity judgment (SJ) and temporal-order judgment (TOJ) tasks. In the former, observers report whether presentation of two stimuli was subjectively simultaneous; in the latter, they report which stimulus was subjectively presented first. SJ and TOJ tasks typically give discrepant results, which has prompted the view that performance is mediated by different processes in each task. We looked at these discrepancies from a model that yields psychometric functions whose parameters characterize the timing, decisional, and response processes involved in SJ and TOJ tasks. We analyzed 12 data sets from published studies in which both tasks had been used in within-subjects designs, all of which had reported differences in performance across tasks. Fitting the model jointly to data from both tasks, we tested the hypothesis that common timing processes sustain simultaneity and temporal-order judgments, with differences in performance arising from task dependent decisional and response processes. The results supported this hypothesis, also showing that model psychometric functions account for aspects of SJ and TOJ data that classical analyses overlook. Implications for research on perception of simultaneity and temporal order are discussed. PMID- 25813740 TI - Individual differences in highly skilled visual perceptual-motor striking skill. AB - Expertise studies into visual perceptual-motor skills have mainly focused their investigation upon group comparisons rather than individual comparisons. This study investigated the pick-up of visual information to time weight transfer and bat kinematics within an exemplar group of striking sport experts using an in situ temporal occlusion paradigm. Highly skilled cricket batsmen faced bowlers and attempted to strike delivered balls, whilst their vision was either temporally occluded through occlusion glasses prior to ball bounce or not occluded (control condition). A chronometric analysis was conducted on trials in the occlusion condition to quantify the pick-up of visual information to time biomechanical variables. Results indicated that initiation of weight transfer and bat downswing, as well as bat downswing completion, was significantly different between some individual batsmen. No significant difference was found between individual batsmen for time of weight transfer completion. Unexpectedly, it was found that achievement of the goal to strike delivered balls, that is, the frequency of bat-ball contacts was not significantly different between batsmen. Collectively, the findings indicate that individual differences exist in the coordination pattern of a complex whole body visual perceptual-motor skill, but these different patterns are used to achieve a similar outcome, which is known as motor equivalence. PMID- 25813741 TI - Effects of bowing on perception of attractiveness. AB - Bowing is a greeting behavior. The present study examined the modulation effect of bowing on perception of attractiveness. In each trial, a portrait digitized from university yearbooks was presented on a computer screen. The portrait was mildly tilted toward participants to simulate a greeting bow (25-degree angle). Participants evaluated the subjective attractiveness of the face using a visual analog scale (0-100). The mean attractiveness judgment of the bowing portrait was significantly higher relative to that of the bending-backward or standing-still control conditions (Experiment 1). Additional control experiments revealed that alternative accounts relying on apparent spatial proximity and physical characteristics could not solely explain the effect of bowing (Experiment 2) and indicated that the effect was specific to objects perceived as faces (Experiment 3). Furthermore, observers' in-return bowing behavior did not reduce the bowing effect (Experiment 4), and bowing motion increased the ratings of subjective politeness and submissiveness (Experiment 5). Finally, tilting the 3D faces elicited the same effect from observers as did tilting the still photos (Experiment 6). These results suggest that a tilting motion of portraits (or images of face-like objects) mimicking bowing enhances perceived attractiveness, at least as measured in a culture familiar with greeting by bowing. PMID- 25813742 TI - Temporal cues derived from statistical patterns can overcome resource limitations in the attentional blink. AB - Previous studies have shown that humans are sensitive to statistical patterns indicating the likely locations, identities, and timings of visual targets. Here we tested whether participants can also use this kind of information to ameliorate the attentional blink (AB)-a reduction in accuracy for the second of two targets (T1, T2) presented at brief intertarget intervals (lags). In particular, we asked whether participants can use patterns arising from differential distributions of intertarget lags across trials to predict the arrival of T2. We tested this by comparing the ABs in an aging versus a nonaging distribution of trials, where aging refers to the increased likelihood of T2, given that it has not yet occurred, when lags occur with equal frequencies. Experiments 1 and 2 showed that the aging condition yielded greater T2 accuracy at longer lags than did the nonaging condition. In Experiment 3, we used a more sensitive response time measure to show faster T2 discrimination at shorter lags in the nonaging condition. These results demonstrate that participants can predict the likely onset of T2 by using statistical patterns present in the AB task, and that they can use this ability to more effectively direct limited processing resources. PMID- 25813743 TI - Erratum to: The hands shield attention from visual interference. PMID- 25813745 TI - Part III: Principal component analysis: bridging the gap between strain, sex and drug effects. AB - Previous work has identified the adolescent period as particularly sensitive to the short- and long-term effects of marijuana and its main psychoactive component Delta9-tetrahydrocannabinol (THC). However, other studies have identified certain backgrounds as more sensitive than others, including the sex of the individual or the strain of the rat used. Further, the effects of THC may be specific to certain behavioural tasks (e.g. measures of anxiety), and the consequences of THC are not seen equally across all behavioural measures. Here, data obtained from adolescent male and female Long-Evans and Wistar rats exposed to THC and tested as adults, which, using standard ANOVA testing, showed strain- and sex-specific effects of THC, was analyzed using principal component analysis (PCA). PCA allowed for the examination of the relative contribution of our variables of interest to the variance in the data obtained from multiple behavioural tasks, including the skilled reaching task, the Morris water task, the discriminative fear-conditioning to context task, the elevated plus maze task and the conditioned place preference task to a low dose of amphetamine, as well as volumetric estimates of brain volumes and cfos activation. We observed that early life experience accounted for a large proportion of variance across data sets, although its relative contribution varied across tasks. Additionally, THC accounted for a very small proportion of the variance across all behavioural tasks. We demonstrate here that by using PCA, we were able to describe the main variables of interest and demonstrate that THC exposure had a negligible effect on the variance in the data set. PMID- 25813746 TI - Cognitive bias, hand preference and welfare of common marmosets. AB - Common marmosets (Callithrix jacchus) have hand preferences for grasping pieces of food and holding them while eating and these are stable throughout adult life. We report here that left-handed marmosets have negative cognitive bias compared to right-handed marmosets. Twelve marmosets were trained to expect a food reward from a bowl with a black lid and not from one with a white lid, or vice versa. In probe tests with ambiguous, grey-lidded bowls a left-handed group (N=7) were less likely to remove the lid to inspect the bowl than a right-handed group (N=5). This difference between left- and right-handed marmosets was not dependent on rate of learning, sex or age. In fact, hand-preference was not associated with rate of learning the task. Furthermore, retrospective examination of colony records of 39 marmosets revealed that more aggression was directed towards left- than right-handed marmosets. Hence, hand preference, which can be measured easily, could serve as an indicator of cognitive bias and may signal a need for particular care in laboratory environments. We explain the results by arguing that hand preference reflects more frequent (or dominant) use of the opposite hemisphere and this predisposes individuals to behave differently. PMID- 25813747 TI - Memory formation and retention are affected in adult miR-132/212 knockout mice. AB - The miR-132/212 family is thought to play an important role in neural function and plasticity, while its misregulation has been observed in various neurodegenerative disorders. In this study, we analyzed 6-month-old miR-132/212 knockout mice in a battery of cognitive and non-cognitive behavioral tests. No significant changes were observed in reflexes and basic sensorimotor functions as determined by the SHIRPA primary screen. Accordingly, miR-132/212 knockout mice did not differ from wild-type controls in general locomotor activity in an open field test. Furthermore, no significant changes of anxiety were measured in an elevated plus maze task. However, the mutant mice showed retention phase defects in a novel object recognition test and in the T-water maze. Moreover, the learning and probe phases in the Barnes maze were clearly altered in knockout mice when compared to controls. Finally, changes in BDNF, CREB, and MeCP2 were identified in the miR-132/212-deficient mice, providing a potential mechanism for promoting memory loss. Taken together, these results further strengthen the role of miR-132/212 in memory formation and retention, and shed light on the potential consequences of its deregulation in neurodegenerative diseases. PMID- 25813748 TI - Experience affects immediate early gene expression in response to conspecific call notes in black-capped chickadees (Poecile atricapillus). AB - Black-capped chickadees (Poecile atricapillus) produce numerous vocalizations, including the acoustically complex chick-a-dee call that is composed of A, B, C, and D notes. D notes are longer in duration and lower in frequency than the other note types and contain information regarding flock and species identification. Adult wild-caught black-capped chickadees have been shown to have similar amounts of immediate early gene (IEG) expression following playback of vocalizations with harmonic-like acoustic structure, similar to D notes. Here we examined how different environmental experiences affect IEG response to conspecific D notes. We hand-reared black-capped chickadees under three conditions: (1) with adult conspecifics, (2) with adult heterospecific mountain chickadees, and (3) without adults. We presented all hand-reared birds and a control group of field-reared black-capped chickadees, with conspecific D notes and quantified IEG expression in the caudomedial mesopallium (CMM) and caudomedial nidopallium (NCM). We found that field-reared birds that heard normal D notes had a similar neural response as a group of field-reared birds that heard playback of reversed D notes. Field reared birds that heard normal D notes also had a similar neural response as birds reared with adult conspecifics. Birds reared without adults had a significantly reduced IEG response, whereas the IEG expression in birds reared with heterospecifics was at intermediate levels between birds reared with conspecifics and birds reared without adults. Although acoustic characteristics have been shown to drive IEG expression, our results demonstrate that experience with adults or normal adult vocalizations is also an important factor. PMID- 25813749 TI - Brain functional network changes following Prelimbic area inactivation in a spatial memory extinction task. AB - Several studies suggest a prefrontal cortex involvement during the acquisition and consolidation of spatial memory, suggesting an active modulating role at late stages of acquisition processes. Recently, we have reported that the prelimbic and infralimbic areas of the prefrontal cortex, among other structures, are also specifically involved in the late phases of spatial memory extinction. This study aimed to evaluate whether the inactivation of the prelimbic area of the prefrontal cortex impaired spatial memory extinction. For this purpose, male Wistar rats were implanted bilaterally with cannulae into the prelimbic region of the prefrontal cortex. Animals were trained during 5 consecutive days in a hidden platform task and tested for reference spatial memory immediately after the last training session. One day after completing the training task, bilateral infusion of the GABAA receptor agonist Muscimol was performed before the extinction protocol was carried out. Additionally, cytochrome c oxidase histochemistry was applied to map the metabolic brain activity related to the spatial memory extinction under prelimbic cortex inactivation. Results show that animals acquired the reference memory task in the water maze, and the extinction task was successfully completed without significant impairment. However, analysis of the functional brain networks involved by cytochrome oxidase activity interregional correlations showed changes in brain networks between the group treated with Muscimol as compared to the saline-treated group, supporting the involvement of the mammillary bodies at a the late stage in the memory extinction process. PMID- 25813750 TI - Protein synthesis is not required for acquisition, consolidation, and extinction of high foot-shock active avoidance training. AB - Long-term memory of active avoidance in mice is not disturbed by administration of protein synthesis inhibitors (PSIs) when relatively high levels of training are used, whereas a detrimental effect is produced with lower levels of training. PSIs also disrupt extinction of avoidance behaviors in rodents, but it is not clear whether PSIs also affect this form of learning when the behavior to be extinguished was produced by a high level of training. Experiment 1 demonstrated that rats treated with the PSI cycloheximide (CXM) 30 min before training developed normal acquisition after training with either high or low foot-shock stimulation, but that memory consolidation was hindered only after low foot-shock training. Experiment 2 demonstrated that CXM disrupted extinction when administered before the first of a series of extinction sessions when low foot shock intensity was used during training; in contrast, after training with a higher foot-shock, the PSI treatment only interfered transiently with extinction. These results indicate that acquisition, consolidation, and extinction of active avoidance learning produced by high aversive stimulation are not dependent on protein synthesis and that these processes are governed by mechanisms different from those underlying moderate forms of learning. PMID- 25813751 TI - Children's weight status, body esteem, and self-concept after maternal gastric bypass surgery. AB - BACKGROUND: There is little research on the effects of Roux-en-Y gastric bypass (RYGB) surgery on the patients' offspring's weight and psychosocial well-being. The present study investigates how children are affected in terms of weight status, body esteem, and self-concept after maternal RYGB. METHODS: Sixty-nine women and their families were recruited from RYGB waiting lists at 5 Swedish hospitals. Data was collected during home visits 3 months before and 12 months after RYGB. Anthropometrical measures were taken, and the children completed the Body Esteem Scale (BES) and the Beck Self-Concept Inventory (BYI-S). RESULTS: Prevalence or relative risk in weight status between the time points were explored using Poisson regression models (General Estimating Equations). We found stronger statistical evidence for a decreased risk of overweight (RR = .85, 57.0% versus 48.6%, P = .048), than for obesity (RR = .87, 18.2% versus 15.9%, P = .447). The boys' body esteem increased slightly, whilst the girls' did not. There were no significant differences in mean BYI-S scores. CONCLUSIONS: The reasons behind the statistically significant decrease in overweight but not obesity risk in children after maternal RYGB may be caused by insufficient statistical power to detect changes in obesity risk alone. Body esteem seems to be slightly positively affected in boys 9 months after maternal RYGB. Longer follow-up times and larger samples would be useful in future research. PMID- 25813752 TI - Safety and effectiveness of bariatric surgery in dialysis patients and kidney transplantation candidates. AB - BACKGROUND: Chronic renal disease is known to adversely affect the results of bariatric surgery. There is a paucity of literature on the safety and effectiveness of bariatric surgery on dialysis patients who are at very advanced stages in their renal disease. The objective of this study was to determine the safety and effectiveness of bariatric surgery in dialysis patients. METHODS: A retrospective review of a prospectively collected database was conducted for dialysis patients who underwent bariatric surgery between January 2006 and January 2012. Age, gender, body mass index (BMI), cause of renal failure, associated co-morbidities, type of surgery, early and late complications, and mortality were collected. RESULTS: Of the 3048 patients undergoing bariatric surgery during the study period, 21 dialysis patients (.7%) were identified. Eighteen patients underwent laparoscopic Roux-en-Y gastric bypass (LRYGB), 2 patients underwent laparoscopic sleeve gastrectomy, and 1 patient underwent laparoscopic adjustable gastric banding. Mean preoperative BMI was 47.1+/-5.5 kg/m(2), and BMI decreased to 35.3+/-8.4 kg/m(2) after a mean follow-up period of 27.6 months (range = 1.4-78.0 mo). Early major complications (<30 days of surgery) occurred in 2 patients (1 anastomotic leak and 1 anastomotic stricture). Four patients had a late complication, including 1 marginal ulcer with bleeding managed endoscopically, 1 small bowel obstruction requiring laparoscopic lysis of adhesions, 1 cholecystitis requiring cholecystectomy, and 1 anastomotic stricture requiring endoscopic dilation. There was 1 death in this cohort, at 45 days after LRYGB, that was unrelated to a surgery. CONCLUSIONS: Chronic renal failure requiring dialysis should not be considered a contraindication to bariatric surgery. Our experience with this patient population has shown excellent medium term weight loss and an acceptable (albeit increased) risk/benefit ratio. PMID- 25813753 TI - Does the closure of mesenteric defects during laparoscopic gastric bypass surgery cause complications? AB - BACKGROUND: A well-known complication of laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) is bowel obstruction due to internal herniation (IH). Evidence suggests that mesenteric defects should be closed during LRYGB to reduce the risk of IH. Therefore, surgeons are now closing mesenteric defects during LRYGB using sutures, clips, or fibrin glue. However, it has been reported that complications may arise due to the closure of mesenteric defects. The aim of this review was to summarize the reported possible complications associated with the closure of mesenteric defects during LRYGB. METHODS: A literature search of PubMed and EMBASE was performed to identify studies related to the closure of mesenteric defects during LRYGB. The studies were screened for the listing of possible complications associated with the closure of mesenteric defects. This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis recommendations. RESULTS: Thirty studies complied with the inclusion criteria for our analysis, which included 21,789 patients. Reported complications related to closure of the mesenteric defects were: small bowel obstruction because of IH, kinking, and adhesions. IH occurred because of incomplete closure of the mesenteric defects in 1.4% of all patients, 1.2% by the antecolic approach, and 1.9% by the retrocolic approach, respectively. Kinking of the small bowel occurred in .2% of 1630 patients after closure of the mesenteric defects with clips and adhesion formation was found among 4.6% of 152 patients after closure of the mesenteric defects with nonabsorbable sutures. CONCLUSIONS: The reported risk of complications caused by closure of the mesenteric defects during LRYGB seems low. PMID- 25813754 TI - Duodenal-jejunal bypass with sleeve gastrectomy versus the sleeve gastrectomy procedure alone: the role of duodenal exclusion. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (SG) has become accepted as a stand alone procedure as a less complex operation than laparoscopic duodenojejunal bypass with sleeve gastrectomy (DJB-SG). OBJECTIVES: The aim of this study was to compare one-year results between DJB-SG and SG. SETTING: University hospital. METHODS: A total of 89 patients who received a DJB-SG surgery were matched with a group of SG that were equal in age, sex, and body mass index (BMI). Complication rates, weight loss, and remission of co-morbidities were evaluated after 12 months. RESULTS: The mean preoperative patient BMI in the DJB-SG and SG groups was similar. There were more patients with type 2 diabetes mellitus (T2DM) in the DJB-SG group than in the SG group. The mean operative time and length of hospital stay (LOS) were significantly longer in the DJB-SG group than in the SG group. At 12 months after surgery, the BMI was lower and excess weight loss higher in DJB SG than SG. Remission of T2DM was greater in the DJB-SG group. Low-density lipoprotein, total cholesterol, and metabolic syndrome (MS) improved after operation in both groups. CONCLUSIONS: In this study DJB-SG was superior to SG in T2DM remission, triglyceride improvement, excess weight loss, and lower BMI at 1 year after surgery. Adding duodenal switch to sleeve gastrectomy increases the effect of diabetic control and MS resolution. PMID- 25813755 TI - Water relations and gas exchange of fan bryophytes and their adaptations to microhabitats in an Asian subtropical montane cloud forest. AB - Fan life forms are bryophytes with shoots rising from vertical substratum that branch repeatedly in the horizontal plane to form flattened photosynthetic surfaces, which are well suited for intercepting water from moving air. However, detailed water relations, gas exchange characteristics of fan bryophytes and their adaptations to particular microhabitats remain poorly understood. In this study, we measured and analyzed microclimatic data, as well as water release curves, pressure-volume relationships and photosynthetic water and light response curves for three common fan bryophytes in an Asian subtropical montane cloud forest (SMCF). Results demonstrate high relative humidity but low light levels and temperatures in the understory, and a strong effect of fog on water availability for bryophytes in the SMCF. The facts that fan bryophytes in dry air lose most of their free water within 1 h, and a strong dependence of net photosynthesis rates on water content, imply that the transition from a hydrated, photosynthetically active state to a dry, inactive state is rapid. In addition, fan bryophytes developed relatively high cell wall elasticity and the osmoregulatory capacity to tolerate desiccation. These fan bryophytes had low light saturation and compensation point of photosynthesis, indicating shade tolerance. It is likely that fan bryophytes can flourish on tree trunks in the SMCF because of substantial annual precipitation, average relative humidity, and frequent and persistent fog, which can provide continual water sources for them to intercept. Nevertheless, the low water retention capacity and strong dependence of net photosynthesis on water content of fan bryophytes indicate a high risk of unbalanced carbon budget if the frequency and severity of drought increase in the future as predicted. PMID- 25813756 TI - Subarachnoid hemorrhage due to aneurysm rupture in a young woman with Alagille syndrome - A rare cause of sudden death. AB - The Alagille syndrome (AGS) or arteriohepatic dysplasia is a rare, autosomal dominant inherited disease with a prevalence of approximately 1:100,000. AGS was first described in 1969 and affects liver, heart, arterial blood vessels, skeleton and the eyes. The expression of AGS is variable. In severe cases a liver transplantation is required. Presented is the case of a 25-year-old woman with AGS. At the age of 7 and 8years she had liver transplantations. Other typical findings associated with Alagille syndrome (e.g. pulmonary or renal anomalies) were also present. The young woman apparently died suddenly and unexpectedly in a good health condition despite regular medical treatment. Cause of death was a subarachnoid hemorrhage with invasion of the hemorrhage into the ventricle system caused by a rupture of previously unknown large aneurysm in the terminal basilary artery. Intracranial vascular malformations are a common finding in patients with AGS and cause death in up to 16% of them. Life expectancy in AGS patients depends on the severity of changes of the affected liver. But AGS is also responsible for various vascular abnormalities in several other organs which can cause lethal complications. Due to the high rate of vascular complications and intracranial hemorrhage with the leading cause of mortality in patients with AGS, vascular screening by the use of noninvasive imaging techniques (CT or MR angiography) is required to avoid unexpected sudden death. PMID- 25813757 TI - Estimation of sex from the anthropometric ear measurements of a Sudanese population. AB - The external ear and its prints have multifaceted roles in medico-legal practice, e.g., identification and facial reconstruction. Furthermore, its norms are essential in the diagnosis of congenital anomalies and the design of hearing aids. Body part dimensions vary in different ethnic groups, so the most accurate statistical estimations of biological attributes are developed using population specific standards. Sudan lacks comprehensive data about ear norms; moreover, there is a universal rarity in assessing the possibility of sex estimation from ear dimensions using robust statistical techniques. Therefore, this study attempts to establish data for normal adult Sudanese Arabs, assessing the existence of asymmetry and developing a population-specific equation for sex estimation. The study sample comprised 200 healthy Sudanese Arab volunteers (100 males and 100 females) in the age range of 18-30years. The physiognomic ear length and width, lobule length and width, and conchal length and width measurements were obtained by direct anthropometry, using a digital sliding caliper. Moreover, indices and asymmetry were assessed. Data were analyzed using basic descriptive statistics and discriminant function analyses employing jackknife validations of classification results. All linear dimensions used were sexually dimorphic except lobular lengths. Some of the variables and indices show asymmetry. Ear dimensions showed cross-validated sex classification accuracy ranging between 60.5% and 72%. Hence, the ear measurements cannot be used as an effective tool in the estimation of sex. However, in the absence of other more reliable means, it still can be considered a supportive trait in sex estimation. Further, asymmetry should be considered in identification from the ear measurements. PMID- 25813758 TI - MRI is more accurate than CT for patient-specific total knee arthroplasty. AB - Previous reports have stated that MRI is less accurate than CT for patient specific guide creation in total knee arthroplasty (TKA). Twenty-three TKAs were performed with CT-based guides and 27 with MRI-based guides. A mechanical axis through the central third of the knee was achieved in 88.9% of MRI-guided TKA versus 69.6% of CT-guided TKA (p=0.07). There were nine component outliers in the CT group (39.1%) and two in the MRI group (7.4%, p=0.00768). The relative risk of having an outlier using a CT-based guide was 5.28 times that of an MRI-based guide. Superior overall alignment and fewer outliers were achieved with the use of MRI compared with CT. MRI is the best imaging modality for surgeons wishing to utilize patient specific guides for TKA. PMID- 25813759 TI - Kinematic alignment produces near-normal knee motion but increases contact stress after total knee arthroplasty: A case study on a single implant design. AB - BACKGROUND: Kinematically aligned total knee arthroplasty (TKA) is of increasing interest because this method might improve postoperative patient satisfaction. In kinematic alignment the femoral component is implanted in a slightly more valgus and internally rotated position, and the tibial component is implanted in a slightly more varus and internally rotated position, than in mechanical alignment. However, the biomechanics of kinematically aligned TKA remain largely unknown. The aim of this study was to compare the kinematics and contact stresses of mechanically and kinematically aligned TKAs. METHODS: A musculoskeletal computer simulation was used to determine the effects of mechanically or kinematically aligned TKA. Knee kinematics were examined for mechanically aligned, kinematically aligned, and kinematically aligned outlier models. Patellofemoral and tibiofemoral contact forces were measured using finite element analysis. RESULTS: Greater femoral rollback and more external rotation of the femoral component were observed with kinematically aligned TKA than mechanically aligned TKA. However, patellofemoral and tibiofemoral contact stresses were increased in kinematically aligned TKA. CONCLUSIONS: These findings suggest that kinematically aligned TKA produces near-normal knee kinematics, but that concerns for long-term outcome might arise because of high contact stresses. PMID- 25813760 TI - The influence of vehicle front-end design on pedestrian ground impact. AB - Accident data have shown that in pedestrian accidents with high-fronted vehicles (SUVs and vans) the risk of pedestrian head injuries from the contact with the ground is higher than with low-fronted vehicles (passenger cars). However, the reasons for this remain poorly understood. This paper addresses this question using multibody modelling to investigate the influence of vehicle front height and shape in pedestrian accidents on the mechanism of impact with the ground and on head ground impact speed. To this end, a set of 648 pedestrian/vehicle crash simulations was carried out using the MADYMO multibody simulation software. Impacts were simulated with six vehicle types at three impact speeds (20, 30, 40km/h) and three pedestrian types (50th % male, 5th % female, and 6-year-old child) at six different initial stance configurations, stationary and walking at 1.4m/s. Six different ground impact mechanisms, distinguished from each other by the manner in which the pedestrian impacted the ground, were identified. These configurations have statistically distinct and considerably different distributions of head-ground impact speeds. Pedestrian initial stance configuration (gait and walking speed) introduced a high variability to the head ground impact speed. Nonetheless, the head-ground impact speed varied significantly between the different ground impact mechanisms identified and the distribution of impact mechanisms was strongly associated with vehicle type. In general, impact mechanisms for adults resulting in a head-first contact with the ground were more severe with high fronted vehicles compared to low fronted vehicles, though there is a speed dependency to these findings. With high fronted vehicles (SUVs and vans) the pedestrian was mainly pushed forward and for children this resulted in high head ground contact speeds. PMID- 25813761 TI - Valuation of safety under reference-dependent evaluation of income. AB - We analyze data of a Spanish nationally-representative survey where subjects reported their willingness to pay (WTP) for road safety improvements, specifically they hypothetically paid for a reduction of the risk of a road fatality and several injuries. Respondents also reported their current income (CI) and permanent income (PI). The latter refers to their normal income once they considered various stages of low/high earnings throughout their entire lives. Consequently, we define relative income as the comparison of CI with respect to PI. Three income frames are generated as explanatory variables: gain (with CI>PI); neutral (with CI=PI); and loss scenario (with CI45), being about three or four times higher than for the younger subset. Possible interpretations of the role of PI as a reference point are considered given the results. A reference-dependent utility function of income, where PI is the reference point, is proposed to describe the monetary valuation of safety within the theoretical framework previously developed in the safety economics literature. PMID- 25813762 TI - Assessment of safety effects for widening urban roadways in developing crash modification functions using nonlinearizing link functions. AB - Since a crash modification factor (CMF) represents the overall safety performance of specific treatments in a single fixed value, there is a need to explore the variation of CMFs with different roadway characteristics among treated sites over time. Therefore, in this study, we (1) evaluate the safety performance of a sample of urban four-lane roadway segments that have been widened with one through lane in each direction and (2) determine the relationship between the safety effects and different roadway characteristics over time. Observational before-after analysis with the empirical Bayes (EB) method was assessed in this study to evaluate the safety effects of widening urban four-lane roadways to six lanes. Moreover, the nonlinearizing link functions were utilized to achieve better performance of crash modification functions (CMFunctions). The CMFunctions were developed using a Bayesian regression method including the estimated nonlinearizing link function to incorporate the changes in safety effects of the treatment over time. Data was collected for urban arterials in Florida, and the Florida-specific full SPFs were developed and used for EB estimation. The results indicated that the conversion of four-lane roadways to six-lane roadways resulted in a crash reduction of 15 percent for total crashes, and 24 percent for injury crashes on urban roadways. The results show that the safety effects vary across the sites with different roadway characteristics. In particular, LOS changes, time changes, and shoulder widths are significant parameters that affect the variation of CMFs. Moreover, it was found that narrowing shoulder and median widths to make space for an extra through lane shows a negative safety impact. It was also found that including the nonlinearizing link functions in developing CMFunctions shows more reliable estimates, if the variation of CMFs with specific parameters has a nonlinear relationship. The findings provide insights into the selection of roadway sites for adding through lanes. PMID- 25813763 TI - Measuring vasoreactivity in pulmonary hypertension: a simple test, but do we understand it? PMID- 25813764 TI - Waiting with a failing right heart. PMID- 25813765 TI - Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study. AB - BACKGROUND: In the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase - Stimulator Trial 1 (CHEST-1) study, riociguat improved 6 minute walking distance (6MWD) vs placebo in patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. In this study, the proportion of patients who achieved responder thresholds that correlate with improved outcome in patients with pulmonary arterial hypertension was determined at baseline and at the end of CHEST-1. METHODS: Patients received placebo or riociguat individually adjusted up to 2.5 mg 3 times a day for 16 weeks. Response criteria were defined as follows: 6MWD increase >=40 m, 6MWD >=380 m, cardiac index >=2.5 liters/min/m(2), pulmonary vascular resistance <500 dyn?sec?cm(-5), mixed venous oxygen saturation >=65%, World Health Organization functional class I/II, N terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg. RESULTS: Riociguat increased the proportion of patients with 6MWD >=380 m, World Health Organization functional class I/II, and pulmonary vascular resistance <500 dyn?sec?cm(-5) from 37%, 34%, and 25% at baseline to 58%, 57%, and 50% at Week 16, whereas there was little change in placebo-treated patients (6MWD >=380 m, 43% vs 44%; World Health Organization functional class I/II, 29% vs 38%; pulmonary vascular resistance <500 dyn?sec?cm(-5), 27% vs 26%). Similar changes were observed for thresholds for cardiac index, mixed venous oxygen saturation, N-terminal pro-brain natriuretic peptide, and right atrial pressure. CONCLUSIONS: In this exploratory analysis, riociguat increased the proportion of patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy achieving criteria defining a positive response to therapy. PMID- 25813766 TI - Balloon atrial septostomy in pulmonary arterial hypertension: effect on survival and associated outcomes. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive disease that, without early identification and treatment, may lead to right heart failure, multi-organ dysfunction and early death. In severe PAH, in addition to maximal medical therapy, balloon atrial septostomy (BAS) may be used for palliation and as a bridge to lung transplantation. We present our contemporary institutional experience utilizing BAS in adult and pediatric patients with severe PAH. METHODS: We performed a retrospective analysis of 46 BASs performed in 32 patients with PAH from 2002 to 2013. Data obtained included vital status, functional class, medications, hemodynamic measurements from right heart catheterizations and biomarkers. Lung transplantation-free and repeat-BAS-free survival was analyzed. RESULTS: Median age at BAS was 23 (range 1 to 56) years. The most common indications were symptomatic right heart failure (21 of 46 patients) and pre-syncope/syncope (19 of 46 patients); 69% of patients were WHO Functional Class III or IV pre-BAS. There were no procedural complications or deaths. There were no significant differences in biomarkers or hemodynamic findings between pre-BAS and 1 year or latest follow-up. Seven patients were successfully bridged to lung transplantation. Lung transplantation-free and repeat-BAS-free survival at 30 days, 1 year and 5 years was 87%, 61% and 32%, respectively. CONCLUSIONS: In our experienced center, BAS was shown to be safe in patients with severe PAH on maximal medical management, with no procedural deaths or complications. BAS was safely used as a bridge to lung transplantation or to alleviate right heart failure symptoms and/or syncope. Other potential benefits for end-organ function and overall survival remain to be determined. PMID- 25813767 TI - Adverse pulmonary vascular remodeling in the Fontan circulation. AB - BACKGROUND: The Fontan circulation is a palliation for patients with a functionally univentricular heart. It is characterized by gradual attrition over time. An increase in pulmonary vascular resistance could be a key factor in the long-term failure of the Fontan circulation. In this study we aimed to identify pulmonary vascular remodeling in patients with a Fontan circulation. METHODS: Pulmonary vascular histomorphometric analysis and immunohistochemistry were performed in lung tissue obtained at autopsy from 12 Fontan patients. These patients had died either peri-operatively (Group A: death during or <15 days after Fontan completion; n = 5) or in mid to long-term follow-up (Group B: death >5 years after Fontan completion; n = 7). Two age-matched control groups (n = 10 and n = 14, respectively) were included. RESULTS: Intra-acinar pulmonary vessels in the Fontan Group B patients showed decreased medial thickness (p = 0.028) compared with age-matched controls, whereas intimal thickness was increased (p = 0.002). Intimal thickness in the Fontan Group B patients correlated with age at death (r = 0.964, p < 0.001) and with the length of time that the Fontan circulation had been in place (r = 0.714, p = 0.036). Immunohistochemistry revealed a reduction of vascular smooth muscles cells in the medial layer of the intra-acinar pulmonary vessels. The eccentric intimal thickening was composed of mainly acellular fibrosis with collagen deposition. CONCLUSIONS: We observed a unique pattern of adverse pulmonary vascular remodeling in patients with a long standing Fontan circulation who had died during follow-up. This remodeling pattern may play a major role in long-term attrition of the Fontan circulation. PMID- 25813768 TI - Right atrial volume and reservoir function are novel independent predictors of clinical worsening in patients with pulmonary hypertension. AB - BACKGROUND: Symptoms and signs and indices of right heart function are predictors of clinical outcomes in patients with pulmonary hypertension (PH). However, the significance of right atrial (RA) indices has not been sufficiently investigated. We investigated whether RA parameters predict outcomes in patients with pre capillary PH. METHODS: Study subjects were 68 patients with pre-capillary PH. RA size and function (systolic, reservoir, and conduit functions) were evaluated by cardiac magnetic resonance imaging. RESULTS: During the mean follow-up period of 24 months, 16 of 68 patients experienced clinical worsening (CW), defined as hospitalization because of right heart failure, lung transplantation, or PH related death. Kaplan-Meier and log-rank test showed that World Health Organization functional class, pericardial effusion, increased brain natriuretic peptide concentration, reduced right ventricular ejection fraction (RVEF), increased minimum RA volume index, and decreased RA reservoir volume were associated with CW-free survival. The combination of RVEF and RA reservoir function was a better predictor of CW-free survival. In univariate Cox hazard proportional analysis, CW was associated with the RA reservoir volume index (hazard ratio [HR] = 0.80). In multivariate analysis, CW was associated with World Health Organization functional class (HR = 4.3), RA minimum volume index (HR = 1.07), and RA reservoir volume index (HR = 0.73). CONCLUSIONS: RA volume and reservoir function and their combined use with RVEF are novel predictors of CW in patients with pre-capillary PH. PMID- 25813769 TI - Pulmonary hypertension is associated with increased post-lung transplant mortality risk in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Pulmonary hypertension associated with lung disease (PHLD) has been shown to be a predictor of disease severity and survival in patients awaiting lung transplantation. Little is known about the relationship of PHLD and survival after lung transplantation or how this may vary by disease. This study evaluated the effect of PHLD on 1-year survival after lung transplantation for patients with the 3 most common indications for transplantation: chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF). METHODS: Organ Procurement and Transplantation Network data were obtained for all lung transplant recipients who received an allograft between May 2005 and June 2010. The relationship between PHLD and 1-year survival after lung transplantation for each diagnostic group was examined with Kaplan-Meier estimates and Cox regression. Covariates included in the model were those defined in the current Lung Allocation Score system post-transplant survival model, including age, serum creatinine, percentage predicted forced vital capacity, functional status, and mechanical ventilation use at time of transplant. The estimated relative risk was calculated using Poisson regression with robust error variance and adjustment for covariates. RESULTS: Sample sizes for COPD, IPF, and CF patients were 2,025, 2,304, and 866, respectively. The 1-year post-transplant survival for COPD patients with PHLD was 76.9% vs 86.2% for COPD patients without PHLD (p = 0.001). In multivariate Cox regression analysis COPD patients with PHLD had a 1.74 (95% confidence interval, 1.3-2.3) times higher risk of 1-year post transplant mortality (p = 0.001). Similar analyses for IPF and CF diagnostic groups showed no significant difference in survival between patients with and without PHLD. CONCLUSIONS: COPD patients with PHLD have increased post-transplant 1-year mortality. No significant difference was seen in patients with IPF or CF. Further studies to evaluate the potential mechanisms for this difference between diagnoses are needed. PMID- 25813770 TI - Limitations of right heart catheterization in the diagnosis and risk stratification of patients with pulmonary hypertension related to left heart disease: insights from a wireless pulmonary artery pressure monitoring system. AB - BACKGROUND: Although right heart catheterization (RHC) remains the gold standard for assessment of hemodynamics in patients with known or suspected pulmonary hypertension (PH), there are significant limitations to this type of assessment. The current study evaluates the limitations of RHC in the diagnosis of left heart related PH (World Health Organization group II) among patients enrolled in the CHAMPION trial and discusses insights into patient risk from home implantable hemodynamic monitor (IHM) data that were not identified at the time of the RHC procedure. METHODS: The CHAMPION trial enrolled 550 New York Heart Association functional class III patients who had been hospitalized for heart failure (HF) in the previous year, regardless of left ventricular ejection fraction or etiology. Hemodynamic data obtained during baseline RHC were compared with IHM data obtained during the first week of home readings. HF hospitalization rates and mortality were analyzed to assess patient risk. RESULTS: The study population for this retrospective analysis comprised 537 patients with available IHM data. For 320 patients in the PHRHC group, home IHM data confirmed the RHC findings with similar mean pulmonary artery pressures obtained from both methods (36 mm Hg vs 36 mm Hg, p = 0.5066). However, of the 217 patients in the No PHRHC group, 106 patients (48.8%) exhibited PH based on the home IHM data (PHIHM group). The remaining 111 patients (51.2%) in the No PHRHC group had no evidence of PH on the IHM data (No PHIHM group). Patients in the No PHRHC/PHIHM group had significantly higher mean PA pressures on IHM than patients in the No PHRHC/No PHIHM group (31 mm Hg vs 18 mm Hg, p < 0.0001). Patients in the No PHRHC/No PHIHM group had significantly lower HF hospitalization rates than patients in the No PHRHC/PHIHM group (0.25 vs 0.49, incidence rate ratio = 0.51, 95% confidence interval = 0.33 0.77, p = 0.0007). CONCLUSIONS: Using only RHC, World Health Organization group II PH may be significantly under-diagnosed. In patients with left-sided HF and resting mean PA pressure <=25 mm Hg during RHC, more frequent PA pressure monitoring using an IHM device can provide additional data for improved diagnosis and patient risk stratification compared with a single RHC alone. PMID- 25813771 TI - The impact of flooding on people living with HIV: a case study from the Ohangwena Region, Namibia. AB - BACKGROUND: Floods are a disaster situation for all affected populations and especially for vulnerable groups within communities such as children, orphans, women, and people with chronic diseases such as HIV and AIDS. They need functioning health care, sanitation and hygiene, safe water, and healthy food supply, and are critically dependent on their social care and support networks. A study carried out in the Ohangwena region, Namibia, where HIV prevalence is high and extensive flooding frequently occurs, aims to provide a deeper understanding of the impact that flooding has on people living with HIV (PLWHIV) as well as on HIV service providers in the region. DESIGN: The qualitative research applying grounded theory included semi-structured interviews with PLWHIV, focus group discussions with HIV service providers, and a national feedback meeting. The findings were interpreted using the sustainable livelihoods framework, the natural hazard research approach, and health behaviour theories. RESULTS: The study reveals that flooding poses major problems to PLWHIV in terms of their everyday lives, affecting livelihoods, work, income, and living conditions. The factors threatening them under normal conditions - poverty, malnutrition, unsafe water, sanitation and hygiene, limited access to health facilities, a weak health status, and stigma - are intensified by flood-related breakdown of infrastructure, insecurity, malnutrition, and diseases evolving over the course of a flood. A potential dual risk exists for their health: the increased risk both of infection and disease due to the inaccessibility of health services and antiretroviral treatment. A HIV and Flooding Framework was developed to display the results. CONCLUSIONS: This study demonstrates that vulnerabilities and health risks of PLWHIV will increase in a disaster situation like flooding if access to HIV prevention, treatment, care and support are not addressed and ensured. The findings and the HIV and Flooding Framework are not specific to Ohangwena and can be transferred to any flood-affected region that has a high HIV prevalence and relies mainly on subsistence agriculture. They serve as a model case for analysing vulnerabilities related to health and health service provision under disaster conditions. The impact will vary according to the physical, geographical, climatological, social, and behavioural characteristics of the region and the people affected. In the Ohangwena region, a disaster risk management mechanism is already in place which addresses people with HIV during flooding. However, preparedness could be improved further by applying the HIV and Flooding Framework. PMID- 25813772 TI - ASEAN integration and health services. PMID- 25813773 TI - Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial. AB - OBJECTIVE: This study determined the effects of insulin versus liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy, including metformin. RESEARCH DESIGN AND METHODS: Thirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications were randomized to receive insulin glargine or liraglutide therapy for 12 weeks. The liver proton density fat fraction (PDFF) was measured by MRS. The mean liver PDFF, the total liver volume, and the total liver fat index were measured by MRI. The Student t test, the Fisher exact test, and repeated-measures ANOVA were used for statistical analysis. RESULTS: Insulin treatment was associated with a significant improvement in glycated hemoglobin (7.9% to 7.2% [62.5 to 55.2 mmol/mol], P = 0.005), a trend toward a decrease in MRS-PDFF (12.6% to 9.9%, P = 0.06), and a significant decrease in liver mean MRI-PDFF (13.8% to 10.6%, P = 0.005), liver volume (2,010.6 to 1,858.7 mL, P = 0.01), and the total liver fat index (304.4 vs. 209.3 % ? mL, P = 0.01). Liraglutide treatment was also associated with a significant improvement in glycated hemoglobin (7.6% to 6.7% [59.8 to 50.2 mmol/mol], P < 0.001) but did not change MRS-PDFF (P = 0.80), liver mean MRI-PDFF (P = 0.15), liver volume (P = 0.30), or the total liver fat index (P = 0.39). CONCLUSIONS: The administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes. However, the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group. PMID- 25813774 TI - Suppression of dedifferentiation and hypertrophy in canine chondrocytes through lentiviral vector expression of Sox9 and induced pluripotency stem cell factors. AB - OBJECTIVES: Prolonged in vitro culture of primary articular chondrocytes results in dedifferentiation to a fibroblast-like cell with reduced expression of the Sox9 transcription factor and the extracellular matrix protein collagen II. The ability to genetically-modify chondrocytes to allow both proliferation and maintenance of an articular phenotype may provide increased numbers of appropriate cells for regeneration of large cartilage defects. RESULTS: Canine chondrocytes were expanded in monolayer culture and transduced with a lentiviral vector expressing Sox9 or in combination with a multicistronic lentiviral vector expressing the four induced pluripotency stem (iPS) cell factors, Oct4, Klf4, Sox2 and c-Myc (OSKM). 3D pellet cultures of transduced cells in the presence of TGFbeta-3 revealed increased pellet size and higher levels of total glycosaminoglycan in both Sox9 and Sox9+ OSKM co-transduced chondrocytes compared to untransduced and green fluorescent protein expressing controls. Immunohistochemical detection of Sox9 and collagen II was evident in transduced cells (Sox9, OSKM, or Sox9+ OSKM) with very low levels in untransduced chondrocytes, demonstrating a dedifferentiated state (P < 0.01). The marker for chondrocyte hypertrophy, collagen X was highly expressed in Sox9 transduced chondrocytes but lower in OSKM or Sox9+ OSKM cells (P < 0.05). CONCLUSION: A combination of Sox9 and OSKM gene delivery to canine chondrocytes allows continuous proliferation in monolayer culture with a higher expression of col2a1 without an increase in the hypertrophy marker collagen X in 3D pellet cultures. PMID- 25813775 TI - Hex1-related transcriptome of Trichoderma atroviride reveals expression patterns of ABC transporters associated with tolerance to dichlorvos. AB - OBJECTIVES: The tolerance to organophosphate pesticide, dichlorvos, is essential for the application of Trichoderma in bioremediation and integrated pest management, although the molecular events associated with the tolerance process have not yet been elucidated. RESULTS: RNA-seq analysis of wild-type Trichoderma atroviride T23 and the hex1-deleted mutant under dichlorvos stress was designed to search for genes involved in the tolerance process. A total of 5382 differentially expressed genes were identified, highlighting the complex transcriptional changes of T. atroviride in response to dichlorvos stress. 137 genes were regulated by dichlorvos and hex1, encoding major facilitator superfamilies, cytochrome P450, glutathione-S-transferase, flavoprotein, Hsp70, Hsp90, etc. Pathway and expression analysis indicated that ABC transporters were affected by the disruption of hex1 gene and might play a vital role in the tolerance process. Expression patterns of seven selected ABC transporter genes were confirmed by qRT-PCR after exposure to dichlorvos for 2, 6 and 24 h. CONCLUSIONS: The present study provides insights into the genetic basis of dichlorvos tolerance in Trichoderma that may be exploited for further development of bioremediation or biocontrol agents. PMID- 25813776 TI - Association between risk perception, subjective knowledge, and depression in community-dwelling elderly people in Japan. AB - Risk perception is one of the core factors in theories of health behavior promotion. However, the association between knowledge, risk perception, and depressed mood in depression is unknown. The aim of this study was to clarify the relationships between subjective knowledge, risk perception, and objective scores of depression in community-dwelling elderly people in Japan. A total of 747 elderly participants (mean age: 76.1, female: 59.8%) who completed the 15-item Geriatric Depression Scale (GDS-15) along with items assessing subjective knowledge and risk perception were included in the analysis. We assessed the correlation between subjective knowledge and risk perception, and then compare GDS-15 scores by level of subjective knowledge and risk perception. Subjective knowledge was weakly associated with risk perception and related to lower GDS-15 scores in a dose-response pattern, which did not change after adjusting for age, gender, basic activities of daily living (ADL), instrumental ADL, years of education and history of depression. There was no significant association between risk perception and GDS-15 scores. The relationship between knowledge, risk perception, and depressed mood in younger generations is unclear, but warrants examination. PMID- 25813777 TI - Technique Tip: The Use of McGlamry Elevator to Assist Suture Passing in the Dorsal Technique of Plantar Plate Repair With Weil Osteotomy for Lesser Metatarsophalangeal Joint Instability. AB - The combination of a dorsal approach to the plantar plate with a Weil's metatarsal osteotomy has been shown to provide an adequate exposure for plantar plate repair. However, soft tissues in a restricted area of the metatarsophalangeal joint could present as a technical difficulty during suture retrieval during repair of the plantar plate. The purpose of this article is to describe the use of the McGlamry elevator for assistance in the retrieval of sutures through the proximal phalanx. LEVEL OF EVIDENCE: Level V: Expert opinion. PMID- 25813778 TI - Topical Review: Use of Fetal Tissue in Foot and Ankle Surgery. AB - Fetal tissues are well known for their therapeutic potential. They contain numerous growth factors, cytokines, and matrix components that promote regeneration of tissues while downregulating inflammation and scar formation. As a result, use of these treatments has expanded over the previous 20 years throughout various surgical specialties, including orthopaedics. With improved methods of sterilization, processing, and storage, surgeons need to be informed about the potential benefits of fetal tissue in foot and ankle surgery. The aim of this review is to provide a brief historical background, basic anatomy and physiology, and a current review of the literature in regard to chronic wounds, diabetic foot ulcerations, plantar fasciitis, tendon repair, adhesion prevention, nerve repair, and bone healing. LEVELS OF EVIDENCE: Level V: Expert Opinion. PMID- 25813779 TI - 2013 Subtalar Arthroereisis Survey: The Current Practice Patterns of Members of the AOFAS. AB - BACKGROUND: Subtalar arthroereisis (SA) has been a procedure used for the correction of painful flexible flatfoot deformity in adults and children. Clinical studies of patients who had a SA are sparse and with mixed results and variable indications. The purpose of this study was to determine the current practice among orthopaedic foot and ankle specialists regarding SA. METHODS: Web based questionnaires were e-mailed to members of the American Orthopaedic Foot and Ankle Society (AOFAS). Requested information included demographics and practice patterns in regard to performing SA surgery. A total of 572 respondents completed the survey (32% response rate). RESULTS: A total of 273 respondents (48%) have performed SA. Of this group, 187 respondents (69%) still perform this procedure (33% of total respondents currently perform SA). Of the respondents, 401 (70%) practice in the United States, 40% have performed SA, and 60% of those still perform this procedure. Of non-US respondents, 66% have performed SA, and 80% of those still perform it. The most common US indications are painful congenital flatfoot, posterior tibial tendon dysfunction, and flatfoot associated with accessory navicular. CONCLUSION: Many doctors have performed SA, and a significant number no longer perform this procedure for various reasons. A greater percentage of non-US practitioners have performed and continue to perform SA than their counterparts in the United States. There is a common list of surgical indications. Most doctors who still perform this procedure have removed the implants, commonly for pain. SA is still being performed in the United States and throughout the world. PMID- 25813780 TI - Magnocellular-dorsal pathway function is associated with orthographic but not phonological skill: fMRI evidence from skilled Chinese readers. AB - Numerous studies have shown that magnocellular-dorsal (MD) pathway function is highly associated with reading ability, which is mostly indexed by phonological skill in alphabetic languages. However, it is less clear how MD pathway function influences phonological skill. As a logographic language, Chinese does not follow grapheme-phoneme correspondence rules, and thus provides a tool for delineating the effects of orthographic and phonological processing on reading. The current study used functional magnetic resonance imaging (fMRI) to measure MD pathway function in a coherent motion detection task for readers skilled in Chinese. A series of tests was used to assess participants' reading abilities, including orthographic and phonological processing skills. Results showed that several cortical regions of the MD pathway, including bilateral middle temporal visual motion areas (MT+) and the right posterior parietal cortex (PPC), were activated during the coherent motion detection task. Moreover, the activation was positively correlated with rapid naming speed, and greater activation in the left MT+ was associated with superior fluency and reduced accuracy in reading, suggesting that this pathway is also involved in modulating the speed of visual processing during reading. The most important finding was that activation of the right PPC was associated with orthographic awareness, but MD pathway activation was not related to phonological awareness. The results suggest that the MD pathway is highly associated with orthographic processing, which in turn influences more general aspects of reading skill. PMID- 25813785 TI - Education section--Evidence Aid, present and future. PMID- 25813787 TI - MTCH2 is differentially expressed in rat testis and mainly related to apoptosis of spermatocytes. AB - MTCH2 has been described in liver as a protein involved in the intrinsic apoptotic pathway, although new evidence also associates this protein with cellular metabolism. In this work, the expression of MTCH2 in testis (an organ in which high levels of apoptosis normally take place as part of the spermatogenic process) is analyzed in rat, both at the mRNA and at the protein levels. Our results showed that MTCH2 was highly expressed in testis compared with other tissues and was differentially expressed according to developmental stage and testicular cell type. Protein expression was initially detected during the first spermatogenic wave at the time of meiosis onset and its levels increased in adulthood, with the highest expression levels being detected in meiotic prophase I. Specific differences in MTCH2 expression levels at the various stages of the adult seminiferous epithelium were also observed. Co-staining with TUNEL revealed a differential MTCH2 staining pattern in TUNEL-positive cells, mainly in dying primary spermatocytes, i.e., meiotic prophase I cells. Furthermore, upon mild hyperthermia (treatment shown to increase apoptosis in testis), MTCH2 levels rose concomitantly with a massive appearance of TUNEL-positive cells within the seminiferous tubules; these cells exhibited a differential MTCH2 distribution. Thus, MTCH2 is related to testicular apoptosis, especially during meiotic prophase. PMID- 25813788 TI - Expression of odorant receptor Olfr78 in enteroendocrine cells of the colon. AB - The precise regulation of digestive and other physiological processes in the gastrointestinal tract in accordance with the food ingested requires continuous monitoring of the luminal content by chemosensory cells. With regard to the detection of chemical compounds in the lumen of the gastrointestinal tract, G protein-coupled receptors (GPCRs) are interesting signaling proteins, since some of them are well known to bind to macronutrients, including sugars, amino acids and lipids. We report that Olfr78, a member of the odorant receptor (OR) class of GPCRs, is expressed in the murine gut. Our results support the concept that Olfr78 is activated by propionate, an important nutrient generated in the colon by microbiota. In situ hybridization and immunohistochemical approaches show that Olfr78 is expressed in the colon but is absent from other gastrointestinal compartments, such as the stomach and small intestine. In the colon, Olfr78 is expressed by a subset of epithelial cells lining the crypts; these cells are endowed with an apical process protruding towards the crypt lumen. The Olfr78 positive cells in the colon co-express the hormonal peptide YY (PYY), a marker for given enteroendocrine cells. The expression of the propionate receptor Olfr78 in epithelial enteroendocrine cells of the colon suggests that Olfr78 is involved in the regulation of hormone secretion from such cells, as evoked by nutritional compounds. PMID- 25813789 TI - The effect of psychosocial factors on outcomes of cochlear implantation. AB - CONCLUSION: Psychosocial factors should be considered during cochlear implantation (CI). There were differences in psychosocial characteristics according to the etiology of deafness. The outcomes may be affected by psychosocial variables such as the severity of mental distress and social problems as well as duration of deafness. OBJECTIVE: To evaluate the psychosocial characteristics of deaf people undergoing CI and to determine which psychosocial factors affect performance after CI. METHODS: A total of 289 subjects who underwent CI were enrolled. The participants were classified into prelingually deaf (pre-LD) and postlingually deaf groups (post-LD), including progressive and sudden deafness subgroups. The Minnesota Multiphasic Personality Inventory (MMPI) was administered before CI to measure psychosocial and emotional problems. To measure CI outcomes, speech perception ability was assessed by the open-set Korean version of the Central Institute of Deafness (K-CID) test and categories of auditory performance (CAP) scores before and after CI. RESULTS: Approximately 45% of subjects experienced psychological problems before undergoing CI. Subjects in the Pre-LD group had more psychosocial distress and were more likely to be oversensitive in interpersonal situations, while those in the post-LD group were more depressed. Deafness duration and psychosocial factors significantly predicted hearing ability after CI. Deafness duration directly and indirectly affected the outcome of CI. That is, duration of deafness caused psychosocial problems, which may have resulted in negative effects on outcomes of CI. PMID- 25813791 TI - Inhaled nitric oxide in acute pulmonary embolism: a systematic review. AB - Acute pulmonary embolism (PE) is usually a complication secondary to migration of a deep venous clot or thrombi to lungs, but other significant etiologies include air, amniotic fluid, fat, and bone marrow. Regardless of the underlying etiology, little progress has been made in finding an effective pharmacologic intervention for this serious complication. Among the wide spectrum of PE, massive PE is associated with considerable morbidity and mortality, primarily due to severely elevated pulmonary vascular resistance leading to right ventricular failure, hypoxemia, and cardiogenic shock. We currently have limited therapeutic options at our disposal. Inhaled nitric oxide (iNO) has been proposed as a potential therapeutic agent in cases of acute PE in which hemodynamic compromise secondary to increased pulmonary vascular resistance is present, based on iNO's selective dilation of the pulmonary vasculature and antiplatelet activity. A systematic search of studies using the PubMed database was undertaken in order to assess the available literature. Although there are currently no published randomized controlled trials on the subject, except a recently publish phase I trial involving eight patients, several case reports and case series describe and document the use of iNO in acute PE. The majority of published reports have documented improvements in oxygenation and hemodynamic variables, often within minutes of administration of iNO. These reports, when taken together, raise the possibility that iNO may be a potential therapeutic agent in acute PE. However, based on the current literature, it is not possible to conclude definitively whether iNO is safe and effective. These case reports underscore the need for randomized controlled trials to establish the safety and efficacy of iNO in the treatment of massive acute PE. The purpose of this article is to review the current literature in the use of iNO in the setting of PE given how acute PE causes acute onset of pulmonary hypertension. PMID- 25813792 TI - The Mystery of High-density Lipoprotein: Quantity or Quality? Update on Therapeutic Strategies. AB - This review summarizes the data challenging the concept that cardiovascular protection through high-density lipoprotein (HDL) is only associated with its serum concentration. This conventional impression about its protective role now appears obsolete. New aspects of its mechanisms are revealed and novel therapeutic strategies are based on them. However, data from long-term cost effectiveness studies of treating HDL are still needed. There is a need for biomarkers that represent the functional characteristics of HDL in order to better quantify the total cardiovascular risk. PMID- 25813790 TI - Multivariate neural biomarkers of emotional states are categorically distinct. AB - Understanding how emotions are represented neurally is a central aim of affective neuroscience. Despite decades of neuroimaging efforts addressing this question, it remains unclear whether emotions are represented as distinct entities, as predicted by categorical theories, or are constructed from a smaller set of underlying factors, as predicted by dimensional accounts. Here, we capitalize on multivariate statistical approaches and computational modeling to directly evaluate these theoretical perspectives. We elicited discrete emotional states using music and films during functional magnetic resonance imaging scanning. Distinct patterns of neural activation predicted the emotion category of stimuli and tracked subjective experience. Bayesian model comparison revealed that combining dimensional and categorical models of emotion best characterized the information content of activation patterns. Surprisingly, categorical and dimensional aspects of emotion experience captured unique and opposing sources of neural information. These results indicate that diverse emotional states are poorly differentiated by simple models of valence and arousal, and that activity within separable neural systems can be mapped to unique emotion categories. PMID- 25813793 TI - Heart failure with preserved ejection fraction: an insight into its prevalence, predictors, and implications of early detection. AB - Heart failure with preserved ejection fraction (HFPEF) is common, and at least half of patients presenting with signs and symptoms of heart failure are found to have preserved left ventricular systolic function. They have high mortality and morbidity and exert a substantial impact on health care costs worldwide. A range of conditions has been shown to predispose individuals to development of diastolic dysfunction and HFPEF. Chronic hypertension is the most common cause; it has been suggested that up to 60% of patients with HFPEF are hypertensive. Coronary artery disease, obesity, and diabetes are some of the other common contributory factors. Early detection of asymptomatic patients identified as at risk of developing this syndrome has the potential to reduce the risk of subsequent heart failure; this may be of benefit to focus our attention on prevention and intervention strategies in this population. PMID- 25813794 TI - Laboratory-induced Mental Stress, Cardiovascular Response, and Psychological Characteristics. AB - Vulnerable populations, such as firefighters and patients with coronary artery disease, are susceptible to mental stress-induced cardiac events, including death. Mental stress tests are widely applied to investigate the mechanisms linking psychological stress to cardiovascular consequences and to predict the risk of death in those susceptible populations. However, some aspects of mental stress tests have not been thoroughly understood, which impairs their reliability and validity as a research and clinical tool. This review identifies types of mental stress tests applied in recent research and the exact cardiovascular responses induced by each mental stress test, along with the consideration of the influence of psychological characteristics on cardiovascular reactivity. PMID- 25813795 TI - Current advances in endovascular therapy for infrapopliteal artery disease. AB - Peripheral arterial disease (PAD) is a systemic disease with significant morbidity and mortality. A substantial number of patients with PAD have infrapopliteal disease; however, diagnosis based solely on symptoms and ankle brachial index can lead to delayed or missed opportunities to provide improved quality of life and limb salvage, and potentially reduce mortality. Advances in techniques and devices, and modification of classification systems have shown that an endovascular approach should be the primary therapeutic option for critical limb ischemia resulting from infrapopliteal disease. PMID- 25813796 TI - Newer modalities for imaging nonischemic cardiomyopathy. AB - Cardiomyopathies are practically classified as either ischemic or nonischemic based on the presence or absence of coronary artery disease. Although conventional twodimensional echocardiography can assess left ventricular ejection fraction, wall motion, and diastolic function, it does not fully capture myocardial mechanics or tissue characterization, and does not accurately identify patients with nonischemic cardiomyopathy (NICMP) at risk for sudden cardiac death. This article discusses advanced imaging modalities for assessment of NICMP, namely, three-dimensional echocardiography, strain imaging, cardiac magnetic resonance, cardiac computed tomography, and sympathetic innervation imaging. PMID- 25813797 TI - A Novel Inhibitor of Protease-activated Receptor 1: A Review of Chemical Structure and Mode of Action. AB - Limitations of current antiplatelet therapies have led to the discovery of new antiplatelet agents with new modes of action. Vorapaxar has been developed as a thrombin receptor antagonist. This drug works against the protease-activated receptor 1 (PAR1) and inhibits platelet aggregation mediated by PAR1. This article reviews this new class of antiplatelet therapy in detail with an acute focus on the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) and TRA 2 degrees P-TIMI 50 (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) trials. Vorapaxar has proven to be beneficial when administered to stable atherosclerotic patients. However, it has been shown to increase risk of intracranial hemorrhage in patients with known, previous history of cerebrovascular incidence. Despite these limitations, TRA 2 degrees P-TIMI 50 results showed that vorapaxar appears to have a definitive therapeutic benefit when administered alongside aspirin or when it is used as an addition to dual antiplatelet therapy for patients with stable atherosclerosis. PMID- 25813798 TI - Best of the 2014 TCT Annual Meeting. PMID- 25813799 TI - The clot thickens: unusual presentation of a left atrial thrombus. AB - Left atrial thrombi are a significant cause of cardioembolic morbidity and mortality. Transesophageal echocardiography is the preferred method for complete visualization of atrial thrombi, and has a sensitivity and specificity of up to 100% and 99%, respectively. Cardiac magnetic resonance imaging has been shown to be useful in identifying tissue characteristics that may aid in differentiating between atrial myxoma and thrombi. This is an unusual case of a large, free floating atrial thrombus with a cystic appearance that was surgically removed. The echocardiographic appearance of the cystic atrial mass led to the consideration of another potential etiology for a cardiac mass, namely, atrial myxoma. Histopathologic analyses of the mass led to the final diagnosis of an atrial thrombus. PMID- 25813800 TI - An example of the deleterious effects of right ventricular apical pacing. AB - Pacemaker implantation remains the mainstay of treatment in patients with symptomatic sinus node disease or severe heart block. Despite the dramatic benefits of this therapy, a high burden of ventricular pacing is known to have its disadvantages. Reported is the case of an 85-year-old woman with a history of sick sinus syndrome who presented with congestive heart failure after her atrioventricular sequential pacemaker defaulted to ventricular pacing mode as a result of battery depletion. After replacement of her generator and reinstitution of atrial pacing, dramatic improvements in her symptoms and echocardiographic findings were observed. Although it is difficult to predict which patients will ultimately develop cardiac decompensation as a result of ventricular pacing, closer follow-up and early recognition of these complications is essential to prevent adverse outcomes. PMID- 25813801 TI - Pulmonary valve papillary fibroelastoma: a rare tumor and rare location. AB - Although rare, papillary fibroelastomas (PFEs) are considered the third most common cause of primary cardiac neoplasm. They are usually asymptomatic and are found during routine echocardiography. PFEs of the pulmonary valve are extremely rare. They are usually benign; however, because of their potential to embolize to the pulmonary circulation, it is often recommended that they be removed. This article reviews a case of an asymptomatic PFE of the pulmonary valve, incidentally found in a patient who presented with three-vessel coronary artery disease. PMID- 25813802 TI - Correction to "The Potential Role of Anti-PCSK9 Monoclonal Antibodies in the Management of Hypercholesterolemia". PMID- 25813803 TI - Differential regulation of apoptosis in slow and fast twitch muscles of aged female F344BN rats. AB - Age-related muscle atrophy is characterized by decreases in muscle mass and is thought be mediated, at least in part, by increases in myocyte apoptosis. Recent data has demonstrated that the degree of muscle loss with aging may differ between males and females while other work has suggested that apoptosis as indicated by DNA fragmentation may be regulated differently in fast- and slow twitch muscles. Herein, we investigate how aging affects the regulation of muscle apoptosis in the fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles of young (6-month), aged (26-month), and very aged (30-month) female Fischer 344/NNiaHSD * Brown Norway/BiNia (F344BN) rats. Tissue sections were stained with hydroethidium for ROS and protein extract was subjected to immunoblotting for assessing apoptotic markers. Our data suggest that decreases in muscle mass were associated with increased DNA fragmentation (TUNEL positive) and increases in reactive oxygen species (ROS) as determined by hydroethidium staining in both the EDL and soleus. Similar to our previous work using aged male animals, we observed that the time course and magnitude of changes in Bax, Bcl-2, caspase-3, caspase-9, and cleavage of alpha-fodrin protein were regulated differently between muscles. These data suggest that aging in the female F344BN rat is associated with decreases in muscle mass, elevations in ROS level, increased muscle cell DNA fragmentation, and alterations in cell membrane integrity and that apoptotic mechanisms may differ between fiber types. PMID- 25813804 TI - Ontogeny and aging of the distal skin temperature rhythm in humans. AB - In circadian terms, human ontogeny is characterized by the emergence of a daily pattern, from a previous ultradian pattern, for most variables during the first 6 months of life. Circadian aging in humans is characterized by a phase advance, accompanied by rhythm fragmentation and flattening. Despite an expanding body of literature focused on distal skin temperature, little information is available about the ontogeny and practically nothing about age-related changes in this rhythm. Thus, the aim was to evaluate the degree of maturation and aging of the circadian pattern of distal skin temperature to identify those parameters that are modified throughout life and could be used to differentiate subjects according to their age. For this, distal skin temperature was measured in 197 volunteers (55 % women), including babies aged 15 days (30 subjects), 1 month (28 subjects), 3 months (31 subjects), and 6 months (10 subjects); young adults aged 19 years (37 subjects); middle-aged persons aged 46 years (27 subjects); older people aged 72 (34 subjects). Circadian system maturation was associated with an increase in amplitude and a reduction in skin temperature during sleep. During adulthood, women showed a more robust pattern (lower fragmentation, and higher night-time temperature, amplitude, circadian function index, and first harmonic relative power); however, these differences were lost with aging, a period of life that was consistently associated with a phase advance of the rhythm. In summary, distal skin temperature pattern can be used as a robust variable to discern between different ages throughout the life. PMID- 25813805 TI - Alveolar bone dynamics in osteoporotic rats treated with raloxifene or alendronate: confocal microscopy analysis. AB - In this study, the characteristics of the alveolar bone of rats with induced osteoporosis were examined. Thirty-two rats were divided into four groups according to the induction of osteoporosis and drugs administered: OG, osteoporotic rats without treatment (negative control); SG, rats which underwent sham surgery ovariectomy (SHAM); alendronate (AG), osteoporotic rats treated with alendronate; and RG, osteoporotic rats treated with raloxifene (RG). On the 8th day after ovariectomy and SHAM surgeries, drug therapy was started with AG or RG. On the 52nd day, 20 mg/kg calcein was administered to all of the rats, and on the 80th day, 20 mg/kg alizarin red was administered. Euthanasia was performed on the 98th day. The bone area marked by fluorochromes was calculated and data were subjected to two-way ANOVA test and Tukey's post-hoc test (p < 0.05). The comparison of the induced osteoporosis groups showed no statistically significant differences in bone turnover only between RG and SG (p = 0.074) and AG and OG (p = 0.138). All other comparisons showed significant differences (p < 0.001). The largest bone turnover was observed in RG and SG groups. RG was the medication that improved the dynamics of the alveolar bone of rats with induced osteoporosis, resembling that of healthy rats. PMID- 25813806 TI - Duplicate publication: copy, salami, and imalas. PMID- 25813807 TI - Certificate or license. PMID- 25813808 TI - A Review on Usage and Effectiveness of e-Learning in Medical Education. AB - E-learning is recently considered as a critical strategy to improve the effectiveness and efficiency of education. Although the use of e-learning has been growing rapidly in medical education, there are not sufficient data applying e-learning and evidence of the effectiveness. The purpose of the study is to review the recent literatures on applying e-learning in medical education settings and to identify usage types and educational effectiveness appeared in the research. The results demonstrated the types applying e-learning in medical education were categorized into the blended learning, online education, and virtual learning environment. The educational effectiveness of e-learning were the improvements of knowledge, clinical skill, attitude, and satisfaction. The study suggested the recommendations based on the results in order to apply e learning effectively to medical education. PMID- 25813809 TI - Investigation of the requirements of 'good teaching' to improve teaching professionalism in medical education. AB - PURPOSE: The purpose of this study is to survey the awareness of faculty (F) and students (S) on 'good teaching' and to analyze an example of good lesson, finally to identify the requirements of 'good teaching' in medical education. METHODS: Quantitative and qualitative methods were applied simultaneously. First, survey using a questionnaire was analyzed by frequency analysis and verified using chi square-test, Mann-Whitney test. Second, the case of good teaching and qualitative data were analyzed by 'priori codes coding' and 'open coding'. RESULTS: The results of survey are as follows: Both faculty and students regarded lessons that taught important content easy to understand (F: 50%; S: 69.1%); Lessons that allow students make sure important information (F: 48.6%; S: 51.4%); Lessons that prepare and plan considering the student's level and interest (F: m=3.78; S: m=3.76) were good lessons. Faculty wanted lessons that improve student's academic achievement (35.7%), while students choose lessons that deliver curriculum effectively using appropriate teaching method (47.1%). According to the results of case analysis, it turned out that characteristics of good teaching were as follows: Thorough plan and preparation of content, various teaching methods and materials, encouragement of intellectual inquiry and curiosity, active interaction between faculty and students, clear feedback and reasonable evaluation. CONCLUSION: Requirements of good teaching are open to faculty at school of medicine and are to be utilized as guidelines to monitor and improve their instruction. PMID- 25813810 TI - Analysis of Medical School Alumni's Perception on the Importance and Educational Needs of Outcomes. AB - PURPOSE: This study examined how important graduates consider the 15 items of educational outcomes (importance) and how much they feel that they have achieved at graduation (accomplishment), determined whether outcomes varied according to profession, and assessed what graduates' educational needs are. METHODS: A questionnaire was given to 85 graduates of Ajou University School of Medicine. The data were analyzed by Kruskal-Wallis test using SPSS 12.0. The Borich formula was used to examine graduates' educational needs. RESULTS: Educational outcomes, such as medical knowledge and clinical skills at the basic medical levels, communication skills, and social accountabilities, were considered important in every profession. The Kruskal-Wallis test results demonstrated that the 15 items of educational outcomes were not significantly different between careers (p>0.05), but the average scores were. Doctors in private practice placed an emphasis on keeping a healthy body and mind and continuing lifelong learning; doctors in general hospitals emphasized understanding the health care industry's policies; and professors at university hospitals focused on proper medical ethics the house staff emphasized teamwork with colleagues. CONCLUSION: These test results can be used as basic materials for reflecting on educational objectives, student performance, and revision of the curricula. Further studies on how to measure educational outcomes are necessary. PMID- 25813811 TI - Correlation of communication skills for emotional empathy and academic achievement on clinical performance examinations. AB - PURPOSE: The purpose of this study was to identify the correlation between communication skills for emotional empathy and academic achievement on the Clinical Performance Examination (CPX). METHODS: One hundred twelve medical school students were observed to determine the extent to which they applied communication skills for emotional empathy (preparation stage: interview attitude, respect; rapport stage: encouragement, active listening, will for support; empathy stage: verbal expression empathy, nonverbal expression empathy, acceptance) to the CPX, as well as their level of understanding of these skills to calculate the Pearson r, which can be used to determine the correlation between communication skills and academic achievement (hematochezia, fatigue, abnormal menstruation, chest pain, alcohol problems). RESULTS: Male students had higher scores than females for all communicational skills except verbal expression empathy. Fourth-year students had statistically more significant correlations than third-year students with regard to the rapport stage 'active listening' and empathy stage 'nonverbal expression' and abnormal menstruation and chest pain. Correlations were also more significant for hematochezia in the preparation stage 'interview attitude,' rapport stage 'encouragement,' and empathy stages 'verbal and nonverbal expression' and 'acceptance.' The empathy stage 'nonverbal expressions' was more significant for fourth-year students with alcohol problems. Third-year students largely had negative correlations between emotional empathy communication skills and CPX academic achievement, especially between the preparation stage 'respect' and abnormal menstruation, and between the rapport stage 'encouragement' and hematochezia. CONCLUSION: There was a significant correlation between hematochezia, wherein MS students deliver bad news to patients, and communication skills for emotional empathy. PMID- 25813812 TI - Analysis of Verbal Interactions in Problem-based Learning. AB - PURPOSE: Problem-based learning (PBL) is a constructive learning environment that solves ill-structured problems through collaborative learning. The purpose of this study was to analyze the interaction of students and a tutor in a small group PBL discussion. This study examined how the types of interactions are composed over the meeting. METHODS: Fourteen third-year subjects from Chonnam National University Medical School, Korea formed two tutorial groups. Two tutorial sessions were videotaped and analyzed. All videotapes were transcribed to analyze the interaction type. The criteria of interaction analysis were learning-oriented interaction (exploratory questioning, cumulative reasoning, handling conflicts about the knowledge), procedural interactions, and irrelevant task interactions. RESULTS: Nearly all discourses between tutors and students were learning-oriented interactions. The results showed that students spent more time on cumulative reasoning. In contrast, tutors implemented more exploratory questioning. Little time was spent on handling conflicts about knowledge and procedural and irrelevant/off-task interactions. CONCLUSION: To improve critical thinking and problem-solving competence in PBL, we should consider various efforts to encourage discussion about conflicting knowledge. A PBL tutor training program should be provided to facilitate PBL group discussions. PMID- 25813813 TI - The Relationship between the Level of I-conscousness We-consciousness and Interpersonal Problems of Korean Medical Students. AB - PURPOSE: In Korea, students should have the consciousness of 'I' and 'we' to adapt well in society. Medical students in Korea must develop interpersonal and intrapersonal characteristics that are in accordance with Korean culture. This study intends to determine the relationship between the level of I consciousness/we-consciousness and interpersonal problems in medical students. METHODS: The I-consciousness/we-consciousness Inventory and the Inventory of Interpersonal Problems were used for 212 first year medical students and 191 second year medical students at Yonsei University College of Medicine in 2008. RESULTS: The levels of I-consciousness/we-consciousness and interpersonal problems in medical students were higher than those of other general college students. There was a significant inverse correlation between the level of I consciousness/we-consciousness and interpersonal problems for 118 of 130 factors. The higher the level of I-consciousness/we-consciousness in medical students is, the fewer interpersonal problems there are. CONCLUSION: Educational programs that take into account the consciousness of 'I' and 'we' are useful for the development of medical students' personalities. PMID- 25813814 TI - The importance of nonverbal communication skills. PMID- 25813815 TI - Handbook of individual differences, learning, and instruction. PMID- 25813816 TI - Pocket guide to teaching for medical instructors. PMID- 25813817 TI - Molecular detection of genes related to biofilm formation in multidrug-resistant Acinetobacter baumannii isolated from clinical settings. AB - Acinetobacter baumannii is a Gram-negative bacteria associated with hospital acquired infections. Definitely, antimicrobial resistance and biofilm formation capabilities of clinical isolates have threading potential to persistence in the hospital environment and colonization on medical equipment. Twenty-seven multidrug-resistant clinical isolates were selected from a collection of A. baumannii samples isolated from clinical settings. PCR assays showed the frequencies of genes related to biofilm formation: ompA (100%), bap (30%) and blaPER-1 (44%). Polyclonal antibodies against recombinant AbOmpA8-346 and Bap1 487 proteins were obtained by the mouse immunization method. Western blotting revealed all isolates expressed AbOmpA and only eight isolates were positive for Bap factor. Two strains that had their bap gene disrupted with ISAba125 did not express Bap protein. Our findings showed that all double-negative bap/blaPER-1 isolates were recovered from the bloodstream and had low biofilm formation capabilities, and mostly belonged to type D wrinkled colony morphology. However, clinical isolates extracted from the throats of patients were blaPER-1-positive and had a great capacity to form biofilm, and also mostly belonged to type C wrinkled colony morphology. PMID- 25813818 TI - Burden of varicella in Italy, 2001-2010: analysis of data from multiple sources and assessment of universal vaccination impact in three pilot regions. AB - Varicella represents the most widespread vaccine-preventable childhood infectious disease in Italy. The purpose of this retrospective study was to assess the burden of varicella in Italy and in three regions that first implemented universal varicella vaccination. Four data sources were analysed: statutory notification data, the National Hospital Discharge Database, mortality data, and the vaccination coverage reached in Sicilia, Veneto and Apulia. The incidence rates per 100,000 population were calculated using the Italian resident population provided by the Italian Institute of Statistics in 2001-2010. In 2001 2010, the mean annual incidence of notifications of varicella was 150.7 cases per 100,000 population, reaching 948.6 cases per 100,000 population in the paediatric age group. The annual incidence declined to 102.6 per 100,000 population in 2010. During the period considered, 20,295 hospitalizations for varicella were observed. The mean annual incidence was 3.4 per 100,000 population, reaching a minimum of 2.5 per 100,000 in 2009 and 2010. Of the hospitalizations, 68.4% occurred in the paediatric age group. The median length of hospital stay was 4 days. During 2001-2003 and 2006-2010, 33 deaths were reported. In the three regions considered, vaccination coverage increased steadily, reaching 81.5% in Sicily, 79.4% in Veneto and 75.6% in Apulia in 2010. During the same period, hospitalization and notification rates decreased significantly. This study demonstrated that varicella continues to represent a relevant health problem in Italy, especially in the paediatric age group. Data obtained from the three Italian regions that first introduced universal vaccination demonstrated that vaccination reduces the incidence of varicella and hospitalization rates. PMID- 25813819 TI - Mechanism of resistance and antibacterial susceptibility in extended-spectrum beta-lactamase phenotype Klebsiella pneumoniae and Klebsiella oxytoca isolated between 2000 and 2010 in Japan. AB - Clinical isolates of Klebsiella pneumoniae and Klebsiella oxytoca collected from 20 Japanese medical facilities between 2000 and 2010 were analysed to evaluate the mechanisms of resistance and antibacterial susceptibilities to 14 antimicrobials. Overall, eight of 484 (1.6%) K. pneumoniae and 19 of 359 (5.3%) K. oxytoca were determined to be extended-spectrum beta-lactamase (ESBL) phenotype isolates, and the identified ESBLs amongst the K. pneumoniae isolates were CTX-M-2, -3, -14 and -15, and SHV-12. In contrast, overproduction of chromosomal beta-lactamase OXY-2, which was due to a distinct mutation at the - 10 promoter region of this gene, conferred the ESBL phenotype to all the K. oxytoca isolates except one. Based on the Clinical and Laboratory Standards Institute breakpoints, all the ESBL phenotype K. pneumoniae were susceptible to doripenem, flomoxef, moxalactam (latamoxef), cefmetazole and tazobactam/piperacillin, whereas the ESBL phenotype K. oxytoca were susceptible to ceftazidime and ceftibuten in addition to the above, with the exception of tazobactam/piperacillin. Amongst the oral antimicrobials, ceftibuten was relatively effective against both ESBL phenotype Klebsiella species compared with levofloxacin and amoxicillin/clavulanic acid. PMID- 25813820 TI - Prevalence and virulence characteristics of enteroaggregative Escherichia coli in a case-control study among patients from Iran. AB - Enteroaggregative Escherichia coli (EAEC) is an important agent of diarrhoeal diseases worldwide. The role of EAEC virulence factors in the clinical outcome of infection is not completely defined. This case-control study investigated the prevalence of EAEC, its virulence genes and the antimicrobial resistance profile of adult patients with and without diarrhoea attending three different hospitals in Zanjan, Iran. A total of 550 individual stool specimens (350 from diarrhoeal patients and 200 from patients without diarrhoea) were collected. One hundred and forty-one EAEC isolates were identified by a HEp-2 cell assay and PCR. EAEC isolates were detected with slightly higher frequency in patients with (27.7%) than in patients without (22%) diarrhoea (P >= 0.05). The EAEC genes aggR, aap and pet were identified more frequently in case patients compared with controls (P <= 0.05). Many of the EAEC isolates from the diarrhoeal patients had two or more virulence genes compared with those without diarrhoea (P <= 0.05). EAEC isolates exhibited high-level resistance to amoxicillin (82.3%), co-amoxiclav (78%), aztreonam (73.8%), tetracycline (66.6%) and ceftazidime (63.8%). In addition, 53.2% of isolates were resistant to at least three different classes of antimicrobial agents and were considered to be multidrug resistant. These results indicate a high prevalence and heterogeneity of gene profiles of EAEC in diarrhoeal and control patients, and suggest that the presence of aggR, aap and pet, the number of genes present and the antimicrobial resistance profile may be markers for more-virulent EAEC isolates. PMID- 25813821 TI - Effects of erythromycin on the phenotypic and genotypic biofilm expression in two clinical Staphylococcus capitis subspecies and a functional analysis of Ica proteins in S. capitis. AB - The ica operon encoding polysaccharide intercellular adhesion, which facilitates biofilm formation in staphylococci, has been extensively studied in Staphylococcus epidermidis and Staphylococcus aureus. Based on in silico analysis, we suggest the following functional model for Ica proteins in S. capitis. IcaA is responsible for polysaccharide synthesis. IcaA and IcaD complete transferring the growing sugar chain to the cell surface; IcaB is a deacetylase, with the same function as IcaB of S. epidermidis. IcaC mainly modifies the synthesized glucan by acetylation. We also examined the effects of subinhibitory concentrations of erythromycin on phenotypic biofilm expression and transcription of biofilm-related genes, using isolates representing the two subspecies of Staphylococcus capitis and different biofilm and resistance phenotypes. On induction with erythromycin, biofilm density was strongly elevated in two erythromycin-resistant S. capitis, but not in three susceptible isolates. In the representative erythromycin-resistant S. capitis subsp. urealyticus, there were significant upregulations of the icaA gene and its positive regulator sarA on transition to the stationary phase without erythromycin induction. There were also significant increases in the transcription levels of icaA, rsbU and sigB corresponding to a very strong biofilm phenotype in the stationary phase on erythromycin stress. In contrast, the representative erythromycin-susceptible S. capitis subsp. capitis displayed upregulation only of altE on entry into the stationary phase with erythromycin induction, but this change was not associated with enhancement of biofilm production. These findings suggest that the two subspecies of S. capitis adopt different pathogenesis and survival strategies to adapt to a hostile environment. PMID- 25813822 TI - Loss of Leucine Zipper Putative Tumor Suppressor 1 (LZTS1) Expression Contributes to Lymph Node Metastasis of Breast Invasive Micropapillary Carcinoma. AB - Breast invasive micropapillary carcinoma (IMPC) is a rare subtype of breast cancer with a high potential of lymph node metastasis, aggressive clinical behavior, and poor disease-free or overall survival. Expression of leucine zipper putative tumor suppressor 1 (LZTS1) was frequently lost or reduced in breast cancer tissues. This study investigated the expression of LZTS1 protein in breast IMPC tissues using immunohistochemistry. In addition, somatic LZTS1 mutations and promoter methylation were assessed to determine an association with clinicopathological data from IMPC patients. LZTS1 protein was downregulated in 62 (62 %) of 100 IMPC tissue samples and was significantly associated with lymph node metastasis (P < 0.05). A LZTS1 exon mutation occurred in one of the 53 IMPC cases analyzed, whereas a LZTS1 intron mutation occurred in 26 of 53 cases. Moreover, LZTS1 promoter was frequently methylated in IMPC samples and was associated with reduced LZTS1 expression levels in IMPC tissues. These data demonstrated that the loss of LZTS1 expression was associated with lymph node metastasis in patients with IMPC, and LZTS1 promoter methylation could be responsible for the loss of LZTS1 expression. PMID- 25813823 TI - Hypertrophy of the Left Liver in Patients with Large Tumors in the Right Liver. AB - BACKGROUND: It has been speculated that, when right-sided major hepatectomy (RSMH) is planned for patients with large tumors in the right liver, it may not lead to a marked decrease in normally functional hepatic mass. METHODS: We collected data for patients who had undergone RSMH for tumors more than 8 cm in diameter (n=50) and compared them with control patients who had undergone RSMH for tumors less than 5 cm in diameter (n=21). RESULTS: The ratio of the remnant left liver volume to the nontumorous liver volume (left liver ratio) in the patients with large tumors was significantly greater than that in the control group (50.0+/-12.8% vs. 40.2+/-8.3%, p=0.002). Left liver ratio was significantly correlated with tumor volume (p<0.001). Preoperative portal vein embolization was performed in only four of the 50 patients with large tumors. None of the patients with large tumors developed postoperative liver failure. CONCLUSIONS: Left liver volume in patients with large tumors in the right liver was larger than usual, perhaps reducing the risk of postoperative liver insufficiency after RSMH. PMID- 25813824 TI - Laparoscopic Simultaneous Resection of Colorectal Primary Tumor and Liver Metastases: Results of a Multicenter International Study. AB - BACKGROUND: With the advance of modern laparoscopic technology, laparoscopic colorectal surgery and laparoscopic liver surgery are both worldwide accepted. Preliminary brief series have shown the feasibility of combined laparoscopic resection of colorectal cancer (CRC) and synchronous colorectal liver metastases (SCRLM). We aim to report a large International multicenter series of laparoscopic simultaneous resection of CRC and SCRLM. METHODS: Between 1997 and 2013, 142 laparoscopic liver resections were performed with simultaneous colorectal surgery for SCRLM. The surgical and postoperative variables evaluated were the duration of the intervention, blood loss, transfusion rate, conversion rate, resection margin, specific and overall morbidity, perioperative mortality, length of hospital stay, and survival. Univariate and multivariate analyses were performed examining postoperative morbidity in the all cohort of patients. RESULTS: The median number of liver lesions was 1 (1-9) and the median larger diameter at diagnosis was 28 (2-100) mm. The median operative time was 360 (120 690) min. Seven patients (4.9%) required conversion. The global morbidity was 31.0% and the mortality was 2.1%. After a median follow-up of 29 (1-108) months, 40 patients (28.2%) developed tumor recurrence. Curative treatment of recurrence was possible in 17 patients (12.0%), including a second liver resection in 13 patients (9.1%), which was performed by laparoscopy in 7 patients (4.9%). Overall 1-, 3-, and 5-year survivals were 98.8, 82.1, and 71.9%, respectively. By multivariate analysis, ASA score>=3 [OR 13.6 (1.8-99.6); P=0.01] and operative time [OR 1.008 (1.001-1.016); P=0.03] were independent predictors of postoperative morbidity. CONCLUSIONS: Our combined data show that in experienced centers, simultaneous laparoscopic approach is technically feasible, safe, and associated with good oncological outcomes. PMID- 25813826 TI - Analysis of calretinin early expression in the rat hippocampus after beta amyloid (1-42) peptide injection. AB - It has already been reported that cannabinoids are neuroprotective agents against excitotoxicity in vitro and increase after acute brain damage in vivo. This background prompted us to study the localization and expression of the calcium binding protein calretinin in a condition similar to Alzheimer disease and its possible relationship with cannabinoids and their supposed protective role. We carried out quantitative analysis of the transient changes in calretinin expression shown by hybridochemistry within neuronal cell populations in the hippocampus of a beta amyloid-treated rat model of Alzheimer's disease and their correlation with endocannabinoid increase. Calretinin expression increases throughout the first week after cortical amyloid-beta peptide injection, and then decreases towards normal levels in the rat hippocampus during the following weeks, indicating that decreased calretinin gene expression may be associated with either increase of endocannabinoids or VDM11-induced accumulation of endocannabinoids. In contrast, SR1, an antagonist, which limits the cannabinoid effect by selective binding to the cannabinoid receptor CB1, up-regulates calretinin expression with respect to non-treated rats. This could mean that the SR1 endocannabinoid-blocking action through CB1 receptors, that are normally stimulated by endocannabinoids to inhibit calcium increase, might cause a higher calretinin expression. This would allow us to speculate on a possible reverse relationship between endocannabinoid and calretinin levels in the hippocampal calcium-homeostasis balance. PMID- 25813825 TI - Celastrol supports survival of retinal ganglion cells injured by optic nerve crush. AB - The present study evaluates the effect of celastrol on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). Celastrol, a quinine methide triterpene extracted from the perennial vine Tripterygium wilfordii (Celastraceae), has been identified as a potential neuroprotective candidate in a comprehensive drug screen against various neurodegenerative diseases. Two weeks after ONC, the average density of remaining RGCs in retinas of animals treated with daily intraperitoneal (i.p.) injections of celastrol (1mg/kg) was approximately 1332 cells/mm(2), or 40.8% of the Celastrol/Control group. In retinas of the Vehicle/ONC group about 381 RGCs/mm(2) were counted, which is 9.6% of the total number of RGCs in the DMSO/Control group. This corresponds to approximately a 250% increase in RGC survival mediated by celastrol treatment compared to Vehicle/ONC group. Furthermore, the average RGC number in retinas of ONC animals treated with a single intravitreal injection of 1mg/kg or 5mg/kg of celastrol was increased by approximately 80% (760 RGCs/mm(2)) and 78% (753 RGCs/mm(2)), respectively, compared to Vehicle/ONC controls (422 cells/mm(2)). Injection of 0.2mg/kg of celastrol had no significant effect on cell survival, with the average number of RGCs being 514 cells/mm(2) in celastrol-treated animals versus 422 cells/mm(2) in controls. The expression levels of Hsp70, Hsf1, Hsf2, HO-1 and TNF-alpha in the retina were analyzed to evaluate the roles of these proteins in the celastrol-mediated protection of injured RGCs. No statistically significant change in HO-1, Hsf1 and Hsp70 levels was seen in animals with ONC. An approximately 2 fold increase in Hsf2 level was observed in celastrol-treated animals with or without injury. Hsf2 level was also increased 1.8 fold in DMSO-treated animals with ONC injury compared to DMSO-treated animals with no injury suggesting that Hsf2 induction has an injury-induced component. Expression of TNF-alpha in retinas of celastrol-treated uninjured and ONC animals was reduced by approximately 2 and 1.5 fold compared to vehicle treated animals, respectively. The observed results suggest that mechanisms underlying celastrol's RGC protective effect are associated with inhibition of TNF-alpha-mediated cell death. PMID- 25813827 TI - The influence of emotional salience on the integration of person names into context. AB - Previous event-related potentials (ERP) studies on the processing of emotional information in sentence/discourse context have yielded inconsistent findings. An important reason for the discrepancies is the different lexico-semantic properties of the emotional words. The present study controlled for the lexico semantic meaning of emotional information by endowing the same person names with either positive or negative valence. ERPs were computed for positively and negatively valenced person names that were either congruent or incongruent to previous emotional contexts. We found that positive names elicited an N400 effect while negative names elicited a P600 effect in response to the incongruence. These results suggest that the integration of positive and negative information into emotional context exhibits different time courses, with a relatively delayed integration for negative information. Our study demonstrates that using person names constitutes a new and improved tool for investigating the integration of emotional information into context. PMID- 25813830 TI - Journal of dairy Science(r) 2014 editorial report. PMID- 25813829 TI - Rates of TB across Europe are not falling quickly enough, officials warn. PMID- 25813828 TI - Interaction of astrocytes and T cells in physiological and pathological conditions. AB - The central nervous system (CNS) has long been recognized as a site of 'immune privilege' because of the existence of the blood brain barrier (BBB) which presumably isolates CNS from the peripheral immunosurveillance. Different from the peripheral organs, CNS is unique in response to all forms of CNS injury and disease which is mainly mediated by resident microglia and astrocyte. There is increasing evidence that immune cells are not only involved in neuroinflammation process but also the maintenance of CNS homeostasis. T cells, an important immune cell population, are involved in the pathogenesis of some neurological diseases by inducing either innate or adaptive immune responses. Astrocytes, which are the most abundant cell type in the CNS, maintain the integrity of BBB and actively participate in the initiation and progression of neurological diseases. Surprisingly, how astrocytes and T cells interact and the consequences of their interaction are not clear. In this review we briefly summarized T cells diversity and astrocyte function. Then, we examined the evidence for the astrocytes and T cells interaction under physiological and pathological conditions including ischemic stroke, multiple sclerosis, viral infection, and Alzheimer's disease. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke. PMID- 25813831 TI - Arthur Ferguson MacCallan: trachoma pioneer in Egypt 1903-1923. PMID- 25813832 TI - Evaluation of the distribution pattern of the circumpapillary retinal nerve fibre layer from the nasal hemiretina. AB - BACKGROUND/AIMS: Chiasmal compression affects the crossed nerve fibres originating from the nasal hemiretina, as opposed to the uncrossed fibres from the temporal hemiretina. The objectives were to evaluate circumpapillary retinal nerve fibre layer (cpRNFL) thickness by spectral-domain optical coherence tomography in eyes with band atrophy (BA) accompanying temporal hemianopia due to chiasmal damage and to estimate the distribution pattern of cpRNFL from the nasal hemiretina. METHODS: This cross-sectional study included 53 eyes with optic neuropathy due to chiasmal lesions and 72 normal eyes. Visual field sensitivity (VFS) was evaluated by standard automated perimetry. Eyes with abnormalities in the nasal visual hemifield were excluded. The structure-function relationships (cpRNFL thickness and VFS in the temporal hemifield) were evaluated in eyes with BA. The base levels composed of only non-neuronal elements and cpRNFL from the temporal hemiretina were estimated in the average and 12 sector-cpRNFL thicknesses using regression analysis. RESULTS: The base level in the average cpRNFL thickness was 71.2 um in eyes with BA, which corresponded to 70% of average thickness of normal controls. However, the estimated base level of 12 sector-cpRNFL thicknesses represented the unique distribution pattern, in which base level-thickness localised at the 1 o'clock and 5 o'clock sectors was extensively reduced, with an even distribution of base levels at other sectors. CONCLUSIONS: The RNFL originating from the nasal hemiretina is estimated to enter into the optic disc predominantly at the 1 o'clock and 5 o'clock angles. PMID- 25813834 TI - Hypothesis-driven research for hypothesis-driven application. PMID- 25813833 TI - Updates on artemisinin: an insight to mode of actions and strategies for enhanced global production. AB - Application of traditional Chinese drug, artemisinin, originally derived from Artemisia annua L., in malaria therapy has now been globally accepted. Artemisinin and its derivatives, with their established safety records, form the first line of malaria treatment via artemisinin combination therapies (ACTs). In addition to its antimalarial effects, artemisinin has recently been evaluated in terms of its antitumour, antibacterial, antiviral, antileishmanial, antischistosomiatic, herbicidal and other properties. However, low levels of artemisinin in plants have emerged various conventional, transgenic and nontransgenic approaches for enhanced production of the drug. According to WHO (2014), approximately 3.2 billion people are at risk of this disease. However, unfortunately, artemisinin availability is still facing its short supply. To fulfil artemisinin's global demand, no single method alone is reliable, and there is a need to collectively use conventional and advanced approaches for its higher production. Further, it is the unique structure of artemisinin that makes it a potential drug not only against malaria but to other diseases as well. Execution of its action through multiple mechanisms is probably the reason behind its wide spectrum of action. Unfortunately, due to clues for developing artemisinin resistance in malaria parasites, it has become desirable to explore all possible modes of action of artemisinin so that new generation antimalarial drugs can be developed in future. The present review provides a comprehensive updates on artemisinin modes of action and strategies for enhanced artemisinin production at global level. PMID- 25813835 TI - Effect of Dietary Selenomethionine Supplementation on Growth Performance, Tissue Se Concentration, and Blood Glutathione Peroxidase Activity in Kid Boer Goats. AB - We used 240 kid Boer goats that were divided into six groups. The control group was fed a basal diet containing 0.05 mg of selenium (Se)/kg dry matter (DM). Trial groups received the basal diet supplemented with 0.1, 0.2, 0.3, 0.4, or 0.5 mg Se/kg DM (using a commercial selenomethionine product). Trial groups showed an improvement in growth performance (P < 0.05) despite no change in average daily feed intakes (ADFIs) (P > 0.05) compared to the control group A, quadratic model showed a correlation between glutathione peroxidase activity level in whole blood and dietary Se concentration (R(2) = 0.883, P < 0.04). The best linear model showed that increasing concentrations of Se in the blood (R(2) = 0.968, P < 0.001) and muscle (R(2) = 0.942, P < 0.001) corresponded to increasing Se concentrations in feed. Accumulation of Se in different tissues and organs corresponded to increasing Se concentrations in the diet as well as to the total time goats spent feeding on supplemented diet. Kidney and muscle tissues showed the highest and lowest accumulation of Se, respectively. Thus, Se in goat meat can be increased by adding between 0.1 and 0.5 mg/kg of selenomethionine to the diet of goats. PMID- 25813836 TI - The dynamic shear moduli of whale blubber. AB - BACKGROUND: Blubber is a thick adipose tissue located beneath the dermas. Its viscoelastic properties affect whale tracking tag design, hydrodynamics, and acoustical properties that can be used to study animal behavior and avoid ship strikes. OBJECTIVE: Measure the dynamic shear storage and loss moduli for whale blubber at distances below the dermas for several species. Also, measure the non collagen and collagen protein content to explore a correlation to viscoelastic properties. METHODS: Blubber samples were obtained from whale strandings (humpback, sperm, and two gray) in the Pacific Northwest. Shear moduli were measured at oscillation frequencies of 0.31 Hz to 25 Hz using a rotational rheometer. Protein content was measured using a staining protocol. RESULTS: Storage modulus and loss modulus variation with frequency was very consistent across all samples tested. Log-linear and extended polynomials respectively had R squared values of at least 0.96. Variation of both moduli with depth was fit reasonably well by fourth-order polynomials. Protein content trends varied with species. CONCLUSIONS: The samples used in this study were necrotic tissue, however the variation with frequency and to a lesser extent depth was very consistent and may have a broader applicability. Protein content was not found to correlate to moduli values. PMID- 25813837 TI - Sudden cardiac death. Foreword. PMID- 25813838 TI - Sudden cardiac death. AB - Sudden death accounts for 300,000-400,000 deaths annually in the United States. Most sudden deaths are cardiac, and most sudden cardiac deaths are related to arrhythmias secondary to structural heart disease or primary electrical abnormalities of the heart. The most common structural disease leading to sudden death is ischemic heart disease. Nonischemic cardiomyopathy and other structural abnormalities such as arrhythmogenic ventricular dysplasia and hypertrophic cardiomyopathy may also be causative. Patients without structural disease have a primary electrical abnormality, such as long-QT syndrome or Brugada syndrome. Severe left ventricular systolic dysfunction is the main marker for sudden death in patients with ischemic or nonischemic cardiomyopathy. In other conditions, other markers for structural heart disease and electrical abnormalities need to be considered. It is seen that beta-blocker therapy is associated with a reduction in sudden cardiac death across a broad range of disorders. Nevertheless, the implantable cardioverter defibrillator remains the most effective treatment strategy in selected patients. PMID- 25813839 TI - Physicians' knowledge, perceptions and behaviour towards antibiotic prescribing: a systematic review of the literature. AB - BACKGROUND: Knowledge, perceptions and prescribing behaviour are key to antibiotic prescribing. The aim of this paper is to systematically review this. METHOD: An extensive literature search from 1990 to 2014. RESULTS: Nineteen articles were included; eight in ambulatory care, seven in hospital settings and four in both, across all countries. Physicians still have inadequate knowledge and misconceptions about antibiotic prescribing. Moreover, some physicians, although aware that antibiotics are of limited benefit in some conditions, still prescribed them. Several factors influenced prescribing, including patients' expectations, severity and duration of infections, uncertainty over diagnosis, potentially losing patients and influence of pharmaceutical companies. Pocket sized guidelines seen as an important source of information for physicians. CONCLUSION: Inadequate knowledge of prescribing is prevalent among physicians. However, many physicians were interested in improving their antibiotic prescribing. Multifaceted interventions targeting all key stakeholders, including patients, are needed to improve future antibiotic prescribing. PMID- 25813840 TI - Hyaluronic Acid-Based Nanogels Produced by Microfluidics-Facilitated Self Assembly Improves the Safety Profile of the Cationic Host Defense Peptide Novicidin. AB - PURPOSE: Cationic host defence peptides constitute a promising class of therapeutic drug leads with a wide range of therapeutic applications, including anticancer therapy, immunomodulation, and antimicrobial activity. Although potent and efficacious, systemic toxicity and low chemical stability have hampered their commercial development. To overcome these challenges a novel nanogel-based drug delivery system was designed. METHOD: The peptide novicidin was self-assembled with an octenyl succinic anhydride-modified analogue of hyaluronic acid, and this formulation was optimized using a microfluidics-based quality-by-design approach. RESULTS: By applying design-of-experiment it was demonstrated that the encapsulation efficiency of novicidin (15% to 71%) and the zeta potential (-24 to -57 mV) of the nanogels could be tailored by changing the preparation process parameters, with a maximum peptide loading of 36 +/- 4%. The nanogels exhibited good colloidal stability under different ionic strength conditions and allowed complete release of the peptide over 14 days. Furthermore, self-assembly of novicidin with hyaluronic acid into nanogels significantly improved the safety profile at least five-fold and six-fold when tested in HUVECs and NIH 3T3 cells, respectively, whilst showing no loss of antimicrobial activity against Escherichia coli and Staphylococcus aureus. CONCLUSION: Formulation in nanogels could be a viable approach to improve the safety profile of host defence peptides. PMID- 25813841 TI - Organochlorine pesticides and PCBs in Southern Right Whales (Eubalaena australis) breeding at Peninsula Valdes, Argentina. AB - Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were assessed in blubber from 35 dead Southern Right Whales (SRW - Eubalaena australis) stranded at Peninsula Valdes, Argentina. The life cycle includes a feeding period in high productivity areas of the South West Atlantic and a reproductive period in coastal template waters of Argentina. Organochlorine pesticides showed higher concentrations (22.6+/-13.8 ng.g(-1)ww) than PCBs (7.5+/ 10 ng.g(-1)ww). Among pesticides, HCHs, DDTs, endosulfans, dieldrin, chlordans, heptachlor epoxide, and trans-nonachlor were detected. p,p'-DDE and p,p'-DDT were present in 69% and 26% of samples, respectively. p,p'-DDT/p,p'-DDE ratio showed low values (<0.33) as a result of aged DDT inputs. However, the occurrence of only p,p'-DDT in some samples suggests a recent pesticide input. alpha-HCH/gamma HCH ratio (2 decades before the onset of dementia. Although the Abeta hypothesis of Alzheimer causation does not explain all features of this multifactorial syndrome, experimental agents that lower or neutralize Abeta have become the major focus of therapeutic research. Several clinical trials in mild to-moderate AD have not met standard cognitive and functional endpoints, but there were important shortcomings in the agent and/or the trial design in each case. Based on the lessons learned, the field has moved on to test potentially disease-modifying agents in mild AD patients or via secondary prevention in presymptomatic subjects bearing amyloid plaques. Immunotherapeutic agents are receiving the most study, but other antiamyloid strategies and, importantly, nonamyloid targets such as tau and neuroinflammation are of great interest. The pace of recent developments augurs well for 1 or more experimental agents being shown to slow cognitive decline without major side effects. However, research funding from all sources will need to increase dramatically and soon to stave off the approaching tsunami of AD. PMID- 25813843 TI - Comments on Singh et al.: Laser vaginal rejuvenation: not ready for prime time. PMID- 25813844 TI - Laser vaginal rejuvenation: not ready for prime time-response to comments by Maggiore et al. PMID- 25813845 TI - A comparison of chemical shift sensitivity of trifluoromethyl tags: optimizing resolution in 19F NMR studies of proteins. AB - The elucidation of distinct protein conformers or states by fluorine ((19)F) NMR requires fluorinated moieties whose chemical shifts are most sensitive to subtle changes in the local dielectric and magnetic shielding environment. In this study we evaluate the effective chemical shift dispersion of a number of thiol-reactive trifluoromethyl probes [i.e. 2-bromo-N-(4-(trifluoromethyl)phenyl)acetamide (BTFMA), N-(4-bromo-3-(trifluoromethyl)phenyl)acetamide (3-BTFMA), 3-bromo-1,1,1 trifluoropropan-2-ol (BTFP), 1-bromo-3,3,4,4,4-pentafluorobutan-2-one (BPFB), 3 bromo-1,1,1-trifluoropropan-2-one (BTFA), and 2,2,2-trifluoroethyl-1-thiol (TFET)] under conditions of varying polarity. In considering the sensitivity of the (19)F NMR chemical shift to the local environment, a series of methanol/water mixtures were prepared, ranging from relatively non-polar (MeOH:H2O = 4) to polar (MeOH:H2O = 0.25). (19)F NMR spectra of the tripeptide, glutathione ((2S)-2-amino 4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid), conjugated to each of the above trifluoromethyl probes, revealed that the BTFMA tag exhibited a significantly greater range of chemical shift as a function of solvent polarity than did either BTFA or TFET. DFT calculations using the B3LYP hybrid functional and the 6-31G(d,p) basis set, confirmed the observed trend in chemical shift dispersion with solvent polarity. PMID- 25813847 TI - Introduction. Hypoadrenocorticism. PMID- 25813846 TI - Human gephyrin is encompassed within giant functional noncoding yin-yang sequences. AB - Gephyrin is a highly conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis and other diverse functions. Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases. Here we report a remarkable yin-yang haplotype pattern encompassing gephyrin. Yin-yang haplotypes arise when a stretch of DNA evolves to present two disparate forms that bear differing states for nucleotide variations along their lengths. The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution. Several independent lines of evidence indicate strong positive selection on the region and suggest these high-frequency haplotypes represent two distinct functional mechanisms. This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history. PMID- 25813848 TI - Canine hypoadrenocorticism: pathogenesis, diagnosis, and treatment. AB - Hypoadrenocorticism (Addison disease) is an uncommon condition in dogs and even more rare in cats. Hypoadrenocorticism is most often caused by immune-mediated destruction of the adrenal glands resulting in decreased mineralocorticoid and glucocorticoid production. Although less common, some dogs with hypoadrenocorticism have normal serum electrolytes. Hypoadrenocorticism causes a wide variety of clinical symptoms including gastrointestinal upset, weakness, weight loss, and hypovolemia. Laboratory and diagnostic findings vary, but classic abnormalities include hyperkalemia, hyponatremia, azotemia, anemia, and lack of a stress leukogram. However, many other diseases present with similar symptoms and diagnostic findings. Definitive diagnosis requires adrenocorticotropic hormone (ACTH) stimulation testing to demonstrate low basal and post-ACTH cortisol levels. In some cases, ACTH level or basal- and ACTH stimulated aldosterone levels must also be measured. The prognosis for hypoadrenocorticism is good with appropriate mineralocorticoid and glucocorticoid supplementation. PMID- 25813849 TI - A review of the genetics of hypoadrenocorticism. AB - Hypoadrenocorticism is an uncommon disease in dogs and rare in humans, where it is known as Addison disease (ADD). The disease is characterized by a deficiency in corticosteroid production from the adrenal cortex, requiring lifelong hormone replacement therapy. When compared with humans, the pathogenesis of hypoadrenocorticism in dogs is not well established, although the evidence supports a similar autoimmune etiology of adrenocortical pathology. Several immune response genes have been implicated in determining susceptibility to Addison disease in humans, some of which are shared with other autoimmune syndromes. Indeed, other types of autoimmune disease are common (approximately 50%) in patients affected with ADD. Several lines of evidence suggest a genetic component to the etiology of canine hypoadrenocorticism. Certain dog breeds are overrepresented in epidemiologic studies, reflecting a likely genetic influence, supported by data from pedigree analysis. Molecular genetic studies have identified similar genes and signaling pathways, involved in ADD in humans, to be also associated with susceptibility to canine hypoadrenocorticism. Immune response genes such as the dog leukocyte antigen (DLA) and cytotoxic T-lymphocyte associated protein 4 (CTLA4) genes seem to be particularly important. It is clear that there are genetic factors involved in determining susceptibility to canine hypoadrenocorticism, although similar to the situation in humans, this is likely to represent a complex genetic disorder. PMID- 25813850 TI - Swimming kinematic and flotation analysis of conscious and sedated dogs using 3 canine flotation devices. AB - Canine flotation devices (CFDs) are very popular; however, their efficacy is still under debate. There is no oversight to standardize device testing, certification, or qualification for use. We set out to assess the biomechanical and behavioral effects of 3 CFDs on swim and flotation characteristics of dogs. High-speed video recordings were used to measure behavior, range of motion (ROM), maximum flexion angle, and cycles of motion per minute while swimming and roll, yaw, and fear or panic scoring while floating. Predictably, swimming with no CFD yielded the largest ROM and flexion angles. CFDINF was associated with the least ROM. During flotation, CFDAB and CFDRW caused significant rolling and fear, whereas CFDINF was the most stable. CFDAB was associated with cranial downpitch in 2 dogs. Interpretation of the kinematics for CFDAB and CFDRW suggests that decreased stability in the water leads to a greater forced ROM when the position of the dog was conducive to swimming. When positioning forced the dog into a downward pitch, ROM was decreased because of the increased effort for the dogs to keep their head above water. CFDINF was most stable overall owing to a decreased swim effort, with most dogs showing the lowest fear scores and absolute relaxation. CFDAB and CFDRW caused the dogs significant rolling, fear, and distress, with obvious fighting of sedation. We hope to disseminate these results to dog owners in the hopes of providing a valid assessment of these devices. PMID- 25813851 TI - Phenobarbital-responsive sialadenosis in dogs: case series. AB - Phenobarbital-responsive sialadenosis (PRS) is a rare idiopathic disease in dogs. Vomiting, retching, and gulping with bilateral enlargement of the submandibular salivary glands are the more frequent clinical signs. A thorough diagnostic examination must be performed to rule out the most important systemic etiologies involved with chronic vomiting, as there is no specific test to diagnose PRS. Diagnosis is confirmed clinically by a rapid and dramatic improvement of clinical signs after instauration of phenobarbital treatment. The aim of this article is to describe the clinical presentation, diagnostic findings, and outcome of a case series of 4 dogs with presumptive PRS. PMID- 25813852 TI - A case report of percutaneous endoscopic gastrostomy left-side gastropexy to resolve a recurrent gastric dilatation in a dog previously treated with right side gastropexy for gastric dilatation volvulus. AB - A 6-year-old, large-breed, female dog was evaluated for gastric dilatation (GD). The dog was affected by GD volvulus, which had been surgically treated with gastric derotation and right incisional gastropexy. Recurrence of GD appeared 36 hours after surgery. The dilatation was immediately treated with an orogastric probe but still recurred 4 times. Therefore, a left-side gastropexy by percutaneous endoscopic gastrostomy (PEG) was performed to prevent intermittent GD. After PEG tube placement, the patient recovered rapidly without side effects. Several techniques of gastropexy have been described as a prophylactic method for gastric dilatation volvulus, but to the authors' knowledge, this is the first report of left-sided PEG gastropexy performed in a case of canine GD recurrence after an incisional right gastropexy. PMID- 25813853 TI - Carotid Baroreceptor Stimulation in Resistant Hypertension and Heart Failure. AB - A significant number of hypertensive subjects fail to achieve adequate blood pressure control despite adherence to maximal doses of several antihypertensive drugs. In the same way although medical and device therapies continue to improve the clinical course of heart failure patients, morbidity, mortality and healthcare costs remain high. Electrical stimulation of the carotid sinus is a new interesting approach for the treatment of resistant hypertension and heart failure. The purpose of this paper is to overview the argument starting from physiological background and evaluating the clinical results obtained with this approach in these pathophysiological conditions. PMID- 25813854 TI - [The year of the horse and cancer of the urinary bladder]. PMID- 25813855 TI - Ischemic preconditioning increases GSK-3beta/beta-catenin levels and ameliorates liver ischemia/reperfusion injury in rats. AB - Ischemic preconditioning (IPC) ameliorates ischemia/reperfusion (I/R) injury in a number of organs, and the glycogen synthase kinase-3beta (GSK-3beta)/beta-catenin signaling pathway regulates I/R-induced proliferation and apoptosis in the central nervous system and heart. However, the function of this signaling pathway in IPC during liver I/R remains unclear. Thus, in this study, we aimed to investigte the role of the GSK-3beta/beta-catenin pathway during I/R and following ischemic preconditioning. For this purpose, 30 Sprague-Dawley rats were randomly divided into the sham-operated, the I/R and the IPC groups (n=10). Following reperfusion, liver pathology, as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST), maleic dialdehyde (MDA) and superoxide dismutase (SOD) levels were assessed. Western blot analysis was performed to quantify the GSK-3beta, Ser9-phospho-GSK-3beta (p-GSK-3beta), cytosolic and nuclear beta-catenin, vascular endothelial growth factor (VEGF), Bcl-2 and survivin levels. In addition, the Bcl-2 and survivin mRNA levels were assessed by RT-qPCR. Compared with the sham-operated group, I/R increased serum ALT, AST and MDA activity and decreased SOD levels, while IPC significantly decreased serum ALT, AST and MDA activity and increased SOD levels, compared with the I/R group. Simultaneously, I/R increased p-GSK-3beta protein expression, and decreased Bcl-2 and survivin protein and mRNA levels. IPC further increased the protein expression of p-GSK-3beta, and also increased cytosolic and nuclear beta-catenin and VEGF expression compared with the I/R group; the expression of Bcl-2 and survivin was also increased by IPC, both at the mRNA and protein level. The total GSK-3beta expression remained unaltered in all the groups. In conclusion, our data demonstrate that IPC exerts protective effects against liver injury induced by I/R and activates the GSK-3beta/beta-catenin signaling pathway. PMID- 25813856 TI - Conventional and advanced (DTI/SWI) neuroimaging findings in pediatric oligodendroglioma. AB - PURPOSE: Oligodendroglioma are rare pediatric brain tumors. The literature about neuroimaging findings is scant. A correct presurgical diagnosis is important to plan the therapeutic approach. Here, we evaluated the conventional and advanced neuroimaging features in our cohort of pediatric oligodendrogliomas and discuss our findings in the context of the current literature. METHODS: Clinical histories were reviewed for tumor grading, neurologic manifestation, treatment, and clinical status at the last follow-up. Neuroimaging studies were retrospectively evaluated for tumor morphology and characteristics on conventional and advanced magnetic resonance imaging (MRI). RESULTS: Five children with oligodendroglioma were included in this study. Four children were diagnosed with a low-grade oligodendroglioma. The location of the tumors included the frontal and temporal lobe in two cases each and the fronto-parietal lobe in one. In all oligodendrogliomas, tumor margins appeared sharp. In the high-grade oligodendroglioma, a cystic and partially hemorrhagic component was seen. In all children, the tumor showed a T1-hypointense and T2-hyperintense signal. The signal intensity on fluid attenuation inversion recovery (FLAIR) images was hyperintense in four and mixed hypo-hyperintense in one child. The anaplastic oligodendroglioma showed postcontrast enhancement and decreased diffusion while the low-grade oligodendrogliomas showed increased diffusion. One low-grade oligodendroglioma showed calcifications on susceptibility weighted imaging. CONCLUSION: Conventional MRI findings of pediatric oligodendrogliomas are nonspecific. Advanced MRI sequences may differentiate (1) low-grade and high grade pediatric oligodendrogliomas and (2) pediatric oligodendrogliomas and other brain tumors. PMID- 25813858 TI - Elucidation of several neglected reactions in the GC-MS identification of sialic acids as heptafluorobutyrates calls for an urgent reassessment of previous claims. AB - The current analytical protocol used for the GC-MS determination of free or 1,7 lactonized natural sialic acids (Sias), as heptafluorobutyrates, overlooks several transformations. Using authentic reference standards and by combining GC MS and NMR analyses, flaws in the analytical protocol were pinpointed and elucidated, thus establishing the scope and limitations of the method. It was demonstrated that (a) Sias 1,7-lactones, even if present in biological samples, decompose under the acidic hydrolysis conditions used for their release; (b) Sias 1,7-lactones are unpredicted artifacts, accidentally generated from their parent acids; (c) the N-acetyl group is quantitatively exchanged with that of the derivatizing perfluorinated anhydride; (d) the partial or complete failure of the Sias esterification-step with diazomethane leads to the incorrect quantification and structure attribution of all free Sias. While these findings prompt an urgent correction and improvement of the current analytical protocol, they could be instrumental for a critical revision of many incorrect claims reported in the literature. PMID- 25813857 TI - Taxonomic and functional annotation of gut bacterial communities of Eisenia foetida and Perionyx excavatus. AB - Epigeic earthworms can significantly hasten the decomposition of organic matter, which is known to be mediated by gut associated microflora. However, there is scanty information on the abundance and diversity of the gut bacterial flora in different earthworm genera fed with a similar diet, particularly Eisenia foetida and Perionyx excavatus. In this context, 16S rDNA based clonal survey of gut metagenomic DNA was assessed after growth of these two earthworms on lignocellulosic biomass. A set of 67 clonal sequences belonging to E. foetida and 75 to P. excavatus were taxonomically annotated using MG-RAST and RDP pipeline servers. Highest number of sequences were annotated to Proteobacteria (38-44%), followed by unclassified bacteria (14-18%) and Firmicutes (9.3-11%). Comparative analyses revealed significantly higher abundance of Actinobacteria and Firmicutes in the gut of P. excavatus. The functional annotation for the 16S rDNA clonal libraries of both the metagenomes revealed a high abundance of xylan degraders (12.1-24.1%). However, chitin degraders (16.7%), ammonia oxidizers (24.1%) and nitrogen fixers (7.4%) were relatively higher in E. foetida, while in P. excavatus; sulphate reducers and sulphate oxidizers (12.1-29.6%) were more abundant. Lignin degradation was detected in 3.7% clones of E. foetida, while cellulose degraders represented 1.7%. The gut microbiomes showed relative abundance of dehalogenators (17.2-22.2%) and aromatic hydrocarbon degraders (1.7 5.6%), illustrating their role in bioremediation. This study highlights the significance of differences in the inherent microbiome of these two earthworms in shaping the metagenome for effective degradation of different types of biomass under tropical conditions. PMID- 25813859 TI - Continuous topical drug delivery using osmotic pump in animal cochlear implant model: Continuous steroid delivery is effective for hearing preservation. AB - CONCLUSIONS: Continuous topical drug delivery using an osmotic pump is an effective supplementary technique for hearing preservation after cochlear implantation, as demonstrated in a guinea pig model. OBJECTIVE: To evaluate the effect of continuous topical steroid delivery via an osmotic pump in an animal cochlear implant model. METHODS: Twenty-three guinea pigs were used for the study. The animals were divided into three groups: control group (n = 8), simple topical dexamethasone delivery group (sDEXA group, n = 7) and continuous topical dexamethasone delivery group (cDEXA, n = 8). The hearing thresholds of all animals were measured by pre-operative auditory brain stem responses (ABRs) at 2, 8, 16, 24, and 32 kHz. ABRs were re-evaluated after cochlear implantation, and the animals were sacrificed for hematoxylin and eosin staining. RESULTS: The ABR threshold at 1 week post-operatively was significantly lower in the cDEXA group than in the control and sDEXA groups at most frequencies. Threshold shifts from baseline were statistically smaller in the cDEXA group than in the control and sDEXA groups at all frequencies. Histological analysis revealed decreased numbers of multi-nucleated giant cells and thinner histiocyte layers. PMID- 25813861 TI - Yeast transcription co-activator Sub1 and its human homolog PC4 preferentially bind to G-quadruplex DNA. AB - Using a G-quadruplex bait, we identified the transcription co-activator Sub1 as a G-quadruplex binding protein by quantitative LC-MS/MS and demonstrated in vivo G quadruplex binding by ChIP. In vitro, Sub1, and its human homolog PC4, bind preferentially to G-quadruplexes. This provides a possible mechanism by which G quadruplexes can influence gene transcription. PMID- 25813862 TI - Hynobiidae origin in middle Cretaceous corroborated by the new mitochondrial genome of Hynobius chinensis. AB - Hynobius chinensis was first described by Gunther in the nineteenth century. At present, the origins of the extinct Hynobius chinensis on the Zhoushan Island (Hynobius chinensis-ZI) remain a mystery. It is the only species of family Hynobiidae on the Zhoushan Island. However, there is very little empirical evidence regarding Hynobius chinensis-ZI phylogenetic relationship, and when or how did its ancestors colonized the island. Here, we used mitochondrial genome data to recover the phylogeny of family Hynobiidae. Results suggested that the origin of Hynobiidae was most likely in Middle Cretaceous (~112.9 Mya), and some Hynobius species of Taiwan and Japan diverged earlier than that of the mainland of China. Hynobius chinensis-ZI diverged from its closest living relative (Hynobius yiwuensis) around 6.5 Mya, and Hynobius chinensis-ZI was isolated on Zhoushan Island since the postglacial transgression in Holocene period. PMID- 25813860 TI - Signaling Pathways and Gene Regulatory Networks in Cardiomyocyte Differentiation. AB - Strategies for harnessing stem cells as a source to treat cell loss in heart disease are the subject of intense research. Human pluripotent stem cells (hPSCs) can be expanded extensively in vitro and therefore can potentially provide sufficient quantities of patient-specific differentiated cardiomyocytes. Although multiple stimuli direct heart development, the differentiation process is driven in large part by signaling activity. The engineering of hPSCs to heart cell progeny has extensively relied on establishing proper combinations of soluble signals, which target genetic programs thereby inducing cardiomyocyte specification. Pertinent differentiation strategies have relied as a template on the development of embryonic heart in multiple model organisms. Here, information on the regulation of cardiomyocyte development from in vivo genetic and embryological studies is critically reviewed. A fresh interpretation is provided of in vivo and in vitro data on signaling pathways and gene regulatory networks (GRNs) underlying cardiopoiesis. The state-of-the-art understanding of signaling pathways and GRNs presented here can inform the design and optimization of methods for the engineering of tissues for heart therapies. PMID- 25813863 TI - Label-free in vivo molecular imaging of underglycosylated mucin-1 expression in tumour cells. AB - Alterations in mucin expression and glycosylation are associated with cancer development. Underglycosylated mucin-1 (uMUC1) is overexpressed in most malignant adenocarcinomas of epithelial origin (for example, colon, breast and ovarian cancer). Its counterpart MUC1 is a large polymer rich in glycans containing multiple exchangeable OH protons, which is readily detectable by chemical exchange saturation transfer (CEST) MRI. We show here that deglycosylation of MUC1 results in >75% reduction in CEST signal. Three uMUC1(+) human malignant cancer cell lines overexpressing uMUC1 (BT20, HT29 and LS174T) show a significantly lower CEST signal compared with the benign human epithelial cell line MCF10A and the uMUC1(-) tumour cell line U87. Furthermore, we demonstrate that in vivo CEST MRI is able to make a distinction between LS174T and U87 tumour cells implanted in the mouse brain. These results suggest that the mucCEST MRI signal can be used as a label-free surrogate marker to non-invasively assess mucin glycosylation and tumour malignancy. PMID- 25813864 TI - Aberrant hypomethylation-mediated CD147 overexpression promotes aggressive tumor progression in human prostate cancer. AB - Our previous study revealed the potential role of CD147 in human prostate cancer (PCa). Here, we investigated the CD147 promoter methylation status and the correlation with tumorigenicity in human PCa. CD147 mRNA and protein expression levels were both significantly higher in the 4 PCa cell lines, than in the 2 non tumorigenic benign human prostatic epithelial cell lines (all P<0.01). We showed hypomethylation of promoter regions of CD147 in PCa cell lines with significant CD147 expression as compared to non-tumorigenic benign human prostatic epithelial cell lines slowly expressing CD147. Additionally, the treatment of methylated cell lines with 5-aza-2'-deoxycytidine increased CD147 expression significantly in low-expressing cell lines and also activated the expression of matrix metalloproteinase (MMP)-2, which may be one of the most important downstream targets of CD147. Furthermore, PCa tissues displayed decreased DNA methylation in the promoter region of CD147 compared to the corresponding non-cancerous prostate tissues, and methylation intensity correlated inversely with the CD147 mRNA levels. There was a significant negative correlation between CD147 mRNA levels and the number of methylated sites in PCa tissues (r=-0.467, P<0.01). In conclusion, our data offer convincing evidence for the first time that the DNA promoter hypomethylation of CD147 may be one of the regulatory mechanisms involved in the cancer-related overexpression of CD147 and may play a crucial role in the tumorigenesis of PCa. PMID- 25813865 TI - Health in middle-aged and elderly women: A conceptual framework for healthy menopause. AB - Middle-aged and elderly women constitute a large and growing proportion of the population. The peri and postmenopausal period constitutes a challenging transition time for women's health, and menopausal health is a crucial aspect in healthy and successful aging. Currently, no framework for the concept of healthy menopause exists, despite its recognized importance. Therefore, we aimed to: (i) characterize healthy menopause; (ii) identify aspects that contribute to it; and (iii) explore potential approaches to measure it. We propose healthy menopause as a dynamic state, following the permanent loss of ovarian function, which is characterized by self-perceived satisfactory physical, psychological and social functioning, incorporating disease and disability, allowing the attainment of a woman's desired ability to adapt and capacity to self-manage. The concept of healthy menopause applies to all women from the moment they enter the menopausal transition, up until they reach early and late postmenopause and includes women with spontaneous, iatrogenic, and premature menopause. This conceptualization can be considered as a further step in the maintenance and improvement of health in menopausal women from different perspectives, foremost the woman's own perspective, followed by the clinical, public health, and societal perspectives, and can be seen as a further step in delineating lines for future research. Furthermore, it could facilitate the improvement of adequate preventive and treatment strategies, guide scientific efforts, and aid education and communication to health care practitioners and the general public, allowing women the achievement of their potential and the fulfillment of their fundamental role in society. PMID- 25813866 TI - Erratum to: Isoprenoid Drugs, Biofuels, and Chemicals--Artemisinin, Farnesene, and Beyond. PMID- 25813867 TI - Defining the Role of the Tibial Tubercle-Trochlear Groove and Tibial Tubercle Posterior Cruciate Ligament Distances in the Work-up of Patients With Patellofemoral Disorders. AB - BACKGROUND: The radiological work-up of patients with patellofemoral disorders continues to be debated. The interchangeability of the tibial tubercle-trochlear groove (TT-TG) distance between computed tomography (CT) and magnetic resonance imaging (MRI) has recently been questioned. In addition, a new measurement-the tibial tubercle-posterior cruciate ligament (TT-PCL) distance-has shown that not all patients with a pathological TT-TG distance (>20 mm) have lateralization of the tibial tubercle. Another factor to consider when looking at the position of the tibial tubercle is the knee joint rotation, defined as the angle between the femoral dorsal condylar line and the tibial dorsal condylar line. PURPOSE: To determine, with a larger population, if the TT-TG measurements can be used interchangeably between CT and MRI and to confirm the correlation between the TT PCL and TT-TG distances in determining tibial tubercle lateralization. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Patients with patellofemoral disorders and MRI and CT scans of the same knee (n = 141) were identified. The TT-PCL, the knee joint rotation, and TT-TG were measured independently by 2 fellowship-trained orthopaedic surgeons. Thirty measurements were repeated on a separate occasion to allow for an assessment of the intrarater reliability. The intraclass correlation coefficient (ICC) was used to assess reliability of the measurements. RESULTS: The mean TT-TG was 4.16 mm less on MRI (P < .05), with the mean TT-TG +/- SD being 17.72 +/- 5.15 mm on CT (range, 6.97 31.33 mm) and 13.56 +/- 6.07 mm on MRI (range, 2-30.04 mm). The ICC for each rater comparing the 2 imaging modalities was only fair (0.54 and 0.48). The mean TT-PCL measurement was 20.32 +/- 3.45 mm (range, 10.11-32.01 mm) with excellent interobserver and intraobserver reliability (>0.75). Based on the TT-TG and TT PCL measurements, 4 groups of patients can be established. When knee joint rotation is compared among groups, an increased TT-TG may result from true lateralization of the tibial tubercle, an increased knee joint rotation, or both. CONCLUSION: Based on a statistically significant mean difference (4.11 mm) and only a fair ICC (0.54 and 0.48) for raters comparing the 2 modalities, the measurements for the TT-TG cannot be used interchangeably between CT and MRI. Therefore, currently accepted values for TT-TG based on CT scans should not be applied to an MRI scan. The TT-PCL measurement is a measure of true lateralization of the tibial tubercle, while the TT-TG is an amalgamated measure of true lateralization and knee joint rotation. PMID- 25813868 TI - Mortality in female and male French Olympians: a 1948-2013 cohort study. AB - BACKGROUND: Whereas intense physical activity has been associated with deleterious effects on elite athletes' health, in particular due to cardiovascular anomalies, long-term follow-ups have suggested lower mortality rates among elite athletes. Causes of death for French Olympic athletes and female elite athletes have not been studied. HYPOTHESIS/PURPOSE: We aimed to measure overall and disease-specific mortality of French female and male Olympians compared with the French general population. We hypothesize that Olympians, both women and men, have lower mortality rates. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: French elite athletes (601 women and 1802 men) participating in summer or winter Olympic Games from 1948 to 2010 had their vital status verified by national sources and were followed until 2013. Causes of death were obtained via the National Death registry from 1968 to 2012. Overall and disease-specific mortalities of Olympians were compared with those of the French general population through standardized mortality ratios (SMRs) and 95% CIs. Olympians' observed and expected survivals were illustrated by Kaplan-Meier curves. RESULTS: At the endpoint of the study, 13 women and 222 men had died. Overall mortality in Olympians compared with that of their compatriots was 51% lower (SMR, 0.49; 95% CI, 0.26-0.85) among women and 49% lower (SMR, 0.51; 95% CI, 0.45-0.59) among men. Olympic athletes' survival is significantly superior to that of the French general population (women, P = .03; men, P < .001). According to the total deaths occurring from 1968 to 2012 (12 among women, 202 among men), female Olympians died from neoplasm (50.0%), external causes (33.3%), and cardiovascular diseases (16.6%). The main causes of death among men were related to neoplasms (36.1%), cardiovascular diseases (24.3%), and external causes (14.4%). Regarding the main causes of mortality among male Olympic athletes, the SMRs were as follows: 0.55 for neoplasms (95% CI, 0.43-0.69), 0.55 for cardiovascular diseases (95% CI, 0.41-0.73), and 0.66 for external causes (95% CI, 0.44-0.94). CONCLUSION: French Olympians live longer than their compatriots: A lower overall mortality of similar magnitude is observed among male and female athletes compared with the general population. The main causes of death in French Olympians are neoplasms, cardiovascular diseases, and external causes. PMID- 25813870 TI - Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria. AB - In 1964, Miyoshi reported a series of patients with diverse symptoms after receiving treatment with silicone or paraffin fillers. Miyoshi named this condition 'human adjuvant disease'. Since then, the literature has been flooded with case reports and case series of granulomatous and systemic autoimmune disorders related to vaccines, infection or other adjuvants such as silicone and other biomaterials. A new term -autoimmune/inflammatory syndrome induced by adjuvants--has recently been coined for a process that includes several clinical features previously described by Miyoshi plus other clinical and laboratory parameters related to exposure to diverse external stimuli. Disorders such as siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, sick building syndrome and post-vaccination syndrome have been included in autoimmune/inflammatory syndrome induced by adjuvants. Disorders such as Spanish toxic oil syndrome and Ardystil syndrome could also be included. Furthermore, biomaterials other than silicone should also be considered as triggering factors for these adjuvant-related syndromes. New diagnostic criteria in this field have been proposed. Nevertheless, many of these criteria are too subjective, leading to some patients being diagnosed with chronic fatigue syndrome or other 'central sensitization syndromes'. Diagnostic criteria based only on objective clinical and laboratory data to be further discussed and validated are proposed herein. PMID- 25813869 TI - Stimulation of the superficial zone protein and lubrication in the articular cartilage by human platelet-rich plasma. AB - BACKGROUND: Platelet-rich plasma (PRP) contains high concentrations of autologous growth factors that originate from platelets. Intra-articular injections of PRP have the potential to ameliorate the symptoms of osteoarthritis in the knee. Superficial zone protein (SZP) is a boundary lubricant in articular cartilage and plays an important role in reducing friction and wear and therefore is critical in cartilage homeostasis. PURPOSE: To determine if PRP influences the production of SZP from human joint-derived cells and to evaluate the lubricating properties of PRP on normal bovine articular cartilage. STUDY DESIGN: Controlled laboratory study. METHODS: Cells were isolated from articular cartilage, synovium, and the anterior cruciate ligament (ACL) from 12 patients undergoing ACL reconstruction. The concentrations of SZP in PRP and culture media were measured by enzyme-linked immunosorbent assay. Cellular proliferation was quantified by determination of cell numbers. The lubrication properties of PRP from healthy volunteers on bovine articular cartilage were investigated using a pin-on-disk tribometer. RESULTS: In general, PRP stimulated proliferation in cells derived from articular cartilage, synovium, and ACL. It also significantly enhanced SZP secretion from synovium- and cartilage-derived cells. An unexpected finding was the presence of SZP in PRP (2.89 +/- 1.23 MUg/mL before activation and 3.02 +/- 1.32 MUg/mL after activation). In addition, under boundary mode conditions consisting of high loads and low sliding speeds, nonactivated and thrombin-activated PRP decreased the friction coefficient (MU = 0.012 and MU = 0.015, respectively) compared with saline (MU = 0.047, P < .004) and high molecular weight hyaluronan (MU = 0.080, P < .006). The friction coefficient of the cartilage with PRP was on par with that of synovial fluid. CONCLUSION: PRP significantly stimulates cell proliferation and SZP secretion by articular cartilage and synovium of the human knee joint. Furthermore, PRP contains endogenous SZP and, in a functional bioassay, lubricates bovine articular cartilage explants. CLINICAL RELEVANCE: These findings provide evidence to explain the biochemical and biomechanical mechanisms underlying the efficacy of PRP treatment for osteoarthritis or damage in the knee joint. PMID- 25813871 TI - Primary prophylaxis to prevent obstetric complications in asymptomatic women with antiphospholipid antibodies: a systematic review. AB - OBJECTIVE: Obstetric complications are common in patients with antiphospholipid syndrome. However, the impact of antiphosholipid antibodies (aPL) in the pregnancy outcomes of asymptomatic aPL carriers is uncertain. The aim of this systematic review is to assess whether primary prophylaxis is beneficial to prevent obstetric complications during pregnancy in asymptomatic women positive for aPL who have no history of recurrent pregnancy loss or intrauterine fetal death. METHODS: Studies evaluating the effect of prophylactic treatment versus no treatment in asymptomatic pregnant aPL carriers were identified in an electronic database search. Design, population and outcome homogeneity of studies was assessed and meta-analysis was performed. The pooled Mantel-Haenszel relative risk of specific pregnancy outcomes was obtained using random effects models. Heterogeneity was measured with the I(2) statistic. All analyses were conducted using Review Manager 5.3. RESULTS: Data from five studies involving 154 pregnancies were included and three studies were meta-analysed. The risk ratio and 95% confidence interval (CI) of live birth rates, preterm birth, low birth weight and overall pregnancy complications in treated and untreated pregnancies were 1.14 (0.18-7.31); 1.71 (0.32-8.98); 0.98 (0.07-13.54) and 2.15 (0.63 7.33),respectively. Results from the meta-analysis revealed that prophylactic treatment with aspirin is not superior to placebo to prevent pregnancy complications in asymptomatic aPL carriers. CONCLUSION: This systematic review did not find evidence of the superiority of prophylactic treatment with aspirin compared to placebo or usual care to prevent unfavourable obstetric outcomes in otherwise healthy women with aPL during the first pregnancy. PMID- 25813872 TI - Outcome of patients with systemic lupus erythematosus on chronic dialysis: an observational study of incident patients of the French National Registry 2002 2012. AB - OBJECTIVES: The objective of this article is to describe the outcome (mortality, kidney transplantation) of patients with systemic lupus erythematosus (SLE) on chronic dialysis. METHODS: The overall and cardiovascular (CV) mortality and access to kidney transplantation were studied in all SLE patients incident on chronic dialysis in France between 2002 and 2012 (REIN registry). They were compared to age- and sex-matched patients with diabetic nephropathy and with autosomal dominant polycystic kidney disease (PKD) on chronic dialysis. RESULTS: A total of 368 SLE patients were included in the national REIN registry between 2002 and 2012. Cumulative incidence of death was 16.9% at five years, with no difference between haemodialysis and peritoneal dialysis. Independent risk factors of death were age, past history of cardiovascular disease (CVD) and chronic respiratory insufficiency. At five years, CV and all-cause mortality in SLE patients were lower than in matched diabetic patients, but three-fold higher than in matched PKD patients. Access to the kidney transplant waiting list and to kidney transplantation was higher in SLE patients than in matched diabetic patients, but lower than in matched PKD patients. CONCLUSIONS: SLE patients on chronic dialysis are a population at high risk of death influenced by CV burden and chronic respiratory failure, but not by the method of dialysis. Their outcome, in terms of mortality and access to kidney transplantation, is intermediate between diabetic patients and patients with PKD. PMID- 25813873 TI - Prohibitin-2 gene reveals sex-related differences in the salmon louse Caligus rogercresseyi. AB - Prohibitins are evolutionarily conserved proteins present in multiple cellular compartments, and are involved in diverse cellular processes, including steroid hormone transcription and gametogenesis. In the present study, we report for the first time the characterization of the prohibitin-2 (Phb2) gene in the sea lice Caligus rogercresseyi. The CrPhb2 cDNA showed a total length of 1406 bp, which contained a predicted open reading frame (ORF) of 894 base pairs (bp) encoding for 298 amino acids. Multiple sequence alignments of prohibitin proteins from other arthropods revealed a high degree of amino acid sequence conservation. In silico Illumina read counts and RT-qPCR analyses showed a sex-dependent differential expression, with mRNA levels exhibiting a 1.7-fold (RT-qPCR) increase in adult females compared with adult males. A total of nine single nucleotide polymorphisms (SNPs) were identified, three were located in the 5' UTR of the Phb2 messenger and six in the ORF, but no mutations associated with sex were found. These results contribute to expand the present knowledge of the reproduction-related genes in C. rogercresseyi, and may be useful in future experiments aimed at controlling the impacts of sea lice in fish farming. PMID- 25813874 TI - Genomic context drives transcription of insertion sequences in the bacterial endosymbiont Wolbachia wVulC. AB - Transposable elements (TEs) are DNA pieces that are present in almost all the living world at variable genomic density. Due to their mobility and density, TEs are involved in a large array of genomic modifications. In eukaryotes, TE expression has been studied in detail in several species. In prokaryotes, studies of IS expression are generally linked to particular copies that induce a modification of neighboring gene expression. Here we investigated global patterns of IS transcription in the Alphaproteobacterial endosymbiont Wolbachia wVulC, using both RT-PCR and bioinformatic analyses. We detected several transcriptional promoters in all IS groups. Nevertheless, only one of the potentially functional IS groups possesses a promoter located upstream of the transposase gene, that could lead up to the production of a functional protein. We found that the majority of IS groups are expressed whatever their functional status. RT-PCR analyses indicate that the transcription of two IS groups lacking internal promoters upstream of the transposase start codon may be driven by the genomic environment. We confirmed this observation with the transcription analysis of individual copies of one IS group. These results suggest that the genomic environment is important for IS expression and it could explain, at least partly, copy number variability of the various IS groups present in the wVulC genome and, more generally, in bacterial genomes. PMID- 25813875 TI - Interleukin and growth factor gene variants and risk of carpal tunnel syndrome. AB - Recent research has identified DNA sequence variants within genes encoding structural components of the collagen fibril, the basic structural unit of tendons, to modify the risk of carpal tunnel syndrome (CTS). Since the expression of these previously associated genes are regulated by cytokine and growth factor signalling pathways, the aim of this study was to determine whether variants within these cell signalling pathway genes, namely interleukin 1beta (IL-1beta), IL-6, interleukin 6 receptor (IL-6R) and vascular endothelial growth factor A(VEGFA), are also associated with CTS. One hundred and three self-reported Coloured participants, with a history of carpal tunnel release surgery (CTS) and 149 matched control participants (CON) without any reported history of CTS symptoms were genotyped for the functional IL-1beta rs16944 (-511C/T), IL-6 rs1800795 (-174G/C), IL-6R rs2228145 (C/A) and VEGFA rs699947 (-2578C/A) variants. Only the IL-6R variant was significantly associated with CTS (p=0.005, OR=0.41, 95% CI 0.22-0.75). When the previously reported associated COL5A1 and BGN variants were included in the analysis, gene-gene interactions were also shown to significantly modulate the risk of CTS. In conclusion, the AA genotype of IL-6R rs2228145 was independently associated with reduced risk of CTS in a South African Coloured population. The IL-6R variant interacted with the previously reported COL5A1 and BGN variants to modulate CTS risk. This highlights that interleukin and growth factor gene variants should also be considered, in addition to the extracellular matrix proteins, for future research in determining the aetiology of CTS. PMID- 25813876 TI - Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling. AB - Alpha-synuclein (alpha-Syn) is a major component of Lewy bodies, a pathological feature of Parkinson's and other neurodegenerative diseases collectively known as synucleinopathies. Among the possible mechanisms of alpha-Syn-mediated neurotoxicity is interference with cytoprotective pathways such as insulin signaling. Insulin receptor substrate (IRS)-1 is a docking protein linking IRs to downstream signaling pathways such as phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K)1; the latter exerts negative feedback control on insulin signaling, which is impaired in Alzheimer's disease. Our previous study found that alpha-Syn overexpression can inhibit protein phosphatase (PP)2A activity, which is involved in the protective mechanism of insulin signaling. In this study, we found an increase in IRS-1 phosphorylation at Ser636 and decrease in tyrosine phosphorylation, which accelerated IRS-1 turnover and reduced insulin-Akt signaling in alpha-Syn overexpressing SK-N-SH cells and transgenic mice. The mTOR complex (C)1/S6K1 blocker rapamycin inhibited the phosphorylation of IRS-1 at Ser636 in cells overexpressing alpha-Syn, suggesting that mTORC1/S6K1 activation by alpha-Syn causes feedback inhibition of insulin signaling via suppression of IRS-1 function. alpha-Syn overexpression also inhibited PP2A activity, while the PP2A agonist C2 ceramide suppressed both S6K1 activation and IRS-1 Ser636 phosphorylation upon alpha-Syn overexpression. Thus, alpha-Syn overexpression negatively regulated IRS-1 via mTORC1/S6K1 signaling while activation of PP2A reverses this process. These results provide evidence for a link between alpha Syn and IRS-1 that may represent a novel mechanism for alpha-Syn-associated pathogenesis. PMID- 25813877 TI - Celsr3 and Fzd3 in axon guidance. AB - The assembly of functional neuronal circuits depends on the correct wiring of axons and dendrites. To reach their targets, axons are guided by a variety of extracellular guidance cues, including Netrins, Ephrins, Semaphorins and Slits. Corresponding receptors in the growth cone, the dynamic structure at the tip of the growing axon, sense and integrate these positional signals, and activate downstream effectors to regulate cytoskeletal organization. In addition to the four canonical families of axon guidance cues mentioned above, some proteins that regulate planar cell polarity were recently found to be critical for axon guidance. The seven-transmembrane domain receptors Celsr3 and Fzd3, in particular, control the development of most longitudinal tracts in the central nervous system, and axon navigation in the peripheral, sympathetic and enteric nervous systems. Despite their unequivocally important role, however, underlying molecular mechanisms remain elusive. We do not know which extracellular ligands they recognize, whether they have co-receptors in the growth cone, and what their downstream effectors are. Here, we review some recent advances and discuss future trends in this emerging field. PMID- 25813878 TI - A polyhedral oligomeric silsesquioxane functionalized copper trimesate. AB - A metal-organic framework (MOF), copper trimesate (Cu3(BTC)2), was selectively functionalized with aminopropylisooctyl polyhedral oligomeric silsesquioxane (O POSS) to make the external surface of Cu3(BTC)2 hydrophobic and thereby enhance the stability of the material against humidity. POSS modification was also successfully applied to other MOFs such as MOF-74 and MIL-100. PMID- 25813879 TI - Parallel reductions in phenolic constituents resulting from the domestication of eggplant. AB - Crop domestication is often accompanied by changes in metabolite compositions that alter traits such as flavor, color, or other beneficial properties. Fruits of eggplants (Solanum melongena L.) and related species are abundant and diverse in pharmacologically interesting phenolic compounds, particularly hydroxycinnamic acid (HCA) conjugates such as the antioxidant caffeoylquinic acids (CQA) and HCA polyamine amides (HCAA). To understand metabolite variability through the lens of natural and artificial selection, HPLC-DAD was used to generate phenolic profiles for 32 compounds in fruits from 93 accessions representing 9 Solanum species. Profiles were used for identification of species-level and infraspecific chemical patterns across both genetic distance and landscape. Sampling of plant lines included the undomesticated progenitor of eggplant and Asian landraces with a genetic background associated with three Asian regions near proposed separate centers of domestication to test whether chemical changes were convergent despite different origins. Results showed ten compounds were unique to species, and ten other compounds varied significantly in abundance among species. Five CQAs and three HCA-polyamine conjugates were more abundant in wild (undomesticated) versus domesticated eggplant, indicating that artificial selection may have led to reduced phenolic levels. No chemical abundance patterns were associated with site origin. However, one genetically distinct lineage of geographically-restricted SE Asian eggplants (S. melongena subsp. ovigerum) had a higher HCAA content and diversity than other lineages, which is suggested to be related to artificial selection for small, firm fruit. Overall, patterns show that fruit size, palatability and texture were preferentially selected over health-beneficial phytochemical content during domestication of several nightshade crops. PMID- 25813880 TI - Interconverting flavonostilbenes with antibacterial activity from Sophora alopecuroides. AB - Five flavonostilbenes (alopecurones H, I, J, K and L) and five known ones were isolated from roots of Sophora alopecuroides, in addition to ten other phenolic compounds. A non-enzymatic interconversion of the lavandulyl-substituted flavonostilbenes was observed among alopecurones A, H, I, and K through a Wessely Moser rearrangement reaction; this was proven by 1D and 2D NMR, HPLC-CD-PDA and HRMS analyses. Bioassay results suggested that flavonostilbenes exhibit significant antibacterial and anti-biofilm formation activities against Staphylococcus epidermidis with MIC values ranging from 3.1 to 12.5MUg/mL. PMID- 25813881 TI - Geriatric assessment of older patients with cancer in Australia--a multicentre audit. AB - OBJECTIVE: The aim of this study is to determine the frequency of geriatric assessment in patients aged over 70 years in Australian medical oncology clinics. MATERIAL AND METHODS: This was a multicentre audit in two parts: a retrospective file review of initial consultations with an oncologist and prospective audit of case presentations at multidisciplinary meetings (MDMs). Patients aged over 70 years presenting to a medical oncology clinic or being discussed at an MDM were eligible. Data was collected at six oncology centres in Victoria, NSW and Canberra from October 2009 to March 2010. RESULTS: Data was collected from 251 file reviews and 108 MDM discussions in a total of 304 patients. Median age was 76 years (range 70-95). The geriatric assessment (GA) domains most frequently assessed during an initial consultation were the presence of comorbidities (92%), social situation-living alone or with someone (80%), social supports (63%), any mention of at least one Activity of Daily Living (ADL) (50%) and performance status (49%). Less frequently assessed were any Instrumental Activity of Daily Living (IADL) (26%), presence of a geriatric syndrome (24%), polypharmacy (29%) and creatinine clearance (11%). Only one patient had all components of ADLs and IADLs assessed. During MDMs all the geriatric domains were comparatively less frequently assessed. No patients had all ADL and IADL components discussed formally in an MDM. CONCLUSION: This is the first multicentre audit that reveals the low rates of GA in Australian medical oncology practice and describes the GA domains considered important by oncology clinicians. PMID- 25813883 TI - Atypical manifestations of leptospirosis. AB - Leptospirosis is an illness with a wide spectrum of clinical manifestations and severe illness affects nearly all organ systems. Serious and potentially life threatening clinical manifestations of acute leptospirosis are caused by both direct tissue invasion by spirochaetes and by the host immune responses. In its severe form, leptospirosis can cause multi-organ dysfunction and death in a matter of days. Therefore it is critical to suspect and recognize the disease early, in order to initiate timely treatment. While the classical presentation of the disease is easily recognized by experienced clinicians practising in endemic regions, rarer manifestations can be easily missed. In this systematic review, we summarize the atypical manifestations reported in literature in patients with confirmed leptospirosis. Awareness of these unusual manifestations would hopefully guide clinicians towards early diagnosis. PMID- 25813882 TI - A systematic review and meta-analysis of surgeries performed for treating deep seated cerebral cavernous malformations. AB - OBJECTIVE: The clinical benefit of surgery for treatment of deep-seated cerebral cavernous malformations (CCMs) is still a matter of debate. Although the surgical removal of CCMs is widely accepted, the benefits of reducing the rate of haemorrhage must be balanced against the risk of peri-operative morbidity. Here, we provide a systematic review and meta-analysis of the clinical benefits of surgery for treating deeply localised CCMs. METHODS: A comprehensive search of PubMed and Embase was conducted to identify relevant studies. The rate and a 95% confidence interval (CI) were used to measure the risk of haemorrhage and adverse outcomes. RESULTS: A total of 34 cohort studies reporting surgeries on CCMs were included in our analysis. Overall, the average post-surgical haemorrhage rate was 1.0% (95% CI: 0.7-1.4%). Nine per cent (95% CI: 6.9-11.3%) of the patients developed adverse events at follow-up following the surgical resection of deep seated CCMs. The percentage of transient neural defects following surgical resection was 34.6% (95% CI: 29.4-39.9%). The proportions of transient focal neurological defect before and after the year 2006 were 44.9% (95% CI: 34.1 55.8%) and 30.3% (95% CI: 25.1-35.9%), respectively. CONCLUSIONS: Our meta analysis demonstrates post-surgical haemorrhage rate and complications related to surgeries on deep-seated CCMs. The post-surgical haemorrhage rate was low with a relatively high rate of post-surgical complications. PMID- 25813884 TI - Regional differences in the placental levels of oxidative stress markers in pre eclampsia. AB - OBJECTIVE: To examine placental malondialdehyde (MDA), catalase, and glutathione peroxidase (GPx) levels in four placental regions among women with and without pre-eclampsia. METHODS: A cross-sectional study was conducted among women aged 18 35 years with a singleton pregnancy in Pune, India, between May 3, 2013, and June 16, 2014. Three groups were enrolled: normotensive; pre-eclampsia, delivered at term; and pre-eclampsia, delivered preterm. Samples were collected from the central and peripheral placental regions (maternal and fetal sides) immediately after delivery. RESULTS: A total of 60 women were enrolled (35 normotensive; 11 with pre-eclampsia delivered at term; 14 with pre-eclampsia, delivered preterm). MDA levels were higher in all regions of the placenta among the pre-eclampsia versus normotensive groups (P<0.01). MDA levels were higher in the central maternal region than in the central fetal region in the preterm pre-eclampsia group (P=0.023). The MDA levels in the central maternal region were also higher in the preterm than in the term pre-eclampsia group (P=0.014). Catalase activity was lower in the peripheral maternal (P=0.036) and fetal (P=0.050) regions in the preterm pre-eclampsia group versus the normotensive group. The activity of GPx was higher in the peripheral maternal region than in the central fetal region in the normotensive group (P=0.033). CONCLUSION: Pre-eclampsia might be characterized by differential placental oxidative stress and antioxidant enzyme activity. PMID- 25813885 TI - Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. AB - Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vascularization and, in time, acquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastatic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, such as the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic drugs, as well as the development of multidrug resistance, support the need to find new effective targeted treatments based on the changes in the molecular biology of the tumor cells. These novel targeted therapies, of increasing interest as evidenced by FDA-approved targeted cancer drugs in recent years, block biologic transduction pathways and/or specific cancer proteins to induce the death of cancer cells by means of apoptosis and stimulation of the immune system, or specifically deliver chemotherapeutic agents to cancer cells, minimizing the undesirable side effects. Although targeted therapies can be achieved directly by altering specific cell signaling by means of monoclonal antibodies or small molecules inhibitors, this review focuses on indirect targeted approaches that mainly deliver chemotherapeutic agents to molecular targets overexpressed on the surface of tumor cells. In particular, we offer a detailed description of different cytotoxic drug carriers, such as liposomes, carbon nanotubes, dendrimers, polymeric micelles, polymeric conjugates and polymeric nanoparticles, in passive and active targeted cancer therapy, by enhancing the permeability and retention or by the functionalization of the surface of the carriers, respectively, emphasizing those that have received FDA approval or are part of the most important clinical studies up to date. These drug carriers not only transport the chemotherapeutic agents to tumors, avoiding normal tissues and reducing toxicity in the rest of the body, but also protect cytotoxic drugs from degradation, increase the half-life, payload and solubility of cytotoxic agents and reduce renal clearance. Despite the many advantages of all the anticancer drug carriers analyzed, only a few of them have reached the FDA approval, in particular, two polymer-protein conjugates, five liposomal formulations and one polymeric nanoparticle are available in the market, in contrast to the sixteen FDA approval of monoclonal antibodies. However, there are numerous clinical trials in progress of polymer-protein and polymer-drug conjugates, liposomal formulations, including immunoliposomes, polymeric micelles and polymeric nanoparticles. Regarding carbon nanotubes or dendrimers, there are no FDA approvals or clinical trials in process up to date due to their unresolved toxicity. Moreover, we analyze in detail the more promising and advanced preclinical studies of the particular case of polymeric nanoparticles as carriers of different cytotoxic agents to active and passive tumor targeting published in the last 5 years, since they have a huge potential in cancer therapy, being one of the most widely studied nano-platforms in this field in the last years. The interest that these formulations have recently achieved is stressed by the fact that 90% of the papers based on cancer therapeutics with polymeric nanoparticles have been published in the last 6 years (PubMed search). PMID- 25813886 TI - Comparative examination of adsorption of serum proteins on HSA- and PLGA-based nanoparticles using SDS-PAGE and LC-MS. AB - The behavior of nanosized drug carrier systems under cell culture conditions and therefore also the destiny in the body are highly influenced by the protein corona, which is formed upon entering a biological environment. Some of the adsorbed proteins, named opsonins, lead to a shortened plasma circulation half life of the nanoparticles. Others are attributed to promote the transport of nanoparticles into other compartments of the body, just to mention two examples. Hence, detailed knowledge concerning the composition of the protein corona is of great importance. The aim of this work was to investigate the influence of the nanoparticle starting material and the surface modification on the composition of the adsorbed serum proteins in a cell culture environment. Therefore, positively charged nanoparticles based on the biodegradable polymer poly(dl-lactide-co glycolide) (PLGA) stabilized with didodecyldimethylammonium bromide (DMAB) and negatively charged nanoparticles based on human serum albumin (HSA) were prepared and modified with hydrophilic polymers. By incubating the nanoparticles with fetal bovine serum (FBS) the adsorption of serum proteins on the colloidal system was investigated. Using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) a semi-quantitative analysis of the protein corona was performed and after enzymatic in-solution-digestion the adsorbed proteins were identified using high resolution LC-MS. Our study accentuates the influence of the core material, surface charge, and surface modification on the amount and nature of the adsorbed proteins. The combination of SDS-PAGE and LC-MS turns out to be a simple and reliable method to investigate the protein corona of nanoparticles. PMID- 25813887 TI - Spatial updating of map-acquired representation. AB - In the present study, we examined whether people can update a map-acquired spatial representation. The participants learned a spatial layout from a map displayed on a computer screen, and then performed spatial judgments at a novel position either in the same room (Exp. 1) or in a distal room (Exp. 2). They were required to imagine the spatial layout from a perspective aligned with the learning direction, aligned with their facing direction during testing, or toward a novel direction misaligned with the two directions mentioned above. In both the immediate and nonimmediate environments, the participants performed better from the learning direction than from the novel direction, and also performed better from the facing direction than from the novel direction. These results reveal that people establish an orientation-specific spatial representation through map learning, and that they can update a map-acquired representation during locomotion. PMID- 25813888 TI - Structure-directing star-shaped block copolymers: supramolecular vesicles for the delivery of anticancer drugs. AB - Amphiphilic polycarbonate/PEG copolymer with a star-like architecture was designed to facilitate a unique supramolecular transformation of micelles to vesicles in aqueous solution for the efficient delivery of anticancer drugs. The star-shaped amphipilic block copolymer was synthesized by initiating the ring opening polymerization of trimethylene carbonate (TMC) from methyl cholate through a combination of metal-free organo-catalytic living ring-opening polymerization and post-polymerization chain-end derivatization strategies. Subsequently, the self-assembly of the star-like polymer in aqueous solution into nanosized vesicles for anti-cancer drug delivery was studied. DOX was physically encapsulated into vesicles by dialysis and drug loading level was significant (22.5% in weight) for DOX. Importantly, DOX-loaded nanoparticles self-assembled from the star-like copolymer exhibited greater kinetic stability and higher DOX loading capacity than micelles prepared from cholesterol-initiated diblock analogue. The advantageous disparity is believed to be due to the transformation of micelles (diblock copolymer) to vesicles (star-like block copolymer) that possess greater core space for drug loading as well as the ability of such supramolecular structures to encapsulate DOX. DOX-loaded vesicles effectively inhibited the proliferation of 4T1, MDA-MB-231 and BT-474 cells, with IC50 values of 10, 1.5 and 1.0mg/L, respectively. DOX-loaded vesicles injected into 4T1 tumor bearing mice exhibited enhanced accumulation in tumor tissue due to the enhanced permeation and retention (EPR) effect. Importantly, DOX-loaded vesicles demonstrated greater tumor growth inhibition than free DOX without causing significant body weight loss or cardiotoxicity. The unique ability of the star like copolymer emanating from the methyl cholate core provided the requisite modification in the block copolymer interfacial curvature to generate vesicles of high loading capacity for DOX with significant kinetic stability that have potential for use as an anti-cancer drug delivery carrier for cancer therapy. PMID- 25813889 TI - Theoretical foundations for the measurement of environmental factors and their impact on participation among people with disabilities. AB - The ascendance of the World Health Organization's International Classification of Functioning, Disability and Heath (ICF) as the global standard for describing and characterizing aspects of disability has refocused attention on the role that environmental factors (EFs) have on the health and participation of people with disabilities, both as individuals and as a group. There has been a rise in the development of instruments designed to measure EFs alone and in relation to participation. Some instrument developers have used the ICF as a theoretical base for instrument development and to substantiate content validity claims. We contend that this is a misapplication of the ICF. There is a need to step back and reexamine the role that environmental theories can play in developing a conceptually driven approach to measuring the interaction between EFs and participation. For this review, we draw on the fields of social, community, and developmental psychology; disability studies; gerontology; public health; and rehabilitation. We discuss different approaches to the measurement of EFs. We suggest that given the complex nature of EFs and their influence on participation, there is a need for a fresh approach to EF measurement. The thoughtful application of theories and the use of advanced psychometric, measurement, and e-technologies and data visualization methods may enable researchers and clinicians to better quantify, document, and communicate the dynamic interrelationship between EFs and participation and health outcomes for people with disabilities at the individual, group, and population levels. PMID- 25813891 TI - Decisions about driving for persons with neurodegenerative conditions. PMID- 25813890 TI - Environmental barriers and supports to everyday participation: a qualitative insider perspective from people with disabilities. AB - OBJECTIVE: To describe environmental factors that influence participation of people with disabilities. DESIGN: Constant comparative, qualitative analyses of transcripts from 36 focus groups across 5 research projects. SETTING: Home, community, work, and social participation settings. PARTICIPANTS: Community dwelling people (N=201) with diverse disabilities (primarily spinal cord injury, traumatic brain injury, and stroke) from 8 states. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Environmental barriers and supports to participation. RESULTS: We developed a conceptual framework to describe how environmental factors influence the participation of people with disabilities, highlighting 8 domains of environmental facilitators and barriers (built, natural, assistive technology, transportation, information and technology access, social support and attitudes, systems and policies, economics) and a transactional model showing the influence of environmental factors on participation at the micro (individual), mesa (community), and macro (societal) levels. Focus group data validated some International Classification of Functioning, Disability and Health environmental categories while also bringing unique factors (eg, information and technology access, economic quality of life) to the fore. Data were used to construct items to enable people with disabilities to assess the impact of environmental factors on everyday participation from their firsthand experience. CONCLUSIONS: Participants with disabilities voiced the need to evaluate the impact of the environment on their participation at the immediate, community, and societal levels. The results have implications for assessing environmental facilitators and barriers to participation within rehabilitation and community settings, evaluating outcomes of environmental interventions, and effecting system and policy changes to target environmental barriers that may result in societal participation disparities versus opportunities. PMID- 25813892 TI - Driving after traumatic brain injury. PMID- 25813893 TI - Dexmedetomidine and regulation of splenic sympathetic nerve discharge in aged F344 rats. AB - Sedatives influence the immune system and centrally-acting alpha2-adrenergic receptor agonists, including Dexmedetomidine (Dex), modulate sympathetic nerve discharge (SND). Because sedatives are used under medical conditions that include elderly patients, and because advancing age attenuates SND responsivity to various interventions, we tested the hypothesis that splenic sympathoinhibitory responses to Dex would be attenuated in aged compared with young Fischer 344 rats. Dex-mediated reductions in splenic SND were similar in aged and young baroreceptor-intact and -denervated rats, indicating that SND changes to Dex administration occur in an age-independent manner. These findings provide new information regarding interactions between alpha2-adrenergic agonists, advanced age, and SND regulation. PMID- 25813894 TI - Mechanistic insight into ultrasound induced enhancement of simultaneous saccharification and fermentation of Parthenium hysterophorus for ethanol production. AB - This paper presents investigations into mechanism of ultrasound assisted bioethanol synthesis using Parthenium hysterophorus biomass through simultaneous saccharification and fermentation (SSF) mode. Approach of coupling experimental results to mathematical model for SSF using Genetic Algorithm based optimization has been adopted. Comparison of model parameters for experiments with mechanical shaking and sonication (10% duty cycle) give an interesting mechanistic account of influence of ultrasound on SSF system. A 4-fold rise in ethanol and cell mass productivity is seen with ultrasound. The analysis reveals following facets of influence of ultrasound on SSF: increase in Monod constant for glucose for cell growth, maximal specific growth rate and inhibition constant of cell growth by glucose and reduction in specific cell death rate. Values of inhibition constant of cell growth by ethanol (K3E), and constants for growth associated (a) and non growth associated (b) ethanol production remained unaltered with sonication. Beneficial effects of ultrasound are attributed to enhanced cellulose hydrolysis, enhanced trans-membrane transport of substrate and products as well as dilution of the toxic substances due to micro-convection induced by ultrasound. Intrinsic physiological functioning of cells remained unaffected by ultrasound as indicated by unaltered values of K3E, a and b. PMID- 25813895 TI - SmartWADO: an Extensible WADO Middleware for Regional Medical Image Sharing. AB - Medical image sharing is an important problem in modern radiology, with wide applications in Internet and mobile devices. Some important features need to be added and optimized to medical image sharing. In this paper, we present an extensible Web Access to DICOM Persistent Objects (WADO) middleware based on image cache and real-time Web monitor technology for regional medical image sharing. We first develop the extension method of WADO standard and workflow of extended WADO service. Then, we design a medical image cache method to improve the performance of medical image on-demand transmission. Using the real-time monitor can discover the performance bottlenecks and optimized critical points. The experimental results show that the middleware effectively delivers medical images and reports to Web clients over the Internet, regardless of the platform used for access. It can be deployed in one hospital to provide WADO service to medical workers and also can be applied to regional picture archiving and communication systems (PACS) to transmit medical images and reports to Internet users in a way that is transparent to end-user applications. PMID- 25813896 TI - Synthesis of N-methylarylnitrones derived from alkyloxybenzaldehydes and antineoplastic effect on human cancer cell lines. AB - New O-isoprenylated-N-methylarylnitrones derived from isomeric o, m and p hydroxybenzaldehydes have been prepared and the antineoplastic effects on human cancer cell lines were evaluated. The O-geranylated nitrone LQB-278 (1b) and its isomers 2b and 3b inhibited the NO production, but the anti-leukemic activity was drastically dependent on nitrone isomer, with the 1b being the most effective one (IC50 of 6.7 MUM) on Jurkat leukemia cell, by MTT assay. In addition, 1b up regulated p21CIP1/WAF1/Sdi1 protein expression (flow cytometry), a cell cycle inhibitor, reduced cell growth, and induced DNA fragmentation (increased sub-G1 phase cells) and phosphatidylserine externalization in plasmatic membrane (increased annexin V positive cells). Finally, the 1b up-regulation of p21 expression and apoptosis induction seem to be the mechanisms by which it promotes its anti-leukemic effects, making this new molecular architecture a promising prototype for leukemia intervention. PMID- 25813897 TI - alpha-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one. AB - This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for alpha1- and alpha2-adrenoceptors were assessed. The compound with highest affinity for the alpha1-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1 yl]-butyl}-pyrrolidin-2-one (10 h) with pKi=7.30. Compound with pKi (alpha1) ?6.44 were evaluated in functional bioassays for intrinsic activity at alpha1A- and alpha1B-adrenoceptors. All compounds tested were antagonists of the alpha1B adrenoceptors. Additionally, compounds 10e and 10h were alpha1A-adrenoceptors antagonist. The dual alpha1A-/alpha1B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0 mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour. PMID- 25813898 TI - Mental representations of magnitude and order: a dissociation by sensorimotor learning. AB - Numbers and spatially directed actions share cognitive representations. This assertion is derived from studies that have demonstrated that the processing of small- and large-magnitude numbers facilitates motor behaviors that are directed to the left and right, respectively. However, little is known about the role of sensorimotor learning for such number-action associations. In this study, we show that sensorimotor learning in a serial reaction-time task can modify the associations between number magnitudes and spatially directed movements. Experiments 1 and 3 revealed that this effect is present only for the learned sequence and does not transfer to a novel unpracticed sequence. Experiments 2 and 4 showed that the modification of stimulus-action associations by sensorimotor learning does not occur for other sets of ordered stimuli such as letters of the alphabet. These results strongly suggest that numbers and actions share a common magnitude representation that differs from the common order representation shared by letters and spatially directed actions. Only the magnitude representation, but not the order representation, can be modified episodically by sensorimotor learning. PMID- 25813899 TI - Electrophysiological difference between the representations of causal judgment and associative judgment in semantic memory. AB - Causally related concepts like "virus" and "epidemic" and general associatively related concepts like "ring" and "emerald" are represented and accessed separately. The Evoked Response Potential (ERP) procedure was used to examine the representations of causal judgment and associative judgment in semantic memory. Participants were required to remember a task cue (causal or associative) presented at the beginning of each trial, and assess whether the relationship between subsequently presented words matched the initial task cue. The ERP data showed that an N400 effect (250-450 ms) was more negative for unrelated words than for all related words. Furthermore, the N400 effect elicited by causal relations was more positive than for associative relations in causal cue condition, whereas no significant difference was found in the associative cue condition. The centrally distributed late ERP component (650-750 ms) elicited by the causal cue condition was more positive than for the associative cue condition. These results suggested that the processing of causal judgment and associative judgment in semantic memory recruited different degrees of attentional and executive resources. PMID- 25813900 TI - A simple HPLC-UV method for the determination of ciprofloxacin in human plasma. AB - A rapid and sensitive HPLC-UV method for the determination of ciprofloxacin in human plasma is described. Protein precipitation with acetonitrile was used to separate the drug from plasma protein. An ACE((r)) 5 C18 column (250 mm*4.6 mm, 5 MUm) with an isocratic mobile phase consisting of phosphate buffer (pH 2.7) and acetonitrile (77:23, v/v) was used for separation. The UV detector was set at 277 nm. The method was validated in the linear range of 0.05-8 MUg/ml with acceptable inter- and intra-assay precision, accuracy and stability. The method is simple and rapid and can be used to quantify this widely used antibiotic in the plasma of patients suffering from Peripheral Arterial Disease. PMID- 25813901 TI - A HPLC-fluorescence method for the quantification of abiraterone in plasma from patients with metastatic castration-resistant prostate cancer. AB - Abiraterone acetate is an oral prodrug of abiraterone, a selective inhibitor of CYP17, used for patients with metastatic castration-resistant prostate cancer (mCRPC). To date, a single liquid chromatographic-tandem mass spectroscopy method has been reported to assay abiraterone concentration in plasma from mCRPC patients. The aim of this study was to develop a simple and sensitive high performance liquid chromatographic (HPLC) method with fluorescence detection for quantification of abiraterone in plasma from mCRPC patients. After protein precipitation with acetonitrile and a liquid-liquid extraction with diethyl ether, abiraterone, and hydroxy-itraconazole (internal standard) were separated on a C8 Xterra((r)) MS column using a mobile phase of acetonitrile and glycine buffer 88.4 mM (pH 9.0) (60:40, v/v). Samples were eluted isocratically at a flow rate of 0.9 ml/min throughout an 11-min run. Fluorescence wavelengths' excitation and emission were 255 and 373 nm, respectively. The calibration was linear in the range 1.75-50 ng/ml. Inter- and intraday imprecision were less than 3.5 and 7%, respectively. This method is simple, sensitive, and selective. This analytical method was successfully applied to determine the steady-state plasma exposure to abiraterone in mCRPC patients. This method can be used in routine clinical practice to monitor plasma abiraterone concentrations in mCRPC patients. PMID- 25813902 TI - A sensitive and rapid HPLC-MS/MS method for the quantitative determination of trace amount of bromocriptine in small clinical prolactinoma tissue. AB - Usually, insufficient intratumoral concentration of therapeutic drugs is one of the reasons for tumor treatment failure. However, little is known about intratumoral distribution of bromocriptine in non-responding prolactinomas because of extremely low drug concentration and small prolactinoma tissue samples. In this study, a sensitive, rapid and high-throughput quantitative bioanalytical method has been established by using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the determination of bromocriptine at trace level in human prolactinoma tissue. As little as 20 mg (wet weight) tissue sample was required and total analysis time was 6 min in this method. The assay quantifies over a linear range of 50 fg/mg to 5 pg/mg, and has a 25 fg/mg limit of detection at a signal/noise ratio of 3. This validated method was successfully used to quantitatively determine bromocriptine in clinical post operative bromocriptine-sensitive and -resistant prolactinomas. The results revealed bromocriptine concentration in resistant prolactinomas (0.49-1.25 pg/mg) was significantly higher than that in sensitive prolactinomas (0.057-0.47 pg/mg). These results provided direct evidence to demonstrate the reseaon for failure of bromocriptine treatment in some patients with prolactinoma was "intrinsic" tumor (cell) resistence, rather than insufficient drug concentration in tumor tissue. Additionaly, this HPLC-MS/MS method has been shown to be suitable for bromocriptine analysis in small amount tissue sample and could be adapted for therapeutic drug monitoring of other clinical medicine. PMID- 25813903 TI - Determination of the metabolic profile of gentianine after oral administration to rats by high performance liquid chromatography/electrospray ionization-trap mass spectrometry. AB - We investigated the metabolic fate of gentianine after oral administration to Wistar rats for the first time. Liquid chromatography/ion trap mass spectrometry detected four metabolites secogentianoxide, gentiandiol, gentianepoxide and gentianoxide in rat plasma together with the original compound gentianine. The structures of the metabolites were identified by comparing the retention times, as well as MS (mass) and MS/MS (tandem mass) spectra with those of authentic compounds, which were synthesized from gentianine or isolated from the urine. Three of the metabolites, secogentianoxide, gentianepoxide and gentianoxide, are novel compounds. The major in vivo metabolic processes associated with gentianine include N-oxide, epoxidation, dihydroxylation of double bond and hydrolysis of lactone. Gentianine together with the metabolites in plasma were quantified using gentianone as the internal standard. The mean C(max) of G0, G1, G2 and G3 are 425.76, 287.56, 188.45 and 85.05 ng/mL, respectively. The mean T(max) of G0, G1, G2 and G3 are 1.16, 3.87, 6.23 and 4.28 h, respectively. The mean T(1/2) of G0, G1, G2 and G3 are 5.23, 12.34, 7.78 and 5.64 h, respectively. A comprehensive metabolic pathway was proposed. The new metabolites may shed light on clinical efficacy of gentianine. PMID- 25813904 TI - X-ray fluorescence microscopy demonstrates preferential accumulation of a vanadium-based magnetic resonance imaging contrast agent in murine colonic tumors. AB - Contrast agents that specifically enhance cancers on magnetic resonance imaging (MRI) will allow earlier detection. Vanadium-based chelates (VCs) selectively enhance rodent cancers on MRI, suggesting selective uptake of VCs by cancers. Here we report x-ray fluorescence microscopy (XFM) of VC uptake by murine colon cancer. Colonic tumors in mice treated with azoxymethane/dextran sulfate sodium were identified by MRI. Then a gadolinium-based contrast agent and a VC were injected intravenously; mice were sacrificed and colons sectioned. VC distribution was sampled at 120 minutes after injection to evaluate the long-term accumulation. Gadolinium distribution was sampled at 10 minutes after injection due to its rapid washout. XFM was performed on 72 regions of normal and cancerous colon from five normal mice and four cancer-bearing mice. XFM showed that all gadolinium was extracellular, with similar concentrations in colon cancers and normal colon. In contrast, the average VC concentration was twofold higher in cancers versus normal tissue (p < .002). Cancers also contained numerous "hot spots" with intracellular VC concentrations sixfold higher than the concentration in normal colon (p < .0001). No hot spots were detected in normal colon. This is the first direct demonstration that VCs selectively accumulate in cancer cells and thus may improve cancer detection. PMID- 25813905 TI - Improving adjuvant systems for polyclonal egg yolk antibody (IgY) production in laying hens in terms of productivity and animal welfare. AB - The antibody production in the egg yolks of immunized laying hens is seen as a way of improving animal welfare compared with conventional production by mammals. Immunoglobulin Y (IgY) technology, however, has still to address welfare issues linked to the widespread use of an adjuvant in vaccines. Currently, Freund's adjuvants, complete (FCA) or incomplete (FIA), remain the standard. This study sought to evaluate various approaches used to enhance egg yolk antibody production in terms of both productivity and avian welfare. The outer membrane protein (OMP) of Salmonella Typhimurium was used as the prototype antigen. At 20 weeks of age, 56 ISA Brown hens, with specific-Salmonella-free status, were divided into seven groups (n=8) and received an initial intramuscular immunization. Hens in the two negative control groups received phosphate buffered saline (PBS) or FIA alone. Hens in the other groups received 80MUg of Salmonella OMP emulsified with one of the following adjuvants: 200MUl of FIA alone (T1); 200MUl of FIA supplemented with 8MUg of C-phosphate-guanosine oligodeoxynucleotides (CpG-ODN) (T2); and 280MUl of Montanide ISA 70 VG (T4). Birds in the T3 group received the antigen in emulsion with FIA and were given the tested immunostimulatory component (l-carnitine) via their feed (100mg/kg). A positive control group (PC) received FCA for the first and final immunizations and FIA for the other boosters. Immunization was repeated after 20, 46, 82 and 221 days. Eggs were collected regularly until 242 days after the first immunization and the anti-Salmonella Typhimurium activities in the yolk were determined by ELISA. After 242 days, the birds were euthanized and the injection sites were evaluated for gross and microscopic lesions. Among the tested immunostimulatory approaches, supplementation of FIA with CpG-ODN led to a significant and long-lasting enhancement of the specific antibody response. This treatment was even higher than the positive benchmark using FCA in the first immunization. The study results showed that a clinical examination of injection sites is insufficient for drawing conclusions about the local tolerance of vaccines. Tissue damage was noticeable in all treatment groups. The birds receiving the Montanide adjuvant, however, had fewer and less severe lesions. Given these limited side-effects, Montanide ISA 70 VG could provide the depot effect needed to ensure the immunomodulatory efficiency of CpG-ODN. The association of these two adjuvants could prove a promising alternative to Freund's adjuvants (FA). PMID- 25813906 TI - A comparison of chewing rate between overweight and normal BMI individuals. AB - OBJECTIVE: Previous attempts to identify an 'obese eating style' have led to conflicting findings. This observational study compared the chewing features of overweight or obese young adults with those of normal range BMI. We hypothesised that chewing features are individual-specific and differ between participants of a normal BMI and high BMI. METHODS: Fourteen overweight to obese participants (BMI>=25.0) were pairwise matched with 14 normal range BMI participants (18.50.05), whereas chewing power was significantly higher in high BMI participants (p<0.05). No other differences in chewing characteristics were found between BMI groups. Participants chewed at similar rate in the natural environment (pizza) and in the laboratory (rice) setting (p>0.05). Masticatory performance did not differ significantly (p>0.05) between the high (55.9%) and normal (52.4%) BMI groups. CONCLUSIONS: Within the limitations of the present study, chewing characteristics appear to be individual-specific with wide variability. Overweight participants chew at a similar rate to control participants, albeit slightly stronger. Our preliminary findings need to be replicated in larger samples. PMID- 25813908 TI - Low serum TNF-related apoptosis-inducing ligand (TRAIL) levels are associated with acute ischemic stroke severity. AB - BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor receptor superfamily and its serum level is known to be closely associated with future cardiovascular events and prognosis of various cardiovascular diseases. We investigated whether serum TRAIL levels are associated with the severity of acute ischemic stroke and specific stroke subtype. METHODS: We used an enzyme-linked immunosorbent assay to measure the serum TRAIL levels of 293 patients with acute ischemic stroke within 7 days of onset. Stroke subtype was classified as large artery atherosclerosis, cardioembolism, small vessel occlusion and other determined etiology. We used National Institute of Health Stroke Scale (NIHSS) score of first hospital day and stroke volume on diffusion-weighted imaging within 7 days of stroke onset for measuring the severity of acute ischemic stroke. RESULTS: The level of serum TRAIL showed significant negative correlations with NIHSS score and stroke volume. Serum TRAIL levels significantly decreased as the tertile of NIHSS score and stroke volume increased. The relative risk of patients with serum TRAIL<64.0 pg/mL for the presence of highest tertile of NIHSS score was significantly increased (adjusted OR [95%CI]; 7.07 [3.64-13.74]). Regarding stroke volume, the relative risk of patients with serum TRAIL<71.5 pg/mL for the presence of highest tertile of stroke volume was also significantly increased (adjusted OR [95%CI]; 2.81 [1.61-4.92]). There are no significant differences of serum TRAIL level among stroke subtypes. CONCLUSIONS: Low serum TRAIL levels were significantly associated with the acute ischemic stroke severity. This finding suggests that serum TRAIL might also have a role in acute ischemic stroke as well as other cardiovascular diseases. PMID- 25813907 TI - The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids. AB - The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis. PMID- 25813909 TI - Ethanol production from rape straw by a two-stage pretreatment under mild conditions. AB - The growing interest on rape oil as raw material for biodiesel production has resulted in an increasing availability of rape straw, an agricultural residue that is an attractive renewable source for the production of second-generation bioethanol. Pretreatment is one of the key steps in such a conversion process. In this work, a sequential two-stage pretreatment with dilute sulfuric acid (130 degrees C, 60 min, 2% w/v H2SO4) followed by H2O2 (1-5% w/v) in alkaline medium (NaOH) at low temperature (60, 90 degrees C) and at different pretreatment times (30-90 min) was investigated. The first-acid stage allows the solubilisation of hemicellulose fraction into fermentable sugars. The second-alkaline peroxide stage allows the delignification of the solid material whilst the cellulose remaining in rape straw turned highly digestible by cellulases. Simultaneous saccharification and fermentation with 15% (w/v) delignified substrate at 90 degrees C, 5% H2O2 for 60 min, led to a maximum ethanol production of 53 g/L and a yield of 85% of the theoretical. PMID- 25813910 TI - Dynamic Intraligamentary Stabilization (DIS) for treatment of acute anterior cruciate ligament ruptures: case series experience of the first three years. AB - BACKGROUND: In recent years, the scientific discussion has focused on new strategies to enable a torn anterior cruciate ligament (ACL) to heal into mechanically stable scar tissue. Dynamic intraligamentary stabilization (DIS) was first performed in a pilot study of 10 patients. The purpose of the current study was to evaluate whether DIS would lead to similarly sufficient stability and good clinical function in a larger case series. METHODS: Acute ACL ruptures were treated by using an internal stabilizer, combined with anatomical repositioning of torn bundles and microfracturing to promote self-healing. Clinical assessment (Tegner, Lysholm, IKDC, and visual analogue scale [VAS] for patient satisfaction scores) and assessment of knee laxity was performed at 3, 6, 12, and 24 months. A one-sample design with a non-inferiority margin was chosen to compare the preoperative and postoperative IKDS and Lysholm scores. RESULTS: 278 patients with a 6:4 male to female ratio were included. Average patient age was 31 years. Preoperative mean IKDC, Lysholm, and Tegner scores were 98.8, 99.3, and 5.1 points, respectively. The mean anteroposterior (AP) translation difference from the healthy contralateral knee was 4.7 mm preoperatively. After DIS treatment, the mean 12-month IKDC, Lysholm, and Tegner scores were 93.6, 96.2, and 4.9 points, respectively, and the mean AP translation difference was 2.3 mm. All these outcomes were significantly non-inferior to the preoperative or healthy contralateral values (p < 0.0001). Mean patient satisfaction was 8.8 (VAS 0-10). Eight ACL reruptures occurred and 3 patients reported insufficient subjective stability of the knee at the end of the study period. CONCLUSIONS: Anatomical repositioning, along with DIS and microfracturing, leads to clinically stable healing of the torn ACL in the large majority of patients. Most patients exhibited almost normal knee function, reported excellent satisfaction, and were able to return to their previous levels of sporting activity. Moreover, this strategy resulted in stable healing of all sutured menisci, which could lower the rate of osteoarthritic changes in future. The present findings support the discussion of a new paradigm in ACL treatment based on preservation and self healing of the torn ligament. PMID- 25813911 TI - Preventive effects of bortezomib on denervation-induced atrophy of the intrinsic laryngeal muscles: an experimental study in the rat. AB - CONCLUSION: Bortezomib was effective in attenuating atrophy of the posterior cricoarytenoid (PCA) muscle, but not the thyroarytenoid (TA) muscle. This was probably due to differences in the fiber composition of the two muscles. The PCA muscle is composed of a combination of fast- and slow-twitch fibers, and therefore is more resistant to atrophy than the TA muscle, which is composed solely of fast-twitch fibers. OBJECTIVES: To investigate the preventive effects of bortezomib on denervation-induced atrophy of the TA and PCA muscles in the rat. METHODS: Following transection of the left recurrent laryngeal nerve, bortezomib (100 MUg/kg) was administered subcutaneously on post-denervation days 1 and 4, followed by a 10-day rest period every 14 days; each 2-week period constituted a single treatment cycle. In controls, saline was administered instead. Animals were killed for histological examination at 4 (n = 6), 8 (n = 7), and 12 (n = 7) weeks post-denervation. Muscle atrophy was assessed using three indices: wet muscle weight, muscle fiber cross-sectional area, and the number of muscle fibers/mm(2). The effects of bortezomib were evaluated by comparing the left (L) and right (R) muscles, with sequential changes in the L/R ratio assessed. RESULTS: In saline-administered animals, atrophy of the left sided TA and PCA muscles progressed rapidly during the first 4 weeks post denervation, following which progression slowed. Atrophy was greater in the TA compared with the PCA muscle, although this difference was not statistically significant. In bortezomib-administered animals, atrophy of the PCA muscle was attenuated significantly at post-denervation weeks 8 and 12; no such reduction in atrophy was observed for the TA muscle. PMID- 25813912 TI - Severe cytomegalovirus infection in a second kidney transplant recipient treated with ganciclovir, leflunomide, and immunoglobulins, with complications including seizures, acute HCV infection, drug-induced pancytopenia, diabetes, cholangitis, and multi-organ failure with fatal outcome: a case report. AB - BACKGROUND: Cytomegaly remains one of the most common infectious complications in organ transplant recipients, and the course of the infection may have a negative effect on survival of the transplant and recipient. CASE REPORT: We describe the case of a 32-year-old female patient who received a second kidney transplant from a cadaveric donor in July 2012, treated successfully with ganciclovir for primary CMV infection in August 2012 and then re-treated from November due to re infection. The viral load at the start of re-treatment was 6 million copies. In view of ganciclovir treatment failure, Sando immunoglobulins were administered. Subsequently, when CMV viral load increased to 18 million copies, a decision was made to use combination treatment with leflunomide and ganciclovir. Immunosuppressive treatment was also modified by administering everolimus in view of its potential antiviral activity. Seizures, pancytopenia, diabetes, diarrhoea, and (probably) drug-induced liver damage and cholangitis were observed in the course of treatment. At 3 months of hospitalization, the patient was discharged home with viral load of 8000 copies. As treatment continuation, she received valganciclovir at the full therapeutic dose in view of very good kidney function (creatinine 0.7 mg/dl). The patient was re-hospitalized after 10 days due to fever and cough. Due to abnormal liver function test results and negative serum markers of viral hepatitis, HCV RNA was tested, with a positive result (above 10^8 copies). Subsequently, decline in clinical status, overhydration, increasing creatinine levels, hepatic failure signs, and renewed CMV DNA increase to 520 000 copies were observed. Despite intensive treatment, the patient died of multi organ failure. CONCLUSIONS: The case described illustrates the difficulties in the treatment of CMV infection and its possible dramatic complications. PMID- 25813913 TI - Spectrally encoded slit confocal microscopy using a wavelength-swept laser. AB - We present an implementation of spectrally encoded slit confocal microscopy. The method employs a rapid wavelength-swept laser as the light source and illuminates a specimen with a line focus that scans through the specimen as the wavelength sweeps. The reflected light from the specimen is imaged with a stationary line scan camera, in which the finite pixel height serves as a slit aperture. This scanner-free operation enables a simple and cost-effective implementation in a small form factor, while allowing for the three-dimensional imaging of biological samples. PMID- 25813914 TI - Errata: Two-stage multi-Gaussian fitting of conduit artery photoplethysmography waveform during induced unilateral hemodynamic events. PMID- 25813915 TI - Patterns of Child Mental Health Service Delivery in a Public System: Rural Children and the Role of Rural Residence. AB - This study uses existing data from Hawaii's public mental health system for children and youth as an example of a state-level examination of service use patterns and health care disparities. The purpose of this study was to compare differences in mental health service utilization between rural and non-rural children, especially use of residential services. This study used a performance measure approach to conduct multi-level modeling on existing administrative data to examine the impact of community factors on service utilization. Rural children were found to have the most serious levels of mental health problems at intake, more likely to be placed in out-of-home care, more likely to receive only out-of home care, more likely to in stay out-of-home longer, and less likely to receive follow-up care than their non-rural counterparts. Practice, policy, and research implications are discussed. PMID- 25813917 TI - Multiple regenerative nodular hyperplasia in the left infrarenal vena cava accompanied by Abernethy malformation. AB - The current study presents the case of a 19-year-old male patient who was detected with an increased alanine aminotransferase and aspartate transaminase levels during a preoperative evaluation of the right inguinal hernia operation and was later found to have Abernethy malformation accompanied by multiple regenerative nodular hyperplasia and left intra renal inferior vena cava. Regenerative nodular hyperplasia accompanying these two abnormalities is extremely rare and to the best of our knowledge, such a case has not been reported to date. Abdominal ultrasound (US) and color Doppler US, dynamic abdominal magnetic resonance imaging (MRI), and portography examinations were performed and a type 2 Abernethy malformation, partial malrotation of the inferior vena cava, and regenerative nodular hyperplasia were detected. We aimed to discuss the radiological signs of these two accompanying abnormalities with a literature review. PMID- 25813916 TI - Compromised small-world efficiency of structural brain networks in schizophrenic patients and their unaffected parents. AB - Several lines of evidence suggest that efficient information integration between brain regions is disrupted in schizophrenia. Abnormalities in white matter tracts that interconnect brain regions may be directly relevant to this pathophysiological process. As a complex mental disorder with high heritability, mapping abnormalities in patients and their first-degree relatives may help to disentangle the risk factors for schizophrenia. We established a weighted network model of white matter connections using diffusion tensor imaging in 25 nuclear families with schizophrenic probands (19 patients and 41 unaffected parents) and two unrelated groups of normal controls (24 controls matched with patients and 26 controls matched with relatives). The patient group showed lower global efficiency and local efficiency. The decreased regional efficiency was localized in hubs such as the bilateral frontal cortices, bilateral anterior cingulate cortices, and left precuneus. The global efficiency was negatively correlated with cognition scores derived from a 5-factor model of schizophrenic psychopathology. We also found that unaffected parents displayed decreased regional efficiency in the right temporal cortices, left supplementary motor area, left superior temporal pole, and left thalamus. The global efficiency tended to be lower in unaffected parents. Our data suggest that (1) the global efficiency loss in neuroanatomical networks may be associated with the cognitive disturbances in schizophrenia; and (2) genetic vulnerability to schizophrenia may influence the anatomical organization of an individual's brain networks. PMID- 25813918 TI - A rare case of impacted maxillary first premolar. AB - Among the dental and maxillary anomalies, impacted teeth are frequently encountered. However, the incidence of impaction of maxillary first premolars is very low. Herewith, we report a rare case of impacted maxillary left first premolar, in a vertical position, with the apical two-thirds of the root situated in the angle between the medial and antero-lateral walls of the maxillary sinus. The persistence of the maxillary left primary canine was also observed. The cone beam computed tomography evaluation of the case identified the close proximity of the impacted tooth with the root of the permanent canine and the nasal fossa. The finding may be helpful to dental practitioners, not only to anticipate the difficulties which may occur during surgical interventions, but also to prevent possible complications, such as maxillary infections or root resorptions. PMID- 25813919 TI - Coexpression of type 2 immune targets in sputum-derived epithelial and dendritic cells from asthmatic subjects. AB - BACKGROUND: Noninvasive sputum sampling has enabled the identification of biomarkers in asthmatic patients. Studies of discrete cell populations in sputum can enhance measurements compared with whole sputum in which changes in rare cells and cell-cell interactions can be masked. OBJECTIVE: We sought to enrich for sputum-derived human bronchial epithelial cells (sHBECs) and sputum-derived myeloid type 1 dendritic cells (sDCs) to describe transcriptional coexpression of targets associated with a type 2 immune response. METHODS: A case-control study was conducted with patients with mild asthma (asthmatic cases) and healthy control subjects. Induced sputum was obtained for simultaneous enrichment of sHBECs and sDCs by using flow cytometry. Quantitative PCR was used to measure mRNA for sHBEC thymic stromal lymphopoietin (TSLP), IL33, POSTN, and IL25 and downstream targets in sDCs (OX40 ligand [OX40L], CCL17, PPP1R14A, CD1E, CD1b, CD80, and CD86). RESULTS: Final analyses for the study sample were based on 11 control subjects and 13 asthmatic cases. Expression of TSLP, IL33, and POSTN mRNA was increased in sHBECs in asthmatic cases (P = .001, P = .05, and P = .04, respectively). Expression of sDC OX40L and CCL17 mRNA was increased in asthmatic cases (P = .003 and P = .0001, respectively). sHBEC TSLP mRNA expression was strongly associated with sDC OX40L mRNA expression (R = 0.65, P = .001) and less strongly with sDC CCL17 mRNA expression. sHBEC IL33 mRNA expression was associated with sDC OX40L mRNA expression (R = 0.42, P = .04) but not sDC CCL17 mRNA expression. CONCLUSIONS: Noninvasive sampling and enrichment of select cell populations from sputum can further our understanding of cell-cell interactions in asthmatic patients with the potential to enhance endotyping of asthmatic patients. PMID- 25813920 TI - Effect of radial head implant shape on joint contact area and location during static loading. AB - PURPOSE: To examine the effect of implant shape on radiocapitellar joint contact area and location in vitro. METHODS: We used 8 fresh-frozen cadaveric upper extremities. An elbow loading simulator examined joint contact in pronation, neutral rotation, and supination with the elbow at 90 degrees flexion. Muscle tendons were attached to pneumatic actuators to allow for computer-controlled loading to achieve the desired forearm rotation. We performed testing with the native radial head, an axisymmetric implant, a reverse-engineered patient specific implant, and a population-based quasi-anatomic implant. Implants were inserted using computer navigation. Contact area and location were quantified using a casting technique. RESULTS: We found no significant difference between contact locations for the native radial head and the 3 implants. All of the implants had a contact area lower than the native radial head; however, only the axisymmetric implant was significantly different. There was no significant difference in contact area between implant shapes. CONCLUSIONS: The similar contact areas and locations of the 3 implant designs suggest that the shape of the implant may not be important with respect to radiocapitellar joint contact mechanics when placed optimally using computer navigation. Further work is needed to explore the sensitivity of radial head implant malpositioning on articular contact. The lower contact area of the radial head implants relative to the native radial head is similar to previous benchtop studies and is likely the result of the greater stiffness of the implant. CLINICAL RELEVANCE: Radial head implant shape does not appear to have a pronounced influence on articular contact, and both axisymmetric and anatomic metal designs result in elevated cartilage stress relative to the intact state. PMID- 25813921 TI - Implications of radial head hemiarthroplasty dish depth on radiocapitellar contact mechanics. AB - PURPOSE: To investigate the effect of radial head implant dish depth on radiocapitellar joint contact mechanics. METHODS: Computed tomography images of 13 fresh-frozen cadaveric humeri were reconstructed into 3-dimensional finite element models with accurate cartilage geometry. Native humeri were paired with the corresponding native radial heads and axisymmetric radial head prosthesis models of the following dish depths: 1.0 mm, 1.5 mm, 2.0 mm, 2.5 mm, and 3.0 mm. Radiocapitellar contact mechanics were quantified at 4 different flexion angles (0 degrees , 45 degrees , 90 degrees , and 135 degrees ) with a 100-N axial load applied to the radial head using a modeling protocol previously validated by cadaveric studies. The radial head was permitted to translate freely to its optimal position while the humerus was fully constrained. Output variables were contact area and peak contact stress. RESULTS: All prostheses had significantly decreased contact area and increased peak contact stress at all flexion angles relative to the native radiocapitellar joint. Contact area increased with prosthesis dish depth until reaching a plateau with a predicted local maximum at a mean depth of 3.2 +/- 0.7 mm. Peak contact stress was elevated for both the shallowest and deepest models and reached a predicted local minimum at a mean depth of 1.8 +/- 0.3 mm. CONCLUSIONS: Contact area and peak contact stress were dependent on radial head prosthesis dish depth. There was an optimal implant dish depth for radiocapitellar contact mechanics at approximately 2 mm. CLINICAL RELEVANCE: Optimizing radiocapitellar contact mechanics using rigorous and systematic prosthesis design techniques may lead to better clinical outcomes due to reduced capitellar cartilage degradation. PMID- 25813922 TI - Commentary on "Trends in carpal tunnel surgery: an online survey of members of the American Society for Surgery of the Hand". PMID- 25813923 TI - Accredited hand surgery fellowship Web sites: analysis of content and accessibility. AB - PURPOSE: To assess the accessibility and content of accredited hand surgery fellowship Web sites. METHODS: A list of all accredited hand surgery fellowships was obtained from the online database of the American Society for Surgery of the Hand (ASSH). Fellowship program information on the ASSH Web site was recorded. All fellowship program Web sites were located via Google search. Fellowship program Web sites were analyzed for accessibility and content in 3 domains: program overview, application information/recruitment, and education. RESULTS: At the time of this study, there were 81 accredited hand surgery fellowships with 169 available positions. Thirty of 81 programs (37%) had a functional link on the ASSH online hand surgery fellowship directory; however, Google search identified 78 Web sites. Three programs did not have a Web site. Analysis of content revealed that most Web sites contained contact information, whereas information regarding the anticipated clinical, research, and educational experiences during fellowship was less often present. Furthermore, information regarding past and present fellows, salary, application process/requirements, call responsibilities, and case volume was frequently lacking. Overall, 52 of 81 programs (64%) had the minimal online information required for residents to independently complete the fellowship application process. CONCLUSIONS: Hand fellowship program Web sites could be accessed either via the ASSH online directory or Google search, except for 3 programs that did not have Web sites. Although most fellowship program Web sites contained contact information, other content such as application information/recruitment and education, was less frequently present. CLINICAL RELEVANCE: This study provides comparative data regarding the clinical and educational experiences outlined on hand fellowship program Web sites that are of relevance to residents, fellows, and academic hand surgeons. This study also draws attention to various ways in which the hand surgery fellowship application process can be made more user-friendly and efficient. PMID- 25813924 TI - Thumb ligament injuries. AB - Thumb ligament injuries are common, particularly those involving the metacarpophalangeal joint. Our understanding and treatment of these injuries continues to evolve. This article provides a comprehensive review of recent literature with updates pertaining to the anatomy, function, diagnosis, and treatment of thumb ligament injuries. PMID- 25813925 TI - In reply. PMID- 25813926 TI - Response to "Direct radial to ulnar nerve transfer to restore intrinsic muscle function in combined proximal median and ulnar nerve injury: case report and surgical technique". PMID- 25813927 TI - Bunnell technique and bidirectional barbed suture for flexor tendon repair. PMID- 25813928 TI - In reply. PMID- 25813929 TI - Letter regarding "Restoration of the central slip in congenital form of boutonniere deformity: case report". PMID- 25813930 TI - In reply. PMID- 25813931 TI - In reply. PMID- 25813932 TI - Regarding "The effect of brachioradialis release during distal radius fracture fixation on elbow flexion strength and wrist function". PMID- 25813933 TI - Letter regarding "Radiocapitellar joint contact pressures following radial head arthroplasty". PMID- 25813934 TI - In reply. PMID- 25813935 TI - Anti-cancer effects of cerium oxide nanoparticles and its intracellular redox activity. AB - Data on medical applications of cerium oxide nanoparticles CeO2 (CONP) are promising, yet information regarding their action in cells is incomplete and there are conflicting reports about in vitro toxicity. Herein, we have studied cytotoxic effect of CONP in several cancer and normal cell lines and their potential to change intracellular redox status. The IC50 was achieved only in two of eight tested cell lines, melanoma 518A2 and colorectal adenocarcinoma HT-29. Self-propagating room temperature method was applied to produce CONP with an average crystalline size of 4 nm. The results confirmed presence of Ce(3+) and O(2-) vacancies. The induction of cell death by CONP and the production of reactive oxygen species (ROS) were analyzed by flow-cytometry. Free radicals related antioxidant capacity of the cells was studied by the reduction of stable free radical TEMPONE using electron spin resonance spectroscopy. CONP showed low or moderate cytotoxicity in cancer cell lines: adenocarcinoma DLD1 and multi-drug resistant DLD1-TxR, non-small cell lung carcinoma NCI-H460 and multi-drug resistant NCI-H460/R, while normal cell lines (keratinocytes HaCaT, lung fetal fibroblasts MRC-5) were insensitive. The most sensitive were 518A2 melanoma and HT-29 colorectal adenocarcinoma cell lines, with the IC50 values being between 100 and 200 MUM. Decreased rate of TEMPONE reduction and increased production of certain ROS species (peroxynitrite and hydrogen peroxide anion) indicates that free radical metabolism, thus redox status was changed, and antioxidant capacity damaged in the CONP treated 518A2 and HT-29 cells. In conclusion, changes in intracellular redox status induced by CONP are partly attributed to the prooxidant activity of the nanoparticles. Further, ROS induced cell damages might eventually lead to the cell death. However, low inhibitory potential of CONP in the other human cell lines tested indicates that CONP may be safe for human usage in industry and medicine. PMID- 25813936 TI - Use of transgenic mouse models to understand the oral disposition and drug-drug interaction potential of cobimetinib, a MEK inhibitor. AB - Data from the clinical absolute bioavailability (F) study with cobimetinib suggested that F was lower than predicted based on its low hepatic extraction and good absorption. The CYP3A4 transgenic (Tg) mouse model with differential expression of CYP3A4 in the liver (Cyp3a(-/-)Tg-3A4Hep) or intestine (Cyp3a(-/ )Tg-3A4Int) and both liver and intestine (Cyp3a(-/-)Tg-3A4Hep/Int) were used to study the contribution of intestinal metabolism to the F of cobimetinib. In addition, the effect of CYP3A4 inhibition and induction on cobimetinib exposures was tested in the Cyp3a(-/-)Tg-3A4Hep/Int and PXR-CAR-CYP3A4/CYP3A7 mouse models, respectively. After i.v. administration of 1 mg/kg cobimetinib to wild-type [(WT) FVB], Cyp3a(-/-)Tg-3A4Hep, Cyp3a(-/-)Tg-3A4Int, or Cyp3a(-/-)Tg-3A4Hep/Int mice, clearance (CL) (26-35 ml/min/kg) was similar in the CYP3A4 transgenic and WT mice. After oral administration of 5 mg/kg cobimetinib, the area under the curve (AUC) values of cobimetinib in WT, Cyp3a(-/-)Tg-3A4Hep, Cyp3a(-/-)Tg-3A4Int, or Cyp3a(-/-)Tg-3A4Hep/Int mice were 1.35, 3.39, 1.04, and 0.701 MUM?h, respectively. The approximately 80% lower AUC of cobimetinib in transgenic mice when intestinal CYP3A4 was present suggested that the intestinal first pass contributed to the oral CL of cobimetinib. Oxidative metabolites observed in human circulation were also observed in the transgenic mice. In drug-drug interaction (DDI) studies using Cyp3a(-/-)Tg-3A4Hep/Int mice, 8- and 4-fold increases in oral and i.v. cobimetinib exposure, respectively, were observed with itraconazole co-administration. In PXR-CAR-CYP3A4/CYP3A7 mice, rifampin induction decreased cobimetinib oral exposure by approximately 80%. Collectively, these data support the conclusion that CYP3A4 intestinal metabolism contributes to the oral disposition of cobimetinib and suggest that under certain circumstances the transgenic model may be useful in predicting clinical DDIs. PMID- 25813940 TI - Current issues in medical education: what is important? PMID- 25813937 TI - Evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans. AB - Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8- and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6- and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways. PMID- 25813938 TI - A role for antizyme inhibitor in cell proliferation. AB - The polyamines are important for a variety of cellular functions, including cell growth. Their intracellular concentrations are controlled by a complex network of regulatory mechanisms, in which antizyme (Az) has a key role. Az reduces the cellular polyamine content by down-regulating both the enzyme catalysing polyamine biosynthesis, ornithine decarboxylase (ODC), and the uptake of polyamines. The activity of Az is repressed by the binding of a protein, named Az inhibitor (AzI), which is an enzymatically inactive homologue of ODC. Two forms of AzI have been described: AzI1, which is ubiquitous, and AzI2 which is expressed in brain and testis. In the present study, we have investigated the role of AzI1 in polyamine homeostasis and cell proliferation in breast cancer cells. The results obtained showed that the cellular content of AzI increased transiently after induction of cell proliferation by diluting cells in fresh medium. Inhibition of polyamine biosynthesis induced an even larger increase in the cellular AzI content, which remained significantly elevated during the 7-day experimental period. However, this increase was not a consequence of changes in cell cycle progression, as demonstrated by flow cytometry. Instead, the increase appeared to correlate with the cellular depletion of polyamines. Moreover, induced overexpression of AzI resulted in an increased cell proliferation with a concomitant increase in ODC activity and putrescine content. During mitosis, AzI1 was localised in a pattern that resembled that of the two centrosomes, confirming earlier observations. Taken together, the results indicate that AzI fulfils an essential regulatory function in polyamine homeostasis and cell proliferation. PMID- 25813939 TI - Site-selective solid phase synthesis of carbonylated peptides. AB - The aim of our research was to design an efficient method for the solid phase synthesis of carbonylated peptides. For this purpose, we designed and synthesized a fully protected derivative Fmoc-amino(2,5,5-trimetyhyl-1,3-dioxolan-2-yl)acetic acid (Fmoc-Atda-OH) of a novel unnatural amino acid (Thr(O)-2-amino-3-oxo butanoic acid). To obtain the mentioned derivative, two synthetic strategies were investigated using different reagents for carbonyl protection, ethane-1,2-diol and 2,2-dimethyl-propane-1,3-diol. The racemization of oxidized threonine was also analyzed and discussed. We successfully carried out the solid phase synthesis of peptides containing a Thr(O) moiety using Fmoc-Atda-OH according to the standard Fmoc strategy. The application of the designed building block allows the synthesis of peptides containing D,L-Thr(O) residue, which may be used as models of oxidatively modified peptides which occur in biological systems and are related to many diseases. PMID- 25813941 TI - Comparison of Patient-Physician Interaction (PPI) Evaluation between Different Grade Medical Students. AB - PURPOSE: A proper patient-physician interaction (PPI) creates rapport between doctors and patients and improves medical outcomes. The importance of PPI evaluation items was evaluated in each medical student in grades 3 and 4, before and after their clinical clerkship. METHODS: Six PPI evaluation guidelines (SEGUE, Kalamazoo Consensus, Calgary-Cambridge Guide, Macy guideline, 2 Korean Consortium guidelines) were selected and importance of each guideline was evaluated through the structured questionnaire in 73 pre-clinical clerkship (3rd grade) and 78 post-clinical clerkship (4th-grade) medical students. RESULTS: The importance of medical communication items among total clinical performance, students-rated PPI portion was 21+/-9.7%. In SEGUE recommendations, 'Elicit information' was evaluated to be most important items before (58.3%) and after (65.8%) clinical clerkship. In Kalamazoo Consensus, 'Gathering information' was evaluated to be most important (49.3%/42.3%), same as in Calgary-Cambridge Guide (52.1%/56.4%) and Daegu Gyeongbuk Consortium (47.9%/43.6%). In the Macy guideline, 'Listening' was evaluated to be most important (28.8%/33.3%). In the Seoul Gyeonggi Consortium, 'Buidling relationships' was evaluated to be most important (23.3%/28.2%). CONCLUSION: In the 4th-grade post-clerkship medical students after clinical clerkship, importance of 'Gathering information' was evaluated to be less important, however, 'Giving information' and 'Understanding the patient perspective' was evaluated to be more important, compared to pre clerkship students 3rd-grade students. PMID- 25813942 TI - Comprehension of Patient-Physician Interaction through Analysis of Relationships between Domains in Clinical Performance Examination. AB - PURPOSE: This research investigated the psychometric properties of the patient physician interaction (PPI) domain in the clinical performance examination (CPX). This research aimed to understand the PPI domain in the CPX through a psychometric and relationship analysis between the domains. METHODS: Data were drawn from 1,302 examinees on a set of 6 common CPX cases and 1,066 on a 'bad news delivery' case. All cases included 7 PPI items, among which we calculated internal consistency reliability. Correlations were made between PPI and the other domains. Analyses using the structural equation model (SEM) were conducted to assess the relationships between latent factors and controlled measurement errors. To calculate the disparity between colleges, we performed a multi-level analysis. Also, we conducted t-tests to investigate the consistency of the PPI and information sharing (IS) scores in the 'bad news delivery' case. RESULTS: Correlation between the mean PPI score and the total CPX score was high (0.707). The correlations between PPI and other domains were; 0.904 for the patient's overall satisfaction, 0.41 for history taking, and 0.327 for patient education. In SEM, these correlations between latent variables increased. The proportion of level-2 (between-school component) variance in PPI was 4.1%. For 'bad news delivery', the group that checked 'yes' on the IS items had higher PPI scores (mostly p<0.01). CONCLUSION: PPI is an influential domain of the CPX and is highly related with the patient's overall satisfaction, clinical courtesy, and history taking. Disparities between schools in PPI are relatively small, such that the PPI could be due to individual factors rather than the school. PMID- 25813943 TI - Development of a patient-doctor communication skills model for medical students. AB - PURPOSE: Communication is a core clinical skill that can be taught and learned. The authors intended to develop a patient-doctor communication model for teaching and assessing undergraduate medical students in Korea. METHODS: To develop a model, literature reviews and an iterative process of discussion between faculty members of a communication skills course for second year medical students were conducted. The authors extracted common communication skill competencies by comparing the Kalamazoo Consensus Statement, SEGUE framework communication skills, the Calgary Cambridge Observation Guides, and previous communication skills lists that have been used by the authors. The content validity, with regard to clinical importance and feasibility, was surveyed by both faculty physicians and students. RESULTS: The first version of the model consisted of 36 items under 7 categories: initiating the session (8 items), building a relationship (6), gathering information (8), understanding a patient's perspectives (4), sharing information (4), reaching an agreement (3), and closing the session (3). It was used as a guide for both students and teachers in an actual communication skills course. At the end of the course, student performance was assessed using two 7-minute standardized patient interviews with a 34-item checklist. This assessment tool was modified from the first version of the model to reflect the case specificity of the scenarios. A patient-doctor communication model, which can be taught to those with limited patient care experience, was finally developed. CONCLUSION: We recommended a patient-doctor communication skills model that can be used for teaching and evaluating preclinical and clinical students. Further studies are needed to verify its validity and reliability. PMID- 25813944 TI - Relationship between Learning Strategies and Academic Achievement in Medical College and Graduate Medical School Students. AB - PURPOSE: Cognitive researchers assume that learning strategies are related to three types of learning processes: 'surface learning,' 'strategy learning,' and 'deep learning.' A 'deep learning' approach is widely accepted to be associated with long-term success in medical school, contributing to the development of doctors who take desirable approaches to self-directed learning and studying in medical practice. Therefore, this study measured how medical students learn and determined whether the use of learning strategies differs between high and low academic performers. In addition, we compared medical college students with graduate medical school students with regard to the use of learning strategies. METHODS: To explore the learning strategies of students and their relation to academic achievement, we performed LIST (Learning Strategies in Higher Education Inventory) in a sample of 111 Year 1 medical students. RESULTS: Medical students with high academic performance scored higher in most learning strategies than low performers. Additionally, learning strategies were used more frequently by graduate medical school students than medical students, specifically with regard to organization, elaboration, critical thinking, and time management. CONCLUSION: We conclude that learning strategy instruments provide information that enables medical students to optimize their study. To foster deep learning and intrinsic motivation in students, it might also be necessary to adopt more changes in teaching and assessment in medical schools. PMID- 25813945 TI - The effects of perfectionism on academic achievement in medical students. AB - PURPOSE: The purpose of this study was to explore the differential effects of multi-dimensional perfectionism on academic achievement, depression, engagement, and burnout in medical students. Also, the mediating effects of engagement on perfectionism and academic achievement, as well as the effects of burnout on perfectionism and depression, were examined. METHODS: Two hundred eight medical students participated, and 167 students completed questionnaires, including the Frost Multi-dimensional Perfectionism Scale (FMPS), Hewitt & Flett Multi dimensional Perfectionism Scale (HFMPS), Beck Depression Inventory (BDI), Schaufeli Engagement Scale (SES), and Malslach Burnout Inventory-General Survey (MBI-GS). Academic achievement was measured as the grade point average (GPA) of the previous semester. Data were analyzed by correlation analyses, independent t tests, and Structural Equation Model (SEM) for path analysis. RESULTS: Adaptive perfectionism (personal standard, self-oriented perfectionism) was associated with GPA (r=0.164, p<0.05; r=0.173, p<0.05) and engagement (r=0.394, p<0.01; r=0.449, p<0.01), and maladaptive perfectionism (parental criticism, concern over mistakes, socially prescribed perfectionism) was associated with depression (r=0.208, p<0.01; r=0.254, p<0.01; r=0.234, p<0.01) and burnout (r=0.218, p<0.01; r=0.236, p<0.01; r=0.280, p<0.01). Engagement had mediating effects on adaptive perfectionism and GPA, and burnout had mediating effects on maladaptive perfectionism and depression. Students who experienced academic failure had lower engagement than those who did not. CONCLUSION: This study demonstrates that academic achievement and emotional difficulties such as depression are determined by adaptive and maladaptive perfectionism, respectively, in medical students. PMID- 25813946 TI - The school effect on the reliability of clinical performance examination in medical schools. AB - PURPOSE: The purpose of this study is to test the reliability of the clinical performance examination (CPX) using Generalizability theory (G-theory). Through G theory, the effects of not only students and tasks but also the school will be analyzed as primary sources of error, which can affect the interpretation of the reliability of the CPX. METHODS: One thousand three hundred nineteen students from 16 medical schools that participated in the Seoul-Gyeonggi CPX Consortium 2008 were enrolled. In our research design, we suppose that student is nested within school and crossed with task. Data analysis was conducted with urGenova. RESULTS: According to our analysis, the percentage of error variance was 6.2% for school, 14.9% for student nested within school, 14.4% for task, and 3% for interaction between school and task. An effect of school on students was observed, but the interaction between task and school was insignificant. When student is nested within school, the universe score decreased and the g coefficient was less than the g-coefficient of the p x t (p: studentm, t: task) design. CONCLUSION: The results show that generalizability theory is useful in detecting various error components in the CPX. Using the generalizability theory to improve the technical quality of performance assessments provides us with greater information compared with traditional test theories. PMID- 25813948 TI - Tips on measuring medical professionalism. PMID- 25813947 TI - Implementation of a problem-based learning program combined with team-based learning. AB - PURPOSE: The purpose of this study was to evaluate the implementation of problem based learning (PBL), in combination with team-based learning (TBL), in an integrated curriculum at Gachon University School of Medicine. METHODS: The study methods included in-depth interviews and an open questionnaire. The subjects of the study comprised 5 faculty members and 38 second-year graduate students. RESULTS: PBL, combined with TBL, was not helpful in enhancing student ability with regard to reasoning and self-directed learning. This program also had negative effects, increasing student tension and interfering with the dynamics of discussions due to frequent tutor intervention. CONCLUSION: Overall, PBL that is combined with TBL was a less useful method than PBL only. We recommended understanding the characteristics of each program and attempting to develop better programs that mix the positive aspects of TBL and PBL. PMID- 25813949 TI - Computerized testing. PMID- 25813950 TI - Degradability in vitro of polyurethanes based on synthetic atactic poly[(R,S)-3 hydroxybutyrate]. AB - The aim of the present study was to determine the degradability of aliphatic polyurethanes, based on a different amount of synthetic, atactic poly[(R,S)-3 hydroxybutyrate] (a-PHB), in hydrolytic (phosphate buffer) and oxidative (H2O2/CoCl2) solutions. The soft segments were built with atactic poly[(R,S)-3 hydroxybutyrate] and polycaprolactone or polyoxytetramethylenediols, whereas hard segments were the reaction product of 4,4'-methylenedicyclohexyl diisocyanate and 1,4-butanediol.The selected properties - density and morphology of polymer surfaces - which could influence the sensitivity of polymers to degradation processes - were analyzed.The analysis of molecular mass (GPC), thermal properties (DSC) and the sample weight changes were undertaken to estimate the degree of degradability of polymer samples after incubation in environments studied.Investigated polyurethanes were amorphous with the very low amount of crystalline phases of hard segments.The polyurethane synthesized with a poly[(R,S)-3-hydroxybutyrate] and polyoxytetramethylenediol at a molar ratio of NCO:OH=3.7:1 (prepolymer step) appeared as the most sensitive for both degradative solutions. Its weight and molecular mass losses were the highest in comparison to other investigated polyurethanes.It could be expected that playing with the amount of poly[(R,S)-3-hydroxybutyrate] in polyurethane synthesis the rate of polyurethane degradation after immersion in living body would be modeled. PMID- 25813951 TI - Fabrication of Ti/HA composite and functionally graded implant by three dimensional printing. AB - The aim of this study is to evaluate the feasibility of fabricating titanium(Ti)/hydroxyapatite(HA) composite and functionally graded implant by three-dimensional printing (3DP) technology. Nano-scale Ti and HA powders were mixed at the ratio of 8:2 and prepared with water-soluble binder. The Ti/HA composite CAD model was designed to be in cylinder shape (25 mm in diameter, 20 mm in height) with the 100% bond area in each layer. The functionally graded implant was 25 mm in diameter and 10 mm in height with two segments. The upper segment was composed of 100% Ti in each layer, whereas the lower was composed of 80%Ti/20%HA. The composite and functionally graded implant were fabricated by 3DP and sintered at 1200 degrees C under protective argon atmosphere. There occurred a chemical reaction between Ti and HA, in which new resultants of Ca3(PO4)2, CaTiO3, TiO2 and CaO were created. The sintered Ti/HA composite had the aperture size from 50 to 150 MUm and the compressive strength of 184.3+/-27.1 MPa. The result of this study demonstrated that it was feasible to fabricate Ti/HA composite and functionally graded implant by 3DP technology. The microstructure and mechanical properties of Ti/HA composite and functionally graded implant were conductive to bone cell ingrowth, resulting in the wide application of this biocomposite. PMID- 25813952 TI - Determining the solubility parameter and the cross-link density of medical grade silicones: effect of increasing the range of swelling liquids. AB - Four samples of four medical grade silicones were swollen in six "good" liquids (i.e. those with a good swelling ability, in which silicones swell appreciably) at 25 degrees C, until they reached constant mass (i.e. equilibrium). The volume fraction, phi, of the silicone in the swollen sample was calculated for each grade of silicone. Using a combination of the six phi values obtained in this study and four of those obtained in a previous study, for each silicone grade, phi was plotted against deltal, the liquid solubility parameter for the ten liquids used. Using a curve fitting technique a second-order polynomial was plotted through the data points; the minimum in this polynomial provided a value for deltap (the polymer solubility parameter). Furthermore, the results showed that the deltap values obtained in this study (using ten liquids) were slightly but significantly greater (p<0.05) than those obtained in a previous study (using four liquids), for grade C6-165 only. Similarly, the chi and upsilon values obtained in the two studies were only significantly different (p<0.05) from each other, for grade C6-165. PMID- 25813953 TI - Therapeutic effects of transdermal systems containing zinc-related materials on thermal burn rats. AB - OBJECTIVE: The aim of the present study is to evaluate the efficacy of slow zinc (Zn) release from beta-tricalcium phosphate powder (ZnTCP) containing 10 mol% Zn on rats with thermal burns. METHODS: The first-aid tapes were contained zinc sulfate (ZnSO4) solution, ZnTCP suspensions or zinc oxide ointment. After thermal burn treatments were performed on Zn-deficient rats, the groups D1, D2 and D3 were treated with tapes containing ZnTCP, ZnSO4 and zinc oxide ointment. The effects of the tapes on wound area, plasma Zn levels and alkaline phosphatase activity (Alp) were investigated. RESULTS: The wound area profiles of all rat groups could be separated into before and after the scab formation at around day 6. The area under the curve (Aw-AUC) for wound area profiles, therefore, was evaluated as an index of therapeutic scores for the thermal wound. The order of Aw-AUC was D3>C>D2>D1. The degree of expansion at the initial stage by thermal burns of group D1 was the lowest and that of group D2 was the highest, and the order was D1 0.5). Sodium was significantly altered after 3-5 Gy (p < 0.01, r > 0.5), except 1 and 2 Gy, whereas changes in sodium level were nonsignificant (p > 0.5). Urea, total protein, and amylase levels were also significantly increased as the radiation dose increased (p < 0.01) with large effect size of difference (r > 0.5). This study suggests that salivary parameters were sensitive toward radiation even at low radiation dose which can be used as a predictor of radiation injury. PMID- 25813963 TI - Will changes to patent infringements attract drug research in the UK? AB - Ever since the introduction of the 'Bolar' exemption into the national laws of the EU Member States, the UK has been perceived to be a relatively difficult territory in which to conduct clinical trials, as compared to EU territories having very broad 'Bolar' exemptions, such as France and Germany. This problem for the UK has now been comprehensively eliminated by an amendment to UK patent law that came into force on 1 October 2014. However, whilst addressing a problem faced by the pharmaceutical industry in connection with conducting clinical trials, the manner in which UK patent law has been amended raises important but as yet unanswered questions about the knock-on effects for enforcement of European patents having unitary effect, if and when the laws governing such patents come into force. PMID- 25813964 TI - New scoring system predicts cardiovascular disease risk worldwide. PMID- 25813965 TI - Natural background groundwater composition in the Azores archipelago (Portugal): a hydrogeochemical study and threshold value determination. AB - Groundwater discharges were sampled in selected springs from Sao Miguel (Furnas and Fogo trachytic central volcanoes) and Santa Maria islands (Azores, Portugal), in order to characterize natural background levels (NBLs) and proceed to the determination of threshold values (TVs). Besides being a key issue in order to fully assess the anthropogenic pressures, NBLs are also instrumental to derive TVs, therefore complying with requirements from the European Union Groundwater Directive. The composition of groundwater corresponds mainly to low mineralized Na-HCO3 to Na-Cl water types, the latter dominant in Santa Maria island, with a decreasing order of Na>Ca>Mg>K and Cl>HCO3>SO4>NO3 for cations and anion respectively. The majority of the samples are slightly acid to slightly alkaline (pH range of 5.45-7.43), and the electrical conductivity range between 180 and 1458 MUS/cm. Groundwater composition is controlled by two major drivers, addition of sea salts and dissolution of silicate minerals. Results shown that TVs established along the present study are in general in the lower rank when compared to the range of values proposed by the several EU member states, with the main exception of NO3, reflecting the impact of agriculture activities over water quality in the Azores, and lower than the national ones. The comparison between the estimated NBL and TV with values derived with another dataset from the Azores, usually higher, depicts the effect of a larger and diverse number of groundwater sources over calculations. On the other hand, all samples which show a contribution from volcanic/hydrothermal systems were excluded from the dataset, which explains why the derived NBLs and TVs are lower comparing to other active volcanic areas, which is also a conservative approach on a subject that has regulatory implications. PMID- 25813966 TI - Subcellular partitioning of metals in Aporrectodea caliginosa along a gradient of metal exposure in 31 field-contaminated soils. AB - Subcellular fractionation of metals in organisms was proposed as a better way to characterize metal bioaccumulation. Here we report the impact of a laboratory exposure to a wide range of field-metal contaminated soils on the subcellular partitioning of metals in the earthworm Aporrectodea caliginosa. Soils moderately contaminated were chosen to create a gradient of soil metal availability; covering ranges of both soil metal contents and of several soil parameters. Following exposure, Cd, Pb and Zn concentrations were determined both in total earthworm body and in three subcellular compartments: cytosolic, granular and debris fractions. Three distinct proxies of soil metal availability were investigated: CaCl2-extractable content dissolved content predicted by a semi mechanistic model and free ion concentration predicted by a geochemical speciation model. Subcellular partitionings of Cd and Pb were modified along the gradient of metal exposure, while stable Zn partitioning reflected regulation processes. Cd subcellular distribution responded more strongly to increasing soil Cd concentration than the total internal content, when Pb subcellular distribution and total internal content were similarly affected. Free ion concentrations were better descriptors of Cd and Pb subcellular distribution than CaCl2 extractable and dissolved metal concentrations. However, free ion concentrations and soil total metal contents were equivalent descriptors of the subcellular partitioning of Cd and Pb because they were highly correlated. Considering lowly contaminated soils, our results raise the question of the added value of three proxies of metal availability compared to soil total metal content in the assessment of metal bioavailability to earthworm. PMID- 25813967 TI - Assessment of PAH dissipation processes in large-scale outdoor mesocosms simulating vegetated road-side swales. AB - Biofilters have been implemented in urban areas due to their ability to improve road runoff quality. However, little is known about the role of soil microorganisms and plants on pollutant remediation in planted swales. Therefore, four large-scale outdoor mesocosms were built and co-contaminated with metals and model polycyclic aromatic hydrocarbons (PAHs) (phenanthrene (Phen), pyrene (Pyr) and benzo[a]pyrene (BaP)), to better understand the complex functioning of swale like environments. Three macrophyte plant species were tested for enhanced remediation of PAHs: Juncus effusus, Iris pseudacorus, Phalaris arundinacea and a grass mix. Long-term dynamics of PAHs in water outflow and soil was studied. Results showed that only 0.07 to 0.22% of total PAHs were released in water outflow after one year. Two years after contamination, soil sample analyses showed a dissipation of 99.6% for Phen and 99.4% for Pyr whatever the mesocosm considered and ranging from 75.5 to 91% for BaP, depending on plant species. Furthermore, dissipation time-courses may be described by a biphasic process. Experiments showed that the grass mix facilitated BaP long-term biodegradation. Grass appeared also to be the best filter for suspended solids because of its dense rhizosphere, which prevents the transfer of BaP to groundwater. PMID- 25813968 TI - Biodegradation of 1,4-dioxane: effects of enzyme inducers and trichloroethylene. AB - 1,4-Dioxane is a groundwater contaminant and probable human carcinogen. In this study, two well-studied degradative bacteria Mycobacterium vaccae JOB5 and Rhodococcus jostii RHA1 were examined for their 1,4-dioxane degradation ability in the presence and absence of its co-contaminant, trichloroethylene (TCE), under different oxygenase-expression conditions. These two strains were precultured with R2A broth (complex nutrient medium) before supplementation with propane or 1 butanol to induce the expression of different oxygenases. Both propane- and 1 butanol-induced JOB5 and RHA1 were able to degrade 1,4-dioxane, TCE, and mixtures of 1,4-dioxane/TCE. Complete degradation of 1,4-dioxane/TCE mixture was observed only in propane-induced strain JOB5. Inhibition was observed between 1,4-dioxane and TCE for all cells. Furthermore, product toxicity caused incomplete degradation of 1,4-dioxane by 1-butanol-induced JOB5. In general, the more TCE degraded, the greater extent of product toxicity cells experienced; however, susceptibility to product toxicity was found to be both strain- and inducer dependent. The findings of this study provide fundamental basis for developing an effective in-situ remediation method for 1,4-dioxane-contaminated ground water and the first known study of 1,4-dioxane degradation by wild-type strain RHA1. PMID- 25813969 TI - An approach to using heart rate monitoring to estimate the ventilation and load of air pollution exposure. AB - BACKGROUND: The effects of air pollution on health are associated with the amount of pollutants inhaled which depends on the environmental concentration and the inhaled air volume. It has not been clear whether statistical models of the relationship between heart rate and ventilation obtained using laboratory cardiopulmonary exercise test (CPET) can be applied to an external group to estimate ventilation. OBJECTIVES: To develop and evaluate a model to estimate respiratory ventilation based on heart rate for inhaled load of pollutant assessment in field studies. METHODS: Sixty non-smoking men; 43 public street workers (public street group) and 17 employees of the Forest Institute (park group) performed a maximum cardiopulmonary exercise test (CPET). Regression equation models were constructed with the heart rate and natural logarithmic of minute ventilation data obtained on CPET. Ten individuals were chosen randomly (public street group) and were used for external validation of the models (test group). All subjects also underwent heart rate register, and particulate matter (PM2.5) monitoring for a 24-hour period. RESULTS: For the public street group, the median difference between estimated and observed data was 0.5 (CI 95% -0.2 to 1.4) l/min and for the park group was 0.2 (CI 95% -0.2 to 1.2) l/min. In the test group, estimated values were smaller than the ones observed in the CPET, with a median difference of -2.4 (CI 95% -4.2 to -1.8) l/min. The mixed model estimated values suggest that this model is suitable for situations in which heart rate is around 120-140bpm. CONCLUSION: The mixed effect model is suitable for ventilation estimate, with good accuracy when applied to homogeneous groups, suggesting that, in this case, the model could be used in field studies to estimate ventilation. A small but significant difference in the median of external validation estimates was observed, suggesting that the applicability of the model to external groups needs further evaluation. PMID- 25813970 TI - Sete Cidades and Furnas lake eutrophication (Sao Miguel, Azores): analysis of long-term monitoring data and remediation measures. AB - Eutrophication of lakes in the Azores archipelago (Portugal) has been described since the 80s, and due to water quality deterioration several remediation methodologies were applied. Long-term monitoring data on water quality from Sete Cidades and Furnas lakes (Sao Miguel island) were analyzed in order to address that the success of the ongoing policy reverses their eutrophic status. Sete Cidades lake (4.46 km2), made by two branches (so-called Green and Blue lakes), has a water volume equal to 58*10(6) m3 and a depth in the range between 24 and 28.5m. Furnas lake (1.87 km2) has a volume equal to 14*10(6) m3 and a maximum depth of 15m. In Sete Cidades lake mean water temperature and pH range respectively between 13.4 degrees C to 17.7 degrees C and 7.04 to 8.06. Instead, mean temperature in Lake Furnas ranges between 16.6 degrees C and 17.2 degrees C, with a pH between 7.36 and 7.84. Mean water conductivity shows that both lakes correspond to very diluted waters, with values between 98.1 and 136.5 MUS/cm. Water chemistry is influenced by the monomictic character of the lakes, as anoxic environment in the hypolimnion due to O2 consumption during the summer, when stratification prevents mixing along the water column, explains sharp increase in TP, TN, N-ammoniacal, Mn and Fe. Major-ion content is rather constant along time, with some seasonal fluctuations, despite a decrease in SO4 observed in Sete Cidades lake which is suggested to be a result of runoff diversion, a result also shown by the decrease of the molal ratio TN/TP in both studied lakes. Nevertheless, the application of the trophic state index (TSITP) does not suggest an improvement in what concerns trophic status, which is explained by the internal P-loading, a source that have to be managed by environmental authorities in the near future in order to revert eutrophication. PMID- 25813971 TI - Insights from nature for cybersecurity. AB - The alarming rise in the quantity of malware in the past few years poses a serious challenge to the security community and requires urgent response. However, current countermeasures seem no longer to be effective. Thus, it is our belief that it is now time for researchers and security experts to turn to nature in the search for novel inspiration for defense systems. Nature has provided species with a whole range of offensive and defensive techniques, which have been developing and improving over the course of billions of years of evolution. Extremely diverse living conditions have promoted a large variation in the devised biosecurity solutions. In this article we introduce a novel Protection framework in which common denominators of the encountered offensive and defensive means are proposed and presented. The bio-inspired solutions are discussed in the context of cybersecurity, where some principles have already been adopted. The deployment of the whole nature-based framework should aid in the design and improvement of modern cyberdefense systems. PMID- 25813972 TI - Health security preparedness and industry trends. AB - Given the number and diversity of risks in today's complex society, it is essential to focus on global risks that can be reduced through affordable, feasible approaches. Thus, the risks that should command the greatest focus are emergent infectious diseases. Fortunately, preparing responses to such threats can be entirely agnostic as to source or intent of the threat. This article considers the emergent infectious clinical threats, characterizes the steps that are essential to take to prepare for such threats, and discusses the roles that the biomedical industry should play in both the preparation for and response to such threats. The author assesses the readiness of the industry to play its role and suggests steps to consider to enable a more robust response. PMID- 25813973 TI - Are US jurisdictions prepared to dispense medical countermeasures through open points of dispensing? Findings from a national study. AB - Communities will rely on open points of dispensing (PODs) for mass dispensing of medical countermeasures following a bioterrorism attack or a pandemic. US Cities Readiness Initiative (CRI) open POD preparedness is assessed using the Technical Assistance Review (TAR) but focuses on oral prophylaxis dispensing; mass vaccination readiness is not well measured. Non-CRI preparedness had not been studied. In 2013 an online questionnaire was sent to all 456 CRIs and a random sample of 500 non-CRIs to measure open POD preparedness and exercise participation. Hierarchical linear regression was used to describe factors associated with higher POD preparedness and exercise participation scores. In total, 257 subjects participated, for a 41% response rate. Almost all open PODs have existing written plans and/or a layout for each site (93.4%, n=240, and 87.0%, n=220). Only half (46.7%, n=120) have an alternative dispensing modality in place, and even fewer (42.6%, n=104) report having adequate staffing. Determinants of open POD preparedness were perceived preparedness, participation in more POD exercises, and more closed POD coverage. Most jurisdictions conducted a full-scale exercise and a staff notification drill (83.7%, n=215 for both). Fewer than half (40.5%, n=104) have conducted a vaccination clinic exercise. Determinants of increased POD exercises were perceived preparedness, years of work experience, community type (nontribal), and larger population. Because successful open POD deployment is critical, jurisdictions need to plan for mass vaccination, use of alternative dispensing modalities, and recruitment strategies to increase POD staffing. PMID- 25813975 TI - Marburg biosafety and biosecurity scale (MBBS): a framework for risk assessment and risk communication. AB - Current risk assessment and risk communication of biosafety and biosecurity concerns lack a convenient metric and conceptual framework. The absence of such a systematic tool makes communication more difficult and can lead to ambiguous public perception of and response to laboratory biosafety incidents and biosecurity threats. A new 7-category scoring scale is proposed for incidents and situations in laboratories related to the handling of human and animal pathogens. The scale aims to help clarify risk categories, facilitate coordination and communication, and improve public understanding of risk related to biosafety and biosecurity. PMID- 25813974 TI - Are human service agencies ready for disasters? Findings from a mixed-methods needs assessment and planning project. AB - A mixed-methods design was used to assess the current capacity of human service agencies to provide services in a major disaster, identify challenges and successful strategies for providing those services, and formulate specific recommendations for government planners and the nonprofit sector to promote the integration of human service agencies into emergency preparedness and response. A web-based survey was completed by 188 unique human service agencies, 31 semistructured interviews were conducted with human service agency and government leaders from southeastern Pennsylvania and the mid-Atlantic region, and a collaborative planning meeting was held to review the findings and develop systems-based recommendations. Survey results indicated that human service agencies serve the most vulnerable communities during disasters and would welcome integration into preparedness and response plans, but they currently face challenges that include a lack of real-time communication and opportunities for collaborative planning with government partners. Interview findings were grouped according to 5 themes that emerged: capacity, coordination, communication, training, and leadership. This study identified recommendations to assist human service agencies, local health departments, and emergency management agencies as they work to ensure that needed human services are available during disasters, despite the resource challenges that most agencies face. PMID- 25813976 TI - Multiplex PCR for species-level identification of Bacillus anthracis and detection of pXO1, pXO2, and related plasmids. AB - The Bacillus anthracis virulence plasmids pXO1 and pXO2 have critical implications for biosafety and select agent status. The proper identification and characterization of B. anthracis and its plasmid profile is important to the biodefense research community. Multiplex PCR was used to simultaneously detect a B. anthracis-specific chromosomal mutation, 4 targets distributed across pXO1, 3 targets distributed across pXO2, and highly conserved regions of the 16S gene, allowing an internal positive control for each sample. The multiplex PCR can produce as many as 9 easily separable and distinguishable amplicons, ranging in size from 188 to 555 bp. The PCR results were used to characterize DNA samples extracted from B. anthracis, other Bacillus species, and other bacterial species from many different genera. With the exception of 2 novel putative plasmids discovered, testing against inclusion and extensive exclusion panels showed 100% correlation to previously published and expected results. Upon testing 29 previously unpublished B. anthracis strains, 10 (34.5%) were pXO1(+)/pXO2(+), 9 (31.0%) were pXO1(+)/pXO2(-), 7 (24.1%) were pXO1(-)/pXO2(+), and 3 (10.3%) were pXO1(-)/pXO2(-). The present work presents a novel 9-target multiplex PCR assay capable of species-level identification of B. anthracis via a unique chromosomal marker and the detection of pXO1 and pXO2 via multiply redundant targets on each. PMID- 25813977 TI - Implications drawn from a military bioterror exercise in Israel. AB - Orange Flame is an Israeli preparedness build-up project, conducted by the Ministry of Health, that is aimed at improving national readiness and preparedness for unusual biological events. The project is intended for both medical and nonmedical organizations, and, since 2011, the exercise has also included operational units outside the medical corps. This has provided valuable insights into the consequences of bioterror or naturally occurring outbreaks for operative functionality and for the unique medical, logistical, and administrative efforts required from the armed forces in such an event. The 2-day drill reported on here executed a notional scenario in which category A bioterror agents were dispersed, causing civil and military casualties. Military personnel observed and assessed the performances of all participating organizations and observed the employment of emergency protocols during the drill. Military sustainment and operative capabilities were significantly affected by the occurrence of an unusual biological event. Comprehensive actions to be executed during such a scenario included quarantining military bases, considering postponement of military operations, and transferring on-call missions to other bases. Logistic consequences included the need for manpower and equipment reinforcement, as well as food and water supplies in cases of suspected source contamination. The project unveiled many operational and logistic quandaries and exposed various potential effects of a bioterror attack in the military. Lessons learned were used to revise preevent national and military doctrine for unusual biological events. PMID- 25813978 TI - Development of drug-approval regulations for medical countermeasures against CBRN agents in Japan. AB - To develop approval regulations for drugs against chemical, biological, radiological, or nuclear (CBRN) agents in Japan, and to help inform arguments about the development of anti-CBRN agents, we analyzed documentation describing approval processes and data for drugs against CBRN agents. Sixteen countermeasure products against 10 CBRN agents have been approved in Japan. Approval schemes were grouped into 3 categories: application for off-label uses, expedited review for antiterrorism measures, and expedited review. Ten drug applications were designated "priority reviews," and the median review time was 4.4 months. No application relied exclusively on clinical trials to expose patients to CBRN threats. Clinical experience with drugs in victims of unexpected exposure was not necessarily important for approval. The United States is the most advanced country in terms of developing medical countermeasure products against CBRN agents. Japan has similarities with the US in approved products and application packages, but there were 3 unapproved products or indications that were approved under the Animal Rule in the US. The Animal Rule might encourage development of a novel product by providing efficacy evaluation in animal studies. The US also has regulations that do not exist in Japan that authorize administration of an investigational drug outside a clinical trial for patients. Introduction of the Animal Rule and expanded access of investigational drugs could contribute to development and approvals of novel countermeasure products and improve an emergency response in a crisis in Japan. PMID- 25813979 TI - Public engagement and the governance of gain-of-function research. AB - The White House recently called for a "robust and broad deliberative process" to assess the risks and benefits of select gain-of-function studies, pausing current experiments and further grants until new federal policy on research funding and oversight is developed. At issue is whether and under what conditions laboratory studies that enhance the transmissibility and/or virulence of potential pandemic pathogens such as the H5N1 avian influenza virus should go forward. To date, professionals from medicine, public health, and the life sciences have dominated the debate, and each side of the controversy has cited the public's well-being as the principal motivator for their position. A major stakeholder, the general public, has not yet actively and systematically weighed in on the matter. This commentary considers in what form and with what benefit public participation may materialize in the current debate regarding the governance of gain-of-function research. PMID- 25813980 TI - Dispensing medical countermeasures: emergency use authorities and liability protections. AB - The Pandemic and All-Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) enhances emergency use authorities with respect to both approved and unapproved medical countermeasures (MCMs). PAHPRA authorities can also be critical to preserving tort liability protections for public health stakeholders, since these protections are often contingent upon appropriate authorizations for the MCMs utilized. This article details the evolution of emergency use authorities and liability protections, analyzes how these separate legal doctrines can intersect in practice, and discusses implications for facilitating preparedness and response activities and for protecting associated personnel. PMID- 25813981 TI - Considering a career in neurology research? Heed these words. PMID- 25813982 TI - EGFR participates downstream of ERalpha in estradiol-17beta-D-glucuronide-induced impairment of Abcc2 function in isolated rat hepatocyte couplets. AB - Estradiol-17beta-D-glucuronide (E17G) induces acute endocytic internalization of canalicular transporters, including multidrug resistance-associated protein 2 (Abcc2) in rat, generating cholestasis. Several proteins organized in at least two different signaling pathways are involved in E17G cholestasis: one pathway involves estrogen receptor alpha (ERalpha), Ca(2+)-dependent protein kinase C and p38-mitogen activated protein kinase, and the other pathway involves GPR30, PKA, phosphoinositide 3-kinase/AKT and extracellular signal-related kinase 1/2. EGF receptor (EGFR) can potentially participate in both pathways since it interacts with GPR30 and ERalpha. Hence, the aim of this study was to analyze the potential role of this receptor and its downstream effectors, members of the Src family kinases in E17G-induced cholestasis. In vitro, EGFR inhibition by Tyrphostin (Tyr), Cl-387785 or its knockdown with siRNA strongly prevented E17G-induced impairment of Abcc2 function and localization. Activation of EGFR was necessary but not sufficient to impair the canalicular transporter function, whereas the simultaneous activation of EGFR and GPR30 could impair Abcc2 transport. The protection of Tyr was not additive to that produced by the ERalpha inhibitor ICI neither with that produced by Src kinase inhibitors, suggesting that EGFR shared the signaling pathway of ERalpha and Src. Further analysis of ERalpha, EGFR and Src activations induced by E17G, demonstrated that ERalpha activation precedes that of EGFR and EGFR activation precedes that of Src. In conclusion, activation of EGFR is a key factor in the alteration of canalicular transporter function and localization induced by E17G and it occurs before that of Src and after that of ERalpha. PMID- 25813983 TI - ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype. AB - Basal-like breast cancer (BLBC) is a heterogeneous disease with poor prognosis; however, its cellular origins and aetiology are poorly understood. In this study, we show that inhibitor of differentiation 4 (ID4) is a key regulator of mammary stem cell self-renewal and marks a subset of BLBC with a putative mammary basal cell of origin. Using an ID4GFP knock-in reporter mouse and single-cell transcriptomics, we show that ID4 marks a stem cell-enriched subset of the mammary basal cell population. ID4 maintains the mammary stem cell pool by suppressing key factors required for luminal differentiation. Furthermore, ID4 is specifically expressed by a subset of human BLBC that possess a very poor prognosis and a transcriptional signature similar to a mammary stem cell. These studies identify ID4 as a mammary stem cell regulator, deconvolute the heterogeneity of BLBC and link a subset of mammary stem cells to the aetiology of BLBC. PMID- 25813984 TI - Associations between sleep difficulties and risk factors for cardiovascular disease in veterans and active duty military personnel of the Iraq and Afghanistan conflicts. AB - Recent evidence suggests that sleep disturbance may play an important role in the development of cardiovascular disease (CVD). Despite the prevalence of sleep complaints among service members of recent military conflicts, few studies have examined associations between sleep and risk factors for CVD in this population. Symptom checklist items regarding distress about "trouble falling asleep" and "restless/disturbed sleep" were used as proxies for sleep onset and maintenance difficulties to examine these associations in US military service members of recent conflicts. Veterans having both sleep onset and maintenance difficulties had greater odds of being a current smoker and having psychiatric symptoms and diagnoses. Increased odds of a self-reported hypertension diagnosis and elevated systolic blood pressure were also found in certain subsets of this sample. Findings highlight the need for greater recognition of sleep difficulties as a CVD risk factor in a population known to be at increased risk for this condition. PMID- 25813985 TI - The effect of disease risk probability and disease type on interest in clinic based versus direct-to-consumer genetic testing services. AB - The effect of disease-specific cognitions on interest in clinic-based and direct to-consumer (DTC) genetic testing was assessed. Participants (N = 309) responded to an online hypothetical scenario and received genetic testing-related messages that varied by risk probability (25, 50, 75 %) and disease type (Alzheimer's disease vs. Type 2 Diabetes). Post-manipulation interest increased for both testing types, but was greater for clinic-based testing. Interest was greater for Type 2 Diabetes than for Alzheimer's disease, the latter perceived as more severe and likely, and less treatable and preventable. For DTC testing only, participants allocated to the high risk condition (75 %) had greater testing interest than those in the low (25 %) category. DTC testing is perceived as a viable, but less preferred, option compared with clinic-based testing. Particularly when considering DTC genetic testing, there is a need to emphasize subjective disease-related perceptions, including risk probability. PMID- 25813987 TI - Recent advances in the role of cortisol and metabolic syndrome in age-related degenerative diseases. AB - The metabolic syndrome (MetS) presents an increasing prevalence in elderly people. A significant role in MetS is played by the stress response and cortisol. The hypothalamic-pituitary-adrenal (HPA) axis activity is increased by central (loss of hippocampal glucocorticoid receptors) and peripheral (11beta hydroxysteroid dehydrogenase type 1, 11beta-HSD1, hyperactivity) mechanisms. The HPA hyperactivity has been found in chronic diseases affecting the endocrine (abdominal obesity with MetS, type 2 diabetes), cardiovascular (atherosclerosis, essential hypertension), and nervous systems (dementia, depression), in aging. A novel therapeutic approach (11beta-HSD1 inhibition) is promising in treating the HPA axis hyperactivity in chronic diseases with MetS. A large-scale national clinical trial (AGICO, AGIng, and COrtisol study) has been proposed by our group to evaluate the role of cortisol and MetS in the main pathologies of aging (vascular and degenerative dementia, cardiovascular diseases, type 2 diabetes, abdominal obesity). PMID- 25813986 TI - Classification of pro-inflammatory status for interleukin-6 affects relative muscle strength in obese elderly women. AB - BACKGROUND: Obesity, defined by an excess amount of body fat or a percent body fat higher than 30 % for women is a complex chronic disorder with multifactorial etiology and is accompanied by chronic low-grade inflammation, which results in elevated pro-inflammatory cytokines. AIMS: The aim of this study was to compare muscle strength between high and low pro-inflammatory status in obese elderly women and to verify the relationship of IL-6 with muscle strength and fat-free mass. METHODS: Eighty-nine elderly women (age 69.47 +/- 6.07 years; body mass 64.70 +/- 12.04 kg; height 1.52 +/- 0.06 m; body mass index 27.78 +/- 4.75 kg/m(2)) were divided into two groups: high and low inflammatory status for IL-6. Lower limb muscle strength was tested using bilateral leg extension with the ten repetitions maximum test, IL-6 was measured by ELISA and body composition by dual energy X-ray absorptiometry. RESULTS: Women classified from the high pro inflammatory status presented lower relative muscle strength (P = 0.056) when compared with the low inflammatory status group, with no differences for absolute muscle strength (P = 0.18). There was a significant negative correlation of IL-6 with relative muscle strength (P = 0.03, R = -0.22) and a considerable trend toward significance (P = 0.06, R = -0.19) and negative association with fat-free mass (P = 0.84, R = -0.02). CONCLUSIONS: This study provides insights that a high pro-inflammatory status in sedentary obese elderly women might impair muscle strength and negatively affect fat-free mass. Thus, elderly women classified with high pro-inflammatory status for IL-6 should receive further health care attention to prevent this deleterious condition. PMID- 25813988 TI - Analysis of Circadian Rhythm Gene Expression With Reference to Diurnal Pattern of Intraocular Pressure in Mice. AB - PURPOSE: To determine the expression of circadian rhythm clock genes in the iris ciliary body complex of mice and their association with the diurnal pattern of intraocular pressure (IOP). METHODS: Thirty wild-type C57BL/6 mice were acclimated to a 12-hour light-dark cycle. Intraocular pressure was measured with a rebound tonometer at six time points daily (circadian time [CT] 2, 6, 10, 14, 18, and 22 hours) for five consecutive days. On day 6, mice were euthanized at CT 2, 6, 10, 14, 18, and 22. Eyes were flash-frozen or fixed in 4% phosphate buffered paraformaldehyde. Total RNA was extracted from the iris-ciliary body complex, and RNA expression of circadian rhythm genes Bmal1, Clock, Cry1, Cry2, Per1, and Per2 was assessed by quantitative real-time PCR. Fixed eyes were paraffin embedded, and immunohistochemistry was performed to localize corresponding proteins (BMAL1, CLOCK, CRY1, CRY2, PER1, and PER2). Linear regression analysis was performed to correlate gene expression with IOP. RESULTS: Intraocular pressure demonstrated a consistent circadian pattern. The clock genes Bmal1, Clock, Cry1, Cry2, Per1, and Per2 showed a circadian pattern of expression in the iris-ciliary body complex of mice. Bmal1, Clock, Cry1, Per1, and Per2 gene expression demonstrated statistically significant correlations with diurnal variations of IOP. BMAL1, CLOCK, CRY1, CRY2, PER1, and PER2 proteins were found to be expressed locally in the nonpigmented epithelium of the ciliary body. CONCLUSIONS: Expression patterns of candidate circadian rhythm genes correlates with the diurnal pattern variation of IOP in mouse eyes, indicating a possible mechanism of IOP regulation through these genes. PMID- 25813990 TI - Test-Retest Repeatability of Microperimetry at the Border of Deep Scotomas. AB - PURPOSE: The purpose of this study was to examine the test-retest repeatability of microperimetric sensitivity at the border of deep scotomas. METHODS: Thirty normal participants underwent two examinations, each on the Macular Integrity Assessment (MAIA) microperimeter and on the MP-1 microperimeter (four examinations in total). A customized stimulus pattern allowed microperimetric sensitivity to be measured at the border of the optic nerve head (ONH), which acted as a model for the border of a deep scotoma-and also at the macular and peripapillary region. RESULTS: There were no significant changes in average point wise sensitivity (PWS) values between the two examinations for all three regions using the MAIA microperimeter (P >= 0.262). The PWS coefficient of repeatability (CoR) was +/-12.99 dB at the border of the ONH, which was significantly larger than points in the macular and peripapillary regions (P > 0.001). A significant decrease in average PWS, using the MP-1 microperimeter at the macular and peripapillary region (P < 0.001), meant that the PWS CoR could not be determined in these regions. No significant changes in average PWS were observed at the border of the ONH (P = 0.223), and the PWS CoR was +/-7.52 dB in this region. CONCLUSIONS: Microperimetric test-retest repeatability at the border of a deep scotoma was worse than at other areas of normal retina, and this highlights the limitation of applying a single estimate of test-retest repeatability to determine whether significant functional decline has occurred at the border of a deep scotoma. PMID- 25813991 TI - Peripapillary choroidal thickness in nonarteritic anterior ischemic optic neuropathy. AB - PURPOSE: To compare peripapillary choroidal thickness, macular thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness between the affected eyes of patients with nonarteritic anterior ischemic optic neuropathy (NAION) and their unaffected eyes and the eyes of normal control subjects. METHODS: Thirty two eyes with NAION, 25 unaffected fellow eyes, and 25 normal control subjects met the inclusion criteria in this prospective comparative study at a single academic institution. Optic disc area, macular thickness, and RNFL thickness were evaluated at last follow up time using spectral-domain optical coherence tomography (OCT). Enhanced depth imaging OCT was obtained to evaluate peripapillary choroidal thickness. RESULTS: Mean follow up time was 4.9 +/-0.8 months and all data was collected from the last follow up. The mean optic disc area in NAION eyes and their unaffected fellow eyes were significantly smaller than normal control disc area measurements (P<0.001). Average PCT and all regional values were significantly greater in the NAION eyes and unaffected fellow eyes than in the control eyes (P=0.01). In all subjects, optic disc area was correlated with average PCT (r = -0.33, P = 0.002). In addition, RNFL thickness and macular thickness values were significantly lesser in the NAION eyes than in the unaffected fellow eyes and control eyes. CONCLUSIONS: PCT is thicker in NAION eyes and unaffected fellow eyes than control eyes. Thick peripapillary choroid might contribute to the development of NAION. PMID- 25813992 TI - An Eye on Brain Integrity: Acute Optic Neuritis Affects Resting State Functional Connectivity. AB - PURPOSE: Currently, the ability for imaging to capture brain adaptations to injury that occurs in multiple sclerosis (MS) is limited. In particular, how the brain initially contends with the earliest clinical manifestations of white matter injury has yet to be defined. The purpose of this study was to determine the impact of acute optic neuritis (ON) on resting state functional connectivity magnetic resonance imaging (rs-fcMRI). METHODS: Fifteen patients with a clinically isolated syndrome of acute ON were evaluated at an academic center in a prospective study. Subjects were assessed with structural and functional vision measures, including optical coherence tomography (OCT), high- and low-contrast letter acuity testing, and visual fields and quality-of-life measures (VFQ-25). The rs-fcMRI was compared with age- and sex-matched healthy controls. RESULTS: We observed reduced functional connectivity within the visual system and a loss of anticorrelations between the visual system and nonvisual networks. Stronger functional connectivity between visual regions correlated with better quality of life, as measured by the VFQ-25, and better acuity scores for both high- and low contrast testing in the affected eye. CONCLUSIONS: The rs-fcMRI functional connectivity changes within (intranetwork) and between (internetwork) resting state networks occur after acute ON, indicating immediate cortical responses to focal inflammatory demyelination. Thus, focal white matter injury in the central nervous system acutely results in widespread network alterations that may lead to functional neurologic changes seen in MS. PMID- 25813993 TI - Tumor Regression After Brachytherapy for Choroidal Melanoma: Reduction of Thickness and Cross-Sectional Area by Shape and Regression Pattern. AB - PURPOSE: To model regression rate of thickness and cross-sectional area of choroidal melanomas after ruthenium and iodine brachytherapy by shape and regression pattern (RP). METHODS: We enrolled 330 of 388 consecutive uveal melanomas from 2000 to 2008 and analyzed images from I3 System-ABD 10-MHz B-Scan at diagnosis and during a 3-year-long follow-up. We classified tumor shape by Collaborative Ocular Melanoma Study definitions and RP according to an earlier study. We plotted regression over time and compared thickness and cross-sectional area. RESULTS: The observed RP by thickness was classified as decrease (D) in 43%, stable (S) in 5%, increase (I) in 1%, and other in 40% of eyes; main subpatterns were decrease-stable (DS) in 16% and zigzag in 10% of eyes. The corresponding percentages by area were 42%, 3%, 1%, 45%, 16%, and 14%. Regression pattern was discordant in 34% of eyes for thickness versus area. Area reduced faster than thickness when shape was oval to dome or mushroom and if RP was D. Pooled patterns D, DS, decrease-increase (DI), and zigzag corresponded with progressive but increasingly less pronounced regression for 3 years (56% by thickness and 69% by area), 2 years (50% and 52%), 6 months (29% and 33%), and 6 months (19% and 23%), respectively. First-order exponential decay function fitted thickness and area regression for every shape and for patterns D, DS, DI, and zigzag. CONCLUSIONS: Heterogeneity in RP, variation in shape, and tumor cross sectional area as an alternative measure must be considered when tumor regression rate is used in outcome analysis. PMID- 25813989 TI - The Project MACULA Retinal Pigment Epithelium Grading System for Histology and Optical Coherence Tomography in Age-Related Macular Degeneration. AB - PURPOSE: To seek pathways of retinal pigment epithelium (RPE) fate in age-related macular degeneration via a morphology grading system; provide nomenclature, visualization targets, and metrics for clinical imaging and model systems. METHODS: Donor eyes with geographic atrophy (GA) or choroidal neovascularization (CNV) and one GA eye with previous clinical spectral-domain optical coherence tomography (SDOCT) imaging were processed for histology, photodocumented, and annotated at predefined locations. Retinal pigment epithelial cells contained spindle-shaped melanosomes, apposed a basal lamina or basal laminar deposit (BLamD), and exhibited recognizable morphologies. Thicknesses and unbiased estimates of frequencies were obtained. RESULTS: In 13 GA eyes (449 locations), 'Shedding,' 'Sloughed,' and 'Dissociated' morphologies were abundant; 22.2% of atrophic locations had 'Dissociated' RPE. In 39 CNV eyes (1363 locations), 37.3% of locations with fibrovascular/fibrocellular scar had 'Entombed' RPE; 'Sloughed,' 'Dissociated,' and 'Bilaminar' morphologies were abundant. Of abnormal RPE, CNV and GA both had ~35% 'Sloughed'/'Intraretinal,' with more Intraretinal in CNV (9.5% vs. 1.8%). 'Shedding' cells associated with granule aggregations in BLamD. The RPE layer did not thin, and BLamD remained thick, with progression. Granule-containing material consistent with three morphologies correlated to SDOCT hyperreflective foci in the previously examined GA patient. CONCLUSIONS: Retinal pigment epithelium morphology indicates multiple pathways in GA and CNV. Atrophic/scarred areas have numerous cells capable of transcribing genes and generating imaging signals. Shed granule aggregates, possibly apoptotic, are visible in SDOCT, as are 'Dissociated' and 'Sloughed' cells. The significance of RPE phenotypes is addressable in longitudinal, high-resolution imaging in clinic populations. Data can motivate future molecular phenotyping studies. PMID- 25813994 TI - The Effects of Sonic Hedgehog on Retinal Muller Cells Under High-Glucose Stress. AB - PURPOSE: To investigate sonic hedgehog (SHH) expression and its effects on retinal Muller cells in diabetic rats and in vitro culture systems under high glucose stress. METHODS: Diabetic rats were induced by intraperitoneal injection of streptozotocin. Primary rat retinal Muller cells were grown in medium containing 5.5 or 35 mM glucose with SHH and/or cyclopamine. Retinas' and primary Muller cells' expression of SHH pathway components protein and mRNA were determined by Western blot analysis and real-time PCR. The effects of exogenous SHH and its inhibitor cyclopamine on retinal ganglion cells (RGCs) survival after 3-month diabetes were examined by the counting of Brn-3a-labeled RGCs. Phosphoinositide 3-kinase (PI3K), extracellular signal regulated kinases 1 and 2 (ERK1/2), and P38 were detected by Western blot. RESULTS: Both mRNA and protein expression of SHH, SMO, GLI1, and glial fibrillary acidic protein (GFAP) in the retinas of diabetic rats and high-glucose cultured Muller cells increased in a time-dependent manner. Exogenous SHH increased the mRNA and protein expression of SHH, SMO, and GLI1 and cyclopamine reversed that effect. Three months after onset of diabetes, administration of SHH inhibited gliosis significantly and promoted RGC survival. Exogenous SHH upregulated the phosphorylation of PI3K and downregulated ERK1/2, but did not affect the expression of P38. CONCLUSIONS: Sonic hedgehog signaling pathway was upregulated in diabetic rat retina and high glucose cultured Muller cells, and SHH exerted neuroprotective effects on damaged RGCs in a rat diabetes model. The neuroprotective effects of SHH may act indirectly, via Muller cells, through PI3K or ERK1/2 pathways. PMID- 25813995 TI - Time-Dependent Changes of Cell Proliferation After Laser Photocoagulation in Mouse Chorioretinal Tissue. AB - PURPOSE: This study investigated the time course of cell proliferation after laser photocoagulation and analyzed the cell types of proliferating cells. METHODS: C57BL/6J mice received unilateral laser photocoagulation. Intraperitoneal bromodeoxyuridine (BrdU) injection was performed, and mice were divided into two groups according to the injection paradigm: group 1 with continuous injection and group 2 with periodic injection. Each group was again divided into four subgroups according to injection period: 0 to 3 days (n = 11), 0 to 7 days (n = 14), 0 to 14 days (n = 6), and 0 to 28 days (n = 6) after laser photocoagulation for group 1; and 0 to 3 days (n = 11), 4 to 7 days (n = 6), 8 to 14 days (n = 6), and 15 to 28 days (n = 6) after laser photocoagulation for group 2. The eyes were examined with immunohistochemistry using anti-BrdU antibody and other various antibodies for identification of proliferating cells. Manual cell counting and flow cytometry were performed for quantification. RESULTS: In group 1, the number of BrdU+ cells showed marked increase during the first 3 days of laser lesioning, reaching its maximum after 7 days (P < 0.05). Group 2 also demonstrated peak proliferation during the first 3 days, but a significantly reduced number of BrdU+ cells were detected during 4 to 7 days, 8 to 14 days, and 15 to 28 days of laser treatment (P < 0.05). BrdU+ cells colocalized with CD11b, F4/80, iba1, RPE65, CD31, and glial fibrillary acidic protein (GFAP) labeling, and CD11b+, F4/80+, and iba1+ cells constituted the main fraction of BrdU+ cells. CONCLUSIONS: Laser photocoagulation induced cell proliferation mostly during the first 3 days, and many proliferating cells were identified as inflammatory cells, RPE cells, endothelial cells, and Muller cells. PMID- 25813996 TI - Automatic computer-aided diagnosis of retinal nerve fiber layer defects using fundus photographs in optic neuropathy. AB - PURPOSE: To evaluate the validity of an automatic computer-aided diagnosis (CAD) system for detection of retinal nerve fiber layer (RNFL) defects on fundus photographs of glaucomatous and nonglaucomatous optic neuropathy. METHODS: We have proposed an automatic detection method for RNFL defects on fundus photographs in various cases of glaucomatous and nonglaucomatous optic neuropathy. In order to detect the vertical dark bands as candidate RNFL defects, the nonuniform illumination of the fundus image was corrected, the blood vessels were removed, and the images were converted to polar coordinates with the center of the optic disc. False positives (FPs) were reduced by using knowledge-based rules. The sensitivity and FP rates for all images were calculated. RESULTS: We tested 98 fundus photographs with 140 RNFL defects and 100 fundus photographs of healthy normal subjects. The proposed method achieved a sensitivity of 90% and a 0.67 FP rate per image and worked well with RNFL defects with variable depths and widths, with uniformly high detection rates regardless of the angular widths of the RNFL defects. The average detection accuracy was approximately 0.94. The overall diagnostic accuracy of the proposed algorithm for detecting RNFL defects among 98 patients and 100 healthy individuals was 86% sensitivity and 75% specificity. CONCLUSIONS: The proposed CAD system successfully detected RNFL defects in optic neuropathies. Thus, the proposed algorithm is useful for the detection of RNFL defects. PMID- 25813997 TI - Effects of Gelatin Hydrogel Loading Mitomycin C on Conjunctival Scarring in a Canine Filtration Surgery Model. AB - PURPOSE: To investigate the effects and toxicities of gelatin hydrogel (GH) loading mitomycin C (MMC) on IOP and conjunctival scarring in a canine model of glaucoma surgery in comparison with conventional MMC application. METHODS: Glaucoma surgery models were made in six beagles. An MMC-loaded GH was implanted under the conjunctiva of one eye (GH-MMC group) and 0.04% MMC-soaked sponges were placed under the conjunctiva of the other eye (MMC group) for 5 minutes. Intraocular pressures and bleb features were then assessed for 4 weeks postoperative, followed by histological evaluation. The ratio of conjunctival area to scleral area, the densities of collagen and the numbers of fibroblasts, vessels, and proliferative cell nuclear antigen (PCNA)-positive cells were then quantified. RESULTS: In both groups, IOP reduction and bleb formation were maintained in a similar manner for 4 weeks postoperative. No significant difference in the ratio of conjunctival area to scleral area was found between the two groups. Collagen density and the numbers of fibroblasts and vessels were significantly lower in the MMC-treated group than in the GH-MMC-treated group. No significant difference in PCNA-positive cells was found between the two groups. CONCLUSIONS: Implantation of MMC-loaded GH ameliorated toxicity to conjunctiva compared with the 5-minute placement of MMC, whereas its effect on IOP reduction and bleb formation was similar. These results suggest that using GH for the application of MMC is a safer method than the conventional application of MMC in glaucoma filtration surgery. PMID- 25813998 TI - Catalase therapy corrects oxidative stress-induced pathophysiology in incipient diabetic retinopathy. AB - PURPOSE: Preclinical studies have highlighted retinal oxidative stress in the pathogenesis of diabetic retinopathy. We evaluated whether a treatment designed to enhance cellular catalase reduces oxidative stress in retinal cells cultured in high glucose and in diabetic mice corrects an imaging biomarker responsive to antioxidant therapy (manganese-enhanced magnetic resonance imaging [MEMRI]). METHODS: Human retinal Muller and pigment epithelial cells were chronically exposed to normal or high glucose levels and treated with a cell-penetrating derivative of the peroxisomal enzyme catalase (called CAT-SKL). Hydrogen peroxide (H2O2) levels were measured using a quantitative fluorescence-based assay. For in vivo studies, streptozotocin (STZ)-induced diabetic C57Bl/6 mice were treated subcutaneously once a week for 3 to 4 months with CAT-SKL; untreated age-matched nondiabetic controls and untreated diabetic mice also were studied. MEMRI was used to analytically assess the efficacy of CAT-SKL treatment on diabetes-evoked oxidative stress-related pathophysiology in vivo. Similar analyses were performed with difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase. RESULTS: After catalase transduction, high glucose-induced peroxide production was significantly lowered in both human retinal cell lines. In diabetic mice in vivo, subnormal intraretinal uptake of manganese was significantly improved by catalase supplementation. In addition, in the peroxisome-rich liver of treated mice catalase enzyme activity increased and oxidative damage (as measured by lipid peroxidation) declined. On the other hand, DFMO was largely without effect in these in vitro or in vivo assays. CONCLUSIONS: This proof-of-concept study raises the possibility that augmentation of catalase is a therapy for treating the retinal oxidative stress associated with diabetic retinopathy. PMID- 25814000 TI - Sildenafil Acutely Decreases Visual Responses in ON and OFF Retinal Ganglion Cells. AB - PURPOSE: Sildenafil (Viagra), a cGMP-specific phosphodiesterase type 5 inhibitor, is widely used for the treatment of erectile dysfunction and pulmonary hypertension. Clinical studies have reported transient visual impairments in patients after single-dose sildenafil use, suggesting neural involvement in several retinal layers, and also, possibly, retinal ganglion cells (RGCs), which provide the unique output of visual information to the brain. However, the effect of sildenafil on the RGC light responses is poorly understood. We therefore evaluated its effect on RGC spiking activity. METHODS: We measured spontaneous and light-induced RGC spiking activity in Long-Evans rat ex vivo retinas by using the multielectrode array technique. Sildenafil citrate (0.3-30 MUM) was applied to retinal preparations under continuous perfusion, during 10 to 60 minutes, followed by sildenafil washout. RESULTS: A high concentration (30 MUM) of sildenafil decreased the magnitudes of both ON- and OFF-type RGC light responses, to 26.3% +/- 17% and 18.3% +/- 7%, respectively, of the initial value, in a reversible and concentration-dependent fashion, while in 50% of RGCs all light responses were completely suppressed. Sildenafil also greatly increased the latency of both types of light responses. In this study, we provided evidence that extended exposure to both sildenafil and repeated light stimulation potentiates drug effects and delays recovery. CONCLUSIONS: We found transient and concentration-dependent alterations of light responses at the RGC level after sildenafil exposure that are relevant for a better understanding of the acute visual effects of administration of this compound in humans. PMID- 25814001 TI - [Sentinel lymph node biopsy. Editorial]. PMID- 25814002 TI - Salidroside inhibits the growth of human breast cancer in vitro and in vivo. AB - Salidroside has been identified as one of the most potent compounds isolated from the plant Rhodiola rosea, and was found to have several important biological properties, including antioxidant and anti-inflammatory activity; however, its anticancer effects are poorly understood. Thus, the present study focused on evaluating the effects of purified salidroside on the growth of human breast cancer in vitro and in vivo, and on further investigating its possible molecular mechanisms. The human breast cancer cell line, MCF-7, was incubated with various concentrations of salidroside, and cell proliferation, colony formation, cell cycle distribution, apoptosis, migration and invasion were assayed by several in vitro approaches. As a result, it was found that salidroside treatment significantly inhibited cell proliferation, colony formation, migration and invasion, as well as induced cell apoptosis and cell cycle arrest at the G0/G1 phase in vitro. In addition, we also evaluated the effect of salidroside on tumor growth in a nude mouse model, and found that salidroside treatment significantly suppressed tumor growth in vivo. We also further disclosed that salidroside treatment significantly inhibited the intracellular reactive oxygen species (ROS) formation and MAPK pathway activation, which may contribute to the inhibition of tumor growth of breast cancer and reduction of oxidative stress. In conclusion, these findings suggest that salidroside may be a promising candidate target for the prevention and treatment of human breast cancer. PMID- 25813999 TI - Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. AB - PURPOSE: The pathophysiology of ocular hypertension (OH) leading to primary open angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder. METHODS: A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait. RESULTS: An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5' end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-beta. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells. CONCLUSIONS: Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH. PMID- 25814003 TI - Minimally invasive repair of pectus excavatum: analyzing contemporary practice in 50 ACS NSQIP-pediatric institutions. AB - BACKGROUND: Minimally invasive repair of pectus excavatum (MIRPE) is a well established procedure. However, morbidity rate varies widely among institutions, and the incidence of major complications remains unknown. STUDY DESIGN: The American College of Surgeons 2012 National Surgical Quality Improvement Program Pediatric (NSQIP-P) participant user file was utilized to identify patients who underwent MIRPE at 50 participant institutions. Outcomes of interest were overall 30-day morbidity, hospital readmission, and reoperation. RESULTS: Chest wall repair designated MIRPE accounted for 0.6% (n = 264) of all surgical cases included in the NSQIP-P database in 2012. The median age at surgical repair was 15.2 years. Thoracoscopy was used in 83.7% of cases. No mediastinal injuries or perioperative blood transfusions were identified. The 30-day readmission rate was 3.8%. Three patients (1.1%) required re-operation due to the following complications: superficial site infection, bar displacement and pneumothorax. The overall morbidity was 3.8% with no incidences of mortality. CONCLUSIONS: This analysis of a large prospective multicenter dataset demonstrates that major complications following MIRPE are uncommon in contemporary practice. Wound infection is the most common complication and the main cause of hospital readmission. Targeted quality improvement initiative should be focused on perioperative strategy to further reduce wound occurrences and hospital readmission. PMID- 25814004 TI - An ecosystem approach to understanding and managing within-host parasite community dynamics. AB - Hosts are typically coinfected by multiple parasite species, resulting in potentially overwhelming levels of complexity. We argue that an individual host can be considered to be an ecosystem in that it is an environment containing a diversity of entities (e.g., parasitic organisms, commensal symbionts, host immune components) that interact with each other, potentially competing for space, energy, and resources, ultimately influencing the condition of the host. Tools and concepts from ecosystem ecology can be applied to better understand the dynamics and responses of within-individual host-parasite ecosystems. Examples from both wildlife and human systems demonstrate how this framework is useful in breaking down complex interactions into components that can be monitored, measured, and managed to inform the design of better disease-management strategies. PMID- 25814005 TI - Chemo-, regio-, and stereoselective Heck-Matsuda arylation of allylic alcohols under mild conditions. AB - Heck arylation with allylic alcohol is extremely challenging due to chemo-, regio , and stereoselective scrambling. Here we report a mild protocol for the alcohol selective beta- and alpha-arylation of allylic and cinnamyl alcohols respectively with aryldiazonium salts. The steric and electronic parameters of the alkene play a prominent role in the regioselectivity. PMID- 25814006 TI - Head elevation and improved laryngoscopic view. PMID- 25814007 TI - Reliability and interpretation of pulmonary function tests when morbid obesity combines with chronic obstructive pulmonary disease and neuromuscular weakness. PMID- 25814008 TI - Comparison of acute toxicities associated with cetuximab-based bioradiotherapy and platinum-based chemoradiotherapy for head and neck squamous cell carcinomas: A single-institution retrospective study in Japan. AB - CONCLUSION: Grade >= 3 mucositis/stomatitis and inability to feed orally were problematic for patients undergoing cetuximab-based bioradiotherapy (BRT) as well as platinum-based chemoradiotherapy (CRT). Severe mucositis/stomatitis and radiation dermatitis should be addressed carefully in patients undergoing cetuximab-based BRT as well. OBJECTIVES: The efficacy of cetuximab-based BRT in locally advanced head and neck squamous cell carcinomas has been established. However, the safety of cetuximab-based BRT in comparison with platinum-based CRT is currently under investigation. METHOD: This study retrospectively analyzed 14 patients undergoing cetuximab-based BRT and 29 patients undergoing platinum-based CRT to compare the incidence of acute toxicities. In the BRT group, an initial cetuximab loading dose of 400 mg/m(2) was delivered 1 week before the start of radiotherapy. Seven weekly infusions of 250 mg/m(2) of cetuximab followed during the definitive radiotherapy. In the CRT group, cisplatin was administered at a dose of 40 mg/m(2) weekly during the definitive radiotherapy. RESULTS: The BRT group had a higher incidence of Grade >= 3 radiation dermatitis than did the CRT group (43% vs 3%, respectively, p < 0.01). The incidence rate of Grade >= 3 mucositis/stomatitis was 64.3% and 41.4% in the BRT and CRT group, respectively (p = 0.1484), while the incidence rate of the inability to feed orally was 38.5% and 55.2%, respectively (p = 0.2053). PMID- 25814009 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Current status in the World and Japan]. AB - Proximal femoral fracture in osteoporotic fracture is related to the life prognosis in the most severe. Many also report that has been reduced due to the spread of osteoporosis treatment in the world. In Japan in 1985 for the first time, we investigated all patients with hip fractures who were admitted to all hospitals with an orthopedic department in the Niigata Prefecture. We also have investigated the secular trends in the hip fracture incidence from 1985-2010. Proximal femoral fracture has been increasing in 2010, and there are no reports that have decreased. In Japan, where an aging society is to continue in the future, we need urgent countermeasure. PMID- 25814010 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Risk factor for hip fracture]. AB - Many risk factors have been identified for hip fracture, including female, advanced age, osteoporosis, previous fractures, low body weight or low body mass index, alcohol drinking, smoking, family history of fractures, use of glucocorticoid, factors related to falls, and bone strength. The factors related to falls are number of fall, frail, post stroke, paralysis, muscle weakness, anti anxiety drugs, anti-depression drugs, and sedatives. Dementia and respiratory disease and others have been reported to be risk factors for secondary hip fracture. PMID- 25814011 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Medicines that prevent hip fracture]. AB - Based on the results of numbers of the clinical trials, the medicines that prevent hip fracture are alendronate, risedronate, and denosumab, which are all antiresorptive. Although currently evidence is not available, combination anabolic and antiresoprtive therapy using teriparatide and denosumab is expected to efficiently prevent hip fracture because such therapy increases hip bone mineral density more than either drug alone. PMID- 25814012 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Mortality and functional disability after hip fracture]. AB - Factors associated with lower physical performance after hip fracture are physical function before hip fracture and cognitive impairment. The 1-year survival rate following hip fracture is a little lower than the expected survival rate ; while, the survival rate in subsequent years was lower than the expected survival rate. Factors associated with mortality are male sex, impaired walking ability before injury, cognitive impairment, diabetes mellitus, history of gastrectomy or colonectomy, and pneumonia during hospitalization. Long-term rehabilitation to maintain physical performance after hip fracture is needed. PMID- 25814013 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Multidisciplinary approach for the treatment of proximal femoral fractures]. AB - Multidisciplinary approach for proximal femoral fracture was organized in the hospital. Inter and intra division obstacles were discussed. After general consensus of the team was obtained, manuals and guidelines of the each division were prepared. In addition to this, the electrical chart specific for the proximal femoral fracture was made which enables to eliminate in-hospital reference letters. As the results, all patients were examined by internal medicine doctors at the time of admission. Average interval from the time of admission to surgery became 1.3 days. Closer relationship with psychiatrist made early detection and treatment of delirium possible. After changing the system to check the antiosteoporosis medication at the time of discharge by the ward pharmacist dramatically increased the prescription rate form 39 percent to 95 percent. PMID- 25814014 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. What do we need to close care gaps in treating hip fracture?--How to include the UK experience into the care in Japan]. AB - Various care gaps are noted in and between acute and rehabilitation hospitals, and after discharge from hospitals in Japan. In the most of acute care hospitals physicians take care of elderly fractured patients only by a request of orthopaedic team. This made a mean time until surgery was 4.5 days (2011). A critical pathway in treating hip fracture has certainly shortened days in the acute hospitals, care gaps may exist between hospitals. Although osteoporosis medication has started on discharge, it may be discontinued at home, in health or social care facilities under the care of primary care physicians. Even though it was estimated approximately 160,000 hip fractures per year in Japan, management of patients' address is not well established after discharge. In order to include the UK experience in Japan, two proposals were made for hospitals in treating hip fracture as follows. 1. Clinical auditing may be added to improve quality of care. An audit protocol is to be developed multidisciplinarily by orthopaedic surgeons and geriatricians, with interprofessional collaboration. 2. A fracture liaison service is to be established to make interprofessional care-mix possible, such as an increase of adherence of osteoporosis drugs and prevention of falls after discharge. A fracture liaison coordinator is to be assigned to the service in making a team approach possible to a patient and his/her family. PMID- 25814015 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Prevention of the secondary hip fractures utilizing the regional post-referral treatment plan]. AB - Fragility fracture can result in a series of fractures, with the need for the prevention of secondary hip fractures seen as increasingly pertinent in Japan. In 2006, regional post-referral treatment plans for femoral neck fracture came into effect in Japan, but treatment of fracture and prevention of secondary fracture were fragmented. Patient education about prevention included on explanation forms were commenced, but the levels of discharge prescription for osteoporosis medications did not indicate an improvement. We evaluated a fracture liaison service for post-referral treatment plans for femoral neck fracture, by registering rehabilitation-stage hospitals and surveying data over a six-month period about whether there was prescription of osteoporosis medications on discharge, and the varieties of medication prescribed. PMID- 25814016 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Practice of the secondary fracture prevention of the proximal femoral fracture by the Osteoporosis Liaison Service]. AB - The proximal femoral fracture number of patients increases with age, and it is predicted that patients over 90 years old will increase in future. It causes a decline of ADL and the QOL, mortality aggravation, a remarkable rise of medical care, the nursing-care cost when they present with a fracture. Primary prevention is important to prevent osteoporotic fracture, but the secondary prevention for the prior or new fracture patient is particularly important. For the practice of the secondary prevention, cooperation of a doctor and the medical staff who included not only the hospital but also the cooperation with the medical institution in the area is indispensable. This report introduces osteoporosis liaison service working on in our hospital and is happy if it is with consideration of the practice of the secondary prevention of the proximal femoral fracture. PMID- 25814017 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Osteoporosis liaison service in Japan]. AB - Osteoporosis liaison service (OLS) is a coordinator-based service provided by Japan Osteoporosis Society. Fracture Liaison Services, commonly known as FLS, are coordinator-based, secondary fracture prevention services implemented by health care systems for the treatment of osteoporotic patients. OLS includes not only FLS but also educational program, medical check-up for bone fragility and risk assessment for primary fracture in osteoporotic subjects. Japan Osteoporosis Society gives coordinators the certificate as a specialist for OLS since 2015. OLS in Japan should facilitate better performance of the treatment of osteoporosis and should contribute the reduction of clinical fractures. PMID- 25814018 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Surgical treatment of femoral proximal fracture]. AB - Fragility fracture is increasing with increasing in population of elderly. Especially hip fracture is increasing rapidly and has many problems such as deterioration of QOL and growing medical expenses. In hip fracture, it is necessary to leave the bed in early period after injury and begin the rehabilitation for start to walk again. So surgical treatment is usually advocated as soon as possible after injury. Hip fracture is mainly classified to femoral neck fracture which is intra-articular fracture of hip joint and trochanteric fracture which is extra-articular fracture. Surgical treatment is different in these fractures. In this article, diagnosis and treatment of these femoral neck fracture and trochanteric fracture, especially surgical methods are mentioned. PMID- 25814019 TI - [Hip Fracture--Epidemiology, Management and Liaison Service. Rehabilitation for the hip fracture]. AB - In Japan, the number of patients with hip fracture has been increasing year by year with a drastic increase in the number of ages. Hip fractures are not only the more significant osteoporotic fracture, but make activity in daily life (ADL) , health outcome, and quality of life (QOL) more difficult. To rehabilitate patients with hip fracture through a multidisciplinary approach is important in the early phases of fracture incidents in order to keep their ADL and QOL at a high level. PMID- 25814020 TI - Quantitative analysis of Si/SiGeC superlattices using atom probe tomography. AB - SiGe and its alloys are used as key materials in innovative electronic devices. The analysis of these materials together with the localisation of dopants and impurities on a very fine scale is of crucial importance for better understanding their electronic properties. The quantification of carbon and germanium in an as grown Si/SiGeC superlattice has been investigated using Atom Probe Tomography as a function of analysis conditions and sample anneal temperature. The mass spectrum is heavily influenced by the analysis conditions and chemical identification is needed. It was found that quantitative results are obtained using a intermediate electric field. The evaporation of carbon ions shows a strong spatial and temporal correlation. A series of annealed samples have been analysed, presenting an inhomogeneous carbon distribution, appearing in the shape of small clusters. These findings confirm previous results and give a better understanding of the processes occurring in these technologically important materials. PMID- 25814021 TI - Tetrabenzanthanthrenes by mitigation of rearrangements in the planarization of ortho-phenylene hexamers. AB - In general, ortho-phenylene hexamers are not good substrates for oxidative planarization because of competing backbone rearrangements. However, by first planarizing the ends, a target tetrabenzanthanthrene has been obtained by oxidation in good yield. DFT calculations suggest that the larger polycyclic aromatic subunits of the preplanarized substrate increase the rate of planarization relative to that of rearrangement. By implication, it may be possible to prepare graphene structures that cannot be made directly from simple polyphenylenes by instead designing precursors with larger polycyclic aromatic moieties. The photophysical properties of the tetrabenzanthanthrene core indicate that it may have promise as a functional chromophore. PMID- 25814023 TI - Identification of glutathione adducts of alpha-chlorofatty aldehydes produced in activated neutrophils. AB - alpha-Chlorofatty aldehydes (alpha-ClFALDs) are produced by hypochlorous acid targeting plasmalogens during neutrophil activation. This study investigated the reaction of the alpha-chlorinated carbon of alpha-ClFALD with the nucleophile, GSH. Utilizing ESI/MS/MS, the reaction product of GSH and the 16-carbon alpha ClFALD, 2-chlorohexadecanal (2-ClHDA), was characterized. The resulting conjugate of 2-ClHDA and GSH (HDA-GSH) has an intact free aldehyde, and the chlorine at the alpha-carbon is ejected. Stable isotope-labeled [d4]HDA-GSH was synthesized, which further confirmed the structure, and was used to quantify natural alpha ClFALD conjugates of GSH (FALD-GSH) using reverse-phase LC with detection by ESI/MS/MS using selected reaction monitoring. HDA-GSH is elevated in RAW 264.7 cells treated with physiologically relevant concentrations of exogenous 2-ClHDA. Furthermore, PMA-treated primary human neutrophils have elevated levels of HDA GSH and the conjugate of 2-chlorooctadecanal (2-ClODA) and GSH (ODA-GSH), as well as elevated levels of 2-ClHDA and 2-ClODA. Production of both conjugates in PMA stimulated neutrophils was reduced by 3-aminotriazole pretreatment, which also blocks endogenous alpha-ClFALD production. Additionally, plasma FALD-GSH levels were elevated in the K/BxN mouse arthritis model. Taken together, these studies demonstrate novel peptidoaldehydes derived from GSH and alpha-ClFALD in activated human neutrophils and in vivo in K/BxN mice. PMID- 25814022 TI - Lipid phosphate phosphatases and their roles in mammalian physiology and pathology. AB - Lipid phosphate phosphatases (LPPs) are a group of enzymes that belong to a phosphatase/phosphotransferase family. Mammalian LPPs consist of three isoforms: LPP1, LPP2, and LPP3. They share highly conserved catalytic domains and catalyze the dephosphorylation of a variety of lipid phosphates, including phosphatidate, lysophosphatidate (LPA), sphingosine 1-phosphate (S1P), ceramide 1-phosphate, and diacylglycerol pyrophosphate. LPPs are integral membrane proteins, which are localized on plasma membranes with the active site on the outer leaflet. This enables the LPPs to degrade extracellular LPA and S1P, thereby attenuating their effects on the activation of surface receptors. LPP3 also exhibits noncatalytic effects at the cell surface. LPP expression on internal membranes, such as endoplasmic reticulum and Golgi, facilitates the metabolism of internal lipid phosphates, presumably on the luminal surface of these organelles. This action probably explains the signaling effects of the LPPs, which occur downstream of receptor activation. The three isoforms of LPPs show distinct and nonredundant effects in several physiological and pathological processes including embryo development, vascular function, and tumor progression. This review is intended to present an up-to-date understanding of the physiological and pathological consequences of changing the activities of the different LPPs, especially in relation to cell signaling by LPA and S1P. PMID- 25814024 TI - Coronary artery spasm: mimicry, misdiagnosis and misfortune. PMID- 25814025 TI - Dilation balloon rupture during percutaneous dilational tracheostomy: using Blue Dolphin kit. AB - A 72-year-old man presented to the high dependency unit following an elective incisional hernia repair. He was extubated in the immediate postoperative period. Following established type 2 respiratory failure (secondary to hospital-acquired pneumonia), he required tracheal intubation and was ventilated in the intensive care unit (ICU). He failed extubation and subsequently had a percutaneous single stage dilational tracheostomy fitted as indicated. During the tracheostomy, while inflating the dilation balloon (used to dilate the trachea), the balloon burst in the trachea, at a pressure of 3 atmospheres. Following this, the entire dilating unit and tracheostomy tube were removed; no debris was left inside the trachea as confirmed by bronchoscope (used throughout the procedure). He made good recovery and was discharged to a surgical ward. This case report summarises the indications for tracheostomy, and reports the rare event of balloon rupture and how to manage it within the ICU setting. PMID- 25814026 TI - Successful emergency splenectomy during cardiac arrest due to cytomegalovirus induced atraumatic splenic rupture. AB - A 27-year-old woman was admitted to the emergency department with fever and a petechial rash on suspicion of meningitis. Shortly after arriving she developed cardiac arrest. Blood work up showed severe lactate acidosis, anaemia and thrombocytopenia. A focused assessment with sonography in trauma scan showed free intraperitoneal fluid and an emergency laparotomy revealed massive bleeding from a ruptured spleen. The patient was successfully resuscitated. She proved to be infected with cytomegalovirus causing idiopathic thrombocytopenic purpura, splenomegaly and splenic rupture. She was treated for 14 days with ganciclovir and meropenem and discharged on recovery. Atraumatic splenic rupture caused by viral infection is a rare condition although well described. In the case of our patient, thrombocytopenia added to the severity of the splenic rupture. A multidisciplinary team approach was essential for the management and the eventual recovery of the patient. PMID- 25814027 TI - Acute appendicitis in a child with swine influenza (H1N1). AB - Swine flu is a multisystemic disease and can affect the gastrointestinal system. There are only three published reports of swine flu cases with acute appendicitis; two of them in children under 16 years of age. We present an unusual case of acute appendicitis in a child already diagnosed with swine flu infection. A 91/2-year-old girl presented with febrile illness and mild abdominal pain. PCR (+) was positive for H1N1. 3 days after hospital admission she developed acute appendicitis and was operated on. On the fourth postoperative day she developed right upper lobe atelectasis; she was started on antiviral treatment to which she responded very well. She was discharged on day 7 without further consequences in her postoperative course. Children with swine flu may be susceptible to rapidly deteriorating and complicated acute appendicitis. This calls for more caution especially in periods of epidemics. PMID- 25814028 TI - Cystic meningioma: diagnostic difficulties and utility of MRI in diagnosis and management. AB - We report the case of a patient presenting with convulsions in the emergency department. A CT examination revealed a mixed solid and cystic frontal peripheral mass. The intra-axial or extra-axial location and the differentiation between primary or secondary origin were not evident so MRI was performed. The most probable diagnosis was cystic meningioma with intratumoural cysts. Based on MRI findings, the neurosurgeon resected the mass together with its cystic components. The histological report verified the diagnosis and the patient had an excellent outcome. PMID- 25814030 TI - Special issue in honor of William Fenical, a pioneer in marine natural products discovery and drug development. PMID- 25814029 TI - Oncolytic reovirus enhances rituximab-mediated antibody-dependent cellular cytotoxicity against chronic lymphocytic leukaemia. AB - The naturally occurring oncolytic virus (OV), reovirus, replicates in cancer cells causing direct cytotoxicity, and can activate innate and adaptive immune responses to facilitate tumour clearance. Reovirus is safe, well tolerated and currently in clinical testing for the treatment of multiple myeloma, in combination with dexamethasone/carfilzomib. Activation of natural killer (NK) cells has been observed after systemic delivery of reovirus to cancer patients; however, the ability of OV to potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) is unexplored. This study elucidates the potential of oncolytic reovirus for the treatment of chronic lymphocytic leukaemia (CLL), both as a direct cytotoxic agent and as an immunomodulator. We demonstrate that reovirus: (i) is directly cytotoxic against CLL, which requires replication competent virus; (ii) phenotypically and functionally activates patient NK cells via a monocyte-derived interferon-alpha (IFNalpha)-dependent mechanism; and (iii) enhances ADCC-mediated killing of CLL in combination with anti-CD20 antibodies. Our data provide strong preclinical evidence to support the use of reovirus in combination with anti-CD20 immunotherapy for the treatment of CLL. PMID- 25814031 TI - Dactylomelane diterpenes from the sea hare Aplysia depilans. AB - A chemical investigation of the organic extract of the sea hare Aplysia depilans, collected off Skyros Island, Greece, yielded eight new brominated diterpenes (1 8), featuring the rare dactylomelane skeleton, together with the previously reported luzodiol (9). The structure elucidation and the assignment of the relative configurations of the new natural products were based on extensive NMR spectroscopic and MS spectrometric analyses. Compounds 1-9 were evaluated for their cytotoxic activities against five human tumor cell lines, but were proven inactive. PMID- 25814032 TI - Positioning and joining of organic single-crystalline wires. AB - Organic single-crystal, one-dimensional materials can effectively carry charges and/or excitons due to their highly ordered molecule packing, minimized defects and eliminated grain boundaries. Controlling the alignment/position of organic single-crystal one-dimensional architectures would allow on-demand photon/electron transport, which is a prerequisite in waveguides and other optoelectronic applications. Here we report a guided physical vapour transport technique to control the growth, alignment and positioning of organic single crystal wires with the guidance of pillar-structured substrates. Submicrometre wide, hundreds of micrometres long, highly aligned, organic single-crystal wire arrays are generated. Furthermore, these organic single-crystal wires can be joined within controlled angles by varying the pillar geometries. Owing to the controllable growth of organic single-crystal one-dimensional architectures, we can present proof-of-principle demonstrations utilizing joined wires to allow optical waveguide through small radii of curvature (internal angles of ~90-120 degrees ). Our methodology may open a route to control the growth of organic single-crystal one-dimensional materials with potential applications in optoelectronics. PMID- 25814033 TI - Twenty years trends and socio-demographic characteristics of HIV prevalence in women giving birth in Catalonia (Spain). AB - BACKGROUND: Studies of the prevalence of HIV in sentinel populations are one of the key strategies to monitor the HIV epidemic. We describe HIV prevalence trends and identify differences across time in the sociodemographic characteristics of HIV-infected women giving birth in Catalonia. METHODS: We used dried blood specimens, residual to newborn screening, which have been collected in Catalonia every 2 months since 1994. The total number of samples obtained until 2009 and in 2013 represented half of yearly newborns. From 2010 to 2012, the total number of samples obtained represented a quarter of yearly newborns. We studied the prevalence by year and place of current residence (Barcelona-city, cities>200,000 inhabitants and cities <= 200,000 inhabitants) and by the mother's birth country. A total of 624,912 infants were tested for HIV antibodies from January 1994 to December 2013. RESULTS: HIV prevalence trends among women giving birth in Catalonia decreased until 2007. Thereafter, there was a change to a steady trend until 2013. However, among foreign women giving birth and living in cities <= 200,000 inhabitants, the prevalence of HIV increased from 2007 to 2013. CONCLUSION: To ensure early identification and treatment of HIV-infected mothers, it is essential to maintain HIV surveillance programs and pre- and post-natal screening programs, both in Barcelona and in cities with 200,000 inhabitants or less, especially in immigrant women. PMID- 25814034 TI - Optimization and dissolution performance of spray-dried naproxen nano-crystals. AB - The purpose of this study was to investigate the in vitro dissolution performance of the different sized spray-dried nano-crystalline powders of naproxen. A DoE approach was used to formulate and optimize nano-crystalline suspensions. The critical wet milling operation parameters were i.e., drug concentration, drug-to stabilizer ratio, stabilizer type (HPMC E15 or Tween 80) and milling intensity. The nano-crystalline suspensions were optimized for size and physical stability and then spray-dried to obtain nano-crystalline powders. Trehalose and lactose were investigated as spray-drying auxiliary excipients to achieve non-aggregating powders. Particle size, DSC and PXRD were utilized for characterization of powder formulations. A modified USP apparatus II was utilized to determine the in vitro release/dissolution of powder formulations. The size of the nano-crystalline suspensions was dependent on drug concentration and milling intensity. HPMC E15 containing formulations were better in terms of the spray-dried powder yield compared to Tween 80 containing formulations. Trehalose was selected to formulate non-aggregating nano-crystalline powders. No polymorphic changes were observed following the wet milling and spray-drying processes. Size dependent in vitro dissolution profiles, utilizing a dialysis sac method were obtained for the crystalline powders. PMID- 25814035 TI - Tuning dual-drug release from composite scaffolds for bone regeneration. AB - This work presents the tuning of drug-loaded scaffolds for bone regeneration as dual-drug delivery systems. Two therapeutic substances, zoledronic acid (anti osteoporotic drug) and ibuprofen (anti-inflammatory drug) were successfully incorporated in a controlled manner into three dimensional designed porous scaffolds of apatite/agarose composite. A high-performance liquid chromatography method was optimized to separate and simultaneously quantify the two drugs released from the dual-drug codelivery system. The multifunctional porous scaffolds fabricated show a very rapid delivery of anti-inflammatory (interesting to reduce inflammation after implantation), whereas the anti-osteoporotic drug showed sustained release behaviour (important to promote bone regeneration). Since ibuprofen release was faster than desired, this drug was encapsulated in chitosan spheres which were then incorporated into the scaffolds, obtaining a release profile suitable for clinical application. The results obtained open the possibility to simultaneously incorporate two or more drugs to an osseous implant in a controlled way improving it for bone healing application. PMID- 25814036 TI - Lead optimization attrition analysis (LOAA): a novel and general methodology for medicinal chemistry. AB - Herein, we report a novel and general method, lead optimization attrition analysis (LOAA), to benchmark two distinct small-molecule lead series using a relatively unbiased, simple technique and commercially available software. We illustrate this approach with data collected during lead optimization of two independent oncology programs as a case study. Easily generated graphics and attrition curves enabled us to calibrate progress and support go/no go decisions on each program. We believe that this data-driven technique could be used broadly by medicinal chemists and management to guide strategic decisions during drug discovery. PMID- 25814037 TI - Laser cooling of BH and GaF: insights from an ab initio study. AB - The feasibility of laser cooling BH and GaF is investigated using ab initio quantum chemistry. The ground state X (1)Sigma(+) and first two excited states (3)Pi and (1)Pi of BH and GaF are calculated using the multireference configuration interaction (MRCI) level of theory. For GaF, the spin-orbit coupling effect is also taken into account in the electronic structure calculations at the MRCI level. Calculated spectroscopic constants for BH and GaF show good agreement with available theoretical and experimental results. The highly diagonal Franck-Condon factors (BH: f00 = 0.9992, f11 = 0.9908, f22 = 0.9235; GaF: f00 = 0.997, f11 = 0.989, f22 = 0.958) for the (1)Pi (v' = 0-2) -> X (1)Sigma(+) (v = 0-2) transitions in BH and GaF are determined, which are found to be in good agreement with the theoretical and experimental data. Radiative lifetime calculations of the (1)Pi (v' = 0-2) state (BH: 131, 151, and 187 ns; GaF: 2.26, 2.36, and 2.48 ns) are found to be short enough for rapid laser cooling. The proposed laser cooling schemes that drive the (1)Pi (v' = 0) -> X (1)Sigma(+) (v = 0) transition use just one laser wavelength lambda00 (BH: 436 nm, GaF: 209 nm). Though the cooling wavelength of GaF is deep in the UVC, a frequency quadrupled Ti:sapphire laser (189-235 nm) could be capable of generating useful quantities of light at this wavelength. The present results indicate that BH and GaF are two good choices of molecules for laser cooling. PMID- 25814038 TI - Quantitative detection of syntrophic fatty acid-degrading bacterial communities in methanogenic environments. AB - In methanogenic habitats, volatile fatty acids (VFA), such as propionate and butyrate, are major intermediates in organic matter degradation. VFA are further metabolized to H(2), acetate and CO(2) by syntrophic fatty acid-degrading bacteria (SFAB) in association with methanogenic archaea. Despite their indispensable role in VFA degradation, little is known about SFAB abundance and their environmental distribution. To facilitate ecological studies, we developed four novel genus-specific quantitative PCR (qPCR) assays, with primer sets targeting known SFAB: Syntrophobacter, Smithella, Pelotomaculum and Syntrophomonas. Primer set specificity was confirmed using in silico and experimental (target controls, clone libraries and melt-curve analysis) approaches. These qPCR assays were applied to quantify SFAB in a variety of mesophilic methanogenic habitats, including a laboratory propionate enrichment culture, pilot- and full-scale anaerobic reactors, cow rumen, horse faeces, an experimental rice paddy soil, a bog stream and swamp sediments. The highest SFAB 16S rRNA gene copy numbers were found in the propionate enrichment culture and anaerobic reactors, followed by the bog stream and swamp sediment samples. In addition, it was observed that SFAB and methanogen abundance varied with reactor configuration and substrate identity. To our knowledge, this research represents the first comprehensive study to quantify SFAB in methanogenic habitats using qPCR-based methods. These molecular tools will help investigators better understand syntrophic microbial communities in engineered and natural environments. PMID- 25814039 TI - Non-pathogenic Neisseria: members of an abundant, multi-habitat, diverse genus. AB - The genus Neisseria contains the important pathogens Neisseria meningitidis and Neisseria gonorrhoeae. These Gram-negative coccoid bacteria are generally thought to be restricted to humans and inhabit mucosal surfaces in the upper respiratory and genito-urinary tracts. While the meningococcus and gonococcus have been widely studied, far less attention has been paid to other Neisseria species. Here we review current knowledge of the distribution of commensal Neisseria in humans and other hosts. Analysis of the microbiome has revealed that Neisseria is an abundant member of the oropharyngeal flora, and we review its potential impact on health and disease. Neisseria also exhibit remarkable diversity, exhibiting both coccoid and rod-shaped morphologies, as well as environmental strains which are capable of degrading complex organic molecules. PMID- 25814040 TI - Simple and sensitive microRNA labeling by terminal deoxynucleotidyl transferase. PMID- 25814041 TI - Adherence to highly active antiretroviral therapy impact on clinical and economic outcomes for Medicaid enrollees with human immunodeficiency virus and hepatitis C coinfection. AB - We examined the impact of antiretroviral treatment adherence among hepatitis C (HCV) coinfected human immunodeficiency virus (HIV) patients on survival and clinical outcomes. We analyzed Medicaid claims data from 14 southern states from 2005 to 2007, comparing survival and clinical outcomes and cost of treatment for HIV and HCV coinfected patients (N = 4115) at different levels of adherence to antiretroviral therapy (ART). More than one in five patients (20.5%) showed less than 50% adherence to antiretroviral treatment, but there were no racial/ethnic or gender disparities. Significant survival benefit was demonstrated at each incremental level of adherence to ART (one-year mortality ranging from 3.5% in the highest adherence group to 26.0% in the lowest). Low-adherence patients also had higher rates of hospitalization and emergency department visits. Relative to patients with high (>95%) ART adherence, those with less than 25% treatment adherence had fourfold greater risk of death (adjusted odds ratio 4.22 [95% CI: 3.03, 5.87]). Nondrug Medicaid expenditures were lower for high-adherence patients, but cost of medications drove total Medicaid expenditures higher for high-adherence patients. Cost per quality-adjusted life year (QALY) saved (relative to the <25% low-adherence group) ranged from $21,874 for increasing adherence to 25-50% to $37,229 for increasing adherence to 75-95%. Adherence to ART for patients with HIV and HCV coinfection is associated with lower adverse clinical outcomes at a Medicaid cost per QALY commensurate with other well accepted treatment and prevention strategies. Further research is needed to identify interventions which can best achieve optimal ART adherence at a population scale. PMID- 25814042 TI - Efficacy of tobramycin aerosol in nasal polyposis. AB - CONTEXT: Treatment of infected nasal polyposis. MATERIAL AND METHODS: Multicenter interventional prospective double-blind randomized study with matched groups: treatment with tobramycin aerosol versus isotonic saline aerosol. The study population included 55 patients: 23 receiving isotonic saline aerosol and 32 receiving tobramycin. A novel device (Easynose(r)) was used with an original principle limiting pulmonary deposition and ensuring homogeneous peripheral deposition in the nasal cavities. OBJECTIVES: The principal objective was to compare bacteriological eradication between tobramycin 150mg/3ml versus isotonic saline, both administered by nebulization via the Easynose(r) device. RESULTS AND CONCLUSION: Tobramycin aerosol administered via the Easynose(r) device showed significantly better bacteriological eradication than isotonic saline. PMID- 25814043 TI - Comment on "Policy Review: Japan-Philippines Economic Partnership Agreement (JPEPA)-Analysis of a failed nurse migration policy". PMID- 25814044 TI - Predictors of public support for family presence during cardiopulmonary resuscitation: A population based study. AB - BACKGROUND: The debate on whether individuals want their family to be present during cardiopulmonary resuscitation continues to be a contentious issue, but there is little analysis of the predictors of the general public's opinion. The aim of this population based study was to identify factors that predict public support for having family present during cardiopulmonary resuscitation. DESIGN: Data for this cross-sectional population based study were collected via computer assisted-telephone-interviews of people (n=1208) residing in Central Queensland, Australia. RESULTS: Participants supported family members being present should their child (75%), an adult relative (52%) or they themselves (51%) require cardiopulmonary resuscitation. Reasons cited for not wanting to be present were; distraction for the medical team (30.4%), too distressing (30%) or not known/not considered the option (19%). Sex and prior exposure to being present during the resuscitation of adults and children were both predictors of support (p<0.05). Reasons for not wanting to be present differed significantly for males and females (p=0.001). CONCLUSION: Individual support for being present during cardiopulmonary resuscitation varies according to; sex, prior exposure and if the family member who is being resuscitated is a family member, their child or the person themselves. A considerable proportion of the public have not considered nor planned for the option of being present during a cardiac arrest of an adult relative. Clinicians may find it useful to explain the experiences of other people who have been present when supporting families to make informed decisions about their involvement in emergency interventions. PMID- 25814045 TI - Josh Gordon suspended by the NFL "for at least one year" for substance abuse. PMID- 25814046 TI - Neurosteroidal modulation of in vitro epileptiform activity is enhanced in pilocarpine-treated epileptic rats. AB - We employed field potential recordings in brain slices obtained from pilocarpine treated epileptic (4-5weeks following a pilocarpine-induced status epilepticus) and age-matched, non-epileptic control (NEC) rats to establish the effects of the neurosteroid allotetrahydrodeoxycorticosterone (THDOC) on the epileptiform activity - including high frequency oscillations (HFOs; ripples: 80-200Hz, fast ripples: 250-500Hz) - induced by 4-aminopyridine (4AP) in piriform (PC) and entorhinal (EC) cortices. Both structures are highly susceptible to generate seizures and may also be involved in epileptogenesis. We found that THDOC application to pilocarpine-treated slices: (i) decreased interictal discharge frequency in PC while increasing it in EC; (ii) abolished ictal discharges in both areas in approx. one third of the experiments and reduced them in frequency and duration in the remaining experiments; and (iii) increased the occurrence of ripples and fast ripples associated to interictal events, and modified their pattern of occurrence during ictal discharges in both PC and EC. These effects were either weaker or absent in NEC tissue. Our results demonstrate that THDOC plays a structure-dependent modulatory role in epileptiform synchronization in the pilocarpine-treated epileptic rat brain where its actions are more pronounced than in NEC tissue. This evidence supports the application of neurosteroids as potential antiepileptic tools. PMID- 25814047 TI - Potential role of adolescent alcohol exposure-induced amygdaloid histone modifications in anxiety and alcohol intake during adulthood. AB - Binge drinking is common during adolescence and can lead to the development of psychiatric disorders, including alcoholism in adulthood. Here, the role and persistent effects of histone modifications during adolescent intermittent ethanol (AIE) exposure in the development of anxiety and alcoholism in adulthood were investigated. Rats received intermittent ethanol exposure during post-natal days 28-41, and anxiety-like behaviors were measured after 1 and 24 h of the last AIE. The effects of AIE on anxiety-like and alcohol-drinking behaviors in adulthood were measured with or without treatment with the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). Amygdaloid brain regions were collected to measure HDAC activity, global and gene-specific histone H3 acetylation, expression of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated (Arc) protein and dendritic spine density (DSD). Adolescent rats displayed anxiety-like behaviors after 24 h, but not 1 h, of last AIE with a concomitant increase in nuclear and cytosolic amygdaloid HDAC activity and HDAC2 and HDAC4 levels leading to deficits in histone (H3-K9) acetylation in the central (CeA) and medial (MeA), but not in basolateral nucleus of amygdala (BLA). Interestingly, some of AIE-induced epigenetic changes such as, increased nuclear HDAC activity, HDAC2 expression, and decreased global histone acetylation persisted in adulthood. In addition, AIE decreased BDNF exons I and IV and Arc promoter specific histone H3 acetylation that was associated with decreased BDNF, Arc expression and DSD in the CeA and MeA during adulthood. AIE also induced anxiety-like behaviors and enhanced ethanol intake in adulthood, which was attenuated by TSA treatment via normalization of deficits in histone H3 acetylation of BDNF and Arc genes. These novel results indicate that AIE induces long-lasting effects on histone modifications and deficits in synaptic events in the amygdala, which are associated with anxiety-like and alcohol drinking behaviors in adulthood. PMID- 25814048 TI - Efficacy of coupled low-volume plasma exchange with plasma filtration adsorption in treating pigs with acute liver failure: A randomised study. AB - BACKGROUND & AIMS: Extracorporeal blood purification systems for supportive therapy of liver failure are widely used. We developed a novel blood purification system, named Li's artificial liver system (Li-ALS), which couples low-volume plasma exchange (low-volume PE) with plasma filtration adsorption (PFA). This study aims to evaluate the efficacy of our novel system in pigs with acute liver failure (ALF). METHODS: Thirty-two pigs were infused with D-galactosamine (1.3g/kg) to induce ALF. All animals were equally and randomly divided into four groups: the ALF control group received intensive care, the PFA group underwent five hour plasma recycling filtration and adsorption purification, the low-volume PE group received one hour low-volume PE, and the Li-ALS group underwent one hour low-volume PE, followed by five hour PFA. Intervention was initiated 36hours after drug administration. The efficacy of each treatment was assessed by survival time and improvement in hematological, biochemical, and immunohistological parameters. RESULTS: Pigs in the Li-ALS group survived longer than those in the other groups (p<0.001, ALF control: 60+/-2h; PFA group: 74+/ 2h; low-volume PE group: 75+/-2h; and Li-ALS group: 90+/-3h). Liver enzyme, bilirubin, bile acid and blood ammonia levels were decreased significantly after Li-ALS treatment, and increases in inflammatory cytokines were ameliorated. A higher hepatocyte regeneration index was also observed in the Li-ALS group. CONCLUSION: Our novel Li-ALS could expedite liver regeneration and improve survival time; hence, it could be promising for treating ALF. PMID- 25814049 TI - Inflammation in cystic fibrosis lung disease: Pathogenesis and therapy. AB - Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options. PMID- 25814050 TI - Randomized, controlled pilot trial of solifenacin succinate for overactive bladder in Parkinson's disease. AB - OBJECTIVE: To evaluate the efficacy of solifenacin succinate in Parkinson's disease (PD) patients suffering from overactive bladder (OAB). BACKGROUND: Urinary dysfunction is a commonly encountered non-motor feature in PD that significantly impacts patient quality of life. DESIGN/METHODS: This was a double blind, randomized, placebo-controlled, 3-site study with an open label extension phase to determine the efficacy of solifenacin succinate in idiopathic PD patients with OAB. Patients were randomized to receive solifenacin succinate 5-10 mg daily or placebo for 12 weeks followed by an 8-week open label extension. The primary outcome measure was the change in the mean number of micturitions per 24 h period. Secondary outcome measures included the change in the mean number of urinary incontinence episodes and the mean number of nocturia episodes. RESULTS: Twenty-three patients were randomized in the study. There was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). In the open label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01). Adverse events included constipation and xerostomia, which resolved after treatment was discontinued. CONCLUSIONS: In this pilot trial, solifenacin succinate treatment led to an improvement in urinary incontinence, despite persistence in other OAB symptoms. PMID- 25814051 TI - [Overweight and obesity in young adults: relevance of job-related changes of exercise on fat, lean body and body mass in students]. AB - Early adulthood is related to changes in lifestyle that negatively affect body weight and health. The aim of the study was to determine the effect of exercise changes on the development of weight and body composition in college students.Sixty-one randomly selected dental (ZMS) and 53 sport students (SLS) were accompanied over 5 years. Body mass, fat and lean body mass (LBM) were determined via DXA-technique. Exercise and physical activity were assessed by questionnaires and interviews.All exercise indices significantly increased in the SLS and significantly decreased in the ZMS. Physical activity slightly increased in both groups. Both cohorts comparably gained body mass, however, the increase in the SLS group can be attributed to LBM-changes with minor changes of fat-mass (2.4 % +/- 3.3 % vs. 0.1 +/- 1.0 %) whereas ZMS gained fat and LBM in a proportion of 2:1.Maintenance/increase of exercise compensate the negative effects of lifestyle changes on body composition during young adulthood. PMID- 25814052 TI - Measuring obesity in the absence of a gold standard. AB - Reliable measures of body composition are essential to develop effective policies to tackle obesity. The lack of an acceptable gold-standard for measuring fatness has made it difficult to evaluate alternative measures of obesity. We use latent class analysis to characterise existing diagnostics. Using data on US adults we show that measures based on body mass index and bioelectrical impedance analysis misclassify large numbers of individuals. For example, 45% of obese White women are misclassified as non-obese using body mass index, while over 50% of non-obese White women are misclassified as being obese using bioelectrical impedance analysis. In contrast the misclassification rates are low when waist circumference is used to measure obesity. These results have important implications for our understanding of differences in obesity rates across time and groups, as well as posing challenges for the econometric analysis of obesity. PMID- 25814053 TI - Race, response to chemotherapy, and outcome within clinical breast cancer subtypes. AB - The effect of race on breast cancer outcome is confounded by tumor and treatment heterogeneity. We examined a cohort of women with stage II-III breast cancer treated uniformly with neoadjuvant chemotherapy to identify factors associated with racial differences in chemotherapeutic response and long-term survival. Using a prospective database, we identified women with stage II-III breast cancer treated with neoadjuvant chemotherapy from 1998 to 2011. Race was categorized as African-American (AA) or non-AA. Preplanned subtype analyses were stratified by hormone receptor (HR) and HER2. Pathologic response to chemotherapy (pCR), time to recurrence (TTR), and overall survival (OS) were assessed using logistic regression, Kaplan-Meier method, and Cox proportional hazards regression analyses. Of 349 women identified, 102 (29 %) were AA, who were younger (p = 0.03), more obese (p < 0.001), and less likely to have HR+/HER2- tumors (p = 0.01). No significant differences in pCR rate by race were found. At median follow-up of 6.5 years, AA had worse TTR (hazard ratio 1.51, 95 % CI 1.02-2.24), which was attenuated in multivariable modeling, and there was no significant difference in OS. When stratified by HR, worse outcomes were limited to HR+AA (TTR hazard ratio 1.85, 95 % CI 1.09-3.14; OS hazard ratio 2.42 95 % CI 1.37 4.28), which remained significant in multivariable analysis including pCR rate and BMI. With long-term follow-up, racial disparity in outcome was limited to HR+ breast cancer, with no apparent contribution of chemotherapy sensitivity. This suggests that disparity root causes may be driven by HR+ factors such as unmeasured molecular differences, endocrine therapy sensitivity, or adherence. PMID- 25814054 TI - The effect of YOCAS(c)(r) yoga for musculoskeletal symptoms among breast cancer survivors on hormonal therapy. AB - Up to 50% of breast cancer survivors on aromatase inhibitor therapy report musculoskeletal symptoms such as joint and muscle pain, significantly impacting treatment adherence and discontinuation rates. We conducted a secondary data analysis of a nationwide, multi-site, phase II/III randomized, controlled, clinical trial examining the efficacy of yoga for improving musculoskeletal symptoms among breast cancer survivors currently receiving hormone therapy (aromatase inhibitors [AI] or tamoxifen [TAM]). Breast cancer survivors currently receiving AI (N = 95) or TAM (N = 72) with no participation in yoga during the previous 3 months were randomized into 2 arms: (1) standard care monitoring and (2) standard care plus the 4-week yoga intervention (2x/week; 75 min/session) and included in this analysis. The yoga intervention utilized the UR Yoga for Cancer Survivors (YOCAS(c)((r))) program consisting of breathing exercises, 18 gentle Hatha and restorative yoga postures, and meditation. Musculoskeletal symptoms were assessed pre- and post-intervention. At baseline, AI users reported higher levels of general pain, muscle aches, and total physical discomfort than TAM users (all P <= 0.05). Among all breast cancer survivors on hormonal therapy, participants in the yoga group demonstrated greater reductions in musculoskeletal symptoms such as general pain, muscle aches and total physical discomfort from pre- to post-intervention than the control group (all P <= 0.05). The severity of musculoskeletal symptoms was higher for AI users compared to TAM users. Among breast cancer survivors on hormone therapy, the brief community-based YOCAS(c)(r) intervention significantly reduced general pain, muscle aches, and physical discomfort. PMID- 25814055 TI - An interview with Nora Volkow. PMID- 25814056 TI - Disruptions in aromatase expression in the brain, reproductive behavior, and secondary sexual characteristics in male guppies (Poecilia reticulata) induced by tributyltin. AB - Although bioaccumulation of tributyltin (TBT) in fish has been confirmed, information on possible effects of TBT on reproductive system of fish is still relatively scarce, particularly at environmentally relevant levels. To evaluate the adverse effects and intrinsic toxicological properties of TBT in male fish, we studied aromatase gene expression in the brain, sex steroid contents, primary and secondary sexual characteristics, and reproductive behavior in male guppies (Poecilia reticulata) exposed to tributyltin chloride at the nominal concentrations of 5, 50, and 500 ng/L for 28 days in a semi-static exposure system. Radioimmunoassay demonstrated that treatment with 50 ng/L TBT caused an increase in systemic levels of testosterone of male guppies. Gonopodial index, which showed a positive correlation with testosterone levels, was elevated in the 5 ng/L and 50 ng/L TBT treated groups. Real-time PCR revealed that TBT exposure had inhibiting effects on expression of two isoforms of guppy aromatase in the brain, and these changes at the molecular levels were associated with a disturbance of reproductive behavior of the individuals, as measured by decreases in frequencies of posturing, sigmoid display, and chase activities when males were paired with females. This study provides the first evidence that TBT can cause abnormalities of secondary sexual characteristics in teleosts and that suppression of reproductive behavior in teleosts by TBT is due to its endocrine disrupting action as an aromatase inhibitor targeting the nervous system. PMID- 25814057 TI - Active and passive biomonitoring suggest metabolic adaptation in blue mussels (Mytilus spp.) chronically exposed to a moderate contamination in Brest harbor (France). AB - Brest harbor (Bay of Brest, Brittany, France) has a severe past of anthropogenic chemical contamination, but inputs tended to decrease, indicating a reassessment of its ecotoxicological status should be carried out. Here, native and caged mussels (Mytilus spp.) were used in combination to evaluate biological effects of chronic chemical contamination in Brest harbor. Polycyclic aromatic hydrocarbon (PAH) contamination was measured in mussel tissues as a proxy of harbor and urban pollution. Biochemical biomarkers of xenobiotic biotransformation, antioxidant defenses, generation of reducing equivalents, energy metabolism and oxidative damage were studied in both gills and digestive glands of native and caged mussels. In particular, activities of glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), NADP-dependent isocitrate dehydrogenase (IDP), pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) were measured and lipid peroxidation was assessed by malondialdehyde (MDA) quantification. In addition, a condition index was calculated to assess the overall health of the mussels. Moderate PAH contamination was detected in digestive glands of both native and caged individuals from the exposed site. Modulations of biomarkers were detected in digestive glands of native harbor mussels indicating the presence of a chemical pressure. In particular, results suggested increased biotransformation (GST), antioxidant defenses (CAT), NADPH generation (IDP) and gluconeogenesis (PEPCK), which could represent a coordinated response against chemically-induced cellular stress. Lipid peroxidation assessment and condition index indicated an absence of acute stress in the same mussels suggesting metabolic changes could, at least partially, offset the negative effects of contamination. In caged mussels, only GR was found modulated compared to non-exposed mussels but significant differences in oxidative stress and energy-related biomarkers were observed compared to native harbor mussels. Overall, these results suggested mussels chronically exposed to contamination have set up metabolic adaptation, which may contribute to their survival in the moderately contaminated harbor of Brest. Whether these adaptive traits result from phenotypic plasticity or genetic adaptation needs to be further investigated. PMID- 25814058 TI - Enzymatic characterization of in vitro-expressed Baikal seal cytochrome P450 (CYP) 1A1, 1A2, and 1B1: implication of low metabolic potential of CYP1A2 uniquely evolved in aquatic mammals. AB - This study aimed to elucidate the catalytic function of cytochrome P450 (CYP) 1 enzymes in aquatic mammals. Alkoxyresorufin O-dealkylation (AROD) activities including methoxy- (MROD), ethoxy- (EROD), pentoxy- (PROD), and benzyloxyresorufin O-dealkylation (BROD), and 2- and 4-hydroxylation activities of 17beta-estradiol (E2) were measured by using yeast-expressed Baikal seal (Pusa sibirica) CYP1A1, 1A2, and 1B1 proteins. Heterologous protein expression of the Baikal seal CYP1s (bsCYP1s) in yeast microsomes was confirmed by reduced CO difference spectra and immunoblotting. Heterologously expressed human CYP1 enzyme (hCYP1) activities were simultaneously measured and compared with those of bsCYP1 isozymes. Recombinant bsCYP1A1 protein showed the highest Vmax of EROD, followed by MROD, PROD, and BROD, similar to that of hCYP1A1. Vmax/Km ratios of all AROD activities catalyzed by bsCYP1A1 were lower than those catalyzed by hCYP1A1, suggesting less potential for AROD by bsCYP1A1. Enzymatic assays for bsCYP1A2 showed no or minimal AROD activities, while hCYP1A2 displayed MROD and EROD activities. bsCYP1B1 showed an AROD profile (EROD>BROD>MROD>>PROD) similar to that of hCYP1B1; however, Vmax/Km ratios of all AROD activities by bsCYP1B1 were higher. Yeast microsomes containing bsCYP1A1 and 1B1 and hCYP1A1, 1A2, and 1B1 metabolized E2 to 2-OHE2 and 4-OHE2, whereas bsCYP1A2 showed no such activity. Comparison of 4- and 2-hydroxylations of E2 by CYP1As suggests that bsCYP1A1, hCYP1A1, and 1A2 preferentially catalyze 2- rather than 4-hydroxylation. As for CYP1B1, the Vmax/Km ratios suggest that both Baikal seal and human CYPs catalyze 4- rather than 2-hydroxylation. Interspecies comparison showed that bsCYP1B1 has higher metabolic potencies for both E2 hydroxylations than does hCYP1B1, whereas the activity of bsCYP1A1 was lower than that of hCYP1A1. Messenger RNA expression levels of bsCYP1s in the liver of Baikal seals indicated that bsCYP1A1 and 1A2 enzymes contributed to 16.2% and 83.7% of total CYP1s, respectively; bsCYP1B1 accounted for only 0.06%. Addition of anti-human CYP1A1 antibody in seal liver microsomes suppressed EROD activity more than did anti-human CYP1A2 antibody. Therefore, EROD may be catalyzed by hepatic bsCYP1A1 but not bsCYP1A2, consistent with the results of yeast-expressed bsCYP1A1 and 1A2. In silico substrate-docking models of bsCYP1s suggested that the defect in bsCYP1A2 enzymatic activities may be accounted for by the Pro substitution of highly conserved Thr in the I-helix, which is involved in formation of a hydrogen bond with the hydroperoxy intermediate on the heme. This Thr-Pro substitution is evolutionarily conserved across aquatic mammals and could explain their lower metabolic potential for persistent organic pollutants. PMID- 25814059 TI - When stable-stage equilibrium is unlikely: integrating transient population dynamics improves asymptotic methods. AB - BACKGROUND AND AIMS: Evaluation of population projection matrices (PPMs) that are focused on asymptotically based properties of populations is a commonly used approach to evaluate projected dynamics of managed populations. Recently, a set of tools for evaluating the properties of transient dynamics has been expanded to evaluate PPMs and to consider the dynamics of populations prior to attaining the stable-stage distribution, a state that may never be achieved in disturbed or otherwise ephemeral habitats or persistently small populations. This study re evaluates data for a tropical orchid and examines the value of including such analyses in an integrative approach. METHODS: Six small populations of Lepanthes rubripetala were used as a model system and the R software package popdemo was used to produce estimates of the indices for the asymptotic growth rate (lambda), sensitivities, reactivity, first-time step attenuation, maximum amplification, maximum attenuation, maximal inertia and maximal attenuation. The response in lambda to perturbations of demographic parameters using transfer functions and multiple perturbations on growth, stasis and fecundity were also determined. The results were compared with previously published asymptotic indices. KEY RESULTS: It was found that combining asymptotic and transient dynamics expands the understanding of possible population changes. Comparison of the predicted density from reactivity and first-time step attenuation with the observed change in population size in two orchid populations showed that the observed density was within the predicted range. However, transfer function analysis suggests that the traditional approach of measuring perturbation of growth rates and persistence (inertia) may be misleading and is likely to result in erroneous management decisions. CONCLUSIONS: Based on the results, an integrative approach is recommended using traditional PPMs (asymptotic processes) with an evaluation of the diversity of dynamics that may arise when populations are not at a stable stage distribution (transient processes). This method is preferable for designing rapid and efficient interventions after disturbances, and for developing strategies to establish new populations. PMID- 25814060 TI - Ripening of pepper (Capsicum annuum) fruit is characterized by an enhancement of protein tyrosine nitration. AB - BACKGROUND AND AIMS: Pepper (Capsicum annuum, Solanaceae) fruits are consumed worldwide and are of great economic importance. In most species ripening is characterized by important visual and metabolic changes, the latter including emission of volatile organic compounds associated with respiration, destruction of chlorophylls, synthesis of new pigments (red/yellow carotenoids plus xanthophylls and anthocyanins), formation of pectins and protein synthesis. The involvement of nitric oxide (NO) in fruit ripening has been established, but more work is needed to detail the metabolic networks involving NO and other reactive nitrogen species (RNS) in the process. It has been reported that RNS can mediate post-translational modifications of proteins, which can modulate physiological processes through mechanisms of cellular signalling. This study therefore examined the potential role of NO in nitration of tyrosine during the ripening of California sweet pepper. METHODS: The NO content of green and red pepper fruit was determined spectrofluorometrically. Fruits at the breaking point between green and red coloration were incubated in the presence of NO for 1 h and then left to ripen for 3 d. Profiles of nitrated proteins were determined using an antibody against nitro-tyrosine (NO2-Tyr), and profiles of nitrosothiols were determined by confocal laser scanning microscopy. Nitrated proteins were identified by 2-D electrophoresis and MALDI-TOF/TOF analysis. KEY RESULTS: Treatment with NO delayed the ripening of fruit. An enhancement of nitrosothiols and nitroproteins was observed in fruit during ripening, and this was reversed by the addition of exogenous NO gas. Six nitrated proteins were identified and were characterized as being involved in redox, protein, carbohydrate and oxidative metabolism, and in glutamate biosynthesis. Catalase was the most abundant nitrated protein found in both green and red fruit. CONCLUSIONS: The RNS profile reported here indicates that ripening of pepper fruit is characterized by an enhancement of S-nitrosothiols and protein tyrosine nitration. The nitrated proteins identified have important functions in photosynthesis, generation of NADPH, proteolysis, amino acid biosynthesis and oxidative metabolism. The decrease of catalase in red fruit implies a lower capacity to scavenge H2O2, which would promote lipid peroxidation, as has already been reported in ripe pepper fruit. PMID- 25814061 TI - Zygomorphy evolved from disymmetry in Fumarioideae (Papaveraceae, Ranunculales): new evidence from an expanded molecular phylogenetic framework. AB - BACKGROUND AND AIMS: Fumarioideae (20 genera, 593 species) is a clade of Papaveraceae (Ranunculales) characterized by flowers that are either disymmetric (i.e. two perpendicular planes of bilateral symmetry) or zygomorphic (i.e. one plane of bilateral symmetry). In contrast, the other subfamily of Papaveraceae, Papaveroideae (23 genera, 230 species), has actinomorphic flowers (i.e. more than two planes of symmetry). Understanding of the evolution of floral symmetry in this clade has so far been limited by the lack of a reliable phylogenetic framework. Pteridophyllum (one species) shares similarities with Fumarioideae but has actinomorphic flowers, and the relationships among Pteridophyllum, Papaveroideae and Fumarioideae have remained unclear. This study reassesses the evolution of floral symmetry in Papaveraceae based on new molecular phylogenetic analyses of the family. METHODS: Maximum likelihood, Bayesian and maximum parsimony phylogenetic analyses of Papaveraceae were conducted using six plastid markers and one nuclear marker, sampling Pteridophyllum, 18 (90 %) genera and 73 species of Fumarioideae, 11 (48 %) genera and 11 species of Papaveroideae, and a wide selection of outgroup taxa. Floral characters recorded from the literature were then optimized onto phylogenetic trees to reconstruct ancestral states using parsimony, maximum likelihood and reversible-jump Bayesian approaches. KEY RESULTS: Pteridophyllum is not nested in Fumarioideae. Fumarioideae are monophyletic and Hypecoum (18 species) is the sister group of the remaining genera. Relationships within the core Fumarioideae are well resolved and supported. Dactylicapnos and all zygomorphic genera form a well-supported clade nested among disymmetric taxa. CONCLUSIONS: Disymmetry of the corolla is a synapomorphy of Fumarioideae and is strongly correlated with changes in the androecium and differentiation of middle and inner tepal shape (basal spurs on middle tepals). Zygomorphy subsequently evolved from disymmetry either once (with a reversal in Dactylicapnos) or twice (Capnoides, other zygomorphic Fumarioideae) and appears to be correlated with the loss of one nectar spur. PMID- 25814062 TI - Eddy-driven subduction exports particulate organic carbon from the spring bloom. AB - The export of particulate organic carbon (POC) from the surface ocean to depth is traditionally ascribed to sinking. Here, we show that a dynamic eddying flow field subducts surface water with high concentrations of nonsinking POC. Autonomous observations made by gliders during the North Atlantic spring bloom reveal anomalous features at depths of 100 to 350 meters with elevated POC, chlorophyll, oxygen, and temperature-salinity characteristics of surface water. High-resolution modeling reveals that during the spring transition, intrusions of POC-rich surface water descend as coherent, 1- to 10-kilometer-scale filamentous features, often along the perimeter of eddies. Such a submesoscale eddy-driven flux of POC is unresolved in global carbon cycle models but can contribute as much as half of the total springtime export of POC from the highly productive subpolar oceans. PMID- 25814064 TI - Ice sheets. Volume loss from Antarctic ice shelves is accelerating. AB - The floating ice shelves surrounding the Antarctic Ice Sheet restrain the grounded ice-sheet flow. Thinning of an ice shelf reduces this effect, leading to an increase in ice discharge to the ocean. Using 18 years of continuous satellite radar altimeter observations, we have computed decadal-scale changes in ice-shelf thickness around the Antarctic continent. Overall, average ice-shelf volume change accelerated from negligible loss at 25 +/- 64 cubic kilometers per year for 1994-2003 to rapid loss of 310 +/- 74 cubic kilometers per year for 2003 2012. West Antarctic losses increased by ~70% in the past decade, and earlier volume gain by East Antarctic ice shelves ceased. In the Amundsen and Bellingshausen regions, some ice shelves have lost up to 18% of their thickness in less than two decades. PMID- 25814063 TI - Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates. AB - Zaire ebolavirus is the causative agent of the current outbreak of hemorrhagic fever disease in West Africa. Previously, we showed that a whole Ebola virus (EBOV) vaccine based on a replication-defective EBOV (EBOVDeltaVP30) protects immunized mice and guinea pigs against lethal challenge with rodent-adapted EBOV. Here, we demonstrate that EBOVDeltaVP30 protects nonhuman primates against lethal infection with EBOV. Although EBOVDeltaVP30 is replication-incompetent, we additionally inactivated the vaccine with hydrogen peroxide; the chemically inactivated vaccine remained antigenic and protective in nonhuman primates. EBOVDeltaVP30 thus represents a safe, efficacious, whole-EBOV vaccine candidate that differs from other EBOV vaccine platforms in that it presents all viral proteins and the viral RNA to the host immune system, which might contribute to protective immune responses. PMID- 25814065 TI - Superconductivity. Quasiparticle mass enhancement approaching optimal doping in a high-T(c) superconductor. AB - In the quest for superconductors with higher transition temperatures (T(c)), one emerging motif is that electronic interactions favorable for superconductivity can be enhanced by fluctuations of a broken-symmetry phase. Recent experiments have suggested the existence of the requisite broken-symmetry phase in the high T(c) cuprates, but the impact of such a phase on the ground-state electronic interactions has remained unclear. We used magnetic fields exceeding 90 tesla to access the underlying metallic state of the cuprate YBa2Cu3O(6+delta) over a wide range of doping, and observed magnetic quantum oscillations that reveal a strong enhancement of the quasiparticle effective mass toward optimal doping. This mass enhancement results from increasing electronic interactions approaching optimal doping, and suggests a quantum critical point at a hole doping of p(crit) ~ 0.18. PMID- 25814068 TI - Synthesis and antiproliferative evaluation of some novel B-nor-D-homosteroids. AB - Using 3beta-hydroxy-5-androsten-17-one as a starting material, a series of novel nitrogen-containing B-nor-D-homosteroids were designed and synthesized by the oximation, Beckman rearrangement, ozonation, cyclization and condensation reaction. The structures of all new compounds were determined by analysis of their NMR, MS and IR spectra. The antiproliferative activity of compounds was evaluated against HT-29 (colonic carcinoma), HeLa (human cervical carcinoma) and Bel 7404 (human liver carcinoma) cells. PMID- 25814066 TI - Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. AB - Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity. PMID- 25814067 TI - Virology. Mutation rate and genotype variation of Ebola virus from Mali case sequences. AB - The occurrence of Ebola virus (EBOV) in West Africa during 2013-2015 is unprecedented. Early reports suggested that in this outbreak EBOV is mutating twice as fast as previously observed, which indicates the potential for changes in transmissibility and virulence and could render current molecular diagnostics and countermeasures ineffective. We have determined additional full-length sequences from two clusters of imported EBOV infections into Mali, and we show that the nucleotide substitution rate (9.6 * 10(-4) substitutions per site per year) is consistent with rates observed in Central African outbreaks. In addition, overall variation among all genotypes observed remains low. Thus, our data indicate that EBOV is not undergoing rapid evolution in humans during the current outbreak. This finding has important implications for outbreak response and public health decisions and should alleviate several previously raised concerns. PMID- 25814069 TI - Synthesis of conjugated bile acids/azastilbenes as potential antioxidant and photoprotective agents. AB - A series of 14 bile acids/azastilbenes conjugates (1a-g and 2a-g) was prepared through the condensation of bile amides (1 and 2) and aromatic aldehydes. The newly synthesized conjugates were evaluated in vitro for their antioxidant and photoprotective activities. Six compounds (1, 1a, 1b, 2, 2a and 2b) showed promising antioxidant activity with IC50 values of 19.60-31.83 MUg mL(-1). The synthesized compounds presented a varied photoprotection profile, with the SPF ranging from 2 to 9. Among the 16 compounds tested for the protection against UVB sunrays, 3 compounds (2c, 2e and 2g) presented more significant protection than resveratrol and the free azastilbene 3; while the UVAPF increased from 2 in resveratrol and 5 in 3 to 5-11 in the majority of the conjugates. PMID- 25814070 TI - Increased plant sterol deposition in vascular tissue characterizes patients with severe aortic stenosis and concomitant coronary artery disease. AB - The aim of the study was to evaluate the relationship between phytosterols, oxyphytosterols, and other markers of cholesterol metabolism and concomitant coronary artery disease (CAD) in patients with severe aortic stenosis who were scheduled for elective aortic valve replacement. Markers of cholesterol metabolism (plant sterols and cholestanol as markers of cholesterol absorption and lathosterol as an indicator of cholesterol synthesis) and oxyphytosterols were determined in plasma and aortic valve tissue from 104 consecutive patients with severe aortic stenosis (n=68 statin treatment; n=36 no statin treatment) using gas chromatography-flame ionization and mass spectrometry. The extent of CAD was determined by coronary angiography prior to aortic valve replacement. Patients treated with statins were characterized by lower plasma cholesterol, cholestanol, and lathosterol concentrations. However, statin treatment did not affect the sterol concentrations in cardiovascular tissue. The ratio of campesterol-to-cholesterol was increased by 0.46+/-0.34MUg/mg (26.0%) in plasma of patients with CAD. The absolute values for the cholesterol absorption markers sitosterol and campesterol were increased by 18.18+/-11.59ng/mg (38.8%) and 11.40+/-8.69ng/mg (30.4%) in the tissues from patients with documented CAD compared to those without concomitant CAD. Campesterol oxides were increased by 0.06+/-0.02ng/mg (17.1%) in the aortic valve cusps and oxidized sitosterol-to cholesterol ratios were up-regulated by 0.35+/-0.2ng/mg (22.7%) in the plasma of patients with CAD. Of note, neither cholestanol nor the ratio of cholestanol-to cholesterol was associated with CAD. Patients with concomitant CAD are characterized by increased deposition of plant sterols, but not cholestanol in aortic valve tissue. Moreover, patients with concomitant CAD were characterized by increased oxyphytosterol concentrations in plasma and aortic valve cusps. PMID- 25814071 TI - Laparoscopic mini-gastric bypass in patients age 60 and older. AB - BACKGROUND: Bariatric surgery in patients over age 60 was previously not considered, due to higher risk. The author presents a study of patients >=60 years who underwent laparoscopic mini-gastric bypass (LMGB), to evaluate outcomes with follow-up to 6 years. METHODS: From 2007-2013, a prospectively maintained database was reviewed and patients >=60 years were identified. Demographics evaluated included age, sex, weight, BMI, comorbidities, operative time, complications, length of stay (LOS) and %EWL up to 72 months. RESULTS: From 2007 2013, a total of 758 LMGBs were performed by one surgeon (CP). Eighty-eight (12%) were >=60 years old, with 62% female. Mean age of this cohort at operation was 64 (60-74), and mean weight and BMI were 118 kg (78-171) and 43 kg/m(2) (33-61), respectively. Comorbidities were present in all patients, and one-third had previous abdominal operations. All patients underwent LMGB, without conversion to open. Mean operative time was 70 min (43-173). Only one patient required overnight ICU admission. Average LOS was 1.2 days (1-3). Overall complication rate was 4.5% (all minor); there were no major complications. Readmission rate was 1.2% (one patient). There was no surgical-related mortality. Follow-up to 90 days was 89%, but steadily declined to 42% at 6 years (72 months). The %EWL was 72% at 72 months. CONCLUSION: LMGB can be safely performed with good weight loss in patients >=60 years old, despite numerous comorbidities and previous abdominal operations. PMID- 25814072 TI - Endoscopic predictors for undifferentiated histology in differentiated gastric neoplasms prior to endoscopic resection. AB - BACKGROUND: There is often a discrepancy between results from endoscopic forceps biopsy and resected specimen. We aimed to identify endoscopic predictors for undifferentiated histology in differentiated gastric neoplasms prior to endoscopic resection. METHODS: Medical records of the patients who underwent endoscopic submucosal dissection (ESD) for biopsy-proven differentiated gastric neoplasms at Seoul National University Hospital between July 2005 and July 2014 were retrospectively reviewed. The lesions were divided into two groups based on the final histologic result of ESD: differentiated adenocarcinoma (DA group) and undifferentiated histology (UDH group). The discordant rate, clinicopathologic characteristics, and endoscopic factors were analyzed. RESULTS: A total of 1641 early gastric cancers from 1615 patients were included. Of these, 1556 (94.8%) were diagnosed as DA and 85 (5.2%) as UDH. The mean age was significantly lower, and number of women was higher in the UDH group than in the DA group. On multivariate analysis, age <65 years [odds ratio (OR) 1.75, 95 % confidence interval (CI) 1.10-2.80], female sex (OR 3.19, 95% CI 2.00-5.08), endoscopic size >10 mm (OR 1.81, 95% CI 1.12-2.92), depressed type (OR 2.85, 95% CI 1.56-5.21), nodularity (OR 2.83, 95% CI 1.59-5.05), and whitish discoloration (OR 19.64, 95% CI 6.98-55.25) were independent predictors. CONCLUSIONS: Female sex, age <65 years, large endoscopic size, depressed morphology, surface nodularity, and whitish discoloration were predictors for UDH. Meticulous attention should be paid to the lesions with these endoscopic predictors for determining the risk of UDH prior to endoscopic resection. PMID- 25814073 TI - Hybrid NOTES: TEO for transanal total mesorectal excision: intracorporeal resection and anastomosis. AB - BACKGROUND: Laparoscopic surgery for rectal TME achieves better patient recovery, lower morbidity, and shorter hospital stay than open surgery. However, in laparoscopic rectal surgery, the overall conversion rate is nearly 20%. Transanal TME combined with laparoscopy, known as Hybrid NOTES, is a less invasive procedure that provides adequate solutions to some of the limitations of rectal laparoscopy. Transanal TME via TEO with technical variants (intracorporeal resection and anastomosis, TEO review of the anastomosis) attempts to standardize and simplify the procedure. METHOD: Prospective observational study was used describe and assess the technique in terms of conversion to open surgery, overall morbidity, surgical site infection and hospital stay. The sample comprised consecutive patients diagnosed with rectal tumor less than 10 cm from the anal verge who were candidates for low anterior resection using TME (except T4). Demographic, surgical, postoperative, and pathological variables were analyzed, as well as morbidity rates. RESULTS: From September 2012 to August 2014, 32 patients were included. The conversion rate was 0%. Overall morbidity was 31.3%, SSI rate was 9.4%, and mean hospital stay was 8 days. Oncological radical criteria were achieved with pathological parameters of 94% of complete TME and a median circumferential margin of 13 mm. CONCLUSION: The introduction of technical variants of TEO for transanal resection can facilitate a procedure that requires extensive experience in transanal and laparoscopic surgery. Studies of sphincter function, quality of life, and long-term oncological outcome are now necessary. PMID- 25814074 TI - Predictors of poor glycaemic control in older patients with type 2 diabetes mellitus. AB - INTRODUCTION: We assessed the predictors of poor glycaemic control among older patients with type 2 diabetes mellitus (T2DM) in Malaysia. METHODS: This cross sectional study used the data of 21,336 patients aged >= 60 years with T2DM from the Adult Diabetes Control and Management Registry 2008-2009. RESULTS: Predictors of poor glycaemic control were: age groups 60-69 years (odds ratio [OR] 1.96, 95% confidence interval [CI] 1.66-2.33) and 70-79 years (OR 1.43, 95% CI 1.20-1.71); Malay (OR 1.53, 95% CI 1.41-1.66) and Indian (OR 1.32, 95% CI 1.19-1.46) ethnicities; T2DM durations of 5-10 years (OR 1.46, 95% CI 1.35-1.58) and > 10 years (OR 1.75, 95% CI 1.59-1.91); the use of oral antidiabetic agents only (OR 5.86, 95% CI 3.32-10.34), insulin only (OR 17.93, 95% CI 9.91-32.43), and oral antidiabetic agents and insulin (OR 29.42, 95% CI 16.47-52.53); and elevated blood pressure (OR 1.10, 95% CI 1.01-1.20), low-density lipoprotein cholesterol (OR 1.48, 95% CI 1.38-1.59) and triglycerides (OR 1.61, 95% CI 1.51-1.73). Hypertension (OR 0.71, 95% CI 0.64-0.80), hypertension and dyslipidaemia (OR 0.68, 95% CI 0.61-0.75), pre-obesity (OR 0.89, 95% CI 0.82-0.98) and obesity (OR 0.76, 95% CI 0.70-0.84) were less likely to be associated with poor glycaemic control. CONCLUSION: Young-old and middle-old age groups (i.e. < 80 years), Malay and Indian ethnicities, longer T2DM duration, the use of pharmacological agents, and elevated blood pressure and lipid levels were associated with poor glycaemic control. The presence of comorbidities, pre-obesity and obesity were less likely to be associated with poor glycaemic control. PMID- 25814075 TI - Morphology of distal radius curvatures: a CT-based study on the Malaysian Malay population. AB - INTRODUCTION: The purpose of this study was to examine the differing curves of the volar distal radius of healthy Malaysian Malays, so as to obtain detailed morphological information that will further the understanding of volar plate osteosynthesis in Malaysian Malays. METHODS: Computed tomography with three dimensional reconstruction was performed on the wrists of 16 healthy Malaysian Malay volunteers. Profile measurements were made using a software program. A novel parameter, the pronator quadratus curve angle, was explored and introduced in this study. Interclass correlation coefficients were calculated to assess the level of agreement between the data collected by the principal investigator and that collected by an independent radiologist. RESULTS: The mean +/- standard deviation of the arc radii on the radial aspect was 17.50 degrees +/- 5.40 degrees , while the median (interquartile range [IQR]) of the arc radii on the ulnar aspect was 25.27 degrees (IQR 5.80 degrees ). The mean +/- standard deviation of the curvature of the pronator quadratus line was 40.52 degrees +/- 2.48 degrees . The arc radii on the radial aspect was significantly lower than the arc radii on the ulnar aspect (p = 0.001). Different radial and ulnar arcs were observed in 56.25% of the radii; the arc was deeper on the ulnar aspect in 93.75% of the radii. CONCLUSION: Based on the findings of this study, the likelihood of achieving anatomical reduction with uniformly curved, fixed-angle volar plates is questionable. Changes in the design of these implants may be needed to optimise their usage in the Malaysian Malay population. PMID- 25814076 TI - CML--Where do we stand in 2015? PMID- 25814077 TI - Natural course and biology of CML. AB - Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and 'indolent' symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease. PMID- 25814078 TI - The choice of first-line chronic myelogenous leukemia treatment. AB - Imatinib has represented a revolution in the treatment of chronic myeloid leukemia (CML), inducing an overall survival never seen with previous therapies. However, with the commonly used dosage of 400 mg, one third of the treated patients does not reach the criteria associated with an optimal outcome and could potentially benefit from a different treatment strategy. Several trials exploring modified imatinib-based treatments or second-generation tyrosine-kinase as front line therapy have been performed. In some studies, high-dose (800 mg per day) or dose-adapted imatinib or imatinib plus interferon was reported to be able to induce better cytogenetic and molecular responses compared with standard-dose imatinib, although no improvements in progression-free survival (PFS) or overall survival (OS) have been so far reported. At the moment, these approaches are still considered investigational. On the other side, on the basis of their capacity to induce very fast and deep molecular responses, including major molecular responses (MMRs) and the newly defined very deep molecular responses MR4 and MR(4.5), and to prevent at least part of the early progressions to AP/BC that still occur during the first 2-3 years from diagnosis, dasatinib and nilotinib have been approved and registered by FDA and EMA as the first-line therapy for CML patients, opening the possibility to use different therapeutic strategies for newly diagnosed CML patients and a consequent intense debate among hematologists. PMID- 25814079 TI - Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients. AB - For patients with chronic myelogenous leukemia who fail first-line therapy, several factors should be considered for the decision of the next treatment option. Second-generation tyrosine kinase inhibitors (TKIs) dasatinib, nilotinib, and bosutinib offer improved potency and a high likelihood of success for these patients. Overall, efficacy data are comparable for these agents, and so physicians should consider the BCR-ABL1 mutation profile and the patient's history to make a decision on the best choice. Only a few BCR-ABL1 mutations seem to be less responsive to any of the three drugs, and it is recommended to choose the second-line TKI that has shown clinical activity against the specific mutation in these cases. For patients with all other mutations and for patients with no mutations, it is recommended to choose the second-generation TKI based on the patient's disease history. The third-generation TKI ponatinib is available after dasatinib or nilotinib failure or for patients with T315I mutations. However, optimal dose of ponatinib is still under investigation. Overall, it is recommended to select a drug that minimizes the likelihood of worsening the patient's past side effects or comorbid conditions. In any case, chance and risk of allogeneic stem cell transplantation should be compared with the long-term outcome of TKI therapy in patients eligible for this procedure. PMID- 25814080 TI - A review of the European LeukemiaNet recommendations for the management of CML. AB - Several guidelines and recommendations on the management of chronic myeloid leukemia (CML) have been prepared by several scientific societies. The European LeukemiaNet (ELN) appointed a panel of experts who submitted their recommendations to peer-reviewed scientific journals in 2006, 2009, and 2013. Here, we make a critical review of the last, 2013, ELN recommendations, concerning the use of the five available tyrosine kinase inhibitors (TKIs), the evaluation of cytogenetic and molecular response, and the strategy of treatment. Three TKIs (imatinib, nilotinib, dasatinib) are recommended first-line. Bosutinib and ponatinib are available second-line; ponatinib is particularly indicated in case of the T315I mutation. Achieving an optimal response, not only for survival but also for a deeper, stable, treatment-free remission, requires a BCR-ABL transcripts level <= 10 % at 3 months, <= 1 % at 6 months, <= 0.1 % at 1 year, and <= 0.01 % later on. Molecular monitoring must include mutational analysis in every case of failure. A successful treatment of accelerated and blastic phase requires TKIs, and in many cases also allogeneic stem cell transplantation. PMID- 25814081 TI - Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. AB - Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein represent an outstanding progress in chronic myeloid leukemia (CML), and long-term survival has become a reality. However, the majority of patients need to be treated during their entire life span; thus, outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. TKIs have an overall favorable safety profile in clinical practice. Although many patients may encounter adverse events, these usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care. Whenever treatment interruption is necessary, re-exposition to the same TKI or switch to an alternative TKI is successful in the majority of the cases. However, long-term safety issues have not been fully elucidated at present, especially for new generation TKIs. Recent evidence has emerged that these new agents may sometimes impinge on vital organs such as the heart and lung in an irreversible fashion especially when comorbidities are present; thus, decision regarding of which TKI should be used must take into account disease-related, TKI-related, and patient related variables. The purpose of this article is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be optimally managed. PMID- 25814082 TI - Management of chronic myeloid leukemia in blast crisis. AB - Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure. PMID- 25814083 TI - Managing pregnancy in chronic myeloid leukaemia. AB - Over the past decade, we have witnessed significant advances in knowledge of the biology and treatment of chronic myeloid leukaemia (CML). The development of molecular-targeted therapy with tyrosine kinase inhibitors (TKIs) has fundamentally changed the outcome of this disease. Treatment with TKIs is now the standard of care in patients with CML and has dramatically improved long-term survival in the majority of patients. Patients who achieve major molecular response (MMR) after 2 years of treatment with imatinib have survival rates comparable to those of the general population. The success of TKIs has led to durable molecular response and possibility of normal life expectancies, such that it is now timely to address quality of life aspects such as fertility, pregnancy and family planning. Pregnancy in CML presents specific management and therapeutic challenges for the patient and the physician. Despite the recent treatment advances, we still have limited data on the safety of TKIs in pregnancy and its effect on fertility. However, there is a cause for concern and heightened awareness following the occurrence of a constellation of rare congenital malformations and spontaneous abortions in association with imatinib therapy. When a patient becomes pregnant whilst receiving TKI therapy, the difficulty lies in balancing the risk to the foetus of continuing therapy versus the risk to the patient of treatment interruption and potentially losing optimal disease response. All couples should be counselled on the risks associated with pregnancy whilst receiving TKI therapy. This is an essential aspect in patient care and frequently not emphasized enough by physicians. At the time of diagnosis, fertility preservation should be discussed with both male and female patients of childbearing potential. They should be made aware of fertility options which are available such as semen cryopreservation, ovarian or oocyte retrieval and storage and embryo cryopreservation in view of the potential detrimental effect of TKIs on fertility and gonadal function. The recommendation given to patients planning pregnancy differs according to their disease response to TKI therapy, which is the most important prognostic factor in CML. PMID- 25814084 TI - The role of hematopoietic stem cell transplantation in chronic myeloid leukemia. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is currently recommended as 2nd or 3rd line therapy for patients with chronic myeloid leukemia (CML) in first chronic phase or as salvage for patients with very advanced disease. As a consequence, numbers of HSCT in chronic phase have dropped significantly since the introduction of tyrosine kinase inhibitors (TKI), numbers of transplants in advanced disease to a lesser extent. These current recommendations consider primarily disease risk, defined as failure of TKI therapy; they might need to be adapted. We propose a more balanced appraisal of HSCT for individual patients which should include disease risk, transplant risk, and macroeconomic aspects. HSCT should be integrated into the treatment algorithms from diagnosis and be considered very early at first TKI failure for patients with high disease but low transplant risk. For patients with very advanced disease and high transplant risk in contrast, HSCT might only be recommended in a restricted research setting. PMID- 25814085 TI - Discontinuation of tyrosine kinase therapy in CML. AB - Over the past decade, a broad array of drugs designed to selectively inhibit protein tyrosine kinases (tyrosine kinase inhibitors or TKIs) have emerged as novel therapies for cancer patients. Chronic myeloid leukemia (CML) is one of the best examples of successful targeted therapy with a TKI. The overall survival of CML patients who respond to treatment is close to that of the healthy population. The response in many patients is so profound that it is possible to consider stopping their treatment and with time, the number of patients in this group has increased to the point where the issue of treatment cessation has become of utmost importance. This has led to the development of a new concept in the evaluation of CML entitled treatment-free remission. It will be the criterion to evaluate the success of future clinical trials, especially if we want to improve the management of the disease to the point where we can claim to have cured CML. PMID- 25814086 TI - The interferon-alpha revival in CML. AB - Interferon-alpha (IFNalpha) was once the standard of frontline treatment for chronic myeloid leukemia (CML). Its pleiotropic mechanism of action in CML includes immune activation and specific targeting of CML stem cells. Early studies of IFNalpha in CML demonstrated that patients in chronic phase could attain extremely stable remissions, which correlated with long-term survival. Some patients even sustained their remission after discontinuing therapy, but the mechanism underlying this phenomenon is not well understood. Today, BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, induce remarkable responses in CML patients and have become the mainstay of CML therapy. Although TKIs target the pathogenic BCR-ABL protein in CML, they cannot fully eradicate CML stem cells. Some of the clinical trials testing IFNalpha plus imatinib combination therapy suggest that addition of IFNalpha increases the speed and rate of responses with imatinib therapy. However, the undesirable side effects of IFNalpha can make this therapy difficult to deliver, and the optimal therapeutic window for using IFNalpha in combination therapy is unknown. Further studies are needed to clarify the best niche for IFNalpha use in CML. PMID- 25814087 TI - Prognostic scores for patients with chronic myeloid leukemia under particular consideration of competing causes of death. AB - Nowadays in many fields of medicine, prognostic scores are used to predict the outcome for individual patients. In chronic myeloid leukemia (CML), the Sokal, the Euro, and the EUTOS score are established prognostic scores which were addressed by the CML management recommendations of the European LeukemiaNet. This review provides a general definition of prognostic scores and explains their meaning. Main differences between the Sokal, the Euro, and the EUTOS score are highlighted. Due to the therapeutic success of tyrosine kinase inhibitors, the proportion of patients with causes of death unrelated to CML is growing. To assess the potential of a drug to prevent dying of CML, causes of death unrelated to CML need to be considered as competing risks. Supported by data of patients randomized to imatinib-based treatments within the German CML study IV, this review also explores the prognostic performance of the established scores if the primary event is death due to CML only and explains the implicit statistical particularities when treating other causes of death as competing risks. In the presence of competing risks, the application of both the cause-specific hazard model and the subdistribution hazard model is recommended when investigating the influence of prognostic factors on the event of interest. Another purpose of this work is to foster the ability of hematologists to interpret the outcome of a cause-specific hazard and a subdistribution hazard model and to understand the differences between them. PMID- 25814088 TI - Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization. AB - Serial quantification of BCR-ABL1 messenger RNA (mRNA) is an important therapeutic indicator for patients with chronic myeloid leukemia, but historically, there has been substantial variation in results reported by different laboratories. To help improve the comparability of results, an international scale (IS) for BCR-ABL1 was proposed which is being implemented by testing laboratories worldwide. This is being achieved most commonly by the derivation of laboratory-specific conversion factors, but increasingly by the use of kits or reagents that are calibrated to the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL1 mRNA. Recent attention has focused on the need to define and validate levels of deeper molecular response (MR) within the context of the IS. While there has been substantial progress in the alignment of results, BCR-ABL1 measurement is technically challenging and standardization is an ongoing process. PMID- 25814089 TI - Response-related predictors of survival in CML. AB - The assessment of response to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) does not only reflect tumor burden at a given time but has been shown to be linked to long-term survival outcomes as well. Therefore, the quantification of molecular or cytogenetic response as early as 3 months on treatment allows a prognostic stratification of a patient's individual risk. With competing TKI regimens available, a timely switch of treatment can be considered if unfavorable outcome has to be expected due to early response failure. Numerous studies have demonstrated the association of long-term outcome with early response for first-line treatment with imatinib, with second generation TKI and for second-line TKI treatment as well. PMID- 25814090 TI - Epidemiology of chronic myeloid leukaemia: an update. AB - National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7-1.0/100,000, a median age at diagnosis of 57-60 years and a male/female ratio of 1.2-1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10 12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research. PMID- 25814091 TI - Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU. AB - Imatinib is an oral tyrosine kinase inhibitor and considered to be the most successful targeted anti-cancer agent yet developed given its substantial efficacy in treating chronic myeloid leukemia (CML) and other malignant diseases. In the USA and the European Union (EU), Novartis' composition of matter patent on imatinib will expire in 2016. The potential impact on health system spending levels for CML after generic imatinib becomes available is the subject of significant interest among stakeholders. The extent of the potential savings largely depends on whether and to what extent prices decline and use stays the same or even increases. These are also empirical questions since the likely spending implications following generic imatinib's availability are predicated on multiple factors: physicians' willingness to prescribe generic imatinib, molecule characteristics, and health system priorities. This article discusses each of these issues in turn. We then review their implications for the development of country-specific cost-effectiveness models to predict the implications for cost and quality of care from generic imatinib. PMID- 25814092 TI - Paraoxonase-1 enzyme activity assay for clinical samples: validation and correlation studies. AB - BACKGROUND: Paraoxonase-1 (PON1) enzyme is reported in various types of tissues and linked to numerous pathophysiological disorders. It is a potential biomarker in many pathological conditions such as cardiovascular diseases. MATERIAL AND METHODS: We conducted several small-scale studies to evaluate PON1 performance as affected by sample types, storage, and interferences. We also carried out short term studies to compare the performance of the widely used PON1 assay to the similar commercially available PON1 kit assay method; sample size for the method comparison was N=40, and the number varied for other validation experiments. RESULTS: Our studies using various types of anticoagulants show that samples collected in tubes with NaF, citrate, EDTA, clot activator, and sodium heparin have increased PON1 levels that are 49%, 24.5%, 19.8%, 11.4%, and 8%, respectively, higher compared to serum samples collected in plain tubes. However, samples collected in lithium heparin tubes demonstrated 10.4% lower PON1 levels compared to serum collected in plain tubes. Biological interference such as hemolysis has little effect on PON1 levels; however, samples spiked with lipids have shown 13% lower PON 1 levels. Our studies comparing the PON1 method commonly available for PON1 assay and a similar non-ELISA commercially available PON1 kit method showed a weak Spearman correlation coefficient of R2=0.40 for the range of 104.9-245.6 U/L. CONCLUSIONS: The current study provides new validation data on enzyme PON1 performance. While no appreciable change was seen with storage, samples type affects the enzyme performance. Our results should encourage additional clinical studies to investigate other aspects of factors known to affect PON1 enzyme function and performance. PMID- 25814093 TI - Preoperative diagnosis of sentinel lymph node (SLN) metastasis using 3D CT lymphography (CTLG). AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) became a standard procedure for patients with early breast cancer, however, an indication of SLN navigation to metastatic disease may lead to misdiagnosis for staging. Preoperative CTLG with a water-soluble iodinated contrast medium visualizes the correct primary SLNs and its afferent lymphatic channels surrounding detailed anatomy, therefore it can predict LN metastasis by visualizing the lymph vessel obstruction or stain defect of the SLN by tumor. The current study presents the value of CTLG for preoperative prediction for SLN status. METHODS: A total of 228 patients with Tis T2 breast cancer who did not receive primary chemotherapy were studied. SLN metastasis was diagnosed according to the following staining patterns of SLNs and afferent lymphatic vessels: stain defect of SLN, obstruction, stagnation, dilation, and detour of the lymphatic vessels by tumor occupation. The diagnosis was compared with the pathological results to evaluate the accuracy of prediction for SLN metastasis using CTLG. RESULTS: Twenty-seven of 228 patients had metastatic SLN pathologically. Twenty-five of these were diagnosed as metastatic preoperatively. The accuracy for metastatic diagnosis using CTLG was 89.0%, sensitivity was 92.6%, and specificity was 88.6%. The positive predictive value was 52.1% and negative predictive value was 98.8%. CONCLUSION: CTLG can select the candidate with truly node negative cases in early breast cancer patients, because it predicts lymph node metastasis preoperatively from natural status of the lymphographic image. It also might omit the SLN biopsy itself. PMID- 25814094 TI - Pediatric emergency update: cyclic vomiting syndrome. PMID- 25814095 TI - Clinical Decision Making in Triage: An Integrative Review. PMID- 25814096 TI - ED Technician Educator: An Innovative Extension of the Nurse Educator Role. PMID- 25814097 TI - Response to "a comparison of paper documentation to electronic documentation for trauma resuscitations at a level I pediatric trauma center". PMID- 25814098 TI - Intra-operative augmented reality in distal locking. AB - PURPOSE: To design an augmented reality solution that assists surgeons during the distal locking of intramedullary nailing procedures. METHOD: Traditionally, the procedure is performed under X-ray guidance and requires a significant amount of time and radiation exposure. To absolve these complications, we propose video guidance that allows surgeons to achieve both the down-the-beam position of the intramedullary nail and its subsequent locking. For the down-the-beam position, the IM nail pose in X-ray is calculated using a 2D/3D registration scheme and later related to the patient leg pose which is calculated using video-tracked AR markers. For the distal locking, surgeons use an augmented radiolucent drill in which its tip position is detected and tracked in real-time under video guidance. VALIDATION: To evaluate the feasibility of our solution, we performed a preclinical study on dry bone phantom with the participation of four clinicians. RESULTS: Participants achieved 100 % success rate in the down-the beam positioning and 93 % success rate in distal locking using only two X-ray images in 100 s. CONCLUSIONS: We confirmed that intra-operative navigation using augmented reality provides an alternative way to perform distal locking in a safe and timely manner. PMID- 25814100 TI - An unsteady state retention model for fluid desorption from sorbents. AB - New studies regarding the sorption of fluids by solids are published every day. In performance testing, after the sorbent has reached saturation, it is usually removed from the sorbate bath and allowed to drain. The loss of liquid from the sorbents with time is of prime importance in the real-world application of sorbents, such as in oil spill response. However, there is currently no equation used for modeling the unsteady state loss of the liquid from the dripping sorbent. Here, an analytical model has been provided for modeling the dynamic loss of liquid from the sorbent in dripping experiments. Data from more than 60 sorbent-sorbate systems has been used to validate the model. The proposed model shows excellent agreement with experimental results and is expressed as: U(t)=U(L)e(-Kt)+U(e) In which U(t) (kg/kg) is the uptake capacity of the sorbent at any time t (s) during dripping, U(L) (kg/kg) is the uptake capacity lost due to dripping, and U(e) (kg/kg) is the equilibrium uptake capacity reached after prolonged dripping. K (1/s) is defined as the Kamaan coefficient and controls the curvature of the retention profile. Kamaan ([symbol: see text] IPA phonetics: kaemalphan) is an Iranian (Farsi/Persian) word meaning "arc" or "curve" and hence the letter K has been designated. PMID- 25814101 TI - Forces, pressures and energies associated with liquid rising in nonuniform capillary tubes. AB - In this theoretical study, the forces, pressures, energies and kinetics for liquid rising in three types of capillary tubes were analyzed: one type was chemically homogeneous and the other two were nonuniform with chemical gradients. The tubes with chemical gradients were "designed" such that the liquid would still rise and attain the same ultimate height as an equivalent homogenous tube, but as shown here, the energies and kinetics of these inhomogeneous tubes are anticipated to be quite different from their homogeneous counterpart. PMID- 25814099 TI - Examining endogenous dopamine in treated schizophrenia using [11C]-(+)-PHNO positron emission tomography: A pilot study. AB - BACKGROUND: Using positron emission tomography (PET) it is possible to estimate endogenous dopamine (DA) occupying D2/3 receptors (D2/3R) in the living human brain. Persons with schizophrenia (SZ) (previously medicated and naive) have increased endogenous DA occupying D2/3R in the caudate. It is unknown whether currently medicated patients demonstrate increased DA levels at D2/3R. Moreover, DA levels have not been estimated in SZ using agonist radiotracers, which may offer a more sensitive quantification over antagonists. METHODS: Using the agonist radiotracer [(11)C]-(+)-PHNO, DA levels were estimated at D2/3R (DeltaBP(ND)) in three patients with SZ (male, mean age=30+/-16). Patients were currently being treated long-term with Olanzapine (147+/-88 nmol/L). Results were compared to ten healthy controls (HCs). RESULTS: Medicated persons with SZ had greater DeltaBP(ND) in the left caudate (U=2, Z=-2.20, p=.03) and right putamen (U=2, Z=-2.20, p=.03). No differences were observed in the ventral striatum or globus pallidus. CONCLUSIONS: It is possible to estimate endogenous DA at D2/3R in SZ patients currently taking antipsychotics. Despite medication, patients continue to have increased endogenous DA at D2/3R. This lends more biological support to the clinical observation that relapses in symptoms can occur in the face of complete antipsychotic discontinuation. Future studies with larger samples are warranted. PMID- 25814102 TI - Reduction and control of domain spacing by additive inclusion: morphology and orientation effects of glycols on microphase separated PS-b-PEO. AB - Cylindrical phase polystyrene-b-polyethylene oxide (PS-b-PEO) block copolymer (BCP) was combined with lower molecular weight poly/ethylene glycols at different concentrations and their effect on the microphase separation of BCP thin films were studied. Well-ordered microphase separated, periodic nanostructures were realized using a solvent annealing approach for solution cast thin films. By optimizing solvent exposure time, the nature and concentration of the additives etc. the morphology and orientation of the films can be controlled. The addition of the glycols to PS-b-PEO enables a simple method by which the microdomain spacing of the phase separated BCP can be controlled at dimensions below 50 nm. Most interestingly, the additives results in an expected increase in domain spacing (i.e. pitch size) but in some conditions an unexpected reduction in domain spacing. The pitch size achieved by modification is in the range of 16-31 nm compared to an unmodified BCP system which exhibits a pitch size of 25 nm. The pitch size modification achieved can be explained in terms of chemical structure, solubility parameters, crystallinity and glass transition temperature of the PEO because the additives act as PEO 'stress cracking agents' whereas the PS matrix remains chemically unaffected. PMID- 25814103 TI - Cardiac risk stratification and protection. AB - The goal of preoperative cardiac evaluation is to screen for undiagnosed cardiac disease or to find evidence of known conditions that are poorly controlled to allow management that reduces the risk of perioperative cardiac complications. A careful history and physical examination combined with the procedure-specific risk is the cornerstone of this assessment. This article reviews a brief history of prior cardiac risk stratification indexes, explores current practice guidelines by the American College of Cardiology and the American Heart Association Task Force, reviews current methods for preoperative evaluation, discusses revascularization options, and evaluates perioperative medication recommendations. PMID- 25814104 TI - Prevention of postoperative pulmonary complications. AB - Postoperative pulmonary complications (PPCs) occur frequently among general surgical patients. The spectrum of illness is broad and includes preventable causes of morbidity and death. Careful preoperative evaluation can identify undiagnosed and undertreated illness and allow for preoperative intervention. Optimization of patient, surgical, and anesthetic factors is crucial in the prevention of PPCs. PMID- 25814105 TI - Perioperative nutrition. AB - Perioperative nutrition is a vitally important yet often overlooked aspect of surgical care. Significant disparity exists between evidenced-based recommendations and practices encouraged by traditional surgical teaching. The metabolic response to surgical stress is complex. Poor nutrition has been demonstrated to correlate with adverse surgical outcomes. Perioperative nutrition encompasses preoperative, intraoperative, and postoperative care. Preoperative nutritional assessment identifies at-risk patients who benefit from supplementation before surgery. Prehabilitation seeks to prepare patients for the impending surgical stress. Immunonutrition seems to provide a benefit, although its precise mechanisms are unknown. This article provides a review of the current state of perioperative nutrition. PMID- 25814106 TI - Prophylactic antibiotics and prevention of surgical site infections. AB - Healthcare-associated infections present a significant source of preventable morbidity and mortality. More than 30% of all healthcare-associated infections are represented by surgical site infections, making them the most common subtype. Studies suggest that 40% to 60% of these infections are preventable, yet many hospitals have yet to implement evidence-based best practices. This article reviews the impact of surgical site infections, describes their measurement and reporting, and most importantly provides perioperative strategies for their prevention with a focus on the appropriate use of prophylactic antibiotics. PMID- 25814107 TI - Deep venous thrombosis and venous thromboembolism prophylaxis. AB - "Venous thromboembolism (VTE) remains a significant risk for all surgical patients, despite validated guidelines. Development of VTE remains a high risk in hospitalized surgical patients, leading to complications in up to 30%. The stratification of patient risk factors and subsequent utilization of a validated prophylaxis and treatment regimen is, therefore, of utmost importance. Familiarity with the current guidelines and recommendations ultimately results in decreased morbidity, mortality, and health care costs. This article discusses the risk factors for developing VTE and management strategies based on the currently available guidelines." PMID- 25814108 TI - Postoperative pain control. AB - Prevention and control of postoperative pain are essential. Inadequate treatment of postoperative pain continues to be a major problem after many surgeries and leads to worse outcomes, including chronic postsurgical pain. Optimal management of postoperative pain requires an understanding of the pathophysiology of pain, methods available to reduce pain, invasiveness of the procedure, and patient factors associated with increased pain, such as anxiety, depression, catastrophizing, and neuroticism. Use of a procedure-specific, multimodal perioperative pain management provides a rational basis for enhanced postoperative pain control, optimization of analgesia, decrease in adverse effects, and improved patient satisfaction. PMID- 25814109 TI - Endpoints of resuscitation. AB - Despite the multiple causes of the shock state, all causes possess the common abnormality of oxygen supply not meeting tissue metabolic demands. Compensatory mechanisms may mask the severity of hypoxemia and hypoperfusion, since catecholamines and extracellular fluid shifts initially compensate for the physiologic derangements associated with patients in shock. Despite the achievement of normal physiologic parameters after resuscitation, significant metabolic acidosis may continue to be present in the tissues, as evidenced by increased lactate levels and metabolic acidosis. This review discusses the major endpoints of resuscitation in clinical use. PMID- 25814110 TI - Optimal glucose management in the perioperative period. AB - Hyperglycemia is a common finding in surgical patients during the perioperative period. Factors contributing to poor glycemic control include counterregulatory hormones, hepatic insulin resistance, decreased insulin-stimulated glucose uptake, use of dextrose-containing intravenous fluids, and enteral and parenteral nutrition. Hyperglycemia in the perioperative period is associated with increased morbidity, decreased survival, and increased resource utilization. Optimal glucose management in the perioperative period contributes to reduced morbidity and mortality. To readily identify hyperglycemia, blood glucose monitoring should be instituted for all hospitalized patients. PMID- 25814111 TI - Essentials of sepsis management. AB - Despite remarkable advances in the knowledge of infection and human response to it, sepsis continues to be one of the most common challenges surgeons and critical care providers face. Surgeons confront the problem of infection every day, in treating established infections or reacting to a consequence of surgical intervention. Infections after surgery continue to be a problem despite massive efforts to prevent them. Patients rely on the surgeon's ability to recognize infection and treat it. Also, preventing nosocomial infection and antibiotic resistance is a primary responsibility. This article describes diagnostic and therapeutic measures for sepsis in the perioperative surgical patient. PMID- 25814112 TI - Transfusion and management of surgical patients with hematologic disorders. AB - Clinical trials have provided guidance in developing triggers for transfusing in the hemodynamically stable patient. These studies have identified that improved outcomes can be obtained in the massively transfused patient when platelets and fresh frozen plasma are transfused with packed red blood cells. Studies that characterize the complications of transfusions, such as transfusion-related acute lung injury and poor cancer-related outcomes, are discussed. Emerging data that characterize the risk factors associated with transfusion-related acute lung injury and suggest metastasis and local recurrence occur at a higher rate in the transfused patient are discussed. Hematologic disorders commonly encountered by surgeons are discussed. PMID- 25814113 TI - Perioperative management of obese patients. AB - Obesity prevalence has quadrupled since the 1980s in the United States. It is estimated that 30% of the population is obese or has a body mass index of greater than or equal to 30 as defined by the World Health Organization. Surgeons are likely to engage in the care of obese patients and need to be adept in every aspect of the patients' care in order to have a successful hospital course. There is significant controversy in perioperative management of obese patients. This article discusses perioperative management of obese patients to provide guidelines, education, and discussion of current issues. PMID- 25814114 TI - Perioperative management of elderly patients. AB - The older population only represents 13.7% of the US population but has grown by 21% since 2002. The centenarian population is growing at a faster rate than the total US population. This unprecedented growth has significantly increased surgical demand. The establishment of quality and performance improvement data has allowed researchers to focus attention on the older patient population, resulting in an exponential increase in studies. Although there is still much work to be done in this field, overlying themes regarding the perioperative management of elderly patients are presented in this article based on a thorough literature review. PMID- 25814116 TI - Management of pregnant patients undergoing general surgical procedures. AB - Pregnant patients have a 0.2% to 0.75% chance of developing a medical condition that requires a general surgical intervention during pregnancy. To safely and appropriately care for patients, surgeons must be cognizant of the maternal physiologic changes in pregnancy as well as of the unique risk to both mothers and fetuses of diagnostic modalities, anesthetic care, operative intervention, and postoperative management. Surgeons can be assured that, if these risks are understood and considered, operating during pregnancy, even in the abdomen, can be safely undertaken. PMID- 25814115 TI - Perioperative management in the patient with substance abuse. AB - Drug and alcohol use is a pervasive problem in the general population and in those requiring anesthesia for an operation. History and screening can help delineate those who may be acutely intoxicated or chronic drug and alcohol users. Both acute intoxication and chronic abuse of these substances present challenges for anesthetic management during and after an operation. The clinician should be aware of problems that may be encountered during any part of anesthesia or postoperative care. PMID- 25814117 TI - Advance directives, living wills, and futility in perioperative care. AB - Patient autonomy is preserved through the use of advance directives. A living will defines treatment by establishing parameters under which patients want to be treated. A durable power of attorney for health care establishes a surrogate for patients if they are unable to make decisions for themselves. In the perioperative setting, advance directives are applied with significant variation between surgeons, likely due to surgeons implying from informed consent discussions that patients want to pursue aggressive treatment. Futility is a rare occurrence in patient care that is difficult to define; however, there are some classic surgical conditions in which futility is part of the decision process. PMID- 25814118 TI - Perioperative management. PMID- 25814119 TI - Perioperative management. PMID- 25814120 TI - Prof. Graeme Richard Hanson (16/7/1955-25/2/2015). PMID- 25814121 TI - Porcine epidemic diarrhea virus infection induces NF-kappaB activation through the TLR2, TLR3 and TLR9 pathways in porcine intestinal epithelial cells. AB - Porcine epidemic diarrhea virus (PEDV) is a coronavirus that induces persistent diarrhoea in swine, resulting in severe economic losses in swine-producing countries. Insights into the interplay between PEDV infection and the innate immune system are necessary for understanding the associated mechanism of pathogenesis. The transcription factor NF-kappaB plays an important role in regulating host immune responses. Here, we elucidated for the first time to our knowledge the potential mechanism of PEDV-mediated NF-kappaB activation in porcine small intestinal epithelial cells (IECs). During PEDV infection, NF kappaB p65 was found to translocate from the cytoplasm to the nucleus, and PEDV dependent NF-kappaB activity was associated with viral dose and active replication. Using small interfering RNAs to screen different mRNA components of the Toll-like receptor (TLR) or RIG-I-like receptor signalling pathways, we demonstrated that TLR2, TLR3 and TLR9 contribute to NF-kappaB activation in response to PEDV infection, but not RIG-I. By screening PEDV structural proteins for their ability to induce NF-kappaB activities, we found that PEDV nucleocapsid protein (N) could activate NF-kappaB and that the central region of N was essential for NF-kappaB activation. Furthermore, TLR2 was involved in PEDV N induced NF-kappaB activation in IECs. Collectively, these findings provide new avenues of investigation into the molecular mechanisms of NF-kappaB activation induced by PEDV infection. PMID- 25814122 TI - Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes. AB - INTRODUCTION: Obesity is a major factor that is linked to the development of type 2 diabetes (T2D). Excess circulating fatty acids (FAs), which characterize obesity, induce insulin resistance, steatosis, beta cells dysfunction and apoptosis. These deleterious effects have been defined as lipotoxicity. AREAS COVERED: FAs are metabolized to different lipid species, including ceramides which play a crucial role in lipotoxicity. The action of ceramides on tissues, such as muscle, liver, adipose tissue and pancreatic beta cells, during the development of T2D will also be reviewed. In addition, the potential antagonist action of other sphingolipids, namely sphingoid base phosphates, on lipotoxicity in skeletal muscle and beta cells will be addressed. EXPERT OPINION: Ceramide is a critical mediator to the development of T2D linked to obesity. Targeting proteins involved in ceramide's deleterious action has not been possible due to their involvement in many other intracellular signaling pathways. A possible means of counteracting ceramide action would be to prevent the accumulation of the specific ceramide species involved in both insulin resistance and beta-cell apoptosis/dysfunction. Another possibility would be to adjust the dynamic balance between ceramide and sphingoid base phosphate, both known to display opposing properties on the development of T2D-linked obesity. PMID- 25814123 TI - Intrasellar abscess following pituitary surgery. AB - PURPOSE: Intrasellar abscess is an uncommon cause of mass lesions in the sella turcica. Few cases have been reported in the literature, and much remains unknown about the etiology and diagnosis of these lesions. We sought to review a series of patients with intrasellar abscess encountered at our institution and identify defining characteristics of their presentation and management. METHODS: We conducted a retrospective chart review for intrasellar infection cases associated with a mass lesion. Included cases had clear demonstration of a mass lesion on imaging with subsequent positive microbiological cultures. Clinical presentation, management, post-operative course, neuroimaging, microbiology, and any perturbations in serum pituitary biochemical markers were examined. RESULTS: All examined patients had a history of antecedent transsphenoidal pituitary surgery within the preceding 10 months. All presented with headaches, three with progressive visual loss, one with meningismus, one with fever in the setting of an active cerebrospinal fluid leak, and one with fever, meningismus, hypotension, and progressive somnolence. No patient presented with acute endocrine abnormalities. A majority did not initially have any diffusion restriction present on MRI, but in one case we were able to track the evolution of diffusion restriction over sequential MRI scans. Two patients had complete resolution of presenting symptoms, while three experienced improvement or stabilization of their neurologic deficit. There were no mortalities. CONCLUSIONS: Pituitary abscess remains a rare diagnosis that can be difficult to make and to confirm. In our series we found a strong association between culture-positive abscess and recent pituitary surgery. When present, prompt treatment with surgical drainage and aggressive post-operative antibiotics can lead to a favorable outcome. PMID- 25814124 TI - Nebulised hypertonic saline does not reduce hospital length of stay in acute bronchiolitis. PMID- 25814126 TI - How to make a 'good doctor'. PMID- 25814127 TI - The way of making a good doctor. PMID- 25814125 TI - Clinical management of patients with gastric neuroendocrine neoplasms associated with chronic atrophic gastritis: a retrospective, multicentre study. AB - To provide data regarding clinical presentation, pathological features, management, and response to different treatments of patients with type I gastric neuroendocrine tumors in stages 0-2A. The study design consist of an Italian multicentre, retrospective analysis of patients with type I gastric neuroendocrine tumors managed with different therapeutic approaches: surgery, endoscopic surveillance, endoscopic resection, or somatostatin analog therapy. Among the 97 patients included, 3 underwent surgery, 45 (46.4%) radical endoscopic resection of the neoplastic lesions, 13 (13.4%) follow-up with upper endoscopy, and 36 (37.1%) somatostatin analog therapy. At the end of the follow up, all patients were alive and there was no evidence of metastatic disease. Somatostatin analog therapy resulted in a complete response in 76.0% of the patients and stable disease in 24.0%. A prolonged period of therapy, the use of a full dose of somatostatin analogs and higher gastrin levels at diagnosis were related to a complete response to the therapy. The recurrence rate was 26.3% in patients treated with somatostatin analog therapy and 26.2% in patients treated with endoscopic resection, without a statistically significant difference in terms of disease-free survival. Regarding recurrence of the disease, no statistical difference was found according to type of therapy, number of neoplastic lesions, and 2010 WHO classification. The only risk factor for tumor recurrence was a short period of medical treatment. In conclusion, our study suggested that endoscopic surveillance, endoscopic resection and somatostatin analog therapy represent valid options in the management of patients with type I gastric neuroendocrine tumors in stages 0-2A. PMID- 25814128 TI - A systematic review of training that use an integrated patient simulator. AB - The purpose of this article is to systematically review the literature that describes training and assessment that use an integrated patient simulator (IPS). We also tried to determine how to train learners with simulators, plan, and perform research on simulator-based education. Literature searches were conducted to identify articles from PubMed, EMBASE, and KMbase that were related to training and assessment that use an IPS, published from January 1999 to September 2008. Forty articles met the criteria and were analyzed. The results were as follows: Studies on IPS are the most common in graduate medical education (GME). The impact of IPS-based education is relatively greater in GME versus undergraduate medical education (UME) or continuing medical education (CME). IPS research in GME is characterized by addressing the effectiveness of clinical application, the training of procedures, and algorithms, rather than knowledge or simple skills. And research design is more elaborate in GME than UME or CME. IPS training in CME focuses mostly on specific clinical skills. Most training sessions in UME are offered to groups, but assessment is performed for a single student. Also, inter-rater reliability is checked unsatisfactorily in UME. IPS research in UME is characterized by limitations in design due to connections to the regular curriculum. According to findings above, we propose that: more detailed research design should be performed to overcome the limitations of UME research. For GME, increasing simulator-based training opportunities is desired, because its effectiveness and adaptability are relatively high. PMID- 25814129 TI - Correlations of Communication and Interpersonal Skills between Medical Students and Residents. AB - PURPOSE: Medical students' communication and interpersonal skills can be evaluated by standardized patients in a clinical performance examination (CPX). The purpose of this study is to investigate which communication and interpersonal skills are more closely correlated between medical students and residents. METHODS: This study included 2nd-year residents in 2009 who took the eight station CPX as 4th-year medical students in 2006. In-patients who were cared for by the residents were asked the seven items related to interpersonal and communication skills. The correlation between the scores of these seven items in the 2006 CPX and the scores in the 2009 patient survey was evaluated. RESULTS: Twenty-six residents, 11 in medical wards and 15 in surgical wards, participated in the study. The medical students' total scores tended to be correlated with the residents' scores (r=0.381, p=0.055). There was significant correlation between the scores for students and residents for 'Explaining more explicably' (r=0.470, p=0.015), and marginally significant correlation (r=0.385, p=0.052) for 'Listening attentively.' There was no significant correlation for the other five items. CONCLUSION: 'Explaining more explicably' and 'Listening attentively', these skills were more closely correlated between medical students and residents. These basic communication skills should be included in graduate or licensing evaluations. PMID- 25814130 TI - Impacts of problem-based professionalism course in dental education. AB - PURPOSE: This study explores the effects of a professionalism course based on problem-based learning (PBL) for 2nd year dental students on professional role concept and on ethical reasoning. It also investigates students' attitudes toward professionalism development program. METHODS: The experimental group (n=36) participated in the 5-week professionalism course, which uses PBL approach while the control group (n=89) did not receive the professionalism instruction during the same period. The professionalism development program was implemented via discussions among students in small-group tutorial. Four professors, who served as group facilitators participated in faculty seminars before every tutorial. After each tutorial, students had to write essays on the cases they discussed in their groups. Both groups completed Professional Role Orientation Inventory and Defining Issue Test (KDIT) prior to and post intervention period. The experimental group also responded to questionnaires about the value of professionalism program. RESULTS: Analysis of covariance indicated that the experimental group's responsibility score significantly improved (F=32.552, p<0.001) while their perception of agency decreased (F=29.510, p<0.001). The program had little influence on ethical reasoning measured by DIT. Twenty-eight students (78%) responded that they learned the value of other opinions. Seventy percent of the students responded that the course is worthwhile or very worthwhile. CONCLUSION: The result reveals that students' professional role concept is associated with the learning experience in professionalism program based on PBL. Opportunities to think of professionalism in clinical situations improved students' sense of responsibility as dentist. PMID- 25814131 TI - Breast examination instruction by a standardized patient instructor. AB - PURPOSE: The purpose of this research was to identify the effectiveness of a standardized patient (SP) instructor. The study was performed to compare the effects of two types of instruction on breast examination skills by an SP instructor and a professor. METHODS: Fifty-four medical students in the third year and 4 SPs participated in the study. In a pretest, each student was judged by the SP individually in performing a breast examination and completed a questionnaire about perception. Next, students were randomly assigned to 2 experimental groups (small-group instruction by an SP instructor or professor). A posttest of performance and perception was administered using the same procedures as in the pretest. To identify the effectiveness of the SP instructor, differences in student scores between the groups were analyzed by t-test. RESULTS: In the posttest of student performance on the breast examination, there was no significant difference between the groups (p=0.270). With regard to student perception, scores on self-confidence in the breast examination were significantly different (p=0.026) between the groups, of which students who received instruction from the professor showed a higher level. Additionally, there was a significant effect on students' perceived reliability of instruction by the SP instructor (p=0.011), and students who were instructed by the SP demonstrated higher reliability compared with professor-taught students. CONCLUSION: Instruction by an SP instructor has the same effectiveness as instruction by a professor. SP instructors have very powerful effects on student performance and perception. PMID- 25814132 TI - Content Analysis of Standardized-Patients' Descriptive Feedback on Student Performance on the CPX. AB - PURPOSE: The goal of this study was to explore what kind of additional information is provided by the descriptive comments other than the rating scales, on the physician-patient interaction (PPI) in the clinical performance examination (CPX) and its feedback role in identifying students' strengths and weaknesses in communication skills. METHODS: The data were collected from 18 medical schools in Seoul and Gyeonggi region, which participated in the CPX for fourth-year medical students in 2006 and 2007. In total 12,650 examination cases in 2006 and 12,814 cases in 2007 were analyzed. Descriptive comments from the standardized patients (SPs) were analyzed by content analysis, which includes a 4 step process: coding, conceptualizing, categorizing and explanation. RESULTS: Ten categories (41 concepts) for 'strength' and 11 for 'weakness' (40 concepts) in the PPI were extracted. Among them, 10 categories were the same in both strength and weakness: providing adequate interview atmosphere, attentive listening, providing emotional support, non-verbal behaviors, professional attitude, questioning, explanation, reaching agreement, counseling & education and conducting adequate physical examination. For the 'structured and organized interview', only weakness was described. In 'providing emotional support' and 'adequate interview atmosphere', comments on strengths were more frequently mentioned than weaknesses. However, communication skills that were related to non verbal behaviors were more frequently considered weaknesses rather than strengths. The numbers and content of the SP's comments on students' strengths and weaknesses in the PPI varied depending on the case specificities. CONCLUSION: The results suggest that the SPs' descriptive comments on student' performance on the CPX can provide additional information versus structured quantitative assessment tools such as performance checklists and rating scales. In particular, this information can be used as valuable feedback to identify the advantages and dicadvantages of the PPI and to enhance students' communication skills. PMID- 25814133 TI - Effect of patient safety education in surgical clerkship to develop competencies for managing and preventing medical errors. AB - PURPOSE: The aims of this study were to define the necessity and effectiveness of patient safety education during surgical clerkship to develop competency for managing and preventing medical errors. METHODS: Fifty 3rd-year students participated in the patient safety education program during a 4-week surgical clerkship. The students were divided into 4 groups: control group, pretest-only group, education-only group, and pretest and education group. Students were assessed using short essays and an oral exam for reasoning skills, clinical performance exams for patient education and communication skills, and multisource feedback and direct observation of error reporting for real-world problem-solving skills. The results were analyzed with SPSS 14.0K. The reliability (Cronbach alpha) of the entire assessment was 0.893. RESULTS: There was no difference in scores between early and late clerkship groups. Reasoning skills were improved by the pretest. Reasoning, patient education, and error reporting skills were much more developed by patient safety education. Real-world error identification, reporting, and communication did not change after the 4-week course. CONCLUSIONS: Patient safety education during surgical clerkship is necessary and effective. Error prevention and competency management in the real world should developed. PMID- 25814134 TI - Exploration of a leadership competency model for medical school faculties in Korea. AB - PURPOSE: To adapt to rapid and turbulent changes in the field of medicine, education, and society, medical school faculties need appropriate leadership. To develop leadership competencies through education, coaching, and mentoring, we need a leadership competency model. The purpose of this study was to develop a new leadership competency model that is suitable for medical school faculties in Korea. METHODS: To collect behavioral episodes with regard to leadership, we interviewed 54 subjects (faculties, residents, nurses) and surveyed 41 faculties with open-ended questionnaires. We classified the behavioral episodes based on Quinn and Cameron's leadership competency model and developed a Likert scale questionnaire to perform a confirmatory factor analysis. Two hundred seven medical school faculties responded to the questionnaire. RESULTS: The competency clusters that were identified by factor analysis were professionalism, citizenship, leadership, and membership to an organization. Accordingly, each cluster was linked with a dimension: self, society, team (that he/she is leading), and organization (to which he/she belongs). The clusters of competencies were: professional ability, ethics/morality, self-management, self development, and passion; public interest, networking, social participation, and active service; motivating, caring, promoting teamwork, nurturing, conflict management, directing, performance management, and systems thinking; organizational orientation, collaboration, voluntary participation, and cost benefit orientation. CONCLUSION: This competency model that fits medical school faculties in Korea can be used to design and develop selection plans, education programs, feedback tools, diagnostic evaluation tools, and career plan support programs. PMID- 25814135 TI - Where can I find the free item analysis program based on item response theory, computer-based testing and computerized adaptive testing? PMID- 25814136 TI - Medical education: past, present, and future. PMID- 25814138 TI - Erratum to: behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D2 receptor mutant mice. PMID- 25814137 TI - 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons. AB - RATIONALE: The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown. OBJECTIVES: We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means. RESULTS: The cannabinoid receptor type 1 (CB1) antagonist SR141716 (3 mg/kg) caused an increase in conditioned freezing upon repeated tone presentation on three consecutive days. The cannabinoid receptor type 2 (CB2) antagonist AM630 (3 mg/kg), in contrast, had opposite effects during the first tone presentation, with no effects of the transient receptor potential vanilloid receptor type 1 (TRPV1) antagonist SB366791 (1 and 3 mg/kg). Administration of the CB2 agonist JWH133 (3 mg/kg) failed to affect the acute freezing response, whereas the CB1 agonist CP55,940 (50 MUg/kg) augmented it. The endocannabinoid uptake inhibitor AM404 (3 mg/kg), but not VDM11 (3 mg/kg), reduced the acute freezing response. Its co-administration with SR141716 or SB366791 confirmed an involvement of CB1 and TRPV1. AEA degradation inhibition by URB597 (1 mg/kg) decreased, while 2-AG degradation inhibition by JZL184 (4 and 8 mg/kg) increased freezing response. As revealed in conditional CB1-deficient mutants, CB1 on cortical glutamatergic neurons alleviates whereas CB1 on GABAergic neurons slightly enhances fear expression. Moreover, 2-AG fear promoting effects depended on CB1 signaling in GABAergic neurons, while an involvement of glutamatergic neurons remained inconclusive due to the high freezing shown by vehicle-treated Glu-CB1-KO. CONCLUSIONS: Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons. PMID- 25814140 TI - Nanoscale determination of the mass enhancement factor in the lightly doped bulk insulator lead selenide. AB - Bismuth chalcogenides and lead telluride/selenide alloys exhibit exceptional thermoelectric properties that could be harnessed for power generation and device applications. Since phonons play a significant role in achieving these desired properties, quantifying the interaction between phonons and electrons, which is encoded in the Eliashberg function of a material, is of immense importance. However, its precise extraction has in part been limited due to the lack of local experimental probes. Here we construct a method to directly extract the Eliashberg function using Landau level spectroscopy, and demonstrate its applicability to lightly doped thermoelectric bulk insulator PbSe. In addition to its high energy resolution only limited by thermal broadening, this novel experimental method could be used to detect variations in mass enhancement factor at the nanoscale level. This opens up a new pathway for investigating the local effects of doping and strain on the mass enhancement factor. PMID- 25814141 TI - Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings. AB - Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients. PMID- 25814143 TI - Monash editorial. PMID- 25814144 TI - Concurrent urologic and palliative care after cystectomy for treatment of muscle invasive bladder cancer. AB - PURPOSE: To characterize the effect of palliative care provided concurrently with usual urologic care for patients with bladder cancer undergoing cystectomy. MATERIALS AND METHODS: Prospective, 6-month, serial cohort study comparing 33 participants receiving usual care with cystectomy for muscle-invasive bladder cancer, with 30 participants also receiving concurrent palliative care. Patients and family caregivers completed validated symptom assessment and satisfaction surveys preoperatively and at 2, 4, and 6 months postoperatively. RESULTS: The intervention group saw improvements in most symptom measures over the 6 months following cystectomy compared with the control group. Depression and anxiety decreased over the 6-month period for the intervention group patients but increased over this time among the controls (P = 0.01). Fatigue decreased to a minimum for the intervention group participants at 4 months, whereas it peaked at this time for control participants (0.002). Quality-of-life and posttraumatic growth scores followed a similar pattern, with scores peaking at 4 months for the intervention group whereas controls reported their lowest scores at this time (P = 0.01 and P = 0.03, respectively). Changes in pain scores did not reach statistical significance. Neither family caregiver burden nor patient satisfaction showed statistically significant changes over time. CONCLUSIONS: Patients who received concurrent palliative care in addition to usual urologic care following radical cystectomy for muscle-invasive bladder cancer had better outcomes, including improved fatigue, depression, quality of life, and posttraumatic growth. Although further research on this topic is needed, our results suggest that providing palliative care services in addition to usual urologic care for patients with bladder cancer may significantly reduce postoperative symptoms. PMID- 25814142 TI - Neonatal Levels of T-cell Receptor Excision Circles (TREC) in Patients with 22q11.2 Deletion Syndrome and Later Disease Features. AB - PURPOSE: Newborns with severe T-cell lymphopenia, including those with 22q11.2 deletion syndrome (DS), have low numbers of T-cell receptor excision circles (TRECs). The aim of this study was to determine a possible correlation between neonatal TRECs in 22q11.2DS and the development of different phenotypes to elucidate the prognostic value of TREC in this disease. METHODS: In this national survey including 46 patients with 22q11.2DS born after 2005, TREC levels were determined using stored newborn screening blood spots on filter cards. Patients were grouped into quartiles according to their TREC values, except the two infants with thymus aplasia. RESULTS: The two patients with thymic aplasia had no detectable TREC. The rest had no severe clinical immunodeficiency. There was a significant correlation between low TRECs and the proportion of patients with CD3(+)CD4(+)T-cells below the 5th percentile of healthy infants (p = 0.027) as well as the proportion with an abnormal thymus feature either no thymus or remnant thymus as observed during heart surgery (p = 0.022). Significantly lower TRECs (p = 0.019) were found in patients with cardiac defects compared to no such defects. Patients within the lowest quartile of TREC values (<71 TRECs/MUL, n = 11) had more frequent severe cardiac defects than the other quartiles (p = 0.010). Eight of these patients in the lowest quartile needed an operation/intervention within two weeks after birth or died because of a cardiac defect. CONCLUSION: The low TREC values not only correlate with decreased T-cell immunity, but also with the occurrence of heart defects in the patients. PMID- 25814147 TI - [Otorhinolaryngology thematic issue. Presentation]. PMID- 25814146 TI - The effect of age on functional outcomes after radical prostatectomy. AB - OBJECTIVES: As life expectancy increases, functional outcomes in elderly patients after radical prostatectomy (RP) become a more important factor to consider in treatment selection. The aim of this study was to determine age-dependent differences in functional outcomes after RP. PATIENTS AND METHODS: A total of 8,295 patients who underwent RP from January 2009 to July 2013 were analyzed. Univariate and multivariate logistic regressions were used to estimate the effect of age and other covariates on 3- and 12-month continence and potency rates. Continence was achieved if no more than one safety pad was used per day. Potency was defined as an international index of erectile function (IIEF)-5 score of 18 or higher. RESULTS: In the entire cohort, 12-month (3-mo) continence and potency rates were 91.0% (76.1%) and 54.6% (40.9%), respectively. The 1-year continence rates for age groups < 65, >= 65 and < 70, >= 70 and < 75, and >= 75 years were 93.2%, 90.8%, 86.0%, and 86.5%, respectively. The corresponding 1-year potency rates were 59.3%, 46.9%, 44.4%, and 31.3%. In both, univariate and multivariate analyses, older age had a significant negative effect on functional outcomes. Moreover, nerve sparing, pT category, and patients' body mass index were significantly associated with continence. Nerve sparing, pT category, patients' body mass index, and use of PDE5 inhibitor or intracavernous injection therapy significantly influenced potency. CONCLUSIONS: Older age has a significant adverse effect on recovery of continence and potency. Although functional outcomes in elderly patients and especially in patients aged 75 years or older are still good, they should be educated about the increased risk of incontinence and impotence after RP. PMID- 25814145 TI - Gemcitabine and cisplatin neoadjuvant chemotherapy for muscle-invasive urothelial carcinoma: Predicting response and assessing outcomes. AB - PURPOSE: To evaluate gemcitabine-cisplatin (GC) neoadjuvant cisplatin-based chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer and identify clinical parameters associated with pR. MATERIALS AND METHODS: We studied 150 consecutive cases of muscle-invasive bladder cancer that received GC NAC followed by open RC (2000-2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance. RESULTS: No significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non-muscle invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (P = 0.99). NAC pR (<= pT1) demonstrated improved 5 year CSS rates (90.6% vs. 27.1%, P < 0.01) and decreased nodal positivity rates (0% vs. 41.3%, P<0.01) when compared with nonresponders (>= pT2). Clinicopathologic outcomes were inferior in NAC pathologic nonresponders when compared with the entire RC-only-treated cohort. A lower pathologic nonresponder rate was seen in patients tolerating sufficient dosing of NAC as stratified by the Johns Hopkins Hospital Dose Index (P = 0.049), congruent with the National Comprehensive Cancer Network guidelines. A multivariate classification tree model demonstrated 60 years of age or younger and clinical stage cT2 as significant of NAC response (P< 0.05). CONCLUSIONS: Pathologic nonresponders fare worse than patients proceeding directly to RC alone do. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients who are most likely to benefit from GC NAC. PMID- 25814148 TI - [The main points of the otorhinolaryngology special issue]. PMID- 25814149 TI - Doctors must speak out about adverse effects on health of austerity and extremism, conference hears. PMID- 25814150 TI - Supervising culturally and linguistically diverse (CALD) nursing students: A challenge for clinical educators. AB - This paper presents and discusses the challenges faced by a group of clinical educators in teaching and assessing nursing students from culturally and linguistically diverse (CALD) backgrounds in Australian English-speaking hospitals. A questionnaire was administered to eight university-appointed clinical educators external to the clinical venues in order to find out what issues they had experienced with CALD students and how they had responded to them. The educators' responses were contextualised with the perspectives of 19 CALD students who responded to a student questionnaire, and analysed using Yoder's (1996) framework of instructional responses to ethnically diverse students. It was found that the clinical educators encountered difficulties in responding to CALD students with an instructional response that was not patronising, assimilationist or demeaning for the students. The findings suggest that most educators would have benefitted from targeted support by the school of nursing to develop a pedagogically appropriate approach to interacting with CALD students. This study points to the need for continuing education in cross cultural communication for nurses working in clinical education roles and provides ideas to this respect that build on CALD students' strengths and participants' suggestions. PMID- 25814151 TI - Test-retest reliability of the Clinical Learning Environment, Supervision and Nurse Teacher (CLES + T) scale. AB - The Clinical Learning Environment, Supervision and Nurse Teacher (CLES + T) scale evaluates the student nurses' perception of the learning environment and supervision within the clinical placement. It has never been tested in a replication study. The aim of the present study was to evaluate the test-retest reliability of the CLES + T scale. The CLES + T scale was administered twice to a group of 42 student nurses, with a one-week interval. Test-retest reliability was determined by calculations of Intraclass Correlation Coefficients (ICCs) and weighted Kappa coefficients. Standard Error of Measurements (SEM) and Smallest Detectable Difference (SDD) determined the precision of individual scores. Bland Altman plots were created for analyses of systematic differences between the test occasions. The results of the study showed that the stability over time was good to excellent (ICC 0.88-0.96) in the sub-dimensions "Supervisory relationship", "Pedagogical atmosphere on the ward" and "Role of the nurse teacher". Measurements of "Premises of nursing on the ward" and "Leadership style of the manager" had lower but still acceptable stability (ICC 0.70-0.75). No systematic differences occurred between the test occasions. This study supports the usefulness of the CLES + T scale as a reliable measure of the student nurses' perception of the learning environment within the clinical placement at a hospital. PMID- 25814152 TI - Does the difference between PART and Alzheimer's disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Abeta and propagation of tau? PMID- 25814154 TI - Dendrimer-encapsulated Pd nanoparticles as catalysts for C-C cross-couplings in flow microreactors. AB - The inner walls of glass microreactors were functionalized with dendrimer encapsulated Pd nanoparticles. The catalysts were efficient for the Heck-Cassar (copper-free Sonogashira) and Suzuki-Miyaura (SMC) cross-coupling reactions. For the Heck-Cassar reaction between iodobenzene and phenylacetylene, the catalytic system exhibited a high turnover frequency (TOF) and on average required milder reaction conditions as compared to other continuous flow cross-couplings. A study of the substituent effect of para-substituted aryl halides revealed a beneficial effect of electron-withdrawing side groups for the SMC. Moreover, a reaction constant (rho) of 1.5, determined from the Hammett plot, indicated a possible rate-determining step other than the oxidative addition. PMID- 25814153 TI - Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin alpha-4-transduced outside-in signalling. AB - Human brain microvascular endothelial cells forming the blood-brain barrier (BBB) release soluble vascular cell adhesion molecule-1 (sVCAM-1) under inflammatory conditions. Furthermore, sVCAM-1 serum levels in untreated patients with multiple sclerosis (MS) correlate with a breakdown of the BBB as measured by gadolinium enhanced MRI. To date, it is unknown whether sVCAM-1 itself modulates BBB permeability. Here, we provide evidence that human brain endothelium expresses integrin alpha-4/beta-1, the molecular binding partner of sVCAM-1, and that sVCAM 1 directly impairs BBB function by inducing intracellular signalling events through integrin alpha-4. Primary human brain microvascular endothelial cells showed low to moderate integrin alpha-4 and strong beta-1 but no definite beta-7 expression in vitro and in situ. Increased brain endothelial integrin alpha-4 expression was observed in active MS lesions in situ and after angiogenic stimulation in vitro. Exposure of cultured primary brain endothelial cells to recombinant sVCAM-1 significantly increased their permeability to the soluble tracer dextran, which was paralleled by formation of actin stress fibres and reduced staining of tight junction-associated molecules. Soluble VCAM-1 was also found to activate Rho GTPase and p38 MAP kinase. Chemical inhibition of these signalling pathways partially prevented sVCAM-1-induced changes of tight junction arrangement. Importantly, natalizumab, a neutralising recombinant monoclonal antibody against integrin alpha-4 approved for the treatment of patients with relapsing-remitting MS, partially antagonised the barrier-disturbing effect of sVCAM-1. In summary, we newly characterised sVCAM-1 as a compromising factor of brain endothelial barrier function that may be partially blocked by the MS therapeutic natalizumab. PMID- 25814155 TI - Liver injury is uncommon in chronic gastrointestinal ischemia. PMID- 25814156 TI - Sperm DNA fragmentation, recurrent implantation failure and recurrent miscarriage. AB - Evidence is increasing that the integrity of sperm DNA may also be related to implantation failure and recurrent miscarriage (RM). To investigate this, the sperm DNA fragmentation in partners of 35 women with recurrent implantation failure (RIF) following in vitro fertilization, 16 women diagnosed with RM and seven recent fathers (control) were examined. Sperm were examined pre- and post density centrifugation by the sperm chromatin dispersion (SCD) test and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. There were no significant differences in the age of either partner or sperm concentration, motility or morphology between three groups. Moreover, there were no obvious differences in sperm DNA fragmentation measured by either test. However, whilst on average sperm DNA fragmentation in all groups was statistically lower in prepared sperm when measured by the SCD test, this was not seen with the results from the TUNEL assay. These results do not support the hypothesis that sperm DNA fragmentation is an important cause of RIF or RM, or that sperm DNA integrity testing has value in such patients. It also highlights significant differences between test methodologies and sperm preparation methods in interpreting the data from sperm DNA fragmentation tests. PMID- 25814157 TI - Roles of the Y chromosome genes in human cancers. AB - Male and female differ genetically by their respective sex chromosome composition, that is, XY as male and XX as female. Although both X and Y chromosomes evolved from the same ancestor pair of autosomes, the Y chromosome harbors male-specific genes, which play pivotal roles in male sex determination, germ cell differentiation, and masculinization of various tissues. Deletions or translocation of the sex-determining gene, SRY, from the Y chromosome causes disorders of sex development (previously termed as an intersex condition) with dysgenic gonads. Failure of gonadal development results not only in infertility, but also in increased risks of germ cell tumor (GCT), such as gonadoblastoma and various types of testicular GCT. Recent studies demonstrate that either loss of Y chromosome or ectopic expression of Y chromosome genes is closely associated with various male-biased diseases, including selected somatic cancers. These observations suggest that the Y-linked genes are involved in male health and diseases in more frequently than expected. Although only a small number of protein-coding genes are present in the male-specific region of Y chromosome, the impacts of Y chromosome genes on human diseases are still largely unknown, due to lack of in vivo models and differences between the Y chromosomes of human and rodents. In this review, we highlight the involvement of selected Y chromosome genes in cancer development in men. PMID- 25814159 TI - From bench to bedside: bipolar androgen therapy in a pilot clinical study. AB - Prostate cancer remains a leading cause of cancer death in Europe and the United States and is an emerging problem in Asia despite significant improvements in available treatments over the last few decades. Androgen deprivation therapy (ADT) has been the core treatment of advance-staged disease since the discovery of prostate cancer's androgen dependence in 1941 by Huggins et al. [1] Options for initial medical treatment include gonadotropin-releasing hormone analogues such as leuprolide (LHRH agonist) and degarelix (LHRH antagonist) and androgen receptor (AR) binding agents such as bicalutamide. Although most patients will initially respond to either surgical or medical castration, there is almost always progression to castration-resistant prostate cancer (CRPC) necessitating treatment with more novel agents. [2] However, even drugs such as abiraterone and enzalutamide, two next-generation agents used commonly in metastatic CRPC, have failed to demonstrate persistent efficacy in most patients. [3] ,[4]. PMID- 25814158 TI - The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis. AB - The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring. PMID- 25814160 TI - A new simple technique of epididymal sperm collection for obstructive azoospermia. PMID- 25814161 TI - Comment on reversal of hypogonadotropic hypogonadism in a Chinese cohort. PMID- 25814162 TI - First finding of spontaneous infections with Cryptosporidium baileyi and C. meleagridis in the red-legged partridge Alectoris rufa from an aviary in the Czech Republic. AB - This paper represents the first report of spontaneous infection with Cryptosporidium baileyi and Cryptosporidium meleagridis in the red-legged partridge (Alectoris rufa), as well as the percentage of positive samples and age associated dynamics of cryptosporidial infections in an aviary in the Czech Republic. The entire infection process was monitored over two semesters (July December 2012 and 2013) until release of birds for hunting purposes. Coprological examination of 663 pooled fecal samples and 89 post-mortem examinations of red legged partridges were carried out. Our results indicated that infections with C. baileyi only occurred in 5-7 week-old birds during 2013 (percentage of positivity, 1%) and those with C. meleagridis in 18-22 week (17%) and 17-21 week old birds (24%) during 2012 and 2013, respectively. Molecular characterization of isolates of C. baileyi and C. meleagridis heat shock protein 70 and actin genes were analyzed in order to support our coprological results. DNA sequence analysis of the 60kDa glycoprotein gene was used to subtype C. meleagridis. Our findings extend the host range for C. baileyi. PMID- 25814163 TI - Activity of ceftaroline and comparator agents tested against Staphylococcus aureus from patients with bloodstream infections in US medical centres (2009-13). AB - OBJECTIVES: The objective of this study was to evaluate the in vitro antimicrobial activity of ceftaroline and comparator agents tested against Staphylococcus aureus isolates causing bloodstream infection (BSI). METHODS: A total of 4426 S. aureus isolates from patients with BSI were collected in 150 medical centres in the USA in 2009-13 and tested for susceptibility to ceftaroline and comparators by the CLSI broth microdilution method. RESULTS: Overall, 45.5% of isolates were MRSA. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.9% of S. aureus isolates at <=1 mg/L (highest MIC, 2 mg/L). Daptomycin (MIC50/90, 0.25/0.5 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L) were active against >=99.8% of isolates at the respective susceptible breakpoints. Susceptibility rates for clindamycin (MIC50/90, <=0.25/>2 mg/L) and levofloxacin (MIC50/90, <=0.5/>4 mg/L) were 80.8% and 59.2%, respectively. Against MSSA, ceftaroline (MIC50/90, 0.25/0.25 mg/L; 100.0% susceptible) was 16-, 4-8- and 4-fold more active in vitro (based on MIC50/90) than ceftriaxone (MIC50/90, 4/4 mg/L), linezolid (MIC50/90, 1/2 mg/L) and vancomycin (MIC50/90, 1/1 mg/L), respectively, and slightly more potent than daptomycin (MIC50/90, 0.25/0.5 mg/L). When tested against MRSA, ceftaroline was active against 95.4% and 100.0% of isolates at <=1 and <=2 mg/L, respectively. Moreover, ceftaroline retained significant activity against S. aureus with reduced susceptibility to vancomycin, daptomycin, clindamycin, levofloxacin and trimethoprim/sulfamethoxazole. CONCLUSIONS: Ceftaroline demonstrated potent in vitro activity when tested against a large collection of contemporary (2009-13) S. aureus isolates causing BSI in US hospitals. PMID- 25814164 TI - Associations between individual and relationship characteristics and genital herpes disclosure. AB - Disclosure is often a challenge for individuals living with genital herpes. This study explores determinants of genital herpes disclosure with one's most recent sexual partner using an online questionnaire (n = 93). The majority of participants reported (80.4%) disclosure. Among non-disclosers, fear of negative partner reactions was the primary reason for non-disclosure. Age, relationship commitment, time in relationship, and expectations of partner's reaction were statistically significant predictors at the bivariate level. Reaction expectations and relationship commitment remained significant in the multivariate logistic regression model. Findings indicate that future disclosure research should focus on relationship context and managing negative expectations to increase disclosure. PMID- 25814166 TI - A dual-responsive supra-amphiphile based on a water-soluble pillar[7]arene and a naphthalene diimide-containing guest. AB - A dual-responsive supra-amphiphile was firstly constructed based on a water soluble pillar[7]arene and a naphthalene diimide-containing guest with a long alkyl chain and a trimethylammonium group. The morphologies of the self-assembly formed from this supra-amphiphile could be adjusted by changing solution pH or adding alpha-cyclodextrin. PMID- 25814165 TI - The five-factor model of personality and self-reported versus biomarker diabetic control. AB - Five-factor personality was examined as an element of self-report diabetic control accuracy versus biomarker control (HbA1c) for 1474 diabetics in the 2006 and 2008 Health and Retirement Study. Correlations of extraversion and self reported control (r = -.06, p < .01), and extraversion and HbA1c (r = .03, non significant), were significantly different (t = 2.87, p < .01). Correlations of openness and self-reported control (r = -.05, p < .05), and openness and HbA1c (r = .01, non-significant), were significantly different (t = 1.91, p < .05). Associations were found between self-reported control and conscientiousness (r = .05, p < .05), neuroticism (r = .04, p < .05), and openness (r = -.05, p < .05). Neuroticism was associated with self-reports that diabetes was worse (r = .07, p < .01). Other correlations and comparisons were non-significant. PMID- 25814167 TI - Lipoxins exert antiangiogenic and anti-inflammatory effects on Kaposi's sarcoma cells. AB - Lipoxin A4 (LXA4) is an endogenously produced host molecule with anti inflammatory resolution effects. Previous studies demonstrated it to be involved in anti-vascular endothelial growth factor (VEGF)-mediated angiogenesis and in a possible anticancer role via interaction with its receptor, lipoxin A 4 receptor (ALXR). Here, we examined the effects of LXA4 and its epimer 15-epi-LXA4 in inhibiting proinflammatory and angiogenic functions in a human Kaposi's sarcoma tumor-derived cell line (KS-IMM). KS-IMM cells expressed increased levels of inflammatory cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LO) pathway enzymes when compared with human microvascular dermal endothelial cells (HMVEC-d). KS-IMM cells secreted high levels of prostaglandin E2 (PGE2) and chemotactic leukotriene B4 (LTB4). Treatment with LXA4 or 15-epi-LXA4 effectively reduced the levels of COX-2, 5-LO proteins, and secretion of PGE2 and LTB4 in KS-IMM cells. LXA4 or 15 epi-LXA4 treatment also decreased secretion of proinflammatory interleukin 6 (IL 6) and IL-8 cytokines but induced the secretion of anti-inflammatory IL-10. LXA4 treatment reduced the phosphorylation of VEGF receptor (VEGFR) and ephrin family receptor tyrosine kinases. LXA4 treatment effectively induced dephosphorylation of multiple cellular kinases such as Focal Adhesion Kinase, Protein kinase B, nuclear factor kappa-light-chain-enhancer of activated B cells, and Extracellular signal-regulated kinases (ERK)1/2, and reduced angiogenic factor VEGF-C secretion in KS cells. LX treatment drastically induced the Src-homology 2 domain containing phosphatase tyrosine (Y542) phosphatase and reduced VEGFR-2 phosphorylation at sites Y1059, Y1175, and Y1212. Treatment of KS-IMM cells with LXA4 resulted in selective localization of VEGFR-2 in nonlipid raft (non-LR) and ALXR to LR fractions. These results demonstrated that LXA4 or 15-epi-LXA4 induce anti-inflammatory and antiangiogenic effects in KS cells and suggest that treatment with LXs is an attractive novel strategy against KS. PMID- 25814168 TI - Polycystic ovary syndrome (PCOS): metformin. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is classically characterised by an accumulation of incompletely developed follicles in the ovaries due to anovulation. However, since the publication of the Rotterdam criteria, there is acceptance that menstrual cycle and endocrine dysfunction with hyperandrogenism is more important in reaching the diagnosis than ultrasound findings. It is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole varies from 10% to 20%, depending on which diagnostic criteria are used. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of metformin on hirsutism and menstrual frequency in women with PCOS? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: metformin compared with placebo/no treatment, metformin compared with weight loss intervention, or metformin compared with cyproterone acetate-ethinylestradiol. PMID- 25814170 TI - Founder mutation causes classical Fukuyama congenital muscular dystrophy (FCMD) in Chinese patients. AB - PURPOSE: Fukuyama congenital muscular dystrophy (FCMD) is a congenital muscular dystrophy rarely reported outside Japan. Here, we report three patients with Fukuyama congenital muscular dystrophy (FCMD) in China who shared a similar clinical phenotype and 3-kb insertion in the FKTN 3' untranslated region. METHODS: Immunofluorescence staining was undertaken on muscle biopsies from three patients using alpha dystroglycan antibody (IIH6). Genomic DNA from patients and parents was extracted from peripheral blood leukocytes. Polymerase chain reaction and DNA sequencing were employed to analyze the exons and surrounding intron sequences of the fukutin (FKTN) gene to detect mutations. Haplotype analysis was also performed on each patient and their parents. RESULTS: All patients had delayed mental and motor development, febrile convulsions, muscle weakness, and moderate to significant raised levels of serum creatine kinase (7000-11,160 U/L, 25-60*normal). Brain MRI scans showed micropolygyria and extensive dysplasia in the white matter and brainstem. Electromyography revealed myopathic changes. Muscle immunofluorescence studies demonstrated reduced IIH6 staining. Genetic testing showed compound heterozygous mutations of FKTN. Cases 1 and 2 had a c.139C>T (p.Arg47(*)) heterozygous mutation. Case 3 had a c.346C>T (p.Gln116(*)) heterozygous mutation. CONCLUSION: All patients had a heterozygous 3-kb insertion in the FKTN 3' untranslated region. Haplotype analyses suggested that these patients had the same haplotype as Japanese patients. PMID- 25814171 TI - [Aerobic capacity and quality of life in school children from 8 to 12]. AB - Aerobic capacity is a powerful physiological indicator of the overall health status. The objective of this study was to analyse the relationship between aerobic capacity and quality of life in a sample of 298 (159 girls) school children aged 8-12 years. Aerobic capacity was tested using the Course-Navette test. Quality of life was assessed using the KIDSCREEN-10 Index scale. Males showed higher performance in the Course-Navette test and highest values of VO2max (P<.001 for both). ANOVA statistical analysis showed that the quality of life was significantly higher in school children with increased level of aerobic capacity compared to those with a low level (P=.001). Children with high aerobic capacity showed higher quality of life scores in relation to their peers with low scores (P<.001). As for the females, significant differences were found among those with high aerobic capacity level and their peers low levels (P<.031). The results of this study suggest that school children with higher level of aerobic capacity show better results in the quality of life index. Long-term intervention studies are needed to verify if an aerobic capacity development programme may upgrade the quality of life of children and adolescents. PMID- 25814169 TI - Signatures of the Giant Pairing Vibration in the 14C and 15C atomic nuclei. AB - Giant resonances are collective excitation modes for many-body systems of fermions governed by a mean field, such as the atomic nuclei. The microscopic origin of such modes is the coherence among elementary particle-hole excitations, where a particle is promoted from an occupied state below the Fermi level (hole) to an empty one above the Fermi level (particle). The same coherence is also predicted for the particle-particle and the hole-hole excitations, because of the basic quantum symmetry between particles and holes. In nuclear physics, the giant modes have been widely reported for the particle-hole sector but, despite several attempts, there is no precedent in the particle-particle and hole-hole ones, thus making questionable the aforementioned symmetry assumption. Here we provide experimental indications of the Giant Pairing Vibration, which is the leading particle-particle giant mode. An immediate implication of it is the validation of the particle-hole symmetry. PMID- 25814172 TI - A novel method for selectively labelling olivocochlear collaterals in the rat. AB - Axons of olivocochlear neurons originate from the brainstem and project to the cochlea. A subpopulation, medial olivocochlear (MOC) neurons, also projects collateral branches to the cochlear nucleus. The precise targets of these collaterals are as yet unknown. Previous methods for labelling these collaterals include firstly, cochlear injections of retrograde tracers, but this is technically demanding and can also label afferent projections or secondly, labelling by injecting tracers into the nuclei of origin of MOC neurons. However, this latter method is non-specific because it also labels non-MOC projections. A technique was used to specifically label MOC collaterals, which involved injections of the tracer biocytin at the floor of the fourth ventricle and fixation 3 hours later. Biocytin injections resulted in labelled neurons in the ventral nucleus of the trapezoid body and rostral periolivary nucleus, confirming MOC axonal labelling. Labelled neurons in dorsal cochlear nucleus indicated labelling of the dorsal acoustic stria and these injections were discarded. After selective MOC labelling, collateral branches were found to innervate granule cell regions, medial edge and core of the ventral cochlear nucleus, as well as the dorsal cochlear nucleus, in agreement with previous data. Therefore we conclude that injections at the floor of the fourth ventricle provide a simple, rapid and specific technique for labelling the majority of MOC axons and their collaterals and this technique may assist in defining the precise neuronal targets of olivocochlear collaterals in cochlear nucleus. PMID- 25814174 TI - A fluorescent receptor for halide recognition: clues for the design of anion chemosensors. AB - The chemosensing properties of the polyaza-macrocycle 1-(6,7)-acridine-3,6,9,12 tetraaza-tridecaphane have been investigated by means of emission fluorescence spectroscopy, considering halide ions as substrates. As in the case of the free ligand, the fluorescence emission of the complexes is due to the acridinium species which are formed after photoinduced proton transfer reaction. The complexation constants have been obtained for the bi- and tri-protonated ligands in deoxygenated aqueous solutions. Two different emission behaviours have been observed varying the anion. Fluoride and chloride give rise to fluorescence enhancement whereas bromide and iodide strongly quench the emission. The macrocycle shows an unusual higher selectivity towards the chloride anion rather than fluoride. The fluorescence emission has been modelled considering a modified Stern-Volmer equation, taking into account the quenching effects of the largest anions, which can be considered negligible for fluoride and chloride anions. Ab initio calculations allow us to interpret the fluorescence emission of the complexes in terms of activation energy related to the proton transfer reaction responsible for the emission process. PMID- 25814173 TI - Monocyte and plasma expression of TAM ligand and receptor in renal failure: Links to unregulated immunity and chronic inflammation. AB - Chronic inflammation is increased in patients with chronic kidney disease (CKD) and contributes to cardiovascular morbidity and mortality. Specific immune mechanisms and pathways that drive and maintain chronic inflammation in CKD are not well described. The TAM ligands (Gas6 and protein S) and receptors (Axl and Mer) have been recently recognized as playing a prominent role in immune regulation. The receptors exist in both soluble and cell-bound forms; the soluble receptors (sAxl and sMer) are believed to compete with the bound receptors and thus inhibit their function. In this study, we determined the expression of cell bound and soluble TAM proteins in patients with CKD. CKD patients had significantly lower expression of Mer in monocytes, yet increased expression of soluble TAM receptors sAxl and sMer in plasma compared to controls. The metalloproteinase ADAM 17, responsible for cleavage of Mer to its soluble form, was increased in patient monocytes. Elevated levels of soluble TAM receptors were more evident in patients with progressive renal failure. These observations suggest that functional deficiency of TAM receptor-mediated regulation of inflammation may contribute to chronic inflammation in patients with CKD. PMID- 25814175 TI - Coronary thromboembolic acute myocardial infarction due to paroxysmal atrial fibrillation occurring after non-cardiac surgery. AB - Acute myocardial infarction is a well know precipitant of atrial fibrillation, but it is also becoming increasingly recognised that atrial fibrillation is a direct and indirect cause of acute myocardial infarction. Current guidelines do not recommend anticoagulation therapy in patients undergoing cardiac surgery who have a brief episode of atrial fibrillation lasting less than 48 h. However, recommendations for the management of atrial fibrillation following non-cardiac surgery are less clear. We describe the case of a 70-year-old man undergoing non cardiac surgery, who developed a short episode of perioperative atrial fibrillation and later presented with thromboembolic acute myocardial infarction due to a thrombotic occlusion of the right coronary artery. PMID- 25814176 TI - Vitamin D3 modulates the function of chicken macrophages. AB - Vitamin D3 is known to modulate both innate and adaptive immune responses in mammals, but there is little information on its effects on avian immune system cells. Here, we studied the effects of vitamin D3 on chicken macrophages. Chicken macrophages expressed vitamin D receptor (VDR) and lipopolysaccharide (LPS) stimulation increased their VDR expression. Macrophages were treated with 1,25(OH)2D3 in the presence or absence of Toll-like receptor ligands, such as LPS and Pam3CSK4. Subsequently, macrophage activation was assessed by measuring nitric oxide (NO) and expression of CXCL8 and interleukin (IL)-1beta. In addition, changes in major histocompatibility complex (MHC)-II and CD86 were examined. Treatment of cells with 1,25(OH)2D3 increased the ability of macrophages to respond to stimuli and produce NO, but vitamin D3 alone did not activate macrophages and resulted in the down-regulation of CD86, MHC-II, CXCL8 and IL-1beta. These findings suggest that vitamin D3 has an immunomodulatory role in chicken macrophages. PMID- 25814177 TI - An experimental fatigue study of a porous scaffold for the regeneration of articular cartilage. AB - The aim of this experimental study is to predict the long-term mechanical behavior of a porous scaffold implanted in a cartilage defect for tissue engineering purpose. Fatigue studies were performed by up to 100,000 unconfined compression cycles in a polycaprolactone (PCL) scaffold with highly interconnected pores architecture. The scaffold compliance, stress-strain response and hysteresis energy have been measured after different number of fatigue cycles, while the morphology has been observed by scanning electron microscopy at the same fatigue times. To simulate the growing tissue in the scaffold/tissue construct, the scaffold was filled with an aqueous solution of polyvinyl alcohol (PVA) and subjected to repeating cycles of freezing and thawing that increase the hydrogel stiffness. Fatigue studies show that the mechanical loading provokes failure of the dry scaffold at a smaller number of deformation cycles than when it is immersed in water, and also that 100,000 compressive dynamic cycles do not affect the scaffold/gel construct. This shows the stability of the scaffold implanted in a chondral defect and gives a realistic simulation of the mechanical performance from implantation of the empty scaffold to regeneration of the new tissue inside the scaffold's pores. PMID- 25814178 TI - Swelling significantly affects the material properties of the menisci in compression. AB - This study has evaluated the swelling of meniscal test samples associated with altered osmotic environments. Meniscal samples were cut and weighed, then placed in one of 3 solutions: deionized water, phosphate buffered saline (PBS) or 2* concentration PBS. The amount of swelling in meniscal samples was solution independent with average swelling greater than 20%. The effect of this swelling on the mechanical properties of the samples was evaluated under confined compression testing. Samples were measured using a photogrammetric technique at the time of sample preparation and again after 1h in PBS. Meniscal samples used for mechanical testing swelled on average 18% in thickness after 1h in isotonic PBS. Free-swollen tissue was 1/3 as stiff at equilibrium as those that were recompressed to their original thickness prior to testing. Secant moduli at peak stress were nine times greater in the recompressed samples than the free-swollen samples. Relaxation times were faster in swollen samples, indicating increased permeability compared to recompressed specimen. Swelling pressure in the tissue averaged 14.4kPa in isotonic PBS, identifying that the menisci are pre-stressed structures within the knee joint. Histological analysis identified that the quantity of swelling is related to both the osmotic pressure generated by proteoglycans and the local collagen architecture in the sample. This is the first study to quantify the amount and swelling in meniscal test samples. This swelling behavior significantly influences the properties of the tissue in compression and should be addressed in future mechanical testing and protocol development for the menisci. PMID- 25814180 TI - Three-dimensional intervertebral kinematics in the healthy young adult cervical spine during dynamic functional loading. AB - The objective of this study was to determine the intervertebral kinematics of the young, healthy cervical spine during dynamic, three-dimensional, functional loading. Intervertebral motion was characterized by the range of motion (ROM) and the helical axis of motion (HAM). Biplane radiographs of the cervical spine were collected at 30 images/s as 29 participants (20-35 yr) performed dynamic flexion?extension, axial rotation, and lateral bending. Vertebral motion (C1-T1 in flexion?extension, C3-T1 in lateral bending and axial rotation) was tracked with sub-millimeter accuracy using a validated volumetric model-based tracking process that matched subject-specific CT-based bone models to the radiographs. Flexion?extension ROM was smallest at the C2-C3 motion segment (12.7+/-2.6 degrees ) and largest at the C5-C6 motion segment (19.7+/-3.7 degrees ). During head lateral bending and axial rotation, the intervertebral bending ROM was greater than the rotation ROM at every motion segment. The HAM demonstrated differences among motion segments and among movements. During flexion?extension, the helical axis of motion was directed nearly perpendicular to the sagittal plane for the C2-C3 through C7-T1 motion segments. During lateral bending, the angle between the HAM and the transverse plane progressively increased from the C6-C7 motion segment (approximately +/-22 degrees ) to the C3-C4 motion segment (approximately +/-40 degrees ). During axial rotation, the angle between the transverse plane and the HAM was approximately +/-42 degrees at the C3-C4 through C5-C6 motion segments, and approximately +/-32 degrees at the C6-C7 motion segment. This study provides valuable reference data for evaluating the effects of age, degeneration, and surgical procedures on cervical spine kinematics during three-dimensional dynamic functional loading. PMID- 25814179 TI - Predicted loading on the menisci during gait: The effect of horn laxity. AB - Radiographic measurements have established a link between meniscus extrusion and meniscus degeneration as well as with knee osteoarthritis. The presented work combines medical imaging with motion capture data from two healthy female subjects to create subject specific knee models that predict tibio-menisco femoral contact forces and ligament forces during muscle driven simulations of barefoot gait. The developed computational models were used to explore the relationship between the extent of meniscal extrusion and biomechanical function by altering the laxity of the meniscal horn attachments during gait. The extrusion distance increased as laxity increased and the amount of contact force transferred through the menisci during gait decreased rapidly as the meniscal attachments became more lax. Horn attachment lengths that were 20% longer than MRI attachment lengths resulted in an almost complete loss of force transfer through the menisci during the gait cycle. Relatively small changes (2-3mm) in the lengths at which horn bundles first become taut, manifested in large changes in the capacity of the tissue to transmit forces. As meniscal horn attachment laxity increased from 80% to 120% of the MRI measured horn distance, medial meniscus extrusion increased 3.9mm for the first subject and 2.7mm for the second subject. For the same horn laxity changes, the percent of medial tibiofemoral contact force transmitted through the medial meniscus during early stance decreased from 51% to 8% and from 36% to 14% for the two subjects. The results of our study show that increased meniscal extrusion occurs with increased laxity of the meniscal tibia attachments and this increased laxity results in loss of meniscal function. PMID- 25814181 TI - Tradeoffs between impact loading rate, vertical impulse and effective mass for walkers and heel strike runners wearing footwear of varying stiffness. AB - Humans experience repetitive impact forces beneath the heel during walking and heel strike running that cause impact peaks characterized by high rates and magnitudes of loading. Impact peaks are caused by the exchange of momentum between the ground and a portion of the body that comes to a full stop (the effective mass) during the period of the impact peak. A number of factors can influence this exchange of momentum, including footwear stiffness. This study presents and tests an impulse-momentum model of impact mechanics which predicts that effective mass and vertical impulse is greater in walkers and heel strike runners wearing less stiff footwear. The model also predicts a tradeoff between impact loading rate and effective mass, and between impact loading rate and vertical impulse among individuals wearing footwear of varying stiffness. We tested this model using 19 human subjects walking and running in minimal footwear and in two experimental footpads. Subjects walked and ran on an instrumented treadmill and 3D kinematic data were collected. As predicted, both vertical impulse (walking: F(2,54)=52.0, p=2.6E-13; running: F(2,54)=25.2, p=1.8E-8) and effective mass (walking: F(2,54)=12.1, p=4.6E-5; running: F(2,54)=15.5, p=4.7E-6) increase in less stiff footwear. In addition, there is a significant inverse relationship between impact loading rate and vertical impulse (walking: r=-0.88, p<0.0001; running: r=-0.78, p<0.0001) and between impact loading rate and effective mass (walking: r=-0.88, p<0.0001; running: r=-0.82, p<0.0001). The tradeoff relationships documented here raise questions about how and in what ways the stiffness of footwear heels influence injury risk during human walking and running. PMID- 25814182 TI - Care Network for ST-elevation Myocardial Infarction: What Is the Ideal Catchment Area for Primary Angioplasty? PMID- 25814184 TI - Construction of amorphous TiO2/BiOBr heterojunctions via facets coupling for enhanced photocatalytic activity. AB - Facets coupled BiOBr with amorphous TiO2 composite photocatalysts are synthesized via an in situ direct growth approach under microwave irradiation. XRD, SEM and HRTEM characterizations indicate that the heterointerface between BiOBr and amorphous TiO2 occurs mainly on the {001} facets of BiOBr. BET and TEM verify that the heterojunctions possess higher specific surface areas and smaller amorphous TiO2 particle size than bare BiOBr and amorphous TiO2, exhibiting the inhibition function of BiOBr on the growth of TiO2 particles. XPS verifies the interaction between the two components. The degradation of methyl orange (MO) and phenol are used as the objective reaction to evaluate the photocatalytic activity of the as-prepared samples. The reaction rate constant of 15% TiO2/BiOBr composite is 3.4 times greater than that of pure BiOBr, which is attributed to its higher surface area, and efficient separation of photo-generated electron hole pairs between BiOBr and amorphous TiO2. PMID- 25814183 TI - Quality of Vitamin K Antagonist Anticoagulation in Spain: Prevalence of Poor Control and Associated Factors. AB - INTRODUCTION AND OBJECTIVES: To study the prevalence of poorly controlled vitamin K antagonist anticoagulation in Spain in patients with nonvalvular atrial fibrillation, and to identify associated factors. METHODS: We studied 1056 consecutive patients seen at 120 cardiology clinics in Spain between November 2013 and March 2014. We analyzed the international normalized ratio from the 6 months prior to the patient's visit, calculating the prevalence of poorly controlled anticoagulation, defined as < 65% time in therapeutic range using the Rosendaal method. RESULTS: Mean age was 73.6 years (standard deviation, 9.8 years); women accounted for 42% of patients. The prevalence of poorly controlled anticoagulation was 47.3%. Mean time in therapeutic range was 63.8% (25.9%). The following factors were independently associated with poorly controlled anticoagulation: kidney disease (odds ratio = 1.53; 95% confidence interval, 1.08 2.18; P = .018), routine nonsteroidal anti-inflammatory drugs (odds ratio = 1.79; 95% confidence interval, 1.20-2.79; P = .004), antiplatelet therapy (odds ratio = 2.16; 95% confidence interval, 1.49-3.12; P < .0001) and absence of angiotensin receptor blockers (odds ratio = 1.39; 95% confidence interval, 1.08-1.79; P = .011). CONCLUSIONS: There is a high prevalence of poorly controlled vitamin K antagonist anticoagulation in Spain. Factors associated with poor control are kidney disease, routine nonsteroidal anti-inflammatory drugs, antiplatelet use, and absence of angiotensin receptor blockers. PMID- 25814185 TI - Investigation of disinfection byproducts formation in ferrate(VI) pre-oxidation of NOM and its model compounds followed by chlorination. AB - This study investigated the effect of disinfection by-products (DBPs) formation in pre-oxidation with ferrate(VI) (Fe(VI)O4(2-), Fe(VI)) and relationship between subsequent chlorination of Suwannee river natural organic matter (SRNOM) and eight model compounds containing moieties of alcohol, aldehyde, amines, amino acids, and phenol. The DBPs studied were trihalomethanes (THMs), chloral hydrate (CH), haloacetonitriles (HANs), and trichloronitromethane (TCNM). When the interaction of Fe(VI) and SRNOM was independently examined at pH 7.0, a decrease was seen in dissolved organic carbon and in the hydrophobic and hydrophilic fractions of NOM. With the model compounds, the results showed that Fe(VI) pre oxidation and subsequent chlorination decreased the formation of THMs with most of the compounds except amines and glycine. The effect of Fe(VI) preoxidation on CH and HANs formation from model compounds varied and was dependent on ferrate doses. Fe(VI) pre-oxidation significantly enhanced TCNM formation, compared to without pre-oxidation, from subsequent chlorination of methylamine, dimethylamine and glycine and the formation increased with increasing doses of ferrate. Correlations of DBPs formation between SRNOM and model compounds were sought to identify the moieties involved in influencing the formation of DBPs. The generation of DBPs is described using the parent molecules and the kinetics and reaction products of Fe(VI)/chlorine oxidation. PMID- 25814186 TI - Effect of resveratrol on experimental non-alcoholic steatohepatitis. AB - Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) are increasing clinical problems for which effective treatments are required. The polyphenol resveratrol prevents the development of fatty liver disease in a number of experimental studies. We hypothesized that it could revert steatohepatitis, including hepatic inflammation and fibrosis, in an experimental NASH model. To induce hepatic steatohepatitis, a 65% fat, 2% cholesterol and 0.5% cholate (HFC) diet was fed to rats for 1 or 16 weeks, prior to treatment. Subsequently, the diet was supplemented with resveratrol (approx. 100mg/rat/day) to three intervention groups; week 2-4, 2-7 or 17-22. Treated animals were sacrificed at the end of each intervention period with appropriate control and HFC diet controls. Blood and liver were harvested for analysis. When commenced early, resveratrol treatment partially mitigated transaminase elevations, hepatic enlargement and TNFalpha induced protein-3 protein expression, but generally resveratrol treatment had no effect on elevated hepatic triglyceride levels, histological steatohepatitis or fibrosis. We observed a slight reduction in Collagen1alpha1 mRNA expression and no reduction in the mRNA expression of other markers of fibrosis, inflammation or steatosis (TGFbeta, TNFalpha, alpha2-MG, or SREBP-1c). Resveratrol metabolites were detected in serum, including trans resveratrol-3-O-sulphate/trans-resveratrol-4'-O-sulphate (mean concentration 7.9 MUg/ml). Contrary to the findings in experimental steatosis, resveratrol treatment had no consistent therapeutic effect in alleviating manifest experimental steatohepatitis. PMID- 25814187 TI - Hepatic steatosis after islet transplantation: Can ultrasound predict the clinical outcome? A longitudinal study in 108 patients. AB - Percutaneous intra-portal islet transplantation (PIPIT) is a less invasive, safer, and repeatable therapeutic option for brittle type 1 diabetes, compared to surgical pancreas transplantation. Hepatic steatosis is a consequence of the islet engraftment but it is curiously present in a limited number of patients and its meaning is controversial. The aims of this study were to assess hepatic steatosis at ultrasound (US) after PIPIT investigating its relationship with graft function and its role in predicting the clinical outcome. From 1996 to 2012, 108 patients underwent PIPIT: 83 type-1 diabetic patients underwent allo transplantation, 25 auto-transplantation. US was performed at baseline, 6, 12, and 24 months, recording steatosis prevalence, first detection, duration, and distribution. Contemporaneously, steatotic and non-steatotic patients were compared for the following parameters: infused islet mass, insulin independence rate, beta-score, C-peptide, glycated hemoglobin, exogenous insulin requirement, and fasting plasma glucose. Steatosis at US was detected in 21/108 patients, 20/83 allo-transplanted and 1/25 auto-transplanted, mostly at 6 and 12 months. Infused islet mass was significantly higher in steatotic than non-steatotic patients (IE/kg: S=10.822; NS=6138; p=0.001). Metabolically, steatotic patients had worse basal conditions, but better islet function when steatosis was first detected, after which progressive islet exhaustion, along with steatosis disappearance, was observed. Conversely, in non-steatotic patients these parameters remained stable in time. Number of re-transplantations was significantly higher in steatotic than in non-steatotic patients (1.8 vs 1.1; p=0.001). Steatosis at US seems to be related to the islet mass and local overworking activity. It precedes metabolic alterations and can predict graft dysfunction addressing to therapeutic decisions before islet exhaustion. If steatosis does not appear, no conclusion can be drawn. PMID- 25814188 TI - A tryptophanol-derived oxazolopiperidone lactam is cytotoxic against tumors via inhibition of p53 interaction with murine double minute proteins. AB - Inactivation of the p53 tumor suppressor protein by interaction with murine double minute (MDM) proteins, MDM2 and MDMX, is a common event in human tumors expressing wild-type p53. In these tumors, the simultaneous inhibition of these interactions with MDMs, for a full p53 reactivation, represents a promising anticancer strategy. Herein, we report the identification of a dual inhibitor of the p53 interaction with MDM2 and MDMX, the (S)-tryptophanol derivative OXAZ-1, from the screening of a small library of enantiopure tryptophanol-derived oxazolopiperidone lactams, using a yeast-based assay. With human colon adenocarcinoma HCT116 cell lines expressing wild-type p53 (HCT116 p53(+/+)) and its p53-null isogenic derivative (HCT116 p53(-/-)), it was shown that OXAZ-1 induced a p53-dependent tumor growth-inhibitory effect. In fact, OXAZ-1 induced p53 stabilization, up-regulated p53 transcription targets, such as MDM2, MDMX, p21, Puma and Bax, and led to PARP cleavage, in p53(+/+), but not in p53(-/-), HCT116 cells. In addition, similar tumor cytotoxic effects were observed for OXAZ 1 against MDMX-overexpressing breast adenocarcinoma MCF-7 tumor cells, commonly described as highly resistant to MDM2-only inhibitors. In HCT116 p53(+/+) cells, the disruption of the p53 interaction with MDMs by OXAZ-1 was further confirmed by co-immunoprecipitation. It was also shown that OXAZ-1 potently triggered a p53 dependent mitochondria-mediated apoptosis, characterized by reactive oxygen species generation, mitochondrial membrane potential dissipation, Bax translocation to mitochondria, and cytochrome c release, and exhibited a p53 dependent synergistic effect with conventional chemotherapeutic drugs. Collectively, in this work, a novel selective activator of the p53 pathway is reported with promising antitumor properties to be explored either alone or combined with conventional chemotherapeutic drugs. Moreover, OXAZ-1 may represent a promising starting scaffold to search for new dual inhibitors of the p53-MDMs interaction. PMID- 25814190 TI - Guillain-Barre syndrome associated with Mycobacterium bovis lymphadenitis. AB - Guillain-Barre syndrome (GBS) is an autoimmune disease that can be triggered by different infectious agents. Here we report the case of a 26-year-old Algerian woman who developed GBS associated with a Mycobacterium bovis cervical lymphadenitis. Following intravenous immunoglobulin therapy, the patient's neurologic state returned to normal after 3 months. The lymphadenitis responded more slowly to the antituberculous treatment and an excision of necrotic cervical lymph nodes had to be performed four times. Antibiotics were administered for 16 months: ethambutol was stopped after 2 months, and rifampicin and isoniazid pursued for 14 months. An extensive etiological investigation showed that, in this case, the only likely infectious trigger GBS was the concomitant M. bovis infection. To our knowledge, this is the first report of GBS triggered by M. bovis. We performed a literature review revealing that the association between tuberculosis and Guillain-Barre syndrome is very rare (only seven cases previously reported) but is not coincidental. Physicians should be aware that tuberculosis can be a cause of GBS. PMID- 25814191 TI - Time orientation and eating behavior: Unhealthy eaters consider immediate consequences, while healthy eaters focus on future health. AB - Time orientation could play an important role in eating behavior. The current study investigated whether eating behavior is associated with the Consideration of Future Consequences scale (CFC). Specifically, it was examined whether unhealthy eaters consider the future less and are more concerned with immediate gratification. A related measure of time orientation is delay discounting, a process by which a reinforcer becomes less valuable when considered later in time. Recent research argues that the relation between time orientation and health behaviors is measured best at a behavior-specific level. In the current study, we explored the relationships between CFC and discount rate - both general and food-specific - and their influence on healthy eating. Participants with ages 18 to 60 (N = 152; final sample N = 146) filled in an online questionnaire consisting of the CFC, a food-specific version of the CFC (CFC-food), the Monetary Choice Questionnaire (MCQ) and an adapted MCQ version with snack food as a reinforcer. Self-reported healthy eating was positively related to the future subscale (r = .48, p < .001) and negatively to the immediate subscale of the CFC food (r = -.43, p < .001). The general CFC and discount rate (MCQ and MCQ-snack) were not related to healthy eating (all p > .05). In order to predict behavior, measurements of time orientation should thus be tailored to the behavior of interest. Based on current results, shifting one's concern from the immediate consequences of eating to a more future-oriented perspective may present an interesting target for future interventions aimed at promoting healthy eating and reducing overweight. PMID- 25814192 TI - The association between diet quality and mental health during the perinatal period. A systematic review. AB - BACKGROUND: While maternal nutrition during pregnancy is known to play a critical role in the health of both mother and offspring, the magnitude of this association has only recently been realized. Novel, epigenetic data suggest that maternal dietary intake has permanent phenotypic consequences for offspring, highlighting the potency of antenatal diet. To date, the relationship between poor antenatal diet and maternal mental health specifically, remains poorly understood. Therefore, we aimed to systematically review evidence that has examined associations between antenatal diet quality and the experience of depressive, anxiety and stress symptoms during the perinatal period. METHODS: A search for peer-reviewed papers was conducted using Medline Complete, PsycINFO, CINAHL, Academic Search Premiere and Psychology and Behavioral Science Collection. RESULTS: Nine studies (cohort = 4, cross-sectional = 5) published between 2005 and 2013 were eligible for inclusion in this review. A synthesis of findings revealed positive associations between poor quality and unhealthy diets and antenatal depressive and stress symptoms. Healthy diets were inversely associated with antenatal depressive and anxiety symptoms. Postnatal depressive symptoms demonstrated inconsistent results. CONCLUSIONS: Given the paucity of research examining diet quality and mental health in women during the perinatal period, further sufficiently powered studies are urgently required to examine this association. PMID- 25814189 TI - Re-engineering islet cell transplantation. AB - We are living exciting times in the field of beta cell replacement therapies for the treatment of diabetes. While steady progress has been recorded thus far in clinical islet transplantation, novel approaches are needed to make cell-based therapies more reproducible and leading to long-lasting success. The multiple facets of diabetes impose the need for a transdisciplinary approach to attain this goal, by targeting immunity, promoting engraftment and sustained functional potency. We discuss herein the emerging technologies applied to this rapidly evolving field. PMID- 25814193 TI - The immediate effect of atlanto-axial high velocity thrust techniques on blood flow in the vertebral artery: A randomized controlled trial. AB - BACKGROUND: High velocity thrust (HVT) cervical techniques have been associated with serious vertebral artery (VA) trauma. Despite numerous studies, the nature of this association is uncertain. Previous studies have failed to demonstrate haemodynamic effects on the VA in simulated pre-thrust positions. No study has investigated haemodynamic affects during or immediately following HVT, nor sufficiently controlled for the influence of the thrust. OBJECTIVES: To investigate the immediate effects of HVT of the atlanto-axial joint upon haemodynamics in the sub-occipital portion of the vertebral artery (VA3). DESIGN: Randomized Controlled Trial. METHOD: Twenty-three healthy participants (14 women, 9 men; mean age 40, range 27-69 years of age) were randomly assigned to two groups: an intervention group (MANIP, n = 11) received HVT to the atlanto-axial segment whilst a control group (CG, n = 12) was held in the pre-manipulative hold position. Colour-flow Doppler ultrasound was used to measure VA3 haemodynamics. Primary outcome measures were peak systolic (PSV) and end diastolic velocities (EDV) of three cardiac cycles measured at neutral (N1), pre-HVT (PreMH), post-HVT (PostMH), post-HVT-neutral (N2) positions. RESULTS: Test-retest reliability for the Doppler measures demonstrated intra-class correlation coefficient (ICC) of 0.99 (95% CI 0.98-1.0) for PSV and 0.91 (95% CI 0.84-0.96) for EDV. Visually, EDV were lower in the MANIP group than in the CONTROL group across the four measurements. However, there were no significantly different changes (at p <= 0.01) between the MANIP and CONTROL groups for any measurement variable. CONCLUSIONS: HVT to the atlanto-axial joint segment does not affect the haemodynamics of the sub-occipital portion of the vertebral artery during or immediately following HVT in healthy subjects. PMID- 25814195 TI - Blood and Hair Mercury Concentrations in the Pacific Harbor Seal (Phoca vitulina richardii) Pup: Associations with Neurodevelopmental Outcomes. AB - Monomethylmercury (MeHg(+)) is an environmental pollutant, which at sufficiently high exposures, has induced neurotoxicosis in several animal species, including humans. Adverse neurological effects due to gestational exposure are of particular concern as MeHg(+) readily crosses the blood-brain and placental barriers. The degree to which environmental concentrations in marine prey affect free-living piscivorous wildlife, however, remains largely undetermined. We examined associations of gestational exposures to mercury on neurodevelopment and survival using hair and blood concentrations of total mercury ([THg]) in a stranded population of Pacific harbor seal pups from central California. A positive association was determined for the presence of abnormal neurological symptoms and increasing [THg] in blood (P = 0.04), but not hair. Neither hair nor blood [THg] was significantly associated with survival, or the neurodevelopmental milestone 'free-feeding', which was measured from the onset of hand-assisted feeding to the time at which pups were able to consume fish independently. Both hair and blood [THg] exceeded threshold values considered potentially toxic to humans and other mammalian wildlife species. The higher [THg] in blood associated with abnormal neurological symptoms may indicate an adverse effect of this pollutant on neurodevelopment in harbor seal pups. These data have broader implications with respect to human health and public policy as harbor seals and humans consume similar fish species, and it is possible that safeguard levels established for marine mammals could also extend to human populations that regularly consume fish. PMID- 25814194 TI - PICan: An integromics framework for dynamic cancer biomarker discovery. AB - Modern cancer research on prognostic and predictive biomarkers demands the integration of established and emerging high-throughput technologies. However, these data are meaningless unless carefully integrated with patient clinical outcome and epidemiological information. Integrated datasets hold the key to discovering new biomarkers and therapeutic targets in cancer. We have developed a novel approach and set of methods for integrating and interrogating phenomic, genomic and clinical data sets to facilitate cancer biomarker discovery and patient stratification. Applied to a known paradigm, the biological and clinical relevance of TP53, PICan was able to recapitulate the known biomarker status and prognostic significance at a DNA, RNA and protein levels. PMID- 25814196 TI - Warthin's tumour: Aetiopathogenesis dilemma, ten years of our experience. AB - Despite the volume of studies written after the initial report by Hildebrand (1895) on Warthin's tumour (WT), its aetiopathogenesis continues to be an unresolved and controversial question. Many different genetic and/or environmental aetiological factors seem to act on heterotopic ductal inclusions and may give rise to WT following an unknown tumorigenic event. Recent studies discussed the importance of immunological reactions during the formation of the tumour. A hypersensitive/allergic reaction may play a role in epithelial proliferation and may stimulate the reactivity of the germinal centres in the lymphoid stroma as showed at histological examination. The aim of this study was to inform readers of the current understanding of possible risk factors with a suggested aetiological role in Warthin's tumorigenesis. From 2001 to 2011, a total of 342 patients with benign salivary neoplasm were admitted in the Department of Maxillofacial Surgery of the University of Naples "Federico II". A histological diagnosis of WT was made in 115 of the patients (33.6%); these were retrospectively investigated in our study. Correlation between the onset of WT and positivity for autoimmune diseases and smoking habits was calculated. The incidence rate of autoimmune thyroiditis in our series (9.5%) was significantly greater than that of the general population (0.58%) (p < 0.001). Analysis of our series and review of the literature support the hypothesis that this tumour is the result of an autoimmune reaction. Further studies and larger series are required to confirm this hypothesis and investigate the role of other aetiological factors in WT genesis. PMID- 25814198 TI - Computed tomography angiography and magnetic resonance angiography imaging of the mesenteric vasculature. AB - Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) are highly accurate cross-sectional vascular imaging modalities that have almost completely replaced diagnostic catheter angiography for the evaluation of the mesenteric vasculature. CTA is the technique of choice when evaluating patients with suspected mesenteric ischemia; it permits to differentiate between occlusive and nonocclusive etiologies, to evaluate indirect signs of bowel ischemia, and in some instances, to provide alternative diagnoses. MRA has the advantage of not using ionizing radiation and iodinated contrast agents and can be appropriate in the nonacute setting. Both CTA and MRA are suitable for the assessment of patients with suspected chronic mesenteric ischemia, allowing to evaluate the degree of atherosclerotic steno-occlusive disease and the existence of collateral circulation, as well as other nonatherosclerotic vascular pathologies such as fibromuscular dysplasia and median arcuate ligament syndrome. CTA provides excellent depiction of visceral aneurysms and has an important role to plan therapy for both occlusive and aneurysmal diseases and in the follow-up of patients after open or endovascular mesenteric revascularization procedures. This article provides an introduction to the CTA and MRA imaging protocol to study the mesenteric vasculature, the imaging findings in patients presenting with acute and chronic mesenteric ischemia and visceral aneurysms, and the value of these imaging techniques for therapy planning and follow-up. PMID- 25814199 TI - Endovascular management of visceral arterial aneurysms. AB - Visceral artery aneurysms are rare entities involving the celiac, superior mesenteric or inferior mesenteric arteries and their branches. While the natural history of these aneurysms is not well known as many are found incidentally, a definite risk of rupture and subsequent mortality has been demonstrated. There are several endovascular methods that an operator may choose to treat visceral artery aneurysms, and selection of the appropriate technique depends on the type and size of aneurysm and the anatomy of the affected artery. It is the aim of this paper to describe the indications, technical considerations and endovascular methods of treatment of visceral artery aneurysms and pseudoaneurysms. The following techniques of angiographic intervention are presented and discussed: isolation, covered stents, coil packing, liquid embolic agents and percutaneous thrombin injection. Where appropriate, individual aneurysm and artery specific treatment considerations are emphasized. To guide and assist practice, a suggested treatment algorithm is presented. PMID- 25814200 TI - Acute mesenteric ischemia. AB - Acute mesenteric ischemia is a life-threatening condition that occurs when an abrupt decrease in blood flow results in inadequate supply to the intestines, leading to bowel infarction. Etiologies may include arterial embolus, arterial or venous thrombosis, and nonocclusive mesenteric ischemia. Other causes include vasculitis, traumatic injury, dissection of the aorta, cholesterol emboli, and intestinal obstruction. Mortality rates can approach 90% in the setting of bowel infarction. As such, it is important to establish an early diagnosis before the onset of bowel infarction. Treatment has traditionally involved surgical management. However, endovascular approaches have been increasingly reported in multiple case series describing success with initial endovascular therapy followed by open surgical intervention in some cases. Acuity of presentation, presence of bowel infarction, etiology of the ischemia, and risk factors may influence a planned treatment approach. The key to successful treatment of acute mesenteric ischemia involves early clinical recognition based on a detailed history and physical examination along with assessment of contributory risk factors, rapid acquisition of appropriate diagnostics to confirm a diagnosis, and early intervention to correct the underlying abnormality. PMID- 25814202 TI - Managing mesenteric vasculitis. AB - Mesenteric vasculitis is a rare diagnosis, but it comprises a group of disorders that may have devastating manifestations. It is often difficult to diagnose using clinical symptoms and biomarkers. Vascular imaging often provides the best opportunity for the noninvasive diagnosis of vasculitis and obviates the need for performing a biopsy. The medical management of vasculitis involves controlling the inflammatory process with the use of steroids or other immunosuppressants, but medical therapy does not consistently provide regression of the vascular changes (ie, aneurysms or vascular occlusions) seen at the time of the initial diagnosis. Operative management remains the mainstay of therapy for focal occlusive or aneurysms, but the treatment options for multifocal disease remain challenging. Endovascular treatment is increasingly being used as a first line of treatment for symptomatic vasculitis. Interventionalists should be familiar with the indications and outcomes associated with the various therapeutic options for mesenteric vasculitis-associated occlusive disease and aneurysms. PMID- 25814203 TI - Median arcuate ligament compression of the mesenteric vasculature. AB - Compression of the celiac artery by fibrous bands of the diaphragmatic crura has been associated with gastrointestinal symptoms such as postprandial pain and delayed gastric emptying, a phenomenon known as median arcuate ligament syndrome. The hemodynamic effects of this compression have also been implicated in the development of aneurysms of the celiac artery or its visceral collaterals. Both open surgical decompression and laparoscopic decompression of the celiac artery have proven effective in the treatment of the compressive syndrome. Endovascular stent placement has largely supplanted open surgical reconstruction for residual stenosis following surgical decompression but is not recommended as the sole treatment modality due to high failure rates. Endovascular techniques have also become the mainstay of management of aneurysmal disease associated with celiac artery compression. PMID- 25814201 TI - Chronic mesenteric ischemia. AB - Endovascular management and treatment of chronic mesenteric ischemia has taken on an increasing role in recent years. The safety, efficacy, and cost-effectiveness have been validated in several studies. The procedure is best performed by an operator with a complete understanding of the pertinent imaging findings; a thorough knowledge of the risks, benefits, limitations, and technical challenges of the procedure; and understanding of the importance and necessity of long-term clinical management. This article outlines a general approach to endovascular management of chronic mesenteric ischemia and discusses indications, potential complications, and technical aspects of the procedure. PMID- 25814204 TI - Isolated stenosis of the inferior mesenteric artery: to treat or not to treat? AB - The indication for treatment of inferior mesenteric artery (IMA) is generally not clear. The IMA is frequently ignored owing to its size and the presence of alternate pathways within the mesenteric vasculature. However, IMA treatment may be indicated in certain clinical scenarios. In this article, we focus on the indications for IMA treatment and technical considerations when treatment is indicated. PMID- 25814206 TI - The effect of graded glass-zirconia structure on the bond between core and veneer in layered zirconia restorations. AB - OBJECTIVE: The aim of this study was to test the hypothesis that a graded glass zirconia structure can strengthen the core-veneer bond in layered zirconia materials. METHODS: A graded glass-zirconia structure was fabricated by infiltrating glass compositions developed in our laboratory into a presintered yttria tetrahedral zirconia polycrystal (Y-TZP) substrate by the action of capillary forces. The wettability of the infiltrated glass and Y-TZP substrate was investigated by the sessile drop technique. The microstructures of the graded glass-zirconia structure were examined by scanning electron microscopy (SEM). The phase structure characterization in the graded glass-zirconia structure were identified by X-ray diffraction (XRD) analysis. The elastic modulus and hardness of the graded glass-zirconia structure were evaluated from nanoindentations. Further, the shear bond strength (SBS) of the graded glass-zirconia structure and veneering porcelain was also evaluated. RESULTS: SEM images confirmed the formation of the graded glass-zirconia structure. Glass frits wet the Y-TZP substrate at 1200 degrees C with a contact angle of 43.2 degrees . Only a small amount of t-m transformation was observed in as-infiltrated Y-TZP specimens. Nanoindentation studies of the glass-zirconia graded structure showed that the elastic modulus and hardness of the surface glass layer were higher than those of the dense Y-TZP layer. The mean SBS values for the graded glass-zirconia structure and veneering porcelain (24.35 +/- 0.40 MPa) were statistically higher than those of zirconia and veneering porcelain (9.22 +/- 0.20 MPa) (P<0.05). CONCLUSIONS: A graded glass-zirconia structure can be fabricated by the glass infiltration/densification technique, and this structure exhibits a strong core veneer bond. PMID- 25814205 TI - Predictors of caregiving satisfaction in informal caregivers of people with dementia. AB - OBJECTIVE: The prevalence of dementia is increasing and consequently the demands from families, institutions and healthcare system. Although a substantial amount of research on caregiving has emphasized the negative aspects of caregiving, specifically on caregiver burden and depression, less attention has been paid to the positive aspects of caregiving. The aim of the present work was to study the phenomenon of caregiving satisfaction in informal caregivers of people with dementia by assessing their likely predictors. METHODS: A stress process model was used to study caregiver's satisfaction (measured using the Revised Caregiving Satisfaction Scale) on 101 informal caregivers of patients with dementia in relation to the caregiver's background and context, stress-related factors, and mediators. RESULTS: The regression model has an adjusted R(2) of 0.20, which indicates that having a consanguinity relationship with the care recipient, suffering from lower levels of subjective burden, and managing individuals with severe cognitive impairment are the most important predictors of higher caregiving satisfaction. CONCLUSION: Interventions focused on the enhancement of the caregiving satisfaction by increasing the understanding of the disease, should be especially addressed to caregivers without a consanguinity relationship and with high levels of subjective burden, and to those managing care recipients with mild or moderate stages of dementia. PMID- 25814207 TI - A Darwinian approach to the origin of life cycles with group properties. AB - A selective explanation for the evolution of multicellular organisms from unicellular ones requires knowledge of both selective pressures and factors affecting the response to selection. Understanding the response to selection is particularly challenging in the case of evolutionary transitions in individuality, because these transitions involve a shift in the very units of selection. We develop a conceptual framework in which three fundamental processes (growth, division, and splitting) are the scaffold for unicellular and multicellular life cycles alike. We (i) enumerate the possible ways in which these processes can be linked to create more complex life cycles, (ii) introduce three genes based on growth, division and splitting that, acting in concert, determine the architecture of the life cycles, and finally, (iii) study the evolution of the simplest five life cycles using a heuristic model of coupled ordinary differential equations in which mutations are allowed in the three genes. We demonstrate how changes in the regulation of three fundamental aspects of colonial form (cell size, colony size, and colony cell number) could lead unicellular life cycles to evolve into primitive multicellular life cycles with group properties. One interesting prediction of the model is that selection generally favors cycles with group level properties when intermediate body size is associated with lowest mortality. That is, a universal requirement for the evolution of group cycles in the model is that the size-mortality curve be U shaped. Furthermore, growth must decelerate with size. PMID- 25814208 TI - Renal function in adult women with urinary tract infection in childhood. AB - BACKGROUND: The risk of deterioration of renal function in patients with urinary tract infection (UTI)-associated renal damage over several decades is incompletely known but of importance in regard to follow-up. METHODS: A population-based cohort of women followed from their first UTI in childhood was studied at median age of 27 years and now at 41 years. Renal damage was evaluated by (99m)Tc-dimercaptosuccinic acid scan and glomerular filtration rate (GFR) by (51)Cr-edetic acid clearance. Extent of individual kidney damage was graded as class 1 to 3. RESULTS: Eighty-six women completed the investigation, 58 with renal damage, and 28 without. Of those with damage, one had chronic kidney disease (CKD) stage 3, 14 stage 2, and 43 stage 1. Women with bilateral damage had lower GFR than those with no or unilateral damage (p < 0.0001). Women with class 3 damage had numerically but not significantly lower GFR than the others with damage (p = 0.07). Between the two studies there was significant decrease of GFR in the group with bilateral damage (p = 0.01). CONCLUSIONS: Women with UTI associated renal damage had remarkably well preserved renal function, but those with bilateral or severe individual kidney damage may be considered for regular monitoring of GFR and blood pressure. PMID- 25814209 TI - Reply: Is the electrocardiogram different in recurrent episodes of Takotsubo syndrome involving 2 different left ventricular territories in the same patient? PMID- 25814210 TI - Normal blood catecholamines, recurrent ventricular fibrillation, and "ventricular scar", in a patient with Takotsubo syndrome. PMID- 25814211 TI - 3-D assessment of infective endocarditis with anterior mitral valve perforation and flail posterior leaflet. PMID- 25814212 TI - Increased prothrombotic profile in the left atrial appendage of atrial fibrillation patients. AB - BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk for thromboembolic events. While observational data demonstrated that the majority of clots are formed within the left atrial appendage, the mechanisms behind this finding remain unclear also due to the fact that vitro studies so far have been hampered by the inability to isolate and culture cells from the atrial appendages. METHODS: Patients suffering from AF undergoing cardiac surgery were recruited for this study and endocardial cells from their left (LAA) and right atrial appendage (RAA) were isolated and cultured according to a novel established protocol. Once in culture, cells were stimulated with TNF-alpha (10 ng/mL) and the expression of prothrombotic as well as proinflammatory markers was analyzed. RESULTS: FACS analysis confirmed a high purity (98%) of isolated LAA endocardial cells. TNF-alpha significantly increased tissue factor (TF) and PAI-1 expression (n=5; P<0.005), while TFPI remained unchanged. Similarly, expression of VCAM-1 was significantly higher in the LAA as compared to the RAA (n=5; P<0.0001). CONCLUSION: According to our newly established cell isolation protocol, this study reveals that in patients with AF, the endocardium of the LAA displays an increased prothrombotic and proinflammatory profile as compared to the RAA. This novel observation may constitute an important mechanism to explain the increased propensity of the LAA for clot formation, as well as the predominance of LAA-related thromboembolic complications in AF patients, and may have important implications for the development of novel treatment strategies. PMID- 25814213 TI - 17-year trends in incidence and prognosis of cardiogenic shock in patients with acute myocardial infarction in western Sweden. AB - BACKGROUND: Cardiogenic shock remains the leading cause of in hospital death in acute myocardial infarction (AMI) and is associated with a mortality rate of approximately 50%. Here we investigated the 17-year trends in incidence and prognosis of AMI-induced cardiogenic shock in Vastra Gotaland in western Sweden, an area with approximately 1.6 million inhabitants. The study period includes the transition from thrombolysis to primary percutaneous coronary intervention (PCI) as the region-wide therapy of choice for patients with ST-elevation myocardial infarction (STEMI). METHODS: Data on patients hospitalized in cardiac care units in Vastra Gotaland, Sweden between 1995 and 2013 were obtained from the Swedish Websystem for Enhancement of Evidence-based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART). We determined the incidence of cardiogenic shock among patients diagnosed with AMI and the risk of death associated with developing cardiogenic shock. We fitted logistic regression models to study which factors predicted post-AMI cardiogenic shock. Analyses were performed on complete case data as well as after multiple imputation of missing data. RESULTS: Incidence of cardiogenic shock as a complication of AMI declined in western Sweden in the past decade, from 14% in 1995 to 4% in 2012. The risk of dying once cardiogenic shock had developed increased during the study period (p<0.01). Patients presenting with STEMI were more likely to develop cardiogenic shock than patients presenting with non STEMI (p<0.001). CONCLUSIONS: The incidence of cardiogenic shock has declined but cardiogenic shock carries a worse prognosis today than in 1995. PMID- 25814214 TI - Evaluation of tissue accumulation levels of advanced glycation end products by skin autofluorescence: A novel marker of vascular complications in high-risk patients for cardiovascular disease. AB - A non-enzymatic reaction between reducing sugars and the amino groups of proteins, lipids and nucleic acids is known as the "Maillard reaction". The reactions have progressed in a normal aging process and at an accelerated rate under hyperglycemic, inflammatory, and/or oxidative stress conditions, thus leading to the formation and accumulation of advanced glycation end products (AGEs). Cross-linking modification of organic matrix proteins such as collagen by AGEs not only leads to an increase in vascular and myocardial stiffness, but also deteriorates structural integrity and physiological function of multiple organ systems. Furthermore, there is a growing body of evidence that interaction of AGEs with a cell surface receptor RAGE elicits oxidative stress generation and subsequently evokes inflammatory, thrombogenic and fibrotic reactions, thereby being involved in the development and progression of various age- or diabetes related disorders, including cardiovascular disease (CVD), Alzheimer's disease, osteoporosis, cancer growth and metastasis. Skin AGE levels measured in biopsy specimens are associated with the development and progression of diabetic microangiopathy. Recently, accumulation levels of AGEs in the skin can be measured non-invasively by autofluorescence. Accumulating evidence has suggested that skin autofluorescence (SAF) is correlated with the presence and severity of vascular complications of diabetes and could predict future cardiovascular events and death in patients with diabetes. This review summarizes the pathophysiological role of tissue accumulation levels of AGEs in vascular damage in high-risk patients, especially focusing on the association between SAF and cardiorenal disorder. PMID- 25814216 TI - A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3. AB - PURPOSE: The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells. METHODS: The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were >=grade 3 optimally treated non-hematological toxicity; >=grade 3 infusion-related reactions refractory to supportive care; >=grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2. RESULTS: Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 ug catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade >=3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-ug dose level was considered a DLT. The first patient at 10 ug experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study. CONCLUSIONS: The MTD of weekly intravenous catumaxomab was 7 ug. Major toxicities were cytokine release related symptoms and hepatotoxicity. PMID- 25814217 TI - Protective effects of C-type natriuretic peptide on cisplatin-induced nephrotoxicity in mice. AB - PURPOSE: Cisplatin is a highly effective chemotherapeutic agent used to treat various malignancies, but its utility is compromised by its nephrotoxicity. C type natriuretic peptide (CNP), a member of the natriuretic peptide family, exhibits anti-inflammatory effects by activating its specific receptor, guanylyl cyclase (GC)-B. CNP and GC-B receptor are known to be expressed in both the vascular endothelium and the kidney. The objective of this study was to investigate the renoprotective effects of CNP in a mouse model of cisplatin induced nephrotoxicity. METHODS: C57BL/6 mice were divided into three groups: normal control mice; cisplatin (20 mg/kg, intraperitoneal) mice treated with vehicle; and cisplatin mice treated with CNP (2.5 ug/kg/min, subcutaneous). At 72 h after cisplatin injection, urine, blood and kidney samples were collected. Urine and blood samples were examined biochemically. Histological findings and gene expression in kidney tissue were evaluated. RESULTS: CNP reduced histological renal tubular damage and apoptosis induced by cisplatin and suppressed plasma blood urea nitrogen and creatinine levels, which were elevated by cisplatin administration. CNP treatment decreased the expression of kidney injury molecule-1 and monocyte chemoattractant protein-1, which were elevated in the kidney by cisplatin administration. CNP treatment attenuated the decrease in GC-B expression in cisplatin-induced kidney injury. CONCLUSIONS: The present study is the first to show that CNP inhibits nephrotoxicity and kidney cell damage induced by cisplatin. The mechanism of action may involve down-regulation of inflammatory cytokine expression in cisplatin-induced kidney injury and attenuation of apoptosis in renal tubular cells. PMID- 25814218 TI - Influence of cardiac stress protocol on myocardial perfusion imaging accuracy: The role of exercise level on the evaluation of ischemic burden. AB - BACKGROUND: Some specifics of cardiac stress protocols, i.e., stressor used or exercise level achieved, may impact myocardial perfusion imaging (MPI) accuracy. METHODS: Four-hundred and seventy-five patients were submitted to MPI and coronary angiography. MPI was performed after exercise (303 patients) or dipyridamole stress (172 patients). A coronary stenosis >=70% was considered significant. In case of exercise test, a peak heart rate (HR) <85% of the maximal age predicted was considered submaximal and categorized as follows: >75% and <85% ("Group 1"); <75% ("Group 2"). RESULTS: At coronary angiography, 312/475 (66%) patients showed significant stenosis. In the overall population, MPI showed a high accuracy in unmasking significant coronary stenosis, independently of the stress protocol adopted (AUC .76 for exercise vs .78 for vasodilator; P = NS). However, in case of an exercise stress test, a significant interaction between peak %HR and MPI diagnostic power was evident. While an elevated accuracy was still maintained in "Group 1" patients (AUC .79; P vs maximal exercise = NS), a significant drop was demonstrated in "Group 2" patients (AUC .66; P vs maximal exercise = .012, and P vs "Group 1" = .042). CONCLUSIONS: The accuracy of MPI is not influenced by the stress protocol adopted. Exercise MPI maintains an elevated accuracy as long as the %HR remains >75%. PMID- 25814219 TI - Beyond ischemia evaluation: The potential for assessing and addressing physical inactivity in the cardiac stress laboratory. PMID- 25814220 TI - The next generation of prognostic series: Where we can improve on risk stratification? PMID- 25814221 TI - Erratum to: Increased Regional Epicardial Fat Volume Associated with Reversible Myocardial Ischemia in Patient's with Suspected Coronary Artery Disease. PMID- 25814222 TI - Intense moving intestinal activity as a source of artifact on myocardial perfusion SPECT study. PMID- 25814223 TI - Hospital length of stay and clinical outcomes in older STEMI patients after primary PCI: a report from the National Cardiovascular Data Registry. AB - BACKGROUND: There has been a decline in hospital length of stay (LOS) after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: The objective of this study was to examine whether shorter LOS is safe for older patients undergoing PPCI for STEMI. METHODS: The study analyzed patients' characteristics and 30-day outcomes by LOS (short, <=3 days; medium, 4 to 5 days; long >5 days; where LOS was the discharge date minus the admission date plus 1) among 33,920 patients with STEMI in the linked CathPCI Registry-Centers for Medicare & Medicaid Services dataset who were >=65 years of age and treated with PPCI from 2004 to 2009. RESULTS: Percents of patients in each category were as follows: 26.9%, 46.3%, and 26.8% for short, medium, and long LOS, respectively. Patients with a long LOS were generally older, female, and had more comorbidities, including cardiogenic shock and multivessel disease. Patients with a short LOS generally had higher ejection fraction and single-vessel disease. There was no significant difference in 30-day all-cause mortality (hazard ratio [HR]: 1.00; 95% confidence interval [CI]: 0.74 to 1.34) or major adverse cardiac events (MACE) (death, readmission for myocardial infarction, unplanned revascularization: HR: 1.03; 95% CI: 0.86 to 1.25) for medium versus short LOS. There was a significant increase in adjusted mortality (HR: 2.30; 95% CI: 1.72 to 3.07) and MACE (HR: 1.75; 95% CI: 1.44 to 2.12) for long versus short LOS. Patients with a very short LOS (1 to 2 days) had significantly increased 30-day mortality and MACE compared with a 3- to 4-day LOS. CONCLUSIONS: Patients discharged as early as 48 h after PPCI have outcomes similar to patients who stay in the hospital for 4 to 5 days. Early, but not very early (<48 h), discharge may be safe among selected older patients with STEMI. PMID- 25814224 TI - Balloon-to-door time: emerging evidence for shortening hospital stay after primary PCI for STEMI. PMID- 25814226 TI - At its heart, homeostasis is about T cells. PMID- 25814225 TI - Increased PTPN22 expression and defective CREB activation impair regulatory T cell differentiation in non-ST-segment elevation acute coronary syndromes. AB - BACKGROUND: Critical impairment of adaptive immune response has been observed in patients with acute coronary syndromes (ACS) with reduced expansion of regulatory T cells (Treg) and enhanced effector T-cell responsiveness, both associated with poorer outcomes. OBJECTIVES: This study investigated the mechanisms underlying T cell dysregulation in ACS. METHODS: We evaluated both early and downstream T-cell receptor activation pathways after ex vivo stimulation with anti-CD3 and anti CD28 crosslink in CD4(+) T cells from 20 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 20 with stable angina (SA), and 20 controls. We reassessed 10 NSTEMI and 10 SA patients after 1 year. RESULTS: Phospho-flow analysis revealed reduced phosphorylation of the zeta-chain-associated protein kinase of 70 kDa at the inhibitory residue tyrosine 292, enhancing T-cell activation, in NSTEMI helper T cells versus SA and controls (each, p < 0.001), resulting from increased expression of the protein tyrosine phosphatase, nonreceptor type, 22 (PTPN22) (p < 0.001 for both comparisons), persisting at follow-up. We also observed reduced phosphorylation (p < 0.001 versus controls) and lower levels of binding to interleukins 2 and 10 core promoter regions of the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB) in NSTEMI (p < 0.05 vs. controls), which recovered at 1 year. Finally, in NSTEMI patients, helper T cells had a reduced ability in T-cell receptor-induced Treg generation (p = 0.002 vs. SA; p = 0.001 vs. controls), partially recovered at 1 year. Restoring CREB activity and silencing PTPN22 enhanced NSTEMI patients' ability to generate Treg. CONCLUSIONS: The persistent overexpression of PTPN22 and the transient reduction of CREB activity, associated with impaired Treg differentiation, might play a role in ACS. PMID- 25814228 TI - Entangled in a heart-ailing quandary: could modified cofilin-2 be a culprit of Alzheimer's disease of the heart? PMID- 25814227 TI - Cofilin-2 phosphorylation and sequestration in myocardial aggregates: novel pathogenetic mechanisms for idiopathic dilated cardiomyopathy. AB - BACKGROUND: Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM), traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. This suggests a potential underlying cause for some of the iDCM cases. [Corrected] OBJECTIVES: This study sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer's disease. METHODS: Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence), and the findings were validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro by using pharmacological and genetic gain- and loss-of-function approaches. RESULTS: Aggregates in human myocardium were enriched for cofilin-2, an actin depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease's morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of "stress like" fibers and severely impaired cardiomyocyte contractility. CONCLUSIONS: Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism connecting certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies. PMID- 25814229 TI - The cardiovascular in-training examination: development, implementation, results, and future directions. AB - BACKGROUND: The American College of Cardiology (ACC), in collaboration with the National Board of Medical Examiners (NBME), developed the first standardized in training examination (ITE) for cardiovascular disease fellows-in-training (FITs). In addition to testing knowledge, this examination uses the newly developed ACC Curricular Milestones to provide specific, competency-based feedback to program directors and FITs. The ACC ITE has been administered more than 5,000 times since 2011. OBJECTIVES: This analysis sought to report the initial experience with the ITE, including feasibility and reliability of test development and implementation, as well as the ability of this process to provide useful feedback in key content areas. METHODS: The annual ACC ITE has been available to cardiovascular disease fellowship programs in the United States since 2011. Questions for this Web-based, secure, multiple-choice examination were developed by a group of cardiovascular disease specialists and each question was analyzed by the NBME to ensure quality. Scores were equated and standardized to allow for comparability. Trainees and program directors were provided detailed feedback, including a list of the curricular competencies tested by those questions answered incorrectly. RESULTS: The ITE was administered 5,118 times. In 2013, the examination was taken by 1,969 fellows, representing 194 training programs. Among the 3 training years, there was consistency in the examination scores. Total test scores and scores within each of the content areas increased with each FIT year (there was a statistically significant difference in each cohort's average scale score across administration years). There was also significant improvement in examination scores across the fellowship years. CONCLUSIONS: The ACC ITE is a powerful tool available to all training programs to assess medical knowledge. This examination also delivers robust and timely feedback addressing individual knowledge gaps, and thus, may serve as a basis for improving training curricula. PMID- 25814230 TI - The American College of Cardiology's in-training examination: a robust assessment tool for fellows, training programs, and the cardiovascular community. PMID- 25814231 TI - Secondary mitral regurgitation in heart failure: pathophysiology, prognosis, and therapeutic considerations. AB - The development of secondary mitral regurgitation (MR) due to left ventricular dysfunction, also known as functional MR, is strongly associated with a poor prognosis in patients with heart failure. The mechanisms underlying secondary MR are multifactorial; accurate imaging assessment of secondary MR may be challenging and nuanced; and the appropriate roles of medical, surgical, and interventional therapies for management of secondary MR are controversial and evolving. In this review, the pathophysiology, evaluation, and prognosis of secondary MR in patients with heart failure are discussed, and we evaluate in detail the evidence for the various therapeutic approaches for secondary MR, including guideline-directed medication for left ventricular dysfunction, cardiac resynchronization therapy and revascularization when appropriate, and mitral valve surgery and transcatheter interventions. The role of a multidisciplinary heart team in determining the optimal management strategy for secondary MR is also discussed. PMID- 25814233 TI - Journalists and researchers: equal responsibility in protecting the public. PMID- 25814232 TI - New perspectives on the prevalence of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is an important genetic heart muscle disease for which prevalence in the general population has not been completely resolved. For the past 20 years, most data have supported the occurrence of HCM at about 1 in 500. However, the authors have interrogated a number of relevant advances in cardiovascular medicine, including widespread fee-for-service genetic testing, population genetic studies, and contemporary diagnostic imaging, as well as a greater index of suspicion and recognition for both the clinically expressed disease and the gene-positive-phenotype-negative subset (at risk for developing the disease). Accounting for the potential impact of these initiatives on disease occurrence, the authors have revisited the prevalence of HCM in the general population. They suggest that HCM is more common than previously estimated, which may enhance its recognition in the practicing cardiovascular community, allowing more timely diagnosis and the implementation of appropriate treatment options for many patients. PMID- 25814234 TI - Build-a-cardiologist: the cardiologist of the future--the business of certification. PMID- 25814235 TI - Bradycardia and asystole is the predominant mechanism of sudden cardiac death in patients with chronic kidney disease. PMID- 25814236 TI - RNA sequencing analysis identifies new human collagen genes involved in cardiac remodeling. PMID- 25814237 TI - Omega-3 highly unsaturated fatty acids and arrhythmia risk: influences of load conditions and a differential endogenous metabolism. PMID- 25814238 TI - Applying cluster analysis to data of previously published chronic heart failure trials. PMID- 25814239 TI - Systems biology and clinical phenotypes of heart failure syndrome. PMID- 25814240 TI - Reply: applying cluster analysis to data of previously published chronic heart failure trials: systems biology and clinical phenotypes of heart failure syndrome. PMID- 25814241 TI - Reply: applying cluster analysis to data of previously published chronic heart failure trials. PMID- 25814242 TI - Matrix Metalloproteinase Inhibitor as an Antimicrobial Agent to Eradicate Enterococcus faecalis Biofilm. AB - INTRODUCTION: Successful endodontic treatment outcomes require new strategies for the complete eradication of microbial biofilms in the root canal system. Matrix metalloproteinases (MMPs) are essential enzymes in microbial cell growth and homeostasis, and they require transition metal ion cofactors to function. Targeting MMP activity also preserves dentin collagen integrity. In this study, 1,10-phenanthroline-5,6-dione (Phendione), a metal chelator, was tested as a potentially novel antimicrobial agent against Enterococcus faecalis and inhibitor of human MMP in the root canal. METHODS: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Phendione on E. faecalis were determined. The antimicrobial properties of Phendione in the presence of dentin powder and various transition metal ions were examined. The ability of Phendione to inhibit human MMP-2 was subsequently tested. The efficacy of Phendione against E. faecalis biofilm was determined by exposure of 7-day-old E. faecalis biofilms to Phendione. RESULTS: The MIC and MBC of Phendione were 2.0 MUg/mL and 16 MUg/mL, respectively, whereas 64 MUg/mL was required to kill E. faecalis biofilm. Phendione completely eradicated E. faecalis despite dentin preincubation. The presence of Zn(2+), and to a lesser extent Fe(2+), abrogated the antimicrobial effect of Phendione. In addition, Phendione at MIC and MBC significantly inhibited human MMP-2 activity. CONCLUSIONS: Phendione effectively eradicated E. faecalis biofilms and significantly inhibited human MMP-2 through its ability to chelate metal ions. The antibacterial property of Phendione was preserved in the presence of dentin. Phendione can potentially be applied in endodontic treatment as both an antimicrobial agent and MMP inhibitor. PMID- 25814243 TI - In Vivo Intracanal Temperature Evolution during Endodontic Treatment after the Injection of Room Temperature or Preheated Sodium Hypochlorite. AB - INTRODUCTION: Heating a sodium hypochlorite solution improves its effectiveness. The aim of this study was to measure the in vivo temperature changes of sodium hypochlorite solutions that were initially preheated to 66 degrees C or at room temperature inside root canals during routine irrigation. METHODS: Thirty-five root canals were prepared to ISO size 40 with 4% taper. A type K (nickel-chromium nickel) thermocouple microprobe (Testo NV, Ternat, Belgium) was positioned within 3 mm of the working length to measure the temperature at 1-second intervals. In each canal, 2 test protocols were evaluated in a randomized order with 3% sodium hypochlorite solutions: (1) preheated to 66 degrees C and (2) at room temperature. The temperature measurements began 5 seconds before the 25 seconds of irrigant injections and continued for 240 seconds. This resulted in 270 data points for each protocol. RESULTS: The temperature of the irrigant at room temperature increased from the initial intracanal temperature after injection of 20.7 degrees C (+/-1.2 degrees C) to 30.9 degrees C (+/-1.3 degrees C) in 10 seconds and to 35 degrees C (+/-0.9 degrees C) after 240 seconds. The temperature of the preheated to 66 degrees C solution decreased from 56.4 degrees C (+/-2.7 degrees C) to 45.4 degrees C (+/-3.0 degrees C) after 5 seconds, reached 37 degrees C (+/-0.9 degrees C) after 60 seconds, and reached 35.7 degrees C (+/-0.8 degrees C) after 240 seconds. CONCLUSIONS: The original temperatures of the sodium hypochlorite solutions were buffered inside the root canal and tended to rapidly evolve to equilibrium. The findings of this study contribute to an improved understanding of the thermodynamic behaviors of irrigant solutions inside root canals in vivo. PMID- 25814244 TI - Varicella Zoster Virus and Internal Root Resorption: A Case Report. AB - Herpes zoster is a viral infection caused by the reactivation of the varicella zoster virus. One of the less well-recognized maxillofacial complications is tooth root resorption. To our knowledge, this is the first case report about internal resorption associated with varicella zoster virus involving different dental quadrants. A 38-year-old woman presented with internal resorption of maxillary canine and first premolar tooth roots on the right quadrant and generalized internal resorption of second molars of both mandibular quadrants. The patient's medical history showed mild oral lichen planus and infection with varicella zoster virus (chickenpox) with severe clinical manifestations 5 years previously. The patient developed diabetes mellitus type I and hypothyroidism a short time after varicella zoster virus infection, and by the time of infection with this virus, oral lichen planus had progressed from the reticular pattern to the generalized severe erosive form. Viral etiology could also be considered in these diseases. The root canals of the affected teeth were debrided, irrigated, and dried, and calcium hydroxide paste was placed in the root canals for a week during the first treatment session. The root canals were obturated during the second session. Six-month follow-up showed improvement of oral lichen planus and resolution of widening of periodontal ligament of the affected teeth, with follow up radiographs revealing no periapical problems. It appears some cases of internal root resorption classified as idiopathic might have viral etiology. Therefore, it is recommended that patients be questioned about a history of chickenpox and herpes zoster. PMID- 25814246 TI - Switching to zebrafish neurobehavioral models: The obsessive-compulsive disorder paradigm. AB - Obsessive-compulsive disorder (OCD) is the tenth most disabling illness of any kind. OCD stands as a paradigm for complex neurobehavioral disorders due to its polygenic origin. It presents heterogenic clinical presentation, variable disease onset, progression and treatment responses, what makes its understanding a major neuropsychiatric challenge. Like with other neurobehavioral disorders, animal models are essential tools for decoding OCD genetic complexity, understanding its biological base and discovering novel treatments and diagnostic methods. 20 years of rodent OCD modeling have helped to understand the disease better, but multiple questions remain regarding OCD. Innovative whole genome sequencing (WGS) approaches might provide important answers on OCD risk associated genes. However, exploiting those large data sets through the use of traditional animal models is costly and time consuming. Zebrafish might be an appropriate animal model to streamline the pipeline of gene functional validation. This animal model shows several advantages versus rodent models, such as faster and cheaper genetic manipulation, strong impact on the 3Rs implementation, behavioral phenotypic reproducibility of OCD-like behaviors (obsessions and compulsions) and feasibility to develop high-throughput assays for novel OCD drug therapies discovery. In conclusion, zebrafish could be an innovative and relevant model for understanding OCD. PMID- 25814245 TI - Enhancing screening and early detection among women transitioning to Medicare from the NBCCEDP in Georgia. AB - PURPOSE: The National Breast and Cervical Cancer Early Detection Program through each state's administration serves millions of low-income and uninsured women aged 40-64. Our purpose was to assess whether cases screened through Georgia's Breast and Cervical Cancer Program (BCCP) were diagnosed at an earlier stage of disease and whether those who used the state's program regularly continued to obtain age-appropriate screens as they aged out of BCCP into Medicare between 2000 and 2005. METHODS: We used BCCP screening data to identify women with more than one screen and an interval of 18 months or less between screens as "regular" users of BCCP. Using the linked BCCP and Medicare enrollment/claims data, we tested whether women with any BCCP use (n = 3,134) or "regular" users (n = 1,590) were more likely than women not using BCCP (n = 10,086) to exhibit regular screening under Medicare. We used linked BCCP and Georgia Cancer Registry data to examine breast cancer incidence and stage at diagnosis of BCCP women compared to the Georgia population. RESULTS: Under Medicare, almost 63 % of women with any BCCP use were re-screened versus 51 % of non-BCCP users. The probability of being screened within 18 months of Medicare enrollment was 3.5 % points higher for any BCCP user and 17.7 points higher for "regular" BCCP users, compared to nonusers. Among Black non-Hispanics, the difference for any BCCP user was 13.7 % points and for regular users, 22.4 % points. A larger percentage of BCCP users were diagnosed at in situ or localized disease stage than overall. CONCLUSIONS: The majority of women aging out of the GA BCCP 2000-2005 had used the program to obtain regular mammography. Regular users of GA BCCP continued to be screened within appropriate intervals once enrolled in Medicare due perhaps to educational and support components of BCCP. PMID- 25814247 TI - Translational value of animal models of obesity-Focus on dogs and cats. AB - A prolonged imbalance between a relative increase in energy intake over a decrease in energy expenditure results in the development of obesity; extended periods of a positive energy balance eventually lead to the accumulation of abnormally high amounts of fat in adipose tissue but also in other organs. Obesity is considered a clinical state of impaired general heath in which the excessive increase in adipose tissue mass may be associated with metabolic disorders such as type 2 diabetes mellitus, hyperlipidemia, hypertension and cardiovascular diseases. This review discusses briefly the use of animal models for the study of obesity and its comorbidities. Generally, most studies are performed with rodents, such as diet induced obesity and genetic models. Here, we focus specifically on two different species, namely dogs and cats. Obese dogs and cats show many features of human obesity. Interestingly, however, dogs and cats differ from each other in certain aspects because even though obese dogs may become insulin resistant, this does not result in the development of diabetes mellitus. In fact, diabetes in dogs is typically not associated with obesity because dogs present a type 1 diabetes-like syndrome. On the other hand, obese cats often develop diabetes mellitus which shares many features with human type 2 diabetes; feline and human diabetes are similar in respect to their pathophysiology, underlying risk factors and treatment strategies. Our review discusses genetic and endocrine factors in obesity, discusses obesity induced changes in lipid metabolism and includes some recent findings on the role of gut microbiota in obesity. Compared to research in rodent models, the array of available techniques and tools is unfortunately still rather limited in dogs and cats. Hence, even though physiological and pathophysiological phenomena are well described in dogs and cats, the underlying mechanisms are often not known and studies investigating causality specifically are scarce. PMID- 25814248 TI - Translational value of animal models of kidney failure. AB - Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with decreased renal function and increased mortality risk, while the therapeutic armamentarium is unsatisfactory. The availability of adequate animal models may speed up the discovery of biomarkers for disease staging and therapy individualization as well as design and testing of novel therapeutic strategies. Some longstanding animal models have failed to result in therapeutic advances in the clinical setting, such as kidney ischemia-reperfusion injury and diabetic nephropathy models. In this regard, most models for diabetic nephropathy are unsatisfactory in that they do not evolve to renal failure. Satisfactory models for additional nephropathies are needed. These include anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, anti phospholipase-A2-receptor (PLA2R) membranous nephropathy and Fabry nephropathy. However, recent novel models hold promise for clinical translation. Thus, the AKI to CKD translation has been modeled, in some cases with toxins of interest for human CKD such as aristolochic acid. Genetically modified mice provide models for Alport syndrome evolving to renal failure that have resulted in clinical recommendations, polycystic kidney disease models that have provided clues for the development of tolvaptan, that was recently approved for the human disease in Japan; and animal models also contributed to target C5 with eculizumab in hemolytic uremic syndrome. Some ongoing trials explore novel concepts derived from models, such TWEAK targeting as tissue protection for lupus nephritis. We now review animal models reproducing diverse, genetic and acquired, causes of AKI and CKD evolving to kidney failure and discuss the contribution to clinical translation and prospects for the future. PMID- 25814250 TI - Generation of improved mouse models for the study of hepatitis C virus. AB - Approximately 3% of the world's population suffers from chronic infections with hepatitis C virus (HCV). Although current treatment regimes are capable of effectively eradicating HCV infection from these patients, the cost of these combinations of direct-acting antivirals are prohibitive. Approximately 80% of untreated chronic HCV carriers will be at high risk for developing severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. A vaccine is urgently needed to lessen this global burden. Besides humans, HCV infection can be experimentally transmitted to chimpanzees, and this is the best model for studies of HCV infection and related innate and adaptive immune responses. Although the chimpanzee model yielded valuable insight, limited availability, high cost and ethical considerations limit their utility. The only small animal models of robust HCV infection are highly immunodeficient mice with human chimeric livers. However, these mice cannot be used to study adaptive immune responses and therefore a more relevant animal model is needed to assist in vaccine development. Novel strains of immunodeficient mice have been developed that allow for the engraftment of human hepatopoietic stem cells, as well as functional human lymphoid cells and tissues, effectively creating human immune systems in otherwise immunodeficient mice. These humanized mice are rapidly emerging as pre-clinical bridges for numerous pathogens that, like HCV, only cause infectious disease in humans. This review highlights the potential these new models have for changing the current landscape for HCV research and vaccine development. PMID- 25814249 TI - Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research. AB - Type 1 diabetes currently affects 20-40 million people worldwide. Insulin treatment is standard, but a majority of patients still experience glycemic instability and associated comorbidity: there is an unmet medical need for novel therapeutics. Animal models have been indispensable in testing innovative medicinal approaches since the early testing of insulin in dogs almost a century ago. Models include mainly rodents with spontaneous diabetes, or rodents and nonhuman primates in which diabetes is induced by chemicals that are toxic to insulin-producing pancreatic beta-cells, or by pancreatectomy. To a less extent models in pigs are used. Rodent models have shown value in studies on pathogenesis and disease prevention, while models in nonhuman primates have translational value in testing beta-cell replacement products and immunosuppressives to prevent rejection. Evidently, for many immunosuppressives this validation follows from the close similarity in immune function. Gene therapy approaches are being tested in both rodents and nonhuman primates. We present an overview of models used to answer various research questions, with particular focus on their translational value. This includes a consideration of divergence between the animal model and the clinical condition, and a consideration of the species and model difference in pathogenesis, especially the induction of the diabetic state. Careful attention should be given to managing diabetic animals: outcome measures in the model are highly stress-sensitive and parameters that have potential for confounding should be addressed, i.e., environment, metabolic management, and handling. This review concludes with a few recommendations on how to make animal models more clinical-like. PMID- 25814251 TI - Carpentier-Edwards aortic pericardial bioprosthetic valve as a valid control in preclinical in vivo ovine studies. AB - To progress into clinical practice, a bioprosthetic heart valve must first pass through the preclinical evaluation phase. The International Standards Organization (ISO) recommends implantation of concurrent controls in any evaluation of a new or modified heart valve. A total of 8 adult sheep underwent aortic valve replacement, receiving either the CE Perimount Magna 3000 aortic pericardial bioprosthetic valve or the CE Perimount RSR aortic pericardial bioprosthetic valve, Model 2800. We performed serial blood sampling, echocardiography, angiography and necropsy after euthanasia. All 8 sheep survived until the end of their study term. Our 2-dimensional echocardiographic analysis showed a mean pressure gradient of 37.4+/-6.0mmHg at 14 days and 37.0+/-5.9mmHg at 90 days; mean cardiac output was 10.0+/-2.8l/min at 14 days and 9.6+/-1.6l/min at 90 days. Angiography before euthanasia showed a mean aortic transvalvular gradient of 32.3+/-15.3mmHg. At euthanasia, we saw no evidence of calcification in any of the valves. In our study, we found that both models of the CE bioprosthetic heart valve we tested proved to be valid controls, in the aortic position, in sheep-with no evidence of calcification. Most important, the valves we tested had a few model-related problems, allowing a clear determination of their suitability for introduction into a clinical trial. Investigators now have additional insight into the safety of these 2 models of valves and perhaps will be able to reduce the number of controls implanted. PMID- 25814252 TI - The utility of animal models in developing immunosuppressive agents. AB - The immune system comprises an integrated network of cellular interactions. Some responses are predictable, while others are more stochastic. While in vitro the outcome of stimulating a single type of cell may be stereotyped and reproducible, in vivo this is often not the case. This phenomenon often merits the use of animal models in predicting the impact of immunosuppressant drugs. A heavy burden of responsibility lies on the shoulders of the investigator when using animal models to study immunosuppressive agents. The principles of the three R's: refine (less suffering,), reduce (lower animal numbers) and replace (alternative in vitro assays) must be applied, as described elsewhere in this issue. Well designed animal model experiments have allowed us to develop all the immunosuppressive agents currently available for treating autoimmune disease and transplant recipients. In this review, we examine the common animal models used in developing immunosuppressive agents, focusing on drugs used in transplant surgery. Autoimmune diseases, such as multiple sclerosis, are covered elsewhere in this issue. We look at the utility and limitations of small and large animal models in measuring potency and toxicity of immunosuppressive therapies. PMID- 25814253 TI - Cardiovascular pharmacotherapy: Innovation stuck in translation. AB - Systematic reviews of animal studies have revealed serious limitations in internal and external validity strongly affecting the reliability of this research. In addition inter-species differences are likely to further limit the predictive value of animal research for the efficacy and tolerability of new drugs in humans. Important changes in the research process are needed to allow efficient translation of preclinical discoveries to the clinic, including improvements in the laboratory and publication practices involving animal research and early incorporation of human proof-of-concept studies to optimize the interpretation of animal data for its predictive value for humans and the design of clinical trials. PMID- 25814254 TI - The translational value of non-human primates in preclinical research on infection and immunopathology. AB - The immune system plays a central role in the defense against environmental threats - such as infection with viruses, parasites or bacteria - but can also be a cause of disease, such as in the case of allergic or autoimmune disorders. In the past decades the impressive development of biotechnology has provided scientists with biological tools for the development of highly selective treatments for the different types of disorders. However, despite some clear successes the translation of scientific discoveries into effective treatments has remained challenging. The often-disappointing predictive validity of the preclinical animal models that are used in the selection of the most promising vaccine or drug candidates is the Achilles heel in the therapy development process. This publication summarizes the relevance and usage of non-human primates as pre-clinical model in infectious and autoimmune diseases, in particular for biologicals, which due to their high species-specificity are inactive in lower species. PMID- 25814255 TI - From mice to mind: Strategies and progress in translating neuroregeneration. AB - Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer's disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man. PMID- 25814256 TI - Experimental colitis models: Insights into the pathogenesis of inflammatory bowel disease and translational issues. AB - Inflammatory bowel diseases, ulcerative colitis and Crohn's disease are characterized by chronic relapsing inflammation of the gastrointestinal tract of unknown etiology that seems to be the consequence of a genetically driven dysregulated immune response against various local and environmental triggers through a defective epithelial barrier. During the last decades, a large number of animal experimental models of intestinal inflammation have been generated and provided valuable insights into the mechanisms that either maintain mucosal homeostasis or drive intestinal inflammation. Their study enabled the identification of various treatment targets and the development a large pipeline of new drugs, mostly biologics. Safety and therapeutic efficacy of these agents have been evaluated in a large number of clinical trials but only a minority has reached the clinic so far. Translational successes but mostly translational failures have prompted to re-evaluate results of efficacy and safety generated by pre-clinical testing and to re-examine the way to interpret experimental in vivo data. This review examines the contribution of the most popular experimental colitis models to our understanding of the pathogenesis of human inflammatory bowel diseases and their translational input in drug development and discusses ways to improve translational outcome. PMID- 25814257 TI - Regulatory acceptance of animal models of disease to support clinical trials of medicines and advanced therapy medicinal products. AB - The utility of animal models of disease for assessing the safety of novel therapeutic modalities has become an increasingly important topic of discussion as research and development efforts focus on improving the predictive value of animal studies to support accelerated clinical development. Medicines are approved for marketing based upon a determination that their benefits outweigh foreseeable risks in specific indications, specific populations, and at specific dosages and regimens. No medicine is 100% safe. A medicine is less safe if the actual risks are greater than the predicted risks. The purpose of preclinical safety assessment is to understand the potential risks to aid clinical decision making. Ideally preclinical studies should identify potential adverse effects and design clinical studies that will minimize their occurrence. Most regulatory documents delineate the utilization of conventional "normal" animal species to evaluate the safety risk of new medicines (i.e., new chemical entities and new biological entities). Animal models of human disease are commonly utilized to gain insight into the pathogenesis of disease and to evaluate efficacy but less frequently utilized in preclinical safety assessment. An understanding of the limitations of the animal disease models together with a better understanding of the disease and how toxicity may be impacted by the disease condition should allow for a better prediction of risk in the intended patient population. Importantly, regulatory authorities are becoming more willing to accept and even recommend data from experimental animal disease models that combine efficacy and safety to support clinical development. PMID- 25814259 TI - Back to the future of psychopharmacology: A perspective on animal models in drug discovery. AB - Psychopharmacology has had some bad publicity lately. Frankly, there have been some major problems along the way in developing new effective drugs for psychiatric disorders. After a prolonged period of high investments but low success rates, big pharmaceutical companies seem to retract their activities in the psychopharmacology field. Yet, the burden of mental disorders is likely to keep on growing in the next decades. In this position paper, we focus on drug development for depression and anxiety disorders, to narrow the scope of the assay. We describe the current situation of the psychopharmacology field, and analyse some of the methods and paradigms that have brought us here, but which should perhaps change to bring us even further. In addition, some of the factors contributing to the current stagnation in psychopharmacology are discussed. Finally, we suggest a number of changes that could lead to a more rational strategy for central nervous system drug development and which may circumvent some of the pitfalls leading to "me too" approaches. Central to the suggested changes, is the notion that mental disorders do not lead to several symptoms, but a network of causally related symptoms convolutes into a mental disorder. We call upon academia to put these changes in the early phases of drug development into effect. PMID- 25814258 TI - Rapamycin ameliorates brain metabolites alterations after transient focal ischemia in rats. AB - Rapamycin has been shown to protect against middle cerebral artery occlusion (MCAo) induced ischemic injury. In this study, the neuroprotective effect of rapamycin on the metabolic changes induced by MCAo was evaluated using nuclear magnetic resonance (NMR) spectroscopy of brain tissues. MCAo in rats was induced by insertion of nylon filament. One hour after ischemia, rapamycin (250 ug/kg, i.p.) in dimethyl sulfoxide was administered. Reperfusion was done 2h after ischemia. Twenty-four hours after ischemia phospholipase A2 (PLA2) levels and metabolic changes were assessed. Perchloric acid extraction was performed on the brain of all animals (n=7; sham, vehicle; DMSO and rapamycin 250 ug/kg) and the various brain metabolites were assessed by NMR spectroscopy. In all 44 metabolites were assigned in the proton NMR spectrum of rat brain tissues. In the vehicle group, we observed increased lactate levels and decreased levels of glutamate/glutamine, choline containing compounds, creatine/phosphocreatine (Cr/PCr), taurine, myo-inositol, gamma-amino butryic acid (GABA), N-aspartyl aspartate (NAA), purine and pyrimidine metabolites. In rapamycin treated rats, there was increase in the levels of choline containing compounds, NAA, myo inositol, glutamate/glutamine, GABA, Cr/PCr and taurine as compared to those of vehicle control (P<0.05). Rapamycin treatment reduced PLA2 levels as compared to vehicle group (P<0.05). Our findings indicated that rapamycin reduced the increased PLA2 levels and altered brain metabolites after MCAo. These protective effects might be attributed to its effect on cell membrane metabolism; glutamate induced toxicity and calcium homeostasis in stroke. PMID- 25814260 TI - Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models. AB - Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman's correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path forward to critically evaluate and improve animal models of human disease. PMID- 25814261 TI - Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: From food intake to metabolic disease. AB - (Mini)pigs have proven to be a valuable animal model in nutritional, metabolic and cardiovascular research and in some other biomedical research areas (toxicology, neurobiology). The large resemblance of (neuro)anatomy, the gastro intestinal tract, body size, body composition, and the omnivorous food choice and appetite of the pig are additional reasons to select this large animal species for (preclinical) nutritional and pharmacological studies. Both humans and pigs are prone to the development of obesity and related cardiovascular diseases such as hypertension and atherosclerosis. Bad cholesterol (LDL) is high and good cholesterol (HDL) is low in pigs, like in humans. Disease-relevant pig models fill the gap between rodent models and primate species including humans. Diet induced obese pigs show a phenotype related to the metabolic syndrome including high amounts of visceral fat, fatty organs, insulin resistance and high blood pressure. However, overt hyperglycaemia does not develop within 6 months after initiation of high sugar-fat feeding. Therefore, to accelerate the induction of obese type 2 diabetes, obese pigs can be titrated with streptozotocin, a chemical agent which selectively damages the insulin-producing pancreatic beta-cells. However, insulin is required to maintain obesity. With proper titration of streptozotocin, insulin secretion can be restrained at such a level that hyperglycaemia will be induced but lipolysis is still inhibited due to the fact that inhibition of lipolysis is more sensitive to insulin compared to stimulation of glucose uptake. This strategy may lead to a stable hyperglycaemic, non-ketotic obese pig model which remains anabolic with time without the necessity of exogenous insulin treatment. PMID- 25814262 TI - Animal models for osteoporosis. AB - The major types of osteoporosis in humans are postmenopausal osteoporosis, disuse osteoporosis, and glucocorticoid-induced osteoporosis. Animal models for postmenopausal osteoporosis are generated by ovariectomy. Bone loss occurs in estrogen deficiency due to enhanced bone resorption and impaired osteoblast function. Estrogen receptor alpha induces osteoclast apoptosis, but the mechanism for impaired osteoblast function remains to be clarified. Animal models for unloading are generated by tail suspension or hind limb immobilization by sciatic neurectomy, tenotomy, or using plaster cast. Unloading inhibits bone formation and enhances bone resorption, and the involvement of the sympathetic nervous system in it needs to be further investigated. The osteocyte network regulates bone mass by responding to mechanical stress. Osteoblast-specific BCL2 transgenic mice, in which the osteocyte network is completely disrupted, can be a mouse model for the evaluation of osteocyte functions. Glucocorticoid treatment inhibits bone formation and enhances bone resorption, and markedly reduces cancellous bone in humans and large animals, but not consistently in rodents. PMID- 25814264 TI - Comparative Effectiveness of Multifaceted Outreach to Initiate Colorectal Cancer Screening in Community Health Centers: A Randomized Controlled Trial. AB - INTRODUCTION: Colorectal cancer (CRC) screening rates are low among vulnerable populations. Fecal immunochemical tests (FITs) are one screening modality with few barriers. Studies have shown that outreach can improve CRC screening, but little is known about its effectiveness among individuals with no CRC screening history. We sought to determine whether outreach increases FIT uptake among patients with no CRC screening history compared to usual care. METHODS: This study was a patient-level randomized controlled trial, including 420 patients who had never completed CRC screening and were eligible for FIT; 66% were female, 62.1% were Latino, and 70.7% were uninsured. The main outcome measure was FIT completion within 6 months of the randomization date. We assessed FIT completion at different time points corresponding to receipt of outreach components. All analyses were re-run with 12-month data. RESULTS: Patients who received outreach were more likely to complete FIT than those in usual care (36.7% vs. 14.8%; p < 0.001). FIT completion was more common among patients with increased clinic visits. The difference in FIT completion between the outreach and usual care groups decreased over time. DISCUSSION: The intervention improved FIT uptake among patients with no CRC screening history. However, the intervention was less effective than in a previous trial targeting patients due for repeat screening. Additional research is needed to determine the best methods for improving CRC screening among this hard-to-reach group. PMID- 25814265 TI - Association Between Study Quality and Publication Rates of Medical Education Abstracts Presented at the Society of General Internal Medicine Annual Meeting. AB - BACKGROUND: Studies reveal that 44.5% of abstracts presented at national meetings are subsequently published in indexed journals, with lower rates for abstracts of medical education scholarship. OBJECTIVE: We sought to determine whether the quality of medical education abstracts is associated with subsequent publication in indexed journals, and to compare the quality of medical education abstracts presented as scientific abstracts versus innovations in medical education (IME). DESIGN: Retrospective cohort study. PARTICIPANTS: Medical education abstracts presented at the Society of General Internal Medicine (SGIM) 2009 annual meeting. MAIN MEASURES: Publication rates were measured using database searches for full text publications through December 2013. Quality was assessed using the validated Medical Education Research Study Quality Instrument (MERSQI). KEY RESULTS: Overall, 64 (44%) medical education abstracts presented at the 2009 SGIM annual meeting were subsequently published in indexed medical journals. The MERSQI demonstrated good inter-rater reliability (intraclass correlation range, 0.77 1.00) for grading the quality of medical education abstracts. MERSQI scores were higher for published versus unpublished abstracts (9.59 vs. 8.81, p = 0.03). Abstracts with a MERSQI score of 10 or greater were more likely to be published (OR 3.18, 95% CI 1.47-6.89, p = 0.003). ). MERSQI scores were higher for scientific versus IME abstracts (9.88 vs. 8.31, p < 0.001). Publication rates were higher for scientific abstracts (42 [66%] vs. 37 [46%], p = 0.02) and oral presentations (15 [23%] vs. 6 [8%], p = 0.01). CONCLUSIONS: The publication rate of medical education abstracts presented at the 2009 SGIM annual meeting was similar to reported publication rates for biomedical research abstracts, but higher than publication rates reported for medical education abstracts. MERSQI scores were associated with higher abstract publication rates, suggesting that attention to measures of quality--such as sampling, instrument validity, and data analysis--may improve the likelihood that medical education abstracts will be published. PMID- 25814266 TI - Children's mathematical performance: five cognitive tasks across five grades. AB - Children in elementary school, along with college adults, were tested on a battery of basic mathematical tasks, including digit naming, number comparison, dot enumeration, and simple addition or subtraction. Beyond cataloguing performance to these standard tasks in Grades 1 to 5, we also examined relationships among the tasks, including previously reported results on a number line estimation task. Accuracy and latency improved across grades for all tasks, and classic interaction patterns were found, for example, a speed-up of subitizing and counting, increasingly shallow slopes in number comparison, and progressive speeding of responses especially to larger addition and subtraction problems. Surprisingly, digit naming was faster than subitizing at all ages, arguing against a pre-attentive processing explanation for subitizing. Estimation accuracy and speed were strong predictors of children's addition and subtraction performance. Children who gave exponential responses on the number line estimation task were slower at counting in the dot enumeration task and had longer latencies on addition and subtraction problems. The results provided further support for the importance of estimation as an indicator of children's current and future mathematical expertise. PMID- 25814267 TI - hBMP-2 and hTGF-beta1 expressed in implanted BMSCs synergistically promote the repairing of segmental bone defects. AB - OBJECTIVE: To evaluate the effects of co-expressing hBMP-2 and hTGF-beta1 in BMSCs (bone marrow-derived mesenchymal stem cells) on the repairing process of radial segmental defects in rats. METHODS: BMSCs were infected with a high titer recombinant adenovirus carrying hTGF-betal and/or hBMP-2 genes. Expression of exogenous genes in BMSCs was confirmed by RT-PCR and ELISA assays. In vitro effects of exogenous genes were assessed by MTT and ALP activity tests. A left radial defect model was created using 120 SD rats. Genetically modified or unmodified BMSCs were implanted with collagen sponge scaffolds into the 5-mm radial defect. The bone repair process was systematically monitored and evaluated by X-ray examinations, gross anatomic examinations, histological analyses, and biomechanical tests. RESULTS: Expression of hBMP-2 and hTGF-beta1 showed synergistic effects on promoting BMSC proliferation and enhancing ALP activity in vitro. Bone repair assays showed that hBMP-2 and hTGF-beta1 promoted the production of chondrocytes and osteoblasts. Implanted BMSCs transfected with both hBMP-2 and hTGF-beta1 led to the best bone repair outcome. CONCLUSION: hBMP-2 and hTGF-beta1 can synergistically improve the bone repair process. Our results suggest a potential clinical value of combining hBMP-2 and hTGF-beta1 in repairing bone defects. PMID- 25814263 TI - Investigating the mechanism(s) underlying switching between states in bipolar disorder. AB - Bipolar disorder (BD) is a unique disorder that transcends domains of function since the same patient can exhibit depression or mania, states with polar opposite mood symptoms. During depression, people feel helplessness, reduced energy, and risk aversion, while with mania behaviors include grandiosity, increased energy, less sleep, and risk preference. The neural mechanism(s) underlying each state are gaining clarity, with catecholaminergic disruption seen during mania, and cholinergic dysfunction during depression. The fact that the same patient cycles/switches between these states is the defining characteristic of BD however. Of greater importance therefore, is the mechanism(s) underlying cycling from one state - and its associated neural changes - to another, considered the 'holy grail' of BD research. Herein, we review studies investigating triggers that induce switching to these states. By identifying such triggers, researchers can study neural mechanisms underlying each state and importantly how such mechanistic changes can occur in the same subject. Current animal models of this switch are also discussed, from submissive- and dominant behaviors to kindling effects. Focus however, is placed on how seasonal changes can induce manic and depressive states in BD sufferers. Importantly, changing photoperiod lengths can induce local switches in neurotransmitter expression in normal animals, from increased catecholaminergic expression during periods of high activity, to increased somatostatin and corticotrophin releasing factor during periods of low activity. Identifying susceptibilities to this switch would enable the development of targeted animal models. From animal models, targeted treatments could be developed and tested that would minimize the likelihood of switching. PMID- 25814268 TI - Fatigue Experiences Among OCD Outpatients. AB - Patients with OCD are impaired in multiple domains of functioning and quality of life. While associated psychopathology complaints and neuropsychological deficits were reported, the subjective experience of general fatigue and mental fatigue was scarcely investigated. In this single-center case-control study we compared 50 non-depressed OCD outpatients consecutively recruited and 50 panic disorder (PD) outpatients, to determine whether they experienced fatigue differently. Assessment consisted of structured clinical interview for DSM-IV criteria by using the SCID-I and the SCID-II. Symptom severity was assessed using the Yale Brown Obsessive-Compulsive Scale, the Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, the Clinical Global Impressions Scale, severity and the Global Assessment of Functioning Scale. Fatigue was assessed by using the Multidimensional Fatigue Inventory (MFI). Regarding MFI physical fatigue, an OR of 0.196 (95 % CI 0.080-0.478) was found, suggesting that its presence is associated with lower odds of OCD compared to PD. The same can be said for MFI mental fatigue, as an OR of 0.138 (95 % CI 0.049-0.326) was found, suggesting that its presence is associated with lower odds of OCD. Notably, OCD patients with OCDP co-morbidity reported higher scores of mental fatigue. In this study fatigue, including mental fatigue, seems not to be a prominent experience among adult non-depressed OCD patients. PMID- 25814270 TI - A range of personality traits and health beliefs influence mental health help seeking behaviour in young people. PMID- 25814269 TI - Does retirement reduce the risk of mental disorders? A national registry-linkage study of treatment for mental disorders before and after retirement of 245,082 Danish residents. AB - OBJECTIVES: The effect of retirement on mental health is not well understood. We examined the prevalence of hospital treatment for depression and purchase of antidepressant medication before, during and after retirement in a Danish population sample. We hypothesised that retirement was followed by reduced prevalence of hospital treatment for depression and antidepressant purchase. METHODS: Participants were 245,082 Danish workers who retired between 2000 and 2006. Information on retirement, hospital treatment and antidepressant purchases were obtained from Danish national registers. The yearly prevalence of hospital treatment for depression and antidepressant purchases was estimated in relation to the year of retirement from 5 years prior to the retirement year to 5 years after retirement. Using logistic regressions with generalised estimating equations we analysed the trends in prevalence before, during and after the retirement. RESULTS: Two of 1000 participants were hospitalised with depression in the year of their retirement and 63 of 1000 purchased antidepressant medication during the retirement year. The prevalence of hospital treatment for depression increased before and around retirement, followed by a slight decline from 2 years after retirement with the prevalence of hospitalisation dropping from 0.21%(retirement +2 years) to 0.16% (retirement +5 years). For antidepressants, we observed a steady increase in purchases before retirement (retirement -2 years). This increase levelled off in the years around retirement, but continued after retirement (retirement +2 years). CONCLUSIONS: Overall, this study did not confirm the hypothesis that retirement is beneficial for mental health measured by hospitalisation with depression and treatment with antidepressants. Although the temporary levelling off of the increase in antidepressant treatment around time of retirement might indicate a beneficial effect, this possible effect was only short-term. PMID- 25814271 TI - The application of HPLC and microprobe NMR spectroscopy in the identification of metabolites in complex biological matrices. AB - Nuclear magnetic resonance (NMR)-based metabolomics can be used directly to identify a variety of metabolites in biological fluids and tissues. Metabolite analysis is an important part of life science and metabolomics research. However, the identification of some metabolites using NMR spectroscopy remains a big challenge owing to low abundance or signal overlap. It is important to develop a method to measure these compounds accurately. Two-dimensional NMR spectroscopy, metabolite prediction software packages, and spike-in experiments with authentic standards are often used to solve these problems, but they are costly and time consuming. In this study, methods were developed to identify metabolites in complex biological mixtures using both high-performance liquid chromatography (HPLC) and off-line microprobe NMR spectroscopy. With use of these methods, 83 and 73 metabolites were identified in Sprague Dawley rat urine and feces, respectively. Among them, 40 and 45 metabolites, respectively, could not be identified with traditional NMR methods. Our research revealed that the combination of HPLC and NMR techniques could significantly improve the accuracy of trace and overlapped metabolite identification, while offering an effective and convenient approach to identify potential biomarkers in complex biological systems. PMID- 25814272 TI - Determining fatty acids by desorption/ionization mass spectrometry using thin layer chromatography substrates. AB - In this study, we demonstrate the application of ambient mass spectrometry for measuring fatty acids from various biological sample matrices such as olive oil, fish oil, salmon, and human serum. Optimum performance was obtained after spotting samples onto thin-layer chromatography (TLC) plates as sample substrates for a custom-built solvent-assisted desorption/ionization mass spectrometry (DI MS) interface. Good to excellent linearities (coefficients of determination, 0.9856 to 0.9977) and reproducibilities (average 6 % relative standard deviation (RSD) using syringe deposition) were obtained after application of an internal standard. Signal suppression phenomena were minimized by separating the analytes by TLC to some extent prior to DI-MS, leading to a fourfold increase of signal-to noise ratios as compared to single spot mixture analysis without TLC separation. Graphical Abstract Solvent-assisted desorption/ionization-mass spectrometry. PMID- 25814273 TI - A multiresidue liquid chromatographic/tandem mass spectrometric method for the detection and quantitation of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) in bovine meat and milk. AB - This study concerns a validated liquid chromatographic/tandem mass spectrometric (LC-MS/MS) multiresidue method for the simultaneous detection, identification, and quantitation of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) in bovine meat and milk. The NSAIDs considered are carprofen, diclofenac, flufenamic acid, flunixin (5-hydroxyflunixin as marker metabolite in milk), ketoprofen, mefenamic acid, meloxicam, 4-methylaminoantipyrine (marker metabolite of metamizole in meat and milk), naproxen, niflumic acid, phenylbutazone (and metabolite oxyphenbutazone), ramifenazone, salicylic acid, and tolfenamic acid. These compounds were chosen as representatives of different chemical subclasses of NSAIDs. Flunixin-d3, diclofenac-d4, 4-aminoantipyrine-d3, and phenylbutazone-d10 were used as internal standards. Performance characteristics were validated according to the Commission Decision 2002/657/EC (Off J Eur Communities, L221: 8 36). Recovery percentages varied between 81 and 114% for bovine meat and between 79 and 118% for milk. Repeatability percentages were within the range of 1-12% for meat and between 1 and 17% for milk, whereas the intralaboratory reproducibility varied between 3 and 19% for meat and between 3 and 23% for milk. The decision limit and the detection capability for bovine meat were within the range of 0.5-579 MUg kg(-1)and 0.6-642 MUg kg(-1), respectively. Those for milk were within the range of 0.12-55 MUg kg(-1) and 0.14-61 MUg kg(-1), respectively. The methods developed were successfully applied for proficiency test samples and routine samples analyzed in the laboratory. The methodology concerns fast, user friendly, and sensitive methods, which can be easily extended for other compounds and matrices. In general, such multiresidue methods contribute to the reduction of human exposure to these veterinary drug residues by consumption of contaminated bovine-derived products such as meat and milk. PMID- 25814275 TI - Multiplex detection of food allergens and gluten. AB - To help safeguard the food supply and detect the presence of undeclared food allergens and gluten, most producers and regulatory agencies rely on commercial test kits. Most of these are ELISAs with a few being PCR-based. These methods are very sensitive and analyte specific, requiring different assays to detect each of the different food allergens. Mass spectrometry offers an alternative approach whereby multiple allergens may be detected simultaneously. However, mass spectrometry requires expensive equipment, highly trained analysts, and several years before a quantitative approach can be achieved. Using multianalyte profiling (xMAP(r)) technology, a commercial multiplex test kit based on the use of established antibodies was developed for the simultaneous detection of up to 14 different food allergens plus gluten. The assay simultaneously detects crustacean seafood, egg, gluten, milk, peanut, soy, and nine tree nuts (almond, Brazil nut, cashew, coconut, hazelnut, macadamia, pine nut, pistachio, and walnut). By simultaneously performing multiple tests (typically two) for each analyte, this magnetic bead-based assay offers built-in confirmatory analyses without the need for additional resources. Twenty-five of the assays were performed on buffer extracted samples, while five were conducted on samples extracted using reduced-denatured conditions. Thus, complete analysis for all 14 allergens and gluten requires only two wells of a 96-well microtiter plate. This makes it possible to include in a single analytical run up to 48 samples. All 30 bead sets in this multiplex assay detected 5 ng/mL of food allergen and gluten with responses greater than background. In addition, 26 of the bead sets displayed signal/noise ratios of five or greater. The bead-based design makes this 30-plex assay expandable to incorporate new antibodies and capture/detector methodologies by ascribing these new detectors to any of the unassigned bead sets that are commercially available. PMID- 25814274 TI - pH sensitivity of FRET reporters based on cyan and yellow fluorescent proteins. AB - It is generally acknowledged that the popular cyan and yellow fluorescent proteins carried by genetically encoded reporters suffer from strong pH sensitivities close to the physiological pH range. We studied the consequences of these pH responses on the intracellular signals of model Forster resonant energy transfer (FRET) tandems and FRET-based reporters of cAMP-dependent protein kinase activity (AKAR) expressed in the cytosol of living BHK cells, while changing the intracellular pH by means of the nigericin ionophore. Although the simultaneous pH sensitivities of the donor and the acceptor may mask each other in some cases, the magnitude of the perturbations can be very significant, as compared to the functional response of the AKAR biosensor. Replacing the CFP donor by the spectrally identical, but pH-insensitive Aquamarine variant (pK1/2 = 3.3) drastically modifies the biosensor pH response and gives access to the acid transition of the yellow acceptor. We developed a simple model of pH-dependent FRET and used it to describe the expected pH-induced changes in fluorescence lifetime and ratiometric signals. This model qualitatively accounts for most of the observations, but reveals a complex behavior of the cytosolic AKAR biosensor at acid pHs, associated to additional FRET contributions. This study underlines the major and complex impact of pH changes on the signal of FRET reporters in the living cell. PMID- 25814278 TI - Can medical students study happily? PMID- 25814277 TI - Endorsement of Criminal Behavior Amongst Offenders: Implications for DSM-5 Gambling Disorder. AB - The fifth edition of the diagnostic and statistical manual (DSM) has changed the scoring threshold for a gambling disorder (GD) from five criteria to four and eliminated the illegal acts criterion. The impact of these changes was examined with data from a correctional population (N = 676) in Ontario, Canada. The offenders completed a self-report survey that included the Canadian problem gambling index, the South Oaks Gambling Screen and the DSM-IV criteria. Changing the threshold from 5 to 4 improved the convergent validity for GD and resulted in an increase in the percentage of offenders diagnosed with a GD from 7.4 to 10.2 %. The results also indicate that the illegal acts criterion contributes to the convergent validity of GD. The evidence supports the change in the threshold from five to four, but also reinforces the importance of examining illegal acts when dealing with an offender population. The incorporation of illegal acts into the "lying to others" criteria appears to make up, to some extent, for the removal of the illegal acts criterion. PMID- 25814279 TI - What kind of physicians should we foster? PMID- 25814280 TI - "I'm Not Happy, But I Don't Care": Help-Seeking Behavior, Academic Difficulties, and Happiness. AB - PURPOSE: Medical education is perceived as being very stressful, which leads to declines in subjective well-being in medical students. Therefore, student counseling is becoming an exigent issue. The goal of this study was to investigate the academic difficulties and subjective well-being of medical students to identify their needs with regard to counseling. In addition, we analyzed help-seeking behaviors of students to develop an effective counseling program. METHODS: We performed a survey (n=205) to determine the extent to which medical students encounter academic difficulties in their lives in medical school and how they attempt to resolve their problems. In addition, we used the Oxford Happiness Scale to examine the relationships between academic performance, previous help-seeking behavior, and happiness in medical students. RESULTS: Of various types of problems, 62% of medical students perceived learning difficulties to be the most serious issue in medical school. Despite encountering difficulties, more than 67% of students failed to seek help from faculty or their fellow students. There was a significant relationship between happiness score and previous help-seeking behavior. A lack of perceived seriousness was identified as the most significant barrier to seeking help. CONCLUSION: Access to counseling programs must be improved for students with apparent academic difficulties who do not seek counseling. Through such programs, students can learn and practice methods of coping with their difficulties and develop medical and professional competence. PMID- 25814276 TI - Mediational Role of Age of Onset in Gambling Disorder, a Path Modeling Analysis. AB - The aim of the study is to assess a mediational pathway, which includes patients' sex, personality traits, age of onset of gambling disorder (GD) and gambling related variables. The South Oaks Gambling Screen, the Symptom Checklist (SCL-90 R) and the Temperament and Character Inventory-R were administered to a large sample of 1632 outpatients attending a specialized outpatient GD unit. Sociodemographic variables were also recorded. A Structural Equation Model was adjusted to assess the pathway. Age of onset mediated between personality profile (novelty seeking and self-transcendence) and GD severity and depression symptoms (measured by SCL-90-R). Sex had a direct effect on GD onset and depression symptoms: men initiated the GD earlier and reported fewer depression symptoms. Age of onset is a mediating variable between sex, personality traits, GD severity and depression symptoms. These empirical results provide new evidence about the underlying etiological process of dysfunctional behaviors related to gambling, and may help to guide the development of more effective treatment and prevention programs aimed at high-risk groups such as young men with high levels of novelty seeking and self-transcendence. PMID- 25814281 TI - The effect of counseling for interpersonal relationship using myers-briggs type indicator. AB - PURPOSE: There are large differences between medical school curricula and those of other disciplines and graduate schools. Counseling program is designed to help participants understand their innate tendencies and have indirect experiences with the 16 Myers-Briggs Type Indicator (MBTI) types, which can lead to better interpersonal relationships. METHODS: The experimental and control groups, which were sampled randomly, comprised 34 students each. Each group was consisted of 17 females and 17 males. We implemented a counseling program (understanding oneself, understanding others) only to the experimental group, not the control group. The effects of the program were analyzed by t-test and analysis of covariance (ANCOVA). The data were analyzed using SPSS 17.0 Window. RESULTS: For the Human relationship scale as a whole, the experimental group showed an increase from 3.641 to 3.846 (p=0.001). With regard to the subcategories, satisfaction increased from 3.705 to 4.022 (p=0.000), trust increased from 3.480 to 3.715 (p=0.015), intimacy increased from 3.833 to 4.019 (p=0.007), and openness increased from 3.435 to 3.700 (p=0.006). CONCLUSION: This program improved interpersonal relationships by helping new students understand each other, build a rapport, and understand their personalities well with open minded attitudes. Their relationships gradually became more intimate than awkward through this program. PMID- 25814282 TI - Experience of Teaching a Class with a Film: Cognitive Changes with Regard to HIV. AB - PURPOSE: The aim of this study was to describe our experience of a class, using a film that deals with the social issues of human immunodeficiency virus (HIV), and the results of surveys before and after the class. METHODS: One hundred fifty-six second-year medical students were surveyed with self-questionnaires (9-point Likert scale) before, immediately after, and 2 years after a class that viewed a film ('Philadelphia', 1993). The same survey, comprising 4 items, was administered to 81 non-medical students in the same university. RESULTS: In 156 medical students, 153 (98%) answered the questionnaires. Before the class, there was no significant difference between medical and non-medical students with regard to the cognition of social isolation of HIV-infected persons (4.13 vs. 4.43, p=0.307). immediately after the class, medical student' cognition changed significantly in the positive direction on all items, irrespective of age, sex, and course grade. Two years after the class, this positive effect remained significant on 2 items: 'social isolation of HIV-infected persons' and 'casual contact with an HIV-infected person.' CONCLUSION: A film can be used to reinforce medical education in the affective domain. PMID- 25814284 TI - Experience of Bedside Teaching during Clerkship in Pulmonary Medicine for Improving Clinical Performance. AB - PURPOSE: Although the importance of bedside teaching is generally recognized, there is no published report on the actual experience or effects of bedside teaching in Korea. We aimed to study the effects and share the experience of bedside teaching during a clerkship in pulmonary medicine. METHODS: Bedside teaching was administered to 120 students through Year 3. To evaluate the improvement in clinical performance as a result of bedside teaching, students took the clinical performance examination (CPX) pre- and post-clerkship. They also completed a questionnaire about their perception of self-competence with regard to clinical performance. We analyzed the CPX scores and questionnaires. RESULTS: After introducing bedside teaching, CPX score on the pulmonary case increased from 48.9 to 60.1 between pre- and post-clerkship, respectively (p<0.001). Students had higher self-assessments of competency on the CPX, and their satisfaction with the clerkship increased. CONCLUSION: This study demonstrates that bedside teaching is effective in improving the clinical performance of medical students. PMID- 25814283 TI - Usefulness of a PC-Based Digitalized Recording System for Cystoscopy in Medical Education. AB - PURPOSE: Multimedia can be used to understand the basic anatomy and pathological features of the bladder, providing more intuitive knowledge than traditional education methods. Cystoscopy is one of the most fundamental and important diagnostic procedures for detecting pathology in the bladder. Thus, we developed a PC-based digitalized recording device and electronic document to create an electronic medical record to perform cystoscopy and used them for medical education. METHODS: To share them with an educatee, cystoscopic images from a camera unit were shown on the monitor of a personal computer, which was installed with an interface device with an S-VHS input. With these cystoscopic images, the operator could provide some information on important structures in the bladder, such as bilateral ureteral orifices, the verumontanum and the trigone to the educatee. Also, simple questionnaires were given to medical students to evaluate the effectiveness and value of this system. RESULTS: Cystoscopic images could be transferred to the monitor with considerable ease and quality through the personal computer. This system was effective and valuable in teaching the normal anatomy and pathology of the bladder. Also, based on the results of the questionnaire, we concluded that this system provides high-quality images that are sufficient to relay medical information and is superior to traditional methods with regard to educational effectiveness and increasing one's understanding of medical diseases. CONCLUSION: The PC-based recording system for cystoscopy substitutes for commercial recording devices for medical purposes, and provides sufficient medical information to medical students to allow them to understand the normal anatomy and pathological structure of the bladder. PMID- 25814285 TI - Developing and testing an evaluation tool to measure clinical teaching. AB - PURPOSE: Teaching evaluation tools can be used to provide feedback to medical educators and help them improve their teaching skills. The purpose of this study was to develop a clinical teaching evaluation tool and test its efficacy. METHODS: The draft tool was developed based on clinical education literature and was modified by the stakeholder groups. To examine the quality of the instrument, content and construct validity, as well as reliability and fitness were analyzed. Content validity was tested by the stakeholder groups using a survey, and construct validity was verified by confirmatory factor analysis using LISREL 8.8. Internal consistency of items was assessed thorough Cronbach alpha estimation. Rasch analysis using Winstep 3.65 was performed to estimate the fitness of the tool. RESULTS: The resulting tool consisted of 4 large categories, 25 small categories, and 43 items. According to the test results, the average importance of all 43 items was 4.03 (3.63 to 4.29). Cronbach alpha was 0.9689, and the correlation coefficients between the items were high. With regard to construct validity, 10 items needed minor modifications in the category setting. As the infit (0.76 to 1.23) and outfit (0.75 to 1.40) indices show, 42 items were fit to the item response theory. CONCLUSION: The clinical teaching evaluation tool that has been developed in this study is valid and reliable and fits the item response theory. It can be used as an evaluation method in a variety of clinical teaching settings. PMID- 25814286 TI - The strategies of feedback to improve medical students' performance. PMID- 25814288 TI - LRG1 suppresses the migration and invasion of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a malignant tumor driven by complex pathological mechanisms and is characterized by fast progression and poor prognosis. The main cause of death in HCC patients is tumor metastasis. However, underlying molecular mechanisms of metastasis are largely unknown in HCC. In the present study, a novel metastasis-related gene, leucine-rich-alpha-2-glycoprotein 1 (LRG1), was identified in HCC. We revealed that LRG1 expression was downregulated in HCC tissues by quantitative real-time PCR and immunohistochemical staining. In vitro assays demonstrated LRG1 had no effect on cell proliferation. Migratory and invasive potential of HCC cells was reduced by ectopic overexpression of LRG1, whereas silencing LRG1 could enhance migration and invasion of HCC cells. Furthermore, exogenous recombinant human protein of LRG1 could inhibit migration and invasion of HCC cells in vitro. The above findings indicate that LGR1 is involved in the inhibition of HCC metastasis and it may function as a novel metastasis suppressor in HCC. PMID- 25814287 TI - Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer. AB - Wingless-type (Wnt) family of secreted glycoproteins is a group of signal molecules implicated in oncogenesis. Abnormal activation of Wnt signal pathway is associated with a variety of human cancers, including non-small cell lung cancer (NSCLC). Wnt antagonists, such as the secreted frizzled-related protein (SFRP) family, Wnt inhibitory factor-1 (WIF-1) and cerberus, inhibit Wnt signal pathway by directly binding to Wnt molecules. Norcantharidin (NCTD) is known to possess anticancer activity but less nephrotoxicity than cantharidin. In this study, we found that NCTD inhibited cell proliferation, induced apoptosis, arrested cell cycle and suppressed cell invasion/migration in vitro. Additionally, Wnt signal pathway transcription was also suppressed. NCTD treatment blocked cytoplasmic translocation of beta-catenin into the nucleus. Alterations of apoptosis-related proteins, such as Bax, cleaved caspase-3 (pro-apoptotic) and Bcl-2 (anti apoptotic), had been detected. Furthermore, the expression levels of WIF-1 and SFRP1 were significantly increased in NCTD-treated groups compared with negative control (NC) groups. Abnormal methylation was observed in NC groups, while NCTD treatment promoted WIF-1 demethylation. The present study revealed that NCTD activated WIF-1 via promoter demethylation, inhibiting the canonical Wnt signal pathway in NSCLC, which may present a new therapeutic target in vivo. PMID- 25814289 TI - Detection of Autoantibodies Against Myelin Oligodendrocyte Glycoprotein in Multiple Sclerosis and Related Diseases. AB - Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with different inflammatory demyelinating diseases of the central nervous system, such as childhood multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica spectrum disorders (NMOSD). We describe here in detail a sensitive cell-based assay that allows the identification of autoantibodies against MOG in serum. PMID- 25814290 TI - Reprint of "Mathematics as verbal behavior". AB - "Behavior which is effective only through the mediation of other persons has so many distinguishing dynamic and topographical properties that a special treatment is justified and indeed demanded" (Skinner, 1957, p. 2). Skinner's demand for a special treatment of verbal behavior can be extended within that field to domains such as music, poetry, drama, and the topic of this paper: mathematics. For centuries, mathematics has been of special concern to philosophers who have continually argued to the present day about what some deem its "special nature." Two interrelated principal questions have been: (1) Are the subjects of mathematical interest pre-existing in some transcendental realm and thus are "discovered" as one might discover a new planet; and (2) Why is mathematics so effective in the practices of science and engineering even though originally such mathematics was "pure" with applications neither contemplated or even desired? I argue that considering the actual practice of mathematics in its history and in the context of acquired verbal behavior one can address at least some of its apparent mysteries. To this end, I discuss some of the structural and functional features of mathematics including verbal operants, rule-and contingency-modulated behavior, relational frames, the shaping of abstraction, and the development of intuition. How is it possible to understand Nature by properly talking about it? Essentially, it is because nature taught us how to talk. PMID- 25814291 TI - Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats. AB - Insulin resistance is the primary characteristic of type 2 diabetes and results from insulin signaling defects. Cocoa has been shown to exert anti-diabetic effects by lowering glucose levels. However, the molecular mechanisms responsible for this preventive activity and whether cocoa exerts potential beneficial effects on the insulin signaling pathway in the liver remain largely unknown. Thus, in this study, the potential anti-diabetic properties of cocoa on glucose homeostasis and insulin signaling were evaluated in type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed a significant decrease in body weight gain, glucose and insulin levels, as well as an improved glucose tolerance and insulin resistance. Cocoa-rich diet further ameliorated the hepatic insulin resistance by abolishing the increased serine-phosphorylated levels of the insulin receptor substrate 1 and preventing the inactivation of the glycogen synthase kinase 3/glycogen synthase pathway in the liver of cocoa-fed ZDF rats. The anti hyperglycemic effect of cocoa appeared to be at least mediated through the decreased levels of hepatic phosphoenolpyruvate carboxykinase and increased values of glucokinase and glucose transporter 2 in the liver of ZDF-Co rats. Moreover, cocoa-rich diet suppressed c-Jun N-terminal kinase and p38 activation caused by insulin resistance. These findings suggest that cocoa has the potential to alleviate both hyperglycemia and hepatic insulin resistance in type 2 diabetic ZDF rats. PMID- 25814292 TI - Patient care is at risk as NHS faces substantial deficit, says think tank. PMID- 25814294 TI - [Medicina Intensiva: a task of all of us]. PMID- 25814293 TI - Capturing the cloud of diversity reveals complexity and heterogeneity of MRSA carriage, infection and transmission. AB - Genome sequencing is revolutionizing clinical microbiology and our understanding of infectious diseases. Previous studies have largely relied on the sequencing of a single isolate from each individual. However, it is not clear what degree of bacterial diversity exists within, and is transmitted between individuals. Understanding this 'cloud of diversity' is key to accurate identification of transmission pathways. Here, we report the deep sequencing of methicillin resistant Staphylococcus aureus among staff and animal patients involved in a transmission network at a veterinary hospital. We demonstrate considerable within host diversity and that within-host diversity may rise and fall over time. Isolates from invasive disease contained multiple mutations in the same genes, including inactivation of a global regulator of virulence and changes in phage copy number. This study highlights the need for sequencing of multiple isolates from individuals to gain an accurate picture of transmission networks and to further understand the basis of pathogenesis. PMID- 25814295 TI - Sonographic assessment of lower uterine segment thickness at term in women with previous cesarean delivery. AB - AIM: The purpose of this study was to establish the validity of abdominal sonographic evaluation of lower uterine segment (LUS) thickness in full-term pregnancies with a single previous cesarean section, and to assess the usefulness of measuring LUS thickness in predicting the risk of uterine dehiscence. METHODS: Three hundred and thirty-six women with a single previous cesarean section who had an ultrasound measurement of the LUS thickness in pregnancy were enrolled. Abdominal sonographic assessment of LUS was carried out within 2 weeks of delivery. Sonographic measurements were correlated visual finding of a uterine scar at the time of the iterative cesarean section. Receiver operating curve analyses has been used to determine the detection rate and the risk of each actual value of LUS thickness vs. a thin uterine scar. RESULTS: In our present study, 2.5 mm was considered the critical cut-off value of the LUS thickness. This critical cut-off value was derived from the ROC curve with sensitivity, specificity, PPV, and NPV of 90.9, 84, 71.4, and 95.5 %, respectively (using transabdominal ultrasound). The linear regression model analysis revealed that full LUS thickness of <2.5 mm was the only factor to be correlated with translucent lower uterine segment (C3) (8.8 vs. 0 %; P = 0.02). CONCLUSION: Full LUS thickness of <2.5 mm is associated with a higher risk of uterine dehiscence. PMID- 25814296 TI - Identifying the impact of inflammatory breast cancer on survival: a retrospective multi-center cohort study. AB - PURPOSE: Inflammatory breast cancer (IBC) represents a rare and aggressive form of cancer with negative prognosis and high rate of recurrence. The purpose of this retrospective multi-center study was to evaluate the effect of IBC on overall and disease-free survival. Furthermore we analyzed the influence of hormone and Her2 receptor expression on inflammatory breast cancer cells on the clinical outcome of patients. METHODS: This retrospective German multi-center study included 11,780 patients with primary breast cancer recruited from 1992 to 2008. In this sub-group analysis we focused on 70 patients with IBC. RESULTS: Despite the relatively small sample size, we could confirm the aggressiveness of inflammatory breast cancer and the different clinical behavior of IBC subtypes. It could be demonstrated that the lack of expression of hormone receptors on tumor cells is associated with a more aggressive clinical course and decreased overall and disease-free survival. Higher incidence of Her2 overexpression, that is typically associated with poor prognostic outcome among women with non-IBC tumors, seems however to have no prognostic significance. CONCLUSIONS: This BRENDA sub-group analysis, on a German cohort of breast cancer patients confirmed the negative outcome of IBC and the different clinical behavior of IBC subtypes. The best management of IBC requires intensive coordination and cooperation between various clinical disciplines involved in the treatment of IBC patients. Moreover there is a need to identify IBC-specific targeted therapies to improve the curing prospects of this subtype of cancer. PMID- 25814297 TI - Dual-energy contrast-enhanced spectral mammography (CESM). AB - Dual-energy contrast-enhanced mammography is one of the latest developments in breast care. Imaging with contrast agents in breast cancer was already known from previous magnetic resonance imaging and computed tomography studies. However, high costs, limited availability-or high radiation dose-led to the development of contrast-enhanced spectral mammography (CESM). We reviewed the current literature, present our experience, discuss the advantages and drawbacks of CESM and look at the future of this innovative technique. PMID- 25814298 TI - Cerebral aneurysm in a 12-year-old boy with a STAT3 mutation (hyper-IgE syndrome). PMID- 25814299 TI - Acute discrimination between superficial-partial and deep-partial thickness burns in a preclinical model with laser speckle imaging. AB - A critical need exists for a robust method that enables early discrimination between superficial-partial and deep-partial thickness burn wounds. In this study, we report on the use of laser speckle imaging (LSI), a simple, non invasive, optical imaging modality, to measure acute blood flow dynamics in a preclinical burn model. We used a heated brass comb to induce burns of varying severity to nine rats and collected raw speckle reflectance images over the course of three hours after burn. We induced a total of 12 superficial-partial and 18 deep-partial thickness burn wounds. At 3h after burn we observed a 28% and 44% decrease in measured blood flow for superficial-partial and deep-partial thickness burns, respectively, and that these reductions were significantly different (p=0.00007). This preliminary data suggests the potential role of LSI in the clinical management of burn wounds. PMID- 25814301 TI - Tuberculosis and survival in past populations: A paleo-epidemiological appraisal. AB - Historical assessments of the last two centuries consistently placed tuberculosis as the leading cause of mortality. However, for earlier periods, we can only calculate the frequencies of archaeological bone lesions, which tell us little about the real impact of the disease on mortality. These lesions are usually observed in individuals who have developed immune resistance, which is visible as healed osteo-articular lesions. This study aimed to test the differential impacts of tuberculosis, cribra orbitalia and cribra femoris on adult survival and sex based survival. We analyzed 28 French adult samples from the Antiquity and the Early Middle Ages. The age-at-death of 1480 individuals was estimated using cementochronology. Survival curves and median age-at-death were calculated to test new hypotheses that challenge the parasitic and deficiency theories of bone stress markers. Comparisons between carriers and non-carriers provided new information concerning the plausible causes of bone stress markers related to infections and TB. The most likely hypothesis is skeletal demineralization and osteoclastic resorption, which are usually observed close to tubercular granuloma or distant from active lesions. The bone marrow niche of Mycobacterium tuberculosis within CD271(+) BM-MSCs stem cells is the proposed explanation for the localized cortical resorption that is observed in bone stress markers. PMID- 25814300 TI - Two positive tuberculosis cases in the late Nigrovits family, 18th century, Vac, Hungary. AB - Two mummies of the Hungarian mummy collection from Vac were the subjects of anthropological, paleopathological, radiological, paleomicrobiological, paleohistological and paleoproteomic studies. Both individuals belonged to the same family. The father, Jozsef Nigrovits (No 29), died at the age of 55 on the 11th of November 1793; his son, Antal Nigrovits (No 54), died on the 16th of July 1803, at the age of 22. They lived in the 18th century in Vac, a small town in northern Hungary. The macroscopic examination of the son showed a severely deformed neck and back region; the father has no visible mark of any illnesses. As earlier researches showed that tuberculosis was widespread in the community, the etiology of these deformities was examined. The paleomicrobiological results found that both individuals were infected with tuberculosis. Although they suffered from TB, the CT scan data of the bodies and their 3D reconstructions showed no skeletal evidence of tuberculosis. The deformity of the son turned to be a developmental abnormality of unknown origin, but no Pott's gibbus was present. PMID- 25814302 TI - Prevalence of drug resistant Mycobacterium tuberculosis among children in China. AB - The available data on the epidemic of drug resistant tuberculosis (TB) among children in China is limited. This study attempted to clarify the drug resistance profiles of clinical strains isolated from children and estimate risk factors related to acquisition of drug resistance. All Mycobacterium tuberculosis strains from children (age <15 years) and adolescent (age 15-18 years) TB patients received in the strain library of Chinese Center for Disease Control and Prevention between January 2005 and December 2012 were included in the study. A study collection included 450 clinical isolates (100 from children, 159 from adolescents, and 191 from adults) from all over China. Drug susceptibility testing was performed by a proportion method. As a result, the drug resistance and multi-drug resistance (MDR) rates in children were 55% (55/100) and 22% (22/100), respectively. In children with MDR-TB, new cases accounted for 40.9% (9/22). Compared with adults, the drug resistance rates were similar in all subgroups (new cases, previously treated cases and all cases) of children (P > 0.05), except for the lower resistance rate to isoniazid in total cases of children (P = 0.011). Patient related information was included in the MDR-TB association analysis. The treatment history was found to be strongly associated with MDR-TB in all three age groups (P < 0.05). Our results demonstrate that the prevalence of drug resistant TB in children in China is alarmingly high and similar to that seen in adults. In contrast, in adolescents, the drug resistance rate to most tested drugs was lower than in adults. Primary transmission and inadequate treatment are two equally important factors for the high MDR-TB rate in children. Thus, major efforts in the TB control in children should focus on decreasing the transmission of drug resistant TB and early testing of drug resistance. PMID- 25814303 TI - [Association of air-pollution with acute myocardial infarction: A case-crossover study]. AB - BACKGROUND: A large number of studies have demonstrated an association between ambient air pollutant exposures and acute myocardial infarctions (AMI). Case crossover methods are frequently used for analyzing the acute health effects of air pollution. Nevertheless, only a few studies controlled for potential confounders like other air pollutants and temperature. METHODS: The defined geographic entity for the collection of acute myocardial infarctions was composed of 15 municipalities in Charleroi. Charleroi is a relatively highly polluted region in Wallonia, the South of Belgium. The analyses presented hereafter concern patients in the 25-74 years age range over time from 1999 to 2009. Ambient concentrations of PM10, O3, NO2, CO and temperature were available from stationary monitors during this time period. A time-stratified case-crossover approach was applied. Season stratified analysis and analysis matching for environmental confounders were also performed. RESULTS: A total of 3303 AMIs were analyzed during the study period. For the entire year, O3 was significantly associated with AMI, OR=1.028 (CI95%: 1.003-1.054). The highest associations (for a 10 MUg.m(-3) rise in pollutant levels) between air pollution and myocardial infarction were observed for PM10 and O3 during the warm period, OR=1.086 (CI95%: 1.020-1.151) and 1.064 (CI95%: 1.024-1.105), respectively. Matching cases and controls for temperature produced weaker association between O3 and AMI (OR=1.003, CI95%: 0.974-1.032). In contrast, this matching had no effect on the association between PM10 and AMI. The adjustment for NO2 concentration decreased the association between PM10 and AMI. CONCLUSIONS: The results of this study reinforce the evidence of the short-term effects of air pollution on acute myocardial infarction, especially during the warm season. This also suggests that the case-crossover method is a suitable tool in studying the association between acute events and air pollution. Controlling for potential environmental confounding effects is also feasible with this method. PMID- 25814304 TI - Cause, correlation, conjecture. PMID- 25814305 TI - New genomes clarify mimicry evolution. AB - For over 100 years, it has been known that polymorphic mimicry is often switched by simple mendelian factors, yet the physical nature of these loci had escaped characterization. Now, the genome sequences of two swallowtail butterfly (Papilio) species have enabled the precise identification of a locus underlying mimicry, adding to unprecedented recent discoveries in mimicry genetics. PMID- 25814306 TI - Transcriptional mimicry by tumor-associated stroma. AB - Recent molecular classification of colorectal cancer (CRC) has identified a poor prognosis transcriptional subtype associated with mesenchymal traits. New studies used CRC transcriptomic data to show that tumor-associated stroma mimics the gene signature of epithelial-to-mesenchymal transition (EMT) and found no evidence for EMT of colorectal tumor cells. PMID- 25814307 TI - Symbiotic plant-fungi interactions stripped down to the root. AB - Mycorrhizal fungi live in the roots of host plants and are crucial components of all forest ecosystems. A large-scale study of fungal genomics provides new insights into the evolution of mycorrhizae and a deep exploration of mycorrhizal diversity that helps to uncover the molecular and genetic details of fungal symbiotic relationships with plants. PMID- 25814313 TI - Corrigendum: Common variants in ACYP2 influence susceptibility to cisplatin induced hearing loss. PMID- 25814314 TI - Introduction for the special issue on bioactive heterocycles. PMID- 25814316 TI - Attentional Bias in Psychopathy: An Examination of the Emotional Dot-Probe Task in Male Jail Inmates. AB - Numerous studies have identified differences in the identification of emotional displays between psychopaths and non-psychopaths; however, results have been equivocal regarding the nature of these differences. The present study investigated an alternative approach to examining the association between psychopathy and emotion processing by examining attentional bias to emotional faces; we used a modified dot-probe task to measure attentional bias toward emotional faces in comparison with neutral faces, among a sample of male jail inmates assessed using the Psychopathy Checklist-Revised (PCL-R). Results indicated a positive association between psychopathy and attention toward happy versus neutral faces, and that this association was attributable to Factor 1 of the psychopathy construct. PMID- 25814315 TI - Cricothyroid Muscle Botulinum Toxin Injection to Improve Airway for Bilateral Recurrent Laryngeal Nerve Paralysis, A Case Series. AB - Bilateral vocal fold paralysis most commonly results from iatrogenic trauma to the recurrent laryngeal nerve during surgical procedures in the anterior neck. Patients may require tracheostomy because of acute or gradual onset of dyspnea and airway compromise. The intralaryngeal injection of Botox has been considered as a possible therapy for these airway symptoms of bilateral vocal fold paralysis. Chronic unopposed activity of intact cricothyroid muscles could potentially result in gradual medialization of the vocal folds in patients with bilateral recurrent laryngeal nerve paralysis. This case series describes three patients who successfully underwent injections of botulinum toxin into the bilateral cricothyroid muscles to offer sustained relief of dyspnea resulting from bilateral vocal fold paralysis. PMID- 25814317 TI - Low Self-Control Among South Korean Adolescents: A Test of Gottfredson and Hirschi's Generality Hypothesis. AB - Theoretical propositions and empirical tests of Gottfredson and Hirschi's general theory continue to permeate the criminological literature. Nevertheless, the vast majority of studies have been conducted in North America and some European countries. Only a handful of empirical works have been conducted in East Asia. To further test the generality assertion of Gottfredson and Hirschi, the current study examines low self-control's efficacy in predicting the involvement of South Korean adolescents in typical delinquency, drinking, smoking, Internet addiction, and smartphone addiction. The presented findings largely support the generality hypothesis, although the theorists' assertion seems to be somewhat overstated. PMID- 25814318 TI - Pharmacokinetics, safety, and tolerability of single and multiple-doses of pinocembrin injection administered intravenously in healthy subjects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pinocembrin is the most abundant flavonoid in propolis. Preclinical studies have suggested that pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro. To investigate the safety, tolerability and pharmacokinetics of a new neuroprotective agent, pinocembrin. MATERIALS AND METHOD: A double-blind, placebo controlled, randomized study was carried out in 58 healthy subjects. Single ascending doses of pinocembrin (20-150 mg) were evaluated in 5 cohorts. Multi dose was studied at pinocembrin 60 mg. RESULTS: Pinocembrin was well tolerated. No serious adverse events occurred. No subjects were discontinued because of a treatment emergent AE. Treatment related adverse event was acute urticaria. Two subjects in 150 mg cohort developed grade II urticaria during the study. One subject discontinued after 3 days at 60 mg bid because of diarrhea. In the single dose study, the mean peak plasma pinocembrin concentration was obtained at the end of the 30-min infusion. The Cmax ranged from 0.28 MUg mL(-1) to 2.46 MUg mL( 1). AUC (0,infinity) ranged from 10.34 MUg mL(-1) min to 89.34 MUg mL(-1) min. The T1/2 was similar across 5 dose groups, ranging from 40 to 55 min. Both urinary and feces excretion levels of pinocembrin were extremely low and similar among each dose groups, with mean values ranging from 0.07% to 0.17% and 0.94% to 1.94% of the administered dose, respectively. Linear increases in Cmax and AUC(0,infinity) were observed. The pharmacokinetics of pinocembrin in multiple dose was similar to those observed in the single-dose study, with no evidence of accumulation. Both urinary and feces excretion levels of pinocembrin were extremely low. CONCLUSIONS: Pinocembrin displayed linear plasma pharmacokinetics over the dose range, 20-150 mg and was well tolerated up to 120 mg day(-1) when administered intravenously to healthy adults. No major safety concerns were identified that would preclude further clinical development of pinocembrin injection. PMID- 25814319 TI - Ethnobotanical survey of medicinally important shrubs and trees of Himalayan region of Azad Jammu and Kashmir, Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Present study was commenced with an aim to document the indigenous knowledge of medicinally important shrubs and trees of Himalayan region of Azad Jammu and Kashmir, Pakistan. This is the first contribution to the quantitative ethnobotany of this region, as no reported data focusing on shrubs and trees from the area have been published. Study reported the ethnobotanical significance of medicinal plants for the treatment of various diseases. METHOD: Study was conducted during 2012-2014 following standard ethnobotanical methods. The ethnomedicinal data was collected through informed consent semi- structured interviews of 160 key informants. Documented data was analyzed by using quantitative indices of informant consensus factor (ICF), fidelity level (FL), use value (UV) and relative frequency citation (RFC). RESULTS: A total of 73 shrub and tree species belonging to 56 genera and 37 families were reported to be used ethnomedicinally for the treatment of various ailments. Medicinal plant diversity showed that Rosaceae was dominating family with (9 spp.) followed by Moraceae (7 spp.), Euphorbiaceae, Mimosaceae, Pinaceae, Rhamnaceae (4 spp. each), Oleaceae (3 spp.), Apocynaceae, Caesalpinaceae, Ebenaceae, Fagaceae, Lythraceae, Papilionaceae, Acanthaceae, Verbenaceae (2 spp. each) while remaining 22 families were represented by one species each. Leaves (23%) were highly utilized plant parts, followed by fruits (22%), bark (18%), seeds (10%), roots (9%), flowers (8%), whole plant and aerial parts (4% each) and stem (2%). Modes of preparation fall into 14 categories including powder (33 reports) followed by decoction (29 reports), paste (22 reports), juice (18 reports), infusion (12 reports), raw (8 reports), extract and latex (5 reports each), gum and oil (4 reports each), fresh part and pulp (2 reports each), chewed and cooked (1 report each). The highest FIC was recorded for Gastro-intestinal disorders (0.58) followed by nail, skin and hair disorders (0.44). Maximum fidelity level (FL=100%) was expressed by Abies pindrow, Adhatoda vasica, Bauhinia variegata and Cedrela serrata. Based on use value Juglans regia (0.88) was found most significant species followed by Acacia nilotica (0.83), Phyllanthus emblica (0.81), Pinus roxburghii (0.75) and Punica granatum (0.71). CONCLUSION: The area has a rich diversity of medicinally important shrub and tree species. The tradition of using plants for medicinal purposes is still alive in the local community but recently this tradition is gradually declining in new generation. Therefore awareness is needed to be raised among the local people on sustainable use and conservation of local flora. PMID- 25814320 TI - Correlation between ATLS training and junior doctors' anatomical knowledge of intercostal chest drain insertion. AB - OBJECTIVE: To review the ability of junior doctors (JDs) in identifying the correct anatomical site for intercostal chest drain insertion and whether prior Advanced Trauma Life Support (ATLS) training influences this. DESIGN: We performed a prospective, observational study using a structured survey and asked a group of JDs (postgraduate year 1 [PGY1] or year 2 [PGY2]) to indicate on a photograph the exact preferred site for intercostal chest drain insertion. SETTING: This study was conducted in a large metropolitan university hospital in South Africa. RESULTS: A total of 152 JDs participated in the study. Among them, 63 (41%) were men, and the mean age was 24 years. There were 90 (59%) PGY1 doctors and 62 (41%) PGY2 doctors. Overall, 28% (42/152) of all JDs correctly identified the site that was located within the accepted safe triangle. A significantly higher proportion of PGY2 doctors selected the correct site when compared with PGY1 doctors (39% vs 20%, p = 0.026). Those who had prior ATLS provider training were 6.8 times more likely to be able to identify the correct site (RR = 6.8, 95% CI: 3.7-12.5). CONCLUSIONS: Most of the JDs do not have sufficient anatomical knowledge to identify the safe insertion site for intercostal chest drain. Those who had undergone ATLS training were more likely to be able to identify the safe insertion site. PMID- 25814322 TI - Knockdown of adipokinetic hormone synthesis increases susceptibility to oxidative stress in Drosophila--a role for dFoxO? AB - Insect adipokinetic hormones (AKHs) are pleiotropic hormones known to play a protective role in response to oxidative stress (OS). However, the precise signaling pathways are unclear. We present evidence that AKH may primarily employ the Forkhead box class O transcription factor (FoxO) to exert this effect. The impact of knocking down AKH synthesis or its over-expression in its response to OS was studied in Drosophila melanogaster. AKH knockdown (AKH-RNAi) as well as AKH overexpression (AKH-oex) was achieved using the Gal-4/UAS system and controls were w(1118) (+/+), AKH-Gal4/+, UAS-AKH/+ and UAS-AKH-RNAi/+. Exposure to 80 MUM hydrogen peroxide (HP) revealed that AKH-RNAi flies showed significantly higher mortality than AKH-oex or the respective control lines. This susceptibility was evidenced by significantly enhanced levels of protein carbonyls - a biomarker of OS, in AKH-RNAi flies compared to controls and AKH-oex flies. Interestingly, AKH oex flies had the least amount of protein carbonyls. AKH-RNAi flies had significantly less dFoxO transcript and translated protein compared to control and AKH-oex flies in un-challenged condition as well as when challenged with HP. Sestrin - a major antioxidant defense protein and one of the targets of dFoxO - was also significantly down-regulated (both at mRNA and protein level) in AKH RNAi flies (both unchallenged and challenged with HP) compared to control flies and flies with over-expressed AKH. These findings imply that dFoxO may act downstream of AKH as a transcription factor to mediate response to OS in D. melanogaster. PMID- 25814321 TI - Accumulation and effects of metal mixtures in two seaweed species. AB - Metal pollution, due to various anthropogenic sources, may pose a threat to marine ecosystems. Metals can be introduced into food chains via bioaccumulation in primary producers, and may potentially lead to toxic effects. Macroalgae are used as food by a wide variety of organisms, and are therefore extremely important in aquatic systems. This study investigated the accumulation and effects of metals in two macroalgae species. The green seaweed, Ulva lactuca and the red seaweed, Agardhiella subulata were each concurrently exposed to five metals (Cu, Ni, Pb, Cd, and Zn) and U. lactuca was also exposed to each metal individually for 48 h. Metal accumulation in the seaweed was measured, and various photosynthetic parameters were assessed, using imaging pulse amplitude modulated (PAM) fluorometry. Increased metal accumulation occurred in both seaweed species after 48 h exposure to metal mixtures and each metal individually. The distribution of metals in both seaweed species changed with increasing metal exposure concentrations, resulting in higher proportions of Cu and Zn in the metal-exposed groups, as compared to respective controls. Further, U. lactuca accumulated higher concentrations of metals when exposed to each metal individually rather than in metal mixtures, suggesting interactions among metals for uptake and/or bioaccumulation. Significant impairment of photosynthetic parameters in U. lactuca was observed after exposure to 100 and 1000 MUg/L metal mixtures, as well as 100 MUg/L of either Cd or Cu. These results demonstrate metal bioaccumulation and toxic effects in important primary producers, and may have implications for higher trophic levels. PMID- 25814323 TI - A digital implementation of neuron-astrocyte interaction for neuromorphic applications. AB - Recent neurophysiologic findings have shown that astrocytes play important roles in information processing and modulation of neuronal activity. Motivated by these findings, in the present research, a digital neuromorphic circuit to study neuron astrocyte interaction is proposed. In this digital circuit, the firing dynamics of the neuron is described by Izhikevich model and the calcium dynamics of a single astrocyte is explained by a functional model introduced by Postnov and colleagues. For digital implementation of the neuron-astrocyte signaling, Single Constant Multiply (SCM) technique and several linear approximations are used for efficient low-cost hardware implementation on digital platforms. Using the proposed neuron-astrocyte circuit and based on the results of MATLAB simulations, hardware synthesis and FPGA implementation, it is demonstrated that the proposed digital astrocyte is able to change the firing patterns of the neuron through bidirectional communication. Utilizing the proposed digital circuit, it will be illustrated that information processing in synaptic clefts is strongly regulated by astrocyte. Moreover, our results suggest that the digital circuit of neuron astrocyte crosstalk produces diverse neural responses and therefore enhances the information processing capabilities of the neuromorphic circuits. This is suitable for applications in reconfigurable neuromorphic devices which implement biologically brain circuits. PMID- 25814325 TI - Evolutionary fire ecology: lessons learned from pines. AB - Macroevolutionary studies of the genus Pinus provide the oldest current evidence of fire as an evolutionary pressure on plants and date back to ca. 125 million years ago (Ma). Microevolutionary studies show that fire traits are variable within and among populations, especially among those subject to different fire regimes. In addition, there is increasing evidence of an inherited genetic basis to variability in fire traits. Added together, pines provide compelling evidence that fire can exert an evolutionary pressure on plants and, thus, shape biodiversity. In addition, evolutionary fire ecology is providing insights to improve the management of pine forests under changing conditions. The lessons learned from pines may guide research on the evolutionary ecology of other taxa. PMID- 25814326 TI - Translocator proteins, porphyrins and abiotic stress: new light? AB - After four decades of extensive studies, the role of membrane-bound Translocator proteins (TSPOs) remains unclear and even controversial. In light of recent insights into the structure and activity of TSPOs, showing that they cannot only bind, but also enzymatically photodegrade protoporphyrin IX, we discuss their emerging physiological roles and regulation. PMID- 25814324 TI - Relationship between metabolic control and self-monitoring of blood glucose in insulin-treated patients with diabetes mellitus. AB - OBJECTIVE: To assess the relationship between metabolic control (MC) and frequency of self-monitoring of blood glucose (SMBG) in insulin-treated patients with type 1 (T1DM) and type 2 (T2DM) diabetes mellitus, and to analyze the factors associated to MC. MATERIAL AND METHODS: A multicenter, cross-sectional, observational study was conducted in which endocrinologists enrolled diabetic patients treated with insulin who used a glucometer. The cut-off value for MC was HbA1c <= 7%. Grade of acceptance of the glucometer was assessed using a visual analogue scale (VAS). RESULTS: A total of 341 patients (53.5% males) with a mean age (SD) 52.8 (16.3) years, mean HbA1c of 7.69% (1.25) and 128 (37.5%) with T1DM and 211 (61.9%) with T2DM were evaluable. SMBG was done by 86.1% at least once weekly. No relationship was seen between MC and SMBG (P=.678) in the overall sample or in the T1DM (P=.940) or T2DM (P=.343) subgroups. In the logistic regression model, hyperglycemic episodes (Exp-b [risk] 1.794, P=0.022), falsely elevated HbA1c values (Exp-b 3.182, P=.005), and VAS (Exp-b 1.269, P=.008) were associated to poor MC in the total sample. Hyperglycemic episodes (Exp-b 2.538, P=.004), falsely elevated HbA1c values (Exp-b 3.125, P=.012), and VAS (Exp-b 1.316, P=.026) were associated to poor MC in the T2DM subgroup, while body mass index (Exp-b 1.143, P=.046) was associated to poor MC in the T1DM subgroup. CONCLUSIONS: In this retrospective, non-controlled study on patients with DM treated with insulin who used a glucometer, no relationship was seen between the degree of metabolic control and frequency of use of the glucometer. PMID- 25814327 TI - Saying no to drugs. AB - Illicit drug use, and the associated health problems, is a frequent issue encountered by medical providers. Because of its salience as a piece of health care information, drug use history is often included in patient charts and presentations by house staff and medical students. However, if used and recorded inappropriately, drug use history can have significant long-lasting effects on the perception of patients in a system where they have little agency. PMID- 25814328 TI - Palliative medicine fellows attend to compassion fatigue using John Stone's 'Talking to the Family'. AB - For graduate medical education trainees, as well as contemporary practitioners, developing skills in recognizing compassion fatigue and practising self-care is vital to professional sustainability. The field of palliative medicine is no exception. In our fellowship programme, we use John Stone's poem, 'Talking to the Family,' to engage trainees in a professional development workshop on personal experiences and strategies for self-care. PMID- 25814329 TI - Competency-based veterinary education: an integrative approach to learning and assessment in the clinical workplace. AB - When graduating from veterinary school, veterinary professionals must be ready to enter the complex veterinary profession. Therefore, one of the major responsibilities of any veterinary school is to develop training programmes that support students' competency development on the trajectory from novice student to veterinary professional. The integration of learning and assessment in the clinical workplace to foster this competency development in undergraduate veterinary education was the central topic of this thesis. PMID- 25814330 TI - Reflecting upon multisource feedback as 'assessment for learning'. PMID- 25814331 TI - Assessment of comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry based methods for investigating 206 dioxin-like micropollutants in animal-derived food matrices. AB - This paper evaluates different multiresidue methods based on comprehensive two dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC*GC TOF/MS) to analyze dioxin-related micropollutants in complex food matrices. In a first step, the column sets Rtx-PCB/BPX-50 and Rtx-Dioxin2/BPX-50 were compared in terms of peak shape (width and symmetry) and resolution for the separation of polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p dioxins/dibenzofurans (PCDD/Fs) in solvent. A satisfactory separation of 206 dioxin-related micropollutants including the 17 toxic PCDD/Fs was achieved in 75 min with the column set Rtx-Dioxin2/BPX-50. In a second time, the GC*GC-TOF/MS method was spread to the analysis of dioxin-related micropollutants in complex food matrices. An extraction procedure including accelerated solvent extraction (ASE), centrifugal evaporation and gel permeation chromatography (GPC) was optimized. Starting with meat as a model matrix, a micropollutant spiking method was then set up by comparing seven methods in terms of recoveries and reproducibility. The method combining immersion of the meat in a large volume of solvent containing micropollutants followed by homogenization by blender induced recoveries in the acceptable range of 70-130% and satisfactory standard deviations (<=10%) for most of the compounds studied. Limits of detection of the GC*GC-TOF/MS method ranged between 50 and 100 pg/g of spiked fresh meat for PCBs and between 65 and 227 pg/g for PCDD/Fs. Potential applications of this method are discussed. PMID- 25814332 TI - Evaluation of injection methods for fast, high peak capacity separations with low thermal mass gas chromatography. AB - Low thermal mass gas chromatography (LTM-GC) was evaluated for rapid, high peak capacity separations with three injection methods: liquid, headspace solid phase micro-extraction (HS-SPME), and direct vapor. An Agilent LTM equipped with a short microbore capillary column was operated at a column heating rate of 250 degrees C/min to produce a 60s separation. Two sets of experiments were conducted in parallel to characterize the instrumental platform. First, the three injection methods were performed in conjunction with in-house built high-speed cryo focusing injection (HSCFI) to cryogenically trap and re-inject the analytes onto the LTM-GC column in a narrower band. Next, the three injection methods were performed natively with LTM-GC. Using HSCFI, the peak capacity of a separation of 50 nl of a 73 component liquid test mixture was 270, which was 23% higher than without HSCFI. Similar peak capacity gains were obtained when using the HSCFI with HS-SPME (25%), and even greater with vapor injection (56%). For the 100 MUl vapor sample injected without HSCFI, the preconcentration factor, defined as the ratio of the maximum concentration of the detected analyte peak relative to the analyte concentration injected with the syringe, was determined to be 11 for the earliest eluting peak (most volatile analyte). In contrast, the preconcentration factor for the earliest eluting peak using HSCFI was 103. Therefore, LTM-GC is demonstrated to natively provide in situ analyte trapping, although not to as great an extent as with HSCFI. We also report the use of LTM-GC applied with time of-flight mass spectrometry (TOFMS) detection for rapid, high peak capacity separations from SPME sampled banana peel headspace. PMID- 25814333 TI - Room-temperature cataluminescence from CO oxidation in a non-thermal plasma assisted catalysis system. AB - Cataluminescence (CTL) is a kind of chemiluminescence during catalytic reaction on surface of catalysts under a heated condition. Due to the low catalytic reactivity of CO, normally low intensity of CTL is obtained during heterogeneously catalytic oxidation of CO under heated conditions (normally higher than 150 degrees C), even catalyzed by precious-metal-based catalysts. Therefore, seeking enhanced CTL of CO at room temperature and using low-cost catalysts becomes significant. Here, CTL generated from CO oxidation was firstly reported at room temperature, which was carried out in a non-thermal plasma assisted (NTPA) catalysis system. With air acting as discharge gas, carrier gas as well as oxidant, a Mn/SiO2 nanomaterials-based NTPA catalysis system was fabricated for CO catalytic oxidation at room temperature, whose temperature was much lower than previous CTL methods. Relatively high and selective CTL responses were acquired during CO oxidation on surface of Mn/SiO2 nanomaterials, whereas no significant CTL signal was recorded without plasma assistance or on other metals doped SiO2 catalysts. Without any excitation light source or heating element, a low cost and simple CO sensor was fabricated by using common and easily synthesized catalysts. The present work has greatly simplified the constructions, and enlarged CTL applications. PMID- 25814334 TI - Interactions of nano-oxides with low-molecular-weight organic acids in a contaminated soil. AB - Various low-molecular-weight organic acids (LMWOAs) play an important role in the mobilisation of contaminants and their subsequent uptake by plants. Nano maghemite (NM) and an amorphous Mn oxide (AMO) were investigated for their stabilisation potential under simulated rhizosphere conditions in terms of their use during chemical stabilisation and aided phytostabilisation of metal(loid)s in contaminated soils. In order to understand the reactivity of these potential sorbents of contaminants in soils and subsequent mobility of metal(loid)s, a set of time-dependent batch leaching experiments was performed using a mix of acetic, lactic, citric, malic and formic acids simulating root exudates. Despite being relatively unstable under given conditions, the AMO proved to be an efficient amendment for rapid stabilisation of both metals and As compared to NM. Generally, low pH (~ 4) and the presence of citrate complexes resulted in higher mobility of metals in the non- and NM-amended soil. In contrast, the presence of AMO in the soil accelerated the neutralisation reactions related to pH increase and (co-) precipitation of secondary Fe/Mn/Al oxyhydroxides. Mineralogical transformations of the AMO showed to be crucial for contaminant immobilisation. PMID- 25814335 TI - A novel two-dimensional liquid chromatographic system for the online toxicity prediction of pharmaceuticals and related substances. AB - In this study, a novel two-dimensional liquid chromatographic (2D-LC) system was developed for simultaneous separation and toxicity prediction of pharmaceutical and its related substances. A conventional ODS column was used on the 1st-D to separate the sample; while, bio-partitioning micellar chromatography served as the 2nd-D to predict toxicity of the components. The established system was tested for the toxicity of ibuprofen and its impurities with known toxicity. With only one injection, ibuprofen and its impurities were separated on the 1st-D; and LC50 values of individual impurity were obtained based on the quantitative retention-activity relationships, which agreed well with the reported data. Furthermore, LC50 values of photolysis transformation products (TPs) of carprofen, ketoprofen and diclofenac acid (as unknown compounds) were screened in this 2D-LC system, which could be an indicator of the toxicity of these TPs and was meaningful for the environmental monitoring and drinking water treatment. The established 2D-LC system was cost-effective, time-saving and reliable, and was promising for fast online screening of toxicity of known and unknown analytes in the complex sample in a single step. It may find applications in environment, pharmaceutical and food, etc. PMID- 25814336 TI - Discrete limit and monotonicity properties of the Floquet eigenvalue in an age structured cell division cycle model. AB - We consider a cell population described by an age-structured partial differential equation with time periodic coefficients. We assume that division only occurs within certain time intervals at a rate [Formula: see text] for cells who have reached minimal positive age (maturation). We study the asymptotic behavior of the dominant Floquet eigenvalue, or Perron-Frobenius eigenvalue, representing the growth rate, as a function of the maturation age, when the division rate [Formula: see text] tends to infinity (divisions become instantaneous). We show that the dominant Floquet eigenvalue converges to a staircase function with an infinite number of steps, determined by a discrete dynamical system. This indicates that, in the limit, the growth rate is governed by synchronization phenomena between the maturation age and the length of the time intervals in which division may occur. As an intermediate result, we give a sufficient condition which guarantees that the dominant Floquet eigenvalue is a nondecreasing function of the division rate. We also give a counter example showing that the latter monotonicity property does not hold in general. PMID- 25814337 TI - Material deprivation and unemployment affect coercive sex among young people in the urban slums of Blantyre, Malawi: A multi-level approach. AB - We explore relations among material deprivation (measured by insufficient housing, food insecurity and poor healthcare access), socio-economic status (employment, income and education) and coercive sex. A binary logistic multi level model is used in the estimation of data from a survey of 1071 young people aged 18-23 years, undertaken between June and July 2013, in the urban slums of Blantyre, Malawi. For young men, unemployment was associated with coercive sex (odds ratio [OR]=1.77, 95% confidence interval [CI]: 1.09-3.21) while material deprivation (OR=1.34, 95% CI: 0.75-2.39) was not. Young women in materially deprived households were more likely to report coercive sex (OR=1.37, 95% CI: 1.07-2.22) than in non-materially deprived households. Analysis of local indicators of deprivation is critical to inform the development of effective strategies to reduce coercive sex in urban slums in Malawi. PMID- 25814339 TI - Population and forensic data for three sets of forensic genetic markers in four ethnic groups from Iran: Persians, Lurs, Kurds and Azeris. AB - A total of 255 individuals (Persians, Lurs, Kurds and Azeris) from Iran were typed for three sets of forensic genetic markers with the NGM SElectTM, DIPplex((r)) and Argus X-12 kits. Statistically significant deviations (P<=0.002) from Hardy-Weinberg expectations were observed for the insertion-deletion markers HLD97 and HLD93 after Holm-Sidak correction. Statistically significant (P<0.05) levels of linkage disequilibrium were observed between markers within two of the four studied X-chromosomal linkage groups. AMOVA analyses of the three sets of markers did not show population structure when the individuals were grouped according to their ethnic group. The Iranian population grouped closely to populations living geographically near to Iran based on pairwise FST distances. The matching probabilities ranged from 1 in 3.2*10(7) males by using haplotype frequencies of four X-chromosomal haplogroups to 1 in 3.4*10(21) individuals for the 16 autosomal STRs. PMID- 25814338 TI - Neighbourhood demolition, relocation and health. A qualitative longitudinal study of housing-led urban regeneration in Glasgow, UK. AB - We conducted a qualitative longitudinal study to explore how adult residents of disadvantaged urban neighbourhoods (Glasgow, UK) experienced neighbourhood demolition and relocation. Data from 23 households was collected in 2011 and 2012. Some participants described moves to new or improved homes in different neighbourhoods as beneficial to their and their families' wellbeing. Others suggested that longstanding illnesses and problems with the new home and/or neighbourhood led to more negative experiences. Individual-level contextual differences, home and neighbourhood-level factors and variations in intervention implementation influence the experiences of residents involved in relocation programmes. PMID- 25814341 TI - Monogenic autoinflammatory diseases: Cytokinopathies. AB - Rapid advances in genetics are providing unprecedented insight into functions of the innate immune system with identification of the mutations that cause monogenic autoinflammatory disease. Cytokine antagonism is profoundly effective in a subset of these conditions, particularly those associated with increased interleukin-1 (IL-1) activity, the inflammasomopathies. These include syndromes where the production of IL-1 is increased by mutation of innate immune sensors such as NLRP3, upstream signalling molecules such as PSTPIP1 and receptors or downstream signalling molecules, such as IL-1Ra. Another example of this is interferon (IFN) and the interferonopathies, with mutations in the sensors STING and MDA5, the upstream signalling regulator AP1S3, and a downstream inhibitor of IFN signalling, ISG15. We propose that this can be extended to cytokines such as IL-36, with mutations in IL-36Ra, and IL-10, with mutations in IL-10RA and IL 10RB, however mutations in sensors or upstream signalling molecules are yet to be described in these instances. Additionally, autoinflammatory diseases can be caused by multiple cytokines, for example with the activation of NF-kappaB/Rel, for which we propose the term Relopathies. This nosology is limited in that some cytokine pathways may be degenerate in their generation or execution, however provides insight into likely autoinflammatory disease candidates and the cytokines with which newly identified mutations may be associated, and therefore targeted. PMID- 25814340 TI - History of interleukin-4. AB - The history of the discovery and the development of our knowledge of IL-4 exemplifies the path of progress in biomedical science. There are unanticipated twists and turns although progress is made, sometimes quickly, other times far too slowly. Illustrative is the extended time from the first report of IL-4 in 1982 to the establishment of the efficacy of blocking IL-4 and its congener IL-13 in the treatment of moderate to severe asthma and atopic dermatitis, a period of 31years. The author was "present at the creation" and has been a participant or a witness to virtually all the major advances and recounts here his recollection of this history. PMID- 25814342 TI - Controlling the unfolded protein response-mediated life and death decisions in cancer. AB - Cancer cells are exposed to intrinsic (oncogene) or extrinsic (microenvironmental) challenges, leading to activation of stress response pathways. The unfolded protein response (UPR) is the cellular response to endoplasmic reticulum (ER) stress and plays a pivotal role in tumor development. Depending on ER stress intensity and duration, the UPR is either pro-survival to preserve ER homeostasis or pro-death if the stress cannot be resolved. On one hand, the adaptive arm of the UPR is essential for cancer cells to survive the harsh conditions they are facing, and on the other hand, cancer cells have evolved mechanisms to bypass ER stress-induced cell death, thereby conferring them with a selective advantage for malignant transformation. Therefore, the mechanisms involved in the balance between survival and death outcomes of the UPR may be exploited as therapeutic tools to treat cancer. PMID- 25814343 TI - Living donor bone banking: processing and discarding--from procurement to therapeutic use. AB - Skeletal muscle and osteoarticular tissue banks are responsible to procure, process, store and distribute tissues, from living and cadaveric donors. The procedures involve the application of protocols covering all aspects of the banking, ensuring the best tissue quality and maximum safety for the recipient. An analysis on the causes of bone tissue discarded by Biotar Tissue Bank between January 2005 and December 2012 was carried. Bone tissue was obtained from both hip and knee replacement (femoral heads and tibial plateau respectively) in living donors treated at different medical-surgical institutions in Argentina. These tissues were processed at the Bank to produce both frozen and lyophilized cancellous bone. Out of 3413 donated bones received by the Bank, 77.55 % resulted in final product, while the remaining 22.44 % was discarded in compliance with the quality standards of both the Bank and the regulatory authority. Comparing the last and the first year of the studied period, the number of discarded tissue increased 3.6 times, while the number of collected bones was approximately 10 times higher. Related to total disposed tissue, reactive serology was the most frequent cause (62.14 %), followed by inappropriate collection/storage of blood sample (30.81 %). A progressive reduction in the percentages of total discard was observed, and this was proportional to inappropriate collection/storage of blood sample. No significant differences were found in the discard rates due to positive serology throughout all the years studied. The success of a tissue bank requires full commitment of all the personnel especially the team members responsible for donor selection and the processing of allografts. It is important to critically screen donors in the early stages of donor recruitment. All of the procedures carried out by the tissue bank are parts of the quality control system which must be strictly carried out. Biotar Tissue Bank is continuously committed to ensure safety to the recipients. PMID- 25814344 TI - Can anxiety and depression, separately or in combination predict subjective health status 10 years post-PCI? PMID- 25814345 TI - Re: Wasfy et al. Guidelines versus decision analysis is the wrong conversation. PMID- 25814346 TI - Percutaneous treatment of aorto-ostial coronary lesions: Current challenges and future directions. AB - Flow-limiting aorto-ostial coronary lesions are clinically important because they subtend a large myocardial territory and may induce extensive myocardial ischemia. Diagnosis and treatment of these lesions is challenging and procedural success and clinical outcomes are inferior to non-ostial lesions. The purpose of this review is to summarize current knowledge regarding aorto-ostial percutaneous coronary intervention and to suggest novel approaches for optimizing these procedures. PMID- 25814347 TI - Testosterone may influence left ventricular diastolic function depending on previous myocardial infarction and smoking. PMID- 25814348 TI - Hybrid ABSORB bioresorbable vascular scaffold and drug eluting stent or hybrid BVS-DES percutaneous coronary intervention: Method and rationale for hybrid overlapping PCI. PMID- 25814350 TI - A case of intracerebral hemorrhage and apical ballooning: An important differential diagnosis in ST-segment elevation. PMID- 25814349 TI - Progression of matrixin and cardiokine expression patterns in an ovine model of heart failure and recovery. AB - BACKGROUND: The molecular mechanisms underlying the geometrical changes of the left ventricle during the progression to heart failure and recovery are not well defined. OBJECTIVE: Here we investigate the involvement of matrixins and cardiokines in an ovine model of pressure-induced left ventricular failure (LVF). METHODS: Fifteen sheep underwent supracoronary aortic banding with an inflatable cuff. A controlled and progressive increase of LV pressure was monitored echocardiographically. Endomyocardial biopsies were collected throughout the development of LVF and subsequent recovery after pressure unloading. RESULTS: Thirteen sheep developed LVF with a subsequent recovery. Peak left ventricular hypertrophy (LVH) and dilatation (LVD) occurred at 31.5 +/- 1.6 weeks and 102.7 +/- 2.2 weeks post-banding respectively, with an increase in LV internal diameter in diastole (LVIDd 5.11 +/- 0.12 compared to the control 3.37 +/- 0.07 cm, p<0.001), with preserved LV ejection fraction (LVEF). Reduced LVEF became evident 116.5 +/- 2.7 weeks post-banding. Clinical and echocardiographic improvements were observed following deflation of the aortic banding cuff. By 138.1 +/- 3.1 weeks cardiac performance recovered with restoration of LVEF. Significant changes in the expression of matrix metalloproteinases (MMP)-1, -2, -3, vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF)-2, interferon (INF)-alpha-2 and soluble CD40 ligand (sCD40L) were observed throughout the progression to failure and recovery. CONCLUSIONS: We used an ovine model to study reversible LV remodelling without interruption and found significant changes in matrixin and cardiokine expression during LV progression to failure and recovery. PMID- 25814351 TI - Uncertainties in insurances for adults with congenital heart disease. PMID- 25814352 TI - Coronary microvascular dysfunction in patients with diabetes, hypertension and metabolic syndrome. PMID- 25814353 TI - Complete versus culprit-only revascularization in patients with multi-vessel disease undergoing primary percutaneous coronary intervention: A meta-analysis of randomized trials. AB - BACKGROUND: The best approach for revascularization of multi-vessel coronary disease in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) is controversial. METHODS: We searched the Medline and Web of Science databases, the Cochrane Register of Controlled Trials, and major conference proceedings for clinical trials that randomized STEMI patients with multi-vessel disease to a complete versus culprit only revascularization strategy. Random effects summary risk ratios (RR) were constructed using a DerSimonian-Laird model. RESULTS: A total of 6 trials met our selection criteria, which yielded 1,190 patients. The mean follow-up duration was 20.5 months. The incidence of major adverse cardiac events was significantly reduced in the complete revascularization group versus the culprit-only revascularization group (RR 0.57, 95% confidence interval (CI) 0.41-0.78, p < 0.001). This was due to a lower risk of urgent revascularization with complete revascularization (RR 0.55, 95% CI 0.35-0.86, p = 0.01). A non-significant reduction was observed with complete versus culprit-only revascularization for the combined outcome of mortality or myocardial infarction (RR 0.56, 95% CI 0.30 1.04, p = 0.06). CONCLUSION: Complete revascularization of significant coronary lesions at the time of primary PCI in patients with STEMI and multi-vessel disease was associated with better outcomes. This was primarily due to a reduction in the need for urgent revascularization. Larger trials are needed to determine if complete revascularization reduces death or myocardial infarction. PMID- 25814354 TI - Successful heart transplantation in an adult patient with partial anomalous pulmonary venous return from the left upper lobe. PMID- 25814355 TI - The controversy about the association between depression and coronary slow flow phenomenon. PMID- 25814356 TI - Long-term follow-up of the viability guided angioplasty after acute myocardial infarction (VIAMI) trial. AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) not treated with primary or rescue percutaneous coronary intervention (PCI) are at risk for recurrent ischemia. In non-high risk patients, with proven viability in the infarct-area, the VIAMI trial showed benefit of early in-hospital stenting of the infarct-related coronary artery for the composite of death, myocardial infarction (MI), or unstable angina (UA) at 1 year follow-up. In this study we evaluated the long-term outcome (median 8 years) of patients included in the VIAMI-trial. METHODS: After being stable during the first 48 h of their acute MI, we randomly assigned 216 patients with viability to an invasive (PCI) or a conservative (ischemia-guided) strategy. The primary outcome was the composite endpoint of death from any cause, recurrent myocardial infarction, or unstable angina. The secondary outcome of this study was the need for (repeat) revascularization. RESULTS: The combined endpoint of death, recurrent MI and UA was 20.8% in the invasive group and 32.7% in the conservative group (hazard ratio 0.59; 95% CI 0.36-0.99, p = 0.049). No differences were seen in death (8.5% vs. 8.2%, p = 0.80) or MI (7.5% vs. 10.9%, p = 0.48). Only UA showed a significant difference (4.7% vs. 13.6%, p = 0.002). Repeated revascularization was performed in 22.6% of the invasive group and 41.8% of the conservative group (hazard ratio 0.43; 95% CI 0.29-0.74, p < 0.001).' CONCLUSION: In patients with acute MI (treated with thrombolysis or without reperfusion therapy) and proven viability in the infarct area, we demonstrated a long-term benefit of early in-hospital stenting of the infarct-related coronary artery. PMID- 25814357 TI - Is anemia a new cardiovascular risk factor? AB - Anemia is frequent in patients with cardiovascular disease and is often characterized as the fifth cardiovascular risk factor. It is considered to develop due to a complex interaction of iron deficiency, cytokine production and impaired renal function, although other factors, such as blood loss, may also contribute. Unfortunately, treatment of anemia in cardiovascular disease lacks clear targets and specific therapy is not defined. Treatment with erythropoietin stimulating agents in combination with iron is the basic strategy but clear guidelines are not currently available. This review aims to clarify poorly investigated and defined issues concerning the relation of anemia and cardiovascular risk--in particular in patients with acute coronary syndromes and chronic heart failure--as well as the current therapeutic strategies in these clinical conditions. PMID- 25814358 TI - Right ventricular mural thrombus formation superimposed on previous anterior myocardial infarction. PMID- 25814359 TI - ISB news from the Chair of the Student and New Professionals Group. AB - An update from the new Chair of the Students and New Professionals Group of the International Society of Biometeorology. PMID- 25814360 TI - Introduction to the ECR Special Issue on Molecular Motors. PMID- 25814361 TI - Synaptic vesicle pools: Principles, properties and limitations. PMID- 25814362 TI - SUV420H2 suppresses breast cancer cell invasion through down regulation of the SH2 domain-containing focal adhesion protein tensin-3. AB - The genome-wide loss of histone H4 lysine 20 tri-methylation (H4K20me3) is observed in multiple types of cancer, including breast tumors. Since H4K20me3 is preferentially targeted to repetitive elements in the pericentromeric and telomeric heterochromatin and plays a role in chromatin integrity, the pathological effects of disrupted H4K20me3 in tumors have been attributed to genomic instability. However, in this report, we show that loss of H4K20me3 modulates gene expression profiles, leading to increased cell invasion. Reduced H4K20me3 levels in tumor cells are often accompanied by a decrease in the expression of the H4K20-specific methyltransferase, SUV420H2. Exogenous delivery of SUV420H2 into MDA-MB-231 human breast cancer cells induced selective and specific changes in the expression of cancer-related genes. One of the most downregulated genes in response to SUV420H2 expression was the Src substrate, tensin-3, a focal adhesion protein that contributes to cancer cell migration. Depletion of tensin-3 suppressed breast cancer cell invasiveness. Furthermore, silencing of tensin-3 was associated with enrichment of H4K20me3 immediately upstream of the tensin-3 transcription start site, suggesting that the loss of H4K20me3 in tumor cells induced the expression of cancer-promoting genes. These findings connect the loss of H4K20me3 with tumor progression, through the transcriptional activation of cancer-promoting genes. PMID- 25814363 TI - Lipocalin-2 inhibits osteoclast formation by suppressing the proliferation and differentiation of osteoclast lineage cells. AB - Lipocalin-2 (LCN2) is a member of the lipocalin superfamily and plays a critical role in the regulation of various physiological processes, such as inflammation and obesity. In this study, we report that LCN2 negatively modulates the proliferation and differentiation of osteoclast precursors, resulting in impaired osteoclast formation. The overexpression of LCN2 in bone marrow-derived macrophages or the addition of recombinant LCN2 protein inhibits the formation of multinuclear osteoclasts. LCN2 suppresses macrophage colony-stimulating factor (M CSF)-induced proliferation of osteoclast precursor cells without affecting their apoptotic cell death. Interestingly, LCN2 decreases the expression of the M-CSF receptor, c-Fms, and subsequently blocks its downstream signaling cascades. In addition, LCN2 inhibits RANKL-induced osteoclast differentiation and attenuates the expression of c-Fos and nuclear factor of activated T cells c1 (NFATc1), which are important modulators in osteoclastogenesis. Mechanistically, LCN2 inhibits NF-kappaB signaling pathways, as demonstrated by the suppression of IkappaBalpha phosphorylation, nuclear translocation of p65, and NF-kappaB transcriptional activity. Thus, LCN2 is an anti-osteoclastogenic molecule that exerts its effects by retarding the proliferation and differentiation of osteoclast lineage cells. PMID- 25814364 TI - Glucagon--Early breakthroughs and recent discoveries. AB - Glucagon was discovered in 1922 as a hyperglycemic factor in the pancreas. During its early history up to 1970, glucagon was shown to increase circulating glucose through stimulating glycogenolysis in the liver. It was also shown to be a constituent of islet non-beta cells and to signal through G protein coupled receptors and cyclic AMP. Furthermore, its chemical characteristics, including amino acid sequence, and its processing from the preproglucagon gene had been established. During the modern research during the last 40 years, glucagon has been established as a key hormone in the regulation of glucose homeostasis, including a key role for the glucose counterregulation to hypoglycemia and for development of type 2 diabetes, and today glucagon is a potential target for treatment of the disease. Glucagon has also been shown to be a key factor beyond glucose control and involved in many processes. For the coming, future research, studies will be focused on alpha-cell biology beyond glucagon, hyperglucagonemia in other conditions than diabetes, its involvement in the regulation of body weight and energy expenditure and the potential of glucagon as a target for other diseases than type 2 diabetes, such as type 1 diabetes and obesity. This review summarizes the more than 90 years history of this important hormone as well as discusses potential future research regarding glucagon. PMID- 25814366 TI - Pancreatic Resection Results in a Statewide Surgical Collaborative. PMID- 25814365 TI - Improving the Accuracy of Axillary Lymph Node Surgery in Breast Cancer with Ultrasound-Guided Wire Localization of Biopsy Proven Metastatic Lymph Nodes. AB - BACKGROUND: This study aimed to evaluate whether the use of preoperative ultrasound (US)-guided wire localization of metastatic axillary lymph nodes (LN) assessed previously by core needle biopsy (CNB) and clip placement in breast cancer patients improves successful surgical removal. METHODS: A retrospective review examined breast cancer patients who underwent US-guided CNB of an axillary LN and biopsy clip placement as well as axillary lymph node dissection (ALND) or sentinel node lymph node biopsy (SLNB) from 1 January 2010 to 30 September 2013. Preoperative needle localization status, neoadjuvant chemotherapy, and type of axillary LN surgery were reviewed. Confirmation that the metastatic LN had been surgically removed was determined on the specimen image, by pathologic report confirmation, or by pre-radiation therapy computed tomography (CT) scan. RESULTS: Preoperative US-guided needle localization was performed for 68.2 % (73/107) of the patients, with 97.3 % (n = 71) demonstrating confirmation of biopsy clip and LN removal versus 79.4 % (n = 27) of the 34 patients showing no performance of needle localization (p = 0.0043). Subgroup analysis showed a significant difference in removal of metastatic LN between the patients who received neoadjuvant chemotherapy [97 % of LNs removed with wire localization (n = 65/67) vs. 83.3 % of LNs removed without wire localization (n = 20/24; p = 0.04)] and the patients who had ALND, [96.3 % of LNs removed with wire localization (n = 52/54) vs. 77.8 % of LNs removed without wire localization (n = 21/27; p = 0.015)]. CONCLUSION: US-guided wire localization of metastatic axillary LNs that have had biopsy with clip placement significantly improves the success rate of surgical removal, allowing more accurate staging and decreasing the false negative rates of SLNB after neoadjuvant therapy. PMID- 25814367 TI - The effect of atrial fibrillation on outcomes in patients undergoing carotid endarterectomy or stent placement in general practice. AB - BACKGROUND: Atrial fibrillation is a common comorbid condition among patients undergoing carotid endarterectomy (CEA) and carotid artery stent placement (CAS); however, the outcomes of patients with atrial fibrillation undergoing CAS have not been fully examined. We sought to investigate the impact of atrial fibrillation on outcomes of CEA and CAS in general practice. METHODS: We analyzed the data from the National Inpatient Sample (NIS), which is representative of all admissions in the United States from 2005 to 2009. The primary end point was postoperative stroke, cardiac complication, postoperative mortality, and composite of these end points. Univariate and multivariate regression analyses were performed to determine, first, the association of atrial fibrillation (compared to without atrial fibrillation) and, second, the association of CEA (compared with CAS) in patients with atrial fibrillation with the occurrence of postoperative stroke, cardiac complication, or death. Covariates included in the logistic regression were the patient's gender, age, race/ethnicity, comorbid conditions, and symptom status (symptomatic vs asymptomatic status) and the hospital's characteristics. RESULTS: Of the total 672,074 patients who underwent CAS or CEA, 8.8% (95% confidence interval [CI], 8.7-8.9) of the procedures were performed in patients with atrial fibrillation. Atrial fibrillation was associated with an increased risk of postoperative stroke in patients undergoing CEA (n = 879 [1.7%]; P < .0001; odds ratio [OR], 1.57; 95% CI, 1.32-1.86) but not in patients undergoing CAS. The relative risk of the composite end point of postoperative stroke, cardiac complications, and mortality was increased in patients with atrial fibrillation undergoing CAS (OR, 1.43; 95% CI, 1.18-1.74) and in those undergoing CEA (OR, 3.18; 95% CI, 2.89-3.49). After adjustment for potential confounders, the odds of the composite end point of postoperative stroke, cardiac complications, and mortality (OR, 1.31; 95% CI, 1.08-1.59) in atrial fibrillation patients were significantly higher among patients who underwent CEA (compared with those who underwent CAS). An opposite relationship was seen in patients without atrial fibrillation, in whom the composite end point was significantly lower in patients undergoing CEA. CONCLUSIONS: Our analysis suggests that almost 10% of CAS and CEA is performed in patients with atrial fibrillation in general practice, and higher rates of adverse events are observed among these patients, particularly those undergoing CEA. PMID- 25814369 TI - Invited commentary. PMID- 25814368 TI - The vascular surgeon-scientist: a 15-year report of the Society for Vascular Surgery Foundation/National Heart, Lung, and Blood Institute-mentored Career Development Award Program. AB - The Society for Vascular Surgery (SVS) Foundation partnered with the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) in 1999 to initiate a competitive career development program that provides a financial supplement to surgeon-scientists receiving NIH K08 or K23 career development awards. Because the program has been in existence for 15 years, a review of the program's success has been performed. Between 1999 and 2013, 41 faculty members applied to the SVS Foundation program, and 29 from 21 different institutions were selected as awardees, resulting in a 71% success rate. Three women (10%) were among the 29 awardees. Nine awardees (31%) were supported by prior NIH F32 or T32 training grants. Awardees received their K award at an average of 3.5 years from the start of their faculty position, at the average age of 39.8 years. Thirteen awardees (45%) have subsequently received NIH R01 awards and five (17%) have received Veterans Affairs Merit Awards. Awardees received their first R01 at an average of 5.8 years after the start of their K award at the average age of 45.2 years. The SVS Foundation committed $9,350,000 to the Career Development Award Program. Awardees subsequently secured $45,108,174 in NIH and Veterans Affairs funds, resulting in a 4.8-fold financial return on investment for the SVS Foundation program. Overall, 23 awardees (79%) were promoted from assistant to associate professor in an average of 5.9 years, and 10 (34%) were promoted from associate professor to professor in an average of 5.2 years. Six awardees (21%) hold endowed professorships and four (14%) have secured tenure. Many of the awardees hold positions of leadership, including 12 (41%) as division chief and two (7%) as vice chair within a department of surgery. Eight (28%) awardees have served as president of a regional or national society. Lastly, 47 postdoctoral trainees have been mentored by recipients of the SVS Foundation Career Development Program on training grants or postdoctoral research fellowships. The SVS Foundation Career Development Program has been an effective vehicle to promote the development and independence of vascular surgeon scientists in the field of academic vascular surgery. PMID- 25814370 TI - Aortic fibrosarcoma presenting as rupture of an abdominal aortic aneurysm. PMID- 25814371 TI - Gigantic 25-cm abdominal aortic aneurysm. PMID- 25814372 TI - Adjunct endovascular interventions in carotid body tumors. AB - OBJECTIVE: Most patients presenting with carotid body tumors (CBTs) seek medical attention when tumors have grown to exceed Shamblin I stage, rendering surgery a challenging undertaking and the associated morbidity a continuing threat to the clinical outcome. This study examined the availability, applicability, and overall clinical efficacy of adjunct endovascular interventions performed alongside CBT surgery and their potential in clinical decision making and clinical practice. METHODS: Studies reporting the feasibility, applicability, and clinical efficacy of adjunct endovascular interventions in the surgical management of CBTs were thoroughly searched using the Medline database from January 1967 to August 2013. RESULTS: There were no randomized studies on the efficacy of endovascular interventions in CBT surgery. Sixty studies met our inclusion criteria, reporting 465 patients (526 CBTs) with a mean age of 39.8 years. The treated CBTs were a mean size of 4.9 cm. Patients treated with surgery with the use of adjunct endovascular interventions had a mean blood loss of 368.4 mL (range, 25-to 2000 mL). There were 57 cranial nerve injuries, of which 28 (49.1%) were permanent. Cerebrovascular accident occurred in nine patients, of which one died. Hospital stay was a mean of 4.4 days (range, 2-17 days). CONCLUSIONS: Preoperative selective endovascular embolization in patients with Shamblin II and Shamblin III CBTs may be beneficial when competently performed by interventional physicians proficient in neurovascular microcatheterization/embolization procedures. PMID- 25814373 TI - Is a gift authorship really a grift authorship? PMID- 25814374 TI - Aspirin therapy inhibits NLRP1 (nucleotide-binding domain-like receptor protein 1) inflammasome gene expression in patients with peripheral artery disease. PMID- 25814375 TI - Erratum to: Isolation, culture, and induced multiple differentiation of Mongolian sheep bone marrow-derived mesenchymal stem cells. PMID- 25814376 TI - WHO's new end TB strategy. PMID- 25814377 TI - Metal coordination study at Ag and Cd sites in crown thioether complexes through DFT calculations and hyperfine parameters. AB - Structural and electronic properties of [C12H24S6X], [C13H26S6OX], and [C14H28S6OX] (X: Ag(+), Cd(2+)) crown thioether complexes were investigated within the framework of the density functional theory (DFT) using the projector augmented wave (PAW) method. The theoretical results were compared with time differential perturbed gamma-gamma angular correlations (TDPAC) experiments reported in the literature using the (111)Ag->(111)Cd probe. In the case of X=Ag(+), a refinement of the structure was performed and the predicted equilibrium structures compared with available X-ray diffraction experimental data. Structural distortions induced by replacing Ag(+) with Cd(2+) were investigated as well as the electric-field gradient (EFG) tensor at the Cd(2+) sites. Our results suggest that the EFG at Cd(2+) sites corresponds to the Ag(+) coordination sphere structure, i.e., before the structural relaxations of the molecule with X=Cd(2+) are completed. The results are discussed in terms of the characteristics of the TDPAC (111)Ag->(111)Cd probe and the time window of the measurement, and provide an interesting tool with which to probe molecular relaxations. PMID- 25814378 TI - Isolated Conglutin gamma from Lupin, but not Phytate, Lowers Serum Cholesterol Without Influencing Vascular Lesion Development in the ApoE-deficient Mouse Model. AB - Conglutin gamma and phytate are considered as potential biofunctional compounds of lupin protein isolate, but their impact on vascular health is unknown. This study aimed to investigate the effect of conglutin gamma and phytate, respectively, on circulating levels of sterols, markers of cholesterol biosynthesis and minerals, and on the development and progression of aortic lesions in apoE-deficient mice. To this end, mice were fed a western diet with either casein (200 g/kg; served as a control), conglutin gamma from L. angustifolius (200 g/kg) or casein (200 g/kg) supplemented with phytate (5 g/kg) for 16 weeks. Here we found that conglutin gamma but not phytate was capable of reducing the circulating concentration of cholesterol. Plasma levels of desmosterol and lathosterol as markers of the cholesterol synthesis were not affected, and 7-dehydrocholesterol was even higher in mice fed conglutin gamma than in mice fed casein or casein + phytate. All mice developed pronounced aortic lesions, but histological characterization of plaque area and composition showed no differences between the three groups of mice. Conclusively, conglutin gamma exerts cholesterol-lowering effects but appears to have no anti-atherosclerotic properties in the apoE-deficient mice. Phytate neither affected plasma cholesterol nor aortic lesion development. PMID- 25814379 TI - Excitability of the infraspinatus, but not the middle deltoid, is affected by shoulder elevation angle. AB - Although both the rotator cuff and deltoid muscle serve as shoulder abductors, they play different roles in shoulder movement. While the deltoid is a primary abductor, the rotator cuff is a stabilizer. They have different anatomic structures for force production and demonstrate different neuromuscular control at different shoulder angles, as measured by electromyographic activity. Corticospinal excitability may be associated with different neuromuscular control of the deltoid and rotator cuff at different angles. The purpose of this study was to investigate how shoulder joint position influences the corticospinal excitability of the deltoid and rotator cuff muscles. Transcranial magnetic stimulation was used to measure the corticospinal excitability of the middle deltoid and infraspinatus at 0 degrees and 90 degrees of arm elevation. Three parameters, a plateau value, exponential parameter, and threshold, were calculated from the input-output curve of the corticospinal pathway. The plateau value of the infraspinatus was significantly higher at 90 degrees of arm elevation, while there is no difference in the excitability in the middle deltoid between elevation angles. The plateau value of the middle deltoid at 90 degrees was 5 % lower than that at 0 degrees , but the plateau value of infraspinatus at 90 degrees was 55 % higher than that at 0 degrees . This suggests that the modulation of excitability varies with shoulder angle and reveals different neurological mechanism for the roles of the deltoid and rotator cuff. PMID- 25814380 TI - Disruption of the auditory response to a regular click train by a single, extra click. AB - It has been hypothesized that the steady-state response to a periodic sequence of clicks can be modeled as the superposition of responses to single clicks. Here, this hypothesis is challenged by presenting an extra click halfway between two consecutive clicks of a regular series, while measuring the auditory evoked field. After a solitary click at time zero, the click series sounded from 100 to 900 ms, with the extra click presented around 500 ms. The silent period between two stimulus sequences was 310-390 ms (uniformly distributed) so that one stimulation cycle lasted, on average, 1250 ms. Five different click rates between 20 and 60 Hz were examined. The disturbance caused by the extra click was revealed by subtracting the estimated steady-state response from the joint response to the click series and the extra click. The early peaks of the single click response effectively coincide with same-polarity peaks of the 20-Hz steady state response. Nevertheless, prediction of the latter from the former proved impossible. However, the 40-Hz steady-state response can be predicted reasonably well from the 20-Hz steady-state response. Somewhat surprisingly, the amplitude of the evoked response to the extra click grew when the click rate of the train was increased from 20 to 30 Hz; the opposite effect would have been expected from research on adaptation. The smaller amplitude at lower click rates might be explained by forward suppression. In this case, the apparent escape from suppression at higher rates might indicate that the clicks belonging to the periodic train are being integrated into an auditory stream, possibly in much the same manner as in classical stream segregation experiments. PMID- 25814382 TI - Arginine Functionally Improves Clinically Relevant Human Galactose-1-Phosphate Uridylyltransferase (GALT) Variants Expressed in a Prokaryotic Model. AB - Classic galactosemia is a rare genetic disease of the galactose metabolism, resulting from deficient activity of galactose-1-phosphate uridylyltransferase (GALT). The current standard of care is lifelong dietary restriction of galactose, which however fails to prevent the development of long-term complications. Structural-functional studies demonstrated that the most prevalent GALT mutations give rise to proteins with increased propensity to aggregate in solution. Arginine is a known stabilizer of aggregation-prone proteins, having already shown a beneficial effect in other inherited metabolic disorders.Herein we developed a prokaryotic model of galactose sensitivity that allows evaluating in a cellular context the mutations' impact on GALT function, as well as the potential effect of arginine in functionally rescuing clinically relevant variants.This study revealed that some hGALT variants, previously described to exhibit no detectable activity in vitro, actually present residual activity when determined in vivo. Furthermore, it revealed that arginine presents a mutation specific beneficial effect, particularly on the prevalent p.Q188R and p.K285N variants, which led us to hypothesize that it might constitute a promising therapeutic agent in classic galactosemia. PMID- 25814381 TI - Risk Factors Associated with HCV Among Opioid-Dependent Patients in a Multisite Study. AB - We examined risk factors associated with hepatitis C virus (HCV) infection among opioid-dependent patients enrolled into medication-assisted therapy (buprenorphine or methadone) to determine factors affecting chronic infection. Patients (N = 1039) were randomized as part of a larger, multisite clinical trial sponsored by the National Drug Abuse Treatment Clinical Trials Network assessing liver function. HCV status was first assessed with an antibody screen; if positive, then current infection was determined with an antigen screen testing for detectable virus. Patients were classified as HCV negative, HCV positive but have cleared the virus, or as having chronic HCV. Logistic regression analysis was used to examine demographic and behavioral correlates of the three groups. Thirty-four percent of patients were classified with chronic infection and 14% had evidence of prior infection with apparent clearing of the virus. Chronic infection was associated with recent injection drug use and cocaine use. Chronic HCV infection was also associated with being older and Hispanic. Age, ethnicity, and current drug use increase the likelihood of being chronically infected with HCV. Strategies targeting high risk subgroups can aid in preventing further disease escalation. PMID- 25814383 TI - Clinical Severity of PGK1 Deficiency Due To a Novel p.E120K Substitution Is Exacerbated by Co-inheritance of a Subclinical Translocation t(3;14)(q26.33;q12), Disrupting NUBPL Gene. AB - Carriers of cytogenetically similar, apparently balanced familial chromosome translocations not always exhibit the putative translocation-associated disease phenotype. Additional genetic defects, such as genomic imbalance at breakpoint regions or elsewhere in the genome, have been reported as the most plausible explanation.By means of comprehensive molecular and functional analyses, additional to careful dissection of the t(3;14)(q26.33;q12) breakpoints, we unveil a novel X-linked PGK1 mutation and examine the contribution of these to the extremely severe clinical phenotype characterized by hemolytic anemia and neuromyopathy.The 3q26.33 breakpoint is 40 kb from the 5' region of tetratricopeptide repeat domain 14 gene (TTC14), whereas the 14q12 breakpoint is within IVS6 of nucleotide-binding protein-like gene (NUBPL) that encodes a mitochondrial complex I assembly factor. Disruption of NUBPL in translocation carriers leads to a decrease in the corresponding mRNA accompanied by a decrease in protein level. Exclusion of pathogenic genomic imbalance and reassessment of familial clinical history indicate the existence of an additional causal genetic defect. Consequently, by WES a novel mutation, c.358G>A, p.E120K, in the X-linked phosphoglycerate kinase 1 (PGK1) was identified that segregates with the phenotype. Specific activity, kinetic properties, and thermal stability of this enzyme variant were severely affected. The novel PGK1 mutation is the primary genetic alteration underlying the reported phenotype as the translocation per se only results in a subclinical phenotype. Nevertheless, its co-inheritance presumably exacerbates PGK1-deficient phenotype, most likely due to a synergistic interaction of the affected genes both involved in cell energy supply. PMID- 25814384 TI - MEF2D overexpression contributes to the progression of osteosarcoma. AB - The underlying molecular pathogenesis of osteosarcoma remains poorly understood. The transcription factor MEF2D promotes the survival of various types of cells and functions as an oncogene in liver cancer. However, its potential contribution to osteosarcoma has not been explored. In this study, we investigated MEF2D expression and function in osteosarcoma, finding that MEF2D elevation in osteosarcoma clinical specimens was associated with patients' poor prognosis. MEF2D suppression was shown to decrease the proliferation of osteosarcoma cells, while forced expression of MEF2D was able to promote the proliferation of normal bone fibroblast. Notably, MEF2D silencing abolished osteosarcoma tumorigenicity in an animal model. Mechanistic investigations revealed that MEF2D silencing triggered G2-M arrest in osteosarcoma cells by suppressing RPRM and CDKN1A. miR 144 was found to suppress the expression of MEF2D in osteosarcoma cells. Collectively, our results demonstrated that MEF2D is a candidate oncogene for osteosarcoma and a potential molecular target for cancer therapy. PMID- 25814385 TI - (De)criminalisation of possession of drugs for personal use - A view from the Czech Republic. PMID- 25814386 TI - Fractures in School Going Children. PMID- 25814387 TI - Suppressor of Deltex mediates Pez degradation and modulates Drosophila midgut homeostasis. AB - Pez functions as an upstream negative regulator of Yorkie (Yki) to regulate intestinal stem cell (ISC) proliferation and is essential for the activity of the Hippo pathway specifically in the Drosophila midgut epithelium. Here we report that Suppressor of Deltex (Su(dx)) acts as a negative regulator of Pez. We show that Su(dx) targets Pez for degradation both in vitro and in vivo. Overexpression of Su(dx) induces proliferation in the fly midgut epithelium, which can be rescued by overexpressed Pez. We also demonstrate that the interaction between Su(dx) and Pez, bridged by WW domains and PY/PPxY motifs, is required for Su(dx) mediated Pez degradation. Furthermore, we find that Kibra, a binding partner of Pez, stabilizes Pez via WW-PY/PPxY interaction. Moreover, PTPN14, a Pez mammalian homolog, is degraded by overexpressed Su(dx) or Su(dx) homologue WWP1 in mammalian cells. These results reveal a previously unrecognized mechanism of Pez degradation in maintaining the homeostasis of Drosophila midgut. PMID- 25814388 TI - Internet-orientated Assessment of QOL and Actual Treatment Status in Japanese Patients with Inflammatory Bowel Disease: The 3I survey. AB - BACKGROUND AND AIMS: This survey aimed to compare actual lifestyle factors and QOL between Japanese IBD patients and healthy Japanese controls, by questionnaire using an internet-web system. METHODS: Through the internet-web system, we asked 464 patients with Crohn's disease [CD], 360 patients with ulcerative colitis [UC], and 4100 healthy controls to answer a questionnaire including an eight-item short-form health survey [SF-8]. The survey was conducted until data had been accumulated from the predetermined numbers of patients [120 patients each with CD and UC] and healthy controls [240 subjects]. RESULTS: QOL assessment by SF-8 revealed scores for six of the eight subscale items and the summary score for the mental component to be significantly lower in the CD and UC groups than in controls. There was a significant negative correlation between each SF-8 score and the degree of CD and UC symptoms. The marriage rate in adult patients was significantly lower in the CD than in the UC group or the controls. The mean annual income and the employment rate were significantly lower in the CD than in the UC group or the controls. CD patients receiving biologicals were more frequently satisfied with the efficacy of treatment than UC patients were with their treatment regimens [56% vs 29%]. CONCLUSIONS: Actual lifestyle factors and QOL appear to be impaired in Japanese patients with IBD, especially those with CD. The subjective efficacy of biologicals might be greater in CD than in UC. PMID- 25814389 TI - Surgical findings and auditory performance after cochlear implant revision surgery. AB - The objective of this study was to review cochlear reimplantation outcomes in the tertiary hospital and analyze whether facts such as type of failure, surgical findings, or etiology of deafness have an influence. A retrospective study including 38 patients who underwent cochlear implant revision surgery in a tertiary center is performed. Auditory outcomes (pure tone audiometry, % disyllabic words) along with etiology of deafness, type of complication, issues with insertion, and cochlear findings are included. Complication rate is 2.7 %. Technical failure rate is 57.9 % (50 % hard failure and 50 % soft failure), and medical failure (device infection or extrusion, migration, wound, or flap complication) is seen in 42.1 % of the cases. Management of cochlear implant complications and revision surgery is increasing due to a growing number of implantees. Cases that require explantation and reimplantation of the cochlear implant are safe procedures, where the depth of insertion and speech perception results are equal or higher in most cases. Nevertheless, there must be an increasing effort on using minimally traumatic electrode arrays and surgical techniques to improve currently obtained results. PMID- 25814390 TI - Somatosensory evoked potentials in neonates with hypoxic-ischemic encephalopathy treated with hypothermia. AB - OBJECTIVE: Somatosensory evoked potentials (SEPs) are reported to have high positive predictive value (PPV) for neurodevelopmental impairment (NDI) in neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). Our objective was to assess if this predictive value remains high with the use of therapeutic hypothermia. METHODS: A cohort of HIE neonates treated with hypothermia was recruited between September 2008 and September 2010. SEPs were elicited after hypothermia and classified as bilateral absent N19, abnormal N19 (i.e., delayed or unilateral absent), or normal. Qualitative evaluation of MRI was also performed. The primary outcome was moderate or severe NDI around 2 years of age. RESULTS: SEPs were performed after hypothermia in 26 of 34 neonates submitted to hypothermia with adequate follow-up at a median day of life 11 (IQR 9, 13). Twenty-three (88%) had moderate encephalopathy. Eleven neonates (42%) had bilateral absent N19, 4 of whom had NDI, while fifteen neonates (58%) had either abnormal or normal N19, of whom only one had NDI. SEPs thus had a PPV of 0.36 (4/11) and a negative predictive value (NPV) of 0.93 (14/15). Eighteen neonates (69%) had brain injury on MRI. MRI thus had a PPV of 0.28 (5/18) and an NPV of 1.00 (8/8). CONCLUSIONS: Neonates with HIE treated with hypothermia with bilateral absent N19 potentials may have a better prognosis than reported in the pre-hypothermia era. MRI also had a low PPV and high NPV. SEPs should be interpreted with caution in this new population and need to be re-evaluated in larger studies. PMID- 25814392 TI - Obama chides Republicans as he marks health law's fifth anniversary. PMID- 25814391 TI - Antiepileptic drugs in Rett Syndrome. AB - PURPOSE: We investigated drugs most often used to treat epilepsy in Rett Syndrome and their efficacy in a large cohort of Italian patients. METHODS: This is a multi-centre retrospective study. Data of 165 Rett subjects were collected from the patients' files, and hospital charts. The efficacy of antiepileptic drugs (AEDs) was classified as follows: not effective; decrease in seizure frequency >=50% for at least 6 months; seizure-free for at least 2 years. Phenotypic and genetic categorization of patients was performed and it was considered in AEDs efficacy evaluation. RESULTS: There were 130 epileptic patients.Sodium valproate (VPA) was the most commonly administered AED (44.3%) at seizure onset, followed by Carbamazepine (CBZ) (25.4%) and Phenobarbital (PB) (13%). Monotherapy was the first treatment option in most patients. VPA and CBZ proved to be equally effective in Rett patients who presented seizures within the typical age range (4 5 years), while Lamotrigine (LTG) was effective for patients in whom epilepsy started later. Overall, the frequency of side effects was low and the most often observed ones were restlessness and somnolence. CONCLUSION: Our study suggests that LTG, VPA and CBZ can be used as drugs of first choice in Rett Syndrome. The association of four drugs should be avoided since it did not result in any significant clinical improvement. PMID- 25814393 TI - Lymphadenectomy extent and survival of patients with gastric carcinoma: a systematic review and meta-analysis of time-to-event data from randomized trials. AB - BACKGROUND: The extent of lymph node dissection in patients with resectable non metastatic primary carcinoma of the stomach is still a controversial matter of debate, with special regard to its effect on survival. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of time-to-event data from randomized controlled trials (RCTs) comparing the three main types of lymphadenectomy (D1, D2, and D3) for gastric cancer. Hazard ratio (HR) was considered the effect measure for both overall (OS), disease-specific (DSS) and disease-free survival (DFS). The quality of the available evidence was assessed using the GRADE system. RESULTS: Eight RCTs enrolling 2515 patients were eligible. The meta-analysis of four RCTs (n=1599) showed a significant impact of D2 versus D1 lymphadenectomy on DSS (summary HR=0.807, CI: 0.705-0.924, P=0.002), the corresponding number-to-treat being equal to ten. This effect remained clinically valuable even after adjustment for postoperative mortality. However, the quality of evidence was graded as moderate due to inconsistency issues. When OS and DFS were considered, the meta-analysis of respectively five (n=1653) and three RCTs (n=1332) found no significant difference between D2 and D1 lymph node dissection (summary HR=0.911, CI: 0.708-1.172, P=0.471, and summary HR=0.946, CI: 0.840-1.066, P=0.366, respectively). However, at subgroup analysis D2 type resulted superior to D1 type lymphadenectomy in terms of OS considering the two RCTs carried out in Eastern countries (summary HR=0.627, CI: 0.396-0.994, P=0.047). As regards the D3 vs D2 comparison, the meta-analysis of the three available RCTs (n=862) showed no significant impact of more extended lymphadenectomy on OS (summary HR=0.990, CI: 0.814-1.205, P=0.924). CONCLUSIONS: Our findings support the superiority of D2 versus D1 lymphadenectomy in terms of survival benefit. However, this advantage is mainly limited to DSS, the level of evidence is moderate, and the interaction with other factors affecting patient survival (such as complementary medical therapy) remains to be elucidated. PMID- 25814394 TI - ENIGMA: crowdsourcing meets neuroscience. PMID- 25814395 TI - Challenges and opportunities in detecting Taenia solium tapeworm carriers in Los Angeles County California, 2009-2014. AB - Carriers of the pork tapeworm, Taenia solium, are the sole source of neurocysticercosis, a parasitic tissue infection that can be chronic and severe. Identifying T. solium tapeworm carriers is challenging. Many are asymptomatic and go undetected and unreported. In addition, T. solium is difficult to distinguish from other Taenia species of less concern. From 2009 to 2014, 24 taeniasis cases were reported to the Los Angeles County (LAC) Department of Public Health. Twenty reports were received solely from our automated electronic laboratory reporting system (ELR), two from health care providers, and two were generated internally from investigation of households with a reported neurocysticercosis case. Further investigation identified one T. solium carrier originally reported by ELR and one identified from a neurocysticercosis case investigation. These results suggest that T. solium tapeworm carriers can be identified from investigation of ELR reports of unspeciated Taenia cases as well as from households of neurocysticercosis cases. PMID- 25814396 TI - Relationship between oral clinical conditions and daily performances among young adults in India - a cross sectional study. AB - Objective of the present study was to investigate relationship between oral health-related quality of life using Oral Impacts on Daily Performances (OIDP) scale and specific clinical dental measures. A cross sectional descriptive survey was conducted among 800 students. Oral health status and impacts were assessed using WHO guidelines and OIDP index respectively. Chi square test and multiple logistic regressions were employed for statistical analysis. Participants with caries were significantly (p?0.05) more likely to have an impact on cleaning (OR=2.487) and sleeping and relaxing (OR=8.996). Similarly participants with oral mucosal conditions were more likely to have an impact on eating (OR=3.97), cleaning (OR=2.966) and physical activities (OR=11.190). Dental Aesthetic Index (DAI) impacted on cleaning (OR=2.134), emotional stability (OR=3.957) and social contact (OR=3.21). OIDP Index showed acceptable psychometric properties in the context of an oral health survey. Subjects presented a strong and consistent relationship between dental status and perceived impacts. PMID- 25814397 TI - Changes in the elasticity of fibroadenoma during the menstrual cycle determined by real-time sonoelastography. AB - OBJECTIVE: Shear-wave elastography (SWE) presents quantitative data that thought to represent intrinsic features of the target tissue. Factors affecting the metabolism of the breast parenchyma as well as age, menstrual cycle, hormone levels, pregnancy and lactation, pre-compression artifact during the examination could affect these elastic intrinsic features. Aim of our study is to determine variation of fibroadenoma elasticity during the menstrual cycle (MC) by means of real-time shear-wave elastography (SWE) and identify the optimal time for SWE evaluation. METHODS: Thirty volunteers (aged 20-40 years) who had biopsy-proven fibroadenoma greater than 1cm in diameter, with regular menstrual cycle and without contraceptive medication underwent SWE (ShearWave on Aixplorer, France) once weekly during MC. Statistical data were processed by using the software Statistical Package for the Social Sciences (SPSS) 19.0. A repeated measures analysis of variance was used for each lesion where the repeated factor was the elastographic measurements (premenstrual, menstrual and postmenstrual). Pillai's trace test was used. Pairwise correlation was calculated using Bonferroni correction. Values of p<0.05 were considered statistically significant. RESULTS: The mean elasticity value of fibroadenomas in mid-cycle was 28.49 +/- 12.92 kPa, with the highest value obtained in the third week corresponding to the premenstrual stage (32.98 +/- 13.35 kPa) and the lowest value obtained in the first week corresponding to the postmenstrual stage (25.39 +/- 10.21 kPa). Differences between the elasticity values of fibroadenomas in premenstrual and postmenstrual periods were statistically significant (p<0.001). There were no significant differences in lesion size between the different phases of the menstrual cycle (p>0.05). CONCLUSION: In this study, we found that there is significant difference between the elasticity values of fibroadenomas on premenstrual and postmenstrual period. We propose that one week after menstruation would be appropriate time to perform breast SWE. PMID- 25814398 TI - The impact of PET/CT on the management of hepatic and extra hepatic metastases from gastrointestinal cancers. AB - PURPOSE: To investigate the efficacy of positron emission tomography/computed tomography (PET/CT) in detection and management of hepatic and extrahepatic metastases from gastrointestinal cancers. MATERIALS AND METHODS: Between February 2008 and July 2010, patients histopathologically diagnosed with gastrointestinal cancer and showing suspected metastasis on CT screening were subsequently evaluated with PET/CT. All patients were subgrouped according to histopathological origin and localization of the primary tumor. Localization of gastrointestinal cancers was further specified as lower gastrointestinal system (GIS), upper GIS, or hepato-pancreato-biliary (HPB). Both accuracy and impact of CT and PET/CT on patient management were retrospectively evaluated. RESULTS: One hundred and thirteen patients diagnosed histopathologically with gastrointestinal cancers were retrospectively evaluated. Seventy-nine patients had adenocarcinoma and 34 patients other gastrointestinal tumors. Forty-one patients were in the upper GIS group, 30 patients in the HPB group, and 42 patients in the lower GIS group. Evaluation the diagnostic performance of PET/CT for suspected metastasis according to histopathological origin of the tumor, revealed that the sensitivity of PET/CT - although statistically not different - was higher in adenocarcinomas than in non-adenocarcinomas (90% (95% CI, 0.78-0.96) vs. 71.4% (95% CI, 0.45 0.88), P=0.86). The specificity was not significantly different (85.7% (95% CI, 0.70-0.93) vs. 85% (95% CI, 0.63-0.94), P=1.00). In the overall patient group; CT was significantly more sensitive than PET/CT for detection of hepatic metastases (94.7% vs. 78.9%, P=0.042), whereas PET/CT was significantly more specific than CT (48% vs. 98.7%, P<0.001). In subgroup analysis, sensitivity was not significantly different (P>0.05) but specificity was significantly higher in PET/CT than CT (P<0.05). The specificity of PET/CT was highest in upper GIS (100%) and HPB (100%) subgroups. In the overall patient group; for detection of extrahepatic metastasis, the sensitivity of CT (75%) and PET/CT (87.5%) showed no significant difference (P=0.437). However, PET/CT was significantly more specific than CT (88.7% vs. 70.4%, P=0.007). In subgroup analysis, no significant difference was found between CT and PET/CT either in sensitivity or in specificity (P>0.05). The specificity of PET/CT was highest in the lower GIS subgroup (93%). The management of 45 patients (39.8%) was revised after PET/CT evaluation. CONCLUSIONS: PET/CT has a higher specificity than CT in detecting suspected hepatic and extrahepatic metastases of gastrointestinal cancers, and has an impact of nearly 40% on changing patient management strategies. PMID- 25814399 TI - Medial meniscal posterior root/horn radial tears correlate with cartilage degeneration detected by T1rho relaxation mapping. AB - OBJECTIVE: This study aimed to identify factors on routine pulse sequence MRI associated with cartilage degeneration observed on T1rho relaxation mapping. MATERIALS AND METHODS: This study included 137 subjects with knee pain. T1rho values were measured in the regions of interest on the surface layer of the cartilage on mid-coronal images of the femorotibial joint. Assessment of cartilage, subchondral bone, meniscus and ligaments was performed using routine pulse sequence MRI. Radiographic evaluation for osteoarthritis was also performed. RESULTS: Multiple regression analysis revealed posterior root/horn tears to be independent factors increasing the T1rho values of the cartilage in the medial compartment of the femorotibial joint. Even when adjusted for radiographically defined early-stage osteoarthritis, medial posterior meniscal radial tears significantly increased the T1rho values. CONCLUSIONS: This study showed that posterior root/horn radial tears in the medial meniscus are particularly important MRI findings associated with cartilage degeneration observed on T1rho relaxation mapping. Morphological factors of the medial meniscus on MRI provide findings useful for screening early-stage osteoarthritis. PMID- 25814400 TI - Immune biomarkers: the promises and pitfalls of personalized medicine. AB - Substantial progress in molecular immunology, coupled with an increasing focus on translational research and an enthusiasm for personalized medicine, has resulted in a rapid expansion in the field of immune biomarkers in recent years. In this Science and Society article, we provide a conceptual overview of the field and discuss the progress that has been made so far, as well as the future potential in the context of the scientific, logistical, financial, legal and ethical framework within which this research is being carried out and translated into clinical use. PMID- 25814401 TI - Tumour immunology: A triple blow for cancer. PMID- 25814402 TI - [Cystic mass of the kidney]. PMID- 25814403 TI - Estimates of absolute treatment benefit for individual patients required careful modeling of statistical interactions. AB - OBJECTIVES: We aimed to compare modeling approaches to estimate the individual survival benefit of treatment with either coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) for patients with complex coronary artery disease. STUDY DESIGN AND SETTING: We estimated survival with Cox regression models that included the treatment variable (CABG/PCI) interacting with either an internally developed overall prognostic index (PI) or with individual prognostic factors. We analyzed data of patients who were randomized in the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery trial (1,800 patients, 178 deaths). RESULTS: A negligible interaction with the PI (P = 0.51) led to 4-year survival estimates in favor of CABG for all patients. In contrast, individual interactions indicated substantial relative treatment effect heterogeneity (overall interaction P = 0.004), and estimates of 4-year survival were numerically in favor of CABG for 1,275 of 1,800 patients (71%; 519 with 95% confidence). To test the more complex model with individual interactions, we first used penalized regression, resulting in smaller but largely consistent individual estimates of the survival difference between CABG and PCI. Second, strong treatment interactions were confirmed at external validation in 2,891 patients from a multinational registry. CONCLUSION: Modeling strategies that omit interactions may result in misleading estimates of absolute treatment benefit for individual patients with the potential hazard of suboptimal decision making. PMID- 25814405 TI - Triple tumor markers assay based on carbon-gold nanocomposite. AB - A sandwich-format electrochemical immunosensor for simultaneous determination of three cancer biomarkers using the carbon-gold nanocomposite (CGN) as immunoprobes was introduced. The CGN were fabricated through a simple microwave-assisted carbonization of glucose and deposition of gold nanoparticles (AuNPs). This nanocomposite showed great adsorption ability to the redox probes such as some organic dyes and metal ions, due to the abundant reactive oxygen functional groups on its surface. The AuNPs decorated on the nanocomposite provided extra binding sites for the three antibodies carcinoembryonic antigen (CEA), prostate specific antigen (PSA), alpha-fetoprotein (AFP), respectively. The ionic liquid reduced graphene oxide was combined with poly(sodium-p-styrenesulfonate) as substrate to attach the three different antibodies through electrostatic adsorption. Three separate signals can be detected directly in a single run through square wave voltammetry. Under optimized conditions, the electrochemical immunosensor exhibited good sensitivity and selectivity for the simultaneous determination of CEA, PSA and AFP with linear ranges of 0.01-100 ng mL(-1). The detection limit for CEA, PSA and AFP is 2.7, 4.8 and 3.1 pg mL(-1), respectively. This method was applied for the analysis of CEA, PSA and AFP levels in clinical serum samples, and the results were in good agreement with those of enzyme linked immunosorbent assay (ELISA). This approach gives a promising simple and sensitive immunoassay strategy for the identification and validation of specific early cancer. PMID- 25814406 TI - Immobilization of Fab' fragments onto substrate surfaces: A survey of methods and applications. AB - Antibody immobilization onto surfaces has widespread applications in many different fields. It is desirable to bind antibodies such that their fragment antigen-binding (Fab) units are oriented away from the surface in order to maximize analyte binding. The immobilization of only Fab' fragments yields benefits over the more traditional whole antibody immobilization technique. Bound Fab' fragments display higher surface densities, yielding a higher binding capacity for the analyte. The nucleophilic sulfide of the Fab' fragments allows for specific orientations to be achieved. For biosensors, this indicates a higher sensitivity and lower detection limit for a target analyte. The last thirty years have shown tremendous progress in the immobilization of Fab' fragments onto gold, Si-based, polysaccharide-based, plastic-based, magnetic, and inorganic surfaces. This review will show the current scope of Fab' immobilization techniques available and illustrate methods employed to minimize non-specific adsorption of undesirables. Furthermore, a variety of examples will be given to show the versatility of immobilized Fab' fragments in different applications and future directions of the field will be addressed, especially regarding biosensors. PMID- 25814404 TI - Deep Brain Stimulation Influences Brain Structure in Alzheimer's Disease. AB - BACKGROUND: Deep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological disorders by modulating activity within dysfunctional brain circuits. To date, there is no evidence that DBS counteracts progressive neurodegeneration in any particular disorder. OBJECTIVE/HYPOTHESIS: We hypothesized that DBS applied to the fornix in patients with Alzheimer's Disease (AD) could have an effect on brain structure. METHODS: In six AD patients receiving fornix DBS, we used structural MRI to assess one-year change in hippocampal, fornix, and mammillary body volume. We also used deformation-based morphometry to identify whole-brain structural changes. We correlated volumetric changes to hippocampal glucose metabolism. We also compared volumetric changes to those in an age-, sex-, and severity-matched group of AD patients (n = 25) not receiving DBS. RESULTS: We observed bilateral hippocampal volume increases in the two patients with the best clinical response to fornix DBS. In one patient, hippocampal volume was preserved three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower in the DBS group compared to the matched AD group, and no matched AD patients demonstrated bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based morphometry in DBS patients revealed local volume expansions in several regions typically atrophied in AD. CONCLUSION: We present the first in-human evidence that, in addition to modulating neural circuit activity, DBS may influence the natural course of brain atrophy in a neurodegenerative disease. PMID- 25814407 TI - A novel colorimetric triple-helix molecular switch aptasensor for ultrasensitive detection of tetracycline. AB - Detection methods of antibiotic residues in blood serum and animal derived foods are of great interest. In this study a colorimetric aptasensor was designed for sensitive, selective and fast detection of tetracycline based on triple-helix molecular switch (THMS) and gold nanoparticles (AuNPs). As a biosensor, THMS shows distinct advantages including high stability, sensitivity and preserving the selectivity and affinity of the original aptamer. In the absence of tetracycline, THMS is stable, leading to the aggregation of AuNPs by salt and an obvious color change from red to blue. In the presence of tetracycline, aptamer binds to its target, signal transduction probe (STP) leaves the THMS and adsorbs on the surface of AuNPs. So the well-dispersed AuNPs remain stable against salt induced aggregation with a red color. The presented aptasensor showed high selectivity toward tetracyclines with a limit of detection as low as 266 pM for tetracycline. The designed aptasensor was successfully applied to detect tetracycline in serum and milk. PMID- 25814408 TI - Aptamer fluorescence anisotropy sensors for adenosine triphosphate by comprehensive screening tetramethylrhodamine labeled nucleotides. AB - We previously reported a fluorescence anisotropy (FA) approach for small molecules using tetramethylrhodamine (TMR) labeled aptamer. It relies on target binding induced change of intramolecular interaction between TMR and guanine (G) base. TMR-labeling sites are crucial for this approach. Only terminal ends and thymine (T) bases could be tested for TMR labeling in our previous work, possibly causing limitation in analysis of different targets with this FA strategy. Here, taking the analysis of adenosine triphosphate (ATP) as an example, we demonstrated a success of conjugating TMR on other bases of aptamer adenine (A) or cytosine (C) bases and an achievement of full mapping various labeling sites of aptamers. We successfully constructed aptamer fluorescence anisotropy (FA) sensors for adenosine triphosphate (ATP). We conjugated single TMR on adenine (A), cytosine (C), or thymine (T) bases or terminals of a 25-mer aptamer against ATP and tested FA responses of 14 TMR-labeled aptamer to ATP. The aptamers having TMR labeled on the 16th base C or 23rd base A were screened out and exhibited significant FA-decreasing or FA-increasing responses upon ATP, respectively. These two favorable TMR-labeled aptamers enabled direct FA sensing ATP with a detection limit of 1 uM and the analysis of ATP in diluted serum. The comprehensive screening various TMR labeling sites of aptamers facilitates the successful construction of FA sensors using TMR-labeled aptamers. It will expand application of TMR-G interaction based aptamer FA strategy to a variety of targets. PMID- 25814409 TI - Urchin-like (gold core)@(platinum shell) nanohybrids: A highly efficient peroxidase-mimetic system for in situ amplified colorimetric immunoassay. AB - The development of signal-amplified colorimetric immunoassay relies on the design of highly efficient signal-transduction tags. One promising route is to exploit a novel enzyme mimetic system as the signal label. Herein, we report that urchin like (gold core)@(platinum shell) nanohybrids (Au@PtNHs) can be utilized as a highly efficient peroxidase mimetic system for in situ amplified colorimetric immunoassay of prostate-specific antigen (PSA, one kind of tumor marker). Initially, urchin-like Au@PtNHs were discovered to outperform horseradish peroxidase (HRP) by a vast margin in terms of the turnover number toward hydrogen peroxide (H2O2)-3,3',5,5'-tetramethylbenzidine (TMB) system and the stability against high temperatures and HRP inhibitors. Based on this discovery, the assay was simply carried out on a capture antibody-immobilized microplate by using the Au@PtNH-labeled detection antibody as a signal-transduction tag with a sandwich type assay mode. The colorimetric signal stemmed from the labeled Au@PtNHs toward catalytic oxidation of TMB-H2O2 system. Experimental results indicated that the Au@PtNH-based colorimetric immunoassay could display a good colorimetric response toward PSA in the dynamic working range of 5-500 pg mL(-1) with a low detection limit of 2.9 pg mL(-1). Meanwhile, the developed immunoassay exhibited good precision and reproducibility, high specificity and acceptable accuracy for the detection of clinical serum samples. These results open up a new horizon for the development of highly sensitive, highly stable and inexpensive non-enzyme immunoassay platforms as an alternative to conventional enzyme-based immunoassay platforms. PMID- 25814410 TI - Reply to the Editor-More Awarenessless Risk-Interpretation of Ablation Risk Caused by Coronary Arterial Anatomy. PMID- 25814411 TI - Letter to Editor-Maneuvers in diagnosing permanent junctional reciprocating tachycardia. PMID- 25814412 TI - Letter to the Editor--Amiodarone and risk of acute pancreatitis. PMID- 25814414 TI - Reply to the editor--amiodarone and risk of acute pancreatitis. PMID- 25814416 TI - Catheter ablation for atrial fibrillation in patients with left atrial appendage closure devices. PMID- 25814413 TI - Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition ameliorates arrhythmias elicited by junctin ablation under stress conditions. AB - BACKGROUND: Aberrant calcium signaling is considered one of the key mechanisms contributing to arrhythmias, especially in the context of heart failure. In human heart failure, there is significant down-regulation of the sarcoplasmic reticulum (SR) protein junctin, and junctin deficiency in mice is associated with stress induced arrhythmias. OBJECTIVE: The purpose of this study was to determine whether the increased SR Ca(2+) leak and arrhythmias associated with junctin ablation may be associated with increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity and phosphorylation of the cardiac ryanodine receptor (RyR2) and whether pharmacologic inhibition of CaMKII activity may prevent these arrhythmias. METHODS: Using a combination of biochemical, cellular, and in vivo approaches, we tested the ability of KN-93 to reverse aberrant CaMKII phosphorylation of RyR2. Specifically, we performed protein phosphorylation analysis, in vitro cardiomyocyte contractility and Ca(2+) kinetics, and in vivo ECG analysis in junctin-deficient mice. RESULTS: In the absence of junctin, RyR2 channels displayed CaMKII-dependent hyperphosphorylation. Notably, CaMKII inhibition by KN-93 reduced the in vivo incidence of stress-induced ventricular tachycardia by 65% in junctin null mice. At the cardiomyocyte level, KN-93 reduced the percentage of junctin null cells exhibiting spontaneous Ca(2+) aftertransients and aftercontractions under stress conditions by 35% and 37%, respectively. At the molecular level, KN-93 blunted the CaMKII-mediated hyperphosphorylation of RyR2 and phospholamban under stress conditions. CONCLUSION: Our data suggest that CaMKII inhibition is effective in preventing arrhythmogenesis in the setting of junctin ablation through modulation of both SR Ca(2+) release and uptake. Thus, it merits further investigation as promising molecular therapy. PMID- 25814415 TI - New insight into scar-related ventricular tachycardia circuits in ischemic cardiomyopathy: Fat deposition after myocardial infarction on computed tomography -A pilot study. AB - BACKGROUND: Myocardial fat deposition (FAT-DEP) has been frequently observed in regions of chronic myocardial infarction in patients with ischemic cardiomyopathy. The role of FAT-DEP within scar-related ventricular tachycardia (VT) circuits has not been investigated. OBJECTIVE: This pilot study aimed to assess the impact of myocardial FAT-DEP on local electrograms and VT circuits in patients with ischemic cardiomyopathy. METHODS: Contrast-enhanced computed tomography was performed in 22 patients with ischemic VT. Electroanatomic map points were registered to the corresponding contrast-enhanced computed tomography images. Myocardial FAT-DEP was identified and characterized using a postprocessing image overlay that highlighted areas below 0 Hounsfield units (HU). The mean attenuation of local myocardial regions corresponding to sampled electrograms was measured on short-axis images. The associations of mean attenuation with bipolar and unipolar amplitudes, left ventricular wall thickness, and VT circuit sites were investigated. RESULTS: Of 1801 electroanatomic map points, 519 (28.8%) were located in regions with FAT-DEP. Significant differences were observed in mean intensity (23.2 +/- 35.6 HU vs 81.7 +/- 21.9 HU; P < .001), bipolar (0.75 +/- 0.83 mV vs 2.9 +/- 2.4 mV; P < .001) and unipolar (3.1 +/- 1.7 mV vs 7.4 +/- 4.3 mV; P < .001) amplitudes, and left ventricular wall thickness (5.2 +/- 1.7 mm vs 8.2 +/- 2.5 mm; P < .001) between regions with and without FAT-DEP. Lower HU was strongly associated with lower bipolar and unipolar amplitudes (P < .0001, respectively). Importantly, FAT-DEP was associated with critical VT circuit sites with fractionated or isolated potentials. CONCLUSION: FAT-DEP was associated with electrogram characteristics and VT circuit sites. Further work will be needed to determine whether FAT-DEP plays a causal role in the generation of ischemic scar-related VT circuits. PMID- 25814417 TI - Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. OBJECTIVES: We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. METHODS: Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with beta-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload induced calcium release activity of the mutant channel in HEK293 cells. RESULTS: We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload-induced calcium release activity under conditions that mimic catecholaminergic stress. CONCLUSION: Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on beta-adrenergic stimulation. PMID- 25814419 TI - A narrow complex tachycardia with varying RP intervals: What is the mechanism? PMID- 25814420 TI - Outcomes of nonpharmacologic treatment of atrial fibrillation in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Limited data exist regarding the outcome of atrial fibrillation (AF) surgery and catheter ablation in patients with hypertrophic cardiomyopathy (HCM). OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of nonpharmacologic treatment of AF in HCM. METHODS: One hundred forty-seven patients (46 female, age 55 +/- 11 years, ejection fraction [EF] 58% +/- 8%) with symptomatic paroxysmal (58%), persistent (31%), and long-standing persistent AF (11%) refractory to antiarrhythmic drugs who presented for their first catheter ablation (n = 79) or AF surgery (n = 68) were included. RESULTS: After follow-up of 35 months (interquartile range 13, 60), 29% of patients who underwent catheter ablation and 51% of those who had undergone AF surgery had no documented recurrent atrial arrhythmia after a single procedure. Repeat ablation was performed in 55% of patients with recurrent arrhythmia in the catheter group and 24% in the surgery group, increasing the success rate to 39% and 53%, respectively, after 1 or more procedures. Predictors of success after the first procedure in a multivariable setting included higher baseline EF and male gender. Persistent or long-standing AF and log of AF duration were associated with lower success. Major complications occurred in 6% of the catheter ablation group and 18% of the AF surgery group. During follow-up, 16 patients died (9 in catheter group, 7 in surgery group) and 1 underwent heart replacement. Lower baseline EF and older age were independently associated with death. CONCLUSION: Catheter ablation and AF surgery are associated with symptomatic improvement in HCM patients. However, long-term success is lower and complications are higher than previously reported. PMID- 25814418 TI - Race- and sex-related differences in care for patients newly diagnosed with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of stroke and death. Uniform utilization of appropriate therapies for AF may help reduce those risks. OBJECTIVE: We sought to determine whether significant race and sex differences exist in the treatment of newly diagnosed AF in Medicare beneficiaries. METHODS: We used administrative encounter data for Medicare beneficiaries to identify patients with newly diagnosed AF during 2010-2011. Services received after initial AF diagnosis were cataloged, including visits with a cardiologist or electrophysiologist, catheter ablation procedures, and use of oral anticoagulants, rate control agents, and antiarrhythmic drugs. RESULTS: Overall, 517,941 patients met study criteria, of whom 452,986 (87%) were white, 36,425 (7%) black, and 28,530 (6%) Hispanic. Male patients comprised 209,788 (41%) of the cohort. In multivariate analysis, there were statistically significant differences in the use of AF-related services by both race and sex, with white patients and male patients receiving the most care. The most notable disparities were for catheter ablation (Hispanic vs white: adjusted hazard ratio [AHR] 0.70; 95% confidence interval [CI] 0.63-0.79; P < .001; female vs male: AHR 0.65; 95% CI 0.63-0.68; P < .001) and receipt of oral anticoagulation (black vs white: AHR 0.94; 95% CI 0.92-0.95; P < .001; Hispanic vs white: AHR 0.94; 95% CI 0.93-0.97; P < .001; female vs male: AHR 0.93; 95% CI 0.93-0.94; P < .001). CONCLUSION: Race and sex appear to have a significant effect on the health care provided to this cohort of Medicare beneficiaries diagnosed with AF. Possible explanations include racial differences in access, patient preferences, treatment bias, and unmeasured clinical characteristics. PMID- 25814421 TI - Reply the editor--a tachycardia using a decrementally conducting concealed accessory pathway between the superior caval vein-right atrial junction and the right ventricle. PMID- 25814422 TI - To the Editor - More awarenessless risk-Interpretation of ablation risk caused by coronary arterial anatomy. PMID- 25814423 TI - Imipramine for incessant ventricular arrhythmias in 2 unrelated patients with Andersen-Tawil syndrome. PMID- 25814424 TI - Isolation and characterization of StERF transcription factor genes from potato (Solanum tuberosum L.). AB - Ethylene response factor (ERF) is a major subfamily of the AP2/ERF family and plays significant roles in the regulation of abiotic- and biotic-stress responses. ERF proteins can interact with the GCC-box cis-element and then initiate a transcriptional cascade activating downstream ethylene response and enhancing plant stress tolerance. In this research, we cloned five StERF genes from potato (Solanum tuberosum L.). The expressional analysis of StERF genes revealed that they showed tissue- or organ-specific expression patterns and the expression levels in leaf, stem, root, flower, and tuber were different. The assays of quantitative real-time polymerase chain reaction (qRT-PCR) and the reverse transcription-PCR (RT-PCR) showed that the expression of five StERF genes was regulated by ethephon, methyl jasmonate (MeJA), salt and drought stress. The result from the yeast one-hybrid experiment showed that five StERFs had trans activation activity and could specifically bind to the GCC-box cis-elements. The StERFs responded to abiotic factors and hormones suggested that they possibly had diverse roles in stress and hormone regulation of potato. PMID- 25814425 TI - A Review of the Key Clinical Trials of 2014. AB - INTRODUCTION: Over the last year, multiple, potentially practice-changing, cardiology trials or studies have been published or presented at international meetings including the American College of Cardiology, European Association for Percutaneous Cardiovascular Interventions, European Society of Cardiology, Transcatheter Cardiovascular Therapeutics, Heart Failure Congress, Heart Rhythm Society, Heart Failure Society of America, American Society of Hypertension and the American Heart Association. METHODS: Clinical trial results presented at major cardiology conferences during 2014 were reviewed by the authors. Search terms included heart failure (HF), acute coronary syndrome, stable coronary disease, interventional cardiology, atrial fibrillation, electrophysiology and coronary prevention. Selection criteria were trials of broad relevance to the cardiology community, those with potential to change current practice and those with potential to guide further phase III research. RESULTS: In this paper, the authors describe and place in clinical context, new HF, data including neprilysin inhibitors, intravenous ferric carboxymaltose, potassium-absorbing compounds, quadripolar leads for cardiac resynchronization therapy and intraventricular device intervention. New trial data are also described for acute coronary syndromes (clopidogrel, prasugrel, ticagrelor), stable coronary artery disease (ivabradine), percutaneous coronary intervention (the role of thrombectomy or treatment of non-culprit lesions during primary intervention, pressure wire studies and outcomes of new stent designs), transcatheter aortic valve intervention data, atrial fibrillation (anticoagulation and direct current cardioversion), electrophysiology (leadless pacemaker devices, use of quinidine in Brugada syndrome) and coronary prevention (landmark Ezetimibe outcome data, PCSK9 clinical trials, childhood prevalence of hypertension, renal denervation for resistant hypertension and the role of cardiac computerized tomography in cardiovascular screening). CONCLUSION: This paper summarizes key clinical trials during 2014 and should be of practical interest to clinicians and cardiology researchers. PMID- 25814426 TI - [In Process Citation]. PMID- 25814427 TI - Anterior eye health recording. AB - AIMS: To survey eye care practitioners from around the world regarding their current practice for anterior eye health recording to inform guidelines on best practice. METHODS: The on-line survey examined the reported use of: word descriptions, sketching, grading scales or photographs; paper or computerised record cards and whether these were guided by proforma headings; grading scale choice, signs graded, level of precision, regional grading; and how much time eye care practitioners spent on average on anterior eye health recording. RESULTS: Eight hundred and nine eye care practitioners from across the world completed the survey. Word description (p<0.001), sketches (p=0.002) and grading scales (p<0.001) were used more for recording the anterior eye health of contact lens patients than other patients, but photography was used similarly (p=0.132). Of the respondents, 84.5% used a grading scale, 13.5% using two, with the original Efron (51.6%) and CCLRU/Brien-Holden-Vision-Institute (48.5%) being the most popular. The median features graded was 11 (range 1-23), frequency from 91.6% (bulbar hyperaemia) to 19.6% (endothelial blebs), with most practitioners grading to the nearest unit (47.4%) and just 14.7% to one decimal place. The average time taken to report anterior eye health was reported to be 6.8+/-5.7 min, with the maximum time available 14.0+/-11 min. CONCLUSIONS: Developed practice and research evidence allows best practice guidelines for anterior eye health recording to be recommended. It is recommended to: record which grading scale is used; always grade to one decimal place, record what you see live rather than based on how you intend to manage a condition; grade bulbar and limbal hyperaemia, limbal neovascularisation, conjunctival papillary redness and roughness (in white light to assess colouration with fluorescein instilled to aid visualisation of papillae/follicles), blepharitis, meibomian gland dysfunction and sketch staining (both corneal and conjunctival) at every visit. Record other anterior eye features only if they are remarkable, but indicate that the key tissue which have been examined. PMID- 25814428 TI - Tear break-up time for tear film evaluation: Are moistening solutions interchangeable? AB - PURPOSE: It was the main purpose of this study to investigate the influence of the moistening solution on TBUT measurements in an asymptomatic population. METHODS: An online survey was employed to determine the compliance of Spanish eye care practitioners with the recommended normalized procedure to administer TBUT. For the purpose of examining the clinical relevance of discrepancies from the recommended procedure, a randomized, double-masked, bilateral study was designed in which a micropipette was used to moisten fluorescein strips with a controlled volume of six different solutions, commonly available in the contact lens office, and TBUT was measured in 58 non-dry eye (OSDI<15) subjects (age from 19 to 32 years). RESULTS: Results from the online survey revealed that 64% of Spanish practitioners frequently use (or have used) different solutions to moisten fluorescein strips during TBUT assessment. Statistically significant differences in TBUT values were found between the various solutions as a whole (chi(2)=198.384, p<0.001), as well as between all solutions when explored pair wise (all p<0.001), except for the two saline solutions. CONCLUSIONS: The present findings support the relevance of selecting the appropriate solution when conducting TBUT for the evaluation of the tear film. Deviations from the recommended procedure may result in misdiagnosis of dry eye and unnecessary patient referral. PMID- 25814429 TI - The Prevalence of ADHD in Fayoum City (Egypt) Among School-Age Children: Depending on a DSM-5-Based Rating Scale. AB - OBJECTIVE: In the present study, we created a new valid rating scale to estimate the prevalence of ADHD among school-age children in Fayoum City. METHOD: We conducted two consequential studies (Studies 1 and 2). In Study 1, the sample comprised 106 children. The ages of the sample participants ranged between 6 and 14 years. The purpose of that study was to validate a new Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5)-based ADHD rating scale. In Study 2, the sample consisted of 420 children with ages ranging from 6 to 14 years. We used the new rating scale to estimate the prevalence of ADHD. RESULTS: The first study showed that the new rating scale for ADHD was valid. The second study revealed that the prevalence of ADHD in Fayoum City was 20.5%, with 33.8% among boys and 6.8% among girls. CONCLUSION: We validated a new ADHD rating scale and estimated the prevalence of ADHD in Fayoum City for the first time in Egypt. PMID- 25814430 TI - Prioritization of Companion Animal Transmissible Diseases for Policy Intervention in Europe. AB - A number of papers have been published on the prioritization of transmissible diseases in farm animals and wildlife, based either on semiquantitative or truly quantitative methods, but there is no published literature on the prioritization of transmissible diseases in companion animals. In this study, available epidemiological data for diseases transmissible from companion animals to man were analysed with the aim of developing a procedure suitable for their prioritization within a European framework. A new method and its associated questionnaire and scoring system were designed based on methods described by the World Organisation for Animal Health (OIE). Modifications were applied to allow for the paucity of specific information on companion animal transmissible diseases. The OIE method was also adapted to the subject and to the regional scope of the interprofessional network addressing zoonotic diseases transmitted via companion animals in Europe: the Companion Animals multisectoriaL interprofessionaL Interdisciplinary Strategic Think tank On zoonoses (CALLISTO). Adaptations were made based on information collected from expert groups on viral, bacterial and parasitic diseases using a structured questionnaire, in which all questions were closed-ended. The expert groups were asked to select the most appropriate answer for each question taking into account the relevance and reliability of the data available in the scientific literature. Subsequently, the scoring of the answers obtained for each disease covered by the questionnaire was analysed to obtain two final overall scores, one for human health impact and one for agricultural economic impact. The adapted method was then applied to select the 15 most important pathogens (five for each pathogen group: viral, bacterial and parasitic) on the basis of their overall impact on public health and agriculture. The result of the prioritization exercise was a joint priority list (available at www.callistoproject.eu) of relevant pathogens according to these two criteria. As the scope of CALLISTO was comprehensive in terms of geographical area, animal species involved and impact of the diseases, the list of prioritized diseases had to accommodate the realities in different European countries and the differences in biology and animal-human relationships in a wide range of species including cats and dogs, pet pigs and sheep as well as captive reptiles. The methodology presented in this paper can be used to generate accurate priority lists according to narrower and more specific objectives. PMID- 25814431 TI - Prototheca zopfii Genotype 2-induced Nasal Dermatitis in a Cat. AB - Few published cases of feline protothecosis exist; all of these were restricted to the skin and speciation of the causative organism revealed an infection with Prototheca wickerhamii in each case. This report describes Prototheca zopfii genotype 2-induced inflammation of the nasal skin and cutaneous mucosa of the right nostril in a 14-year-old neutered female domestic shorthair cat. Microscopical examination revealed marked pyogranulomatous inflammation with numerous intralesional algae. These had a round to ovoid shape, were 8-21 MUm in diameter, formed endospores and displayed a positive immunoreaction for Prototheca zopfii antigen. By 18S rRNA gene amplification and sequencing the intralesional algae were confirmed as Prototheca zopfii and further characterized as Prototheca zopfii genotype 2. This case report reveals Prototheca zopfii as an additional Prototheca species associated with feline protothecosis. PMID- 25814432 TI - Progression from optimal blood glucose and pre-diabetes to type 2 diabetes in a high risk population with or without hypertension in Isfahan, Iran. AB - AIM: To estimate the progression rates from normal glucose tolerance (NGT), isolated impaired glucose tolerance (IGT), isolated impaired fasting glucose (IFG) and combined IFG/IGT to type 2 diabetes (T2D) in a high risk population with and without hypertension (HTN) in Isfahan, Iran. METHODS: During a mean (SD) follow-up period of 6.8 (1.7) years, 1489 non-diabetic first-degree relatives of patients with T2D with or without HTN were followed for the occurrence of T2D. At baseline and through follow-ups, participants underwent a standard 75g 2-h oral glucose tolerance test. Blood pressure was measured by standardised protocols and HTN was defined according to the criteria of the JNC7. RESULTS: The progression rate (95% confidence interval) from NGT, isolated IFG, isolated IGT, and combined IFG/IGT to T2D was 10.0 (4.3, 19.6), 21.7 (9.5, 42.3), 28.2 (12.3, 54.7) and 64.7 (41.0, 96.4) per 1000 person-years in participants with HTN and 3.1 (1.5, 4.7), 16.3 (10.3, 24.2), 25.9 (17.0, 37.7) and 57.9 (46.1, 71.7) per 1000 person-years in participants without HTN based on 10,134 person-years of follow-up. Compared with individuals with NGT and without HTN, individuals with NGT and HTN, isolated IFG, isolated IGT, and combined IFG/IGT with or without HTN at baseline were more likely to progress to T2D. Compared with participants without HTN, individuals with concomitant HTN were not significantly more likely to progress to T2D. CONCLUSIONS: Compared with individuals without HTN, the presence of NGT, isolated IFG, isolated IGT, and combined IFG/IGT with concomitant HTN was not associated with higher likelihood of progression to T2D in high-risk individuals in Iran. PMID- 25814434 TI - Molecular profile of clonal strains of human skeletal stem/progenitor cells with different potencies. AB - Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) are fibroblastic reticular cells, a subset of which is composed of multipotent skeletal stem cells (SSCs). SSCs/BMSCs are able to recreate a bone/marrow organ in vivo. To determine differences between clonogenic multipotent SSCs and similarly clonogenic but non-multipotent BMSCs, we established single colony-derived strains (SCDSs, initiated by individual Colony Forming Unit-Fibroblasts) and determined their differentiation capacity by vivo transplantation. In this series of human SCDSs (N=24), 20.8% formed fibrous tissue (F), 66.7% formed bone (B), and 12.5% formed a bone/marrow organ, and thus were multipotent (M). RNA isolated from 12 SCDSs just prior to transplantation was analyzed by microarray. Although highly similar, there was variability from one SCDS to another, and SCDSs did not strictly segregate into the three functional groups (F, B or M) by unsupervised hierarchical clustering. We then compared 3 F-SCDSs to 3 M-SCDSs that did segregate. Genes associated with skeletogenesis, osteoblastogeneis, hematopoiesis, and extracellular matrix were over-represented in M-SCDSs compared with F-SCDSs. These results highlight the heterogeneity of SSCs/BMSCs, even between functionally similar SCDSs, but also indicate that differences can be detected that may shed light on the character of the SSC. PMID- 25814435 TI - Differential Roles of PIN1 and PIN2 in Root Meristem Maintenance Under Low-B Conditions in Arabidopsis thaliana. AB - Boron (B) is an essential element for plants; its deficiency causes rapid cessation of root elongation. In addition, B influences auxin accumulation in plants. To assess the importance of auxin transport in B-dependent root elongation, Arabidopsis thaliana pin1-pin4 mutants were grown under low-B conditions. Among them, only the pin2/eir1-1 mutant showed a significantly shorter root under low-B conditions than under control conditions. Moreover, the root meristem size of pin2/eir1-1 was reduced under low-B conditions. Among the PIN-FORMED (PIN) family, PIN1 and PIN2 are important for root meristem growth/maintenance under normal conditions. To investigate the differential response of pin1 and pin2 mutants under low-B conditions, the effect of low-B on PIN1-green fluorescent protein (GFP) and PIN2-GFP accumulation and localization was examined. Low-B did not affect PIN2-GFP, while it reduced the accumulation of PIN1-GFP. Moreover, no signal from DII-VENUS, an auxin sensor, was detected under the low-B condition in the stele of wild-type root meristems. Taken together, these results indicate that under low-B conditions PIN1 is down-regulated and PIN2 plays an important role in root meristem maintenance. PMID- 25814436 TI - Effect of Transmural Transport Properties on Atheroma Plaque Formation and Development. AB - We propose a mathematical model of atheroma plaque initiation and early development in coronary arteries using anisotropic transmural diffusion properties. Our current approach is on the process on plaque initiation and intimal thickening rather than in severe plaque progression and rupture phenomena. The effect of transport properties, in particular the anisotropy of diffusion properties of the artery, on plaque formation and development is investigated using the proposed mathematical model. There is not a strong influence of the anisotropic transmural properties on LDL, SMCs and collagen distribution and concentrations along the artery. On the contrary, foam cells distribution strongly depends on the value of the radial diffusion coefficient of the substances [Formula: see text] and the ratio [Formula: see text]. Decreasing [Formula: see text] or diffusion coefficients ratio means a higher concentration of the foam cells close to the intima. Due to the fact that foam cells concentration is associated to the necrotic core formation, the final distribution of foam cells is critical to evolve into a vulnerable or fibrotic plaque. PMID- 25814437 TI - Staffing subsidies and the quality of care in nursing homes. AB - Concerns about the quality of state-financed nursing home care has led to the wide-scale adoption by states of pass-through subsidies, in which Medicaid reimbursement rates are directly tied to staffing expenditure. We examine the effects of Medicaid pass-through on nursing home staffing and quality of care by adapting a two-step FGLS method that addresses clustering and state-level temporal autocorrelation. We find that pass-through subsidies increases staffing by about 1% on average and 2.7% in nursing homes with a low share of Medicaid patients. Furthermore, pass-through subsidies reduce the incidences of pressure ulcer worsening by about 0.9%. PMID- 25814438 TI - Combining confocal and single molecule localisation microscopy: A correlative approach to multi-scale tissue imaging. AB - Many biological questions require information at different spatial scales that include molecular, organelle, cell and tissue scales. Here we detail a method of multi-scale imaging of human cardiac tissue by correlatively combining nano-scale data of direct stochastic optical reconstruction microscopy (dSTORM) with cellular and tissue level data provided by confocal microscopy. By utilising conventional fluorescence dyes the same cellular structures can be imaged with both modalities. Human cardiac tissue was first imaged at the nanoscale to identify macro-molecular membrane complexes containing the cardiac muscle proteins junctophilin (JPH) and the ryanodine receptor (RyR). The distribution of these proteins and an additional cell membrane marker (wheat germ agglutinin, WGA) were subsequently imaged by confocal microscopy. By segmenting dSTORM data into membrane and non-membrane components we demonstrate increased colocalization of RyR with JPH at the plasma-membrane as compared to intracellular compartments. Strategies for antibody labelling, quality control, locating and aligning structures between modalities, and analysis of combined multi-scaled data sets are described. PMID- 25814439 TI - Near infrared lasers in flow cytometry. AB - Technology development in flow cytometry has closely tracked laser technology, the light source that flow cytometers almost exclusively use to excite fluorescent probes. The original flow cytometers from the 1970s and 1980s used large water-cooled lasers to produce only one or two laser lines at a time. Modern cytometers can take advantage of the revolution in solid state laser technology to use almost any laser wavelength ranging from the ultraviolet to the near infrared. Commercial cytometers can now be equipped with many small solid state lasers, providing almost any wavelength needed for cellular analysis. Flow cytometers are now equipped to analyze 20 or more fluorescent probes simultaneously, requiring multiple laser wavelengths. Instrument developers are now trying to increase this number by designing fluorescent probes that can be excited by laser wavelength at the "edges" of the visible light range, in the near ultraviolet and near-infrared region. A variety of fluorescent probes have been developed that excite with violet and long wavelength ultraviolet light; however, the near-infrared range (660-800 nm) has yet seen only exploitation in flow cytometry. Fortunately, near-infrared laser diodes and other solid state laser technologies appropriate for flow cytometry have been in existence for some time, and can be readily incorporated into flow cytometers to accelerate fluorescent probe development. The near infrared region represents one of the last "frontiers" to maximize the number of fluorescent probes that can be analyzed by flow cytometry. In addition, near infrared fluorescent probes used in biomedical tracking and imaging could also be employed for flow cytometry with the correct laser wavelengths. This review describes the available technology, including lasers, fluorescent probes and detector technology optimal for near infrared signal detection. PMID- 25814440 TI - An optimized procedure for exosome isolation and analysis using serum samples: Application to cancer biomarker discovery. AB - Exosomes are RNA and protein-containing nanovesicles secreted by all cell types and found in abundance in body fluids, including blood, urine and cerebrospinal fluid. These vesicles seem to be a perfect source of biomarkers, as their cargo largely reflects the content of parental cells, and exosomes originating from all organs can be obtained from circulation through minimally invasive or non invasive means. Here we describe an optimized procedure for exosome isolation and analysis using clinical samples, starting from quick and robust extraction of exosomes with Total exosome isolation reagent, then isolation of RNA followed by qRT-PCR. Effectiveness of this workflow is exemplified by analysis of the miRNA content of exosomes derived from serum samples - obtained from the patients with metastatic prostate cancer, treated prostate cancer patients who have undergone prostatectomy, and control patients without prostate cancer. Three promising exosomal microRNA biomarkers were identified, discriminating these groups: hsa miR375, hsa-miR21, hsa-miR574. PMID- 25814441 TI - Drosophila and experimental neurology in the post-genomic era. AB - For decades, the fruit fly, Drosophila melanogaster, has been among the premiere genetic model systems for probing fundamental neurobiology, including elucidation of mechanisms responsible for human neurologic disorders. Flies continue to offer virtually unparalleled versatility and speed for genetic manipulation, strong genomic conservation, and a nervous system that recapitulates a range of cellular and network properties relevant to human disease. I focus here on four critical challenges emerging from recent advances in our understanding of the genomic basis of human neurologic disorders where innovative experimental strategies are urgently needed: (1) pinpointing causal genes from associated genomic loci; (2) confirming the functional impact of allelic variants; (3) elucidating nervous system roles for novel or poorly studied genes; and (4) probing network interactions within implicated regulatory pathways. Drosophila genetic approaches are ideally suited to address each of these potential translational roadblocks, and will therefore contribute to mechanistic insights and potential breakthrough therapies for complex genetic disorders in the coming years. Strategic collaboration between neurologists, human geneticists, and the Drosophila research community holds great promise to accelerate progress in the post-genomic era. PMID- 25814442 TI - Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study. AB - PURPOSE: Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. METHODS: Adults with esophageal cancer treated with chemotherapy consisting of 5 fluorouracil and cisplatin and 45-50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. RESULTS: Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. CONCLUSIONS: This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted. PMID- 25814443 TI - Guideline sheets on the side effects of anticancer drugs are useful for general practitioners. AB - PURPOSE: General practitioners (GPs) are more and more involved in the treatment of cancer patients but feel not informed enough about anticancer treatments and associated side effects. Better communication with treatment centers is needed. We hypothesized that information sheets could improve communication. METHODS: This prospective, multicentric, and interventionist study aimed at implementing and assessing therapeutic sheets describing the side effects of anticancer drugs used for digestive and gynecological cancers and their recommended management. GPs' phone interviews were done through three successive phases and two independent cohorts. The first phase (T1; 242 GPs with one patient recently treated) listed their expectations, the second (T2; 158 GPs with one patient beginning treatment) assessed the GPs' opinion regarding the sheets, and the third (T3; responder GPs 4 months after the start of T2) assessed their usefulness in practice. RESULTS: In T1, 94% of GPs declared their need of having information sheets, notably for the management of side effects. Thirty-one one page sheets were created. In T2, 83.5% gave a favorable opinion about sheets and 80% envisaged their use in the case of side effect. In T3, 56% of GPs whose patient had experienced a side effect had used successfully the sheets for its management, and 21% of patients with side effect were hospitalized. A strong correlation existed between the use of the sheet by GPs and the hospitalization (OR 7.35 in the case of no use vs use). CONCLUSION: The guideline sheets represent a simple and low-cost solution to help GPs managing drugs' side effects and perhaps decrease the rate of unplanned hospitalizations. PMID- 25814444 TI - Sexual concerns of women diagnosed with breast cancer-related lymphedema. AB - PURPOSE: Lymphedema is a common side effect of breast cancer treatment that may negatively impact on a woman's physical and psychological well-being. This study aimed to understand the impact of breast cancer-related lymphedema on women's sexual functioning, and to identify key concerns of these women regarding sexual issues. METHODS: Purposive sampling recruited 17 women aged 38-67 years with mild to severe lymphedema. Telephone interviews concerning sexual issues were transcribed verbatim and thematic analysis undertaken. RESULTS: Women perceived sexual concerns arising from lymphedema to exacerbate concerns arising from breast cancer. Four interrelated factors determined the extent of lymphedema's sexual impact: (a) swelling severity and location, (b) needing to wear a compression garment, (c) body image concerns raised by lymphedema and breast cancer treatment, and (d) their sexual partner's acceptance and supportiveness. In particular, a supportive partner was instrumental in assisting women to overcome sexual issues caused by severe swelling and/or body image concerns. Few women reported being asked about sexual issues by any health professional, and most women indicated that they were unwilling to discuss sexual concerns with health professionals, friends, or family. CONCLUSIONS: Lymphedema had the potential to accentuate sexual issues caused by breast cancer, but most women were reluctant to discuss issues with anyone other than their partner. These findings are relevant to health professionals designing breast cancer psychosexual interventions and future research addressing lymphedema-specific sexual concerns. PMID- 25814445 TI - Re: Loss of heterozygosity at the CYP2D6 locus in breast cancer: implications for germline pharmacogenetic studies. PMID- 25814446 TI - Interleukin-33 and Behcet disease: Another cytokine among others. AB - Since the discovery of interleukin-33 (IL-33) ligand for the ST2 receptor, scarce studies have implicated this cytokine in the pathogenesis of Behcet's disease (BD). IL-33 is member of the IL-1 superfamily of cytokines that is expressed by epithelial cells, endothelial cells, inflammatory cells and central nervous tissue. Its expression is upregulated following pro-inflammatory situations making IL-33 essential to innate immunity. IL-33 can function both as a traditional cytokine and as a nuclear factor regulating gene transcription. It is thought to function as an "alarmin" which is released following cell necrosis to alert the immune system of tissue damage or stress. This short review highlights the emerging roles of IL-33 protein and raises many interrogations about its involvement in BD. PMID- 25814447 TI - The dilemma of DQ HLA-antibodies. AB - Accurate identification of antibody reactivity against HLA-DQ antigens was difficult by using the old serological assays because of the strong linkage disequilibrium between HLA-DR and HLA-DQ (the usual inheritance of a certain HLA DR molecule that ties together with the same DQ molecule within a racial group). The accurate and precise identifications of anti-HLA-antibodies of DQ specificities were made possible with the introduction of multiplex-bead arrays (Luminex), using single antigen bead (SAB) assay. The SAB assay is also considered today to be the most sensitive and specific method for alloimmunization assessment even for the low titer anti-HLA-antibodies. However, it is becoming clear that the detection of the HLA antibodies by SAB is not absolutely perfect due to the variation in densities, conformations and orientations of the antigen coated beads. Unlike HLA-DR, the HLA-DQ antigens are made of two polymorphic chains, both (alpha and beta chains) can contribute to the process of immunization individually or jointly. Routine SAB testing approach, which assigns the specificities based on beta chains and ignores the contribution of the DQalpha chains, can lead to erroneous DQ-antibody assignments. Therefore, it is important to recognize both the peculiarity of the HLA-DQ antigens as well as the nature of the assay format used in order to reach the correct antibody assignments. Erroneous donor specific antibodies (DSA) assignment may lead to denial of an otherwise immunologically compatible organ transplant, or exposing transplant recipients to unnecessary investigations or immunosuppression. The following two patients presented with HLA-antibodies against DQ antigens (anti-DQ-Abs) highlight these two scenarios. PMID- 25814448 TI - Large-scale determination of absolute phosphorylation stoichiometries in human cells by motif-targeting quantitative proteomics. AB - Our ability to model the dynamics of signal transduction networks will depend on accurate methods to quantify levels of protein phosphorylation on a global scale. Here we describe a motif-targeting quantitation method for phosphorylation stoichiometry typing. Proteome-wide phosphorylation stoichiometry can be obtained by a simple phosphoproteomic workflow integrating dephosphorylation and isotope tagging with enzymatic kinase reaction. Proof-of-concept experiments using CK2-, MAPK- and EGFR-targeting assays in lung cancer cells demonstrate the advantage of kinase-targeted complexity reduction, resulting in deeper phosphoproteome quantification. We measure the phosphorylation stoichiometry of >1,000 phosphorylation sites including 366 low-abundance tyrosine phosphorylation sites, with high reproducibility and using small sample sizes. Comparing drug-resistant and sensitive lung cancer cells, we reveal that post-translational phosphorylation changes are significantly more dramatic than those at the protein and messenger RNA levels, and suggest potential drug targets within the kinase substrate network associated with acquired drug resistance. PMID- 25814450 TI - Teleneurocritical care and telestroke. AB - Telestroke and teleneurologic intensive care units (teleneuro-ICUs) optimize the diagnosis and treatment of neurologic emergencies. Establishment of a telestroke or teleneuro-ICU program relies on investment in experienced stroke and neurocritical care personnel as well as advanced telecommunications technologies. Telemanagement of neurologic emergencies can be standardized to improve outcomes, but it is essential to have a relationship with a tertiary care facility that can use endovascular, neurosurgical, and neurocritical care advanced therapies after stabilization. The next stage in telestroke/teleneuro-ICU management involves the use of mobile stroke units to shorten the time to treatment in neurocritically ill patients. PMID- 25814449 TI - Telemedicine in the intensive care unit: state of the art. AB - Critical care medicine is at a crossroads in which limited numbers of staff care for increasing numbers of patients as the population ages and use of ICUs increases. Also at this time health care spending must be curbed. The high intensity intensivist staffing model has been linked to improved mortality, complications, and costs. Tele-ICU uses technology to implement this high intensity staffing model in areas that are relatively underserved. When implemented correctly and in the right populations this technology has improved outcomes. Future studies regarding implementation, organization, staffing, and innovation are needed to determine the optimal use of this critical care professional enhanced technology. PMID- 25814452 TI - Telemedicine in the intensive care unit: its role in emergencies and disaster management. AB - Disasters and emergencies lead to an overburdened health care system after the event, so additional telemedicine support can improve patient outcomes. If telemedicine is going to become an integral part of disaster response, there needs to be improved preparation for the use of telemedicine technologies. Telemedicine can improve patient triage, monitoring, access to specialists, health care provider burnout, and disaster recovery. However, the evidence for telemedicine and tele-intensive care in the disaster setting is limited, and it should be further studied to identify situations in which it is the most clinically effective and cost-effective. PMID- 25814451 TI - Outcomes related to telemedicine in the intensive care unit: what we know and would like to know. AB - Telemedicine has been increasingly used in the intensive care unit setting (Tele ICU) for providing care. Given the shortage of qualified intensivists and critical care nurses in the United States and the ever-increasing demand for intensive care services, Tele-ICU has been proposed as a strategy to bridge this supply/demand gap. The Tele-ICU staffing model provides for many important outcome benefits that have been evaluated over the years by several studies. In this review, the authors summarize the existing evidence and identify areas where further evaluation is warranted. PMID- 25814453 TI - Increasing quality through telemedicine in the intensive care unit. AB - This article explores the hypothesis that a telemedicine intensive care unit (Tele-ICU) platform is uniquely suited to facilitate quality performance improvement (PI). This article addresses some substantial hurdles to overcome that may limit the effectiveness of a Tele-ICU platform to achieve PI objectives. Lastly, this article describes the author's experience with a PI project to improve ventilator management conducted via a Tele-ICU hub interacting with 11 geographically dispersed ICUs. Using this example to illustrate the concepts, the author hopes to shed some light on the successes and lessons learned so as to generate best-practice guidelines for Tele-ICU-directed PI initiatives. PMID- 25814454 TI - The role of telemedicine in pediatric critical care. AB - Telemedicine technologies involve real-time, live, interactive video and audio communication and allow pediatric critical care physicians to have a virtual presence at the bedsides of critically ill children. Telemedicine use is increasing and will be a common in remote emergency departments, inpatient wards, and intensive care units for pediatric care. Hospitals and physicians that use telemedicine technologies provide higher quality of care, are more efficient in resource use with improved cost-effectiveness, and have higher satisfaction among patients, parents, and remote providers. More research will result in improved access to pediatric critical care expertise. PMID- 25814455 TI - Telemedicine and the patient with sepsis. AB - Severe sepsis remains a significant medical problem affecting up to 18 million individuals worldwide. Mortality remains high ranging between 28% and 50%. Owing to this and the time-sensitive nature of this disease state, early identification and prompt interventions are necessary to improve outcomes. Technology associated with telemedicine may help in screening, identifying, and monitoring the attainment of the severe sepsis bundle elements in a timely manner. However, the heterogeneity of systemic inflammatory response syndrome and clinical assessment necessary to diagnose and assess patients with severe sepsis makes technology alone insufficient to improve the outcomes in these patients. PMID- 25814456 TI - The impact of telemedicine in cardiac critical care. AB - Telemedicine was recognized in the 1970s as a legitimate entity for applying the use of modern information and communications technologies to the delivery of health services. Telecardiology is one of the fastest growing fields in telemedicine. The advancement of technologies and Web-based applications has allowed better transmission of health care delivery. This article discusses current advancements, the scope of telemedicine in cardiology, and its application to the critically ill. The impact of telecardiology consultation continues to evolve and includes many promising applications with potential positive implications for admission rates, morbidity, and mortality. PMID- 25814457 TI - Practice challenges of intensive care unit telemedicine. AB - For more than 20 years, a 100-year-old state-based system for medical licensure has not progressed commensurate with the level of 21st century technology development. Despite government and nongovernment organizational attempts, each state maintains a process of variable and time-consuming requirements with lack of reciprocity. Lack of available reimbursement for Tele-ICU physician services is thought to be a long-standing and significant barrier to the rapid adoption of Tele-ICU programs. By reviewing the reimbursement guidelines for telehealth services across all major patient financial classes, a model is discussed for developing financial projections to determine exactly what reimbursement is available for Tele-ICU programs. PMID- 25814458 TI - Options for tele-intensive care unit design: centralized versus decentralized and other considerations: it is not just a "another black sedan". AB - This article seeks assist physicians or administrators considering establishing a Tele-ICU. Owing to an apparent domination of the Tele-ICU field by a single vendor, some may believe that there is only one design option. In fact, there are many alternative design formats that do not require the consumer to possess high level technical expertise. As when purchasing any major item, if the consumer can formulate basic concepts of design and research the various vendors, then the consumer can develop the Tele-ICU system best for their facility, finances, availability of staff, coverage model, and quality metric goals. PMID- 25814459 TI - Telemedicine in the ICU. PMID- 25814460 TI - Mediating Role of Psychological Resources on the Association Between Childhood Socioeconomic Status and Current Health in the Community Adult Population of Japan. AB - BACKGROUND: The majority of studies on the role of psychological resources linking childhood socioeconomic status (SES) and adult health have been conducted in Western countries. Empirical evidence for mediation effects of psychological resources is currently lacking in Japan. PURPOSE: The purpose of this study was to investigate the mediating effect of psychological resources (mastery and sense of coherence [SOC]) on the association between childhood SES and current health. METHOD: Analyses were conducted on cross-sectional data (1,497 men and 1,764 women) from the Japanese Study of Stratification, Health, Income, and Neighborhood Study (J-SHINE) in Tokyo. Psychological resources (mastery and SOC), childhood SES (parents' education and perceived childhood SES), and current health of adults (psychological distress measured by K6 and self-rated health) were measured using a self-report questionnaire. RESULTS: Mastery and SOC significantly and independently mediated the association between childhood SES and current health in the total sample after adjusting for age, gender, and respondent education, regardless of type of SES or health outcome indicators. Similar mediation effects were observed for both men and women. A few gender differences were observed; specifically, SOC significantly mediated the association between parents' education and current health only among women, and it mediated the association between perceived childhood SES and current health only among men. CONCLUSIONS: Overall, the findings underscore the importance of the mediating role of psychological resources in the association between childhood SES and current health. PMID- 25814462 TI - Automatic evaluation of hypernasality based on a cleft palate speech database. AB - The hypernasality is one of the most typical characteristics of cleft palate (CP) speech. The evaluation outcome of hypernasality grading decides the necessity of follow-up surgery. Currently, the evaluation of CP speech is carried out by experienced speech therapists. However, the result strongly depends on their clinical experience and subjective judgment. This work aims to propose an automatic evaluation system for hypernasality grading in CP speech. The database tested in this work is collected by the Hospital of Stomatology, Sichuan University, which has the largest number of CP patients in China. Based on the production process of hypernasality, source sound pulse and vocal tract filter features are presented. These features include pitch, the first and second energy amplified frequency bands, cepstrum based features, MFCC, short-time energy in the sub-bands features. These features combined with KNN classier are applied to automatically classify four grades of hypernasality: normal, mild, moderate and severe. The experiment results show that the proposed system achieves a good performance. The classification rates for four hypernasality grades reach up to 80.4%. The sensitivity of proposed features to the gender is also discussed. PMID- 25814461 TI - Psychological Treatments for Chronic Pain in East and Southeast Asia: A Systematic Review. AB - BACKGROUND: Psychological treatments are recognised as generally effective for chronic pain. However, little is known about the evidence for psychological treatments for chronic pain in Asia. PURPOSE: This study aimed (1) to identify all treatment outcome studies in the area of psychological approaches to chronic pain in adult populations of East Asia and Southeast Asia and (2) to evaluate the treatment types, the evidence for treatment outcomes and research design quality with regard to these studies. METHODS: We identified all psychologically based treatment outcome studies for chronic pain in East and Southeast Asia by searching CENTRAL, EMBASE, PsycINFO, MEDLINE (via Ovid), Global Health and Web of Science from the beginning of each abstracting service until December 2014 (week 4). RESULTS: Seventeen studies met inclusion criteria including a total of N = 1,890 participants. Four were randomised controlled trials (RCTs), five controlled clinical trials (CCTs) and eight cohort studies. Treatment outcomes included pain, disability, depression and anxiety. Overall, the studies included in this review showed small to medium within-group effect sizes for all four outcomes. A majority of the studies were rated as weak in design quality. Three RCTs were found to be of strong quality, one of moderate quality and only one CCT of moderate quality. CONCLUSION: The current available literature on psychological treatments for chronic pain in East and Southeast Asia is generally small in scale, mostly preliminary and lags behind on some developments occurring in North America and Europe. Further development of treatment methods and research designs is warranted. PMID- 25814463 TI - Study on the stereoselective degradation of three triazole fungicides in sediment. AB - The stereoselective degradation behaviors of chiral triazole fungicides (hexaconazole, flutriafol and tebuconazole) in sediment were investigated under laboratory conditions. The enantiomers were completely separated by high performance liquid chromatography on a cellulose tris(3-chloro-4 methylphenylcarbamate) (Lux Cellulose-2) column. The mean recoveries of hexaconazole, flutriafol and tebuconazole in sediment ranged from 86.7% to 105.9%. The methods were successfully applied for the enantioselective degradation analysis of fungicides in sediment. The results showed that the dissipation of hexaconazole, flutriafol and tebuconazole stereoisomers in sediment followed first-order kinetics (R(2)>0.95). The degradation rate of the enantiomers was different in sediment, and the (-)-enantiomer (t(1/2) was 86 days for hexaconazole, 139 for flutriafol and 136 for tebuconazole) degraded faster than the (+)-enantiomer (t(1/2) was 94 days for hexaconazole, 144 for flutriafol and 151 for tebuconazole) in native condition. The fungicides were degraded slowly, and no significant enantioselective degradation were observed under sterilized conditions. The results may hold promising implications for the environmental and ecological risk assessment of three important chiral triazole fungicides. PMID- 25814465 TI - Halogen-bonded photoresponsive materials. AB - The aim of the present review is to illustrate to the reader the state of the art on the construction of supramolecular azobenzene-containing materials formed by halogen bonding. These materials include several examples of polymeric, liquid crystalline or crystalline species whose performances are either superior to the corresponding performances of their hydrogen-bonded analogues or simply distinctive of the halogen-bonded species. PMID- 25814464 TI - Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase. AB - Butyrylcholinesterase (BChE) gene therapy is emerging as a promising concept for treatment of cocaine addiction. BChE levels after gene transfer can rise 1000 fold above those in untreated mice, making this enzyme the second most abundant plasma protein. For months or years, gene transfer of a BChE mutated into a cocaine hydrolase (CocH) can maintain enzyme levels that destroy cocaine within seconds after appearance in the blood stream, allowing little to reach the brain. Rapid enzyme action causes a sharp rise in plasma levels of two cocaine metabolites, benzoic acid (BA) and ecgonine methyl ester (EME), a smooth muscle relaxant that is mildly hypotensive and, at best, only weakly rewarding. The present study, utilizing Balb/c mice, tested reward effects and cardiovascular effects of administering EME and BA together at molar levels equivalent to those generated by a given dose of cocaine. Reward was evaluated by conditioned place preference. In this paradigm, cocaine (20 mg/kg) induced a robust positive response but the equivalent combined dose of EME + BA failed to induce either place preference or aversion. Likewise, mice that had undergone gene transfer with mouse CocH (mCocH) showed no place preference or aversion after repeated treatments with a near-lethal 80 mg/kg cocaine dose. Furthermore, a single administration of that same high cocaine dose failed to affect blood pressure as measured using the noninvasive tail-cuff method. These observations confirm that the drug metabolites generated after CocH gene transfer therapy are safe even after a dose of cocaine that would ordinarily be lethal. PMID- 25814466 TI - IR Spectroscopic Techniques to Study Isolated Biomolecules. AB - The combination of mass spectrometry, infrared action spectroscopy and quantum chemical calculations provides a variety of approaches to the study of the structure of biologically relevant molecules in vacuo. This chapter reviews some of the experimental methods that are currently in use, which can roughly be divided into two main categories: (1) low-temperature neutral molecules in a molecular beam environment, which can be investigated in a conformationally selective manner by the application of double-resonance laser spectroscopy and (2) ionized species which can conveniently be manipulated and selected by mass spectrometric methods and which can be investigated spectroscopically by wavelength-dependent photo-dissociation. Both approaches rely on the application of infrared tunable laser spectroscopy and the laser sources most commonly used in current studies are briefly reviewed in Sect. 3. Along with quantum-chemical calculations, reviewed in Chapter 3 of this book (Gaigeot and Spezia, Top Curr Chem doi:10.1007/128_2014_620), the experimental IR spectra reveal a wealth of information on the structural properties of the biological species. PMID- 25814467 TI - Upregulation of NKG2C+ natural killer cells, TLR-2 expression on monocytes and downregulation of regulatory T-cells influence PEG-IFN treatment efficacy in entecavir-suppressed patients with CHB. AB - BACKGROUND: There is increasing evidence that host immune responses influence antiviral efficacy in chronic hepatitis B (CHB). The aim of this study was to characterize the immunological features responsible for improved treatment responses with pegylated interferon (PEG-IFN)-alpha2a in entecavir (ETV) suppressed patients with CHB. METHODS: Peripheral natural killer (NK) cells, Toll like receptors (TLRs), T-cell subsets, regulatory T-cells (Tregs) and programmed death 1 (PD-1) were evaluated dynamically in 77 patients undergoing a clinical trial (OSST trial, NCT00940485) by flow cytometry. Response was defined as hepatitis B e antigen (HBeAg) seroconversion, hepatitis B surface antigen (HBsAg) loss and HBsAg seroconversion (either as singular events or in combination at week 48). RESULTS: Compared with ETV responders or PEG-IFN-alpha non-responders, PEG-IFN-alpha responders exhibited a significant decline in HBsAg during treatment (P=0.033 and P<0.001, respectively) and a significant decline in Treg proportions from week 12 to week 24 (P=0.036 and P=0.004, respectively). Moreover, PEG-IFN-alpha responders showed a significantly higher increase in the NKG2C(+) NK cell proportions from baseline to week 12 (P=0.0073) and of TLR2(+) monocytes at week 12 than PEG-IFN-alpha non-responders (P=0.039). CONCLUSIONS: Successful response to PEG-IFN-alpha correlates with an early significant restoration of impaired immune responses. Although antiviral treatment response can be achieved by both IFN and ETV, the underlying immunological features vary which may explain the generally observed difference in off-treatment durability of response between the two treatments, as well as effects on HBsAg. PMID- 25814468 TI - The effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in the high-fat-fed ovariectomized rats. AB - Previous studies reported that statins showed positive effects on bone in both human and animal models. This study aimed to investigate the effects of atorvastatin on the prevention of osteoporosis and dyslipidemia in ovariectomized rats fed with high-fat emulsion. The 3-month-old female rats were subjected to either sham operations (n = 8) or ovariectomized operations (OVX, n = 24). The OVX rats were orally administered deionized water (n = 8) or standardized high fat emulsion without (n = 8) or with atorvastatin (n = 8). All rats were injected twice with calcein before sacrificed for the purpose of double in vivo labeling. After 12 weeks, all rats were sacrificed under anesthesia. Biochemistry, histomorphometry, mechanical test, micro-computed tomography analysis, mechanical test, histology, and component analysis were performed. We found that high-fat emulsion significantly decreased body weight, bone formation, collagen content of bone, and bone biomechanics, while increased blood, liver, and bone marrow lipids. Atorvastatin treatment prevented dyslipidemia, reversed hepatic steatosis, optimized composition of bone, and improved bone mechanical properties. The current study provided further evidence that atorvastatin might be useful for the treatment of osteoporotic patients with dyslipidemia. PMID- 25814469 TI - Reduced cortical thickness in gambling disorder: a morphometric MRI study. AB - Gambling disorder has recently been recognized as a prototype 'behavioral addiction' by virtue of its inclusion in the DSM-5 category of 'Substance-Related and Addictive Disorders.' Despite its newly acquired status and prevalence rate of 1-3 % globally, relatively little is known regarding the neurobiology of this disorder. The aim of this study was to explore cortical morphometry in untreated gambling disorder, for the first time. Subjects with gambling disorder (N = 16) free from current psychotropic medication or psychiatric comorbidities, and healthy controls (N = 17), were entered into the study and undertook magnetic resonance imaging (3T MRI). Cortical thickness was quantified using automated segmentation techniques (FreeSurfer), and group differences were identified using permutation cluster analysis, with stringent correction for multiple comparisons. Gambling disorder was associated with significant reductions (average 15.8-19.9 %) in cortical thickness, versus controls, predominantly in right frontal cortical regions. Pronounced right frontal morphometric brain abnormalities occur in gambling disorder, supporting neurobiological overlap with substance disorders and its recent reclassification as a behavioral addiction. Future work should explore the trait versus state nature of the findings and whether similarities exist with other not-yet-reclassified putative behavioral addictions. PMID- 25814472 TI - Clarification: surnames and social mobility in England. PMID- 25814470 TI - Classical conditioning in borderline personality disorder: an fMRI study. AB - Previous research suggests disturbed emotional learning and memory in borderline personality disorder (BPD). Studies investigating the neural correlates of aversive differential delay conditioning in BPD are currently lacking. We aimed to investigate acquisition, within-session extinction, between-session extinction recall, and reacquisition. We expected increased activation in the insula, amygdala, and anterior cingulate, and decreased prefrontal activation in BPD patients. During functional magnetic resonance imaging, 27 medication-free female BPD patients and 26 female healthy controls (HC) performed a differential delay aversive conditioning paradigm. An electric shock served as unconditioned stimulus, two neutral pictures as conditioned stimuli (CS+/CS-). Dependent variables were blood-oxygen-level-dependent response, skin conductance response (SCR), and subjective ratings (valence, arousal). No significant between-group differences in brain activation were found [all p(FDR) > 0.05]. Within-group comparisons for CS+unpaired > CS- revealed increased insula activity in BPD patients but not in HC during early acquisition; during late acquisition, both groups recruited fronto-parietal areas [p(FDR) < 0.05]. During extinction, BPD patients rated both CS+ and CS- as significantly more arousing and aversive than HC and activated the amygdala in response to CS+. In contrast, HC showed increased prefrontal activity in response to CS+ > CS during extinction. During extinction recall, there was a trend for stronger SCR to CS+ > CS in BPD patients. Amygdala habituation to CS+paired (CS+ in temporal contingency with the aversive event) during acquisition was found in HC but not in patients. Our findings suggest altered temporal response patterns in terms of increased vigilance already during early acquisition and delayed extinction processes in individuals with BPD. PMID- 25814471 TI - Viperin is induced following toll-like receptor 3 (TLR3) ligation and has a virus responsive function in human trophoblast cells. AB - INTRODUCTION: Viperin, a virus-inducible antiviral protein, has been reported to inhibit the replication of a variety of viruses. However, its expression and function in trophoblast cells remains unclear. Toll-like receptor 3 (TLR3) is a key component of the innate immune system that recognizes viral double-stranded RNA and triggers immune reactions by producing type I interferon. We hypothesized that viperin inhibits the replication of human cytomegalovirus (HCMV) in trophoblast cells. METHODS: In situ examinations of viperin expression was conducted in the human first-trimester placenta by immunohistochemical staining. Using a human trophoblast cell culture system, we studied the effect of TLR-3 ligation on viperin expression by treating trophoblasts with polyinosinic polycytidylic acid [Poly (I: C)] (a synthetic double-stranded RNA, which mimics viral RNA). Viperin mRNA and protein expression were evaluated by real-time PCR and Western blot analysis. In a HCMV infected Swan 71 cell model, HCMV immediate early 1 (IE1) protein mRNA expression was evaluated by real-time PCR after viperin RNA interference. RESULTS: Viperin was localized in trophoblast cells. Poly (I: C) induced viperin expression in a dosage and time-dependent manner. Blocking of TLR3 signaling by neutralizing antibody against IFN-beta abolished the stimulation of viperin expression. After HCMV infection, expression of viperin mRNA and protein was unregulated. HCMV IE1 mRNA expression was significantly inhibited by viperin RNA interference. DISCUSSION: Viperin is a virus-responsive protein that is constitutively expressed in human trophoblast cells. However, contrary to our hypothesis, viperin facilitates HCMV replication post infection. PMID- 25814473 TI - Measurement invariance of English and French Health Education Impact Questionnaire (heiQ) empowerment scales validated for cancer. AB - PURPOSE: If measurement invariance (MI) is demonstrated for a scale completed by respondents from two different language groups, it means that the scale measures the same construct in the same way in both groups. We assessed MI of the French- and English-language versions of the five Health Education Impact Questionnaire (heiQ) empowerment scales validated for the cancer setting. METHODS: Data came from two cross-sectional studies of Canadian cancer survivors (704 English, 520 French). Single-group confirmatory factor analysis (CFA) was used to test whether the hypothesized factor structure of the French-language heiQ empowerment scales fit the data. Multi-group CFAs were conducted to assess different levels of MI conditions (configural, metric, scalar, strict, as well as MI of factor variances, covariances, and latent means) of the French- and English-language heiQ empowerment scales. RESULTS: The correlated five-factor model showed good fit in both language groups (goodness-of-fit indices: CFI >= .97; RMSEA <= .07). Goodness-of-fit indices and tests of differences in fit between models supported MI of the five-factor model across the two language groups (?CFI <= -.010 combined with ?RMSEA <= .015). CONCLUSIONS: The French- and English-language heiQ empowerment scales measure the same five dimensions of empowerment in the same way across both language groups. Thus, any observed similarities or differences between French- and English-speaking respondents completing these scales are valid and reflect similarities or differences in empowerment across language groups, not measurement artifact. Consequently, heiQ empowerment data from English- and French-speaking respondents can be directly pooled or contrasted in data analyses. PMID- 25814474 TI - A Lifetime of Allograft Function with Kidneys from Older Donors. AB - Strategies to increase expanded criteria donor (ECD) transplantation are needed. We quantified the extent to which ECD kidneys provide recipients with a lifetime of allograft function by determining the difference between patient survival and death-censored allograft survival (graft survival). Initial analyses compared 5 year outcomes in the Eurotransplant Senior Program (European) and the United States Renal Data System. Among European recipients >=65 years, patient survival exceeded graft survival, and ECD recipients returned to dialysis for an average of 5.2 months after transplant failure. Among United States recipients >=60 years, graft survival exceeded patient survival. Although patient survival in elderly recipients in the United States was low (49% at 5 years), the average difference in patient survival at 10 years in elderly recipients in the United States with an ECD versus non-ECD transplant was only 7 months. The probability of patient survival with a functioning allograft at 5 years was higher with ECD transplantation within 1 year after activation to the waiting list than with delayed non-ECD transplantation >=3 years after activation to the waiting list. Subsequent analyses demonstrated that ECD transplants do not provide a lifetime of allograft function in recipients <50 years in the United States. These findings should encourage ECD transplantation in patients >=60 years, demonstrate that rapid ECD transplantation is superior to delayed non-ECD transplantation, and challenge the policy in the United States of allowing patients <50 years to receive an ECD transplant. PMID- 25814476 TI - EEG Duration: The Long and the Short of It. AB - Current American Clinical Neurophysiology Society guidelines require a minimum of 20 minutes of artifact-free EEG recording; however, the optimum duration for routine EEGs is not established. Our hypothesis was that an EEG recording of 40 minutes' duration would yield more information than a 20-minute EEG in capturing epileptiform abnormalities and in obtaining sleep. We retrospectively studied 150 consecutive EEGs of 40 minutes' duration performed at St Christopher's Hospital for Children. Although the majority (89%) of interictal EEG abnormalities can be identified within the first 20 minutes of a routine EEG, extending the time of a routine EEG increases the yield significantly by identifying an additional 11% of abnormal studies (P = .0001), precluding the need for further long-term monitoring in these patients. Forty-three percent of interictal epileptiform abnormalities were found during sleep. We recommend that routine EEGs be performed for 40 minutes, whenever possible, to improve yield in a cost-effective manner. PMID- 25814475 TI - Neuropsychological Impairment in School-Aged Children Born to Mothers With Gestational Diabetes. AB - The aim of this study was to determine whether school-aged children born to mothers with gestational diabetes show delays in their neuropsychological development. Several key neuropsychological characteristics of 32 children aged 7 to 9 years born to mothers with gestational diabetes were examined by comparing their performance on cognitive tasks to that of 28 children aged 8 to 10 years whose mothers had glucose levels within normal limits during pregnancy. The gestational diabetes group showed low performance on graphic, spatial, and bimanual skills and a higher presence of soft neurologic signs. Lower scores for general intellectual level and the working memory index were also evident. Our results suggest that gestational diabetes is associated with mild cognitive impairment. PMID- 25814478 TI - Industry's pledges to limit harms of alcohol are unlikely to work, research finds. PMID- 25814479 TI - Progress in studying intrinsically disordered proteins with atomistic simulations. AB - Intrinsically disordered proteins are increasingly the focus of biological research since their significance was acknowledged over a decade ago. Due to their importance in biomolecular interactions, they are found to play key roles in many diseases such as cancers and amyloidoses. However, because they lack stable structure they pose a challenge for many experimental methods that are traditionally used to study proteins. Atomistic molecular dynamics simulations can help get around many of the problems faced by such methods provided appropriate timescales are sampled and underlying empirical force fields are applicable. This review presents recent works that highlight the power and potential of atomistic simulations to transform the investigatory pipeline by providing critical insights into the behavior and interactions of intrinsically disordered proteins. PMID- 25814480 TI - The role of TRPV1 in improving VSMC function and attenuating hypertension. AB - The transient receptor potential vanilloid type 1 (TRPV1) channel, a ligand-gated cation channel of the TRP subfamily, can be activated by multiple stimuli, including capsaicin. Currently, cumulative studies have demonstrated an interesting link between TRPV1 and cardiovascular diseases, including hypertension. Additionally, the protective effect of TRPV1 against hypertension and its related disorders has been proved to be partly involved with the improved action of vascular smooth muscle cells (VSMCs). This review focuses on the current knowledge of TRPV1 in improving VSMC function and attenuating hypertension. PMID- 25814481 TI - Low-dose adefovir dipivoxil may induce Fanconi syndrome: clinical characteristics and long-term follow-up for Chinese patients. AB - BACKGROUND: Adefovir dipivoxil (ADV) nephrotoxicity is well known at a dose of 60 mg day(-1) or 120 mg day(-1). However, renal toxicity at a low-dose of 10 mg ADV for HBV-infected patients is not fully described. Our objective was to analyse the clinical features and outcomes of ADV-related Fanconi's syndrome in the Chinese population. METHODS: This was a retrospective study. A total of 35 patients with ADV-related Fanconi's syndrome were studied. Clinical manifestations and biochemical parameters were analysed. 19 patients were from Peking Union Medical College Hospital (PUMCH) included from August 2010 to December 2012. A total of 16 patients were eligible from case reports in the Chinese population retrieved in PUBMED, WANFANG and CNKI database. Bone mineral density and biochemical parameters including serum phosphate, calcium, creatinine, alkaline phosphatase (ALP) were measured before and after ADV cessation and during the follow-up. RESULTS: All recruited patients had hypophosphataemia, increased urinary phosphate excretion and elevated alkaline phosphatase. Serum phosphate levels rapidly increased especially within the 4 weeks after ADV cessation. Serum creatinine remained high or at the upper limit of normal range even after ADV cessation for 1 year. ALP increased in the first three months of ADV cessation and decreased at the 24th week. Bone mineral density was significantly improved after 6 months cessation of ADV. CONCLUSIONS: ADV can be nephrotoxic at prolonged low doses of 10 mg. For those who take ADV long term, regular monitoring of serum phosphate, creatinine levels and urine routine tests are required. PMID- 25814482 TI - Expression of Thyroid Hormone Receptors in Villous Trophoblasts and Decidual Tissue at Protein and mRNA Levels Is Downregulated in Spontaneous and Recurrent Miscarriages. AB - Thyroid hormones are essential for the maintenance of pregnancy, and a deficiency in maternal thyroid hormones has been associated with early pregnancy losses. The expression of THRalpha1, THRbeta1 and THRalpha2 increases with gestational age. The aim of this study was the investigation of the protein and mRNA-levels of THR isoforms THRalpha1, THRalpha2, THRbeta1 and THRbeta2 in normal, spontaneous and recurrent miscarriages. The identification of THR-expressing cells in the decidua was done with double immunofluorescence. The nuclear expression of THRalpha1, THRalpha2, THRbeta1 and THRbeta2 is downregulated at protein level in spontaneous and recurrent miscarriages in villous trophoblast tissue. In decidual tissue, we found a significant downregulation only for THRalpha1 in spontaneous miscarriages. For recurrent miscarriages, THRalpha1 and THRbeta1 were both significantly downregulated in decidual tissue. By applying HLA-G as a trophoblast marker, we found a significant co-expression only for THRbeta2. The results of our study show that thyroid hormone receptors THRalpha1, THRalpha2, THRbeta1 and THRbeta2 are downregulated in spontaneous and recurrent miscarriages. The majority of cells expressing the thyroid hormone receptors in the decidua are decidual stromal cells. PMID- 25814483 TI - The process of development of a prioritization tool for a clinical decision support build within a computerized provider order entry system: Experiences from St Luke's Health System. AB - To establish a process for the development of a prioritization tool for a clinical decision support build within a computerized provider order entry system and concurrently to prioritize alerts for Saint Luke's Health System. The process of prioritizing clinical decision support alerts included (a) consensus sessions to establish a prioritization process and identify clinical decision support alerts through a modified Delphi process and (b) a clinical decision support survey to validate the results. All members of our health system's physician quality organization, Saint Luke's Care as well as clinicians, administrators, and pharmacy staff throughout Saint Luke's Health System, were invited to participate in this confidential survey. The consensus sessions yielded a prioritization process through alert contextualization and associated Likert-type scales. Utilizing this process, the clinical decision support survey polled the opinions of 850 clinicians with a 64.7 percent response rate. Three of the top rated alerts were approved for the pre-implementation build at Saint Luke's Health System: Acute Myocardial Infarction Core Measure Sets, Deep Vein Thrombosis Prophylaxis within 4 h, and Criteria for Sepsis. This study establishes a process for developing a prioritization tool for a clinical decision support build within a computerized provider order entry system that may be applicable to similar institutions. PMID- 25814484 TI - Magnetotransport of single crystalline NbAs. AB - We report transport measurement in zero and applied magnetic field on a single crystal of NbAs. Transverse and longitudinal magnetoresistance in the plane of this tetragonal structure does not saturate up to 9 T. In the transverse configuration (H ? c, I ? c) it is 230,000% at 2 K. The Hall coefficient changes sign from hole-like at room temperature to electron-like below ~150 K. The electron carrier density and mobility calculated at 2 K based on a single band approximation are 1.8 * 10(19) cm(-3) and 3.5 * 10(5) cm(2) Vs(-1), respectively. These values are similar to reported values for TaAs and NbP, and further emphasize that this class of noncentrosymmetric, transition-metal monopnictides is a promising family to explore the properties of Weyl semimetals and the consequences of their novel electronic structure. PMID- 25814485 TI - Life after ibrutinib? A new unmet need in CLL. AB - In this issue of Blood, Jain et al reported on the poor outcomes of patients with chronic lymphocytic leukemia (CLL) after the discontinuation of ibrutinib. PMID- 25814486 TI - New prognostic tools for myeloma. AB - In this issue of Blood, Palumbo et al show, in a study performed with the cooperation of the International Myeloma Working Group (IMWG), that detailed systematic geriatric assessment of elderly myeloma patients might be a useful tool for identifying fit and frail individuals. Like most malignancies, multiple myeloma mainly affects elderly patients. Even so, in daily clinical practice, we usually only consider chronological age (i.e., is the patient under or above 65 years of age?). However, it is quite obvious that there is a huge difference between a 70-year-old fit patient and a frail patient above the age of 80. PMID- 25814487 TI - When the brain tells the blood how to clot. AB - In this issue of Blood, Tian et al report that during traumatic brain injury, small membrane vesicles, called microparticles, disseminate procoagulant factors from the brain into the systemic circulation. The delivery appears to occur through the disrupted blood-brain barrier. PMID- 25814488 TI - Long-term outcomes in MPS-IH: throwing stars. AB - After a herculean data-gathering effort, in this issue of Blood, Aldenhoven and colleagues from Europe and North America provide an eye-opening assessment of long-term neurocognitive, organ, joint, and tissue function after allogeneic transplantation of children with mucopolysaccharidosis type I-Hurler syndrome (MPS-IH), along with an analysis defining a path to better these outcomes. PMID- 25814489 TI - Population-based study on the impact of the familial form of Waldenstrom macroglobulinemia on overall survival. PMID- 25814490 TI - A roadmap for discovery and translation in lymphoma. PMID- 25814491 TI - Improving fMRI reliability in presurgical mapping for brain tumours. AB - PURPOSE: Functional MRI (fMRI) is becoming increasingly integrated into clinical practice for presurgical mapping. Current efforts are focused on validating data quality, with reliability being a major factor. In this paper, we demonstrate the utility of a recently developed approach that uses receiver operating characteristic-reliability (ROC-r) to: (1) identify reliable versus unreliable data sets; (2) automatically select processing options to enhance data quality; and (3) automatically select individualised thresholds for activation maps. METHODS: Presurgical fMRI was conducted in 16 patients undergoing surgical treatment for brain tumours. Within-session test-retest fMRI was conducted, and ROC-reliability of the patient group was compared to a previous healthy control cohort. Individually optimised preprocessing pipelines were determined to improve reliability. Spatial correspondence was assessed by comparing the fMRI results to intraoperative cortical stimulation mapping, in terms of the distance to the nearest active fMRI voxel. RESULTS: The average ROC-r reliability for the patients was 0.58+/-0.03, as compared to 0.72+/-0.02 in healthy controls. For the patient group, this increased significantly to 0.65+/-0.02 by adopting optimised preprocessing pipelines. Co-localisation of the fMRI maps with cortical stimulation was significantly better for more reliable versus less reliable data sets (8.3+/-0.9 vs 29+/-3 mm, respectively). CONCLUSIONS: We demonstrated ROC-r analysis for identifying reliable fMRI data sets, choosing optimal postprocessing pipelines, and selecting patient-specific thresholds. Data sets with higher reliability also showed closer spatial correspondence to cortical stimulation. ROC-r can thus identify poor fMRI data at time of scanning, allowing for repeat scans when necessary. ROC-r analysis provides optimised and automated fMRI processing for improved presurgical mapping. PMID- 25814493 TI - Lifting the veil: how to use clinical neuropsychology to assess dementia. AB - Neurologists often struggle to interpret the results of neuropsychological testing, even though cognitive assessments are an integral component of the diagnostic process in dementia syndromes. This article reviews the principles underlying clinical neuropsychology, background on common neuropsychological tests, and tips on how to interpret the results when assessing patients with dementia. General cognitive screening tools, appropriate for use by general neurologists and psychiatrists, as well as specific cognitive tests examining the main cognitive domains (attention and orientation, memory, visuospatial function, language and executive function) in patients with dementia are considered. Finally, the pattern of deficits, helpful in defining clinical dementia phenotypes and sometimes in predicting the underlying molecular pathology, are outlined. Such clinicopathological associations will become invaluable as disease modifying treatments for dementia are developed and implemented. PMID- 25814492 TI - What causes intracerebral bleeding after thrombolysis for acute ischaemic stroke? Recent insights into mechanisms and potential biomarkers. AB - The overall population benefit of intravascular recombinant tissue plasminogen activator (rtPA) on functional outcome in ischaemic stroke is clear, but there are some treated patients who are harmed by early symptomatic intracranial haemorrhage (ICH). Although several clinical and radiological factors increase the risk of rtPA-related ICH, none of the currently available risk prediction tools are yet useful for practical clinical decision-making, probably reflecting our limited understanding of the underlying mechanisms. Finding new methods to identify patients at highest risk of rtPA-related ICH, or new measures to limit risk, are urgent challenges in acute stroke therapy research. In this article, we focus on the potential underlying mechanisms of rtPA-related ICH, highlight promising candidate risk biomarkers and suggest future research directions. PMID- 25814494 TI - Sialylated IgG-Fc: a novel biomarker of chronic inflammatory demyelinating polyneuropathy. AB - OBJECTIVE: Sialylation in Fc portion of IgG plays a crucial role in the pathogenesis of autoimmune diseases and the working mechanism of intravenous immunoglobulin (IVIG). We aim to test whether IgG-Fc sialylation is a biomarker of disease activity for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: By using specific lectins for sialylation, galactosylation and agalactosylation, lectin-enzyme assay and lectin blotting with pretreatment of IgG degradating enzyme of Streptococcus pyogenes were performed to compare the glycosylation levels of serum IgG-Fc (1) between patients of untreated CIDP (n=107) and normal control subjects (n=27), (2) among patients with untreated CIDP of different clinical severities and (3) before and after IVIG treatment of patients with CIDP (n=12). RESULTS: Sialylation and galactosylation of IgG-Fc were significantly reduced in patients with CIDP than normal control subjects (p=0.003 and 0.033, respectively), whereas agalactosylation was increased in CIDP (p=0.21). Ratios of sialylated/agalactosylated IgG-Fc levels were significantly reduced in CIDP (p<0.001) and inversely related to disease severity (p=0.044). After IVIG treatment, levels of sialylated IgG-Fc significantly increased (p=0.003). CONCLUSIONS: Sialylation of IgG-Fc is reduced in CIDP. Its level correlated with clinical severity and increased after IVIG treatment. Sialylated as well as ratio of sialylated/agalactosylated IgG-Fc could be new measures to monitor the disease severity and treatment status in CIDP. PMID- 25814495 TI - Turning the tide or riding the waves? Impacts of antibiotic stewardship and infection control on MRSA strain dynamics in a Scottish region over 16 years: non linear time series analysis. AB - OBJECTIVES: To explore temporal associations between planned antibiotic stewardship and infection control interventions and the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: Retrospective ecological study and time-series analysis integrating typing data from the Scottish MRSA reference laboratory. SETTING: Regional hospital and primary care in a Scottish Health Board. PARTICIPANTS: General adult (N=1,051,993) or intensive care (18,235) admissions and primary care registrations (460,000 inhabitants) between January 1997 and December 2012. INTERVENTIONS: Hand-hygiene campaign; MRSA admission screening; antibiotic stewardship limiting use of macrolides and '4Cs' (cephalosporins, coamoxiclav, clindamycin and fluoroquinolones). OUTCOME MEASURES: Prevalence density of MRSA clonal complexes CC22, CC30 and CC5/Other in hospital (isolates/1000 occupied bed days, OBDs) and community (isolates/10,000 inhabitant-days). RESULTS: 67% of all clinical MRSA isolates (10,707/15,947) were typed. Regional MRSA population structure was dominated by hospital epidemic strains CC30, CC22 and CC45. Following declines in overall MRSA prevalence density, CC5 and other strains of community origin became increasingly important. Reductions in use of '4Cs' and macrolides anticipated declines in sublineages with higher levels of associated resistances. In multivariate time-series models (R(2)=0.63-0.94) introduction of the hand-hygiene campaign, reductions in mean length of stay (when >4 days) and bed occupancy (when >74 to 78%) predicted declines in CC22 and CC30, but not CC5/other strains. Lower importation pressures, expanded MRSA admission screening, and reductions in macrolide and third generation cephalosporin use (thresholds for association: 135 141, and 48-81 defined daily doses/1000 OBDs, respectively) were followed by declines in all clonal complexes. Strain-specific associations with fluoroquinolones and clindamycin reflected resistance phenotypes of clonal complexes. CONCLUSIONS: Infection control measures and changes in population antibiotic use were important predictors of MRSA strain dynamics in our region. Strategies to control MRSA should consider thresholds for effects and strain specific impacts. PMID- 25814496 TI - Workplace violence against nurses in Chinese hospitals: a cross-sectional survey. AB - OBJECTIVES: To determine the prevalence of workplace violence that Chinese nurses have encountered, identify risk factors and provide a basis for future targeted interventions. SETTING: Heilongjiang, a province in northeast China. METHODS: A cross-sectional survey. PARTICIPANTS: A total of 588 nurses provided data. There were also in-depth interviews with 12 nurses, 7 hospital administrators and 6 health officials. RESULTS: A total of 7.8% of the nurses reported physically violent experiences and 71.9% reported non-physically violent experiences in the preceding year. Perpetrators were patients or their relatives (93.5% and 82%, respectively), and 24% of nurses experienced non-physical violence that involved Yi Nao (gangs specifically targeting hospitals). Inexperienced nurses were more likely to report physical (13.2%) or non-physical (89.5%) violence compared with experienced nurses. Graduate-level nurses were more likely to perceive and report non-physical violence (84.6%). Nurses who worked rotating shifts were 3.668 times (95% CI 1.275 to 10.554) more likely to experience physical violence, and 1.771 times (95% CI 1.123 to 2.792) more likely to experience non-physical violence compared with nurses who worked fixed day shifts. Higher anxiety levels about workplace violence and work types were associated with violence. Interviewees perceived financial burdens, unsatisfactory treatment outcomes and miscommunications as influencing factors for workplace violence. CONCLUSIONS: Preplacement education should focus on high-risk groups to reduce workplace violence. Increased awareness from the public and policymakers is necessary to develop effective control strategies at individual, hospital and national levels. PMID- 25814497 TI - Is exposure to e-cigarette communication associated with perceived harms of e cigarette secondhand vapour? Results from a national survey of US adults. AB - OBJECTIVES: E-cigarettes are frequently advertised and portrayed in the media as less harmful compared with regular cigarettes. Earlier surveys reported public perceptions of harms to people using e-cigarettes; however, public perceptions of harms from exposure to secondhand vapour (SHV) have not been studied. We examined associations between self-reported exposure to e-cigarette advertising, media coverage, and interpersonal discussion and perceived harms of SHV. DESIGN: Observational study. SETTING: National online sample of US adults aged >=18 years. PARTICIPANTS: 1449 US adults (mean age 49.5 years), 51.3% female, 76.6% non-Hispanic Caucasian, 7.5% African-American, 10.0% Hispanic and 5.9% other races. OUTCOMES: Perceived harm measures included (1) harmfulness of SHV to one's health, (2) concern about health impact of breathing SHV and (3) comparative harm of SHV versus secondhand smoke (SHS). Predictors were (1) self-reported frequency of exposure to e-cigarette advertising, media coverage and interpersonal discussion (close friends or family) and (2) perceived valence of exposure from each source. Covariates were demographic characteristics, cigarette smoking status and e-cigarette use, and were weighted to the general US adult population. RESULTS: More frequent interpersonal discussion was associated with lower perceived harmfulness of SHV to one's health and lower perceived comparative harm of SHV versus SHS. Frequency of e-cigarette ad and other media exposure were not significant predictors. Perceived negative valence of ad exposure and interpersonal discussion (vs no exposure) was associated with higher perceived harm across all three outcomes, while negative valence of media coverage was associated with higher concern about health impact of breathing SHV. Perceived positive valence (vs no exposure) of interpersonal discussion was associated with lower perceived harm across all three outcomes about health impact of breathing SHV. CONCLUSIONS: Exposure to information about e-cigarettes through advertising, media coverage and interpersonal discussion could play a role in shaping public perceptions of the harmfulness of SHV. PMID- 25814498 TI - Accuracy of popular media reporting on tobacco cessation therapy in substance abuse and mental health populations. AB - BACKGROUND: Tobacco cessation therapy is not consistently provided for alcohol, drug abuse and mental health (ADM) populations, despite the enormous health consequences of tobacco addiction in these groups and research supporting the effectiveness of treatment. Policymakers, however, tend to rely on popular media reports rather than the scientific literature in regulating treatment. Our goal was to determine whether popular reporting accurately reflects findings from the scientific literature on tobacco cessation treatment for ADM populations in treatment. METHODS: We compared the results of systematic reviews on tobacco cessation therapy published before 2004 with articles published in traditional media and on the internet over the following 8 years. We searched LexisNexis and Google and assessed them using the Index of Scientific Quality (ISQ). RESULTS: We found that popular reporting on this topic was consistent with findings reported in contemporaneous scientific literature. Our results suggest that the failure to consistently provide tobacco cessation therapy to ADM populations in treatment is not due to poor research translation. CONCLUSIONS: Our findings also suggest that in this topic area, scientific research findings have diffused relatively quickly. Further study of journalism in this area may suggest new strategies for effective translation of scientific findings into popular reporting on tobacco control. PMID- 25814500 TI - Erratum: Action-specific disruption of perceptual confidence. AB - Fleming, S. M., Maniscalco, B., Ko, Y., Amendi, N., Ro, T., & Lau, H. (2015). Action-specific disruption of perceptual confidence. Psychological Science, 26, 89-98. (Original DOI: 10.1177/0956797614557697). PMID- 25814502 TI - Conspiracist ideation as a predictor of climate-science rejection: an alternative analysis. PMID- 25814499 TI - Mitochondrial and plastid genome architecture: Reoccurring themes, but significant differences at the extremes. AB - Mitochondrial and plastid genomes show a wide array of architectures, varying immensely in size, structure, and content. Some organelle DNAs have even developed elaborate eccentricities, such as scrambled coding regions, nonstandard genetic codes, and convoluted modes of posttranscriptional modification and editing. Here, we compare and contrast the breadth of genomic complexity between mitochondrial and plastid chromosomes. Both organelle genomes have independently evolved many of the same features and taken on similar genomic embellishments, often within the same species or lineage. This trend is most likely because the nuclear-encoded proteins mediating these processes eventually leak from one organelle into the other, leading to a high likelihood of processes appearing in both compartments in parallel. However, the complexity and intensity of genomic embellishments are consistently more pronounced for mitochondria than for plastids, even when they are found in both compartments. We explore the evolutionary forces responsible for these patterns and argue that organelle DNA repair processes, mutation rates, and population genetic landscapes are all important factors leading to the observed convergence and divergence in organelle genome architecture. PMID- 25814501 TI - The robust relationship between conspiracism and denial of (climate) science. PMID- 25814504 TI - The Influence of Interpersonal Style on the Appraisal of Intimate Partner Violence. AB - Intimate partner violence (IPV) is a common type of violence that is associated with a number of psychological problems among women who experience it. Recent research suggests that interpersonal style may influence the degree to which women exhibit psychological problems following IPV exposure. One possible mechanism through which interpersonal style may exert its effects is by influencing appraisals of the violence they experience, although this has not yet been tested empirically. In this study, we examined the effects of dimensions of interpersonal style (dominance and warmth) on IPV appraisals in a sample of young adult women (N = 219) who reported experiencing physical and/or sexual violence from their romantic partner in the past year using a Bayesian approach to multiple linear regression. Our results indicated that both dominance and warmth were associated with less negative (i.e., less betrayed, self-blaming, fearful, alienated, angry, and shameful) appraisals of IPV, exhibiting small- to medium sized effects when controlling for severity of violence. However, this effect was more prominent for dominance than for warmth. These findings shed light on the role of interpersonal style in the response to IPV and indicate directions for future research. PMID- 25814505 TI - Childhood Maltreatment and Revictimization in a Homeless Population. AB - We examined the hypothesis that exposure to childhood maltreatment increases the vulnerability to Adult Victimization (AV) in a homeless population (N = 500). We also investigated the effects of specific types (emotional, physical, and sexual) and cumulative experience of childhood maltreatment on AV, and whether gender moderates these relationships. All three groups with AV experience (emotional, physical, and sexual) indicated higher exposure to childhood abuse and cumulative maltreatment, and those who were sexually victimized as an adult showed higher exposure to childhood neglect. In addition, exposure to childhood maltreatment had type-specific and cumulative effects on AV. Exposure to all types of childhood abuse maintained a strong direct association with AV, regardless of demographic characteristics, including age, ethnicity, marital status, education level, and housing situation. In addition, exposure to physical neglect showed a significant relationship with Adult Sexual Victimization. Cumulative experience of childhood maltreatment was consistently associated with cumulative risk of experiencing AV. Gender had no significant effect on these relationships. Findings suggest that intervention programs in homeless population should consider the history of childhood maltreatment and its characteristics to increase the effectiveness of intervention strategies for AV in this population. PMID- 25814506 TI - The Relationship Between Exposure to Violence and Anger in Thai Adolescents. AB - Youth violence is a serious public health problem in Thailand, and yet is poorly understood and is thought to vary considerably between metropolitan and rural areas. This article reports the findings of a cross-sectional study involving 1,170 technical college students who completed self-report questionnaires assessing the frequency of violent acts, antisocial behavior, and angry emotion. There were no differences in self-reported violent activities between metropolitan and rural participants, but those attending colleges in the metropolitan areas reported more acts involving weapons. Scores on the measure of anger expression predicted physical and verbal assault, specifically punching and name calling, suggesting that the implementation of interventions which help students to improve control over anger may be a useful violence prevention approach. PMID- 25814507 TI - Prevalence of Post-Traumatic Stress Disorder Due to Community Violence Among University Students in the World's Most Dangerous Megacity: A Cross-Sectional Study From Pakistan. AB - Community violence among the youth can lead to a number of adverse psychiatric outcomes including post-traumatic stress disorder (PTSD). However, little research has been conducted in non-Western countries to assess this problem. This study aims to fill the void by assessing the lifetime exposure to traumatic events and burden of probable PTSD among university students in Karachi, Pakistan. A cross-sectional study was conducted at four private institutions in Karachi. Self-administered questionnaires were filled out by 320 students. Lifetime exposure and symptoms of PTSD were assessed using modified Composite International Diagnostic Interview (CIDI) and Post-Traumatic Stress Disorder Checklist-Civilian Version (PCL-C) questionnaires, respectively. A PCL-C score of 44 or above was used as cutoff for probable PTSD. Pearson chi-square test was used to assess the association between PTSD and different variables at a level of significance of 5%. Ninety-three percent of the respondents reported having lifetime exposure to at least one traumatic event with sudden unexpected death of a loved one (n = 187) and assaultive violence (n = 169) being the commonest reported traumatic events. Positive association for PTSD was seen with enduring physical attacks and motor vehicle accidents. Over a quarter of the students screened positive for probable PTSD, among them almost one third were male and 17% were female. Our results indicate a high exposure to violent events and elevated rates of lifetime PTSD among urban youth. Reduction in violence and better access to mental health facilities is warranted to decrease the health burden of PTSD in Pakistan. PMID- 25814509 TI - Cognitive impairment in Parkinson's disease. AB - Cognitive impairment is a significant non-motor symptom of Parkinson's disease (PD). Longitudinal cohort studies have demonstrated that approximately 50% of those with PD develop dementia after 10 years, increasing to over 80% after 20 years. Deficits in cognition can be identified at the time of PD diagnosis in some patients and this mild cognitive impairment (PD-MCI) has been studied extensively over the last decade. Although PD-MCI is a risk factor for developing Parkinson's disease dementia there is evidence to suggest that PD-MCI might consist of distinct subtypes with different pathophysiologies and prognoses. The major pathological correlate of Parkinson's disease dementia is Lewy body deposition in the limbic system and neocortex although Alzheimer's related pathology is also an important contributor. Pathological damage causes alteration to neurotransmitter systems within the brain, producing behavioural change. Management of cognitive impairment in PD requires a multidisciplinary approach and accurate communication with patients and relatives is essential. PMID- 25814508 TI - Impaired Organization of Paired-Pulse TMS-Induced I-Waves After Human Spinal Cord Injury. AB - Paired-pulse transcranial magnetic stimulation (TMS) of the human motor cortex results in consecutive facilitatory motor-evoked potential (MEP) peaks in surface electromyography in intact humans. Here, we tested the effect of an incomplete cervical spinal cord injury (SCI) on early (first) and late (second and third) MEP peaks in a resting intrinsic finger muscle. We found that all peaks had decreased amplitude in SCI subjects compared with controls. The second and third peaks were delayed with the third peak also showing an increased duration. The delay of the third peak was smaller than that seen in controls at lower stimulation intensity, suggesting lesser influence of decreased corticospinal inputs. A mathematical model showed that after SCI the third peak aberrantly contributed to spinal motoneurone recruitment, regardless on the motor unit threshold tested. Temporal and spatial aspects of the late peaks correlated with MEP size and hand motor output. Thus, early and late TMS-induced MEP peaks undergo distinct modulation after SCI, with the third peak likely reflecting a decreased ability to summate descending volleys at the spinal level. We argue that the later corticospinal inputs on the spinal cord might be crucial for recruitment of motoneurones after human SCI. PMID- 25814510 TI - Parent preferences for telephone coaching to prevent and manage childhood obesity. AB - OBJECTIVE: To assess parent preferences for utilisation of a parent-focused, telephone-based coaching service, or 'FITLINE,' to prevent or manage childhood obesity. METHODS: A cross-sectional survey of parents of children aged 2-12 years was conducted at a paediatric practice in Greater Boston, Massachusetts, USA, between July 2012 and May 2013. Parents received questionnaires with clinic visit paperwork and opted-in to the study by returning them to clinic staff or by mail. The anonymous pen-to-paper questionnaire assessed parents' potential FITLINE utilisation, preferences regarding educational content and logistics, and parent/child demographics. Simple logistical regression was used to assess associations between parent and child factors and FITLINE interest. RESULTS: Among n=114 participants, most parents reported being very likely (n=53, 48%) or somewhat likely (n=44, 40%) to use a FITLINE-promoting healthy habits for children if it was made available. Interest in a FITLINE was greatest among overweight or obese parents (OR 3.12, CI 1.17 to 8.30) and those with children aged <5 years (OR 2.42, CI 1.02 to 5.73). Parents desired to discuss their own health and fitness goals (84%) along with educational topics such as healthy food shopping on a budget (91%) and how to meet children's physical activity needs (81%). Most parents preferred to obtain a FITLINE referral from a paediatrician or nurse (73%), instead of a school nurse (42%) or child-care provider (26%). CONCLUSIONS: Given strong interest among parents in a FITLINE and the urgency of the youth obesity epidemic, implementation of a pilot phone-based service should be strongly considered. PMID- 25814511 TI - Improving medical students' written communication skills: design and evaluation of an educational curriculum. AB - BACKGROUND AND OBJECTIVES: Written and verbal communication skills are important skills for all physicians. While verbal skills are taught and assessed in medical school, medical students report limited instruction in written communication skills. This study examined the impact of a curriculum delivered during a 6-week clinical rotation in Internal Medicine on the objective assessment of medical students' written communication skills. METHODS: The curriculum consisted of two educational programmes: a medical student communication tutorial and a resident feedback workshop. The study was conducted from March 2012 to January 2013 at McMaster University in Hamilton, Ontario, Canada. The study featured three arms: (1) control, (2) medical student communication tutorial alone and (3) student tutorial and resident feedback workshop. Data were collected on 126 students during 6-week Internal Medicine clerkship rotations. Students' written consultation notes were collected prior to the educational programmes and at 6 weeks. Blinded faculty assessors used an independently validated Assessment Checklist to evaluate consultation notes. RESULTS: Consultation note scores improved from week 1 to week 6 across all study arms. However, the change was statistically significant only in arm 3, featuring both the medical student tutorial and the resident feedback workshop, with mean scores improving from 4.75 (SD=1.496) to 5.56 (SD=0.984) out of 7. The mean difference between week 1 and week 6 was significantly different (0.806, p=0.002, 95% CI 0.306 to 1.058). CONCLUSIONS: The combination of a resident feedback workshop with medical student written communication tutorial improves objective evaluations of consultation note scores over student tutorial alone. PMID- 25814512 TI - Evaluating elements of trust: Race and class in risk communication in post Katrina New Orleans. AB - This study seeks to determine the relative influence of race and class on trust in sources of messages of environmental risk in post-Katrina New Orleans. It poses two hypotheses to test that influence: H1-African-Americans ("Blacks") trust risk message sources less than European American ("Whites") do and H2-The higher the socioeconomic class, the lower the trust in risk message sources. A 37 question telephone survey (landlines and cellphones) was conducted in Orleans Parish in 2012 (n = 414). The overall margin of error was +/-4.8% at a 95% confidence interval. A hierarchical regression analysis revealed that the first hypothesis was rejected, while the second was supported. Additional data analysis revealed that frequency of use of sources of risk information appears to be a positive factor in building trust. PMID- 25814513 TI - Measuring the perceived uncertainty of scientific evidence and its relationship to engagement with science. AB - Many scholars have argued for the need to communicate openly not only scientific successes to the public but also limitations, such as the tentativeness of research findings, in order to enhance public trust and engagement. Yet, it has not been quantitatively assessed how the perception of scientific uncertainties relates to engagement with science on an individual level. In this article, we report the development and testing of a new questionnaire in English and German measuring the perceived uncertainty of scientific evidence. Results indicate that the scale is reliable and valid in both language versions and that its two subscales are differentially related to measures of engagement: Science-friendly attitudes were positively related only to 'subjectively' perceived uncertainty, whereas interest in science as well as behavioural engagement actions and intentions were largely uncorrelated. We conclude that perceiving scientific knowledge to be uncertain is only weakly, but positively related to engagement with science. PMID- 25814514 TI - Toxic cerebellar syndrome due to methotrexate. PMID- 25814516 TI - Modifying the Poor Prognosis Associated with 18F-FDG-Avid NET with Peptide Receptor Chemo-Radionuclide Therapy (PRCRT). PMID- 25814517 TI - Molecular imaging of infectious and inflammatory diseases: a terra incognita. PMID- 25814515 TI - The Novel Ribonucleotide Reductase Inhibitor COH29 Inhibits DNA Repair In Vitro. AB - COH29 [N-(4-(3,4-dihydroxyphenyl)-5-phenylthiazol-2-yl)-3,4-dihydroxybenzamide], a novel antimetabolite drug developed at City of Hope Cancer Center, has anticancer activity that stems primarily from the inhibition of human ribonucleotide reductase (RNR). This key enzyme in deoxyribonucleotide biosynthesis is the target of established clinical agents such as hydroxyurea and gemcitabine because of its critical role in DNA replication and repair. Herein we report that BRCA-1-defective human breast cancer cells are more sensitive than wild-type BRCA-1 counterparts to COH29 in vitro and in vivo. Microarray gene expression profiling showed that COH29 reduces the expression of DNA repair pathway genes, suggesting that COH29 interferes with these pathways. It is well established that BRCA1 plays a role in DNA damage repair, especially homologous recombination (HR) repair, to maintain genome integrity. In BRCA1-defective HCC1937 breast cancer cells, COH29 induced more double-strand breaks (DSBs) and DNA-damage response than in HCC1937 + BRCA1 cells. By EJ5- and DR-green fluorescent protein (GFP) reporter assay, we found that COH29 could inhibit nonhomologous end joining (NHEJ) efficiency and that no HR activity was detected in HCC1937 cells, suggesting that repression of the NHEJ repair pathway may be involved in COH29-induced DSBs in BRCA1-deficient HCC1937 cells. Furthermore, we observed an accumulation of nuclear Rad51 foci in COH29-treated HCC1937 + BRCA1 cells, suggesting that BRCA1 plays a crucial role in repairing and recovering drug-induced DNA damage by recruiting Rad51 to damage sites. In summary, we describe here additional biologic effects of the RNR inhibitor COH29 that potentially strengthen its use as an anticancer agent. PMID- 25814518 TI - Development of a Widely Usable Amino Acid Tracer: 76Br-alpha-Methyl-Phenylalanine for Tumor PET Imaging. AB - Radiolabeled amino acids are superior PET tracers for the imaging of malignant tumors, and amino acids labeled with (76)Br, an attractive positron emitter because of its relatively long half-life (16.2 h), could potentially be a widely usable tumor imaging tracer. In this study, in consideration of its stability and tumor specificity, we designed two (76)Br-labeled amino acid derivatives, 2 (76)Br-bromo-alpha-methyl-l-phenylalanine (2-(76)Br-BAMP) and 4-(76)Br-bromo alpha-methyl-l-phenylalanine (4-(76)Br-BAMP), and investigated their potential as tumor imaging agents. METHODS: Both (76)Br- and (77)Br-labeled amino acid derivatives were prepared. We performed in vitro and in vivo stability studies and cellular uptake studies using the LS180 colon adenocarcinoma cell line. Biodistribution studies in normal mice and in LS180 tumor-bearing mice were performed, and the tumors were imaged with a small-animal PET scanner. RESULTS: Both (77)Br-BAMPs were stable in the plasma and in the murine body. Although both (77)Br-BAMPs were taken up by LS180 cells and the uptake was inhibited by L-type amino acid transporter 1 inhibitors, 2-(77)Br-BAMP exhibited higher uptake than 4 (77)Br-BAMP. In the biodistribution studies, 2-(77)Br-BAMP showed more rapid blood clearance and lower renal accumulation than 4-(77)Br-BAMP. More than 90% of the injected radioactivity was excreted in the urine by 6 h after the injection of 2-(77)Br-BAMP. High tumor accumulation of 2-(77)Br-BAMP was observed in tumor bearing mice, and PET imaging with 2-(76)Br-BAMP enabled clear visualization of the tumors. CONCLUSION: 2-(77)Br-BAMP exhibited preferred pharmacokinetics and high LS180 tumor accumulation, and 2-(76)Br-BAMP enabled clear visualization of the tumors by PET imaging. These findings suggest that 2-(76)Br-BAMP could constitute a potential new PET tracer for tumor imaging and may eventually enable the wider use of amino acid tracers. PMID- 25814520 TI - Correlation of BRAFV600E Mutation and Glucose Metabolism in Thyroid Cancer Patients: An 18F-FDG PET Study. AB - There is significant interest in a better understanding of the genetic underpinnings of the increased glucose metabolic rates of cancer cells. Thyroid cancer demonstrates a broad variability of (18)F-FDG uptake as well as several well-characterized oncogenic mutations. In this study, we evaluated the differences in glucose metabolism of the BRAF(V600E) mutation versus BRAF wild type (BRAF-WT) in patients with metastatic differentiated thyroid cancer (DTC) and poorly differentiated thyroid cancer (PDTC). METHODS: Forty-eight DTC and 34 PDTC patients who underwent (18)F-FDG PET/CT for tumor staging were identified from a database search. All patients were tested for the BRAF(V600E) mutation and assigned to 1 of 2 groups: BRAF(V600E) mutated and BRAF-WT. (18)F-FDG uptake of tumor tissue was quantified by maximum standardized uptake value (SUVmax) of the hottest malignant lesion in 6 prespecified body regions (thyroid bed, lymph nodes, lung, bone, soft tissue, and other). When there were multiple lesions in 1 of the prespecified body regions, only the 1 with the highest (18)F-FDG uptake was analyzed. RESULTS: In the DTC cohort, 24 tumors harbored a BRAF(V600E) mutation, whereas 24 tumors were BRAF-WT. (18)F-FDG uptake of BRAF(V600E) positive lesions (median SUVmax, 6.3; n = 53) was significantly higher than that of BRAF-WT lesions (n = 39; median SUVmax, 4.7; P = 0.019). In the PDTC group, only 5 tumors were BRAF(V600E)-positive, and their (18)F-FDG uptake was not significantly different from the BRAF-WT tumors. There was also no significant difference between the SUVmax of all DTCs and PDTCs, regardless of BRAF mutational status (P = 0.90). CONCLUSION: These data suggest that BRAF(V600E) mutated DTCs are significantly more (18)F-FDG-avid than BRAF-WT tumors. The effect of BRAF(V600E) on tumor glucose metabolism in PDTC needs further study in larger groups of patients. PMID- 25814519 TI - The Effect of Bi-Terminal PEGylation of an Integrin alphavbeta6-Targeted 18F Peptide on Pharmacokinetics and Tumor Uptake. AB - Radiotracers based on the peptide A20FMDV2 selectively target the cell surface receptor integrin alphavbeta6. This integrin has been identified as a prognostic indicator correlating with the severity of disease for several challenging malignancies. In previous studies of A20FMDV2 peptides labeled with 4-(18)F fluorobenzoic acid ((18)F-FBA), we have shown that the introduction of poly(ethylene glycol) (PEG) improves pharmacokinetics, including increased uptake in alphavbeta6-expressing tumors. The present study evaluated the effect of site specific C-terminal or dual (N- and C-terminal) PEGylation, yielding (18)F-FBA A20FMDV2-PEG28 (4) and (18)F-FBA-PEG28-A20FMDV2-PEG28 (5), on alphavbeta6 targeted tumor uptake and pharmacokinetics. The results are compared with (18)F FBA -labeled A20FMDV2 radiotracers (1- 3) bearing either no PEG or different PEG units at the N terminus. METHODS: The radiotracers were prepared and radiolabeled on solid phase. Using 3 cell lines, DX3purobeta6 (alphavbeta6+), DX3puro (alphavbeta6-), and BxPC-3 (alphavbeta6+), we evaluated the radiotracers in vitro (serum stability; cell binding and internalization) and in vivo in mouse models bearing paired DX3purobeta6-DX3puro and, for 5, BxPC-3 xenografts. RESULTS: The size and location of the PEG units significantly affected alphavbeta6 targeting and pharmacokinetics. Although the C-terminally PEGylated 4 showed some improvements over the un-PEGylated (18)F-FBA-A20FMDV2 (1), it was the bi terminally PEGylated 5 that displayed the more favorable combination of high alphavbeta6 affinity, selectivity, and pharmacokinetic profile. In vitro, 5 bound to alphavbeta6-expressing DX3purobeta6 and BxPC-3 cells with 60.5% +/- 3.3% and 48.8% +/- 8.3%, respectively, with a significant fraction of internalization (37.2% +/- 4.0% and 37.6% +/- 4.1% of total radioactivity, respectively). By comparison, in the DX3puro control 5: showed only 3.0% +/- 0.5% binding and 0.9% +/- 0.2% internalization. In vivo, 5: maintained high, alphavbeta6-directed binding in the paired DX3purobeta6-DX3puro model (1 h: DX3purobeta6, 2.3 +/- 0.2 percentage injected dose per gram [%ID/g]; DX3purobeta6/DX3puro ratio, 6.5:1; 4 h: 10.7:1). In the pancreatic BxPC-3 model, uptake was 4.7 +/- 0.9 %ID/g (1 h) despite small tumor sizes (20-80 mg). CONCLUSION: The bi-PEGylated radiotracer 5 showed a greatly improved pharmacokinetic profile, beyond what was predicted from individual N- or C-terminal PEGylation. It appears that the 2 PEG units acted synergistically to result in an improved metabolic profile including high alphavbeta6+ tumor uptake and retention. PMID- 25814521 TI - Creativity and Bipolar Disorder: Igniting a Dialogue. AB - Bipolar disorder (BD) has been related to heightened creativity, yet core questions remain unaddressed about this association. We used qualitative methods to investigate how highly creative individuals with BD understand the role of symptoms and treatment in their creativity, and possible mechanisms underpinning this link. Twenty-two individuals self-identified as highly creative and living with BD took part in focus groups and completed quantitative measures of symptoms, quality of life (QoL), and creativity. Using thematic analysis, five themes emerged: the pros and cons of mania for creativity, benefits of altered thinking, the relationship between creativity and medication, creativity as central to one's identity, and creativity's importance in stigma reduction and treatment. Despite reliance on a small sample who self-identified as having BD, findings shed light on previously mixed results regarding the influence of mania and treatment and suggest new directions for the study of mechanisms driving the creative advantage in BD. PMID- 25814522 TI - Recursive Health Care Structures and Choice in the Manner of Our Dying: An Auto Ethnographic Account. AB - Science has shaped our understanding of the diseases we are diagnosed with. Medical treatment has transformed their natural courses. The law has married medical knowledge and experience to the legal competence of physicians to make ultimate decisions for the patient at the end of life. When it is our time to die, we will confront a pre-structured health care landscape affording some courses of action while limiting others. In this article, I provide an auto ethnographic account of the dying of one woman, my wife, diagnosed with ovarian cancer. It speaks of our meeting with oncology, her refusal of aggressive treatment, and the palliative care allies we found for her way of dying. It also speaks of the opportunities for choice in dying that emerge when participants in the care collective accept that one of them must die while the others live on. PMID- 25814523 TI - Methotrexate in IBD: the return of the prodigal son. PMID- 25814524 TI - Pediatric Anterior Mediastinal Mass: A Review Article. AB - One of the more challenging cases facing a pediatric anesthesiologist is the management of patients presenting with an anterior mediastinal mass (AMM). Patients with an AMM may have severe cardiopulmonary compromise that can be exacerbated when undergoing general anesthesia. Several case reports have documented cardiopulmonary collapse during induction or maintenance of general anesthesia and even for procedures done without anesthesia. Despite increased understanding and management of these patients, perioperative complications, defined as anything from transient decreases in blood pressure correcting with fluids or mild airway obstruction requiring no intervention, to complete cardiopulmonary collapse, are still estimated to occur during 9% to 20% of anesthetic procedures. The purpose of this review article is to provide foundational knowledge of the anatomy and physiology of a patient with an AMM, with particular emphasis on the pediatric patient. It will assist in recognizing presenting signs and symptoms and discuss the appropriate preoperative testing, which together can help assess perioperative risk and determine the appropriate anesthetic management plan for the patient's safety and comfort. PMID- 25814525 TI - An unusual case of native mitral valve thrombosis and obstruction. PMID- 25814527 TI - Granulocyte colony-stimulating factor reprograms bone marrow stromal cells to actively suppress B lymphopoiesis in mice. AB - The mechanisms that mediate the shift from lymphopoiesis to myelopoiesis in response to infectious stress are largely unknown. We show that treatment with granulocyte colony-stimulating factor (G-CSF), which is often induced during infection, results in marked suppression of B lymphopoiesis at multiple stages of B-cell development. Mesenchymal-lineage stromal cells in the bone marrow, including CXCL12-abundant reticular (CAR) cells and osteoblasts, constitutively support B lymphopoiesis through the production of multiple B trophic factors. G CSF acting through a monocytic cell intermediate reprograms these stromal cells, altering their capacity to support B lymphopoiesis. G-CSF treatment is associated with an expansion of CAR cells and a shift toward osteogenic lineage commitment. It markedly suppresses the production of multiple B-cell trophic factors by CAR cells and osteoblasts, including CXCL12, kit ligand, interleukin-6, interleukin 7, and insulin-like growth factor-1. Targeting bone marrow stromal cells is one mechanism by which inflammatory cytokines such as G-CSF actively suppress lymphopoiesis. PMID- 25814526 TI - Hyperglycemia repression of miR-24 coordinately upregulates endothelial cell expression and secretion of von Willebrand factor. AB - An elevated level of von Willebrand factor (VWF) in diabetic patients is associated with increased risk of thrombotic cardiovascular events. The underlying mechanism of how VWF expression is upregulated in diabetes mellitus is poorly understood. We now report that hyperglycemia-induced repression of microRNA-24 (miR-24) increases VWF expression and secretion in diabetes mellitus. In diabetic patients and diabetic mouse models (streptozotocin/high-fat diet induced and db/db mice), miR-24 is reduced in both tissues and plasma. Knockdown of miR-24 in mice leads to increased VWF mRNA and protein levels and enhanced platelet tethering (spontaneous thrombosis). miR-24 tightly controls VWF levels through pleiotropic effects, including direct binding to the 3' untranslated region of VWF and targeting FURIN and the histamine H1 receptor, known regulators of VWF processing and secretion in endothelial cells. We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc. These findings support a critical role for hyperglycemic repression of miR-24 in VWF-induced pathology. miR-24 represents a novel therapeutic target to prevent adverse thrombotic events in patients with diabetes mellitus. PMID- 25814528 TI - Thymic expression of a T-cell receptor targeting a tumor-associated antigen coexpressed in the thymus induces T-ALL. AB - T-cell receptors (TCRs) and chimeric antigen receptors recognizing tumor associated antigens (TAAs) can now be engineered to be expressed on a wide array of immune effectors. Engineered receptors targeting TAAs have most commonly been expressed on mature T cells, however, some have postulated that receptor expression on immune progenitors could yield T cells with enhanced potency. We generated mice (survivin-TCR-transgenic [Sur-TCR-Tg]) expressing a TCR recognizing the immunodominant epitope (Sur20-28) of murine survivin during early stages of thymopoiesis. Spontaneous T-cell acute lymphoblastic leukemia (T-ALL) occurred in 100% of Sur-TCR-Tg mice derived from 3 separate founders. The leukemias expressed the Sur-TCR and signaled in response to the Sur20-28 peptide. In preleukemic mice, we observed increased cycling of double-negative thymocytes expressing the Sur-TCR and increased nuclear translocation of nuclear factor of activated T cells, consistent with TCR signaling induced by survivin expression in the murine thymus. beta2M(-/-) Sur-TCR-Tg mice, which cannot effectively present survivin peptides on class I major histocompatibility complex, had significantly diminished rates of leukemia. We conclude that TCR signaling during the early stages of thymopoiesis mediates an oncogenic signal, and therefore expression of signaling receptors on developing thymocytes with specificity for TAAs expressed in the thymus could pose a risk for neoplasia, independent of insertional mutagenesis. PMID- 25814529 TI - Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia. AB - There is limited information on body composition, energy balance, and fitness among survivors of childhood acute lymphoblastic leukemia (ALL), especially those treated without cranial radiation therapy (CRT). This analysis compares these metrics among 365 ALL survivors with a mean age of 28.6 +/- 5.9 years (149 treated with and 216 without CRT) and 365 age-, sex-, and race-matched peers. We also report risk factors for outcomes among survivors treated without CRT. Male survivors not exposed to CRT had abnormal body composition when compared with peers (% body fat, 26.2 +/- 8.2 vs 22.7 +/- 7.1). Survivors without CRT had similar energy balance but had significantly impaired quadriceps strength (-21.9 +/- 6.0 Newton-meters [Nm]/kg, 60 degrees /s) and endurance (-11.4 +/- 4.6 Nm/kg, 300 degrees /s), exercise capacity (-2.0 +/- 2.1 ml/kg per minute), low-back and hamstring flexibility (-4.7 +/- 1.6 cm), and dorsiflexion range of motion (-3.1 +/- 0.9 degrees ) and higher modified total neuropathy scores (+1.6 +/- 1.1) than peers. Cumulative asparaginase dose >=120,000 IU/m(2) was associated with impaired flexibility, vincristine dose >=39 mg/m(2) with peripheral neuropathy, glucocorticoid (prednisone equivalent) dose >=8000 mg/m(2) with hand weakness, and intrathecal methotrexate dose >=225 mg with dorsiflexion weakness. Physical inactivity was associated with hand weakness and decreased exercise capacity. Smoking was associated with peripheral neuropathy. Elimination of CRT from ALL therapy has improved, but not eliminated, body-composition outcomes. Survivors remain at risk for impaired fitness. PMID- 25814530 TI - B7-H3 expression in donor T cells and host cells negatively regulates acute graft versus-host disease lethality. AB - Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3(-/-) vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3(-/-) vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3(-/-) Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications. PMID- 25814533 TI - Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. AB - Usp9x was recently shown to be highly expressed in myeloma patients with short progression-free survival and is proposed to enhance stability of the survival protein Mcl-1. In this study, we found that the partially selective Usp9x deubiquitinase inhibitor WP1130 induced apoptosis and reduced Mcl-1 protein levels. However, short hairpin RNA-mediated knockdown (KD) of Usp9x in myeloma cells resulted in transient induction of apoptosis, followed by a sustained reduction in cell growth. A compensatory upregulation of Usp24, a deubiquitinase closely related to Usp9x, in Usp9x KD cells was noted. Direct Usp24 KD resulted in marked induction of myeloma cell death that was associated with a reduction of Mcl-1. Usp24 was found to sustain myeloma cell survival and Mcl-1 regulation in the absence of Usp9x. Both Usp9x and Usp24 were expressed and activated in primary myeloma cells whereas Usp24 protein overexpression was noted in some patients with drug-refractory myeloma and other B-cell malignancies. Furthermore, we improved the drug-like properties of WP1130 and demonstrated that the novel compound EOAI3402143 dose-dependently inhibited Usp9x and Usp24 activity, increased tumor cell apoptosis, and fully blocked or regressed myeloma tumors in mice. We conclude that small-molecule Usp9x/Usp24 inhibitors may have therapeutic activity in myeloma. PMID- 25814531 TI - The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. AB - Interleukin (IL)-33 binding to the receptor suppression of tumorigenicity 2 (ST2) produces pro-inflammatory and anti-inflammatory effects. Increased levels of soluble ST2 (sST2) are a biomarker for steroid-refractory graft-versus-host disease (GVHD) and mortality. However, whether sST2 has a role as an immune modulator or only as a biomarker during GVHD was unclear. We show increased IL-33 production by nonhematopoietic cells in the gastrointestinal (GI) tract in mice post-conditioning and patients during GVHD. Exogenous IL-33 administration during the peak inflammatory response worsened GVHD. Conversely, GVHD lethality and tumor necrosis factor-alpha production was significantly reduced in il33(-/-) recipients. ST2 was upregulated on murine and human alloreactive T cells and sST2 increased as experimental GVHD progressed. Concordantly, st2(-/-) vs wild-type (WT) donor T cells had a marked reduction in GVHD lethality and GI histopathology. Alloantigen-induced IL-18 receptor upregulation was lower in st2( /-) T cells, and linked to reduced interferon-gamma production by st2(-/-) vs WT T cells during GVHD. Blockade of IL-33/ST2 interactions during allogeneic hematopoietic cell transplantation by exogenous ST2-Fc infusions had a marked reduction in GVHD lethality, indicating a role of ST2 as a decoy receptor modulating GVHD. Together, these studies point to the IL-33/ST2 axis as a novel and potent target for GVHD therapy. PMID- 25814532 TI - Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high dose posttransplantation cyclophosphamide. AB - Related HLA-haploidentical blood or marrow transplantation (BMT) with high-dose posttransplantation cyclophosphamide (PTCy) is being increasingly used because of its acceptable safety profile. To better define outcomes of nonmyeloablative (NMA) HLA-haploidentical BMT with PTCy, 372 consecutive adult hematologic malignancy patients who underwent this procedure were retrospectively studied. Risk-stratified outcomes were evaluated using the refined Disease Risk Index (DRI), developed to stratify disease risk across histologies and allogeneic BMT regimens. Patients received uniform conditioning, T-cell-replete allografting, then PTCy, mycophenolate mofetil, and tacrolimus. Six-month probabilities of nonrelapse mortality and severe acute graft-versus-host disease were 8% and 4%. With 4.1-year median follow-up, 3-year probabilities of relapse, progression-free survival (PFS), and overall survival (OS) were 46%, 40%, and 50%, respectively. By refined DRI group, low (n = 71), intermediate (n = 241), and high/very high (n = 60) risk groups had 3-year PFS estimates of 65%, 37%, and 22% (P < .0001), with corresponding 3-year OS estimates of 71%, 48%, and 35% (P = .0001). On multivariable analyses, the DRI was statistically significantly associated with relapse, PFS, and OS (each P < .001). This analysis demonstrates that the DRI effectively risk stratifies recipients of NMA HLA-haploidentical BMT with PTCy and also suggests that this transplantation platform yields similar survivals to those seen with HLA-matched BMT. PMID- 25814535 TI - Correction to "The tumor proteasome is a primary target for the natural anticancer compound withaferin A isolated from 'Indian winter cherry'". PMID- 25814536 TI - Speeding new antibiotics to market: a fake fix? PMID- 25814534 TI - Value of pentraxin-3 and galectin-3 in acute coronary syndrome: a short-term prospective cohort study. AB - BACKGROUND: Acute coronary syndrome (ACS) continues to be a leading cause of morbidity and mortality worldwide. Galectin-3 and pentraxin-3 are two prognostic biomarkers that have been studied in heart failure (HF). However, there are limited data on these biomarkers in the ACS population. The objective of the study was to determine the variables that are most affected by high concentrations of pentraxin-3 and galectin-3, and the influence they have on outcomes of all-cause mortality in patients with ACS. METHODS: We included a total of 160 patients [ST elevation myocardial infarction (STEMI),n = 64; non STEMI/unstable angina (NSTEMI/UA), n = 38; and control subjects with chronic stable angina (CSA)/microvascular angina (MVA) n = 58]. Plasma pentraxin-3 and galectin-3 levels were assessed from these patients at the time of hospital admission. Major adverse cardiovascular events including all-cause mortality, rehospitalizations and coronary artery bypass graft surgery (CABG) were assessed at 6 months. RESULTS: The median concentration of pentraxin-3 and galectin-3 were significantly higher in STEMI than in NSTEMI patients (p < 0.005) or controls (p < 0.005). Greater numbers of deaths (4 versus 0) were observed in STEMI patients with higher levels of these biomarkers. In addition, ACS patients with high levels of pentraxin-3 and galectin-3 had lower left ventricular ejection fraction (LVEF) (p < 0.005), and a moderate correlation was observed between LVEF and pentraxin-3 levels (r = -0.45, p < 0.005). Patients with higher galectin-3 levels were also observed to have a lower estimated glomerular fraction rate (eGFR), and a moderate correlation was observed between them (r = -0.34, p < 0.005). CONCLUSION: Pentraxin-3 and galectin-3 hold much promise in the ACS population as prognostic biomarkers. PMID- 25814537 TI - Commentary: Will 20th century patient safeguards be reversed in the 21st century? PMID- 25814539 TI - Visual analytics in healthcare--opportunities and research challenges. PMID- 25814540 TI - A novel tool for visualizing chronic kidney disease associated polymorbidity: a 13-year cohort study in Taiwan. AB - OBJECTIVE: The aim of this study is to analyze and visualize the polymorbidity associated with chronic kidney disease (CKD). The study shows diseases associated with CKD before and after CKD diagnosis in a time-evolutionary type visualization. MATERIALS AND METHODS: Our sample data came from a population of one million individuals randomly selected from the Taiwan National Health Insurance Database, 1998 to 2011. From this group, those patients diagnosed with CKD were included in the analysis. We selected 11 of the most common diseases associated with CKD before its diagnosis and followed them until their death or up to 2011. We used a Sankey-style diagram, which quantifies and visualizes the transition between pre- and post-CKD states with various lines and widths. The line represents groups and the width of a line represents the number of patients transferred from one state to another. RESULTS: The patients were grouped according to their states: that is, diagnoses, hemodialysis/transplantation procedures, and events such as death. A Sankey diagram with basic zooming and planning functions was developed that temporally and qualitatively depicts they had amid change of comorbidities occurred in pre- and post-CKD states. DISCUSSION: This represents a novel visualization approach for temporal patterns of polymorbidities associated with any complex disease and its outcomes. The Sankey diagram is a promising method for visualizing complex diseases and exploring the effect of comorbidities on outcomes in a time-evolution style. CONCLUSIONS: This type of visualization may help clinicians foresee possible outcomes of complex diseases by considering comorbidities that the patients have developed. PMID- 25814541 TI - Update on informatics-focused certification and accreditation activities. PMID- 25814542 TI - Junior doctor is struck off after prescribing errors and "disgraceful" conduct. PMID- 25814546 TI - The effect of eye movements and blinks on afterimage appearance and duration. AB - The question of whether eye movements influence afterimage perception has been asked since the 18th century, and yet there is surprisingly little consensus on how robust these effects are and why they occur. The number of historical theories aiming to explain the effects are more numerous than clear experimental demonstrations of such effects. We provide a clearer characterization of when eye movements and blinks do or do not affect afterimages with the aim to distinguish between historical theories and integrate them with a modern understanding of perception. We found neither saccades nor pursuit reduced strong afterimage duration, and blinks actually increased afterimage duration when tested in the light. However, for weak afterimages, we found saccades reduced duration, and blinks and pursuit eye movements did not. One interpretation of these results is that saccades diminish afterimage perception because they cause the afterimage to move unlike a real object. Furthermore, because saccades affect weak afterimages but not strong ones, we suggest that their effect is modulated by the ambiguity of the afterimage signal. PMID- 25814545 TI - Modeling peripheral visual acuity enables discovery of gaze strategies at multiple time scales during natural scene search. AB - Like humans, monkeys make saccades nearly three times a second. To understand the factors guiding this frequent decision, computational models of vision attempt to predict fixation locations using bottom-up visual features and top-down goals. How do the relative influences of these factors evolve over multiple time scales? Here we analyzed visual features at fixations using a retinal transform that provides realistic visual acuity by suitably degrading visual information in the periphery. In a task in which monkeys searched for a Gabor target in natural scenes, we characterized the relative importance of bottom-up and task-relevant influences by decoding fixated from nonfixated image patches based on visual features. At fast time scales, we found that search strategies can vary over the course of a single trial, with locations of higher saliency, target-similarity, edge-energy, and orientedness looked at later on in the trial. At slow time scales, we found that search strategies can be refined over several weeks of practice, and the influence of target orientation was significant only in the latter of two search tasks. Critically, these results were not observed without applying the retinal transform. Our results suggest that saccade-guidance strategies become apparent only when models take into account degraded visual representation in the periphery. PMID- 25814547 TI - Tolerance for local and global differences in the integration of shape information. AB - Shape is a critical cue to object identity. In psychophysical studies, radial frequency (RF) patterns, paths deformed from circular by a sinusoidal modulation of radius, have proved valuable stimuli for the demonstration of global integration of local shape information. Models of the mechanism of integration have focused on the periodicity in measures of curvature on the pattern, despite the fact that other properties covary. We show that patterns defined by rectified sinusoidal modulation also exhibit global integration and are indistinguishable from conventional RF patterns at their thresholds for detection, demonstrating some indifference to the modulating function. Further, irregular patterns incorporating four different frequencies of modulation are globally integrated, indicating that uniform periodicity is not critical. Irregular patterns can be handed in the sense that mirror images cannot be superimposed. We show that mirror images of the same irregular pattern could not be discriminated near their thresholds for detection. The same irregular pattern and a pattern with four cycles of a constant frequency of modulation completing 2pi radians were, however, perfectly discriminated, demonstrating the existence of discrete representations of these patterns by which they are discriminated. It has previously been shown that RF patterns of different frequencies are perfectly discriminated but that patterns with the same frequency but different numbers of cycles of modulation were not. We conclude that such patterns are identified, near threshold, by the set of angles subtended at the center of the pattern by adjacent points of maximum convex curvature. PMID- 25814548 TI - Investigation of interocular blur suppression using luminance-modulated and contrast-modulated noise stimuli. AB - Presenting two sufficiently dissimilar images, one to each eye, may result in interocular suppression. The present study measured interocular suppression depth and extent in binocularly normal participants when blurring one eye only with varying dioptric lens powers (+0.5, +1, +2, and +4 D). Visual stimuli consisted of eight concentric rings of alternate polarity, divisible into eight sectors, within the central circular 24 degrees visual field. Binocular "ring" stimuli therefore consisted of 64 individually testable dichoptic sectors. Using a two alternative forced choice paradigm with a staircase procedure, signal strength of each dichoptic sector in the blurred eye was adjusted to perceptually match that of the surrounding ring from the nonblurred eye, determining the point of subjective equality. Rings were defined by differences in luminance (L), luminance-modulated noise (LM), or contrast-modulated noise (CM). Suppression depth was similar irrespective of sector location within the visual field and increased with increasing difference in interocular blur. Adding dynamic noise (LM vs. L stimuli) reduced the effect of blur on measured suppression depth. Significantly deeper suppression was measured for CM than for LM stimuli, both created using dynamic noise, the difference increasing at higher levels of interocular blur. As binocularity is disrupted with interocular blur, this result suggests that CM envelope combination may be processed by later mechanisms receiving binocular input than those required for the processing of LM stimuli. Differences in suppression depth between LM and CM stimuli could not be attributed to differences in spatial summation properties, stimulus visibility, noise modulation, or differential effects on blur discriminability. PMID- 25814549 TI - Why hearts flutter: Distorted dim motions. AB - When a display of red spots or hearts on a blue surround is moved around under dim light, the spots appear to wobble or flutter relative to the surround (the "fluttering hearts" effect). We explain this as follows: Rods and cones both respond to the hearts. Rods are more sluggish than cones, with a latency of ~50 ms, and they are also much more sensitive to blue than to red (the Purkinje shift; Purkinje, 1825). Thus a red spot oscillating on a blue ground produces a double image: a light spot seen by the cones, followed by a trailing dark spot seen by the rods. These interacting spots of opposite luminance polarity move like "reverse phi" (Anstis, 1970) and this generates the fluttering hearts effect. We find that hearts flutter most markedly at or near mesopic equiluminance, when the red is lighter than the blue as seen by the cones, but darker than the blue as seen by the rods. These same red/blue luminance ratios give rise to two new illusions: the ghostly twin illusion, and the reversal of red/blue grating movement. PMID- 25814552 TI - Industry's pledges to limit harms of alcohol are unlikely to work, research finds. PMID- 25814553 TI - Prehypertension in midlife is associated with worse cognition a decade later in middle-aged and older women. AB - BACKGROUND: previous studies raised the possibility that adverse health effects associated with elevated blood pressure (BP) begin at prehypertension levels (BP = 120-139/80-89 mmHg), yet few studies have examined the effects of prehypertension on cognitive functioning. OBJECTIVE: to examine the relationship between BP categories and cognitive functions in middle-aged and older women. SUBJECTS AND METHODS: two hundred and forty-seven women from the Women's Healthy Ageing Project had their BP measured twice, at mean ages 50 and 60 years. Tests of executive function, processing speed and verbal episodic memory were also administered at follow-up. Analyses of co-variance were performed to evaluate the associations between BP categories and cognitive performance. RESULTS: prehypertensive BP at age 50 years is a significant predictor of reduced processing speed and verbal episodic memory a decade later. Cross-sectional measurements at age 60 years showed that untreated hypertensive women performed significantly worse on verbal episodic memory compared with their prehypertensive peers. CONCLUSION: hypertension is a modifiable cardiovascular risk factor, and our results suggest that reducing midlife BP, even at prehypertensive levels, may be an effective prevention strategy to reduce risk for subsequent cognitive decline in middle-aged and older women. PMID- 25814554 TI - Phospho-tyrosine dependent protein-protein interaction network. AB - Post-translational protein modifications, such as tyrosine phosphorylation, regulate protein-protein interactions (PPIs) critical for signal processing and cellular phenotypes. We extended an established yeast two-hybrid system employing human protein kinases for the analyses of phospho-tyrosine (pY)-dependent PPIs in a direct experimental, large-scale approach. We identified 292 mostly novel pY dependent PPIs which showed high specificity with respect to kinases and interacting proteins and validated a large fraction in co-immunoprecipitation experiments from mammalian cells. About one-sixth of the interactions are mediated by known linear sequence binding motifs while the majority of pY-PPIs are mediated by other linear epitopes or governed by alternative recognition modes. Network analysis revealed that pY-mediated recognition events are tied to a highly connected protein module dedicated to signaling and cell growth pathways related to cancer. Using binding assays, protein complementation and phenotypic readouts to characterize the pY-dependent interactions of TSPAN2 (tetraspanin 2) and GRB2 or PIK3R3 (p55gamma), we exemplarily provide evidence that the two pY dependent PPIs dictate cellular cancer phenotypes. PMID- 25814556 TI - Kinase-two-hybrid: towards the conditional interactome. AB - The dynamics of the protein-protein interaction network and how it responds to biological perturbations remain difficult to assay by most traditional techniques. A novel kinase-dependent yeast two-hybrid framework by Stelzl and colleagues (Grossmann et al, 2015) provides a new prism to study how tyrosine phosphorylation regulates the changes in the interactome under varying conditions. PMID- 25814557 TI - Integrity--not just a federal issue. PMID- 25814555 TI - Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis. AB - Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAF(V) (600E) melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti-tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single-cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax ? 1). Among these cascades, we identify a role for JNK/c-Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response. PMID- 25814559 TI - Planetary Science. Mars rover finds long-chain organic compounds. PMID- 25814560 TI - Planetary Science. 'Fixed' nitrogen found in martian soil. PMID- 25814562 TI - Glaciology. Himalayan ice can fool climate studies. PMID- 25814561 TI - Chemical Regulation. Reform of toxics law is contentious. PMID- 25814563 TI - Neuroscience. A ?1 billion brain reboot. PMID- 25814564 TI - Infectious Diseases. A reassuring snapshot of Ebola. PMID- 25814565 TI - Social Sciences. Measuring child abuse's legacy. PMID- 25814566 TI - Cause of death. PMID- 25814567 TI - Infectious Disease. How to bolster the antifungal pipeline. PMID- 25814568 TI - Materials Science. Exploiting weak interactions in DNA self-assembly. PMID- 25814569 TI - Neuroscience. Treating brain disorders with neuromodulation. PMID- 25814570 TI - Environmental Economics. Do biofuel policies seek to cut emissions by cutting food? PMID- 25814571 TI - Genetics. For complex disease genetics, collaboration drives progress. PMID- 25814572 TI - Applied Optics. Sorting out light. PMID- 25814573 TI - Brazil's drought: beware deforestation. PMID- 25814574 TI - Brazil's drought: protect biodiversity. PMID- 25814577 TI - Dynamic DNA devices and assemblies formed by shape-complementary, non-base pairing 3D components. AB - We demonstrate that discrete three-dimensional (3D) DNA components can specifically self-assemble in solution on the basis of shape-complementarity and without base pairing. Using this principle, we produced homo- and heteromultimeric objects, including micrometer-scale one- and two-stranded filaments and lattices, as well as reconfigurable devices, including an actuator, a switchable gear, an unfoldable nanobook, and a nanorobot. These multidomain assemblies were stabilized via short-ranged nucleobase stacking bonds that compete against electrostatic repulsion between the components' interfaces. Using imaging by electron microscopy, ensemble and single-molecule fluorescence resonance energy transfer spectroscopy, and electrophoretic mobility analysis, we show that the balance between attractive and repulsive interactions, and thus the conformation of the assemblies, may be finely controlled by global parameters such as cation concentration or temperature and by an allosteric mechanism based on strand-displacement reactions. PMID- 25814576 TI - The structure of the dynactin complex and its interaction with dynein. AB - Dynactin is an essential cofactor for the microtubule motor cytoplasmic dynein-1. We report the structure of the 23-subunit dynactin complex by cryo-electron microscopy to 4.0 angstroms. Our reconstruction reveals how dynactin is built around a filament containing eight copies of the actin-related protein Arp1 and one of beta-actin. The filament is capped at each end by distinct protein complexes, and its length is defined by elongated peptides that emerge from the alpha-helical shoulder domain. A further 8.2 angstrom structure of the complex between dynein, dynactin, and the motility-inducing cargo adaptor Bicaudal-D2 shows how the translational symmetry of the dynein tail matches that of the dynactin filament. The Bicaudal-D2 coiled coil runs between dynein and dynactin to stabilize the mutually dependent interactions between all three components. PMID- 25814578 TI - Ab initio calculation of the neutron-proton mass difference. AB - The existence and stability of atoms rely on the fact that neutrons are more massive than protons. The measured mass difference is only 0.14% of the average of the two masses. A slightly smaller or larger value would have led to a dramatically different universe. Here, we show that this difference results from the competition between electromagnetic and mass isospin breaking effects. We performed lattice quantum-chromodynamics and quantum-electrodynamics computations with four nondegenerate Wilson fermion flavors and computed the neutron-proton mass-splitting with an accuracy of 300 kilo-electron volts, which is greater than 0 by 5 standard deviations. We also determine the splittings in the Sigma, Xi, D, and Xicc isospin multiplets, exceeding in some cases the precision of experimental measurements. PMID- 25814579 TI - Crystallization in Ising quantum magnets. AB - Dominating finite-range interactions in many-body systems can lead to intriguing self-ordered phases of matter. For quantum magnets, Ising models with power-law interactions are among the most elementary systems that support such phases. These models can be implemented by laser coupling ensembles of ultracold atoms to Rydberg states. Here, we report on the experimental preparation of crystalline ground states of such spin systems. We observe a magnetization staircase as a function of the system size and show directly the emergence of crystalline states with vanishing susceptibility. Our results demonstrate the precise control of Rydberg many-body systems and may enable future studies of phase transitions and quantum correlations in interacting quantum magnets. PMID- 25814580 TI - Distances with <4% precision from type Ia supernovae in young star-forming environments. AB - The luminosities of type Ia supernovae (SNe), the thermonuclear explosions of white-dwarf stars, vary systematically with their intrinsic color and the rate at which they fade. From images taken with the Galaxy Evolution Explorer (GALEX), we identified SNe Ia that erupted in environments that have high ultraviolet surface brightness and star-formation surface density. When we apply a steep model extinction law, we calibrate these SNe using their broadband optical light curves to within ~0.065 to 0.075 magnitude, corresponding to <4% in distance. The tight scatter, probably arising from a small dispersion among progenitor ages, suggests that variation in only one progenitor property primarily accounts for the relationship between their light-curve widths, colors, and luminosities. PMID- 25814581 TI - The nongravitational interactions of dark matter in colliding galaxy clusters. AB - Collisions between galaxy clusters provide a test of the nongravitational forces acting on dark matter. Dark matter's lack of deceleration in the "bullet cluster" collision constrained its self-interaction cross section sigma(DM)/m < 1.25 square centimeters per gram (cm(2)/g) [68% confidence limit (CL)] (sigma(DM), self-interaction cross section; m, unit mass of dark matter) for long-ranged forces. Using the Chandra and Hubble Space Telescopes, we have now observed 72 collisions, including both major and minor mergers. Combining these measurements statistically, we detect the existence of dark mass at 7.6sigma significance. The position of the dark mass has remained closely aligned within 5.8 +/- 8.2 kiloparsecs of associated stars, implying a self-interaction cross section sigma(DM)/m < 0.47 cm(2)/g (95% CL) and disfavoring some proposed extensions to the standard model. PMID- 25814582 TI - The in vivo dynamics of antigenic variation in Trypanosoma brucei. AB - Trypanosoma brucei, a causative agent of African Sleeping Sickness, constantly changes its dense variant surface glycoprotein (VSG) coat to avoid elimination by the immune system of its mammalian host, using an extensive repertoire of dedicated genes. However, the dynamics of VSG expression in T. brucei during an infection are poorly understood. We have developed a method, based on de novo assembly of VSGs, for quantitatively examining the diversity of expressed VSGs in any population of trypanosomes and monitored VSG population dynamics in vivo. Our experiments revealed unexpected diversity within parasite populations and a mechanism for diversifying the genome-encoded VSG repertoire. The interaction between T. brucei and its host is substantially more dynamic and nuanced than previously expected. PMID- 25814583 TI - Redox cycling of Fe(II) and Fe(III) in magnetite by Fe-metabolizing bacteria. AB - Microorganisms are a primary control on the redox-induced cycling of iron in the environment. Despite the ability of bacteria to grow using both Fe(II) and Fe(III) bound in solid-phase iron minerals, it is currently unknown whether changing environmental conditions enable the sharing of electrons in mixed-valent iron oxides between bacteria with different metabolisms. We show through magnetic and spectroscopic measurements that the phototrophic Fe(II)-oxidizing bacterium Rhodopseudomonas palustris TIE-1 oxidizes magnetite (Fe3O4) nanoparticles using light energy. This process is reversible in co-cultures by the anaerobic Fe(III) reducing bacterium Geobacter sulfurreducens. These results demonstrate that Fe ions bound in the highly crystalline mineral magnetite are bioavailable as electron sinks and electron sources under varying environmental conditions, effectively rendering magnetite a naturally occurring battery. PMID- 25814584 TI - Intergenerational transmission of child abuse and neglect: real or detection bias? AB - The literature has been contradictory regarding whether parents who were abused as children have a greater tendency to abuse their own children. A prospective 30 year follow-up study interviewed individuals with documented histories of childhood abuse and neglect and matched comparisons and a subset of their children. The study assessed maltreatment based on child protective service (CPS) agency records and reports by parents, nonparents, and offspring. The extent of the intergenerational transmission of abuse and neglect depended in large part on the source of the information used. Individuals with histories of childhood abuse and neglect have higher rates of being reported to CPS for child maltreatment but do not self-report more physical and sexual abuse than matched comparisons. Offspring of parents with histories of childhood abuse and neglect are more likely to report sexual abuse and neglect and that CPS was concerned about them at some point in their lives. The strongest evidence for the intergenerational transmission of maltreatment indicates that offspring are at risk for childhood neglect and sexual abuse, but detection or surveillance bias may account for the greater likelihood of CPS reports. PMID- 25814586 TI - Strength in disability. PMID- 25814585 TI - Spring-loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover. AB - During intracellular membrane trafficking, N-ethylmaleimide-sensitive factor (NSF) and alpha-soluble NSF attachment protein (alpha-SNAP) disassemble the soluble NSF attachment protein receptor (SNARE) complex for recycling of the SNARE proteins. The molecular mechanism by which NSF disassembles the SNARE complex is largely unknown. Using single-molecule fluorescence spectroscopy and magnetic tweezers, we found that NSF disassembled a single SNARE complex in only one round of adenosine triphosphate (ATP) turnover. Upon ATP cleavage, the NSF hexamer developed internal tension with dissociation of phosphate ions. After latent time measuring tens of seconds, NSF released the built-up tension in a burst within 20 milliseconds, resulting in disassembly followed by immediate release of the SNARE proteins. Thus, NSF appears to use a "spring-loaded" mechanism to couple ATP hydrolysis and unfolding of substrate proteins. PMID- 25814587 TI - Accreditation process for clinical trials in India moves a step closer. PMID- 25814588 TI - Draft Genome Sequences of Sanguibacteroides justesenii, gen. nov., sp. nov., Strains OUH 308042T (= ATCC BAA-2681T) and OUH 334697 (= ATCC BAA-2682), Isolated from Blood Cultures from Two Different Patients. AB - We announce here the draft genome sequences of Sanguibacteroides justesenii, gen. nov., sp. nov., strains OUH 308042(T) (= DSM 28342(T) = ATCC BAA-2681(T)) and OUH 334697 (= DSM 28341 = ATCC BAA-2682), isolated from blood cultures from two different patients and composed of 51 and 39 contigs for totals of 3,385,516 and 3,410,672 bp, respectively. PMID- 25814589 TI - Genome Sequence of Phytophthora fragariae var. fragariae, a Quarantine Plant Pathogenic Fungus. AB - Phytophthora fragariae var. fragariae is a serious plant-pathogenic fungus causing red core disease in strawberries, resulting in a larger number of fruit produced, and the fungus has been regulated as a quarantine pest of many countries and regions. Here, we announce the genome sequence of P. fragariae var. fragariae, and this information might provide insight into the mechanism of pathogenicity and host specificity of this pathogen, as well as help us further identify targets for fungicides. PMID- 25814590 TI - Human BK Polyomavirus Plasmid pBKV (34-2) (Dunlop) Contains Mutations Not Found in the Originally Published Sequences. AB - The plasmid pBKV (34-2) (ATCC 45025) contains the entire BK polyomavirus Dunlop genome. Sequencing revealed 12 point mutations compared to the GenBank sequence, but only 4 point mutations compared to the published sequence. The origin of these differences is unknown, but may impact virological as well as diagnostic research and development. PMID- 25814592 TI - Draft Genome Sequence of Lysinibacillus sp. Strain A1, Isolated from Malaysian Tropical Soil. AB - In this work, we describe the genome of Lysinibacillus sp. strain A1, which was isolated from tropical soil. Analysis of its genome sequence shows the presence of a gene encoding for a putative peptidase responsible for nitrogen compounds. PMID- 25814591 TI - Complete Genome Sequence of the Hypervirulent Bacterium Clostridium difficile Strain G46, Ribotype 027. AB - Clostridium difficile is one of the leading causes of antibiotic-associated diarrhea in health care facilities worldwide. Here, we report the genome sequence of C. difficile strain G46, ribotype 027, isolated from an outbreak in Glamorgan, Wales, in 2006. PMID- 25814593 TI - Whole-Genome Sequences of Nonencapsulated Haemophilus influenzae Strains Isolated in Italy. AB - Haemophilus influenzae is an important human pathogen involved in invasive disease. Here, we report the whole-genome sequences of 11 nonencapsulated H. influenzae (ncHi) strains isolated from both invasive disease and healthy carriers in Italy. This genomic information will enrich our understanding of the molecular basis of ncHi pathogenesis. PMID- 25814594 TI - Draft Genome Sequence of the Phenazine-Producing Pseudomonas fluorescens Strain 2 79. AB - Pseudomonas fluorescens strain 2-79, a natural isolate of the rhizosphere of wheat (Triticum aestivum L.), possesses antagonistic potential toward several fungal pathogens. We report the draft genome sequence of strain 2-79, which comprises 5,674 protein-coding sequences. PMID- 25814595 TI - Whole-genome sequencing of a pandoravirus isolated from keratitis-inducing acanthamoeba. AB - Following the recent discovery of two Pandoravirus species in 2013, a previously described endocytobiont isolated from the inflamed eye of a patient with keratitis was subjected to whole-genome sequencing (WGS). Here, we present the complete genome sequence of a new Pandoravirus isolate. PMID- 25814596 TI - Draft Genome Sequence of the Beneficial Rhizobacterium Pseudomonas fluorescens DSM 8569, a Natural Isolate of Oilseed Rape (Brassica napus). AB - Pseudomonas fluorescens DSM 8569 represents a natural isolate of the rhizosphere of oilseed rape (Brassica napus) in Germany and possesses antagonistic potential toward the fungal pathogen Verticillium. We report here the draft genome sequence of strain DSM 8569, which comprises 5,914 protein-coding sequences. PMID- 25814597 TI - Complete genomic sequence of rabies virus from an ethiopian wolf. AB - Ethiopian wolves are the rarest canid in the world, with only 500 found in the Ethiopian highlands. Rabies poses the most immediate threat to their survival, causing epizootic cycles of mass mortality. The complete genome sequence of a rabies virus (RABV) derived from an Ethiopian wolf during the most recent epizootic is reported here. PMID- 25814598 TI - Complete genome sequence of a chikungunya virus imported from bali to Germany. AB - Chikungunya virus (CHIKV) strain DH130003 was isolated from a traveler with Chikungunya fever returning from Bali to Germany. Although strains of the east central/south African lineage bearing the A226V mutation have predominated in most parts of Asia since 2005, CHIKV DH130003 belongs to the Asian lineage. PMID- 25814599 TI - Draft Genome Sequences of Four Bacillus thermoamylovorans Strains Isolated from Milk and Acacia Gum, a Food Ingredient. AB - The thermophilic bacterium Bacillus thermoamylovorans produces highly heat resistant spores that can contaminate food products, leading to their spoilage. Here, we present the whole-genome sequences of four B. thermoamylovorans strains, isolated from milk and acacia gum. PMID- 25814600 TI - Draft Genome Sequence of the Yeast Starmerella bombicola NBRC10243, a Producer of Sophorolipids, Glycolipid Biosurfactants. AB - The yeast Starmerella bombicola NBRC10243 is an excellent producer of sophorolipids (SLs) from various feedstocks. Here, we report the draft genome sequence of S. bombicola NBRC10243. Analysis of the sequence may provide insight into the properties of this yeast that make it superior for use in the production of functional glycolipids and biomolecules, leading to the further development of S. bombicola NBRC10243 for industrial applications. PMID- 25814601 TI - Complete Genome Sequences of Escherichia coli Strains 1303 and ECC-1470 Isolated from Bovine Mastitis. AB - Escherichia coli is the leading causative agent of acute bovine mastitis. Here, we report the complete genome sequence of E. coli O70:H32 strain 1303, isolated from an acute case of bovine mastitis, and E. coli Ont:Hnt strain ECC-1470, isolated from a persistent infection. PMID- 25814603 TI - Draft Genome Sequence of Pedobacter sp. Strain NL19, a Producer of Potent Antibacterial Compounds. AB - Here, we report the draft genome sequence of Pedobacter sp. strain NL19. The genome has 5.99 Mbp and a G+C content of 39.0%. NL19 was isolated from sludge from an abandoned uranium mine in the north of Portugal, and it produces potent antibacterials against Gram-positive and Gram-negative bacteria. PMID- 25814602 TI - Complete Genome Sequence and Annotation of Corynebacterium singulare DSM 44357, Isolated from a Human Semen Specimen. AB - Corynebacterium singulare DSM 44357 is a urease-positive microorganism isolated from human semen. The complete genome sequence of C. singulare DSM 44357 comprises 2,830,519 bp with a mean G+C content of 60.12% and 2,581 protein-coding genes. The deduced antibiotic resistance pattern of this strain includes macrolides, lincosamides, aminoglycosides, chloramphenicol, and tetracyline. PMID- 25814604 TI - Genome Sequence of Organophosphorus Pesticide-Degrading Bacterium Pseudomonas stutzeri Strain YC-YH1. AB - Pseudomonas stutzeri strain YC-YH1, isolated from pesticide-polluted soil, efficiently degrades organophosphorus pesticides (OPPs) such as chlorpyrifos, parathion-methyl, triazophos, and parathion. Here, we report the genome sequence (4.83 Mb) of P. stutzeri YC-YH1 to facilitate further investigation of the OPP degrading mechanism. PMID- 25814606 TI - Draft Genome Sequence of the Deinococcus-Thermus Bacterium Meiothermus ruber Strain A. AB - The draft genome sequence of the Deinococcus-Thermus group bacterium Meiothermus ruber strain A, isolated from a cyanobacterial enrichment culture obtained from Octopus Spring (Yellowstone National Park, WY), comprises 2,968,099 bp in 170 contigs. It is predicted to contain 2,895 protein-coding genes, 44 tRNA-coding genes, and 2 rRNA operons. PMID- 25814605 TI - Whole-Genome Sequencing of Mycoplasma mycoides subsp. mycoides Italian Strain 57/13, the Causative Agent of Contagious Bovine Pleuropneumonia. AB - Mycoplasma mycoides subsp. mycoides is generally considered one of most pathogenic Mycoplasma species, and it is the etiological agent of contagious bovine pleuropneumonia (CBPP). Here, we present the annotated genome sequence of M. mycoides subsp. mycoides Italian strain 57/13, isolated in 1992 during CBPP outbreaks in Italy. PMID- 25814607 TI - Genome Sequence of Polycyclovorans algicola Strain TG408, an Obligate Polycyclic Aromatic Hydrocarbon-Degrading Bacterium Associated with Marine Eukaryotic Phytoplankton. AB - Polycyclovorans algicola strain TG408 is a recently discovered bacterium associated with marine eukaryotic phytoplankton and exhibits the ability to utilize polycyclic aromatic hydrocarbons (PAHs) almost exclusively as sole sources of carbon and energy. Here, we present the genome sequence of this strain, which is 3,653,213 bp, with 3,477 genes and an average G+C content of 63.8%. PMID- 25814608 TI - Draft Genome Sequence of Kitasatospora griseola Strain MF730-N6, a Bafilomycin, Terpentecin, and Satosporin Producer. AB - We report here the draft genome sequence of Kitasatospora griseola strain MF730 N6, a known producer of bafilomycin, terpentecin, and satosporins. The current assembly comprises 8 contigs covering 7.97 Mb. Genome annotation revealed 7,225 protein coding sequences, 100 tRNAs, 40 rRNA genes, and 23 secondary metabolite biosynthetic gene clusters. PMID- 25814610 TI - Draft Genome of the Multidrug-Resistant Acinetobacter baumannii Strain A155 Clinical Isolate. AB - Acinetobacter baumannii is a bacterial pathogen with serious implications on human health, due to increasing reports of multidrug-resistant strains isolated from patients. Total DNA from the multidrug-resistant A. baumannii strain A155 clinical isolate was sequenced to greater than 65* coverage, providing high quality contig assemblies. PMID- 25814609 TI - Genome Sequence of Vibrio campbellii Strain UMTGB204, a Marine Bacterium Isolated from a Green Barrel Tunicate. AB - Vibrio campbellii strain UMTGB204 was isolated from a green barrel tunicate. The genome of this strain comprises 5,652,224 bp with 5,014 open reading frames, 9 rRNAs, and 116 tRNAs. It contains genes related to virulence and environmental tolerance. Gene clusters for the biosynthesis of nonribosomal peptides and bacteriocin were also identified. PMID- 25814611 TI - Draft Genome Sequence of Clostridium tyrobutyricum Strain DIVETGP, Isolated from Cow's Milk for Grana Padano Production. AB - We announce the draft genome sequence of Clostridium tyrobutyricum strain DIVETGP. This strain was isolated from cow's milk used for Grana Padano cheese production. The genome was obtained using Illumina HiSeq technology and comprises 45 contigs for 3,018,999 bp, with a G+C content of 30.8%. PMID- 25814612 TI - Complete Genome Sequences of a Clinical Isolate and an Environmental Isolate of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is the leading cause of seafood-borne infections in the United States. We report complete genome sequences for two V. parahaemolyticus strains isolated in 2007, CDC_K4557 and FDA_R31 of clinical and oyster origin, respectively. These two sequences might assist in the investigation of differential virulence of this organism. PMID- 25814613 TI - Draft Genome Sequences of Pseudomonas fluorescens Strains SF39a and SF4c, Potential Plant Growth Promotion and Biocontrol Agents. AB - Pseudomonas fluorescens SF4c and SF39a, strains isolated from wheat rhizosphere, have potential applications in plant growth promotion and biocontrol of fungal diseases of crop plants. We report the draft genome sequences of SF4c and SF39a with estimated sizes of 6.5 Mb and 5.9 Mb, respectively. PMID- 25814614 TI - Draft Genome Sequence of Cupriavidus pauculus Strain KF709, a Biphenyl-Utilizing Bacterium Isolated from Biphenyl-Contaminated Soil. AB - We report the draft genome sequence of Cupriavidus pauculus strain KF709, which comprises 6,826,799 bp with 6,272 coding sequences. The strain KF709 utilizes biphenyl and degrades low-chlorinated biphenyls; however, it possesses fewer coding sequences involved in the degradation of aromatic compounds than other strains belonging to the Betaproteobacteria. PMID- 25814615 TI - Complete Genome Sequences of Sulfurospirillum Strains UCH001 and UCH003 Isolated from Groundwater in Japan. AB - Sulfurospirillum strains UCH001 and UCH003 were isolated from anaerobic cis-1,2 dichloroethene-dechlorinating microbial consortia derived from groundwater in Japan. Here, we report the complete genome sequences of strains UCH001 and UCH003. PMID- 25814616 TI - Whole-Genome Sequence of Clostridium botulinum A2B3 87, a Highly Virulent Strain Involved in a Fatal Case of Foodborne Botulism in Italy. AB - Here, we report the genome sequence of a rare bivalent strain of Clostridium botulinum, A2B3 87. The strain was isolated from a foodborne botulism case that occurred in Italy in 1995. The case was characterized by rapid evolution of the illness and failure of conventional treatments. PMID- 25814617 TI - Whole-Genome Sequencing of a Vibrio cholerae El Tor Strain Isolated in the Imported Cholera Focus in Siberia. AB - The draft genome sequence of Vibrio cholerae O1 strain I-1263, isolated from a patient in the imported focus in Siberia, was determined. The established structural features of the mobile genetic elements indicate stage-by-stage formation of a highly pathogenic V. cholerae clone and promote understanding of the mechanisms of evolutionary pathogen transformations. PMID- 25814618 TI - Complete Genome Sequence of Feline Panleukopenia Virus Strain HRB-CS1, Isolated from a Domestic Cat in Northeastern China. AB - Here, we report the complete genome sequence of feline panleukopenia virus (FPLV) strain HRB-CS1, isolated from a dead domestic cat showing enteric symptoms in China in 2014. The genome of HRB-CS1 was sequenced and analyzed, which will help to understand the genetic characteristics and evolution of FPLV in China. PMID- 25814619 TI - Syrian doctors risk arrest and deportation for treating fellow refugees in Lebanon and Jordan. PMID- 25814620 TI - Pushing the limits of chemistry point-of-care testing for the management of patients under investigation for Ebola virus disease. AB - BACKGROUND: With the recent outbreak in West Africa, hospitals worldwide have been developing protocols for suspect of cases of Ebola virus disease. Patients with Ebola virus disease present with a severe gastroenteritis leading to dehydration and electrolyte abnormalities and as such, routine chemistry analysis is essential for patient management. While point-of-care testing can be used with additional precautions for rapid chemistry analyses in a laboratory setting, significant delays could ensue before specimens arrive to the laboratory. This study evaluated the stability of eight chemistry analytes up to 4 h post collection. METHODS: Blood was collected by venipuncture from 20 healthy volunteers and tested at times 0, 30, 60, 90, 120 and 240 h. Approximately 100 ul of blood was dispensed into a CHEM 8+Cartridge and processed on a model 300 i STAT 1 Analyzer (Abbott Point of Care Inc.) and ANOVA was used to assess statistical significant difference from the initial time point. RESULTS: While the manufacturer recommends testing within 30 min of collection, no significant variation was observed for most analytes with time points extending up to 4 h. In contrast, glucose concentrations decreased significantly (P < 0.0001) over time at an average rate of 0.0032 mmol/L per min. CONCLUSIONS: This study provides supporting data suggesting that delays up to 4 h can be tolerated, giving ample time for collection and transport of specimens to the clinical laboratory. For glucose, POC testing could still be used, taking into account the collection time and the average rate of decrease. PMID- 25814621 TI - Association of irisin concentrations with the presence of diabetic nephropathy and retinopathy. AB - OBJECTIVE: Irisin, a recently identified myokine, is involved in the protection of mice against obesity and diabetes. This study aims to determine the serum and vitreous concentrations of irisin in patients with diabetic nephropathy and diabetic retinopathy. METHODS: A total of 178 patients with type 2 diabetes mellitus, as well as 22 type 2 diabetes mellitus patients without diabetic retinopathy and 35 patients with proliferative diabetic retinopathy were enrolled in this study. RESULTS: Serum irisin concentrations were significantly elevated in the control group compared with those in type 2 diabetes mellitus patients. Furthermore, type 2 diabetes mellitus patients with macroalbuminuria exhibited significantly lower serum irisin concentrations than the controls and type 2 diabetes mellitus patients with normoalbuminuria and microalbuminuria. Simple regression analysis showed that the serum irisin concentrations in type 2 diabetes mellitus patients were negatively correlated with age, fasting plasma glucose, homeostasis model assessment of insulin resistance, blood urea nitrogen, creatinine, and positively correlated with creatinine clearance and angiotensin converting enzyme inhibitors/angiotensin receptor blockers treatment. Proliferative diabetic retinopathy patients showed significantly decreased serum and vitreous irisin concentrations compared with the control group and type 2 diabetes mellitus patients without diabetic retinopathy. Furthermore, decreased serum and vitreous irisin concentrations were found in type 2 diabetes mellitus patients without diabetic retinopathy than those in the controls. CONCLUSION: Irisin concentrations are associated with the presence of diabetic nephropathy and diabetic retinopathy. PMID- 25814622 TI - UK government apologises for contaminated blood scandal. PMID- 25814623 TI - Glucocorticoid therapy for Duchenne cardiomyopathy: A Hobson's choice? PMID- 25814624 TI - Staging lymphocyte presence in human atherosclerosis: a tale told by numbers. PMID- 25814625 TI - Myocardial fibrosis burden predicts left ventricular ejection fraction and is associated with age and steroid treatment duration in duchenne muscular dystrophy. AB - BACKGROUND: Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort. METHODS AND RESULTS: We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with >=4 cardiac magnetic resonance studies) for left ventricular ejection fraction (LVEF) and presence of late gadolinium enhancement (LGE), a marker for myocardial fibrosis. LVEF was modeled by examining LGE status, myocardial fibrosis burden (as assessed by the number of LGE-positive left ventricular segments), patient age, and steroid treatment duration. An age-only model demonstrated that LVEF declined 0.58 +/- 0.10% per year. In patients with both LGE-negative and LGE positive studies (n=51), LVEF did not decline significantly over time if LGE was absent but declined 2.2 +/- 0.31% per year when LGE was present. Univariate modeling showed significant associations between LVEF and steroid treatment duration, presence of LGE, and number of LGE-positive left ventricular segments; multivariate modeling showed that LVEF declined by 0.93 +/- 0.09% for each LGE positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of LGE-positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age-related increases. CONCLUSION: Progressive myocardial fibrosis, as detected by LGE, was strongly correlated with the LVEF decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age-related increase in myocardial fibrosis burden. PMID- 25814627 TI - A Comparative Descriptive Study of Characteristics of Early- and Late-Onset Dementia Family Caregivers. AB - Characteristics of early- and late-onset dementia family caregivers were described and compared. Based on a theoretical model of role transition, data were collected through structured interviews from 48 caregivers of adults with Alzheimer's disease or a related dementia older than the age of 70 and 48 caregivers of similarly diagnosed adults younger than the age of 60. A significantly higher proportion of caregivers of younger adults were spouses and gainfully employed compared with those of older adults; they had more years of schooling, took care of a person with more severe impairments, received more help, perceived themselves as better prepared to deal with future needs, and better informed about services. They did not differ from caregivers of older adults in terms of psychological distress, role confidence, self-efficacy, and social support. This study highlights differences and similarities to be considered in the development of services tailored to the specific needs of each group. PMID- 25814626 TI - A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis. AB - BACKGROUND: Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease. METHODS AND RESULTS: A systematic analysis was performed on 114 well-characterized perirenal aortic specimens with immunostaining for T cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non-Th1/Th17 ratio (CD4(+)T bet(+)/CD4(+)T-bet(-)/CD4(+)/interleukin-17(+) double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B-cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (~1:5 CD4/CD8 T-cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process. CONCLUSIONS: Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a "critical" change in the inflammatory footprint before and during plaque destabilization. PMID- 25814628 TI - Nasal Inoculation of the Commensal Neisseria lactamica Inhibits Carriage of Neisseria meningitidis by Young Adults: A Controlled Human Infection Study. AB - BACKGROUND: Herd protection by meningococcal vaccines is conferred by population level reduction of meningococcal nasopharyngeal colonization. Given the inverse epidemiological association between colonization by commensal Neisseria lactamica and meningococcal disease, we investigated whether controlled infection of human volunteers with N. lactamica prevents colonization by Neisseria meningitidis. METHODS: In a block-randomized human challenge study, 310 university students were inoculated with 10(4) colony-forming units of N. lactamica or were sham inoculated, and carriage was monitored for 26 weeks, after which all participants were reinoculated with N. lactamica and resampled 2 weeks later. RESULTS: At baseline, natural N. meningitidis carriage in the control group was 22.4% (36/161), which increased to 33.6% (48/143) by week 26. Two weeks after inoculation of N. lactamica, 33.6% (48/143) of the challenge group became colonized with N. lactamica. In this group, meningococcal carriage reduced from 24.2% (36/149) at inoculation to 14.7% (21/143) 2 weeks after inoculation (-9.5%; P = .006). The inhibition of meningococcal carriage was only observed in carriers of N. lactamica, was due both to displacement of existing meningococci and to inhibition of new acquisition, and persisted over at least 16 weeks. Crossover inoculation of controls with N. lactamica replicated the result. Genome sequencing showed that inhibition affected multiple meningococcal sequence types. CONCLUSIONS: The inhibition of meningococcal carriage by N. lactamica is even more potent than after glycoconjugate meningococcal vaccination. Neisseria lactamica or its components could be a novel bacterial medicine to suppress meningococcal outbreaks. This observation explains the epidemiological observation of natural immunity conferred by carriage of N. lactamica. CLINICAL TRIALS REGISTRATION: NCT02249598. PMID- 25814629 TI - Reply to Tubiana et al. PMID- 25814631 TI - Echocardiography in Patients With Enterococcal Bacteremia. PMID- 25814630 TI - Enhancing Resident Safety by Preventing Healthcare-Associated Infection: A National Initiative to Reduce Catheter-Associated Urinary Tract Infections in Nursing Homes. AB - Preventing healthcare-associated infection (HAI) is a key contributor to enhancing resident safety in nursing homes. In 2013, the U.S. Department of Health and Human Services approved a plan to enhance resident safety by reducing HAIs in nursing homes, with particular emphasis on reducing indwelling catheter use and catheter-associated urinary tract infection (CAUTI). Lessons learned from a recent multimodal Targeted Infection Prevention program in a group of nursing homes as well as a national initiative to prevent CAUTI in over 950 acute care hospitals called "On the CUSP: STOP CAUTI" will now be implemented in nearly 500 nursing homes in all 50 states through a project funded by the Agency for Healthcare Research and Quality (AHRQ). This "AHRQ Safety Program in Long-Term Care: HAIs/CAUTI" will emphasize professional development in catheter utilization, catheter care and maintenance, and antimicrobial stewardship as well as promoting patient safety culture, team building, and leadership engagement. We anticipate that an approach integrating technical and socio-adaptive principles will serve as a model for future initiatives to reduce other infections, multidrug resistant organisms, and noninfectious adverse events among nursing home residents. PMID- 25814632 TI - Administration Technique and Acceptance of Inhaler Devices in Patients With Asthma or COPD. AB - BACKGROUND: Correct technique and patient acceptance of inhalation devices for lung disease influence successful long-term management. Patient ability to use the proper technique may differ depending on the device as well as patient factors. OBJECTIVES: The objectives of our study are to measure self-reported level of acceptability of inhaler devices in community settings and compare correct use of inhaler devices using a novel scale for measuring appropriate inhaler technique. METHODS: This prospective observational study enrolled patients from 3 different practice sites with asthma and/or chronic obstructive pulmonary disease (COPD) who were using an inhaler device. In addition to describing the samples' overall acceptability and correct use scores for the different inhalers, acceptability and correct use scores were compared based on patient characteristics. RESULTS: A total of 161 patients completed the study. The results show that acceptability was lowest for the pressurized metered dose inhaler (pMDI) with a spacer (S); effective use was best demonstrated with pMDI and poorest with pMDI-S. Older patients were found to be more accepting of the HandiHaler device than younger patients. Patients reporting taking more inhaled drugs were found to be more accepting of the pMDI-S than those taking fewer drugs. Finally, patients reporting taking more inhaled drugs demonstrated less effective use of the HandiHaler device than patients taking fewer drugs. CONCLUSION: Pulmonary disease duration does not ensure improved use for all inhalers; patients taking more drugs demonstrate less-effective use for some devices. Assessment of patient acceptance and factors that predict the ability to use a device should be considered to individualize therapy. PMID- 25814633 TI - Increasing Sibling Relative Risk of Survival to Older and Older Ages and the Importance of Precise Definitions of "Aging," "Life Span," and "Longevity". AB - The lack of a formal definition of human longevity continues to generate confusion about its genetic and nongenetic determinants. In order to characterize how differences in birth year cohorts and percentiles of survival are associated with familial contribution to variation in survival, we estimated sibling relative risk of living to increasingly rare percentiles of survival based on a dataset of 1,917 validated sibships each containing at least one individual living to age 90 years. About 1,042 of the sibships included at least one individual who survived to age 100 and 511 included at least one individual who survived to age 105 and older. We show that sibling relative risk increases with older ages, sex, and earlier birth year cohorts of the proband and siblings of male 90-year-olds (5th percentile of survival) have 1.73 (95% CI: 1.5; 2.0) times the chance of living to age 90, while siblings of both male and female probands who survived to age 105 years (~0.01 percentile of survival) have 35.6 (95%CI: 15.1; 67.7) times the chance of living to age 105 compared with population controls. These results emphasize the importance of consistently defining the longevity phenotype in terms of rarity of survival for appropriate comparisons across studies. PMID- 25814634 TI - Maximal fat oxidation during exercise is positively associated with 24-hour fat oxidation and insulin sensitivity in young, healthy men. AB - Disturbances in fat oxidation have been associated with an increased risk of obesity and metabolic disorders such as insulin resistance. There is large intersubject variability in the capacity to oxidize fat when a person is physically active, although the significance of this for metabolic health is unclear. We investigated whether the maximal capacity to oxidize fat during exercise is related to 24-h fat oxidation and insulin sensitivity. Maximal fat oxidation (MFO; indirect calorimetry during incremental exercise) and insulin sensitivity (Quantitative Insulin Sensitivity Check Index) were measured in 53 young, healthy men (age 24 +/- 7 yr, Vo2max 52 +/- 6 ml.kg(-1).min(-1)). Fat oxidation over 24 h (24-h FO; indirect calorimetry) was assessed in 16 young, healthy men (age 26 +/- 8 yr, Vo2max 52 +/- 6 ml.kg(-1).min(-1)) during a 36-h stay in a whole-room respiration chamber. MFO (g/min) was positively correlated with 24-h FO (g/day) (R = 0.65, P = 0.003; R = 0.46, P = 0.041 when controlled for Vo2max [l/min]), 24-h percent energy from FO (R = 0.58, P = 0.009), and insulin sensitivity (R = 0.33, P = 0.007). MFO (g/min) was negatively correlated with 24-h fat balance (g/day) (R = -0.51, P = 0.021) but not significantly correlated with 24-h respiratory quotient (R = -0.29, P = 0.142). Although additional investigations are needed, our data showing positive associations between MFO and 24-h FO, and between MFO and insulin sensitivity in healthy young men suggests that a high capacity to oxidize fat while one is physically active could be advantageous for the maintenance of metabolic health. PMID- 25814635 TI - Self-paced exercise in hot and cool conditions is associated with the maintenance of %VO2peak within a narrow range. AB - This study examined the time course and extent of decrease in peak oxygen uptake (VO2peak) during self-paced exercise in HOT (35 degrees C and 60% relative humidity) and COOL (18 degrees C and 40% relative humidity) laboratory conditions. Ten well-trained cyclists completed four consecutive 16.5-min time trials (15-min self-paced effort with 1.5-min maximal end-spurt to determine VO2peak) interspersed by 5 min of recovery on a cycle ergometer in each condition. Rectal temperature increased significantly more in HOT (39.4 +/- 0.7 degrees C) than COOL (38.6 +/- 0.3 degrees C; P < 0.001). Power output was lower throughout HOT compared with COOL (P < 0.001). The decrease in power output from trial 1 to 4 was ~16% greater in HOT (P < 0.001). Oxygen uptake (Vo2) was lower throughout HOT than COOL (P < 0.05), except at 5 min and during the end-spurt in trial 1. In HOT, VO2peak reached 97, 89, 85, and 85% of predetermined maximal Vo2, whereas in COOL 97, 94, 93, and 92% were attained. Relative exercise intensity (%VO2peak) during trials 1 and 2 was lower in HOT (~84%) than COOL (~86%; P < 0.05), decreasing slightly during trials 3 and 4 (~80 and ~85%, respectively; P < 0.05). However, heart rate was higher throughout HOT (P = 0.002), and ratings of perceived exertion greater during trials 3 and 4 in HOT (P < 0.05). Consequently, the regulation of self-paced exercise appears to occur in conjunction with the maintenance of %VO2peak within a narrow range (80-85% VO2peak). This range widens under heat stress, however, when exercise becomes protracted and a disassociation develops between relative exercise intensity, heart rate, and ratings of perceived exertion. PMID- 25814636 TI - In vivo behavior of the human soleus muscle with increasing walking and running speeds. AB - The interaction between the muscle fascicle and tendon components of the human soleus (SO) muscle influences the capacity of the muscle to generate force and mechanical work during walking and running. In the present study, ultrasound based measurements of in vivo SO muscle fascicle behavior were combined with an inverse dynamics analysis to investigate the interaction between the muscle fascicle and tendon components over a broad range of steady-state walking and running speeds: slow-paced walking (0.7 m/s) through to moderate-paced running (5.0 m/s). Irrespective of a change in locomotion mode (i.e., walking vs. running) or an increase in steady-state speed, SO muscle fascicles were found to exhibit minimal shortening compared with the muscle-tendon unit (MTU) throughout stance. During walking and running, the muscle fascicles contributed only 35 and 20% of the overall MTU length change and shortening velocity, respectively. Greater levels of muscle activity resulted in increasingly shorter SO muscle fascicles as locomotion speed increased, both of which facilitated greater tendon stretch and recoil. Thus the elastic tendon contributed the majority of the MTU length change during walking and running. When transitioning from walking to running near the preferred transition speed (2.0 m/s), greater, more economical ankle torque development is likely explained by the SO muscle fascicles shortening more slowly and operating on a more favorable portion (i.e., closer to the plateau) of the force-length curve. PMID- 25814637 TI - Integrating physiology across scales and formalizing hypothesis exploration with agent-based modeling. PMID- 25814639 TI - Asynchrony of lingual muscle recruitment during sleep in obstructive sleep apnea. AB - Pharyngeal collapsibility during sleep increases primarily due to decline in dilator muscle activity. However, genioglossus EMG is known to increase during apneas and hypopneas, usually without reversing upper airway obstruction or inspiratory flow limitation. The present study was undertaken to test the hypothesis that intense activation of the genioglossus fails to prevent pharyngeal obstruction during sleep, and to evaluate if sleep-induced changes in tongue muscle coordination may be responsible for this phenomenon. We compared genioglossus and tongue retractors EMG activity in 13 obstructive sleep apnea (OSA) patients during wakefulness, while breathing through inspiratory resistors, to the activity observed at the end of apneas and hypopneas after 25 mg of brotizolam, before arousal, at equal esophageal pressure. During wakefulness, resistive breathing triggered increases in both genioglossus and retractor EMG. Activation of agonist tongue muscles differed considerably from that of the arm, as both genioglossus and retractors were activated similarly during all tongue movements. During sleep, flow limitation triggered increases in genioglossal EMG that could reach more than twofold the level observed while awake. In contrast, EMGs of the retractors reached less than half the wakefulness level. In sleeping OSA patients, genioglossal activity may increase during obstructed breathing to levels that exceed substantially those required to prevent pharyngeal collapse during wakefulness. In contrast, coactivation of retractors is deficient during sleep. These findings suggest that sleep-induced alteration in tongue muscle coordination may be responsible for the failure of high genioglossal EMG activity to alleviate flow limitation. PMID- 25814640 TI - Biomarkers of multiorgan injury in a preclinical model of exertional heat stroke. AB - It is likely that the pathophysiology of exertional heat stroke (EHS) differs from passive heat stroke (PHS), but this has been difficult to verify experimentally. C57Bl/6 mice were instrumented with temperature transponders and underwent 3 wk of training using voluntary and forced running wheels. An EHS group was exposed to environmental temperatures (Tenv) of 37.5, 38.5, or 39.5 degrees C at either 30, 50, or 90% relative humidities (RH) while exercising on a forced running wheel. Results were compared with sham-matched exercise controls (EXC) and naive controls (NC). In EHS, mice exercised in heat until they reached limiting neurological symptoms (loss of consciousness). The symptom-limited maximum core temperatures achieved were between 42.1 and 42.5 degrees C at 50% RH. All mice that were followed for 4 days survived. Additional groups were killed at 0.5, 3, 24, and 96 h, post-EHS or -EXC. Histopathology revealed extensive damage in all regions of the small intestine, liver, and kidney. Plasma creatine kinase, blood urea nitrogen, alanine transaminase, and intestinal fatty acid binding protein-2 were significantly elevated compared with matched EXC and NC, suggesting multiple organ injury to striated muscle, kidney, liver, and intestine, respectively. EHS mice were hypoglycemic immediately following EHS but exhibited sustained hyperglycemia through 4 days. The results demonstrate unique features of survivable EHS in the mouse that included loss of consciousness, extensive organ injury, and rhabdomyolysis. PMID- 25814638 TI - Noninvasive assessment of muscle temperature during rest, exercise, and postexercise recovery in different environments. AB - We introduced noninvasive and accurate techniques to estimate muscle temperature (Tm) of vastus lateralis (VL), triceps brachii (TB), and trapezius (TRAP) during rest, exercise, and postexercise recovery using the insulation disk (iDISK) technique. Thirty-six volunteers (24 men, 12 women; 73.0 +/- 12.2 kg; 1.75 +/- 0.07 m; 24.4 +/- 5.5 yr; 49.2 +/- 6.8 ml.kg(-1).min(-1) peak oxygen uptake) underwent periods of rest, cycling exercise at 40% of peak oxygen uptake, and postexercise recovery in three environments: Normal (24 degrees C, 56% relative humidity), Hot-Humid (30 degrees C, 60% relative humidity), and Hot-Dry (40 degrees C, 24% relative humidity). Participants were randomly allocated into the "model" and the "validation" groups. Results in the model group demonstrated that Tm (VL: 36.65 +/- 1.27 degrees C; TB: 35.76 +/- 1.73 degrees C; TRAP: 36.53 +/- 0.96 degrees C) was increased compared with iDISK (VL: 35.67 +/- 1.71 degrees C; TB: 34.77 +/- 2.27 degrees C; TRAP: 35.98 +/- 1.34 degrees C) across all environments (P < 0.001). Stepwise regression analysis generated models that accurately predicted Tm (predTm) of VL (R(2) = 0.73-0.91), TB (R(2) = 0.85-0.93), and TRAP (R(2) = 0.84-0.86) using iDISK and the difference between the current iDISK temperature and that recorded between 1 and 4 min before. Cross-validation analyses in the validation group demonstrated small differences (P < 0.05) of no physiological significance, small effect size of the differences, and strong associations (r = 0.85-0.97; P < 0.001) between Tm and predTm. Moreover, narrow 95% limits of agreement and low percent coefficient of variation were observed between Tm and predTm. It is concluded that the developed noninvasive, practical, and inexpensive techniques provide accurate estimations of VL, TB, and TRAP Tm during rest, cycling exercise, and postexercise recovery. PMID- 25814641 TI - Quantitative assessment of multiscale structural and functional alterations in asthmatic populations. AB - Relationships between structural and functional variables in asthmatic lungs at local and global (or lobar) levels remain to be discovered. This study aims to investigate local alterations of structural variables [bifurcation angle, circularity, airway wall thickness (WT), and hydraulic diameter (Dh)] in asthmatic subjects, and their correlations with other imaging and pulmonary function test-based global and lobar metrics, including lung shape, air-trapping, regional volume change, and more. Sixty-one healthy subjects, and 67 nonsevere and 67 severe asthmatic subjects were studied. The structural variables were derived from computed tomography images at total lung capacity (TLC). Air trapping was measured at functional residual capacity, and regional volume change (derived from image registration) was measured between functional residual capacity and TLC. The tracheal diameter and WT predicted by 61 healthy subjects were used to normalize the Dh and WT. New normalization schemes allowed for the dissociation of luminal narrowing and wall thickening effects. In severe asthmatic subjects, the alteration of bifurcation angle was found to be correlated with a global lung shape at TLC, and circularity was significantly decreased in the right main bronchus. While normalized WT increased especially in the upper lobes of severe asthmatic subjects, normalized Dh decreased in the lower lobes. Among local structural variables, normalized Dh was the most representative variable, because it was significantly correlated with alterations of functional variables, including pulmonary function test's data. In conclusion, understanding multiscale phenomena may help to provide guidance in the search for potential imaging-based phenotypes for the development and outcomes assessment of therapeutic intervention. PMID- 25814643 TI - Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes. AB - BACKGROUND: Genome-wide association studies enabled us to discover a large number of variants and genomic loci contributing to cardiovascular and metabolic disorders. However, because the vast majority of the identified variants are thought to merely be proxies for other functional variants, the causal mechanisms remain to be elucidated. We hypothesized that the part of the functional variants involved in deregulating cardiometabolic genes is located in microRNA (miRNA) binding sites. METHODS AND RESULTS: Using the largest genome-wide association studies available on glycemic indices, lipid traits, anthropometric measures, blood pressure, coronary artery diseases, and type 2 diabetes mellitus, we identified 11,067 variants that are associated with cardiometabolic phenotypes. Of these, 230 variants are located within miRNA-binding sites in the 3' untranslated region of 155 cardiometabolic genes. Thirty-seven of 230 variants were found to fulfill our predefined criteria for being functional in their genomic loci. Ten variants were subsequently selected for experimental validation based on genome-wide association studies results, expression quantitative trait loci (eQTL) analyses, and coexpression of their host genes and regulatory miRNAs in relevant tissues. Luciferase reporter assays revealed an allele-specific regulation of genes hosting the variants by miRNAs. These cotransfection experiments showed that rs174545 (FADS1:miR-181a-2), rs1059611 (LPL:miR-136), rs13702 (LPL:miR-410), rs1046875 (FN3KRP:miR-34a), rs7956 (MKRN2:miR-154), rs3217992 (CDKN2B:miR-138-2-3p), and rs11735092 (HSD17B13:miR-375) decrease or abrogate miRNA-dependent regulation of the genes. Conversely, 2 variants, rs6857 (PVRL2:miR-320e) and rs907091 (IKZF3:miR-326), were shown to enhance the activity of miRNAs on their host genes. CONCLUSIONS: We provide evidence for a model in which polymorphisms in miRNA-binding sites can both positively and negatively affect miRNA-mediated regulation of cardiometabolic genes. PMID- 25814642 TI - Spinal segment-specific transcutaneous stimulation differentially shapes activation pattern among motor pools in humans. AB - Transcutaneous and epidural electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Recently, we observed selective activation of proximal and distal motor pools during epidural spinal stimulation. In the present study, we hypothesized that the characteristics of recruitment curves obtained from leg muscles will reflect a relative preferential activation of proximal and distal motor pools based on their arrangement along the lumbosacral enlargement. The purpose was to describe the electrophysiological responses to transcutaneous stimulation in leg muscles innervated by motoneurons from different segmental levels. Stimulation delivered along the rostrocaudal axis of the lumbosacral enlargement in the supine position resulted in a selective topographical recruitment of proximal and distal leg muscles, as described by threshold intensity, slope of the recruitment curves, and plateau point intensity and magnitude. Relatively selective recruitment of proximal and distal motor pools can be titrated by optimizing the site and intensity level of stimulation to excite a given combination of motor pools. The slope of the recruitment of particular muscles allows characterization of the properties of afferents projecting to specific motoneuron pools, as well as to the type and size of the motoneurons. The location and intensity of transcutaneous spinal electrical stimulation are critical to target particular neural structures across different motor pools in investigation of specific neuromodulatory effects. Finally, the asymmetry in bilateral evoked potentials is inevitable and can be attributed to both anatomical and functional peculiarities of individual muscles or muscle groups. PMID- 25814645 TI - Gene expression profiles of the cochlea and vestibular endorgans: localization and function of genes causing deafness. AB - OBJECTIVES: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. METHODS: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. RESULTS: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. CONCLUSIONS: The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function. PMID- 25814647 TI - Clockwatching--is that really hate? AB - OBJECTIVE: To consider experiences of hate, which occur in clinical encounters. METHOD: A review of the electronic and manual literatures. RESULTS: Hate has become diluted to a euphemism, the 'difficult patient'. CONCLUSION: Retaining use of the word hate avoids overlooking subtle cues in the unfolding relationship. PMID- 25814644 TI - Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease. AB - BACKGROUND: Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. METHODS AND RESULTS: Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P<0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-beta2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-beta signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/beta-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF beta2 increased beta-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-beta2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. CONCLUSIONS: These data support a new disease framework whereby activation of TGF-beta2, bone morphogenetic protein 4, Wnt/beta-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD. PMID- 25814646 TI - Pulmonary Rehabilitation After Total Laryngectomy: A Multicenter Time-Series Clinical Trial Evaluating the Provox XtraHME in HME-Naive Patients. AB - BACKGROUND: Both the immediate beneficial physiological changes in a laboratory setting and the long-term clinical outcomes of heat and moisture exchanger (HME) use are well described. So far, there has not been any research published that provides detailed insight in the pattern of changes in both respiratory function and patients' experiences with HMEs in the first weeks of use. METHODS: A multicenter time-series study design with a 2-week double baseline period. All patients used the XtraHME for 12 weeks afterward. Data were collected 2 weeks, 6 weeks, and 12 weeks after the start of HME use. RESULTS: Data of 30 patients were analyzed. Pulmonary symptoms decreased significantly during the 12 weeks of HME use. After 2 weeks, a significant decrease in daily coughs and daily forced expectorations was seen. The general quality of life showed a significant increase throughout the study. More general physical complaints also significantly decreased with HME use. Patient satisfaction with the HME was high. CONCLUSIONS: This study shows that there is a significant influence of the XtraHME on pulmonary status that can already be observed after 2 weeks of using the XtraHME and continues to improve further after 6 weeks of XtraHME use. PMID- 25814648 TI - Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancer. AB - OBJECTIVE: Cancer immunology is a growing field of research whose aim is to develop innovative therapies and diagnostic tests. Starting from the hypothesis that immune cells promptly respond to harmful stimuli, we used peripheral blood monocytes in order to characterise a distinct gene expression profile and to evaluate its potential as a candidate diagnostic biomarker in patients with colorectal cancer (CRC), a still unmet clinical need. DESIGN: We performed a case control study including 360 peripheral blood monocyte samples from four European oncological centres and defined a gene expression profile specific to CRC. The robustness of the genetic profile and disease specificity were assessed in an independent setting. RESULTS: This screen returned 43 putative diagnostic markers, which we refined and validated in the confirmative multicentric analysis to 23 genes with outstanding diagnostic accuracy (area under the curve (AUC)=0.99 (0.99 to 1.00), Se=100.0% (100.0% to 100.0%), Sp=92.9% (78.6% to 100.0%) in multiple-gene receiver operating characteristic analysis). The diagnostic accuracy was robustly maintained in prospectively collected independent samples (AUC=0.95 (0.85 to 1.00), Se=92.6% (81.5% to 100.0%), Sp=92.3% (76.9% to 100.0%). This monocyte signature was expressed at early disease onset, remained robust over the course of disease progression, and was specific for the monocytic fraction of mononuclear cells. The gene modulation was induced specifically by soluble factors derived from transformed colon epithelium in comparison to normal colon or other cancer histotypes. Moreover, expression changes were plastic and reversible, as they were abrogated upon withdrawal of these tumour-released factors. Consistently, the modified set of genes reverted to normal expression upon curative treatment and was specific for CRC. CONCLUSIONS: Our study is the first to demonstrate monocyte plasticity in response to tumour-released soluble factors. The identified distinct signature in tumour-educated monocytes might be used as a candidate biomarker in CRC diagnosis and harbours the potential for disease follow-up and therapeutic monitoring. PMID- 25814649 TI - Genetic variants of lipase activity in chronic pancreatitis. PMID- 25814651 TI - Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset. PMID- 25814650 TI - Understanding the concept of resilience in relation to looked after children: A Delphi survey of perceptions from education, social care and foster care. AB - There has been a surge of interest regarding the application of resilience theory in childcare practice and how resilience can be promoted among vulnerable children, in particular, looked after children. However, little is known about how people working with looked after children understand the concept of resilience. This study aimed to explore how social workers, teachers and foster carers, working with looked after children, understand resilience and whether there is consensus as to what constitutes resilience. The study also sought to explore whether there are differences in how resilience is constructed across these groups. In total, 106 participants took part in a Delphi survey (34 teachers, 36 foster carers, 36 social workers). There was moderate consensus that resilience related to survival, coping and a sense of self-worth. Resilience was not considered a panacea but a concept that also had limitations. Participants understood resilience in ways that were both similar and different to existing conceptualisations within the literature. However, there were many aspects of resilience for which there was no consensus or significant difference of opinion between the participant groups. The need for further training and research is discussed, in order to support attempts to promote resilience among looked after children. PMID- 25814652 TI - On the HUNT for cardiovascular risk factors and disease in patients with psoriatic arthritis: population-based data from the Nord-Trondelag Health Study. AB - OBJECTIVE: To compare the presence of cardiovascular (CV) risk factors and established CV disease in patients with psoriatic arthritis (PsA) and the general population and to compare the 10-year risk of a fatal CV event calculated by the Systematic Coronary Risk Evaluation (SCORE) algorithm. METHODS: Patients with PsA (n=338) and controls (n=50 468) were recruited from the Nord-Trondelag Health Study 3. Age-adjusted and sex-adjusted prevalence rates of CV risk factors and comorbidity were calculated and the SCORE algorithm was applied. RESULTS: There was an increased prevalence of angina pectoris (5.0% vs 3.6%, p=0.01), history of percutaneous coronary intervention (2.4% vs 1.4%, p=0.04), hypertension (45.3% vs 39.3%, p=0.01), obesity (32.0% vs 22.4%) and tobacco smoking (21.3% vs 16.4%, p=0.02) in patients with PsA compared with controls. Patients with PsA had elevated levels of C reactive protein (CRP; p<0.001), body mass index (BMI; p<0.001) and triglycerides (p=0.01). The median calculated CV risk in patients with PsA was low and comparable with controls (0.87 vs 0.83, p=0.24). The distribution across CV risk classes was similar among patients with PsA and controls. CONCLUSIONS: Patients with PsA have a higher risk of CV disease than the background population, although there was no difference between groups in 10 year risk of a fatal CV event estimated by SCORE. However, patients with PsA had elevated levels of CV risk factors not included in the SCORE algorithm, such as BMI, triglycerides and CRP. PMID- 25814653 TI - MicroRNAs in cardiovascular disease: an introduction for clinicians. AB - MicroRNAs (miRNAs) are small, non-coding, RNA molecules approximately 22 nucleotides in length which act as post-transcriptional regulators of gene expression. Individual miRNAs have been shown to regulate the expression of multiple genes. Conversely, the expression of individual genes can be regulated by multiple miRNAs. Consequently, since their discovery just over 20 years ago, miRNAs have been identified as key regulators of complex biological processes linked to multiple cardiovascular pathologies, including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension and arrhythmias. Furthermore, since the finding that miRNAs are present in the circulation, they have been investigated as novel biomarkers, especially in the context of acute myocardial infarction (AMI) and heart failure. While there is little convincing evidence that miRNAs can outperform traditional biomarkers, such as cardiac troponins, in the diagnosis of AMI, there is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post AMI prognosis. Encouragingly, the concept of miRNA-based therapeutics is developing, with synthetic antagonists of miRNAs (antagomiRs) currently in phase II trials for the treatment of chronic hepatitis C virus infection. In the cardiovascular field, promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome. Through this review, we provide clinicians with a brief overview of the ever-expanding world of miRNAs. PMID- 25814654 TI - Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of gamma-secretase activity. AB - The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for gamma-secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimer's disease (FAD) only the K115Efx10 mutation of PSEN2 causes truncation of the open reading frame. If translated, the truncated product would resemble a naturally occurring isoform of PSEN2 named PS2V that is induced by hypoxia and found at elevated levels in late onset Alzheimer's disease (AD) brains. The function of PS2V is largely unexplored. We show that zebrafish possess a PS2V-like isoform, PS1IV, produced from the fish's PSEN1 rather than PSEN2 orthologous gene. The molecular mechanism controlling formation of PS2V/PS1IV was probably present in the ancient common ancestor of the PSEN1 and PSEN2 genes. Human PS2V and zebrafish PS1IV have highly divergent structures but conserved abilities to stimulate gamma-secretase activity and to suppress the unfolded protein response (UPR) under hypoxia. The putative protein truncation caused by K115Efx10 resembles PS2V in its ability to increase gamma secretase activity and suppress the UPR. This supports increased Abeta levels as a common link between K115Efx10 early onset AD and sporadic, late onset AD. The ability of mutant variants of PS2V to stimulate gamma-secretase activity partially correlates with their ability to suppress the UPR. The cytosolic, transmembrane and luminal domains of PS2V are all critical to its gamma-secretase and UPR-suppression activities. Our data support a model in which chronic hypoxia in aged brains promotes excessive Notch signalling and accumulation of Abeta that contribute to AD pathogenesis. PMID- 25814656 TI - Treatment of Benign Thyroid Nodules: Comparison of Surgery with Radiofrequency Ablation. AB - BACKGROUND AND PURPOSE: Nodular goiter is one of the most common benign lesions in thyroid nodule. The main treatment of the disease is still the traditional surgical resection, however there are many problems such as general anesthesia, surgical scar, postoperative thyroid or parathyroid function abnormalities, and high nodules recurrence rate in residual gland. The purpose of this study was to compare the efficacy, safety, and cost-effectiveness of 2 treatment methods, surgery and radiofrequency ablation, for the treatment of benign thyroid nodules. MATERIALS AND METHODS: From May 2012 to September 2013, 200 patients with nodular goiters who underwent surgery (group A) and 200 patients treated by radiofrequency ablation (group B) were enrolled in this study. Inclusion criteria were the following: 1) cosmetic problem, 2) nodule-related symptoms, 3) hyperfunctioning nodules related to thyrotoxicosis, and 4) refusal of surgery (for group B). An internally cooled radiofrequency ablation system and an 18-ga internally cooled electrode were used. We compared the 2 groups in terms of efficacy, safety, and cost-effectiveness during a 1-year follow-up. RESULTS: After radiofrequency ablation, the nodule volume decreased significantly from 5.4 to 0.4 mL (P = .002) at the 12-month follow-up. The incidence of complications was significantly higher from surgery than from radiofrequency ablation (6.0% versus 1.0%, P = .002). Hypothyroidism was detected in 71.5% of patients after surgery but in none following radiofrequency ablation. The rate of residual nodules (11.9% versus 2.9%, P = .004) and hospitalization days was significantly greater after surgery (6.6 versus 2.1 days, P < .001), but the cost difference was not significant. CONCLUSIONS: Surgical resection and radiofrequency ablation are both effective treatments of nodular goiter. Compared with surgery, the advantages of radiofrequency ablation include fewer complications, preservation of thyroid function, and fewer hospitalization days. Therefore, radiofrequency ablation should be considered a first-line treatment for benign thyroid nodules. PMID- 25814655 TI - Expanded GAA repeats impair FXN gene expression and reposition the FXN locus to the nuclear lamina in single cells. AB - Abnormally expanded DNA repeats are associated with several neurodegenerative diseases. In Friedreich's ataxia (FRDA), expanded GAA repeats in intron 1 of the frataxin gene (FXN) reduce FXN mRNA levels in averaged cell samples through a poorly understood mechanism. By visualizing FXN expression and nuclear localization in single cells, we show that GAA-expanded repeats decrease the number of FXN mRNA molecules, slow transcription, and increase FXN localization at the nuclear lamina (NL). Restoring histone acetylation reverses NL positioning. Expanded GAA-FXN loci in FRDA patient cells show increased NL localization with increased silencing of alleles and reduced transcription from alleles positioned peripherally. We also demonstrate inefficiencies in transcription initiation and elongation from the expanded GAA-FXN locus at single cell resolution. We suggest that repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur. PMID- 25814657 TI - Negative Susceptibility Vessel Sign and Underlying Intracranial Atherosclerotic Stenosis in Acute Middle Cerebral Artery Occlusion. AB - BACKGROUND AND PURPOSE: The role of MR imaging in predicting underlying intracranial atherosclerotic stenosis before endovascular stroke therapy has not been studied. Our aim was to determine the diagnostic value of the negative susceptibility vessel sign on T2*-weighted gradient-echo MR imaging for predicting underlying intracranial atherosclerotic stenosis in patients with acute MCA occlusion. MATERIALS AND METHODS: Ninety-one consecutive patients with acute stroke because of MCA occlusion underwent gradient-echo MR imaging and MRA before endovascular therapy. The negative susceptibility vessel sign was defined as an absence of a hypointense signal change within the occluded MCA on gradient echo imaging. Underlying intracranial atherosclerotic stenosis was determined by conventional angiography. The sensitivity, specificity, predictive values, and accuracy of the negative susceptibility vessel sign for predicting the presence of underlying intracranial atherosclerotic stenosis were assessed. RESULTS: The negative susceptibility vessel sign was identified in 42 (46.1%) of 91 patients, and 18 (19.8%) patients had an underlying intracranial atherosclerotic stenosis responsible for acute ischemic symptoms. The negative susceptibility vessel sign was more frequently observed in patients with intracranial atherosclerotic stenosis than in those without it (100% versus 32.9%, P < .001). In the prediction of an underlying intracranial atherosclerotic stenosis, the negative susceptibility vessel sign had 100% sensitivity, 67.1% specificity, 42.9% positive predictive value, 100% negative predictive value, and an accuracy of 73.6%. CONCLUSIONS: The negative susceptibility vessel sign on gradient-echo MR imaging is a sensitive marker with a high negative predictive value for the presence of an underlying intracranial atherosclerotic stenosis in patients with acute ischemic stroke because of MCA occlusions. The susceptibility vessel sign can be used in decision-making when performing subsequent endovascular revascularization therapy in patients with acute MCA occlusions. PMID- 25814658 TI - Imaging the Parasinus Region with a Third-Generation Dual-Source CT and the Effect of Tin Filtration on Image Quality and Radiation Dose. AB - BACKGROUND AND PURPOSE: CT is the imaging technique of choice in the evaluation of midface trauma or inflammatory disease. We performed a systematic evaluation of scan protocols to optimize image quality and radiation exposure on third generation dual-source CT. MATERIALS AND METHODS: CT protocols with different tube voltage (70-150 kV), current (25-300 reference mAs), prefiltration, pitch value, and rotation time were systematically evaluated. All images were reconstructed with iterative reconstruction (Advanced Modeled Iterative Reconstruction, level 2). To individually compare results with otherwise identical factors, we obtained all scans on a frozen human head. Conebeam CT was performed for image quality and dose comparison with multidetector row CT. Delineation of important anatomic structures and incidental pathologic conditions in the cadaver head was evaluated. RESULTS: One hundred kilovolts with tin prefiltration demonstrated the best compromise between dose and image quality. The most dose-effective combination for trauma imaging was Sn100 kV/250 mAs (volume CT dose index, 2.02 mGy), and for preoperative sinus surgery planning, Sn100 kV/150 mAs (volume CT dose index, 1.22 mGy). "Sn" indicates an additional prefiltration of the x-ray beam with a tin filter to constrict the energy spectrum. Exclusion of sinonasal disease was possible with even a lower dose by using Sn100 kV/25 mAs (volume CT dose index, 0.2 mGy). CONCLUSIONS: High image quality at very low dose levels can be achieved by using a Sn100-kV protocol with iterative reconstruction. The effective dose is comparable with that of conventional radiography, and the high image quality at even lower radiation exposure favors multidetector row CT over conebeam CT. PMID- 25814659 TI - Intravenous Infusion of Nitroglycerine Leads to Increased Permeability on Dynamic Contrast-Enhanced MR Imaging in Pig Brains. AB - BACKGROUND AND PURPOSE: It has been suggested that off-label use of transdermal nitroglycerine patches to prevent frostbite may lead to severe acute mountain sickness and ataxia. The aim of this study was to investigate the effect of nitroglycerine on brain vascular permeability by using dynamic contrast-enhanced MR imaging in a swine model. MATERIALS AND METHODS: Eight Danish Landrace Yorkshire-Danish Landrace pigs of approximately 20-25 kg were scanned with a dynamic contrast-enhanced MR perfusion protocol with and without nitroglycerine intravenous infusion. Compartmental analysis was performed on the basis of the Tofts model, and voxel-based quantitative values of the volume transfer constants from the vascular to the extracellular space were determined. RESULTS: The scan with nitroglycerine infusion resulted in significantly higher volume transfer constant values than values derived from the first scan without nitroglycerine infusion. Increased volume transfer constant values were observed in 6 of 8 animals. CONCLUSIONS: Infusion of nitroglycerine increases the vascular permeability of the swine brain on the basis of the transfer constant estimated from dynamic contrast-enhanced MR imaging. PMID- 25814660 TI - Cranial Nerve Abnormalities in Oculo-Auriculo-Vertebral Spectrum. AB - BACKGROUND AND PURPOSE: Cranial nerve abnormalities might be observed in hemifacial microsomia and microtia (oculo-auriculo-vertebral spectrum), but the rate, features, and relationship with functional impairment or phenotype severity have not yet been defined. This study aimed at investigating absence/asymmetry, abnormal origin, morphology and course of cranial nerves, and presence/asymmetry of the foramen ovale and inferior alveolar nerve canal in a cohort of oculo auriculo-vertebral spectrum patients. MATERIALS AND METHODS: Twenty-nine patients with oculo-auriculo-vertebral spectrum (mean age, 7 years; age range, 0.2-31 years; 12 females) underwent brain MR imaging, CT, and neurologic evaluation; 19 patients had a more severe phenotype (Goldenhar syndrome). RESULTS: Cranial nerve abnormalities were detected only in patients with Goldenhar syndrome (17/19, bilaterally in 8) and were involved the second (4/19), third (1/18), fifth (11/19), sixth (8/16), seventh (11/18), and eighth (8/18) cranial nerves. Multiple cranial nerve abnormalities were common (11/17). Eleven patients showed bone foramina abnormalities. Trigeminal and facial nerve dysfunctions were common (44% and 58%, respectively), especially in patients with Goldenhar syndrome. Trigeminal abnormalities showed a good correlation with ipsilateral dysfunction (P = .018), which further increased when bone foramina abnormalities were included. The facial nerve showed a trend toward correlation with ipsilateral dysfunction (P = .081). Diplopia was found only in patients with Goldenhar syndrome and was associated with third and sixth cranial nerve abnormalities (P = .006). CONCLUSIONS: Among patients with oculo-auriculo-vertebral spectrum, cranial nerve morphologic abnormalities are common, correlate with phenotype severity, and often entail a functional impairment. The spectrum of cranial nerve abnormalities appears wider than simple hypo-/aplasia and includes an anomalous cisternal course and partial/complete fusion of diverse cranial nerves. PMID- 25814661 TI - Intratympanic Contrast in the Evaluation of Meniere Disease: Understanding the Limits. AB - BACKGROUND AND PURPOSE: Studies describing endolymphatic hydrops in Meniere disease after off-label intratympanic gadolinium-based contrast have been limited by long acquisition times. We aimed to demonstrate the feasibility of post intratympanic imaging on a 3T MR imaging system within a clinically tolerable acquisition time and to address potential pitfalls in acquisition or interpretation. MATERIALS AND METHODS: FDA Investigational New Drug 115,342 and institutional review board approval were obtained for intratympanic injection of 8-fold diluted Gd-DTPA into the more symptomatic ear of 6 adults with Meniere disease. 3T MR imaging was performed using a 3-inch surface coil before and up to 28 hours after injection using FLAIR to define the nonenhancing endolymphatic space within the enhancing perilymph. Variable FLAIR TI images were used to determine the impact of fluid-suppression on interpretation. Image quality was assessed for perilymphatic and extralabyrinthine contrast enhancement, definition of endolymphatic anatomy, and other anatomic variants or pathologic findings. RESULTS: The surface coil afforded 0.375 * 0.375 mm in-plane FLAIR resolution in <4 minutes 30 seconds, sufficient to perceive the nonenhancing spiral lamina, interscalar septa, and endolymphatic structures. Coronal views highlighted a potential interpretation pitfall of vestibular endolymphatic distention overestimation due to partial volume averaging. Varying FLAIR TI resulted in visible changes in the perception of the cochlear endolymphatic space. CSF enhancement was detectable at the internal auditory canal fundus on the injected side in half of the patients, which may confound interpretation. CONCLUSIONS: Using a surface coil preserves high resolution within a clinically acceptable acquisition time. Pitfalls remain regarding the interpretation of these images and optimizing protocols across platforms in the absence of a clear internal reference for standardization. PMID- 25814662 TI - 4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL. AB - Early growth response transcription factor Egr1 controls multiple aspects of cell physiology and metabolism. In particular, Egr1 suppresses lipolysis and promotes fat accumulation in adipocytes by inhibiting the expression of adipose triglyceride lipase. According to current dogma, regulation of the Egr1 expression takes place primarily at the level of transcription. Correspondingly, treatment of cultured adipocytes with insulin stimulates expression of Egr1 mRNA and protein. Unexpectedly, the MEK inhibitor PD98059 completely blocks insulin stimulated increase in the Egr1 mRNA but has only a moderate effect on the Egr1 protein. At the same time, mTORC1 inhibitors rapamycin and PP242 suppress expression of the Egr1 protein and have an opposite effect on the Egr1 mRNA. Mouse embryonic fibroblasts with genetic ablations of TSC2 or 4E-BP1/2 express less Egr1 mRNA but more Egr1 protein than wild type controls. (35)S-labeling has confirmed that translation of the Egr1 mRNA is much more effective in 4E-BP1/2 null cells than in control. A selective agonist of the CB1 receptors, ACEA, up regulates Egr1 mRNA, but does not activate mTORC1 and does not increase Egr1 protein in adipocytes. These data suggest that although insulin activates both the Erk and the mTORC1 signaling pathways in adipocytes, regulation of the Egr1 expression takes place predominantly via the mTORC1/4E-BP-mediated axis. In confirmation of this model, we show that 4E-BP1/2-null MEFs express less ATGL and accumulate more fat than control cells, while knock down of Egr1 in 4E-BP1/2-null MEFs increases ATGL expression and decreases fat storage. PMID- 25814663 TI - Ethylene Regulates Levels of Ethylene Receptor/CTR1 Signaling Complexes in Arabidopsis thaliana. AB - The plant hormone ethylene is perceived by a five-member family of receptors in Arabidopsis thaliana. The receptors function in conjunction with the Raf-like kinase CTR1 to negatively regulate ethylene signal transduction. CTR1 interacts with multiple members of the receptor family based on co-purification analysis, interacting more strongly with receptors containing a receiver domain. Levels of membrane-associated CTR1 vary in response to ethylene, doing so in a post transcriptional manner that correlates with ethylene-mediated changes in levels of the ethylene receptors ERS1, ERS2, EIN4, and ETR2. Interactions between CTR1 and the receptor ETR1 protect ETR1 from ethylene-induced turnover. Kinetic and dose-response analyses support a model in which two opposing factors control levels of the ethylene receptor/CTR1 complexes. Ethylene stimulates the production of new complexes largely through transcriptional induction of the receptors. However, ethylene also induces turnover of receptors, such that levels of ethylene receptor/CTR1 complexes decrease at higher ethylene concentrations. Implications of this model for ethylene signaling are discussed. PMID- 25814664 TI - Glycogen Synthase Kinase-3beta (GSK-3beta) Inhibition Enhances Dendritic Cell based Cancer Vaccine Potency via Suppression of Interferon-gamma-induced Indoleamine 2,3-Dioxygenase Expression. AB - Indoleamine 2,3-dioxygenase (IDO) functions as a crucial mediator of tumor mediated immune tolerance by causing T-cell suppression via tryptophan starvation in a tumor environment. Glycogen synthase kinase-3beta (GSK-3beta) is also involved in immune and anti-tumor responses. However, the relativity of these proteins has not been as well defined. Here, we found that GSK-3beta-dependent IDO expression in the dendritic cell (DC) plays a role in anti-tumor activity via the regulation of CD8(+) T-cell polarization and cytotoxic T lymphocyte activity. By the inhibition of GSK-3beta, attenuated IDO expression and impaired JAK1/2 Stat signaling crucial for IDO expression were observed. Protein kinase Cdelta (PKCdelta) activity and the interaction between JAK1/2 and Stat3, which are important for IDO expression, were also reduced by GSK-3beta inhibition. CD8(+) T cell proliferation mediated by OVA-pulsed DC was blocked by interferon (IFN) gamma-induced IDO expression via GSK-3beta activity. Specific cytotoxic T lymphocyte activity mediated by OVA-pulsed DC against OVA-expressing EG7 thymoma cells but not OVA-nonexpressing EL4 thymoma cells was also attenuated by the expressed IDO via IFN-gamma-induced activation of GSK-3beta. Furthermore, tumor growth that was suppressed with OVA-pulsed DC vaccination was restored by IDO expressing DC via IFN-gamma-induced activation of GSK-3beta in an OVA-expressing murine EG7 thymoma model. Taken together, DC-based immune response mediated by interferon-gamma-induced IDO expression via GSK-3beta activity not only regulates CD8(+) T-cell proliferation and cytotoxic T lymphocyte activity but also modulates OVA-pulsed DC vaccination against EG7 thymoma. PMID- 25814665 TI - Identification of Equine Lactadherin-derived Peptides That Inhibit Rotavirus Infection via Integrin Receptor Competition. AB - Human rotavirus is the leading cause of severe gastroenteritis in infants and children under the age of 5 years in both developed and developing countries. Human lactadherin, a milk fat globule membrane glycoprotein, inhibits human rotavirus infection in vitro, whereas bovine lactadherin is not active. Moreover, it protects breastfed infants against symptomatic rotavirus infections. To explore the potential antiviral activity of lactadherin sourced by equines, we undertook a proteomic analysis of milk fat globule membrane proteins from donkey milk and elucidated its amino acid sequence. Alignment of the human, bovine, and donkey lactadherin sequences revealed the presence of an Asp-Gly-Glu (DGE) alpha2beta1 integrin-binding motif in the N-terminal domain of donkey sequence only. Because integrin alpha2beta1 plays a critical role during early steps of rotavirus host cell adhesion, we tested a minilibrary of donkey lactadherin derived peptides containing DGE sequence for anti-rotavirus activity. A 20-amino acid peptide containing both DGE and RGD motifs (named pDGE-RGD) showed the greatest activity, and its mechanism of antiviral action was characterized; pDGE RGD binds to integrin alpha2beta1 by means of the DGE motif and inhibits rotavirus attachment to the cell surface. These findings suggest the potential anti-rotavirus activity of equine lactadherin and support the feasibility of developing an anti-rotavirus peptide that acts by hindering virus-receptor binding. PMID- 25814666 TI - A motif from Lys216 to Lys222 in human BUB3 protein is a nuclear localization signal and critical for BUB3 function in mitotic checkpoint. AB - Human BUB3 is a key mitotic checkpoint factor that recognizes centromeric components and recruits other mitotic checkpoint molecules to the unattached kinetochore. The key amino acid residues responsible for its localization are not yet defined. In this study, we identified a motif from Lys(216) to Lys(222) in BUB3 as its nuclear localization signal. A BUB3 mutant with deletion of this motif (Del216-222) was found to localize to both the cytoplasm and the nucleus, distinct from the exclusively nuclear distribution of wild-type BUB3. Further analysis revealed that residues Glu(213), Lys(216), Lys(217), Lys(218), Tyr(219), and Phe(221), but not Lys(222), contribute to nuclear localization. Interestingly, the nuclear localization signal was also critical for the kinetochore localization of BUB3. The deletion mutant Del216-222 and a subtle mutant with four residue changes in this region (E213Q/K216E/K217E/K218E (QE)) did not localize to the kinetochore efficiently or mediate mitotic checkpoint arrest. Protein interaction data suggested that the QE mutant was able to interact with BUB1, MAD2, and BubR1 but that its association with the centromeric components CENP-A and KNL1 was impaired. A motif from Leu(61) to Leu(65) in CENP A was found to be involved in the association of BUB3 and CENP-A in cells; however, further assays suggested that CENP-A does not physically interact with BUB3 and does not affect BUB3 localization. Our findings help to dissect the mechanisms of BUB3 in mitotic checkpoint signaling. PMID- 25814667 TI - The roles of family B and D DNA polymerases in Thermococcus species 9 degrees N Okazaki fragment maturation. AB - During replication, Okazaki fragment maturation is a fundamental process that joins discontinuously synthesized DNA fragments into a contiguous lagging strand. Efficient maturation prevents repeat sequence expansions, small duplications, and generation of double-stranded DNA breaks. To address the components required for the process in Thermococcus, Okazaki fragment maturation was reconstituted in vitro using purified proteins from Thermococcus species 9 degrees N or cell extracts. A dual color fluorescence assay was developed to monitor reaction substrates, intermediates, and products. DNA polymerase D (polD) was proposed to function as the replicative polymerase in Thermococcus replicating both the leading and the lagging strands. It is shown here, however, that it stops before the previous Okazaki fragments, failing to rapidly process them. Instead, Family B DNA polymerase (polB) was observed to rapidly fill the gaps left by polD and displaces the downstream Okazaki fragment to create a flap structure. This flap structure was cleaved by flap endonuclease 1 (Fen1) and the resultant nick was ligated by DNA ligase to form a mature lagging strand. The similarities to both bacterial and eukaryotic systems and evolutionary implications of archaeal Okazaki fragment maturation are discussed. PMID- 25814668 TI - MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium induced Cell Death. AB - Parkinson disease is associated with decreased activity of the mitochondrial electron transport chain. This defect can be recapitulated in vitro by challenging dopaminergic cells with 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that inhibits complex I of electron transport chain. Consequently, oxidative phosphorylation is blocked, and cells become dependent on glycolysis for ATP production. Therefore, increasing the rate of glycolysis might help cells to produce more ATP to meet their energy demands. In the present study, we show that microRNA-7, a non-coding RNA that protects dopaminergic neuronal cells against MPP(+)-induced cell death, promotes glycolysis in dopaminergic SH-SY5Y and differentiated human neural progenitor ReNcell VM cells, as evidenced by increased ATP production, glucose consumption, and lactic acid production. Through a series of experiments, we demonstrate that targeted repression of RelA by microRNA-7, as well as subsequent increase in the neuronal glucose transporter 3 (Glut3), underlies this glycolysis-promoting effect. Consistently, silencing Glut3 expression diminishes the protective effect of microRNA-7 against MPP(+). Further, microRNA-7 fails to prevent MPP(+)-induced cell death when SH-SY5Y cells are cultured in a low glucose medium, as well as when differentiated ReNcell VM cells or primary mouse neurons are treated with the hexokinase inhibitor, 2-deoxy d-glucose, indicating that a functional glycolytic pathway is required for this protective effect. In conclusion, microRNA-7, by down-regulating RelA, augments Glut3 expression, promotes glycolysis, and subsequently prevents MPP(+)-induced cell death. This protective effect of microRNA-7 could be exploited to correct the defects in oxidative phosphorylation in Parkinson disease. PMID- 25814669 TI - Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity. AB - Alzheimer disease (AD) is characterized neuropathologically by synaptic disruption, neuronal loss, and deposition of amyloid beta (Abeta) protein in brain structures that are critical for memory and cognition. There is increasing appreciation, however, that astrocytes, which are the major non-neuronal glial cells, may play an important role in AD pathogenesis. Unlike neurons, astrocytes are resistant to Abeta cytotoxicity, which may, in part, be related to their greater reliance on glycolytic metabolism. Here we show that, in cultures of human fetal astrocytes, pharmacological inhibition or molecular down-regulation of a main enzymatic regulator of glycolysis, 6-phosphofructo-2-kinase/fructose 2,6-biphosphatase (PFKFB3), results in increased accumulation of Abeta within and around astrocytes and greater vulnerability of these cells to Abeta toxicity. We further investigated age-dependent changes in PFKFB3 and astrocytes in AD transgenic mice (TgCRND8) that overexpress human Abeta. Using a combination of Western blotting and immunohistochemistry, we identified an increase in glial fibrillary acidic protein expression in astrocytes that paralleled the escalation of the Abeta plaque burden in TgCRND8 mice in an age-dependent manner. Furthermore, PFKFB3 expression also demonstrated an increase in these mice, although at a later age (9 months) than GFAP and Abeta. Immunohistochemical staining showed significant reactive astrogliosis surrounding Abeta plaques with increased PFKFB3 activity in 12-month-old TgCRND8 mice, an age when AD pathology and behavioral deficits are fully manifested. These studies shed light on the unique bioenergetic mechanisms within astrocytes that may contribute to the development of AD pathology. PMID- 25814670 TI - Low pH-driven folding of WW45-SARAH domain leads to stabilization of the WW45 Mst2 complex. AB - The scaffolding protein Salvador (Sav) plays a key role in the Hippo (Hpo) signalling pathway, which controls tissue growth by inhibiting cell proliferation and promoting apoptosis. Dysregulation of the Hippo pathway contributes to cancer development. Since the identification of the first Sav gene in 2002, very little is known regarding the molecular basis of Sav-SARAH mediating interactions due to its insolubility. In this study, refolding of the first Sav (known as WW45)-SARAH provided insight into the biochemical and biophysical properties, indicating that WW45-SARAH exhibits properties of a disordered protein, when the domain was refolded at a neutral pH. Interestingly, WW45-SARAH shows folded and rigid conformations relative to the decrease in pH. Further, diffracting crystals were obtained from protein refolded under acidic pH, suggesting that the refolded WW45 protein at low pH has a homogeneous and stable conformation. A comparative analysis of molecular properties found that the acidic-stable fold of WW45-SARAH enhances a heterotypic interaction with Mst2-SARAH. In addition, using an Mst2 mutation that disrupts homotypic dimerization, we showed that the monomeric Mst2 SARAH domain could form a stable complex of 1:1 stoichiometric ratio with WW45 refolded under acidic pH. PMID- 25814671 TI - Targeting Abl kinases to regulate vascular leak during sepsis and acute respiratory distress syndrome. AB - The vascular endothelium separates circulating fluid and inflammatory cells from the surrounding tissues. Vascular leak occurs in response to wide-spread inflammatory processes, such as sepsis and acute respiratory distress syndrome, because of the formation of gaps between endothelial cells. Although these disorders are leading causes of mortality in the intensive care unit, no medical therapies exist to restore endothelial cell barrier function. Recent evidence highlights a key role for the Abl family of nonreceptor tyrosine kinases in regulating vascular barrier integrity. These kinases have well-described roles in cancer progression and neuronal morphogenesis, but their functions in the vasculature have remained enigmatic until recently. The Abl family kinases, c-Abl (Abl1) and Abl related gene (Arg, Abl2), phosphorylate several cytoskeletal effectors that mediate vascular permeability, including nonmuscle myosin light chain kinase, cortactin, vinculin, and beta-catenin. They also regulate cell-cell and cell-matrix junction dynamics, and the formation of actin-based cellular protrusions in multiple cell types. In addition, both c-Abl and Arg are activated by hyperoxia and contribute to oxidant-induced endothelial cell injury. These numerous roles of Abl kinases in endothelial cells and the current clinical usage of imatinib and other Abl kinase inhibitors have spurred recent interest in repurposing these drugs for the treatment of vascular barrier dysfunction. This review will describe the structure and function of Abl kinases with an emphasis on their roles in mediating vascular barrier integrity. We will also provide a critical evaluation of the potential for exploiting Abl kinase inhibition as a novel therapy for inflammatory vascular leak syndromes. PMID- 25814672 TI - Hic-5 Mediates TGFbeta-Induced Adhesion in Vascular Smooth Muscle Cells by a Nox4 Dependent Mechanism. AB - OBJECTIVE: Focal adhesions (FAs) link the cytoskeleton to the extracellular matrix and as such play important roles in growth, migration, and contractile properties of vascular smooth muscle cells. Recently, it has been shown that downregulation of Nox4, a transforming growth factor (TGF) beta-inducible, hydrogen peroxide (H2O2)-producing enzyme, affects the number of FAs. However, the effectors downstream of Nox4 that mediate FA regulation are unknown. The FA resident protein H2O2-inducible clone (Hic)-5 is H2O2 and TGFbeta inducible, and a binding partner of the heat shock protein (Hsp) 27. The objective of this study was to elucidate the mechanism, by which Hic-5 and Hsp27 participate in TGFbeta induced, Nox4-mediated vascular smooth muscle cell adhesion and migration. APPROACH AND RESULTS: Through a combination of molecular biology and biochemistry techniques, we found that TGFbeta, by a Nox4-dependent mechanism, induces the expression and interaction of Hic-5 and Hsp27, which is essential for Hic-5 localization to FAs. Importantly, we found that Hic-5 expression is required for the TGFbeta-mediated increase in FA number, adhesive forces and migration. Mechanistically, Nox4 downregulation impedes Smad (small body size and mothers against decapentaplegic) signaling by TGFbeta, and Hsp27 and Hic-5 upregulation by TGFbeta is blocked in small body size and mothers against decapentaplegic 4 deficient cells. CONCLUSIONS: Hic-5 and Hsp27 are effectors of Nox4 required for TGFbeta-stimulated FA formation, adhesion strength and migration in vascular smooth muscle cell. PMID- 25814673 TI - Histone Methyltransferase SET1 Mediates Angiotensin II-Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice. AB - OBJECTIVE: Endothelin-1 is a potent vasoconstrictor derived from vascular endothelium. Elevated endothelin-1 levels are observed in a host of cardiovascular pathologies including cardiomyopathy. The epigenetic mechanism responsible for endothelin-1 induction in these pathological processes remains elusive. APPROACH AND RESULTS: We report here that induction of endothelin-1 expression in endothelial cells by angiotensin II (Ang II) was accompanied by the accumulation of histone H3K4 trimethylation, a preeminent histone modification for transcriptional activation, on the endothelin-1 promoter. In the meantime, Ang II stimulated the expression and the occupancy of Suv, Ez, and Trithorax domain 1 (SET1), a mammalian histone H3K4 trimethyltransferase, on the endothelin 1 promoter, both in vitro and in vivo. SET1 was recruited to the endothelin-1 promoter by activating protein 1 (c-Jun/c-Fos) and synergized with activating protein 1 to activate endothelin-1 transcription in response to Ang II treatment. Knockdown of SET1 in endothelial cells blocked Ang II-induced endothelin-1 synthesis and abrogated hypertrophy of cultured cardiomyocyte. Finally, endothelial-specific depletion of SET1 in mice attenuated Ang II-induced pathological hypertrophy and cardiac fibrosis. CONCLUSIONS: Our data suggest that SET1 epigenetically activates endothelin-1 transcription in endothelial cells, thereby contributing to Ang II-induced cardiac hypertrophy. As such, screening of small-molecule compound that inhibits SET1 activity will likely offer a new therapeutic solution to the treatment of cardiomyopathy. PMID- 25814674 TI - Impairment of Wound Healing in Patients With Type 2 Diabetes Mellitus Influences Circulating MicroRNA Patterns via Inflammatory Cytokines. AB - OBJECTIVE: MicroRNAs (miRNA/miR) are stably present in body fluids and are increasingly explored as disease biomarkers. Here, we investigated influence of impaired wound healing on the plasma miRNA signature and their functional importance in patients with type 2 diabetes mellitus. APPROACH AND RESULTS: miRNA array profiling identified 41 miRNAs significantly deregulated in diabetic controls when compared with patients with diabetes mellitus-associated peripheral arterial disease and chronic wounds. Quantitative real-time polymerase chain reaction validation confirmed decrease in circulating miR-191 and miR-200b levels in type 2 diabetic versus healthy controls. This was reverted in diabetic subjects with associated peripheral arterial disease and chronic wounds, who also exhibited higher circulating C-reactive protein and proinflammatory cytokine levels compared with diabetic controls. miR-191 and miR-200b were significantly correlated with C-reactive protein or cytokine levels in patients with diabetes mellitus. Indeed, proinflammatory stress increased endothelial- or platelet derived secretion of miR-191 or miR-200b. In addition, dermal cells took up endothelial-derived miR-191 leading to downregulation of the miR-191 target zonula occludens-1. Altered miR-191 expression influenced angiogenesis and migratory capacities of diabetic dermal endothelial cells or fibroblasts, respectively, partly via its target zonula occludens-1. CONCLUSIONS: This study reports that (1) inflammation underlying nonhealing wounds in patients with type 2 diabetes mellitus influences plasma miRNA concentrations and (2) miR-191 modulates cellular migration and angiogenesis via paracrine regulation of zonula occludens-1 to delay the tissue repair process. PMID- 25814676 TI - PDE1C negatively regulates growth factor receptor degradation and promotes VSMC proliferation. PMID- 25814675 TI - Endothelial uncoupling protein 2 regulates mitophagy and pulmonary hypertension during intermittent hypoxia. AB - OBJECTIVES: Pulmonary hypertension (PH) is a process of lung vascular remodeling, which can lead to right heart dysfunction and significant morbidity. The underlying mechanisms leading to PH are not well understood, and therapies are limited. Using intermittent hypoxia (IH) as a model of oxidant-induced PH, we identified an important role for endothelial cell mitophagy via mitochondrial uncoupling protein 2 (Ucp2) in the development of IH-induced PH. APPROACH AND RESULTS: Ucp2 endothelial knockout (VE-KO) and Ucp2 Flox (Flox) mice were subjected to 5 weeks of IH. Ucp2 VE-KO mice exhibited higher right ventricular systolic pressure and worse right heart hypertrophy, as measured by increased right ventricle weight/left ventricle plus septal weight (RV/LV+S) ratio, at baseline and after IH. These changes were accompanied by increased mitophagy. Primary mouse lung endothelial cells transfected with Ucp2 siRNA and subjected to cyclic exposures to CoCl2 (chemical hypoxia) showed increased mitophagy, as measured by PTEN-induced putative kinase 1 and LC3BII/I ratios, decreased mitochondrial biogenesis, and increased apoptosis. Similar results were obtained in primary lung endothelial cells isolated from VE-KO mice. Moreover, silencing PTEN-induced putative kinase 1 in the endothelium of Ucp2 knockout mice, using endothelial-targeted lentiviral silencing RNA in vivo, prevented IH-induced PH. Human pulmonary artery endothelial cells from people with PH demonstrated changes similar to Ucp2-silenced mouse lung endothelial cells. CONCLUSIONS: The loss of endothelial Ucp2 leads to excessive PTEN-induced putative kinase 1-induced mitophagy, inadequate mitochondrial biosynthesis, and increased apoptosis in endothelium. An endothelial Ucp2-PTEN-induced putative kinase 1 axis may be effective therapeutic targets in PH. PMID- 25814677 TI - Small HDL promotes cholesterol efflux by the ABCA1 pathway in macrophages: implications for therapies targeted to HDL. PMID- 25814678 TI - Long noncoding RNAs in diabetic retinopathy. PMID- 25814679 TI - Thrombi and neutrophils. PMID- 25814680 TI - Conserved microRNA program as key to mammalian cardiac regeneration: insights from zebrafish. PMID- 25814681 TI - Cholesterol homeostasis regulation by miR-223: basic science mechanisms and translational implications. PMID- 25814682 TI - Harnessing the heart of big data. PMID- 25814683 TI - "String theory" of c-kit(pos) cardiac cells: a new paradigm regarding the nature of these cells that may reconcile apparently discrepant results. AB - Although numerous preclinical investigations have consistently demonstrated salubrious effects of c-kit(pos) cardiac cells administered after myocardial infarction, the mechanism of action remains highly controversial. We and others have found little or no evidence that these cells differentiate into mature functional cardiomyocytes, suggesting paracrine effects. In this review, we propose a new paradigm predicated on a comprehensive analysis of the literature, including studies of cardiac development; we have (facetiously) dubbed this conceptual construct "string theory" of c-kit(pos) cardiac cells because it reconciles multifarious and sometimes apparently discrepant results. There is strong evidence that, during development, the c-kit receptor is expressed in different pools of cardiac progenitors (some capable of robust cardiomyogenesis and others with little or no contribution to myocytes). Accordingly, c-kit positivity, in itself, does not define the embryonic origins, lineage capabilities, or differentiation capacities of specific cardiac progenitors. C kit(pos) cells derived from the first heart field exhibit cardiomyogenic potential during development, but these cells are likely depleted shortly before or after birth. The residual c-kit(pos) cells found in the adult heart are probably of proepicardial origin, possess a mesenchymal phenotype (resembling bone marrow mesenchymal stem/stromal cells), and are capable of contributing significantly only to nonmyocytic lineages (fibroblasts, smooth muscle cells, and endothelial cells). If these 2 populations (first heart field and proepicardium) express different levels of c-kit, the cardiomyogenic potential of first heart field progenitors might be reconciled with recent results of c-kit(pos) cell lineage tracing studies. The concept that c-kit expression in the adult heart identifies epicardium-derived, noncardiomyogenic precursors with a mesenchymal phenotype helps to explain the beneficial effects of c-kit(pos) cell administration to ischemically damaged hearts despite the observed paucity of cardiomyogenic differentiation of these cells. PMID- 25814688 TI - Letter by McLean and Oudit regarding article, "myostatin regulates energy homeostasis in the heart and prevents heart failure". PMID- 25814687 TI - Getting to the heart of the matter: new insights into cardiac fibrosis. AB - Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of alpha-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-beta, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis. PMID- 25814684 TI - Endothelial cell metabolism in normal and diseased vasculature. AB - Higher organisms rely on a closed cardiovascular circulatory system with blood vessels supplying vital nutrients and oxygen to distant tissues. Not surprisingly, vascular pathologies rank among the most life-threatening diseases. At the crux of most of these vascular pathologies are (dysfunctional) endothelial cells (ECs), the cells lining the blood vessel lumen. ECs display the remarkable capability to switch rapidly from a quiescent state to a highly migratory and proliferative state during vessel sprouting. This angiogenic switch has long been considered to be dictated by angiogenic growth factors (eg, vascular endothelial growth factor) and other signals (eg, Notch) alone, but recent findings show that it is also driven by a metabolic switch in ECs. Furthermore, these changes in metabolism may even override signals inducing vessel sprouting. Here, we review how EC metabolism differs between the normal and dysfunctional/diseased vasculature and how it relates to or affects the metabolism of other cell types contributing to the pathology. We focus on the biology of ECs in tumor blood vessel and diabetic ECs in atherosclerosis as examples of the role of endothelial metabolism in key pathological processes. Finally, current as well as unexplored EC metabolism-centric therapeutic avenues are discussed. PMID- 25814690 TI - Correction. PMID- 25814685 TI - Readers, writers, and erasers: chromatin as the whiteboard of heart disease. AB - Dynamic packaging of DNA into strings of nucleosomes is a major mechanism whereby eukaryotic cells regulate gene expression. Intricate control of nucleosomal structure and assembly governs access of RNA polymerase II to DNA and consequent RNA synthesis. As part of this, post-translational modifications of histone proteins are central to the regulation of chromatin structure, playing vital roles in regulating the activation and repression of gene transcription. In the heart, dynamic homeostasis of histone modification-driven by the actions of modifiers and recruitment of downstream effectors-is a fundamental regulator of the transcriptional reprogramming that occurs in the setting of disease-related stress. Here, we examine the growing evidence for histone modification as a key mechanism governing pathological growth and remodeling of the myocardium. PMID- 25814689 TI - Response to letter regarding "myostatin regulates energy homeostasis in the heart and prevents heart failure". PMID- 25814686 TI - Innate immunity and the failing heart: the cytokine hypothesis revisited. AB - Elevated levels of inflammatory mediators have been identified in patients with heart failure, including heart failure with reduced and preserved ejection fraction, as well as acute decompensated heart failure. Moreover, experimental studies have shown repeatedly that activation of inflammation in the heart provokes left ventricular remodeling and left ventricular dysfunction. Nonetheless, phase III clinical trials that have attempted to antagonize inflammatory mediators have been negative with respect to the primary end points of the trials, and in some patients, resulted in worsening heart failure or death. The following review will discuss how recent developments in the field of innate immunity have advanced our understanding of the role of inflammation in the pathogenesis of heart failure and will discuss the negative outcomes of the existing clinical trials in light of this new information. PMID- 25814691 TI - Correction. PMID- 25814693 TI - How to avoid haste and waste in occupational, environmental and public health research. PMID- 25814692 TI - Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain. AB - RATIONALE: Collagen- and calcium-binding EGF domain-containing protein 1 (CCBE1) is essential for lymphangiogenesis in vertebrates and has been associated with Hennekam syndrome. Recently, CCBE1 has emerged as a crucial regulator of vascular endothelial growth factor-C (VEGFC) signaling. OBJECTIVE: CCBE1 is a secreted protein characterized by 2 EGF domains and 2 collagen repeats. The functional role of the different CCBE1 protein domains is completely unknown. Here, we analyzed the functional role of the different CCBE1 domains in vivo and in vitro. METHODS AND RESULTS: We analyzed the functionality of several CCBE1 deletion mutants by generating knock-in mice expressing these mutants, by analyzing their ability to enhance Vegfc signaling in vivo in zebrafish, and by testing their ability to induce VEGFC processing in vitro. We found that deleting the collagen domains of CCBE1 has a much stronger effect on CCBE1 activity than deleting the EGF domains. First, although CCBE1DeltaCollagen mice fully phenocopy CCBE1 knock out mice, CCBE1DeltaEGF knock-in embryos still form rudimentary lymphatics. Second, Ccbe1DeltaEGF, but not Ccbe1DeltaCollagen, could partially substitute for Ccbe1 to enhance Vegfc signaling in zebrafish. Third, CCBE1DeltaEGF, similarly to CCBE1, but not CCBE1DeltaCollagen could activate VEGFC processing in vitro. Furthermore, a Hennekam syndrome mutation within the collagen domain has a stronger effect than a Hennekam syndrome mutation within the EGF domain. CONCLUSIONS: We propose that the collagen domains of CCBE1 are crucial for the activation of VEGFC in vitro and in vivo. The EGF domains of CCBE1 are dispensable for regulation of VEGFC processing in vitro, however, they are necessary for full lymphangiogenic activity of CCBE1 in vivo. PMID- 25814694 TI - Improving the evidence base on public health assets--the way ahead: a proposed research agenda. PMID- 25814695 TI - A longitudinal study of hepatitis C virus testing and infection status notification on behaviour change in people who inject drugs. AB - BACKGROUND: Hepatitis C virus (HCV) testing and counselling have the potential to impact individual behaviour and transmission dynamics at the population level. Evidence of the impact of an HCV-positive status notification on injection risk reduction is limited. The objective of our study was to (1) assess drug and alcohol use and injection risk behaviours following notification; (2) to compare behaviour change in people who inject drugs (PWID) who received a positive test result and those who remained negative; and (3) to assess the effect of age on risk behaviour. METHODS: Data from the International Collaboration of Incident HIV and HCV Infection in Injecting Cohorts (InC3 Study) were analysed. Participants who were initially HCV seronegative were followed prospectively with periodic HCV blood testing and post-test disclosure and interview-administered questionnaires assessing drug use and injection behaviours. Multivariable generalised estimating equations were used to assess behavioural changes over time. RESULTS: Notification of an HCV-positive test was independently associated with a small increase in alcohol use relative to notification of a negative test. No significant differences in postnotification injection drug use, receptive sharing of ancillary injecting equipment and syringe borrowing postnotification were observed between diagnosis groups. Younger PWID receiving a positive HCV test notification demonstrated a significant increase in subsequent alcohol use compared with younger HCV negative. CONCLUSIONS: The proportion of PWID reporting alcohol use increased among those receiving an HCV-positive notification, increased the frequency of alcohol use postnotification, while no reduction in injection drug use behaviours was observed between notification groups. These findings underscore the need to develop novel communication strategies during post-test notification to improve their impact on subsequent alcohol use and risk behaviours. PMID- 25814696 TI - High-Throughput Analysis and Automation for Glycomics Studies. AB - This review covers advances in analytical technologies for high-throughput (HTP) glycomics. Our focus is on structural studies of glycoprotein glycosylation to support biopharmaceutical realization and the discovery of glycan biomarkers for human disease. For biopharmaceuticals, there is increasing use of glycomics in Quality by Design studies to help optimize glycan profiles of drugs with a view to improving their clinical performance. Glycomics is also used in comparability studies to ensure consistency of glycosylation both throughout product development and between biosimilars and innovator drugs. In clinical studies there is as well an expanding interest in the use of glycomics-for example in Genome Wide Association Studies-to follow changes in glycosylation patterns of biological tissues and fluids with the progress of certain diseases. These include cancers, neurodegenerative disorders and inflammatory conditions. Despite rising activity in this field, there are significant challenges in performing large scale glycomics studies. The requirement is accurate identification and quantitation of individual glycan structures. However, glycoconjugate samples are often very complex and heterogeneous and contain many diverse branched glycan structures. In this article we cover HTP sample preparation and derivatization methods, sample purification, robotization, optimized glycan profiling by UHPLC, MS and multiplexed CE, as well as hyphenated techniques and automated data analysis tools. Throughout, we summarize the advantages and challenges with each of these technologies. The issues considered include reliability of the methods for glycan identification and quantitation, sample throughput, labor intensity, and affordability for large sample numbers. PMID- 25814697 TI - Male genital lichen sclerosus. AB - Male genital lichen sclerosus (MGLSc) is a chronic inflammatory skin disease responsible for male sexual dyspareunia and urological morbidity. An afeared complication is squamous cell carcinoma (SCC) of the penis. The precise etiopathogenesis of MGLSc remains controversial although genetic, autoimmune and infective (such as human papillomavirus (HPV) hepatitis C (HCV), Epstein-Barr virus (EBV) and Borrelia) factors have been implicated: Consideration of all the evidence suggests that chronic exposure of susceptible epithelium to urinary occlusion by the foreskin seems the most likely pathomechanism. The mainstay of treatment is topical ultrapotent corticosteroid therapy. Surgery is indicated for cases unresponsive to topical corticosteroid therapy, phimosis, meatal stenosis, urethral stricture, carcinoma in situ (CIS) and squamous cell carcinoma. PMID- 25814699 TI - Serendipity and its role in dermatology. AB - Serendipity is a pleasant surprise of finding a particularly useful information while not looking for it. Significant historic events occurring as a result of serendipity include the discovery of the law of buoyancy (Archimedes principle) by the Greek mathematician Archimedes, of the Americas by Christopher Columbus and of gravity by Sir Isaac Newton. The role of serendipity in science has been immensely beneficial to mankind. A host of important discoveries in medical science owe their origin to serendipity of which perhaps the most famous is the story of Sir Alexander Fleming and his discovery of Penicillin. In the field of dermatology, serendipity has been responsible for major developments in the therapy of psoriasis, hair disorders, aesthetic dermatology and dermatosurgery. Besides these many other therapeutic modalities in dermatology were born as a result of such happy accidents. PMID- 25814698 TI - Immunomodulators in warts: Unexplored or ineffective? AB - Cutaneous warts are known to be recurrent and often resistant to therapy. Resistant warts may reflect a localized or systemic cell mediated immune (CMI) deficiency to HPV. Many modalities of treatment are in use; most of the provider administered therapies are destructive and cause scarring, such as cryotherapy, chemical cauterisation, curettage, electrodessication and laser removal. Most patient-applied agents like podophyllotoxin have the risk of application-site reactions and recurrence. Thus immunotherapy is a promising modality which could lead to resolution of warts without any physical changes or scarring and in addition would augment the host response against the causative agent, thereby leading to complete resolution and decreased recurrences. Immunomodulators can be administered systemically, intralesionally or intradermally, and topically. A few agents have been tried and studied extensively such as cimetidine and interferons; others are new on the horizon, such as Echinacea, green tea catechins and quadrivalent HPV vaccine, and their efficacy is yet to be completely established. Though some like levamisole have shown no efficacy as monotherapy and are now used only in combination, other more recent agents require large and long term randomized placebo-controlled trials to clearly establish their efficacy or lack of it. In this review, we focus on the immunomodulators that have been used for the treatment of warts and the studies that have been conducted on them. PMID- 25814700 TI - Zinc-responsive acral hyperkeratotic dermatosis-A novel entity or a subset of some well-known dermatosis? AB - BACKGROUND: We are reporting a series of interesting cases, which presented to us with psoriasiform lesions distributed over the acral regions of the body. The cases are unusual because they were resistant to conventional treatment modalities like topical corticosteroids, tacrolimus and oral methotrexate but showed significant improvement on oral zinc therapy. MATERIALS AND METHODS: Ten patients with characteristic clinical features of distinctive hyperkeratotic plaque in the acral areas, who were resistant to treatment by different modalities including potent topical steroids and oral methotrexate, were included for detailed investigations. A proper history was taken and relevant laboratory investigations were done which included blood count, urine, liver function, renal function, hepatitis-C virus serology and serum zinc levels. Patients were followed up every 2 weeks. Histopathological examinations of the lesional tissue were done at baseline and after 6 weeks of therapy. Patients were given oral zinc daily and no other treatment during the 6 weeks course. RESULTS: All our patients were non-reactive to hepatitis-C. Of the ten patients only one patient (10%) showed low titer of serum zinc, another (10%) showed higher zinc level, while the rest of the patients had normal zinc level. Five of our patients had chronic renal failure, one had Grave's disease and the remaining had no associated systemic illness. Histopathology mostly showed hyperkeratosis, acanthosis, prominent granular layer, spongiosis and dermal infiltrate. After 6 weeks of follow up, all patients showed rapid and remarkable therapeutic response with zinc. CONCLUSIONS: We here report a series of patients, discernible because of their uniform clinical presentation of acral hypekeratotic plaques and in showing a noticeable response to zinc. Clinical, histopathological and laboratory investigations were done to rule out diseases of similar morphology including psoriasis, acral necrolytic erythema and lichen simplex chronicus. Authors understand that further studies with greater number cases and more detailed investigations are required to establish exact etio-pathogenesis and nomenclature of this distinct subset of patients. PMID- 25814701 TI - Quality of life and psychological morbidity in vitiligo patients: a study in a teaching hospital from north-East India. AB - BACKGROUND: Vitiligo is an acquired discoloration of skin and mucous membrane of great cosmetic importance affecting 1-4% of the world's population. It causes disfiguration in all races, more so in dark-skinned people because of strong contrast. Men, women, and children with vitiligo face severe psychological and social disadvantage. AIM: To assess the impact of the disease on the quality of life of patients suffering from vitiligo, also to ascertain any psychological morbidity like depression associated with the disease and to compare the results with that of healthy control group. MATERIALS AND METHODS: Dermatology Life Quality Index (DLQI) and Hamilton Depression Rating Scale (HAMD) are administered to 100 vitiligo patients presenting to the Dermatology OPD and 50 age- and sex matched healthy controls. Results were analyzed and compared with that of control group. Findings are also correlated in relation to demographic and clinical profile of the disease. Statistical analysis is made to see the significance. RESULTS: Vitiligo-affected patients had significantly elevated total DLQI scores (P < 0.001) compared to healthy controls. There is increase in parameters like itch, embarrassment, social and leisure activities in the patient cohort than the control group. Patients of vitiligo are also found to be more depressed (P < 0.001) than the controls. CONCLUSION: Quality of life (QOL) in patients affected with vitiligo declined more severely, and also there is increase in incidence of depression than in the control group. These changes are critical for the psychosocial life of the affected people. PMID- 25814702 TI - Glycolic Acid peels/azelaic Acid 20% cream combination and low potency triple combination lead to similar reduction in melasma severity in ethnic skin: results of a randomized controlled study. AB - BACKGROUND: Numerous therapeutic options have been tried in the management of melasma. AIMS AND OBJECTIVES: This prospective randomized study was planned to assess the efficacy of low potency triple combination (TC) cream (TC-hydroquinone 2%/tretinoin 0.05%/fluocinolone 0.01%) versus glycolic acid (GA) peels/azelaic acid (AA) 20% cream (GA/AA) combination in melasma. MATERIALS AND METHODS: Forty patients with melasma were recruited into this study and randomized into two groups. Group A consisting 20 patients received TC cream once a day for night time application for 3 months. Group B comprising of 20 patients received GA/AA 20% cream combination for 3 months. The disease severity was monitored with digital photography, melasma area and severity index (MASI) score, which was calculated at baseline, 6 weeks and 12 weeks, and visual analog scale (VAS) score, which was calculated at baseline and 12 weeks. RESULTS: Of 40 patients, 38 were completed the study. A significant reduction in MASI and VAS was recorded after 6 weeks and 12 weeks of treatment in both groups A and B (P = 0.001). However, there was no significant difference in the mean MASI scores between the two groups at baseline, 6 weeks and 12 weeks. Similarly, there was no difference in the mean VAS scores between the two groups at baseline and 12 weeks. Four patients in group A and 3 in group B experienced adverse effects such as irritation, dryness, and photosensitivity. CONCLUSION: Both low potency TC cream and GA/AA 20% cream combination are effective in treating melasma among Indian patients. PMID- 25814703 TI - Clinico-mycological study of dermatophyte toenail onychomycosis in new delhi, India. AB - INTRODUCTION: There is a constant need to define the epidemiological and mycological characteristics of onychomycosis (OM) for optimal management strategies. OBJECTIVES: To define the epidemiological and mycological characteristics of patients with dermatophyte toenail OM in a tertiary care hospital. MATERIALS AND METHODS: Hundred consecutive patients of KOH and culture positive dermatophyte toenail OM were subjected to detailed history, clinical examination and investigations. RESULTS: Maximum number of patients (40%) belonged to 31-45 years age group and there was a male preponderance (M:F = 6.7:1). The mean duration of disease was 54 months. Thirty-three patients had fingernail involvement in addition to the toenail OM and 37% had co-existent cutaneous dermatophyte infection. Discoloration was the most common symptom (98%). Ninety-four (94%) patients had distal lateral subungual onychomycosis (DSLO) while two had superficial onychomycosis (SO) and only one had proximal superficial onychomycosis (PSO). Trichophyton interdigitale was the most common etiological agent (61%) followed by Trichophyton rubrum and Trichophyton verrucosum. CONCLUSIONS: Toenail OM is more common in males. DSLO was the most common clinical variant and T. interdigitale the most common etiological fungus responsible for toenail OM in our region. The importance of early diagnosis and treatment is highlighted as long-standing toenail OM predisposes to fingernail onychomycosis and recurrent tinea pedis. PMID- 25814704 TI - Skin prick test in patients with chronic allergic skin disorders. AB - BACKGROUND: Chronic allergic skin disorders are the inflammatory and proliferative conditions in which both genetic and environmental factors play important roles. Chronic idiopathic urticaria (CIU) and atopic dermatitis (AD) are among the most common chronic allergic skin disorders. These can be provoked by various food and aeroallergens. Skin prick tests (SPTs) represent the cheapest and most effective method to diagnose type I hypersensitivity. Positive skin tests with a history suggestive of clinical sensitivity strongly incriminate the allergen as a contributor to the disease process. AIMS AND OBJECTIVES: To determine the incidence of positive SPT in patients with chronic allergic skin disorders and to identify the various allergens implicated in positive SPT. METHODS: Fifty patients of chronic allergic disorders were recruited in this study. They were evaluated by SPT with both food and aeroallergens. RESULTS: In our study, SPT positivity in patients of CIU was 63.41% and in AD was 77.78%. Out of the 41 patients of CIU, the most common allergen groups showing SPT positivity were dust and pollen, each comprising 26.83% patients. SPT reaction was positive with food items (21.6%), insects (17.07%), fungus (12.20%), and Dermatophagoides farinae, that is, house dust mite (HDM) (7.32%). The allergen which showed maximum positivity was grain dust wheat (19.51%). Among nine patients of AD, maximum SPT positivity was seen with Dermatophagoides farinae, pollen Amaranthus spinosus, grain dust wheat, and cotton mill dust; each comprising 22.22% of patients. CONCLUSION: Our study showed that a significant number of patients of CIU and AD showed sensitivity to dust, pollen, insects, Dermatophagoides farinae, and fungi on SPT. Thus, it is an important tool in the diagnosis of CIU and AD. PMID- 25814705 TI - Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient. AB - Facial angiofibromas are the most visible and unsightly of all the cutaneous manifestations of tuberous sclerosis (TSC). A 17-year-old female, a known case of TSC, presented for the treatment of cosmetically disfiguring facial angiofibromas. She was started on twice daily application of 0.1% sirolimus ointment prepared from crushed tablets of sirolimus compounded in white soft paraffin. After 3 months of use, there was visible decrease in the erythema and the size of the angiofibromas. In an attempt to accelerate the response, the concentration was further increased to 1% sirolimus which was used for a month, resulting in a decrease not only in the size and redness but also in the number of the angiofibromas. The patient did not experience any cutaneous or systemic complications related to therapy. Sirolimus belongs to a novel class of anticancer drugs known as mTOR (mammalian target of Rapamycin) inhibitors. Sirolimus has been used as a targeted therapy for the renal and neurological manifestations of TSC. Topical preparation of sirolimus is not commercially available till date and hence preparations from crushed tablets or oral solution of sirolimus have been used with beneficial effects in treatment of angiofibromas especially in younger patients with flatter lesions. Randomized controlled trials are necessary to enable us to confirm the efficacy, long-term safety, the optimal dosage and possibility of reappearance once the drug is withdrawn. This is possibly the first case report of the use of topical sirolimus in India. PMID- 25814706 TI - Novel uses of skin biopsy punches in dermatosurgery. AB - The skin punch or surgical punch is an instrument which is used almost exclusively by dermatologists. It is a circular hollow blade attached to a pencil like handle ranging in size from 0.5 to 10 mm. It is available as a disposable, reusable, and automated instrument. The punch can be used as a diagnostic, therapeutic, and cosmetic tool in dermatology. We have used punch as a diagnostic, therapeutic, and cosmetic tool in our dermatosurgery practice in our hospital. Various original research articles, text book publications, and review articles were studied and compiled. Techniques used by various authors and our own experiences with punch have been described. This article aims at providing the novel usefulness of skin biopsy punch in dermatology as the basic punch surgery is quick and easy to learn. Complications such as bleeding and infection are minimal. PMID- 25814707 TI - Cutaneous B cell lymphomas: Report of two interesting cases. AB - Cutaneous B cell lymphomas can arise primarily from the skin or may occur due to secondary spread from nodal lymphomas. Primary lymphomas are confined to the skin without systemic spread and they differ from secondary lymphomas in their clinical behavior, treatment and prognosis. Cutaneous lymphomas being relatively rare, lack of precise definition and understanding of their clinical behavior diseases leads to pitfalls in the diagnosis. We report two cases of cutaneous B cell lymphomas who presented with fever of unknown origin initially and later found to have skin lesions. Hence, skin can be a potential diagnostic clue in the evaluation of patients with fever of unknown origin. The distinctions between the primary and the secondary lymphomas become important in choosing the treatment and assessing the prognosis. PMID- 25814708 TI - Diffuse cutaneous mastocytosis with bullous lesions and pulmonary involvement: a rare case. AB - Mastocytosis is defined as a heterogeneous group of disorders characterized by an accumulation of mast cells in one or more organs, particularly in the skin, bone marrow, liver, spleen and lymph nodes. However here we describe an 11-month-old girl child presented with diffuse cutaneous mastocytosis with bullous lesion, having pulmonary involvement, which is very rare and there is no available case report from India. PMID- 25814709 TI - Multiple synchronous verrucous carcinomas of the scalp in the background of generalized verruca vulgaris. AB - Verrucous carcinoma (VC) is a clinicopathologic entity which is defined as a locally aggressive, clinically exophytic, slow-growing, well-differentiated, squamous cell carcinoma with negligible metastatic potential. The cutaneous form of VC is typically known to arise from the palmoplantar and the genitocrural areas. Involvement of the scalp is extremely rare. Multiple synchronous involvement of the scalp by VC along with associated generalized verruca vulgaris has possibly never been reported before. We present this unique report of VC in a 38-year-old male patient with emphasis on its atypical clinical presentation and the resultant challenges in management. Interestingly, the tumor cells of our patient were confirmed to be positive for human papillomavirus infection by polymerase chain reaction and by p16 immunohistochemistry. PMID- 25814710 TI - Dermatitis neglecta -- a dirty dermatosis: report of three cases. AB - Dermatitis neglecta is a condition that results from inadequate frictional cleansing leading to accumulation of corneocytes, sebum and sweat ultimately resulting in hyper-pigmented patch or verrucous plaque. Recognizing this condition avoids unnecessary, aggressive diagnostic and therapeutic procedures. Here we report three cases of dermatitis neglecta in whom the dermatitis developed as a result of intentional neglect of personal hygiene. PMID- 25814711 TI - A rare case of subungual melanoma. AB - A 51-year-old male presented with blackish discoloration of nails of 10 months duration. Examination revealed black dystrophic left thumb finger nail. Detailed examination showed a mass under the dystrophic nail. Hutchinson sign was positive. Histopathology revealed characteristic features of melanoma. A detailed evaluation revealed no features of local or distant metastasis. The entire lesion was then removed surgically along with disarticulation at the interphalangeal joint. Resection-free margin was confirmed. This case is being reported for the rare occurrence of subungual melanoma in the Indian population and also for presentation with a long history of lesion with no evidence of metastasis. PMID- 25814712 TI - Secondary Syphilid Developing Over Healed Lesions of Varicella: Wolf's Isotopic Response? AB - Isotopic response is a distinctive phenomenon in which a new skin disorder occurs at the site of another, unrelated, and already healed skin disease. Most of the cases documented in the literature were associated with herpes zoster as primary disease while the list of "second" diseases is quite long. We report here a hitherto unreported occurrence of isotopic response in which secondary syphilis occurred on the healed lesions of varicella. PMID- 25814713 TI - Psoriatic erythroderma and hypothalamus-pituitary axis suppression due to misuse of systemic steroid: two challenging cases. AB - Adding corticosteroid in homeopathic pills, self medication of steroid in the backdrop permanent cure in cases of psoriasis is not very uncommon in clinical practice in Indian subcontinent. First case a 52 year man, a known case of psoriasis vulgaris with psoriatic arthropathy of 15 years duration received multiple modalities of therapies without any satisfactory response. He was on self medication of tab prednisolone 10 mg daily with Cushingoid features. Second case a 22 year old boy, a known case of psoriasis from last 06 years was on Homeopathic treatment with Cushinoid features. Tapering of systemic steroid in first case and discontinuation of homeopathic drug in second case resulted in erythroderma and features of adrenal insufficiiency. Investigation revealed low morning cortisol and low cortisol following ACTH stimulation suggestive of HPA axis suppression. Planned withdrawal of steroid under the cover of short acting systemic steroid for short duration along with combination of immunosuppressants and supportive care gave an excellent result in both the cases. PMID- 25814714 TI - An Open Label Prospective Randomized Trial to Compare the Efficacy of Coal Tar salicylic Acid Ointment Versus Calcipotriol/Betamethasone Dipropionate Ointment in the Treatment of Limited Chronic Plaque Psoriasis. PMID- 25814715 TI - Authors' reply. PMID- 25814716 TI - Benign Lymphangiomatous Papules or Plaques after Radiotherapy is the Correct Terminology. PMID- 25814717 TI - Author's Reply. PMID- 25814718 TI - Amniotic band: a rare presentation. PMID- 25814719 TI - Hemilateral proteus syndrome: an unusual hamartomatous disorder with significant cerebellar tonsillar herniation. PMID- 25814720 TI - Autologous platelet rich plasma in pyoderma gangrenosum - two case reports. PMID- 25814721 TI - Multiple painless cutaneous nodules. PMID- 25814722 TI - Erratum: Remission of psoriasis and psoriatic arthritis during bevacizumab therapy for renal cell cancer: Erratum. PMID- 25814723 TI - Development of a guideline to approach plagiarism in Indian scenario: Retraction. AB - [This retracts the article on p. 473 in vol. 59, PMID: 25284853.]. PMID- 25814724 TI - Neonatal pustular dermatosis: an overview. AB - Neonatal pustular eruption is a group of disorders characterized by various forms of pustulosis seen in first 4 weeks of life. Its presentation is often similar with some subtle differences, which can be further established by few simple laboratory aids, to arrive at a definite diagnosis. Given their ubiquitous presentation, it is sometimes difficult to differentiate among self-limiting, noninfectious, pustular dermatosis such as erythema toxicum neonatorum, transient neonatal pustular melanosis, miliaria pustulosa, etc., and potentially life threatening infections such as herpes simplex virus and varicella zoster virus infections. This review article tries to address the chronological, clinical, morphological, and histological differences among the various pustular eruptions in a newborn, in order to make it easier for a practicing dermatologist to diagnose and treat these similar looking but different entities of pustulation with a clear demarcation between the physiological benign pustular rashes and the infectious pustular lesions. PMID- 25814725 TI - Bacterial contamination in cutaneous leishmaniasis: its effect on the lesions' healing course. AB - BACKGROUND: The colonization of aerobic and anaerobic microbial agents on cutaneous leishmaniasis (CL) lesions, especially acute erosive ulcerative ones, has been mentioned in previous studies showing controversial results on the healing course of lesions with the use of antibiotics. AIMS: The purpose of this study was to evaluate the prevalence of secondary bacterial infections in CL lesions and the effect of its elimination on the lesions' improvement rate. MATERIALS AND METHODS: This cross-sectional clinical trial was performed on 84 acute CL patients. The required skin samples were taken. Cultivation for bacteria was conducted. Patients with positive culture results were divided into two groups. Both groups received standard anti-leishmania treatment, whereas only one group was treated with cephalexin 40-50 mg/kg/day for 10 days. The improvement rate was evaluated in the following visits based on changes in the lesions' induration size. RESULTS: Among the 84 studied patients, 22.6% had a negative culture result whereas the result was positive in 77.4%. The most common pathogenic germs were Staphylococcus aureus (52.3%) and Staphylococcus epidermidis (9.5%); 34/5% of the positive lesions received antibiotic treatment. Finally, among the lesions with a 75-100% improvement rate, no significant difference was observed between the antibiotic-treated and -untreated groups (36.1% vs. 63.9%, respectively, P = 0.403). CONCLUSIONS: The most common pathogen was S. aureus and, as a primary outcome, the simultaneous treatment for microbial agents did not have any considerable effect on the improvement rate of CL lesions. PMID- 25814726 TI - G-231A and G+70C Polymorphisms of Endothelin Receptor Type-A Gene could Affect the Psoriasis Area and Severity Index Score and Endothelin 1 Levels. AB - BACKGROUND: The etiopathogenesis of psoriasis has not been clearly elucidated although the role of chronic inflammation, imbalance between pro- and anti inflammatory cytokines, and many immunological events have been established. Endothelin 1 (EDN1) and endothelin receptor type-A (EDNRA) are implicated in the inflammatory process. The relationships between EDN1 and EDNRA polymorphisms with several diseases have been found. AIMS AND OBJECTIVES: This study examined the possible association of EDN1 (G5665T and T-1370G) and EDNRA (G-231A and G + 70C) single nucleotide polymorphisms (SNPs) with the occurence of psoriasis, and evaluated the relationship between genotypes and clinical/laboratory manifestation of psoriasis. MATERIALS AND METHODS: We analyzed genotype and allele distributions of the above-mentioned polymorphisms in 151 patients with psoriasis and 152 healthy controls by real-time PCR combined with melting curve analysis. RESULTS: We did not find significant differences in the genotype and allele distributions of EDN1 T-1370G, EDNRA G-231A, and EDNRA G+70C polymorphisms between patients with psoriasis and healthy controls. Psoriasis area and severity index (PASI) score of EDNRA -231 polymorphic A allele carrying subjects (AA and AA + AG) was higher than that of wild homozygotes (P = 0.044 and P = 0.027, respectively). In addition, EDN1 levels in EDNRA+70 polymorphic C allele carriers (CC + CG) were elevated when compared with GG genotype; however, the difference was at borderline significance (P = 0.05). CONCLUSION: Although there were no associations between studied polymorphisms and psoriasis susceptibility, the PASI score and EDN1 levels seem to be affected by EDNRA G-231A and G + 70C polymorphisms. PMID- 25814727 TI - Gender differences in depression and anxiety among atopic dermatitis patients. AB - BACKGROUND: Dermatological patients invariably suffer one or the other psychological problems which may escalate to the extent of a mental disorder. One of the most common dermatological disorders is atopic dermatitis (AD), but the literature has limited data on gender differences for psychiatric morbidity in such patients. AIMS: To evaluate and compare gender differences in the prevalence of depression and anxiety in AD. MATERIALS AND METHODS: This cross-sectional study with consecutive sampling was done in an outpatient clinic of Dermatology at a Tertiary Care Center. AD subjects giving informed consent were evaluated on a brief semi-structured performa for collecting demographic and clinical information. Primary Care Evaluation of Mental Disorders (PRIME-MD) was used to assess the presence of psychiatric symptoms in these patients. Descriptive analysis was done for the socio-demographic profile and independent sample t test, Chi-square and Cramer's V test was carried out to find in-between group differences for males and females. RESULTS: A total of 81 patients were included in the final analysis (males = 36, females = 45) with no significant difference in mean age between male and female subjects (36.14 +/- 17.62 and 33.98 +/- 14.49 years, respectively; P = 0.54). When including moderate to severe grade of depression or anxiety, the current study found prevalence rates of 15% and 12% respectively. Females had significantly more anxiety and depression scores than males (P = 0.04 and P = 0.03 respectively). CONCLUSIONS: There is a female preponderance of depression and anxiety disorder in AD patients. PMID- 25814728 TI - Role of Interleukin-2 in Uremic Pruritus Among Attendants of AL-Zahraa Hospital Dialysis Unit. AB - BACKGROUND: Uremic pruritus (UP) is a very distressing symptom and remains one of the most frustrating and potentially disabling symptoms in patients with end stage renal disease (ESRD). Its etiopathogenesis remains unclear and complex. The aim of this study was to investigate the possible role of interleukin-2 (IL-2) in UP, and correlate its level with the severity of itching in ESRD patients. PATIENTS AND METHODS: This study was carried out on 60 patients on maintenance hemodialysis (HD), 30 patients with UP and 30 patients without UP, and 30 apparently healthy age- and sex-matched subjects as controls. Itch intensity was scored as mild, moderate, and severe using five-dimensional itch scale. Some relevant clinical parameters (age, sex, xerosis, presence of neuropathy, duration of dialysis, complete medical history, and history of pruritic skin diseases) and laboratory findings including creatinine, urea, calcium, phosphorus, parathyroid hormone, and serum levels of IL-2 were evaluated. RESULTS: In our study, we found a statistically significant difference in IL-2 level between patients and controls. However, there was no statistically significant difference in IL-2 levels between cases with pruritus and cases without pruritus. Also, there was a statistically significant relation between IL-2 level and duration of the disease. CONCLUSION: Further studies are needed to understand the contribution of IL-2 and possibly other cytokines in the pathogenesis of this distressing symptom in ESRD. PMID- 25814729 TI - Body-art practices among undergraduate medical university students in dar es salaam, Tanzania, 2014. AB - BACKGROUND: Body-art practices are increasing among adolescents and young adults. Although substantial data are available in developed countries, little has been documented about body-art practices in developing countries. OBJECTIVE: To determine the magnitude, types and reasons for practicing body-art practices among undergraduate medical University students in Dar es Salaam, Tanzania. MATERIALS AND METHODS: A cross-sectional descriptive study was conducteed among undergraduate University students in Dar es Salaam involving 536 respondents from two Universities. We used a self-administered questionnaire to collect data. Analyses were based on summary measures and bivariate analyses. RESULTS: While 7.5% of undergraduate students reported having tattoos, 20% reported having body puncturing or piercing. Body piercing is reported more among female university undergraduate students than their male counterparts. Reported main reasons for undergoing body-art include "a mark of beauty," 24%, "just wanted one," 18% and "a mark of femininity or masculinity," 17%. The majority (98%) of students were aware that unsafe body-art practices may lead to contracting HIV and more than half (52%) reported awareness of the risk of Hepatitis B infection. CONCLUSIONS: Despite high awareness of the potential risks involved in unsafe body arts that include tattoo and piercing, these practices are increasing among adolescents and young adults. There is need to have educational and counseling efforts so as to minimize associated health risks. PMID- 25814730 TI - Aquagenic keratoderma treated with tap water iontophoresis. AB - Aquagenic keratoderma (AK) is a rare acquired skin condition characterized by recurrent and transient white papules and plaques associated with a burning sensation, pain, pruritus and/or hyperhidrosis on the palms and more rarely, soles triggered by sweat or contact with water. Often AK cause significant discomfort, thus requiring an appropriate therapy. Topical aluminum-based products are the most commonly used medications, but they are not always effective. We report a case of AK unresponsive to topical 20% of aluminum chloride successfully treated with tap water iontophoresis. PMID- 25814731 TI - A tumor hidden beneath the nail plate: report of a rare case of onychomatricoma with three-dimensional histopathological analysis and immunohistochemical study. AB - Onychomatricoma is a tumor of the nail matrix which often presents with alterations in the nail plate while the tumor itself is concealed beneath the nail plate. It is a benign, biphasic fibroepithelial tumor which has to be differentiated from other subungual and periungual tumors. We report a rare case of onychomatricoma and describe a three-dimensional histopathological analysis and immunohistochemical patterns of onychomatricoma. PMID- 25814732 TI - Tumor-Infiltrating CD8+ Lymphocytes Effect on Clinical Outcome of Muco-Cutaneous Melanoma. AB - BACKGROUND: Recent data have changed our views of prognostic factors in cutaneous melanoma, while some newer methods have yielded better prognostic information. Tumor-infiltrating lymphocytes are believed to represent the immune reaction/response to melanoma cells which is often found in melanocytic cancer. AIM AND OBJECTIVE: We carried out an analysis, aiming to establish pooled estimates for clinical outcomes based on the presence of CD8+ T cell in melanocytic cancer. MATERIALS AND METHODS: We have included 42 patients with primary cutaneous melanocytic cancer without preoperative treatments in our study. We next analyzed the proliferative activity of CD8+ T cells that infiltrated in tumor cell nests. The intratumoral and adjacent to invasive margin of tumor CD+ T-cell infiltration were analyzed which could also reflect antitumor immunity. RESULTS: The total number of CD8+ cells especially adjacent to invasive margin of tumor was positively correlated with anatomical tumor thickness (P < .001) and not correlated with patient's age and sex. The stage of tumor which is related to vascular-neural invasion, regional lymph nodes involvement and tumor thickness shows positive correlation with CD8+ infiltration in tumor (P < .004, P < .005, P < .001), respectively. Acral melanoma shows more CD8 lymphocytes infiltration and also recurrence rate of tumor (P < .005). CONCLUSION: We believe that CD8+ T-cell infiltration in primary cutaneous melanocytic cancer represents the immune reaction/response to melanoma which could be an important new therapy for melanoma although more research is needed on this treatment modality. PMID- 25814733 TI - Fluconazole-induced acute generalized exanthematous pustulosis. AB - Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction and is usually caused by drugs. It is characterized by fever and acute, extensive occurrence of disseminated sterile pustules, accompanied by fever, malaise and peripheral blood leucocytosis. There have been several reports to date of AGEP following exposure to antifungals. In particular, terbinafine is included in the list of the agents conferring the highest risk of AGEP. The authors report the case of a 70-year-old male patient who developed AGEP shortly after commencing treatment with fluconazole, which has been reported in association with AGEP in a single case report. To our knowledge, this is the first reported case of AGEP associated with positive fluconazole patch test. PMID- 25814734 TI - Cost of care of atopic dermatitis in India. AB - BACKGROUND: Atopic dermatitis (AD) is a common dermatologic condition with a prevalence varying from 5% to 15%, and it has been rising over time. Several studies from developed countries have revealed the substantial economic burden of AD on health care budgets. There has been no research however on the cost of care of AD from India a country where health care is self-funded with no health insurance or social security provided by the government. AIM: The aim of our study was to assess prospectively the cost of care of AD in children in an outpatient hospital setting in India. METHODS: A total of 40 children with AD, <10 years of age, registered in the pediatric dermatology clinic at our institute were enrolled for the study. All patients were followed-up for 6 months. Demographic information, clinical profile, severity, and the extent of AD were recorded in predesigned performa. Caregivers were asked to fill up a cost assessment questionnaire specially designed for the study. It had a provision for measuring direct, indirect, and provider costs. RESULTS: Of the 40 patients, 37 completed the study. Mean total cost for AD was Rs. 6235.00 +/- 3514.00. Direct caregiver cost was Rs. 3022.00 +/- 1620.00 of which treatment cost constituted 77.2 +/- 11.1%. The total provider cost (cost of consultation, nursing/paramedical staff and infrastructure was Rs. 948.00, which was 15.2% of the total cost of care and the mean indirect cost calculated by adding loss of earnings of parents due to hospital visits was Rs. 2264.00 +/- 2392.00 (range: 0 13,332). The mean total cost depending on the severity of AD was Rs. 3579.00 +/- 948.00, Rs. 6806.00 +/- 3676.00 and Rs. 8991.00 +/- 3129.00 for mild, moderate and severe disease, respectively. CONCLUSIONS: AD causes a considerable drain on the financial resources of families in India since the treatment is mostly self funded. Cost of care of AD is high and comparable to those of chronic physical illness, such as diabetes mellitus, and this cost is higher in severely ill patients. This study is an attempt to highlight the cost of care of AD and the need for conducting more studies to sensitize the government and insurance agencies to economic aspects of AD. PMID- 25814735 TI - Histology of psoriatic erythroderma in infants: analytical study of eight cases. AB - BACKGROUND: Erythroderma in infants is a rare condition of varied etiology. Psoriasis is now emerging as the most common cause of erythroderma in infants. Early diagnosis of the etiological cause much depends upon the histological confirmation, which is essential for an early and appropriate treatment. AIM: It was aimed to study the histological findings in psoriatic erythroderma in infants. MATERIALS AND METHODS: A total of 8 infants up to 1 year of age presenting with erythroderma, clinically suspected to be of psoriatic etiology attending private clinic were included. After detailed history taking and astute clinical exam, all of them were biopsied. In case 6, with a positive family history of psoriasis and asthma in parents, biopsy was taken from two sites. The histological findings of all nine biopsies were studied and analyzed. RESULTS: Histology of all eight children showed psoriasi form pattern with acanthosis (AC) and dilated papillary capillaries (PC). Spongiform (SF) pattern was seen in the second biopsy (6b) of child with features of both psoriasis and atopy. SF pustule of Kogoj or Munro's abscess was not seen in any of them. CONCLUSION: Regular AC and PC dilatation were the consistent histological findings observed in infants with erythrodermic psoriasis. These were the early findings observed in younger infants. Co-existence of psoriasis with atopic dermatitis may indicate a common pathogenic mechanism or an immunogenetic spin-off. PMID- 25814736 TI - Isolated tenosynovitis as a sole manifestation: the great mimicker still continues to surprise us. AB - A middle aged male presented with non-tender cystic swelling over left distal forearm since 1 year. No other cutaneous abnormality could be found except mild paresthesia of the overlying skin and equivocal thickening of the ipsilateral ulnar nerve. Routine investigation was within normal limits. Detailed workup of the patient including MRI of the lesion suggested the diagnosis as tenosynovitis with a soft tissue mass. Fine needle aspiration cytology from the cyst showed foamy macrophages and acid fast bacilli; while PCR of the aspirate confirmed the etiological agent as M. leprae. We, thus, report a unique case of isolated tenosynovitis as a sole manifestation of pure neural leprosy which is extremely rare in world literature. PMID- 25814737 TI - Fruit and food eponyms in dermatology. AB - Dermatology world is brimming with myriad of interesting clinical conditions, signs and syndromes. It is infinite, which has systemic clinical connotations too. Complicated pronunciations of diagnosis have always placed residents in an intricate state. Each one is trying his best to make this cumbersome subject comparatively more acceptable and convenient. The present paper is an attempt to further simplify the subject by correlating difficult conditions with commonly used and seen things such as fruit and food. A total of 45 dermatological conditions were found to be based on fruit and food eponyms. For example, strawberries can remind us of strawberry gums of Wegener's granulomatosis and strawberry nevus. PMID- 25814739 TI - A Case of Multifocal Skin Metastases from Lung Cancer Presenting with Vasculitic type Cutaneous Nodule. AB - Although cutaneous metastasis occurs usually at the terminal stage of the disease, it may be rarely concurrent with the diagnosis and may also present as the first sign of the illness. A 55-year-old male patient presented with vasculitic-type cutaneous nodular lesions and a necrotic distal phalangeal lesion developed over the last month. He was a tradesman and smoked 40 packets year. On physical examination, he was found to have multiple cutaneous lesions on the skin of the face, limbs, neck, scalp, dorsal side, fingers, subungual side, right leg, and feet. A skin lesion punch biopsy was performed and squamous cell carcinoma metastasis was detected. He was diagnosed as having squamous cell lung cancer with bronchoscopic biopsy. Although it is very rare, cutaneous metastases that is concurrent with the diagnosis of lung cancer may be the first sign of the disease. In patients with suspicious skin lesions, the patient's age, smoking history, and other symptoms should be evaluated and a biopsy should be performed. PMID- 25814738 TI - Thalidomide in dermatology: revisited. AB - The use of thalidomide in relation to dermatology is well- known and enough data is available in the literature about various aspects of thalidomide. Despite being an interesting and useful drug for many dermatoses, it is associated with many health hazards including the birth defects, phocomelia. We hereby present a comprehensive review about thalidomide and its application in dermatology. PMID- 25814740 TI - Generalized eruptive syringoma. AB - Eruptive syringoma is a very rare variant of syringoma. It is a benign adnexal tumor of the intraepidermal portion of eccrine sweat ducts. Here we report a 32 year-old female presented with classical asymptomatic eruptive syringomas involving her face and extremities. PMID- 25814741 TI - Co-existence of various clinical and histopathological features of mycosis fungoides in a young female. AB - Mycosis fungoides is the most common type of cutaneous T-cell lymphoma (CTCL) and a rare disorder that typically affects older adults with erythematous scaling patches and plaques. Hypopigmented patches are a rare clinical variant of the disease. Granulomatous mycosis fungoides (GMF) is also a rare type of CTCL. No particular clinical criteria are available for the diagnosis of GMF, because of its variable presentations, and so the detection of GMF is primarily considered as a histopathological diagnosis. Rarely, a co-existence of more than one clinical or histopathological feature of mycosis fungoides may be present. To the best of our knowledge this is the first report of MF that shows the simultaneous co-existence of more than one clinical and histopathological variant of MF. We present a 29-year-old female with clinical presentations of both classic and hypopigmented mycosis fungoides (MF), and also the histopathological features of the classic and granulomatous types of the disease. PMID- 25814742 TI - De novo histoid leprosy: a case report from a post-elimination area. AB - Histoid leprosy is an uncommon variant of lepromatous leprosy that usually follows treatment failure. Occasionally it occurs de novo without any history of previous inadequate or irregular treatment. We, hereby, report a case of de novo histoid leprosy in a 25-year-old man from the post-elimination area of Kashmir, where the prevalence rate of the disease was reported to be 0.17/10000 in March, 2013 (NLEP). PMID- 25814743 TI - Multiple trichofolliculomas mimicking multiple trichoepitheliomas. AB - Trichofolliculomas are benign hair follicle hamartomas which were initially considered as hair follicle tumors. Usually presenting as a solitary lesion associated with a tuft of vellus hairs, multiple trichofolliculomas are rare. Trichofolliculomas are characterized by a histopathological feature of dermal keratin cyst with cyst wall showing radiating hair follicles. We report this case for the rare presentation of multiple trichofolliculomas on the face which clinically mimicked multiple trichoepitheliomas. PMID- 25814744 TI - Basal cell carcinoma with halo phenomenon in a young female: significance of dermatoscopy in early diagnosis. AB - Halo phenomenon of nevus may be observed as a circular reaction, although it is unusual around tumors. A 29-year-old woman presented with a pigmented lesion on the cheek since three years. She noted whitening of the skin around the lesion almost after a year following its appearance. Dermatologic examination revealed a pigmented nodular lesion with a hypopigmented halo on the left infraorbital region. The clinical impression was halo nevus, whereas basal cell carcinoma (BCC) was considered in dermatoscopic differential diagnosis. The diagnosis was infiltrative-type BCC histopathologically. The persistence of a perilesional halo around an enlarging pigmented lesion should be carefully examined with accompanying dermatoscopic findings even in young patients for early diagnosis of tumoral lesions. PMID- 25814745 TI - Keloids: an unwanted spontaneity in rubinstein-taybi syndrome. AB - Rubinstein-Taybi syndrome (RTS) is a rare developmental disorder comprising of mental retardation, unusual facial appearance, broad thumbs, and big toes. It is frequently associated with molecular lesions in the cAMP response element binding protein. Many cutaneous abnormalities are associated with RTS. Multiple spontaneous keloids are some of them. We hereby report a case of this rare syndrome associated with keloids without any preceding trauma. PMID- 25814746 TI - Scleromyxedema, a therapeutic dilemma. AB - Scleromyxedema is characterized by indurated erythematous papules disseminated on the face, chest and limbs. About twenty cases treated with thalidomide, stem cells, melphalan and immunoglobulin with varying results have been described. We present the case of a 28-year-old male patient diagnosed with scleromyxedema not associated with monoclonal gammopathy, multi-treated with anti-leprosy drugs, UVA1, and thalidomide for 4 years with no improvement. PMID- 25814747 TI - Peripheral T cell lymphoma: not otherwise specified. AB - Peripheral T cell lymphoma (PTCL) is a heterogeneous group of hematological tumors originating from mature T cells, which constitutes less than 15% of all non-Hodgkins lymphomas in adults. Primary cutaneous PTCL-not otherwise specified (NOS) represent a subgroup of PTCLs with no consistent immunophenotypic, genetic or clinical features. PTCL-NOS frequently has an aggressive course with a tendency for systemic involvement, however, a well-defined therapeutic and prognostic approach has not been outlined yet. We report a case of PTCL-NOS with multiple cutaneous lesions in a young adult male with an emphasis on the treatment modality used. PMID- 25814748 TI - Rowell's Syndrome to ds-DNA Negative Lupus Nephritis: A Yet Unreported Progression. AB - Rowell's syndrome is now identified as a subtype of subacute lupus erythematosus (LE) with erythema multiforme-like skin lesions, positive serum rheumatoid factor, anti-Ro La positivity and speckled pattern of antinuclear antibodies. Here we describe a case of Rowell's syndrome in an 18-year-old female who was found to be ds-DNA negative, who later progressed to develop stage V lupus nephritis (LN) over a course of 4 months. Although extremely rare, most cases of LN are drug induced. Of only seven cases of non-drug induced LN with negative dsDNA, none had cutaneous involvement. Ours was a unique case of progression of Rowells syndrome to ds-DNA negative LN. PMID- 25814749 TI - Primary anetoderma in a young male involving palms, soles and the scalp: rarest of the rare. AB - Primary anetoderma is a rare idiopathic disease of the skin, characterized by circumscribed areas of loose skin, and loss of elastic fibers upon histopathologic examination. Two forms are traditionally distinguished, primary and secondary. Primary anetoderma occurs when there is no underlying associated skin disease, whereas the latter refers to an abnormal repair mechanism of preexisting skin lesions. We are reporting a case of primary anetoderma with lesions present all over the body, including the scalp, palms and soles, the sites that are not known to be involved in this condition. PMID- 25814751 TI - Ulceronecrotic penicillosis. AB - A 40-year-old male human immunodeficiency virus (HIV) -positive patient on highly active antiretroviral therapy (HAART) developed bilateral cervical lymphadenopathy with fine needle aspiration cytology (FNAC) showing yeast cells of Penicillium marneffei. The adenopathy disappeared after 9 months of itraconazole therapy at a dose of 200 mg/day. Seven years later and 2 days following second-line HAART, the patient presented with generalized papulonodules and ulceronecrotic lesions. Biopsy of the skin lesion revealed plenty of yeast forms dividing by binary fission morphologically resembling Penicillium marneffei. Significant improvement was observed at 2 weeks of starting itraconazole 400 mg/day. After 3 months, the dose was reduced to 200 mg/day and advised to continue for 6 months. Penicillosis presenting initially in the form of cervical adenopathy and later, developing typical skin lesions rapidly progressing to ulcerative and necrotic erosions may be due to continued immunosuppression followed by immune reconstitution inflammatory syndrome (IRIS). PMID- 25814750 TI - Subcutaneous rhinosporidiosis masquerading as soft tissue tumor: diagnosed by fine-needle aspiration cytology. AB - Rhinosporidiosis is a chronic granulomatous lesion caused by Rhinosporidium seeberi. It frequently involves nasopharynx and ocular region. Presenting as cutaneous and subcutaneous mass is extremely rare. This report describes the FNA cytology of rhinosporidiosis occurring as a soft tissue mass in the right mid thigh region. We present a rare case of a 71-year-old male, who presented with multiple subcutaneous soft tissue mass lesions in the posteromedial aspect of mid right thigh region since 2 weeks. Local examination revealed multiple firm to hard mass with skin over the swelling was unremarkable. CT of the right thigh showed a heterogeneous lesion with infiltrative margins in the thigh. Clinically soft tissue sarcoma was considered. Diagnostic FNAC was performed showing numerous mature and immature sporangias with giant cell reaction. Hence, an excision biopsy confirmed the rhinosporidiosis. To conclude, the FNAC diagnosis of rhinosporidiosis is specific. Preoperative diagnosis is possible even in cases with unusual clinical presentations. PMID- 25814752 TI - Goltz syndrome: a newborn with ectrodactyly and skin lesions. AB - Goltz syndrome or Focal Dermal Hypoplasia is a rare multisystem disorder, involving all the three germ cell layers. The disease is thought to be inherited in X-linked dominant fashion with heterogeneous mutations of the PORCN gene at Xp11.23 locus. Majority of the cases are sporadic, mainly due to postzygotic somatic mutations. The clinical spectrum includes characteristic cutaneous manifestations, multiple skeletal anomalies, and involvement of the eyes, hair, nails, kidneys, and so on. Considerable variability is noted in the clinical expression of the disease probably due to genomic mosaicism. Around 300 cases of Goltz syndrome have been reported in the literature. Here, we report such a case with characteristic skin lesions, multiple bony defects, distinctive facial features, coloboma of iris, and bilateral hydronephrosis. The diagnosis was evident immediately after birth due to the characteristic clinical picture of the baby. PMID- 25814753 TI - Poikiloderma vasculare atrophicans: a distinct clinical entity? AB - This paper describes a typical case of poikiloderma vasculare atrophicans (PVA) in a 48-year-old female. Histologically, the features were suggestive of PVA with the absence of Pautrier's microabscess or atypical lymphoid cells. The biopsy specimen was positive for cluster of differentiation (CD) 8 on immunohistochemical staining. Its exact pathogenesis remains obscure, and it remains unclear whether PVA actually is mycosis fungoides (MF), a forme fruste of MF, or a distinct and benign dermatosis with CD8+ phenotype that can perhaps be labeled as PVA. However, it has a long benign clinical course without progression to tumor stage of MF in most cases, and its status within the spectrum of cutaneous T-cell lymphoma remains poorly understood. Yet it is imperative to distinguish PVA from poikilodermic MF. PMID- 25814754 TI - Emopamil binding protein mutation in conradi-hunermann-happle syndrome representing plaque-type psoriasis. AB - Conradi-Hunermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones, and eyes. CDPX2 patients display skin defects, including ichthyotic lesions, follicular atrophoderma, cicatricial alopecia, and less frequently ichthyosiform erythroderma, cataracts, and skeletal abnormalities consisting of short stature, asymmetric shortening of the limbs, epiphyseal stippling, and craniofacial defects. CDPX2 results from mutations in emopamil binding protein (EBP) gene. The aim of our study is to identify EBP mutation in a unique case of Conradi-Hunermann-Happle syndrome with rare psoriasiform lesions. PMID- 25814755 TI - An Overlap of Angiolymphoid Hyperplasia with Eosinophilia and Kimura's Disease: Successful Treatment of Skin Lesions with Cryotherapy. AB - Kimura's disease is characterized by a triad of painless subcutaneous masses, eosinophilia in the peripheral blood and in tissues with marked increase in Serum Ig E. Angiolymphoid hyperplasia with eosinophilia (ALHE) manifests with the presence of dermal papules and nodules. Unique clinical, histopathological, and biochemical findings are noted in these individual entities. A 32-year-female presented with multiple nodules in the axillae for 2 years. Peripheral smear showed eosinophilia with AEC of 6080. Histopathological examination showed features of overlap. Antinuclear antibody immunoflorescence was was negative. CD31, CD34, and FVIII were positive in vascular component. A CT chest revealed left axillary lymphadenopathy. The patient was treated with Cryotherapy and there was complete regression of skin lesions, with no recurrence after 1 year of follow-up. ALHE and KD are common in the head and neck region, but no reports of an overlap, presenting with lesions in the axillae are available to date, to the best of our knowledge. Response of skin lesions to cryotherapy is highlighted. PMID- 25814756 TI - Leishmaniasis recidiva cutis of the lips mimicking granulomatous cheilitis. AB - Leishmaniasis recidiva cutis (LRC) is an unusual form of acute cutaneous leishmaniasis. Herein, we present a case of LRC of the lips mimicking granulomatous cheilitis. An 8-year-old, Syrian child admitted with a swelling and disfigurement of his lips for 4 years. Abundant intra and extracellular Leishmania amastigotes were determined in the smear prepared from the lesion with Giemsa stain. Histopathology showed foamy histiocytes and leishmania parasites within the cytoplasm of macrophages in the epidermis and a dense dermal mixed type inflammatory cell infiltrate composed of lymphocytes, foamy histiocytes with multinucleated giant cells. On the basis of anamnestic data, the skin smears results, clinical and histopathologic findings, LRC was diagnosed. The patient was treated with meglumine antimoniate intramuscularly and fluconazole orally. Cryotherapy was applied to the residual papular lesions. The lesion improved markedly at the first month of the treatment. PMID- 25814757 TI - Juvenile localized scleroderma with port wine stain: coincidental or possible common pathogenetic association. AB - Port wine stain and juvenile localized scleroderma are two different dermatoses usually encountered in pediatric age group. Up to now, there are reports of morphea patients initially diagnosed and treated as port wine stain. Coexistence of both diseases is not found yet. We herein present a case of juvenile localized scleroderma on the left side of trunk, with congenital port wine stain located on the ipsilateral face at V1-V2 distribution. PMID- 25814758 TI - Gorlin-goltz syndrome: a rare case. AB - Gorlin-Goltz syndrome or nevoid basal cell carcinoma syndrome is characterized by multiple basocellular epitheliomas, keratocysts in the jaws, bifid ribs, palmar and/or plantar pits and ectopic calcifications of the falx cerebri. We describe a case of Gorlin-Goltz syndrome illustrating the importance of a thorough examination including the examination of palms and soles and detailed investigations in a patient having lesions suggestive of basal cell carcinoma and multiple naevi. PMID- 25814759 TI - Lymphoepithelioma-like carcinoma of the skin: an exceedingly rare primary skin tumor. AB - Primary lymphoepithelioma-like carcinoma of the skin (LE-lCS) is a very rare cutaneous malignancy of uncertain origin. The neoplasm reveals typical morphological similarity to undifferentiated nasopharyngeal carcinoma (lymphoepithelioma). This case report presents a 47-year-old man with a 5 mm erythematous papule on dorsal nose of six months duration. The patient underwent complete surgical excision and is disease free 7 months later. PMID- 25814760 TI - Familial atypical multiple mole melanoma syndrome in an adult Indian male-case report and literature review. AB - Familial atypical multiple mole melanoma syndrome (FAMMMS) is an autosomal dominant genodermatosis characterized by multiple melanocytic nevi, usually more than 50, and a family history of melanoma. It is known to be associated with carcinoma of pancreas and other malignancies involving gastrointestinal tract, breast, lung, larynx, and skin in the kindred. There is no published report of FAMMMS in dark-skinned individuals. We report a case of FAMMMS in a dark-skinned adult Indian male, who had multiple extensive nevi all over the body and oral mucosa; associated with malignant melanoma, squamous cell carcinoma (Marjolin's ulcer), and carcinoma of pancreas. His father had died of carcinoma of lung and his sister had a partial phenotypic expression. The clinical presentation of the case is discussed with review of literature. PMID- 25814761 TI - A case of genital porokeratosis and review of literature. AB - We present a case of a 64-year-old uncircumcised male who initially presented to the provider with a 1 year history of a solitary lesion on the glans penis that was clinically diagnosed as porokeratosis of Mabelli. A biopsy on a follow-up visit confirmed provider's clinical suspicion. This article highlights the progression and treatment options for porokeratosis on the male genitalia. PMID- 25814762 TI - Acroangiodermatitis associated with iatrogenic arteriovenous fistula mimicking verruca vulgaris. PMID- 25814764 TI - Agminated spitz nevus on sole of elderly. PMID- 25814763 TI - Bloom syndrome with extensive pulmonary involvement in a child. PMID- 25814765 TI - Disseminated cutaneous rhinosporidiosis: a polymorphic presentation in an immunocompetent patient. PMID- 25814766 TI - Concurrent occurrence of pemphigus vulgaris and oral submucous fibrosis: an unusual presentation. PMID- 25814767 TI - Effectiveness of a multidisciplinary itch clinic in the management of chronic pruritus. PMID- 25814768 TI - Necrotic plaque on the calf and thigh of a woman with cryptogenic cirrhosis. PMID- 25814769 TI - Solitary plaque with recurrent blistering on the finger of a child. PMID- 25814770 TI - In situ preparation, electrical and surface analytical characterization of pentacene thin film transistors. AB - The fabrication of organic thin film transistors with highly reproducible characteristics presents a very challenging task. We have prepared and analyzed model pentacene thin film transistors under ultra-high vacuum conditions, employing surface analytical tools and methods. Intentionally contaminating the gold contacts and SiO2 channel area with carbon through repeated adsorption, dissociation, and desorption of pentacene proved to be very advantageous in the creation of devices with stable and reproducible parameters. We mainly focused on the device properties, such as mobility and threshold voltage, as a function of film morphology and preparation temperature. At 300 K, pentacene displays Stranski-Krastanov growth, whereas at 200 K fine-grained, layer-like film growth takes place, which predominantly influences the threshold voltage. Temperature dependent mobility measurements demonstrate good agreement with the established multiple trapping and release model, which in turn indicates a predominant concentration of shallow traps in the crystal grains and at the oxide semiconductor interface. Mobility and threshold voltage measurements as a function of coverage reveal that up to four full monolayers contribute to the overall charge transport. A significant influence on the effective mobility also stems from the access resistance at the gold contact-semiconductor interface, which is again strongly influenced by the temperature dependent, characteristic film growth mode. PMID- 25814771 TI - Intimacy and Emotion Work in Lesbian, Gay, and Heterosexual Relationships. AB - Knowledge about how gender shapes intimacy is dominated by a heteronormative focus on relationships involving a man and a woman. In this study, the authors shifted the focus to consider gendered meanings and experiences of intimacy in same-sex and different-sex relationships. They merged the gender-as-relational perspective-that gender is co-constructed and enacted within relationships-with theoretical perspectives on emotion work and intimacy to frame an analysis of in depth interviews with 15 lesbian, 15 gay, and 20 heterosexual couples. They found that emotion work directed toward minimizing and maintaining boundaries between partners is key to understanding intimacy in long-term relationships. Moreover, these dynamics, including the type and division of emotion work, vary for men and women depending on whether they are in a same-sex or different-sex relationship. These findings push thinking about diversity in long-term relationships beyond a focus on gender difference and toward gendered relational contexts. PMID- 25814772 TI - Surface Polar Lipids Differ in Male and Female Phlebotomus papatasi (Diptera: Psychodidae). AB - The polar lipids on the surface of the Old World sand fly, Phlebotomus papatasi (Scopoli), were analyzed by high-resolution mass spectrometry. Blood-fed females and nonblood-fed females and males were separately analyzed and compared. The major polar lipids were found to be long-chain diols and fatty acids. Relatively high levels of diacylglycerols were found in blood-fed females and in males. A wide variety of lipids were found at low levels, including esters, sterols, monoacylglycerols, and hydroxy fatty acids. Blood-fed females had several lyso lipids and N-acyl amino acids that were not found on unfed females or males. These substances may be surfactants used in blood feeding. Heneicosenoic acid was found on females at more than twice the level of males, suggesting it could be a component of a female pheromone. Four substances were identified on males at twofold higher levels than on females: tetradienoic acid, methoxyhexadecasphinganine, butyl octadecanoate, and diacylglycerol(14:1/12:0/0:0). These could be short-range pheromones involved in courtship, and they will be further analyzed in future behavioral bioassays. PMID- 25814773 TI - On linear combinations of units with bounded coefficients and double-base digit expansions. AB - Let [Formula: see text] be the maximal order of a number field. Belcher showed in the 1970s that every algebraic integer in [Formula: see text] is the sum of pairwise distinct units, if the unit equation [Formula: see text] has a non trivial solution [Formula: see text]. We generalize this result and give applications to signed double-base digit expansions. PMID- 25814774 TI - 2-Supernilpotent Mal'cev algebras. AB - In this note we prove that a Mal'cev algebra is 2-supernilpotent ([1, 1, 1] = 0) if and only if it is polynomially equivalent to a special expanded group. This generalizes Gumm's result that a Mal'cev algebra is abelian if and only if it is polynomially equivalent to a module over a ring. PMID- 25814775 TI - The Suicidal Animal: Science and the Nature of Self-Destruction. PMID- 25814776 TI - Peatland Microbial Communities as Indicators of the Extreme Atmospheric Dust Deposition. AB - We investigated a peat profile from the Izery Mountains, located within the so called Black Triangle, the border area of Poland, Czech Republic, and Germany. This peatland suffered from an extreme atmospheric pollution during the last 50 years, which created an exceptional natural experiment to examine the impact of pollution on peatland microbes. Testate amoebae (TA), Centropyxis aerophila and Phryganella acropodia, were distinguished as a proxy of atmospheric pollution caused by extensive brown coal combustion. We recorded a decline of mixotrophic TA and development of agglutinated taxa as a response for the extreme concentration of Al (30 g kg-1) and Cu (96 mg kg-1) as well as the extreme amount of fly ash particles determined by scanning electron microscopy (SEM) analysis, which were used by TA for shell construction. Titanium (5.9 %), aluminum (4.7 %), and chromium (4.2 %) significantly explained the highest percentage of the variance in TA data. Elements such as Al, Ti, Cr, Ni, and Cu were highly correlated (r > 0.7, p < 0.01) with pseudostome position/body size ratio and pseudostome position. Changes in the community structure, functional diversity, and mechanisms of shell construction were recognized as the indicators of dust pollution. We strengthen the importance of the TA as the bioindicators of the recent atmospheric pollution. PMID- 25814777 TI - Whale sharks target dense prey patches of sergestid shrimp off Tanzania. AB - Large planktivores require high-density prey patches to make feeding energetically viable. This is a major challenge for species living in tropical and subtropical seas, such as whale sharks Rhincodon typus. Here, we characterize zooplankton biomass, size structure and taxonomic composition from whale shark feeding events and background samples at Mafia Island, Tanzania. The majority of whale sharks were feeding (73%, 380 of 524 observations), with the most common behaviour being active surface feeding (87%). We used 20 samples collected from immediately adjacent to feeding sharks and an additional 202 background samples for comparison to show that plankton biomass was ~10 times higher in patches where whale sharks were feeding (25 vs. 2.6 mg m-3). Taxonomic analyses of samples showed that the large sergestid Lucifer hanseni (~10 mm) dominated while sharks were feeding, accounting for ~50% of identified items, while copepods (<2 mm) dominated background samples. The size structure was skewed towards larger animals representative of L.hanseni in feeding samples. Thus, whale sharks at Mafia Island target patches of dense, large, zooplankton dominated by sergestids. Large planktivores, such as whale sharks, which generally inhabit warm oligotrophic waters, aggregate in areas where they can feed on dense prey to obtain sufficient energy. PMID- 25814778 TI - BRCA genetic screening in Middle Eastern and North African: mutational spectrum and founder BRCA1 mutation (c.798_799delTT) in North African. AB - BACKGROUND: The contribution of BRCA1 mutations to both hereditary and sporadic breast and ovarian cancer (HBOC) has not yet been thoroughly investigated in MENA. METHODS: To establish the knowledge about BRCA1 mutations and their correlation with the clinical aspect in diagnosed cases of HBOC in MENA populations. A systematic review of studies examining BRCA1 in BC women in Cyprus, Jordan, Egypt, Lebanon, Morocco, Algeria, and Tunisia was conducted. RESULTS: Thirteen relevant references were identified, including ten studies which performed DNA sequencing of all BRCA1 exons. For the latter, 31 mutations were detected in 57 of the 547 patients ascertained. Familial history of BC was present in 388 (71%) patients, of whom 50 were mutation carriers. c.798_799delTT was identified in 11 North African families, accounting for 22% of total identified BRCA1 mutations, suggesting a founder allele. A broad spectrum of other mutations including c.68_69delAG, c.181T>G, c.5095C>T, and c.5266dupC, as well as sequence of unclassified variants and polymorphisms, was also detected. CONCLUSION: The knowledge of genetic structure of BRCA1 in MENA should contribute to the assessment of the necessity of preventive programs for mutation carriers and clinical management. The high prevalence of BC and the presence of frequent mutations of the BRCA1 gene emphasize the need for improving screening programs and individual testing/counseling. PMID- 25814779 TI - Secernin-1 contributes to colon cancer progression through enhancing matrix metalloproteinase-2/9 exocytosis. AB - Emerging evidence shows that exocytosis plays a key role in tumor development and metastasis. Secernin-1 (SCRN1) is a novel regulator of exocytosis. Our previous work identified SCRN1 as a tumor-associated gene by bioinformatics analysis of transcriptomes. In this study, we demonstrated the aberrant overexpression of SCRN1 at mRNA and protein level in colon cancer. We also revealed that overexpression of SCRN1 was significantly associated with the tumor development and poor prognosis. Experiments in vitro validated that SCRN1 may promote cancer cell proliferation and secretion of matrix metalloproteinase-2/9 (MMP-2/9) proteins to accelerate tumor progression. PMID- 25814780 TI - Effect of periodontal surgery on osteoprotegerin levels in gingival crevicular fluid, saliva, and gingival tissues of chronic periodontitis patients. AB - OBJECTIVES: This study was undertaken to investigate the OPG profiles in gingival crevicular fluid (GCF), saliva, and gingival tissues of chronic periodontitis (CP) patients in response to open flap debridement (OFD). SUBJECTS AND METHODS: The study included 30 subjects divided into 2 groups: 20 CP patients and 10 periodontally healthy subjects. Plaque index, gingival index, pocket depth, and clinical attachment level measurements were recorded for all subjects. GCF, salivary, and gingival samples were collected from all 30 subjects at baseline and 3 and 6 month after OFD from the 20 CP patients. GCF and salivary OPG levels were assessed by ELISA assay, while OPG expression in gingival tissues was examined by immunohistochemistry. RESULTS: GCF, salivary and gingival OPG profiles were significantly higher in control subjects compared to CP patients at baseline (P < 0.001). Within CP group, OPG levels in GCF, saliva, and gingival samples showed a significant increase at 3 and 6 months after OFD (P < 0.001) compared to baseline. Although OPG values increased significantly in gingival samples and insignificantly in saliva after 3 months compared to 6 months, yet GCF levels were significantly decreased. CONCLUSIONS: OPG might be considered as a diagnostic and prognostic biomarker of periodontal bone destruction. This trial is registered with NCT02160613. PMID- 25814781 TI - 3-nitrotyrosine modified proteins in atherosclerosis. AB - Cardiovascular disease is the leading cause of premature death worldwide, and atherosclerosis is the main contributor. Lipid-laden macrophages, known as foam cells, accumulate in the subendothelial space of the lesion area and contribute to consolidate a chronic inflammatory environment where oxygen and nitrogen derived oxidants are released. Oxidatively modified lipids and proteins are present both in plasma as well as atherosclerotic lesions. A relevant oxidative posttranslational protein modification is the addition of a nitro group to the hydroxyphenyl ring of tyrosine residues, mediated by nitric oxide derived oxidants. Nitrotyrosine modified proteins were found in the lesion and also in plasma from atherosclerotic patients. Despite the fact of the low yield of nitration, immunogenic, proatherogenic, and prothrombotic properties acquired by 3-nitrotyrosine modified proteins are in agreement with epidemiological studies showing a significant correlation between the level of nitration found in plasma proteins and the prevalence of cardiovascular disease, supporting the usefulness of this biomarker to predict the outcome and to take appropriate therapeutic decisions in atherosclerotic disease. PMID- 25814782 TI - Identification of endogenous controls for analyzing serum exosomal miRNA in patients with hepatitis B or hepatocellular carcinoma. AB - Serum exosomal microRNAs (miRNAs) have received considerable attention as potential biomarkers for diagnosing cancer. The canonical technique for measuring miRNA transcript levels is reverse transcription quantitative polymerase chain reaction (RT-qPCR). One prerequisite for validating RT-qPCR data is proper normalization with respect to stably expressed endogenous reference genes. However, genes that meet all of the criteria of a control gene for exosomal miRNAs have not yet been identified. To find out the control gene for exosomal miRNAs, we evaluated the expression stability of 11 well-known reference genes in circulating exosomes. In this study, we found that the combination of miR-221, miR-191, let-7a, miR-181a, and miR-26a can be an optimal gene reference set for normalizing the expression of liver-specific miRNAs. This combination enhanced the robustness of the relative quantification analyses. These findings highlight the importance of validating reference genes before quantifying target miRNAs. Furthermore, our findings will improve studies that monitor hepatitis progression and will aid in the discovery of noninvasive biomarkers to diagnose early stage HCC. PMID- 25814783 TI - Conservation of the Tsc/Rheb/TORC1/S6K/S6 Signaling in Fission Yeast. AB - The TSC/Rheb/TORC1/S6K/S6 signaling pathway plays critical roles in regulating protein synthesis and growth in eukaryotes. Our recent work using fission yeast Schizosaccharomyces pombe revealed that this signaling pathway is conserved from humans to fission yeast. In addition to target of rapamycin (TOR) homologsand tuberous sclerosis complex (TSC) homologs, fission yeast but not budding yeast, has a functional homolog of Rheb, a small G-protein acting as an activator of TOR complex 1 (TORC1). Several lines of genetic evidence suggest that the Tsc1-Tsc2 complex and Rheb act as upstream players of TORC1 in fission yeast. We have recently demonstrated that TORC1, but not TORC2, regulates phosphorylation of ribosomal protein S6 in response to nutrient availability. Candidate S6 kinase (S6K) protein has been identified. In addition, we find that rapamycin prevents a subset of TORC1 activity to regulate S6 phosphorylation in fission yeast. PMID- 25814784 TI - Losses in Ferroelectric Materials. AB - Ferroelectric materials are the best dielectric and piezoelectric materials known today. Since the discovery of barium titanate in the 1940s, lead zirconate titanate ceramics in the 1950s and relaxor-PT single crystals (such as lead magnesium niobate-lead titanate and lead zinc niobate-lead titanate) in the 1980s and 1990s, perovskite ferroelectric materials have been the dominating piezoelectric materials for electromechanical devices, and are widely used in sensors, actuators and ultrasonic transducers. Energy losses (or energy dissipation) in ferroelectrics are one of the most critical issues for high power devices, such as therapeutic ultrasonic transducers, large displacement actuators, SONAR projectors, and high frequency medical imaging transducers. The losses of ferroelectric materials have three distinct types, i.e., elastic, piezoelectric and dielectric losses. People have been investigating the mechanisms of these losses and are trying hard to control and minimize them so as to reduce performance degradation in electromechanical devices. There are impressive progresses made in the past several decades on this topic, but some confusions still exist. Therefore, a systematic review to define related concepts and clear up confusions is urgently in need. With this objective in mind, we provide here a comprehensive review on the energy losses in ferroelectrics, including related mechanisms, characterization techniques and collections of published data on many ferroelectric materials to provide a useful resource for interested scientists and engineers to design electromechanical devices and to gain a global perspective on the complex physical phenomena involved. More importantly, based on the analysis of available information, we proposed a general theoretical model to describe the inherent relationships among elastic, dielectric, piezoelectric and mechanical losses. For multi-domain ferroelectric single crystals and ceramics, intrinsic and extrinsic energy loss mechanisms are discussed in terms of compositions, crystal structures, temperature, domain configurations, domain sizes and grain boundaries. The intrinsic and extrinsic contributions to the total energy dissipation are quantified. In domain engineered ferroelectric single crystals and ceramics, polarization rotations, domain wall motions and mechanical wave scatterings at grain boundaries are believed to control the mechanical quality factors of piezoelectric resonators. We show that a thorough understanding on the kinetic processes is critical in analyzing energy loss behavior and other time-dependent properties in ferroelectric materials. At the end of the review, existing challenges in the study and control of losses in ferroelectric materials are analyzed, and future perspective in resolving these issues is discussed. PMID- 25814785 TI - Epigenetic regulation of inflammatory cytokines and associated genes in human malignancies. AB - Inflammation is a multifaceted defense response of immune system against infection. Chronic inflammation has been implicated as an imminent threat for major human malignancies and is directly linked to various steps involved in tumorigenesis. Inflammatory cytokines, interleukins, interferons, transforming growth factors, chemokines, and adhesion molecules have been associated with chronic inflammation. Numerous cytokines are reported to be aberrantly regulated by different epigenetic mechanisms like DNA methylation and histone modifications in tumor tissues, contributing to pathogenesis of tumor in multiple ways. Some of these cytokines also work as epigenetic regulators of other crucial genes in tumor biology, either directly or indirectly. Such regulations are reported in lung, breast, cervical, gastric, colorectal, pancreatic, prostate, and head and neck cancers. Epigenetics of inflammatory mediators in cancer is currently subject of extensive research. These investigations may help in understanding cancer biology and to develop effective therapeutic strategies. The purpose of this paper is to have a brief view of the aberrant regulation of inflammatory cytokines in human malignancies. PMID- 25814787 TI - Cardiac migration of endogenous mesenchymal stromal cells in patients with inflammatory cardiomyopathy. AB - Introduction. Mesenchymal stromal cells (MSC) have immunomodulatory features. The aim of this study was to investigate the migration and homing potential of endogenous circulating MSC in virus negative inflammatory cardiomyopathy (CMi). Methods. In 29 patients with (n = 23) or without (n = 6) CMi undergoing endomyocardial biopsies (EMB), transcardiac gradients (TCGs) of circulating MSC were measured by flow cytometry from blood simultaneously sampled from aorta and coronary sinus. The presence of MSC in EMB, cardiac inflammation, and SDF-1alpha mRNA expression were detected via immunohistochemistry and real-time PCR. Results. MSC defined as CD45(-)CD34(-)CD11b(-)CD73(+)CD90(+) cells accounted for 0.010 [0.0025-0.048]%/peripheral mononuclear cell (PMNC) and as CD45(-)CD34( )CD11b(-)CD73(+)CD105(+) cells for 0.019 [0.0026-0.067]%/PMNC, both with similar counts in patients with or without cardiac inflammation. There was a 29.9% (P < 0.01) transcardiac reduction of circulating MSC in patients with CMi, correlating with the extent of cardiac inflammation (P < 0.05, multivariate analysis). A strong correlation was found between the TCG of circulating MSC and numbers of MSC (CD45(-)CD34(-)CD90(+)CD105(+)) in EMB (r = -0.73, P < 0.005). SDF-1alpha was the strongest predictor for increased MSC in EMB (P < 0.005, multivariate analysis). Conclusions. Endogenous MSC continuously migrate to the heart in patients with CMi triggered by cardiac inflammation. PMID- 25814786 TI - The chaperone balance hypothesis: the importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management. AB - Recent evidence shows divergence between the concentrations of extracellular 70 kDa heat shock protein [eHSP70] and its intracellular concentrations [iHSP70] in people with type 2 diabetes (T2DM). A vital aspect regarding HSP70 physiology is its versatility to induce antagonistic actions, depending on the location of the protein. For example, iHSP70 exerts a powerful anti-inflammatory effect, while eHSP70 activates proinflammatory pathways. Increased eHSP70 is associated with inflammatory and oxidative stress conditions, whereas decreased iHSP70 levels are related to insulin resistance in skeletal muscle. Serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C-reactive protein, monocyte count, and TNF-alpha, while strategies to enhance iHSP70 (e.g., heat treatment, chemical HSP70 inducers or coinducers, and physical exercise) are capable of reducing the inflammatory profile and the insulin resistance state. Here, we present recent findings suggesting that imbalances in the HSP70 status, described by the [eHSP70]/[iHSP70] ratio, may be determinant to trigger a chronic proinflammatory state that leads to insulin resistance and T2DM development. This led us to hypothesize that changes in this ratio value could be used as a biomarker for the management of the inflammatory response in insulin resistance and diabetes. PMID- 25814788 TI - Secretion of one adipokine Nampt/Visfatin suppresses the inflammatory stress induced NF-kappaB activity and affects Nampt-dependent cell viability in Huh-7 cells. AB - Nampt/visfatin acts in both intracellular and extracellular compartments to regulate multiple biological roles, including NAD metabolism, cancer, inflammation, and senescence. However, its function in chronic inflammation and carcinogenesis in hepatocellular carcinoma (HCC) has not been well-defined. Here we use Huh-7 hepatoma cells as a model to determine how Nampt/visfatin affects cellular survival under oxidative stress. We found that the transition of Nampt/visfatin from intracellular into extracellular form was induced by H2O2 treatment in 293T cells and confirmed that this phenomenon was not due to cell death but through the secretion of Nampt/visfatin. In addition, Nampt/visfatin suppressed cell viability in oxidative treatment in Huh-7 cells and acted on the inhibition of hepatoma cell growth. Oxidative stress also reduced the Nampt mediated activation of NF-kappaB gene expression. In this study, we identify a novel feature of Nampt/visfatin which functions as an adipokine that can be secreted upon cellular stress. Our results provide an example to understand how adipokine interacts with chemotherapeutic treatment by oxidative stress in HCC. PMID- 25814790 TI - From Editor's desk. PMID- 25814789 TI - Inflammasome in platelets: allying coagulation and inflammation in infectious and sterile diseases? AB - Platelets are crucial effector cells in hemostasis. In addition, platelets are increasingly recognized as major inflammatory cells with key roles in innate and adaptive immune responses. Activated platelets have key thromboinflammatory activities linking coagulation to inflammatory response in a variety of coagulation disorders and vasculopathies. Recently identified inflammatory activities of platelets include the synthesis of IL-1beta from spliced pre-RNA, as well as the presence and assembly of inflammasome which intermediate IL-1beta secretion. Here we review the mechanisms by which platelets activate translation machinery and inflammasome assembly to synthesize and release IL-1beta. The contributions of these processes to protective and pathogenic responses during infectious and inflammatory diseases are discussed. PMID- 25814791 TI - Bronchopleural fistula treatment: From the archetype of surgery to the future of stem cell therapy. PMID- 25814793 TI - A stepwise approach to the etiologic diagnosis of pleural effusion in respiratory intensive care unit and short-term evaluation of treatment. AB - BACKGROUND: Pleural effusions in respiratory intensive care unit (RICU) are associated with diseases of varied etiologies and often carry a grave prognosis. This prospective study was conducted to establish an etiologic diagnosis in a series of such patients before starting treatment. MATERIALS AND METHODS: Fifty consecutive patients, diagnosed with pleural effusion on admission or during their stay in RICU, were further investigated by a two-step approach. (1) Etiologic diagnosis was established by sequential clinical history and findings on physical examination, laboratory tests, chest radiograph, CECT/HRCT/PET-CT and pleural fluid analysis. (2) Patients who remained undiagnosed were subjected to fiber-optic bronchoscopy, video-assisted thoracoscopic pleural biopsy, and histopathology. RESULTS: Etiologic diagnosis of pleural effusion was established in 44 (88%) Metastases (24%); para-pneumonia (22%); congestive cardiac failure (18%); tuberculosis (14%); hemothorax (4%); trapped lung, renal failure, and liver cirrhosis (2% each). Six patients (12%) remained undiagnosed, as the final diagnostic thoracoscopic biopsy could not be performed in five and tissue histopathology findings were inconclusive in one. Out of the 50 patients, 10 died in the hospital; 2 left against medical advice; and 2 were referred to oncology center for further treatment. The remaining 36 patients were clinically stabilized and discharged. During a 3-month follow-up, eight of them were re hospitalized, of which four died. CONCLUSIONS: Pleural effusion in RICU carries a high risk of mortality. Etiologic diagnosis can be established in most cases. PMID- 25814792 TI - Clinico-radiological profile and risk factors in patients with anthracosis. AB - BACKGROUND: Anthracosis is the black pigmentation of the mucosal lining of the tracheo-bronchial tree. The significance of this finding is not known and often ignored. The aim of the present study is to find the association of anthracosis with demographic variables, biomass fuel and occupational exposure, respiratory diseases, radiological pattern and functional morbidity. MATERIALS AND METHODS: Enrolment of the subjects for the study was done at SMS hospital, Jaipur. Patients with anthracosis evident on bronchoscopy were included as the cases. Patients without anthracosis on bronchoscopy, matched according to age, gender and smoking habits, were included in the control group. Subjects in both the arms completed a questionnaire and also underwent computed tomography (CT) of the chest and six minute walk test (6MWT). RESULTS: Thirty cases and 53 controls were included in the study. The patients with anthracosis presented with symptoms ranging from cough (76.65%), hemoptysis (46.6%), fever (26.6%), dyspnea (90%) and malaise (73.3%). Biomass fuel exposure for the cases was 35.13 +/- 55.86 hours in a year and for the controls was 28.15 +/- 40.09 hours in a year (P > 0.05). Stone mining was significantly associated with anthracosis (P < 0.05). CT chest revealed fibrosis (43.3%), consolidation (33.3%), cavitation (16.6%) and mass (46.6%) in the cases. Sixty percent of cases and 15% of controls were diagnosed to have either old or active pulmonary tuberculosis (P < 0.05). CONCLUSIONS: Anthracosis is associated with pulmonary tuberculosis. Biomass exposure is not significantly associated with anthracosis. Post tubercular fibrosis is more common on CT chest of patients with anthracosis. PMID- 25814794 TI - Congenital cystic lesions of the lungs: The perils of misdiagnosis - A single center experience. AB - BACKGROUND: A majority of cystic lesions in the western world are detected antenatally, whereas, the diagnosis in our setup occurs once the child becomes symptomatic. Surgical management is primarily dictated by the presence of symptoms, recurrent infection, and rarely by the potential risk of malignant transformation. MATERIALS AND METHODS: A retrospective analysis was carried out on all consecutive patients with cystic lung lesions managed at our center from January 2000 through June 2011 for antenatal diagnosis, presentation, diagnostic modalities, treatment, and complications. RESULTS: Forty cystic lung lesions were identified. Only 8% were antenatally detected. Out of 40, the final diagnosis was congenital cystic adenomatoid malformation in 19, congenital lobar emphysema in 11, and bronchogenic cysts and pulmonary sequestration in five each. Of these, 20% had received a course of prior antitubercular therapy and 30% had an intercostal drain inserted prior to referral to our center. Postoperative morbidity in the form of bronchopleural fistula, pneumothorax, and non-expansion of the residual lung was noted in 10% of the patients. CONCLUSION: Antenatal diagnosis of these lesions is still uncommon in third world countries. Prior to referral to a pediatric surgical center a large number of patients received antitubercular drugs and an intercostal drain insertion, due to incorrect diagnosis. PMID- 25814795 TI - Utility of semi-rigid thoracoscopy in undiagnosed exudative pleural effusion. AB - BACKGROUND: Semi-rigid thoracoscopy is a safe and efficacious procedure in patients with undiagnosed pleural effusion. Literature on its utility from developing countries is limited. We herein describe our initial experience on the utility of semi-rigid thoracoscopy from a tertiary care teaching and referral center in north India. We also perform a systematic review of studies reporting the utility of semi-rigid thoracoscopy from India. PATIENTS AND METHODS: The primary objective was to evaluate the diagnostic utility of semi-rigid thoracoscopy in patients with undiagnosed exudative pleural effusion. Semi-rigid thoracoscopy was performed under local anesthesia and conscious sedation in the bronchoscopy suite. RESULTS: A total of 48 patients underwent semi-rigid thoracoscopy between August 2012 and December 2013 for undiagnosed pleural effusion. Mean age was 50.9 +/- 14.1 years (range: 17-78 years). Pre-procedure clinico-radiological diagnoses were malignant pleural effusion [36 patients (75%)], tuberculosis (TB) [10 (20.83%) patients], and empyema [2 patients (4.17%)]. Patients with empyema underwent the procedure for pleural biopsy, optimal placement of intercostal tube and adhesiolysis. Thoracoscopic pleural biopsy diagnosed pleural malignancy in 30 (62.5%) patients and TB in 2 (4.17%) patients. Fourteen (29.17%) patients were diagnosed with non-specific pleuritis and normal pleura was diagnosed on a pleural biopsy in 2 (4.17%) patients. Overall, a definitive diagnosis of either pleural malignancy or TB was obtained in 32 (66.7%) patients. Combined overall sensitivity, specificity, positive predictive value and negative predictive value of thoracoscopic pleural biopsy for malignant pleural effusion were 96.77%, 100%, 100% and 66.67%, respectively. There was no procedure-related mortality. On performing a systematic review of literature, four studies on semi-rigid thoracoscopy from India were identified. CONCLUSION: Semi-rigid thoracoscopy is a safe and efficacious procedure in patients with undiagnosed exudative pleural effusions. PMID- 25814796 TI - First-line anti-tubercular drug resistance of mycobacterial strains from re treatment cases that were smear-positive at 4(th) month onwards under the Revised National Tuberculosis Control Program. AB - BACKGROUND: Programmatic management of drug-resistant TB (PMDT) under the RNTCP is being implemented in West Bengal in a phased manner since 2011. During the initial years MDR-TB cases were identified based on criteria A. This study examines the first line anti-tubercular drug resistance pattern of mycobacteria cultured from sputum samples of MDR suspects who were retreatment cases smear positive from 4(th) month onwards. MATERIALS AND METHODS: In the following retrospective record based study, data on Drug Sensitivity Testing (DST) of sputum samples of MDR suspects between September 2011 and August 2012 were collected from the IRL Kolkata and analysed. Sputum samples, collected in the districts maintaining adequate aseptic containment measures, were decontaminated and centrifuged and the sediment inoculated on LJ medium. Probable M. tuberculosis colonies were identified by typical colony characteristics and Ziehl Neelsen (ZN) staining. Sensitivity of the four 1(st) line drugs (Streptomycin, Isoniazid, Ethambutol and Rifampicin) was deduced by the economic variant of the proportion method. RESULTS: Of all the 917 MDR suspects whose sputum was examined, 64 mycobacteria culture positive strains (6.98%) were mono-resistant to any of the four first line anti-tubercular drugs. Among the mono-resistant strains 43 (4.69%) were resistant to Rifampicin while 12 (1.31%) were resistant to INH. There were a total 78 (8.51%) poly drug-resistant strains. MDR-TB strains were seen in 741 (80.81%) samples. CONCLUSION: The magnitude of drug resistance were very high among retreatment patients that were smear positive from 4(th) months onwards probably because of repeated courses of anti-tubercular drugs prior to drug sensitivity testing (DST). The decision of the PMDT to enlist all retreatment patients as MDR suspects at initiation will result in early identification and treatment of MDR-TB patients. PMID- 25814797 TI - Assessment of spontaneous pneumothorax in adults in a tertiary care hospital. AB - CONTEXT: Pneumothorax continues to be a major cause of morbidity and mortality among respiratory patients, but there is a paucity of data regarding etiology, clinical profile, management, and outcome of spontaneous pneumothorax (SP), from this part of the world. AIMS: To assess the patients of spontaneous pneumothorax in adults with special reference to the etiology, clinical presentation, management, and outcome of SP. SETTINGS AND DESIGN: Prospective, observational study conducted in a tertiary care institution over a period of one year. MATERIALS AND METHODS: All adult patients of SP attending the department of pulmonary medicine in a tertiary hospital were studied and detailed clinical, radiological, and management data were recorded and analyzed. RESULTS: Sixty consecutive patients, who satisfied the inclusion criteria were included in the study. Among them 10 had primary spontaneous pneumothorax (PSP) and 50 had secondary spontaneous pneumothorax (SSP). The overall male to female ratio was 4:1. The mean age of the PSP patients was 26.3 +/- 2.19 years, whereas, that of the SSP patients was 53.42 +/- 2.07 years (P < 0.0001). Seventy percent of the patients were smokers. The most common clinical manifestation of PSP was chest pain (80%) in contrast to dyspnea in SSP (96%). The most common cause of SSP (42%) was found to be chronic obstructive pulmonary disease (COPD) followed by pulmonary tuberculosis (30%). The cases were managed with intercostal tube drainage (85%), simple aspiration (8.33%), and observation (6.67%). Full expansion of the lung was noted in 91.67% of the cases. CONCLUSION: Spontaneous pneumothorax was more common in men. SSP was far more common in this study, and the predominant underlying cause of SSP was COPD, which surpassed tuberculosis as the leading cause of SSP. This is in contrast to the results from previous studies done in our country. Intercostal tube drainage was the mainstay of treatment and the response was good. PMID- 25814798 TI - Subclinical atherosclerotic vascular disease in chronic obstructive pulmonary disease: Prospective hospital-based case control study. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is an important non communicable disease worldwide with a rising global incidence. COPD is associated with multiple co-morbidities. Patients with COPD are at increased risk of atherosclerosis and other cardiovascular events. Cardiovascular diseases are an important cause of morbidity and mortality in COPD. The present case-control study was designed to assess the relationship between sub-clinical atherosclerotic vascular diseases with COPD. METHODS: It was a prospective case control blinded observational study. There were 142 COPD patients and 124 age-and sex-matched controls without COPD and cardiovascular diseases. Frequency of sub clinical atherosclerosis was assessed by the carotid B-mode duplex ultrasonography assessment of carotid wall intima medial thickness (IMT). Plaque was defined as IMT of more than 1.2 mm. RESULTS: Prevalence of carotid plaqing was significantly higher amongst patients of COPD (38.7%) compared to controls (13.7%, odds ratio 3.9, P < 0.0001). Multinomial logistic regression analysis revealed COPD as an independent predictor of carotid plaqing (r = 0.85, P < 0.023). CONCLUSION: The frequency of carotid plaqing is high in COPD patients. Carotid plaqing may be due to shared risk factors or the presence of low-grade systemic inflammation. Presence of increased CIMT and carotid plaqing in COPD patients identifies early atherosclerotic changes and future cardiovascular risk. Hence screening of CIMT should be a part of cardiovascular assessment in patients with COPD. PMID- 25814800 TI - Intercostal muscle flap for repair of bronchopleural fistula. AB - A 50-year-old male patient, a known case of chronic obstructive pulmonary disease (COPD), presented with the features of bronchopleural fistula (BPF) on the right side for 1 month. The patient was a chronic smoker and did not give any history suggestive of pulmonary Koch's. The patient had sudden-onset breathlessness and chest pain 1 month before, which was diagnosed to be due to spontaneous pneumothorax. An intercostal drain was inserted but even after 1 month of all conservative measures, the lung remained collapsed and there was large air leak in the intercostal drain. Computed tomogram (CT) of the chest revealed collapsed and entrapped lung with surgical emphysema of the subcutaneous tissues due to rupture of the emphysematous bulla on the right side along with the presence of emphysematous bullae on the left upper lobe also. Surgical intervention in the form of decortication of entrapped lung and repair of the BPF with intercostal muscle flap was performed. The patient recovered well and was discharged after 10 days. PMID- 25814801 TI - Rare Endobronchial metastasis from uterine leiomyosarcoma. AB - Uterine sarcomas are rare and represent approximately 3.2% of all invasive uterine cancers. The annual incidence rate is less than two per 100,000 women. The median age at which uterine sarcoma diagnosed is 56 years. The most common histologic pattern is leiomyosarcoma (LMS) which originates from the myometrium or myometrial vessels. Uterine LMSs are aggressive tumors with high rates of recurrence. The most common mode of spread is hematogenous, with lymphatic spread being rare. Recurrences of up to 70% are reported in stage I and II disease with the site of recurrence being distal, most commonly the lungs or the upper abdomen. But the intra bronchial spread is extremely rare. Here we are reporting a case of uterine LMS with endobronchial metastasis causing whole lung collapse. PMID- 25814799 TI - Anemia in Chronic obstructive pulmonary disease: Prevalence, pathogenesis, and potential impact. AB - Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable lifestyle-related disease with high global prevalence. COPD is associated with significant morbidity and mortality worldwide. Comorbidities are important events in the natural history of the disease and have a negative effect on the morbidity and mortality of COPD patients. Cardiac diseases, lung cancer, osteoporosis, and depression are common comorbidities reported for COPD. Recently, anemia has been recognized as a frequent comorbidity in COPD patients. The prevalence of anemia in patients with COPD varies from 7.5% to 33%. Anemia of chronic disease (ACD) is probably the most common type of anemia associated with COPD. ACD is driven by COPD-mediated systemic inflammation. Anemia in COPD is associated with greater healthcare resource utilization, impaired quality of life, decreased survival, and a greater likelihood of hospitalization. We need large prospective studies to discern the association between anemia and COPD. PMID- 25814802 TI - Management of severe obstructive sleep apnea using mandibular advancement devices with auto continuous positive airway pressures. AB - The use of continuous positive airway pressures (CPAP) is considered standard treatment of moderate to severe obstructive sleep apnea (OSA). Treatment of the disease poses a great challenge not only for its diagnostic purpose but also for its treatment part. In about 29-83% of the patients, treatment is difficult because of non-compliance resulting due to high pressures, air leaks and other related issues. In such situations, alternative methods of treatment need to be looked for so as to ascertain better management. Mandibular advancement devices along with CPAP may show better treatment outcome in specific situations. PMID- 25814803 TI - Serial bronchoscopic lung lavage in pulmonary alveolar proteinosis under local anesthesia. AB - Pulmonary alveolar proteinosis (PAP) is a rare disease, characterized by alveolar accumulation of surfactant composed of proteins and lipids due to defective surfactant clearance by alveolar macrophages. Mainstay of treatment is whole lung lavage, which requires general anesthesia. Herein, we report a case of primary PAP, successfully treated with serial bronchoscopic lung lavages under local anesthesia. PMID- 25814804 TI - Pulmonary nocardiosis revisited: A case series. AB - Pulmonary nocardiosis is a rising bacterial infection, with a high propensity for misdiagnosis. On account of a paucity of prospective studies, there is limited understanding on various aspects of its diagnosis and treatment. We present three patients with pulmonary nocardiosis, with emphasis on the predisposing factors, variable disease course, and treatment issues. There is a need to understand the basis of these discrepancies so as to rationalize the management of this potentially fatal infection. PMID- 25814805 TI - Unexplained dyspnea in a patient of chronic arsenicosis: A diagnostic challenge and learning curve for physicians. AB - Chronic arsenic exposure causes cutaneous effects like hyperkeratosis, peripheral vascular disease, hypertension, ischemic heart disease, non-cirrhotic portal hypertension, hepatomegaly, peripheral neuropathy, respiratory involvement, bad obstetrical outcome, hematological disturbances, and diabetes mellitus. Here we present a case of a 24-year-old lady, with chronic exposure to arsenic, presenting to us with progressive dyspnea. We found pulmonary arterial hypertension (PAH) as a cause of her dyspnea. PAH can occur in arsenicosis, secondary to arsenic-induced chronic obstructive pulmonary disease (COPD), lung fibrosis, and portal hypertension, which we excluded by appropriate investigations in our case. We also excluded a familial or heritable form of PAH. Thus, with the exclusion of all these secondary causes of PAH, as well as a hereditary cause, we came to a conclusion that this PAH might be due to chronic arsenic exposure. To the best of our knowledge, no case of PAH in chronic arsenicosis has been reported to date. PMID- 25814806 TI - Tubercular and bacterial coinfection: A case series. AB - Tuberculosis (TB) is a major public health issue in India. Although dual infection with tuberculosis and bacteria/fungi has been reported in immunocompromised patients, their co-occurrence in individuals with preserved immunity may complicate the clinical presentation, leading to inadequate treatment and unsatisfactory outcomes. In patients with pulmonary tuberculosis, the occurrence of tubercular lesions in atypical locations may further confound the clinical picture if only one of the pathogens is isolated, initially leading to a suboptimal therapeutic response. A strong index of suspicion and additional diagnostic testing may be required for diagnosis and treatment of the second infection. We report three unusual cases of concurrent tubercular and bacterial infection, of which two are pulmonary and one is extrapulmonary. PMID- 25814807 TI - Diffuse alveolar hemorrhage due to valproic acid: Case report and review of the literature. AB - Valproic acid (VPA) is one of the most frequently used antiepileptic drugs for the treatment of focal and generalized epilepsies, absence seizures, and Lennox Gastaut syndrome (LGS). VPA has been demonstrated to have a negative effect on both the intrinsic and extrinsic coagulation systems and controversy exists about the clinical relevance of such hematological abnormalities. We describe a case of reversible lung hemorrage due to VPA. In English-language literature only two other similar cases (one of which fatal) have been described so far. PMID- 25814808 TI - Respiratory failure with hilar mass: Role of endobronchial ultrasound-guided transbronchial needle aspiration in the medical intensive care unit. AB - We report the case of a 58-year-old man on chronic steroid therapy, who developed a rapidly progressive right upper lobe infiltrate/mass that extended into the right hilum. Respiratory failure necessitated endotracheal intubation. Broad spectrum antibiotics were initiated without clinical improvement and because of his immunosuppressive therapy opportunistic pathogens were considered. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed in the Medical Intensive Care Unit (MICU) with rapid onsite evaluation. Specimens obtained from the right hilar mass revealed organisms suspicious for cryptococcal infection, subsequently confirmed via a culture. No complications occurred during the EBUS procedure despite the patient requiring vasopressor support and 100% inspired oxygen. Little data exists regarding the use of EBUS in patients admitted to the MICU with respiratory failure of unknown etiology and mediastinal/hilar lymphadenopathy. This case illustrates the potential safe use of EBUS-TBNA in patients presenting with respiratory failure, with a mediastinal or hilar mass and suspected infectious etiology. PMID- 25814809 TI - Mutifaceted care of OSA: The role of mandibular advancement splints. PMID- 25814810 TI - Peripheral wedge-shaped radiographic lung opacity in a young patient. PMID- 25814811 TI - Diffuse cystic lung disease in a child. PMID- 25814812 TI - Tuberculosis of palate. PMID- 25814813 TI - Advanced large cell lung tumor with neuroendocrine differentiation in an HIV positive patient. PMID- 25814814 TI - Hemodynamically asymptomatic spontaneous rupture of the descending thoracic aorta masquerading as a lung mass. PMID- 25814815 TI - An unusual case of mesothelioma. PMID- 25814816 TI - POEMS syndrome with pulmonary nocardiosis: A unique presentation. PMID- 25814817 TI - Diagnostic utility of conventional transbronchial needle aspiration without rapid on-site evaluation in patients with lung cancer. PMID- 25814818 TI - The relationship between lung function and indoor air pollution among rural women in the Niger Delta region of Nigeria. PMID- 25814819 TI - Osteoporosis in chronic obstructive pulmonary disease. PMID- 25814820 TI - Retrospective cohort versus case-control study - A comment on chronic obstructive pulmonary disease and low bone mass: A case-control study. PMID- 25814821 TI - Respond to Vitamin D status in adult critically ill patients in Eastern India: An observational retrospective study. PMID- 25814822 TI - 'Oorja' in India: Assessing a large-scale commercial distribution of advanced biomass stoves to households. AB - Replacing traditional stoves with advanced alternatives that burn more cleanly has the potential to ameliorate major health problems associated with indoor air pollution in developing countries. With a few exceptions, large government and charitable programs to distribute advanced stoves have not had the desired impact. Commercially-based distributions that seek cost recovery and even profits might plausibly do better, both because they encourage distributors to supply and promote products that people want and because they are based around properly incentivized supply chains that could more be scalable, sustainable, and replicable. The sale in India of over 400,000 "Oorja" stoves to households from 2006 onwards represents the largest commercially-based distribution of a gasification-type advanced biomass stove. BP's Emerging Consumer Markets (ECM) division and then successor company First Energy sold this stove and the pelletized biomass fuel on which it operates. We assess the success of this effort and the role its commercial aspect played in outcomes using a survey of 998 households in areas of Maharashtra and Karnataka where the stove was sold as well as detailed interviews with BP and First Energy staff. Statistical models based on this data indicate that Oorja purchase rates were significantly influenced by the intensity of Oorja marketing in a region as well as by pre existing stove mix among households. The highest rate of adoption came from LPG using households for which Oorja's pelletized biomass fuel reduced costs. Smoke- and health-related messages from Oorja marketing did not significantly influence the purchase decision, although they did appear to affect household perceptions about smoke. By the time of our survey, only 9% of households that purchased Oorja were still using the stove, the result in large part of difficulties First Energy encountered in developing a viable supply chain around low-cost procurement of "agricultural waste" to make pellets. The business orientation of First Energy allowed the company to pivot rapidly to commercial customers when the household market encountered difficulties. The business background of managers also facilitated the initial marketing and distribution efforts that allowed the stove distribution to reach scale. PMID- 25814823 TI - Factors that may Facilitate or Hinder a Family-Focus in the Treatment of Parents with a Mental Illness. AB - Children with mentally ill parents are at risk of developing mental health problems themselves. To enhance early support for these children may prevent mental health problems from being transmitted from one generation to the next. The sample (N = 219) included health professionals in a large university hospital, who responded to a web-based survey on the routines of the mental health services, attitudes within the workforce capacity, worker's knowledge on the impact of parental mental illness on children, knowledge on legislation concerning children of patients, experience, expectations for possible outcomes of change in current clinical practice and demographic variables. A total of 56 % reported that they did not identify whether or not patients had children. There were no significant differences between the groups (identifiers and non identifiers) except for the two scales measuring aspects of knowledge, i.e., Knowledge Children and Knowledge Legislation where workers who identified children had higher scores. The results also showed that younger workers with a medium level of education scored higher on Positive Attitudes. Furthermore, workers who reported to have more knowledge about children and the impact of mental illness on the parenting role were less concerned about a child-focussed approach interfering with the patient-therapist relation. PMID- 25814824 TI - CFH Y402H polymorphism is associated with elevated vitreal GM-CSF and choroidal macrophages in the postmortem human eye. AB - PURPOSE: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people 50 years of age or older in developed countries. The homozygous CC genotype in the complement factor H (CFH) Y402H single nucleotide polymorphism (SNP; rs1061170) is widely recognized as a risk factor for the development of AMD. In this study, we examined vitreal levels of granulocyte macrophage colony-stimulating factor (GM-CSF), a hematopoietic cytokine, and macrophages in the choroid of postmortem human eyes genotyped for the CFH Y402H SNP. METHODS: Twenty-two pairs of postmortem, non-diseased, human donor eyes were obtained. The vitreous and retinal tissues of the left eyes were collected for GM-CSF level measurement and CFH Y402H genotyping, respectively. The right eyes were paraffin-embedded and sectioned for immunohistochemistry using a macrophage and microglia marker, CD68. Cell cultures of RPE cells were stimulated with complement C3a, C5a, 4-hydroxynonenal (HNE), or tumor necrosis factor alpha (TNF-alpha), and GM-CSF expression was measured with a suspension assay or quantitative PCR. RESULTS: Eyes genotyped with the CC or the CT risk variant of the CFH Y402H SNP showed significantly increased levels of GM-CSF in the vitreous compared to eyes with the protective TT variant (mean +/- standard error of mean, 607.54+/-85.83 pg/ml or 656.32+/-15.20 pg/ml versus 286.69+/-81.96 pg/ml, p<0.05). The choroid of eye tissues genotyped with the CC variant showed higher levels of CD68 immunoreactivity than the tissues genotyped with the TT variant (p<0.05). The GM-CSF levels detected in the supernatant of RPE cells in culture treated with HNE or TNF-alpha were significantly higher compared to the non-treated control (145.88+/-5.06 pg/ml and 149.32+/-3.76 pg/ml versus 123.27+/ 4.05 pg/ml, p<0.05). Furthermore, the gene expression of GM-CSF detected in the lysate of RPE cells stimulated with complement C3a or C5a showed significantly increased fold changes compared to the non-treated control (C3a: 2.38+/-0.31 fold, p<0.05; C5a: 2.84+/-0.54 fold, p<0.01). CONCLUSIONS: Our data showed a relationship between the CFH Y402H polymorphism and GM-CSF levels in the vitreous and accumulation of choroidal macrophages in the postmortem eye. These data suggest that the at-risk variant of the CFH gene may contribute to the dysregulation of proinflammatory cytokines locally in the eye. PMID- 25814826 TI - Analysis of rare variants in the CFH gene in patients with the cuticular drusen subtype of age-related macular degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) and cuticular drusen (CD), a clinical subtype of AMD, have been linked to genetic variants in the complement factor H (CFH) gene. In this study, we aimed to investigate the frequency of rare variants in the CFH gene in 180 cases with CD. In addition, we aimed to determine the frequency of a previously reported rare, highly penetrant CFH variant (p.Arg1210Cys) in a Dutch-German non-CD-type AMD case-control cohort, and to describe the phenotype of patients carrying the p.Arg1210Cys variant. METHODS: Study subjects were selected from the European Genetic Database (EUGENDA), a joint AMD database of the Radboud University Medical Centre and the University Hospital of Cologne, and graded at the Cologne Image Reading Centre and Laboratory (CIRCL). Additionally, two CD cases were recruited from the VU Medical Centre in Amsterdam. The CFH gene was analyzed in 180 CD cases with Sanger sequencing. All identified variants were analyzed for potential damaging effects with prediction software tools Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen). In addition, we genotyped the p.Arg1210Cys variant in 813 non-CD type AMD cases and 1175 controls. RESULTS: Sequencing identified 11 rare, heterozygous missense variants, one frameshift variant, and one splice acceptor site variant in 16 CD cases. The p.Arg1210Cys variant was identified in two CD cases but was not identified in our Dutch-German non-CD-type AMD case-control cohort. CONCLUSIONS: The present study identified the presence of rare variants in the CFH gene in 16 (8.8%) of 180 patients with the CD subtype of AMD. The carriers of rare CFH variants displayed a significantly earlier age at onset than non-carriers (p=0.016). The rare missense variant p.Arg1210Cys was identified in two CD cases, but was not detected in 813 non-CD type AMD cases or in the 1,175 controls of our Dutch-German cohort. The current study suggests that the p.Arg1210Cys variant may be restricted to a subset of patients with the CD subtype of AMD. Detailed clinical phenotyping, including fluorescein angiography, of patients with AMD carrying the p.Arg1210Cys variant in other cohorts is required to confirm this finding. PMID- 25814825 TI - Presence of rd8 mutation does not alter the ocular phenotype of late-onset retinal degeneration mouse model. AB - PURPOSE: A spontaneous frameshift mutation, c.3481delC, in the Crb1 gene is the underlying cause of dysplasia and retinal degeneration in rd8 mice. The rd8 mutation is found in C57BL/6N but not in C57BL/6J mouse sub-strains. The development of ocular pathology in single knockout Ccl2-/-, Cx3cr1-/- and in double knockout Ccl2-/-, Cx3cr1-/- mice raised on a C57BL/6 background has been reported to depend on the presence of a rd8 mutation. In this study, we investigated the influence of the rd8 mutation on the retinal pathology that we previously described in the late-onset retinal degeneration (L-ORD) mouse model with a heterozygous S163R mutation in the C1q-tumor necrosis factor-related protein-5Ctrp5+/- gene that was generated on a C57BL/6J background. METHODS: Mouse lines carrying the Ctrp5 S163R and rd8 mutations (Ctrp5+/-;rd8/rd8), corresponding controls without the rd8 mutation (Ctrp5+/-;wt/wt), and wild-type mice with and without the rd8 mutation (Wtrd8/rd8 and Wtwt/wt, respectively) were generated by systematic breeding of mice in our L-ORD mouse colony. Genotyping the mice for the rd8 (del C at nt3481 in Crb1) and Ctrp5 S163R mutations was performed with allelic PCR or sequencing. Retinal morphology was studied with fundus imaging, histology, light microscopy, electron microscopy, and immunohistochemistry. RESULTS: Genotype analysis of the mice in L-ORD mouse colony detected the rd8 mutation in the homozygous and heterozygous state. Fundus imaging of wild-type mice without the rd8 mutation (Wtwt/wt) revealed no autofluorescence (AF) spots up to 6-8 months and few AF spots at 21 months. However, the accumulation of AF lesions accelerated with age in the Ctrp5+/- mice that lack the rd8 mutation (Ctrp5+/-;wt/wt). The number of AF lesions was significantly increased (p<0.001), and they were small and uniformly distributed throughout the retina in the 21-month-old Ctrp5+/-;wt/wt mice when compared to the age-matched controls. Wild-type and Ctrp5+/- mice with the rd8 mutation (Wtrd8/rd8 and Ctrp5+/-;rd8/rd8, respectively) revealed an integrated retinal architecture with well-defined outer segments/inner segments (OS/IS), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). The presence of pseudorosette structures reported in the rd8 mice between the ONL and the INL in the ventral quadrant of the retina was not observed in all genotypes studied. Further, the external limiting membrane was continuous in the Ctrp5+/-;rd8/rd8 and Wtrd8/rd8 mice. Evaluation of the retinal phenotype revealed that the Ctrp5+/-;wt/wt mice developed characteristic L-ORD pathology including age-dependent accumulation of AF spots, development of sub-retinal, sub-RPE, and basal laminar deposits, and Bruch's membrane abnormalities at older age, while these changes were not observed in the age-matched littermate WTwt/wt mice. CONCLUSIONS: The Wtrd8/rd8 and Ctrp5+/-;rd8/rd8 mice raised on C57BL/6J did not develop early onset retinal changes that are characteristic of the rd8 phenotype, supporting the hypothesis that manifestation of rd8-associated pathology depends on the genetic background. The retinal pathology observed in mice with the Ctrp5+/-;wt/wt genotype is consistent with the L-ORD phenotype observed in patients and with the phenotype we described previously. The lack of rd8 associated retinal pathology in the Ctrp5+/-;wt/wt mouse model raised on the C57BL/6J background and the development of the L-ORD phenotype in these mice in the presence and absence of the rd8 mutation suggests that the pathology observed in the Ctrp5+/-;wt/wt mice is primarily associated with the S163R mutation in the Ctrp5 gene. PMID- 25814827 TI - Cytokine changes in tears and relationship to contact lens discomfort. AB - PURPOSE: To determine the reproducibility of a multiplex bead assay for measuring cytokines in tears and correlations between ocular discomfort with or without contact lens wear and the concentration of cytokines in tears. METHODS: Ninety participants (divided into two groups) were enrolled in this prospective study. They were asked to rate their ocular comfort and collect their tears in the morning and just before sleep for 10 days with or without contact lenses. The participants collected their tears using a glass microcapillary tube for both stages. Galyfilcon A lenses were worn on a daily disposable basis during the contact lens stage, and comfort scores and tears were collected before lens insertion and prior to lens removal at the end of the day. Tears were analyzed for cytokine concentrations using a 27-plex multibead assay. Correlations were sought between cytokine concentrations and comfort. RESULTS: There was a significant (p<0.022) decrease in ocular comfort over the day with or without lens wear. The magnitude of ocular discomfort was significantly greater (p<0.009) with lens wear. The concentrations of 12 cytokines differed significantly between the groups; thus, these cytokines were not analyzed further. For the remaining 15 cytokines, interleukin-8 (IL-8) was the only cytokine that changed in both groups during the day without (reduced by >-0.5 Log pg/ml, p<0.001) or with lens wear (reduced by >-0.2 Log pg/ml, p<0.001). The change in the vascular endothelial growth factor (VEGF) concentration only in tears was correlated to ocular comfort, but this was not changed by contact lens wear. CONCLUSIONS: Ocular comfort during the day is magnified by contact lens wear. However, the increase in the change in comfort during lens wear was not associated with changes in 15 cytokines in the tear film. PMID- 25814828 TI - Novel homozygous large deletion including the 5' part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family. AB - PURPOSE: To identify the genetic defect in a consanguineous Israeli Muslim Arab family with juvenile retinitis pigmentosa (RP). METHODS: DNA samples were collected from the index patient, her parents, her affected sister, and two non affected siblings. Genome-wide linkage analysis with 250 K single nucleotide polymorphism (SNP) arrays was performed using DNA from the two affected patients. Owing to consanguinity in the family, we applied homozygosity mapping to identify the disease-causing gene. The candidate gene SPATA7 was screened for mutations with PCR amplifications and direct Sanger sequencing. RESULTS: Following high density SNP arrays, we identified several homozygous genomic regions one of which included the SPATA7 gene. Several mutations in SPATA7 have been reported for various forms of retinal dystrophy, including Leber congenital amaurosis (LCA) and juvenile RP. PCR-based sequence content mapping, long-distance PCR amplifications, and subsequent sequencing analysis revealed a homozygous 63.4 kb large deletion that encompasses the 5' part of the SPATA7 gene including exons 1 5. The mutation showed concordant segregation with the phenotype in the family as expected for autosomal recessive mode of inheritance and is consistent with a diagnosis of juvenile RP. CONCLUSIONS: We report a novel homozygous large deletion in SPATA7 associated with juvenile RP in a consanguineous Israeli Muslim Arab family. This is the first larger deletion mutation reported for SPATA7. PMID- 25814829 TI - Lens capsule structure assessed with atomic force microscopy. AB - PURPOSE: To image the ultrastructure of the anterior lens capsule at the nanoscale level using atomic force microscopy (AFM). METHODS: Experiments were performed on anterior lens capsules maintained in their in situ location surrounding the lens from six human cadavers (donor age range: 44-88 years), four cynomolgus monkeys (Macaca fascicularis age range: 4.83-8.92 years), and seven pigs (<6 months). Hydration of all samples was maintained using Dulbecco's Modified Eagle Medium (DMEM). Whole lenses were removed from the eye and placed anterior side up in agarose gel before gel hardening where only the posterior half of the lens was contained within the gel. After the gel hardened, the Petri dish was filled with DMEM until the point where the intact lens was fully submerged. AFM was used to image the anterior lens surface in contact mode. An integrated analysis program was used to calculate the interfibrillar spacing, fiber diameter, and surface roughness of the samples. RESULTS: The AFM images depict a highly ordered fibrous structure at the surface of the lens capsule in all three species. The interfibrillar spacing for the porcine, cynomolgus monkey, and human lens capsules was 0.68+/-0.25, 1.80+/-0.39, and 1.08+/-0.25 MUm, respectively. In the primate, interfibrillar spacing significantly decreased linearly as a function of age. The fiber diameters ranged from 50 to 950 nm. Comparison of the root mean square (RMS) and average deviation demonstrate that the surface of the porcine lens capsule is the smoothest, and that the human and cynomolgus monkey capsules are significantly rougher. CONCLUSIONS: AFM was successful in providing high-resolution images of the nanostructure of the lens capsule samples. Species-dependent differences were observed in the overall structure and surface roughness. PMID- 25814830 TI - Synthesis and Interfacial Activity of Novel Heterogemini Sulfobetaines in Aqueous Solution. AB - Three new heterogemini sulfobetaines and their chloride salts were synthesised. The interfacial activities of the obtained chlorides in aqueous solution were studied by equilibrium and dynamic surface tension measurements. The critical micelle concentration, surface excess concentration, minimum area per surfactant molecule and standard Gibbs energy of adsorption as well as micelle lifetime and diffusion coefficient were determined. The adsorption properties and micelle lifetime of these compounds significantly depend on the length of alkyl chain. The critical micelle concentration decreases with increasing chain length of the compounds considered. The values of the diffusion coefficient of N-alkyl-N-methyl N-(3-sulfopropyl)-6-(N-alkyl-N-methylamino)hexylammonium chloride tend to decrease as the concentration is increased. PMID- 25814831 TI - Developing a Co-Regulated, Cue-Based Feeding Practice: The Critical Role of Assessment and Reflection. AB - Assessment of early feeding skills of vulnerable infants is common practice in neonatal care centers. However, assessment is often merely an identification of feeding outcomes, rather than a description of the infant's capacities and methods of adapting to the feeding challenge. Descriptive assessment of the feeding process takes into account the dynamic nature of feeding and notes changes that occur as the infant matures and gains feeding experience. Assessment of the variability that occurs during the feeding as the challenge changes, due to fatigue or physiologic instability, are critical to understanding the infant's feeding skills. As individual components of the feeding are assessed, such as sucking, swallowing and breathing, a reflective process builds understanding of the patterns of coordination of system components in relation to one another. Taking the whole into account and considering the dynamics of the process is necessary if we are going to select appropriate interventions targeted to the individual infant's feeding skills. Using a very preterm infant case, this paper will illustrate assessment of early feeding skills and demonstrate how reflection on and integration of the components of the assessment identifies potential targets for co-regulated, cue-based feeding. PMID- 25814832 TI - Acetic Acid Mediated Synthesis of Phosphonate-Substituted Titanium Oxo Clusters. AB - New phosphonate/acetate-substituted titanium oxo/alkoxo clusters were prepared from Ti(OiPr)4 and bis(trimethylsilyl) phosphonates in the presence of acetic acid, which served to generate water in situ through ester formation. The process led to clusters with a higher degree of condensation than in previously known phosphonate-substituted titanium oxo clusters. The clusters [Ti6O4(OiPr)10(OAc)2(O3PR)2] (OAc = acetate) were obtained for a large variety of functional and non-functional groups R under a range of reaction conditions. This cluster type, which is also retained in solution, therefore appears to be very robust. Two other clusters, [Ti5O(OiPr)11(OAc)(O3PCH2CH2CH2Br)3] and [Ti5O3(OiPr)6(OAc)4(O3P-xylyl)2], were only isolated in special cases. PMID- 25814833 TI - Mixed-Metal Oxo Clusters Structurally Derived from Ti6O4(OR)8(OOCR')8. AB - The mixed-metal oxo clusters FeTi5O4(OiPr)4(OMc)10 (OMc = methacrylate), Zn2Ti4O4(OiPr)2(OMc)10, Cd4Ti2O2(OAc)2(OMc)10(HOiPr)2, [Ca2Ti4O4(OAc)2(OMc)10] n , and [Sr2Ti4O4(OMc)12(HOMc)2] n were obtained from the reaction of titanium alkoxides with the corresponding metal acetates and methacrylic acid. Their structures are derived from Ti clusters with the composition Ti6O4(OR)8(OOCR')8. The Ca and Sr derivatives consist of chains of condensed clusters. PMID- 25814835 TI - Opposite-side flavour tagging of B mesons at the LHCb experiment. AB - The calibration and performance of the opposite-side flavour tagging algorithms used for the measurements of time-dependent asymmetries at the LHCb experiment are described. The algorithms have been developed using simulated events and optimized and calibrated with B+->J/psiK+, B0->J/psiK*0 and B0->D*-MU+nuMU decay modes with 0.37 fb-1 of data collected in pp collisions at [Formula: see text] during the 2011 physics run. The opposite-side tagging power is determined in the B+->J/psiK+ channel to be (2.10+/-0.08+/-0.24) %, where the first uncertainty is statistical and the second is systematic. PMID- 25814836 TI - Measurement of Upsilon production in pp collisions at [Formula: see text]. AB - The production of Upsilon(1S), Upsilon(2S) and Upsilon(3S) mesons in proton proton collisions at the centre-of-mass energy of [Formula: see text] is studied with the LHCb detector. The analysis is based on a data sample of 25 pb-1 collected at the Large Hadron Collider. The Upsilon mesons are reconstructed in the decay mode Upsilon->MU+MU- and the signal yields are extracted from a fit to the MU+MU- invariant mass distributions. The differential production cross sections times dimuon branching fractions are measured as a function of the Upsilon transverse momentum pT and rapidity y, over the range pT <15 GeV/c and 2.0J/psi+gamma, with the photon converting into an e+e- pair for J/psi rapidity |y(J/psi)|<1.0 and photon transverse momentum pT(gamma)>0.5 GeV/c. The measurement is given for six intervals of pT(J/psi) between 7 and 25 GeV/c. The results are compared to theoretical predictions. PMID- 25814843 TI - Search for charged Higgs bosons in e+e- collisions at [Formula: see text]. AB - A search is made for charged Higgs bosons predicted by Two-Higgs-Doublet extensions of the Standard Model (2HDM) using electron-positron collision data collected by the OPAL experiment at [Formula: see text], corresponding to an integrated luminosity of approximately 600 pb-1. Charged Higgs bosons are assumed to be pair-produced and to decay into [Formula: see text], taunutau or AW+/-. No signal is observed. Model-independent limits on the charged Higgs-boson production cross section are derived by combining these results with previous searches at lower energies. Under the assumption [Formula: see text], motivated by general 2HDM type II models, excluded areas on the [Formula: see text] plane are presented and charged Higgs bosons are excluded up to a mass of 76.3 GeV at 95 % confidence level, independent of the branching ratio BR(H+/-->taunutau ). A scan of the 2HDM type I model parameter space is performed and limits on the Higgs-boson masses [Formula: see text] and mA are presented for different choices of tanbeta. PMID- 25814849 TI - The post-Higgs MSSM scenario: habemus MSSM? AB - We analyze the Minimal Supersymmetric extension of the Standard Model that we have after the discovery of the Higgs boson at the LHC, the hMSSM (habemus MSSM?), i.e. a model in which the lighter h boson has a mass of approximately 125 GeV which, together with the non-observation of superparticles at the LHC, indicates that the SUSY-breaking scale MS is rather high, MS ?1 TeV. We first demonstrate that the value Mh ~125 GeV fixes the dominant radiative corrections that enter the MSSM Higgs boson masses, leading to a Higgs sector that can be described, to a good approximation, by only two free parameters. In a second step, we consider the direct supersymmetric radiative corrections and show that, to a good approximation, the phenomenology of the lighter Higgs state can be described by its mass and three couplings: those to massive gauge bosons and to top and bottom quarks. We perform a fit of these couplings using the latest LHC data on the production and decay rates of the light h boson and combine it with the limits from the negative search of the heavier H,A and H+/- states, taking into account the current uncertainties. PMID- 25814845 TI - Measurement of psi(2S) meson production in pp collisions at [Formula: see text]. AB - The differential cross-section for the inclusive production of psi(2S) mesons in pp collisions at [Formula: see text] has been measured with the LHCb detector. The data sample corresponds to an integrated luminosity of 36 pb-1. The psi(2S) mesons are reconstructed in the decay channels psi(2S)->MU+MU- and psi(2S) >J/psipi+pi-, with the J/psi meson decaying into two muons. Results are presented both for promptly produced psi(2S) mesons and for those originating from b-hadron decays. In the kinematic range pT(psi(2S))<=16 GeV/c and 2MU+MU- is performed to measure the polarization of prompt J/psi mesons produced in pp collisions at [Formula: see text]. The dataset corresponds to an integrated luminosity of 0.37 fb-1 collected with the LHCb detector. The measurement is presented as a function of transverse momentum, pT, and rapidity, y, of the J/psi meson, in the kinematic region 2e+e- has been measured and found to be in agreement with models implementing QED at leading order. PMID- 25814850 TI - Energy dependence of the transverse momentum distributions of charged particles in pp collisions measured by ALICE. AB - Differential cross sections of charged particles in inelastic pp collisions as a function of pT have been measured at [Formula: see text] at the LHC. The pT spectra are compared to NLO-pQCD calculations. Though the differential cross section for an individual [Formula: see text] cannot be described by NLO-pQCD, the relative increase of cross section with [Formula: see text] is in agreement with NLO-pQCD. Based on these measurements and observations, procedures are discussed to construct pp reference spectra at [Formula: see text] up to pT=50 GeV/c as required for the calculation of the nuclear modification factor in nucleus-nucleus and proton-nucleus collisions. PMID- 25814837 TI - Measurement of the charge asymmetry in top quark pair production in pp collisions at [Formula: see text] using the ATLAS detector. AB - A measurement of the top-antitop production charge asymmetry AC is presented using data corresponding to an integrated luminosity of 1.04 fb-1 of pp collisions at [Formula: see text] TeV collected by the ATLAS detector at the LHC. Events are selected with a single lepton (electron or muon), missing transverse momentum and at least four jets of which at least one jet is identified as coming from a b-quark. A kinematic fit is used to reconstruct the [Formula: see text] event topology. After background subtraction, a Bayesian unfolding procedure is performed to correct for acceptance and detector effects. The measured value of AC is [Formula: see text], consistent with the prediction from the MC@NLO Monte Carlo generator of AC =0.006+/-0.002. Measurements of AC in two ranges of invariant mass of the top-antitop pair are also shown. PMID- 25814838 TI - Search for lepton flavour violation in the eMU continuum with the ATLAS detector in [Formula: see text]pp collisions at the LHC. AB - This paper presents a search for the t-channel exchange of an R-parity violating scalar top quark ([Formula: see text]) in the e+/-MU? continuum using 2.1 fb-1 of data collected by the ATLAS detector in [Formula: see text]pp collisions at the Large Hadron Collider. Data are found to be consistent with the expectation from the Standard Model backgrounds. Limits on R-parity-violating couplings at 95 % C.L. are calculated as a function of the scalar top mass ([Formula: see text]). The upper limits on the production cross section for pp->eMUX, through the t channel exchange of a scalar top quark, ranges from 170 fb for [Formula: see text] to 30 fb for [Formula: see text]. PMID- 25814859 TI - Performance of the LHCb RICH detector at the LHC. AB - The LHCb experiment has been taking data at the Large Hadron Collider (LHC) at CERN since the end of 2009. One of its key detector components is the Ring Imaging Cherenkov (RICH) system. This provides charged particle identification over a wide momentum range, from 2-100 GeV/c. The operation and control, software, and online monitoring of the RICH system are described. The particle identification performance is presented, as measured using data from the LHC. Excellent separation of hadronic particle types (pi, K, p) is achieved. PMID- 25814858 TI - Measurement of the forward energy flow in pp collisions at [Formula: see text]. AB - The energy flow created in pp collisions at [Formula: see text] is studied within the pseudorapidity range 1.90.25 GeV/c. Jets are reconstructed from charged-particles only and required to have pT>5 GeV/c. The distributions of jet pT, average pT of charged particles belonging to the underlying event or to jets, jet rates, and jet shapes are presented as functions of Nch and compared to the predictions of the pythia and herwig event generators. Predictions without multi-parton interactions fail completely to describe the Nch-dependence observed in the data. For increasing Nch, pythia systematically predicts higher jet rates and harder pT spectra than seen in the data, whereas herwig shows the opposite trends. At the highest multiplicity, the data-model agreement is worse for most observables, indicating the need for further tuning and/or new model ingredients. PMID- 25814862 TI - Measurements of the branching fractions of [Formula: see text] decays. AB - The branching fractions of the decay [Formula: see text] for different intermediate states are measured using data, corresponding to an integrated luminosity of 1.0 fb-1, collected by the LHCb experiment. The total branching fraction, its charmless component [Formula: see text] and the branching fractions via the resonant [Formula: see text] states etac (1S) and psi(2S) relative to the decay via a J/psi intermediate state are [Formula: see text] Upper limits on the B+ branching fractions into the etac (2S) meson and into the charmonium-like states X(3872) and X(3915) are also obtained. PMID- 25814840 TI - Measurement of the top quark mass with the template method in the [Formula: see text] channel using ATLAS data. AB - The top quark mass has been measured using the template method in the [Formula: see text] channel based on data recorded in 2011 with the ATLAS detector at the LHC. The data were taken at a proton-proton centre-of-mass energy of [Formula: see text] and correspond to an integrated luminosity of 1.04 fb-1. The analyses in the e+jets and MU+jets decay channels yield consistent results. The top quark mass is measured to be mtop=174.5+/-0.6stat+/-2.3syst GeV. PMID- 25814861 TI - Measurement of inelastic, single- and double-diffraction cross sections in proton proton collisions at the LHC with ALICE. AB - Measurements of cross sections of inelastic and diffractive processes in proton proton collisions at LHC energies were carried out with the ALICE detector. The fractions of diffractive processes in inelastic collisions were determined from a study of gaps in charged particle pseudorapidity distributions: for single diffraction (diffractive mass MX <200 GeV/c2) [Formula: see text], and [Formula: see text], respectively at centre-of-mass energies [Formula: see text]; for double diffraction (for a pseudorapidity gap Deltaeta>3) sigmaDD/sigmaINEL=0.11+/ 0.03,0.12+/-0.05, and [Formula: see text], respectively at [Formula: see text]. To measure the inelastic cross section, beam properties were determined with van der Meer scans, and, using a simulation of diffraction adjusted to data, the following values were obtained: [Formula: see text] mb at [Formula: see text] and [Formula: see text] at [Formula: see text]. The single- and double-diffractive cross sections were calculated combining relative rates of diffraction with inelastic cross sections. The results are compared to previous measurements at proton-antiproton and proton-proton colliders at lower energies, to measurements by other experiments at the LHC, and to theoretical models. PMID- 25814853 TI - Measurement of the sum of WW and WZ production with W+dijet events in pp collisions at [Formula: see text]. AB - A measurement of the inclusive WW+WZ diboson production cross section in proton proton collisions is reported, based on events containing a leptonically decaying W boson and exactly two jets. The data sample, collected at [Formula: see text] with the CMS detector at the LHC, corresponds to an integrated luminosity of 5.0 fb-1. The measured value of the sum of the inclusive WW and WZ cross sections is sigma(pp->WW+WZ)=68.9+/-8.7 (stat.)+/-9.7 (syst.)+/-1.5 (lum.) pb, consistent with the standard model prediction of 65.6+/-2.2 pb. This is the first measurement of WW+WZ production in pp collisions using this signature. No evidence for anomalous triple gauge couplings is found and upper limits are set on their magnitudes. PMID- 25814842 TI - Measurement of tau polarization in W->taunu decays with the ATLAS detector in pp collisions at [Formula: see text]. AB - In this paper, a measurement of tau polarization in W->taunu decays is presented. It is measured from the energies of the decay products in hadronic tau decays with a single final state charged particle. The data, corresponding to an integrated luminosity of 24 pb-1, were collected by the ATLAS experiment at the Large Hadron Collider in 2010. The measured value of the tau polarization is [Formula: see text], in agreement with the Standard Model prediction, and is consistent with a physically allowed 95 % CL interval [-1,-0.91]. Measurements of tau polarization have not previously been made at hadron colliders. PMID- 25814844 TI - A search for [Formula: see text] resonances with the ATLAS detector in 2.05 fb-1 of proton-proton collisions at [Formula: see text]. AB - A search for top quark pair resonances in final states containing at least one electron or muon has been performed with the ATLAS experiment at the CERN Large Hadron Collider. The search uses a data sample corresponding to an integrated luminosity of 2.05 fb-1, which was recorded in 2011 at a proton-proton centre-of mass energy of 7 TeV. No evidence for a resonance is found and limits are set on the production cross-section times branching ratio to [Formula: see text] for narrow and wide resonances. For narrow Z' bosons, the observed 95 % Bayesian credibility level limits range from 9.3 pb to 0.95 pb for masses in the range of mZ'=500 GeV to mZ'=1300 GeV. The corresponding excluded mass region for a leptophobic topcolour Z' boson (Kaluza-Klein gluon excitation in the Randall Sundrum model) is mZ'<880 GeV ([Formula: see text]). PMID- 25814869 TI - QCD corrections to [Formula: see text] in FDR. AB - I apply FDR-a recently introduced four-dimensional approach to quantum field theories (QFTs)-to the computation of the NLO QCD corrections to [Formula: see text] in the large top mass limit. The calculation involves all key ingredients of QCD-namely ultraviolet, infrared, and collinear divergences, besides [Formula: see text] renormalization-and paves the way for successful use of FDR in massless one-loop QFT computations. I show in detail how the correct result emerges in FDR, and discuss the translation rules to dimensional regularization. PMID- 25814870 TI - Higgs characterisation via vector-boson fusion and associated production: NLO and parton-shower effects. AB - Vector-boson fusion and associated production at the LHC can provide key information on the strength and structure of the Higgs couplings to the Standard Model particles. Using an effective field theory approach, we study the effects of next-to-leading order (NLO) QCD corrections matched to a parton shower on selected observables for various spin-0 hypotheses. We find that inclusion of NLO corrections is needed to reduce the theoretical uncertainties on the total rates as well as to reliably predict the shapes of the distributions. Our results are obtained in a fully automatic way via FeynRules and MadGraph5_aMC@NLO. PMID- 25814841 TI - Search for heavy neutrinos and right-handed W bosons in events with two leptons and jets in pp collisions at [Formula: see text] with the ATLAS detector. AB - This letter reports on a search for hypothetical heavy neutrinos, N, and right handed gauge bosons, WR, in events with high transverse momentum objects which include two reconstructed leptons and at least one hadronic jet. The results were obtained from data corresponding to an integrated luminosity of 2.1 fb-1 collected in proton-proton collisions at [Formula: see text] with the ATLAS detector at the CERN Large Hadron Collider. No excess above the Standard Model background expectation is observed. Excluded mass regions for Majorana and Dirac neutrinos are presented using two approaches for interactions that violate lepton and lepton-flavor numbers. One approach uses an effective operator framework, the other approach is guided by the Left-Right Symmetric Model. The results described in this letter represent the most stringent limits to date on the masses of heavy neutrinos and WR bosons obtained in direct searches. PMID- 25814852 TI - Measurement of jet shapes in top-quark pair events at [Formula: see text] using the ATLAS detector. AB - A measurement of jet shapes in top-quark pair events using 1.8 fb-1 of [Formula: see text]pp collision data recorded by the ATLAS detector at the LHC is presented. Samples of top-quark pair events are selected in both the single lepton and dilepton final states. The differential and integrated shapes of the jets initiated by bottom-quarks from the top-quark decays are compared with those of the jets originated by light-quarks from the hadronic W-boson decays [Formula: see text] in the single-lepton channel. The light-quark jets are found to have a narrower distribution of the momentum flow inside the jet area than b-quark jets. PMID- 25814857 TI - Search for supersymmetry in pp collisions at [Formula: see text] TeV in events with a single lepton, jets, and missing transverse momentum. AB - : Results are reported from a search for new physics processes in events containing a single isolated high-transverse-momentum lepton (electron or muon), energetic jets, and large missing transverse momentum. The analysis is based on a 4.98 fb-1 sample of proton-proton collisions at a center-of-mass energy of 7 TeV, obtained with the CMS detector at the LHC. Three separate background estimation methods, each relying primarily on control samples in the data, are applied to a range of signal regions, providing complementary approaches for estimating the background yields. The observed yields are consistent with the predicted standard model backgrounds. The results are interpreted in terms of limits on the parameter space for the constrained minimal supersymmetric extension of the standard model, as well as on cross sections for simplified models, which provide a generic description of the production and decay of new particles in specific, topology based final states. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1140/epjc/s10052-013-2404-z) contains supplementary material, which is available to authorized users. PMID- 25814854 TI - Jet energy resolution in proton-proton collisions at [Formula: see text] recorded in 2010 with the ATLAS detector. AB - The measurement of the jet energy resolution is presented using data recorded with the ATLAS detector in proton-proton collisions at [Formula: see text]. The sample corresponds to an integrated luminosity of 35 pb-1. Jets are reconstructed from energy deposits measured by the calorimeters and calibrated using different jet calibration schemes. The jet energy resolution is measured with two different in situ methods which are found to be in agreement within uncertainties. The total uncertainties on these measurements range from 20 % to 10 % for jets within |y|<2.8 and with transverse momenta increasing from 30 GeV to 500 GeV. Overall, the Monte Carlo simulation of the jet energy resolution agrees with the data within 10 %. PMID- 25814855 TI - Measurement of the [Formula: see text] production cross section in the tau + jets channel using the ATLAS detector. AB - A measurement of the top quark pair production cross section in the final state with a hadronically decaying tau lepton and jets is presented. The analysis is based on proton-proton collision data recorded by the ATLAS experiment at the LHC, with a centre-of-mass energy of 7 TeV. The data sample corresponds to an integrated luminosity of 1.67 fb-1. The cross section is measured to be [Formula: see text] and is in agreement with other measurements and with the Standard Model prediction. PMID- 25814865 TI - Search for physics beyond the standard model in events with tau leptons, jets, and large transverse momentum imbalance in pp collisions at [Formula: see text]. AB - A search for physics beyond the standard model is performed with events having one or more hadronically decaying tau leptons, highly energetic jets, and large transverse momentum imbalance. The data sample corresponds to an integrated luminosity of 4.98 fb-1 of proton-proton collisions at [Formula: see text] collected with the CMS detector at the LHC in 2011. The number of observed events is consistent with predictions for standard model processes. Lower limits on the mass of the gluino in supersymmetric models are determined. PMID- 25814868 TI - Search for supersymmetry in hadronic final states with missing transverse energy using the variables alphaT and b-quark multiplicity in pp collisions at [Formula: see text]. AB - An inclusive search for supersymmetric processes that produce final states with jets and missing transverse energy is performed in pp collisions at a centre-of mass energy of 8 TeV. The data sample corresponds to an integrated luminosity of 11.7 fb-1 collected by the CMS experiment at the LHC. In this search, a dimensionless kinematic variable, alphaT, is used to discriminate between events with genuine and misreconstructed missing transverse energy. The search is based on an examination of the number of reconstructed jets per event, the scalar sum of transverse energies of these jets, and the number of these jets identified as originating from bottom quarks. No significant excess of events over the standard model expectation is found. Exclusion limits are set in the parameter space of simplified models, with a special emphasis on both compressed-spectrum scenarios and direct or gluino-induced production of third-generation squarks. For the case of gluino-mediated squark production, gluino masses up to 950-1125 GeV are excluded depending on the assumed model. For the direct pair-production of squarks, masses up to 450 GeV are excluded for a single light first- or second generation squark, increasing to 600 GeV for bottom squarks. PMID- 25814864 TI - Search for a standard-model-like Higgs boson with a mass in the range 145 to 1000 GeV at the LHC. AB - A search for a standard-model-like Higgs boson in the H->WW and H->ZZ decay channels is reported, for Higgs boson masses in the range 145lnu events at [Formula: see text] with the ATLAS detector. AB - A measurement of splitting scales, as defined by the kT clustering algorithm, is presented for final states containing a W boson produced in proton-proton collisions at a centre-of-mass energy of 7 TeV. The measurement is based on the full 2010 data sample corresponding to an integrated luminosity of 36 pb-1 which was collected using the ATLAS detector at the CERN Large Hadron Collider. Cluster splitting scales are measured in events containing W bosons decaying to electrons or muons. The measurement comprises the four hardest splitting scales in a kT cluster sequence of the hadronic activity accompanying the W boson, and ratios of these splitting scales. Backgrounds such as multi-jet and top-quark-pair production are subtracted and the results are corrected for detector effects. Predictions from various Monte Carlo event generators at particle level are compared to the data. Overall, reasonable agreement is found with all generators, but larger deviations between the predictions and the data are evident in the soft regions of the splitting scales. PMID- 25814890 TI - Infrared saturation and phases of gauge theories with BRST symmetry. AB - We investigate the infrared limit of the quantum equation of motion of the gauge boson propagator in various gauges and models with a BRST symmetry. We find that the saturation of this equation at low momenta distinguishes between the Coulomb, Higgs and confining phase of the gauge theory. The Coulomb phase is characterized by a massless gauge boson. Physical states contribute to the saturation of the transverse equation of motion of the gauge boson at low momenta in the Higgs phase, while the saturation is entirely due to unphysical degrees of freedom in the confining phase. This corollary to the Kugo-Ojima confinement criterion in linear covariant gauges also is sufficient for confinement in general covariant gauges with BRST and anti-BRST symmetry, maximal Abelian gauges with an equivariant BRST symmetry, non-covariant Coulomb gauge and in the Gribov Zwanziger theory. PMID- 25814863 TI - Search for a light charged Higgs boson in the decay channel [Formula: see text] in [Formula: see text] events using pp collisions at [Formula: see text] with the ATLAS detector. AB - A search for a charged Higgs boson (H+) in [Formula: see text] decays is presented, where one of the top quarks decays via t->H+b, followed by H+-> two jets ([Formula: see text]). The other top quark decays to Wb, where the W boson then decays into a lepton (e/MU) and a neutrino. The data were recorded in pp collisions at [Formula: see text] by the ATLAS detector at the LHC in 2011, and correspond to an integrated luminosity of 4.7 fb-1. With no observation of a signal, 95 % confidence level (CL) upper limits are set on the decay branching ratio of top quarks to charged Higgs bosons varying between 5 % and 1 % for H+ masses between 90 GeV and 150 GeV, assuming [Formula: see text]. PMID- 25814867 TI - Improved luminosity determination in pp collisions at [Formula: see text] using the ATLAS detector at the LHC. AB - The luminosity calibration for the ATLAS detector at the LHC during pp collisions at [Formula: see text] in 2010 and 2011 is presented. Evaluation of the luminosity scale is performed using several luminosity-sensitive detectors, and comparisons are made of the long-term stability and accuracy of this calibration applied to the pp collisions at [Formula: see text]. A luminosity uncertainty of [Formula: see text] is obtained for the 47 pb-1 of data delivered to ATLAS in 2010, and an uncertainty of [Formula: see text] is obtained for the 5.5 fb-1 delivered in 2011. PMID- 25814872 TI - Measurement of the [Formula: see text] production cross-section using [Formula: see text] events with [Formula: see text]-tagged jets in [Formula: see text] collisions at [Formula: see text] and 8 TeV with the ATLAS detector. AB - The inclusive top quark pair ([Formula: see text]) production cross-section [Formula: see text] has been measured in proton-proton collisions at [Formula: see text] and [Formula: see text] with the ATLAS experiment at the LHC, using [Formula: see text] events with an opposite-charge [Formula: see text] pair in the final state. The measurement was performed with the 2011 7 TeV dataset corresponding to an integrated luminosity of 4.6 [Formula: see text] and the 2012 8 TeV dataset of 20.3 [Formula: see text]. The numbers of events with exactly one and exactly two [Formula: see text]-tagged jets were counted and used to simultaneously determine [Formula: see text] and the efficiency to reconstruct and [Formula: see text]-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section was measured to be: [Formula: see text]where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, knowledge of the integrated luminosity and of the LHC beam energy. The results are consistent with recent theoretical QCD calculations at next-to-next-to-leading order. Fiducial measurements corresponding to the experimental acceptance of the leptons are also reported, together with the ratio of cross-sections measured at the two centre-of mass energies. The inclusive cross-section results were used to determine the top quark pole mass via the dependence of the theoretically predicted cross-section on [Formula: see text] giving a result of [Formula: see text][Formula: see text] GeV. By looking for an excess of [Formula: see text] production with respect to the QCD prediction, the results were also used to place limits on the pair production of supersymmetric top squarks [Formula: see text] with masses close to the top quark mass, decaying via [Formula: see text] to predominantly right handed top quarks and a light neutralino [Formula: see text], the lightest supersymmetric particle. Top squarks with masses between the top quark mass and 177 GeV are excluded at the 95 % confidence level. PMID- 25814888 TI - Measurement of the [Formula: see text] meson lifetime using [Formula: see text] decays. AB - The lifetime of the [Formula: see text] meson is measured using semileptonic decays having a [Formula: see text] meson and a muon in the final state. The data, corresponding to an integrated luminosity of [Formula: see text], are collected by the LHCb detector in [Formula: see text] collisions at a centre-of mass energy of 8 TeV. The measured lifetime is [Formula: see text]where the first uncertainty is statistical and the second is systematic. PMID- 25814889 TI - Measurement of [Formula: see text] polarisation in [Formula: see text] collisions at [Formula: see text] = 7 TeV. AB - The polarisation of prompt [Formula: see text] mesons is measured by performing an angular analysis of [Formula: see text] decays using proton-proton collision data, corresponding to an integrated luminosity of 1.0[Formula: see text], collected by the LHCb detector at a centre-of-mass energy of 7 TeV. The polarisation is measured in bins of transverse momentum [Formula: see text] and rapidity [Formula: see text] in the kinematic region [Formula: see text] and [Formula: see text], and is compared to theoretical models. No significant polarisation is observed. PMID- 25814874 TI - Measurement of differential cross sections for the production of a pair of isolated photons in pp collisions at [Formula: see text]. AB - A measurement of differential cross sections for the production of a pair of isolated photons in proton-proton collisions at [Formula: see text] is presented. The data sample corresponds to an integrated luminosity of 5.0[Formula: see text] collected with the CMS detector. A data-driven isolation template method is used to extract the prompt diphoton yield. The measured cross section for two isolated photons, with transverse energy above 40 and 25[Formula: see text] respectively, in the pseudorapidity range [Formula: see text], [Formula: see text] and with an angular separation [Formula: see text], is [Formula: see text][Formula: see text]. Differential cross sections are measured as a function of the diphoton invariant mass, the diphoton transverse momentum, the azimuthal angle difference between the two photons, and the cosine of the polar angle in the Collins-Soper reference frame of the diphoton system. The results are compared to theoretical predictions at leading, next-to-leading, and next-to-next-to-leading order in quantum chromodynamics. PMID- 25814891 TI - Measurement of charged particle multiplicities and densities in [Formula: see text] collisions at [Formula: see text]TeV in the forward region. AB - Charged particle multiplicities are studied in proton-proton collisions in the forward region at a centre-of-mass energy of [Formula: see text]TeV with data collected by the LHCb detector. The forward spectrometer allows access to a kinematic range of [Formula: see text] in pseudorapidity, momenta greater than [Formula: see text] and transverse momenta greater than [Formula: see text]. The measurements are performed using events with at least one charged particle in the kinematic acceptance. The results are presented as functions of pseudorapidity and transverse momentum and are compared to predictions from several Monte Carlo event generators. PMID- 25814873 TI - Measurements of jet vetoes and azimuthal decorrelations in dijet events produced in [Formula: see text] collisions at [Formula: see text] using the ATLAS detector. AB - Additional jet activity in dijet events is measured using [Formula: see text] collisions at ATLAS at a centre-of-mass energy of [Formula: see text], for jets reconstructed using the [Formula: see text] algorithm with radius parameter [Formula: see text]. This is done using variables such as the fraction of dijet events without an additional jet in the rapidity interval bounded by the dijet subsystem and correlations between the azimuthal angles of the dijet s. They are presented, both with and without a veto on additional jet activity in the rapidity interval, as a function of the scalar average of the transverse momenta of the dijet s and of the rapidity interval size. The double differential dijet cross section is also measured as a function of the interval size and the azimuthal angle between the dijet s. These variables probe differences in the approach to resummation of large logarithms when performing QCD calculations. The data are compared to powheg, interfaced to the pythia 8 and herwig parton shower generators, as well as to hej with and without interfacing it to the ariadne parton shower generator. None of the theoretical predictions agree with the data across the full phase-space considered; however, powheg+pythia 8 and hej+ariadne are found to provide the best agreement with the data. These measurements use the full data sample collected with the ATLAS detector in [Formula: see text][Formula: see text] collisions at the LHC and correspond to integrated luminosities of [Formula: see text] and [Formula: see text] for data collected during 2010 and 2011, respectively. PMID- 25814894 TI - Comprehensive Bayesian analysis of rare (semi)leptonic and radiative [Formula: see text] decays. AB - The available data on [Formula: see text] decays are in good agreement with the Standard Model when permitting subleading power corrections of about [Formula: see text] at large hadronic recoil. Constraining new-physics effects in [Formula: see text], [Formula: see text], [Formula: see text], the data still demand the same size of power corrections as in the Standard Model. In the presence of chirality-flipped operators, all but one of the power corrections reduce substantially. The Bayes factors are in favor of the Standard Model. Using new lattice inputs for [Formula: see text] form factors and under our minimal prior assumption for the power corrections, the favor shifts toward models with chirality-flipped operators. We use the data to further constrain the hadronic form factors in [Formula: see text] and [Formula: see text] transitions. PMID- 25814876 TI - Search for heavy neutrinos and [Formula: see text] bosons with right-handed couplings in proton-proton collisions at [Formula: see text]. AB - A search for heavy, right-handed neutrinos, [Formula: see text] ([Formula: see text]), and right-handed [Formula: see text] bosons, which arise in the left right symmetric extensions of the standard model, has been performed by the CMS experiment. The search was based on a sample of two lepton plus two jet events collected in proton-proton collisions at a center-of-mass energy of 8[Formula: see text] corresponding to an integrated luminosity of 19.7 [Formula: see text]. For models with strict left-right symmetry, and assuming only one [Formula: see text] flavor contributes significantly to the [Formula: see text] decay width, the region in the two-dimensional [Formula: see text] mass plane excluded at a 95 % confidence level extends to approximately [Formula: see text] and covers a large range of neutrino masses below the [Formula: see text] boson mass, depending on the value of [Formula: see text]. This search significantly extends the [Formula: see text] exclusion region beyond previous results. PMID- 25814896 TI - Study of the photon's pole structure in the noncommutative Schwinger model. AB - The photon self-energy of the noncommutative Schwinger model at two- and three loop order is analyzed. It is shown that the mass spectrum of the model does not receive any correction from the noncommutativity parameter ([Formula: see text]) at these orders. Also it remains unchanged to all orders. The exact one-loop effective action for the photon is also calculated. PMID- 25814885 TI - Measurement of the top-quark mass in all-jets [Formula: see text] events in pp collisions at [Formula: see text] TeV. AB - The mass of the top quark is measured using a sample of [Formula: see text] candidate events with at least six jets in the final state. The sample is selected from data collected with the CMS detector in pp collisions at [Formula: see text] TeV in 2011 and corresponds to an integrated luminosity of 3.54 [Formula: see text]. The mass is reconstructed for each event employing a kinematic fit of the jets to a [Formula: see text] hypothesis. The top-quark mass is measured to be [Formula: see text] GeV. A combination with previously published measurements in other decay modes by CMS yields a mass of [Formula: see text] GeV. PMID- 25814897 TI - The CMSSM and NUHM1 after LHC Run 1. AB - We analyze the impact of data from the full Run 1 of the LHC at 7 and 8 TeV on the CMSSM with [Formula: see text] and [Formula: see text] and the NUHM1 with [Formula: see text], incorporating the constraints imposed by other experiments such as precision electroweak measurements, flavour measurements, the cosmological density of cold dark matter and the direct search for the scattering of dark matter particles in the LUX experiment. We use the following results from the LHC experiments: ATLAS searches for events with [Formula: see text] accompanied by jets with the full 7 and 8 TeV data, the ATLAS and CMS measurements of the mass of the Higgs boson, the CMS searches for heavy neutral Higgs bosons and a combination of the LHCb and CMS measurements of [Formula: see text] and [Formula: see text]. Our results are based on samplings of the parameter spaces of the CMSSM for both [Formula: see text] and [Formula: see text] and of the NUHM1 for [Formula: see text] with 6.8[Formula: see text], 6.2[Formula: see text] and 1.6[Formula: see text] points, respectively, obtained using the MultiNest tool. The impact of the Higgs-mass constraint is assessed using FeynHiggs 2.10.0, which provides an improved prediction for the masses of the MSSM Higgs bosons in the region of heavy squark masses. It yields in general larger values of [Formula: see text] than previous versions of FeynHiggs, reducing the pressure on the CMSSM and NUHM1. We find that the global [Formula: see text] functions for the supersymmetric models vary slowly over most of the parameter spaces allowed by the Higgs-mass and the [Formula: see text] searches, with best-fit values that are comparable to the [Formula: see text] for the best Standard Model fit. We provide 95 % CL lower limits on the masses of various sparticles and assess the prospects for observing them during Run 2 of the LHC. PMID- 25814899 TI - The effect of LHC jet data on MSTW PDFs. AB - We consider the effect on LHC jet cross sections on partons distribution functions (PDFs), in particular the MSTW2008 set of PDFs. We first compare the published inclusive jet data to the predictions using MSTW2008, finding a very good description. We also use the parton distribution reweighting procedure to estimate the impact of these new data on the PDFs, finding that the combined ATLAS 2.76 and 7 TeV data, and CMS 7 TeV data have some significant impact. We then also investigate the impact of ATLAS, CMS and DO dijet data using the same techniques. In this case we investigate the effect of using different scale choices for the NLO cross section calculation. We find that the dijet data is generally not completely compatible with the corresponding inclusive jet data, often tending to pull PDFs, particularly the gluon distribution, away from the default values. However, the effect depends on the dijet dataset used as well as the scale choice. We also note that conclusions may be affected by limiting the pull on the data luminosity chosen by the best fit, which is sometimes a number of standard deviations. Finally we include the inclusive jet data in a new PDF fit explicitly. This enables us to check the consistency of the exact result with that obtained from the reweighting procedure. There is generally good, but not full quantitative agreement. Hence, the conclusion remains that MSTW2008 PDFs already fit the published jet data well, but the central values and uncertainties are altered and improved, respectively, to a significant, but not dramatic extent by inclusion of these data. PMID- 25814875 TI - Measurement of the muon reconstruction performance of the ATLAS detector using 2011 and 2012 LHC proton-proton collision data. AB - This paper presents the performance of the ATLAS muon reconstruction during the LHC run with [Formula: see text] collisions at [Formula: see text]-8 TeV in 2011 2012, focusing mainly on data collected in 2012. Measurements of the reconstruction efficiency and of the momentum scale and resolution, based on large reference samples of [Formula: see text], [Formula: see text] and [Formula: see text] decays, are presented and compared to Monte Carlo simulations. Corrections to the simulation, to be used in physics analysis, are provided. Over most of the covered phase space (muon [Formula: see text] and [Formula: see text] GeV) the efficiency is above [Formula: see text] and is measured with per-mille precision. The momentum resolution ranges from [Formula: see text] at central rapidity and for transverse momentum [Formula: see text] GeV, to [Formula: see text] at large rapidity and [Formula: see text] GeV. The momentum scale is known with an uncertainty of [Formula: see text] to [Formula: see text] depending on rapidity. A method for the recovery of final state radiation from the muons is also presented. PMID- 25814901 TI - Dipole operator constraints on composite Higgs models. AB - Flavour- and CP-violating electromagnetic or chromomagnetic dipole operators in the quark sector are generated in a large class of new physics models and are strongly constrained by measurements of the neutron electric dipole moment and observables sensitive to flavour-changing neutral currents, such as the [Formula: see text] branching ratio and [Formula: see text]. After a model-independent discussion of the relevant constraints, we analyze these effects in models with partial compositeness, where the quarks get their masses by mixing with vector like composite fermions. These scenarios can be seen as the low-energy limit of composite Higgs or warped extra dimensional models. We study different choices for the electroweak representations of the composite fermions motivated by electroweak precision tests as well as different flavour structures, including flavour anarchy and [Formula: see text] or [Formula: see text] flavour symmetries in the strong sector. In models with "wrong-chirality" Yukawa couplings, we find a strong bound from the neutron electric dipole moment, irrespective of the flavour structure. In the case of flavour anarchy, we also find strong bounds from flavour-violating dipoles, while these constraints are mild in the flavour symmetric models. PMID- 25814902 TI - The extent of the stop coannihilation strip. AB - Many supersymmetric models such as the constrained minimal supersymmetric extension of the Standard Model (CMSSM) feature a strip in parameter space where the lightest neutralino [Formula: see text] is identified as the lightest supersymmetric particle, the lighter stop squark [Formula: see text] is the next to-lightest supersymmetric particle (NLSP), and the relic [Formula: see text] cold dark matter density is brought into the range allowed by astrophysics and cosmology by coannihilation with the lighter stop squark [Formula: see text] NLSP. We calculate the stop coannihilation strip in the CMSSM, incorporating Sommerfeld enhancement effects, and we explore the relevant phenomenological constraints and phenomenological signatures. In particular, we show that the [Formula: see text] may weigh several TeV, and its lifetime may be in the nanosecond range, features that are more general than the specific CMSSM scenarios that we study in this paper. PMID- 25814903 TI - The effect on PDFs and [Formula: see text] due to changes in flavour scheme and higher twist contributions. AB - I consider the effect on MSTW partons distribution functions (PDFs) due to changes in the choices of theoretical procedure used in the fit. I first consider using the 3-flavour fixed flavour number scheme instead of the standard general mass variable flavour number scheme used in the MSTW analysis. This results in the light quarks increasing at all relatively small [Formula: see text] values, the gluon distribution becoming smaller at high values of [Formula: see text] and larger at small [Formula: see text], the preferred value of the coupling constant [Formula: see text] falling, particularly at NNLO, and the fit quality deteriorates. I also consider lowering the kinematic cut on [Formula: see text] for DIS data and simultaneously introducing higher twist terms which are fit to data. This results in much smaller effects on both PDFs and [Formula: see text] than the scheme change, except for quarks at very high [Formula: see text]. I show that the structure function one obtains from a fixed input set of PDFs using the fixed flavour scheme and variable flavour scheme differ significantly for [Formula: see text] at high [Formula: see text], and that this is due to the fact that in the fixed flavour scheme there is a slow convergence of large logarithmic terms of the form [Formula: see text] relevant for this regime. I conclude that some of the most significant differences in PDF sets are largely due to the choice of flavour scheme used. PMID- 25814877 TI - Measurement of flow harmonics with multi-particle cumulants in Pb+Pb collisions at [Formula: see text] TeV with the ATLAS detector. AB - ATLAS measurements of the azimuthal anisotropy in lead-lead collisions at [Formula: see text] TeV are shown using a dataset of approximately 7 [Formula: see text]b[Formula: see text] collected at the LHC in 2010. The measurements are performed for charged particles with transverse momenta [Formula: see text] GeV and in the pseudorapidity range [Formula: see text]. The anisotropy is characterized by the Fourier coefficients, [Formula: see text], of the charged particle azimuthal angle distribution for [Formula: see text]-4. The Fourier coefficients are evaluated using multi-particle cumulants calculated with the generating function method. Results on the transverse momentum, pseudorapidity and centrality dependence of the [Formula: see text] coefficients are presented. The elliptic flow, [Formula: see text], is obtained from the two-, four-, six- and eight-particle cumulants while higher-order coefficients, [Formula: see text] and [Formula: see text], are determined with two- and four-particle cumulants. Flow harmonics [Formula: see text] measured with four-particle cumulants are significantly reduced compared to the measurement involving two-particle cumulants. A comparison to [Formula: see text] measurements obtained using different analysis methods and previously reported by the LHC experiments is also shown. Results of measurements of flow fluctuations evaluated with multi-particle cumulants are shown as a function of transverse momentum and the collision centrality. Models of the initial spatial geometry and its fluctuations fail to describe the flow fluctuations measurements. PMID- 25814892 TI - Study of the production of charged pions, kaons, and protons in pPb collisions at [Formula: see text]5.02[Formula: see text]. AB - Spectra of identified charged hadrons are measured in pPb collisions with the CMS detector at the LHC at [Formula: see text]. Charged pions, kaons, and protons in the transverse-momentum range [Formula: see text]-1.7[Formula: see text] and laboratory rapidity [Formula: see text] are identified via their energy loss in the silicon tracker. The average [Formula: see text] increases with particle mass and the charged multiplicity of the event. The increase of the average [Formula: see text] with charged multiplicity is greater for heavier hadrons. Comparisons to Monte Carlo event generators reveal that Epos Lhc, which incorporates additional hydrodynamic evolution of the created system, is able to reproduce most of the data features, unlike Hijing and Ampt. The [Formula: see text] spectra and integrated yields are also compared to those measured in pp and PbPb collisions at various energies. The average transverse momentum and particle ratio measurements indicate that particle production at LHC energies is strongly correlated with event particle multiplicity. PMID- 25814895 TI - Probing color coherence effects in pp collisions at [Formula: see text]. AB - A study of color coherence effects in pp collisions at a center-of-mass energy of 7[Formula: see text] is presented. The data used in the analysis were collected in 2010 with the CMS detector at the LHC and correspond to an integrated luminosity of 36 pb[Formula: see text]. Events are selected that contain at least three jets and where the two jets with the largest transverse momentum exhibit a back-to-back topology. The measured angular correlation between the second- and third-leading jet is shown to be sensitive to color coherence effects, and is compared to the predictions of Monte Carlo models with various implementations of color coherence. None of the models describe the data satisfactorily. PMID- 25814908 TI - Lurking pseudovectors below the TeV scale. AB - If electroweak symmetry breaking is driven by a new strongly coupled dynamical sector, one expects the bound states to appear at the TeV scale or slightly below. However, electroweak precision data imposes severe constraints on most of the existing models, putting them under strain. Conventional models require the new composite states to come in pairs of rather heavy, close to degenerate spin-1 resonances. In this paper I argue that spin-1 states can actually be lighter without clashing with experimental bounds. As an example, I consider a composite model with a light pseudovector resonance that couples to the Standard Model gauge boson, fermion, and scalar fields. I show how such a resonance leaves basically no imprint on the NLO corrections to the Standard Model. This happens not through parameter tuning, but rather as a consequence of generic properties of realistic UV completions. This pseudovector is mostly unconstrained by existing data and could be as light as 600 GeV. In the last part of the paper I briefly discuss its most characteristic signatures for direct detection at colliders. PMID- 25814905 TI - Measurement of quarkonium production at forward rapidity in [Formula: see text] collisions at [Formula: see text]TeV. AB - The inclusive production cross sections at forward rapidity of [Formula: see text], [Formula: see text], [Formula: see text](1S) and [Formula: see text](2S) are measured in [Formula: see text] collisions at [Formula: see text] with the ALICE detector at the LHC. The analysis is based on a data sample corresponding to an integrated luminosity of 1.35 pb[Formula: see text]. Quarkonia are reconstructed in the dimuon-decay channel and the signal yields are evaluated by fitting the [Formula: see text] invariant mass distributions. The differential production cross sections are measured as a function of the transverse momentum [Formula: see text] and rapidity [Formula: see text], over the ranges [Formula: see text] GeV/c for [Formula: see text], [Formula: see text] GeV/c for all other resonances and for [Formula: see text]. The measured cross sections integrated over [Formula: see text] and [Formula: see text], and assuming unpolarized quarkonia, are: [Formula: see text] [Formula: see text]b, [Formula: see text] [Formula: see text]b, [Formula: see text] nb and [Formula: see text] nb, where the first uncertainty is statistical and the second one is systematic. The results are compared to measurements performed by other LHC experiments and to theoretical models. PMID- 25814893 TI - Search for direct top squark pair production in events with a [Formula: see text] boson, [Formula: see text]-jets and missing transverse momentum in [Formula: see text] TeV [Formula: see text] collisions with the ATLAS detector. AB - A search is presented for direct top squark pair production using events with at least two leptons including a same-flavour opposite-sign pair with invariant mass consistent with the [Formula: see text] boson mass, jets tagged as originating from [Formula: see text]-quarks and missing transverse momentum. The analysis is performed with proton-proton collision data at [Formula: see text] collected with the ATLAS detector at the LHC in 2012 corresponding to an integrated luminosity of 20.3 fb[Formula: see text]. No excess beyond the Standard Model expectation is observed. Interpretations of the results are provided in models based on the direct pair production of the heavier top squark state ([Formula: see text]) followed by the decay to the lighter top squark state ([Formula: see text]) via [Formula: see text], and for [Formula: see text] pair production in natural gauge mediated supersymmetry breaking scenarios where the neutralino ([Formula: see text]) is the next-to-lightest supersymmetric particle and decays producing a [Formula: see text] boson and a gravitino ([Formula: see text]) via the [Formula: see text] process. PMID- 25814904 TI - Measurement of WZ and ZZ production in pp collisions at [Formula: see text] in final states with b-tagged jets. AB - Measurements are reported of the WZ and ZZ production cross sections in proton proton collisions at [Formula: see text][Formula: see text] in final states where one Z boson decays to b-tagged jets. The other gauge boson, either W or Z, is detected through its leptonic decay (either [Formula: see text], [Formula: see text] or [Formula: see text], [Formula: see text], or [Formula: see text]). The results are based on data corresponding to an integrated luminosity of 18.9 fb[Formula: see text] collected with the CMS detector at the Large Hadron Collider. The measured cross sections, [Formula: see text] and [Formula: see text], are consistent with next-to-leading order quantum chromodynamics calculations. PMID- 25814898 TI - The differential production cross section of the [Formula: see text](1020) meson in [Formula: see text] = 7 TeV [Formula: see text] collisions measured with the ATLAS detector. AB - A measurement is presented of the [Formula: see text] production cross section at [Formula: see text] = 7 TeV using [Formula: see text] collision data corresponding to an integrated luminosity of 383 [Formula: see text], collected with the ATLAS experiment at the LHC. Selection of [Formula: see text](1020) mesons is based on the identification of charged kaons by their energy loss in the pixel detector. The differential cross section is measured as a function of the transverse momentum, [Formula: see text], and rapidity, [Formula: see text], of the [Formula: see text](1020) meson in the fiducial region 500 [Formula: see text] 1200 MeV, [Formula: see text] 0.8, kaon [Formula: see text] 230 MeV and kaon momentum [Formula: see text] 800 MeV. The integrated [Formula: see text] meson production cross section in this fiducial range is measured to be [Formula: see text] = 570 [Formula: see text] 8 (stat) [Formula: see text] 66 (syst) [Formula: see text] 20 (lumi) [Formula: see text]. PMID- 25814900 TI - Electron reconstruction and identification efficiency measurements with the ATLAS detector using the 2011 LHC proton-proton collision data. AB - Many of the interesting physics processes to be measured at the LHC have a signature involving one or more isolated electrons. The electron reconstruction and identification efficiencies of the ATLAS detector at the LHC have been evaluated using proton-proton collision data collected in 2011 at [Formula: see text] TeV and corresponding to an integrated luminosity of 4.7 fb[Formula: see text]. Tag-and-probe methods using events with leptonic decays of [Formula: see text] and [Formula: see text] bosons and [Formula: see text] mesons are employed to benchmark these performance parameters. The combination of all measurements results in identification efficiencies determined with an accuracy at the few per mil level for electron transverse energy greater than 30 GeV. PMID- 25814906 TI - Search for invisible decays of Higgs bosons in the vector boson fusion and associated ZH production modes. AB - A search for invisible decays of Higgs bosons is performed using the vector boson fusion and associated ZH production modes. In the ZH mode, the Z boson is required to decay to a pair of charged leptons or a [Formula: see text] quark pair. The searches use the 8?a[Formula: see text] pp collision dataset collected by the CMS detector at the LHC, corresponding to an integrated luminosity of up to 19.7?a[Formula: see text]. Certain channels include data from 7?a[Formula: see text] collisions corresponding to an integrated luminosity of 4.9?a[Formula: see text]. The searches are sensitive to non-standard-model invisible decays of the recently observed Higgs boson, as well as additional Higgs bosons with similar production modes and large invisible branching fractions. In all channels, the observed data are consistent with the expected standard model backgrounds. Limits are set on the production cross section times invisible branching fraction, as a function of the Higgs boson mass, for the vector boson fusion and ZH production modes. By combining all channels, and assuming standard model Higgs boson cross sections and acceptances, the observed (expected) upper limit on the invisible branching fraction at [Formula: see text]?a[Formula: see text] is found to be 0.58?a(0.44) at 95?a% confidence level. We interpret this limit in terms of a Higgs-portal model of dark matter interactions. PMID- 25814913 TI - Large J expansion in ABJM theory revisited. AB - Recently there has been progress in the computation of the anomalous dimensions of gauge theory operators at strong coupling by making use of the AdS/CFT correspondence. On the string theory side they are given by dispersion relations in the semiclassical regime. We revisit the problem of a large-charge expansion of the dispersion relations for simple semiclassical strings in an [Formula: see text] background. We present the calculation of the corresponding anomalous dimensions of the gauge theory operators to an arbitrary order using three different methods. Although the results of the three methods look different, power series expansions show their consistency. PMID- 25814915 TI - Higgs characterisation at NLO in QCD: CP properties of the top-quark Yukawa interaction. AB - At the LHC the CP properties of the top-quark Yukawa interaction can be probed through Higgs production in gluon fusion or in association with top quarks. We consider the possibility for both CP-even and CP-odd couplings to the top quark to be present, and study CP-sensitive observables at next-to-leading order (NLO) in QCD, including parton-shower effects. We show that the inclusion of NLO corrections sizeably reduces the theoretical uncertainties, and confirm that di jet correlations in [Formula: see text] jet production through gluon fusion and correlations of the top-quark decay products in [Formula: see text] production can provide sensitive probes of the CP nature of the Higgs interactions. PMID- 25814916 TI - Oxaliplatin analogues with carboxy derivatives of boldine with enhanced antioxidant activity. AB - A new oxaliplatin analog [Pt(dach)(L5)] (1) was synthesized and characterized as a continuation of a study of the previously reported [Pt(dach)(L6)] (2), where dach = (1R,2R)-diaminocyclohexane, L5 = 3-carboxyboldine, and L6 = 3 carboxypredicentrine. Compounds 1 and 2 exhibited a substantially enhanced antioxidant activity compared to oxaliplatin (130 and 30 times for 1 and 13 and 4 times for 2 using the DPPH and FRAP assays, resp.). In addition, 1 and 2 exhibited cytotoxic activity in the same range as oxaliplatin toward the two human tumor cell lines (MCF-7 and HT-29) studied and two to four times lower activity in the human colon nontumor cell line (CCD-841). Preadministration of L5 or L6 to the colon tumor (HT-29) and the colon nontumor (CCD-841) cell lines prior to oxaliplatin addition increased the viability of the nontumor cell line to a greater extent than that of the tumor cell line. PMID- 25814917 TI - A Hybrid Approach to Finding Relevant Social Media Content for Complex Domain Specific Information Needs. AB - While contemporary semantic search systems offer to improve classical keyword based search, they are not always adequate for complex domain specific information needs. The domain of prescription drug abuse, for example, requires knowledge of both ontological concepts and "intelligible constructs" not typically modeled in ontologies. These intelligible constructs convey essential information that include notions of intensity, frequency, interval, dosage and sentiments, which could be important to the holistic needs of the information seeker. In this paper, we present a hybrid approach to domain specific information retrieval that integrates ontology-driven query interpretation with synonym-based query expansion and domain specific rules, to facilitate search in social media on prescription drug abuse. Our framework is based on a context-free grammar (CFG) that defines the query language of constructs interpretable by the search system. The grammar provides two levels of semantic interpretation: 1) a top-level CFG that facilitates retrieval of diverse textual patterns, which belong to broad templates and 2) a low-level CFG that enables interpretation of specific expressions belonging to such textual patterns. These low-level expressions occur as concepts from four different categories of data: 1) ontological concepts, 2) concepts in lexicons (such as emotions and sentiments), 3) concepts in lexicons with only partial ontology representation, called lexico ontology concepts (such as side effects and routes of administration (ROA)), and 4) domain specific expressions (such as date, time, interval, frequency and dosage) derived solely through rules. Our approach is embodied in a novel Semantic Web platform called PREDOSE, which provides search support for complex domain specific information needs in prescription drug abuse epidemiology. When applied to a corpus of over 1 million drug abuse-related web forum posts, our search framework proved effective in retrieving relevant documents when compared with three existing search systems. PMID- 25814919 TI - Anti-inflammatory effects of Cordyceps mycelium (Paecilomyces hepiali, CBG-CS-2) in Raw264.7 murine macrophages. AB - Cordyceps (CS) is a traditional Chinese herb with various biological effects that include immune modulation. CBG-CS-2 is a strain, Paecilomyces hepiali, of the Cordyceps spp. The anti-inflammatory effects of CBG-CS-2 were investigated. The water-soluble fraction of CBG-CS-2 has high anti-inflammatory activity in LPS induced Raw264.7 macrophages. We tested the role of CBG-CS-2 on the anti inflammation cascade in LPS-stimulated Raw264.7 cells. CBG-CS-2 significantly decreased NO production, iNOS expression, and pro-inflammatory cytokine secretion in a dose-dependent manner. To investigate the mechanism by which CBG-CS-2 inhibits NO, iNOS, and pro-inflammatory cytokines, we examined the activities of NF-kappaB and AP-1 in LPS-activated macrophages. The results demonstrate that CBG CS-2 suppresses the production and expression of NO, iNOS, and pro-inflammatory cytokines in LPS-activated macrophages via inhibition of NF-kappaB and AP-1, which may play an important role in inflammation. These findings suggest that CBG CS-2 has modulatory effects on the inflammatory system in macrophages, and that it can serve as a useful anti-inflammatory dietary supplement or drug. PMID- 25814918 TI - Plasma metabolomics reveals a potential panel of biomarkers for early diagnosis in acute coronary syndrome. AB - Discovery of new biomarkers is critical for early diagnosis of acute coronary syndrome (ACS). Recent advances in metabolomic technologies have drastically enhanced the possibility of improving the knowledge of its physiopathology through the identification of the altered metabolic pathways. In this study, analyses of peripheral plasma from non-ST segment elevation ACS patients and healthy controls by gas chromatography-mass spectrometry (GC-MC) permitted the identification of 15 metabolites with statistical differences (p < 0.05) between experimental groups. Additionally, validation by GC-MC and liquid chromatography MC permitted us to identify a potential panel of biomarkers formed by 5-OH tryptophan, 2-OH-butyric acid and 3-OH-butyric acid. This panel of biomarkers reflects the oxidative stress and the hypoxic state that suffers the myocardial cells and consequently constitutes a metabolomic signature of the atherogenesis process that could be used for early diagnosis of ACS. PMID- 25814921 TI - Comparison between cigarette smoke-induced emphysema and cigarette smoke extract induced emphysema. AB - BACKGROUND AND OBJECTIVE: Emphysema is the main pathological feature of COPD and also is the focus of the related research. Although several emphysema animal models have been established, exact comparison of findings is seldom. The present study aimed to compare cigarette smoke (CS) exposure-induced emphysema model and intraperitoneal injection of cigarette smoke extract (CSE)-induced emphysema model to evaluate the effectiveness of the two different modeling methods. METHODS: Six-week-old male C57BL/6 J mice were used and randomly divided into two groups: CS exposure and intraperitoneal injection of CSE. Each group was subdivided into two subgroups: control and CS or CSE. Lung function, mean linear intercept (MLI), destructive index (DI), apoptotic index (AI), total and differential cells count in broncholavolar lavage fluid (BALF), SOD and IL-6 concentration in serum were measured. RESULTS: Compared with their respective controls, lung function was significantly decreased in CS and CSE groups (P < 0.01); MLI, DI, and AI of lung tissue were significantly higher in CS and CSE groups (P < 0.01); total number of leukocytes, the number and percentage of neutrophils (NEUs), and the number of macrophages (MAC) in BALF were significantly higher in CS and CSE groups (P < 0.01); SOD concentration in serum was significantly decreased in CS and CSE groups (P < 0.01); IL-6 concentration in serum was significantly increased in in CS and CSE groups (P < 0.01). There was no significant difference between CS group and CSE group in any of the parameters described above. CONCLUSIONS: Both CS exposure and intraperitoneal injection of CSE could induce emphysema and the effectiveness of the two different modeling methods were equal. PMID- 25814920 TI - E-cigarettes versus NRT for smoking reduction or cessation in people with mental illness: secondary analysis of data from the ASCEND trial. AB - BACKGROUND: People with mental illness have higher rates of smoking than the general population and are at greater risk of smoking-related death and disability. In smokers from the general population, electronic cigarettes (e cigarettes) have been shown to have a similar effect on quit rates as nicotine replacement therapy, but little is known about their effect in smokers with mental illness. METHODS: Secondary analysis of data from the ASCEND trial involving 657 dependent adult smokers motivated to quit, randomised to 16 mg nicotine e-cigarette, 21 mg nicotine patch, or 0 mg nicotine e-cigarette, with minimal behavioural support. Using self-reported medication use and the Anatomical Therapeutic Chemical Classification System, we identified 86 participants with mental illness and analysed their cessation and smoking reduction outcomes. RESULTS: For e-cigarettes alone, and all interventions pooled, there was no statistically significant difference in biochemically verified quit rates at six months between participants with and without mental illness, nor in smoking reduction, adverse events, treatment compliance, or acceptability. Rates of relapse to smoking were higher in participants with mental illness. Among this group, differences between treatments were not statistically significant for cessation (patch 14% [5/35], 16 mg e-cigarette 5% [2/39], 0 mg e-cigarette 0% [0/12], p = 0.245), adverse events or relapse rates. However, e-cigarette users had higher levels of smoking reduction, treatment compliance, and acceptability. CONCLUSIONS: The use of e-cigarettes for quitting appears to be equally effective, safe, and acceptable for people with and without mental illness. For people with mental illness, e-cigarettes may be as effective and safe as patches, yet more acceptable, and associated with greater smoking reduction. TRIAL REGISTRATION: Australian New Zealand Clinical trials Registry, number: ACTRN12610000866000. PMID- 25814923 TI - Population finiteness is not a concern for null hypothesis significance testing when studying human behavior. A reply to Pollet (2013). PMID- 25814922 TI - Eye movements reveal sexually dimorphic deficits in children with fetal alcohol spectrum disorder. AB - BACKGROUND: We examined the accuracy and characteristics of saccadic eye movements in children with fetal alcohol spectrum disorder (FASD) compared with typically developing control children. Previous studies have found that children with FASD produce saccades that are quantifiably different from controls. Additionally, animal studies have found sex-based differences for behavioral effects after prenatal alcohol exposure. Therefore, we hypothesized that eye movement measures will show sexually dimorphic results. METHODS: Children (aged 5 18 years) with FASD (n = 71) and typically developing controls (n = 113) performed a visually-guided saccade task. Saccade metrics and behavior were analyzed for sex and group differences. RESULTS: Female control participants had greater amplitude saccades than control males or females with FASD. Accuracy was significantly poorer in the FASD group, especially in males, which introduced significantly greater variability in the data. Therefore, we conducted additional analyses including only those trials in which the first saccade successfully reached the target within a +/- 1 degrees window. In this restricted amplitude dataset, the females with FASD made saccades with significantly lower velocity and longer duration, whereas the males with FASD did not differ from the control group. Additionally, the mean and peak deceleration were selectively decreased in the females with FASD. CONCLUSIONS: These data support the hypothesis that children with FASD exhibit specific deficits in eye movement control and sensory motor integration associated with cerebellar and/or brain stem circuits. Moreover, prenatal alcohol exposure may have a sexually dimorphic impact on eye movement metrics, with males and females exhibiting differential patterns of deficit. PMID- 25814924 TI - Transcriptomal changes and functional annotation of the developing non-human primate choroid plexus. AB - The choroid plexuses are small organs that protrude into each brain ventricle producing cerebrospinal fluid that constantly bathes the brain. These organs differentiate early in development just after neural closure at a stage when the brain is little vascularized. In recent years the plexus has been shown to have a much more active role in brain development than previously appreciated thereby it can influence both neurogenesis and neural migration by secreting factors into the CSF. However, much of choroid plexus developmental function is still unclear. Most previous studies on this organ have been undertaken in rodents but translation into humans is not straightforward since they have a different timing of brain maturation processes. We have collected choroid plexus from three fetal gestational ages of a non-human primate, the baboon, which has much closer brain development to humans. The transcriptome of the plexuses was determined by next generation sequencing and Ingenuity Pathway Analysis software was used to annotate functions and enrichment of pathways of changes in the transcriptome. The number of unique transcripts decreased with development and the majority of differentially expressed transcripts were down-regulated through development suggesting a more complex and active plexus earlier in fetal development. The functional annotation indicated changes across widespread biological functions in plexus development. In particular we find age-dependent regulation of genes associated with annotation categories: Gene Expression, Development of Cardiovascular System, Nervous System Development and Molecular Transport. Our observations support the idea that the choroid plexus has roles in shaping brain development. PMID- 25814925 TI - Molecular cloning and characterization of the allatotropin precursor and receptor in the desert locust, Schistocerca gregaria. AB - Allatotropins (ATs) are pleiotropic neuropeptides initially isolated from the tobacco hornworm, Manduca sexta. In 2008, the first receptor for AT-like peptides (ATR) was characterized in Bombyx mori. Since then, ATRs have also been characterized in M. sexta, Tribolium castaneum, Aedes aegypti and Bombus terrestris. These receptors show sequence similarity to vertebrate orexin (ORX) receptors. When generating an EST-database of the desert locust (Schistocerca gregaria) central nervous system, we found cDNA sequences encoding the Schgr-AT precursor and a fragment of its putative receptor. This receptor cDNA has now been completed and functionally expressed in mammalian cell lines. Activation of this receptor, designated as Schgr-ATR, by Schgr-AT caused an increase in intracellular calcium ions, as well as cyclic AMP (cAMP), with an EC50 value in the nanomolar range. In addition, the transcript distribution of both the Schgr AT precursor and Schgr-ATR was investigated by means of quantitative real-time PCR. Moreover, we found more evidence for the myotropic and allatostimulatory actions of Schgr-AT in the desert locust. These data are discussed and situated in a broader context by comparison with literature data on AT and ATR in insects. PMID- 25814926 TI - Ubiquitin-dependent proteolysis in yeast cells expressing neurotoxic proteins. AB - Critically impaired protein degradation is discussed to contribute to neurodegenerative disorders, including Parkinson's, Huntington's, Alzheimer's, and motor neuron diseases. Misfolded, aggregated, or surplus proteins are efficiently degraded via distinct protein degradation pathways, including the ubiquitin-proteasome system, autophagy, and vesicular trafficking. These pathways are regulated by covalent modification of target proteins with the small protein ubiquitin and are evolutionary highly conserved from humans to yeast. The yeast Saccharomyces cerevisiae is an established model for deciphering mechanisms of protein degradation, and for the elucidation of pathways underlying programmed cell death. The expression of human neurotoxic proteins triggers cell death in yeast, with neurotoxic protein-specific differences. Therefore, yeast cell death models are suitable for analyzing the role of protein degradation pathways in modulating cell death upon expression of disease-causing proteins. This review summarizes which protein degradation pathways are affected in these yeast models, and how they are involved in the execution of cell death. I will discuss to which extent this mimics the situation in other neurotoxic models, and how this may contribute to a better understanding of human disorders. PMID- 25814928 TI - Heat shock response and homeostatic plasticity. AB - Heat shock response and homeostatic plasticity are mechanisms that afford functional stability to cells in the face of stress. Each mechanism has been investigated independently, but the link between the two has not been extensively explored. We explore this link. The heat shock response enables cells to adapt to stresses such as high temperature, metabolic stress and reduced oxygen levels. This mechanism results from the production of heat shock proteins (HSPs) which maintain normal cellular functions by counteracting the misfolding of cellular proteins. Homeostatic plasticity enables neurons and their target cells to maintain their activity levels around their respective set points in the face of stress or disturbances. This mechanism results from the recruitment of adaptations at synaptic inputs, or at voltage-gated ion channels. In this perspective, we argue that heat shock triggers homeostatic plasticity through the production of HSPs. We also suggest that homeostatic plasticity is a form of neuroprotection. PMID- 25814929 TI - The pattern of c-Fos expression and its refractory period in the brain of rats and monkeys. AB - Intense activation of neurons triggers the appearance of immediate expression genes, including c-Fos. This gene is related to various signal cascades involved in biochemical processes such as neuronal plasticity, cell growth and mitosis. Here we investigate the expression pattern and the refractory period of c-Fos in rats and monkey's brains after stimulation with pentylenetetrazol. Rats and monkeys were sacrificed at various times after PTZ-induced seizure. Here we show that rats and monkeys already showed c-Fos expression at 0.5 h after seizure. Yet, the pattern of protein expression was longer in monkeys than rats, and also was not uniform (relative intensity) across different brain regions in monkeys as opposed to rats. In addition monkeys had a regional brain variation with regard to the temporal profile of c-Fos expression, which was not seen in rats. The refractory period after a second PTZ stimulation was also markedly different between rats and monkeys with the latter even showing a summatory effect on c-Fos expression after a second stimulation. However, assessment of c-Fos mRNA in rats indicated a post-transcriptional control mechanism underlying the duration of the refractory period. The difference in the protein expression pattern in rodents and primates characterizes a functional aspect of brain biochemistry that differs between these mammalian orders and may contribute for the more developed primate cognitive complexity as compared to rodents given c-Fos involvement in cognitive and learning tasks. PMID- 25814927 TI - Making sense of Wnt signaling-linking hair cell regeneration to development. AB - Wnt signaling is a highly conserved pathway crucial for development and homeostasis of multicellular organisms. Secreted Wnt ligands bind Frizzled receptors to regulate diverse processes such as axis patterning, cell division, and cell fate specification. They also serve to govern self-renewal of somatic stem cells in several adult tissues. The complexity of the pathway can be attributed to the myriad of Wnt and Frizzled combinations as well as its diverse context-dependent functions. In the developing mouse inner ear, Wnt signaling plays diverse roles, including specification of the otic placode and patterning of the otic vesicle. At later stages, its activity governs sensory hair cell specification, cell cycle regulation, and hair cell orientation. In regenerating sensory organs from non-mammalian species, Wnt signaling can also regulate the extent of proliferative hair cell regeneration. This review describes the current knowledge of the roles of Wnt signaling and Wnt-responsive cells in hair cell development and regeneration. We also discuss possible future directions and the potential application and limitation of Wnt signaling in augmenting hair cell regeneration. PMID- 25814930 TI - Matrix metalloproteinase 9 (MMP-9) is indispensable for long term potentiation in the central and basal but not in the lateral nucleus of the amygdala. AB - It has been shown that matrix metalloproteinase 9 (MMP-9) is required for synaptic plasticity, learning and memory. In particular, MMP-9 involvement in long-term potentiation (LTP, the model of synaptic plasticity) in the hippocampus and prefrontal cortex has previously been demonstrated. Recent data suggest the role of MMP-9 in amygdala-dependent learning and memory. Nothing is known, however, about its physiological correlates in the specific pathways in the amygdala. In the present study we show that LTP in the basal and central but not lateral amygdala (LA) is affected by MMP-9 knock-out. The MMP-9 dependency of LTP was confirmed in brain slices treated with a specific MMP-9 inhibitor. The results suggest that MMP-9 plays different roles in synaptic plasticity in different nuclei of the amygdala. PMID- 25814931 TI - Numb is not a critical regulator of Notch-mediated cell fate decisions in the developing chick inner ear. AB - The Notch signaling pathway controls differentiation of hair cells and supporting cells in the vertebrate inner ear. Here, we have investigated whether Numb, a known regulator of Notch activity in Drosophila, is involved in this process in the embryonic chick. The chicken homolog of Numb is expressed throughout the otocyst at early stages of development and is concentrated at the basal pole of the cells. It is asymmetrically allocated at some cell divisions, as in Drosophila, suggesting that it could act as a determinant inherited by one of the two daughter cells and favoring adoption of a hair-cell fate. To test the implication of Numb in hair cell fate decisions and the regulation of Notch signaling, we used different methods to overexpress Numb at different stages of inner ear development. We found that sustained or late Numb overexpression does not promote hair cell differentiation, and Numb does not prevent the reception of Notch signaling. Surprisingly, none of the Numb-overexpressing cells differentiated into hair cells, suggesting that high levels of Numb protein could interfere with intracellular processes essential for hair cell survival. However, when Numb was overexpressed early and more transiently during ear development, no effect on hair cell formation was seen. These results suggest that in the inner ear at least, Numb does not significantly repress Notch activity and that its asymmetric distribution in dividing precursor cells does not govern the choice between hair cell and supporting cell fates. PMID- 25814932 TI - The choroid plexus-a multi-role player during infectious diseases of the CNS. AB - The choroid plexus (CP) is the source of cerebrospinal fluid (CSF) production and location of the blood-CSF barrier (BCSFB), which is constituted by the epithelial cells of the CP. Several infectious pathogens including viruses, bacteria, fungi and parasites cross the BCSFB to enter the central nervous system (CNS), ultimately leading to inflammatory infectious diseases like meningitis and meningoencephalitis. The CP responds to this challenge by the production of chemokines and cytokines as well as alterations of the barrier function of the BCSFB. During the course of CNS infectious disease host immune cells enter the CNS, eventually contributing to the cellular damage caused by the disease. Additional complications, which are in certain cases caused by choroid plexitis, can arise due to the response of the CP to the pathogens. In this review we will give an overview on the multiple functions of the CP during brain infections highlighting the CP as a multi-role player during infectious diseases of the CNS. In this context the importance of tools for investigation of these CP functions and a possible suitability of the CP as therapeutic target will be discussed. PMID- 25814934 TI - Brain region-specific gene expression profiles in freshly isolated rat microglia. AB - Microglia are important cells in the brain that can acquire different morphological and functional phenotypes dependent on the local situation they encounter. Knowledge on the region-specific gene signature of microglia may hold valuable clues for microglial functioning in health and disease, e.g., Parkinson's disease (PD) in which microglial phenotypes differ between affected brain regions. Therefore, we here investigated whether regional differences exist in gene expression profiles of microglia that are isolated from healthy rat brain regions relevant for PD. We used an optimized isolation protocol based on a rapid isolation of microglia from discrete rat gray matter regions using density gradients and fluorescent-activated cell sorting. Application of the present protocol followed by gene expression analysis enabled us to identify subtle differences in region-specific microglial expression profiles and show that the genetic profile of microglia already differs between different brain regions when studied under control conditions. As such, these novel findings imply that brain region-specific microglial gene expression profiles exist that may contribute to the region-specific differences in microglia responsivity during disease conditions, such as seen in, e.g., PD. PMID- 25814933 TI - Prenatal stress is a vulnerability factor for altered morphology and biological activity of microglia cells. AB - Several lines of evidence suggest that the dysregulation of the immune system is an important factor in the development of depression. Microglia are the resident macrophages of the central nervous system and a key player in innate immunity of the brain. We hypothesized that prenatal stress (an animal model of depression) as a priming factor could affect microglial cells and might lead to depressive like disturbances in adult male rat offspring. We investigated the behavioral changes (sucrose preference test, Porsolt test), the expression of C1q and CD40 mRNA and the level of microglia (Iba1 positive) in 3-month-old control and prenatally stressed male offspring rats. In addition, we characterized the morphological and biochemical parameters of potentially harmful (NO, iNOS, IL 1beta, IL-18, IL-6, TNF-alpha, CCL2, CXCL12, CCR2, CXCR4) and beneficial (insulin like growth factor-1 (IGF-1), brain derived neurotrophic factor (BDNF)) phenotypes in cultures of microglia obtained from the cortices of 1-2 days old control and prenatally stressed pups. The adult prenatally stressed rats showed behavioral (anhedonic- and depression-like) disturbances, enhanced expression of microglial activation markers and an increased number of Iba1-immunopositive cells in the hippocampus and frontal cortex. The morphology of glia was altered in cultures from prenatally stressed rats, as demonstrated by immunofluorescence microscopy. Moreover, in these cultures, we observed enhanced expression of CD40 and MHC II and release of pro-inflammatory cytokines, including IL-1beta, IL-18, TNF-alpha and IL-6. Prenatal stress significantly up-regulated levels of the chemokines CCL2, CXCL12 and altered expression of their receptors, CCR2 and CXCR4 while IGF-1 production was suppressed in cultures of microglia from prenatally stressed rats. Our results suggest that prenatal stress may lead to excessive microglia activation and contribute to the behavioral changes observed in depression in adulthood. PMID- 25814935 TI - Caloric restriction protects against electrical kindling of the amygdala by inhibiting the mTOR signaling pathway. AB - Caloric restriction (CR) has been shown to possess antiepileptic properties; however its mechanism of action is poorly understood. CR might inhibit the activity of the mammalian or mechanistic target of rapamycin (mTOR) signaling cascade, which seems to participate crucially in the generation of epilepsy. Thus, we investigated the effect of CR on the mTOR pathway and whether CR modified epilepsy generation due to electrical amygdala kindling. The former was studied by analyzing the phosphorylation of adenosine monophosphate-activated protein kinase, protein kinase B and the ribosomal protein S6. The mTOR cascade is regulated by energy and by insulin levels, both of which may be changed by CR; thus we investigated if CR altered the levels of energy substrates in the blood or the level of insulin in plasma. Finally, we studied if CR modified the expression of genes that encode proteins participating in the mTOR pathway. CR increased the after-discharge threshold and tended to reduce the after-discharge duration, indicating an anti-convulsive action. CR diminished the phosphorylation of protein kinase B and ribosomal protein S6, suggesting an inhibition of the mTOR cascade. However, CR did not change glucose, beta-hydroxybutyrate or insulin levels; thus the effects of CR were independent from them. Interestingly, CR also did not modify the expression of any investigated gene. The results suggest that the anti-epileptic effect of CR may be partly due to inhibition of the mTOR pathway. PMID- 25814936 TI - Object similarity affects the perceptual strategy underlying invariant visual object recognition in rats. AB - In recent years, a number of studies have explored the possible use of rats as models of high-level visual functions. One central question at the root of such an investigation is to understand whether rat object vision relies on the processing of visual shape features or, rather, on lower-order image properties (e.g., overall brightness). In a recent study, we have shown that rats are capable of extracting multiple features of an object that are diagnostic of its identity, at least when those features are, structure-wise, distinct enough to be parsed by the rat visual system. In the present study, we have assessed the impact of object structure on rat perceptual strategy. We trained rats to discriminate between two structurally similar objects, and compared their recognition strategies with those reported in our previous study. We found that, under conditions of lower stimulus discriminability, rat visual discrimination strategy becomes more view-dependent and subject-dependent. Rats were still able to recognize the target objects, in a way that was largely tolerant (i.e., invariant) to object transformation; however, the larger structural and pixel wise similarity affected the way objects were processed. Compared to the findings of our previous study, the patterns of diagnostic features were: (i) smaller and more scattered; (ii) only partially preserved across object views; and (iii) only partially reproducible across rats. On the other hand, rats were still found to adopt a multi-featural processing strategy and to make use of part of the optimal discriminatory information afforded by the two objects. Our findings suggest that, as in humans, rat invariant recognition can flexibly rely on either view invariant representations of distinctive object features or view-specific object representations, acquired through learning. PMID- 25814937 TI - Midbrain catecholaminergic neurons co-express alpha-synuclein and tau in progressive supranuclear palsy. AB - OBJECTIVE: To analyze the frequency and distribution of alpha-synuclein deposits in progressive supranuclear palsy (PSP). METHODS: The brains of 25 cases of pathologically confirmed PSP were evaluated with immunohistochemistry for alpha synuclein and tau. Multiple immunofluorescent stains were applied to analyze the expression of tau and alpha-synuclein aggregates in catecholaminergic neurons. Patients' clinical symptoms were retrospectively recorded. RESULTS: Deposits alpha-synuclein in the form of typical Lewy bodies (LBs) were only found in two PSP cases (8%) that fulfilled the clinical subtype of PSP known as Richardson's syndrome (RS). LBs were present in the locus ceruleus (LC), substantia nigra pars compacta (SNc), basal forebrain, amygdala and cingulated cortex in a distribution mimicking that of Parkinson's disease (PD). Triple-immunolabeling revealed co expression of alpha-synuclein and tau proteins in some tyrosine hydroxilase (TH) positive neurons of the LC and SNc. CONCLUSIONS: There is no apparent clinical correlation between the presence of LBs in PSP. Tau protein co-aggregate with alpha-synuclein in catecholaminergic neurons of PSP brains suggesting a synergistic interaction between the two proteins. This is in keeping with the current view of neurodegenerative disorders as "misfolded protein diseases". PMID- 25814938 TI - Anatomical inputs to sulcal portions of areas 9m and 8Bm in the macaque monkey. AB - Neuronal activities recorded from the dorsal bank of the anterior cingulate sulcus have suggested that this cortical area is involved in control of search vs. repetition, goal-based action selection and encoding of prediction error regarding action value. In this study, to explore potential anatomical bases for these neuronal activities, we injected retrograde tracers (CTB-Alexa-488 and CTB gold) into the dorsal bank of the anterior cingulate sulcus and examined the distribution of labeled cell bodies in macaque monkey brains. The Nissl staining showed that the cortex in the dorsal bank of the anterior cingulate sulcus has consistent layer 4 which means that the cortical region is a part of the granular prefrontal cortex. The injection site belonged to the sulcal portion of area 9m in two cases and the sulcal portion of area 8Bm in one case. In addition to the continuous distribution of labeled cells in the two areas (areas 9m and 8Bm) around the injection site, the labeled cells were densely distributed in the cingulate areas (areas 24, 32, and 23) in all the cases. The dense labeling of cells was also found in other prefrontal areas (areas 46, 10, 11, and 12) in the two cases with injection into the sulcal portion of area 9m, whereas the dense labeling of cells was found in pre-motor areas (F6 and F7) in the case with injection into the sulcal portion of area 8Bm. The dense labeling of cells in the prefrontal and premotor areas was more similar to those previously found after injections into dorsal parts of areas 9 and 8B. Subcortical distribution of labeled cells was found in the mediodorsal nucleus of thalamus, claustrum, and substantia nigra pars compacta in all the cases. PMID- 25814939 TI - Preserving cortico-striatal function: deep brain stimulation in Huntington's disease. AB - Huntington's disease (HD) is an incurable neurodegenerative disease characterized by the triad of chorea, cognitive dysfunction and psychiatric disturbances. Since the discovery of the HD gene, the pathogenesis has been outlined, but to date a cure has not been found. Disease modifying therapies are needed desperately to improve function, alleviate suffering, and provide hope for symptomatic patients. Deep brain stimulation (DBS), a proven therapy for managing the symptoms of some neurodegenerative movement disorders, including Parkinson's disease, has been reported as a palliative treatment in select cases of HD with debilitating chorea with variable success. New insights into the mechanism of action of DBS suggest it may have the potential to circumvent other manifestations of HD including cognitive deterioration. Furthermore, because DBS is already widely used, reversible, and has a risk profile that is relatively low, new studies can be initiated. In this article we contend that new clinical trials be considered to test the effects of DBS for HD. PMID- 25814940 TI - Corrigendum: Valenced action/inhibition learning in humans is modulated by a genetic variant linked to dopamine D2 receptor expression. AB - [This corrects the article on p. 140 in vol. 8, PMID: 25147510.]. PMID- 25814942 TI - The inhibitory avoidance discrimination task to investigate accuracy of memory. AB - The present study was aimed at developing a new inhibitory avoidance task, based on training and/or testing rats in multiple contexts, to investigate accuracy of memory. In the first experiment, male Sprague-Dawley rats were given footshock in an inhibitory avoidance apparatus and, 48 h later, retention latencies of each rat were assessed in the training apparatus (Shock box) as well as in a novel, contextually modified, apparatus. Retention latencies in the Shock box were significantly longer than those in the Novel box, indicating accurate memory of the training context. When the noradrenergic stimulant yohimbine (0.3 mg/kg, sc) was administered after the training, 48-h retention latencies in the Shock box, but not Novel box, were increased, indicating that the noradrenergic activation enhanced memory of the training experience without reducing memory accuracy. In the second experiment, rats were trained on an inhibitory avoidance discrimination task: They were first trained in an inhibitory avoidance apparatus without footshock (Non-Shock box), followed 1 min later by footshock training in a contextually modified apparatus (Shock box). Forty-eight-hour retention latencies in the Shock and Non-Shock boxes did not differ from each other but were both significantly longer than those in a Novel box, indicating that rats remembered the two training contexts but did not have episodic-like memory of the association of footshock with the correct training context. When the interval between the two training episodes was increased to 2 min, rats showed accurate memory of the association of footshock with the training context. Yohimbine administered after the training also enhanced rats' ability to remember in which training context they had received actual footshock. These findings indicate that the inhibitory avoidance discrimination task is a novel variant of the well established inhibitory avoidance task suitable to investigate accuracy of memory. PMID- 25814941 TI - Reconceptualizing anhedonia: novel perspectives on balancing the pleasure networks in the human brain. AB - Anhedonia, the lack of pleasure, has been shown to be a critical feature of a range of psychiatric disorders. Yet, it is currently measured primarily through subjective self-reports and as such has been difficult to submit to rigorous scientific analysis. New insights from affective neuroscience hold considerable promise in improving our understanding of anhedonia and for providing useful objective behavioral measures to complement traditional self-report measures, potentially leading to better diagnoses and novel treatments. Here, we review the state-of-the-art of hedonia research and specifically the established mechanisms of wanting, liking, and learning. Based on this framework we propose to conceptualize anhedonia as impairments in some or all of these processes, thereby departing from the longstanding view of anhedonia as solely reduced subjective experience of pleasure. We discuss how deficits in each of the reward components can lead to different expressions, or subtypes, of anhedonia affording novel ways of measurement. Specifically, we review evidence suggesting that patients suffering from depression and schizophrenia show impairments in wanting and learning, while some aspects of conscious liking seem surprisingly intact. Furthermore, the evidence suggests that anhedonia is heterogeneous across psychiatric disorders, depending on which parts of the pleasure networks are most affected. This in turn has implications for diagnosis and treatment of anhedonia. PMID- 25814943 TI - The frequency of hippocampal theta rhythm is modulated on a circadian period and is entrained by food availability. AB - The hippocampal formation plays a critical role in the generation of episodic memory. While the encoding of the spatial and contextual components of memory have been extensively studied, how the hippocampus encodes temporal information, especially at long time intervals, is less well understood. The activity of place cells in hippocampus has previously been shown to be modulated at a circadian time-scale, entrained by a behavioral stimulus, but not entrained by light. The experimental procedures used in the previous study of this phenomenon, however, necessarily conflated two alternative entraining stimuli, the exposure to the recording environment and the availability of food, making it impossible to distinguish between these possibilities. Here we demonstrate that the frequency of theta-band hippocampal EEG varies with a circadian period in freely moving animals and that this periodicity mirrors changes in the firing rate of hippocampal neurons. Theta activity serves, therefore, as a proxy of circadian modulated hippocampal neuronal activity. We then demonstrate that the frequency of hippocampal theta driven by stimulation of the reticular formation also varies with a circadian period. Because this effect can be observed without having to feed the animal to encourage movement we were able to identify what stimulus entrains the circadian oscillation. We show that with reticular-activated recordings started at various times of the day the frequency of theta varies quasi-sinusoidally with a 25 h period and phase-aligned when referenced to the animal's regular feeding time, but not the recording start time. Furthermore, we show that theta frequency consistently varied with a circadian period when the data obtained from repeated recordings started at various times of the day were referenced to the start of food availability in the recording chamber. This pattern did not occur when data were referenced to the start of the recording session or to the actual time of day when this was not also related to feeding time. This double dissociation demonstrates that hippocampal theta is modulated with a circadian timescale, and that this modulation is strongly entrained by food. One interpretation of this finding is that the hippocampus is responsive to a food entrainable oscillator (FEO) that might modulate foraging behavior over circadian periods. PMID- 25814944 TI - Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. AB - Recent studies have indicated that the serotonin receptor subtype 7 (5-HT7R) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life. Here we show that pharmacological stimulation of 5-HT7R using a highly selective agonist, LP-211, enhances neurite outgrowth in neuronal primary cultures from the cortex, hippocampus and striatal complex of embryonic mouse brain, through multiple signal transduction pathways. All these signaling systems, involving mTOR, the Rho GTPase Cdc42, Cdk5, and ERK, are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth. Indeed, our data indicate that neurite elongation stimulated by 5-HT7R is modulated by drugs affecting actin polymerization. In addition, we show, by 2D Western blot analyses, that treatment of neuronal cultures with LP-211 alters the expression profile of cofilin, an actin binding protein involved in microfilaments dynamics. Furthermore, by using microfluidic chambers that physically separate axons from the soma and dendrites, we demonstrate that agonist-dependent activation of 5-HT7R stimulates axonal elongation. Our results identify for the first time several signal transduction pathways, activated by stimulation of 5-HT7R, that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation. Therefore, the activation of 5-HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development. PMID- 25814909 TI - Measurement of jet multiplicity distributions in [Formula: see text] production in pp collisions at [Formula: see text]. AB - The normalised differential top quark-antiquark production cross section is measured as a function of the jet multiplicity in proton-proton collisions at a centre-of-mass energy of 7[Formula: see text] at the LHC with the CMS detector. The measurement is performed in both the dilepton and lepton+jets decay channels using data corresponding to an integrated luminosity of 5.0[Formula: see text]. Using a procedure to associate jets to decay products of the top quarks, the differential cross section of the [Formula: see text] production is determined as a function of the additional jet multiplicity in the lepton+jets channel. Furthermore, the fraction of events with no additional jets is measured in the dilepton channel, as a function of the threshold on the jet transverse momentum. The measurements are compared with predictions from perturbative quantum chromodynamics and no significant deviations are observed. PMID- 25814945 TI - Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome. AB - Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP 211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome. PMID- 25814947 TI - Editorial on emerging neuroimaging tools for studying normal and abnormal human brain development. PMID- 25814946 TI - Pre-reproductive maternal enrichment influences rat maternal care and offspring developmental trajectories: behavioral performances and neuroplasticity correlates. AB - Environmental enrichment (EE) is a widely used paradigm for investigating the influence of complex stimulations on brain and behavior. Here we examined whether pre-reproductive exposure to EE of female rats may influence their maternal care and offspring cognitive performances. To this aim, from weaning to breeding age enriched females (EF) were reared in enriched environments. Females reared in standard conditions were used as controls. At 2.5 months of age all females were mated and reared in standard conditions with their offspring. Maternal care behaviors and nesting activity were assessed in lactating dams. Their male pups were also behaviorally evaluated at different post-natal days (pnd). Brain BDNF, reelin and adult hippocampal neurogenesis levels were measured as biochemical correlates of neuroplasticity. EF showed more complex maternal care than controls due to their higher levels of licking, crouching and nest building activities. Moreover, their offspring showed higher discriminative (maternal odor preference T-maze, pnd 10) and spatial (Morris Water Maze, pnd 45; Open Field with objects, pnd 55) performances, with no differences in social abilities (Sociability test, pnd 35), in comparison to controls. BDNF levels were increased in EF frontal cortex at pups' weaning and in their offspring hippocampus at pnd 21 and 55. No differences in offspring reelin and adult hippocampal neurogenesis levels were found. In conclusion, our study indicates that pre-reproductive maternal enrichment positively influences female rats' maternal care and cognitive development of their offspring, demonstrating thus a transgenerational transmission of EE benefits linked to enhanced BDNF-induced neuroplasticity. PMID- 25814907 TI - Measurement of the centrality and pseudorapidity dependence of the integrated elliptic flow in lead-lead collisions at [Formula: see text] TeV with the ATLAS detector. AB - The integrated elliptic flow of charged particles produced in Pb+Pb collisions at [Formula: see text] TeV has been measured with the ATLAS detector using data collected at the Large Hadron Collider. The anisotropy parameter, [Formula: see text], was measured in the pseudorapidity range [Formula: see text] with the event-plane method. In order to include tracks with very low transverse momentum [Formula: see text], thus reducing the uncertainty in [Formula: see text] integrated over [Formula: see text], a [Formula: see text] data sample recorded without a magnetic field in the tracking detectors is used. The centrality dependence of the integrated [Formula: see text] is compared to other measurements obtained with higher [Formula: see text] thresholds. The integrated elliptic flow is weakly decreasing with [Formula: see text]. The integrated [Formula: see text] transformed to the rest frame of one of the colliding nuclei is compared to the lower-energy RHIC data. PMID- 25814948 TI - Improper activation of D1 and D2 receptors leads to excess noise in prefrontal cortex. AB - The dopaminergic system has been shown to control the amount of noise in the prefrontal cortex (PFC) and likely plays an important role in working memory and the pathophysiology of schizophrenia. We developed a model that takes into account the known receptor distributions of D1 and D2 receptors, the changes these receptors have on neuron response properties, as well as identified circuitry involved in working memory. Our model suggests that D1 receptor under stimulation in supragranular layers gates internal noise into the PFC leading to cognitive symptoms as has been proposed in attention disorders, while D2 over stimulation gates noise into the PFC by over-activation of cortico-striatal projecting neurons in infragranular layers. We apply this model in the context of a memory-guided saccade paradigm and show deficits similar to those observed in schizophrenic patients. We also show set-shifting impairments similar to those observed in rodents with D1 and D2 receptor manipulations. We discuss how the introduction of noise through changes in D1 and D2 receptor activation may account for many of the symptoms of schizophrenia depending on where this dysfunction occurs in the PFC. PMID- 25814951 TI - Clinical trial design of serious gaming in mild cognitive impairment. PMID- 25814949 TI - Mismatch negativity latency as a biomarker of amnestic mild cognitive impairment in chinese rural elders. AB - The aim was to evaluate the mismatch negativity (MMN) component, a correlate of the automatic detection of changes in the acoustic environment, in healthy adults, and adults with amnestic mild cognitive impairment (aMCI). Forty-three aMCI subjects and 43 healthy Chinese older adults were arranged into experimental group and control group, respectively. Their MMN amplitude and latency were measured at the FZ, FCZ, and CZ electrode sites under a passive auditory oddball task. The results showed that the latencies obtained from the FZ, FCZ, and CZ electrode sites were significantly longer in the aMCI adults than in the control adults (P < 0.01) while there were no significant differences in MMN amplitude between two groups (P > 0.05). The MMN latency was found to be a sensitive and specific biomarker of aMCI. PMID- 25814952 TI - Effect of a water-maze procedure on the redox mechanisms in brain parts of aged rats. AB - The Morris water maze (MWM) is a tool for assessment of age-related modulations spatial learning and memory in laboratory rats. In our work was investigated the age-related decline of MWM performance in 11-month-old rats and the effect exerted by training in the MWM on the redox mechanisms in rat brain parts. Young adult (3-month-old) and aged (11-month-old) male rats were trained in the MWM. Intact animals of the corresponding age were used as the reference groups. The level of pro- and antioxidant capacity in brain tissue homogenates was assessed using the chemiluminescence method. A reduced performance in the MWM test was found in 11-month-old rats: at the first day of training they showed only 30% of successful MWM trials. However, at the last training day the percentage of successful trials was equal for young adult and aged animals. This indicates that the aged 11-month-old rats can successfully learn in MWM. Therewith, the MWM spatial learning procedure itself produces changes in different processes of redox homeostasis in 11-month-old and 3-month-old rats as compared to intact animals. Young adult rats showed a decrease in prooxidant capacity in all brain parts, while 11-month-old rats demonstrated an increase in antioxidant capacity in the olfactory bulb, pons + medulla oblongata and frontal lobe cortex. Hence, the MWM procedure activates the mechanisms that restrict the oxidative stress in brain parts. The obtained results may be an argument for further development of the animal training procedures aimed to activate the mechanisms that can prevent the age-related deterioration of performance in the learning test. This may be useful not only for the development of training procedures applicable to human patients with age-related cognitive impairments, but also for their rehabilitation. PMID- 25814950 TI - Emotional memory for musical excerpts in young and older adults. AB - The emotions evoked by music can enhance recognition of excerpts. It has been suggested that memory is better for high than for low arousing music (Eschrich et al., 2005; Samson et al., 2009), but it remains unclear whether positively (Eschrich et al., 2008) or negatively valenced music (Aube et al., 2013; Vieillard and Gilet, 2013) may be better recognized. Moreover, we still know very little about the influence of age on emotional memory for music. To address these issues, we tested emotional memory for music in young and older adults using musical excerpts varying in terms of arousal and valence. Participants completed immediate and 24 h delayed recognition tests. We predicted highly arousing excerpts to be better recognized by both groups in immediate recognition. We hypothesized that arousal may compensate consolidation deficits in aging, thus showing more prominent benefit of high over low arousing stimuli in older than younger adults on delayed recognition. We also hypothesized worst retention of negative excerpts for the older group, resulting in a recognition benefit for positive over negative excerpts specific to older adults. Our results suggest that although older adults had worse recognition than young adults overall, effects of emotion on memory do not seem to be modified by aging. Results on immediate recognition suggest that recognition of low arousing excerpts can be affected by valence, with better memory for positive relative to negative low arousing music. However, 24 h delayed recognition results demonstrate effects of emotion on memory consolidation regardless of age, with a recognition benefit for high arousal and for negatively valenced music. The present study highlights the role of emotion on memory consolidation. Findings are examined in light of the literature on emotional memory for music and for other stimuli. We finally discuss the implication of the present results for potential music interventions in aging and dementia. PMID- 25814954 TI - Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn. AB - BACKGROUND: Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood. AIM: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms. RESULTS: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1alpha expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFkappaB. CONCLUSION: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFkappaB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN. PMID- 25814956 TI - Arginase induction and activation during ischemia and reperfusion and functional consequences for the heart. AB - Induction and activation of arginase is among the fastest responses of the heart to ischemic events. Induction of arginase expression and enzyme activation under ischemic conditions shifts arginine consumption from nitric oxide formation (NO) to the formation of ornithine and urea. In the heart such a switch in substrate utilization reduces the impact of the NO/cGMP-pathway on cardiac function that requires intact electromechanical coupling but at the same time it induces ornithine-dependent pathways such as the polyamine metabolism. Both effects significantly reduce the recovery of heart function during reperfusion and thereby limits the success of reperfusion strategies. In this context, changes in arginine consumption trigger cardiac remodeling in an unfavorable way and increases the risk of arrhythmia, specifically in the initial post-ischemic period in which arginase activity is dominating. However, during the entire ischemic period arginase activation might be a meaningful adaptation that is specifically relevant for reperfusion following prolonged ischemic periods. Therefore, a precise understanding about the underlying mechanism that leads to arginase induction as well as of it's mechanistic impact on post-ischemic hearts is required for optimizing reperfusion strategies. In this review we will summarize our current understanding of these processes and give an outlook about possible treatment options for the future. PMID- 25814953 TI - Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei. AB - Drug resistance in pathogenic protozoa is very often caused by changes to the 'transportome' of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (DA; Berenil((r))), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (melarsoprol/pentamidine cross resistance, MPXR) is the result of loss of a separate high affinity pentamidine transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the "selectivity region" of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this remarkable ability. PMID- 25814958 TI - Online social networking sites and mental health research. PMID- 25814959 TI - Addressing stigma relating to mental illness in low- and middle-income countries. PMID- 25814957 TI - Neural stem cells respond to stress hormones: distinguishing beneficial from detrimental stress. AB - Neural stem cells (NSCs), the progenitors of the nervous system, control distinct, position-specific functions and are critically involved in the maintenance of homeostasis in the brain. The responses of these cells to various stressful stimuli are shaped by genetic, epigenetic, and environmental factors via mechanisms that are age and developmental stage-dependent and still remain, to a great extent, elusive. Increasing evidence advocates for the beneficial impact of the stress response in various settings, complementing the extensive number of studies on the detrimental effects of stress, particularly in the developing brain. In this review, we discuss suggested mechanisms mediating both the beneficial and detrimental effects of stressors on NSC activity across the lifespan. We focus on the specific effects of secreted factors and we propose NSCs as a "sensor," capable of distinguishing among the different stressors and adapting its functions accordingly. All the above suggest the intriguing hypothesis that NSCs are an important part of the adaptive response to stressors via direct and indirect, specific mechanisms. PMID- 25814960 TI - Encouraging 5-year olds to attend to landmarks: a way to improve children's wayfinding strategies in a virtual environment. AB - Wayfinding is defined as the ability to learn and remember a route through an environment. Previous researchers have shown that young children have difficulties remembering routes. However, very few researchers have considered how to improve young children's wayfinding abilities. Therefore, we investigated ways to help children increase their wayfinding skills. In two studies, a total of 72 5-year olds were shown a route in a six turn maze in a virtual environment and were then asked to retrace this route by themselves. A unique landmark was positioned at each junction and each junction was made up of two paths: a correct path and an incorrect path. Two different strategies improved route learning performance. In Experiment 1, verbally labeling on-route junction landmarks during the first walk reduced the number of errors and the number of trials to reach a learning criterion when the children retraced the route. In Experiment 2, encouraging children to attend to on-route junction landmarks on the first walk reduced the number of errors when the route was retraced. This was the first study to show that very young children can be taught route learning skills. The implications of our results are discussed. PMID- 25814955 TI - Can endurance exercise preconditioning prevention disuse muscle atrophy? AB - Emerging evidence suggests that exercise training can provide a level of protection against disuse muscle atrophy. Endurance exercise training imposes oxidative, metabolic, and heat stress on skeletal muscle which activates a variety of cellular signaling pathways that ultimately leads to the increased expression of proteins that have been demonstrated to protect muscle from inactivity -induced atrophy. This review will highlight the effect of exercise induced oxidative stress on endogenous enzymatic antioxidant capacity (i.e., superoxide dismutase, glutathione peroxidase, and catalase), the role of oxidative and metabolic stress on PGC1-alpha, and finally highlight the effect heat stress and HSP70 induction. Finally, this review will discuss the supporting scientific evidence that these proteins can attenuate muscle atrophy through exercise preconditioning. PMID- 25814961 TI - Judgment of musical emotions after cochlear implantation in adults with progressive deafness. AB - While cochlear implantation is rather successful in restoring speech comprehension in quiet environments (Nimmons et al., 2008), other auditory tasks, such as music perception, can remain challenging for implant users. Here, we tested how patients who had received a cochlear implant (CI) after post-lingual progressive deafness perceive emotions in music. Thirteen adult CI recipients with good verbal comprehension (dissyllabic words >=70%) and 13 normal hearing participants matched for age, gender, and education listened to 40 short musical excerpts that selectively expressed fear, happiness, sadness, and peacefulness ( Vieillard et al., 2008). The participants were asked to rate (on a 0-100 scale) how much the musical stimuli expressed these four cardinal emotions, and to judge their emotional valence (unpleasant-pleasant) and arousal (relaxing-stimulating). Although CI users performed above chance level, their emotional judgments (mean correctness scores) were generally impaired for happy, scary, and sad, but not for peaceful excerpts. CI users also demonstrated deficits in perceiving arousal of musical excerpts, whereas rating of valence remained unaffected. The current findings indicate that judgments of emotional categories and dimensions of musical excerpts are not uniformly impaired after cochlear implantation. These results are discussed in relation to the relatively spared abilities of CI users in perceiving temporal (rhythm and metric) as compared to spectral (pitch and timbre) musical dimensions, which might benefit the processing of musical emotions (Cooper et al., 2008). PMID- 25814962 TI - Intrusions of a drowsy mind: neural markers of phenomenological unpredictability. AB - The transition from a relaxed to a drowsy state of mind is often accompanied by hypnagogic experiences: most commonly, perceptual imagery, but also linguistic intrusions, i.e., the sudden emergence of unpredictable anomalies in the stream of inner speech. This study has sought to describe the contents of such intrusions, to verify their association with the progression of sleep onset, and to investigate the electroencephalographic processes associated with linguistic intrusions as opposed to more common hypnagogic perceptual imagery. A single participant attended 10 experimental sessions in the EEG laboratory, where he was allowed to drift into a drowsy state of mind, while maintaining metacognition of his own experiences. Once a linguistic intrusion or a noticeable perceptual image occurred, the participant pressed a button and reported it verbally. An increase in the EEG-defined depth of drowsiness as assessed by the Hori system of sleep onset was observed in the last 20 s before a button press. Likewise, EEG Dimension of Activation values decreased before the button press, indicating that the occurrence of cognitively incongruous experiences coincides with the rapid change of EEG predictability patterns. EEG hemispheric asymmetry analysis showed that linguistic intrusions had a higher alpha and gamma power in the left hemisphere electrodes, whereas perceptual imagery reports were associated with a higher beta power over the right hemisphere. These findings indicate that the modality as well as the incongruence of drowsiness-related hypnagogic experiences is strongly associated with distinct EEG signatures in this participant. Sleep onset may provide a unique possibility to study the neural mechanisms accompanying the fragmentation of the stream of consciousness in healthy individuals. PMID- 25814963 TI - An improved cognitive model of the Iowa and Soochow Gambling Tasks with regard to model fitting performance and tests of parameter consistency. AB - The Iowa Gambling Task (IGT) and the Soochow Gambling Task (SGT) are two experience-based risky decision-making tasks for examining decision-making deficits in clinical populations. Several cognitive models, including the expectancy-valence learning (EVL) model and the prospect valence learning (PVL) model, have been developed to disentangle the motivational, cognitive, and response processes underlying the explicit choices in these tasks. The purpose of the current study was to develop an improved model that can fit empirical data better than the EVL and PVL models and, in addition, produce more consistent parameter estimates across the IGT and SGT. Twenty-six opiate users (mean age 34.23; SD 8.79) and 27 control participants (mean age 35; SD 10.44) completed both tasks. Eighteen cognitive models varying in evaluation, updating, and choice rules were fit to individual data and their performances were compared to that of a statistical baseline model to find a best fitting model. The results showed that the model combining the prospect utility function treating gains and losses separately, the decay-reinforcement updating rule, and the trial-independent choice rule performed the best in both tasks. Furthermore, the winning model produced more consistent individual parameter estimates across the two tasks than any of the other models. PMID- 25814964 TI - Women are underrepresented in fields where success is believed to require brilliance. AB - Women's underrepresentation in science, technology, engineering, and mathematics (STEM) fields is a prominent concern in our society and many others. Closer inspection of this phenomenon reveals a more nuanced picture, however, with women achieving parity with men at the Ph.D. level in certain STEM fields, while also being underrepresented in some non-STEM fields. It is important to consider and provide an account of this field-by-field variability. The field-specific ability beliefs (FAB) hypothesis aims to provide such an account, proposing that women are likely to be underrepresented in fields thought to require raw intellectual talent-a sort of talent that women are stereotyped to possess less of than men. In two studies, we provide evidence for the FAB hypothesis, demonstrating that the academic fields believed by laypeople to require brilliance are also the fields with lower female representation. We also found that the FABs of participants with college-level exposure to a field were more predictive of its female representation than those of participants without college exposure, presumably because the former beliefs mirror more closely those of the field's practitioners (the direct "gatekeepers"). Moreover, the FABs of participants with college exposure to a field predicted the magnitude of the field's gender gap above and beyond their beliefs about the level of mathematical and verbal skills required. Finally, we found that beliefs about the importance of brilliance to success in a field may predict its female representation in part by fostering the impression that the field demands solitary work and competition with others. These results suggest new solutions for enhancing diversity within STEM and across the academic spectrum. PMID- 25814965 TI - Corrigendum: Measuring the crowd within again: a pre-registered replication study. AB - [This corrects the article on p. 786 in vol. 5, PMID: 25120505.]. PMID- 25814966 TI - Attention is complex: causes and effects. PMID- 25814912 TI - Searches for electroweak production of charginos, neutralinos, and sleptons decaying to leptons and W, Z, and Higgs bosons in pp collisions at 8 TeV. AB - Searches for the direct electroweak production of supersymmetric charginos, neutralinos, and sleptons in a variety of signatures with leptons and [Formula: see text], [Formula: see text], and Higgs bosons are presented. Results are based on a sample of proton-proton collision data collected at center-of-mass energy [Formula: see text] with the CMS detector in 2012, corresponding to an integrated luminosity of 19.5 [Formula: see text]. The observed event rates are in agreement with expectations from the standard model. These results probe charginos and neutralinos with masses up to 720 [Formula: see text], and sleptons up to 260 [Formula: see text], depending on the model details. PMID- 25814967 TI - Criterion and incremental validity of the emotion regulation questionnaire. AB - Although research on emotion regulation (ER) is developing, little attention has been paid to the predictive power of ER strategies beyond established constructs. The present study examined the incremental validity of the Emotion Regulation Questionnaire (ERQ; Gross and John, 2003), which measures cognitive reappraisal and expressive suppression, over and above the Big Five personality factors. It also extended the evidence for the measure's criterion validity to yet unexamined criteria. A university student sample (N = 203) completed the ERQ, a measure of the Big Five, and relevant cognitive and emotion-laden criteria. Cognitive reappraisal predicted positive affect beyond personality, as well as experiential flexibility and constructive self-assertion beyond personality and affect. Expressive suppression explained incremental variance in negative affect beyond personality and in experiential flexibility beyond personality and general affect. No incremental effects were found for worry, social anxiety, rumination, reflection, and preventing negative emotions. Implications for the construct validity and utility of the ERQ are discussed. PMID- 25814968 TI - The intersection of turn-taking and repair: the timing of other-initiations of repair in conversation. AB - The transitions between turns at talk in conversation tend to occur quickly, with only a slight gap of ~100-300 ms between them. This estimate of central tendency, however, hides a wealth of complex variation, as a number of factors, such as the type of turns involved, have been shown to influence the timing of turn transitions. This article considers one specific type of turn that does not conform to the statistical trend, namely turns that deal with troubles of speaking, hearing, and understanding, known as other-initiations of repair (OIR). The results of a quantitative analysis of 169 OIRs in face-to-face conversation reveal that the most frequent cases occur after gaps of ~700 ms. Furthermore, OIRs that locate a source of trouble in a prior turn specifically tend to occur after shorter gaps than those that do not, and those that correct errors in a prior turn, while rare, tend to occur without delay. An analysis of the transitions before OIRs, using methods of conversation analysis, suggests that speakers use the extra time (i) to search for a late recognition of the problematic turn, (ii) to provide an opportunity for the speaker of the problematic turn to resolve the trouble independently, and (iii) to produce visual signals, such as facial gestures. In light of these results, it is argued that OIRs take priority over other turns at talk in conversation and therefore are not subject to the same rules and constraints that motivate fast turn transitions in general. PMID- 25814969 TI - Events and children's sense of time: a perspective on the origins of everyday time-keeping. AB - In this article I discuss abstract or pure time versus the content of time, (i.e., events, activities, and other goings-on). Or, more specifically, the utility of these two sorts of time in time-keeping or temporal organization. It is often assumed that abstract, uniform, and objective time is a universal physical entity out there, which humans may perceive of. However, this sort of evenly flowing time was only recently introduced to the human community, together with the mechanical clock. Before the introduction of mechanical clock-time, there were only events available to denote the extent of time. Events defined time, unlike the way time may define events in our present day culture. It is therefore conceivable that our primeval or natural mode of time-keeping involves the perception, estimation, and coordination of events. I find it likely that events continues to subserve our sense of time and time-keeping efforts, especially for children who have not yet mastered the use of clock-time. Instead of seeing events as a distraction to our perception of time, I suggest that our experience and understanding of time emerges from our perception of events. PMID- 25814975 TI - Pedagogical psychology: beyond the 21st century. PMID- 25814970 TI - Beyond practices and values: toward a physio-bioecological analysis of sleeping arrangements in early infancy. PMID- 25814971 TI - Reward learning and negative emotion during rapid attentional competition. AB - Learned stimulus-reward associations influence how attention is allocated, such that stimuli rewarded in the past are favored in situations involving limited resources and competition. At the same time, task-irrelevant, high-arousal negative stimuli capture attention and divert resources away from tasks resulting in poor behavioral performance. Yet, investigations of how reward learning and negative stimuli affect perceptual and attentional processing have been conducted in a largely independent fashion. We have recently reported that performance based monetary rewards reduce negative stimuli interference during perception. The goal of the present study was to investigate how stimuli associated with past monetary rewards compete with negative stimuli during a subsequent attentional task when, critically, no performance-based rewards were at stake. Across two experiments, we found that target stimuli that were associated with high reward reduced the interference effect of potent, negative distractors. Similar to our recent findings with performance-based rewards, our results demonstrate that reward-associated stimuli reduce the deleterious impact of negative stimuli on behavior. PMID- 25814972 TI - New frontiers and applications of attachment theory. PMID- 25814976 TI - Breathing for answering: the time course of response planning in conversation. AB - We investigate the timing of pre-answer inbreaths in order to shed light on the time course of response planning and execution in conversational turn-taking. Using acoustic and inductive plethysmography recordings of seven dyadic conversations in Dutch, we show that pre-answer inbreaths in conversation typically begin briefly after the end of questions. We also show that the presence of a pre-answer inbreath usually co-occurs with substantially delayed answers, with a modal latency of 576 vs. 100 ms for answers not preceded by an inbreath. Based on previously reported minimal latencies for internal intercostal activation and the production of speech sounds, we propose that vocal responses, either in the form of a pre-utterance inbreath or of speech proper when an inbreath is not produced, are typically launched in reaction to information present in the last portion of the interlocutor's turn. We also show that short responses are usually made on residual breath, while longer responses are more often preceded by an inbreath. This relation of inbreaths to answer length suggests that by the time an inbreath is launched, typically during the last few hundred milliseconds of the question, the length of the answer is often prepared to some extent. Together, our findings are consistent with a two-stage model of response planning in conversational turn-taking: early planning of content often carried out in overlap with the incoming turn, and late launching of articulation based on the identification of turn-final cues. PMID- 25814973 TI - Stroop effects from newly learned color words: effects of memory consolidation and episodic context. AB - The Stroop task is an excellent tool to test whether reading a word automatically activates its associated meaning, and it has been widely used in mono- and bilingual contexts. Despite of its ubiquity, the task has not yet been employed to test the automaticity of recently established word-concept links in novel-word learning studies, under strict experimental control of learning and testing conditions. In three experiments, we thus paired novel words with native language (German) color words via lexical association and subsequently tested these words in a manual version of the Stroop task. Two crucial findings emerged: When novel word Stroop trials appeared intermixed among native-word trials, the novel-word Stroop effect was observed immediately after the learning phase. If no native color words were present in a Stroop block, the novel-word Stroop effect only emerged 24 h later. These results suggest that the automatic availability of a novel word's meaning depends either on supportive context from the learning episode and/or on sufficient time for memory consolidation. We discuss how these results can be reconciled with the complementary learning systems account of word learning. PMID- 25814974 TI - Feedforward and feedback processes in vision. PMID- 25814977 TI - The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. AB - Fatigue is one of the most pervasive symptoms of multiple sclerosis (MS), and has engendered hundreds of investigations on the topic. While there is a growing literature using various methods to study fatigue, a unified theory of fatigue in MS is yet to emerge. In the current review, we synthesize findings from neuroimaging, pharmacological, neuropsychological, and immunological studies of fatigue in MS, which point to a specific hypothesis of fatigue in MS: the dopamine imbalance hypothesis. The communication between the striatum and prefrontal cortex is reliant on dopamine, a modulatory neurotransmitter. Neuroimaging findings suggest that fatigue results from the disruption of communication between these regions. Supporting the dopamine imbalance hypothesis, structural and functional neuroimaging studies show abnormalities in the frontal and striatal regions that are heavily innervated by dopamine neurons. Further, dopaminergic psychostimulant medication has been shown to alleviate fatigue in individuals with traumatic brain injury, chronic fatigue syndrome, and in cancer patients, also indicating that dopamine might play an important role in fatigue perception. This paper reviews the structural and functional neuroimaging evidence as well as pharmacological studies that suggest that dopamine plays a critical role in the phenomenon of fatigue. We conclude with how specific aspects of the dopamine imbalance hypothesis can be tested in future research. PMID- 25814978 TI - Retinoid receptors in bone and their role in bone remodeling. AB - Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARalpha, RARbeta, RARgamma). RARs and closely related retinoid X receptors (RXRalpha, RXRbeta, RXRgamma) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass. Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRA's effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented. PMID- 25814979 TI - Early social environment affects the endogenous oxytocin system: a review and future directions. AB - Endogenous oxytocin plays an important role in a wide range of human functions including birth, milk ejection during lactation, and facilitation of social interaction. There is increasing evidence that both variations in the oxytocin receptor (OXTR) and concentrations of oxytocin are associated with differences in these functions. The causes for the differences that have been observed in tonic and stimulated oxytocin release remain unclear. Previous reviews have suggested that across the life course, these differences may be due to individual factors, e.g., genetic variation (of the OXTR), age or sex, or be the result of early environmental influences, such as social experiences, stress, or trauma partly by inducing epigenetic changes. This review has three aims. First, we briefly discuss the endogenous oxytocin system, including physiology, development, individual differences, and function. Second, current models describing the relationship between the early life environment and the development of the oxytocin system in humans and animals are discussed. Finally, we describe research designs that can be used to investigate the effects of the early environment on the oxytocin system, identifying specific areas of research that need further attention. PMID- 25814980 TI - Subgingival microbiota in health compared to periodontitis and the influence of smoking. AB - The etiology of periodontitis has traditionally been associated to a consortium of three bacterial species-the so-called "red-complex" of periodontal disease which has been the target for most diagnostic and therapeutic strategies. However, other species have also been found to correlate with disease severity. In addition, the influence of smoking on periodontal microbiota is poorly understood. In the current manuscript, the composition of the subgingival microbiota in healthy individuals vs. patients with chronic periodontitis has been investigated using 16S pyrosequencing and the influence of smoking on periodontal composition has been examined. Subgingival bacterial communities were sampled from 82 patients: 22 non-smoking healthy controls, 28 non-smoking periodontal patients, and 32 smoking periodontal patients. Bacterial diversity was higher in periodontal patients than in healthy subjects, which could be interpreted as the consequence of a nutritionally richer environment or a reduced immune competence. Periodontal patients showed a significantly higher prevalence/relative abundance of "established" periopathogens but also other taxa whose role is not well-established and that should be targets for future research. These include Anaeroglobus, Bulleidia, Desulfobulbus, Filifactor, Mogibacterium, Phocaeicola, Schwartzia or TM7. The microbial community of smoking associated periodontitis is less diverse and distinct from that of non-smokers, indicating that smoking has an influence on periodontal ecology. Interestingly, the high sequencing coverage allowed the detection at low proportions of periodontal pathogens in all healthy individuals, indicating that chronic periodontitis cannot be strictly considered an infectious disease but the outcome of a polymicrobial dysbiosis, where changes in the proportions of microbial consortia trigger the inflammatory and tissue-degradation responses of the host. PMID- 25814981 TI - The Pseudomonas aeruginosa antimetabolite L -2-amino-4-methoxy-trans-3-butenoic acid (AMB) is made from glutamate and two alanine residues via a thiotemplate linked tripeptide precursor. AB - The Pseudomonas aeruginosa toxin L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) is a non-proteinogenic amino acid which is toxic for prokaryotes and eukaryotes. Production of AMB requires a five-gene cluster encoding a putative LysE-type transporter (AmbA), two non-ribosomal peptide synthetases (AmbB and AmbE), and two iron(II)/alpha-ketoglutarate-dependent oxygenases (AmbC and AmbD). Bioinformatics analysis predicts one thiolation (T) domain for AmbB and two T domains (T1 and T2) for AmbE, suggesting that AMB is generated by a processing step from a precursor tripeptide assembled on a thiotemplate. Using a combination of ATP-PPi exchange assays, aminoacylation assays, and mass spectrometry-based analysis of enzyme-bound substrates and pathway intermediates, the AmbB substrate was identified to be L-alanine (L-Ala), while the T1 and T2 domains of AmbE were loaded with L-glutamate (L-Glu) and L-Ala, respectively. Loading of L-Ala at T2 of AmbE occurred only in the presence of AmbB, indicative of a trans loading mechanism. In vitro assays performed with AmbB and AmbE revealed the dipeptide L Glu-L-Ala at T1 and the tripeptide L-Ala-L-Glu-L-Ala attached at T2. When AmbC and AmbD were included in the assay, these peptides were no longer detected. Instead, an L-Ala-AMB-L-Ala tripeptide was found at T2. These data are in agreement with a biosynthetic model in which L-Glu is converted into AMB by the action of AmbC, AmbD, and tailoring domains of AmbE. The importance of the flanking L-Ala residues in the precursor tripeptide is discussed. PMID- 25814982 TI - Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study. AB - Sepsis is a clinical syndrome that can be caused by bacteria or fungi. Early knowledge on the nature of the causative agent is a prerequisite for targeted anti-microbial therapy. Besides currently used detection methods like blood culture and PCR-based assays, the analysis of the transcriptional response of the host to infecting organisms holds great promise. In this study, we aim to examine the transcriptional footprint of infections caused by the bacterial pathogens Staphylococcus aureus and Escherichia coli and the fungal pathogens Candida albicans and Aspergillus fumigatus in a human whole-blood model. Moreover, we use the expression information to build a random forest classifier to classify if a sample contains a bacterial, fungal, or mock-infection. After normalizing the transcription intensities using stably expressed reference genes, we filtered the gene set for biomarkers of bacterial or fungal blood infections. This selection is based on differential expression and an additional gene relevance measure. In this way, we identified 38 biomarker genes, including IL6, SOCS3, and IRG1 which were already associated to sepsis by other studies. Using these genes, we trained the classifier and assessed its performance. It yielded a 96% accuracy (sensitivities >93%, specificities >97%) for a 10-fold stratified cross validation and a 92% accuracy (sensitivities and specificities >83%) for an additional test dataset comprising Cryptococcus neoformans infections. Furthermore, the classifier is robust to Gaussian noise, indicating correct class predictions on datasets of new species. In conclusion, this genome-wide approach demonstrates an effective feature selection process in combination with the construction of a well-performing classification model. Further analyses of genes with pathogen-dependent expression patterns can provide insights into the systemic host responses, which may lead to new anti-microbial therapeutic advances. PMID- 25814983 TI - Microbial communities in dark oligotrophic volcanic ice cave ecosystems of Mt. Erebus, Antarctica. AB - The Earth's crust hosts a subsurface, dark, and oligotrophic biosphere that is poorly understood in terms of the energy supporting its biomass production and impact on food webs at the Earth's surface. Dark oligotrophic volcanic ecosystems (DOVEs) are good environments for investigations of life in the absence of sunlight as they are poor in organics, rich in chemical reactants and well known for chemical exchange with Earth's surface systems. Ice caves near the summit of Mt. Erebus (Antarctica) offer DOVEs in a polar alpine environment that is starved in organics and with oxygenated hydrothermal circulation in highly reducing host rock. We surveyed the microbial communities using PCR, cloning, sequencing and analysis of the small subunit (16S) ribosomal and Ribulose-1,5-bisphosphate Carboxylase/Oxygenase (RubisCO) genes in sediment samples from three different caves, two that are completely dark and one that receives snow-filtered sunlight seasonally. The microbial communities in all three caves are composed primarily of Bacteria and fungi; Archaea were not detected. The bacterial communities from these ice caves display low phylogenetic diversity, but with a remarkable diversity of RubisCO genes including new deeply branching Form I clades, implicating the Calvin-Benson-Bassham (CBB) cycle as a pathway of CO2 fixation. The microbial communities in one of the dark caves, Warren Cave, which has a remarkably low phylogenetic diversity, were analyzed in more detail to gain a possible perspective on the energetic basis of the microbial ecosystem in the cave. Atmospheric carbon (CO2 and CO), including from volcanic emissions, likely supplies carbon and/or some of the energy requirements of chemoautotrophic microbial communities in Warren Cave and probably other Mt. Erebus ice caves. Our work casts a first glimpse at Mt. Erebus ice caves as natural laboratories for exploring carbon, energy and nutrient sources in the subsurface biosphere and the nutritional limits on life. PMID- 25814984 TI - von Willebrand Factor is elevated in HIV patients with a history of thrombosis. AB - BACKGROUND: Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation. METHODS: We reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis and compared plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). RESULTS: During a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21, and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2.36 SD +/- 0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD +/- 0.82 IU/ml vs. 2.20 SD +/- 0.77 IU/ml; p = 0.024). This difference remained significant for recurrent events (mean 2.78 SD +/- 0.75; p = 0.043). sCD14 was positively correlated with LPS (r = 0.255; p = 0.003). CONCLUSION: The incidence of venous thrombosis was two-fold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels as well as a correlation of vWF to first and recurrent venous thrombo embolic events. These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis. PMID- 25814985 TI - Association of blaOXA-23 and bap with the persistence of Acinetobacter baumannii within a major healthcare system. AB - OBJECTIVES: Acinetobacter baumannii is an emerging opportunistic nosocomial pathogen. Two factors that may enhance persistence in healthcare settings are antimicrobial resistance and biofilm-forming ability. The aim of this work was to determine whether A. baumannii isolates that persist in healthcare settings (endemic), can be differentiated from sporadic isolates based upon their ability to resist antibiotics and their biofilm-forming capability. METHODS: Two hundred and ninety A. baumannii isolates were isolated over 17 months in the Detroit Medical Center (DMC). The isolates were genotyped using repetitive extragenic palindromic-PCR (REP-PCR). REP-types appearing greater than 10 times during active surveillance were considered endemic. The in vitro biofilm-forming ability and antibiotic resistance profile of each isolate were evaluated. Isolates were tested for the presence of two genetic markers-one implicated in biofilm formation (bap) and the other in antibiotic resistance (blaOXA-23). RESULTS: Of the 290 isolates evaluated, 84% carried bap and 36% carried blaOXA-23 . Five unique REP-PCR banding-types were detected >10 times (endemic) and constituted 58% of the 290 isolates. These five endemic REP-PCR types were 5.1 times more likely than sporadic isolates to carry both bap and blaOXA-23 . Furthermore, endemic isolates were resistant to 3 more antibiotic classes, on average, than sporadic isolates and four of the five endemic REP-PCR types formed denser biofilms in vitro than sporadic isolates. CONCLUSIONS: Endemic A. baumannii isolates are more likely than sporadic isolates to possess factors that increase virulence and enhance survival within a large healthcare system. PMID- 25814986 TI - Selective pressure of antibiotics on ARGs and bacterial communities in manure polluted freshwater-sediment microcosms. AB - The aim of this study was to investigate selective pressure of antibiotics on antibiotic resistance genes (ARGs) and bacterial communities in manure-polluted aquatic environment. Three treatment groups were set up in freshwater-sediment microcosms: tetracyclines group, sulfonamides group and fluoroquinolones group. Sediment and water samples were collected on day 14 after treatment. Antibiotic concentrations, ARGs abundances and bacterial community composition were analyzed. Antibiotic concentrations were determined by ultra-performance liquid chromatography-electrospray tandem mass spectrometry. ARGs abundances were quantified by real time quantitative PCR. Bacterial community composition was analyzed based on amplicon sequencing. Of the three classes of antibiotics analyzed in the treatment groups, accumulation amounts were tetracyclines> fluoroquinolone> sulfonamides in the sediment samples, while they were sulfonamides> fluoroquinolone> tetracyclines in the water samples. In the treatment groups, the relative abundances of some tet resistance genes [tet(W) and tet(X)] and plasmid-mediated quinolone resistance (PMQR) genes [oqx(B) and aac(6')-Ib] in sediment samples were significantly higher than those in the paired water samples. Tetracyclines significantly selected the bacterial classes including Gammaproteobacteria, Clostridia, and the genera including Salmonella, Escherichia/Shigella, Clostridium, Stenotrophomonas in sediment samples. The significant selection on bacterial communities posed by sulfonamides and fluoroquinolones was also observed. The results indicated that sediment may supply an ideal setting for maintenance and persistence of tet resistance genes [tet(W) and tet(X)] and PMQR genes [oqx(B) and aac(6')-Ib] under antibiotic pollution. The results also highlighted that antibiotics significantly selected specific bacterial communities including the taxa associated with opportunistic pathogens. PMID- 25814987 TI - Single gene-based distinction of individual microbial genomes from a mixed population of microbial cells. AB - Recent progress in environmental microbiology has revealed vast populations of microbes in any given habitat that cannot be detected by conventional culturing strategies. The use of sensitive genetic detection methods such as CARD-FISH and in situ PCR have been limited by the cell wall permeabilization requirement that cannot be performed similarly on all cell types without lysing some and leaving some nonpermeabilized. Furthermore, the detection of low copy targets such as genes present in single copies in the microbial genomes, has remained problematic. We describe an emulsion-based procedure to trap individual microbial cells into picoliter-volume polyacrylamide droplets that provide a rigid support for genetic material and therefore allow complete degradation of cellular material to expose the individual genomes. The polyacrylamide droplets are subsequently converted into picoliter-scale reactors for genome amplification. The amplified genomes are labeled based on the presence of a target gene and differentiated from those that do not contain the gene by flow cytometry. Using the Escherichia coli strains XL1 and MC1061, which differ with respect to the presence (XL1), or absence (MC1061) of a single copy of a tetracycline resistance gene per genome, we demonstrate that XL1 genomes present at 0.1% of MC1061 genomes can be differentiated using this method. Using a spiked sediment microbial sample, we demonstrate that the method is applicable to highly complex environmental microbial communities as a target gene-based screen for individual microbes. The method provides a novel tool for enumerating functional cell populations in complex microbial communities. We envision that the method could be optimized for fluorescence-activated cell sorting to enrich genetic material of interest from complex environmental samples. PMID- 25814910 TI - Light-quark and gluon jet discrimination in [Formula: see text] collisions at [Formula: see text] with the ATLAS detector. AB - A likelihood-based discriminant for the identification of quark- and gluon initiated jets is built and validated using 4.7 fb[Formula: see text] of proton proton collision data at [Formula: see text] [Formula: see text] collected with the ATLAS detector at the LHC. Data samples with enriched quark or gluon content are used in the construction and validation of templates of jet properties that are the input to the likelihood-based discriminant. The discriminating power of the jet tagger is established in both data and Monte Carlo samples within a systematic uncertainty of [Formula: see text] 10-20 %. In data, light-quark jets can be tagged with an efficiency of [Formula: see text] while achieving a gluon jet mis-tag rate of [Formula: see text] in a [Formula: see text] range between [Formula: see text] and [Formula: see text] for jets in the acceptance of the tracker. The rejection of gluon-jets found in the data is significantly below what is attainable using a Pythia 6 Monte Carlo simulation, where gluon-jet mis tag rates of 10 % can be reached for a 50 % selection efficiency of light-quark jets using the same jet properties. PMID- 25814988 TI - Electrifying microbes for the production of chemicals. AB - Powering microbes with electrical energy to produce valuable chemicals such as biofuels has recently gained traction as a biosustainable strategy to reduce our dependence on oil. Microbial electrosynthesis (MES) is one of the bioelectrochemical approaches developed in the last decade that could have critical impact on the current methods of chemical synthesis. MES is a process in which electroautotrophic microbes use electrical current as electron source to reduce CO2 to multicarbon organics. Electricity necessary for MES can be harvested from renewable resources such as solar energy, wind turbine, or wastewater treatment processes. The net outcome is that renewable energy is stored in the covalent bonds of organic compounds synthesized from greenhouse gas. This review will discuss the future of MES and the challenges that lie ahead for its development into a mature technology. PMID- 25814989 TI - Adhesion, biofilm formation, cell surface hydrophobicity, and antifungal planktonic susceptibility: relationship among Candida spp. AB - We have performed the characterization of the adhesion profile, biofilm formation, cell surface hydrophobicity (CSH) and antifungal susceptibility of 184 Candida clinical isolates obtained from different human reservoirs. Adhesion was quantified using a flow cytometric assay and biofilm formation was evaluated using two methodologies: XTT and crystal violet assay. CSH was quantified with the microbial adhesion to hydrocarbons test while planktonic susceptibility was assessed accordingly the CLSI protocol for yeast M27-A3 S4. Yeast cells of non albicans species exhibit increased ability to adhere and form biofilm. However, the correlation between adhesion and biofilm formation varied according to species and also with the methodology used for biofilm assessment. No association was found between strain's site of isolation or planktonic antifungal susceptibility and adhesion or biofilm formation. Finally CSH seemed to be a good predictor for biofilm formation but not for adhesion. Despite the marked variability registered intra and inter species, C. tropicalis and C. parapsilosis were the species exhibiting high adhesion profile. C. tropicalis, C. guilliermondii, and C. krusei revealed higher biofilm formation values in terms of biomass. C. parapsilosis was the species with lower biofilm metabolic activity. PMID- 25814991 TI - Virus Infections and Sudden Death in Infancy: The Role of Interferon-gamma. AB - Respiratory infections have been implicated in sudden infant death syndrome (SIDS). As interferon-gamma (IFN-gamma) is a major response to virus infection, we examined (1) the frequency of single nucleotide polymorphism (SNP), IFNG T + 874A, in SIDS infants, their parents, and ethnic groups with different incidences of SIDS; (2) model systems with a monocytic cell line (THP-1) and human peripheral blood monocytes (PBMC) for effects of levels of IFN-gamma on inflammatory responses to bacterial antigens identified in SIDS; (3) interactions between genetic and environmental factors on IFN-gamma responses. IFNG T + 874A genotypes were determined for SIDS infants from three countries; families who had a SIDS death; populations with high (Indigenous Australian), medium (Caucasian), and low (Bangladeshi) SIDS incidences. The effect of IFN-gamma on cytokine responses to endotoxin was examined in model systems with THP-1 cells and human PBMC. The IFN-gamma responses to endotoxin and toxic shock syndrome toxin (TSST 1) were assessed in relation to genotype, gender, and reported smoking. There was a marginal association with IFNG T + 874A genotype and SIDS (p = 0.06). Indigenous Australians had significantly higher proportions of the IFNG T + 874A SNP (TT) associated with high responses of IFN-gamma. THP-1 cells showed a dose dependent effect of IFN-gamma on cytokine responses to endotoxin. For PBMC, IFN gamma enhanced interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha responses but reduced IL-8 and IL-10 responses. Active smoking had a suppressive effect on baseline levels of IFN-gamma. There was no effect of gender or genotype on IFN-gamma responses to bacterial antigens tested; however, significant differences were observed between genotypes in relation to smoking. The results indicate virus infections contribute to dysregulation of cytokine responses to bacterial antigens and studies on physiological effects of genetic factors must include controls for recent or concurrent infection and exposure to cigarette smoke. PMID- 25814992 TI - Our Journey from the Study of Human Autoantibodies to the microRNA World. PMID- 25814993 TI - Unity in diversity, a systems approach to regulating plant cell physiology by 2 oxoglutarate-dependent dioxygenases. AB - Could a disjoint group of enzymes synchronize their activities and execute a complex multi-step, measurable, and reproducible response? Here, I surmise that the alpha-ketoglutarate dependent superfamily of non-haem iron (II) dioxygenases could influence cell physiology as a cohesive unit, and that the broad spectra of substrates transformed is an absolute necessity to this portrayal. This eclectic group comprises members from all major taxa, and participates in pesticide breakdown, hypoxia signaling, and osmotic stress neutralization. The oxidative decarboxylation of 2-oxoglutarate to succinate is coupled with a concomitant substrate hydroxylation and, in most cases, is followed by an additional specialized conversion. The domain profile of a protein sequence was used as an index of miscellaneous reaction chemistry and interpreted alongside existent kinetic data in a linear model of integrated function. Statistical parameters were inferred by the creation of a novel, empirically motivated flat-file database of over 3800 sequences (DB2OG) with putative 2-oxoglutarate dependent activity. The collated information was categorized on the basis of existing annotation schema. The data suggests that 2OG-dependent enzymes incorporate several desirable features of a systems level player. DB2OG, is free, accessible without a login to all users, and available at the following URL (http://comp biol.theacms.in/DB2OG.html). PMID- 25814990 TI - Metabolic reprograming of mononuclear phagocytes in progressive multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS). Accumulation of brain damage in progressive MS is partly the result of mononuclear phagocytes (MPs) attacking myelin sheaths in the CNS. Although there is no cure yet for MS, significant advances have been made in the development of disease modifying agents. Unfortunately, most of these drugs fail to reverse established neurological deficits and can have adverse effects. Recent evidence suggests that MPs polarization is accompanied by profound metabolic changes, whereby pro-inflammatory MPs (M1) switch toward glycolysis, whereas anti-inflammatory MPs (M2) become more oxidative. It is therefore possible that reprograming MPs metabolism could affect their function and repress immune cell activation. This mini review describes the metabolic changes underpinning macrophages polarization and anticipates how metabolic re-education of MPs could be used for the treatment of MS. KEY POINTS: Inflammation in progressive MS is mediated primarily by MPs.Cell metabolism regulates the function of MPs.DMAs can re-educate the metabolism of MPs to promote healing. PMID- 25814995 TI - Biological control of the cucurbit powdery mildew pathogen Podosphaera xanthii by means of the epiphytic fungus Pseudozyma aphidis and parasitism as a mode of action. AB - Epiphytic yeasts, which colonize plant surfaces, may possess activity that can be harnessed to help plants defend themselves against various pathogens. Due to their unique characteristics, epiphytic yeasts belonging to the genus Pseudozyma hold great potential for use as biocontrol agents. We identified a unique, biologically active isolate of the epiphytic yeast Pseudozyma aphidis that is capable of inhibiting Botrytis cinerea via a dual mode of action, namely induced resistance and antibiosis. Here, we show that strain L12 of P. aphidis can reduce the severity of powdery mildew caused by Podosphaera xanthii on cucumber plants with an efficacy of 75%. Confocal and scanning electron microscopy analyses demonstrated P. aphidis proliferation on infected tissue and its production of long hyphae that parasitize the powdery mildew hyphae and spores as an ectoparasite. We also show that crude extract of P. aphidis metabolites can inhibit P. xanthii spore germination in planta. Our results suggest that in addition to its antibiosis as mode of action, P. aphidis may also act as an ectoparasite on P. xanthii. These results indicate that P. aphidis strain L12 has the potential to control powdery mildew. PMID- 25814994 TI - Enriching rice with Zn and Fe while minimizing Cd risk. AB - Enriching iron (Fe) and zinc (Zn) content in rice grains, while minimizing cadmium (Cd) levels, is important for human health and nutrition. Natural genetic variation in rice grain Zn enables Zn-biofortification through conventional breeding, but limited natural Fe variation has led to a need for genetic modification approaches, including over-expressing genes responsible for Fe storage, chelators, and transporters. Generally, Cd uptake and allocation is associated with divalent metal cations (including Fe and Zn) transporters, but the details of this process are still unknown in rice. In addition to genetic variation, metal uptake is sometimes limited by its bioavailability in the soil. The availability of Fe, Zn, and Cd for plant uptake varies widely depending on soil redox potential. The typical practice of flooding rice increases Fe while decreasing Zn and Cd availability. On the other hand, moderate soil drying improves Zn uptake but also increases Cd and decreases Fe uptake. Use of Zn- or Fe-containing fertilizers complements breeding efforts by providing sufficient metals for plant uptake. In addition, the timing of nitrogen fertilization has also been shown to affect metal accumulation in grains. The purpose of this mini review is to identify knowledge gaps and prioritize strategies for improving the nutritional value and safety of rice. PMID- 25814996 TI - Target or barrier? The cell wall of early- and later-diverging plants vs cadmium toxicity: differences in the response mechanisms. AB - Increasing industrialization and urbanization result in emission of pollutants in the environment including toxic heavy metals, as cadmium and lead. Among the different heavy metals contaminating the environment, cadmium raises great concern, as it is ecotoxic and as such can heavily impact ecosystems. The cell wall is the first structure of plant cells to come in contact with heavy metals. Its composition, characterized by proteins, polysaccharides and in some instances lignin and other phenolic compounds, confers the ability to bind non-covalently and/or covalently heavy metals via functional groups. A strong body of evidence in the literature has shown the role of the cell wall in heavy metal response: it sequesters heavy metals, but at the same time its synthesis and composition can be severely affected. The present review analyzes the dual property of plant cell walls, i.e., barrier and target of heavy metals, by taking Cd toxicity as example. Following a summary of the known physiological and biochemical responses of plants to Cd, the review compares the wall-related mechanisms in early- and later-diverging land plants, by considering the diversity in cell wall composition. By doing so, common as well as unique response mechanisms to metal/cadmium toxicity are identified among plant phyla and discussed. After discussing the role of hyperaccumulators' cell walls as a particular case, the review concludes by considering important aspects for plant engineering. PMID- 25814997 TI - Phenotype and transcriptome analysis reveals chloroplast development and pigment biosynthesis together influenced the leaf color formation in mutants of Anthurium andraeanum 'Sonate'. AB - Leaf color is one of the well-sought traits in breeding program for Anthurium andraeanum Lind. Knowledge of mechanisms in anthuriums to produce leaves with different shades of green would help to effectively select desirable traits. In this study, the micro- and ultra-structural and physiological features of leaves on wild type and leaf color mutants (dark green, rubescent, etiolated, albino) in A. andraeanum 'Sonate' were analyzed. Results show that chloroplasts of leaf color mutants exhibited abnormal morphology and distribution. Using next generation sequencing technology followed by de novo assembly, leaf transcriptomes comprising of 41,017 unigenes with an average sequence length of 768 bp were produced from wild type and rubescent mutant. From the 27,539 (67.1%) unigenes with annotated functions, 858 significantly differently expressed genes (DEGs) were identified, consisting of 446 up-regulated genes and 412 down regulated genes. Genes that affect chloroplasts development and division, and chlorophyll biosynthesis were included in the down-regulated DEGs. Quantitative real-time PCR (qRT-PCR) analysis validated that the expression level of those genes was significantly lower in the rubescent, etiolated, and albino mutant compared to wild type plants, which concurs with the differences in micro- and ultra-structures and physiological features between these two types of plants. Conclusively, the leaf color formation is greatly affected by the activity of chloroplast development and pigment biosynthesis. And the possible formation pathway of leaf color mutant of A. andraeanum 'Sonate' is deduced based on our results. PMID- 25814999 TI - Large genetic screens for gynogenesis and androgenesis haploid inducers in Arabidopsis thaliana failed to identify mutants. AB - Gynogenesis is a process in which the embryo genome originates exclusively from female origin, following embryogenesis stimulation by a male gamete. In contrast, androgenesis is the development of embryos that contain only the male nuclear genetic background. Both phenomena are of great interest in plant breeding as haploidization is an efficient tool to reduce the length of breeding schemes to create varieties. Although few inducer lines have been described, the genetic control of these phenomena is poorly understood. We developed genetic screens to identify mutations that would induce gynogenesis or androgenesis in Arabidopsis thaliana. The ability of mutant pollen to induce either gynogenesis or androgenesis was tested by crossing mutagenized plants as males. Seedlings from these crosses were screened with recessive phenotypic markers, one genetically controlled by the female genome and another by the male genome. Positive and negative controls confirmed the unambiguous detection of both gynogenesis and androgenesis events. This strategy was applied to 1,666 EMS-mutagenised lines and 47 distant Arabidopsis strains. While an internal control suggested that the mutagenesis reached saturation, no gynogenesis or androgenesis inducer was found. However, spontaneous gynogenesis was observed at a frequency of 1/10,800. Altogether, these results suggest that no simple EMS-induced mutation in the male genome is able to induce gynogenesis or androgenesis in Arabidopsis. PMID- 25814998 TI - Possible roles for polycomb repressive complex 2 in cereal endosperm. AB - The polycomb repressive complex 2 (PRC2) is an evolutionarily conserved multimeric protein complex in both plants and animals. In contrast to animals, plants have evolved a range of different components of PRC2 and form diverse complexes that act in the control of key regulatory genes at many stages of development during the life cycle. A number of studies, particularly in the model species Arabidopsis thaliana, have highlighted the role of PRC2 and of epigenetic controls via parent-of-origin specific gene expression for endosperm development. However, recent research in cereal plants has revealed that although some components of PRC2 show evolutionary conservation with respect to parent-of origin specific gene expression patterns, the identity of the imprinted genes encoding PRC2 components is not conserved. This disparity may reflect the facts that cereal plant genomes have undergone different patterns of duplication during evolution compared to A. thaliana and that the endosperm development program is not identical in monocots and eudicots. In this context, we focus this review on the expression of imprinted PRC2 genes and their roles in endosperm development in cereals. PMID- 25815000 TI - Opening Pandora's box: cause and impact of errors on plant pigment studies. PMID- 25814914 TI - Measurement of top quark-antiquark pair production in association with a W or Z boson in pp collisions at [Formula: see text][Formula: see text]. AB - A measurement of the cross section for the production of top quark-antiquark pairs ([Formula: see text]) in association with a vector boson V (W or Z) in proton-proton collisions at [Formula: see text][Formula: see text] is presented. The results are based on a dataset corresponding to an integrated luminosity of 19.5 fb[Formula: see text] recorded with the CMS detector at the LHC. The measurement is performed in three leptonic (e and [Formula: see text]) channels: a same-sign dilepton analysis targeting [Formula: see text] events, and trilepton and four-lepton analyses designed for [Formula: see text] events. In the same sign dilepton channel, the [Formula: see text] cross section is measured as [Formula: see text], corresponding to a significance of 1.6 standard deviations over the background-only hypothesis. Combining the trilepton and four-lepton channels, a direct measurement of the [Formula: see text] cross section, [Formula: see text], is obtained with a significance of 3.1 standard deviations. The measured cross sections are compatible with standard model predictions within their experimental uncertainties. The inclusive [Formula: see text] process is observed with a significance of 3.7 standard deviations from the combination of all three leptonic channels. PMID- 25815001 TI - Common bean reaction to angular leaf spot comprises transcriptional modulation of genes in the ALS10.1 QTL. AB - Genetic resistance of common bean (Phaseolus vulgaris L.) against angular leaf spot (ALS), caused by the fungus Pseudocercospora griseola, is conferred by quantitative trait loci (QTL). In this study, we determined the gene content of the major QTL ALS10.1 located at the end of chromosome Pv10, and identified those that are responsive to ALS infection in resistant (CAL 143) and susceptible (IAC UNA) genotypes. Based on the current version of the common bean reference genome, the ALS10.1 core region contains 323 genes. Gene Ontology (GO) analysis of these coding sequences revealed the presence of genes involved in signal perception and transduction, programmed cell death (PCD), and defense responses. Two putative R gene clusters were found at ALS10.1 containing evolutionary related coding sequences. Among them, the Phvul.010G025700 was consistently up-regulated in the infected IAC-UNA suggesting its contribution to plant susceptibility to the fungus. We identified six other genes that were regulated during common bean response to P. griseola; three of them might be negative regulators of immunity as they showed opposite expression patterns during resistant and susceptible reactions at the initial phase of fungal infection. Taken together, these findings suggest that common bean reaction to P. griseola involves transcriptional modulation of defense genes in the ALS10.1 locus, contributing to resistance or susceptibility depending on the plant-pathogen interaction. PMID- 25815002 TI - Intracellular iron sensing by the direct binding of iron to regulators. PMID- 25815004 TI - Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts. AB - Mutations in PARK2, encoding Parkin, cause an autosomal recessive form of juvenile Parkinson Disease (JPD). The aim of the present study was to investigate the impact of PARK2 mutations on mitochondrial function and morphology in human skin fibroblasts. We analyzed cells obtained from four patients clinically characterized by JPD, harboring recessive mutations in PARK2. By quantitative PCR we found a reduction (<50%) of PARK2 transcript in all patients but one; however Western Blot analysis demonstrated the virtual absence of Parkin protein in all mutant fibroblasts. Respiration assays showed an increment of oxygen consumption, which was uncoupled to ATP cellular levels. This finding was probably due to presence of altered mitochondrial membrane potential (DeltaPsim), confirmed by JC 1 analysis. The mitochondrial network was comparable between mutant and control cells but, interestingly, a "chain-like" network was found only in mutant fibroblasts. Dissipation of DeltaPsim usually leads to mitochondrial fragmentation in healthy cells and eventually to mitophagy; however, this behavior was not observed in patients' fibroblasts. The absence of mitochondrial fragmentation in mutant Parkin fibroblasts could results in accumulation of damaged mitochondria not targeted to mitophagy. This condition should increase the oxidative stress and lead to cellular dysfunction and death. Our results suggest that PARK2 mutations cause mitochondrial impairment, in particular reduction in ATP cellular levels and alteration of DeltaPsim, even in non neuronal cells and confirm the hypothesis that Parkin holds a pivotal role in pro fission events. PMID- 25815003 TI - Genetic variation in the functional ENG allele inherited from the non-affected parent associates with presence of pulmonary arteriovenous malformation in hereditary hemorrhagic telangiectasia 1 (HHT1) and may influence expression of PTPN14. AB - HHT shows clinical variability within and between families. Organ site and prevalence of arteriovenous malformations (AVMs) depend on the HHT causative gene and on environmental and genetic modifiers. We tested whether variation in the functional ENG allele, inherited from the unaffected parent, alters risk for pulmonary AVM in HHT1 mutation carriers who are ENG haploinsufficient. Genetic association was found between rs10987746 of the wild type ENG allele and presence of pulmonary AVM [relative risk = 1.3 (1.0018-1.7424)]. The rs10987746-C at-risk allele associated with lower expression of ENG RNA in a panel of human lymphoblastoid cell lines (P = 0.004). Moreover, in angiogenically active human lung adenocarcinoma tissue, but not in uninvolved quiescent lung, rs10987746-C was correlated with expression of PTPN14 (P = 0.004), another modifier of HHT. Quantitative TAQMAN expression analysis in a panel of normal lung tissues from 69 genetically heterogeneous inter-specific backcross mice, demonstrated strong correlation between expression levels of Eng, Acvrl1, and Ptpn14 (r2 = 0.75-0.9, P < 1 * 10(-12)), further suggesting a direct or indirect interaction between these three genes in lung in vivo. Our data indicate that genetic variation within the single functional ENG gene influences quantitative and/or qualitative differences in ENG expression that contribute to risk of pulmonary AVM in HHT1, and provide correlative support for PTPN14 involvement in endoglin/ALK1 lung biology in vivo. PTPN14 has been shown to be a negative regulator of Yap/Taz signaling, which is implicated in mechanotransduction, providing a possible molecular link between endoglin/ALK1 signaling and mechanical stress. EMILIN2, which showed suggestive genetic association with pulmonary AVM, is also reported to interact with Taz in angiogenesis. Elucidation of the molecular mechanisms regulating these interactions in endothelial cells may ultimately provide more rational choices for HHT therapy. PMID- 25815006 TI - DDR-mediated crosstalk between DNA-damaged cells and their microenvironment. AB - The DNA damage response (DDR) is an evolutionarily conserved signaling cascade that senses and responds to double-strand DNA breaks by organizing downstream cellular events, ranging from appropriate DNA repair to cell cycle checkpoints. In higher organisms, the DDR prevents neoplastic transformation by directly protecting the information contained in the genome and by regulating cell fate decisions, like apoptosis and senescence, to ensure the removal of severely damaged cells. In addition to these well-studied cell-autonomous effects, emerging evidence now shows that the DDR signaling cascade can also function in a paracrine manner, thus influencing the biology of the surrounding cellular microenvironment. In this context, the DDR plays an emerging role in shaping the damaged tumor microenvironment through the regulation of tissue repair and local immune responses, thereby providing a promising avenue for novel therapeutic interventions. Additionally, while DDR-mediated extracellular signals can convey information to surrounding, undamaged cells, they can also feedback onto DNA damaged cells to reinforce selected signaling pathways. Overall, these extracellular DDR signals can be subdivided into two time-specific waves: a rapid bystander effect occurring within a few hours of DNA damage; and a late, delayed, senescence-associated secretory phenotype generally requiring multiple days to establish. Here, we highlight and discuss examples of rapid and late DDR-mediated extracellular alarm signals. PMID- 25815005 TI - DNA methyltransferase 1 mutations and mitochondrial pathology: is mtDNA methylated? AB - Autosomal dominant cerebellar ataxia-deafness and narcolepsy (ADCA-DN) and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E) are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine 5)-methyltransferase 1 (DNMT1). DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy, and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA) suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however, mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is regulated and executed? PMID- 25815007 TI - The rule of declining adaptability in microbial evolution experiments. AB - One of the most recurrent observations after two decades of microbial evolution experiments regards the dynamics of fitness change. In a given environment, low fitness genotypes are recurrently observed to adapt faster than their more fit counterparts. Since adaptation is the main macroscopic outcome of Darwinian evolution, studying its patterns of change could potentially provide insight into key issues of evolutionary theory, from fixation dynamics to the genetic architecture of organisms. Here, we re-analyze several published datasets from experimental evolution with microbes and show that, despite large differences in the origin of the data, a pattern of inverse dependence of adaptability with fitness clearly emerges. In quantitative terms, it is remarkable to observe little if any degree of idiosyncrasy across systems as diverse as virus, bacteria and yeast. The universality of this phenomenon suggests that its emergence might be understood from general principles, giving rise to the exciting prospect that evolution might be statistically predictable at the macroscopic level. We discuss these possibilities in the light of the various theories of adaptation that have been proposed and delineate future directions of research. PMID- 25815008 TI - KLF15 and PPARalpha Cooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation. AB - The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARalpha) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARalpha operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARalpha mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARalpha and provides fundamental insights into the molecular regulation of cardiac lipid metabolism. PMID- 25815009 TI - Real-Life Report on Chemoembolization Using DEBIRI for Liver Metastases from Colorectal Cancer. AB - Background. Transarterial chemoembolization (TACE) has been investigated in patients with liver metastases from colorectal cancer (LMCRC). Limited experience and available data suggest that TACE can achieve disease stabilization or improvement, even in heavily pretreated patients. Methods. Patients with LMCRC, ECOG 0-2, who failed at least 1 line of systemic chemotherapy, received embolizations with 2 mL of microspheres preloaded with 100 mg of irinotecan. Beads were delivered selectively into hepatic arteries. Primary endpoint was overall survival (OS), analyzed using the Kaplan-Meier method. Secondary endpoint was safety, assessed using CTCAE version 4.0. Results. 27 patients were treated using DEBIRI. Patient median age was 57 years (range was 45-82 years). The median number of total embolizations was 1.3 (range 1-3). The median OS was 5.4 months (95% CI; 1.1-22.7 months). The most reported postembolization events were nausea (8/27), vomiting (6/27), right upper quadrant pain (16/27), fatigue (9/27), and the development of ascites (6/27). 5/26 patients required hospitalization after TACE for severe pain. Hospitalization was also required for 1 case of allergic reaction and 1 case of infection. Conclusion. Our data suggest that TACE with DEBIRI could be efficacious in a palliative setting for patients with LMCRC, but they do not necessarily support routine use in clinical practice. PMID- 25815010 TI - The estimation of first-phase insulin secretion by using components of the metabolic syndrome in a chinese population. AB - Aims. There are two phases of insulin secretion, the first (FPIS) and second phase (SPIS). In this study, we built equations to predict FPIS with metabolic syndrome (MetS) components and fasting plasma insulin (FPI). Methods. Totally, 186 participants were enrolled. 75% of participants were randomly selected as the study group to build equations. The remaining 25% of participants were selected as the external validation group. All participants received a frequently sampled intravenous glucose tolerance test, and acute insulin response after the glucose load (AIRg) was obtained. The AIRg was considered as FPIS. Results. When MetS components were only used, the following equation was built: log (FPIS) = 1.477 - 0.119 * fasting plasma glucose (FPG) + 0.079 * body mass index (BMI) - 0.523 * high-density lipoprotein cholesterol (HDL-C). After FPI was added, the second equation was formulated: log (FPIS) = 1.532 - 0.127 * FPG + 0.059 * BMI - 0.511 * HDL-C + 0.375 * log (FPI), which provided a better accuracy than the first one. Conclusions. Using MetS components, the FPIS could be estimated accurately. After adding FPI into the equation, the predictive power increased further. We hope that these equations could be widely used in daily practice. PMID- 25815011 TI - Evaluation of the Clinical Impact of ISO 4049 in Comparison with Miniflexural Test on Mechanical Performances of Resin Based Composite. AB - The aim of this study was to evaluate the effect of different specimens dimensions on the mechanical properties of a commercial microfilled resin composite by using a modified ISO 4049 standard protocol, that generally provides specimen dimensions of 25 mm length * 2 mm width * 2 mm height; these standard dimensions are not clinically realistic considering the teeth diameter and length average. Furthermore, the overlapping irradiations required lead to specimens that are not homogeneous with the presence of some flaws due to packaging steps. For this reason, a miniflexural test was employed in this work both to simulate clinically realistic dimensions and to concentrate fewer defects. The flexural tests were performed at varying span length, in the range between 18.5 mm as stated by the ISO 4049 flexural test (IFT) and 10.5 mm according to the miniflexural test (MFT), at the increasing of layers with a 1 mm buildup multilayering technique. The results evidenced the impact of specimen dimensions on mechanical performances and consequently stability of resin-based composite with the formation of an asymmetrical structure which possesses higher stiffness and strength at increasing layering steps. PMID- 25815013 TI - Intertoe Squamous Cell Carcinoma Developed in a Patient with Rheumatoid Arthritis under Etanercept Therapy. AB - The use of tumor necrosis factor-alpha (TNF-alpha) inhibitors in the treatment of various inflammatory conditions has altered the field of medical therapeutics. Squamous cell carcinoma is the second most common cancer of the skin, usually affecting sun-exposed areas of the body. We present here the case of a 75-year old woman with rheumatoid arthritis, who developed an intertoe squamous cell carcinoma (SCC) of the right foot. According to her history, she received etanercept and methotrexate for 5 years for rheumatoid arthritis. The rare localization of this cancer could suggest a possible linkage of the malignancy to the chronic intake of anti-TNF-alpha treatment. This is the first reported case of an interdigital SCC developed under the use of an anti-TNF-alpha agent. PMID- 25815012 TI - Correlation of endometrial glycodelin expression and pregnancy outcome in cases with polycystic ovary syndrome treated with clomiphene citrate plus metformin: a controlled study. AB - Objective. The purpose of this study was to evaluate the relationship between clomiphene citrate (CC) plus metformin treatment and endometrial glycodelin expression and to then correlate this relationship with pregnancy outcomes. Material and Methods. A total of 30 patients diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria constituted our study group. All had been admitted to the gynecology outpatient clinic between June 1, 2011, and January 1, 2012, for infertility treatment. Our control group consisted of 20 patients admitted for routine Pap smear control. They had no history of infertility and were not using contraceptives and they were actively attempting pregnancy. Midluteal progesterone measurement and pipelle endometrial biopsies were performed with both groups. For PCOS patients, metformin treatment was initiated right after the biopsy and CC was added in the second menstrual cycle. Pipelle endometrial biopsies were repeated. Histological dating and immunohistochemistry for glycodelin were performed by a single pathologist who was blinded to the patients' clinical data. Result(s). The posttreatment ovulation rate in the study group was 93.3%. No pregnancies were achieved in either group when glycodelin expression was not present, even in the presence of ovulation. When glycodelin expression was high in PCOS group, the pregnancy rate was 60% and all pregnancies ended in live births. In weak expression group, however, three out of four pregnancies ended as early pregnancy losses. Conclusion(s). Endometrial glycodelin expression is an important predictor of pregnancy outcomes in both PCOS and fertile groups. PMID- 25815014 TI - Granulomatosis with polyangiitis presenting as a parotid gland abscess. AB - Granulomatosis with polyangiitis (GPA) is a small-vessel vasculitis consisting of necrotizing granulomatous lesions in airways and focal necrotizing glomerulonephritis. However, it may affect other sites such as the skin, central nervous system, eyes, heart, gastrointestinal tract, and liver. We describe a rare case of GPA in which the initial manifestation was the involvement of the parotid gland mimicking a pyogenic abscess. PMID- 25815015 TI - Mesenchymal stem cell therapy in nonhematopoietic diseases. PMID- 25815016 TI - Successful strategies to engage research partners for translating evidence into action in community health: a critical review. AB - OBJECTIVES: To undertake a critical review describing key strategies supporting development of participatory research (PR) teams to engage partners for creation and translation of action-oriented knowledge. METHODS: Sources are four leading PR practitioners identified via bibliometric analysis. Authors' publications were identified in January 1995-October 2009 in PubMed, Embase, ISI Web of Science and CAB databases, and books. Works were limited to those with a process description describing a research project and practitioners were first, second, third, or last author. RESULTS: Adapting and applying the "Reliability Tested Guidelines for Assessing Participatory Research Projects" to retained records identified five key strategies: developing advisory committees of researchers and intended research users; developing research agreements; using formal and informal group facilitation techniques; hiring co-researchers/partners from community; and ensuring frequent communication. Other less frequently mentioned strategies were also identified. CONCLUSION: This review is the first time these guidelines were used to identify key strategies supporting PR projects. They proved effective at identifying and evaluating engagement strategies as reported by completed research projects. Adapting these guidelines identified gaps where the tool was unable to assess fundamental PR elements of power dynamics, equity of resources, and member turnover. Our resulting template serves as a new tool to measure partnerships. PMID- 25815017 TI - Multicenter historical cohort study of the relationship between shift work and blood pressure. AB - BACKGROUND: Regarding the relationship between blood pressure (BP) and shift work (SW), previous studies have reported contradictory results. In the present study, we used Bayesian multilevel modeling to evaluate the association of SW and BP after controlling some confounding factors. METHODS: Data of this multicenter historical study were extracted from annual observations of the male workers of Isfahan's Mobarakeh Steel Company (IMSC) and Polyacryl Iran Corporation (PIC) in Isfahan, Iran, between 2003 and 2011. In this research, we assessed the effect of SW on systolic BP (SBP) and diastolic BP (DPB) with controlling body mass index, age, work experience, marriage, and education status. RESULTS: A total of 8613 (IMSC, n = 5314 and PIC, n = 3299) workers participated in this study with a mean [standard deviation (SD)] age of 41.60 (8.30) and mean (SD) work experience of 16.17 (7.89) years. In this study, after controlling confounding factors, we found no significant relationship between SW and SBP and DBP. CONCLUSION: In general, the results of this multicenter cohort study did not support a relationship between SW and BP. We suggest prospective studies with controlling more confounding factors in this area. PMID- 25815018 TI - Dabigatran versus Enoxaparin in the prevention of venous thromboembolism after total knee arthroplasty: A randomized clinical trial. AB - BACKGROUND: Venous thromboembolism (VTE) and deep vein thrombophlebitis (DVT) is a serious problem with high mortality and morbidity rates. This study was conducted to compare efficacy and safety results of the two types of VTE preventing in patients underwent total knee arthroplasty (TKA). METHODS: Having considered exclusion criteria, 90 patients of 136 ones were registered in the study. Our patients of TKA were split randomly in two groups. Totally, 45 patients received enoxaparin, 40 mg 12 h before surgery and treated by 40 mg daily up to 15 days. The second group (45 patients) were treated by dabigatran 150 mg 4 h after surgery and 225 mg daily up to 15 days. Efficacy was evaluated by Doppler sonography after 15 days for the presence of DVT and safety was determined by 3 months follow-up for all-cause mortality and any major or minor bleedings. RESULTS: Two groups were similar in baseline characteristics. The efficacy outcome events occurred in 2.2% (2 of 90) of the patients (1 symptomatic VTE in dabigatran and 1 in the enoxaparin group) without significant statistical difference between groups (P = 0.64). In terms of safety, 3 patients (6.6%) in dabigatran and 2 patients (4.4%) in enoxaparin group had major bleeding (P = 0.66) and 8 patients (17.7%) in dabigatran and 7 patients (15.7%) in enoxaparin group had non-major bleeding event (P = 0.81). There were no death, pulmonary emboli, and cardiac events during follow-up. CONCLUSION: Three months follow-up did not show statistical difference in efficacy and safety between dabigatran and enoxaparin. Future studies with mentioning to later outcomes for checking safety are warranted. PMID- 25815019 TI - The effects of different doses of atorvastatin on serum lipid profile, glycemic control, and liver enzymes in patients with ischemic cerebrovascular accident. AB - BACKGROUND: Despite established effects of atorvastatin on level of serum lipid profile in patients with different underlying clinical conditions, the effects of this drug on other serum biomarkers remain uncertain. We examined the effects of atorvastatin therapy on lipid profile, glycemic control, and liver enzymes in patients with ischemic cerebrovascular accident without any history or clinical evidences of diabetes, heart failure, renal failure, or hepatic disease. METHODS: In a randomized double-blinded controlled trial, 140 hospitalized patients with an ischemic cerebrovascular accident were included and randomly assigned to receive either atorvastatin 40 mg (n = 70) or atorvastatin 20 mg daily (n = 70) for 3 months. The levels of biomarkers were measured at the time of administrating drugs as well as at the time of completing the treatment. RESULTS: A significant reduction was revealed in serum triglyceride, total cholesterol, low-density lipoprotein, non-high-density lipoprotein (HDL) cholesterol, and also aspartate aminotransferase levels as well as a significant increase in serum HDL level following administration of atorvastatin in both case and control groups who received the atorvastatin 40 mg/day and 20 mg/day, respectively (all P < 0.050). Although a significant increase in fasting blood sugar and hemoglobin A1c was observed in the case group received atorvastatin 40 mg/day (both P < 0.001), but this elevation was not occurred in another group treated with lower dose of the drug (both P > 0.050). CONCLUSION: Daily administration of 20 mg and 40 mg doses of atorvastatin for 3 months provides improvement in serum lipid profiles; however, because of interfering effect of high-dose atorvastatin on glycemic control status, the use of the former dose may be preferred. This is very important in these patients because the positive effects of high-dose atorvastatin in stroke patients are not confirmed. PMID- 25815020 TI - Rheumatoid factor, anti-nuclear antibody in ischemic heart disease: Acute versus chronic patients. AB - BACKGROUND: Immunopathological and inflammatory processes play important roles in the initiation and development of ischemic heart disease. Hence, this study aimed to evaluate the relationship between serum levels rheumatoid factor (RF) and anti nuclear antibodies (ANA) and severity of coronary stenotic lesions. METHODS: Totally 140 patients with acute coronary syndrome (ACS) (n = 70) and chronic stable angina (CSA) (n = 70) that undergoing coronary angiography were enrolled in this study. ANA by the enzyme-linked immunosorbent assay (ELISA) and serum level of RF was measured by latex method. The severity of coronary stenotic lesions calculated by Gensini score. To analyze the correlations of ANA and RF to Gensini score Pearson correlation test was used. To adjust the effect of age and other confounder factors such hypertension, diabetes, hyperlipidemia and smoking multiple linear regression was used. RESULTS: The mean serum levels of RF and ANA in CSA group were significantly higher than ACS group after adjusting for the confounder factors (P < 0.050 for ANA). Serum levels of ANA significantly correlated with severity of coronary stenotic lesions calculated by Gensini score (r = 0.40 and P < 0.050). After adjusting confounders, multiple linear regression analysis showed ANA remained independently associated with Gensini scores in ACS group (B = 0.505, P < 0.001). CONCLUSION: Higher serum levels of ANA may be considered as independent risk factors for ACS. PMID- 25815021 TI - Evaluating factors associated with uncontrolled hypertension: Isfahan cohort study, Iran. AB - BACKGROUND: Hypertension (HTN) considers as one of the most common risk factors, which potentially raises the risk of cardiovascular disease. Regarding high prevalence of HTN among Iranian population this study designed to examine a range of socio-demographic and clinical variables to determine the association with failure to achieve blood pressure control in a cohort of hypertensive subjects. METHODS: This retrospective cohort study is a part of Isfahan cohort study which carried out on adults aged 35 years old or more. Subjects with confirmed HTN entered in this sub-study. For all subjects questionnaire included socio demographic characteristics, clinical data and lifestyle behavior completed by trained nurses. Uncontrolled HTN was defined as systolic and diastolic blood pressure more than 140/90 in the presence or absent of pharmacological treatment. RESULTS: The prevalence of uncontrolled men was significantly higher than controlled in both 2001 and 2007 (P < 0.001). A significant association was found between sex and control of blood pressure: compared with women, being men [odds ratio (OR) = 2.31; 95 % confidence interval (CI) = 1.64-3.24] was significantly associated with uncontrolled HTN in 2001 and (OR = 2.38; 95% CI = 1.78-3.18). Among lifestyle behaviors, tendency for more consumption of salty foods increased the risk of uncontrolled HTN in 2001 by 1.73 times [OR = 1.73, 95% CI = 1.20 2.50, (P = 0.003)]. Patients who were naive to mono-therapy without considering the type of antihypertensive drug were found to be associated with uncontrolled blood pressure (OR = 0.14; 95 % CI =0.1-0.2). CONCLUSION: Uncontrolled HTN was sex, marital status, diabetes, tendency to salty foods and medication adherence. Assessment of them presence of these risk factors is warranted to recommend an aggressive HTN management with the goal of reducing excessive risk of cardiovascular events caused by uncontrolled HTN. PMID- 25815023 TI - A case of Marfan's syndrome with multi-level aortic dissections. AB - BACKGROUND: Although Marfan's syndrome is a disease with various phenotypes, but the major mechanism of death is cardiovascular complication. Aortic dissection is a major cause of death in Marfan syndrome. CASE REPORT: A 30-year-old man with severe refractory chest and left flank pain and history of previously surgically repaired Type A aortic dissection was referred to the hospital. His typical manifestations of Marfan's syndrome were identified. Cardiovascular imaging showed an acute spiral dissection in the descending aorta extending to the left renal and femoral arteries with no evidence of thrombosis in its huge false lumen (8 cm). By the diagnosis of acute, expanded, spiral, Type B aortic dissection, he underwent the stent grafting of dissected aorta. He discharged without any complication. On follow-up cardiovascular imaging, thrombosed false lumen in stented aorta from descending aorta to the proximal abdominal aorta was seen. CONCLUSION: Endovascular treatment of Type B dissection is an effective treatment in Type B dissection, even in patients with Marfan syndrome. PMID- 25815022 TI - Self-efficacy strategies to improve exercise in patients with heart failure: A systematic review. AB - BACKGROUND: Despite exercise is recommended as an adjunct to medication therapy in patients with heart failure (HF), non-adherence to exercise is a major problem. While improving self-efficacy is an effective way to increase physical activity, the evidence concerning the relationship between strategies to enhance self-efficacy and exercise among HF has not been systematically reviewed. The objective of this systematic review is to assess the effect of interventions to change the self-efficacy on exercise in patients with HF. METHODS: A systematic database search was conducted for articles reporting exercise self-efficacy interventions. Databases such as PubMed, ProQuest, CINAHL, Scopus, and PsycINFO, and the Cochrane Library were searched with restrictions to the years 2000-June 2014. A search of relevant databases identified 10 studies. Published randomized controlled intervention studies focusing strategies to change self-efficacy to exercise adherence in HF were eligible for inclusion. In addition, studies that have applied self-efficacy-based interventions to improve exercise are discussed. RESULTS: Limited published data exist evaluating the self-efficacy strategies to improve exercise in HF. Dominant strategies to improve patients' self-efficacy were performance accomplishments, vicarious experience, verbal persuasion, emotional arousal. CONCLUSION: Evidence from some trials supports the view that incorporating the theory of self-efficacy into the design of an exercise intervention is beneficial. Moreover, exercise interventions aimed at integrating the four strategies of exercise self-efficacy can have positive effects on confidence and the ability to initiate exercise and recover HF symptoms. Findings of this study suggest that a positive relationship exists between self-efficacy and initiating and maintaining exercise in HF, especially in the short-term period. PMID- 25815024 TI - Methadone induced torsades de pointes and ventricular fibrillation: A case review. AB - BACKGROUND: Methadone is a synthetic opioid, which has been successfully used in treating heroin addiction and chronic pain syndrome in palliative care for more than 30 years. This drug is a potent blocker of the delayed rectifier potassium ion channel, which may result in corrected QT (QTc) interval prolongation and increased risk of torsades de pointes (TdP) in susceptible individuals. CASE REPORT: We describe here a case of methadone-induced TdP that deteriorated into ventricular fibrillation, which was resolved after treatment with IV magnesium, potassium, and Lidocaine. Our purpose in this case review was to highlight the risk of cardiac arrhythmias, in particular QTc interval prolongation leading to TdP in a heroin-dependent patient receiving methadone substitution therapy, and then to present a perspective on treatment and prevention strategies of methadone induced prolonged QTc. CONCLUSION: Methadone-induced TdP is a potentially fatal complication of methadone therapy. As the popularity of methadone use grows, clinicians will encounter more cases of methadone induced TdP, especially in our region, Iran. Hence, a thorough patient history and electrocardiogram monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary. PMID- 25814911 TI - Muon reconstruction efficiency and momentum resolution of the ATLAS experiment in proton-proton collisions at [Formula: see text] TeV in 2010. AB - This paper presents a study of the performance of the muon reconstruction in the analysis of proton-proton collisions at [Formula: see text] TeV at the LHC, recorded by the ATLAS detector in 2010. This performance is described in terms of reconstruction and isolation efficiencies and momentum resolutions for different classes of reconstructed muons. The results are obtained from an analysis of [Formula: see text] meson and [Formula: see text] boson decays to dimuons, reconstructed from a data sample corresponding to an integrated luminosity of 40 pb[Formula: see text]. The measured performance is compared to Monte Carlo predictions and deviations from the predicted performance are discussed. PMID- 25815025 TI - In Vitro and In Vivo Antileishmanial Effects of Pistacia khinjuk against Leishmania tropica and Leishmania major. AB - The present study aims to evaluate the in vitro and in vivo antileishmanial activities of Pistacia khinjuk Stocks (Anacardiaceae) alcoholic extract and to compare its efficacy with a reference drug, meglumine antimoniate (MA, Glucantime), against Leishmania tropica and Leishmania major. This extract (0-100 ug/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of L. tropica (MRHO/IR/75/ER) and then tested on cutaneous leishmaniasis (CL) in male BALB/c mice with L. major to reproduce the antileishmanial activity topically. In vitro, P. khinjuk extract significantly (P < 0.05) inhibited the growth rate of promastigote (IC50 58.6 +/- 3.2 ug/mL) and intramacrophage amastigotes (37.3 +/- 2.5 ug/mL) of L. tropica as a dose-dependent response. In the in vivo assay, after 30 days of treatment, 75% recovery was observed in the infected mice treated with 30% extract. After treatment of the subgroups with the concentration of 20 and 30% of P. khinjuk extract, mean diameter of lesions was significantly (P < 0.05) reduced. To conclude, the present investigation demonstrated that P. vera extract had in vitro and in vivo effectiveness against L. major. Obtained findings also provide the scientific evidences that natural plants could be used in the traditional medicine for the prevention and treatment of CL. PMID- 25815028 TI - The effects and possible mechanisms of puerarin to treat endometriosis model rats. AB - Objective. To explore the effects of puerarin to treat endometriosis (EMT) model rats and the possible regulatory mechanisms. Methods. EMT model rats were surgically induced by autotransplantion of endometrial tissues. The appropriate dosage of puerarin to treat EMT model rats was determined by observing the pathologic morphology of ectopic endometrial tissues and by detecting the levels of estradiol (E2) and prostaglandin E2 (PGE2) of both serum and ectopic endometrial tissues. The related genes and proteins of ectopic endometrial tissues were analyzed by Real-time PCR and immunohistochemistry (IHC) to explore the possible mechanisms. Results. Puerarin could reduce the levels of E2 and PGE2 and prevent the growth of ectopic endometrium tissues by inhibiting the expression of aromatase cytochrome P450 (p450arom) and cyclooxygenase-2 (cox-2); puerarin could adjust the anabolism of E2 by upregulating the expression of 17beta-hydroxysteroid-2 (17beta-hsd-2) and downregulating the expression of 17beta-hydroxysteroid-1 (17beta-hsd-1) of the ectopic endometrium tissues; puerarin could increase the expression of ERbeta and improve the inflammatory microenvironment of EMT model rats. Conclusions. Our data suggest that puerarin has a therapeutic effect on EMT model rats and could be a potential therapeutic agent for the treatment of EMT in clinic. PMID- 25815030 TI - Therapeutic Effects of TianDiJingWan on the Abeta 25-35-Induced Alzheimer's Disease Model Rats. AB - The main purpose of this study was to demonstrate the therapeutic effects and mechanism of TDJW, a modern Chinese medicine prescription developed based on the basic traditional Chinese medicine theory of "tonifying the kidney essence," on the Abeta 25-35-induced AD rats. The AD model was established by the intracerebroventricular administrations of Abeta 25-35 into the hippocampus CA1 tissue of SD male rats. 72 rats were randomly divided into six groups: sham operation, AD model, donepezil, high TDJW group, medium TDJW group, and low TDJW group. After oral administration of TDJW, the results of Morris water maze and step-down test showed that the learning and memory abilities of AD rats were significantly improved. And biochemical measurement demonstrated that Ach and Glu in hippocampus tissues of AD rats were increased as well. Moreover, the Abeta deposits and p-Tau aggregations in hippocampus CA1 tissues of AD rats were attenuated as observed in the micrographs of immunohistochemistry study, and the results of ELISA indicated that the expressions of TNF-alpha, IL-1beta, and IL-6 in hippocampus tissues were significantly decreased. In conclusion, the present study demonstrated that TDJW could be used as a promising therapeutic agent for the clinical applications of AD treatment in patients. PMID- 25815031 TI - The Prescription Pattern of Chinese Herbal Products Containing Ginseng among Tamoxifen-Treated Female Breast Cancer Survivors in Taiwan: A Population-Based Study. AB - Background. The purpose of our study is to analyze the association between prescribed Chinese herbal products (CHPs) containing Ginseng and the risk of endometrial cancer among tamoxifen (TMX) users and to identify any possible interactive effects between Ginseng and TMX with respect to preventing the development of subsequent endometrial cancer in an estrogen-dependent breast cancer population in Taiwan. Methods. All patients newly diagnosed with invasive breast cancer receiving tamoxifen treatment from January 1, 1998, to December 31, 2008, were selected from the National Health Insurance Research Database. The usage, frequency of service, and CHP-Ginseng prescribed across the 30,556 TMX treated breast cancer (BC) survivors were evaluated. Logistic regression was employed to estimate the odds ratios (ORs) for the utilization of CHP-Ginseng. Cox's proportional hazard regression was performed to calculate the hazard ratios (HRs) for endometrial cancer associated with Ginseng use among the TMX-treated BC cohort. Results. The HR for the development of endometrial cancer among breast cancer survivors who had ever taken Ginseng after TXM treatment was significantly decreased compared to those who never used CHP. Conclusion. A significant inhibitory relationship between Ginseng consumption and subsequent endometrial cancer less than 2 years after TMX treatment was detected among BC survivors. PMID- 25815027 TI - The th17/treg immune balance in ulcerative colitis patients with two different chinese syndromes: dampness-heat in large intestine and spleen and kidney yang deficiency syndrome. AB - Objective. To investigate the Th17/Treg immune balance in the ulcerative colitis (UC) patients with two Chinese syndrome: dampness-heat in large intestine (DHLI) and spleen and kidney Yang deficiency (SKYD). Methods. Ninety UC patients (45 were diagnosed with DHLI and 45 with SKYD syndrome) and 23 healthy people were recruited. The serumIL-17 and TGF-beta1 levels of these participants were measured with ELISA; the expression of IL-17 and TGF-beta 1 in colonic mucosa tissue was determined with immunohistochemistry and the percentage of Th17 and Treg in peripheral blood with flow cytometry. Results. The levels of IL-17 and Th17 were significantly higher in both DHLI and SKYD groups than in healthy control group and higher in DHLI than in SKYD group (P < 0.05). The levels of TGF beta1 and Treg were significantly lower in the two UC patients groups than in healthy control group; and lower in SKYD group than in DHLI group (P < 0.05). Conclusions. UC with DHLI syndrome could be characterized by the elevation of Th17 and IL-17 levels, which indicated an accentuation of inflammatory reaction; UC with SKYD syndrome could be characterized by the reduction of serum Treg and TGF-beta1 levels, which represented a depression of immune tolerance. PMID- 25815029 TI - Propolis Is an Efficient Fungicide and Inhibitor of Biofilm Production by Vaginal Candida albicans. AB - Vulvovaginal candidiasis (VVC) is one of the most common genital infections in women. The therapeutic arsenal remains restricted, and some alternatives to VVC treatment are being studied. The present study evaluated the influence of a propolis extractive solution (PES) on biofilm production by Candida albicans isolated from patients with VVC. Susceptibility testing was used to verify the minimum inhibitory concentration (MIC) of PES, with fluconazole and nystatin as controls. The biofilm formation of 29 vaginal isolates of C. albicans and a reference strain that were exposed to PES was evaluated using crystal violet staining. Colony-forming units were evaluated, proteins and carbohydrates of the matrix biofilm were quantified, and scanning electron microscopy was performed. The MIC of PES ranged from 68.35 to 546.87 MUg/mL of total phenol content in gallic acid. A concentration of 546.87 MUg/mL was able to cause the death of 75.8% of the isolates. PES inhibited biofilm formation by C. albicans from VVC. Besides antifungal activity, PES appears to present important antibiofilm activity on abiotic surfaces, indicating that it may have an additional beneficial effect in the treatment of VVC. PMID- 25815032 TI - The Protective Effects of Areca catechu Extract on Cognition and Social Interaction Deficits in a Cuprizone-Induced Demyelination Model. AB - Schizophrenia is a serious psychiatric illness with an unclear cause. One theory is that demyelination of white matter is one of the main pathological factors involved in the development of schizophrenia. The current study evaluated the protective effects of Areca catechu nut extract (ANE) on a cuprizone-induced demyelination mouse model. Two doses of ANE (1% and 2%) were administered orally in the diet for 8 weeks. Animals subjected to demyelination showed impaired spatial memory and less social activity. In addition, mice subjected to demyelination displayed significant myelin damage in cortex and demonstrated a higher expression of NG2 and PDGFRalpha and AMPK activation. ANE treatment not only significantly enhanced cognitive ability and social activity, but also protected myelin against cuprizone toxicity by promoting oligodendrocyte precursor cell (OPC) differentiation. In addition, ANE treatment demonstrated significant dephosphorylation of AMPKalpha, indicating a regulatory role for ANE in schizophrenia. This study showed that ANE treatment may enhance cognitive ability and social activity by facilitating OPC differentiation and protecting against myelin damage in cortex. Results also suggest the AMPK signaling pathway may be involved in this process. PMID- 25815026 TI - Efficacy and safety of pomegranate medicinal products for cancer. AB - Preclinical in vitro and in vivo studies demonstrate potent effects of pomegranate preparations in cancer cell lines and animal models with chemically induced cancers. We have carried out one systematic review of the effectiveness of pomegranate products in the treatment of cancer and another on their safety. The PubMed search provided 162 references for pomegranate and cancer and 122 references for pomegranate and safety/toxicity. We identified 4 clinical studies investigating 3 pomegranate products, of which one was inappropriate because of the low polyphenol content. The evidence of clinical effectiveness was poor because the quality of the studies was poor. Although there is no concern over safety with the doses used in the clinical studies, pomegranate preparations may be harmful by inducing synthetic drug metabolism through activation of liver enzymes. We have analysed various pomegranate products for their content of anthocyanins, punicalagin, and ellagic acid in order to compare them with the benchmark doses from published data. If the amount of coactive constituents is not declared, patients risk not benefiting from the putative pomegranate effects. Moreover, pomegranate end products are affected by many determinants. Their declaration should be incorporated into the regulatory guidance and controlled before pomegranate products enter the market. PMID- 25815034 TI - The anti-porcine parvovirus activity of nanometer propolis flavone and propolis flavone in vitro and in vivo. AB - Objectives. The present study was conducted to evaluate the activity of nanometer propolis flavone (NPF) on inhibiting porcine parvovirus (PPV) in vitro and in vivo. Methods. In vitro, the effect of NPF on cellular infectivity of PPV was carried out before and after adding drug and simultaneous adding and PPV after being mixed. In vivo, the anti-PPV effect of NPF in guinea pigs was performed. Results. The results showed that NPF could significantly inhibit PPV infecting porcine kidney- (PK-) 15 cells compared with propolis flavone (PF), and the activity of NPF was the best in preadding drug pattern. NPF at high and medium doses was able to observably restrain PPV copying in lung, gonad, blood, and spleen, decrease the impact of PPV on weight of guinea pigs, and improve hemagglutination inhibition (HI) of PPV in serum. In addition, it could also increase the contents of IL-2 and IL-6 in serum after PPV challenge. Conclusion. These results indicated that NPF could significantly improve the anti-PPV activity of PF, and its high concentration possessed the best efficacy. Therefore, NPF would be expected to be exploited into a new-style antiviral drug. PMID- 25815033 TI - Effects of Passive Hydrotherapy WATSU (WaterShiatsu) in the Third Trimester of Pregnancy: Results of a Controlled Pilot Study. AB - Background. WATSU (WaterShiatsu) is a complementary therapeutic treatment method comprising passive stretches and massage techniques administered in 35 degrees C warm water. Pregnant women claim safe methods to reduce pain, stress, and fatigue. Therefore, we conducted a pilot study evaluating the effects of WATSU on pregnancy-related complaints in third trimester pregnant women. Methods. Nine healthy pregnant women at gestational week >=34 were included in an intervention group (receiving WATSU) and compared to eight women in a passive control group (receiving no treatment). WATSU was performed on days 1 and 4 of the study, accompanied by ultrasound examinations. Outcomes include physiological and psychometric as well as qualitative data. Participants in the control group completed questionnaires only. Results. WATSU was found to significantly lower participants' levels of stress and pain and to improve their mental health related quality of life and mood. In comparison to the passive control group, participants in the intervention group reported reduction in perceived stress from day 1 to day 8 (P = 0.036, Cohen's f = 0.57). Qualitative data indicate that WATSU was appreciated as enjoyable and deeply relaxing. No negative side effects were reported. Conclusion. Our findings support the notion that WATSU yields therapeutic benefits for pregnant women and warrant further research. This study has been registered at ClinicalTrials.gov: NCT01708018. PMID- 25815035 TI - Enhanced evidence-based chinese medicine clinical practice guidelines in Hong Kong: a study protocol for three common diseases. AB - We presented a study protocol of developing Chinese medicine clinical practice guidelines for three common diseases in Hong Kong, including insomnia, chronic gastritis, and cerebral infarction. This research project will be conducted in three phases. First phase is the preparation stage which consists of the establishment of steering committee and panel. Second phase involves 6 steps, which are searching and identifying evidence, text mining process, Delphi survey, synthesizing of data, consensus conference, and drafting guidelines. In this phase, text mining technique, evidence-based method, and formal consensus method are combined to get consolidated supporting data as the source of CM CPGs. The final phase comprised external reviews, dissemination, and updating. The outputs from this project will provide three CM CPGs for insomnia, chronic gastritis, and cerebral infarction for Hong Kong local use. PMID- 25815036 TI - Manual medicine related injuries experienced by physicians: a missing aspect in therapies using manipulation of joints. AB - Background. In 2010 Manual Medicine (MM) was the second most common additional qualification among physicians in Germany, which is recommended to be used in several guidelines. Aim of this analysis was to raise the amount of information on MM related injuries (MMri) experienced by physicians at any point of their career while applying MM. Methods. Data on MMri of a questionnaire that was used to gain first insights into MM in Germany from a health services research perspective was analysed. Results. A total of 301 physicians (20% female) participated in this study. The participants' mean age was 46. 11% of the participants experienced some kind of MMri during their career as a MM provider. In the three worst cases these MMri were fractures and therefore classified as moderate. Mild MMri were joint dysfunction syndromes (N = 30), distortions of fingers (N = 7), and shoulder pain (N = 3). Subgroup analyses showed no significant differences in the rate of MMri when comparing gender, provider organizations for postgraduate MM courses, and medical disciplines. Conclusion. Our analysis shows risks for providers of MM. As this analysis suffers from the risk of recall bias, future studies should be performed to get more insights into this aspect of MM. PMID- 25815037 TI - Preclinical evaluation on the tumor suppression efficiency and combination drug effects of fermented wheat germ extract in human ovarian carcinoma cells. AB - Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 MUg/mL and 246.11 MUg/mL after 48 h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES 2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients. PMID- 25815038 TI - Chinese herbal decoction based on syndrome differentiation as maintenance therapy in patients with extensive-stage small-cell lung cancer: an exploratory and small prospective cohort study. AB - Objective. To investigate the treatment effect and treatment length of Chinese herbal decoction (CHD) as maintenance therapy on patients with extensive-stage small-cell lung cancer (ES-SCLC) and to reflect the real syndrome differentiation (Bian Zheng) practices of traditional Chinese medicine (TCM). Patients and Methods. Different CHDs were prescribed for each patient based on syndrome differentiation. The length of CHD treatment was divided into two phases for analyzing progression-free survival (PFS) and postprogression survival (PPS). Results. Three hundred and fifty-seven CHDs were prescribed based on syndrome differentiation during the study period. Median PFS was significantly longer in patients who received CHD >3 months than patients who received CHD <=3 months in the first phase (8.7 months versus 4.5 months; hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.41-0.99; P = 0.0009). Median PPS was significantly longer in patients who received CHD >7 months than patients who received CHD <=7 months in the second phase (11.7 months versus 5.1 months; HR, 2.32; 95% CI, 1.90 2.74; P = 0.002). Conclusion. CHD could improve PFS and PPS, which are closely related to treatment time and deepness of response of first-line therapy. In addition, CHD could improve body function and keep patients in a relatively stable state. PMID- 25815040 TI - Study on TCM Syndrome Differentiation of Primary Liver Cancer Based on the Analysis of Latent Structural Model. AB - Primary liver cancer (PLC) is one of the most common malignant tumors because of its high incidence and high mortality. Traditional Chinese medicine (TCM) plays an active role in the treatment of PLC. As the most important part in the TCM system, syndrome differentiation based on the clinical manifestations from traditional four diagnostic methods has met great challenges and questions with the lack of statistical validation support. In this study, we provided evidences for TCM syndrome differentiation of PLC using the method of analysis of latent structural model from clinic data, thus providing basis for establishing TCM syndrome criteria. And also we obtain the common syndromes of PLC as well as their typical clinical manifestations, respectively. PMID- 25815039 TI - Ancient records and modern research on the mechanisms of chinese herbal medicines in the treatment of diabetes mellitus. AB - Over the past decades, Chinese herbal medicines (CHM) have been extensively and intensively studied through from both clinical and experimental perspectives and CHM have been proved to be effective in the treatment of diabetes mellitus (DM). This study, by searching ancient records and modern research papers, reviewed CHM in terms of their clinical application and principal mechanism in the treatment of DM. We summarized the use of CHM mentioned in 54 famous ancient materia medica monographs and searched papers on the hypoglycemic effect of several representative CHM. Main mechanisms and limitations of CHM and further research direction for DM were discussed. On the basis of the study, we were led to conclude that TCM, as a main form of complementary and alternative medicine (CAM), was well recorded in ancient literatures and has less adverse effects as shown by modern studies. The mechanisms of CHM treatment of DM are complex, multilink, and multitarget, so we should find main hypoglycemic mechanism through doing research on CHM monomer active constituents. Many CHM monomer constituents possess noteworthy hypoglycemic effects. Therefore, developing a novel natural product for DM and its complications is of much significance. It is strongly significant to pay close attention to CHM for treatment of DM and its complications. PMID- 25815041 TI - Personal prayer in patients dealing with chronic illness: a review of the research literature. AB - Background. Prayer is commonly used among patients for health purposes. Therefore, this review focused on three main questions: (1) why do people turn to prayer in times of illness?, (2) what are the main topics of their prayers?, and (3) how do they pray? Method. We undertook a systematic review of the literature by searching the databases PubMed, Medline, and PsycINFO. The following inclusion criteria were used: (1) participants in the study were patients dealing with an illness, (2) the study examined the use of private rather than intercessory prayer, and (3) the content and purpose of prayer rather than its effects were investigated. Results. 16 articles were included in the final review. Participants suffered from a variety of chronic diseases, mostly cancer. Five main categories for the reasons and topics of prayer were found: (1) disease centered prayer, (2) assurance-centered prayer, (3) God-centered prayer, (4) others-centered prayer, and (5) lamentations. Among these, disease-centered prayer was most common. Conclusions. Although most patients with chronic diseases do pray for relief from their physical and mental suffering, the intention of their prayers is not only for healing. Rather, prayer can be a resource that allows patients to positively transform the experience of their illness. PMID- 25815043 TI - A hybrid intelligent diagnosis approach for quick screening of Alzheimer's disease based on multiple neuropsychological rating scales. AB - Neuropsychological testing is an effective means for the screening of Alzheimer's disease. Multiple neuropsychological rating scales should be used together to get subjects' comprehensive cognitive state due to the limitation of a single scale, but it is difficult to operate in primary clinical settings because of the inadequacy of time and qualified clinicians. Aiming at identifying AD's stages more accurately and conveniently in screening, we proposed a computer-aided diagnosis approach based on critical items extracted from multiple neuropsychological scales. The proposed hybrid intelligent approach combines the strengths of rough sets, genetic algorithm, and Bayesian network. There are two stages: one is attributes reduction technique based on rough sets and genetic algorithm, which can find out the most discriminative items for AD diagnosis in scales; the other is uncertain reasoning technique based on Bayesian network, which can forecast the probability of suffering from AD. The experimental data set consists of 500 cases collected by a top hospital in China and each case is determined by the expert panel. The results showed that the proposed approach could not only reduce items drastically with the same classification precision, but also perform better on identifying different stages of AD comparing with other existing scales. PMID- 25815042 TI - A clinical decision support system for the diagnosis, fracture risks and treatment of osteoporosis. AB - Expanding medical knowledge increases the potential risk of medical errors in clinical practice. We present, OPAD, a clinical decision support system in the field of the medical care of osteoporosis. We utilize clinical information from international guidelines and experts in the field of osteoporosis. Physicians are provided with user interface to insert standard patient data, from which OPAD provides instant diagnostic comments, 10-year risk of fragility fracture, treatment options for the given case, and when to offer a follow-up DXA evaluation. Thus, the medical decision making is standardized according to the best expert knowledge at any given time. OPAD was evaluated in a set of 308 randomly selected individuals. OPAD's ten-year fracture risk computation is nearly identical to FRAX (r = 0.988). In 58% of cases OPAD recommended DXA evaluation at the present time. Following a DXA measurement in all individuals, 71% of those that were recommended to have DXA at the present time received recommendation for further investigation or specific treatment by the OPAD. In only 5.9% of individuals in which DXA was not recommended, the result of the BMD measurement changed the recommendations given by OPAD. PMID- 25815044 TI - Application of a hybrid method combining grey model and back propagation artificial neural networks to forecast hepatitis B in china. AB - Accurate incidence forecasting of infectious disease provides potentially valuable insights in its own right. It is critical for early prevention and may contribute to health services management and syndrome surveillance. This study investigates the use of a hybrid algorithm combining grey model (GM) and back propagation artificial neural networks (BP-ANN) to forecast hepatitis B in China based on the yearly numbers of hepatitis B and to evaluate the method's feasibility. The results showed that the proposal method has advantages over GM (1, 1) and GM (2, 1) in all the evaluation indexes. PMID- 25815045 TI - Community-based decision making and priority setting using the R software: the community priority index. AB - This paper outlines how to compute community priority indices in the context of multicriteria decision making in community settings. A simple R function was developed and validated with community needs assessment data. Particularly, the first part of this paper briefly overviews the existing methods for priority setting and reviews the utility of a multicriteria decision-making approach for community-based prioritization. The second part illustrates how community priority indices can be calculated using the freely available R program to handle community data by showing the computational and mathematical steps of CPI (Community Priority Index) with bootstrapped 95% confidence intervals. PMID- 25815046 TI - Particle swarm optimization algorithm for optimizing assignment of blood in blood banking system. AB - This paper reports the performance of particle swarm optimization (PSO) for the assignment of blood to meet patients' blood transfusion requests for blood transfusion. While the drive for blood donation lingers, there is need for effective and efficient management of available blood in blood banking systems. Moreover, inherent danger of transfusing wrong blood types to patients, unnecessary importation of blood units from external sources, and wastage of blood products due to nonusage necessitate the development of mathematical models and techniques for effective handling of blood distribution among available blood types in order to minimize wastages and importation from external sources. This gives rise to the blood assignment problem (BAP) introduced recently in literature. We propose a queue and multiple knapsack models with PSO-based solution to address this challenge. Simulation is based on sets of randomly generated data that mimic real-world population distribution of blood types. Results obtained show the efficiency of the proposed algorithm for BAP with no blood units wasted and very low importation, where necessary, from outside the blood bank. The result therefore can serve as a benchmark and basis for decision support tools for real-life deployment. PMID- 25815047 TI - An agent-based epidemic simulation of social behaviors affecting HIV transmission among Taiwanese homosexuals. AB - Computational simulations are currently used to identify epidemic dynamics, to test potential prevention and intervention strategies, and to study the effects of social behaviors on HIV transmission. The author describes an agent-based epidemic simulation model of a network of individuals who participate in high risk sexual practices, using number of partners, condom usage, and relationship length to distinguish between high- and low-risk populations. Two new concepts free links and fixed links-are used to indicate tendencies among individuals who either have large numbers of short-term partners or stay in long-term monogamous relationships. An attempt was made to reproduce epidemic curves of reported HIV cases among male homosexuals in Taiwan prior to using the agent-based model to determine the effects of various policies on epidemic dynamics. Results suggest that when suitable adjustments are made based on available social survey statistics, the model accurately simulates real-world behaviors on a large scale. PMID- 25815048 TI - Effectiveness of brace treatment for adolescent idiopathic scoliosis. AB - OBJECTIVES: Effectiveness of brace treatment for adolescent idiopathic scoliosis (AIS) was demonstrated by the BrAIST study in 2013. Objectives of this study were to confirm its effectiveness by analyzing our results and to clarify the factors affecting the results of the treatment. MATERIALS AND METHODS: According to the Scoliosis Research Society AIS brace studies standardization criteria, patients with age 10 years or older, Risser 0 to II, less than 1 year post-menarche, curve magnitude 25 to 40 degrees before brace treatment and who received no prior treatment were included in the study. At skeletal maturity, the rate of the patients whose curve was stabilized, exceeded 45 degrees, and who were recommended or underwent surgery were investigated. Additionally, initial correction rate by the brace and factors affecting the results were investigated. RESULTS: A total of 33 patients (27 females and 6 males) could be followed-up until their skeletal maturity and included in the analysis. An average age was 11.9 years, average Cobb angle was 30.8 degrees , and Risser sign was 0 in 13 patients, I in 5, and II in 15 patients before treatment. There were 13 thoracic curves, 14 thoracolumbar or lumbar curves, and 6 double curves. Initial correction rate by the brace was 53.8% for the total curves. In terms of curve pattern, 34.4% for thoracic curve, 73.9% for thoracolumbar or lumbar curve, and 48.8% for double curve. After an average follow-up period of 33 months, 8 patients improved in more than 6 degrees, change of 17 patients were within 6 degrees, and 8 progressed in more than 6 degrees. Therefore, totally, 76% (25/33) of the curves were stabilized by the treatment. Four curves (12%) exceeded 45 degrees and one patient (3%) underwent surgery. Our results were better than the reported natural history. Factors that affected the results were hump degree before treatment and initial correction rate by the brace. CONCLUSIONS: 76% of the curve with AIS could be stabilized by brace treatment. Brace treatment was effective for treatment of AIS. Factors affecting the results were hump degrees and initial correction rate. PMID- 25815049 TI - Differences between pre-existing type and de novo type left convex thoracolumbar / lumbar scoliosis. AB - BACKGROUND: Lenke 5C type adolescent idiopathic scoliosis (AIS) with a Cobb angle of over 30 degrees has high risk of progression. The need for corrective surgeries for degenerative lumbar scoliosis has been increasing these days and some of those cases are pre-existing type scoliosis. However, it is said to be difficult to differentiate pre-existing type scoliosis from de novo type scoliosis. The purpose of this study is to analyze the relevant X ray metrics of degenerative lumbar scoliosis and to discover differences between pre-existing and de novo type scoliosis. METHODS: Of 54 consecutive patients who were diagnosed as candidates for corrective surgery for left convex thoracolumbar / lumbar scoliosis since December 2008, 19 patients over age 50 were included in this study. The average age was 60 years old (50-80 years old). All patients were female. Coronal and sagittal parameters were contrasted between two groups divided according to the existence of scoliosis in their adolescence; clear (AIS) and unclear (de novo). RESULTS: Eleven were AIS, and 8 were de novo. The average age was 54.0 years old for AIS and 67.4 for de novo (p<0.05). Cobb angles (69 degrees , 49 degrees ) and L4 tilt (30 degrees , 22 degrees ) were found to be significantly greater in AIS. Nash-Moe rotation assessment showed that rotational deformity was greater in AIS type than in de novo type. Lumbar lordosis (28 degrees , 32 degrees ), thoracolumbar kyphosis (24 degrees , 12 degrees ), sagittal vertical axis (37mm, 58mm), and pelvic incidence (51 degrees , 60 degrees ) showed no significant difference between the groups, however, pelvic tilt (24 degrees , 33 degrees ) showed significant difference. CONCLUSIONS: Among patients over 50 with degenerative thoracolumbar / lumbar scoliosis, those with pre-existing type scoliosis were found to have greater Cobb angle, greater L4 tilt, greater rotational deformity, less pelvic tilt, and were candidates for surgery at a younger age than those with de novo type scoliosis. In other words, those with de novo type scoliosis have less coronal deformity and worse sagittal pelvic alignment than those with pre-existing type scoliosis and are not considered candidates for surgery until a more advanced age. This study demonstrates some differences between pre-existing and de novo type scoliosis, contrasts the natural history of the two types of candidates for thoracolumbar / lumbar scoliosis surgery, and suggests the importance of performing surgery for Lenke 5C type adolescent idiopathic scoliosis at a younger age. PMID- 25815050 TI - Measurement of axial vertebral rotation using three-dimensional ultrasound images. AB - BACKGROUND: Axial vertebral rotation (AVR) is one of the important parameters to evaluate the severity and predict the progression of scoliosis. However, the AVR measurements on radiographs may underestimate its actual value. This pilot study investigated a new three-dimensional (3D) ultrasound method to measure AVR. METHODS: Three cadaveric vertebrae T7, L1, and L3 were scanned with a 3D medical ultrasound system. Nine sets of ultrasound data, the vertebral rotation from 0 to 40 degrees with 5 degrees increments, were recorded from each vertebra. An in house program was developed to reconstruct and measure the 3D vertebral images. The rotation of each reconstructed vertebra was determined by the angle between the line going through the centres of either laminae (L-L) or transverse processes (TP-TP) and a reference vertical plane. Three raters measured the rotation in 3 sessions, in which they used the mouse pointer to select the L-L or TP-TP according to their knowledge of vertebral anatomy. The program detected the 3D coordinates of these points and calculated the AVR. The intra-class correlation coefficients (ICCs) were used to calculate the intra-reliability and inter-reliability. The mean absolute difference (MAD+/-SD) and the range of difference (RD) between the actual values and the average measurements of each rater were computed to evaluate the accuracy of methods. RESULTS: When rotation was greater than 30 degrees for both L1 and L3, all raters found it difficult to determine one of the lamina areas due to the lack of ultrasound information in an area behind the spinous process. Therefore, the corresponding measurements were excluded. The ICC values of the intra-reliability (L-L, TP-TP) for the three raters were (0.987, 0.991), (0.989, 0.998) and (0.997, 1.000), respectively; meanwhile, the inter-reliability were 0.991 for (L-L) and 0.992 for (TP-TP). All ICC values were greater than 0.98 indicating both methods were highly reliable. The MAD+/-SD values (L-L, TP-TP) for the three raters were (1.5+/-0.3 degrees , 1.2+/-0.2 degrees ), (1.6+/-0.3 degrees , 1.3+/-0.3 degrees ), and (1.7+/-0.5 degrees , 0.9+/-0.2 degrees ), respectively. The RD (L-L, TP-TP) were (0-4.5 degrees , 0-3.5 degrees ), (0-5.1 degrees , 0-4.3 degrees ), and (0-5.1 degrees , 0-2.8 degrees ) for the three raters, respectively. CONCLUSIONS: The (L-L) and (TP-TP) methods could be used to measure AVR reliability from the 3D ultrasound images. PMID- 25815051 TI - Which is the best schedule of autologous blood storage for preoperative adolescent idiopathic scoliosis patients? AB - BACKGROUND: It is critically important for AIS patients to avoid perioperative allogeneic blood transfusions. Toward this aim, many institutes use autologous blood storage to perform perioperative transfusions. However, there is no standard timeline for collecting blood for storage. Therefore, the objective of this prospective cohort study was to compare the outcome of two different schedules for collecting autologous blood before operation in adolescent idiopathic scoliosis (AIS) patients. METHODS: Inclusion criteria are AIS patients, younger than 20 years old, female, operated between 2009 and 2013 with posterior spinal fusion and instrumentation who had 1600 mL autologous blood collected before operation. A total of 61 patients were participated in this study. They were randomly divided into 2 groups based on the storage interval. Weekly group (1W-G) consisted of 30 patients with a total of 1600mL blood collected weekly beginning 4 weeks before the operation. Biweekly group (2W-G) consisted of 31 patients with a total of 1600 mL blood collected biweekly beginning 8 weeks before the operation. The instrumented levels, total bleeding, complications during blood transfusion, and hematological examinations (RBC, Hb, Hct, MCH, MCV, MCHC) were evaluated. A hematological examination was performed before blood collection, before the operation, and on postoperative days 1, 3, and 7. Vasovagal reflex (VVR) was evaluated as complications during blood drawing. RESULT: Mean age, height, and weight did not differ significantly between the 2 groups. There were no significant differences in instrumented levels, bleeding during operation, after operation, and collected blood during operation. With the autologous blood, allogeneic blood transfusion was completely avoided. VVR was more frequent in the biweekly group significantly (1W-G 4.2% vs 2W-G 15.3%). In terms of hematological examination, all values showed no significant differences between two groups in the pre-drawing and the pre operation stage. However, the postoperative Hb and Hct values were higher in the weekly group. Also, MCV and MCHC showed the same behavior with higher values in the weekly group. CONCLUSION: A weekly schedule of autologous blood storage is better than a biweekly storage schedule. PMID- 25815052 TI - Prescriptive analytics applied to brace treatment for AIS: a pilot demonstration. AB - BACKGROUND: Prescriptive analytics is a concept combining statistical and computer sciences to prescribe an optimal course of action, based on predictions of possible future events. In this simulation study we investigate using prescriptive analytics to recommend optimal in-brace corrections for braced Adolescent Idiopathic Scoliosis (AIS) patients. The objectives were to estimate the efficacy of these recommendations, ultimately working toward improved brace design protocols. METHODS: Data was obtained for 90 AIS patients who had finished brace treatment at our center (60 full-time and 30 nighttime braces). Rates of >=6 degree progression were 53% for daytime and 30% for nighttime braces. A modeling technique previously developed by our group was used to predict these patients' likely treatment outcomes given a range of in-brace corrections - the model was blinded to the true outcomes during this process. Each patient's 'recommended' correction was identified as the least aggressive correction resulting in a desirable predicted outcome. The efficacy of these recommendations was estimated using a technique called "clinical trial simulation" (CTS). This technique used a statistical model to predict progression rate under the model recommended treatment, and compared it to the true progression rate, observed retrospectively, under the actual treatment. Significance was calculated using a permutation test. RESULTS: Model-recommended corrections ranged from 20%-58% for daytime and 65%-130% for nighttime braces, roughly corresponding with previous literature. Interestingly, in 37% of cases the recommended correction was less than that which had actually been applied, suggesting some opportunity for less aggressive (more comfortable) braces without compromising treatment outcome. The CTS estimated 26% fewer progressive cases using the model-recommended in-brace correction, over the actual correction observed retrospectively in the charts (p=0.05). The patients whose correction decreased under the model's recommendation did not show an increased progression rate. CONCLUSIONS: Optimal correction may be less than the maximum achievable correction. The preliminary results suggest that considering model-generated recommendations during brace fitting could improve outcomes. Future work will expand the system to recommend wear-times as well as corrections, improving its clinical relevance. We envision this pilot demonstration to promote development of model-based decision support in scoliosis treatment, and prompt discussion on its future role. PMID- 25815053 TI - A new corrective technique for adolescent idiopathic scoliosis: convex manipulation using 6.35 mm diameter pure titanium rod followed by concave fixation using 6.35 mm diameter titanium alloy. AB - BACKGROUND: It has been thought that corrective posterior surgery for adolescent idiopathic scoliosis (AIS) should be started on the concave side because initial convex manipulation would increase the risk of vertebral malrotation, worsening the rib hump. With the many new materials, implants, and manipulation techniques (e.g., direct vertebral rotation) now available, we hypothesized that manipulating the convex side first is no longer taboo. METHODS: Our technique has two major facets. (1) Curve correction is started from the convex side with a derotation maneuver and in situ bending followed by concave rod application. (2) A 6.35 mm diameter pure titanium rod is used on the convex side and a 6.35 mm diameter titanium alloy rod on the concave side. Altogether, 52 patients were divided into two groups. Group N included 40 patients (3 male, 37 female; average age 15.9 years) of Lenke type 1 (23 patients), type 2 (2), type 3 (3), type 5 (10), type 6 (2). They were treated with a new technique using 6.35 mm diameter different-stiffness titanium rods. Group C included 12 patients (all female, average age 18.8 years) of Lenke type 1 (6 patients), type 2 (3), type 3 (1), type 5 (1), type 6 (1). They were treated with conventional methods using 5.5 mm diameter titanium alloy rods. Radiographic parameters (Cobb angle/thoracic kyphosis/correction rates) and perioperative data were retrospectively collected and analyzed. RESULTS: Preoperative main Cobb angles (groups N/C) were 56.8 degrees /60.0 degrees , which had improved to 15.2 degrees /17.1 degrees at the latest follow-up. Thoracic kyphosis increased from 16.8 degrees to 21.3 degrees in group N and from 16.0 degrees to 23.4 degrees in group C. Correction rates were 73.2% in group N and 71.7% in group C. There were no significant differences for either parameter. Mean operating time, however, was significantly shorter in group N (364 min) than in group C (456 min). CONCLUSION: We developed a new corrective surgical technique for AIS using a 6.35 mm diameter pure titanium rod initially on the convex side. Correction rates in the coronal, sagittal, and axial planes were the same as those achieved with conventional methods, but the operation time was significantly shorter. PMID- 25815054 TI - Comparison of biomechanical behavior between a cast material torso jacket and a polyethylene based jacket. AB - BACKGROUND: Numerous designs are used to the treatment of Early Onset Scoliosis. For example, a Thoraco-Lumbo-Sacral Orthosis (TLSO) is constructed using Polyethylene (PE). In addition, a series of castings has been implemented using cast material (3M, BSN Medical). The cast material has some significant advantages over the PE design including: growth preserving, improved compliance, decreased invasiveness, delaying or avoiding surgery, and the ability to allow the skin to breathe. However, the mechanical effectiveness of the cast material brace as compared to the TLSO is unknown, thus providing the objective of this study. METHODS: A total of 23 standardized tensile tests were performed on the Delta-Cast Soft((r)) and 3M(TM) Scotchcast(TM) Plus Casting Tape in order to obtain mechanical properties (Young's and shear moduli and Poisson ratios). Using a radiograph of a thoracic spine, the size of twelve vertebrae and eleven intervertebral discs were measured and used to create a finite element spine model. Simulations using this model were used to establish mechanical loads which were then applied to finite element models of the TLSO and cast jacket. The thicknesses and number of material layers was varied in these models. Multiple simulations were performed. RESULTS: It was found that a 6.6.mm thick cast jacket made of Delta-Cast Soft((r)) had a maximum deformation of 4.7 mm, a maximum stress of 2.9 MPa and a structural factor of safety of 5.71. On the other hand, a 4 mm thick jacket made of PE had a maximum deformation of 2 mm, a maximum stress of 8.9 MPa and a structural factor of safety of 2.70. The cast jacket was 3.5 times lighter and had a material of cost 1/5 of the PE brace. CONCLUSIONS: Based on the results, either design will generate the proper constraint forces to maintain spinal correction. But, based on the design parameters (thickness, mechanical properties, structural factor of safety and cost) the brace made of cast material, though slightly thicker has superior structural and cost benefits. Thus, from the biomechanical point of view, the cast brace is more efficient than the PE brace. PMID- 25815055 TI - Mid- and long-term clinical outcomes of corrective fusion surgery which did not achieve sufficient pelvic incidence minus lumbar lordosis value for adult spinal deformity. AB - BACKGROUND: Recent studies have demonstrated sagittal spinal balance was more important than coronal balance in terms of clinical result of surgery for adult spinal deformity. Notably, Schwab reported that one of the target spinopelvic parameters for corrective surgery was that pelvic incidence (PI) minus lumbar lordosis (LL) should be within +/- 10 degrees . The present study aimed to investigate whether the clinical outcome of corrective fusion surgery was really poor for patients who could not acquire sufficient PI-LL value through the surgery. METHODS: The present study included 13 patients (mean 68.5 yrs old) with adult spinal deformity. Inclusion criteria were corrective fusion surgery more than 4 intervertebral levels, PI-LL >=10 degrees on the whole spine X-ray immediately after surgery, and follow-up period >=3 years. All surgeries were performed by posterior approach. Parameters using SRS-Schwab classification, proximal junctional kyphosis (PJK) of >=15 degrees , implants loosening, and non union were investigated using the total standing spinal X-ray. Clinical outcomes were evaluated by Japanese Orthopaedic Association scores (JOA score), Oswestry Disability Index, SF-36, Visual Analog Scale for low back pain, and satisfaction for surgery using SRS-22 questionnaire. RESULTS: All patients showed the PI-LL >=20 degrees before surgery. Although the LL were acquired mean 23.6 degrees after surgery, significant loss of correction was observed at final follow up. The acquired coronal spinal alignment was maintained within the follow-up period. However, sagittal vertical axis (SVA) was shifted forward significantly, from mean 4.5cm immediately after surgery to 11.1cm at final follow-up. Five patients showed PJK, 10 patients showed implants loosening, 8 patients showed non-union at final follow-up. The JOA score and mental health summary measures of SF-36 were significantly improved at final follow-up. The satisfaction score was mean 3.3 points, including 3 patients with >=4 points, at final follow-up. The satisfaction score correlated negatively with SVA at final follow-up (rho=-0.58 p=0.03). CONCLUSIONS: The forward shift of SVA was frequently observed, and SVA at final follow-up related to the patient's satisfaction of surgery. This study indicated the importance of postoperative PI-LL value, but also noted 23% of patients acquired good SVA and satisfaction nevertheless they had inadequate postoperative LL. PMID- 25815056 TI - Radiological assessment of shoulder balance following posterior spinal fusion for thoracic adolescent idiopathic scoliosis. AB - BACKGROUND: The objective of this study was to evaluate shoulder balance following posterior spinal fusion for thoracic adolescent idiopathic scoliosis (AIS). METHODS: Twenty-four patients (22 females) with thoracic AIS who had undergone posterior fusion with segmental pedicle screws were retrospectively reviewed. The mean follow-up duration was 29 (range, 24-55) months. Fifteen patients had type 1 curves, seven had type 2 curves, and two had type 3 curves according to the Lenke classification. The proximal thoracic (PT) and main thoracic (MT) Cobb angles, percent correction of PT (PTC) and MT (MTC) curves, T1 tilt, and shoulder asymmetry according to radiographic shoulder height (RSH) were measured on preoperative, immediately postoperative, and final follow-up radiographs. The preoperative PT and MT curve side-bending percent correction (PTBC and MTBC) were also measured. The PTC:MTC ratio was employed as an index of PTC and MTC matching. Patients were divided into two groups according to radiographic findings immediately postoperatively: the balanced group (|RSH| <20 mm) and imbalanced group (|RSH| >=20 mm). The preoperative indices (RSH, PTBC, MTBC, PTC, and MTC), preoperative and postoperative T1 tilt, and PTC:MTC ratio were compared between the two groups. RESULTS: The mean PT and MT were 33.0 degrees and 64.2 degrees preoperatively, 16.1 degrees (50.5%) and 16.8 degrees (74.0%) immediately postoperatively, and 16.9 degrees (49.0%) and 19.2 degrees (70.3%) at final follow-up, respectively. The mean preoperative RSH of -12.3 mm changed to +11.1 mm immediately postoperatively and improved to +5.7 mm at final follow-up. Seventeen patients were "balanced" and seven were "imbalanced" immediately postoperatively. There were significant differences in the PTC (p=0.04), postoperative T1 tilt (p=0.04), and PTC:MTC ratio (p=0.02) between the two groups (Wilcoxon rank-sum test). Only one patient had an imbalanced shoulder at the final follow-up. She had marked shoulder imbalance immediately postoperatively (RSH: +40 mm). CONCLUSIONS: Sufficient correction of PT curves that is matched with correction of MT curves is necessary to prevent postoperative shoulder imbalance. Almost all patients in our series had satisfactory results in terms of shoulder balance at final follow-up, but one patient with marked shoulder imbalance immediately postoperatively may have residual long-term shoulder imbalance. PMID- 25815057 TI - Significance of peak height velocity as a predictive factor for curve progression in patients with idiopathic scoliosis. AB - BACKGROUND: Much attention has been paid to peak height velocity (PHV) as a possible predictor of curve progression in patients with idiopathic scoliosis (IS). The aim of this study was to analyze the relationship between the magnitude of the Cobb angle at PHV and scoliosis progression, defined as having surgery prior to skeletal maturity in female patients with IS. METHODS: A retrospective review identified 56 skeletally immature female IS patients who were followed until maturity. The mean age and the mean pubertal status at the initial visit were 10 years and 24 months before menarche respectively, with a follow-up period of 5 years. They were divided into two groups: non-surgery group (NS) and surgery group (S), depending on their treatment method in use at the final follow-up visit. Surgery group was defined as an ultimately having surgery due to Cobb angle greater than 45 degrees prior to skeletal maturity regardless of conservative management. Height measurements were recorded at each visit; height velocity was calculated as the height change, in cm, divided by the time interval, in years. The PHV, chronological age at PHV (APHV), height at PHV (HPHV), and final height (FH) were determined for each group. In patients with Cobb angle greater than 30 degrees, the corrected height was calculated by Kono formula and corrected height velocity values were provided. The sensitivity, specificity, and area under the curve (AUC) of the receiver-operating characteristic (ROC) analysis were calculated to predict spinal curve progression for various Cobb-angle cutoff values at PHV. RESULTS: The corrected PHV had a mean value of 8.5 and 8.9 cm/year in the NS-group and S-group, respectively. The APHV was 11.9 and 11 years, the corrected HPHV was 152.9, and 149.3 cm, and the corrected FH was 159.9 and 159.3 cm, respectively. When a Cobb angle of 31.5 degrees was at PHV, ROC analysis revealed 78% sensitivity, 82% specificity, and an AUC of 0.93, acceptable values for curve progression in patients with IS. CONCLUSIONS: These findings indicate that 31.5 degrees of spinal curvature when patients are at PHV is a significant predictive indicator for progression of the curve to a magnitude requiring surgery. We suggest that the curve-progression risk assessment in patients with IS should include PHV, along with measures of skeletal and non-skeletal maturities. PMID- 25815058 TI - Reliability study for the Rib Index in chest radiographs of a control group. AB - BACKGROUND: The Rib Index, (RI), extracted from the double rib contour sign (DRCS) on lateral spinal radiographs to evaluate rib hump deformity, (RHD), in idiopathic scoliosis, (IS), patients, has been previously introduced. Although various papers using the RI have been published, no study on its reproducibility has been reported. The aim of this report is to estimate the variations of the RI in a number of a pair set of lateral chest radiographs (LCRs). The hypothesis was that the RI should have minimal variability for each subject having successive LCRs. METHODS: Seventy randomized patients who were treated in the hospital for lung diseases (mainly pneumonia or other communicable lung diseases), were initially included in the study. Each of these patients had two successive LCRs (named A and B group of radiographs) at the radiological department of the hospital, by the same technician, during the course of their treatment. The radiation source - patient distance was constant. LCRs obtained at an incorrect patient's position, or from patients who underwent a thoracic intervention and all LCRs with symmetric hemi-thoraces were excluded from the study. The LCRs of 49 patients were deemed suitable for inclusion in the study. The RI was calculated in both (A and B) LCRs of each patient. The statistical analysis included the following techniques: paired t-test, Pearson correlation coefficient and intra- and inter-observer error using the formula (SD/?2)/2, where SD is this of the differences of the two sets of measurement (As-Bs). The SPSS v16 statistical package was used. RESULTS: In the 49 pairs of LCRs there was no statistical difference of the RI, (paired t-test p< 0.314). The RI in the A and B group of LCRs was perfectly correlated (correlation coefficient = 0,924, p < 0.0001). The intra-observer error was 0.0080 while the inter-observer error 0.0213 in terms of 95% CI. CONCLUSION: The RI proves to be a reliable method to evaluate the thoracic deformity and the effect of surgical or non-operative treatment on the IS RHD. RI is a simple method, a safe reproducible way to assess the RHD based on lateral radiographs, without the need for any further special radiographs and exposure to additional radiation. PMID- 25815059 TI - Current management approach to hidradenocarcinoma: a comprehensive review of the literature. AB - Hidradenocarcinoma is a rare malignant adnexal tumour which arises from the intradermal duct of eccrine sweat glands. The head and neck are the most common sites of hidradenocarcinoma, but rarely it can occur on the extremities. As it is an aggressive tumour, regional lymph nodes and distant viscera are the most common sites of metastasis. Diagnosis is confirmed by histopathology and immunohistochemistry. Hidradenocarcinoma should be differentiated from benign and malignant adnexal tumours. Being an aggressive and rare tumour, no uniform treatment guidelines have been documented so far for metastatic hidradenocarcinoma. Wide local excision is the mainstay of the treatment, but because of high local recurrence, radiotherapy in a dose of 50Gy-70Gy and/or 5 fluorouracil and capecitabine-based combination chemotherapy may be given to further improve local control. Other treatment strategies are targeted therapies like trastuzumab, EGFR inhibitors, PI3K/Akt/mTOR pathway inhibitors, hormonal agents like antiandrogens, electrochemotherapy, or clinical trials. PMID- 25815060 TI - The Restaurant Food Hot Potato: Stop Passing it on-A Commentary on Mah and Timming's, 'Equity in Public Health Ethics: The Case of Menu Labelling Policy at the Local Level'. AB - In the case discussion, 'Equity in Public Health Ethics: The Case of Menu Labelling Policy at the Local Level' (2014), Mah and Timming state that menu labelling would 'place requirements for information disclosure on private sector food businesses, which, as a policy instrument, is arguably less intrusive than related activities such as requiring changes to the food content'. In this commentary on Mah and Timming's case study, I focus on discussing how menu labelling policy permits governments to avoid addressing the heart of the problem, which is high-calorie, high-sodium restaurant food. Menu labelling policy does not address food content in a way that is meaningful for change, instead relying on individuals to change their behaviour given new information. Besides having questionable efficacy, this raises concerns about moralizing food choices. PMID- 25815061 TI - Bacterial rose garden for metagenomic SNP-based phylogeny visualization. AB - BACKGROUND: One of the most challenging tasks in genomic analysis nowadays is metagenomics. Biomedical applications of metagenomics give rise to datasets containing hundreds and thousands of samples from various body sites for hundreds of patients. Inherently metagenome is by far more complex than a single genome as it varies in time by the amount of bacteria comprising it. Other levels of data complexity include geography of the samples and phylogenetic distance between the genomes of the same operational taxonomic unit (OTU). We have developed the visualization concept for the representation of multilayer metagenomics data - the bacterial rose garden. The approach allows to display the taxonomic distance between the representatives of the same OTU in different samples and use variety of the metadata for display. RESULTS: We have developed the principle of visualization allowing for multilayer information representation. We have incorporated data on OTU diversity across metagenomes and origin of the samples. The visual representation we have called "rose" is focused on the phylogenetic distance between the representatives of the same OTU. The visual representation is realized as interactive data chart which allows user to interact with data and explore variables. It is known that classical representation of the taxonomic tree is a reduction of information from original pairwise distance matrix. The visualization presented is a way to save all the information available through projection of distance matrix into single dimensional space of one sample. It could serve as a basis for further more complex information representation. We have used the principle proposed for visualization of 101 bacterial OTUs phylogenetic distances, finally we provide open code for the web page generation. CONCLUSIONS: Bacterial rose garden is a versatile visualization principle coping with the major difficulties of metagenomic big-data visualization without loss of data. The method proposed is showing the interconnectedness of variables and is realized as user-friendly web page allowing for dynamic data exploration. The concept provided serves as one of the original approaches for metagenomic data representation and sharing. Full functional prototype could be found at http://rosegarden.datalaboratory.ru. PMID- 25815062 TI - Wikipedia Chemical Structure Explorer: substructure and similarity searching of molecules from Wikipedia. AB - BACKGROUND: Wikipedia, the world's largest and most popular encyclopedia is an indispensable source of chemistry information. It contains among others also entries for over 15,000 chemicals including metabolites, drugs, agrochemicals and industrial chemicals. To provide an easy access to this wealth of information we decided to develop a substructure and similarity search tool for chemical structures referenced in Wikipedia. RESULTS: We extracted chemical structures from entries in Wikipedia and implemented a web system allowing structure and similarity searching on these data. The whole search as well as visualization system is written in JavaScript and therefore can run locally within a web page and does not require a central server. The Wikipedia Chemical Structure Explorer is accessible on-line at www.cheminfo.org/wikipedia and is available also as an open source project from GitHub for local installation. CONCLUSIONS: The web based Wikipedia Chemical Structure Explorer provides a useful resource for research as well as for chemical education enabling both researchers and students easy and user friendly chemistry searching and identification of relevant information in Wikipedia. The tool can also help to improve quality of chemical entries in Wikipedia by providing potential contributors regularly updated list of entries with problematic structures. And last but not least this search system is a nice example of how the modern web technology can be applied in the field of cheminformatics. Graphical abstractWikipedia Chemical Structure Explorer allows substructure and similarity searches on molecules referenced in Wikipedia. PMID- 25815064 TI - Is the risk of Alzheimer's disease and dementia declining? AB - BACKGROUND: The number of older adults with dementia will increase around the world in the decades ahead as populations age. Current estimates suggest that about 4.2 million adults in the US have dementia and that the attributable economic cost of their care is about $200 billion per year. The worldwide dementia prevalence is estimated at 44.3 million people and the total cost at $604 billion per year. It is expected that the worldwide prevalence will triple to 135.5 million by 2050. However, a number of recent population-based studies from countries around the world suggest that the age-specific risk of dementia may be declining, which could help moderate the expected increase in dementia cases that will accompany the growing number of older adults. DISCUSSION: At least nine recent population-based studies of dementia incidence or prevalence have shown a declining age-specific risk in the US, England, The Netherlands, Sweden, and Denmark. A number of factors, especially rising levels of education and more aggressive treatment of key cardiovascular risk factors such as hypertension and hypercholesterolemia, may be leading to improving 'brain health' and declining age-specific risk of Alzheimer's disease and dementia in countries around the world. SUMMARY: Multiple epidemiological studies from around the world suggest an optimistic trend of declining population dementia risk in high-income countries over the past 25 years. Rising levels of education and more widespread and successful treatment of key cardiovascular risk factors may be the driving factors accounting for this decline in dementia risk. Whether this optimistic trend will continue in the face of rising worldwide levels of obesity and diabetes and whether this trend is also occurring in low- and middle-income countries are key unanswered questions which will have enormous implications for the extent of the future worldwide impact of Alzheimer's disease and dementia on patients, families, and societies in the decades ahead. PMID- 25815065 TI - 3alpha,5alpha-Cyclocholestan-6beta-yl ethers as donors of the cholesterol moiety for the electrochemical synthesis of cholesterol glycoconjugates. AB - 3alpha,5alpha-Cyclocholestan-6beta-yl alkyl and aryl ethers were proved to be efficient cholesteryl donors in the electrochemical synthesis of glycoconjugates. 3alpha,5alpha-Cyclocholestan-6beta-ol (i-cholesterol) and its tert butyldimethylsilyl ether can also be used for this purpose. The i-cholesterol derivatives show similar reactivities to those of previously studied 3alpha,5alpha-cyclocholestan-6beta-thioethers. PMID- 25815063 TI - Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review. AB - INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer. PMID- 25815066 TI - Enhancing the reactivity of 1,2-diphospholes in cycloaddition reactions. AB - Two different approaches have been employed to enhance the reactivity of 1-alkyl 1,2-diphospholes - the introduction of electron-withdrawing groups either at the phosphorus atoms or in the para-position of the arene ring. The alkylation of sodium 1,2-diphospha-3,4,5-triphenylcyclopentadienide with alkyl halides Hal-CH2 R (R = CN, COOEt, OMe, CH2OEt) results in corresponding 1-alkyl-3,4,5-triphenyl 1,2-diphospholes (alkyl = CH2CN (1a), CH2COOEt (1b), CH2OMe (1c), and (CH2)2OEt (1d)), which spontaneously undergo the intermolecular [4 + 2] cycloaddition reactions at room temperature to form the mixture of the cycloadducts, 2a-c, respectively. However the alkylation of sodium 1,2-diphospha-3,4,5-tri(p fluorophenyl)cyclopentadienide with ethyl iodide leads to stable 1-ethyl-3,4,5 tris(p-fluorophenyl)-1,2-diphosphole (1e), which forms the [4 + 2] cycloadduct 2,3,4,4a,5,6-hexa(p-fluorophenyl)-1-ethyl-1,7,7a-triphospha-4,7 (ethylphosphinidene)indene (2e) only upon heating up to 60 degrees C. With further heating to 120 degrees C with N-phenylmaleimide, the cycloadducts 2a-c and 2e undergo the retro-Diels-Alder reaction and form only one product of the [4 + 2] cycloaddition reaction 3a-s, 3e with good yields up to 65%. PMID- 25815067 TI - Electrochemical selenium- and iodonium-initiated cyclisation of hydroxy functionalised 1,4-dienes. AB - The cobalt(I)-catalysed 1,4-hydrovinylation reaction of allyloxytrimethylsilane and allyl alcohol with substituted 1,3-dienes leads to hydroxy-functionalised 1,4 dienes in excellent regio- and diastereoselective fashion. Those 1,4-dienols can be converted into tetrahydrofuran and pyran derivatives under indirect electrochemical conditions generating selenium or iodonium cations. The reactions proceed in good yields and regioselectivities for the formation of single diastereomers. PMID- 25815068 TI - Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization. AB - The reaction of the diamidite, (iPr2N)2PH, with acyl chlorides proceeds with the loss of HCl to give the corresponding acyl diamidites, RC(O)P(N(iPr)2)2 (R = Me (7), Ph (9)), without the intervention of sodium to give a phosphorus anion. The structure of 9 was confirmed by single-crystal X-ray diffraction. The coupling of the diamidites 7 and 9 with 5'-O-DMTr-thymidine was carried out with N methylimidazolium triflate as the activator to give the monoamidites 3'-O (P(N(iPr)2)C(O)R)-5'-O-DMTr-thymidine, and further coupling with 3'-O-(tert butyldimethylsilyl)thymidine was carried out with activation by pyridinium trifluoroacetate/N-methylimidazole. The new dinucleoside acylphosphonites could be further oxidized, hydrolyzed to the H-phosphonates, and sulfurized to give the known mixture of diastereomeric phosphorothioates. The goal of this work was the measurement of the barrier to inversion of the acylphosphonites, which was expected to be low by analogy to the low barrier found in acylphosphines. However, the barrier was found to be high as no epimerization was detected up to 150 degrees C, and consistent with this, density functional theory calculations give an inversion barrier of over 40 kcal/mol. PMID- 25815069 TI - Properties of cationic monosubstituted tetraalkylammonium cyclodextrin derivatives - their stability, complexation ability in solution or when deposited on solid anionic surface. AB - The thermal stability of the monosubstituted cationic cyclodextrin (CD) derivatives PEMEDA-beta-CD and PEMPDA-beta-CD, which differ in their substituent linker length (ethylene and propylene, respectively), was studied via (1)H NMR experiments. PEMPDA-beta-CD exhibited higher resistance towards the Hofmann degradation and was chosen as a more suitable host molecule for further studies. Inclusion properties of PEMPDA-beta-CD in solution with a series of simple aromatic guests (salicylic acid, p-methoxyphenol and p-nitroaniline) were determined by isothermal titration calorimetry (ITC) and compared to the native beta-CD. Permanently charged cationic CD derivatives were successfully deposited on the anionic solid surface of polymeric Nafion((r)) 117 membrane via electrostatic interactions. Deposition kinetics and coverage of the surface were determined by ELSD. Finally, the ability of the CD derivatives bound to the solid surface to encapsulate aromatic compounds from aqueous solution was measured by UV-vis spectroscopy. The obtained results are promising for future industrial applications of the monosubstituted beta-CD derivatives, because the preparation of cationic CD derivatives is applicable in large scale, without the need of chromatographic purification. Their ionic deposition on a solid surface is simple, yet robust and a straightforward process as well. PMID- 25815070 TI - Cathodic reductive coupling of methyl cinnamate on boron-doped diamond electrodes and synthesis of new neolignan-type products. AB - The electroreduction reaction of methyl cinnamate on a boron-doped diamond (BDD) electrode was investigated. The hydrodimer, dimethyl 3,4-diphenylhexanedioate (racemate/meso = 74:26), was obtained in 85% yield as the major product, along with small amounts of cyclic methyl 5-oxo-2,3-diphenylcyclopentane-1-carboxylate. Two new neolignan-type products were synthesized from the hydrodimer. PMID- 25815071 TI - Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin. AB - BACKGROUND: The aim of this study was to design and evaluate hybrid cyclodextrin (CD) nanocapsules intended for the oral delivery of the anticancer agent camptothecin (CPT) in order to maintain drug stability in the body and to improve its eventual bioavailability. For this reason, an amphiphilic cyclodextrin (CD) derivative per-modified on the primary face 6OCAPRO was used as core molecule to form nanocapsules with the nanoprecipitation technique. Nanocapsules were further coated with the cationic polymer chitosan to improve the cellular uptake and interaction with biological membranes through positive surface charge. Nanocapsules were evaluated for their in vitro characteristics such as particle size, zeta potential, drug loading and release profiles followed by cell culture studies with the MCF-7 and Caco-2 cell line evaluating their anticancer efficacy and permeability. The CD nanocapsules were imaged by scanning electron microscopy (SEM). The concentration of CPT entrapped in nanocapsules was determined by reversed phase HPLC. The in vitro release study of CPT was performed with a dialysis bag method under sink conditions mimicking the gastric and intestinal pH. The hydrolytic stability of CPT in nanocapsules was investigated in simulated gastric and intestinal fluids (SGF, SIF). RESULTS: The mean particle sizes of both anionic and cationic CPT-loaded nanocapsules were in the range of 180-200 nm with polydispersity indices lower than 0.400 indicating monodisperse size distribution of nanocapsules with favourable potential for intracellular drug delivery to tumour cells. Surface charges of anionic and cationic nanocapsules were demonstrated as -21 mV and +18 mV, respectively. The stability of CPT in simulated release media, SGF and SIF were maintained suggesting the improved protection of the drug molecule from rapid hydrolysis degradation or gastrointestinal pH in nanocapsule oily core. Furthermore CD nanocapsules showed higher anticancer efficacy than CPT solution against the MCF-7 cell line. Permeation of CPT across Caco-2 cells was found to be 3 fold higher when incorporated in hybrid CD nanocapsules compared with a DMSO solution. CONCLUSION: Oral CD nanocapsules indicating increased oral bioavailability might be a promising strategy to maintain the physiological stability and to improve the oral bioavailability of problematic anticancer drugs such as CPT which may contribute to patient quality of life and drug efficacy in cancer therapy. PMID- 25815072 TI - Copper-catalyzed cascade reactions of alpha,beta-unsaturated esters with keto esters. AB - A copper-catalyzed cascade reaction of alpha,beta-unsaturated esters with keto esters is reported. It features a copper-catalyzed reductive aldolization followed by a lactonization. This method provides a facile approach to prepare gamma-carboxymethyl-gamma-lactones and delta-carboxymethyl-delta-lactones under mild reaction conditions. PMID- 25815074 TI - 2-(1-Hydroxypropyn-2-yl)-1-vinylpyrroles: the first successful Favorsky ethynylation of pyrrolecarbaldehydes. AB - 1-Vinylpyrrole-2-carbaldehydes react with acetylene at atmospheric pressure in a NaOH/EtOH/DMSO system at 7-10 degrees C to afford 2-(1-hydroxypropyn-2-yl)-1 vinylpyrroles in 53-94% yield. Thus, the first base-mediated direct ethynylation of pyrrolecarbaldehydes with free acetylene under modified conditions of the Favorsky reaction has been implemented to pave an expedient route to important biomolecules containing a pyrrole ring. PMID- 25815073 TI - TEMPO-derived spin labels linked to the nucleobases adenine and cytosine for probing local structural perturbations in DNA by EPR spectroscopy. AB - Three 2'-deoxynucleosides containing semi-flexible spin labels, namely (T)A, (U)A and (U)C, were prepared and incorporated into deoxyoligonucleotides using the phosphoramidite method. All three nucleosides contain 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO) connected to the exocyclic amino group; (T)A directly and (U)A as well as (U)C through a urea linkage. (T)A and (U)C showed a minor destabilization of a DNA duplex, as registered by a small decrease in the melting temperature, while (U)A destabilized the duplex by more than 10 degrees C. Circular dichroism (CD) measurements indicated that all three labels were accommodated in B-DNA duplex. The mobility of the spin label (T)A varied with different base-pairing partners in duplex DNA, with the (T)A*T pair being the least mobile. Furthermore, (T)A showed decreased mobility under acidic conditions for the sequences (T)A*C and (T)A*G, to the extent that the EPR spectrum of the latter became nearly superimposable to that of (T)A*T. The reduced mobility of the (T)A*C and (T)A*G mismatches at pH 5 is consistent with the formation of (T)AH(+)*C and (T)AH(+)*G, in which protonation of N1 of A allows the formation of an additional hydrogen bond to N3 of C and N7 of G, respectively, with G in a syn-conformation. The urea-based spin labels (U)A and (U)C were more mobile than (T)A, but still showed a minor variation in their EPR spectra when paired with A, G, C or T in a DNA duplex. (U)A and (U)C had similar mobility order for the different base pairs, with the lowest mobility when paired with C and the highest when paired with T. PMID- 25815075 TI - Novel biphenyl-substituted 1,2,4-oxadiazole ferroelectric liquid crystals: synthesis and characterization. AB - Two novel series of unsymmetrically substituted 1,2,4-oxadiazole viz., R.Ox.C(*)C n compounds are synthesized and characterized. An optically active, (S)-(+) methyl 3-hydroxy-2-methylpropionate is used to introduce a chiral center in the molecule. A biphenyl moiety prepared by Suzuki coupling reaction is directly attached to the oxadiazole core at C-5 position. Investigations for the phase behavior revealed that the series with a benzyl group on one end of the oxadiazole core exhibits an 1D orthogonal smectic-A phase while the second series with dodecyl flexible end chain shows orthogonal smectic-A and tilted chiral smectic-C (SmC*) phases over a wide range of temperatures. The smectic-C phase exhibits ferroelectric (FE) polarization switching. The mesomorphic thermal stabilities of these compounds are discussed in the domain of the symmetry and the flexibility of the alkyloxy end chain length attached to the chiral center. PMID- 25815076 TI - Switching the reaction pathways of electrochemically generated beta haloalkoxysulfonium ions - synthesis of halohydrins and epoxides. AB - beta-Haloalkoxysulfonium ions generated by the reaction of electrogenerated Br(+) and I(+) ions stabilized by dimethyl sulfoxide (DMSO) reacted with sodium hydroxide and sodium methoxide to give the corresponding halohydrins and epoxides, respectively, whereas the treatment with triethylamine gave alpha halocarbonyl compounds. PMID- 25815078 TI - Synthesis of the furo[2,3-b]chromene ring system of hyperaspindols A and B. AB - The synthesis of the unique furo[2,3-b]chromene ring system found in hyperaspidinols A and B, acylphloroglucinols from Hypericum chinense has been achieved in twelve steps. By comparison of the NMR spectra of the synthesized compounds with those of the natural products, a relative stereochemistry is suggested, especially that of the ketal carbon. PMID- 25815077 TI - Natural phenolic metabolites with anti-angiogenic properties - a review from the chemical point of view. AB - Considering the many secondary natural metabolites available from plants, phenolic compounds play a particularly important role in human health as they occur in significant amounts in many fruits, vegetables and medicinal plants. In this review natural phenolic compounds of plant origin with significant anti angiogenic properties are discussed. Thirteen representatives from eight different natural or natural-like phenolic subclasses are presented with an emphasis on their synthesis and methods to modify the parent compounds. When available, the consequence of structural variation on the pharmacological activity of the molecules is described. PMID- 25815079 TI - Superstructures with cyclodextrins: Chemistry and applications II. PMID- 25815080 TI - Anionic sigmatropic-electrocyclic-Chugaev cascades: accessing 12-aryl-5 (methylthiocarbonylthio)tetracenes and a related anthra[2,3-b]thiophene. AB - 1,4-Diols resulting from the double addition of ArCCLi (Ar = Ph, substituted phenyl, 2-thienyl) to ortho-C6H4(CHO)2 undergo cascades to tetracenes on simple admixture of LiHDMS, CS2 and MeI. Acene formation proceeds by [3,3]-sigmatropic rearrangement of xanthate anions followed by 6pi electrocyclisations. The reactions are terminated by E2 or anionic Chugaev-type eliminations. Structural packing motifs and electronic properties are reported for the tetracenes. PMID- 25815081 TI - Photovoltaic-driven organic electrosynthesis and efforts toward more sustainable oxidation reactions. AB - The combination of visible light, photovoltaics, and electrochemistry provides a convenient, inexpensive platform for conducting a wide variety of sustainable oxidation reactions. The approach presented in this article is compatible with both direct and indirect oxidation reactions, avoids the need for a stoichiometric oxidant, and leads to hydrogen gas as the only byproduct from the corresponding reduction reaction. PMID- 25815082 TI - Selective methylation of kaempferol via benzylation and deacetylation of kaempferol acetates. AB - A strategy for selective mono-, di- and tri-O-methylation of kaempferol, predominantly on the basis of selective benzylation and controllable deacetylation of kaempferol acetates, was developed. From the selective deacetylation and benzylation of kaempferol tetraacetate (1), 3,4',5,-tri-O acetylkaempferol (2) and 7-O-benzyl-3,4'5,-tri-O-acetylkaempferol (8) were obtained, respectively. By controllable deacetylation and followed selective or direct methylation of these two intermediates, eight O-methylated kaempferols were prepared with 51-77% total yields from kaempferol. PMID- 25815083 TI - Stereoselective cathodic synthesis of 8-substituted (1R,3R,4S)-menthylamines. AB - The electrochemical generation of menthylamines from the corresponding menthone oximes equipped with an additional substituent in position 8 is described. Due to 1,3-diaxial interactions a pronounced diastereoselectivity for the menthylamines is found. PMID- 25815084 TI - Azirinium ylides from alpha-diazoketones and 2H-azirines on the route to 2H-1,4 oxazines: three-membered ring opening vs 1,5-cyclization. AB - Strained azirinium ylides derived from 2H-azirines and alpha-diazoketones under Rh(II)-catalysis can undergo either irreversible ring opening across the N-C2 bond to 2-azabuta-1,3-dienes that further cyclize to 2H-1,4-oxazines or reversibly undergo a 1,5-cyclization to dihydroazireno[2,1-b]oxazoles. Dihydroazireno[2,1-b]oxazoles derived from 3-aryl-2H-azirines and 3 diazoacetylacetone or ethyl diazoacetoacetate are able to cycloadd to acetyl(methyl)ketene generated from 3-diazoacetylacetone under Rh(II) catalysis to give 4,6-dioxa-1-azabicyclo[3.2.1]oct-2-ene and/or 5,7-dioxa-1 azabicyclo[4.3.1]deca-3,8-diene-2-one derivatives. According to DFT calculations (B3LYP/6-31+G(d,p)), the cycloaddition can involve two modes of nucleophilic attack of the dihydroazireno[2,1-b]oxazole intermediate on acetyl(methyl)ketene followed by aziridine ring opening into atropoisomeric oxazolium betaines and cyclization. Azirinium ylides generated from 2,3-di- and 2,2,3-triaryl substituted azirines give rise to only 2-azabuta-1,3-dienes and/or 2H-1,4 oxazines. PMID- 25815085 TI - An unusually stable chlorophosphite: What makes BIFOP-Cl so robust against hydrolysis? AB - Two chlorophosphites, the biphenyl-based BIFOP-Cl and the diphenyl ether-based O BIFOP-Cl, exhibit striking differences regarding their reaction with water. While BIFOP-Cl is nearly completely unreactive, its oxo-derivative O-BIFOP-Cl reacts instantly with water, yielding a tricyclic hydrocarbon unit after rearrangement. The analysis of the crystal structure of O-BIFOP-Cl and BIFOP-Cl revealed that the large steric demand of encapsulating fenchane units renders the phosphorus atom nearly inaccessible by nucleophilic reagents, but only for BIFOP-Cl. In addition to the steric effect, a hypervalent P(III)-O interaction as well as an electronic conjugation effect causes the high reactivity of O-BIFOP-Cl. A DFT study of the hydrolysis in BIFOP-Cl verifies a higher repulsive interaction to water and a decreased leaving tendency of the chloride nucleofuge, which is caused by the fenchane units. This high stability of BIFOP-Cl against nucleophiles supports its application as a chiral ligand, for example, in Pd catalysts. PMID- 25815086 TI - A simple and efficient method for the preparation of 5-hydroxy-3-acyltetramic acids. AB - Oxidation of the bisenolates of 3-acyltetramic acid to the corresponding 5 hydroxylated compounds using molecular oxygen is reported. The deprotection of the resulting compounds was also achieved. PMID- 25815087 TI - C-5'-Triazolyl-2'-oxa-3'-aza-4'a-carbanucleosides: Synthesis and biological evaluation. AB - A novel series of 2'-oxa-3'-aza-4'a-carbanucleosides, featured with a triazole linker at the 5'-position, has been developed by exploiting a click chemistry reaction of 5'-azido-2'-oxa-3'-aza-4'a-carbanucleosides with substituted alkynes. Biological tests indicate an antitumor activity for the synthesized compounds: most of them inhibit cell proliferation of Vero, BS-C-1, HEp-2, MDCK, and HFF cells with a CC50 in the range of 5.0-40 MUM. The synthesized compounds do not show any antiviral activity. PMID- 25815088 TI - Functionalized branched EDOT-terthiophene copolymer films by electropolymerization and post-polymerization "click"-reactions. AB - The electrocopolymerization of 3,4-ethylenedioxythiophene (EDOT) with the branched thiophene building block 2,2':3',2"-terthiophene (3T) is presented as a versatile route to functional polymer films. Comparisons to blend systems of the respective homopolymers PEDOT and P3T by in situ spectroelectrochemistry and Raman spectroscopy prove the successful copolymer formation and the access to tailored redox properties and energy levels. The use of EDOT-N3 as co-monomer furthermore allows modifications of the films by polymer analogous reactions. Here, we exemplarily describe the post-functionalization with ionic moieties by 1,3-dipolar cycloaddition ("click"-chemistry) which allows to tune the surface polarity of the copolymer films from water contact angles of 140 degrees down to 40 degrees . PMID- 25815089 TI - IR and electrochemical synthesis and characterization of thin films of PEDOT grown on platinum single crystal electrodes in [EMMIM]Tf2N ionic liquid. AB - Thin films of PEDOT synthesized on platinum single electrodes in contact with the ionic liquid 1-ethyl-2,3-dimethylimidazolium triflimide ([EMMIM]Tf2N) were studied by cyclic voltammetry, chronoamperometry, infrared spectroscopy and atomic force microscopy. It was found that the polymer grows faster on Pt(111) than on Pt(110) or Pt(100) and that the redox reactions associated with the PEDOT p-doping process are much more reversible in [EMMIM]Tf2N than in acetonitrile. Finally, the ion exchange and charge carriers' formation during the p-doping reaction of PEDOT were studied using in situ FTIR spectroscopy. PMID- 25815091 TI - Immunological dysfunction during or after antiviral therapy for recurrent hepatitis C reduces graft survival. AB - INTRODUCTION: Pegylated interferon and ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after liver transplantation (LT) is associated with a lower sustained virological response (SVR) rate as well as more frequent side effects compared to non-transplant patients. We aimed to determine the incidence and clinical characteristics of LT recipients with recurrent hepatitis C who developed immunological dysfunction (ID) during or after PEG-IFN/RBV therapy and to assess its impact on patient and graft survival. METHODS: Seventy-four deceased donor LT recipients with histological recurrence of hepatitis C were treated with PEG-IFN/RBV from 1/00 to 12/08. ID was defined as biopsy-proven rejection or moderate plasma cell hepatitis. Patients were followed up until death, re-LT or 30 September 2011. RESULTS: Twelve patients (16 %) had ID, 8 (10.7 %) had cholestasis without ID, while 54 had no ID/cholestasis during or after discontinuation of PEG-IFN/RBV therapy. Biopsy-proven acute cellular rejection prior to (hazard ratio = 4.87, p = 0.009) and type of immunosuppression at the time of initiation of PEG-IFN/RBV were the only independent predictors of ID. Patients who were on tacrolimus at the time of initiation of PEG-IFN/RBV had a significantly lower risk of ID compared to those who were on cyclosporine (HR 0.254, p = 0.023). Patients with ID had a trend toward a lower SVR rate (25 vs. 54 %, p = 0.18) and a significantly higher rate of graft failure (33 vs. 4 %, p = 0.004) compared to patients with no ID/cholestasis. CONCLUSIONS: ID is common during or after PEG-IFN/RBV therapy for recurrent hepatitis C and frequently associated with decreased graft survival, trending toward low rates of SVR. Careful monitoring of liver biochemistries during or after PEG-IFN/RBV therapy with a low threshold to biopsy patients and particularly those receiving cyclosporine-based immunosuppression may improve outcomes in these patients. PMID- 25815090 TI - Nanocrystalline cerium dioxide efficacy for gastrointestinal motility: potential for prokinetic treatment and prevention in elderly. AB - BACKGROUND: Constipation is a common condition, with prevalence after 65 years, is a major colorectal cancer risk factor. Recent works have demonstrated advances in personalized, preventive nanomedicine, leading to the construction of new materials and nanodrugs, in particular, nanocrystalline cerium dioxide (NCD), having strong antioxidative prebiotic effect. The aim of our study was to investigate the influence of NCD on motor function of the stomach and colon in vivo and contractive activity of smooth muscles in different year-old rats. METHODS: We included 80 rats: 3- (weight 130-160 g, n = 40) and 24-month old (weight 390-450 g, n = 40), divided into four groups as follows: I-control group; rats of II-IV groups were injected intragastrically one injection per day during 10 days, 3 ml of water 3 ml/kg stabilizing solution, and 1 mmol/ml NCD, respectively. In all animals, we recorded spontaneous and carbachol-stimulated (0.01 mg/kg) gastrointestinal tract motor activity. We used the index of motor activity (IMA), expressed in cmH2O, for characterization of the motor function. We investigated smooth muscle contraction by tenzometric method, studied the spontaneous and stimulated motility by ballonographic method. RESULTS: IMA reduced by 21.1 + 0.2% (p < 0.01) in the old rats of the control group compared with the young rats. A 10-day administration of NCD increased IMA in the stomach of young rats by 9.3% (r < 0.001) vs the control group. The exposure of NCD increased the amplitude of contraction to 34.2 +/- 5.4 mN (n = 10) in the stomach of old rats and increased by 32.1 +/- 2.4% vs the control group (p < 0.05). NCD did not influence acetylcholine (ACh) contractions in the stomach of young rats; however, in the stomach of old rats, V nr increased by 90 +/- 15.2% (r < 0.001). CONCLUSIONS: The index of motor activity is decreased in old rats. Nanocrystalline cerium dioxide increased the index of motor activity in all groups of rats and also evoked a significant increase of colon contractions in old rats. PMID- 25815092 TI - Investigation to determine staff exposure and describe animal bite surveillance after detection of a rabid zebra in a safari lodge in Kenya, 2011. AB - INTRODUCTION: Rabies is a fatal viral infection, resulting in >55,000 deaths globally each year. In August 2011, a young orphaned zebra at a Kenyan safari lodge acquired rabies and potentially exposed >150 tourists and local staff. An investigation was initiated to determine exposures among the local staff, and to describe animal bite surveillance in the affected district. METHODS: We interviewed lodge staff on circumstances surrounding the zebra's illness and assessed their exposure status. We reviewed animal bite report forms from the outpatient department at the district hospital. RESULTS: The zebra was reported bitten by a dog on 31(st) July 2011, became ill on 23(rd)August, and died three days later. There were 22 employees working at the lodge during that time. Six (27%) had high exposure due to contact with saliva (bottle feeding, veterinary care) and received four doses of rabies vaccine and one of immune-globulin, and 16 (73%) had low exposure due to casual contact and received only four doses of rabies vaccine. From January 2010 to September 2011, 118 cases of animal bites were reported in the district; 67 (57%) occurred among males, 65 (57%) in children <15 years old, and 61 (52%) were inflicted in a lower extremity. Domestic and stray dogs accounted for 98% of reported bites. CONCLUSION: Dog bites remains the main source of rabies exposure in the district, but exposure can result from wildlife. This highlights the importance of a one health approach with strong communication between wildlife, veterinary, and human health sectors to improve rabies prevention and control. PMID- 25815093 TI - Knowledge, attitude and practices of HIV post exposure prophylaxis amongst health workers in Lagos University Teaching Hospital. AB - INTRODUCTION: Timely PEP after needle stick exposure to high risk body fluids can reduce the rate of occupational transmission significantly. Ignorance of this may increase the risk of seroconversion to HIV for healthcare workers. This study was conducted with the aim of demonstrating the current level of knowledge and practise of healthcare workers as regards PEP. METHODS: This was a cross sectional study, pretested questionnaire were self administered to 372 health workers from various clinical specialties. The responses were collated and analyzed; results were presented in frequency tables. RESULTS: This study revealed a high level of awareness among the respondents as 83.3% were aware of PEP. Despite the high level of awareness, respondents still have an inadequate knowledge about PEP, only 32% of the respondents could name at least two of the recommended drugs for PEP, only 54.0% of respondents knew when to commence PEP following occupational exposure to HIV. There was a low level of practice of PEP among the respondents as only 6.3% of respondents had PEP despite occurrence of needle stick injury. CONCLUSION: This study revealed a general low level use of PEP despite the average knowledge of PEP and the favourable attitude towards HIV PEP amongst the respondents. PMID- 25815094 TI - [Lisch nodules in Von Recklinghausen disease]. PMID- 25815095 TI - [Giant angioma of the liver]. PMID- 25815096 TI - [Partial invasive and metastatic hydatidiform mole: report of a case]. PMID- 25815097 TI - The uterine choriocarcinoma in postmenopausal women: specificities of diagnosis and treatment. AB - Choriocarcinoma is a gestational trophoblastic tumor that mainly affects women of childbearing age. Cases of choriocarcinoma in postmenopausal women are exceptional. Through an observation and literature review, we propose to study the specific diagnosis and treatment features of this tumor in menopausal women. We report the observation of a pure uterine choriocarcinoma, which occurred in post-menopause. The diagnosis was made on the analysis of surgical specimens confirmed by measurement of hCG. Chemotherapy was started after a total hysterectomy and bilateral salpingo-oophorectomy first. The improvement was dramatic after 3 courses of chemotherapy and the patient is in complete remission after five years of monitoring. The primitive forms of pure choriocarcinoma in postmenopausal women are exceptional. Their etiology is poorly understood and their treatment based on chemotherapy. PMID- 25815099 TI - Mental health of doctors in a tertiary hospital in Nigeria. AB - INTRODUCTION: Doctors are vulnerable to psychiatric morbidity as a result of their busy schedules and multiple role obligations. Yet, they often don't admit they have mental health problems nor are they readily subjected to mental health evaluation by their colleagues due to fear of labeling and general stigma. METHODS: A cross-sectional survey of doctors in the service of University of Ilorin Teaching Hospital, Ilorin, Nigeria was done using a socio-demographic questionnaire and the twelve items General Health Questionnaire (GHQ-12) using a cut-off point of 3 to indicate possibility of psychiatric disorder (GHQ-12 positive). Non-parametric analysis and regression test of factors associated with psychiatric morbidity was done using SPSS. Level of significance was set at 0.05 p-value. RESULTS: Two hundred and forty one doctors representing 68.9% of the doctors participated in the survey. The point prevalence of psychiatric morbidity among the doctors using the GHQ-12 was 14.9%. Being married, non-participation in social activities and perception of work load as being "heavy" were significantly associated with psychiatric morbidity (p-value < 0.05). CONCLUSION: The prevalence of psychiatric morbidity among doctors at the University of Ilorin Teaching Hospital was higher than the general population prevalence. Measures to lessen the negative effect of marriage and the perceived heavy work load on mental health of doctors, such as provision of recreational facilities within the hospital and encouragement of doctors' participation in social activities are advanced. PMID- 25815098 TI - Prevalence of extensively drug-resistant gram negative bacilli in surgical intensive care in Egypt. AB - INTRODUCTION: The prevalence of extensively drug resistant gram negative bacilli (XDR-GNB) is rapidly progressing; however in Egypt data are sparse. We conducted the present study to quantify the incidence, risk factors and outcome of patients harboring XDR-GNB. METHODS: A one year prospective study was done by collecting all the bacteriological reports for cultures sent from the surgical intensive care unit, Cairo university teaching hospital. XDR-GNB were defined as any gram negative bacilli resistant to three or more classes of antimicrobial agents. Patients with XDR-GNB compared with those sustaining non extensively drug resistant infection. A multivariate logistic regression model was created to identify independent predictors of multi-resistance. RESULTS: During one-year study period, a total of 152 samples (65%) out of 234 gram negative bacilli samples developed extensively drug resistant infection. XDR strains were significantly higher in Acinetobacterspp (86%), followed by Pseudomonas (63%), then Proteus (61%), Klebsiella (52%), and E coli (47%). Fourth generation cephalosporine (Cefipime) had the lowest susceptibility (10%) followed by third generation cephalosporines (11%), Quinolones (31%), Amikacin (42%), Tazobactam (52%), Carbapinems (52%), and colistin (90%). Relaparotomy was the only significant risk factor for acquisition of XDR infection. CONCLUSION: Extensively drug-resistant gram negative infections are frequent in our ICU. This is an alarming health care issue in Egypt which emphasizes the need to rigorously implement infection control practices. PMID- 25815100 TI - [ENT primitive extranodal tuberculosis: about 15 cases]. PMID- 25815101 TI - Discrete papular lichen myxedematosus: a rare entity or an under- diagnosed disease? AB - Primary cutaneous mucinoses are characterized by abnormal mucin deposits in the skin. Discrete papular lichenmyxedematosus (DPLM) is an unusual subtype which is characterized by the presence of multiples smooth, waxy, or flesh-colored papules, 2 to 5 mm in size affecting the trunk and limbs and most commonly proximal sites. We report a 42-year-old man with both the clinical and histopathological described criteria. PMID- 25815102 TI - Dyslipidemia, obesity and other cardiovascular risk factors in the adult population in Senegal. AB - INTRODUCTION: According to the WHO, 50% of deaths worldwide (40.1% in developing countries) are due to chronic non-communicable diseases (NCDs). Of these chronic NCDs, cardiovascular diseases remain the leading cause of death and disability in developed countries. The Framingham study has shown the importance of hypercholesterolemia as a primary risk factor. In Senegal, the epidemiology of dyslipidemia and obesity are still poorly understood due to the lack of comprehensive studies on their impact on the general population. This motivated this study to look into the key epidemiologic and socio-demographic determinants of these risk factors. METHODS: It was a cross-sectional descriptive epidemiological survey which included 1037 individuals selected by cluster sampling. Data were collected using a questionnaire following the WHO STEPwise approach. Socio-demographic, health and biomedical variables were collected. P value <0.05 was considered to be statistically significant. RESULTS: The average age was 48 years with a female predominance (M: F of 0.6). The literacy rate was 65.2% and 44.7% of participants were from rural areas. The prevalence of hypercholesterolemia, hyperLDLemia, hypoHDLemia, hypertriglyceridemia and mixed hyperlipidemia were 56%, 22.5%, 12.4%, 7.11% and 1.9% respectively. One in four was obese (BMI> 30kg/m2) and 34.8% had abdominal obesity. The main factors significantly associated with dyslipidemia were obesity, urban dwelling, physical inactivity and a family history of dyslipidemia. CONCLUSION: The prevalence of dyslipidemia, obesity and other risk factors in the population was high needing immediate care for those affected and implementation of prevention strategies. PMID- 25815103 TI - [Seroprevalence of hepatitis C at the Military Hospital Mohammed V of Rabat]. PMID- 25815104 TI - [Vitamin D deficiency in adults in Gabon: isolated case or unrecognized problem?]. PMID- 25815105 TI - Syntax. AB - Syntax is the cognitive capacity of human beings that allows us to connect linguistic meaning with linguistic form. The study of syntax is a huge field that has generated a great deal of empirical and theoretical work over the decades. This article outlines why understanding our syntactic capacity is important to cognitive science in general and why the data of syntactic research is to be taken seriously. It then provides an overview of a number of broad findings about the character of the syntax of human language, including evidence for abstract constituent structure, core properties of constituents, the importance of functional categories, the link between syntactic structure and meaning, and the range of types of syntactic dependencies, including dependencies of form, dependencies of position, and dependencies that create new meanings. WIREs Cogn Sci 2015, 6:131-147. doi: 10.1002/wcs.1332 This article is categorized under: Linguistics > Language in Mind and Brain Linguistics > Linguistic Theory Psychology > Language. PMID- 25815106 TI - P2X7 receptor as a key player in oxidative stress-driven cell fate in nonalcoholic steatohepatitis. AB - Incidences of nonalcoholic fatty liver disease parallels increase in the global obesity epidemic. NAFLD has been shown to be associated with risks of cardiometabolic disorders and kidney disturbances. It is accompanied by insulin and leptin resistance that complicate the diagnosis and treatment of this public health menace. Though significant research is underway for understanding the molecular mechanisms of NAFLD and its subsequent inflammatory and fibrotic manifestations like nonalcoholic steatohepatitis, the role of purinergic receptors has been unclear. It is increasingly being recognized that damage associated molecular patterns like NAD and ATP that are released from injured cells via hepatocellular injury either by oxidative stress or lipotoxicity from steatosis activate the purinergic receptor. Based on evidence from inflammatory responses in the airways and vasculature and autoimmune complications in humans and rodents, it is beyond doubt that hepatocellular inflammation such as that seen in NASH can result from the activation of purinergic receptors. This event can result in the formation of inflammasomes and can be an important pathway for the progression of NASH. The present review evaluates the current knowledge of the role of oxidative stress and its signaling via P2X7 receptors in hepatocellular injury that might contribute to the NASH pathophysiology. PMID- 25815108 TI - Role of circulating miRNAs as biomarkers in idiopathic pulmonary arterial hypertension: possible relevance of miR-23a. AB - Idiopathic pulmonary hypertension (IPAH) is a rare disease characterized by a progressive increase in pulmonary vascular resistance leading to heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that control the expression of genes, including some involved in the progression of IPAH, as studied in animals and lung tissue. These molecules circulate freely in the blood and their expression is associated with the progression of different vascular pathologies. Here, we studied the expression profile of circulating miRNAs in 12 well-characterized IPAH patients using microarrays. We found significant changes in 61 miRNAs, of which the expression of miR23a was correlated with the patients' pulmonary function. We also studied the expression profile of circulating messenger RNA (mRNAs) and found that miR23a controlled 17% of the significantly changed mRNA, including PGC1alpha, which was recently associated with the progression of IPAH. Finally we found that silencing of miR23a resulted in an increase of the expression of PGC1alpha, as well as in its well-known regulated genes CYC, SOD, NRF2, and HO1. The results point to the utility of circulating miRNA expression as a biomarker of disease progression. PMID- 25815109 TI - Association of age-related macular degeneration with erythrocyte antioxidant enzymes activity and serum total antioxidant status. AB - The aim was to estimate association of the oxidative stress with the occurrence of age-related macular degeneration (AMD). The activities of erythrocyte antioxidant enzymes: superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) and additionally serum total antioxidant status (TAS) were used as indicators of the oxidative stress level. 57 AMD patients (32 early and 25 late AMD) and 50 healthy, age and gender matched controls were included. GPx activity (P < 0.001) and serum TAS (P = 0.015) were significantly lower in AMD patients. The difference was not significant for SOD or CAT activities. Significant interaction between GPx and SOD was detected (P = 0.003). At high levels of SOD activity (over 75th percentile), one standard deviation decrease in GPx increases the odds for AMD for six times (OR = 6.22; P < 0.001). ROC analysis revealed that combined values of GPx activity and TAS are significant determinants of AMD status. Accuracy, sensitivity, specificity, and positive and negative predictive values were 75%, 95%, 52%, 69%, and 90%, respectively. The study showed that low GPx activity and TAS are associated with AMD. SOD modulates the association of GPx and AMD. The results suggest that erythrocyte antioxidant enzymes activity and serum TAS could be promising markers for the prediction of AMD. PMID- 25815107 TI - Protective actions of 17beta-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds. AB - Steroid hormones synthesized in and secreted from peripheral endocrine glands pass through the blood-brain barrier and play a role in the central nervous system. In addition, the brain possesses an inherent endocrine system and synthesizes steroid hormones known as neurosteroids. Increasing evidence shows that neuroactive steroids protect the central nervous system from various harmful stimuli. Reports show that the neuroprotective actions of steroid hormones attenuate oxidative stress. In this review, we summarize the antioxidative effects of neuroactive steroids, especially 17beta-estradiol and progesterone, on neuronal injury in the central nervous system under various pathological conditions, and then describe our recent findings concerning the neuroprotective actions of 17beta-estradiol and progesterone on oxidative neuronal injury induced by organometallic compounds, tributyltin, and methylmercury. PMID- 25815110 TI - Diabetes and Alzheimer disease, two overlapping pathologies with the same background: oxidative stress. AB - There are several oxidative stress-related pathways interconnecting Alzheimer's disease and type II diabetes, two public health problems worldwide. Coincidences are so compelling that it is attractive to speculate they are the same disorder. However, some pathological mechanisms as observed in diabetes are not necessarily the same mechanisms related to Alzheimer's or the only ones related to Alzheimer's pathology. Oxidative stress is inherent to Alzheimer's and feeds a vicious cycle with other key pathological features, such as inflammation and Ca(2+) dysregulation. Alzheimer's pathology by itself may lead to insulin resistance in brain, insulin resistance being an intervening variable in the neurodegenerative disorder. Hyperglycemia and insulin resistance from diabetes, overlapping with the Alzheimer's pathology, aggravate the progression of the neurodegenerative processes, indeed. But the same pathophysiological background is behind the consequences, oxidative stress. We emphasize oxidative stress and its detrimental role in some key regulatory enzymes. PMID- 25815111 TI - SIRT1 and stem cells: In the forefront with cardiovascular disease, neurodegeneration and cancer. AB - Cardiovascular disease, nervous system disorders, and cancer in association with other diseases such as diabetes mellitus result in greater than sixty percent of the global annual deaths. These noncommunicable diseases also affect at least one third of the population in low and middle-income countries and lead to hypertension, elevated cholesterol, malignancy, and neurodegenerative disorders such as Alzheimer's disease and stroke. With the climbing lifespan of the world's population, increased prevalence of these disorders is expected requiring the development of new therapeutic strategies against these disabling disease entities. Targeting stem cell proliferation for cardiac disease, vascular disorders, cancer, and neurodegenerative disorders is receiving great enthusiasm, especially those that focus upon SIRT1, a mammalian homologue of the yeast silent information regulator-2. Modulation of the cellular activity of SIRT1 can involve oversight by nicotinamide/nicotinic acid mononucleotide adenylyltransferase, mammalian forkhead transcription factors, mechanistic of rapamycin pathways, and cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma over-expressed gene family members that can impact cytoprotective outcomes. Ultimately, the ability of SIRT1 to control the programmed cell death pathways of apoptosis and autophagy can determine not only cardiac, vascular, and neuronal stem cell development and longevity, but also the onset of tumorigenesis and the resistance against chemotherapy. SIRT1 therefore has a critical role and holds exciting prospects for new therapeutic strategies that can offer reparative processes for cardiac, vascular, and nervous system degenerative disorders as well as targeted control of aberrant cell growth during cancer. PMID- 25815112 TI - Substrates for clinical applicability of stem cells. AB - The capability of human pluripotent stem cells (hPSCs) to differentiate into a variety of cells in the human body holds great promise for regenerative medicine. Many substrates exist on which hPSCs can be self-renewed, maintained and expanded to further the goal of clinical application of stem cells. In this review, we highlight numerous extracellular matrix proteins, peptide and polymer based substrates, scaffolds and hydrogels that have been pioneered. We discuss their benefits and shortcomings and offer future directions as well as emphasize commercially available synthetic peptides as a type of substrate that can bring the benefits of regenerative medicine to clinical settings. PMID- 25815113 TI - Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment. AB - The tumor microenvironment (TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancer associated adipocyte (CAA) and the cancer-associated fibroblast (CAF). In the clinic, the presence of CAAs and CAFs in the TME translates to poor prognosis in multiple tumor types. CAAs and CAFs have an activated phenotype and produce growth factors, inflammatory factors, cytokines, chemokines, extracellular matrix components, and proteases in an accelerated and aberrant fashion. Through this activated state, CAAs and CAFs remodel the TME, thereby driving all aspects of tumor progression, including tumor growth and survival, chemoresistance, tumor vascularization, tumor invasion, and tumor cell metastasis. Similarities in the tumor-promoting functions of CAAs and CAFs suggest that a multipronged therapeutic approach may be necessary to achieve maximal impact on disease. While CAAs and CAFs are thought to arise from tissues adjacent to the tumor, multiple alternative origins for CAAs and CAFs have recently been identified. Recent studies from our lab and others suggest that the hematopoietic stem cell, through the myeloid lineage, may serve as a progenitor for CAAs and CAFs. We hypothesize that the multiple origins of CAAs and CAFs may contribute to the heterogeneity seen in the TME. Thus, a better understanding of the origin of CAAs and CAFs, how this origin impacts their functions in the TME, and the temporal participation of uniquely originating TME cells may lead to novel or improved anti-tumor therapeutics. PMID- 25815114 TI - Role of nanotopography in the development of tissue engineered 3D organs and tissues using mesenchymal stem cells. AB - Recent regenerative medicine and tissue engineering strategies (using cells, scaffolds, medical devices and gene therapy) have led to fascinating progress of translation of basic research towards clinical applications. In the past decade, great deal of research has focused on developing various three dimensional (3D) organs, such as bone, skin, liver, kidney and ear, using such strategies in order to replace or regenerate damaged organs for the purpose of maintaining or restoring organs' functions that may have been lost due to aging, accident or disease. The surface properties of a material or a device are key aspects in determining the success of the implant in biomedicine, as the majority of biological reactions in human body occur on surfaces or interfaces. Furthermore, it has been established in the literature that cell adhesion and proliferation are, to a great extent, influenced by the micro- and nano-surface characteristics of biomaterials and devices. In addition, it has been shown that the functions of stem cells, mesenchymal stem cells in particular, could be regulated through physical interaction with specific nanotopographical cues. Therefore, guided stem cell proliferation, differentiation and function are of great importance in the regeneration of 3D tissues and organs using tissue engineering strategies. This review will provide an update on the impact of nanotopography on mesenchymal stem cells for the purpose of developing laboratory-based 3D organs and tissues, as well as the most recent research and case studies on this topic. PMID- 25815115 TI - Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance. AB - In this review we evaluate evidence for three different hypotheses that explain how the corneal epithelium is maintained. The limbal epithelial stem cell (LESC) hypothesis is most widely accepted. This proposes that stem cells in the basal layer of the limbal epithelium, at the periphery of the cornea, maintain themselves and also produce transient (or transit) amplifying cells (TACs). TACs then move centripetally to the centre of the cornea in the basal layer of the corneal epithelium and also replenish cells in the overlying suprabasal layers. The LESCs maintain the corneal epithelium during normal homeostasis and become more active to repair significant wounds. Second, the corneal epithelial stem cell (CESC) hypothesis postulates that, during normal homeostasis, stem cells distributed throughout the basal corneal epithelium, maintain the tissue. According to this hypothesis, LESCs are present in the limbus but are only active during wound healing. We also consider a third possibility, that the corneal epithelium is maintained during normal homeostasis by proliferation of basal corneal epithelial cells without any input from stem cells. After reviewing the published evidence, we conclude that the LESC and CESC hypotheses are consistent with more of the evidence than the third hypothesis, so we do not consider this further. The LESC and CESC hypotheses each have difficulty accounting for one main type of evidence so we evaluate the two key lines of evidence that discriminate between them. Finally, we discuss how lineage-tracing experiments have begun to resolve the debate in favour of the LESC hypothesis. Nevertheless, it also seems likely that some basal corneal epithelial cells can act as long term progenitors if limbal stem cell function is compromised. Thus, this aspect of the CESC hypothesis may have a lasting impact on our understanding of corneal epithelial maintenance, even if it is eventually shown that stem cells are restricted to the limbus as proposed by the LESC hypothesis. PMID- 25815116 TI - Imprinted Zac1 in neural stem cells. AB - Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging. PMID- 25815117 TI - Induced pluripotent stem cells: Mechanisms, achievements and perspectives in farm animals. AB - Pluripotent stem cells are unspecialized cells with unlimited self-renewal, and they can be triggered to differentiate into desired specialized cell types. These features provide the basis for an unlimited cell source for innovative cell therapies. Pluripotent cells also allow to study developmental pathways, and to employ them or their differentiated cell derivatives in pharmaceutical testing and biotechnological applications. Via blastocyst complementation, pluripotent cells are a favoured tool for the generation of genetically modified mice. The recently established technology to generate an induced pluripotency status by ectopic co-expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc allows to extending these applications to farm animal species, for which the derivation of genuine embryonic stem cells was not successful so far. Most induced pluripotent stem (iPS) cells are generated by retroviral or lentiviral transduction of reprogramming factors. Multiple viral integrations into the genome may cause insertional mutagenesis and may increase the risk of tumour formation. Non-integration methods have been reported to overcome the safety concerns associated with retro and lentiviral-derived iPS cells, such as transient expression of the reprogramming factors using episomal plasmids, and direct delivery of reprogramming mRNAs or proteins. In this review, we focus on the mechanisms of cellular reprogramming and current methods used to induce pluripotency. We also highlight problems associated with the generation of iPS cells. An increased understanding of the fundamental mechanisms underlying pluripotency and refining the methodology of iPS cell generation will have a profound impact on future development and application in regenerative medicine and reproductive biotechnology of farm animals. PMID- 25815118 TI - Cardiac disease modeling using induced pluripotent stem cell-derived human cardiomyocytes. AB - Causative mutations and variants associated with cardiac diseases have been found in genes encoding cardiac ion channels, accessory proteins, cytoskeletal components, junctional proteins, and signaling molecules. In most cases the functional evaluation of the genetic alteration has been carried out by expressing the mutated proteins in in-vitro heterologous systems. While these studies have provided a wealth of functional details that have greatly enhanced the understanding of the pathological mechanisms, it has always been clear that heterologous expression of the mutant protein bears the intrinsic limitation of the lack of a proper intracellular environment and the lack of pathological remodeling. The results obtained from the application of the next generation sequencing technique to patients suffering from cardiac diseases have identified several loci, mostly in non-coding DNA regions, which still await functional analysis. The isolation and culture of human embryonic stem cells has initially provided a constant source of cells from which cardiomyocytes (CMs) can be obtained by differentiation. Furthermore, the possibility to reprogram cellular fate to a pluripotent state, has opened this process to the study of genetic diseases. Thus induced pluripotent stem cells (iPSCs) represent a completely new cellular model that overcomes the limitations of heterologous studies. Importantly, due to the possibility to keep spontaneously beating CMs in culture for several months, during which they show a certain degree of maturation/aging, this approach will also provide a system in which to address the effect of long term expression of the mutated proteins or any other DNA mutation, in terms of electrophysiological remodeling. Moreover, since iPSC preserve the entire patients' genetic context, the system will help the physicians in identifying the most appropriate pharmacological intervention to correct the functional alteration. This article summarizes the current knowledge of cardiac genetic diseases modelled with iPSC. PMID- 25815119 TI - Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy? AB - Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells (regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient's immune system, and repairs the injured tissue. PMID- 25815121 TI - Mesenchymal stem cells as a therapeutic tool to treat sepsis. AB - Sepsis is a clinical syndrome caused by a deregulated host response to an infection. Sepsis is the most frequent cause of death in hospitalized patients. Although knowledge of the pathogenesis of sepsis has increased substantially during the last decades, attempts to design effective and specific therapies targeting components of the derailed host response have failed. Therefore, there is a dramatic need for new and mechanistically alternative therapies to treat this syndrome. Based on their immunomodulatory properties, adult mesenchymal stem or stromal cells (MSCs) can be a novel therapeutic tool to treat sepsis. Indeed, MSCs reduce mortality in experimental models of sepsis by modulating the deregulated inflammatory response against bacteria through the regulation of multiple inflammatory networks, the reprogramming of macrophages and neutrophils towards a more anti-inflammatory phenotype and the release of anti-microbial peptides. This report will review the current knowledge on the effects of MSC treatment in preclinical experimental small animal models of sepsis. PMID- 25815120 TI - "Second-generation" stem cells for cardiac repair. AB - Over the last years, stem cell therapy has emerged as an inspiring alternative to restore cardiac function after myocardial infarction. A large body of evidence has been obtained in this field but there is no conclusive data on the efficacy of these treatments. Preclinical studies and early reports in humans have been encouraging and have fostered a rapid clinical translation, but positive results have not been uniformly observed and when present, they have been modest. Several types of stem cells, manufacturing methods and delivery routes have been tested in different clinical settings but direct comparison between them is challenging and hinders further research. Despite enormous achievements, major barriers have been found and many fundamental issues remain to be resolved. A better knowledge of the molecular mechanisms implicated in cardiac development and myocardial regeneration is critically needed to overcome some of these hurdles. Genetic and pharmacological priming together with the discovery of new sources of cells have led to a "second generation" of cell products that holds an encouraging promise in cardiovascular regenerative medicine. In this report, we review recent advances in this field focusing on the new types of stem cells that are currently being tested in human beings and on the novel strategies employed to boost cell performance in order to improve cardiac function and outcomes after myocardial infarction. PMID- 25815123 TI - Tooth-derived stem cells: Update and perspectives. AB - Tissue engineering is an emerging field of science that focuses on creating suitable conditions for the regeneration of tissues. The basic components for tissue engineering involve an interactive triad of scaffolds, signaling molecules, and cells. In this context, stem cells (SCs) present the characteristics of self-renewal and differentiation capacity, which make them promising candidates for tissue engineering. Although they present some common markers, such as cluster of differentiation (CD)105, CD146 and STRO-1, SCs derived from various tissues have different patterns in relation to proliferation, clonogenicity, and differentiation abilities in vitro and in vivo. Tooth-derived tissues have been proposed as an accessible source to obtain SCs with limited morbidity, and various tooth-derived SCs (TDSCs) have been isolated and characterized, such as dental pulp SCs, SCs from human exfoliated deciduous teeth, periodontal ligament SCs, dental follicle progenitor cells, SCs from apical papilla, and periodontal ligament of deciduous teeth SCs. However, heterogeneity among these populations has been observed, and the best method to select the most appropriate TDSCs for regeneration approaches has not yet been established. The objective of this review is to outline the current knowledge concerning the various types of TDSCs, and discuss the perspectives for their use in regenerative approaches. PMID- 25815122 TI - Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury. AB - Neglected for years, astrocytes are now recognized to fulfill and support many, if not all, homeostatic functions of the healthy central nervous system (CNS). During neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI), astrocytes in the vicinity of degenerating areas undergo both morphological and functional changes that might compromise their intrinsic properties. Evidence from human and animal studies show that deficient astrocyte functions or loss-of-astrocytes largely contribute to increased susceptibility to cell death for neurons, oligodendrocytes and axons during ALS and SCI disease progression. Despite exciting advances in experimental CNS repair, most of current approaches that are translated into clinical trials focus on the replacement or support of spinal neurons through stem cell transplantation, while none focus on the specific replacement of astroglial populations. Knowing the important functions carried out by astrocytes in the CNS, astrocyte replacement-based therapies might be a promising approach to alleviate overall astrocyte dysfunction, deliver neurotrophic support to degenerating spinal tissue and stimulate endogenous CNS repair abilities. Enclosed in this review, we gathered experimental evidence that argue in favor of astrocyte transplantation during ALS and SCI. Based on their intrinsic properties and according to the cell type transplanted, astrocyte precursors or stem cell derived astrocytes promote axonal growth, support mechanisms and cells involved in myelination, are able to modulate the host immune response, deliver neurotrophic factors and provide protective molecules against oxidative or excitotoxic insults, amongst many possible benefits. Embryonic or adult stem cells can even be genetically engineered in order to deliver missing gene products and therefore maximize the chance of neuroprotection and functional recovery. However, before broad clinical translation, further preclinical data on safety, reliability and therapeutic efficiency should be collected. Although several technical challenges need to be overcome, we discuss the major hurdles that have already been met or solved by targeting the astrocyte population in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology. PMID- 25815124 TI - Could cancer and infection be adverse effects of mesenchymal stromal cell therapy? AB - Multipotent mesenchymal stromal cells [also referred to as mesenchymal stem cells (MSCs)] are a heterogeneous subset of stromal cells. They can be isolated from bone marrow and many other types of tissue. MSCs are currently being tested for therapeutic purposes (i.e., improving hematopoietic stem cell engraftment, managing inflammatory diseases and regenerating damaged organs). Their tropism for tumors and inflamed sites and their context-dependent potential for producing trophic and immunomodulatory factors raises the question as to whether MSCs promote cancer and/or infection. This article reviews the effect of MSCs on tumor establishment, growth and metastasis and also susceptibility to infection and its progression. Data published to date shows a paradoxical effect regarding MSCs, which seems to depend on isolation and expansion, cells source and dose and the route and timing of administration. Cancer and infection may thus be adverse or therapeutic effects arising form MSC administration. PMID- 25815125 TI - Mitochondria as therapeutic targets for cancer stem cells. AB - Cancer stem cells (CSCs) are maintained by their somatic stem cells and are responsible for tumor initiation, chemoresistance, and metastasis. Evidence for the CSCs existence has been reported for a number of human cancers. The CSC mitochondria have been shown recently to be an important target for cancer treatment, but clinical significance of CSCs and their mitochondria properties remain unclear. Mitochondria-targeted agents are considerably more effective compared to other agents in triggering apoptosis of CSCs, as well as general cancer cells, via mitochondrial dysfunction. Mitochondrial metabolism is altered in cancer cells because of their reliance on glycolytic intermediates, which are normally destined for oxidative phosphorylation. Therefore, inhibiting cancer specific modifications in mitochondrial metabolism, increasing reactive oxygen species production, or stimulating mitochondrial permeabilization transition could be promising new therapeutic strategies to activate cell death in CSCs as well, as in general cancer cells. This review analyzed mitochondrial function and its potential as a therapeutic target to induce cell death in CSCs. Furthermore, combined treatment with mitochondria-targeted drugs will be a promising strategy for the treatment of relapsed and refractory cancer. PMID- 25815126 TI - Vital roles of stem cells and biomaterials in skin tissue engineering. AB - Tissue engineering essentially refers to technology for growing new human tissue and is distinct from regenerative medicine. Currently, pieces of skin are already being fabricated for clinical use and many other tissue types may be fabricated in the future. Tissue engineering was first defined in 1987 by the United States National Science Foundation which critically discussed the future targets of bioengineering research and its consequences. The principles of tissue engineering are to initiate cell cultures in vitro, grow them on scaffolds in situ and transplant the composite into a recipient in vivo. From the beginning, scaffolds have been necessary in tissue engineering applications. Regardless, the latest technology has redirected established approaches by omitting scaffolds. Currently, scientists from diverse research institutes are engineering skin without scaffolds. Due to their advantageous properties, stem cells have robustly transformed the tissue engineering field as part of an engineered bilayered skin substitute that will later be discussed in detail. Additionally, utilizing biomaterials or skin replacement products in skin tissue engineering as strategy to successfully direct cell proliferation and differentiation as well as to optimize the safety of handling during grafting is beneficial. This approach has also led to the cells' application in developing the novel skin substitute that will be briefly explained in this review. PMID- 25815127 TI - Neural differentiation from embryonic stem cells in vitro: An overview of the signaling pathways. AB - Neurons derived from embryonic stem cells (ESCs) have gained great merit in both basic research and regenerative medicine. Here we review and summarize the signaling pathways that have been reported to be involved in the neuronal differentiation of ESCs, particularly those associated with in vitro differentiation. The inducers and pathways explored include retinoic acid, Wnt/beta-catenin, transforming growth factor/bone morphogenetic protein, Notch, fibroblast growth factor, cytokine, Hedgehog, c-Jun N-terminal kinase/mitogen activated protein kinase and others. Some other miscellaneous molecular factors that have been reported in the literature are also summarized and discussed. These include calcium, calcium receptor, calcineurin, estrogen receptor, Hox protein, ceramide, glycosaminioglycan, ginsenoside Rg1, opioids, two pore channel 2, nitric oxide, chemically defined medium, cell-cell interactions, and physical stimuli. The interaction or crosstalk between these signaling pathways and factors will be explored. Elucidating these signals in detail should make a significant contribution to future progress in stem cell biology and allow, for example, better comparisons to be made between differentiation in vivo and in vitro. Of equal importance, a comprehensive understanding of the pathways that are involved in the development of neurons from ESCs in vitro will also accelerate their application as part of translational medicine. PMID- 25815128 TI - Importance of the stem cell microenvironment for ophthalmological cell-based therapy. AB - Cell therapy is a promising treatment for diseases that are caused by cell degeneration or death. The cells for clinical transplantation are usually obtained by culturing healthy allogeneic or exogenous tissue in vitro. However, for diseases of the eye, obtaining the adequate number of cells for clinical transplantation is difficult due to the small size of tissue donors and the frequent needs of long-term amplification of cells in vitro, which results in low cell viability after transplantation. In addition, the transplanted cells often develop fibrosis or degrade and have very low survival. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS) are also promising candidates for cell therapy. Unfortunately, the differentiation of ESCs can bring immune rejection, tumorigenicity and undesired differentiated cells, limiting its clinical application. Although iPS cells can avoid the risk of immune rejection caused by ES cell differentiation post-transplantation, the low conversion rate, the risk of tumor formation and the potentially unpredictable biological changes that could occur through genetic manipulation hinder its clinical application. Thus, the desired clinical effect of cell therapy is impaired by these factors. Recent research findings recognize that the reason for low survival of the implanted cells not only depends on the seeded cells, but also on the cell microenvironment, which determines the cell survival, proliferation and even reverse differentiation. When used for cell therapy, the transplanted cells need a specific three-dimensional structure to anchor and specific extra cellular matrix components in addition to relevant cytokine signaling to transfer the required information to support their growth. These structures present in the matrix in which the stem cells reside are known as the stem cell microenvironment. The microenvironment interaction with the stem cells provides the necessary homeostasis for cell maintenance and growth. A large number of studies suggest that to explore how to reconstruct the stem cell microenvironment and strengthen its combination with the transplanted cells are key steps to successful cell therapy. In this review, we will describe the interactions of the stem cell microenvironment with the stem cells, discuss the importance of the stem cell microenvironment for cell-based therapy in ocular diseases, and introduce the progress of stem cell-based therapy for ocular diseases. PMID- 25815129 TI - Using induced pluripotent stem cells as a tool for modelling carcinogenesis. AB - Cancer is a highly heterogeneous group of diseases that despite improved treatments remain prevalent accounting for over 14 million new cases and 8.2 million deaths per year. Studies into the process of carcinogenesis are limited by lack of appropriate models for the development and pathogenesis of the disease based on human tissues. Primary culture of patient samples can help but is difficult to grow for a number of tissues. A potential opportunity to overcome these barriers is based on the landmark study by Yamanaka which demonstrated the ability of four factors; Oct4, Sox2, Klf4, and c-Myc to reprogram human somatic cells in to pluripotency. These cells were termed induced pluripotent stem cells (iPSCs) and display characteristic properties of embryonic stem cells. This technique has a wide range of potential uses including disease modelling, drug testing and transplantation studies. Interestingly iPSCs also share a number of characteristics with cancer cells including self-renewal and proliferation, expression of stem cell markers and altered metabolism. Recently, iPSCs have been generated from a number of human cancer cell lines and primary tumour samples from a range of cancers in an attempt to recapitulate the development of cancer and interrogate the underlying mechanisms involved. This review will outline the similarities between the reprogramming process and carcinogenesis, and how these similarities have been exploited to generate iPSC models for a number of cancers. PMID- 25815130 TI - CD271 as a marker to identify mesenchymal stem cells from diverse sources before culture. AB - Mesenchymal stem cells, due to their characteristics are ideal candidates for cellular therapy. Currently, in culture these cells are defined by their adherence to plastic, specific surface antigen expression and multipotent differentiation potential. However, the in vivo identification of mesenchymal stem cells, before culture, is not so well established. Pre-culture identification markers would ensure higher purity than that obtained with selection based on adherence to plastic. Up until now, CD271 has been described as the most specific marker for the characterization and purification of human bone marrow mesenchymal stem cells. This marker has been shown to be specifically expressed by these cells. Thus, CD271 has been proposed as a versatile marker to selectively isolated and expand multipotent mesenchymal stem cells with both immunosuppressive and lymphohematopoietic engraftment-promoting properties. This review focuses on this marker, specifically on identification of mesenchymal stem cells from different tissues. Literature revision suggests that CD271 should not be defined as a universal marker to identify mesenchymal stem cells before culture from different sources. In the case of bone marrow or adipose tissue, CD271 could be considered a quite suitable marker; however this marker seems to be inadequate for the isolation of mesenchymal stem cells from other tissues such as umbilical cord blood or wharton's jelly among others. PMID- 25815131 TI - Adult stem cells in neural repair: Current options, limitations and perspectives. AB - Stem cells represent a promising step for the future of regenerative medicine. As they are able to differentiate into any cell type, tissue or organ, these cells are great candidates for treatments against the worst diseases that defy doctors and researchers around the world. Stem cells can be divided into three main groups: (1) embryonic stem cells; (2) fetal stem cells; and (3) adult stem cells. In terms of their capacity for proliferation, stem cells are also classified as totipotent, pluripotent or multipotent. Adult stem cells, also known as somatic cells, are found in various regions of the adult organism, such as bone marrow, skin, eyes, viscera and brain. They can differentiate into unipotent cells of the residing tissue, generally for the purpose of repair. These cells represent an excellent choice in regenerative medicine, every patient can be a donor of adult stem cells to provide a more customized and efficient therapy against various diseases, in other words, they allow the opportunity of autologous transplantation. But in order to start clinical trials and achieve great results, we need to understand how these cells interact with the host tissue, how they can manipulate or be manipulated by the microenvironment where they will be transplanted and for how long they can maintain their multipotent state to provide a full regeneration. PMID- 25815132 TI - Development of cancer-initiating cells and immortalized cells with genomic instability. AB - Cancers that develop after middle age usually exhibit genomic instability and multiple mutations. This is in direct contrast to pediatric tumors that usually develop as a result of specific chromosomal translocations and epigenetic aberrations. The development of genomic instability is associated with mutations that contribute to cellular immortalization and transformation. Cancer occurs when cancer-initiating cells (CICs), also called cancer stem cells, develop as a result of these mutations. In this paper, we explore how CICs develop as a result of genomic instability, including looking at which cancer suppression mechanisms are abrogated. A recent in vitro study revealed the existence of a CIC induction pathway in differentiating stem cells. Under aberrant differentiation conditions, cells become senescent and develop genomic instabilities that lead to the development of CICs. The resulting CICs contain a mutation in the alternative reading frame of CDKN2A (ARF)/p53 module, i.e., in either ARF or p53. We summarize recently established knowledge of CIC development and cellular immortality, explore the role of the ARF/p53 module in protecting cells from transformation, and describe a risk factor for genomic destabilization that increases during the process of normal cell growth and differentiation and is associated with the downregulation of histone H2AX to levels representative of growth arrest in normal cells. PMID- 25815133 TI - Adult stem-like cells in kidney. AB - Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration. PMID- 25815134 TI - Niche interactions in epidermal stem cells. AB - Within the epidermis and dermis of the skin, cells secrete and are surrounded by the extracellular matrix (ECM), which provides structural and biochemical support. The ECM of the epidermis is the basement membrane, and collagen and other dermal components constitute the ECM of the dermis. There is significant variation in the composition of the ECM of the epidermis and dermis, which can affect "cell to cell" and "cell to ECM" interactions. These interactions, in turn, can influence biological responses, aging, and wound healing; abnormal ECM signaling likely contributes to skin diseases. Thus, strategies for manipulating cell-ECM interactions are critical for treating wounds and a variety of skin diseases. Many of these strategies focus on epidermal stem cells, which reside in a unique niche in which the ECM is the most important component; interactions between the ECM and epidermal stem cells play a major role in regulating stem cell fate. As they constitute a major portion of the ECM, it is likely that integrins and type IV collagens are important in stem cell regulation and maintenance. In this review, we highlight recent research-including our previous work-exploring the role that the ECM and its associated components play in shaping the epidermal stem cell niche. PMID- 25815135 TI - Neural stem cells could serve as a therapeutic material for age-related neurodegenerative diseases. AB - Progressively loss of neural and glial cells is the key event that leads to nervous system dysfunctions and diseases. Several neurodegenerative diseases, for instance Alzheimer's disease, Parkinson's disease, and Huntington's disease, are associated to aging and suggested to be a consequence of deficiency of neural stem cell pool in the affected brain regions. Endogenous neural stem cells exist throughout life and are found in specific niches of human brain. These neural stem cells are responsible for the regeneration of new neurons to restore, in the normal circumstance, the functions of the brain. Endogenous neural stem cells can be isolated, propagated, and, notably, differentiated to most cell types of the brain. On the other hand, other types of stem cells, such as mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells can also serve as a source for neural stem cell production, that hold a great promise for regeneration of the brain. The replacement of neural stem cells, either endogenous or stem cell-derived neural stem cells, into impaired brain is highly expected as a possible therapeutic mean for neurodegenerative diseases. In this review, clinical features and current routinely treatments of age-related neurodegenerative diseases are documented. Noteworthy, we presented the promising evidence of neural stem cells and their derivatives in curing such diseases, together with the remaining challenges to achieve the best outcome for patients. PMID- 25815136 TI - Molecular mechanism of extrinsic factors affecting anti-aging of stem cells. AB - Scientific evidence suggests that stem cells possess the anti-aging ability to self-renew and maintain differentiation potentials, and quiescent state. The objective of this review is to discuss the micro-environment where stem cells reside in vivo, the secreted factors to which stem cells are exposed, the hypoxic environment, and intracellular factors including genome stability, mitochondria integrity, epigenetic regulators, calorie restrictions, nutrients, and vitamin D. Secreted tumor growth factor-beta and fibroblast growth factor-2 are reported to play a role in stem cell quiescence. Extracellular matrices may interact with caveolin-1, the lipid raft on cell membrane to regulate quiescence. N-cadherin, the adhesive protein on niche cells provides support for stem cells. The hypoxic micro-environment turns on hypoxia-inducible factor-1 to prevent mesenchymal stem cells aging through p16 and p21 down-regulation. Mitochondria express glucosephosphate isomerase to undergo glycolysis and prevent cellular aging. Epigenetic regulators such as p300, protein inhibitors of activated Stats and H19 help maintain stem cell quiescence. In addition, calorie restriction may lead to secretion of paracrines cyclic ADP-ribose by intestinal niche cells, which help maintain intestinal stem cells. In conclusion, it is crucial to understand the anti-aging phenomena of stem cells at the molecular level so that the key to solving the aging mystery may be unlocked. PMID- 25815137 TI - Mesenchymal stem cells and collagen patches for anterior cruciate ligament repair. AB - AIM: To investigate collagen patches seeded with mesenchymal stem cells (MSCs) and/or tenocytes (TCs) with regards to their suitability for anterior cruciate ligament (ACL) repair. METHODS: Dynamic intraligamentary stabilization utilizes a dynamic screw system to keep ACL remnants in place and promote biological healing, supplemented by collagen patches. How these scaffolds interact with cells and what type of benefit they provide has not yet been investigated in detail. Primary ACL-derived TCs and human bone marrow derived MSCs were seeded onto two different types of 3D collagen scaffolds, Chondro-Gide((r)) (CG) and Novocart((r)) (NC). Cells were seeded onto the scaffolds and cultured for 7 d either as a pure populations or as "premix" containing a 1:1 ratio of TCs to MSCs. Additionally, as controls, cells were seeded in monolayers and in co cultures on both sides of porous high-density membrane inserts (0.4 MUm). We analyzed the patches by real time polymerase chain reaction, glycosaminoglycan (GAG), DNA and hydroxy-proline (HYP) content. To determine cell spreading and adherence in the scaffolds microscopic imaging techniques, i.e., confocal laser scanning microscopy (cLSM) and scanning electron microscopy (SEM), were applied. RESULTS: CLSM and SEM imaging analysis confirmed cell adherence onto scaffolds. The metabolic cell activity revealed that patches promote adherence and proliferation of cells. The most dramatic increase in absolute metabolic cell activity was measured for CG samples seeded with tenocytes or a 1:1 cell premix. Analysis of DNA content and cLSM imaging also indicated MSCs were not proliferating as nicely as tenocytes on CG. The HYP to GAG ratio significantly changed for the premix group, resulting from a slightly lower GAG content, demonstrating that the cells are modifying the underlying matrix. Real-time quantitative polymerase chain reaction data indicated that MSCs showed a trend of differentiation towards a more tenogenic-like phenotype after 7 d. CONCLUSION: CG and NC are both cyto-compatible with primary MSCs and TCs; TCs seemed to perform better on these collagen patches than MSCs. PMID- 25815138 TI - Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action. AB - A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled. PMID- 25815139 TI - Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors. AB - Designing multitarget drugs remains a significant challenge in current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase I/II and HDAC with good antiproliferative and apoptotic activities. This proof-of concept study also validated the effectiveness of discovering triple topoisomerase I/II and HDAC inhibitors as novel antitumor agents. PMID- 25815140 TI - Identification of 8-aminoadenosine derivatives as a new class of human concentrative nucleoside transporter 2 inhibitors. AB - Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was required. By modifying adenosine, an hCNT2 substrate, we successfully identified 8-aminoadenosine derivatives as a new class of hCNT2 inhibitors. Compound 12 moderately inhibited hCNT2 (IC50 = 52 +/- 3.8 MUM), and subsequent structure activity relationship studies led to the discovery of compound 48 (IC50 = 0.64 +/ 0.19 MUM). Here we describe significant findings about structural requirements of 8-aminoadenosine derivatives for exhibiting potent hCNT2 inhibitory activity. PMID- 25815141 TI - Synthesis and Evaluation of Conjugates of Novel TLR7 Inert Ligands as Self Adjuvanting Immunopotentiators. AB - During the design and synthesis of a series of 8-hydroxy-2-(2-methoxyethoxy) adenine derivatives bearing various substituted -RCOOH groups at the 9-position, we identified a TLR7-inert ligand, which does not activate TLR7 signaling pathway. Of interest, the coupling of weakly immunogenic antigens via the -RCOOH group was able to significantly enhance the immunogenicity of the antigens. Herein, an inert ligand, 9-(3-carboxypropyl)-8-hydroxy-2-(2-methoxyethoxy) adenine (5, GD2), was synthesized and conjugated to 5 different weakly immunogenic antigens (BSA, OVA, MSA, MG7, and thymosin). Compared with the GD2 and the potent agonist UC-1 V150, all conjugates demonstrated potent immunogenicity in vitro and in vivo. All conjugates induced prolonged increases, while UC-1 V150 showed a rapid decline in the levels of proinflammatory cytokines following initial increases. These data indicate that the immunostimulatory activity of TLR7-inert ligands could be amplified and prolonged by conjugation to antigens, thus broadening the potential therapeutic application of these agents. PMID- 25815142 TI - Pyrimidinone nicotinamide mimetics as selective tankyrase and wnt pathway inhibitors suitable for in vivo pharmacology. AB - The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germline mutations of several Wnt pathway components, such as Axin, APC, and beta-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARP) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100-fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms. PMID- 25815144 TI - Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist. AB - GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic beta-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats. PMID- 25815143 TI - N (1)-Fluoroalkyltryptophan Analogues: Synthesis and in vitro Study as Potential Substrates for Indoleamine 2,3-Dioxygenase. AB - Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of l-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive properties in inflammatory and tumoral tissues. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-FETrp) and 1-((1-(2 fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N (1)-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of hIDO show that 1-FETrp is a good and specific substrate of hIDO. Therefore, its radioactive isotopomer, 1-[(18)F]FETrp, should be a molecule of choice to visualize tumoral and inflammatory tissues and/or to validate new potential inhibitors. PMID- 25815145 TI - Synthesis of a New Peptide-Coumarin Conjugate: A Potential Agent against Cryptococcosis. AB - Antimicrobial peptides (AMPs) are currently being investigated as potential sources of novel therapeutics against an increasing number of microorganisms resistant to conventional antibiotics. The conjugation of an AMP to other bioactive compounds is an interesting approach for the development of new derivatives with increased antimicrobial efficiency and broader spectra of action. In this work, the synthesis of a new peptide-coumarin conjugate via copper(I)-catalyzed azide-alkyne cycloaddition is described. The conjugate was assayed for in vitro cytotoxicity and displayed antifungal activity against Cryptococcus gattii and Cryptococcus neoformans. Additionally, the conjugate exhibited increased antifungal efficacy when compared with the individual peptide, coumarin, or triazole moieties. Treatment of C. gattii with the peptide coumarin conjugate enhanced the production of reactive oxygen species, suggesting that the oxidative burst plays an important role in the mechanism of action of the conjugate. PMID- 25815146 TI - Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors. AB - A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12. PMID- 25815147 TI - Synthesis and Structure-Activity Relationship Study of 1-Phenyl-1-(quinazolin-4 yl)ethanols as Anticancer Agents. AB - A quinazoline derivative PVHD121 (1a) was shown to have strong antiproliferative activity against various tumor-derived cell lines, including A549 (lung), NCI H460 (lung), HCT116 (colon), MCF7 (breast), PC3 (prostate), and HeLa (cervical) cells with IC50 values from 0.1 to 0.3 MUM. A structure-activity relationship (SAR) study at the 2- and 4-position of the quinazoline core lead to the discovery of more potent anticancer agents (14, 16, 17, 19, 24, and 31). The results of an in vitro tubulin polymerization assay and fluorescent-based colchicine site competition assay with purified tubulin indicated that 1a inhibits tubulin polymerization by binding to the colchicine site. PMID- 25815148 TI - alpha-Carbonic Anhydrases Possess Thioesterase Activity. AB - The alpha-carbonic anhydrases (CAs, EC 4.2.1.1) show catalytic versatility acting as esterases with carboxylic, sulfonic, and phosphate esters. Here we prove by kinetic, spectroscopic, and MS studies that they also possess thioesterase activity with a dithiocarbamate ester as a substrate (PhSO2NHCSSMe). Its CA mediated hydrolysis leads to benzenesulfonamide, methyl mercaptan, and COS. The CA thioesterase activity may be useful for designing prodrug enzyme inhibitors, whereas some CA isoforms may use this activity for modulating physiologic/pathologic processes, which are possibly amenable to drug discovery of agents with multiple mechanisms of action. PMID- 25815149 TI - Design and Synthesis of Acetylenyl Benzamide Derivatives as Novel Glucokinase Activators for the Treatment of T2DM. AB - Novel acetylenyl-containing benzamide derivatives were synthesized and screened using an in vitro assay measuring increases in glucokinase activity stimulated by 10 mM glucose concentration and glucose uptake in rat hepatocytes. Lead optimization of an acetylenyl benzamide series led to the discovery of several active compounds via in vitro enzyme assays (EC50 < 40 nM) and in vivo OGTT assays (AUC reduction > 40% at 50 mg/kg). Of the active compounds tested, 3-(3 amino-phenylethynyl)-5-(2-methoxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl) benzamide (19) was identified as a potent glucokinase activator exhibiting an EC50 of 27 nM and eliciting a 2.16-fold increase in glucose uptake. Compound 19 caused a glucose AUC reduction of 47.4% (30 mg/kg) in an OGTT study in C57BL/6J mice compared to 22.6% for sitagliptin (30 mg/kg). Single treatment of the compound 19 in C57BL/6J mice elicited basal glucose lowering activity without any significant evidence for hypoglycemia risk. Compound 19 was therefore selected as a candidate for further preclinical development for the treatment of type 2 diabetes. PMID- 25815150 TI - Discovery of potent hexapeptide agonists to human neuromedin u receptor 1 and identification of their serum metabolites. AB - Neuromedin U (NMU) and S (NMS) display various physiological activities, including an anorexigenic effect, and share a common C-terminal heptapeptide amide sequence that is necessary to activate two NMU receptors (NMUR1 and NMUR2). On the basis of this knowledge, we recently developed hexapeptide agonists 2 and 3, which are highly selective to human NMUR1 and NMUR2, respectively. However, the agonists are still less potent than the endogenous ligand, hNMU. Therefore, we performed an additional structure-activity relationship study, which led to the identification of the more potent hexapeptide 5d that exhibits similar NMUR1 agonistic activity as compared to hNMU. Additionally, we studied the stability of synthesized agonists, including 5d, in rat serum, and identified two major biodegradation sites: Phe(2)-Arg(3) and Arg(5)-Asn(6). The latter was more predominantly cleaved than the former. Moreover, substitution with 4 fluorophenylalanine, as in 5d, enhanced the metabolic stability at Phe(2)-Arg(3). These results provide important information to guide the development of practical hNMU agonists. PMID- 25815151 TI - Synthesis and Evaluation of Quinazolines as Inhibitors of the Bacterial Cell Division Protein FtsZ. AB - The bacterial cell division protein FtsZ is one of many potential targets for the development of novel antibiotics. Recently, zantrin Z3 was shown to be a cross species inhibitor of FtsZ; however, its specific interactions with the protein are still unknown. Herein we report the synthesis of analogues that contain a more tractable core structure and an analogue with single-digit micromolar inhibition of FtsZ's GTPase activity, which represents the most potent inhibitor of Escherichia coli FtsZ reported to date. In addition, the zantrin Z3 core has been converted to two potential photo-cross-linking reagents for proteomic studies that could shed light on the molecular interactions between FtsZ and molecules related to zantrin Z3. PMID- 25815152 TI - Improved angiostatic activity of dasatinib by modulation with hydrophobic chains. AB - Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-beta and SFKs in both tumor cells and tumor-associated endothelial cells, dasatinib inhibits tumor growth and angiogenesis. Herein, dasatinib derivatives modified with hydrophobic chains were prepared and evaluated for their in vitro antiproliferative selectivity and their in vivo antiangiogenic activity. For one of the derivatives, modified with a long perfluorinated chain, a significant enhancement in antiangiogenic activity was observed. Combined, these results suggest a possible generic route to modulate the angiostatic activity of drugs. PMID- 25815153 TI - Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT). AB - 3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors. PMID- 25815154 TI - Synthesis of New DPP-4 Inhibitors Based on a Novel Tricyclic Scaffold. AB - A novel molecular scaffold has been synthesized, and its synthesis and incorporation into new analogues of biologically active molecules will be discussed. A comparison of the inhibitory activity of these compounds to the known type-2 diabetes compound (sitagliptin) against dipeptidyl peptidase-4 (DPP 4) will be shown. PMID- 25815155 TI - Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists. AB - A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization. PMID- 25815156 TI - Positron emission tomography to elucidate pharmacokinetic differences of regioisomeric retinoid x receptor agonists. AB - RXR partial agonist NEt-4IB (2a, 6-[ethyl-(4-isobutoxy-3 isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, E max = 55%) showed a blood concentration higher than its E max after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A(y) mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (1a), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [(11)C]1a, [(11)C]2a and fluorinated derivatives [(18)F]1b, [(18)F]2b, which have longer half-lives, to examine the reason why 1a and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with 1a. PMID- 25815157 TI - Exploiting the Polypharmacology of beta-Carbolines to Disrupt O. volvulus Molting. AB - Onchocerciasis is an infection caused by the filarial worm Onchocerca volvulus, which can eventually result in blindness. The lack of an effective macrofilaricide and the possible development of ivermectin-resistant strains of O. volvulus necessitate the need for alternative treatment strategies. We have shown that targeting the L3-stage-specific chitinase OvCHT1 impairs the shedding of the filarial cuticle. In our continued efforts to discover OvCHT1 inhibitors, we identified the beta-carboline alkaloid scaffolding as a chitinase inhibitor that is capable of penetrating the worm cuticle. Herein, we disclose the rich polypharmacology of the beta-carboline class of compounds as an approach to abrogate the molting of the parasite and thus the initiation of infection in the human host. PMID- 25815158 TI - Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries. AB - Farnesyl diphosphate synthase (FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Here, we report five new structures including two having unique bound ligand geometries. The diamidine inhibitor 7 binds to human FPPS close to the homoallylic (S2) and allosteric (S3) sites and extends into a new site, here called S4. With the bisphosphonate inhibitor 8, two molecules bind to Trypanosoma brucei FPPS, one molecule in the allylic site (S1) and the other close to S2, the first observation of two bisphosphonate molecules bound to FPPS. We also report the structures of apo-FPPS from T. brucei, together with two more bisphosphonate-bound structures (2,9), for purposes of comparison. The diamidine structure is of particular interest because 7 could represent a new lead for lipophilic FPPS inhibitors, while 8 has low micromolar activity against T. brucei, the causative agent of human African trypanosomiasis. PMID- 25815159 TI - Phenolic diterpenoid derivatives as anti-influenza a virus agents. AB - A series of diterpenoid derivatives based on podocarpic acid were synthesized and evaluated as anti-influenza A virus agents. Several of the novel podocarpic acid derivatives exhibited nanomolar activities against an H1N1 influenza A virus (A/Puerto Rico/8/34) that was resistant to two anti-influenza drugs, oseltamivir and amantadine. This class of compounds inhibits the influenza virus by targeting the viral hemagglutinin-mediated membrane fusion. These results indicated that podocarpic acid derivatives may serve as potential drug candidates to fight drug resistant influenza A virus infections. PMID- 25815160 TI - Homeopathy and integrative medicine: keeping an open mind. AB - Some physicians have incorporated some forms of complementary and alternative medicine (CAM) or related medicinal products in their clinical practices, suggesting that an unconventional treatment approach might be seen as an integration rather than as an alternative to standard medical practice. Among the various CAMs, homeopathy enjoys growing popularity with the lay population, but it is not acknowledged by academia or included in medical guidelines. The major problem is to establish the effectiveness of this clinical approach using the strict criteria of evidence-based medicine. This issue of the Journal of Medicine and the Person collects contributions from some of the most prestigious centers and research groups working in the field of homeopathy and integrative medicine. These contributions are not specialized information but are of general interest, focusing on this discipline as one of the emerging fields of personalized medical treatment. PMID- 25815161 TI - eNanoMapper: harnessing ontologies to enable data integration for nanomaterial risk assessment. AB - Engineered nanomaterials (ENMs) are being developed to meet specific application needs in diverse domains across the engineering and biomedical sciences (e.g. drug delivery). However, accompanying the exciting proliferation of novel nanomaterials is a challenging race to understand and predict their possibly detrimental effects on human health and the environment. The eNanoMapper project (www.enanomapper.net) is creating a pan-European computational infrastructure for toxicological data management for ENMs, based on semantic web standards and ontologies. Here, we describe the development of the eNanoMapper ontology based on adopting and extending existing ontologies of relevance for the nanosafety domain. The resulting eNanoMapper ontology is available at http://purl.enanomapper.net/onto/enanomapper.owl. We aim to make the re-use of external ontology content seamless and thus we have developed a library to automate the extraction of subsets of ontology content and the assembly of the subsets into an integrated whole. The library is available (open source) at http://github.com/enanomapper/slimmer/. Finally, we give a comprehensive survey of the domain content and identify gap areas. ENM safety is at the boundary between engineering and the life sciences, and at the boundary between molecular granularity and bulk granularity. This creates challenges for the definition of key entities in the domain, which we also discuss. PMID- 25815162 TI - A Far-Red Emitting Probe for Unambiguous Detection of Mobile Zinc in Acidic Vesicles and Deep Tissue. AB - Imaging mobile zinc in acidic environments remains challenging because most small molecule optical probes display pH-dependent fluorescence. Here we report a reaction-based sensor that detects mobile zinc unambiguously at low pH. The sensor responds reversibly and with a large dynamic range to exogenously applied Zn2+ in lysosomes of HeLa cells, endogenous Zn2+ in insulin granules of MIN6 cells, and zinc-rich mossy fiber boutons in hippocampal tissue from mice. This long-wavelength probe is compatible with the green-fluorescent protein, enabling multicolor imaging, and facilitates visualization of mossy fiber boutons at depths of >100 um, as demonstrated by studies in live tissue employing two-photon microscopy. PMID- 25815163 TI - Surface modification processes during methane decomposition on Cu-promoted Ni ZrO2 catalysts. AB - The surface chemistry of methane on Ni-ZrO2 and bimetallic CuNi-ZrO2 catalysts and the stability of the CuNi alloy under reaction conditions of methane decomposition were investigated by combining reactivity measurements and in situ synchrotron-based near-ambient pressure XPS. Cu was selected as an exemplary promoter for modifying the reactivity of Ni and enhancing the resistance against coke formation. We observed an activation process occurring in methane between 650 and 735 K with the exact temperature depending on the composition which resulted in an irreversible modification of the catalytic performance of the bimetallic catalysts towards a Ni-like behaviour. The sudden increase in catalytic activity could be explained by an increase in the concentration of reduced Ni atoms at the catalyst surface in the active state, likely as a consequence of the interaction with methane. Cu addition to Ni improved the desired resistance against carbon deposition by lowering the amount of coke formed. As a key conclusion, the CuNi alloy shows limited stability under relevant reaction conditions. This system is stable only in a limited range of temperature up to ~700 K in methane. Beyond this temperature, segregation of Ni species causes a fast increase in methane decomposition rate. In view of the applicability of this system, a detailed understanding of the stability and surface composition of the bimetallic phases present and the influence of the Cu promoter on the surface chemistry under relevant reaction conditions are essential. PMID- 25815164 TI - Life at the mesoscale: the self-organised cytoplasm and nucleoplasm. AB - The cell contains highly dynamic structures exploiting physical principles of self-organisation at the mesoscale (100 nm to 10 MUm). Examples include non membrane bound cytoplasmic bodies, cytoskeleton-based motor networks and multi scale chromatin organisation. The challenges of mesoscale self-organisation were discussed at a CECAM workshop in July 2014. Biologists need approaches to observe highly dynamic, low affinity, low specificity associations and to perturb single structures, while biological physicists and biomathematicians need to work closely with biologists to build and validate quantitative models. A table of terminology is included to facilitate multidisciplinary efforts to reveal the richness and diversity of mesoscale cell biology. PMID- 25815165 TI - Bacterial and viral identification and differentiation by amplicon sequencing on the MinION nanopore sequencer. AB - BACKGROUND: The MinIONTM nanopore sequencer was recently released to a community of alpha-testers for evaluation using a variety of sequencing applications. Recent reports have tested the ability of the MinIONTM to act as a whole genome sequencer and have demonstrated that nanopore sequencing has tremendous potential utility. However, the current nanopore technology still has limitations with respect to error-rate, and this is problematic when attempting to assemble whole genomes without secondary rounds of sequencing to correct errors. In this study, we tested the ability of the MinIONTM nanopore sequencer to accurately identify and differentiate bacterial and viral samples via directed sequencing of characteristic genes shared broadly across a target clade. RESULTS: Using a 6 hour sequencing run time, sufficient data were generated to identify an E. coli sample down to the species level from 16S rDNA amplicons. Three poxviruses (cowpox, vaccinia-MVA, and vaccinia-Lister) were identified and differentiated down to the strain level, despite over 98% identity between the vaccinia strains. The ability to differentiate strains by amplicon sequencing on the MinIONTM was accomplished despite an observed per-base error rate of approximately 30%. CONCLUSIONS: While nanopore sequencing, using the MinIONTM platform from Oxford Nanopore in particular, continues to mature into a commercially available technology, practical uses are sought for the current versions of the technology. This study offers evidence of the utility of amplicon sequencing by demonstrating that the current versions of MinIONTM technology can accurately identify and differentiate both viral and bacterial species present within biological samples via amplicon sequencing. PMID- 25815166 TI - An outbreak of carbapenem-resistant OXA-48 - producing Klebsiella pneumonia associated to duodenoscopy. AB - BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) have become a major problem for healthcare systems worldwide. While the first reports from European hospitals described the introduction of CPE from endemic countries, there is now a growing number of reports describing outbreaks of CPE in European hospitals. Here we report an outbreak of Carbapenem-resistant K. pneumoniae in a German University hospital which was in part associated to duodenoscopy. FINDINGS: Between December 6, 2012 and January 10, 2013, carbapenem-resistant K. pneumoniae (CRKP) was cultured from 12 patients staying on 4 different wards. The amplification of carbapenemase genes by multiplex PCR showed presence of the bla OXA-48 gene. Molecular typing confirmed the identity of all 12 isolates. Reviewing the medical records of CRKP cases revealed that there was a spatial relationship between 6 of the cases which were located on the same wards. The remaining 6 cases were all related to endoscopic retrograde cholangiopancreatography (ERCP) which was performed with the same duodenoscope. The outbreak ended after the endoscope was sent to the manufacturer for maintenance. CONCLUSIONS: Though the outbreak strain was also disseminated to patients who did not undergo ERCP and environmental sources or medical personnel also contributed to the outbreak, the gut of colonized patients is the main source for CPE. Therefore, accurate and stringent reprocessing of endoscopic instruments is extremely important, which is especially true for more complex instruments like the duodenoscope (TJF Q180V series) involved in the outbreak described here. PMID- 25815167 TI - Crystalline-induced kidney disease: a case for urine microscopy. PMID- 25815168 TI - Atazanavir nephrotoxicity. AB - Atazanavir is commonly used as one of the key drugs in combination antiretroviral therapy for human immunodeficiency virus (HIV). However, atazanavir has the potential to yield its crystalline precipitation in urine and renal interstitial tissues, leading to crystalluria, urolithiasis, acute kidney injury (AKI) or chronic kidney disease (CKD). In epidemiological studies, atazanavir/ritonavir alone or in combination with tenofovir has been associated with increased risk of progression to CKD. However, renal biopsies were not provided in these studies. Case reports showing an association between atazanavir use and tubulointerstitial nephritis among HIV-infected individuals provide clues as to the potential causes of atazanavir nephrotoxicity. We now review atazanavir-related kidney disease including urolithiasis, renal dysfunction and interstitial nephritis and illustrate the review with a further case of atazanavir-associated kidney injury with sequential renal biopsies. There are two forms of atazanavir-associated tubulointerstitial nephritis: acute tubulointerstitial nephritis that may develop AKI rapidly (in weeks) after initiation of atazanavir, and chronic tubulointerstitial nephritis that may develop progressive CKD slowly (in years) with granuloma and intrarenal precipitation of atazanavir crystals as well as crystalluria. Caution should be exercised when prescribing atazanavir to patients at high risk of CKD, and therapy should be reevaluated if renal function deteriorates, especially associated with crystalluria and hematuria. PMID- 25815169 TI - What is new in the management of rapidly progressive glomerulonephritis? AB - Rapidly progressive glomerulonephritis (RPGN) results from severe crescentic damage to glomeruli and leads to irreversible kidney failure if not diagnosed and managed in a timely fashion. Traditional treatment has relied on glucocorticoids and cyclophosphamide, with additional plasmapheresis for certain conditions. Here we describe updates in the management of RPGN, according to the underlying renal pathology. However, there remains a paucity of trials that have enrolled patients with more advanced renal disease, dialysis dependence or with RPGN, and we are therefore still reliant on extrapolation of data from studies of patients with a less severe form of disease. In addition, reporting bias results in publication of cases or cohorts showing benefit for newer agents in advanced disease or RPGN, but it remains unclear how many unsuccessful outcomes in these circumstances take place. Since clinical trials specifically in RPGN are unlikely, use of biologic registries or combination of sufficient sized cohort series may provide indications of benefit outside of a clinical trial setting and should be encouraged, in order to provide some evidence for the efficacy of therapeutic regimens in RPGN and advanced renal disease. PMID- 25815170 TI - Real-time ultrasound-guided percutaneous renal biopsy with needle guide by nephrologists decreases post-biopsy complications. AB - BACKGROUND: Percutaneous renal biopsy (PRB) can result in serious complications. The study is aimed to compare the biopsy yield and complications rate of the real time ultrasonagram (USG)-guided PRB and needle tracking with and without needle guide in two different study periods. METHODS: We compared the yield and complications of 2138 kidney biopsies performed in two different periods, 1510 biopsies during the first period from April 2004-December 2010 and 628 biopsies during second period from January 2011-March 2013. All biopsies in both periods were performed by nephrologists. Radiologists provided the real-time image without needle guide during the first period while nephrologists performed both imaging and biopsy with needle guide during the second period. RESULTS: Of all the 2138 patients, 226 (10.5%) patients developed 118 minor and 108 major complications. Only 13 (2.1%) major complications occurred in the second period and 95 (6.7%) in the first period (P < 0.001). The relative risk of developing a major complication without guide was 3.04 times greater than that of the biopsies performed with use of the guide. The mean number of glomeruli per biopsy obtained during the second period (17.98 +/- 6.75) was significantly greater than that of the first period (14.14 +/- 6.01) (P = 0.004). The number of passes to acquire adequate tissue (P = 0.001) and percentage of cortex on biopsy (P = 0.001) were also significantly better in the second period. The optimal observation period post biopsy is 24 h. CONCLUSIONS: Real-time USG imaging supported by needle guide device is associated with better biopsy yield and fewer complications. PMID- 25815171 TI - Histiocytic glomerulopathy associated with macrophage activation syndrome. AB - We present an interesting case of a 37-year old man with acute renal failure following a febrile illness. Laboratory results showed features of macrophage activation syndrome (MAS) with anemia, thrombocytopenia, hypofibrinogenemia and elevated ferritin levels. Renal biopsy was then done to determine the cause of renal failure and showed unique glomerular findings with massive histiocytic infiltration ('histiocytic glomerulopathy') and evidence of endothelial injury. Recognizing that the histiocytic infiltrate and endothelial injury is a part of MAS is important because early recognition and treatment is of utmost importance since the disease can be fatal. PMID- 25815172 TI - Iron-based phosphate binders: do they offer advantages over currently available phosphate binders? AB - Increased cardiovascular morbidity and mortality has been associated with the hyperphosphatemia seen in patients with end-stage chronic kidney disease (CKD). Oral phosphate binders are prescribed in these patients to prevent intestinal absorption of dietary phosphate and reduce serum phosphate. In prospective observational cohorts they have shown to decrease all-cause and cardiovascular mortality risk. Different problems have been associated with currently available phosphate binders as positive calcium balance and impaired outcomes with calcium based phosphate binders or increased costs with non-calcium-based phosphate binders. Iron-based phosphate binders represent a new class of phosphate binders. Several iron-based phosphate binders have undergone testing in clinical trials. Ferric citrate (JTT-751) and sucroferric oxyhydroxide (PA21) are the two iron based binders that have passed to the clinical field after being found safe and effective in decreasing serum phosphate. Iron from ferric citrate is partially absorbed compared to sucroferric oxyhydroxide. Ferric citrate usage could result in an important reduction in erythropoiesis-stimulating agent (ESA) and IV iron usage, resulting in significant cost savings. Sucroferric oxyhydroxide was effective in lowering serum phosphorus in dialysis patients with similar efficacy to sevelamer carbonate, but with lower pill burden, and better adherence. Ferric citrate may be more suited for the treatment of chronic hyperphosphatemia in CKD patients requiring iron supplements but its use may have been hampered by potential aluminum overload, as citrate facilitates its absorption; sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplementation, with low pill burden. PMID- 25815175 TI - Treatment of adynamic bone disease in a haemodialysis patient with teriparatide. AB - Prevalence of adynamic bone disease (ABD), characterized by low bone turnover and absence or a reduced number of osteoblasts and osteoclasts, is increasing steadily over the last years. We present a dialysis patient, with recurrent bone fractures and biopsy-proven ABD, who was treated with teriparatide. Nine months after initiation of treatment, iPTH plasma levels increased to 520 pg/mL and a second bone biopsy revealed high bone turnover, normal mineralization and normal bone volume. Two years later, iPTH was 250-350 pg/dL and bone metabolism parameters within normal range. The probable utility of teriparatide in the treatment of ABD in dialysis patients is discussed. PMID- 25815173 TI - The intestine and the kidneys: a bad marriage can be hazardous. AB - The concept that the intestine and chronic kidney disease influence each other, emerged only recently. The problem is multifaceted and bidirectional. On one hand, the composition of the intestinal microbiota impacts uraemic retention solute production, resulting in the generation of essentially protein-bound uraemic toxins with strong biological impact such as vascular damage and progression of kidney failure. On the other hand, the uraemic status affects the composition of intestinal microbiota, the generation of uraemic retention solutes and their precursors and causes disturbances in the protective epithelial barrier of the intestine and the translocation of intestinal microbiota into the body. All these elements together contribute to the disruption of the metabolic equilibrium and homeostasis typical to uraemia. Several measures with putative impact on intestinal status have recently been tested for their influence on the generation or concentration of uraemic toxins. These include dietary measures, prebiotics, probiotics, synbiotics and intestinal sorbents. Unfortunately, the quality and the evidence base of many of these studies are debatable, especially in uraemia, and often results within one study or among studies are contradictory. Nevertheless, intestinal uraemic metabolite generation remains an interesting target to obtain in the future as an alternative or additive to dialysis to decrease uraemic toxin generation. In the present review, we aim to summarize (i) the role of the intestine in uraemia by producing uraemic toxins and by generating pathophysiologically relevant changes, (ii) the role of uraemia in modifying intestinal physiology and (iii) the therapeutic options that could help to modify these effects and the studies that have assessed the impact of these therapies. PMID- 25815174 TI - Calcitonin, the forgotten hormone: does it deserve to be forgotten? AB - Calcitonin is a 32 amino acid hormone secreted by the C-cells of the thyroid gland. Calcitonin has been preserved during the transition from ocean-based life to land dwellers and is phylogenetically older than parathyroid hormone. Calcitonin secretion is stimulated by increases in the serum calcium concentration and calcitonin protects against the development of hypercalcemia. Calcitonin is also stimulated by gastrointestinal hormones such as gastrin. This has led to the unproven hypothesis that postprandial calcitonin stimulation could play a role in the deposition of calcium and phosphate in bone after feeding. However, no bone or other abnormalities have been described in states of calcitonin deficiency or excess except for diarrhea in a few patients with medullary thyroid carcinoma. Calcitonin is known to stimulate renal 1,25 (OH)2 vitamin D (1,25D) production at a site in the proximal tubule different from parathyroid hormone and hypophosphatemia. During pregnancy and lactation, both calcitonin and 1,25D are increased. The increases in calcitonin and 1,25D may be important in the transfer of maternal calcium to the fetus/infant and in the prevention and recovery of maternal bone loss. Calcitonin has an immediate effect on decreasing osteoclast activity and has been used for treatment of hypercalcemia. Recent studies in the calcitonin gene knockout mouse have shown increases in bone mass and bone formation. This last result together with the presence of calcitonin receptors on the osteocyte suggests that calcitonin could possibly affect osteocyte products which affect bone formation. In summary, a precise role for calcitonin remains elusive more than 50 years after its discovery. PMID- 25815176 TI - Optimization of the convection volume in online post-dilution haemodiafiltration: practical and technical issues. AB - In post-dilution online haemodiafiltration (ol-HDF), a relationship has been demonstrated between the magnitude of the convection volume and survival. However, to achieve high convection volumes (>22 L per session) detailed notion of its determining factors is highly desirable. This manuscript summarizes practical problems and pitfalls that were encountered during the quest for high convection volumes. Specifically, it addresses issues such as type of vascular access, needles, blood flow rate, recirculation, filtration fraction, anticoagulation and dialysers. Finally, five of the main HDF systems in Europe are briefly described as far as HDF prescription and optimization of the convection volume is concerned. PMID- 25815177 TI - Venovenous haemodiafiltration for the management of dabigatran overdose in intensive care unit. AB - Dabigatran is a direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with non-valvular atrial fibrillation. The procedure to manage dabigatran-associated haemorrhages is not well formalized. Conventional haemodialysis has been evaluated with good results. Patients with dabigatran associated bleeding may be unstable and convective techniques like venovenous haemodiafiltration (HDF) can be interesting. We report the case of a 74-year-old, critically ill patient with haemorrhagic shock and dabigatran overexposure due to acute kidney injury. He underwent HDF and dabigatran blood concentrations decreased from 325.3 ng/mL to 160.5 ng/mL. We report here key pharmacokinetics parameters (half-life, extraction coefficient, clearance). PMID- 25815179 TI - The curious right-sided predominance of peritoneal dialysis-related hydrothorax. AB - A known complication of peritoneal dialysis is the movement of dialysate into the pleural space, termed hydrothorax. Peritoneal dialysis-related hydrothorax is almost uniformly right-sided and represents one of many presentations of the porous diaphragm syndrome. In addition to diaphragm porosity, the inherent intestinal circulation, lower hydrostatic pressure in the right upper quadrant and liver capsule may contribute to this right-sided predominance. Similar right sided presentations have been described in Meigs syndrome, bilious effusions with gastric or duodenal perforations, hepatic hydrothorax and nephrotic syndrome related chylothorax. PD-related hydrothorax can be repaired by pleurodesis or video-assisted thoracoscopy followed by resumption of peritoneal dialysis. PMID- 25815178 TI - Strategies for preserving residual renal function in peritoneal dialysis patients. AB - Although there have been many advancements in the treatment of patients with chronic kidney disease (CKD) over the last 50 years, in terms of reducing cardiovascular risk, mortality remains unacceptably high, particularly for those patients who progress to stage 5 CKD and initiate dialysis (CKD5d). As mortality risk increases exponentially with progressive CKD stage, the question arises as to whether preservation of residual renal function once dialysis has been initiated can reduce mortality risk. Observational studies to date have reported an association between even small amounts of residual renal function and improved patient survival and quality of life. Dialysis therapies predominantly provide clearance for small water-soluble solutes, volume and acid-base control, but cannot reproduce the metabolic functions of the kidney. As such, protein-bound solutes, advanced glycosylation end-products, middle molecules and other azotaemic toxins accumulate over time in the anuric CKD5d patient. Apart from avoiding potential nephrotoxic insults, observational and interventional trials have suggested that a number of interventions and treatments may potentially reduce the progression of earlier stages of CKD, including targeted blood pressure control, reducing proteinuria and dietary intervention using combinations of protein restriction with keto acid supplementation. However, many interventions which have been proven to be effective in the general population have not been equally effective in the CKD5d patient, and so the question arises as to whether these treatment options are equally applicable to CKD5d patients. As strategies to help preserve residual renal function in CKD5d patients are not well established, we have reviewed the evidence for preserving or losing residual renal function in peritoneal dialysis patients, as urine collections are routinely collected, whereas few centres regularly collect urine from haemodialysis patients, and haemodialysis dialysis patients are at risk of sudden intravascular volume shifts associated with dialysis treatments. On the other hand, peritoneal dialysis patients are exposed to a variety of hypertonic dialysates and episodes of peritonitis. Whereas blood pressure control, using an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and low-protein diets along with keto acid supplementation have been shown to reduce the rate of progression in patients with earlier stages of CKD, the strategies to preserve residual renal function (RRF) in dialysis patients are not well established. For peritoneal dialysis patients, there are additional technical factors that might aggravate the rate of loss of residual renal function including peritoneal dialysis prescriptions and modality, bio incompatible dialysis fluid and over ultrafiltration of fluid causing dehydration. In this review, we aim to evaluate the evidence of interventions and treatments, which may sustain residual renal function in peritoneal dialysis patients. PMID- 25815180 TI - Plasma nitrate/nitrite removal by peritoneal dialysis might predispose infants with low blood pressure to cerebral ischaemia. AB - The underlying pathogenic mechanisms of neurological complications in infants undergoing peritoneal dialysis (PD) are poorly understood. We report on four male infants treated with PD who developed symptomatic cerebral ischaemia. Blood pressure (BP) levels were low both before the event and at presentation. In two patients, we observed that the removal of nitrate and nitrite by PD could have impaired the nitrate/nitrite--nitrite oxide (NO) pathway, a system that generates NO independently of NO synthase. Our observation suggests that low BP and reduced NO bioavailability puts infants treated with PD at risk for impaired cerebral blood flow and consequently for brain ischaemia. PMID- 25815181 TI - Peritoneal ultrafiltration in end-stage chronic heart failure. AB - BACKGROUND: Cardiorenal syndrome type 2 (CRS-2) is common in end-stage chronic heart failure (CHF). Peritoneal ultrafiltration (pUF) may entail clinical functional improvement and a reduction in hospitalizations. METHODS: Thirty-nine consecutive end-stage CHF patients with stable CRS-2 were initiated on ambulatory pUF after interdisciplinary cardiological/nephrological evaluation and prospectively followed for 1 year. All-cause hospitalization was the primary end point. Secondary end points included mortality, treatment alteration and change in weight, NYHA functional class or quality of life (QoL). Outcomes were compared both within the pUF cohort (365 prior to initiation) and with 39 matched CHF patients receiving standard medical treatment. RESULTS: Compared with pretreatment, there was a trend to a reduction in 1-year hospitalization days in the pUF group (P = 0.07). One-year mortality was 33% in the pUF group and 23% in the matched control cohort. pUF was stopped in eight patients (18%) due to recurrent peritonitis (n = 3), insufficient ultrafiltration (n = 3) or cardiac recompensation (n = 1). Compared with standard medical treatment, pUF significantly improved volume overload (P < 0.05), NYHA functional class (P < 0.001) and mental health (P < 0.05). Moreover, hospitalization days for all causes as well as cardiovascular hospitalization days were significantly reduced during the interim periods in the pUF group (P < 0.05 and P < 0.001, respectively). CONCLUSIONS: pUF is effective in improving the clinical condition of end-stage CHF patients suffering from CRS-2. Randomized controlled trials are needed to clarify the effects of pUF on hospitalization and mortality in these patients. PMID- 25815182 TI - Advanced chronic kidney disease in non-valvular atrial fibrillation: extending the utility of R2CHADS2 to patients with advanced renal failure. AB - BACKGROUND: The R2CHADS2 is a new prediction rule for stroke risk in atrial fibrillation (AF) patients wherein R stands for renal risk. However, it was created from a cohort that excluded patients with advanced renal failure (defined as glomerular filtration rate of <30 mL/min). Our study extends the use of R2CHADS2 to patients with advanced renal failure and aims to compare its predictive power against the currently used CHADS and CHA2DS2VaSc. METHODS: This retrospective cohort study analyzed the 1-year risk for stroke of the 524 patients with AF at Metropolitan Hospital Center. AUC and C statistics were calculated using three groups: (i) the entire cohort including patients with advanced renal failure, (ii) a cohort excluding patients with advanced renal failure and (iii) all patients with GFR < 30 mL/min only. RESULTS: R2CHADS2, as a predictor for stroke risk, consistently performs better than CHADS2 and CHA2DS2VsC in groups 1 and 2. The C-statistic was highest in R2CHADS compared with CHADS or CHADSVASC in group 1 (0.718 versus 0.605 versus 0.602) and in group 2 (0.724 versus 0.584 versus 0.579). However, there was no statistically significant difference in group 3 (0.631 versus 0.629 versus 0.623). CONCLUSION: Our study supports the utility of R2CHADS2 as a clinical prediction rule for stroke risk in patients with advanced renal failure. PMID- 25815183 TI - Remission of aHUS neurological damage with eculizumab. AB - Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by haemolytic microangiopathic anaemia, thrombocytopaenia and acute onset of renal failure, in the absence of Escherichia coli infection. Renal damage usually progresses to end-stage renal disease (ESRD), sometimes being accompanied by signs of extrarenal thrombotic microangiopathy (TMA). We report a case of full neurological and haematological recovery after eculizumab treatment in a patient with ESRD secondary to chronic aHUS refractory to plasmatherapy while she was under dialysis. It highlights the use of eculizumab for controlling extrarenal manifestations of aHUS in this population. PMID- 25815184 TI - Light and heavy chain deposition disease associated with CH1 deletion. AB - Light and heavy chain deposition disease (LHCDD) is a rare complication of monoclonal gammopathy. In all documented cases, LHCDD is the association of deposits of a monoclonal light chain with a normal heavy chain, especially in the kidneys. We describe here a 78-year-old woman whose renal biopsy showed nodular glomerulosclerosis, initially diagnosed as diabetic nephropathy. Detailed kidney biopsy immunofluorescence study corrected the diagnosis to gamma1-kappa-LHCDD. Advanced immunoblot analysis showed deletion of CH1 in the both blood and kidney heavy chain. We report here, to our knowledge, the first case of gamma1 LHCDD associated with a deletion of CH1. PMID- 25815186 TI - Invasive candidiasis presenting multiple pulmonary cavitary lesions on chest computed tomography. AB - We herein report a case of invasive candidiasis presenting rare findings on chest computed tomography (CT). The chest CT scan showed multiple small cavitary lesions and nodules with surrounding ground-glass opacity, and also bilateral pleural effusion. Although this CT finding is thought as specific for pulmonary aspergillosis, two sets of blood culture specimens were drawn which yielded Candida albicans in our case. Antifungal therapy was started and the chest CT findings showed a remarkable improvement. To our knowledge, this is the first case report describing multiple pulmonary cavitary lesions in invasive candidiasis. PMID- 25815185 TI - Perturbation and restoration of the fathead minnow gut microbiome after low-level triclosan exposure. AB - BACKGROUND: Triclosan is a widely used antimicrobial compound and emerging environmental contaminant. Although the role of the gut microbiome in health and disease is increasingly well established, the interaction between environmental contaminants and host microbiome is largely unexplored, with unknown consequences for host health. This study examined the effects of low, environmentally relevant levels of triclosan exposure on the fish gut microbiome. Developing fathead minnows (Pimephales promelas) were exposed to two low levels of triclosan over a 7-day exposure. Fish gastrointestinal tracts from exposed and control fish were harvested at four time points: immediately preceding and following the 7-day exposure and after 1 and 2 weeks of depuration. RESULTS: A total of 103 fish gut bacterial communities were characterized by high-throughput sequencing and analysis of the V3-V4 region of the 16S rRNA gene. By measures of both alpha and beta diversity, gut microbial communities were significantly differentiated by exposure history immediately following triclosan exposure. After 2 weeks of depuration, these differences disappear. Independent of exposure history, communities were also significantly structured by time. This first detailed census of the fathead minnow gut microbiome shows a bacterial community that is similar in composition to those of zebrafish and other freshwater fish. Among the triclosan-resilient members of this host-associated community are taxa associated with denitrification in wastewater treatment, taxa potentially able to degrade triclosan, and taxa from an unstudied host-associated candidate division. CONCLUSIONS: The fathead minnow gut microbiome is rapidly and significantly altered by exposure to low, environmentally relevant levels of triclosan, yet largely recovers from this short-term perturbation over an equivalently brief time span. These results suggest that even low-level environmental exposure to a common antimicrobial compound can induce significant short-term changes to the gut microbiome, followed by restoration, demonstrating both the sensitivity and resilience of the gut flora to challenges by environmental toxicants. This short term disruption in a developing organism may have important long-term consequences for host health. The identification of multiple taxa not often reported in the fish gut suggests that microbial nitrogen metabolism in the fish gut may be more complex than previously appreciated. PMID- 25815188 TI - Parents' perceptions on offspring risk and prevention of anxiety and depression: a qualitative study. AB - BACKGROUND: Offspring of patients with anxiety or depression are at high risk for developing anxiety or depression. Despite the positive findings regarding effectiveness of prevention programs, recruitment for prevention activities and trials is notoriously difficult. Our randomized controlled prevention trial was terminated due to lack of patient inclusion. Research on mentally-ill parents' perceptions of offspring's risk and need for preventive intervention may shed light on this issue, and may enhance family participation in prevention activities and trials. METHODS: Qualitative data were collected through semi structured interviews with 24 parents (patients with anxiety or depression, or their partners). An inductive content analysis of the data was performed. Five research questions were investigated regarding parents' perceptions of anxiety, depression, and offspring risk; anxiety, depression, and parenting; the need for offspring intervention and prevention; and barriers to and experiences with participation in preventive research. RESULTS: Parental perceptions of the impact of parental anxiety and depression on offspring greatly differed. Parents articulated concerns about children's symptomatology, however, most parents did not perceive a direct link between parent symptoms and offspring quality of life. They experienced an influence of parental symptoms on family quality of life, but chose not to discuss that with their children in order to protect them. Parents were not well aware of the possibilities regarding professional help for offspring and preferred parent-focused rather than offspring-focused interventions such as parent psycho-education. Important barriers to participation in preventive research included parental overburden, shame and stigma, and perceived lack of necessity for intervention. CONCLUSIONS: This study highlights the importance of educating parents in adult health care. Providing psycho-education regarding offspring risk, communication in the family, and parenting in order to increase parental knowledge and parent-child communication, and decrease guilt and shame are important first steps in motivating parents to participate in preventive treatment. PMID- 25815187 TI - Best practice in bereavement photography after perinatal death: qualitative analysis with 104 parents. AB - BACKGROUND: Postmortem memento photography has emerged in Western hospitals as part of compassionate bereavement care for parents facing perinatal death. Many parents endorse this psychosocial intervention, yet implementation varies greatly and little research on parents' specific needs guides health care professionals. Parents are in crisis and vulnerable after the death of their child, thus best practice is crucial. This study contributes 104 parents' experiences and opinions toward the understanding of best practice in perinatal bereavement photography. METHODS: Parents who experienced the perinatal death of their child were recruited from U.S.-based bereavement organizations and social media sites. Volunteers completed an anonymous internet survey with open- and closed-ended questions. Direct recommendations and pertinent statements regarding the process of postmortem photography were analyzed for thematic content in keeping with conventional content analysis. Recurrent themes and sub-themes were counted to identify response patterns. RESULTS: Of 93 parents with pictures, 92 endorsed them. Of 11 without pictures, nine wanted them. Parents made a variety of recommendations regarding appropriate psychosocial support, the consent process, obstacles to photography, logistics of photography, and material aspects of photographs themselves. Overall, parents wanted many pictures and much variety. Some wanted professional photography while others wanted support for taking their own pictures. Parents wanted guidance from staff who respected their particular needs. Many said decisions were difficult during their crisis. Parents who were initially resistant expressed current appreciation for pictures or expressed regret that they had not participated. Parents recommended that professionals strongly encourage parents to create memento photos despite parents' initial reservations. Persistent cultural reasons against photography emerged in one case. Quotes by parents illuminate themes and enable respondents to speak directly to health care professionals. CONCLUSIONS: Parents overwhelmingly support postmortem bereavement photography when conducted sensitively, even if imperfectly executed. Providers significantly influence parents during their crises; mindful, patient-centered care with appropriate respect for difference is necessary. Providers must understand the importance of postmortem photographs to parents who have limited opportunity to capture memories of their child. Hospitals should provide education and support for this important psychosocial intervention. PMID- 25815189 TI - A mediation model of mindfulness and decentering: sequential psychological constructs or one and the same? AB - BACKGROUND: Mindfulness and decentering are closely related processes both assumed to promote well-being. While some researchers claim that mindfulness and decentering can be clearly differentiated others suggest to use these concepts interchangeably. The precise relation between mindfulness and decentering remains unclear and therefore the present study aims to determine the relation between mindfulness and decentering. METHODS: In a structural equation modeling framework, a mediation model was tested among a sample group of 495 university students (average age 20.8 years, 30.3% female). RESULTS: The identified model shows an acceptable fit to the data and illustrates the role of decentering as a mediator of the relationship between mindfulness and depressive symptoms by complementary mediation and indirect-only mediation. CONCLUSION: The present results cannot sustain previous research, which converted mindfulness and decentering into one single variable. Rather the data suggests to treat mindfulness and decentering as two separable concepts and to regard decentering as an important working mechanism of mindfulness. PMID- 25815190 TI - Attachment-oriented psychological intervention for couples facing breast cancer: protocol of a randomised controlled trial. AB - BACKGROUND: There is evidence that both breast cancer patients and their partners are affected emotionally, when facing a breast cancer diagnosis. Several couple interventions have been evaluated, but there is a need for couple intervention studies with a clear theoretical basis and a strong design. The Hand in Hand intervention is designed to enhance interdependent coping in the couples and to address patients and partners that are both initially distressed and non distressed. METHODS: The Hand in Hand study is a randomised controlled trial among 199 breast cancer patients and their partners. Couples were randomised to 4 8 couple sessions with a psychologist in addition to usual care, or to usual care only, approximately 2 months after the patients' primary surgery date. The intervention was delivered within 3 months, and outcomes were assessed prior to randomisation and 5 and 10 months after primary surgery date. The primary outcome is patients' cancer-specific distress at the 5-month follow-up measured by the Impact of Event Scale. Secondary outcomes are assessed for both breast cancer patients and partners. These outcomes are: general distress, symptoms of anxiety and depression, health-related quality of life and measures of dyadic adjustment, intimacy and partner involvement. Cancer-specific distress is also assessed for partners. Eligible patients were women >= 18 years newly diagnosed with primary breast cancer, cohabiting with a male partner, having no previous cancer diagnoses, receiving no neo-adjuvant treatment, having no history of hospitalisation due to psychosis, and able to read and speak Danish. Partners were eligible if they could read and speak Danish and were >= 18 years. DISCUSSION: This study investigates the effect of an attachment-oriented psychological intervention for breast cancer patients and their partners. The intervention has a theoretical framework and a strong design. If proven effective, this intervention would be helpful in optimising psychosocial care and rehabilitation of couples coping with breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01368380. PMID- 25815191 TI - Gender-differences in risk factors for suicidal behaviour identified by perceived burdensomeness, thwarted belongingness and acquired capability: cross-sectional analysis from a longitudinal cohort study. AB - BACKGROUND: The Interpersonal-Psychological Theory of Suicidal Behavior (IPT) is supported by recent epidemiological data. Unique risk factors for the IPT constructs have been identified in community epidemiological studies. Gender differences in these risk factors may contribute substantially to our understanding of suicidal risk, and require further investigation. The present study explores gender differences in the predictors and correlates of perceived burdensomeness, thwarted belongingness and acquired capability for suicide. METHODS: Participants (547 males, 739 females) aged 32-38 from the PATH through Life study, an Australian population-based longitudinal cohort study (n=1,177) were assessed on perceived burdensomeness, thwarted belongingness and acquired capability for suicide using the Interpersonal Needs Questionnaire and Acquired Capability for Suicide Survey, and on a range of demographic, social support, psychological, mental health and physical health measures. Gender differences in the predictors of the IPT constructs were assessed using linear regression analyses. RESULTS: Higher perceived burdensomeness increased suicide ideation in both genders, while higher thwarted belongingness increased suicide ideation only in females. In females, thwarted belongingness was uniquely related to perceived burdensomeness, while greater physical health was significantly associated with greater thwarted belongingness in males but not in females. There were trends suggesting greater effects of being single and greater perceived burdensomeness for men, and stronger effects of less positive friendship support for women associated with greater thwarted belongingness. CONCLUSIONS: Men and women differ in the pattern of psychological characteristics that predict suicide ideation, and in the factors predicting vulnerability. Suicide prevention strategies need to take account of gender differences. PMID- 25815192 TI - A short tool to screen HIV-infected patients for mild neurocognitive disorders - a pilot study. AB - BACKGROUND: We aimed to evaluate the accuracy and acceptability of a short screening test battery for mild neurocognitive deficits. METHODS: HIV-infected individuals with a suppressed viral load were examined at the University Hospital Basel with a screening test consisting of a questionnaire and selected cognitive tests, administered by trained nurses, followed by an in-depth neuropsychological examination. Test acceptance was evaluated with a questionnaire. RESULTS: 30 patients were included in this study (median age of 52.5 years (interquartile range (IQR) 47-64), prior AIDS-defining condition in 37%, median CD4 cell count 658 (IQR 497-814) cells/MUl). Overall, 25 (83%) patients were diagnosed with HIV associated neurocognitive disorders (HAND) on in-depth neuropsychological assessment (16 patients had asymptomatic neurocognitive impairment (ANI), 8 a mild neurocognitive disorder (MND) and 1 patient HIV-associated dementia (HAD). Among 25 patients with HAND, only 9 patients (36%) were complaining of memory loss. The screening battery revealed neurocognitive deficits in 17 (57%) patients (sensitivity 64%, specificity 80%, positive predictive value 94% and negative predictive value 31%). Most patients (83%) estimated the screening test as valuable and not worrisome. CONCLUSIONS: A questionnaire combined with selected neuropsychological tests is a short, easy-to-perform very well accepted screening tool for mild neurocognitive disorders in asymptomatic HIV-infected individuals. PMID- 25815193 TI - Rumination and interoceptive accuracy predict the occurrence of the thermal grill illusion of pain. AB - BACKGROUND: While the neurophysiological mechanisms underlying the thermal grill illusion of pain (TGI) have been thoroughly studied, psychological determinants largely remain unknown. The present study aimed to investigate whether cognitive and affective personality traits encompassing rumination, interoception, and suggestibility may be identified as characteristics favouring the elicitation of paradoxical pain experiences. METHODS: The dominant hand of 54 healthy volunteers was stimulated with a water-bath driven thermal grill providing an interlaced temperature combination of 15 and 41 degrees C. Pain intensity and pain unpleasantness perceptions were rated on a combined verbal-numerical scale (NRS). Traits were assessed via questionnaires, the heartbeat-tracking task, and warmth suggestions. RESULTS: Logistic regression analyses uncovered trait rumination and interoceptive accuracy (IA) as major predictors of the likelihood of the illusive pain occurrence (all p < .05). Rumination and suggestibility had an impact on unpleasant pain perceptions. CONCLUSION: Our findings allowed identifying psychological factors substantially involved in the individual pre-disposition to reporting painful sensations in the thermal grill paradigm. These psychological characteristics may also be relevant in the context of central neuropathic pain, which to a large extent incorporates the same neural pathways. PMID- 25815194 TI - The Strengths and Difficulties Questionnaire: psychometric properties of the parent and teacher version in children aged 4-7. AB - BACKGROUND: The Strengths and Difficulties Questionnaire is one of the most employed screening instruments. Although there is a large research body investigating its psychometric properties, reliability and validity are not yet fully tested using modern techniques. Therefore, we investigate reliability, construct validity, measurement invariance, and predictive validity of the parent and teacher version in children aged 4-7. Besides, we intend to replicate previous studies by investigating test-retest reliability and criterion validity. METHODS: In a Dutch community sample 2,238 teachers and 1,513 parents filled out questionnaires regarding problem behaviors and parenting, while 1,831 children reported on sociometric measures at T1. These children were followed-up during three consecutive years. Reliability was examined using Cronbach's alpha and McDonald's omega, construct validity was examined by Confirmatory Factor Analysis, and predictive validity was examined by calculating developmental profiles and linking these to measures of inadequate parenting, parenting stress and social preference. Further, mean scores and percentiles were examined in order to establish norms. RESULTS: Omega was consistently higher than alpha regarding reliability. The original five-factor structure was replicated, and measurement invariance was established on a configural level. Further, higher SDQ scores were associated with future indices of higher inadequate parenting, higher parenting stress and lower social preference. Finally, previous results on test retest reliability and criterion validity were replicated. CONCLUSIONS: This study is the first to show SDQ scores are predictively valid, attesting to the feasibility of the SDQ as a screening instrument. Future research into predictive validity of the SDQ is warranted. PMID- 25815195 TI - Oncologists' perception of depressive symptoms in patients with advanced cancer: accuracy and relational correlates. AB - BACKGROUND: Health care providers often inaccurately perceive depression in cancer patients. The principal aim of this study was to examine oncologist patient agreement on specific depressive symptoms, and to identify potential predictors of accurate detection. METHODS: 201 adult advanced cancer patients (recruited across four French oncology units) and their oncologists (N = 28) reported depressive symptoms with eight core symptoms from the BDI-SF. Various indices of agreement, as well as logistic regression analyses were employed to analyse data. RESULTS: For individual symptoms, medians for sensitivity and specificity were 33% and 71%, respectively. Sensitivity was lowest for suicidal ideation, self-dislike, guilt, and sense of failure, while specificity was lowest for negative body image, pessimism, and sadness. Indices independent of base rate indicated poor general agreement (median DOR = 1.80; median ICC = .30). This was especially true for symptoms that are more difficult to recognise such as sense of failure, self-dislike and guilt. Depression was detected with a sensitivity of 52% and a specificity of 69%. Distress was detected with a sensitivity of 64% and a specificity of 65%. Logistic regressions identified compassionate care, quality of relationship, and oncologist self-efficacy as predictors of patient-physician agreement, mainly on the less recognisable symptoms. CONCLUSIONS: The results suggest that oncologists have difficulty accurately detecting depressive symptoms. Low levels of accuracy are problematic, considering that oncologists act as an important liaison to psychosocial services. This underlines the importance of using validated screening tests. Simple training focused on psychoeducation and relational skills would also allow for better detection of key depressive symptoms that are difficult to perceive. PMID- 25815196 TI - Chronic pain in multi-traumatized outpatients with a refugee background resettled in Norway: a cross-sectional study. AB - BACKGROUND: Traumatized refugees often report significant levels of chronic pain in addition to posttraumatic stress disorder symptoms, and more information is needed to understand pain in refugees exposed to traumatic events. This study aimed to assess the frequency of chronic pain among refugee psychiatric outpatients, and to compare outpatients with and without chronic pain on trauma exposure, psychiatric morbidity, and psychiatric symptom severity. METHODS: We conducted a cross-sectional study of sixty-one psychiatric outpatients with a refugee background using structured clinical diagnostic interviews to assess for traumatic events [Life Events Checklist (LEC)], PTSD (Posttraumatic Stress Disorder) and complex PTSD [Structured Clinical Interview for DSM-IV PTSD Module (SCID-PTSD) and Structured Interview for Disorders of Extreme Stress (SIDES)], chronic pain (SIDES Scale VI) and psychiatric symptoms [M.I.N.I. International Neuropsychiatric Interview (M.I.N.I.)]. Self-report measures were used to assess symptoms of posttraumatic stress [Impact of Event Scale-revised (IES-R)], depression and anxiety [Hopkins Symptom Checklist (HSCL-25)] and several markers of acculturation in Norway. RESULTS: Of the 61 outpatients included, all but one reported at least one chronic pain location, with a mean of 4.6 locations per patient. Chronic pain at clinical levels was present in 66% of the whole sample of outpatients, and in 88% of the outpatients with current PTSD diagnosis. The most prevalent chronic pain locations were head (80%), chest (74%), arms/legs (66%) and back (62%). Women had significantly more chronic pain locations than men. Comorbid PTSD and chronic pain were found in 57% of the outpatients. Significant differences were found between outpatients with and without chronic pain on posttraumatic stress, psychological distress, and DESNOS severity. CONCLUSIONS: Chronic pains are common in multi-traumatized refugees in outpatient clinics in Norway, and are positively related to symptomatology and severity of psychiatric morbidity. The presence of chronic pain, as well as comorbid chronic pain and PTSD, in psychiatric outpatients with a refugee background call for an integrated assessment and treatment for both conditions. PMID- 25815197 TI - The "child size medicines" concept: policy provisions in Uganda. AB - BACKGROUND: In 2007, the World Health Organization (WHO) launched the 'make medicines child size' (MMCS) campaign by urging countries to prioritize procurement of medicines with appropriate strengths for children's age and weight and, in child-friendly formulations of rectal and flexible oral solid formulations. This study examined policy provisions for MMCS recommendations in Uganda. METHODS: This was an in-depth case study of the Ugandan health policy documents to assess provisions for MMCS recommendations in respect to oral and rectal medicine formulations for malaria, pneumonia and diarrhea, the major causes of morbidity and mortality among children in Uganda- diseases that were also emphasized in the MMCS campaign. Asthma and epilepsy were included as conditions that require long term care. Schistomiasis was included as a neglected tropical disease. Content analysis was used to assess evidence of policy provisions for the MMCS recommendations. RESULTS: For most medicines for the selected diseases, appropriate strength for children's age and weight was addressed especially in the EMHSLU 2012. However, policy documents neither referred to 'child size medicines' concept nor provided for flexible oral solid dosage formulations like dispersible tablets, pellets and granules- indicating limited adherence to MMCS recommendations. Some of the medicines recommended in the clinical guidelines as first line treatment for malaria and pneumonia among children were not evidence-based. CONCLUSION: The Ugandan health policy documents reflected limited adherence to the MMCS recommendations. This and failure to use evidence based medicines may result into treatment failure and or death. A revision of the current policies and guidelines to better reflect 'child size', child appropriate and evidence based medicines for children is recommended. PMID- 25815198 TI - What variables should be considered in allocating Primary health care Pharmaceutical budgets to districts in Uganda? AB - OBJECTIVES: A key policy question for the government of Uganda is how to equitably allocate primary health care pharmaceutical budgets to districts. This paper seeks to identify variables influencing current primary health care pharmaceutical expenditure and their usefulness in allocating prospective pharmaceutical budgets to districts. METHODS: This was a cross sectional, retrospective observational study using secondary administrative data. We collected data on the value of pharmaceuticals procured by primary health care facilities in each district from National Medical Stores for the financial year 2011/2012. The dependent variable was expressed as per capita district pharmaceutical expenditure. By reviewing literature we identified 26 potential explanatory variables. They include supply, need and demand, and health system organization variables that may influence the demand and supply of health services and the corresponding pharmaceutical expenditure. We collected secondary data for these variables for all the districts in Uganda (n = 112). We performed econometric analysis to estimate parameters of various regression models. RESULTS: There is a significant correlation between per capita district pharmaceutical expenditure and total district population, rural poverty, access to drinking water and outpatient department (OPD) per capita utilisation.(P < 0.01). The percentage of health centre IIIs (HC III) among each district's health facilities is significantly correlated with per capita pharmaceutical expenditure (P < 0.05). OPD per capita utilisation has a relatively strong correlation with per capita pharmaceutical expenditure (r = 0.498); all the other significant factors are weakly correlated with per capita pharmaceutical expenditure (r < 0.5). From several iterations of an initially developed model, the proposed final model for explaining per capita pharmaceutical expenditure explains about 53% of the variation in pharmaceutical expenditure among districts in Uganda (Adjusted R(2) = 0.528). All variables in the model are significant (p < 0.01). CONCLUSIONS: From evaluation of the various models, proposed variables to consider in allocating prospective primary health care pharmaceutical budgets to districts in Uganda are: district outpatient department attendance per capita, total district population, total number of government health facilities in the district and the district human poverty index. PMID- 25815199 TI - Pharmaceutical policy Part 1 The challenge to pharmacists to engage in policy development. AB - Across the world medicines are the ubiquitous technology in the diagnosis, treatment and prevention of disease. Pharmaceutical policy, as part of national health care policy, is concerned with the provision and use of medicines. Pharmacists are critical to the medicines management process, yet are often largely detached from policy development. Logically, they should inform Government policies which impact on their work or where their skills could be best applied to implement health care policy and medicines utilisation in particular. It therefore makes it critically important that the pharmaceutical profession engages with national policy makers and in the strategic planning for health care. This is the first of two articles directed to this specific issue. Firstly, it identifies a number of the practice challenges for pharmacy and medicines management, their implications for policy and the need for a balanced approach. Drawing from a range of international experiences some key learning points in respect of formulating and implementing national medicines policies are presented. Finally, reference is made to several authoritative evidence bases to inform the development of pharmaceutical practice and medicines management policies. PMID- 25815200 TI - Patient access schemes in Asia-pacific markets: current experience and future potential. AB - OBJECTIVES: Patient access (or risk-sharing) schemes are alternative market access agreements between healthcare payers and medical product manufacturers for conditional coverage of promising health technologies. This study aims to identify and characterize patient access schemes to date in the Asia-Pacific region. METHODS: We reviewed the literature on patient access schemes over the last two decades using publicly available databases, Internet, and grey literature searches. We extracted key features of each scheme identified, including the drug, clinical indication, stakeholders involved, and details of the scheme. We categorized schemes according to a previously published taxonomy of scheme types and by country. RESULTS: We identified 3 schemes in South Korea, 5 in New Zealand, and 98 in Australia. Most (97.2%; n = 103) schemes focused on pharmaceuticals, few on medical technologies. More than half of the schemes related to treatments for cancer and inflammatory diseases such as rheumatoid arthritis. The majority (77.4%; n =82) involved pricing arrangements. Evidence generation schemes were rarely used. About half (41.8%; n = 41) of schemes in Australia were hybrid by nature, consisting of pricing arrangements with a conditional treatment continuation component. CONCLUSIONS: Australia has the most experience with patient access schemes and its experience may provide useful insights for other Asia-Pacific countries. The main targets are pharmaceuticals likely to have high budget impact (due to high per-patient costs and/or large volumes of use), and pharmaceuticals that may be adopted more widely than indicated. With the proliferation of high-cost medicines, the use of schemes may increase to address rising cost pressures, consumer demands, and uncertainties, while attempting to provide patient access to innovative care within finite budgets. Future research is warranted to evaluate the performance of patient access schemes. PMID- 25815201 TI - Uptake of new antidiabetic medications in three emerging markets: a comparison between Brazil, China and Thailand. AB - OBJECTIVES: New antidiabetic medications such as insulin analogues and thiazolidinediones have been introduced over the last decade. This study compares the uptake of new agents in three emerging pharmaceutical markets: Brazil, China, and Thailand. METHODS: Using longitudinal IMS Health sales data, we calculated the quarterly percentage market share for types of insulins and oral hypoglycemic agents from 2002 through 2012 in each country. New oral hypoglycemic agents included: alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, and non-sulfonylurea secretagogues. RESULTS: While China had the highest use of insulin cartridges and pens (85.6% in 2010), Brazil was the earliest adopter of insulin analogues and had the greatest use of these products overall (44.6% of the insulin market) in 2010, which then decreased by almost half by 2012. Together, sulfonylureas and metformin dominated the markets in Brazil and Thailand (~89% and ~96% respectively) over the 10-year period. Between 2002 and 2012, there was a shift in use from sulfonylureas to metformin; the market share of newer agents remained 10% or less in both countries. In China, however, market share of new oral agents grew rapidly from 13.1% to 44.4%. While metformin use was relatively stable in China (one-third of the market), sulfonylureas declined substantially over the 10-year period (41.5% to 20.8%). CONCLUSION: Given large cost differentials between newer and older insulins and among oral hypoglycemic agents, it is important to evaluate uptake of newer products over time. Uptake patterns differed in the study countries, likely due to different medicines policy approaches. Future research should evaluate how trends in use of antidiabetic products align with national clinical practice guidelines and pharmaceutical policies, as well as the impacts of different patterns of use on cost and clinical outcomes. PMID- 25815202 TI - Onion membrane: an efficient adsorbent for decoloring of wastewater. AB - BACKGROUND: Recently, researchers have tried to design synthetic materials by replicating natural materials as an adsorbent for removing various types of environmental pollutants, which have reached to the risky levels in nature for many countries in the world. In this research, the potential of onion membrane obtained from intermediate of onion shells for adsorption of methylene blue (MB) as a model cationic dye was exhibited. METHODS: Before and after adsorption, the membrane was characterized by Fourier transform infrared spectroscopy (FTIR) and optical and scanning electron microscopy in order to prove its dye adsorption capability. The various experimental conditions affecting dye adsorption were explored to achieve maximum adsorption capacity. RESULTS: The dye adsorption capacity of the membrane was found to be 1.055 g.g(-1) with 84.45% efficiency after one hour and 1.202 g.g(-1) with 96.20% efficiency after eight hours in contact with the dye solution (0.3 g.L(-1)). Moreover, the kinetic, thermodynamic and adsorption isotherm models were employed to described the MB adsorption processes. The results show that the data for adsorption of MB onto the membrane fitted well with the Freundlich isotherm and pseudo-second-order kinetic models. In addition, the MB adsorption from room temperature to ~50 degrees C is spontaneous and thermodynamically favorable. CONCLUSIONS: Evidently, the high efficiency and fast removal of methylene blue using onion membrane suggest the synthesis of polymer-based membranes with similar physical and chemical properties of onion membrane as a valuable and promising wastewater decoloring agents in water treatment. PMID- 25815203 TI - The estimation of per capita loadings of domestic wastewater in Tehran. AB - The amount of wastewater characteristics loading is one of the main parameters in the design of wastewater collection and treatment systems. The generation per capita per day (GPCD) of wastewater characteristics was estimated by analyzing the monthly data of nine wastewater treatment plants in Tehran, capital city of Iran. GPCD values were calculated from measured collected wastewater flow, the population and concentration data. The results indicated the values of 32.96 +/- 1.91, 49.25 +/- 2.49, 37.31 +/- 2.44, 6.77 +/- 0.53, 1.96 +/- 0.11, 92.23 +/- 5.68, 2.07 +/- 0.39 and 128.96 +/- 6.69 g/d.cap of GPCD for BOD5, COD, TSS, TKN, P, TDS, ON and TS, respectively, for Tehran's wastewater. The per capita estimated for the wastewater production and treatment were determined to be 186.06 +/- 7.85 and 136.72 +/- 5.43 L/d.cap, respectively. It is estimated that about 504 m(3)/d and 346 m(3)/d of sludge, will be produced and waste as excrement raw sludge, respectively, in Tehran. Simple regression models were presented the relationships such as the change of collected and treated wastewater with population and changes of GPCD parameters with each other. It was revealed that the Tehran's wastewater may be classified as highly degradable, but during recent decades its Biodegradability Index (BI) has been reduced up to 15%. The new suggested revised per capita parameters can be used for design purposes in Tehran, and possibly, in areas with similar characteristics, substituting the classical values obtained from foreign textbooks. These values could help in designing more accurate treatment systems and may lower the required capacity for the treatment of wastewater up to 40% in Tehran. PMID- 25815204 TI - Healthcare resource implications of hypoglycemia-related hospital admissions and inpatient hypoglycemia: retrospective record-linked cohort studies in England. AB - OBJECTIVE: Using a retrospective cohort study, the mean length of hospital stay (LoS) and total per-patient expenditure for hypoglycemia requiring admission to hospital were estimated. In a separate matched retrospective cohort study, the effect of inpatient hypoglycemia on LoS, expenditure, and risk of all-cause mortality while admitted was investigated. METHODS: The cohorts consisted of patients aged >=18 years with a diagnosis of type 1 or 2 diabetes between January 1, 2002 and October 30, 2012 in the Clinical Practice Research Datalink database, who had initiated insulin treatment and had a recording of hypoglycemia in the same period. In the matched retrospective cohort study, exposed patients (who experienced hypoglycemia in hospital) were case-matched with patients who did not experience hypoglycemia during admission (unexposed). Generalized linear regression was used to estimate LoS. Risk of all-cause mortality was evaluated via logistic regression. RESULTS: In the retrospective cohort study (1131 patients), mean LoS was 5.46 (95% CI 4.62 to 6.45) days for type 1 diabetes, and 5.04 (95% CI 4.46 to 5.71) days for type 2 diabetes. Mean cost per admission was L1034 (95% CI L855 to L1253). In the matched retrospective cohort study (1079 pairs of patients), exposed patients had a mean LoS of 11.91 days (95% CI 10.96 to 12.94 days) versus 4.80 (95% CI 4.41 to 5.23) for unexposed patients, p<0.0001. Exposed patients had a higher mortality risk compared with unexposed patients (OR 1.439 (95% CI 1.060to 1.952), p=0.0195). Total average per-patient cost for exposed patients was GBP (L)2235, 40% (p<0.0001) higher than total average admission cost in unexposed patients. CONCLUSIONS: Hypoglycemia has a significant negative impact on patient outcomes, healthcare resource use, and expenditure. PMID- 25815205 TI - Durability of oral hypoglycemic agents in drug naive patients with type 2 diabetes: report from the Swedish National Diabetes Register (NDR). AB - OBJECTIVE: To analyze the durability of monotherapy with different classes of oral hypoglycemic agents (OHAs) in drug naive patients with type 2 diabetes mellitus (T2DM) in real life. METHODS: Men and women with T2DM, who were new users of OHA monotherapy and registered in the Swedish National Diabetes Register July 2005-December 2011, were available (n=17 309) and followed for up to 5.5 years. Time to monotherapy failure, defined as discontinuation of continuous use with the initial agent, switch to a new agent, or add-on treatment of a second agent, was analyzed as a measure of durability. Baseline characteristics were balanced by propensity score matching 1:5 between groups of sulfonylurea (SU) versus metformin (n=4303) and meglitinide versus metformin (n=1308). HRs with 95% CIs were calculated using Cox regression models. RESULTS: SU and meglitinide, as compared with metformin, were associated with increased risk of monotherapy failure (HR 1.74; 95% CI 1.56 to 1.94 and 1.66; 1.37 to 2.00 for SU and meglitinide, respectively). When broken down by type of monotherapy failure, SU and meglitinide were associated with an increased risk of add-on treatment of a second agent (HR 3.14; 95% CI 2.66 to 3.69 and 2.52; 1.89 to 3.37 for SU and meglitinide, respectively) and of switch to a new agent (HR 2.81; 95% CI 2.01 to 3.92 and 3.78; 2.25 to 6.32 for SU and meglitinide, respectively). The risk of discontinuation did not differ significantly between the groups. CONCLUSIONS: In this nationwide observational study reflecting clinical practice, SU and meglitinide showed substantially increased risk of switch to a new agent or add on of a second agent compared with metformin. These results indicate superior glycemic durability with metformin compared with SU and also meglitinide in real life. PMID- 25815206 TI - Plasma 1-deoxysphingolipids are predictive biomarkers for type 2 diabetes mellitus. AB - OBJECTIVE: Serine palmitoyltransferase (SPT) catalyzes the condensation of serine and palmitoyl coenzyme A, the first step in the de novo sphingolipid synthesis. Apart from these canonical substrates, SPT can also metabolize alanine and other acyl coenzyme As. This forms a spectrum of atypical sphingoid bases which are altered in the context of the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). We investigated whether atypical sphingolipids can be used as prospective markers to predict the incidence of T2DM. RESEARCH DESIGN AND METHODS: Using liquid chromatography/mass spectrometry, we analyzed the sphingoid base profile in a prospective cohort with 339 individuals. All individuals were followed up for a period of 8 years. RESULTS: Confirming earlier results, we found 1-deoxysphingolipids (1-deoxySLs) to be significantly elevated in patients with MetS, impaired fasting glucose, and T2DM. Patients who developed T2DM during the follow-up period (n=32) showed significantly higher 1-deoxySL levels at baseline compared with those who did not develop T2DM until the end of the study (n=70). 1-Deoxysphingosine levels were independent predictors for T2DM even after adjusting for glycated hemoglobin (standardized adjusted OR=2.1, CI 95% (1.19 to 3.71); p=0.010), MetS (standardized adjusted OR=1.97, CI 95% (1.13 to 3.43); p=0.017), and other risk factors such as age, sex, BMI, and lipid-lowering drugs. Similar results were observed for the 1-deoxysphinganine levels. CONCLUSIONS: Our results support a novel role for 1-deoxySL as predictive biomarkers for the development of T2DM in risk patients and warrants further larger prospective trials in lower risk cohorts. PMID- 25815207 TI - Cardiovascular disease in HIV patients: from bench to bedside and backwards. AB - HIV patients are exposed to a higher risk of adverse cardiovascular events, due to complex interactions between traditional risk factors and HIV infection itself in terms of ongoing endothelial dysfunctional immune activation/inflammation and increased risk of thrombosis. On the other hand, long-span antiretroviral therapy administration still raises questions on its long-term safety in an era in which life expectancy is becoming longer and longer while treatment of non-HIV-related serious events is increasingly raising concern. In this article, we will critically analyse the current knowledge of pathological and clinical aspects pertaining to the increased risk of cardiovascular events associated with HIV. PMID- 25815208 TI - Coronary artery stenosis risk and time course in Kawasaki disease patients: experience at a US tertiary pediatric centre. AB - OBJECTIVE: Despite treatment with intravenous immunoglobulin (IVIG), the natural progression to coronary artery stenosis in Kawasaki disease is not well defined and remains a potential cause of long-term morbidity. We present a novel study, at a US tertiary paediatric care centre, identifying risk factors for stenosis. METHODS: We reviewed charts of all children who underwent cardiac catheterisation for coronary artery abnormalities, from 1998 to January 2014, at a tertiary paediatric care centre. Demographic and diagnostic data included time intervals to echocardiographic changes and confirmed catheterisation cases of stenosis. Multivariate survival analysis was used to evaluate risk factors with stenosis formation as the main outcome measure. RESULTS: 53 children met the inclusion criteria and 18 (34.6%) developed stenosis. Only those with giant coronary aneurysms (GCA) developed stenosis, with the highest risk group overall being children under the age of 6 months (hazard ratio (HR) 2.82 3.79, p=0.004). In a subset of only cases of GCA (33), a majority went on to develop stenosis (18/33). Median time to diagnosis was 190 days. In this group, children under the age of 6 months were again at highest risk (HR 2.62, p=0.04). IVIG administration, sex and ethnicity were not statistically significant predictors. CONCLUSIONS: This retrospective study demonstrates a relatively high incidence of stenosis in children with Kawasaki disease and coronary vascular abnormalities. Overall, a majority of cases with GCA progressed into stenosis, with children under the age of 6 months being at highest risk. PMID- 25815209 TI - SWI enhances vein detection using gadolinium in multiple sclerosis. AB - Susceptibility weighted imaging (SWI) combined with the FLAIR sequence provides the ability to depict in vivo the perivenous location of inflammatory demyelinating lesions - one of the most specific pathologic features of multiple sclerosis (MS). In addition, in MS white matter (WM) lesions, gadolinium-based contrast media (CM) can increase vein signal loss on SWI. This report focuses on two cases of WM inflammatory lesions enhancing on SWI images after CM injection. In these lesions in fact the CM increased the contrast between the parenchyma and the central vein allowing as well, in one of the two cases, the detection of a vein not visible on the same SWI sequence acquired before CM injection. PMID- 25815210 TI - Comparison of vertebroplasty using directional versus straight needle. AB - BACKGROUND: Percutaneous vertebroplasty is a minimally invasive procedure that can be performed to treat pain and immobility associated with vertebral compression fractures. Previous studies have shown that a single injection can achieve adequate fill across the midline of the vertebral body. PURPOSE: To compare the radiological outcomes of using a novel steerable needle with using a conventional, straight needle in unipedicular vertebroplasty. MATERIAL AND METHODS: Data were collected from 19 patients who were operated at our institute between 1 September 2010 and 31 March 2011. Outcomes were measured in terms of radiological evidence of midline crossing of cement. The available pre- and postoperative pain scores and complications were reviewed. Student's t-test was used to compare mean cement projection across the midline in both groups with P < 0.05 considered to be statistically significant. RESULTS: Mean fill across the midline was significantly greater with the steerable needle (58%) compared with the straight needle (35%) (P = 0.046). Cement leakage was higher with the steerable needle (44% versus 30%); however no clinical complications were reported in either group. CONCLUSION: Percutaneous vertebroplasty using a directional needle is an excellent example of advancement and refinement in spinal surgery without increased clinical risk. Our results indicate that the novel technique can potentially provide better radiological outcomes when compared with a straight needle. A larger, randomized multicenter prospective trial would be valuable in confirming these findings. PMID- 25815211 TI - The ACE2/Apelin Signaling, MicroRNAs, and Hypertension. AB - The renin-angiotensin aldosterone system (RAAS) plays a pivotal role in the development of hypertension. Angiotensin converting enzyme 2 (ACE2), which primarily metabolises angiotensin (Ang) II to generate the beneficial heptapeptide Ang-(1-7), serves as a negative regulator of the RAAS. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardiovascular protective peptide. The physiological effects of Apelin are exerted through binding to its receptor APJ, a seven-transmembrane G protein coupled receptor that shares significant homology with the Ang II type 1 receptor (AT1R). The deregulation of microRNAs, a class of short and small noncoding RNAs, has been shown to involve cardiovascular remodeling and pathogenesis of hypertension via the activation of the Ang II/AT1R pathway. MicroRNAs are linked with modulation of the ACE2/Apelin signaling, which exhibits beneficial effects in the cardiovascular system and hypertension. The ACE2-coupled crosstalk among the RAAS, the Apelin system, and microRNAs provides an important mechanistic insight into hypertension. This paper focuses on what is known about the ACE2/Apelin signaling and its biological roles, paying particular attention to interactions and crosstalk among the ACE2/Apelin signaling, microRNAs, and hypertension, aiming to facilitate the exploitation of new therapeutic medicine to control hypertension. PMID- 25815212 TI - Whole-foods, plant-based diet alleviates the symptoms of osteoarthritis. AB - Objective. To evaluate the effectiveness of a whole-foods, plant-based diet (WFPB) to reduce symptoms of osteoarthritis. Methods. Six-week, prospective randomized open-label study of patients aged 19-70 with osteoarthritis. Participants were randomized to a WFPB (intervention) or continuing current diet (control). Outcomes were assessed by mixed models analysis of participant self assessed weekly SF-36v2 domain t scores, weekly Patient Global Impression of Change (PGIC) scales, and mean weekly Visual Analog Scale (VAS) pain assessment. Mixed models analysis also evaluated pre-post change from baseline level for standard clinical measures: weight, BMI, body temperature, pulse, and blood pressure. Results. Forty participants were randomized. Thirty-seven of them, 18 control and 19 intervention, completed the study. The intervention group reported a significantly greater improvement than the control group in SF-36v2 energy/vitality, physical functioning, role physical, and the physical component summary scale. The differences between the intervention and control PGIC scales were statistically significant over time. Intervention group improvement in VAS weekly mean was also significantly greater than that of the control group from week 2 onward. Conclusion. Study results suggest that a whole-foods, plant-based diet significantly improves self-assessed measures of functional status among osteoarthritis patients. PMID- 25815213 TI - Effects of Statin versus the Combination of Ezetimibe plus Statin on Serum Lipid Absorption Markers in Patients with Acute Coronary Syndrome. AB - Background. The use of statins is essential for aggressive lipid-lowering treatment in acute coronary syndrome (ACS) patients with dyslipidemia. Recently, elevation of sitosterol, a lipid absorption marker, was reported to be associated with premature atherosclerosis. The purpose of the present study was to examine the impact of ezetimibe, a selective intestinal cholesterol transporter inhibitor, in ACS patients. Methods. A total of 197 ACS patients were randomized to pitavastatin + ezetimibe (n = 100) or pitavastatin (n = 97). Low-density lipoprotein cholesterol (LDL-C) and sitosterol levels were evaluated on admission and after 12 weeks. Results. After 12 weeks, the pitavastatin + ezetimibe group showed a significantly greater decrease of sitosterol (baseline versus after 12 weeks; 2.9 +/- 2.5 versus 1.7 +/- 1.0 ng/mL, P < 0.001) than the pitavastatin group (2.7 +/- 1.5 versus 3.0 +/- 1.4 ng/mL). The baseline sitosterol level was significantly higher in patients with achieved LDL-C levels >= 70 mg/dL than in patients with levels < 70 mg/dL (3.2 +/- 2.5 versus 2.4 +/- 1.3 ng/mL, P = 0.006). Conclusions. Ezetimibe plus statin therapy in ACS patients with dyslipidemia decreased LDL-C and sitosterol levels more than statin therapy solo. Sitosterol Elevation was a predictor of poor response to aggressive lipid lowering treatment in ACS patients. PMID- 25815214 TI - Treatment of the Developmental Dysplasia of the Hip with an Abduction Brace in Children up to 6 Months Old. AB - Introduction. Use of Pavlik harness for the treatment of DDH can be complicated for parents. Any misuse or failure in the adjustments may lead to significant complications. An abduction brace was introduced in our institution, as it was thought to be easier to use. Aim. We assess the results for the treatment of DDH using our abduction brace in children of 0-6 months old and compare these results with data on treatments using the Pavlik harness. Method. Retrospective analysis of patients with DDH from 0 to 6 months old at diagnosis, performed from 2004 to 2009. Outcomes were rates of reduction of the hip and avascular necrosis of the femoral head (AVN). Follow-up was at one year and up to 4 years old. Results. Hip reduction was successful in 28 of 33 patients (85%), with no AVN. Conclusion. Our results in terms of hip reduction rate and AVN rate are similar to those found in literature assessing Pavlik harness use, with a simpler and comfortable treatment procedure. PMID- 25815215 TI - Hyponatraemia after fracture is often caused by hypovolaemia, not SIADH. PMID- 25815216 TI - Anesthesia management of a 20-month-old patient with giant unilateral wilms tumor. AB - Wilms tumour (WT) (or nephroblastoma) is one of the most common malignant kidney tumors in children. On subsequent stages clinically it is often characterized by abdominal hypertension syndrome, which, in turn, leads to development of respiratory insufficiency. Other symptoms comprise renal deficiency, hypertension, and abnormalities of hemostasis and hemogram. Treatment includes rounds of preoperative chemotherapy and subsequent surgery. We report a case of perioperative management for nephrectomy in 20-month-old patient with a giant unilateral WT. The complexity of anesthesia was determined by the size of tumor, increased intra-abdominal pressure, respiratory deficiency, and hypercoagulation. PMID- 25815217 TI - Fulminant hepatic failure secondary to primary hepatic angiosarcoma. AB - Background. Hepatic angiosarcoma is a rare and aggressive tumor that often presents at an advanced stage with nonspecific symptoms. Objective. To report a case of primary hepatic angiosarcoma in an otherwise healthy man with normal liver function tests two months prior to presenting with a short period of jaundice that progressed to fulminant hepatic failure. Methods. Case report and review of literature. Conclusion. This case illustrates the rapidity of progression to death after the onset of symptoms in a patient with hepatic angiosarcoma. Research on early diagnostic strategies and newer therapies are needed to improve prognosis in this rare and poorly understood malignancy with limited treatment options. PMID- 25815219 TI - Retracted: Anti-GBM of Pregnancy: Acute Renal Failure Resolved after Spontaneous Abortion, Plasma Exchange, Hemodialysis, and Steroids. AB - [This retracts the article DOI: 10.1155/2014/243746.]. PMID- 25815218 TI - Combined treatment with antiviral therapy and rituximab in patients with mixed cryoglobulinemia: review of the literature and report of a case using direct antiviral agents-based antihepatitis C virus therapy. AB - Mixed cryoglobulinemia (MC) is an autoimmune/B-cell lymphoproliferative disorder associated with Hepatitis C Virus (HCV) infection, manifesting as a systemic vasculitis. In the last decade, antiviral treatment (AT) with pegylated interferon (Peg-IFN) plus ribavirin (RBV) was considered the first therapeutic option for HCV-MC. In MC patients ineligible or not responsive to antivirals, the anti-CD20 monoclonal antibody rituximab (RTX) is effective. A combined AT plus RTX was also suggested. Since the introduction of direct acting antivirals (DAAs), few data were published about MC and no data about a combined schedule. Here, we report a complete remission of MC after a sustained virological response following a combined RTX/Peg-IFN+RBV+DAA (boceprevir) treatment and review the literature about the combined RTX/AT. PMID- 25815220 TI - Rare occurrence of lip spindle cell lipoma. AB - Spindle cell lipoma (SCL) is a rare distinct variant of lipoma, which presents as a painless, circumscribed, slow-growing, superficial lesion on the lip and can mimic a minor salivary gland tumour. We present a slow growing lower lip lesion and its management. Case Report. A 38-year-old female gave an eight-year history of a slow-growing mass on her lower lip with intermittent change in size. She presented with a submucosal nodule and thin overlying mucosa adjacent to the vermilion border. Surgical excision was carried as the diagnostic and therapeutic approach. Conclusion. Lip SCL is rare, and surgical excision is advocated in order to exclude underlying pathology and minor salivary gland tumours. PMID- 25815221 TI - Descemet membrane endothelial keratoplasty: intraoperative and postoperative imaging spectral-domain optical coherence tomography. AB - We describe a case report of using the same handheld spectral-domain anterior segment optical coherence tomography (ASOCT) for rapid intraoperative and postoperative imaging in a case of Descemet membrane endothelial keratoplasty (DMEK). A 67-year-old woman, with Fuchs dystrophy and corneal decompensation, underwent DMEK with intraoperative ASOCT imaging using the handheld Envisu spectral domain ASOCT system (Bioptigen, Inc., Morrisville, NC, USA). We found that this easy-to-use portable system with handheld probe allowed for rapid imaging of the anterior segment during donor manipulation to visualize the orientation of the DMEK donor, as well as to confirm the initial adhesion of the DMEK donor. Moreover, the same system may be used for postoperative monitoring of graft adhesion, corneal thickness, and stromal remodeling in the clinic with very high-definition images. PMID- 25815222 TI - Bilateral and symmetrical anteromedial bowing of the lower limbs in a patient with neurofibromatosis type-I. AB - An 8-year-old girl was referred to our department because of generalized bowing of long bones (radii, ulnae, and femora) and significant bilateral and symmetrical posteromedial bowing of the tibiae and fibulae. The femora were laterally bowed whereas the tibiae and fibulae showed posteromedial bowing between the middle and distal thirds of the tibia with posterior cortical thickening effectively causing the development of bilateral congenital anterolateral bowing of the tibiae and fibulae. We referred to closing-wedge osteotomy of the left tibia along with fibular osteotomy in order to realign the deformity. Due to the delayed appearance of skin stigmata in her early life, the diagnosis of neurofibromatosis was ruled out. At the age of 9 years, cafe-au-lait spots and axillary freckling were apparent. Genetic tests confirmed von Recklinghausen disease (neurofibromatosis type-I (NF1)) (gene has been localised to 17q22). Interestingly, bilateral and symmetrical anteromedial bowing of the tibiae and fibulae has not been described in patients with NF-I. PMID- 25815223 TI - Conversion of a surgical elbow arthrodesis to total elbow arthroplasty. AB - Arthrodesis of the elbow joint addresses pain due to intra-articular pathology, but with significant functional limitations. Loss of motion at the elbow is not completely compensated by the wrist and shoulder joints and elbow fusion is thus purely a salvage procedure. Advances in joint arthroplasty have allowed surgeons to address the functional limitations of arthrodesis, but despite these advances the elbow is still one of the joint replacements with higher complication rate. Conversion of a joint fusion to arthroplasty has been reported for the hip, knee, shoulder, and ankle. The takedown of a surgically fused elbow was reported in German literature in 2013. We present the first such case report in the English literature with a 49-year-old male whose status is elbow fusion performed for trauma 31 years prior. PMID- 25815224 TI - Arthroscopic quadriceps tendon repair: two case reports. AB - Recently, although some studies of open repair of the tendon of the quadriceps femoris have been published, there have been no reports in the literature on primary arthroscopic repair. In our present study, we present two cases of quadriceps tendon injury arthroscopically repaired with excellent results. Case 1 involved a 68-year-old man who was injured while shifting his weight to prevent a fall. MRI showed complete rupture at the insertion of the patella of the quadriceps tendon. The rupture was arthroscopically repaired using both suture anchor and pull-out suture fixation methods via bone tunnels (hereafter, pull-out fixation). Two years after surgery, retearing was not observed on MRI and both Japan Orthopedic Association (JOA) Knee and Lysholm scores had recovered to 100. Case 2 involved a 50-year-old man who was also injured when shifting his weight to prevent a fall. MRI showed incomplete superficial rupture at the insertion of the patella of the quadriceps tendon. The rupture was arthroscopically repaired using pull-out fixation of six strand sutures. One year after surgery, MRI revealed a healed tendon and his JOA and Lysholm scores were 95 and 100, respectively. Thus, arthroscopic repair may be a useful surgical method for repairing quadriceps tendon injury. PMID- 25815225 TI - Hybrid tumor of the parotid gland: a case report and review of the literature. AB - The parotid gland is the most common location of benign neoplasms affecting major salivary glands. Hybrid tumors are very rare tumor entities which are composed of two different tumor types, each of which conforms to an exactly defined tumor category. The tumor entities of a hybrid tumor are not separated but have an identical origin within the same topographical area. This report describes a 51 year-old male with three neoplasms occurring within a single parotid gland tumor. The clinical, radiological, and histologic features are described in addition to a review of the literature. PMID- 25815226 TI - A surprising finding after external ear polypectomy in a deaf mute patient. AB - Introduction. External auditory canal polyps usually reflect an inflammatory process. Rarely, they may reflect a serious condition that warrants urgent intervention. Case Report. A 19-year-old deaf mute female presented to our department with persistent left ear discharge and a reddish mass in the ear. After surgery, the cause was identified as a neglected foreign body. Tympanic membrane was intact. Conclusion. Aural polyp that is resistant to medical treatment should raise the suspicion of an inflammatory polyp with underlying chronic suppurative otitis media or foreign body. Rarer neoplastic and immunological causes should also be considered. PMID- 25815227 TI - Thoracocervicofacial Emphysema after Heimlich's Maneuvre. AB - We report an extremely rare example of a thoracocervicofacial subcutaneous emphysema after Heimlich maneuver case. PMID- 25815228 TI - Unusual initial presentation of herpes simplex virus as inguinal lymphadenopathy. AB - Genital herpes simplex virus (HSV) infections are a common cause of inguinal lymphadenopathy. However, surgical excision of enlarged inguinal nodes is almost never performed to initially diagnose genital herpes simplex virus, due to the distinct external presentation of genital herpetic vesicles that usually occur with the first symptoms of infection. Therefore, the histologic and immunophenotypic features of HSV-associated inguinal lymphadenopathy are unfamiliar to most pathologists. The current report describes the lymph node pathology of two immunocompetent patients, whose initial HSV diagnosis was established through surgical excision of enlarged inguinal lymph nodes. Histologic examination showed features consistent with viral lymphadenopathy, including florid follicular hyperplasia, monocytoid B-cell hyperplasia, and paracortical hyperplasia without extensive necrosis. Immunohistochemical stains for HSV antigens, using polyclonal anti-HSV I and II antibodies, demonstrate strong immunoreactivity for HSV in a small number of cells in the subcapsular sinuses, especially in areas with monocytoid B-cell hyperplasia. Rare scattered HSV-positive cells also are identified in paracortical areas and germinal centers. We conclude that an initial diagnosis of genital HSV infection may be established by inguinal lymph node biopsy. PMID- 25815229 TI - Hepatocellular carcinoma with both fibrolamellar and classical components: an unusual morphological pattern. AB - Fibrolamellar carcinoma (FLC) is an uncommon form of primary liver malignancy with unique clinical, histological, and biological characteristics. It is usually seen in young adults without underlying liver disease. Histologically, it shows large cells with abundant eosinophilic cytoplasm, large vesicular nuclei, prominent nucleoli, and lamellar type fibrosis. In contrast, classical hepatocellular carcinoma (HCC) is typically present in elderly male patients with cirrhosis. It is the most common histological subtype, and it is characterized by its resemblance to the normal liver, both in its growth pattern and its cytology. The unusual case of a liver carcinoma that presented with histological features of both FLC and classical HCC is herein reported. This was the case of a 37-year old female complaining of diffuse abdominal discomfort and epigastric pain for two months. She was referred to us for further management after she was diagnosed with HCC in a noncirrhotic liver. She underwent a left-sided hepatectomy. A yellow nodular mass with well-defined borders and a necrotic center was present in the resection specimen. The morphological features and immunohistochemical studies were consistent with a diagnosis of FLC mixed with classical HCC. The patient was followed up for five months, and no signs of recurrence were evident. PMID- 25815230 TI - Cytological features of mammary analogue secretory carcinoma of the parotid gland in a 15-year-old girl: a case report with review of the literature. AB - Mammary analogue secretory carcinoma (MASC) is a recently recognized tumor of salivary glands characterized by the ETV6-NTRK3 fusion gene. This tumor is very rare in children and adolescents. We report a case of MASC in a 15-year-old girl, the fifth youngest case so far reported. The patient complained of a left infra auricular mass that gradually enlarged for a year. Fine-needle aspiration cytology/imprint cytology showed individual tumor cells that had faintly eosinophilic granular cytoplasm with secretion granules sometimes seen adjacent to the tumor cells. These cytological features overlapped between those of zymogen granule-poor acinic cell carcinoma (AciCC) and MASC. In addition to the case report, we present a review of the related literature with a focus on the cytological features of MASC. The differential diagnostic clues are also discussed. PMID- 25815231 TI - Systemic steroid treatment for severe expanding pneumococcal pneumonia. AB - The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic therapy and supportive care such as intravenous fluids and supplemental oxygen. There is no available data regarding the use of steroids in CAP in children. We present an unusual case of a child with severe respiratory distress, on the brink of mechanical ventilation, due to a rapidly expanding pneumococcal pneumonia. The administration of systemic steroids resulted in a dramatic response with rapid improvement of clinical and radiological abnormalities followed by improvement of laboratory abnormalities. This case report should raise the awareness of the potential benefits of steroids in the treatment of severe pneumonia in children. Prospective randomized trials are needed to confirm the efficacy of steroids in this setting and to determine which patients would benefit most from this. PMID- 25815232 TI - Pulmonary epithelioid hemangioendothelioma in a patient with Crohn's disease. AB - Pulmonary epithelioid hemangioendothelioma (PEH) is a rare neoplasm, largely unresponsive to chemotherapeutic medications, and with varied prognosis. Imaging on computerized tomography may demonstrate perivascular nodules, but diagnosis is ultimately made on biopsy with immunohistochemical analysis. Here we describe a case of PEH in a 14-year-old male with Crohn's disease, which, to our knowledge, has not previously been described in the literature. PMID- 25815233 TI - Corrigendum to "Gitelman Syndrome in a School Boy Who Presented with Generalized Convulsion and Had a R642H/R642W Mutation in the SLC12A3 Gene". AB - [This corrects the article DOI: 10.1155/2014/279389.]. PMID- 25815234 TI - Costello syndrome with severe nodulocystic acne: unexpected significant improvement of acanthosis nigricans after oral isotretinoin treatment. AB - We report the case of 17-year-old female diagnosed with Costello syndrome. Genetic testing provided a proof with G12S mutation in the HRAS gene since 3 years of age with a presentation of severe nodulocystic acne on her face. After 2 months of oral isotretinoin treatment, improvement in her acne was observed. Interestingly, an unexpected significant improvement of acanthosis nigricans on her neck and dorsum of her hands was found as well. We present this case as a successful treatment option by using oral isotretinoin for the treatment of acanthosis nigricans in Costello syndrome patients. PMID- 25815235 TI - Ischemic cardiomyopathy and cerebral infarction in a young patient associated with khat chewing. AB - Khat is a stimulating agent used by many people in the Horn of Africa and the Arabian peninsula. Khat chewing is a known cardiovascular risk factor and is thought to cause vasoconstriction, systemic hypertension, and thrombogenicity. A 33-year-old Somalian man initially presented with loss of neurological function of the left arm, hazy vision, and headache. He smokes tobacco and chews two bundles of khat a week for more than 10 years. His ECG on admission showed a Q wave in V1 and V2 and 2 mm ST-elevations in V1, V2, and V3 and a terminal negative T wave in I, aVL, V2, V3, and V4, consistent with a recent, evolving anterior infarction. A noncontrast enhanced CT of the brain showed ischemia in the right middle cerebral artery vascular territory. An MRI showed recent ischemia in the vascular territory of the posterior division of the right middle cerebral artery. Coronary angiography showed a 70% stenosis with haziness of the proximal left anterior descending artery. Diagnostic tests and imaging are consistent with recent myocardial infarction in the LAD vascular territory because of coronary spasm and cerebral infarction in the middle cerebral artery vascular territory probably related to khat chewing. PMID- 25815236 TI - Rhabdomyolysis Occurring under Statins after Intense Physical Activity in a Marathon Runner. AB - Statins are widely used in the treatment of hypercholesterolemia and their side effects on muscles are well established. Conversely, data are sparse regarding the safety of this class of drugs in subjects who engage in sports, particularly those who have intense sports activity. We report the case of a marathon runner who presented with acute rhabdomyolysis during competition while being under rosuvastatin treatment. This case raises the question of the need for temporary discontinuation of statin therapy when intense physical activity is planned. PMID- 25815237 TI - Retroperitoneal perforation of the appendix presenting as a right thigh abscess. AB - A rare case of a retroperitoneal rupture of the appendix is being reported here. A 53-year-old male presented to us with a right sided thigh abscess. There were not any abdominal complaints at presentation. There was continuous discharge after incision and drainage from the thigh. Isolation, in culture, of an enteric bacterium from the pus prompted an evaluation of the gastrointestinal tract as a possible source. An MRI scan revealed fluid tracking from the right paracolic gutter over the psoas sheath and paraspinal muscle into the thigh. A CT scan revealed the perforation at the base of the appendix into the retroperitoneum. At laparotomy the above findings were confirmed. A segmental ileocaecal resection was done. The patient made an uneventful recovery. The absence of abdominal symptoms at presentation leads to delay in diagnosis in such cases. Nonresolving thigh and groin abscesses should lead to the evaluation of the gastrointestinal tract as origin. Diagnostic clues may also be provided by culture reports what as happened in this case. PMID- 25815238 TI - A case of ruptured aortic arch aneurysm successfully treated by thoracic endovascular aneurysm repair with chimney graft. AB - We report the case of aortic arch aneurysm rupture treated successfully with thoracic endovascular aneurysm repair (TEVAR) accompanied by aortic arch debranching using the chimney graft technique. A 94-year-old man was transported to the hospital after complaining of chest pain for one day. Contrast-enhanced computed tomographic (CT) images revealed an aortic arch aneurysm rupture. Considering the patient's age and postoperative activities of daily living, TEVAR was used. In order to place an indwelling stent graft from the ascending aorta to the periphery, the chimney graft technique was used to debranch the brachiocephalic artery. Hemodynamics was stabilized postsurgically. Plain CT performed 20 days postoperatively confirmed that the intrathoracic hematoma had decreased in size. Although respiratory failure was persistent, there were improvements and the patient was extubated 34 days postoperatively and discharged from the intensive care unit 37 days postoperatively. On postoperative day 75, he was discharged from the hospital to an elder care facility. Few reports have focused on stent grafting for treating aortic arch aneurysm rupture. TEVAR using the chimney graft technique could be an effective treatment option for patients with a decreased ability to tolerate surgery. PMID- 25815239 TI - Unusual fungal infections in renal transplant recipients. AB - Fungal infections are an important cause of morbidity and mortality in renal transplant recipients. The causative agent and the risk factors differ depending on the period after the kidney transplant. Also the incidence varies according to the geographical area. We are reporting three cases of fungal infections in renal transplant recipients. Two of them have etiological agents which are common among immunosuppressed patients, but with an atypical clinical presentation, while one of them is a subcutaneous infection caused by a less frequent dematiaceous fungus, Aureobasidium pullulans. These cases highlight how a high index of clinical suspicion and prompt diagnosis is very much essential for better outcome. The emerging fungal infections and paucity of data regarding their management pose a challenge to the transplant physicians. PMID- 25815240 TI - TAP-Stenting Technique for Bifurcation Stenosis of Celiac Artery. AB - We report a clinical course of a patient who developed severe ischemic liver injury and total occlusion of the celiac artery (CA). A 40-year-old man presented with abdominal pain. Computed tomography indicated total occlusion of the CA. Laboratory data demonstrated markedly elevated hepatic enzymes. An exploratory laparotomy was not necessitated due to absence of peritonism. The patient was successfully treated by endovascular recanalization of the CA occlusion via transcatheter balloon angioplasty and TAP-stenting (T-stenting and small protrusion) technique. Endovascular intervention in patients solely with liver failure appears practicable and early treatment is advised. PMID- 25815241 TI - Teaching and Learning Medical Biochemistry: Perspectives from a Student and an Educator. PMID- 25815242 TI - Dual-Energy CT: What the Neuroradiologist Should Know. AB - Because of the different attenuations of tissues at different energy levels, dual energy CT offers tissue differentiation and characterization, reduction of artifacts, and remodeling of contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR), hereby creating new opportunities and insights in CT imaging. The applications for dual-energy imaging in neuroradiology are various and still expanding. Automated bone removal is used in CT angiography and CT venography of the intracranial vessels. Monoenergetic reconstructions can be used in patients with or without metal implants in the brain and spine to reduce artifacts, improve CNR and SNR, or to improve iodine conspicuity. Differentiation of iodine and hemorrhage is used in high-density lesions, after intra-arterial recanalization in stroke patients or after administration of contrast media. Detection of underlying (vascular and non-vascular) pathology and spot sign can be used in patients presenting with (acute) intracranial hemorrhage. PMID- 25815243 TI - Personality, Emotions, and the Emotional Disorders. AB - We examined symptom-level relations between the emotional disorders and general traits within the five-factor model of personality. Neuroticism correlated strongly with the general distress/negative affectivity symptoms (depressed mood, anxious mood, worry) that are central to these disorders; more moderately with symptoms of social phobia, affective lability, panic, posttraumatic stress disorder, lassitude, checking, and obsessive intrusions; and more modestly with agoraphobia, specific phobia, and other symptoms of depression and obsessive compulsive disorder. Extraversion was negatively correlated with symptoms of social anxiety/social phobia and was positively related to scales assessing expansive positive mood and increased social engagement in bipolar disorder. Conscientiousness, agreeableness, and openness showed weaker associations and generally added little to the prediction of these symptoms. It is noteworthy, moreover, that our key findings replicated well across (a) self-rated versus (b) interview-based symptom measures. We conclude by discussing the diagnostic and assessment implications of these data. PMID- 25815244 TI - Comparison of dose distributions hippocampus in high grade gliomas irradiation with linac-based imrt and volumetric arc therapy: a dosimetric study. AB - The aim of this study was to assess the feasibility of sparing contralateral hippocampus during partial brain radiotherapy in high grade gliomas. 20 previously treated patients were replanned to 60 Gy in 30 fractions with sparing intensity-modulated radiotherapy (IMRT) and volumetric modulated arctherapy (VMAT) using the following planning objectives: 100 % of PTV covered by 95% isodose without violating organs at risk (OAR) and hot spot dose constraints. For each, standard intensity-modulated radiotherapy (IMRT) plans were generated, as well as sparing IMRT and VMAT plans which spared contralateral (hemispheric cases) hippocampus. When the three plans were compared, there was equivalent PTV coverage, homogeneity, and conformality. Sparing IMRT significantly reduced maximum, mean, V20, V30 and V40 hippocampus doses compared with standart IMRT and VMAT (p < 0.05). VMAT significantly reduced maximum left lens and mean eye doses compared with standart IMRT and sparing IMRT (p < 0.05). Brainstem, chiasm, left and right optic nerves, right eyes and lens doses were similar. VMAT significantly reduced monitor units compared with standart IMRT and sparing IMRT (p < 0.05). It is possible to spare contralateral hippocampus during PBRT for high grade gliomas using IMRT. This approach may reduce late cognitive sequelae of cranial radiotherapy. PMID- 25815245 TI - Clinical characteristics and treatment-related biomarkers associated with response to high-dose interleukin-2 in metastatic melanoma and renal cell carcinoma: retrospective analysis of an academic community hospital's experience. AB - BACKGROUND: Immunotherapy in the treatment of metastatic melanoma and renal cell carcinoma can produce durable therapeutic responses, which may improve survival. We aimed to identify clinical characteristics and biomarkers associated with response to high-dose interleukin-2 therapy (IL-2) in patients with metastatic melanoma and renal cell carcinoma treated at an academic community hospital. PATIENTS/METHODS: We retrospectively analyzed clinical variables and biomarkers of 50 consecutive metastatic melanoma or renal cell carcinoma patients treated at our institution with IL-2 during 2004 - 2012. We evaluated clinical characteristics: metastatic sites of disease, prior therapies, number of IL-2 doses per cycle, response duration, autoimmune phenomena, and peak fever, as well as laboratory biomarkers: baseline LDH, platelet nadir, and baseline and highest absolute lymphocyte count (ALC). Survival outcomes were calculated using Kaplan Meier curves. RESULTS: Variables differing between responders (clinical benefit group) and non-responders (no clinical benefit group) in metastatic melanoma included platelet nadir during treatment (p = 0.015), autoimmune phenomena (p = 0.049), and in renal cell carcinoma, platelet nadir (p = 0.026). There were no significant differences between number of doses of IL-2 received per cycle and response in either cancer subtype. Clinical benefit occurred in 25% of patients (9/36) when IL-2 was given as first-line therapy. Median overall survival for the clinical benefit group from the initiation of IL-2 to death or last follow-up was 61 months versus 17 months for the no clinical benefit group (p < 0.001) for metastatic melanoma. In renal cell carcinoma overall survival for clinical benefit patients was 48 months versus 17 months. No treatment-related deaths occurred. CONCLUSIONS: High-dose IL-2 can be safely administered by an experienced team in a non-intensive care oncology unit. The clinical benefit group developed autoimmune phenomena (melanoma patients), lower platelet nadir, and on average, received the same number of IL-2 doses as the no clinical benefit group, suggesting a response relationship to the patient's baseline immune status. Further investigation of immune predictors of response may be useful to select appropriate patients for this therapy. PMID- 25815246 TI - Prognostic value of the lymph node ratio for lymph-node-positive breast cancer- is it just a denominator problem? AB - PURPOSE: To examine the prognostic value of lymph node ratio (LNR) for patients with node-positive breast cancer with varying numbers of minimum nodes removed (>5, > 10 and > 15 total node count). METHODS: This study examined the original histopathological reports of 332 node-positive patients treated in the state of New South Wales (NSW), Australia between 1 April 1995 and 30 September 1995. The LNR was defined as the number of positive lymph nodes (LNs) over the total number of LNs removed. The LNR cutoffs were defined as low-risk, 0.01-0.20; intermediate risk, 0.21- 0.65; and high-risk, LNR >0.65. RESULTS: The median follow-up was 10.3 years. In multivariate analysis, LNR was an independent predictor of 10-year breast cancer specific survival when > 5 nodes were removed. However, LNR was not an independent predictor when > 15 nodes were removed. In a multivariate analysis the relative risk of death (RR) decreased from 2.20 to 1.05 for intermediate-risk LNR and from 3.07 to 2.64 for high-risk while P values increased from 0.027 to 0.957 for intermediate-risk LNR and 0.018 to 0.322 for high-risk with the number of nodes removed increasing from > 5 to > 15. CONCLUSIONS: Although LNR is important for patients with low node denominators, for patients with macroscopic nodal metastases in several nodes following an axillary dissection who have more than 15 nodes dissected, the oncologist can be satisfied that prognosis, selection of adjuvant chemotherapy and radiotherapy fields can be based on the numerator of the positive nodes. PMID- 25815247 TI - The flavonoid profile of pigeonpea, Cajanus cajan: a review. AB - BACKGROUND: Pigeonpea is ranked as the sixth largest grain legume produced by volume and as such is a major global food crop for livestock and human consumption. We show that pigeonpea contains a number of flavonoids and report their distribution and concentration within different parts of the plant. FINDINGS: There are a total of 27 flavonoids reported in the literature representing seven flavonoid classes. We found no published evidence of flavanols (catechins/flavan-3-ols) or aurones reported from pigeonpea, nor any study of the flavonoids from pigeonpea flowers. CONCLUSIONS: Despite over 40 years of research in to various aspects of pigeonpea we identified research gaps related to the phytochemical properties of pigeonpea. We explain how addressing these gaps could help to realise the full potential of pigeonpea in agricultural production. PMID- 25815248 TI - New method to determine proton trajectories in the equatorial plane of a dipole magnetic field. AB - A parametric description of proton trajectories in the equatorial plane of Earth's dipole magnetic field has been derived. The exact expression of the angular coordinate contains an integral to be performed numerically. The radial coordinate results from the initial conditions by basic mathematical operations and by using trigonometric functions. With the approximate angular coordinate formula, applicable for a wide variety of cases of protons trapped in Earth's radiation belts, no numerical integration is needed. The results of exact and approximate expressions were compared for a specific case and small differences were found. PMID- 25815250 TI - Is lithium potentially a trace element? AB - Lithium, a naturally occurring element, is widely used in clinical settings for psychiatric treatment. Several studies showed that micro-dose lithium (e.g., lithium in drinking water) could have anti-aging and anti-dementia effects in addition to an anti-suicidal effect, although anti-mania and psychosis or anti cancer effects are yet to be determined. Although these studies do not provide conclusive evidence, further studies are warranted to investigate whether lithium is trace element. If so, future studies would need to determine what levels are required to maintain mental health. PMID- 25815249 TI - Placebo eff ects in psychiatry: mediators and moderators. AB - A strong placebo response in psychiatric disorders has been noted for the past 50 years and various attempts have been made to identify predictors of it, by use of meta-analyses of randomised controlled trials and laboratory studies. We reviewed 31 meta-analyses and systematic reviews of more than 500 randomised placebo controlled trials across psychiatry (depression, schizophrenia, mania, attention deficit hyperactivity disorder, autism, psychosis, binge-eating disorder, and addiction) for factors identified to be associated with increased placebo response. Of 20 factors discussed, only three were often linked to high placebo responses: low baseline severity of symptoms, more recent trials, and unbalanced randomisation (more patients randomly assigned to drug than placebo). Randomised controlled trials in non-drug therapy have not added further predictors, and laboratory studies with psychological, brain, and genetic approaches have not been successful in identifying predictors of placebo responses. This comprehensive Review suggests that predictors of the placebo response are still to be discovered, the response probably has more than one mediator, and that different and distinct moderators are probably what cause the placebo response within psychiatry and beyond. PMID- 25815251 TI - Culturally sanctioned suicide: Euthanasia, seppuku, and terrorist martyrdom. AB - Suicide is one of the greatest concerns in psychiatric practice, with considerable efforts devoted to prevention. The psychiatric view of suicide tends to equate it with depression or other forms of mental illness. However, some forms of suicide occur independently of mental illness and within a framework of cultural sanctioning such that they aren't regarded as suicide at all. Despite persistent taboos against suicide, euthanasia and physician-assisted suicide in the context of terminal illness is increasingly accepted as a way to preserve autonomy and dignity in the West. Seppuku, the ancient samurai ritual of suicide by self-stabbing, was long considered an honorable act of self-resolve such that despite the removal of cultural sanctioning, the rate of suicide in Japan remains high with suicide masquerading as seppuku still carried out both there and abroad. Suicide as an act of murder and terrorism is a practice currently popular with Islamic militants who regard it as martyrdom in the context of war. The absence of mental illness and the presence of cultural sanctioning do not mean that suicide should not be prevented. Culturally sanctioned suicide must be understood in terms of the specific motivations that underlie the choice of death over life. Efforts to prevent culturally sanctioned suicide must focus on alternatives to achieve similar ends and must ultimately be implemented within cultures to remove the sanctioning of self-destructive acts. PMID- 25815253 TI - Smoking in schizophrenic patients: A critique of the self-medication hypothesis. AB - A common remark among laypeople, and notably also among mental health workers, is that individuals with mental illnesses use drugs as self-medication to allay clinical symptoms and the side effects of drug treatments. Roots of the self medication concept in psychiatry date back at least to the 1980s. Observations that rates of smokers in schizophrenic patients are multiple times the rates for regular smoking in the general population, as well as those with other disorders, proved particularly tempting for a self-medication explanation. Additional evidence came from experiments with animal models exposed to nicotine and the identification of neurobiological mechanisms suggesting self-medication with smoking is a plausible idea. More recently, results from studies comparing smoking and non-smoking schizophrenic patients have led to the questioning of the self-medication hypothesis. Closer examination of the literature points to the possibility that smoking is less beneficial on schizophrenic symptomology than generally assumed while clearly increasing the risk of cancer and other smoking related diseases responsible for early mortality. It is a good time to examine the evidence for the self-medication concept as it relates to smoking. Our approach is to focus on data addressing direct or implied predictions of the hypothesis in schizophrenic smokers. PMID- 25815254 TI - Raising attention to attention deficit hyperactivity disorder in schizophrenia. AB - Schizophrenia and attention deficit hyperactivity disorder (ADHD) are two psychiatric disorders with a negative impact on quality of life of individuals affected. Although they are classified into distinct disorders categories, attentional dysfunction is considered as a core feature in both conditions, either at the clinical then pathophysiological level. Beyond the obvious clinical overlap between these disorders, the Research Domain Criteria approach might offer an interesting perspective for disentangling common circuits underpinning both disorders. Hence, we review evidences regarding the overlap between schizophrenia and ADHD, at the clinical level, and at the level of underlying brain mechanisms. The evidence regarding the influence of environmental risk factors in the emergence of both disorders, and their developmental trajectories is also reviewed. Among these, we will try to elucidate the complex relationship between stimulants use and psychotic symptoms, discussing the potential role of ADHD medication in inducing psychosis or in exacerbating it. We aim that, taken together, these findings may promote further investigation with important implications both for clinicians and research. In fact, considering the amounting evidence on the overlap between schizophrenia and ADHD, the delineation of their boundaries might help in the decision for diagnosis and treatment. Moreover, it may help to promote interventions focused on the prevention of both schizophrenia and ADHD, by the reduction of recognized environmental risk factors. PMID- 25815255 TI - Assessment of psychological predictors of weight loss: How and what for? AB - Obesity is a multifactorial disease and the prominent factors playing a role in its pathogenesis are biological, environmental and psychological. There is a growing interest in understanding psychological functioning of obese subjects and the influence of psychological factors on treatment outcome. The aim of the present narrative review is to critically analyze the current literature, in order to point out the most common psychological constructs studied in obesity and to give an overview of the main existing tools investigating psychological features which have been considered significant for the prediction of success in weight loss and maintenance programs in obese patients. In this framework, the most common psychological constructs studied are: self-motivation, self-efficacy, locus of control, health related quality of life, self-esteem, self-control, concerns about body image, outcome expectations, and personality traits. These features have been explored through a wide variety of psychometric instruments. However, as an overall, studies evaluating the association between psychological features and treatment outcome failed to give consistent results. A possible explanation may consist on the fact that many tools widely used to explore psychological features were not specifically designed for obese patients and none of them was comprehensive of all possible psychological features involved. The identification of well-defined sub-groups of patients and the validation of more reliable and comprehensive tools, specifically designed for obese subjects, should be forecasted in order to reach a better knowledge of psychological functioning of obese individuals and to improve the outcome of weight loss programs. PMID- 25815252 TI - Role of perinatal long-chain omega-3 fatty acids in cortical circuit maturation: Mechanisms and implications for psychopathology. AB - Accumulating translational evidence suggests that the long-chain omega-3 fatty acid docosahexaenoic acid (DHA) plays a role in the maturation and stability of cortical circuits that are impaired in different recurrent psychiatric disorders. Specifically, rodent and cell culture studies find that DHA preferentially accumulates in synaptic and growth cone membranes and promotes neurite outgrowth, dendritic spine stability, and synaptogenesis. Additional evidence suggests that DHA may play a role in microglia-mediated synaptic pruning, as well as myelin development and resilience. In non-human primates n-3 fatty acid insufficiency during perinatal development leads to widespread deficits in functional connectivity in adult frontal cortical networks compared to primates raised on DHA-fortified diet. Preterm delivery in non-human primates and humans is associated with early deficits in cortical DHA accrual. Human preterm birth is associated with long-standing deficits in myelin integrity and cortical circuit connectivity and increased risk for attention deficit/hyperactivity disorder (ADHD), mood, and psychotic disorders. In general, ADHD and mood and psychotic disorders initially emerge during rapid periods of cortical circuit maturation and are characterized by DHA deficits, myelin pathology, and impaired cortical circuit connectivity. Together these associations suggest that early and uncorrected deficits in fetal brain DHA accrual may represent a modifiable risk factor for cortical circuit maturation deficits in psychiatric disorders, and could therefore have significant implications for informing early intervention and prevention strategies. PMID- 25815256 TI - Effects of music and music therapy on mood in neurological patients. AB - Mood disorder and depressive syndromes represent a common comorbid condition in neurological disorders with a prevalence rate that ranges between 20% and 50% of patients with stroke, epilepsy, multiple sclerosis, and Parkinson's disease. Notwithstanding, these conditions are often under-diagnosed and under-treated in the clinical practice and negatively affect the functional recovery, the adherence to treatment, the quality of life, and even the mortality risk. In addition, a bidirectional association between depression and neurological disorders may be possible being that depressive syndromes may be considered as a risk factor for certain neurological diseases. Despite the large amount of evidence regarding the effects of music therapy (MT) and other musical interventions on different aspects of neurological disorders, no updated article reviewing outcomes such as mood, emotions, depression, activity of daily living and so on is actually available; for this reason, little is known about the effectiveness of music and MT on these important outcomes in neurological patients. The aim of this article is to provide a narrative review of the current literature on musical interventions and their effects on mood and depression in patients with neurological disorders. Searching on PubMed and PsycInfo databases, 25 studies corresponding to the inclusion criteria have been selected; 11 of them assess the effects of music or MT in Dementia, 9 explore the efficacy on patients with Stroke, and 5 regard other neurological diseases like Multiple Sclerosis, Amyotrophic Lateral Sclerosis/motor neuron disease, Chronic quadriplegia, Parkinson's Disease, and Acquired Brain dysfunctions. Selected studies are based on relational and rehabilitative music therapy approaches or concern music listening interventions. Most of the studies support the efficacy of MT and other musical interventions on mood, depressive syndromes, and quality of life on neurological patients. PMID- 25815257 TI - Sensation/novelty seeking in psychotic disorders: A review of the literature. AB - The evaluation of personality traits is important for the better understanding of the person suffering from psychosis and for treatment individualization. However literature on patients' personality and character in such disorders is limited. The aim of this review was to summarize the literature on sensation/novelty seeking (SNS), a trait which is biologically based and highly heritable and is associated with dopamine activity, and refers to a person's tendency to seek varied, novel, complex, and intense sensations and experiences. A total of 38 studies were included in this review, involving 2808 patients and 2039 healthy controls. There is consistent evidence that this trait is independently associated with alcohol and substance abuse in patients with schizophrenia and related disorders. The estimation of SNS would help clinicians to identify patients at risk for abuse. There is also some evidence that higher SNS levels may relate to medication non-adherence and seem to increase the risk of patients' aggressive and violent behavior, but studies are scarce. SNS was found not to be related to suicidality, whereas in the fields of patients' quality of life and psychopathology results are contradictory, but most studies show no possible association. Several studies suggest that SNS is lower in psychotic patients compared to controls, whereas most yield no differences. The evidence for this trait as a potential endophenotype of schizophrenia is weak. SNS may be implicated in psychotic disorders' course and prognosis in several ways and should be always inquired for. This trait can be reliably measured with the use of easily applicable self-rated instruments, and patients' accounts could inform clinicians when planning management and delivering individualized treatment. PMID- 25815259 TI - Postpartum depression: A systematic review of the genetics involved. AB - Postpartum depression is one of the most prevalent psychopathologies. Its prevalence is estimated to be between 10% and 15%. Despite its multifactorial etiology, it is known that genetics play an important role in the genesis of this disorder. This paper reviews epidemiological evidence supporting the role of genetics in postpartum depression (PPD). The main objectives of this review are to determine which genes and polymorphisms are associated with PPD and discuss how this association may occur. In addition, this paper explores whether these genes are somehow related to or even the same as those linked to Major Depression (MD). To identify gaps in the current knowledge that require investigation, a systematic review was conducted in the electronic databases PubMed, LILACS and SciELO using the index terms "postpartum depression" and "genetics". Literature searches for articles in peer-reviewed journals were made until April 2014. PPD was indexed 56 times with genetics. The inclusion criteria were articles in Portuguese, Spanish or English that were available by institutional means or sent by authors upon request; this search resulted in 20 papers. Genes and polymorphisms traditionally related to MD, which are those involved in the serotonin, catecholamine, brain-derived neurotrophic factor and tryptophan metabolism, have been the most studied, and some have been related to PPD. The results are conflicting and some depend on epigenetics, which makes the data incipient. Further studies are required to determine the genes that are involved in PPD and establish the nature of the relationship between these genes and PPD. PMID- 25815258 TI - Transcranial direct current stimulation in psychiatric disorders. AB - The interest in non-invasive brain stimulation techniques is increasing in recent years. Among these techniques, transcranial direct current stimulation (tDCS) has been the subject of great interest among researchers because of its easiness to use, low cost, benign profile of side effects and encouraging results of research in the field. This interest has generated several studies and randomized clinical trials, particularly in psychiatry. In this review, we provide a summary of the development of the technique and its mechanism of action as well as a review of the methodological aspects of randomized clinical trials in psychiatry, including studies in affective disorders, schizophrenia, obsessive compulsive disorder, child psychiatry and substance use disorder. Finally, we provide an overview of tDCS use in cognitive enhancement as well as a discussion regarding its clinical use and regulatory and ethical issues. Although many promising results regarding tDCS efficacy were described, the total number of studies is still low, highlighting the need of further studies aiming to replicate these findings in larger samples as to provide a definite picture regarding tDCS efficacy in psychiatry. PMID- 25815260 TI - Review of the genetic basis of emotion dysregulation in children and adolescents. AB - Previous evidence suggests that emotion dysregulation may have different biological correlates between adults and children/adolescents. Although the role of genetic factors has been extensively studied in adult-onset emotion dysregulation, the genetic basis for pediatric-onset emotion dysregulation remains elusive. The current review article presents a summary of previous studies that have suggested a few genetic variants associated with pediatric emotion dysregulation. Among these candidate loci, many prior studies have been focused on serotonin transporter promoter gene polymorphism 5-HTTLPR. Certain alleles of the 5-HTTLPR gene polymorphism have been found to be associated with traits associated with emotion dysregulation, such as aggression, affect reactivity, and insecure attachment. Additionally, genetic variants involving dopamine and neurophysiological biomarkers like the COMT Val158Met (rs460) and dopamine receptor D2/ ankyrin repeat and kinase domain containing one polymorphisms may play a role in emotion dysregulation. Inconsistent findings have been noted, possibly due to the heterogeneity in study designs and characteristics of different populations. Further research on the role of genetic predetermination of emotion dysregulation in children and adolescents is warranted. PMID- 25815261 TI - Associative stigma in family members of psychotic patients in Flanders: An exploratory study. AB - AIM: To assess presence and severity of associative stigma in family members of psychotic patients and factors for higher associative stigma. METHODS: Standardized semi-structured interview of 150 family members of psychotic patients receiving full time treatment. This study on associative stigma in family members of psychotic patients was part of a larger research program on the burden of the family, using "Interview for the Burden of the Family" and the chapters stigma, treatment and attribution from the "Family interview Schedule". The respondents were relatives, one per patient, either partner or parent. The patients had been diagnosed with schizophrenia or schizo-affective disorder. All contacts with patients and relatives were in Dutch. Relatives were deemed suitable to participate in this research if they saw the patient at least once a week. Recruitment took place in a standardized way: after obtaining the patient's consent, the relatives were approached to participate. The results were analyzed using SPSS Version 18.0. RESULTS: The prevalence of associative stigma in this sample is 86%. Feelings of depression in the majority of family members are prominent. Twenty-one point three percent experienced guilt more or less frequent, while shame was less pronounced. Also, 18.6% of all respondents indicated that they tried to hide the illness of their family member for others regularly or more. Three six point seven percent really kept secret about it in certain circumstances and 29.3% made efforts to explain what the situation or psychiatric condition of their family member really is like. Factors with marked significance towards higher associative stigma are a worsened relationship between the patient and the family member, conduct problems to family members, the patients' residence in a residential care setting, and hereditary attributional factors like genetic hereditability and character. The level of associative stigma has significantly been predicted by the burden of aggressive disruptions to family housemates of the psychotic patient. CONCLUSION: Family members of psychotic patients in Flanders experience higher associative stigma compared to previous international research. Disruptive behavior by the patient towards in-housing family members is the most accurate predictor of higher associative stigma. PMID- 25815262 TI - Mood Spectrum Model: Evidence reconsidered in the light of DSM-5. AB - AIM: to investigate studies conducted with the Mood Spectrum Structured Interviews and Self-Report versions (SCI-MOODS and MOODS-SR). METHODS: We conducted a review of studies published between 1997 and August 2014. The search was performed using Pubmed and PsycINFO databases. Analysis of the papers followed the inclusion and exclusion criteria recommended by the PRISMA Guidelines, namely: (1) articles that presented a combination of at least two terms, "SCI-MOODS" [all fields] or "MOODS-SR" [all fields] or "mood spectrum" [all fields]; (2) manuscript in English; (3) original articles; and (4) prospective or retrospective original studies (analytical or descriptive), experimental or quasi-experimental studies. Exclusion criteria were: (1) other study designs (case reports, case series, and reviews); (2) non-original studies including editorials, book reviews and letters to the editor; and (3) studies not specifically designed and focused on SCI-MOODS or MOODS-SR. RESULTS: The search retrieved 43 papers, including 5 reviews of literature or methodological papers, and 1 case report. After analyzing their titles and abstracts, according to the eligibility criteria, 6 were excluded and 37 were chosen and included. The SCI MOODS and the MOODS-SR have been tested in published studies involving 52 different samples across 4 countries (Italy, United States, Spain and Japan). The proposed mood spectrum approach has demonstrated its usefulness mainly in 3 different areas: (1) Patients with the so-called "pure" unipolar depression that might manifest hypomanic atypical and/or sub-threshold aspects systematically detectable with the mood questionnaire; (2) Spectrum features not detected by other instruments are clinically relevant, because they might manifest in waves during the lifespan, sometimes together, sometimes alone, sometimes reaching the severity for a full-blown disorder, sometimes interfering with other mental disorders or complicating the course of somatic diseases; and (3) Higher scores on the MOODS-SR factors assessing "psychomotor disturbances", "mixed instability" and "suicidality" delineate subtypes of patients characterized by the more severe forms of mood disorders, the higher risk for psychotic symptoms, and the lower quality of life after the remission of the full-blown-episode. CONCLUSION: The mood spectrum model help researchers and clinicians in the systematic assessment of those areas of psychopathology that are still neglected by the Diagnostic and Statistical Manual of Mental Disorders 5 classification. PMID- 25815263 TI - Light treatment for seasonal Winter depression in African-American vs Caucasian outpatients. AB - AIM: To compare adherence, response, and remission with light treatment in African-American and Caucasian patients with Seasonal Affective Disorder. METHODS: Seventy-eight study participants, age range 18-64 (51 African-Americans and 27 Caucasians) recruited from the Greater Baltimore Metropolitan area, with diagnoses of recurrent mood disorder with seasonal pattern, and confirmed by a Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV, were enrolled in an open label study of daily bright light treatment. The trial lasted 6 wk with flexible dosing of light starting with 10000 lux bright light for 60 min daily in the morning. At the end of six weeks there were 65 completers. Three patients had Bipolar II disorder and the remainder had Major depressive disorder. Outcome measures were remission (score <= 8) and response (50% reduction) in symptoms on the Structured Interview Guide for the Hamilton Rating Scale for Depression (SIGH-SAD) as well as symptomatic improvement on SIGH-SAD and Beck Depression Inventory-II. Adherence was measured using participant daily log. Participant groups were compared using t-tests, chi square, linear and logistic regressions. RESULTS: The study did not find any significant group difference between African-Americans and their Caucasian counterparts in adherence with light treatment as well as in symptomatic improvement. While symptomatic improvement and rate of treatment response were not different between the two groups, African-Americans, after adjustment for age, gender and adherence, achieved a significantly lower remission rate (African Americans 46.3%; Caucasians 75%; P = 0.02). CONCLUSION: This is the first study of light treatment in African-Americans, continuing our previous work reporting a similar frequency but a lower awareness of SAD and its treatment in African Americans. Similar rates of adherence, symptomatic improvement and treatment response suggest that light treatment is a feasible, acceptable, and beneficial treatment for SAD in African-American patients. These results should lead to intensifying education initiatives to increase awareness of SAD and its treatment in African-American communities to increased SAD treatment engagement. In African American vs Caucasian SAD patients a remission gap was identified, as reported before with antidepressant medications for non-seasonal depression, demanding sustained efforts to investigate and then address its causes. PMID- 25815264 TI - Systematic review of evidence for different treatment settings in anorexia nervosa. AB - AIM: To compare outcomes in anorexia nervosa (AN) in different treatment settings: inpatient, partial hospitalization and outpatient. METHODS: Completed and published in the English language, randomized controlled trials comparing treatment in two or more settings or comparing different lengths of inpatient stay, were identified by database searches using terms "anorexia nervosa" and "treatment" dated to July 2014. Trials were assessed for risk of bias and quality according to the Cochrane handbook by two authors (Madden S and Hay P) Data were extracted on trial quality, participant features and setting, main outcomes and attrition. RESULTS: Five studies were identified, two comparing inpatient treatment to outpatient treatment, one study comparing different lengths of inpatient treatment, one comparing inpatient treatment to day patient treatment and one comparing day patient treatment with outpatient treatment. There was no difference in treatment outcomes between the different treatment settings and different lengths of inpatient treatment. Both outpatient treatment and day patient treatment were significantly cheaper than inpatient treatment. Brief inpatient treatment followed by evidence based outpatient care was also cheaper than prolonged inpatient care for weight normalization also followed by evidence based outpatient care. CONCLUSION: There is preliminary support for AN treatment in less restrictive settings but more research is needed to identify the optimum treatment setting for anorexia nervosa. PMID- 25815265 TI - Brain-derived neurotrophic factor levels in first episode of psychosis: A systematic review. AB - AIM: To systematically review studies measuring peripheric brain-derived neurotrophic factor (BDNF) levels on first-episode psychosis patients and variables related to them. METHODS: A systematic search was made of articles published in the Medline database from 2002 up to June 2014. Included are original studies that report enzyme-linked immunosorbent assay measurement of BDNF levels in serum or plasma in patients with a diagnosis of first episode psychosis (FEP) and age- and gender- matched healthy controls. RESULTS: Of the initially identified 147 articles, only 18 satisfied the inclusion criteria. Of this, 15 found a significant reduction in patients with FEP compared with age- and gender - matched controls. CONCLUSION: Peripheral BDNF levels are generally reduced in FEP patients. There are some factors that may influence BDNF levels that need to be further studied. Furthermore, a future meta-analysis in this topic is needed. PMID- 25815266 TI - Bioengineered stem cells as an alternative for islet cell transplantation. AB - Type 1 diabetes is an autoimmune and increasingly prevalent condition caused by immunological destruction of beta cells. Insulin remains the mainstay of therapy. Endeavours in islet transplantation have clearly demonstrated that type 1 diabetes is treatable by cellular replacement. Many challenges remain with this approach. The opportunity to use bioengineered embryonic or adult pluripotential stem cells, or islets derived from porcine xenograft sources could address future demands, but are still associated with considerable challenges. This detailed review outlines current progress in clinical islet transplantation, and places this in perspective for the remarkable scientific advances now occurring in stem cell and regenerative medicine approaches in the treatment of future curative treatment of diabetes. PMID- 25815268 TI - Conversion from calcineurin inhibitors to mTOR inhibitors stabilizes diabetic and hypertensive nephropathy after liver transplant. AB - AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors (mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine. METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation (OLT), including all liver recipients with worsening renal function before conversion to mTORi (n = 55 patients) and recipients with normal renal function who converted to mTORi for other reasons (n = 31 patients). We identified patients with diabetes mellitus (n = 28), arterial hypertension (n = 27), proteinuria (n = 27) and all three factors (n = 8) (some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus (DM), hypertension (HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction. RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function (2.14 to 1.77 mg/dL) (P = 0.02). Patients with DM showed no improvement of serum creatinine levels (1.31 mg/dL to 1.37 mg/dL) compared with non DM patients (1.31 mg/dL to 1.15 mg/dL) (P = 0.01), HT patients (1.48 mg/dL to 1.5 mg/dL) with non HT patients (1.21mg/dL to 1.08 mg/dL) and patients with proteinuria (1.44 mg/dL to 1.41 mg/dL) and no proteinuria (1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to mTORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to mTORi; it also stabilizes renal function. Conversion to mTORi should only be avoided in patients with diabetes, hypertension and proteinuria. PMID- 25815269 TI - Underestimation of chronic renal dysfunction after liver transplantation: ICEBERG study. AB - AIM: To compare prevalence of chronic renal dysfunction (CRD) according to serum creatinine (sCr) vs estimated glomerular filtration rate (eGFR) among maintenance liver transplant patients. METHODS: The ICEBERG study was an observational, retrospective, cross-sectional, and multicenter study. Consecutive adult patients (aged 18 years or older) with liver transplantation (LT) performed at least two years previously were recruited. Multi-organ transplant recipients were excluded. Chronic renal dysfunction was defined according to sCr based criteria in routine clinical practice (>= 2 mg/dL) and eGFR using MDRD-4 equation (< 60 mL/min per 1.73 m(2)). Agreement between sCr definition and eGFR assessment was evaluated using the Kappa index. Cox regression analysis was applied to identify predictive factors for developing CRD after LT. RESULTS: A total of 402 patients were analyzed (71.6% males). Mean +/- SD age at transplant was 52.4 +/- 9.8 years. Alcoholic cirrhosis without hepatocellular carcinoma was the most common reason for LT (32.8%). Mean time since LT was 6.9 +/- 3.9 years. Based on sCr assessment, 35.3% of patients (95%CI: 30.6-40.0) had CRD; 50.2% (95%CI: 45.3 55.1) according to eGFR. In 32.2% of cases, sCr assessment had underestimated CRD. Multivariate analysis showed the following factors associated with developing CRD: eGFR < 60 mL/min per 1.73 m(2) at three months post-transplant [hazard ratio (HR) = 4.76; 95%CI: 2.78-8.33; P < 0.0001]; calcineurin inhibitor use (HR = 2.31; 95%CI: 1.05-5.07; P = 0.0371); male gender (HR = 1.98; 95%CI: 1.09-3.60; P = 0.0260); and >= 10 years post-transplantation (HR = 1.95; 95%CI: 1.08-3.54; P = 0.0279). CONCLUSION: Seven years after LT, CRD affected half our patients, which was underestimated by sCr. An eGFR < 60 mL/min per 1.73 m(2) three months post-LT was predictive of subsequent CRD. PMID- 25815270 TI - Diagnostic dilemma of coagulation problems in an HIV-positive patient with end stage liver disease undergoing liver transplantation. AB - Human immunodeficiency virus (HIV) may result in devastating multi-organ complications, including cirrhosis. Consequently, liver transplantation is often required for these patients. We report a case of a 43-year-old female with cryptogenic cirrhosis and HIV on highly active antiretroviral therapy, presenting for non-related living donor liver transplantation. The intra-operative course was complicated by hepatic artery and portal vein thrombosis, requiring thrombectomy. On postoperative day-3, the patient required re-transplantation with a cadaveric donor organ due to primary graft failure. PMID- 25815267 TI - Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity. AB - After the first observation of the immunosuppressive effects of ultraviolet (UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells (Tregs). Antigen specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40(th) anniversary of its discovery. PMID- 25815271 TI - Neuropsychological assessment of individuals with brain tumor: comparison of approaches used in the classification of impairment. AB - Approaches to classifying neuropsychological impairment after brain tumor vary according to testing level (individual tests, domains, or global index) and source of reference (i.e., norms, controls, and pre-morbid functioning). This study aimed to compare rates of impairment according to different classification approaches. Participants were 44 individuals (57% female) with a primary brain tumor diagnosis (mean age = 45.6 years) and 44 matched control participants (59% female, mean age = 44.5 years). All participants completed a test battery that assesses pre-morbid IQ (Wechsler adult reading test), attention/processing speed (digit span, trail making test A), memory (Hopkins verbal learning test-revised, Rey-Osterrieth complex figure-recall), and executive function (trail making test B, Rey-Osterrieth complex figure copy, controlled oral word association test). Results indicated that across the different sources of reference, 86-93% of participants were classified as impaired at a test-specific level, 61-73% were classified as impaired at a domain-specific level, and 32-50% were classified as impaired at a global level. Rates of impairment did not significantly differ according to source of reference (p > 0.05); however, at the individual participant level, classification based on estimated pre-morbid IQ was often inconsistent with classification based on the norms or controls. Participants with brain tumor performed significantly poorer than matched controls on tests of neuropsychological functioning, including executive function (p = 0.001) and memory (p < 0.001), but not attention/processing speed (p > 0.05). These results highlight the need to examine individuals' performance across a multi-faceted neuropsychological test battery to avoid over- or under-estimation of impairment. PMID- 25815273 TI - Cognitive screening in brain tumors: short but sensitive enough? AB - Cognitive deficits in brain tumors are generally thought to be relatively mild and non-specific, although recent evidence challenges this notion. One possibility is that cognitive screening tools are being used to assess cognitive functions but their sensitivity to detect cognitive impairment may be limited. For improved sensitivity to recognize mild and/or focal cognitive deficits in brain tumors, neuropsychological evaluation tailored to detect specific impairments has been thought crucial. This study investigates the sensitivity of a cognitive screening tool, the Montreal Cognitive Assessment (MoCA), compared to a brief but tailored cognitive assessment (CA) for identifying cognitive deficits in an unselected primary brain tumor sample (i.e., low/high-grade gliomas, meningiomas). Performance is compared on broad measures of impairment: (a) number of patients impaired on the global screening measure or in any cognitive domain; and (b) number of cognitive domains impaired and specific analyses of MoCA-Intact and MoCA-Impaired patients on specific cognitive tests. The MoCA-Impaired group obtained lower naming and word fluency scores than the MoCA-Intact group, but otherwise performed comparably on cognitive tests. Overall, based on our results from patients with brain tumor, the MoCA has extremely poor sensitivity for detecting cognitive impairments and a brief but tailored CA is necessary. These findings will be discussed in relation to broader issues for clinical management and planning, as well as specific considerations for neuropsychological assessment of brain tumor patients. PMID- 25815274 TI - Census of solo LuxR genes in prokaryotic genomes. AB - luxR genes encode transcriptional regulators that control acyl homoserine lactone based quorum sensing (AHL QS) in Gram negative bacteria. On the bacterial chromosome, luxR genes are usually found next or near to a luxI gene encoding the AHL signal synthase. Recently, a number of luxR genes were described that have no luxI genes in their vicinity on the chromosome. These so-called solo luxR genes may either respond to internal AHL signals produced by a non-adjacent luxI in the chromosome, or can respond to exogenous signals. Here we present a survey of solo luxR genes found in complete and draft bacterial genomes in the NCBI databases using HMMs. We found that 2698 of the 3550 luxR genes found are solos, which is an unexpectedly high number even if some of the hits may be false positives. We also found that solo LuxR sequences form distinct clusters that are different from the clusters of LuxR sequences that are part of the known luxR-luxI topological arrangements. We also found a number of cases that we termed twin luxR topologies, in which two adjacent luxR genes were in tandem or divergent orientation. Many of the luxR solo clusters were devoid of the sequence motifs characteristic of AHL binding LuxR proteins so there is room to speculate that the solos may be involved in sensing hitherto unknown signals. It was noted that only some of the LuxR clades are rich in conserved cysteine residues. Molecular modeling suggests that some of the cysteines may be involved in disulfide formation, which makes us speculate that some LuxR proteins, including some of the solos may be involved in redox regulation. PMID- 25815272 TI - Modulation of Immune Cell Functions by the E3 Ligase Cbl-b. AB - Maintenance of immunological tolerance is a critical hallmark of the immune system. Several signaling checkpoints necessary to balance activating and inhibitory input to immune cells have been described so far, among which the E3 ligase Cbl-b appears to be a central player. Cbl-b is expressed in all leukocyte subsets and regulates several signaling pathways in T cells, NK cells, B cells, and different types of myeloid cells. In most cases, Cbl-b negatively regulates activation signals through antigen or pattern recognition receptors and co stimulatory molecules. In line with this function, cblb-deficient immune cells display lower activation thresholds and cblb knockout mice spontaneously develop autoimmunity and are highly susceptible to experimental autoimmunity. Interestingly, genetic association studies link CBLB-polymorphisms with autoimmunity also in humans. Vice versa, the increased activation potential of cblb-deficient cells renders them more potent to fight against malignancies or infections. Accordingly, several reports have shown that cblb knockout mice reject tumors, which mainly depends on cytotoxic T and NK cells. Thus, targeting Cbl-b may be an interesting strategy to enhance anti-cancer immunity. In this review, we summarize the findings on the molecular function of Cbl-b in different cell types and illustrate the potential of Cbl-b as target for immunomodulatory therapies. PMID- 25815275 TI - Comparison of whole genome sequences from human and non-human Escherichia coli O26 strains. AB - Shiga toxin-producing Escherichia coli (STEC) O26 is the second leading E. coli serogroup responsible for human illness outbreaks behind E. coli O157:H7. Recent outbreaks have been linked to emerging pathogenic O26:H11 strains harboring stx 2 only. Cattle have been recognized as an important reservoir of O26 strains harboring stx 1; however the reservoir of these emerging stx 2 strains is unknown. The objective of this study was to identify nucleotide polymorphisms in human and cattle-derived strains in order to compare differences in polymorphism derived genotypes and virulence gene profiles between the two host species. Whole genome sequencing was performed on 182 epidemiologically unrelated O26 strains, including 109 human-derived strains and 73 non-human-derived strains. A panel of 289 O26 strains (241 STEC and 48 non-STEC) was subsequently genotyped using a set of 283 polymorphisms identified by whole genome sequencing, resulting in 64 unique genotypes. Phylogenetic analyses identified seven clusters within the O26 strains. The seven clusters did not distinguish between isolates originating from humans or cattle; however, clusters did correspond with particular virulence gene profiles. Human and non-human-derived strains harboring stx 1 clustered separately from strains harboring stx 2, strains harboring eae, and non-STEC strains. Strains harboring stx 2 were more closely related to non-STEC strains and strains harboring eae than to strains harboring stx 1. The finding of human and cattle-derived strains with the same polymorphism derived genotypes and similar virulence gene profiles, provides evidence that similar strains are found in cattle and humans and transmission between the two species may occur. PMID- 25815276 TI - A systematic review and meta-analysis of the epidemiology of pathogenic Escherichia coli of calves and the role of calves as reservoirs for human pathogenic E. coli. AB - Escherichia coli bacteria are the most common causes of diarrhea and septicemia in calves. Moreover, calves form a major reservoir for transmission of pathogenic E. coli to humans. Systematic reviews and meta-analyses of publications on E. coli as calf pathogens and the role of calves as reservoir have not been done so far. We reviewed studies between 1951 and 2013 reporting the presence of virulence associated factors (VAFs) in calf E. coli and extracted the following information: year(s) and country of sampling, animal number, health status, isolate number, VAF prevalence, serotypes, diagnostic methods, and biological assays. The prevalence of VAFs or E. coli pathotypes was compared between healthy and diarrheic animals and was analyzed for time courses. Together, 106 papers with 25,982 E. coli isolates from 27 countries tested for VAFs were included. F5, F17, and F41 fimbriae and heat-stable enterotoxin (ST) - VAFs of enterotoxigenic E. coli (ETEC) were significantly associated with calf diarrhea. On the contrary, ETEC VAF F4 fimbriae and heat-labile enterotoxin as well as enteropathogenic (EPEC), Shiga toxin-producing (STEC), and enterohemorrhagic E. coli (EHEC) were not associated with diarrhea. The prevalence increased overtime for ST-positive isolates, but decreased for F5- and STEC-positive isolates. Our study provides useful information about the history of scientific investigations performed in this domain so far, and helps to define etiological agents of calf disease, and to evaluate calves as reservoir hosts for human pathogenic E. coli. PMID- 25815277 TI - Rab11 in disease progression. AB - Membrane/protein trafficking in the secretory/biosynthetic and endocytic pathways is mediated by vesicles. Vesicle trafficking in eukaryotes is regulated by a class of small monomeric GTPases: the Rab protein family. Rab proteins represent the largest branch of the Ras superfamily GTPases, and have been concerned in a variety of intracellular vesicle trafficking and different intracellular signalling pathways. Rab11 (a subfamily of the Ypt/Rab gene family), an evolutionarily conserved ubiquitously expressed subfamily of Rab GTPases, has been implicated in regulating vesicular trafficking through the recycling of endosomes. Rabs have been grouped into different subfamilies based on the distinct unambiguous sequence motifs. Three members: Rab11a, Rab11b and Rab25 make up the Rab11 GTPase subfamily. In this review article, we describe an overview over Rab11 subfamily with a brief structural aspect and its roles in implicating different disease progression. PMID- 25815278 TI - Capability of Cartilage Extract to In Vitro Differentiation of Rat Mesenchymal Stem Cells (MSCs) to Chondrocyte Lineage. AB - The importance of mesenchymal stem cells (MSCs), as adult stem cells (ASCs) able to divide into a variety of different cells is of utmost importance for stem cell researches. In this study, the ability of cartilage extract to induce differentiation of rat derived omentum tissue MSCs (rOT-MSCs) into chondrocyte cells (CCs) was investigated. After isolation of rOT-MSCs, they were co-cultured with different concentrations of hyaline cartilage extract and chondrocyte differentiation was monitored. Expression of MSCs markers was analyzed via flow cytometry. Moreover, expression of octamer- binding transcription factor-4 (Oct 4), Wilm's tumor suppressor gene-1 (WT-1), aggrecan (AG), collagen type-II (CT II) and collagen type-X (CT-X) was analyzed using RT-PCR on 16, 18 and 21 days. Furthermore, immunocytochemistry and western blot were performed for CT-II production. Finally, proteoglycans (PGs) were examined using toluidine blue and alcian blue staining. The phenotypic characterization revealed the positive expression of CD90, CD44 and negative expression of CD45 in rOT-MSCs. These cells also expressed mRNA of Oct-4 and WT-1 as markers of omentum tissue. Differentiated rOT-MSCs in the presence of 20 ug/ ml cartilage extract expressed AG, CT-II, CT-X, and PGs as specific markers of CCs. These observations suggest that cartilage extract is potentially able to induce differentiation of MSCs into chondrocyte lineage and may be considered as an available source for imposing tissue healing on the damaged cartilage. More investigations are needed to prove in vivo cartilage repair via cartilage extract or its effective factors. PMID- 25815279 TI - In vitro differentiation of neural stem cells into noradrenergic-like cells. AB - Neural stem cells (NSCs) as a heterogeneous multipotent and self- renewal population are found in different areas in the developing mammalian nervous system, as well as the sub-ventricular zone (SVZ) and the hippocampus of the adult brain. NSCs can give rise to neurons, astrocytes and oligodendrocytes. The aim of this study was to differentiate neural stem cells into noradrenergic-like cells in vitro. Neural stem cells were harvested from SVZ of newborn rat brains. The cells were cultured in DMEM12, B-27 supplemented with 20 ng/ ml (hFGF) and 20 ng/ ml (EGF) for 2 weeks. Neurospheres were differentiated in neurobasal medium, B-27 supplemented with BDNF (50 ng/ ml) and GDNF (30 ng/ ml) for 3 and 5 days. Cell culture techniques and immunocytochemistry were applied to examine neurospheres and tyrosine hydroxylase positive cells. The number of neurites was counted 3 and 5 days after the induction of differentiation. Nestin and Sox2 were expressed in NSCs and neurospheres. NSCs were differentiated into noradrenergic- like cells (NACs). Tyrosine hydroxylase was detected in these cells. The results of NSCs differentiation for 5 days culture had a significant decrease (P<=0.05) in the number of TH positive cells with one or two neurite per cell, and a significant increase (P<=0.05) in the number of TH positive cells with three, four or more neurites per cell, compared with 3 days culture. Based on these results, NSCs have the ability to differentiate into noradrenergic cells in the presence of BDNF and GDNF growth factors. PMID- 25815280 TI - Evaluation of miR-141, miR-200c, miR-30b Expression and Clinicopathological Features of Bladder Cancer. AB - Bladder cancer (BC) ranks the second most common genitourinary tract malignant tumor with high mortality and 70% recurrence rate worldwide. MiRNAs expression has noticeable role in bladder tumorigenesis. The purpose of this study was to assess miR-200c, miR-30b and miR-141 in tissue samples of patients with BC and healthy adjacent tissue samples and their association with muscle invasion, grade and the size of the tumor. Transurethral resection tissue samples were collected from thirty- five newly diagnosed untreated patients with BC from 2013 to 2014. The control group consisted of adjacent normal urothelium. All samples, observed by two pathologists, were diagnosed transitional cell carcinomas (TCC) with the proportion of tumor cells greater than 80%. Total RNA including miRNAs was extracted from about 50 mg tissue samples by applying TRIzol reagent. 2(( DeltaDelta CT)) method was used to calculate relative quantification of miRNA expression. Two of 35 patients were females and the other 33 were males. Invasion to bladder muscle was observed in 13 (37%) cases. MiR-141, miR-200-c and miR30-b were up-regulated in 91%, 79% and 64% of malignant tissues, respectively. Down regulation of miR-141 had a strong association with muscle invasion (P= 0.017). Significant inverse correlation between grading and miRNA-141 level was observed (P= 0.043). PMID- 25815281 TI - Lack of Association between miRNA-146a rs2910164 and miRNA-499 rs3746444 Gene Polymorphisms and Susceptibility to Pulmonary Tuberculosis. AB - Single-nucleotide polymorphisms (SNPs) in miRNAsmay alter its expression levels or processing and contribute to susceptibility to a wide range of diseases. Our study aimed to evaluate the possible association between miRNA-146a rs2910164 and miRNA-499 rs3746444 polymorphisms and susceptibility to pulmonary tuberculosis (PTB) in a sample of Iranian population. This case- control study was performed on 202 PTB patients and 204 healthy individuals. Genotyping was performed using tetra amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR). The results indicated that neither miRNA-499 rs3746444 nor miRNA-146a rs2910164 are associated with the risk of PTB in a sample of Iranian population. Larger studies with different ethnicities are required to validate our findings. PMID- 25815282 TI - Characterization of Carbapenemases in Extensively Drug Resistance Acinetobacter baumannii in a Burn Care Center in Iran. AB - The emergence of multidrug resistance (MDR) and extensively drug resistance (XDR) in Acinetobacter baumannii has made an important challenge in the treatment of infections caused by this organism. The ability of carbapenemase production is one of the main mechanisms for the emergence of MDR and/or XDR in A. baumannii. The aim of this study was to detect carbapenemase producer A. baumannii. In this study, 65 imipenem resistant A. baumannii were collected from burned patients. Biochemical identification, antibiotic susceptibility test and multiplex polymerase chain reactions for the detection of carbapenemases genes were performed. The results showed that all strains carried bla OXA-51. 83%, 12.5% and 9.23% strains harbored bla OXA-23, bla VIM and bla KPC genes, respectively. None of the isolates carried bla IMP, bla OXA-48, blaNDM-1 and bla SPM-1 genes. The results of this study indicate the emergence of Klebsiella pneumoniae Carbapenemase (KPC) in A. baumannii causing nosocomial infections in burned patients which can be important for hospital infection prevention systems in Iran. PMID- 25815283 TI - RNA Extraction from Animal and Human's Cancerous Tissues: Does Tissue Matter? AB - The reliability of gene expression profiling, based technologies and methods to find transcriptional differences representative of the original samples is influenced by the quality of the extracted RNA. Hence, RNA extraction is the first step to investigate the gene expression and its function. Consequently, the quality of extracted RNA is really significant. Correspondingly, this research was accomplished to optimize the RNA extraction methods and compare the amounts of tissue or quality of tissue. Relatively, the cancerous tissue of human stomach in fresh and frozen conditions and also the mouse fresh tissue were studied. Some factors like the amount of samples, efficacy differences of diverse extraction buffers (TriPure, Trizol) and also the efficacy of b-mercaptoethanol were compared and investigated. The results indicated that the less amount (1-2 mg) compared to other amounts (2-5 mg, 5-15 mg) yielded the best quality and the RNA bands (5S, 18S, 28S) were observed perfectly. Relatively, comparing and measuring some kinds of buffers (Trizol, TriPure) indicated no difference in RNA extraction quality. The last investigated factor was the effect of b- mercaptoethanol which was used along with TriPure to remove the RNAse. Conclusively, no effective impression was observed. PMID- 25815284 TI - The effect of adiponectin on osteonectin gene expression by oxidized low density lipoprotein-treated vascular smooth muscle cells. AB - Osteonectin is a bone- associated protein involved in vascular calcification. Adiponectin may protect against cardiovascular disease but possible effects on vascular calcification have been poorly studied. The aim of this study was to investigate the modulatory effect of adiponectin on oxidized low density lipoprotein (oxLDL)- induced expression of osteonectin in human aorta vascular smooth muscle cells (HA/VSMCs). HA/VSMCs were cultured in F12K media and then treated with oxLDL (100 ug/mL) in the presence or absence of adoponectin (5 ug/mL) for 24 and 48 hours. mRNA expression and protein level of osteonectin were determined by quantitative real-time PCR and western blot analysis, respectively. After exposure to oxLDL, osteonectin expression increased 1.62 +/- 0.23- and 6.62 +/- 0.48-fold after 24 and 48 hours respectively compared to the control. Adiponectin increased oxLDL- induced osteonectin expression in a time-dependent manner after 24 and 48 hours (3.24 +/- 0.39- and 24.93 +/- 2.15-fold, respectively). Western blotting confirmed that osteonectin protein was upregulated by adiponectin.Our data suggest that OxLDL might cause the increase of osteonectin expression both at mRNA and protein level. This upregulation is intensified by adiponectin. PMID- 25815285 TI - Tagging polyketides/non-ribosomal peptides with a clickable functionality and applications. AB - Bioorthogonal chemistry has recently emerged to be one of the most powerful tools in drug discovery and chemical biology. The exploration of it has successfully advanced the field of natural product research. In this Perspective, we survey current strategies for the installation of chemical handles into the molecular scaffolds of several major classes of natural products, including polyketides (PKs), non-ribosomal peptides (NRPs), and their hybrids. By tagging these natural products with chemical handles and coupling them with subsequent bioorthogonal reactions, researchers have visualized and studied the mode of action of natural products, as well as synthesized derivatives with better pharmaceutical properties. We conclude this Perspective by considering two questions: is there a general way to synthesize tagged PKs/NRPs? Does natural product labeling have a broader impact in the field of natural product research beyond current known applications? PMID- 25815286 TI - Two-dimensional correlation spectroscopy in polymer study. AB - This review outlines the recent works of two-dimensional correlation spectroscopy (2DCOS) in polymer study. 2DCOS is a powerful technique applicable to the in depth analysis of various spectral data of polymers obtained under some type of perturbation. The powerful utility of 2DCOS combined with various analytical techniques in polymer studies and noteworthy developments of 2DCOS used in this field are also highlighted. PMID- 25815287 TI - Exploring the conformational landscape of menthol, menthone, and isomenthone: a microwave study. AB - The rotational spectra of the monoterpenoids menthol, menthone, and isomenthone are reported in the frequency range of 2-8.5 GHz, obtained with broadband Fourier transform microwave spectroscopy. For menthol only one conformation was identified under the cold conditions of the molecular jet, whereas three conformations were observed for menthone and one for isomenthone. The conformational space of the different molecules was extensively studied using quantum chemical calculations, and the results were compared with molecular parameters obtained by the measurements. Finally, a computer program is presented, which automatically identifies different species in a dense broadband microwave spectrum using calculated ab initio rotational constants as initial input parameters. PMID- 25815288 TI - Relationships among ergot alkaloids, cytochrome P450 activity, and beef steer growth. AB - Determining a grazing animal's susceptibility to ergot alkaloids has been a research topic for decades. Our objective was to determine if the PromegaTM P450 Glo assay could be used to indirectly detect ergot alkaloids or their metabolites in urine of steers. The first experiment validated the effects of ergot alkaloids [0, 20, and 40 MUM of ergotamine (ET), dihydroergotamine (DHET), and ergonovine (EN)] on human CYP3A4 using the P450-Glo assay (PromegaTM V9800). With this assay, luminescence is directly proportional to CYP450 activity. Relative inhibition of in vitro cytochrome P450 activity was affected (P < 0.001) by an interaction between alkaloids and concentration. That interaction resulted in no concentration effect of EN, but within ET and DHET 20 and 40 MUM concentrations inhibited CYP450 activity when compared with controls. In experiment 2, urine was collected from Angus-sired crossbred steers (n = 39; 216 +/- 2.6 days of age; 203 +/- 1.7 kg) after grazing tall fescue pastures for 105 days. Non-diluted urine was added to the PromegaTM P450-Glo assay, and observed inhibition (3.7 % +/- 2.7 of control). Urine content of total ergot alkaloids (331.1 ng/mg of creatinine +/ 325.7) was determined using enzyme linked immunosorbent assay. Urine inhibition of CYP450 activity and total alkaloids were correlated (r = -0.31; P < 0.05). Steers were genotyped at CYP450 single nucleotide polymorphism, C994G. Steer genotype affected (P < 0.03) inhibition of CYP450 activity by urine; heterozygous steers had the least amount of CYP450 inhibition suggesting that genotyping cattle may be a method of identifying animals that are susceptible to ergot alkaloids. Although, additional research is needed, we demonstrate that the PromegaTM P450-Glo assay is sensitive to ergot alkaloids and urine from steers grazing tall fescue. With some refinement the P450-Glo assay has potential as a tool for screening cattle for their exposure to fescue toxins. PMID- 25815289 TI - Age and the means of bypassing stasis influence the intrinsic subtype of immortalized human mammary epithelial cells. AB - Based on molecular features, breast cancers are grouped into intrinsic subtypes that have different prognoses and therapeutic response profiles. With increasing age, breast cancer incidence increases, with hormone receptor-positive and other luminal-like subtype tumors comprising a majority of cases. It is not known at what stage of tumor progression subtype specification occurs, nor how the process of aging affects the intrinsic subtype. We examined subtype markers in immortalized human mammary epithelial cell lines established following exposure of primary cultured cell strains to a two-step immortalization protocol that targets the two main barriers to immortality: stasis (stress-associated senescence) and replicative senescence. Cell lines derived from epithelial cells obtained from non-tumorous pre- and post-menopausal breast surgery tissues were compared. Additionally, comparisons were made between lines generated using two different genetic interventions to bypass stasis: transduction of either an shRNA that down-regulated p16(INK4A), or overexpressed constitutive active cyclin D1/CDK2. In all cases, the replicative senescence barrier was bypassed by transduction of c-Myc. Cells from all resulting immortal lines exhibited normal karyotypes. Immunofluorescence, flow cytometry, and gene expression analyses of lineage-specific markers were used to categorize the intrinsic subtypes of the immortalized lines. Bypassing stasis with p16 shRNA in young strains generated cell lines that were invariably basal-like, but the lines examined from older strains exhibited some luminal features such as keratin 19 and estrogen receptor expression. Overexpression of cyclin D1/CDK2 resulted in keratin 19 positive, luminal-like cell lines from both young and old strains, and the lines examined from older strains exhibited estrogen receptor expression. Thus age and the method of bypassing stasis independently influence the subtype of immortalized human mammary epithelial cells. PMID- 25815290 TI - The value of proteomics in lung cancer. AB - Many studies have identified the prognostic and predictive value of proteins or peptides in lung cancer but most failed to provide strong evidence for their clinical applicability. The strongest predictive proteins seem to be fatty acid binding protein heart (H-FABP), and the 8-peak mass spectrography signature of VeriStrat. When focusing on VeriStrat, a 'VeriStrat good' profile did not discriminate between chemotherapy and erlotinib. The 'VeriStrat poor' profile showed a better outcome to chemotherapy than to erlotinib. VeriStrat is a prognostic test and only the "poor profile" discriminates for the type of therapy that should be chosen. Whether it adds useful information in patients with advanced non-small cell lung cancer (NSCLC) and wild type EGFR mutations is still doubtful. The position of the VeriStrat test in clinical practice is still not clear and we are waiting for prospective studies where biomarker test are involved in clinical decision. PMID- 25815291 TI - A new proteomic test could guide treatment decision in second-line therapy for patients with EGFR unselected non-small cell lung cancer? PMID- 25815292 TI - Clinical perspective on PROSE: does VeriStrat testing improve selection of second line treatment for patients with non-small cell lung cancer? PMID- 25815293 TI - Writing in PROSE proteomic-based selection for second line treatment in non-small cell lung cancer. PMID- 25815294 TI - Intra-articular versus intravenous tranexamic acid in primary total knee replacement. PMID- 25815295 TI - Innate immunity and adaptive immunity in Crohn's disease. PMID- 25815296 TI - Towards the prophylactic and therapeutic use of human neutralizing monoclonal antibodies for Middle East respiratory syndrome coronavirus (MERS-CoV). PMID- 25815297 TI - Real-time liquid biopsies become a reality in cancer treatment. PMID- 25815298 TI - Non-intubated thoracic surgery-A survey from the European Society of Thoracic Surgeons. AB - BACKGROUND: A survey amongst the European Society of Thoracic Surgeons (ESTS) members has been performed to investigate the currents trends, rates of adoption as well as potential for future expansion of non-intubated thoracic surgery (NITS) performed under spontaneous ventilation. METHODS: A 14-question-based questionnaire has been e-mailed to ESTS members. To facilitate the completion of the questionnaire, questions entailed either quantitative or multiple-choice answers. Investigated issues included previous experience with NITS and number of procedures performed, preferred types of anesthesia protocols (i.e., thoracic epidural anesthesia, intercostal or paravertebral blocks, laryngeal mask, use of additional sedation), type of procedures, ideal candidates for NITS, main advantages and technical disadvantages. Non-univocal answer to multiple-choice questions was permitted. RESULTS: Out of 105 responders, 62 reported an experience with NITS. The preferred types of anesthesia were intercostal blocks with (59%) or without (50%) sedation, followed by laryngeal mask with sedation (43%) and thoracic epidural anesthesia with sedation (20%). The most frequently performed procedures included thoracoscopic management of recurrent pleural effusion (98%), pleural decortication for empyema thoracis and lung biopsy for interstitial lung disease (26% each); pericardial window and mediastinal biopsy (20% each). More complex procedures such as lobectomy, lung volume reduction surgery and thymectomy have been performed by a minority of responders (2% each). Poor-risk patients due to co-morbidities (70%) and patients with poor pulmonary function (43%) were considered the ideal candidates. Main advantages included faster, recovery (67%), reduced morbidity (59%) and shorter hospital stay with decreased costs (43% each). Reported technical disadvantages included coughing (59%) and poor maneuverability due to diaphragmatic and lung movements (56%). Overall, 69% of responders indicated that NITS procedures will be likely to increase in the near future. CONCLUSIONS: Results of this survey, suggest that NITS is already quite widely adopted by ESTS members to perform simple thoracoscopic procedures. A future expanded adoption of this strategy is also hypothesized. PMID- 25815299 TI - Rate of early onset Alzheimer's disease: a systematic review and meta-analysis. AB - It is generally accepted that the population rate of early onset Alzheimer's disease (EOAD) in Alzheimer's disease (AD) is 1-2%. However, the true population based rate of EOAD has never been verified by a systematic review and meta analysis. We used electronic searches of Cochrane Library, Embase, Medline and PubMed databases to identify published related studies. The systematic review and meta-analysis was then to be conducted to calculate a pooled rate of EOAD and make comparisons between studies and geographic distribution. A total of 13 papers were included in our systematic review and meta-analysis. The rate of EOAD, 5.5% [95% confidence interval (CI): 0.039-0.079, P<0.001], was generated after pooled analysis of all studies in random effect model. The pooled analysis of the rate in developed country was 5.9% (95% CI: 0.040-0.085, P<0.001). The pooled analysis of the rate in developing countries was 4.4% (95% CI: 0.028 0.066, P<0.001). Our study showed that the rate of EOAD in AD is 5.5%, not 1-2% as usually demonstrated. And our results indicated that the rate in developed countries was relative higher than in developing countries. Further trials with larger samples across more countries and more careful designed of experiments are required to confirm whether our findings are truly significant. PMID- 25815300 TI - Neuroprotective effects of porphyran derivatives against 6-hydroxydopamine induced cytotoxicity is independent on mitochondria restoration. AB - We previously reported that acetylated and phosphorylated derivatives of porphyran extracted from Porphyra haitanensis exhibit antioxidant activity in cell-free system. The aim of the present study was to investigate the neuroprotective effects of porphyran and its derivatives on 6-hydroxydopamine (6 OHDA)-induced cytotoxicity. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure cell viability. Changes in the mitochondrial transmembrane potential (DeltaPsim) were measured by rhodamine123 using flow cytometry. The results showed that porphyran and its two derivatives, acetylated porphyran (AP) and phosphorylated porphyran (PP) (<1 mg/mL) alone did not have any toxic effects on MES23.5 cells. The cell viability decreased when cells were treated with 25 umol/L 6-OHDA. Both AP and PP, rather than porphyran, significantly antagonized 25 umol/L 6-OHDA-induced cytotoxicity. However, neither AP nor PP could antagonize 6-OHDA-induced mitochondrial transmembrane potential (DeltaPsim) collapse. None of the three materials were effective on cell survival when cells were cotreated with 75 umol/L 6-OHDA. These results suggest that two derivatives of porphyran, AP and PP, could antagonize the weak toxicity of 6-OHDA on MES23.5 dopaminergic cells, possessing minor neuroprotective effects independent of mitochondria restoration. PMID- 25815301 TI - Pneumothorax as a complication of central venous catheter insertion. AB - The central venous catheter (CVC) is a catheter placed into a large vein in the neck [internal jugular vein (IJV)], chest (subclavian vein or axillary vein) or groin (femoral vein). There are several situations that require the insertion of a CVC mainly to administer medications or fluids, obtain blood tests (specifically the "central venous oxygen saturation"), and measure central venous pressure. CVC usually remain in place for a longer period of time than other venous access devices. There are situations according to the drug administration or length of stay of the catheter that specific systems are indicated such as; a Hickman line, a peripherally inserted central catheter (PICC) line or a Port-a Cath may be considered because of their smaller infection risk. Sterile technique is highly important here, as a line may serve as a port of entry for pathogenic organisms, and the line itself may become infected with organisms such as Staphylococcus aureus and coagulase-negative Staphylococci. In the current review we will present the complication of pneumothorax after CVC insertion. PMID- 25815302 TI - Pneumothorax from diagnosis to treatment, hands on course: Part II. AB - Pneumothorax is a situation where air is inserted in the pleural space that separates the lung from the chest wall. Pneumothorax can be primary or secondary. There is also a third type called; tensioned. Based on the concentration of air and type of pneumothorax the proper treatment has to be selected. There are cases where the concentration is minimal and observation is enough and more severe cases where surgery is required. Currently there are many techniques used for the biopsy of lung lesions. The bronchoscope (forceps, fine needle aspiration), fine needle aspiration under computed tomography scan and endobronchial ultrasound (EBUS) are commonly used. However, all these techniques have in common a possible side effect; pneumothorax. In our current issue we will focus on the different minimally invasive techniques of pneumothorax management. Moreover, a presentation will be made for several systems that are being used for air or fluid aspiration. PMID- 25815305 TI - The Ming-Yi Medical Charity Foundation of Guangdong Province endorses Annals of Translational Medicine. PMID- 25815303 TI - Pacemaker insertion. AB - A pacemaker (PM) (or artificial PM, so as not to be confused with the heart's natural PM) is a medical device that uses electrical impulses, delivered by electrodes contracting the heart muscles, to regulate the beating of the heart. The primary purpose of this device is to maintain an adequate heart rate, either because the heart's natural PM is not fast enough, or there is a block in the heart's electrical conduction system. Modern PMs are externally programmable and allow the cardiologist to select the optimum pacing modes for individual patients. Some combine a PM and defibrillator in a single implantable device. PMs can be temporary or permanent. Temporary PMs are used to treat short-term heart problems, such as a slow heartbeat that's caused by a heart attack, heart surgery, or an overdose of medicine. Permanent PMs are used to control long-term heart rhythm problems. A PM can relieve some arrhythmia symptoms, such as fatigue and fainting. A PM also can help a person who has abnormal HRs resume a more active lifestyle. In the current mini review we will focus on the insertion of a PM and the possible pneumothorax that can be caused. PMID- 25815304 TI - Chest drainage systems in use. AB - A chest tube is a flexible plastic tube that is inserted through the chest wall and into the pleural space or mediastinum. It is used to remove air in the case of pneumothorax or fluid such as in the case of pleural effusion, blood, chyle, or pus when empyema occurs from the intrathoracic space. It is also known as a Bulau drain or an intercostal catheter. Insertion of chest tubes is widely performed by radiologists, pulmonary physicians and thoracic surgeons. Large catheters or small catheters are used based on each situation that the medical doctor encounters. In the current review we will focus on the chest drain systems that are in use. PMID- 25815306 TI - Validation of simple sequence length polymorphism regions of commonly used mouse strains for marker assisted speed congenics screening. AB - Marker assisted speed congenics technique is commonly used to facilitate backcrossing of mouse strains in nearly half the time it normally takes otherwise. Traditionally, the technique is performed by analyzing PCR amplified regions of simple sequence length polymorphism (SSLP) markers between the recipient and donor strains: offspring with the highest number of markers showing the recipient genome across all chromosomes is chosen for the next generation. Although there are well-defined panels of SSLP makers established between certain pairs of mice strains, they are incomplete for most strains. The availability of well-established marker sets for speed congenic screens would enable the scientific community to transfer mutations across strain backgrounds. In this study, we tested the suitability of over 400 SSLP marker sets among 10 mouse strains commonly used for generating genetically engineered models. The panel of markers presented here can readily identify the specified strains and will be quite useful in marker assisted speed congenic screens. Moreover, unlike newer single nucleotide polymorphism (SNP) array methods which require sophisticated equipment, the SSLP markers panel described here only uses PCR and agarose gel electrophoresis of amplified products; therefore it can be performed in most research laboratories. PMID- 25815307 TI - Biologically active and antimicrobial peptides from plants. AB - Bioactive peptides are part of an innate response elicited by most living forms. In plants, they are produced ubiquitously in roots, seeds, flowers, stems, and leaves, highlighting their physiological importance. While most of the bioactive peptides produced in plants possess microbicide properties, there is evidence that they are also involved in cellular signaling. Structurally, there is an overall similarity when comparing them with those derived from animal or insect sources. The biological action of bioactive peptides initiates with the binding to the target membrane followed in most cases by membrane permeabilization and rupture. Here we present an overview of what is currently known about bioactive peptides from plants, focusing on their antimicrobial activity and their role in the plant signaling network and offering perspectives on their potential application. PMID- 25815308 TI - Current and potential applications of host-defense peptides and proteins in urology. AB - The use of antibiotics has become increasingly disfavored as more multidrug resistant pathogens are on the rise. A promising alternative to the use of these conventional drugs includes antimicrobial peptides or host-defense peptides. These peptides typically consist of short amino acid chains with a net cationic charge and a substantial portion of hydrophobic residues. They mainly target the bacterial cell membrane but are also capable of translocating through the membrane and target intracellular components, making it difficult for bacteria to gain resistance as multiple essential cellular processes are being targeted. The use of these peptides in the field of biomedical therapies has been examined, and the different approaches to using them under various settings are constantly being discovered. In this review, we discuss the current and potential applications of these host-defense peptides in the field of urology. Besides the use of these peptides as antimicrobial agents, the value of these biological molecules has recently been expanded to their use as antitumor and anti-kidney stone agents. PMID- 25815309 TI - Lutein has a protective effect on hepatotoxicity induced by arsenic via Nrf2 signaling. AB - Arsenic produces liver disease through the oxidative stress. While lutein can alleviate cytotoxic and oxidative injury, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway plays a critical role in defending oxidative species. However, the mechanisms by which lutein protects the liver against the effect of arsenic are not known. Therefore, this study aims to investigate the mechanisms involved in the action of lutein using mice model in which hepatotoxicity was induced by arsenic. We found that mice treatment with lutein could reverse changes in morphological and liver indexes and result in a significant improvement in hepatic function comparing with arsenic trioxide group. Lutein treatment improved the activities of antioxidant enzymes and attenuated increasing of ROS and MDA induced by arsenic trioxide. Lutein could increase the mRNA and protein expression of Nrf2 signaling related genes (Nrf2, Nqo1, Ho-1, and Gst). These findings provide additional evidence that lutein may be useful for reducing reproductive injury associated with oxidative stress by the activation of Nrf2 signaling. Our findings suggest a possible mechanism of antioxidant lutein in preventing the hepatotoxicity, which implicate that a dietary lutein may be a potential treatment for liver diseases, especially for arsenicosis therapy. PMID- 25815310 TI - Lack of association between JAK3 gene polymorphisms and cardiovascular disease in Spanish patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. JAK/STAT signalling pathway is involved in autoimmune diseases and in the atherosclerotic process. JAK3 is a highly promising target for immunomodulatory drugs and polymorphisms in JAK3 gene have been associated with CV events in incident dialysis patients. Therefore, the aim of this study was to assess the potential role of JAK3 polymorphisms in the development of CV disease in patients with RA. 2136 Spanish RA patients were genotyped for the rs3212780 and rs3212752 JAK3 gene polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 539 of these patients by carotid ultrasonography (US). No statistically significant differences were found when each polymorphism was assessed according to carotid intima-media thickness values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV events after adjusting for potential confounders. In conclusion, our results do not confirm association between JAK3 polymorphisms and CV disease in RA. PMID- 25815311 TI - Genome-wide identification, evolutionary, and expression analyses of histone H3 variants in plants. AB - Histone variants alter the nucleosome structure and play important roles in chromosome segregation, transcription, DNA repair, and sperm compaction. Histone H3 is encoded by many genes in most eukaryotic species and is the histone that contains the largest variety of posttranslational modifications. Compared with the metazoan H3 variants, little is known about the complex evolutionary history of H3 variants proteins in plants. Here, we study the identification, evolutionary, and expression analyses of histone H3 variants from genomes in major branches in the plant tree of life. Firstly we identified all the histone three related (HTR) genes from the examined genomes, then we classified the four groups variants: centromeric H3, H3.1, H3.3 and H3-like, by phylogenetic analysis, intron information, and alignment. We further demonstrated that the H3 variants have evolved under strong purifying selection, indicating the conservation of HTR proteins. Expression analysis revealed that the HTR has a wide expression profile in maize and rice development and plays important roles in development. PMID- 25815312 TI - Hematopoietic cancer cell lines can support replication of Sabin poliovirus type 1. AB - Viral vaccines can be produced in adherent or in suspension cells. The objective of this work was to screen human suspension cell lines for the capacity to support viral replication. As the first step, it was investigated whether poliovirus can replicate in such cell lines. Sabin poliovirus type 1 was serially passaged on five human cell lines, HL60, K562, KG1, THP-1, and U937. Sabin type 1 was capable of efficiently replicating in three cell lines (K562, KG1, and U937), yielding high viral titers after replication. Expression of CD155, the poliovirus receptor, did not explain susceptibility to replication, since all cell lines expressed CD155. Furthermore, we showed that passaged virus replicated more efficiently than parental virus in KG1 cells, yielding higher virus titers in the supernatant early after infection. Infection of cell lines at an MOI of 0.01 resulted in high viral titers in the supernatant at day 4. Infection of K562 with passaged Sabin type 1 in a bioreactor system yielded high viral titers in the supernatant. Altogether, these data suggest that K562, KG1, and U937 cell lines are useful for propagation of poliovirus. PMID- 25815313 TI - Analysis of monocytic and granulocytic myeloid-derived suppressor cells subsets in patients with hepatitis C virus infection and their clinical significance. AB - Myeloid-derived suppressor cells (MDSCs) have been shown to inhibit T-cell responses in many diseases, but, in hepatitis C virus (HCV) infected patients, MDSCs are still poorly studied. In this assay, we investigated the phenotype and frequency of two new populations of MDSCs denoted as monocytic and granulocytic MDSCs (M-MDSCs and G-MDSCs) in HCV infected patients and analyzed their clinical significance in these patients respectively. We found that the frequency of CD14(+)HLA-DR(-/low) cells (M-MDSCs) from HCV infected patients (mean +/- SE, 3.134% +/- 0.340%) was significantly increased when compared to healthy controls (mean +/- SE, 1.764% +/- 0.461%) (Z = -2.438, P = 0.015), while there was no statistical difference between the frequency of HLA-DR( /low)CD33(+)CD11b(+)CD15(+) (G-MDSCs) of HCV infected patients and healthy donors (0.201% +/- 0.038% versus 0.096% +/- 0.026%, P > 0.05), which suggested that HCV infection could cause the proliferation of M-MDSCs instead of G-MDSCs. Besides, we found that the frequency of M-MDSCs in HCV infected patients had certain relevance with age (r = 0.358, P = 0.003); patients older than 40 years old group (mean +/- SE, 3.673% +/- 0.456%) had a significantly higher frequency of M-MDSCs than that of age less than 40 years old group (mean +/- SE, 2.363% +/- 0.482%) (Z = -2.685, P = 0.007). The frequency of M-MDSCs, however, had no correlation with HCV RNA loads, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the level of liver inflammation degree. PMID- 25815314 TI - Dengue patients exhibit higher levels of PrM and E antibodies than their asymptomatic counterparts. AB - Dengue virus infection is a common tropical disease which often occurs without being detected. These asymptomatic cases provide information in relation to the manifestation of immunological aspects. In this study, we developed an ELISA method to compare neutralizing effects of dengue prM and E antibodies between dengue patients and their asymptomatic household members. Recombinant D2 premembrane (prM) was constructed, cloned, and tested for antigenicity. The recombinant protein was purified and tested with controls by using an indirect ELISA method. Positive dengue serum samples with their asymptomatic pair were then carried out onto the developed ELISA. In addition, commercially available recombinant envelope (E) protein was used to develop an ELISA which was tested with the same set of serum samples in the prM ELISA. Asymptomatic individuals showed preexisting heterotypic neutralizing antibodies. The recombinant prM was antigenically reactive in the developed ELISA. Dengue patients had higher prM and E antibodies compared to their household members. Our study highlights the neutralizing antibodies levels with respect to dengue prM and E between dengue patients and asymptomatic individuals. PMID- 25815315 TI - Curcumin mitigates accelerated aging after irradiation in Drosophila by reducing oxidative stress. AB - Curcumin, belonging to a class of natural phenol compounds, has been extensively studied due to its antioxidative, anticancer, anti-inflammatory, and antineurodegenerative effects. Recently, it has been shown to exert dual activities after irradiation, radioprotection, and radiosensitization. Here, we investigated the protective effect of curcumin against radiation damage using D. melanogaster. Pretreatment with curcumin (100 MUM) recovered the shortened lifespan caused by irradiation and increased eclosion rate. Flies subjected to high-dose irradiation showed a mutant phenotype of outstretched wings, whereas curcumin pretreatment reduced incidence of the mutant phenotype. Protein carbonylation and formation of gammaH2Ax foci both increased following high-dose irradiation most likely due to generation of reactive oxygen species. Curcumin pretreatment reduced the amount of protein carbonylation as well as formation of gammaH2Ax foci. Therefore, we suggest that curcumin acts as an oxidative stress reducer as well as an effective protective agent against radiation damage. PMID- 25815316 TI - Effect of recombinant prophenin 2 on the integrity and viability of Trichomonas vaginalis. AB - Trichomonas vaginalis is the causal agent of trichomoniasis, which is associated with preterm child delivery, low birth weight, and an increased risk of infection by human papilloma virus and human immunodeficiency virus following exposure. Several reports have established increasing numbers of trichomoniasis cases resistant to metronidazole, the agent used for treatment, and it is therefore important to identify new therapeutic alternatives. Previously, our group reported the effect of tritrpticin, a synthetic peptide derived from porcine prophenin, on T. vaginalis; however, the hemolytic activity of this small peptide complicates its possible use as a therapeutic agent. In this study, we report that the propeptide and the processed peptide of prophenin 2 (cleaved with hydroxylamine) affected the integrity and growth of T. vaginalis and that pro prophenin 2 displays some resistance to proteolysis by T. vaginalis proteinases at 1 h. Its effect on T. vaginalis as well as its low hemolytic activity and short-time stability to parasite proteinases makes prophenin 2 an interesting candidate for synergistic or alternative treatment against T. vaginalis. PMID- 25815317 TI - Antibacterial activity of synthetic peptides derived from lactoferricin against Escherichia coli ATCC 25922 and Enterococcus faecalis ATCC 29212. AB - Peptides derived from human and bovine lactoferricin were designed, synthesized, purified, and characterized using RP-HPLC and MALDI-TOF-MS. Specific changes in the sequences were designed as (i) the incorporation of unnatural amino acids in the sequence, the (ii) reduction or (iii) elongation of the peptide chain length, and (iv) synthesis of molecules with different number of branches containing the same sequence. For each peptide, the antibacterial activity against Escherichia coli ATCC 25922 and Enterococcus faecalis ATCC 29212 was evaluated. Our results showed that Peptides I.2 (RWQWRWQWR) and I.4 ((RRWQWR)4K2Ahx2C2) exhibit bigger or similar activity against E. coli (MIC 4-33 MUM) and E. faecalis (MIC 10-33 MUM) when they were compared with lactoferricin protein (LF) and some of its derivate peptides as II.1 (FKCRRWQWRMKKLGA) and IV.1 (FKCRRWQWRMKKLGAPSITCVRRAE). It should be pointed out that Peptides I.2 and I.4, containing the RWQWR motif, are short and easy to synthesize; our results demonstrate that it is possible to design and obtain synthetic peptides that exhibit enhanced antibacterial activity using a methodology that is fast and low-cost and that allows obtaining products with a high degree of purity and high yield. PMID- 25815318 TI - Chronic ingestion of high dosed Phikud Navakot extraction induces mesangiolysis in rats with alteration of AQP1 and Hsp60 expressions. AB - Phikud Navakot (PN) is commonly used in Thai traditional medicine for alleviation of cardiovascular and cerebrovascular symptoms; however little is known about the chronic toxicity effects of the extracts from the herbs in PN. Repeated extraction doses of 10, 100, and 1,000 mg/kg/day were randomly administered to both male and female Sprague Dawley rats for 12 months. Histopathological study revealed that mesangiolysis was predominately found at the highest dose. Aquaporin 1 (AQP1) expression in the mesangiolytic glomeruli was significantly lower than in the intact glomeruli. This may be relevant to an imbalance of vascular function manifested by AQP1 alteration. In the mesangiolytic glomeruli, 60 kDa heat shock protein (Hsp60) was significantly upregulated on the endothelial lining cells of aneurysm and vascular cyst. Hsp60 increase may be related to endothelial cell damage due to its intracellular protective role. Blood urea nitrogen and creatinine levels remained within their normal range indicating well-functioning renal reserve function. In conclusion, high dosed PN may affect the endothelium leading to inability of vascular permeability and consequence to mesangiolysis. Our results suggest that only a high dose of chronic oral administration of PN is relatively toxic in association with mesangiolysis. The NOAEL was determined to be 100 mg/kg/day. PMID- 25815320 TI - A game system for cognitive rehabilitation. AB - Brain injury such as traumatic brain injury (TBI) and stroke is the major cause of long-term disabilities in many countries. The increasing rate of brain damaged victims and the heterogeneity of impairments decrease rehabilitation effectiveness and competence resulting in higher cost of rehabilitation treatment. On the other hand, traditional rehabilitation exercises are boring, thus leading patients to neglect the prescribed exercises required for recovery. Therefore, we propose game-based approach to address these problems. This paper presents a rehabilitation gaming system (RGS) for cognitive rehabilitation. The RGS is developed based on a proposed conceptual framework which has also been presented in this paper. PMID- 25815319 TI - Vitamin supplementation as possible prophylactic treatment against migraine with aura and menstrual migraine. AB - Migraine is the most common form of headache disorder globally. The etiology of migraine is multifactorial, with genetic components and environmental interactions considered to be the main causal factors. Some researchers postulate that deficits in mitochondrial energy reserves can cause migraine or an increase in homocysteine levels can lead to migraine attacks; therefore, vitamins could play a vital role in migraine prevention. For instance, riboflavin influences mitochondrial dysfunction and prevents migraine. Genes such as flavoenzyme 5,10 methylenetetrahydrofolate reductase (MTHFR), especially the C677T variant, have been associated with elevated plasma levels of homocysteine and migraine with aura. Homocysteine catalyzation requires the presence of vitamins B6, B12, and folic acid, which can decrease the severity of migraine with aura, making these vitamins potentially useful prophylactic agents for treating migraine with aura. Menstrual migraine, on the other hand, is associated with increased prostaglandin (PG) levels in the endometrium, indicating a role for vitamin E, which is an anti PG. Vitamin C can also be used as a scavenger of reactive oxygen species for treating neurogenic inflammation in migraine patients. This paper reviews possible therapies based on vitamin supplementation for migraine prophylaxis, focusing on migraine with aura and menstrual migraine. PMID- 25815321 TI - Current and emerging cell culture manufacturing technologies for influenza vaccines. AB - Annually, influenza virus infects millions of people worldwide. Vaccination programs against seasonal influenza infections require the production of hundreds of million doses within a very short period of time. The influenza vaccine is currently produced using a technology developed in the 1940s that relies on replicating the virus in embryonated hens' eggs. The monovalent viral preparation is inactivated and purified before being formulated in trivalent or tetravalent influenza vaccines. The production process has depended on a continuous supply of eggs. In the case of pandemic outbreaks, this mode of production might be problematic because of a possible drastic reduction in the egg supply and the low flexibility of the manufacturing process resulting in a lack of supply of the required vaccine doses in a timely fashion. Novel production systems using mammalian or insect cell cultures have emerged to overcome the limitations of the egg-based production system. These industrially well-established production systems have been primarily selected for a faster and more flexible response to pandemic threats. Here, we review the most important cell culture manufacturing processes that have been developed in recent years for mass production of influenza vaccines. PMID- 25815322 TI - EULAR task force recommendations on annual cardiovascular risk assessment for patients with rheumatoid arthritis: an audit of the success of implementation in a rheumatology outpatient clinic. AB - OBJECTIVE: EULAR recommendations for cardiovascular disease (CVD) risk management include annual CVD risk assessments for patients with rheumatoid arthritis (RA). We evaluated the recording of CVD risk factors (CVD-RF) in a rheumatology outpatient clinic, where EULAR recommendations had been implemented. Further, we compared CVD-RF recordings between a regular rheumatology outpatient clinic (RegROC) and a structured arthritis clinic (AC). METHODS: In 2012, 1142 RA patients visited the rheumatology outpatient clinic: 612 attended RegROC and 530 attended AC. We conducted a search in the patient journals to ascertain the rate of CVD-RF recording. RESULTS: The overall CVD-RF recording rate was 40.1% in the rheumatology outpatient clinic, reflecting a recording rate of 59.1% in the AC and 23.6% in the RegROC. The odds ratios for having CVD-RFs recorded for patients attending AC compared to RegROC were as follows: blood pressure: 12.4, lipids: 5.0-6.0, glucose: 9.1, HbA1c: 6.1, smoking: 1.4, and for having all the CVD-RFs needed to calculate the CVD risk by the systematic coronary risk evaluation (SCORE): 21.0. CONCLUSION: The CVD-RF recording rate was low in a rheumatology outpatient clinic. However, a systematic team-based model was superior compared to a RegROC. Further measures are warranted to improve CVD-RF recording in RA patients. PMID- 25815323 TI - Effect of luteolin and apigenin on the expression of Oct-4, Sox2, and c-Myc in dental pulp cells with in vitro culture. AB - INTRODUCTION: Dental pulp cells (DPCs) are promising cell source for dental tissue regeneration. Recently, small molecules which optimize microenvironment or activate the reprogramming network provide a new way to enhance the pluripotency. Two promising bioflavonoids luteolin and apigenin were reported to enhance reprogramming efficiency in mouse embryonic fibroblast (MEF). However, their effect and underlying mechanism in cell fate determination of human DPCs remain unclear. METHODS: To elucidate the effect of luteolin and apigenin on the cell fate determination of DPCs, we explored the cell proliferation, cell cycle, senescence, apoptosis, expression of pluripotency markers Oct-4, Sox2, and c-Myc, and multilineage differentiation capability of DPCs with luteolin or apigenin treatment. RESULTS: We demonstrated that luteolin and apigenin inhibited cell proliferation, arrested DPCs in G2/M and S phase, and upregulated PI value and apoptosis. Moreover, luteolin and apigenin increased telomerase activity, maintained DPCs in a presenescent state, and activated the expression of Oct-4, Sox2, and c-Myc at a dose- and time-dependent pattern in DPCs even at late passages, albeit repressed lineage-specific differentiation. CONCLUSIONS: Addition of luteolin and apigenin in the culture medium might provide an effective way to maintain DPCs in an undifferentiated stage and inhibit lineage specific differentiation. PMID- 25815324 TI - Effect of supplemental lutein and zeaxanthin on serum, macular pigmentation, and visual performance in patients with early age-related macular degeneration. AB - PURPOSE: To compare the 2-year effect of multiple doses of lutein/zeaxanthin on serum, macular pigmentation, and visual performance on patients with early age related macular degeneration (AMD). METHODS: In this randomized, double-blinded, and placebo-controlled trial, 112 early AMD patients randomly received either 10 mg lutein, 20 mg lutein, a combination of lutein (10 mg) and zeaxanthin (10 mg), or placebo daily for 2 years. Serum concentration of lutein/zeaxanthin, macular pigment optical density (MPOD), visual functions including best-spectacle corrected visual acuity (BCVA), contrast sensitivity (CS), flash recovery time (FRT), and vision-related quality of life (VFQ25) was quantified. RESULTS: Serum lutein concentration and MPOD significantly increased in all the active treatment groups. Supplementation with 20 mg lutein was the most effective in increasing MPOD and CS at 3 cycles/degree for the first 48 weeks. However, they both significantly increased to the same peak value following supplementation with either 10 mg or 20 mg lutein during the intervention. No statistical changes of BCVA or FRT were observed during the trial. CONCLUSIONS: Long-term lutein supplementation could increase serum lutein concentration, MPOD, and visual sensitivities of early AMD patients. 10 mg lutein daily might be an advisable long-term dosage for early AMD treatment. PMID- 25815325 TI - A novel rat model of vitamin D deficiency: safe and rapid induction of vitamin D and calcitriol deficiency without hyperparathyroidism. AB - Vitamin D deficiency is associated with a range of clinical disorders. To study the mechanisms involved and improve treatments, animal models are tremendously useful. Current vitamin D deficient rat models have important practical limitations, including time requirements when using, exclusively, a vitamin D deficient diet. More importantly, induction of hypovitaminosis D causes significant fluctuations in parathyroid hormone (PTH) and mineral levels, complicating the interpretation of study results. To overcome these shortcomings, we report the successful induction of vitamin D deficiency within three weeks, with stable serum PTH and minerals levels, in Wistar rats. We incorporated two additional manoeuvres compared to a conventional diet. Firstly, the vitamin D depleted diet is calcium (Ca) enriched, to attenuate the development of secondary hyperparathyroidism. Secondly, six intraperitoneal injections of paricalcitol during the first two weeks are given to induce the rapid degradation of circulating vitamin D metabolites. After three weeks, serum 25-hydroxyvitamin D3 (25D) and 1,25-dihydroxyvitamin D3 (1,25D) levels had dropped below detection limits, with unchanged serum PTH, Ca, and phosphate (P) levels. Therefore, this model provides a useful tool to examine the sole effect of hypovitaminosis D, in a wide range of research settings, without confounding changes in PTH, Ca, and P. PMID- 25815326 TI - Molecular detection and sensitivity to antibiotics and bacteriocins of pathogens isolated from bovine mastitis in family dairy herds of central Mexico. AB - Thirty-two farms (n = 535 cows) located in the state of Guanajuato, Mexico, were sampled. Pathogens from bovine subclinical mastitis (SCM) and clinical mastitis (CLM) were identified by 16S rDNA and the sensitivity to both antibiotics and bacteriocins of Bacillus thuringiensis was tested. Forty-six milk samples were selected for their positive California Mastitis Test (CMT) (>=3) and any abnormality in the udder or milk. The frequency of SCM and CLM was 39.1% and 9.3%, respectively. Averages for test day milk yield (MY), lactation number (LN), herd size (HS), and number of days in milk (DM) were 20.6 kg, 2.8 lactations, 16.7 animals, and 164.1 days, respectively. MY was dependent on dairy herd (DH), LN, HS, and DM (P < 0.01), and correlations between udder quarters from the CMT were around 0.49 (P < 0.01). Coagulase-negative staphylococci were mainly identified, as well as Staphylococcus aureus, Streptococcus uberis, Brevibacterium stationis, B. conglomeratum, and Staphylococcus agnetis. Bacterial isolates were resistant to penicillin, clindamycin, ampicillin, and cefotaxime. Bacteriocins synthesized by Bacillus thuringiensis inhibited the growth of multiantibiotic resistance bacteria such as S. agnetis, S. equorum, Streptococcus uberis, Brevibacterium stationis, and Brachybacterium conglomeratum, but they were not active against S. sciuri, a microorganism that showed an 84% resistance to antibiotics tested in this study. PMID- 25815327 TI - Temozolomide and radiotherapy versus radiotherapy alone in high grade gliomas: a very long term comparative study and literature review. AB - Temozolomide (TMZ) is the first line drug in the care of high grade gliomas. The combined treatment of TMZ plus radiotherapy is more effective in the care of brain gliomas then radiotherapy alone. Aim of this report is a survival comparison, on a long time (>10 years) span, of glioma patients treated with radiotherapy alone and with radiotherapy + TMZ. MATERIALS AND METHODS: In this report we retrospectively reviewed the outcome of 128 consecutive pts with diagnosis of high grade gliomas referred to our institutions from April 1994 to November 2001. The first 64 pts were treated with RT alone and the other 64 with a combination of RT and adjuvant or concomitant TMZ. RESULTS: Grade 3 (G3) haematological toxicity was recorded in 6 (9%) of 64 pts treated with RT and TMZ. No G4 haematological toxicity was observed. Age, histology, and administration of TMZ were statistically significant prognostic factors associated with 2 years overall survival (OS). PFS was for GBM 9 months, for AA 11. CONCLUSIONS: The combination of RT and TMZ improves long term survival in glioma patients. Our results confirm the superiority of the combination on a long time basis. PMID- 25815328 TI - Patient-specific simulation of coronary artery pressure measurements: an in vivo three-dimensional validation study in humans. AB - Pressure measurements using finite element computations without the need of a wire could be valuable in clinical practice. Our aim was to compare the computed distal coronary pressure values with the measured values using a pressure wire, while testing the effect of different boundary conditions for the simulation. Eight coronary arteries (lumen and outer vessel wall) from six patients were reconstructed in three-dimensional (3D) space using intravascular ultrasound and biplane angiographic images. Pressure values at the distal and proximal end of the vessel and flow velocity values at the distal end were acquired with the use of a combo pressure-flow wire. The 3D lumen and wall models were discretized into finite elements; fluid structure interaction (FSI) and rigid wall simulations were performed for one cardiac cycle both with pulsatile and steady flow in separate simulations. The results showed a high correlation between the measured and the computed coronary pressure values (coefficient of determination [r(2)] ranging between 0.8902 and 0.9961), while the less demanding simulations using steady flow and rigid walls resulted in very small relative error. Our study demonstrates that computational assessment of coronary pressure is feasible and seems to be accurate compared to the wire-based measurements. PMID- 25815330 TI - Ascorbic acid, ultraviolet C rays, and glucose but not hyperthermia are elicitors of human beta-defensin 1 mRNA in normal keratinocytes. AB - Hosts' innate defense systems are upregulated by antimicrobial peptide elicitors (APEs). Our aim was to investigate the effects of hyperthermia, ultraviolet A rays (UVA), and ultraviolet C rays (UVC) as well as glucose and ascorbic acid (AA) on the regulation of human beta-defensin 1 (DEFB1), cathelicidin (CAMP), and interferon-gamma (IFNG) genes in normal human keratinocytes (NHK). The indirect in vitro antimicrobial activity against Staphylococcus aureus and Listeria monocytogenes of these potential APEs was tested. We found that AA is a more potent APE for DEFB1 than glucose in NHK. Glucose but not AA is an APE for CAMP. Mild hypo- (35 degrees C) and hyperthermia (39 degrees C) are not APEs in NHK. AA dependent DEFB1 upregulation below 20 mM predicts in vitro antimicrobial activity as well as glucose- and AA-dependent CAMP and IFNG upregulation. UVC upregulates CAMP and DEFB1 genes but UVA only upregulates the DEFB1 gene. UVC is a previously unrecognized APE in human cells. Our results suggest that glucose upregulates CAMP in an IFN-gamma-independent manner. AA is an elicitor of innate immunity that will challenge the current concept of late activation of adaptive immunity of this vitamin. These results could be useful in designing new potential drugs and devices to combat skin infections. PMID- 25815331 TI - The role of cingulate cortex in vicarious pain. AB - Vicarious pain is defined as the observation of individuals in pain. There is growing neuroimaging evidence suggesting that the cingulate cortex plays a significant role in self-experienced pain processing. Yet, very few studies have directly tested the distinct functions of the cingulate cortex for vicarious pain. In this review, one EEG and eighteen neuroimaging studies reporting cingulate cortex activity during pain observation were discussed. The data indicate that there is overlapping neural activity in the cingulate cortex during self- and vicarious pain. Such activity may contribute to shared neural pain representations that permit inference of the affective state of individuals in pain, facilitating empathy. However, the exact location of neuronal populations in which activity overlaps or differs for self- and observed pain processing requires further confirmation. This review also discusses evidence suggesting differential functions of the cingulate cortex in cognitive, affective, and motor processing during empathy induction. While affective processing in the cingulate cortex during pain observation has been explored relatively more often, its attention and motor roles remain underresearched. Shedding light on the neural correlates of vicarious pain and corresponding empathy in healthy populations can provide neurobiological markers and intervention targets for empathic deficits found in various clinical disorders. PMID- 25815332 TI - Genetic and metabolic intraspecific biodiversity of Ganoderma lucidum. AB - Fourteen Ganoderma lucidum strains from different geographic regions were identified using ITS region sequencing. Based on the sequences obtained, the genomic relationship between the analyzed strains was determined. All G. lucidum strains were also genetically characterized using the AFLP technique. G. lucidum strains included in the analysis displayed an AFLP profile similarity level in the range from 9.6 to 33.9%. Biolog FF MicroPlates were applied to obtain data on utilization of 95 carbon sources and mitochondrial activity. The analysis allowed comparison of functional diversity of the fungal strains. The substrate utilization profiles for the isolates tested revealed a broad variability within the analyzed G. lucidum species and proved to be a good profiling technology for studying the diversity in fungi. Significant differences have been demonstrated in substrate richness values. Interestingly, the analysis of growth and biomass production also differentiated the strains based on the growth rate on the agar and sawdust substrate. In general, the mycelial growth on the sawdust substrate was more balanced and the fastest fungal growth was observed for GRE3 and FCL192. PMID- 25815329 TI - HIV-associated neurocognitive disorders: the relationship of HIV infection with physical and social comorbidities. AB - The prevalence of HIV (human immunodeficiency virus) associated neurocognitive disorders (HAND) will undoubtedly increase with the improved longevity of HIV infected persons. HIV infection, itself, as well as multiple physiologic and psychosocial factors can contribute to cognitive impairment and neurologic complications. These comorbidities confound the diagnosis, assessment, and interventions for neurocognitive disorders. In this review, we discuss the role of several key comorbid factors that may contribute significantly to the development and progression of HIV-related neurocognitive impairment, as well as the current status of diagnostic strategies aimed at identifying HIV-infected individuals with impaired cognition and future research priorities and challenges. PMID- 25815333 TI - Plant antimicrobial peptides as potential anticancer agents. AB - Antimicrobial peptides (AMPs) are part of the innate immune defense mechanism of many organisms and are promising candidates to treat infections caused by pathogenic bacteria to animals and humans. AMPs also display anticancer activities because of their ability to inactivate a wide range of cancer cells. Cancer remains a cause of high morbidity and mortality worldwide. Therefore, the development of methods for its control is desirable. Attractive alternatives include plant AMP thionins, defensins, and cyclotides, which have anticancer activities. Here, we provide an overview of plant AMPs anticancer activities, with an emphasis on their mode of action, their selectivity, and their efficacy. PMID- 25815335 TI - Optical coherence tomography in patients with Chiari I malformation. AB - BACKGROUND/AIMS: To evaluate optic nerve head with spectral domain optical coherence tomography (OCT) in patients with Chiari I malformation (CMI) compared to healthy controls. METHODS: Cross-sectional study. OCT of the optic nerve head of 22 patients with CMI and 22 healthy controls was quantitatively analyzed. The healthy controls were matched for age and sex with the study population. Mean retinal nerve fiber layer (RNFL) thickness was calculated for both eyes; the mean thickness value was also registered for each quadrant and for each subfield of the four quadrants. RESULTS: CMI patients showed a reduction of the RNFL thickness in both eyes. This reduction was more statistically significant (P < 0.05) for the inferior quadrant in the right eye and in each quadrant than nasal one in the left eye. CONCLUSION: A distress of the retinal nerve fibers could explain the observed reduction of the RNFL thickness in patients with CMI; in our series the reduction of the RNFL thickness seems lower when CMI is associated with syringomyelia. PMID- 25815334 TI - Generation of neurospheres from human adipose-derived stem cells. AB - Transplantation of neural stem cells (NSCs) to treat neurodegenerative disease shows promise; however, the clinical application of NSCs is limited by the invasive procurement and ethical concerns. Adipose-derived stem cells (ADSCs) are a source of multipotent stem cells that can self-renew and differentiate into various kinds of cells; this study intends to generate neurospheres from human ADSCs by culturing ADSCs on uncoated culture flasks in serum-free neurobasal medium supplemented with B27, basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF); the ADSCs-derived neurospheres were terminally differentiated after growth factor withdrawal. Expression of Nestin, NeuN, MAP2, and GFAP in ADSCs and terminally differentiated neurospheres was shown by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and immunocytochemistry; cell proliferation in neurospheres was evaluated by cell cycle analyses, immunostaining, and flow cytometry. These data strongly support the conclusion that human ADSCs can successfully differentiate into neurospheres efficiently on uncoated culture flasks, which present similar molecular marker pattern and proliferative ability with NSCs derived from embryonic and adult brain tissues. Therefore, human ADSCs may be an ideal alternative source of stem cells for the treatment of neurodegenerative diseases. PMID- 25815336 TI - Increased incidence of atrial fibrillation in patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate the incidence of atrial fibrillation (AF) among patients with rheumatoid arthritis (RA) compared to the general population. METHODS: A population-based inception cohort of Olmsted County, Minnesota, residents with incident RA in 1980-2007 and a cohort of non-RA subjects from the same population base were assembled and followed until 12/31/2008. The occurrence of AF was ascertained by medical record review. RESULTS: The study included 813 patients with RA and 813 non-RA subjects (mean age 55.9 (SD:15.7) years, 68% women in both cohorts). The prevalence of AF was similar in the RA and non-RA cohorts at RA incidence/index date (4% versus 3%; P = 0.51). The cumulative incidence of AF during follow-up was higher among patients with RA compared to non-RA subjects (18.3% versus 16.3% at 20 years; P = 0.048). This difference persisted after adjustment for age, sex, calendar year, smoking, and hypertension (hazard ratio: 1.46; 95% CI: 1.07, 2.00). There was no evidence of a differential impact of AF on mortality in patients with RA compared to non-RA subjects (hazard ratio 2.5 versus 2.8; interaction P = 0.31). CONCLUSION: The incidence of AF is increased in patients with RA, even after adjustment for AF risk factors. AF related mortality risk did not differ between patients with and without RA. PMID- 25815337 TI - Predicting the functions of long noncoding RNAs using RNA-seq based on Bayesian network. AB - Long noncoding RNAs (lncRNAs) have been shown to play key roles in various biological processes. However, functions of most lncRNAs are poorly characterized. Here, we represent a framework to predict functions of lncRNAs through construction of a regulatory network between lncRNAs and protein-coding genes. Using RNA-seq data, the transcript profiles of lncRNAs and protein-coding genes are constructed. Using the Bayesian network method, a regulatory network, which implies dependency relations between lncRNAs and protein-coding genes, was built. In combining protein interaction network, highly connected coding genes linked by a given lncRNA were subsequently used to predict functions of the lncRNA through functional enrichment. Application of our method to prostate RNA seq data showed that 762 lncRNAs in the constructed regulatory network were assigned functions. We found that lncRNAs are involved in diverse biological processes, such as tissue development or embryo development (e.g., nervous system development and mesoderm development). By comparison with functions inferred using the neighboring gene-based method and functions determined using lncRNA knockdown experiments, our method can provide comparable predicted functions of lncRNAs. Overall, our method can be applied to emerging RNA-seq data, which will help researchers identify complex relations between lncRNAs and coding genes and reveal important functions of lncRNAs. PMID- 25815338 TI - MicroRNA-146b-3p regulates retinal inflammation by suppressing adenosine deaminase-2 in diabetes. AB - Hyperglycemia- (HG-) Amadori-glycated albumin- (AGA-) induced activation of microglia and monocytes and their adherence to retinal vascular endothelial cells contribute to retinal inflammation leading to diabetic retinopathy (DR). There is a great need for early detection of DR before demonstrable tissue damages become irreversible. Extracellular adenosine, required for endogenous anti-inflammation, is regulated by the interplay of equilibrative nucleoside transporter with adenosine deaminase (ADA) and adenosine kinase. ADA, including ADA1 and ADA2, exists in all organisms. However, because ADA2 gene has not been identified in mouse genome, how diabetes alters adenosine-dependent anti-inflammation remains unclear. Studies of pig retinal microglia and human macrophages revealed a causal role of ADA2 in inflammation. Database search suggested miR-146b-3p recognition sites in the 3'-UTR of ADA2 mRNA. Coexpression of miR-146b-3p, but not miR-146-5p or nontargeting miRNA, with 3'-UTR of the ADA2 gene was necessary to suppress a linked reporter gene. In the vitreous of diabetic patients, decreased miR-146b-3p is associated with increased ADA2 activity. Ectopic expression of miR-146b-3p suppressed ADA2 expression, activity, and TNF-alpha release in the AGA-treated human macrophages. These results suggest a regulatory role of miR-146b-3p in diabetes related retinal inflammation by suppressing ADA2. PMID- 25815339 TI - Regulation of miRNAs affects radiobiological response of lung cancer stem cells. AB - Radiotherapy (RT) is a key therapeutic strategy for lung cancer, the most common cause of cancer-related deaths worldwide, but radioresistance often occurs and leads to failure of RT. It is therefore important to clarify the mechanism underlying radioresistance in lung cancer. Cancer stem cells (CSCs) are considered the fundamental reason for radioresistance. MicroRNAs (miRNAs) have been regarded as important regulatory molecules of CSCs, carcinogenesis, and treatment response of cancers. It is crucial to clarify how regulation of miRNAs affects repair of DNA damage, redistribution, repopulation, reoxygenation, and radiosensitivity (5R) of lung cancer stem cells (LCSCs). A thorough understanding of the regulation of miRNAs affecting 5R of LCSCs has potential impact on identifying novel targets and thus may improve the efficacy of lung cancer radiotherapy. PMID- 25815340 TI - The differential effects of a selective kappa-opioid receptor agonist, U50488, in guinea pig heart tissues. AB - The differential effects of a selective kappa- (kappa-) opioid receptor agonist, U50488, were elucidated by monitoring the contraction of isolated guinea pig atrial and ventricular muscles. In electrically driven left atria, U50488 in nanomolar concentration range decreased the contractile force. Norbinaltorphimine (norBNI), a selective kappa-receptor antagonist, and pertussis toxin (PTX) abolished the negative inotropic effect of U50488. In contrast, the inhibitory effect was not affected by the pretreatment of atropine or propranolol. Even though U50488 exerted a negative inotropic effect in the left atrium, it did not affect the contractile force of the right atrium and ventricles paced at 2 Hz. Similarly, the beating rate of the spontaneously beating right atrium was also unaffected by U50488. These results indicate that the activation of kappa-opioid receptors can only produce negative inotropic effect in left atria via activation of PTX-sensitive G protein in guinea pigs. The absence of negative inotropic effects in right atria and ventricles suggests that there may be a greater distribution of functional kappa-opioid receptors in guinea pig left atria than in right atria and ventricles, and the distribution of the receptors may be species-specific. PMID- 25815341 TI - Association of IL-6 polymorphism -174G/C and metabolic syndrome in hypertensive patients. AB - INTRODUCTION: Visceral obesity, the central core of metabolic syndrome (MetS), is conceived as the pathogenic basis of an increased cardiovascular burden and is related with changes in cytokines. We investigated whether IL-6-174G/C gene polymorphism is associated with MetS prevalence in hypertensive patients. METHOD: A population of hypertensive patients was included and stratified by the presence of MetS according to IDF criteria and evaluated by Framingham risk score. The IL 6-174G/C genotyping was performed by polymerase chain reaction and the prevalence of MetS was compared between "C" carrier and "non-C" carrier groups. RESULTS: From an original sample of 664 patients, 612 (34.2% men, age 57.3 +/- 10.1, 30.4% diabetics) were included. MetS was diagnosed in 51.3% of total population and "C" carriers demonstrated high prevalence of MetS (P < 0.05) and each of its components. On binary logistic regression, it was observed that the IL-6 polymorphism was independently associated with occurrence of MetS, even after adjusting for covariates (OR 1.13-2.37, 95% CI, P < 0.05). CONCLUSION: The C allele at the -174 locus of IL-6 gene is independently associated with the occurrence of metabolic syndrome, emphasizing the importance of inflammatory genetic background in the pathogenesis of visceral obesity and related cardiovascular burden. PMID- 25815342 TI - Evolution of action potential alternans in rabbit heart during acute regional ischemia. AB - This study investigates the development of the spatiotemporal pattern of action potential alternans during acute regional ischemia. Experiments were carried out in isolated Langendorff-perfused rabbit heart using a combination of optical mapping and microelectrode recordings. The alternans pattern significantly changed over time and had a biphasic character reaching maximum at 6-9 min after occlusion. Phase I (3-11 minutes of ischemia) is characterized by rapid increase in the alternans magnitude and expansion of the alternans territory. Phase I is followed by gradual decline of alternans (Phase II) in both magnitude and territory. During both phases we observed significant beat-to-beat variations of the optical action potential amplitude (OAPA) alternans. Simultaneous microelectrode recordings from subepicardial and subendocardial layers showed that OAPA alternans coincided with intramural 2 : 1 conduction blocks. Our findings are consistent with the modeling studies predicting that during acute regional ischemia alternans can be driven by 2 : 1 conduction blocks in the ischemic region. PMID- 25815343 TI - Cholesterol-induced hepatic inflammation does not underlie the predisposition to insulin resistance in dyslipidemic female LDL receptor knockout mice. AB - Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition towards insulin resistance in low-density lipoprotein receptor knock-out (Ldlr (-/-)) mice. For this, wild type (WT) and Ldlr (-/-) mice were fed a chow diet, a high fat (HF) diet, or a high fat, high cholesterol (HFC) diet for 2 weeks. Plasma lipid levels were elevated in chow-fed Ldlr (-/-) mice compared to WT mice. Although short term HF or HFC feeding did not result in body weight gain and adipose tissue inflammation, dyslipidemia was worsened in Ldlr (-/-) mice compared to WT mice. In addition, dyslipidemic HF-fed Ldlr (-/-) mice had a higher hepatic glucose production rate than HF-fed WT mice, while peripheral insulin resistance was unaffected. This suggests that HF-fed Ldlr (-/-) mice suffered from hepatic insulin resistance. While HFC-fed Ldlr (-/-) mice displayed the anticipated increased hepatic inflammation, this did neither exacerbate systemic nor hepatic insulin resistance. Therefore, our results show that hepatic insulin resistance is unrelated to cholesterol-induced hepatic inflammation in Ldlr (-/-) mice, indicating that hepatic inflammation may not contribute to metabolic dysfunction per se. PMID- 25815344 TI - The value of a panel of autoantibodies for predicting the activity of lupus nephritis at time of renal biopsy. AB - Few studies have correlated serum biomarkers with renal histology, the gold standard for renal activity, in lupus nephritis (LN). We tested a panel of autoantibodies and complement at the time of kidney biopsy and after treatment. Anti-dsDNA, anti-nucleosome, anti-ribosome P, and anti-C1q antibodies and C3/C4 were measured in 107 patients with LN at the time of renal biopsy and after 6-12 months and were correlated with clinical/histological parameters. At multivariate analysis, high titers of anti-C1q antibodies or of anti-dsDNA antibodies (P = 0.005, OR = 8.67, CI: 2.03-37.3) were the independent predictors that discriminate proliferative from nonproliferative LN. All the immunological parameters, except anti-ribosome, showed a significant correlation with activity index but not with chronicity index. Only anti-C1q showed a significant correlation with the amount of proteinuria (R = 0.2, P = 0.03). None of the immunological parameters were predictive of remission at 6 and 12 months. We found that anti-C1q alone or in combination with anti-dsDNA emerged as the most reliable test in differentiating proliferative and nonproliferative LN. Anti-C1q was the only test correlated with the clinical presentation of LN. After treatment, the titre of the autoantibodies was significantly reduced, but none was predictive of remission. PMID- 25815345 TI - PGE2-induced IDO1 inhibits the capacity of fully mature DCs to elicit an in vitro antileukemic immune response. AB - In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3 dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2 matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2 mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN gamma secreting CD4(+) and CD8(+) T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2. PMID- 25815346 TI - Effective binding of a phosphatidylserine-targeting antibody to Ebola virus infected cells and purified virions. AB - Ebola virus is responsible for causing severe hemorrhagic fevers, with case fatality rates of up to 90%. Currently, no antiviral or vaccine is licensed against Ebola virus. A phosphatidylserine-targeting antibody (PGN401, bavituximab) has previously been shown to have broad-spectrum antiviral activity. Here, we demonstrate that PGN401 specifically binds to Ebola virus and recognizes infected cells. Our study provides the first evidence of phosphatidylserine targeting antibody reactivity against Ebola virus. PMID- 25815347 TI - Neutrophil migration in the activation of the innate immune response to different Flavobacterium psychrophilum vaccines in zebrafish (Danio rerio). AB - Flavobacterium psychrophilum is a Gram-negative bacterium, responsible for the bacterial cold-water disease and the rainbow trout fry syndrome in freshwater salmonid fish. At present, there is only one commercial vaccine in Chile, made with two Chilean F. psychrophilum isolates and another licensed in Europe. The present study analyzed neutrophil migration, as a marker of innate immune activation, in zebrafish (Danio rerio) in response to different F. psychrophilum bath vaccines, which is the first step in evaluating vaccine effectiveness and efficiency in fish. Results indicated that bacterins of the LM-02-Fp isolate were more immunogenic than those from the LM-13-Fp isolate. However, no differences were observed between the same bacteria inactivated by either formaldehyde or heat. Importantly, the same vaccine formulation without an adjuvant only triggered a mild neutrophil migration compared to the complete vaccine. Observations also found that, after a year of storage at 4 degrees C, the activation of the innate immune system by the different vaccines was considerably decreased. Finally, new vaccine formulations prepared with heat and formaldehyde inactivated LM-02-Fp were significantly more efficient than the available commercial vaccine in regard to stimulating the innate immune system. PMID- 25815348 TI - Connexin 43 communication channels in follicular dendritic cell development and in follicular lymphomas. AB - Follicular dendritic cells (FDC) show homo- and heterocellular metabolic coupling through connexin 43 (Cx43) gap junctions and support B cell selection and maturation in germinal centers. In follicular lymphomas B cells escape apoptosis while FDC develop abnormally. Here we tested Cx43 channels in reactive FDC development and follicular lymphomas. In culture, the treatment of FDC-B cell clusters (resembling to "ex vivo" germinal centers) with Gap27 peptide, mimicking the 2nd extracellular loop of Cx43 protein, significantly impaired FDC-B cell cluster formation and cell survival. In untreated cultures of intact clusters, cell proliferation showed a moderate reduction. In tissues, Cx43 protein levels run parallel with the density of FDC both in reactive germinal centers and in malformed follicles of follicular lymphomas and showed strong upregulation in newly generated and/or degrading bi-/multinuclear FDC of rudimentary processes. However, the inverse correlation between Cx43 expression and B cell proliferation seen in reactive germinal centers was not detected in follicular lymphomas. Furthermore, Cx43 levels were not associated with either lymphoma grade or bone marrow involvement. Our results suggest that Cx43 channels are critical in FDC and "ex vivo" germinal center development and in the persistence of FDC in follicular lymphomas but do not affect tumor progression. PMID- 25815350 TI - A plasma diagnostic model of human T-cell leukemia virus-1 associated myelopathy. AB - OBJECTIVE: Human T-cell leukemia virus-1 (HTLV-1) associated myelopathy/tropic spastic paraparesis (HAM/TSP) is induced by chronic inflammation in spinal cord due to HTLV-1 infection. Cerebrospinal fluid (CSF) neopterin or proviral load are clinically measured as disease grading biomarkers, however, they are not exactly specific to HAM/TSP. Therefore, we aimed to identify HAM/TSP-specific biomarker molecules and establish a novel less-invasive plasma diagnostic model for HAM/TSP. METHODS: Proteome-wide quantitative profiling of CSFs from six asymptomatic HTLV-1 carriers (AC) and 51 HAM/TSP patients was performed. Fourteen severity grade biomarker proteins were further examined plasma enzyme-linked immunosorbent assay (ELISA) assays (n = 71). Finally, we constructed three-factor logistic regression model and evaluated the diagnostic power using 105 plasma samples. RESULTS: Quantitative analysis for 1871 nonredundant CSF proteins identified from 57 individuals defined 14 CSF proteins showing significant correlation with Osame's motor disability score (OMDS). Subsequent ELISA experiments using 71 plasma specimens confirmed secreted protein acidic and rich in cysteine (SPARC) and vascular cell adhesion molecule-1 (VCAM-1) demonstrated the same correlations in plasma (R = -0.373 and R = 0.431, respectively). In this training set, we constructed a HAM/TSP diagnostic model using SPARC, VCAM1, and viral load. Sensitivity and specificity to diagnose HAM/TSP patients from AC (AC vs. OMDS 1-11) were 85.3% and 81.1%, respectively. Importantly, this model could be also useful for determination of therapeutic intervention point (OMDS 1-3 + AC vs. OMDS 4-11), exhibiting 80.0% sensitivity and 82.9% specificity. INTERPRETATION: We propose a novel less-invasive diagnostic model for early detection and clinical stratification of HAM/TSP. PMID- 25815349 TI - Variation in longevity gene KLOTHO is associated with greater cortical volumes. AB - OBJECTIVE: Identifying genetic variation associated with brain structures in aging may elucidate new biologic mechanisms underlying resilience to cognitive decline. We investigated whether carrying one copy of the protective haplotype "KL-VS" in longevity gene KLOTHO (KL) is associated with greater gray matter volume in healthy human aging compared to carrying no copies. METHODS: We performed unbiased whole-brain analysis in cognitively normal older adults from two independent cohorts to assess the relationship between KL-VS and gray matter volume using voxel-based morphometry. RESULTS: We found that KL-VS heterozygosity was associated with greater volume in right dorsolateral prefrontal cortex (rDLPFC). Because rDLPFC is important for executive function, we analyzed working memory and processing speed in individuals. KL-VS heterozygosity was associated with enhanced executive function. Larger rDLPFC volume correlated with better executive function across the lifespan examined. Statistical analysis suggested that volume partially mediates the effect of genotype on cognition. INTERPRETATION: These results suggest that variation in KL is associated with bigger brain volume and better function. PMID- 25815351 TI - Passive immunotherapy of tauopathy targeting pSer413-tau: a pilot study in mice. AB - OBJECTIVE: Cellular inclusions of hyperphosphorylated tau are a hallmark of tauopathies, which are neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive immunization against hyperphosphorylated tau has been shown to attenuate phenotypes in model mice. We developed new monoclonal antibodies to hyperphosphorylated tau and sought high therapeutic efficacy for future clinical use. METHODS: Using more than 20 antibodies, we investigated which sites on tau are phosphorylated early and highly in the tauopathy mouse models tau609 and tau784. These mice display tau hyperphosphorylation, synapse loss, memory impairment at 6 months, and tangle formation and neuronal loss at 15 months. We generated mouse monoclonal antibodies to selected epitopes and examined their effects on memory and tau pathology in aged tau609 and tau784 mice by the Morris water maze and by histological and biochemical analyses. RESULTS: Immunohistochemical screening revealed that pSer413 is expressed early and highly. Monoclonal antibodies to pSer413 and to pSer396 (control) were generated. These antibodies specifically recognized pathological tau in AD brains but not normal tau in control brains according to Western blots. Representative anti pSer413 and anti-pSer396 antibodies were injected intraperitoneally into 10-11- or 14-month-old mice once a week at 0.1 or 1 mg/shot 5 times. The anti-pSer413 antibody significantly improved memory, whereas the anti-pSer396 antibodies showed less effect. The cognitive improvement paralleled a reduction in the levels of tau hyperphosphorylation, tau oligomer accumulation, synapse loss, tangle formation, and neuronal loss. INTERPRETATION: These results indicate that pSer413 is a promising target in the treatment of tauopathy. PMID- 25815352 TI - AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models. AB - OBJECTIVE: Dysferlinopathies are a family of untreatable muscle disorders caused by mutations in the dysferlin gene. Lack of dysferlin protein results in progressive dystrophy with chronic muscle fiber loss, inflammation, fat replacement, and fibrosis; leading to deteriorating muscle weakness. The objective of this work is to demonstrate efficient and safe restoration of dysferlin expression following gene therapy treatment. METHODS: Traditional gene therapy is restricted by the packaging capacity limit of adeno-associated virus (AAV), however, use of a dual vector strategy allows for delivery of over-sized genes, including dysferlin. The two vector system (AAV.DYSF.DV) packages the dysferlin cDNA utilizing AAV serotype rh.74 through the use of two discrete vectors defined by a 1 kb region of homology. Delivery of AAV.DYSF.DV via intramuscular and vascular delivery routes in dysferlin deficient mice and nonhuman primates was compared for efficiency and safety. RESULTS: Treated muscles were tested for dysferlin expression, overall muscle histology, and ability to repair following injury. High levels of dysferlin overexpression was shown for all muscle groups treated as well as restoration of functional outcome measures (membrane repair ability and diaphragm specific force) to wild-type levels. In primates, strong dysferlin expression was demonstrated with no safety concerns. INTERPRETATION: Treated muscles showed high levels of dysferlin expression with functional restoration with no evidence of toxicity or immune response providing proof of principle for translation to dysferlinopathy patients. PMID- 25815353 TI - Optimizing multiple sclerosis diagnosis: gene expression and genomic association. AB - OBJECTIVE: The diagnosis of multiple sclerosis (MS) at disease onset is sometimes masqueraded by other diagnostic options resembling MS clinically or radiologically (NonMS). In the present study we utilized findings of large-scale Genome-Wide Association Studies (GWAS) to develop a blood gene expression-based classification tool to assist in diagnosis during the first demyelinating event. METHODS: We have merged knowledge of 110 MS susceptibility genes gained from MS GWAS studies together with our experimental results of differential blood gene expression profiling between 80 MS and 31 NonMS patients. Multiple classification algorithms were applied to this cohort to construct a diagnostic classifier that correctly distinguished between MS and NonMS patients. Accuracy of the classifier was tested on an additional independent group of 146 patients including 121 MS and 25 NonMS patients. RESULTS: We have constructed a 42 gene-transcript expression-based MS diagnostic classifier. The overall accuracy of the classifier, as tested on an independent patient population consisting of diagnostically challenging cases including NonMS patients with positive MRI findings, achieved a correct classification rate of 76.0 +/- 3.5%. INTERPRETATION: The presented diagnostic classification tool complements the existing diagnostic McDonald criteria by assisting in the accurate exclusion of other neurological diseases at presentation of the first demyelinating event suggestive of MS. PMID- 25815354 TI - Anti-tau antibody reduces insoluble tau and decreases brain atrophy. AB - OBJECTIVE: We previously found a strong reduction in tau pathology and insoluble tau in P301S tau transgenic mice following intracerebroventricular infusion of the anti-tau antibody HJ8.5. We sought to determine the effects of HJ8.5 in the same model following peripheral administration. METHODS: The primary objective was to determine if HJ8.5 administered at a dose of 50 mg kg(-1) week(-1) by intraperitoneal (IP) injection to 6-month-old P301S mice for 3 months would influence phospho-tau (p-tau) accumulation, tau insolubility, and neurodegeneration. RESULTS: Treatment with HJ8.5 at 50 mg/kg showed a very strong decrease in detergent-insoluble tau. Importantly, HJ8.5 significantly reduced the loss of cortical and hippocampal tissue volumes compared to control treated mice. HJ8.5 treatment reduced hippocampal CA1 cellular layer staining with the p-tau antibody AT8 and thio-S-positive tau aggregates in piriform cortex and amygdala. Moreover, mice treated with HJ8.5 at 50 mg/kg showed a decrease in motor/sensorimotor deficits compared to vehicle-treated mice. Some effects of HJ8.5, including reduction in brain atrophy, and p-tau immunostaining were also seen with a dose of 10 mg kg(-1) week(-1). In BV2-microglial cells, we observed significantly higher uptake of P301S tau aggregates in the presence of HJ8.5. HJ8.5 treatment also resulted in a large dose-dependent increase of tau in the plasma. INTERPRETATION: Our results indicate that systemically administered anti tau antibody HJ8.5 significantly decreases insoluble tau, decreases brain atrophy, and improves motor/sensorimotor function in a mouse model of tauopathy. These data further support the idea that anti-tau antibodies should be further assessed as a potential treatment for tauopathies. PMID- 25815355 TI - Cannabinoid agonist rescues learning and memory after a traumatic brain injury. AB - Traumatic brain injury can cause persistent challenges including problems with learning and memory. Previous studies suggest that the activation of the cannabinoid 1 receptor after a traumatic brain injury could be beneficial. We tested the hypothesis that posttraumatic brain injury administration of a cannabinoid 1 receptor agonist can rescue deficits in learning and memory. Young adult male rats were subjected to a moderately severe controlled cortical impact brain injury, with a subset given postinjury i.p. injections of a cannabinoid receptor agonist. Utilizing novel object recognition and the morris water task, we found that the brain-injured animals treated with the agonist showed a marked recovery. PMID- 25815356 TI - Histopathology and clinical course of MOG-antibody-associated encephalomyelitis. AB - We present histological, MRI, and clinical features of an adult patient with relapsing encephalomyelitis and antibodies against myelin oligodendrocyte glycoprotein (MOG). Furthermore, we report molecular details of the recognized epitope that is specific for human MOG. A brain biopsy revealed multiple sclerosis (MS)-type II pathology. Some features overlapped with both MS and neuromyelitis optica spectrum disorders (NMOSD), whereas others were distinct from both MS and NMOSD. Immunoadsorption and rituximab induced clinical stabilization. This case contributes a new, so far missing link in the emerging spectrum of MOG-antibody-associated encephalomyelitis. PMID- 25815357 TI - ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout. AB - Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (P = 0.0027), but significantly associated with later Parkinson's disease onset (P = 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease. PMID- 25815360 TI - Human RNASET2 derivatives as potential anti-angiogenic agents: actin binding sequence identification and characterization. AB - Human RNASET2 (hRNASET2) has been demonstrated to exert antiangiogenic and antitumorigenic effects independent of its ribonuclease capacity. We suggested that RNASET2 exerts its antiangiogenic and antitumorigenic activities via binding to actin and consequently inhibits cell motility. We focused herein on the identification of the actin binding site of hRNASET2 using defined sequences encountered within the whole hRNASET2 protein. For that purpose we designed 29 different hRNASET2-derived peptides. The 29 peptides were examined for their ability to bind immobilized actin. Two selected peptides-A103-Q159 consisting of 57 amino acids and peptide K108-K133 consisting of 26 amino acids were demonstrated to have the highest actin binding ability and concomitantly the most potent anti-angiogenic activity. Further analyses on the putative mechanisms associated with angiogenesis inhibition exerted by peptide K108-K133 involved its location during treatment within the HUVE cells. Peptide K108-K133 readily penetrates the cell membrane within 10 min of incubation. In addition, supplementation with angiogenin delays the entrance of peptide K108-K133 to the cell suggesting competition on the same cell internalization route. The peptide was demonstrated to co-localize with angiogenin, suggesting that both molecules bind analogous cellular epitopes, similar to our previously reported data for ACTIBIND and trT2-50. PMID- 25815358 TI - A practical algorithm for managing Alzheimer's disease: what, when, and why? AB - Alzheimer's disease (AD) is the most common form of dementia and its prevalence is increasing. Recent developments in AD management provide improved ways of supporting patients and their caregivers throughout the disease continuum. Managing cardiovascular risk factors, maintaining an active lifestyle (with regular physical, mental and social activity) and following a Mediterranean diet appear to reduce AD risk and may slow cognitive decline. Pharmacologic therapy for AD should be initiated upon diagnosis. All of the currently available cholinesterase inhibitors (ChEIs; donepezil, galantamine, and rivastigmine) are indicated for mild-to-moderate AD. Donepezil (10 and 23 mg/day) and rivastigmine transdermal patch (13.3 mg/24 h) are indicated for moderate-to-severe AD. Memantine, an N-methyl-d-aspartate receptor antagonist, is approved for moderate to-severe AD. ChEIs have been shown to improve cognitive function, global clinical status and patients' ability to perform activities of daily living. There is also evidence for reduction in emergence of behavioral symptoms with ChEI therapy. Treatment choice (e.g., oral vs. transdermal) should be based on patient or caregiver preference, ease of use, tolerability, and cost. Treatment should be individualized; patients can be switched from one ChEI to another if the initial agent is poorly tolerated or ineffective. Memantine may be introduced in moderate-to-severe disease stages. Clinicians will regularly monitor symptoms and behaviors, manage comorbidities, assess function, educate and help caregivers access information and support, evaluate patients' fitness to drive or own firearms, and provide advice about the need for legal and financial planning. Review of caregiver well-being and prompt referral for support is vital. PMID- 25815361 TI - Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib. AB - Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that accounts for 2% of all leukemia. Recent identification of the recurrent V600E BRAF mutation in a majority of HCL patients has led some teams to evaluate the clinical potential of vemurafenib, a BRAF V600 specific inhibitor in a limited number of refractory HCL patients. Recently, we published the case of an HCL patient successfully treated with a low dose of vemurafenib. Eight months after the ending of treatment this patient relapsed. We present here the successful retreatment of this patient with a second line of vemurafenib. Our data suggest for the first time that vemurafenib at the dose of 240 mg once a day could be sufficient to maintain a complete hematological remission after an initial induction treatment with low-dose vemurafenib (2 * 240 mg) daily without inducing major toxicity. PMID- 25815362 TI - Simple, rapid and accurate molecular diagnosis of acute promyelocytic leukemia by loop mediated amplification technology. AB - The diagnostic work-up of acute promyelocytic leukemia (APL) includes the cytogenetic demonstration of the t(15;17) translocation and/or the PML-RARA chimeric transcript by RQ-PCR or RT-PCR. This latter assays provide suitable results in 3-6 hours. We describe here two new, rapid and specific assays that detect PML-RARA transcripts, based on the RT-QLAMP (Reverse Transcription Quenching Loop-mediated Isothermal Amplification) technology in which RNA retrotranscription and cDNA amplification are carried out in a single tube with one enzyme at one temperature, in fluorescence and real time format. A single tube triplex assay detects bcr1 and bcr3 PML-RARA transcripts along with GUS housekeeping gene. A single tube duplex assay detects bcr2 and GUSB. In 73 APL cases, these assays detected in 16 minutes bcr1, bcr2 and bcr3 transcripts. All 81 non-APL samples were negative by RT-QLAMP for chimeric transcripts whereas GUSB was detectable. In 11 APL patients in which RT-PCR yielded equivocal breakpoint type results, RT-QLAMP assays unequivocally and accurately defined the breakpoint type (as confirmed by sequencing). Furthermore, RT-QLAMP could amplify two bcr2 transcripts with particularly extended PML exon 6 deletions not amplified by RQ-PCR. RT-QLAMP reproducible sensitivity is 10(-3) for bcr1 and bcr3 and 10(-)2 for bcr2 thus making this assay particularly attractive at diagnosis and leaving RQ-PCR for the molecular monitoring of minimal residual disease during the follow up. In conclusion, PML-RARA RT-QLAMP compared to RT-PCR or RQ-PCR is a valid improvement to perform rapid, simple and accurate molecular diagnosis of APL. PMID- 25815363 TI - Alpha-fetoprotein activates AKT/mTOR signaling to promote CXCR4 expression and migration of hepatoma cells. AB - CXCR4, stromal cell-derived factor-1alpha(SDF 1alpha) receptor, stimulates growth and metastasis of hepatocellular carcinoma (HCC). Alpha-fetoprotein(AFP) governs the expression of some metastasis-related genes. Here we report that AFP and CXCR4 levels correlated in HCC tissues. AFP-expressing vectors induced CXCR4. In agreement, AFP depletion by siRNA decreased CXCR4. AFP co-localized and interacted with PTEN, thus inducing CXCR4 by activating AKT(Ser473) phosphorylation. In turn, phospho-mTOR(Ser2448) entered the nucleus and bound the CXCR4 gene promoter. Thus, AFP promoted migration of HCC cells. In concusion, AFP induced CXCR4 by activating the AKT/mTOR signal pathway. PMID- 25815364 TI - Fatal acute liver failure with hepatitis B virus infection during nataluzimab treatment in multiple sclerosis. PMID- 25815365 TI - Erratum: Fatal acute liver failure with hepatitis B virus infection during natalizumab treatment in multiple sclerosis. PMID- 25815366 TI - Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. AB - Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer (CRC), the third leading cause of cancer-related death in the US. In addition to their well-characterized function in driving tumor progression, KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC. Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor (EGFR) targeting antibodies, including cetuximab and panitumumab. Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells. However, the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear. Despite intensive efforts, directly targeting mutant KRAS has been largely unsuccessful. This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC, highlighting several recently developed agents and strategies for targeting mutant KRAS, such as synthetic lethal interactions. PMID- 25815367 TI - The roles of interferon-inducible p200 family members IFI16 and p204 in innate immune responses, cell differentiation and proliferation. AB - p204 is a member of the interferon-inducible p200 family proteins in mice. The p200 family has been reported to be multifunctional regulators of cell proliferation, differentiation, apoptosis and senescence. Interferon-inducible protein 16 (IFI16) is regarded as the human ortholog of p204 in several studies. This is possibly due to the similarity of their structures. However the consistency of their functions is still elusive. Currently, an emerging focus has been placed upon the role of the p200 proteins as sensors for microbial DNA in innate immune responses and provides new insights into infections as well as autoimmune diseases. This review specially focuses on IFI16 and p204, the member of p200 family in human and murine respectively, and their pathophysiological roles in innate immune responses, cell differentiation and proliferation. PMID- 25815369 TI - Ionospheric correction based on ingestion of global ionospheric maps into the NeQuick 2 model. AB - The global ionospheric maps (GIMs), generated by Jet Propulsion Laboratory (JPL) and Center for Orbit Determination in Europe (CODE) during a period over 13 years, have been adopted as the primary source of data to provide global ionospheric correction for possible single frequency positioning applications. The investigation aims to assess the performance of new NeQuick model, NeQuick 2, in predicting global total electron content (TEC) through ingesting the GIMs data from the previous day(s). The results show good performance of the GIMs-driven NeQuick model with average 86% of vertical TEC error less than 10 TECU, when the global daily effective ionization indices (Az) versus modified dip latitude (MODIP) are constructed as a second order polynomial. The performance of GIMs driven-NeQuick model presents variability with solar activity and behaves better during low solar activity years. The accuracy of TEC prediction can be improved further through performing a four-coefficient function expression of Az versus MODIP. As more measurements from earlier days are involved in the Az optimization procedure, the accuracy may decrease. The results also reveal that more efforts are needed to improve the NeQuick 2 model capabilities to represent the ionosphere in the equatorial and high-latitude regions. PMID- 25815370 TI - Modelling the effect of SPION size in a stent assisted magnetic drug targeting system with interparticle interactions. AB - Cancer is a leading cause of death worldwide and it is caused by the interaction of genomic, environmental, and lifestyle factors. Although chemotherapy is one way of treating cancers, it also damages healthy cells and may cause severe side effects. Therefore, it is beneficial in drug delivery in the human body to increase the proportion of the drugs at the target site while limiting its exposure at the rest of body through Magnetic Drug Targeting (MDT). Superparamagnetic iron oxide nanoparticles (SPIONs) are derived from polyol methods and coated with oleic acid and can be used as magnetic drug carrier particles (MDCPs) in an MDT system. Here, we develop a mathematical model for studying the interactions between the MDCPs enriched with three different diameters of SPIONs (6.6, 11.6, and 17.8 nm) in the MDT system with an implanted magnetizable stent using different magnetic field strengths and blood velocities. Our computational analysis allows for the optimal design of the SPIONs enriched MDCPs to be used in clinical applications. PMID- 25815371 TI - Free vibrations of a cantilevered SWCNT with distributed mass in the presence of nonlocal effect. AB - The Hamilton principle is applied to deduce the free vibration frequencies of a cantilever single-walled carbon nanotube (SWCNT) in the presence of an added mass, which can be distributed along an arbitrary part of the span. The nonlocal elasticity theory by Eringen has been employed, in order to take into account the nanoscale effects. An exact formulation leads to the equations of motion, which can be solved to give the frequencies and the corresponding vibration modes. Moreover, two approximate semianalytical methods are also illustrated, which can provide quick parametric relationships. From a more practical point of view, the problem of detecting the mass of the attached particle has been solved by calculating the relative frequency shift due to the presence of the added mass: from it, the mass value can be easily deduced. The paper ends with some numerical examples, in which the nonlocal effects are thoroughly investigated. PMID- 25815372 TI - Flavonoids: separation and quantitation. PMID- 25815368 TI - Sustained high level transgene expression in mammalian cells mediated by the optimized piggyBac transposon system. AB - Sustained, high level transgene expression in mammalian cells, especially stem cells, may be desired in many cases for studying gene functions. Traditionally, stable transgene expression has been accomplished by using retroviral or lentiviral vectors. However, such viral vector-mediated transgene expression is often at low levels and can be reduced over time due to low copy numbers and/or chromatin remodeling repression. The piggyBac transposon has emerged as a promising non-viral vector system for efficient gene transfer into mammalian cells. Despite its inherent advantages over lentiviral and retroviral systems, piggyBac system has not been widely used, at least in part due to the limited availability of piggyBac vectors with manipulation flexibilities. Here, we seek to optimize piggyBac-mediated transgene expression and generate a more efficient, user-friendly piggyBac system. By engineering a panel of versatile piggyBac vectors and constructing recombinant adenoviruses expressing piggyBac transposase (PBase), we demonstrate that adenovirus-mediated PBase expression significantly enhances the integration efficiency and expression level of transgenes in mesenchymal stem cells and osteosarcoma cells, compared to that obtained from co transfection of the CMV-PBase plasmid. We further determine the drug selection timeline to achieve optimal stable transgene expression. Moreover, we demonstrate that the transgene copy number of piggyBac-mediated integration is approximately 10 times higher than that mediated by retroviral vectors. Using the engineered tandem expression vector, we show that three transgenes can be simultaneously expressed in a single vector with high efficiency. Thus, these results strongly suggest that the optimized piggyBac system is a valuable tool for making stable cell lines with sustained, high transgene expression. PMID- 25815373 TI - Using shadow page cache to improve isolated drivers performance. AB - With the advantage of the reusability property of the virtualization technology, users can reuse various types and versions of existing operating systems and drivers in a virtual machine, so as to customize their application environment. In order to prevent users' virtualization environments being impacted by driver faults in virtual machine, Chariot examines the correctness of driver's write operations by the method of combining a driver's write operation capture and a driver's private access control table. However, this method needs to keep the write permission of shadow page table as read-only, so as to capture isolated driver's write operations through page faults, which adversely affect the performance of the driver. Based on delaying setting frequently used shadow pages' write permissions to read-only, this paper proposes an algorithm using shadow page cache to improve the performance of isolated drivers and carefully study the relationship between the performance of drivers and the size of shadow page cache. Experimental results show that, through the shadow page cache, the performance of isolated drivers can be greatly improved without impacting Chariot's reliability too much. PMID- 25815374 TI - Clinical effects of a natural extract of urinary human menopausal gonadotrophin in normogonadotropic infertile patients. AB - Purified human menopausal gonadotropin (HMG) is a natural product extracted from the urine of postmenopausal women that contains pituitary follicle-stimulating hormone (FSH), luteinizing hormone (LH), and a small amount of human chorionic gonadotropin (HCG). Here we retrospectively conducted a clinical pharmaceutical study on a cohort of normogonadotropic infertile patients addressed to long GnRH agonist protocol with serum LH concentration ranging from 0.5 IU/L to 1.5 IU/L during the midfollicle phase, aiming at evaluating the effects of purified HMG supplementation during ovarian stimulation. There was no significant difference in either the basic clinical features of the patients or the pregnancy rate (71.4% versus 66.3%, P > 0.05) or other related indicators of pregnancy outcome. However, there was a higher level of serum oestradiol (E2) on the day of human chorionic gonadotropin (HCG) (1999.10 +/- 860.50 IU/L versus 2883.29 +/- 1427.382 IU/L, P = 0.000) but lower fertilization rate (89.1% versus 69.6%, P < 0.000) in patients getting HMG supplementation and a higher risk of developing ovarian hyperstimulation syndrome (OHSS). We suppose that exogenous LH supplementation is not needed when serum LH concentration of the midfollicle phase is around 0.5-1.5 IU/L during the long GnRH-agonist protocol. Adding exogenous HMG may decrease the fertilization rate and increase the risk of developing OHSS. PMID- 25815375 TI - Temporal trends in chorioamnionitis by maternal race/ethnicity and gestational age (1995-2010). AB - Objective. To characterize trends in chorioamnionitis (CAM) by maternal race/ethnicity and gestational age. Study Design. We examined trends in CAM from 1995-2010 among singleton births in all Kaiser Permanente Southern California hospitals (n = 471,821). Data were extracted from Perinatal Service System and clinical utilization records. Gestational age- and race/ethnicity-specific biannual diagnosis rates were estimated using the Poisson regression after adjusting for potential confounding factors. Results. Overall diagnosis rates of CAM increased from 2.7% in 1995-1996 to 6.0% in 2009-2010 with a relative increase of 126% (95% confidence intervals [CI] 113%-149%). From 1995-1996 to 2009-2010, CAM increased among the Whites (1.8% to 4.3%, P-value for trend <.001), Blacks (2.2% to 3.7%, P-value for trend <.001), Hispanics (2.4% to 5.8%, P-value for trend <.001), and Asian/Pacific Islanders (3.6% to 9.0%, P-value for trend <.001). The adjusted relative percentage change in CAM from 1995-1996 to 2009-2010 was for Whites [preterm 21% (9%-78%), term 138% (108%-173%)], for Blacks [preterm 24% (-9%-81%), term 62% (30%-101%)], for Hispanics [preterm 31% (3%-66%), term 135% (114%-159%)], and for Asian/Pacific Islanders [preterm 44% (9%-127%), term 145% (109%-188%)]. Conclusion. The findings suggest that CAM diagnosis rate has increased for all race/ethnic groups. This increase is primarily due to increased diagnosis at term gestation. PMID- 25815376 TI - Endosome traffic machinery meets the p53-p21 axis. AB - SIRT1 regulates p53 transcriptional activation in response to genotoxic insult by deacetylating key lysine residues. We recently identified the multifunctional protein PACS-2 as a SIRT1 inhibitor. After DNA damage, PACS-2 binds and inhibits SIRT1 to increase p53-dependent transactivation of the CDK inhibitor p21 (CDKN1A) and induce cell cycle arrest. PMID- 25815377 TI - Specialist consensus. PMID- 25815379 TI - Guideline for the diagnosis and management of dentin hypersensitivity. PMID- 25815378 TI - An overview of detection and screening of oral cancer in Taiwan. AB - Oral cancer is a fatal disease, which accounts for the fourth highest incidence of malignancy in males and the seventh highest in the general population of Taiwan. About 95% of oral cancer is oral squamous cell carcinoma (OSCC). The relatively high prevalence of OSCC in Taiwan is mainly because a high-risk group of the population exists, made up of 2.5 million people and who exhibit habits of betel nut chewing as well as cigarette smoking. Unfortunately, about 50% of the new OSCC cases found in medical centers presented with TNM stage III or IV cancer lesions leading to a low 5-year survival. Therefore, it is generally accepted that the prevention and screening of OSCC at early stages or premalignant levels in the high-risk group of the population is as equally important as treatment. In this review article, we describe the current status of OSCC in Taiwan regarding epidemiology. Furthermore we research and highlight the importance of various conventional and novel methods in the detection of this disease. PMID- 25815380 TI - Outlining a preventive oral health care system for China. AB - The most recent Chinese health care reform, scheduled to run until 2020, has been underway for a number of years. Oral health care has not been explicitly mentioned in the context of this reform. However, oral health is an integral part of general health and the under-servicing of the Chinese population in the area of dental care is particularly high. The article describes how this problem could be addressed. Based on present scientific knowledge,specifically on evidence based strategies and long-term empirical experience from Western industrialised countries, as well as findings from Chinese pilot studies, the author outlines a preventive oral health care system tailored specifically to the conditions prevailing in China. He describes the background and rationale for a clearly structured, preventive system and summarises the scientific cornerstones on which this concept is founded. The single steps of this model, that are adapted specifically to China, are presented so as to facilitate a critical discussion on the pros and cons of the approach. The author concludes that, by implementing preventive oral care, China could gradually reduce the under-servicing of great parts of the population with dental care that largely avoids dental disease and preserves teeth at a price that is affordable to both public health and patients. This approach would minimise the danger of starting a cycle of re-restorations, owing to outdated treatment methods. The proposal would both fit in well with and add to the current blueprint for Chinese health care reform. PMID- 25815381 TI - Effect of Fe2O3on optical properties of zirconia dental ceramic. AB - OBJECTIVES: To evaluate the effect of Fe2O3on the optical properties of yttria stabilised tetragonal zirconia (Y-TZP) dental ceramic when added, and to determine the correct content required to mimic the natural dentin. METHODS: Disc shaped Y-TZP specimens (0.50 +/- 0.01 mm in thickness) containing various contents of Fe2O3were fabricated by cold isostatic pressing and pressureless sintering, and then compared with human dentin slices (n = 40) under different moisture conditions. The visible light transmittance and colour parameters were recorded by a computer-controlled spectrocolourimeter. Sintered density and microstructure were investigated with the Archimedes' method and scanning electron microscopy (SEM), respectively. RESULTS: With the reduction of moisture in dentin slices, the direct transmittance dropped from 1.58% to 0.87%. The direct transmittance of coloured zirconia specimens, ranging from 1.22% to 1.40%, covered the range of dentin. With increasing Fe2O3content, the L* value of the coloured specimens decreased from 88.95 to 84.18, while b* increased from 3.43 to 12.02. The relative densities of all groups were over 99% of the theoretical value. The SEM indicated that zirconia with various amounts of Fe2O3retained the compact microcrystalline tetragonal structure. CONCLUSION: Small amounts of colourant additions affected the colour and the transmittance slightly, but had no influence on the sintered density and microstructure. Y-TZP could be improved by the control of colourant additives of Fe2O3in order to mimic the natural colour of dentin and to obtain a better aesthetical appearance of restorations, especially when the content was around 0.08 wt%. PMID- 25815382 TI - Prevalence of non-carious cervical lesions and associated risk indicators in middle-aged and elderly populations in Southern China. AB - OBJECTIVE: To explore the prevalence of NCCL and associated risk indicators in 35 to 44-year-olds and 65- to 74-year-olds from both urban and suburban districts of Guangzhou, Southern China. METHODS: A cross-sectional survey was conducted on NCCL with a sample of 768 35- to 44-year-olds and 991 65- to 74-year-olds, and the Tooth wear index was applied to record the tooth wear. Data on socioeconomic status, health behaviour and general health condition were obtained from a structured questionnaire. RESULTS: The prevalence of NCCL was 76.8% and 81.3% in middle-aged and elderly populations, respectively. The results from the analysis of covariance (ANCOVA) demonstrated that for the 35- to 44-year-olds, those who were male, older, living in the suburban district and used toothpicks frequently, they tended to have more teeth with NCCL. Men, who were aged between 65 and 74 years old, who used toothpicks frequently, drank vinegar beverages, ate hard food and had not visited a dentist in a year; tended to have more teeth with NCCL. CONCLUSION: NCCL was very common amongst middle-aged and elderly populations in South China. Older men who had unhealthy oral habits like using toothpicks, eating hard food and drinking vinegar beverages tended to have more teeth with NCCL. Oral health education would benefit those at risk. PMID- 25815383 TI - Early dental treatments for patients with cleidocranial dysplasia. AB - OBJECTIVE: To explore the early dental interventional strategies for adolescent patients and a child patient with cleidocranial dysplasia (CCD). METHODS: Surgical exposure using the apically repositioned flap technique combined with orthodontic traction was used in the adolescent patients whose ideal treatment time for initiating treatment was missed. For the child patient whose ideal treatment time for initiating treatment was not missed, the simple surgical exposure method was carried out in order to promote the eruption of the impacted incisors. RESULTS: All the impacted maxillary incisors of the three CCD patients were successfully positioned into a proper alignment either through the two stages of crown exposure and the elastic traction or simple surgical exposure. CONCLUSION: Crown exposure surgery combined with light force orthodontic traction provides an effective approach to treat the typical dental abnormalities of adolescent CCD patients. Simple surgical exposure was also an effective way for a child CCD patient for whom the most ideal time for initiation of treatment was not missed. PMID- 25815384 TI - Prevalence of tooth agenesis in adolescent Chinese populations with or without orthodontics. AB - OBJECTIVE: To determine the prevalence of hypodontia in the general population and orthodontic population in adolescent Chinese Hans. METHODS: Two groups named the general population (6015 subjects) and the orthodontic population (2781 subjects) were investigated, respectively. The former came from the students of three general universities in North China and the latter came from patients coming to the Department of Orthodontics, Peking University School and Hospital of Stomatology for orthodontic consulting during the summer and winter holidays in 2008. The prevalence and average missing number of hypodontic teeth was investigated in the two groups. The distribution of missing teeth was analysed between jaw positions and between genders. RESULTS: The prevalence of tooth agenesis was found to be 5.89% for the general population group and 7.48% for orthodontic subjects. Tooth agenesis was more frequently found in females than in males in both of the two groups and showed a statistically significant difference (P < 0.01). Tooth agenesis was found more frequently in the mandible than in the maxilla in the general population but had no difference in the orthodontic population. The prevalence and the number of missing teeth were higher in the orthodontic population than in the general population. Tooth agenesis showed different characteristics in the two populations. The congenital absence of the second mandibular premolars and the maxillary lateral incisors increased in the orthodontic population. Gender difference in hypodontia expressed an opposite effect in the two groups. Although tooth agenesis was more frequently found in females than in males, males missed more teeth than females in the orthodontic population. CONCLUSION: Tooth agenesis showed different characteristics between the general and orthodontic adolescent Chinese populations. PMID- 25815385 TI - A quantitative metabolomics peek into planarian regeneration. AB - The fresh water planarian species Schmidtea mediterranea is an emerging stem cell model because of its capability to regenerate a whole animal from a small piece of tissue. It is one of the best model systems to address the basic mechanisms essential for regeneration. Here, we are interested in studying the roles of various amines, thiols and nucleotides in planarian regeneration, stem cell function and growth. We developed mass spectrometry based quantitative methods and validated the differential enrichment of 35 amines, 7 thiol metabolites and 4 nucleotides from both intact and regenerating planarians. Among the amines, alanine in sexual and asparagine in asexual are the highest (>1000 ng/mg) in the intact planarians. The levels of thiols such as cysteine and GSH are 651 and 1107 ng mg(-1) in planarians. Among the nucleotides, the level of cGMP is the lowest (0.03 ng mg(-1)) and the level of AMP is the highest (187 ng mg(-1)) in both of the planarian strains. We also noticed increasing levels of amines in both anterior and posterior regenerating planarians. The blastema from day 3 regenerating planarians also showed higher amounts of many amines. Interestingly, the thiol (cysteine and GSH) levels are well maintained during planarian regeneration. This suggests an inherent and effective mechanism to control induced oxidative stress because of the robust regeneration and stem cell proliferation. Like in intact planarians, the level of cGMP is also very low in regenerating planarians. Surprisingly, the levels of amines and thiols in head regenerating blastemas are ~3 times higher compared to those for tail regenerating blastemas. Thus our results strongly indicate the potential roles of amines, thiols and nucleotides in planarian regeneration. PMID- 25815386 TI - Healthy eating on a budget. PMID- 25815387 TI - Dr Donald Lloyd-Jones, MD, ScM, to address the controversies of the 2013 prevention guidelines at the Preventive Cardiovascular Nurses Association 21st Annual Symposium. PMID- 25815388 TI - Position statement: HIV criminalization laws and policies promote discrimination and must be reformed. PMID- 25815389 TI - Fungal endocarditis after hybrid periventricular closure of muscular ventricular septal defect by Amplatzer occluder in a child. PMID- 25815390 TI - Letter by Herzig regarding article, "Electronic cigarettes: a scientific review". PMID- 25815392 TI - Letter by Psaty et al regarding article, "Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes". PMID- 25815391 TI - Response to letter regarding article, "Electronic cigarettes: a scientific review". PMID- 25815393 TI - Response to letter regarding article, "Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes". PMID- 25815394 TI - Core facilities: Shared support. PMID- 25815396 TI - All in good time. Does the time of day you exercise matter in blood glucose management? PMID- 25815395 TI - Survey of staff and family members of patients in Bulgarian hospices on the concept of "good death". AB - The concept of a "good death" has been intensely discussed over the past decades. The objective of this study is to investigate this concept among staff and patients' relatives in 29 Bulgarian hospices and 5 palliative care units. Self administered questionnaires were completed by 190 members of staff and 216 patients' relatives. Death without pain and suffering and death in one's sleep were leading concepts in both the groups. Staff preferred death in the presence of relatives, while relatives preferred fast and sudden death. Although we were able to define the common concept of a good death as painless and sudden death in one's sleep, death is unique phenomenon and good palliative care should be based on communication with patients about their idea of a good death. PMID- 25815397 TI - Stopping damage before it starts. PMID- 25815398 TI - Manual maintenance. How to ensure your agency's policy manual is relevent and respected. PMID- 25815399 TI - ECG changes in acute coronary syndrome. How to identify and understand the significance of ECG changes occurring throughout acute coronary syndrome. PMID- 25815400 TI - Protein Attachment on Nanodiamonds. AB - A recent advance in nanotechnology is the scale-up production of small and nonaggregated diamond nanoparticles suitable for biological applications. Using detonation nanodiamonds (NDs) with an average diameter of ~4 nm as the adsorbents, we have studied the static attachment of three proteins (myoglobin, bovine serum albumin, and insulin) onto the nanoparticles by optical spectroscopy, mass spectrometry, and dynamic light scattering, and electrophoretic zeta potential measurements. Results show that the protein surface coverage is predominantly determined by the competition between protein protein and protein-ND interactions, giving each protein a unique and characteristic structural configuration in its own complex. Specifically, both myoglobin and bovine serum albumin show a Langmuir-type adsorption behavior, forming 1:1 complexes at saturation, whereas insulin folds into a tightly bound multimer before adsorption. The markedly different adsorption patterns appear to be independent of the protein concentration and are closely related to the affinity of the individual proteins for the NDs. The present study provides a fundamental understanding for the use of NDs as a platform for nanomedical drug delivery. PMID- 25815403 TI - Report of the Canadian Nurses Association's National Expert Commission on the future of healthcare. PMID- 25815402 TI - One-pot synthesis of highly substituted N-fused heteroaromatic bicycles from azole aldehydes. AB - An efficient route to substituted N-fused aromatic heterocycles, including indolizines, imidazo[1,2-a]pyridines, and imidazo[1,5-a]pyridines from azole aldehydes, is reported. Wittig olefination of the aldehydes with fumaronitrile and triethylphosphine affords predominantly E-alkenes that undergo rapid cyclization upon treatment with a mild base. Substituent control of the 1-, 2-, and 3-positions of the resulting heteroaromatic bicycles is shown. Alternatively, the isolable E-alkene undergoes selective alkylation with electrophiles, followed by in situ annulation to indolizines additionally substituted at the 6-position. PMID- 25815404 TI - Reflection I. PMID- 25815401 TI - Analytical validation of a melanoma diagnostic gene signature using formalin fixed paraffin-embedded melanocytic lesions. AB - AIM: These studies were to validate the analytical performance of a gene expression signature that differentiates melanoma and nevi, using RNA expression from 14 signature genes and nine normalization genes that generates a melanoma diagnostic score (MDS). MATERIALS & METHODS: Formalin-fixed paraffin-embedded melanocytic lesions were evaluated in these studies. RESULTS: The overall SD of the assay was determined to be 0.69 MDS units. Individual amplicons within the signature had an average amplification efficiency of 92% and a SD less than 0.5 CT. The MDS was reproducible across a 2000-fold dilution range of input RNA. Melanin, an inhibitor of PCR, does not interfere with the signature. CONCLUSION: These studies indicate this signature is robust and reproducible and is analytically validated on formalin-fixed paraffin-embedded melanocytic lesions. PMID- 25815405 TI - Future-proofing nursing education. AB - The origin of future-proofing seems lost in the mists of recent history. Dictionaries date its use from about 1991, referring to the prevention of obsolescence in information technology manufacturing and occasionally in organizational systems. However, closer analysis in healthcare demonstrates it can be traced back to the Rand Corporation and the studies commissioned there in the 1960s. These aimed at identifying the predictive factors in planning healthcare, including development of the workforce. It is a managerial concept that helps to project a vision of change that is not simply reactive or short term. It permits a focus on leadership and the maximising of learning opportunities and includes analysis of the policy horizon. It held within it an assumption about the importance of establishing the cognitive frameworks that would influence long-term behaviours and not focus simply on short-term gains. This paper utilises this approach to explore options for future-proofing of nurse education. PMID- 25815406 TI - Implications of the fundamentals of care for nursing education. AB - Nursing education grounds clinical practice. The Fundamentals of Care pose challenges to current education and outline opportunities to improve education in the future. In my essay, I specify the current challenge presented by the Fundamentals of Care for nursing today and my approach in addressing that challenge. I go on to outline conceptual and evidentiary highlights within the realm of the Fundamentals of Care and select related topics. Finally, I synthesize implications for nursing education from the challenge juxtaposed against conceptual and evidentiary ideas. PMID- 25815407 TI - Reflection II. PMID- 25815408 TI - The imperative for new approaches for managing and leading in healthcare for the 21st century--observations from the Canadian Nurses Association's National Expert Commission Experience and Report. AB - The Canadian healthcare system must change to meet current and future realities, particularly to respond effectively to changing age and cultural demographics and new medical/scientific technologies. To meet its ongoing policy role, the Canadian Nurses Association established a National Expert Commission in 2011, mandated to prepare a report on healthcare reform and transformation, with a clear focus on the role individual nurses and the nursing profession generally could play in ensuring better health, better care and better value for Canadians. In this paper, Commission co-chair, health law specialist Maureen McTeer, outlines the key findings and recommendations of their final report, titled A Nursing Call to Action: The Health of our Nation, the Future of our Health System which she and co-chair Dr. Marlene Smadu presented originally at the CNA's biennial meeting in Vancouver, in June, 2012. The discussion focuses on the rationale behind the commission's recommendation for a new registered nursing education curriculum and approach to training. PMID- 25815409 TI - Global perspectives on nursing and its contribution to healthcare and health policy: thoughts on an emerging policy model. AB - We know from rigorous evidence that nurses can exert an incredible impact on the everyday lives of people and their health. Nurses can also contribute in much wider spheres of influence by applying their knowledge and skills to address broader issues affecting population health across communities, nations and globally. Despite the prevalence of so many vexing health and social issues, nurses often fail to think globally, or even regionally, when they are lobbying for change. And while much political influence is local, some issues are simply too complex to rely on local influence alone. Importantly in all this, we must acknowledge the ways these complex health issues are shaped by economic and political agendas and not necessarily by healthcare agendas. As such, the nursing community has to act globally and locally, both within and outside of the nursing arena. This paper explores early thinking about an evolving model of spheres--or "bubbles"--of policy influence in which nurses can and must operate to more effectively impact key global health and healthcare challenges. PMID- 25815410 TI - Leading healthcare in complexity. AB - Healthcare institutions and providers are in complexity. Networks of interconnections from relationships and technology create conditions in which interdependencies and non-linear dynamics lead to surprising, unpredictable outcomes. Previous effective approaches to leadership, focusing on top-down bureaucratic methods, are no longer effective. Leading in complexity requires leaders to accept the complexity, create an adaptive space in which innovation and creativity can flourish and then integrate the successful practices that emerge into the formal organizational structure. Several methods for doing adaptive space work will be discussed. Readers will be able to contrast traditional leadership approaches with leading in complexity. They will learn new behaviours that are required of complexity leaders, along with challenges they will face, often from other leaders within the organization. PMID- 25815411 TI - Some wicked thoughts on nursing leadership. AB - Nursing is everywhere in healthcare and at all levels, and is among other things numerically dominant. Yet it arguably plays a less prominent role in charting the future course of the system than it should. As in any complex system, power matters in health, and the history of healthcare and gender relations explains a good deal of why nursing's influence has not rivaled that of medicine. But society has progressed immensely in the last century and nursing has both contributed to and benefited from these broader social trajectories. If the profession is to expand its leadership role in healthcare, it will have to reflect on its internal politics, its culture of representation and decision making, and how to translate its diversity into a coherent change agenda. Perhaps above all it must champion and focus on the public interest to avoid being defined as just another interest group. PMID- 25815412 TI - Na/Ca Intermixing around Silicate and Phosphate Groups in Bioactive Phosphosilicate Glasses Revealed by Heteronuclear Solid-State NMR and Molecular Dynamics Simulations. AB - We characterize the intermixing of network-modifying Na(+)/Ca(2+) ions around the silicate (QSi(n)) and phosphate (QP(n)) tetrahedra in a series of 16 Na2O-CaO SiO2-P2O5 glasses, whose P content and silicate network connectivity were varied independently. The set includes both bioactive and bioinactive compositions and also encompasses two soda-lime-silicate members devoid of P, as well as two CaO SiO2 glasses and one Na2O-SiO2-P2O5 glass. The various Si/P<->Na/Ca contacts were probed by molecular dynamics (MD) simulations together with heteronuclear magic angle-spinning (MAS) nuclear magnetic resonance (NMR) experimentation utilizing (23)Na{(31)P} and (23)Na{(29)Si} REDOR, as well as (31)P{ (23)Na} and (29)Si{(23)Na} REAPDOR. We introduce an approach for quantifying the extent of Na(+)/Ca(2+) ordering around a given QP(n) or QSi(n) group, encoded by the preference factor 0? PM ? 1 conveying the relative weights of a random cation intermixing (PM = 0) and complete preference/ordering (PM = 1) for one of the species M, which represents either Na(+) or Ca(2+). The MD-derived preference factors reveal phosphate and silicate species surrounded by Na(+)/Ca(2+) ions intermixed nearly randomly (PM ? 0.15), except for the QSi(4) and QSi(1) groups, which manifest more significant cation ordering with preference for Na+ and Ca2+, respectively. The overall weak preferences are essentially independent of the Si and P contents of the glass, whereas PM primarily correlates with the total amount of network modifiers: as the latter is increased, the Na/Ca distribution around the {QP(0), QSi(1), QSi(2)} groups with preference for Ca2(+ )tend to randomize (i.e., PCa decreases), while the PNa-values grow slightly for the {QP(1), QSi(3), QSi(4)} species already preferring coordination of Na. The set of experimental preference factors {PCa} for the orthophosphate (QP(0)) groups extracted from (31)P{(23)Na} REAPDOR NMR-derived M2(P-Na) dipolar second moments agrees well with the MD-generated counterparts. Our results on the Na/Ca intermixing in soda-lime-silicate glasses are discussed in relation to previous reports, highlighting the dependence of the conclusion on the approach to data evaluation. PMID- 25815413 TI - Synthesis and potent antimalarial activity of kalihinol B. AB - Of the 50+ kalihinane diterpenoids reported to date, only five had been tested for antimalarial activity, in spite of the fact that kalihinol A is the most potent among the members of the larger family of antimalarial isocyanoterpenes. We have validated a strategy designed to access many of the kalihinanes with a 12 step enantioselective synthesis of kalihinol B, the tetrahydrofuran isomer of kalihinol A (a tetrahydropyran). Kalihinol B shows similarly high potency against chloroquine-resistant Plasmodium falciparum. PMID- 25815414 TI - Real-time in situ probing of high-temperature quantum dots solution synthesis. AB - Understanding the formation mechanism of colloidal nanocrystals is of paramount importance in order to design new nanostructures and synthesize them in a predictive fashion. However, reliable data on the pathways leading from molecular precursors to nanocrystals are not available yet. We used synchrotron-based time resolved in situ small and wide-angle X-ray scattering to experimentally monitor the formation of CdSe quantum dots synthesized in solution through the heating up of precursors in octadecene at 240 degrees C. Our experiment yields a complete movie of the structure of the solution from the self-assembly of the precursors to the formation of the quantum dots. We show that the initial cadmium precursor lamellar structure melts into small micelles at 100 degrees C and that the first CdSe nuclei appear at 218.7 degrees C. The size distributions and concentration in nanocrystals are measured in a quantitative fashion as a function of time. We show that a short nucleation burst lasting 30 s is followed by a slow decrease of nanoparticle concentration. The rate-limiting process of the quantum dot formation is found to be the thermal activation of selenium. PMID- 25815415 TI - Selective reversible hydrogenation of Mg(B3H8)2/MgH2 to Mg(BH4)2: pathway to reversible borane-based hydrogen storage? AB - Mg(B3H8)2.2THF (THF = tetrahydrofuran) was prepared by the addition of BH3.THF to Mg/Hg amalgam. Heating a 1:2 molar mixture of Mg(B3H8)2.2THF and MgH2 to 200 degrees C under 5 MPa H2 for 2 h leads to nearly quantitative conversion to Mg(BH4)2. The differential scanning calorimetry profile of the reaction measured under 5 MPa H2 shows an initial endothermic feature at ~65 degrees C for a phase change of the compound followed by a broad exothermic feature that reaches a maximum at 130 degrees C corresponding to the hydrogenation of Mg(B3H8)2 to Mg(BH4)2. Heating Mg(B3H8)2.2THF to 200 degrees C under 5 MPa H2 pressure in the absence of MgH2 gives predominantly MgB12H12 as well as significant amounts of MgB10H10 and Mg(BH4)2. Hydrogenation of a mixture of Mg(B3H8)2.2THF and LiH in a 1:4 molar ratio at 130 degrees C under 5 MPa H2 yields [B12H12](2-) in addition to [BH4](-), while a 1:4 molar ratio of Mg(B3H8)2.2THF and NaH yields [BH4](-) and a new borane, likely [B2H7](-). Hydrogenation of the NaH-containing mixture at 130 degrees C gives primarily the alternative borane, indicating it is an intermediate in the two-step conversion of the triborane to [BH4](-). The solvent free triborane Mg(B3H8)2, derived from the low-temperature dehydrogenation of Mg(BH4)2, also produces Mg(BH4)2, but higher temperature and pressure is required to effect the complete transformation of the Mg(B3H8)2. These results show that the reversible transformation of the triborane depends on the stability of the metal hydride. The more stable the metal hydride, that is, LiH > NaH > MgH2, the lower is the "regeneration" efficiency. PMID- 25815416 TI - Not whether but when, and what that means for why: the disastrous mathematical myopia of those who should know better. PMID- 25815417 TI - Gallium-catalyzed domino arylation/oxycyclization of allenes with phenols. AB - The synthesis of dihydrobenzofuran-appended oxindoles has been accomplished taking advantage of an unprecedented reaction between allenols and phenols under metal catalysis. PMID- 25815418 TI - Amygdala Hyperactivity at Rest in Paranoid Individuals With Schizophrenia. AB - OBJECTIVE: The amygdala's role in threat perception suggests that increased activation of this region may be related to paranoid ideation. However, investigations of amygdala function in paranoid individuals with schizophrenia, compared with both healthy individuals and nonparanoid individuals with schizophrenia, have consistently reported reduced task-related activation. The reliance of blood-oxygen-level-dependent functional MRI on a contrast between events and baseline, and the inability to quantitatively measure this baseline, may account for these counterintuitive findings. The present study tested for differences in baseline levels of amygdala activity in paranoid and nonparanoid individuals with schizophrenia using arterial spin labeling perfusion MRI. METHOD: Resting cerebral blood flow (CBF) and task-related activation of the amygdala were measured in 25 healthy individuals, 16 individuals with schizophrenia who were actively paranoid at the time of scanning, and 16 individuals with schizophrenia who were not paranoid. RESULTS: Analysis of relative CBF values extracted from the amygdala bilaterally revealed significantly increased activity in the left amygdala in paranoid patient volunteers compared with healthy comparison subjects and nonparanoid patient volunteers. Increased CBF was also evident in the right amygdala but did not reach the level of statistical significance. Paranoid volunteers also showed significantly decreased task-related activation of the amygdala compared with the two other groups. CONCLUSIONS: These findings suggest that amygdala hyperactivation may underlie paranoia in schizophrenia. Additionally, the reported differences between paranoid and nonparanoid patient volunteers emphasize the importance of considering symptom-based subgroups and baseline levels of activity in future investigations of neural activation in schizophrenia. PMID- 25815419 TI - Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial. AB - OBJECTIVE: The study aims were 1) to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2) to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications. METHOD: Participants 18-65 years of age (N=1,008) who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed effects model using the intent-to-treat sample compared the groups' symptom score trajectories, and logistic regression compared likelihood of remission (defined as a score <=5 on the 16-item Quick Inventory of Depressive Symptomatology-Self Report). RESULTS: Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect. CONCLUSIONS: There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection. PMID- 25815420 TI - ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial. AB - OBJECTIVE: The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment. METHOD: The authors genotyped 10 ABCB1 single-nucleotide polymorphisms (SNPs) in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended release venlafaxine (all substrates for P-glycoprotein) in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16 item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests. RESULTS: The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment. CONCLUSIONS: The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment. PMID- 25815422 TI - Adiponectin-mediated antilipotoxic effects in regenerating pancreatic islets. AB - Pathways that stimulate beta-cell regeneration remain of great clinical interest, yet effective therapeutic avenues that promote survival or reconstitution of beta cell mass remain elusive. Using a mouse model with inducible beta-cell apoptosis followed by adiponectin-mediated regeneration, we aimed to identify key molecules boosting beta-cell viability. In the regenerating pancreatic islets, we examined changes within the transcriptome and observed an extensive up-regulation of genes encoding proteins involved in lipid transport and metabolism. The most prominent targets were further confirmed by quantitative PCR and immunofluorescence. Among the upstream regulators predicted by pathway analysis of the transcriptome, we detected enhanced levels of 2 key transcription factors, Hepatocyte Nuclear Factor 4alpha and Peroxisome Proliferator-Activated Receptoralpha. Our data suggest that improving pancreatic islet lipid metabolism as an important antilipotoxic phenomenon to boost beta-cell regeneration. This is primarily mediated by the adipokine adiponectin that exerts its action on both the beta cell directly as well as on the adipocyte. Adiponectin induces lipid metabolism gene expression in regenerating islets through Hepatocyte Nuclear Factor 4alpha and Peroxisome Proliferator-Activated Receptoralpha. Adiponectin also modulates leptin levels via preserving adipose tissue mass in the insulinopenic state. PMID- 25815423 TI - Ion-transfer voltammetric behavior of propranolol at nanoscale liquid-liquid interface arrays. AB - In this work, the ion-transfer voltammetric detection of the protonated beta blocker propranolol was explored at arrays of nanoscale interfaces between two immiscible electrolyte solutions (ITIES). Silicon nitride nanoporous membranes with 400 pores in a hexagonal arrangement, with either 50 or 17 nm radius pores, were used to form regular arrays of nanoITIES. It was found that the aqueous-to organic ion-transfer current continuously increased steadily rather than reaching a limiting current plateau after the ion-transfer wave; the slope of this limiting current region was concentration dependent and associated with the high ion flux at the nanointerfaces. Electrochemical data were examined in terms of an independent nanointerface approach and an equivalent microdisc approach, supported by finite element simulation. In comparison to the larger interface configuration (50 nm radius), the array of 17 nm radius nanoITIES exhibited a 6.5 times higher current density for propranolol detection due to the enhanced ion flux arising from the convergent diffusion to smaller electrochemical interfaces. Both nanoITIES arrays achieved the equivalent limits of detection, 0.8 MUM, using cyclic voltammetry. Additionally, the effect of scan rate on the charging and faradaic currents at these nanoITIES arrays, as well as their stability over time, was investigated. The results demonstrate that arrays of nanoscale liquid liquid interfaces can be applied to study electrochemical drug transfer, and provide the basis for the development of miniaturized and integrated detection platforms for drug analysis. PMID- 25815421 TI - The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice. AB - Although named "ovarian cancer," it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53(R172H), into conditional Dicer-Pten double knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53(R172H)-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high grade serous ovarian cancer in mice. PMID- 25815424 TI - Prevention of cardiovascular risk in women who had hypertension during pregnancy after 36 weeks gestation. AB - OBJECTIVE: To analyse preventive interventions of women with cardiovascular risk factors postpartum. METHODS: 3.5 years postpartum, women with history of hypertension in pregnancy were invited for a questionnaire, 1 year after a cardiovascular risk assessment. RESULTS: Two hundred and fifty-seven women completed the questionnaire. At risk factor analyses, 35% had hypertension, 37% abnormal lipid- or glucose levels, 63% BMI >= 25 and 19% smoked. One year later, 36% of women with hypertension used anti-hypertensives, 0% of women with abnormal laboratory findings used anti-cholesterol and 1% anti-diabetes medication, 31% of the obese women achieved BMI reduction (>= 5%), 42% of the women who smoked, quit. CONCLUSION: A minority improved their risk profile. PMID- 25815425 TI - Characterization of Skin Aging-Associated Secreted Proteins (SAASP) Produced by Dermal Fibroblasts Isolated from Intrinsically Aged Human Skin. AB - Most molecular hallmarks of cellular senescence have been identified in studies of cells aged in vitro by driving them into replicative or stress-induced senescence. Comparatively, less is known about the characteristic features of cells that have aged in vivo. Here we provide a systematic molecular analysis of normal human dermal fibroblasts (NHDFs) that were isolated from intrinsically aged human skin of young versus middle aged versus old donors. Intrinsically aged NHDFs in culture exhibited more frequently nuclear foci positive for p53 binding protein 1 and promyelocytic leukemia protein reminiscent of 'DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS)'. Formation of such foci was neither accompanied by increased DNA double strand breaks, nor decreased cell viability, nor telomere shortening. However, it was associated with the development of a secretory phenotype, indicating incipient cell senescence. By quantitative analysis of the entire secretome present in conditioned cell culture supernatant, combined with a multiplex cytokine determination, we identified 998 proteins secreted by intrinsically aged NHDFs in culture. Seventy of these proteins exhibited an age-dependent secretion pattern and were accordingly denoted 'skin aging-associated secreted proteins (SAASP)'. Systematic comparison of SAASP with the classical senescence-associated secretory phenotype (SASP) revealed that matrix degradation as well as proinflammatory processes are common aspects of both conditions. However, secretion of 27 proteins involved in the biological processes of 'metabolism' and 'adherens junction interactions' was unique for NHDFs isolated from intrinsically aged skin. In conclusion, fibroblasts isolated from intrinsically aged skin exhibit some, but not all, molecular hallmarks of cellular senescence. Most importantly, they secrete a unique pattern of proteins that is distinct from the canonical SASP and might reflect specific processes of skin aging. PMID- 25815428 TI - Improved selectivity for partial oxidation of methane to methanol in the presence of nitrite ions and BiVO4 photocatalyst. AB - Nitrite ions are shown to have significant influence on the selectivity of the photocatalytic oxidation of methane to methanol. An almost complete inhibition of undesired CO2 has been achieved with BiVO4 in the presence of a low concentration of nitrite, which might act both as a UV filter and as a hydroxyl radical scavenger. PMID- 25815426 TI - Regulation and Function of the Caspase-1 in an Inflammatory Microenvironment. AB - The inflammasome is a complex of proteins that has a critical role in mounting an inflammatory response in reply to a harmful stimulus that compromises the homeostatic state of the tissue. The NLRP3 inflammasome, which is found in a wound-like environment, is comprised of three components: the NLRP3, the adaptor protein ASC and caspase-1. Interestingly, although ASC levels do not fluctuate, caspase-1 levels are elevated in both physiological and pathological conditions. Despite the observation that merely raising caspase-1 levels is sufficient to induce inflammation, the crucial question regarding the mechanism governing its expression is unexplored. We found that, in an inflammatory microenvironment, caspase-1 is regulated by NF-kappaB. Consistent with this association, the inhibition of caspase-1 activity parallels the effects on wound healing caused by the abrogation of NF-kappaB activation. Surprisingly, not only does inhibition of the NF-kappaB/caspase-1 axis disrupt the inflammatory phase of the wound-healing program, but it also impairs the stimulation of cutaneous epithelial stem cells of the proliferative phase. These data provide a mechanistic basis for the complex interplay between different phases of the wound-healing response in which the downstream signaling activity of immune cells can kindle the amplification of local stem cells to advance tissue repair. PMID- 25815429 TI - "I'm Still Here": Resilience Among Older Survivors of Breast Cancer. AB - BACKGROUND: Cancer presents a severe adversity that calls on intrinsic strength factors such as resilience. Breast cancer is especially common among older women. Understanding the interaction between the mechanisms of resilience and the psychosocial impact of cancer requires consideration of developmental age. OBJECTIVE: This research explores resilience from the point of view of older women who recently completed treatment for early-stage breast cancer. METHODS: Constructivist grounded theory directed data collection and analysis of 31 personal, semistructured interviews with 18 women aged 70 to 94 years. RESULTS: Faced with overcoming the adversity of a first cancer experience, participants rebounded and restored balance to their lives with a sense that they did the work of managing cancer with self-efficacy and autonomy. Resilience was evidenced as a multidimensional process containing a natural interaction of attributes. Self reliance, optimism, and persevering were embedded in human interconnectedness. CONCLUSIONS: The process of cancer survivorship was positioned in the larger picture of the joys and hardships of having lived a long life. The core self continued through these changing times, connecting the past, present, and anticipated future, as exemplified by "I'm still here." Regaining balance required tenacity, pragmatism, and dedication to do the work that needed to be done to treat cancer and move on with life. IMPLICATIONS FOR PRACTICE: Resilience is a valuable resource in strength-based approaches in healthcare. Practical examples for clinicians who follow a strength-based approach to promote adaptation for the continuing challenges of breast cancer survivorship among older women include acknowledging unique individual expressions of resilience. Gero-oncology is a salient field for multidisciplinary teams who seek to study resilience. PMID- 25815427 TI - Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling. AB - Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRAS(Q61K) and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition. PMID- 25815430 TI - Factors Influencing Adherence in Cancer Patients Taking Oral Tyrosine Kinase Inhibitors: A Qualitative Study. AB - BACKGROUND: Nonadherence in cancer patients taking oral anticancer drugs is common. Reasons for nonadherence are still not really understood as influencing factors are often complex, dynamic, and interrelated. OBJECTIVE: A qualitative study was conducted to gain insight into (non-)adherence behavior in patients taking oral tyrosine kinase inhibitors by exploring (1) processes and factors influencing (non-)adherence and (2) their interrelatedness. METHODS: Semistructured interviews were held with 30 patients of different ages and with different types of cancer. A grounded theory approach was used. RESULTS: Three foci were found when dealing with oral tyrosine kinase inhibitors: (1) a focus on survival, (2) a focus on quality of life, and (3) a balance between survival and quality of life. The process of adherence was determined by a set of complex and interrelated influencing factors: treatment-related side effects, hope, anxiety, trust, and feedback mechanisms. CONCLUSIONS: This qualitative study gives insight into processes and factors influencing (non-)adherence behavior in patients taking oral tyrosine kinase inhibitors. The results of this study can help healthcare professionals understand why patients taking oral tyrosine kinase inhibitors do not always adhere to their therapy. IMPLICATIONS FOR PRACTICE: Conditions should be created by which patients get maximum opportunity to establish a balance between survival and quality of life. An open climate and a trust-based relationship should be established in which patients feel comfortable to openly discuss their therapy and the difficulties they experience. PMID- 25815432 TI - Eating disorder prevention initiatives for athletes: A review. AB - A substantial amount of evidence suggests that collegiate and elite athletes involved in weight-sensitive sports are at greater risk of developing eating disorders (EDs) than the general population. With the limited effectiveness of treatment for EDs, prevention of EDs has been broadly considered in the literature. The present paper reviewed the existing literature on ED prevention programmes for athletes in order to determine the current status of prevention programmes and recommend future directions. The available literature suggests that selective, primary interventions with multiple targets and an interactive multimodal approach appear most effective. Current challenges in the field, including lack of longitudinal research, hesitation by the sport community to be involved in ED research and poor cross-field communication and collaboration, are also explored. The lack of dissemination of evidence-based prevention programmes and the simultaneous promotion of prevention programmes that have not yet been empirically examined are also discussed. Based on these observations future directions are recommended. PMID- 25815431 TI - Opioid-induced hyperalgesia in community-dwelling adults with chronic pain. AB - The hyperalgesic effects of long-term opioid use in community-dwelling adults with chronic pain have not been widely reported. Therefore, the primary aim of this study was to determine the associations between opioid use and heat pain (HP) perception in a sample of community-dwelling adults with chronic pain. The study cohort involved 187 adults (85 opioid and 102 nonopioid) with chronic pain consecutively admitted to an outpatient interdisciplinary pain treatment program. Heat pain perception was assessed using a validated quantitative sensory test method of levels. An effect of opioid use was observed for nonstandardized (P = 0.004) and standardized (P = 0.005) values of HP 5-0.5 in which values of the opioid group were lower (more hyperalgesic) compared with those of the nonopioid group. HP 5-0.5 is a measure of the slope of the line connecting HP 0.5 (HP threshold) and HP 5 (intermediate measure of HP tolerance). In univariable (P = 0.019) and multiple variable (P = 0.003) linear regression analyses (adjusted for age, sex, body mass index, work status, pain diagnosis, pain severity, depression, and pain catastrophizing), opioid use was associated with lower (more hyperalgesic) nonstandardized values of HP 5-0.5. Similarly, in univariable (P = 0.004) and multiple variable (P = 0.011) linear regression analyses (adjusted for work status, pain diagnosis, pain severity, depression, and pain catastrophizing), opioid use was associated with lower standardized values of HP 5-0.5. In this sample of community-dwelling adults, these observations suggest that long-term opioid use was associated with hyperalgesia independent of other clinical factors known to influence HP perception. PMID- 25815433 TI - Switching mechanism in two-terminal vanadium dioxide devices. AB - Two-terminal thin film VO2 devices show an abrupt decrease of resistance when the current or voltage applied exceeds a threshold value. This phenomenon is often described as a field-induced metal-insulator transition. We fabricate nano-scale devices with different electrode separations down to 100 nm and study how the dc switching voltage and current depend on device size and temperature. Our observations are consistent with a Joule heating mechanism governing the switching. Pulsed measurements show a switching time to the high resistance state of the order of one hundred nanoseconds, consistent with heat dissipation time. In spite of the Joule heating mechanism which is expected to induce device degradation, devices can be switched for more than 10(10) cycles making VO2 a promising material for nanoelectronic applications. PMID- 25815435 TI - Controlling Clusters of Colloidal Platelets: Effects of Edge and Face Surface Chemistries on the Behavior of Montmorillonite Suspensions. AB - The structural and rheological consequences of adsorbing pyrophosphate anions to the edges and polyetheramines to the faces of montmorillonite platelets in aqueous suspension were investigated. Oscillatory rheology and scattering experiments showed that the two surface treatments act in different regions of the phase diagram and that this can be attributed to modifications of local particle interactions resulting in changes to the behavior and morphology of platelet clusters. The polyetheramine was found to neutralize surface charge, reducing electrostatic repulsion between platelets and therefore allowing them to come into closer proximity. This reduces the effective volume fraction of the clusters and reverses jamming in low ionic strength arrested phases. Conversely, the adsorption of pyrophosphate was found to introduce a high concentration of negative charge to the particle edge, resisting the formation of bonded percolating gels at high ionic strength. The two separate surface chemistries can be applied in parallel with no adverse effects and thus have the potential to be applied to dual functionalization of two-dimensional colloids such as platelets. This has implications for finer formulation design where targeted rheology modification could be achieved by careful selection of chemistry at one surface accompanied by an additional function at the other. PMID- 25815434 TI - Hemocompatibility of Poly(vinyl alcohol)-Gelatin Core-Shell Electrospun Nanofibers: A Scaffold for Modulating Platelet Deposition and Activation. AB - In this study, we evaluate coaxial electrospun nanofibers with gelatin in the shell and poly(vinyl alcohol) (PVA) in the core as a potential vascular material by determining fiber surface roughness, as well as human platelet deposition and activation under varying conditions. PVA scaffolds had the highest surface roughness (Ra=65.5+/-6.8 nm) but the lowest platelet deposition (34.2+/-5.8 platelets) in comparison to gelatin nanofibers (Ra=36.8+/-3.0 nm and 168.9+/-29.8 platelets) and coaxial nanofibers (1 Gel:1 PVA coaxial, Ra=24.0+/-1.5 nm and 150.2+/-17.4 platelets. 3 Gel:1 PVA coaxial, Ra=37.1+/-2.8 nm and 167.8+/-15.4 platelets). Therefore, the chemical structure of the gelatin nanofibers dominated surface roughness in platelet deposition. Due to their increased stiffness, the coaxial nanofibers had the highest platelet activation rate, rate of thrombin formation, in comparison to gelatin and PVA fibers. Our studies indicate that mechanical stiffness is a dominating factor for platelet deposition and activation, followed by biochemical signals, and lastly surface roughness. Overall, these coaxial nanofibers are an appealing material for vascular applications by supporting cellular growth while minimizing platelet deposition and activation. PMID- 25815437 TI - Extracts of Scutellariae Radix inhibit low-density lipoprotein oxidation and the lipopolysaccharide-induced macrophage inflammatory response. AB - Traditional herbal formulas made from Scutellariae Radix (SR), the root of Scutellaria baicalensis, have previously been used in the treatment of inflammatory diseases, such as atherosclerosis. The aim of the present study was to investigate the effects of SR on low-density lipoprotein (LDL) oxidation and inflammation in macrophages, which are early events in the development of atherosclerosis. High-performance liquid chromatography photo-diode array analysis was used to obtain a three-dimensional chromatogram of SR. The antioxidative effects of SR were evaluated by determining its scavenging activities against ABTS and DPPH radicals. The inhibitory effect of SR on LDL oxidation was examined using a thiobarbituric acid-reactive substance assay and a relative electrophoretic mobility assay. In addition, the anti-inflammatory effects of SR were evaluated in lipopolysaccharide (LPS)-induced RAW264.7 murine macrophage cells. The results showed that SR exhibited radical-scavenging activities in a dose-dependent manner; in addition, SR attenuated the Cu2+ induced oxidation of LDL as well as significantly inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in LPS-induced RAW264.7 cells. Furthermore, SR induced the protein expression of heme oxygenase-1 (HO-1) in RAW264.7 cells. In conclusion, the results of the present study demonstrated that SR decreased the oxidation of LDL and suppressed inflammatory responses in macrophages, which occurred at least in part via the induction of HO-1. These results therefore suggested that SR may be a potential therapeutic agent for the treatment of atherosclerosis. PMID- 25815436 TI - Antitumorigenic effect of plumbagin by induction of SH2-containing protein tyrosine phosphatase 1 in human gastric cancer cells. AB - A recent study reported that plumbagin downregulated the activity of Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway to show various antitumor effects in multiple myeloma cells. We aimed in this in vitro study to demonstrate the inhibition of JAK2/STAT3 pathway by plumbagin through inducing SH2-containing protein tyrosine phosphatase 1 (SHP1) expression in the MKN-28 gastric cancer cell line. We performed western blot analysis to measure SHP1, phosphor-JAK2/STAT3 level, and observed that plumbagin induced SHP1 expression and simultaneously downregulated phosphor-JAK2/STAT3 in MKN-28 cells, with negative SHP1 expression. This effect was consistent when JAK2/STAT3 signaling was activated by interleukin-6 (IL-6), and ameliorated when cells were treated with prevanadate, a protein tyrosin phosphatase inhibitor. Furthermore, plumbagin significantly reduced gene expression of cyclin D1, vascular endothelial growth factor (VEGF)-1, Bcl-xL, survivin and matrix metalloproteinase 9 (MMP-9), known target products of STAT3 activation in gastric carcinogenesis by reverse transcription-polymerase chain reaction (RT-PCR). Several functional studies such as water soluble tetrazolium salt-1 (WST-1) assay, wound closure assay, Matrigel invasion assay and Annexin V assay were also performed, and we validated the functional effect of plumbagin for inhibition of cell proliferation, migration and invasion, and induction of apoptosis. Collectively, our findings suggest that plumbagin is a potential regulator of cellular growth, migration, invasion and apoptosis by inhibiting both constitutive and inducible STAT3 activity through induction of SHP1 in gastric cancer cells. PMID- 25815438 TI - Biomarkers of "Linguistic Anxiety" in aphasia: a proof-of-concept case study. AB - This is a proof-of-concept case study designed to evaluate the presence of "Linguistic Anxiety" in a person with mild aphasia. The participant (aged 68) was tested on linguistic and non-linguistic cognitive tasks administered under conditions that differed in levels of anxiety. A validated anxiety-induction technique rarely used in previous aphasia studies was employed: the participant was instructed to prepare for a public speaking presentation. Measures of linguistic and non-linguistic cognitive performance, and anxiety (self-report and psychophysiologic) were obtained. The participant exhibited increased psychophysiologic stress reactivity (heart rate, skin conductance and self-report ratings) in the high-anxiety condition. In the state of increased anxiety, performance on language tasks, in particular discourse production, declined relative to performance in low-anxiety settings. Even in mild aphasia, language based anxiety can interfere with language performance. This finding provides a basis for carrying out a study with a larger sample that can open a new path to assessment and treatment of persons with aphasia. PMID- 25815440 TI - Resveratrol suppresses vascular endothelial growth factor secretion via inhibition of CXC-chemokine receptor 4 expression in ARPE-19 cells. AB - The present study characterizes the effects of resveratrol (Res) on vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelial (RPE) cells. ARPE-19 cells were treated with CoCl2, a hypoxia mimetic agent. CoCl2 treatment increased protein levels of hypoxia inducible factor-1alpha (HIF 1alpha) and CXC-chemokine receptor 4 (CXCR4), and secretion of VEGF. To confirm the effects of Res on VEGF secretion, the human umbilical vein endothelial cell tube formation assay was performed with conditioned medium from Res-treated ARPE 19 cells. The well-known antioxidant Res effectively blocked these effects and reduced phosphorylation of nuclear factor (NF)-kappaB, an upstream activator of CXCR4. Furthermore, Res also suppressed VEGF secretion induced by SDF-1, a ligand of CXCR4. Conditioned medium from Res-treated ARPE-19 cells clearly suppressed tube formation compared with hypoxia-treated conditioned medium. The results demonstrated that Res inhibited the hypoxia mimetic CoCl2-induced expression of VEGF in ARPE-19 cells. Res suppressed CXCR4 expression through decreased phosphorylation of NF-kappaB, resulting in downregulation of VEGF secretion. PMID- 25815441 TI - Upregulation of microRNA-492 induced by epigenetic drug treatment inhibits the malignant phenotype of clear cell renal cell carcinoma in vitro. AB - Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer of the renal parenchyma. MicroRNAs (miRNAs) are non-coding RNAs of ~22 nucleotides in length, which function as post-transcriptional regulators. Recently, the downregulation of miRNA (miR)-492 was observed to be associated with ccRCC; however, the molecular mechanism by which miR492 inhibited ccRCC remained to be elucidated. In the present study, it was demonstrated that miR-492 was markedly downregulated in ccRCC tissues when compared with adjacent normal tissues, as determined by reverse transcription-quantitative poymerase chain reaction (PCR). This downregulation was predominantly due to the hypermethylation of the CpG island of the miR-492 promoter, which was detected by methylation specific PCR and bisulfite genomic sequencing PCR, and was shown to inhibit miR-492 transcription. Through the use of a DNA demethylation agent, 5-aza-2' deoxycytidine or the histone deacetylase inhibitor 4-phenylbutyric acid, the expression level of miR-492 was significantly upregulated in ccRCC cells, which further inhibited cell proliferation and invasion, while promoting cell apoptosis and adhesion. In conclusion, the present study provided novel insights into the potential mechanisms involved in ccRCC and it is hypothesized that miR-492 may become a promising therapeutic agent in the treatment of ccRCC. PMID- 25815442 TI - Overexpression of Tyro3 receptor tyrosine kinase leads to the acquisition of taxol resistance in ovarian cancer cells. AB - The majority of patients with ovarian cancer are diagnosed at the advanced stages (III/IV) and their 5-year-survival rate is relatively low. One of the major causes of the poor prognosis of ovarian cancer is the development of resistance to first-line chemotherapy, including platinum and taxol. Therefore, improvements in current understanding of chemoresistance is required for the successful treatment of ovarian cancer. In the present study, taxol-resistant ovarian cancer cells, SKOV3/TR, were established by exposing parental SKOV3 cells to increasing concentrations of taxol. . Briefly, cells were treated with 1.5 nM (for 4 weeks), 3 nM (for 4 weeks), 6 nM (for 5 weeks), 12 nM (for 5 weeks) and 24 nM taxol (for 8 weeks) over 6 months. The SKOV3/TR cells were found to be smaller in size and rounder in shape compared with their parental cells. Cell viability and colony formation assays demonstrated an increase in the population doubling time of the SKOV3/TR cells, indicating a reduction in the proliferative capacity of these cells. Reverse transcription-polymerase chain reaction and western blot analysis revealed that, among the TAM receptor tyrosine kinases (RTKs), the mRNA and protein expression levels of Tyro3 RTK were increased, while those of Axl and Mer RTK were decreased in the SKOV3/TR cells. In addition, restoration of the level of Tyro3 by transfecting Tyro3-specific small interfering RNA into the SKOV3/TR cells reduced the proliferative capacity of the cells, indicating that upregulation of the expression of Tyro3 in SKOV3/TR cells may promote survival in the presence of taxol, which eventually resulted in the acquisition of resistance upon taxol treatment. The present study subsequently found that, in the SKOV3/TR cells, the level of intracellular reactive oxygen species (ROS) was elevated, and antioxidant treatment with N-acetyl cysteine (NAC) exerted more profound antiproliferative effects compared with the parental cells. The western blot analysis demonstrated that treatment of the SKOV3/TR cells with NAC reduced the protein expression of Tyro3, and the inhibitory effect of NAC on the phosphorylation of Akt was increased, which may have had a positive effect on the proliferation of the SKOV3/TR cells. The levels of phosphorylation and protein expression of signal transducers and activators of transcription 3 (STAT3) were not affected by NAC treatment, indicating that the phosphorylation of Akt, but not expression or phosphorylation of STAT3, was associated with the increased intracellular ROS level in the SKOV3/TR cells. Taken together, the results of the present study demonstrated that the acquired taxol resistance of ovarian cancer cells was associated with ROS-dependent upregulation in the expression of Tyro3 RTK and the subsequent activation of Akt. PMID- 25815443 TI - High purity microfluidic sorting and analysis of circulating tumor cells: towards routine mutation detection. AB - A new generation of the Ephesia cell capture technology optimized for CTC capture and genetic analysis is presented, characterized in depth and compared with the CellSearch system as a reference. This technology uses magnetic particles bearing tumour-cell specific EpCAM antibodies, self-assembled in a regular array in a microfluidic flow cell. 48,000 high aspect-ratio columns are generated using a magnetic field in a high throughput (>3 ml h(-1)) device and act as sieves to specifically capture the cells of interest through antibody-antigen interactions. Using this device optimized for CTC capture and analysis, we demonstrated the capture of epithelial cells with capture efficiency above 90% for concentrations as low as a few cells per ml. We showed the high specificity of capture with only 0.26% of non-epithelial cells captured for concentrations above 10 million cells per ml. We investigated the capture behavior of cells in the device, and correlated the cell attachment rate with the EpCAM expression on the cell membranes for six different cell lines. We developed and characterized a two-step blood processing method to allow for rapid processing of 10 ml blood tubes in less than 4 hours, and showed a capture rate of 70% for as low as 25 cells spiked in 10 ml blood tubes, with less than 100 contaminating hematopoietic cells. Using this device and procedure, we validated our system on patient samples using an automated cell immunostaining procedure and a semi-automated cell counting method. Our device captured CTCs in 75% of metastatic prostate cancer patients and 80% of metastatic breast cancer patients, and showed similar or better results than the CellSearch device in 10 out of 13 samples. Finally, we demonstrated the possibility of detecting cancer-related PIK3CA gene mutation in 20 cells captured in the chip with a good correlation between the cell count and the quantitation value Cq of the post-capture qPCR. PMID- 25815444 TI - Network challenges for cyber physical systems with tiny wireless devices: a case study on reliable pipeline condition monitoring. AB - The synergy of computational and physical network components leading to the Internet of Things, Data and Services has been made feasible by the use of Cyber Physical Systems (CPSs). CPS engineering promises to impact system condition monitoring for a diverse range of fields from healthcare, manufacturing, and transportation to aerospace and warfare. CPS for environment monitoring applications completely transforms human-to-human, human-to-machine and machine to-machine interactions with the use of Internet Cloud. A recent trend is to gain assistance from mergers between virtual networking and physical actuation to reliably perform all conventional and complex sensing and communication tasks. Oil and gas pipeline monitoring provides a novel example of the benefits of CPS, providing a reliable remote monitoring platform to leverage environment, strategic and economic benefits. In this paper, we evaluate the applications and technical requirements for seamlessly integrating CPS with sensor network plane from a reliability perspective and review the strategies for communicating information between remote monitoring sites and the widely deployed sensor nodes. Related challenges and issues in network architecture design and relevant protocols are also provided with classification. This is supported by a case study on implementing reliable monitoring of oil and gas pipeline installations. Network parameters like node-discovery, node-mobility, data security, link connectivity, data aggregation, information knowledge discovery and quality of service provisioning have been reviewed. PMID- 25815446 TI - Integration of GPS precise point positioning and MEMS-based INS using unscented particle filter. AB - Integration of Global Positioning System (GPS) and Inertial Navigation System (INS) integrated system involves nonlinear motion state and measurement models. However, the extended Kalman filter (EKF) is commonly used as the estimation filter, which might lead to solution divergence. This is usually encountered during GPS outages, when low-cost micro-electro-mechanical sensors (MEMS) inertial sensors are used. To enhance the navigation system performance, alternatives to the standard EKF should be considered. Particle filtering (PF) is commonly considered as a nonlinear estimation technique to accommodate severe MEMS inertial sensor biases and noise behavior. However, the computation burden of PF limits its use. In this study, an improved version of PF, the unscented particle filter (UPF), is utilized, which combines the unscented Kalman filter (UKF) and PF for the integration of GPS precise point positioning and MEMS-based inertial systems. The proposed filter is examined and compared with traditional estimation filters, namely EKF, UKF and PF. Tightly coupled mechanization is adopted, which is developed in the raw GPS and INS measurement domain. Un differenced ionosphere-free linear combinations of pseudorange and carrier-phase measurements are used for PPP. The performance of the UPF is analyzed using a real test scenario in downtown Kingston, Ontario. It is shown that the use of UPF reduces the number of samples needed to produce an accurate solution, in comparison with the traditional PF, which in turn reduces the processing time. In addition, UPF enhances the positioning accuracy by up to 15% during GPS outages, in comparison with EKF. However, all filters produce comparable results when the GPS measurement updates are available. PMID- 25815445 TI - Performance and stress analysis of metal oxide films for CMOS-integrated gas sensors. AB - The integration of gas sensor components into smart phones, tablets and wrist watches will revolutionize the environmental health and safety industry by providing individuals the ability to detect harmful chemicals and pollutants in the environment using always-on hand-held or wearable devices. Metal oxide gas sensors rely on changes in their electrical conductance due to the interaction of the oxide with a surrounding gas. These sensors have been extensively studied in the hopes that they will provide full gas sensing functionality with CMOS integrability. The performance of several metal oxide materials, such as tin oxide (SnO2), zinc oxide (ZnO), indium oxide (In2O3) and indium-tin-oxide (ITO), are studied for the detection of various harmful or toxic cases. Due to the need for these films to be heated to temperatures between 250 degrees C and 550 degrees C during operation in order to increase their sensing functionality, a considerable degradation of the film can result. The stress generation during thin film deposition and the thermo-mechanical stress that arises during post deposition cooling is analyzed through simulations. A tin oxide thin film is deposited using the efficient and economical spray pyrolysis technique, which involves three steps: the atomization of the precursor solution, the transport of the aerosol droplets towards the wafer and the decomposition of the precursor at or near the substrate resulting in film growth. The details of this technique and a simulation methodology are presented. The dependence of the deposition technique on the sensor performance is also discussed. PMID- 25815448 TI - High-speed incoming infrared target detection by fusion of spatial and temporal detectors. AB - This paper presents a method for detecting high-speed incoming targets by the fusion of spatial and temporal detectors to achieve a high detection rate for an active protection system (APS). The incoming targets have different image velocities according to the target-camera geometry. Therefore, single-target detector-based approaches, such as a 1D temporal filter, 2D spatial filter and 3D matched filter, cannot provide a high detection rate with moderate false alarms. The target speed variation was analyzed according to the incoming angle and target velocity. The speed of the distant target at the firing time is almost stationary and increases slowly. The speed varying targets are detected stably by fusing the spatial and temporal filters. The stationary target detector is activated by an almost zero temporal contrast filter (TCF) and identifies targets using a spatial filter called the modified mean subtraction filter (M-MSF). A small motion (sub-pixel velocity) target detector is activated by a small TCF value and finds targets using the same spatial filter. A large motion (pixel velocity) target detector works when the TCF value is high. The final target detection is terminated by fusing the three detectors based on the threat priority. The experimental results of the various target sequences show that the proposed fusion-based target detector produces the highest detection rate with an acceptable false alarm rate. PMID- 25815447 TI - Design of a hybrid (wired/wireless) acquisition data system for monitoring of cultural heritage physical parameters in Smart Cities. AB - Preventive conservation represents a working method and combination of techniques which helps in determining and controlling the deterioration process of cultural heritage in order to take the necessary actions before it occurs. It is acknowledged as important, both in terms of preserving and also reducing the cost of future conservation measures. Therefore, long-term monitoring of physical parameters influencing cultural heritage is necessary. In the context of Smart Cities, monitoring of cultural heritage is of interest in order to perform future comparative studies and load information into the cloud that will be useful for the conservation of other heritage sites. In this paper the development of an economical and appropriate acquisition data system combining wired and wireless communication, as well as third party hardware for increased versatility, is presented. The device allows monitoring a complex network of points with high sampling frequency, with wired sensors in a 1-wire bus and a wireless centralized system recording data for monitoring of physical parameters, as well as the future possibility of attaching an alarm system or sending data over the Internet. This has been possible with the development of three board's designs and more than 5000 algorithm lines. System tests have shown an adequate system operation. PMID- 25815449 TI - Adaptive software architecture based on confident HCI for the deployment of sensitive services in Smart Homes. AB - Smart spaces foster the development of natural and appropriate forms of human computer interaction by taking advantage of home customization. The interaction potential of the Smart Home, which is a special type of smart space, is of particular interest in fields in which the acceptance of new technologies is limited and restrictive. The integration of smart home design patterns with sensitive solutions can increase user acceptance. In this paper, we present the main challenges that have been identified in the literature for the successful deployment of sensitive services (e.g., telemedicine and assistive services) in smart spaces and a software architecture that models the functionalities of a Smart Home platform that are required to maintain and support such sensitive services. This architecture emphasizes user interaction as a key concept to facilitate the acceptance of sensitive services by end-users and utilizes activity theory to support its innovative design. The application of activity theory to the architecture eases the handling of novel concepts, such as understanding of the system by patients at home or the affordability of assistive services. Finally, we provide a proof-of-concept implementation of the architecture and compare the results with other architectures from the literature. PMID- 25815450 TI - An adaptive supervisory sliding fuzzy cerebellar model articulation controller for sensorless vector-controlled induction motor drive systems. AB - This paper presents the implementation of an adaptive supervisory sliding fuzzy cerebellar model articulation controller (FCMAC) in the speed sensorless vector control of an induction motor (IM) drive system. The proposed adaptive supervisory sliding FCMAC comprised a supervisory controller, integral sliding surface, and an adaptive FCMAC. The integral sliding surface was employed to eliminate steady-state errors and enhance the responsiveness of the system. The adaptive FCMAC incorporated an FCMAC with a compensating controller to perform a desired control action. The proposed controller was derived using the Lyapunov approach, which guarantees learning-error convergence. The implementation of three intelligent control schemes--the adaptive supervisory sliding FCMAC, adaptive sliding FCMAC, and adaptive sliding CMAC--were experimentally investigated under various conditions in a realistic sensorless vector-controlled IM drive system. The root mean square error (RMSE) was used as a performance index to evaluate the experimental results of each control scheme. The analysis results indicated that the proposed adaptive supervisory sliding FCMAC substantially improved the system performance compared with the other control schemes. PMID- 25815451 TI - A wafer level vacuum encapsulated capacitive accelerometer fabricated in an unmodified commercial MEMS process. AB - We present the design and fabrication of a single axis low noise accelerometer in an unmodified commercial MicroElectroMechanical Systems (MEMS) process. The new microfabrication process, MEMS Integrated Design for Inertial Sensors (MIDIS), introduced by Teledyne DALSA Inc. allows wafer level vacuum encapsulation at 10 milliTorr which provides a high Quality factor and reduces noise interference on the MEMS sensor devices. The MIDIS process is based on high aspect ratio bulk micromachining of single-crystal silicon layer that is vacuum encapsulated between two other silicon handle wafers. The process includes sealed Through Silicon Vias (TSVs) for compact design and flip-chip integration with signal processing circuits. The proposed accelerometer design is sensitive to single axis in-plane acceleration and uses a differential capacitance measurement. Over +/-1 g measurement range, the measured sensitivity was 1 fF/g. The accelerometer system was designed to provide a detection resolution of 33 milli-g over the operational range of +/-100 g. PMID- 25815452 TI - Application of HFCT and UHF sensors in on-line partial discharge measurements for insulation diagnosis of high voltage equipment. AB - Partial discharge (PD) measurements provide valuable information for assessing the condition of high voltage (HV) insulation systems, contributing to their quality assurance. Different PD measuring techniques have been developed in the last years specially designed to perform on-line measurements. Non-conventional PD methods operating in high frequency bands are usually used when this type of tests are carried out. In PD measurements the signal acquisition, the subsequent signal processing and the capability to obtain an accurate diagnosis are conditioned by the selection of a suitable detection technique and by the implementation of effective signal processing tools. This paper proposes an optimized electromagnetic detection method based on the combined use of wideband PD sensors for measurements performed in the HF and UHF frequency ranges, together with the implementation of powerful processing tools. The effectiveness of the measuring techniques proposed is demonstrated through an example, where several PD sources are measured simultaneously in a HV installation consisting of a cable system connected by a plug-in terminal to a gas insulated substation (GIS) compartment. PMID- 25815453 TI - An analytical model for squeeze-film damping of perforated torsional microplates resonators. AB - Squeeze-film damping plays a significant role in the performance of micro resonators because it determines their quality factors. Perforations in microstructures are often used to control the squeeze-film damping in micro resonators. To model the perforation effects on the squeeze-film damping, many analytical models have been proposed, however, most of the previous models have been concerned with the squeeze-film damping due to the normal motion between the perforated vibrating plate and a fixed substrate, while there is a lack of works that model the squeeze-film damping of perforated torsion microplates, which are also widely used in MEMS devices. This paper presents an analytical model for the squeeze-film damping of perforated torsion microplates. The derivation in this paper is based on a modified Reynolds equation that includes compressibility and rarefaction effects. The pressure distribution under the vibrating plate is obtained using the double sine series. Closed-form expressions for the stiffness and the damping coefficients of the squeeze-film are derived. The accuracy of the model is verified by comparing its results with the finite element method (FEM) results and the experimental results available in the literature. The regime of validity and limitations of the present model are assessed. PMID- 25815454 TI - Comparison of Surgical Pleth Index-guided Analgesia with Conventional Analgesia Practices in Children: A Randomized Controlled Trial. AB - BACKGROUND: To compare surgical pleth index (SPI)-guided analgesia with conventional analgesia by evaluating intraoperative analgesic requirements, postoperative pain, and emergence agitation in children. METHODS: This study was designed as a parallel, two-arm, double-blind, randomized controlled trial. Forty five children undergoing elective adenotonsillectomy were randomly allocated to SPI-guided group (SPI-guided analgesia group, n = 21) or control group (conventional analgesia group, n = 24). Anesthesia was maintained with sevoflurane 2 to 3 vol% in 50% nitrous oxide and oxygen to achieve state entropy between 40 and 60. Intraoperative fentanyl 0.5 MUg/kg was administered for the first event persisting 3 min and subsequent events persisting 5 min. An event was defined as an SPI over 50 (SPI-guided group) or a blood pressure or heart rate 20% above the baseline (control group). The primary outcome was intraoperative fentanyl requirement. Secondary outcomes included intraoperative sevoflurane consumption, postoperative emergence agitation and pain score, and postoperative rescue analgesic requirements. RESULTS: Intraoperative fentanyl requirement was lower in SPI-guided group than in control group (0.43 +/- 0.53 vs. 1.73 +/- 0.59 MUg/kg; P < 0.001). Intraoperative sevoflurane consumption was similar. The proportion of patients with high emergence agitation scores (4 to 5) was greater in SPI-guided group (61.9 vs. 25.0%; P = 0.01). The postoperative pain score and rescue fentanyl consumption were higher in SPI-guided group (7 [4.5; 9] vs. 3 [2; 6.75]; P = 0.002; 0.50 +/- 0.34 vs. 0.29 +/- 0.30 MUg/kg; P = 0.04). CONCLUSIONS: As currently constructed, SPI does not appear to be valid in children. This may be due to both differences in blood vessel distensibility and baseline increased heart rates in children versus adults. PMID- 25815455 TI - TRPV4 Is Required for Hypoxic Pulmonary Vasoconstriction. AB - BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is critically important in regionally heterogeneous lung diseases by directing blood toward better oxygenated lung units, yet the molecular mechanism of HPV remains unknown. Transient receptor potential (TRP) channels are a large cation channel family that has been implicated in HPV, specifically in the pulmonary artery smooth muscle cell (PASMC) Ca and contractile response to hypoxia. In this study, the authors probed the role of the TRP family member, TRPV4, in HPV. METHODS: HPV was assessed by using isolated perfused mouse lungs or by intravital microscopy to directly visualize pulmonary arterioles in mice. In vitro experiments were performed in primary human PASMC. RESULTS: The hypoxia-induced pulmonary artery pressure increase seen in wild-type mice (5.6 +/- 0.6 mmHg; mean +/- SEM) was attenuated both by inhibition of TRPV4 (2.8 +/- 0.5 mmHg), or in lungs from TRPV4 deficient mice (Trpv4) (3.4 +/- 0.5 mmHg; n = 7 each). Functionally, Trpv4 mice displayed an exaggerated hypoxemia after regional airway occlusion (paO2 71% of baseline +/- 2 vs. 85 +/- 2%; n = 5). Direct visualization of pulmonary arterioles by intravital microscopy revealed a 66% reduction in HPV in Trpv4 mice. In human PASMC, inhibition of TRPV4 blocked the hypoxia-induced Ca influx and myosin light chain phosphorylation. TRPV4 may form a heteromeric channel with TRPC6 as the two channels coimmunoprecipitate from PASMC and as there is no additive effect of TRPC and TRPV4 inhibition on Ca influx in response to the agonist, 11,12-epoxyeicosatrienoic acid. CONCLUSION: TRPV4 plays a critical role in HPV, potentially via cooperation with TRPC6. PMID- 25815456 TI - Resolution of Small Bowel Follicular Lymphoma With Treatment of Concomitant Hepatitis B. AB - We report a case of small bowel follicular lymphoma regression with hepatitis B virus treatment. Our patient underwent surveillance colonoscopy that showed profound nodularity in the terminal ileum that was consistent with non-Hodgkin's lymphoma (NHL) on biopsy. Upon further testing the patient was found to be infected with hepatitis B virus. We decided to treat hepatitis B first to prevent its reactivation if the patient underwent therapy for NHL and with the thought that NHL can be stimulated by immunological response to antigens. Our patient was started on Entecavir, and fortunately the NHL regressed with no recurrence on follow-up endoscopies and biopsies. PMID- 25815457 TI - Feasibility of Ultrasound-Guided Sacroiliac Joint Injections in Children Presenting with Sacroiliitis. AB - PURPOSE: To evaluate the feasibility and effectiveness of US-guided sacroiliac joint injection in the treatment of sacroiliitis in children. MATERIALS AND METHODS: This study was approved by the institutional review board and informed oral and written consent was obtained from the patients and their parents. In 13 patients (7 females and 6 males), 9 - 16 years (mean +/- std 11.39 +/-1.98), 18 sacroiliac joint (SI joint) injections were performed under US guidance. All patients suffered from severe sacroiliitis. US scanning was performed using a linear-array transducer operating at 5 - 18 MHz. Rating of the patients pain using a 0 - 10 dolorimetry scale on a visual analog score (VAS) was recorded before, immediately after and 3 months after injection to monitor severity and therapeutic response. RESULTS: Injection could be performed in all patients without complication and showed good response immediately and 3 months after the injection with a decrease of the VAS (from mean +/- std 9.44 +/- 1.097 to 3.89 +/ 3.82, p < 0.001 and to 0.56 +/- 1.097, p < 0.05, respectively). CONCLUSION: US guided SI joint injection was feasible in all children, relatively quick and easy to perform and appeared effective in the treatment of children with sacroiliitis. PMID- 25815460 TI - Access to patients' health records for drug therapy problem determination by pharmacists. AB - Objectives: To evaluate differences in the number and type of drug therapy problems (DTPs) identified by pharmacists with and without access to patients' primary care health records; determine the confidence level of pharmacists in their assessment of DTPs with and without access to health records; and determine the type of information pharmacists need to confirm their assessment. Methods: The study design was an exploratory and comparative evaluation of comprehensive medication management assessments. Pharmacists initially completed patient assessments without access to the patient's primary care health record. Pharmacists documented the visit according to the standard of care and documented the assessment in a standardized study form. Pharmacists then reviewed the patient's primary care health record and documented a revised assessment in the standardized study form. The standardized form included sections about the number of DTPs, the classification of DTPs, the pharmacist's confidence level in identifying DTPs, and the information needed to increase the pharmacist's confidence level in identifying DTPs. Results: Pharmacists evaluated 24 patients and identified 132 DTPs. After reviewing patients' primary care health records, 31 DTPs were deemed "false DTPs," 3 DTPs were recategorized, and 9 new DTPs were identified. Practitioner confidence levels in DTP determination improved after reviewing patients' primary care health records. The health information most frequently identified as desirable after the initial review was laboratory tests. Conclusion: Pharmacists identified more DTPs with lower confidence levels without access to patients' primary care health records. Fewer DTPs were deemed "confirmed DTPs" and confidence in the practitioners' assessments improved after review of the primary care health records. Access to primary care health records can help community pharmacists build an efficient and comprehensive medication management practice. PMID- 25815458 TI - Glioblastoma: molecular pathways, stem cells and therapeutic targets. AB - Glioblastoma (GBM), a WHO-defined Grade IV astrocytoma, is the most common and aggressive CNS malignancy. Despite current treatment modalities, the survival time remains dismal. The main cause of mortality in patients with this disease is reoccurrence of the malignancy, which is attributed to treatment-resistant cancer stem cells within and surrounding the primary tumor. Inclusion of novel therapies, such as immuno- and DNA-based therapy, may provide better means of treating GBM. Furthermore, manipulation of recently discovered non-coding microRNAs, some of which regulate tumor growth through the development and maintenance of GBM stem cells, could provide new prospective therapies. Studies conducted by The Cancer Genome Atlas (TCGA) also demonstrate the role of molecular pathways, specifically the activated PI3K/AKT/mTOR pathway, in GBM tumorigenesis. Inhibition of the aforementioned pathway may provide a more direct and targeted method to GBM treatment. The combination of these treatment modalities may provide an innovative therapeutic approach for the management of GBM. PMID- 25815459 TI - cMET in NSCLC: Can We Cut off the Head of the Hydra? From the Pathway to the Resistance. AB - In the last decade, the tyrosine kinase receptor cMET, together with its ligand hepatocyte growth factor (HGF), has become a target in non-small cell lung cancer (NSCLC). Signalization via cMET stimulates several oncological processes amongst which are cell motility, invasion and metastasis. It also confers resistance against several currently used targeted therapies, e.g., epidermal growth factor receptor (EGFR) inhibitors. In this review, we will discuss the basic structure of cMET and the most important signaling pathways. We will also look into aberrations in the signaling and the effects thereof in cancer growth, with the focus on NSCLC. Finally, we will discuss the role of cMET as resistance mechanism. PMID- 25815461 TI - Cbl participates in shikonin-induced apoptosis by negatively regulating phosphoinositide 3-kinase/protein kinase B signaling. AB - Shikonin, a naturally occurring naphthoquinone, exhibits anti-tumorigenic activity. However, its precise mechanisms of action have remained elusive. In the present study, the involvement in the action of shikonin of the ubiquitin ligases Cbl-b and c-Cbl, which are negative regulators of phosphoinositide 3-kinase (PI3K) activation, was investigated. Shikonin was observed to reduce cell viability and induce apoptosis and G2/M phase arrest in lung cancer cells. In addition, shikonin increased the protein levels of B-cell lymphoma 2 (Bcl-2) associated X and p53 and reduced those of Bcl-2. Additionally, shikonin inhibited PI3k/Akt activity and upregulated Cbl protein expression. In addition, a specific inhibitor of PI3K, LY294002, was observed to have a synergistic effect on the proliferation inhibition and apoptotic induction of A549 cells with shikonin. In conclusion, the results of the present study suggested that Cbl proteins promote shikonin-induced apoptosis by negatively regulating PI3K/Akt signaling in lung cancer cells. PMID- 25815462 TI - Apoptosis of HL-60 human leukemia cells induced by Asiatic acid through modulation of B-cell lymphoma 2 family proteins and the mitogen-activated protein kinase signaling pathway. AB - The toxicities of conventional chemotherapeutic agents to normal cells restrict their dosage and clinical efficacy in acute leukemia; therefore, it is important to develop novel chemotherapeutics, including natural products, which selectively target cancer-specific pathways. The present study aimed to explore the effect of the chemopreventive agent asiatic acid (AA) on the proliferation and apoptotic rate of the leukemia cell line HL-60 and investigated the mechanisms underlying its anti-tumor activity. The effect of AA on the proliferation of HL-60 cells was evaluated using the MTT assay. Annexin V-fluorescein isothiocyanate/propidium iodide double staining followed by flow cytometric analysis as well as Hoechst 33258 staining were used to analyze the apoptotic rate of the cells. Furthermore, changes of survivin, B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 expressions were detected by western blot analysis. AA blocked the growth of HL-60 cells in a dose- and time-dependent manner. The IC50-value of AA on HL-60 cells was 46.67 +/- 5.08 umol/l for 24 h. AA induced apoptosis in a dose dependent manner, which was inhibited in the presence of Z-DEVD-FMK, a specific inhibitor of caspase. The anti-apoptotic proteins Bcl-2, Mcl-1 and survivin were downregulated by AA in a dose-dependent manner. Concurrently, AA inhibited ERK and p38 phosphorylation in a dose-dependent manner, while JNK phosphorylation was not affected. In conclusion, the present study indicated that the p38 and ERK pathways, as well as modulation of Bcl-2 family and survivin proteins were key regulators of apoptosis induced in HL-60 cells in response to AA. PMID- 25815463 TI - Epigenetic modification and preliminary investigation of the mechanism of the immune evasion of HL-60 cells. AB - The aim of the present study was to explore the effect of epigenetic modification of class II transactivator (CIITA) methylation on histocompatibility complex (MHC) class II expression and the immune evasion of leukemia HL-60 cells. HL-60 cells were treated with various concentrations of 5-aza-2'deoxycytidine (5-Aza CdR) and 0.5 umol/l suberoylanilide hydroxamic acid (SAHA) for 24 h and then stimulated by interferon gamma (IFN-gamma) for 48 h. The mRNA levels of MHC class I, II and co-stimulatory molecules were quantified by reverse transcription polymerase chain reaction (RT-PCR). The levels of CIITA protein were determined by western blot analysis, and the CpG island methylation ratios in the CIITA promoter IV (CIITApIV) were analyzed by bisulfite-sequencing PCR (BSP). MHC I as well as the co-stimulatory molecules CD40 and CD80 were significantly increased following treatment with 5-Aza-CdR + SAHA + IFN-gamma (epigenetic groups) compared with those in the control group and IFN-gamma group (P<0.05). The expression of MHC class II and CIITA was restored and increased in an 5-Aza-CdR concentration-dependent manner in the three epigenetic groups. The results of the BSP assay showed that the methylation rate of CIITApIV CpG sites decreased with the treatment of epigenetic modification and negatively correlated to the 5-Aza CdR concentration. This demonstrated that the negative expression of CIITA protein was the key reason for the loss of MHC II expression in HL-60 cells. The results of the present study may help to illustrate the mechanism of immune evasion in HL-60 cells. PMID- 25815465 TI - Correction: Multimeric scaffolds displaying the HIV-1 envelope MPER induce MPER specific antibodies and cross-neutralizing antibodies when co-immunized with gp160 DNA. PMID- 25815464 TI - GAGA factor maintains nucleosome-free regions and has a role in RNA polymerase II recruitment to promoters. AB - Previous studies have shown that GAGA Factor (GAF) is enriched on promoters with paused RNA Polymerase II (Pol II), but its genome-wide function and mechanism of action remain largely uncharacterized. We assayed the levels of transcriptionally engaged polymerase using global run-on sequencing (GRO-seq) in control and GAF RNAi Drosophila S2 cells and found promoter-proximal polymerase was significantly reduced on a large subset of paused promoters where GAF occupancy was reduced by knock down. These promoters show a dramatic increase in nucleosome occupancy upon GAF depletion. These results, in conjunction with previous studies showing that GAF directly interacts with nucleosome remodelers, strongly support a model where GAF directs nucleosome displacement at the promoter and thereby allows the entry Pol II to the promoter and pause sites. This action of GAF on nucleosomes is at least partially independent of paused Pol II because intergenic GAF binding sites with little or no Pol II also show GAF-dependent nucleosome displacement. In addition, the insulator factor BEAF, the BEAF-interacting protein Chriz, and the transcription factor M1BP are strikingly enriched on those GAF-associated genes where pausing is unaffected by knock down, suggesting insulators or the alternative promoter-associated factor M1BP protect a subset of GAF-bound paused genes from GAF knock-down effects. Thus, GAF binding at promoters can lead to the local displacement of nucleosomes, but this activity can be restricted or compensated for when insulator protein or M1BP complexes also reside at GAF bound promoters. PMID- 25815467 TI - Correction: Profiling of serum and urinary microRNAs in children with atopic dermatitis. PMID- 25815466 TI - The distribution of ocular Chlamydia prevalence across Tanzanian communities where trachoma is declining. AB - BACKGROUND: Mathematical models predict an exponential distribution of infection prevalence across communities where a disease is disappearing. Trachoma control programs offer an opportunity to test this hypothesis, as the World Health Organization has targeted trachoma for elimination as a public health concern by the year 2020. Local programs may benefit if a single survey could reveal whether infection was headed towards elimination. Using data from a previously-published 2009 survey, we test the hypothesis that Chlamydia trachomatis prevalence across 75 Tanzanian communities where trachoma had been documented to be disappearing is exponentially distributed. METHODS/FINDINGS: We fit multiple continuous distributions to the Tanzanian data and found the exponential gave the best approximation. Model selection by Akaike Information Criteria (AICc) suggested the exponential distribution had the most parsimonious fit to the data. Those distributions which do not include the exponential as a special or limiting case had much lower likelihoods of fitting the observed data. 95% confidence intervals for shape parameter estimates of those distributions which do include the exponential as a special or limiting case were consistent with the exponential. Lastly, goodness-of-fit testing was unable to reject the hypothesis that the prevalence data came from an exponential distribution. CONCLUSIONS: Models correctly predict that infection prevalence across communities where a disease is disappearing is best described by an exponential distribution. In Tanzanian communities where local control efforts had reduced the clinical signs of trachoma by 80% over 10 years, an exponential distribution gave the best fit to prevalence data. An exponential distribution has a relatively heavy tail, thus occasional high-prevalence communities are to be expected even when infection is disappearing. A single cross-sectional survey may be able to reveal whether elimination efforts are on-track. PMID- 25815468 TI - Detection of powdery mildew in two winter wheat plant densities and prediction of grain yield using canopy hyperspectral reflectance. AB - To determine the influence of plant density and powdery mildew infection of winter wheat and to predict grain yield, hyperspectral canopy reflectance of winter wheat was measured for two plant densities at Feekes growth stage (GS) 10.5.3, 10.5.4, and 11.1 in the 2009-2010 and 2010-2011 seasons. Reflectance in near infrared (NIR) regions was significantly correlated with disease index at GS 10.5.3, 10.5.4, and 11.1 at two plant densities in both seasons. For the two plant densities, the area of the red edge peak (Sigmadr680-760 nm), difference vegetation index (DVI), and triangular vegetation index (TVI) were significantly correlated negatively with disease index at three GSs in two seasons. Compared with other parameters Sigmadr680-760 nm was the most sensitive parameter for detecting powdery mildew. Linear regression models relating mildew severity to Sigmadr680-760 nm were constructed at three GSs in two seasons for the two plant densities, demonstrating no significant difference in the slope estimates between the two plant densities at three GSs. Sigmadr680-760 nm was correlated with grain yield at three GSs in two seasons. The accuracies of partial least square regression (PLSR) models were consistently higher than those of models based on Sigmadr680760 nm for disease index and grain yield. PLSR can, therefore, provide more accurate estimation of disease index of wheat powdery mildew and grain yield using canopy reflectance. PMID- 25815471 TI - Correction: Comprehensive selection of reference genes for gene expression normalization in sugarcane by real time quantitative RT-PCR. PMID- 25815469 TI - Characterization of binding and inhibitory properties of TAK-063, a novel phosphodiesterase 10A inhibitor. AB - Phosphodiesterase 10A (PDE10A) inhibition is a novel and promising approach for the treatment of central nervous system disorders such as schizophrenia and Huntington's disease. A novel PDE10A inhibitor, TAK-063 [1-[2-fluoro-4-(1H pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one] has shown high inhibitory activity and selectivity for human recombinant PDE10A2 in vitro; the half-maximal inhibitory concentration was 0.30 nM, and selectivity over other phosphodiesterases (PDEs) was more than 15000-fold. TAK-063 at 10 uM did not show more than 50% inhibition or stimulation of 91 enzymes or receptors except for PDEs. In vitro autoradiography (ARG) studies using rat brain sections revealed that [3H]TAK-063 selectively accumulated in the caudate putamen (CPu), nucleus accumbens (NAc), globus pallidus, substantia nigra, and striatonigral projection, where PDE10A is highly expressed. This [3H]TAK-063 accumulation was almost entirely blocked by an excess amount of MP-10, a PDE10A selective inhibitor, and the accumulation was not observed in brain slices of Pde10a knockout mice. In rat brain sections, [3H]TAK-063 bound to a single high-affinity site with mean +/- SEM dissociation constants of 7.2 +/- 1.2 and 2.6 +/- 0.5 nM for the CPu and NAc shell, respectively. Orally administered [14C]TAK-063 selectively accumulated in PDE10A expressing brain regions in an in vivo ARG study in rats. Striatal PDE10A occupancy by TAK-063 in vivo was measured using T 773 as a tracer and a dose of 0.88 mg/kg (p.o.) was calculated to produce 50% occupancy in rats. Translational studies with TAK-063 and other PDE10A inhibitors such as those presented here will help us better understand the pharmacological profile of this class of potential central nervous system drugs. PMID- 25815470 TI - Rapid adsorption of copper(II) and lead(II) by rice straw/Fe3O4 nanocomposite: optimization, equilibrium isotherms, and adsorption kinetics study. AB - Rice straw/magnetic nanocomposites (RS/Fe3O4-NCs) were prepared via co precipitation method for removal of Pb(II) and Cu(II) from aqueous solutions. Response surface methodology (RSM) was utilized to find the optimum conditions for removal of ions. The effects of three independent variables including initial ion concentration, removal time, and adsorbent dosage were investigated on the maximum adsorption of Pb (II) and Cu (II). The optimum conditions for the adsorption of Pb(II) and Cu(II) were obtained (100 and 60 mg/L) of initial ion concentration, (41.96 and 59.35 s) of removal time and 0.13 g of adsorbent for both ions, respectively. The maximum removal efficiencies of Pb(II) and Cu(II) were obtained 96.25% and 75.54%, respectively. In the equilibrium isotherm study, the adsorption data fitted well with the Langmuir isotherm model. The adsorption kinetics was best depicted by the pseudo-second order model. Desorption experiments showed adsorbent can be reused successfully for three adsorption desorption cycles. PMID- 25815472 TI - Cardiovascular toxicity of multi-tyrosine kinase inhibitors in advanced solid tumors: a population-based observational study. AB - BACKGROUND: Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events. Warnings of cardiovascular events are common in drug labels of many TKIs. Despite these warnings, cardiovascular toxicity of patients treated with TKIs remains unclear. Here, we evaluate the cardiovascular outcomes of advanced cancer patients treated with small molecule tyrosine kinase inhibitors. METHODS: A population based cohort study was undertaken involving adults aged >18 years in Ontario, Canada, diagnosed with any advanced malignancy between 2006 and 2012. Data were extracted from linked administrative governmental databases. Adults with advanced cancer receiving TKIs were identified and followed throughout the time period. The main outcomes of interest were rates of hospitalization for ischemic heart disease (acute myocardial infarction and angina) or cerebrovascular accidents and death. RESULTS: 1642 patients with a mean age of 62.5 years were studied; 1046 were treated with erlotinib, 166 with sorafenib and 430 with sunitinib. Over the 380 day median follow-up period (range 6-1970 days), 1.1% of all patients had ischemic heart events, 0.7% had cerebrovascular accidents and 72.1% died. Rates of cardiovascular events were similar to age and gender-matched individuals without cancer. In a subgroup analysis of treatment patients with a prior history of ischemic heart disease, 3.3% had ischemic heart events while 1.2% had cerebrovascular accidents. CONCLUSIONS: TKIs do not appear to increase the cause-specific hazard of ischemic heart disease and cerebrovascular accidents compared to age and gender-matched individuals without advanced cancer. PMID- 25815473 TI - Molecular signatures discriminating the male and the female sexual pathways in the pearl oyster Pinctada margaritifera. AB - The genomics of economically important marine bivalves is studied to provide better understanding of the molecular mechanisms underlying their different reproductive strategies. The recently available gonad transcriptome of the black lip pearl oyster Pinctada margaritifera is a novel and powerful resource to study these mechanisms in marine mollusks displaying hermaphroditic features. In this study, RNAseq quantification data of the P. margaritifera gonad transcriptome were analyzed to identify candidate genes in histologically-characterized gonad samples to provide molecular signatures of the female and male sexual pathway in this pearl oyster. Based on the RNAseq data set, stringent expression analysis identified 1,937 contigs that were differentially expressed between the gonad histological categories. From the hierarchical clustering analysis, a new reproduction model is proposed, based on a dual histo-molecular analytical approach. Nine candidate genes were identified as markers of the sexual pathway: 7 for the female pathway and 2 for the male one. Their mRNA levels were assayed by real-time PCR on a new set of gonadic samples. A clustering method revealed four principal expression patterns based on the relative gene expression ratio. A multivariate regression tree realized on these new samples and validated on the previously analyzed RNAseq samples showed that the sexual pathway of P. margaritifera can be predicted by a 3-gene-pair expression ratio model of 4 different genes: pmarg-43476, pmarg-foxl2, pmarg-54338 and pmarg-fem1-like. This 3-gene-pair expression ratio model strongly suggests only the implication of pmarg-foxl2 and pmarg-fem1-like in the sex inversion of P. margaritifera. This work provides the first histo-molecular model of P. margaritifera reproduction and a gene expression signature of its sexual pathway discriminating the male and female pathways. These represent useful tools for understanding and studying sex inversion, sex differentiation and sex determinism in this species and other related species for aquaculture purposes such as genetic selection programs. PMID- 25815474 TI - Delta-tocotrienol suppresses radiation-induced microRNA-30 and protects mice and human CD34+ cells from radiation injury. AB - We reported that microRNA-30c (miR-30c) plays a key role in radiation-induced human cell damage through an apoptotic pathway. Herein we further evaluated radiation-induced miR-30 expression and mechanisms of delta-tocotrienol (DT3), a radiation countermeasure candidate, for regulating miR-30 in a mouse model and human hematopoietic CD34+ cells. CD2F1 mice were exposed to 0 (control) or 7-12.5 Gy total-body gamma-radiation, and CD34+ cells were irradiated with 0, 2 or 4 Gy of radiation. Single doses of DT3 (75 mg/kg, subcutaneous injection for mice or 2 MUM for CD34+ cell culture) were administrated 24 h before irradiation and animal survival was monitored for 30 days. Mouse bone marrow (BM), jejunum, kidney, liver and serum as well as CD34+ cells were collected at 1, 4, 8, 24, 48 or 72 h after irradiation to determine apoptotic markers, pro-inflammatory cytokines interleukin (IL)-1beta and IL-6, miR-30, and stress response protein expression. Our results showed that radiation-induced IL-1beta release and cell damage are pathological states that lead to an early expression and secretion of miR-30b and miR-30c in mouse tissues and serum and in human CD34+ cells. DT3 suppressed IL 1beta and miR-30 expression, protected against radiation-induced apoptosis in mouse and human cells, and increased survival of irradiated mice. Furthermore, an anti-IL-1beta antibody downregulated radiation-induced NFkappaBp65 phosphorylation, inhibited miR-30 expression and protected CD34+ cells from radiation exposure. Knockdown of NFkappaBp65 by small interfering RNA (siRNA) significantly suppressed radiation-induced miR-30 expression in CD34+ cells. Our data suggest that DT3 protects human and mouse cells from radiation damage may through suppression of IL-1beta-induced NFkappaB/miR-30 signaling. PMID- 25815475 TI - A Nurr1 agonist causes neuroprotection in a Parkinson's disease lesion model primed with the toll-like receptor 3 dsRNA inflammatory stimulant poly(I:C). AB - Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1). Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson's disease (PD) pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o.) entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg) for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly(I:C) and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were associated with changes in microglial morphology indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced. We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD. PMID- 25815476 TI - Expression patterns of bovine CD1 in vivo and assessment of the specificities of the anti-bovine CD1 antibodies. AB - Research addressing the in vivo effects of T cell activation by lipids, glycolipids, and lipopeptides is hampered by the absence of a suitable animal model. Mice and rats do not express CD1a, CD1b, and CD1c molecules that present pathogen-derived lipid antigens in humans. In cattle, two CD1A and three CD1B genes are transcribed. The proteins encoded by these genes differ in their antigen binding domains and in their cytoplasmic tails, suggesting that they may traffic differently in the cell and thus have access to different antigens. In the current study, we describe the genomic organization of the bovine CD1 locus and transcription of bovine CD1 genes in freshly isolated dendritic cells and B cells from different tissues. After determining the specificity of previously only partly characterized anti-CD1 antibodies by testing recombinant single chain bovine CD1 proteins and CD1-transfected cells, we were able to determine cell surface protein expression on freshly isolated cells. Our study suggests that CD1b1 and CD1b3 are more broadly expressed than CD1b5, and CD1a2 is more broadly expressed than CD1a1. Pseudoafferent lymph dendritic cells express CD1B genes, but no transcription is detected in lymph nodes. Even though B cells transcribe CD1B genes, there is no evidence of protein expression at the cell surface. Thus, patterns of CD1 protein expression are largely conserved among species. PMID- 25815477 TI - Volumetric modulated arc therapy vs. c-IMRT for the treatment of upper thoracic esophageal cancer. AB - OBJECTIVE: To compare plans using volumetric-modulated arc therapy (VMAT) with conventional sliding window intensity-modulated radiation therapy (c-IMRT) to treat upper thoracic esophageal cancer (EC). METHODS: CT datasets of 11 patients with upper thoracic EC were identified. Four plans were generated for each patient: c-IMRT with 5 fields (5F) and VMAT with a single arc (1A), two arcs (2A), or three arcs (3A). The prescribed doses were 64 Gy/32 F for the primary tumor (PTV64). The dose-volume histogram data, the number of monitoring units (MUs) and the treatment time (TT) for the different plans were compared. RESULTS: All of the plans generated similar dose distributions for PTVs and organs at risk (OARs), except that the 2A- and 3A-VMAT plans yielded a significantly higher conformity index (CI) than the c-IMRT plan. The CI of the PTV64 was improved by increasing the number of arcs in the VMAT plans. The maximum spinal cord dose and the planning risk volume of the spinal cord dose for the two techniques were similar. The 2A- and 3A-VMAT plans yielded lower mean lung doses and heart V50 values than the c-IMRT. The V20 and V30 for the lungs in all of the VMAT plans were lower than those in the c-IMRT plan, at the expense of increasing V5, V10 and V13. The VMAT plan resulted in significant reductions in MUs and TT. CONCLUSION: The 2A-VMAT plan appeared to spare the lungs from moderate-dose irradiation most effectively of all plans, at the expense of increasing the low dose irradiation volume, and also significantly reduced the number of required MUs and the TT. The CI of the PTVs and the OARs was improved by increasing the arc-number from 1 to 2; however, no significant improvement was observed using the 3A-VMAT, except for an increase in the TT. PMID- 25815478 TI - Hybridization and back-crossing in giant petrels (Macronectes giganteus and M. halli) at Bird Island, South Georgia, and a summary of hybridization in seabirds. AB - Hybridization in natural populations provides an opportunity to study the evolutionary processes that shape divergence and genetic isolation of species. The emergence of pre-mating barriers is often the precursor to complete reproductive isolation. However, in recently diverged species, pre-mating barriers may be incomplete, leading to hybridization between seemingly distinct taxa. Here we report results of a long-term study at Bird Island, South Georgia, of the extent of hybridization, mate fidelity, timing of breeding and breeding success in mixed and conspecific pairs of the sibling species, Macronectes halli (northern giant petrel) and M. giganteus (southern giant petrel). The proportion of mixed-species pairs varied annually from 0.4-2.4% (mean of 1.5%), and showed no linear trend with time. Mean laying date in mixed-species pairs tended to be later than in northern giant petrel, and always earlier than in southern giant petrel pairs, and their breeding success (15.6%) was lower than that of conspecific pairs. By comparison, mixed-species pairs at both Marion and Macquarie islands always failed before hatching. Histories of birds in mixed species pairs at Bird Island were variable; some bred previously or subsequently with a conspecific partner, others subsequently with a different allospecific partner, and some mixed-species pairs remained together for multiple seasons. We also report the first verified back-crossing of a hybrid giant petrel with a female northern giant petrel. We discuss the potential causes and evolutionary consequences of hybridization and back-crossing in giant petrels and summarize the incidence of back-crossing in other seabird species. PMID- 25815479 TI - Control group design, contamination and drop-out in exercise oncology trials: a systematic review. AB - PURPOSE: Important considerations for exercise trials in cancer patients are contamination and differential drop-out among the control group members that might jeopardize the internal validity. This systematic review provides an overview of different control groups design characteristics of exercise-oncology trials and explores the association with contamination and drop-out rates. METHODS: Randomized controlled exercise-oncology trials from two Cochrane reviews were included. Additionally, a computer-aided search using Medline (Pubmed), Embase and CINAHL was conducted after completion date of the Cochrane reviews. Eligible studies were classified according to three control group design characteristics: the exercise instruction given to controls before start of the study (exercise allowed or not); and the intervention the control group was offered during (any (e.g., education sessions or telephone contacts) or none) or after (any (e.g., cross-over or exercise instruction) or none) the intervention period. Contamination (yes or no) and excess drop-out rates (i.e., drop-out rate of the control group minus the drop-out rate exercise group) were described according to the three design characteristics of the control group and according to the combinations of these three characteristics; so we additionally made subgroups based on combinations of type and timing of instructions received. RESULTS: 40 exercise-oncology trials were included based on pre-specified eligibility criteria. The lowest contamination (7.1% of studies) and low drop-out rates (excess drop-out rate -4.7+/-9.2) were found in control groups offered an intervention after the intervention period. When control groups were offered an intervention both during and after the intervention period, contamination (0%) and excess drop-out rates (-10.0+/-12.8%) were even lower. CONCLUSIONS: Control groups receiving an intervention during and after the study intervention period have lower contamination and drop-out rates. The present findings can be considered when designing future exercise-oncology trials. PMID- 25815481 TI - Risk behaviours among female sex workers in China: a systematic review and data synthesis. AB - BACKGROUND: Commercial sex is one of the major modes of HIV transmission in China. Understanding HIV risk behaviours in female sex workers (FSW) is of great importance for prevention. This study aims to assess the magnitude and temporal changes of risk behaviours in Chinese FSW. METHOD: Five electronic databases were searched to identify peer-reviewed English and Chinese language articles published between January 2000 and December 2012 that reported risk behaviours among FSW in China, including condom use, HIV testing, and drug use. Linear regression and Spearman's rank correlation were used to examine temporal trends in these risk factors. The study followed PRISMA guidelines for meta-analyses and was registered in the PROSPERO database for systematic reviews. RESULTS: A total of 583 articles (44 English, 539 Chinese) investigating 594,583 Chinese FSW were included in this review. At last sex, condom use was highest with commercial partners (clients), increasing from 53.7% in 2000 to 84.9% in 2011. During this same time period, condom use increased with regular partners from 15.2% to 40.4% and with unspecified partners from 38.6% to 82.5%. Increasing trends were also found in the proportion of sampled FSW who reported testing for HIV in the past 12 months (from 3.2% in 2000 to 48.0% in 2011), while drug use behaviours decreased significantly from 10.9% to 2.6%. CONCLUSION: During the first decade of 2000, Chinese FSWs' self-reported risk behaviours have decreased significantly while HIV testing has increased. Further outreach and intervention efforts are needed to encourage condom use with regular partners, continue promotion of HIV testing, and provide resources for the most vulnerable FSW, particularly low tier FSW, who may have limited access to sexual health and prevention programs. PMID- 25815480 TI - Classification and characterization of species within the genus lens using genotyping-by-sequencing (GBS). AB - Lentil (Lens culinaris ssp. culinaris) is a nutritious and affordable pulse with an ancient crop domestication history. The genus Lens consists of seven taxa, however, there are many discrepancies in the taxon and gene pool classification of lentil and its wild relatives. Due to the narrow genetic basis of cultivated lentil, there is a need towards better understanding of the relationships amongst wild germplasm to assist introgression of favourable genes into lentil breeding programs. Genotyping-by-sequencing (GBS) is an easy and affordable method that allows multiplexing of up to 384 samples or more per library to generate genome wide single nucleotide Polymorphism (SNP) markers. In this study, we aimed to characterize our lentil germplasm collection using a two-enzyme GBS approach. We constructed two 96-plex GBS libraries with a total of 60 accessions where some accessions had several samples and each sample was sequenced in two technical replicates. We developed an automated GBS pipeline and detected a total of 266,356 genome-wide SNPs. After filtering low quality and redundant SNPs based on haplotype information, we constructed a maximum-likelihood tree using 5,389 SNPs. The phylogenetic tree grouped the germplasm collection into their respective taxa with strong support. Based on phylogenetic tree and STRUCTURE analysis, we identified four gene pools, namely L. culinaris/L. orientalis/L. tomentosus, L. lamottei/L. odemensis, L. ervoides and L. nigricans which form primary, secondary, tertiary and quaternary gene pools, respectively. We discovered sequencing bias problems likely due to DNA quality and observed severe run-to-run variation in the wild lentils. We examined the authenticity of the germplasm collection and identified 17% misclassified samples. Our study demonstrated that GBS is a promising and affordable tool for screening by plant breeders interested in crop wild relatives. PMID- 25815482 TI - Heritable CRISPR/Cas9-mediated genome editing in the yellow fever mosquito, Aedes aegypti. AB - In vivo targeted gene disruption is a powerful tool to study gene function. Thus far, two tools for genome editing in Aedes aegypti have been applied, zinc-finger nucleases (ZFN) and transcription activator-like effector nucleases (TALEN). As a promising alternative to ZFN and TALEN, which are difficult to produce and validate using standard molecular biological techniques, the clustered regularly interspaced short palindromic repeats/CRISPR-associated sequence 9 (CRISPR/Cas9) system has recently been discovered as a "do-it-yourself" genome editing tool. Here, we describe the use of CRISPR/Cas9 in the mosquito vector, Aedes aegypti. In a transgenic mosquito line expressing both Dsred and enhanced cyan fluorescent protein (ECFP) from the eye tissue-specific 3xP3 promoter in separated but tightly linked expression cassettes, we targeted the ECFP nucleotide sequence for disruption. When supplying the Cas9 enzyme and two sgRNAs targeting different regions of the ECFP gene as in vitro transcribed mRNAs for germline transformation, we recovered four different G1 pools (5.5% knockout efficiency) where individuals still expressed DsRed but no longer ECFP. PCR amplification, cloning, and sequencing of PCR amplicons revealed indels in the ECFP target gene ranging from 2-27 nucleotides. These results show for the first time that CRISPR/Cas9 mediated gene editing is achievable in Ae. aegypti, paving the way for further functional genomics related studies in this mosquito species. PMID- 25815483 TI - Type, number or both? A population-based matched case-control study on the risk of fall injuries among older people and number of medications beyond fall inducing drugs. AB - OBJECTIVES: Drug use is a modifiable risk factor for fall-related injuries in older people. Whereas the injurious effect of polypharmacy is established, that of low numbers of medications has not been fully ascertained. Neither do we know whether it is the number per se or the type of medications that actually matters. We assessed this question for fall injuries leading to hospitalization. DESIGN: National register-based, population-based, matched case-control study. SETTING: Community dwellers aged 65+ years living in Sweden between March 2006 and December 2009. METHODS: Cases (n = 64,399) were identified in the national inpatient register and four controls per case were randomly matched by gender, date of birth and residential area. The association between number of prescribed medications, assessed through linkage with the Swedish prescribed drug register, and the risk of injurious falls was estimated with odds ratios with 95% confidence intervals using conditional logistic regression, adjusted for demographic and health status. RESULTS: The number of medications was associated with an increased risk of fall injury in a dose-response fashion, even after adjustment for marital status, comorbidity and number of fall-risk-inducing drugs (FRIDs). Using ten or more medications was associated with an almost two-fold higher risk (adjusted OR: 1.76, 95% CI: 1.66 to 1.88). When stratified by use (or not) of at least one FRID, the association weakened slightly among both non-users (adjusted OR: 1.50, 95% CI: 1.34 to 1.67) and users (adjusted OR: 1.67, 95% CI: 1.58 to 1.77). CONCLUSION: In older people, not only large but also small numbers of medications may affect the risk for them to sustain injurious falls. Although the mechanisms lying behind this are complex, the finding challenges the prevention strategies targeting either specific types of medications (FRIDs) or high numbers of them. PMID- 25815485 TI - [Colonization and development of intestinal bifidobacteria in early infancy]. AB - OBJECTIVE: To study the characteristics of the colonization of 8 species of bifidobacteria by systematically profiling fecal bifidobacterial community in the early life of infants. METHODS: Fresh fecal samples including meconium samples were collected for culture and isolation of fecal bifidobacteria from 16 cases of full-term newborn infants born between March and April 2013 at their life of 2, 4, 7, 10, 14, 28, and 90 days. The isolated fecal bifidobacteria were taxonomically identified to genus and 8 species with PCR analysis. RESULTS: One hundred and fifty-two predominant bifidobacteria strains were detected in the fecal samples, the detection rate of B. breve (22.4%) were the highest. Bifidobacteria were found in the feces of 8% infants 4 days after birth. The colonization rates increased to 54% and 60% at 28 days and 3 months respectively, significantly exceeding the colonization rate at 4 days after birth (P<0.05). Adult-type bifidobacteria B. catenulatum were found in the infants 10 days after birth, and infant-type bifidobacteria B. infantis were found at 14 days after birth, but infant-type bifidobacteria B. infantis were detected at a high level until 3 months after birth. The most tested infants had 2 species or less of bifidobacteria. CONCLUSIONS: Intestinal bifidobacteria in infants might have less diversity in early infancy. Infant-type bifidobacteria appear late, while adult type bifidobacteria colonize earlier. PMID- 25815486 TI - [Clinical efficacy of preferred use of high-frequency oscillatory ventilation in treatment of neonatal pulmonary hemorrhage]. AB - OBJECTIVE: To investigate the clinical efficacy and safety of preferred use of high-frequency oscillatory ventilation (HFOV) in the treatment of neonatal pulmonary hemorrhage. METHODS: The clinical efficacy of preferred use of HFOV (preferred use group) and rescue use of HFOV after conventional mechanical ventilation proved ineffective (rescue use group) in the treatment of 26 cases of neonatal pulmonary hemorrhage was retrospectively analyzed. The oxygenation index (OI), pulmonary hemorrhage time, hospitalization time, ventilation time, oxygen therapy time, complications, and outcome of the two groups were compared. RESULTS: Compared with the rescue use group, the preferred use group had significantly lower IO values at 1, 6, 12, 24, 48, and 72 hours after treatment (P<0.05). Compared with the rescue use group, the preferred use group had a significantly lower incidence of ventilator associated pneumonia (VAP) (P<0.05) and a significantly higher cure rate (P<0.05). There were no statistically significant differences in the incidences of pneumothorax, intracranial hemorrhage, and digestive tract hemorrhage between the two groups (P>0.05). Compared with those in the rescue use group, children who survived in the preferred use group had significantly shorter pulmonary hemorrhage time, hospitalization time, ventilation time, and oxygen therapy time (P<0.05). CONCLUSIONS: Compared with the rescue use of HFOV, preferred use of HFOV can better improve oxygenation function, reduce the incidence of VAP, shorten the course of disease, and increase cure rate while not increasing the incidence of adverse effects. PMID- 25815487 TI - [Relationship between placental inflammation and fetal inflammatory response syndrome and brain injury in preterm infants]. AB - OBJECTIVE: To explore the relationship between histological chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) and brain injury in preterm infants. METHODS: One hundred and three singleton infants with premature rupture of membranes (PROM) (gestation ages of less than 34 weeks) were enrolled. All the placentas were submitted for pathological evaluation. Umbilical cord blood interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor alpha (TNF alpha) and granulocyte-colony stimulating factor (G-CSF) levels were measured with liquid chip. All preterm infants accepted brain imaging examinations. Based on the placental pathological examination and umbilical cord blood level of IL-6, the 103 infants were classified into HCA- FIRS-, HCA+ FIRS-, and HCA+ FIRS+ groups. RESULTS: The incidences of HCA, FIRS, and brain injury were 53.4%, 20.4% and 38.8% respectively. The prevalence of brain injury in HCA- FIRS-, HCA+ FIRS-, and HCA+ FIRS+ cases was 21%, 41%, and 76% respectively (P<0.01). The grade 2 and grade 3 of placental inflammation and the inflammation at stage 2 and stage 3 increased the risk of brain injury. The cord blood levels of IL-8, TNF-alpha, and G-CSF in the HCA+ FIRS+ group were significantly higher than in the other two groups, and the levels of the above parameters in the HCA+ FIRS- were higher than in the HCA- FIRS- group (P<0.05). CONCLUSIONS: Placental inflammation and FIRS are associated with brain injury in preterm infants. Preterm infants exposed to severe placental inflammation have an increased risk of brain injury. Cord blood IL-8, TNF-alpha and G-CSF may be involved in the process of brain injury in preterm infants with placental inflammation and FIRS. PMID- 25815484 TI - P247 and p523: two in vivo-expressed megalocytivirus proteins that induce protective immunity and are essential to viral infection. AB - Megalocytivirus is a DNA virus with a broad host range among teleost fish. Although the complete genome sequences of a number of megalocytivirus isolates have been reported, the functions of most of the genes of this virus are unknown. In this study, we selected two megalocytivirus immunogens, P247 and P523, which were expressed during host infection and, when in the form of DNA vaccines (pCN247 and pCN523 respectively), elicited strong protectivity against lethal megalocytivirus challenge in a turbot (Scophthalmus maximus) model. Compared to control fish, fish vaccinated with pCN247 and pCN523 exhibited drastically reduced viral loads in tissues and high levels of survival rates. Immune response analysis showed that pCN247 and pCN523 (i) induced production of specific serum antibodies, (ii) caused generation of cytotoxic immune cells and specific memory immune cells that responded to secondary antigen stimulation, and (iii) upregulated the expression of genes involved in innate and adaptive immunity. To examine the potential role of P247 and P523 in viral infection, the expression of P247 and P523 was knocked down by siRNA. Subsequent in vivo infection study showed that P247 and P523 knockdown significantly impaired viral replication. Furthermore, whole-genome transcriptome analysis revealed that P247 and P523 knockdown altered the expression profiles of 26 and 41 viral genes, respectively, putatively participating in diverse aspects of viral infection. Taken together, these results indicate that P247 and P523 induce protective immunity in teleost and play fundamental roles essential to viral replication. These observations provide the first evidence that suggests a likely link between the protectivity of viral immunogens and their biological significance in viral replication. PMID- 25815488 TI - [Significance of trace deposition of immunoglobulin M in glomerular mesangium in children with minimal change nephrotic syndrome]. AB - OBJECTIVE: To study the significance of trace immunoglobulin M (IgM) deposits in glomerular mesangium in children with minimal change primary nephrotic syndrome (PNS). METHODS: One hundred and six children who were clinically diagnosed with PNS and pathologically diagnosed with minimal change disease (MCD) and trace deposition of IgM in renal tissues were enrolled as subjects. Eighty-one PNS children with MCD but no deposition of immune complexes were used as the control group. The clinical characteristics and efficacies of glucocorticoids and immunosuppressants were retrospectively analyzed in the two groups. All patients were given full-dose prednisone by oral administration, and patients with glucocorticoid resistance or frequent relapses were additionally given immunosuppressants. RESULTS: The incidence of glucocorticoid resistance in the IgM deposit group was significantly higher than that in the control group (27.2% vs 12.3%; P<0.05). The incidence of frequent relapses in the IgM deposit group was also significantly higher than that in the control group (48.1% vs 10.4%; P<0.05). The complete remission rate for glucocorticoid-resistant patients treated with prednisone combined with mycophenolate mofetil (MMF) was 68% and 62% respectively in the IgM deposit and control groups (P>0.05). The relapse frequency in patients with frequent relapses was significantly reduced in both groups after treatment with prednisone and MMF in combination (P<0.05). CONCLUSIONS: Trace deposition of IgM in renal tissues may be an important factor for glucocorticoid resistance and frequent relapses in PNS children with MCD. Prednisone combined with MMF may be a better choice in the treatment of patients with glucocorticoid resistance or frequent relapses. PMID- 25815489 TI - [Value of determination of haptoglobin and alpha1-antitrypsin in predicting response to glucocorticoid therapy in children with primary nephrotic syndrome]. AB - OBJECTIVE: To study the value of the determination of serum and urine haptoglobin (HP) and alpha 1-antitrypsin (AAT) in predicting the response to glucocorticoid therapy in children with primary nephrotic syndrome (PNS). METHODS: A total of 84 children with PNS were classified to steroid-sensitive nephrotic syndrome (SSNS) (n=58) and steroid-resistant nephrotic syndrome (SRNS) groups (n=26). Forty healthy children were randomly selected for the control group. HP and AAT levels in blood and urinary samples were determined using ELISA. The efficiency of HP and AAT in predicting the response to glucocorticoid treatment of PNS was evaluated by the receiver operating characteristic (ROC) curve. RESULTS: Compared with the control group, both the SSNS and SRNS groups had significantly higher serum HP concentrations and urine AAT/Cr ratio before treatment (P<0.05); compared with the SSNS group, the SRNS group had significantly higher serum HP concentrations and urine AAT/Cr ratio before treatment and after one week and four weeks of treatment (P<0.05). Serum HP had the highest efficiency in predicting the response to glucocorticoid treatment of PNS at the concentration of 37.935 mg/mL, with the sensitivity and specificity being 92.3% and 86.2% respectively. Urine AAT/Cr ratio had the highest prediction efficiency at 0.0696, with the sensitivity and specificity being 100% and 79.3% respectively. ROC curve analysis of serum HP combined with urine AAT/Cr ratio showed a better prediction efficiency, with the sensitivity and specificity being 92.3% and 96.6% respectively. CONCLUSIONS: The increase in serum HP level or urine AAT/Cr ratio may indicate glucocorticoid resistance in the early stage of PNS. A combination of the two can achieve better efficiency in the prediction of SRNS. PMID- 25815490 TI - [Association between angiotensin-converting enzyme 2 gene polymorphisms and childhood primary nephrotic syndrome]. AB - OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) gene polymorphisms have been shown to be implicated in hypertension, diabetic nephropathy, and other diseases. However, it remains unclear whether ACE2 gene polymorphisms are involved in the development of primary nephrotic syndrome (PNS) in children. The aim of this study was to assess the association between A9570G polymorphisms of ACE2 gene and PNS in a group of Han children in Guangdong Province, China. METHODS: The genotype distribution and allele frequency of ACE2 gene A9570G in 66 children with PNS and 60 healthy subjects (control group) were analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Allele frequency and genotype distribution showed no significant difference between the PNS and control groups whether in female or in male children (P>0.05). The PNS group was classified into the glucocorticoid-sensitive and glucocorticoid resistant subgroups according to glucocorticoid treatment response. Subgroup analysis revealed that in female children, the frequency of GG genotype was 17% in the glucocorticoid-sensitive group vs 45% in the glucocorticoid-sensitive group (P=0.018); the frequency of G allele was 31% in the glucocorticoid sensitive group vs 61% in the glucocorticoid-resistant group (P=0.023). In male children, the frequency of G genotype/G allele was 36% in the glucocorticoid sensitive group vs 64% in the glucocorticoid-resistant group (P=0.017). CONCLUSIONS: There is no clear association between ACE2 gene A9570G polymorphisms and childhood PNS, but ACE2 gene A9570G polymorphisms might be associated with glucocorticoid treatment response in children with PNS. The G allele might be a genetic susceptibility factor of glucocorticoid resistance in children with PNS. PMID- 25815491 TI - [Efficacy of regular or intermittent inhalation of corticosteroids in treatment of asthma and its effects on growth and development in children]. AB - OBJECTIVE: To observe the efficacy of regular or intermittent inhalation of salmeterol/fluticasone propionate (SM/FP) in the treatment of bronchial asthma and its effects on growth and development in children. METHODS: A total of 112 children diagnosed with bronchial asthma between September 2012 and October 2013 were assigned to standardized treatment (standard group, n=56) and non standardized treatment (intermittent group, n=56). Comparisons of clinical symptom scores and main pulmonary function indicators between the two groups were carried out before treatment and at 6 and 12 months after treatment. The growth velocity and changes in body mass index (BMI) were observed in the two groups. RESULTS: At 6 and 12 months after the treatment, the standard group had significantly reduced clinical symptom scores and significantly increased pulmonary function indicators (percentage of predicted peak expiratory flow, PEF%; percentage of forced expiratory volume in 1 second, FEV1%) (P<0.05); the intermittent group had significantly reduced clinical symptom scores and significantly increased FEV1% (P<0.05), but PEF% was significantly increased only at 6 months after treatment (P<0.05). At 12 months after treatment, the standard group had significantly lower clinical symptom scores and significantly higher PEF% and FEV1% when compared with the intermittent group (P<0.05). The growth velocity and BMI showed no significant differences between the two groups at 6 and 12 months after treatment (P>0.05). CONCLUSIONS: Compared with intermittent inhalation, long-term regular inhalation of SM/FP performs better in controlling clinical symptoms and enhancing pulmonary function in children with asthma. Inhalation of SM/FP for one year reveals no apparent effect on the growth and development of these children. PMID- 25815492 TI - [Association of ORMDL3 single nucleotide polymorphisms with lysophosphatidylcholine and apolipoprotein B levels in children with asthma]. AB - OBJECTIVE: To study the association of ORMDL3 single nucleotide polymorphisms (SNP) with lysophosphatidylcholine (LysoPC) and apolipoprotein B (apoB) levels. METHODS: A total of 300 children diagnosed with bronchial asthma between January 2010 and December 2012 were selected for the asthma group, and 298 children diagnosed with upper respiratory tract infection in the same period were selected for the control group. Serum LysoPC and apoB levels were measured using enzyme linked immunosorbent assay. Genotype analysis was performed using the TaqMan probe. RESULTS: LysoPC and apoB levels were significantly higher in the asthma group than in the control group (P<0.01). Among children with various genotypes of ORMDL3 gene at locus rs12603332, the asthma group had significantly higher LysoPC and apoB levels than the control group (P<0.01). Among the children with asthma, those with CC genotype had significantly higher LysoPC and apoB levels than those with CT and TT genotypes (P<0.01). CONCLUSIONS: LysoPC and apoB may intervene in the pathological process of asthma. Pro-inflammatory gene ORMDL3 SNP rs12603332 may be associated with high LysoPC and apoB levels, which leads to the occurrence of childhood asthma. PMID- 25815493 TI - [Risk factors for the development of acute respiratory distress syndrome in children with measles]. AB - OBJECTIVE: To study the risk factors for the development of acute respiratory distress syndrome (ARDS) in children with measles. METHODS: The clinical data of 55 children with measles were retrospectively studied. Of the 55 children, 11 were complicated by ARDS. The risk factors for the development of ARDS were investigated by univariate analysis and multivariate non-conditional logistic regression analysis. RESULTS: The univariate analysis showed that there were significant differences in the oxygen inhalation mode (nasal catheter/mask), the rate of sepsis, blood C-reactive protein (CRP) levels and lymphocyte counts at admission between the ARDS and non-ARDS groups (P<0.05). The presence of sepsis and higher blood CRP levels were identified as the major risk factors for the development of ARDS by the multivariate logistic regression analysis (OR=116.444, 1.050 respectively; P<0.05). CONCLUSIONS: The children with measles who have sepsis and higher blood CRP levels are at risk of ARDS. PMID- 25815494 TI - [Clinical characteristics and prognostic factors of children with critical hand foot-mouth disease treated with mechanical ventilation]. AB - OBJECTIVE: To investigate the clinical characteristics of children with critical hand-foot-mouth disease (HFMD) who were treated with mechanical ventilation and to explore the risk factors for poor prognosis. METHODS: The clinical data of 63 children with critical HFMD who were admitted to the pediatric intensive care unit between April 2012 and September 2013 and needed mechanical ventilation were retrospectively analyzed. RESULTS: Among the 63 children, 43 were boys and 20 were girls, and their mean age was 25 +/- 18 months, with 81% under 3 years old. The four death cases were all under three years old. Compared with the cured cases, the death cases had a significantly lower mean age (8 +/- 3 months vs 25 +/- 18 months; P<0.05). Poor peripheral circulation above the elbow or knee joint, pulmonary edema involving at least two thirds of the lung field, and pulmonary hemorrhage were all closely related to death (P<0.01). The death cases and cured cases had significantly different peripheral white blood cell counts, blood lactic acid, and blood glucose (24 +/- 11* 109/L vs 12 +/- 5*109/L; 6.6 +/- 1.8 mmol/L vs 3.6 +/- 1.7 mmol/L; 16.4 +/- 2.5 mmol/L vs 10.0 +/- 3.0 mmol/L). The cases with critical illness score <90 had a significantly higher death risk (P<0.01). CONCLUSIONS: Children with critical HFMD are mainly under 3 years old. The children face extremely high risk of death when they suffer from poor peripheral circulation above the elbow or knee joint, pulmonary edema involving at least two thirds of the lung field, and pulmonary hemorrhage. Significant increases in peripheral white blood cell counts, blood lactic acid, and blood glucose are risk factors for poor prognosis. Critical illness score is also related to poor prognosis. PMID- 25815495 TI - [Plasma proteomic analysis in children with infectious mononucleosis]. AB - OBJECTIVE: To explore the abnormal expression of plasma proteins by analysis of proteomic expression profile in children with infectious mononucleosis (IM). METHODS: Two dimensional gel electrophoresis (2-DE) followed by the mass spectrometry was used to examine important protein spots with different expression levels between children with IM and normal controls. RESULTS: Seven differential proteins were obtained: hemopexin, vitamin D binding protein, fetuin A, C-reactive protein, apolipoprotein A, haptoglobin and transthyretin. Compared with the control group, haptoglobin showed a higher expression level in children with IM, and the expression levels of the other proteins were obviously down regulated. CONCLUSIONS: The expression changes of differential proteins identified in this study are all related with the liver acute injury, suggesting that children with IM are associated with acute liver injury. Further studies on the characteristics of above proteins will contribute to the diagnosis and treatment of pediatric IM. PMID- 25815497 TI - [Efficacy and safety of the WT-2009 chemotherapy protocol in treatment of Wilms' tumor in children]. AB - OBJECTIVE: To evaluate the efficacy and safety of the WT-2009 chemotherapy protocol for Wilms' tumor (WT) in children. METHODS: The clinical data of 34 children with newly-diagnosed WT between July 2009 and December 2013 were retrospectively analyzed. Among the 34 children, 2 died before treatment, 6 children did not accept therapy and 26 accepted the chemotherapy based on the WT 2009 chemotherapy protocol. Kaplan-Meier method was used to estimate the 2-year survival rate. RESULTS: The pathological analysis revealed the favorable histology WT was common (88%, 30/34). The most common first manifestation was abdominal masses (56%, 19/34). Among the 26 patients who accepted the chemotherapy based on the WT-2009 protocol, complete remission was achieved in 24 cases (92%), partial remission was achieved in 1 case (4%), and disease relapse was found in 1 case (4%). Severe pulmonary infection occurred in 1 case in the course of treatment. The 2-year overall survival rate and event-free survival rate were 100% and 89.7% respectively. CONCLUSIONS: Favorable histology is most common pathological type in children with WT. The chemotherapy based on the WT 2009 protocol for WT can produce a favorable prognosis and a high tolerance. PMID- 25815496 TI - [Measurement of Foxp3 and NFAT1 in children with aplastic anemia]. AB - OBJECTIVE: To study the expression of Foxp3 and NFAT1 protein in peripheral blood (PB) in children with aplastic anemia (AA) and their roles in the pathogenesis of AA. METHODS: The expression levels of Foxp3 and NFAT1 protein of mononuclear cells in PB were measured by Western blot in 68 children with AA before and after treatment and in 60 normal children (control group). The correlation between Foxp3 and NFAT1 protein expression and the correlation of the Foxp3 and NFAT1 protein expression with blood Hb, WBC and platelet levels were analyzed. RESULTS: The expression levels of Foxp3 and NFAT1 protein in PB in the acute phase in the AA group were significantly lower than in the control group (P<0.05). After treatment (recovery phase) the expression levels of Foxp3 and NFAT1 protein increased obviously compared with those in the acute phase (P<0.05). The Foxp3 protein level was positively correlated with the NFAT1 protein level (r=0.812, P<0.05). Both the Foxp3 and NFAT1 protein levels were positively correlated with blood Hb, WBC and platelet levels in children with AA in the recovery phase (r=0.537, 0.579, 0.655 respectively; P<0.05). CONCLUSIONS: The Foxp3 and NFAT1 protein levels in PB are reduced in children with AA, suggesting that they are involved in the pathogenesis of AA. The measurement of Foxp3 and NFAT1 protein levels may be useful in the severity evaluation of AA. PMID- 25815498 TI - [Risk factors for type 1 diabetes among Uyghur children in Xinjiang, China]. AB - OBJECTIVE: To investigate the risk factors for type 1 diabetes among Uygur children in Xinjiang, China, in order to provide a basis for the prevention of this disease among Uygur children in Xinjiang. METHODS: The clinical data of 94 Uygur children with type 1 diabetes (case group) and 96 Uygur children without diabetes (control group) between January, 2003 and December, 2013, were retrospectively analyzed. The risk factors for type 1 diabetes among Uyghur children in Xinjiang were explored using univariate and multivariate analyses. RESULTS: According to the result of univariate analysis, there were significant differences in age, prodromal infection, residence, feeding method, time for intake of starchy foods, time for intake of high-fat foods, family history, islet cell antibodies (ICA), insulin autoantibodies (IAA), and glutamic acid decarboxylase antibodies between the case and the control groups (P<0.05). According to the result of multivariate logistic analysis, older age, early intake of starchy foods, early intake of high-fat foods, prodromal infection, positive ICA, and positive IAA were major risk factors for type 1 diabetes, and breastfeeding was a protective factor. CONCLUSIONS: Type 1 diabetes among Uyghur children in Xinjiang is caused by multiple factors. Prevention and reduction of prodromal infection, reasonable diet, and promotion of breastfeeding can reduce the risk of disease. PMID- 25815499 TI - [Association between rs1079595 polymorphisms in the DRD2 gene and the distractibility based the temperament in school-age children]. AB - OBJECTIVE: To study the association between rs1079595 polymorphisms in the DRD2 gene and the distractibility in school-age children. METHODS: The genotyping at rs1079595 was performed and the distractibility was measured based on the temperament questionnaire in 120 8-12 years old school-age children in order to analyze the effects of the rs1079595 polymorphism and its interaction with the gender, age and delivery mode on the distractibility. RESULTS: There was an association between the distractibility and rs1079595 polymorphisms. The distractibility score in children with GG/GT genotypes was significantly higher than in children with the TT genotype (4.3 +/- 0.6 vs 4.0 +/- 0.7; P<0.05). The interaction between rs1079595 polymorphisms and the delivery mode produced an effect on the distractibility. The normal delivery children with T alleles were associated with a low distractibility (OR=0.037, P<0.01). CONCLUSIONS: The distractibility based the temperament might be influenced by the rs1079595 polymorphism and its interaction with the delivery mode in school-age children. PMID- 25815500 TI - [Roles of PKCbeta/P66Shc oxidative stress signal pathway in mediating hyperoxia induced ROS production in alveolar epithelial cells]. AB - OBJECTIVE: To explore the roles of PKCbeta/P66Shc oxidative stress signal pathway in mediating hyperoxia-induced reactive oxgen species (ROS) production in alveolar epithelial cells (A549) and the protective effects of PKCbeta inhibitor on hyperoxia-induced injuries of alveolar epithelial cells. METHODS: A549 cells were cultured in vitro and randomly divided into three groups: control, hyperoxia and PKCbeta inhibitor LY333531 treatment. The hyperoxia group was exposed to a mixture of O2 (950 mL/L) and CO2 (50 mL/L) for 10 minutes and then cultured in a closed environment. The LY333531 group was treated with PKCbeta inhibitor LY333531 of 10 umol/L for 24 hours before hyperoxia induction. Cells were collected 24 hours after culture and the levels of PKCbeta, Pin1, P66Shc and P66Shc-Ser36 were detected by Western blot. The intracellular translocation of P66Shc, the production of ROS and cellular mitochondria membrane potential were measured using the confocal microscopy. RESULTS: Compared with the control group, the levels of PKCbeta, Pin1, P66Shc and P-P66Shc-Ser36 in A549 cells 24 hours after culture increased significantly in the hyperoxia group. These changes in the hyperoxia group were accompanied with an increased translocation rate of P66Shc from cytoplasm into mitochondria, an increased production of mitochondrial ROS, and a reduced mitochondrial membrane potential. Compared with the hyperoxia group, the levels of Pin1, P66Shc and P66Shc-Ser36 in A549 cells, the translocation rate of P66Shc from cytoplasm into mitochondria and the production of mitochondrial ROS decreased significantly, while the mitochondrial membrane potential increased significantly in the LY333531 treatment group. However, there were significant differences in the above mentioned measurements between the LY333531 treatment and control groups. CONCLUSIONS: Hyperoxia can increase the expression of PKCbeta in alveolar epithelial cells and production of mitochondrial ROS and decrease mitochondrial membrane potential. PKCbeta inhibitor LY333531 can partially disrupt these changes and thus alleviate the hyperoxia-induced alveolar epithelial cell injury. PMID- 25815501 TI - [Effects of Shenfu injection on calreticulin expression and neuronal apoptosis in the cerebral cortex of neonatal rats with hypoxic-ischemic brain damage]. AB - OBJECTIVE: To examine the expression of calreticulin (CRT) and the changes of intracellular free calcium and neuronal apoptosis in the cerebral cortex of neonatal rats with hypoxic-ischemic brain damage (HIBD), and to investigate the intervention effects of Shenfu injection. METHODS: Seven-day-old rats were randomly assigned to three groups: control, hypoxic-ischemia (HI) and Shenfu treated. Each group (n=50) was subdivided into 5 groups sacrificed at 3, 6, 12, 24 and 72 hours. Rat models of HIBD were prepared according to the Rice's method. Rats in the control group only underwent the separation of right common carotidartery. Shenfu injection was administered by intraperitoneal injections right after HI insults and then once daily at a dosage of 10 mL/kg for 3 days in the Shenfu-treated group. The expression of CRT in the cerebral cortex was detected by RT-PCR and Western blot. The free calcium concentrations were determined under a fluorescent microscope. The apoptosis rate was measured by the flow cytometry. RESULTS: Compared with the control group, the expression levels of CRT in the HI and the Shenfu-treated groups were obviously up-regulated (P<0.05), and the expression levels of CRT in the Shenfu-treated group were notably higher than those in the HI group (P<0.05) at all time points. The concentrations of intracellular free calcium and the apoptosis rate of neurons in the cerebral cortex in the Shenfu-treated group were significantly reduced compared with those in the HI group (P<0.05), but increased significantly compared with those in the control group at all time points (P<0.05). CONCLUSIONS: Shenfu injection may have neuroprotective effects against HIBD by up regulation of CRT expression and relief of calcium overload. PMID- 25815502 TI - [Effect of non-usage of prophylactic antibiotics on nosocomial infections following interventional therapy for congenital heart disease in children]. PMID- 25815504 TI - [Mediastinal primitive neuroectodermal tumor in a newborn infant]. PMID- 25815503 TI - [Autistic spectrum disorders associated with chromosome Mar15q11.2: a case report]. PMID- 25815505 TI - [Advance in therapy for Duchenne/Becker muscular dystrophy]. AB - Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common X-linked recessive inherited neuromuscular disease, characterized by progressive muscle weakness. Mutations in the dystrophin gene are responsible for this disease. Treatment for this disease has always been a topic of interest. With the development of diagnosis and treatment technology of molecular biology, promising therapies have been developed. This review article summarizes the advance in traditional therapy, cell transplantation and gene therapy for this disease. PMID- 25815507 TI - Risk of sudden sensorineural hearing loss in patients with common preexisting sensorineural hearing impairment: a population-based study in Taiwan. AB - OBJECTIVE: The role of preexisting sensorineural hearing impairment on the risk for sudden sensorineural hearing loss (SSHL) is still unclear. In this study, we aimed to assess the risk of SSHL in patients with common preexisting sensorineural hearing impairment using population-based data. METHODS: A population-based case-control study design was used to analyze claims data between January 2001 and December 2011 obtained from the Taiwan National Health Insurance Research Database. The cases consisted of 514 patients with SSHL and the controls were frequency matched to 2,570 cases by sex, 10-year age group, and year of index date. Common sensorineural hearing impairments were retrospectively assessed in the cases and controls. Associations between sensorineural hearing impairment and risk of SSHL were evaluated using unconditional univariate and multivariate logistic regression analyses. RESULTS: The mean age for the 3,084 study subjects was 53.1 years (standard deviation, S.D. = 15.6). Of the 514 cases, 49 (9.5%) had sensorineural hearing impairment while only 44 (1.7%) of the 2,570 controls had the same condition. Univariate logistic regression analyses indicated that preexisting sensorineural hearing impairment was significantly associated with SSHL (odds ratio, OR = 6.05, p < 0.001). Other comorbidities including hypertension, diabetes mellitus, and hyperlipidemia also showed significant associations with SSHL. Similar results were obtained when the association between SSHL and sensorineural hearing impairment was adjusted with either all the covariates (adjusted OR = 6.22, p < 0.001) or with only those selected using a backward elimination procedure (adjusted OR = 6.20, p < 0.001). CONCLUSIONS: Results from this population-based case-control study revealed that common sensorineural hearing impairment might be a novel risk factor for SSHL. PMID- 25815506 TI - Exome and transcriptome sequencing of Aedes aegypti identifies a locus that confers resistance to Brugia malayi and alters the immune response. AB - Many mosquito species are naturally polymorphic for their abilities to transmit parasites, a feature which is of great interest for controlling vector-borne disease. Aedes aegypti, the primary vector of dengue and yellow fever and a laboratory model for studying lymphatic filariasis, is genetically variable for its capacity to harbor the filarial nematode Brugia malayi. The genome of Ae. aegypti is large and repetitive, making genome resequencing difficult and expensive. We designed exome captures to target protein-coding regions of the genome, and used association mapping in a wild Kenyan population to identify a single, dominant, sex-linked locus underlying resistance. This falls in a region of the genome where a resistance locus was previously mapped in a line established in 1936, suggesting that this polymorphism has been maintained in the wild for the at least 80 years. We then crossed resistant and susceptible mosquitoes to place both alleles of the gene into a common genetic background, and used RNA-seq to measure the effect of this locus on gene expression. We found evidence for Toll, IMD, and JAK-STAT pathway activity in response to early stages of B. malayi infection when the parasites are beginning to die in the resistant genotype. We also found that resistant mosquitoes express anti-microbial peptides at the time of parasite-killing, and that this expression is suppressed in susceptible mosquitoes. Together, we have found that a single resistance locus leads to a higher immune response in resistant mosquitoes, and we identify genes in this region that may be responsible for this trait. PMID- 25815508 TI - Changes in the radiocarbon reservoir age in Lake Xingyun, Southwestern China during the Holocene. AB - Chronology is a necessary component of paleoclimatology. Radiocarbon dating plays a central role in determining the ages of geological samples younger than ca. 50 ka BP. However, there are many limitations for its application, including radiocarbon reservoir effects, which may cause incorrect chronology in many lakes. Here we demonstrate temporal changes in the radiocarbon reservoir age of Lake Xingyun, Southwestern China, where radiocarbon ages based on bulk organic matter have been reported in previous studies. Our new radiocarbon ages, determined from terrestrial plant macrofossils suggest that the radiocarbon reservoir age changed from 960 to 2200 years during the last 8500 cal a BP years. These changes to the reservoir effect were associated with inputs from either pre aged organic carbon or 14C-depleted hard water in Lake Xingyun caused by hydrological change in the lake system. The radiocarbon reservoir age may in return be a good indicator for the carbon source in lake ecosystems and depositional environment. PMID- 25815509 TI - Individual and temporal variation in habitat association of an alien carnivore at its invasion front. AB - Gathering information on how invasive species utilize the habitat is important, in order to better aim actions to reduce their negative impact. We studied habitat use and selection of 55 GPS-marked raccoon dogs (30 males, 25 females) at their invasion front in Northern Sweden, with particular focus on differences between males and females, between movement states, and between seasons and times of the day. Daily movement pattern was used to classify GPS-locations into dispersing and settled. We focused on both anthropogenic and natural landscape characteristics. Since we did not have any a priori knowledge about the spatial scale of raccoon dog habitat selection, we first assessed how landscape characteristics of random points changed with distance from the GPS-location they were paired to. Because changes in habitat use became less pronounced at approximately 5 km for all variables, we focused on habitat use at two spatial scales: fine (500 m) and coarse (5 km). Habitat selection was strongest at the coarse scale, and reflected the results found for habitat use. Raccoon dogs selected agricultural areas and wetlands, lower altitudes, and shallow slopes, and avoided forests, open natural areas, and areas close to water and roads. There were no differences in habitat selection between males and females, or between movement states. This lack of sexual segregation increases the probability of encountering potential mates during dispersal, and therefore the likelihood for reproduction in new areas. The seasonal and diurnal pattern of habitat use may provide guidance for where and when to aim management efforts. PMID- 25815510 TI - Theory of choice in bandit, information sampling and foraging tasks. AB - Decision making has been studied with a wide array of tasks. Here we examine the theoretical structure of bandit, information sampling and foraging tasks. These tasks move beyond tasks where the choice in the current trial does not affect future expected rewards. We have modeled these tasks using Markov decision processes (MDPs). MDPs provide a general framework for modeling tasks in which decisions affect the information on which future choices will be made. Under the assumption that agents are maximizing expected rewards, MDPs provide normative solutions. We find that all three classes of tasks pose choices among actions which trade-off immediate and future expected rewards. The tasks drive these trade-offs in unique ways, however. For bandit and information sampling tasks, increasing uncertainty or the time horizon shifts value to actions that pay-off in the future. Correspondingly, decreasing uncertainty increases the relative value of actions that pay-off immediately. For foraging tasks the time-horizon plays the dominant role, as choices do not affect future uncertainty in these tasks. PMID- 25815511 TI - Obstructive sleep apnoea syndrome, endothelial function and markers of endothelialization. Changes after CPAP. AB - STUDY OBJECTIVES: This study tries to assess the endothelial function in vivo using flow-mediated dilatation (FMD) and several biomarkers of endothelium formation/restoration and damage in patients with obstructive sleep apnoea (OSA) syndrome at baseline and after three months with CPAP therapy. DESIGN: Observational study, before and after CPAP therapy. SETTING AND PATIENTS: We studied 30 patients with apnoea/hypopnoea index (AHI) >15/h that were compared with themselves after three months of CPAP therapy. FMD was assessed non invasively in vivo using the Laser-Doppler flowmetry. Circulating cell-free DNA (cf-DNA) and microparticles (MPs) were measured as markers of endothelial damage and the vascular endothelial growth factor (VEGF) was determined as a marker of endothelial restoration process. MEASUREMENTS AND RESULTS: After three month with CPAP, FMD significantly increased (1072.26 +/- 483.21 vs. 1604.38 +/- 915.69 PU, p< 0.005) cf-DNA and MPs significantly decreased (187.93 +/- 115.81 vs. 121.28 +/ 78.98 pg/ml, p<0.01, and 69.60 +/- 62.60 vs. 39.82 +/- 22.14 U/MUL, p<0.05, respectively) and VEGF levels increased (585.02 +/- 246.06 vs. 641.11 +/- 212.69 pg/ml, p<0.05). These changes were higher in patients with more severe disease. There was a relationship between markers of damage (r = -0.53, p<0.005) but not between markers of damage and restoration, thus suggesting that both types of markers should be measured together. CONCLUSIONS: CPAP therapy improves FMD. This improvement may be related to an increase of endothelial restoration process and a decrease of endothelial damage. PMID- 25815512 TI - A promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP gene is associated with decreased risk of ischemic stroke in two independent Chinese populations. AB - No coding sequence variants of the gene encoding 5-lipoxygenase-activating protein (ALOX5AP) leading to amino acid substitutions have been identified. Therefore, variants in the ALOX5AP promoter region have received attention recently. The purpose of this study was to explore whether the promoter polymorphism rs17222919 is involved in the etiology of ischemic stroke (IS) in the Chinese Han population. We investigated the rs17222919 polymorphism by TaqMan genotyping in two independent Chinese Han samples: the first comprised 910 IS patients and 925 healthy inhabitants from the northern Henan Province, while the second included 1003 IS patients and 889 healthy controls from the southern Henan Province. Functional characterization of rs17222919 was performed by an in vitro luciferase assay. After adjusting for conventional risk factors, the G allele frequencies in the IS groups were significantly lower than that in the control groups of the two independent Chinese cohorts (19.0% vs. 22.9%, P = 0.004, odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.675-0.929; 18.8% vs. 22.9%, P = 0.002, OR = 0.782, 95% CI = 0.668-0.915, respectively). This was also observed in the large-artery atherosclerosis (LAA) and stroke of other undetermined etiology (SUE) subtypes (P = 0.019, OR = 0.815, 95% CI = 0.687 0.967; P = 0.021, OR = 0.815, 95% CI = 0.685-0.970, respectively). Additionally, the TG genotype and G allele frequencies were significantly lower in the IS compared with the control group in two female cohorts (P<0.05). Finally, the in vitro luciferase assay demonstrated that the G allele has a significantly lower transcription activity than the T allele (P = 0.031). Our study provides evidence that the promoter single nucleotide polymorphism (SNP) rs17222919 is a potential genetic protective factor for IS in the Chinese Han population. PMID- 25815513 TI - A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability. AB - Microdeletions in chromosome 17q22, where the NOG gene resides, have been reported leading to the NOG-related symphalangism spectrum disorder (NOG-SSD), intellectual disability and other developmental abnormalities. In this study we reported a dominant Chinese Han family segregating with typical NOG-SSD symptoms including proximal symphalangism, conductive hearing loss, amblyopia and strabismus, but not intellectual disability. Sanger sequencing identified no pathogenic mutation in the coding regions of candidate genes NOG, GDF5 and FGF9. SNP genotyping in the genomic region surrounding NOG identified loss of heterozygosity in the affected family members. By array comparative genomic hybridization and quantitative real-time polymerase chain reaction, we identified and mapped the breakpoints of a novel 1.6-Mb microdeletion in chromosome 17q22 that included NOG and twelve other genes. It is the first microdeletion reported in chromosome 17q22 that is associated with NOG-SSD only but not with intellectual disability. Our results may help identifying the dosage sensitive genes for intellectual disability and other developmental abnormalities in chromosome 17q22. Our study also suggested that genomic deletions in chromosome 17q22 should be screened in the NOG-SSD patients in which no pathogenic mutation is identified by conventional sequencing methods. PMID- 25815515 TI - Pure, single crystal Ge nanodots formed using a sandwich structure via pulsed UV excimer laser annealing. AB - In this paper, a sandwich structure comprising a SiO2 capping layer, amorphous Germanium (a-Ge) nanodots (NDs), and a pit-patterned Silicon (Si) substrate is developed, which is then annealed by utilizing a pulsed ultraviolet excimer laser in order to fabricate an array of pure, single crystal Ge NDs at room temperature. A wide bandgap SiO2 capping layer is used as a transparent thermally isolated layer to prevent thermal loss and Si-Ge intermixing. The two-dimensional pit-patterned Si substrate is designed to confine the absorbed laser energy, reduce the melting point, and block the surface migration of the Ge. After optimizing the laser radiation parameters such that the laser energy density is 200 mJ cm(-2), the laser annealing period is 10 s, and the number of laser shots is 10, pure, single crystal Ge NDs that have both a regular arrangement and a uniform size distribution are obtained in the pits of the Si substrates. The Raman spectrum shows a highly symmetric Ge transversal optical peak with a full width at half maximum of 4.2 cm(-1) at 300.7 cm(-1), which is close to that of the original Ge wafer. In addition, the high-resolution transmission electron microscopy image for the Ge NDs and the corresponding selected area electron diffraction pattern shows a clear single crystalline structure without any impurities. PMID- 25815514 TI - Comparison of discectomy versus sequestrectomy in lumbar disc herniation: a meta analysis of comparative studies. AB - BACKGROUND: Lumbar disc removal is currently the standard treatment for lumbar disc herniation. No consensus has been achieved whether aggressive disc resection with curettage (discectomy) versus conservative removal of the offending disc fragment alone (sequestrectomy) provides better outcomes. This study aims to compare the reherniation rate and clinical outcomes between discectomy and sequestrectomy by literature review and a meta-analysis. METHODS: A systematic search of PubMed, Medline, Embase and the Cochrane Library was performed up to June 1, 2014. Outcomes of interest assessing the two techniques included demographic and clinical baseline characteristics, perioperative variables, complications, recurrent herniation rate and post-operative functional outcomes. RESULTS: Twelve eligible trials evaluating discectomy vs sequestrectomy were identified including one randomized controlled study, five prospective and six retrospective comparative studies. By contrast to discectomy, sequestrectomy was associated with significantly less operative time (p<0.001), lower visual analogue scale (VAS) for low back pain (p<0.05), less post-operative analgesic usage (p<0.05) and better patients' satisfaction (p<0.05). Recurrent herniation rate, reoperation rate, intraoperative blood loss, hospitalization duration and VAS for sciatica were without significant difference. CONCLUSIONS: According to our pooled data, sequestrectomy entails equivalent reherniation rate and complications compared with discectomy but maintains a lower incidence of recurrent low back pain and higher satisfactory rate. High-quality prospective randomized controlled trials are needed to firmly assess these two procedures. PMID- 25815516 TI - Taurolithocholic acid promotes intrahepatic cholangiocarcinoma cell growth via muscarinic acetylcholine receptor and EGFR/ERK1/2 signaling pathway. AB - Cholangiocarcinoma (CCA) is a malignant cancer of the biliary tract and its occurrence is associated with chronic cholestasis which causes an elevation of bile acids in the liver and bile duct. The present study aimed to investigate the role and mechanistic effect of bile acids on the CCA cell growth. Intrahepatic CCA cell lines, RMCCA-1 and HuCCA-1, were treated with bile acids and their metabolites to determine the growth promoting effect. Cell viability, cell cycle analysis, EdU incorporation assays were conducted. Intracellular signaling proteins were detected by western immunoblotting. Among eleven forms of bile acids and their metabolites, only taurolithocholic acid (TLCA) concentration dependently (1-40 uM) increased the cell viability of RMCCA-1, but not HuCCA-1 cells. The cell cycle analysis showed induction of cells in the S phase and the EdU incorporation assay revealed induction of DNA synthesis in the TLCA-treated RMCCA-1 cells. Moreover, TLCA increased the phosphorylation of EGFR, ERK 1/2 and also increased the expression of cyclin D1 in RMCCA-1 cells. Furthermore, TLCA induced RMCCA-1 cell growth could be inhibited by atropine, a non-selective muscarinic acetylcholine receptor (mAChR) antagonist, AG 1478, a specific EGFR inhibitor, or U 0126, a specific MEK 1/2 inhibitor. These results suggest that TLCA induces CCA cell growth via mAChR and EGFR/EKR1/2 signaling pathway. Moreover, the functional presence of cholinergic system plays a certain role in TLCA-induced CCA cell growth. PMID- 25815517 TI - Vaccarin promotes endothelial cell proliferation in association with neovascularization in vitro and in vivo. AB - Angiogenesis is a major pathological component of several diseases, including traumatic vascular disease and coronary heart disease. The purpose of the present study was to determine the effects of vaccarin on endothelial cell migration and neovascularization, which are important and necessary components of wound healing. The present study investigated and confirmed neovascularization induced by vaccarin in vitro and in vivo. In vitro, the effects of vaccarin (1.08 and 2.15 uM) on proliferation, migration and tube formation of human microvascular endothelial cells (HMEC)-1 were evaluated via sulforhodamine B assay and migration and tube formation assay, respectively. Furthermore, a mouse Matrigel plus model was used to detect capillary-like tube structures in vivo. Immunohistochemistry was used to detect the protein expression of cluster of differentiation 31 (CD31), p-AKT and p-extracellular-signal-regulated kinases (Erk). Vaccarin significantly promoted HMEC-1 proliferation and migration and tube formation of HMEC-1 at a dose of 2.15 uM. In vivo, vaccarin delivered by daily oral administration significantly improved epidermal growth factor-induced angiogenesis in an intradermal inoculation mouse model. The mouse Matrigel model study also revealed that vaccarin significantly promoted neovascularization via detection of CD31 levels and enhanced protein expression of p-Akt and p-Erk. In addition, vaccarin also promoted expression of CD31. PMID- 25815518 TI - Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms. AB - The aim of the present study was to investigate the synergistic effects of valproic acid (VPA) and arsenic trioxide (ATO) on the proliferation of RPMI8226 cells and the possible underlying mechanisms. Cell apoptosis was assessed by flow cytometry. The mRNA expression levels were analyzed by semi-quantitative polymerase chain reaction, and the protein expression levels were analyzed by western blotting. The histone acetylation and methylation states of the gene promoters were detected using a chromatin immunoprecipitation technique. The apoptotic rates of the RPMI8226 cells in the combined drug groups were significantly increased compared with those of the single drug groups (P<0.05). The mRNA and protein expression levels of Bcl-2 and the expression levels of HDAC1 mRNA and H3K9me2 protein decreased significantly in the combined groups compared with the single drug groups. The mRNA and protein expression levels of Bax, Caspase 8, Caspase 9 and LSD1, and the protein expression of acetylated H3 increased significantly in the combination groups compared with the single drug groups. Histone methylation and acetylation of the Bcl-2 and bax gene promoters were increased in the combination groups compared with the single drug groups. VPA and ATO had synergistic effects on the proliferation of RPMI8226 cells, which may have been associated with the decreased expression of Bcl-2 and the increased expression levels of Bcl-2-associated X protein, Caspase 8 and Caspase 9. Therefore, the expression levels of the Bcl-2 gene family may have been regulated by the levels of gene promoter methylation and acetylation. PMID- 25815519 TI - Litsea japonica extract inhibits neuronal apoptosis and the accumulation of advanced glycation end products in the diabetic mouse retina. AB - The retinal accumulation of advanced glycation end products (AGEs) is a condition, which is found in diabetic retinopathy. The purpose of the present study was to investigate the protective effect of Litsea japonica extract (LJE) and to elucidate its underlying protective mechanism in model diabetic db/db mice. Male, 7 -week-old db/db mice were treated with LJE (100 or 250 mg/kg body weight) once a day orally for 12 weeks. The expression levels of AGEs and their receptor (RAGE) were subsequently assessed by immunohistochemistry. An electrophoretic mobility shift assay and southwestern histochemistry were used to detect activated nuclear factor kappaB (NF-kappaB). The immunohistochemical analysis demonstrated that LJE significantly reduced the expression levels of the AGEs and RAGE in the neural retinas of the db/db mice. LJE markedly inhibited the apoptosis of retinal ganglion cells. In addition, LJE suppressed the activation of NF-kappaB. These results suggested that LJE may be beneficial for the treatment of diabetes-induced retinal neurodegeneration, and the ability of LJE to attenuate retinal ganglion cell loss may be mediated by inhibition of the accumulation of AGEs. PMID- 25815521 TI - Anti-inflammatory effects of Gualou Guizhi decoction in transient focal cerebral ischemic brains. [Corrected]. AB - The aim of the present study was to explore the neuroprotective effects of Gualou Guizhi decoction (GLGZD) in a rat model of middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were divided into three groups: Sham (no MCAO), MCAO (MCAO with no GLGZD treatment) and GLGZD (MCAO with GLGZD treatment). Rats in the MCAO and GLGZD groups were subjected to permanent occlusion of the left middle cerebral artery. Neurological function and infarct volume were measured. Microglial activation and inflammatory cell accumulation were measured using immunohistochemistry. mRNA and protein expression of inflammatory mediators were examined using reverse transcription-quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay. The expression of proteins associated with the nuclear factor kappa-B (NF-kappaB) inflammation signaling pathway was analyzed using western blotting. The results of the present study suggested that infarct size was significantly reduced and neurological behavior function was improved in rats with MCAO treated with GLGZD compared with rats in the MCAO group. Amoeboid microglial expansion and inflammatory cell migration were observed in the infarcted areas of rats in the GLGZD group and were not identified in those of the MCAO group. Target mRNA and protein levels, and inflammatory cell infiltration were significantly reduced in the GLGZD group compared with the MCAO model group. Notably, GLGZD treatment induced neuroprotective effects, reducing inflammation and inhibiting NF-kappaB signaling compared with the MCAO group. Therefore, GLGZD may exhibit anti-inflammatory effects against ischemia-reperfusion brain injury and may be a therapeutic target for ischemic stroke. PMID- 25815520 TI - Effects of OsteoKing on osteoporotic rabbits. AB - Heng-Gu-Gu-Shang-Yu-He-Ji, also known as OsteoKing, is used as a herbal Traditional Chinese Medicine for the treatment of bone disease, including femoral head necrosis and osteoarthritis. However, whether OsteoKing has anti osteoporotic properties has remained to be elucidated. The purpose of the present study was therefore to investigate the effects of OsteoKing on ovariectomy induced osteoporosis in rabbits. Female New Zealand white rabbits were randomly divided into an ovariectomized (OVX) group and a sham-surgery group. The rabbits in the OVX group were subjected to an ovariectomy, while the rabbits in the sham group were subjected to the removal of an area of fat near the two ovaries. Bone mineral density, mechanical properties, serum biochemical parameters and micro architecture were examined at 150 days post-OVX to characterize the experimental animal model. Once the osteoporotic rabbit model had been established, the rabbits in the OVX group were divided into the following groups: Model group, nilestriol group and 300 and 600 mg/kg OsteoKing groups, containing 16 rabbits in each group. OsteoKing and nilestriol were administered orally. The bone mineral density, mechanical properties, serum biochemical parameters, histology and micro architecture were examined using dual-energy X-ray absorptiometric analysis, mechanical assessments, enzyme-linked immunosorbent assays, histopathological evaluation and micro-computerized tomography examination following 60 days and 120 days of treatment, respectively. Treatment with OsteoKing led to an elevation in the bone mineral density of the vertebra and serum phosphorus levels, reduced serum concentrations of osteocalcin, procollagen type I N-terminal peptide, tartrate-resistant acid phosphatase 5b and cross-linked N-telopeptide of type I collagen, improved mechanical properties (maximum load, stiffness and energy absorption capacity), and micro-architecture of the lumbar vertebra in the OVX osteoporotic rabbit model following treatment for 120 days. In conclusion, it was demonstrated that OsteoKing is effective in the prevention of estrogen deficiency associated bone loss and may be a promising drug for the treatment of post menopausal osteoporosis. PMID- 25815522 TI - A low-cost wheat bran medium for biodegradation of the benzidine-based carcinogenic dye Trypan Blue using a microbial consortium. AB - Environmental release of benzidine-based dyes is a matter of health concern. Here, a microbial consortium was enriched from textile dye contaminated soils and investigated for biodegradation of the carcinogenic benzidine-based dye Trypan Blue using wheat bran (WB) as growth medium. The PCR-DGGE analysis of enriched microbial consortium revealed the presence of 15 different bacteria. Decolorization studies suggested that the microbial consortium has high metabolic activity towards Trypan Blue as complete removal of 50 mg?L-1 dye was observed within 24 h at 30 +/- 0.2 degrees C and pH 7. Significant reduction in TOC (64%) and COD (88%) of dye decolorized broths confirmed mineralization. Induction in azoreductase (500%), NADH-DCIP reductase (264%) and laccase (275%) proved enzymatic decolorization of dye. HPLC analysis of dye decolorized products showed the formation of six metabolites while the FTIR spectrum indicated removal of diazo bonds at 1612.30 and 1581.34 cm-1. The proposed dye degradation pathway based on GC-MS and enzyme analysis suggested the formation of two low molecular weight intermediates. Phytotoxicity and acute toxicity studies revealed the less toxic nature of the dye degradation products. These results provide experimental evidence for the utilization of agricultural waste as a novel low-cost growth medium for biodegradation of benzidine-based dyes, and suggested the potential of the microbial consortium in detoxification. PMID- 25815523 TI - Association between air pollutants and cardiovascular disease mortality in Wuhan, China. AB - We examined the associations of daily mean concentrations of ambient air pollutants (particulate matter (PM10), sulfur dioxide (SO2), nitric oxide (NO2)) and daily cardiovascular diseases (CVD) mortality in Wuhan, China using a case crossover design to analyze four years of data (2006-2009) collected from the Hubei Provincial Center for Disease Control and Prevention and the Wuhan Environmental Protection Bureau. From 2006 to 2009, daily average concentrations of PM10, SO2 and NO2 were 115.60 ug/m3, 53.21 ug/m3 and 53.08 ug/m3, respectively. After adjusting for temperature and relative humidity, a 10 ug/m3 increase in SO2 and NO2 over a 24-h period was associated with CVD mortality relative risk (R.R.) of 1.010 (95% CI: 1.000, 1.020) for SO2 and 1.019 (95% CI: 1.005, 1.033) for NO2, but there was no significant association between increases in PM10 and mortality. Subgroup analysis on by gender showed a significant association of 1.026 (95% CI: 1.007, 1.045) between NO2 and CVD among males, while no significant statistical effect was shown among females. Subgroup analysis by age showed that for those older than 65 years, every 10 ug/m3 increase in NO2 was associated with a 1.6% (95% CI: 0.1%, 3.1%) increase in CVD mortality. Subgroup analysis on different types of CVD showed that every 10 ug/m3 increase in PM10 and SO2 were significantly associated with an approximately 1.012 (95% CI: 1.002, 1.022) and 1.021 (95% CI: 1.002, 1.040) increase, respectively, in ischemic heart disease (ICH) mortality. In conclusion, exposure to NO2 is significantly associated with CVD mortality. Larger, multi-center studies in Chinese cities are being currently conducted to validate these findings. PMID- 25815525 TI - Antibody microarray profiling of osteosarcoma cell serum for identifying potential biomarkers. AB - The aim of the present study was to identify biomarkers in osteosarcoma (OS) cell serum by antibody microarray profiling, which may be used for OS diagnosis and therapy. An antibody microarray was used to detect the expression levels of cytokines in serum samples from 20 patients with OS and 20 healthy individuals. Significantly expressed cytokines in OS serum were selected when P<0.05 and fold change >2. An enzyme-linked immunosorbent assay (ELISA) was used to validate the antibody microarray results. Finally, classification accuracy was calculated by cluster analysis. Twenty one cytokines were significantly upregulated in OS cell serum samples compared with control samples. Expression of interleukin-6, monocyte chemoattractant protein-1, tumor growth factor-beta, growth-related oncogene, hepatocyte growth factor, chemokine ligand 16, Endoglin, matrix metalloproteinase-9 and platelet-derived growth factor-AA was validated by ELISAs. OS serum samples and control samples were distinguished by significantly expressed cytokines with an accuracy of 95%. The results demonstrated that expressed cytokines identified by antibody microarray may be used as biomarkers for OS diagnosis and therapy. PMID- 25815526 TI - Heart failure as an independent predictor of thrombus persistence in nonvalvular atrial fibrillation: a transesophageal echocardiography-based study. AB - INTRODUCTION: Formation of left atrial (LA) thrombus is one of the most serious complications in patients with atrial fibrillation (AF). OBJECTIVES: The aim of our study was to determine the predictors of LA thrombus resolution among patients with AF receiving oral anticoagulation. PATIENTS AND METHODS: After a retrospective analysis of 1877 transesophageal echocardiographic examinations (TEEs) performed in our department between January 2009 and June 2013, we included 64 patients (women, 36%; mean age at diagnosis, 64 +/-8.8 years) with nonvalvular AF and LA thrombi on TEE into the study. All patients received oral anticoagulation and underwent follow-up TEE within a few months since diagnosis. RESULTS: After a mean follow-up period of 88 +/-107 days, thrombus resolution was observed in 30 patients (47%). The univariate Cox proportional regression model showed that heart failure and reduced left ventricular ejection fraction were associated with the persistence of LA thrombus (hazard ratio [HR], 2.72; 95% confidence interval [CI], 1.32-5.61; P = 0.007 and HR, 0.97; 95% CI, 0.94-0.99; P = 0.04; respectively). The international normalized ratio and CHA2DS2-VASc score were not prognostic for thrombus resolution (HR, 0.64; 95% CI, 0.37-1.1; P = 0.1 and HR 1.10; 95% CI, 0.91-1.33; P = 0.3; respectively). In a multivariate analysis, heart failure was the only independent factor predicting unsuccessful resolution of LA thrombus (P = 0.04). CONCLUSIONS: Heart failure is an independent negative predictor of LA thrombus resolution in patients with AF receiving oral anticoagulation. PMID- 25815524 TI - Sevoflurane ameliorates intestinal ischemia-reperfusion-induced lung injury by inhibiting the synergistic action between mast cell activation and oxidative stress. AB - Preconditioning with sevoflurane (SEV) can protect against ischemia-reperfusion injury in several organs, however, the benefits of SEV against acute lung injury (ALI), induced by intestinal ischemia-reperfusion (IIR), and the underlying mechanisms remain to be elucidated. The present study was designed to investigate the effects of SEV preconditioning on IIR-mediated ALI and the associated mechanisms in a rat model. Female Sprague-Dawley rats treated with 2.3% SEV or apocynin (AP), an inhibitor of NADPH oxidase, were subjected to 75 min superior mesenteric artery occlusion followed by 2 h reperfusion in the presence or absence of the mast cell degranulator compound 48/80 (CP). SEV and AP were observed to downregulate the protein expression levels of p47(phox) and gp91(phox) in the lungs of normal rats. IIR resulted in severe lung injury, characterized by significant increases in pathological injury scores, lung wet/dry weight ratio, protein expression levels of p4(7phox), gp91(phox) and ICAM 1, the presence of hydrogen peroxide, malondydehyde and interleukin-6, and the activity of myeloperoxidase. In addition, significant reductions were observed in the expression of prosurfactant protein C, accompanied by an increase in MC degranulation, demonstrated by significant elevations in the number of mast cells, expression levels of tryptase and the concentration of beta hexosaminidase. These changes were further augmented in the presence of CP. In addition, SEV and AP preconditioning significantly alleviated the above alterations induced by IIR alone or in combination with CP. These findings suggested that SEV and AP attenuated IIR-induced ALI by inhibiting NADPH oxidase and the synergistic action between oxidative stress and mast cell activation. PMID- 25815527 TI - Doppler-Resolved Kinetics of Saturation Recovery. AB - Frequency-modulated laser transient absorption has been used to monitor the ground-state rotational energy-transfer rates of CN radicals in a double resonance, depletion recovery experiment. When a pulsed laser is used to burn a hole in the equilibrium ground-state population of one rotational state without velocity selection, the population recovery rate is found to depend strongly on the Doppler detuning of a narrow-band probe laser. Similar effects should be apparent for any relaxation rate process that competes effectively with velocity randomization. Alternative methods of extracting thermal rate constants in the presence of these non-thermal conditions are evaluated. Total recovery rate constants, analogous to total removal rate constants in an experiment preparing a single initial rotational level, are in good agreement with quantum scattering calculations, but are slower than previously reported experiments and show qualitatively different rotational state dependence between Ar and He collision partners. Quasi-classical trajectory studies confirm that the differing rotational state dependence is primarily a kinematic effect. PMID- 25815528 TI - Synthesis of diazatricyclic common structure of madangamine alkaloids. AB - A general synthetic route toward a diazatricyclic core common to the madangamine family is described. Ring-closing metathesis and palladium-catalyzed cycloisomerization provided the cis-fused diazadecalin structure, accompanied by formation of the N-Boc-enamine, which was utilized as an N-acyliminium ion equivalent. Direct cyclization from the N-Boc-enamine was achieved through the in situ formation of an N,O-acetal. PMID- 25815529 TI - Direct Aerobic Carbonylation of C(sp2)-H and C(sp3)-H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source. AB - The direct carbonylation of aromatic sp(2) and unactivated sp(3) C-H bonds of amides was achieved via nickel/copper catalysis under atmospheric O2 with the assistance of a bidentate directing group. The sp(2) C-H functionalization showed high regioselectivity and good functional group compatibility. The sp(3) C-H functionalization showed high site-selectivity by favoring the C-H bonds of alpha methyl groups over those of the alpha-methylene, beta- or gamma-methyl groups. Moreover, this reaction showed a predominant preference for functionalizing the alpha-methyl over alpha-phenyl group. Mechanistic studies revealed that nickel/copper synergistic catalysis is involved in this process. PMID- 25815530 TI - Approved Drugs Containing Thiols as Inhibitors of Metallo-beta-lactamases: Strategy To Combat Multidrug-Resistant Bacteria. AB - Resistance to beta-lactam antibiotics can be mediated by metallo-beta-lactamase enzymes (MBLs). An MBL inhibitor could restore the effectiveness of beta-lactams. We report on the evaluation of approved thiol-containing drugs as inhibitors of NDM-1, VIM-1, and IMP-7. Drugs were assessed by a novel assay using a purchasable fluorescent substrate and thermal shift. Best compounds were tested in antimicrobial susceptibility assay. Using these orthogonal screening methods, we identified drugs that restored the activity of imipenem. PMID- 25815532 TI - Correlated visible-light absorption and intrinsic magnetism of SrTiO3 due to oxygen deficiency: bulk or surface effect? AB - The visible-light absorption and luminescence of wide band gap (3.25 eV) strontium titanate (SrTiO3) are well-known, in many cases, to originate from the existence of natural oxygen deficiency in the material. In this study based on density functional theory (DFT) calculations, we provide, to the best of our knowledge, the first report indicating that oxygen vacancies in the bulk and on the surfaces of SrTiO3 (STO) play different roles in the optical and magnetic properties. We found that the doubly charged state of oxygen vacancy (VO(2+)) is dominant in bulk SrTiO3 and does not contribute to the sub-band gap photoexcitation or intrinsic magnetism of STO. Neutral oxygen vacancies (VO(0)) on (001) surfaces terminated with both TiO2 and SrO layers induce magnetic moments, which are dependent on the charged state of VO. The calculated absorption spectra for the (001) surfaces exhibit mid-infrared absorption (<0.5 eV) and sub-band gap absorption (2.5-3.1 eV) due to oxygen vacancies. In particular, VO(0) on the TiO2-terminated surface has a relatively low formation energy and magnetic moments, which can explain the recently observed spin dependent photon absorptions of STO in a magnetic circular dichroism measurement [Rice, W. D.; et al. Nat. Mater.13, 481, 2014]. PMID- 25815533 TI - Soft Nanocomposites--From Interface Control to Interphase Formation. AB - We report measurements of structure, mechanical properties, glass transition temperature, and contact angle of a novel nanocomposite material consisting of swellable silsesquioxane nanoparticles with grafted poly(ethyl methacrylate) (PEMA) brushes and PEMA matrices with varying molecular weight. We measured the interparticle distance at the surface of the composites using scanning probe microscopy (SPM) and in the bulk of ~0.5 MUm thick films by grazing incidence small angle X-ray scattering (GISAXS). For a given molecular weight of the brush unstable dispersions at high molecular weight of the matrix indicate an intrinsic incompatibility between polymer-grafted-nanoparticles and homopolymer matrices. This incompatibility is affirmed by a high contact angle between the polymer grafted-nanoparticles and the high molecular weight matrix as measured by SPM. For unstable dispersions, we measured a decreased glass transition temperature along with a decreased plateau modulus by dynamic mechanical thermal analysis (DMTA) which indicates the formation of a liquid-like layer at the brush-matrix interface. This proves the ability to decouple the structural and mechanical properties from the potential to be swollen with small molecules. It opens a new area of use of these soft nanocomposites as slow release materials with tailored mechanical properties. PMID- 25815531 TI - A Hidden State in Light-Harvesting Complex II Revealed By Multipulse Spectroscopy. AB - Light-harvesting complex II (LHCII) is pivotal both for collecting solar radiation for photosynthesis, and for protection against photodamage under high light intensities (via a process called nonphotochemical quenching, NPQ). Aggregation of LHCII is associated with fluorescence quenching, and is used as an in vitro model system of NPQ. However, there is no agreement on the nature of the quencher and on the validity of aggregation as a model system. Here, we use ultrafast multipulse spectroscopy to populate a quenched state in unquenched (unaggregated) LHCII. The state shows characteristic features of lutein and chlorophyll, suggesting that it is an excitonically coupled state between these two compounds. This state decays in approximately 10 ps, making it a strong competitor for photodamage and photochemical quenching. It is observed in trimeric and monomeric LHCII, upon re-excitation with pulses of different wavelengths and duration. We propose that this state is always present, but is scarcely populated under low light intensities. Under high light intensities it may become more accessible, e.g. by conformational changes, and then form a quenching channel. The same state may be the cause of fluorescence blinking observed in single-molecule spectroscopy of LHCII trimers, where a small subpopulation is in an energetically higher state where the pathway to the quencher opens up. PMID- 25815534 TI - Highly ordered binary assembly of silica mesochannels and surfactant micelles for extraction and electrochemical analysis of trace nitroaromatic explosives and pesticides. AB - The rapid and sensitive detection of nitroaromatic compounds is of great significance for human health, the environment, and public security. The present work reports on the extraction and electrochemical analysis of trace nitroaromatic compounds, such as explosives and organophosphate pesticides (OPs), using the indium tin oxide (ITO) electrodes modified with a highly ordered and aligned binary assembly of silica mesochannels and micelles (BASMM). With a pore diameter of ca. 2-3 nm, silica mesochannels (SMs) perpendicularly oriented to the ITO electrode surface can provide hard and robust supports to confine the soft cylindrical micelles formed by the aggregation of cationic surfactants, namely, cetyltrimethylammonium bromide (CTAB). Due to the organized self-assembly of hydrocarbon tails of CTAB surfactants, each micelle has a hydrophobic core, which acts as an excellent adsorbent for rapid extraction and preconcentration of trace nitroaromatic compounds from aqueous solutions via the hydrophobic effect. Furthermore, the cylindrical micelles are directly in contact with the underlying electrode surface, to which extracted compounds can freely diffuse and then be reduced therein, thus allowing their determination by means of voltammetry. Using the BASMM/ITO sensor, electrochemical analysis of trace nitroaromatic explosives, including 2,4,6-trinitrotoluene (TNT), 2,4,6-trinitrophenol, 2,6-dinitrotoluene, 3-nitrophenol, and nitrobenzene, and OPs, such as paraoxon, methyl parathion, and fenitrothion, was achieved with a fast response, wide linear range, high sensitivity, and low detection limit at the ppb level. TNT and paraoxon in real apple, tea, and water samples were also determined. By combining the heterogeneous extraction and determination in one ordered binary nanostructure, the BASMM sensor provides a very simple, rapid, and cost-effective way for analysis of nitroaromatic compounds and can be extended to a wide range of lipophilic yet redox-active analytes. PMID- 25815535 TI - Pregnancy in kidney transplanted women: what are the optimal conditions for a better pregnancy outcome? AB - BACKGROUND: Motherhood has long been not recommended for kidney transplanted women for fear of adverse effects on the graft and the risks to the fetus. AIMS: This article aimed to provide evidence based answer to the following questions regarding pregnancy in kidney transplanted women: 1. what are the nephrologic and obstetrical parameters that can influence the pregnancy outcome? 2. What is the impact of pregnancy on graft? 3. What are the optimal conditions for pregnancy planning in kidney transplanted women? METHODS: A literature search was conducted using as key words "pregnancy", "renal transplant", "renal graft survival" in the PubMed database over the period from January 1994 to December 2011. RESULTS: Recovery of renal function in kidney transplanted patients is followed by restoration of endocrine function. Knowledge of the initial nephropathy assesses the risk of recurrence after transplantation, which may affect the graft. Chronic glomerular nephropathies are the most frequent from 32 to 76.1%. Duration of hemodialysis (over 2 years) is associated with a risk of preterm delivery and growth retardation. A period of 1 year between renal transplantation and conception seems reasonable to stabilize renal function and reduce the doses of immunosuppressants. The number of unintended pregnancies remains high (50%). The incidence of pregnancy after renal transplantation varies between 3 and 21.2%. Graft survival in patients who carried a pregnancy is equivalent to that of patients who were not pregnant. CONCLUSIONS: Pregnancy in kidney transplanted patients is a highrisk pregnancy, but it does not seem to affect graft function through certain conditions. PMID- 25815537 TI - [Audit of sterilization practices in two Tunisian hospitals: current situation and perspectives]. AB - BACKGROUND: In most Tunisian hospitals, medical devices (MD) are sterilized at surgical or medicine departments. AIM: to overview during one month the practice of sterilization. aterial METHODS: An audit of practices through direct observation was carried out at the neonatology and gynaecology departments at the Maternity and Neonatology Center of Tunis and the surgical department at the Salah Azaiz Institute. An assessment grid has been defined and the non-compliance rates have been calculated. A score has been drawn for four evaluation categories of MD treatment. 123 criteria were assessed. RESULTS: The level of non-compliance ranges from 53% to 62% depending on the department. Scores interpretation underlines that the present situation is behind the required level of safety. Traceability stands at the most critical position. Staff and environment safety present scores of 26/54 and 28/62 respectively for the Maternity and Neonatology Center of Tunis and the Salah Azaiz Institute. The less critical situation is that of patient safety, even if it is far below the expected level. CONCLUSION: This audit has highlighted major malfunctions in the sterilization process. This is related to the absence of a strict regulation. A corrective action plan has been implemented for the short, medium and long terms. PMID- 25815536 TI - [Weekly variation of sudden cardiac death in northen Tunisia]. AB - BACKGROUND: The sudden cardiac death remains a major public health problem. Several studies have reported weekly variation of this dramatic event. AIM: The aim of this work is to determine the day-of-week variability in sudden cardiac death in northen Tunisia. METHODS: We prospectively collected clinical, socio demographic and autopsic data of victims of sudden cardiac death occurring in the northern Tunisia between october 1 st ,2010 and september 30,2012. RESULTS: The study population included 392 men and 108 women with a mean age of 52.27 + / - 15.8 years. Three quarters of the victims was sedentary, 57.9% were smoker and a family history of sudden death was identified in 9.8% of cases. The vast majority of deaths had occurred either in a public place (41.4%) or at home (36.6%). Ischemic heart disease was the leading cause of death with 267 cases (53.4%); however a negative autopsy was found in 13.9% of victims. The highest sudden death occurrence was on Sundays (17.8%) and the lowest on Mondays (11.4% p: 0.01).The same weekly variation was noted among both men and women , and also in victims > 60 years, a minimum of events occurred on Mondays (11.6%) and a maximum on Sundays (21.9%). In addition, we found the same peak of mortality on Sunday (18.8%) in young adults and the nadir on Monday (10.3%). CONCLUSIONS: The present study demonstrates marked variation in the occurrence of sudden cardiac death in the northern Tunisia with peak on Sundays and nadir on Mondays. No age or gender- related differences were found in weekly variation of sudden death. PMID- 25815538 TI - [Schizophrenia and education: about 32 Tunisian students suffering from schizophrenia]. AB - AIM: To study the schooling among school and university students suffering from schizophrenia. METHODS: A retrospective, descriptive and analytic study based on information from medical records of patients treated in Psychopedagogy Unit in psychiatry department "B" of the Hedi Chaker Hospital University of Sfax, during the period from 1995 to 2009. Inclusion criteria were: diagnosis of schizophrenia (DSM-IV-TR) and follow-up duration of at least one year. RESULTS: Thirty-two patients were included. The sex ratio (M/F) was 2.2. The average age was 20.7 years at the first consultation and 19.17 years at the disease onset which was insidious in 75% of cases. Undifferentiated (46.8%) and paranoid (31.2%) were the most frequent types of schizophrenia. The education level at the disease onset was secondary (62.5%) and high (37.5%). The school results were low in 62.5%. Patients who received at least one blank year were 56.3% and those who were reoriented 12.5%. They dropped out in 75% of cases. Grade repetition after the onset of schizophrenia (53.1%) was correlated with two factors: low socioeconomic status (p= 0.008) and conventional antipsychotic treatment (p= 0.021). CONCLUSION: Our results confirm the negative impact of schizophrenia on the normal course of schooling. Collaboration between psychiatrist, school doctor and teacher becomes a necessity to guarantee early schizophrenia diagnosis and adequate medical and educational care. PMID- 25815539 TI - [Cutaneous melanoma: about 200 cases]. AB - AIM: To analyze the clinical and pathological aspects of cutaneous melanoma and to determine the prognostic factors. METHODS: This is a retrospective study about 200 cases of cutaneous melanoma collected in Salah Azaiz Institute over a period of 36 years (1969-2005). RESULTS: The mean age was 55.4 years, with a slight female predominance. The tumour was developed on a pre-existent lesion in 31.5% of cases. The average delay of consultation was 18 months. The mean tumor size was 37 mm (10-180 mm). The ulcero exophytic appearance represented 45% of the cases. The tumor was metastatic in 19.5 % of cases. Hands and feet represented 53% of the tumour localizations. The treatment was curative in 71% of cases and palliative in 13% of cases. The lymph node dissection was performed in 59% of the patients. Histologically, nodular melanoma and Grade V of Clark represented 43.5 and 35% of the cases, respectively. The mean tumoral thickness was 14 mm. Chemotherapy, immunotherapy and radiotherapy were performed in 5.5%, 3.5% and 5.5% of cases respectively. The lymph node recurrences were noted in 43.6% of the patients treated with curative intent. The mean recurrence free survival was 76 months. Tumour size > 2 cm, the localization on the leg, Clark level invasion IV and the involvement of the tumour margin were significant prognostic factors for the recurrence free survival. The prognostic factors for the metastasis free survival were: tumour size, tumour localization, type of resection and finally the lymph node dissection. The 5-year overall survival was 28.5% and was influenced significantly by the tumour size, tumour localization, type of resection, involvement of the tumour margins, Clark grade, tumour thickness and finally the lymph node involvement. CONCLUSION: The dismal prognosis can be improved by early diagnosis and especially the prevention based on the photo protection and surveillance of patients at high risk. PMID- 25815540 TI - [Bacteriological aspects of catheter cultures: study over 24 months]. AB - BACKGROUND: Catheter-related infections are the sixth leading cause of nosocomial infections with approximately 7% of cases. AIM: The aim of this work was to establish the bacterial epidemiology of the catheter and TIC culture (totally implantable catheter) at the Mohamed V Military Teaching Hospital (MVHMI), and to study the antibiotic susceptibility of bacteria isolated. METHODS: this is a retrospective study over 24 months, including the venous and arterial catheters as well as the TIC treated at the Microbiology laboratory of the MVHMI. The culture was realized by the quantitative Brun Buisson method. The antibiotic susceptibility was made according to the French Society guidelines. RESULTS: We have collected 282 cases with 255 catheters and 27 TIC. The significant rate culture was 51,42% (n=145) for catheters and TIC, including 90,43% catheters and 9,57% TIC. These catheters and TIC with positive culture emanated primarily from hemodialysis (32,41%) and surgical intensive care unit (28,97%) services. The microorganisms distribution by species showed the prevalence of Staphylococcus aureus (15,91%) followed by Acinetobacter baumannii (14,77%) and Pseudomonas aeruginosa (7,39%). The meticilline resistance rate in Staphylococcus aureus was 7,14%. The Acinetobacter baumannii resistance rate was 64%, and 80,8% for imipenem and ceftazidime respectively. The rate of resistance of Pseudomonas aeruginosa to imipenem and ceftazidime was 69.23% for each. CONCLUSION: The bacterial epidemiology of the catheters and TIC cultures is dominated by the potentially nosocomial bacteria. Multidrug resistance of A. baumannii and P. aeruginosa requires an improved catheters management and strengthening nosocomial infections prevention. PMID- 25815541 TI - [Dietary intake in Crohn's disease: results of a prospective comparative study]. AB - BACKGROUND: Diet is thought to have an important role in the etiopathogenesis of Crohn's disease. In the other hand, Crohn's disease is frequently associated with nutritional deficiencies probably as result of disease activity and poor oral intake. AIMS: To investigate the dietary intake in patients with Crohn's disease in comparison with matched population controls and to assess the correlation between the results of the dietary enquete, nutritional status and disease activity. METHODS: We conducted a prospective case control study in patients with Crohn's disease and matched controls. All subjects were evaluated in respect of dietary intake (based on "NUTISTAR" logiciel) and nutritional status. RESULTS: We studied 23 patients and 23 controls. There was no statistical difference between patients and controls according to the proportion of carbohydrates, fat and protein intakes. Energy intakes were significantly lower in patients with Crohn's disease (1991 + 678 kcal/j) compared to controls (2537 + 345 kcal/j) (p=0.007) ; and in active disease (1353 + 308 kcal/j) compared to inactive disease patients (2481 + 415 kcal/j) (p<0.0001). In Crohn's disease patients, correlation study showed that energy intakes were correlated with CDAI (p<0.0001 ; r = - 0.74) and BMI (p=0.03 ; r = 0.45). CONCLUSION: In Crohn's disease, an inadequate dietary intake is correlated with nutritional status and disease activity. PMID- 25815542 TI - [Socio-medical profile of post-polio syndrome patients in center east of Tunisia]. AB - BACKGROUND: The diagnosis of the post polio syndrome is purely clinic. It occurs few decade after poliomyelitis. It associates recent appearance or progressive worsening of muscular weakness, pain, muscular fatigue or atrophy. It remains not recognized in Tunisia. AIM: of our study is to identify the socio-medical profile of the postpolio population in the Tunisian east central region through a check of the risk factors and the clinical characteristics of these patients. METHODS: Descriptive study analyzing 32 files (medical expertise) of post polio syndrome patients RESULTS: The risk factors of post polio syndrome such us female gender, obesity, low educational level, early age of poliomyelitis appearance and the importance of physical effort at work, were observed in our study and are in agreement with the literature data. Average delay of post polio syndrome occurrence was 40 years. Most Disturbing symptom was the muscular pain. All our patients indicated negative impact on their everyday life and their work. They all asked for their right for incapacity or long-term disease beside the National health insurance fund (CNAM). CONCLUSION: Recognition of patients affected by the Post polio syndrome and their social and medical needs are necessary. PMID- 25815543 TI - [National survey of maternal mortality of 2010 : data of Tunisia]. AB - BACKGROUND: Tunisia has investigated maternal mortality in 2010 to determine maternal mortality ratio (MMR) nationally and regionally, in addition to the indentifying main causes of this mortality. OBJECTIVES: Describe methodology of this study and its principal findings in the region of Tunis and discuss the national maternal mortality strategy. METHODOLOGY: This is a Ramos study (Reproductive Ag Mortality Studies) that consists on identifying maternal deaths from reproductive age group (RAG) women deaths. We started by the a rehearsal and targeting of (RAG) women deaths , then we investigated a next of kin person of the decedent women by verbal autopsy, thereafter we identified maternal deaths to be confidentially investigated to judge the potential avoidability of the death. The study took place in 2010, it was carried out by 5 couples of investigators supervised by a coordinator doctor. RESULTS: A total of 200 deaths of (RAG) women were found in Tunis, 7 deaths among them were maternal deaths, that corresponds to an MMR of 41/100000 live births. The mean age of the deceased women was 35 years. The main causes of maternal deaths were hemorrhage (3/7), thrombo-embolic diseases (2 times for7) and HELLP syndrome (1/7). Four of a total of 4 deaths (3 deaths were not marked), were avoidable. The majority of late women had a satisfying educational level, 4 of 7 had financial autonomy. All of them had pregnancy monitoring, 5 times of 7 in university hospital. All the childbirth were medically assisted, Caesarean section was carried in 6 of 7 cases. Nationally, the MMR was estimated to 44.8/100 000 LB, that to say a decrease of 35% compared to 1993. The decrease was significant for all the regions of the country, except the great Tunis where opposite trend was recorded. This could be more likely related to quality of care rather than socio-economic conditions seeing that social determinants in Tunis are favorable. In fact, the Tunisian maternal mortality strategy had essentially focused on the monitoring system of maternal deaths rather than the quality of care improvement interventions, results were disappointing due to the lack of institutional engagement. The achievement of the OMD5 objectives is compromised, due to socio-economic constraint especially in certain regions, poor governance and lack of engagement of ministry of health in reducing maternal mortality. CONCLUSION: Tunisian maternal mortality strategy should be revised and adapted to regional context, also should includ multisectoral interventions. Priority would be given to quality of care improvement, by launching the experience of care setting accreditation in one hand, and in the other improving partnership between different levels of care. PMID- 25815544 TI - [Cervical spondylodiscitis in hospital environment in Lome (Togo)]. AB - BACKGROUND: The spine is a frequent site of infection but cervical spine localization seems to be rare. OBJECTIVE: to determine the frequency and features of cervical spondylodiscitis in patients attending the Sylvanus Olympio University Hospital Center in Togo. METHODS: A retrospective study of patients hospitalized in the Department of Rheumatology over a 20-year period was conducted. The positive diagnosis of infectious spondylodiscitis has been clinical and radiological. The etiological presumption was founded on clinical and epidemiological arguments. RESULTS: Of the 2881 patients hospitalized, 356 had infectious spondylodiscitis of which 15 cases of cervical spondylodiscitis (eight men and seven women). The average age of these 15 patients was 37 years at the onset of the disease of which the mean disease duration was six months. The disease was essentially located at the levels of C3C4 (seven patients) and C5C6 (four patients). Spondylodiscitis was related to presumptive tuberculosis in 10 patients and banal germ in the remaining five others. There were three HIV infected patients. The onset of the symptomatology was progressive in all the 10 patients suffering from tuberculosis spondylodiscitis. The symptomatology has been characterized by inflammatory pains (10 patients), mechanic pains (five patients), and a gibbosity (four patients). CONCLUSION: This study attests of the scarcity of the cervical spondylodiscitis. PMID- 25815545 TI - [Prevalence of specific learning disorders in a cohort of children with school failure]. AB - BACKGROUND: Specific learning disorders (SLD) are poorly known and studied in Tunisia. A National research project on their prevalence was launched recently. Aim of this study was to estimate prevalence of SLD in a cohort of children with school failure. METHODS: Cross-sectional descriptive study with a population of 287 First and Third grade Primary School students, screened by their teachers as facing learning problems through a systematic screening process based on achievement and behavior. Multidisciplinary assessment consisted in general medical examination, child psychiatry, child neurology, speech therapy and psychology (cognitive). 180 students have been assessed. RESULTS: Prevalence of SLD over study population was 32%, which gives a general population prevalence 6.4%. Most common SLDs were dyslexia and dyscalculia. Most of children with SLD came from disadvantaged social groups. CONCLUSION: Despite methodological limitations, this first study on SLD sheds some light on their prevalence in Tunisian students, and opens perspectives for future more focused studies and interventions for their management in Tunisia. PMID- 25815546 TI - Applicability of the Old European Respiratory Society/European Community for Steel and Coal reference equations for spirometry interpretation in Tunisian adult population. AB - BACKGROUND: Tunisian pulmonary functional laboratories accept the default settings for reference equations (European Respiratory Society/European Community for Steel and Coal (ERS/ECSC1983) offered by the manufacturer even though adult Tunisian reference equations (Tunisian1995) are available. OBJECTIVE: To compare the spirometric profile of Tunisian subjects, according to the two reference equations. POPULATION AND METHODS: Spirometric data were recorded from 1192 consecutive spirometry procedures in adults aged 18-60 years. Reference values and lower limits of normality (LLN) were calculated using the two reference equations. Applied definitions: large airway obstructive ventilatory defect (LAOVD): ratio between the 1st second expiratory volume and forced vital capacity (FEV1/FVC) < LLN. Small AOVD (SAOVD): FEV1/FVC > LLN and FVC > LLN and maximal midexpiratory flow < LLN. Tendency through a restrictive ventilatory defect (TRVD): FEV1 and FVC < LLN. The spirometric profile, according the two reference equations, was determined. RESULTS: Using Tunisian1995 reference equations, 34%, 7%, 37% and 19% of spirometry records were interpreted as normal, and as having, LAOVD, SAOVD and TRVD, respectively. Using ERS/ECSC1983 reference equations, 85%, 3%, 9% and 2% of spirometry records were interpreted as normal, and as having, LAOVD, SAOVD and TRVD, respectively. Using the ERS/ECSC1983 reference equations, misclassification was worse for LAOVD, for SAOVD and for TRVD, respectively, 68%, 94% and 89%. CONCLUSION: Our results showed that the use of the old Caucasian reference equations resulted in misinterpretation of spirometry data in a significant proportion of subjects. This could result in inappropriate diagnosis and/or management. PMID- 25815547 TI - [Acute steroid-induced psychosis in active microscopic polyangiitis]. PMID- 25815548 TI - Unusual and extensive presentation of Merkel cell carcinoma. PMID- 25815549 TI - [Malignant external otitis due to Aspergillus niger in leukemic patient: a case report]. PMID- 25815550 TI - [Diffuse calcinosis complicating an adult onset dermatomyositis]. PMID- 25815551 TI - [Example of traveler's pathology: atypical boil-like papules]. PMID- 25815552 TI - [Chaotic atrial tachycardia of the child: a case report]. PMID- 25815553 TI - Epilepsy, pemphigus and celiac disease: an exceptional association. PMID- 25815554 TI - [Implantation of appendix on cecal diverticulum: a rare variant anatomy]. PMID- 25815555 TI - [The mediastinum: an unusual location of synovial sarcoma]. PMID- 25815556 TI - [Rupture of splenic artery aneurysm during pregnancy: a diagnosis not to be missed]. PMID- 25815557 TI - [Wegener's granulomatosis revealed by an involvment of the lacrimal gland]. PMID- 25815558 TI - [Atypic central serous chorioretinopathy in patient treated by systemic corticosteroid therapy]. PMID- 25815559 TI - Amine-Functionalized Titanate Nanosheet-Assembled Yolk@Shell Microspheres for Efficient Cocatalyst-Free Visible-Light Photocatalytic CO2 Reduction. AB - Exploiting advanced semiconductor photocatalyst with superior activity and selectivity for the conversion of CO2 into solar fuels and valuable chemicals is of worldwide interest. In this report, hierarchical amine-functionalized titanate nanosheets based yolk@shell microspheres were synthesized via one-pot organic amine mediated anhydrous alcoholysis of titanium(IV) butoxide. The selected organic amine, diethylenetriamine, played multiple roles. First, it was essential for the crystallographic, morphological and textural control of the synthesized titanate nanoarchitectures. Second, it was crucial for the in situ functionalization of titanate nanosheets by concurrent interlayer intercalation and surface grafting, which gave rise to the strong visible-light absorption ability and high CO2 adsorption capacity. As a consequence of the synergetic tuning in multilevel microstructures, an integrated engineering of the multifunctional modules of the titanate-based photocatalysts was achieved for efficient CO2 reduction toward solar fuels. PMID- 25815560 TI - Numts: an impediment to DNA barcoding of Polyclinids, Tunicata. AB - The mitochondrial cytochrome c oxidase subunit I (COI) gene, a widely accepted molecular marker for species identification and classification, has been questioned because of the presence of Numts. In this study we found the presence of Numts in the COI chromatogram of two tunicates, Polyclinum indicum and Polyclinum madrasensis belonging to the genus Polyclinum. Numts were also present in our sequence (Accession Number: KJ944391) and in other sequences belonging to genus Polyclinum in the GenBank record. The GeneBank database of genus Polyclinum contains COI-like sequences and COI pseudogenes, but no record of COI gene from Polyclinids. The prevalence of Numts in Polyclinids belonging to Tunicata, is an impediment to DNA barcoding studies of Polyclinum species. PMID- 25815561 TI - The complete mitochondrial genome of the white-rot fungus Ganoderma meredithiae (Polyporales, Basidiomycota). AB - Complete nucleotide sequence of the 78,447 bp mitochondrial genome of the white rotting fungus Ganoderma meredithiae Adask. & Gilb. has been determined by next generation sequencing technology. The circular molecule encodes a set of mitochondrial protein and RNA genes, including 15 conserved proteins, 29 tRNAs, large and small ribosomal RNAs, and 18 homing endonucleases, with a GC content of 26.14%. All structural genes are located on the same strand except trnW-CCA. Compared with previously sequenced mtDNAs of G. lucidum and G. sinense, the gene order of protein and rRNA genes among the three mitogenomes is highly conserved; however, the tRNA composition is slightly different. The mitochondrial genome of G. meredithiae will contribute to understanding the phylogeny and evolution of Ganoderma and Ganodermataceae, the group containing many species with high medicinal values. PMID- 25815562 TI - van der Waals Interactions on the Mesoscale: Open-Science Implementation, Anisotropy, Retardation, and Solvent Effects. AB - The self-assembly of heterogeneous mesoscale systems is mediated by long-range interactions, including van der Waals forces. Diverse mesoscale architectures, built of optically and morphologically anisotropic elements such as DNA, collagen, single-walled carbon nanotubes, and inorganic materials, require a tool to calculate the forces, torques, interaction energies, and Hamaker coefficients that govern assembly in such systems. The mesoscale Lifshitz theory of van der Waals interactions can accurately describe solvent and temperature effects, retardation, and optically and morphologically anisotropic materials for cylindrical and planar interaction geometries. The Gecko Hamaker open-science software implementation of this theory enables new and sophisticated insights into the properties of important organic/inorganic systems: interactions show an extended range of magnitudes and retardation rates, DNA interactions show an imprint of base pair composition, certain SWCNT interactions display retardation dependent nonmonotonicity, and interactions are mapped across a range of material systems in order to facilitate rational mesoscale design. PMID- 25815563 TI - The influence of day care centres for people with dementia on family caregivers: an integrative review of the literature. AB - OBJECTIVES: Day care centres (DCC) for people with dementia (PWD) have received increased attention recently, due to a shift in policy from the use of residential care towards home-based services. The aim of this study is to provide an extended understanding of the influence of DCCs on family caregivers (FCs). METHOD: An integrative review including 19 studies was used: qualitative (n = 2), quantitative non-randomised (n = 8), quantitative descriptive studies (n = 7), and with mixed-method design (n = 2). The quality of the studies was evaluated by the mixed-methods appraisal tool (MMAT). RESULTS: FC experienced the DCC both as a respite service, and to some extent as a support service, improving their competence in caring for the PWD. The quality of the DCC influenced its use, and the FC's motivation to care for the PWD. FC's gender, role, individual needs, PWD behavioural problems and need for assistance played an important role. CONCLUSION: As a respite and support service, DCCs have the potential to give FCs a feeling of safety and relief, reduce the caregiver's burden, and increase their motivation towards their role as caregivers. These outcomes depend on the quality of treatment, and how the service meets the FC's needs for flexibility, support, information, and responsibility sharing. PMID- 25815564 TI - Major depression and electrovestibulography. AB - OBJECTIVES: No electrophysiological neuroimaging or genetic markers have been established that strongly relate to a diagnosis of major depression or its severity. The objective of this paper is to describe the preliminary evaluation of a potential new biomarker for depression utilizing the recording of electrical activity from the outer ear canal referred to as electrovestibulography (EVestG). METHODS: Sensory oto-acoustic features were extracted from EVestG data to compare 31 healthy age- and gender-matched individuals as controls to 43 major depressive disorder (MDD) subjects (22 symptomatic (MDD-S), 21 reduced symptomatic (MDD-R)). The stimulus was a single supine-vertical translation. The six features examined were based on the measured firing pattern interval histogram and the shape of the average field potential response. RESULTS: An unbiased classification accuracy of 85, 87 and 77% was achieved for separating Control from MDD-S, Control from MDD, and MDD-S from MDD-R groups respectively. Features used showed low but significant correlations (P < 0.05) with MADRS and CORE assessments. CONCLUSIONS: The results support the use of separate features for measuring MDD symptomatology versus diagnosing MDD, representing plausible different mechanisms of brain function in MDD-S and MDD-R. The first evidence of the successful application of sensory oto-acoustic features toward diagnosing and measuring the symptomatology of MDD is presented. PMID- 25815570 TI - Effect of dantrolene premedication on various cardiovascular and biochemical variables and the recovery in healthy isoflurane-anesthetized horses. AB - OBJECTIVE: To determine the effect of dantrolene premedication on various cardiovascular and biochemical variables and recovery in isoflurane-anesthetized horses. ANIMALS: 6 healthy horses. PROCEDURES: Each horse was anesthetized twice with a 21- to 28-day washout period between anesthetic sessions. Food was not withheld from horses before either session. During each session, dantrolene (6 mg/kg in 2 L of water) or water (2 L) was administered via a nasogastric tube 1 hour before anesthesia was induced. Anesthesia was maintained with isoflurane for 90 minutes, during which blood gas analyses and lithium-dilution cardiac output (CO) measurements were obtained every 10 minutes. Serum creatine kinase activity was measured before and at 4, 8, and 12 hours after anesthesia. RESULTS: When horses were premedicated with dantrolene, CO at 25, 35, and 45 minutes after induction of anesthesia was significantly lower than that when horses were premedicated with water after which time difficulty in obtaining valid measurements suggested a continued decrease in CO; plasma potassium concentration progressively increased during anesthesia, whereas serum creatine kinase activity remained fairly stable and within reference limits through 12 hours after anesthesia; and 2 of 6 horses developed cardiac arrhythmias that required medical intervention. The quality of anesthetic recovery was slightly better when horses were premedicated with dantrolene versus water, although the time required for recovery did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that dantrolene premedication prevented muscle damage without affecting anesthetic recovery but impaired CO and precipitated hyperkalemia and cardiac arrhythmias in healthy isoflurane anesthetized horses. PMID- 25815565 TI - Lower brain-derived neurotrophic factor levels associated with worsening fatigue in prostate cancer patients during repeated stress from radiation therapy. AB - OBJECTIVES: Fatigue during cancer treatment is associated with depression. Neurotrophic factors play a major role in depression and stress and might provide insight into mechanisms of fatigue. This study investigated the association between plasma concentrations of three neurotrophic factors (BDNF, brain-derived neurotrophic factor; GDNF, glial-derived neurotrophic factor; and SNAPIN, soluble N-ethylmaleimide sensitive fusion attachment receptor-associated protein) and initial fatigue intensification during external beam radiation therapy (EBRT) in euthymic non-metastatic prostate cancer men. METHODS: Fatigue, as measured by the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and plasma neurotrophic factors were collected at baseline (prior to EBRT) and mid-EBRT. Subjects were categorized into fatigue and no fatigue groups using a > 3-point change in FACT-F scores between the two time points. Multiple linear regressions analysed the associations between fatigue and neurotrophic factors. RESULTS: FACT F scores of 47 subjects decreased from baseline (43.95 +/- 1.3) to mid-EBRT (38.36 +/- 1.5, P < 0.001), indicating worsening fatigue. SNAPIN levels were associated with fatigue scores (rs = 0.43, P = 0.005) at baseline. A significant decrease of BDNF concentration (P = 0.008) was found in fatigued subjects during EBRT (n = 39). CONCLUSIONS: Baseline SNAPIN and decreasing BDNF levels may influence worsening fatigue during EBRT. Further investigations are warranted to confirm their role in the pathophysiology and therapeutics of fatigue. PMID- 25815571 TI - Neuromuscular blocking effects of vecuronium in dogs with autosomal-recessive centronuclear myopathy. AB - OBJECTIVE: To evaluate the potency of vecuronium and duration of vecuronium induced neuromuscular blockade in dogs with centronuclear myopathy (CNM). ANIMALS: 6 Labrador Retrievers with autosomal-recessive CNM and 5 age- and weight matched control dogs. PROCEDURES: Dogs were anesthetized on 2 occasions (1-week interval) with propofol, dexmedetomidine, and isoflurane. Neuromuscular function was monitored with acceleromyography and train-of-four (TOF) stimulation. In an initial experiment, potency of vecuronium was evaluated by a cumulative-dose method, where 2 submaximal doses of vecuronium (10 MUg/kg each) were administered IV sequentially. For the TOF's first twitch (T1), baseline twitch amplitude and maximal posttreatment depression of twitch amplitude were measured. In the second experiment, dogs received vecuronium (50 MUg/kg, IV) and the time of spontaneous recovery to a TOF ratio (ie, amplitude of TOF's fourth twitch divided by amplitude of T1) >= 0.9 and recovery index (interval between return of T1 amplitude to 25% and 75% of baseline) were measured. RESULTS: Depression of T1 after each submaximal dose of vecuronium was not different between groups. Median time to a TOF ratio >= 0.9 was 76.7 minutes (interquartile range [IQR; 25th to 75th percentile], 66.7 to 99.4 minutes) for dogs with CNM and 75.0 minutes (IQR, 47.8 to 96.5 minutes) for controls. Median recovery index was 18.0 minutes (IQR, 9.7 to 23.5 minutes) for dogs with CNM and 20.2 minutes (IQR, 8 to 25.1 minutes) for controls. CONCLUSIONS AND CLINICAL RELEVANCE: For the study dogs, neither potency nor duration of vecuronium-induced neuromuscular blockade was altered by CNM. Vecuronium can be used to induce neuromuscular blockade in dogs with autosomal-recessive CNM. PMID- 25815572 TI - Renal, gastrointestinal, and hemostatic effects of oral administration of meloxicam to Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To investigate renal, gastrointestinal, and hemostatic effects associated with oral administration of multiple doses of meloxicam to healthy Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS: 12 Hispaniolan Amazon parrots. PROCEDURES: Birds were assigned to receive meloxicam oral suspension (1.6 mg/kg, PO, q 12 h) and 2.5 mL of tap water inserted into the crop by use of a gavage tube (n = 8) or the equivalent volume of tap water only (control group; 4) for 15 days. Urine and feces were collected 2 hours after treatment administration each day. Feces were evaluated for occult blood. Results of a CBC and serum biochemical analysis and measured N-acetyl-beta-d-glucosaminidase (NAG) activity and whole blood clotting time were evaluated before, during, and after completion of treatments. Results of urinalysis and measured urine NAG activity were also evaluated. RESULTS: Birds treated with meloxicam had a significant increase in number of WBCs and decrease in PCV from before to after treatment. The PCV also decreased significantly, compared with results for the control group; however, WBC count and PCV for all birds remained within reference ranges throughout the study. One parrot treated with meloxicam had a single high value for urine NAG activity. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam administered orally at the dosage used in this study caused no apparent negative changes in several renal, gastrointestinal, or hemostatic variables in healthy Hispaniolan Amazon parrots. Additional studies to evaluate adverse effects of NSAIDs in birds will be needed. PMID- 25815573 TI - Application of in vivo microdialysis for investigation of unbound drug concentrations of intravenously administered sulfadimidine in the paranasal sinus mucosa of horses. AB - OBJECTIVE: To monitor concentrations of sulfadimidine in the paranasal sinus mucosa (PSM) of unsedated horses following IV administration of trimethoprim sulfadimidine via in vivo microdialysis. ANIMALS: 10 healthy adult horses. PROCEDURES: Concentric microdialysis probes were implanted into the subepithelial layers of the frontal sinus mucosa of standing sedated horses. Four hours after implantation, trimethoprim-sulfadimidine (30 mg/kg) was administered IV every 24 hours for 2 days; dialysate and plasma samples were collected at intervals during that 48-hour period and analyzed for concentrations of sulfadimidine. The dialysate concentration and relative loss of sulfadimidine from the perfusate were used to calculate the PSM concentration. RESULTS: Microdialysis probe implantation and subsequent in vivo microdialysis were successfully performed for all 10 horses. Following the first and second administration of trimethoprim sulfadimidine, mean +/- SD peak concentrations of sulfadimidine were 55.3 +/- 10.3 MUg/mL and 51.5 +/- 8.7 MUg/mL, respectively, in plasma and 9.6 +/- 4.5 MUg/mL and 7.0 +/- 3.3 MUg/mL, respectively, in the PSM. Peak sulfadimidine concentrations in the PSM were detected at 5.9 +/- 2.7 hours and 5.4 +/- 2.3 hours following the first and second drug administrations, respectively. For 12 hours, mean PSM sulfadimidine concentration remained greater than the minimum inhibitory concentration indicative of sulfonamide susceptibility of equine bacterial isolates (4.75 MUg/mL). CONCLUSIONS AND CLINICAL RELEVANCE: In vivo microdialysis for continuous monitoring of PSM sulfadimidine concentrations in unsedated horses was feasible. Intravenous administration of trimethoprim (5 mg/kg) and sulfadimidine (25 mg/kg) proved likely to be efficient for treating sinusitis caused by highly susceptible pathogens, providing that the dosing interval is 12 hours. PMID- 25815574 TI - Platelet activation in a population of critically ill dogs as measured with whole blood flow cytometry and thromboelastography. AB - OBJECTIVE: To determine whether critically ill dogs had increased platelet activation and whether the proportion of activated platelets correlated with severity of illness. ANIMALS: 82 dogs in the intensive care unit of a veterinary teaching hospital and 24 healthy control dogs. PROCEDURES: Flow cytometry with monoclonal mouse anti-human CD61 and CD62 antibodies in resting and ADP-treated samples and kaolin-activated thromboelastography were used to compare platelet activation in blood samples of critically ill and control dogs. Serum antithrombin, von Willebrand factor, fibrinogen, and activated protein C concentrations; prothrombin time (PT); and activated partial thromboplastin time (aPTT) were measured. Revised survival prediction index, acute patient physiology and laboratory evaluation, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome scores were used to estimate severity of illness. Severity of illness scores and platelet activation measurements were compared with survival time and duration and cost of hospitalization. RESULTS: Critically ill and control dogs had no differences in platelet activation for non-ADP treated samples measured. Critically ill dogs had significantly increased platelet activation in response to 2, 6, and 10 MUM ADP. Critically ill dogs had significantly increased maximum amplitude, alpha angle, and global clot strength and significantly decreased clot formation time. Critically ill dogs had significantly increased fibrinogen concentration, PT, and aPTT and significantly decreased antithrombin concentration. Survivors and nonsurvivors had similar flow cytometry and thromboelastography values. Three dogs developed macrothrombosis. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, critically ill dogs had hyperreactive platelets, which may have contributed to a high incidence of hypercoagulability in this patient population. PMID- 25815575 TI - Effects of postexercise feeding of a supplemental carbohydrate and protein bar with or without astaxanthin from Haematococcus pluvialis to exercise-conditioned dogs. AB - OBJECTIVE: To characterize the postprandial nutrient profiles of exercise conditioned dogs fed a supplemental carbohydrate and protein bar with or without astaxanthin from Haematococcus pluvialis immediately after exercise. ANIMALS: 34 exercise-conditioned adult Husky-Pointer dogs. PROCEDURES: The study had 2 phases. During phase 1, postprandial plasma glucose concentration was determined for dogs fed a bar containing 25% protein and 18.5% or 37.4% maltodextrin plus dextrin (rapidly digestible carbohydrate; RDC), or dry kibble (30% protein and 0% RDC) immediately after exercise. During phase 2, dogs were exercised for 3 days and fed a bar (25% protein and 37.4% RDC) with (CPA; n = 8) or without (CP; 8) astaxanthin or no bar (control; 8) immediately after exercise. Pre- and postexercise concentrations of plasma biochemical analytes and serum amino acids were determined on days 1 and 3. RESULTS: Phase 1 postexercise glucose concentration was increased when dogs were provided the 37.4% RDC bar, but not 0% or 18.5% RDC. On day 3 of phase 2, the CPA group had the highest pre-exercise triglyceride concentration and significantly less decline in postexercise glucose concentration than did the CP and control groups. Mean glucose concentration for the CP and CPA groups was significantly higher than that for the control group between 15 and 60 minutes after bar consumption. Compared to immediately after exercise, branched-chain amino acid, tryptophan, leucine, and threonine concentrations 15 minutes after exercise were significantly higher for the CP and CPA groups, but were lower for the control group. CONCLUSIONS AND CLINICAL RELEVANCE: Dogs fed a bar with 37.4% RDCs and 25% protein immediately after exercise had increased blood nutrient concentrations for glycogen and protein synthesis, compared with control dogs. PMID- 25815576 TI - Effect of oral administration of cyclosporine on Toxoplasma gondii infection status of cats. AB - OBJECTIVE: To evaluate whether anti-inflammatory doses of cyclosporine activate Toxoplasma gondii in chronically infected cats or potentiate infection in cats exposed for the first time. ANIMALS: 30 T gondii-negative cats. PROCEDURES: Cats were assigned to 1 of 3 groups (10 cats/group). Group 1 (control) cats were administered a placebo for 126 days; group 2 cats were administered a placebo for 84 days, followed by cyclosporine at 7.5 mg/kg/d, PO, for 42 days; and group 3 cats were administered cyclosporine at 7.5 mg/kg/d, PO, for 126 days. Cats were orally inoculated with T gondii on day 42. Results for fecal flotations, PCR assays, and histologic examinations and IgM and IgG titers were analyzed. Cyclosporine concentrations were measured on selected days. RESULTS: All cats were infected by T gondii and developed signs of self-limiting gastrointestinal tract infection. Group 3 had the highest incidence and severity of CNS and pulmonary histopathologic findings typical of toxoplasmosis. One cat in group 3 died of systemic toxoplasmosis; that cat had a cyclosporine concentration of 1,690 ng/mL. Group 2 cats infected with T gondii before cyclosporine administration did not have repeated oocyst shedding. Group 3 cats shed fewer oocysts for a shorter time than did control cats of group 1. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of cyclosporine in accordance with the protocol for this study did not potentiate the enteroepithelial phase of T gondii infection. Cats with high cyclosporine blood concentrations at the time of primary T gondii infection may be at risk of developing systemic toxoplasmosis. PMID- 25815578 TI - Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs. AB - OBJECTIVE: To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. ANIMALS: 30 healthy adult dogs. PROCEDURES: In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. RESULTS: Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 MUg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone. PMID- 25815577 TI - Characterization of discrete equine intestinal epithelial cell lineages. AB - OBJECTIVE: To characterize epithelial cells of the small intestine and colon in horses without clinical gastrointestinal abnormalities with an emphasis on the stem cell niche constituents. SAMPLE: Mucosal biopsy specimens from small and large intestines obtained from 12 horses euthanized for reasons unrelated to gastrointestinal disease or systemic disease. PROCEDURES: Intestinal biopsy specimens were collected by sharp dissection immediately following euthanasia. Specimens were prepared for immunohistochemical, immunofluorescence, and transmission electron microscopic imaging to detect and characterize each epithelial cell type. Antibodies against protein biomarkers for cellular identification were selected on the basis of expression in other mammalian species. RESULTS: Intestinal epithelial cell types were identified by means of immunostaining and morphological characterization with transmission electron microscopy. Some differences in biomarker expression and antibody cross reactivity were identified in equine tissue, compared with other species. However, each known type of mucosal epithelial cell was identified in equine tissue. CONCLUSIONS AND CLINICAL RELEVANCE: The methodology used can enhance detection of stem cells and progenitor cells as well as postmitotic cell lineages in equine intestinal tissues. Results may have relevance to regenerative potential of intestinal mucosa and survival in horses with colic. PMID- 25815579 TI - In vitro mechanical evaluation of equine laryngeal tie-forward constructs prepared with different suture materials and placement patterns. AB - OBJECTIVE: To compare the mechanical properties of laryngeal tie-forward (LTF) constructs prepared with different suture materials and suture placement patterns during single load to failure testing. SAMPLE: Larynges harvested from 50 horse cadavers and 5 intact horse cadavers. PROCEDURES: In vitro LTF constructs were created by a standard technique with polyester sutures, a standard technique with polyethylene sutures, a modified technique with metallic implants and polyester sutures, a modified technique with metallic implants and polyethylene sutures, or a modified tie-off technique with polyester sutures (10 of each type of construct). Mechanical properties including maximal load (N) at failure and failure mode were compared among constructs. Also, maximal loads at failure of the in vitro LTF constructs were compared with the loads exerted on the sutures tightened to achieve rostral laryngeal advancement in intact cadavers. RESULTS: Constructs prepared by a standard technique with polyethylene sutures had a significantly higher pull out strength than those prepared by a modified technique with metallic implants and either polyester or polyethylene sutures. For constructs prepared by a standard technique with polyethylene sutures or similarly placed polyester sutures, maximal load at failure did not differ but the failure mode did differ significantly. The load to failure for all in vitro constructs was higher than the maximal load measured during a range of motion test in intact horse cadavers. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that LTF procedures can be performed in live horses with any of the suture materials and techniques tested. PMID- 25815581 TI - Dual-head wireless powered video capsule based on new type of receiving coils. AB - Wireless capsule endoscopy (WCE) has been a great breakthrough in visually detecting the pathological changes of gastrointestinal (GI) wall, but the limit of viewing angle and power by batteries still hinder the wide application of WCE. In order to address these shortcomings, a dual-head video capsule system based on new type of receiving coils is presented. First, the dual-head video capsule system is designed, which could capture images of the whole GI tract in two channels, transforming the images into NTSC videos at a frame rate of 30 f s(-1) and transmitting the signals outside the body. Second, the wireless power transmission platform with new type of receiving coils is established to provide at least 108 mW of continuous, stable energy for the capsule. Then a prototype was fabricated and applied in animal experiments. The designed dual-head video capsule system is proved to be feasible and a potential solution for future clinical application. PMID- 25815580 TI - Success of Laparoscopic Robot-Assisted Approaches to Ureteropelvic Junction Obstruction Based on Preoperative Renal Function. AB - BACKGROUND AND PURPOSE: No literature exists examining the risk factors for failure after robot-assisted laparoscopic pyeloplasty for ureteropelvic junction obstruction (UPJO) in children. The goal of this study was to compare the success of robot-assisted pyeloplasty between UPJO kidneys with preoperative renal function <30% versus >30%. METHODS: We performed a retrospective review of all patients who underwent a robot-assisted laparoscopic pyeloplasty for UPJO at a single institution from June 2009 to September 2013 by four surgeons. A failed procedure was defined as necessitating a second surgery for the UPJO, nonresolution of symptoms with no improvement of washout on postoperative mercaptoacetyltriglycine (MAG)-3 scan, and/or a reduction in renal function of the obstructed kidney to <10%. Success was compared between patients with <30% and >30% preoperative differential renal function via the Fisher exact test. RESULTS: There were 116 patients who were included. At a mean follow-up of 507 days after the surgical procedure, there were eight (8%) failures. The majority of the failures (5/8) were in kidneys whose preoperative function was <30%. There was a significant difference in the success of procedures performed on kidneys with >30% (86/89, 97%) versus <30% (7/12, 58%) preoperative renal function (P=0.0005). CONCLUSIONS: In this large cohort of patients, kidneys with preoperative function >30%, robot-assisted pyeloplasty had a 97% success rate. This was significantly different than the success of robot-assisted pyeloplasty (58%) in kidneys with preoperative function <30%. This information is useful for patient counseling as these patients may be at higher risk for a secondary procedure such as a subsequent nephrectomy or may benefit from a preoperative trial of nephrostomy tube drainage. PMID- 25815582 TI - Thermal ablative treatment of uterine fibroids. AB - In addition to surgical methods of treating uterine fibroids, numerous non invasive treatments have been developed. Many of these involve the use of hyperthermia, the heating of tissue by a variety of methods. These include the use of lasers, radiofrequency, microwave energy and high intensity focused ultrasound, guided by both ultrasound and magnetic resonance imaging. In this review we examine the technology behind these treatment modalities and review the current evidence for their use. PMID- 25815583 TI - Post-transcriptional regulation of satellite cell quiescence by TTP-mediated mRNA decay. AB - Skeletal muscle satellite cells in their niche are quiescent and upon muscle injury, exit quiescence, proliferate to repair muscle tissue, and self-renew to replenish the satellite cell population. To understand the mechanisms involved in maintaining satellite cell quiescence, we identified gene transcripts that were differentially expressed during satellite cell activation following muscle injury. Transcripts encoding RNA binding proteins were among the most significantly changed and included the mRNA decay factor Tristetraprolin. Tristetraprolin promotes the decay of MyoD mRNA, which encodes a transcriptional regulator of myogenic commitment, via binding to the MyoD mRNA 3' untranslated region. Upon satellite cell activation, p38alpha/beta MAPK phosphorylates MAPKAP2 and inactivates Tristetraprolin, stabilizing MyoD mRNA. Satellite cell specific knockdown of Tristetraprolin precociously activates satellite cells in vivo, enabling MyoD accumulation, differentiation and cell fusion into myofibers. Regulation of mRNAs by Tristetraprolin appears to function as one of several critical post-transcriptional regulatory mechanisms controlling satellite cell homeostasis. PMID- 25815586 TI - Optimized electrospinning synthesis of iron-nitrogen-carbon nanofibers for high electrocatalysis of oxygen reduction in alkaline medium. AB - To achieve iron-nitrogen-carbon (Fe-N-C) nanofibers with excellent electrocatalysis for replacing high-cost Pt-based catalysts in the cathodes of fuel cells and metal-air batteries, we have investigated and evaluated the effects of polyacrylonitrile (PAN) concentration and the proportion of iron to PAN, along with voltage and flow rate during the electrospinning process, and thus proposed three criteria to optimize these parameters for ideal nanofiber catalysts. The best half-wave potential of an optimized catalysts is 0.82 V versus reversible hydrogen electrode in an alkaline medium, which reaches the best range of the non-precious-metal catalysts reported and is very close to that of commercial Pt/C catalysts. Furthermore, the electron-transfer number of our catalysts is superior to that of the Pt/C, indicating the catalysts undergo a four-electron process. The durability of the optimized Fe-N-C nanofibers is also better than that of the Pt/C, which is attributed to the homogeneous distribution of the active sites in our catalysts. PMID- 25815585 TI - Bovine F1Fo ATP synthase monomers bend the lipid bilayer in 2D membrane crystals. AB - We have used a combination of electron cryo-tomography, subtomogram averaging, and electron crystallographic image processing to analyse the structure of intact bovine F(1)F(o) ATP synthase in 2D membrane crystals. ATPase assays and mass spectrometry analysis of the 2D crystals confirmed that the enzyme complex was complete and active. The structure of the matrix-exposed region was determined at 24 A resolution by subtomogram averaging and repositioned into the tomographic volume to reveal the crystal packing. F(1)F(o) ATP synthase complexes are inclined by 16 degrees relative to the crystal plane, resulting in a zigzag topology of the membrane and indicating that monomeric bovine heart F(1)F(o) ATP synthase by itself is sufficient to deform lipid bilayers. This local membrane curvature is likely to be instrumental in the formation of ATP synthase dimers and dimer rows, and thus for the shaping of mitochondrial cristae. PMID- 25815584 TI - Juxtaposition of heterozygous and homozygous regions causes reciprocal crossover remodelling via interference during Arabidopsis meiosis. AB - During meiosis homologous chromosomes undergo crossover recombination. Sequence differences between homologs can locally inhibit crossovers. Despite this, nucleotide diversity and population-scaled recombination are positively correlated in eukaryote genomes. To investigate interactions between heterozygosity and recombination we crossed Arabidopsis lines carrying fluorescent crossover reporters to 32 diverse accessions and observed hybrids with significantly higher and lower crossovers than homozygotes. Using recombinant populations derived from these crosses we observed that heterozygous regions increase crossovers when juxtaposed with homozygous regions, which reciprocally decrease. Total crossovers measured by chiasmata were unchanged when heterozygosity was varied, consistent with homeostatic control. We tested the effects of heterozygosity in mutants where the balance of interfering and non interfering crossover repair is altered. Crossover remodeling at homozygosity heterozygosity junctions requires interference, and non-interfering repair is inefficient in heterozygous regions. As a consequence, heterozygous regions show stronger crossover interference. Our findings reveal how varying homolog polymorphism patterns can shape meiotic recombination. PMID- 25815587 TI - Upregulated microRNA-16 as an oncogene in renal cell carcinoma. AB - MicroRNAs (miRs) are small, endogenous noncoding RNAs that serve a significant function in various biologic processes, including those involved in cancer. The present study aimed to determine the expression and function of miR-16 in renal cell carcinoma (RCC). Quantitative polymerase chain reaction was used to quantify the expression of miR-16 in 48 paired RCC tissues and adjacent normal tissues. The impact of miR-16 on cell proliferation, migration and apoptosis was analyzed by transfecting miR-16 mature molecules into the renal cancer cell lines 786-O and ACHN. The results indicated that miR-16 was significantly upregulated in RCC tissues (P<0.05). Downregulation of miR-16 resulted in reduced cell proliferation and migration and increased levels of apoptosis, while overexpression of miR-16 resulted in accelerated cellular proliferation and migration, suggesting that miR 16 may function as an oncogene in RCC. The present study demonstrated for the first time, to the best of our knowledge, that miR-16 is upregulated in RCC and acts as an oncogene by inducing cellular proliferation, migration and reducing apoptosis. Further study of miR-16 in RCC may clarify the molecular mechanisms of RCC carcinogenesis and aid in the development of novel biomarkers and therapeutic options. PMID- 25815588 TI - A novel molecular probe 131I-K237 targeting tumor angiogenesis in human prostate cancer xenografts. AB - Specific molecular probes are essential for the early diagnosis of prostate cancer. In addition, peptides have been shown to have numerous uses as diagnostic and therapeutic molecular probes. The K237 peptide binds to the vascular endothelial growth factor receptor with high affinity and specificity, and was predicted to have potential use as a probe in tumor angiogenesis. The overall aim of the present study was to assess the diagnostic potential of 131I-K237 as a molecular probe for prostate cancer. The K237 peptide was radiolabeled with 131I using an Iodogen method. The radiolabeling efficiency and radiochemical purity were found to be 73.7 +/- 3.2 and 96.7 +/- 0.6%, respectively, which were determined using thin layer chromatography and high performance liquid chromatography in vitro. Cellular uptake and competition binding experiments were used to identify the affinity of 131I-K237 to LNCaP prostate cancer cells. The binding ratio of 131I-K237 to LNCaP cells in the experimental group was 95.8 +/- 1.5%, whereas the binding ratios in the 5 kBq Na131I, 10 kBq Na131I, 15 kBq Na131I and PBS groups were 8.2 +/- 0.4, 8.3 +/- 0.2, 8.5 +/- 0.2 and 0.0%, respectively. In addition, the binding ratio of 131I-K237 to LNCaP significantly decreased with the increased dose of unlabeled K237. A total of 40 male BALB/c mice with LNCaP xenografts were used for biodistribution and single photon emission computed tomography imaging analysis. An image was obtained and tumors were visible from 2 h post injection of 131I-K237. In conclusion, the results of the present study showed that 131I-K237 had a high affinity for LNCaP cells and may be considered as a candidate diagnostic molecular probe for prostate cancer. PMID- 25815589 TI - Association study of polymorphisms in interferon-gamma receptor genes with the risk of pulmonary tuberculosis. AB - Tuberculosis (TB) is an infectious disease caused by mycobacterium, which most commonly affects the lungs. The adaptive immune response in Mycobacterium tuberculosis is predominantly mediated by the interferon-gamma (IFN-gamma) signaling pathway, which is regulated by IFN-gamma receptors (IFNGR). IFN-gamma activates the transcription of a number of genes that are important in immune responses, thus the appropriate function of IFNGR appears to be important in host defense against mycobacteria. In the present study, 22 genetic variants in IFNGR1 and IFNGR2 were genotyped in 673 patients and 592 normal controls to investigate the association between IFNGR1 and IFNGR2 polymorphisms and the risk of TB. Statistical analyses revealed that four genetic variants in IFNGR1, rs9376269, rs9376268, rs9376267 and rs56251346 were marginally associated with the risk of TB (P = 0.02-0.04), while other single nucleotide polymorphisms in IFNGR1 and IFNGR2 did not exhibit any associations. However, the significance of the four genetic variants rs9376269, rs9376268, rs9376267 and rs56251346 was eliminated following a multiple testing correction of the data (P>0.05). The present results revealed that certain genetic variants in IFNGR genes may be associated with TB development, which may be useful preliminary data for future investigation. PMID- 25815590 TI - Effects of cinobufacini injection on cell proliferation and the expression of topoisomerases in human HepG-2 hepatocellular carcinoma cells. AB - The present study aimed to investigate the effects of cinobufacini injection on the proliferation and expression of topoisomerases in human HepG-2 hepatocarcinoma cells. The cells were divided into a control group and an experimental group, in which 0.105, 0.21, 0.42 mg/l cinobufacini was injected. Cell proliferation was assessed using a 3-(4,5-dimethylthiazol-2-yl) -2,5 diphenyltetrazolium bromide assay, levels of apoptosis were detected using annexin V/propidium iodide staining and cell cycles were analyzed using flow cytometric analysis. The mRNA and protein expression levels of topoisomerase (TOPO) I and TOPO II were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. Cinobufacini injection significantly inhibited the proliferation of the HepG-2 cells (P<0.05), induced apoptosis (P<0.05) in a dose- and time-dependent manner, induced tumor cell arrest at the S phase in a dose-dependent manner, and downregulated the mRNA and protein expression levels of TOPO I and TOPO II (P<0.05) in a dose-dependent manner. Therefore, cinobufacini was found to inhibit human HepG-2 hepatocellular carcinoma cell proliferation, and downregulation of the expression levels of TOPO I and TOPO II may contribute to the effect on proliferation observed in the Hep G2 cells following cinobbufacini injection. PMID- 25815591 TI - Effects of silencing the ATP-binding cassette protein E1 gene by electroporation on the proliferation and migration of EC109 human esophageal cancer cells. AB - In the present study, the gene expression of ATP-binding cassette protein E1 (ABCE1) in the EC109 human esophageal cancer cell line was silenced using electroporation to examine the effect if the ABCE1 gene on the growth migration and cell cycle of cancer cells. The small interference (si)RNA sequence of ABCE1 was designed and synthesized to transfect the EC109 cells by electroporation. The mRNA and protein expression levels of ABCE1 were then detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The analysis of the cell cycle and apoptosis was performed using flow cytometry. The effect of silencing the ABCE1 gene on the proliferation, migration and invasive ability of the EC109 human esophageal cancer cells were assessed using a Cell counting kit-8 (CCK-8) and with proliferation, wound-healing and cell invasion assays. The mRNA and protein expression levels of ABCE1 were significantly lower in the experimental group compared with the control group (P<0.05). The apoptotic rate of the experimental group was markedly higher than the control group and blank group (P<0.01). The CCK-8 proliferation assay revealed that, compared with the control and blank groups, the proliferation of the EC109 cells in the experimental group was significantly inhibited (P<0.05). The wound healing assay revealed that the migration capacity of the cells in the experimental group was significantly decreased (P<0.05). The Transwell chamber assay demonstrated that the invasive ability of the EC109 cells in the experimental group was significantly decreased (P<0.01). These results revealed that ABCE1 is closely associated with cell proliferation, invasion and migration in esophageal cancer and silencing the ABCE1 gene by electroporation can significantly reduce the proliferation, invasion and migration capacity of EC109 cells in vitro. PMID- 25815592 TI - Limitations and extensions of the lock-and-key principle: differences between gas state, solution and solid state structures. AB - The lock-and-key concept is discussed with respect to necessary extensions. Formation of supramolecular complexes depends not only, and often not even primarily on an optimal geometric fit between host and guest. Induced fit and allosteric interactions have long been known as important modifications. Different binding mechanisms, the medium used and pH effects can exert a major influence on the affinity. Stereoelectronic effects due to lone pair orientation can lead to variation of binding constants by orders of magnitude. Hydrophobic interactions due to high-energy water inside cavities modify the mechanical lock and-key picture. That optimal affinities are observed if the cavity is only partially filled by the ligand can be in conflict with the lock-and-key principle. In crystals other forces than those between host and guest often dominate, leading to differences between solid state and solution structures. This is exemplified in particular with calixarene complexes, which by X-ray analysis more often than other hosts show guest molecules outside their cavity. In view of this the particular problems with the identification of weak interactions in crystals is discussed. PMID- 25815595 TI - Towards understanding the decomposition/isomerism channels of stratospheric bromine species: ab initio and quantum topology study. AB - The present study aims at a fundamental understanding of bonding characteristics of the C-Br and O-Br bonds. The target molecular systems are the isomeric CH3OBr/BrCH2OH system and their decomposition products. Calculations of geometries and frequencies at different density functional theory (DFT) and Hartree-Fock/Moller-Plesset (HF/MP2) levels have been performed. Results have been assessed and evaluated against those obtained at the coupled cluster single double (Triplet) (CCSD(T)) level of theory. The characteristics of the C-Br and O Br bonds have been identified via analysis of the electrostatic potential, natural bond orbital (NBO), and quantum theory of atoms in molecules (QTAIM). Analysis of the electrostatic potential (ESP) maps enabled the quantitative characterization of the Br sigma-holes. Its magnitude seems very sensitive to the environment and the charge accumulated in the adjacent centers. Some quantum topological parameters, namely N2rho, ellipticity at bond critical points and the Laplacian bond order, were computed and discussed. The potential energy function for internal rotation has been computed and Fourier transformed to characterize the conformational preferences and origin of the barriers. NBO energetic components for rotation about the C-Br and O-Br bonds as a function of torsion angle have been computed and displayed. PMID- 25815594 TI - In silico analysis of the genes encoding proteins that are involved in the biosynthesis of the RMS/MAX/D pathway revealed new roles of Strigolactones in plants. AB - Strigolactones were described as a new group of phytohormones in 2008 and since then notable large number of their functions has been uncovered, including the regulation of plant growth and development, interactions with other organisms and a plant's response to different abiotic stresses. In the last year, investigations of the strigolactone biosynthesis pathway in two model species, Arabidopsis thaliana and Oryza sativa, resulted in great progress in understanding the functions of four enzymes that are involved in this process. We performed in silico analyses, including the identification of the cis-regulatory elements in the promoters of genes encoding proteins of the strigolactone biosynthesis pathway and the identification of the miRNAs that are able to regulate their posttranscriptional level. We also searched the databases that contain the microarray data for the genes that were analyzed from both species in order to check their expression level under different growth conditions. The results that were obtained indicate that there are universal regulations of expression of all of the genes that are involved in the strigolactone biosynthesis in Arabidopsis and rice, but on the other hand each stage of strigolactone production may be additionally regulated independently. This work indicates the presence of crosstalk between strigolactones and almost all of the other phytohormones and suggests the role of strigolactones in the response to abiotic stresses, such as wounding, cold or flooding, as well as in the response to biotic stresses. PMID- 25815593 TI - Understanding FRET as a research tool for cellular studies. AB - Communication of molecular species through dynamic association and/or dissociation at various cellular sites governs biological functions. Understanding these physiological processes require delineation of molecular events occurring at the level of individual complexes in a living cell. Among the few non-invasive approaches with nanometer resolution are methods based on Forster Resonance Energy Transfer (FRET). FRET is effective at a distance of 1-10 nm which is equivalent to the size of macromolecules, thus providing an unprecedented level of detail on molecular interactions. The emergence of fluorescent proteins and SNAP- and CLIP- tag proteins provided FRET with the capability to monitor changes in a molecular complex in real-time making it possible to establish the functional significance of the studied molecules in a native environment. Now, FRET is widely used in biological sciences, including the field of proteomics, signal transduction, diagnostics and drug development to address questions almost unimaginable with biochemical methods and conventional microscopies. However, the underlying physics of FRET often scares biologists. Therefore, in this review, our goal is to introduce FRET to non-physicists in a lucid manner. We will also discuss our contributions to various FRET methodologies based on microscopy and flow cytometry, while describing its application for determining the molecular heterogeneity of the plasma membrane in various cell types. PMID- 25815596 TI - Preservation of renal blood flow by the antioxidant EUK-134 in LPS-treated pigs. AB - Sepsis is associated with an increase in reactive oxygen species (ROS), however, the precise role of ROS in the septic process remains unknown. We hypothesized that treatment with EUK-134 (manganese-3-methoxy N,N'-bis(salicyclidene)ethylene diamine chloride), a compound with superoxide dismutase and catalase activity, attenuates the vascular manifestations of sepsis in vivo. Pigs were instrumented to measure cardiac output and blood flow in renal, superior mesenteric and femoral arteries, and portal vein. Animals were treated with saline (control), lipopolysaccharide (LPS; 10 ug.kg-1.h-1), EUK-134, or EUK-134 plus LPS. Results show that an LPS-induced increase in pulmonary artery pressure (PAP) as well as a trend towards lower blood pressure (BP) were both attenuated by EUK-134. Renal blood flow decreased with LPS whereas superior mesenteric, portal and femoral flows did not change. Importantly, EUK-134 decreased the LPS-induced fall in renal blood flow and this was associated with a corresponding decrease in LPS induced protein nitrotyrosinylation in the kidney. PO2, pH, base excess and systemic vascular resistance fell with LPS and were unaltered by EUK-134. EUK-134 also had no effect on LPS-associated increase in CO. Interestingly, EUK-134 alone resulted in higher CO, BP, PAP, mean circulatory filling pressure, and portal flow than controls. Taken together, these data support a protective role for EUK 134 in the renal circulation in sepsis. PMID- 25815597 TI - Nano SiO2 and MgO improve the properties of porous beta-TCP scaffolds via advanced manufacturing technology. AB - Nano SiO2 and MgO particles were incorporated into beta-tricalcium phosphate (beta-TCP) scaffolds to improve the mechanical and biological properties. The porous cylindrical beta-TCP scaffolds doped with 0.5 wt % SiO2, 1.0 wt % MgO, 0.5 wt % SiO2 + 1.0 wt % MgO were fabricated via selective laser sintering respectively and undoped beta-TCP scaffold was also prepared as control. The phase composition and mechanical strength of the scaffolds were evaluated. X-ray diffraction analysis indicated that the phase transformation from beta-TCP to alpha-TCP was inhibited after the addition of MgO. The compressive strength of scaffold was improved from 3.12 +/- 0.36 MPa (beta-TCP) to 5.74 +/- 0.62 MPa (beta-TCP/SiO2), 9.02 +/- 0.55 MPa (beta-TCP/MgO) and 10.43 +/- 0.28 MPa (beta TCP/SiO2/MgO), respectively. The weight loss and apatite-forming ability of the scaffolds were evaluated by soaking them in simulated body fluid. The results demonstrated that both SiO2 and MgO dopings slowed down the degradation rate and improved the bioactivity of beta-TCP scaffolds. In vitro cell culture studies indicated that SiO2 and MgO dopings facilitated cell attachment and proliferation. Combined addition of SiO2 and MgO were found optimal in enhancing both the mechanical and biological properties of beta-TCP scaffold. PMID- 25815598 TI - Sex-specific diurnal immobility induced by forced swim test in wild type and clock gene deficient mice. AB - OBJECTIVE: The link between alterations in circadian rhythms and depression are well established, but the underlying mechanisms are far less elucidated. We investigated the circadian characteristics of immobility behavior in wild type (WT) mice and mice with mutations in core Clock genes. METHODS: All mice were tested with forced swim test (FST) at 4 h intervals. RESULTS: These experiments revealed significant diurnal rhythms associated with immobility behavior in both male and female WT mice with sex-different circadian properties. In addition, male mice showed significantly less immobility during the night phase in comparison to female mice. Female Per1Brdm1 mice also showed significant rhythmicity. However, the timing of rhythmicity was very different from that observed in female wild type mice. Male Per1Brdm1 mice showed a pattern of rhythmicity similar to that of wild type mice. Furthermore, female Per1Brdm1 mice showed higher duration of immobility in comparison to male Per1Brdm1 mice in both daytime and early night phases. Neither Per2Brdm1 nor ClockDelta19 mice showed significant rhythmicity, but both female Per2Brdm1 and ClockDelta19 mice had lower levels of immobility, compared to males. CONCLUSIONS: This study highlights the differences in the circadian characteristics of immobility induced by FST in WT, ClockDelta19, Per1, and Per2 deficient mice. PMID- 25815601 TI - Ser49Gly polymorphism in the beta-adrenergic receptor 1 gene in a population sample from Rio de Janeiro state, Brazil, stratified by self-identified skin color and genetic ancestry. AB - Cardiovascular diseases (CVD) have the highest worldwide mortality rate of any type of disease. In recent years, genetic research regarding CVD has been conducted using association studies, in which the presence of a genetic polymorphism associated with a specific cell signaling pathway in a lower or in a higher frequency among patients may be interpreted as a possible causal factor. Genetic polymorphisms that occur in the beta-adrenergic receptor 1 (beta-ADR1) can result in significant changes in its function that may result in physiopathologies. Ambiguous categorizations, such as skin color and self reported ethnicity have been used in pharmacogenetic studies as phenotypic proxies for ancestry; however, admixed populations present a particular challenge to the effectiveness of this approach. The main objective of the present study was to estimate the diversity and the frequency of the Ser49Gly polymorphism of the beta-ADR1 gene in a sample of 188 male individuals from the population of Rio de Janeiro. The Ser49Gly frequencies were analyzed by two forms of sample stratification: The phenotypic criterion of black or non-black skin color, and African or non-African ancestry, defined using Y-chromosome single nucleotide polymorphisms and autosomal indel markers. These results were used to evaluate whether marker-based ancestry criteria and/or skin color were associated with the frequency of the Ser49Gly polymorphisms in the heterogeneous Rio de Janeiro/Brazilian population. The DNA fragments of interest were amplified by polymerase chain reaction with specific primers for the Ser49Gly marker, and genotyping reactions were performed by restriction with the enzyme Eco0109I. Heterozygosity values ranging from 0.25 to 0.50 and 0.20 to 0.41 were found for the groups stratified by ancestry and skin color, respectively. Using the Hardy Weinberg equilibrium at the ser49Gly marker, it was found that there was no significant deviation in the genotype distribution of the whole Rio de Janeiro sample or the stratified sample. Analysis of the allelic distribution in the Rio de Janeiro population sample revealed frequencies of 80.30 and 19.70% for the wild-type (Ser49) and mutated (Gly49) alleles, respectively. Significant differences were observed in the allele frequencies of the Ser49Gly marker between the self-defined black and non-black phenotype, and the African and non African descendant genotype population samples. A significant difference was also observed between blacks and African-descendant individuals, with a lesser degree of genetic differentiation. The results presented in the present study suggest that the Ser49Gly marker has a distribution that is influenced by an ancestral component, due to the increased prevalence of the Gly49 polymorphism in the black and African descendant populations of the Rio de Janeiro state. This evidence, in combination with clinical studies, may contribute to a detailed analysis of the pattern of susceptibility to CVD involved in beta-ADR1 receptor mechanism failure. PMID- 25815602 TI - A Steady-State Approximation to the Two-Dimensional Master Equation for Chemical Kinetics Calculations. AB - In the field of chemical kinetics, the solution of a two-dimensional master equation that depends explicitly on both total internal energy (E) and total angular momentum (J) is a challenging problem. In this work, a weak-E/fixed-J collisional model (i.e., weak-collisional internal energy relaxation/free collisional angular momentum relaxation) is used along with the steady-state approach to solve the resulting (simplified) two-dimensional (E,J)-grained master equation. The corresponding solutions give thermal rate constants and product branching ratios as functions of both temperature and pressure. We also have developed a program that can be used to predict and analyze experimental chemical kinetics results. This expedient technique, when combined with highly accurate potential energy surfaces, is cable of providing results that may be meaningfully compared to experiments. The reaction of singlet oxygen with methane proceeding through vibrationally excited methanol is used as an illustrative example. PMID- 25815600 TI - Differentiation of human umbilical cord mesenchymal stem cells into germ-like cells in mouse seminiferous tubules. AB - Our previous study demonstrated that human umbilical cord mesenchymal stem cells (HUMSCs) were capable of differentiation into germ cells in vitro. To assess this potential in vivo, HUMSCs were microinjected into the lumen of seminiferous tubules of immunocompetent mice, which were treated with busulfan to destroy endogenous spermatogenesis. Bromodeoxyuridine labeling studies demonstrated that HUMSCs survived in the tubule for at least 120 days, exhibited a round cell shape typical of proliferating or differentiating germ cells, migrated to the basement of the tubule, where proliferating spermatogonia reside and returned to the luminal compartment, where differentiating spermatids and spermatozoa reside. The migration pattern resembled that of germ cell development in vivo. Immunohistochemical and colocalization studies revealed that transplanted HUMSCs expressed the germ cell markers octamer-binding transcription factor 4, alpha6 integrin, C-kit and VASA, confirming the germ cell differentiation. In addition, it was observed that tubules transplanted with HUMSCs exhibited marked improvement in the histological features damaged by the chemotherapeutic busulfan, as judged by morphology and quantitative histology. Taken together, these data demonstrated the capacity of HUMSCs to form germ cells in the testes and to repair testicular tissue. These findings suggest a potential utility of HUMSCs to treat the infertility and testicular insufficiency caused by cancer therapeutics. PMID- 25815599 TI - Hepatitis A virus genotype distribution during a decade of universal vaccination of preadolescents. AB - A universal vaccination program among preadolescents was implemented in Catalonia, Spain, during the period of 1999-2013 and its effectiveness has been clearly demonstrated by an overall significant attack rate reduction. However, reductions were not constant over time, and increases were again observed in 2002 2009 due to the occurrence of huge outbreaks. In the following years, in the absence of large outbreaks, the attack rate decreased again to very low levels. However, an increase of symptomatic cases in the <5 age group has recently been observed. This is an unexpected observation since children younger than 6 are mostly asymptomatic. Such a long vaccination campaign offers the opportunity to analyze not only the effectiveness of vaccination, but also the influence of the circulating genotypes on the incidence of hepatitis A among the different age groups. This study has revealed the emergence of genotype IC during a foodborne outbreak, the short-lived circulation of vaccine-escape variants isolated during an outbreak among the men-having-sex-with-men group, and the association of genotype IIIA with the increase of symptomatic cases among the very young. From a public health perspective, two conclusions may be drawn: vaccination is better at an early age, and the vaccination schedule must be complete and include all recommended vaccine doses. PMID- 25815604 TI - H-bonded supramolecular polymer for the selective dispersion and subsequent release of large-diameter semiconducting single-walled carbon nanotubes. AB - Semiconducting, single-walled carbon nanotubes (SWNTs) are promising candidates for applications in thin-film transistors, solar cells, and biological imaging. To harness their full potential, however, it is necessary to separate the semiconducting from the metallic SWNTs present in the as-synthesized SWNT mixture. While various polymers are able to selectively disperse semiconducting SWNTs, the subsequent removal of the polymer is challenging. However, many applications require semiconducting SWNTs in their pure form. Toward this goal, we have designed a 2-ureido-6[1H]-pyrimidinone (UPy)-based H-bonded supramolecular polymer that can selectively disperse semiconducting SWNTs. The dispersion purity is inversely related to the dispersion yield. In contrast to conventional polymers, the polymer described herein was shown to disassemble into monomeric units upon addition of an H-bond-disrupting agent, enabling isolation of dispersant-free, semiconducting SWNTs. PMID- 25815603 TI - Accumulation potentials of perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs) in maize (Zea mays). AB - Uptake of perfluoroalkyl acids (PFAAs) by maize represents a potential source of exposure for humans, either directly or indirectly via feed for animals raised for human consumption. The aim of the following study was, therefore, to determine the accumulation potential of perfluoroalkyl carboxylic acids (PFCAs) and perfluoroalkyl sulfonic acids (PFSAs) in maize (Zea mays). Two different concentrations of PFAAs were applied as aqueous solution to the soil to attain target concentrations of 0.25 mg or 1.00 mg of PFAA per kg of soil. Maize was grown in pots, and after harvesting, PFAA concentrations were measured in the straw and kernels of maize. PFCA and PFSA concentrations of straw decreased significantly with increasing chain length. In maize kernels, only PFCAs with a chain length <= C8 as well as perfluorobutanesulfonic acid (PFBS) were detected. The highest soil-to-plant transfer for both straw and kernels was determined for short-chained PFCAs and PFSAs. PMID- 25815605 TI - Iridium-catalyzed chemoselective reductive nucleophilic addition to N methoxyamides. AB - Iridium-catalyzed reductive nucleophilic addition to N-methoxyamides is reported. The reaction took place in high yields in the presence of a variety of sensitive functional groups such as esters and nitro groups. Mechanistic studies revealed that the reaction of N-methoxyamides proceeded without equilibrium to an enamine intermediate in contrast to that with tert-amides. PMID- 25815606 TI - Stable radicals from commonly used precursors trichlorosilane and diphenylchlorophosphine. AB - Intermediate species dichlorosilylene was generated in situ from trichlorosilane and inserted into the P-Cl bond of diphenylchlorophosphine (Ph2P-Cl) to obtain Ph2P-SiCl3 (1). Monodechlorination of 1 by cyclic alkyl(amino) carbenes (cAACs)/KC8 in THF at low temperature led to the formation of stable radicals Ph2P-Si(cAAC.)Cl2 (2a,b). Compounds 2a,b were characterized by X-ray single crystal diffraction, mass spectrometry and studied by cyclic voltammetry and theoretical calculations. Radical properties of 2 are confirmed by EPR measurements that suggest the radical electron in 2 couples with (14)N (I = 1), (35/37)Cl (I = 3/2), and (31)P (I = 1/2) nuclei leading to multiple hyperfine lines. Hyperfine coupling parameters computed from DFT calculations are in good agreement with those of experimental values. Electronic distributions obtained from the theoretical calculations suggest that the radical electron mostly resides on the carbene C of 2. PMID- 25815608 TI - Early stage P22 viral capsid self-assembly mediated by scaffolding protein: atom resolved model and molecular dynamics simulation. AB - Molecular dynamics simulation of an atom-resolved bacteriophage P22 capsid model is used to delineate the underlying mechanism of early stage P22 self-assembly. A dimer formed by the C-terminal fragment of scaffolding protein with a new conformation is demonstrated to catalyze capsomer (hexamer and pentamer) aggregation efficiently. Effects of scaffolding protein/coat protein binding patterns and scaffolding protein concentration on efficiency, fidelity, and capsid curvature of P22 self-assembly are identified. PMID- 25815609 TI - Iron-bismuth halido compounds: molecules, clusters, and polymers. AB - The pentamethylcyclopentadienyl substituted iron-bismuth halides [Bi{FeCp*(CO)2}X2] [X = Cl (1), Br (2), I (3); Cp* = eta(5)-C5Me5] were synthesized starting from [FeCp*(CO)2]2 and BiX3 (X = Cl, Br), followed by halogen exchange reaction with KI in case of 3. From a reaction mixture of [FeCp*(CO)2]2 with BiCl3 in CH2Cl2 to which CH3CN had been added, a novel coordination polymer of the formula [FeCp*(CO)2(CH3CN)]2n[Bi4Cl14]n (4) was isolated. The change of the molar ratio from 1:1 to 1:2 in the reaction of [FeCp*(CO)2]2 with BiBr3 afforded the novel ionic complex [{FeCp*(CO)2Br]2[Bi6Br22{FeCp*(CO)2}].CH2Cl2 (5.CH2Cl2). It is demonstrated that treatment of [FeCp*(CO)2X] (X = Cl, Br) with BiCl3 and BiBr3, respectively, is a more convenient route to synthesize the new halido bismuthates 4 and 5. PMID- 25815607 TI - Blood-brain barrier permeability of Gualou Guizhi granules and neuroprotective effects in ischemia/reperfusion injury. AB - The present study aimed to estimate the blood-brain barrier (BBB) permeability of Gualou Guizhi granules (GLGZG) in normal rats and in rat models of ischemia/reperfusion (I/R) injury, and to examine the neuroprotective effects of GLGZG. A sensitive high-performance liquid chromatography-quadrupole-time of flight-mass spectrometry analytical method was developed to determinate the components of GLGZG in the plasma and brain tissue. Middle cerebral artery occlusion (MCAO) in rats served as a model of in vivo I/R. Citrulline, gallic acid, albiflorin, peoniflorin, liquiritin apioside, liquiritin, isoliquiritin apioside, isoliquiritin, liquiritigenin, isoliquiritigenin and glycyrrhizinic acid rapidly passed into the bloodstream. Citrulline, albiflorin, peoniflorin, liquiritin apioside, liquiritin, liquiritigenin, isoliquiritigenin and glycyrrhizinic acid also passed the BBB and reached the brain tissue of MCAO rats, while isoliquiritigenin and glycyrrhizinic acid were not detected in the brain tissue of the normal rats. The potential neuroprotective effect of GLGZG was determined in MCAO rats. The intragastric administration of GLGZG following reperfusion of rats for 2 h decreased the neurological defects and infarction volume, attenuated pathological changes of brain tissue and exerted a significant protective effect in cerebral ischemia injury. In conclusion, certain components of GLGZG passed through the BBB, particularly following cerebral ischemia injury, and this may be therapeutically effective for the treatment of cerebral ischemia injury in the human brain. PMID- 25815610 TI - Oligolayer-coated nanoparticles: impact of surface topography at the nanobio interface. AB - Layer-by-layer coating of nanoparticles with a layer number in the single-digit range has gained increasing attention in the field of nanomedicinal research. However, the impact of using various polyelectrolytes on oligolayer formation and, more importantly, their influence on the interaction with the biological system has not often been considered in the past. Hence, we investigated the polyelectrolyte deposition profiles and resulting surface topographies of up to three polyelectrolyte layers on a flat gold sensor surface using three different polycations, namely, poly(ethylene imine) (PEI), poly(allylamine hydrochloride) (PAH), and poly(diallylammonium chloride) (PD), each in combination with poly(styrenesulfonate) (PSS). Surface plasmon resonance spectroscopy and atomic force microscopy revealed that the PEI/PSS pair in particular showed a so-called overshoot phenomenon, which is associated with partial polyelectrolyte desorption from the surface. This is also reflected by a significant increase in the surface roughness. Then, after having transferred the oligolayer assembly onto nanoparticles of ~32 nm, we realized that quite similar surface topographies must have emerged on a curved gold surface. A major finding was that the extent of surface roughness contributes significantly to the fashion by which the oligolayer-coated nanoparticles interact with serum proteins and associate with cells. For example, for the PEI/PSS system, both the surface roughness and protein adsorption increased by a factor of ~12 from the second to third coating layer and, at the same time, the cell association massively decreased to only one third. Our study shows that surface roughness, along with other particle properties such as size, shape, zeta potential, and hydrophobicity, is another decisive factor for nanoparticles in a biological context, which has indeed been discussed previously but has not to date been investigated for oligolayers. PMID- 25815611 TI - [Sexuality in the elderly]. AB - Sustaining and strengthening the ability of the elderly to continue their sexual needs can be realized as part of improving their quality of life, health and well being. There is no age at which ends the expression of sexuality and intimacy. Through education, quality of life and advances in medicine, the average life expectancy is still increasing. Sexual activity of older people society usually describe using pejorative terms as an inappropriate, bizarre or obscene, but these labels are different than reality. Hormonal changes and other physiological changes associated with aging affect sexual interest. Erectile dysfunction is a problem in men increasing with age. There is no evidence that premature ejaculation is more common in older age. Cross-sectional studies showed no difference in sexual dysfunction between older and younger women. Age is not a barrier to sexually transmitted diseases. The most common pathogenetic factors for male erectile dysfunction are vascular diseases. In women, the most important symptoms of sexual dysfunction are lack of emotional wellbeing and a sense of intimacy during sexual intercourse. PMID- 25815612 TI - [Obesity as a factor in the development of cancer in type 2 diabetes]. AB - AIM: The aim of this study was to evaluate the prevalence of malignant tumors in patients with type 2 diabetes and the factors contributing to the development of cancer. MATERIALS AND METHODS: Medical records of 1087 patients with type 2 diabetes were retrospectively analyzed and a group of 74 (6.8%) patients with malignant tumor were found during treatment of diabetes. RESULTS: The most common sites of malignancies in patients with type 2 diabetes were: kidney (33.3%) and colorectal cancer (26.7%). The highest mean body mass index (BMI) was in the group of patients with uterus cancer and amounted to 36.1 kg/m2. The next highest BMI recorded in the case of breast cancer - 32.6 kg/m2, cancer of the kidney - 31.6 kg/m2 and colorectal cancer - 31.3 kg/m2. The lowest BMI values were observed in gallbladder cancer - 25.2 kg/m2 and lung cancer - 26.4 kg/m2. BMI in the various types of cancer were not statistically significant. In the group with normal BMI prostate cancer was most common. In the group of overweight and obesity patients kidney and colon cancers occurred more frequently, while in obese women - breast and uterus tumors. More than 80% of patients with type 2 diabetes who were diagnosed with cancer were overweight or obese. In the group of obese patients the highest average glycated hemoglobin was observed and if compared to those with normal weight it was significantly higher (p = 0.01). CONCLUSIONS: In the group of obese patients, the most common tumors were renal and colorectal cancer, and cancer of the breast and uterus in a group of obese women. The use of metformin in the presence of other risk factors do not protect against the development of cancer. PMID- 25815613 TI - [Primary squamous cell carcinoma of the breast - a case report]. AB - Breast cancer is the most common malignant tumor among women in Poland. According to the Center of Oncology (The National Cancer Registry) in 2010 in our country 15,784 new cases have been noted. Since 1970s worldwide growth of new cases of breast cancer have been reported. Among the well-known histological types of breast tumors, small percentage - only 0.1% - include squamous cell component. CASE REPORT: A 69-year-old female met her doctor because of the right breast tumor. After two months of observation, in the last two weeks before the visit, the tumor started to grow very rapidly. As the diagnosis from fine needle aspiration biopsy (squamous cell carcinoma) was very rare for this location, and considering the other clinical symptoms the woman reported, it was suspected to be metastatic. Finally, as the other origins of the primary tumor have been declined and as the patient's condition begun to worsen very rapidly, the urgent treatment: mastectomy (toilet mastectomy) and adjuvant chemotherapy afterward, according to the pathological report were performed. CONCLUSIONS: Rare histological types of the breast cancer use to suggest a metastatic origin or behave as tumors with highly malignant histological grade. PMID- 25815614 TI - [Does acetylsalicylic acid and vitamin K antagonists are risk factors of macular degeneration related with age?]. AB - AIM: The aim of this study was to evaluate the effects of chronic use of acetylsalicylic acid (ASA) and vitamin K antagonists (VKA) on the incidence of age related macular degeneration (AMD). MATERIALS AND METHODS: The study included 292 individuals (187 women, 105 men, aged 45-94 (mean 73.2 +/- 10.2 years). All individuals completed a survey and underwent a full eye examination. Patients were divided into four groups according to the presence or absence of degenerative changes at the bottom of an eye: group D - 80 patients with drusen (23 men and 57 women), 27,4% of studied population, group GA - 25 patients with geographic atrophy (10 men, 15 women), 8,56% of studied population, group CNV - 52 patients with neovascular form of AMD (28 men, 24 women), 17,81% of studied population, group Z - 135 healthy people (44 men, 91 women), 46,23% of studied population. Among study group 79 patients (27,1%) used aspirin, 32 people (11%) used vitamin K antagonists (acenocoumarol or warfarin), 181 people (61,9%) didn't use any drug. RESULTS: Patients from D and CNV group took ASA and VKA more often than patients from GA and Z group. The percentages were: in a group Z - 30,37%, in group D - 46,25%, in group GA - 32%, in group CNV - 48,08% (p=0,0407). There was no relationship between belonging to a group and use of ASA (p=0,3169). A statistically significant relationship between belonging to a group and use of VKA was discovered. The number of people using VKA in group D and CNV was statistically significantly higher than in the healthy control group and percentage were as follows: in group Z - 8,15%, in group D - 17,5%, in group GA 0%, in group CNV - 13,46% (p=0,0159). Patient groups differed statistically significantly due to age (p=0,0043), sex (p=0,0197), family history of macular diseases (p <0,0001), smoking (p=0,011), prevalence of hypercholesterolemia (p=0,0437), ischemic heart disease (p= 0,0173). The consumption of fish at least once a week and eating fruits and vegetables more often than once a day was associated with a reduced incidence of AMD p=0,0009, p=0,0003. Patients without AMD assessed their quality of life at a higher level than people with AMD (p<0,0001). ASA and VKA intake was found not to be an independent risk factor for AMD. Positive family history was an independent risk factor for AMD in all groups. Also age >=75, fish consumption > 1 week, male gender were independent risk factors for AMD in specified groups. CONCLUSIONS: Patients with drusen and exudative form of AMD took ASA and VKA more often than healthy people and patients with geographic atrophy. ASA or VKA intake was found not to be an independent risk factor for AMD. Positive family history was an independent risk factor for AMD in all groups. In selected groups: age >=75, male gender and reduced consumption of fish was found to be an independent risk factor for AMD. Number of people taking ASA and VKA is increasing and further studies are needed to assess their impact on the organ of vision. PMID- 25815615 TI - [The effect of high-frequency current and ultrasonic wave on selected indicators of body weight]. AB - Effective change the appearance of the body through available both invasive and non-invasive methods such as treatment has been documented in numerous clinical trials. Liposuction and lipoplasty are currently the most widely used methods of reducing fat deposits. Technological advances made has become increasingly popular use of invasive procedures using energy fields and high-frequency ultrasonic wave. It is now one of the most effective and safe methods of treatment, based on the principle of mechanical and thermal stimulation of the physiological processes leading to the reduction of locally accumulated fat. AIM: The aim of the study was to evaluate the behavior of selected parameters of body weight in patients undergoing fat reduction BTL Exilis device. MATERIALS AND METHODS: IThe study included a 50-group of women who are patients of the Specialist Outpatient Clinic Al-Med in Kolobrzeg. Taken twice the measurement of body weight, waist circumference and thickness measurement of skinfolds before the first treatment, and after a series of treatments. Treatment consisted of 4 sessions while maintaining the 10-day interval between treatments. RESULTS: In the study a statistically significant reduction in the studied parameters such as actual body weight, waist circumference, fat mass and thickness of the skinfolds were showed. CONCLUSIONS: The effect of treatment with the energy field of highfrequency ultrasonic wave in a reduction in the size of fat body mass and improving the contour shape. Willingness to continue participation examined in this type of surgery proves positive reception of therapy and its effectiveness. PMID- 25815616 TI - [Quality of life, acceptance of illness and a sense of health control in patients with chronic musculoskeletal disorders during the rehabilitation process]. AB - In medical science it is accepted that in order to determine the state of physical, mental as well as the progress of treatment, the concept of quality of life is applicable. However, the most popular use of the term is in the case of chronic diseases and particularly in the lives of those who are sick. Examples of such diseases are diseases of the musculoskeletal system and especially osteoarthritis of the knee and hip. The level of quality of life in chronic disease are also affected by psychological factors that can significantly help people in the healing process as well as acceptance of existing disease. AIM: The aim of study was to evaluate the association between quality of life, acceptance of illness and sense of control over own health in patients with chronic motor disability during the rehabilitation course. MATERIALS AND METHODS: The study included 105 patients (76 women and 29 men) with osteoarthritis of the hip and knee, undergoing rehabilitation at the Municipal Clinic "Lecznica" in Lodz. The study used a questionnaire in the development of their own - specifying the basic socio-demographic data subjects, the SF-36 questionnaire - evaluating the quality of life of patients, Acceptance of Illness Scale (AIS BJ Felton, TA Revenson, Hinrichsen GA) in the adaptation of the Z. Juczynski and Multidimensional Scale Health Locus of Control MHLC (KA wallstone, BS wallstone, R. DeVellis) in adaptation of Z. Juczynski. RESULTS: The distribution of respondents by type of disease is as follows: diseases of the knee -63.81%, hip - 23.81% and knee and hip disorders - 12.38%. A similar breakdown occurs in women and men. The average level of quality of life in this population of patients was 88.63, which is not too high. Evaluation of the results of health locus of control scale laid the equal distribution of respondents, taking into account all the studied rocks. Thanks to the use of Pearson's correlation coefficient allowed the conclusion that the level of quality of life correlates positively with the acceptance of the disease and internal locus of control pain in patients. CONCLUSIONS: Quality of life of the patients in the general dimension is in significant correlation with the acceptance of the disease and with a sense of control over their own health internally. Patients who have a high sense of control health by others or by accident is characterized by a lower level of acceptance of his illness. Acceptance of the disease and a sense of control over their own health may be important factors for health behaviors. PMID- 25815617 TI - [Fixed appliance therapy in patients with impaired short-circuit in the anterior part of the maxilla]. AB - Malocclusion in the anterior segment of maxilla and mandible are easily visible not only for dentists but also for the doctors of other specialties. Early diagnosis and appropriate therapy is important not only for occlusion but also for aesthetic reasons. AIM: The aim of the paper is to evaluate the anterior segment of maxilla and mandible in patients with malocclusion in this part and correct occlusion in the lateral segments. MATERIALS AND METHODS: Medical documentation, i.e. medical history, extra- and intraoral radiograms, diagnostic casts, panoramic and lateral cephalometric radiograms of patients aged 7-12 diagnosed with malocclusion in the anterior segment of maxilla and mandible and who were treated with a fixed sectional appliance and facemask was analyzed. Descriptive and cephalometric features were analyzed before (T1) and after (T2) the treatment in 25 children. The differences between the status before and after the treatment, and the extent of change between T1 and T2 were analyzed. RESULTS: Statistical analysis of mean values of selected metrical features before (at T1) and after (at T2) the treatment has revealed that all metrical features concerning soft, bony and dental tissues determining the facial profile, the shape of the bony and dental structures have changed and have reached values which are closer to the norm for the population for selected features. The changes were statistically significant (p<0.0001). CONCLUSIONS: Treatment with fixed appliances segment facemask resulted in statistically significant improvement in the parameters investigated, which demonstrates the applicability of this therapy in the treatment of anterior maxillary segment in patients with mixed dentition. PMID- 25815618 TI - Polymyalgia rheumatica in a patient with splenic marginal zone lymphoma - a case report. AB - Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly people. We present a case of a 49-year-old woman diagnosed with PMR. The treatment with prednisone resulted in a rapid resolution of clinical symptoms. However, inflammatory markers remained elevated. Ultrasonography and computed tomography revealed the presence of a large splenic lesion. A cyst was suspected but, because of the high risk of splenic rupture, a splenectomy was performed. The histopathological examination revealed the presence of splenic marginal zone lymphoma. Inflammatory markers returned to normal after splenectomy. Prednisone was tapered but clinical symptoms of PMR reappeared after lowering the dose of prednisone <10 mg/day. Thus, treatment with methotrexate was started, which allowed for further tapering of prednisone. PMID- 25815619 TI - The use of dermoscopy in diagnostics of a pilonidal cyst ("jeep disease") - case reports. AB - The differential diagnosis of pinkish, firm nodules is difficult and has been based mainly on the morphology of vessels in dermoscopy. The aim of the study was to present dermoscopic features of two nodular pilonidal cysts in the diagnostic procedure of pink nodular lesions. The cases presented here belong to a rare variety of nodular pilonidal cysts known as the "motorcyclist's" or " jeep driver's nodule". Dermoscopy reveals an irregular, whitish and pink-colored background, with centrally located confluent, whitish streaks extending within the lesion, radial from the center to the periphery. Moreover, multiple, diffused, dotted vessels, arranged peripherally and the small central ulceration have also been observed. Described cases have shown doctors the importance of the utmost vigilance when conducting the dermoscopy of pink nodules, which may suggest amelanocytic melanoma, basal and squamous cell carcinoma, pyogenic granuloma, lymphoma, pseudolymphoma and even the pilonidal cyst. PMID- 25815620 TI - [Influence of exogenous and endogenous factors on the course of psoriasis]. AB - Psoriasis is a chronic, inflammatory disease, which symptoms appear mainly within the skin. Genetic and environmental factors are known to play a key role in etiopathogenesis of psoriasis. Therapy directed against psoriasis includes the topical and the systemic treatment. The immunotherapy (biologicals) is known to be relatively less harmful, due to action strictly against proinflammatory molecules, responsible in part for the progression of psoriasis. Because of substantial role of environmental factors in the etiopathogenesis of psoriasis, it is possible to get a clinical improvement of psoriatic lesions by modification of patients dietary habits and their lifestyle. Reduction of the calorific value of meals, the bodyweight reduction, the diet rich in unsaturated fats and antioxidants, likewise, abstinence and the reduction of stress level in everyday life, are known to have a positive effect on the course of psoriasis. It is stated that psoriatic patients are suffering from many other diseases e.g. cardiovascular, respiratory and hormonal diseases, whose treatment might exacerbate psoriasis. Thus, patients with psoriasis following the appropriate recommendations can greatly reduce disease progression. PMID- 25815621 TI - [Milk fat - the only existing for any reason]. AB - The milk fat is characterized by an unique composition (over 400 different fatty acids) and stereospecific structure of triglycerides, similar to human milk fat. Almost entirely it is encircled by envelopes made of phosphorolipids and proteins, making the fat stabile oxidatively and resistant for hydrolysis. The envelope of fatty spherule ensures stability of emulsions, as well, as very high extent of dispersion, making milk fat the most easily digested fat in human diet. Phosphorolipids, proteins, peptides and numerous enzymes present inside the envelope are characterized by very high biological activity. All - without any exception - components of milk fat, also saturated fatty acids considered as atherogenic, are extremely biologically active. Lipophylic antioxidants (conjugated linoleic acid, alpha-tocopherol, vitamin A and beta-carotene, coenzyme Q10, vitamin D3 and phospholipids) are efficient in inhibition of processes of lipids peroxidation within cell structures and of plasma lipoproteins. The unique components of milk fat i.e. conjugated linoleic acid and ether lipids (alkyloglyceroles and alkyloglycerophospholipids) possess the broadest spectrum of pro-health activity. PMID- 25815622 TI - [Interpersonal games as a method for doctors' occupational stress]. AB - Doctors are frequently expose to stress during their occupational work. It is mainly the result of burdens caused by taking care of patients, dysfunctional arrangements of the health care system and difficult relationships in their workplace. Chronic stress brings negative emotions and they need to cope with them . Doctors, willing to achieve it, may initiate interpersonal games with the hidden motive of restoring their internal balance. Based on transactional analysis, the authors describe some of the games which may be found in doctors' environment: "How to get out of there", "Mine is better than yours", "Scapegoat", "Fault" and "double bind". The outcome of the games may be receiving a support, proving a benefit derived from stress, getting the feeling of being not guilty, justification, or releasing emotions in apparently unintended way. Interpersonal games may help stressed doctors to get rid of internal tension but at the same time they may be a source of stress for other participants in the games. The way to limit their destructive impact is to create such administrative and organizational solutions which allow to make working conditions more friendly. PMID- 25815623 TI - [Abortion and conscientious objection]. AB - Polish laws specify the parties responsible for lawful medical care in the availability of abortion differently than the Resolution of the Council of Europe. According to Polish regulations they include all Polish doctors while according to the Resolution, the state. Polish rules should not discriminate against anyone in connection with his religion or belief, even more so because the issue of abortion is an example of an unresolved ethical dispute. The number of lawful abortion in Poland does not exceed 1000 per year and can be carried out by only a few specialists contracted by the National Health Fund. Sufficient information and assistance should be provided to all pregnant women by the National Health Fund. The participation of all physicians in the informing process is not necessary, as evidenced by the lack of complaints to provide information on where in vitro fertilization treatment can be found - until recently only available when paid for by the individual and performed in much larger numbers than abortion. Entities performing this paid procedure made sure to provide information on their own. The rejection of the right to the conscientious objection clause by negating the right to refuse information may lead some to give up the profession or cause the termination of certain professionals on the basis of the professed worldview. Meanwhile, doctors are not allowed to be discriminated against on the basis of their conscience or religion. PMID- 25815624 TI - Investigating the mechanisms of amylolysis of starch granules by solution-state NMR. AB - Starch is a prominent component of the human diet and is hydrolyzed by alpha amylase post-ingestion. Probing the mechanism of this process has proven challenging, due to the intrinsic heterogeneity of individual starch granules. By means of solution-state NMR, we demonstrate that flexible polysaccharide chains protruding from the solvent-exposed surfaces of waxy rice starch granules are highly mobile and that during hydrothermal treatment, when the granules swell, the number of flexible residues on the exposed surfaces increases by a factor of 15. Moreover, we show that these flexible chains are the primary substrates for alpha-amylase, being cleaved in the initial stages of hydrolysis. These findings allow us to conclude that the quantity of flexible alpha-glucan chains protruding from the granule surface will greatly influence the rate of energy acquisition from digestion of starch. PMID- 25815625 TI - Long-circulating iodinated albumin-gadolinium nanoparticles as enhanced magnetic resonance and computed tomography imaging probes for osteosarcoma visualization. AB - Multimodal imaging probes represent an extraordinary tool for accurate diagnosis of diseases due to the complementary advantages of multiple imaging modalities. The purpose of the work was to fabricate a simple dual-modality MR/CT probe for osteosarcoma visualization in vivo. Protein-directed synthesis methods offer a suitable alternative to MR/CT probe produced by synthetic chemistry. Bovine serum albumin (BSA) bound to gadolinium nanoparticles (GdNPs) was first prepared via a biomimetic synthesis method and was subsequently iodinated by chloramine-T method. The final iodinated BSA-GdNPs (I-BSA-GdNPs) showed excellent chemical stability and biocompatibility, intense X-ray attenuation coefficient, and good MR imaging ability. However, an iodinated protein nanoparticles synthesis for MR/CT imaging, as well as its useful application, has not been reported yet. Intravenous injection of I-BSA-GdNPs into orthotopic osteosarcoma-bearing rats led to its accumulation and retention by the tumor, allowing for a noninvasive tumor dual-modality imaging through the intact thigh. The long-circulating dual model I-BSA-GdNPs probes possess potential application for image-guided drug delivery and image-guided surgery. Our study is therefore highlighting the properties of albumin in this field combined with its useful use in dual-model MR/CT osteosarcoma visualization, underlining its potential use as a drug carrier for a future therapy on cancer. PMID- 25815626 TI - Metallothioneins in the lung cancer. AB - Metallothioneins (MTs) are low weight proteins involved in several key cellular processes such as metal ions homeostasis, detoxification and scavenging of free radicals. Four groups of MTs are distinguished: MT-1, MT-2, MT-3 and MT-4. Regardless of the type, MTs are characterized by high content of cysteine, responsible for their biological properties such as binding of relevant zinc and copper ions, as well as toxic ions such as lead and cadmium. MTs were additionally shown to protect cells against oxidative stress damage and participate in differentiation, proliferation and/or apoptosis of normal and cancer cells. Many studies of different neoplasms showed association of elevated MTs levels with occurrence of chemo- and radiotherapy resistance and poor patients' outcome. In this review, we summarize and discuss the potential mechanism of action of metallotioneins in lung physiology and pathology. PMID- 25815628 TI - Argon ion irradiation induced morphological instability of bare and thiol functionalized Au(111) surfaces. AB - Ar ion irradiation-induced changes in the morphology of bare and 1-dodecanethiol self-assembled monolayer (SAM) covered Au(111) surfaces have been investigated systematically. The changes were followed by scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy (XPS) measurements while varying the ion charge (Ar(+),Ar(4+)), energy (10-40 keV) and fluency (10(12)-10(13) ions per cm(2)). The impact of flame-annealing of the Au(111) surface on subsequent ion bombardment was considered and more prominent related surface morphology changes were noted. The irradiation of Au(111) surfaces generated Au vacancy and adatom islands and caused roughening of step edges. The size and abundance of these islands and the level of deformation on the step edges depended strongly on the ion energy and fluency. In case of the SAM functionalized surface, the gold vacancy islands present on the surface already from the SAM formation were modified, step edges roughened and gold adatom islands formed. Similarly to the bare surface, the level of surface deformation increased as a function of ion energy and fluency. The Ar(4+) irradiation caused on the average slightly larger vacancy islands on the SAM modified surfaces than the Ar(+) irradiation. Irradiation to fluency of 10(12) ions per cm(2) mostly maintained standing-up orientation of the thiolates whereas irradiation to higher fluency resulted in reduced surface coverage and flat-lying molecules. As a general trend the DDT covered surfaces were more susceptible for irradiation-induced surface morphology changes than the unmodified Au surfaces. PMID- 25815627 TI - Neuropathic alterations of the myenteric plexus neurons following subacute intraperitoneal administration of salsolinol. AB - INTRODUCTION: Impairment of the enteric nervous system has been suggested to occur within the pathogenesis of neurodegenerative diseases. Thus, in the current study, we consider salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4 tetrahydroisoquinoline, SAL) as a substance that can potentially induce myenteric neurodegen-eration. MATERIAL AND METHODS: Male Wistar rats were subjected to continuous intraperitoneal dosing of salsolinol (200 mg/kg in total) with osmotic mini-pumps for either two or four weeks. An equivalent group of rats served as the control. Jejunal myenteric neurons were subjected to immunofluorescence staining to detect neuron specific protein - protein gene product (pan-neuronal marker, PGP 9.5), nitric oxide synthase (NOS), choline acetyltransferase (ChAT), Bax-protein and alpha-synuclein. In search of any functional impairment within the gastrointestinal tract, gut motility was assessed by determining the residual solid food contents in the stomach and the small and large intestine transit. RESULTS: The myenteric neuron count, the mean size of the neuron body, the area of ganglia and the diameter of nerve strands were decreased in both of the salsolinol-treated groups compared with the controls. The number of NOS-positive cells was lower in the salsolinol-treated groups, while the number of ChAT positive cells remained unchanged in comparison with the controls. Neurons expressing the pro-apoptotic Bax protein and alpha-synuclein deposits were observed among the myenteric neurons of the salsolinol-treated rats. CONCLUSIONS: Salsolinol evokes enteric neuronal cell death via initiation of apoptosis and leads to the formation of pathological aggregates of alpha-synuclein. Impairment of myenteric neurons, mainly the inhibitory motor neurons, might be responsible for the abnormal intestinal transit. Thus, salsolinol might be regarded as a suitable compound for inducing experimental enteric neurodegeneration in rats. PMID- 25815629 TI - All-wurtzite ZnO/ZnSe hetero-nanohelix: formation, mechanics and luminescence. AB - A unique all-wurtzite ZnO/ZnSe hetero-nanohelix is formed via growing wurtzite ZnSe nanoteeth on ZnO nanobelts through a one step thermal evaporation method. The microstructure and growth mechanism of the hetero-nanohelix are investigated in detail. The formation of metastable wurtzite ZnSe is attributed to the wurtzite ZnO template. Mechanical forces, thermal expansion and polar plane in hexagonal crystals are suggested to contribute to the bending of the nanohelix. A boomerang-like structural block is proposed to assemble the zigzag ZnO nanobelts. The incorporation of Se into ZnO results in a strong orange emission. The heterostructure of the ZnO/ZnSe nanohelix is confirmed by elemental mapping and luminescence imaging. The fabrication of such a hetero-nanohelix may provide insights into the growth mechanism of the rich family of ZnO-based nanostructures. PMID- 25815630 TI - Reversibly Cross-Linkable Thermoresponsive Self-Folding Hydrogel Films. AB - This paper reports a novel approach for the design of self-folding films using reversibly cross-linkable thermoresponsive polymers with coumarin groups: poly(N isopropylacrylamide-co-7-(2-methacryloyloxyethoxy)-4-methylcoumarin). We demonstrated that, depending on the structure of the films and the conditions of cross-linking/de-cross-linking, one can fabricate a variety of different forms ranging from simple tubes to complex centipede-like structures. The demonstrated approach opens new perspectives for the design of 3D self-assembling materials. PMID- 25815631 TI - Intramedullary spinal epidermoid presenting after thoracic meningocele repair: case report. AB - A 4-year-old girl with a history of thoracic meningocele repair at the age of 3 months presented with progressive myelopathy. An intramedullary thoracic epidermoid was identified on MRI. The patient underwent excision of the epidermoid and subsequently returned to neurological baseline. This case illustrates the potential for delayed development of intraspinal epidermoid after initial repair of a simple meningocele. PMID- 25815632 TI - Multimodal treatment strategies for complex pediatric cerebral arteriovenous fistulas: contemporary case series at Barrow Neurological Institute. AB - OBJECT Pediatric cerebral arteriovenous fistulas (AVFs) are rare but potentially lethal vascular lesions. Management strategies for these lesions have undergone considerable evolution in the last decade with the advent of new endovascular, surgical, and radiosurgical technologies. This study sought to review current treatment strategies and long-term clinical outcomes at a high-volume cerebrovascular institute. METHODS A retrospective chart review was performed on patients with a diagnosis of cerebral AVF from 1999 to 2012. Patients with carotid-cavernous fistulas, vein of Galen malformations, and age > 18 years were excluded from final analysis. Medical history, surgical and nonsurgical treatment, and clinical outcomes were documented. Pre- and postoperative angiograms were analyzed to assess for obliteration of the fistula. RESULTS Seventeen patients with pial AVFs (29.4%), dural AVFs (64.7%), or mixed pial/dural AVFs (5.9%) were identified. The majority of lesions were paramedian (70.6%) and supratentorial (76.5%). The study population had a mean age of 6.4 years, with a slight male predominance (52.9%), and the most common presenting symptoms were seizures (23.5%), headaches (17.6%), congestive heart failure (11.7%), and enlarging head circumference (11.7%). Among patients who underwent intervention (n = 16), 56.3% were treated with endovascular therapy alone, 6.3% were treated with open surgery alone, and 37.5% required a multimodal approach. Overall, 93.8% of the treated patients received endovascular treatment, 43.8% received open surgery, and 12.5% received radiosurgery. Endovascular embolysates included Onyx (n = 5), N-butyl cyanoacrylate (NBCA; n = 4), or coil embolization (n = 7) with or without balloon assistance (n = 2). Complete angiographic obliteration was achieved in 87.5% at the last follow-up evaluation (mean follow up 3.1 years). One infant with incomplete AVF obliteration died of congestive heart failure, and 1 patient with complete obliteration died of acute sinus thrombosis, with an overall complication rate of 18.8%. CONCLUSIONS Pediatric cerebral AVFs are challenging neurosurgical lesions. Although advancements in endovascular therapy in the last decade have greatly changed the natural course of this disease, a multidisciplinary approach remains necessary for a large subset of patients. Surgeon experience with a thorough analysis of preoperative imaging is paramount to achieving acceptable clinical outcomes. PMID- 25815633 TI - Transoccipital endoscopic fenestration of atrial cysts causing ventricular entrapment. AB - OBJECT Cystic lesions in the atrium (trigone) of the lateral ventricle may become symptomatic due to obstruction of physiological CSF circulation and/or from mass effect on adjacent structures. A minimally invasive approach that not only allows for straightforward access to multiple regions of the atrial cyst wall, but also enables direct inspection of the entire lateral ventricular system, has not been elaborated. In this paper the authors describe their experience with the endoscopic transoccipital horn approach for treating cystic lesions in the atrium of the lateral ventricle. METHODS A retrospective review was performed of all patients who underwent endoscopic surgical treatment for cysts in the atrium of the lateral ventricle between 1999 and 2014. RESULTS The cohort consisted of 13 consecutive patients who presented with symptomatic lateral ventricular entrapment due to the presence of an atrial cyst. There were 9 male and 4 female patients, with a median age of 5 years. Headache was the most common complaint at presentation. The transoccipital horn approach facilitated successful cyst reduction and fenestration in all cases. Temporal and occipital horn entrapment was reversed in all cases, with reestablishment of a physiological CSF flow pattern throughout the ventricles. Hydrocephalus was also reversed in all patients presenting with this neuroimaging finding at presentation. No cyst or ventricular entrapment was noted to recur during a mean follow-up period of 36 months. No patient in the study cohort required repeat surgery or permanent CSF diversion postoperatively. CONCLUSIONS The endoscopic transoccipital horn approach represents a safe and effective treatment strategy for patients with symptomatic atrial cysts of the lateral ventricle. Using this minimally invasive technique, all poles of the lateral ventricular system can be visualized and the unobstructed flow of CSF can be confirmed after cyst resection obviating the need for additional diversion. PMID- 25815634 TI - Yawning as a presenting symptom of Chiari malformation Type I: report of 2 cases. AB - Yawning is thought to be a behavior regulated by the brainstem. Although excessive yawning has been reported in brainstem strokes, demyelination, and tumors, the cases presented here are the first reports of excessive yawning in patients with Chiari malformation Type I (CM-I). The authors believe that brainstem compression at the craniocervical junction and ensuing edema were implicated in this curious symptomatology. They describe excessive yawning as a presenting feature of CM-I in 2 adolescent females. The presentation was acute in the first case and more chronic in the second. Both patients underwent foramen magnum decompression, which resulted in complete cessation of the excessive yawning. PMID- 25815635 TI - Even mild depression is associated with among-day blood pressure variability, including masked non-dipping assessed by 7-d/24-h ambulatory blood pressure monitoring. AB - The effect of mild depression on blood pressure (BP) was assessed in 116 Japanese (32-79 years). As compared to non-depressive (Geriatric Depression Scale, GDS-15 score <5) subjects, mild depressives (GDS-15 score: 1-15) had shorter sleep duration (p = 0.021), lower subjective quality of life (health: p = 0.016; life satisfaction: p < 0.001; and happiness: p < 0.001), and higher 7-d systolic BP (p < 0.05). "Masked non-dipping" (dipping on day 1, but non-dipping on at least 1 of the following 6 d) was more frequent among depressive than non-depressive normotensives (p = 0.008). Among-day BP variability may underlie cardiovascular disease accompanying a key component of psychological depression. PMID- 25815637 TI - Comprehensive kinetic analysis and influence of reaction components for chlorzoxazone 6-hydroxylation in human liver microsomes with CYP antibodies. AB - 1. Chlorzoxazone (CLZ) is currently being used as a marker substrate in vitro/vivo studies to quantify cytochrome P450 2E1 (CYP2E1) activity in humans. Although in CLZ 6-hydroxylation several CYPs are responsible, previous studies have presented the monophasicity of the reaction in human liver microsomes (HLMs). Furthermore, the Km values of CYP2E1 for the 6-hydroxylation in HLMs were reported to be lower than those of its recombinant enzymes. 2. This study aimed to provide the comprehensive Km values for the CLZ 6-hydroxylation in HLMs using CYP antibodies. The Eadie-Hofstee plots revealed a biphasic profile and indicate that the reaction was mainly mediated by CYP1A2 as well as CYP2E1. The formation of 6-hydroxychlorzoxazone was more specific for CYP2E1 activity at higher substrate concentration in HLMs. 3. Moreover, KOH as a vehicle for substrate or sucrose included in HLMs preparation had some effect on the activity of CLZ 6 hydroxylase. These constituents seemed to be casually related to the apparent monophasic kinetics and variability in Km values for the CLZ 6-hydroxylation in HLMs. 4. The Km of CYP1A2 and CYP2E1 in HLMs was 3.8 umol/L and 410 umol/L, respectively, and the value of CYP2E1 was close to that of recombinant CYP2E1. PMID- 25815638 TI - Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity. AB - 1. Rhein, an active ingredient in the root of rhubarb, is used for its beneficial effects in a variety of clinical applications including the treatment of osteoarthritis and diabetic nephropathy. However, its hepatotoxicity has been reported in recent years. Rhein belongs to the conjugate structure which could be activated to reactive metabolites (RMs) inducing side-effects. This study is to explore the relationship between RMs and hepatotoxicity. 2. Based on the early detection of RMs, we have established a series of key technologies to research rhein hepatotoxicity mechanism: IC50 shift experiments and reduced glutathione (GSH) trapping experiment are adopted to identify RMs. The model of low activity of CYP450 enzymes (CYPs) in primary rat hepatocyte is constructed to analyze the relationship between the primary metabolic enzyme and hepatotoxicity of rhein better. 3. The IC50 shift value for CYP2C19 is 1.989, it suggests that CYP2C19 could activate rhein to RM. The structure of RM is epoxide intermediate. Besides, it is found that CYP2C19 is a primary metabolic enzyme for rhein. In the cytotoxicity assay, it is reported that rhein could cause mitochondrial dysfunction. Furthermore, mitochondrial membrane potential (Deltapsim) and AST levels could be restored by adding inhibitor of CYP2C19 together with rhein, which further shows that CYP2C19 could mediate the hepatotoxicity of rhein. 4. We put forward the possible mechanism that reactive metabolite activation by CYP2C19 mediated rhein hepatotoxicity, it provides important information on predicting in vivo drug-induced liver injury (DILI). PMID- 25815639 TI - Real-time evaluation of cell viability using nanoprobes. PMID- 25815636 TI - A nonapoptotic role for BAX and BAK in eicosanoid metabolism. AB - BCL-2 proteins are key regulators of programmed cell death. The interplay between pro and antiapoptotic BCL-2 members has important roles in many cancers. In addition to their apoptotic function, recent evidence supports key nonapoptotic roles for several BCL-2 proteins. We used an unbiased lipidomics strategy to reveal that the proapoptotic proteins BAX, and to a lesser extent BAK, regulate the cellular inflammatory response by mediating COX-2 expression and prostaglandin biosynthesis. COX-2 upregulation in response to the bacterial endotoxin lipopolysaccharide is blunted in the absence of BAX, and Bax(-/-) mouse embryonic fibroblasts display altered kinetics of NFkappaB and MAPK signaling following endotoxin treatment. Our approach uncovers a novel, nonapoptotic function for BAX in regulation of the cellular inflammatory response and suggests that inflammation and apoptosis are more tightly connected than previously anticipated. PMID- 25815640 TI - Determinants of clinician adoption of regenerative therapies in the UK and Canada: an ophthalmology perspective. AB - The determinants of adoption of regenerative medicine therapies are currently poorly understood. This study aims to draw comparison between the UK and Canada in terms of factors likely to affect healthcare adoption of future regenerative therapies in ophthalmology. Conducting semi-structured interviews with senior ophthalmologists in the UK and Canada, their perceptions of factors either enabling or limiting adoption were recorded and analyzed. A number of key concepts were extracted from the interview data, perceived by stakeholders to contribute to adoption. The core factors developed in this work will be of use to those looking to understand the opportunities and risks involved in securing clinician adoption in both the UK and Canada. PMID- 25815644 TI - The Causes of Their Death Appear (Unto Our Shame Perpetual): Why Root Cause Analysis Is Not the Best Model for Error Investigation in Mental Health Services. AB - OBJECTIVES: Root cause analysis (RCA) is the model of accident investigation mandated by the New South Wales Ministry of Health in Australia to review all serious incidents. Anecdotal evidence suggests that the RCA model is not suitable for reviewing adverse events in mental health services such as suicides and homicides. The aims of the research were to evaluate the impact of RCA on improving patient outcomes in a regional mental health service in New South Wales, Australia, and to discover whether the RCA model is the most appropriate model in mental health. METHODS: The literature on RCA was reviewed. The effectiveness of implementation of RCA recommendations was evaluated using quantitative and qualitative data. RESULTS: Suicides and homicides, which constitute 90% of serious critical incidents in mental health, do not always lend themselves well to identification of a root cause. There is evidence for low clinician engagement in the recommendations that arise from RCAs and a poor level of evidence that implementation of RCA recommendations results in safer patient care. Most troubling is the finding that RCAs frequently make recommendations that repeat existing policy or previous recommendations. CONCLUSIONS: Although the RCA model offers a formal and systematic approach to the review of serious critical incidents in mental health, it is not the model of best fit. Only 65% of recommendations made through RCA reviews are implemented within 12 months. PMID- 25815641 TI - CaMKII Phosphorylation of Na(V)1.5: Novel in Vitro Sites Identified by Mass Spectrometry and Reduced S516 Phosphorylation in Human Heart Failure. AB - The cardiac voltage-gated sodium channel, Na(V)1.5, drives the upstroke of the cardiac action potential and is a critical determinant of myocyte excitability. Recently, calcium (Ca(2+))/calmodulin(CaM)-dependent protein kinase II (CaMKII) has emerged as a critical regulator of Na(V)1.5 function through phosphorylation of multiple residues including S516, T594, and S571, and these phosphorylation events may be important for the genesis of acquired arrhythmias, which occur in heart failure. However, phosphorylation of full-length human Na(V)1.5 has not been systematically analyzed and Na(V)1.5 phosphorylation in human heart failure is incompletely understood. In the present study, we used label-free mass spectrometry to assess phosphorylation of human Na(V)1.5 purified from HEK293 cells with full coverage of phosphorylatable sites and identified 23 sites that were phosphorylated by CaMKII in vitro. We confirmed phosphorylation of S516 and S571 by LC-MS/MS and found a decrease in S516 phosphorylation in human heart failure, using a novel phospho-specific antibody. This work furthers our understanding of the phosphorylation of Na(V)1.5 by CaMKII under normal and disease conditions, provides novel CaMKII target sites for functional validation, and provides the first phospho-proteomic map of full-length human Na(V)1.5. PMID- 25815646 TI - Usefulness of dual-phase 18F-FDG PET/CT for diagnosing small pancreatic tumors. AB - OBJECTIVES: The usefulness of dual-phase F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) for pancreatic tumors was investigated including numerous small tumors. METHODS: Consecutive 116 patients with solid pancreatic tumors were subjected. Maximum standard uptake values (SUVmax) at 1 and 2 hours after FDG injection were defined as early and delayed SUVmax, respectively. Receiver operating characteristic curve was used to determine the optimal cutoff value of early SUVmax. Diagnostic accuracy of dual phase FDG PET/CT was compared with that of single phase. RESULTS: The mean +/- SD tumor size was 25 +/-12 mm in diameter. The level of early SUVmax and proportion of elevated SUVmax in delayed phase were significantly higher in malignancy than those in benignancy for less than 25 mm tumors (4.1 +/- 2.6 vs 1.9 +/- 0.5, P < 0.001; 89% vs 17%, P < 0.0001) although they did not reach statistical significance for greater than or equal to 25 mm tumors. When diagnostic criteria of dual-phase FDG PET/CT for less than 25 mm tumors were determined as (1) early SUVmax greater than or equal to 2.1 and/or (2) delayed SUVmax greater than early SUVmax, sensitivity, specificity, and over all accuracy of dual-phase FDG PET/CT were better than that of single phase for less than 25 mm tumor (93%, 83%, and 91% vs 79%, 83%, and 80%, respectively). CONCLUSIONS: Dual-phase FDG PET/CT might be useful for diagnosing small pancreatic tumors. PMID- 25815645 TI - High phosphate serum levels correlate with the severity of experimental severe acute pancreatitis: insight into the purinergic system. AB - OBJECTIVES: Extracellular purines are a component of the systemic inflammatory response, and their levels are modulated by ectonucleotidases. In addition, nucleotide hydrolysis releases phosphate. We studied serum phosphate levels as a predictor of severity in acute pancreatitis (AP) and their correlation with extracellular purinergic metabolism. METHODS: Acute pancreatitis was induced by the retrograde injection of sodium taurocholate. The AP group was compared with animals submitted to a model of sepsis by cecal ligation and puncture. The sham group was submitted to laparotomy and closure. We measured the phosphate and purine levels in serum and the expression of 5'-nucleotidase (CD73) and the adenosine A2a receptor in pancreatic tissue by quantitative real-time polymerase chain reaction. RESULTS: Serum phosphate levels were higher in severe AP and correlated with severity. Severe AP led to increased serum levels of adenosine diphosphate, adenosine monophosphate, and adenosine. In addition, adenosine monophosphate conversion to adenosine in serum was accelerated in the AP groups. We found a positive correlation between serum adenosine and phosphate in the AP groups. The expression levels of CD73 and the adenosine A2a receptor in the pancreas were not altered. CONCLUSIONS: Our study suggests that serum phosphate correlates with severity in AP and implicates extracellular purines in the systemic response to severe AP. PMID- 25815647 TI - Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011. AB - OBJECTIVES: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, a nationwide epidemiological survey was conducted. METHODS: Patients with AIP who had visited selected hospitals in 2011 were surveyed. Autoimmune pancreatitis was diagnosed according to the revised clinical diagnostic criteria for AIP (Japan Pancreas Society 2011). The study consisted of 2 stage surveys; the number of patients with AIP was estimated by the first questionnaire, and their clinical features were assessed by the second questionnaire. RESULTS: The estimated total number of AIP patients in 2011 was 5745 (95% confidence interval, 5325-6164), with an overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP was estimated to be 1808 (95% confidence interval, 1597-2018), with an annual incidence rate of 1.4 per 100,000 population. The sex ratio (male to female) was 3.2, and the mean age was 66.3 (11.5). Among the 936 patients whose detailed clinical information was obtained, 86.4% of the patients presented high serum immunoglobulin G4 levels (>=135 mg/dL), and 82.3% received steroid therapy. CONCLUSIONS: The data represent the current clinical features of AIP in Japan. PMID- 25815648 TI - In vitro activity of calcium sulfate and hydroxyapatite antifungal disks loaded with amphotericin B or voriconazole in consideration for adjunctive osteomyelitis management. AB - BACKGROUND: Regarding antibiotic-loaded cements, there is an abundant amount of literature regarding the antibacterial in vitro inhibitory and clinical applications for the treatment of osteomyelitis. The opposite can be said about literature regarding in vitro antifungal-loaded cement drug delivery for the treatment of fungal osteomyelitis. METHODS: Aspergillus fumigatus and Candida (ATCC 1023ATCC, Manassas, Virginia) were plated on antibiotic/antifungal-free plates. Voriconazole- and amphotericin B-impregnated calcium sulfate and hydroxyapatite (HA) disks, calcium sulfate + HA control disks, and control polymethylmethacrylate disks were laid separately onto plates separately inoculated with Aspergillus and Candida spp. The zones of inhibition obtained were measured in millimeters at 24, 36, and 96 hours. RESULTS: Etest (bioMerieux, Marcy l'Etoile, France) results demonstrated susceptibility of Aspergillus and Candida to amphotericin B and voriconazole. The zone of inhibition data demonstrated that voriconazole and amphotericin B retained their antifungal activity when mixed into the calcium sulfate + HA bone void filler and eluted at biologically effective antifungal concentrations over 96 hours. CONCLUSIONS: The calcium sulfate + HA bone void filler is a biocompatible ceramic carrier vehicle that can successfully deliver the antifungal drugs voriconazole and amphotericin B in the adjunctive treatment of fungal osteomyelitis. It is a reliable strategy in the local delivery of antifungal drugs to an area of osteomyelitis. PMID- 25815649 TI - Isolation of dermatophytes (and other fungi) from human nail and skin dust produced by podiatric medical treatments in Australia. AB - BACKGROUND: Podiatric physicians routinely use electric drills for the treatment of nail and skin conditions. The grinding process produces human nail and skin dust that is generally vacuumed into bags in the grinding unit. Many of the nails are thought to be mycotic, particularly because they are obtained from patients with symptoms of dermatophyte infections. Currently, there is limited information available on the detection of fungi from nail dust samples. Herein, we attempt to address this situation and outline some of the difficulties that pathology laboratories face in isolating and identifying dermatophytes from nail samples. METHODS: Fifty nail dust bags from podiatric medical clinics across all of the states and territories of Australia were collected and analyzed. Samples from the bags were inoculated onto primary isolation media. Fungal colonies that grew were then inoculated onto potato dextrose agar for identification using standard morphological (macroscopic and microscopic) features. RESULTS: One hundred fifty one colonies of dermatophytes were identified from 43 of the 50 samples. In addition 471 nondermatophyte molds were isolated, along with some yeasts and bacteria. CONCLUSIONS: The most common dermatophytes isolated were from the Trichophyton mentagrophytes/interdigitale complexes. Trichophyton rubrum, Trichophyton tonsurans, Trichophyton soudanense, and Epidermophyton floccosum were also isolated. An unidentified group of dermatophytes was also present. The three most common genera of nondermatophyte molds were Aspergillus, Penicillium, and Scopulariopsis, all of which have been implicated in onychomycosis and more general disease. The presence of viable fungal pathogens in the dust could potentially pose a health problem to podiatric physicians. PMID- 25815650 TI - The prevalence of interdigital erythrasma: a prospective study from an outpatient clinic in Turkey. AB - BACKGROUND: Erythrasma is a superficial skin infection caused by Corynebacterium minutissimum . Interdigital erythrasma is the most common form and is easily confused with tinea pedis. The aim of this study was to determine the prevalence of interdigital erythrasma in patients with clinically suspected tinea pedis. METHODS: This study was performed between January 1, 2011, and January 31, 2012. It included 182 patients who presented with concerns about interdigital lesions. All of the patients were examined with a Wood's lamp, and smears were stained with Gram's method. Direct examination with 20% potassium hydroxide was performed. RESULTS: Of 182 patients with interdigital lesions, 73 (40.1%) were diagnosed as having erythrasma. The mean +/- SD age of the patients with erythrasma was 45.52 +/- 10.83 years (range, 22-70 years). Most of the patients with erythrasma were women (56.2%). The most often clinical finding was desquamation. Using only Wood's lamp examination or Gram's staining resulted in 31 (42.5%) or 14 (19.2%) positive patients, respectively. Using Wood's lamp examination and Gram's staining concurrently resulted in 28 positive patients (38.4%). CONCLUSIONS: Interdigital erythrasma is a common condition and can be difficult to differentiate from tinea pedis. Simple and rapid diagnosis can be made with Wood's lamp examination, but Gram's staining is also a useful method, especially in patients with negative Wood's lamp examination findings. PMID- 25815651 TI - Pseudomonas aeruginosa: an uncommon cause of diabetic foot infection. AB - BACKGROUND: Pseudomonas aeruginosa has traditionally been considered a common pathogen in diabetic foot infection (DFI), yet the 2012 Infectious Diseases Society of America guideline for DFI states that "empiric therapy directed at P aeruginosa is usually unnecessary." The objective of this study was to evaluate the frequency of P aeruginosa isolated from bone or tissue cultures from patients with DFI. METHODS: This study is a cross-sectional survey of diabetic patients presenting with a foot infection to an urban county hospital between July 1, 2012, and December 31, 2013. All of the patients had at least one debridement procedure during which tissue or bone cultures from operative or bedside debridements were obtained. The chi(2) test and the t test of means were used to determine relationships between variables and the frequency of P aeruginosa in culture. RESULTS: The median number of bacteria isolated from DFI was two. Streptococcus spp and Staphylococcus aureus were the most commonly isolated organisms; P aeruginosa was isolated in only five of 112 patients (4.5%). The presence of P aeruginosa was not associated with the patient's age, glycosylated hemoglobin level, tobacco abuse, the presence of osteomyelitis, a prescription for antibiotic drugs in the preceding 3 months, or the type of operative procedure. CONCLUSIONS: Pseudomonas aeruginosa was an infrequent isolate from DFI in this urban, underserved diabetic population. The presence of P aeruginosa was not associated with any measured risk factors. By introducing a clinical practice guideline, we hope to discourage frontline providers from using routine antipseudomonal antibiotic drugs for DFI. PMID- 25815652 TI - Occupational stress among Australian podiatric physicians in general and geriatric practice. AB - BACKGROUND: High levels of occupational stress have been reported in podiatric physicians practicing in Australia. One possible stressor is the predominance of the treatment of aged patients with chronic disease in podiatric medical practice. METHODS: Forty podiatric physicians attending a regional podiatric medical conference were invited to participate in the research using a convenience sampling method. Podiatric physicians were asked to complete a survey examining occupational stress in general and specifically in relation to practice with older adults (defined as those older than 65 years). RESULTS: The survey of sources of occupational stress among podiatrists identified patient demands and expectations as the most significant stressor in general and geriatric practice for the podiatric physician. The perceived limited clinical gains and chronic nature of the conditions in older patients was also ranked highly as a stressor. CONCLUSIONS: Working with the elderly is a substantial part of podiatric medical practice and, as such, needs to be seen with a more positive attitude by many practitioners. The development of geriatric practice as a speciality within the profession may help raise the value of working with the elderly. This has implications for preparing podiatric physicians for practice with the geriatric population along with the need for strategies to avoid or minimize these work stressors. PMID- 25815653 TI - Ultrasound diagnosis and evaluation of plantar heel pain. AB - BACKGROUND: One of the most common causes of heel pain is plantar fasciitis; however, there are other pathologic disorders that can mimic the symptoms and clinical presentation of this disorder. The purpose of this study was to retrospectively review the prevalence of various pathologic disorders on ultrasound in patients with proximal plantar heel pain. METHODS: The medical records and diagnostic ultrasound reports of patients presenting with plantar heel pain between March 1, 2006, and March 31, 2007, were reviewed retrospectively, and the prevalence of various etiologies was collected. The inclusion criteria were based on their clinical presentation of plantar fasciitis or previous diagnosis of plantar fasciitis from an unknown source. Ultrasound evaluation was then performed to confirm the clinical diagnosis. RESULTS: We examined 175 feet of 143 patients (62 males and 81 females; age range, 16-79 years). Plantar fibromas were present in 90 feet (51%). Plantar fasciitis was diagnosed in 128 feet (73%). Coexistent plantar fibroma and plantar fascial thickening was found in 63 feet (36%). Of the 47 feet that were negative for plantar fasciitis on ultrasound, 27 (57%) revealed the presence of plantar fibroma. CONCLUSIONS: Diagnostic ultrasound can effectively and safely identify the prevalence of various etiologies of heel pain. The high prevalence of plantar fibromas and plantar fascial tears cannot be determined by clinical examination alone, and, therefore, ultrasound evaluation should be performed for confirmation of diagnosis. PMID- 25815654 TI - Radiographic anatomy of the foot and ankle-part 5. The phalanges. AB - BACKGROUND: The normal radiographic anatomy of the foot and ankle, aside from my previous work, has been addressed only superficially or sparingly in the medical literature. This project correlates the detailed radiographic anatomy of the entire adult foot and ankle (two-dimensional) to osteology (three-dimensional). METHODS: Each bone's position was determined after meticulous examination and correlation to an articulated skeleton relative to the image receptor and direction of the x-ray beam, with correlation to the radiograph for confirmation. RESULTS: Images of each foot and distal leg bone ("front" and "back" perspectives) are presented alongside a corresponding radiographic image for comparison. The normal gross and radiographic anatomy is correlated and described for each radiographic positioning technique. CONCLUSIONS: Foundational knowledge is provided that future researchers can use as a baseline ("normal") and that students and practitioners can use for comparison when interpreting radiographs and distinguishing abnormal findings. The results of the original project, owing to its broad scope, have been divided into five parts: the lower leg, the greater tarsus, the lesser tarsus, the metatarsals, and the phalanges (the focus of this article). PMID- 25815655 TI - Entrapment of the superficial peroneal nerve: an anatomical insight. AB - Entrapment of the superficial peroneal nerve is an uncommon neuropathy that may occur because of mechanical compression of the nerve, usually at its exit from the crural fascia. The symptoms include sensory alterations over the distribution area of the superficial peroneal nerve. Clinical examination, electrophysiologic findings, and imaging techniques can establish the diagnosis. Variations in the superficial peroneal sensory innervation over the dorsum of the foot may lead to variable results during neurologic examination and variable symptomatology in patients with nerve entrapment or lesions. Knowledge of the nerve's anatomy at the lower leg, foot, and ankle is of essential significance for the neurologist and surgeon intervening in the area. PMID- 25815656 TI - Fracture healing: an appraisal of the effects of frequently prescribed medications. AB - BACKGROUND: Recognizing the existence of adverse drug effects of frequently prescribed drugs can empower a clinician with knowledge to avoid dangerous adverse effects that may result in hazardous, negative patient outcomes on either fracture healing or bone health. Pharmacovigilance reports have described the influence of medications, allowing for bone health to be quite unpredictable. METHODS: First, mechanisms found in the medical literature of potential drug adverse effects regarding fracture healing are presented. Second, the 100 most frequently prescribed medications in 2010 are reviewed regarding adverse effects on fracture healing. These reported adverse effects are evaluated for medical causation. Last, a data table describing the 100 reviewed medications and their reported effects on fracture healing is provided. RESULTS: The actual number of different medications in the review was 72. Reported drug adverse effects on bone and fracture healing occurred with 59 of the 72 drugs (81.9%). These adverse effects are either described as a definitive statement or represented by postmarketing case reports. Thirteen of the 72 review drugs (18.1%) did not have any description of the possible effects on bone health. A total of 301 cases reports describing delayed union, malunion, and nonunion of fractures represent 31 of the 72 medications reviewed (43.1%). CONCLUSIONS: This review offers the health-care provider information regarding potential adverse drug effects on bone health. Empowered with this information, clinicians may assist their patients in maximizing pharmacologic outcomes by avoiding these reported harmful adverse effects. PMID- 25815657 TI - Severe chronic heel pain in a diabetic patient with plantar fasciitis successfully treated through transcranial direct current stimulation. AB - BACKGROUND: Recently, transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, was proposed as a suitable method for the treatment of several chronic pain syndromes. We describe a case of severe heel pain in a diabetic patient with plantar fasciitis successfully treated with tDCS. METHODS: The present study investigated whether tDCS treatment could reduce pain and pain-related anxiety in a 65-year-old diabetic man affected by treatment resistant right heel pain due to plantar fasciitis. The patient underwent five tDCS treatment sessions on 5 consecutive days. Each session consisted of 20-min anodal tDCS over the left primary motor cortex leg area. RESULTS: The neurostimulation protocol induced a decrease in pain intensity and pain-related anxiety that outlasted the stimulation (1 week). Furthermore, the patient stopped the intake of opioid medication. CONCLUSIONS: Therapeutic neuromodulation with tDCS may represent an alternative option for treating severe lower-extremity pain. PMID- 25815659 TI - A rare presentation of foot pain: bilateral navicular-medial cuneiform coalition. AB - In this case report, we discuss a rare tarsal coalition occurring bilaterally between the navicular and the medial cuneiform in a 15-year-old girl and highlight the management of such cases. PMID- 25815658 TI - Multiple simultaneous metatarsal stress fractures in the same foot. AB - Metatarsal stress fractures are common overuse injuries in athletes, military recruits, and ballet dancers, usually occurring in the second, third, and fourth metatarsals, respectively. Such fractures may also occur in a variety of other individuals, regardless of demographic characteristics, sex, or profession, and they are highly associated with excessive activity. Moreover, these types of fractures are usually diagnosed late and have poor outcomes. To our knowledge, there has been only one case report of an individual with stress fractures of all three central metatarsals in the same foot. We describe herein a racehorse training jockey who presented with multiple simultaneous metatarsal stress fractures in the same foot. We also discuss the possible mechanisms by which this entity occurred, as well as its management and outcome. PMID- 25815660 TI - To cipro or not to cipro: bilateral achilles ruptures with the use of quinolones. AB - Ciprofloxacin and other fluoroquinolones are commonly used broad-spectrum antimicrobial agents for treating bacterial infections. This class of antibiotic drugs has uncommon adverse effects that include tendonitis, tendon ruptures, and other tendon abnormalities. We describe a patient with spontaneous bilateral complete Achilles tendon rupture after ciprofloxacin treatment. Surgical repair was performed successfully, and the patient completed physical rehabilitation without incident. Care should be exercised when selecting pharmaceutical agents to maintain a positive benefit-to-risk balance. PMID- 25815661 TI - Acral lentiginous melanoma of the foot misdiagnosed as a traumatic ulcer. A cautionary case. AB - The incidence of cutaneous melanoma is rising faster than that of almost any other cancer in the United States. Acral lentiginous melanoma is a subtype of melanoma that involves the palms, soles, and nail beds. Although it is one of the rarer types of melanoma, it has a poorer prognosis than other more common subtypes. We describe a case of plantar acral melanoma in a 66-year-old woman that was initially misdiagnosed as a traumatic foot ulcer. We highlight this case to emphasize the importance of close observation and biopsy of ulcerative lesions of the foot that have atypical features or are refractory to standard treatment. PMID- 25815662 TI - Red, exophytic nodule of the plantar foot an unusual presentation of a pyogenic granuloma. AB - Pyogenic granulomas are benign vascular tumors characterized histologically by a lobular proliferation of capillaries. We report an unusual presentation of a pyogenic granuloma in an elderly patient with a bleeding red nodule on the plantar surface of the foot. Nodular exophytic plantar foot lesions often present a diagnostic challenge, as the differential diagnosis includes benign and malignant entities ranging from eccrine poroma and pyogenic granuloma to Kaposi's sarcoma and amelanotic melanoma. This case highlights the need for an adequate biopsy technique to confirm the diagnosis and guide management. PMID- 25815663 TI - The role of podiatric medicine in the health-care team. A paradigm shift. AB - As physicians, podiatric medical doctors should not define themselves as medical professionals who treat the foot and ankle but rather as medical professionals who prevent, diagnose, and treat people who have foot and ankle problems. Patients who come to see podiatric physicians often have other health-care issues, and because of the education and training that doctors of podiatric medicine receive, they are uniquely qualified to identify and respond to findings not only related to the pedal extremity but also that may affect overall health, have a major effect on quality of life, and even help reduce overall health-care costs. The role of podiatric medicine as a truly integrated branch of medical care needs to be reassessed. PMID- 25815664 TI - The 1-percent solution. PMID- 25815669 TI - Synthesis and biological evaluation of novel 3-substituted amino-4 hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents. AB - A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC50 of 0.10 mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC50 of 0.18 mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4 MUg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents. PMID- 25815668 TI - Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl 4(3H)quinazolinone analogues. AB - A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2 ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4 dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6 methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl) propanamide have shown amazing broad spectrum antitumor activity with mean GI(50) (10.47, 7.24 and 14.12 uM. respectively), and are nearly 1.5-3.0-fold more potent compared with the positive control 5-FU with mean GI50, 22.60 uM. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032. PMID- 25815670 TI - Design, synthesis, antimicrobial evaluation and molecular docking studies of some new 2,3-dihydrothiazoles and 4-thiazolidinones containing sulfisoxazole. AB - Microbial resistance to the available drugs poses a serious threat in modern medicine. We report the design, synthesis and in vitro antimicrobial evaluation of new functionalized 2,3-dihydrothiazoles and 4-thiazolidinones tagged with sulfisoxazole moiety. Compound 8d was most active against Bacillis subtilis (MIC, 0.007 ug/mL). Moreover, compounds 7c-d and 8c displayed significant activities against B. subtilis and Streptococcus pneumoniae (MIC, 0.03-0.06 ug/mL and 0.06 0.12 ug/mL versus ampicillin 0.24 ug/mL and 0.12 ug/mL; respectively). Compounds 7a and 7c-d were highly potent against Escherichia coli (MIC, 0.49-0.98 ug/mL versus gentamycin 1.95 ug/mL). On the other hand, compounds 7e and 9c were fourfolds more active than amphotericin B against Syncephalastrum racemosum. Molecular docking studies showed that the synthesized compounds could act as inhibitors for the dihydropteroate synthase enzyme (DHPS). This study is a platform for the future design of more potent antimicrobial agents. PMID- 25815671 TI - Phosphoramidate-based peptidomimetic inhibitors of membrane type-1 matrix metalloproteinase. AB - Membrane-type I matrix metalloproteinases (MT1-MMP) is an enzyme critical to the remodeling and homeostasis of extracellular matrix, and when over expressed it contributes to metastasis and cancer cell progression. Because of its role and implication as a biomarker that is upregulated in various cancers, MT1-MMP has become an attractive target for drug discovery. A small pilot library of peptidomimetics containing a phosphoramidate core as a zinc-binding group was synthesized and tested for inhibitory potency against MT1-MMP. From this library, a novel two residue peptidomimetic scaffold was identified that confers potency against MT1-MMP at submicromolar concentrations. The results of this study confirm that for this scaffold, valine is favored as a P1 residue and leucine in the P1' position. Furthermore, steric tolerance was observed for the N-terminus, thus implicating that a second-generation library could be constructed to extend the scaffold to P2 without concomitant loss of affinity within the MT1-MMP catalytic domain. PMID- 25815672 TI - Effects of Eicosapentaenoic Acid on the Cytoprotection Through Nrf2-Mediated Heme Oxygenase-1 in Human Endothelial Cells. AB - Consumption of omega-3 polyunsaturated fatty acid, particularly eicosapentaenoic acid (EPA), is associated with a significant reduction in the risk of developing cardiovascular disease. The aim of this study was to investigate whether heme oxygenase-1 (HO-1) induction contributes to the cytoprotective effects of EPA in endothelial cells threatened with oxidative damage. In this study, we investigated the effect of EPA on the induction of HO-1 by NF-E2-related factor 2 (Nrf2) in human umbilical vein endothelial cells. In cells treated with low concentrations of EPA (10-25 MUM), HO-1 expression increased in a time- and concentration-dependent manner. Additionally, EPA treatment increased Nrf2 nuclear translocation and antioxidant response element activity, leading to the upregulation of HO-1 expression. Furthermore, treatment with EPA reduced hydrogen peroxide (H(2)O(2))-induced cell death. The reduction in cell death was reversed by treatment with zinc protoporphyrin, an inhibitor of HO-1, indicating that HO-1 contributed to the protective effect of EPA. These data suggest that EPA protects against H(2)O(2)-induced oxidative stress in endothelial cells by activating Nrf2 and inducting HO-1 expression. PMID- 25815674 TI - Cytoprotective Role of Alpha-1 Antitrypsin in Vascular Endothelial Cell Under Hypoxia/Reoxygenation Condition. AB - Ischemia/reperfusion (IR) injury is a critical factor in the pathogenesis of tissue injury after myocardial infarction, multiple organ failure, and other acute ischemic events. Previous studies suggest that alpha1-antitrypsin (AAT) plays a cytoprotective role in beta cells and human pulmonary cells. We hypothesize that AAT may have the potential to reduce IR-induced vascular injury involved in cell apoptosis and permeability. In this study, we investigate the role of AAT in human umbilical vein endothelial cells using a model wherein endothelial cell monolayers are exposed to hypoxia/reoxygenation (HR). We found that exogenous AAT alleviated HR injury in a dose- and time-dependent manner. Furthermore, by gain and loss function experiments, we demonstrated that overexpression of AAT decreased cell apoptosis and promoted proliferation by inhibiting Rac1/PAK/p38 signaling and against oxidative stress, and also reduced cellular permeability by increasing ZO-1 and occludin expression. Thus, we provided evidences to illustrate that AAT played a cytoprotective role in vascular endothelial cell under HR condition, suggesting that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular injury. PMID- 25815673 TI - Inhibition of Myogenic Tone in Rat Cremaster and Cerebral Arteries by SKA-31, an Activator of Endothelial KCa2.3 and KCa3.1 Channels. AB - Endothelial KCa2.3 and KCa3.1 channels contribute to the regulation of myogenic tone in resistance arteries by Ca(2+)-mobilizing vasodilatory hormones. To define further the functional role of these channels in distinct vascular beds, we have examined the vasodilatory actions of the KCa channel activator SKA-31 in myogenically active rat cremaster and middle cerebral arteries. Vessels pressurized to 70 mm Hg constricted by 80-100 MUm (ie, 25%-45% of maximal diameter). SKA-31 (10 MUM) inhibited myogenic tone by 80% in cremaster and ~65% in middle cerebral arteries, with IC50 values of ~2 MUM in both vessels. These vasodilatory effects were largely prevented by the KCa2.3 blocker UCL1684 and the KCa3.1 blocker TRAM-34 and abolished by endothelial denudation. Preincubation with N(G) nitro L-arginine methyl ester (L-NAME, 0.1 mM) did not affect the inhibitory response to SKA-31, but attenuated the ACh-evoked dilation by ~45%. Penitrem-A, a blocker of BK(Ca) channels, did not alter SKA-31 evoked vasodilation but did reduce the inhibition of myogenic tone by ACh, the BKCa channel activator NS1619, and sodium nitroprusside. Collectively, these data demonstrate that SKA-31 produces robust inhibition of myogenic tone in resistance arteries isolated from distinct vascular beds in an endothelium-dependent manner. PMID- 25815675 TI - Improvements in CYP2C9 Genotyping Accuracy Are Needed: A Report of the First Proficiency Testing for Warfarin-related CYP2C9 and VKORC1 Genotyping in China. AB - Warfarin is the most commonly used oral anticoagulant in clinical practice. The cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been confirmed to be associated with warfarin dose requirements. Accurate genotyping results are of particular importance for obtaining reliable genotype-guided warfarin dosing information. This study aims to determine analytic performance of laboratories offering CYP2C9 and VKORC1 testing in China. A proficiency panel of 15 validated cell samples covering common CYP2C9 and VKORC1 genetic polymorphisms was provided to 31 participating laboratories, and their genotyping results were evaluated. Fourteen data sets (45.2%) performed well with the entire panel of samples, and 17 data sets (54.8%) reported at least one genotyping error. For VKORC1 (-1639G>A), participating laboratories were 100% successful in detecting genotypes of GG, GA, and AA. For CYP2C9, participants were greater than 90% successful in detecting genotypes of *1/*1, *1/*2, *1/*3, *2/*3, and *3/*3. However, 15 laboratories failed to detect rarely encountered variant genotype *2/*2. The poor performance of CYP2C9 genotyping may be because of the limitation of methodologies used for detecting CYP2C9*2 allele. The proficiency testing survey highlighted the need for improving genotyping accuracy for some laboratories in this field. PMID- 25815676 TI - Effect of Glucagon-like Peptide-1 on High-Glucose-induced Oxidative Stress and Cell Apoptosis in Human Endothelial Cells and Its Underlying Mechanism. AB - Glucagon-like peptide-1 (GLP-1) has been demonstrated to play an important role in type 2 diabetes mellitus, leading to cardiovascular diseases. This study aimed to examine the GLP-1 regulation of high-glucose-induced oxidative stress and cell apoptosis in human umbilical vein endothelial cells (HUVECs) and its underlying mechanism. HUVECs were isolated from healthy umbilical cords and cultured. GLP-1 and the GLP-1R antagonist, exendin (9-39), were used to pretreat the cells. The expression of NADPH oxidase subunits gp91 and p22 messenger RNA was detected by real-time quantitative polymerase chain reaction. Reactive oxygen species production was detected with flow cytometry and fluorescence microscopy. Lucigenin assay was used to measure the NADPH oxidase activity. The terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay was used to investigate endothelial cell apoptosis. Apoptosis proteins were detected by immunoblotting. GLP-1 decreased high-glucose-induced oxidative stress, the expression of gp91 and p22phox messenger RNAs, and NADPH oxidase activation. Exendin (9-39) antagonized the effects of GLP-1 on high-glucose-induced oxidative stress. GLP-1 also increased HUVEC's high-glucose-induced proliferation and inhibited apoptosis. GLP-1 inhibited high-glucose-induced oxidative stress and cell apoptosis in HUVECs through GLP-1R-dependent and GLP-1 (9-36)-related pathways. GLP-1 suppressed high-glucose-induced oxidative stress and consequently may have an antiatherosclerosis effect on diabetes mellitus patients. PMID- 25815677 TI - Nasolacrimal System Fractures: A Description of Radiologic Findings and Associated Outcomes. AB - BACKGROUND: Fractures of the bony nasolacrimal system (NLS), including the lacrimal sac fossa and nasolacrimal canal, have not been comprehensively described in patients with facial trauma. Characterization of these injuries may help facial trauma surgeons better predict which patients will develop lacrimal outflow obstruction symptoms including epiphora and dacryocystitis and who may eventually need lacrimal surgery. METHODS: CT images for all patients seen at the University of Wisconsin Hospital and Clinics for craniofacial trauma were reviewed from January 2001 to December 2005. Patients were included if they had a NLS fracture and at least 1 year of follow-up. Fracture patterns were described and correlated with clinical outcomes documented in the medical record. Outcomes, including the development of epiphora or dacryocystitis and the need for lacrimal surgery, were analyzed using Fisher exact test. RESULTS: We identified 104 patients with NLS fractures among 1980 patients with craniofacial trauma who had at least 1 year of follow-up. Eleven patients (10.6%) developed epiphora or dacryocystitis, and 2 patients (1.9%) required dacryocystorhinostomy (DCR). Ten radiographic injury patterns were characterized. Avulsion of the lacrimal crest, bone fragment in the lacrimal sac fossa or duct, duct compression greater than 50%, and nasomaxillary buttress displacement were significantly associated with the development of epiphora or dacryocystitis (P < 0.05). Nasomaxillary buttress displacement was significantly associated with the eventual need for DCR (P = 0.03). CONCLUSIONS: Patients with radiographic evidence of NLS fracture have an approximately 10% risk of developing epiphora or dacryocystitis. We describe 5 NLS fracture findings that are significantly associated with the development of lacrimal outflow obstruction. The presence of nasomaxillary buttress fracture and displacement suggests a significantly higher risk of eventually needing lacrimal surgery. PMID- 25815678 TI - User perceptions of existing home access solutions and a novel home access device. AB - PURPOSE: This study aimed to evaluate end user perspectives of four existing home access solutions (HAS) and a newly designed experimental device (the ARISE). METHOD: A cross-sectional design was used to evaluate the ARISE prototype against other HAS. Specifically, participants trialed stairs, a ramp, a platform lift (PL), a stair glide and the ARISE, after which they completed questionnaires aimed at soliciting their perspectives of these solutions. The time taken by participants to use each HAS was also collected. RESULTS: Five HAS design features were deemed as important by 90% of participants: ease of use, ability to use independently, reliability, safety and security. Time taken to use each HAS from fastest to slowest was: stairs, the ARISE, ramp, PL and stair glide. The ARISE prototype was rated as the first or second most preferred device by the most number of participants, followed by the PL, then the ramp. CONCLUSIONS: Results from this study provide greater understanding of user perspectives of HAS. End user feedback on a novel prototype device has provided valuable insight into its usability and function, which should not only guide future development of this device, but also provide direction for other innovations around home access. Implications for Rehabilitation It is anticipated that gaining a better understanding of strengths and weaknesses of home access solutions will: assist clinicians and end users in finding solutions that meet the individuals' needs. lead to the development of new or improved solutions that more closely address user needs. encourage further innovation in the area. PMID- 25815679 TI - The impact of mobility assistive technology devices on participation for individuals with disabilities. AB - AIM: This study aims to address the gap in research and contribute to the body of knowledge on the perspectives assistive technology device users have toward their devices. METHOD: Mixed methods were used to better understand the impact of mobility assistive technology devices (MATDs) on participation for individuals with disabilities. The Functional Mobility Assessment was administered in conjunction with two qualitative questions developed by the research team allowing participants to expound on the impact of their MATD experience. Participants were recruited online via the National Spinal Cord Injury Association website and in-person at Abilities Expo in Atlanta, Georgia, and the International Seating Symposium in Nashville, Tennessee. RESULTS: Results are consistent with findings from prior research regarding accessibility for individuals with disabilities. Corresponding findings were found in both the quantitative and qualitative data and are categorized into several major themes: environment (indoor and outdoor), surface heights, transportation, dependence, independence, quality of life and participation. CONCLUSION: Quantitative data from this study indicate that users of MATD are satisfied with the way in which their devices enable maneuvering indoors, while qualitative data suggest otherwise. Implications for healthcare practitioners are described and future recommendations are provided. Implications for Rehabilitation Healthcare professionals should advocate for proper mobility assistive technology devices (MATDs) for their patients in order to enable increased independence, safety and efficiency. Healthcare professionals must be cognizant of the impact of the environment and/or environmental barriers when prescribing MATD. Additional areas of interest for future research may include investigating the impact of MATD in association with date of onset of disability, according to diagnoses, or specific to length of time since acquiring the device. PMID- 25815681 TI - Development and evaluation of a hand tracker using depth images captured from an overhead perspective. AB - PURPOSE: We present the development and evaluation of a robust hand tracker based on single overhead depth images for use in the COACH, an assistive technology for people with dementia. The new hand tracker was designed to overcome limitations experienced by the COACH in previous clinical trials. METHODS: We train a random decision forest classifier using ~5000 manually labeled, unbalanced, training images. Hand positions from the classifier are translated into task actions based on proximity to environmental objects. Tracker performance is evaluated using a large set of ~24 000 manually labeled images captured from 41 participants in a fully-functional washroom, and compared to the system's previous colour-based hand tracker. RESULTS: Precision and recall were 0.994 and 0.938 for the depth tracker compared to 0.981 and 0.822 for the colour tracker with the current data, and 0.989 and 0.466 in the previous study. CONCLUSIONS: The improved tracking performance supports integration of the depth-based tracker into the COACH toward unsupervised, real-world trials. Implications for Rehabilitation The COACH is an intelligent assistive technology that can enable people with cognitive disabilities to stay at home longer, supporting the concept of aging-in-place. Automated prompting systems, a type of intelligent assistive technology, can help to support the independent completion of activities of daily living, increasing the independence of people with cognitive disabilities while reducing the burden of care experienced by caregivers. Robust motion tracking using depth imaging supports the development of intelligent assistive technologies like the COACH. Robust motion tracking also has application to other forms of assistive technologies including gaming, human-computer interaction and automated assessments. PMID- 25815680 TI - A scoping review of video gaming in rehabilitation. AB - PURPOSE: To examine the scope of the peer-reviewed literature on the use of commercially available video gaming in rehabilitation. METHODS: Five databases (SCOPUS, Cochrane, PsycINFO, PubMed and CINAHL) were searched for articles published between January 1990 and January 2014. The reference lists of selected articles were also reviewed to identify other relevant studies. RESULTS: Thirty articles met the inclusion criteria. Commercially available video gaming in rehabilitation was most commonly recommended by physiotherapists (50% or 15/30 studies) for populations at risk for falls or with decreased balance (67% or 19/30 studies). The most commonly used target outcomes were those assessing balance and/or fall prevention, with the Berg Balance Scale being the most frequently used (53% or 16/30 studies) outcome measure. The Nintendo Wii was the most prevalent gaming system (90% or 27/30 studies) used in the identified studies. CONCLUSION: Video gaming in rehabilitation is widely used by clinicians. Preliminary findings show that video gaming technology can be applied across a wide variety of rehabilitation populations, with some evidence showing clinical gains in physical functioning (e.g. gait and balance). There is a need for more robust clinical trials evaluating the efficacy of using video game systems as an adjunct to conventional rehabilitation. Implications for Rehabilitation Video gaming is a readily available technology that has been suggested as an enjoyable and motivating activity that engages patients in rehabilitation programming. Video gaming is becoming an increasingly popular adjunct to traditional therapy. Video gaming is most commonly used by physical therapists in a hospital setting for those with balance impairments. Video gaming has been shown to improve functional outcomes. PMID- 25815682 TI - Exploring assistive technology and post-school outcomes for students with severe disabilities. AB - PURPOSE: This study sought to understand the extent to which students with severe disabilities receive assistive technology in school and out-of-school, and the relationship between receipt of assistive technology in school and post-school outcomes for these students. METHOD: This study was a secondary analysis of the National Longitudinal Transition Study-2 (NLTS2) from the USA. To analyze the data in this correlational study, researchers conducted frequency distributions, Chi Square Tests of Associations, significance tests and logistic regressions. RESULTS: The main results suggest (a) receipt of assistive technology in school varied greatly by disability identification; (b) receipt of assistive technology post-school also varied by disability identification, but receipt was generally lower; and (c) few statistically significant post-school outcome differences existed between students who received assistive technology and those who did not. CONCLUSION: An under-utilization of assistive technology exists in practice in the USA for students with severe disabilities. Implications for Rehabilitation An under-utilization of assistive technology for secondary students and adults with severe disabilities likely exists. A need exists for improved collaboration between professionals in rehabilitation and professionals in schools to ensure continuation of needed services or aids, such as assistive technology. Additional research is needed to better understand the adult life (or post-school) outcomes of individuals with severe disabilities, factors from PK-12 schooling or post school services that positively and negative impact those outcomes. PMID- 25815684 TI - MicroRNA-21 promotes osteogenic differentiation by targeting small mothers against decapentaplegic 7. AB - Previous studies have suggested that microRNAs (miRNAs/miRs) may positively or negatively control osteogenic differentiation and mineralization by targeting negative regulators of osteogenesis or important osteogenic factors. miR-21 is important in osteoblast differentiation and Smad7 is a critical regulator of osteogenic differentiation, which inhibits proliferation, differentiation and mineralization in mouse osteoblast cells. However, the association between Smad7 and miR-21 remain to be elucidated. In the present study, miR-21 was found to promote the level of osteogenic differentiation and increase matrix mineralization in MC3T3-E1 cells. Furthermore, Smad7 was identified as a direct target of miR-21 in the MC3T3-E1 cells. The overexpression of miR-21 affected the protein levels of SMAD7, but not the mRNA levels, which suggested that miR-21 regulates the levels of SMAD7 by inhibiting translation, rather than by promoting mRNA decay. Forced expression of miR-21 promoted osteogenic differentiation and mineralization, while inhibition of miR-21 suppressed these processes. The present study also identified for the first time, to the best of our knowledge, the promotion of osteogenic differentiation and mineralization by miR-21, by repressing the expression of Smad7. PMID- 25815685 TI - Oscillatory motion in layered materials: graphene, boron nitride, and molybdenum disulfide. AB - Offset-driven self-retraction and oscillatory motion of bilayer graphene has been observed experimentally and is potentially relevant for nanoscale technological applications. In a previous article, we showed that friction between laterally offset graphene layers is controlled by roughness and proposed a simple reduced order model based on density-functional theory (DFT) and molecular dynamics (MD) data, with which predictions on the experimental size-scale could be made. In this article, we extend our study to other layered materials, with emphasis on boron nitride (BN) and molybdenum disulfide (MoS2). Using MD and DFT simulations of these systems and a generalized version of the reduced-order model, we predict that BN will exhibit behavior similar to graphene (heavily-damped oscillation with a decay rate that increases with roughness) and that MoS2 shows no oscillatory behavior even in the absence of roughness. This is attributed to the higher energy barrier for sliding in MoS2 as well as the surface structure. Our generalized reduced-order model provides a guide to predicting and tuning experimental oscillation behavior using a few parameters that can be derived from simulation data. PMID- 25815683 TI - Neurofibromin controls macropinocytosis and phagocytosis in Dictyostelium. AB - Cells use phagocytosis and macropinocytosis to internalise bulk material, which in phagotrophic organisms supplies the nutrients necessary for growth. Wildtype Dictyostelium amoebae feed on bacteria, but for decades laboratory work has relied on axenic mutants that can also grow on liquid media. We used forward genetics to identify the causative gene underlying this phenotype. This gene encodes the RasGAP Neurofibromin (NF1). Loss of NF1 enables axenic growth by increasing fluid uptake. Mutants form outsized macropinosomes which are promoted by greater Ras and PI3K activity at sites of endocytosis. Relatedly, NF1 mutants can ingest larger-than-normal particles using phagocytosis. An NF1 reporter is recruited to nascent macropinosomes, suggesting that NF1 limits their size by locally inhibiting Ras signalling. Our results link NF1 with macropinocytosis and phagocytosis for the first time, and we propose that NF1 evolved in early phagotrophs to spatially modulate Ras activity, thereby constraining and shaping their feeding structures. PMID- 25815686 TI - DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair. AB - The mechanisms underlying lung cancer radioresistance remain to be fully elucidated. The DNA repair pathway is a predominant target of radiotherapy, which is considered to be involved in the acquired radioresistance of cancer cells. The present study aimed to establish a radioresistant cell model using the A549 human lung cancer cell line, and to further investigate the potential mechanisms underlying the radioresistance. The A549R radioresistant lung cancer cell variant was established by exposing the parental A549 cells to repeated gamma-ray irradiation at a total dose of 60 Gy. Colony formation assays were then used to determine cell survival following gamma-ray exposure. The established radioresistant cells were subsequently treated with or without the NU7026 DNA PKcs inhibitor. The levels of DNA damage were determined by counting the number of fluorescent gamma-H2AX foci in the cells. The cellular capacity for DNA repair was assessed using antibodies for the detection of various DNA repair pathway proteins. The radioresistant sub-clones exhibited significantly decreased survival following NU7026 treatment, compared with the parental cells, as determined by colony formation assays (P<0.05), and this finding was found to be dose-dependent. Treatment with the DNA-dependent protein kinase (DNA-PK) inhibitor significantly reduced gamma-H2AX foci formation (P<0.05) following acute radiation exposure in the radioresistant sub-clones, compared with the parental control cells. The decreased levels of gamma-H2AX were accompanied by an increase in the percentage of apoptotic cells in the radioresistant cell line following post-radiation treatment with the DNA-PKcs inhibitor. The expression levels of proteins associated with the DNA repair pathway were altered markedly in the cells treated with NU7026. The results of the present study suggested that radioresistance may be associated with enhanced DNA repair following exposure to radiation, resulting in reduced apoptosis. Therefore, the quantity of gamma-H2AX determines the radioresistance of cells. The DNA repair pathway is important in mediating radioresistance, and treatment with the DNA-PKcs inhibitor, NU7026 restored the acquired radiation resistance. PMID- 25815687 TI - MicroRNA-133a inhibits proliferation and invasion, and induces apoptosis in gastric carcinoma cells via targeting fascin actin-bundling protein 1. AB - Fascin actin-bundling protein 1 (FSCN1) is associated with tumor progression. In addition, deregulation of the expression of FSCN1 has been observed in certain types of cancer. However, the detailed role of FSCN1 in gastric cancer remains to be elucidated. In the present study, downregulation of microRNA (miR)-133a and upregulation of FSCN1 were both observed in gastric cancer tissues and cell lines. Functional studies have revealed that miR-133a is able to bind to the 3' untranslated region of FSCN1 mRNA, and overexpression of miR-133a causes downregulation of FSCN1 expression, while downregulation of miR-133a leads to an increased FSCN1 expression in gastric cancer cells. Furthermore, overexpression of miR-133a inhibited proliferation and invasion, but promoted apoptosis of gastric cancer cells, which may be reversed by upregulation of FSCN1. By contrast, downregulation of miR-133a enhanced proliferation and invasion, but suppressed apoptosis in gastric cancer cells. In conclusion, the anti-oncogenic activity of miR-133a may involve the inhibition of the target gene FSCN1. The present study suggested that miR-133a may be a potential therapeutic target in the treatment of gastric cancer. PMID- 25815688 TI - Effects of hearing and aging on sentence-level time-gated word recognition. AB - PURPOSE: Aging is known to influence temporal processing, but its relationship to speech perception has not been clearly defined. To examine listeners' use of contextual and phonetic information, the Revised Speech Perception in Noise test (R-SPIN) was used to develop a time-gated word (TGW) task. METHOD: In Experiment 1, R-SPIN sentence lists were matched on context, target-word length, and median word segment length necessary for target recognition. In Experiment 2, TGW recognition was assessed in quiet and in noise among adults of various ages with normal hearing to moderate hearing loss. Linear regression models of the minimum word duration necessary for correct identification and identification failure rates were developed. Age and hearing thresholds were modeled as continuous predictors with corrections for correlations among multiple measurements of the same participants. RESULTS: While aging and hearing loss both had significant impacts on task performance in the most adverse listening condition (low context, in noise), for most conditions, performance was limited primarily by hearing loss. CONCLUSION: Whereas hearing loss was strongly related to target-word recognition, the effect of aging was only weakly related to task performance. These results have implications for the design and evaluation of studies of hearing and aging. PMID- 25815689 TI - Modulatory role of resveratrol on cytotoxic activity of cisplatin, sensitization and modification of cisplatin resistance in colorectal cancer cells. AB - Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Cisplatin (CIS) is one of the most active cytotoxic agents in current use and it has proven efficacy against various human malignancies. However, its clinical usefulness has been restricted by detrimental side effects, including nephrotoxicity and myelosuppression. The aim of the present study was to attempt to decrease the required dose of CIS, in order to minimize its side effects, and increase its capability to arrest, delay or reverse carcinogenesis. In addition, the present study aimed to ameliorate CIS-resistance in CRC cells, using the natural compound resveratrol (RSVL). RSVL (3,4', 5-trihydroxy-trans-stilbene) is a naturally occurring polyphenol present in the roots of white hellebore (Veratrum grandiflorum O. Loes) and extracted from >70 other plant species. RSVL can exert antioxidant and anti-inflammatory activities, and it has been shown to be active in the regulation of numerous cellular events associated with carcinogenesis. The present study evaluated the effects of RSVL on sensitization of both parent and CIS-resistant HCT-116 CRC cells to the action of cisplatin. The CIS was administered at a dose of 5 and 20 ug/ml, and CIS cytotoxicity, apoptosis, cell cycle and cisplatin cellular uptake were examined in the presence and absence of RSVL (15 ug/ml). RSVL treatment showed anti-proliferative effects and enhanced the cytotoxic effects of cis against the growth of both parent and CIS-resistant HCT-116 CRC cells, with a half maximal inhibitory concentration of 4.20 ug/ml and 4.72 ug/ml respectively. RSVL also induced a significant increase in the early apoptosis fraction and enhanced the subsequent apoptotic effects of CIS. The cellular uptake of CIS was significantly increased in the presence of RSVL, as compared with CIS treatment alone, and RSVL treatment sensitized the CIS resistant HCT-116 cells. In conclusion, RSVL treatment increased the cytotoxic activity of CIS against the growth of both parent and CIS-resistant HCT-116 CRC cells. PMID- 25815691 TI - Tumor necrosis factor-like weak inducer of apoptosis regulates particle-induced inflammatory osteolysis via the p38 mitogen-activated protein kinase signaling pathway. AB - Periprosthetic osteolysis is the predominant cause of artificial joint loosening. Previous studies have demonstrated that p38 mitogen-activated protein kinase (p38 MAPK) may be involved in periprosthetic osteolysis. Tumor necrosis factor (TNF) like weak inducer of apoptosis (TWEAK) is a member of the TNF family and is a multifunctional cytokine, which regulates cellular proliferation, angiogenesis, inflammation and apoptosis via the p38 MAPK signaling pathway. The present study investigated the expression levels of TWEAK and p38 MAPK in periprosthetic interface membranes and in RAW264.7 monocyte/macrophage cells, which were treated with titanium (Ti) particle stimulation, with or without a p38 inhibitor (SB203580). This was performed to determine whether TWEAK was involved in the particle-induced inflammatory osteolysis via the p38 MAPK signaling pathway. The expression levels of TWEAK, p38 MAPK and phosphorylated (p-)p38 MAPK were evaluated in the periprosthetic interface membrane tissues and the RAW cells by reverse transcription-quantitative polymerase chain reaction and western blotting. The contents of interleukin-6 and monocyte chemoattractant protein-1 in the supernatant were measured by ELISA. The results demonstrated that the expression levels of TWEAK and p-p38 MAPK increased in the periprosthetic interface membrane tissues and the RAW cells stimulated with Ti particles, suggesting that TWEAK was involved in particle-induced inflammatory osteolysis via the p38 MAPK signaling pathway. PMID- 25815690 TI - Resveratrol analog piceatannol restores the palmitic acid-induced impairment of insulin signaling and production of endothelial nitric oxide via activation of anti-inflammatory and antioxidative heme oxygenase-1 in human endothelial cells. AB - Growing evidence suggests that the elevation of free fatty acids, including palmitic acid (PA), are associated with inflammation and oxidative stress, which may be involved in endothelial dysfunction, characterized by the reduced bioavailability of nitric oxide (NO) synthesized from endothelial NO synthase (eNOS). Heme oxygenase-1 (HO-1) is important in the preservation of NO bioavailability. Piceatannol (Pic), with similar chemical structure to resveratrol, is suggested to possess similar protective effects as resveratrol. In the present study, human umbilical vein endothelial cells (HUVECs), stimulated with PA, were used to examine the endothelial protective effects of Pic. Pic increased the expression of HO-1 via nuclear factor erythroid-2-related factor-2 activation in the HUVECs, and decreased the PA-induced secretions of interleukin 6 and tumor necrosis factor-alpha, and the formation of reactive oxygen species ROS via inhibition of NF-kappaB activation. Notably, following inhibition of HO-1 activity by tin protoporphryin-IX, Pic did not prevent cytokine secretion, ROS formation, and NF-kappaB activation in the PA-stimulated HUVECs. PA attenuated insulin-mediated insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, leading to decreased glucose uptake, and phosphorylation of eNOS, leading to a reduction in the production of NO. Pic effectively mitigated the inhibitory effects of PA on the insulin-mediated phosphorylation of IRS-1 and eNOS, which was not observed following inhibition of HO-1 activity. The results of the present study suggested that Pic may have the potential to prevent PA-induced impairment of insulin signaling and eNOS function, by inducing the expression of the anti-inflammatory and antioxidant, HO-1. PMID- 25815694 TI - (Arylimido)vanadium(V)-alkylidene complexes containing fluorinated aryloxo and alkoxo ligands for fast living ring-opening metathesis polymerization (ROMP) and highly cis-specific ROMP. AB - (Arylimido)vanadium(V)-alkylidene complexes, V(CHSiMe3)(N-2,6 X2C6H3)(OC6F5)(PMe3)2 [X = Me (2), Cl (4)], exhibited remarkable catalytic activities for ring-opening metathesis polymerization (ROMP) of norbornene, and the ROMP by 2 proceeded in a living manner, affording ultrahigh molecular weight polymers. Cis-specific ROMP was achieved with the alkoxo analogues, V(CHSiMe3)(N 2,6-X2C6H3)[OC(CH3)(CF3)2]-(PMe3)2 [X = Me (5), Cl (6)]. Both the activity and the selectivity increased upon addition of PMe3, even at 50 degrees C. PMID- 25815692 TI - Atrophic vaginitis in breast cancer survivors: a difficult survivorship issue. AB - Management of breast cancer includes systematic therapies including chemotherapy and endocrine therapy can lead to a variety of symptoms that can impair the quality of life of many breast cancer survivors. Atrophic vaginitis, caused by decreased levels of circulating estrogen to urinary and vaginal receptors, is commonly experienced by this group. Chemotherapy induced ovarian failure and endocrine therapies including aromatase inhibitors and selective estrogen receptor modulators can trigger the onset of atrophic vaginitis or exacerbate existing symptoms. Symptoms of atrophic vaginitis include vaginal dryness, dyspareunia, and irritation of genital skin, pruritus, burning, vaginal discharge, and soreness. The diagnosis of atrophic vaginitis is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Lifestyle modifications can be helpful but are usually insufficient to significantly improve symptoms. Non-hormonal vaginal therapies may provide additional relief by increasing vaginal moisture and fluid. Systemic estrogen therapy is contraindicated in breast cancer survivors. Continued investigations of various treatments for atrophic vaginitis are necessary. Local estrogen-based therapies, DHEA, testosterone, and pH-balanced gels continue to be evaluated in ongoing studies. Definitive results are needed pertaining to the safety of topical estrogens in breast cancer survivors. PMID- 25815693 TI - Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis. AB - It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of alpha-smooth muscle actin (alpha-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury. PMID- 25815695 TI - Microbial Degradation Mechanism and Pathway of the Novel Insecticide Paichongding by a Newly Isolated Sphingobacterium sp. P1-3 from Soil. AB - Using 1-((6-chloropydidin-3-yl)methyl)-7-methyl-8-nitro-5propoxy-1,2,3,5,6,7 hexahydroimidazo[1,2-alpha-]-pyridine (IPP) as the sole carbon source, we isolated a strain with a higher activity of IPP-degrading bacterium Sphingobacterium sp. P1-3 from soil. At 30 degrees C, pH 7.0 ,and 10 mg L(-1) IPP content, the degradation rate of IPP by Sphingobacterium sp. P1-3 could reach 57.75 and 62.47% in 20 and 30 days, respectively. The value of DT50 of IPP was 27 d at the level of 30 mg L(-1) IPP, while DT50 in the blank test was 151 d. During the IPP biodegradation process, five intermediates (M1-M5) were monitored and identified. On the basis of the identified metabolites and their biodegradation courses, a possible biodegradation pathway was proposed. IPP biodegradation mainly occurred on the tetrahydropyridine ring. IPP was transformed to five different metabolites by strain P1-3 through the oxidation and elimination of methyl, propyl, and nitro groups. Moreover, a new pathway involving M2 (1-((6 chloropydidin-3-yl)methyl)-7-methyl-8-hydroxy-5-propoxy-1,2,3,5,6,7 hexahydroimidazo [1,2-alpha-]-pyridine), M3 (1-((6-chloropydidin-3-yl)methyl)-7 methyl-5-carbonyl-1,2,3,5,6,7-hexahydroimidazo[1,2-alpha-]-pyridine), and M5 (8 amino-1,2,3,5,6,7-hexahydroimidazo[1,2-alpha-]-pyridine) was first monitored and identified. PMID- 25815696 TI - Experimental and Chemical Kinetics Study of the Effects of Halon 1211 (CF2BrCl) on the Laminar Flame Speed and Ignition of Light Hydrocarbons. AB - In this study, the effect of Halon 1211 (CF2BrCl) on the ignition delay time and laminar flame speed of CH4, C2H4, and C3H8 were investigated experimentally for the first time. The results showed that the effects of Halon 1211 on the ignition delay time are strongly dependent on the hydrocarbon: the ignition delay time of CH4 is significantly decreased by Halon 1211 addition, while a significant increase in the ignition delay time was observed with C2H4 for the lowest temperatures investigated. Ignition delay times for C3H8 were slightly increased, mostly on the low-temperature side and for the fuel-rich case. A significant reduction in the laminar flame speed was observed for all of the fuels. A tentative chemical kinetics model was assembled from existing models and completed with reactions that have been determined in the literature or estimated when necessary. The experimental results were reproduced satisfactorily by the model, and a chemical analysis showed that most of the effects of Halon 1211 on the ignition delay times of C2H4 and C3H8 are due to the consumption of H radical through the reaction HBr + H ? Br + H2. In the case of methane, the CF2 radical promotes the formation of H via CF2 + CH3 ? CH2:CF2 + H, which then promotes the branching reaction H + O2 ? OH + O. The laminar flame speed results can be explained using catalytic cycles involving Br atoms that are similar to those reported in the literature for CF3Br. This study exhibits the need for a better estimation of the chlorine atom chemistry during the combustion of hydrocarbons in the presence of fire suppressants. PMID- 25815698 TI - Probing the influence of phosphonate bonding modes to uranium(VI) on structural topology and stability: a complementary experimental and computational investigation. AB - Systematic control of the reactions between U(VI) and 1,4 phenylenebis(methylene))bis(phosphonic acid) (pmbH4) allows for alterations in the bonding between these constituents and affords three uranyl phosphonate compounds with chiral one-dimensional (1D), two-dimensional (2D), and three dimensional (3D) structures, namely, [TPA][UO2(pmbH3)(pmbH2)H2O].2H2O (1), [NH4]2[UO2(pmb)] (2), UO2(pmbH2) (3), and the first uranyl mixed phosphite/phosphonate compound [TMA]2[(UO2)2(pmb)(HPO3)] (4) (TPA = NPr4+, TMA = NMe4+). These compounds crystallize in the space groups P212121, P1, P21/c, and Cmcm, respectively. Further investigation of the local uranyl coordination environment reveals that in 1 only oxygen atoms from P=O moieties ligate the uranium centers; whereas in 2 only P-O(-) oxygen atoms are involved in bonding and yield a layered topology. Compound 3 differs sharply from the first two in that conjugated P=O and P-O(-) oxygen atoms chelate the uranium centers resulting in a 3D framework. In compound 4, a phosphonate group bridges three uranyl centers further coordinated with a phosphite ligand HPO32-, which is a product of pmbH4 decomposing, forming a 2D layered structure. Compounds 3 and 4 also contain a different coordination environment for U(VI) than that found in 1 or 2. In this case, tetragonal bipyramidal UO6 units occur instead of the far more common UO7 pentagonal bipyramids found in 1 and 2. Interestingly, 1 converts to 3 at elevated reaction temperatures, indicating that the formation of 1 is likely under kinetic control. This is supported by thermal analysis, which reveals that 3 has higher thermal stability than 1 or 2. UV-vis-near-IR absorption and fluorescence spectroscopy show that the absorption and photoluminescence intensity increases from 1 to 4. Density functional theory electronic structure calculations provide insight into the nature of the interactions between U(VI) and the phosphonate ligands. PMID- 25815697 TI - Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis. AB - Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E selectin antagonist for the prevention of hematogenous metastasis of ER( )/CD44(+) breast cancer. PMID- 25815699 TI - Risk factors for peritoneal dissemination of gastric cancer. AB - AIM: Tumor dissemination, lymphnode involvement and surgical resection technique are the most important factors affecting patient prognosis with gastric cancer. Peritoneal dissemination adversely affects the survival rate in patients. Microscopic peritoneal dissemination can be detected with peritoneal lavage cytological examination. Peroperatively detected microscopic peritoneal dissemination changes the treatment plan for patients and can be useful when selecting patients who should undergo adjuvant chemotherapy. METHODS: At the Trakya Universtity Faculty of Medicine, General Surgery Department, a 41-year-old patient who was macroscopic peritoneal dissemination during the dates January December 2011 was included in the study. Perioperative peritoneal lavage was performed and cytological examination of peritoneal aspirate carried out. Using tumor markers the relationship between lymph node metastasis, prognostic type, tumor location and perineural invasion was investigated on the serum and peritoneal fluid. RESULTS: Forty-one patients were operated on; 10 of them (24.4%) had positive malignant cytology and 31 (75.7%) had negative cytology. Just 1 (7.2%) patient was found to have positive cytology out of 13 (31.7%) that did not have serous invasion. Of the 28 (68.3%) patients with serous invasion, 9 patients (32.1%) were found to have positive cytology. No significant pattern was detected in the carcino-embryionic antigen, cancer antigen 19-9 and AFP levels in both the positive and negative cytology serum and peritoneal lavage fluid. Of the 41 patients operated on 5 (12.2%) were found to have cardia dissemination and 13 (31.7%) were found to have dissemination located at the corpus. Peritoneal dissemination was found to be significantly high in gastric cancer located in the cardia and corpus. Fourteen (34.1%) of the patients had stage I and stage II cancer and 27 (65.9%) of patient's had cancer in stages III and IV. Just 1 (7.1%) patient with stage I or II cancer was found to have positive malignant cytology, however 9 (33.3%) patient's of stage III and IV gastric cancer patients were tested positively for malignant cytology. CONCLUSION: A positive relationship was detected in the positive peritoneal cell malignancy with cancer stage, age, invasion depth and tumor location in patients. PMID- 25815700 TI - [Treatment of persistent postmastectomy pain with 5% Lidocaine medicated plaster]. AB - Persistent postmastectomy pain (PPMP) syndrome is characterized by neuropathic pain that develops following surgery in breast cancer patients. The reported incidence of PPMP ranges between 30% and 50% and is estimated to increase as the number of women surviving cancer continues to rise. Though effective, today's drug treatments are poorly tolerated, limiting their use and reducing adherence to therapy. Since neuropathic pain is localized, international guidelines suggest that topical treatment with 5% Lidocaine medicated plaster either alone or combined with systemic drugs can be considered for pain management. In this retrospective study we reviewed the medical records of 11 patients treated with 5% lidocaine medicated plaster for moderate-to-severe PPMP at our institute between November 2013 and October 2014. Analysis showed that treatment with 5% Lidocaine medicated plaster, either alone or in combination with systemic drugs, achieved significant pain control already after the first week of therapy. The effectiveness and tolerability of 5% Lidocaine medicated plaster we observed suggests that it is a viable option in the management of PPMP. PMID- 25815701 TI - Distinguishing bicontinuous lipid cubic phases from isotropic membrane morphologies using (31)P solid-state NMR spectroscopy. AB - Nonlamellar lipid membranes are frequently induced by proteins that fuse, bend, and cut membranes. Understanding the mechanism of action of these proteins requires the elucidation of the membrane morphologies that they induce. While hexagonal phases and lamellar phases are readily identified by their characteristic solid-state NMR line shapes, bicontinuous lipid cubic phases are more difficult to discern, since the static NMR spectra of cubic-phase lipids consist of an isotropic (31)P or (2)H peak, indistinguishable from the spectra of isotropic membrane morphologies such as micelles and small vesicles. To date, small-angle X-ray scattering is the only method to identify bicontinuous lipid cubic phases. To explore unique NMR signatures of lipid cubic phases, we first describe the orientation distribution of lipid molecules in cubic phases and simulate the static (31)P chemical shift line shapes of oriented cubic-phase membranes in the limit of slow lateral diffusion. We then show that (31)P T2 relaxation times differ significantly between isotropic micelles and cubic-phase membranes: the latter exhibit 2 orders of magnitude shorter T2 relaxation times. These differences are explained by the different time scales of lipid lateral diffusion on the cubic-phase surface versus the time scales of micelle tumbling. Using this relaxation NMR approach, we investigated a DOPE membrane containing the transmembrane domain (TMD) of a viral fusion protein. The static (31)P spectrum of DOPE shows an isotropic peak, whose T2 relaxation times correspond to that of a cubic phase. Thus, the viral fusion protein TMD induces negative Gaussian curvature, which is an intrinsic characteristic of cubic phases, to the DOPE membrane. This curvature induction has important implications to the mechanism of virus-cell fusion. This study establishes a simple NMR diagnostic probe of lipid cubic phases, which is expected to be useful for studying many protein-induced membrane remodeling phenomena in biology. PMID- 25815702 TI - Phosphine-catalyzed enantioselective intramolecular [3+2] annulations to generate fused ring systems. AB - Substantial progress has been described in the development of asymmetric variants of the phosphine-catalyzed intermolecular [3+2] annulation of allenes with alkenes; however, there have not been corresponding advances for the intramolecular process, which can generate a higher level of complexity (an additional ring and stereocenter(s)). In this study, we describe the application of chiral phosphepine catalysts to address this challenge, thereby providing access to useful scaffolds that are found in bioactive compounds, including diquinane and quinolin-2-one derivatives, with very good stereoselectivity. The products of the [3+2] annulation can be readily transformed into structures that are even more stereochemically rich. Mechanistic studies are consistent with beta addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle, followed by a concerted [3+2] cycloaddition to the pendant olefin. PMID- 25815703 TI - Fetuin-A 742 (C/T) and 766 (C/G) polymorphic sites are associated with increased risk of myocardial infarction in older patients (>= 40 years of age). AB - Inflammation and genetics have key roles in the pathogenesis of atherosclerosis, and the etiology of myocardial infarction (MI). Recent studies have indicated that lower serum levels of fetuin-A may accelerate the vascular mineralization process, which leads to pathophysiological conditions, such as coronary heart disease and chronic renal failure. The aim of the present study was to evaluate the association between specific fetuin-A polymorphisms (742 and 766) that are associated with circulating serum levels, and MI cases. The study consisted of 292 participants; 146 healthy control subjects and 146 patients with MI. The patient group was divided into two subgroups: 56 MI <= 40 years and 90 MI >= 40 years. The genotype distribution of fetuin 742 (C/T) and fetuin 766 (C/G) were determined by restriction enzyme digestion of polymerase chain reaction products. A significant difference was determined between the patients with MI and the control subjects with regards to fetuin-A 742 C/T gene polymorphism (P=0.028), regardless of age. Genotype distributions of fetuin-A 742 (C/G, P=0.004) and 766 (C/T, P=0.017) were statistically different in the older patients with MI (MI >= 40 years old), as compared with the healthy controls; however, there were no significant differences between the younger patients with MI and the controls, with regards to fetuin-A 742 C/T (P=0.519) and 766 C/G (P=0.653) gene polymorphisms. In addition, an association was observed between the presence of fetuin-A 742 T and 766 G alleles, and MI cases. The present study demonstrates that fetuin-A 742 (C/T) and 766 (C/G) genotypes may be risk factors for MI in patients older than 40 years of age. PMID- 25815705 TI - Large-scale fabrication and application of magnetite coated Ag NW-core water dispersible hybrid nanomaterials. AB - In this work, we report a large scale synthetic procedure that allows attachment of magnetite nanoparticles onto Ag NWs in situ, which was conducted in a triethylene glycol (TREG) solution with iron acetylacetonate and Ag NWs as starting materials. The as-prepared Ag NW/Fe3O4 NP composites are well characterized by SEM, TEM, XRD, XPS, FT-IR, and VSM techniques. It was found that the mass ratio of iron acetylacetonate to Ag NWs plays a crucial role in controlling the amount of magnetite nanoparticles decorated on the Ag NWs. The resulting Ag NW/Fe3O4 NP composites exhibit superparamagnetic properties at room temperature, and can be well dispersed in aqueous and organic solutions, which is greatly beneficial for their application and functionality. Thus, the as-prepared magnetic silver nanowires show good catalytic activity, using the catalytic reduction of methylene blue (MB) as a model reaction. Furthermore, the Ag NW/Fe3O4 NP composites can be functionalized with polydopamine (Pdop), resorcinol formaldehyde resin (PFR), and SiO2, respectively, in aqueous/ethanol solution. Meanwhile they can also be coated with polyphosphazene (PZS) in organic solution, resulting in a unique nanocable with well-defined core shell structures. Besides, taking Ag NW/Fe3O4@SiO2 as an example, a hollow magnetic silica nanotube can be obtained with the use of Ag NWs as physical templates and a solution of ammonium and H2O2. These can greatly improve the application of the Ag NW/Fe3O4 NP composites. The as-synthesized above nanocomposites have high potential for applications in the fields of polymers, wastewater treatment, sensors, and biomaterials. PMID- 25815704 TI - Bayesian model selection applied to the analysis of fluorescence correlation spectroscopy data of fluorescent proteins in vitro and in vivo. AB - Fluorescence correlation spectroscopy (FCS) is a powerful technique to investigate molecular dynamics with single molecule sensitivity. In particular, in the life sciences it has found widespread application using fluorescent proteins as molecularly specific labels. However, FCS data analysis and interpretation using fluorescent proteins remains challenging due to typically low signal-to-noise ratio of FCS data and correlated noise in autocorrelated data sets. As a result, naive fitting procedures that ignore these important issues typically provide similarly good fits for multiple competing models without clear distinction of which model is preferred given the signal-to-noise ratio present in the data. Recently, we introduced a Bayesian model selection procedure to overcome this issue with FCS data analysis. The method accounts for the highly correlated noise that is present in FCS data sets and additionally penalizes model complexity to prevent over interpretation of FCS data. Here, we apply this procedure to evaluate FCS data from fluorescent proteins assayed in vitro and in vivo. Consistent with previous work, we demonstrate that model selection is strongly dependent on the signal-to-noise ratio of the measurement, namely, excitation intensity and measurement time, and is sensitive to saturation artifacts. Under fixed, low intensity excitation conditions, physical transport models can unambiguously be identified. However, at excitation intensities that are considered moderate in many studies, unwanted artifacts are introduced that result in nonphysical models to be preferred. We also determined the appropriate fitting models of a GFP tagged secreted signaling protein, Wnt3, in live zebrafish embryos, which is necessary for the investigation of Wnt3 expression and secretion in development. Bayes model selection therefore provides a robust procedure to determine appropriate transport and photophysical models for fluorescent proteins when appropriate models are provided, to help detect and eliminate experimental artifacts in solution, cells, and in living organisms. PMID- 25815706 TI - Direct deposit laminate nanocomposites with enhanced propellent properties. AB - One of the challenges in the use of energetic nanoparticles within a polymer matrix for propellant applications is obtaining high particle loading (high energy density) while maintaining mechanical integrity and reactivity. In this study, we explore a new strategy that utilizes laminate structures. Here, a laminate of alternating layers of aluminum nanoparticle (Al-NPs)/copper oxide nanoparticle (CuO-NPs) thermites in a polyvinylidene fluoride (PVDF) reactive binder, with a spacer layer of PVDF was fabricated by a electrospray layer-by layer deposition method. The deposited layers containing up to 60 wt % Al-NPs/CuO NPs thermite are found to be uniform and mechanically flexible. Both the reactive and mechanical properties of laminate significantly outperformed the single-layer structure with the same material composition. These results suggest that deploying a multilayer laminate structure enables the incorporation of high loadings of energetic materials and, in some cases, enhances the reactive properties over the corresponding homogeneous structure. These results imply that an additive manufacturing approach may yield significant advantages in developing a tailored architecture for advanced propulsion systems. PMID- 25815707 TI - Intravenous immunoglobulin for suspected or proven infection in neonates. AB - BACKGROUND: Neonates are at higher risk of infection due to immuno-incompetence. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks' gestation, and endogenous synthesis begins several months after birth. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody-dependent cytotoxicity and improve neutrophilic chemo-luminescence. Theoretically, infectious morbidity and mortality could be reduced by the administration of IVIG. OBJECTIVES: To assess the effects of IVIG on mortality and morbidity caused by suspected or proven infection at study entry in neonates. To assess in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. SEARCH METHODS: For this update, MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials involving newborn infants (< 28 days old); IVIG for treatment of suspected or proven bacterial or fungal infection compared with placebo or no intervention; and where one of the following outcomes was reported, mortality, length of hospital stay or psychomotor development at follow up. DATA COLLECTION AND ANALYSIS: Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH), all with 95% confidence intervals (CIs), and the I(2) statistic to examine for statistical heterogeneity. MAIN RESULTS: The updated search identified one published study that was previously ongoing. A total of 9 studies evaluating 3973 infants were included in this review. Mortality during hospital stay in infants with clinically suspected infection was not significantly different after IVIG treatment (9 studies (n = 2527); typical RR 0.95, 95% CI 0.80 to 1.13; typical RD -0.01, 95% CI - 0.04 to 0.02; I(2) = 23% for RR and 29% for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (1 study (n = 1985); RR 0.98, 95% CI 0.88 to 1.09; RD -0.01, 95% CI -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (1 trial (n = 1446); RR 0.95, 95% CI 0.74 to 1.21; RD -0.01, 95% CI -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (1 trial (n = 1393); RR 1.03, 95% CI 0.91 to 1.18; RD 0.01, 95% CI -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3493); RR 1.00, 95% CI 0.86 to 1.16; RD 0.00, 95% CI - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3493); RR 1.00, 95% CI 0.92 to 1.09; RD -0.00, 95% CI -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected or proven infection at trial entry (1 study (n = 3493); mean difference (MD) 0.00 days, 95% CI -0.61 to 0.61). No significant difference in mortality during hospital stay after administration of IgM-enriched IVIG for suspected infection at trial entry was reported in 4 studies (n = 266) (typical RR 0.68, 95% CI 0.39 to 1.20; RD -0.06, 95% CI -0.14 to 0.02; I(2) = 17% for RR and 53% for RD). AUTHORS' CONCLUSIONS: The undisputable results of the INIS trial, which enrolled 3493 infants, and our meta analyses (n = 3973) showed no reduction in mortality during hospital stay, or death or major disability at two years of age in infants with suspected or proven infection. Although based on a small sample size (n = 266), this update provides additional evidence that IgM-enriched IVIG does not significantly reduce mortality during hospital stay in infants with suspected infection. Routine administration of IVIG or IgM-enriched IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended. No further research is recommended. PMID- 25815709 TI - Counter-ion-dependent alkyne iminium ion cyclization for divergent synthesis of N fused indolylidine, indole, and indoline derivatives promoted by the Lewis/Bronsted acid. AB - Divergent synthesis of N-fused indolylidine, indole, and indoline derivatives using alkyne iminium ion cyclization is described. Trapping of vinyl cation intermediate generated after alkyne iminium ion cyclization was found to be dependent on the Lewis/Bronsted acid and solvent used. N-Fused indolylidine triflate could be used in the divergent synthesis of N-fused indole derivatives. PMID- 25815710 TI - Effects of daily walking on office, home and 24-h blood pressure in hypertensive patients. AB - Aerobic exercise has been recommended in the management of hypertension. However, few studies have examined the effect of walking on ambulatory blood pressure (BP), and no studies have employed home BP monitoring. We investigated the effects of daily walking on office, home, and 24-h ambulatory BP in hypertensive patients. Sixty-five treated or untreated patients with essential hypertension (39 women and 26 men, 60 +/- 9 years) were examined in a randomized cross-over design. The patients were asked to take a daily walk of 30-60 min to achieve 10 000 steps/d for 4 weeks, and to maintain usual activities for another 4 weeks. The number of steps taken and home BP were recorded everyday. Measurement of office and ambulatory BP, and sampling of blood and urine were performed at the end of each period. The average number of steps were 5349 +/- 2267/d and 10 049 +/- 3403/d in the control and walking period, respectively. Body weight and urinary sodium excretion did not change. Office, home, and 24-h BP in the walking period were lower compared to the control period by 2.6 +/- 9.4/1.3 +/- 4.9 mmHg (p < 0.05), 1.6 +/- 6.8/1.5 +/- 3.7 mmHg (p < 0.01), and 2.4 +/- 7.6/1.8 +/- 5.3 mmHg (p < 0.01), respectively. Average 24-h heart rate and serum triglyceride also decreased significantly. The changes in 24-h BP with walking significantly correlated with the average 24-h BP in the control period. In conclusion, daily walking lowered office, home, and 24-h BP, and improved 24-h heart rate and lipid metabolism in hypertensive patients. However, the small changes in BP may limit the value of walking as a non-pharmacologic therapy for hypertension. PMID- 25815708 TI - Multiscale Speciation of U and Pu at Chernobyl, Hanford, Los Alamos, McGuire AFB, Mayak, and Rocky Flats. AB - The speciation of U and Pu in soil and concrete from Rocky Flats and in particles from soils from Chernobyl, Hanford, Los Alamos, and McGuire Air Force Base and bottom sediments from Mayak was determined by a combination of X-ray absorption fine structure (XAFS) spectroscopy and X-ray fluorescence (XRF) element maps. These experiments identify four types of speciation that sometimes may and other times do not exhibit an association with the source terms and histories of these samples: relatively well ordered PuO2+x and UO2+x that had equilibrated with O2 and H2O under both ambient conditions and in fires or explosions; instances of small, isolated particles of U as UO2+x, U3O8, and U(VI) species coexisting in close proximity after decades in the environment; alteration phases of uranyl with other elements including ones that would not have come from soils; and mononuclear Pu-O species and novel PuO2+x-type compounds incorporating additional elements that may have occurred because the Pu was exposed to extreme chemical conditions such as acidic solutions released directly into soil or concrete. Our results therefore directly demonstrate instances of novel complexity in the A and MUm-scale chemical speciation and reactivity of U and Pu in their initial formation and after environmental exposure as well as occasions of unexpected behavior in the reaction pathways over short geological but significant sociological times. They also show that incorporating the actual disposal and site conditions and resultant novel materials such as those reported here may be necessary to develop the most accurate predictive models for Pu and U in the environment. PMID- 25815711 TI - Design and optimization of lipid-modified poly(amidoamine) dendrimer coated iron oxide nanoparticles as probes for biomedical applications. AB - Superparamagnetic iron oxide nanoparticles with a wide size range (2.6-14.1 nm) were synthesized and coated with the amphiphilic poly(amidoamine) PAMAM-C12 dendrimer. The resulting well dispersed and stable water suspensions were fully characterized in order to explore their possible use in biomedical applications. The structural and magnetic properties of the nanoparticles were preserved during the coating and were related to their relaxometric behaviour. The Nuclear Magnetic Resonance Dispersion (NMRD) profiles were found to be in accordance with the Roch model. The biocompatibility was assessed by means of cell viability tests and Transmission Electron Microscopy (TEM) analysis. The nanoparticles' capability of being detected via Magnetic Resonance Imaging (MRI) was investigated by means of clinical MRI scanners both in water and agar gel phantoms, and in a mouse model. PMID- 25815714 TI - Coalescence, Cracking, and Crack Healing in Drying Dispersion Droplets. AB - The formation of a uniform film from a polymer dispersion is a complex phenomenon involving the interplay of many processes: evaporation and resulting fluid flows through confined geometries, particle packing and deformation, coalescence, and cracking. Understanding this multidimensional problem has proven challenging, precluding a clear understanding of film formation to date. This is especially true for drying dispersion droplets, where the particular geometry introduces additional complexity such as lateral flow toward the droplet periphery. We study the drying of these droplets using a simplified approach in which we systematically vary a single parameter: the glass transition temperature (Tg) of the polymer. We combine optical with scanning electron microscopy to elucidate these processes from the macroscopic down to the single-particle level, both qualitatively and quantitatively, over times ranging from seconds to days. Our results indicate that the polymer Tg has a marked influence on the time evolution of particle deformation and coalescence, giving rise to a distinct and sudden cracking transition. Moreover, in cracked droplets it affects the frequently overlooked time scale of crack healing, giving rise to a second transition from self-healing to permanently cracked droplets. These findings are in line with the classical Routh-Russel model for film formation yet extend its scope from particle-level dynamics to long-range polymer flow. PMID- 25815713 TI - Indomethacin-induced gastric ulceration in rats: Ameliorative roles of Spondias mombin and Ficus exasperata. AB - CONTEXT: Spondias mombin Linn (Anacardiaceae) and Ficus exasperata Valh (Moraceae) are botanicals with known phytotherapeutic potentials in the traditional system of medicine in the world. OBJECTIVE: The objective of this study is to investigate the quantitative polyphenolic constituents and gastroprotective effects of aqueous leaf extracts of Spondias mombin and Ficus exasperata against indomethacin-induced gastric ulcer in rats. MATERIALS AND METHODS: Ulceration was induced by a single oral administration of indomethacin (30 mg/kg body weight (b.w.)). Ulcerated rats were orally administered with esomeprazole (a reference drug) at a dose of 20 mg/kg body weight, and Spondias mombin and Ficus exasperata at a dose of 100 and 200 mg/kg b.w. once daily for 21 d after ulcer induction. Gastric secretions and antioxidant parameters were thereafter evaluated. RESULTS: The significantly increased (p < 0.05) ulcer index, gastric volume, malondialdehyde level, and pepsin activity by indomethacin were effectively reduced by 65.40, 36.47, 45.71, and 53.79%, respectively, following treatment with F. exasperata at 200 mg/kg b.w. S. mombin at this regimen also attenuated these parameters by 71.70, 46.62, 50.16, and 55.73%. Moreover, the extracts significantly increase the reduced activity of superoxide dismutase as well as pH and mucin content in the ulcerated rats. DISCUSSION AND CONCLUSION: These findings are indicative of gastroprotective and antioxidative potentials of the extracts which is also evident in the degree of % inhibition against ulceration. The available data in this study suggest that the extracts proved to be capable of ameliorating indomethacin-induced gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition. PMID- 25815712 TI - Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation. AB - The microbial world offers a rich source of bioactive compounds for those able to sift through it. Technologies capable of quantitatively detecting natural products while simultaneously identifying known compounds would expedite the search for new pharmaceutical leads. Prior efforts have targeted histone deacetylases in fungi to globally activate the production of new secondary metabolites, yet no study has directly assessed its effects with minimal bias at the metabolomic level. Using untargeted metabolomics, we monitored changes in >1000 small molecules secreted from the model fungus, Aspergillus nidulans, following genetic or chemical reductions in histone deacetylase activity (HDACi). Through quantitative, differential analyses, we found that nearly equal numbers of compounds were up- and down-regulated by >100 fold. We detected products from both known and unknown biosynthetic pathways and discovered that A. nidulans is capable of producing fellutamides, proteasome inhibitors whose expression was induced by ~100 fold or greater upon HDACi. This work adds momentum to an "omics" driven resurgence in natural products research, where direct detection replaces bioactivity as the primary screen for new pharmacophores. PMID- 25815715 TI - Quantification of the host response proteome after herpes simplex virus type 1 infection. AB - Viruses employ numerous host cell metabolic functions to propagate and manage to evade the host immune system. For herpes simplex virus type 1 (HSV1), a virus that has evolved to efficiently infect humans without seriously harming the host in most cases, the virus-host interaction is specifically interesting. This interaction can be best characterized by studying the proteomic changes that occur in the host during infection. Previous studies have been successful at identifying numerous host proteins that play important roles in HSV infection; however, there is still much that we do not know. This study identifies host metabolic functions and proteins that play roles in HSV infection, using global quantitative stable isotope labeling by amino acids in cell culture (SILAC) proteomic profiling of the host cell combined with LC-MS/MS. We showed differential proteins during early, mid and late infection, using both cytosolic and nuclear fractions. We identified hundreds of differentially regulated proteins involved in fundamental cellular functions, including gene expression, DNA replication, inflammatory response, cell movement, cell death, and RNA post transcriptional modification. Novel differentially regulated proteins in HSV infections include some previously identified in other virus systems, as well as fusion protein, involved in malignant liposarcoma (FUS) and hypoxia up-regulated 1 protein precursor (HYOU1), which have not been identified previously in any virus infection. PMID- 25815716 TI - Ccr4-not regulates RNA polymerase I transcription and couples nutrient signaling to the control of ribosomal RNA biogenesis. AB - Ribosomal RNA synthesis is controlled by nutrient signaling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 regulates ribosomal RNA expression by affecting RNA Polymerase I (Pol I)-dependent transcription of the ribosomal DNA (rDNA) but the mechanisms involved remain obscure. This study provides evidence that the Ccr4-Not complex, which regulates RNA Polymerase II (Pol II) transcription, also functions downstream of mTORC1 to control Pol I activity. Ccr4-Not localizes to the rDNA and physically associates with the Pol I holoenzyme while Ccr4-Not disruption perturbs rDNA binding of multiple Pol I transcriptional regulators including core factor, the high mobility group protein Hmo1, and the SSU processome. Under nutrient rich conditions, Ccr4-Not suppresses Pol I initiation by regulating interactions with the essential transcription factor Rrn3. Additionally, Ccr4-Not disruption prevents reduced Pol I transcription when mTORC1 is inhibited suggesting Ccr4-Not bridges mTORC1 signaling with Pol I regulation. Analysis of the non-essential Pol I subunits demonstrated that the A34.5 subunit promotes, while the A12.2 and A14 subunits repress, Ccr4-Not interactions with Pol I. Furthermore, ccr4Delta is synthetically sick when paired with rpa12Delta and the double mutant has enhanced sensitivity to transcription elongation inhibition suggesting that Ccr4-Not functions to promote Pol I elongation. Intriguingly, while low concentrations of mTORC1 inhibitors completely inhibit growth of ccr4Delta, a ccr4Delta rpa12Delta rescues this growth defect suggesting that the sensitivity of Ccr4-Not mutants to mTORC1 inhibition is at least partially due to Pol I deregulation. Collectively, these data demonstrate a novel role for Ccr4-Not in Pol I transcriptional regulation that is required for bridging mTORC1 signaling to ribosomal RNA synthesis. PMID- 25815717 TI - Suboptimal effectiveness of the 2011-2012 seasonal influenza vaccine in adult Korean populations. AB - BACKGROUND: The effectiveness of the 2011-2012 seasonal influenza vaccine was evaluated in adult Korean populations with regard to how well it could prevent laboratory-confirmed influenza and influenza-related complications. MATERIALS AND METHODS: A retrospective case-control and retrospective cohort study was conducted among patients who visited four selected hospitals from September 2011 to May 2012. The analysis included 1,130 laboratory-confirmed influenza patients. For each influenza case, one control patient was chosen at a ratio of 1:1. A control was defined as an age group-matched patient who visited the same hospital with influenza-like illness within 48 hours of symptom onset but for whom laboratory tests were negative for influenza. Age group and visit date were matched between the cases and controls. Vaccine effectiveness (VE) was defined as [100 * (1-odds ratio for influenza in vaccinated versus non-vaccinated persons)]. The patients with laboratory-confirmed influenza were followed for at least one month through reviewing the medical records and conducting a telephone interview. RESULTS: The VE of the 2011-2012 seasonal influenza vaccine was 3.8% [95% confidence interval (CI), -16.5% to 20.6%] for preventing laboratory-confirmed influenza, -16.1% (95% CI, -48.3 to 9.1) for influenza A and 26.2% (95% CI, -2.6 to 46.2) for influenza B. The age-specific adjusted VE was 0.3% (95% CI, -29.4 to 23.1) among participants aged 19 to 49 years, 11.9% (95% CI, -34.3 to 42.2) among those aged 50 to 64 years and -3.9% (-60.1 to 32.5) among those aged >=65 years. The adjusted VE for preventing any influenza-related complications was -10.7% (95% CI, -41.1% to 42.2%). CONCLUSIONS: The 2011-2012 seasonal influenza vaccine was not effective in preventing laboratory-confirmed influenza or influenza related complications in adult Korean populations. PMID- 25815718 TI - The ubiquitin ligase UBE3A dampens ERK pathway signalling in HPV E6 transformed HeLa cells. AB - Signalling through the ERK MAP kinase pathway plays an important role in many biological processes and it is often deregulated in disease states such as cancer. One major effect of MAP kinase signalling is to promote gene expression through the phosphorylation and activation of transcription factors like ELK1. ELK1 in turn controls the activity of immediate-early genes such as FOS. Here we have used ELK1 activation in HeLa cells as a read out to conduct a genome-wide siRNA screen to identify negative regulators of ERK-mediated immediate-early gene activation. One of the candidates that we identified was the E3 ubiquitin ligase UBE3A/E6-AP. Reductions in UBE3A levels cause increased basal levels of ERK activity, a loss of growth factor-mediated ERK activation and concomitant defects in immediate-early gene expression. Thus, UBE3A acts to dampen down basal level ERK activation and to prime the pathway for growth factor-mediated activation. Mechanistically, we demonstrate that UBE3A functions in HeLa cells through its binding partner, HPV18 E6 protein and the E6 target protein p53. Loss of either E6 or p53 blocks the effect of UBE3A depletion on ERK pathway signalling, indicating that in the context of oncogenic viral protein expression, UBE3A plays an important role in negating the consequences of p53 activation on ERK pathway signalling. PMID- 25815719 TI - Variable importance and prediction methods for longitudinal problems with missing variables. AB - We present prediction and variable importance (VIM) methods for longitudinal data sets containing continuous and binary exposures subject to missingness. We demonstrate the use of these methods for prognosis of medical outcomes of severe trauma patients, a field in which current medical practice involves rules of thumb and scoring methods that only use a few variables and ignore the dynamic and high-dimensional nature of trauma recovery. Well-principled prediction and VIM methods can provide a tool to make care decisions informed by the high dimensional patient's physiological and clinical history. Our VIM parameters are analogous to slope coefficients in adjusted regressions, but are not dependent on a specific statistical model, nor require a certain functional form of the prediction regression to be estimated. In addition, they can be causally interpreted under causal and statistical assumptions as the expected outcome under time-specific clinical interventions, related to changes in the mean of the outcome if each individual experiences a specified change in the variable (keeping other variables in the model fixed). Better yet, the targeted MLE used is doubly robust and locally efficient. Because the proposed VIM does not constrain the prediction model fit, we use a very flexible ensemble learner (the SuperLearner), which returns a linear combination of a list of user-given algorithms. Not only is such a prediction algorithm intuitive appealing, it has theoretical justification as being asymptotically equivalent to the oracle selector. The results of the analysis show effects whose size and significance would have been not been found using a parametric approach (such as stepwise regression or LASSO). In addition, the procedure is even more compelling as the predictor on which it is based showed significant improvements in cross-validated fit, for instance area under the curve (AUC) for a receiver-operator curve (ROC). Thus, given that 1) our VIM applies to any model fitting procedure, 2) under assumptions has meaningful clinical (causal) interpretations and 3) has asymptotic (influence-curve) based robust inference, it provides a compelling alternative to existing methods for estimating variable importance in high dimensional clinical (or other) data. PMID- 25815720 TI - The effects of extraversion, social support on the posttraumatic stress disorder and posttraumatic growth of adolescent survivors of the Wenchuan earthquake. AB - OBJECTIVE: The aim of this study was to examine the relationships among extraversion, social support, posttraumatic stress disorder and posttraumatic growth among adolescent survivors of the Wenchuan earthquake. METHODS: Six hundred thirty-eight participants were selected from the survivors of the 2008 Wenchuan earthquake. Participants completed four main questionnaires, including the Extraversion Subscale, the Social Support Scale, the Child PTSD Symptom Scale, and the Posttraumatic Growth Inventory. RESULTS: A bivariate correlation analysis revealed significant correlations among extraversion, social support, posttraumatic stress disorder and posttraumatic growth. Extraversion had significant indirect effects on posttraumatic stress disorder (beta = -.037, p < .01) and posttraumatic growth (beta = .077, p < .001) through social support. The results also indicated that extraversion had a significant direct effect on posttraumatic growth and a nonsignificant direct effect on posttraumatic stress disorder. CONCLUSIONS: Social support fully mediates the relationship between extraversion and posttraumatic stress disorder and partially mediates the relationship between extraversion and posttraumatic growth. Psychological interventions and care for survivors of the earthquake should include the various functions and sources of social support and how they serve to benefit individuals. PMID- 25815721 TI - Rapid identification of major QTLs associated with rice grain weight and their utilization. AB - To uncover the genetics of rice grain weight, we constructed an RIL population derived from a cross between a large grain accession M201 and a small size variety JY293. Specific Locus Amplified Fragment Sequencing (SLAF-Seq) technology was used to genotype two bulked DNA pools made from individual DNA of the heaviest 30 lines and the lightest 30 lines according to the 1000 grain weight (TGW). Bulked segregant analysis (BSA) was used to identify SLAFs strongly associated with TGW. Two marker-intensive regions at 24,600,000-24,850,000 bp and 25,000,000-25,350,000 bp on chromosome 3 were identified tightly related to the TGW. Then a linkage map of chromosome 3 was constructed with SSR markers and some SLAF derived single nucleotide polymorphisms (SNPs). Quantitative trait locus (QTL) mapping for TGW, grain length, grain width, and grain thickness revealed one major QTL in the second hot-region and two other minor QTLs for grain weight. These three QTLs displayed hierarchical effects on grain length and grain weight in order of qTGW3.2 (qGL3) qTGW3.1 (GS3) qTGW3.3. Multiple comparisons of means among the eight combinations of 3 QTLs revealed that the lines with two of three QTLs deriving from M201 displayed a large grain weight phenotype (TGW 40.2g, average data of three years) and lines with both qTGW3.1 and qTGW3.3 alleles from M201 (42.5g) had similar grain weight to the qTGW3.2 (40.8g) alone. Two strategies with similar effectiveness were proposed to improve grain weight by marker-assisted selection (MAS). One is to introduce the novel qTGW3.2 allele alone, and the other is to pyramid qTGW3.1 and qTGW3.3 alleles together. One new allele of GS3 (39 bp deletion in intron 1) and two SNPs in coding sequence of qGL3 identified in this study from M201 are useful in pyramiding elite alleles for molecular breeding for improvement of rice yield. PMID- 25815722 TI - Vitamin D prevents hypoxia/reoxygenation-induced blood-brain barrier disruption via vitamin D receptor-mediated NF-kB signaling pathways. AB - Maintaining blood-brain barrier integrity and minimizing neuronal injury are critical components of any therapeutic intervention following ischemic stroke. However, a low level of vitamin D hormone is a risk factor for many vascular diseases including stroke. The neuroprotective effects of 1,25(OH)2D3 (vitamin D) after ischemic stroke have been studied, but it is not known whether it prevents ischemic injury to brain endothelial cells, a key component of the neurovascular unit. We analyzed the effect of 1,25(OH)2D3 on brain endothelial cell barrier integrity and tight junction proteins after hypoxia/reoxygenation in a mouse brain endothelial cell culture model that closely mimics many of the features of the blood-brain barrier in vitro. Following hypoxic injury in bEnd.3 cells, 1,25(OH)2D3 treatment prevented the decrease in barrier function as measured by transendothelial electrical resistance and permeability of FITC-dextran (40 kDa), the decrease in the expression of the tight junction proteins zonula occludin-1, claudin-5, and occludin, the activation of NF-kB, and the increase in matrix metalloproteinase-9 expression. These responses were blocked when the interaction of 1,25(OH) )2D3 with the vitamin D receptor (VDR) was inhibited by pyridoxal 5' phosphate treatment. Our findings show a direct, VDR-mediated, protective effect of 1,25(OH) )2D3 against ischemic injury-induced blood-brain barrier dysfunction in cerebral endothelial cells. PMID- 25815723 TI - Low dose nicotine attenuates Abeta neurotoxicity through activation early growth response gene 1 pathway. AB - Epidemiological studies indicate that smoking is negatively correlated with the incidence and development of Alzheimer's disease (AD). Nicotine was reported to be the active factor. However, the detailed mechanisms still remain to be fully elucidated. Early growth response gene 1 (EGR-1) plays important roles in several important biological processes such as promoting cell growth, differentiation, anti oxidative stress, and apoptosis, but few in the pathogenesis of AD. In the present study, we show that nicotine can activate the MAPK/ERK/EGR-1 signaling pathway partially through alpha7 nAChR. In addition, the up-regulation of EGR-1 by nicotine can also increase the phosphorylation of CyclinD1 which contributes to the attenuation of amyloid-beta (Abeta(25-35)) -induced neurotoxicity. Although nicotine and Abeta(25-35) can activate EGR-1, the expression of EGR-1 is down-regulated following treatment with nicotine and Abeta(25-35). This study demonstrates that low dose nicotine attenuates Abeta(25-35)-induced neurotoxicity in vitro and in vivo through activating EGR-1 pathway. PMID- 25815724 TI - Culicidae community composition and temporal dynamics in Guapiacu Ecological Reserve, Cachoeiras de Macacu, Rio de Janeiro, Brazil. AB - A temporal observational study was conducted of the Culicidae fauna in a remnant area of Atlantic Forest within a private reserve (Guapiacu Ecological Reserve REGUA) presenting typical vegetation cover of dense rain forest, with some patches recovering a floristic composition similar to that of the original community. Research was carried out to analyze the influence of climatic factors (mean monthly temperature, rainfall, and air relative humidity) on the temporal dynamics of the mosquito communities that occur in the reserve. The completeness of the mosquito inventory was assessed with individual-based rarefaction extrapolation curves. Differences in species composition between sites and months were tested with PERMANOVA. True diversities of orders 0, 1, and 2 (effective numbers) were estimated and compared between sites, months, and years. Multiple stepwise regressions were used to assess relationships between climatic variables, measures of diversity, and abundances of the most common species. There were significant interactive effects between year and site on measures of diversity. However, diversity estimates showed little variation among months, and these were weakly correlated with climatic variables. Abundances of the most common species were significantly related to temperature or relative humidity, but not rainfall. The presence of mosquito species known to be vectors of human diseases combined with an intermittent flow of visitors to the study area suggests there is a risk of disease transmission that warrants further monitoring. PMID- 25815725 TI - DNA methylation combinations in adjacent normal colon tissue predict cancer recurrence: evidence from a clinical cohort study. AB - Accumulating evidence has suggested the requirement for further stratification of patients in the same tumor stage according to molecular factors. We evaluate the combination of cancer stage and DNA methylation status as an indicator of the risk of recurrence and mortality among patients with colorectal cancer (CRC). A cohort study of 215 patients with CRC (mean age 64.32 years; 50.5% of men) from Tri-Service General Hospital in Taiwan examined the association between cancer stage and risk of CRC recurrence and mortality. A Cox proportional hazard model was used to analyze patient methylation status and clinical information at study entry, and their associations with CRC recurrence and mortality during follow-up. The advanced stage patients with p16, hMLH1, and MGMT methylation were associated with higher risk of CRC recurrence compared with the local stage patients with unmethylation status in tumor tissues, with adjusted hazard ratios (HRs) (95% confidence interval [CI]) of 9.64 (2.92-31.81), 8.29 (3.40-20.22), and 11.83 (3.49-40.12), respectively. When analyzing normal tissues, we observed similar risk of CRC recurrence with adjusted HRs (95% CI) of 10.85 (4.06-28.96), 9.04 (3.79-21.54), and 12.61 (4.90-32.44), respectively. For combined analyses, the risk of recurrence in the patients in advanced stage with DNA methylation in both normal and tumor tissues, compared with local stage with unmethylation, was increased with adjusted HR (95% CI) of 9.37 (3.36-26.09). In the advanced stage patients, methylation status and tissue subtype were associated with increased risk of 5-year cumulative CRC recurrence (p < 0.001). This study demonstrates that clustering DNA methylation status according to cancer stage and tissue subtype is critical for the assessment of risk of recurrence in CRC patients and also indicated an underlying mechanism. PMID- 25815726 TI - Associations of blood pressure with body composition among Afro-Caribbean children in Barbados. AB - Despite complex presentation of adult hypertension and a concomitant obesity epidemic, little is known about overweight in relation to blood pressure among Caribbean children. We examined blood pressure in relation to body size in a cross-sectional study of 573 Barbadian children aged 9-10 years (2010-2011). The United States normative blood pressure percentiles were used to identify children with high (>=95th percentile) or high normal blood pressure (90th-95th percentile). The World Health Organization body mass index cut-off points were used to assess weight status. MAJOR FINDINGS: Thirty percent of children were overweight/obese. Percentage fat mass differed between girls (20.4%) and boys (17.72%) (p<0.05). Mean systolic blood pressure among girls was 106.11 (95% CI 105.05, 107.17) mmHg and 105.23 (104.09, 106.38) for boys. The percentages with high or high-normal mean systolic blood pressure were 14.38% (10.47, 18.29) for girls and 8.08% (4.74, 11.41) for boys. Height and body mass index were independent correlates of systolic and diastolic blood pressure. Mean systolic blood pressure was related to lean mass but not fat mass, while diastolic blood pressure was associated with fat mass index and overweight. PRINCIPAL CONCLUSION: One third of 9-10 year old children in Barbados were overweight/obese and 12% had elevated mean systolic blood pressure. BP was related to body size. These findings signal potential adverse trends in weight gain and BP trends for children growing up in the context of a country that has recently undergone rapid economic transition. PMID- 25815728 TI - Protruding structures on caterpillars are controlled by ectopic Wnt1 expression. AB - Spine-like or protruding structures, which may be aposematic for predators, are often observed in multiple segments of lepidopteran larvae (caterpillars). For example, the larvae of the Chinese wheel butterfly, Byasa alcinous, display many protrusions on their backs as a warning that they are toxic. Although these protrusions are formed by an integument lined with single-layered epidermal cells, the molecular mechanisms underlying their formation have remained unclear. In this study, we focused on a spontaneous mutant of the silkworm, Bombyx mori, Knobbed, which shows similar protrusions to B. alcinous and demonstrates that Wnt1 plays a crucial role in the formation of protrusion structures. Using both transgene expression and RNAi-based knockdown approaches, we showed that Wnt1 designates the position where epidermal cells excessively proliferate, leading to the generation of knobbed structures. Furthermore, in the B. alcinous larvae, Wnt1 was also specifically expressed in association with the protrusions. Our results suggest that Wnt1 plays a role in the formation of protrusions on the larval body, and is conserved broadly among diverse species in Lepidoptera. PMID- 25815727 TI - A resorbable antibiotic-eluting polymer composite bone void filler for perioperative infection prevention in a rabbit radial defect model. AB - Nearly 1.3 million total joint replacement procedures are performed in the United States annually, with numbers projected to rise exponentially in the coming decades. Although finite infection rates for these procedures remain consistently low, device-related infections represent a significant cause of implant failure, requiring secondary or revision procedures. Revision procedures manifest several fold higher infection recurrence rates. Importantly, many revision surgeries, infected or not, require bone void fillers to support the host bone and provide a sufficient tissue bed for new hardware placement. Antibiotic-eluting bone void fillers (ABVF), providing both osteoconductive and antimicrobial properties, represent one approach for reducing rates of orthopedic device-related infections. Using a solvent-free, molten-cast process, a polymer-controlled antibiotic-eluting calcium carbonate hydroxyapatite (HAP) ceramic composite BVF (ABVF) was fabricated, characterized, and evaluated in vivo using a bacterial challenge in a rabbit radial defect window model. ABVF loaded with tobramycin eliminated the infectious burden in rabbits challenged with a clinically relevant strain of Staphylococcus aureus (inoculum as high as 107 CFU). Histological, microbiological, and radiographic methods were used to detail the effects of ABVF on microbial challenge to host bone after 8 weeks in vivo. In contrast to the HAP/BVF controls, which provided no antibiotic protection and required euthanasia 3 weeks post-operatively, tobramycin-releasing ABVF animals showed no signs of infection (clinical, microbiological, or radiographic) when euthanized at the 8 week study endpoint. ABVF sites did exhibit fibrous encapsulation around the implant at 8 weeks. Local antibiotic release from ABVF to orthopedic sites requiring bone void fillers eliminated the periprosthetic bacterial challenge in this 8-week in vivo study, confirming previous in vitro results. PMID- 25815729 TI - The roles of phosphorylation and SHAGGY-like protein kinases in geminivirus C4 protein induced hyperplasia. AB - Even though plant cells are highly plastic, plants only develop hyperplasia under very specific abiotic and biotic stresses, such as when exposed to pathogens like Beet curly top virus (BCTV). The C4 protein of BCTV is sufficient to induce hyperplasia and alter Arabidopsis development. It was previously shown that C4 interacts with two Arabidopsis Shaggy-like protein kinases, AtSK21 and 23, which are negative regulators of brassinosteroid (BR) hormone signaling. Here we show that the C4 protein interacts with five additional AtSK family members. Bikinin, a competitive inhibitor of the seven AtSK family members that interact with C4, induced hyperplasia similar to that induced by the C4 protein. The Ser49 residue of C4 was found to be critical for C4 function, since: 1) mutagenesis of Ser49 to Ala abolished the C4-induced phenotype, abolished C4/AtSK interactions, and resulted in a mutant protein that failed to induce changes in the BR signaling pathway; 2) Ser49 is phosphorylated in planta; and 3) plant-encoded AtSKs must be catalytically active to interact with C4. A C4 N-myristoylation site mutant that does not localize to the plasma membrane and does not induce a phenotype, retained the ability to bind AtSKs. Taken together, these results suggest that plasma membrane associated C4 interacts with and co-opts multiple AtSKs to promote its own phosphorylation and activation to subsequently compromise cell cycle control. PMID- 25815730 TI - Transcriptional factor DLX3 promotes the gene expression of enamel matrix proteins during amelogenesis. AB - Mutation of distal-less homeobox 3 (DLX3) is responsible for human tricho-dento osseous syndrome (TDO) with amelogenesis imperfecta, indicating a crucial role of DLX3 in amelogenesis. However, the expression pattern of DLX3 and its specific function in amelogenesis remain largely unknown. The aim of this study was to investigate the effects of DLX3 on enamel matrix protein (EMP) genes. By immunohistochemistry assays of mouse tooth germs, stronger immunostaining of DLX3 protein was identified in ameloblasts in the secretory stage than in the pre secretory and maturation stages, and the same pattern was found for Dlx3 mRNA using Realtime PCR. In a mouse ameloblast cell lineage, forced expression of DLX3 up-regulated the expression of the EMP genes Amelx, Enam, Klk4, and Odam, whereas knockdown of DLX3 down-regulated these four EMP genes. Further, bioinformatics, chromatin immunoprecipitation, and luciferase assays revealed that DLX3 transactivated Enam, Amelx, and Odam through direct binding to their enhancer regions. Particularly, over-expression of mutant-DLX3 (c.571_574delGGGG, responsible for TDO) inhibited the activation function of DLX3 on expression levels and promoter activities of the Enam, Amelx, and Odam genes. Together, our data show that DLX3 promotes the expression of the EMP genes Amelx, Enam, Klk4, and Odam in amelogenesis, while mutant-DLX3 disrupts this regulatory function, thus providing insights into the molecular mechanisms underlying the enamel defects of TDO disease. PMID- 25815731 TI - Helicobacter pylori seropositivity's association with markers of iron, 1-carbon metabolism, and antioxidant status among US adults: a structural equations modeling approach. AB - OBJECTIVES: We tested a model in which Helicobacter pylori seropositivity (Hps) predicted iron status, which in turn acted as a predictor for markers of 1-C metabolism that were then allowed to predict antioxidant status. METHODS: National Health and Nutrition Examination Surveys (NHANES 1999-2000) cross sectional data among adults aged 20-85 y were analyzed (n = 3,055). Markers of Hps, iron status (serum ferritin and transferrin saturation (TS)); 1-C metabolism (serum folate (FOLserum), B-12, total homocysteine (tHcy), methylmalonic acid (MMA)) and antioxidant status (vitamins A and E) were entered into a structural equations model (SEM). RESULTS: Predictors of Hps included older age, lower education and income, racial/ethnic groups (lowest among Non-Hispanic Whites), and lifetime cigarette smoking. SEM modeling indicated that Hps had a direct inverse relationship with iron status (combining serum ferritin and TS) which in turn was positively related to 1-C metabolites (higher serum folate, B-12 or lower tHcy/MMA) that were positively associated with antioxidant status (combining serum vitamins A and E). Another pathway that was found bypassed 1-C metabolites (Hps -> Iron_st -> Antiox). The sum of all indirect effects from Hps combining both pathways and the other indirect pathways in the model (Hps -> Iron_st -> OneCarbon; Hps ->OneCarbon ->Antiox) was estimated at beta = -0.006+/ 0.003, p<0.05. CONCLUSIONS: In sum, of the total effect of H. pylori seropositivity on antioxidant status, two significant indirect pathways through Iron status and 1-Carbon metabolites were found. Randomized controlled trials should be conducted to uncover the concomitant causal effect of H. pylori eradication on improving iron status, folate, B-12 and antioxidant status among H. pylori seropositive individuals. PMID- 25815732 TI - Age and gender adjusted comparison of clinical features between severe cases infected with H7N9 and H1N1pdm influenza A in Jiangsu Province, China. AB - BACKGROUND: Influenza H7N9 and H1N1pdm can cause severe human infections. It is important to investigate the distinguishing clinical features between these two diseases. Several studies have compared the differences in general, however, age and gender adjusted comparisons may be more useful and informative to the health professionals. METHODS: A total of 184 severe H1N1pdm patients and 37 severe H7N9 patients from Jiangsu Province were included in this analysis to perform age and gender adjusted comparison of clinical features. RESULTS: After adjusting age and gender, no significant differences in chronic medical conditions or treatment were found between severely ill patients with H7N9 and H1N1pdm. Severely ill patients with H7N9 had significantly longer interval from onset of illness to neuraminidase inhibitor treatment and to death. They were more likely to have complications such as acute respiratory distress syndrome (ARDS), liver and renal dysfunctions, and had a significantly higher risk of death. CONCLUSION: Our results suggests that age and gender should be adjusted as important confounding factors when comparing the clinical features between severe H7N9 and H1N1pdm patients to avoid any misunderstanding regarding the differences between these two diseases particularly in terms of clinical severity and prognosis. PMID- 25815733 TI - Exploring regulation genes involved in the expression of L-amino acid oxidase in Pseudoalteromonas sp. Rf-1. AB - Bacterial L-amino acid oxidase (LAAO) is believed to play important biological and ecological roles in marine niches, thus attracting increasing attention to understand the regulation mechanisms underlying its production. In this study, we investigated genes involved in LAAO production in marine bacterium Pseudoalteromonas sp. Rf-1 using transposon mutagenesis. Of more than 4,000 mutants screened, 15 mutants showed significant changes in LAAO activity. Desired transposon insertion was confirmed in 12 mutants, in which disrupted genes and corresponding functionswere identified. Analysis of LAAO activity and lao gene expression revealed that GntR family transcriptional regulator, methylase, non ribosomal peptide synthetase, TonB-dependent heme-receptor family, Na+/H+ antiporter and related arsenite permease, N-acetyltransferase GCN5, Ketol-acid reductoisomerase and SAM-dependent methytransferase, and their coding genes may be involved in either upregulation or downregulation pathway at transcriptional, posttranscriptional, translational and/or posttranslational level. The nhaD and sdmT genes were separately complemented into the corresponding mutants with abolished LAAO-activity. The complementation of either gene can restore LAAO activity and lao gene expression, demonstrating their regulatory role in LAAO biosynthesis. This study provides, for the first time, insights into the molecular mechanisms regulating LAAO production in Pseudoalteromonas sp. Rf-1, which is important to better understand biological and ecological roles of LAAO. PMID- 25815734 TI - Processing of Horizontal Sound Localization Cues in Newborn Infants. AB - OBJECTIVES: By measuring event-related brain potentials (ERPs), the authors tested the sensitivity of the newborn auditory cortex to sound lateralization and to the most common cues of horizontal sound localization. DESIGN: Sixty-eight healthy full-term newborn infants were presented with auditory oddball sequences composed of frequent and rare noise segments in four experimental conditions. The authors tested in them the detection of deviations in the primary cues of sound lateralization (interaural time and level difference) and in actual sound source location (free-field and monaural sound presentation). ERP correlates of deviance detection were measured in two time windows. RESULTS: Deviations in both primary sound localization cues and the ear of stimulation elicited a significant ERP difference in the early (90 to 140 msec) time window. Deviance in actual sound source location (the free-field condition) elicited a significant response in the late (290 to 340 msec) time window. CONCLUSIONS: The early differential response may indicate the detection of a change in the respective auditory features. The authors suggest that the late differential response, which was only elicited by actual sound source location deviation, reflects the detection of location deviance integrating the various cues of sound source location. Although the results suggest that all of the tested binaural cues are processed by the neonatal auditory cortex, utilizing the cues for locating sound sources of these cues may require maturation and learning. PMID- 25815735 TI - Correction: Antiarrhythmic agents and the risk of malignant neoplasm of liver and intrahepatic bile ducts. PMID- 25815736 TI - Severe spinal cord compression due to extramedullary hematopoiesis. PMID- 25815737 TI - Bilateral cerebellopontine arachnoid cyst: A rare entity. AB - Bilateral cerebellopontine angle (CPA) arachnoid cysts (ACs) are very rare: only one case is reported in literature. Pathogenesis of those cysts is unknown; they are thought to be congenital. The presenting symptoms of CPA AC are frequently nonspecific or otological. The management of ACs of the CPA is controversial. We are reporting two cases of bilateral CPA AC with their pathophysiology and review of literature. PMID- 25815739 TI - Not quite a win-win: the corporate agenda of the stay at work/return to work project. AB - The idea that efforts are necessary to transform the dominant framework of workplace safety and health in the United States, from one of compensation and disability to one of stay at work/return to work (SAW/RTW) for workers injured or made ill on the job, has become increasingly widespread. SAW/RTW advocates argue that everyone "wins" when unnecessary disability is reduced. Toward this end, advocates have put forward a program and implemented a strategy with strong proponents among a coalition of corporate-connected professionals. The seemingly obvious conclusions of their arguments bear closer critical scrutiny, however. Addressing key questions-why injured workers do not SAW/RTW, who the coalition of SAW/RTW proponents includes, and what the coalition proposes-reveals that the SAW/RTW approach mainly benefits employers and the corporate-connected advocates. These assertions are detailed, and principles of an alternative approach that will serve the needs of injured workers are outlined. PMID- 25815738 TI - Noninvasive assessment of hemodynamics: a comparative analysis of fingertip pulse contour analysis and impedance cardiography. AB - OBJECTIVE: Systemic hemodynamic assessment is useful for characterizing the underlying physiology of hypertension, selecting individualized treatment approaches, and understanding the underlying mechanisms of action of interventions. Invasive methods are not suitable for routine clinic or research use, and noninvasive methods such as impedance cardiography have technical and practical limitations. Fingertip pulse contour analysis using the Nexfin device is a novel alternative to noninvasive assessment of blood pressure and hemodynamics. Although both impedance cardiography and the Nexfin have been validated against invasive methods, the extent to which they are correlated with each other is unknown. This study is a comparative analysis of data simultaneously obtained by impedance cardiography and using the Nexfin device. METHODS: As part of a larger clinical trial, 13 adults with type 2 diabetes completed cardiovascular reactivity testing on three occasions: at study baseline and after two 4-week dietary treatment periods. Blood pressure, hemodynamics, and heart rate variability were assessed at rest and during acute mental stress. RESULTS: Blood pressure, heart rate, and heart rate variability data were significantly correlated between the two devices, but hemodynamic data (stroke volume, cardiac output, total peripheral resistance) were not significantly correlated. Both techniques detected treatment-related changes in blood pressure and total peripheral resistance, but significantly differed in the magnitude and/or direction of treatment effects. CONCLUSION: We conclude that Nexfin is not an appropriate alternative to impedance cardiography for measurement of underlying hemodynamics in psychophysiological research, but may be useful for beat-to-beat monitoring of blood pressure and heart rate variability. PMID- 25815740 TI - Teen worker safety training: methods used, lessons taught, and time spent. AB - Safety training is strongly endorsed as one way to prevent teens from performing dangerous tasks at work. The objective of this mixed methods study was to characterize the safety training that teenagers receive on the job. From 2010 through 2012, focus groups and a cross-sectional survey were conducted with working teens. The top methods of safety training reported were safety videos (42 percent) and safety lectures (25 percent). The top lessons reported by teens were "how to do my job" and "ways to spot hazards." Males, who were more likely to do dangerous tasks, received less safety training than females. Although most teens are getting safety training, it is inadequate. Lessons addressing safety behaviors are missing, training methods used are minimal, and the time spent is insignificant. More research is needed to understand what training methods and lessons should be used, and the appropriate safety training length for effectively preventing injury in working teens. In addition, more research evaluating the impact of high-quality safety training compared to poor safety training is needed to determine the best training programs for teens. PMID- 25815741 TI - Development of a safety communication and recognition program for construction. AB - Leading-indicator-based (e.g., hazard recognition) incentive programs provide an alternative to controversial lagging-indicator-based (e.g., injury rates) programs. We designed a leading-indicator-based safety communication and recognition program that incentivized safe working conditions. The program was piloted for two months on a commercial construction worksite and then redesigned using qualitative interview and focus group data from management and workers. We then ran the redesigned program for six months on the same worksite. Foremen received detailed weekly feedback from safety inspections, and posters displayed worksite and subcontractor safety scores. In the final program design, the whole site, not individual subcontractors, was the unit of analysis and recognition. This received high levels of acceptance from workers, who noted increased levels of site unity and team-building. This pilot program showed that construction workers value solidarity with others on site, demonstrating the importance of health and safety programs that engage all workers through a reliable and consistent communication infrastructure. PMID- 25815742 TI - Community perspectives on the risk of indoor air pollution arising from contaminated groundwater. AB - The migration of volatile contaminants into overlying buildings, known as vapor intrusion, is a health concern for people living above contaminated groundwater. As public health and environmental agencies develop protocols to evaluate vapor intrusion exposure, little attention has been paid to the experiences and opinions of communities likely to be affected by vapor intrusion. Using a community-driven research approach and qualitative interviews, we explored community perspectives on the vapor intrusion pathway and the perceived impact on community health and well-being among neighbors living atop a large, shallow chlorinated solvent plume in San Antonio, TX. Most participants associated vapor intrusion with health risks, expressing concern about the unavoidable and uncontrollable nature of their exposure. Few were satisfied with the responsiveness of public officials. Above all, participants wanted more accurate, transparent information and additional independent scientific investigations. PMID- 25815743 TI - Reducing lead in air and preventing childhood exposure near lead smelters: learning from the U.S. experience. AB - Childhood lead exposure and poisoning near primary lead smelters continues in developed and developing countries. In the United States, the problem of lead poisoning in children caused by smelter emissions was first documented in the early 1970s. In 1978, Environmental Protection Agency set National Ambient Air Quality Standards for lead. Attainment of this lead standard in areas near operating lead smelters took twenty to thirty years. Childhood lead exposure and poisoning continued to occur after the lead National Ambient Air Quality Standards were set and before compliance was achieved. This article analyzes and discusses the factors that led to the eventual achievement of the 1978 lead National Ambient Air Quality Standards near primary smelters and the reduction of children's blood lead levels in surrounding communities. Factors such as federal and state regulation, monitoring of emissions, public health activities such as blood lead surveillance and health education, relocation of children, environmental group and community advocacy, and litigation all played a role. PMID- 25815744 TI - Occupational health and safety for agricultural workers in Thailand: gaps and recommendations, with a focus on pesticide use. AB - Over 16.7 million workers in Thailand (42 percent of the working population) are engaged in agriculture, disproportionately from the lower socioeconomic strata of Thai society. Most agricultural workers (over 93 percent) work in the informal sector without the protections of regulations or enforcement of labor or health and safety laws or enrollment in a social security system. Although Thailand's use of herbicides, fungicides, and insecticides is growing, there is little regulation of the sale, use, or application of these potentially toxic chemicals. This paper summarizes the research to date on occupational health and safety for Thai agricultural workers, identifies gaps in pesticide regulations and the current systems for occupational health and safety and social support for Thai agricultural workers, and makes recommendations for future policy and research initiatives to fill the identified gaps. PMID- 25815745 TI - Working Behind Wyoming's Carbon Curtain. AB - Dan Neal, formerly the Executive Director of the Equality State Policy Center in Casper, Wyoming, was presented the Lorin Kerr Award by the Occupational Health and Safety Section of the American Public Health Association at its annual meeting in November 2014. The Kerr Award recognizes individuals who have stepped up to provide new leadership in occupational health and safety activism with sustained and outstanding efforts and dedication to improving the lives of workers. (Lorin Kerr [1909-1991] was a life-long activist and served for over forty years as a physician for the United Mine Workers. He was dedicated to improving access to health care for coal miners and other workers and to obtaining compensation for and preventing black lung disease.) Neal's acceptance speech introduces us to the health and safety concerns in Wyoming's expanding energy sector and explains how a coalition for occupational safety and health is organizing to address these concerns. PMID- 25815749 TI - Accidental poisoning with 6-MP in a sibling of pediatric patient treated with maintenance chemotherapy. PMID- 25815748 TI - Lamp-lit bridges as dual light-traps for the night-swarming mayfly, Ephoron virgo: interaction of polarized and unpolarized light pollution. AB - Ecological photopollution created by artificial night lighting can alter animal behavior and lead to population declines and biodiversity loss. Polarized light pollution is a second type of photopollution that triggers water-seeking insects to ovisposit on smooth and dark man-made objects, because they simulate the polarization signatures of natural water bodies. We document a case study of the interaction of these two forms of photopollution by conducting observations and experiments near a lamp-lit bridge over the river Danube that attracts mass swarms of the mayfly Ephoron virgo away from the river to oviposit on the asphalt road of the bridge. Millions of mayflies swarmed near bridge-lights for two weeks. We found these swarms to be composed of 99% adult females performing their upstream compensatory flight and were attracted upward toward unpolarized bridge lamp light, and away from the horizontally polarized light trail of the river. Imaging polarimetry confirmed that the asphalt surface of the bridge was strongly and horizontally polarized, providing a supernormal ovipositional cue to Ephoron virgo, while other parts of the bridge were poor polarizers of lamplight. Collectively, we confirm that Ephoron virgo is independently attracted to both unpolarized and polarized light sources, that both types of photopollution are being produced at the bridge, and that spatial patterns of swarming and oviposition are consistent with evolved behaviors being triggered maladaptively by these two types of light pollution. We suggest solutions to bridge and lighting design that should prevent or mitigate the impacts of such scenarios in the future. The detrimental impacts of such scenarios may extend beyond Ephoron virgo. PMID- 25815750 TI - Dicarbonyl L-xylulose reductase (DCXR), a "moonlighting protein" in the bovine epididymis. AB - During maturation and the acquisition of their fertilization potential, male germ cells are subjected to various sequential modifications that occur in the epididymis. Protein addition, reorganization or withdrawal, comprise some of these modifications. Dicarbonyl L-xylulose reductase (DCXR), a multifunctional protein involved in various enzymatic and protein interaction processes in different physiological systems, is one of the proteins added to spermatozoa in the epididymis. DCXR is a well-conserved protein with multiple characteristics including enzymatic activities and mediation of cell-cell interaction. In this study, we characterized the DCXR gene and protein expression in the bovine epididymis. Dicarbonyl L-xylulose reductase mRNA is differentially expressed in the caput, corpus, and cauda epididymide epithelial cells with a higher level observed in the cauda region. Tissue protein expression follows the same pattern as the corresponding mRNA expression with a cytoplasmic and apical distribution in the corpus and cauda epithelial cells, respectively. The protein can also be found with a nuclear localization in cauda epididymidis epithelial cells. Dicarbonyl L-xylulose reductase is secreted in the epididymis luminal compartment in the soluble fraction and is associated with microvesicular elements named epididymosomes. In spermatozoa, the DCXR protein was found in the cytoplasmic and membranous fractions. Expression of the DCXR protein is higher on caput spermatozoa but finally shows a weak detection in semen. These data describe DCXR in the bovine epididymis and reveal that its behavior differs from that found in humans. It seems that, in this model, the DCXR protein might have a questionable involvement in the fertilization process. PMID- 25815751 TI - Strong isotope effects on melting dynamics and ice crystallisation processes in cryo vitrification solutions. AB - The nucleation and growth of crystalline ice during cooling, and further crystallization processes during re-warming are considered to be key processes determining the success of low temperature storage of biological objects, as used in medical, agricultural and nature conservation applications. To avoid these problems a method, termed vitrification, is being developed to inhibit ice formation by use of high concentration of cryoprotectants and ultra-rapid cooling, but this is only successful across a limited number of biological objects and in small volume applications. This study explores physical processes of ice crystal formation in a model cryoprotective solution used previously in trials on vitrification of complex biological systems, to improve our understanding of the process and identify limiting biophysical factors. Here we present results of neutron scattering experiments which show that even if ice crystal formation has been suppressed during quench cooling, the water molecules, mobilised during warming, can crystallise as detectable ice. The crystallisation happens right after melting of the glass phase formed during quench cooling, whilst the sample is still transiting deep cryogenic temperatures. We also observe strong water isotope effects on ice crystallisation processes in the cryoprotectant mixture. In the neutron scattering experiment with a fully protiated water component, we observe ready crystallisation occurring just after the glass melting transition. On the contrary with a fully deuteriated water component, the process of crystallisation is either completely or substantially supressed. This behaviour might be explained by nuclear quantum effects in water. The strong isotope effect, observed here, may play an important role in development of new cryopreservation strategies. PMID- 25815752 TI - Impairment and disability in persons with MS: do functional performance or functional limitations matter? AB - Persons with multiple sclerosis (MS) often demonstrate impairment in cardiorespiratory and musculoskeletal systems that may be associated with functional performance, functional limitations, and disability limitations. This study examined such relationships in persons with MS using Nagi's disablement model and its subsequent conceptual modifications. The sample included 63 persons with MS (75% relapsing-remitting MS, median EDSS = 4.0, and mean MS duration = 13.1 years) who underwent measurements of aerobic fitness and muscular strength (i.e. impairment), functional performance, functional limitations, and disability limitations. The data were primarily examined using path analysis in Mplus 7.0. Our final model provided an excellent fit for the data (chi2 = 0.67, df = 3, p = 0.88, SRMR = 0.01, and CFI = 1.00). The final model indicated that aerobic fitness and muscular strength were indirectly associated with disability limitations in persons with MS through a pathway that included functional limitations (indirect path coefficients of 0.29 and 0.20, respectively), but not functional performance. Aerobic fitness and muscular strength may be the important targets of exercise training interventions for improving perceived functional limitations and disability limitations in persons with MS. PMID- 25815753 TI - MUC1 selectively targets human pancreatic cancer in orthotopic nude mouse models. AB - The goal of this study was to determine whether MUC1 antibody conjugated with a fluorophore could be used to visualize pancreatic cancer. Anti-MUC1 (CT2) antibody was conjugated with 550 nm or 650 nm fluorophores. Nude mouse were used to make subcutaneous and orthotopic models of pancreatic cancer. Western blot and flow cytometric analysis confirmed the expression of MUC1 in human pancreatic cancer cell lines including BxPC-3 and Panc-1. Immunocytochemistry with fluorophore conjugated anti-MUC1 antibody demonstrated fluorescent areas on the membrane of Panc-1 cancer cells. After injecting the conjugated anti-MUC1 antibodies via the tail vein, subcutaneously transplanted Panc-1 and BxPC-3 tumors emitted strong fluorescent signals. In the subcutaneous tumor models, the fluorescent signal from the conjugated anti-MUC1 antibody was noted around the margin of the tumor and space between the cells. The conjugated anti-MUC1 antibody bound the tumor in orthotopically-transplanted Panc-1 and BxPC-3 models enabling the tumors to be imaged. This study showed that fluorophore conjugated anti-MUC1 antibodies could visualize pancreatic tumors in vitro and in vivo and may help to improve the diagnosis and treatment of pancreatic cancer. PMID- 25815754 TI - Long-Term, Open-Label, Safety Study of Edivoxetine 12 to 18 mg Once Daily as Adjunctive Treatment for Patients With Major Depressive Disorder Who Are Partial Responders to Selective Serotonin Reuptake Inhibitor Treatment. AB - Long-term safety, tolerability, and efficacy of adjunctive edivoxetine hydrochloride (hereafter edivoxetine), a highly selective and potent norepinephrine reuptake inhibitor, was assessed in patients with major depressive disorder (MDD) experiencing partial response to selective serotonin reuptake inhibitor treatment. Data are from a multicenter, 54-week, open-label trial of adjunctive edivoxetine 12 to 18 mg once daily in patients with MDD who had experienced partial response by history to 6 or more weeks of current selective serotonin reuptake inhibitor therapy and who had a 17-item GRID Hamilton Rating Scale for Depression total score 16 or higher at study entry. Safety measures included discontinuation rate, treatment-emergent adverse events, serious adverse events, and vital signs. Efficacy measures included the Montgomery-Asberg Depression Rating Scale. Of 608 patients, 328 (54%) completed the open-label adjunctive treatment. Study discontinuation due to adverse events occurred in 17.0%, and there were 13 serious adverse events (1 death). Treatment-emergent adverse events 5% or higher were nausea, hyperhidrosis, constipation, headache, dry mouth, dizziness, vomiting, insomnia, and upper respiratory tract infection. Mean increases were observed in systolic blood pressure (range, 0.0-2.3 mm Hg), diastolic blood pressure (range, 1.9-3.3 mm Hg), and pulse (range, 5.9-8.4 beats per minute). Mean improvements on the Montgomery-Asberg Depression Rating Scale ( 17.0) were observed from baseline to week 54. The safety profile from this study provides an overview of outcomes associated with edivoxetine and norepinephrine reuptake inhibition as an adjunctive treatment in patients with MDD who were treated up to 1 year. PMID- 25815755 TI - Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship. AB - Emerging evidence suggests that sexual dysfunction emerging during treatment with selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) persists in some patients beyond drug discontinuation (post-SSRI sexual dysfunction [PSSD]). We sought to identify and characterize a series of such cases and explore possible explanatory factors and exposure response relationship. Subjects who responded to an invitation in a forum dedicated to PSSD filled out a survey via online software. Case probability was defined according to the following 3 categories of increasing presumed likelihood of PSSD. Noncases did not meet the criteria for possible cases. Possible cases were subjects with normal pretreatment sexual function who first experienced sexual disturbances while using a single SSRI/SNRI, which did not resolve upon drug discontinuation for 1 month or longer as indicated by Arizona Sexual Experience Scale scores. High-probability cases were also younger than 50-year olds; did not have confounding medical conditions, medications, or drug use; and had normal scores on the Hospital Anxiety and Depression Scale. Five hundred thirty-two (532) subjects completed the survey, among which 183 possible cases were identified, including 23 high-probability cases. Female sex, genital anesthesia, and depression predicted current sexual dysfunction severity, but dose/defined daily dose ratio and anxiety did not. Genital anesthesia did not correlate with depression or anxiety, but pleasureless orgasm was an independent predictor of both depression and case probability. Limitations of the study include retrospective design and selection and report biases that do not allow generalization or estimation of incidence. However, our findings add to previous reports and support the existence of PSSD, which may not be fully explained by alternative nonpharmacological factors related to sexual dysfunction, including depression and anxiety. PMID- 25815756 TI - Restless legs syndrome associated with the combined use of duloxetine plus paroxetine. PMID- 25815757 TI - Hospice and palliative care: differences matter. PMID- 25815758 TI - Communicating with patients and their families about palliative and end-of-life care: comfort and educational needs of nurses. AB - INTRODUCTION: Effectively discussing palliative care with patients and families requires knowledge and skill. The purpose of this study was to determine perceived needs of inpatient nurses for communicating with patients and families about palliative and end-of-life (EoL) care. METHOD: A non-experimental design was used. In total, 60 inpatient nurses from one hospital in Idaho completed the End of Life Professional Caregiver Survey (EPCS), which examines three domains: patient and family-centered communication, cultural and ethical values, and effective care delivery. RESULTS: The number of years' experience nurses had (F(9,131.57)=2.22, p=0.0246; Wilk's ^=0.709) and the unit they worked on (F(6,110)=2.49, p=0.0269; Wilk's ^=0.775) had a significant effect on their comfort discussing EoL and palliative care with patients and their families. For all three domains, years of nursing experience was positively associated with comfort in communicating about EoL care. Oncology nurses were most comfortable with regard to patient and family-centered communication. DISCUSSION: The success and sustainability of this service is dependent on education for health-care providers. Studies are needed to determine the most effective ways to meet this educational challenge. PMID- 25815759 TI - Fentanyl pectin nasal spray for breakthrough cancer pain. PMID- 25815760 TI - Deathbed phenomena reported by patients in palliative care: clinical opportunities and responses. AB - BACKGROUND: Reports from patients on seeing or hearing a dead relative or dreaming a highly significant dream at the end of life can be perplexing for health professionals who may wonder how best to respond. AIM: The aim of this study was to systematically review the literature on deathbed phenomena (DBP), and provide suggestions for a clinical response to dying patients' recounts of these hard-to-explain phenomena. METHODS: The authors searched for relevant studies which reported on DBP within a palliative care context. Eligibility criteria were established, a review process was employed and a narrative synthesis approach was used to interpret the data. RESULTS: In total, eight papers met the inclusion criteria. Reported prevalence of DBP ranged from 24-51% with common themes described. Distinguishing between DBP and hallucinations was discussed, requiring very different clinical responses. Phenomena were timed most often in the last hours or days before death. Experiencing a DBP was, in most cases, deeply meaningful, bringing comfort, peace and reassurance. Health professionals were not surprised to hear of a DBP, but were not always well prepared to respond appropriately. CONCLUSIONS: Rather than simply dismissing DBP as medication related or the physiological effects of dying, the significance of these events and the comfort afforded by them to patients and carers should be recognised. Disclosure of DBP may enable health professionals to discuss more spiritual and existential concerns, which have the potential to offer hope, meaning and connection. We propose strategies and approaches for strengthening compassionate clinical practice in this area. PMID- 25815761 TI - The unmet palliative care needs of those dying with dementia. AB - An estimated 33.9 million people are living with dementia worldwide. The overall estimated median survival time from onset of dementia to death is 4.1 years for men and 4.6 years for women, with longer survival times in those with early-onset dementia. Much has been discussed about the needs of this vulnerable group of people particularly in terms of their health-care and end-of-life care (EoLC) needs. However, the literature suggests that people with end-stage dementia are still not receiving adequate or appropriate EoLC. Difficulty diagnosing dementia, a stigma surrounding the disease, lack of education of the dementia disease process and the ability to identify complications encountered at end-stage dementia by health-care providers, families and carers are some of the factors preventing those with dementia receiving effective EoLC. Great strides have been made to improve dementia palliative care; however, this cohort of patients still receive fewer referrals to appropriate palliative care services than other terminally ill patients. PMID- 25815762 TI - The role of UK district nurses in providing care for adult patients with a terminal diagnosis: a meta-ethnography. AB - AIM: To explore the role of UK district nurses in providing care for adult patients with a terminal diagnosis by reviewing qualitative research. DESIGN: Meta-ethnography was used to conduct the synthesis. DATA SOURCES: CINAHL, MEDLINE and British Nursing Index (BNI) were searched comprehensively for primary research relating to the role of UK district nurses in palliative care. REVIEW METHODS: The abstracts and titles of 700 papers were screened against inclusion criteria, of these 97 full papers were appraised. Some 24 studies reported in 25 papers were selected for inclusion in the synthesis. FINDINGS: In total, five key themes were identified: valuing the role; practical role; relationships with patients and families; providing psychological support; and role uncertainty. Further synthesis yielded two 'lines of argument'. The concept of the 'expert friend' argues that the atypical relationship district nurses cultivate with patients underpins district nurses' provision of palliative care and profoundly influences the nature of psychological support given. Secondly, the concept of 'threat and opportunity' encapsulates the threat district nurses can feel to their traditional role in palliative care through changing health and social policy, while recognising the benefits that access to specialist knowledge and better training can bring. CONCLUSION: The findings have implications for understanding the motivators and barriers experienced by district nurses delivering palliative care in a time of unprecedented change to community health services. PMID- 25815763 TI - Palliative approach education for rural nurses and health-care workers: a mixed method study. AB - BACKGROUND: The aim of this mixed-method study was to evaluate the outcomes of an educational intervention in a palliative approach for rural nurses and health care workers (HCWs) using a team-based method. METHODS: Pre- and post-test measures using the Palliative Care Nursing Self-Competence (PCSNC) scale and the Self-Perceived Palliative Care Knowledge instrument were used to evaluate learning outcomes. Participant post-test scores were also compared to normative provincial data. FINDINGS: At post-test, HCWs showed statistically significant improvements across 7 of 10 domains in self-perceived competence and 6 of 12 domains in self-perceived knowledge; all scores were equivalent to or better than provincial normative data. Nurses' self-perceived knowledge showed statistically significant improvements in 3 of 12 domains; all post-test scores were equivalent to provincial normative data. Qualitative data indicated improvements in familiarity with the resources available for palliative care and in communication among the nursing team. CONCLUSION: An educational intervention can improve the competence and knowledge of rural HCWs and nurses in a palliative approach. PMID- 25815767 TI - Accelerated and synchronized oviposition induced by flight of young females may intensify larval outbreaks of the rice leaf roller. AB - Physiological management of migration-reproduction trade-offs in energy allocation often includes a package of adaptions referred to as the oogenesis flight syndrome. In some species, this trade-off may be overestimated, because factors like flight behavior and environmental conditions may mitigate it. In this study, we examined the reproductive consequences induced by different flight scenarios in an economically-important Asian migrant insect, Cnaphalocrocis medinalis. We found that the influences of flight on reproduction are not absolutely positive or negative, but instead depend on the age at which the moth begins flight, flight duration, and how many consecutive nights they are flown. Adult flight on the 1st or 2nd night after emergence, flight for 6 h or 12 h nightly, and flight on the first two consecutive nights after emergence significantly accelerated onset of oviposition or enhanced synchrony of egg laying. The latter can contribute to subsequent larval outbreaks. However, flight after the 3rd night, flight for 18 h at any age, or flight on more than 3 consecutive nights after adult emergence did not promote reproductive development, and in some scenarios even constrained adult reproduction. These results indicate that there is a migration/reproduction trade-off in C.medinalis, but that it is mitigated or eliminated by flight under appropriate conditions. The strategy of advanced and synchronized oviposition triggered by migratory flight of young females may be common in other migratory insect pests. PMID- 25815766 TI - Gut microbiota and tacrolimus dosing in kidney transplantation. AB - Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2 +/- 1.1 mg/day vs. 3.8 +/- 0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6 +/- 2.4 mg/day vs. 3.3 +/- 1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient +/- standard error of 1.0 +/- 0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels. PMID- 25815769 TI - Kinematic analysis of males with transtibial amputation carrying military loads. AB - The biomechanical responses to load carriage, a common task for dismounted troops, have been well studied in nondisabled individuals. However, with recent shifts in the rehabilitation and retention process of injured servicemembers, there remains a substantial need for understanding these responses in persons with lower-limb amputations. Temporal-spatial and kinematic gait parameters were analyzed among 10 male servicemembers with unilateral transtibial amputation (TTA) and 10 uninjured male controls. Participants completed six treadmill walking trials in all combinations of two speeds (1.34 and 1.52 m/s) and three loads (none, 21.8, and 32.7 kg). Persons with TTA exhibited biomechanical compensations to carried loads that are comparable to those observed in uninjured individuals. However, several distinct gait changes appear to be unique to those with TTA, notably, increased dorsiflexion (deformation) of the prosthetic foot/ankle, less stance knee flexion on the prosthetic limb, and altered trunk forward lean/excursion. Such evidence supports the need for future work to assess the risk for overuse injuries with carried loads in this population in addition to guiding the development of adaptive prosthetic feet/components to meet the needs of redeployed servicemembers or veterans/civilians in physically demanding occupations. PMID- 25815768 TI - Time-calibrated phylogenomics of the classical swine fever viruses: genome-wide bayesian coalescent approach. AB - The phylogeny of classical swine fever virus (CSFV), the causative agent of classical swine fever (CSF), has been investigated extensively. However, no evolutionary research has been performed using the whole CSFV genome. In this study, we used 37 published genome sequences to investigate the time-calibrated phylogenomics of CSFV. In phylogenomic trees based on Bayesian inference (BI) and Maximum likelihood (ML), the 37 isolates were categorized into five genetic types (1.1, 1.2, 2.1, 2.3, and 3.4). Subgenotype 1.1 is divided into 3 groups and 1 unclassified isolate, 2.1 into 4 groups, 2.3 into 2 groups and 1 unclassified isolate, and subgenotype 1.2 and 3.4 consisted of one isolate each. We did not observe an apparent temporal or geographical relationship between isolates. Of the 14 genomic regions, NS4B showed the most powerful phylogenetic signal. Results of this evolutionary study using Bayesian coalescent approach indicate that CSFV has evolved at a rate of 13*.010-4 substitutions per site per year. The most recent common ancestor of CSFV appeared 2770.2 years ago, which was about 8000 years after pig domestication. The effective population size of CSFV underwent a slow increase until the 1950s, after which it has remained constant. PMID- 25815770 TI - Association of Parkinson's Disease and Its Subtypes with Agricultural Pesticide Exposures in Men: A Case-Control Study in France. AB - BACKGROUND: Pesticides have been associated with Parkinson's disease (PD), but there are few data on important exposure characteristics such as dose-effect relations. It is unknown whether associations depend on clinical PD subtypes. OBJECTIVES: We examined quantitative aspects of occupational pesticide exposure associated with PD and investigated whether associations were similar across PD subtypes. METHODS: As part of a French population-based case-control study including men enrolled in the health insurance plan for farmers and agricultural workers, cases with clinically confirmed PD were identified through antiparkinsonian drug claims. Two controls were matched to each case. Using a comprehensive occupational questionnaire, we computed indicators for different dimensions of exposure (duration, cumulative exposure, intensity). We used conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) among exposed male farmers (133 cases, 298 controls). We examined the relation between pesticides and PD subtypes (tremor dominant/non-tremor dominant) using polytomous logistic regression. RESULTS: There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models, as well as a synergistic interaction between duration and intensity (p-interaction = 0.04). High-intensity exposure to insecticides was positively associated with PD among those with low-intensity exposure to fungicides and vice versa, suggesting independent effects. Pesticide exposure in farms that specialized in vineyards was associated with PD (OR = 2.56; 95% CI: 1.31, 4.98). The association with intensity of pesticide use was stronger, although not significantly (p-heterogeneity = 0.60), for tremor-dominant (p-trend < 0.01) than for non-tremor-dominant PD (p-trend = 0.24). CONCLUSIONS: This study helps to better characterize different aspects of pesticide exposure associated with PD, and shows a significant association of pesticides with tremor-dominant PD in men, the most typical PD presentation. CITATION: Moisan F, Spinosi J, Delabre L, Gourlet V, Mazurie JL, Benatru I, Goldberg M, Weisskopf MG, Imbernon E, Tzourio C, Elbaz A. 2015. Association of Parkinson's disease and its subtypes with agricultural pesticide exposures in men: a case-control study in France. Environ Health Perspect 123:1123-1129; http://dx.doi.org/10.1289/ehp.1307970. PMID- 25815772 TI - A simple criterion for determining the static friction force between nanowires and flat substrates using the most-bent-state method. AB - A simple criterion was developed to assess the appropriateness of the currently available models that estimate the static friction force between nanowires and substrates using the 'most-bent-state' method. Our experimental testing of the static friction force between Al2O3 nanowires and Si substrate verified our theoretical analysis, as well as the establishment of the criterion. It was found that the models are valid only for the bent nanowires with the ratio of wire length over the minimum curvature radius [Formula: see text] no greater than 1. For the cases with [Formula: see text] greater than 1, the static friction force was overestimated as it neglected the effect of its tangential component. PMID- 25815771 TI - Systematic analysis and identification of stress-responsive genes of the NAC gene family in Brachypodium distachyon. AB - Plant-specific NAC proteins are one of the largest families of transcription factors in plants, and members of this family have been characterized with roles in the regulation of diverse biological processes, including development and stress responses. In the present study, we identified 101 putative NAC domain encoding genes (BdNACs) through systematic sequence analysis in Brachypodium distachyon, a new model plant of family Poaceae. BdNAC proteins were phylogenetically clustered into 13 groups, and each group possesses similar motif compositions. Phylogenetic analysis using known stress-related NACs from Arabidopsis and rice as query sequences identified 18 BdNACs as putative stress responsive genes. In silico promoter analysis showed that almost all BdNAC genes contain putative stress-related cis-elements in their promoter regions. Expression profile of BdNAC genes in response to abiotic stresses and phytohormones was analyzed by quantitative real-time RT-PCR. Several putative stress-responsive BdNAC genes, including BdNAC003 and BdNAC044 which is ortholog of known stress-responsive rice gene SNAC1 and SNAC2, respectively, were highly regulated by multiple abiotic stresses and stress-related phytohormone treatments. Taken together, our results presented here would be helpful in laying the foundation for understanding of the complex mechanisms of NAC mediated abiotic stress signaling transduction pathways in B. distachyon. PMID- 25815773 TI - Association of the glucocorticoid receptor D641V variant with steroid-resistant asthma: a case-control study. AB - OBJECTIVES: Several mutations of the glucocorticoid receptor (GR) gene cause malfunction of the protein, resulting in steroid resistance. In diseases other than asthma, the GR variants I559N, D641V, and V729I have been linked to steroid resistance. The aim of this study was to evaluate the link of these GR variants in steroid-resistant (SR) asthma in the Chinese Han population. METHODS: GR polymorphisms were determined in 64 SR asthma patients, 217 steroid-sensitive (SS) asthma patients and 221 healthy control (CTR) individuals. The analysis of the GR variants was performed using PCR-sequence specific primers according to the European Molecular Biology Laboratory database (NC_000005.8). In addition, ligand binding and serum cortisol levels were determined. RESULTS: Compared with SS asthma patients and CTRs, a significant lower frequency of the GR D641V variant AA genotype (P=0.003, 0.014, respectively) and the A allele (P=0.001, 0.009, respectively) was found in SR asthma patients. Furthermore, the equilibrium dissociation constant (Kd) of GR ligand binding in SR asthma patients with the GR D641V variant AA genotype was significantly lower compared with the AT or the TT genotype carriers (P=0.006, 0.016, respectively). There was no significant difference between the I559N and V729I GR variants on comparing SR asthma patients with SS asthma patients or CTRs. CONCLUSION: This study suggests that the D641V variant of the GR is probably associated with SR asthma in the Chinese Han population. PMID- 25815774 TI - Clinical validation study of genetic markers for capecitabine efficacy in metastatic colorectal cancer patients. AB - BACKGROUND AND AIM: Pharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine. PATIENTS AND METHODS: Germline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival. RESULTS: In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup. CONCLUSION: With the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy. PMID- 25815775 TI - Identification of active ingredients in Wuzhuyu decoction improving migraine in mice by spectral efficiency association. AB - Wuzhuyu decoction is a traditional Chinese medicine used for the effective treatment of migraines, termed 'Jueyin headache', in China. However, there have been few investigations to clarify the composition of Wuzhuyu decoction for the treatment of migraines. In the present study, 10 types of Wuzhuyu decoction were analyzed by chromatograms. 5-hydroxytryptamine (5-HT)-depletion mouse models of migraine were prepared by subcutaneous injection of reserpine and placement of autologous blood clots in the cerebral cortex. The levels of 5-HT, noradrenaline (NE), dopamine (DA), nitric oxide (NO) and nitric oxide synthase (NOS) in the brain tissues and sera of the mice were determined. The ingredients and pharmacodynamic indices of the Wuzhuyu decoctions were analyzed using spectral efficiency association by partial least squares regression. The levels of 5-HT, NE and DA in the mouse brain tissues were reduced to 337.785 +/- 84.504, 171.173 +/- 65.172 and 242.075 +/- 158.621 mg/g brain tissue, respectively. The level of NO in the brain tissues increased to 0.425 +/- 0.184 umol/g protein and the activities of NOS in the brain tissues and sera increased to 0.719 +/- 0.477 U/mg and 50.688 +/- 8.132 U/ml, respectively. Regarding the ingredients of the Wuzhuyu decoction, those with significant regression coefficients were ginsenoside-Rg1, Re, Rb1, rutaevine (Rv), limonin (Li), evodiamine (Ev), rutaecarpine (Ru) and substance X (awaiting identification). Rg1, Re, Rb1, Rv, Li, Ev, Ru and X in the Wuzhuyu decoction were observed to yield the pharmacological effects, whereas Rb1, Rv and Ev were important in index improvement. PMID- 25815776 TI - MicroRNA-509-3p inhibits cancer cell proliferation and migration by targeting the mitogen-activated protein kinase kinase kinase 8 oncogene in renal cell carcinoma. AB - microRNAs (miRNAs; miR) are a class of small non-coding RNA molecules, which are involved in the pathogenesis of human diseases through the negative regulation of gene expression. Previous studies have demonstrated that miR-509-3p is a novel miRNA associated with cell proliferation and migration in 786-O renal cell carcinoma (RCC) cells. However, the mechanism of action of miR-509-3p in RCC remains to be elucidated. The present study aimed to examine the functional role and mechanism of miR-509-3p in the development of RCC. The results demonstrated that the expression levels of miR-509-3p were downregulated in the 786-O and ACHN RCC cell lines compared with the normal tissues of 10 patients with RCC, as determined by reverse transcription-quantitative polymerase chain reaction. The mRNA expression levels of mitogen-activated protein kinase kinase kinase 8 (MAP3K8) were upregulated in the RCC cell lines. Functional investigations demonstrated that the overexpression of miR-509-3p inhibited the migration and proliferation of the RCC cells, as determined by wound scratch and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Luciferase reporter assays revealed that the overexpression of miR-509-3p reduced the transcriptional activity of MAP3K8. Furthermore, the present study demonstrated that the ectopic transfection of miR-509-3p led to a significant reduction in the mRNA and protein expression levels of MAP3K8 in the RCC cells. Finally, knockdown of MAP3K8 inhibited the migration and proliferation of the RCC cells. Therefore, the results of the present study demonstrated that the miR-509-3p RCC suppressor was a significant regulator of the MAP3K8 oncogene, suggesting that it may have a potential therapeutic role in the treatment of RCC. PMID- 25815778 TI - Treatment for Acquired Apraxia of Speech: A Systematic Review of Intervention Research Between 2004 and 2012. AB - Objectives: The aim was for the appointed committee of the Academy of Neurological Communication Disorders and Sciences to conduct a systematic review of published intervention studies of acquired apraxia of speech (AOS), updating the previous committee's review article from 2006. Method: A systematic search of 11 databases identified 215 articles, with 26 meeting inclusion criteria of (a) stating intention to measure effects of treatment on AOS and (b) data representing treatment effects for at least 1 individual stated to have AOS. Results: All studies involved within-participant experimental designs, with sample sizes of 1 to 44 (median = 1). Confidence in diagnosis was rated high to reasonable in 18 of 26 studies. Most studies (24/26) reported on articulatory kinematic approaches; 2 applied rhythm/rate control methods. Six studies had sufficient experimental control for Class III rating according to the Clinical Practice Guidelines Process Manual (American Academy of Neurology, 2011), with 15 others satisfying all criteria for Class III except use of independent or objective outcome measurement. Conclusions: The most important global clinical conclusion from this review is that the weight of evidence supports a strong effect for both articulatory-kinematic and rate/rhythm approaches to AOS treatment. The quantity of work, experimental rigor, and reporting of diagnostic criteria continue to improve and strengthen confidence in the corpus of research. PMID- 25815777 TI - cDNA microarray analysis of the effect of cantharidin on DNA damage, cell cycle and apoptosis-associated gene expression in NCI-H460 human lung cancer cells in vitro. AB - Cantharidin (CTD) induces cytotoxic effects in different types of human cancer cell; however, to date, there have been no studies on the effects of CTD on gene expression in human lung cancer cells and the potential associated signaling pathways. Therefore, the present study aimed to investigate how CTD affects the expression of key genes and functional pathways of human H460 lung cancer cells using complementary DNA microarray analysis. Human H460 lung cancer cells were cultured for 24 h in the presence or absence of 10 uM CTD; gene expression was then examined using microarray analysis. The results indicated that 8 genes were upregulated > 4-fold, 29 genes were upregulated >3-4-fold and 156 genes were upregulated >2-3-fold. In addition, 1 gene was downregulated >4 fold, 14 genes were downregulated >3-4-fold and 150 genes were downregulated >2-3 fold in H460 cells following exposure to CTD. It was found that CTD affected DNA damage genes, including DNIT3 and GADD45A, which were upregulated 2.26- and 2.60-fold, respectively, as well as DdiT4, which was downregulated 3.14-fold. In addition, the expression of genes associated with the cell cycle progression were altered, including CCND2, CDKL3 and RASA4, which were upregulated 2.72-, 2.19- and 2.72 fold, respectively; however, CDC42EP3 was downregulated 2.16-fold. Furthermore, apoptosis-associated genes were differentially expressed, including CARD6, which was upregulated 3.54-fold. In conclusion, the present study demonstrated that CTD affected the expression of genes associated with DNA damage, cell cycle progression and apoptotic cell death in human lung cancer H460 cells. PMID- 25815779 TI - Site-specific analysis of protein hydration based on unnatural amino acid fluorescence. AB - Hydration of proteins profoundly affects their functions. We describe a simple and general method for site-specific analysis of protein hydration based on the in vivo incorporation of fluorescent unnatural amino acids and their analysis by steady-state fluorescence spectroscopy. Using this method, we investigate the hydration of functionally important regions of dehalogenases. The experimental results are compared to findings from molecular dynamics simulations. PMID- 25815780 TI - DNA methylation consistency implicates the primary tumor cell origin of recurrent hepatocellular carcinoma. AB - AIMS: To investigate if DNA methylation pattern assay could be a new approach to identifying the primary tumor cell origin of the recurrent hepatocellular carcinoma (HCC). MATERIALS & METHODS: Methylation of 24 genes and expression of 22 cancer stem cell (CSC) biomarkers were quantitatively measured in 10 paired primary and recurrent HCC specimens. The HBV viral-host junctions were determined in six pairs of them with HBV infection. RESULTS: Similar DNA methylation patterns were observed among nine of ten pairs of primary and recurrent tumors. In five of six paired specimens with HBV infection, exactly same HBV DNA integrations were identified in each paired tumors. The expression of seven CSC biomarkers increased significantly in either primary or recurrent tumor tissues. CONCLUSION: Recurrent HCCs mostly originate from their primary tumors. Assay of DNA methylation patterns could provide a new approach to determining the origin of recurrent HCC. PMID- 25815782 TI - Gene expression changes in human mesenchymal stem cells from patients with osteoporosis. AB - The aim of the present study was to investigate the underlying molecular mechanisms of osteoporosis and to identify novel candidate genes involved in this disease. The gene expression profile of GSE35958 was downloaded from Gene Expression Omnibus, including five samples of human mesenchymal stem cells from patients with osteoporosis and four control samples. Differentially expressed genes (DEGs) were initially identified following an analysis using Student's t test. Subsequently, a protein-protein interaction (PPI) network of the significant pathways was constructed, based on the Human Protein Reference Database. In the significant pathways, DEGs were screened using cut-off criteria of FDR<0.1 and |log(2)FC|>1.5. A co-change network for pathways was also constructed using the method of cumulative hypergeometric probability distribution. Finally, the transcriptional regulatory network for DEGs was constructed based on the TRANSFAC database. In total, 1,127 DEGs, including 554 upregulated and 573 downregulated DEGs, were screened. The constructed PPI network for the DEGs involved in the two significant pathways, including focal adhesion and lysosome, demonstrated that the five DEGs with a high degree (>60) were beta-catenin, SHC-transforming protein 1, RAC-alpha serine/threonine-protein kinase, caveolin 1 and filamin A, with degrees of 135, 117, 117, 73 and 63, respectively. The pathway with the degree of 22 in the constructed co-change network was neuroactive ligand receptor interaction. The nine genes with a high (>= 9) degree in the constructed transcriptional regulatory network were REL associated protein, upstream stimulatory factor 1, specificity protein 1, Fos related antigen 1, cyclin-dependent kinase inhibitor 1A, upstream stimulatory factor 2, ETS domain-containing protein Elk1, JUND and retinoic acid receptor alpha, with degrees of 29, 27, 19, 18, 17, 13, 11, 11 and 9, respectively. The DEGs with high degree in the PPI and transcriptional regulatory networks may be candidate target molecules, which may be used to monitor, diagnose and treat osteoporosis. PMID- 25815784 TI - Novel synthetic approach to charge-compensated phosphonio-nido-carboranes. Synthesis and structural characterization of neutral mono and bis(phosphonio) nido-ortho-carboranes. AB - A number of monosubstituted n-(triphenylphosphonio)-7,8-dicarba-nido undecaboranes (2a, n = 1; 2b, n = 3; 2c, n = 5; 2d, n = 9) were prepared via a cross-coupling reaction between the tetrabutylammonium iodo-7,8-dicarba-nido undecaborates (1a-d) and PPh3 in the presence of a Pd(PPh3)4 catalyst. The substitution rate was found to depend on the iodine position in the carborane cage. Under similar conditions, the reaction of 5,6-diiodo- (3) and 9,11-diiodo 7,8-dicarba-nido-undecaborate (5) anions exclusively yielded the monosubstitution products 5-iodo-6-(triphenylphosphonio)-7,8-dicarba-nido-undecaborane (4) and 9 iodo-11-(triphenylphosphonio)-7,8-dicarba-nido-undecaborane (6), respectively. The reaction of tetrabutylammonium 6,9-diiodo-7,8-dicarba-nido-undecaborate (7) exclusively produced the phosphine substitution product in the open face of the nido-carborane, 6-iodo-9-triphenylphosphonio-7,8-dicarba-nido-undecaborane (8). The addition of a base (Cs2CO3, NaH) to the reactions of 3 and 5 with PPh3 afforded the corresponding bis(triphenylphosphonio)-7,8-dicarba-nido undecaboranes, 9 and 10. Compound 10 was also prepared from 6 using the general procedure. The reaction of the triiodocarborane tetrabutylammonium 5,6,9-triiodo 7,8-dicarba-nido-undecaborate (11) with excess PPh3 in the presence of Cs2CO3 and Pd(PPh3)4 only produced neutral 5-iodo-6,9-bis(triphenylphosphonio)-7,8-dicarba nido-undecaborane (12); no positively charged tris(phosphonio) species formed. The compositions of all prepared compounds were determined by multinuclear NMR spectroscopy and high-resolution mass spectrometry. The structures of compounds 2c, 6, 8, 9, and 12 were established by the X-ray diffraction analysis of single crystals. PMID- 25815783 TI - Combinatorial Consensus Scoring for Ligand-Based Virtual Fragment Screening: A Comparative Case Study for Serotonin 5-HT(3)A, Histamine H(1), and Histamine H(4) Receptors. AB - In the current study we have evaluated the applicability of ligand-based virtual screening (LBVS) methods for the identification of small fragment-like biologically active molecules using different similarity descriptors and different consensus scoring approaches. For this purpose, we have evaluated the performance of 14 chemical similarity descriptors in retrospective virtual screening studies to discriminate fragment-like ligands of three membrane-bound receptors from fragments that are experimentally determined to have no affinity for these proteins (true inactives). We used a complete fragment affinity data set of experimentally determined ligands and inactives for two G protein-coupled receptors (GPCRs), the histamine H1 receptor (H1R) and the histamine H4 receptor (H4R), and one ligand-gated ion channel (LGIC), the serotonin receptor (5-HT3AR), to validate our retrospective virtual screening studies. We have exhaustively tested consensus scoring strategies that combine the results of multiple actives (group fusion) or combine different similarity descriptors (similarity fusion), and for the first time systematically evaluated different combinations of group fusion and similarity fusion approaches. Our studies show that for these three case study protein targets both consensus scoring approaches can increase virtual screening enrichments compared to single chemical similarity search methods. Our cheminformatics analyses recommend to use a combination of both group fusion and similarity fusion for prospective ligand-based virtual fragment screening. PMID- 25815785 TI - PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation. AB - Stimulator of interferon genes (STING, also known as MITA and ERIS) is critical in protecting the host against DNA pathogen invasion. However, the molecular mechanism underlying the regulation of STING remains unclear. Here, we show that PPM1A negatively regulates antiviral signaling by targeting STING in its phosphatase activity-dependent manner, and in a line with this, PPM1A catalytically dephosphorylates STING and TBK1 in vitro. Importantly, we provide evidence that whereas TBK1 promotes STING aggregation in a phosphorylation dependent manner, PPM1A antagonizes STING aggregation by dephosphorylating both STING and TBK1, emphasizing that phosphorylation is crucial for the efficient activation of STING. Our findings demonstrate a novel regulatory circuit in which STING and TBK1 reciprocally regulate each other to enable efficient antiviral signaling activation, and PPM1A dephosphorylates STING and TBK1, thereby balancing this antiviral signal transduction. PMID- 25815781 TI - Engineering protocells: prospects for self-assembly and nanoscale production lines. AB - The increasing ease of producing nucleic acids and proteins to specification offers potential for design and fabrication of artificial synthetic "organisms" with a myriad of possible capabilities. The prospects for these synthetic organisms are significant, with potential applications in diverse fields including synthesis of pharmaceuticals, sources of renewable fuel and environmental cleanup. Until now, artificial cell technology has been largely restricted to the modification and metabolic engineering of living unicellular organisms. This review discusses emerging possibilities for developing synthetic protocell "machines" assembled entirely from individual biological components. We describe a host of recent technological advances that could potentially be harnessed in design and construction of synthetic protocells, some of which have already been utilized toward these ends. More elaborate designs include options for building self-assembling machines by incorporating cellular transport and assembly machinery. We also discuss production in miniature, using microfluidic production lines. While there are still many unknowns in the design, engineering and optimization of protocells, current technologies are now tantalizingly close to the capabilities required to build the first prototype protocells with potential real-world applications. PMID- 25815786 TI - Identification of KRAS and PIK3CA but not BRAF mutations in patients with gastric cancer. AB - Cetuximab, an immunoglobulin G1 chimeric monoclonal antibody directed against the epidermal growth factor receptor, is currently considered to be the strategy with the most potential for the treatment of gastric cancer due to the low frequency of KRAS mutations in patients with gastric cancer. However, the therapeutic success of cetuximab in colorectal cancer (CRC) has demonstrated that the clinical effect of cetuximab is closely dependent not only on KRAS mutations, but also BRAF and phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutations. In the present study, the status of KRAS, BRAF and PIK3CA mutations in gastric cancer were investigated concomitantly in order to aid the selection of patients eligible for treatment with cetuximab. Mutations in KRAS (exon 2), BRAF (exon 15) and PIK3CA (exon 9 and exon 20) were retrospectively evaluated by high resolution melting analysis and DNA direct sequencing in samples from 156 patients with gastric cancer. Mutations in either KRAS or PIK3CA were identified in 13 samples (8.3%), 7 samples with KRAS mutations and 6 samples with PIK3CA mutations. No mutations in the BRAF gene were identified. The frequency of mutations in either KRAS or PIK3CA were significantly higher in patients without lymph node metastasis than those with. Furthermore, KRAS and PIK3CA mutations were mutually exclusive. The present study, therefore, suggested that it may be necessary to evaluate KRAS and PIK3CA mutations concomitantly for the selection of patients eligible for treatment with cetuximab. PMID- 25815787 TI - Mapping shape to visuomotor mapping: learning and generalisation of sensorimotor behaviour based on contextual information. AB - Humans can learn and store multiple visuomotor mappings (dual-adaptation) when feedback for each is provided alternately. Moreover, learned context cues associated with each mapping can be used to switch between the stored mappings. However, little is known about the associative learning between cue and required visuomotor mapping, and how learning generalises to novel but similar conditions. To investigate these questions, participants performed a rapid target-pointing task while we manipulated the offset between visual feedback and movement end points. The visual feedback was presented with horizontal offsets of different amounts, dependent on the targets shape. Participants thus needed to use different visuomotor mappings between target location and required motor response depending on the target shape in order to "hit" it. The target shapes were taken from a continuous set of shapes, morphed between spiky and circular shapes. After training we tested participants performance, without feedback, on different target shapes that had not been learned previously. We compared two hypotheses. First, we hypothesised that participants could (explicitly) extract the linear relationship between target shape and visuomotor mapping and generalise accordingly. Second, using previous findings of visuomotor learning, we developed a (implicit) Bayesian learning model that predicts generalisation that is more consistent with categorisation (i.e. use one mapping or the other). The experimental results show that, although learning the associations requires explicit awareness of the cues' role, participants apply the mapping corresponding to the trained shape that is most similar to the current one, consistent with the Bayesian learning model. Furthermore, the Bayesian learning model predicts that learning should slow down with increased numbers of training pairs, which was confirmed by the present results. In short, we found a good correspondence between the Bayesian learning model and the empirical results indicating that this model poses a possible mechanism for simultaneously learning multiple visuomotor mappings. PMID- 25815788 TI - Serum microRNA-125a-5p, a useful biomarker in liver diseases, correlates with disease progression. AB - It has been demonstrated that liver microRNA-125a-5p (miR-125a-5p) is correlated with disease progression in different liver diseases, including liver fibrosis and hepatocellular carcinoma (HCC). The present study investigated whether serum miR-125a-5p correlated with the progression of different liver diseases. Serum samples were obtained from healthy individuals, patients with chronic hepatitis B who had undergone a liver biopsy, and patients with HCC and were analyzed for the levels of miR-125a-5p. Compared with the healthy controls, the serum levels of miR-125a-5p were significantly higher in the liver fibrosis serum, and were reduced in HCC. With the development of liver fibrosis, there was a significant increase in the expression of miR-125a-5p (P<0.05). In comparing histological activity index (HAI) scores, higher expression levels of miR125a-5p were observed in the high HAI score group (P<0.05). Furthermore, correlation between serum miR 125a-5p and viral replication (P<0.001) was observed. Notably, miR-125a-5p demonstrated significant correlation with other markers in the liver fibrosis group (P<0.001). In the patients with HCC, lower serum levels of miR-125a-5p were correlated with a poor prognosis, determined by Kaplan-Meier curve analysis (P=0.009). In the liver fibrosis and HCC groups, different expression levels of serum miR-125a-5p were observed, and were correlated with disease progression. The results of the present study suggested that serum miR-125a-5p may be used as a non-invasive biomarker for monitoring disease progression in liver diseases. PMID- 25815789 TI - Development and validation of a 3-Plex RT-qPCR assay for the simultaneous detection and quantitation of the three PML-RARa fusion transcripts in acute promyelocytic leukemia. AB - Rapid diagnosis of acute promyelocytic leukemia (APL) with promyelocytic leukemia retinoic acid receptor alpha (PML-RARa) contributes to a highly effective therapy with all-trans retinoic acid (ATRA). Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) is a valuable tool to diagnose APL with PML RARa. However, a single RT-qPCR analysis, which is laborious and costly, has to be performed in three reactions to determine whether one of the three PML-RARa transcripts is present and to quantify the involved transcript. This paper describes a novel TaqMan MGB probe-based 3-plex RT-qPCR assay in a single reaction to detect simultaneously the three PML-RARa transcripts. Specific primers and probe were designed, and the results were further normalized to the Abelson gene. The detection results for the serially diluted plasmid indicate that the analytical sensitivity was 10 copies per reaction for PML-RARa bcr1, bcr2, and bcr3. A relatively high sensitivity of 10-4 was achieved with this assay when analyzing the bcr1 transcripts obtained from the NB4 cell line. The reproducibility was satisfactory because the coefficients of variation of cycle threshold values were less than 3% for both inter- and intra-assays. After testing 319 newly diagnosed patients with leukemia (including 61 APL cases), the results of the 3-plex RT-qPCR assay completely agreed with the traditional methods used for the detection of PML-RARa. The quantitative results of the 3 plex RT-qPCR were highly correlated with the single RT-qPCR and showed similar assay sensitivity for 60 PML-RARa positive APL samples at diagnosis and 199 samples from 57 patients during follow-up. Interestingly, one PML-RARa bcr2 case at diagnosis with breakpoint at 1579, which was not detected by the single RT-q PCR, was detected by the 3-plex RT-qPCR assay. The 3-plex RT-qPCR assay is a specific, sensitive, stable, and cost-effective method that can be used for the rapid diagnosis and treatment monitoring of APL with PML-RARa. PMID- 25815792 TI - In Silico and in Vitro Study of Binding Affinity of Tripeptides to Amyloid beta Fibrils: Implications for Alzheimer's Disease. AB - Self-assembly of Abeta peptides into amyloid aggregates has been suggested as the major cause of Alzheimer's disease (AD). Nowadays, there is no medication for AD, but experimental data indicate that reversion of the process of amyloid aggregation reduces the symptoms of disease. In this paper, all 8000 tripeptides were studied for their ability to destroy Abeta fibrils. The docking method and the more sophisticated MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method were employed to calculate the binding affinity and mode of tripeptides to Abeta fibrils. The ability of these peptides to depolymerize Abeta fibrils was also investigated experimentally using atomic force microscopy and fluorescence spectroscopy (Thioflavin T assay). It was shown that tripeptides prefer to bind to hydrophobic regions of 6Abeta9-40 fibrils. Tripeptides WWW, WWP, WPW and PWW were found to be the most potent binders. In vitro experiments showed that tight-binding tripeptides have significant depolymerizing activities and their DC50 values determined from dose-response curves were in micromolar range. The ability of nonbinding (GAM, AAM) and weak-binding (IVL and VLA) tripeptides to destroy Abeta fibrils was negligible. In vitro data of tripeptide depolymerizing activities support the predictions obtained by molecular docking and all-atom simulation methods. Our results suggest that presence of multiple complexes of heterocycles forming by tryptophan and proline residues in tripeptides is crucial for their tight binding to Abeta fibrils as well as for extensive fibril depolymerization. We recommend PWW for further studies as it has the lowest experimental binding constant. PMID- 25815791 TI - High glucose promotes gastric cancer chemoresistance in vivo and in vitro. AB - The aim of the present study was to determine whether gastric cancer chemoresistance was increased under high glucose conditions by means of a clinical case study and experimental cytology. The expression of nicotinamide phosphoribosyltransferase (Nampt), silent information regulator 1 (sirt1), p53, p glycoprotein (P-gp) and topoisomerase (topo)-IIalpha was evaluated in gastric cancer tissues and gastric cancer with diabetes tissues by immunohistochemistry. Subsequently, the survival time of the patients was assessed. For further investigation, the human gastric cancer cell line SGC7901 was subjected to different glucose concentrations and the aforementioned proteins were detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Finally, cell sensitivity to chemotherapy treatment was examined in order to elucidate the role of high glucose in MDR. Positive expression of Nampt, Sirt1, p53, P-gp and Topo-IIalpha was observed to be higher in gastric cancer with diabetes patients compared with gastric cancer patients (P=0.01, 0.003, 0.0025, 0.016 and 0.336, respectively) with reduced survival time. Similar results were observed in SGC7901 cells. Additionally, cell proliferation rates of SGC7901 cells increased at glucose concentrations of 4,500 and 9,000 mg/l. Notably, the inhibition rates of 5-fluorouracil on cells decreased over 48 h when treated with 4,500 and 9,000 mg/l glucose compared with 1,000 mg/l. In conclusion, patients suffering from gastric cancer and diabetes exhibited greater negative effects, such as a poorer response to chemotherapy and had a lower survival time. High glucose conditions promoted gastric cancer cell proliferation and reduced susceptibility to chemotherapy drugs. These data provided a potential diagnostic and therapeutic strategy for gastric cancer chemoresistance. PMID- 25815794 TI - Total internal reflection fluorescence spectrometry using a dual optical fiber sample cell. AB - A novel total internal reflection fluorescence (TIRF) spectrometric technique using a dual optical fiber sample cell was developed. A conventional silica optical fiber was used for exciting fluorescence compounds in its evanescent wave field. A liquid core waveguide (LCW) was used to collect the fluorescence photons emitted from fluorescence compounds existing in an excitation fiber's evanescent wave field. The collected fluorescence photons were guided through the LCW and sent to a fluorescence spectrometer for detection. The spatial separation of excitation light and fluorescence light reduces the excitation-light-related optical noise signal, which is the major factor limiting fluorescence techniques from achieving lower detection limit. Preliminary results obtained from this work indicate that the optical fiber TIRF system of this work can detect 4.6*10(-18) mole rhodamine 6G (2.7*10(6) molecules) existing in the evanescent wave field of the excitation optical fiber. PMID- 25815793 TI - Mass Spectrometric Characterization of Human Serum Albumin Adducts Formed with N Oxidized Metabolites of 2-Amino-1-methylphenylimidazo[4,5-b]pyridine in Human Plasma and Hepatocytes. AB - 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogenic heterocyclic aromatic amine formed in cooked meats, is metabolically activated to electrophilic intermediates that form covalent adducts with DNA and protein. We previously identified an adduct of PhIP formed at the Cys(34) residue of human serum albumin following reaction of albumin with the genotoxic metabolite 2 hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (HONH-PhIP). The major adducted peptide recovered from a tryptic/chymotryptic digest was identified as the missed-cleavage peptide LQQC*([SO2PhIP])PFEDHVK, a [cysteine-S-yl-PhIP]-S dioxide linked adduct. In this investigation, we have characterized the albumin adduction products of N-sulfooxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-sulfooxy-PhIP), which is thought to be a major genotoxic metabolite of PhIP formed in vivo. Targeted and data-dependent scanning methods showed that N sulfooxy-PhIP adducted to the Cys(34) of albumin in human plasma to form LQQC*([SO2PhIP])PFEDHVK at levels that were 8-10-fold greater than the adduct levels formed with N-(acetyloxy)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-acetoxy-PhIP) or HONH-PhIP. We also discovered that N-sulfooxy-PhIP forms an adduct at the sole tryptophan (Trp(214)) residue of albumin in the sequence AW*([PhIP])AVAR. However, stable adducts of PhIP with albumin were not detected in human hepatocytes. Instead, PhIP and 2-amino-1-methyl-6-(5 hydroxy)phenylimidazo[4,5-b]pyridine (5-HO-PhIP), a solvolysis product of the proposed nitrenium ion of PhIP, were recovered during the proteolysis, suggesting a labile sulfenamide linkage had formed between an N-oxidized intermediate of PhIP and Cys(34) of albumin. A stable adduct was formed at the Tyr(411) residue of albumin in hepatocytes and identified as a deaminated product of PhIP, Y(*[desaminoPhIP])TK, where the 4-HO-tyrosine group bound to the C-2 imidazole atom of PhIP. PMID- 25815796 TI - Non-aggregated Zn(ii)octa(2,6-diphenylphenoxy) phthalocyanine as a hole transporting material for efficient perovskite solar cells. AB - A non-aggregated Zn(ii)octa(2,6-diphenylphenoxy) phthalocyanine (coded as TT80) has been used as a hole-transporting material for perovskite solar cells. The cells were fabricated under three different configurations by changing the uptake solvent (chlorobenzene or toluene) and incorporating additives (bis(trifluoromethane) sulfonimide lithium salt (LiTFSI) and 4-tert-butylpyridine (TBP). A power conversion efficiency of 6.7% (AM1.5G standard conditions) was achieved for the best cell under optimized configuration. PMID- 25815795 TI - Sheath-flow microfluidic approach for combined surface enhanced Raman scattering and electrochemical detection. AB - The combination of hydrodynamic focusing with embedded capillaries in a microfluidic device is shown to enable both surface enhanced Raman scattering (SERS) and electrochemical characterization of analytes at nanomolar concentrations in flow. The approach utilizes a versatile polystyrene device that contains an encapsulated microelectrode and fluidic tubing, which is shown to enable straightforward hydrodynamic focusing onto the electrode surface to improve detection. A polydimethyslsiloxane (PDMS) microchannel positioned over both the embedded tubing and SERS active electrode (aligned ~200 MUm from each other) generates a sheath flow that confines the analyte molecules eluting from the embedded tubing over the SERS electrode, increasing the interaction between the Riboflavin (vitamin B2) and the SERS active electrode. The microfluidic device was characterized using finite element simulations, amperometry, and Raman experiments. This device shows a SERS and amperometric detection limit near 1 and 100 nM, respectively. This combination of SERS and amperometry in a single device provides an improved method to identify and quantify electroactive analytes over either technique independently. PMID- 25815797 TI - Smac therapeutic Peptide nanoparticles inducing apoptosis of cancer cells for combination chemotherapy with Doxorubicin. AB - Smac-conjugated nanoparticle (Smac-NP) was designed to induce the apoptosis of cancer cells and as a drug carrier for combination therapy. It contained three parts, a SmacN7 peptide which could induce apoptosis of cancer cells by interacting with XIAPs, the cell penetrating domain rich in arginine, and four hydrophobic tails for self-assembled Smac-NP. We demonstrated that Smac-NPs exerted an antitumor effect in breast cancer cell MDA-MB-231 and nonsmall lung cancer (NSCLC) cell H460, which efficiently inhibited cancer cells proliferation without influencing normal liver cell lines LO2. Smac-NPs also significantly induced apoptosis of MDA-MB-231 and H460 cells through activating pro-caspase-3, down-regulating the expression of antiapoptotic protein Bcl-2 and up-regulating the pro-apoptotic protein Bax. Furthermore, Smac-NPs could be explored as a drug delivery system to load hydrophobic drug such as DOX for combination therapy. The DOX-loaded nanoparticles (DOX-Smac-NPs) exhibited higher cellular uptake efficiency and antitumor effect. Our work provided a new insight into therapeutic peptides integrated with drug simultaneously in one system for cancer combination treatment. PMID- 25815799 TI - Average and local structure, debye temperature, and structural rigidity in some oxide compounds related to phosphor hosts. AB - The average and local structure of the oxides Ba2SiO4, BaAl2O4, SrAl2O4, and Y2SiO5 are examined to evaluate crystal rigidity in light of recent studies suggesting that highly connected and rigid structures yield the best phosphor hosts. Simultaneous momentum-space refinements of synchrotron X-ray and neutron scattering yield accurate average crystal structures, with reliable atomic displacement parameters. The Debye temperature ThetaD, which has proven to be a useful proxy for structural rigidity, is extracted from the experimental atomic displacement parameters and compared with predictions from density functional theory calculations and experimental low-temperature heat capacity measurements. The role of static disorder on the measured displacement parameters, and the resulting Debye temperatures, are also analyzed using pair distribution function of total neutron scattering, as refined over varying distance ranges of the pair distribution function. The interplay between optimal bonding in the structure, structural rigidity, and correlated motion in these structures is examined, and the different contributions are delineated. PMID- 25815798 TI - Effect of cerium oxide doping on the performance of CaO-based sorbents during calcium looping cycles. AB - A series of CaO-based sorbents were synthesized through a sol-gel method and doped with different amounts of CeO2. The sorbent with a Ca/Ce molar ratio of 15:1 showed an excellent absorption capacity (0.59 gCO2/g sorbent) and a remarkable cycle durability (up to 18 cycles). The admirable capture performance of CaCe-15 was ascribed to its special morphology formed by the doping of CeO2 and the well-distributed CeO2 particles. The sorbents doped with CeO2 possessed a loose shell-connected cross-linking structure, which was beneficial for the contact between CaO and CO2. CaO and CeO2 were dispersed homogeneously, and the existence of CeO2 also decreased the grain size of CaO. The well-dispersed CeO2, which could act as a barrier, effectively prevented the CaO crystallite from growing and sintering, thus the sorbent exhibited outstanding stability. The doping of CeO2 also improved the carbonation rate of the sorbent, resulting in a high capacity in a short period of time. PMID- 25815800 TI - Acceptable macronutrient distribution ranges and hypertension. AB - Acceptable macronutrient distribution ranges (AMDRs) for carbohydrate, fat, and protein have been set by considering epidemiological evidences that suggest consumption within these ranges plays a role in reducing risk of chronic diseases. Little evidence has been presented on the relationship between the intake outside the AMDR for macronutrient and hypertension. Therefore, this study was performed to examine the association between the intake outside the AMDR and hypertension in Korean adults. This study was based on data obtained from the fifth Korean National Health and Nutrition Examination Survey. The AMDR for carbohydrate is 55-70%, for fat is 15-25%, and for protein is 7-20% of the energy intake for adults. The subjects who did not meet the AMDRs for carbohydrate, fat and protein were considered to be the non-AMDR group. The odds ratio of the non AMDR group was 1.25 (95% CI, 1.02-1.53) in the hypertensive subjects without anti hypertensive medication and 1.25 (95% CI, 1.06-1.48) in the hypertensive subjects with anti-hypertensive medication after adjustment for age, sex, current smoking, heavy drinking, physical inactivity, obesity, diabetes mellitus, dyslipidemia, total energy intake, high sodium intake, and vitamin D deficiency. The intake outside the AMDR was significantly associated with hypertension in Korean adults. The AMDR might be useful nutritional requirement for dietary management of hypertension. In the future, these findings need to be verified through prospective population-based studies. PMID- 25815801 TI - Ni3+ doped monolayer layered double hydroxide nanosheets as efficient electrodes for supercapacitors. AB - Ni(3+) doped NiTi layered double hydroxide (NiTi-LDH) monolayer nanosheets with a particle size of ~ 20 nm and a thickness of ~ 0.9 nm have been successfully prepared through a facile bottom-up approach. These NiTi-LDH monolayer nanosheets exhibit excellent supercapacitor performance, including a high specific pseudocapacitance (2310 F g(-1) at 1.5 A g(-1)) and long durability compared with bulk LDH, owing to highly exposed conductive Ni(3+) species (NiOOH) which lead to the increased mobility rate of surface charge and electrolyte-transfer. Therefore, this work is expected to take a significant step towards exploring novel 2D monolayer electrode materials with unique physical and chemical properties for applications in energy storage and conversion. PMID- 25815802 TI - 3-way networks: application of hypergraphs for modelling increased complexity in comparative genomics. AB - We present and develop the theory of 3-way networks, a type of hypergraph in which each edge models relationships between triplets of objects as opposed to pairs of objects as done by standard network models. We explore approaches of how to prune these 3-way networks, illustrate their utility in comparative genomics and demonstrate how they find relationships which would be missed by standard 2 way network models using a phylogenomic dataset of 211 bacterial genomes. PMID- 25815803 TI - Whole-Body Diffusion-weighted Imaging in Hodgkin Lymphoma and Diffuse Large B Cell Lymphoma. AB - Whole-body imaging, in particular molecular imaging with fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET), is essential to management of lymphoma. The assessment of disease extent provided by use of whole body imaging is mandatory for planning appropriate treatment and determining patient prognosis. Assessment of treatment response allows clinicians to tailor the treatment strategy during therapy if necessary and to document complete remission at the end of treatment. Because of rapid technical developments, such as echo-planar sequences, parallel imaging, multichannel phased-array surface coils, respiratory gating, and moving examination tables, whole-body diffusion weighted (DW) magnetic resonance (MR) imaging that reflects cell density is now feasible in routine clinical practice. Whole-body DW MR imaging allows anatomic assessment as well as functional and quantitative evaluation of tumor sites by calculation of the apparent diffusion coefficient (ADC). Because of their high cellularity and high nucleus-to-cytoplasm ratio, lymphomatous lesions have low ADC values and appear hypointense on ADC maps. As a result, whole-body DW MR imaging with ADC mapping has become a promising tool for lymphoma staging and treatment response assessment. The authors review their 4 years of experience with 1.5-T and 3-T whole-body DW MR imaging used with (18)F-FDG PET/computed tomography at baseline, interim, and end of treatment in patients with Hodgkin lymphoma and diffuse large B-cell lymphoma and discuss the spectrum of imaging findings and potential pitfalls, limitations, and challenges associated with whole-body DW MR imaging in these patients. PMID- 25815804 TI - Electroactive polypyrrole nanowire arrays: synergistic effect of cancer treatment by on-demand drug release and photothermal therapy. AB - An electroresponsive drug release system based on polypyrrole (Ppy) nanowires was developed to induce the local delivery of anticancer drug, doxorubicin (DOX), according to the applied electric field. DOX-conjugated Ppy nanowire (NW) (DOX/Ppy NW) array was initially prepared by electrochemical deposition of a mixture of pyrrole monomers and biotin as dopants in the anodic alumina oxide membrane as a sacrificial template. Morphological observation by scanning electron microscopy revealed free-standing and 3D nanotopographical features with large surface area and high density. In addition, we investigated the antitumor efficacy of DOX released from DOX/Ppy NW array in response to the external electric field using two kinds of cancer cell lines, human oral squamous carcinoma cells (KB cells) and human breast cancer cells (MCF7 cells). Meanwhile, strong photothermal effect as a result of a near-infrared absorbing ability of Ppy synergistically maximizes the chemotherapeutic efficacy. Our results suggested that the proposed multifunctional Ppy platform possessing several beneficial features is very promising for many therapeutic applications including cancer. PMID- 25815805 TI - Anterior transpedicular screw fixation of cervical spine: Is it safe? Morphological feasibility, technical properties, and accuracy of manual insertion. AB - OBJECT Due to lack of construct stability of the current anterior cervical approaches, supplemental posterior cervical approaches are frequently employed. The use of an anterior-only approach with anterior transpedicular screws (ATPSs) has been proposed as a means of providing 3-column fixation. This study was designed to investigate the feasibility of anterior transpedicular screw (ATPS) fixation of cervical spine, to obtain the morphological measurements for technical prerequisites, and to evaluate the accuracy of the ATPS using fluoroscopy. METHODS The study included both radiological and anatomical investigations. The radiological investigations were based on data from cervical spine CT scans performed in 65 patients. Technical prerequisites of ATPS were calculated using OsiriX for Mac OS. In the anatomical part of the study, 30 pedicles (C3-7) from 6 formalin-preserved cadavers were manually instrumented. Measurements obtained included pedicle width (PW), pedicle height (PH), pedicle transverse angle (PTA), distance of the entry point from the midline (DEPM), and distance of the entry point from the superior endplate (DEPSEP). The authors also analyzed screw position in the manually instrumented vertebrae. RESULTS The mean PW and PH values showed a tendency to increase from C-3 to C-7 in both males and females. The means were significantly larger for both PW and PH in males than in females at all levels (p = 0.001). The overall mean PTA value was significantly lower at C-7 (p < 0.0001). The mean value for the distance of entry point from the midline (DEPM) represented a point at the contralateral side of the pedicle for every level except C-7. The mean DEPSEP values showed significant differences between all levels (p < 0.0001). Seven of the 30 screws were identified as breaching the pedicle (23.3%); these screw malplacements were seen at C-3 (3 screws), C-4 (2 screws), and C-5 (2 screws). CONCLUSIONS The morphological measurements of this study demonstrated that ATPS fixation is feasible in selected cases. They indicate that ATPS insertion using a fluoroscopy-assisted pedicle axis view is safe at the C-6 and C-7 levels, but the results at the other levels did not prove the safety of this technique. PMID- 25815806 TI - Soft-tissue reconstruction after total en bloc sacrectomy. AB - OBJECT Total en bloc sacrectomy is a dramatic procedure that results in extensive sacral defects. The authors present a series of patients who underwent flap reconstruction after total sacrectomy, report clinical outcomes, and provide a treatment algorithm to guide surgical care of this unique patient population. METHODS After institutional review board approval, data were collected for all patients who underwent total sacrectomy between 2002 and 2012 at The Johns Hopkins Hospital. Variables included demographic data, medical history, tumor characteristics, surgical details, postoperative complications, and clinical outcomes. All subtotal sacrectomies were excluded. RESULTS Between 2002 and 2012, 9 patients underwent total sacrectomy with flap reconstruction. Diagnoses included chordoma (n = 5), osteoblastoma (n = 1), sarcoma (n = 2), and metastatic colon cancer (n = 1). Six patients received gluteus maximus (GM) flaps with a prosthetic rectal sling following a single-stage, posterior sacrectomy. Four required additional paraspinous muscle (PSM) or pedicled latissimus dorsi (LD) fasciocutaneous flaps. Three patients underwent multistage sacrectomy with an anterior-posterior approach, 2 of whom received pedicled vertical rectus abdominis myocutaneous (VRAM) flaps, and 1 of whom received local GM, LD, and PSM flaps. Flap complications included dehiscence (n = 4) and infection (n = 1). During the 1st year of follow-up, 2 of 9 patients (22%) were able to ambulate with an assistive device by the 1st postoperative month, and 6 of 9 (67%) were ambulatory with a walker by the 3rd postoperative month. By postoperative Month 12, 5 of 9 patients (56%)-or 5 of 5 patients not lost to follow-up (100%)-were able to able to ambulate independently. CONCLUSIONS The authors' experience suggests that the GM and pedicled VRAM flaps are reliable options for softtissue reconstruction of total sacrectomy defects. For posterior-only operations, GM flaps with or without a prosthetic rectal sling are generally used. For multistage operations including a laparotomy, the authors consider the pedicled VRAM flap to be the gold standard for simultaneous reconstruction of the pelvic diaphragm and obliteration of dead space. PMID- 25815807 TI - Editorial: Total sacrectomy for malignant sacral tumors via a posterior-only approach. PMID- 25815808 TI - Laminoplasty versus laminectomy and fusion for multilevel cervical myelopathy: a meta-analysis of clinical and radiological outcomes. AB - OBJECT Posterior cervical surgery, expansive laminoplasty (EL) or laminectomy followed by fusion (LF), is usually performed in patients with multilevel (>= 3) cervical spondylotic myelopathy (CSM). However, the superiority of either of these techniques is still open to debate. The aim of this study was to compare clinical outcomes and postoperative kyphosis in patients undergoing EL versus LF by performing a meta-analysis. METHODS Included in the meta-analysis were all studies of EL versus LF in adults with multilevel CSM in MEDLINE (PubMed), EMBASE, and the Cochrane library. A random-effects model was applied to pool data using the mean difference (MD) for continuous outcomes, such as the Japanese Orthopaedic Association (JOA) grade, the cervical curvature index (CCI), and the visual analog scale (VAS) score for neck pain. RESULTS Seven studies comprising 302 and 290 patients treated with EL and LF, respectively, were included in the final analyses. Both treatment groups showed slight cervical lordosis and moderate neck pain in the baseline state. Both groups were similarly improved in JOA grade (MD 0.09, 95% CI -0.37 to 0.54, p = 0.07) and neck pain VAS score (MD 0.33, 95% CI -1.50 to 0.84, p = 0.58). Both groups evenly lost cervical lordosis. In the LF group lordosis seemed to be preserved in long-term follow-up studies, although the difference between the 2 treatment groups was not statistically significant. CONCLUSIONS Both EL and LF lead to clinical improvement and loss of lordosis evenly. There is no evidence to support EL over LF in the treatment of multilevel CSM. Any superiority between EL and LF remains in question, although the LF group shows favorable long-term results. PMID- 25815809 TI - Is total en bloc sacrectomy using a posterior-only approach feasible and safe for patients with malignant sacral tumors? AB - OBJECT In this study the authors' aim was to describe their experience with total en bloc sacrectomy using a posterioronly approach and to assess the outcome of patients with malignant sacral tumors who underwent this procedure at their center. METHODS The authors identified and retrospectively reviewed the records of 10 patients with malignant sacral tumors who underwent a total en bloc sacrectomy via a single posterior approach at their center. The pathological diagnosis was chordoma in 4 patients, chondrosarcoma in 1, osteosarcoma in 1, malignant schwannoma in 1, malignant giant cell tumor in 1, and Ewing's sarcoma in 2. Radiological examination revealed that the tumor involved S1-5 in 7 patients, S1-4 in 1, S1-3 in 1, and S1-2 in 1. RESULTS All 10 patients were stable during the perioperative period. The mean surgery duration was 282 minutes (range 250-310 minutes). The median estimated blood loss was 2595 ml (range 1500 3200 ml). All patients were followed up for 13-29 months (mean 22 months). Two patients had a local recurrence. Two patients died of disease, 1 patient was alive with disease, and 7 patients were alive without evidence of disease. Among the 8 surviving patients, 6 were able to walk without assistive devices, and 2 were able to walk with crutches. The total complication rate was 40% (4 of 10). Wound complications (deep infection and wound healing problems) occurred in 3 patients, and a distal deep vein thrombosis occurred in 1 patient. CONCLUSIONS Total en bloc sacrectomy using a posterior-only approach is feasible and safe in selected patients and is an important procedure for the treatment of primary malignant tumor involving the entire sacrum or only the top portion. PMID- 25815811 TI - A biased competition theory of cytotoxic T lymphocyte interaction with tumor nodules. AB - The dynamics of the interaction between Cytotoxic T Lymphocytes (CTL) and tumor cells has been addressed in depth, in particular using numerical simulations. However, stochastic mathematical models that take into account the competitive interaction between CTL and tumors undergoing immunoediting, a process of tumor cell escape from immunesurveillance, are presently missing. Here, we introduce a stochastic dynamical particle interaction model based on experimentally measured parameters that allows to describe CTL function during immunoediting. The model describes the competitive interaction between CTL and melanoma cell nodules and allows temporal and two-dimensional spatial progression. The model is designed to provide probabilistic estimates of tumor eradication through numerical simulations in which tunable parameters influencing CTL efficacy against a tumor nodule undergoing immunoediting are tested. Our model shows that the rate of CTL/tumor nodule productive collisions during the initial time of interaction determines the success of CTL in tumor eradication. It allows efficient cytotoxic function before the tumor cells acquire a substantial resistance to CTL attack, due to mutations stochastically occurring during cell division. Interestingly, a bias in CTL motility inducing a progressive attraction towards a few scout CTL, which have detected the nodule enhances early productive collisions and tumor eradication. Taken together, our results are compatible with a biased competition theory of CTL function in which CTL efficacy against a tumor nodule undergoing immunoediting is strongly dependent on guidance of CTL trajectories by scout siblings. They highlight unprecedented aspects of immune cell behavior that might inspire new CTL-based therapeutic strategies against tumors. PMID- 25815810 TI - Systems biology of tissue-specific response to Anaplasma phagocytophilum reveals differentiated apoptosis in the tick vector Ixodes scapularis. AB - Anaplasma phagocytophilum is an emerging pathogen that causes human granulocytic anaplasmosis. Infection with this zoonotic pathogen affects cell function in both vertebrate host and the tick vector, Ixodes scapularis. Global tissue-specific response and apoptosis signaling pathways were characterized in I. scapularis nymphs and adult female midguts and salivary glands infected with A. phagocytophilum using a systems biology approach combining transcriptomics and proteomics. Apoptosis was selected for pathway-focused analysis due to its role in bacterial infection of tick cells. The results showed tissue-specific differences in tick response to infection and revealed differentiated regulation of apoptosis pathways. The impact of bacterial infection was more pronounced in tick nymphs and midguts than in salivary glands, probably reflecting bacterial developmental cycle. All apoptosis pathways described in other organisms were identified in I. scapularis, except for the absence of the Perforin ortholog. Functional characterization using RNA interference showed that Porin knockdown significantly increases tick colonization by A. phagocytophilum. Infection with A. phagocytophilum produced complex tissue-specific alterations in transcript and protein levels. In tick nymphs, the results suggested a possible effect of bacterial infection on the inhibition of tick immune response. In tick midguts, the results suggested that A. phagocytophilum infection inhibited cell apoptosis to facilitate and establish infection through up-regulation of the JAK/STAT pathway. Bacterial infection inhibited the intrinsic apoptosis pathway in tick salivary glands by down-regulating Porin expression that resulted in the inhibition of Cytochrome c release as the anti-apoptotic mechanism to facilitate bacterial infection. However, tick salivary glands may promote apoptosis to limit bacterial infection through induction of the extrinsic apoptosis pathway. These dynamic changes in response to A. phagocytophilum in I. scapularis tissue specific transcriptome and proteome demonstrated the complexity of the tick response to infection and will contribute to characterize gene regulation in ticks. PMID- 25815812 TI - Enhanced hepatogenic transdifferentiation of human adipose tissue mesenchymal stem cells by gene engineering with Oct4 and Sox2. AB - Adipose tissue mesenchymal stem cells (ATMSCs) represent an attractive tool for the establishment of a successful stem cell-based therapy in the field of liver regeneration medicine. ATMSCs overexpressing Oct4 and Sox2 (Oct4/Sox2-ATMSCs) showed enhanced proliferation and multipotency. Hence, we hypothesized that Oct4 and Sox2 can increase "transdifferentiation" of ATMSCs into cells of the hepatic lineage. In this study, we generated Oct4- and Sox2-overexpressing human ATMSCs by liposomal transfection. We confirmed the expression of mesenchymal stem cell surface markers without morphological alterations in both red-fluorescent protein (RFP) (control)- and Oct4/Sox2-ATMSCs by flow cytometry. After induction of differentiation into hepatocyte-like cells, the morphology of ATMSCs changed and they began to appear as round or polygonal epithelioid cells. Hepatic markers were evaluated by reverse transcription-polymerase chain reaction and confirmed by immunofluorescence. The results showed that albumin was strongly expressed in hepatogenic differentiated Oct4/Sox2-ATMSCs, whereas the expression level of alpha-fetoprotein was lower than that of RFP-ATMSCs. The functionality of hepatocytes was evaluated by periodic acid-Schiff (PAS) staining and urea assays. The number of PAS-positive cells was significantly higher and urea production was significantly higher in Oct4/Sox2-ATMSCs compared to that in RFP-ATMSCs. Taken together, the hepatocyte-like cells derived from Oct4/Sox2-ATMSCs were mature hepatocytes, possibly functional hepatocytes with enhanced capacity to store glycogen and produce urea. In this study, we demonstrated the enhanced transdifferentiation of Oct4- and Sox2-overexpressing ATMSCs into hepatocyte-like cells that have enhanced hepatocyte-specific functions. Therefore, we expect that Oct4/Sox2-ATMSCs may become a very useful source for hepatocyte regeneration or liver cell transplantation. PMID- 25815813 TI - Participation of the classical speech areas in auditory long-term memory. AB - Accumulating evidence suggests that storing speech sounds requires transposing rapidly fluctuating sound waves into more easily encoded oromotor sequences. If so, then the classical speech areas in the caudalmost portion of the temporal gyrus (pSTG) and in the inferior frontal gyrus (IFG) may be critical for performing this acoustic-oromotor transposition. We tested this proposal by applying repetitive transcranial magnetic stimulation (rTMS) to each of these left-hemisphere loci, as well as to a nonspeech locus, while participants listened to pseudowords. After 5 minutes these stimuli were re-presented together with new ones in a recognition test. Compared to control-site stimulation, pSTG stimulation produced a highly significant increase in recognition error rate, without affecting reaction time. By contrast, IFG stimulation led only to a weak, non-significant, trend toward recognition memory impairment. Importantly, the impairment after pSTG stimulation was not due to interference with perception, since the same stimulation failed to affect pseudoword discrimination examined with short interstimulus intervals. Our findings suggest that pSTG is essential for transforming speech sounds into stored motor plans for reproducing the sound. Whether or not the IFG also plays a role in speech-sound recognition could not be determined from the present results. PMID- 25815814 TI - Distracted by the Unthought - Suppression and Reappraisal of Mind Wandering under Stereotype Threat. AB - Previous research has found that subtle reminders of negative stereotypes about one's group can lead individuals to underperform on stereotype-relevant tests (e.g., women in math, ethnic minorities on intelligence tests). This so called stereotype threat effect can contribute to systematic group differences in performance that can obscure the true abilities of certain social groups and thereby sustain social inequalities. In the present study, we examined processes underlying stereotype threat effects on women's math performance, specifically focusing on the role of suppression of mind wandering (i.e., task-irrelevant thinking) in stereotype threat (ST) and no threat (NT) situations. Based on a process model of stereotype threat effects on performance, we hypothesized that women under stereotype threat spontaneously suppress mind wandering, and that this suppression impairs performance. An alternative regulation strategy that prevents suppression (i.e., reappraising task-irrelevant thoughts as normal) was predicted to prevent stereotype threat effects on performance. We manipulated stereotype threat (ST vs. NT) and cognitive regulation strategy (suppression, reappraisal, or no strategy) and measured women's performance on a math and a concentration task (N = 113). We expected three groups to perform relatively more poorly: Those in ST with either no strategy or suppression and those in NT with a suppression strategy. We tested the performance of these groups against the remaining three groups hypothesized to perform relatively better: those in NT with no strategy or reappraisal and those in ST with reappraisal. The results showed the expected pattern for participants' math performance, but not for concentration achievement. This pattern suggests that ineffective self-regulation by suppressing mind wandering can at least partly explain stereotype threat effects on performance, whereas a reappraisal strategy can prevent this impairment. We discuss implications for the understanding of processes underlying stereotype threat effects and the benefits of reappraising subjective experience under threat. PMID- 25815815 TI - Simultaneous detection of P300 and steady-state visually evoked potentials for hybrid brain-computer interface. AB - OBJECTIVE: We study the feasibility of a hybrid Brain-Computer Interface (BCI) combining simultaneous visual oddball and Steady-State Visually Evoked Potential (SSVEP) paradigms, where both types of stimuli are superimposed on a computer screen. Potentially, such a combination could result in a system being able to operate faster than a purely P300-based BCI and encode more targets than a purely SSVEP-based BCI. APPROACH: We analyse the interactions between the brain responses of the two paradigms, and assess the possibility to detect simultaneously the brain activity evoked by both paradigms, in a series of 3 experiments where EEG data are analysed offline. MAIN RESULTS: Despite differences in the shape of the P300 response between pure oddball and hybrid condition, we observe that the classification accuracy of this P300 response is not affected by the SSVEP stimulation. We do not observe either any effect of the oddball stimulation on the power of the SSVEP response in the frequency of stimulation. Finally results from the last experiment show the possibility of detecting both types of brain responses simultaneously and suggest not only the feasibility of such hybrid BCI but also a gain over pure oddball- and pure SSVEP based BCIs in terms of communication rate. PMID- 25815816 TI - Anthropometry and body composition of adolescents in cracow, poland. AB - BACKGROUND AND OBJECTIVE: The aim of the present study was to determine the level of adiposity and obesity in Polish adolescents and compare the results with earlier studies conducted in this population as well as those carried out in other populations. METHODS: The study group consisted of 456 boys and 514 girls aged 14-18 years living in Cracow chosen from randomly selected secondary schools. Weight, height, waist, and hip circumference (WC, HC) as well as triceps, biceps, subscapular, and suprailiac skinfold thickness (SFT) were measured. Body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), subscapular/triceps skinfold ratio (STR), and percentage body fat were computed. The prevalence of overweight and obesity based on Polish children growth reference were calculated and age-dependent and gender-specific smoothed percentile curves for BMI and ROC curves were generated. RESULTS: Weight, height, WC, HC (up 16yr), WHtR (up 15yr), and WHR were considerably higher in males than females. Weight, height, and HC increased with age; WHtR remained the same. The prevalence of overweight and obesity were 10.2% (boys 10.3%; girls 10.1%) and 4.2% (boys 5.3%; girls 3.3%). ROC analysis revealed that WHtR was the best tool for detection of obesity (AUC of 0.982+/-0.007) in males, whereas the sum of four SFTs (AUC: 0.968+/-0.011) and WHtR (AUC: 0.963+/-0.012) were the best predictors of obesity in females. CONCLUSIONS: The level of adiposity in Cracow adolescents increased during the last decade. However, it is still lower than in other well developed societies struggling with obesity epidemics. PMID- 25815817 TI - Avoidant personality disorder versus social phobia: the significance of childhood neglect. AB - OBJECTIVES: Avoidant personality disorder (AvPD) and social phobia (SP) are common disorders both in the community and in clinical settings. Whether the two disorders represent different severity levels of social anxiety disorder is currently in dispute. The relationship between AvPD and SP is probably more complex than previously assumed. Several environmental, temperamental, and constitutional factors may play a role in the etiology of AvPD and SP. Better knowledge about childhood experiences may shed light on similarities and differences between the two disorders. The aim of this study was to compare self reported childhood experiences in AvPD and SP patients. DESIGN: This is a cross sectional multi-site study of 91 adult patients with AvPD and/ or SP. We compared patients with AvPD with and without SP (AvPD group) to patients with SP without AvPD (SP group). METHODS: The patients were examined using structured diagnostic interviews and self-report measures, including Child Trauma Questionnaire, Parental Bonding Instrument, and Adult Temperament Questionnaire. RESULTS: Both AvPD and SP were associated with negative childhood experiences. AvPD patients reported more severe childhood neglect than patients with SP, most pronounced for physical neglect. The difference between the disorders in neglect remained significant after controlling for temperamental factors and concurrent abuse. CONCLUSIONS: The study indicates that childhood neglect is a risk factor for AvPD and may be one contributing factor to phenomenological differences between AvPD and SP. PMID- 25815819 TI - Walking the straight and narrow: the moderating effect of evaluation apprehension on the relationship between collectivism and corruption. AB - Previous studies obtained mixed results regarding the association between collectivism and corruption. To make sense of the mixed results, the current research examined the moderating role of evaluation apprehension on the relationship between collectivism and corruption. Study 1, using a bribery scenario, indicated that collectivism facilitated corruption only when evaluation apprehension was low. Study 2, using a real money bribery game, confirmed the moderated model found in Study 1. Study 3 further demonstrated the different effects of vertical/horizontal collectivism on corruption. Our results suggest that a society may effectively combat corruption by increasing its social costs while, at the same time, retaining its collectivistic values. PMID- 25815818 TI - Cleavage of Dicer protein by I7 protease during vaccinia virus infection. AB - Dicer is the key component in the miRNA pathway. Degradation of Dicer protein is facilitated during vaccinia virus (VV) infection. A C-terminal cleaved product of Dicer protein was detected in the presence of MG132 during VV infection. Thus, it is possible that Dicer protein is cleaved by a viral protease followed by proteasome degradation of the cleaved product. There is a potential I7 protease cleavage site in the C-terminus of Dicer protein. Indeed, reduction of Dicer protein was detected when Dicer was co-expressed with I7 protease but not with an I7 protease mutant protein lack of the protease activity. Mutation of the potential I7 cleavage site in the C-terminus of Dicer protein resisted its degradation during VV infection. Furthermore, Dicer protein was reduced dramatically by recombinant VV vI7Li after the induction of I7 protease. If VV could facilitate the degradation of Dicer protein, the process of miRNA should be affected by VV infection. Indeed, accumulation of precursor miR122 was detected after VV infection or I7 protease expression. Reduction of miR122 would result in the suppression of HCV sub-genomic RNA replication, and, in turn, the amount of viral proteins. As expected, significant reduction of HCVNS5A protein was detected after VV infection and I7 protease expression. Therefore, our results suggest that VV could cleave Dicer protein through I7 protease to facilitate Dicer degradation, and in turn, suppress the processing of miRNAs. Effect of Dicer protein on VV replication was also studied. Exogenous expression of Dicer protein suppresses VV replication slightly while knockdown of Dicer protein does not affect VV replication significantly. PMID- 25815820 TI - A comprehensive alanine-scanning mutagenesis study reveals roles for salt bridges in the structure and activity of Pseudomonas aeruginosa elastase. AB - The relationship between salt bridges and stability/enzymatic activity is unclear. We studied this relationship by systematic alanine-scanning mutation analysis using the typical M4 family metalloprotease Pseudomonas aeruginosa elastase (PAE, also known as pseudolysin) as a model. Structural analysis revealed seven salt bridges in the PAE structure. We constructed ten mutants for six salt bridges. Among these mutants, six (Asp189Ala, Arg179Ala, Asp201Ala, Arg205Ala, Arg245Ala and Glu249Ala) were active and four (Asp168Ala, Arg198Ala, Arg253Ala, and Arg279Ala) were inactive. Five mutants were purified, and their catalytic efficiencies (kcat/Km), half-lives (t1/2) and thermal unfolding curves were compared with those of PAE. Mutants Asp189Ala and Arg179Ala both showed decreased thermal stabilities and increased activities, suggesting that the salt bridge Asp189-Arg179 stabilizes the protein at the expense of catalytic efficiency. In contrast, mutants Asp201Ala and Arg205Ala both showed slightly increased thermal stability and slightly decreased activity, suggesting that the salt bridge Asp201-Arg205 destabilizes the protein. Mutant Glu249Ala is related to a C-terminal salt bridge network and showed both decreased thermal stability and decreased activity. Furthermore, Glu249Ala showed a thermal unfolding curve with three discernable states [the native state (N), the partially unfolded state (I) and the unfolded state (U)]. In comparison, there were only two discernable states (N and U) in the thermal unfolding curve of PAE. These results suggest that Glu249 is important for catalytic efficiency, stability and unfolding cooperativity. This study represents a systematic mutational analyses of salt bridges in the model metalloprotease PAE and provides important insights into the structure-function relationship of enzymes. PMID- 25815821 TI - The gloves are off: let battle commence. PMID- 25815822 TI - Ebola survivor Will Pooley honoured at BJN Awards. PMID- 25815823 TI - Nasogastric feeding for stroke patients: practice and education. AB - BACKGROUND AND AIMS: Dysphagia is common after stroke, so feeding through a nasogastric (NG) tube may be necessary. These tubes are frequently dislodged, causing interruption to feeding and hydration, and potential aspiration of feed or fluids into the lungs. Interventions to prevent this may include taping tubes to the face; the application of hand mittens or bandaging patients' hands; inserting the NG tube into the nostril on the stroke-affected side; and nasal bridles. The aims of this survey were to investigate the management of NG feeding for stroke patients, including current tube confirmation and securing techniques, and associated nurse education. This was part of a three-phased sequential mixed methods study. This paper reports on the second quantitative phase. METHODS: A quantitative postal survey, based on initial qualitative findings, was sent to registered nurses (n=528) from the National Stroke Nurses Forum and Scottish Stroke Nurses Forum, in addition to registered nurses working on stroke units within the local health board. RESULTS: The overall response rate was 59% (n=314/528). Tape was the most commonly used method for securing tube position, followed by inserting the tube on the stroke-affected side. Hand mittens were used more frequently than the nasal bridle; bandaging hands was reported once. Taping was considered to be more acceptable and safer than hand mittens or the nasal bridle, but less effective. Training in inserting NG feeding tubes was received by 56% (n=176/314). Methods used for confirming tube position included aspiration and X-ray. Provision of training in confirmation techniques varied. CONCLUSIONS: This study shows that the management of NG feeding for dysphagic stroke patients requires standardisation, as does the education for nurses to ensure that this intervention is carried out safely, effectively and acceptably. PMID- 25815824 TI - The value of Master's degrees for registered nurses. AB - The value of graduates in the nursing workforce has been recognised in the move to all-graduate preparation of pre-registration nurses in England ( Nursing and Midwifery Council, 2010 ). Increasingly, after registration continuing professional development programmes for nurses are being offered at Master's level. However, there is limited evidence of the relationship between postgraduate study and improved patient outcomes. Evidence that does exist suggests that nurses who engage in postgraduate study are more likely to have improved critical thinking and decision-making skills, demonstrate leadership qualities to empower them to challenge poor practice, and have the skills needed for advanced clinical practice roles. This article explores these issues and makes recommendations for further work in this area. PMID- 25815825 TI - 'Not a job for a man': factors in the use of touch by male nursing staff. AB - While the numbers of male nursing staff are growing in both the UK and the USA, there remains a significant imbalance both in terms of the total number and the specialities in which male staff choose to work. Management, education and technology-dominated roles, characterised as 'high-tech, low-touch' specialities attract disproportionately larger numbers of male nursing staff. AIM: The aim of this narrative literature review was to explore and critically review the factors that influence the perception and use of touch by male nursing staff in contemporary healthcare settings. METHOD: A comprehensive review of the literature was undertaken using significant online databases focusing on evidence from peer-reviewed journals published in English. RESULTS: Key influential factors arising from 11 selected studies included male nurses' definitions of touch; fear of touch misinterpretation; coping strategies employed; the assessment of certain groups of patients; gender-derived stressors; the emotional experiences of male staff; and the limited consideration of these issues in the pre-registration nursing curriculum. CONCLUSION: A range of factors regarding touch impact on the way male nurses use touch when caring for patients. A lack of research-based education in the preparation of male students leads to the development of various protective strategies. There is a need for the particular challenges facing male students and staff to be explicitly addressed within undergraduate and post-qualifying education and training programmes. PMID- 25815826 TI - The meaning of compassion. PMID- 25815827 TI - Revalidation: what does it mean? PMID- 25815828 TI - The role of nurses' and patients' personal beliefs in nursing care. AB - In this monthly column, Aysha Mendes discusses the need for nurses to acknowledge their own beliefs and worldview, and the impact these may have on how they care for patients-and the importance of acknowledging patients' own perspectives. PMID- 25815829 TI - Will nurses be enabled to speak up when things go wrong? AB - Professor Alan Glasper of the University of Southampton discusses the Government's efforts to provide support for whistleblowers who wish to escalate healthcare concerns in institutions in England. PMID- 25815830 TI - Applying the lessons of the Francis Inquiries: Culture Change. AB - In this two-part column John Tingle discusses the Department of Health's progress report on applying the lessons learned from the tragic events at Mid Staffordshire NHS Foundation Trust. PMID- 25815831 TI - Relationships: from staff nurse to nurse consultant. Part 2: nurse-patient relationships. PMID- 25815832 TI - Is Magnet hospital status for us? PMID- 25815833 TI - Correction: Evolving a 24-hr oscillator in budding yeast. PMID- 25815834 TI - The higher temperature in the areola supports the natural progression of the birth to breastfeeding continuum. AB - Numerous functional features that promote the natural progression of the birth to breastfeeding continuum are concentrated in the human female's areolar region. The aim of this study was to look more closely into the thermal characteristics of areola, which are said to regulate the local evaporation rate of odors and chemical signals that are uniquely important for the neonate's 'breast crawl'. A dermatological study of the areolae and corresponding intern breast quadrants was undertaken on the mothers of 70 consecutive, healthy, full-term breastfed infants. The study took place just after the births at the Policlinico Abano Terme, in Italy from January to February 2014. Temperature, pH and elasticity were assessed one day postpartum using the Soft Plus 5.5 (Callegari S.P.A., Parma, Italy). The mean areolar temperature was found to be significantly higher than the corresponding breast quadrant (34.60 +/-1.40 degrees C vs. 34.04 +/-2.00 degrees C, p<0.001) and the pH was also significantly higher (4.60+/-0.59 vs. 4.17+/-0.59, p<0.001). In contrast, the elasticity of the areolar was significantly lower (23.52+/-7.83 vs. 29.02+/-8.44%, p<0.003). Our findings show, for the first time, that the areolar region has a higher temperature than the surrounding breast skin, together with higher pH values and lower elasticity. We believe that the higher temperature of the areolar region may act as a thermal signal to guide the infant directly to the nipple and to the natural progression of the birth to breastfeeding continuum. PMID- 25815835 TI - Identification of prognostic factors in early stage low rectal cancer to optimize surgical treatment; local excision or abdominoperineal resection. PMID- 25815836 TI - Proliferation of cultured mouse choroid plexus epithelial cells. AB - The choroid plexus (ChP) epithelium is a multifunctional tissue found in the ventricles of the brain. The major function of the ChP epithelium is to produce cerebrospinal fluid (CSF) that bathes and nourishes the central nervous system (CNS). In addition to the CSF, ChP epithelial cells (CPECs) produce and secrete numerous neurotrophic factors that support brain homeostasis, such as adult hippocampal neurogenesis. Accordingly, damage and dysfunction to CPECs are thought to accelerate and intensify multiple disease phenotypes, and CPEC regeneration would represent a potential therapeutic approach for these diseases. However, previous reports suggest that CPECs rarely divide, although this has not been extensively studied in response to extrinsic factors. Utilizing a cell-cycle reporter mouse line and live cell imaging, we identified scratch injury and the growth factors insulin-like growth factor 1 (IGF-1) and epidermal growth factor (EGF) as extrinsic cues that promote increased CPEC expansion in vitro. Furthermore, we found that IGF-1 and EGF treatment enhances scratch injury induced proliferation. Finally, we established whole tissue explant cultures and observed that IGF-1 and EGF promote CPEC division within the intact ChP epithelium. We conclude that although CPECs normally have a slow turnover rate, they expand in response to external stimuli such as injury and/or growth factors, which provides a potential avenue for enhancing ChP function after brain injury or neurodegeneration. PMID- 25815838 TI - Population structure of the bacterial pathogen Xylella fastidiosa among street trees in Washington D.C. AB - Bacterial leaf scorch, associated with the bacterial pathogen Xylella fastidiosa, is a widely established and problematic disease of landscape ornamentals in Washington D.C. A multi-locus sequence typing analysis was performed using 10 housekeeping loci for X. fastidiosa strains in order to better understand the epidemiology of leaf scorch disease in this municipal environment. Samples were collected from 7 different tree species located throughout the District of Columbia, consisting of 101 samples of symptomatic and asymptomatic foliage from 84 different trees. Five strains of the bacteria were identified. Consistent with prior data, these strains were host specific, with only one strain associated with members of the red oak family, one strain associated with American elm, one strain associated with American sycamore, and two strains associated with mulberry. Strains found for asymptomatic foliage were the same as strains from the symptomatic foliage on individual trees. Cross transmission of the strains was not observed at sites with multiple species of infected trees within an approx. 25 m radius of one another. X. fastidiosa strain specificity observed for each genus of tree suggests a highly specialized host-pathogen relationship. PMID- 25815837 TI - Mechanisms underlying early rapid increases in creatinine in paraquat poisoning. AB - BACKGROUND: Acute kidney injury (AKI) is common after severe paraquat poisoning and usually heralds a fatal outcome. The rapid large increases in serum creatinine (Cr) exceed that which can be explained by creatinine kinetics based on loss of glomerular filtration rate (GFR). METHODS AND FINDINGS: This prospective multi-centre study compared the kinetics of two surrogate markers of GFR, serum creatinine and serum cystatin C (CysC), following paraquat poisoning to understand and assess renal functional loss after paraquat poisoning. Sixty six acute paraquat poisoning patients admitted to medical units of five hospitals were included. Relative changes in creatinine and CysC were monitored in serial blood and urine samples, and influences of non-renal factors were also studied. RESULTS: Forty-eight of 66 patients developed AKI (AKIN criteria), with 37 (56%) developing moderate to severe AKI (AKIN stage 2 or 3). The 37 patients showed rapid increases in creatinine of >100% within 24 hours, >200% within 48 hours and >300% by 72 hours and 17 of the 37 died. CysC concentration increased by 50% at 24 hours in the same 37 patients and then remained constant. The creatinine/CysC ratio increased 8 fold over 72 hours. There was a modest fall in urinary creatinine and serum/urine creatinine ratios and a moderate increase in urinary paraquat during first three days. CONCLUSION: Loss of renal function contributes modestly to the large increases in creatinine following paraquat poisoning. The rapid rise in serum creatinine most probably represents increased production of creatine and creatinine to meet the energy demand following severe oxidative stress. Minor contributions include increased cyclisation of creatine to creatinine because of acidosis and competitive or non-competitive inhibition of creatinine secretion. Creatinine is not a good marker of renal functional loss after paraquat poisoning and renal injury should be evaluated using more specific biomarkers of renal injury. PMID- 25815839 TI - Membrane translocation of IL-33 receptor in ventilator induced lung injury. AB - Ventilator-induced lung injury is associated with inflammatory mechanism and causes high mortality. The objective of this study was to discover the role of IL 33 and its ST2 receptor in acute lung injury induced by mechanical ventilator (ventilator-induced lung injury; VILI). Male Wistar rats were intubated after tracheostomy and received ventilation at 10 cm H2O of inspiratory pressure (PC10) by a G5 ventilator for 4 hours. The hemodynamic and respiratory parameters were collected and analyzed. The morphological changes of lung injury were also assessed by histological H&E stain. The dynamic changes of lung injury markers such as TNF-alpha and IL-1beta were measured in serum, bronchoalveolar lavage fluid (BALF), and lung tissue homogenization by ELISA assay. During VILI, the IL 33 profile change was detected in BALF, peripheral serum, and lung tissue by ELISA analysis. The Il-33 and ST2 expression were analyzed by immunohistochemistry staining and western blot analysis. The consequence of VILI by H&E stain showed inducing lung congestion and increasing the expression of pro inflammatory cytokines such as TNF-alpha and IL-1beta in the lung tissue homogenization, serum, and BALF, respectively. In addition, rats with VILI also exhibited high expression of IL-33 in lung tissues. Interestingly, the data showed that ST2L (membrane form) was highly accumulated in the membrane fraction of lung tissue in the PC10 group, but the ST2L in cytosol was dramatically decreased in the PC10 group. Conversely, the sST2 (soluble form) was slightly decreased both in the membrane and cytosol fractions in the PC10 group compared to the control group. In conclusion, these results demonstrated that ST2L translocation from the cytosol to the cell membranes of lung tissue and the down expression of sST2 in both fractions can function as new biomarkers of VILI. Moreover, IL-33/ST2 signaling activated by mechanically responsive lung injury may potentially serve as a new therapy target. PMID- 25815840 TI - Modeling the potential effects of new tobacco products and policies: a dynamic population model for multiple product use and harm. AB - BACKGROUND: Recent declines in US cigarette smoking prevalence have coincided with increases in use of other tobacco products. Multiple product tobacco models can help assess the population health impacts associated with use of a wide range of tobacco products. METHODS AND FINDINGS: We present a multi-state, dynamical systems population structure model that can be used to assess the effects of tobacco product use behaviors on population health. The model incorporates transition behaviors, such as initiation, cessation, switching, and dual use, related to the use of multiple products. The model tracks product use prevalence and mortality attributable to tobacco use for the overall population and by sex and age group. The model can also be used to estimate differences in these outcomes between scenarios by varying input parameter values. We demonstrate model capabilities by projecting future cigarette smoking prevalence and smoking attributable mortality and then simulating the effects of introduction of a hypothetical new lower-risk tobacco product under a variety of assumptions about product use. Sensitivity analyses were conducted to examine the range of population impacts that could occur due to differences in input values for product use and risk. We demonstrate that potential benefits from cigarette smokers switching to the lower-risk product can be offset over time through increased initiation of this product. Model results show that population health benefits are particularly sensitive to product risks and initiation, switching, and dual use behaviors. CONCLUSION: Our model incorporates the variety of tobacco use behaviors and risks that occur with multiple products. As such, it can evaluate the population health impacts associated with the introduction of new tobacco products or policies that may result in product switching or dual use. Further model development will include refinement of data inputs for non cigarette tobacco products and inclusion of health outcomes such as morbidity and disability. PMID- 25815841 TI - A prospective, observational study on the application of ultra-wide-field angiography in the evaluation and management of patients with anterior uveitis. AB - PURPOSE: Evaluation of peripheral retinal vascular changes in anterior uveitis using ultra-wide-field fluorescein angiography. DESIGN: A prospective, observational study of a case series of patients diagnosed with anterior uveitis. METHODS: SETTING: Clinical observation at an academic medical center. Patient or Study Population: A total of 65 eyes of 33 patients corresponded with the research criteria of anterior uveitis in the opinion of specialists of Peking University First Hospital. OBSERVATION PROCEDURES: Patients were diagnosed primarily through clinical examinations and conventional fluorescein angiography. Subsequently, ultra-wide-field fluorescein angiograms were obtained for each patient. MAIN OUTCOME MEASURES: The main outcome was the detection of peripheral retinal changes by ultra-wide-field fluorescein angiography, and how these changes influenced the evaluation and management of the disease. RESULTS: Peripheral vessel leakage was detected in 27 eyes (42%) with anterior uveitis, of which 15 eyes displayed active inflammation and 12 eyes displayed inactive inflammation. Peripheral vessel leakage was found in seven of eight eyes with cystoid macular edema. Cystoid macular edema was detected in 7 of 27 eyes (26%) with peripheral vessel leakage, whereas 1 of 38 eyes (3%) did not display peripheral vessel leakage (p<0.01). 44.4% of the patients with peripheral vessel leakage had a specific etiology. The relevant treatment strategies were modified based on the results of the ultra-wide-field fluorescein angiography. 12 patients with peripheral vessel leakage and a quiescent anterior segment were added to those receiving topical glucocorticoids, while 3 patients with serious peripheral vessel leakage and an active anterior segment received a sub-Tenon injection of triamcinolone acetonide. CONCLUSIONS: Ultra-wide-field fluorescein angiography was very effective in detecting peripheral retinal vascular pathology in anterior uveitis. The changes found in the periphery were important in the evaluation and management of anterior uveitis. PMID- 25815842 TI - From the guest editor: an integrated multidisciplinary view of tumor metabolism. PMID- 25815844 TI - Drivers of the Warburg phenotype. AB - The Warburg effect was first described by Otto Warburg in the 1920s and describes the preferential conversion of glucose to lactate as opposed to its metabolism through the citric acid cycle to fuel oxidative phosphorylation in the mitochondria, even in the presence of oxygen. This phenotype is a common feature of malignant cells and is also observed in some highly proliferative normal tissues. The selective advantage provided by this phenotype is not entirely clear. Adopting this metabolic state may allow tumor cells to balance their need for ATP, biosynthetic precursor molecules, and reducing power in order to respond to growth and proliferation signals and may provide a selective advantage in the hypoxic and acidic microenvironments that are often a feature of solid tumors. Oncogenic signaling pathways and responses to the local microenvironment combine to produce this metabolic phenotype via a number of molecular mechanisms. A better understanding of these mechanisms in both tumor and normal tissues and a more complete understanding of how the Warburg effect interacts with the rest of the tumor metabolic network should provide opportunities for novel clinical intervention. PMID- 25815843 TI - Alternative fuels for cancer cells. AB - Tumor metabolism is significantly altered to support the various metabolic needs of tumor cells. The most prominent change is the increased tumor glycolysis that leads to increased glucose uptake and utilization. However, it has become obvious that many non-glucose nutrients, such as amino acids, lactate, acetate, and macromolecules, can serve as alternative fuels for cancer cells. This knowledge reveals an unexpected flexibility and evolutionarily conserved model in which cancer cells uptake nutrients from their external environment to fulfill their necessary energetic needs. Tumor cells may have evolved the ability to utilize different carbon sources because of the limited supply of nutrients in their microenvironment, which can be driven by oncogenic mutations or tumor microenvironmental stresses. In certain cases, these factors permanently alter the tumor cells' metabolism, causing certain nutrients to become indispensable and thus creating opportunities for therapeutic intervention to eradicate tumors by their metabolic vulnerabilities. PMID- 25815847 TI - Common responses of tumors and wounds to hypoxia. AB - Hypoxia is a characteristic of tumors and wounds. Hypoxic cells develop 2 common strategies to face hypoxia: the glycolytic switch and the angiogenic switch. At the onset of hypoxia, alleviation of the Pasteur effect ensures short-term cell survival. Long-term hypoxic cell survival requires a further acceleration of the glycolytic flux under the control of hypoxia-inducible factor 1 that stimulates the expression of most glycolytic transporters and enzymes, uncouples glycolysis from the TCA cycle, and rewires glycolysis to lactic fermentation. Hypoxic cells also trigger angiogenesis, a process that aims to restore normal microenvironmental conditions. Transcription factors (hypoxia-inducible factor 1, nuclear factor kappaB, activator protein 1) and lactate cooperate to stimulate the expression of proangiogenic agents. Cancer cells differ from normal hypoxic cells by their proliferative agenda and by a high metabolic heterogeneity. These effects in tumor account for further molecular and metabolic changes and for a persistent stimulation of angiogenesis. PMID- 25815845 TI - Novel therapeutic targets of tumor metabolism. AB - The study of tumor metabolism has resulted in new understandings of how cancer cells modify metabolic pathways that control cellular energetics to allow increased proliferation and survival. Tumor cells have been shown to alter metabolic pathways involved in glucose, glutamine, and mitochondrial metabolism to generate raw materials needed for rapid cellular proliferation, maintain favorable cellular redox environments, modify cellular epigenetics, and even promote and maintain oncogenic transformation. As a consequence, there has been intense scientific and clinical interest in targeting metabolic alterations that are commonly adopted by tumor cells for therapeutic purposes. In this review, we describe common metabolic alterations seen in tumor cells and discuss how these alterations are being investigated as potential targets for pharmacological intervention in preclinical and clinical settings. We also discuss some of the challenges associated with using tumor metabolism as a therapeutic target in cancer therapy, along with potential avenues to overcome these challenges. PMID- 25815846 TI - Metformin, an old drug, brings a new era to cancer therapy. AB - Metformin is the most commonly prescribed drug for type 2 diabetes mellitus as it is inexpensive, safe, and efficient in ameliorating hyperglycemia and hyperinsulinemia. Epidemiological and clinical observation studies have shown that metformin use reduces risk of cancer in patients with type 2 diabetes mellitus and improves prognosis and survival rate of the cancer patients. Furthermore, ongoing clinical trials of metformin in cancer therapy are extending to nondiabetic population. Thus, metformin is emerging as an attractive candidate for cancer prevention and treatment. This review summarizes recent progress in studies of metformin use in cancer and discusses the possibility to enhance its efficacy and to prevent cancer metastasis. PMID- 25815850 TI - Lifestyle and cancer risk. AB - The global incidence of cancer is expected to increase substantially over the next decades. This trend is very much driven by a rise in lifestyle-related cancers due to economic and demographic transitions worldwide. Lifestyle factors, such as smoking, alcohol consumption, obesity, diet, and physical inactivity, and also reproductive and hormonal factors are considered as causes of cancer and main targets for primary prevention. While smoking, which may be responsible for around 20% to 30% of all incident cancers, is clearly the strongest lifestyle related risk factor overall, followed by alcohol consumption and obesity, the importance of specific factors for individual cancer types and subtypes varies greatly. Remarkably, it has been argued that half of all cancers in industrially developed and affluent societies could be avoided by nonsmoking, reducing alcohol consumption, weight control and physical activity, a plant-based diet, and breast feeding. PMID- 25815848 TI - Metabolism and its sequelae in cancer evolution and therapy. AB - Cancers progress through a series of events that can be characterized as "somatic evolution." A central premise of Darwinian evolutionary theory is that the environment imparts pressure to select for species that are most fit within that particular microenvironmental context. Furthermore, the rate of evolution is proportional to both (1) the strength of the environmental selection and (2) the phenotypic variance of the selected population. It is notable that, during the progression of cancers from carcinogenesis to local invasion to metastasis, the selective landscape continuously changes, and throughout this process, there is increased selection for cells that have altered metabolic phenotypes: implying that these phenotypes impart a selective advantage during the process of environmental selection. One of the most prevalent selected phenotypes is that of aerobic glycolysis, that is, the continued fermentation of glucose even in the presence of adequate oxygen. The mechanisms of this so-called "Warburg effect" have been well studied, and there are multiple models to explain how this occurs at the molecular level. Herein, we propose that unifying insights can be gained by evaluating the environmental context within which this phenotype arises. In other words, we focus not on the "how" but the "why" do cancer cells exhibit high aerobic glycolysis. This is best approached by examining the sequelae of aerobic glycolysis that may impart a selective advantage. Many of these have been considered, including generation of anabolic substrates, response rates of glycolysis vis-a-vis respiration, and generation of antioxidants. A further sequeala considered here is that aerobic glycolysis results in a high rate of lactic acid production; resulting in acidification of the extracellular space. Indeed, it has been shown that a low extracellular pH promotes local invasion, promotes metastasis, and inhibits antitumor immunity. In naturally occurring cancers, low extracellular pH is a strong negative prognostic indicator of metastasis-free survival. Furthermore, it has been shown that inhibition of extracellular acidosis can inhibit metastasis and promote antitumor immunity. Hence, we propose that excess acid production confers a selective advantage for cells during the somatic evolution of cancers. PMID- 25815849 TI - Stress, metabolism and cancer: integrated pathways contributing to immune suppression. AB - The potential for immune cells to control cancers has been recognized for many decades, but only recently has real excitement begun to spread through the oncology community following clear evidence that therapeutic blockade of specific immune-suppressive mechanisms is enough to make a real difference in survival for patients with several different advanced cancers. However, impressive and encouraging as these new clinical data are, it is clear that more effort should be devoted toward understanding the full spectrum of factors within cancer patients, which have the potential to block or weaken antitumor activity by immune cells. The goal of this brief review is to highlight recent literature revealing interactive stress and metabolic pathways, particularly those mediated by the sympathetic nervous system, which may conspire to block immune cells from unleashing their full killing potential. There is exciting new information regarding the role of neurogenesis by tumors and adrenergic signaling in cancer progression (including metabolic changes associated with cachexia and lipolysis) and in regulation of immune cell function and differentiation. However, much more work is needed to fully understand how the systemic metabolic effects mediated by the brain and nervous system can be targeted for therapeutic efficacy in the setting of immunotherapy and other cancer therapies. PMID- 25815851 TI - Effects of exercise on tumor physiology and metabolism. AB - Exercise is a potent regulator of a range of physiological processes in most tissues. Solid epidemiological data show that exercise training can reduce disease risk and mortality for several cancer diagnoses, suggesting that exercise training may directly regulate tumor physiology and metabolism. Here, we review the body of literature describing exercise intervention studies performed in rodent tumor models and elaborate on potential mechanistic effects of exercise on tumor physiology. Exercise has been shown to reduce tumor incidence, tumor multiplicity, and tumor growth across numerous different transplantable, chemically induced or genetic tumor models. We propose 4 emerging mechanistic effects of exercise, including (1) vascularization and blood perfusion, (2) immune function, (3) tumor metabolism, and (4) muscle-to-cancer cross-talk, and discuss these in details. In conclusion, exercise training has the potential to be a beneficial and integrated component of cancer management, but has yet to fully elucidate its potential. Understanding the mechanistic effects of exercise on tumor physiology is warranted. Insight into these mechanistic effects is emerging, but experimental intervention studies are still needed to verify the cause-effect relationship between these mechanisms and the control of tumor growth. PMID- 25815852 TI - Cancer cachexia, recent advances, and future directions. AB - Cancer cachexia is defined as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass with or without loss of fat mass. The syndrome cannot be fully reversed by conventional nutritional support, and despite an increased number of studies related to cancer cachexia, the underlying mechanisms are still poorly defined, and therapeutic options are limited. This review focuses on recent studies investigating mechanisms and pathways in cancer cachexia. The role of molecular and functional imaging in identifying cachexia at an earlier stage, in identifying potential metabolic targets and pathways, and in assessing treatment efficacy is also reviewed. PMID- 25815853 TI - Imaging tumor metabolism using in vivo magnetic resonance spectroscopy. AB - Magnetic resonance spectroscopy (MRS) is a powerful tool for noninvasively investigating normal and abnormal metabolism. When used in combination with imaging strategies, multinuclear MRS methods provide detailed biochemical information that can be directly correlated with anatomical features. Hyperpolarized C MRS is a new technology that reflects real-time metabolic conversion and is likely to be extremely valuable in managing patients with cancer. This article reviews the use of in vivo P, H, and C MRS for assessing cancer metabolism in order to provide information for diagnosis, planning treatment, assessing response to therapy, and predicting survival for patients with cancer. PMID- 25815856 TI - Difficulties in Daily Life Reported by Patients With Homonymous Visual Field Defects. AB - BACKGROUND: Homonymous visual field defects (HVFD) are common after postchiasmatic acquired brain injury and may have a significant impact on independent living and participation in society. Vision-related difficulties experienced in daily life are usually assessed using questionnaires. The current study 1) links the content of 3 of these questionnaires to the International Classification of Functioning, Disability and Health (ICF) and 2) provides analyses of vision-related difficulties reported by patients with HVFD and minimal comorbidities. METHODS: Fifty-four patients with homonymous hemianopia or quadrantanopia were asked about difficulties experienced in daily life because of their HVFD. This was performed during a structured interview including 3 standardized questionnaires: National Eye Institute Visual Functioning Questionnaire, Independent Mobility Questionnaire, and Cerebral Visual Disorders Questionnaire. The reported difficulties were linked to the ICF according to the ICF linking rules. Main outcome measures were presence or absence of experienced difficulties. RESULTS: The ICF linking procedure resulted in a classification table that can be used in future studies of vision-related difficulties. Besides well-known difficulties related to reading, orientation, and mobility, a high proportion of patients with HVFD reported problems that previously have not been documented in the literature, such as impaired light sensitivity, color vision, and perception of depth. CONCLUSIONS: A systematic inventory of difficulties experienced in daily life by patients with HVFD was performed using the ICF. These findings have implications for future study, assessment and rehabilitation of patients with HVFD. PMID- 25815857 TI - Dermatomyositis-Related Nonischemic Central Retinal Vein Occlusion. AB - A 25-year-old woman with dermatomyositis suffered a right central retinal vein occlusion (CRVO) with visual acuity of 20/40. Examination of the right eye showed vitreous cells, suggesting inflammation of the central retinal vein leading to a CRVO as the presumed mechanism. She was admitted to hospital, and extensive evaluation was negative. She was maintained on corticosteroids to manage her dermatomyositis. One month later, she had macular edema and elevated intraocular pressure. Both resolved with dorzolamide, timolol, and intravitreal bevacizumab, and vision returned to 20/20 in the right eye. PMID- 25815854 TI - Imaging tumor metabolism using positron emission tomography. AB - Positron emission tomography (PET) is an extraordinarily sensitive clinical imaging modality for interrogating tumor metabolism. Radiolabeled PET substrates can be traced at subphysiological concentrations, allowing noninvasive imaging of metabolism and intratumoral heterogeneity in systems ranging from advanced cancer models to patients in the clinic. There are a wide range of novel and more established PET radiotracers, which can be used to investigate various aspects of the tumor, including carbohydrate, amino acid, and fatty acid metabolism. In this review, we briefly discuss the more established metabolic tracers and describe recent work on the development of new tracers. Some of the unanswered questions in tumor metabolism are considered alongside new technical developments, such as combined PET/magnetic resonance imaging scanners, which could provide new imaging solutions to some of the outstanding diagnostic challenges facing modern cancer medicine. PMID- 25815855 TI - Attenuated age-impact on systemic inflammatory markers in the presence of a metabolic burden. AB - BACKGROUND: The overall burden of chronic disease, inflammation and cardiovascular risk increases with age. Whether the relationship between age and inflammation is impacted by presence of an adverse metabolic burden is not known. METHODS: We determined inflammatory markers in humans (336 Caucasians and 224 African Americans) and in mice, representing a spectrum of age, weight and metabolic burden. RESULTS: In humans, levels of inflammatory markers increased significantly with age in subjects without the metabolic syndrome, (P=0.009 and P=0.037 for C-reactive protein, P<0.001 and P=0.001 for fibrinogen, P<0.001 and P=0.005 for serum amyloid-A, for Caucasians and African Americans, respectively). In contrast, trend patterns of inflammatory markers did not change significantly with age in subjects with metabolic syndrome in either ethnic group, except for fibrinogen in Caucasians. A composite z-score for systemic inflammation increased significantly with age in subjects without metabolic syndrome (P=0.004 and P<0.006 for Caucasians and African Americans, respectively) but not in subjects with metabolic syndrome (P=0.009 for difference in age trend between metabolic syndrome and non-metabolic syndrome). In contrast, no similar age trend was found in vascular inflammation. The findings in humans were paralleled by results in mice as serum amyloid-A levels increased across age (range 2-15 months, P<0.01) and were higher in ob/ob mice compared to control mice (P<0.001). CONCLUSIONS: Presence of a metabolic challenge in mice and humans influences levels of inflammatory markers over a wide age range. Our results underscore that already at a young age, presence of a metabolic burden enhances inflammation to a level that appears to be similar to that of decades older people without metabolic syndrome. PMID- 25815858 TI - Nerve Fiber Layer Infarcts in Thiamine Deficiency. AB - Thiamine deficiency classically manifests as the triad of Wernicke encephalopathy: acute confusional state, ataxic gait, and ocular motor dysfunction. However, most patients do no present with this classic triad. Optic neuropathy in thiamine deficiency is a rare manifestation and is usually associated with fundus appearances of optic disc swelling or optic disc pallor. We present 2 unique cases of thiamine deficiency where the fundus demonstrated peripapillary retinal nerve fiber layer thickening without florid disc swelling or pallor. PMID- 25815859 TI - Can AST/ALT ratio indicate recovery after acute paracetamol poisoning? The authors reply. PMID- 25815861 TI - Animal models for some important RNA viruses of public health concern in SEARO countries: viral hemorrhagic fever. AB - Viral hemorrhagic fevers (VHFs) are major public health problems in the South East Asia Regional (SEAR) countries. VHFs are a group of illnesses; that are caused by four families of viruses, viz. Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. All VHFs have common features: they affect several organs and damage the blood vessels. These symptoms are often accompanied by hemorrhage. To understand pathogenesis, genetic and environmental influence that increase the risk of VHFs, efficacy and safety studies on candidate vaccines and testing of various therapeutic agents, appropriate animal models are essential tools in public and animals health. In the current review, the suitable animal models for Flavivirus [Dengue hemorhagic fever (DHF), Kyasanur forest disease (KFD)]; Bunyavirus [Crimean-Congo hemorrhagic fever (CCHF), Hantavirus fever (HF)]; and Paramyxovirus [Nipah virus fever (NiV)] have been reviewed with specific emphasis on emerging and reemerging viruses in SEAR countries. PMID- 25815862 TI - Computational approach for elucidating interactions of cross-species miRNAs and their targets in Flaviviruses. AB - BACKGROUND & OBJECTIVES: Combating viral diseases has been a challenging task since time immemorial. Available molecular approaches are limited and not much effective for this daunting task. MicroRNA based therapies have shown promise in recent times. MicroRNAs are tiny non-coding RNAs that regulate translational repression of target mRNA in highly specific manner. METHODS: In this study, we have determined the target regions for human and viral microRNAs in the conserved genomic regions of selected viruses of Flaviviridae family using miRanda and performed a comparative target selectivity analysis among them. RESULTS: Specific target regions were determined and they were compared extensively among themselves by exploring their position to determine the vicinity. Based on the multiplicity and cooperativity analysis, interaction maps were developed manually to represent the interactions between top-ranking miRNAs and genomes of the viruses considered in this study. Self-organizing map (SOM) was used to cluster the best-ranked microRNAs based on the vital physicochemical properties. INTERPRETATION & CONCLUSION: This study will provide deep insight into the interrelation of the viral and human microRNAs interactions with the selected Flaviviridae genomes and will help to identify cross-species microRNA targets on the viral genome. PMID- 25815860 TI - Urinary Bisphenol A Levels during Pregnancy and Risk of Preterm Birth. AB - BACKGROUND: Preterm birth (PTB), a leading cause of infant mortality and morbidity, has a complex etiology with a multitude of interacting causes and risk factors. The role of environmental contaminants, particularly bisphenol A (BPA), is understudied with regard to PTB. OBJECTIVES: In the present study we examined the relationship between longitudinally measured BPA exposure during gestation and PTB. METHODS: A nested case-control study was performed from women enrolled in a prospective birth cohort study at Brigham and Women's Hospital in Boston, Massachusetts, during 2006-2008. Urine samples were analyzed for BPA concentrations at a minimum of three time points during pregnancy on 130 cases of PTB and 352 randomly assigned controls. Clinical classifications of PTB were defined as "spontaneous," which was preceded by spontaneous preterm labor or preterm premature rupture of membranes, or "placental," which was preceded by preeclampsia or intrauterine growth restriction. RESULTS: Geometric mean concentrations of BPA did not differ significantly between cases and controls. In adjusted models, urinary BPA averaged across pregnancy was not significantly associated with PTB. When examining clinical classifications of PTB, urinary BPA late in pregnancy was significantly associated with increased odds of delivering a spontaneous PTB. After stratification on infant's sex, averaged BPA exposure during pregnancy was associated with significantly increased odds of being delivered preterm among females, but not males. CONCLUSIONS: These results provide little evidence of a relationship between BPA and prematurity, though further research may be warranted given the generalizability of participant recruitment from a tertiary teaching hospital, limited sample size, and significant associations among females and within the clinical subcategories of PTB. CITATION: Cantonwine DE, Ferguson KK, Mukherjee B, McElrath TF, Meeker JD. 2015. Urinary bisphenol A levels during pregnancy and risk of preterm birth. Environ Health Perspect 123:895-901; http://dx.doi.org/10.1289/ehp.1408126. PMID- 25815863 TI - Genetic variability of Trypanosoma cruzi TcI isolates from rural and urban areas of Venezuela. AB - BACKGROUND & OBJECTIVES: Several studies have demonstrated genetic heterogeneity in populations of Trypanosoma cruzi that allowed the identification of six different discrete typing units (DTU) classified as TcI, TcII, TcIII, TcIV, TcV and TcVI. Furthermore, some characterization studies have described genetic variability within TcI isolates from endemic regions. The objective of the present study was to analyze Venezuelan T. cruzi isolates, obtained from triatomine-vectors, mammal-hosts including infected humans, detected in both rural and urban areas from diverse geographic origins. METHODS: Molecular characterization of 44 Venezuelan T. cruzi isolates, obtained from triatomine vectors, mammalian hosts and human patients from both rural and urban areas of different geographic origins, were carried out. Samples were analyzed by PCR amplification of the intergenic region of the mini-exon gene, 24Salpha rDNA and 18S rDNA, followed by sequencing of the amplification products. RESULTS: The TcI amplification pattern was found in 42 out of 44 (95.5%) isolates; a TcIII strain and one possible TcIV were also found. The sequence analysis of the TcI Venezuelan isolates showed genetic variability among them. Urban isolates formed a homogeneous group, with differences in their sequences, when compared to rural isolates. INTERPRETATION & CONCLUSION: The results showed genetic heterogeneity in Venezuelan TcI strains, probably in response to different environmental conditions. PMID- 25815864 TI - Effect of tumour necrosis factor-alpha and interleukin-6 promoter polymorphisms on course of Crimean-Congo hemorrhagic fever in Turkish patients. AB - OBJECTIVE: In this case-control study, we investigated whether IL-6 (-174G/C) and TNF-alpha (-308G/A) gene polymorphisms affect the clinical course and outcome of CCHF. METHODS: Total 150 patients with CCHF and 170 controls were examined in this study. Genotyping of these polymorphisms were performed by PCR-RFLP methods. RESULTS: We found no statistically significant differences in genotype and allele frequencies of these polymorphisms between patients and controls [(chi2 = 1.31, p = 0.51 for TNF-alpha) and (chi2 = 2.61, p = 0.27 for IL-6)]. Either TNF-alpha AA or IL-6 CC genotypes in dead cases were not observed in this study. Frequency of heterozygous genotypes in both IL-6 (GC) and TNF-alpha (GA) was higher in dead patients than living patients. However, the difference was not statistically significant. A significant difference was found in AST levels and INR when compared to patients with CCHF who died and who survived [OR = 13.9 (95% CI = 1.79-107) for INR, p = 0.01] and [OR = 23.3 (95% CI = 3.62-149) for AST, p = 0.001], respectively. CONCLUSION: We did not find a significant association of IL 6 -174G/C and TNF-alpha -308G/A polymorphisms on the prognosis of CCHF and mortality in this study. We suggest that AST and INR may be important biomarkers for determining the risk of severity and death as a result of infection with Crimean-Congo hemorrhagic fever virus (CCHFV). PMID- 25815865 TI - Vitamin D status in children with Crimean-Congo hemorrhagic fever. AB - BACKGROUND & OBJECTIVES: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease, causing severe viral hemorrhagic fever outbreaks. This study aimed at determining the serum vitamin D levels and investigated the association between Crimean-Congo hemorrhagic fever (CCHF) and serum vitamin D levels in children with CCHF. METHODS: A total of 45 children aged between 5 and 15 yr, viz. 15 healthy control (HC) and 30 pediatric patients diagnosed with CCHF with real-time polymerase chain reaction (PCR) (patient group) were selected for the study. RESULTS: Analysis of the blood serum samples taken from the said individuals revealed that vitamin D, parathyroid hormone and calcium levels of the patients and the control groups were statistically different. INTERPRETATION & CONCLUSION: It was found that the serum vitamin D levels of the pediatric patients with CCHF were lower when compared to those of the controls, and that a low vitamin D level could negatively affect the reaction of the body to infections in children having CCHF. PMID- 25815866 TI - Morphological and molecular characterization of the ecological, biological and behavioural variants of the JE vector Culex tritaeniorhynchus: an assessment of its taxonomic status. AB - BACKGROUND & OBJECTIVES: Culex tritaeniorhynchus (Diptera: Culicidae), an important vector of Japanese encephalitis belongs to the Culex vishnui subgroup which includes two other vector species namely, Cx. Vishnui and Cx. pseudovishnui. Many varieties and types of Cx. tritaeniorhynchus have been reported, besides populations that exhibit behavioural and biological differences. This study was undertaken to find out whether Cx. tritaeniorhynchus populations exhibiting behavioural and biological variations, and those from different geographical areas, are comprised of more than one taxon or belong to a single taxon. METHODS: Morphological characterization was done by examining 153 morphological and morphometric characters in the larval (75), pupal (60) and adult stages (18) of five geographical populations of Cx. tritaeniorhynchus. Molecular characterization was done by PCR amplification of mitochondrial cytochrome c oxidase (COI) gene sequences (DNA barcodes) and another hypervariable genetic marker, the ribosomal DNA (16S). One-way ANOVA, principal component analysis (PCA) and discriminant factor analysis (DFA) were done for statistical analyses using the statistical package SPSS IBM version 19.0. RESULTS: Morphological characterization showed that no intraspecific differentiation can be made among the five geographical populations of Cx. tritaeniorhynchus. Molecular characterization done by DNA barcoding also showed that the COI sequences of all the five populations of Cx. tritaeniorhynchus grouped into a single taxonomic clade plus the genetic differentiation among these was non-significant and the overall gene flow among the populations was very high. Analysis of the ribosomal DNA also confirmed that the Cx. tritaeniorhynchus populations belonged to a single taxon. INTERPRETATION & CONCLUSION: Culex tritaeniorhynchus is a taxon that does not involve cryptic species. PMID- 25815867 TI - Isolation and characterization of Vagococcus sp from midgut of Culex quinquefasciatus (Say) mosquito. AB - BACKGROUND & OBJECTIVES: Mosquito gut is a rich source of microorganisms. These microorganisms exhibit close association and contribute various physiological processes taking place in mosquito gut. The present study is aimed to characterize two bacterial isolates M19 and GB11 recovered from the gut of Culex quinquefasciatus mosquito collected from Bhuj and Jamnagar districts of Gujarat, India. METHODS: Both the strains were characterized using polyphasic approach including, phenotypic characterization, whole cell protein profiling and sequencing of 16S rRNA gene and groESL region. RESULTS: Sequences of 16S rRNA gene of M19 and GB11 were 99% similar to Vagococcus carniphilus and Vagococcus fluvialis. But phenotypic profile, whole cell protein profile and sequence of groESL region of both isolates were found to be similar to V. fluvialis. CONCLUSION: Based on phenotypic, genotypic and protein profiling, both the strains were identified as V. fluvialis. So far this species was known from domestic animals and human sources only. This is the first report of V. fluvialis inhabiting midgut of Cx. quinquefasciatus mosquito collected from Arabian sea coastal of India. PMID- 25815869 TI - Biodiversity of culicid mosquitoes in rural Neka township of Mazandaran province, northern Iran. AB - BACKGROUND & OBJECTIVES: This paper presents the results of a study on ecological parameters including diversity indices applied on populations of Culicidae mosquitoes (Diptera: Culicidae) from three rural areas (Darvishan, Chalmardi and Khairabad) of Neka township in Mazandaran province, northern Iran. METHODS: Adult and larval stages of mosquitoes were systematically sampled to obtain data required for measuring diversity of mosquitoes in these areas. Alfa and beta indices were analyzed to compare mosquito diversity. A total of 5270 specimens belonging to four genera and 14 different species were collected and identified. RESULTS: Evaluation of dominance structure of species showed that culicid mosquitoes of Neka rangelands include one eudominant species, two dominant species, two subdominant species, two rare species and eight subrare species when Heydemann classification was used. INTERPRETATION & CONCLUSION: Data analysis revealed a higher diversity of mosquitoes in Khairabad with a low degree of interspecific dominance, while Darvishan and Chalmardi recorded the lowest observed diversity and a high degree of interspecific dominance. The cluster analysis based on Jaccard's index indicated the relationship between the categories and indicates that Darvishan and Khairabad are the closest categories in their specific composition. PMID- 25815868 TI - Cost-effective medium for the production of mosquito pupicidal lipopeptide from Bacillus subtilis subsp. subtilis (VCRC B471). AB - BACKGROUND & OBJECTIVES: A cyclic lipopeptide (CLP), surfactin produced by a strain of Bacillus subtilis subsp. subtilis (VCRC B471) was found to exhibit mosquitocidal activity. The present study was carried out to enhance the surfactin level using low cost material in the production medium. METHODS: Two carbon sources, glucose and common sugar, and two nitrogen sources, ammonium nitrate and soya were used in the study. Different concentrations of 'C' and 'N' sources were used in the production medium to enhance the production of surfactin. RESULTS: A new medium (SS7) containing 2% sugar, 6% soya and 0.5% common salt with micronutrients was designed which was found to enhance the production of surfactin. The crude mosquitocidal metabolite (CMM) produced in this medium was 3 g/l which was two times higher than that obtained using synthetic medium NYSM. The LC50 dosage of the CMM to the pupal stages of An. stephensi (2.3 MUg/ml) was comparable to that obtained with CMM from the conventional medium. INTERPRETATION & CONCLUSION: The newly designed cost effective medium designated as sugar soya medium (SSM) enhanced the production of surfactin and the cost of production was estimated as [symbol: see text] 6 per litre, which is six times lesser than that of the conventional medium. Replacement of sodium chloride with cooking salt further reduced the cost of the medium. PMID- 25815870 TI - A bibliometric profile of lymphatic filariasis research in India. AB - BACKGROUND & OBJECTIVES: Tropical and vector borne diseases have always been a challenge for the medical science and society and exerted high impact on society in terms of financial, economical and psychological relevance. Lymphatic filariasis (LF) is one of the tropical diseases which is prevalent in under developing and developed countries. The objective of this study is to analyze the literature published in the area of filariasis research. The focus is to see the Indian contribution and its impact in terms of global publication and share, citation analysis and its impact, productive Indian institutions engaged in filariasis research and their impact, international collaborative research, productive journals, and highly cited papers published by Indian authors. METHODS: The data for this study was obtained from Scopus, a multidisciplinary database, for the period of forty years (1973-2012) using key words lymphatic filariasis, elephantiasis, Wuchereria bancrofti, Brugia malayi and Brugia timori available in the title, abstract and key words fields. The citation count has been taken as the number of citations scored by the papers since their publication. The international collaboration by Indian authors in filariasis research has been manually analyzed through author's affiliation field. RESULTS: The search strategy using key words yielded 13,598 articles on different aspects of filariasis published during the forty years period. Indian authors have published 1970 articles which is 14.49% of global share, making it second highest productive country on filariasis research. United States holds first rank with 2956 articles (21.74% share). In terms of citation count, Indian research have quite good impact and has been ranked third; and in terms of average citation per paper it is far behind, while Ghana and Nigeria holds top two ranks. INTERPRETATION & CONCLUSION: There have been continued efforts in providing better facilities for research, though Indian filariasis research has to go long way in order to remove the incidence of the disease from Indian population and the results presented through this study shall be helpful for stakeholders in framing policies in this direction. PMID- 25815871 TI - Effect of salinity on the behavior of Aedes aegypti populations from the coast and plateau of southeastern Brazil. AB - BACKGROUND & OBJECTIVES: Mosquito larvae can develop in fresh, salty and brackish water. The larvae of Aedes aegypti develop in fresh water. However, in laboratory studies, tolerance of this species for oviposition and hatching in brackish water was observed. Immature forms of Ae. aegypti have also been found developing in brackish water in coastal areas. The purpose of the study was to compare the effects of salt on the biological cycle of Ae. aegypti populations from coastal and plateau areas of southeastern Brazil. METHODS: Aedes aegypti were collected from plateau (Taubate) and coastal (Sao Sebastiao) municipalities to establish colonies. Specimens of the F1 generation were exposed to five salt concentrations (3.5, 7, 10.5, 14 and 17.5%) to assess the oviposition and cycle development from egg hatching to adult eclosion. Deionized water was used in the control groups. RESULTS: Both Taubate and Sao Sebastiao populations oviposited in all salt concentrations tested; however, development occurred in all except in the 17.5% concentration. Significant differences in development and adult size were observed at intermediate concentrations (Sao Sebastiao from 10.5% and Taubate from 7%, for both variables) between the two populations. INTERPRETATION & CONCLUSION: The results of this study showed different response patterns to salinity between the two populations, suggesting better adaptive adjustment of the coastal population to the metabolic constraints exerted by salt. The implications of this adaptation are discussed, and additional studies are suggested to evaluate the mechanisms that determinate the adaptive processes of Ae. aegypti in brackish water and the implications to its vectorial capacity. PMID- 25815872 TI - Screening of some weeds for larvicidal activity against Aedes albopictus, a vector of dengue and chikungunya. AB - BACKGROUND & OBJECTIVES: Screening of crude extracts of plants facilitates the establishment of highly effective extract for mosquito control. This practice should be preferred before in depth study of plant extracts rather than spending much efforts and energy in detailed examinations for practically ineffective extracts. In this study, leaf powders of four weed plants were used for the quick screening of effective plant extract as larvicide against III instar larvae of Aedes albopictus Skuse. At the same time, effect of different seasons on the larvicidal efficacy of plants and selection of proper solvents for further investigation were also studied. METHODS: Leaves of Vernonia cinerea, Prosopis juliflora, Hyptis suaveolens and Malvastrum coromandelianum plants were collected in summer, winter and rainy seasons from Madhya Pradesh region (India). To assess the larvicidal efficacy the suspensions of leaf powders in different solvents (isopropanol, methanol, acetone, dimethylsulfoxide and water) were used for larvicidal bioassay. The mortality counts were made after 24 h and the LC50 and LC90 values were calculated. RESULTS: Results showed that leaf powder of V. cinerea in acetone collected during summer showed highest efficacy with LC50 value of 0.22 g/l and LC90 of 0.96 g/l followed by methanolic solution of P. juliflora with LC50 of 0.44 g/l and LC90 value as 1.85 g/l. Amongst all solvents, leaf powder in acetone; while among seasons, summer collected plant materials were found to be more effective larvicides as compared to others. INTERPRETATION & CONCLUSION: Summer and winter collected leaves of V. cinerea and P. juliflora dissolved in the solvents of medium polarity range showed significant larval toxicity and thus suggests a detailed study on these plants as potential larval control agents. PMID- 25815873 TI - Status of DDT and pyrethroid resistance in Indian Aedes albopictus and absence of knockdown resistance (kdr) mutation. AB - BACKGROUND & OBJECTIVES: Aedes albopictus is one of the vectors for dengue and chikungunya and emergence of pyrethroid resistance in this species could be of a major concern in controlling the vector. This study reports insecticide susceptibility status of Ae. albopictus to DDT and pyrethroids in some Indian populations and status of presence of knockdown resistance (kdr) mutations. METHODS: Three to four day old adult female Ae. albopictus collected from Delhi, Gurgaon (Haryana), Hardwar (Uttarakhand), Guwahati (Assam) and Kottayam (Kerala) were bio-assayed with DDT (4%), permethrin (0.75%) and deltamethrin (0.05%) impregnated papers using WHO standard susceptibility test kit. Mosquitoes were PCRgenotyped for F1534C kdr-mutation in the voltage-gated sodium channel (VGSC) gene. DDT and pyrethroid resistant individuals were sequenced for partial domain II, III and IV of VGSC targeting residues S989, I1011, V1016, F1534 and D1794 where kdr mutations are reported in Ae. aegypti. RESULTS: Adult bioassays revealed varying degree of resistance against DDT among five populations of Ae. albopictus with corrected mortalities ranging between 61 and 92%. Kerala and Delhi populations showed incipient resistance against permethrin and deltamethrin respectively. All other populations were susceptible for both the synthetic pyrethroids. None of the kdr mutations was detected in any of DDT, deltamethrin and permethrin resistant individuals. INTERPRETATION & CONCLUSION: Ae. albopictus has developed resistance against DDT and there is emergence of incipient resistance against pyrethroids in some populations. So far, there is no evidence of presence of knockdown resistance (kdr) mutation in Ae. albopictus. PMID- 25815874 TI - Chlorfenapyr: irritant effect compared to other insecticides and its intrinsic toxicity in multiple-insecticide-susceptible and -resistant Anopheles stephensi (Diptera: Culicidae). AB - BACKGROUND & OBJECTIVES: For effective management of vector resistance there is a need for new insecticide molecules with novel modes of action. For desired toxic effect of an insecticide, apart from other behavioural aspects, toxicity and chemical nature of the molecule are important that may cause irritability in the mosquito to the insecticide affecting the uptake. In this study, a pyrrole class insecticide, chlorfenapyr (a late acting insecticide) was tested for its irritability against multiple-insecticide-susceptible and -resistant strains of Anopheles stephensi Liston 1901 (Diptera: Culicidae). METHODS: Studies were conducted to assess the irritability due to chlorfenapyr, DDT, malathion, deltamethrin and permethrin and intrinsic toxicity of chlorfenapyr in multiple insecticide-susceptible and -resistant laboratory strains of An. stephensi following standard WHO methods. RESULTS: Chlorfenapyr molecule has shown least irritant effect against susceptible and resistant strains among all the insecticides tested allowing more landing time to the vector species on the impregnated surfaces to pick-up lethal dose. CONCLUSION: Chlorfenapyr could be an ideal insecticide for management of multiple-insecticide-resistance including pyrethroids. PMID- 25815875 TI - Spatial distribution of Aedes mosquitoes with special attention to bionomics of Aedes albopictus subpopulations collected from various parts of Odisha. PMID- 25815876 TI - Blood feeding behaviour of mosquitoes in Japanese encephalitis endemic and non endemic areas. PMID- 25815877 TI - Rapid diagnosis of dengue infection in acute phase. PMID- 25815878 TI - Antineoplastic effect of a novel chemopreventive agent, neokestose, on the Caco-2 cell line via inhibition of expression of nuclear factor-kappaB and cyclooxygenase-2. AB - Neokestose is a 6G-fructooligosaccharide (FOS) and an important prebiotic. When FOS are ingested by patients with colorectal cancer, they may come into contact with cancer cells prior to being fermented by bifidobacteria in the colon. In the present study, the effects of neokestose on cell proliferation, cell cycle and apoptosis of the colorectal cancer cell line Caco-2 were investigated to evaluate its anti-cancer effect. An MTT assay showed that neokestose-treated Caco-2 cells exhibited a significant and dose-dependent loss of viability. Flow cytometric analysis indicated that the sub-G1 population of Caco-2 cells was significantly increased following treatment with neokestose, and the percentage of Caco-2 cells in the stage of late apoptosis was also significantly increased in a dose dependent manner. Western blot analysis showed that the overexpression of nuclear factor-kappaB, a central molecule responsible for the transition from inflammation to cancer, and cyclooxygenase-2, an important enzyme in colorectal tumorigenesis, in colorectal carcinoma cells was inhibited by neokestose. Accordingly, the present study provided in vitro evidence that neokestose may be used as a dietary chemopreventive agent, whose application is more rational than that of COX-2 inhibitors or aspirin for preventing colorectal cancer. PMID- 25815879 TI - AIB-OR: improving onion routing circuit construction using anonymous identity based cryptosystems. AB - The rapid growth of Internet applications has made communication anonymity an increasingly important or even indispensable security requirement. Onion routing has been employed as an infrastructure for anonymous communication over a public network, which provides anonymous connections that are strongly resistant to both eavesdropping and traffic analysis. However, existing onion routing protocols usually exhibit poor performance due to repeated encryption operations. In this paper, we first present an improved anonymous multi-receiver identity-based encryption (AMRIBE) scheme, and an improved identity-based one-way anonymous key agreement (IBOWAKE) protocol. We then propose an efficient onion routing protocol named AIB-OR that provides provable security and strong anonymity. Our main approach is to use our improved AMRIBE scheme and improved IBOWAKE protocol in onion routing circuit construction. Compared with other onion routing protocols, AIB-OR provides high efficiency, scalability, strong anonymity and fault tolerance. Performance measurements from a prototype implementation show that our proposed AIB-OR can achieve high bandwidths and low latencies when deployed over the Internet. PMID- 25815880 TI - Upregulated microRNA-214 enhances cardiac injury by targeting ITCH during coxsackievirus infection. AB - Viral myocarditis (VM), a severe clinical condition characterized by cardiac inflammation, is most frequently induced as a result of coxsackievirus infection. Evidence suggests that microRNAs may have significant roles in the progression of cardiac injury during coxsackievirus infection. Concurrently, microRNA (miR)-214 was found to be upregulated in the plasma and myocardial cells during this process. In the present study, eight candidate miRNAs, the functions of which are associated with myocarditis, were selected and their expression levels were evaluated by reverse transcription-quantitative polymerase chain reaction. miR 146b and miR-214 were found to have significantly upregulated expression levels in the heart tissues of patients with VM compared with those of the control subjects. Predictions via the use of online bioinformatics tools and confirmed by dual-luciferase assay and western blot analysis, revealed that ITCH, an NF-kappaB signaling suppressor, was a target gene of miR-214. To investigate the biological function of miR-214, tumor necrosis factor-alpha and interleukin-6 expression levels were evaluated in HeLa cell culture supernatant. The results revealed that miR-214 overexpression enhanced the expression of the two cytokines. In addition, the function of miR-214 was partially rescued by ITCH overexpression. Subsequently, concurrent results were obtained following experiments in murine cardiac myocytes. In conclusion, the results of the present study demonstrated that miR-214 contributed to the adverse inflammatory response to viral infection of the heart during coxsackievirus infection and is therefore a potential therapeutic target for the treatment of viral myocarditis. PMID- 25815881 TI - Ego-resiliency reloaded: a three-component model of general resiliency. AB - Ego-resiliency (ER) is a capacity that enables individuals to adapt to constantly changing environmental demands. The goal of our research was to identify components of Ego-resiliency, and to test the reliability and the structural and convergent validity of the refined version of the ER11 Ego-resiliency scale. In Study 1 we used a factor analytical approach to assess structural validity and to identify factors of Ego-resiliency. Comparing alternative factor-structures, a hierarchical model was chosen including three factors: Active Engagement with the World (AEW), Repertoire of Problem Solving Strategies (RPSS), and Integrated Performance under Stress (IPS). In Study 2, the convergent and divergent validity of the ER11 scale and its factors and their relationship with resilience were tested. The results suggested that resiliency is a double-faced construct, with one function to keep the personality system stable and intact, and the other function to adjust the personality system in an adaptive way to the dynamically changing environment. The stability function is represented by the RPSS and IPS components of ER. Their relationship pattern is similar to other constructs of resilience, e.g. the Revised Connor-Davidson Resilience Scale (R-CD-RISC). The flexibility function is represented by the unit of RPSS and AEW components. In Study 3 we tested ER11 on a Hungarian online representative sample and integrated the results in a model of general resiliency. This framework allows us to grasp both the stability-focused and the plasticity-focused nature of resiliency. PMID- 25815882 TI - Diagnose human colonic tissues by terahertz near-field imaging. AB - Based on a terahertz (THz) pipe-based near-field imaging system, we demonstrate the capability of THz imaging to diagnose freshly surgically excised human colonic tissues. Through THz near-field scanning the absorbance of the colonic tissues, the acquired images can clearly distinguish cancerous tissues from healthy tissues fast and automatically without pathological hematoxylin and eosin stain diagnosis. A statistical study on 58 specimens (20 healthy tissues and 38 tissues with tumor) from 31 patients (mean age: 59 years; range: 46 to 79 years) shows that the corresponding diagnostic sensitivity and specificity on colonic tissues are both 100%. Due to its capability to perform quantitative analysis, our study indicates the potential of the THz pipe-based near-field imaging for future automation on human tumor pathological examinations. PMID- 25815883 TI - H-ferritin-regulated microRNAs modulate gene expression in K562 cells. AB - In a previous study, we showed that the silencing of the heavy subunit (FHC) offerritin, the central iron storage molecule in the cell, is accompanied by a modification in global gene expression. In this work, we explored whether different FHC amounts might modulate miRNA expression levels in K562 cells and studied the impact of miRNAs in gene expression profile modifications. To this aim, we performed a miRNA-mRNA integrative analysis in K562 silenced for FHC (K562shFHC) comparing it with K562 transduced with scrambled RNA (K562shRNA). Four miRNAs, namely hsa-let-7g, hsa-let-7f, hsa-let-7i and hsa-miR-125b, were significantly up-regulated in silenced cells. The remarkable down-regulation of these miRNAs, following FHC expression rescue, supports a specific relation between FHC silencing and miRNA-modulation. The integration of target predictions with miRNA and gene expression profiles led to the identification of a regulatory network which includes the miRNAs up-regulated by FHC silencing, as well as91 down-regulated putative target genes. These genes were further classified in 9 networks; the highest scoring network, "Cell Death and Survival, Hematological System Development and Function, Hematopoiesis", is composed by 18 focus molecules including RAF1 and ERK1/2. We confirmed that, following FHC silencing, ERK1/2 phosphorylation is severely impaired and that RAF1 mRNA is significantly down-regulated. Taken all together, our data indicate that, in our experimental model, FHC silencing may affect RAF1/pERK1/2 levels through the modulation of a specific set of miRNAs and add new insights in to the relationship among iron homeostasis and miRNAs. PMID- 25815884 TI - Lung fibroblasts share mesenchymal stem cell features which are altered in chronic obstructive pulmonary disease via the overactivation of the Hedgehog signaling pathway. AB - BACKGROUND: Alteration of functional regenerative properties of parenchymal lung fibroblasts is widely proposed as a pathogenic mechanism for chronic obstructive pulmonary disease (COPD). However, what these functions are and how they are impaired in COPD remain poorly understood. Apart from the role of fibroblasts in producing extracellular matrix, recent studies in organs different from the lung suggest that such cells might contribute to repair processes by acting like mesenchymal stem cells. In addition, several reports sustain that the Hedgehog pathway is altered in COPD patients thus aggravating the disease. Nevertheless, whether this pathway is dysregulated in COPD fibroblasts remains unknown. OBJECTIVES AND METHODS: We investigated the stem cell features and the expression of Hedgehog components in human lung fibroblasts isolated from histologically normal parenchymal tissue from 25 patients--8 non-smokers/non-COPD, 8 smokers-non COPD and 9 smokers with COPD--who were undergoing surgery for lung tumor resection. RESULTS: We found that lung fibroblasts resemble mesenchymal stem cells in terms of cell surface marker expression, differentiation ability and immunosuppressive potential and that these properties were altered in lung fibroblasts from smokers and even more in COPD patients. Furthermore, we showed that some of these phenotypic changes can be explained by an over activation of the Hedgehog signaling in smoker and COPD fibroblasts. CONCLUSIONS: Our study reveals that lung fibroblasts possess mesenchymal stem cell-features which are impaired in COPD via the contribution of an abnormal Hedgehog signaling. These processes should constitute a novel pathomechanism accounting for disease occurrence and progression. PMID- 25815885 TI - Ulinastatin reduces the resistance of liver cancer cells to epirubicin by inhibiting autophagy. AB - During chemotherapy, drug resistance caused by autophagy remains a major challenge to successful treatment of cancer patients. The purpose of this study is to show that ulinastatin (UTI), a trypsin inhibitor, could reduce the resistance of liver cancer cells to chemotherapeutic agent epirubicin (EPI). We achieved this conclusion by analyzing the effect of EPI alone or UTI plus EPI on SMMC-7721 and MHCC-LM3 liver cancer cells. We also generated an EPI-resistant liver cancer cell line (MHCC-LM3er cells), and found that UTI could sensitize the LM3er cells to EPI. Autophagy usually functions to protect cancer cells during chemotherapy. Our study showed that UTI inhibited the autophagy induced by EPI in liver cancer cells, which promoted apoptosis, and therefore, reduced the resistance of the cancer cells to EPI. Further studies showed that the UTI mediated inhibition on autophagy was achieved by inhibiting transcriptional factor nuclear factor-kappaB (NF-kappaB) signaling pathway. To verify our results in vivo, we injected MHCC-LM3 liver cancer cells or EPI-resistant LM3er cells into mice, and found that EPI could only effectively inhibit the growth of tumor in MHCC-LM3 cell-injected mice, but not in LM3er cell-injected mice. However, when UTI was also administered, the growth of tumor was inhibited in the MHCC LM3er cell-injected mice as well. Our results suggest that UTI may be used in combination with anti-cancer drugs, such as EPI, to improve the outcome of cancer therapy. PMID- 25815886 TI - Primary treatment response rather than front line stem cell transplantation is crucial for long term outcome of peripheral T-cell lymphomas. AB - Outcome of systemic peripheral T-cell lymphomas (PTCL) is unsatisfactory and no controlled clinical study guides the therapy. Phase II studies suggest to consolidate response achieved after front-line treatment with stem cell transplant (SCT). We retrospectively evaluate the impact of front-line SCT consolidation in a single Center cohort of 209 patients treated during the last two decades. Median age was 49 years (range 15-85) with a prevalence of male sex (61%), advanced stage (68%) while IPI was >2 in 44%. Primary treatment was MACOP B (39%) CHO(E)P (39%), intensive regimens (18%) or others (4%). Complete response to primary treatment (i.e. before SCT) was 60% (5% partial remission). Forty-four patients further proceeded to SCT while 92 did not receive consolidation. Outcome of primary responders was good, with a 3-year overall survival of 74% (82% in ALCL ALK+ and 69% for the other histologies). By multivariate analysis a better overall survival was significantly associated with IPI<2 (P=0.001), primary response (P=0.000), and ALCL ALK+ (P=0.012). The multivariate analysis performed on responders, showed that only IPI was predictive of a better survival while ALCL ALK+ and undergoing SCT were not. Response to primary treatment rather than post-remission programs is the crucial determinant of PTCL outcome. PMID- 25815887 TI - Comparison of diagnostic accuracy of microscopy and flow cytometry in evaluating N-methyl-D-aspartate receptor antibodies in serum using a live cell-based assay. AB - N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune neurological disease, diagnosed by a specific autoantibody against NMDAR. Antibody testing using commercially available cell-based assays (CBA) or immunohistochemistry on rat brain tissue has proven high specificity and sensitivity. Here we compare an immunofluorescence live CBA to a flow cytometry (FACS) based assay to detect NMDAR antibodies by their binding to the surface of HEK293A cells functionally expressing NMDAR. Both assays were first established using a discovery group of 76 individuals and then validated in a group of 32 patients in a blinded manner. In the CBA, 23 of 23 patients with NMDAR encephalitis were positive for NMDAR antibodies and 0 of 85 controls (32 healthy controls and 53 patients with other neurological diseases), resulting in a sensitivity and specificity of 100% (95% confidence intervals (CI) 85.1-100.0 and 95.7-100.0, respectively). The FACS based assay detected NMDAR antibodies in 20 of 23 patients and in 0 of 85 controls. Therefore, with an equally high specificity (95% CI 95.7-100.0) the sensitivity of the FACS based assay was 87% (95% CI 66.4-97.2). Comparing antibody titers from CBA with delta median fluorescence intensities from FACS showed a high concordance (kappa = 0.943, p<0.0001) and correlation (r = 0.697, p<0.0001). In conclusion, evaluation of the FACS based assay revealed a lower sensitivity and high inter-assay variation, making the CBA a more reliable detection method. PMID- 25815889 TI - Design, fabrication and metrological evaluation of wearable pressure sensors. AB - Pressure sensors are valuable transducers that are necessary in a huge number of medical application. However, the state of the art of compact and lightweight pressure sensors with the capability of measuring the contact pressure between two surfaces (contact pressure sensors) is very poor. In this work, several types of wearable contact pressure sensors are fabricated using different conductive textile materials and piezo-resistive films. The fabricated sensors differ in size, the textile conductor used and/or the number of layers of the sandwiched piezo-resistive film. The intention is to study, through the obtaining of their calibration curves, their metrological properties (repeatability, sensitivity and range) and determine which physical characteristics improve their ability for measuring contact pressures. It has been found that it is possible to obtain wearable contact pressure sensors through the proposed fabrication process with satisfactory repeatability, range and sensitivity; and that some of these properties can be improved by the physical characteristics of the sensors. PMID- 25815888 TI - Immune response in a wild bird is predicted by oxidative status, but does not cause oxidative stress. AB - The immune system provides vital protection against pathogens, but extensive evidence suggests that mounting immune responses can entail survival and fecundity costs. The physiological mechanisms that underpin these costs remain poorly understood, despite their potentially important role in shaping life histories. Recent studies involving laboratory models highlight the possibility that oxidative stress could mediate these costs, as immune-activation can increase the production of reactive oxygen species leading to oxidative stress. However, this hypothesis has rarely been tested in free-ranging wild populations, where natural oxidative statuses and compensatory strategies may moderate immune responses and their impacts on oxidative status. Furthermore, the possibility that individuals scale their immune responses according to their oxidative status, conceivably to mitigate such costs, remains virtually unexplored. Here, we experimentally investigate the effects of a phytohaemagglutinin (PHA) immune challenge on oxidative status in wild male and female white-browed sparrow weavers, Plocepasser mahali. We also establish whether baseline oxidative status prior to challenge predicts the scale of the immune responses. Contrary to previous work on captive animals, our findings suggest that PHA-induced immune activation does not elicit oxidative stress. Compared with controls (n = 25 birds), PHA-injected birds (n = 27 birds) showed no evidence of a differential change in markers of oxidative damage or enzymatic and non-enzymatic antioxidant protection 24 hours after challenge. We did, however, find that the activity of a key antioxidant enzyme (superoxide dismutase, SOD) prior to immune-activation predicted the scale of the resulting swelling: birds with stronger initial SOD activity subsequently produced smaller swellings. Our findings (i) suggest that wild birds can mount immune responses without suffering from systemic oxidative stress, and (ii) lend support to biomedical evidence that baseline oxidative status can impact the scale of immune responses; a possibility not yet recognised in ecological studies of immunity. PMID- 25815890 TI - The effect of cholesterol on the long-range network of interactions established among sea anemone Sticholysin II residues at the water-membrane interface. AB - Actinoporins are alpha-pore forming proteins with therapeutic potential, produced by sea anemones. Sticholysin II (StnII) from Stichodactyla helianthus is one of its most extensively characterized members. These proteins remain stably folded in water, but upon interaction with lipid bilayers, they oligomerize to form a pore. This event is triggered by the presence of sphingomyelin (SM), but cholesterol (Chol) facilitates pore formation. Membrane attachment and pore formation require changes involving long-distance rearrangements of residues located at the protein-membrane interface. The influence of Chol on membrane recognition, oligomerization, and/or pore formation is now studied using StnII variants, which are characterized in terms of their ability to interact with model membranes in the presence or absence of Chol. The results obtained frame Chol not only as an important partner for SM for functional membrane recognition but also as a molecule which significantly reduces the structural requirements for the mentioned conformational rearrangements to occur. However, given that the DOPC:SM:Chol vesicles employed display phase coexistence and have domain boundaries, the observed effects could be also due to the presence of these different phases on the membrane. In addition, it is also shown that the Arg51 guanidinium group is strictly required for membrane recognition, independently of the presence of Chol. PMID- 25815891 TI - Occurrence of lipophilic marine toxins in shellfish from Galicia (NW of Spain) and synergies among them. AB - Lipophilic marine toxins pose a serious threat for consumers and an enormous economic problem for shellfish producers. Synergistic interaction among toxins may play an important role in the toxicity of shellfish and consequently in human intoxications. In order to study the toxic profile of molluscs, sampled during toxic episodes occurring in different locations in Galicia in 2014, shellfish were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), the official method for the detection of lipophilic toxins. The performance of this procedure was demonstrated to be fit for purpose and was validated in house following European guidelines. The vast majority of toxins present in shellfish belonged to the okadaic acid (OA) group and some samples from a particular area contained yessotoxin (YTX). Since these toxins occur very often with other lipophilic toxins, we evaluated the potential interactions among them. A human neuroblastoma cell line was used to study the possible synergies of OA with other lipophilic toxins. Results show that combination of OA with dinophysistoxin 2 (DTX2) or YTX enhances the toxicity triggered by OA, decreasing cell viability and cell proliferation, depending on the toxin concentration and incubation time. The effects of other lipophilic toxins as 13-desmethyl Spirolide C were also evaluated in vitro. PMID- 25815892 TI - Cadmium-containing carbonic anhydrase CDCA1 in marine diatom Thalassiosira weissflogii. AB - The Carbon Concentration Mechanism (CCM) allows phytoplakton species to accumulate the dissolved inorganic carbon (DIC) necessary for an efficient photosynthesis even under carbon dioxide limitation. In this mechanism of primary importance for diatoms, a key role is played by carbonic anhydrase (CA) enzymes which catalyze the reversible hydration of CO2, thus taking part in the acquisition of inorganic carbon for photosynthesis. A novel CA, named CDCA1, has been recently discovered in the marine diatom Thalassiosira weissflogii. CDCA1 is a cambialistic enzyme since it naturally uses Cd2+ as catalytic metal ion, but if necessary can spontaneously exchange Cd2+ to Zn2+. Here, the biochemical and structural features of CDCA1 enzyme will be presented together with its putative biotechnological applications for the detection of metal ions in seawaters. PMID- 25815893 TI - Identification and bioactivity of compounds from the fungus Penicillium sp. CYE 87 isolated from a marine tunicate. AB - In the course of our continuous interest in identifying bioactive compounds from marine microbes, we have investigated a tunicate-derived fungus, Penicillium sp. CYE-87. A new compound with the 1,4-diazepane skeleton, terretrione D (2), together with the known compounds, methyl-2-([2-(1H-indol-3 yl)ethyl]carbamoyl)acetate (1), tryptamine (3), indole-3-carbaldehyde (4), 3,6 diisobutylpyrazin-2(1H)-one (5) and terretrione C (6), were isolated from Penicillium sp. CYE-87. The structures of the isolated compounds were established by spectral analysis, including 1D (1H, 13C) and 2D (COSY, multiplicity edited HSQC and HMBC) NMR and HRESIMS, as well as comparison of their NMR data with those in the literature. The compounds were evaluated for their antimigratory activity against the human breast cancer cell line (MDA-MB-231) and their antiproliferation activity against HeLa cells. Compounds 2 and 6 showed significant antimigratory activity against MDA-MB-231, as well as antifungal activity against C. albicans. PMID- 25815894 TI - Ameliorative effects of Gualou Guizhi decoction on inflammation in focal cerebral ischemic-reperfusion injury. AB - Gualou Guizhi decoction (GLGZD) is a well-established Traditional Chinese Medicinal formulation which has long been used to treat stroke in a clinical setting in China. The present study investigated the ameliorative effects of GLGZD on inflammation in focal cerebral ischemic-reperfusion injury. A rat model of middle cerebral artery occlusion (MCAO) was employed. Rats were administrated GLGZD (7.2 and 14.4 g/kg per day) or saline as control 2 h after reperfusion and daily over the following seven days. Neurological deficit score and screen test were evaluated at 1, 3, 5 and 7 days after MCAO. Brain infarct size and brain histological changes were observed via 2,3,5-triphenyltetrazolium chloride staining and regular hematoxylin & eosin staining. Furthermore, inflammation mediators and nuclear factor-kappaB (NF-kappaB) were investigated using ELISA and immunohistochemistry. GLGZD treatment significantly improved neurological function, ameliorated histological changes to the brain and decreased infarct size in focal cerebral ischemic-reperfusion injury. GLGZD was found to significantly reduce interleukin (IL)-1, tumor necrosis factor-alpha and NF kappaB levels, while increasing levels of IL-10. In conclusion, the present study suggested that GLGZD has a neuroprotective effect on focal cerebral ischemic reperfusion injury and this effect is likely to be associated with the anti inflammatory function of GLGZD. PMID- 25815895 TI - Explaining diversity in metagenomic datasets by phylogenetic-based feature weighting. AB - Metagenomics is revolutionizing our understanding of microbial communities, showing that their structure and composition have profound effects on the ecosystem and in a variety of health and disease conditions. Despite the flourishing of new analysis methods, current approaches based on statistical comparisons between high-level taxonomic classes often fail to identify the microbial taxa that are differentially distributed between sets of samples, since in many cases the taxonomic schema do not allow an adequate description of the structure of the microbiota. This constitutes a severe limitation to the use of metagenomic data in therapeutic and diagnostic applications. To provide a more robust statistical framework, we introduce a class of feature-weighting algorithms that discriminate the taxa responsible for the classification of metagenomic samples. The method unambiguously groups the relevant taxa into clades without relying on pre-defined taxonomic categories, thus including in the analysis also those sequences for which a taxonomic classification is difficult. The phylogenetic clades are weighted and ranked according to their abundance measuring their contribution to the differentiation of the classes of samples, and a criterion is provided to define a reduced set of most relevant clades. Applying the method to public datasets, we show that the data-driven definition of relevant phylogenetic clades accomplished by our ranking strategy identifies features in the samples that are lost if phylogenetic relationships are not considered, improving our ability to mine metagenomic datasets. Comparison with supervised classification methods currently used in metagenomic data analysis highlights the advantages of using phylogenetic information. PMID- 25815896 TI - DNA methyltransferase 3, a target of microRNA-29c, contributes to neuronal proliferation by regulating the expression of brain-derived neurotrophic factor. AB - Alzheimer's disease (AD), the most common form of dementia in the aged population, presents an increasing clinical challenge in terms of diagnosis and treatment. Neurodegeneration is one of the hallmarks of AD, which consequently induces cognitive impairment. Brain-derived neurotrophic factor (BDNF), a neuroprotective factor, has been implicated in neuronal survival and proliferation. The epigenetic mechanism of BDNF methylation may be responsible for the reduced expression of BDNF in patients with AD. DNA methyltransferase may contribute to the methylation of BDNF, which is involved in neuroprotection in AD. In addition, epigenetic modifications, including a combination of microRNAs (miRNAs/miRs) and DNA methylation, have been suggested as regulatory mechanisms in the control of neuronal survival. In the present study, the expression of miR 29c was determined in the cerebrospinal fluid (CSF) of patients with AD and of healthy control individuals. A marked decrease in the expression of miR-29c was observed in the AD group compared with the normal control group, accompanied by a decreased in the expression of BDNF. Additionally, a significant increase in the expression of DNA methyltransferase 3 (DNMT3) was observed in the CSF from the patients with AD. Correlation analysis revealed that the expression of miR-29c was positively correlated with BDNF and negatively correlated with DNMT3 protein in the CSF of patients with AD. In addition, the regulatory association between miR-29c, DNMT3 and BDNF were also examined in vitro. It was demonstrated that miR 29c directly targeted DNMT3 and contributed to neuronal proliferation by regulating the expression of BDNF, at least partially, through enhancing the activity of the tyrosine receptor kinase B/extracellular signal-regulated kinase signaling pathway. In conclusion, the present study suggested that miR-29c may be a promising potential therapeutic target in the treatment of AD. PMID- 25815899 TI - One-pot enzymatic conversion of carbon dioxide and utilization for improved microbial growth. AB - We developed a process for one-pot CO2 conversion and utilization based on simple conversion of CO2 to bicarbonate at ambient temperature with no energy input, by using the cross-linking-based composites of carboxylated polyaniline nanofibers (cPANFs) and carbonic anhydrase. Carbonic anhydrase was immobilized on cPANFs via the approach of magnetically separable enzyme precipitate coatings (Mag-EPC), which consists of covalent enzyme attachment, enzyme precipitation, and cross linking with amine-functionalized magnetic nanoparticles. Mag-EPC showed a half life of 236 days under shaking, even resistance to 70% ethanol sterilization, and recyclability via facile magnetic separation. For one-pot CO2 conversion and utilization, Mag-EPC was used to accelerate the growth of microalga by supplying bicarbonate from CO2, representing 1.8-fold increase of cell concentration when compared to the control sample. After two repeated uses via simple magnetic separation, the cell concentration with Mag-EPC was maintained as high as the first cycle. This one-pot CO2 conversion and utilization is an alternative as well as complementary process to adsorption-based CO2 capture and storage as an environmentally friendly approach, demanding no energy input based on the effective action of the stabilized enzyme system. PMID- 25815900 TI - Correction to cooperative binding of ferrocenylnaphthalene diimide carrying beta cyclodextrin converts double-stranded DNA to a rod-like structure. PMID- 25815898 TI - Lipidomic analysis links mycobactin synthase K to iron uptake and virulence in M. tuberculosis. AB - The prolonged survival of Mycobacterium tuberculosis (M. tb) in the host fundamentally depends on scavenging essential nutrients from host sources. M. tb scavenges non-heme iron using mycobactin and carboxymycobactin siderophores, synthesized by mycobactin synthases (Mbt). Although a general mechanism for mycobactin biosynthesis has been proposed, the biological functions of individual mbt genes remain largely untested. Through targeted gene deletion and global lipidomic profiling of intact bacteria, we identify the essential biochemical functions of two mycobactin synthases, MbtK and MbtN, in siderophore biosynthesis and their effects on bacterial growth in vitro and in vivo. The deletion mutant, DeltambtN, produces only saturated mycobactin and carboxymycobactin, demonstrating an essential function of MbtN as the mycobactin dehydrogenase, which affects antigenicity but not iron uptake or M. tb growth. In contrast, deletion of mbtK ablated all known forms of mycobactin and its deoxy precursors, defining MbtK as the essential acyl transferase. The mbtK mutant showed markedly reduced iron scavenging and growth in vitro. Further, DeltambtK was attenuated for growth in mice, demonstrating a non-redundant role of hydroxamate siderophores in virulence, even when other M. tb iron scavenging mechanisms are operative. The unbiased lipidomic approach also revealed unexpected consequences of perturbing mycobactin biosynthesis, including extreme depletion of mycobacterial phospholipids. Thus, lipidomic profiling highlights connections among iron acquisition, phospholipid homeostasis, and virulence, and identifies MbtK as a lynchpin at the crossroads of these phenotypes. PMID- 25815897 TI - Lipopolysaccharide-induced middle ear inflammation disrupts the cochlear intra strial fluid-blood barrier through down-regulation of tight junction proteins. AB - Middle ear infection (or inflammation) is the most common pathological condition that causes fluid to accumulate in the middle ear, disrupting cochlear homeostasis. Lipopolysaccharide, a product of bacteriolysis, activates macrophages and causes release of inflammatory cytokines. Many studies have shown that lipopolysaccharides cause functional and structural changes in the inner ear similar to that of inflammation. However, it is specifically not known how lipopolysaccharides affect the blood-labyrinth barrier in the stria vascularis (intra-strial fluid-blood barrier), nor what the underlying mechanisms are. In this study, we used a cell culture-based in vitro model and animal-based in vivo model, combined with immunohistochemistry and a vascular leakage assay, to investigate lipopolysaccharide effects on the integrity of the mouse intra-strial fluid-blood barrier. Our results show lipopolysaccharide-induced local infection significantly affects intra-strial fluid-blood barrier component cells. Pericytes and perivascular-resident macrophage-like melanocytes are particularly affected, and the morphological and functional changes in these cells are accompanied by substantial changes in barrier integrity. Significant vascular leakage is found in the lipopolysaccharide treated-animals. Consistent with the findings from the in vivo animal model, the permeability of the endothelial cell monolayer to FITC albumin was significantly higher in the lipopolysaccharide-treated monolayer than in an untreated endothelial cell monolayer. Further study has shown the lipopolysaccharide-induced inflammation to have a major effect on the expression of tight junctions in the blood barrier. Lipopolysaccharide was also shown to cause high frequency hearing loss, corroborated by previous reports from other laboratories. Our findings show lipopolysaccharide-evoked middle ear infection disrupts inner ear fluid balance, and its particular effects on the intra-strial fluid-blood barrier, essential for cochlear homeostasis. The barrier is degraded as the expression of tight junction-associated proteins such as zona occludens 1, occludin, and vascular endothelial cadherin are down-regulated. PMID- 25815901 TI - "Elastic" property of mesoporous silica shell: for dynamic surface enhanced Raman scattering ability monitoring of growing noble metal nanostructures via a simplified spatially confined growth method. AB - The Raman enhancing ability of noble metal nanoparticles (NPs) is an important factor for surface enhanced Raman scattering (SERS) substrate screening, which is generally evaluated by simply mixing as-prepared NPs with Raman reporters for Raman signal measurements. This method usually leads to incredible results because of the NP surface coverage nonuniformity and reporter-induced NP aggregation. Moreover, it cannot realize in situ, continuous SERS characterization. Herein, we proposed a dynamic SERS monitoring strategy for NPs with precisely tuned structures based on a simplified spatially confined NP growth method. Gold nanorod (AuNR) seed NPs were coated with a mesoporous silica (mSiO2) shell. The permeability of mSiO2 for both reactive species and Raman reporters rendered the silver overcoating reaction and SERS indication of NP growth. Additionally, the mSiO2 coating ensured monodisperse NP growth in a Raman reporter-rich reaction system. Moreover, "elastic" features of mSiO2 were observed for the first time, which is crucial for holding the growing NP without breakage. This feature makes the mSiO2 coating adhere to metal NPs throughout the growing process, providing a stable Raman reporter distribution microenvironment near the NPs and ensuring that the substrate's SERS ability comparison is accurate. Three types of NPs, i.e., core-shell Au@AgNR@mSiO2, Au@AuNR@mSiO2, and yolk-shell Au@void@AuNR@mSiO2 NPs, were synthesized via core-shell overgrowth and galvanic replacement methods, showing the versatility of the approach. The living cell SERS labeling ability of Au@AgNR@mSiO2-based tags was also demonstrated. This strategy addresses the problems of multiple batch NP preparation, aggregation, and surface adsorption differentiation, which is a breakthrough for the dynamic comparison of SERS ability of metal NPs with precisely tuned structures and optical properties. PMID- 25815902 TI - The first example of a mixed valence ternary compound of silver with random distribution of Ag(I) and Ag(II) cations. AB - The reaction between colourless AgSbF6 and sky-blue Ag(SbF6)2 (molar ratio 2 : 1) in gaseous HF at 323 K yields green Ag3(SbF6)4, a new mixed-valence ternary fluoride of silver. Unlike in all other Ag(I)/Ag(II) systems known to date, the Ag(+) and Ag(2+) cations are randomly distributed on a single 12b Wyckoff position at the 4 axis of the I43d cell. Each silver forms four short (4 * 2.316(7) A) and four long (4 * 2.764(6) A) contacts with the neighbouring fluorine atoms. The valence bond sum analysis suggests that such coordination would correspond to a severely overbonded Ag(I) and strongly underbonded Ag(II). Thorough inspection of thermal ellipsoids of the fluorine atoms closest to Ag centres reveals their unusual shape, indicating that silver atoms must in fact have different local coordination spheres; this is not immediately apparent from the crystal structure due to static disorder of fluorine atoms. The Ag K-edge XANES analysis confirmed that the average oxidation state of silver is indeed close to +11/3. The optical absorption spectra lack features typical of a metal thus pointing out to the semiconducting nature of Ag3(SbF6)4. Ag3(SbF6)4 is magnetically diluted and paramagnetic (MU(eff) = 1.9 MU(B)) down to 20 K with a very weak temperature independent paramagnetism. Below 20 K weak antiferromagnetism is observed (Theta = -4.1 K). Replacement of Ag(I) with potassium gives K(I)2Ag(II)(SbF6)4 which is isostructural to Ag(I)2Ag(II)(SbF6)4. Ag3(SbF6)4 is a genuine mixed-valence Ag(I)/Ag(II) compound, i.e. Robin and Day Class I system (localized valences), despite Ag(I) and Ag(II) adopting the same crystallographic position. PMID- 25815904 TI - Contribution of dihydrouridine in folding of the D-arm in tRNA. AB - Posttranscriptional modifications of transfer RNAs (tRNAs) are proven to be critical for all core aspects of tRNA function. While the majority of tRNA modifications were discovered in the 1970s, their contribution in tRNA folding, stability, and decoding often remains elusive. In this work an NMR study was performed to obtain more insight in the role of the dihydrouridine (D) modification in the D-arm of tRNAi(Met) from S. pombe. While the unmodified oligonucleotide adopted several undefined conformations that interconvert in solution, the presence of a D nucleoside triggered folding into a hairpin with a stable stem and flexible loop region. Apparently the D modification is required in the studied sequence to fold into a stable hairpin. Therefore we conclude that D contributes to the correct folding and stability of D-arm in tRNA. In contrast to what is generally assumed for nucleic acids, the sharp 'imino' signal for the D nucleobase at 10 ppm in 90% H2O is not indicative for the presence of a stable hydrogen bond. The strong increase in pKa upon loss of the aromatic character in the modified nucleobase slows down the exchange of its 'imino' proton significantly, allowing its observation even in an isolated D nucleoside in 90% H2O in acidic to neutral conditions. PMID- 25815903 TI - Waldenstrom macroglobulinemia: prognosis and management. AB - Waldenstrom macroglobulinemia (WM) is a B-cell lymphoplasmacytic lymphoma characterized by monoclonal immunoglobulin M protein in the serum and infiltration of bone marrow with lymphoplasmacytic cells. Asymptomatic patients can be observed without therapy. First-line therapy should consist of the monoclonal anti-CD20 antibody, rituximab, given typically in combination with other agents. We prefer dexamethasone, rituximab, cyclophosphamide (DRC) as initial therapy for most patients with symptomatic WM. Other reasonable options are bortezomib, rituximab, dexamethasone (BoRD) or bendamustine plus rituximab (BR). All of these regimens are associated with excellent response and tolerability. Initial therapy is usually administered for 6 months, followed by observation. Response to therapy is assessed using the standard response criteria developed by the International Working Group on Waldenstrom macroglobulinemia. Relapse is almost inevitable in WM but may occur years after initial therapy. In symptomatic patients relapsing more than 1-2 years after initial therapy, the original treatment can be repeated. For relapse occurring sooner, an alternative regimen is used. In select patients, high-dose chemotherapy followed by autologous hematopoietic cell transplantation may be an option at relapse. Options for therapy of relapsed WM besides regimens used in the front-line setting include ibrutinib, purine nucleoside analogs (cladribine, fludarabine), carfilzomib and immunomodulatory agents (thalidomide, lenalidomide). PMID- 25815905 TI - Coexistence of PM2.5 and low temperature is associated with morning hypertension in hypertensives. AB - We tested the hypothesis that concentration of PM2.5 is associated with home BP level. We analyzed home BP data for 91 consecutive days in 40 hypertensives. PM2.5 solely was not correlated with home BP levels, but low temperature was associated with a 1.6-fold increased likelihood of morning hypertension (p < 0.001) under the condition of high PM2.5 concentration. In addition, coexistence of low temperature and high PM2.5 was associated with a 2.3-fold increased likelihood of morning hypertension (p < 0.001) compared with high temperature and low PM2.5 condition. Environmental and meteorological factors could be important causes of enhanced home BP elevation. PMID- 25815906 TI - Neurogenic Potential Assessment and Pharmacological Characterization of 6-Methoxy 1,2,3,4-tetrahydro-beta-carboline (Pinoline) and Melatonin-Pinoline Hybrids. AB - 6-Methoxy-1,2,3,4-tetrahydro-beta-carboline (pinoline) and N-acetyl-5 methoxytryptamine (melatonin) are both structurally related to 5 hydroxytryptamine (serotonin). Here we describe the design, synthesis, and characterization of a series of melatonin rigid analogues resulting from the hybridization of both pinoline and melatonin structures. The pharmacological evaluation of melatonin-pinoline hybrids comprises serotonergic and melatonergic receptors, metabolic enzymes (monoamine oxidases), antioxidant potential, the in vitro blood-brain barrier permeability, and neurogenic studies. Pinoline at trace concentrations and 2-acetyl-6-methoxy-1,2,3,4-tetrahydro-beta-carboline (2) were able to stimulate early neurogenesis and neuronal maturation in an in vitro model of neural stem cells isolated from the adult rat subventricular zone. Such effects are presumably mediated via serotonergic and melatonergic stimulation, respectively. PMID- 25815908 TI - Topological states in a one-dimensional fermi gas with attractive interaction. AB - We describe a novel topological superfluid state, which forms in a one dimensional Fermi gas with Rashba-like spin-orbit coupling, a Zeeman field, and intrinsic attractive interactions. In spite of total number conservation and the presence of gapless excitations, Majorana-like zero modes appear in this system and can be linked with interfaces between two distinct phases that naturally form at different regions of the harmonic trap. As a result, the low lying collective excitations of the system, including the dipole oscillations and the long wavelength phonons are all doubly degenerate. While backscattering from point impurities can lead to a splitting of the degeneracies that scales algebraically with the system size, the smooth confining potential can only cause an exponentially small splitting. We show that the topological state can be uniquely probed by a pumping effect induced by a slow sweep of the Zeeman field from a high initial value down to zero. The effect is expected to be robust to introducing a finite temperature as long as it is much smaller than the interaction induced single particle gap in the final state of the sweep. PMID- 25815907 TI - CT Urography for Evaluation of the Ureter. AB - Over the past decade, computed tomographic (CT) urography has emerged as the primary imaging modality for evaluating the urinary tract in various clinical settings, including the initial workup of hematuria. With the widespread implementation of CT urography, it is critical for radiologists to understand normal ureteral anatomy and the varied appearance of pathologic ureteral conditions at CT urography. Pathologic findings at CT urography include congenital abnormalities, filling defects, dilatation, narrowing, and deviations in course. These abnormalities are reviewed, along with the indications for CT urography, current imaging protocols with specific techniques for optimal evaluation of the ureter, and dose reduction strategies. PMID- 25815909 TI - Two copies of the Einstein-Podolsky-Rosen state of light lead to refutation of EPR ideas. AB - Bell's theorem applies to the normalizable approximations of original Einstein Podolsky-Rosen (EPR) state. The constructions of the proof require measurements difficult to perform, and dichotomic observables. By noticing the fact that the four mode squeezed vacuum state produced in type II down-conversion can be seen both as two copies of approximate EPR states, and also as a kind of polarization supersinglet, we show a straightforward way to test violations of the EPR concepts with direct use of their state. The observables involved are simply photon numbers at outputs of polarizing beam splitters. Suitable chained Bell inequalities are based on the geometric concept of distance. For a few settings they are potentially a new tool for quantum information applications, involving observables of a nondichotomic nature, and thus of higher informational capacity. In the limit of infinitely many settings we get a Greenberger-Horne-Zeilinger type contradiction: EPR reasoning points to a correlation, while quantum prediction is an anticorrelation. Violations of the inequalities are fully resistant to multipair emissions in Bell experiments using parametric down conversion sources. PMID- 25815910 TI - Nonlinear entanglement and its application to generating cat States. AB - The Einstein-Podolsky-Rosen (EPR) paradox, which was formulated to argue for the incompleteness of quantum mechanics, has since metamorphosed into a resource for quantum information. The EPR entanglement describes the strength of linear correlations between two objects in terms of a pair of conjugate observables in relation to the Heisenberg uncertainty limit. We propose that entanglement can be extended to include nonlinear correlations. We examine two driven harmonic oscillators that are coupled via third-order nonlinearity can exhibit quadraticlike nonlinear entanglement which, after a projective measurement on one of the oscillators, collapses the other into a cat state of tunable size. PMID- 25815911 TI - Asymptotic bound for heat-bath algorithmic cooling. AB - The purity of quantum states is a key requirement for many quantum applications. Improving the purity is limited by fundamental laws of thermodynamics. Here, we are probing the fundamental limits for a natural approach to this problem, namely, heat-bath algorithmic cooling (HBAC). The existence of the cooling limit for HBAC techniques was proved by Schulman, Mor, and Weinstein. A bound for this value was found by Elias et al. and numerical testing supported the hypothesis that their bound may be the actual limit. A proof or disproof of whether their bound was the actual limit remained open for the past decade. Here, for the first time, we prove this limit. In the context of quantum thermodynamics, this corresponds to the maximum extractable work from the quantum system. We also establish, in the case of higher dimensional reset systems, how the performance of HBAC depends on the energy spectrum of the reset system. PMID- 25815912 TI - Atom interferometry in an optical cavity. AB - We propose and demonstrate a new scheme for atom interferometry, using light pulses inside an optical cavity as matter wave beam splitters. The cavity provides power enhancement, spatial filtering, and a precise beam geometry, enabling new techniques such as low power beam splitters (<100 MUW), large momentum transfer beam splitters with modest power, or new self-aligned interferometer geometries utilizing the transverse modes of the optical cavity. As a first demonstration, we obtain Ramsey-Raman fringes with >75% contrast and measure the acceleration due to gravity, g, to 60 MUg/sqrt[Hz] resolution in a Mach-Zehnder geometry. We use >10(7) cesium atoms in the compact mode volume (600 MUm 1/e(2) waist) of the cavity and show trapping of atoms in higher transverse modes. This work paves the way toward compact, high sensitivity, multiaxis interferometry. PMID- 25815913 TI - Spin-orbital exchange of strongly interacting fermions in the p band of a two dimensional optical lattice. AB - Mott insulators with both spin and orbital degeneracy are pertinent to a large number of transition metal oxides. The intertwined spin and orbital fluctuations can lead to rather exotic phases such as quantum spin-orbital liquids. Here, we consider two-component (spin 1/2) fermionic atoms with strong repulsive interactions on the p band of the optical square lattice. We derive the spin orbital exchange for quarter filling of the p band when the density fluctuations are suppressed, and show that it frustrates the development of long-range spin order. Exact diagonalization indicates a spin-disordered ground state with ferro orbital order. The system dynamically decouples into individual Heisenberg spin chains, each realizing a Luttinger liquid accessible at higher temperatures compared to atoms confined to the s band. PMID- 25815914 TI - Entanglement swapping between discrete and continuous variables. AB - We experimentally realize "hybrid" entanglement swapping between discrete variable (DV) and continuous-variable (CV) optical systems. DV two-mode entanglement as obtainable from a single photon split at a beam splitter is robustly transferred by means of efficient CV entanglement and operations, using sources of squeezed light and homodyne detections. The DV entanglement after the swapping is verified without postselection by the logarithmic negativity of up to 0.28+/-0.01. Furthermore, our analysis shows that the optimally transferred state can be postselected into a highly entangled state that violates a Clauser-Horne Shimony-Holt inequality by more than 4 standard deviations, and thus it may serve as a resource for quantum teleportation and quantum cryptography. PMID- 25815915 TI - Solution to the quantum Zermelo navigation problem. AB - The solution to the problem of finding a time-optimal control Hamiltonian to generate a given unitary gate, in an environment in which there exists an uncontrollable ambient Hamiltonian (e.g., a background field), is obtained. In the classical context, finding the time-optimal way to steer a ship in the presence of a background wind or current is known as the Zermelo navigation problem, whose solution can be obtained by working out geodesic curves on a space equipped with a Randers metric. The solution to the quantum Zermelo problem, which is shown here to take a remarkably simple form, is likewise obtained by finding explicit solutions to the geodesic equations of motion associated with a Randers metric on the space of unitary operators. The result reveals that the optimal control in a sense "goes along with the wind." PMID- 25815916 TI - Randomized benchmarking of single-qubit gates in a 2D array of neutral-atom qubits. AB - We characterize single-qubit Clifford gate operations with randomized benchmarking in a 2D array of neutral-atom qubits and demonstrate global and site selected gates with high fidelity. An average fidelity of F2=0.9983(14) is measured for global microwave-driven gates applied to a 49-qubit array. Single site gates are implemented with a focused laser beam to Stark shift the microwaves into resonance at a selected site. At Stark selected single sites we observe F2=0.9923(7) and an average spin-flip crosstalk error at other sites of 0.002(9). PMID- 25815917 TI - Absence of diffusion in an interacting system of spinless fermions on a one dimensional disordered lattice. AB - We study the infinite temperature dynamics of a prototypical one-dimensional system expected to exhibit many-body localization. Using numerically exact methods, we establish the dynamical phase diagram of this system based on the statistics of its eigenvalues and its dynamical behavior. We show that the nonergodic phase is reentrant as a function of the interaction strength, illustrating that localization can be reinforced by sufficiently strong interactions even at infinite temperature. Surprisingly, within the accessible time range, the ergodic phase shows subdiffusive behavior, suggesting that the diffusion coefficient vanishes throughout much of the phase diagram in the thermodynamic limit. Our findings strongly suggest that Wigner-Dyson statistics of eigenvalue spacings may appear in a class of ergodic but subdiffusive systems. PMID- 25815918 TI - Quantum imaging by coherent enhancement. AB - Conventional wisdom dictates that to image the position of fluorescent atoms or molecules, one should stimulate as much emission and collect as many photons as possible. That is, in this classical case, it has always been assumed that the coherence time of the system should be made short, and that the statistical scaling ~1/?t defines the resolution limit for imaging time t. However, here we show in contrast that given the same resources, a long coherence time permits a higher resolution image. In this quantum regime, we give a procedure for determining the position of a single two-level system and demonstrate that the standard errors of our position estimates scale at the Heisenberg limit as ~1/t, a quadratic, and notably optimal, improvement over the classical case. PMID- 25815920 TI - Sequestration of vacuum energy and the end of the universe. AB - Recently, we proposed a mechanism for sequestering the standard model vacuum energy that predicts that the Universe will collapse. Here we present a simple mechanism for bringing about this collapse, employing a scalar field whose potential is linear and becomes negative, providing the negative energy density required to end the expansion. The slope of the potential is chosen to allow for the expansion to last until the current Hubble time, about 10^{10} years, to accommodate our Universe. Crucially, this choice is technically natural due to a shift symmetry. Moreover, vacuum energy sequestering selects radiatively stable initial conditions for the collapse, which guarantee that immediately before the turnaround the Universe is dominated by the linear potential which drives an epoch of accelerated expansion for at least an e fold. Thus, a single, technically natural choice for the slope ensures that the collapse is imminent and is preceded by the current stage of cosmic acceleration, giving a new answer to the "why now?" PMID- 25815921 TI - Reconstructing the nature of the first cosmic sources from the anisotropic 21-cm signal. AB - The redshifted 21-cm background is expected to be a powerful probe of the early Universe, carrying both cosmological and astrophysical information from a wide range of redshifts. In particular, the power spectrum of fluctuations in the 21 cm brightness temperature is anisotropic due to the line-of-sight velocity gradient, which in principle allows for a simple extraction of this information in the limit of linear fluctuations. However, recent numerical studies suggest that the 21-cm signal is actually rather complex, and its analysis likely depends on detailed model fitting. We present the first realistic simulation of the anisotropic 21-cm power spectrum over a wide period of early cosmic history. We show that on observable scales, the anisotropy is large and thus measurable at most redshifts, and its form tracks the evolution of 21-cm fluctuations as they are produced early on by Lyman-alpha radiation from stars, then switch to x-ray radiation from early heating sources, and finally to ionizing radiation from stars. In particular, we predict a redshift window during cosmic heating (at z~15), when the anisotropy is small, during which the shape of the 21-cm power spectrum on large scales is determined directly by the average radial distribution of the flux from x-ray sources. This makes possible a model independent reconstruction of the x-ray spectrum of the earliest sources of cosmic heating. PMID- 25815922 TI - Measuring the speed of light with baryon acoustic oscillations. AB - In this Letter, we describe a new method to use baryon acoustic oscillations (BAO) to derive a constraint on the possible variation of the speed of light. The method relies on the fact that there is a simple relation between the angular diameter distance (D(A)) maximum and the Hubble function (H) evaluated at the same maximum-condition redshift, which includes speed of light c. We note the close analogy of the BAO probe with a laboratory experiment: here we have D(A) which plays the role of a standard (cosmological) ruler, and H^{-1}, with the dimension of time, as a (cosmological) clock. We evaluate if current or future missions such as Euclid can be sensitive enough to detect any variation of c. PMID- 25815919 TI - Joint analysis of BICEP2/keck array and Planck Data. AB - We report the results of a joint analysis of data from BICEP2/Keck Array and Planck. BICEP2 and Keck Array have observed the same approximately 400 deg^{2} patch of sky centered on RA 0 h, Dec. -57.5 degrees . The combined maps reach a depth of 57 nK deg in Stokes Q and U in a band centered at 150 GHz. Planck has observed the full sky in polarization at seven frequencies from 30 to 353 GHz, but much less deeply in any given region (1.2 MUK deg in Q and U at 143 GHz). We detect 150*353 cross-correlation in B modes at high significance. We fit the single- and cross-frequency power spectra at frequencies >=150 GHz to a lensed LambdaCDM model that includes dust and a possible contribution from inflationary gravitational waves (as parametrized by the tensor-to-scalar ratio r), using a prior on the frequency spectral behavior of polarized dust emission from previous Planck analysis of other regions of the sky. We find strong evidence for dust and no statistically significant evidence for tensor modes. We probe various model variations and extensions, including adding a synchrotron component in combination with lower frequency data, and find that these make little difference to the r constraint. Finally, we present an alternative analysis which is similar to a map-based cleaning of the dust contribution, and show that this gives similar constraints. The final result is expressed as a likelihood curve for r, and yields an upper limit r_{0.05}<0.12 at 95% confidence. Marginalizing over dust and r, lensing B modes are detected at 7.0sigma significance. PMID- 25815924 TI - Exclusive window onto Higgs Yukawa couplings. AB - We show that both flavor-conserving and flavor-violating Yukawa couplings of the Higgs boson to first- and second-generation quarks can be probed by measuring rare decays of the form h->MV, where M denotes a vector meson and V indicates either gamma, W or Z. We calculate the branching ratios for these processes in both the standard model and its possible extensions. We discuss the experimental prospects for their observation. The possibility of accessing these Higgs couplings appears to be unique to the high-luminosity LHC and future hadron colliders, providing further motivation for those machines. PMID- 25815927 TI - Association of atoms into universal dimers using an oscillating magnetic field. AB - In a system of ultracold atoms near a Feshbach resonance, pairs of atoms can be associated into universal dimers by an oscillating magnetic field with a frequency near that determined by the dimer binding energy. We present a simple expression for the transition rate that takes into account many-body effects through a transition matrix element of the contact. In a thermal gas, the width of the peak in the transition rate as a function of the frequency is determined by the temperature. In a dilute Bose-Einstein condensate of atoms, the width is determined by the inelastic scattering rates of a dimer with zero-energy atoms. Near an atom-dimer resonance, there is a dramatic increase in the width from inelastic atom-dimer scattering and from atom-atom-dimer recombination. The recombination contribution provides a signature for universal tetramers that are Efimov states consisting of two atoms and a dimer. PMID- 25815925 TI - Effects of heavy sea quarks at low energies. AB - We present a factorization formula for the dependence of light hadron masses and low energy hadronic scales on the mass M of a heavy quark: apart from an overall mass-independent factor Q, ratios such as r_{0}(M)/r_{0}(0) are computable in perturbation theory at large M. The perturbation theory part is stable concerning different loop orders. Our nonperturbative Monte Carlo results obtained in a model calculation, where a doublet of heavy quarks is decoupled, match quantitatively to the perturbative prediction. Upon taking ratios of different hadronic scales at the same mass, the perturbative function drops out and the ratios are given by the decoupled theory up to M^{-2} corrections. We verify-in the continuum limit-that the sea quark effects of quarks with masses around the charm mass are very small in such ratios. PMID- 25815926 TI - Polarization shaping for unidirectional rotational motion of molecules. AB - Control of the orientation of the angular momentum of linear molecules is demonstrated by means of laser polarization shaping. For this purpose, we combine two orthogonally polarized and partially time-overlapped femtosecond laser pulses so as to produce a spinning linear polarization which in turn induces unidirectional rotation of N2 molecules. The evolution of the rotational response is probed by a third laser beam that can be either linearly or circularly polarized. The physical observable is the frequency shift imparted to the probe beam as a manifestation of the angular Doppler effect. Our experimental results are confirmed by theoretical computations, which allow one to gain a deep physical insight into the laser-molecule interaction. PMID- 25815928 TI - Two-state wave packet for strong field-free molecular orientation. AB - We demonstrate strong laser-field-free orientation of absolute-ground-state carbonyl sulfide molecules. The molecules are oriented by the combination of a 485-ps-long nonresonant laser pulse and a weak static electric field. The edges of the laser pulse create a coherent superposition of two rotational states resulting in revivals of strong transient molecular orientation after the laser pulse. The experimentally attained degree of orientation ?costheta?~0.6 corresponds to the theoretical maximum for mixing of the two states. Switching off the dc field would provide the same orientation completely field free. PMID- 25815929 TI - Signatures of molecular orbital structure in lateral electron momentum distributions from strong-field ionization. AB - Strong-field ionization of aligned diatomic and polyatomic molecules such as O2, N2, C2H4, and others in circularly polarized laser fields is investigated theoretically. By calculating the emission-angle-resolved lateral width of the momentum distribution perpendicular to the polarization plane, we show that nodal planes in molecular orbitals are directly imprinted on the angular dependence of the width. We demonstrate that orbital symmetries can be distinguished with the information obtained by observing the lateral width in addition to the angular distributions. PMID- 25815930 TI - Molecular orbital imaging of the acetone S2 excited state using time-resolved (e, 2e) electron momentum spectroscopy. AB - We report a time-resolved (e, 2e) experiment on the deuterated acetone molecule in the S2 Rydberg state with a lifetime of 13.5 ps. The acetone S2 state was prepared by a 195 nm pump laser and probed with electron momentum spectroscopy using a 1.2 keV incident electron beam of 1 ps temporal width. In spite of the low data statistics as well as of the limited time resolution (+/-35 ps) due to velocity mismatch, the experimental results clearly demonstrate that electron momentum spectroscopy measurements of short-lived transient species are feasible, opening the door to time-resolved orbital imaging in momentum space. PMID- 25815931 TI - Conditional ramsey spectroscopy with synchronized atoms. AB - We investigate Ramsey spectroscopy performed on a synchronized ensemble of two level atoms. The synchronization is induced by the collective coupling of the atoms to a heavily damped mode of an optical cavity. We show that, in principle, with this synchronized system it is possible to observe Ramsey fringes indefinitely, even in the presence of spontaneous emission and other sources of individual-atom dephasing. This could have important consequences for atomic clocks and a wide range of precision metrology applications. PMID- 25815932 TI - Nonclassicality phase-space functions: more insight with fewer detectors. AB - Systems of on-off detectors are well established for measuring radiation fields in the regime of small photon numbers. We propose to combine these detector systems with unbalanced homodyning with a weak local oscillator. This approach yields phase-space functions, which represent the click counterpart of the s parametrized quasiprobabilities of standard photoelectric detection theory. This introduced class of distributions can be directly sampled from the measured click counting statistics. Therefore, our technique visualizes nonclassical effects without further data processing. Surprisingly, a small number of on-off diodes can yield more insight than perfect photon number resolution. Quantum signatures in the particle and wave domain of the quantized radiation field, as shown by photon number and squeezed states, respectively, will be uncovered in terms of negativities of the sampled phase-space functions. Application in the vast fields of quantum optics and quantum technology will benefit from our efficient nonclassicality characterization approach. PMID- 25815933 TI - Hard-X-ray directional dark-field imaging using the speckle scanning technique. AB - X-ray dark-field imaging can provide inaccessible and complementary information compared to conventional absorption contrast imaging. However, extraction of the dark-field signal is difficult, and sophisticated optics are often required. In this Letter, we report a novel approach to generate high-quality dark-field images using a simple membrane. The dark-field image is extracted from the maximum correlation coefficient by applying a cross-correlation algorithm to a stack of speckle images collected by scanning a membrane in a transverse direction to the incident x-ray beam. The new method can also provide directional dark-field information, which is extremely useful for the study of strongly ordered systems. The potential of the proposed technique for nondestructive x-ray imaging is demonstrated by imaging representative samples. PMID- 25815934 TI - Gauge field optics with anisotropic media. AB - By considering gauge transformations on the macroscopic Maxwell's equations, a two-dimensional gauge field, with its pseudomagnetic field in the real space, is identified as tilted anisotropy in the constitutive parameters. We show that the optical spin Hall effect with broadband response and one-way edge states become possible simply by using anisotropic media. The proposed gauge field also allows us to obtain unidirectional propagation for a particular pseudospin based on the Aharonov-Bohm effect. Our approach will be useful in spoof magneto-optics with arbitrary magnetic fields mimicked by metamaterials with subwavelength unit cells. It also serves as a generic way to design polarization-dependent devices. PMID- 25815935 TI - Radially polarized light for detection and nanolocalization of dielectric particles on a planar substrate. AB - A fast noninvasive method based on scattering from a focused radially polarized light to detect and localize subwavelength nanoparticles on a substrate is presented. The technique relies on polarization matching in the far field between scattered and spurious reflected fields. Results show a localization uncertainty of ~10^{-4}lambda^{2} is possible for a particle of area ~lambda^{2}/16. The effect of simple pupil shaping is also shown. PMID- 25815936 TI - Theory of the antibubble collapse. AB - A theory of the collapse of a punctured antibubble is developed. The motion of the rim of air formed at the edge of the collapsing air film cannot be described by a potential flow and is characterized by high Reynolds numbers. The rim velocity is not constant but gradually decreases with time and is determined by the balance between the surface tension and hydrodynamic drag forces. A collapse equation is derived and solved. The agreement between the theory and existing experiments is shown. PMID- 25815937 TI - Observation of a multimode plasma response and its relationship to density pumpout and edge-localized mode suppression. AB - Density pumpout and edge-localized mode (ELM) suppression by applied n=2 magnetic fields in low-collisionality DIII-D plasmas are shown to be correlated with the magnitude of the plasma response driven on the high-field side (HFS) of the magnetic axis but not the low-field side (LFS) midplane. These distinct responses are a direct measurement of a multimodal magnetic plasma response, with each structure preferentially excited by a different n=2 applied spectrum and preferentially detected on the LFS or HFS. Ideal and resistive magneto hydrodynamic (MHD) calculations find that the LFS measurement is primarily sensitive to the excitation of stable kink modes, while the HFS measurement is primarily sensitive to resonant currents (whether fully shielding or partially penetrated). The resonant currents are themselves strongly modified by kink excitation, with the optimal applied field pitch for pumpout and ELM suppression significantly differing from equilibrium field alignment. PMID- 25815938 TI - Pedestal bifurcation and resonant field penetration at the threshold of edge localized mode suppression in the DIII-D Tokamak. AB - Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression. PMID- 25815939 TI - Enhancement of maximum attainable ion energy in the radiation pressure acceleration regime using a guiding structure. AB - Radiation pressure acceleration is a highly efficient mechanism of laser-driven ion acceleration, with the laser energy almost totally transferrable to the ions in the relativistic regime. There is a fundamental limit on the maximum attainable ion energy, which is determined by the group velocity of the laser. In the case of tightly focused laser pulses, which are utilized to get the highest intensity, another factor limiting the maximum ion energy comes into play, the transverse expansion of the target. Transverse expansion makes the target transparent for radiation, thus reducing the effectiveness of acceleration. Utilization of an external guiding structure for the accelerating laser pulse may provide a way of compensating for the group velocity and transverse expansion effects. PMID- 25815940 TI - Softening of roton and phonon modes in a Bose-Einstein condensate with spin-orbit coupling. AB - Roton-type excitations usually emerge from strong correlations or long-range interactions, as in superfluid helium or dipolar ultracold atoms. However, in a weakly short-range interacting quantum gas, the recently synthesized spin-orbit (SO) coupling can lead to various unconventional phases of superfluidity and give rise to an excitation spectrum of roton-maxon character. Using Bragg spectroscopy, we study a SO-coupled Bose-Einstein condensate of ^{87}Rb atoms and show that the excitation spectrum in a "magnetized" phase clearly possesses a two branch and roton-maxon structure. As Raman coupling strength Omega is decreased, a roton-mode softening is observed, as a precursor of the phase transition to a stripe phase that spontaneously breaks spatially translational symmetry. The measured roton gaps agree well with theoretical calculations. Furthermore, we determine sound velocities both in the magnetized and in the nonmagnetized phases, and a phonon-mode softening is observed around the phase transition in between. The validity of the f-sum rule is examined. PMID- 25815941 TI - Anisotropic phases of superfluid ^{3}he in compressed aerogel. AB - It has been shown that the relative stabilities of various superfluid states of ^{3}He can be influenced by anisotropy in a silica aerogel framework. We prepared a suite of aerogel samples compressed up to 30% for which we performed pulsed NMR on ^{3}He imbibed within the aerogel. We identified A and B phases and determined their magnetic field-temperature phase diagrams as a function of strain. From these results, we infer that the B phase is distorted by negative strain forming an anisotropic superfluid state more stable than the A phase. PMID- 25815942 TI - Anomalous quantum glass of bosons in a random potential in two dimensions. AB - We present a quantum Monte Carlo study of the "quantum glass" phase of the two dimensional Bose-Hubbard model with random potentials at filling rho=1. In the narrow region between the Mott and superfluid phases, the compressibility has the form kappa~exp(-b/T^{alpha})+c with alpha<1 and c vanishing or very small. Thus, at T=0 the system is either incompressible (a Mott glass) or nearly incompressible (a Mott-glass-like anomalous Bose glass). At stronger disorder, where a glass reappears from the superfluid, we find a conventional highly compressible Bose glass. On a path connecting these states, away from the superfluid at larger Hubbard repulsion, a change of the disorder strength by only 10% changes the low-temperature compressibility by more than 4 orders of magnitude, lending support to two types of glass states separated by a phase transition or a sharp crossover. PMID- 25815943 TI - Spin-dependent acoustic response in the nonunitary A1 and A2 phases of superfluid 3He under high magnetic fields. AB - The transverse acoustic impedance of superfluid ^{3}He was measured in the A1 and A2 phases up to 13 T to investigate the surface states in nonunitary superfluids. The temperature dependence of the impedance was much larger in the A1 phase than in the A2 phase. This nonsymmetric behavior indicates that momentum exchange with walls for spin-down surface states is quite different from that for spin-up surface states. The spin-dependent response might be a reflection of an essential feature of the nonunitary states where gap amplitudes depend on spin states. Weak coupling theories ignore any spin-dependent processes and do not account for the nonsymmetric behavior. PMID- 25815944 TI - Molecular to atomic phase transition in hydrogen under high pressure. AB - The metallization of high-pressure hydrogen, together with the associated molecular to atomic transition, is one of the most important problems in the field of high-pressure physics. It is also currently a matter of intense debate due to the existence of conflicting experimental reports on the observation of metallic hydrogen on a diamond-anvil cell. Theoretical calculations have typically relied on a mean-field description of electronic correlation through density functional theory, a theory with well-known limitations in the description of metal-insulator transitions. In fact, the predictions of the pressure-driven dissociation of molecules in high-pressure hydrogen by density functional theory is strongly affected by the chosen exchange-correlation functional. In this Letter, we use quantum Monte Carlo calculations to study the molecular to atomic transition in hydrogen. We obtain a transition pressure of 447(3) GPa, in excellent agreement with the best experimental estimate of the transition 450 GPa based on an extrapolation to zero band gap from experimental measurements. Additionally, we find that C2/c is stable almost up to the molecular to atomic transition, in contrast to previous density functional theory (DFT) and DFT+quantum Monte Carlo studies which predict large stability regimes for intermediary molecular phases. PMID- 25815945 TI - Morphological instability of grain boundaries in two-phase coherent solids. AB - We show both computationally and analytically that grain boundaries that exhibit shear-coupled motion become morphologically unstable in solid alloys that phase separate into coherent domains of distinct chemical compositions. We carry out simulations of continuum models demonstrating that this instability is mediated by long-range elastic interaction between compositional domains and grain boundaries. In addition, we perform a linear stability analysis that predicts the range of unstable wavelengths in good quantitative agreement with simulations. In nonlinear stages, this pattern-forming instability leads to the breakup of low angle grain boundaries, thereby strongly impacting microstructural evolution in a wide range of phase-separating materials. PMID- 25815946 TI - Competing kinetics and he bubble morphology in W. AB - The growth process of He bubbles in W is investigated using molecular dynamics and parallel replica dynamics for growth rates spanning 6 orders of magnitude. Fast and slow growth regimes are defined relative to typical diffusion hopping times of W interstitials around the He bubble. Slow growth rates allow the diffusion of interstitials around the bubble, favoring the biased growth of the bubble towards the surface. In contrast, at fast growth rates interstitials do not have time to diffuse around the bubble, leading to a more isotropic growth and increasing the surface damage. PMID- 25815947 TI - Big data of materials science: critical role of the descriptor. AB - Statistical learning of materials properties or functions so far starts with a largely silent, nonchallenged step: the choice of the set of descriptive parameters (termed descriptor). However, when the scientific connection between the descriptor and the actuating mechanisms is unclear, the causality of the learned descriptor-property relation is uncertain. Thus, a trustful prediction of new promising materials, identification of anomalies, and scientific advancement are doubtful. We analyze this issue and define requirements for a suitable descriptor. For a classic example, the energy difference of zinc blende or wurtzite and rocksalt semiconductors, we demonstrate how a meaningful descriptor can be found systematically. PMID- 25815948 TI - From mild to wild fluctuations in crystal plasticity. AB - Macroscopic crystal plasticity is classically viewed as an outcome of uncorrelated dislocation motions producing Gaussian fluctuations. An apparently conflicting picture emerged in recent years emphasizing highly correlated dislocation dynamics characterized by power-law distributed fluctuations. We use acoustic emission measurements in crystals with different symmetries to show that intermittent and continuous visions of plastic flow are not incompatible. We demonstrate the existence of crossover regimes where strongly intermittent events coexist with a Gaussian quasiequilibrium background and propose a simple theoretical framework compatible with these observations. PMID- 25815949 TI - Distinct metallization and atomization transitions in dense liquid hydrogen. AB - We perform molecular dynamics simulations driven by accurate quantum Monte Carlo forces on dense liquid hydrogen. There is a recent report of a complete atomization transition between a mixed molecular-atomic liquid and a completely dissociated fluid in an almost unaccessible pressure range [Nat. Commun. 5, 3487 (2014)]. Here, instead, we identify a different transition between the fully molecular liquid and the mixed-atomic fluid at ~400 GPa, i.e., in a much more interesting pressure range. We provide numerical evidence supporting the metallic behavior of this intermediate phase. Therefore, we predict that the metallization at finite temperature occurs in this partially dissociated molecular fluid, well before the complete atomization of the liquid. At high temperature this first order transition becomes a crossover, in very good agreement with the experimental observation. Several systematic tests supporting the quality of our large scale calculations are also reported. PMID- 25815950 TI - Local observation of the site occupancy of Mn in a MnFePSi compound. AB - MnFePSi compounds are promising materials for magnetic refrigeration as they exhibit a giant magnetocaloric effect. From first principles calculations and experiments on bulk materials, it has been proposed that this is due to the Mn and Fe atoms preferentially occupying two different sites within the atomic lattice. A recently developed technique was used to deconvolve the obscuring effects of both multiple elastic scattering and thermal diffuse scattering of the probe in an atomic resolution electron energy-loss spectroscopy investigation of a MnFePSi compound. This reveals, unambiguously, that the Mn atoms preferentially occupy the 3g site in a hexagonal crystal structure, confirming the theoretical predictions. After deconvolution, the data exhibit a difference in the Fe L_{2,3} ratio between the 3f and 3g sites consistent with differences in magnetic moments calculated from first principles, which are also not observed in the raw data. PMID- 25815951 TI - Universality class of the mott transition. AB - Pressure dependence of the conductivity and thermoelectric power is measured through the Mott transition in the layer organic conductor EtMe_{3}P[Pd(dmit)_{2}]_{2}. The critical behavior of the thermoelectric effect provides a clear and objective determination of the Mott-Hubbard transition during the isothermal pressure sweep. Above the critical end point, the metal insulator crossing, determined by the thermoelectric effect minimum value, is not found to coincide with the maximum of the derivative of the conductivity as a function of pressure. We show that the critical exponents of the Mott-Hubbard transition fall within the Ising universality class regardless of the dimensionality of the system. PMID- 25815952 TI - Strong localization of Majorana end States in chains of magnetic adatoms. AB - A recent experiment [Nadj-Perge et al, Science 346, 602 (2014)] gives possible evidence for Majorana bound states in chains of magnetic adatoms placed on a superconductor. While many features of the observed end states are naturally interpreted in terms of Majorana states, their strong localization remained puzzling. We consider a linear chain of Anderson impurities on a superconductor as a minimal model and treat it largely analytically within mean-field theory. We explore the phase diagram, the subgap excitation spectrum, and the Majorana wave functions. Owing to a strong velocity renormalization, the latter are localized on a scale which is parametrically small compared to the coherence length of the host superconductor. PMID- 25815953 TI - Signatures of fractional exclusion statistics in the spectroscopy of quantum Hall droplets. AB - We show how spectroscopic experiments on a small Laughlin droplet of rotating bosons can directly demonstrate Haldane fractional exclusion statistics of quasihole excitations. The characteristic signatures appear in the single particle excitation spectrum. We show that the transitions are governed by a "many-body selection rule" which allows one to relate the number of allowed transitions to the number of quasihole states on a finite geometry. We illustrate the theory with numerically exact simulations of small numbers of particles. PMID- 25815954 TI - Chiral projected entangled-pair state with topological order. AB - We show that projected entangled-pair states (PEPS) can describe chiral topologically ordered phases. For that, we construct a simple PEPS for spin-1/2 particles in a two-dimensional lattice. We reveal a symmetry in the local projector of the PEPS that gives rise to the global topological character. We also extract characteristic quantities of the edge conformal field theory using the bulk-boundary correspondence. PMID- 25815955 TI - Approaching truly freestanding graphene: the structure of hydrogen-intercalated graphene on 6H-SiC(0001). AB - We measure the adsorption height of hydrogen-intercalated quasifreestanding monolayer graphene on the (0001) face of 6H silicon carbide by the normal incidence x-ray standing wave technique. A density functional calculation for the full (6?3*6?3)-R30 degrees unit cell, based on a van der Waals corrected exchange correlation functional, finds a purely physisorptive adsorption height in excellent agreement with experiments, a very low buckling of the graphene layer, a very homogeneous electron density at the interface, and the lowest known adsorption energy per atom for graphene on any substrate. A structural comparison to other graphenes suggests that hydrogen-intercalated graphene on 6H-SiC(0001) approaches ideal graphene. PMID- 25815956 TI - Novel relativistic plasma excitations in a gated two-dimensional electron system. AB - The microwave response of a two-dimensional electron system (2DES) covered by a conducting top gate is investigated in the relativistic regime for which the 2D conductivity sigma_{2D}>c/2pi. Weakly damped plasma waves are excited in the gated region of the 2DES. The frequency and amplitude of the resulting plasma excitations show a very unusual dependence on the magnetic field, conductivity, gate geometry, and separation from the 2DES. We show that such relativistic plasmons survive for temperatures up to 300 K, allowing for new room-temperature microwave and terahertz applications. PMID- 25815957 TI - Topological index for periodically driven time-reversal invariant 2D systems. AB - We define a new Z2-valued index to characterize the topological properties of periodically driven two dimensional crystals when the time-reversal symmetry is enforced. This index is associated with a spectral gap of the evolution operator over one period of time. When two such gaps are present, the Kane-Mele index of the eigenstates with eigenvalues between the gaps is recovered as the difference of the gap indices. This leads to an expression for the Kane-Mele invariant in terms of the Wess-Zumino amplitude. We illustrate the relation of the new index to the edge states in finite geometries by numerically solving an explicit model on the square lattice that is periodically driven in a time-reversal invariant way. PMID- 25815958 TI - Controlling the spin of co atoms on pt(111) by hydrogen adsorption. AB - We investigate the effect of H adsorption on the magnetic properties of individual Co atoms on Pt(111) with scanning tunneling microscopy. For pristine Co atoms, we detect no inelastic features in the tunnel spectra. Conversely, CoH and CoH2 show a number of low-energy vibrational features in their differential conductance identified by isotope substitution. Only the fcc-adsorbed species present conductance steps of magnetic origin, with a field splitting identifying their effective spin as Seff=2 for CoH and 3/2 for CoH2. The exposure to H2 and desorption through tunnel electrons allow the reversible control of the spin in half-integer steps. Because of the presence of the surface, the hydrogen-induced spin increase is opposite to the spin sequence of CoHn molecules in the gas phase. PMID- 25815959 TI - Phase diagram of cuprate high-temperature superconductors described by a field theory based on anharmonic oxygen degrees of freedom. AB - In high temperature superconductors, although some phenomena such as the Mott transition (MT) at low doping are clearly driven by electron correlations, recent experimental data imply that anharmonic oxygen degrees of freedom-characteristic of perovskite materials-are playing a significant role. A key test of the role of anharmonic oxygen is to reproduce the complex cuprate phase diagram from a simple model. Here, we show that a field theory based on nonlinear coupling to anharmonic oxygens, parametrized from ab initio calculations, quantitatively reproduces the cuprate phase diagram for dopings above the MT. Pairing is mediated by renormalized oxygen vibrations transmuted into excitations of the pseudogap. The observed strong dependence of gap to transition temperature ratio on Tc also emerges from this field theory. This work suggests that including vibrational degrees of freedom is key to developing a complete understanding of the cuprates. PMID- 25815960 TI - Glide-plane symmetry and superconducting gap structure of iron-based superconductors. AB - We consider the effect of glide-plane symmetry of the Fe-pnictogen/chalcogen layer in Fe-based superconductors on pairing in spin fluctuation models. Recent theories have proposed that so-called eta-pairing states with nonzero total momentum can be realized and possess exotic properties such as odd parity spin singlet symmetry and time-reversal symmetry breaking. Here we show that eta pairing is inevitable when there is orbital weight at the Fermi level from orbitals with even and odd mirror reflection symmetry in z; however, by explicit calculation, we conclude that the gap function that appears in observable quantities is identical to that found in earlier, 1 Fe per unit cell pseudocrystal momentum calculations. PMID- 25815962 TI - Tunable giant spin hall conductivities in a strong spin-orbit semimetal: Bi(1-x) Sb(x). AB - Intrinsic spin Hall conductivities are calculated for strong spin-orbit Bi(1 x)Sb(x) semimetals, from the Kubo formula and using Berry curvatures evaluated throughout the Brillouin zone from a tight-binding Hamiltonian. Nearly crossing bands with strong spin-orbit interaction generate giant spin Hall conductivities in these materials, ranging from 474 (h/e)(Omega cm)^{-1} for bismuth to 96 (h/e)(Omega cm)^{-1} for antimony; the value for bismuth is more than twice that of platinum. The large spin Hall conductivities persist for alloy compositions corresponding to a three-dimensional topological insulator state, such as Bi(0.83)Sb(0.17). The spin Hall conductivity could be changed by a factor of 5 for doped Bi, or for Bi(0.83)Sb(0.17), by changing the chemical potential by 0.5 eV, suggesting the potential for doping or voltage tuned spin Hall current. PMID- 25815963 TI - Electric-field-induced modification of the magnon energy, exchange interaction, and curie temperature of transition-metal thin films. AB - The electric-field-induced modification in the Curie temperature of prototypical transition-metal thin films with the perpendicular magnetic easy axis, a freestanding Fe(001) monolayer and a Co monolayer on Pt(111), is investigated by first-principles calculations of spin-spiral structures in an external electric field (E field). An applied E field is found to modify the magnon (spin-spiral formation) energy; the change arises from the E-field-induced screening charge density in the spin-spiral states due to p-d hybridizations. The Heisenberg exchange parameters obtained from the magnon energy suggest an E-field-induced modification of the Curie temperature, which is demonstrated via Monte Carlo simulations that take the magnetocrystalline anisotropy into account. PMID- 25815961 TI - Detection of a superconducting phase in a two-atom layer of hexagonal Ga film grown on semiconducting GaN(0001). AB - The recent observation of the superconducting state at atomic scale has motivated the pursuit of exotic condensed phases in two-dimensional (2D) systems. Here we report on a superconducting phase in two-monolayer crystalline Ga films epitaxially grown on wide-band-gap semiconductor GaN(0001). This phase exhibits a hexagonal structure and only 0.552 nm in thickness, nevertheless, brings about a superconducting transition temperature Tc as high as 5.4 K, confirmed by in situ scanning tunneling spectroscopy and ex situ electrical magnetotransport and magnetization measurements. The anisotropy of critical magnetic field and Berezinski-Kosterlitz-Thouless-like transition are observed, typical for the 2D superconductivity. Our results demonstrate a novel platform for exploring atomic scale 2D superconductors, with great potential for understanding the interface superconductivity. PMID- 25815964 TI - Three-particle complexes in two-dimensional semiconductors. AB - We evaluate binding energies of trions X+/-, excitons bound by a donor or acceptor charge X^{D(A)}, and overcharged acceptors or donors in two-dimensional atomic crystals by mapping the three-body problem in two dimensions onto one particle in a three-dimensional potential treatable by a purposely developed boundary-matching-matrix method. We find that in monolayers of transition metal dichalcogenides the dissociation energy of X^{+/-} is typically much larger than that of localized exciton complexes, so that trions are more resilient to heating, despite the fact that their recombination line in optics is less redshifted from the exciton line than the line of X^{D(A)}. PMID- 25815965 TI - Ultrafast terahertz probes of interacting dark excitons in chirality-specific semiconducting single-walled carbon nanotubes. AB - Ultrafast terahertz spectroscopy accesses the dark excitonic ground state in resonantly excited (6,5) single-walled carbon nanotubes via internal, direct dipole-allowed transitions between the lowest-lying dark-bright pair state of ~6 meV. An analytical model reproduces the response that enables the quantitative analysis of transient densities of dark excitons and e-h plasma, oscillator strength, transition energy renormalization, and dynamics. Nonequilibrium, yet stable, quasi-one-dimensional quantum states with dark excitonic correlations rapidly emerge even with increasing off-resonance photoexcitation and experience a unique crossover to complex phase-space filling of both dark and bright pair states, different from dense two- and three-dimensional excitons influenced by the thermalization, cooling, and ionization to free carriers. PMID- 25815966 TI - Exciton mapping at subwavelength scales in two-dimensional materials. AB - Spatially resolved electron-energy-loss spectroscopy (EELS) is performed at diffuse interfaces between MoS2 and MoSe2 single layers. With a monochromated electron source (20 meV) we successfully probe excitons near the interface by obtaining the low loss spectra at the nanometer scale. The exciton maps clearly show variations even with a 10 nm separation between measurements; consequently, the optical band gap can be measured with nanometer-scale resolution, which is 50 times smaller than the wavelength of the emitted photons. By performing core-loss EELS at the same regions, we observe that variations in the excitonic signature follow the chemical composition. The exciton peaks are observed to be broader at interfaces and heterogeneous regions, possibly due to interface roughness and alloying effects. Moreover, we do not observe shifts of the exciton peak across the interface, possibly because the interface width is not much larger than the exciton Bohr radius. PMID- 25815967 TI - Identifying structural flow defects in disordered solids using machine-learning methods. AB - We use machine-learning methods on local structure to identify flow defects-or particles susceptible to rearrangement-in jammed and glassy systems. We apply this method successfully to two very different systems: a two-dimensional experimental realization of a granular pillar under compression and a Lennard Jones glass in both two and three dimensions above and below its glass transition temperature. We also identify characteristics of flow defects that differentiate them from the rest of the sample. Our results show it is possible to discern subtle structural features responsible for heterogeneous dynamics observed across a broad range of disordered materials. PMID- 25815968 TI - Calcium alternans is due to an order-disorder phase transition in cardiac cells. AB - Electromechanical alternans is a beat-to-beat alternation in the strength of contraction of a cardiac cell, which can be caused by an instability of calcium cycling. Using a distributed model of subcellular calcium we show that alternans occurs via an order-disorder phase transition which exhibits critical slowing down and a diverging correlation length. We apply finite size scaling along with a mapping to a stochastic coupled map model, to show that this transition in two dimensions is characterized by critical exponents consistent with the Ising universality class. These findings highlight the important role of cooperativity in biological cells, and suggest novel approaches to investigate the onset of the alternans instability in the heart. PMID- 25815970 TI - Interactions and stress relaxation in monolayers of soft nanoparticles at fluid fluid interfaces. AB - Nanoparticles with grafted layers of ligand molecules behave as soft colloids when they adsorb at fluid-fluid interfaces. The ligand brush can deform and reconfigure, adopting a lens-shaped configuration at the interface. This behavior strongly affects the interactions between soft nanoparticles at fluid-fluid interfaces, which have proven challenging to probe experimentally. We measure the surface pressure for a stable 2D interfacial suspension of nanoparticles grafted with ligands, and extract the interaction potential from these data by comparison to Brownian dynamics simulations. A soft repulsive potential with an exponential form accurately reproduces the measured surface pressure data. A more realistic interaction potential model is also fitted to the data to provide insights into the ligand configuration at the interface. The stress of the 2D interfacial suspension upon step compression exhibits a single relaxation time scale, which is also attributable to ligand reconfiguration. PMID- 25815969 TI - Emergence of upstream swimming via a hydrodynamic transition. AB - We demonstrate that upstream swimming of sperm emerges via an orientation disorder-order transition. The order parameter, the average orientation of the sperm head against the flow, follows a 0.5 power law with the deviation from the critical flow shear rate (gamma-gamma_{c}). This transition is successfully explained by a hydrodynamic bifurcation theory, which extends the sperm upstream swimming to a broad class of near surface microswimmers that possess front-back asymmetry and circular motion. PMID- 25815971 TI - Friction boosted by equilibrium misalignment of incommensurate two-dimensional colloid monolayers. AB - Colloidal two-dimensional monolayers sliding in an optical lattice are of recent importance as a frictional system. In the general case when the monolayer and optical lattices are incommensurate, we predict two important novelties, one in the static equilibrium structure, the other in the frictional behavior under sliding. Structurally, realistic simulations show that the colloid layer should possess in full equilibrium a small misalignment rotation angle relative to the optical lattice, an effect so far unnoticed but visible in some published experimental moire patterns. Under sliding, this misalignment has the effect of boosting the colloid monolayer friction by a considerable factor over the hypothetical aligned case discussed so far. A frictional increase of similar origin must generally affect other incommensurate adsorbed monolayers and contacts, to be sought out case by case. PMID- 25815972 TI - Burstiness and aging in social temporal networks. AB - The presence of burstiness in temporal social networks, revealed by a power-law form of the waiting time distribution of consecutive interactions, is expected to produce aging effects in the corresponding time-integrated network. Here, we propose an analytically tractable model, in which interactions among the agents are ruled by a renewal process, that is able to reproduce this aging behavior. We develop an analytic solution for the topological properties of the integrated network produced by the model, finding that the time translation invariance of the degree distribution is broken. We validate our predictions against numerical simulations, and we check for the presence of aging effects in a empirical temporal network, ruled by bursty social interactions. PMID- 25815973 TI - Human alveolar epithelial cell responses to core-shell superparamagnetic iron oxide nanoparticles (SPIONs). AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have been prepared and coated with positively (-NH3(+)) and negatively (-COO(-)) charged shells. These NPs, as well as their "bare" precursor, which actually contain surface hydroxyl groups, have been characterized in vitro, and their influence on a human epithelial cell line has been assessed in terms of cell metabolic activity, cellular membrane lysis, mitochondrial activity, and reactive oxygen species production. Their physicochemical characterizations and protein-nanoparticle interactions have been determined using dynamic light scattering, high-resolution transmission electron microscopy, matrix-assisted laser desorption/ionization time-of-flight (MALDI TOF) spectrometry, and Coomassie Blue fast staining. Cell-SPION interactions have been determined by PrestoBlue resazurin-based, Trypan Blue dye exclusion-based, and MTS cell proliferation assays as well as by reactive oxygen species determination. The results show that different surface characteristics cause different protein corona and cell responses. Some proteins (e.g., albumin) are adsorbed only on positively charged coatings and others (e.g., fibrinogen) only on negatively charged coating. No cell deaths occur, but cell proliferation is influenced by surface chemistry. Proliferation reduction is dose dependent and highest for bare SPIONs. Negatively charged SPIONs were the most biocompatible. PMID- 25815974 TI - Interaction between physical and psychosocial risk factors on the presence of neck/shoulder symptoms and its consequences. AB - This study aimed to quantify the interaction between physical and psychosocial factors on the presence of neck/shoulder symptoms (NSS) and its consequences (reduced activities and absenteeism) among 1294 coal mining workers in Indonesia. A self-administered questionnaire was used to obtain information on current workplace exposure and NSS and its consequences. Participants were grouped into one of four combination exposure groups: low physical and low psychosocial (as the reference group); low physical and high psychosocial; high physical and low psychosocial, and high physical and high psychosocial (HPhyHPsy). The attributable proportion (AP) due to interaction between both factors was examined. Individuals in the HPhyHPsy group were most likely to report NSS [odds ratio (OR) 4.83, 95% confidence interval (CI) 2.43-9.58], reduced activities (OR 3.90, 95% CI 2.36-6.43), and absenteeism (OR 3.91, 95% CI 2.11-7.25). This study has shown an interaction between physical and psychosocial factors that increases the OR of NSS (AP 0.49, 95% CI 0.08-0.89). Practitioner Summary: Although physical and psychosocial factors are known to be predictors for NSS, little is known about their interaction. Self-reported questionnaire was used to obtain information about physical and psychosocial factors at work. This study found an interaction between the physical and psychosocial risk factors that increases the odds ratio of NSS. PMID- 25815975 TI - Differential modulation of synaptic plasticity and local circuit activity in the dentate gyrus and CA1 regions of the rat hippocampus by corticosterone. AB - Depending on its severity, timing and context, stress has been shown to have a differential regional effect on hippocampal synaptic plasticity. While the focus of attention in most recent studies is on excitatory synapses and generation, modifications of inhibitory synapses and local interneurons cannot be ignored. We have now examined the effects of corticosterone (CORT) on extrinsic afferent and local circuit plasticity of the perforant path on the dentate gyrus (DG) and the ventral hippocampal commissure on CA1. Local circuit activity was measured by responses to paired-pulse stimulation. Control rats expressed afferent long-term potentiation (LTP) and local circuit plasticity in both the DG and CA1. Administration of a high dosage of CORT-reduced paired-pulse inhibition and increased facilitation in DG but not in CA1, whereas administration of a moderate CORT dosage had no effect. Moderate CORT doses caused enhancement of LTP in the DG but not in CA1, while high CORT doses converted LTP to long-term depression in the CA1 but had no effect in the DG. CORT blocked theta burst stimulation-induced local circuit plasticity otherwise found in control DG. These findings suggest that elevation of the level of CORT results in a regionally differentiated physiological response. In addition, the results indicate that CORT affects aspects of local circuit activity and plasticity in the DG but less so in the CA1. It is possible that these differentiated alterations underlie some of the behavioral consequences and memory processes under stressful conditions. PMID- 25815976 TI - Evolving nutritional strategies in the presence of competition: a geometric agent based model. AB - Access to nutrients is a key factor governing development, reproduction and ultimately fitness. Within social groups, contest-competition can fundamentally affect nutrient access, potentially leading to reproductive asymmetry among individuals. Previously, agent-based models have been combined with the Geometric Framework of nutrition to provide insight into how nutrition and social interactions affect one another. Here, we expand this modelling approach by incorporating evolutionary algorithms to explore how contest-competition over nutrient acquisition might affect the evolution of animal nutritional strategies. Specifically, we model tolerance of nutrient excesses and deficits when ingesting nutritionally imbalanced foods, which we term 'nutritional latitude'; a higher degree of nutritional latitude constitutes a higher tolerance of nutritional excess and deficit. Our results indicate that a transition between two alternative strategies occurs at moderate to high levels of competition. When competition is low, individuals display a low level of nutritional latitude and regularly switch foods in search of an optimum. When food is scarce and contest competition is intense, high nutritional latitude appears optimal, and individuals continue to consume an imbalanced food for longer periods before attempting to switch to an alternative. However, the relative balance of nutrients within available foods also strongly influences at what levels of competition, if any, transitions between these two strategies occur. Our models imply that competition combined with reproductive skew in social groups can play a role in the evolution of diet breadth. We discuss how the integration of agent based, nutritional and evolutionary modelling may be applied in future studies to further understand the evolution of nutritional strategies across social and ecological contexts. PMID- 25815977 TI - Evaluating the toxicity of silver nanoparticles by detecting phosphorylation of histone H3 in combination with flow cytometry side-scattered light. AB - Post-translational modification of histones is linked to a variety of biological processes and disease states. This paper focuses on phosphorylation of histone H3 at serine 10 (p-H3S10), induced by silver nanoparticles (AgNPs) and discusses the usefulness of p-H3S10 as a marker to evaluate the toxicity of AgNPs. Cultured human cells showed remarkable p-H3S10 immediately after treatment with AgNPs but not with Ag microparticles. p-H3S10 lasts up to 24 h and strongly depends upon the cellular uptake of AgNPs. Removal of Ag ions suppressed p-H3S10, while adding an excess of Ag ions augmented p-H3S10. We expected that p-H3S10 requires two events: cellular uptake of AgNPs and continuous release of Ag ions from intracellular AgNPs. AgNPs enhanced the expression of the proto-oncogene c-jun, and p-H3S10 increased in the promoter sites of the gene, indicating that p-H3S10 might indicate a biological reaction related to carcinogenesis. We previously showed that side-scattered light from flow cytometry could be used to measure the uptake potential of nanoparticles [ Suzuki , H. ; Toyooka , T. ; Ibuki , Y. Simple and easy method to evaluate uptake potential of nanoparticles in mammalian cells using a flow cytometric light scatter analysis . Environ. Sci. Technol. 2007 , 41 ( 8 ), 3018 - 3024 ]. Our current findings suggest that p-H3S10 can be used to evaluate the toxicity of AgNPs and Ag ion release in combination with detection of side-scattered light from flow cytometry. PMID- 25815978 TI - Biophysics of molecular gastronomy. AB - Chefs and scientists exploring biophysical processes have given rise to molecular gastronomy. In this Commentary, we describe how a scientific understanding of recipes and techniques facilitates the development of new textures and expands the flavor palette. The new dishes that result engage our senses in unexpected ways. PAPERCLIP. PMID- 25815979 TI - Food for the brain. AB - Diet is a major issue facing humanity. To combat malnourishment and diseases associated with overnutrition, both research and technological breakthroughs are needed. PMID- 25815980 TI - Modeling human nutrition using human embryonic stem cells. AB - Nutrition presents unanswered scientific questions of high public health importance. We envision model systems composed of interacting gastrointestinal and metabolic tissues derived from human embryonic stem cells, populated by gut microbiota. The culture will be embedded in 3D scaffolds, creating a controlled experimental system that enables tissue sampling and imaging. PMID- 25815981 TI - Putting the balance back in diet. AB - The notion of dietary balance is fundamental to health yet is not captured by focusing on the intake of energy or single nutrients. Advances in nutritional geometry have begun to unravel and integrate the interactive effects of multiple nutrients on health, lifespan, aging, and reproduction. PMID- 25815982 TI - Multisensory flavor perception. AB - The perception of flavor is perhaps the most multisensory of our everyday experiences. The latest research by psychologists and cognitive neuroscientists increasingly reveals the complex multisensory interactions that give rise to the flavor experiences we all know and love, demonstrating how they rely on the integration of cues from all of the human senses. This Perspective explores the contributions of distinct senses to our perception of food and the growing realization that the same rules of multisensory integration that have been thoroughly explored in interactions between audition, vision, and touch may also explain the combination of the (admittedly harder to study) flavor senses. Academic advances are now spilling out into the real world, with chefs and food industry increasingly taking the latest scientific findings on board in their food design. PMID- 25815984 TI - Fermented foods as experimentally tractable microbial ecosystems. AB - Microbial communities of fermented foods have provided humans with tools for preservation and flavor development for thousands of years. These simple, reproducible, accessible, culturable, and easy-to-manipulate systems also provide opportunities for dissecting the mechanisms of microbial community formation. Fermented foods can be valuable models for processes in less tractable microbiota. PMID- 25815983 TI - Cultivating healthy growth and nutrition through the gut microbiota. AB - Microbiota assembly is perturbed in children with undernutrition, resulting in persistent microbiota immaturity that is not rescued by current nutritional interventions. Evidence is accumulating that this immaturity is causally related to the pathogenesis of undernutrition and its lingering sequelae. Preclinical models in which human gut communities are replicated in gnotobiotic mice have provided an opportunity to identify and predict the effects of different dietary ingredients on microbiota structure, expressed functions, and host biology. This capacity sets the stage for proof-of-concept tests designed to deliberately shape the developmental trajectory and configurations of microbiota in children representing different geographies, cultural traditions, and states of health. Developing these capabilities for microbial stewardship is timely given the global health burden of childhood undernutrition, the effects of changing eating practices brought about by globalization, and the realization that affordable nutritious foods need to be developed to enhance our capacity to cultivate healthier microbiota in populations at risk for poor nutrition. PMID- 25815985 TI - Meeting the global food demand of the future by engineering crop photosynthesis and yield potential. AB - Increase in demand for our primary foodstuffs is outstripping increase in yields, an expanding gap that indicates large potential food shortages by mid-century. This comes at a time when yield improvements are slowing or stagnating as the approaches of the Green Revolution reach their biological limits. Photosynthesis, which has been improved little in crops and falls far short of its biological limit, emerges as the key remaining route to increase the genetic yield potential of our major crops. Thus, there is a timely need to accelerate our understanding of the photosynthetic process in crops to allow informed and guided improvements via in-silico-assisted genetic engineering. Potential and emerging approaches to improving crop photosynthetic efficiency are discussed, and the new tools needed to realize these changes are presented. PMID- 25815987 TI - Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. AB - The circadian clock, a highly specialized, hierarchical network of biological pacemakers, directs and maintains proper rhythms in endocrine and metabolic pathways required for organism homeostasis. The clock adapts to environmental changes, specifically daily light-dark cycles, as well as rhythmic food intake. Nutritional challenges reprogram the clock, while time-specific food intake has been shown to have profound consequences on physiology. Importantly, a critical role in the clock-nutrition interplay appears to be played by the microbiota. The circadian clock appears to operate as a critical interface between nutrition and homeostasis, calling for more attention on the beneficial effects of chrono nutrition. PMID- 25815986 TI - Nutrient-sensing mechanisms across evolution. AB - For organisms to coordinate their growth and development with nutrient availability, they must be able to sense nutrient levels in their environment. Here, we review select nutrient-sensing mechanisms in a few diverse organisms. We discuss how these mechanisms reflect the nutrient requirements of specific species and how they have adapted to the emergence of multicellularity in eukaryotes. PMID- 25815990 TI - The hunger genes: pathways to obesity. AB - The global rise in the prevalence of obesity and associated co-morbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. The biological response to increased consumption of palatable foods or a reduction in energy expenditure is highly variable between individuals. A more detailed mechanistic understanding of the molecular, physiological, and behavioral pathways involved in the development of obesity in susceptible individuals is critical for identifying effective mechanism-based preventative and therapeutic interventions. PMID- 25815988 TI - I'm eating for two: parental dietary effects on offspring metabolism. AB - It has long been understood that the pathogenesis of complex diseases such as diabetes includes both genetic and environmental components. More recently, it has become clear that not only does an individual's environment influence their own metabolism, but in some cases, the environment experienced by their parents may also contribute to their risk of metabolic disease. Here, we review the evidence that parental diet influences metabolic phenotype in offspring in mammals and provide a current survey of our mechanistic understanding of these effects. PMID- 25815989 TI - Promoting health and longevity through diet: from model organisms to humans. AB - Reduced food intake, avoiding malnutrition, can ameliorate aging and aging associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily. PMID- 25815994 TI - SnapShot: GI tract development. AB - The endoderm germ layer contributes to the respiratory and gastrointestinal (GI) lineages during development, giving rise to an array of specialized epithelial cell types lining organs, including the thyroid, thymus, lungs, liver, biliary system, pancreas, and intestines. This SnapShot timelines and summarizes key stages following gastrulation, including endoderm patterning, organ specification, and organogenesis. A lineage tree of the developing endocrine pancreas is outlined to further illustrate this process. PMID- 25815991 TI - Neural control of energy balance: translating circuits to therapies. AB - Recent insights into the neural circuits controlling energy balance and glucose homeostasis have rekindled the hope for development of novel treatments for obesity and diabetes. However, many therapies contribute relatively modest beneficial gains with accompanying side effects, and the mechanisms of action for other interventions remain undefined. This Review summarizes current knowledge linking the neural circuits regulating energy and glucose balance with current and potential pharmacotherapeutic and surgical interventions for the treatment of obesity and diabetes. PMID- 25815995 TI - Pressure ulcers: how much do nursing students really know? AB - AIM: Taking care of patients with pressure ulcers requires a high level of knowledge. The purpose of this study was to determine the level of nursing students' knowledge of pressure ulcer prevention, classification and management. METHODS: The study was conducted in two nursing colleges (Razi Nursing and Midwifery College and Shahrekord Nursing and Midwifery College) in Iran. All final-year bachelors nursing students in both colleges were invited to participate in the study. Data were collected using Pieper's Pressure Ulcer Knowledge Test (PPUKT). RESULTS: Participants answered correctly 67% of all 41 items in three sections (prevention, classification and evaluation). The students' rate of correct answers in the pressure ulcer evaluation category was significantly higher than the correct answers in the other two categories. CONCLUSION: The study revealed that nursing students had insufficient knowledge of pressure ulcers. It was concluded that courses aimed at raising students' knowledge of pressure ulcers are needed in nurse education. PMID- 25815993 TI - A century of cholesterol and coronaries: from plaques to genes to statins. AB - One-fourth of all deaths in industrialized countries result from coronary heart disease. A century of research has revealed the essential causative agent: cholesterol-carrying low-density lipoprotein (LDL). LDL is controlled by specific receptors (LDLRs) in liver that remove it from blood. Mutations that eliminate LDLRs raise LDL and cause heart attacks in childhood, whereas mutations that raise LDLRs reduce LDL and diminish heart attacks. If we are to eliminate coronary disease, lowering LDL should be the primary goal. Effective means to achieve this goal are currently available. The key questions are: who to treat, when to treat, and how long to treat. PMID- 25815996 TI - Drains and gauze-based NPWT in the management of extensive tissue loss. PMID- 25815997 TI - Wounds with exudate and odour. PMID- 25815998 TI - Deep bone infections following surgery. PMID- 25816000 TI - Deaths and pressure ulcers: should death certificate reporting be mandatory? PMID- 25815999 TI - Pressure-ulcer reduction using low-friction fabric bootees. AB - At St Helens and Knowsley Teaching Hospitals NHS Trust, implementation of pressure management measures has reduced the incidence of hospital-acquired pressure ulcers. There is now a focus on those pressure ulcers still occurring despite these measures, particularly grade 2 ulcers on the heel, which are often attributed to friction and shear. During 2012 and 2013 low friction fabric bootees (Parafricta(r)) were used on at-risk patients (where possible) to attempt to address this issue. The bootees were first introduced in 2012. There was a decline in heel ulcers of 78% in the 2 years, which accounted for a sizeable portion of the overall decline in all grade 2 pressure ulcers. There was also a substantial change in the ratio of heel to all other grade 2 pressure ulcers, which fell from 0.67 to 0.24. On the basis of heel pressure ulcers avoided, there is an implied net saving to the NHS. The trust concluded that routine use of low friction fabric bootees made a significant further contribution towards achieving zero harm targets and had done so while providing substantial cost benefits. PMID- 25816001 TI - Electronic versus paper records: documentation of pressure ulcer data. AB - BACKGROUND: The documentation of patient data on health records is a vital component of the care process. Accurate and complete recording of this data is a necessary practice. The adoption of electronic health records to improve the quality of nursing documentation is on the rise. OBJECTIVES: This study compares the accuracy and completeness of pressure ulcer data documentation between electronic and paper records. DESIGN: A descriptive, comparative design with a retrospective review of patient records. Settings and sample: Two hospitals were chosen purposefully, one using electronic recording of patient data and the other using paper records. METHODS: In the first phase, all hospitalised patients aged 18 years and over were inspected for pressure ulcers. In the second phase, the files of patients with pressure ulcers were audited. RESULTS: Of the 52 patients with ulcers found in the hospital that used an electronic system, 43 of their records documented the pressure ulcers (83%). Of the 55 patients with pressure ulcers in the hospital using paper records, 39 files had corresponding documentation of the presence of a pressure ulcer (71%). CONCLUSION: In terms of accuracy and completeness, more comprehensive documentation practice was found on the electronic health records compared with paper records. However, both types of systems have shortcomings in the practice of pressure ulcer data documentation. PMID- 25815992 TI - Immune regulation of metabolic homeostasis in health and disease. AB - Obesity is an increasingly prevalent disease worldwide. While genetic and environmental factors are known to regulate the development of obesity and associated metabolic diseases, emerging studies indicate that innate and adaptive immune cell responses in adipose tissue have critical roles in the regulation of metabolic homeostasis. In the lean state, type 2 cytokine-associated immune cell responses predominate in white adipose tissue and protect against weight gain and insulin resistance through direct effects on adipocytes and elicitation of beige adipose. In obesity, these metabolically beneficial immune pathways become dysregulated, and adipocytes and other factors initiate metabolically deleterious type 1 inflammation that impairs glucose metabolism. This review discusses our current understanding of the functions of different types of adipose tissue and how immune cells regulate adipocyte function and metabolic homeostasis in the context of health and disease and highlights. We also highlight the potential of targeting immuno-metabolic pathways as a therapeutic strategy to treat obesity and associated diseases. PMID- 25816002 TI - Use of fibre dressings in children with severe epidermolysis bullosa. AB - This non-comparative study explored the benefits of a natural gelling fibre dressing in 10 children with epidermolysis bullosa (EB). The clinical challenge in managing these children is that they often present with recalcitrant wounds that are perpetuated by critical colonisation, presence of biofilms and infection. KytoCel(r) (Aspen Medical) is a highly absorbent dressing composed of natural, biodegradable acylated chitosan. These fibres bond with wound exudate to form a clear gel that locks in fluid absorbs pathogens and is conformable to the wound bed. It also has haemostatic properties. ( Dutta PK et al, 2004 ; Lee et al, 2009 ; Stephen Haynes et al, 2014 ). Factors considered were whether the dressing could aid healing, reduce bleeding, reduce bioburden, be atraumatic and comfortable during wear time and removal. PMID- 25816004 TI - Lead tissue viability nurse. PMID- 25816003 TI - Pressure-ulcer management and prevention in acute and primary care. AB - This article describes a study to ascertain what it is like to follow the processes in practice for prevention and management of pressure ulcers as one aspect of care among others. The participants in this study were bands 5 and 6 staff nurses and healthcare assistants (HCAs) (n=72) recruited from two acute and two primary NHS trusts. Data were gathered from open-ended questions via an online survey (n=61) and interviews (n=11). The interviews were transcribed and all the data were analysed by thematic analysis. The findings show that participants believe there has been a high-profile imposition of guidelines and policies by management during at least the past 18 months, resulting in perceived good outcomes in the form of fewer pressure ulcers generally and less fragmentation of care, particularly within primary care. However, a number of perceived obstacles to the implementation of recommended interventions remain, notably lack of time and lack of knowledge. PMID- 25816006 TI - Robotic neurorehabilitation in patients with chronic stroke: psychological well being beyond motor improvement. AB - Although gait abnormality is one of the most disabling events following stroke, cognitive, and psychological impairments can be devastating. The Lokomat is a robotic that has been used widely for gait rehabilitation in several movement disorders, especially in the acute and subacute phases. The aim of this study was to evaluate the effectiveness of gait robotic rehabilitation in patients affected by chronic stroke. Psychological impact was also taken into consideration. Thirty patients (13 women and 17 men) affected by chronic stroke entered the study. All participants underwent neurological examination with respect to ambulation, Ashworth, Functional Independence Measure, and Tinetti scales to assess their physical status, and Hamilton Rating Scale for Depression, Psychological General Well-being Index, and Coping Orientation to Problem Experienced to evaluate the Lokomat-related psychological impact before and after either a conventional treatment or the robotic training. During each rehabilitation period (separated by a no-treatment period), patients underwent a total of 40 1 h training sessions (i.e. five times a week for 8 weeks). After the conventional treatment, the patients did not achieve a significant improvement in the functional status, except balance (P<0.001) and walking ability (P<0.01), as per the Tinetti scale. Indeed, after the robotic rehabilitation, significant improvements were detected in almost all the motor and psychological scales that we investigated, particularly for Psychological General Well-being Index and Coping Orientation to Problem Experienced. Manual and robotic-assisted body weight-supported treadmill training optimizes the sensory inputs relevant to step training, repeated practice, as well as neuroplasticity. Several controlled trials have shown a superior effect of Lokomat treatment in stroke patients' walking ability and velocity in particular. Therefore, our preliminary results proved that active robotic training not only facilitates gait and physical function but also the psychological status, even in patients affected by chronic stroke. PMID- 25816005 TI - HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. AB - Hereditary hearing loss is a clinically and genetically heterogeneous disorder. More than 80 genes have been implicated to date, and with the advent of targeted genomic enrichment and massively parallel sequencing (TGE+MPS) the rate of novel deafness-gene identification has accelerated. Here we report a family segregating post-lingual progressive autosomal dominant non-syndromic hearing loss (ADNSHL). After first excluding plausible variants in known deafness-causing genes using TGE+MPS, we completed whole exome sequencing in three hearing-impaired family members. Only a single variant, p.Arg185Pro in HOMER2, segregated with the hearing-loss phenotype in the extended family. This amino acid change alters a highly conserved residue in the coiled-coil domain of HOMER2 that is essential for protein multimerization and the HOMER2-CDC42 interaction. As a scaffolding protein, HOMER2 is involved in intracellular calcium homeostasis and cytoskeletal organization. Consistent with this function, we found robust expression in stereocilia of hair cells in the murine inner ear and observed that over expression of mutant p.Pro185 HOMER2 mRNA causes anatomical changes of the inner ear and neuromasts in zebrafish embryos. Furthermore, mouse mutants homozygous for the targeted deletion of Homer2 present with early-onset rapidly progressive hearing loss. These data provide compelling evidence that HOMER2 is required for normal hearing and that its sequence alteration in humans leads to ADNSHL through a dominant-negative mode of action. PMID- 25816007 TI - A phosphorylation-related variant ADD1-rs4963 modifies the risk of colorectal cancer. AB - It is well-established that abnormal protein phosphorylation could play an essential role in tumorgenesis by disrupting a variety of physiological processes such as cell growth, signal transduction and cell motility. Moreover, increasing numbers of phosphorylation-related variants have been identified in association with cancers. ADD1 (alpha-adducin), a versatile protein expressed ubiquitously in eukaryotes, exerts an important influence on membrane cytoskeleton, cell proliferation and cell-cell communication. Recently, a missense variant at the codon of ADD1's phosphorylation site, rs4963 (Ser586Cys), was reported to modify the risk of non-cardia gastric cancer. To explore the role of ADD1-rs4963 in colorectal cancer (CRC), we conducted a case-control study with a total of 1054 CRC cases and 1128 matched controls in a Chinese population. After adjustment for variables including age, gender, smoking and drinking, it was demonstrated that this variant significantly conferred susceptibility to CRC (G versus C: OR = 1.16, 95% CI = 1.03-1.31, P = 0.016; CG versus CC: OR = 1.25, 95% CI = 1.02-1.55, P = 0.036; GG versus CC: OR = 1.35, 95% CI = 1.06-1.72, P = 0.015). We further investigated the interaction of ADD1-rs4963 with smoking or drinking exposure, but found no significant result. This study is the first report of an association between ADD1 and CRC risk, promoting our knowledge of the genetics of CRC. PMID- 25816008 TI - Mechanisms of gain control by voltage-gated channels in intrinsically-firing neurons. AB - Gain modulation is a key feature of neural information processing, but underlying mechanisms remain unclear. In single neurons, gain can be measured as the slope of the current-frequency (input-output) relationship over any given range of inputs. While much work has focused on the control of basal firing rates and spike rate adaptation, gain control has been relatively unstudied. Of the limited studies on gain control, some have examined the roles of synaptic noise and passive somatic currents, but the roles of voltage-gated channels present ubiquitously in neurons have been less explored. Here, we systematically examined the relationship between gain and voltage-gated ion channels in a conductance based, tonically-active, model neuron. Changes in expression (conductance density) of voltage-gated channels increased (Ca2+ channel), reduced (K+ channels), or produced little effect (h-type channel) on gain. We found that the gain-controlling ability of channels increased exponentially with the steepness of their activation within the dynamic voltage window (voltage range associated with firing). For depolarization-activated channels, this produced a greater channel current per action potential at higher firing rates. This allowed these channels to modulate gain by contributing to firing preferentially at states of higher excitation. A finer analysis of the current-voltage relationship during tonic firing identified narrow voltage windows at which the gain-modulating channels exerted their effects. As a proof of concept, we show that h-type channels can be tuned to modulate gain by changing the steepness of their activation within the dynamic voltage window. These results show how the impact of an ion channel on gain can be predicted from the relationship between channel kinetics and the membrane potential during firing. This is potentially relevant to understanding input-output scaling in a wide class of neurons found throughout the brain and other nervous systems. PMID- 25816010 TI - Fast or slow? Compressions (or not) in number-to-line mappings. AB - We investigated, in a university student population, spontaneous (non-speeded) fast and slow number-to-line mapping responses using non-symbolic (dots) and symbolic (words) stimuli. Seeking for less conventionalized responses, we used anchors 0-130, rather than the standard 0-100. Slow responses to both types of stimuli only produced linear mappings with no evidence of non-linear compression. In contrast, fast responses revealed distinct patterns of non-linear compression for dots and words. A predicted logarithmic compression was observed in fast responses to dots in the 0-130 range, but not in the reduced 0-100 range, indicating compression in proximity of the upper anchor 130, not the standard 100. Moreover, fast responses to words revealed an unexpected significant negative compression in the reduced 0-100 range, but not in the 0-130 range, indicating compression in proximity to the lower anchor 0. Results show that fast responses help revealing the fundamentally distinct nature of symbolic and non symbolic quantity representation. Whole number words, being intrinsically mediated by cultural phenomena such as language and education, emphasize the invariance of magnitude between them-essential for linear mappings, and therefore, unlike non-symbolic (psychophysical) stimuli, yield spatial mappings that don't seem to be influenced by the Weber-Fechner law of psychophysics. However, high levels of education (when combined with an absence of standard upper anchors) may lead fast responses to overestimate magnitude invariance on the lower end of word numerals. PMID- 25816009 TI - In silico screening based on predictive algorithms as a design tool for exon skipping oligonucleotides in Duchenne muscular dystrophy. AB - The use of antisense 'splice-switching' oligonucleotides to induce exon skipping represents a potential therapeutic approach to various human genetic diseases. It has achieved greatest maturity in exon skipping of the dystrophin transcript in Duchenne muscular dystrophy (DMD), for which several clinical trials are completed or ongoing, and a large body of data exists describing tested oligonucleotides and their efficacy. The rational design of an exon skipping oligonucleotide involves the choice of an antisense sequence, usually between 15 and 32 nucleotides, targeting the exon that is to be skipped. Although parameters describing the target site can be computationally estimated and several have been identified to correlate with efficacy, methods to predict efficacy are limited. Here, an in silico pre-screening approach is proposed, based on predictive statistical modelling. Previous DMD data were compiled together and, for each oligonucleotide, some 60 descriptors were considered. Statistical modelling approaches were applied to derive algorithms that predict exon skipping for a given target site. We confirmed (1) the binding energetics of the oligonucleotide to the RNA, and (2) the distance in bases of the target site from the splice acceptor site, as the two most predictive parameters, and we included these and several other parameters (while discounting many) into an in silico screening process, based on their capacity to predict high or low efficacy in either phosphorodiamidate morpholino oligomers (89% correctly predicted) and/or 2'O Methyl RNA oligonucleotides (76% correctly predicted). Predictions correlated strongly with in vitro testing for sixteen de novo PMO sequences targeting various positions on DMD exons 44 (R2 0.89) and 53 (R2 0.89), one of which represents a potential novel candidate for clinical trials. We provide these algorithms together with a computational tool that facilitates screening to predict exon skipping efficacy at each position of a target exon. PMID- 25816011 TI - Association of neonatal necrotizing enterocolitis with myeloid differentiation-2 and GM2 activator protein genetic polymorphisms. AB - The aim of the present study was to investigate the association of neonatal necrotizing enterocolitis (NEC) with myeloid differentiation-(MD-2) and GM2 activator protein (GM2A) genetic polymorphisms. Gene resequencing of the MD-2 and GM2A gene exons was performed on 42 neonates, diagnosed with NEC (NEC group), as well as in the rs11465996 locus, located in the MD-2 gene promoter region. The aim was to detect the genetic polymorphisms present in the neonates with NEC and compare the functional polymorphic loci with 83 neonates without NEC (control group), who had been born during the same period. A polymorphic locus with abnormal frequency was detected in the exon region of the MD-2 gene. In the NEC group, the frequency of genotypes carrying the low frequency allele (G) in the rs11465996 locus (MD-2 promoter region) was significantly higher compared with the control group (chi(2)=4.388, P=0.036). Furthermore, the frequencies of genotypes carrying the low frequency A and C alleles in the rs1048719 (GM2A gene exon 1) and rs2075783 loci (GM2A intron), respectively, were significantly higher in the NEC group compared with the control group (chi(2)=4.316, P=0.038; and chi(2)=13.717, P=0.000, respectively). In addition, the rs11465996 polymorphism in the MD-2 gene promoter region was found to be associated with the severity of NEC. Furthermore, the rs2075783 polymorphism in the GM2A gene exon 1 and the rs1048719 polymorphism in the intron region of this gene, were associated with the occurrence of NEC. The present study demonstrated that gene polymorphisms of MD-2 and GM2A were associated with the occurrence or severity of NEC; however, further in-depth exploration is required to clarify the associations between genetic predispositions to polymorphisms, and NEC. PMID- 25816013 TI - Identification and validation of novel chromosomal integration and expression loci in Escherichia coli flagellar region 1. AB - Escherichia coli is used as a chassis for a number of Synthetic Biology applications. The lack of suitable chromosomal integration and expression loci is among the main hurdles of the E. coli engineering efforts. We identified and validated chromosomal integration and expression target sites within E. coli K12 MG1655 flagellar region 1. We analyzed five open reading frames of the flagellar region 1, flgA, flgF, flgG, flgI, and flgJ, that are well-conserved among commonly-used E. coli strains, such as MG1655, W3110, DH10B and BL21-DE3. The efficiency of the integration into the E. coli chromosome and the expression of the introduced genetic circuit at the investigated loci varied significantly. The integrations did not have a negative impact on growth; however, they completely abolished motility. From the investigated E. coli K12 MG1655 flagellar region 1, flgA and flgG are the most suitable chromosomal integration and expression loci. PMID- 25816012 TI - Concerted activity of IgG1 antibodies and IL-4/IL-25-dependent effector cells trap helminth larvae in the tissues following vaccination with defined secreted antigens, providing sterile immunity to challenge infection. AB - Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRgamma chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Ralpha- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations. PMID- 25816014 TI - Anatomical confirmation of computed tomography-based diagnosis of the atherosclerosis discovered in 17th century Korean mummy. AB - In the present study on a newly discovered 17th century Korean mummy, computed tomography (CT) revealed multiple aortic calcifications within the aortic wall that were indicative of ancient atherosclerosis. The CT-based findings were confirmed by our subsequent post-factum dissection, which exhibited possible signs of the disease including ulcerated plaques, ruptured hemorrhages, and intimal thickening where the necrotic core was covered by the fibrous cap. These findings are strong indicators that the mummy suffered from aortic atherosclerosis during her lifetime. The present study is a good example of how CT images of vascular calcifications can be a useful diagnostic tool in forming at least preliminary diagnoses of ancient atherosclerosis. PMID- 25816015 TI - The impact of immunosenescence on humoral immune response variation after influenza A/H1N1 vaccination in older subjects. AB - BACKGROUND: Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly. METHODS: We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles - TREC content, peripheral white blood cell telomerase - TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination. RESULTS: TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28 low T cells, IgD+CD27- naive B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1 specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively). CONCLUSION: Our data suggest that influenza specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity. PMID- 25816016 TI - Folate receptor-alpha (FOLR1) expression and function in triple negative tumors. AB - Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options. PMID- 25816018 TI - Retraction Note: Novel two-stage surgical treatment for Cantrell syndrome complicated by severe pulmonary hypertension: a case report. PMID- 25816017 TI - Retinal vascular fractal dimension, childhood IQ, and cognitive ability in old age: the Lothian Birth Cohort Study 1936. AB - PURPOSE: Cerebral microvascular disease is associated with dementia. Differences in the topography of the retinal vascular network may be a marker for cerebrovascular disease. The association between cerebral microvascular state and non-pathological cognitive ageing is less clear, particularly because studies are rarely able to adjust for pre-morbid cognitive ability level. We measured retinal vascular fractal dimension (Df) as a potential marker of cerebral microvascular disease. We examined the extent to which it contributes to differences in non pathological cognitive ability in old age, after adjusting for childhood mental ability. METHODS: Participants from the Lothian Birth Cohort 1936 Study (LBC1936) had cognitive ability assessments and retinal photographs taken of both eyes aged around 73 years (n = 648). IQ scores were available from childhood. Retinal vascular Df was calculated with monofractal and multifractal analysis, performed on custom-written software. Multiple regression models were applied to determine associations between retinal vascular Df and general cognitive ability (g), processing speed, and memory. RESULTS: Only three out of 24 comparisons (two eyes * four Df parameters * three cognitive measures) were found to be significant. This is little more than would be expected by chance. No single association was verified by an equivalent association in the contralateral eye. CONCLUSIONS: The results show little evidence that fractal measures of retinal vascular differences are associated with non-pathological cognitive ageing. PMID- 25816019 TI - In-stent restenosis because of nickel hypersensitivity: a bioresorbable solution? PMID- 25816020 TI - Acute and chronic total occlusion of the left circumflex artery following unprotected left main stenting: two contrasting cases. PMID- 25816021 TI - FOCUS--Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists. AB - Communication of data and ideas within a medicinal chemistry project on a global as well as local level is a crucial aspect in the drug design cycle. Over a time frame of eight years, we built and optimized FOCUS, a platform to produce, visualize, and share information on various aspects of a drug discovery project such as cheminformatics, data analysis, structural information, and design. FOCUS is tightly integrated with internal services that involve-among others-data retrieval systems and in-silico models and provides easy access to automated modeling procedures such as pharmacophore searches, R-group analysis, and similarity searches. In addition, an interactive 3D editor was developed to assist users in the generation and docking of close analogues of a known lead. In this paper, we will specifically concentrate on issues we faced during development, deployment, and maintenance of the software and how we continually adapted the software in order to improve usability. We will provide usage examples to highlight the functionality as well as limitations of FOCUS at the various stages of the development process. We aim to make the discussion as independent of the software platform as possible, so that our experiences can be of more general value to the drug discovery community. PMID- 25816022 TI - Calcium oxalate crystals: an integral component of the Sclerotinia sclerotiorum/Brassica carinata pathosystem. AB - Oxalic acid is an important virulence factor for disease caused by the fungal necrotrophic pathogen Sclerotinia sclerotiorum, yet calcium oxalate (CaOx) crystals have not been widely reported. B. carinata stems were infected with S. sclerotiorum and observed using light microscopy. Six hours post inoculation (hpi), CaOx crystals were evident on 46% of stem sections and by 72 hpi on 100%, demonstrating that the secretion of oxalic acid by S. sclerotiorum commences before hyphal penetration. This is the first time CaOx crystals have been reported on B. carinata infected with S. sclerotiorum. The shape of crystals varied as infection progressed. Long tetragonal rods were dominant 12 hpi (68% of crystal-containing samples), but by 72 hpi, 50% of stems displayed bipyramidal crystals, and only 23% had long rods. Scanning electron microscopy from 24 hpi revealed CaOx crystals in all samples, ranging from tiny irregular crystals (< 0.5 MUm) to large (up to 40 MUm) highly organized arrangements. Crystal morphology encompassed various forms, including tetragonal prisms, oval plates, crystal sand, and druses. Large conglomerates of CaOx crystals were observed in the hyphal mass 72 hpi and these are proposed as a strategy of the fungus to hold and detoxify Ca2+ions. The range of crystal morphologies suggests that S. sclerotiorum growth and infection controls the form taken by CaOx crystals. PMID- 25816023 TI - Comparative analysis of the influence of Fructus Ligustri Lucidi on a rat lumbar disc herniation model. AB - Lumbar disc herniation (LDH) is a term used for a group of conditions, including back pain, femoral nerve pain and sciatica. Currently available treatments and surgical options are insufficient for patients with LDH. Fructus Ligustri Lucidi (FLL) is a herb that is used for treating age-associated diseases. The results of the present study suggested that FLL may be used for treatment of patients with LDH. In the present study, matrix metalloproteinase-1, -3, -8 and -9 (MMP-1, -3, 8 and -9) protein and mRNA expression downregulation was observed in patients with LDH according to western blotting and reverse transcription-quantitative polymerase chain reaction. By contrast, upregulation of interleukin-2 (IL-2), IL 6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) expression was observed in patients with LDH, according to an enzyme-linked immunosorbent assay. Mechanical allodynia was observed in rats with LDH not treated with FLL; however, not in FLL treated rats. IL-2, IL-6, IL-8 and TNF-alpha expression levels in the serum from untreated rats were significantly higher than that of the FLL-treated rat models. Protein expression levels of MMPs in FLL-treated rats were lower than those in untreated rats. However, the mechanisms underlying the association between FLL and protein expression levels require further investigation. PMID- 25816024 TI - Predominant virulent IbA10G2 subtype of Cryptosporidium hominis in human isolates in Barcelona: a five-year study. AB - BACKGROUND: Cryptosporidium infection is a worldwide cause of diarrheal disease. To gain insight into the epidemiology of the infection in a certain geographic area, molecular methods are needed to determine the species/genotypes and subtypes. METHODOLOGY/PRINCIPAL FINDINGS: From 2004 to 2009, 161 cryptosporidiosis cases were detected in two hospitals in Barcelona. Diagnosis was performed by microscopic observation of oocysts in stool specimens following modified Ziehl-Neelsen staining. Most cases (82%) occurred in children. The number of cases increased in summer and autumn. Molecular characterization of Cryptosporidium was performed in 69 specimens, and C. hominis and C. parvum were identified in 88.4% and 10.1% of the cases, respectively. C. meleagridis was detected in one specimen. Subtyping based on the gp60 polymorphism showed six subtypes, four C. hominis and two C. parvum. Subtype IbA10G2 was the most prevalent subtype corresponding to 90% of all C. hominis isolates. This is the first report on the distribution of specific Cryptosporidium subtypes from humans in Spain. CONCLUSIONS/SIGNIFICANCE: In our geographic area, the anthroponotic behavior of C. hominis, the lower infective dose, and the higher virulence of certain subtypes may contribute to the high incidence of human cryptosporidiosis caused by the IbA10G2 subtype. Further studies should include populations with asymptomatic shedding of the parasite. PMID- 25816025 TI - Urinary CXCL1: a novel predictor of IgA nephropathy progression. AB - BACKGROUND: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. In recent years, consistent efforts have been made to develop new non-invasive biomarkers for IgAN progression. In our previous in vitro study we found mesangial derived CXCL1 as a contributor for kidney injury, and observed higher urinary CXCL1 levels in patients with IgAN. It implied that the urinary CXCL1 might be a potential biomarker. METHODS: In the present study, we enrolled 425 IgAN patients with follow-up data and detected their urinary CXCL1 levels at the time of renal biopsy, to explore the predictive value of urinary CXCL1 in IgAN progression. Urinary CXCL1 levels were measured using enzyme-linked immunosorbent assay. RESULTS: Urinary CXCL1 levels were associated with presently well established predictors of IgAN progression, including SBP (r = 0.138, p = 0.004), DBP (r = 0.114, p = 0.019), proteinuria (r = 0.155, p = 0.001), eGFR (r = -0.259, p<0.001) and tubular atrophy and interstitial fibrosis (r = 0.181, p<0.001). After adjusted for them, higher levels of urinary CXCL1 were independently associated with a greater risk of deterioration in renal function (HR, per s.d. increment of natural log-transformed CXCL1: 1.748; 95% CI: 1.222-2.499, P = 0.002). Furthermore, time-dependent receiver operating characteristic (ROC) curve showed that urinary CXCL1, when combined with proteinuria and eGFR, could enhance the prognostic value of these traditional predictors for IgAN progression. CONCLUSIONS: The results in our present study suggested urinary CXCL1 as a new non-invasive predictor of IgAN progression. PMID- 25816026 TI - Severe cholestatic hepatitis due to temozolomide: an adverse drug effect to keep in mind. Case report and review of literature. AB - Temozolomide is the current standard of therapy for postoperative patients with glioblastoma starting adjuvant radiotherapy. Hematologic adverse events are the most frequent side effects of temozolomide, while liver toxicity has been reported only in the post-marketing period. Here we report a case of severe temozolomide-induced liver injury during concurrent radiotherapy treatment, at a dose level of 75 mg/m2. The aim of this case report is to focus on the problems of temozolomide-induced hepatotoxicity. In conclusion, a close monitoring of liver function tests is recommended during treatment with temozolomide. PMID- 25816027 TI - Road accident due to a pancreatic insulinoma: a case report. AB - Insulinoma is a rare pancreatic endocrine tumor, typically sporadic and solitary. Although the Whipple triad, consisting of hypoglycemia, neuroglycopenic symptoms, and symptoms relief with glucose administration, is often present, the diagnosis may be challenging when symptoms are less typical. We report a case of road accident due to an episode of loss of consciousness in a patient with pancreatic insulinoma. In the previous months, the patient had occasionally reported nonspecific symptoms. During hospitalization, endocrine examinations were compatible with an insulin-producing tumor. Abdominal computerized tomography and magnetic resonance imaging allowed us to identify and localize the tumor. The patient underwent a robotic distal pancreatectomy with partial omentectomy and splenectomy. Insulin-producing tumors may go undetected for a long period due to nonspecific clinical symptoms, and may cause episodes of loss of consciousness with potentially lethal consequences. Robot-assisted procedures can be performed with the same techniques of the traditional surgery, reducing surgical trauma, intraoperative blood loss, and hospital stays. PMID- 25816028 TI - Safe contrast volumes for preventing contrast-induced nephropathy in elderly patients with relatively normal renal function during percutaneous coronary intervention. AB - The aim of this study was to evaluate contrast media volume to creatinine clearance (V/CrCl) ratio for predicting contrast-induced nephropathy (CIN) and to determine a safe V/CrCl cut off value to avoid CIN in elderly patients with relatively normal renal function during percutaneous coronary intervention (PCI). We prospectively enrolled 1020 consecutive elderly patients (age >=65 years) with relative normal renal function (baseline serum creatinine <1.5 mg/dL) undergoing PCI. Receiver operating characteristic (ROC) curves were used to identify the optimal cut off value of V/CrCl for detecting CIN. The predictive value of V/CrCl for CIN was assessed with a multivariate logistic regression. Thirty-nine patients (3.8%) developed CIN. There was a significant association between a higher V/CrCl ratio and CIN risk (P < 0.001). ROC curve analysis indicated that a V/CrCl ratio of 2.74 was a fair discriminator for CIN (C statistic = 0.68). After adjusting for other known CIN risk factors, V/CrCl ratios >2.74 remained significantly associated with CIN (odds ratio = 3.21, 95% confidence interval [CI] 1.45-7.09, P = 0.004) and worse long-term mortality (hazard ratio = 1.96, 95% CI 1.14-3.38, P = 0.016). A V/CrCl ratio >2.74 was a significant independent predictor of CIN and was independently associated with long-term mortality in elderly patients with relatively normal renal function. PMID- 25816029 TI - Improving hospital discharge time: a successful implementation of Six Sigma methodology. AB - Delays in discharging patients can impact hospital and emergency department (ED) throughput. The discharge process is complex and involves setting specific challenges that limit generalizability of solutions. The aim of this study was to assess the effectiveness of using Six Sigma methods to improve the patient discharge process. This is a quantitative pre and post-intervention study. Three hundred and eighty-six bed tertiary care hospital. A series of Six Sigma driven interventions over a 10-month period. The primary outcome was discharge time (time from discharge order to patient leaving the room). Secondary outcome measures included percent of patients whose discharge order was written before noon, percent of patients leaving the room by noon, hospital length of stay (LOS), and LOS of admitted ED patients. Discharge time decreased by 22.7% from 2.2 hours during the preintervention period to 1.7 hours post-intervention (P < 0.001). A greater proportion of patients left their room before noon in the postintervention period (P < 0.001), though there was no statistical difference in before noon discharge. Hospital LOS dropped from 3.4 to 3.1 days postintervention (P < 0.001). ED mean LOS of patients admitted to the hospital was significantly lower in the postintervention period (6.9 +/- 7.8 vs 5.9 +/- 7.7 hours; P < 0.001). Six Sigma methodology can be an effective change management tool to improve discharge time. The focus of institutions aspiring to tackle delays in the discharge process should be on adopting the core principles of Six Sigma rather than specific interventions that may be institution-specific. PMID- 25816030 TI - Quality appraisal of clinical practice guidelines on pancreatic cancer: a PRISMA compliant article. AB - Clinical practice guidelines (CPGs) play an important role in health care. The guideline development process should be precise and rigorous to ensure that the results are reproducible and not vague. To determine the quality of guidelines, the Appraisal of Guidelines and Research and Evaluation (AGREE) instrument was developed and introduced. The objective of this study is to assess the methodological quality of CPGs on pancreatic cancer. Five databases (included MEDLINE and EMBASE) and guideline websites were searched till April, 2014. The methodological quality of the guidelines was assessed by 4 authors independently using the AGREE II instrument. From 2526 citations, 21 relevant guidelines were included. The overall agreement among reviewers was moderate (intraclass correlation coefficient = 0.86, 95% confidence interval 0.64-0.96). The mean scores were moderate for the domains "scope and purpose" and "clarity of presentation"; however, they were low for the domains "stakeholder involvement" (31.22), "rigor of development", "applicability", and "editorial independence". These domain scores were lower when compared with international levels. There are 5 (23.81%) guidelines that described the systematic methods for searching. Moreover, only 5 (23.81%) guidelines reported that methodological expertise were included in the guideline developing teams. The quality and transparency of the development process and the consistency in the reporting of pancreatic cancer guidelines need to be improved. Many other methodological disadvantages were identified. In the future, pancreatic cancer CPGs should base on the best available evidence rigorously developed and reported. Greater efforts are needed to provide high-quality guidelines that serve as a useful and reliable tool for clinical decision making in this field. PMID- 25816031 TI - Trunk restraint therapy: the continuous use of the harness could promote feedback dependence in poststroke patients: a randomized trial. AB - The objective of this study was to evaluate the long-term effects of the task specific training with trunk restraint compared with the free one in poststroke reaching movements. The design was randomized trial. The setting was University of Campinas (Unicamp). Twenty hemiparetic chronic stroke patients were selected and randomized into 2 training groups: trunk restraint group (TRG) (reaching training with trunk restraint) and trunk free group (TFG) (unrestraint reaching). Twenty sessions with 45 minutes of training were accomplished. The patients were evaluated in pretreatment (PRE), posttreatment (POST) and 3 months after the completed training (RET) (follow-up). Main outcome measures were modified Ashworth scale, Barthel index, Fugl-Meyer scale, and kinematic analysis (movement trajectory, velocity, angles). A significant improvement, which maintained in the RET test, was found in the motor (P < 0.001) and functional (P = 0.001) clinical assessments for both groups. For trunk displacement, only TFG obtained a reduction statistical significance from PRE to the POST test (P = 0.002), supporting this result in the RET test. Despite both groups presenting a significant increase in the shoulder horizontal adduction (P = 0.003), only TRG showed a significant improvement in the shoulder (P = 0.001--PRE to POST and RET) and elbow (P = 0.038--PRE to RET) flexion extension, and in the velocity rate (P = 0.03--PRE to RET). The trunk restraint therapy showed to be a long-term effective treatment in the enhancement of shoulder and elbow active joint range and velocity rate but not in the maintenance of trunk retention. Trial registration: NCT02364141. PMID- 25816032 TI - Solid serous cystadenoma of the pancreas: a case report of 2 patients revealing vimentin, beta-catenin, alpha-1 antitrypsin, and alpha-1 antichymotrypsin as new immunohistochemistry staining markers. AB - Solid serous cystadenoma (SCA) of the pancreas is a rare type of pancreatic solid tumors. Postoperative pathological evaluation is of particular importance for distinguishing solid SCA of the pancreas from other pancreatic solid tumors. Here we present 2 cases of solid SCA of the pancreas, both preoperatively diagnosed with pancreatic neuroendocrine tumors. One case had positive OctreoScan test. Surgical resections were done for both cases. Postoperative immunohistochemistry assays were conducted with marker panels for SCA and 2 types of pancreatic solid tumors, which were neuroendocrine tumor (pNET) and solid pseudopapillary tumor (SPT). Two cases showed typical staining patterns for SCA markers. Notably, both cases showed positivity for 4 SPT markers (vimentin, beta-catenin, alpha-1 antitrypsin, and alpha-1 antichymotrypsin). Emphasis should be paid to those 4 new markers for future pathological diagnosis of solid SCA of the pancreas. PMID- 25816033 TI - Simulated activity but real trauma: a systematic review on Nintendo Wii injuries based on a case report of an acute anterior cruciate ligament rupture. AB - Video gaming injuries are classically regarded as eccentric accidents and novelty diagnoses. A case of an anterior cruciate ligament (ACL) tear sustained during Wii boxing spurned us to review the literature for other Wii-related injuries and Wii-based posttraumatic rehabilitation. The English literature listed in PubMed was systematically reviewed by searching for "Wii (trauma or injury or fracture)." Full-text articles were included after duplicate, blinded review. The type and treatment of injury as well as the Wii-based rehabilitation programs found were analyzed. Additionally, a new case of an acute ACL tear-sustained playing, Wii boxing, is additionally presented. After exclusion of irrelevant articles, 13 articles describing Wii-related injuries were included reporting on 3 fractures, 6 nonosseous, 2 overuse injuries, and 2 rehabilitation programs using Wii for posttraumatic rehabilitation. Among the presented Wii-related injuries, only 12.5% were treated conservatively, whereas 87.5% underwent either surgical or interventional treatment. Because of the reported case, the literature search was limited to Wii-related injuries excluding other video games. Another limitation of this article lies in the fact that mainly case reports but no controlled trials exist on the topic. Assumingly, primarily the more severe injuries are reported in the literature with an unknown number of possibly minor injuries. Motion-controlled video games, such as Wii, are becoming increasingly popular as a recreational entertainment. Because of their wide acceptance and entertaining nature, they are also increasingly recognized as a tool in rehabilitation. However, although the activity is simulated, injuries are real. Our systematic review shows that Wii gaming can lead to severe injuries, sometimes with lasting limitations. PMID- 25816034 TI - Nonalcoholic fatty liver disease as a risk factor of arterial stiffness measured by the cardioankle vascular index. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with risk factors for cardiovascular disease. The cardioankle vascular index (CAVI), a new measure of arterial stiffness, was recently developed and is independent of blood pressure. We investigated whether NAFLD is associated with arterial stiffness as measured using the CAVI in an apparently healthy population.A total of 2954 subjects without any known liver diseases were enrolled. NAFLD was diagnosed via typical ultrasonography. The clinical characteristics examined included age, sex, body mass index (BMI), waist circumference (WC), and the levels of aspartate aminotransferase, alanine aminotransferase, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol triglycerides, and glucose. Arterial stiffness was defined using an age- and sex-specific threshold of the upper quartile of the CAVI.NAFLD was found in 1249 (42.3%) of the analyzed subjects. Using an age-, sex-, and BMI-adjusted model, NAFLD was associated with a 42% increase in the risk for arterial stiffness (highest quartile of the CAVI). The risk for arterial stiffness increased according to the severity of NAFLD (adjusted odds ratio [95% confidence interval], 1.27 [1.02 - 1.57] vs 1.78 [1.37 2.31], mild vs moderate-to-severe, respectively). When adjusted for other risk factors, including BMI, WC, smoking status, diabetes, and hypertension, these relationships remained statistically significant.Patients with NAFLD are at a high risk for arterial stiffness regardless of classical risk factors. The presence of cardiometabolic risk factors may attenuate the prediction of arterial stiffness by means of NAFLD presence. Thus, physicians should carefully assess subjects with NAFLD for atherosclerosis and associated comorbidities. PMID- 25816035 TI - Serum Golgi protein 73 (GP73) is a diagnostic and prognostic marker of chronic HBV liver disease. AB - Alanine aminotransferase (ALT) is the most commonly used marker of liver injury, but normal ALT levels are seen in a proportion of chronic hepatitis B virus (HBV) infected patients with severe liver injury. Golgi protein 73 (GP73) is a promising alternative marker of liver injury. This study assessed the relation between GP73 levels and liver disease severity, monitored the kinetic changes in GP73 levels in chronic HBV patients receiving entecavir (ETV) therapy, and investigated the potential diagnostic and prognostic values of serum GP73 as a new liver injury biomarker in chronic HBV infections. This study enrolled 1150 patients with chronic HBV infections, 200 of whom were retrospectively enrolled in this study after receiving 1 year of ETV treatment. GP73 expression in liver tissue was detected by immunohistochemistry. GP73 levels in single or serial serum samples were measured by enzyme-linked immunosorbent assay. Immunohistochemical analysis indicated that GP73 protein expression in the liver increased progressively with pathologic progression from nonexistent or mild hepatitis to severe hepatitis and cirrhosis during chronic HBV infection. Serum GP73 levels were positively correlated with the disease severity of chronic HBV infections (r = 0.58, P < 0.001). In patients with normal ALT levels, serum GP73 concentrations were significantly higher in patients with prominent hepatic inflammatory injury and fibrosis than in patients without hepatic inflammatory injury or fibrosis. Serum GP73 concentrations and GP73 protein expression were decreased in the liver tissues of patients whose ALT levels normalized after 1 year of ETV antiviral therapy. Changes in serum GP73 levels were closely associated with changes in liver injury severity, and, therefore, GP73 may be an effective new liver inflammatory injury biomarker, and could be useful for monitoring the prognosis of chronic HBV infectious patients with normal ALT levels. PMID- 25816036 TI - TNM staging of pancreatic neuroendocrine tumors: an observational analysis and comparison by both AJCC and ENETS systems from 1 single institution. AB - We aimed to analyze the clinical characteristics and compare the surgical outcome of pancreatic neuroendocrine tumors (p-NETs) using the 2 tumor-node-metastasis (TNM) systems by both the American Joint Committee on Cancer (AJCC) Staging Manual (seventh edition) and the European Neuroendocrine Tumor Society (ENETS). Moreover, we sought to validate the prognostic value of the new AJCC criterion. Data of 145 consecutive patients who were all surgically treated and histologically diagnosed as p-NETs from January 2002 to June 2013 in our single institution were retrospectively collected and analyzed. The 5-year overall survival (OS) rates for AJCC classifications of stages I, II, III, and IV were 79.5%, 63.1%, 15.0%, and NA, respectively, (P < 0.005). As for the ENETS system, the OS rates at 5 years for stages I, II, III, and IV were 75.5%, 72.7%, 29.0%, and NA, respectively, (P < 0.005). Both criteria present no statistically notable difference between stage I and stage II (P > 0.05) but between stage I and stages III and IV (P < 0.05), as well as those between stage II and stages III and IV (P < 0.05). Difference between stage III and IV by ENETS was significant (P = 0.031), whereas that by the AJCC was not (P = 0.144). What's more, the AJCC Staging Manual (seventh edition) was statistically significant in both uni- and multivariate analyses by Cox regression (P < 0.005 and P = 0.025, respectively). Our study indicated that the ENETS TNM staging system might be superior to the AJCC Staging Manual (seventh edition) for the clinical practice of p-NETs. Together with tumor grade and radical resection, the new AJCC system was also validated to be an independent predictor for p-NETs. PMID- 25816037 TI - Characteristics of lumbar disc herniation with exacerbation of presentation due to spinal manipulative therapy. AB - The aim of this article was to delineate the characteristics of lumbar disc herniation (LDH) in patients with exacerbation of symptoms caused by spinal manipulative therapy (SMT). The main emphasis should be on the prevention of this condition by identifying relevant risk factors. Detailed clinico-radiological profiles of a total number of 10 LDH patients with exacerbation of presentation after SMT were reviewed. All the patients underwent neurological and magnetic resonance imaging examinations. Laminectomy and discectomy were performed, and follow-up was carried out in all patients. The duration of symptoms in the patients before SMT was 4-15 years. After the therapy, an acute exacerbation of back and radicular pain was observed within 24 h. Magnetic resonance imaging showed that L4-L5 was the most frequently affected level observed (7 patients), and each patient had a large disc fragment in the spinal canal. The disc fragments were classified into 3 types according to their localizations. The time internal between the exacerbation of presentation and surgery was 23.1 days. No perioperative complications were noted. All the patients were relieved of radicular pain a few days after surgery. During postoperative follow-up, all patients regained the ability to walk; one patient received catheterization for 1 month and another for 6 months. Eight patients reported a complete resolution of presentation and the rest 2 patients were significantly improved. SMT should be prohibited in some LDH patients to prevent neurological damages, in whom there are 5 possible risk factors. Surgical results for these patients are encouraging. PMID- 25816038 TI - Medium-based noninvasive preimplantation genetic diagnosis for human alpha thalassemias-SEA. AB - To develop a noninvasive medium-based preimplantation genetic diagnosis (PGD) test for alpha-thalassemias-SEA. The embryos of alpha-thalassemia-SEA carriers undergoing in vitro fertilization (IVF) were cultured. Single cells were biopsied from blastomeres and subjected to fluorescent gap polymerase chain reaction (PCR) analysis; the spent culture media that contained embryo genomic DNA and corresponding blastocysts as verification were subjected to quantitative-PCR (Q PCR) detection of alpha-thalassemia-SEA. The diagnosis efficiency and allele dropout (ADO) ratio were calculated, and the cell-free DNA concentration was quantitatively assessed in the culture medium. The diagnosis efficiency of medium based alpha-thalassemias-SEA detection significantly increased compared with that of biopsy-based fluorescent gap PCR analysis (88.6% vs 82.1%, P < 0.05). There is no significant difference regarding ADO ratio between them. The optimal time for medium-based alpha-thalassemias-SEA detection is Day 5 (D5) following IVF. Medium based alpha-thalassemias-SEA detection could represent a novel, quick, and noninvasive approach for carriers to undergo IVF and PGD. PMID- 25816039 TI - Epidemiology and long-term survival in HIV-infected patients with Pneumocystis jirovecii pneumonia in the HAART era: experience in a university hospital and review of the literature. AB - As highly active antiretroviral treatment (HAART) is widely available, the incidence of Pneumocystis jirovecii pneumonia (PJP) has decreased significantly but still represents a significant cause of morbidity and mortality in developed countries. We analyzed all the cases with PJP in human immunodeficiency virus (HIV)-infected patients from 2000 to 2013 in a university hospital in Barcelona, Spain, and conducted a systematic literature review to evaluate data regarding incidence, mortality, and long-term survival after PJP in developed settings. One hundred thirty-six episodes of PJP were analyzed. During the study period, the incidence decreased significantly (from 13.4 cases/1000 patients-year to 3.3 cases/1000 patients-year, P < 0.001). Oppositely, median age of the patients increased from 34 years in 2000 to 45 in 2013 (P = 0.024). PJP preceded HIV diagnosis in nearly 50% of the cases. Fifteen (11%) patients died during the PJP episode. The main risk factor for in-hospital mortality in our cohort was age >50 years (odds ratio 4.96, 95% confidence interval [CI] 1.45-15.14). Patients who survived were followed-up during a mean time of 44 months. Overall 5-year survival of patients after hospital discharge was 73%. Survival likelihood was 54% higher (88% [95% CI 81-96]) among HAART-adherent patients. Mean age and the proportion of patients with unknown HIV infection at the time of PJP diagnosis have increased in developed countries in the HAART era. Although the incidence has decreased, in-hospital mortality remains stable in this setting. Long-term survival is very high among HAART-adherent patients. PMID- 25816040 TI - Clinicopathological features and prognostic factors of young patients with surgically treated liver cancer. AB - This article compares the clinical characteristics and prognosis of young patients in different age groups with liver cancer (LC). In this retrospective study, we searched the Surveillance, Epidemiology, and End Results population based database and identified 2641 patients who had been diagnosed with LC between 1988 and 2005. These patients were categorized into 2 different age ranges: Group 1 (<=35 years) and Group 2 (36-45 years). Five-year cancer-specific survival (CSS) data were obtained. Kaplan-Meier methods and multivariable Cox regression models were used to analyze the long-term survival outcomes and risk factors. There were significant differences between the age groups for stage and tumor size (P < 0.001). The 5-year liver CSS rate was 20.4% and 14.5%, respectively (P < 0.001). Univariate and multivariate analysis also confirmed the difference (P < 0.001). Further analysis showed that this significant difference existed in localized, regional, and distant-stage patients. Young patients with LC of age 18 to 45 years are inherently heterogeneous. Patients aged <=35 years have better CSS than those aged 36 to 45 years, despite exhibiting unfavorable clinicopathological characteristics. PMID- 25816041 TI - Cardiovascular dysfunction due to sympathetic hypoactivity after complete cervical spinal cord injury: a case report and literature review. AB - Spinal cord injury (SCI) is one of the most devastating of all traumatic events; it may cause permanent dysfunction in several organ systems and lead to motor and sensory impairment. Cardiovascular dysfunction has been recognized to be the leading cause of morbidity and mortality in the acute and chronic stages following SCI. Although cardiovascular dysfunction causes the deaths of many SCI patients, most clinicians are unfamiliar with the phenomenon. The purpose of reporting our case is to remind clinicians to consider the possibility of cardiovascular dysfunction in patients with complete SCI. The patient signed informed consent for publication of this case report and any accompanying image. The ethical approval of this study was waived by the ethics committee of the Chonbuk National University Hospital, Jeonju, Korea, because this study was a case report and the number of patients was <3. A 63-year-old man was transferred to our emergency room after a fall. He complained of weakness and numbness of the lower extremity. Radiologic evaluation revealed C7/T1 unilateral facet dislocation with spinal cord contusion. On neurologic examination, the patient exhibited a paraplegic state below the T4 dermatome because of complete SCI. His vital signs were stable, but respiration was shallow. We performed intraoperative manual reduction and anterior interbody fusion. On the second postoperative day, the patient experienced sudden cardiac arrest after he was shifted from a supine to a semilateral position. Upon position change, heart rate was decreased <40 beats/min and blood pressure could not be checked. We immediately started cardiac massage and administered atropine 0.5 mg and epinephrine 1 mg, and the patient was successfully resuscitated. Cardiac arrest recurred when we performed endotracheal suction or changed patient's position. Echocardiographic and Holter monitoring findings demonstrated normal heart function and sinus bradycardia, and there was no evidence of pulmonary thromboembolism. We concluded that cardiac arrest was induced by sympathetic hypoactivity following complete SCI. Two months later, this phenomenon had resolved, and 4 months after presentation, he was discharged reliant on a home ventilator. Through this report, we emphasize that a thorough understanding of cardiovascular dysfunction following SCI is important for establishing a diagnosis and optimizing clinical outcomes. PMID- 25816044 TI - Insufficient dollars and qualified personnel to meet United States mental health needs. AB - The American populace currently supports the need for providing additional mental health services for adolescents who frequently express anger and mood instability and maybe are at risk for major psychiatric disorders and behavioral problems; Vietnam, Iraqi, and Afghanistan veterans or military personnel still on duty diagnosed with posttraumatic stress disorder, depression, or other similar combat related disabilities; the approximately 1 million prisoners currently incarcerated primarily because of substance abuse and needing medically related rehabilitative services; and senior citizens who experience dementia and depression and require improved therapeutics. The problems outlined herein are as follows: far too limited monies are being spent for mental health services (5.6% of total US expenditures for health or roughly one fifth of what is consumed for hospital care); effective therapies are often lacking; and there is a shortage of qualified mental health personnel except in upscale urban and suburban areas. Unfortunately, these problems are so immense that, even with enhanced prioritization of our available resources, they are still not entirely solvable. The American public may continue to impart lip service when attempting to respond to our nation's mental health needs or may decide to spend vastly more money for such care. The latter choice may not be forthcoming in the near future for various cultural-societal-clinical-fiscal reasons. PMID- 25816042 TI - C-arm cone-beam CT-guided transthoracic lung core needle biopsy as a standard diagnostic tool: an observational study. AB - C-arm cone-beam computed tomography (CT)-guided transthoracic lung core needle biopsy (CNB) is a safe and accurate procedure for the evaluation of patients with pulmonary nodules. This article will focus on the clinical features related to CNB in terms of diagnostic performance and complication rate. Moreover, the concept of categorizing pathological diagnosis into 4 categories, which could be used for clinical management, follow-up, and quality assurance is also introduced. We retrospectively collected data regarding 375 C-arm cone-beam CT guided CNBs from January 2010 and June 2014. Clinical and radiological variables were evaluated in terms of success or failure rate. Pathological reports were inserted in 4 homogenous groups (nondiagnostic--L1, benign--L2, malignant not otherwise specified--L3, and malignant with specific histotype--L4), defining for each category a hierarchy of suggested actions. The sensitivity, specificity, and positive and negative predictive value and accuracy for patients subjected to CNBs were of 96.8%, 100%, 100%, 100%, and 97.2%, respectively. Roughly 75% of our samples were diagnosed as malignant, with 60% lung adenocarcinoma diagnoses. Molecular analyses were performed on 85 malignant samples to verify applicability of targeted therapy. The rate of "nondiagnostic" samples was 12%. C-arm cone-beam CT-guided transthoracic lung CNB can represent the gold standard for the diagnostic evaluation of pulmonary nodules. A clinical and pathological multidisciplinary evaluation of CNBs was needed in terms of integration of radiological, histological, and oncological data. This approach provided exceptional performances in terms of specificity, positive and negative predictive values; sensitivity in our series was lower compared with other large studies, probably due to the application of strong criteria of adequacy for CNBs (L1 class rate). The satisfactory rate of collected material was evaluated not only in terms of merely diagnostic performances but also for predictive results by molecular analysis. PMID- 25816043 TI - Retinal nerve fiber layer thickness in myopic, emmetropic, and hyperopic children. AB - The purpose of this study was to investigate the peripapillary retinal nerve fiber layer (RNFL) thickness in myopic, emmetropic, and hyperopic children using optical coherence tomography. Two-hundred one right eyes of subjects aged 4 to 18 years were divided into 3 groups based on their postcycloplegic spherical equivalent: myopes (<-1.0 D), emmetropes (>=-1.0 to <=+1.0 D), and hyperopes (>+1.0 D). The RNFL was correlated with age, spherical equivalent, and axial length. The RNFL was compared between the 3 groups before and after age adjustment. The RNFL was thickest in the hyperopic group (107.2 +/- 10.13 MUm, n = 73), followed by the emmetropic group (102.5 +/- 9.2 MUm, n = 61), and then the myopic group (95.7 +/- 10.3, n = 67) (all P < 0.0001). The myopic group (9.6 +/- 3.9 years) was significantly older than the emmetropic (6.9 +/- 2.7 years) and hyperopic (6.5 +/- 1.9 years) groups (both P < 0.0001). When adjusted for age, myopes had a thinner RNFL than the other 2 groups (all P < 0.0001), but there was no RNFL thickness difference between the emmetropic and hyperopic groups (P > 0.05). A thinner RNFL was associated with an older age (r = -0.4, P < 0.0001), a more myopic spherical equivalent (r = 0.5, P < 0.0001), and a longer axial length (r = -0.4, P < 0.0001) on Pearson correlation analysis. The apparently thicker RNFL in hyperopic and emmetropic children was attributed to their younger age as compared with their myopic counterparts. When adjusted for age, only myopia was associated with a thinner RNFL, with emmetropic and hyperopic children having equal RNFL thicknesses. Advancing age, a more myopic spherical equivalent, and a longer axial length were associated with a thinner RNFL in children. PMID- 25816045 TI - Despair or hope: the future of mental health service delivery in the United States. PMID- 25816046 TI - Religious vs. conventional cognitive behavioral therapy for major depression in persons with chronic medical illness: a pilot randomized trial. AB - We examine the efficacy of conventional cognitive behavioral therapy (CCBT) versus religiously integrated CBT (RCBT) in persons with major depression and chronic medical illness. Participants were randomized to either CCBT (n = 67) or RCBT (n = 65). The intervention in both groups consisted of ten 50-minute sessions delivered remotely during 12 weeks (94% by telephone). Adherence to treatment was similar, except in more religious participants in whom adherence to RCBT was slightly greater (85.7% vs. 65.9%, p = 0.10). The intention-to-treat analysis at 12 weeks indicated no significant difference in outcome between the two groups (B = 0.33; SE, 1.80; p = 0.86). Response rates and remission rates were also similar. Overall religiosity interacted with treatment group (B = 0.10; SE, 0.05; p = 0.048), suggesting that RCBT was slightly more efficacious in the more religious participants. These preliminary findings suggest that CCBT and RCBT are equivalent treatments of major depression in persons with chronic medical illness. Efficacy, as well as adherence, may be affected by client religiosity. PMID- 25816047 TI - Correcting errors in Turkington et al. (2014): taking criticism seriously. PMID- 25816048 TI - Cognitive behavioral techniques for psychosis: a biostatistician's perspective. PMID- 25816049 TI - Increased Hair Cortisol Concentrations and BMI in Patients With Pituitary-Adrenal Disease on Hydrocortisone Replacement. AB - CONTEXT: Intrinsic imperfections and lack of reliable biomarkers preclude optimal individual dosing of hydrocortisone replacement in adrenal insufficiency (AI). However, the clinical relevance of optimal dosing is exemplified by frequently occurring side effects of overreplacement and the dangers of underreplacement. Cortisol in scalp hair has been identified as a retrospective biomarker for long term cortisol exposure. We compared hair cortisol concentrations (CORT(hair)) of patients with primary or secondary AI on replacement therapy with those of patient controls with a pituitary disease without AI (PCs) and of healthy controls (HCs). METHODS: In this cross-sectional study, hair samples and anthropometric data were collected in 132 AI patients (52 males), 42 PCs (11 males), and 195 HCs (90 males). The proximal 3 cm of hair were used. CORT(hair) were measured using an ELISA. RESULTS: CORT(hair) were higher in AI patients than in HCs and PCs (P < .001), and hydrocortisone dose correlated with CORT(hair) (P = .04). Male AI patients demonstrated higher CORT(hair) than female patients (P < .001). AI patients had higher body mass index (BMI) than HCs (P < .001), and BMI correlated with CORT(hair) in the whole sample (P < .001). CONCLUSION: Physiological hydrocortisone replacement is associated with increased CORT(hair). The association between CORT(hair) and BMI could suggest a mild overtreatment that may lead to adverse anthropomorphic side effects, especially in males. CORT(hair) measurements may be a promising additional tool to monitor cumulative hydrocortisone replacement in AI. PMID- 25816050 TI - Association of Plasma Ceramides and Sphingomyelin With VLDL apoB-100 Fractional Catabolic Rate Before and After Rosuvastatin Treatment. AB - INTRODUCTION: The objective of the study was to examine post hoc associations between plasma sphingolipids and lipoprotein kinetics in men with the metabolic syndrome after rosuvastatin treatment. MATERIALS AND METHODS: Plasma sphingolipid profiling, determined by tandem mass spectrometry, was performed in a randomized, double-blind, triple-crossover trial (n = 12) of 5-week treatment periods with placebo or rosuvastatin (10 or 40 mg/d) with 2-week washouts between treatments. RESULTS AND DISCUSSION: Baseline plasma ceramides were associated with very low density lipoprotein (VLDL) apolipoprotein (apo)-B-100 concentration (r = 0.58, P < .05) and inversely with VLDL apoB-100 fractional catabolic rate (FCR; r = 0.67, P = .02). Posttreatment changes with rosuvastatin (40 mg/d) in plasma ceramides were inversely associated with VLDL apoB-100 FCR (r = -0.62, P = .03) independent of changes in plasma triglycerides, cholesterol, and low-density lipoprotein-cholesterol. By contrast, baseline and postrosuvastatin treatment plasma sphingomyelin levels were not associated with apoB-100 kinetics. Plasma ceramides and sphingomyelin were not associated with the kinetics or concentrations of high-density lipoprotein apoA-I, and low-density lipoprotein apoB. In the metabolic syndrome, the ability of rosuvastatin to increase VLDL apoB-100 FCR may reflect ceramide-specific mechanistic actions and/or sphingolipid exchange. PMID- 25816051 TI - Plasma GAD65, a Marker for Early beta-Cell Loss After Intraportal Islet Cell Transplantation in Diabetic Patients. AB - CONTEXT AND OBJECTIVE: Intraportal islet transplantation can restore insulin production in type 1 diabetes patients, but its effect is subject to several interfering processes. To assess the influence of beta-cell loss before and during engraftment, we searched for a real-time marker of beta-cell destruction. Previous studies showed that 65-kDa isoform of glutamate decarboxylase (GAD65) is discharged by chemically damaged rat beta-cells. We therefore examined the utility of the GAD65 assay to detect and quantify destruction of human beta-cells in vitro and in vivo. DESIGN AND PARTICIPANTS: A time-resolved fluorescence immunoassay was used to measure GAD65 discharge from beta-cells after administration of toxins or after intraportal transplantation. The study in patients involved type 1 diabetes recipients of 56 implants. RESULTS: GAD65 was discharged from cultured human beta-cells between 4 and 24 hours after acute insult and proportional to the number of dying cells. It was also detected in plasma during the first 24 hours after intraportal transplantation of human islet cell grafts. Diabetic nude rat recipients without hyperglycemic correction exhibited higher plasma GAD65 levels than those with normalization. In type 1 diabetes recipients of grafts with 2-5 * 10(6) beta-cells per kilogram of body weight, five of six with plasma GAD65 greater than 1 ng/mL failed to increase plasma C-peptide by greater than 0.5 ng/mL at posttransplant month 2, whereas five of six with undetectable plasma GAD 65 and 15 of 19 with intermediate levels did result in such increase. CONCLUSION: Plasma GAD65 qualifies as a marker for early beta-cell loss after intraportal transplantation. Further studies are needed to extend its clinical utility. PMID- 25815923 TI - Search for monotop signatures in proton-proton collisions at ?s=8 TeV. AB - Results are presented from a search for new decaying massive particles whose presence is inferred from an imbalance in transverse momentum and which are produced in association with a single top quark that decays into a bottom quark and two light quarks. The measurement is performed using 19.7 fb^{-1} of data from proton-proton collisions at a center-of-mass energy of 8 TeV, collected with the CMS detector at the CERN LHC. No deviations from the standard model predictions are observed and lower limits are set on the masses of new invisible bosons. In particular, scalar and vector particles, with masses below 330 and 650 GeV, respectively, are excluded at 95% confidence level, thereby substantially extending a previous limit published by the CDF Collaboration. PMID- 25816052 TI - The impact of matrix metalloproteinase 2 on prognosis and clinicopathology of breast cancer patients: a systematic meta-analysis. AB - BACKGROUNDS: Matrix metalloproteinase 2 (MMP-2) plays a crucial role in the progression of breast cancer (BC). The prognostic role of MMP-2 expression in BC patients has been widely reported, but the results were inconsistent. Thus, a meta-analysis was conducted to gain a better insight into the impact of MMP-2 expression on survival and clinicopathological features of BC patients. METHODS: Identical search strategies were used to search relevant literatures in electronic databases update to August 1, 2014. Individual hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were extracted and pooled to evaluate the strength of the association between positive MMP-2 expression and survival results and clinicopathological features of BC patients. Begg's tests, Egger's tests and funnel plots were used to evaluate publication bias. Heterogeneity and sensitivity analysis were also assessed. All the work was completed using STATA. RESULTS: Pooled HRs and 95% CIs suggested that MMP-2 expression had an unfavorable impact on both OS (HR: 1.53, 95% CI: 1.29-1.82) and DFS/RFS/DDFS (HR: 1.41, 95% CI: 1.07-1.86) in BC patients. Furthermore, MMP-2 expression was significantly associated with lymph node metastasis (positive vs negative: OR 1.91, 95% CI 1.17-3.12). CONCLUSION: In conclusion, positive MMP-2 expression might be a significant predictive factor for poor prognosis in patients with BC. PMID- 25816053 TI - Lymphatic transport of orally administered probucol-loaded mPEG-DSPE micelles. AB - CONTEXT: Transporting drugs through the lymphatic system has attracted increasing attention. Lipid-based formulations have been proved to be an effective way to improve systemic bioavailability of highly lipophilic drugs by increasing intestinal lymphatic transport. OBJECTIVE: The formulation of polymer micelle was developed for probucol to improve its intestinal lymphatic transport. MATERIALS AND METHODS: Methoxy-polyethylenelglycol-distearyl phosphatidyl-ethanolamine (mPEG-DSPE) polymer was chosen to develop the micelles for probucol. The physicochemical properties were characterized. Caco-2 cell model, unconscious and conscious lymph duct cannulated rat models were established for in vitro and in vivo evaluation of lymphatic transport. RESULTS: In vitro evaluation in the Caco 2 cell model showed that the micellar formulation could significantly increase the uptake and transport of probucol. The study in unconscious and conscious lymph duct cannulated rat models further verified the significant enhancement of lymphatic transport of probucol by mPEG-DSPE micelles. DISCUSSION AND CONCLUSION: These results suggested that mPEG-DSPE micellar formulation could provide a useful alternative approach for improving the lymphatic transport of hydrophobic compounds. PMID- 25816054 TI - Pattern recognition of monosaccharides via a virtual lectin array constructed by boronate affinity-based pH-featured encoding. AB - Lectin array is an important tool in the fields of carbohydrate chemistry, glycobiology, and glycomics. Because natural lectins are associated with some apparent disadvantages such as tedious purification and easy loss of activity, artificial materials are applied to overcome such shortages by mimicking and replacing lectins in an artificial lectin array, among which boronate affinity based materials are very outstanding and widely used. However, complicated synthetic works are often involved to design and create boronate affinity-based lectin-mimics. In this work, a facile and novel method was proposed to establish a virtual lectin array based on boronate affinity-based pH-featured encoding for discrimination of monosaccharides by pattern recognition. The dependence of boronate affinity on environmental pH was selected to encode each monosaccharide for feature generation, and the pH-featured encoding was used to construct the virtual lectin array. On the basis of the virtual array, pattern recognition algorithms were applied for data analysis. Monosaccharides were discriminated by principal component analysis, and the relations in the virtual lectin array were unraveled by cluster analysis. In this proof-of-concept work, without complicated synthesis or preparation, the proposed method was successful in mimicking lectin array and discriminating nine elementary monosaccharides found in nature, and it was also a new way of encoding in expanding the applications of boronate affinity based materials and methods in the field of biomimetics. PMID- 25816056 TI - Differential MR delayed enhancement patterns of chronic myocardial infarction between extracellular and intravascular contrast media. AB - OBJECTIVES: Because the distribution volume and mechanism of extracellular and intravascular MR contrast media differ considerably, the enhancement pattern of chronic myocardial infarction with extracellular or intravascular media might also be different. This study aims to investigate the differences in MR enhancement patterns of chronic myocardial infarction between extracellular and intravascular contrast media. MATERIALS AND METHODS: Twenty pigs with myocardial infarction underwent cine MRI, first pass perfusion MRI and delayed enhancement MRI with extracellular or intravascular media at four weeks after coronary occlusion. Myocardial blood flow (MBF) was determined with microsphere measurement. The infarction histopathological changes were evaluated by hematoxylin and eosin staining and Masson's trichrome method. RESULTS: Cine MRI revealed the reduced wall thickening in chronic infarction compared with normal myocardium. Moreover, significant wall thinning in chronic infarction was observed in cine MRI. Peak first-pass signal intensity didn't significantly differ between chronic infarction and normal myocardium no matter what kinds of contrast media. At the following delayed enhancement phase, extracellular media enhanced signal intensity was significantly higher in chronic infarction than in normal myocardium. Conversely, intravascular media-enhanced signal intensity was almost equivalent among chronic infarction and normal myocardium. At four weeks after infarction, MBF in chronic infarction approached to that in normal myocardium. Large thick-walled vessels were detected at peri-infarction zones. The cardiomyocytes were replaced by scar tissue consisting of dilated blood vessels and discrete fibers of collagen. CONCLUSIONS: Chronic infarction was characterized by the significantly reduced wall thickening and the definite wall thinning. First-pass myocardial perfusion defect was not detected in chronic infarction with two media due to the significantly recovered MBF and well developed collateral vessels. Infarction remodeling enlarged the extracellular compartment, which was available for extracellular media but not accessible to intravascular media. Extracellular media identified chronic infarction as the hyper-enhancement; nonetheless, intravascular media didn't provide delayed enhancement. PMID- 25816055 TI - Air Pollution from Road Traffic and Systemic Inflammation in Adults: A Cross Sectional Analysis in the European ESCAPE Project. AB - BACKGROUND: Exposure to particulate matter air pollution (PM) has been associated with cardiovascular diseases. OBJECTIVES: In this study we evaluated whether annual exposure to ambient air pollution is associated with systemic inflammation, which is hypothesized to be an intermediate step to cardiovascular disease. METHODS: Six cohorts of adults from Central and Northern Europe were used in this cross-sectional study as part of the larger ESCAPE project (European Study of Cohorts for Air Pollution Effects). Data on levels of blood markers for systemic inflammation-high-sensitivity C-reactive protein (CRP) and fibrinogen were available for 22,561 and 17,428 persons, respectively. Land use regression models were used to estimate cohort participants' long-term exposure to various size fractions of PM, soot, and nitrogen oxides (NOx). In addition, traffic intensity on the closest street and traffic load within 100 m from home were used as indicators of traffic air pollution exposure. RESULTS: Particulate air pollution was not associated with systemic inflammation. However, cohort participants living on a busy (> 10,000 vehicles/day) road had elevated CRP values (10.2%; 95% CI: 2.4, 18.8%, compared with persons living on a quiet residential street with < 1,000 vehicles/day). Annual NOx concentration was also positively associated with levels of CRP (3.2%; 95% CI: 0.3, 6.1 per 20 MUg/m3), but the effect estimate was more sensitive to model adjustments. For fibrinogen, no consistent associations were observed. CONCLUSIONS: Living close to busy traffic was associated with increased CRP concentrations, a known risk factor for cardiovascular diseases. However, it remains unclear which specific air pollutants are responsible for the association. PMID- 25816057 TI - 3,3'-Diindolylmethane attenuates cardiac H9c2 cell hypertrophy through 5' adenosine monophosphate-activated protein kinase-alpha. AB - 3,3'-Diindolylmethane (DIM) is the major product of the acid-catalyzed condensation of indole-3-carbinol (I3C), a component of extracts of Brassica food plants. Numerous studies have suggested that DIM has several beneficial biological activities, including elimination of free radicals, antioxidant and anti-angiogenic effects and activation of apoptosis of various tumor cells. In the present study, an in vitro model was established, using 1 uM angiotensin II (Ang II) in cultured rat cardiac H9c2 cells, to observe the effects of DIM on cardiac hypertrophy. Following 24 h stimulation with DIM (1, 5, and 10 uM) with or without Ang II, cells were characterized by immunofluorescence to analyze cardiac alpha-actinin expression. Cardiomyocyte hypertrophy and molecular markers of cardiac hypertrophy were assessed by quantitative polymerase chain reaction. Atrial natriuretic peptide, brain natriuretic peptide and myosin heavy chain beta mRNA expression were induced by Ang II in H9c2 cells treated with the optimal concentration of DIM for 6, 12, and 24 h. The levels of phosphorylated and total proteins of the 5' AMP-activated protein kinase alpha (AMPKalpha)/mitogen activated protein kinase (MAPK)/mechanistic target of rapamycin (mTOR) signaling pathways in H9c2 cells treated with DIM for 0, 15, 30, and 60 min induced by Ang II were determined by western blot analysis. The results showed that DIM attenuated cellular hypertrophy in vitro, enhanced the phosphorylation of AMPKalpha and inhibited the MAPK-mTOR signaling pathway in response to hypertrophic stimuli. PMID- 25816058 TI - [Differential diagnoses of paranasal sinus disorders: a radiological approach]. PMID- 25816061 TI - [Bursitis trochanterica as a sequela of tendinitis calcarea of the m. gluteus med. tendon]. PMID- 25816060 TI - Integrative teaching in radiology - a survey. AB - PURPOSE: To survey integrative teaching in radiology at German universities. MATERIALS AND METHODS: A questionnaire about radiological education was sent electronically to all 37 chairpersons of university radiology departments in Germany. The questions included the course type, teaching methods, concept, perception, and advantages and disadvantages of integrative teaching. Statistical analysis was performed with nonparametric statistics and chi-square test. RESULTS: The survey was considered representative with a return rate of 68 %. Integrative teaching is established at 4/5 of all departments. Integrative teaching is well accepted with an acceptance rate that is significantly higher in so-called "Modellstudiengangen" [model courses of study] (100 %) compared to conventional courses of study (72 %). The advantages of integrative teaching include linking of content (92 %) and preparation for interdisciplinary work (76 %). The disadvantages include high effort (75 %) and time (67 %) for organization. Furthermore, there is a risk that basic radiological facts and knowledge cannot be conveyed and that the visibility of radiology as an independent discipline is lost. Conventional radiological teaching has a similarly high acceptance (84 %) compared to integrative courses (76 %). CONCLUSION: Integrative teaching has a high acceptance among chairpersons in radiology in Germany despite the greater effort. A good interdisciplinary collaboration is essential for integrative teaching and at the same time this can be conveyed to the students. However, the visibility of radiology as a discipline and the possibility to cover basic radiological content must be ensured. Therefore, both conventional courses and integrative teaching seems reasonable, especially in cross-disciplinary subjects such as radiology. KEY POINTS: Both integrative teaching and conventional radiological teaching are highly accepted. The advantages include the linking of multidisciplinary content and the preparation for interdisciplinary cooperation. The disadvantages include more time and effort for organization and reduced visibility of cross-disciplinary subjects. PMID- 25816067 TI - [Chief executive officer participation as medical coworker based on legal and labor law requirements]. PMID- 25816068 TI - De novo transcriptomic analysis of peripheral blood lymphocytes from the Chinese goose: gene discovery and immune system pathway description. AB - BACKGROUND: The Chinese goose is one of the most economically important poultry birds and is a natural reservoir for many avian viruses. However, the nature and regulation of the innate and adaptive immune systems of this waterfowl species are not completely understood due to limited information on the goose genome. Recently, transcriptome sequencing technology was applied in the genomic studies focused on novel gene discovery. Thus, this study described the transcriptome of the goose peripheral blood lymphocytes to identify immunity relevant genes. PRINCIPAL FINDINGS: De novo transcriptome assembly of the goose peripheral blood lymphocytes was sequenced by Illumina-Solexa technology. In total, 211,198 unigenes were assembled from the 69.36 million cleaned reads. The average length, N50 size and the maximum length of the assembled unigenes were 687 bp, 1,298 bp and 18,992 bp, respectively. A total of 36,854 unigenes showed similarity by BLAST search against the NCBI non-redundant (Nr) protein database. For functional classification, 163,161 unigenes were comprised of three Gene Ontology (Go) categories and 67 subcategories. A total of 15,334 unigenes were annotated into 25 eukaryotic orthologous groups (KOGs) categories. Kyoto Encyclopedia of Genes and Genomes (KEGG) database annotated 39,585 unigenes into six biological functional groups and 308 pathways. Among the 2,757 unigenes that participated in the 15 immune system KEGG pathways, 125 of the most important immune relevant genes were summarized and analyzed by STRING analysis to identify gene interactions and relationships. Moreover, 10 genes were confirmed by PCR and analyzed. Of these 125 unigenes, 109 unigenes, approximately 87%, were not previously identified in the goose. CONCLUSION: This de novo transcriptome analysis could provide important Chinese goose sequence information and highlights the value of new gene discovery, pathways investigation and immune system gene identification, and comparison with other avian species as useful tools to understand the goose immune system. PMID- 25816069 TI - Altered hemodynamic activity in conduct disorder: a resting-state FMRI investigation. AB - BACKGROUND: Youth with conduct disorder (CD) not only inflict serious physical and psychological harm on others, but are also at greatly increased risk of sustaining injuries, developing depression or substance abuse, and engaging in criminal behaviors. The underlying neurobiological basis of CD remains unclear. OBJECTIVE: The present study investigated whether participants with CD have altered hemodynamic activity under resting-state conditions. METHODS: Eighteen medication-naive boys with CD and 18 age- and sex- matched typically developing (TD) controls underwent functional magnetic resonance imaging (MRI) scans in the resting state. The amplitude of low-frequency fluctuations (ALFF) was measured and compared between the CD and TD groups. RESULTS: Compared with the TD participants, the CD participants showed lower ALFF in the bilateral amygdala/parahippocampus, right lingual gyrus, left cuneus and right insula. Higher ALFF was observed in the right fusiform gyrus and right thalamus in the CD participants compared to the TD group. CONCLUSIONS: Youth with CD displayed widespread functional abnormalities in emotion-related and visual cortical regions in the resting state. These results suggest that deficits in the intrinsic activity of resting state networks may contribute to the etiology of CD. PMID- 25816070 TI - Progressive thinning of visual cortex in primary open-angle glaucoma of varying severity. AB - The aim of this study was to investigate possible changes of cortical thickness in the visual cortex in primary open-angle glaucoma (POAG) of varying severity. Twenty normal controls (NC), 20 mild (MP) and 17 severe (SP) POAG patients were recruited and scanned using magnetic resonance imaging. Cortical thickness analyses with regions of interest (V1, V2, ventral V3, V4 and V5/MT+) were used to assess the cortical changes among the three groups. Furthermore, the associations of cortical thickness with retinal nerve fiber layer (RNFL) thickness and mean deviation of visual field were analyzed. Compared with the NC group, decreased cortical thickness was detected in the bilateral V5/MT+ areas in the MP group and the left V1, bilateral V2 and V5/MT+ areas in the SP group. Cortical thinning of the bilateral V2 areas was detected in the SP group compared with the MP group. In addition, cortical thinning of these visual areas was related to the ophthalmologic measurements. In conclusion, POAG patients exhibit cortical thinning in the bilateral V5/MT+ in the early stage of disease. The cortical degeneration in visual areas is discrepant with disease progressing and the dorsal pathway might be selectively damaged in POAG. Therefore, the cortical thinning of these visual areas may play a key role in the progression of POAG and can serve as a novel biomarker for accurately evaluating the severity of POAG. PMID- 25816071 TI - Salubrinal protects cardiomyocytes against apoptosis in a rat myocardial infarction model via suppressing the dephosphorylation of eukaryotic translation initiation factor 2alpha. AB - The aim of the present study was to examine the role of eIF2alpha in cardiomyocyte apoptosis and evaluate the cardioprotective role of salubrinal in a rat myocardial infarction (MI) model. Rat left anterior descending coronary arteries were ligated and the classical proteins involved in the endoplasmic reticulum stress (ERS)-induced apoptotic pathway were analyzed using quantitative polymerase chain reaction and western blot analysis. Salubrinal was administered to the rats and cardiomyocyte apoptosis and infarct size were evaluated by a specific staining method. Compared with the sham surgery group, the rate of cardiomyocyte apoptosis in the MI group was increased with the development of the disease. It was also demonstrated that the mRNA and protein levels of GRP78, caspase-12, CHOP and the protein expression of p-eIF2alpha were increased in the MI group. Furthermore, the results showed that treatment with salubrinal can decrease cardiomyocyte apoptosis and infarct size by increasing eIF2alpha phosphorylation and decreasing the expression of caspase-12 and CHOP. The present study suggests that salubrinal protects against ER stress-induced rat cadiomyocyte apoptosis via suppressing the dephosphorylation of eIF2alpha in the ERS-associated pathway. PMID- 25816072 TI - Elevated survivin expression in peripheral blood mononuclear cells is central to collateral formation in coronary chronic total occlusion. AB - Survivin is essential to angiogenesis and revascularization, but its role in coronary collateral formation remains unclear. The role of survivin in peripheral blood mononuclear cells (PBMCs) of coronary chronic total occlusion (CTO) patients was investigated. Coronary CTO patients (n=46; mean age 60.1+/-8.5, male 54.3%) (CTO group) and normal control patients (n=18; mean age 58.0+/-10.0, male 55.6%) underwent angiographic collateral vessel grading by Rentrop classification (C0 - C3) and provided peripheral blood between June 2006 and February 2007. Rat hind limb ischemia models were constructed using four equal groups of Sprague Dawley rats (n=36): normal control, sham operation, operation and granulocyte macrophage colony-stimulating factor (GM-CSF). PBMC numbers and characteristics, collateral vessels, survivin, CD4, CD8, CD44, vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) expression were determined using RT-PCR, flow cytometry, immunocytochemistry and western blot analysis. PBMC survivin mRNA and protein expression levels were higher in patients with good collateral circulation (C2 + C3) than in patients with no collateral flow (C0) (all P<0.05). Survivin single-positive and survivin and CD8, VEGF and ICAM-1 double-positive percentages were elevated in patients with good collateral circulation compared to those with normal and no collateral flow (all P<0.05), consistent with the rat model results, wherein higher survivin levels produced significantly larger and more visible collateral vessels. In conclusion, elevated survivin expression in PBMCs, particularly survivin and CD8, VEGF, and ICAM-1 double-positive PBMCs, may be crucial for good collateral formation in patients with coronary CTO, as confirmed by assessment of a rat model. PMID- 25816073 TI - Agmatine protects Muller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition. AB - Neural injury is associated with the development of diabetic retinopathy. Muller cells provide structural and metabolic support for retinal neurons. High glucose concentrations are known to induce Muller cell activity. Agmatine is an endogenous polyamine, which is enzymatically formed in the mammalian brain and has exhibited neuroprotective effects in a number of experimental models. The aims of the present study were to investigate whether agmatine protects Muller cells from glucose-induced damage and to explore the mechanisms underlying this process. Lactate dehydrogenase activity and tumor necrosis factor-alpha mRNA expression were significantly reduced in Muller cells exposed to a high glucose concentration, following agmatine treatment, compared with cells not treated with agmatine. In addition, agmatine treatment inhibited glucose-induced Muller cell apoptosis, which was associated with the regulation of Bax and Bcl-2 expression. Agmatine treatment suppressed glucose-induced phosphorylation of mitogen activated protein kinase (MAPK) protein in Muller cells. The present study demonstrated that the protective effects of agmatine on Muller cells were inhibited by N-methyl-D-aspartic acid (NMDA). The results of the present study suggested that agmatine treatment protects Muller cells from high-concentration glucose-induced cell damage. The underlying mechanisms may relate to the anti inflammatory and antiapoptotic effects of agmatine, as well as to the inhibition of the MAPK pathway, via NMDA receptor suppression. Agmatine may be of use in the development of novel therapeutic approaches for patients with diabetic retinopathy. PMID- 25816074 TI - Assessment of turbulence models for pulsatile flow inside a heart pump. AB - Computational fluid dynamics (CFD) is applied to study the unsteady flow inside a pulsatile pump left ventricular assist device, in order to assess the sensitivity to a range of commonly used turbulence models. Levels of strain and wall shear stress are directly relevant to the evaluation of risk from haemolysis and thrombosis, and thus understanding the sensitivity to these turbulence models is important in the assessment of uncertainty in CFD predictions. The study focuses on a positive displacement or pulsatile pump, and the CFD model includes valves and moving pusher plate. An unstructured dynamic layering method was employed to capture this cyclic motion, and valves were simulated in their fully open position to mimic the natural scenario, with in/outflow triggered at control planes away from the valves. Six turbulence models have been used, comprising three relevant to the low Reynolds number nature of this flow and three more intended to investigate different transport effects. In the first group, we consider the shear stress transport (SST) [Formula: see text] model in both its standard and transition-sensitive forms, and the 'laminar' model in which no turbulence model is used. In the second group, we compare the one equation Spalart-Almaras model, the standard two equation [Formula: see text] and the full Reynolds stress model (RSM). Following evaluation of spatial and temporal resolution requirements, results are compared with available experimental data. The model was operated at a systolic duration of 40% of the pumping cycle and a pumping rate of 86 BPM (beats per minute). Contrary to reasonable preconception, the 'transition' model, calibrated to incorporate additional physical modelling specifically for these flow conditions, was not noticeably superior to the standard form of the model. Indeed, observations of turbulent viscosity ratio reveal that the transition model initiates a premature increase of turbulence in this flow, when compared with both experimental and higher order numerical results previously reported in the literature. Furthermore, the RSM is indicated to provide the most accurate prediction over much of the flow, due to its ability to more correctly account for three-dimensional effects. Finally, the clinical relevance of the results is reported along with a discussion on the impact of such modelling uncertainties. PMID- 25816075 TI - DNA-Tile Structures Induce Ionic Currents through Lipid Membranes. AB - Self-assembled DNA nanostructures have been used to create man-made transmembrane channels in lipid bilayers. Here, we present a DNA-tile structure with a nominal subnanometer channel and cholesterol-tags for membrane anchoring. With an outer diameter of 5 nm and a molecular weight of 45 kDa, the dimensions of our synthetic nanostructure are comparable to biological ion channels. Because of its simple design, the structure self-assembles within a minute, making its creation scalable for applications in biology. Ionic current recordings demonstrate that the tile structures enable ion conduction through lipid bilayers and show gating and voltage-switching behavior. By demonstrating the design of DNA-based membrane channels with openings much smaller than that of the archetypical six-helix bundle, our work showcases their versatility inspired by the rich diversity of natural membrane components. PMID- 25816076 TI - Efficient labeling in vitro with non-ionic gadolinium magnetic resonance imaging contrast agent and fluorescent transfection agent in bone marrow stromal cells of neonatal rats. AB - Although studies have been undertaken on gadolinium labeling-based molecular imaging in magnetic resonance imaging (MRI), the use of non-ionic gadolinium in the tracking of stem cells remains uncommon. To investigate the efficiency in tracking of stem cells with non-ionic gadolinium as an MRI contrast agent, a rhodamine-conjugated fluorescent reagent was used to label bone marrow stromal cells (BMSCs) of neonatal rats in vitro, and MRI scanning was undertaken. The fluorescent-conjugated cell uptake reagents were able to deliver gadodiamide into BMSCs, and cell uptake was verified using flow cytometry. In addition, the labeled stem cells with paramagnetic contrast medium remained detectable by an MRI monitor for a minimum of 28 days. The present study suggested that this method can be applied efficiently and safely for the labeling and tracking of bone marrow stromal cells in neonatal rats. PMID- 25816077 TI - Economical synthesis of 13C-labeled opiates, cocaine derivatives and selected urinary metabolites by derivatization of the natural products. AB - The illegal use of opiates and cocaine is a challenge world-wide, but some derivatives are also valuable pharmaceuticals. Reference samples of the active ingredients and their metabolites are needed both for controlling administration in the clinic and to detect drugs of abuse. Especially, (13)C-labeled compounds are useful for identification and quantification purposes by mass spectroscopic techniques, potentially increasing accuracy by minimizing ion alteration/suppression effects. Thus, the synthesis of [acetyl-(13)C4]heroin, [acetyl-(13)C4-methyl-(13)C]heroin, [acetyl-(13)C2-methyl-(13)C]6-acetylmorphine, [N-methyl-(13)C-O-metyl-(13)C]codeine and phenyl-(13)C6-labeled derivatives of cocaine, benzoylecgonine, norcocaine and cocaethylene was undertaken to provide such reference materials. The synthetic work has focused on identifying (13)C atom-efficient routes towards these derivatives. Therefore, the (13)C-labeled opiates and cocaine derivatives were made from the corresponding natural products. PMID- 25816078 TI - Identification of floral scent in chrysanthemum cultivars and wild relatives by gas chromatography-mass spectrometry. AB - The objective of this study was to identify the major volatile compounds and their relative concentrations in flowers of different chrysanthemum cultivars and their wild relatives. The volatile organic components of fresh flowers were analyzed using a headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry. In total, 193 volatile organic components were detected; the major scent components were monoterpenoids and oxygenated monoterpenoids, which accounted for 68.59%-99.93% of the total volatiles in all tested materials except for Chrysanthemum indicum collected from Huangshan, in which they accounted for only 37.45% of total volatiles. The major volatile compounds were camphor, alpha-pinene, chrysanthenone, safranal, myrcene, eucalyptol, 2,4,5,6,7,7ab-hexahydro-1H-indene, verbenone, beta-phellandrene and camphene. In a hierarchical cluster analysis, 39 accessions of Chrysanthemum and its relatives formed six clusters based on their floral volatile compounds. In a principal component analysis, only spider type flowers were located closely on the score plot. The results of this study provide a basis for breeding chrysanthemum cultivars which desirable floral scents. PMID- 25816079 TI - Synthesis, antiproliferative activity and molecular properties predictions of galloyl derivatives. AB - The present study was designed to investigate the in vitro antiproliferative activity against ten human cancer cell lines of a series of galloyl derivatives bearing substituted-1,3,4-oxadiazole and carbohydrazide moieties. The compounds were also assessed in an in silico study of the absorption, distribution, metabolism and excretion (ADME) in the human body using Lipinski's parameters, the topological polar surface area (TPSA) and percentage of absorption (%ABS). In general, the introduction of N'-(substituted)-arylidene galloyl hydrazides 4-8 showed a moderate antitumor activity, while the 2-methylthio- and 2-thioxo-1,3,4 oxadiazol-5-yl derivatives 9 and 10 led to increased inhibition of cancer cell proliferation. The precursor compound methyl gallate 2 and the intermediary galloyl hydrazide 3 showed greater antiproliferative activity with GI50 values < 5.54 uM against all human tumor cell lines tested. A higher inhibition effect against ovarian cancer (OVCAR-3) (GI50 = 0.05-5.98 uM) was also shown, with compounds 2, 3, 9 and 10 with GI50 <= 0.89 uM standing out in this respect. The in silico study revealed that the compounds showed good intestinal absorption. PMID- 25816081 TI - Neurological morbidity and mortality associated with the endovascular treatment of cerebral arteriovenous malformations before and during the Onyx era. AB - OBJECT: The widespread implementation of the embolic agent Onyx has changed the endovascular management of cerebral arteriovenous malformations (AVMs). Recent data suggest that outcomes following embolization and resection may have worsened in the Onyx era. It has been hypothesized that there may be increased complications with Onyx embolization and increased surgical aggressiveness in patients treated with Onyx. In this study the authors analyzed their institutional experience with the endovascular treatment of cerebral AVMs prior to and after the introduction of Onyx to determine factors associated with periprocedural neurological morbidity and mortality. METHODS: A retrospective review was performed of all patients with cerebral AVMs undergoing embolization at the Barrow Neurological Institute from 1995 to 2012. RESULTS: Endovascular treatment of 342 cerebral AVMs was performed over 446 treatment sessions (mean age 37.8 years, range 1-83 years). Clinical presentation included hemorrhage in 47.6%, seizures in 21.9%, headaches in 11.1%, and no symptoms in 10% of cases. The endovascular pretreatment strategy was preoperative in 78.9%, preradiosurgery in 9.1%, palliative in 5.3%, targeted in 4.4%, and curative in 2.3%. The median Spetzler-Martin grade was III. The mean number of arteries embolized was 3.5 (range 0-13 arteries), and the mean number of treatment sessions was 1.3 (range 1 4 sessions). Onyx was used in 105 AVMs (30.7%), and N-butyl cyanoacrylate (NBCA) without Onyx was used in 229 AVMs (67%). AVMs treated with Onyx had a higher mean number of arterial pedicles embolized than did NBCA cases (4.3 +/- 2.7 vs 3.2 +/- 2.4, respectively; p < 0.001) and a greater number of sessions (1.5 +/- 0.7 vs 1.2 +/- 0.5, respectively; p < 0.05). Unexpected immediate postprocedural permanent neurological deficits were present in 9.6% of AVMs, while transient deficits were present in 1.8%. There was 1 death (0.3%). Spetzler-Martin grade was not associated with differences in outcome, as permanent neurological deficits were observed in 12%, 9%, 13%, 11%, and 13% of AVMs for Spetzler-Martin Grades I-V, respectively (p = 0.91). The use of Onyx compared with NBCA was not associated with differences in periprocedural morbidity (p = 0.23). This lack of a difference persisted even when controlling for number of arteries and sessions (p = 0.14). Sex was not associated with differences in outcome. CONCLUSIONS: Permanent and transient postprocedural neurological deficits were noted in 9.6% and 1.8% of all cases, respectively. AVM grade was not associated with endovascular outcome. Despite the greater number of sessions required and arteries embolized for Onyx cases, there was no statistically significant difference in the risk of neurological deficits following cerebral AVM embolization with Onyx and NBCA. PMID- 25816080 TI - Extended orbital exenteration for sinonasal malignancy with orbital apex extension: surgical technique and clinical analysis. AB - OBJECT: The majority of sinonasal malignancies present with advanced disease, and cure rates are generally poor. Surgical extirpation remains the mainstay of treatment. In cases of sinonasal malignancy with orbital apex extension, gross total tumor resection requires orbital exenteration and bony skull base resection around the orbital apex to provide sufficient margins. In this retrospective study, the authors describe their surgical strategy in and technique for orbital exenteration with orbital apex resection in patients at Tokyo Medical and Dental University who had sinonasal malignancy with orbital apex extension. They also analyzed the clinical features of and the results in these patients. METHODS: Between February 2001 and August 2012 at the authors' institution, sinonasal malignancy with orbital apex extension was treated using craniofacial tumor resection with orbital exenteration including skull base bone around the orbital apex. The authors describe this technique and analyze the surgical indications, extent of resection, primary tumor location, outcome, pathological findings, and neoadjuvant and adjuvant therapies of the patients who underwent the technique. RESULTS: The patients consisted of 12 men and 3 women with a mean age of 47.7 years (range 14-79 years). The longest postoperative follow-up was 9.5 years, and the shortest was 0.67 year (mean 3.0 years). Tumor originated at the ethmoid sinus in 6 patients (40%), maxillary sinus in 5 (33%), nasal cavity in 2 (13%), and orbital cavity and maxillary bone in 1 patient each (7%). Histological analysis of tumor specimens revealed squamous cell carcinoma in 9 patients (60%), rhabdomyosarcoma in 2 (13%), and small cell carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, and Ewing sarcoma in 1 patient each (7%). Two patients experienced recurrences at 1 and 5 months after treatment; these patients died at 5 and 10 months after surgery, respectively. Estimated 5-year recurrence-free survival (RFS) was 86.7%, and estimated 5-year overall survival (OS) was 86.2%; there was no perioperative mortality. None of the patients had new neurological deficits as a result of the surgery, but 5 patients suffered infectious complications from the graft transplanted into the cavity after resection. There were no other perioperative complications. CONCLUSIONS: These authors are the first to describe a technique for extended orbital exenteration with orbital apex skull base resection. The technique provided sufficient margins for gross-total resection of the sinonasal malignancy with orbital apex extension. The estimated 5-year OS and RFS rates were high, and the perioperative complication rate was acceptably low, demonstrating the safety and efficacy of this technique. PMID- 25816082 TI - Combined rigid and flexible endoscopy for tumors in the posterior third ventricle. AB - OBJECT: Tumors leading to occlusion of the sylvian aqueduct include those of pineal, thalamic, and tectal origins. These tumors cause obstructive hydrocephalus and thus necessitate a CSF diversion procedure such as an endoscopic third ventriculostomy (ETV), often coupled with an endoscopic biopsy (EBX). Lesions located posterior to the massa intermedia pose a technical challenge, as the use of a rigid endoscope for performing both an ETV and EBX is limited. The authors describe their experience using a combined rigid and flexible endoscopic procedure through a single bur hole for both procedures in patients with posterior third ventricular tumors. METHODS: Since January 2012, patients with posterior third ventricular tumors causing hydrocephalus underwent dual ETV and EBX procedures using the combined rigid-flexible endoscopic technique. Following institutional review board approval, data from clinical, radiological, surgical, and pathological records were retrospectively collected. RESULTS: Six patients 3.5-53 years of age were included. Lesion locations included pineal (n = 3), fourth ventricle (n = 1), aqueduct (n = 1), and tectum (n = 1). The ETV and EBX were successful in all cases. Pathologies included pilocytic astrocytoma, pineoblastoma, ependymoma Grade II, germinoma, low-grade glioneural tumor, and atypical choroid plexus papilloma. One patient experienced an immediate postoperative intraventricular hemorrhage necessitating evacuation of the clots and resection of the tumor, eventually leading to the patient's death. CONCLUSIONS: The authors recommend using a combined rigid-flexible endoscope for endoscopic third ventriculostomy and biopsy to approach posterior third ventricular tumors (behind the massa intermedia). This technique overcomes the limitations of using a rigid endoscope by reaching 2 distant regions. PMID- 25816083 TI - A successful case of multiple stereotactic radiosurgeries for ipsilateral recurrent trigeminal neuralgia. AB - Trigeminal neuralgia is a common pain syndrome primarily managed medically, although many patients require surgical or radiotherapeutic intervention. Stereotactic radiosurgery has become a preferred method of treatment given its high efficacy rates and relatively favorable toxicity profile. However, many patients have refractory pain even after repeat courses of stereotactic radiosurgery. Historically, 2 courses have been the limit in such patients. The authors present a case of multiply recurrent trigeminal neuralgia treated with a third course of radiosurgery in which the patient had successful pain control and no additional toxicity. Meticulous attention to the therapeutic technique allows the continued application of stereotactic radiosurgery in patients. PMID- 25816084 TI - Plaque morphology (the PLAC Scale) on CT angiography: predicting long-term anatomical success of primary carotid stenting. AB - OBJECT: Carotid angioplasty and stenting has emerged as an alternative to carotid endarterectomy for the treatment of atherosclerotic carotid stenosis. Primary carotid stenting, performed using self-expanding stents alone without deliberate use of embolic protection devices and balloon angioplasty, has been shown to be effective and faster, cheaper, and potentially safer than conventional techniques. However, the long-term morphological results of this technique have not been established. The aim of this study was to determine whether preprocedural carotid plaque imaging at the site of maximal stenosis by using CT angiography (CTA) could predict the long-term morphological outcome of primary carotid stenting. METHODS: One hundred eighty-one patients were treated over an 11-year period. Preprocedural CTA was performed in 102 of these. A morphological scale (the Predicting Long-term outcome with Angioplasty of the Carotid artery [PLAC] Scale), with grades from 0 to 4 and A or B, was used to evaluate the circumferential degree of plaque calcification, and the presence or absence of soft plaque. All patients were followed using duplex carotid ultrasound and plain radiographs. Satisfactory morphological outcome was defined as a peak systolic velocity < 120 cm/s and internal carotid artery/common carotid artery ratio < 1.4. RESULTS: The average follow-up duration was 29.7 months (median 24.5 months, range 0.3-87 months). Univariate logistic regression demonstrated that a low calcification grade (p < 0.001), less thick calcification (p < 0.001), and moderate amounts of soft plaque (p < 0.001) are factors that are highly associated with good long-term outcome. Multivariate analyses confirmed that these factors are independent of each other in predicting outcome. CONCLUSIONS: The long-term morphological outcome of primary carotid stenting was predicted with considerable accuracy by using a straightforward CTA carotid plaque grading scale. PMID- 25816085 TI - Microrecording and image-guided stereotactic biopsy of deep-seated brain tumors. AB - OBJECT: Image-guided stereotactic brain tumor biopsy cannot easily obtain samples of small deep-seated tumor or selectively sample the most viable region of malignant tumor. Image-guided stereotactic biopsy in combination with depth microrecording was evaluated to solve such problems. METHODS: Operative records, MRI findings, and pathological specimens were evaluated in 12 patients with small deep-seated brain tumor, in which image-guided stereotactic biopsy was performed with the aid of depth microrecording. The tumors were located in the caudate nucleus (1 patient), thalamus (7 patients), midbrain (2 patients), and cortex (2 patients). Surgery was performed with a frameless stereotactic system in 3 patients and with a frame-based stereotactic system in 9 patients. Microrecording was performed to study the electrical activities along the trajectory in the deep brain structures and the tumor. The correlations were studied between the electrophysiological, MRI, and pathological findings. Thirty-two patients with surface or large brain tumor were also studied, in whom image-guided stereotactic biopsy without microrecording was performed. RESULTS: The diagnostic yield in the group with microrecording was 100% (low-grade glioma 4, high-grade glioma 4, diffuse large B-cell lymphoma 3, and germinoma 1), which was comparable to 93.8% in the group without microrecording. The postoperative complication rate was as low as that of the conventional image-guided method without using microelectrode recording, and the mortality rate was 0%, although the target lesions were small and deep-seated in all cases. Depth microrecording revealed disappearance of neural activity in the tumor regardless of the tumor type. Neural activity began to decrease from 6.3 +/- 4.5 mm (mean +/- SD) above the point of complete disappearance along the trajectory. Burst discharges were observed in 6 of the 12 cases, from 3 +/- 1.4 mm above the point of decrease of neural activity. Injury discharges were often found at 0.5-1 mm along the trajectory between the area of decreased and disappeared neural activity. Close correlations between electrophysiological, MRI, and histological findings could be found in some cases. CONCLUSIONS: Image-guided stereotactic biopsy performed using depth microrecording was safe, it provided accurate positional information in real time, and it could distinguish the tumor from brain structures during surgery. Moreover, this technique has potential for studying the epileptogenicity of the brain tumor. PMID- 25816086 TI - Editorial: Arteriovenous malformations and embolization. PMID- 25816087 TI - Assessing early unplanned reoperations in neurosurgery: opportunities for quality improvement. AB - OBJECT: Review of morbidities and mortality has been the primary method used to assess surgical quality by physicians, hospitals, and oversight agencies. The incidence of reoperation has been proposed as a candidate quality indicator for surgical care. The authors report a comprehensive assessment of reoperations within a neurosurgical department and discuss how such data can be integrated into quality improvement initiatives to optimize value of care delivery. METHODS: All neurosurgical procedures performed in the main operating room or the outpatient surgery center at the Ronald Reagan UCLA Medical Center and UCLA Santa Monica Medical Center from July 2008 to December 2012 were considered for this study. Interventional radiology and stereotactic radiosurgery procedures were excluded. Early reoperations within 7 days of the index surgery were reviewed and their preventability status was evaluated. RESULTS: The incidence of early unplanned reoperation was 2.6% (occurring after 183 of 6912 procedures). More than half of the patients who underwent early unplanned reoperation initially had surgery for shunt-related conditions (34.4%) or intracranial tumor (23.5%). Shunt failure was the most common indication for early unplanned reoperation (34.4%), followed by postoperative bleeding (20.8%) and postoperative elevated intracranial pressure (9.8%). The average time interval (+/- SD) between the index surgery and reoperation was 3.0 +/- 1.9 days. The average length of stay following reoperation was 12.1 +/- 14.4 days. CONCLUSIONS: This study enabled an in-depth assessment of reoperations within an academic neurosurgical practice and identification of strategic opportunities for department-wide quality improvement initiatives. The authors provide a nuanced discussion regarding the use of absolute reoperations as a quality indicator for neurosurgical patient populations. PMID- 25816089 TI - Editorial: Management of hemangioblastomas in patients with von Hippel-Lindau disease: stereotactic radiosurgery compared to surgical excision. PMID- 25816088 TI - Stereotactic radiosurgery for intracranial hemangioblastomas: a retrospective international outcome study. AB - OBJECT: The purpose of this study was to evaluate the role of stereotactic radiosurgery (SRS) in the management of intracranial hemangioblastomas. METHODS: Six participating centers of the North American Gamma Knife Consortium and 13 Japanese Gamma Knife centers identified 186 patients with 517 hemangioblastomas who underwent SRS. Eighty patients had 335 hemangioblastomas associated with von Hippel-Lindau disease (VHL) and 106 patients had 182 sporadic hemangioblastomas. The median target volume was 0.2 cm(3) (median diameter 7 mm) in patients with VHL and 0.7 cm(3) (median diameter 11 mm) in those with sporadic hemangioblastoma. The median margin dose was 18 Gy in VHL patients and 15 Gy in those with sporadic hemangioblastomas. RESULTS: At a median of 5 years (range 0.5 18 years) after treatment, 20 patients had died of intracranial disease progression and 9 patients had died of other causes. The overall survival after SRS was 94% at 3 years, 90% at 5 years, and 74% at 10 years. Factors associated with longer survival included younger age, absence of neurological symptoms, fewer tumors, and higher Karnofsky Performance Status. Thirty-three (41%) of the 80 patients with VHL developed new tumors and 17 (16%) of the106 patients with sporadic hemangioblastoma had recurrences of residual tumor from the original tumor. The 5-year rate of developing a new tumor was 43% for VHL patients, and the 5-year rate of developing a recurrence of residual tumor from the original tumor was 24% for sporadic hemangioblastoma patients. Factors associated with a reduced risk of developing a new tumor or recurrences of residual tumor from the original tumor included younger age, fewer tumors, and sporadic rather than VHL associated hemangioblastomas. The local tumor control rate for treated tumors was 92% at 3 years, 89% at 5 years, and 79% at 10 years. Factors associated with an improved local tumor control rate included VHL-associated hemangioblastoma, solid tumor, smaller tumor volume, and higher margin dose. Thirteen patients (7%) developed adverse radiation effects (ARE) after SRS, and one of these patients died due to ARE. CONCLUSIONS: When either sporadic or VHL-associated tumors were observed to grow on serial imaging studies, SRS provided tumor control in 79%-92% of tumors. PMID- 25816090 TI - Intraoperative subcortical mapping of a language-associated deep frontal tract connecting the superior frontal gyrus to Broca's area in the dominant hemisphere of patients with glioma. AB - OBJECT: The deep frontal pathway connecting the superior frontal gyrus to Broca's area, recently named the frontal aslant tract (FAT), is assumed to be associated with language functions, especially speech initiation and spontaneity. Injury to the deep frontal lobe is known to cause aphasia that mimics the aphasia caused by damage to the supplementary motor area. Although fiber dissection and tractography have revealed the existence of the tract, little is known about its function. The aim of this study was to determine the function of the FAT via electrical stimulation in patients with glioma who underwent awake surgery. METHODS: The authors analyzed the data from subcortical mapping with electrical stimulation in 5 consecutive cases (3 males and 2 females, age range 40-54 years) with gliomas in the left frontal lobe. Diffusion tensor imaging (DTI) and tractography of the FAT were performed in all cases. A navigation system and intraoperative MRI were used in all cases. During the awake phase of the surgery, cortical mapping was performed to find the precentral gyrus and Broca's area, followed by tumor resection. After the cortical layer was removed, subcortical mapping was performed to assess language-associated fibers in the white matter. RESULTS: In all 5 cases, positive responses were obtained at the stimulation sites in the subcortical area adjacent to the FAT, which was visualized by the navigation system. Speech arrest was observed in 4 cases, and remarkably slow speech and conversation was observed in 1 case. The location of these sites was also determined on intraoperative MR images and estimated on preoperative MR images with DTI tractography, confirming the spatial relationships among the stimulation sites and white matter tracts. Tumor removal was successfully performed without damage to this tract, and language function did not deteriorate in any of the cases postoperatively. CONCLUSIONS: The authors identified the left FAT and confirmed that it was associated with language functions. This tract should be recognized by clinicians to preserve language function during brain tumor surgery, especially for tumors located in the deep frontal lobe on the language-dominant side. PMID- 25816091 TI - MicroRNA-218 and microRNA-520a inhibit cell proliferation by downregulating E2F2 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer type worldwide and the third leading cause of cancer-associated mortality. To date, its pathogenesis has remained poorly understood. Previous studies have demonstrated that deregulated microRNA (miR) participates in hepatocarcinogenesis. In the present study, miR-218 and miR-520a were observed to be downregulated in human HCC cells relative to normal hepatic cells. Overexpression of miR-218 or miR-520a inhibited cell proliferation and induced cell cycle arrest at the G0/G1 phase checkpoint. Furthermore, a dual-luciferase reporter assay identified that E2F2 was a novel direct target of miR-218 but not miR-520a in HCC. In addition, miR-218 and miR 520a were observed to negatively regulate E2F2 mRNA and protein levels. This suggested that miR-218 regulated the expression of E2F2 via directly binding to its 3'-untranslated region, whereas miR-520a affected E2F2 expression indirectly. In conclusion, these results indicated that miR-218 and miR-520a are crucial in the development of HCC via the inhibition of cell proliferation and cycle progression by downregulating E2F2. PMID- 25816092 TI - Synthesis of fluorophosphate nucleotide analogues and their characterization as tools for 19F NMR studies. AB - To broaden the scope of existing methods based on (19)F nucleotide labeling, we developed a new method for the synthesis of fluorophosphate (oligo)nucleotide analogues containing an O to F substitution at the terminal position of the (oligo)phosphate moiety and evaluated them as tools for (19)F NMR studies. Using three efficient and comprehensive synthetic approaches based on phosphorimidazolide chemistry and tetra-n-butylammonium fluoride, fluoromonophosphate, or fluorophosphate imidazolide as fluorine sources, we prepared over 30 fluorophosphate-containing nucleotides, varying in nucleobase type (A, G, C, U, m(7)G), phosphate chain length (from mono to tetra), and presence of additional phosphate modifications (thio, borano, imido, methylene). Using fluorophosphate imidazolide as fluorophosphorylating reagent for 5' phosphorylated oligos we also synthesized oligonucleotide 5'-(2 fluorodiphosphates), which are potentially useful as (19)F NMR hybridization probes. The compounds were characterized by (19)F NMR and evaluated as (19)F NMR molecular probes. We found that fluorophosphate nucleotide analogues can be used to monitor activity of enzymes with various specificities and metal ion requirements, including human DcpS enzyme, a therapeutic target for spinal muscular atrophy. The compounds can also serve as reporter ligands for protein binding studies, as exemplified by studying interaction of fluorophosphate mRNA cap analogues with eukaryotic translation initiation factor (eIF4E). PMID- 25816093 TI - Is cadmium exposure associated with the burden, vulnerability and rupture of human atherosclerotic plaques? AB - The general population is exposed to cadmium from food and smoking. Cadmium is a widely spread toxic pollutant that seems to be associated with cardiovascular diseases, although little is known if it contributes to the occurrence of atherosclerotic plaques and the process whereby plaques become vulnerable and are prone to rupture. We tested the hypotheses that cadmium exposure is associated not only with an increased subclinical burden of atherosclerotic plaques in different vascular territories and early signs of plaque vulnerability, but also with cadmium content and plaque-rupture in the clinical phase of the disease. Ultrasound technique was used to measure plaque prevalence and echogenicity in the carotid and femoral arteries in a population sample of women (n = 599) in whom blood cadmium was measured. In addition cadmium was measured in snap-frozen endarterectomies and whole blood obtained from patients who were referred to surgery because of symptomatic carotid plaques (n = 37). Sixteen endarterectomies were divided into three parts corresponding to different flow conditions and plaque vulnerability. In the population sample blood cadmium was associated with the number of vascular territories with plaques (p = 0.003 after adjustment for potential confounders). The cadmium concentrations in symptomatic plaques were 50 fold higher in plaque tissue than in blood. Cadmium levels in blood and plaque correlated, also after adjustment for smoking and other cardiovascular risk factors (p<0.001). Compared with the other parts of the plaque, the cadmium content was double as high in the part where plaque rupture usually occurs. In conclusion, the results show that cadmium exposure is associated with the burden of subclinical atherosclerosis in middle-aged women with different degrees of glucose tolerance, and that the content of cadmium in symptomatic plaques in patients is related to that in blood, but much higher, and preferentially located in the part of plaque where rupture often occurs. PMID- 25816094 TI - Actin-mediated gene expression depends on RhoA and Rac1 signaling in proximal tubular epithelial cells. AB - Morphological alterations of cells can lead to modulation of gene expression. An essential link is the MKL1-dependent activation of serum response factor (SRF), which translates changes in the ratio of G- and F-actin into mRNA transcription. SRF activation is only partially characterized in non-transformed epithelial cells. Therefore, the impact of GTPases of the Rho family and changes in F-actin structures were analyzed in renal proximal tubular epithelial cells. Activation of SRF signaling was compared to the regulation of a known MKL1/SRF target gene, connective tissue growth factor (CTGF). In the human proximal tubular cell line HKC-8 overexpression of two actin mutants either favoring or preventing the formation of F-actin fibers regulated SRF-mediated transcription as well as CTGF expression. Only overexpression of constitutively active RhoA activated SRF dependent gene expression whereas no effect was detected upon overexpression of Rac1 mutants. To elucidate the functional role of Rho kinases as downstream mediators of RhoA, pharmacological inhibition and genetic inhibition by transient siRNA knock down were compared. Upon stimulation with lysophosphatidic acid (LPA) Rho kinase inhibitors partially suppressed SRF-mediated transcription, whereas interference with Rho kinase expression by siRNA reduced activation of SRF, but barely affected CTGF expression. Together with the partial inhibition of CTGF expression by the pharmacological inhibitors Y27432 and H1154, Rho kinases seem to be less important in mediating RhoA signaling related to CTGF expression in HKC-8 epithelial cells. Short term pharmacological inhibition of Rac1 activity by EHT1864 reduced SRF-dependent CTGF expression in HKC-8 cells, but was overcome by a stimulatory effect after prolonged incubation after 4-6 h. Similarly, human primary cells of proximal but not of distal tubular origin showed inhibitory as well as stimulatory effects of Rac1 inhibition. Thus, RhoA signaling activates MKL1-SRF-mediated CTGF expression in proximal tubular cells, whereas Rac1 signaling is more complex with adaptive cellular responses. PMID- 25816095 TI - Hypothermia augments neuroprotective activity of mesenchymal stem cells for neonatal hypoxic-ischemic encephalopathy. AB - Though hypothermia is the only clinically available treatment for neonatal hypoxic-ischemic encephalopathy (HIE), it is not completely effective in severe cases. We hypothesized that combined treatment with hypothermia and transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) would synergistically attenuate severe HIE compared to stand-alone therapy. To induce hypoxia-ischemia (HI), male Sprague-Dawley rats were subjected to 8% oxygen for 120 min after unilateral carotid artery ligation on postnatal day (P) 7. After confirmation of severe HIE involving >50% of the ipsilateral hemisphere volume as determined by diffusion-weighted brain magnetic resonance imaging (MRI) within 2 h after HI, intraventricular MSC transplantation (1 * 105 cells) and/or hypothermia with target temperature at 32 degrees C for 24 h were administered 6 h after induction of HI. Follow-up brain MRI at P12 and P42, sensorimotor function tests at P40-42, evaluation of cytokines in the cerebrospinal fluid (CSF) at P42, and histologic analysis of peri-infarct tissues at P42 were performed. Severe HI resulted in progressively increased brain infarction over time as assessed by serial MRI, increased number of cells positive for terminal deoxynucleotidyl transferase nick-end labeling, microgliosis and astrocytosis, increased CSF cytokine levels, and impaired function in behavioral tests such as rotarod and cylinder tests. All of the abnormalities observed in severe HIE showed greater improvement after combined treatment with hypothermia and MSC transplantation than with either therapy alone. Overall, these findings suggest that combined treatment with hypothermia and human UCB-derived MSC transplantation might be a novel therapeutic modality to improve the prognosis of severe HIE, an intractable disease that currently has no effective treatment. PMID- 25816096 TI - Differential phenotypic and functional profiles of TcCA-2 -specific cytotoxic CD8+ T cells in the asymptomatic versus cardiac phase in Chagasic patients. AB - It has been reported that the immune response mediated by T CD8+ lymphocytes plays a critical role in the control of Trypanosoma cruzi infection and that the clinical symptoms of Chagas disease appear to be related to the competence of the CD8+ T immune response against the parasite. Herewith, in silico prediction and binding assays on TAP-deficient T2 cells were used to identify potential HLA A*02:01 ligands in the T. cruzi TcCA-2 protein. The TcCA-2-specific CD8+ T cells were functionality evaluated by Granzyme B and cytokine production in peripheral blood mononuclear cells (PBMC) from Chagas disease patients stimulated with the identified HLA-A*02:01 peptides. The specific cells were phenotypically characterized by flow cytometry using several surface markers and HLA-A*02:01 APC labeled dextramer loaded with the peptides. In the T. cruzi TcCA-2 protein four T CD8+ epitopes were identified which are processed and presented during Chagas disease. Interestingly, a differential cellular phenotypic profile could be correlated with the severity of the disease. The TcCA-2-specific T CD8+ cells from patients with cardiac symptoms are mainly effector memory cells (TEM and TEMRA) while, those present in the asymptomatic phase are predominantly naive cells (TNAIVE). Moreover, in patients with cardiac symptoms the percentage of cells with senescence features is significantly higher than in patients at the asymptomatic phase of the disease. We consider that the identification of these new class I-restricted epitopes are helpful for designing biomarkers of sickness pathology as well as the development of immunotherapies against T. cruzi infection. PMID- 25816097 TI - C-C chemokine receptor 2 inhibitor ameliorates hepatic steatosis by improving ER stress and inflammation in a type 2 diabetic mouse model. AB - Hepatic steatosis is the accumulation of excess fat in the liver. Recently, hepatic steatosis has become more important because it occurs in the patients with obesity, type 2 diabetes, and hyperlipidemia and is associated with endoplasmic reticulum (ER) stress and insulin resistance. C-C chemokine receptor 2 (CCR2) inhibitor has been reported to improve inflammation and glucose intolerance in diabetes, but its mechanisms remained unknown in hepatic steatosis. We examined whether CCR2 inhibitor improves ER stress-induced hepatic steatosis in type 2 diabetic mice. In this study, db/db and db/m (n = 9) mice were fed CCR2 inhibitor (2 mg/kg/day) for 9 weeks. In diabetic mice, CCR2 inhibitor decreased plasma and hepatic triglycerides levels and improved insulin sensitivity. Moreover, CCR2 inhibitor treatment decreased ER stress markers (e.g., BiP, ATF4, CHOP, and XBP-1) and inflammatory cytokines (e.g., TNFalpha, IL 6, and MCP-1) while increasing markers of mitochondrial biogenesis (e.g., PGC 1alpha, Tfam, and COX1) in the liver. We suggest that CCR2 inhibitor may ameliorate hepatic steatosis by reducing ER stress and inflammation in type 2 diabetes mellitus. PMID- 25816098 TI - Diacerein improves left ventricular remodeling and cardiac function by reducing the inflammatory response after myocardial infarction. AB - BACKGROUND: The inflammatory response has been implicated in the pathogenesis of left ventricular (LV) remodeling after myocardial infarction (MI). An anthraquinone compound with anti-inflammatory properties, diacerein inhibits the synthesis and activity of pro-inflammatory cytokines, such as tumor necrosis factor and interleukins 1 and 6. The purpose of this study was to investigate the effects of diacerein on ventricular remodeling in vivo. METHODS AND RESULTS: Ligation of the left anterior descending artery was used to induce MI in an experimental rat model. Rats were divided into two groups: a control group that received saline solution (n = 16) and a group that received diacerein (80 mg/kg) daily (n = 10). After 4 weeks, the LV volume, cellular signaling, caspase 3 activity, and nuclear factor kappa B (NF-kappaB) transcription were compared between the two groups. After 4 weeks, end-diastolic and end-systolic LV volumes were reduced in the treatment group compared to the control group (p < .01 and p < .01, respectively). Compared to control rats, diacerein-treated rats exhibited less fibrosis in the LV (14.65%+/- 7.27% vs. 22.57%+/- 8.94%; p < .01), lower levels of caspase-3 activity, and lower levels of NF-kappaB p65 transcription. CONCLUSIONS: Treatment with diacerein once a day for 4 weeks after MI improved ventricular remodeling by promoting lower end-systolic and end-diastolic LV volumes. Diacerein also reduced fibrosis in the LV. These effects might be associated with partial blockage of the NF-kappaB pathway. PMID- 25816100 TI - Association between metabolic syndrome, smoking status and coronary artery calcification. AB - Coronary artery calcification (CAC), an indicator of coronary artery stenosis, is an independent risk factor of ischemic heart disease. Smoking increases the risk of metabolic syndrome (MS) and cardiovascular disease. Almost no previous studies have evaluated the combined effect of MS and smoking status on CAC. Therefore, in this study we examined the relationships between CAC, MS, and smoking. This study included 775 adult males without histories of cardiovascular disease who visited the Health Promotion Center at the University Hospital in Gyeonggi-do, Republic of Korea from January 2, 2010 to December 31, 2012. All subjects were screened for CAC by multi-detector computed tomography (MDCT). CAC increased significantly with age and body mass index (BMI). Among MS components, abdominal obesity and elevated fasting blood glucose were correlated with CAC. After adjusting for age and BMI, MS was associated with a 1.46-fold increase in CAC (95% CI:1.02-2.09), abdominal obesity was associated with a 1.45-fold increase (95% CI:1.04-2.04), elevated fasting blood glucose was associated with a 2-fold increase (95% CI:1.36 2.94), and MS and smoking combined were associated with 2.44-fold increase in CAC. Thus, the combination of smoking and MS had a greater impact on CAC than any single factor alone. MS is correlated with an increased risk of CAC, and a combination of MS and smoking is associated with even greater risk. These findings can be used to prevent cardiovascular disease in adults. PMID- 25816099 TI - The roles of variants in human multidrug resistance (MDR1) gene and their haplotypes on antiepileptic drugs response: a meta-analysis of 57 studies. AB - OBJECTIVE: Previous studies reported the associations between the ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1) polymorphisms and their haplotypes with risk of response to antiepileptic drugs in epilepsy, however, the results were inconclusive. METHODS: The Pubmed, Embase, Web of Science, CNKI and Chinese Biomedicine databases were searched up to July 15, 2014. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model based on heterogeneity tests. Meta regression and Galbraith plot analysis were carried out to explore the possible heterogeneity. RESULTS: A total of 57 studies involving 12407 patients (6083 drug resistant and 6324 drug-responsive patients with epilepsy) were included in the pooled-analysis. For all three polymorphisms (C3435T, G2677T/A, and C1236T), we observed a wide spectrum of minor allele frequencies across different ethnicities. A significantly decreased risk of AEDs resistance was observed in Caucasian patients with T allele of C3435T variant, which was still significant after adjusted by multiple testing corrections (T vs C: OR=0.83, 95%CI=0.71-0.96, p=0.01). However, no significant association was observed between the other two variants and AEDs resistance. Of their haplotypes in ABCB1 gene (all studies were in Indians and Asians), no significant association was observed with AEDs resistance. Moreover, sensitivity and Cumulative analysis showed that the results of this meta-analysis were stable. CONCLUSION: In summary, this meta-analysis demonstrated that effect of C3435T variant on risk of AEDs resistance was ethnicity-dependent, which was significant in Caucasians. Additionally, further studies in different ethnic groups are warranted to clarify possible roles of haplotypes in ABCB1 gene in AEDs resistance, especially in Caucasians. PMID- 25816101 TI - Synergistic interactions between Drosophila orthologues of genes spanned by de novo human CNVs support multiple-hit models of autism. AB - Autism spectrum disorders (ASDs) are highly heritable and characterised by deficits in social interaction and communication, as well as restricted and repetitive behaviours. Although a number of highly penetrant ASD gene variants have been identified, there is growing evidence to support a causal role for combinatorial effects arising from the contributions of multiple loci. By examining synaptic and circadian neurological phenotypes resulting from the dosage variants of unique human:fly orthologues in Drosophila, we observe numerous synergistic interactions between pairs of informatically-identified candidate genes whose orthologues are jointly affected by large de novo copy number variants (CNVs). These CNVs were found in the genomes of individuals with autism, including a patient carrying a 22q11.2 deletion. We first demonstrate that dosage alterations of the unique Drosophila orthologues of candidate genes from de novo CNVs that harbour only a single candidate gene display neurological defects similar to those previously reported in Drosophila models of ASD associated variants. We then considered pairwise dosage changes within the set of orthologues of candidate genes that were affected by the same single human de novo CNV. For three of four CNVs with complete orthologous relationships, we observed significant synergistic effects following the simultaneous dosage change of gene pairs drawn from a single CNV. The phenotypic variation observed at the Drosophila synapse that results from these interacting genetic variants supports a concordant phenotypic outcome across all interacting gene pairs following the direction of human gene copy number change. We observe both specificity and transitivity between interactors, both within and between CNV candidate gene sets, supporting shared and distinct genetic aetiologies. We then show that different interactions affect divergent synaptic processes, demonstrating distinct molecular aetiologies. Our study illustrates mechanisms through which synergistic effects resulting from large structural variation can contribute to human disease. PMID- 25816103 TI - Analysis of the cytotoxicity of carbon-based nanoparticles, diamond and graphite, in human glioblastoma and hepatoma cell lines. AB - Nanoparticles have attracted a great deal of attention as carriers for drug delivery to cancer cells. However, reports on their potential cytotoxicity raise questions of their safety and this matter needs attentive consideration. In this paper, for the first time, the cytotoxic effects of two carbon based nanoparticles, diamond and graphite, on glioblastoma and hepatoma cells were compared. First, we confirmed previous results that diamond nanoparticles are practically nontoxic. Second, graphite nanoparticles exhibited a negative impact on glioblastoma, but not on hepatoma cells. The studied carbon nanoparticles could be a potentially useful tool for therapeutics delivery to the brain tissue with minimal side effects on the hepatocytes. Furthermore, we showed the influence of the nanoparticles on the stable, fluorescently labeled tumor cell lines and concluded that the labeled cells are suitable for drug cytotoxicity tests. PMID- 25816105 TI - Quantitative Assessment of Tendon Healing by Using MR T2 Mapping in a Rabbit Achilles Tendon Transection Model Treated with Platelet-rich Plasma. AB - PURPOSE: To determine if magnetic resonance (MR) imaging T2 mapping can be used to quantify histologic tendon healing by using a rabbit Achilles tendon transection model treated with platelet-rich plasma (PRP). MATERIALS AND METHODS: Experiments were approved by the Institutional Animal Care and Use Committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected, and PRP (in the test group) or saline (in the control group) was injected into the transection site. The rabbits were sacrificed 2, 4, 8, and 12 weeks after surgery. Thereafter, T2 mapping and histologic evaluations were performed by using the Bonar scale. A mixed-model multivariate analysis of variance was used to test the effects of time and PRP treatment on the T2 value and Bonar grade, respectively. The correlation between the T2 value and Bonar grade was also assessed by using the Spearman correlation coefficient. RESULTS: The Bonar scale values decreased in both groups during tendon healing. The T2 value also shortened over time (P < .001 for both groups). The T2 values were positively correlated with the Bonar grade (rho = 0.78, P < .001). Both the T2 value and Bonar scale value were lower in the PRP group than in the control group at 4, 8, and 12 weeks; however, there was no significant effect of PRP treatment on the T2 value or Bonar grade. CONCLUSION: The T2 value changes reflected histologic tendon healing. While T2 and Bonar grade were lower at all time points in tendons treated with PRP, there was no significant difference between the treatment and control tendons. PMID- 25816102 TI - Nanoscale materials for hyperthermal theranostics. AB - Recently, the use of nanoscale materials has attracted considerable attention with the aim of designing personalized therapeutic approaches that can enhance both spatial and temporal control over drug release, permeability, and uptake. Potential benefits to patients include the reduction of overall drug dosages, enabling the parallel delivery of different pharmaceuticals, and the possibility of enabling additional functionalities such as hyperthermia or deep-tissue imaging (LIF, PET, etc.) that complement and extend the efficacy of traditional chemotherapy and surgery. This mini-review is focused on an emerging class of nanometer-scale materials that can be used both to heat malignant tissue to reduce angiogenesis and DNA-repair while simultaneously offering complementary imaging capabilities based on radioemission, optical fluorescence, magnetic resonance, and photoacoustic methods. PMID- 25816104 TI - Chronic Lung Allograft Dysfunction: Oxygen-enhanced T1-Mapping MR Imaging of the Lung. AB - PURPOSE: To evaluate oxygen-enhanced T1-mapping magnetic resonance (MR) imaging of the lungs for detection of chronic lung allograft dysfunction (CLAD) in patients who have undergone double lung transplantation. MATERIALS AND METHODS: The local ethics committee approved this study. Seventy-six recipients of double lung allografts who underwent MR imaging of the lungs during an outpatient visit between 2011 and 2013 were included in this study after they provided written informed consent. Patients were classified as having CLAD on the basis of spirometric results and were divided into three groups: no CLAD (bronchiolitis obliterans syndrome level 0 [BOS 0]), early CLAD (BOS 0p), and late-stage CLAD (BOS 1-3). Coronal T1 maps of the lungs were acquired with the patient breathing room air and 100% oxygen by using an inversion-recovery snapshot fast low-angle shot sequence at 1.5 T. The median and interquartile range of T1 values at room air and at 100% oxygen and the oxygen transfer function were calculated. Statistical analysis was performed with analysis of variance and the Tukey honestly significant difference test or the Kruskal-Wallis test and the Mann Whitney U test (alpha = 0.05). Bonferroni correction was applied for multiple comparisons. RESULTS: The oxygen transfer function was significantly lower in patients in the BOS 0p (P = .025) and BOS 1-3 groups (P = .003) than it was in the patients with BOS 0. Absolute T1 values (room air, P = .66; 100% oxygen, P = .67) did not differ significantly among the groups. The heterogeneity of T1 values, measured by using the interquartile range, showed a strong trend toward higher values in patients with BOS (room air, P = .06; 100% oxygen, P = .08). CONCLUSION: Oxygen transfer function may serve as an early marker for detection of CLAD. PMID- 25816106 TI - Prognostic Role of Diffusion-weighted MR Imaging for Resectable Gastric Cancer. AB - PURPOSE: To prospectively investigate the role of apparent diffusion coefficient (ADC) calculated from diffusion-weighted magnetic resonance (MR) imaging as a potential prognostic biomarker in the evaluation of the aggressiveness of gastric cancer. MATERIALS AND METHODS: This prospective study had institutional review board approval. Informed consent was obtained from all patients. Between October 2009 and December 2013, a total of 99 patients (65 men, 34 women; mean age, 62.02 years; age range, 32.33-85.15 years) with biopsy-proved cancer (28 esophagogastric junction and 71 gastric cancers) were examined with a 1.5-T MR imaging system, including T1-, T2-, and diffusion-weighted sequences. ADC measurements were obtained. Seventy-one patients were directly treated with surgery, while 28 underwent neoadjuvant chemotherapy beforehand. Pathologic ADC, pathologic T and N stages, tumor location, surgical approach, and histologic subtype were investigated with univariate and multivariate analyses by using the Cox regression model. RESULTS: At a total median follow-up period of 21 months, 31 patients had died. The median follow-up was 25 months for the surgery-only group (19 of 31 events [61%]) and 28 months for the chemotherapy group (12 of 31 events [39%]). In the multivariate analysis, ADC values of 1.5 * 10(-3) mm(2)/sec or lower were associated with a negative prognosis, both in the total population (log-relative risk, 1.73; standard error, 0.56; P = .002) and in the surgery-only (log-relative risk, 1.97; standard error, 0.66; P = .003) and chemotherapy (log relative risk, 2.93; standard error, 1.41; P = .03) groups, along with other significant prognostic factors (in particular, pathologic T and N stages). CONCLUSION: Pathologic ADC represents a strong independent prognostic factor in the evaluation of the aggressiveness of gastric cancer, in addition to clinical and surgical variables. PMID- 25816107 TI - Cognitive factors influencing treatment decision-making in patients with localised prostate cancer: development of a standardised questionnaire. AB - BACKGROUND: Men diagnosed with localised prostate cancer have to make a well informed treatment choice between (robot-assisted) radical prostatectomy, external beam radiotherapy and, in selected cases, brachytherapy and active surveillance. We developed and validated a questionnaire to determine the cognitive reasons motivating this choice. MATERIALS AND METHODS: The Prostate Cancer Decision-Making Questionnaire (PC-DMQ) was designed in-house and validated through the Delphi method. Finally, we tested the questionnaire in a cohort of 24 men, recently diagnosed with localised PC, before undergoing RARP (n = 16), EBRT (n = 6), brachytherapy (n = 1) or active surveillance (n = 1). RESULTS: The experts reached consensus after three rounds. In the patient cohort, 75% of men undergoing RARP chose this treatment because 'it provides the best chance of cure'. Reasons to choose EBRT were not as explicit: 33.3% chose this treatment because 'it provides the best chance of cure' and 33.3% because 'the maintenance of potency is important to them'. CONCLUSIONS: The PC-DMQ is a comprehensive and standardised tool that allows further research into cognitive factors that influence treatment decision-making in patients with localised PC. PMID- 25816108 TI - Binder-free Si nanoparticle electrode with 3D porous structure prepared by electrophoretic deposition for lithium-ion batteries. AB - A binder-free silicon (Si) based electrode for lithium-ion battery was fabricated in an organic solvent through one-step electrophoretic deposition (EPD). The nanosized Si and acetylene black (AB) particles were bonded tightly together to form a homogeneous co-deposited film with 3D porous structure through the EPD process. The 3D porous structure provides buffer spaces to alleviate the mechanical stress due to silicon volume change during the cycling and improves lithium-ion conductivity by shortening ion diffusion length and better ion conducting pathway. The electrode prepared with 5 s deposition duration shows the best cycling performance among electrodes fabricated by EPD method, and thus, it was selected to be compared with the silicon electrode prepared by the conventional method. Our results demonstrate that the Si nanoparticle electrode prepared through EPD exhibits smaller cycling capacity decay rate and better rate capability than the electrode prepared by the conventional method. PMID- 25816109 TI - Aquatic photochemical kinetics of benzotriazole and structurally related compounds. AB - Benzotriazole corrosion inhibitors are not completely removed during wastewater treatment and are frequently detected in surface waters. Here, the photochemical kinetics of benzotriazoles and structurally related compounds were assessed for natural aqueous environments. The direct photochemical half-lives during exposure to simulated sunlight ranged from 1.3 to 1.8 days for benzotriazole and its derivatives (4-methyl-, 5-methyl-, 4-hydroxy-substituted benzotriazoles). Benzotriazole is more resistant to direct photodegradation than indazole (0.28 days) and indole (0.09 days), while benzimidazole showed no significant decay. Hydroxyl radicals (1.6 * 10(-16) M) and singlet oxygen (2.5 * 10(-13) M) are formed during simulated sunlight exposure in the presence of dissolved organic matter (13 mgC L(-1)). All tested compounds reacted rapidly with hydroxyl radicals near the diffusion-controlled limit (8.3 to 12 * 10(9) M(-1) s(-1)). Only 4-hydroxybenzotriazole and indole showed significant reactivity towards singlet oxygen and their photochemical half-lives in the presence of organic matter were shorter (0.1 days for both) than for benzotriazole and its methylated derivatives (1.4-1.5 days). The photochemical half-lives determined here are relatively long and support the persistence of benzotriazoles in the environment. At the same time, these results suggest that photochemical transformation can be supplementary to microbial degradation. While the presented study focused on environmental photodegradation kinetics, the relevance of transformation products remains to be investigated. PMID- 25816111 TI - Growth and setting of gas bubbles in a viscoelastic matrix imaged by X-ray microtomography: the evolution of cellular structures in fermenting wheat flour dough. AB - X-ray tomography is a relevant technique for the dynamic follow-up of gas bubbles in an opaque viscoelastic matrix, especially using image analysis. It has been applied here to pieces of fermenting wheat flour dough of various compositions, at two different voxel sizes (15 and 5 MUm). The resulting evolution of the main cellular features shows that the creation of cellular structures follows two regimes that are defined by a characteristic time of connectivity, tc [30 and 80 min]: first (t <= tc), bubbles grow freely and then (t >= tc) they become connected since the percolation of the gas phase is limited by liquid films. During the first regime, bubbles can be tracked and the local strain rate can be measured. Its values (10(-4)-5 * 10(-4) s(-1)) are in agreement with those computed from dough viscosity and internal gas pressure, both of which depend on the composition. For higher porosity, P = 0.64 in our case, and thus occurring in the second regime, different cellular structures are obtained and XRT images show deformed gas cells that display complex shapes. The comparison of these images with confocal laser scanning microscopy images suggests the presence of liquid films that separate these cells. The dough can therefore be seen as a three-phase medium: viscoelastic matrix/gas cell/liquid phase. The contributions of the different levels of matter organization can be integrated by defining a capillary number (C = 0.1-1) that makes it possible to predict the macroscopic dough behavior. PMID- 25816112 TI - Investigation of Line Width Narrowing and Spectral Jumps of Single Stable Defect Centers in ZnO at Cryogenic Temperature. AB - Finding new solid state defect centers in novel host materials is crucial for realizing integrated hybrid quantum photonic devices. We present a preparation method for defect centers with photostable bright single photon emission in zinc oxide, a material with promising properties in terms of processability, availability, and applications. A detailed optical study reveals a complex dynamic of intensity fluctuations at room temperature. Measurements at cryogenic temperatures show very sharp (<60 GHz) zero phonon lines (ZPLs) at 580 nm to 620 nm (~ 2.0 eV) with frozen out fast fluctuations. Remaining discrete jumps of the ZPL, which depend on the excitation power, are observed. The low temperature results will narrow down speculations on the origin of visible-near-infrared (NIR) wavelength defect emission in zinc oxide and provide a basis for improved theoretical models. PMID- 25816110 TI - Benefit of losartan/hydrochlorothiazide-fixed dose combination treatment for isolated morning hypertension: The MAPPY study. AB - Morning hypertension is an established risk factor for cardiovascular events. In the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study, a 50-mg losartan/12.5-mg hydrochlorothiazide combination (Los/HCTZ) lowered morning blood pressure (BP) more effectively than 100-mg losartan (High-Los) in treated hypertensive patients with morning hypertension. The aim of this MAPPY study sub-analysis was to determine whether Los/HCTZ was effective for controlling isolated morning hypertension (morning BP >= 135/85 mmHg and evening BP < 135/85 mmHg), sustained hypertension (morning and evening BP >= 135/85 mmHg), or both. Of the 110 patients studied, 25 (22.7%) had isolated morning hypertension, and 85 (77.3%) had sustained hypertension at baseline. After 3-month treatment, isolated morning hypertension developed into controlled hypertension (morning and evening BP < 135/85 mmHg) in 9 of 11 Los/HCTZ patients (81.8%) and 3 of 14 High-Los patients (21.4%) (p = 0.003, chi square test). Sustained hypertension developed into controlled hypertension in 21 of 44 Los/HCTZ patients (47.7%) and 13 of 41 High-Los patients (31.7%)(NS). The rates of achievement of SBP < 135 mmHg both in the morning and evening were: 81.8% and 21.4% in Los/HCTZ- and High-Los-treated isolated morning hypertension (p = 0.003), respectively; and 61.4% and 36.6% in Los/HCTX- and High-Los-treated sustained hypertension (p = 0.022), respectively. In conclusion, Los/HCTZ was effective for controlling both types of morning hypertension, especially isolated morning hypertension. Los/HCTZ was superior to High-Los in treating both types of morning hypertension. PMID- 25816113 TI - Changes in inorganic fine particulate matter sensitivities to precursors due to large-scale US emissions reductions. AB - We examined the impact of large US emissions changes, similar to those estimated to have occurred between 2005 and 2012 (high and low emissions cases, respectively), on inorganic PM2.5 sensitivities to further NOx, SO2, and NH3 emissions reductions using the chemical transport model GEOS-Chem. Sensitivities to SO2 emissions are larger year-round and across the US in the low emissions case than the high emissions case due to more aqueous-phase SO2 oxidation. Sensitivities to winter NOx emissions are larger in the low emissions case, more than 2* those of the high emissions case in parts of the northern Midwest. Sensitivities to NH3 emissions are smaller (~40%) in the low emissions case, year round, and across the US. Differences in NOx and NH3 sensitivities indicate an altered atmospheric acidity. Larger sensitivities to SO2 and NOx in the low emissions case imply that reducing these emissions may improve air quality more now than they would have in 2005; conversely, NH3 reductions may not improve air quality as much as previously assumed. PMID- 25816115 TI - Optimization of image quality and patient dose in radiographs of paediatric extremities using direct digital radiography. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of beam quality on the image quality (IQ) of ankle radiographs of paediatric patients in the age range of 0-1 year whilst maintaining constant effective dose (ED). METHODS: Lateral ankle radiographs of an infant foot phantom were taken at a range of tube potentials (40.0-64.5 kVp) with and without 0.1-mm copper (Cu) filtration using a Trixell Pixium 4600 detector (Trixell, Morains, France). ED to the patient was computed for the default exposure parameters using PCXMC v. 2.0 and was fixed for other beam qualities by modulating the tube current-time product. The contrast-to noise ratio (CNR) was measured between the tibia and adjacent soft tissue. The IQ of the phantom images was assessed by three radiologists and a reporting radiographer. Four IQ criteria were defined each with a scale of 1-3, giving a maximum score of 12. Finally, a service audit of clinical images at the default and optimum beam qualities was undertaken. RESULTS: The measured CNR for the 40 kVp/no Cu image was 12.0 compared with 7.6 for the default mode (55 0.1 mm Cu). An improvement in the clinical IQ scores was also apparent at this lower beam quality. CONCLUSION: Lowering tube potential and removing filtration improved the clinical IQ of paediatric ankle radiographs in this age range. ADVANCES IN KNOWLEDGE: There are currently no UK guidelines on exposure protocols for paediatric imaging using direct digital radiography. A lower beam quality will produce better IQ with no additional dose penalty for infant extremity imaging. PMID- 25816114 TI - Behavioral modeling of human choices reveals dissociable effects of physical effort and temporal delay on reward devaluation. AB - There has been considerable interest from the fields of biology, economics, psychology, and ecology about how decision costs decrease the value of rewarding outcomes. For example, formal descriptions of how reward value changes with increasing temporal delays allow for quantifying individual decision preferences, as in animal species populating different habitats, or normal and clinical human populations. Strikingly, it remains largely unclear how humans evaluate rewards when these are tied to energetic costs, despite the surge of interest in the neural basis of effort-guided decision-making and the prevalence of disorders showing a diminished willingness to exert effort (e.g., depression). One common assumption is that effort discounts reward in a similar way to delay. Here we challenge this assumption by formally comparing competing hypotheses about effort and delay discounting. We used a design specifically optimized to compare discounting behavior for both effort and delay over a wide range of decision costs (Experiment 1). We then additionally characterized the profile of effort discounting free of model assumptions (Experiment 2). Contrary to previous reports, in both experiments effort costs devalued reward in a manner opposite to delay, with small devaluations for lower efforts, and progressively larger devaluations for higher effort-levels (concave shape). Bayesian model comparison confirmed that delay-choices were best predicted by a hyperbolic model, with the largest reward devaluations occurring at shorter delays. In contrast, an altogether different relationship was observed for effort-choices, which were best described by a model of inverse sigmoidal shape that is initially concave. Our results provide a novel characterization of human effort discounting behavior and its first dissociation from delay discounting. This enables accurate modelling of cost-benefit decisions, a prerequisite for the investigation of the neural underpinnings of effort-guided choice and for understanding the deficits in clinical disorders characterized by behavioral inactivity. PMID- 25816116 TI - Hantavirus pulmonary syndrome, Southern Chile, 1995-2012. AB - Hantavirus is endemic to the Region de Los Lagos in southern Chile; its incidence is 8.5 times higher in the communes of the Andean area than in the rest of the region. We analyzed the epidemiologic aspects of the 103 cases diagnosed by serology and the clinical aspects of 80 hospitalized patients during 1995-2012. Cases in this region clearly predominated during winter, whereas in the rest of the country, they occur mostly during summer. Mild, moderate, and severe disease was observed, and the case-fatality rate was 32%. Shock caused death in 75% of those cases; high respiratory frequency and elevated creatinine plasma level were independent factors associated with death. Early clinical suspicion, especially in rural areas, should prompt urgent transfer to a hospital with an intensive care unit and might help decrease the high case-fatality rate. PMID- 25816117 TI - Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats. AB - The present study aimed to determine whether artesunate has beneficial effects on bleomycin-induced pulmonary fibrosis in rats and to examine the possible mechanisms underlying these effects. All experiments were performed with male Sprague Dawley rats weighing 180-250 g. Animals were randomly divided into four experimental groups that were administered either saline alone, artesunate alone, bleomycin alone or bleomycin + artesunate. Lung histopathology was investigated by hematoxylin and eosin staining and Masson staining. Lung profibrotic molecules were analyzed by reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry. In rats treated with artesunate, pulmonary fibrosis induced by bleomycin was significantly reduced. Administration of artesunate significantly improved bleomycin-induced morphological alterations. Profibrotic molecules, including transforming growth factor-beta1, Smad3, heat shock protein 47, alpha-smooth muscle actin and collagen type I were also reduced by artesunate. These findings suggest that artesunate improves bleomycin-induced pulmonary fibrosis pathology in rats possibly by inhibiting profibrotic molecules associated with pulmonary fibrosis. PMID- 25816118 TI - Computational networks of activating transcription factor 3 gene in Huh7 cell lines and hepatitis C virus-infected Huh7 cell lines. AB - Activating transcription factor 3 (ATF3) is an adaptive-response gene of the ATF family. ATF3 activity may be induced in response to a number of different stress associated signals and ATF3 is involved in a variety of cellular processes. However, the functions of ATF3 and its molecular networks in human hepatoma cells lines and hepatitis C virus-infected Huh7 (HCV-Huh7) cells are not well understood. In the present study, ATF3 regulatory networks in Huh7 and HCV-Huh7 cell lines were established using the linear programming-based GRNinfer software and molecule annotation system 3.0 software. The gene expression omnibus dataset, GSE20948, was analyzed. The resulting network consisted of clusters located upstream and downstream of ATF3 in Huh7 and HCV-Huh7 cell lines. Using the annotation, visualization and integrated discovery (DAVID) software, 10 activation and 2 inhibition enriched functional annotation clusters were identified downstream of ATF3 in HCV-Huh7 cells. However, there were no enriched functional annotation clusters identified upstream of ATF3 in HCV-Huh7 cells. Furthermore, no clusters were identified downstream nor upstream of ATF3 in Huh7 cells. Gene ontology term and Kyoto encyclopedia of genes and genomes pathway analyses demonstrated that ATF3 may be involved in a number of biological processes, in particular, in metabolism regulation in HCV-Huh7 cells. It is hypothesized that the ATF3 pathway may be activated in Huh7 cells following HCV infection and that it is a potential 'hub' in the network of HCV-Huh7 cells. PMID- 25816121 TI - Correction: Crystal structure of calcium binding protein-5 from Entamoeba histolytica and its involvement in initiation of phagocytosis of human erythrocytes. PMID- 25816119 TI - An International Normalized Ratio-Based Definition of Acute Traumatic Coagulopathy Is Associated With Mortality, Venous Thromboembolism, and Multiple Organ Failure After Injury. AB - OBJECTIVES: Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy's relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio-based definitions for acute traumatic coagulopathy. DESIGN: Multicenter prospective observational study. SETTING: Nine level I trauma centers in the United States. PATIENTS: A total of 1,031 blunt trauma patients with hemorrhagic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p < 0.001), hemorrhagic shock-associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p < 0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes. CONCLUSIONS: Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold. PMID- 25816120 TI - Middle-aged women's decisions about body weight management: needs assessment and testing of a knowledge translation tool. AB - OBJECTIVE: This study aims to assess middle-aged women's needs when making body weight management decisions and to evaluate a knowledge translation tool for addressing their needs. METHODS: A mixed-methods study used an interview-guided theory-based survey of professional women aged 40 to 65 years. The tool summarized evidence to address their needs and enabled women to monitor actions taken. Acceptability and usability were reported descriptively. RESULTS: Sixty female participants had a mean body mass index of 28.0 kg/m(2) (range, 17.0-44.9 kg/m(2)), and half were premenopausal. Common options for losing (82%) or maintaining (18%) weight included increasing physical activity (60%), eating healthier (57%), and getting support (40%). Decision-making involved getting information on options (52%), soliciting others' decisions/advice (20%), and being self-motivated (20%). Preferred information sources included written information (97%), counseling (90%), and social networking websites (43%). Five professionals (dietitian, personal trainer, occupational therapist, and two physicians) had similar responses. Of 53 women sent the tool, 27 provided acceptability feedback. They rated it as good to excellent for information on menopause (96%), body weight changes (85%), and managing body weight (85%). Most would tell others about it (81%). After 4 weeks of use, 25 women reported that the wording made sense (96%) and that the tool had clear instructions (92%) and was easy to use across time (88%). The amount of information was rated as just right (64%), but the tool had limited space for responding (72%). CONCLUSIONS: When making decisions about body weight management, women's needs were "getting information" and "getting support." The knowledge translation tool was acceptable and usable, but further evaluation is required. PMID- 25816122 TI - Efficacy of IPL device combined with intralesional corticosteroid injection for the treatment of keloids and hypertrophic scars with regards to the recovery of skin barrier function: A pilot study. AB - BACKGROUND: Keloids and hypertrophic scars are prevalent and psychologically distressful dermatologic conditions. Various treatment modalities have been tried but without complete success by any one method. OBJECTIVE: We evaluated the efficacy of a combination of intense pulsed light (IPL) device and intralesional corticosteroid injection for the treatment of keloids and hypertrophic scars with respect to the recovery of skin barrier function. METHODS: Totally 52 Korean patients were treated by the combined treatment at 4-8-week intervals. Using digital photographs, changes in scar appearance were assessed with modified Vancouver Scar Scale (MVSS), physicians' global assessment (PGA) and patient's satisfaction score. In 12 patients, the stratum corneum (SC) barrier function was assessed by measuring transepidermal water loss (TEWL) and SC capacitance. RESULTS: Most scars demonstrated significant clinical improvement in MVSS, PGA and patient's satisfaction score after the combined therapy. A significant decrease of TEWL and elevation of SC capacitance were also documented after the treatment. CONCLUSION: The combination therapy (IPL + corticosteroid injection) not only improves the appearance of keloids and hypertrophic scars but also increases the recovery level of skin hydration status in terms of the skin barrier function. PMID- 25816124 TI - Rehabilitation of moderate-to-severe traumatic brain injury. AB - Traumatic brain injury (TBI) is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force. Traumatic brain injury is a leading cause of morbidity and disability and is considered a major public health concern. Traumatic brain injury sequelae can lead to long-term impairments in physical, cognitive, behavioral, and social function. Traumatic brain injury rehabilitation requires an interdisciplinary holistic team approach in the management of medical complications, the prevention of further disability, and helping patients return to their highest level of independence. The authors review TBI pathophysiology, grading severity, common medical complications, cognitive rehabilitation, prognosis, and common outcomes used in TBI rehabilitation. PMID- 25816123 TI - In Utero Fine Particle Air Pollution and Placental Expression of Genes in the Brain-Derived Neurotrophic Factor Signaling Pathway: An ENVIRONAGE Birth Cohort Study. AB - BACKGROUND: Developmental processes in the placenta and the fetal brain are shaped by the same biological signals. Recent evidence suggests that adaptive responses of the placenta to the maternal environment may influence central nervous system development. OBJECTIVES: We studied the association between in utero exposure to fine particle air pollution with a diameter <= 2.5 MUm (PM2.5) and placental expression of genes implicated in neural development. METHODS: Expression of 10 target genes in the brain-derived neurotrophic factor (BDNF) signaling pathway were quantified in placental tissue of 90 mother-infant pairs from the ENVIRONAGE birth cohort using quantitative real-time polymerase chain reaction. Trimester-specific PM2.5 exposure levels were estimated for each mother's home address using a spatiotemporal model. Mixed-effects models were used to evaluate the association between the target genes and PM2.5 exposure measured in different time windows of pregnancy. RESULTS: A 5-MUg/m3 increase in residential PM2.5 exposure during the first trimester of pregnancy was associated with a 15.9% decrease [95% confidence interval (CI): -28.7, -3.2%, p = 0.015] in expression of placental BDNF at birth. The corresponding estimate for synapsin 1 (SYN1) was a 24.3% decrease (95% CI: -42.8, -5.8%, p = 0.011). CONCLUSIONS: Placental expression of BDNF and SYN1, two genes implicated in normal neurodevelopmental trajectories, decreased with increasing in utero exposure to PM2.5. Future studies are needed to confirm our findings and evaluate the potential relevance of associations between PM2.5 and placental expression of BDNF and SYN1 on neurodevelopment. We provide the first molecular epidemiological evidence concerning associations between in utero fine particle air pollution exposure and the expression of genes that may influence neurodevelopmental processes. PMID- 25816125 TI - Mechanisms of traumatic brain injury. AB - The authors describe the mechanisms of traumatic brain injury (TBI), examining in depth the characteristics of closed head, penetrating, and blast-related TBI. Events on a structural as well as cellular level are reviewed. Blast-related brain injury, in particular, affects military service members preferentially, but is also relevant in cases of industrial accidents as well as terrorist events. PMID- 25816126 TI - Improving Nursing Knowledge of Alcohol Withdrawal: Second Generation Education Strategies. AB - Christiana Care Health System implemented a Care Management Guideline for Alcohol Withdrawal Symptom Management, which provided direction for inpatient screening for alcohol withdrawal risk, assessment, and treatment. Nurses educated on its use expressed confusion with the use of the assessment tools, pharmacokinetics, and pathophysiology of alcohol withdrawal and delirium tremens. Reeducation was provided by nursing professional development specialists. Pre- and postsurveys revealed that nurses were more confident in caring for patients with alcohol withdrawal. PMID- 25816127 TI - Cyclometalated iridium complex-based label-free photoelectrochemical biosensor for DNA detection by hybridization chain reaction amplification. AB - Photoactive material is the most crucial factor which intimately determines analytical performances of the photoelectrochemical sensor. On the basis of the high affinity of dipyrido [3,2-a:2',3'-c] phenazine (dppz) with DNA helix, a novel photoactive intercalator, [(ppy)2Ir(dppz)](+)PF6(-)(ppy = 2-phenylpyridine and dppz = dipyrido [3,2-a:2',3'-c] phenazine) was prepared and characterized by UV-vis absorption spectroscopy, fluorescence spectroscopy, and cyclic voltammetry. The photoelectrochemical properties of the as-prepared iridium(III) complex immobilized on the ITO electrode was investigated. Either cathodic or anodic photocurrent generation can be observed when triethanolamine (TEOA) or dissolved O2 is used as a sacrificial electron donor/acceptor, respectively. The probable photocurrent-generation mechanisms are speculated. A highly sensitive iridium(III) complex-based photoelectrochemical sensor was proposed for DNA detection via hybridization chain reaction (HCR) signal amplification. Under optimal conditions, the biosensor was found to be linearly proportional to the logarithm of target DNA concentration in the range from 0.025 to 100 pmol L(-1) with a detection limit of 9.0 fmol L(-1) (3sigma). Moreover, the proposed sensor displayed high selectivity and good reproducibility, demonstrating efficient and stable photoelectric conversion ability of the Ir(III) complex. PMID- 25816128 TI - Screening and assessment of nutritional status following stroke: results from a national survey of registered dietitians in Canada. AB - PURPOSE: The objective of this study was to survey registered dietitians (RDs) at acute care hospitals across Canada to determine whether valid screening and assessment methods (i.e. those with formal evaluation of the psychometric and/or clinimetric properties of the tool) are used to identify protein-energy malnutrition following stroke. METHODS: One hundred and twenty-five Canadian healthcare institutions admitting high volumes (>=100/year) of acute stroke patients were identified. RDs at these sites who provided services to patients recovering from acute stroke were contacted and invited to participate in an online survey. RESULTS: Ninety-five RDs completed the survey. Sixty dietitians (63%) indicated that patients were screened routinely at their institution, which was conducted primarily by dietitians (n = 64, 67.3%). Ten respondents (10.5%) stated they used a screening tool with previously-established validity, while 32 (33.7%) indicated they used a validated assessment tool. Among dietitians using validated tools, 40% and 64% indicated that they used modified versions of the original screening and assessment tools. The most frequently cited tools used for both screening and assessment purposes were Subjective Global Assessment and Mini Nutritional Assessment. CONCLUSIONS: The results of this national survey suggest that screening and assessment of nutritional status following acute stroke is conducted using tools that have not been validated previously. Implications for Rehabilitation Although the use of valid screening and assessment tools is considered part of evidence-based practice, and recommendations for their adoption are included in several national stroke-specific clinical practice guidelines, the results from an online survey suggest that they are not used in clinical practice by RDs in Canada caring for patients following stroke. There are associated risks with the use of screening and assessment tools, which have not been formally validated. The true nutritional status of patients may not be initially identified correctly, and the response to subsequent nutritional interventions may not be assessed accurately or reliably. While the results of this survey were stroke-specific, we suggest that the results are likely generalizable to dietitians working in other patient areas. PMID- 25816129 TI - Anthelmintic activity in vivo of epiisopiloturine against juvenile and adult worms of Schistosoma mansoni. AB - Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported. PMID- 25816130 TI - Gliotoxin potentiates osteoblast differentiation by inhibiting nuclear factor kappaB signaling. AB - The differentiation of pluripotent mesenchymal stem cells to mature osteoblasts is crucial for the maintenance of the adult skeleton. In rheumatic arthritis, osteoblast differentiation is impaired by the overproduction of cytokine tumor necrosis factor (TNF)-alpha. It has been demonstrated that TNF-alpha is able to inhibit osteoblast differentiation through the activation of nuclear factor (NF) kappaB signaling. As a result of the critical role of TNF-alpha and NF-kappaB in the pathogenesis of bone-loss associated diseases, these factors are regarded as key targets for the development of therapeutic agents. In the current study, the role of the NF-kappaB inhibitor gliotoxin (GTX) in the regulation of osteoblast differentiation was evaluated. The non-toxic GTX doses were determined to be <= 3 ug/ml. It was revealed that GTX was able to block TNF-alpha-induced inhibition of osteoblast differentiation, as indicated by alkaline phosphatase (ALP) activity and ALP staining assays, as well as the expression levels of osteoblast associated genes Col I, Ocn, Bsp, Runx2, Osx and ATF4. Additionally, it was identified that gliotoxin directly promoted bone morphogenetic protein-2-induced osteoblast differentiation. GTX was found to inhibit the accumulation of NF kappaB protein p65 in the nucleus and reduce NF-kappaB transcriptional activity, suggesting that GTX potentiated osteoblast differentiation via the suppression of NF-kappaB signaling. PMID- 25816131 TI - A pulse coupled neural network segmentation algorithm for reflectance confocal images of epithelial tissue. AB - Automatic segmentation of nuclei in reflectance confocal microscopy images is critical for visualization and rapid quantification of nuclear-to-cytoplasmic ratio, a useful indicator of epithelial precancer. Reflectance confocal microscopy can provide three-dimensional imaging of epithelial tissue in vivo with sub-cellular resolution. Changes in nuclear density or nuclear-to cytoplasmic ratio as a function of depth obtained from confocal images can be used to determine the presence or stage of epithelial cancers. However, low nuclear to background contrast, low resolution at greater imaging depths, and significant variation in reflectance signal of nuclei complicate segmentation required for quantification of nuclear-to-cytoplasmic ratio. Here, we present an automated segmentation method to segment nuclei in reflectance confocal images using a pulse coupled neural network algorithm, specifically a spiking cortical model, and an artificial neural network classifier. The segmentation algorithm was applied to an image model of nuclei with varying nuclear to background contrast. Greater than 90% of simulated nuclei were detected for contrast of 2.0 or greater. Confocal images of porcine and human oral mucosa were used to evaluate application to epithelial tissue. Segmentation accuracy was assessed using manual segmentation of nuclei as the gold standard. PMID- 25816132 TI - A GFP expressing influenza A virus to report in vivo tropism and protection by a matrix protein 2 ectodomain-specific monoclonal antibody. AB - The severity of influenza-related illness is mediated by many factors, including in vivo cell tropism, timing and magnitude of the immune response, and presence of pre-existing immunity. A direct way to study cell tropism and virus spread in vivo is with an influenza virus expressing a reporter gene. However, reporter gene-expressing influenza viruses are often attenuated in vivo and may be genetically unstable. Here, we describe the generation of an influenza A virus expressing GFP from a tri-cistronic NS segment. To reduce the size of this engineered gene segment, we used a truncated NS1 protein of 73 amino acids combined with a heterologous dimerization domain to increase protein stability. GFP and nuclear export protein coding information were fused in frame with the truncated NS1 open reading frame and separated from each other by 2A self processing sites. The resulting PR8-NS1(1-73)GFP virus was successfully rescued and replicated as efficiently as the parental PR8 virus in vitro and was slightly attenuated in vivo. Flow cytometry-based monitoring of cells isolated from PR8 NS1(1-73)GFP virus infected BALB/c mice revealed that GFP expression peaked on day two in all cell types tested. In particular respiratory epithelial cells and myeloid cells known to be involved in antigen presentation, including dendritic cells (CD11c+) and inflammatory monocytes (CD11b+ GR1+), became GFP positive following infection. Prophylactic treatment with anti-M2e monoclonal antibody or oseltamivir reduced GFP expression in all cell types studied, demonstrating the usefulness of this reporter virus to analyze the efficacy of antiviral treatments in vivo. Finally, deep sequencing analysis, serial in vitro passages and ex vivo analysis of PR8-NS1(1-73)GFP virus, indicate that this virus is genetically and phenotypically stable. PMID- 25816133 TI - Tumor necrosis factor disrupts claudin-5 endothelial tight junction barriers in two distinct NF-kappaB-dependent phases. AB - Capillary leak in severe sepsis involves disruption of endothelial cell tight junctions. We modeled this process by TNF treatment of cultured human dermal microvascular endothelial cell (HDMEC) monolayers, which unlike human umbilical vein endothelial cells form claudin-5-dependent tight junctions and a high resistance permeability barrier. Continuous monitoring with electrical cell substrate impedance sensing revealed that TNF disrupts tight junction-dependent HDMEC barriers in discrete steps: an ~5% increase in transendothelial electrical resistance over 40 minutes; a decrease to ~10% below basal levels over 2 hours (phase 1 leak); an interphase plateau of 1 hour; and a major fall in transendothelial electrical resistance to < 70% of basal levels by 8-10 hours (phase 2 leak), with EC50 values of TNF for phase 1 and 2 leak of ~30 and ~150 pg/ml, respectively. TNF leak is reversible and independent of cell death. Leak correlates with disruption of continuous claudin-5 immunofluorescence staining, myosin light chain phosphorylation and loss of claudin-5 co-localization with cortical actin. All these responses require NF-kappaB signaling, shown by inhibition with Bay 11 or overexpression of IkappaB super-repressor, and are blocked by H-1152 or Y-27632, selective inhibitors of Rho-associated kinase that do not block other NF-kappaB-dependent responses. siRNA combined knockdown of Rho associated kinase-1 and -2 also prevents myosin light chain phosphorylation, loss of claudin-5/actin co-localization, claudin-5 reorganization and reduces phase 1 leak. However, unlike H-1152 and Y-27632, combined Rho-associated kinase-1/2 siRNA knockdown does not reduce the magnitude of phase 2 leak, suggesting that H 1152 and Y-27632 have targets beyond Rho-associated kinases that regulate endothelial barrier function. We conclude that TNF disrupts TJs in HDMECs in two distinct NF-kappaB-dependent steps, the first involving Rho-associated kinase and the second likely to involve an as yet unidentified but structurally related protein kinase(s). PMID- 25816134 TI - Retinal glia promote dorsal root ganglion axon regeneration. AB - Axon regeneration in the adult central nervous system (CNS) is limited by several factors including a lack of neurotrophic support. Recent studies have shown that glia from the adult rat CNS, specifically retinal astrocytes and Muller glia, can promote regeneration of retinal ganglion cell axons. In the present study we investigated whether retinal glia also exert a growth promoting effect outside the visual system. We found that retinal glial conditioned medium significantly enhanced neurite growth and branching of adult rat dorsal root ganglion neurons (DRG) in culture. Furthermore, transplantation of retinal glia significantly enhanced regeneration of DRG axons past the dorsal root entry zone after root crush in adult rats. To identify the factors that mediate the growth promoting effects of retinal glia, mass spectrometric analysis of retinal glial conditioned medium was performed. Apolipoprotein E and secreted protein acidic and rich in cysteine (SPARC) were found to be present in high abundance, a finding further confirmed by western blotting. Inhibition of Apolipoprotein E and SPARC significantly reduced the neuritogenic effects of retinal glial conditioned medium on DRG in culture, suggesting that Apolipoprotein E and SPARC are the major mediators of this regenerative response. PMID- 25816135 TI - Neonatal Streptococcus pneumoniae infection may aggravate adulthood allergic airways disease in association with IL-17A. AB - Epidemiologic studies have demonstrated that some bacteria colonization or infections in early-life increased the risk for subsequent asthma development. However, little is known about the mechanisms by which early-life bacterial infection increases this risk. The aim of this study was to investigate the effect of neonatal Streptococcus pneumoniae infection on the development of adulthood asthma, and to explore the possible mechanism. A non-lethal S. pneumoniae lung infection was established by intranasal inoculation of neonatal (1-week-old) female mice with D39. Mice were sensitized and challenged with ovalbumin in adulthood to induce allergic airways disease (AAD). Twenty-four hours later, the lungs and bronchoalveolar lavage fluid (BALF) were collected to assess AAD. Neonatal S. pneumoniae infection exacerbated adulthood hallmark features of AAD, with enhanced airway hyperresponsiveness and increased neutrophil recruitment into the airways, increased Th17 cells and interleukin (IL)-17A productions. Depletion of IL-17A by i.p. injection of a neutralizing monoclonal antibody reduced neutrophil recruitment into the airways, alleviated airway inflammation and decreased airway hyperresponsiveness. Furthermore, IL-17A depletion partially restored levels of inteferon-gamma, but had no effect on the release of IL-5 or IL-13. Our data suggest that neonatal S. pneumoniae infection may promote the development of adulthood asthma in association with increased IL 17A production. PMID- 25816136 TI - Tightly regulated expression of Autographa californica multicapsid nucleopolyhedrovirus immediate early genes emerges from their interactions and possible collective behaviors. AB - To infect their hosts, DNA viruses must successfully initiate the expression of viral genes that control subsequent viral gene expression and manipulate the host environment. Viral genes that are immediately expressed upon infection play critical roles in the early infection process. In this study, we investigated the expression and regulation of five canonical regulatory immediate-early (IE) genes of Autographa californica multicapsid nucleopolyhedrovirus: ie0, ie1, ie2, me53, and pe38. A systematic transient gene-expression analysis revealed that these IE genes are generally transactivators, suggesting the existence of a highly interactive regulatory network. A genetic analysis using gene knockout viruses demonstrated that the expression of these IE genes was tolerant to the single deletions of activator IE genes in the early stage of infection. A network graph analysis on the regulatory relationships observed in the transient expression analysis suggested that the robustness of IE gene expression is due to the organization of the IE gene regulatory network and how each IE gene is activated. However, some regulatory relationships detected by the genetic analysis were contradictory to those observed in the transient expression analysis, especially for IE0-mediated regulation. Statistical modeling, combined with genetic analysis using knockout alleles for ie0 and ie1, showed that the repressor function of ie0 was due to the interaction between ie0 and ie1, not ie0 itself. Taken together, these systematic approaches provided insight into the topology and nature of the IE gene regulatory network. PMID- 25816138 TI - Re: Can Spontaneous Correction Loss of the Minor Cures Be Ignored at the Final Follow-up? PMID- 25816139 TI - Accuracies in Measuring Spinopelvic Parameters in Full-Spine Lateral Standing Radiograph. AB - STUDY DESIGN: Prospective comparative study of measuring pelvic incidence (PI) among standing radiographs of whole spine and pelvis and computed tomographic (CT) scans in a cohort of patients. OBJECTIVE: To analyze accuracies in measuring PI and other spinopelvic parameters. SUMMARY OF BACKGROUND DATA: Previous reports indicated relatively low agreement in measuring PI even among experienced spinal surgeons; intra- and inter-rater reliability in manually measuring PI were 0.69 (0.62-0.74) and 0.41 (0.36-0.45), respectively; the mean interclass correlation coefficient value of manually measuring PI was 0.881. No study compared PI on standing radiographs with that measured on CT scans. METHODS: A total of 120 consecutive patients with spinal disease (38 patients had history of hip arthroplasty) who admitted to our hospital from April 2012 for 6 months were enrolled. Subjects had obtained full-spine lateral standing radiograph, standing radiograph of pelvis, and CT scans. Pelvic incidence on full-spine lateral standing radiograph and that on pelvis lateral standing radiograph were measured manually by 2 experienced spinal surgeons. Intra- and interobserver reliability of the measurements were analyzed by using interclass correlation coefficient. On CT scans, PI was measured using 3-dimensional CT scan software (CT-PI). PI among 3 different imaging modalities was evaluated using correlation coefficients. RESULTS: In whole-spine radiographs, the intra- and interobserver agreement rates with measurements in PI (0.84 and 0.79, respectively) and sacral slope (0.87 and 0.83, respectively) were lower than those in pelvic tilt (0.98 and 0.96, respectively) and PI-lumbar lordosis (0.97 and 0.97, respectively). The correlation coefficient between P-PI and CT-PI was higher (0.95) than that between FS-PI and CT-PI (0.81) and between FS-PI and P-PI (0.85). CONCLUSION: The reliability of measuring PI is comparatively lower than that of other spinopelvic parameters, and the variability of PI measurement is mainly due to difficulty of precisely identifying sacral endplate. LEVEL OF EVIDENCE: 2. PMID- 25816137 TI - Pulmonary inflammation is regulated by the levels of the vesicular acetylcholine transporter. AB - Acetylcholine (ACh) plays a crucial role in physiological responses of both the central and the peripheral nervous system. Moreover, ACh was described as an anti inflammatory mediator involved in the suppression of exacerbated innate response and cytokine release in various organs. However, the specific contributions of endogenous release ACh for inflammatory responses in the lung are not well understood. To address this question we have used mice with reduced levels of the vesicular acetylcholine transporter (VAChT), a protein required for ACh storage in secretory vesicles. VAChT deficiency induced airway inflammation with enhanced TNF-alpha and IL-4 content, but not IL-6, IL-13 and IL-10 quantified by ELISA. Mice with decreased levels of VAChT presented increased collagen and elastic fibers deposition in airway walls which was consistent with an increase in inflammatory cells positive to MMP-9 and TIMP-1 in the lung. In vivo lung function evaluation showed airway hyperresponsiveness to methacholine in mutant mice. The expression of nuclear factor-kappa B (p65-NF-kB) in lung of VAChT deficient mice were higher than in wild-type mice, whereas a decreased expression of janus-kinase 2 (JAK2) was observed in the lung of mutant animals. Our findings show the first evidence that cholinergic deficiency impaired lung function and produce local inflammation. Our data supports the notion that cholinergic system modulates airway inflammation by modulation of JAK2 and NF-kB pathway. We proposed that intact cholinergic pathway is necessary to maintain the lung homeostasis. PMID- 25816140 TI - The Impact of Preoperative Angiographic Identification of the Artery of Adamkiewicz on Surgical Decision Making in Patients Undergoing Thoracolumbar Corpectomy. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To investigate the impact of spinal angiography on selection of surgical side in patients undergoing thoracolumbar corpectomy. SUMMARY OF BACKGROUND DATA: The artery of Adamkiewicz provides the major blood supply to the thoracolumbar spinal cord. Its location makes it vulnerable to injury during surgical procedures. Preoperative diagnostic spinal angiography is often used to determine the level and lateralization of the artery. METHODS: Data were gathered regarding level and laterality of the Adamkiewicz artery in 34 patients who underwent lateral extracavitary approaches to the thoracolumbar spine, preceded by diagnostic spinal angiography for localization of that artery. Two experienced spine surgeons were retrospectively polled regarding ideal side of approach for each case. This was compared with the actual side that was selected after angiographic localization. RESULTS: The artery was successfully identified in 71% of patients. The artery was most commonly located on the left side (83%) between T9 and L1 (83%). Diagnostic angiography seemed to have influenced surgical decision making in 54% of cases. In 21% of patients, there was no need to alter the side of approach. In the remaining 25%, the surgical plan was not altered on the basis of angiographic data, presumably due to anatomic limitations. No angiography- or surgery-related complications occurred in any of the patients. CONCLUSION: Preoperative spinal angiography seems to impact surgical decision making with regard to alteration of the side of approach in patients undergoing thoracolumbar corpectomy via lateral extracavitary approaches. LEVEL OF EVIDENCE: 4. PMID- 25816141 TI - Fungal Infections of the Spine. AB - STUDY DESIGN: Review of the literature. OBJECTIVE: To retrospectively examine the frequency of published fungal infections by species and the treatment algorithms used to eradicate the disease. SUMMARY OF BACKGROUND DATA: Fungal infections of the spine present unique challenges to the modern multispecialty treatment team. Although rare in comparison with bacterial infections, fungal infections have been increasing in incidence over the past several decades. Evidences-based practice is limited to referencing smaller case series. METHODS: MEDLINE, Scopus, and EMBASE searches were carried out by one of the authors as well as by the research desk at the University of Miami/Calder Memorial Library. We included peer-reviewed articles published between 1948 and September 2010; case reports, series, and reviews were all examined and compiled into a database. RESULTS: A total of 130 articles, representing 157 cases, were included in the review. Aspergillus (60 cases, 38.2% of the total) and Candida species (36 cases, 22.9% of the total) were the 2 most common organisms. Surgery was associated with a greater survival rate than medical management alone in patients with Aspergillus (26.9% mortality in surgical patients; 60% in medically treated patients) and Candida (0% vs. 28.6%). Overall mortality was 19.3%. The overall recurrence rate was 7.4%. Amphotericin use was associated with a higher mortality rate than azoles. CONCLUSION: Aspergillus is the most common published pathogen in fungal infections of the spine. Recent publications depicting the use of newer antifungal medications such as azoles report higher survival rates. Surgically treated patients in combination with antifungal therapy showed highest frequencies of patient survival in Aspergillus and Candida infections. LEVEL OF EVIDENCE: 3. PMID- 25816142 TI - Point of View. PMID- 25816143 TI - Fast and accurate semi-automated segmentation method of spinal cord MR images at 3T applied to the construction of a cervical spinal cord template. AB - OBJECTIVE: To design a fast and accurate semi-automated segmentation method for spinal cord 3T MR images and to construct a template of the cervical spinal cord. MATERIALS AND METHODS: A semi-automated double threshold-based method (DTbM) was proposed enabling both cross-sectional and volumetric measures from 3D T2 weighted turbo spin echo MR scans of the spinal cord at 3T. Eighty-two healthy subjects, 10 patients with amyotrophic lateral sclerosis, 10 with spinal muscular atrophy and 10 with spinal cord injuries were studied. DTbM was compared with active surface method (ASM), threshold-based method (TbM) and manual outlining (ground truth). Accuracy of segmentations was scored visually by a radiologist in cervical and thoracic cord regions. Accuracy was also quantified at the cervical and thoracic levels as well as at C2 vertebral level. To construct a cervical template from healthy subjects' images (n=59), a standardization pipeline was designed leading to well-centered straight spinal cord images and accurate probability tissue map. RESULTS: Visual scoring showed better performance for DTbM than for ASM. Mean Dice similarity coefficient (DSC) was 95.71% for DTbM and 90.78% for ASM at the cervical level and 94.27% for DTbM and 89.93% for ASM at the thoracic level. Finally, at C2 vertebral level, mean DSC was 97.98% for DTbM compared with 98.02% for TbM and 96.76% for ASM. DTbM showed similar accuracy compared with TbM, but with the advantage of limited manual interaction. CONCLUSION: A semi-automated segmentation method with limited manual intervention was introduced and validated on 3T images, enabling the construction of a cervical spinal cord template. PMID- 25816144 TI - Production of functional human vitamin A transporter/RBP receptor (STRA6) for structure determination. AB - STRA6 is a plasma membrane protein that mediates the transport of vitamin A, or retinol, from plasma retinol binding protein (RBP) into the cell. Mutations in human STRA6 are associated with Matthew-Wood syndrome, which is characterized by severe developmental defects. Despite the obvious importance of this protein to human health, little is known about its structure and mechanism of action. To overcome the difficulties frequently encountered with the production of membrane proteins for structural determination, STRA6 has been expressed in Pichia pastoris as a fusion to green fluorescent protein (GFP), a strategy which has been a critical first step in solving the crystal structures of several membrane proteins. STRA6-GFP was correctly targeted to the cell surface where it bound RBP. Here we report the large-scale expression, purification and characterisation of STRA6-GFP. One litre of culture, corresponding to 175 g cells, yielded about 1.5 mg of pure protein. The interaction between purified STRA6 and its ligand RBP was studied by surface plasmon resonance-based binding analysis. The interaction between STRA6 and RBP was not retinol-dependent and the binding data were consistent with a transient interaction of 1 mole RBP/mole STRA6. PMID- 25816145 TI - NGF and P75NTR gene expression is associated with the hepatic fibrosis stage due to viral and non-viral causes. AB - This study evaluated the relative mRNA expression levels of nerve growth factor (NGF) and the p75 neurothrophin receptor (p75NTR) in different histological stages of human liver disease. Fifty-one liver biopsy specimens obtained from patients with hepatitis B virus (n = 6), hepatitis C virus (n = 28), and non viral hepatitis--(n = 9) and standard histological liver (n = 8) as controls (CT) were subjected to qPCR and histopathological exams. Our data revealed a significant difference in the NGF expression levels between the three patient groups and the Control group. p75NTR expression levels in the HCV and NVH groups were higher than those observed in the HBV and Control groups. In cases of liver cirrhosis, higher p75NTR mRNA expression was observed, whereas NGF was expressed at higher levels in patients with hepatic fibrosis. NGF expression was lower in the F1 liver fibrosis stage, and p75NTR receptor expression continuously and proportionately increased compared to the increase in the degree of fibrosis and was significantly higher in livers in fibrosis stages 3 and 4. The hepatic levels of NGF and p75NTR were decreased and increased, respectively, relative to the stage of inflammatory activity. A positive correlation between p75NTR and NGF gene expression was observed in livers with mild to moderate fibrosis, though not in cases of severe fibrosis and cirrhosis. Conclusion: Our results demonstrate that the course of chronic liver disease can be regulated by NGF and p75NTR, which function by decreasing or inhibiting hepatocyte regeneration and proliferation. PMID- 25816147 TI - Patterns and structures of land use change in the Three Rivers Headwaters Region of China. AB - Located in Qinghai Province of China, the Three Rivers Headwaters Region is the source region of the Yangtze, Yellow and Lantsang Rivers, and plays an important role in biodiversity conservation and regulating water supply. Despite many efforts on land use change in Qinghai, knowledge of the spatial variation of land use change is still lacking. This study examines the patterns of land use change across various watersheds, prefectures and the temple surroundings. Remote sensing images of 1987, 1997 and 2007 were analyzed to derive land use distributions; patterns and structures of the landscape were then quantified with landscape metrics. The results illustrated that the Yangtze River headwater region had more diverse and more evenly distributed landscape, while the Lantsang and the Yellow headwater regions showed a decline in landscape diversity. Comparison of the land use patterns of four prefectures revealed that Yushu Prefecture experienced an increase in landscape diversity from 1987 to 2007 while the land use patches in Guoluo Prefecture exhibited more aggregated patterns than other prefectures. Analysis of the spatial variations of land use change in the temple surroundings illustrated that 19.7% and 35.9% of the temples in Guoluo and Yushu Prefectures, respectively, encountered land use change for their immediate areas within 2 km. Comparison of the surroundings of temples and human settlements found that land use change was not evenly distributed, and that greater land use change had occurred for the surroundings of human settlements. Such findings provided insights into the spatial variation of land use change in the Three Rivers Headwaters Region. PMID- 25816146 TI - Impact of thromboprophylaxis across the US acute care setting. AB - BACKGROUND: The risk of venous thromboembolism (VTE) can be reduced by appropriate use of anticoagulant prophylaxis. VTE prophylaxis does, however, remain substantially underused, particularly among acutely ill medical inpatients. We sought to evaluate the clinical and economic impact of increasing use of American College of Chest Physicians (ACCP)-recommended VTE prophylaxis among medical inpatients from a US healthcare system perspective. METHODS AND FINDINGS: In this retrospective database cost-effectiveness evaluation, a decision-tree model was developed to estimate deaths within 30 days of admission and outcomes attributable to VTE that might have been averted by use of low molecular-weight heparin (LMWH) or unfractionated heparin (UFH). Incremental cost effectiveness ratio was calculated using "no prophylaxis" as the comparator. Data from the ENDORSE US medical inpatients and the US nationwide Inpatient Sample (NIS) were used to estimate the annual number of eligible inpatients who failed to receive ACCP-recommended VTE prophylaxis. The cost-effectiveness analysis indicated that VTE-prevention strategies would reduce deaths by 0.5% and 0.3%, comparing LMWH and UFH strategies with no prophylaxis, translating into savings of $50,637 and $25,714, respectively, per death averted. The ENDORSE findings indicated that 51.1% of US medical inpatients were at ACCP-defined VTE risk, 47.5% of whom received ACCP-recommended prophylaxis. By extrapolating these findings to the NIS and applying cost-effectives analysis results, the full implementation of ACCP guidelines would reduce number of deaths (by 15,875 if using LMWH or 10,201 if using UFH), and was extrapolated to calculate the cost reduction of $803M for LMWH and $262M for UFH. CONCLUSIONS: Efforts to improve VTE prophylaxis use in acutely ill inpatients are warranted due to the potential for reducing VTE-attributable deaths, with net cost savings to healthcare systems. PMID- 25816149 TI - A probably minor role for land-applied goat manure in the transmission of Coxiella burnetii to humans in the 2007-2010 Dutch Q fever outbreak. AB - In 2007, Q fever started to become a major public health problem in the Netherlands, with small ruminants as most probable source. In order to reduce environmental contamination, control measures for manure were implemented because of the assumption that manure was highly contaminated with Coxiella burnetii. The aims of this study were 1) to clarify the role of C. burnetii contaminated manure from dairy goat farms in the transmission of C. burnetii to humans, 2) to assess the impact of manure storage on temperature profiles in dunghills, and 3) to calculate the decimal reduction time of the Nine Mile RSA 493 reference strain of C. burnetii under experimental conditions in different matrices. For these purposes, records on distribution of manure from case and control herds were mapped and a potential relation to incidences of human Q fever was investigated. Additionally, temperatures in two dunghills were measured and related to heat resistance of C. burnetii. Results of negative binomial regression showed no significant association between the incidence of human Q fever cases and the source of manure. Temperature measurements in the core and shell of dunghills on two farms were above 40 degrees C for at least ten consecutive days which would result in a strong reduction of C. burnetii over time. Our findings indicate that there is no relationship between incidence of human Q fever and land applied manure from dairy goat farms with an abortion wave caused by C. burnetii. Temperature measurements in dunghills on two farms with C. burnetii shedding dairy goat herds further support the very limited role of goat manure as a transmission route during the Dutch human Q fever outbreak. It is very likely that the composting process within a dunghill will result in a clear reduction in the number of viable C. burnetii. PMID- 25816150 TI - VP22 mediates intercellular trafficking and enhances the in vitro antitumor activity of PTEN. AB - PTEN acts as a phosphatidylinositol phosphatase with a possible role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. Mutations in PTEN are frequent and their presence is associated with poor prognosis in breast cancer, which is the most common type of non-cutaneous malignancy in females. Delivery of the tumor suppressor PTEN gene represents a powerful strategy for breast cancer therapy, but a present limitation of gene therapy is the ability to deliver sufficient quantities of active proteins to target cells. The capacity of HSV 1VP22 fusion proteins to spread from the primary transduced cell to surrounding cells could improve gene therapeutics, particularly in cancer. To assess the potential efficacy of VP22 as a gene therapy for breast cancer, expression vectors for N- and C-terminal PTEN-VP22 fusion proteins were constructed. VP22 mediated intercellular transport and antitumor efficacy in BT549 (PTEN-null) breast tumor cells were investigated. The results showed that PTEN-VP22 has the same spreading abilities as VP22. In cell proliferation and apoptosis assays, PTEN-VP22 gene transfer induces a stronger anti-proliferative effect and apoptotic activity compared with PTEN gene transfer alone. In addition, VP22 enhanced the PTEN-mediated decrease in the level of phosphorylated AKT. The results show that PTEN-VP22 can spread in vitro and PTEN-VP22 gene induces significantly greater antitumor activity than the PTEN gene alone. This study confirms the utility of VP22-mediated delivery in vitro and suggests that PTEN VP22 may have applications in breast cancer gene therapy. PMID- 25816148 TI - A comparison of technique modifications in laparoscopic donor nephrectomy: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the effectiveness of different technique modifications in laparoscopic donor nephrectomy. DESIGN: Systematic review and meta-analyses. DATA SOURCES: Searches of PubMed, EMBASE, Web of Science and Central from January 1st 1997 until April 1st 2014. STUDY DESIGN: All cohort studies and randomized clinical trials comparing fully laparoscopic donor nephrectomy with modifications of the standard technique including hand-assisted, retroperitoneoscopic and single port techniques, were included. DATA-EXTRACTION AND ANALYSIS: The primary outcome measure was the number of complications. Secondary outcome measures included: conversion to open surgery, first warm ischemia time, estimated blood loss, graft function, operation time and length of hospital stay. Each technique modification was compared with standard laparoscopic donor nephrectomy. Data was pooled with a random effects meta-analysis using odds ratios, weighted mean differences and their corresponding 95% confidence intervals. To assess heterogeneity, the I2 statistic was used. First, randomized clinical trials and cohort studies were analyzed separately, when data was comparable, pooled analysis were performed. RESULTS: 31 studies comparing laparoscopic donor nephrectomy with other technique modifications were identified, including 5 randomized clinical trials and 26 cohort studies. Since data of randomized clinical trials and cohort studies were comparable, these data were pooled. There were significantly less complications in the retroperitoneoscopic group as compared to transperitoneal group (OR 0.52, 95%CI 0.33-0.83, I2 = 0%). Hand assisted techniques showed shorter first warm ischemia and operation times. CONCLUSIONS: Hand-assistance reduces the operation and first warm ischemia times and may improve safety for surgeons with less experience in laparoscopic donor nephrectomy. The retroperitoneoscopic approach was significantly associated with less complications. However, given the, in general, poor to intermediate quality and considerable heterogeneity in the included studies, further high-quality studies are required. TRIAL REGISTRATION: The review protocol was registered in the PROSPERO database before the start of the review process (CRD number 42013006565). PMID- 25816151 TI - Retinoic acid-related orphan receptor RORbeta, circadian rhythm abnormalities and tumorigenesis (Review). AB - Nuclear receptors are a superfamily of transcription factors including the steroid hormone receptors, non-steroid hormone receptors and the orphan nuclear receptor family. Retinoic acid-related orphan receptor (ROR)beta, as a member of the orphan nuclear receptor family, plays an important regulatory role in the maintenance of a variety of physiological and pathological processes. RORbeta has been determined to act as an osteogenic repressor in regulating bone formation, and is involved in regulating circadian rhythm. The findings of recent studies concerning the association between tumorigenesis and circadian rhythm have shown that an aberrant circadian rhythm may promote tumorigenesis and tumor progression. The mechanisms discussed in this review demonstrate how aberrant RORbeta-induced circadian rhythm may become a new direction for future studies on tumorigenesis and strategy design for cancer prevention. PMID- 25816152 TI - Correction: Endocardial tip cells in the human embryo--facts and hypotheses. PMID- 25816153 TI - Ophiopogonin-D suppresses MDA-MB-435 cell adhesion and invasion by inhibiting matrix metalloproteinase-9. AB - Ophiopogonin-D is one of steroidal saponins isolated from the root of the Chinese medicinal plant Ophiopogon japonicas. It has been claimed to possess anti inflammatory and anti-oxidant properties. The present study was the first to examine the anti-tumor metastasis properties of ophiopogonin-D. An MTT assay showed that ophiopogonin-D inhibited the proliferation of MDA-MB-435 melanoma cells, and decreased invasion was demonstrated using a Transwell invasion assay. Furthermore, adhesion of MDA-MB-435 cells to human umbilical vascular endothelial cells and to fibronectin was inhibited by ophiopogonin-D. Gelatin zymography and western blot analysis showed that ophiopogonin-D inhibited the expression and secretion of matrix metalloproteinase-9 (MMP-9), but not that of MMP-2. Inhibition of phosphorylation of p38 by ophiopogonin-D indicated its inhibition of the mitogen-activated protein kinase pathway. Overall, the results suggested that ophiopogonin-D may be considered as a candidate drug for treating or preventing tumor metastasis. PMID- 25816154 TI - The 'slingshot' technique to align palatally impacted canines with elastomeric chain. AB - Orthodontic alignment of palatally ectopic maxillary canines can be challenging. Treatment is usually prolonged and further complicated by the need for surgical exposure. Several methods are commonly used and have been described in the literature. This article presents two cases to describe a relatively unknown yet effective technique using the 'slingshot' method. This method is operator friendly and easily tolerated by patients. PMID- 25816155 TI - Observation of Excitonic Rydberg States in Monolayer MoS2 and WS2 by Photoluminescence Excitation Spectroscopy. AB - We have identified excited exciton states in monolayers of MoS2 and WS2 supported on fused silica by means of photoluminescence excitation spectroscopy. In monolayer WS2, the positions of the excited A exciton states imply an exciton binding energy of 0.32 eV. In monolayer MoS2, excited exciton transitions are observed at energies of 2.24 and 2.34 eV. Assigning these states to the B exciton Rydberg series yields an exciton binding energy of 0.44 eV. PMID- 25816156 TI - The effects of gene polymorphisms in angiotensin II receptors on pregnancy induced hypertension and preeclampsia: a systematic review and meta-analysis. AB - BACKGROUND: To assess whether the polymorphisms of angiotensin II type 1 and type 2 receptors (AT1R, AT2R) are associated with pregnancy-induced hypertension (PIH) and preeclampsia. METHODS: Studies were searched from PubMed, ISI Web of Science and HuGE Navigator. RESULTS: The A1166C polymorphism of AT1R, A1675G and C3123A polymorphisms of AT2R were analyzed. Significant association was found in recessive model (OR = 1.581, 95% confidence interval (CI): 1.054-2.371) and co dominant (GG versus AG) model (OR = 1.900, 95%CI: 1.001-3.604) between the A1675G polymorphism and preeclampsia. No association was found between the other polymorphisms and PIH or preeclampsia. CONCLUSIONS: The A1675G polymorphism might be associated with preeclampsia, but the A1166C and C3123A polymorphisms had no effect on PIH or preeclampsia. PMID- 25816157 TI - Ischemic postconditioning regulates cardiomyocyte autophagic activity following ischemia/reperfusion injury. AB - Ischemic postconditioning (IPostC) is a promising protective mechanism for combating reperfusion injury. However, the role of autophagy in the protective effects of IPostC and the associated signaling pathways have remained to be elucidated. Male Sprague Dawley rats were subjected to 30 min ischemia and 1, 2, 3, 6, 12 and 24 h of reperfusion, with or without IPostC treatment. Autophagic flux was evaluated by detecting mRNA and protein expression levels of microtubule associated protein 1 light chain 3 and p62. Phosphorylated (p)-P70S6 kinase (P70S6K), p-adenosine monophosphate-activated kinase (AMPK) and Beclin 1 protein levels were measured by western blot analysis. Myocardial infarct size was measured using staining with Evans blue dye and myocardial apoptosis was evaluated by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining. Autophagic activity was observed to be inhibited within the first hour of reperfusion, increased during 2-6 h and reduced from 12-24 h following IPostC compared with reperfusion without IPostC. Inhibition of autophagy by chloroquine significantly reversed the effects of IPostC on myocardial infarct size and the levels of apoptosis. IPostC significantly increased Beclin 1 levels, inhibited AMPK activation and increased P70S6K activation within the first hour compared with reperfusion without IPostC. IPostC attenuated the upregulation of Beclin 1 levels, increased AMPK activation and reduced P70S6K activation between 2 and 12 h, and subsequently exerted the opposite effects on these molecules between 12 and 24 h. IPostC was demonstrated to regulate autophagic activity in a time-dependent manner. The Beclin 1 and AMPK mammalian target of rapamycin signaling pathways are suggested to be involved in the regulation of IPostC in autophagy. PMID- 25816159 TI - Enteral nutrition support to treat malnutrition in inflammatory bowel disease. AB - Malnutrition is a common consequence of inflammatory bowel disease (IBD). Diet has an important role in the management of IBD, as it prevents and corrects malnutrition. It is well known that diet may be implicated in the aetiology of IBD and that it plays a central role in the pathogenesis of gastrointestinal tract disease. Often oral nutrition alone is not sufficient in the management of IBD patients, especially in children or the elderly, and must be combined with oral supplementation or replaced with tube enteral nutrition. In this review, we describe several different approaches to enteral nutrition-total parenteral, oral supplementation and enteral tube feeding-in terms of results, patients compliance, risks and and benefits. We also focus on the home enteral nutrition strategy as the future goal for treating IBD while focusing on patient wellness. PMID- 25816158 TI - Detection of sialic acid-utilising bacteria in a caecal community batch culture using RNA-based stable isotope probing. AB - Sialic acids are monosaccharides typically found on cell surfaces and attached to soluble proteins, or as essential components of ganglioside structures that play a critical role in brain development and neural transmission. Human milk also contains sialic acid conjugated to oligosaccharides, glycolipids, and glycoproteins. These nutrients can reach the large bowel where they may be metabolised by the microbiota. However, little is known about the members of the microbiota involved in this function. To identify intestinal bacteria that utilise sialic acid within a complex intestinal community, we cultured the caecal microbiota from piglets in the presence of 13C-labelled sialic acid. Using RNA based stable isotope probing, we identified bacteria that consumed 13C-sialic acid by fractionating total RNA in isopycnic buoyant density gradients followed by 16S rRNA gene analysis. Addition of sialic acid caused significant microbial community changes. A relative rise in Prevotella and Lactobacillus species was accompanied by a corresponding reduction in the genera Escherichia/Shigella, Ruminococcus and Eubacterium. Inspection of isotopically labelled RNA sequences suggests that the labelled sialic acid was consumed by a wide range of bacteria. However, species affiliated with the genus Prevotella were clearly identified as the most prolific users, as solely their RNA showed significantly higher relative shares among the most labelled RNA species. Given the relevance of sialic acid in nutrition, this study contributes to a better understanding of their microbial transformation in the intestinal tract with potential implications for human health. PMID- 25816160 TI - Sourdough fermentation of wheat flour does not prevent the interaction of transglutaminase 2 with alpha2-gliadin or gluten. AB - The enzyme transglutaminase 2 (TG2) plays a crucial role in the initiation of celiac disease by catalyzing the deamidation of gluten peptides. In susceptible individuals, the deamidated peptides initiate an immune response leading to celiac disease. Several studies have addressed lactic fermentation plus addition of enzymes as a means to degrade gluten in order to prevent adverse response in celiacs. Processing for complete gluten degradation is often harsh and is not likely to yield products that are of comparable characteristics as their gluten containing counterparts. We are concerned that incomplete degradation of gluten may have adverse effects because it leads to more available TG2-binding sites on gluten peptides. Therefore, we have investigated how lactic acid fermentation affects the potential binding of TG2 to gluten protein in wheat flour by means of estimating TG2-mediated transamidation in addition to measuring the available TG2 binding motif QLP, in alpha2-gliadin. We show that lactic fermentation of wheat flour, as slurry or as part of sourdough bread, did not decrease the TG2-mediated transamidation, in the presence of a primary amine, to an efficient level (73% 102% of unfermented flour). Nor did the lactic fermentation decrease the available TG2 binding motif QLP in alpha2-gliadin to a sufficient extent in sourdough bread (73%-122% of unfermented control) to be useful for celiac safe food. PMID- 25816161 TI - Improvement in plasma drug activity during the early treatment interval among Tanzanian patients with multidrug-resistant tuberculosis. AB - BACKGROUND: Individual pharmacokinetic variability may be common in patients treated for multidrug-resistant tuberculosis (MDR-TB) but data are sparse from resource-limited settings and across the early treatment interval. METHODS: Plasma drug activity, as measured by the TB Drug Activity (TDA) assay at 2 and 4 weeks of treatment with a standardized MDR-TB regimen was performed in patients with pulmonary MDR-TB from Tanzania. TDA values were correlated with measures of early treatment outcome including every two week collection of sputum for time-to positivity (TTP) in liquid culture from the MGIT 960 automated system. Patients were evaluated at 24 weeks and those surviving without delayed sputum culture conversion (>8 weeks), culture reversion after previously negative, or weight loss were defined as having a favorable outcome. RESULTS: Twenty-five patients were enrolled with a mean age of 37 +/-12 years. All were culture positive from the pretreatment sputum sample with a mean TTP in MGIT of 257 +/-134 hours, and the median time to culture conversion on treatment was 6 weeks. Twenty patients (80%) had an increase in TDA, with the overall mean TDA at 2 weeks of 2.1 +/-0.7 compared to 2.4 +/-0.8 at 4 weeks (p = 0.005). At 2 weeks 13 subjects (52%) had a TDA value > 2-log killing against their own M. tuberculosis isolate compared to 17 subjects (68%) at 4 weeks (McNemar's exact test p = 0.29). An interim treatment outcome was able to be determined in 23 patients (92%), of whom 7 had a poor outcome (30%). An increase in TDA from week 2 to week 4 was associated with favorable outcome, [unadjusted OR = 20.0, 95% CI: 1.61-247.98, exact p = 0.017 and adjusted OR = 19.33, 95% CI: 1.55-241.5, exact p = 0.023]. CONCLUSIONS: The majority of patients with MDR-TB in Tanzania had an increase in plasma drug activity from week 2 to week 4 of treatment as measured by the TDA assay. Understanding the etiology and full impact of this dynamic may inform therapeutic intervention. PMID- 25816163 TI - Fire and worker health and safety: an introduction to the special issue. AB - One century ago, the landmark fire at the Triangle Shirtwaist Factory in New York City claimed the lives of 146 garment workers and helped spur the adoption of fire safety measures and laws targeting dangerous working conditions. Since that time, continuing advances have been made to address the threat of fire-in workplace fire safety practices and regulations, in training and safety requirements for firefighters and first responders, and in hazard communication laws that enhance disaster planning and response. Recent high profile events, including the West, Texas fertilizer plant explosion, derailments of fuel cargo trains, and garment factory fires in Bangladesh, have brought renewed attention to fire as a workplace health and safety issue and to the unevenness of safety standards and regulatory enforcement, in the United States as well as internationally. In this article, we provide an overview of fire as a workplace health and safety hazard and an introduction to the essays included in this special issue of New Solutions on fire and work. PMID- 25816164 TI - Bangladesh: currently the worst, but possibly the future's best. AB - Garment workers in Bangladesh producing clothing for international brands have experienced repeated factory fires and building collapses in the last 10 years, resulting in more than 1,600 deaths and hundreds of disabling injuries. After the Tazreen Fashion fire in December 2012 and the Rana Plaza building collapse in April 2013, more than 190 international clothing brands and retailers signed an "Accord on Fire and Building Safety" with two international union federations. Full implementation of the provisions of the Accord would change "business as usual" in Bangladesh's garment industry and set a positive example for other countries and other industries with global supply chains. The components, challenges, and controversies of the Accord are detailed in the article. PMID- 25816162 TI - Mismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters. AB - Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients' age, but not with patients' gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients' age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers. PMID- 25816165 TI - Preventing fire-related occupational deaths: residential sprinklers save civilians, property, and firefighters. AB - Residential fires are an important public health problem, with proven strategies to prevent death and injury. Residential sprinkler systems are one such strategy. While the benefits of this technology tend to center on civilian lives and property, there are also benefits for firefighters. The purpose of this article is to describe these benefits and discuss residential sprinkler systems as a strategy to reduce the risk of firefighter injury and death. Because of the benefits for firefighter safety, firefighters' knowledge about fire prevention, and their authority on this topic, firefighters are an essential stakeholder for raising awareness among the public and policymakers about the existence of and benefits associated with residential sprinkler systems. PMID- 25816166 TI - Workplace fire-not a misfortune, but an avoidable occupational hazard in Korea. AB - In this article, we argue that workplace fire should be understood within an occupational safety and health context. We selected two cases of fire and explosion with the greatest numbers of fatalities from the annual lists of the "Worst Manslaughter Companies of the Year" in Korea. Through review of information from major media, government, courts, and workers' advocacy organizations, we found that these incidents resulted from violations of basic safety rules by the companies, and that the penalties imposed on them were light. In addition, precarious workers were more vulnerable to such risk, and self regulation did not work even in large corporations. Like other types of occupational hazards, explosions and fires can be prevented, but prevention requires that occupational safety and health regulations be thoroughly enforced and that heavy penalties be imposed in order to eliminate any incentives for regulatory violations. PMID- 25816167 TI - Emerging from the tragedies in Bangladesh: a challenge to voluntarism in the global economy. AB - Under the regime of private company or multi-stakeholder voluntary codes of conduct and industry social auditing, workers have absorbed low wages and unsafe and abusive conditions; labor leaders and union members have become the targets of both government and factory harassment and violence; and trade union power has waned. Nowhere have these private systems of codes and audits so clearly failed to protect workers as in Bangladesh's apparel industry. However, international labor groups and Bangladeshi unions have succeeded in mounting a challenge to voluntarism in the global economy, persuading more than 180 companies to make a binding and enforceable commitment to workers' safety in an agreement with 12 unions. The extent to which this Bangladesh Accord will be able to influence the entrenched global regime of voluntary codes and weak trade unions remains an open question. But if the Accord can make progress in Bangladesh, it can help to inspire similar efforts in other countries and in other industries. PMID- 25816168 TI - Firefighters and flame retardant activism. AB - In the past decade, exposure to flame retardant chemicals has become a pressing health concern and widely discussed topic of public safety for firefighters in the United States. Working through local, state, and national unions and independent health and advocacy organizations, firefighters have made important contributions to efforts to restrict the use of certain flame retardants. Firefighters are key members in advocacy coalitions dedicated to developing new environmental health regulations and reforming flammability standards to reflect the best available fire science. Their involvement has been motivated by substantiated health concerns and critiques of deceptive lobbying practices by the chemical industry. Drawing on observations and interviews with firefighters, fire safety experts, and other involved stakeholders, this article describes why firefighters are increasingly concerned about their exposure to flame retardant chemicals in consumer products, and analyzes their involvement in state and national environmental health coalitions. PMID- 25816169 TI - A growing fire hazard concern in communities: home oxygen therapy and continued smoking habits. AB - The Safe Home Care Project investigated both qualitatively and quantitatively a range of occupational safety and health hazards, as well as injury and illness prevention practices, among home care aides in Massachusetts. This article reports on a hazard identified by aides during the study's initial focus groups: smoking by home care clients on long-term oxygen therapy. Following the qualitative phase we conducted a cross-sectional survey among 1,249 aides and found that medical oxygen was present in 9 percent of aide visits (314 of aides' 3,484 recent client visits) and that 25 percent of clients on oxygen therapy were described as smokers. Based on our findings, the Board of Health in a local town conducted a pilot study to address fire hazards related to medical oxygen. Medical oxygen combined with smoking or other sources of ignition is a serious fire and explosion hazard that threatens not only workers who visit homes but also communities. PMID- 25816170 TI - From infancy to adolescence: the development and future of the national firefighter near-miss reporting system. AB - The National Fire Fighter Near-Miss Reporting System (NFFNMRS) is a voluntary adverse event reporting system designed as a repository to which firefighters submit information on the hazards seen in their work, detailing the events that led to near-misses and injuries. This descriptive article discusses the development of the system since its inception, the strengths and limitations of the resultant data, and the improvements to be made to ensure the system's usefulness. Especially in their infancy, near-miss systems are very dependent on funding and sensitive to any reductions as they head toward steady-state reporting. This sustainability factor has significant implications for continued reporting to the system and the ultimate utility of the data. Very few such data systems exist for occupational health surveillance. PMID- 25816171 TI - Climate change and wildland firefighter health and safety. AB - The author examines how climate change is impacting wildland firefighters. Climate change has made wildland fires more frequent and more intense. The increase in frequency and intensity of fires has pushed the number of fatalities and injuries higher in recent decades. The most common hazards on fires follow the trend of fire in general in that these hazards become more frequent and intense. Burnovers, heat exhaustion, tree hazards, and many other common fire hazards are more likely. The fire suppression agencies are making every effort to improve health and safety on fires by improving communication, weather forecasting, mapping, fire shelters, decision making and more. Despite these efforts, wildfires are becoming ever more hazardous because of climate change and the increasing frequency and intensity of wildfires. PMID- 25816172 TI - Safety sustainability. PMID- 25816173 TI - DNA-directed assembly of gold nanohalo for quantitative plasmonic imaging of single-particle catalysis. AB - Plasmonic imaging under a dark-field microscope (DFM) holds great promise for single-particle analysis in bioimaging, nanophotonics, and nanocatalysis. Here, we designed a DNA-directed programmable assembly strategy to fabricate a halo like Au nanostructure (nanohalo) that couples plasmonic large gold nanoparticles (L-AuNPs) with catalytically active small AuNPs (S-AuNPs) in a single nanoarchitecture. Catalytic reaction occurring on S-AuNPs changes its permittivity, which results in a significant variation of the plasmonic resonance of the nanohalo. Hence, we can indirectly monitor catalytic reactions on a single nanohalo under DFM, on the basis of which we have obtained quantitative information on both nanocatalysis and catalyst poisoning. Our study thus provides a cost-effective means to quantitatively study metal NP-based catalysis at single particle level. PMID- 25816174 TI - Total synthesis of the tetracyclic indole alkaloid ht-13-B. AB - An expedient synthesis corroborating the proposed structure of the tetracyclic indole alkaloid ht-13-B is presented. Key synthetic steps include acyliminium ion allylation, a Mitsunobu reaction, a palladium-catalyzed Stille-Kelly cross coupling reaction, and a carbon monoxide-mediated palladium-catalyzed reductive N heterocyclization. The chiral centers are ultimately derived from commercially available trans-4-hydroxy-l-proline. PMID- 25816175 TI - Artesunate induces apoptosis and inhibits growth of Eca109 and Ec9706 human esophageal cancer cell lines in vitro and in vivo. AB - Esophageal cancer is a common malignant tumor worldwide with a high incidence rate in China and it is a great threat to human health. Combined modality therapy is used for chemotherapeutic treatment of esophageal cancer; however, drug resistance and side effects of the drugs is a major barrier to the success of chemotherapy. As chemotherapy with common drugs is far from providing satisfactory clinical outcomes for patients with esophageal cancer, more efficient drugs are urgently required. Artesunate (Art) is the first-line treatment option for malaria; however, it was recently revealed that Art has remarkable anti-tumor activity, making it a novel candidate for cancer chemotherapy. Although the anti-cancer effects of Art have been well documented, its potential against esophageal cancer has rarely been explored. The present study aimed to investigate the significance and mechanism of the anti proliferative activity of Art on esophageal cancer cells in vitro and in vivo. In the in vitro experiments, Art inhibited the growth as well as induced cell apoptosis and cell cycle arrest of esophageal cancer cell lines (Eca109 and Ec9706) in a concentration-dependent manner. Furthermore, downregulation of mitochondrial membrane potential, B-cell lymphoma-2 (BCL-2) and CDC25A, as well as upregulation of BCL-2-associated X protein (Bax) and caspase-3 expression in Art-treated cells were identified. In addition, an in vivo study showed that Art produced a dose-dependent tumor regression in nude mice, while side effects were low. The anti-tumor activity of 200 mg/kg Art was similar to that of 3 mg/kg cisplatin. In conclusion, Art exerted concentration-dependent inhibitory activity against esophageal cancer in vivo and in vitro by inducing cell apoptosis and cell cycle arrest through affecting mitochondrial membrane potential, BCL-2, Bax, caspase-3 and CDC25A. PMID- 25816178 TI - Executive summary of key concepts. PMID- 25816176 TI - WO3 nanorolls self-assembled as thin films by hydrothermal synthesis. AB - We report a novel type of WO3 nanostructure, i.e. nanorolls obtained as a self assembled thin film on a transparent conductive substrate. The mild conditions of preparation, avoiding the use of HCl, result in an eco-friendly hydrothermal method with reduced crystallization time. FESEM and HR-TEM show that WO3 nanocrystals are made of rolled nanoflakes with a telescope-like appearance at their tip. For their nano-porosity, electrochemical accessibility, good adhesion to substrates and the envisaged presence of nanocavities between the WO3 layers, these materials hold tremendous promise in nano-electronics, electrochromic devices, water photo-splitting cells, Li-ion batteries and nano-templated filters for UV radiation. PMID- 25816179 TI - Can our hospitals survive? PMID- 25816180 TI - The ethics of research, writing, and publication. PMID- 25816181 TI - Comparative analysis of hospital energy use: pacific northwest and scandinavia. AB - OBJECTIVE: This study aimed to establish the potential for significant energy reduction in hospitals in the United States by providing evidence of Scandinavian operational precedents with high Interior Environmental Quality (IEQ) and substantially lower energy profiles than comparable U.S. facilities. These facilities set important precedents for design teams seeking operational examples for achieving aggressive energy and interior environmental quality goals. This examination of operational hospitals is intended to offer hospital owners, designers, and building managers a strong case and concrete framework for strategies to achieve exceptionally high performing buildings. BACKGROUND: Energy efficient hospitals have the potential to significantly impact the U.S.'s overall energy profile, and key stakeholders in the hospital industry need specific, operationally grounded precedents in order to successfully implement informed energy reduction strategies. This study is an outgrowth of previous research evaluating high quality, low energy hospitals that serve as examples for new high performance hospital design, construction, and operation. Through extensive interviews, numerous site visits, the development of case studies, and data collection, this team has established thorough qualitative and quantitative analyses of several contemporary hospitals in Scandinavia and the Pacific Northwest. Many Scandinavian hospitals demonstrate a low energy profile, and when analyzed in comparison with U.S. hospitals, such Scandinavian precedents help define the framework required to make significant changes in the U.S. hospital building industry. METHODS: Eight hospitals, four Scandinavian and four Pacific Northwest, were quantitatively compared using the Environmental Protection Agency's Portfolio Manager, allowing researchers to answer specific questions about the impact of energy source and architectural and mechanical strategies on energy efficiency in operational hospitals. RESULTS: Specific architectural, mechanical, and plant systems make these Scandinavian hospitals more energy efficient than their Pacific Northwest counterparts. More importantly, synergistic systems integration allows for their significant reductions in energy consumption. CONCLUSIONS: This quantitative comparison of operational Scandinavian and Pacific Northwest hospitals resulted in compelling evidence of the potential for deep energy savings in the U.S., and allowed researchers to outline specific strategies for achieving such reductions. PMID- 25816182 TI - Informing Hospital Change Processes through Visualization and Simulation: A Case Study at a Children's Emergency Clinic. AB - OBJECTIVE: To demonstrate the use of visualization and simulation tools in order to involve stakeholders and inform the process in hospital change processes, illustrated by an empirical study from a children's emergency clinic. BACKGROUND: Reorganization and redevelopment of a hospital is a complex activity that involves many stakeholders and demands. Visualization and simulation tools have proven useful for involving practitioners and eliciting relevant knowledge. More knowledge is desired about how these tools can be implemented in practice for hospital planning processes. METHODS: A participatory planning process including practitioners and researchers was executed over a 3-year period to evaluate a combination of visualization and simulation tools to involve stakeholders in the planning process and to elicit knowledge about needs and requirements. RESULTS: The initial clinic proposal from the architect was discarded as a result of the empirical study. Much general knowledge about the needs of the organization was extracted by means of the adopted tools. Some of the tools proved to be more accessible than others for the practitioners participating in the study. The combination of tools added value to the process by presenting information in alternative ways and eliciting questions from different angles. CONCLUSIONS: Visualization and simulation tools inform a planning process (or other types of change processes) by providing the means to see beyond present demands and current work structures. Long-term involvement in combination with accessible tools is central for creating a participatory setting where the practitioners' knowledge guides the process. PMID- 25816183 TI - Space planners' perception of an assessment instrument for briefs in the pre design phase of new healthcare environments. AB - OBJECTIVE: The main purpose of the study was to investigate the usability of a newly developed instrument designed to assess the content and quality briefs (CQB I) in programs for new healthcare environments. We studied the perception of using the instrument on a group of space planners. BACKGROUND: The study is part of a larger project designed to ensure the quality of the planning of new healthcare environments with a focus on documents (programs or briefs) created in the early phases of the planning process. In this study, we used an instrument that measures the clarity of the mission statement for the project based on user needs and care activities that will take place in the new healthcare environment. The instrument further evaluates whether there are clear patient-related outcome measures specified and whether the information in the documents is person oriented and evidence-based. METHODS: The study used a mixed-method design where the relevance and usability of the instrument was estimated and a focus group interview was conducted. RESULTS: The study showed that a CQB-I is perceived to be a relevant instrument primarily as a guide for programming, but also for monitoring the produced programs. CONCLUSIONS: Instruments like CQB-I can help to bring research results into planning and contribute to dialogue and collaboration in the early phases of a planning process by orienting planning participants to user needs and facilitating the discussion and articulation of clear performance indicators. PMID- 25816184 TI - Design characteristics of acute care units in china. AB - OBJECTIVE: To describe the current state of design characteristics of acute care units in China's public hospitals and compare these with characteristics with acute care units in the United States. BACKGROUND: The healthcare construction industry in China is one of the fastest growing sectors in China and, arguably, in the world. Understanding the physical design of acute care units in China is of great importance because it will influence a large population. METHODS: Descriptive study was performed of unit configuration, size, patient visibility, distance to nursing station and supplies, and lighting conditions in 25 units in 19 public hospitals built after 2003. Data and information were collected based on spatial and visibility analysis. RESULTS: The study identified major design characteristics of the recently built (from 2003 onward) acute care units in China, comparing them, where appropriate, with those in U.S. It found there are three dominant types of unit layout: single-corridor (52%), triangular (36%), and double-corridor (12%). The number of private rooms is very low (11%), compared with two- or three-bed rooms. Centralized nursing stations are the only type of nurses' working area. China also has a large unit size in terms of number of patient beds. The average number of patient beds in a unit is 40.6 in China (versus 32.9 in U.S.). The care units in China have longer walking distance from nursing station to patient bedside. The percentage of beds visible from a nursing station is lower in China than in the U.S. The access to natural light and direct sunlight in patient rooms is greater in China compared with those in U.S.-100% of patient rooms in China have natural lighting. A majority of them face south or southeast and thus receiving direct sunlight (91.4%). CONCLUSIONS: Because of the differences in economies and building codes, there are dramatic differences between the spatial characteristics of acute care units in China and the United States. PMID- 25816185 TI - Confirming, Classifying, and Prioritizing Needed Over-the-Bed Table Improvements via Methodological Triangulation. AB - OBJECTIVE: This article presents the results of a qualitative study that confirmed, classified, and prioritized user needs for the design of a more useful, usable, and actively assistive over-the-bed table. BACKGROUND: Manganelli et al. (2014) generated a list of 74 needs for use in developing an actively assistive over-the-bed table. This present study assesses the value and importance of those needs. METHODS: Fourteen healthcare subject matter experts and eight research and design subject matter experts engaged in a participatory and iterative research and design process. A mixed methods qualitative approach used methodological triangulation to confirm the value of the findings and ratings to establish importance. Open and closed card sorts and a Delphi study were used. Data analysis methods included frequency analysis, content analysis, and a modified Kano analysis. RESULTS: A table demonstrating the needs that are of high importance to both groups of subject matter experts and classification of the design challenges each represents was produced. Through this process, the list of 74 needs was refined to the 37 most important need statements for both groups. CONCLUSIONS: Designing a more useful, usable, and actively assistive over the-bed table is primarily about the ability to position it optimally with respect to the user for any task, as well as improving ease of use and usability. It is also important to make explicit and discuss the differences in priorities and perspectives demonstrated between research and design teams and their clients. PMID- 25816186 TI - Development and psychometric testing of a post-occupancy evaluation. PMID- 25816187 TI - Embracing variation. PMID- 25816188 TI - Impact of the design of the built environment on people with dementia: an evidence-based review. AB - OBJECTIVE: In this review the impact of the design of the built environment on people with dementia in long-term care settings is systematically analyzed and summarized. Architects and designers will be provided with credible evidence on which they can confidently base their design decisions. Researchers will be able to determine which environmental aspects have been well investigated and where there are gaps in the current state of the research. BACKGROUND: A great number of studies have established a relationship between the design of the physical environment of long-term care settings and outcomes of people with dementia. However, the methods employed are heterogeneous and the results are often conflicting. Consequently, the process of integrating the best evidence available into architectural designs may be hindered. METHODS: A systematic literature search was conducted reviewing studies that meet certain inclusion criteria. Using an evidence-based approach, the methodical quality of the studies was rated. RESULTS: One hundred sixty-nine studies were found. They were thematically summarized into four main categories: basic design decisions, environmental attributes, ambience, and environmental information. The effectiveness of the interventions on the behavior, cognition, function, well being, social abilities, orientation, and care outcomes on people with dementia was illustrated by matrices. CONCLUSIONS: Results of this review indicate that, with the exception of cognition, specific design interventions are beneficial to the outcomes of people with dementia. Overall, the field of environmental design for people with dementia is well researched in many aspects and only few gaps in knowledge were identified. PMID- 25816189 TI - Design research and the globalization of healthcare environments. AB - OBJECTIVE: Global healthcare practice has expanded in the past 20 years. At the same time the incorporation of research into the design process has gained prominence as a best practice among architects. The authors of this study investigated the status of design research in a variety of international settings. We intended to answer the question, "how pervasive is healthcare design research outside of the United States?" METHOD: The authors reviewed the international literature on the design of healthcare facilities. More than 500 international studies and conference proceedings were incorporated in this literature review. A team of five research assistants searched multiple databases comparing approximately 16 keywords to geographic location. Some of those keywords included: evidence-based design, salutogenic design, design research, and healthcare environment. Additional articles were gathered by contacting prominent researchers and asking for their personal assessment of local health design research studies. RESULTS: While there are design researchers in most parts of the world, the majority of studies focus on the needs of populations in developed countries and generate guidelines that have significant cost and cultural implications that prohibit their implementation in developing countries. Additionally, the body of literature discussing the role of culture in healthcare environments is extremely limited. CONCLUSION: Design researchers must address the cultural implications of their studies. Additionally, we need to expand our research objectives to address healthcare design in countries that have not been previous considered. PMID- 25816191 TI - Letter to the Editors: Comments on Wood-Nartker et al. Article in HERD 7(3). PMID- 25816190 TI - Positive distraction and the rehabilitation hospitals of joao filgueiras lima. AB - OBJECTIVE: This article discusses the use of positive distraction, an evidence based design approach, in rehabilitation hospitals in Brazil through the work of Joao Filgueiras Lima ("Lele"). BACKGROUND: In many parts of the world architects may not formally incorporate theories of positive distraction and evidence-based design, but there are multiple international examples of health facility architects and designers that use nature, daylighting, art, and social interaction to enhance the healing experience. The work of the Brazilian architect Joao Filgueiras Lima is a particularly salient example. Lima has been a dominant figure in 20th and 21st century Brazilian architecture and the architect of several rehabilitation facilities. METHODS: First positive distraction is defined as it relates to nature and art, and in the context of rehabilitation hospitals. Second, rehabilitation facilities are defined. The discussion then focuses on awareness of evidence-based design in Latin America. Next, Brazilian healthcare architecture is discussed along with the history of the Brazilian Sarah rehabilitation hospitals designed by Lele and Lele's role in the history of Brazilian architecture. Last we look at Lele's use of positive distraction. RESULTS: Despite Lele's recognition in Brazil, his work has not gained much international exposure. Lele played a critical role in the design of the Sarah facilities and served on the board of directors for the Technological Center of the Sarah Network (CTRS) in Brazil from 1992 to 2009. Based on our review of his work it was clear that Lele used positive distraction as a tool for creating healing environments. CONCLUSIONS: In spite of the lack of formal integration of evidence-based design in healthcare architecture in Latin America, many of its basic tenets have been incorporated in Brazilian rehabilitation hospitals. Lele's projects are a clear example of this phenomenon and demonstrate an alignment between research and practitioner objectives. The presence of nature, art, and natural light in his rehabilitation hospitals serves as a model for evidence based design in facilities throughout the world and presents an opportunity to measure the benefits of positive distraction on rehabilitation patient outcomes. PMID- 25816192 TI - Letter to the Editors: It's Time to Start Focusing on Service Quality in Healthcare. PMID- 25816194 TI - Monothiolation and Reduction of Graphene Oxide via One-Pot Synthesis: Hybrid Catalyst for Oxygen Reduction. AB - The functionalization of graphene provides diverse possibilities to improve the handling of graphene and enable further chemical transformation on graphene. Graphene functionalized with mainly heteroatom-based functional groups to enhance its chemical and physical properties is intensively pursued but often resulted in grafting of the heteroatoms as various functional groups. Here, we show that graphene oxide can be functionalized with predominantly a single type of sulfur moiety and reduced simultaneously to form monothiol-functionalized graphene. The thiol-functionalized graphene shows a high electrical conductivity and heterogeneous electron transfer rate. Graphene is also embedded with a trace amount of manganese impurities originating from a prior graphite oxidation process, which facilitates the thiol-functionalized graphene to function as a hybrid electrocatalyst for oxygen reduction reactions in alkaline medium with an onset potential lower than for Pt/C. Further characterizations of the graphene are performed with X-ray photoelectron spectroscopy, scanning electron microscopy with energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, Raman spectroscopy, and electrochemical impedance spectroscopy. This material contributes to the class of hybrids that are highly active electrocatalysts. PMID- 25816195 TI - Barnidipine real-life tolerability in arterial hypertension: results from the BASIC-HT study. AB - INTRODUCTION: Blood pressure (BP) is generally poorly controlled in hypertensive patients. One cause is poor adherence to drugs, which can be improved by treatments combining good efficacy and tolerability. Barnidipine is a strong lipophilic calcium channel blocker (CCB) with efficacy similar to other dihydropyridines. OBJECTIVE: BASIC HT is an observational study in a large population of patients with essential hypertension to evaluate the tolerability of barnidipine in a real-life setting. METHODS: 20479 patients were enrolled in the study. Tolerability and efficacy was assessed at 2 visits during a 3-month period. 20275 patients were included in the analysis. RESULTS: Adverse events were reported by 10.6% of the patients, leading to treatment discontinuation in 3%. Events were those expected with CCBs. The drop-out rate was 8%. Mean systolic and diastolic pressure decreased from 159.6 to 138.2 and from 92.5 to 81.7 mmHg. CONCLUSION: The decrease in BP, is probably due to stimulation of good adherence by barnidipine. PMID- 25816196 TI - Easy Access to Metallic Copper Nanoparticles with High Activity and Stability for CO Oxidation. AB - Copper catalysts are very promising, affordable alternatives for noble metals in CO oxidation; however, the nature of the active species remains unclear and differs throughout previous reports. Here, we report the preparation of 8 nm copper nanoparticles (Cu NPs), with high metallic content, directly deposited onto the surface of silica nanopowders by magnetron sputtering deposition. The as prepared Cu/SiO2 contains 85% Cu0 and 15% Cu2+ and was enriched in the Cu0 phase by H2 soft pretreatment (96% Cu0 and 4% Cu2+) or further oxidized after treatment with O2 (33% Cu0 and 67% Cu2+). These catalysts were studied in the catalytic oxidation of CO under dry and humid conditions. Higher activity was observed for the sample previously reduced with H2, suggesting that the presence of Cu-metal species enhances CO oxidation performance. Inversely, a poorer performance was observed for the sample previously oxidized with O2. The presence of water vapor caused only a small increase in the temperature require for the reaction to reach 100% conversion. Under dry conditions, the Cu NP catalyst was able to maintain full conversion for up to 45 h at 350 degrees C, but it deactivated with time on stream in the presence of water vapor. PMID- 25816197 TI - A multicenter, non-comparative study to evaluate the efficacy and safety of fixed dose olmesartan/amlodipine in Korean patients with hypertension who are naive or non-responders to anti-hypertensive monotherapy (ACE-HY study). AB - The purpose of this study was to evaluate the efficacy of a fixed-dose combination (FDC) of olmesartan and amlodipine in Korean hypertensive patients who were naive to or uncontrolled by amlodipine or losartan monotherapy. This was a prospective, open-label, multi-center, non-comparative study with a planned treatment period of 12 weeks. The primary outcome was changed in seated diastolic blood pressure (SeDBP) from baseline to week 12. Secondary outcomes were changed in seated systolic blood pressure (SeSBP), the proportion of patients achieving target blood pressure (BP), and 24-h ambulatory BP. Safety and tolerability were also evaluated. A total of 376 patients were enrolled from 20 centers in Korea. The age of the patients was 52.4 +/- 11.7 years, and 224 (59.6%) were male. Full analysis set included 110 naive (group 1), 132 previously amlodipine-treated (group 2) and 134 previously losartan-treated (group 3) patients. The SeDBP decreased at 12 weeks in all three groups: by 23.1 +/- 7.8 mm Hg (103.3 +/- 3.0 to 80.2 +/- 8.1 mm Hg) in group 1, 14.3 +/- 8.2 mm Hg (94.6 +/- 5.1 to 80.3 +/- 8.6 mm Hg) in group 2, and 15.7 +/- 6.8 mm Hg (94.6 +/- 4.8 to 78.9 +/- 7.0 mm Hg) in group 3 (all p < 0.001). Furthermore, the SeSBP and 24-h ambulatory BP decreased significantly in all three groups, and > 80% of patients achieved their target BP. Overall, the olmesartan/amlodipine FDC was well tolerated, and there were no serious adverse events associated with medication. In conclusion, the olmesartan/amlodipine FDC showed efficacy and safety in Korean patients with hypertension, who had never been treated or were uncontrolled with monotherapy. PMID- 25816198 TI - Changes in ovaries and uterus after aglepristone administration in the third week of luteal phase of non-pregnant bitches. AB - OBJECTIVE: The mechanism of aglepristone action in the placentation time in the bitch remains unclear. The aim of this study was to describe the mechanism by which aglepristone influences ovaries and uterus and to measure the levels of steroid sex hormones in non-pregnant bitches. MATERIALS AND METHODS: Fourteen bitches assigned to a study (n=9) and control (n=5) group were given aglepristone and saline solution, respectively, on the 19th and 20th day after LH peak. On the 26th day after LH peak an ovariohysterectomy was performed. Blood samples were screened for estradiol and progesterone concentrations. Ovaries and uterine horns and bodies were isolated for histological and morphometrical diagnosis and immunohistochemistry analysis of alpha-estrogen and progesterone receptor expression. RESULTS: A decrease of progesterone (p<0.01) and no differences in total estrogen level in the study group were observed. There were no significant differences either in the histomorphometry or alpha-estrogen and progesterone receptors expression in ovaries. Increase in expression of progesterone receptors in endometrium without surface epithelium of horns (p<0.05), endometrial surface epithelium (p<0.05), myometrium of uterine body (p<0.01) and estrogen receptors in endometrium without surface epithelium of horns (p<0.05) was observed. Elevated estrogen receptors probably increased sensitivity of tissues to estrogens in the bloodstream and led to notable inflammation, haemorrhages, and hyperplasia in endometrium with mononuclear immune cell infiltration. The myometrium of horns and endometrium of uterine body of study bitches were significantly thicker than in the control group (p<0.05 and p<0.01). Furthermore myometrium of uterine body was thicker than myometrium of horns (p<0.001) and expression of progesterone receptors was higher in uterine body (p<0.01). No differences were observed between endometrium of horns and body within groups. CONCLUSION: To the knowledge of the authors this is the first study, which describes the inflammatory effect developing in uterus in response to aglepristone administration, and attempts to elucidate its mechanisms. PMID- 25816200 TI - The influence of ethylenediamine tetra acetic acid (EDTA) on the transformation and solubility of metallic palladium and palladium(II) oxide in the environment. AB - The environmental occurrence of elevated concentrations of platinum (Pt), palladium (Pd) and rhodium (Rh) from automotive catalytic converters has been well-documented. Limited information exists regarding their chemical behavior post-emission, however, especially in the presence of commonly occurring complexing agents. The purpose of this study is to examine the influence of ethylenediamine tetra acetic acid (EDTA) on the possible environmental transformation and solubility of Pd by conducting batch experiments using metallic palladium (Pd black) and palladium(ii) oxide (PdO). Changes in the particle surface chemistry of treated samples were analyzed using X-ray Photoelectron Spectroscopy (XPS) and Transition Electron Microscopy/Energy Dispersive X-ray Spectrometry (TEM/EDX) techniques. Metallic palladium was partially transformed into PdOx (x < 1), while PdO remained largely unaffected. The pH of EDTA solutions was observed to modulate Pd solubility, with Pd black demonstrating a higher solubility compared to PdO. Solubility was also found to increase with a corresponding increase in the strength of EDTA solution concentrations, as well as with the length of extraction time. The overall solubility of Pd remained relatively low for most samples (<1 wt%). A dissolution rate of 2.01 +/- 0.17 nmol m(-2) h(-1) was calculated for Pd black in 0.1 M EDTA (pH 7). In contrast to previously held assumptions about the environmental immobility of Pd, small amounts of this element emitted in metallic form are likely to be soluble in the presence of complexing agents such as EDTA. PMID- 25816199 TI - The gene YALI0E20207g from Yarrowia lipolytica encodes an N-acetylglucosamine kinase implicated in the regulated expression of the genes from the N acetylglucosamine assimilatory pathway. AB - The non-conventional yeast Yarrowia lipolytica possesses an ORF, YALI0E20207g, which encodes a protein with an amino acid sequence similar to hexokinases from different organisms. We have cloned that gene and determined several enzymatic properties of its encoded protein showing that it is an N-acetylglucosamine (NAGA) kinase. This conclusion was supported by the lack of growth in NAGA of a strain carrying a YALI0E20207g deletion. We named this gene YlNAG5. Expression of YlNAG5 as well as that of the genes encoding the enzymes of the NAGA catabolic pathway-identified by a BLAST search-was induced by this sugar. Deletion of YlNAG5 rendered that expression independent of the presence of NAGA in the medium and reintroduction of the gene restored the inducibility, indicating that YlNag5 participates in the transcriptional regulation of the NAGA assimilatory pathway genes. Expression of YlNAG5 was increased during sporulation and homozygous Ylnag5/Ylnag5 diploid strains sporulated very poorly as compared with a wild type isogenic control strain pointing to a participation of the protein in the process. Overexpression of YlNAG5 allowed growth in glucose of an Ylhxk1glk1 double mutant and produced, in a wild type background, aberrant morphologies in different media. Expression of the gene in a Saccharomyces cerevisiae hxk1 hxk2 glk1 triple mutant restored ability to grow in glucose. PMID- 25816201 TI - High strain-rate response of injectable PAA hydrogel. AB - Hydrogel materials have been widely considered as potential soft tissue replacements because of their high permeability, hydrophilicity, and biocompatibility, as well as their low coefficient of friction. Injectable (thermo-responsive) hydrogels can provide support and cushioning at irregularly shaped disease sites, and are thus suitable for use in treating osteoarthritis or degenerative disc disease. However, while some injectable hydrogels have been proven to sustain human body weight during daily activities, their mechanical properties under harsh dynamic conditions have not been well documented. A specified injectable polyacrylic acid (PAA) hydrogel was prepared for this study. To simulate sudden impacts or unexpected shocks to the PAA hydrogel, the split Hopkinson pressure bar technique was utilized. The dynamic responses of various hydrogels at confined high strain rates (100-2590 s(-1)) were presented. Hydrogel specimens with 3.37, 6.75, and 13.5% acrylic acid (AAc) concentrations were tested in the following three different material conditions: raw, phosphate buffered saline (PBS) swollen, and PBS swollen with elevated temperature (37 degrees C). The dynamic bulk moduli of the hydrogels varied from 1.55 to 47.8 MPa depending on the given hydrogel's AAc concentration and swollen condition. PMID- 25816202 TI - Characterization of dedifferentiating human mature adipocytes from the visceral and subcutaneous fat compartments: fibroblast-activation protein alpha and dipeptidyl peptidase 4 as major components of matrix remodeling. AB - Mature adipocytes can reverse their phenotype to become fibroblast-like cells. This is achieved by ceiling culture and the resulting cells, called dedifferentiated fat (DFAT) cells, are multipotent. Beyond the potential value of these cells for regenerative medicine, the dedifferentiation process itself raises many questions about cellular plasticity and the pathways implicated in cell behavior. This work has been performed with the objective of obtaining new information on adipocyte dedifferentiation, especially pertaining to new targets that may be involved in cellular fate changes. To do so, omental and subcutaneous mature adipocytes sampled from severely obese subjects have been dedifferentiated by ceiling culture. An experimental design with various time points along the dedifferentiation process has been utilized to better understand this process. Cell size, gene and protein expression as well as cytokine secretion were investigated. Il-6, IL-8, SerpinE1 and VEGF secretion were increased during dedifferentiation, whereas MIF-1 secretion was transiently increased. A marked decrease in expression of mature adipocyte transcripts (PPARgamma2, C/EBPalpha, LPL and Adiponectin) was detected early in the process. In addition, some matrix remodeling transcripts (FAP, DPP4, MMP1 and TGFbeta1) were rapidly and strongly up-regulated. FAP and DPP4 proteins were simultaneously induced in dedifferentiating mature adipocytes supporting a potential role for these enzymes in adipose tissue remodeling and cell plasticity. PMID- 25816204 TI - Transcranial direct current stimulation improves ipsilateral selective muscle activation in a frequency dependent manner. AB - Failure to suppress antagonist muscles can lead to movement dysfunction, such as the abnormal muscle synergies often seen in the upper limb after stroke. A neurophysiological surrogate of upper limb synergies, the selectivity ratio (SR), can be determined from the ratio of biceps brachii (BB) motor evoked potentials to transcranial magnetic stimulation prior to forearm pronation versus elbow flexion. Surprisingly, cathodal transcranial direct current stimulation (c-TDCS) over ipsilateral primary motor cortex (M1) reduces (i.e. improves) the SR in healthy adults, and chronic stroke patients. The ability to suppress antagonist muscles may be exacerbated at high movement rates. The aim of the present study was to investigate whether the selective muscle activation of the biceps brachii (BB) is dependent on altering frequency demands, and whether the c-tDCS improvement of SR is dependent on task frequency. Seventeen healthy participants performed repetitive isometric elbow flexion and forearm pronation at three rates, before and after c-tDCS or sham delivered to ipsilateral left M1. Ipsilateral c-tDCS improved the SR in a frequency dependent manner by selectively suppressing BB antagonist excitability. Our findings confirm that c-tDCS is an effective tool for improving selective muscle activation, and provide novel evidence for its efficacy at rates of movement where it is most likely to benefit task performance. PMID- 25816205 TI - Can direct conversion of used nitrogen to new feed and protein help feed the world? AB - The increase in the world population, vulnerability of conventional crop production to climate change, and population shifts to megacities justify a re examination of current methods of converting reactive nitrogen to dinitrogen gas in sewage and waste treatment plants. Indeed, by up-grading treatment plants to factories in which the incoming materials are first deconstructed to units such as ammonia, carbon dioxide and clean minerals, one can implement a highly intensive and efficient microbial resynthesis process in which the used nitrogen is harvested as microbial protein (at efficiencies close to 100%). This can be used for animal feed and food purposes. The technology for recovery of reactive nitrogen as microbial protein is available but a change of mindset needs to be achieved to make such recovery acceptable. PMID- 25816203 TI - Transcriptomic profiling of Yersinia pseudotuberculosis reveals reprogramming of the Crp regulon by temperature and uncovers Crp as a master regulator of small RNAs. AB - One hallmark of pathogenic yersiniae is their ability to rapidly adjust their life-style and pathogenesis upon host entry. In order to capture the range, magnitude and complexity of the underlying gene control mechanisms we used comparative RNA-seq-based transcriptomic profiling of the enteric pathogen Y. pseudotuberculosis under environmental and infection-relevant conditions. We identified 1151 individual transcription start sites, multiple riboswitch-like RNA elements, and a global set of antisense RNAs and previously unrecognized trans-acting RNAs. Taking advantage of these data, we revealed a temperature induced and growth phase-dependent reprogramming of a large set of catabolic/energy production genes and uncovered the existence of a thermo regulated 'acetate switch', which appear to prime the bacteria for growth in the digestive tract. To elucidate the regulatory architecture linking nutritional status to virulence we also refined the CRP regulon. We identified a massive remodelling of the CRP-controlled network in response to temperature and discovered CRP as a transcriptional master regulator of numerous conserved and newly identified non-coding RNAs which participate in this process. This finding highlights a novel level of complexity of the regulatory network in which the concerted action of transcriptional regulators and multiple non-coding RNAs under control of CRP adjusts the control of Yersinia fitness and virulence to the requirements of their environmental and virulent life-styles. PMID- 25816207 TI - Antiaromatic characteristic analysis of 1,4-diazapentalene derivatives: a theoretical study. AB - 1,4-Diazapentalene heteroacenes are potential n-type semiconductors that could be used as a new type of material for organic field-effect transistors (OFETs), but their synthesis is still challenging due to their antiaromaticity. The study on their structure-stability relationship should provide useful guidance to the design of stable diazapentalenes. We examined the stability of several types of heteroacenes bearing the 1,4-diazapentalene core using NICS(1)zz calculations. The influence of the fusion pattern, the introduction of substituents, and the incorporation of other heterocycles on the antiaromaticity of the central 1,4 diazapentalene core was systematically studied. It was found that the linear fusion of aromatic rings to the antiaromatic core increases the stability of the heteroacene. The fusion of electron-poor heterocyclic rings also enhances the stability effectively, whereas the fusion of electron-rich heterocyclic rings destabilizes the system. In addition, the combination of the linear fusion pattern or introduction of electron-poor heterocyclic rings to the antiaromatic core reduces the reorganization energy for electron transport, suggesting a way to achieve better n-type semiconductors. PMID- 25816208 TI - Apoptin-modified human mesenchymal stem cells inhibit growth of lung carcinoma in nude mice. AB - Human mesenchymal stem cells (MSCs) represent a novel carrier for gene therapy and apoptin is a potential tumor-selective apoptosis-inducing protein. In the present study, the anti-tumoral effect of MSCs modified with apoptin against lung carcinoma was evaluated. Apoptin protein was expressed in a prokaryotic expression system and purified by affinity chromatography. Subsequently, anti apoptin antibody was prepared by immunizing BALB/c mice with purified apoptin protein. Human MSCs were isolated, amplified and transduced with lentiviral vectors encoding full-length apoptin, in which the secretory signal and protein transduction sequence were added into the amino terminus to assist apoptin in entering into target cells. The differentiation and apoptin expression of apoptin modified MSCs were confirmed. Subsequently, the anti-tumor effect of apoptin modified MSCs was measured in vitro and in vivo. Following modification with apoptin, MSCs retained their differentiation capacity, and successfully synthesized and secreted apoptin, which entered target cells and selectively induced lung cancer cell apoptosis through activating caspase-3. The percentage of tumor cells with activated caspase-3 in the apoptin-modified MSCs group was markedly higher than that in the MSCs group (16.5 +/- 2.9% at 24 h and 27.3 +/- 2.0% at 48 h vs. 3.4 +/- 1.1% at 24 h and 2.2 +/- 0.6% at 48 h). When injected into nude mice, apoptin-modified MSCs inhibited the growth of lung carcinoma compared with that in the control groups (0.14 +/- 0.02 g vs. 0.21 +/- 0.04 g vs. 0.31 +/- 0.05 g, P < 0.05). The results of the present study provided preclinical support of apoptin-based cancer therapy with MSCs as cellular vehicles. PMID- 25816209 TI - An in silico insight into novel therapeutic interaction of LTNF peptide-LT10 and design of structure based peptidomimetics for putative anti-diabetic activity. AB - Lethal Toxin Neutralizing Factor (LTNF) obtained from Opossum serum (Didephis virginiana) is known to exhibit toxin-neutralizing activity for envenomation caused by animals, plants and bacteria. Small synthetic peptide- LT10 (10mer) derived from N-terminal fraction of LTNF exhibit similar anti-lethal and anti allergic property. In our in silico study, we identified Insulin Degrading Enzyme (IDE) as a potential target of LT10 peptide followed by molecular docking and molecular dynamic (MD) simulation studies which revealed relatively stable interaction of LT10 peptide with IDE. Moreover, their detailed interaction analyses dictate IDE-inhibitory interactions of LT10 peptide. This prediction of LT10 peptide as a novel putative IDE-inhibitor suggests its possible role in anti diabetic treatment since IDE- inhibitors are known to assist treatment of Diabetes mellitus by enhancing insulin signalling. Furthermore, series of structure based peptidomimetics were designed from LT10 peptide and screened for their inhibitory interactions which ultimately led to a small set of peptidomimetic inhibitors of IDE. These peptidomimetic thus might provide a new class of IDE-inhibitors, those derived from LT10 peptide. PMID- 25816211 TI - Reappearance of chikungunya, formerly called dengue, in the Americas. AB - After an absence of ~200 years, chikungunya returned to the American tropics in 2013. The virus is maintained in a complex African zoonotic cycle but escapes into an urban cycle at 40- to 50-year intervals, causing global pandemics. In 1823, classical chikungunya, a viral exanthem in humans, occurred on Zanzibar, and in 1827, it arrived in the Caribbean and spread to North and South America. In Zanzibar, the disease was known as kidenga pepo, Swahili for a sudden cramp like seizure caused by an evil spirit; in Cuba, it was known as dengue, a Spanish homonym of denga. During the eighteenth century, dengue (present-day chikungunya) was distinguished from breakbone fever (present-day dengue), another febrile exanthem. In the twentieth century, experiments resulted in the recovery and naming of present-day dengue viruses. In 1952, chikungunya virus was recovered during an outbreak in Tanzania, but by then, the virus had lost its original name to present-day dengue viruses. PMID- 25816210 TI - Gallic acid induces necroptosis via TNF-alpha signaling pathway in activated hepatic stellate cells. AB - Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA), a natural phenolic acid widely found in gallnuts, tea leaves and various fruits, possesses several bioactivities against inflammation, oxidation, and carcinogenicity. The beneficial effect of GA on the reduction of animal hepatofibrosis has been indicated due to its antioxidative property. However, the cytotoxicity of GA autoxidation causing cell death has also been reported. Herein, we postulated that GA might target activated hepatic stellate cells (aHSCs), the cell type responsible for hepatofibrosis, to mitigate the process of fibrosis. The molecular cytotoxic mechanisms that GA exerted on aHSCs were then analyzed. The results indicated that GA elicited aHSC programmed cell death through TNF-alpha-mediated necroptosis. GA induced significant oxidative stress through the suppression of catalase activity and the depletion of glutathione (GSH). Elevated oxidative stress triggered the production of TNF-alpha facilitating the undergoing of necroptosis through the up-regulation of key necroptotic regulatory proteins TRADD and receptor-interacting protein 3 (RIP3), and the inactivation of caspase 8. Calmodulin and calpain-1 activation were engaged, which promoted subsequent lysosomal membrane permeabilization (LMP). The TNF-alpha antagonist (SPD-304) and the RIP1 inhibitor (necrostatin-1, Nec-1) confirmed GA-induced TNFR1-mediated necroptosis. The inhibition of RIP1 by Nec-1 diverted the cell death from necroptosis to apoptosis, as the activation of caspase 3 and the increase of cytochrome c. Collectively, this is the first report indicating that GA induces TNF signaling-triggered necroptosis in aHSCs, which may offer an alternative strategy for the amelioration of liver fibrosis. PMID- 25816212 TI - Analysis of the technology acceptance model in examining hospital nurses' behavioral intentions toward the use of bar code medication administration. AB - Serious medication errors continue to exist in hospitals, even though there is technology that could potentially eliminate them such as bar code medication administration. Little is known about the degree to which the culture of patient safety is associated with behavioral intention to use bar code medication administration. Based on the Technology Acceptance Model, this study evaluated the relationships among patient safety culture and perceived usefulness and perceived ease of use, and behavioral intention to use bar code medication administration technology among nurses in hospitals. Cross-sectional surveys with a convenience sample of 163 nurses using bar code medication administration were conducted. Feedback and communication about errors had a positive impact in predicting perceived usefulness (beta=.26, P<.01) and perceived ease of use (beta=.22, P<.05). In a multiple regression model predicting for behavioral intention, age had a negative impact (beta=-.17, P<.05); however, teamwork within hospital units (beta=.20, P<.05) and perceived usefulness (beta=.35, P<.01) both had a positive impact on behavioral intention. The overall bar code medication administration behavioral intention model explained 24% (P<.001) of the variance. Identified factors influencing bar code medication administration behavioral intention can help inform hospitals to develop tailored interventions for RNs to reduce medication administration errors and increase patient safety by using this technology. PMID- 25816213 TI - Knockdown of ubiquitin protein ligase E3A affects proliferation and invasion, and induces apoptosis of breast cancer cells through regulation of annexin A2. AB - The present study used RNA interference (RNAi) to study how the expression of annexin A2 was affected by ubiquitin protein ligase E3A (UBE3A). In addition, the proliferation, apoptosis and invasiveness of BT-549 breast cancer cells was studied following knockdown of UBE3A. Three pairs of small interfering RNA (siRNA) fragments targeting UBE3A were designed and transfected into the BT-549 cells. The effects of silencing UBE3A were detected by reverse transcription polymerase chain reaction and western blotting, and the same methods were used to detect the expression levels of annexin A2. Cell proliferation was determined using the Cell Counting kit-8, and flow cytometry and a Transwell chamber assay were used to assess the rate of cell apoptosis and invasion, respectively. Following transfection with the three siRNAs targeting UBE3A for 72 h, the mRNA expression levels of UBE3A were downregulated, as compared with those in the untreated groups, and siRNA1 was the shown to be the most effective siRNA for silencing UBE3A expression. The protein expression levels were concordant with the mRNA expression levels of UBE3A. In addition, the mRNA and protein expression levels of annexin A2 were downregulated. Cellular proliferation and invasion of the siRNA1 group was inhibited as compared with those in the untreated groups, and apoptosis of UBE3A-siRNA1 cells was increased as compared with that in the untreated groups. The results of the present study indicated that UBE3A may regulate the expression of annexin A2, resulting in promotion of proliferation and invasion and suppression of apoptosis in BT-549 cells. PMID- 25816214 TI - Computed Tomography Angiography With High Flow Rates: An In Vitro and In Vivo Feasibility Study. AB - OBJECTIVE: The aims of this study were to test high-flow application of contrast media (CM) using novel high-flow needles and to assess injection- and flow related parameters in a circulation phantom and in an in vivo population. MATERIALS AND METHODS: A circulation phantom simulating physiological parameters was used. Preheated CM (300 mg/mL) was injected at flow rates varying between 5 and 15 mL/s through a novel 18-gauge high-flow intravenous injection needle. In addition, feasibility of these high-flow needles was tested with administration of flow rates of 9 mL/s in 20 patients referred for pre-transcatheter aortic valve implantation assessment. Injection parameters (eg, peak pressures, peak flow rates) in both phantom and in vivo setup were continuously monitored by a data acquisition program. Attenuation at predefined levels of the aorta (eg, aortic root to common femoral arteries) was measured in all patients to determine clinical applicability. RESULTS: In the phantom setup, injection rates up to 15 mL/s were feasible. An enhancement plateau was reached at 11 mL/s (464 [20] HU). In patients, no pressure- or flow-related complications (eg, extravasation) were recorded (mean [SD] peak pressure, 154 [8] psi; mean [SD] peak flow rate, 9.2 [0.1 mL/s; range, 9.1-9.6]). Diagnostic attenuation values were reached at all predefined levels of the aorta (330.8 [113.1] HU to 622.9 [81.5] HU). CONCLUSIONS: These results indicate that injections with 9 mL/s using high-flow injection needles are safe. The pressure limit of 325 psi was not reached, and the injections resulted in diagnostic attenuation values. Using this dedicated needle, high flow rates should not be considered a drawback for CM application in routine CT angiography examinations. PMID- 25816215 TI - Feasibility of Selective Catheter-Directed Coronary Computed Tomography Angiography Using Ultralow-Dose Intracoronary Contrast Injection in a Swine Model. AB - OBJECTIVE: Selective catheter-directed intracoronary contrast injected coronary computed tomography angiography (selective CCTA) has recently been introduced for on-site evaluation of coronary artery disease during coronary artery catheterization. In this study, we aimed to develop a feasible protocol for selective CCTA using ultralow-dose contrast medium as compared with conventional intravenous CCTA (IV CCTA). MATERIALS AND METHODS: A novel combined system incorporating coronary angiography and a 320-detector row computed tomographic scanner was used to study 4 swine (35-40 kg) under animal institutional review board approval. A selective CCTA scan was simultaneously performed with an injection of 13.13 mgI/mL of modulated contrast medium at multiple different injection rates including 2, 3, and 4 mL/s and different total injection volumes of either 20 or 30 mL. Intravenous CCTA was performed with 60 mL of contrast medium, followed by 30 mL of saline chaser at 5 mL/s. Coronary mean and peak intensity, transluminal attenuation gradient, as well as 3-dimensional maximum intensity projections were obtained. RESULTS: Attenuation values (mean +/- standard error, in Hounsfield units [HUs]) of selective CCTA for the left anterior descending (LAD) and right coronary artery (RCA) using the various combinations of injection rates and total injection volumes were as follows: 20 mL at 2 mL/s (LAD, 270.3 +/- 20.4 HU; RCA, 322.6 +/- 7.4 HU), 20 mL at 3 mL/s (LAD, 262.9 +/- 20.4 HU; RCA, 264.7 +/- 7.4 HU), 30 mL at 3 mL/s (LAD, 276.8 +/- 20.4 HU; RCA, 274.0 +/- 7.4 HU), 20 mL at 4 mL/s (LAD, 268.0 +/- 20.4 HU; RCA, 277.7 +/- 7.4 HU), and 30 mL at 4 mL/s (LAD, 251.3 +/- 20.4 HU; RCA, 334.7 +/- 7.4 HU). The representative protocol of the selective CCTA studies produced results within the optimal enhancement range (approximately 250-350 HU) for all segments, and comparison of transluminal attenuation gradient data with selective CCTA and IV CCTA studies demonstrated that the former method was more homogenous (-1.5245 and -1.7558 for LAD as well as 0.0459 and 0.0799 for RCA, respectively). Notably, the volume of iodine contrast medium used for selective CCTA was reported to be 1.09% (0.2 g) of IV CCTA (24 g). CONCLUSIONS: The current findings demonstrate the feasibility of selective CCTA using ultralow-dose intracoronary contrast injection. This technique may provide additional means of coronary evaluation in patients who may require strategic planning before a procedure using a combined modality system. PMID- 25816216 TI - Aerosol transmission of infectious disease. AB - OBJECTIVE: The concept of aerosol transmission is developed to resolve limitations in conventional definitions of airborne and droplet transmission. METHODS: The method was literature review. RESULTS: An infectious aerosol is a collection of pathogen-laden particles in air. Aerosol particles may deposit onto or be inhaled by a susceptible person. Aerosol transmission is biologically plausible when infectious aerosols are generated by or from an infectious person, the pathogen remains viable in the environment for some period of time, and the target tissues in which the pathogen initiates infection are accessible to the aerosol. Biological plausibility of aerosol transmission is evaluated for Severe Acute Respiratory Syndrome coronavirus and norovirus and discussed for Mycobacterium tuberculosis, influenza, and Ebola virus. CONCLUSIONS: Aerosol transmission reflects a modern understanding of aerosol science and allows physically appropriate explanation and intervention selection for infectious diseases. PMID- 25816217 TI - PET/CT characterization of non-small-cell lung cancer heterogeneity. PMID- 25816219 TI - Quantitative Guidance for Stove Usage and Performance to Achieve Health and Environmental Targets. AB - BACKGROUND: Displacing the use of polluting and inefficient cookstoves in developing countries is necessary to achieve the potential health and environmental benefits sought through clean cooking solutions. Yet little quantitative context has been provided on how much displacement of traditional technologies is needed to achieve targets for household air pollutant concentrations or fuel savings. OBJECTIVES: This paper provides instructive guidance on the usage of cooking technologies required to achieve health and environmental improvements. METHODS: We evaluated different scenarios of displacement of traditional stoves with use of higher performing technologies. The air quality and fuel consumption impacts were estimated for these scenarios using a single-zone box model of indoor air quality and ratios of thermal efficiency. RESULTS: Stove performance and usage should be considered together, as lower performing stoves can result in similar or greater benefits than a higher performing stove if the lower performing stove has considerably higher displacement of the baseline stove. Based on the indoor air quality model, there are multiple performance-usage scenarios for achieving modest indoor air quality improvements. To meet World Health Organization guidance levels, however, three stone fire and basic charcoal stove usage must be nearly eliminated to achieve the particulate matter target (< 1-3 hr/week), and substantially limited to meet the carbon monoxide guideline (< 7-9 hr/week). CONCLUSIONS: Moderate health gains may be achieved with various performance-usage scenarios. The greatest benefits are estimated to be achieved by near-complete displacement of traditional stoves with clean technologies, emphasizing the need to shift in the long term to near exclusive use of clean fuels and stoves. The performance-usage scenarios are also provided as a tool to guide technology selection and prioritize behavior change opportunities to maximize impact. PMID- 25816220 TI - Molecular variability and genetic structure of Chrysodeixis includens (Lepidoptera: Noctuidae), an important soybean defoliator in Brazil. AB - This study provides the first genetic characterization of the soybean looper, Chrysodeixis includens (Walker, 1857), an important defoliating pest species of soybean crops in Brazil. Population genetic variability and the genetic structure of C. includens populations were evaluated by using ISSR markers with samples from the major soybean producing regions in Brazil in the growing seasons 2011/2012. Seven different primers were applied for population characterization of the molecular variability and genetic structure of 8 soybean looper populations from 8 states of Brazil. The seven ISSR loci generated 247 bands in 246 individuals of C. includens sampled. The expected heterozygosity (HE) in the populations varied between 0.093 and 0.106, while the overall HE was 0.099, indicating low genetic diversity. The analysis of molecular variance indicated that 98% of the variability was expressed among individuals within populations (FST = 0.021, p = 0.001). The low level of polymorphism over all populations, the high levels of gene flow, and the low genetic structure are indicatives of the exchange of genetic information between the different sampled regions. Population structuring suggests the presence of two major groups which do not correlate with their geographic sampling location in Brazil. These results may indicate recent recolonization of C. includens in Brazil or migration patterns following source sink dynamics. Furthermore, the presence of two groups within C. includens suggests that a study on development of resistance or any other genetic-based trait needs to be evaluated on both groups, and pest management in soybean fields should be aware that differences may come to the control strategies they use. PMID- 25816221 TI - Comprehensive comparison of three different immunosuppressive regimens for liver transplant patients with hepatocellular carcinoma: steroid-free immunosuppression, induction immunosuppression and standard immunosuppression. AB - The different choices of immunosuppression (IS) regimens influenced the outcomes of liver transplantation. Steroid was applied as a standard IS to prevent and treat rejections. However, steroid-related complications were increasingly prominent. This study compared the efficacy and safety of standard IS regimens with the efficacy and safety of steroid-free IS regimen and induction IS regimen in Chinese liver transplantation recipients for hepatocellular carcinoma (HCC). A total of 329 patients who underwent liver transplantation from January 2008 to December 2012 were retrospectively reviewed. Three different groups of patients received standard triple-drug IS regimen of steroid, tacrolimus (TAC) and mycophenolate mofetil (MMF) (triple-drug regimen group; n=57), induction contained IS regimen of basiliximab, steroid, TAC and MMF (BS group; n=241), and induction-contained and steroid-free regimen of basiliximab, TAC and MMF (SF group; n=31), respectively. There were no significant differences in terms of patient, tumor-free and graft survival rates. The acute rejection rate and rejection time were equivalent in different groups. But compared with BS group, higher incidences of biliary complications (11.52% vs. 30.77%, p=0.013) and graft dysfunction (0.48% vs. 13.64%, p=0.003) were observed in SF group. Furthermore, compared with the two groups, incidence of pleural effusion was also higher in SF group (15.79%, 11.96% vs. 45.45%, respectively, both p<0.01). And a trend towards less proportion of De novo diabetes was revealed in SF group. Although it was found that patient, tumor-free and graft survival rates were equivalent among three IS regimens, higher incidences of complications were demonstrated in steroid-free regimen in patients for HCC. These findings suggested that steroid free IS regimen has no clear advantages in comparison with standard IS regimens for liver transplant recipients with HCC and the postoperative complications should be treated with concentrated attention. PMID- 25816222 TI - CD4 cell count trends after commencement of antiretroviral therapy among HIV infected patients in Tigray, Northern Ethiopia: a retrospective cross-sectional study. AB - BACKGROUND: The rate and extent of CD4 cell recovery varies widely among HIV infected patients with different baseline CD4 cell count strata. The objective of the study was to assess trends in CD4 cell counts in HIV-infected patients after initiation of antiretroviral therapy in Tigray, Northern Ethiopia. METHODS: A retrospective cross-sectional study was conducted by reviewing medical records of HIV patients who received antiretroviral treatment at twenty health centers in Tigray region during 2008-2012. Multi-stage cluster sampling technique was employed to collect data, and the data were analyzed using SPSS version 20.0 software. RESULTS: The median change from baseline to the most recent CD4 cell count was +292 cells/MUl. By 5 years, the overall median (inter-quartile range, IQR) CD4 cell count was 444(263-557) cells/MUl while the median (IQR) CD4 cell count was 342(246-580) cells/MUl among patients with baseline CD4 cell counts <=200 cells/MUl, 500(241-557) cells/MUl among those with baseline CD4 cell counts of 201-350 cells/MUl, and 652(537-767) cells/MUl among those with baseline CD4 cell counts >350 cells/MUl. Higher baseline CD4 cell counts and being male were independently associated with the risk of immunological non-response at 12 months. Furthermore, it was also investigated that these factors were significant predictors of subsequent CD4 cell recovery. CONCLUSIONS: Patients with higher baseline CD4 cell stratum returned to normal CD4 Cell counts though they had an increased risk of immunological non-response at 12 months compared to those with the least baseline CD4 cell stratum. The findings suggest that consideration be given to initiation of HAART at a CD4 cell count >350 cells/MUl to achieve better immune recovery, and to HIV-infected male patients to improve their health seeking behavior. PMID- 25816223 TI - Kinetically-defined component actions in gene repression. AB - Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression. PMID- 25816225 TI - Surface plasmon resonance imaging by holographic enhanced mapping. AB - We designed, constructed and tested a holographic surface plasmon resonance (HoloSPR) objective-based microscope for simultaneous amplitude-contrast and phase-contrast surface plasmon resonance imaging (SPRi). SPRi is a widely spread tool for label-free detection of changes in refractive index and concentration, as well as mapping of thin films. Currently, most of the SPR sensors rely on the detection of amplitude or phase changes of light. Despite the high sensitivities achieved so far, each technique alone has a limited detection range with optimal sensitivity. Here we use a high numerical aperture objective that avoids all the limitations due to the use of a prism-based configuration, yielding highly magnified and distortion-free images. Holographic reconstructions of SPR images and real-time kinetic measurements are presented to show the capability of HoloSPR to provide a versatile imaging method for high-throughput SPR detection complementary to conventional SPR techniques. PMID- 25816224 TI - Early virological and immunological events in asymptomatic Epstein-Barr virus infection in African children. AB - Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14-18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over expansion, rather than virus load per se, is the cause of disease symptoms. PMID- 25816226 TI - Violacein induces p44/42 mitogen-activated protein kinase-mediated solid tumor cell death and inhibits tumor cell migration. AB - Microbial secondary metabolites have emerged as alternative novel drugs for the treatment of human cancers. Violacein, a purple pigment produced by Chromobacterium violaceum, was investigated in the present study for its anti tumor properties in tumor cell lines. Clinically applicable concentrations of violacein were demonstrated to inhibit the proliferative capacity of tumor cell lines according to a crystal violet proliferation assay. The underlying mechanism was the promotion of apoptotic cell death, as indicated by poly(ADP ribose) polymerase cleavage and p44/42 mitogen-activated protein kinase signaling determined by western blot analysis. Collectively, this provided mechanistic evidence that violacein elicits extracellular-signal regulated kinase-induced apoptosis via the intrinsic pathway. The anti-malignant properties of violacein in the present study were further demonstrated by its inhibitory effects on brain tumor cell migration, specifically glioblastomas, one of the most invasive and therapeutically resistant neoplasms in the clinic. Additionally, solid tumors examined in the present study displayed differential cellular responses and sensitivities to violacein as observed by morphologically induced cellular changes that contributed to its anti-migratory properties. In conclusion, violacein is a novel natural product with the potential to kill several types of human tumor cell lines, as well as prevent disease recurrence by antagonizing cellular processes that contribute to metastatic invasion. PMID- 25816227 TI - Evaluation of different RGD ligand densities in the development of cell-based drug delivery systems. AB - BACKGROUND: The inclusion of the tripeptide Arg-Gly-Asp (RGD) in otherwise inert biomaterials employed for cell encapsulation has been observed to be an effective strategy to provide the immobilized cells with a more suitable microenvironment. PURPOSE: The objective of this study was to determine the impact of different RGD densities on the behavior of baby hamster kidney (BHK) fibroblasts able to secrete vascular endothelial growth factor (VEGF) encapsulated in alginate microcapsules. METHODS: Alginate was modified by varying the concentration of RGD peptides in the coupling reaction. After obtaining four different types of alginate, cells were encapsulated in alginate-poly-L-lysine-alginate (APA) microcapsules. RESULTS AND DISCUSSION: The results obtained after viability, cell proliferation and VEGF secretion assays showed that the inclusion of RGD in alginate enhances the functionality of immobilized cells, obtaining the highest values with the intermediate RGD density. CONCLUSION: These results put in evidence that alginate modification influences the behavior of immobilized cells but even more that the employed density of the tripeptide is of crucial importance, obtaining in some cases even excessive activity of the encapsulated cells. PMID- 25816229 TI - MAFCO: a compression tool for MAF files. AB - In the last decade, the cost of genomic sequencing has been decreasing so much that researchers all over the world accumulate huge amounts of data for present and future use. These genomic data need to be efficiently stored, because storage cost is not decreasing as fast as the cost of sequencing. In order to overcome this problem, the most popular general-purpose compression tool, gzip, is usually used. However, these tools were not specifically designed to compress this kind of data, and often fall short when the intention is to reduce the data size as much as possible. There are several compression algorithms available, even for genomic data, but very few have been designed to deal with Whole Genome Alignments, containing alignments between entire genomes of several species. In this paper, we present a lossless compression tool, MAFCO, specifically designed to compress MAF (Multiple Alignment Format) files. Compared to gzip, the proposed tool attains a compression gain from 34% to 57%, depending on the data set. When compared to a recent dedicated method, which is not compatible with some data sets, the compression gain of MAFCO is about 9%. Both source-code and binaries for several operating systems are freely available for non-commercial use at: http://bioinformatics.ua.pt/software/mafco. PMID- 25816228 TI - Genetic recombination between human and animal parasites creates novel strains of human pathogen. AB - Genetic recombination between pathogens derived from humans and livestock has the potential to create novel pathogen strains, highlighted by the influenza pandemic H1N1/09, which was derived from a re-assortment of swine, avian and human influenza A viruses. Here we investigated whether genetic recombination between subspecies of the protozoan parasite, Trypanosoma brucei, from humans and animals can generate new strains of human pathogen, T. b. rhodesiense (Tbr) responsible for sleeping sickness (Human African Trypanosomiasis, HAT) in East Africa. The trait of human infectivity in Tbr is conferred by a single gene, SRA, which is potentially transferable to the animal pathogen Tbb by sexual reproduction. We tracked the inheritance of SRA in crosses of Tbr and Tbb set up by co transmitting genetically-engineered fluorescent parental trypanosome lines through tsetse flies. SRA was readily transferred into new genetic backgrounds by sexual reproduction between Tbr and Tbb, thus creating new strains of the human pathogen, Tbr. There was no evidence of diminished growth or transmissibility of hybrid trypanosomes carrying SRA. Although expression of SRA is critical to survival of Tbr in the human host, we show that the gene exists as a single copy in a representative collection of Tbr strains. SRA was found on one homologue of chromosome IV in the majority of Tbr isolates examined, but some Ugandan Tbr had SRA on both homologues. The mobility of SRA by genetic recombination readily explains the observed genetic variability of Tbr in East Africa. We conclude that new strains of the human pathogen Tbr are being generated continuously by recombination with the much larger pool of animal-infective trypanosomes. Such novel recombinants present a risk for future outbreaks of HAT. PMID- 25816230 TI - Cultural variation in the use of overimitation by the Aka and Ngandu of the Congo Basin. AB - Studies in Western cultures have observed that both children and adults tend to overimitate, copying causally irrelevant actions in the presence of clear causal information. Investigation of this feature in non-Western groups has found little difference cross-culturally in the frequency or manner with which individuals overimitate. However, each of the non-Western populations studied thus far has a history of close interaction with Western cultures, such that they are now far removed from life in a hunter-gatherer or other small-scale culture. To investigate overimitation in a context of limited Western cultural influences, we conducted a study with the Aka hunter-gatherers and neighboring Ngandu horticulturalists of the Congo Basin rainforest in the southern Central African Republic. Aka children, Ngandu children, and Aka adults were presented with a reward retrieval task similar to those performed in previous studies, involving a demonstrated sequence of causally relevant and irrelevant actions. Aka children were found not to overimitate as expected, instead displaying one of the lowest rates of overimitation seen under similar conditions. Aka children copied fewer irrelevant actions than Aka adults, used a lower proportion of irrelevant actions than Ngandu children and Aka adults, and had less copying fidelity than Aka adults. Measures from Ngandu children were intermediate between the two Aka groups. Of the participants that succeeded in retrieving the reward, 60% of Aka children used emulation rather than imitation, compared to 15% of Ngandu children, 11% of Aka adults, and 0% of Western children of similar age. From these results, we conclude that cross-cultural variation exists in the use of overimitation during childhood. Further study is needed under a more diverse representation of cultural and socioeconomic groups in order to investigate the cognitive underpinnings of overimitation and its possible influences on social learning and the biological and cultural evolution of our species. PMID- 25816231 TI - The influence of primary care quality on hospital admissions for people with dementia in England: a regression analysis. AB - OBJECTIVES: To test the impact of a UK pay-for-performance indicator, the Quality and Outcomes Framework (QOF) dementia review, on three types of hospital admission for people with dementia: emergency admissions where dementia was the primary diagnosis; emergency admissions for ambulatory care sensitive conditions (ACSCs); and elective admissions for cataract, hip replacement, hernia, prostate disease, or hearing loss. METHODS: Count data regression analyses of hospital admissions from 8,304 English general practices from 2006/7 to 2010/11. We identified relevant admissions from national Hospital Episode Statistics and aggregated them to practice level. We merged these with practice-level data on the QOF dementia review. In the base case, the exposure measure was the reported QOF register. As dementia is commonly under-diagnosed, we tested a predicted practice register based on consensus estimates. We adjusted for practice characteristics including measures of deprivation and uptake of a social benefit to purchase care services (Attendance Allowance). RESULTS: In the base case analysis, higher QOF achievement had no significant effect on any type of hospital admission. However, when the predicted register was used to account for under-diagnosis, a one-percentage point improvement in QOF achievement was associated with a small reduction in emergency admissions for both dementia ( 0.1%; P=0.011) and ACSCs (-0.1%; P=0.001). In areas of greater deprivation, uptake of Attendance Allowance was consistently associated with significantly lower emergency admissions. In all analyses, practices with a higher proportion of nursing home patients had significantly lower admission rates for elective and emergency care. CONCLUSION: In one of three analyses at practice level, the QOF review for dementia was associated with a small but significant reduction in unplanned hospital admissions. Given the rising prevalence of dementia, increasing pressures on acute hospital beds and poor outcomes associated with hospital stays for this patient group, this small change may be clinically and economically relevant. PMID- 25816232 TI - Intrapericardial administration of mesenchymal stem cells in a large animal model: a bio-distribution analysis. AB - The appropriate administration route for cardiovascular cell therapy is essential to ensure the viability, proliferative potential, homing capacity and implantation of transferred cells. At the present, the intrapericardial administration of pharmacological agents is considered an efficient method for the treatment of cardiovascular diseases. However, only a few reports have addressed the question whether the intrapericardial delivery of Mesenchymal Stem Cells (MSCs) could be an optimal administration route. This work firstly aimed to analyze the pericardial fluid as a cell-delivery vehicle. Moreover, the in vivo biodistribution pattern of intrapericardially administered MSCs was evaluated in a clinically relevant large animal model. Our in vitro results firstly showed that, MSCs viability, proliferative behavior and phenotypic profile were unaffected by exposure to pericardial fluid. Secondly, in vivo cell tracking by magnetic resonance imaging, histological examination and Y-chromosome amplification clearly demonstrated the presence of MSCs in pericardium, ventricles (left and right) and atrium (left and right) when MSCs were administered into the pericardial space. In conclusion, here we demonstrate that pericardial fluid is a suitable vehicle for MSCs and intrapericardial route provides an optimal retention and implantation of MSCs. PMID- 25816234 TI - The differences in health care utilization between Medical Aid and health insurance: a longitudinal study using propensity score matching. AB - STUDY OBJECTIVES: Health care utilization has progressively increased, especially among Medical Aid beneficiaries in South Korea. The Medical Aid classifies beneficiaries into two categories, type 1 and 2, on the basis of being incapable (those under 18 or over 65 years of age, or disabled) or capable of working, respectively. Medical Aid has a high possibility for health care utilization due to high coverage level. In South Korea, the national health insurance (NHI) achieved very short time to establish coverage for the entire Korean population. However there there remaine a number of problems to be solved. Therefore, the objective of this study was to investigate the differences in health care utilization between Medical Aid beneficiaries and Health Insurance beneficiaries. METHODS & DESIGN: Data were collected from the Korean Welfare Panel Study from 2008 to 2012 using propensity score matching. Of the 2,316 research subjects, 579 had Medical Aid and 1,737 had health insurance. We also analyzed three dependent variables: days spent in the hospital, number of outpatient visits, and hospitalizations per year. Analysis of variance and longitudinal data analysis were used. RESULTS: The number of outpatient visits was 1.431 times higher (p<0.0001) in Medical Aid beneficiaries, the number of hospitalizations per year was 1.604 times higher (p<0.0001) in Medical Aid beneficiaries, and the number of days spent in the hospital per year was 1.282 times higher (p<0.268) for Medical Aid beneficiaries than in individuals with Health Insurance. Medical Aid patients had a 0.874 times lower frequency of having an unmet needs due to economic barrier (95% confidence interval: 0.662-1.156). CONCLUSIONS: Health insurance coverage has an impact on health care utilization. More health care utilization among Medical Aid beneficiaries appears to have a high possibility of a moral hazard risk under the Health Insurance program. Therefore, the moral hazard for Medical Aid beneficiaries should be avoided. PMID- 25816233 TI - Separating recognition processes of declarative memory via anodal tDCS: boosting old item recognition by temporal and new item detection by parietal stimulation. AB - There is emerging evidence from imaging studies that parietal and temporal cortices act together to achieve successful recognition of declarative information; nevertheless, the precise role of these regions remains elusive. To evaluate the role of these brain areas in declarative memory retrieval, we applied bilateral tDCS, with anode over the left and cathode over the right parietal or temporal cortices separately, during the recognition phase of a verbal learning paradigm using a balanced old-new decision task. In a parallel group design, we tested three different groups of healthy adults, matched for demographic and neurocognitive status: two groups received bilateral active stimulation of either the parietal or the temporal cortex, while a third group received sham stimulation. Accuracy, discriminability index (d') and reaction times of recognition memory performance were measurements of interest. The d' sensitivity index and accuracy percentage improved in both active stimulation groups, as compared with the sham one, while reaction times remained unaffected. Moreover, the analysis of accuracy revealed a different effect of tDCS for old and new item recognition. While the temporal group showed enhanced performance for old item recognition, the parietal group was better at correctly recognising new ones. Our results support an active role of both of these areas in memory retrieval, possibly underpinning different stages of the recognition process. PMID- 25816235 TI - Genetic population structure accounts for contemporary ecogeographic patterns in tropic and subtropic-dwelling humans. AB - Contemporary human populations conform to ecogeographic predictions that animals will become more compact in cooler climates and less compact in warmer ones. However, it remains unclear to what extent this pattern reflects plastic responses to current environments or genetic differences among populations. Analyzing anthropometric surveys of 232,684 children and adults from across 80 ethnolinguistic groups in sub-Saharan Africa, Asia and the Americas, we confirm that body surface-to-volume correlates with contemporary temperature at magnitudes found in more latitudinally diverse samples (Adj. R2 = 0.14-0.28). However, far more variation in body surface-to-volume is attributable to genetic population structure (Adj. R2 = 0.50-0.74). Moreover, genetic population structure accounts for nearly all of the observed relationship between contemporary temperature and body surface-to-volume among children and adults. Indeed, after controlling for population structure, contemporary temperature accounts for no more than 4% of the variance in body form in these groups. This effect of genetic affinity on body form is also independent of other ecological variables, such as dominant mode of subsistence and household wealth per capita. These findings suggest that the observed fit of human body surface-to-volume with current climate in this sample reflects relatively large effects of existing genetic population structure of contemporary humans compared to plastic response to current environments. PMID- 25816237 TI - Detecting static and dynamic differences between eyes-closed and eyes-open resting states using ASL and BOLD fMRI. AB - Resting-state fMRI studies have increasingly focused on multi-contrast techniques, such as BOLD and ASL imaging. However, these techniques may reveal different aspects of brain activity (e.g., static vs. dynamic), and little is known about the similarity or disparity of these techniques in detecting resting state brain activity. It is therefore important to assess the static and dynamic characteristics of these fMRI techniques to guide future applications. Here we acquired fMRI data while subjects were in eyes-closed (EC) and eyes-open (EO) states, using both ASL and BOLD techniques, at two research centers (NIDA and HNU). Static brain activity was calculated as voxel-wise mean cerebral blood flow (CBF) using ASL, i.e., CBF-mean, while dynamic activity was measured by the amplitude of low frequency fluctuations (ALFF) of BOLD, i.e., BOLD-ALFF, at both NIDA and HNU, and CBF, i.e., CBF-ALFF, at NIDA. We showed that mean CBF was lower under EC than EO in the primary visual cortex, while BOLD-ALFF was higher under EC in the primary somatosensory cortices extending to the primary auditory cortices and lower in the lateral occipital area. Interestingly, mean CBF and BOLD-ALFF results overlapped at the visual cortex to a very small degree. Importantly, these findings were largely replicated by the HNU dataset. State differences found by CBF-ALFF were located in the primary auditory cortices, which were generally a subset of BOLD-ALFF and showed no spatial overlap with CBF mean. In conclusion, static brain activity measured by mean CBF and dynamic brain activity measured by BOLD- and CBF-ALFF may reflect different aspects of resting state brain activity and a combination of ASL and BOLD may provide complementary information on the biophysical and physiological processes of the brain. PMID- 25816239 TI - American College of Radiology Appropriateness Criteria for Infertility. AB - The new American College of Radiology Appropriateness Criteria for Infertility provide updated imaging guidelines for evaluating infertility in females. It provides a meticulous overview of common causes of infertility including ovulatory, uterine, tubal, peritoneal, and pituitary factors. The article provides great detail regarding the imaging modalities for evaluation of infertility in females. The article title mentioned is American College of Radiology Appropriateness Criteria for Infertility, whereas the article discusses female factors of infertility, and the male factors such as obstructive azoospermia, which could be evaluated by imaging, are not been addressed. PMID- 25816238 TI - Affect-laden imagery and risk taking: the mediating role of stress and risk perception. AB - This paper investigates how affect-laden imagery that evokes emotional stress influences risk perception and risk taking in real-life scenarios. In a series of three studies, we instructed participants to imagine the consequences of risky scenarios and then rate the intensity of the experienced stress, perceived risk and their willingness to engage in risky behavior. Study 1 showed that people spontaneously imagine negative rather than positive risk consequences, which are directly related to their lower willingness to take risk. Moreover, this relationship was mediated by feelings of stress and risk perception. Study 2 replicated and extended these findings by showing that imagining negative risk consequences evokes psychophysiological stress responses observed in elevated blood pressure. Finally, in Study 3, we once again demonstrated that a higher intensity of mental images of negative risk consequences, as measured by enhanced brain activity in the parieto-occipital lobes, leads to a lower propensity to take risk. Furthermore, individual differences in creating vivid and intense negative images of risk consequences moderated the strength of the relationship between risk perception and risk taking. Participants who created more vivid and intense images of negative risk consequences paid less attention to the assessments of riskiness in rating their likelihood to take risk. To summarize, we showed that feelings of emotional stress and perceived riskiness mediate the relationship between mental imagery and risk taking, whereas individual differences in abilities to create vivid mental images may influence the degree to which more cognitive risk assessments are used in the risk-taking process. PMID- 25816236 TI - Frequency and geographic distribution of gyrA and gyrB mutations associated with fluoroquinolone resistance in clinical Mycobacterium tuberculosis isolates: a systematic review. AB - BACKGROUND: The detection of mutations in the gyrA and gyrB genes in the Mycobacterium tuberculosis genome that have been demonstrated to confer phenotypic resistance to fluoroquinolones is the most promising technology for rapid diagnosis of fluoroquinolone resistance. METHODS: In order to characterize the diversity and frequency of gyrA and gyrB mutations and to describe the global distribution of these mutations, we conducted a systematic review, from May 1996 to April 2013, of all published studies evaluating Mycobacterium tuberculosis mutations associated with resistance to fluoroquinolones. The overall goal of the study was to determine the potential utility and reliability of these mutations as diagnostic markers to detect phenotypic fluoroquinolone resistance in Mycobacterium tuberculosis and to describe their geographic distribution. RESULTS: Forty-six studies, covering four continents and 18 countries, provided mutation data for 3,846 unique clinical isolates with phenotypic resistance profiles to fluoroquinolones. The gyrA mutations occurring most frequently in fluoroquinolone-resistant isolates, ranged from 21-32% for D94G and 13-20% for A90V, by drug. Eighty seven percent of all strains that were phenotypically resistant to moxifloxacin and 83% of ofloxacin resistant isolates contained mutations in gyrA. Additionally we found that 83% and 80% of moxifloxacin and ofloxacin resistant strains respectively, were observed to have mutations in the gyrA codons interrogated by the existing MTBDRsl line probe assay. In China and Russia, 83% and 84% of fluoroquinolone resistant strains respectively, were observed to have gyrA mutations in the gene regions covered by the MTBDRsl assay. CONCLUSIONS: Molecular diagnostics, specifically the Genotype MTBDRsl assay, focusing on codons 88-94 should have moderate to high sensitivity in most countries. While we did observe geographic differences in the frequencies of single gyrA mutations across countries, molecular diagnostics based on detection of all gyrA mutations demonstrated to confer resistance should have broad and global utility. PMID- 25816240 TI - Changes of soil particle size distribution in tidal flats in the Yellow River Delta. AB - BACKGROUND: The tidal flat is one of the important components of coastal wetland systems in the Yellow River Delta (YRD). It can stabilize shorelines and protect coastal biodiversity. The erosion risk in tidal flats in coastal wetlands was seldom been studied. Characterizing changes of soil particle size distribution (PSD) is an important way to quantity soil erosion in tidal flats. METHOD/PRINCIPAL FINDINGS: Based on the fractal scale theory and network analysis, we determined the fractal characterizations (singular fractal dimension and multifractal dimension) soil PSD in a successional series of tidal flats in a coastal wetland in the YRD in eastern China. The results showed that the major soil texture was from silt loam to sandy loam. The values of fractal dimensions, ranging from 2.35 to 2.55, decreased from the low tidal flat to the high tidal flat. We also found that the percent of particles with size ranging between 0.4 and 126 MUm was related with fractal dimensions. Tide played a great effort on soil PSD than vegetation by increasing soil organic matter (SOM) content and salinity in the coastal wetland in the YRD. CONCLUSIONS/SIGNIFICANCE: Tidal flats in coastal wetlands in the YRD, especially low tidal flats, are facing the risk of soil erosion. This study will be essential to provide a firm basis for the coast erosion control and assessment, as well as wetland ecosystem restoration. PMID- 25816241 TI - Cloning and characterization of the human integrin beta6 gene promoter. AB - The integrin beta6 (ITGB6) gene, which encodes the limiting subunit of the integrin alphavbeta6 heterodimer, plays an important role in wound healing and carcinogenesis. The mechanism underlying ITGB6 regulation, including the identification of DNA elements and cognate transcription factors responsible for basic transcription of human ITGB6 gene, remains unknown. This report describes the cloning and characterization of the human ITGB6 promoter. Using 5'-RACE (rapid amplification of cDNA ends) analysis, the transcriptional initiation site was identified. Promoter deletion analysis identified and functionally validated a TATA box located in the region -24 to -18 base pairs upstream of the ITGB6 promoter. The regulatory elements for transcription of the ITGB6 gene were predominantly located -289 to -150 from the ITGB6 promoter and contained putative binding sites for transcription factors such as STAT3 and C/EBPalpha. Using chromatin immunoprecipitation assays, this study has demonstrated, for the first time, that transcription factors STAT3 and C/EBPalpha are involved in the positive regulation of ITGB6 transcription in oral squamous cell carcinoma cells. These findings have important implications for unraveling the mechanism of abnormal ITGB6 activation in tissue remodeling and tumorigenesis. PMID- 25816242 TI - Proteome analysis identifies the Dpr protein of Streptococcus mutans as an important factor in the presence of early streptococcal colonizers of tooth surfaces. AB - Oral streptococci are primary colonizers of tooth surfaces and Streptococcus mutans is the principal causative agent of dental caries in humans. A number of proteins are involved in the formation of monospecies biofilms by S. mutans. This study analyzed the protein expression profiles of S. mutans biofilms formed in the presence or absence of S. gordonii, a pioneer colonizer of the tooth surface, by two-dimensional gel electrophoresis (2-DE). After identifying S. mutans proteins by Mass spectrometric analysis, their expression in the presence of S. gordonii was analyzed. S. mutans was inoculated with or without S. gordonii DL1. The two species were compartmentalized using 0.2-MUl Anopore membranes. The biofilms on polystyrene plates were harvested, and the solubilized proteins were separated by 2-DE. When S. mutans biofilms were formed in the presence of S. gordonii, the peroxide resistance protein Dpr of the former showed 4.3-fold increased expression compared to biofilms that developed in the absence of the pioneer colonizer. In addition, we performed a competition assay using S. mutans antioxidant protein mutants together with S. gordonii and other initial colonizers. Growth of the dpr-knockout S. mutans mutant was significantly inhibited by S. gordonii, as well as by S. sanguinis. Furthermore, a cell viability assay revealed that the viability of the dpr-defective mutant was significantly attenuated compared to the wild-type strain when co-cultured with S. gordonii. Therefore, these results suggest that Dpr might be one of the essential proteins for S. mutans survival on teeth in the presence of early colonizing oral streptococci. PMID- 25816243 TI - A novel approach for treatment of the impacted maxillary incisor. AB - This case report demonstrates a novel treatment approach to deal with a severely rotated and impacted upper central incisor in an adolescent patient. A precision custom-made gold attachment was fabricated from a prototype using cone beam computerized tomograph (CBCT) scan data and then used to align and de-rotate the impacted central incisor. PMID- 25816244 TI - Seroprotective antibodies to 2011 variant influenza A(H3N2v) and seasonal influenza A(H3N2) among three age groups of US Department of Defense service members. AB - BACKGROUND: In 2011, a new variant of influenza A(H3N2) emerged that contained a recombination of genes from swine H3N2 viruses and the matrix (M) gene of influenza A(H1N1)pdm09 virus. New combinations and variants of pre-existing influenza viruses are worrisome if there is low or nonexistent immunity in a population, which increases chances for an outbreak or pandemic. METHODS: Sera collected in 2011 were obtained from US Department of Defense service members in three age groups: 19-21 years, 32-33 years, and 47-48 years. Pre- and post vaccination samples were available for the youngest age group, and postvaccination samples for the two older groups. Specimens were tested using microneutralization assays for antibody titers against H3N2v (A/Indiana/10/2011) and seasonal H3N2 virus (A/Perth/16/2009). RESULTS: The youngest age group had significantly (p<0.05) higher geometric mean titers for H3N2v with 165 (95% confidence interval [CI]: 105-225) compared with the two older groups, aged 32-33 and 47-48 years, who had geometric mean titers of 68 (95% CI: 55-82) and 46 (95% CI: 24-65), respectively. Similarly, the youngest age group also had the highest geometric mean titers for seasonal H3N2. In the youngest age group, the proportion of patients who seroconverted after vaccination was 12% for H3N2v and 27% for seasonal H3N2. DISCUSSION: Our results were similar to previous studies that found highest seroprotection among young adults and decreasing titers among older adults. The proportion of 19- to 21-year-olds who seroconverted after seasonal vaccination was low and similar to previous findings. Improving our understanding of H3N2v immunity among different age groups in the United States can help inform vaccination plans if H3N2v becomes more transmissible in the future. PMID- 25816245 TI - Human neutrophil peptides induce interleukin-8 in intestinal epithelial cells through the P2 receptor and ERK1/2 signaling pathways. AB - Human neutrophil peptides (HNPs) are antimicrobial peptides produced predominantly by neutrophils. We have previously reported that HNP 1-3 levels are increased in the sera and plasma of patients with active ulcerative colitis. The increased expression of interleukin-8 (IL-8) has also been demonstrated in the colonic mucosa of patients with active ulcerative colitis. HNPs induce IL-8 in lung epithelial cells and monocytes through the P2Y6 signaling pathway. However, the association between HNPs and IL-8 in the intestinal mucosa has not yet been investigated. In the present study, we investigated the effects of HNP-1 on the production of IL-8 by human intestinal epithelial cells and the underlying signaling mechanisms. We observed a significant increase in IL-8 expression in the human colon carcinoma cell line, Caco-2, following treatment with HNP-1. The non-selective P2 receptor antagonists, suramin and pyridoxal phosphate-6-azo (benzene-2,4-disulfonic acid) tetrasodium salt hydrate (PPADS), significantly blocked the HNP-1-induced expression of IL-8 in the Caco-2 cells. The P2Y6 specific antagonist, MRS2578, led to a significant but partial decrease in IL-8 expression, suggesting that P2 receptors in addition to P2Y6 are involved in the HNP-1-induced production of IL-8 by Caco-2 cells. In agreement with this finding, HNP-1 also significantly increased IL-8 production in the P2Y6-negative human colon cancer cell line, HT-29, and this increase was blocked by treatment with suramin and PPADS. HNP-1 significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in the HT-29 cells. However, the HNP-1-induced production of IL-8 was suppressed by the ERK1/2 inhibitor, U0126, but not by the p38 MAPK inhibitor, SB203580. In conclusion, our data demonstrate that HNP-1 induces IL-8 production not only through P2Y6, but also through additional P2 receptors via an ERK1/2-dependent mechanism in intestinal epithelial cells. PMID- 25816246 TI - Smoothing spline ANOVA decomposition of arbitrary splines: an application to eye movements in reading. AB - The Smoothing Spline ANOVA (SS-ANOVA) requires a specialized construction of basis and penalty terms in order to incorporate prior knowledge about the data to be fitted. Typically, one resorts to the most general approach using tensor product splines. This implies severe constraints on the correlation structure, i.e. the assumption of isotropy of smoothness can not be incorporated in general. This may increase the variance of the spline fit, especially if only a relatively small set of observations are given. In this article, we propose an alternative method that allows to incorporate prior knowledge without the need to construct specialized bases and penalties, allowing the researcher to choose the spline basis and penalty according to the prior knowledge of the observations rather than choosing them according to the analysis to be done. The two approaches are compared with an artificial example and with analyses of fixation durations during reading. PMID- 25816247 TI - Behavioral immune system and ingroup derogation: the effects of infectious diseases on ingroup derogation attitudes. AB - From evolutionary reasoning, we derived a novel hypothesis that ingroup derogation is an evolved response of behavioral immune system which follows the smoke detector principle and the functional flexibility principle. This hypothesis was tested and supported across three experiments. In Experiment 1, participants' group membership was manipulated by using a minimal group paradigm. The results indicated that mere social categorization alone - a heuristic cue that implies the differentiation between "us" and "them" - was sufficient to elicit ingroup derogation among Chinese participants, and, such an intergroup bias was positively associated with the perceived vulnerability to diseases, which was also more consistently associated with ingroup attitudes. Experiment 2 extended and partially replicated Experiment 1 by showing that when there were cues of diseases in the immediate physical environment, Chinese participants exaggerated their attitudes of ingroup derogation. The results also showed that this effect was mainly driven by outgroup attraction. Experiment 3 changed the method of disease manipulation, and found that Chinese participants responded more strongly to disease cues originating from ingroup members and that they endorsed more ingroup derogation attitudes even when the ingroup and outgroup members were both displaying cues of diseases. Taken together, these results reveal the previously unexplored effects of infectious diseases on ingroup derogation attitudes, and suggest an interesting linkage between the evolved behavioral immune system and the ingroup derogation. PMID- 25816248 TI - An enzymatic assay for high-throughput screening of cytidine-producing microbial strains. AB - Cytidine is an industrially useful precursor for the production of antiviral compounds and a variety of industrial compounds. Interest in the microbial production of cytidine has grown recently and high-throughput screening of cytidine over-producers is an important approach in large-scale industrial production using microorganisms. An enzymatic assay for cytidine was developed combining cytidine deaminase (CDA) and indophenol method. CDA catalyzes the cleavage of cytidine to uridine and NH3, the latter of which can be accurately determined using the indophenol method. The assay was performed in 96-well plates and had a linear detection range of cytidine of 0.058-10 mM. This assay was used to determine the amount of cytidine in fermentation flasks and the results were compared with that of High Perfomance Liquid Chromatography (HPLC) method. The detection range of the CDA method is not as wide as that of the HPLC, furthermore the correlation factor of CDA method is not as high as that of HPLC. However, it was suitable for the detection of large numbers of crude samples and was applied to high-throughput screening for high cytidine-producing strains using 96-well deep-hole culture plates. This assay was proved to be simple, accurate, specific and suitable for cytidine detection and high-throughput screening of cytidine producing strains in large numbers of samples (96 well or more). PMID- 25816251 TI - Oberholzeria (Fabaceae subfam. Faboideae), a new monotypic legume genus from Namibia. AB - Oberholzeria etendekaensis, a succulent biennial or short-lived perennial shrublet is described as a new species, and a new monotypic genus. Discovered in 2012, it is a rare species known only from a single locality in the Kaokoveld Centre of Plant Endemism, north-western Namibia. Phylogenetic analyses of molecular sequence data from the plastid matK gene resolves Oberholzeria as the sister group to the Genisteae clade while data from the nuclear rDNA ITS region showed that it is sister to a clade comprising both the Crotalarieae and Genisteae clades. Morphological characters diagnostic of the new genus include: 1) succulent stems with woody remains; 2) pinnately trifoliolate, fleshy leaves; 3) monadelphous stamens in a sheath that is fused above; 4) dimorphic anthers with five long, basifixed anthers alternating with five short, dorsifixed anthers, and 5) pendent, membranous, one-seeded, laterally flattened, slightly inflated but indehiscent fruits. PMID- 25816250 TI - Assessing glucose uptake through the yeast hexose transporter 1 (Hxt1). AB - The transport of glucose across the plasma membrane is mediated by members of the glucose transporter family. In this study, we investigated glucose uptake through the yeast hexose transporter 1 (Hxt1) by measuring incorporation of 2-NBDG, a non metabolizable, fluorescent glucose analog, into the yeast Saccharomyces cerevisiae. We find that 2-NBDG is not incorporated into the hxt null strain lacking all glucose transporter genes and that this defect is rescued by expression of wild type Hxt1, but not of Hxt1 with mutations at the putative glucose-binding residues, inferred from the alignment of yeast and human glucose transporter sequences. Similarly, the growth defect of the hxt null strain on glucose is fully complemented by expression of wild type Hxt1, but not of the mutant Hxt1 proteins. Thus, 2-NBDG, like glucose, is likely to be transported into the yeast cells through the glucose transport system. Hxt1 is internalized and targeted to the vacuole for degradation in response to glucose starvation. Among the mutant Hxt1 proteins, Hxt1N370A and HXT1W473A are resistant to such degradation. Hxt1N370A, in particular, is able to neither uptake 2-NBDG nor restore the growth defect of the hxt null strain on glucose. These results demonstrate 2-NBDG as a fluorescent probe for glucose uptake in the yeast cells and identify N370 as a critical residue for the stability and function of Hxt1. PMID- 25816249 TI - Multi-site clinical evaluation of DW-MRI as a treatment response metric for breast cancer patients undergoing neoadjuvant chemotherapy. AB - PURPOSE: To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information. MATERIALS AND METHODS: A total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3-7 days (Hull University), 8 11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (<1hr) MRI examinations, referred to as "test-retest" for examination of repeatability. To further evaluate stability in ADC measurements, a thermally controlled diffusion phantom was used to assess repeatability of diffusion measurements. MRI sequences included contrast-enhanced T1-weighted, when appropriate, and DW images acquired at b-values of 0 and 800 s/mm2. Histogram analysis and a voxel-based analytical technique, the Parametric Response Map (PRM), were used to derive diffusion response metrics for assessment of treatment response prediction. RESULTS: Mean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|DeltaADC|<0.1x10-3mm2/s). This data was used to calculate the 95% CI from the linear fit of tumor voxel ADC pairs of co registered examinations (+/-0.45x10-3mm2/s) for PRM analysis of treatment response. Receiver operating characteristic analysis identified the PRM metric to be predictive of outcome at the 8-11 (AUC = 0.964, p = 0.01) and 35 day (AUC = 0.770, p = 0.05) time points (p<.05) while whole-tumor ADC changes where significant at the later 35 day time interval (AUC = 0.825, p = 0.02). CONCLUSION: This study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements. PMID- 25816252 TI - A novel GTP-binding inhibitor, FX2149, attenuates LRRK2 toxicity in Parkinson's disease models. AB - Leucine-rich repeat kinase-2 (LRRK2), a cytoplasmic protein containing both GTP binding and kinase activities, has emerged as a highly promising drug target for Parkinson's disease (PD). The majority of PD-linked mutations in LRRK2 dysregulate its GTP binding and kinase activities, which may contribute to neurodegeneration. While most known LRRK2 inhibitors are developed to target the kinase domain, we have recently identified the first LRRK2 GTP binding inhibitor, 68, which not only inhibits LRRK2 GTP binding and kinase activities with high potency in vitro, but also reduces neurodegeneration. However, the in vivo effects of 68 are low due to its limited brain penetration. To address this problem, we reported herein the design and synthesis of a novel analog of 68, FX2149, aimed at increasing the in vivo efficacy. Pharmacological characterization of FX2149 exhibited inhibition of LRRK2 GTP binding activity by ~90% at a concentration of 10 nM using in vitro assays. Furthermore, FX2149 protected against mutant LRRK2-induced neurodegeneration in SH-SY5Y cells at 50 200 nM concentrations. Importantly, FX2149 at 10 mg/kg (i.p.) showed significant brain inhibition efficacy equivalent to that of 68 at 20 mg/kg (i.p.), determined by mouse brain LRRK2 GTP binding and phosphorylation assays. Furthermore, FX2149 at 10 mg/kg (i.p.) attenuated lipopolysaccharide (LPS)-induced microglia activation and LRRK2 upregulation in a mouse neuroinflammation model comparable to 68 at 20 mg/kg (i.p.). Our results highlight a novel GTP binding inhibitor with better brain efficacy, which represents a new lead compound for further understanding PD pathogenesis and therapeutic studies. PMID- 25816253 TI - Pediatric Disposition Classification (Reverse Triage) System to Create Surge Capacity. AB - BACKGROUND: Critically insufficient pediatric hospital capacity may develop during a disaster or surge event. Research is lacking on the creation of pediatric surge capacity. A system of "reverse triage," with early discharge of hospitalized patients, has been developed for adults and shows great potential but is unexplored in pediatrics. METHODS: We conducted an evidence-based modified Delphi consensus process with 25 expert panelists to derive a disposition classification system for pediatric inpatients on the basis of risk tolerance for a consequential medical event (CME). For potential validation, critical interventions (CIs) were derived and ranked by using a Likert scale to indicate CME risk should the CI be withdrawn or withheld for early disposition. RESULTS: Panelists unanimously agreed on a 5-category risk-based disposition classification system. The panelists established upper limit (mean) CME risk for each category as <2% (interquartile range [IQR]: 1-2%); 7% (5-10%), 18% (10-20%), 46% (20-65%), and 72% (50-90%), respectively. Panelists identified 25 CIs with varying degrees of CME likelihood if withdrawn or withheld. Of these, 40% were ranked high risk (Likert scale mean >=7) and 32% were ranked modest risk (<=3). CONCLUSIONS: The classification system has potential for an ethically acceptable risk-based taxonomy for pediatric inpatient reverse triage, including identification of those deemed safe for early discharge during surge events. PMID- 25816254 TI - ICRP: past, present, and future. AB - The International Commission on Radiological Protection (ICRP) is a premier international organisation for the protection of workers, patients, and the public against ionising radiation. It was established in 1928 to advance, for the public benefit, the science of radiological protection, with its work in the early years focusing mainly on occupational exposure in medicine. The name 'International Commission on Radiological Protection' was adopted in 1950 to reflect the wider and more diverse areas of work that were being undertaken. ICRP has published 13 sets of general recommendations and these form the basis of radiation safety standards worldwide. ICRP consists of the Main Commission and five standing committees. There are 84 official members of the Main Commission and Committees 1-5, but more than 200 members who work with ICRP through its task groups. ICRP has developed a strategic plan for 2011-2017 and has made progress with some of its initiatives. These include establishing close liaison with other radiological protection organisations, responding to the needs and concerns of the radiological protection community, and identifying areas of work that require scrutiny of science and practice to produce relevant recommendations. This strategy means that ICRP will continue to be a leader in radiological protection for many years to come. PMID- 25816255 TI - International Commission on Radiological Protection Committee 1: current status and future directions. AB - Commission 1 of the International Commission on Radiological Protection considers the risk of induction of cancer and heritable disease (stochastic effects) together with the underlying mechanisms of radiation action. Committee 1 also considers the risks, severity, and mechanisms of induction of tissue/organ damage and developmental defects (deterministic effects). The Committee was significantly revamped in 2013 and last met in Abu Dhabi in October 2013. Committee 1 evaluated progress on two ongoing task groups: Task Group 64 'Cancer Risk from Alpha Emitters' and Task Group 75 'Stem Cell Radiobiology'. Following approval from the Main Commission, Committee 1 established two new task groups: Task Group 91 'Radiation Risk Inference at Low Dose and Low Dose Rate Exposure for Radiological Protection Purposes' and Task Group 92 'Terminology and Definitions'. This article presents a synopsis of the current status of Committee 1 and outlines the tasks that Committee 1 may undertake in the future. PMID- 25816256 TI - Overview of ICRP Committee 2 'Doses from Radiation Exposure'. AB - Over many years, Committee 2 of the International Commission on Radiological Protection (ICRP) has provided sets of dose coefficients to allow users to evaluate equivalent and effective doses for intakes of radionuclides or exposure to external radiation for comparison with dose limits, constraints, and reference levels as recommended by ICRP. Following the 2007 Recommendations, Committee 2 and its task groups are engaged in a substantial programme of work to provide new dose coefficients for various conditions of radiation exposure. The methodology being applied in the calculation of doses can be regarded as state-of-the-art in terms of the biokinetic models used to describe the behaviour of inhaled and ingested radionuclides, and the dosimetric models used to model radiation transport for external and internal exposures. The level of sophistication of these models is greater than required for calculation of the protection quantities with their inherent simplifications and approximations, which were introduced necessarily, for example by the use of radiation and tissue weighting factors. However, ICRP is at the forefront of developments in this area, and its models are used for scientific as well as protection purposes. This overview provides an outline of recent work and future plans, including publications on dose coefficients for adults, children, and in-utero exposures, with new dosimetric phantoms in each case. The Committee has also recently finished a report on radiation exposures of astronauts in space, and is working with members of the other ICRP committees on the development of advice on the use of effective dose. PMID- 25816257 TI - Overview of ICRP Committee 3 'Protection in Medicine'. AB - According to the 2011-2017 strategic plan, Committee 3 develops recommendations and guidance for protection of patients, staff, and the public against radiation exposure when ionising radiation is used for medical diagnosis, therapy, or biomedical research. This paper presents an overview of the work that Committee 3 has accomplished in recent years and describes its current work. The International Commission on Radiological Protection reports dealing with radiological protection in medicine from 2000 to the present cover topics on education and training in radiological protection; preventing accidental exposures in radiation therapy; doses to patients from radiopharmaceuticals; radiation safety aspects of brachytherapy; release of patients after therapy with unsealed radionuclides; and managing radiation dose in interventional radiology, digital radiology, computed tomography, paediatrics, cardiology, and other medical specialties. Current work deals with radiological protection in ion beam therapy, occupational protection in brachytherapy, justification in imaging, radiological protection in cone-beam computed tomography, occupational protection in interventional procedures, diagnostic reference levels for diagnostic and interventional imaging, and an update of an earlier publication on doses to patients and staff from radiopharmaceuticals. Committee 3 is also involved in preparation of a document on effective dose and its use in medicine. PMID- 25816258 TI - Overview of ICRP Committee 5. AB - The International Commission on Radiological Protection (ICRP) established Committee 5 in 2005 in response to the need to provide direct demonstration of environmental protection from radiation in accordance with national law and international agreements. The development of the ICRP system for environmental protection was facilitated by research over the previous decades, as well as by ICRP's evaluation of the ethical and philosophical basis for environmental protection as laid out in ICRP Publication 91. The 2007 Recommendations (Publication 103) incorporated environmental protection as one of the integral elements of the radiation protection system. Over a relatively short time, the system has evolved to incorporate a set of 12 Reference Animals and Plants (RAPs), which is a small enough number to develop comprehensive databases for each RAP, but wide ranging enough to provide some insight into radiation impact and protection against such impact, as appropriate, in terrestrial, freshwater, and marine ecosystems. As necessary, the databases can be used to derive supplementary databases for Representative Organisms typical for a particular exposure situation of concern or under study. The system, to date, details biology of the RAPs (Publication 108); outlines transfer factors for estimation of internal concentrations of radionuclides of environmental significance under different situations (Publication 114); provides further information (Publication 108) on dosimetry, biological effects, and derived consideration reference levels (bands of environmental dose rates where potential detrimental effects may deserve attention); and provides information on application of the system in planned, emergency, and existing exposure situations (Publication 124). Currently, a review of experimental determinations of relative biological effectiveness, to guide derivation of specific weighting factors for use in environmental radiation protection if possible and necessary, is being concluded, as is work on improved dosimetry. Further work in this area involves consolidation of databases, recommendations for derivation of specific databases for Representative Organisms on the basis of the RAP data, and recommendations for application of the system to environmental protection in relation to certain human activities of potential environmental concern. Consideration needs to be made for the wider range of ecosystem effects that may be covered in ecological risk assessments, which incorporate the complete suite of stressors that result from human activity, and their effects, to understand the role of radiation effects in this context. PMID- 25816259 TI - Radiobiology of tissue reactions. AB - Tissue effects of radiation exposure are observed in virtually all normal tissues, with interactions when several organs are involved. Early reactions occur in turnover tissues, where proliferative impairment results in hypoplasia; late reactions, based on combined parenchymal, vascular, and connective tissue changes, result in loss of function within the exposed volume; consequential late effects develop through interactions between early and late effects in the same organ; and very late effects are dominated by vascular sequelae. Invariably, involvement of the immune system is observed. Importantly, latent times of late effects are inversely dependent on the biologically equieffective dose. Each tissue component and--importantly--each individual symptom/endpoint displays a specific dose-effect relationship. Equieffective doses are modulated by exposure conditions: in particular, dose-rate reduction--down to chronic levels--and dose fractionation impact on late responding tissues, while overall exposure time predominantly affects early (and consequential late) reactions. Consequences of partial organ exposure are related to tissue architecture. In 'tubular' organs (gastrointestinal tract, but also vasculature), punctual exposure affects function in downstream compartments. In 'parallel' organs, such as liver or lungs, only exposure of a significant (organ-dependent) fraction of the total volume results in clinical consequences. Forthcoming studies must address biomarkers of the individual risk for tissue reactions, and strategies to prevent/mitigate tissue effects after exposure. PMID- 25816260 TI - Threshold doses and circulatory disease risks. AB - Tissue reactions (deterministic effects) become manifest either early or late after doses above a threshold dose, which is the basis for recommended dose limits for avoiding such effects. Threshold doses have been defined for comparative purposes at 1% incidence of an effect, although the choice of incidence level may be scenario-dependent in practice. Latency time before manifestation is related to cell turnover rates and tissue complexity. In general, threshold doses become lower for longer follow-up times because of the slow progression of injury before manifestation, particularly after lower doses. Radiosensitive individuals may contribute to low threshold doses, which would provide a safety margin for the majority of a population. A threshold dose of 0.5 Gy was proposed for radiation-induced circulatory disease, after acute or chronic exposures, in the International Commission on Radiological Protection Publication 118. However, more recent meta-analyses of low-dose population studies suggest that, if a linear dose-incidence is assumed, the risk of some types of circulatory disease after doses <0.5 Gy or <10 mGy day(-1) may be positive and similar to that for induced cancer. Animal studies show that doses >2 Gy induce the expression of inflammatory and thrombotic molecules in endothelial cells. This causes progressive loss of capillaries in the heart and leads to reduced perfusion, myocardial cell death, and fibrosis. However, doses <1 Gy inhibit both inflammatory cell adhesion to endothelial cells and the development of atherosclerosis in mice. Different mechanisms of injury at low and high doses preclude the simple extrapolation of risk on a linear-quadratic basis from acute to chronic exposures. PMID- 25816261 TI - General tissue reactions and implications for radiation protection. AB - Non-cancer effects and risks at low doses from ionising radiation are controversial topics within the field of radiation protection. These issues are discussed in International Commission on Radiological Protection (ICRP) Publication 118, 'ICRP statement on tissue reactions'. Both non-cancer effects and risks are expected to become increasingly important to the system of radiation protection. Before this can happen, several factors must be considered: thorough characterisation of the relationship between dose and risk; verification of the biological mechanisms for any noted excess risk; and adjustment of noted excess risks through the use of a detriment factor. It is difficult to differentiate the relatively small risks associated with radiation from other risk factors in the low-dose region of the dose-response curve. Several recent papers have indicated the possibility of a non-linear dose-response relationship for non-cancer effects. In addition, there are still many uncertainties associated with the biological mechanisms for non-cancer effects. Finally, it is essential to consider the incorporation of detriment into a well-defined system of radiological protection. Given the recent interest in non-cancer effects, it is essential to facilitate discussions in order to define dose limits more clearly within the existing system of radiation protection for both cancer and non-cancer effects. PMID- 25816262 TI - The lens of the eye: exposures in the UK medical sector and mechanistic studies of radiation effects. AB - The recommendation from the International Commission on Radiological Protection that the occupational equivalent dose limit for the lens of the eye should be reduced to 20 mSv year(-1), averaged over 5 years with no year exceeding 50 mSv, has stimulated a discussion on the practicalities of implementation of this revised dose limit, and the most appropriate risk and protection framework to adopt. This brief paper provides an overview of some of the drivers behind the move to a lower recommended dose limit. The issue of implementation in the medical sector in the UK has been addressed through a small-scale survey of doses to the lens of the eye amongst interventional cardiologists and radiologists. In addition, a mechanistic study of early and late post-irradiation changes in the lens of the eye in in-vivo-exposed mice is outlined. Surveys and studies such as those described can contribute to a deeper understanding of fundamental and practical issues, and therefore contribute to a robust evidence base for ensuring adequate protection of the eye while avoiding undesirable restrictions to working practices. PMID- 25816263 TI - Dosimetric models of the eye and lens of the eye and their use in assessing dose coefficients for ocular exposures. AB - Based upon recent epidemiological studies of ocular exposure, the Main Commission of the International Commission on Radiological Protection (ICRP) in ICRP Publication 118 states that the threshold dose for radiation-induced cataracts is now considered to be approximately 0.5 Gy for both acute and fractionated exposures. Consequently, a reduction was also recommended for the occupational annual equivalent dose to the lens of the eye from 150 mSv to 20 mSv, averaged over defined periods of 5 years. To support ocular dose assessment and optimisation, Committee 2 included Annex F within ICRP Publication 116 . Annex F provides dose coefficients - absorbed dose per particle fluence - for photon, electron, and neutron irradiation of the eye and lens of the eye using two dosimetric models. The first approach uses the reference adult male and female voxel phantoms of ICRP Publication 110. The second approach uses the stylised eye model of Behrens et al., which itself is based on ocular dimensional data given in Charles and Brown. This article will review the data and models of Annex F with particular emphasis on how these models treat tissue regions thought to be associated with stem cells at risk. PMID- 25816264 TI - Dose limits to the lens of the eye: International Basic Safety Standards and related guidance. AB - The International Atomic Energy Agency (IAEA) safety requirements: 'General Safety Requirements Part 3--Radiation protection and safety of radiation sources: International Basic Safety Standards' (BSS) was approved by the IAEA Board of Governors at its meeting in September 2011, and was issued as General Safety Requirements Part 3 in July 2014. The equivalent dose limit for the lens of the eye for occupational exposure in planned exposure situations was reduced from 150 mSv year(-1) to 20 mSv year(-1), averaged over defined periods of 5 years, with no annual dose in a single year exceeding 50 mSv. This reduction in the dose limit for the lens of the eye followed the recommendation of the International Commission on Radiological Protection in its statement on tissue reactions of 21 April 2011. IAEA has developed guidance on the implications of the new dose limit for the lens of the eye. This paper summarises the process that led to the inclusion of the new dose limit for the lens of the eye in the BSS, and the implications of the new dose limit. PMID- 25816265 TI - Implications in medical imaging of the new ICRP thresholds for tissue reactions. AB - The International Commission on Radiological Protection (ICRP) statement on tissue reactions, issued by the Commission in April 2011, reviewed epidemiological evidence and suggested that there are some tissue reactions where threshold doses are or may be lower than those previously considered. For the lens of the eye, the threshold is now considered to be 0.5 Gy. The absorbed dose threshold for circulatory disease in the heart and brain may be as low as 0.5 Gy. These values can be reached in some patients during interventional cardiology or neuroradiology procedures. They may also be of concern for repeated computed tomography examinations of the head. The new thresholds should be considered in optimisation strategies for clinical procedures, especially in patients likely to require repeated interventions. The new dose thresholds also affect occupational protection for operators and staff. Some operators do not protect their eyes or their brain adequately. After several years of work without proper protection, the absorbed doses to the lens of the eye and the brain of staff can exceed 0.5 Gy. More research is needed to understand the biological effects of cumulative incident air kerma and the instantaneous air kerma rates currently used in medical imaging. The new thresholds, and the need for specific occupational dosimetry related to lens doses, should be considered in radiation protection programmes, and should be included in the education and training of professionals involved in fluoroscopy guided procedures and computed tomography. PMID- 25816266 TI - Non-cancer effects: science and values aspects of protection decisions. AB - The Nuclear Energy Agency organised its third workshop on 'Science and values in radiological protection' in November 2012 in Tokyo. One of the issues addressed, non-cancer effects, had also been addressed in the first two science and values workshops (Helsinki, Finland, 2008; Vaux-de-Cernay, France, 2009), but presented several new elements of relevance to International Commission on Radiological Protection discussions of the evolution of the system of radiological protection. Radiological protection science, both epidemiological and biological, now suggests that stroke and heart disease may well be caused by radiation exposure at doses of the order of 0.5 Gy or less. Further, it is possible that such detriments may be caused by either chronic or acute exposures. While significant uncertainties remain, the need to consider non-cancer detriment in risk assessment and in the development of protection strategies is now a significant scientific and ethical question. This paper will present the results of the Nuclear Energy Agency science and values workshop discussion of non-cancer risks, and of the questions and possible future directions raised during the workshop. PMID- 25816267 TI - Implications of the implementation of the revised dose limit to the lens of the eye: the view of IRPA professionals. AB - In April 2011, the International Commission on Radiological Protection issued a statement on reduction of the equivalent dose limits for the lens of the eye, and strongly recommended its consideration in the revision of the International Atomic Energy Agency's International Basic Safety Standards on Radiation Protection. The reduced dose limit was incorporated in the final version of the Basic Safety Standards. As significant concern was expressed by radiation protection professionals worldwide, the International Radiation Protection Association (IRPA) established a task group to assess the impact of implementation of the revised dose limit for the lens of the eye for occupational exposure. IRPA Associate Societies (ASs) were asked for their views using a questionnaire addressing three topics: implications for dosimetry, implications for methods of protection, and wider implications. The responses received indicate various methods of approach and express different points of view, reflecting nuances of particular ASs or specific professional groups. Topic experts nominated by ASs were selected to assist with collation of responses, and a report was produced by the task group. Conclusions were drawn on the three issues, including potential cost implications. A number of recommendations were drawn from the responses received including: the request for more understanding about the relationship between exposure of the lens of the eye and cataract formation, and further guidance to assist implementation; the importance of economic and social considerations when introducing the limits into national regulations; the need to propose or define procedures related to employment of people with existing or pre-cataract conditions; and the practical aspects relating to dosimetry and protective equipment. PMID- 25816268 TI - Engaging with local stakeholders: some lessons from Fukushima for recovery. AB - The Fukushima Daiichi nuclear power plant accident contaminated the soil of densely populated regions in Fukushima prefecture with radioactive caesium, which poses significant risks of internal and external exposure to the residents. Applying the knowledge of post-Chernobyl accident studies, internal exposures in excess of a few mSv per year would be expected to be common in Fukushima. However, extensive whole-body-counter surveys have shown that the internal exposure levels of residents are much lower than estimated; in 2012-2013, the Cs 137 detection percentages (the detection limit being ~300 Bq body(-1)) were approximately 1% for adults and practically 0% for children. These results are consistent with those of many other measurements/studies conducted to date in Fukushima. As a consequence, risks from external exposure assume greater importance for the majority of residents in Fukushima due to the lower contribution from internal exposure. In both cases, average doses remain low, although some residents are exposed to higher-than-average risks; it is these members of the population who need to be identified and followed-up. Consequently, it is essential to re-establish communication at all levels in society. PMID- 25816269 TI - Experience and current issues with recovery management from the Fukushima accident. AB - This paper describes the experiences of, and issues with, recovery management following the accident at Fukushima Daiichi nuclear power plant. The Fukushima accident has brought about socio-economic consequences with inevitable changes to daily life, as well as psychological effects. There is heightened concern amongst the population about the risk and effects of radiation at low doses. Experience has shown that the direct involvement of the affected population and local professionals is a decisive factor for management of the recovery phase. The radiological protection system of the International Commission on Radiological Protection (ICRP) seems to be relevant to the recovery requirements of the Fukushima accident, although some problems remain in implementation. Reference levels could play a role in improving the situation by requiring an iterative optimisation process. The Fukushima experience indicated that a routine, top-down approach using radiological criteria alone was unable to deal with the complexity of the problems, and that stakeholder engagement should be explored. The technical knowledge gap between radiation experts and the public caused a lot of confusion. Experts should understand the ethical values attached to recovery, and ICRP should be more active in promoting trustworthy radiological protection advice. PMID- 25816270 TI - Decision making for late-phase recovery from nuclear or radiological incidents: new guidance from NCRP. AB - In 2010, the US National Council on Radiation Protection and Measurements (NCRP) established a scientific committee (SC5-1) to prepare a comprehensive report on the framework and approach for optimising decision making in late-phase recovery from nuclear or radiological incidents that lead to wide-area contamination. The NCRP report builds on recommendations from the International Commission on Radiological Protection's (ICRP) Publication 111 which specifically addresses the protection of people living in long-term contaminated areas. Based on this approach, the report addresses all relevant dimensions: health, environment, economic, psychological, cultural, ethical, and political. NCRP, like ICRP, considers optimisation to be the best approach to decision making for balancing these multiple risk factors in situations involving wide-area contamination where the conventional clean-up approach may encounter some serious constraints. The NCRP report describes optimisation as an iterative process that can be broken down into a series of steps, all of which involve deliberations with stakeholders as a necessary element for a community-focused recovery effort. The steps, elaborated on in the report, range from defining the situation to a series of actions involving assessing impacts, evaluating options, developing a strategy, and demonstrating its successful implementation. In conclusion, the NCRP report makes a series of recommendations aimed at enhancing and strengthening late-phase recovery following a major nuclear or radiological incident. PMID- 25816271 TI - Review of the ICRP system of protection: the approach to existing exposure situations. AB - The International Commission on Radiological Protection (ICRP) system of protection consists of existing, planned, and emergency exposure situations. With the 2007 Recommendations in ICRP Publication 103, a coherent approach has been established that emphasises the optimisation of protection with appropriate constraints or reference levels in each exposure situation. Existing exposure situations pose unique challenges because the source of exposure already exists, and it may not always be possible to control the source directly. This is the case for naturally occurring sources, which are ubiquitous in the environment and vary widely in the magnitude of exposures that may be received by individuals. Decisions on protection strategies must consider a graded, pragmatic, and flexible approach for dealing with exposure of members of the public, and those that may be occupationally exposed while working with naturally occurring sources. Although limits are not applicable, aspects of the management approach for planned exposure situations may be appropriate, depending upon the magnitude of exposures. PMID- 25816272 TI - Application of the Commission's recommendations to naturally occurring radioactive material. AB - Since publication of the 2007 Recommendations (ICRP Publication 103), the International Commission on Radiological Protection has focused on preparing a series of publications dedicated to different types of existing exposure situations, such as radon exposure, cosmic exposure in aviation, and exposure to naturally occurring radioactive material (NORM). The publication related to NORM will present the main types of corresponding activities, and describe the characteristics of NORM exposure. It will also develop a conceptual framework for the practical application of the Commission's system to NORM exposure. In particular, the publication will explain why NORM activities are generally considered to be existing exposure situations, and when some of them should be managed as planned exposure situations. It will indicate when the workers should be considered as occupationally exposed. It will also provide recommendations regarding application of the three principles of radiological protection. The need to consider the justification of the re-use or recycling of residues carefully will be highlighted. Guidance will be provided for selection of the reference level, and for implementation of the optimisation process through a graded approach including both prevention and mitigation of exposures. Flexibility will be recommended for the application of dose limits, notably when the situation is managed as a planned exposure situation. PMID- 25816273 TI - What should a radiation regulator do about naturally occurring radioactive material? AB - The standard regulatory framework of authorisation, review and assessment, inspection and enforcement, and regulation making is directed principally towards ensuring the regulatory control of planned exposure situations. Some mining and industrial activities involving exposures to naturally occurring radioactive material (NORM), such as uranium mining or the treatment and conditioning of NORM residues, may fit readily within this standard framework. In other cases, such as oil and gas exploration and production, the standard regulatory framework needs to be adjusted. For example, it is not sensible to require that an oil company seek a licence from the radiation regulator before drilling a well. The paper discusses other approaches that a regulator might take to assure protection and safety in such activities involving exposures to NORM, including the use of conditional exemptions from regulatory controls. It also suggests some areas where further guidance from the International Commission on Radiological Protection on application of the system of radiological protection to NORM would assist both regulators and operators. PMID- 25816274 TI - Radiological protection in North American naturally occurring radioactive material industries. AB - All soils and rocks contain naturally occurring radioactive material (NORM). Many ores and raw materials contain relatively high levels of natural radionuclides, and processing such materials can further increase the concentrations of natural radionuclides, sometimes referred to as 'technologically enhanced naturally occurring radioactive material' (TENORM). Examples of NORM minerals include uranium ores, monazite (a source of rare earth minerals), and phosphate rock used to produce phosphate fertiliser. Such activities have the potential to result in above background radiation exposure to workers and the public. The objective of this paper is to review the sources and exposure from NORM in North American industries, and provide a perspective on the potential radiological hazards to workers and the environment. Proper consideration of NORM issues is important and needs to be integrated in the assessment of these projects. Concerns over radioactivity and radiation amongst non-governmental organisations and the local public have resulted in the cancellation of NORM mining and mineral extraction projects, as well as inhibition of the safe use of by-product materials from various NORM industries. This paper also briefly comments on the current regulatory framework for NORM (TENORM) in Canada and the USA, as well as the potential implications of the recent activities of the International Commission on Radiological Protection for NORM industries. PMID- 25816276 TI - ICRP's approach to protection of the living environment under different exposure situations. AB - The International Commission on Radiological Protection's (ICRP) system to protect the living components of the environment is designed to provide a broad and practical framework across all exposure situations. The objectives of ICRP are therefore also set in fairly broad terms, recognising that national and local environmental protection requirements may need to be set within them. The framework recognises the need to be able to demonstrate an adequate level of protection in relation to planned exposure situations, whilst also providing an ability to manage existing situations and accidents, as well as emergency situations, in a rational way. The objects of protection are always real biota in real exposure situations, and the scientific basis for their protection needs to be based on data originating from studies on the relationships between exposure and dose, dose and effects, and effects and consequences in real animals and plants. The framework that has been developed has therefore had to take such realities into account to make the optimum use of the data currently available, whilst being sufficiently flexible to accommodate new scientific information as it arises without having to alter the framework as a whole. PMID- 25816275 TI - Construction of a naturally occurring radioactive material project in the BeAAT hazardous waste facilities. AB - This paper does not necessarily reflect the views of the International Commission on Radiological Protection. Naturally occurring radioactive material (NORM) is produced during exploration and production operations of subsidiaries of the Abu Dhabi National Oil Company (ADNOC) in the United Arab Emirates, and accumulates in drilling tubulars, plant equipment, and components. These NORM hazardous wastes need to be managed in such a way that they do not damage human health and the environment. The primary radionuclides of concern in the oil and gas industries are radium-226 and radium-228. These radioisotopes are the decay products of uranium and thorium isotopes that are present in subsurface formations from which hydrocarbons are produced. While uranium and thorium are largely immobile, radium is slightly more soluble and may become mobilised in the fluid phases of the formation (International Association of Oil & Gas Producers, 2008). In order to treat and dispose of NORM waste products safely, ADNOC's subsidiary 'TAKREER' is developing a new facility, on behalf of all ADNOC subsidiaries, within the existing Central Environmental Protection Facilities (BeAAT) in Ruwais city. The NORM plant is envisaged to treat, handle, and dispose of NORM waste in the forms of scale, sludge, and contaminated equipment. The NORM treatment facility will cover activities such as decontamination, volume reduction, NORM handling, and concrete immobilisation of NORM waste into packages for designated landfilling. PMID- 25816277 TI - Establishing relationships between environmental exposures to radionuclides and the consequences for wildlife: inferences and weight of evidence. AB - Ecological risk assessments for radioactive substances are based on a number of inference rules to compensate for knowledge gaps, and generally require the implementation of a weight-of-evidence approach. Until recently, dose (rate) response relationships used to derive radioprotection criteria for wildlife have mainly relied on laboratory studies from a limited number of species as representatives of biodiversity. There is no doubt that additional knowledge, combined with advanced conceptual and mathematical approaches, is needed to develop general rules and increase confidence when extrapolating from test species to complex biological/ecological systems. Moreover, field data sets based on robust sampling strategies are still needed to validate benchmark values derived from controlled laboratory tests, and to indicate potential indirect ecological effects, if any. This paper illustrates, through several examples, the need for implementing a combined laboratory-field-model approach to obtain science-based benchmark doses (or dose rates) (e.g. screening benchmarks for ecological risk assessments or derived consideration reference levels), based on robust meta-analysis of dose-effect relationships covering ecologically relevant exposure time scales, species, and endpoints. PMID- 25816278 TI - Use of the ICRP system for the protection of marine ecosystems. AB - The International Commission on Radiological Protection (ICRP) recently reinforced the international system of radiological protection, initially focused on humans, by identifying principles of environmental protection and proposing a framework for assessing impacts of ionising radiation on non-human species, based on a reference flora and fauna approach. For this purpose, ICRP developed dosimetric models for a set of Reference Animals and Plants, which are representative of flora and fauna in different environments (terrestrial, freshwater, marine), and produced criteria based on information on radiation effects, with the aim of evaluating the level of potential or actual radiological impacts, and as an input for decision making. The approach developed by ICRP for flora and fauna is consistent with the approach used to protect humans. The International Atomic Energy Agency (IAEA) includes considerations on the protection of the environment in its safety standards, and is currently developing guidelines to assess radiological impacts based on the aforementioned ICRP approach. This paper presents the method developed by IAEA, in a series of meetings with international experts, to enable assessment of the radiological impact to the marine environment in connection with the Convention on the Prevention of Marine Pollution by Dumping of Wastes and Other Matter 1972 (London Convention 1972). This method is based on IAEA's safety standards and ICRP's recommendations, and was presented in 2013 for consideration by representatives of the contracting parties of the London Convention 1972; it was approved for inclusion in its procedures, and is in the process of being incorporated into guidelines. PMID- 25816279 TI - Radiological protection in computed tomography and cone beam computed tomography. AB - The International Commission on Radiological Protection (ICRP) has sustained interest in radiological protection in computed tomography (CT), and ICRP Publications 87 and 102 focused on the management of patient doses in CT and multi-detector CT (MDCT) respectively. ICRP forecasted and 'sounded the alarm' on increasing patient doses in CT, and recommended actions for manufacturers and users. One of the approaches was that safety is best achieved when it is built into the machine, rather than left as a matter of choice for users. In view of upcoming challenges posed by newer systems that use cone beam geometry for CT (CBCT), and their widened usage, often by untrained users, a new ICRP task group has been working on radiological protection issues in CBCT. Some of the issues identified by the task group are: lack of standardisation of dosimetry in CBCT; the false belief within the medical and dental community that CBCT is a 'light', low-dose CT whereas mobile CBCT units and newer applications, particularly C-arm CT in interventional procedures, involve higher doses; lack of training in radiological protection among clinical users; and lack of dose information and tracking in many applications. This paper provides a summary of approaches used in CT and MDCT, and preliminary information regarding work just published for radiological protection in CBCT. PMID- 25816280 TI - Patient dose monitoring in Dubai in radiography and interventional procedures. AB - This paper presents ongoing actions in Dubai on patient dose monitoring in digital radiographic examinations, mammography, interventional procedures, and dental radiological procedures. The aim of Dubai Health Authority (DHA) is to move towards the establishment of local diagnostic reference levels. DHA has participated in national and regional projects under the umbrella of the International Atomic Energy Agency. The need for local radiation protection educational programmes and wider patient dosimetry monitoring and recording emerged from this work. PMID- 25816281 TI - Radiation epidemiology and recent paediatric computed tomography studies. AB - Recent record-linkage studies of cancer risk following computed tomography (CT) procedures among children and adolescents under 21 years of age must be interpreted with caution. The reasons why the examinations were performed were not known, and the dosimetric approaches did not include individual dose reconstructions or account for the possibility for missed examinations. The recent report (2013) on children by the United Nations Scientific Committee on the Effects of Atomic Radiation concluded that the associations may have resulted from confounding by indication (also called 'reverse causation'), and not radiation exposure. The reported cancer associations may very well have been related to the patients' underlying health conditions that prompted the examinations. Reverse causation has been observed in other epidemiological investigations, such as a Swedish study of thyroid cancer risk following I-131 scintillation imaging scans, and in studies of brain cancer risk following Thorotrast for cerebral angiography. Epidemiological patterns reported in the CT studies were also inconsistent with the world's literature. For example, in a UK study, teenagers had a higher risk of brain tumour than young children; in an Australian study, cancers not previously linked to radiation were significantly elevated; and in a Taiwanese study, the risk of benign tumours decreased with age at the time of CT examination. In all studies, solid tumours appeared much earlier than previously reported. Remarkably, in the Australian study, brain cancer excesses were seen regardless of whether or not the CT was to the head, i.e. a significant excess was reported for CT examinations of the abdomen and extremities, which involved no radiation exposure to the brain. In the UK study, the significance of the 'leukaemia' finding was only because myelodysplastic syndrome was added to the category, and there was no significance for leukaemia alone. Without knowledge of why CT examinations were performed, any future studies will be equally difficult to interpret. It is noteworthy that two recent studies of children in France and Germany found no significant excess cancer risk from CT scans once adjustment was made for conditions that prompted the scan, family history, or other predisposing factors known to be associated with increased cancer risk. Nonetheless, such studies have heightened awareness of these relatively high-dose diagnostic procedures, and the need to reduce unnecessary examinations and lower the dose per examination commensurate with the desired image quality. PMID- 25816282 TI - Use of effective dose in medicine. AB - This paper does not necessarily reflect the views of the International Commission on Radiological Protection. The protection quantity 'effective dose' was developed by the International Commission on Radiological Protection (ICRP) for use in the radiological protection of workers and the public. In this context, it is used as a risk-adjusted dosimetric quantity to optimise protection, comparing received or planned doses with constraints, reference levels, and limits expressed in the same quantity. Considering exposures incurred during medical procedures, effective dose can be of practical value for comparing: doses from different diagnostic examinations and interventional procedures; the use of similar technologies and procedures in different hospitals and countries; and the use of different technologies for the same medical examination, provided that the representative patients or patient populations for which the effective doses are derived are similar with regard to age and sex. However, as stated in ICRP Publication 103, '... risk assessment for medical diagnosis and treatment... is best evaluated using appropriate risk values for the individual tissues at risk and for the age and sex distribution of the individuals undergoing the medical procedures'. This topic was explored in a session of the First ICRP Symposium with arguments for and against the use of a new quantity referred to as 'effective risk', and examination of variations in estimated risk for different diagnostic procedures according to the age and sex of the exposed individuals. This paper restates the primary purposes of effective dose, and summarises estimates of variation in individual risk from medical procedures. The authors support the judicious use of effective dose as an indicator of possible risk, but caution against the use of effective risk as compared with the calculation of scientific best estimates of risk with consideration of associated uncertainties. PMID- 25816283 TI - Exposures and effects in the marine environment after the Fukushima accident. AB - This paper does not necessarily reflect the views of the International Commission on Radiological Protection. Radiation doses to marine biota near the Fukushima Daiichi nuclear power plant have been estimated for the immediate aftermath and subsequent period of the accident. Dose estimations using monitoring data have been complemented by means of dynamic transfer modelling, improving on the more traditional equilibrium transfer approach. Earlier assessments using equilibrium transfer models overestimated the exposures in the immediate aftermath of the accident, whereas dynamic transfer modelling brings them more in line with the doses calculated from monitored activity concentrations in the biota. On that basis, marine biota populations in the vicinity of Fukushima do not seem to be at significant risk. The situation in the late post-accident period shows a tendency for lower exposures, but radiocaesium in sediments and biota persists to this day, with some organisms inhabiting local hotspots. Little is known about how long radionuclides will continue to remain in the local environment, or the long term effects on populations due to limited knowledge on the effects of chronic radiation exposures to marine organisms. Therefore, the marine environment at Fukushima needs further study. The Fukushima nuclear accident remains an ongoing problem for marine radioecology, requiring constant re-evaluation of the cumulative extent of contamination and effects on the environment for years to come. PMID- 25816284 TI - MicroRNA profiling of atrial fibrillation in canines: miR-206 modulates intrinsic cardiac autonomic nerve remodeling by regulating SOD1. AB - BACKGROUND: A critical mechanism in atrial fibrillation (AF) is cardiac autonomic nerve remodeling (ANR). MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Numerous miRNAs are involved in diseases of the nervous and cardiovascular systems. OBJECTIVE: We aimed to assess the underlying role of miRNAs in regulating cardiac ANR in AF by right atrial tachypacing (A-TP) in canines. METHODS AND RESULTS: Following 4-week A-TP, the superior left ganglionated plexuses (SLGPs), which are embedded in the fat pads of the left atrium, were subjected to miRNA expression profiling to screen preferentially expressed miRNAs. Sixteen miRNAs showed significantly differential expression between the control and A-TP groups, including miR-206, miR-203, miR-224 and miR-137. In particular, we focused on miR-206, which was elevated ~10-fold in A-TP dogs. Forced expression of miR-206 through lentiviral infection based on A-TP in vivo significantly shortened the atrial effective refractory period (AERP) (81 +/- 7 vs. 98 +/- 7 ms, P < 0.05). Immunohistochemical analysis showed that the regeneration of nerves increased more than 2-fold by miR-206 overexpression (P < 0.01). The expression of superoxide dismutase 1 (SOD1) was repressed by miR-206 overexpression by Western blot and luciferase assay, indicative of SOD1 as a direct target of miR-206. Overexpression of miR-206 increased reactive oxygen species (ROS) levels in vitro and in vivo, whereas miR-206 silencing attenuated irradiation- or A-TP-induced ROS. Knockdown of SOD1 effectively abolished ROS reduction caused by miR-206 silencing. CONCLUSIONS: Our results found the differential expression of miRNAs in response to ANR in AF and elucidated the important role of miR-206 by targeting SOD1. The study illustrated the novel molecular mechanism of ANR and indicated a potential therapeutic target for AF. PMID- 25816285 TI - Improving the performance of an EEG-based motor imagery brain computer interface using task evoked changes in pupil diameter. AB - For individuals with high degrees of motor disability or locked-in syndrome, it is impractical or impossible to use mechanical switches to interact with electronic devices. Brain computer interfaces (BCIs) can use motor imagery to detect interaction intention from users but lack the accuracy of mechanical switches. Hence, there exists a strong need to improve the accuracy of EEG-based motor imagery BCIs attempting to implement an on/off switch. Here, we investigate how monitoring the pupil diameter of a person as a psycho-physiological parameter in addition to traditional EEG channels can improve the classification accuracy of a switch-like BCI. We have recently noticed in our lab (work not yet published) how motor imagery is associated with increases in pupil diameter when compared to a control rest condition. The pupil diameter parameter is easily accessible through video oculography since most gaze tracking systems report pupil diameter invariant to head position. We performed a user study with 30 participants using a typical EEG based motor imagery BCI. We used common spatial patterns to separate motor imagery, signaling movement intention, from a rest control condition. By monitoring the pupil diameter of the user and using this parameter as an additional feature, we show that the performance of the classifier trying to discriminate motor imagery from a control condition improves over the traditional approach using just EEG derived features. Given the limitations of EEG to construct highly robust and reliable BCIs, we postulate that multi-modal approaches, such as the one presented here that monitor several psycho-physiological parameters, can be a successful strategy in making BCIs more accurate and less vulnerable to constraints such as requirements for long training sessions or high signal to noise ratio of electrode channels. PMID- 25816286 TI - An integrative approach for modeling and simulation of heterocyst pattern formation in cyanobacteria filaments. AB - Heterocyst differentiation in cyanobacteria filaments is one of the simplest examples of cellular differentiation and pattern formation in multicellular organisms. Despite of the many experimental studies addressing the evolution and sustainment of heterocyst patterns and the knowledge of the genetic circuit underlying the behavior of single cyanobacterium under nitrogen deprivation, there is still a theoretical gap connecting these two macroscopic and microscopic processes. As an attempt to shed light on this issue, here we explore heterocyst differentiation under the paradigm of systems biology. This framework allows us to formulate the essential dynamical ingredients of the genetic circuit of a single cyanobacterium into a set of differential equations describing the time evolution of the concentrations of the relevant molecular products. As a result, we are able to study the behavior of a single cyanobacterium under different external conditions, emulating nitrogen deprivation, and simulate the dynamics of cyanobacteria filaments by coupling their respective genetic circuits via molecular diffusion. These two ingredients allow us to understand the principles by which heterocyst patterns can be generated and sustained. In particular, our results point out that, by including both diffusion and noisy external conditions in the computational model, it is possible to reproduce the main features of the formation and sustainment of heterocyst patterns in cyanobacteria filaments as observed experimentally. Finally, we discuss the validity and possible improvements of the model. PMID- 25816287 TI - Cessation of mass drug administration for lymphatic filariasis in Zanzibar in 2006: was transmission interrupted? AB - BACKGROUND: Lymphatic filariasis (LF) is targeted for elimination through annual mass drug administration (MDA) for 4-6 years. In 2006, Zanzibar stopped MDA against LF after five rounds of MDA revealed no microfilaraemic individuals during surveys at selected sentinel sites. We asked the question if LF transmission was truly interrupted in 2006 when MDA was stopped. METHODOLOGY/PRINCIPAL FINDINGS: In line with ongoing efforts to shrink the LF map, we performed the WHO recommended transmission assessment surveys (TAS) in January 2012 to verify the absence of LF transmission on the main Zanzibar islands of Unguja and Pemba. Altogether, 3275 children were tested on both islands and 89 were found to be CFA positive; 70 in Pemba and 19 in Unguja. The distribution of schools with positive children was heterogeneous with pronounced spatial variation on both islands. Based on the calculated TAS cut-offs of 18 and 20 CFA positive children for Pemba and Unguja respectively, we demonstrated that transmission was still ongoing in Pemba where the cut-off was exceeded. CONCLUSIONS: Our findings indicated ongoing transmission of LF on Pemba in 2012. Moreover, we presented evidence from previous studies that LF transmission was also active on Unguja shortly after stopping MDA in 2006. Based on these observations the government of Zanzibar decided to resume MDA against LF on both islands in 2013. PMID- 25816288 TI - Comparative genomic analysis reveals a critical role of de novo nucleotide biosynthesis for Saccharomyces cerevisiae virulence. AB - In recent years, the number of human infection cases produced by the food related species Saccharomyces cerevisiae has increased. Whereas many strains of this species are considered safe, other 'opportunistic' strains show a high degree of potential virulence attributes and can cause infections in immunocompromised patients. Here we studied the genetic characteristics of selected opportunistic strains isolated from dietary supplements and also from patients by array comparative genomic hybridization. Our results show increased copy numbers of IMD genes in opportunistic strains, which are implicated in the de novo biosynthesis of the purine nucleotides pathway. The importance of this pathway for virulence of S. cerevisiae was confirmed by infections in immunodeficient murine models using a GUA1 mutant, a key gene of this pathway. We show that exogenous guanine, an end product of this pathway in its triphosphorylated form, increases the survival of yeast strains in ex vivo blood infections. Finally, we show the importance of the DNA damage response that activates dNTP biosynthesis in yeast cells during ex vivo blood infections. We conclude that opportunistic yeasts may use an enhanced de novo biosynthesis of the purine nucleotides pathway to increase survival and favor infections in the host. PMID- 25816289 TI - Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what's the evidence? A systematic review with meta-analysis. AB - OBJECTIVE: Conflicting conclusions have been published regarding breast cancer survival of BRCA1/2 mutation carriers. Here we provide an evidence-based systematic literature review. METHODS: Eligible publications were observational studies assessing the survival of breast cancer patients carrying a BRCA1/2 mutation compared to non-carriers or the general breast cancer population. We performed meta-analyses and best-evidence syntheses for survival outcomes taking into account study quality assessed by selection bias, misclassification bias and confounding. RESULTS: Sixty-six relevant studies were identified. Moderate evidence for a worse unadjusted recurrence-free survival for BRCA1 mutation carriers was found. For BRCA1 and BRCA2 there was a tendency towards a worse breast cancer-specific and overall survival, however, results were heterogeneous and the evidence was judged to be indecisive. Surprisingly, only 8 studies considered adjuvant treatment as a confounder or effect modifier while only two studies took prophylactic surgery into account. Adjustment for tumour characteristics tended to shift the observed risk estimates towards a relatively more favourable survival. CONCLUSIONS: In contrast to currently held beliefs of some oncologists, current evidence does not support worse breast cancer survival of BRCA1/2 mutation carriers in the adjuvant setting; differences if any are likely to be small. More well-designed studies are awaited. PMID- 25816290 TI - Model-independent phenotyping of C. elegans locomotion using scale-invariant feature transform. AB - To uncover the genetic basis of behavioral traits in the model organism C. elegans, a common strategy is to study locomotion defects in mutants. Despite efforts to introduce (semi-)automated phenotyping strategies, current methods overwhelmingly depend on worm-specific features that must be hand-crafted and as such are not generalizable for phenotyping motility in other animal models. Hence, there is an ongoing need for robust algorithms that can automatically analyze and classify motility phenotypes quantitatively. To this end, we have developed a fully-automated approach to characterize C. elegans' phenotypes that does not require the definition of nematode-specific features. Rather, we make use of the popular computer vision Scale-Invariant Feature Transform (SIFT) from which we construct histograms of commonly-observed SIFT features to represent nematode motility. We first evaluated our method on a synthetic dataset simulating a range of nematode crawling gaits. Next, we evaluated our algorithm on two distinct datasets of crawling C. elegans with mutants affecting neuromuscular structure and function. Not only is our algorithm able to detect differences between strains, results capture similarities in locomotory phenotypes that lead to clustering that is consistent with expectations based on genetic relationships. Our proposed approach generalizes directly and should be applicable to other animal models. Such applicability holds promise for computational ethology as more groups collect high-resolution image data of animal behavior. PMID- 25816291 TI - Decorin binding proteins of Borrelia burgdorferi promote arthritis development and joint specific post-treatment DNA persistence in mice. AB - Decorin binding proteins A and B (DbpA and B) of Borrelia burgdorferi are of critical importance for the virulence of the spirochete. The objective of the present study was to further clarify the contribution of DbpA and B to development of arthritis and persistence of B. burgdorferi after antibiotic treatment in a murine model of Lyme borreliosis. With that goal, mice were infected with B. burgdorferi strains expressing either DbpA or DbpB, or both DbpA and B, or with a strain lacking the adhesins. Arthritis development was monitored up to 15 weeks after infection, and bacterial persistence was studied after ceftriaxone and immunosuppressive treatments. Mice infected with the B. burgdorferi strain expressing both DbpA and B developed an early and prominent joint swelling. In contrast, while strains that expressed DbpA or B alone, or the strain that was DbpA and B deficient, were able to colonize mouse joints, they caused only negligible joint manifestations. Ceftriaxone treatment at two or six weeks of infection totally abolished joint swelling, and all ceftriaxone treated mice were B. burgdorferi culture negative. Antibiotic treated mice, which were immunosuppressed by anti-TNF-alpha, remained culture negative. Importantly, among ceftriaxone treated mice, B. burgdorferi DNA was detected by PCR uniformly in joint samples of mice infected with DbpA and B expressing bacteria, while this was not observed in mice infected with the DbpA and B deficient strain. In conclusion, these results show that both DbpA and B adhesins are crucial for early and prominent arthritis development in mice. Also, post-treatment borrelial DNA persistence appears to be dependent on the expression of DbpA and B on B. burgdorferi surface. Results of the immunosuppression studies suggest that the persisting material in the joints of antibiotic treated mice is DNA or DNA containing remnants rather than live bacteria. PMID- 25816292 TI - Prevalence and associated factors of unprotected anal intercourse with regular male sex partners among HIV negative men who have sex with men in China: a cross sectional survey. AB - The HIV prevalence and incidence among men who have sex with men (MSM) in China are high. Unprotected anal intercourse (UAI) with a regular male sex partner (RP), a significant predictor of HIV sero-conversion, was high yet under emphasized among MSM having RP (MSMRP). The present cross-sectional survey interviewed 307 HIV negative MSMRP recruited through convenient sampling from multiple sources, including venue-based outreaching, online recruitment, and referrals made by peers, in Beijing and Chengdu, China. Among MSMRP, the prevalence of UAI with RP in the last three months was 52.4%. The results of the multivariate analysis showed that trust and intimacy within the relationship with RP and presence of clinical depression symptoms were positively associated with UAI with RP in the last three months. Other associated scalar factors derived from the Theory of Planned Behavior were related to perceptions on condom use, including positive attitudes toward condom use (a negative association), subjective norm of the perception that MSM do not usually use condoms during anal intercourse with RP (a positive association), perceived behavioral control over condom use with RP (a negative association), and behavioral intention to use condoms with RP in the coming three months (a negative association). It is seen that MSMRP were at high risk of HIV/STD transmission. The associated factors hence involved those related to perceptions about condom use, mental health, and interpersonal relationship. Future interventions should take these multi dimensional factors into account. In particular, future research to test the efficacy of couple-based interventions that include mental health elements needs to be conducted, as trust and intimacy within the relationship were associated with UAI among MSMRP, and mental health problems may exist for both the MSMRP and their RP. PMID- 25816293 TI - Dissecting antibodies with regards to linear and conformational epitopes. AB - An important issue for the performance and specificity of an antibody is the nature of the binding to its protein target, including if the recognition involves linear or conformational epitopes. Here, we dissect polyclonal sera by creating epitope-specific antibody fractions using a combination of epitope mapping and an affinity capture approach involving both synthesized peptides and recombinant protein fragments. This allowed us to study the relative amounts of antibodies to linear and conformational epitopes in the polyclonal sera as well as the ability of each antibody-fraction to detect its target protein in Western blot assays. The majority of the analyzed polyclonal sera were found to have most of the target-specific antibodies directed towards linear epitopes and these were in many cases giving Western blot bands of correct molecular weight. In contrast, many of the antibodies towards conformational epitopes did not bind their target proteins in the Western blot assays. The results from this work have given us insights regarding the nature of the antibody response generated by immunization with recombinant protein fragments and has demonstrated the advantage of using antibodies recognizing linear epitopes for immunoassay involving wholly or partially denatured protein targets. PMID- 25816294 TI - Transcriptome analysis of Bombyx mori larval midgut during persistent and pathogenic cytoplasmic polyhedrosis virus infection. AB - Many insects can be persistently infected with viruses but do not show any obvious adverse effects with respect to physiology, development or reproduction. Here, Bombyx mori strain Daizo, persistently infected with cytoplasmic polyhedrosis virus (BmCPV), was used to study the host's transcriptional response after pathogenic infection with the same virus in midgut tissue of larvae persistently and pathogenically infected as 2nd and 4th instars. Next generation sequencing revealed that from 13,769 expressed genes, 167 were upregulated and 141 downregulated in both larval instars following pathogenic infection. Several genes that could possibly be involved in B. mori immune response against BmCPV or that may be induced by the virus in order to increase infectivity were identified, whereas classification of differentially expressed transcripts (confirmed by qRT-PCR) resulted in gene categories related to physical barriers, immune responses, proteolytic/metabolic enzymes, heat-shock proteins, hormonal signaling and uncharacterized proteins. Comparison of our data with the available literature (pathogenic infection of persistently vs. non-persistently infected larvae) unveiled various similarities of response in both cases, which suggests that pre-existing persistent infection does not affect in a major way the transcriptome response against pathogenic infection. To investigate the possible host's RNAi response against BmCPV challenge, the differential expression of RNAi related genes and the accumulation of viral small RNAs (vsRNAs) were studied. During pathogenic infection, siRNA-like traces like the 2-fold up-regulation of the core RNAi genes Ago-2 and Dcr-2 as well as a peak of 20 nt small RNAs were observed. Interestingly, vsRNAs of the same size were detected at lower rates in persistently infected larvae. Collectively, our data provide an initial assessment of the relative significance of persistent infection of silkworm larvae on the host response following pathogenic infection with CPV, while they also highlight the relative importance of RNAi as an antiviral mechanism. PMID- 25816295 TI - Reward-related attentional bias and adolescent substance use: a prognostic relationship? AB - Current cognitive-motivational addiction theories propose that prioritizing appetitive, reward-related information (attentional bias) plays a vital role in substance abuse behavior. Previous cross-sectional research has shown that adolescent substance use is related to reward-related attentional biases. The present study was designed to extend these findings by testing whether these reward biases have predictive value for adolescent substance use at three-year follow-up. Participants (N = 657, mean age = 16.2 yrs at baseline) were a sub sample of Tracking Adolescents' Individual Lives Survey (TRAILS), a large longitudinal community cohort study. We used a spatial orienting task as a behavioral index of appetitive-related attentional processes at baseline and a substance use questionnaire at both baseline and three years follow-up. Bivariate correlational analyses showed that enhanced attentional engagement with cues that predicted potential reward and nonpunishment was positively associated with substance use (alcohol, tobacco, and cannabis) three years later. However, reward bias was not predictive of changes in substance use. A post-hoc analysis in a selection of adolescents who started using illicit drugs (other than cannabis) in the follow-up period demonstrated that stronger baseline attentional engagement toward cues of nonpunishment was related to a higher level of illicit drug use three years later. The finding that reward bias was not predictive for the increase in substance use in adolescents who already started using substances at baseline, but did show prognostic value in adolescents who initiated drug use in between baseline and follow-up suggests that appetitive bias might be especially important in the initiation stages of adolescent substance use. PMID- 25816297 TI - Vegetative characters, growth habit and microsporangiate strobilus of lycopsid Minostrobus chaohuensis. AB - Late Devonian Minostrobus chaohuensis is one of the earliest monosporangiate strobilate isoetaleans. Based on new material of this plant, the vegetative axis and microsporangiate strobilus are studied in detail, and the whole plant knowledge is summarized. The vegetative axis is isotomously branched. The stem is up to 55 mm in diameter with helically arranged leaf cushions. Stems and thick branches bear long fusiform leaf cushions and interareas with vertical linear ornamentations. A ligule pit, oblanceolate leaf scar, and vascular bundle scar appear on the leaf cushion. Distal axes have persistent lanceolate leaves and rhombic leaf bases. The microsporangiate strobilus is cylindrical in shape, possesses sporophyll with alate pedicel and long triangular lamina, uniseriate sporangial wall, subarchesporial pad inside the sporangium, and microspore with cingulum. Based on comparisons with other isoetaleans, the usage of the terms "leaf cushion" and "leaf base" is discussed, and Minostrobus chaohuensis is considered as a tree-like lycopsid. It suggests that arborescent isoetaleans with monosporangiate strobili had appeared and diversified in the Late Devonian. The multi-dichotomous branching system of Minostrobus provides new data on the evolution of growth architecture in rhizomorphic lycopsids. PMID- 25816296 TI - Efficacy and safety of sitagliptin added to insulin in Japanese patients with type 2 diabetes: the EDIT randomized trial. AB - AIMS: To clarify the efficacy and safety of adding sitagliptin to insulin therapy in Japanese patients with suboptimally controlled type 2 diabetes (T2DM). STUDY DESIGN AND METHODS: This was a 24-week, prospective, randomized, open-labeled, controlled trial. Patients with T2DM who were suboptimally controlled despite receiving at least twice daily injection of insulin were enrolled in the study. The patients were randomized to continuation of insulin treatment (Insulin group) or addition of sitagliptin 50 to 100 mg daily to insulin treatment (Ins+Sita group). The primary outcome was change in HbA1c at week 24. RESULTS: Adding sitagliptin to insulin significantly reduced HbA1c from 7.9 +/- 1.0% at baseline to 7.0 +/- 0.8% at week 24 (P <0.0001), while there was no significant change in HbA1c in the Insulin group (7.8 +/- 0.7% vs. 7.8 +/- 1.1%, P = 0.32). The difference in HbA1c reduction between the groups was 0.9% (95% confidence interval, 0.4 to 1.5, P = 0.01). There was no significant weight gain in either group. Incidence of hypoglycemia was significantly reduced in the Ins+Sita group compared with the Insulin group. Treatment satisfaction was improved in the Ins+Sita group. Baseline HbA1c level and beta cell function were associated with the magnitude of reduction in HbA1c in the Ins+Sita group. CONCLUSION: Adding sitagliptin to insulin reduced HbA1c without weight gain or increase in hypoglycemia, and improved treatment satisfaction in Japanese patients with T2DM who were suboptimally controlled despite at least twice daily injection of insulin. TRIAL REGISTRATION: The University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004678. PMID- 25816299 TI - Direct medical cost of type 2 diabetes in singapore. AB - Due to the chronic nature of diabetes along with their complications, they have been recognised as a major health issue, which results in significant economic burden. This study aims to estimate the direct medical cost associated with type 2 diabetes mellitus (T2DM) in Singapore in 2010 and to examine both the relationship between demographic and clinical state variables with the total estimated expenditure. The National Healthcare Group (NHG) Chronic Disease Management System (CDMS) database was used to identify patients with T2DM in the year 2010. DM-attributable costs estimated included hospitalisations, accident and emergency (A&E) room visits, outpatient physician visits, medications, laboratory tests and allied health services. All charges and unit costs were provided by the NHG. A total of 500 patients with DM were identified for the analyses. The mean annual direct medical cost was found to be $2,034, of which 61% was accounted for by inpatient services, 35% by outpatient services, and 4% by A&E services. Independent determinants of total costs were DM treatments such as the use of insulin only (p<0.001) and the combination of both oral medications and insulin (p=0.047) as well as having complications such as cerebrovascular disease (p<0.001), cardiovascular disease (p=0.002), peripheral vascular disease (p=0.001), and nephropathy (p=0.041). In this study, the cost of DM treatments and DM-related complications were found to be strong determinants of costs. This finding suggests an imperative need to address the economic burden associated with diabetes with urgency and to reorganise resources required to improve healthcare costs. PMID- 25816298 TI - Low parasitemia in submicroscopic infections significantly impacts malaria diagnostic sensitivity in the highlands of Western Kenya. AB - Asymptomatic malaria infections represent a major challenge in malaria control and elimination in Africa. They are reservoirs of malaria parasite that can contribute to disease transmission. Therefore, identification and control of asymptomatic infections are important to make malaria elimination feasible. In this study, we investigated the extent and distribution of asymptomatic malaria in Western Kenya and examined how varying parasitemia affects performance of diagnostic methods including microscopy, conventional PCR, and quantitative PCR. In addition, we compared parasite prevalence rates and parasitemia levels with respect to topography and age in order to explore factors that influence malaria infection. Over 11,000 asymptomatic blood samples from children and adolescents up to 18 years old representing broad areas of Western Kenya were included. Quantitative PCR revealed the highest parasite positive rate among all methods and malaria prevalence in western Kenya varied widely from less than 1% to over 50%. A significantly lower parasitemia was detected in highland than in lowland samples and this contrast was also observed primarily among submicroscopic samples. Although we found no correlation between parasitemia level and age, individuals of younger age group (aged <14) showed significantly higher parasite prevalence. In the lowlands, individuals of aged 5-14 showed significantly higher prevalence than those under age 5. Our findings highlight the need for a more sensitive and time-efficient assay for asymptomatic malaria detection particularly in areas of low-transmission. Combining QPCR with microscopy can enhance the capacity of detecting submicroscopic asymptomatic malaria infections. PMID- 25816301 TI - Female employment reduces fertility in rural Senegal. AB - Economic growth and modernization of society are generally associated with fertility rate decreases but which forces trigger this is unclear. In this paper we assess how fertility changes with increased labor market participation of women in rural Senegal. Evidence from high-income countries suggests that higher female employment rates lead to reduced fertility rates but evidence from developing countries at an early stage of demographic transition is largely absent. We concentrate on a rural area in northern Senegal where a recent boom in horticultural exports has been associated with a sudden increase in female off farm employment. Using survey data we show that employed women have a significantly higher age at marriage and at first childbirth, and significantly fewer children. As causal identification strategy we use instrumental variable and difference-in-differences estimations, combined with propensity score matching. We find that female employment reduces the number of children per woman by 25%, and that this fertility-reducing effect is as large for poor as for non poor women and larger for illiterate than for literate women. Results imply that female employment is a strong instrument for empowering rural women, reducing fertility rates and accelerating the demographic transition in poor countries. The effectiveness of family planning programs can increase if targeted to areas where female employment is increasing or to female employees directly because of a higher likelihood to reach women with low-fertility preferences. Our results show that changes in fertility preferences not necessarily result from a cultural evolution but can also be driven by sudden and individual changes in economic opportunities. PMID- 25816300 TI - Mutation in MRPS34 compromises protein synthesis and causes mitochondrial dysfunction. AB - The evolutionary divergence of mitochondrial ribosomes from their bacterial and cytoplasmic ancestors has resulted in reduced RNA content and the acquisition of mitochondria-specific proteins. The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only in chordates, whose function we investigated in mice carrying a homozygous mutation in the nuclear gene encoding this protein. The Mrps34 mutation causes a significant decrease of this protein, which we show is required for the stability of the 12S rRNA, the small ribosomal subunit and actively translating ribosomes. The synthesis of all 13 mitochondrially-encoded polypeptides is compromised in the mutant mice, resulting in reduced levels of mitochondrial proteins and complexes, which leads to decreased oxygen consumption and respiratory complex activity. The Mrps34 mutation causes tissue-specific molecular changes that result in heterogeneous pathology involving alterations in fractional shortening of the heart and pronounced liver dysfunction that is exacerbated with age. The defects in mitochondrial protein synthesis in the mutant mice are caused by destabilization of the small ribosomal subunit that affects the stability of the mitochondrial ribosome with age. PMID- 25816302 TI - Prolactin receptors and placental lactogen drive male mouse pancreatic islets to pregnancy-related mRNA changes. AB - Pregnancy requires a higher functional beta cell mass and this is associated with profound changes in the gene expression profile of pancreatic islets. Taking Tph1 as a sensitive marker for pregnancy-related islet mRNA expression in female mice, we previously identified prolactin receptors and placental lactogen as key signalling molecules. Since beta cells from male mice also express prolactin receptors, the question arose whether male and female islets have the same phenotypic resilience at the mRNA level during pregnancy. We addressed this question in vitro, by stimulating cultured islets with placental lactogen and in vivo, by transplanting male or female islets into female acceptor mice. Additionally, the islet mRNA expression pattern of pregnant prolactin receptor deficient mice was compared with that of their pregnant wild-type littermates. When cultured with placental lactogen, or when transplanted in female recipients that became pregnant (day 12.5), male islets induced the 'islet pregnancy gene signature', which we defined as the 12 highest induced genes in non-transplanted female islets at day 12.5 of pregnancy. In addition, serotonin immunoreactivity and beta cell proliferation was also induced in these male transplanted islets at day 12.5 of pregnancy. In order to further investigate the importance of prolactin receptors in these mRNA changes we used a prolactin receptor deficient mouse model. For the 12 genes of the signature, which are highly induced in control pregnant mice, no significant induction of mRNA transcripts was found at day 9.5 of pregnancy. Together, our results support the key role of placental lactogen as a circulating factor that can trigger the pregnancy mRNA profile in both male and female beta cells. PMID- 25816304 TI - Measuring and modelling the radiological impact of a phosphogypsum deposition site on the surrounding environment. AB - Phosphogypsum (PG) is a waste product (residue) from the production of phosphoric acid characterized by technologically enhanced natural radioactivity. Croatia's largest PG deposition site is situated at the edge of Lonjsko Polje Nature Park, a sensitive ecosystem possibly endangered by PG particles. This field study investigates two aspects relevant for the general radiological impact of PG: risk assessment for the environment and risk assessment for occupationally exposed workers and local inhabitants. Activity concentrations of natural radionuclides ((238)U, (235)U, (232)Th, (226)Ra, (210)Pb, and (40)K) were measured in the PG (at the deposition site), soil, and grass samples (in the vicinity of the site). The ERICA Assessment Tool was used to estimate the radiological impact of PG particles on non-human biota of the Lonjsko Polje Nature Park. The average annual effective dose for occupationally exposed workers was 0.4 mSv which was within the worldwide range. PMID- 25816303 TI - Lesion load may predict long-term cognitive dysfunction in multiple sclerosis patients. AB - BACKGROUND: Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS). OBJECTIVES: To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients. METHODS: 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors. RESULTS: AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12 1.97 p = 0.006), PASAT (OR 1.43, CI 1.14-1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35-2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28-2.03 p<0.001), MCST-category (OR 1.52, CI 1.2-1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2-1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02-1.55 p = 0.032). CONCLUSION: In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome. PMID- 25816305 TI - Soluble CD14 and total IgE in the serum of atopic and nonatopic adolescents in relation to environmental factors: a pilot study. AB - The CD14 receptor is expressed on the surfaces of monocytes, macrophages, and, to a lesser extent, of activated granulocytes and B lymphocytes (mCD14). It also exists in soluble form in the serum (sCD14), in which it binds microbial compounds and indoor allergens. The objectives of this study were to see whether serum sCD14 concentrations could be used as a marker of atopic disorders and to estimate the effects of environmental factors (tobacco smoke exposure, childhood residence in urban or rural areas, and having a pet) on sCD14 and IgE values. Mass fraction of sCD14 and total IgE were determined in the sera of atopic (N=53) and non-atopic (N=35) participants using the standard enzyme-linked immunosorbent assay. Exposure to pets and environmental tobacco smoke was estimated based on the International Study of Asthma and Allergies in Childhood questionnaire (ISAAC). Median sCD14 concentration was significantly lower in atopic than in non atopic girls (3.49 vs. 3.83 MUg mL(-1); p<0.010). The number of smokers at home positively correlated with the sCD14 level in atopics, and urban atopics had significantly lower sCD14 levels than rural atopics (3.47 vs. 3.92 MUg mL(-1), p=0.028). Median total IgE concentration was significantly lower in atopic pet owners than in atopics with no pets (161 vs. 252 kIU L(-1); p=0.021). In conclusion, while sex and environmental factors might be involved in sCD14 expression, particularly in atopics, we found no correlation between sCD14 and total IgE concentrations. The usefulness of sCD14 as a marker of atopic disorders should be investigated further, particularly in relation to the severity of allergic disorders. PMID- 25816306 TI - In vivo toxicity of a new antifungal agent 2,4-dithiophenoxy-1-iodo-4-bromo benzene: a follow up on our in vitro study. AB - Triazole fungicide fluconazole has become the most widely used antifungal agent in the world, mainly because of its ability to penetrate well into body fluids and tissues. However, it has been reported to interact with many drugs and because of its common use, the risk of resistance to fluconazole increases. This calls for new anti-fungal drugs that would be able to replace it. In 2006, a new thialo benzene derivative - 2,4-dithiophenoxy-1-iodo-4-bromo benzene (C18H12S2IBr) - was synthesised with a carbon backbone similar to fluconazole, and, according to the early in vitro tests, much greater efficiency. Followed an in vitro test of its cytotoxicity, in which the new drug showed promising results as an alternative to fluconazole. The aim of this study was take the next step and test C18H12S2IBr toxicity in vivo. We opted for a four-week test on Wistar rats, in which the new antifungal agent was orally applied at doses two and a half and five times lower than those of fluconazole. There were no changes in daily food and water consumption, but weight gain in female rats and relative organ weights changed in the treated groups, pointing to sex-related differences in drug metabolism and effects. Fluconazole significantly increased leukocytes and lowered neutrophils whereas C18H12S2IBr did not, while other haematological changes in respect to the vehicle control were similar between the treated groups. Differences in cytochrome c in the liver and kidney suggested greater apoptotic effect of the new drug, but interpretation remains inconclusive, considering that other key indicators (biochemistry and histopathology) do not support greater toxicity. Considering that C18H12S2IBr is more active at lower concentrations and has comparable toxic effects to fluconazole in rats, this new compound shows some promise in the treatment of fungal infections. Future, more detailed animal studies are needed, that will include drug interactions and molecular toxicity pathways. If the results are promising, clinical studies should follow. PMID- 25816307 TI - Atrazine levels in the Jaboticabal water stream (Sao Paulo State, Brazil) and its toxicological effects on the pacu fish Piaractus mesopotamicus. AB - The aim of this study was to determine the environmental concentration of atrazine (ATZ) in five streams located in the north of Sao Paulo state (Brazil) and evaluate its toxicological impact on young specimens of the pacu fish Piaractus mesopotamicus. Samples of water were collected on three occasions between 2010 and 2011, corresponding to periods signifying the beginning, middle, and end of rain season. ATZ levels were estimated by a high-performance liquid chromatography coupled with a mass spectrometry (HPLC-MS/MS) triple quadrupole. Later, the quotient of environmental risk (QR) was determined based on the medium lethal concentration (LC50 48 h), non-observable effect concentration (NOEC), and the estimated environmental concentration (EEC) of ATZ detected in the environment. Histological changes in gills and liver were also studied, along with the brain activity of the enzyme acetylcholinesterase (AChE). The highest concentration of ATZ measured was 10.4 MUg L(-1). The ATZ LC50 (48 h) for young P. mesopotamicus was 24.46 mg L(-1) and the QR was classified as "safe". Although the QR indicated that ATZ could be safe for the tested species, it caused many histological alterations in the liver and gills of the exposed specimens, and an increase in the AChE levels. PMID- 25816308 TI - Can sodium bicarbonate really help in treating metabolic acidosis caused by aluminium phosphide poisoning? PMID- 25816309 TI - [In Process Citation]. PMID- 25816311 TI - Bacteria on a peripheral blood smear as presenting sign of overwhelming post splenectomy infection in a patient with secondary acute myeloid leukemia. PMID- 25816310 TI - A new formula for estimation of low-density lipoprotein cholesterol in an ethnic Chinese population. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is an established risk factor for cardiovascular disease and is usually estimated by the Friedewald formula (FF) calculated from three parameters, namely, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). We aimed to develop a new and simple formula (NF) for LDL-C estimation. METHODS: This cross sectional study enrolled two study populations (a testing group, n=16,749, and a validation group, n=4940). Linear regression analysis was used in the testing group to investigate the association between measured LDL-C (mLDL-C) and TC concentration, and was verified in the validation group. RESULTS: The NF yielded an estimated LDL-C (eLDL-C) equal to 0.75 * total cholesterol-0.6465 (mmol/L). For the subjects with TC between 2.58 and 7.74 mmol/L, the difference between mLDL-C and eLDL-C using the NF was less than that from the FF (testing group: 0.04 to -0.20 vs. -0.28 to -0.38 mmol/L; validation group: 0.01 to -0.12 vs. 0.23 to -0.30 mmol/L; p<0.001, respectively). The predictability of the NF was not inferior to that of the FF in subjects with different triglyceride and HDL-C concentrations, and was not affected by diabetes diagnosis and statin use. However, the NF performed similar to or worse than the FF at TC concentrations <2.58 mmol/L and >7.74 mmol/L, respectively. CONCLUSIONS: In the Chinese population, the accuracy of eLDL-C measurement with the NF was better than that with the FF, especially in subjects with TC levels between 2.58 and 7.74 mmol/L. The NF is simple and may be used for screening as well as for follow-up of patients on lipid lowering agents. PMID- 25816312 TI - Not all fats are created equal: adipose vs. ectopic fat, implication in cardiometabolic diseases. AB - Adipose tissue is a recognized endocrine organ that acts not only as a fuel storage but also is able to secrete adipokines that can modulate inflammation. Most of the fat is composed of white adipocytes (WAT), although also brown/beige adipocytes (BAT/BeAT) have been found in humans. BAT is located close to the neck but also among WAT in the epicardial fat and perivascular fat. Adipocyte hypertrophy and infiltration of macrophages impair adipose tissue metabolism determining "adiposopathy" (i.e., sick fat) and increasing the risk to develop metabolic and cardiovascular diseases. The purpose of this review was to search and discuss the available literature on the impact of different types of fat and fat distribution on cardiometabolic risk. Visceral fat, but also ectopic fat, either in liver, muscle and heart, can increase the risk to develop insulin resistance, type 2 diabetes and cardiovascular diseases. Results recently published showed that BAT could have an impact on cardiometabolic risk, not only because it is implicated in energy metabolism but also because it can modulate glucose and lipid metabolism. Therapeutical interventions that can increase energy expenditure, successfully change fat distribution and reduce ectopic fat, also through BAT activation, were discussed. PMID- 25816314 TI - Temporal analysis of E. coli, TSS and wastewater micropollutant loads from combined sewer overflows: implications for management. AB - A combined sewer overflow (CSO) outfall was monitored to assess the impact of temporal mass loads on the appropriateness of treatment options. Instantaneous loads (mass per s) varied by approximately three orders of magnitude during events (n = 9 in spring, summer and the fall) with no significant seasonal variations. The median fraction of total loads discharged with the first 25% of the total volume ranged from 28% (theophylline) to 40% (Total Suspended Solids (TSS)) and loads remained high for the duration of the events. E. coli and TSS loads originated primarily from wastewater (WW) (63% and 75%, respectively). However, a mix of stormwater (SW) and sewer deposit (SD) resuspension contributed from 73 to 95% for the first 50% of the volume discharged of total TSS loads for 2 events. The contribution of SD resuspension was not negligible for Wastewater Micropollutants (WWMPs), especially for carbamazepine. Sustained high loads over the course of CSOs highlight the need to revisit current CSO and SW management strategies that focus on the treatment of early discharge volumes. PMID- 25816313 TI - alpha7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid beta42 accumulation in the mouse brain to impair memory. AB - Nicotinic acetylcholine receptors (nAChRs) expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of beta-amyloid (Abeta42), memory deficit and neuroinflammation. Previously we found that alpha7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that alpha7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of alpha7 nAChR subunit alpha7(1-208) or injected with bacterial lipopolysaccharide (LPS) for 5 months. We studied their behavior and the presence of alpha3, alpha4, alpha7, beta2 and beta4 nAChR subunits, Abeta40 and Abeta42 and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with alpha7(1-208) resulted in region-specific decrease of alpha7 and alpha4beta2 and increase of alpha3beta4 nAChRs, accumulation of Abeta42 and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred alpha7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1) neuroinflammation is sufficient to provoke the decrease of alpha7 and alpha4beta2 nAChRs, Abeta42 accumulation and memory impairment in mice and (2) alpha7(1-208) nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease. PMID- 25816315 TI - Pharmacokinetics and tolerability of inhaled umeclidinium and vilanterol alone and in combination in healthy Chinese subjects: a randomized, open-label, crossover trial. AB - Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 MUg (delivering 55/22 MUg) and UMEC/VI 125/25 MUg (delivering 113/22 MUg) compared with their monotherapy components (UMEC 62.5 MUg, UMEC 125 MUg and, VI 25 MUg [delivering 55, 113, and 22 MUg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2-4 h for UMEC and 1-2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11-34% based on Cmax and 19-59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25-66% based on Cmax and 17-43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced >=1 adverse event (AE). Six subjects experienced >=1 treatment-related AE; the most commonly reported treatment related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01899638 NCT01899638. PMID- 25816316 TI - Mycetoma in the Sudan: an update from the Mycetoma Research Centre, University of Khartoum, Sudan. AB - This communication reports on the Mycetoma Research Centre of the University of Khartoum, Sudan experience on 6,792 patients seen during the period 1991-2014.The patients were predominately young (64% under 30 years old) males (76%). The majority (68%) were from the Sudan mycetoma belt and 28% were students. Madurella mycetomatis eumycetoma was the most common type (70%). In 66% of the patients the duration of the disease was less than five years, and 81% gave a history of sinuses discharging mostly black grains (78%). History of trauma at the mycetoma site was reported in 20%. Local pain was reported in 27% of the patients, and only 12% had a family history of mycetoma. The study showed that 57% of the patients had previous surgical excisions and recurrence, and only 4% received previous medical treatment for mycetoma. Other concomitant medical diseases were reported in 4% of the patients. The foot (76%) and hand (8%) were the most commonly affected sites. Less frequently affected sites were the leg and knee (7%), thigh (2%), buttock (2%) and arm and forearm (1%). Rare sites included the chest wall, head and neck, back, abdominal wall, perineum, oral cavity, tongue and eye. Multiple sites mycetoma was recorded in 135 (2%) of cases. At presentation, 37% of patients had massive lesions, 79% had sinuses, 8% had local hyper-hydrosis at the mycetoma lesion, 11% had regional lymphadenopathy, while 6% had dilated tortuous veins proximal to the mycetoma lesions. The diagnosis of mycetoma was established by combined imaging techniques and cytological, histopathological, serological tests and grain culture. Patients with actinomycetoma received a combination of antimicrobial agents, while eumycetoma patients received antifungal agents combined with various surgical excisions. Surgical excisions in the form of wide local excision, debridement or amputation were done in 807 patients, and of them 248 patients (30.7%) had postoperative recurrence. Different types of amputations were done in 120 patients (1.7%). PMID- 25816317 TI - Stress and the multiple-role woman: taking a closer look at the "superwoman". AB - In the academic literature there is debate as to whether women who engage in multiple social roles experience more or less stress than women in fewer roles. For the present research we examined the relationship between levels of engagement in seven distinct roles and perceived stress and life satisfaction in a small non-random sample of women in North America (N = 308). We did not find a significant correlation between role engagement and perceived stress, though we did find a small but significant positive correlation between role engagement and life satisfaction. Similarly, in a subset of the participants (N = 31), there was not a significant relationship between the level of role engagement and physiological stress as measured by hair or urinary cortisol levels. We found a significant negative correlation between perceived stress and life satisfaction, and role satisfaction. The results from multiple regression models did not identify the level of role engagement as a significant predictor of either perceived stress or life satisfaction. Role satisfaction in addition to several life style variables such as the frequency of sex and exercise were identified as significant predictors of both outcome variables. We also examined the popularized notion of the "superwoman", which we defined as women who fell within the 4th quartile of role engagement, or those engaged in the wife/mother/worker/homemaker role combination. Based on popular discourses surrounding the superwoman we expected that superwomen would exhibit higher levels of perceived stress. Our results revealed that superwomen do not experience a significantly higher level of perceived stress than non-superwomen. The results of our study therefore suggest that multiple role engagement in women, even at a relatively high level as experienced by "superwomen", is not associated with significantly higher stress, or reduced life satisfaction. PMID- 25816318 TI - Japanese encephalitis virus nonstructural protein NS5 interacts with mitochondrial trifunctional protein and impairs fatty acid beta-oxidation. AB - Infection with Japanese encephalitis virus (JEV) can induce the expression of pro inflammatory cytokines and cause acute encephalitis in humans. beta-oxidation breaks down fatty acids for ATP production in mitochondria, and impaired beta oxidation can induce pro-inflammatory cytokine expression. To address the role of fatty-acid beta-oxidation in JEV infection, we measured the oxygen consumption rate of mock- and JEV-infected cells cultured with or without long chain fatty acid (LCFA) palmitate. Cells with JEV infection showed impaired LCFA beta oxidation and increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha) expression. JEV nonstructural protein 5 (NS5) interacted with hydroxyacyl CoA dehydrogenase alpha and beta subunits, two components of the mitochondrial trifunctional protein (MTP) involved in LCFA beta-oxidation, and NS5 proteins were detected in mitochondria and co-localized with MTP. LCFA beta-oxidation was impaired and higher cytokines were induced in cells overexpressing NS5 protein as compared with control cells. Deletion and mutation studies showed that the N terminus of NS5 was involved in the MTP association, and a single point mutation of NS5 residue 19 from methionine to alanine (NS5-M19A) reduced its binding ability with MTP. The recombinant JEV with NS5-M19A mutation (JEV-NS5-M19A) was less able to block LCFA beta-oxidation and induced lower levels of IL-6 and TNF alpha than wild-type JEV. Moreover, mice challenged with JEV-NS5-M19A showed less neurovirulence and neuroinvasiveness. We identified a novel function of JEV NS5 in viral pathogenesis by impairing LCFA beta-oxidation and inducing cytokine expression by association with MTP. PMID- 25816319 TI - A novel three-filament model of force generation in eccentric contraction of skeletal muscles. AB - We propose and examine a three filament model of skeletal muscle force generation, thereby extending classical cross-bridge models by involving titin actin interaction upon active force production. In regions with optimal actin myosin overlap, the model does not alter energy and force predictions of cross bridge models for isometric contractions. However, in contrast to cross-bridge models, the three filament model accurately predicts history-dependent force generation in half sarcomeres for eccentric and concentric contractions, and predicts the activation-dependent forces for stretches beyond actin-myosin filament overlap. PMID- 25816320 TI - Adenoviruses associated with acute respiratory diseases reported in Beijing from 2011 to 2013. AB - BACKGROUND: Adenovirus is one of the most common causes of viral acute respiratory infections. To identify the types of human adenoviruses (HAdVs) causing respiratory illness in Beijing, a sentinel surveillance project on the viral aetiology of acute respiratory infection was initiated in 2011. PRINCIPAL FINDINGS: Through the surveillance project, 4617 cases of respiratory infections were identified during 2011-2013. Throat swabs (pharynx and tonsil secretions) were collected from all the patients, and 15 different respiratory viruses were screened by multiplex one-step PCR method. 45 were identified as adenovirus positive from sporadic and outbreak cases of respiratory infection by a multiplex one-step RT-PCR method, and a total of 21 adenovirus isolates were obtained. Five HAdV types among three species, including HAdV-3 (species HAdV-B), HAdV-4 (species HAdV-E), HAdV-7 (species HAdV-B), HAdV-55 (species HAdV-B), and an undefined HAdV type (species HAdV-C) were identified. The comparison results of the penton base, hexon, and fiber gene sequences of the Beijing HAdV-3, HAdV-4, HAdV-7, and HAdV-55 strains in this study and those from the GenBank database indicated significant spatial and temporal conservation and stability of sequences within the genome; however, the phylogenetic relationship indicated that both strain BJ04 and strain BJ09 isolated in 2012 and 2013, respectively, may have recombined between HAdV-1 genome and HAdV-2 genome within species HAdV C, indicating intraspecies recombination. CONCLUSIONS: This study confirmed that at least 5 HAdV types including HAdV-3, HAdV-4, HAdV-7, HAdV-55 and an undefined HAdV type were co-circulating and were the causative agents of respiratory tract infections in recent years in Beijing. HAdV-3, HAdV-4, HAdV-7, and HAdV-55 showed the apparent stability of the genomes, while intraspecies recombination was identified in strain BJ04 and BJ09. The recombinants carrying penton base gene of HAdV-1 as well as hexon and fiber genes of HAdV-2 might be a novel type of HAdV worthy of further study. PMID- 25816321 TI - Human dendritic cell DC-SIGN and TLR-2 mediate complementary immune regulatory activities in response to Lactobacillus rhamnosus JB-1. AB - The microbiota is required for optimal host development and ongoing immune homeostasis. Lactobacilli are common inhabitants of the mammalian large intestine and immunoregulatory effects have been described for certain, but not all, strains. The mechanisms underpinning these protective effects are beginning to be elucidated. One such protective organism is Lactobacillus rhamnosus JB-1 (Lb. rhamnosus JB-1). Lb. murinus has no such anti-inflammatory protective effects and was used as a comparator organism. Human monocyte-derived dendritic cells (MDDCs) were co-incubated with bacteria and analysed over time for bacterial adhesion and intracellular processing, costimulatory molecule expression, cytokine secretion and induction of lymphocyte polarization. Neutralising antibodies were utilized to identify the responsible MDDC receptors. Lb. rhamnosus JB-1 adhered to MDDCs, but internalization and intracellular processing was significantly delayed, compared to Lb. murinus which was rapidly internalized and processed. Lb. murinus induced CD80 and CD86 expression, accompanied by high levels of cytokine secretion, while Lb. rhamnosus JB-1 was a poor inducer of costimulatory molecule expression and cytokine secretion. Lb. rhamnosus JB-1 primed MDDCs induced Foxp3 expression in autologous lymphocytes, while Lb. murinus primed MDDCs induced Foxp3, T-bet and Ror-gammat expression. DC-SIGN was required for Lb. rhamnosus JB 1 adhesion and influenced IL-12 secretion, while TLR-2 influenced IL-10 and IL-12 secretion. Here we demonstrate that the delayed kinetics of bacterial processing by MDDCs correlates with MDDC activation and stimulation of lymphocytes. Thus, inhibition or delay of intracellular processing may be a novel strategy by which certain commensals may avoid the induction of proinflammatory responses. PMID- 25816322 TI - Sexual behaviours of homosexual and bisexual men in France: a generational approach. AB - OBJECTIVE: In high-income countries, the social and epidemiological contexts surrounding homosexuality and AIDS have changed profoundly in recent decades. This work sought to examine key indicators of the long-term sexual trajectories of successive generations of men who have sex with men (MSM) in France. METHODS: We performed a longitudinal analysis of the French Gay Press surveys, which were self-administered socio-behavioural questionnaires, repeated from 1985 to 2011 in the gay press, and on the internet in 2004 and 2011. An age-cohort analysis using graphical representations and multivariate logistic regressions was conducted among participants aged 18-59 (N = 38 821). RESULTS: First sexual intercourse occurred more often with a male partner in younger generations than in older ones: 76.0% in MSM who turned 18 in 1956-1959, 75.6% in 1980-1983, 83.7% in 2008 2011, p(overall) = 0.0002). Every generation showed the same pattern of sexual trajectory between 1985 and 2011: globally, the frequency of masturbation increased from the 1985 survey to the early 1990s and then decreased from the late 1990s to the end of the study period. Inversely, the frequency of oral and anal sex decreased in the mid-1980s and increased from 1990 to 2011. The frequency of both oral sex and anal intercourse is currently quite high, regardless of generation (>95% and around 80%, respectively). Compared to their predecessors, recent generations of young MSM reported more frequent oral and anal sex, but fewer male partners in the previous 12 months. DISCUSSION: While the increased frequency of first intercourse with a man over successive generations since the 1970s may be related to reduced social pressure for heterosexuality, there is evidence that sexual norms among MSM are widespread, with practices spreading across age groups and generations. Although AIDS profoundly affected sexual practices in the 1980s, further AIDS-related events (discovery of HIV antiretroviral drugs and their use in prevention) do not appear to have accentuated ongoing trends in sexual practices. PMID- 25816323 TI - MiR-145 inhibits metastasis by targeting fascin actin-bundling protein 1 in nasopharyngeal carcinoma. AB - BACKGROUND: Based on our recent microarray analysis, we found that miR-145 was obviously downregulated in nasopharyngeal carcinoma (NPC) tissues. However, little is known about its function and mechanism involving in NPC development and progression. METHODS: Quantitative RT-PCR was used to detect miR-145 expression in NPC cell lines and clinical samples. Wound healing, Transwell migration and invasion, three-dimension spheroid invasion assays, and lung metastasis model were performed to test the migratory, invasive, and metastatic ability of NPC cells. Luciferase reporter assay, quantitative RT-PCR, and Western blotting were used to verify the target of miR-145. RESULTS: MiR-145 was obviously decreased in NPC cell lines and clinical samples (P<0.01). Ectopic overexpression of miR-145 significantly inhibited the migratory and invasive ability of SUNE-1 and CNE-2 cells. In addition, stably overexpressing of miR-145 in SUNE-1 cells could remarkably restrain the formation of metastatic nodes in the lungs of mice. Furthermore, fascin actin-bundling protein 1 (FSCN1) was verified as a target of miR-145, and silencing FSCN1 with small RNA interfering RNA could suppress NPC cell migration and invasion. CONCLUSIONS: Our findings demonstrated that miR-145 function as a tumor suppressor in NPC development and progression via targeting FSCN1, which could sever as a potential novel therapeutic target for patients with NPC. PMID- 25816325 TI - Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. AB - The analysis of structural mobility in molecular dynamics plays a key role in data interpretation, particularly in the simulation of biomolecules. The most common mobility measures computed from simulations are the Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuations (RMSF) of the structures. These are computed after the alignment of atomic coordinates in each trajectory step to a reference structure. This rigid-body alignment is not robust, in the sense that if a small portion of the structure is highly mobile, the RMSD and RMSF increase for all atoms, resulting possibly in poor quantification of the structural fluctuations and, often, to overlooking important fluctuations associated to biological function. The motivation of this work is to provide a robust measure of structural mobility that is practical, and easy to interpret. We propose a Low-Order-Value-Optimization (LOVO) strategy for the robust alignment of the least mobile substructures in a simulation. These substructures are automatically identified by the method. The algorithm consists of the iterative superposition of the fraction of structure displaying the smallest displacements. Therefore, the least mobile substructures are identified, providing a clearer picture of the overall structural fluctuations. Examples are given to illustrate the interpretative advantages of this strategy. The software for performing the alignments was named MDLovoFit and it is available as free software at: http://leandro.iqm.unicamp.br/mdlovofit. PMID- 25816324 TI - Correlation between activation of PI3K/AKT/mTOR pathway and prognosis of breast cancer in Chinese women. AB - BACKGROUND: Abnormal activation of PI3K/AKT/mTOR (PAM) pathway, caused by PIK3CA mutation, KRAS mutation, PTEN loss, or AKT1 mutation, is one of the most frequent signaling abnormalities in breast carcinoma. However, distribution and frequencies of mutations in PAM pathway are unclear in breast cancer patients from the mainland of China and the correlation between these mutations and breast cancer outcome remains to be identified. METHODS: A total of 288 patients with invasive ductal breast cancer were recruited in this study. Mutations in PIK3CA (exons 4, 9 and 20), KRAS (exon 2) and AKT1 (exon 3) were detected using Sanger sequencing. PTEN loss was measured by immunohistochemistry assay. Correlations between these genetic aberrations and clinicopathological features were analyzed. RESULTS: The frequencies of PIK3CA mutation, KRAS mutation, AKT1 mutation and PTEN loss were 15.6%, 1.8%, 4.4% and 35.3%, respectively. However, except for PTEN loss, which was tied to estrogen receptor (ER) status, these alterations were not associated with other clinicopathological features. Survival analysis demonstrated that PIK3CA mutation, PTEN loss and PAM pathway activation were not associated with disease-free survival (DFS). Subgroup analysis of patients with ER positive tumors revealed that PIK3CA mutation more strongly reduced DFS compared to wild-type PIK3CA (76.2% vs. 54.2%; P = 0.011). PIK3CA mutation was also an independent factor for bad prognosis in ER positive patients. CONCLUSIONS: AKT1, KRAS and PIK3CA mutations and PTEN loss all exist in women with breast cancer in the mainland China. PIK3CA mutation may contribute to the poor outcome of ER positive breast carcinomas, providing evidence for the combination of PI3K/AKT/mTOR inhibitors and endocrine therapy. PMID- 25816326 TI - Incidence and Factors Predicting Venous Thromboembolism After Surgical Treatment of Fractures Below the Hip. AB - OBJECTIVES: This study was designed to investigate the incidence and risk factors of postoperative venous thromboembolism (VTE) in a series of patients with fractures below the hip. In addition, we sought to examine the rates of VTE before and after introduction of thromboprophylaxis. DESIGN: Retrospective review. SETTING: University-based academic medical center. PATIENTS: Nine hundred one consecutive patients met the inclusion criteria. Of the 901 patients, 337 (37.4%) were treated before the initiation of institutional guidelines for thromboprophylaxis and 564 (62.6%) received thromboprophylaxis in accordance with our hospitalization protocol. INTERVENTION: Surgical intervention for fractures occurring in the lower extremity below the hip. MAIN OUTCOME MEASUREMENTS: Symptomatic thromboembolic events within 90 days of surgery and risk factors of postoperative VTE. RESULTS: Of the 901 patients, 25 (2.7%) had confirmed symptomatic deep vein thrombosis and 13 (1.4%) had symptomatic pulmonary embolism. The overall incidence of symptomatic VTE was significantly different between the patients not receiving thromboprophylaxis (6.8%; 23 of 337) and those receiving thromboprophylaxis (2.3%; 13 of 564). Of the 31 variables tested for an association with VTE, an advanced age of more than 60 years, cardiovascular disease, and chronic lung disease were independent risk factors. CONCLUSIONS: Clinically detectable VTE in fractures of the lower extremity below the hip are not uncommon, and thromboprophylaxis seemed to decrease the incidence of postoperative VTE. LEVEL OF EVIDENCE: Prognostic Level II. See the guidelines for authors for a complete description of levels of evidence. PMID- 25816327 TI - Molecular dynamics study of naturally existing cavity couplings in proteins. AB - Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the cell milieu. We have divided this problem into two parts. In the first part, we have explored the presence of cavity couplings in the natural dynamics of 75 proteins, using 20 ns molecular dynamics simulations. For each of these proteins, we have obtained two trajectories around their native state. After applying a stringent filtering procedure, we found significant cavity correlations in 60% of the proteins. We analyze and discuss the structure origins of these correlations, including neighbourhood, cavity distance, etc. In the second part of our study, we have used longer simulations (>=100 ns) from the MoDEL project, to obtain a broader view of cavity couplings, particularly about their dependence on time. Using moving window computations we explored the fluctuations of cavity couplings along time, finding that these couplings could fluctuate substantially during the trajectory, reaching in several cases correlations above 0.25/0.5. In summary, we describe the structural origin and the variations with time of cavity couplings. We complete our work with a brief discussion of the biological implications of these results. PMID- 25816328 TI - A rhizosphere-associated symbiont, Photobacterium spp. strain MELD1, and its targeted synergistic activity for phytoprotection against mercury. AB - Though heavy metal such as mercury is toxic to plants and microorganisms, the synergistic activity between them may offer benefit for surviving. In this study, a mercury-reducing bacterium, Photobacterium spp. strain MELD1, with an MIC of 33 mg x kg(-1) mercury was isolated from a severely mercury and dioxin contaminated rhizosphere soil of reed (Phragmites australis). While the whole genome sequencing of MELD1 confirmed the presence of a mer operon, the mercury reductase MerA gene showed 99% sequence identity to Vibrio shilloni AK1 and implicates its route resulted from the event of horizontal gene transfer. The efficiency of MELD1 to vaporize mercury (25 mg x kg(-1), 24 h) and its tolerance to toxic metals and xenobiotics such as lead, cadmium, pentachlorophenol, pentachloroethylene, 3-chlorobenzoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin is promising. Combination of a long yard bean (Vigna unguiculata ssp. Sesquipedalis) and strain MELD1 proved beneficial in the phytoprotection of mercury in vivo. The effect of mercury (Hg) on growth, distribution and tolerance was examined in root, shoot, leaves and pod of yard long bean with and without the inoculation of strain MELD1. The model plant inoculated with MELD1 had significant increases in biomass, root length, seed number, and increased mercury uptake limited to roots. Biolog plate assay were used to assess the sole-carbon source utilization pattern of the isolate and Indole-3-acetic acid (IAA) productivity was analyzed to examine if the strain could contribute to plant growth. The results of this study suggest that, as a rhizosphere-associated symbiont, the synergistic activity between the plant and MELD1 can improve the efficiency for phytoprotection, phytostabilization and phytoremediation of mercury. PMID- 25816329 TI - An S188V mutation alters substrate specificity of non-stereospecific alpha haloalkanoic acid dehalogenase E (DehE). AB - The non-stereospecific alpha-haloalkanoic acid dehalogenase E (DehE) degrades many halogenated compounds but is ineffective against beta-halogenated compounds such as 3-chloropropionic acid (3CP). Using molecular dynamics (MD) simulations and site-directed mutagenesis we show here that introducing the mutation S188V into DehE improves substrate specificity towards 3CP. MD simulations showed that residues W34, F37, and S188 of DehE were crucial for substrate binding. DehE showed strong binding ability for D-2-chloropropionic acid (D-2CP) and L-2 chloropropionic acid (L-2CP) but less affinity for 3CP. This reduced affinity was attributed to weak hydrogen bonding between 3CP and residue S188, as the carboxylate of 3CP forms rapidly interconverting hydrogen bonds with the backbone amide and side chain hydroxyl group of S188. By replacing S188 with a valine residue, we reduced the inter-molecular distance and stabilised bonding of the carboxylate of 3CP to hydrogens of the substrate-binding residues. Therefore, the S188V can act on 3CP, although its affinity is less strong than for D-2CP and L 2CP as assessed by Km. This successful alteration of DehE substrate specificity may promote the application of protein engineering strategies to other dehalogenases, thereby generating valuable tools for future bioremediation technologies. PMID- 25816331 TI - Condition number estimation of preconditioned matrices. AB - The present paper introduces a condition number estimation method for preconditioned matrices. The newly developed method provides reasonable results, while the conventional method which is based on the Lanczos connection gives meaningless results. The Lanczos connection based method provides the condition numbers of coefficient matrices of systems of linear equations with information obtained through the preconditioned conjugate gradient method. Estimating the condition number of preconditioned matrices is sometimes important when describing the effectiveness of new preconditionerers or selecting adequate preconditioners. Operating a preconditioner on a coefficient matrix is the simplest method of estimation. However, this is not possible for large-scale computing, especially if computation is performed on distributed memory parallel computers. This is because, the preconditioned matrices become dense, even if the original matrices are sparse. Although the Lanczos connection method can be used to calculate the condition number of preconditioned matrices, it is not considered to be applicable to large-scale problems because of its weakness with respect to numerical errors. Therefore, we have developed a robust and parallelizable method based on Hager's method. The feasibility studies are curried out for the diagonal scaling preconditioner and the SSOR preconditioner with a diagonal matrix, a tri-daigonal matrix and Pei's matrix. As a result, the Lanczos connection method contains around 10% error in the results even with a simple problem. On the other hand, the new method contains negligible errors. In addition, the newly developed method returns reasonable solutions when the Lanczos connection method fails with Pei's matrix, and matrices generated with the finite element method. PMID- 25816330 TI - Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice. AB - Many attempts have been made to find novel therapeutic strategies for non alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-beta activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH. PMID- 25816332 TI - Diagnostic accuracy of point-of-care tests for hepatitis C virus infection: a systematic review and meta-analysis. AB - BACKGROUND: Point-of-care tests provide a plausible diagnostic strategy for hepatitis C infection in economically impoverished areas. However, their utility depends upon the overall performance of individual tests. METHODS: A literature search was conducted using the metasearch engine Metta, a query interface for retrieving articles from five leading medical databases. Studies were included if they employed point-of-care tests to detect antibodies of hepatitis C virus and compared the results with reference tests. Two reviewers performed a quality assessment of the studies and extracted data for estimating test accuracy. FINDINGS: Thirty studies that had evaluated 30 tests fulfilled the inclusion criteria. The overall pooled sensitivity, specificity, positive likelihood-ratio, negative likelihood-ratio and diagnostic odds ratio for all tests were 97.4% (95% CI: 95.9-98.4), 99.5% (99.2-99.7), 80.17 (55.35-116.14), 0.03 (0.02-0.04), and 3032.85 (1595.86-5763.78), respectively. This suggested a high pooled accuracy for all studies. We found substantial heterogeneity between studies, but none of the subgroups investigated could account for the heterogeneity. Genotype diversity of HCV had no or minimal influence on test performance. Of the seven tests evaluated in the meta-regression model, OraQuick had the highest test sensitivity and specificity and showed better performance than a third generation enzyme immunoassay in seroconversion panels. The next highest test sensitivities and specificities were from TriDot and SDBioline, followed by Genedia and Chembio. The Spot and Multiplo tests produced poor test sensitivities but high test specificities. Nine of the remaining 23 tests produced poor test sensitivities and specificities and/or showed poor performances in seroconversion panels, while 14 tests had high test performances with diagnostic odds ratios ranging from 590.70 to 28822.20. CONCLUSIONS: Performances varied widely among individual point-of-care tests for diagnosis of hepatitis C virus infection. Physicians should consider this while using specific tests in clinical practice. PMID- 25816333 TI - Identification and expression analysis of the interferon-induced protein with tetratricopeptide repeats 5 (IFIT5) gene in duck (Anas platyrhynchos domesticus). AB - The interferon-induced proteins with tetratricopeptide repeats (IFITs) protein family mediates antiviral effects by inhibiting translation initiation, cell proliferation, and migration in the interferon (IFN) dependent innate immune system. Several members of this family, including IFIT1, IFIT2, IFIT3 and IFIT5, have been heavily studied in mammals. Avian species contain only one family member, IFIT5, and little is known about the role of this protein in birds. In this study, duck IFIT5 (duIFIT5) full-length mRNA was cloned by reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of the cDNA ends (RACE). Based on the sequence obtained, we performed a series of bioinformatics analyses, and found that duIFIT5 was most similar to homologs in other avian species. Also, duIFIT5 contained eight conserved TPR motifs and two conserved multi-domains (TPR_11 and TPR_12). Finally, we used duck hepatitis virus type 1 (DHV-1) and polyriboinosinicpolyribocytidylic acid (poly (I:C)) as a pathogen or a pathogen-associated molecular pattern induction to infect three-day old domestic ducklings. The liver and spleen were collected to detect the change in duIFIT5 transcript level upon infection by quantitative real-time PCR (qRT PCR). DuIFIT5 expression rapidly increased after DHV-1 infection and maintained a high level, while the transcripts of duIFIT5 peaked at 8h after poly (I:C) infection and then returned to normal. Taken together, these results provide a greater understanding of avian IFIT5. PMID- 25816334 TI - Expression quantitative trait loci (eQTL) mapping in Puerto Rican children. AB - BACKGROUND: Expression quantitative trait loci (eQTL) have been identified using tissue or cell samples from diverse human populations, thus enhancing our understanding of regulation of gene expression. However, few studies have attempted to identify eQTL in racially admixed populations such as Hispanics. METHODS: We performed a systematic eQTL study to identify regulatory variants of gene expression in whole blood from 121 Puerto Rican children with (n = 63) and without (n = 58) asthma. Genome-wide genotyping was conducted using the Illumina Omni2.5M Bead Chip, and gene expression was assessed using the Illumina HT-12 microarray. After completing quality control, we performed a pair-wise genome analysis of ~15 K transcripts and ~1.3 M SNPs for both local and distal effects. This analysis was conducted under a regression framework adjusting for age, gender and principal components derived from both genotypic and mRNA data. We used a false discovery rate (FDR) approach to identify significant eQTL signals, which were next compared to top eQTL signals from existing eQTL databases. We then performed a pathway analysis for our top genes. RESULTS: We identified 36,720 local pairs in 3,391 unique genes and 1,851 distal pairs in 446 unique genes at FDR <0.05, corresponding to unadjusted P values lower than 1.5x10-4 and 4.5x10-9, respectively. A significant proportion of genes identified in our study overlapped with those identified in previous studies. We also found an enrichment of disease-related genes in our eQTL list. CONCLUSIONS: We present results from the first eQTL study in Puerto Rican children, who are members of a unique Hispanic cohort disproportionately affected with asthma, prematurity, obesity and other common diseases. Our study confirmed eQTL signals identified in other ethnic groups, while also detecting additional eQTLs unique to our study population. The identified eQTLs will help prioritize findings from future genome wide association studies in Puerto Ricans. PMID- 25816336 TI - Impact of exposure to intimate partner violence on CD4+ and CD8+ T cell decay in HIV infected women: longitudinal study. AB - Intimate partner violence (IPV) is a risk factor for HIV acquisition in many settings, but little is known about its impact on cellular immunity especially in HIV infected women, and if any impact differs according to the form of IPV. We tested hypotheses that exposure to IPV, non-partner rape, hunger, pregnancy, depression and substance abuse predicted change in CD4+ and CD8+ T-cell count in a dataset of 103 HIV infected young women aged 15-26 enrolled in a cluster randomised controlled trial. Multiple regression models were fitted to measure rate of change in CD4 and CD8 and including terms for age, person years of CD4+/CD8+ T-cell observation, HIV positivity at baseline, and stratum. Exposure variables included drug use, emotional, physical or sexual IPV exposure, non partner rape, pregnancy and food insecurity. Mean CD4+ T cell count at baseline (or first HIV+ test) was 567.6 (range 1121-114). Participants were followed for an average of 1.3 years. The magnitude of change in CD4 T-cells was significantly associated with having ever experienced emotional abuse from a current partner at baseline or first HIV+ test (Coeff -132.9 95% CI -196.4, -69.4 p<0.0001) and drug use (Coeff -129.9 95% CI -238.7, -21.2 p=0.02). It was not associated with other measures. The change in CD8 T-cells was associated with having ever experienced emotional abuse at baseline or prior to the first HIV+ test (Coeff -178.4 95%CI 330.2, -26.5 p=0.02). In young ART-naive HIV positive women gender-based violence exposure in the form of emotional abuse is associated with a faster rate of decline in markers of cellular immunity. This highlights the importance of attending to emotional abuse when studying the physiological impact of IPV experience and the mechanisms of its impact on women's health. PMID- 25816335 TI - Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis. AB - Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction. PMID- 25816337 TI - The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes. AB - Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: beta hydroxybutyrate (betaOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular betaOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular betaOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater betaOHB/Acoc ratios were also associated with decreased beta-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of betaOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases. PMID- 25816338 TI - Sediment quality of the SW coastal Laizhou Bay, Bohai Sea, China: a comprehensive assessment based on the analysis of heavy metals. AB - Historically, the Bohai Sea is one of the most important fishing grounds in China. Yet, surrounded by one of the biggest economic rims of China, its ecological functions have been declining rapidly in recent two decades under the heavy anthropogenic impacts. The Laizhou Bay is the smallest one of the three main bays in the Bohai Sea. Owing to the rich brine deposits, chemical industries using brine as raw materials are booming in the southern coast of the Laizhou Bay, the scale of which ranks as the largest one in China. In order to monitor and assess the environmental quality, surface sediments were collected from the coastal waters of southwestern Laizhou Bay and the rivers it connects with during summer and autumn in 2012, and analyzed for heavy metals. Several widely adopted methods were used in the overall assessment of heavy metal pollution status and potential ecological risks in these sediments, and the data were analyzed to infer the main sources of the pollutants. The results showed that the remarkably high concentrations of heavy metals were almost all recorded in a small number of riverine sites. Cr, Cu, Ni and Zn were the main environmental threat according to the sediment quality guidelines. The marine area was generally in good condition with no or low risk from the studied metals and adverse effects on biota could hardly occur. Natural sources dominated the concentrations and distributions of Cu, Ni, Pb and Zn in the marine area. Our results indicated that heavy metal pollution was not a main cause of the ecological degradation of the Laizhou Bay at present. PMID- 25816340 TI - Potential cost savings of medication therapy management in safety-net clinics. AB - OBJECTIVE: To evaluate potential cost savings based on estimated cost avoidance from medication therapy management (MTM) services delivered in safety-net clinics over 4 years. METHODS: High-risk patients taking multiple medications and with chronic conditions were referred for MTM services in primary care safety-net clinics in Maryland from October 1, 2009, to September 30, 2013. Medication related problems (MRPs) were identified and pharmacists' costs determined to evaluate the estimated cost savings and return on investment (ROI). A range of potential economic outcomes for each MRP identified was assigned to a cost avoidance for outpatient visit, urgent care visit, emergency department visit, and/or hospitalization. RESULTS: Over 4 years, 246 patients received MTM, nearly 2,100 medications were reviewed, and 814 MRPs were identified. The most common MRPs identified were subtherapeutic doses, nonadherence, and untreated indications, with respective prevalences of 38%, 19%, and 16%. The corresponding costs of medical services were estimated at $115,220-$614,570 for all MRPs identified, yielding a mean of $141.55-$755.00 per identified MRP. Pharmacists' expenses for encounters were calculated at a total expenditure of $57,307.50 for 16,965 minutes. ROI based on the time spent during billable face-to-face encounters ranged from 1:5 to 1:25. CONCLUSION: Pharmacist-provided MTM in safety net clinics yielded potential economic benefits to the organization. The Primary Care Coalition of Montgomery County plans to expand MTM services to additional clinics to improve patient care and increase cost savings through preventable medical services. PMID- 25816339 TI - Identification of an ADAM17 cleavage region in human CD16 (FcgammaRIII) and the engineering of a non-cleavable version of the receptor in NK cells. AB - CD16a and CD16b are IgG Fc receptors expressed by human natural killer (NK) cells and neutrophils, respectively. Both CD16 isoforms undergo a rapid down-regulation in expression by ADAM17-mediated proteolytic cleavage upon cell activation by various stimuli. We examined soluble CD16 released from activated NK cells and neutrophils by mass spectrometric analysis, and identified three separate cleavage sites in close proximity at P1/P1' positions alanine195/valine196, valine196/serine197, and threonine198/isoleucine199, revealing a membrane proximal cleavage region in CD16. Substitution of the serine at position 197 in the middle of the cleavage region for a proline (S197P) effectively blocked CD16a and CD16b cleavage in cell-based assays. We also show that CD16a/S197P was resistant to cleavage when expressed in the human NK cell line NK92 and primary NK cells derived from genetically-engineered human induced pluripotent stem cells. CD16a is a potent activating receptor and despite blocking CD16a shedding, the S197P mutation did not disrupt IgG binding by the receptor or its activation of NK92 cells by antibody-treated tumor cells. Our findings provide further characterization of CD16 cleavage by ADAM17 and they demonstrate that a non cleavable version of CD16a can be expressed in engineered NK cells. PMID- 25816341 TI - MAP kinase phosphatase 2 regulates macrophage-adipocyte interaction. AB - OBJECTIVE: Inflammation is critical for the development of obesity-associated metabolic disorders. This study aims to investigate the role of mitogen-activated protein kinase phosphatase 2 (MKP-2) in inflammation during macrophage-adipocyte interaction. METHODS: White adipose tissues (WAT) from mice either on a high-fat diet (HFD) or normal chow (NC) were isolated to examine the expression of MKP-2. Murine macrophage cell line RAW264.7 stably expressing MKP-2 was used to study the regulation of MKP-2 in macrophages in response to saturated free fatty acid (FFA) and its role in macrophage M1/M2 activation. Macrophage-adipocyte co culture system was employed to investigate the role of MKP-2 in regulating inflammation during adipocyte-macrophage interaction. c-Jun N-terminal kinase (JNK)- and p38-specific inhibitors were used to examine the mechanisms by which MKP-2 regulates macrophage activation and macrophage-adipocytes interaction. RESULTS: HFD changed the expression of MKP-2 in WAT, and MKP-2 was highly expressed in the stromal vascular cells (SVCs). MKP-2 inhibited the production of proinflammatory cytokines in response to FFA stimulation in macrophages. MKP-2 inhibited macrophage M1 activation through JNK and p38. In addition, overexpression of MKP-2 in macrophages suppressed inflammation during macrophage adipocyte interaction. CONCLUSION: MKP-2 is a negative regulator of macrophage M1 activation through JNK and p38 and inhibits inflammation during macrophage adipocyte interaction. PMID- 25816342 TI - Effects of source- versus household contamination of tubewell water on child diarrhea in rural Bangladesh: a randomized controlled trial. AB - BACKGROUND: Shallow tubewells are the primary drinking water source for most rural Bangladeshis. Fecal contamination has been detected in tubewells, at low concentrations at the source and at higher levels at the point of use. We conducted a randomized controlled trial to assess whether improving the microbiological quality of tubewell drinking water by household water treatment and safe storage would reduce diarrhea in children <2 years in rural Bangladesh. METHODS: We randomly assigned 1800 households with a child aged 6-18 months (index child) into one of three arms: chlorine plus safe storage, safe storage and control. We followed households with monthly visits for one year to promote the interventions, track their uptake, test participants' source and stored water for fecal contamination, and record caregiver-reported child diarrhea prevalence (primary outcome). To assess reporting bias, we also collected data on health outcomes that are not expected to be impacted by our interventions. FINDINGS: Both interventions had high uptake. Safe storage, alone or combined with chlorination, reduced heavy contamination of stored water. Compared to controls, diarrhea in index children was reduced by 36% in the chlorine plus safe storage arm (prevalence ratio, PR = 0.64, 0.55-0.73) and 31% in the safe storage arm (PR = 0.69, 0.60-0.80), with no difference between the two intervention arms. One limitation of the study was the non-blinded design with self-reported outcomes. However, the prevalence of health outcomes not expected to be impacted by water interventions did not differ between study arms, suggesting minimal reporting bias. CONCLUSIONS: Safe storage significantly improved drinking water quality at the point of use and reduced child diarrhea in rural Bangladesh. There was no added benefit from combining safe storage with chlorination. Efforts should be undertaken to implement and evaluate long-term efforts for safe water storage in Bangladesh. TRIAL REGISTRATION: ClinicalTrials.gov NCT01350063. PMID- 25816343 TI - A multi-omics approach identifies key hubs associated with cell type-specific responses of airway epithelial cells to staphylococcal alpha-toxin. AB - Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla treatment including activation of the epidermal growth factor receptor EGFR and mitogen-activated protein kinases MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects. PMID- 25816344 TI - Ligand-target prediction by structural network biology using nAnnoLyze. AB - Target identification is essential for drug design, drug-drug interaction prediction, dosage adjustment and side effect anticipation. Specifically, the knowledge of structural details is essential for understanding the mode of action of a compound on a target protein. Here, we present nAnnoLyze, a method for target identification that relies on the hypothesis that structurally similar binding sites bind similar ligands. nAnnoLyze integrates structural information into a bipartite network of interactions and similarities to predict structurally detailed compound-protein interactions at proteome scale. The method was benchmarked on a dataset of 6,282 pairs of known interacting ligand-target pairs reaching a 0.96 of area under the Receiver Operating Characteristic curve (AUC) when using the drug names as an input feature for the classifier, and a 0.70 of AUC for "anonymous" compounds or compounds not present in the training set. nAnnoLyze resulted in higher accuracies than its predecessor, AnnoLyze. We applied the method to predict interactions for all the compounds in the DrugBank database with each human protein structure and provide examples of target identification for known drugs against human diseases. The accuracy and applicability of our method to any compound indicate that a comparative docking approach such as nAnnoLyze enables large-scale annotation and analysis of compound-protein interactions and thus may benefit drug development. PMID- 25816345 TI - Factors associated with nurses' intention to leave their jobs after the Fukushima Daiichi Nuclear Power plant accident. AB - We conducted a survey among nurses who were working at the Fukushima Medical University Hospital at the time of the Fukushima Daiichi Nuclear Power Plant accident to clarify the factors associated with their intention to leave their jobs during the radiation emergency. We asked 345 nurses (17 men and 328 women) about their intention to leave their jobs after the accident. We also asked about relevant factors including the participants' demographic factors, living situation, working status, and knowledge of radiation health effects. We found that living with preschoolers (OR = 1.87, 95%CI: 1.02-3.44, p = 0.042), anxiety about life in Fukushima City after the accident (OR = 5.55, 95%CI: 1.18-26.13, p = 0.030), consideration of evacuation from Fukushima after the accident (OR = 2.42, 95%CI: 1.45-4.06, p = 0.001), consideration of the possible radiation health effects in children (OR = 1.90, 95%CI: 1.02-3.44, p = 0.042), and anxiety about relationships with colleagues in the hospital after the accident (OR = 3.23, p = 0.001) were independently associated with the nurses' intention to leave their jobs after the accident. On the other hand, the percentage of nurses with knowledge on radiation health effects was relatively low among those who had the intention to leave the job and among those who did not have the intention to leave the job after the accident, with no significant differences between the two groups. Our results suggest the need for an education program for nurses regarding radiation health effects. PMID- 25816346 TI - Playing vs. nonplaying aerobic training in tennis: physiological and performance outcomes. AB - This study compared the effects of playing and nonplaying high intensity intermittent training (HIIT) on physiological demands and tennis stroke performance in young tennis players. Eleven competitive male players (13.4 +/- 1.3 years) completed both a playing and nonplaying HIIT session of equal distance, in random order. During each HIIT session, heart rate (HR), blood lactate, and ratings of perceived exertion (RPE) were monitored. Before and after each HIIT session, the velocity and accuracy of the serve, and forehand and backhand strokes were evaluated. The results demonstrated that both HIIT sessions achieved an average HR greater than 90% HRmax. The physiological demands (average HR) were greater during the playing session compared to the nonplaying session, despite similar lactate concentrations and a lower RPE. The results also indicate a reduction in shot velocity after both HIIT sessions; however, the playing HIIT session had a more deleterious effect on stroke accuracy. These findings suggest that 1) both HIIT sessions may be sufficient to develop maximal aerobic power, 2) playing HIIT sessions provide a greater physiological demand with a lower RPE, and 3) playing HIIT has a greater deleterious effect on stroke performance, and in particular on the accuracy component of the ground stroke performance, and should be incorporated appropriately into a periodization program in young male tennis players. PMID- 25816347 TI - Real-time state estimation in a flight simulator using fNIRS. AB - Working memory is a key executive function for flying an aircraft. This function is particularly critical when pilots have to recall series of air traffic control instructions. However, working memory limitations may jeopardize flight safety. Since the functional near-infrared spectroscopy (fNIRS) method seems promising for assessing working memory load, our objective is to implement an on-line fNIRS based inference system that integrates two complementary estimators. The first estimator is a real-time state estimation MACD-based algorithm dedicated to identifying the pilot's instantaneous mental state (not-on-task vs. on-task). It does not require a calibration process to perform its estimation. The second estimator is an on-line SVM-based classifier that is able to discriminate task difficulty (low working memory load vs. high working memory load). These two estimators were tested with 19 pilots who were placed in a realistic flight simulator and were asked to recall air traffic control instructions. We found that the estimated pilot's mental state matched significantly better than chance with the pilot's real state (62% global accuracy, 58% specificity, and 72% sensitivity). The second estimator, dedicated to assessing single trial working memory loads, led to 80% classification accuracy, 72% specificity, and 89% sensitivity. These two estimators establish reusable blocks for further fNIRS based passive brain computer interface development. PMID- 25816348 TI - Co-encapsulating the fusogenic peptide INF7 and molecular imaging probes in liposomes increases intracellular signal and probe retention. AB - Liposomes are promising vehicles to deliver diagnostic and therapeutic agents to cells in vivo. After uptake into cells by endocytosis, liposomes are degraded in the endolysosomal system. Consequently, the encapsulated cargo molecules frequently remain sequestered in endosomal compartments; this limits their usefulness in many applications (e.g. gene delivery). To overcome this, various fusogenic peptides have been developed to facilitate delivery of liposomally encapsulated molecules into the cytosol. One such peptide is the pH-sensitive influenza-derived peptide INF7. Liposomal delivery of imaging agents is an attractive approach for enabling cell imaging and cell tracking in vivo, but can be hampered by inadequate intracellular accumulation and retention of probes caused by exocytosis (and possible degradation) of endosome-entrapped probes. Such signal loss could be minimized by facilitating escape of probe molecules from endolysosomal compartments into the cytosol. We investigated the ability of co-encapsulated INF7 to release liposomally-delivered rhodamine fluorophores into the cytosol after endosomal acidification/maturation. We co-encapsulated INF7 and fluorescent rhodamine derivatives having vastly different transport properties to show that after endocytosis by CV1 cells, the INF7 peptide is activated by acidic endosomal pH and facilitates efficient release of the fluorescent tracers into the cytosol. Furthermore, we show that INF7-facilitated escape from endosomes markedly enhanced retention of tracers that cannot be actively extruded from the cytosol. Minimizing loss of intracellular probes improves cellular imaging by increasing the signal-to-noise ratio of images and lengthening the time window that imaging can be performed. In particular, this will enhance in vivo electron paramagnetic resonance imaging, an emergent magnetic resonance imaging modality requires exogenous paramagnetic imaging agents and is highly promising for cellular and molecular imaging. PMID- 25816349 TI - Estrogenicity of glabridin in Ishikawa cells. AB - Glabridin is an isoflavan from licorice root, which is a common component of herbal remedies used for treatment of menopausal symptoms. Past studies have shown that glabridin resulted in favorable outcome similar to 17beta-estradiol (17beta-E2), suggesting a possible role as an estrogen replacement therapy (ERT). This study aims to evaluate the estrogenic effect of glabridin in an in-vitro endometrial cell line -Ishikawa cells via alkaline phosphatase (ALP) assay and ER alpha-SRC-1-co-activator assay. Its effect on cell proliferation was also evaluated using Thiazoyl blue tetrazolium bromide (MTT) assay. The results showed that glabridin activated the ER-alpha-SRC-1-co-activator complex and displayed a dose-dependent increase in estrogenic activity supporting its use as an ERT. However, glabridin also induced an increase in cell proliferation. When glabridin was treated together with 17beta-E2, synergistic estrogenic effect was observed with a slight decrease in cell proliferation as compared to treatment by 17beta E2 alone. This suggest that the combination might be better suited for providing high estrogenic effects with lower incidences of endometrial cancer that is associated with 17beta-E2. PMID- 25816350 TI - Decreased HIV-specific T-regulatory responses are associated with effective DC vaccine induced immunity. AB - The role of regulatory T cells (Tregs) in vaccination has been poorly investigated. We have reported that vaccination with ex vivo-generated dendritic cells (DC) loaded with HIV-lipopeptides (LIPO-5-DC vaccine) in HIV-infected patients was well tolerated and highly immunogenic. These responses and their relation to viral replication following analytical treatment interruption (ATI) were variable. Here, we investigated whether the presence of HIV-specific Tregs might explain these differences. Co-expression of CD25, CD134, CD39 and FoxP3 was used to delineate both antigen-specific Tregs and effectors T cells (Teffs). Median LIPO-5 specific-CD25+CD134+ polyfunctional T cells increased from 0.1% (IQR 0-0.3) before vaccination (week -4) to 2.1% (IQR 1.1-3.9) at week 16 following 4 immunizations (p=0.001) and were inversely correlated with maximum viral load following ATI (r=-0.77, p=0.001). Vaccinees who displayed lower levels of HIV-specific CD4+CD134+CD25+CD39+FoxP3+ Tregs responded better to the LIPO-5 DC vaccine. After vaccination, the frequency of HIV-specific Tregs decreased (from 69.3 at week -4 to 31.7% at week 16) and inversely correlated with HIV specific IFN-gamma-producing cells (r=-0.64, p=0.002). We show that therapeutic immunization skewed the HIV-specific response from regulatory to effector phenotype which impacts on the magnitude of viral replication following ATI. PMID- 25816351 TI - The differential expression of OCT4 isoforms in cervical carcinoma. AB - OCT4 is a transcription factor involved in maintaining stem cell phenotype and pluripotential. However, it remains unclear the expression pattern and biological function of OCT4 isoforms in cervical cancer. Here, we reported that both nuclear OCT4A and cytoplasmic OCT4B were overexpressed in CC. OCT4A was responsible for self-renewal of cervical cancer stem-like cells (CCSCs). Furthermore, OCT4B overexpression in SiHa cervical cancer cell line significantly increased cell proliferation and tumorigenesis by inhibiting apoptosis. Moreover, OCT4B enhanced angiogenesis by the upregulation of CD34, VEGF, HIF-1alpha and IL-6, and promoted tumor cell mobility to the surrounding tissue by the upregulation of MMP2 and MMP9, and the induction of epithelial-mesenchymal transition (EMT). In conclusion, nuclear OCT4A may serve as a marker of CCSCs and the driving force for cervical cancer metastasis and recurrence, while cytoplasmic OCT4B may cooperate with OCT4A to regulate the progression of cervical cancer through inducing angiogenesis and EMT. PMID- 25816352 TI - An essential signal peptide peptidase identified in an RNAi screen of serine peptidases of Trypanosoma brucei. AB - The serine peptidases of Trypanosoma brucei have been viewed as potential drug targets. In particular, the S9 prolyl oligopeptidase subfamily is thought to be a good avenue for drug discovery. This is based on the finding that some S9 peptidases are secreted and active in the mammalian bloodstream, and that they are a class of enzyme against which drugs have successfully been developed. We collated a list of all serine peptidases in T. brucei, identifying 20 serine peptidase genes, of which nine are S9 peptidases. We screened all 20 serine peptidases by RNAi to determine which, if any, are essential for bloodstream form T. brucei survival. All S9 serine peptidases were dispensable for parasite survival in vitro, even when pairs of similar genes, coding for oligopeptidase B or prolyl oligopeptidase, were targeted simultaneously. We also found no effect on parasite survival in an animal host when the S9 peptidases oligopeptidase B, prolyl oligopeptidase or dipeptidyl peptidase 8 were targeted. The only serine peptidase to emerge from the RNAi screen as essential was a putative type-I signal peptide peptidase (SPP1). This gene was essential for parasite survival both in vitro and in vivo. The growth defect conferred by RNAi depletion of SPP1 was rescued by expression of a functional peptidase from an RNAi resistant SPP1 gene. However, expression of catalytically inactive SPP1 was unable to rescue cells from the SPP1 depleted phenotype, demonstrating that SPP1 serine peptidase activity is necessary for T. brucei survival. PMID- 25816353 TI - Factors associated with medication adherence among patients with schizophrenia in Mekelle, Northern Ethiopia. AB - BACKGROUND: Non-adherence to antipsychotic medication has a negative impact on the course of illness resulting in increased risk of relapse, rehospitalization and suicide, and increased costs to healthcare systems. The objective of this study was to investigate factors associated with medication adherence among patients with schizophrenia at Ayder Referral Hospital and Mekelle Hospital in Mekelle, Tigray region, Northern Ethiopia. METHODS: The study was a cross sectional survey in which sociodemographic characteristics, drug attitudes, insight and side effects were measured and explored in terms of their relationship with medication adherence. A structured questionnaire as a data collection tool was used. Data were analyzed with the help of SPSS Version 20.0. RESULTS: A total of 393 patients participated, 26.5% were non-adherent to their antipsychotic medication. The factors significantly associated with better adherence were positive treatment attitudes (AOR = 1.40, 95% CI: 1.26, 1.55), fewer side effects (AOR = 0.97, 95% CI: 0.94, 0.99), awareness of illness (AOR = 1.44, 95% CI: 1.12, 1.85) and the ability to relabel symptoms (AOR = 1.57, 95% CI: 1.19, 2.07). However, khat chewers (AOR = 0.24, 95% CI: 0.09, 0.68), being illiterate (AOR = 0.13, 95% CI: 0.03, 0.47) and older age group (AOR = 0.03, 95% CI: 0.01, 0.16) were associated with less medication adherence. CONCLUSIONS: A high prevalence of medication non-adherence was found among patients with schizophrenia. Intervention strategies focused on educating the patients to better understand the illness, medications and their potential side effects might be useful in improving adherence to antipsychotic medication treatment. PMID- 25816355 TI - Development of a Rabbit Model of Radiation-Induced Sciatic Nerve Injury: In Vivo Evaluation Using T2 Relaxation Time Measurements. AB - OBJECTIVES: To develop a rabbit model of radiation-induced sciatic nerve injury (RISNI), using computed tomography (CT)-guided stereotactic radiosurgery, and assess the value of T2 measurements of injured nerves. MATERIALS AND METHODS: Twenty New Zealand rabbits were randomly divided into A (n = 5) and B (n = 15) groups. Group A rabbits underwent CT and magnetic resonance scan and were then killed for comparison of images and anatomy of sciatic nerves. One side of the sciatic nerve of group B rabbits received irradiation doses of 35, 50, or 70 Gy (n = 5 per group). Magnetic resonance imaging and functional assessments were performed before irradiation and 1, 2, 3, and 4 months thereafter. RESULT: The thigh section of the sciatic nerve outside the pelvis could be observed by CT and magnetic resonance imaging. T2 values of the irradiated nerve of the 35-Gy group increased gradually, peaking at 4 months; T2 values of the 50-Gy group increased faster, peaking at 3 months. Significant differences between the 35-Gy and control groups were found at 3 and 4 months, and between the 50-Gy and control groups at 2, 3, and 4 months. Functional scores of the 50-Gy group declined progressively, whereas the 35-Gy group scores reached a low point at 3 months posttreatment and then recovered. Functional scores of the irradiated limbs demonstrated a negative correlation with T2 values (r = -0.591 and -0.595, P < 0.05). Electron microscopy revealed progressive deformation and degeneration of the irradiated nerve in the 35- and 50-Gy groups, which were more severe in the 50-Gy group. CONCLUSIONS: A rabbit RISNI model can be produced using the midthigh segment of the sciatic nerve and single-fraction doses of 35 and 50 Gy. Although T2 values are useful for monitoring RISNI, they may not be sensitive enough to evaluate its severity. PMID- 25816354 TI - Small-quantity lipid-based nutrient supplements, regardless of their zinc content, increase growth and reduce the prevalence of stunting and wasting in young burkinabe children: a cluster-randomized trial. AB - Small-quantity lipid-based nutrient supplements (SQ-LNS) are promising home fortification products, but the optimal zinc level needed to improve growth and reduce morbidity is uncertain. We aimed to assess the impact of providing SQ-LNS with varied amounts of zinc, along with illness treatment, on zinc-related outcomes compared with standard care. In a placebo-controlled, cluster-randomized trial, 34 communities were stratified to intervention (IC) or non-intervention cohorts (NIC). 2435 eligible IC children were randomly assigned to one of four groups:1) SQ-LNS without zinc, placebo tablet; 2) SQ-LNS containing 5mg zinc, placebo tablet; 3) SQ-LNS containing 10mg zinc, placebo tablet; or 4) SQ-LNS without zinc and 5mg zinc tablet from 9-18 months of age. During weekly morbidity surveillance, oral rehydration salts were provided for reported diarrhea and antimalarial therapy for confirmed malaria. Children in NIC (n = 785) did not receive SQ-LNS, tablets, illness surveillance or treatment. At 9 and 18 months, length, weight and hemoglobin were measured in all children. Reported adherence was 97 +/- 6% for SQ-LNS and tablets. Mean baseline hemoglobin was 89 +/- 15g/L. At 18 months, change in hemoglobin was greater in IC than NIC (+8 vs -1g/L, p<0.0001), but 79.1% of IC were still anemic (vs. 91.1% in NIC). Final plasma zinc concentration did not differ by group. During the 9-month observation period, the incidence of diarrhea was 1.10 +/- 1.03 and of malaria 0.54 +/- 0.50 episodes per 100 child-days, and did not differ by group. Length at 18 months was significantly greater in IC compared to NIC (77.7 +/- 3.0 vs. 76.9 +/- 3.4 cm; p<0.001) and stunting prevalence was significantly lower in IC (29.3%) than NIC (39.3%; p<0.0001), but did not differ by intervention group within IC. Wasting prevalence was also significantly lower in IC (8.7%) than in NIC (13.5%; p = 0.0003). Providing SQ-LNS daily with or without zinc, along with malaria and diarrhea treatment, significantly increased growth and reduced stunting, wasting and anemia prevalence in young children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00944281. PMID- 25816356 TI - Effect of HIF-1alpha on biological activation of human tongue squamous cell carcinoma SCC-15 cells in vitro. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a key regulator for tumor cells and tissues to adapt to hypoxic condition. Suppressing the expression of HIF 1alpha is important to evaluate its effect on cancer cells. This study was carried out to analyze the effect of HIF-1alpha on the biological activation of human tongue squamous cell carcinoma (TSCC) SCC-15 cells. In this experiment, deferoxamine mesylate (DFO) was used to induce hypoxic condition. HIF-1alpha gene was suppressed by lentiviral vector. The effect of the level of HIF-1alpha expression was tested on the proliferation, cell cycle, cell apoptosis and cell invasion of SCC-15 cells. We demonstrated that SCC-15 cells showed a more aggressive phenotype after treated with DFO. Additionally, DFO was able to induce the expression of HIF-1alpha protein. Lentiviral vector can effectively inhibit HIF-1alpha expression on mRNA and protein level. Under normoxic or hypoxic conditions, downregulation of HIF-1alpha for SCC-15 cells induced cell apoptosis and inhibited growth and invasion. These results showed that suppressing the expression of HIF-1alpha inhibited the aggressive potential of SCC-15 cells under normoxic and hypoxic condition. Thus, finding an effective and safe pathway to inhibit the expression of HIF-1alpha can help us to improve the survival rate of human TSCC patients. PMID- 25816358 TI - An unusual presentation of oculoauriculovertebral spectrum with a Tessier 30 cleft: report on two cases. AB - Oculoauriculovertebral spectrum (OAVS, OMIM 164210) is a complex condition characterized by defects in aural, oral, and mandibular development. Other craniofacial and extracranial anomalies can be present. With the exception of the Tessier number 7 cleft, atypical clefting has rarely been reported in association with OAVS. Here, we report on two unrelated cases with a typical phenotype of OAVS and a Tessier 30 associated cleft. One of them also had other atypical facial clefts. We discuss the association between atypical facial clefts and OAVS. PMID- 25816359 TI - Chemical composition, antioxidant properties and hepatoprotective effects of chamomile (Matricaria recutita L.) decoction extract against alcohol-induced oxidative stress in rat. AB - The present study assessed the chemical composition, antioxidant properties, and hepatoprotective effects of subacute pre-treatment with chamomile (Matricaria recutita L.) decoction extract (CDE) against ethanol (EtOH)-induced oxidative stress in rats. The colorimetric analysis demonstrated that the CDE is rich in total polyphenols, total flavonoids and condensed tannins, and exhibited an important in vitro antioxidant activity. The use of LC/MS technique allowed us to identify 10 phenolic compounds in CDE. We found that CDE pretreatment, in vivo, protected against EtOH-induced liver injury evident by plasma transaminases activity and preservation of the hepatic tissue structure. The CDE counteracted EtOH-induced liver lipoperoxidation, preserved thiol -SH groups and prevented the depletion of antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). We also showed that acute alcohol administration increased tissue and plasma hydrogen peroxide (H(2)O(2)), calcium and free iron levels. More importantly, CDE pre-treatment reversed all EtOH induced disturbances in intracellular mediators. In conclusion, our data suggest that CDE exerted a potential hepatoprotective effect against EtOH-induced oxidative stress in rat, at least in part, by negatively regulating Fenton reaction components such as H(2)O(2) and free iron, which are known to lead to cytotoxicity mediated by intracellular calcium deregulation. PMID- 25816357 TI - Seeking a mechanism for the toxicity of oligomeric alpha-synuclein. AB - In a number of neurological diseases including Parkinson's disease (PD), alpha synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of alpha-synuclein in vivo. The toxicity of alpha synuclein is popularly attributed to the formation of "toxic oligomers": a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of alpha-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic alpha-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between alpha-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of alpha-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described. PMID- 25816360 TI - System for exposing cultured cells to intermittent hypoxia utilizing gas permeable cultureware. AB - Tissue intermittent hypoxia (IH) occurs in obstructive sleep apnea, sickle cell anemia, physical exercise and other conditions. Poor gas solubility and slow diffusion through culture media hampers mimicking IH-induced transitions of O(2) in vitro. We aimed to develop a system enabling exposure of cultured cells to IH and to validate such exposure by real-time O(2) measurements and cellular responses. Standard 24-well culture plates and plates with bottoms made from a gas permeable film were placed in a heated cabinet. Desired cycling of O(2) levels was induced using programmable solenoids to purge mixtures of 95% N(2) + 5% CO(2) or 95% O(2) + 5% CO(2). Dissolved oxygen, gas pressure, temperature, and water evaporation were measured during cycling. IH-induced cellular effects were evaluated by hypoxia inducible factor (HIF) and NF-kappaB luciferase reporters in HEK296 cells and by insulin secretion in rat insulinoma cells. Oxygen cycling in the cabinet was translated into identical changes of O(2) at the well bottom in gas permeable, but not in standard cultureware. Twenty-four hours of IH exposure increased HIF (112%), NF-kappaB (111%) and insulin secretion (44%). Described system enables reproducible and prolonged IH exposure in cultured cells while controlling for important environmental factors. PMID- 25816361 TI - Biphasic response of cardiodynamic adaptations to swimming exercise in rats. AB - The aim of research was to assess exercise-induced changes in mechanics of hearts isolated from rats, as well as time-course of those changes. Wistar rats (n = 42) were divided into control, moderately trained (swimming 1 hour, 5 days a week for 9 or 12 weeks) and strenuously trained (swimming 2, 3 and 4 times a day for an hour in weeks 10, 11 and 12, respectively) groups. After sacrificing, hearts (weight: 1480.82 +/- 145.38 mg) were isolated and perfused on a Langendorff apparatus. Coronary perfusion pressure (CPP) was gradually increased (from 40 to 120 cm H(2)O) in order to establish coronary autoregulation. Parameters of cardiac contractility were recorded: maximum and minimum rate of change of pressure in the left ventricle (dp/dt max and dp/dt min), systolic and diastolic left ventricular pressure (SLVP and DLVP), heart rate (HR) and coronary flow (CF). Nine weeks of moderate exercise induced slight depression of coronary function (decrease of dp/dt max, dp/dt min, SLVP and DLVP), while 3 additional weeks of moderate training improved hearts function, but not to the extent that the strenuous training program did. The results of our study add evidence about beneficial effects of regular moderate exercise on heart, and furthermore, show that exercising frequently, if the intensity stays within moderate range, may not have detrimental effects on cardiodynamics. PMID- 25816362 TI - The assessment of septal wall motion in patients undergoing CABG by myocardial perfusion-gated SPECT. AB - PURPOSE: In this study, we aimed to assess the presence and prevalence of paradoxical septal motion (PSM) by myocardial perfusion-gated single-photon emission computed tomography (SPECT) imaging in patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 172 patients (145 men and 27 women, with a mean age of 64.81 +/- 8.93 years) undergoing CABG surgery were included in the study. All selected scintigraphic studies of the patients undergoing CABG were reprocessed. Semiquantitative interpretation of septal perfusion, wall motion, and wall thickening was performed with QPS and QGS programs. Phase analysis parameters were also obtained using the Emory Cardiac Toolbox. According to myocardial perfusion-gated SPECT results, the patients were trichotomized as follows: group 1 (nonischemic PSM): regular perfusion and thickening of the septal wall and abnormal motion of the septal wall; group 2 (ischemic PSM): abnormal perfusion, motion, and thickening of the septal wall; group 3 (non-PSM): normal perfusion, motion, and thickening of the septal wall. The data in each of the three groups were compared using Student's t-test and one way analysis of variance. RESULTS: No PSM (normal perfusion, motion, and thickening of the septal wall) was observed in 19.2% of patients undergoing CABG, whereas nonischemic PSM (regular perfusion and thickening of the septal wall and abnormal motion of the septal wall) was observed in 60.5% of patients and ischemic PSM (abnormal perfusion, motion and thickening of the septal wall) was seen in 20.3% of patients. CONCLUSION: According to our study results, PSM is fairly common in patients undergoing CABG. It will be beneficial to use myocardial perfusion scintigraphy-gated SPECT, which is a noninvasive examination method, to identify the presence of PSM and investigate whether it is accompanied by ischemia or infarction. PMID- 25816364 TI - Correction: The genetic basis of variation in clean lineages of Saccharomyces cerevisiae in response to stresses encountered during bioethanol fermentations. PMID- 25816363 TI - Long-Term Ambient Residential Traffic-Related Exposures and Measurement Error Adjusted Risk of Incident Lung Cancer in the Netherlands Cohort Study on Diet and Cancer. AB - BACKGROUND: The International Agency for Research on Cancer (IARC) recently declared air pollution carcinogenic to humans. However, no study of air pollution and lung cancer to date has incorporated adjustment for exposure measurement error, and few have examined specific histological subtypes. OBJECTIVES: Our aim was to assess the association of air pollution and incident lung cancer in the Netherlands Cohort Study on Diet and Cancer and the impact of measurement error on these associations. METHODS: The cohort was followed from 1986 through 2003, and 3,355 incident cases were identified. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals, for long-term exposures to nitrogen dioxide (NO2), black smoke (BS), PM2.5 (particulate matter with diameter <= 2.5 MUm), and measures of roadway proximity and traffic volume, adjusted for potential confounders. Information from a previous validation study was used to correct the effect estimates for measurement error. RESULTS: We observed elevated risks of incident lung cancer with exposure to BS [hazard ratio (HR) = 1.16; 95% CI: 1.02, 1.32, per 10 MUg/m3], NO2 (HR = 1.29; 95% CI: 1.08, 1.54, per 30 MUg/m3), PM2.5 (HR = 1.17; 95% CI: 0.93, 1.47, per 10 MUg/m3), and with measures of traffic at the baseline address. The exposures were positively associated with all lung cancer subtypes. After adjustment for measurement error, the HRs increased and the 95% CIs widened [HR = 1.19 (95% CI: 1.02, 1.39) for BS and HR = 1.37 (95% CI: 0.86, 2.17) for PM2.5]. CONCLUSIONS: These findings add support to a growing body of literature on the effects of air pollution on lung cancer. In addition, they highlight variation in measurement error by pollutant and support the implementation of measurement error corrections when possible. CITATION: Hart JE, Spiegelman D, Beelen R, Hoek G, Brunekreef B, Schouten LJ, van den Brandt P. 2015. Long-term ambient residential traffic-related exposures and measurement error-adjusted risk of incident lung cancer in the Netherlands Cohort Study on Diet and Cancer. Environ Health Perspect 123:860-866; http://dx.doi.org/10.1289/ehp.1408762. PMID- 25816365 TI - Wound edge protectors in open abdominal surgery to reduce surgical site infections: a systematic review and meta-analysis. AB - IMPORTANCE: Surgical site infections remain one of the most frequent complications following abdominal surgery and cause substantial costs, morbidity and mortality. OBJECTIVE: To assess the effectiveness of wound edge protectors in open abdominal surgery in reducing surgical site infections. EVIDENCE REVIEW: A systematic literature search was conducted according to a prespecified review protocol in a variety of data-bases combined with hand-searches for randomized controlled trials on wound edge protectors in patients undergoing laparotomy. A qualitative and quantitative analysis of included trials was conducted. FINDINGS: We identified 16 randomized controlled trials including 3695 patients investigating wound edge protectors published between 1972 and 2014. Critical appraisal uncovered a number of methodological flaws, predominantly in the older trials. Wound edge protectors significantly reduced the rate of surgical site infections (risk ratio 0.65; 95%CI, 0.51-0.83; p = 0.0007; I2 = 52%). The results were robust in a number of sensitivity analyses. A similar effect size was found in the subgroup of patients undergoing colorectal surgery (risk ratio 0.65; 95%CI, 0.44-0.97; p = 0.04; I2 = 56%). Of the two common types of wound protectors double ring devices were found to exhibit a greater protective effect (risk ratio 0.29; 95%CI, 0.15-0.55) than single-ring devices (risk ratio 0.71; 95%CI, 0.54-0.92), but this might largely be due to the lower quality of available data for double-ring devices. Exploratory subgroup analyses for the degree of contamination showed a larger protective effect in contaminated cases (0.44; 95%CI, 0.28-0.67; p = 0.0002, I2 = 23%) than in clean-contaminated surgeries (0.72, 95%CI, 0.57-0.91; p = 0.005; I2 = 46%) and a strong effect on the reduction of superficial surgical site infections (risk ratio 0.45; 95%CI, 0.24-0.82; p = 0.001; I2 = 72%). CONCLUSIONS AND RELEVANCE: Wound edge protectors significantly reduce the rate of surgical site infections in open abdominal surgery. Further trials are needed to explore their effectiveness in different risk constellations. PMID- 25816366 TI - Quantification of cellular viability by automated microscopy and flow cytometry. AB - Cellular viability is usually determined by measuring the capacity of cells to exclude vital dyes such as 4',6-diamidino-2-phenylindole (DAPI), or by assessing nuclear morphology with chromatinophilic plasma membrane-permeant dyes, such as Hoechst 33342. However, a fraction of cells that exclude DAPI or exhibit normal nuclear morphology have already lost mitochondrial functions and/or manifest massive activation of apoptotic caspases, and hence are irremediably committed to death. Here, we developed a protocol for the simultaneous detection of plasma membrane integrity (based on DAPI) or nuclear morphology (based on Hoechst 33342), mitochondrial functions (based on the mitochondrial transmembrane potential probe DiOC6(3)) and caspase activation (based on YO-PRO(r)-3, which can enter cells exclusively upon the caspase-mediated activation of pannexin 1 channels). This method, which allows for the precise quantification of dead, dying and healthy cells, can be implemented on epifluorescence microscopy or flow cytometry platforms and is compatible with a robotized, high-throughput workflow. PMID- 25816367 TI - Activation of AKR1C1/ERbeta induces apoptosis by downregulation of c-FLIP in prostate cancer cells: A prospective therapeutic opportunity. AB - We provide first-time evidence for ERbeta-mediated transcriptional upregulation of c-FLIP as an underlying mechanism in the development of castrate-resistant cancer. While androgens inhibit apoptosis partly through transcriptional upregulation of the anti-apoptotic protein, c-FLIP in androgen-responsive cells, they downregulate c-FLIP in androgen-independent cells. We found that although Sp1 and p65 trans-activate c-FLIP, the combination of Sp1 and p65 has differential effects in a cellular context-dependent manner. We show that activation of the androgen metabolism enzyme, aldo-keto reductase, AKR1C1, relieves androgen independence through activation of 3beta-Adiol-mediated upregulation of ERbeta. ERbeta competes with Sp1 and Sp3 to transcriptionally downregulate c-FLIP in the absence of consensus estrogen-response element in androgen-independent cells. Forced expression of AR in androgen-independent cells show that ERbeta-mediated growth inhibition occurs under conditions of androgen independence. Reactivation of ERbeta with the estrogenic metabolite, 2 methoxyestradiol, decreased enrichment ratio of Sp1/Sp3 at the c-FLIP promoter with concomitant effects on cell growth and death. Expression of Sp1 and c-FLIP are elevated while AKR1C1, ERbeta and Sp3 are significantly low in human prostate tumor samples. ERbeta is epigenetically silenced in prostate cancer patients, therefore our results suggest that combination of ERbeta agonists with ADT would benefit men stratified on the basis of high estrogen levels. PMID- 25816368 TI - Association between Arsenic Exposure from Drinking Water and Longitudinal Change in Blood Pressure among HEALS Cohort Participants. AB - BACKGROUND: Cross-sectional studies have shown associations between arsenic exposure and prevalence of high blood pressure; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking. METHOD: We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every 2 years after baseline. Mixed-effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with annual change in blood pressure during follow-up (median, 6.7 years). RESULT: In the HEALS population, the median water arsenic concentration at baseline was 62 MUg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in systolic blood pressure compared with those in the reference group (beta = 0.48 mmHg/year; 95% CI: 0.35, 0.61, and beta = 0.43 mmHg/year; 95% CI: 0.29, 0.56 for water arsenic and urinary creatinine-adjusted arsenic, respectively) in fully adjusted models. Likewise, individuals in the highest quartile of baseline arsenic exposure had a greater annual increase in diastolic blood pressure for water arsenic and urinary creatinine-adjusted arsenic, (beta = 0.39 mmHg/year; 95% CI: 0.30, 0.49, and beta = 0.45 mmHg/year; 95% CI: 0.36, 0.55, respectively) compared with those in the lowest quartile. CONCLUSION: Our findings suggest that long-term arsenic exposure may accelerate age-related increases in blood pressure. These findings may help explain associations between arsenic exposure and cardiovascular disease. PMID- 25816369 TI - The role of prenatal care and social risk factors in the relationship between immigrant status and neonatal morbidity: a retrospective cohort study. AB - BACKGROUND AND AIM: Literature evaluating association between neonatal morbidity and immigrant status presents contradictory results. Poorer compliance with prenatal care and greater social risk factors among immigrants could play roles as major confounding variables, thus explaining contradictions. We examined whether prenatal care and social risk factors are confounding variables in the relationship between immigrant status and neonatal morbidity. METHODS: Retrospective cohort study: 231 pregnant African immigrant women were recruited from 2007-2010 in northern Spain. A Spanish population sample was obtained by simple random sampling at 1:3 ratio. Immigrant status (Spanish, Sub-Saharan and Northern African), prenatal care (Kessner Index adequate, intermediate or inadequate), and social risk factors were treated as independent variables. Low birth weight (LBW < 2500 grams) and preterm birth (< 37 weeks) were collected as neonatal morbidity variables. Crude and adjusted odds ratios (OR) were estimated by unconditional logistic regression with 95% confidence intervals (95% CI). RESULTS: Positive associations between immigrant women and higher risk of neonatal morbidity were obtained. Crude OR for preterm births in Northern Africans with respect to nonimmigrants was 2.28 (95% CI: 1.04-5.00), and crude OR for LBW was 1.77 (95% CI: 0.74-4.22). However, after adjusting for prenatal care and social risk factors, associations became protective: adjusted OR for preterm birth = 0.42 (95% CI: 0.14-1.32); LBW = 0.48 (95% CI: 0.15-1.52). Poor compliance with prenatal care was the main independent risk factor associated with both preterm birth (adjusted OR inadequate care = 17.05; 95% CI: 3.92-74.24) and LBW (adjusted OR inadequate care = 6.25; 95% CI: 1.28-30.46). Social risk was an important independent risk factor associated with LBW (adjusted OR = 5.42; 95% CI: 1.58-18.62). CONCLUSIONS: Prenatal care and social risk factors were major confounding variables in the relationship between immigrant status and neonatal morbidity. PMID- 25816371 TI - Leaf surface lipophilic compounds as one of the factors of silver birch chemical defense against larvae of gypsy moth. AB - Plant chemical defense against herbivores is a complex process which involves a number of secondary compounds. It is known that the concentration of leaf surface lipophilic compounds (SLCs), particularly those of flavonoid aglycones are increased with the defoliation treatment of silver birch Betula pendula. In this study we investigated how the alteration of SLCs concentration in the food affects the fitness and innate immunity of the gypsy moth Lymantria dispar. We found that a low SLCs concentrations in consumed leaves led to a rapid larval development and increased females' pupae weight (= fecundity) compared to larvae fed with leaves with high SLCs content. Inversely, increasing the compounds concentration in an artificial diet produced the reverse effects: decreases in both larval weight and larval survival. Low SLCs concentrations in tree leaves differently affected larval innate immunity parameters. For both sexes, total hemocytes count in the hemolymph increased, while the activity of plasma phenoloxidase decreased when larvae consume leaves with reduced content of SLCs. Our results clearly demonstrate that the concentration of SLCs in silver birch leaves affects not only gypsy moth fitness but also their innate immune status which might alter the potential resistance of insects against infections and/or parasitoids. PMID- 25816370 TI - The GATA factor elt-1 regulates C. elegans developmental timing by promoting expression of the let-7 family microRNAs. AB - Postembryonic development in Caenorhabditis elegans is a powerful model for the study of the temporal regulation of development and for the roles of microRNAs in controlling gene expression. Stable switch-like changes in gene expression occur during development as stage-specific microRNAs are expressed and subsequently down-regulate other stage-specific factors, driving developmental progression. Key genes in this regulatory network are phylogenetically conserved and include the post-transcriptional microRNA repressor LIN-28; the nuclear hormone receptor DAF-12; and the microRNAs LIN-4, LET-7, and the three LET-7 family miRNAs (miR 48, miR-84, and miR-241). DAF-12 is known to regulate transcription of miR-48, miR-84 and miR-241, but its contribution is insufficient to account for all of the transcriptional regulation implied by the mutant phenotypes. In this work, the GATA-family transcription factor ELT-1 is identified from a genetic enhancer screen as a regulator of developmental timing in parallel to DAF-12, and is shown to do so by promoting the expression of the LET-7, miR-48, miR-84, and miR-241 microRNAs. The role of ELT-1 in developmental timing is shown to be separate from its role in cell-fate maintenance during post-embryonic development. In addition, analysis of Chromatin Immnoprecipitation (ChIP) data from the modENCODE project and this work suggest that the contribution of ELT-1 to the control of let-7 family microRNA expression is likely through direct transcription regulation. PMID- 25816372 TI - Thrombomodulin promotes corneal epithelial wound healing. AB - PURPOSE: To determine the role of thrombomodulin (TM) in corneal epithelial wound healing, and to investigate whether recombinant TM epidermal growth factor-like domain plus serine/threonine-rich domain (rTMD23) has therapeutic potential in corneal epithelial wound healing. METHODS: TM localization and expression in the murine cornea were examined by immunofluorescence staining. TM expression after injury was also studied. The effect of rTMD23 on corneal wound healing was evaluated by in vitro and in vivo assays. RESULTS: TM was expressed in the cornea in normal adult mice. TM expression increased in the early phase of wound healing and decreased after wound recovery. In the in vitro study, platelet-derived growth factor-BB (PDGF-BB) induced TM expression in murine corneal epithelial cells by mediating E26 transformation-specific sequence-1 (Ets-1) via the mammalian target of rapamycin (mTOR) signaling pathway. The administration of rTMD23 increased the rate of corneal epithelial wound healing. CONCLUSIONS: TM expression in corneal epithelium was modulated during the corneal wound healing process, and may be regulated by PDGF-BB. In addition, rTMD23 has therapeutic potential in corneal injury. PMID- 25816373 TI - Sensitivity towards fear of electric shock in passive threat situations. AB - Human judgment and decision-making (JDM) requires an assessment of different choice options. While traditional theories of choice argue that cognitive processes are the main driver to reach a decision, growing evidence highlights the importance of emotion in decision-making. Following these findings, it appears relevant to understand how individuals asses the attractiveness or riskiness of a situation in terms of emotional processes. The following study aims at a better understanding of the psychophysiological mechanisms underlying threat sensitivity by measuring skin conductance responses (SCRs) in passive threat situations. While previous studies demonstrate the role of magnitude on emotional body reactions preceding an outcome, this study focuses on probability. In order to analyze emotional body reactions preceding negative events with varying probability of occurrence, we have our participants play a two-stage card game. The first stage of the card game reveals the probability of receiving an unpleasant electric shock. The second stage applies the electric shock with the previously announced probability. For the analysis, we focus on the time interval between the first and second stage. We observe a linear relation between SCRs in anticipation of receiving an electric shock and shock probability. This finding indicates that SCRs are able to code the likelihood of negative events. We outline how this coding function of SCRs during the anticipation of negative events might add to an understanding of human JDM. PMID- 25816375 TI - Executive Summary of Key Concepts. PMID- 25816374 TI - Effect of interwall interaction on the electronic structure of double-walled carbon nanotubes. AB - Through this study, the results of density functional theory calculations within the local density approximation of the electronic structure of zigzag-zigzag double-walled carbon nanotubes (DWCNTs), with chiral indices (n, 0)@(m, 0) for n = 7-15, and m = 15-26, has been presented and the effects of interwall interaction and orbital hybridization on the electronic structure of these systems has been discussed. It was observed that the electronic band gap of the aforementioned DWCNTs depends on the interwall distance only for metallic semiconductor configurations and on the intrinsic properties of the constituent tubes in all other combinations. It was also observed that the calculated band gap for most of the metallic-metallic DWCNTs was smaller than semiconductor metallic, metallic-semiconductor, and semiconductor-semiconductor configurations. Metallic-semiconductor DWCNTs were found to be desirable for band gap tuning applications because of their dependence on interwall distance, opening up the possibility of using such systems in electronic device applications, such as transistors. Other applications include the use of DWCNTs in macroscopic carbon nanotube conducting wires, for which metallic-metallic and semiconducting metallic zigzag-zigzag DWCNTs were found to be the most desirable configurations due to their small band gaps. PMID- 25816376 TI - A milestone of change. PMID- 25816377 TI - Effects of revised consultation room design on patient-physician communication. AB - OBJECTIVE: To evaluate the impact of a revised consultation room design on patient-physician interaction in an outpatient setting. BACKGROUND: The growth of ambulatory medical care makes outpatient facilities the primary point of health care contact for many Americans. However, the outpatient consultation room design remains largely unchanged, despite its increased use and the adoption of technology-mediated information sharing in clinical encounter. METHODS: A randomized controlled trial used a postvisit questionnaire to assess six domains of interest (satisfaction with the visit and the consultation room, mutual respect, patient trust in the physician, communication quality, people-room interaction, and interpersonal-room interaction) in two different room designs (a traditional room and an experimental room in which a pedestal table had replaced the examination table). RESULTS: Interpersonal-room interaction was enhanced in the experimental consultation room when compared to the traditional consultation room (p = .0038). Participants in the experimental consultation room had better access to the computer screen, increased provider information sharing, and more time engaging providers in conversation about information on the monitor. CONCLUSIONS: Changing the layout of a consultation room has the potential to improve interpersonal communication through better information sharing. Clinicians who are interested in maximizing the benefits of their clinical encounter should consider changing the layout of their consultation room, especially the positioning of the computer screen. PMID- 25816378 TI - Optimizing the patient-centered environment: results of guided tours with health care providers and employees. AB - OBJECTIVE: To examine providers' perspectives on the care environment and patient centered care (PCC) through the eyes of the veteran patient, using guided tours qualitative methodology. BACKGROUND: Environmental factors, such as attractiveness and function, have the potential to improve patients' experiences. Participatory qualitative methods allow researchers to explore the environment and facilitate discussion. METHODS: Guided tours were conducted with 25 health care providers/employees at two Veterans Affairs (VA) health care facilities. In guided tours, participants lead the researcher through an environment, commenting on their surroundings, thoughts, and feelings. The researcher walks along with the participant, asking open-ended questions as needed to foster discussion and gain an understanding of the participant's view. Participants were asked to walk through the facility as though they were a veteran. Tours were audio recorded, with participant permission, and transcribed verbatim by research assistants. Three qualitative researchers were responsible for codebook development and coding transcripts and used data-driven coding approaches. RESULTS: Participants discussed physical appearance of the environment and how that influences perceptions about care. Overall, participants highlighted the need to shed the "institutional" appearance. Differences between VA and non-VA health care facilities were discussed, including availability of private rooms and staff to assist with navigating the facility. They reviewed resources in the facility, such as the information desk to assist patients and families. Finally, they offered suggestions for future improvements, including improvements to waiting areas and quiet areas for patients to relax and "get away" from their rooms. CONCLUSIONS: Participants highlighted many small changes to the care environment that could enhance the patient experience. Additionally, they examined the environment from the patient's perspective, to identify elements that enhance, or detract from, the patient's care experience. PMID- 25816379 TI - Assessing the physical service setting: a look at emergency departments. AB - OBJECTIVE: To determine the attributes of the physical setting that are important for developing a positive service climate within emergency departments and to validate a measure for assessing physical service design. BACKGROUND: The design of the physical setting is an important and contributing factor for creating a service climate in organizations. Service climate is defined as employee perceptions of the practices, procedures, and behaviors that get rewarded, supported, and expected with regard to customer service and customer service quality. There has been research conducted which identifies antecedents within organization that promotes a positive service climate which in turn creates service-oriented behaviors by employees toward clients. The antecedent of the physical setting and its impact on perceptions of service climate has been less commonly explored. METHODS: Using the concept of the physical service setting (which may be defined as aspects of the physical, built environment that facilitate the delivery of quality service), attributes of the physical setting and their relationship with service climate were explored by means of a quantitative paper survey distributed to emergency nurses (n = 180) throughout a province in Canada. RESULTS: The results highlight the validity and reliability of six scales measuring the physical setting and its relation to service. Respondents gave low ratings to the physical setting of their departments, in addition to low ratings of service climate. CONCLUSIONS: Respondents feel that the design of the physical setting in the emergency departments where they work is not conducive to providing quality service to clients. Certain attributes of the physical setting were found to be significant in influencing perceptions of service climate, hence service quality, within the emergency department setting. PMID- 25816380 TI - An Exploration of the Nightstand and Over-the-Bed Table in an Inpatient Rehabilitation Hospital. AB - OBJECTIVE: This study seeks to determine where patients in a rehabilitation hospital keep the greatest percentage of their belongings, that is, in/on the nightstand or on the over-the-bed table. BACKGROUND: This study provides an inventory of patient items located on the over-the-bed table and in/on the nightstand. Understanding the functions of furnishings within the patient room is key for future preparation for designing a next-generation over-the-bed table or for redesigning a more useful nightstand. METHODS: The contents on the top of the nightstand; the contents in the top, middle, and bottom drawers of the nightstand; items next to the nightstand; and the contents on the over-the-bed table within patient rooms were inventoried and placed into categories using similar, patient item categories as the Brooks et al. (2011) study, which examined the contents of the nightstand and the over-the-bed table in assisted living and skilled nursing facilities. RESULTS: Overall, patients in a rehabilitation hospital had a greater percentage of their belongings on the top of the nightstand as compared to their belongings located in all three combined drawers of the nightstand. Overall, patients had a greater percentage of their belongings located on the over-the-bed table as compared to their belongings located on the nightstand. CONCLUSIONS: Tabletop surface area was used extensively in patient rooms at a rehabilitation hospital, but nightstand drawers were underutilized. PMID- 25816381 TI - An empirical examination of the impacts of decentralized nursing unit design. AB - OBJECTIVE: The objective of the study was to examine the impact of decentralization on operational efficiency, staff well-being, and teamwork on three inpatient units. BACKGROUND: Decentralized unit operations and the corresponding physical design solution were hypothesized to positively affect several concerns-productive use of nursing time, staff stress, walking distances, and teamwork, among others. With a wide adoption of the concept, empirical evidence on the impact of decentralization was warranted. METHODS: A multimethod, before-and-after, quasi-experimental design was adopted for the study, focusing on five issues, namely, (1) how nurses spend their time, (2) walking distance, (3) acute stress, (4) productivity, and (5) teamwork. Data on all five issues were collected on three older units with centralized operational model (before move). The same set of data, with identical tools and measures, were collected on the same units after move in to new physical units with decentralized operational model. Data were collected during spring and fall of 2011. RESULTS: Documentation, nurse station use, medication room use, and supplies room use showed consistent change across the three units. Walking distance increased (statistically significant) on two of the three units. Self-reported level of collaboration decreased, although assessment of the physical facility for collaboration increased. CONCLUSIONS: Decentralized nursing and physical design models potentially result in quality of work improvements associated with documentation, medication, and supplies. However, there are unexpected consequences associated with walking, and staff collaboration and teamwork. The solution to the unexpected consequences may lie in operational interventions and greater emphasis on culture change. PMID- 25816383 TI - Institutional Review Boards and Peer-Reviewed Publication. PMID- 25816382 TI - Ambient versus traditional environment in pediatric emergency department. AB - OBJECTIVE: We sought to examine the effect of exposure to an ambient environment in a pediatric emergency department. We hypothesized that passive distraction from ambient lighting in an emergency department would lead to reduction in patient pain and anxiety and increased caregiver satisfaction with services. BACKGROUND: Passive distraction has been associated with lower anxiety and pain in patients and affects perception of wait time. A pediatric ED was designed that optimized passive distraction techniques using colorful ambient lighting. METHODS: Participants were nonrandomly assigned to either an ambient ED environment or a traditional ED environment. Entry and exit questionnaires assessed caregiver expectations and experiences. Pain ratings were obtained with age-appropriate scales, and wait times were recorded. RESULTS: A total of 70 participants were assessed across conditions, that is, 40 in the ambient ED group and 30 in the traditional ED group. Caregivers in the traditional ED group expected a longer wait, had higher anxiety pretreatment, and felt more scared than those in the ambient ED group. Caregivers in the ambient ED group felt more included in the care of their child and rated quality of care higher than caregivers in the traditional ED group. Pain ratings and administrations of pain medication were lower in the ambient ED group. CONCLUSIONS: Mean scores for the ambient ED group were in the expected direction on several items measuring satisfaction with ED experiences. Results were suggestive of less stress in caregivers, less pain in patients, and higher satisfaction levels in the ambient ED group. PMID- 25816385 TI - A Practitioner's Transition to Academic Researcher. PMID- 25816384 TI - Ten trends transforming cancer care and their effects on space planning for academic medical centers. AB - OBJECTIVE: This article aims to define the major trends currently affecting space needs for academic medical center (AMC) cancer centers. It will distinguish between the trends that promote the concentration of services with those that promote decentralization as well as identify opportunities for achieving greater effectiveness in cancer care space planning. BACKGROUND: Changes in cancer care higher survival rates, increased clinical trials, new technology, and changing practice models-increasingly fill hospitals' and clinicians' schedules and strain clinical space resources. Conflicts among these trends are concentrating some services and dispersing others. As a result, AMCs must expand and renovate intelligently to continue providing state-of-the-art, compassionate care. CONCLUSIONS: Although the typical AMC cancer center can expect to utilize more space than it would have 10 years ago, a deeper understanding of the cancer center enterprise can lead to opportunities for more effectively using available facility resources. Each AMC must determine for itself the appropriate balance of patient volume, clinical activity, and services between its main hospital campus and satellite branches. As well, space allocation should be flexible, as care trends, medical technology, and the provider's own priorities shift over time. The goal isn't necessarily more space-it's better space. PMID- 25816386 TI - Positioning patient status monitors in a family waiting room. AB - OBJECTIVE: To determine where to place patient status displays for family members in the operating room family waiting room at The Children's Hospital of Philadelphia. METHODS: We calculated the percentage of seats from which wall monitors placed in hypothetical positions would be usable. We validated the usability of the new monitors by observing nonemployees' use of monitors in the waiting room 1 week before and 1 week after implementation. RESULTS: Compared to the legacy monitor, the new monitors were observed to be used from more locations within the waiting room and more people were observed to use the new monitors soon after entering the waiting room. CONCLUSIONS: Seemingly trivial decisions like where in a waiting room to place monitors can be informed by careful data collection and the consequences can observably impact communication between hospital staff and family members waiting for loved ones in surgery. PMID- 25816388 TI - In search of the happy balance-intuition and evidence. PMID- 25816387 TI - If I were a band-aid, where would I be? Researching the use and location of supplies on two patient units. AB - OBJECTIVE: The purpose of this study was to gain insight into the use and storage of supplies in the neonatal intensive care and women's health units of Parkland Hospital in Dallas, Texas. BACKGROUND: Construction of a new Parkland Hospital is underway, with completion of the 862-bed, 2.5-million square feet hospital in 2014. Leaders from the hospital and representatives from one of its major vendors collaborated on a research study to evaluate the hospital's current supply management system and develop criteria to create an improved system to be implemented at the new hospital. METHOD: Approach includes qualitative and quantitative methods, that is, written survey, researcher observations, focus groups, and evaluation of hospital supply reports. RESULTS: Approaching the ideal location of supplies can be best approached by defining a nurse's activity at the point of care. Determining an optimal supply management system must be approached by understanding the "what" of caregivers' activities and then determining the "where" of the supplies that support those activities. CONCLUSIONS: An ideal supply management system locates supplies as close as possible to the point of use, is organized by activity, and is standardized within and across units. PMID- 25816389 TI - The editor replies. PMID- 25816390 TI - Lundin reacts-a last word. PMID- 25816392 TI - Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil. AB - Pesticides are widespread synthesized substances used for public health protection and agricultural programs. However, they cause environmental pollution and health hazards. This study aimed to examine the protective effects of sesame oil (SO) on the genetic alterations induced by cypermethrin (CYP) in the liver and kidney of Wistar rats. Male rats were divided into four groups, each containing 10 rats: the control group received vehicle, SO group (5 mL/kg b.w), CYP group (12 mg/kg b.w), and protective group received SO (5 mL/kg b.w) plus CYP (12 mg/kg b.w). Biochemical analysis showed an increase in albumin, urea, creatinine, GPT, GOT, and lipid profiles in the CYP group. Co-administration of SO with CYP normalized such biochemical changes. CYP administration decreased both the activity and mRNA expression of the examined antioxidants. SO co administration recovered CYP, downregulating the expression of glutathione-S transferase (GST), catalase, and superoxide dismutase. Additionally, SO co administration with CYP counteracted the CYP- altering the expression of renal interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-alpha), heme oxygenase-1 (HO-1), anigotensinogen (AGT), AGT receptors (AT1), and genes of hepatic glucose and fatty acids metabolism. CYP induced degenerative changes in the kidney and liver histology which are ameliorated by SO. In conclusion, SO has a protective effect against alterations and pathological changes induced by CYP in the liver and kidney at genetic and histological levels. PMID- 25816393 TI - Vulvar sarcomas: Short guideline for histopathological recognition and clinical management. Part 2. AB - Malignant tumors of the female reproductive system are a serious health and social problem, as they are the second most common cause of death among women, after breast cancer. Vulvar tumors represent only 4% of all gynecological neoplasms, and they are fourth in frequency after tumors of the cervix, uterus, and ovary. Ninety-eight percent of all vulvar tumors are benign and only 2% are malignant. Sarcomas of the vulva comprise approximately 1-3% of all vulvar cancers. They are characterized by rapid growth, high metastatic potential, frequent recurrences, aggressive behavior, and high mortality rate. In Part 1 of this paper, we presented the most common forms of sarcoma of the vulva: leiomyosarcoma, epithelioid sarcoma, malignant rhabdoid tumor, and rhabdomyosarcoma. The second part of this review will focus mainly on the rarest variants of vulvar sarcoma: low-grade fibromyxoid sarcoma, synovial sarcoma, monophasic synovial sarcoma, carcinosarcoma, Ewing sarcoma, myeloid sarcoma, dermatofibrosarcoma protuberans, malignant fibrous histiocytoma, angiomatoid fibrous histiocytoma, liposarcoma, malignant peripheral nerve sheath tumor, and malignant mesothelioma. PMID- 25816394 TI - Vulvar sarcomas: Short guideline for histopathological recognition and clinical management. Part 1. AB - Malignant tumors of the female reproductive system are a serious health and social problem, as they are the second most common cause of death among women, after breast cancer. Their incidence has increased dramatically during recent years, probably due to the different sexual habits and changes in the prevalence of HIV/ AIDS and HPV virus carriers, among other factors. Vulvar tumors represent only 4% of all gynecological neoplasms, and they are fourth in frequency after tumors of the cervix, uterus, and ovary. Ninety eight percent of all vulvar tumors are benign and only 2% are malignant. The overall incidence of tumors with vulvar location is between two and seven cases per 100,000 women, and it increases with age, while the death rate is estimated at 0.7 per 100,000 women. Sarcomas of the vulva comprise approximately 1-3% of all vulvar cancers, with leiomyosarcomas, epithelioid sarcomas, and rhabdomyosarcomas being the most common among them. They are characterized by rapid growth, high metastatic potential, frequent recurrences, aggressive behavior, and high mortality rate. In this paper, we present the most common forms of sarcomas of the vulva (leiomyosarcoma, epithelioid sarcoma, malignant rhabdoid tumor, rhabdomyosarcoma) in order to emphasize the broad differential diagnosis, rare appearance, non specific clinical picture, aggressive course, and high mortality. PMID- 25816395 TI - Synthesis, characterization, and efficacy evaluation of a new anti-diabetic vanadyl(II) thiamine hydrochloride complex in streptozotocin-induced diabetic rats. AB - Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to abnormalities in either insulin secretion or action. A range of vanadium complexes have been synthesized and demonstrated to be effective in lowering hyperglycemia. Thiamine administration was also reported to prevent deterioration in fasting glucose and insulin levels, and to improve glucose tolerance in hyperglycemic patients. This study has been conducted to evaluate the ionic vanadyl(II) thiamine hydrochloride complex (VC) as a new anti-diabetic candidate. The new complex was characterized by infrared spectroscopy (FT-IR), electronic spectra, magnetic susceptibility, electron spin resonance (ESR), scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The anti-diabetic effect of VC was investigated in comparison to vanadium sulfate in streptozotocin (STZ)-induced diabetic rats. Treatment of diabetic rats with VC versus vanadyl sulfate showed a more potent effect on reducing serum glucose and cholesterol close to normal levels. VC suppressed the diabetes-induced upregulation of hepatic glucose transporter (GLUT)-2, Phosphoenol pyruvate carboxykinase (PEPCK), and hormone-sensitive lipase (HSL) more significantly than vanadyl sulfate. Either vanadyl sulfate or VC restored hepatic sterol regulatory element-binding protein transcription factor-1c (SREBP-1c) and muscle hexokinase (HK) mRNA expression that was downregulated in diabetic group. Pyruvate kinase (PK) mRNA expression was restored more significantly in VC-treated than vanadyl sulfate-treated diabetic rats. These results indicate that the newly synthesized VC could be an effective anti-diabetic candidate as the anti-diabetic activity of the ionic vanadium was enhanced after being modified with the organic ligand, thiamin. The results also suggest that VC achieves its effect most likely through modulating the transcription of energy metabolizing enzymes. PMID- 25816396 TI - Penile length is a very important factor for cosmesis, function and psychosexual development in patients affected by hypospadias: Results from a long-term longitudinal cohort study. AB - Few studies of long-term outcome of hypospadias treatment in terms of voiding, surgical complications, sexual functioning, intimate relationships and cosmetic results have been investigated and contrasting results have been obtained so far. The aim of our study is to investigate the long-term outcome of urinary and sexual function, cosmesis and the quality of intimate relationships in a series of hypospadias. In this study, 42 patients who underwent surgery for hypospadias were prospectively followed for 15 years. Medical records provided the hypospadias data, the number of reconstructive operations and the reconstruction technique that was used. Patients underwent physical examination, including penile length measurement and completed International Prostatic Symptoms Score (I PSS), International Index Of Erectile Function (IIEF 15) and the Penile Perception Score questionnaire (PPPS). Twenty patients agreed to participate in the study. At the enrolment, the median value of HOSE was 13, as regards PPPS, 18/20 (90%) were satisfied, while in 1998 only 80% were satisfied. No significant statistical difference has been reported from the results obtained at enrolment and those obtained at follow-up, in terms of PPPS (P = 0.81), IPSS and IIEF-15. Penile length was 6.5 cm flaccid and 10.5 cm stretched. Our data show how cosmesis, function and psychosexual development for these patients are highly connected to surgical outcome, which is understood to be a decrease in penile size. PMID- 25816397 TI - Should an increase in cerebral neurochemicals following head kicks in full contact karate influence return to play? AB - BACKGROUND: Cerebral neurochemicals are markers of traumatic brain injury (TBI). OBJECTIVES: The aim of the study was to determine whether kicks to the head (KTH) in full contact karate significantly increased serum concentrations of protein S 100B, and neurone specific enolase (NSE). Kicks to the body (KTB) were also quantified to asses muscle tissue injury. Muscle damage was assessed by analysis of serum total creatine kinase (CK). METHODS: Twenty-four full contact karate practitioners were observed and filmed during actual competition and divided into two main groups post event: (1) Kicks to the head and body group (KTH): n = 12; mean +/- SD; age, 30.4 +/- 6.7 years; height, 1.74 +/- 0.1 m; weight, 79.1 +/- 2.1 kg; and (2): Kicks to the body group (KTB): n = 12; mean +/- SD; age, 28.2 +/ 6.5 years; height, 1.75 +/- 0.1 m; weight, 79.2 +/- 1.7 kg. The KTH group received direct kicks to the head, while group KTB received kicks and punches to the body. Blood samples were taken before and immediately post-combat for analysis of serum S-100B, NSE, CK and cardiac troponin. RESULTS: Significant increases in serum concentrations of S-100B (0.12 +/- 0.17 vs. 0.37 +/- 0.26, ug.L(-1)) and NSE (11.8 +/- 4.1 vs. 20.2 +/- 9.1 ng.mL(-1)) were encountered after combat in the KTH group and CK (123 +/- 53 vs. 184 +/- 103 U.L(-1)) in the KTB group (all P <0.05). CONCLUSIONS: Head kicks in full contact karate cause elevation of neurochemical markers associated with damaged brain tissue. The severity of injury is related to the early post-traumatic release of protein S 100B and NSE. The early kinetics and appearance post injury can reflect intracranial pathology, and suggest S-100B and NSE are extremely sensitive prognostic markers of TBI. PMID- 25816398 TI - Oxymatrine suppresses proliferation and induces apoptosis of hemangioma cells through inhibition of HIF-1a signaling. AB - Oxymatrine (OMT), a natural quinolizidine alkaloid, has been known to have anti inflammation, anti-anaphylaxis, and chemopreventive effects on various cancer cells. To clarify the underlying role and molecular mechanisms of OMT in human hemangioma (HA), in the present study, we examined the expression of hypoxia inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) in different phases of human HA. After HA derived endothelial cells (HDEC) were pretreated with different concentrations of OMT, cell proliferation, apoptosis, and cycle distribution were evaluated by MTT assay and flow cytometry analysis, respectively. The effects of OMT on expression of HIF-1a signaling were determined by real-time PCR and western blot assays. Our results showed that, the expression of HIF-1a and VEGF was significantly increased in proliferating phase HA, but decreased in involuting phase HA. Moreover, OMT in vitro inhibited proliferative activities and induced cell apoptosis and cycle arrest in G0/G1 phase in HA cells with decreased expression of HIF-1a, VEGF, Bcl-2, and CyclinD1, and increased expression of p53. Taken together, our findings suggest that, the expression of HIF-1a and VEGF is increased in proliferating phase HA, and OMT suppresses cell proliferation and induces cell apoptosis and cycle arrest in proliferative phase HA through inhibition of the HIF-1a signaling pathway, suggesting OMT may provide a novel therapeutic strategy for the treatment of HA. PMID- 25816400 TI - Carbon nanotubes: Properties, biomedical applications, advantages and risks in patients and occupationally-exposed workers. AB - Since the beginning of the 21st century, carbon-based nanomaterials (CNTs) have been introduced in pharmacy and medicine for drug delivery system in therapeutics. CNTs have proved able to transport a wide range of molecules across membranes and into living cells; therefore, they have attracted great interest in biomedical applications such as advanced imaging, tissue regeneration, and drug or gene delivery. Although there are many data on the advantages in terms of higher efficacy and less adverse effects, several recent findings have reported unexpected toxicities induced by CNTs. The dose, shape, surface chemistry, exposure route, and purity play important roles in these differential toxicities. Mapping these risks as well as understanding their molecular mechanisms is a crucial step in the development of any CNT-containing nanopharmaceuticals. This paper seeks to provide a comprehensive review of all articles published on cellular response to CNTs, underlining their therapeutic applications and possible toxicity in patients and occupationally exposed workers. PMID- 25816399 TI - Low prevalence of metallo-beta-lactamase in Pseudomonas aeruginosa isolated from a tertiary burn care center in Tehran. AB - Production of metallo-beta-lactamase (MBL) is one of the main mechanisms for resistance in carbapenem antibiotics. Detection of MBL-producer Pseudomonas aeruginosa is crucial in preventing its spread to other gram-negative bacteria. The aim of this study was to evaluate combination disc (CD) for identification of MBL-producer P. aeruginosa by polymerase chain reaction (PCR). A total of 255 imipenem resistant P. aeruginosa were collected from burn patients. Antibiotic susceptibility testing was conducted after purification and identification. Double-disc synergy test (DDST) with EDTA and combination disc test (CDT) with dipicolinic acid were performed for phenotypic detection of MBL and the PCR was carried out for blaVIM, blaIMP, blaNDM-1, blaSPM-1 genes. DDST with EDTA was negative in all cases, but 161 isolates were positive in CDT with dipicolinic acid. Further, blaVIM and blaIMP were detected in five and four strains, respectively. None of the isolates were positive for BlaNDM-1 and blaSPM-1 . The results of this study showed that the prevalence of MBL is low in imipenem resistance P. aeruginosa and that other mechanisms could be involved in resistance to imipenem in this bacterium. PMID- 25816401 TI - Evolution and functions of stanniocalcins in cancer. AB - Stanniocalcin (STC), first isolated from the corpuscles of stannius of teleost fishes, was originally known for its regulation on calcium/phosphate transport. Increasing evidence demonstrates that STCs display the important function in some physiological and pathological behaviors such as calcium regulation, oxidative stress, anti-inflammation, angiogenesis, ischemia reperfusion, nerve diseases, etc. Moreover, STCs are implicated in the development and progression of multiple malignancies through promoting cell growth, proliferation, invasion, metastasis, and apoptotic escape. Some studies have shown that NF-kappaB upregulates STC expression, thereby activating the downstream HIF-1/ERK1/2 signaling pathway, enhancing the transcriptional activity of tumor-related factors (MMP-2/9, cyclinD1, Bcl-2, N-cadherin, etc) and contributing to tumorigenesis. Here, this brief review describes recent progress of STCs in mammalians, focused mainly on their critical functions in cancer. PMID- 25816402 TI - Impact of smoking on guided tissue regeneration using a biocomposite poly (lactic co-glycolic) acid/sub-micron size hydroxyapatite with a rubber dam as an alternative barrier. AB - The purpose of our study was to critically evaluate the results obtained from a guided tissue regeneration technique after 12 months using a bocomposite poly (lactic-co-glycolic) acid/sub-micron size hydroxyapatite (PLGA/HA) with a rubber dam as a barrier in smoking and non-smoking patients. We selected 36 patients (18 current smokers and 18 non-smokers) diagnosed with chronic advanced periodontitis with a periodontal site (probing depth [PD] >5) amenable to regenerative surgery. Twelve months after surgery, the periodontal parameters were found to have statistically improved, when non-smokers were compared with smokers, in: PD reduction (6.3 +/- 2.1 mm vs. 3.6 +/- 1.9 mm); CAL gain (4.4 +/- 1.1 vs. 2.8 +/- 2.2 mm); recession (1.8 +/- 1.4 mm vs. 0.8 +/- 0.9 mm); and hard tissue fill (4.7 +/- 0.8 mm vs. 2.8 +/- 2.1 mm). Furthermore, since we found PD baseline differences between groups, smoking seemed not to influence the outcomes achieved (CAL gain and DeltaREC) 12 months post surgery with respect to PD baseline. The use of PLGA/HA with a rubber dam significantly improved the periodontal parameters in both smoking and non-smoking subjects. This improvement was nevertheless lower in smokers than the non-smokers, confirming the negative impact of smoking on periodontal regeneration. PMID- 25816403 TI - Genetics of presbycusis and presbystasis. AB - Presbycusis and presbystasis represent relevant problems of aging, caused by the increase in life expectancy in developed countries. As such, it is advantageous to better understand the physiopathological mechanisms of these age-related inner ear diseases. The hypothesis that presbycusis and presbystasis have a genetic background was proposed some years ago. Several studies (in humans and animals) are available in the literature, and possible genes involved in the physiopathology of both diseases have been identified. The aim of this paper is to present an overview of the information available in the current medical literature on presbycusis and presbystasis. PMID- 25816404 TI - BRD4 promotes tumor growth and epithelial-mesenchymal transition in hepatocellular carcinoma. AB - Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that play an important role in chromatin remodeling and transcriptional regulation. In this study, we found that BRD4, a BET family member, is significantly upregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent normal tissues. Furthermore, the overexpression of BRD4 in cancer tissues was correlated with poor prognosis in HCC patients. Using shRNA-mediated knockdown of BRD4 or lentivirus-mediated overexpression of BRD4 in HCC cells, we further showed that BRD4 was involved in HCC cell growth and invasion in vitro. Forced expression of BRD4 was sufficient to induce epithelial-mesenchymal transition (EMT) phenotypes in HCC cells. Additionally, BRD4 shRNA significantly inhibited HCC cell proliferation in vivo. Collectively, our study confirmed that BRD4 expression is a valuable predictor of recurrence and survival in patients with HCC. BRD4 can be further used as a potential therapeutic target of HCC. PMID- 25816405 TI - Knockdown of PTTG1 inhibits the growth and invasion of lung adenocarcinoma cells through regulation of TGFB1/SMAD3 signaling. AB - Increased expression of pituitary tumor-transforming gene 1 (PTTG1) is expressed in many tumors and regulates tumor growth and progression. However, the precise function of PTTG1 in the tumorigenesis of lung adenocarcinoma (LAC) is not defined yet. Here, we examined the expression of PTTG1 in human LAC tissues by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was carried out to investigate the effects of lentiviral vector mediated PTTG1 shRNA (shPTTG1) on cell growth and invasive potential in LAC cell lines (A549 and LETPalpha-2), assessed by MTT and Transwell assays. As a consequence, we found that the expression of PTTG1 protein was markedly upregulated in LAC tissues compared with the adjacent non-cancerous tissues (ANCT) (54.0% vs. 28.0%, P = 0.008), and was positively associated with the lymphatic invasion of the tumor (P = 0.01). Moreover, knockdown of PTTG1 expression inhibited tumor proliferation and invasion of LAC cells, companied by the decreased expression of CyclinD1 and MMP-2 and increased expression of p TGFbeta1 and p-SMAD3. Collectively, our findings indicate that high expression of PTTG1 is correlated with the tumor metastasis of LAC patients, and knockdown of PTTG1 suppresses the growth and invasion of LAC cells through upregulation of the TGFbeta1/SMAD3 signaling, suggesting that PTTG1 may be a potential target for developing an effective immunotherapeutic strategy for LAC. PMID- 25816406 TI - Chronic fatigue syndrome: Features of a population of patients from northern Italy. AB - In this study we analyzed the clinical features of a population of Italian patients with chronic fatigue syndrome (CFS) diagnosed according to the CDC-1994 criteria. The aim was to investigate CFS patients and their relatives, in order to search for events related to the onset of the disease and to identify correlations with other diseases. The analysis was carried out by examining medical records belonging to 82 patients suffering from the syndrome. The documentation was collected between 2008 and 2011 and provided by the non-profit Italian organization AMCFS (Associazione Malati di CFS). The influence of gender on the age of onset and association with potential risk factors were investigated in patients and in their relatives. From the results a significant correlation between the age of onset and autoimmunity was observed. PMID- 25816407 TI - Effect of clove and cinnamon extracts on experimental model of acute hematogenous pyelonephritis in albino rats: Immunopathological and antimicrobial study. AB - Recent studies showed prominent antimicrobial activity of some plant extracts on some pathogenic microorganisms so we evaluated antimicrobial activity of aqueous extracts of clove and cinnamon using the agar well diffusion method. An in vivo study was carried out on 40 adult healthy male albino rats divided into four groups: Group 1: negative control group (received intragastric saline solution daily); Group 2: injected with mixed bacterial suspension of S. aureus and E.coli as a model of pyelonephritis then received intragastric saline solution daily; Group 3: injected with the same dose of mixed bacterial suspension then received intragastric clove extract 500 mg/kg/day; and Group (4): injected with mixed bacterial suspension then received intragastric cinnamon 500 mg/kg/day. Five rats from each group were sacrificed after 1 and 4 weeks. Serum and blood samples were collected for lysozymes activity and nitric oxide production, lymphocyte transformation test, as well as counting of both total and differential leukocytes and erythrocytes. Kidney samples were tested histopathologically. Both in vivo and in vitro results confirmed the efficacy of clove extract as natural antimicrobials and suggested the possibility of its use in treatment of such bacterial infections. PMID- 25816409 TI - Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells. AB - Matrix metalloproteinase-12 (MMP12) is involved in many pathological processes including cancer. The expression and function of MMP12 in lung adenocarcinoma (LAC) remain unclear. The present study aimed to investigate the correlation of MMP12 expression with LAC patients and clarify its role in growth and invasion of LAC cells. The expression of MMP12 in human LAC was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was used for observing the effects of lentiviral vector-mediated MMP12 shRNA (shMMP12) on cell growth and invasion in LAC cell lines (A549), indicated by MTT and Transwell assays. We found that the expression of MMP12 protein was significantly increased in LAC tissues compared with that in adjacent non cancerous tissues (ANCT) (57.69% vs. 32.69%, P = 0.019), and was closely correlated with the pathological stage and lymph node metastasis of LAC patients (P = 0.01; P = 0.003). Knockdown of MMP12 inhibited proliferation and invasion of LAC cells followed by the downregulation of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF). In conclusion, our findings show that high expression of MMP12 is correlated with the pathological stage and tumor metastasis of LAC patients, and knockdown of MMP12 suppresses the development of LAC cells, suggesting that MMP12 may be a promising therapeutic target for the treatment of LAC. PMID- 25816408 TI - The protective effects of melatonin against cryopreservation-induced oxidative stress in human sperm. AB - Reactive oxygen species (ROS) production and lipid peroxidation during cryopreservation harm sperm membrane and as a result reduce the recovery of motile sperm. The antioxidant effects of melatonin on different cells have been widely reported. This study was aimed to evaluate changes in post-thaw motility, viability, and intracellular ROS and malondialdehyde (MDA) in response to the addition of melatonin to human sperm freezing extender. Semen of 43 fertile men was collected and each sample was divided into eight equal aliquots. An aliquot was analyzed freshly for viability, motility, and intracellular ROS and MDA. Melatonin was added to the recommended human freezing extender to yield six different final concentrations: 0.001, 0.005, 0.01, 0.05, 0.1, and 1 mM. A control group without melatonin was also included. Two weeks after cryopreservation, samples were thawed and pre-freeze analyses repeated. Obtained results showed that cryopreservation significantly (P <0.05) reduces viability and motility, but increases intracellular ROS and MDA of human sperm. The semen extender supplemented with various doses of melatonin (except for 0.001 mM) significantly (P <0.05) increased motility and viability, but decreased intracellular ROS and MDA levels of cryopreserved sperm after the thawing process, as compared with the control group. We also found that the most effective concentration of melatonin in protecting human spermatozoa from cryopreservation injuries was 0.01 mM. These findings suggest that melatonin exerts its cryoprotective effects on spermatozoa possibly by counteracting intracellular ROS, and thereby reduces MDA generation. This finally leads to increase of post-thaw viability and motility of cryopreserved spermatozoa. PMID- 25816410 TI - Different levels of Cd45pos leukocytes in the semen of patients with low testicular volume. AB - The aim of this study was to evaluate the concentrations of CD45pos leukocytes in the semen samples of infertile patients with low testicular volume (TV) compared to subjects with normal TV. The testis was considered normal in size when it had a volume between 15 and 25 cm(3), low-normal with a volume between 10 and 12 cm(3) and hypotrophic when the volume was <10 cm(3). The patients with low testicular volume (<10 cm(3)) showed significantly higher concentrations of CD45pos leukocytes compared to other groups (P <0.05). The correlation analysis showed the presence of a positive linear relationship between CD45pos leukocytes and the percentage of immature germ elements (r = 0.88; P <0.05) and between CD45pos leukocytes and the percentage of spermatozoa with phosphatidylserine externalisation (r = 0.90; P <0.05) as well as a negative linear relationship between the percentage of spermatozoa with normal morphology and the seminal CD45pos leukocyte concentrations ( r = -0.75; P <0.05). The results of this study showed that patients with low testicular volume (<10 cm(3)) have significantly increased CD45pos leukocyte concentrations associated with increased percentages of immature germ elements, spermatozoa with signs of early apoptosis and spermatozoa with abnormal morphology. PMID- 25816411 TI - From microvasculature to fibroblasts: Contribution of anti-endothelial cell antibodies in systemic sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organ fibrosis, caused by microvascular dysfunction. In recent years, the hypothesis that anti-endothelial cell antibodies (AECA) play a key role in microvascular damage seems to be increasingly convincing. In fact, AECA can induce antibody-dependent cellular apoptosis and stimulate the microvasculature to release pro-inflammatory and pro-fibrotic cytokines. Human-microvascular endothelial-cells (MVECs) were stimulated with SSc sera (with and without AECA) and with sera from healthy donors. The conditioned MVEC culture media were then added to fibroblast cultures obtained from control skin (CTR), non-affected skin of SSc patients (NA), and affected skin of the same sclerodermic (SSc) patients, respectively. AECA contributed to the MVEC increased release of endothelin-1 (ET 1) in the culture medium and to MVEC apoptosis. Fibroblast (CTR, NA, and SSc) proliferation was increased after treatment with AECA-positive conditioned media, compared to AECA-negative and control conditioned media. Furthermore, both AECA positive (in major contribution) and AECA-negative conditioned media were responsible for alpha-smooth-muscle-actin (alphaSMA) over-expression in all fibroblast cultures, compared to control conditioned media. Fibroblast type I collagen synthesis was upregulated by both SSc conditioned media (with and without AECA). Finally, the synthesis of fibroblast transforming-growth-factor beta (TGF-beta) was statistically higher in AECA-positive conditioned media, compared to AECA-negative and control conditioned media. These findings support the concept that AECA may mediate the crosstalk between endothelial damage and dermal-fibroblast activation in SSc. PMID- 25816412 TI - Anti-biofilm activity of pseudoalteromonas haloplanktis tac125 against staphylococcus epidermidis biofilm: Evidence of a signal molecule involvement? AB - Staphylococcus epidermidis is recognized as cause of biofilm-associated infections and interest in the development of new approaches for S. epidermidis biofilm treatment has increased. In a previous paper we reported that the supernatant of Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 presents an anti-biofilm activity against S. epidermidis and preliminary physico-chemical characterization of the supernatant suggested that this activity is due to a polysaccharide. In this work we further investigated the chemical nature of the anti-biofilm P. haloplanktis TAC125 molecule. The production of the molecule was evaluated in different conditions, and reported data demonstrated that it is produced in all P. haloplanktis TAC125 biofilm growth stages, also in minimal medium and at different temperatures. By using a surface coating assay, the surfactant nature of the anti-biofilm compound was excluded. Moreover, a purification procedure was set up and the analysis of an enriched fraction demonstrated that the anti-biofilm activity is not due to a polysaccharide molecule but that it is due to small hydrophobic molecules that likely work as signal. The enriched fraction was also used to evaluate the effect on S. epidermidis biofilm formation in dynamic condition by BioFlux system. PMID- 25816413 TI - TENS effects on salivary stress markers: A pilot study. AB - Transcutaneous electrical nerve stimulation (TENS) is extensively used as pain relief through endorphins release. Moreover, recent findings showed a role in the activation of the autonomic nervous system (ANS); it was evidenced by modification in the heart rate variability and ANS-related marker. The objective of this pilot study is to evaluate salivary alpha amylase (sAA) as a marker of stress in two groups of healthy subjects, one receiving ultra-low frequency transcutaneous electrical nerve stimulation (ULF-TENS) and one without stimulation. Sixty healthy people were enrolled. The test group consisted of 30 participants (15 men, 15 women). The control group consisted of 30 participants (15 men, 15 women). Statistical analysis showed that sAA levels were statistically different between men and women independently from TENS; we hypothesize that treatment could influence sAA levels because it is thought to activate MU opioid receptors. The results of this study seem to indicate that the analysis of sAA, through a non-invasive saliva sample, could be an efficient aid for understanding the functions of the autonomic nervous system. PMID- 25816414 TI - Snake (Vipera berus) bite: The cause of severe anaphylactic shock and hepatocellular injury. AB - Vipera berus bites lead to a variety of clinical manifestations. Local swelling, coagulopathy, nephrotoxicity, cardiac effects and myotoxicity are known to be associated with envenoming by a viper bite. Although a variety of clinical manifestations have been reported in viper bite cases, anaphylactic reactions and liver injury events have not been described. We report a unique case of an anaphylaxis and transitional liver cell injury due to a Vipera berus bite in the case of a 58-year-old man with no past history suggestive of allergy and liver disease. These observations need to be further explored with laboratory studies to identify the venom components which could have pre-disposed the patient to the development of these complications. PMID- 25816415 TI - Protective effect of ginger and zinc chloride mixture on the liver and kidney alterations induced by malathion toxicity. AB - This study was carried out on four groups of male Wistar rats, 10 rats per group. Group I got open access to food intake and water with normal balanced diet. Group II was administered 400 mg ginger per kg body weight (BW) and zinc chloride (ZnCl2) (300 mg/L) diluted in tap water for 4 months. Group III was administered malathion at a dose of 50 mg/kg BW/day in 0.2 mL corn oil via gavages for 4 months. This dose equal to 1/50 of the LD50. Group IV was given a mixture of 400 mg ginger per kg BW and ZnCl2 (300 mg/L) diluted in tap water in addition to 100 mg malathion/kg BW for 4 months. The liver showed histopathological changes include congestion, edema, and leucocytic infiltrations which were ameliorated by the addition of ginger and ZnCl2 mixture. The kidney showed cloudy swelling and hydropic degeneration of the renal tubules. These changes were ameliorated by the addition of ginger and ZnCl2 mixture. Ki67 immunoreactivity was localized in the cytoplasm and nuclear membrane. Its expression was estimated as the percentage of cells positively stained by the antibody in the different groups. In conclusion, malathion was toxic to the liver and kidney and must be avoided and protected by the addition of ginger and zinc mixture. PMID- 25816416 TI - The possible role of glutathione-S-transferase activity in diabetic nephropathy. AB - The most common cause of end stage renal disease is diabetic nephropathy. An early diagnosis may allow an intervention to slow down disease progression. Recently, it has been hypothesized that glutathione-S-transferase (GST) activity may be a marker of severity of chronic kidney disease. In particular, a lower GST activity is present in healthy subjects compared to patients with nephropathy. In the present review we illustrate the scientific evidence underlying the possible role of GST activity in the development of diabetic nephropathy and we analyze its usefulness as a possible early biomarker of this diabetic complication. PMID- 25816417 TI - Development of eosinophilic granulomatosis with poliangiitis (Churg-Strauss syndrome) and brain tumor in a patient after more than 7 years of omalizumab use: A case report. AB - Omalizumab is a monoclonal anti-immunoglobulin E antibody used for the treatment of severe perennial allergic asthma. Previous reports have suggested that omalizumab treatment can be associated with the development of eosinophilic granulomatosis with poliangiitis (EGPA) (formerly known as Churg-Strauss syndrome) and an increased risk of malignancy. Long-term risks of omalizumab treatment are not very well defined. Here, we report the case of a 75-year-old woman with concurrent occurrence of EGPA and brain tumor after more than 7 years of omalizumab treatment. The possibility of EGPA should be borne in mind during long-term treatment with omalizumab. Despite the absence of definitive data, an association may also exist between the development of malignancy and omalizumab use. PMID- 25816418 TI - Bilateral Warthin tumor in psoriatic patients in therapy with multiple immunosuppressive therapy. AB - Anti-TNFalpha drugs have strongly changed the way in which we deal with moderate and severe psoriasis. However, it is debatable whether biological drugs could increase the risk of developing cancer. The correlation between anti-TNFalpha drugs and lymphomas is well-known and is reported in all the technical details of biologic drugs. However, the association between anti-TNFalpha agents and solid tumors is still controversial. The authors report a case of bilateral salivary gland tumor in a psoriatic patient treated with several immunosuppressive therapies including anti-TNFalpha inhibitors. PMID- 25816420 TI - Corrigendum. AB - Acosta YY, Montes-Casado M, Aragoneses L et al. (2014) Suppression of CD4(+) T lymphocyte activation "in vitro" and experimental encephalomyelitis "in vivo" by the phosphatidyl inositol 3-kinase inhibitor PIK-75. International Journal of Immunopathology and Pharmacology 27(1): 53-67. In the Acknowledgements section of this article on page 65, the grant numbers should be as follows: Grants PI10/00650, PI10/00648. PMID- 25816419 TI - Dimerisation increases the immunogenicity of recombinant Parj1/Parj2 allergens. AB - Purified recombinant Parj1 and Parj2 allergens bind an IgE repertoire common to the Parietaria species, allowing their use as marker molecules for diagnosis and therapy of allergic disease induced by the Urticaceae family. Preclinical studies on the in vivo immunogenicity of recombinant Parj1, Parj2 and their isoforms indicated differential capacity to induce IgG1 antibody responses, as indication of potential clinical use. A recombinant hetero-dimeric hybrid derivative (PjED), encompassing the shorter Parj1 isoform (Parj1.0201) and Parj2 allergen, was characterised. In vivo immunisation with PjED induces IgG1 antibodies capable of binding all the isoforms of Parietaria major allergens, overcoming the poor immunogenicity of single monomeric allergens. This feature makes PjED a promising candidate molecule to be further characterised for clinical applications in the treatment of Parietaria allergy. PMID- 25816421 TI - Procedure for the Disposal of Controlled Medication in the School Setting. AB - The disposal of controlled medication left in the school nurse office is problematic for school nurses. Medications are left for a variety of reasons: students transfer out of the district, state, or country; parents and guardians lack transportation to pick up their child's medication; and some families simply forget. The medications of concern are controlled substances, primarily Schedule II medications including Adderall, Concerta, and methylphenidate. Over time, these medications begin to accumulate in a school nurse's office. Schools should establish procedures that address safe disposal of controlled medications as well as liability protection for the school nursing staff. This article will discuss a procedure created for the Christina School District in conjunction with a state board of pharmacy and subsequently shared with other school nurses in the State of Delaware. PMID- 25816422 TI - School Refusal Behavior. AB - School refusal behaviors go beyond a child's dislike or disinterest in school. This article investigates the underlying anxiety, depression, and social phobias that often accompany these behaviors and the importance of early recognition and treatment. Successful treatment and resolution of school refusal behaviors need to be a multidisciplinary approach. Teachers, administrators, guidance counselors, school nurses, and parents need to be involved in the diagnostic, treatment, and readmission processes. School nurses are in a unique position to be able to help identify and provide support for students exhibiting school refusal behaviors. PMID- 25816423 TI - Identifying the Signs of Self-Harm in Students. AB - Self-harm in adolescents is not a new phenomenon. However, the number of adolescents who participate in self-harming behaviors is growing. It can be difficult to detect those who self-harm due to the secrecy that surrounds the act of self-harm itself. This article focuses on providing assistance to school professionals in the identification of signs of self-harm in adolescents and how to deal with this growing epidemic. PMID- 25816424 TI - Recognizing diabetes in children: what does it look like? AB - Both type 1 diabetes and type 2 diabetes are on the rise in children. School nurses should be familiar with these conditions and have an understanding of who is more likely to be affected, what the presenting symptoms are, and how to support the student, family, and school personnel when a diagnosis is made. This article serves as a reference for school nurses and highlights key resources freely available for their use. PMID- 25816425 TI - Insulin Resistance, Metabolic Syndrome, and Polycystic Ovary Syndrome in Obese Youth. AB - School nurses are well aware of the childhood obesity epidemic in the United States, as one in three youth are overweight or obese. Co-morbidities found in overweight or obese adults were not commonly found in youth three decades ago but are now increasingly "normal" as the obesity epidemic continues to evolve. This article is the second of six related articles discussing the co-morbidities of childhood obesity and discusses the complex association between obesity and insulin resistance, metabolic syndrome, and polycystic ovary syndrome. Insulin resistance increases up to 50% during puberty, which may help to explain why youth are more likely to develop co-morbidities as teens. Treatment of these disorders is focused on changing lifestyle habits, as a child cannot change his or her pubertal progression, ethnicity, or family history. School nurses and other personnel can assist youth with insulin resistance, metabolic syndrome, and polycystic ovary syndrome by supporting their efforts to make changes, reinforcing that insulin resistance is not necessarily type 2 diabetes even if the child is taking medication, and intervening with negative peer pressure. PMID- 25816426 TI - School-based blood drive: successful nurse collaboration with parents, students, and the community. AB - The nurses at an independent Pre-K through 12 educational institution in Houston, Texas (The Kinkaid School), expanded the blood drive program to include innovative collaboration with high school student leaders, parents, and school faculty. Methods implemented in this endeavor included technology utilization, science education, and an enhanced parent workforce. By focusing on community involvement and an altruistic reason for donating, the Kinkaid school nurses helped their community break school donation records 2 years in a row. PMID- 25816427 TI - Best Practice at Your Fingertips: The WISHeS School Nurse Procedure Website. AB - School nurses are responsible for providing and supervising school nursing services for children with complex health concerns. Given that school nurses frequently practice in isolation and may have limited access to clinical practice changes, they can benefit from up-to-date, evidence-based resources. Additionally, the resources must account for the fact that the nursing procedures will be performed in the unique setting of a school building and, in many cases, will be performed by school personnel who have limited formal education in health care. This article provides an overview of a newly developed, easy to use, online school nursing procedures website for school nurses and other school personnel. PMID- 25816428 TI - Sailing the "Seven C's" of Leadership. AB - Nurses are increasingly being called upon to lead changes within health care. How do nurses and, in particular, school nurses become leaders? School nurses lead daily in their work but often do not recognize themselves as leaders. The "Five C's of Leadership"-character, commitment, connectedness, compassion, and confidence-identified by Kowalski and Yoder-Wise are foundational to the development of leadership and are particularly relevant to school nurses and their role. Two additional attributes found in the literature-courage and capacity-also undergird school nursing practice. In this article, we describe how school nurses already embody these leadership qualities. Each leadership attribute is reviewed in light of the literature, followed by specific examples to demonstrate how school nurses provide leadership. Through these illustrations, school nurses can recognize and embrace their present leadership abilities. In addition, by using the "Seven C's" of leadership, school nurses can enhance their inherent leadership abilities. PMID- 25816429 TI - Social media for school nurses: promoting school health in the 21st century. AB - People across the globe use social media to connect with one another, stay in touch with friends and family, and exchange information. Health care has embraced social media, and nursing organizations such as the American Nurses Association (ANA) and NASN have a presence in the social media landscape. The students in our schools today are digital natives who grew up with and are at home in the world of technology. With so many options in the digital world, the question is how can school nurses harness this technology to connect with their students and families? More importantly, how can school nurses use social media in a professional and responsible manner and help to enhance the profession of school nursing overall? This article will outline the planning and implementation of an ongoing social media campaign on wellness and healthy behaviors by one Texas suburban school district. PMID- 25816430 TI - School Nurses, Raise Awareness on the Importance for Every Student to Establish a Dental Home. PMID- 25816431 TI - Reducing Sugar-Sweetened Beverage Intake Among Students: School-Based Programs and Policies That Work. AB - The amount of sugar-sweetened beverages (SSBs) consumed by U.S. youth has nearly doubled since the 1970s. The majority of children between 2 and 19 years drink SSBs on any given day. Many serious health problems such as childhood overweight and obesity, type 2 diabetes, kidney disease, and cardiovascular problems have been linked to SSBs. This article provides an overview of school-based interventions and policies that have successfully contributed to a reduction in sugar-sweetened intake among children. School nurses and nurses in other community-based settings are well positioned to promote intake of more healthful beverages among children using strategies recommended in this article. PMID- 25816432 TI - School nursing and the digital age. PMID- 25816435 TI - School nurses-continuous support for education and health. PMID- 25816436 TI - Students requiring personal nursing care in school: nursing care models and a checklist for school nurses. AB - Unprecedented numbers of children in the United States are now surviving extreme conditions and complications of prematurity, severe congenital anomalies, and significant birth trauma. Advances in medical science and technology have given rise to a marked increase in the population of children with special health care needs who require continuous nursing care, including at school. Students who are considered medically complex and/or are health technology-dependent present many rewards and challenges for families, educational staff, district administrators, and school nurses who may not feel prepared to integrate involved health care for students into the school setting. The purpose of this article is to describe care delivery models for success in providing for the health and safety needs of students who require continuous or personal nursing care at school. PMID- 25816437 TI - Understanding type 2 diabetes in students with obesity and the role of the school nurse. AB - Co-morbidities of obesity in children mirror those seen in adults. Virtually any body system can be affected. The January 2015 issue of the NASN School Nurse featured an introductory article on childhood obesity. This article is the first of six related articles focusing on co-morbidities of childhood obesity and focuses on type 2 diabetes (T2D). School nurses can play an integral role in the identification, prevention, and treatment of childhood obesity. With one in three of our nation's school-age children diagnosed as overweight or obese, it is imperative that school nurses join families, public health agencies, and medical communities in mounting a coordinated attack against this threat. PMID- 25816438 TI - IEP, IHP, and Section 504 Primer for New School Nurses. AB - Three types of documents and their frequently used acronyms play a vital role in ensuring that students with disabilities have the planning, services, and accommodations necessary to facilitate attendance and success in the school setting. Federal and state laws, as well as state nurse practice acts, govern the process and eligibility of students for these services. School nurses play a vital role in these processes, and new school nurses benefit from a comparison of the terms along with a historical explanation of the acronyms. PMID- 25816439 TI - Emergency first aid oxygen response in schools: O2 administration in schools by nurses and lay responders. PMID- 25816440 TI - Is It PANS, CANS, or PANDAS? Neuropsychiatric Pediatric Disorders That Are Not Black and White--Implications for the School Nurse. AB - The terms pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), pediatric acute-onset neuropsychiatric syndrome (PANS), and childhood acute neuropsychiatric symptoms (CANS) have all been used to describe certain acute onset neuropsychiatric pediatric disorders. Additionally, controversy is ongoing concerning the diagnosis and etiology of the disorders. The school nurse, as a member of a multidisciplinary team, benefits from an awareness of these disorders, the resulting impact on school performance, and the recommended treatment. The school nurse assists the team through the development of an Individualized Healthcare Plan to help the student to achieve success in school. PMID- 25816441 TI - "Doesn't Anyone Believe How I Feel?": Postural Orthostatic Tachycardia Syndrome (POTS). AB - The school nurse is often the first person with whom a student may discuss untoward health symptoms and concerns. Being cognizant of the clinical features of postural orthostatic tachycardia syndrome (POTS) will help the nurse alleviate some of the student's anxiety. Due to misunderstandings and misconceptions about POTS, family and peers may disbelieve a student who is experiencing symptoms. Displaying compassion and support will help the student understand that someone does believe his or her symptoms. As the student's advocate, the school nurse will champion a plan for the student's health and safety in the academic environment. PMID- 25816442 TI - Leukemia in children: getting back to school-part 1. AB - Cancer is the leading cause of death by disease past infancy. In 2014, nearly 16,000 children and adolescents 0 to 19 years of age will be diagnosed with cancer in the United States. More than 80% of those children will survive at least 5 years after their diagnosis. Much of the increase in survival has been seen in children diagnosed with acute lymphoblastic leukemia (ALL). Once cancer treatment ends, the real battle begins. Getting back to school helps cancer patients return to normal. Part 1 is a brief review of the diagnosis, prognosis, and treatment of ALL in children and adolescents with an introduction to Philadelphia chromosome positive ALL and is written in language that makes it ideal for use in teaching school personnel and other parents about ALL. Part 2 is a reflection of Abby Furco's transition to school after being diagnosed with this type of leukemia at 4 1/2 years of age. The accommodations and strategies employed for this student are likely to be useful and adaptable to assist other families and school communities as they work with children entering school with physical challenges. PMID- 25816443 TI - Leukemia in children: getting back to school, part 2. PMID- 25816444 TI - Transition planning for students with chronic health conditions. AB - It is the position of the National Association of School Nurses that all children with chronic health conditions should receive coordinated and deliberate transition planning to maximize lifelong functioning and wellbeing. Transition planning refers to a coordinated set of activities to assist students with chronic health conditions to begin in school, and then move from one school to another, from hospitalization back to school, and from the secondary school system into the next stage of life (Selekman, Bocheneck, & Lukens, 2013). The registered professional school nurse (hereinafter referred to as school nurse) has the perspective and skills to provide care coordination and lead the planning team to address transitions for students with chronic health conditions. PMID- 25816445 TI - The use of restraints or seclusion in the school setting. AB - It is the position of National Association of School Nurses (NASN) that the registered professional school nurse (hereinafter referred to as school nurse) is an essential advocate for the health and well-being of all students. Promoting a safe and secure environment is vital to the educational success and emotional development of children. The use of restraints or seclusion can potentially cause injury or death and therefore should be used only as a brief intervention where there is the risk of imminent danger to the child, staff, or classmates (Mohr, LeBel, O'Halloran, & Preustch, 2010; United States Department of Education [USDE], 2012). PMID- 25816447 TI - Reducing mortality from emerging diseases. PMID- 25816446 TI - Changing the tide: stigma, school youth, and mental illness. AB - Schools are in a key position not only to identify mental health concerns early but to address issues of stigma that prevent both children and their parents from seeking help with mental illness. Stigma associated with mental illness perpetuates isolative behavior and poor engagement within the academic community. Programs within schools that address mental health issues and support open communication with families can reduce the pain and isolation that is often the experience of youth with undiagnosed and untreated mental and emotional disorders. PMID- 25816448 TI - Meningococcal disease control in countries of the African meningitis belt, 2014. PMID- 25816450 TI - AVMA mission expanded to include member advocacy. PMID- 25816449 TI - Tribute: Dr. Sambhu Nath De: one of the greatest Indian scientists. PMID- 25816451 TI - AVMA had an active 2014, more in store for 2015. PMID- 25816453 TI - Cohn: AVMA leaders must repair trust with members. PMID- 25816452 TI - HOD acts on resolutions. PMID- 25816454 TI - Biologic therapies research gets a boost with $42.5 million donation. PMID- 25816455 TI - AVMA board laying groundwork for future endeavors. PMID- 25816456 TI - Mindfulness for veterinarians. PMID- 25816457 TI - Age-related changes of the eye in dogs. PMID- 25816458 TI - The authors respond. PMID- 25816459 TI - Approach to treatment of aural hematomas. PMID- 25816460 TI - The author respond. PMID- 25816461 TI - The vaccine crisis. New outbreaks underscore old risks. PMID- 25816462 TI - The next best thing to a cure. PMID- 25816463 TI - A different prescription. The pharmacist running CVS wants his drugstores to become your doctor's office. PMID- 25816464 TI - Immune deficiency. Why a measles vaccine has presidential wannabes talking in code. PMID- 25816465 TI - Paying to play. As U.S. spending on medical research lags, a new crowdfunding model emerges. PMID- 25816466 TI - Actual to expected studies--Part 1. AB - In this Part 1 of a two-part series, pivot tables are used to analyze mortality and then a step-by-step process is demonstrated of converting seriatim data that is suitable for pivot table analysis. PMID- 25816467 TI - Serum globulin predicts all-cause mortality for life insurance applicants. AB - OBJECTIVE: Determine the relative mortality in apparently healthy adults with various levels of serum globulin. METHOD: By use of the Social Security Death Master File, mortality in 2010 was determined for 7.7 million life insurance applicants age 20 to 89 providing blood samples with valid globulin results between 1992 and 2006. Relative mortality by Cox regression for bands of globulin values was determined by age-sex group, with age split into 20 to 59 and 60 to 89, with each grouping also including age as a covariate. Further analysis was conducted by excluding applicants with elevations of other test values associated with increased globulin levels and mortality risk. RESULTS: After accounting for the mortality impact of frequently associated laboratory test abnormalities including BMI, alkaline phosphatase and albumin, relative mortality was found to increase gradually for globulin values > 3.2 g/dL. Values > 4.0 were associated with a mortality risk that was approximately doubled. There is also a small increased risk for globulin values < 1.9 g/dL. CONCLUSION: The highest 20% of globulin levels were associated with steadily increasing mortality in life insurance applicants. In many cases, other laboratory findings were not informative of the risk. PMID- 25816468 TI - Long-term mortality after VATS lobectomy for early stage non-small cell lung cancer: a brief review of VATS and estimation of excess risks. AB - A brief description of current developments involving video assisted thoracic surgery (VATS) and calculations of the excess risk of survivors who underwent VATS lobectomy for early stage, non small cell lung cancer (NSCLC). The source article was produced by a Korean university hospital. PMID- 25816469 TI - Prevalence and implications of vitamin D deficiency in applicants for insurance. AB - OBJECTIVE: Ascertain the prevalence of Vitamin D deficiency in applicants for insurance and participants in health and wellness activities. BACKGROUND: Vitamin D deficiency is widespread in people seeking healthcare. Deficiency of vitamin D is strongly associated with the incidence of rickets in children and osteomalacia in adults. All-cause mortality is elevated in people with vitamin D deficiency. Other pathologies strongly associated with sub-optimal levels of vitamin D include: falls in elderly, muscle weakness and pain, and psoriasis. A number of other disorders have a weaker association with deficiency of vitamin D. METHODS: Identified specimens received for testing for various laboratory parameters, as part of application for insurance and from participants in health and wellness activities, were tested for vitamin D levels using Siemens ADVIA Centaur analyzer. The results were analyzed for the prevalence of: (a) low vitamin D, (b) insufficiency of vitamin D, and (c) deficiency of vitamin D. RESULTS: Nearly 90% of the samples tested revealed levels < 30 ng/mL indicating a sub-optimal vitamin D nutritional status and susceptibility to disorders associated with vitamin D deficiency, including an increase in all-cause mortality. Samples with levels < 20 ng/mL and 12 ng/mL were 60% and 19%, respectively. CONCLUSIONS: The findings demonstrate that applicants for insurance, like the general population in the United States, have a high incidence of vitamin D deficiency. The insurance companies may wish to test all applicants and mitigate part of the risk of disease and early death by recommending/requiring readily available and inexpensive replacement therapy. PMID- 25816470 TI - Demographic predictors of false negative self-reported tobacco use status in an insurance applicant population. AB - OBJECTIVES: To identify and quantify demographic correlates of false-negative self-reporting of tobacco use in life insurance applicants. BACKGROUND: Several studies have assessed the sensitivity of self-reporting for tobacco use in various populations, but statistical examination of the causes of misreporting has been rarer. The very large (488,000 confirmed tobacco users) sample size, US wide geographic scope, and unique incentive structure of the life insurance application process permit more robust and insurance industry-specific results in this study. METHODS: Approximately 6.2 million life insurance applicants for whom both tobacco-use interview questions and a confirmatory urine cotinine test were completed between 1999 and 2012 were evaluated for consistency between self reported and laboratory-confirmed tobacco-use status. The data set was subjected to logistic regression to identify predictors of false negative self-reports (FNSR). RESULTS: False-negative self-reporting was found to be strongly associated with male gender, applicant ages of less than 30 or greater than 60, and low cotinine positivity rates in the applicant's state of residence. Policy face value was also moderately predictive, values above $500,000 associated with moderately higher FNSR. CONCLUSIONS: The findings imply that FNSR in life insurance applicants may be the result of complex interactions among financial incentives, geography and presumptive peer groups, and gender. PMID- 25816472 TI - Isolated T-wave inversion in the right precordial leads. PMID- 25816471 TI - Apical hypertrophic cardiomyopathy--a benign condition? AB - Apical hypertrophic cardiomyopathy (ApHCM) is a less common type of hypertrophic cardiomyopathy (HCM) and is often characterized as benign. However, more recent publications indicate that there is significant heterogeneity among individuals with ApHCM and that for many the condition is less than benign. This review will discuss the most recent understanding of ApHCM in the context of a case presentation and will provide a basic framework for risk stratification. PMID- 25816473 TI - CADASIL syndrome. AB - A rare hereditary disorder characterized by migraine headaches, transient ischemic attacks, strokes, cognitive decline, and dementia. PMID- 25816474 TI - Farewell from the York Isis Office. PMID- 25816475 TI - Race and laboratory norms. The critical insights of Julian Herman Lewis (1891 1989). AB - The work of Julian Herman Lewis helps to expose the underlying racial organization of laboratory normality in early twentieth-century medicine. In the 1920s and 1930s, Lewis launched a critique of prevailing racial theory, as he established an academic career in pathology at the University of Chicago. As one of the small number of black research physicians at the time, Lewis met barriers to his work that eventually derailed his career. Although his research fell short of its goals, his work continues to provide a key insight into medical laboratory standards as they became institutionalized in Lewis's field of clinical pathology. By avoiding attributions of race and following prevailing practices of racial exclusion, medical laboratories quietly reasserted social norms in the formation of laboratory normality. An examination of Lewis's critiques and his research sharpens questions about the development of the concept of "normal" in the human sciences and a related tendency in twentieth-century medicine to conflate difference with pathology. PMID- 25816476 TI - Benjamin Delessert's collections between travelers and Candolle's natural method (1803-1847). AB - During the first half of the nineteenth century, while Georges Cuvier ruled over natural history and the Museum d'Histoire Naturelle (MHN) was at its institutional acme, a French banker and industrialist with a Swiss family background, Benjamin Delessert, was developing an important botanical museum in Paris. His private collection included both a rich botanical library and a massive herbarium: the close integration of these two dimensions, together with the magnanimity of Delessert's patronage, contributed to making this private institution a worthy rival to the powerful and state-funded MHN. Delessert's museum had the favor of both professional and amateur naturalists. Knowledgeable and dedicated assistants (Antoine Guillemin and Antoine Lasegue) curated the collections. Moreover, Delessert was an intimate friend of the Genevan botanist Augustin- Pyramus de Candolle. Although Delessert's herbarium followed the Linnaean order, the Delessert Botanical Museum (DBM) contributed to the development of Candolle's natural system, especially through the publication of costly volumes of engravings, the Icones selectae plantarum rariorum. This essay draws together the main steps in the evolution of Delessert's collections, stressing the interdependency between books and dried plants. It focuses on the DBM as a case of cooperation between institutional and amateur expertise, private and public collections, and field collectors and cabinet naturalists. PMID- 25816477 TI - In accordance with a "more majestic order". The new math and the nature of mathematics at midcentury. AB - The "new math" curriculum, one version of which was developed in the 1950s and 1960s by the School Mathematics Study Group under the auspices of the National Science Foundation, occasioned a great deal of controversy among mathematicians. Well before its rejection by parents and teachers, some mathematicians were vocal critics, decrying the new curriculum because of the way it described the practice and history of the discipline. The nature of mathematics, despite the field's triumphs in helping to win World War II and its midcentury promotion as the key to a modern technological society, was surprisingly contested in this period. Supporters of the School Mathematics Study Group, like its director, Edward Begle, emphasized the importance of portraying mathematics as a system of abstract structures, while opponents like Morris Kline argued that math was essentially a tool for understanding the natural world. The debate about the curriculum--and the role of mathematicians in its design--was also a debate about the underlying identity of the subject itself. PMID- 25816478 TI - Focus: the peculiar persistence of the naturalistic fallacy. Introduction. AB - Although "naturalistic fallacy" is a term coined in the twentieth century, scholars have long voiced myriad anxieties over the mechanisms by which their contemporaries have derived moral, social, and political lessons from natural phenomena--often as gambits for advancing their own alternative explanations. The essays in this Focus section explore five episodes in the history of such concerns with naturalistic reasoning in order to shed new light on the persistence of naturalism itself. PMID- 25816479 TI - Greco-Roman ethics and the naturalistic fantasy. AB - To modern scholars, the naturalistic fallacy looks out of place in Greco-Roman antiquity owing to the robust associations between nature, especially human nature, and moral norms. Yet nature was understood by ancient authors not only as a norm but also as a form of necessity. The Greco-Roman philosophical schools grappled with how to reconcile the idea that human nature is given with the idea that it is a goal to be reached. This essay looks at the Stoic concept of oikeiosis as one strategy for effecting such a reconciliation. Drawing on natural history, these Stoic sources used examples of animal behavior to illustrate a process whereby nature "entrusts" all animals, including humans, with the care of their own survival. Nature is thus both what is given to the animal and what the animal achieves in a powerful but also problematic synthesis here called the "naturalistic fantasy". PMID- 25816480 TI - The naturalistic fallacy is modern. AB - The naturalistic fallacy appears to be ubiquitous and irresistible. The avant garde and the rearguard, the devout and the secular, the learned elite and the lay public all seem to want to enlist nature on their side, everywhere and always. Yet a closer look at the history of the term "naturalistic fallacy" and its associated arguments suggests that this way of understanding (and criticizing) appeals to nature's authority in human affairs is of relatively modern origin. To apply this category cross-historically masks considerable variability and naturalizes our own assumptions about the natural and the human. PMID- 25816481 TI - From ought to is physics and the naturalistic fallacy. AB - In the eighteenth and nineteenth centuries there were many attempts to justify political and social systems on the basis of physics and astronomy. By the early twentieth century such moves increasingly also integrated the life and social sciences. The physical sciences gradually became less appealing as a sole source for sociopolitical thought. The details of this transition help explain the contemporary reluctance to capitalize on an ostensibly rich opportunity for naturalistic social reasoning: the anthropic principle in cosmology, which deals with the apparent "fine-tuning" of the universe for life. PMID- 25816483 TI - Getting ahead of one's self? The common culture of immunology and philosophy. AB - During the past thirty years, immunological metaphors, motifs, and models have come to shape much social theory and philosophy. Immunology, so it seems, often has served to naturalize claims about self, identity, and sovereignty--perhaps most prominently in Jacques Derrida's later studies. Yet the immunological science that functions as "nature" in these social and philosophical arguments is derived from interwar and Cold War social theory and philosophy. Theoretical immunologists and social theorists knowingly participated in a common culture. Thus the "naturalistic fallacy" in this case might be reframed as an error of categorization: its conditions of possibility would require ceaseless effort to purify and separate out the categories of nature and culture. The problem- inasmuch as there is a problem-therefore is not so much the making of an appeal to nature as assuming privileged access to an independent, sovereign category called "nature". PMID- 25816482 TI - A field study of con games. AB - In 1978, the evolutionary biologist Robert Trivers and Huey P. Newton, cofounder of the Black Panthers, began a collaboration exploring the evolution of self deception. Together they published a brief paper that used their ideas about the naturalistic basis of deceit and self-deception to explain the crash of Air Florida Flight 90 in Washington, D.C. Given the continued power of the naturalistic fallacy in the modern life sciences, historical attention typically focuses on highly visible controversies with great popular traction. This essay instead mobilizes the muted legacy of Trivers and Newton's publication to underscore the inherent difficulties scientists face in finding a receptive audience for their theories, even naturalistic ones. PMID- 25816484 TI - Mark Russell Finlay (15 September 1960-6 October 2013). PMID- 25816485 TI - One shot to cure them all. PMID- 25816486 TI - Managing end-of-life care revenue cycle processes. PMID- 25816487 TI - Physician practice helps patients tackle high drug costs. PMID- 25816488 TI - 5 strategies for preauthorization success. Specific staff should manage the process. PMID- 25816489 TI - Most cancer is out of our control random. DNA changes are usually to blame. PMID- 25816490 TI - What I learned from my $190,000 surgery. PMID- 25816491 TI - Unscrambling the egg. How to decode confusing label claims. PMID- 25816492 TI - The new way to prevent nut allergies? It's with nuts. PMID- 25816493 TI - The IUD rises. PMID- 25816494 TI - Medical and research ethics in Ethiopia. PMID- 25816495 TI - Analysis of medical malpractice clams and measures proposed by the Health Professionals Ethics Federal Committee of Ethiopia: review of the three years proceedings. AB - BACKGROUND: Mediccil malpractice is professional negligence by a healthcare provider in which the treatment provided falls below the starndard and causes injury or death to the patient. OBJECTIVE: To describe the adverse medical events, claims and decisions taken by the Ethiopian Health Professionals Ethics Committee at the Federal level. METHODS: A three-year report of the Ethics Committee and relevant documents of proclamations and regulations were reviewed. RESULTS: Between January 2011 and December 2013, the committee reviewed 60 complaints against health professionals. About one third of the complaints were filed by the patients and/or their families, about 32% by the police or court and the rest were filed by Addis Ababa health bureau, health professionals and other unrelateed observers. Thirty-nine complaints were related to death of the patient and 15 complaints were about disability. Twenty-five of the claims were against Obstetric and Gynecology specialists and 9 were against general surgeons. The committee verified that 14 of the 60 claims hadethical breach and/or negligence (incompetence). The committee took reasonable time to review complaints and respond the concerned authorities. CONCLUSION: The study showed that of the total claims lower than a quarter (23.3%) were proven beyond the benefit ofdoubt. More than 3/4 (76.7) of the complaints were wrong. Hospitals should lead in preventing patient injury. Creation of more awareness among Obstetrics and Gynecology specialists, General and Orthopaedic Surgeons about medical errors is needed and special training should be given.to those joining these specialities. PMID- 25816496 TI - Review paper on research ethics in Ethiopia: experiences and lessons learnt from Addis Ababa University College of Health Sciences 2007-2012. AB - Health research in Ethiopia is increasing both in volume and type, accompanied with expansion of higher education and research since the past few years. This calls for a proportional competence in the governance of medical research ethics in Ethiopia in the respective research and higher learning institutes. The paper highlights the evolution and progress ofthe ethics review at Addis Ababa University - College of Health Sciences (AAU-CHS) in the given context of health research review system in Ethiopia. Reflections are made on the key lessons to be drawnfrom the formative experiences of the Institutional Review Board (IRB) and their implications to the Ethiopian health research review system. This article is a review paper based on review of published and un published documents on research ethics in Ethiopia and the AAU-CHS (2007-2012). Thematic summaries of review findings are presented in thematic areas - formation of ethics review and key factors in the evolution of ethics review and implications. The IRB at AAU CHS has been pivotal in providing review and follow-up for important clinical studies in Ethiopia. It has been one of the first IRBs to get WHO/SIDCER recognition from Africa and Ethiopia. Important factors in the successes of the IRB among others included leadership commitment, its placement in institutional structure, and continued capacity building. Financial challenges and sustainability issues need to be addressed for the sustained gains registered so far. Similar factors are considered important for the new and younger IRBs within the emergent Universities and research centers in the country. PMID- 25816497 TI - Research ethics review practices: experiences of the Armauer Hansen Research Institute/All Africa Leprosy and Tuberculosis Rehabilitation and Training Center Ethics Review Committee, Ethiopia. AB - The need for ethics review committees (ERCs) is imperative in the conduct of research to ensure the protection of the rights, safety and well-being of research participants. However, the capacities of most ERCs in Africa are limited in terms of trained experts, competence, resources as well as standard operating procedures. The aim of this report is to share experiences of one of the local institutional ERCs, the Armauer Hansen Research Institute (AHRI)/All Africa Leprosy and Tuberculosis Rehabilitation and Training Center (ALERT) Ethics Review Committee (AAERC), to other ERCs found in academic and research institutions in the Country. In this report, we used an empirical approach to review archived documents of the AAERC Secretariat to assess the Committee's strengths and weaknesses. The experiences of the AAERC in terms of its composition, routine work activities, learning practices and pitfalls that require general attention are summarized. In spite of this summary, the Committee strongly acknowledges the functions and roles of other ERCs in the Country. In addition, an independent assessment of the Committee's activity in general is warranted to evaluate its performance and further assess the level of awareness or oversights among researchers about the roles of ERCs. PMID- 25816498 TI - Feasibility of rapid ethical assessment for the Ethiopian health research ethics review system. AB - One of the challenges in the process of ethical medical research in developing countries, including Ethiopia, is translating universal principles of medical ethics into appropriate informed consent documents and their implementation. Rapid Ethical Assessment (REA) has been suggested as a feasible approach to meet this application gap. In the past few years REA has been employed in few research project in Ethiopia and have been found to be a useful and practical approach. Feasibility assessment of REA for the Ethiopian research setting was conducted between 2012-2013 in order to inform the subsequent introduction of REA into research ethics review and governance system in the country. REA was found to be an appropriate, relevant and feasible venture. We argue that REA can be integrated as part of the ethics review and governance system in Ethiopia. REA tools and techniques are considered relevant and acceptable to the Ethiopian research community, with few practical challenges anticipated in their implementation. REA are considered feasible for integration in the Ethiopian ethics review system. PMID- 25816499 TI - Antipsychotics still prescribed inappropriately in primary care. PMID- 25816500 TI - Timely diagnosis and treatment essential in glomerulonephritis. AB - Glomerulonephritis is an important cause of kidney disease and, in the UK, the most common diagnosis in patients receiving chronic dialysis or waiting for kidney transplantation. A key feature is the presence of urinary abnormalities (proteinuria +/- haematuria). Patients with nephrotic syndrome typically present with peripheral oedema, massive urinary protein loss and associated low serum albumin levels. Blood pressure and renal function, as measured by eGFR, are usually normal initially. Patients presenting with nephritic syndrome tend to be hypertensive with dipstick-positive or visible haematuria. There may be rapidly progressive renal dysfunction and fall in eGFR. Many patients will have a background genetic susceptibility to glomerulonephritis which may be triggered by environmental, infective or autoimmune factors. Autoimmunity, in combination with genetic factors, is responsible for a significant proportion of cases of glomerulonephritis. Infective agents such as viruses can precipitate minimal change disease. NSAIDs, lithium, penicillamine and heroin can cause nephrotic syndrome. Timely diagnosis and treatment of glomerulonephritis can help to minimise both the occurrence and severity of complications. All patients with glomerulonephritis should be managed according to CKD guidelines with CKD stage appropriate measurement of renal function, blood pressure, and proteinuria. PMID- 25816501 TI - Improving early detection of chronic kidney disease. AB - Chronic kidney disease (CKD) is defined as either a reduction in measured kidney function (eGFR) or urinary abnormalities (haematuria/proteinuria) or a combination of both, present for more than 3 months. In the most recent NICE guidelines the various CKD stages 1-5 are now represented by G (for GFR) categories (G1-5) which have the same eGFR thresholds as previous CKD guidelines. The urinary albumin:creatinine ratio (ACR) category is denoted as A (for albuminuria) with three categories: A1, A2 or A3. The ACR category has been introduced to emphasise that patients with higher levels of albuminuria have an increased risk of progression to end-stage renal disease. Individuals with newly identified reduced eGFR should have acute kidney injury excluded. All newly identified CKD patients should have blood pressure, dipstick urinalysis, random urine ACR or urine protein:creatinine ratio (PCR), glucose, cholesterol and full blood count checked at the earliest opportunity. An ultrasound scan should be offered to patients at increased risk. Cardiovascular events and progression of CKD are more common if albuminuria or proteinuria is present. Urine ACR has a greater sensitivity for low levels of proteinuria in comparison with PCR. Referral for patients with CKD should be based on assessment of kidney function (eGFR), the severity of proteinuria (urine ACR), concerns about poorly controlled BP, or suspected inherited renal disease. Most cases of CKD in the elderly are caused by the cumulative effect of other disease states, especially hypertension and atherosclerosis. The CKD classification system will identify many elderly patients with a low eGFR but without progressive kidney failure. PMID- 25816502 TI - Managing urticaria in primary care. AB - Urticaria is characterised by transient wheals that consist of a swollen palpable centre often surrounded by an erythematous flare, associated with itching or, less commonly, a burning sensation. Individual wheals usually disappear within 1 to 24 hours leaving normal skin. Wheals may be accompanied by angioedema, a more deep-seated flesh-coloured or erythematous swelling of skin or mucous membrane, which may last longer than 24 hours. Urticaria is classified as acute when it resolves within six weeks and chronic when its duration exceeds six weeks. Chronic urticaria is now sub-classified into chronic spontaneous urticaria (CSU) and chronic inducible urticaria. The prognosis for eventual recovery from spontaneous and inducible urticaria is excellent. However, the time course is unpredictable and may extend to years, often following a relapsing and remitting course. Urticaria results from the release of inflammatory mediators from dermal mast cells, resulting in vasodilatation, plasma extravasation, recruitment of immunologically active cells and sensory nerve stimulation. The cause of urticaria cannot usually be precisely identified for most affected individuals. IgE-mediated food allergy is rarely the cause of CSU in patients with the daily appearance of urticarial lesions, although it should be considered in CSU patients with intermittent symptoms. For patients with CSU a differential full blood count and inflammatory markers are all that are routinely recommended. It is also reasonable to test thyroid function and check for circulating thyroid autoantibodies as there is an association between CSU and thyroid autoimmunity. PMID- 25816504 TI - Eczema. PMID- 25816503 TI - Medical women and the war. 1915. PMID- 25816505 TI - Whose body is it, anyway? PMID- 25816506 TI - [Collection of Vibrio parahaemolyticus species members: phenotypic and genotypic characteristics]. AB - AIM: Formation of Vibrio parahaemolyticus collection according to modern methodical opportunities and understanding of causative agent biology. MATERIALS AND METHODS: Traditional biochemical tests and PCR-testing of species-specific genes were used to confirm species membership. Catalase, DNAse, proteolytic and tweenase activity was determined by common methods. Virulence was evaluated by a complex method: hemolytic activity was determined in Kanagawa test (KT), urease- in Christensen medium, PRC-testing of tdh and-trh genes. Serotyping was carried out with a commercial O/K-sera kit. PCR-genotyping was carried out by marker genes of 7 pathogenicity islands (VPaI-1-7). RESULTS: Species membership was confirmed for the studied strains. Serologic typing allowed to detect members of 18 serologic groups among the collection strains. All the collection cultures were divided into 4 groups based on KT-Ure-tdh-trh features recombination. A number of genetic variants were detected, strains belonging to a pandemic group and O3:K6 serogroup were determined. CONCLUSION: A collection of V. parahaemolyticus cultures was formed and characterized by a large set of pheno- and genotypic features. A database was developed including information on strain origins, pheno- and genetic features, with genetic variants given, for ease of use of the collection. PMID- 25816507 TI - [Prevalence of cytotoxicity effectors in nosocomial Pseudomonas Aeruginosa strains]. AB - AIM: Analysis of occurrence of the third type secretory system (TTSS) effectors in clinical P. aeruginosa strains. MATERIALS AND METHODS: Intra-hospital (n = 164) and extra-hospital (n = 30) strains of P. aeruginosa were studied. Detection of exoS and exoU genes was carried out by PCR in DNA Engine Dyad Thermal Cycler ("Bio-Rad", USA). Metallo-beta-lactamase (MBL) producers were detected by the presence of blaVIM-2 gene. RESULTS: Screening of intra- and extra-hospital strains for the presence of genes coding ExoS and ExoU showed, that exoS is detected in genome of clinical isolates in 59.8% and exoU--31.1% of cases. At the same time, strains with exoS-/exoU+ genotype predominated in lCU (Phi = 0.466; p = 0.0000). A significant association between the presence of the respective effectors and material of strain isolation was not detected. exoU gene was more frequently detected in genome of MBL producers (Phi = 0.784; p = 0.0004). CONCLUSION: A significant association between exoU and blaVIM-2 could be explained by clonal prevalence of P. aeruginosa ST235 VIM-2, circulation of those is noted on all the territory of Russia. As a rule, ExoU is produced by highly virulent poly-antibiotic resistant hospital isolates that determine unfavorable outcomes of pseudomonas infection. PMID- 25816508 TI - [Role of phage LO7 lysogeny in genetic variability of Escherichia coli]. AB - AIM: Determine the possibility of Iysogenization of Escherichia coli single strain DNA (ssDNA) by 1o7 bacteriophage from the Microviridae family and determine the role of phage lo7 lysogeny in genetic variability of these bacteria. MATERIALS AND METHODS: A method of E. coli K12 lysogenization by phage lo7 was developed. A spot-test for the control of resistance of the obtained lysogens against phage lo7 and determination of lysogen lo7 spontaneous production was worked out. Criteria for phage lo7 identification, that is spontaneously produced by E. coli K12 lysogens, were proposed. A kit of isogenic E. coli strains, that vary by mutations in ptsI, ptsH and fruA genes, that code phosphoenolpyruvate (PEP): carbohydrate phosphotransferase system (PTS) proteins, was constructed. RESULTS: The ability of highly virulent bacteriophage lo7 to lysogenize E. coli was shown. A reduction of lo7 titers in ptsI, ptsH and fruA E. coli K12 mutants was demonstrated compared with titers in wild-type bacteria. Lytic bacteriophage lo7 was also able to lysogenize ptsI, ptsH and fruA mutants at a high frequency. Lysogens are resistant to phages lo7, phiX174 of Microvirus genus and spontaneously produce lo7. CONCLUSION: Bacteriophage lo7 of the Microviridae family is able to lysogenize E. coli K12 and vertically transfer genome of this lytic phage. As a result, lytic phage lo7 takes part in bacterial variability as a factor of lysogen selection in bacteria population corresponding to PTS mutants by phenotype. PMID- 25816509 TI - [Features of adhesion of anaerobic periodontopathogenic bacteria and Candida albicans fungi to experimental samples of basis dental plastic depending on surface roughness and polishing method]. AB - AIM: Study the main surface parameters of milled polyacrylic materials using atomic force microscopy and primary microbial adhesion of periodontopathogenic group bacteria and Candida albicans fungi taking into consideration the method of sample polishing. MATERIALS AND METHODS: Studied samples: mill-treated without polishing (control); ergobox polished; polished in dental laboratory conditions; polished by a rubber brush in dentists' office. Microbial strains belonging to periodontopathogenic species (clinical isolates) that had been isolated from periodontal pockets of periodontitis patients: Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus sanguis, C. albicans fungi were used for modelling experiments of primary adhesion of microbes to the material samples. RESULTS: S. sanguis had the highest degree of adhesion to polymer after milling, P. gingivalis, C. albicans--medium, F. nucleatum--low. A significant reduction of adhesion is observed during polishing in dental laboratory conditions or ergobox, less significant--during polishing in dental office. CONCLUSION: The data obtained allow to make a conclusion that the samples from polymer materials for preparation of prosthesis basis have varying degree of intensity of microbial adhesion of members of periodontopathogenic microflora and C. albicans fungi that depends on the polishing method, that accordingly determined the differences in colonization resistance against formation of microbial biofilm during polymer use in clinical conditions. . , PMID- 25816510 TI - [Molecular epidemiology of hepatitis C in centers of hemodialysis in St. Petersburg]. AB - AIM: Study molecular epidemiology of hepatitis C (HC) in 5 departments of hemodialysis (DH) in St. Petersburg. MATERIALS AND METHODS: Sequences of nucleotides of 93 isolates including 67 isolates from patents of 5 DH and 26 isolates from patients, who never had hemodialysis in anamnesis, were obtained in 2010 by a method of limited sequencing of NS5B region of HC virus genome. Phyologenetic analysis was carried out by using PHYLIP veision 3.69 program package. Evolution differences were evaluated in DNADIST program using F84 algorithm. Phylogenetic trees were constructed by using nearest neighbor and UOGMA methods in PHYLIP program package. RESULTS: Subtype 1b was established to dominate in all the DH (69.2 - 92.9%) and the same isolates of HC virus were detected in DH, that were isolated for the first time in 1999. Comparatively higher proportion of isolates of HC subgenotype 3a (26.7 - 30.8%) was detected in 2 of 5 DH in 2010. The same proportion of 3a isolates was detected in the control group. CONCLUSION: The fact that HC 3a virus isolates were detected in DH in a higher proportion is proof that they have successfully integrated into circulation among dialysis patients over the last decade. , PMID- 25816511 TI - [A method for determination of Neisseria meningitidis serogroup A, B, C and W by real-time PCR]. AB - AIM: Development and testing of a real-time PCR method for detection of Neisseria meningitiis serogroup A, B, C and W DNA. MATERIALS AND METHODS: Reference strains and 187 samples of cerebrospinal fluid (CSF) from meningocci meningitis patients were used in the study. Multiplex PCR was carried out in an instrument with 5 channels of fluorescent detection: RESULTS: Analysis of specific serogroup loci of the genome and design of oligonucleotides for the detection of DNA of all the capsule meningococci and 4 serogroups in particular was carried out. PCR conditions were optimized; specificity was shown and analytical sensitivity was evaluated using reference strains. DNA of the following serogroups was detected during study of clinical CSF samples: A--in 103 samples (55%), B--in 45 (24%), C- in 30 (16%), W--in 5 (3%). Only DNA of meningococci capstle gene ctrA was found in 4 samples; presumably, they contained DNA of other serogroups. Multilocus sequence-typing and detection of antigenic determinants of PorA and FetA genes for 27 DNA samples of group A menincococci as well as DNA of 5 group W meningococci and 4 ungroupable was carried out. CONCLUSION: The method proposed allows to carry out serogrouping of no less than 95% of strains or DNA samples isolated from CSF of meningococci infection patients. Combined with other recommended non-cultural methods of genotyping, it may be useful for complex characteristics of pathogenic meningococci. PMID- 25816512 TI - [Genetic characteristics of Staphylococcus aureus No 6. strain--producer of secreted protein-containing compounds possessing protective properties]. AB - AIM: Genotype characteristics of Staphylococcus aureus No 6: strain that is a producer of a protective protein complex. MATERIALS AND METHODS: Features of structure of 9 genes, that code synthesis of pathogenicity factors, of S. aureus- spa, coa, sea, seB, sec, pvl, tst-h, mecA and scc-mecA, that are responsible for synthesis of protein A, coagulase, enterotoxins A, B and C, Panton-Valentine toxin (PVL), heat shock syndrome protein, resistance to methicillin and staphylococci chromosomal cassette, respectively, were studied by amplification in PCR of the respective gene fragments with subsequent conduction of direct sequencing. RESULTS: The S. aureus No 6 strain under study possesses pvl gene fragments, as well as Spa and coagenes, detected in all the studied strains, that belong to t12507 and EMRSA-16 types, respectively. Sea, seb, sec genes responsible for.the synthesis of enterotoxins A, B and C were not detected in it, tst-h, mecA and scc-mecA gene fragments were not present. CONCLUSION: The detection of pvl gene fragment in the strain under study, on the one hand, and protective properties of the secreted protein-containing compound, on the other hand, give evidence in favor of the necessity of further analysis of extracellular proteome of S. aureus No 6. PMID- 25816513 TI - [Influence of Staphylococcus vaccine on functional activity of antigen-presenting cells]. AB - AIM: Study the influence of staphylococcus vaccine on functional activity of antigen-presenting cells. MATERIALS AND METHODS: Mice intraperitoneally received 500 MUg of "Staphylovac" vaccine. Phagocytic activity of peritoneal macrophages against Staphylococcus aureus 1991 was determined in animals at various time intervals. Phagocytic index (PI) and phagocytic number (PN) in smears made at 30 and 60 minutes of incubation were calculated. Dendritic cells (DC) were obtained from bone marrow precursors during cultivation with 20 ng/ml GM-CSF and 20 ng/ml IL-4 (BioSource International Inc., Belgium). At day 6 of incubation staphylococcus vaccine (50 MUg/ml) was added to immature cells for induction pf DC maturation. DC phenotype evaluation was carried out by flow cytometry using monoclonal antibodies against cell antigens (Beckman Culter, USA). RESULTS: PI at 30 and 60 minutes of incubation increased by 0.12 - 1.4 times and 1.11 - 1.52 times, respectively, compared with control. PN at 30 minutes of incubation of cells with microbial suspension increased from 8.6 to 11.4% against 5.9% in control, at 60 minutes of incubation--from 7.7 to 8.1% against 5.1% in control. In DC culture during their incubation with the vaccine, content of cells with expression of intercellular adhesion marker CD38, antigen presenting marker MHCII and DC terminal differentiation marker CD83 increased. Expression of CD34 and CD14 was also noted, that may give evidence on partial direction of cell differentiation to macrophages. CONCLUSION: "Staphylovac" vaccine during intraperitoneal administrationt to mice had activating influence on functional activity of antigen-presenting cells and peritoneal macrophages. PMID- 25816514 TI - [Study of protective activivty of "Staphylovac-2" vaccine]. AB - AIM: Study the protective properties of "Staphylovac-2" vaccinie. MATERIALS AND METHODS: Samples of the vaccine manufactured by SPA "Microgen" based on the developed technology were studied in balb/c mice during 3- and 6-fold immunization schemes. Protective activity of the preparation was determined in experiments with active and passive protection during intraperitoneal infection, seeding of the causative agent from spleen and kidneys during intravenous infection, of animals. RESULTS: In experiments with active protection of mice for both 3- and 6-fold immunization schemes, a significant protective activity of the studied series was determined, compared with the control group of mice. Sera obtained after animal immunization (rabbits, mice) by staphylococcus vaccine had protective properties. A reduction of spleen and kidneys seeding by Staphylococcus aureus in immunized mice compared with the control group was detected in the model of generalized staphylococci infection. CONCLUSION: The preclinical studies carried out with the "Staphylovac-2" vaccine, developed baed on the complex of protective staplylococci antigens, have confirmed the high protective activity of the preparation. PMID- 25816515 TI - [Effect of aluminium hydroxide on innate immunity and immunogenicity of bacterial and synthetic antigens of Streptococcus pneumoniae]. AB - AIM: Study the effect of aluminium hydroxide on molecular-cell mechanisms of innate immunity activation and its adjuvant effect on immunogenicity of natural bacterial and synthetic pneumococci antigens. MATERIALS AND METHODS: Surface markers of dendritic cells (DC), mononuclear leukocytes (ML) and cytokine levels were determined by flow cytometry; IgG titers--by EIA. Protective activity was evaluated in experiments with active protection of mice from infection with virulent pneumococci strains. RESULTS: Aluminium hydroxide increased the ML content of mice spleen expressing TLR2 and TLR4. Its addition into the culture of immature DC induced the appearance of a population of cells with mature DC markers--CD83, CD80, CD86, however, the level of undifferentiated cells (CD34) and cells with adhesion molecules (CD11c, CD38) did not change. DC produced IL 1beta, IL-5, IL-10, IFNgamma into the cultivation medium. An increase of cytokine production took place 2 hours after the administration into mice and was retained for the observation period (24 hours). Th1 (IFNgamma, TNFalpha) and Th2 (IL-5, IL 10, GM-CSF) cytokine production gave evidence on immune response polarization by Th1/Th2, type. After 2 administrations of aluminium hydroxide into mice the number of ML with CD19+, CD5+, NK1.1+, CD25+, MHCII+ markers increased during decrease of CD3+, CD4+ and CD8+ T-lymphocytes. Adaptive immunity activation was characterized by high IgG titers to pneumococci capsule polysaccharide and protection of 90 - 100% of the mice against infection with lethal doses of S. pneumoniae strains, was detected during 2-fold immunization of mice with conjugates of synthetic pneumococci oligosaccharides with BSA,sorbed onto aluminium hydroxide, whereas natural bacterial antigens provided 90 - 100% survival of animals during immunization without the adjuvant. CONCLUSION: Data are provided on the effect of aluminium hydroxide on key effectors of innate immunity: DC, ML, TLRs and cytokine production. A reasonable administration of this adjuvant was shown to be in association with conjugates of pneumococci synthetic oligosaccharides with a carrier protein. PMID- 25816516 TI - [The role of fibronectin in adhesion of corynebacteria to vaginal epitheliocytes]. AB - AIM: Determination of the role of fibronectin in adhesion of corynebacteria to vaginal epitheliocytes. MATERIALS AND METHODS: Corynebacterium genus microorganisms and primary epitheliocytes isolated from the lower reproductive tract of women were used. Adhesive ability of corynebacteria was studied in polystyrene plates against fixed fibronectin and on the model of vaginal epitheliocytes. Changes in adhesion of corynebacteria to vaginal epitheliocytes was evaluated after treatment of the latter with fibronectin. RESULTS: All the studied strains had the adhesion ability to fibronectin and vaginal epitheliocytes. The same strains were attributed to groups of high, moderate or low adhesive using both plate method and method utilizing vaginal epitheliocytes model, that tells of their comparability. During the addition of fibronectin to epitheliocytes, an enhancement of adhesion of all the studied corynebacteria strains took place. Adhesion index in strains isolated from healthy women increased by an average of 46.6%, adhesion index by 10.5 bact. cells/epith. In strains isolated from women with micro-ecologic disruption, adhesion increase was by 15.3% and 4.9 bact. cells/epith., respectively. CONCLUSION: Fibronectin is a factor that determines adhesion of corynebacteria to vaginal epitheliocytes and thus is important for formation of associative symbiosis of reproductive tract of women. The data obtained open perspective of use of fibronectin with the aim of colonizing ability increase of probiotics. PMID- 25816518 TI - [Morphologic changes in listeria cells under the effect of metabolites of human intestinal microflora enterococci]. AB - AIM: Characterization of morphologic changes in listeria cells under the effect of metabolites of human intestine microflora enterococci. MATERIALS AND METHODS: Culture of Listeria monocytogenes 88-BK cells was cultivated in the presence of enterococci waste products (experiment) or without them (control). The samples obtained were studied by atomic-force microscopy (AFM) in contact mode using scanning probe microscope SMM-2000. RESULTS: The character of morpho-functional reaction of indicator culture bacterial cells allows to assume the presence of cationic anti-microbial peptides with membrane-lytic mechanism of action in 30% of the studied enterococci strains. CONCLUSION: The use of atomic-force microscopy allows to detail the mechanisms of anti-microbial activity of bacteriocins of intestine microflora microorganisms against target bacteria under close to native conditions. PMID- 25816517 TI - [Indexes of local cytokine status in individuals with intestine dysbacteriosis]. AB - AIM: Determination of the content of various cytokines in coprofiltrates of individuals with bacteriologically confirmed intestine dysbacteriosis. MATERIALS AND METHODS: Qualitative and quantitative content of large intestine microbiocenosis was studied; IFNgamma, pro-inflammatory (IL-2, IL-6, IL-8, IL 1beta) and anti-inflammatory (IL-4, IL-10) content was determined using EIA in coprofiltrates of 139 individuals aged 18 - 60 years. All the indexes were juxtaposed with the cytokine index (CI): RESULTS. A high content of IL-2, IL-4 and IL-10 with normal levels of IL-1beta, IL-6 and IL-8 was established. A comparable content of bifidobacteria, lactobacilli and escherichia was detected in individuals with various CI index; in individuals with CI above 1 c.u. and above 10 c.u., against the background of proportionally intensifying IFNgamma induction, an increase of quantity of escherichia with decreased enzymatic activity and frequent detection of opportunistic enterobacteria, staphylococci and Candida genus fungi is noted. CONCLUSION: The presence of opportunistic microflora at low content of IFNgamma with CI of less than 1 c.u. could be evaluated as a dysbiotic reaction, and the presence of opportunistic microflora against the background of high IFNgamma content with CI of above 10 c.u.--as a development of systemic inflammation due to translocation of dysbiotic microflora into the bloodflow. PMID- 25816519 TI - [Apoptogenic activity of microbes-associants during Epstein-Barr virus infection]. AB - AIM: Study apoptogenic activity of-microbes-associants during Epstein-Barr virus infection (EBVI) on the model of mice peritoneal macrophages in vitro. MATERIALS AND METHODS: Evaluation of apoptosis induced by bacteria isolated from EBVI patients was carried out by characteristic morphological changes of macrophages in smears stained by May-Grunwald with additional staining by Romanowsky-Giemsa. RESULTS: All the EBVI microbes-associants were established to have apoptogenic activity, however, the highest pathogenic potential was noted in Streptococcus pyogenes. CONCLUSION: The presence of apoptogenic activity in bacterial microflora accompanying EBVI against immune system cells could serve as means of their survival and be the pathogenetic basis for prolonged persistence in the organism. PMID- 25816520 TI - [Persistence of antibodies specific to West Nile virus in blood of reconvalescents of Volgograd region]. AB - AIM: Determine the duration of persistence of IgM and IgG in reconvalescents of West Nile fever (WNF) 1 year after the disease in southern regions of Russia and evaluate effectiveness of PCR method for acute infection diagnostics. MATERIALS AND METHODS: Blood sera of 87 patients with WNF diagnosis was studied for the presence of West Nile virus (WNV) RNA and IgM and IgG by PCR and EIA. Samples of the first sera were collected in 2010 at days 2 - 30 after the onset of the disease, samples of the second sera--at days 5 - 23 and third--264 - 385 days later. RESULTS: During the first 2 weeks of the disease WNV RNA was detected in more than 50% of patients. In all the first sera IgM at titers of >= 1:800 were detected. Seroconversion of IgG titers of 4 and more times was observedin 83% (30/36) of patients. In 2011 IgG were detected in 91% of reconvalescents (79/87), IgM--in 57% (50/87), and in 25% (22/87) IgM titers were >= 1:800. CONCLUSION: The results obtained give evidence on the necessity of using several diagnostic criteria simultaneously for the confirmation of WNF clinical diagnosis. PMID- 25816521 TI - [Risk of introduction and spread of polioviruses in closed-type child-care facilities]. AB - AIM: Compare frequency of isolation of polioviruses in children living in closed type facilities (orphanages) before and after the change in poliomyelitis vaccination scheme. MATERIALS AND METHODS: Feces samples of 207 children from 5 orphanages during immunization with oral poliomyelitis vaccine (OPV) and of 259 children from 4 orphanages during vaccination with inactivated poliomyelitis vaccine (IPV) were studied. Isolation and identification of polioviruses was carried out according to WHO recommendations. RESULTS: In orphanages, where children were immunized with the oral vaccines, 21 polioviruses were isolated. In orphanages, where only inactivated vaccine was used, 10 polioviruses were isolated, the presence of polioviruses in these facilities is associated with their introduction from the outside. The percentage of poliovirus detection in children immunized with OPV was shown to be 16.9 +/- 3.4% and was significantly higher than in children vaccinated with IPV (6.1 +/- 1.9%). Polioviruses isolated from children immunized with OPV belonged to serotypes 1, 2 and 3 in 19.0, 14.3 and 66.7% of cases, respectively. Polioviruses detected in children immunized with IPV belonged to serotypes 1, 2 and 3 in 30, 40 and 30% of cases, respectively. All the isolated polioviruses turned out to be Sabin vaccine strains. CONCLUSION: Implementation of strict prophylaxis measures in orphanages is necessary in order to prevent the possibility of introduction, transmission and circulation of polioviruses. Improvement of control in children from closed type facilities will ensure maintenance of Russian Federation status as the country free of poliomyelitis. PMID- 25816522 TI - [Effect of Corynebacterium non diphtheriae on functional activity and apoptosis of macrophages]. AB - AIM: Determine the ability of Corynebacterium non diphtheriae to induce phagocytosis and apoptosis of macrophages and evaluate regulatory effect of nuetrophilokines (NPK) induced by Corynebacterium non diphtheriae on these processes. MATERIALS AND METHODS: The ability of Corynebacterium non diphtheriae, isolated from upper respiratory tract, skin and urogenital tract (UGT) were studied for the ability to induce phagocytosis and apoptosis of mice macrophages (MP; in vitro during staining by May-Grunwald with additional staining by Romanowsky-Giemsa) before and after the addition of NPK induced by Corynebacterium non diphtheriae. RESULTS: Phagocytic index (PI) was the same for all the Corynebacterium non diphtheriae species, phagocytic number (PN) and index of phagocytosis completion (IPC)--were minimal relative to corynebacteria isolated from UGT. All the studied corynebacteria species induced MP apoptosis; the most pronounced apoptogenic effect was detected in Corynebacterium pseudotuberculosis isolated from UGT. NPK increased PN against corynebacteria isolated from the studied biotopes, IPC--only during studies of corynebacteria isolated from skin. The effect of NPK resulted in a reduction of apoptogenic effect for almost all the Corynebacterium non diphtheriae, regardless of the isolation location. CONCLUSION: A pronounced apoptogenic effect and insufficiency of phagocytosis processes induced by corynebacteria are the means of realization of Corynebacterium non diphtheriae pathogenic effect. NPK use is possible for immune correction of immune deficiency conditions developing against the background of diseases determined by Corynebacterium non diphtheriae. PMID- 25816524 TI - [Effect of thrombodefensins on the course of chronic staphylococci dermatitis on in vivo model]. AB - AIM: Evaluate therapeutic effect of thrombodefensins (TD) on the course of chronic staphylococci dermatitis (CSD) in mice. MATERIALS AND METHODS: TD was obtained from human thrombocytes. 24 CBRB-Rb(8.17)1Iem line female mice were used in the experiment, that were divided into 2 equal groups. Staphylococcus aureus strain producing exfoliative exotoxin was isolated from withers of each mouse with signs of affection. Mice of the experiment group subcutaneously around the locus of affection, received for 4 weeks daily a composition in the volume of 0.2 ml, that contains 1 g of dry lyophilized TD diluted in 10 ml of 0.9% NaCl (final concentration of the preparation--15 MUg/ml). Control group animals similarly received 0.9% solution of NaCl without TD. Area and degree of the affected zone on the back was evaluated in all the mice. Statistical significance of differences in the values of parameters was determined by t-criteria. RESULTS: At the start of the experiment the average area of the affected zone in mice of both groups was 167 +/- 17 mm2. From day 8 to 23 the expansion of the affection zone was observed, however in the experiment group of mice these negative tendencies were less pronounced. At the end of the experiment on day 50 the area of affection was significantly smaller (2.3 times) in the experiment group of mice compared with the control (p < 0.05). CONCLUSION: The anti-staphylococci effect of TD, demonstrated in the study, opens perspective of their clinical use in CSD therapy. PMID- 25816523 TI - [Cross-immunogenicity of various bacterial L-asparaginases]. AB - AIM: Evaluate immune response in mice against various L-asparaginases and determine their cross-immunogenicity. MATERIALS AND METHODS: The studies were carried out in C57Bl(6j) line mice. Immunogenicity of L-asparaginases was studied: Escherichia coli type II (recombinant) (Medak, Germany) (EcA); Erwinia carotovora type II (ErA); Yersinia pseudotuberculosis type II (YpA); Rhodospirillum rubrum type I (RrA); Wollinella succinogenes type II (WsA). Immune response against the administered antigens was determined in EIA. RESULTS: Y. pseudotuberculosis L-asparaginase was the most immunogenic, E. coli--the least immunogenic. E. carotovora, R. rubrum, W. succinogenes asparaginases displayed intermediate immunogenicity. The results of cross-immunogenicity evaluation have established, that blood sera of mice, that had received YpA, showed cross immunogenicity against all the other L-asparaginase preparations except E. carotovora. During immunization with E. coli L-asparaginase the developed antibodies also bound preparation from E. carotovora. Sera from mice immunized with W. succinogenes, E. carotovora and R. rubrum L-asparaginases had cross reaction only with EcA and did not react with other preparations. CONCLUSION: Cross-immunogenicity of the studied L-asparaginases was determined. A sequence of administration of the studied preparation is proposed that allows to minimize L asparaginase neutralization by cross-reacting antibodies. PMID- 25816525 TI - [Effect of immune modulation on immunogenic and protective activity of a live plague vaccine]. AB - AIM: Comparative evaluation of the effect of polyoxidonium and betaleukin on immunogenic and protective activity of a live plague vaccine in model animal experiments. MATERIALS AND METHODS: Plague vaccine EV, polyoxidonium, betaleukin, erythrocytic antigenic diagnosticum for determination of F1 antibodies and immune reagents for detection of lymphocytes with F1 receptors (LFR) in adhesive test developed by the authors were used. The experiments were carried out in 12 rabbits and 169 guinea pigs. RESULTS: Immune modulation accelerated the appearance and disappearance of LFR (early phase) and ensured a more rapid and intensive antibody formation (effector phase). Activation by betaleukin is more pronounced than by polyoxidonium. The more rapid and intensive was the development of early phase, the more effective was antibody response to the vaccine. Immune modulation in the experiment with guinea pigs significantly increased protective activity of the vaccine. CONCLUSION: The use of immune modulators increased immunogenic (in both early and effector phases of antigen specific response) and protective activity of the EV vaccine. A connection between the acceleration of the first phase of antigen-specific response and general intensity of effector phase of immune response to the EV vaccine was detected. , PMID- 25816527 TI - [Etiologic deciphering of community-acquired pneumonia caused by mycoplasma pneumoniae]. AB - AIM: Use of a complex of methods for etiologic deciphering of an acute respiratory infection. MATERIALS AND METHODS: Clinical samples of blood sera, nasopharynx washes and sputum were obtained from 35 patients with acute respiratory disease (ARD). "Difco PPLO Broth" was used for M. pneumoniae cultivation. AHR, IFR, PCR, IFA were used in the study. RESULTS: Results of the study have shown that M. pneumoniae antigens in blood, sera samples were detected in AHR in 32 patients, and specific G and M class antibodies--in 21 and 18 cases, respectively. Simultaneous detection of IgG and IgM was registered in 14 patients. M. pneumoniae cell DNA was detected in 10 of 20 blood sera samples. Circulating immune complexes were isolated from blood sera of 8 patients (4 with pneumonia, 4 with ARD) and M. pneumoniae antigens were detected in them by using direct-IFR. IFR study of sputum and nasopharynx smears has shown that M. pneumoniae antigens were detected in 29 of 35 samples. In 12 of 15 smear samples M. pneumoniae. DNA was detected by PCR. In 10 cases results of antigen detection by IFR as well as DNA in PCR coincided. Results of analysis of all the clinical material have shown that in 33 of 35 patients positive results coincided for 2 or 3 and in some cases 4 of the laboratory study methods used. CONCLUSION: The use of diagnostic test complex significantly increases the accuracy of the study results, and detection of specific antibodies allows to determine disease period. PMID- 25816526 TI - [Skin and mucous membrane microbiocenosis during atopic dermatitis in children]. AB - AIM: Study the microbial landscape and determine the interaction between biocenoses of skin, oropharynx and intestine mucous membranes during atopic dermatitis in children. MATERIALS AND METHODS: 60 children with atopic dermatitis were examined, bacteriologic study of skin, oropharynx, intestine was carried out. RESULTS: Significant changes were detected in both quantitative and qualitative composition of microbiocenosis of skin, oropharynx and intestine mucous membranes. Skin of patients is more frequently colonized by Staphylococcus aureus. Gram-positive bacteria dominated in oropharynx microflora. Comparative characteristics of microflora of skin and oropharynx mucous membrane revealed a direct of correlation. During microbiological study of intestine microflora, all the examined had microbial landscape disruptions of varying severity degree. CONCLUSION: Taking into consideration the direct correlation of microflora of skin and oropharynx mucous membrane during atopic dermatitis, seeding of oropharynx washes are recommended to be included into the examination complex of patients with subsequent correction of microbiocenosis. Examination of all the children with atopic dermatitis for the presence of intestine dysbiosis is advisable. PMID- 25816529 TI - Center of cleft lip-cleft palate and craniofacial deformities, Khon Kaen University in association with "Tawanchai Project" and Faculty of Medicine, Khon Kaen University. PMID- 25816528 TI - [Analysis of population immunity of residents of Russian Federation regions against seasonal and highly pathogenic strains of influenza virus]. AB - AIM: Determine the level of antibodies against socially significant types/serotypes of influenza virus in sera of individuals residing in various regions of Russia. MATERIALS AND METHODS: 1525 samples of blood sera collected in August-December 2013 in 8 regions of Russian Federation were studied in hemagglutination inhibition reaction (HAI) with antigens obtained from A/California/07/09, (H1N1)pdm09, A/Victoria/361/2011(H3N2), B/Brisbane/60/2008 (Victoria line), B/Massachusetts/2/2012 (Yamagata line), A/Commongull/Chany/2006 (H5N1), A/Anhui/01/2013 (H7N9) influenza virus strains. RESULTS: None of the blood sera samples had significant HAI titers against A/H5 and A/H7 antigens. Of all the 1525 samples, 788 (52%) were positive with A(H1N1)pdm09 antigen; 734 (48%) reacted with A(H3N2) antigen; 1010 (66%) samples were positive with B/Victoria antigen and 602 (39%) samples were positive with B/Yamagata antigen. CONCLUSION: Healthcare institutions should pay attention to the correction of population immunity profile in regions for the reduction of social-economic losses from seasonal influenza epidemics. PMID- 25816530 TI - Center of cleft lip-cleft palate and craniofacial deformities, Khon Kaen University in association with "Tawanchai Project" and Faculty of Medicine, Khon Kaen University. PMID- 25816531 TI - Treatment of 4-5 year old patients with cleft lip and cleft palate in Tawanchai Center: prevalence and type of associated malformations. AB - BACKGROUND: Patients with cleft lip/palate may have other associated malformations but the reported prevalence and type of associated malformations varied between different studies. OBJECTIVE: To report the prevalence and the type of associated malformations in Northeastern Thai patients with cleft lip/palate. MATERIAL AND METHOD: A retrospective study of 123 cleft lip/palate patients aged 4-5 years was carried out at the Tawanchai Cleft Center, Khon Kaen University during the periodfrom October to December 2011. Data were collected by reviewing the patients medical records. RESULTS: Seventeen (14%) of the 123patients had associated malformations. Four (21%) of the 19patients with cleft palate, eleven (15%) of the 74 patients with clefts lip and palate, and two (7%) of the 30 patients with cleft lip had associated malformations. The organ systems affected by associated malformations were cardiovascular system (41%), craniofacial anomaly (23%), skeletal system (12%), urogenital system (12%) and central nervous systemn (12%). Atrial septal defect and tetralogy ofFallot were most common associated cardiovascular malformation found. CONCLUSION: The high prevalence of associated malformationsfound in patients with cleft lip/palate emphasizes the needfor a thorough screening of associated malformations and congenital heart disease ofall cleft lip/palatepatients. PMID- 25816532 TI - Oral health status and oral impacts on quality of life in early adolescent cleft patients. AB - OBJECTIVE: To determine the levels of dental caries, periodontal disease and oral health-related quality of life in children with cleft lip and/or cleft palate compared to non-cleft controls. MATERIAL AND METHOD: This cross-sectional study was conducted in Khon Kaen, Thailand. Subjects included 68 oral cleft and 118 non cleft individuals aged 10-14 years, who were interviewed using the Child-Oral Impacts on Daily Pemformance (Child-OIDP) index and received oral examinations. RESULTS: Decayed, missing and filled teeth (DMFT) index in permanent teeth, plaque index (PI), and gingival index (GI) scores were significantly higher in the children with cleft than in the controls. However, there was no significant difference in caries prevalence and decayed, missing and filled teeth (dmnft) index inprimaly teeth between comparison groups. The prevalence of oral impacts on Speaking and Smiling was significantly higher in the cleft children than non cleft controls. The mean impact score between both groups were not significantly different, but the cleft children with impacts had a significantly higher mean impact score (11.9) than did the controls (8.6). The impact score in the cleft children was high for speaking (4.5), emotion control (4.2), eating (3.4) and relaxing (3.4) activities. The main causes of these impacts included having oro nasalftstula, having orthodontics appliance, position of teeth and deformity of mouth or face. CONCLUSION: The cleft children had higher levels ofdental caries and gingivitis, and poorer oral hygiene than the controls. They also had lower quality of life than the controls in most pelformances with different perceived causes. PMID- 25816533 TI - Pre-surgical nasoalveolar molding technique: a literature review. AB - Cleft lip and palate patients have many defects particularly nasal deformities. The nasoalveolar molding (NAM) technique is an adjunctive treatment, which not only corrects deviated alveolar segments but also addresses nasal deformity before cheiloplasty. NAM technique is claimed to facilitate primary surgical correction and to provide favorable esthetic outcomes. However, there is limited evidence to confirm the special benefits ofNAM technique since so far there have been no truly long term controlled clinical trials to evaluate outcomes of treatment based on pre-surgical NAM technique. NAM technique can aid surgeons in their primary repairs ofnasal deformities but there should be concern about cost risk benefits and ability ofparents to manage home care. Further studies based on properly designed and managed long-term clinical trials are still neededfor reaching consensus on special benefits ofNAM technique compared with other treatment protocols. PMID- 25816534 TI - Clinical outcomes of primary palatoplasty in pre-school-aged cleft palate children in Srinagarind hospital: quality of life. AB - BACKGROUND: Cleft lips and cleft palates are common congenital anomalies, which affects facial appearance, speech, hearing, teeth alignment and other structures. Craniofacial anomalies and speech disorders are crucial problems in the preschool aged children (5-6 years old), when they start attending school and become more engaged in the community. This condition, which differentiates them from other students, can lead to teasing or mocking which can cause low-self esteem, an inferiority complex, andfoster bad relationships with friends. Missing class in order to receive treatment and other additional care can affect a student's learning, development and overall-quality of life. OBJECTIVE: The purpose of this research was to study the quality of life in preschool-aged cleftpalate children and satisfaction with their level of speech. MATERIAL AND METHOD: This was a retrospective, descriptive study. The data were collected by reviewing medical records of patients with cleft lip and cleft palate aged 5-6 years old who underwent operation and treatment with the Tawanchai Center at Srinagarind Hospital. There were 39patients in this study. Data collection was conducted for 5 months (June to October 2013). The research instruments were: (1) General Demographic Questionnaire, (2) Quality of Life Questionnaire with 5 Domains, and (3) the Satisfaction of Speech Questionnaire. The descriptive statistics, percentages and the standard deviation were analyzed in the present study. RESULTS: The findings revealedfamily information pertaining to CLP treatment and the impact it has on consumption, speech training, hearing test, development, dental treatment, communication skills, participation, referral treatment as well as the quality ofcoordinationfor advanced treatment. The present study revealed that all ofthe aforementioned criteria were met at a high level. Moreover the child's sickness had only a moderate impact on family life. In conclusion, the overall satisfaction was at a very high level. CONCLUSION: It was concluded that the collaboration of the Tawanchai Cleft Center and the government, as well as with private and non-governmental organizations was exceptional, particularly in regard to providing proper and continuous treatment for patients with cleft lips and/or cleft palate. The findings reflect a good quality of life in the pre schooled children with cleft lip and cleft palate that received treatment from the Tawanchai Cleft Center at Srinagarind Hospital. Furthermore, the study showed that the problems associated with the condition, only affected the family's lives at a minimal level. PMID- 25816535 TI - Enhancing accessibility of patients with cleft lip/palate to healthcare services via a cleft birth registration system. AB - BACKGROUND: Cleft lip/palate is a critical health problem in Thailand; with an incidence rate of 2.49/1,000 live births. To insure the best outcomes, surgery should be performed near the age of three months. However; during the years 1993 2007, only 39.7% of children with a cleft lip/palate underwent an operation by the age of 3-4 months and only 58.18% by the age of 9-12 months. OBJECTIVE: The purpose of the study is to determine if a cleft birth registry might facilitate timely and proper treatment for children with a cleft lip/palate. MATERIAL AND METHOD: A pilot cleft birth registry, developed by the Tawanchai Cleft Center, was made available to hospitals in Khon Kaen, Roi-et, Kalasin, and Mahasarakam provinces, Thailand. Ninety-eight personnel involved in the care of children with a cleft lip/palate were recruited from the participating hospitals to evaluate the system. Assigned to one offour focus groups, participants were asked to evaluate the pilot system in terms of satisfaction and benefit. Following the focus groups, those participants that were traditionally responsible for registration were asked to use the cleft birth registry to register any newborns with a cleft lip/palate that were encountered in the course of their duties. Records were examined to determine how many newborns were properly registered and for those registered, whether proper care was received in a timely manner RESULTS: With 78 focus group participants responding to the satisfaction survey, results indicated mostly high levels of satisfaction with 26 (33%) participants rating satisfaction as very good, 49 (63%) as good and 3 (4%) as fair No participant rated satisfaction below fair. Furthermore, a majority stated that the cleft birth registy would benefit patients and contribute to timely treatment. During two years of active use, one hundred and thirty-seven newborns with a cleft lip/palate were registered into this cleft birth registry. Subsequent examination showed that eighty-eight percent ofregistered cases received proper management in tertiary healthcare settings. CONCLUSION: The fact that most of registered cases received proper care suggests that a cleft birth registry has the potential to facilitate timely and proper care. Howeve,; declining rates of registration over time is cause for concern. One opportunity for improvement in this regard might come from the establishment of an in-service trainingprogram to update knowledge pertaining to current standards of care and effective case management. Further improvements could also be made through better integration with existing referral systems. The researchers also noted that the existing electronic patient records (EPRs) in use by participating hospitals often lacked data structures suitable for effective care of patients with a cleft lip/palate. Thus, to foster useful integration, existing EPRs must also be extended to include data specific to cleft care/management. PMID- 25816536 TI - Clinical outcomes of primary palatoplasty in preschool-aged cleft palate children in Srinagarind Hospital and comparison with other standard cleft centers. AB - BACKGROUND: The purpose of this study was to evaluate the clinical outcomes regarding the rate of hypernasality and oronasal fistula formation in patients with cleft palate who underwvent primaly palatoplasty at our center and under our management protocol. MATERIAL AND METHOD: A Cross-sectional study of 40 consecutive non-syndromnic cleft palates with/or without cleft lips, born between February 2007 and December 2008, who underwent primaty palatoplasty at Srinagarind Hospital, Thailand. Demographic data that were recorded inclutdes: patients with cleft types, age atpalatoplasty, operating surgeons and surgical techniques. RESULTS: 40 consecutive patients. There were 23 boys and 17 girls. Three patients had associated disease; one patient had amniotic band syndrome and clubfeet, two patients had G-6-PD deficiency. Mean age at time of evaluation was 5.7 years (5.0-6.9 years). Mean age atpalatoplasty was 14.1 months (9-64 months). There were three plastic surgeons and plastic surreiy residents. The predominiant cleft lip type was Veau 3 (52.5%) followed by Veau 4 (27.5%) and Veau 1 (20%). Twvo-flap palatoplasty was used in all patients. The rate of hypernasality was 37.5% (15 out of 40 patients). Mild hypernasality was 25% and moderate hypernasality was 12.5%. Oronasalfistula occurred in 10 patients, fistula rate was 25%. Oronasal fistula closure was relformed on nine patients (90%). Two patients (5%) had residual oronasal fistula at the time of the study. There were no statistically significant differences in the cleft types, age at palatoplasty and operating surgeons in hypernality rates and oronas alfistula fomation. CONCLUSION: The rate of hypernasality and oronas alfistu laformation was comparable to resultsfirom other standard cleft. PMID- 25816537 TI - A Relationship between nasolabial appearance and self-esteem in adolescent with repaired cleft lip and cleft palate at Khon Kaen University Cleft Center. AB - OBJECTIVE: To examine levels of self-esteem of adolescents with repaired cleft lip and cleft palate at Khon Kaen University Cleft Center and its correlation with nasolabial appearance. MATERIAL AND METHOD: Across-sectional survey of 93 adolescents with repaired cleft lip and palate. RESULTS: A total nasolabial appearance score was 2.8 +/- 0.36 (fair to good). The mean of the total self esteem score for all respondents was 20.11 +/- 3.27 (maximum 30). There was no significant correlation between nasolabial appearance and self esteem (Pearson product-moment correlation coefficiency (r) = 0.18, p = 0.08. The self-esteem scores of good, fair and poor appearance were 20.5 +/- 0.98, 19.8 +/- 0.32, 19 +/ 2.09 respectively. CONCLUSION: The nasolabial appearance of repaired cleft lip and palate not be the only factor but other psychosocialfactors also may play a role in their self-esteem. The analysis of this study found no relationship between self-esteem and appearance. PMID- 25816538 TI - Cost management of cleft lips under the Universal Health Coverage Program of the Tawanchai Cleft Center, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University. AB - BACKGROUND: The study ofcost management with regard to cleft lip patients under the Universal Health Coverage Program at Tawanchai Cleft Center Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, was conducted in order to provide fundamental information for the administrative team on how best to administrate and manage the organization. OBJECTIVE: To study the cost management of cleft lip patients under the Universal Health Coverage Program. To compare individual patient management costs and costs from the National Health Security Office (NHSO), and to offer proper guidelines for cost management to the organization. MATERIAL AND METHOD: The study was performed retrospectively. The data were collected by reviewing secondary sources of information from patients with cleft lips who consistently underwent treatment at Tawanchai Cleft Center. As for the provider prospects, the cost management did not address the other expenses. The study analyzed the comparison between cost management and income from the Universal Health Coverage Program, which it receivedfrom the National Health Security Office (NHSO). The study was conducted over 2 years (October 1, 2010 to 30 September, 2013). There were 21patients in this study. Microsoft excel was the instrument used to calculate the cost ofmanagement. RESULTS: (1) Total costs were lower than real payments because this cost did not take into account the total cost of the operation room, patient room, common bed, and costs of the medical equipment. Moreover the information regarding the building's price and the facility were not clear enough. The database of materials and equipment was also not yet complete. (2) The average cost ofpatient management was 12,025.14 Bahtperperson, but the compensation receivedfrom the National Health Security Office (NHSO) averaged 10,527.63 Bahtperperson, which was 87.55% ofthe total cost management. The department with the largest expenses was Anesthesia (36.42%). CONCLUSION: This study indicated that the cost of patient management is lower than usual due to the lack of clear cost information. The cost of medical care, which was received from the National Health Security Office (NHSO), was only 87.55%; the department with the highest costs was Anesthesia (36.42%). PMID- 25816539 TI - Difference of clinical phenotypes and immunological features of 22q11.2 deletion syndrome in north-eastern Thai children compare to western countries. AB - BACKGROUND: 22q11.2 deletion syndrome is a common microdeletion syndrome that affected various systems. OBJECTIVE: To determine clinical phenotypes and immunologicalfeatures of 22q11.2 deletion syndrome in north-eastern Thai children compare to western countries. MATERIAL AND METHOD: The authors described the clinical and immunological features in 20 north-eastern Thai children with 22q11.2 deletion syndrome that were followed-up at Srinagarind Hospital. RESULT: Clinical phenotypes were facial dysmorphism (100%), congenital heart disease (80%) and cleft palate (30%). Prevalence of tetralogy of Fallot (TOF) in this syndrome was higher than in western. Serious infections were found including pneumonia, septicemia and brain abscess. Only a patient had panhypogammaglobulinemia and subsequently died. Selective IgA deficiency was not found. There was a twin patient conceivedfrom intracytoplasmic sperm injection (ICSI). CONCLUSION: TOF is more common in Asian patients than in western which different to selective IgA deficiency. The 22q11.2 deletion syndrome could be consequence from ICSI. PMID- 25816540 TI - Effect of knowledge and perception on adherence to iron and folate supplementation during pregnancy in Kathmandu, Nepal. AB - BACKGROUND: Adherence to iron and folate supplementation during pregnancy is considered key to prevention and control of iron deficiency anemia. Nepal-like other developing countries-faces problems with adherence vis-a-vis iron/folate supplementation. OBJECTIVE: This descriptive survey aimed to assess the effect ofknowledge and perception ofpregnant women on adherence to iron/folate supplementation in Kathmandu, Nepal. MATERIAL AND METHOD: The present study was conducted in Paropakar Maternity and Womens' Hospital in Kathmandu. Systematic random sampling was used to select 406 persons who were either given a self administered questionnaire or interviewed. RESULTS: 73.2% of the respondents showed good adherence. Bivariate analysis revealed significant associations between adherence and both knowledge and perception (p<0.05), but through multiple linear regression analysis only perception was found to be statistically associated with adherence (p<0.05). Further multivariate analysis demonstrated that the most important predictors of adherence were: perception of side effects, availability, forgetfulness and reminders from family. CONCLUSION: Adherence to iron/folate supplementation among women during pregnancy needs continuous improvement by minimizing the perception of constraints (viz., side-effects and forgetfulness) and, enhancing availability andfamily support. PMID- 25816542 TI - Vitamin A supplementation for prevention of bronchopulmonary dysplasia in very low-birth-weight premature Thai infants: a randomized trial. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is one ofthe most significant complications among very-low-birth-weight (VLBW) premature infants. Vitamin A deficiency increases the risk of BPD in VLBWinfants. OBJECTIVE: To assess the effect of vitamin A supplementation for prevention of bronchopulmonary dysplasia in VLBW premature Thai infants. STUDY DESIGN: Randomized control trial. MATERIAL AND METHOD: Eighty premature infants weighing <1,500 g who received mechanical ventilation or oxygen supplementation at 24 hours ofage-admitted to Neonatal units ofSrinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand-were assigned to receive either intramuscular vitaminA 5, 000 IU3 times/week (treatment group) or sham procedure (control group) for four weeks. Serum vitamin A levels were measured before and after administration of the vitamin A. RESULTS: The baseline of mean serum vitamin A levels were similar in both groups. The mean serum level of vitamin A was significantly higher in the vitamin A supplemented infants than in the control infants on day 7 (1.41 +/- 0.48 vs. 0.92+0.38 pmol/ L, p<0.001), day 14 (1.48 +/- 0.90 vs. 0.96 +/- 0.36 micromol/L, p = 0.001) and day 28 (1.42 +/- 0.63 vs. 0.76 +/- 0.30 micromol/L, p<0.001) after vitamin A supplementation. None of the infants in the vitamin A supplemented group, compared to 5% of the infants in the control group, had vitamin A level <0.35 micromol/L, (indicating severe vitamin A deficiency) at 28 days. Fewer of the premature infants in the vitamin A supplemented group required oxygen supplementation at 36 weeks postmenstrual age than in the control group albeit not statistically significant (22.5 vs. 35% relative risk 0.71; 95% CI 0.40 +/- 1.26; p = 0.21). Supplementation with vitamin A was also associated with a significant reduction in the duration ofintubation (10.8 +/- 3.1 days vitamin A supplemented group vs. 26.1 +/- 6.4 days control group, p = 0.03), days on oxygen therapy (29.8 +/- 5.1 days vitamin A supplemented group vs. 58.2 +/- 9.1 days control group, p = 0.01) and length of hospital stay (61.9 +/- 4.2 days vitamin A supplemented group vs. 88.3 +/- 7.2 days control group, p = 0.002). CONCLUSION: The dose of vitamin A used in this study reduced biochemical evidence of vitamin A deficiency and, without complications, resulted in reducing duration of intubation, days of oxygen therapy, and length of hospital stay in premature infants suffering VLBW PMID- 25816541 TI - Enamel defect and gingival enlargement in pediatric patients with kidney disease at Srinagarind Hospital, Khon Kaen University, Thailand. AB - BACKGROUND: Although many complications from kidney disease therapy can be prevented or effectively treated, oral health problems are nevertheless a consequence. OBJECTIVE: The objective of this study was to explore the prevalence of enamel defect and gingival enlargement in pediatric patients with kidney disease at Srinagarind Hospital, Khon Kaen University, Thailand. MATERIAL AND METHOD: This cross-sectional study was conducted between January and August 2013, at SrinagarindHospital, Khon Kaen University. Ninety-seven pediatric patients with kidney disease were allowed by their parents to participate in this study. Data were collected from medical records, questionnaires and oral examination records. The enamel defect was recorded using the Developmental Defects of Enamel Index. Gingival enlargement was recorded using the GingivalEnlargement Index. An oral examination was conducted using a mouth mirror, explorer and periodontal probe. RESULTS: The average age of the pediatric patients with kidney disease was 11.53+3.7years (range, 4-17). The majority of subjects were able to (a) come for an appointment (97.9%), (b) take medication according to the medical directions (93.8%) and (c) avoid inappropriatefoodsfor those suffering kidney disease (84.5%). The prevalence of enamel defect was 27.8%. The most common enamel defects were demarcated opacities (13.4%) or diffuse opacities (9.3%). The prevalence ofgingival enlargement was 16.5%. CONCLUSION: This study revealed that the prevalence ofenamel defect was 27.8% and the prevalence ofgingival enlargement was 16.5%. PMID- 25816543 TI - Second trimester genetic ultrasound for Down syndrome screening at Srinagarind Hospital. AB - OBJECTIVE: To assess the value of second trimester genetic ultrasound for screening of Down syndrome conducted at Srinagarind Hospital, Khon Kaen, Thailand. MATERIAL AND METHOD: The present study sample comprised of 4,033 pregnant women at high risk forfetal chromosomal abnormality, from 17th to 23th week, who had performed second trimester genetic ultrasound before genetic amniocentesis between September 1996 and December 2011. Archived medical records relating to results ofgenetic ultrasound and genetic amniocentesis were extracted and studied. MAIN OUTCOME MEASURE: Sensitivity ofgenetic ultrasound in the detection of fetal Down syndrome. Results: There were 3,966 chromosomally normal pregnancies (98.3%), 43 fetuses with Down syndrome (1.1%), and 24 fetuses with other chromosomal abnormality (0.6%). 30 of 43 (69.8%) fetuses with Down syndrome had abnormal genetic ultrasound. The overall sensitivity of second trimester genetic ultrasound for detecting Down syndrome was 69.8% with a false-positive rate of 50.4% and likelihood ratio of 1.38. Of all the sonographic markers, short femur, and short humerus indicated the highest sensitivity at 65.1% and 44.2%. According to likelihood ratio (LR+), chest abnormality, 2 vessel umbilical cord, andfacial abnormality including cleft lip and palate, have highest likelihood ratio (LR+) of 61.49, 46.12, and 46.10, and had sensitivity at 4.7%, 2.3%, and 2.3% respectively. CONCLUSION: The sensitivity of second trimester genetic ultrasound for detection offetal Down syndrome at Srinagarind Hospital was rather high, and probably is an alternative method ofprenatalprediction for high risk pregnant women who refused genetic amniocentesis. PMID- 25816544 TI - The posterior pericardiotomy. Does it reduce the incidence of postoperative atrial fibrillation after coronary artery bypass grafting? AB - Atrial fibrillation (AF) is the most common arrhythmia after coronary artery bypass graft surgery (CABG). Posterior pericardiotomy (PP) has been reported toreduce pericardial effusion, AF triggel; and reduce the length of hospital stay and hospital costs without significant complications. A total of 20 patients, diagnosed with coronary artery diseases to be treated by an elective or urgent CABG between August and December 2013, were randomly divided into two groups; 10 patients received PP (PP group) and 10 patients did not receive PP (control group). The incidence ofAF was equal (40% in both groups). Early pericardial effusion was slightly higher in the PP group (PP 70%, control 60%; p = 1.00). The incidence of left pleural effusion and pneumonia were higher in the PP group than in the control. Moreover, one patient in the PP group developed perioperative myocardial infarction (MI) that required intensive care with medication. The duration of ICU stay of the PP group was significantly longer than that of the control group. In conclusion, PP did not reduce the incidence of postoperative AF nor did early pericardial effusion. Rather, PP increased post-operative complications such asperioperative MI, left pleural effusion, and pneumonia resulting in the prolonged ICU stay. PMID- 25816545 TI - Prevalence and type of associated syndromes in patients with cleft lip and cleft palate who received the treatment in Tawanchai Center until 4-5 years of age. AB - BACKGROUND: Understanding the genetic etiologies of cleft lip and palate (CLP) is important for improved prevention, treatment, and prognosis for patients affected by CLP. OBJECTIVE: To report the prevalence and the type of associated syndromes in Northeastern Thai patients with CLP. MATERIAL AND METHOD: A retrospective study of123 cleft lip/palate children aged 4-5 years was carried out at the Tawanchai Cleft Centel; Khon Kaen University during the period from October to December 2011. Data were collected by reviewing the patient 's medical records. RESULTS: Seventeen (14%) of the 123 children had multiple malformations and five (4%) of these children had associated syndromes. Syndromes were identified in 5 (29%) of the 17 children who had associated malformations. The syndromes were Apert, Cleft lip/palate-ectodermal dysplasia, Kabuki, Oculo-Auriculo-Vertebral Spectrum, and Velocardiofacial syndrome. CONCLUSION: Recognition of the associated syndrome in a patient with CLP is essential to assess the problem of the patient, provide necessaty treatment and the appropriate methodology of prevention. PMID- 25816546 TI - Advanced exudative retinopathy with neovascular glaucoma as the clinical presentation of diabetes mellitus and severe combined hyperlipidemia: a case report. AB - A 50-year-old man presented with bilateralprogressive visual loss for 5 months. Visual acuity was reduced to countingfingers in the right eye and light perception in the left. Although neovascularizations were detected in the angles of the eyes, neovascular glaucoma and rubeosis iridis were demonstrated only in the left. Fundus examination showed bilateral advanced exudative retinopathy in both eyes. Severe attenuated retinal arteries and enlarged cupping with disc pallor were observed in the left eye. Generalized eruptive xanthomas were found on the back and extremities. Extreme dyslipidemia (serum cholesterol 1311 mg/dl and triglycerides 6356 mg/dl) and diabetes mellitus (fasting plasma glucose 325 mg/dl and HbA1 c 12.1%) were first diagnosed. The serum lipid profiles and glucose levels were dramatically decreased within a month after treatment with subcutaneous insulin injections and oral hypolipidemic agents; notwithstanding, his vision was not significantly improved, even after treatment with intravitreal anti-VEGF injection, intravitreal steroid injection and panretinal photocoagulation. CONCLUSION: The principle causes of advanced exudative retinopathy are severe breakdown of the blood-retinal barrier due to diabetes mellitus and altered retinal pigment epithelium lipid metabolism. In ourpatient, central retinal vascular occlusion was also the suspected cause ofneovascular glaucoma. PMID- 25816547 TI - Spontaneous bilateral retinal pigment epithelium rips with good visual acuity. AB - Retinalpigment epithelium (RPE) rips commonly occur in retinochoroidal disorders including age-related macular degeneration, idiopathic polypoid alchoroidal vasculopathy, central serous chorioretinopathy, high myopia andchoroidal neovascularization. Most patients have unilateral involvement and poor visual prognosis. A 55-year-old female presented with decreased vision in her right eye for one week. Her best-corrected visual acuity was 6/12 in the right eye and 6/6 2 in the left. Fundus examination revealed a large juxtafoveal RPE rip in the right eye and multiple small pigment epithelium detachments in the left. No abnormal hyperfluorescent lesions were detected byfundus angiography. High doseoral antioxidant was prescribed. A pigment epithelium detachment (PED) in the left eye grew larger over the follow-up period. Ultimately, a RPE rip also occurred in the left eye in the 17th week offollow-up. Her best-corrected visual acuity was 6/9. Although reinvestigation was done, no other choroidal abnormalities were demonstrated by optical coherence tomography (OCT) and fundus angiography. During the observation, RPE tears were reattached spontaneously in both eyes. A considerable amount of RPE proliferation, migration, and repopulation was also demonstrated by OCT and fundus autofluorescence. After 2.5 years of follow-ups, her best-corrected visual acuity was 6/9 in the right eye and 6/6 in the left. We hypothesize that the increased surface tension of RPE is the etiology of RPE rips in this case. Furthermore, the underlying chorioretinal abnormality directly affects the visual prognosis and further studies are needed in prevention, pathogenesis and treatment. PMID- 25816548 TI - Officer Down. EMS operations at an active shooter incident require careful coordination with law enforcement. PMID- 25816549 TI - The benefits of TXA. Implementing tranexamic acid for trauma patients will result in decreased mortality. PMID- 25816550 TI - Evidence-based EMS: needle decompression. Recent data may cause us to reconsider our preferred thoracostomy location. PMID- 25816551 TI - Health care innovation grant recipients making progress. Agencies seeing results already from their grant programs. PMID- 25816553 TI - Certification experimentation. With EMT-P being phased out, what's a non nationally registered medic to do? PMID- 25816552 TI - Advances in military medic training. How civilian paramedics helped upgrade training for U.S Army flight medics. PMID- 25816554 TI - Arms and 'The Man'. The role of law enforcement in securing violent patients. PMID- 25816555 TI - The seven windows counseling process. A technique for engaging employees to improve performance. PMID- 25816556 TI - The five phases of preceptorship. It takes a unique individual to simultaneously care for a patient while educating and evaluating a student. AB - Clinical teaching has been one of the most important but problematic areas of professional education.10 Clinical knowledge rarely corresponds with the theoretical knowledge that students acquire in the classroom and lab setting, contributing to a theory-practice gap for the patient care provider. This gap leads to the difficulty and disillusionment experienced by students during their field internship. To assist students with transitioning to the prehospital environment, paramedic preceptors are a necessity. However, regardlessof theirprehospitalexperience, paramedic preceptors may not have had proper education in the teaching-learning process and may not have been provided a quality preceptor training program. At present, there isno nationally sponsored preceptor program that effectively prepares field internship preceptors as clinical instructors even though accreditation now requires education for all paramedic preceptors. It is my hope that this article may be useful in the, development of quality preceptor work- shops, which will enhance the overall field internship experience to better prepare future paramedics. PMID- 25816557 TI - Common STEMI imitators: Part 1. There are other causes of ST-segment elevation besides myocardial infarction. PMID- 25816558 TI - Angel Thunder: the largest SAR exercise in the world. PMID- 25816559 TI - Strong Work. It's OK not to be good at everything--and to lean on a crewmate. PMID- 25816560 TI - [Early achievements of the Danish pharmaceutical industry-6 Pharmacia]. AB - The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 6 deals with products from A/S Pharmacia. A/S Pharmacia was established in Copenhagen in 1922 as a Danish limited company by the enterprising pharmacist Edward Jacobsen. Pharmacia was not Jacobsen's first pharmaceutical company as previously he had established a pharmaceutical agency already in 1913 which in 1919 was reorganized to a limited company by the name of A/S Edward Jacobsen. This agency was later extended to include a production of generics. Jacobsen remained the co-owner and manager of Pharmacia until 1934 where he resigned and established another company, A/S Ejco, for the manufacture of generics. It is worth mentioning that already in 1911 a Swedish pharmaceutical company was established named AB Pharmacia. Today we do not know whether Edward Jacobsen knew about this Swedish company. Later on in 1936 AB Pharmacia and A/S Pharmacia made a contract concerning mutual market sharing, and a research cooperation was brought about between the two companies which resulted in an increase of turnover for A/S Pharmacia. In 1955 the cooperation between the two companies was increased as the Swedish company joined as principal shareholder with the purpose of continuing and developing the Danish company as an independent pharmaceutical company with its own research and development as well as manufacture, control and marketing. Therefore Pharmacia in Denmark was able to establish a synthesis factory in Koge and move the domicile to new premises in Hillered. In 1993 Pharmacia was presented in a printed matter as "The largest Nordic pharmaceutical company" as a result of the merger between the Swedish Kabi Pharmacia, formerly established by a merger between Kabi Vitrum and AB Pharmacia, and the Italian Farmitalia Carlo Erba. Only two years later in 1995 Pharmacia merged with the American pharmaceutical company The Upjohn Company under the name of Pharmacia & Upjohn. In 2000 this company was merged with the chemical group Monsanto under a new name, Pharmacia Corporation. Pharmacia Corporation was taken over by Pfizer in 2003. The early activities of A/S Pharmacia included not only the import of raw materials and ready-made articles, such as medicinal products, but also the manufacture of own medicinal products. This is not surprising considering the founder Edward Jacobsen's pharmaceutical career. Pharmacia's early manufacture of own medicinal products consisted mainly of generics, however, not only the expensive foreign medicinal products, but also any available Danish generics such as easily manufactured pharmacopeia products. It is thus worth mentioning that Pharmacia's own technological production capacity at that time was limited and required a cooperation with other (Danish) pharmaceutical companies. Pharmacia was able to produce tablet cores, but the sugarcoating had to be made by external business partners. Pharmacia was able to produce digitalis preparations, but the standardization of these had to be effected elsewhere. The total production of one of Pharmacia's products took place at an external business partner. Pharmacia was established at a time where the increasing use of industrially manufactured medicinal products, both Danish and foreign ones, had resulted in a considerable decrease in sales of pharmacy produced medicinal products. This had for a long time worried The Danish Association of Pharmacies, and this resulted in a reaction from the association, namely the DAK-products which by nature were produced in Denmark and thus became the most essential element in the fight against the industrially manufactured products--a fight which according to the association had to be fought with all legal means. Therefore The Danish Association of Pharmacies obviously reacted precipitated when in 1926 the association in writing stated that Pharmacia's products were not manufactured in Denmark in spite of the fact that they were labelled as such according to agreement with Landsforeningen Dansk Arbejde, i.e., The National Association Danish Work, which in 1925 allowed Pharmacia to use the labels of the association. The unemployment was high in the 1920'ies and increasing so when Pharmacia subsequently took legal action against the Association of Pharmacies and claimed that the statement was unjustified and might harm Pharmacia, it may indicate that the public of that time looked positively upon the manufacture and the use of Danish manufactured products. The Danish Association of Pharmacies lost the case as the claim according to the court was unjustified and thus unlawful. The suspicions of the association were not supported by facts, however, they were not either completely groundless. Following this The National Association Danish Work gave notice to terminate the contract with Pharmacia concerning the right to use the labels of the association. By expanding the cooperation and later on by merging with the Swedish Pharmacia AB the Danish A/S Pharmacia succeeded in continuing and developing a company where research, development and production of innovative medicinal products as well as of generics could take place in Denmark. PMID- 25816561 TI - [Early achievements of the Danish pharmaceutical industry-7]. AB - A/S GEA Farmaceutisk Fabrik was established as a family business in 1927 by the pharmacist Knud L. Gad Andresen who until then had been employed in the pharmaceutical industry. Gad Andresen wanted to run a company focusing on the development of generics, and he wanted this development to take place in a close cooperation with Danish physicians. This has indeed been achieved with success. In 1995 GEA was purchase'd by the American pharmaceutical company Bristol-Myers Squibb who in a press release characterized GEA as Denmark's second largest manufacturer of generics. Immediately after this takeover GEA's R&D department ceased the research in innovative products and from now on exclusively focused on the development of generics. Three years later GEA was sold to the German generic company Hexal who later on resold GEA to the Swiss generic company Sandoz. GEA changed ownership another couple of times until the last owner went bankrupt in 2011. GEA is yet again a model example of an early Danish pharmaceutical company which was established as an individual company, and which had a long commercial success with the production and marketing of generics. GEA's earliest products, the organotherapeutics, were not innovations. The innovative products were developed already in the 1890s in Denmark by Alfred Benzon, and later on copies followed a.o. from Medicinalco and from foreign companies before GEA marketed their generics. Therefore GEA had to promote their preparations as especially qualified medicinal products and to intimate that the products of the competitors were less "active'". At the end of the 1920s the Ministry of Health became aware of the fact that there might be health problems related to the none-existing control of both the or- ganotherapeutic preparations and actually also the other medicinal products of the pharmaceutical industry. Therefore the Ministry had requested the National Board of Health for a statement regarding this problem. The National Board of Health was, however, at that time of the opinion that there were no serious problems with organotherapeutics from those companies marketing such products. It requires studies in the unprinted journals of the Ministry of Health and the National Board of Health to find the background for and the causes of the request from the Ministry at this point concerning the control of the organotherapeutic products of the pharmaceutical industry. Neither were GEA's barbiturates innovative products. The "Gad Andresen Case" is interesting for two reasons. Firstly, it illustrates that the development of generics at this stage could not always take place exclusively in a pharmaceutical-chemical laboratory, but also required a certain minimum of clinical trials including human beings. Secondly, it shows that the industrial products had now slowly, but surely gained market shares and displaced the pharmacy-produced medicinal products to such an extent that it did not only worry the pharmacy owners and their trade orga- nization. Now this concern had also resulted in a counteract so that the pharmacies in the manufacture of their products had to copy the industrial products, however, in certain cases with a dubious result. Gealgica tablets and especially their content of fenacetine is not only a model example of how the opinion of the positive and negative properties of a medicinal product changes over time. It also shows how long time could pass before the health authorities took measures against a substance with problematic side effects in spite of the fact that less damaging substances had been available for a long time, in this case paracetamol. Medicinal products containing fenacetine were on the market for almost 100 years. On the contrary meprobamat is a model example of a drug substance where the opinion of its positive and negative properties changed essentially over a relatively short period. In spite of this it remained on the market for a little less than 40 years. Restenil and Trihistan are mentioned on Knud & Dagny Gad Andresen's homepage (in 2014) as new medicinal products developed by GEA. This is not quite correct. Both drug substances in these preparations had been developed in the USA. In Denmark GEA had the possibility to market these substances under GEA's own brand names along with corresponding foreign brand names. It can be concluded that GEA's own research on the whole was confined to the development of own patentable syntheses of already known drug substances. During the later marketing of generics GEA appealed to the national feeling of the Danish population in the same way as a.o. Pharmacia did in the 1920s. From the very start GEA specialized in the manufacture of generics, and GEA was able to follow this way with commercial success--as a Danish alternative- for almost 90 years. PMID- 25816562 TI - [The factory Ferraton from idea to realization]. PMID- 25816563 TI - [Do you want to know more?]. PMID- 25816564 TI - Antioxidant Houttuynia cordata extract upregulates filaggrin expression in an aryl hydrocarbon-dependent manner. AB - The plant Houttuynia cordata, which is called "dokudami" in Japanese, is known as a potent antioxidant herb that has been traditionally consumed as a folk medicine for various ailments, such as diabetes, obesity, cough, fever and skin diseases, in Asia. However, its antioxidant mechanism remains largely unknown. In the present study, we investigated the effects of Houttuynia cordata extract (HCE) on human keratinocytes. HCE activated aryl hydrocarbon receptor (AHR) and nuclear factor E2-related factor 2, with subsequent induction of the antioxidative enzyme NAD (P)H: quinone oxidoreductase 1 gene. HCE inhibited the generation of reactive oxygen species (ROS) in keratinocytes stimulated with tumor necrosis factor alpha or benzo(alpha)pyrene. Moreover, HCE upregulated the gene expression of filaggrin, an essential skin barrier protein, in an AHR-dependent manner. HCE may be beneficial for treating ROS-related photoaging and barrier-disrupted skin conditions. PMID- 25816565 TI - Late type III endoleak of a Powerlink stent graft: report of a case. AB - We herein report a case of a late type III endoleak caused by disconnection of the aorta extension and main body of a Powerlink four years after implantation. Migration of the main body caused a disconnection of the main body and extension despite the fact that the size of the aneurysm had been decreasing. The endoleak was successfully repaired using the interpolation of an Endurant aortic extender. In case of necessity of implantation of the extension, first implantation of extension before deploying the main body may help to prevent type III endoleaks caused by disconnection of the stentgraft in patients treated with the Powerlink system. To our knowledge, this is the first reported case of a late type III endoleak caused by a Powerlink device. PMID- 25816566 TI - Is Jonathan Bush in a bubble? PMID- 25816567 TI - [Expression of EIIIA+ fibronectin in incised wound of rat's skin]. AB - OBJECTIVE: To explore the relationship between the expression of EIIIA+ fibronectin in incised wound of rat's skin and injury time. METHODS: The wounding model was established by cutting the dorsal skin of 48 adult SD rats. The rats were sacrificed at the pre-set injury time as immediately, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h. The skin samples were taken at the margin of wound. The expression of the EIIIA? fibronectin was detected by immunohistochemistry and Western blotting and the relationship be- tween its expression and injury time was observed. Results The expression of EIIIA+ fibronectin was not observed immediately. The basal cell of skin began to show positive expression 0.5 h after injury. With the extension of injury time, positive staining became stronger. The value of relative optical density was gradually increased with prolonged injury time by the Western blotting analysis. CONCLUSION: The expression of EIIIA+ fibronectin could be used for estimation of injury time in the early stage of skin injury. PMID- 25816568 TI - [Expression of monocyte chemotactic protein-1 and its receptor in sudden coronary death]. AB - OBJECTIVE: To investigate the expression of monocyte chemotactic protein-1 (MCP 1) and its receptor CC chemokine receptor-2 (CCR-2) in coronary atherosclerosis plaques between sidden coronary death (SCD) and non-SCD. Methods The expression levels of MCP-1 and CCR-2 in SCD group, coronary atherosclerosis group (non-SCD), control group (normal coronary artery) were detected by immunohistochemistry. RESULTS: Positive rates of MCP-1 among the three groups were 78%, 47%, and 0%, respectively, with significant expressing differences between each two groups (P<0.05). Positive rates of CCR-2 among three groups were 72%, 47%, and 0%, respectively, with significant expressing differences between the SCD group and coronary atherosclerosis group as well as between the SCD group and control group (P<0.05), but with no significant expressing difference between coronary atherosclerosis group and control group (P>0.05). CONCLUSION: Overexpression of MCP-1 and CCR-2 in coronary atherosclerotic plaques is closely correlated with SCD. PMID- 25816569 TI - [Diagnosis of amniotic fluid embolism with blood samples by liquid-based cytology technique]. AB - OBJECTIVE: To establish the diagnosis of amniotic fluid embolism with blood samples by liquid-based cytology technique and to study the validity of method. METHODS: The blood samples were collected from patients who suffered from amniotic fluid embolism. The components of amniotic fluid in blood samples were examined with blood smear by two direct smear methods (supernatant smear, sediment smear) and two liquid-based cytology methods (automatic smear, manual smear). The positive detection rate of each method was calculated. RESULTS: The positive detection rates of two liquid-based cytology methods (84.6% and 92.3%, respectively) were much higher than those of two direct methods (53.8% and 61.5%, respectively). CONCLUSION: The liquid-based cytology technique could improve the positive detection rate of amniotic fluid embolism. PMID- 25816570 TI - [Correlation between age and general morphology of transverse section of cartilago costalis]. AB - OBJECTIVE: To study the correlation between age and general morphology of transverse section of cartilago costalis and its forensic significance. METHODS: Eighty-six corpses' cartilago costalis from the routine postmortem examination were collected and the morphological features of their transverse section were observed. RESULTS: With the increased age, there were regular changes in the color, structure, and material of the general morphology of transverse section of cartilago costalis. But the changes were not affected by gender. CONCLUSION: The good correlation between general morphology of transverse section of cartilago costalis and age can be used to estimate age of the deceased rapidly. PMID- 25816571 TI - [Automated assessment of developmental levels of epiphysis by support vector machine]. AB - OBJECTIVE: To realize the automated assessment of the levels of epiphysis of distal radius and ulna by support vector machine (SVM). METHODS: The X-ray films of the left wrist joints were taken from 140 teenagers aged from 11 to 19 years old as training samples. The levels of epiphysis of distal radius and ulna were divided into five developmental levels. Each level contained 28 samples. Another 35 cases were selected as independent verifying samples. SVM classification models of the five developmental levels of epiphysis of distal radius and ulna were established. The internal cross validation was made by leave one out cross validation (LOOCV), while the external validation was made by histogram of oriented gradient (HOG), and then the accuracy (PA) of testing results was calculated, respectively. RESULTS: The PA of SVM, LOOCV and HOG of distal radius epiphyseal level were 100%, 78.6%, and 82.8%, respectively; whereas the PA of SVM, LOOCV and HOG of distal ulna epiphyseal level were 100.0%, 80.0% and 88.6%, respectively. CONCLUSION: The SVM-based automatic models of the growth stage of distal ra- dius and ulna appear to have certain feasibility, and may provide a foundation for software development of bone age assessment by forensic medicine. PMID- 25816572 TI - [Application of isokinetic muscle testing in identification of the faked paralysis]. AB - OBJECTIVE: To study the application of isokinetic muscle testing in identification of the faked paralysis to provide scientific data for establishing a standard system of muscle strength in forensic medicine identification. METHODS: Fifty-seven patients with bone fracture or nerve damage as damaged group and 128 normal subjects pretended paralysis as faked paralyzed group were included in this study. Isokinetic muscle testing was performed on bilateral knees of all subjects in the two groups. The peak torque (PT) and peak torque angle (PTA) were compared between both sides in each group. The features of torque-time graph of two groups were classified. RESULTS: In the damaged group, the differences of PT between two sides of flexors and extensors were statistically significant (P<0.05), while the dif- ferences of PTA were not statistically significant (P>0.05). In faked paralyzed group, the differences of PT and PTA between two sides of flexors and extensors were both statistically significant (P<0.05). The torque-time graph of damaged knee presented mostly as single lead peak, while torque-time graph of the faked paralyzed knee presented mostly as multiple peaks. CONCLUSION: The feature of torque-time graph could be useful to identify the faked paralyzed extremities in forensic authentication. PMID- 25816573 TI - [Assessment on the criminal responsibility of drug-induced mental disorders: a questionnaire survey]. AB - OBJECTIVE: To understand the assessment on the criminal responsibility of drug induced mental disorders and judicial experts' opinions. METHODS: The judicial experts from institutes of forensic psychiatry in Shanghai were selected. They were asked to finish a self-made questionnaire of assessment on the criminal responsibility of drug-induced mental disorders by letters and visits. RESULTS: Most of experts knew the special regulation, "not suitable for evaluation" towards the criminal responsibility of drug-induced mental disorders of the guideline promulgated by Ministry of Justice. Before and after the guideline was issued, no expert made a no-responsibility opinion in such cases. After the guideline was issued, some experts made a full-responsibility or limited responsibility opinion in such cases. There was a little disagreement among the experts in the case that the crime was unrelated with mental symptoms or the criminals used drugs even though he knew it could induced insanity. But there were still many obvious disagreements among experts in the case that crime was related to such symptoms and person was no ability to debate. Most experts agreed to settle the disagreements with improved legislative perfection. CONCLUSION: Most experts are not strictly complying with the assessment guidelines during their practice, and there is still an obvious disagreement towards the criminal responsibility of drug-induced mental disorders. PMID- 25816574 TI - [Correlation of daily living activities with location and severity of traumatic brain injury]. AB - OBJECTIVE: To study the correlation of daily living activities with location and severity of trau- matic brain injury (TBI) and to provide a theoretical basis for improving the accuracy of expert opinion. METHODS: Five hundred and one cases of patients with TBI were selected. Detailed records included following: pre-injury situation, location and severity of injury, treatment and education. Daily living activi- ties scale (Barthel index) was applied to test the subjects' daily living activities. The relevance among location and severity of TBI and Barthel index was statistically analyzed. RESULTS: In mild TBI group, there was no significant difference in Barthel index among each location (P>0.05). In moderate TBI group, there were significant differences in Barthel index between subarachnoid hemorrhage and cerebral lobe injury, also between parietal, occipital lobes injury and frontal lobe injury, parietal, occipital lobes injury and temporal lobe (P<0.05), respectively, whereas no significant difference in Barthel index between frontal lobe injury and temporal lobe injury (P>0.05). In severe TBI, there were significant differences in Barthel index between every two different locations (P<0.05). CONCLUSION: There is some correlation between the location of TBI and Barthel index, which provides an important reference value for analyzing and determining daily living activities after TBI. PMID- 25816575 TI - [Linkage disequilibrium and mutation rate analysis of sixteen X-STR loci]. AB - OBJECTIVE: To assess the patterns of linkage disequilibrium (LD) of 16 STR loci on X chromo- some and investigate the genetic stability. METHODS: Genomic DNA samples extracted from blood stains from 500 unrelated individuals and 885 lineage members from Eastern Chinese Han population were genotyped through multiplex amplification using IDtyperX-16 kit by our independent research followed by capillary electrophoresis. LD was assessed by PowerMarker v3.25 software and mutation rate of every locus was analyzed. RESULTS: LD were not found at the 16 X-STR loci. Allele mutations were observed at 10 loci. Among them, mutation rates of DXS6809 and DXS7132 were both up to 0.0048. CONCLUSION: When the 16 X-STR loci included in IDtyperX-16 kit were used for parentage testing, product princi- ples can be applied to calculate the likelihood, but mutation should be taken into consideration in the case that the genotypes do not meet the genetic law (especially at DXS6809 and DXS7132). PMID- 25816576 TI - Genetic polymorphism of nine non-CODIS STR loci in Hunan Province-based Chinese Han population. AB - OBJECTIVE: To determine the allelic frequency distribution and genetic parameters of nine non-CODIS DNA index systems of the short tandem repeat (STR) loci (D2S1772, D6S1043, D7S3048, D8S1132, D11S2368, D12S391, D13S325, D18S1364, and GATA198B05). METHODS: A total of 353 blood samples were collected, extracted, amplified, and analyzed from unrelated healthy individuals of Han nationality in Hunan Province, China. RESULTS: One hundred and fourteen alleles were observed in the population with corresponding allelic frequencies ranged from 0.001 0 to 0.323 0. For all the nine non-CODIS STR loci, the observed genotypic data showed no significant deviations from the Hardy-Weinberg equilibrium. The Ho, He, PIC, DP, and PE of the studied non-CODIS STR loci ranged from 0.1080 to 0.1950, 0.8050 to 0.8920, 0.7700 to 0.8600, 0.9250 to 0.9660 and 0.6070 to 0.7800, respectively. CONCLUSION: Nine non-CODIS STR loci have high degrees of polymorphisms, which may be useful in individual forensic identification and parentage testing in forensic practice. PMID- 25816577 TI - [Forensic validation of goldeneye? DNA ID 26Y system]. AB - OBJECTIVE: To perform the validation and analysis of forensic parameters of Goldeneye DNA ID 26Y system. METHODS: Based on the validation rules of Scientific Working Group on DNA Analysis Methods (SWGDAM), the kit was assessed from several parts, as test of PCR system, reproducibility, accuracy, and sensitivity, etc. And Y-STR loci of 517 unrelated healthy individuals from Eastern China were genotypes by this kit. The distribution and frequency of haplotype were calculated and forensic parameters of the kit were assessed. RESULTS: The complete profiles can be obtained even when the PCR reaction volume with 6.25 microL. And correct profile was obtained with DNA down to 125 pg. No reproducible peaks were detected with the DNA of common animals and microorganism with the kit. For the male-male mixture testing, average 70% of the minor alleles were obtained when the ratios of 1:19 and 19:1. For the male-female mixture testing, results showed that the sensitivity of the kit was no compromised with the addition of female samples. CONCLUSION: The validation studies demonstrated that Goldeneye DNA ID 26Y system has good sensitivity and specificity, and suitable for mixture testing. The polymorphism of 26 Y-STR loci included in this kit are good for forensic application. PMID- 25816578 TI - [Effects of additives in blood collection tubes on testing the alcohol concentration in blood samples]. AB - OBJECTIVE: To discuss blood collection tubes with different additives and their effects on the testing results of alcohol concentration in blood samples. METHODS: Blood samples from 10 volunteers were collected 2 hours after drinking with seven different types of disposable vacuum blood collection tubes, including ordinary tube without anticoagulant, coagulant tube, separating gel-coagulant tube, sodium citrate (1:4) tube, sodium citrate (1:9) tube, sodium citrate (9:1) tube and EDTA-K2 tube. The alcohol concentrations in these blood samples were analyzed by headspace gas chromatography. RESULTS: The concentration testing results of the same blood samples in different types of tubes were different from one to another. The sequence was as follows: separating gel-coagulant tube > coagulant tube > ordi- nary tube without anticoagulant > EDTA-K2 tube> sodium citrate (1:9) tube> sodium citrate (1:4) tube, whereas the results of the same blood sample in sodium citrate (1:9) tube and sodium citrate (9:1) tube showed no obvious difference. CONCLUSION: It is better to collect a suspicious drunk driver's blood sam- ple using a disposable vacuum blood collection tube, with the EDTA-K2 tube being preferred. PMID- 25816579 TI - [A retrospective analysis of 105 drowning victims with psychiatric disorders]. AB - OBJECTIVE: To analyze the features of drowning victims with psychiatric disorders to support further investigation on such cases. METHODS: One hundred and five archives of drowning victims with psychiatric disorders from January 2010 to June 2014 in Harbor Public Security Subbureau, Shanghai Public Security Bureau were reviewed. The decedents' general information, autopsy findings, case investigation data and disease histories were statistically analyzed. RESULTS: Of the 105 cases, 104 were suicides. Most decedents were poorly educated. Most suicides occurred in warm climate, and the corpses were usually found within 2 days. Most decedents had no suicide history and notes, but had abnormal mental or behavior changes before suicide. Depression, depression status and schizophrenia were the main types of psychiatric disorders, and only 9 decedents had received regular therapies before their deaths. CONCLUSION: Mental disorder is a high risk factor in the drowning victims. Guardians should be aware of psychotic abnormal behaviors, especially during warm climate seasons. PMID- 25816580 TI - [Analysis of 163 rib fractures by imaging examination]. AB - OBJECTIVE: To explore the applications of imaging examination on rib fracture sites in forensic identification. METHODS: Features including the sites, numbers of the processed imaging examination and the first radiological technology at diagnosis in 56 cases of rib fractures from 163 injuries were retrospectively analyzed. RESULTS: The detection rate of the rib fractures within 14 days was 65.6%. The initial detection rate of anterior rib fracture proceeded by X-ray was 76.2%, then 90.5% detected at a second time X-ray, while the detection rate of CT was 66.7% and 80.0%, respectively. The initial detec- tion rate of rib fracture in axillary section proceeded by X-ray was 27.6%, then 58.6% detected at a second time X-ray, while the detection rate of CT was 54.3% and 80.4%, respectively. The initial detection rate of posterior rib fracture proceeded by X-ray was 63.6%, then 81.8% detected at a second time X-ray, while the detection rate of CT was 50.0% and 70.0%, respectively. CONCLUSION: It is important to pay attention to the use of combined imaging examinations and the follow-up results. In the cases of suspicious for rib fracture in axillary section, CT examination is suggested in such false X-ray negative cases. PMID- 25816581 TI - [Analysis of pesticides in blood specimen by GC/MS with accelerated solvent extraction]. AB - OBJECTIVE: To develop the accelerated solvent extraction (ASE) for determining pesticides present in blood samples. METHODS: Pesticides were extracted by ASE with optimized parameters to study recovery rate affected by extraction temperature, time and agent. GC/MS was used to perform quantitative analysis. RESULTS: The recovery rates of eight pesticides were 70.6%-92.4%. The coefficient of variation was less than 5.0%. A good linear relationship was obtained at the concentration range of 0.5-5.0 microg/mL. CONCLUSION: The method was fast and simple with high recovery rate and good repeatability. It can be applied to analyze pesticides present in the blood specimen. PMID- 25816582 TI - [Progress of the recovery mechanism of brain injury associated with the gene polymorphism of apolipoproteins E]. AB - Brain injury is a kind of wound by violence on head, which is a mechanical distortion of skull, meninx, cerebral vascular and brain tissue due to outside force acting on head. Apolipoproteins E (ApoE) is a major kind of apolipoproteins, participating in the metabolism of lipid and regulating balance of cholesterol. Some recent investigations show that gene polymorphism of ApoE is associated with various kinds of diseases. Also its immunoreactivity is changed regularly with brain injury. In addition, ApoE has remarkable effect in neurological normal growth and reparative process after brain injury. This article reviews the biological characteristics and mechanism of ApoE in the repair of brain injury and application prospect in forensic medicine, which may be able to provide new ideas for estimation of the brain injury time and related experimental research. PMID- 25816583 TI - [Expression and mechanism of alphaB-crystallin in retina and extraocular tissues and organs]. AB - alphaB-crystallin is the structural protein of vertebrate lens, which is widely expressed in non-lens tissue. As one of the heat shock protein family members, alphaB-crystallin possesses biological properties of molecular chaperones and anti-apoptotic effects. Multi-factor injuries, such as retinopathy, inflammation and nervous system diseases, have a closely relationship with alphaB-crystallin. This paper reviews the research progress of the expression and mechanism of alphaB-crystallin in retina and extraocular tissues and organs. PMID- 25816584 TI - Hydrogen sulfide: metabolism, biological and medical role. AB - Hydrogen sulfide (H2S) is a signaling molecule that is actively synthesized in the tissues and is involved in the regulation of vascular tone, neuromodulation, cytoprotection, inflammation and apoptosis. In recent years, new data on animal and human H2S metabolism and function under the effect of various endogenous and exogenous factors, including drugs were collected. This review is provided to introduce generalized information about the main and alternative H2S metabolism and regulation, peculiarities of transport, signaling, biological role and participation in pathogenesis. Submitted data describe H2S content and activity of H2S-synthesizing enzymes in different organs, H2S effect on blood coagulation and platelet aggregation based on our research results. The working classification of H2S metabolism modulators, which are used in biology and medicine, is proposed: 1) agents that increase H2S content in tissues (inorganic and organic H2S donors; H2S-synthesizing enzymes substrates and their derivatives, H2S-releasing drugs; agents that contain H2S-synthesizing enzymes cofactors and activators, agents that inhibit H2S utilization); 2) agents that reduce H2S content in tissues (specific and nonspecific inhibitors of H2S synthesizing enzymes), 3) agents with uncertain impact on H2S metabolism (some medicines). It was demonstrated that vitamin-microelement and microelement complexes with H2S-synthesizing enzymes cofactors and activators represent a promising approach for H2S content correction in tissues. PMID- 25816585 TI - Functions of tocopherols in the cells of plants and other photosynthetic organisms. AB - Tocopherol synthesis has only been observed in photosynthetic organisms (plants, algae and some cyanobacteria). Tocopherol is synthesized in the inner membrane of chloroplasts and distributed between chloroplast membranes, thylakoids and plastoglobules. Physiological significance of tocopherols for human and animal is well-studied, but relatively little is known about their function in plant organisms. Among the best characterized functions oftocopherols in cells is their ability to scavenge and quench reactive oxygen species and fat-soluble by products of oxidative stress. There are the data on the participation of different mechanisms of alpha-tocopherol action in protecting photosystem II (PS II) from photoinhibition both by deactivation of singlet oxygen produced by PSII and by reduction of proton permeability of thylakoid membranes, leading to acidification of lumen under high light conditions and activation of violaxanthin de-epoxidase. Additional biological activity of tocopherols, independent of its antioxidant functions have been demonstrated. Basic mechanisms for these effects are connected with the modulation of signal transduction pathways by specific tocopherols and, in some instances, by transcriptional activation of gene expression. PMID- 25816586 TI - [Kinetics of inhibitory effect of calix[4]arene C-90 on activity of transporting plasma membrane Ca2+, Mg2+-ATPase of smooth muscle cells]. AB - In experiments on the suspension of myometrium cell plasma membrane, processed by 0.1% digitonin, the inhibitory action of calix[4]arene C-90 (5,11,17,23 tetra(threeftor)methyl(phenilsulphonilimino)-methylamino-25,26,27,28-tetrapropoxy calix[4]arene) on the activity of Ca2+,Mg2+-ATPase was investigated. The authors also examined the influence of calix[4]arene in different concentration on affinity of enzyme (Ca2,Mg2+-ATPase) for the ATP and ions of Mg and Ca, and its influence on cooperative effect and maximum velocity of ATP hydrolysis. It is shown that calix[4]arene does not influence the affinity of Ca2+,Mg2+-ATPase for the ATP, which means that these two compounds have different binding centers. Also calix[4]arene has no influence on affinity and cooperative effect of Ca ions, if it is used in concentration lower than 50 MUM. Calix[4]arene slightly increases coefficient of Ca2+,Mg2+-ATPase activation by magnesium chloride. In all three cases, where ATP, Mg and Ca ions are used to test the impact of calix[4]arene, maximum velocity of ATP hydrolysis significantly decreases. All these results clarify that calix[4]arene implements its inhibitory action through mechanism of uncompetitive inhibition of Ca2+,Mg2+-ATPase activity. PMID- 25816587 TI - [Inhibitory effect of benzimidazole derivatives on cholinesterases of animals in the presence of different substrates]. AB - Specifically synthesized group of benzimidazole derivatives possessing varying degrees of delocalization of the positive charge in the cation group of the molecule has been studied in order to search for potential cholinergically active compounds and to study the role of the Coulomb interaction in cholinesterase catalysis. These compounds were reversible inhibitors of cholinesterase (ChE) of human erythrocytes, horse serum, brain of the frog Rana temporaria and visual ganglia of the Pacific squid Todarodes pacificus in the presence of acetylthiocholine iodide and propionylthiocholine iodide as substrates. The differences in the nature of reversible inhibitory effect were observed. The effect of the inhibitor structure and substrate nature, specific for each of the studied inhibitors, on the character of the process of reversible inhibition was found. PMID- 25816588 TI - [Actomyosin ATPase activity of skeletal muscles and the markers of tissue damage in the blood of rats under prolonged chronic alcoholization]. AB - The activity of creatine kinase and indices of lipid metabolism in the blood and also actomyosin ATPase activity of skeletal muscles of rats under chronic 8-month alcohol abuse were investigated. It is shown that actomyosin K+-ATPase activity of skeletal muscles increases from two months of ethanol use, but actomyosin Mg2+ ATPase activity decreases during 6-8 months of alcoholization. From two months of ethanol use the creatine kinase activity, as an enzyme marker of muscle tissue damage, statistically significantly increases during all the period of the animals alcoholization. The level of total lipid increases after two months of alcohol consumption (in blood plasma by 30% and in erythrocyte mass by 65%). For longer periods of alcoholization (4-8 months) the level of lipids remains almost the same, whereas in erythrocyte mass it does not differ from control values. The level of diene conjugates in the blood plasma reduces and the amount of ketone derivatives of fatty acid residues increases that points to the inhibition of some components of the antioxidant system that control detoxification of hydroperoxides of fatty acids and also to activation of free radical damage of tissues. There were no significant changes of lipid peroxidation level in erythrocyte mass at any stage of alcoholization. PMID- 25816589 TI - NAADP-sensitive Ca2+ stores in permeabilized rat hepatocytes. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a nucleotide that is potent to release calcium from intracellular stores in different cell types. NAADP was shown to target specific type of intracellular store namely endolysosomal system or acidic store. Despite intense studies, its effect on endoplasmatic reticulum (ER) still remains to be elucidated. The main aim of our work was to investigate NAADP-sensitive store in permeabilized rat hepatocytes monitoring the level of Ca2+ inside intracellular organelles using chlorotetracycline (CTC). We have shown that NAADP triggered changes of stored Ca2+ in rat hepatocytes are dependent on concentration of EGTA-Ca2+-buffer in cell incubation medium, i.e. the higher is the EGTA concentration in incubation medium the smaller or absent is the effect of NAADP. Besides, the effect of NAADP was more pronounced upon cells pretreatment with the inhibitory concentration of ryanodine (100 MUM). This might suggest that the effect of NAADP is dependent on ER luminal calcium. We have also found that NAADP-evoked Ca2+ release in permeabilized hepatocytes is sensitive to nigericin, bafilomycin A and thapsigargin. Additionally, NAADP triggered changes in stored Ca2+ were completely abolished by NED-19 as antagonist of NAADP. PMID- 25816590 TI - Dynamics of thrombin-induced exposition of actin on the platelet surface. AB - Platelets play the key role in thrombosis and are also involved in angiogenesis as well as immune and reparative responses. In the function cascade, platelets undergo a complex cell processing, and subcellular fragments, not detectable in the resting state, are exposed on platelet surface after stimulation with agonists. This study has been performed to evaluate dynamic characteristics of actin exposition on the surface of plasma membrane of thrombin-activated platelets. Using flow-cytometric assay, it has been observed that the level of actin presented on activated platelets directly depends on agonist concentration. In the case of platelet stimulation with thrombin in the highest concentration (1.0 U/ml) taken for this study, the level of actin exposed on activated platelets was up to 4.4 times higher as compared with resting cells. Confirmation of the flow cytometry data for cell-surface actin on thrombin-activated platelets was achieved by direct visualization using a confocal laser scanning microscopy. Period of actin exposition appeared to be longer than the time phase corresponding to platelet secretion stage. Functional role of platelet surface actin has required further detailed studying, however, it is thought that superficial actin could interact with various blood plasma proteins, including plasminogen and its activators, serving as a binding site and/or center for their pericellular processing. PMID- 25816591 TI - Study of the sites of plasminogen molecule which are responsible for inhibitory effect of Lys-plasminogen on platelet aggregation. AB - Plasminogen/plasmin system is involved in such important processes as thrombosis, inflammation and cancer. Plasmin and plasminogen mediate their action through plasminogen-binding proteins on the cell surface. Lys-plasminogen, but not Glu plasminogen, shows inhibitory effect on platelet aggregation induced by ADP, collagen and thrombin in preparations of both: platelet-rich plasma and washed platelets. We have shown that the kringle domains of Lys-plasminogen mediate interaction of this proenzyme with platelet- surface proteins. The aim of the work is to study the role of certain kringle domains in the inhibitory effect of Lys-plasminogen and to determine possible plasminogen-binding proteins on the platelet surface. All studied plasminogen fragments (K1-3, K4 and K5) abolished the inhibitory effect of Lys-plasminogen on platelet aggregation. We observed that K5 was more effective than K1-3 and K4. Biotin-labeled Lys-plasminogen, Glu plasminogen and plasminogen fragment K1-3 possessed the highest affinity for actin, whereas the binding of biotin-labeled mini-plasminogen and K4 to actin was negligible. We have suggested that inhibitory effect of Lys-plasminogen is due to the interaction of kringle domains of this proenzyme with membrane-bound proteins which are exposed on the platelet surface during activation and are involved in thrombus formation. PMID- 25816593 TI - Proteolytic activity of IgGs from blood serum of Wistar rats at experimental rheumatoid arthritis. AB - The aim of this work was to study the proteolytic activity of IgGs purified from blood serum of Wistar rats at experimental rheumatoid arthritis (ERA) induced by an injection of bovine collagen of type II. Twenty rats were immunized with a preparation of bovine collagen II (Sigma-Aldrich, USA) in the presence of complete Freund's adjuvant. ERA development was determined by inflammation in limbs of treated animals. IgG preparations were isolated from blood serum of immunized and non-immunized animals by precipitation of antibodies with 33% ammonium sulfate followed by chromatography on the Protein G-Sepharose column. Human histone H1, bovine collagen II, calf thymus histones, myelin basic protein (MBP), bovine serum albumin (BSA), and bovine casein were used as substrates of the proteolytic activity of IgGs. It was found that IgG preparations from blood serum of rats with ERA were capable of cleaving histone H1 and MBP, however, they were catalytically inactive towards collagen II, casein, BSA, and core histones. IgGs from blood serum of non-immunized rats were proteolytically inactive towards all used protein substrates. Thus, we demonstrated that immunization of rats with bovine collagen II induced IgG-antibodies possessing the proteolytic activity towards histone H1 and MBP. This activity might be associated with the development of inflammatory processes in the immunized rats. PMID- 25816592 TI - Relationship between RNA/DNA ratio, growth rate and accumulation of selenium in the cells of wheat leaves under the influence of minerals analcime and trepel. AB - We studied specific effects of different doses of natural minerals--analcime (An) and trepel (Tr)--on the growth rate, selenium (Se) content and functional activity of the genome of wheat leaves measured by the RNA/DNA ratio. Our results show that under the influence of An and Tr, especially at low doses (25 mg/100 g sand), there is a significant increase in the content of Se, increased growth rate of leaves of wheat seedlings and decreased RNA/DNA ratio. We have found significant correlations between studied parameters. Our findings suggest that the RNA/DNA ratio can be used as a convenient, reliable indicator of the biological activity of minerals An and Tr, and for quantitative express estimation of their impact on plant organisms. PMID- 25816594 TI - Multiple molecular forms of adaptor protein Ruk/CIN85 specifically associate with different subcellular compartments in human breast adenocarcinoma MCF-7 cells. AB - Ruk/CIN85 is a receptor-proximal 'signalling' adaptor that possesses three SH3 domains, Pro- and Ser-rich regions and C-terminal coiled-coil domain. It employs distinct domains and motifs to act as a transducer platform in intracellular signaling. Based on cDNA analysis, various isoforms of Ruk/CIN85 with different combination of protein-protein interaction domains as well as additional Ruk/CIN85 forms that are the products of post-translational modifications have been demonstrated. Nevertheless, there is no precise information regarding both the subcellular distribution and the role of Ruk/CIN85 multiple molecular forms in cellular responses. Using MCF-7 human breast adenocarcinoma cells and cell fractionation technique, specific association of Ruk/CIN85 molecular forms with different subcellular compartments was demonstrated. Induction of apoptosis of MCF-7 cells by doxorubicin treatment or by serum deprivation resulted in the system changes of Ruk/CIN85 molecular forms intracellular localization as well as their ratio. The data obtained provide a new insight into potential physiological significance of Ruk/CIN85 molecular forms in the regulation of various cellular functions. PMID- 25816595 TI - [The ROS-generating and antioxidant systems in the liver of rats treated with prednisolone and vitamin D3]. AB - The mechanisms of glucocorticoid-induced disturbances of liver function is currently not fully clarified. Vitamin D3 was previously shown to play an important role in the regulation of impaired oxidative metabolism and detoxification function of the liver associated with the effects of hepatotoxic compounds. The study was undertaken to define the intensity of oxidative metabolism in the rat liver and survival of hepatocytes after prolonged prednisolone administration and to assess whether vitamin D3 is capable to counter glucocorticoid-induced changes. It has been shown that prednisolone (0.5 mg per animal for 30 days) leads to 1.6-fold increase in the percentage of necrotic cells among isolated hepatocytes as compared with the control. The glucocorticoid-induced impairment of hepatocellular function was accompanied by enhanced generation of reactive oxygen species (ROS), accumulation of TBA-active products and carbonylated proteins but reduced levels of free SH-groups of low molecular weight compounds. It was demonstrated a decrease in the activities of key enzymes of antioxidant system (SOD, catalase, glutathione peroxidase), whereas the activities of pro-oxidant enzymes NAD(P)H-quinone oxidoreductase and semicarbazide-sensitive amine oxidase were shown to be increased. Vitamin D3 (and to greater extent in combination with alpha-tocopherol) administration (100 IU) on the background of glucocorticoid therapy caused normalizing effects on the level of ROS formation, oxidative modification of biomolecules and activity of antioxidant enzymes resulting in better survival of hepatocytes. These data suggest a potential role of vitamin D3 in the regulation of oxidative metabolism alterations related to hepatotoxic action of glucocorticoids. PMID- 25816597 TI - [Effect of adaptogenic preparations on Na+/H+-antiporter function in plasma membrane of corn root cells under salinity conditions]. AB - Salinity is a hard stress factor for plant organisms which negative effect is caused chiefly by sodium toxic for plants. Plant cells try to remove Na+ from their cytoplasm outside and to vacuolar space by secondary active Na+/H+ antiporters. Their functions can be intensified by gene engineering methods however we try do it with the help of non-toxic bioactive preparations. A comparison of their effect on the plasma membrane of Na+/H+-antiporters was carried out on corn seedling roots of Zea mays L. exposed at 0.1 M NaCl. Before we have established that Methyure used by seed pretreating possesses a high salt protective ability as against Ivine. It was found that without NaCl exposition Na+/H+-antiporter activity in root plasma membrane was nearly unnoticeable but increased slightly with seedling age. Methyure and Ivine did not influence its activity in control root seedling. One day 0.1 M NaCl exposition evoked a considerable increasing of Na+/H+-antiporter activity and its gene expression but these effects disappeared at 10 day NaCl exposition. Methyure use reinforced Na+/H+-antiporter activity and prolonged it at NaCl exposition without effect on its gene expression whereas Ivine effects on these indexes were insignificant. Obtained results showed that the salt protective capability of Methyure is connected with plasma membrane Na+/H+-antiporter activation which is realized on molecular level. PMID- 25816596 TI - [Influence of heavy metal salts on the activity of trypsin-like hydrolases from Drosophila melanogaster]. AB - The influence of salts of heavy metals on trypsin-like peptide hydrolase of drosophila larvae partly refined by methods of salting-out, gel chromatography and electrophoresis has been researched. It is established that cadmium chloride is characterized by the greatest inhibitory effect, while zinc chloride by the lowest one. Since metal chlorides were used in all cases, it is the differentiated effect of metal ions on manifestations of amidase activity of trypsin-like peptide hydrolase of drosophila larvae, which rather may be considered as proved than the effect of chlorine ions. This, as a whole, agrees with the effect of these ions on proteolytic digestion system at the level of live organisms. PMID- 25816598 TI - [The activity of prooxidant-antioxidant system in loach embryos under the action of microwave radiation]. AB - Electromagnetic radiation (EMR) affects biological organisms, primarily on the cellular level. However, the effects of EMR at low-intensity exposure on animals and state of metabolic systems are not fully defined yet. Thus, research of microwave radiation influence on the processes of lipid peroxidation and antioxidant protection system is important for understanding the mechanisms of EMR action on the cell, in particular, and organism development on the whole. The content of lipid peroxidation products--lipid hydroperoxides, thiobarbituric acid reactive substances and the activity of antioxidant enzymes--superoxide dismutase, glutathione peroxidase and catalase in loach embryos under the action of microwave radiation (GSM-900 MHz, SAR = 1.1 Vt/kg) lasting 1; 5; 10 and 20 min during early embryogenesis were studied. It has been found that content of lipid peroxidation products in germ cells undergoes significant changes under the action of low-intensity EMR. The effect of microwave radiation (1, 5, 10 min) leads to the increase of superoxide dismutase activity, nevertheless, 20 min exposure decreased this index to the level of control values as it is shown. It has been established that EMR at frequencies used for mobile communications reduce the activity of antioxidant protection system components, especially catalase and glutathione peroxidase. The growth of catalase activity at the 10 cell stage of blastomere division (P < 0.05) is an exception. The results of two way analysis of variance attest that microwave radiation factor causes the large part of all observable modifications. PMID- 25816599 TI - Age changes of human serum polyreactive immunoglobulins (PRIG) activity. AB - It has been determined that activity of serum polyreactive immunoglobulins (PRIG) changes with age in practically healthy people at the age from twenty five to seventy. Therewith, the activity of serum IgG PRIG increases most of all (about 3 4 times), while IgM PRIG activity, on the contrary, does not increase, but sometimes even decreases with age. IgA PRIG activity varies significantly more than IgG PRIG activity and, besides, IgA PRIG significantly less depends on age than IgG PRIG. The age changes in the activity of human serum PRIG, belonging to different types of immunoglobulins, may evidence for the important functional role of these immunoglobulins that has to be clarified. PMID- 25816600 TI - [Exchange of bile pigments under the action of ecopathogenic factors on organism]. PMID- 25816601 TI - "Three sources and three component parts" of free oligosaccharides. AB - Metabolism of glycoproteins and glycolipids is accompanied by the appearance of unbound structural analogues of the carbohydrate portion of glycoconjugates or so called free oligosaccharides. There are their several sources inside the cell: 1) multistep pathways of N-glycosylation, 2) the cell quality control and ER associated degradation of misglycosylated and/or misfolded glycoproteins, 3) lysosomal degradation of mature glycoconjugates. In this review the information about the ways of free oligosaccharides appearance in different cell compartments and details of their structures depending on the source is summarized. In addition, extracellular free oligosaccharides, their structures and changes under normal and pathological conditions are discussed. PMID- 25816602 TI - [Ca ion transport in smooth muscle mitochondria]. AB - Review focuses on the analysis of literature data and own results concerning properties of mitochondria Ca2+ transporting systems and their regulation. Three mechanisms for mitochondrial Ca2+ uptake are described: the electrogenic mitochondrial Ca2+ uniporter, a rapid mode of Ca2+ uptake (RaM) and ryanodine sensitive Ca2+ channels (RyR). Two mechanisms of Ca2+ efflux from the mitochondrial matrix have been proposed: Na+-dependent and Na+-independent Ca2+ exchange. The mitochondrial permeability transition pore can also function as a Ca2+ efflux mechanism. Ca2+ accumulation in mitochondria resulted in an increase of mitochondrial membrane potential, ATP synthesis and activation of metabolites transport. The dissipation of mitochondrial membrane potential should prevent mitochondrial Ca2+ uptake. Our data concerning depolarizing effect of calmodulin antagonists and hyperpolarizing effect of calix[4]arenes C-136 and C-137 on the myometrium mitochondria can be applied on the demand of mitochondria membrane potential correction. PMID- 25816603 TI - Role of glycosylation in secretion and stability of micromycetes alpha galactosidase. AB - The effect of the glycosylation inhibitors (tunicamycin and 2-deoxy-D-glucose) on the activity, stability and production of fungal glycosidases has been studied. It was shown that inhibition of N-glycosylation sites did not affect the secretion of Aspergillus niger alpha-galactosidase, however reduced yield of Cladosporium cladosporioides and Penicillium canescens alpha-galactosidases. Changes in the level of O-glycosylation resulted in a significant reduction in the activity and stability of alpha-galactosidases of all three producers tested. Activity of the modified enzymes was significantly lower than that of the native ones, and was 2.6 and 0.33 U/mg for A. niger alpha-galactosidase, 3.3 and 32.5 U/mg for C. cladosporioides alpha-galactosidase, 11.66 and 31.1 U/mg for P. canescens alpha-galactosidase, respectively. A. niger alpha-galactosidase completely lost activity during purification and storage. The decrease of thermal stability at 55 degrees C by 20% was shown for C. cladosporioides and P. canescens alpha-galactosidases. It was also noted that O-deglycosylation led to a decrease in resistance of these enzymes to the action of proteases. PMID- 25816604 TI - [Identification of thiamine monophosphate hydrolyzing enzymes in chicken liver]. AB - In animals, thiamine monophosphate (TMP) is an intermediate on the path of thiamine diphosphate, the coenzyme form of vitamin B1, degradation. The enzymes involved in TMP metabolism in animal tissues are not identified hitherto. The aim of this work was to study TMP hydrolysis in chicken liver. Two phosphatases have been found to contribute to TMP hydrolysis in liver homogenate. The first one, possessing a maximal activity at pH 6.0, is soluble, whereas the second one represents a membrane-bound enzyme with a pH optimum of 9.0. Membrane-bound TMPase activity was enhanced 1.7-fold by 5 mM Mg2+ ions and strongly inhibited by levamisole in uncompetitive manner with K1 of 53 MUM, indicating the involvement of alkaline phosphatase. An apparent Km of alkaline phosphatase for TMP was calculated from the Hanes plot to be 0.6 mM. The soluble TMPase has an apparent Km of 0.7 mM; this enzyme is Mg2+ independent and insensitive to levamisole. As estimated by gel filtration on a Toyopearl HW-55 column, the soluble enzyme has a molecular mass of 17.8 kDa, TMPase activity being eluted simultaneously with peaks of flavinmononucleotide and p-nitrophenyl phosphatase activity. Thus, TMP appears to be a physiological substrate for a low-molecular weight acid phosphatase, also known as low-molecular-weight protein phosphotyrosine phosphatase. PMID- 25816605 TI - Oxidative stress and the enzyme system of aldehyde catabolism in the muscle mitochondria of immobilized pubertal rats. AB - The aim of the work is to find out peculiarities in manifestation of oxidative stress and to determine activity of enzymes, responsible for utilization of endogenous aldehydes in the mitochondrial fraction of the skeletal (femoral) muscle in pubertal rats during immobilization stress. Our study has shown that differently directed changes in the activity of mitochondrial aldehyde dehydrogenases and aldehyde reductases occur in the pubertal immobilized rats, that limits the catabolism effectiveness as regards carbonyl products offree radical oxidation in the muscle cells. Corroboration of the effect under consideration is an increased level of protein free radical oxidation products in the mitochondria of the skeletal muscle. On the basis of the obtained data the authors draw a conclusion about an increased sensitivity of the skeletal muscle to the oxidative stress impact due to modulation in the state of enzyme system, responsible for utilization of endogenous aldehydes in the mitochondria. PMID- 25816606 TI - [Antioxidant defense system state in blood plasma and heart muscle of rats under the influence of histamine and sodium hypochlorite]. AB - There is a wide spectrum of antihistamine drugs in the pharmaceutical market, however all these chemical preparations cause side effects. Therefore, new alternative ways for histamine detoxication are to be found. For this aim in our experiment sodium hypochlorite was used because its solution possesses strong oxidizing properties. The influence of histamine and sodium hypochlorite on the antioxidant defence system state of blood plasma and cardiac muscle in rats has been researched. It was shown, that the investigated factors result in the disruption of the antioxidant system. It was found that histamine injection in concentration of 1 and 8 MUg/kg in plasma leads to the increase of superoxide dismutase activity during all the experiment. When studying enzymes, that catalyze hydroperoxides and H2O2 decomposition it was shown that under the influence of histamine in a dose 1 MUg/kg, the glutathione peroxidase activity increased on the 1st day of the experiment. However, on the 7th day of the experiment the increase of both glutathione peroxidase and catalase activity was fixed. The deviation in superoxide dismutase function in rats plasma under the action of sodium hypochlorite has been established. The activity of enzymes that decompose H2O2 and hydroperoxides were inhibited. Under the influence of histamine in the heart tissues we have stated the disturbance of superoxide dismutase work and increase ofcatalase activity and decrease of glutathione peroxidase activity. The influence of sodium hypochlorite on the myocardium of intact animals as well as joint influence of sodium hypochlorite and histamine result in the increase of superoxide dismutase and catalase activity and lead to the considerable decline of activity of glutathione peroxidase. PMID- 25816607 TI - [Signal function of cytokinin 6-benzylaminopurine in the reaction of Triticum aestivum L. mesophyll cells to hyperthermia]. AB - The signaling effect of 6-benzylaminopurine (BAP) on leaf mesophyll cells of Triticum aestivum L. under hyperthermic conditions was studied. It was found that BAP regulated photosynthetic pigment, hydrogen peroxide content and activity of antioxidant enzymes, namely superoxide dismutase, ascorbate peroxidase and catalase under high-temperature conditions. The additive effect of BAP and high temperature on the activation of cell antioxidant systems was demonstrated. BAP regulated reducing processes in mesophyll leaf cells under high-temperature conditions. PMID- 25816608 TI - Expression of phosphoribosyl pyrophosphate synthetase genes in U87 glioma cells with ERN1 knockdown: effect of hypoxia and endoplasmic reticulum stress. AB - Activation of pentose phosphate pathway is an important factor of enhanced cell proliferation and tumor growth. Phosphoribosyl pyrophosphate synthetase (PRPS) is a key enzyme of this pathway and plays a central role in the synthesis of purines and pyrimidines. Hypoxia as well as ERN1 (from endoplasmic reticulum to nuclei-1) mediated endoplasmic reticulum stress response-signalling pathway is linked to the proliferation because the blockade of ERN1 suppresses tumor growth, including glioma. We studied the expression of different PRPS genes in glioma cells with ERN1 knockdown under hypoxic condition. It was shown that hypoxia decreases the expression of PRPS1 and PRPS2 genes in both types of glioma cells, being more pronounced in cells without ERN1 function, but PRPSAP1 and PRPSAP2 gene expressions are suppressed by hypoxia only in glioma cells with blockade of ERN1. Moreover, the blockade of endoribonuclease activity of ERN1 does not affect the expression of PRPS1 and PRPS2 as well as PPRS-associated protein genes in U87 glioma cells. At the same time, the induction of endoplasmic reticulum stress by tunicamycin in glioma cells with suppressed activity of ERN1 endoribonuclease decreases the expression level of PRPS1 and PRPS2 genes only. Results of this investigation clearly demonstrated that the expression of different genes encoding subunits of PRPS enzyme is affected by hypoxia in U87 glioma cells, but the effect of hypoxia is modified by suppression of endoplasmic reticulum stress signaling enzyme ERN1. PMID- 25816610 TI - Study of antineoplastic action of novel isomeric derivatives of 4-thiazolidinone. AB - Pyrazole- and aryl-substituted derivatives of 4-thiazolidinone belong to a perspective group of compounds with potential antitumor action. Earlier, we have demonstrated high toxicity in vitro of several 4-thiazolidinones derivatives towards tumor cell lines. To further enhance the antitumor activity of novel 4 thiazolidinones, their chemical scaffold was optimized, and new pyrazole thiazolidinones were synthesized. That allowed us to combine in one molecule the potential pharmacophore centres of previously tested compounds. As a result, "hybrid" 4-thiazolidinones exhibit higher toxicity in vitro toward tumor cells of various origin. The molecular mechanisms of antineoplastic activity of these compounds and intensity of induction of apoptosis strongly depended on the position of the substituent in the thiazolidinone cycle. In particular, Les-3661 compound, containing pyrazoline fragment in the 4th position of thiazolidinone core, exhibits 14 times higher cytotoxic activity towards tumor cells (LC50 = 3 MUM) in comparison to its 2-substituted isomer Les-3713 (LC50 = 42 MUM). It is demonstrated that in terms of underlying molecular mechanisms for cytotoxic effect the Les-3661 compound induced caspase-8 and caspase-9 dependent mixed-type of apoptosis, while Les-3713 induced apoptosis mediated only by the caspase-8. PMID- 25816609 TI - [Study of rat blood serum biochemical indicators of cardiotoxic action of novel antitumor 4-thiazolidinone derivatives and doxorubicin in complexes with polyethylene glycol-containing polymeric carrier in the rat blood serum]. AB - The aim of this study was to measure the activity of enzymes which reflect cardiotoxic action in rats of novel synthetic 4-thiazolidone derivatives--3882, 3288 and 3833 that demonstrated antineoplastic effect in vitro towards 60 lines of human tumor cells tested in the framework of the program of screening new anticancer drugs at the National Cancer Institute (USA). Such action of these compounds was compared with the effect of well known anticancer agent doxorubicin and after conjugation of all above mentioned substances with new polyethylenglycol-containing polymeric comb-like carrier that was synthesized by the authors. Among the biochemical indicators of cardiotoxic action of anticancer agents, activity of the following enzymes in rat blood serum showed to be the most informative: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransterase. Tenfold injection of doxorubicin in a dose of 5.5 mg/kg of weight caused rats' death, while 3882, 3288 and 3833 preparations had not such action. Application of the doxorubicin in combination with polymeric carrier prolonged the survival time to 20 days. Thus, the injection of anticancer agents in a complex with polymeric carrier provides a significant decrease in their cardiotoxicity that was confirmed by the corresponding changes in the activity of marker enzymes: creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase in blood serum of treated rats. PMID- 25816611 TI - Functional and dynamic state of inner mitochondrial membrane of sarcoma 37 in mice under administration of sodium dichloroacetate. AB - The activity of enzymes of the respiratory chain and structural-dynamic properties of the inner mitochondrial membrane (IMM) of sarcoma 37 (S37) in mice under sodium dichloroacetate (SDA) administration in a daily dose of 86 mg/kg of body weight starting from the 2nd day after tumor transplantation were investigated. The dynamic and structural state of the IMM components was determined using the fluorescent probes. With S37 growth the intensification of glycolytic metabolism occurred on the background of suppressed functional capacity of mitochondrial respiratory chain enzymes. The changes of conformational properties of protein molecules and the increase of IMM lipid phase microviscosity were shown. The administration of SDA promotes the decrease of lactate content and the increase of pyruvate dehydrogenase activity in S37. This was accompanied by further suppression of the functional activity of the respiratory chain complexes and H+-ATPase coupled with conformational modification ofprotein molecules and changes of the structural orderliness of the IMM lipid phase, possibly due to intensification of reactive oxygen species generation. PMID- 25816612 TI - The effect of N-stearoylethanolamine on cholesterol content, fatty acid composition and protein carbonylation level in rats with alimentary obesity induced insulin resistance. AB - The effect of N-stearoylethanolamine (NSE) on liver free fatty acid composition, cholesterol content and carbonylated protein level in rats with obesity-induced insulin resistance (IR) was studied in the work. The experimental insulin resistance was induced by prolonged high fat diet (58% of energy derived from fat) for 6 months combined with one injection of low-dose (15 mg/kg) of streptozotocin. The lipid assay showed a rise in liver free cholesterol content anda significant reduction in cholesterol esters level. Analyzing liver fatty acid composition, a decrease in polyunsaturated of fatty acid (PUFA) level and an increase in monounsaturated fatty acid (MUFA) content was found. Fatty acid imbalance with high content of MUFA was associated with elevated level ofprotein carbonylation. The NSE administration (50 mg/kg of body weight) for 2 weeks decreased free cholesterol content, increased cholesterol esters level and reduced free oleic fatty acid content in the liver of rats with IR. The effect of NSE on lipid imbalance led to a decrease in protein carbonylation level that may result in improvement of transmembrane protein function under obesity-induced insulin resistance state. PMID- 25816613 TI - Kinetic properties of adenosine triphosphate sulfurylase of intestinal sulfate reducing bacteria. AB - The investigation of specific activity of ATP sulfurylase and kinetic properties of the enzyme in cell-free extracts of intestinal bacterial strains Desulfovibrio piger Vib-7 and Desulfomicrobium sp. Rod-9 is presented. The microbiological, biochemical, biophysical and statistical methods were used in the work. The optimal temperature (35 degrees C) and pH 8.0-8.5 for enzyme reaction were determined. An analysis of kinetic properties of ATP sulfurylase has been carried out. Initial (instantaneous) reaction velocity (V0), maximum amount of the product of reaction (Pmax), the reaction time (half saturation period, tau) and maximum velocity of the ATP sulfurylase reaction (Vmax) have been defined. Michaelis constants (Km(Sulfate), Km(ATP), Km(APS), and Km(Pyrophosphate)) of the enzyme reaction were demonstrated for both D. piger Vib-7 and Desulfomicrobium sp. Rod-9 intestinal bacterial strains. PMID- 25816614 TI - Activity of trypsin-like enzymes and gelatinases in rats with doxorubicin cardiomyopathy. AB - Activity of trypsin-like enzymes (ATLE) and gelatinases A and B were studied in the blood plasma and extracts from cardiac muscle, cerebral cortex and cerebellum of rats with cardiomyopathy caused by anthracycline antibiotic doxorubicin against the background of preventive application of corvitin and alpha ketoglutarate. ATLE significantly increased in blood plasma and extracts from cerebral cortex but decreased in extracts from cardiac muscle and cerebellum in doxorubicin cardiomyopathy (DCMP). In addition, a significant increase of activity of both gelatinases in plasma and tissue extracts was observed. Preventive administration of corvitin and alpha-ketoglutarate resulted in differently directed changes of activity of the above mentioned enzymes in heart and brain tissues. Obtained data confirm the hypothesis about activation of proteolysis under the influence of anthracycline antibiotics and testify to selective effect of corvitin and alpha-ketoglutarate on ATLE and gelatinases. PMID- 25816615 TI - [Correlations of bile acids in the bile of rats in conditions of alloxan induced diabetes melitus]. AB - The ratio of bile acids in the bile of rats with alloxan diabetes was investigated using the method of thin-layer chromatography. Changes of coefficients of conjugation and hydroxylation of bile acids were calculated and analyzed in half-hour samples of bile obtained during the 3-hour experiment. It has been found that the processes of conjugation of cholic acid with glycine and taurine are inhibited in alloxan diabetes. At the same time a significant increase of free threehydroxycholic and dixydroxycholic bile acids and conjugates of the latter ones with taurine has been registered. Coefficients of hydroxylation in alloxan diabetes show the domination of "acidic" pathway in bile acid biosynthesis that is tightly connected with the activity of mitochondrial enzymes. PMID- 25816616 TI - [Protective effect of tiacalix[4]arene-tetrasulphonate on heavy metal inhibition of myometrium myosin subfragment-1 ATP-hydrolase activity]. AB - Heavy metals have a negative effect on the contractility of uterine smooth muscles (myometrium), these effects can lead to various pathologies of a women reproductive system. To overcome these effects the methods for correcting the myometrium contractile activity are to be developed. Catalyzed by myosin ATPase ATP hydrolysis is the most important reaction in the molecular mechanism of myometrium contraction. We have found an inhibitory effect of 0.03-0.3 mM Ni2+, Pb2+ and Cd2+ on enzymatic hydrolysis of ATP by myosin subfragment-1 obtained from swine uterine smooth muscles. We have demonstrated that 100 MUM thiacalix[4]arene-tetrasulphonate (C-798) recovered to the control level of ATPase activity of myosin subfragment-1 in the presence of heavy metal cations. One of the most probable mechanisms of C-798 corrective activity is based on its ability to chelate heavy metals, thus cations Pb, Cd and Ni can be removed from the incubation medium. Computer simulation has demonstrated that the protective effect of C-798 may also be the result of weakening the interaction of heavy metal ions with amino acid residues of the myosin molecule near the active site of ATP hydrolase. The obtained results can be used for further research aimed at assessing the prospects of thiacalix[4]arene-tetrasulfonate as pharmacological compounds. PMID- 25816617 TI - The influence of low-molecular fraction from cord blood (below 5 kDa) on functional and biochemical parameters of cells in vitro. AB - The influence of a low-molecular fraction (below 5 kDa) from the cattle cord blood (CBF) on functional activity of phagocytes, human embryonic fibroblasts, mesenchymal stromal cells and BHK-21 clone 13/04 and PK-15 cells was studied. The low-molecular fraction added to culture medium increases the growth rate of cell cultures. The incubation of leukoconcentrate in the CBF-containing medium results in an increase in phagocytic indices ofneutrophils in the presence of a phagocytosis inhibitor--sodium iodoacetate, leading to a significant increase in intracellular glucose content and alkaline phosphatase activity as compared to the control and the reference drug Actovegin(r). PMID- 25816618 TI - [Sec-butyl ester of dodecenoate: synthesis and attractive properties]. AB - 2-Butyl 2-dodecenoate has been synthesized from lauric acid and sec-butanol. The study of the biological activity of this substance has demonstrated its property as a sex attractant for males of Jordanita graeca, Jordanita globulariae and Theresimima ampellophaga (Lepidoptera: Zygaenidae, Procridinae). The latter species is the grape pest in southern Europe. The attractant obtained can be used for the detection of species, for monitoring their numbers in nature and for the elaboration of ecological methods of pest control. PMID- 25816619 TI - [Avidity of polyreactive immunoglobulins]. AB - An analysis of the mechanism of interaction between polyreactive immunoglobulins (PRIG) and antigen was conducted and it was shown that most of the traditional methods of antibody affinity evaluation are not applicable for PRIG affinity. The comparative assessment of the mouse and human PRIG avidity against ovalbumin and horse myoglobin and the avidity of specific monoclonal antibodies against ovalbumin have shown that the avidity of PRIG not only is much less than the avidity of monoclonal antibodies but even exceeds it. PMID- 25816620 TI - [Effects of rutin on the activity of antioxidant enzymes and xenobiotic metabolizing enzymes in liver of rats fed diets with different level of fat]. AB - The study has been carried out on 6 groups of male Wistar rats, which received semi-synthetic diets within 28 days. Rats of 1st and 4th group received fat-free diet, 2nid.and 5th - diet containing standard amount of fat (10% by weight, 26% by caloric content; lard/sunflower oil - 1/1); 3rd and 6th group - a high-fat diet (30% by weight, 56% by caloric content). During the last 14 days of the experiment rats received rutin in the dose of 40 mg/kg b.w. AOA, MDA level and the activity of paraoxonase I have been evaluated in blood serum. In rat liver along with the parameters of the antioxidant status (MDA level, activity of paraoxonase 1, quinone reductase, heme oxygenase-1) the activity of xenobiotic metabolizing enzymes (XME) (CYP1A1, CYP1A2, CYP3A1, CYP2B1, UDP-glucuronosyl transferase and glutathione transferase) and the activity of lysosomal enzymes (arylsulfatase A and B, beta-galactosidase and beta-glucuronidase) have been investigated. Elevation of the activity of antioxidant enzymes and XME in liver with the increase of diet fat content has been-noted. Rutin admihistration had no effect onparamete6rs of antioxidant status and decreased unsedimentable activity of lysosomal enzymes that did not depend on fat content in the diet. Rutin receiving increased the activity of all studied XME in rats fed standard diet, but practically did not effect on their activity in rats fed by fat-free and high fat diets. Thus, rutin in pharmacological dose has no effect on the activity of antioxidant enzymes that doesn't depend on the level of fat in the diet, while the decrease or increase of diet fat content modulates (weakens) the influence of rutin on the XME activity. PMID- 25816621 TI - [Isomeric specific analysis of hydroxyeicosatetraenoic acid in blood samples from obese patients with non-alcoholic and alcoholic steatohepatitis]. AB - The aim of the study was to perform isomeric analysis of hydroxyeicosatetraenoic acid (HETE) in blood samples from obese patients with non-alcoholic (NASH) and alcoholic (ASH) steatohepatitis. Sixty nine obese patients with liver steatosis according to abdominal US data and chronic ALT elevation were assign into two groups aecoriing to the evaluation of alcohol consumption by GAGE and AUDIT questionnaires: NASH - 39 patients and ASH - 30 patients. The identification and quantification of 5(S)-hydroxyeicosatetraenoic acid (5-HETE), 15-HETE and also non-enzymatic oxidation product 11-HETE in blood plasma were carried out by HPLC MS-TOF with using 2-hydroxyoctanoic acid as internal standard. The position of hydroxyl group in HETE was elucidated by HPLC-MS/MS. The MS/MS transitions were for 15-HETE m/z 319 ---> m/z 219; for 11-HETE m/z 319 --> m/z 167; for5-HETE m/z 319 --> m/z 115. Patients' body composition was evaluated by bioelectrical impedance, resting energy expenditures (REE) were assessed by indirect calorimetry and nutrition pattern was examined by foodfrequency questionnaire. Mean age, BMI and ALT serum level were similar in patients from ASH and NASH groups. Blood plasma 8+12-HETE concentration was also similar in both groups of patients, but concentration of 15-HETE (21,6+/-20,2 vs 11,9+/-13,7ug/ml, p =0,02) and 11-HETE (20,8+/-21,3 vs 11,2+12,9 ug/ml, p =0,03) was significantly higher in NASH patients. ASHpatients demonstrated higher lean body mass (68,1+/-10,6 vs 57,9+/-9,8 kg, p<0,001) and muscle mass (39,3+/-6,1 vs 33,2+/-6,8 kg, p<0,04) and higher rate of protein oxidation (98,5+/-3 1 vs 76,2+/-21,1 g/day, p= 0,02) recalculated from REE. There were no differences found in blood lipids content as well as in consumption of total dietary fat, however, there was a trend to difference in saturated/unsaturated fatty acids ratio between groups (2,3+/ 0,2.in NASH and 1,4+/-0,3 in ASH patients). In conclusion, the rate of production of eicosatetraenoic acid metabolites by lipoxygenase pathway is different in NASH and ASH overweight patients. It means that possibly different mechanisms are responsible for formation of potentially toxic fatty acids metabolites in these two types of patients. It seems likely that differences in fatty acids consumption pattern are related to this metabolic pathway. PMID- 25816622 TI - [Effect of vitamin sufficiency on adaptation syndrome in growing rats]. AB - The influence of vitamin supply of growing male -Wistar rats (n=21) with an initial body weight 53,5+/-0,9 g on their resistance to a single distress induced by the electric shock has been investigated. Control rats within 21 days received a complete semisynthetic diet,providingadequate amounts of vitamins. Combined vitamin deficiency in experimental rats was caused by 5-fold decrease of vitamin mixture amount in the feed and the total vitamin E exclusion from the mixture. On the 21st day, one day before the end of the experiment, both groups of rats were subjected to stress impact (electrocutaneous irritation on paws, 0,4 mA for 8 sec) and then animals were placed in metabolic cages to collect urine. By the end of the experiment, the animals with the combined vitamin deficiency lag behind in growth. Vitamin B2, A, B1 and E liver content decreased in experimental rats by 1,6, 2,3, 4,4 and 15 fold accordingly. Retinol plasma concentration was significantly reduced by 18%, alpha-tocopherol level - by 5 fold, urinary excretionof riboflavin and 4-pyridoxic acid (vitamin B6 metabolite) was significantly reduced by 6,5 and 2,46 times accordingly. MDA blood plasma concentration and the urinary ratio of oxidized and not oxidized form of 8 hydroxy-2'-deoxy-guanosine did not differ in both groups of rats. Urinary excretion of stress biomarker corticosterone in rats with combined vitamin deficit was 2,5-fold higher than in control rats. Thus, reducing of vitamins supply resulted in an increase of urine corticosterone in stressed rats, that characterized the intensity of general adaptation syndrome. This fact shows the importance of optimal sufficiency with vitamins in nonspecific (general) resistance to stress. PMID- 25816623 TI - [Effect of polypeptides isolated from cattle abomasum on stomach regenerative processes in rats]. AB - The effect of polypeptides isolated from cattle abomasum on regenerative processes of rat stomach upon simulating stomach mucosal damage caused by aspirin was studied. Experimental research was carried out on male Wistar rats with initial body weight of 230+/-20 g. The duration of the experiment was 22 days. The rats were divided into 4 equal groups (n=11). The first (control) group consisted of the intact animals; animals from experimental groups 2-4 were intragastrically administered acetylsalicylic acid from the 1st to the 7th day for simulating stomach mucosal damage caused by aspirin (300 mg/100 g body weight). From day 8 to day 22, the animals were intragastrically adminitered the tested samples in the quantity of 2 ml per animal according tothe scheme: the 2nd group - distilled water, the 3d group - native abomasum extract; the 4 th group - thermally treated abomasum extract. Abomasum extract was obtained by extraction with 0,87% aqueous sodium chloride crushed abomasum and represented a liquid of cream color with protein mass content of 1,3 g/100 g of the product with high content of glutamic acid (15,5 g/100 g protein) and B-group vitamins. Electrophoretic analysis of the extract revealed several high molecular weight fractions in the range of 72 to 55 kDa. The bands with molecular masses 52, 43, 40, 37, 34, 26, 17 kDa were most pronounced; the intensive bands in the area 12 kDa and in the range lower than 10 kDa were revealed. The results of the conducted study show that the abomasum extracts both in the native and thermally treated form exert therapeutic action on animal with stomach mucosal damage caused by aspirin, have good antiulcer and gastroprotective activities upon stomach mucosa exposure to chemical damaging agents. The analysis of the hematological indices of the animals from the 3rd and 4th groups, which received the test samples after simulation, revealed the normalization of leukocyte, lymphocyte, granulocyte and monocyte content. This suggests the recovery of the animals after the disease. In the blood serum of these animals concentration of total bilirubin, cholesterol, triglycerides and glucose and the activity of gamma glutamine transferase, ASAT and alkaline phosphatase decreased compared with those in animals with the model of stomach mucosal injury; while the total protein content, including the albumin fraction increased. The examination of the internal organs of the animals from the 3rd and 4th groups showed that the mucosal and submucosal membrane of the stomach were plicate, the signs of edema were absent, the hyperemia, any changes in mucosa, surface and glandular epithelium were not observed. PMID- 25816624 TI - [Study of microbial contamination of processed fresh vegetables and lettuce]. AB - Investigations of microbial contamination and species composition of the Enterobacteriaceae family in fresh vegetables and lettuce has been conducted. The objects of study were new types of fresh ready-to-eat vegetable foods - salads, sliced vegetables and mixtures thereof, sampled at the main stages of production, including washing, antimicrobial treatment with sodium hypochlorite, and packaging in the film under vacuum. Quantitative analysis of Enterobacteriaceae levels in fresh and packaged vegetables and salads showed that their part in the total amount of microbial contaminants is large enough. Average Enterobacteriaceae content ranged from 2,14 to 3,34 lg cfu/g, reaching in some samples values 4,38-4,74 lg, comparable with the levels of total bacteria. Considerable species diversity of microflora contaminating ready-to-eat vegetable products has been found. Bacteria of the genera Enterobactel; Pantoea, Citrobacter, Serratia, Pseudomonas, Kluyvera, Klebsiella, Escherichia, Rahnella, Acinetobacter were found in the salads and sliced vegetables. In the tested samples most frequently detected Enterobacter spp. - 37% of identified strains and Pantoea spp - 25% of strains. The data on the composition and levels of microbial contaminants in vegetable and salad products highlight not only the need to monitor coliform bacteria - traditional indicators of faecal contamination of raw materials, but also the need to introduce criteria for the amount of Enterobacteriaceae. PMID- 25816625 TI - [Determination of deuterium concentration in foods and influence of water with modified isotopic composition on oxidation parameters and heavy hydrogen isotopes content in experimental animals]. AB - The article presents the results of the study of the deuterium (D) content in food products as well as the influence of deuterium depleted water (DDW) on the concentration of heavy hydrogen isotopes in the blood and lyophilized tissues of rats. The most significant difference in the content of D was found between potato and pork fat, which indexes the standard delta notation (delta) D in promille, related to the international standard SMOW (Standard Mean Ocean of Water) amounted to -83,2 per thousand and -250,7 per thousand, respectively (p<0,05). Among the investigated samples of water deuterium concentration ranged from -75,5 per thousand (Narzan) to +72,1 per thousand (Kubai), that indicates the ability of some food products to increase the concentration of heavy hydrogen atoms in the body. The data obtained in the experimental modeling of the diet of male Wistar rats in the age of 5-6 mo (weight 235 +/- 16 g) using DDW (deltaD = 743,2 per thousand) instead of drinking water (deltaD = -37,0 per thousand) with identical mineral composition showed that after 2 weeks significant (p <0,05) formation of isotopic (deuterium-protium, D/H) gradient in the body is possible. Changing the direction of isotopic D/H gradient in laboratory animals in comparison with its physiological indicators (72-127 per thousand, "plasma>>tissue") is due to different rates ofisotopic exchange reactions in plasma and tissues (liver, kidney, heart), which can be explained by entering into the composition of a modified diet of organic substrates with more than DDW concentration D, which are involved in the construction of cellular structures and eventually lead to a redistribution of D and change direction of D/H gradient "plasma<90 ug/l). Though main fish species used by the population (humpback, trout, steelhead) contain relatively high levels of Se (505+/-46, 376+/-32, 413+/-22 ug/kg) and I (187+/-66, 290+/-102, 330+/-116 ug/kg), they are not able to maintain high I and Se status of the inhabitants due to low consumption level. I consumption with fish, being used once per week, reached 21 ug, Se - 35 ug per week. Up to 40% of students and 28% of elderly do not eat fish at all. Children of 2-6 years old residing in Moscow Region compose a specialgroup of ecological risk of I deficiencypossessing significant I deficiency 3 times more frequently than children from Moscow. PMID- 25816627 TI - [Complex of zinc with enzymatic hydrolysate of pigspleen protein - in vivo investigation]. AB - Experimental sample of complex zinc with enzymatic hydrolysate of pigspleen protein (Zn-EHPS) was produced in laboratory with ultra- and nanofiltration technologies; its composition was analyzed; male rats Wister (initial body weight 132+/-2,4 g) were under observation in vivo: rats weregiven zinc-deficient ration (ZDR) "Zinc Deficient Diet, Egg White Base", containing not more than 1,3 mg zinc/kg, and water ad libitum during 18 days. Animals were divided into 3 groups (10 in each): group I was given ZDR and distilled water; group 2 - ZDR and water zinc sulphate solution (ZnSO4) with zinc concentration of 16,3 mcg/ml; group 3 - ZDR and water Zn-EHPS solution with zinc concentration of 16,3 mcg/ml. All rats were daily observed with registration of water consumption. Unconditioned reflex (photophobia) or crossing time from light to darkness on special system before the beginning of experiment was tested out. An increase of body weight (DeltaW) during the experiment, unconditioned reflex stability and training to conditioned passive avoidance reflex (CPAR) after paw painful electric stimulation were studied. On 18 day in 16 hours after paw painful electric stimulation alkaline phosphatase activity (AP) and corticosterone concentration in rat blood serum were examined. Insignificant changes in distribution of peptide fractions according its molecular mass and practical complete remove of free metal ions from final product were observed when Zn-EHPS-technology were used. During experiment in all groups correspondently DeltaW was 23,87 and 82% (p<0,05); AP activity - 1,70+/-0,06; 3,10+/-0,25; 4,19+/- 0,26 mcmol/l/s (p<0,01); corticosterone concentration - 20,7+/-7,2; 21,5+/-6,3; 22,1+/-16,5 ng/ml (p>0,1) were observed. Significant (p<0,05) worse change of unconditioned reflex (photophobia) in group 1 (ZDR) in comparison with group 2 and group 3 (latent period - LP, s: 50,9+/-12,0; 18,2+/-16,0; 16,0+/-4,2) as well as to initial test (LP, s - 16,8+/-8,0) was found on the 14th day of the experiment. According to LP test CPAR in all groups in 24 and in 96 hours after paw painful electric stimulation was found to be maintained. Data obtained let to suggest high bioavailability of new zinc organic form - Zn-EHPS and its usage possibility in fortification of special foods. PMID- 25816628 TI - [Effeciency of usage of natural low caloric protein-vegetable product by patients with excess body weight and hypertension]. AB - The efficiency of the usage of natural low caloric concentrated protein-vegetable food product (LCCF) by 23 persons with excess body weight at the age of 30-44 years (the 1st group) and 30 hypertensive patients at remission stage and overweight at age 45-59 years old (the 2nd group) has been assessed. According to energy expenditure, all examined male persons were classified to II group of physical activity: PhysicalActivity Coefficient (PAC) was 1,35+/-0,14 and 1,34+/ 0,22 respectively. As for dietary intake, authors revealed an excess of protein (up to 20,1%), fat (up to 17,2%) and daily caloric content over daily energy expenditure that led to an increase of body weight along with metabolic and liver function disorders. Initially, body mass index (BMI) was 29,9+/-0,6 kg/m2 in the 1st group and 36,2+/-0,4 kg/m2 in the 2nd group. LCCFP was administrated to persons in studied groups and consisted of fat-free curd, egg white, rye bran, dried apricots, laminaria, leaves of green tea and cowberry. The product was made by cryogenic technology. LCCFP (35 g) was administrated two times per day instead of breakfast and supper during 15 days. Protein content in 1 portion of LCCFP was 5.2 g, fats -3.8 g, carbohydrates - 16.8 g; energy value - 122 kcal. The decrease of daily caloric content was 1225,5 kilocalories (kcal) in the 1st group and 1071,3 kcal in the 2nd group duringperiod of LCCFP administration; the energy value of the diet amounted to an average of 1420 and 1560 kcal per day. During the study, authors found serum protein indices were constant, but revealed the decrease of the level of glucose (by 15,3-18%), cholesterol (18,8-19%), low density lipoprotein cholesterol (13,9-15,8%), triglycerides (20-26,3%) and alanine aminotransferase (39,7-41,4%) and asparagine aminotransferase (40,6 40,7%) activity. This provided evidence of positive influence of the natural protein-vegetable LCCFP on fat and carbohydrate metabolisms as well as liver function. Also, the decrease of atherogenicity index (1,45-1,5 units) gave evidence of effectiveness of used method. The decrease of systolic arterial pressure (by 12,9%) and diastolic arterialpressure (by 20,7%) in patients with hypertension at remission stage and body weightprovided evidence of positive influence of caloric content decrease due to LCCFP administration on function of cardiovascular system in this category of examined persons. PMID- 25816629 TI - [An analysis of the efficacy of low-calorie and isocaloric diets in obese patients with nonalcoholic steatohepatitis]. AB - Diet modification is widely used for the treatment of non.alcoholic steatohepatitis (NASH). Caloric restriction was shown to be effective in normalizing bldod lipid profile, increasing insulin sensitivity and subsequent normalization of aminotrasferases blood level. The aim of the study was to compare low-calorie diet (LCD) with isocaloric diet (ICD) in patients w,ith NASH. 174 NASH patients [86 females (39,43+/-1,53 years old) and 88 males (41,7+/-2,0), BMI 36,8+/-0,8 kg/m2] were randomly assigned (as 1:2) for LCD (1600-1700 kcal/day) or ICD (2500-2700 kcal/day) calculated according to patients'sex, age, resting energy expenditures and daily physical activity. Caloric restriction was achieved by decreasing consumption of carbohydrates and fat in LCD, whereas for ICD the caloric consumption was established according to the recommended daily values for proteins, fat and carbohydrates for ideal BMI for every patient. Blood chemistry and body composition were assessed at baseline and after 1 mo of prescribed diets. Compliance for the diet was also evaluated using previously validated questionnaire. After 1 mo of dietetic interventions total body mass and lean mass significantly decreased in both groups, but in LCD group it was significantly more prominent decrease in compare to ICD group (9,3+/-1,8 vs 6,2+/ 1,7 kg and 6,6+/-0,4 vs 1,4+/-0,6 kg, p<0,05), whereas fat mass decreased better in ICD group (4,8+/-0,7 vs 2, 7+/-0,8kg, p<0,05). Mean ALT level was decreased in ICD group (77,5+/-41,7 vs 98,8+/-45,7, p<0,01), but not in LCD group (81,2+/-50,6 vs 77,2+/-31,8, p=NS) whereas blood cholesterol, triglycerides, high density lipoprotein woere significantly decreased in both groups. Moreover during the diet intervention in 72% of patients from LCD group ALT increased. Compliance index was much higher in ICD group, than in LCD group (85% vs 54%). Thus, one month of lCD leads to decrease in ALT activity in majority of NASH patients, higher loss of fat mass, lower loss of lean mass and associated with better compliance in compare to LCD. PMID- 25816630 TI - [Clinical efficacy instant goat milk in the complex therapy and prevention of osteoporosis in patients with rheumatoid arthritis]. AB - Osteoporosis (OP) in rheumatoid arthritis (RA) refers to a secondary immune mediated metabolic osteopathy characterized by periarticular and systemic decreased bone mass, impaired bone strength and increased risk of fractures. According to some studies, adding milk in the diet helps to increase bone mineral density and to reduce the risk of osteoporosis and maintain normal levels of vitamin D. To study the state of mineral and bone metabolism in RA patients zeith osteopenic syndrome and to evaluate the effectiveness of treatment and prevention of OP by adding dry goat milk "Amalteya" in the diet. The study included 42 patients with a documented diagnosis of RA (ACR, 1987) - 23 men (mean age 59 years) and 19 postmenopausal women (mean age 62 years) with the presence of osteoporosis and osteopenia according to the dual-energy X-ray absorptiometry. 21 (50%) RA patients (main group) received standard antiosteoporotichesky (alendronate 70 mg/week + calcium 1000 mg/day + Vitamin D3 800 IU/day) therapy and milk powder Amalteya(r) (400 ml/day). The control group (21 patients with RA) received only standard antiosteoporotic therapy. Follow-up lasted for 6 months. The concentration of total calcium in the blood of RA patients was on average 2.33 mmol/l, ionized Ca - 1,18 mmol/l and inorganic P - 1,09 mmol/l, which corresponds to normal values. Vitamin D deficiency was found in 17,5% of patients, and failure - in 32,5% of patients with RA. After 6 months of the treatment it was found that b-CrossLaps levels tend to be reducing in both of the groups and with reduction of bone formation marker osteocalcin in the group not receiving goat milk. Also, due to the background of ongoing combinative therapy it was clear that concentrations of 1,25(OH)2D and 25(OH)D in the blood serum are increasing (by 18,5-28,2% at the main group and by 8,0-17,9% at the control group), however, inter-group differences was below the level of the reliable importance. It was strongly marked in the group who received goat's milk "Amalteya(r)". Reduced levels of vitamin D in the blood is typical for 50% of RA patients with osteopenic syndrome with normal values of calcium-phosphorus metabolism. Combination therapy and prevention of osteoporosis in patients with RA with an additional inclusion in the diet of the daily administration of 400 ml of goat's milk Amalthea(r) has a positive impact on bone metabolism. PMID- 25816631 TI - [Biologically active substances of cornelian cherry fruits (Cornus mas L.)]. AB - 10 samples of fresh-frozen cornelian cherry fruits (Cornus mas L.), collected in the Tambov and the Caucasus regions, were investigated for the total amount and composition of the main biologically active substances (BAS): anthocyanins (AC), proanthocyanidins (OPC), dihydroxycinnamic acids (DHCA), iridoids, organic acids, mono- and disaccharides and antiradical activity in the DPPH-test in vitro. Total phenolics content determined by Folin-Ciocalteu method, was 150-400 mg/100 g fresh fruit weight. The OPC content, estimated by Bate-Smith method, varied from 20-25 mg/100 g of unripe cornelian cherries to 80-430 mg/100 g of mature cornelian cherries. Total AC amount evaluated by pH-differential spectrophotometry was minimal in unripe fruits (11,2 mg/100 g), and maximal in mature fruits (92,2 mg/100 g). Profile of individual AC was determined by HPLC with UV/Vis and ESI-TOF-MS detections. 3-galactosides of cyanidin (19,0-80,3%) and pelargonidin (15,1-75,6%) were found as main anthocyanins. An original methodology for iridoid determination based on HPLC with UV and ESI-TOF-MS detection was developed. The main iridoids were identified as loganic acid, loganin, sweroside and cornuside. Total iridoids content was 130-400 mg/100 g, and loganic acid was predominant in all samples (87,6-94,8%). Only minor amount of the DHCA derivatives (<10 mg/100 g) were found. The malic acid was predominant among organic acids, the total content of which varied from 0,4 to 2,8%. Relatively high amount of ascorbic acid (35-60 mg/100 g) was found. The carbohydrates profile of cornielian cherries was represented by fructose (2,2 3,8%) and glucose (2,5-7,0%). 70% water-ethanol extracts of Cornus mas fruits have showed pronounced antiradical activity in DPPH-test (470,5-932,0 mg TE/100 g). The data on specific minor BAS can be used in the standardization and evaluation of potential biological activity of extracts and dietary supplements based on the cornelian cherry fruits. PMID- 25816632 TI - [Catering services bases in the Russian army under military regulation of Peter the Great]. AB - At Peter I the regular army was organized and the system of target state deliveries to troops of the food is created. Provisioning and fodder was normalized as portion and ration. Portion was contained the products forpeoplefood, and ration - fodder for horses food who were used by the serviceman. Portion and ration unit was identical to all categories of the military personnel. Difference in food level consisted in that, how many portions and rations serviceman received. Up to the end of existence of Russian army in 1918 in each rota there were contractor and the cook who were engaged in foodstuff and cooking under sergeant-major and one of rota officers supervision. According to the Charter it was necessary to carry with respect and attention to officers and soldiers, their needs, including in the field of supply and catering services and providing with the food: Despite the lack of scientific justification, soldiers' nutrition was sufficient to provide fighting capacity of the Russian army. PMID- 25816633 TI - [Mechanisms underlying the pathogenesis of neuropathic pain revealing by the role of glial cells]. AB - Injury to the nervous system results in debilitating chronic pain states (called neuropathic pain) whose mechanisms remain unclear. Emerging lines of evidence indicate the pivotal role of spinal glial cells in neuropathic pain. Spinal microglia rapidly respond to peripheral nerve injury (PNI) and become activated with changing expression of a variety of genes. The best known example is purinergic P2X4 receptors, an ATP-gated cation channel. The expression of P2X4 receptors is upregulated in spinal microglia after PNI, and inhibition of P2X4 activity suppresses neuropathic pain. Furthermore, interferon regulatory factor-8 (IRF8) and IRF5 are identified as microglial transcription factors whose expression is upregulated in spinal microglia after PNI, and the IRF8-IRF5 transcriptional cascade is the core process for shifting spinal microglia toward a state with high expression of P2X4 receptors. Astrocytes in the spinal cord show a delayed onset of activation and play an important role in the maintenance of neuropathic pain via the transcription factor STAT3 and the intracellular kinase JNK. These results obtained from glial cell research will advance our understanding of the development and maintenance of neuropathic pain and provide a new target for treating this pain. PMID- 25816634 TI - [Gliaotransmission and brain functions]. AB - Glial cells receive neurotransmitters, respond to them, and then release so called gliotransmitters such as ATP, glutamate or D-serine. Astrocytes in particular have received much attention because synaptic structures are surrounded by astrocytic fine processes, by which astrocytes communicate with neurons via gliotransmitters. Here, we introduce recent progress concerning glia neuron interaction, especially focusing on the major gliotransmitter ATP and astrocytes in parallel with the latest progress in glia-imaging techniques. PMID- 25816635 TI - [Interoception and decision-making]. AB - We sometimes make decisions relying not necessarily on deliberative thoughts but on intuitive and emotional processes in uncertain situations. The somatic marker hypothesis proposed by Damasio argued that interoception, which means bodily responses such as sympathetic activity, can be represented in the insula and anterior cingulate cortex and can play critical roles in decision-making. Though this hypothesis has been criticized in its theoretical and empirical aspects, recent studies are expanding the hypothesis to elucidate multiple bodily responses including autonomic, endocrine, and immune activities that affect decision-making. In addition, cumulative findings suggest that the anterior insula where the inner model of interoception is represented can act as an interface between the brain and body in decision-making. This article aims to survey recent findings on the brain-body interplays underlying decision-making, and to propose hypotheses on the significance of the body in decision-making. PMID- 25816636 TI - [Autonomic nervous status and bioelectric brain activity in adolescents inhabitants of the Polar north]. AB - BACKGROUND: Northern European areas are differing in degree of extreme climatic conditions in the Polar and Subpolar latitudes. Formation of the nervous system in adolescents most of all is affected by these adverse climatic factors. OBJECTIVE: The aim was to study of the autonomic regulation of cardiac activity and brain bioelectric activity in adolescents-inhabitants of the North depending on these autonomic nervous tones. METHODS: 300 adolescents (male and female) aged 15-16 years living in the Polar (67 degrees 40' N) and Subpolar (64 degrees 30' N) northern regions of Russia are examined. Assessment of autonomic nervous tone was determined by the heart rate variability (HRV) and blood pressure parameters. After the initial analysis of these indicators, all subjects in both areas were further divided into groups with vagotonic, normotonic and sympathotonic types. Electroencephalogram (EEG) was recorded in the state of quiet wakefulness with closed eyes (16 standard monopolar leads). EEG characteristic were performed on the values of the amplitude and the index in each frequency band. All described changes were statistically significant atp < 0.05-0.001. RESULTS: According HRV and central hemodynamics among adolescents of the Polar North revealed an increase the proportion of individuals with a predominance ofsympathetic influences on cardiac activity (37.3%) and significant decrease the proportion ofpersons with a predominance of vagal influences (10%). A high activity of diencephalic subcortical brain structures in groups of normotonic and sympathotinic persons in the Polar region was revealed, which manifests itself in the form of increased levels of theta and alpha EEG-activity, as well as increased occurrence hypersynchronous EEG-types (50%). In adolescents-inhabitants of the Subpolar region occurs more intensive age optimization of neural processes then in adolescents- inhabitants of the Polar region. CONCLUSION: The predominance of sympathetic effects on the cardiac activity and higher activity of diencephalic subcortical brain structures in adolescents of the Polar region were revealed. PMID- 25816637 TI - [Calf blood hemodializate reduces neurotoxic effect of hydrogen peroxide on human neuroblastoma cells]. AB - OBJECTIVE: Our aim was to study the effect of calf blood gemodializat on apoptosis and intracellular signaling pathways of neuroblastoma cells SK-N-SH human. METHODS: Apoptosis was recorded by fluorescent microscopy using Hoechst 33342. Necrosis cells was monitored by propidium iodide. The fluorescence of the cells was recorded on a fluorescence inverted microscope Keyence BZ8100 (Japan). Formation of reactive oxygen species (ROS) in the cells of SK-N-SH was determined using nitroblue tetrazolium by absorbance at 620 nm on a plate reader "Uniplan". RESULTS: When adding hydrogen peroxide to the background of the calf blood gemodializat been decreasing apoptosis of these cells with 43 to 17% relative to apoptosis in the presence of a hydrogen peroxide. Under these conditions, the calf blood gemodializat significantly reduced ROS formation in human neuroblastoma cells SK-N-SH by the action of hydrogen peroxide. In these cells, we investigated the influence of calf blood gemodializat on apoptosis and intracellular signaling pathway involving mitogen-activated protein kinase (p38MAPK), extracellular regulatory kinase (ERK), phosphatidylinositol 3-kinase (PI-3K) and-Jun-N-terminal kinase (JNK) using their selective inhibitors. CONCLUSION: It was shown that the mechanism of the protective effect of calf blood gemodializat against peroxide-induced apoptosis in SK-N-SH dominant role is played by p38 MAPK and PI-3K. PMID- 25816638 TI - [Diastolic dysfunction in hypertrophic nonobstructive cardiomyopathy]. AB - OBJECTIVE: The purpose of research was to assess the availability and prevalence of types of diastolic dysfunction of the left ventricle (LV) in hypertrophic nonobstructive cardiomyopathy (NHCM). METHODS: 97 NHCM patients. Mean age 42.5 +/ 14.9 years. Diastolic dysfunction assessed by Doppler echocardiography. RESULTS: Signs of chronic heart failure NYHA class I observed in 44 (45%) patients, class II--in 40 (41%), class II--in 13 (13%) patients. 83% patients had LVdiastolic dysfunction, mainly on the hypertrophic type. One third of the patients had pseudonormal type with uncertain interpretation. Diastolic dysfunction in terms of clinical manifestations determined mainly NYHA class III and syncope. Severity of LV diastolic dysfunction in NHCM depended on the severity of hypertrophy not only left, but the right ventricle too. In 94% of cases we observed not only diastolic dysfunction, but also reduction ofsecondary fibers shortening fraction- as sign of contractile dysfunction. CONCLUSION: Thus, in NHCM dominated diastolic dysfunction of hypertrophic type. Such dysfunction defining a clinic cardiac deficiency or syncope. One third of the patients had pseudonormal transmitral flow type, difficult to assess diastolic function. Diastolic dysfunction in NHCM was combined with impaired contractility of the walls of ventricle. PMID- 25816639 TI - [Depression and cardiovascular diseases]. AB - Depression is considered to be an independent cardiovascular risk factor and it may worsen the symptoms of already established cardiovascular pathology such as coronary heart disease, chronic heart failure, stroke and hypertension. 3 key psychobiological mechanisms by means of which depression influences cardiovascular system: disbalance in stress response of endocrine system, hyperregulation of autonomic nervous system and immune disorders leading to dysregulation of acute phase proteins and proinflammatory cytokines release. In majority of studies in patients with depression and cardiovascular diseases it was shown that antidepressants improve the symptoms. By the way, in some studies controversial results were obtained. Future studies in this direction with involvement of cardiologists and psychiatrists should be held. PMID- 25816640 TI - [Reciprocal formation of mucosal microflora of open cavities of different habitats in women as an important factor of their reproductive health]. AB - This review presents the current data on the human microbiome. In recent increase of erased and primary chronic forms of inflammatory diseases of the female genital organs is observed, in which the clinical manifestations are varied, but the symptoms are not so much related with the changes in the pelvic organs, but with abnormalities in other body systems, secondarily involved in the pathological process. Recent research proved mutual influence of intestinal, vaginal and nasopharyngeal biocenosis. Women with vaginal microbiota disorders often revealed intestinal dysbiosis and chronic diseases of ENT (Ear Nose Throat) organs, which in turn contributes to chronic inflammatory process of pelvic organs, failure of therapeutic interventions, reduced quality of life and increased risk of adverse pregnancy outcomes. PMID- 25816641 TI - [Molecular genetic identification of Staphylococcus aureus strain, caused a foodborne illness outbreak in St. Petersburg in 2013]. AB - BACKGROUND: Staphylococcus aureus is one of the most important human pathogens and causes over 100 nosologicalforms of diseases. The lack of data on the spread of S. aureus genetic types specific for different forms of staphylococcal infections in Russia makes it difficult to timely identify and control strains of this epidemiologically dangerous bacterial pathogen. OBJECTIVE: The aim of the study was to carry out a molecular genetic research of S. aureus isolates obtained during a widespread foodborne illness outbreak among builders at the Pulkovo airport in St. Petersburg in 2013. METHODS: The ability of the isolates to produce staphylococcal enterotoxins was studied by immunoenzyme techniques. Gene typing was carried out by sequence-specific primer-based PCR, as well as by sequencing genomic nucleotide sequences of two independent isolates of the pathogen. RESULTS: An enterotoxin A gene in genomes of S. aureus isolates etiologically associated with the outbreak was identified. The production of enterotoxin A by the isolates was shown. According to the complex analysis all isolates producing staphylococcal enterotoxins were identical and constituted the S. aureus strain, sequence-type ST30 and spa-type t2509. The genome of the identified S. aureus strain carried a set of various staphylococcal toxins. The full genome sequence among other techniques revealed high levels of similarity between genomes of the strain under study and well-known reference strain S aureus MRSA 252. CONCLUSION: The complete molecular genetic study of the S. aureus strain involved into the widespread foodborne illness outbreak was first carried out in Russia, allowing of further using the strain as a Russian reference strain to study potential epidemic outbreaks in the Russian Federation. PMID- 25816642 TI - [Acinetobacter: microbiological, pathogenetic and resistant properties]. AB - Species of the genus Acinetobacter represent opportunistic bacteria with a growing clinical significance. In this literature review, we focus on the current role of Acinetobacter in infectious pathology and describe physiology, taxonomy, ecology, pathogenicity, and antibiotic resistance of these bacteria. Molecular pathogenesis and regulation of virulence factors in Acinetobacter spp. are described in detail. The majority of acinetobacterial infections are associated with A. baumannii and occur predominantly in an immunocompromised host. Usually, acinetobacterial infections are characterized by local purulent inflammation; in severe cases, meningitis and sepsis may develop. Antibiotic resistance ofAcinetobacter is a major clinical problem; therefore we give special attention to laboratory testing of resistance as well as identification of Acinetobacter. In addition, treatment and prophylaxis of acinetobacterial infections are discussed. PMID- 25816643 TI - [Features of mucosal lesions of stomach and duodenum in children with chronic gastroduodenitis with different microflora content]. AB - OBJECTIVE: Our aim was to reveale the features of histological mucosa with different composition of the microflora of stomach and duodenum in children with chronic gastroduodenitis. METHODS: The study included 122 children with chronic gastroduodenitis from 5 to 17 years old. All patients underwent endoscopy with histology of biopsy specimens of gastric and duodenal mucosa in 94 patients and in 48 patients among them with morphometry of biological material. Identification of herpes simplex virus 1, 2 types, cytomegalovirus, human papilloma virus 16, 18 types, Helicobacterpylori was carried out using polymerase chain reaction in biopsies of gastroduodenal mucosa and gastric juice. RESULTS: Children with chronic gastroduodenitis depending on the identified microorganisms were divided into groups: 1st (n = 51)--without detectable microorganisms, 2nd (n = 28)--with associations of H. pylori and viruses, 3rd (n = 15)--only with viruses, 4th (n = 28)--with H. pylori. Thus, in patients with H. pylori inflammation was noted mainly in the antral mucosa and dystrophic changes--in the duodenal mucosa. In the presence of viruses the inflammation was expressed more in the fundal stomach and duodenum. When viral-bacterial associations were observed most pronounced inflammatory-dystrophic process was localized throughout the gastroduodenal mucosa. CONCLUSION: In children with chronic gastroduodenitis in the presence of bacterial, viral and mixed microflora in the stomach and duodenum identified characteristic histological features of the mucosa, manifested in a different localization and severity of inflammatory and dystrophic changes. PMID- 25816644 TI - [Clinical experience of the repeated multilevel injections of the botulinum toxin type A (abobotulinum toxin A) in the spastic forms of cerebral palsy]. AB - OBJECTIVE: Our aim was to analyze the dosages of Abobotulinum toxin A used for each muscle in the clinically effective and safe repeated multilevel injections in CP children, and the intervals between injections. METHODS: Retrospective analysis of 229 injection sessions into 359 muscles of the upper and 361 muscles of the lower extremities in 133 children (2-18 years) with spastic CP. Analysis included only patients who were injected for the first time and demonstrated decrease of spasticity in injected muscles according to modified Ashworth and/or Tardieu scales without significant side effects 2-4 weeks after injections. Motor deficit according to GMFCS was: GMFCS I--16(12%) children, GMFCS II--26 (19.6%), GMFCS III--43 (32.3%), GMFCS IV--30 (22.6%), GMFCS V--18 (13.5%). Repeated injections (up to 5 sessions) were done in 59 children. Maximum follow-up perion was 22 months. 40 patients (30.1%) had one-sided injections, 93 (69.9%)--two sided, 125 (94%)--multilevel injections. RESULTS: We presented minimal and maximal dosages, interquartile ranges for each injected muscle, also "off-label" and our proposition of per-segment calculation of dosages in multilevel injections in CR. We also demonstrated the stability of intervals between repeated injections and dosages per kg in a patient. These results are compared with the official Russian and international recommendations of BTX-A treatment for children. CONCLUSION: We presented our experience of BTX-A dosages calculation for the spastic CP treatment which could be used as a recommendation and guide for the multilevel injections treatment according to the aims of rehabilitation, spasticity level, muscle size and motor deficit of a concrete patient. PMID- 25816646 TI - [Assessment of motor and sensory pathways of the brain using diffusion-tensor tractography in children with cerebral palsy]. AB - BACKGROUND: Diffusion tensor tractography--a new method of magnetic resonance imaging, that allows to visualize the pathways of the brain and to study their structural-functional state. OBJECTIVE: The authors investigated the changes in motor and sensory pathways of brain in children with cerebral palsy using routine magnetic resonance imaging and diffusion-tensor tractography. METHODS: The main group consisted of 26 patients with various forms of cerebral palsy and the comparison group was 25 people with normal psychomotor development (aged 2 to 6 years) and MR-picture of the brain. Magnetic resonance imaging was performed on the scanner with the induction of a magnetic field of 1,5 Tesla. Coefficients of fractional anisotropy and average diffusion coefficient estimated in regions of the brain containing the motor and sensory pathways: precentral gyrus, posterior limb of the internal capsule, thalamus, posterior thalamic radiation and corpus callosum. RESULTS: Statistically significant differences (p < 0.05) values of fractional anisotropy and average diffusion coefficient in patients with cerebral palsy in relation to the comparison group. All investigated regions, the coefficients of fractional anisotropy in children with cerebral palsy were significantly lower, and the average diffusion coefficient, respectively, higher. CONCLUSION: These changes indicate a lower degree of ordering of the white matter tracts associated with damage and subsequent development of gliosis of varying severity in children with cerebral palsy. It is shown that microstructural damage localized in both motor and sensory tracts that plays a leading role in the development of the clinical picture of cerebral palsy. PMID- 25816645 TI - [Case of combination of Beckwith-Wiedemann syndrome with West syndrome]. AB - Beckwith-Wiedemann syndrome (BWS) is etiologically connected with genetic/epigenetic growth dysregulation. The supposed localization of this disorder is a short arm of chromosome 11 (11p 15.5). Its prevalence is 1:13 per 700 newborns. West syndrome is an age-dependent epileptic syndrome related to a group of infantile epileptic encephalopathies and characterized by a triad of basic symptoms: series of infantile spasms, psychomotor retardation and severe paroxysmal EEG changes. The incidence of West syndrome is estimated at 1 case per 2,000-4,000 newborns. The article describes a rare clinical case: a combination of BWS with one of the types of infantile epileptic encephalopathies--West syndrome. A detailed analysis of the West syndrome progression in a female patient with BWS is given, the tactics of antiepileptic therapy is analyzed, and its complexity in terms of metabolic disorders caused by the presence of a genetic syndrome in a patient is shown. The results of a long catamnesis are described. The figures are the fragments of native electroencephalograms at the eruptive phase of West syndrome and against the background of a long-term remission. When describing the clinical case in detail, the authors actively discuss the obtained information and available literature data. The article also presents practical guidelines for the early detection of metabolic disorders in patients with infantile epileptic encephalopathies. In addition to anti-epileptic drugs, the authors propose to include a mandatory metabolic correction in the therapy complex for these patients. PMID- 25816647 TI - [Peculiarities of functional hemispheric asymmetry formation in children and adolescents with hypertension]. AB - OBJECTIVE: Peculiarities and age dynamics of hemispheric asymmetry investigation in children and adolescents with hypertension. METHODS: 196 children and adolescents aged 10 to 17 years (15.0-1.4), including 98 patients with arterial hypertension (AH) (15.1 +/- 1.5) and 98 healthy children of the control group (14.9 +/- 1.3). The number of boys in the comparison group and the main group of patients with AH was 60 (61.2%) and 59 (60.2%), girls--38 (38.8%) and 39 (39.8%), respectively. RESULTS: The majority of children and adolescents with hypertension sensorimotor asymmetry differed by low intensity, indicating a decline in the dominance of the left hemisphere. Accumulation of ambi- and left lateral features traced mainly in motor (53.6%) and auditory (60.2%) system, while asymmetry in the visual analyzer did not differ from the control group. Differences in the degree of hemispheric asymmetry increases in the ontogeny compared to control group. CONCLUSION: Identification of specificity hemispheric interaction in patients with hypertension (low asymmetry and its weak performance in ontogeny) can be considered not only as a pathological consequence of hypertension, but also as a compensatory mechanism for the redistribution of loads to the right hemisphere in terms of the functional deficit of the left hemisphere. It can be assumed that the rearparts of the brain may play a significant role in the processes of adaptation and compensation of occurring disorders in hypertension. PMID- 25816648 TI - [Contribution of non-HLA genes to juvenile idiopathic arthritis susceptibility]. AB - Juvenile idiopathic arthritis (JAL4) is the most common chronic rheumatologic disease in children. JIA is a group of disorders that share the clinical manifestation of chronic joint inflammation. The Human Leukocyte Antigen region (HLA) seems to be a major susceptibility locus for JIA that is estimated to account for 17% of familial segregation of the disease. Genome-wide association studies (GWAS), case-control studies and meta-analyses of the post-GWAS era revealed over 20 non-HLA loci conferring susceptibility to JIA. At least a half of those are shared between JIA and rheumatoid arthritis, an adult rheumatic disease, thereby suggesting for similarity of pathogenic mechanisms of both diseases. New findings also suggest for a likely role of epigenetic alterations in the pathogenesis of JIA that should be investigated in the future. PMID- 25816649 TI - [The morphofunctional condition of structures of the hip in experimental treatment of its dysplasia]. AB - OBJECTIVE: Our aim was to determine the dynamics ofreparative tissue changes in the surgical treatment of hip dysplasia it using autograft in conditions of use externalfixation. METHODS: The experiment was performed on 12 mongrel dogs of both sexes between the ages of 7 to 15 months. Preliminary data of the animals (before the closure of the growth zones of the acetabulum) was performed surgery to obtain acetabular dysplasia. After the formation of the standard pattern of dysplastic 2 degree (subluxation) was performed according to the animal treatment, which combined the use of a semicircular incomplete osteotomy in the supra-acetabular area, an autologous bone graft and the Ilizarov external fixation. The conditions of external fixation provided autograft stability, simultaneous uniloading of the articular surfaces and allowed for dosed joint motion during the treatment by releasing the hinge units thus contributing to the prevention of cartilage degeneration. The external apparatuses were dismounted on day 21 after the operation. The animals for histological study were euthanized on day 14, 21, 51 and 111 after the operation. We used clinical and experimental, radiographic and histological methods. RESULTS: It is found that after 90 days after the frame removal there is a complete replacement of the newly formed bone graft. This maintains a full cartilaginous acetabular coverage presented hyaline cartilage, which revealed minor structural and functional changes in reactive and reparative nature. CONCLUSION: The hip joint has a high adaptive potential. There is a strong trend towards the restoration ofhip joint in new conditions created by an external fixation device. Nevertheless, given the suppression of its own regenerative capabilities of the articular cartilage at the dysplastic process, its maximum possible recovery in the treatment is impossible without the participation of external stimulants chondrogenesis. PMID- 25816650 TI - [Hormonal changes in response to extreme environment factors]. AB - In this paper presented current state about hormonal changes in sympathetic adrenal, hypophysis-adrenal, hypophysis-gonads and thyroid levels from extreme environment factors. It's shown that hypophysis gonads and thyroid endocrine links along with sympathetic adrenal, hypophysis adrenal axes are very important relevance in response to extreme environment factors and organism adaptation. In this time a hormonal secretion changes corresponds as interrelated reactions cascade in mechanisms of homeostasis maintenance. A studying of this mechanisms and revealing of its role in stress pathogenesis is fundamental biomedical investigation task. A problem solving allow to perfect prophylactic and treatment methods against stress diseases. PMID- 25816651 TI - [Mechanisms of immune and cytokine regulation in pathogenesis of ixodes tick borne borreliosis]. AB - BACKGROUND: Our aim was to identify the mechanisms of immune and cytokine regulation in different clinical forms of Ixodes tick-borne borreliosis. METHODS: The clinical observations performed on 581 patients with erythemic (113 patients), non-eritemic (242 patients) forms of Ixodes tick- borne borreliosis and Borrelia co-infection tick-borne encephalitis (226 patients) in the manifestation of the disease. The examination included the determination of the levels of cytokines (interleukin 1beta, 4, 8, and tumor necrosis factor alpha), indicators of cell immunity (CD3+, CD4+, CD8+) and phagocytosis (phagocytic index, the number of phagocytic neutrophils) during the height of the disease and during convalescence. RESULTS: We established the correlations of cytokine production, lymphocyte subpopulations and phagocytosis. Revealed divergent immune mediated mechanisms of pathogenesis, depending on the clinical forms of Ixodes tick-borne borreliosis and period of the disease, indicating the complexity and diversity of the immune system rearrangements. Cytokine regulation of immune response, mainly consists in the synthesis of the chemoattractant interleukin 8 production which is inversely correlated with the number of phagocytic neutrophils (r = -0.440, p < 0.001) with erythemic form of the disease, is directly correlated with the level of interleukin 4 (r = 0.313, p < 0.001) at non eritemic form borreliosis, with the production of interleukin 1beta (r = 0.367, p < 0.001) and interleukin 4 (r = 0.348, p < 0.001) in Borrelia co-infection tick borne encephalitis. CONCLUSION: In the manifestation of acute Borrelia infection, regardless of the clinicalform was typical Th1/Th2 type of immune response and then switches to the period of convalescence for Th1 (cellular) immune response in the form of erythemic Ixodes tick-borne borreliosis and Borrelia co encephalitic tick-borne infection, and Th2 (humoral) immune response when non eritemic form of the disease. PMID- 25816652 TI - [Application of risk-based approach for determination of critical factors in technology transfer of production of medicinal products]. AB - Risk-based approach is used for examination of impact of different factors on quality of medicinal products in technology transfer. A general diagram is offered for risk analysis execution in technology transfer from pharmaceutical development to production. When transferring technology to full- scale commercial production it is necessary to investigate and simulate production process application beforehand in new real conditions. The manufacturing process is the core factorfor risk analysis having the most impact on quality attributes of a medicinal product. Further importantfactors are linked to materials and products to be handled and manufacturing environmental conditions such as premises, equipment and personnel. Usage of risk-based approach in designing of multipurpose production facility of medicinal products is shown where quantitative risk analysis tool RAMM (Risk Analysis and Mitigation Matrix) was applied. PMID- 25816653 TI - [Comparative study of the effects of new neuroactive amino acid derivatives on the postnatal development of the rat's offspring with experimental preeclampsia]. AB - BACKGROUND: Our aim was to investigate the effect of derivatives of GABA and glutamate on the postnatal development of the offspring of rats with experimental preeclampsia. METHODS: The experiments were performed on 35 albino female rats aged 5-7 months, weighing 220-240 g, and their offspring in the amount of 284 individuals. Experimental preeclampsia was modeled by replacing the drinking water by 1.8% NaCl solution to pregnant females from 7 to 21 days ofgestation. Glutamic acid--compound RSPU-135 at a dose of26mg/kg, GABA derivative - compound RSPU-242 at a dose of 23 mg/kg and the reference drug sulodexide in a dose of 30 mg/kg administered to female orally daily, since the 7th day of gestation prior to delivery. Evaluated the physical development of offspring, sensory-motor reflexes, mental functions. RESULTS: It was found that the experimental preeclampsia causes a delay in physical development and maturation of sensory motor reflexes in the offspring, as indicated by the later periods of eruption of the incisors and eye opening, response to the emergence of audio and olfactory stimuli, forming vestibular stability and coordination of movements compared to pups from females with physiological pregnancy. Offspring from females with experimental preeclampsia were noted for lagging behind in mental development, as evidenced by the decline of the orienting-exploratory activity, learning and memory, increase of anxiety level. Compound RSPU-135, to a greater extent, improves physical development, increases the rate of maturation of sensory-motor reflexes, RSPU-242--stimulation of cognitive functions, keeping the memory trace, orienting-exploratory, spontaneous locomotor activity, and reduce of anxiety level. CONCLUSION: The neuroactive amino acid derivatives limit the negative effects of experimental preeclampsia on the offspring. PMID- 25816654 TI - [Monoclonal antibodies in high-grade gliomas]. AB - The review is devoted to a relatively young direction in therapy of malignant gliomas, which is based on applying monoclonal antibodies against tumour associated antigens. The current data on efficacy of main therapeutic agents in clinical practice or clinical trials concerning high-grade gliomas, especially glioblastoma multiforme, is summarized. Of particular interest is bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (anti VEGF), which is widely used in glioblastoma. Major clinical trials devoted to bevacizumab monotherapy and combinations of bevacizumab with other therapeutic modalities in primary and recurrent glioblastoma conducted since 2006 till now are reviewed. The results ofexperimental and clinical application ofmonoclonal antibodies against epidermal growth factor receptor (EGFR) and its mutant variant EGFRvIII are analyzed, showing the most significant clinical effectiveness of nimotuzumab--a humanized monoclonal antibody. Significant part of the review is devoted to discussion of experimental and clinical data concerning efficacy of antibodies against VEGF receptor 2, platelet-derived growth factor receptor alpha, hepatocyte growth factor and its receptor c-Met. Unbiassed analysis of clinical trials on monoclonal antibodies does not allow us to conclude that passive immunotherapy directed against antigens listed above can significantly improve the overall survival of patients suffering from glioblastoma multiforme. This finding has encouraged us to mention several alternative approaches to passive immunotherapy and to list several prospective antigens for developing monoclonal antibodies. PMID- 25816655 TI - [Minimization of approach at laparoscopic cholecystectomy]. AB - OBJECTIVE: The aim of the study was to estimate the influence of the amount of endoscopic approaches on effectiveness of laparoscopic cholecystectomy. METHODS: For the purpose of comparative evaluation of the results of surgical treatment of a three- and fourport laparoscopic approach was a retrospective analysis of case histories of 118 patients. Patients were divided into two groups: operated by using three laparoscopic approaches (60 patients) and unused optional fourth trocar (58 patients). One of the important stages of scientific research was histological morphology characteristic of the removed gallbladder, which was performed in 118 patients who underwent minimally invasive operations. For subjective assessment of the manifestations of pain syndrome used the conventional visual analog scale of pain (VAS). RESULTS: 60 patients underwent three-port laparoscopic cholecystectomy (the main group) and 58 patients underwent four-port LC (group of comparison). In the main group 53 (88.3%) patients showed absence of any pain, and only 3 from them complained of existence easy and 4--moderate pain respectively for the 7th day after surgical intervention. In group of comparison these indicators made: respectively 50 (86.2%), 2 and 6 people. Terms of hospitalization and disability were relatively lower at the minimum number of ports: respectively 3.2 and 4.4 days. In the main group duration of disability made 8.5 days against 10.6 days in group of comparison. CONCLUSION: Reducing the number of laparoscopic approach significantly reduced the frequency of clinical manifestations of pain, achieved maximum cosmetic effect, significantly shortens postoperative rehabilitation period, and comes earlier activation and rehabilitation of patients. PMID- 25816656 TI - [Means and methods of alternative therapy for cancer: acupuncture--the effects and mechanisms of action]. AB - Among means of alternative and complementary therapy for cancer, acupuncture holds a special place. This is because, unlike the most other methods of alternative and complementary therapy for cancer, efficacy and safety of acupuncture in the symptomatic treatment for cancer patients is considered as proven. Not accidentally such leading cancer centers in the USA as the Dana Farber Cancer Institute in Boston, the Memorial Sloan-Kettering Cancer Center in New York, the M.D.Anderson Cancer Center in Houston integrated acupuncture in accepted in these centers treatment standards and are staffed by licensed professionals on acupuncture. Particular attention is drawn to the use of acupuncture in hospices. It is stressed that it is the most effective and safe in the performance by qualified licensed professionals PMID- 25816657 TI - [Isolation of circulating tumor cells in blood by means of "Isolation by SizE of Tumor cells (ISET)"]. AB - There is evidence of the importance of circulating tumor cells in bloodstream as a factor of poor prognosis of cancer. The optimum method for isolating and studying of these cells is not defined. The most common methods are either based on the isolation of tumor genetic material from blood or on immune-mediated isolation of epithelial tumor cells. The first group of methods is characterized by a lack of specificity, while the latter do not allow identifying a pool of cells undergone in bloodstream epithelial-mesenchymal transformation. There is presented an overview of results of clinical trials of a new technique of isolation of tumor cells from bloodstream based on the patients' blood filtration through a membrane with defined pore sizes (ISET-Isolation by SizE of Tumor cells). PMID- 25816658 TI - [The current state of radiologic diagnosis in pancreatic cancer]. AB - The article discusses the role of modalities of radiation imaging in the detection and differential diagnosis of pancreatic cancer. There is presented the problem of diagnosis of pancreatic cancer at the early stages and possible ways of its solving. Analysis of literature finds out that the detection and differential diagnosis of small formations of the pancreas are difficult and require a multimodal approach. None of the modern methods could be considered as the "gold standard" for detection and differential diagnosis of pancreatic cancer. PMID- 25816659 TI - [The observed and relative survival of prostate cancer patients]. AB - Prostate cancer refers to tumor sites with the most favorable prognosis. Prostate cancer is a tumor that affects mainly elderly and senile age groups. For the first time in Russia there were performed estimations of the observed and relative survival of patients with prostate cancer according to the age and stage of disease. Presented calculations could be used as reference material on survival of prostate cancer patients. PMID- 25816660 TI - [Risk assessment of cancer incidence and mortality according to age and gender of the population]. AB - The paper discusses the approaches and methods to obtain comparable estimates of cancer incidence and mortality in the regions of the country based on adjustments of official data as well as on the average age of the population of each region. There are offered procedures of such adjustment per the linear dependence of cancer incidence and mortality on middle-aged population. There are provided modifications of the linear models on 20 malignant tumor sites, reflecting these dependences, on the basis of information from regions of the Russian Federation for 2007-2011. An example of the calculation of the average age-adjusted cancer incidence rate of female population of the Belgorod region is considered. By using the proposed methods there were received the comparative assessments of cancer incidence and mortality in men and women in eighty-three regions of the Russian Federation. Based on these indicators there are defined the rates of variation of the levels of these phenomena on the majority of considered regions and also determined the most advantaged and disadvantaged regions of the country in accordance with these indicators. PMID- 25816661 TI - [Options for pelvic floor reconstruction after extralevatory abdomino-perineal resection of the rectum]. AB - Extralevatory surgery requires a use of additional techniques for closure of extensive defects of the pelvic floor. This study analyzed the results of 55 extralevatory abdomino-perineal extirpations of the rectum using a variety of methods of plastic of defects of the pelvic floor. There were performed 20 simple plastics, 13 alloplastics and 22 myoplastics. Complications in the perineal wound were observed in 10 (50%) cases after a simple plastic, 4 (32%) after plastic using mesh endoprosthesis and 5 (23%) after myoplastic. It is showed that the highest rate of postoperative complications in the perineal wound (up to 50%) occurs in a case of "simple" plastic. Complication rate reduces to 23-32% when alloplastic and myoplastic are used. It is concluded that alloplastic and myoplastic have significant advantages over the simple plastic. PMID- 25816662 TI - [Cytokine status and neutrophil phenotype in the progression of cervical cancer]. AB - There were assessed morphofunctional state of peripheral blood neutrophils and cytokine status in the serum of primary patients with progression of cervical cancer in the dynamics. Against the background of increasing the total number of neutrophils, a significant reduction occurred in the phagocytic activity, aerobic and anaerobic bactericidal activity, an increase of the rigidity of the membrane and the change of cell cytoarchitectonics at Ib-IIa stage of the disease. At the same stage, in neutrophils there were reduced the level of IL-1beta and its receptor IL-1Ra as well as the number of IFN-gamma. Wherein there was increased the level of pro-inflammatory cytokine TNF-alpha. Cytokine status of the serum, characterized by sig- nificant boosting of IL-1Ra and IL-18 while lowering TNF alpha, IFN-gamma and IL-2, was advantageous for tumor progression and was detected at Ib-IIa stage of cervical cancer. The observed changes of cytokine status in the serum and morphofunctional state of neutrophils were discussed in the light of connection with the possibility of potential pro-tumor effect of the latter. PMID- 25816663 TI - [Assessment of the proliferative activity of tumor cells based on long-term phase contrast microscopy CELL-IQ]. AB - This work presents results of long-term phase-contrast microscopy research of proliferative potential of tumor cell lines utilizing live-cell imaging technology Cell-IQ (Chip-Man Technologies Ltd, Finland). It was found that the machine vision technology allowed to obtain sufficient body of evidence about high-quality and quantitative changes of proliferative activity of the tumor cells cultivated in static conditions. The present study demonstrates that modeling of time interval of maximum proliferative activity of tumors cells increases information efficacy and reliability of the analysis of dividing cell patterns using Cell-IQ technology. The models of exponential growth of various tumor cell lines, describing their quantitative and dynamic changes of expansion potential have been received. Modeling of maximum tumor cells proliferative activity can be applied for development of test-system of individual cell sensitivity to anticancer drugs in vitro. PMID- 25816664 TI - [Heterogeneity of chromosomal abnormalities in cultured melanoma cells of human skin]. AB - Karyotypes of 9 malignant melanoma patients has been described. It is ascertained that most often the damage is observed in chromosomes 1, 6, 7, 9 and 17, which is consistent with the data in the literature. Besides chromosomes 5 and 13 are also often involved in different rearrangements. Recurring aberrations are not discovered. Any correlation between survival and non-recurrent chromosomal aberrations is not discovered. PMID- 25816665 TI - [Comparative results of conservative chemoradiotherapy and thermochemoradiotherapy for locally advanced laryngeal cancer]. AB - There were analyzed results of treatment of 58 patients with laryngeal cancer T3 4N0-3M0. Chemoradiotherapy (CRT) was carried out in 27 patients, thermochemoradiotherapy (TCRT)-in 31 patients. Radiotherapy (RT) was performed in hyperfractionated mode (1 Gy + 1 Gy with an interval of 4-5 hours) 5 times a week to CTD 52-60 Gy with a 2-week break after CTD 30-40 Gy. Local hyperthermia (LHT) was carried out 2 times a week before the second fraction of RT in an amount of 3 6 sessions. The first cycle of polychemotherapy was administered at the beginning of RT and the second one-after the break. The local control under the primary tumor category T3 after CRT was equal to 58% and after TCRT--88%, at T4--72% and 25%, respectively. Late radiation damage of the larynx in the form of mucosal edema and perichondritis after CRT was in 2 patients (7%) and after TCRT--in 3 patients (10%). Thus, TCRT for locally advanced laryngeal cancer allows obtaining a higher overall survival and a local control as compared to CRT and does not lead to a significant increase of frequency of perichondritis. PMID- 25816666 TI - [Ultrasonography in the diagnosis and treatment for kidney cancer]. AB - In the structure of all malignant tumors cancer of the kidney takes more than 3%. Among malignancies of the urogenital system, kidney cancer inferiors by frequency just to cancer of the prostate and bladder. The incidence of kidney cancer ranges from 2.0 to 12.0 per 100,000 of the population. The degree of the local spread of tumor process as well as the presence of regional and distant metastases cause a different approach to treatment of these patients. PMID- 25816667 TI - [The distal resection margin in rectal cancer surgery]. AB - Spread of the tumor in the distal direction is an important factor that must be considered when performing organ-serving surgery for rectal cancer. Particular relevance it has acquired in recent years due to the general tendency to expand the indications for the preservation of natural reflex-apparatus in patients with medium- and lower-ampullar part of the rectum. PMID- 25816668 TI - [Morphological assessment of predictive factors in adenocarcinoma of the colon]. AB - Immunohistochemical investigation of 15 different markers in colon adenocarcinoma was carried out. Prognostic significance showed chemokine receptor CXCR4 and Ki 67. Predictive significance was revealed for thymidylate synthase (TS) and thymidine phosphorylase (TP). PMID- 25816669 TI - [Immunohistochemical prognostic factors of primary refractory Hodgkin's lymphoma]. AB - In order to identify immunohistochemical markers associated with primary refractory Hodgkin's lymphoma, 20 patients with primary refractory form at stage IIAB in complete remission underwent histological examination and immunohistochemical determination of Bcl-6, Bcl-2, c-kit (CD117), CD15, CD30, P 53, Ki-67. In the group with primary refractory Hodgkin's lymphoma at stage IIAB Bcl-6 expression was found in 2 patients (10%), Bcl-2 in 14 patients (70%), c-kit (CD117) in 16 patients (80%), CD15 in 9 patients (45%). The expression of CD30 and P-53 was observed in all patients in this group (100%). The expression of Ki 67 ranged from 20% to 100%, 80-100% in 16 patients (80%). As a result, multivariate analysis revealed no immunohistochemical markers of primary refractory Hodgkin's lymphoma. In univariate and multivariate analyzes in a group of primary refractory Hodgkin's lymphoma a high level P-53 expression (80-100%) was significantly associated with decreased overall survival. A 5-year overall survival in patients with Hodgkin's lymphoma with the expression level of P-53 < 80% was 78%, with the expression level of P-53 80-100%-22%. A 5-year overall survival of Hodgkin's lymphoma primary patients in complete remission significantly exceeded the rates of patients with primary refractory Hodgkin's lymphoma--100% vs. 52%. PMID- 25816670 TI - [Associating of polymorphism in the promoter regions of genes of metalloproteinase (MMP2, MMP3, MMP9) with options of the clinical course of breast cancer in Russian women]. AB - There were analyzed associating of functional polymorphism of the promoter regions of genes MMP2 C--1306T, MMP 9 C--1562 T, MMP3 5A--1171 6A in a group of healthy women and breast cancer patients in order to identify informative markers associated with the risk of developing the disease. The study included 395 DNA samples from women with breast cancer and 329 healthy women. Genotyping of polymorphisms was carried out by restriction analysis of amplification products (RFLP-analysis). Among female patients there was revealed significantly seldom a carrier of 6A6A MMP3-1117 and MMP 9-1562TT genotypes and also significantly increased the frequency of MMP3 5A6A genotype. The risk of lymph node metastasis reduced in patients with MMP9-1562CC genotype. Conversely heterozygosis at this position could be regarded as risk factor for metastasis. It was revealed associating of MMP3 5A6A genotype with the degree of malignancy. PMID- 25816671 TI - [Spontaneous tumors in the Campbell hamster: a possible new model of experimental oncology]. AB - The spectrum of spontaneous tumors in the Campbell hamsters has not been described yet. 152 Campbell hamsters (110 females and 42 males), spontaneously died by ordinary death, underwent the necropsy and the histopathological examination. Tumors were found in 50% of males and in 48% of females dead after the achievement of the first tumor development age (430 and 260 days respectively). The main type of tumors in Campbell hamsters was thymoma of B1 type which is known in human, but unusual in laboratory animals. The thymomas had low grade of malignancy, did not induce the wasting syndrome and did not metastasize. It is probable that thymoma B1 kills the animals by the dislocation of mediastinal organs. Frequency of this tumor was 40% in males and 40% in females dead after the achievement of the first tumor development age. Any sex differences were not found although males dead with thymoma had significantly more evident reproductive success in comparison with animals without this tumor. Besides, thymomas, squamous carcinomas of forestomach (in males and females), skin carcinomas (in males and females), adenocarcinomas of reproductive system, kidney and lung (in females only) and small-cell lymphomas (in males only) were found. Hence, spontaneous tumors in Campbell hamsters could be useful as a model for research in the experimental oncology, especially as unique model of human thymoma of B1 type which has not been observed in laboratory mice and rats yet. PMID- 25816672 TI - [A case of successful use of triple approach in a kidney cancer patient with metastatic lesion to the lung and pleural cavity]. AB - Metastasis to the lung is the most common place connected with kidney cancer progression. Wherein metastasectomy is accompanied by satisfactory 5- and 10-year survival achieving 49% and 21% respectively. Pleural lesion due to this tumor develops as a part of systemic metastasis and, as a rule, is a consequence of neoplastic spread from lung parenchyma, which indicates a poor prognosis and is an indication for palliative care. PMID- 25816673 TI - [Communication skills in oncologist's work]. AB - During the process of own professional activities any oncologist has to interact with a patient who experiences severe psycho-emotional stress, accompanied by painful sufferings. Successful communication between a doctor and a patient influences on patient's attitude to treatment. An oncologist should be able to possess professional communication skills, which allow interacting more effectively with patients. Among communication skills the authors consider the following items: presence, empathy, sharing of feelings, active listening, marking the temporal and spatial boundaries. PMID- 25816675 TI - [Ebola virus disease: clinical and diagnostic aspects and organization of treatment-and-prophylactic measures]. AB - The article presents data about world spread of Ebola virus disease, biological characteristics of the pathogen, the laws of the epidemic process in this disease, its pathogenesis, clinical manifestations and diagnosis. Pointed out that the current anti-viral agents, effective for the Ebola virus, have not been developed. Timely performed pathogenetic therapy improves the prognosis of the disease. The basis of this therapy is infusion-detoxification activities and replenishment of losses, of electrolytes, as well as anti-inflammatory and anti emetic drugs. The Armed Forces of the Russian Federation received the guidelines for preventive measure that can reduce Ebola virus disease transmission. Recommendations for emergency anti-epidemic commission consisted of representatives of the command, specialists and medical services and logistics, are given. Fundamentally important condition for the effective anti-epidemic measures is not only the constant readiness of medical personnel in the detection of disease EVD, but also the appropriate level of equipment of medical institutions of medical supplies and equipment. PMID- 25816674 TI - [In memory of A.O. Vereshchinskii--a great colleague with a tragic fate at the N. N. Petrov Oncology Research Institute--at the 120th anniversary of his birth]. AB - The most tragic for the history of any community is a loss of memory or its distortion. Unfortunately we often forget that we grow on the shoulders of previous generations, on their achievements and mistakes. In this regard it would be good to remember our friend, colleague A.O.Vereshchynsky who would have been 120 this year. PMID- 25816677 TI - [The basic directions and experience of use of telemedical technologies in military-medical service]. AB - The authors showed that a promising solution for emergency telemedicine advisory assistance issues in the Armed Forces of the Russian Federation is the implementation of technical opportunity of direct advisory support to any functional unit and specialists from main and central military hospitals. But at the present stage, the current task of the military telemedicine should be regarded as the implementation of several advisory centres focused on the implementation of a separate topic of telemedicine cooperation. In this regard, a complex of activities carried out by establishing a network of tele-consulting centres at the Kirov Military Medical Academy in one of the admission departments, in the department of military surgery and in the hall of the Academic Council of the Academy. PMID- 25816676 TI - [The role of cooperation between the command and district medical service in prophylaxis of acute respiratory diseases]. AB - The problem of increased incidence of respiratory diseases in troops is significant due to reorganization of military staff and redeployment of military units, which led to the deterioration of the terms of accommodation and living conditions of personnel. Significant contribution to the growth of this disease has brought an increase in the number of young recruits after the transition to a one-year compulsory military service, as well as reducing the number of doctors in the military echelon. In the Central Military District has developed a unified system of sanitary and anti-epidemic and preventive measures, an understanding commanders associations, military units and formations of the order and timing of their implementation, establish a uniform procedure for reporting on the sanitary and epidemiological situation in the garrisons as in operational duty, and on medical service. All this allows us time to carry out or correct preventive measures, to achieve a positive result of work on the health of military personnel. Due to the close interaction between the command and the medical service in the district after 2012 reduced the number of cases with respiratory diseases. PMID- 25816678 TI - [Modern approaches to the formation of antidote stocks at medical institutions in Russia and foreign countries]. AB - This article analyses the approaches to the formation of specific treatment of acute poisoning in the various countries. The authors present a systematic review of scientific publications about the formation of reserves of antidote agents at medical institutions of the Russian Federation, the US, Canada, France, Spain, Greece, Norway, Czech Republic, Taiwan and Poland. A search for a variety of databases, as well as by reviewing reference lists of publications on the subject of "stockpiling antidote means". It is concluded that the antidote provision at health care institutions in different countries is insufficient. State of affairs with the formation of antidote stocks is better at hospitals of Czech Republic, France and Spain. To determine the range and volume of the stock of fixed assets necessary antidote coordination and approval of the list and the number of mandatory for every medical institution antidotes. PMID- 25816679 TI - [The use of new sets and medical kits by the medical service of the Armed Forces]. AB - Taken to supply in the Armed Forces of the Russian Federation and included in the modern regulating documents new sets and medical kits are a crucial element of the complete-standard-issue equipment. For the military unit of medical service provided 12 sets and medical kits united into 2 classification groups. They allow medical service to perform any surgical interventions and medical procedures in the military echelon in accordance with modern approaches to health care and treatment of the wounded in wartime, in armed conflict and the elimination of the health consequences of emergencies in peacetime. PMID- 25816680 TI - [Clinical diagnostic and organizational aspects of providing care to patients with pulmonary sarcoidosis in the Armed Forces]. AB - The data on the epidemiology and aetiology of sarcoidosis, the current classifications are presented. The basic provisions of the legal framework of medical management of patients suffering from sarcoidosis are given. The authors provided an analysis of the characteristics of diagnosis and treatment of sarcoidosis in the military, based on which we propose an algorithm of examination of patients with respiratory sarcoidosis in military health care facilities the Russian Defence Ministry, the recommended treatment regimens and order dynamic observation of patients. Invited to provide skilled care to patients with respiratory sarcoidosis selection based on the Main Military Clinical Burdenko Hospital specialized centre (department with bunks for the treatment of patients with sarcoidosis). PMID- 25816681 TI - [Innovative methods of ventricular arrhythmia treatment]. AB - The authors summarized the experience of the use of the stimulus and the activation mapping under fluoroscopic control to search for sources of ventricular ectopic followed by radio-frequency effects on the vulnerable zone arrhythmias. The authors presented an algorithm for finding a pathological focus on the basis of an evaluation of the surface electrocardiogram, followed by sequential endocardial mapping. The results of radiofrequency ablation of ventricular arrhythmia in different localization of the source are presented. The authors generalized and systematized the experience detection and cure of ventricular ectopy in 65 patients. The regularities of changes in the ventricular complex according to surface electrocardiogram in certain localizations of ectopic focus are revealed. Effectiveness of the operation of radiofrequency ablation with ventricular arrhythmias was about 90%, which is generally consistent with data from other clinics. Complications requiring additional interventions were not. Highlight the work areas of the endocardium, analysed the causes of inefficient operations and poor results. Alternative methods of destruction of the endocardium in complex localization of ectopic focus are suggested. PMID- 25816683 TI - [Prospective methods of combat burn injury treatment]. AB - The current article briefly reviews the projects of development of combat burn injury treatment as they have been presented in the US Armed Forces Institute of Regenerative Medicine 2013 annual report. Eleven projects have been reviewed, in particular: P12 polypeptide for limiting burn injury progression, gamma keratose gelfor enhancement skin cell survival, starch-polyurethane iodophor dressing effective against the most common burn infection, microorganisms, autologous stem and progenitor cells for single cell cytotransplantation by "skin gun" spray device or 3D skin bioprinting, a bioreactor for skin autotransplant expansion. PMID- 25816682 TI - [Opportunities for diagnosis and treatment of nocturnal hypoxia in outpatient clinic]. AB - Sleep disordered breathing is an important medical and socio-economic issue. A lot of evidence exists for the impact of sleep apnea on the pathogenesis of cardiovascular diseases, occupational injuries, as well as all-cause mortality. Detection of this type of pathology is challenging due to the complexity and high cost of the procedures. The nocturnal polysomnography was considered as a "gold standard" in the management of any sleep disorders for a long time. However, the development of technology simplified diagnostic equipment and make it possible to diagnose sleep disordered breathing in outpatient department. In this article we reviewed 3-phase approach to the diagnosis and treatment of sleep apnea. Also we describe our own cost-effective experience of implementing of screening examination for sleep apnea in outpatient clinic, using the continuous pulse oximetry monitoring. PMID- 25816684 TI - [Nikolai Illarionovich Kozlov--a scientist, a doctor, an outstanding organizer of Military Medicine (To the 200th anniversary of the birth)]. AB - To Kozlov N.I. (1814-1889) belong numerous achievements in the organization of military medical unit during the Crimean (1853-1856) and the Russian-Turkish (1877-1878) wars, the introduction of women's medical education in Russia, establishment of an improvement system for the military doctors, edition for their medical guidelines, the organization of military health care in Russia. PMID- 25816685 TI - [Shestov V I--the founder of the Department of Organisation and tactics of the naval medical services]. AB - Vasilii Ivanovich Shestov during the Great Patriotic War performed various tasks concerning the organization of medical support in the Leningrad naval base, consulted on an issue of production and use of hospital and medical transport ships, worked on the organization of medical support in Schliessburg and etc. Shestov performed a considerable amount of research and methodological works concerning the establishment of the discipline "Organisation of naval medical support". He is considered as one of the founders of the theory of naval medical evacuation support. PMID- 25816686 TI - [New in the biography of a military doctor A. G. Peredelsky]. AB - The history of activity of the Orenburg department of the Kazan society of adherents of military and sanitary knowledge is shown in article. The department existed in 1912-1914 and united officers and medical officers of the Orenburg garrison and military educational institutions. Members of Department tried to resolve the vital issues of a sanitary condition of Totsky military camp, regiments of the Orenburg military of the garrison. The department managed to publish two releases of the works. On these materials we can judge its activity. In article new data from A.G.Peredelsky's biography (1876-1940) in the period of his life in Orenburg are reported. PMID- 25816688 TI - The influence of two reciprocating single-file and two rotary-file systems on the apical extrusion of debris and its biological relationship with symptomatic apical periodontitis. A systematic review and meta-analysis. AB - This systematic review and meta-analysis investigated the influence of the number of files (full-sequence rotary-file versus reciprocating single-file systems) used during root canal preparation on the apical extrusion of debris and its biological relationship with the occurrence of symptomatic apical periodontitis. An extensive literature research was carried out in the Medline, ISI Web of Science and Cochrane databases, for relevant articles with the keyword search strategy. Based on inclusion and exclusion criteria, two reviewers independently rated the quality of each study determining the level of evidence of the articles selected. The primary outcome for the meta-analysis was determined by the amount of debris extruded into the periapical tissue during root canal preparation with multiple- or single-file systems in four laboratory studies. Analysis of in vivo release of neuropeptides (SP and CGRP) after root canal preparation with single- or multiple-file systems was also carried out. Amongst the 128 articles initially found, 113 were excluded for being nonrelevant or not fulfilling the selection criteria. Another four articles were excluded after methodology evaluation. Finally, nine laboratory studies and two in vivo studies were included in the systematic review. Four of the laboratory studies were further included for meta analysis that revealed greater debris extrusion after the use of single-file techniques when compared to multiple-file systems. Analysis of in vivo neuropeptide expression in the periodontal ligament suggests that the design of the instrument is more important than the number of files used. Both rotary and reciprocating single-file systems generate apical extrusion of debris in laboratory studies, or expression of neuropeptides in vivo. Available evidence is limited, but supports the fact that this inflammatory reaction is not influenced by the number of files but the type of movement and the instrument design. PMID- 25816687 TI - Taurine Chloramine Stimulates Efferocytosis Through Upregulation of Nrf2-Mediated Heme Oxygenase-1 Expression in Murine Macrophages: Possible Involvement of Carbon Monoxide. AB - AIMS: To examine the pro-resolving effects of taurine chloramine (TauCl). RESULTS: TauCl injected into the peritoneum of mice enhanced the resolution of zymosan A-induced peritonitis. Furthermore, when the macrophages obtained from peritoneal exudates were treated with TauCl, their efferocytic ability was elevated. In the murine macrophage-like RAW264.7 cells exposed to TauCl, the proportion of macrophages engulfing the apoptotic neutrophils was also increased. In these macrophages treated with TauCl, expression of heme oxygenase-1 (HO-1) was elevated along with increased nuclear translocation of the nuclear factor E2 related factor 2 (Nrf2). TauCl binds directly to Kelch-like ECH association protein 1 (Keap1), which appears to retard the Keap1-driven degradation of Nrf2. This results in stabilization and enhanced nuclear translocation of Nrf2 and upregulation of HO-1 expression. TauCl, when treated to peritoneal macrophages isolated from either Nrf2 or HO-1 wild-type mice, stimulated efferocytosis (phagocytic engulfment of apoptotic neutrophils by macrophages), but not in the macrophages from Nrf2 or HO-1 knockout mice. Furthermore, transcriptional expression of some scavenger receptors recognizing the phosphatidylserines exposed on the surface of apoptotic cells was increased in RAW264.7 cells treated with TauCl. Pharmacologic inhibition of HO-1 activity or knockdown of HO-1 gene in RAW264.7 cells abolished the TauCl-induced efferocytosis, whereas both overexpression of HO-1 and treatment with carbon monoxide (CO), the product of HO, potentiated the efferocytic activity of macrophages. INNOVATION: This work provides the first evidence that TauCl stimulates efferocytosis by macrophages. The results of this study suggest the therapeutic potential of TauCl in the management of inflammatory disorders. CONCLUSION: TauCl can facilitate resolution of inflammation by increasing the efferocytic activity of macrophages through Nrf2-mediated HO-1 upregulation and subsequent production of CO. PMID- 25816689 TI - Simple gene silencing using the trans-acting siRNA pathway. AB - In plants, particular micro-RNAs (miRNAs) induce the production of a class of small interfering RNAs (siRNA) called trans-acting siRNA (ta-siRNA) that lead to gene silencing. A single miRNA target is sufficient for the production of ta siRNAs, which target can be incorporated into a vector to induce the production of siRNAs, and ultimately gene silencing. The term miRNA-induced gene silencing (MIGS) has been used to describe such vector systems in Arabidopsis. Several ta siRNA loci have been identified in soybean, but, prior to this work, few of the inducing miRNAs have been experimentally validated, much less used to silence genes. Nine ta-siRNA loci and their respective miRNA targets were identified, and the abundance of the inducing miRNAs varies dramatically in different tissues. The miRNA targets were experimentally verified by silencing a transgenic GFP gene and two endogenous genes in hairy roots and transgenic plants. Small RNAs were produced in patterns consistent with the utilization of the ta-siRNA pathway. A side-by-side experiment demonstrated that MIGS is as effective at inducing gene silencing as traditional hairpin vectors in soybean hairy roots. Soybean plants transformed with MIGS vectors produced siRNAs and silencing was observed in the T1 generation. These results complement previous reports in Arabidopsis by demonstrating that MIGS is an efficient way to produce siRNAs and induce gene silencing in other species, as shown with soybean. The miRNA targets identified here are simple to incorporate into silencing vectors and offer an effective and efficient alternative to other gene silencing strategies. PMID- 25816690 TI - Referral patterns for oral squamous cell carcinoma in Australia: 20 years progress. AB - BACKGROUND: The aim of this study was to identify changes in referral patterns and delays in diagnosis and treatment of oral squamous cell carcinoma (OSCC), managed at a tertiary institution in Victoria, Australia. METHODS: The hospital records of all patients with newly diagnosed OSCC, managed by The Royal Melbourne Hospital (RMH) Head and Neck Tumour Stream between January 2008 and December 2010, were retrospectively reviewed. RESULTS: Of the 101 patients, 52% first sought help from general medical practitioners (GMP) while 43% initially attended a general dental practitioner (GDP). The most common site of OSCC was oral tongue (42%). The most common presentation was ulceration (31%). Seventy per cent of patients presented with T1 (39%) or T2 (31%) tumours. The diagnostic delay ranged from 0 to 8 years with an average of 4.5 months. Patient delay ranged from 0 to 1.4 years with an average of 1.8 months. Professional delay ranged from 0 to 8 years with an average of 2 months. CONCLUSIONS: Delays in patients seeking advice have decreased compared to previous studies, while delays in professionals making a diagnosis have not improved considerably. There has been a significant shift towards initial presentation to GMP rather than GDP. Further decrease in delays is possible by improving both population awareness and clinician education. PMID- 25816691 TI - Comparative accessory gene fingerprinting of surface water Escherichia coli reveals genetically diverse naturalized population. AB - AIMS: To utilize comparative accessory gene fingerprinting to discriminate between naturalized and faecal Escherichia coli, with particular emphasis on strains from phylogroup B1. METHODS AND RESULTS: Fourteen accessory genes that were potentially ecotype-specific were selected on the basis of comparative genomic DNA sequence analysis between faecal and environmental strains and also using a literature-based strategy. PCR assays were designed for each gene, and used to screen 107 faecal strains from various hosts and 106 environmental strains from surface water and sediment. While none of the 14 accessory genes were ecotype-specific, six of the genes were ecotype-enriched. Specifically, toxin-antitoxin system genes were more abundant among faecal strains, whereas genes involved in iron acquisition, complement resistance/surface exclusion, and biofilm formation were more abundant among environmental strains. These six genes were used to form composite fingerprints which revealed the presence of several ecotype-specific and -enriched fingerprints. Notably, some of the environmental strain-specific or -enriched fingerprints consisted of strains putatively belonging to clade ET-1, which has been previously recognized as a naturalized subpopulation. CONCLUSIONS: Unlike single genes which did not reliably distinguish between faecal and naturalized phylogroup B1 E. coli strains, composite fingerprints of ecotype-enriched accessory genes may offer a novel method for distinguishing between these two populations. SIGNIFICANCE AND IMPACT OF THE STUDY: Accessory gene fingerprinting may have important practical implications for improving the specificity of methods that are widely used for quantifying and identifying the sources of faecal contamination in surface water. PMID- 25816692 TI - Disinfection of reusable elastomeric respirators by health care workers: a feasibility study and development of standard operating procedures. AB - BACKGROUND: This was a feasibility study in a Department of Veterans Affairs Medical Center to develop a standard operating procedure (SOP) to be used by health care workers to disinfect reusable elastomeric respirators under pandemic conditions. Registered and licensed practical nurses, nurse practitioners, aides, clinical technicians, and physicians took part in the study. METHODS: Health care worker volunteers were provided with manufacturers' cleaning and disinfection instructions and all necessary supplies. They were observed and filmed. SOPs were developed, based on these observations, and tested on naive volunteer health care workers. Error rates using manufacturers' instructions and SOPs were compared. RESULTS: When using respirator manufacturers' cleaning and disinfection instructions, without specific training or supervision, all subjects made multiple errors. When using the SOPs developed in the study, without specific training or guidance, naive health care workers disinfected respirators with zero errors. CONCLUSION: Reusable facial protective equipment may be disinfected by health care workers with minimal training using SOPs. PMID- 25816693 TI - Journal metrics and other measures. PMID- 25816694 TI - Retroperitoneal Robot-Assisted Partial Nephrectomy for Posterior Renal Masses Is Associated with Earlier Hospital Discharge: A Single-Institution Retrospective Comparison. AB - PURPOSE: To compare perioperative outcomes, specifically hospital length of stay (LOS), after retroperitoneal and conventional transperitoneal robot-assisted partial nephrectomy (RAPN). PATIENTS AND METHODS: We retrospectively compared consecutive patients with a posterior renal mass undergoing retroperitoneal RAPN (n=116) versus transperitoneal RAPN (n=97) at our institution between July 2007 and March 2014. The surgical approach was based on patient and tumor characteristics, history of abdominal surgery, and surgeon preference. The primary outcome was postoperative LOS, and secondary outcomes included complication rate, inpatient narcotic pain medication use, and inpatient antiemetic use. RESULTS: Baseline patient and tumor characteristics were similar between groups. A significantly great proportion of patients undergoing retroperitoneal RAPN had LOS equal to 1 day (57% vs 10%, P<0.01). Complication rates were similar between groups (P=0.37). Median pain medication use was also similar between groups (P=0.85). A significantly greater proportion of retroperitoneal RAPN patients, however, needed no antiemetics postoperatively (59% vs 43%, P=0.02). On multivariate analysis, transperitoneal RAPN was a significant predictor of LOS greater than 1 day (odds ratio=7.4, P<0.01), when controlling for age, sex, body mass index, patient comorbidity, previous abdominal surgery, baseline kidney function, nephrometry score, and tumor size. CONCLUSIONS: For patients with posterior renal masses, retroperitoneal RAPN significantly reduces their hospital LOS when compared with transperitoneal RAPN. PMID- 25816696 TI - Nigel Gray MBBS, AO (1928-2014). PMID- 25816698 TI - Metformin and breast cancer: basic knowledge in clinical context. AB - Although preclinical work is vital in unraveling the molecular tenets which apply to metformin action in breast cancer, it is by nature unable to capture the host's response to metformin in terms of insulin-mediated effects and related changes in the hormonal and metabolic asset at the systemic level. The latter might sound seemingly paradoxical when considering the inveterate use of metformin in dysmetabolisms and pathologic conditions with underlying hormonal disruption. Bridging the gap between the molecular target and characteristics of breast cancer patients may help lab-based experiments and clinical work converge into one or more well characterized sub-populations instead of a sub optimally selected one. An appropriate patient selection is the main key to the most suitable outcome interpretation and amelioration, in an attempt to meet our patients needs midway between overestimation of benefits and efficacy dilution for any given intervention and/or co-intervention. PMID- 25816700 TI - Stringent adherence to a cytomegalovirus-prevention protocol is associated with reduced overall costs in the first 6 months after kidney transplantation. AB - BACKGROUND: We previously documented that a stringent implementation of a preemptive cytomegalovirus (CMV) prevention protocol reduced the number of CMV disease episodes after kidney transplantation, when compared with a routine preemptive protocol. The impact on overall costs was assessed. METHODS: Cost comparisons were made for inpatient and outpatient costs and overall costs, using costs provided by the financial department. Variables were analyzed using the Wilcoxon rank-sum test. A multivariable global linear model evaluated the effect of all co-variables on cost differences. In Cohort 1 (n = 84), 74% were followed with a standard CMV preemptive protocol, and 26% received prophylaxis. In Cohort 2 (n = 74), an intensified CMV surveillance protocol was applied in 74% of patients, and 26% were given prophylaxis. RESULTS: Overall, Cohort 1 had significantly higher treatment costs as compared with Cohort 2 (mean Swiss francs [CHF] 104,548 and CHF 76,983, respectively, P = 0.0005). Excluding patients who received prophylaxis reduced these costs to CHF 89,318 in Cohort 1 and CHF 73,652 in Cohort 2. Outcome between Cohort 1 and 2 was comparable. CONCLUSION: A stringent adherence to the CMV prevention protocol was associated with a significant reduction in overall costs. Whether this benefit is because of the demonstrated reduction in the rate of CMV disease needs to be assessed in a randomized trial. PMID- 25816699 TI - Sex-specific predictors of hearing-aid use in older persons: The age, gene/environment susceptibility - Reykjavik study. AB - OBJECTIVE: We estimate the prevalence of hearing-aid use in Iceland and identify sex-specific factors associated with use. DESIGN: Population-based cohort study. STUDY SAMPLE: A total of 5172 age, gene/environment susceptibility - Reykjavik study (AGES-RS) participants, aged 67 to 96 years (mean age 76.5 years), who completed air-conduction and pure-tone audiometry. RESULTS: Hearing-aid use was reported by 23.0% of men and 15.9% of women in the cohort, although among participants with at least moderate hearing loss in the better ear (pure-tone average [PTA] of thresholds at 0.5, 1, 2, and 4 kHz >= 35 dB hearing level [HL]) it was 49.9% and did not differ by sex. Self-reported hearing loss was the strongest predictor of hearing-aid use in men [OR: 2.68 (95% CI: 1.77, 4.08)] and women [OR: 3.07 (95% CI: 1.94, 4.86)], followed by hearing loss severity based on audiometry. Having diabetes or osteoarthritis were significant positive predictors of use in men, whereas greater physical activity and unimpaired cognitive status were important in women. CONCLUSIONS: Hearing-aid use was comparable in Icelandic men and women with moderate or greater hearing loss. Self recognition of hearing loss was the factor most predictive of hearing-aid use; other influential factors differed for men and women. PMID- 25816702 TI - Postpartum SMS reminders to women who have experienced gestational diabetes to test for Type 2 diabetes: the DIAMIND randomized trial. AB - AIMS: This parallel group randomized controlled trial assessed whether an SMS reminder system for women, after gestational diabetes, would increase their attendance for an oral glucose tolerance test (OGTT) by six months postpartum. METHODS: Women were eligible for inclusion if they were diagnosed with gestational diabetes in their recent pregnancy, had a mobile phone and normal blood glucose profile prior to postnatal discharge from the Women's and Children's Hospital, Adelaide. A computer-generated random number sequence and telephone randomization were used. Two hundred and seventy-six women were randomized. Women in the six-week group (n = 140) were sent a text reminder to attend for an OGTT at six weeks postpartum, with further reminders at three and six months if required. Women in the control group (n = 136) received one text reminder at six months postpartum. Blinding was not feasible. The primary outcome was OGTT attendance within six months postpartum. RESULTS: Women in the six-week group did not increase their attendance for an OGTT within six months postpartum compared with women in the control group, 104 (77.6% of 134) versus 103 (76.8% of 134), relative risk (RR) 1.01, 95% confidence interval (CI) 0.89-1.15. CONCLUSIONS: The SMS reminder system did not increase postpartum OGTT, fasting plasma glucose or HbA1c completion, although high rates of test completion were measured in both groups. Further research is required into factors influencing attendance for postpartum testing from the perspective of women, and into optimal counselling relating to Type 2 diabetes risk in the postpartum period for increasing postpartum glucose testing rates. PMID- 25816701 TI - Prevalence of Regulatory T-Cell Subtypes in Preeclampsia. AB - PROBLEM: The prevalence of regulatory T cells (Tregs) is lower in preeclampsia (PE) compared with healthy pregnancy (HP). However, the proportion of recently described Treg subtypes has not been investigated. METHOD: Peripheral blood samples of 19 PE and 21 HP women in the third trimester were evaluated using flow cytometry for the prevalence of activated T cells and naive, effector, thymic, extrathymic, and exhausted Tregs. RESULTS: The prevalence of activated T cells and exhausted Tregs was higher in PE than in HP. The prevalence of the functionally most active effector Tregs is decreased, while naive Tregs appear to be unaffected in PE compared with HP. No difference was detected between Tregs according to their origin (thymic or extrathymic). CONCLUSION: The combination of lower effector Treg and higher exhausted Treg prevalence may account for the decrease in the functionality of Tregs in PE. PMID- 25816703 TI - A pseudoaneurysm of the corpus spongiosum from straddle injury: A rare cause of massive urethral bleeding only during erections. PMID- 25816704 TI - Peripartum pubic symphysis separation--Current strategies in diagnosis and therapy and presentation of two cases. AB - BACKGROUND: During spontaneous vaginal delivery, pubic symphyseal widening is normal. Common changes are reversible after complication-free birth. However, cases of peripartum symphysis separation are rare. There is no consensus in the literature on how to treat pregnancy-related pubic symphysis separation. METHODS: This review used a literature-based search (PubMed, 1900-2013) and analysis of 2 own case reports. Studies with conclusions regarding management were particularly considered. RESULTS: Characteristic symptoms, suprapubic pain and tenderness radiating to the posterior pelvic girdle or lower back, may be noted 48 h after delivery. Pain on movement, especially walking or climbing stairs, is often present. Conservative treatments, such as a pelvic brace with physiotherapy and local interventions such as infiltration, are successful in most cases. Symptom reduction within 6 weeks is the most common outcome, but can take up to 6 months in some cases. Surgical intervention is needed in cases of persistent separation. Anterior plate fixation is offered as a well-known and safe procedure. Minimally invasive SI joint screw fixation is required in cases of combined posterior pelvic girdle lesions. SUMMARY: Postpartum symphyseal rupture can be indicated with the rare occurrence of pelvic pain post-delivery, with sciatica or lumbago and decreased mobility. The diagnosis is made on clinical findings, as well as radiographs of the pelvic girdle. Conservative treatment with a pelvic brace is the gold standard in pre- and postpartum cases of symphysis dysfunction. PMID- 25816705 TI - What is the effect of the weather on trauma workload? A systematic review of the literature. AB - BACKGROUND: Hospital admission rates for a number of conditions have been linked to variations in the weather. It is well established that trauma workload displays significant seasonal variation. A reliable predictive model might enable targeting of high-risk groups for intervention and planning of hospital staff levels. To our knowledge there have been no systematic reviews of the literature on the relationship between weather and trauma workload, and predictive models have thus far been informed by the results of single studies. METHODS: We conducted a systematic review of bibliographic databases and reference lists up to June 2014 to identify primary research papers assessing the effect of specified weather conditions including temperature, rainfall, snow, fog, hail, humidity and wind speed on trauma workload, defined as admission to hospital, fracture or a Road Traffic Accident (RTA) resulting in a seriously injured casualty or fatality. RESULTS: 11,083 papers were found through electronic and reference search. 83 full papers were assessed for eligibility. 28 met inclusion criteria and were included in the final review; 6 of these related to the effect of the weather on trauma admissions, one to ambulance call out for trauma, 13 to fracture rate and 8 to RTAs. Increased temperature is positively correlated with trauma admissions. The rate of distal radius fractures is more sensitive to adverse weather than the rate of hip fractures. Paediatric trauma, both in respect of trauma admissions and fracture rate, is more sensitive to the weather than adult trauma. Adverse weather influences both RTA frequency and severity, but the nature of the relationship is dependent upon the timecourse of the weather event and the population studied. Important methodological differences between studies limit the value of the existing literature in building consensus for a generalisable predictive model. CONCLUSIONS: Weather conditions may have a substantial effect on trauma workload independent of the effects of seasonal variation; the population studied and timecourse of weather events appear critical in determining this relationship. Methodological differences between studies limit the validity of conclusions drawn from analysis of the literature, and we identify a number of areas that future research might address. PMID- 25816706 TI - Selective non-operative management of stab wounds to the posterior abdomen is safe: the Pietermaritzburg experience. AB - INTRODUCTION: The selective non-operative management (SNOM) of stab injuries of the anterior abdomen is well established, but its application to the posterior abdomen remains controversial. MATERIALS AND METHODS: A retrospective review of 1013 patients was undertaken at a major trauma service in South Africa over a five-year period. RESULTS: Ninety per cent of patients were males, and the mean age was 25 years. The mean time from injury to presentation was 4h and 73% of all injuries were inflicted by knives. A total of 9% (93) of patients required a laparotomy [Group A] and 82% (833) were successfully observed without the need for operative intervention [Group B]. CT imaging was performed on 52 patients (5%) who had haematuria [Group C], 25 (3%) who had neurological deficits [Group D], and 10 (1%) with retained weapon injuries [Group E]. The accuracy of physical examination for identifying the presence of organ injury was 88%. All observed patients who required laparotomy declared themselves within 24h. There were no mortalities as direct result of our current management protocol. CONCLUSIONS: Selective management based on active clinical observation and serial physical examination is safe, and when coupled with the judicious use of advanced imaging, is a prudent and reliable approach in a resource constrained environment. PMID- 25816707 TI - Femoral head reduction osteoplasty for fracture dislocation: A surgical technique. AB - BACKGROUND: Femoral head fractures with subchondral impaction and cartilage loss are difficult to treat successfully. Although multiple surgical management options have been described, no one technique has proven superior, particularly in the young high-demand population. TECHNIQUE: A femoral head reduction osteoplasty was performed following a surgical dislocation of the hip. A peripherally based wedge of bone was resected off the damaged central third of the head followed by reduction and fixation of the remaining fragments. This technique resulted in a smaller yet congruent femoral head. METHODS: A healthy 40 year old labourer sustained a traumatic crush injury while at work, resulting in a left femoral head fracture dislocation with an associated posterior wall acetabular fracture. Significant femoral head impaction and cartilage loss limited the treatment options. RESULTS: Intraoperative reduction and postoperative imaging demonstrated near anatomic reconstruction of femoral head with a congruent hip joint. Superiorly at the level of resection, the medial lateral diameter was reduced by 5-6mm (approximately 12-15% the diameter of the original head) by the osteoplasty. At five years, Harris Hip Score was 86, Oxford Hip Score 36, and UCLA score 89. Hip abductor strength was full, range of motion near normal, and the patient ambulated without antalgia. Radiographs demonstrate a congruent joint and patchy avascular necrosis without collapse. The patient maintained full employment as a labourer. CONCLUSIONS: Femoral head reduction osteoplasty is a viable option that may produce durable intermediate-term results for complex femoral head fracture with superior impaction and chondral damage. LEVEL OF EVIDENCE: Level V. PMID- 25816708 TI - How long should patients be kept non-weight bearing after ankle fracture fixation? A survey of OTA and AOFAS members. AB - BACKGROUND: Ankle fractures are common injuries treated routinely by orthopaedic surgeons. A variety of different post-operative protocols have been described with differing periods of non-weight bearing after surgery. The aim of this study was to identify how patient injury characteristics and medical comorbidities contribute to the period of non-weight bearing chosen by orthopaedic surgeons after open reduction and internal fixation of rotational ankle fractures. METHODS: A cross sectional expert opinion survey was administered to members of the AOFAS as well as OTA to determine how long they would instruct patients to be non-weight bearing after open reduction and internal fixation of ankle fractures. Three different injury characteristics were described: supination external rotation type 4 equivalents, bimalleolar, and trimalleolar patterns. These patterns were combined with three different medical statuses: young and healthy, older and healthy, and older with significant medical comorbidity. Respondents selected how long they would keep the patient non-weight bearing after surgery for each of the potential scenarios. Finally, they were directly asked which factors they felt affected their decision about length of time to keep patients non-weight bearing. RESULTS: Seven hundred and two surgeons (31%) responded to the survey. The average time of non-weight bearing selected varied from 4.9 (+/- 3.1) weeks for in young, healthy patients with SER4 equivalent injuries to 7.6 (+/- 6.0) weeks for older patients with medical comorbidities with trimalleolar fractures. Responses had a high degree of heterogeneity, but both injury pattern and medical status were significant predictors of non-weight bearing period (p<0.01), with medical status the stronger determinant. CONCLUSIONS: There is significant variation among orthopaedic surgeons when selecting period of non weight bearing after fixation of ankle fractures, with both injury pattern and medical comorbidity playing a role in decision of time to keep patient non-weight bearing. Further research further evaluating the relationship between these factors and safe periods of non-weight bearing could help identify patients that may benefit from earlier mobilization, and improve surgeon's comfort with early mobilization. LEVEL OF EVIDENCE: Therapeutic Level V. PMID- 25816709 TI - Multicentered patient-based evidence of the role of free light chain ratio normalization in multiple myeloma disease relapse. AB - INTRODUCTION: The normalization of free light chain ratio (FLCr) has been introduced as a marker of stringent complete remission (CR) of multiple myeloma (MM). There is currently a lack of literature assessing the role of FLCr on MM disease progression and remission status. PATIENTS AND METHODS: A multicentered retrospective review of 125 patients with MM in CR and various FLCr values was completed. Parameters of interest included patient demographics, FLCr values, complete remission (CR)/relapse status, and time to progression (TTP). The FLCr values were recorded to provide time-dependent findings on the role of FLCr on progression-free survival and overall survival (OS). RESULTS: The mean follow-up time of 125 patients from five hospitals in the Czech Republic was 31 months. A total of 47.2% of patients relapsed (54 of 125) during the follow-up period. The median TTP of patients with normal FLCr (n = 66) was 54.4 and 40.2 months for patients with abnormal FLCr (n = 59) (P = 0.217). None of the patients reached median overall survival regardless of FLCr values (P = 0.821). In the subgroup of newly diagnosed patients after upfront autologous stem cell transplantation (ASCT), there were 55.6% of patients (35 of 63) with normal FLCr and 44.4% (28 of 64) with abnormal FLCr. A total of 34.9% of patients (22 of 63) relapsed in this subgroup. Within the abnormal FLCr patients, a median TTP was 56.3 months, but no median TTP was reached among the normal FLCr patients (P = 0.746). Median OS in patients with normal (nFLCr) and abnormal FLCr (aFLCr) was not reached (P = 0.787). CONCLUSION: We did not observe any benefit from FLCr normalization in CR in myeloma patients in terms of progression-free survival or overall survival. PMID- 25816710 TI - Purification and Characterization of a Novel Hemagglutinin with Inhibitory Activity toward Osteocarcinoma Cells from Northeast China Black Beans. AB - In the present study, we isolated a novel hemagglutinin from an edible legume and explored its growth-inhibitory effect on osteocarcinoma and liver cancer cells. The protein was purified by liquid chromatography techniques which entailed affinity chromatography on Affi-gel blue gel, ion-exchange chromatography on Mono Q, and gel filtration on Superdex 75 with an FPLC system. The hemagglutinating activity of this hemagglutinin was demonstrated to be ion dependent and stable over a wide range of temperature and pH values. Antiproliferative activity was observed in the tumor cell lines MG-63 and HepG2 but not in the normal cell line WRL 68. Osteocarcinoma cells treated with the hemagglutinin underwent obvious cell shrinkage, chromatin condensation, mitochondrial membrane depolarization, and apoptosis. The mRNA expression level of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-1 beta (IL-1beta), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) were found to be up-regulated to different extents after treatment of this hemagglutinin. PMID- 25816711 TI - Focal hyperhidrosis secondary to eccrine naevus successfully treated with botulinum toxin type A. AB - Eccrine naevus (EN) is a rare skin hamartoma included in the organoid group of epidermal naevi, histologically defined as focal hyperplasia and/or hypertrophy of eccrine glands. Clinically, EN usually presents as hyperhidrotic patches with no visible skin changes, frequently located on the forearms. The decision to treat EN or not usually depends on the grade of hyperhidrosis, but there is no therapeutic consensus because of the rarity of this condition. We present a case diagnosed as EN in an adult patient with severe localized hyperhidrosis, which was successfully treated with botulinum toxin. PMID- 25816712 TI - Detecting initial orthostatic hypotension: a novel approach. AB - Our purpose, by modification of standard bedside tilt-testing, was to search for lesser known but important initial orthostatic hypotension (IOH), occurring transiently within the first 30 seconds of standing, heretofore only detectable with sophisticated continuous photoplethysmographic monitoring systems, not readily available in most medical facilities. In screened outpatients over 60 years of age, supine blood pressure (BP) parameters were recorded. To achieve readiness for immediate BP after standing, the cuff was re-inflated prior to standing, rather than after. Immediate, 1-, and 3-minute standing BPs were recorded. One hundred fifteen patients were studied (mean age, 71.1 years; 50.5% male). Eighteen (15.6%) had OH, of whom 14 (12.1%) had classical OH, and four (3.5%) had IOH. Early standing BP detection time was 20.1 +/- 5.3 seconds. Immediate transient physiologic systolic BP decline was detected in non-OH (-8.8 +/- 9.9 mm Hg; P < .0001). In contrast to classical OH (with lesser but persistent orthostatic BP decrements), IOH patients had immediate mean orthostatic systolic/diastolic BP change of -32.8 (+/-13.8) mm Hg/-14.0 (+/-8.5) mm Hg (P < .02), with recovery back to baseline by 1 minute. Two of the four IOH patients had pre-syncopal symptoms. For the first time, using standard inflation deflation BP equipment, immediate transient standing physiologic BP decrement and IOH were demonstrated. This preliminary study confirms proof of principle that manual BP cuff inflation prior to standing may be useful and practical in diagnosing IOH, and may stimulate direct comparative studies with continuous monitoring systems. PMID- 25816713 TI - Comparison of atenolol versus bisoprolol with noninvasive hemodynamic and pulse wave assessment. AB - We aimed to compare atenolol versus bisoprolol regarding general hemodynamics, central-peripheral blood pressure (BP), pulse wave parameters, and arterial stiffness. In this open-label, crossover study, we recruited 19 hypertensives, untreated or with stable monotherapy. Patients were randomized to receive atenolol (25-50 mg) or bisoprolol (2.5-5 mg), and then switched medications after 4 weeks. Studies were performed at baseline and after each drug period. In pulse wave analyses, both drugs significantly increased augmentation index (P < .01) and ejection duration (P < .02), and reduced heart rate (P < .001), brachial systolic BP (P <= .01), brachial diastolic BP (P <= .001), and central diastolic BP (P <= .001), but not central systolic BP (P >= .06). Impedance cardiographic assessment showed a significantly increased stroke volume (P <= .02). There were no significant differences in the effects between drugs. In conclusion, atenolol and bisoprolol show similar hemodynamic characteristics. Failure to decrease central systolic BP results from bradycardia with increased stroke volume and an earlier reflected aortic wave. PMID- 25816714 TI - A pilot study comparison of a new method for aortic pulse wave velocity measurements using transthoracic bioimpedance and thigh cuff oscillometry with the standard tonometric method. AB - Aortic pulse wave velocity (aPWV) can be measured with different methodologies, including applanation tonometry. These pilot study findings suggest that impedance cardiography combined with thigh oscillometry provides comparable results. Intra- and inter-observer variability was tested by two observers in two subjects. We instrumented 41 patients and 12 healthy normotensive controls for impedance cardiography and consecutive applanation tonometry and compared methods using the Bland-Altman method. Observer variability for the impedance-thigh cuff method (range, 3.61%-7.77%) was comparable with the tonometric method (range, 2.93%-7.37%). Comparison of the two methods based on the Bland-Altman plot revealed a good agreement between methods. The bias between impedance and tonometric measurements was -0.28 +/- 0.37 m/s. Both measurements were significantly correlated (r(2) = 0.94; P < .0001; slope = 1.038).Impedance cardiography combined with thigh oscillometry is an easy to use approach which, in addition to providing hemodynamic information, yields aPWV measurements comparable to applanation tonometry. Following full validation according to current guidelines, the methodology could prove useful in cardiovascular risk stratification. PMID- 25816715 TI - The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase-2 Up-Regulation in Renovascular Hypertension. AB - Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-kB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1C vehicle. PDTC exerted antihypertensive effects after 2 weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension. PMID- 25816716 TI - What role for cities in food policy? PMID- 25816717 TI - Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. AB - Congenital dysfibrinogenemia is a qualitative congenital fibrinogen disorder characterized by normal antigen levels of a dysfunctional fibrinogen. The diagnosis is usually based on discrepancies between fibrinogen activity and antigen levels, but could require more specialized techniques for the assessment of fibrinogen function, owing to some limitations in routine assays. Molecular abnormalities, which are frequently heterozygous missense mutations localized in exon 2 of FGA and exon 8 of FGG, lead to defects in one or more phases of fibrinogen to fibrin conversion, fibrin network formation, and other important functions of fibrinogen. The clinical phenotype is highly heterogeneous, from no manifestations to bleeding and/or thrombotic events. Asymptomatic propositi and relatives with the predisposing genotype are at risk of developing adverse outcomes during the natural course of the disease. Correlations between genotype and phenotype have not yet been clearly established, with the exception of some abnormal fibrinogens that severely increase the risk of thrombosis. Functional analysis of polymerization and fibrinolysis, structural studies of the fibrin network and the viscoelastic properties of fibrin clot could help to predict the phenotype of congenital dysfibrinogenemia, but have not yet been evaluated in detail. The management is essentially based on personal and family history; however, even individuals who are still asymptomatic and without a family history should be carefully assessed and monitored. Particular situations, such as pregnancy, delivery, and surgery, require a multidisciplinary approach. PMID- 25816718 TI - Early feeding after total laryngectomy results in shorter hospital stay without increased risk of complications: a retrospective case-control study. AB - OBJECTIVES: To evaluate the effects of a reduced nil per os (NPO) period after total laryngectomy (TLE) on general and wound-related post-operative complications, swallowing function and duration of hospital stay. DESIGN, SETTING AND PARTICIPANTS: In a retrospective case-control study in 71 patients after TLE with primary closure (i e. without reconstruction with tissue transfer), complications and hospitalisation in 36 patients who started oral feeding on days 3-5 (early feeding) were compared with 30 patients who started oral feeding on days 7-10 (late feeding). MAIN OUTCOME MEASURES: Incidence of complications, swallowing function and duration of hospitalisation. RESULTS: There were no significant differences between the early- and late-feeding groups in the occurrence of pharyngocutaneous fistulae, neopharyngeal stenosis or wound complications in general. Swallowing function was comparable for both groups. Mean overall hospitalisation was 2 days shorter in the early-feeding group (mean: 17.4 days) as compared to the late-feeding group (mean: 19.4 days) (P < 0.05). CONCLUSIONS: Early feeding after TLE without flap reconstruction did not contribute to an increase in complications and led to a shorter hospital stay. PMID- 25816719 TI - How many Epley manoeuvres are required to treat benign paroxysmal positional vertigo? AB - OBJECTIVE: To evaluate the total number of Epley manoeuvres required to provide symptomatic relief to patients newly diagnosed with benign paroxysmal positional vertigo. METHODS: This retrospective audit assessed every patient referred to the audiology department for investigations of their symptoms over a period of one year. Only patients diagnosed with benign paroxysmal positional vertigo confirmed via a positive Dix-Hallpike test result, with no suggestion of dual pathology, were included. RESULTS: Seventy patients with a positive Dix-Hallpike test result were identified. The total number of Epley manoeuvres required ranged from one to five. Thirty-three patients (47 per cent) were asymptomatic following one Epley manoeuvre. Eleven patients (16 per cent) needed 2 manoeuvres and 15 patients (21 per cent) required 3 manoeuvres for symptomatic control. CONCLUSION: Symptomatic control of benign paroxysmal positional vertigo was obtained following a single Epley manoeuvre for 47 per cent of patients. The majority of patients (84 per cent) experienced symptomatic improvement following three Epley manoeuvres. PMID- 25816720 TI - Genotype Correlations With Blood Pressure and Efficacy From a Randomized Phase III Trial of Second-Line Axitinib Versus Sorafenib in Metastatic Renal Cell Carcinoma. AB - BACKGROUND: In the phase III axitinib second-line (AXIS) trial, axitinib significantly prolonged progression-free survival (PFS) versus sorafenib in patients with previously treated metastatic renal cell carcinoma (mRCC). Analyses of associations between germline single-nucleotide polymorphisms (SNPs) and outcomes are reported. PATIENTS AND METHODS: DNA samples from blood were genotyped using TaqMan allelic discrimination. Logistic/Cox regression analyses were used to evaluate association of 15 SNPs in vascular endothelial growth factor (VEGF)-A, VEGF receptor (VEGFR)1, VEGFR2, or hypoxia-inducible factor (HIF)-1alpha with outcomes for blood pressure (BP; Grade >= 3 hypertension, diastolic BP > 90 mm Hg, and increase >= 15 mm Hg from baseline) and efficacy (independent review committee-assessed objective response rate and PFS, and overall survival [OS]). Multivariate analyses assessed SNPs and baseline characteristics as potential predictors of PFS and OS. RESULTS: Genotype data were available for 305 (42.7%) of 714 patients; 159 received axitinib and 146 sorafenib. After Bonferroni adjustment, no SNP was associated with BP outcomes. In axitinib-treated patients, VEGF-A rs699947 (A/A vs. C/C) and rs833061 (C/C vs. T/T) were associated with longer OS (27.0 vs. 13.4 months; hazard ratio [HR], 0.39; Padjusted = .015). In sorafenib-treated patients, VEGFR2 rs2071559 (G/G vs. A/A) was associated with longer OS (26.8 vs. 13.8 months; HR, 0.41; Padjusted = .030). In multivariate analyses, no SNP predicted axitinib efficacy; VEGFR2 rs2071559 predicted PFS (P = .0053) and OS (P = .0027) for sorafenib. Sensitivity/specificity of VEGFR2 rs2071559 for OS was < 80%. CONCLUSION: No SNP predicted axitinib outcomes. Although VEGFR2 rs2071559 predicted sorafenib efficacy in patients with mRCC, sensitivity/specificity limitations preclude its use for selecting individual patients for sorafenib treatment. PMID- 25816721 TI - A novel mechanism for improvement of dry skin by dietary milk phospholipids: Effect on epidermal covalently bound ceramides and skin inflammation in hairless mice. AB - BACKGROUND: Dietary milk phospholipids (MPLs) increase hydration of the stratum corneum and reduced transepidermal water loss (TEWL) in hairless mice fed a standard diet. However, the mechanism by which MPLs improve skin barrier functions has yet to be established. OBJECTIVE: This study was designed to examine the mechanism by which MPLs may affect covalently bound ceramides and markers of skin inflammation and improve the skin barrier defect in hairless mice fed a magnesium-deficient (HR-AD) diet. METHODS: Four-week-old female hairless mice were randomized into four groups (n=10/group), and fed a standard (control) diet, the HR-AD diet, the HR-AD diet supplemented with either 7.0 g/kg MPLs (low [L]-MPL) or 41.0 g/kg MPLs (high [H]-MPL). RESULTS: Dietary MPLs improved the dry skin condition of hairless mice fed the HR-AD diet. MPLs significantly increased the percentage of covalently bound omega-hydroxy ceramides in the epidermis, and significantly decreased both thymus and activation-regulated chemokine (TARC) mRNA and thymic stromal lymphopoietin (TSLP) mRNA levels in skin, compared with the HR-AD diet. Furthermore, the MPL diets significantly decreased serum concentrations of immunoglobulin-E, TARC, TSLP, and soluble P-selectin versus the HR-AD diet. CONCLUSION: Our study showed for the first time that dietary MPLs may modulate epidermal covalently bound ceramides associated with formation of lamellar structures and suppress skin inflammation, resulting in improved skin barrier function. PMID- 25816722 TI - LED 590 nm photomodulation reduces UVA-induced metalloproteinase-1 expression via upregulation of antioxidant enzyme catalase. AB - BACKGROUND: Light at visible spectrum has been associated with anti-inflammatory and anti-aging effects. Ultraviolet A (UVA) radiation is the most important environmental factor associated with exogenous aging via induction of reactive oxygen species (ROS). OBJECTIVE: In this study, we focused on elucidating the molecular mechanisms involved in biological effects associated with 590 nm light delivered from light emitting diode (LED). METHODS: UVA-induced metalloproteinase 1 (MMP-1) expression in dermal fibroblast was used as a model system for investigation. RESULTS: Pretreating cultured human fibroblasts with 590 nm light attenuated UVA-induced ROS, phosphorylated Jun N-terminal kinases, and MMP-1 expressions in a sequential manner. Pretreatment with potent antioxidant N acetylcysteine produced similar effect, suggesting enhanced antioxidant capacity induced by 590 nm photomodulation. Further experiments demonstrated that 590 nm photomodulation attenuated UVA-induced ROS and MMP-1 expressions via mitochondrial retrograde signaling that augments the antioxidant enzyme expression in a peroxisome proliferators-activated receptor gamma coactivator 1alpha-dependent manner. CONCLUSION: Our results provided possible mechanistic insights explaining the effect of visible light on treating clinical conditions associated with ROS-mediated dysfunctions. PMID- 25816723 TI - Forward-viewing versus oblique-viewing echoendoscopes in the diagnosis of upper GI subepithelial lesions with EUS-guided FNA: a prospective, randomized, crossover study. AB - BACKGROUND: The role of the forward-viewing echoendoscope compared with the oblique-viewing echoendoscope for EUS-guided FNA (EUS-FNA) of upper GI subepithelial lesions has not been defined. OBJECTIVE: To compare the diagnostic yield and clinical efficacy of EUS-FNA by using the 2 echoendoscopes in the same upper GI subepithelial lesion. DESIGN: Prospective, randomized, crossover study. SETTING: Tertiary-care medical center. PATIENTS: Forty-one patients with an upper GI subepithelial lesion. INTERVENTIONS: All patients first underwent EUS-FNA with a 19-gauge needle by using both echoendoscopes, based on random selection. When required, 22-gauge or 25-gauge needles were used additionally. MAIN OUTCOME MEASUREMENTS: Comparison of diagnostic yield, tissue sample area, puncture success rates, procedure time, and adverse events. RESULTS: Forty-one patients (median lesion size 22 mm, range 15-63 mm) were enrolled. Rates of histologic diagnosis were 80.5% (33/41) and 73.2% (30/41) (P=.453) by using forward-viewing and oblique-viewing echoendoscopes, respectively. Median tissue sample area in GI stromal tumors (n=22) obtained with the forward-viewing echoendoscope was larger than with the oblique-viewing echoendoscope (2.46 mm2 vs 1.00 mm2; P=.046). Puncture success rates were 39 of 41 (95.1%) and 35 of 41 (85.4%; P=.289) with forward-viewing and oblique-viewing echoendoscopes, respectively. Median procedure time was 21 minutes with the forward-viewing echoendoscope and 27 minutes with the oblique-viewing echoendoscope (P=.009). An infectious adverse event occurred in a patient and was treated with antibiotics. LIMITATIONS: Small sample size. CONCLUSION: Diagnostic yield did not differ between the 2 echoendoscopes. However, tissue sample area and procedure time were superior with the forward-viewing echoendoscope. PMID- 25816725 TI - Inter-rater Reliability and Misclassification of the ABCD(2) Score after Transient Ischemic Attack. AB - BACKGROUND: The ABCD(2) score was initially developed as a simple tool to help first-line clinicians identify patients at highest short-term risk for stroke after transient ischemic attack (TIA). The score is increasingly used for risk stratification of TIA patients, but little is known about its inter-rater reliability. The aim of the present study was to prospectively assess the inter rater reliability of the ABCD(2) score in patients with TIA, including a comparison among raters of different specialties. METHODS: Patients presenting to the emergency department with TIA within 48 hours of onset were prospectively evaluated. TIA was defined as acute onset of focal cerebral or monocular symptoms lasting less than 24 hours and presumed because of a vascular cause. Only patients who were asymptomatic at the time of enrollment were eligible. ABCD(2) scores determined by raters of different specialties were compared with those of a vascular neurology attending. Estimated component and total scores and ABCD(2) risk category were compared between raters. Reliability was assessed using unweighted kappa statistics. RESULTS: A total of 362 evaluations resulting in ABCD(2) scores were performed. In addition to the vascular neurology attending, scores were generated by internal medicine (n = 72), emergency medicine (n = 37), and neurology junior (n = 92) and senior (n = 57) residents. Based on attending scores, 35% of patients were categorized as low risk (ABCD(2) score, 0-3), 50% as moderate risk (ABCD(2) score, 4-5), and 16% as high risk (ABCD(2) score, 6-7). Inter-rater reliability was fair for ABCD(2) total score (kappa = .26) and category (kappa = .29). Raters agreed with the vascular neurology attending 67% (95% confidence interval [CI], 61%-73%) of the time for ABCD(2) category and 52% (95% CI, 46%-58%) of the time for ABCD(2) total score. Disagreement more often resulted in a lower score by the raters as compared with the vascular neurology attending for both ABCD(2) total score and category. Inter-rater reliability of component scores was near perfect for age (kappa = .95) and diabetes (kappa = .81) and substantial for blood pressure (kappa = .67), but only moderate for clinical features (kappa = .55) and duration (kappa = .48). CONCLUSIONS: The inter-rater reliability of the ABCD(2) score is only fair, with rater disagreement of ABCD(2) risk category in nearly one third of patients. PMID- 25816724 TI - Predictors of anxiety after stroke: a systematic review of observational studies. AB - BACKGROUND: Anxiety disorders or symptoms are relatively common after stroke. A better understanding of the predictors of anxiety in stroke patients may improve the management of these disorders. The current review was conducted to determine the predictors of anxiety after stroke. METHODS: Relevant articles concerning population, hospital, or rehabilitation-based studies were identified by searching 10 electronic databases up to May 2014. Methodological quality appraisal, including the validity of prognostic models and data extraction were conducted by 3 reviewers. RESULTS: A total of 18 studies were identified. Data from 3 population-based studies including 8130 patients, 8 hospital-based studies including 1199 patients, and 7 rehabilitation-based studies including 1103 patients were evaluated. Prestroke depression, stroke severity, early anxiety, and dementia or cognitive impairment after stroke were the main predictors of poststroke anxiety. Older age, physical disability or impairment, and use of antidepressant drugs were not associated with the presence of anxiety. Limitations of studies included wide variation in screening tools and cutoff scores, variability in the time frame of screening for anxiety, use of extensive exclusion criteria, and questionable statistical internal and external validity of the models. CONCLUSIONS: Lack of methodological and statistical rigor affects the validity of proposed models to predict anxiety after stroke. Future research should focus on testing proposed models on both internal and external samples to ultimately inform future clinical practice. PMID- 25816726 TI - Nanostructured Amphiphilic Star-Hyperbranched Block Copolymers for Drug Delivery. AB - A robust drug delivery system based on nanosized amphiphilic star-hyperbranched block copolymer, namely, poly(methyl methacrylate-block-poly(hydroxylethyl methacrylate) (PMMA-b-PHEMA) is described. PMMA-b-PHEMA was prepared by sequential visible light induced self-condensing vinyl polymerization (SCVP) and conventional vinyl polymerization. All of the synthesis and characterization details of the conjugates are reported. To accomplish tumor cell targeting property, initially cell-targeting (arginylglycylaspactic acid; RGD) and penetrating peptides (Cys-TAT) were binding to each other via the well-known EDC/NHS chemistry. Then, the resulting peptide was further incorporated to the surface of the amphiphilic hyperbranched copolymer via a coupling reaction between the thiol (-SH) group of the peptide and the hydroxyl group of copolymer by using N-(p-maleinimidophenyl) isocyanate as a heterolinker. The drug release property and targeting effect of the anticancer drug (doxorobucin; DOX) loaded nanostructures to two different cell lines were evaluated in vitro. U87 and MCF-7 were chosen as integrin alphavbeta3 receptor positive and negative cells for the comparison of the targeting efficiency, respectively. The data showed that drug loaded copolymers exhibited enhanced cell inhibition toward U87 cells in compared to MCF-7 cells because targeting increased the cytotoxicity of drug-loaded copolymers against integrin alphavbeta3 receptor expressing tumor cells. PMID- 25816728 TI - The new dyslipidemia guidelines: what is the debate? AB - Dyslipidemia is a major risk factor for the development of atherosclerotic disease. Therefore, lifestyle interventions and pharmacological approaches to decrease cholesterol are widely used in cardiovascular disease prevention. The introduction and widespread use of 3-hydroxy-3 methylglutaryl coenzyme A inhibitors (statins) for individuals at risk of atherosclerotic disease has been an important advance in cardiovascular care. There can be no doubt that better control of dyslipidemia, even in subjects whose low-density lipoprotein cholesterol level is not particularly high, has reduced overall event rates. On a background of lifestyle interventions, statins are routinely used to decrease risk along with aspirin and interventions to control hypertension and diabetes. More than other risk factors, the approach to the identification and treatment of dyslipidemia has been heterogeneous and widely debated. The recent release of the 2013 American College of Cardiology/American Heart Association dyslipidemia guidelines has reignited the controversy over the best approach for risk stratification and treatment. In this article we review the importance of statin therapy for global cardiovascular risk reduction, compare the Canadian Cardiovascular Society dyslipidemia guidelines with other standards, and discuss the points of debate. Despite the seeming variety of recommendations, their common link is a systematic approach to risk stratification and treatment, which will continue to benefit our patients at risk. PMID- 25816729 TI - Whatever will be, will be: spontaneous chest wall hematoma with regular use of low-dose acetylsalicylic Acid. PMID- 25816730 TI - Eosinophilic annular erythema limited on the palms and the soles and possibly associated with thymoma. PMID- 25816731 TI - Serum 25-hydroxyvitamin D is associated with major cardiovascular risk factors and cardiac structure and function in patients with coronary artery disease. AB - BACKGROUND AND AIMS: Vitamin D deficiency has been associated with increased risk for cardiovascular (CV) disease, but the possible effects of Vitamin D on cardiac structure and function are not well characterized. METHODS AND RESULTS: The correlation between 25-hydroxyvitamin D levels and metabolic and cardiac echocardiographic parameters was studied in ARTEMIS study population including 831diabetic and 659 non-diabetic patients with stable coronary artery disease (CAD). Low levels of Vitamin D were associated with high BMI (p < 0.001), high total and LDL cholesterol and triglyceride levels (p < 0.001 for all) in both diabetics and non-diabetics. Among non-diabetic patients, low Vitamin D was also associated independently with elevated systolic and diastolic blood pressure (p < 0.005). Low Vitamin D levels were independently associated with reduced left ventricular (LV) ejection fraction (p < 0.005) and increased left atrial diameter (p < 0.03) measured by cardiac ultrasound by 2-dimensional echo. In the non diabetic group, low Vitamin D levels were associated with impaired LV filling (high E/E') (p < 0.03) and low E/A mitral flow pattern measured by Doppler echocardiography (p < 0.05). Among diabetics, low Vitamin D levels were also related to increased LV end-systolic diameter (p < 0.05) and right ventricular diameter (p < 0.005). The association between LV diastolic filling (E/E') and Vitamin D levels was significant (p < 0.01) after adjustment for the commonly recognized risk factors of diastolic dysfunction in linear regression analysis. CONCLUSIONS: Low Vitamin D is associated with several major cardiovascular risk factors and cardiac structural changes including impaired systolic and diastolic function, which together may explain the association of low Vitamin D to worse cardiovascular outcome. PMID- 25816733 TI - Energy expenditure and heart rate response to breaking up sedentary time with three different physical activity interventions. AB - BACKGROUND AND AIMS: Prolonged sedentary behaviour is associated with increased cardiovascular disease risk and decreased energy expenditure (EE). Workplace interventions breaking up sedentary time have increased EE but the cardiovascular responses are unknown. The practicalities of these interventions, such as required costs and workplace adaptations, are questioned. Calisthenics exercises overcome such limitations, but have not been assessed. The aim of this study was to assess the EE and heart rate (HR) response when breaking up sedentary time with a short bout of standing, walking or calisthenics. METHODS AND RESULTS: Twenty healthy participants (15 male) completed four 30 min conditions: a) 30 min sitting, or breaking up this period with two minutes of b) standing, c) treadmill walking (4 km.h(-1)) or d) a set of calisthenics exercises (including squats and lunges). HR and EE (indirect calorimetry) were assessed throughout. During the activity break, calisthenics caused the highest HR (90 +/- 12 bpm) compared to all other conditions (Sit: 70 +/- 12 bpm; Stand:72 +/- 13 bpm; Walk:84 +/- 10 bpm; p < 0.001) and EE was the highest with calisthenics (13 +/- 5 kcal) compared to all conditions except walking (Sit:3 +/- 1 kcal; Stand:5 +/- 1 kcal; p < 0.001). The recovery following calisthenics had highest total EE (27 +/- 7 kcal) compared to walking (23 +/- 6 kcal) and standing (22 +/- 6 kcal) and also the longest elevation of HR (p < 0.001). CONCLUSION: Calisthenics led to a greater total EE and HR response compared to standing or walking interventions. Calisthenics may be a time efficient method to break up sedentary time without individuals leaving their work environment. Hence calisthenics could be utilised to disrupt workplace sedentary time and improve cardiovascular health and assist in weight management. PMID- 25816732 TI - The lipid theory in the pathogenesis of calcific aortic stenosis. AB - AIMS: Biologically active phenomena, triggered by atherogenesis and inflammation, lead to aortic valve (AV) calcification. Lipids play an important role in activating the cell signaling leading to AV bone deposition. This review, based on evidence from animal and human studies, mainly focused on the involvement of lipids and atherogenic phenomena in the pathogenesis of calcific aortic stenosis (AS). DATA SYNTHESIS: The role of elevated low density lipoproteins for the risk of both vascular atherosclerosis and AS has been elucidated. Lipid disorders act synergistically with other risk factors to increase prevalence of calcific AS. Atherosclerosis is also involved in the pathogenesis of bone demineralization, a typical hallmark of aging, which is associated with ectopic calcification at vascular and valvular levels. Animal studies have recently contributed to demonstrate that lipids play an important role in AS pathogenesis through the activation of molecular cell signalings, such as Wnt/Lrp5 and RANK/RANKL/Osteprotegerin, which induce the transition of valvular myofibroblasts toward an osteogenic phenotype with consequent valvular bone deposition. Although all these evidence strongly support the lipid theory in AS pathogenesis, lipids lowering therapies failed to demonstrate in controlled trials a significant efficacy to slow AS progression. Encouraging results from animal studies indicate that physical activity may counteract the biological processes inducing AV degeneration. CONCLUSIONS: This review indicates a robust interplay between lipids, inflammation, and calcific AS. This new pathophysiological scenario of such an emerging valvular disease paves the way to the next challenge of cardiovascular research: "prevent and care aortic valve stenosis". PMID- 25816735 TI - Corrigendum. PMID- 25816734 TI - Lower bone turnover markers in metabolic syndrome and diabetes: the population based Study of Health in Pomerania. AB - BACKGROUND AND AIMS: Accumulating evidence demonstrates an important interaction between bone and energy metabolism. We aimed to study the associations of three bone turnover markers (BTM: osteocalcin, beta-crosslaps, procollagen type 1 N terminal propeptide) as well as of 25-hydroxyvitamin D and parathyroid hormone with metabolic syndrome (MetS) or type 2 diabetes mellitus (T2DM) in a large population-based cohort. METHODS AND RESULTS: This cross-sectional study comprised 2671 adult men and women participating in the first follow-up of the population-based Study of Health in Pomerania (SHIP-1). Multivariable logistic regression analyses were performed to assess sex-specific associations between the BTMs, 25-hydroxyvitamin D or parathyroid hormone and metabolic disease. All models were adjusted for age, body mass index, smoking status, physical activity, estimated glomerular filtration rate and month of blood sampling. The models for women were further adjusted for menopausal status. Higher BTM or 25 hydroxyvitamin D concentrations were associated with significantly lower odds for metabolic disease, while there was no association between parathyroid hormone and MetS or T2DM. CONCLUSION: Our results contribute to the accumulating evidence of a cross-sectional association between high BTM or 25-hydroxyvitamin D concentrations and a lower prevalence of MetS or T2DM. Further research is necessary to evaluate the mechanisms underlying these results. PMID- 25816737 TI - The role of noninvasive positive pressure ventilation in community-acquired pneumonia: Author's response. PMID- 25816738 TI - SSCP is not suitable as screening technique to detect mutations in ERG11 gene from Candida species. PMID- 25816736 TI - Granulocyte-colony stimulating factor activates JAK2/PI3K/PDE3B pathway to inhibit corticosterone synthesis in a neonatal hypoxic-ischemic brain injury rat model. AB - OBJECTIVE: Our previous study demonstrated that granulocyte-colony stimulating factor (G-CSF)-induced neuroprotection is accompanied by an inhibition of corticosterone production in a neonatal hypoxic-ischemic (HI) rat model. The present study investigates how G-CSF inhibits corticosterone production, using adrenal cortical cells and HI rat pups. METHODS: Cholera toxin was used to induce corticosterone synthesis in a rodent Y1 adrenal cortical cell line by increasing cyclic adenosine monophosphate (cAMP). Both corticosterone and cAMP were quantitatively measured using a commercial enzyme-linked immunosorbent assay (ELISA). The downstream signaling components of the G-CSF receptor, including Janus Kinase 2 (JAK2)/Phosphatidylinositol-3-kinase (PI3K)/Protein kinase B (Akt) and Phosphodiesterase 3B (PDE3B), were detected by western blot. Sprague-Dawley rat pups at the age of 10days (P10) were subjected to unilateral carotid artery ligation followed by hypoxia for 2.5hours. Brain infarction volumes were determined using 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining. RESULTS: G-CSF at 30ng/ml inhibited corticosterone synthesis but lost its inhibitory effect at higher doses. The inhibitory effect of G-CSF was conferred by interfering with cAMP signaling via the activation of the JAK2/PI3K/PDE3B signaling pathway. The degradation of cAMP by G-CSF signaling reduced corticosterone production. This mechanism was further verified in the neonatal HI brain injury rat model, in which inhibition of PDE3B reversed the protective effects of G-CSF. CONCLUSION: Our data suggest that the neuroprotective G-CSF reduces corticosterone synthesis at the adrenal level by degrading intracellular cAMP via activation of the JAK2/PI3K/PDE3B pathway. PMID- 25816739 TI - To facilitate the advance of hydrology, water resources and environmental research in China. PMID- 25816740 TI - 4q12 translocations with GSX2 expression identify a CD7(+) acute myeloid leukaemia subset. PMID- 25816741 TI - Continuous models for cell-cell adhesion. AB - Cell adhesion is the binding of a cell to another cell or to an extracellular matrix component. This process is essential in organ formation during embryonic development and in maintaining multicellular structure. Armstrong et al. (2006) [J. Theor. Biol. 243, pp. 98-113] proposed a nonlocal advection-diffusion system as a possible continuous mathematical model for cell-cell adhesion. Although the system is attractive and challenging, it gives biologically unrealistic numerical solutions under certain situations. We identify the problems and change underlying idea of cell movement from "cells move randomly" to "cells move from high to low pressure regions". Then we provide a modified continuous model for cell-cell adhesion. Numerical experiments illustrate that the modified model is able to replicate not only Steinberg's cell sorting experiments but also some phenomena which cannot be captured at all by Armstrong-Painter-Sherratt model. PMID- 25816742 TI - A sampling formula for ecological communities with multiple dispersal syndromes. AB - Over the past decade, the neutral theory of biodiversity has stirred up community assembly theory considerably by suggesting that stochasticity in the form of ecological drift is an important factor determining community composition and community turnover. The neutral theory assumes that all species within a community are functionally equivalent (the neutrality assumption), and therefore applies best to communities of trophically similar species. Evidently, trophically similar species may still differ in dispersal ability, and therefore may not be completely functionally equivalent. Here we present a new sampling formula that takes into account the partitioning of a community into two guilds that differ in immigration rate. We show that, using this sampling formula, we can accurately detect a subdivision into guilds from species abundance distributions, given ecological data about dispersal ability. We apply our sampling formula to tropical tree data from Barro Colorado Island, Panama. Tropical trees are divided depending on their dispersal mode, where biotically dispersed trees are grouped as one guild, and abiotically dispersed trees represent another guild. We find that breaking neutrality by adding guild structure to the neutral model significantly improves the fit to data and provides a better understanding of community assembly on BCI. Our findings are thus an important step towards an integration of neutral and niche theory. PMID- 25816743 TI - A stochastic model of eye lens growth. AB - The size and shape of the ocular lens must be controlled with precision if light is to be focused sharply on the retina. The lifelong growth of the lens depends on the production of cells in the anterior epithelium. At the lens equator, epithelial cells differentiate into fiber cells, which are added to the surface of the existing fiber cell mass, increasing its volume and area. We developed a stochastic model relating the rates of cell proliferation and death in various regions of the lens epithelium to deposition of fiber cells and radial lens growth. Epithelial population dynamics were modeled as a branching process with emigration and immigration between proliferative zones. Numerical simulations were in agreement with empirical measurements and demonstrated that, operating within the strict confines of lens geometry, a stochastic growth engine can produce the smooth and precise growth necessary for lens function. PMID- 25816744 TI - Factors impact the adherence rate of prophylaxis for deep venous thrombosis in acute ischaemic stroke patients: an analysis of the China National Stroke Registry. AB - OBJECTIVES: Little is known about the clinical practice of deep venous thrombosis (DVT) prophylaxis in patients with acute ischaemic stroke in China. We examined the factors that impact the adherence rate of DVT prophylaxis in stroke patients from the China National Stroke Registry (CNSR). METHODS: Records of 12 173 acute ischaemic stroke patients with follow-up admitted to 132 hospitals in CNSR from September 1, 2007 to August 30, 2008 were reviewed. Data from 4643 patients eligible for DVT prophylaxis were analysed. Generalised estimating equations were used to identify the patient's and hospital's factors that impact the practice of DVT prophylaxis. RESULTS: Among 4643 acute ischaemic stroke patients eligible for DVT prophylaxis, the overall adherence rate of DVT prophylaxis was 59.6%. The median hospital prophylaxis rate was 57.8% (inter quartile range: 33.3(70.2%). Venous thromboembolism was found in 1.6% of patients. Factors associated with increased likelihood of practicing DVT prophylaxis in the multivariable model included history of atrial fibrillation (AF) (P = 0.04), receiving rehabilitation evaluation (P < 0.001), receiving care in the East (P < 0.001) or Central (P = 0.001) regions compared to west regions of China. Increasing age (P = 0.014), NIHSS score on admission (P < 0.001), annual stroke discharges (P = 0.001), and the hospital size (P = 0.003) were associated with lower likelihood of DVT prophylaxis. DISCUSSION: The adherence rate of DVT prophylaxis among non ambulance patients with acute ischaemic stroke was suboptimal in China. It varied among patients by age, stroke severity, and history of AF, and among hospitals by different locations, number of beds and annual stroke discharges. PMID- 25816745 TI - First report of a FXII gene mutation in a Brazilian family with hereditary angio oedema with normal C1 inhibitor. PMID- 25816746 TI - Does training frequency and supervision affect compliance, performance and muscular health? A cluster randomized controlled trial. AB - The aim was to determine the effect of one weekly hour of specific strength training within working hours, performed with the same total training volume but with different training frequencies and durations, or with different levels of supervision, on compliance, muscle health and performance, behavior and work performance. In total, 573 office workers were cluster-randomized to: 1 WS: one 60-min supervised session/week, 3 WS: three 20-min supervised sessions/week, 9 WS: nine 7-min supervised sessions/week, 3 MS: three 20-min sessions/week with minimal supervision, or REF: a reference group without training. Outcomes were diary-based compliance, total training volume, muscle performance and questionnaire-based health, behavior and work performance. Comparisons were made among the WS training groups and between 3 WS and 3 MS. If no difference, training groups were collapsed (TG) and compared with REF. Results demonstrated similar degrees of compliance, mean(range) of 39(33-44)%, and total training volume, 13.266(11.977-15.096)kg. Musculoskeletal pain in neck and shoulders were reduced with approx. 50% in TG, which was significant compared with REF. Only the training groups improved significantly their muscle strength 8(4-13)% and endurance 27(12-37)%, both being significant compared with REF. No change in workability, productivity or self-rated health was demonstrated. Secondary analysis showed exercise self-efficacy to be a significant predictor of compliance. Regardless of training schedule and supervision, similar degrees of compliance were shown together with reduced musculoskeletal pain and improved muscle performance. These findings provide evidence that a great degree of flexibility is legitimate for companies in planning future implementation of physical exercise programs at the workplace. ClinicalTrials.gov, number NCT01027390. PMID- 25816747 TI - Age- and location-related changes in microglial function. AB - Inflammation in the central nervous system (CNS) is primarily regulated by microglia. No longer considered a homogenous population, microglia display a high degree of heterogeneity, immunological diversity and regional variability in function. Given their low rate of self-renewal, the microenvironment in which microglia reside may play an important role in microglial senescence. This study examines age-related changes in microglia in the brain and spinal cord. Using ex vivo flow cytometry analyses, functional assays were performed to assess changes in microglial morphology, oxidative stress, cytokine production, and phagocytic activity with age in both the brain and spinal cord. The regional CNS environment had a significant effect on microglial activity with age. Blood-CNS barrier permeability was greater in the aging spinal cord compared with aging brain; this was associated with increased tissue cytokine levels. Aged microglia had deficits in phagocytosis at baseline and after stimulus-induced activation. The identification of age-specific, high scatter microglia together with the use of ex-vivo functional analyses provides the first functional characterization of senescent microglia. Age and regional-specificity of CNS disease should be taken into consideration when developing immune-modulatory treatments. PMID- 25816748 TI - Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains. AB - Dysfunctional variants of the innate immune cell surface receptor TREM2 (triggering receptor expressed on myeloid cells-2) were identified as major genetic risk factors for Alzheimer's disease and other neurodegenerative conditions. Here we assessed a possible involvement of TREM2 in prion disease. We report that TREM2 expression by microglia is significantly up-regulated upon prion infection. However, depletion of TREM2 did not affect disease incubation time and survival after intracerebral prion infection. Interestingly, markers of microglial activation were attenuated in prion-infected TREM2(-/-) mice, suggesting an involvement of TREM2 in prion-induced microglial activation. Further phenotype profiling of microglia revealed that TREM2 deficiency did not change microglial phenotypes. We conclude that TREM2 is involved in prion-induced microglial activation but does not noticeably modulate the pathogenesis of experimental prion infections. PMID- 25816749 TI - Maintaining gut ecosystems for health: Are transitory food bugs stowaways or part of the crew? AB - Do food ecosystems feed gut ecosystems? And if so... fuel the immune system? Recent developments in metagenomics have provided researchers tools to open the "black box" of microbiome science. These novel technologies have enabled the establishment of correlations between dysbiotic microbial communities and many diseases. The complex interaction of the commensal microbiota with the immune system is a topic of substantial interest due to its relevance to health. The human gastrointestinal tract is composed of an immense number of resident and transient microorganisms. Both may play a direct and vital role in the maintenance of human health and well-being. An understanding of the interactions and mechanisms through which commensal and food-derived microbes shape host immunity and metabolism may yield new insights into the pathogenesis of many immune-mediated diseases. Consequently, by manipulating the contribution of food microbiota to the functionality of the gut ecosystem, there is great hope for development of new prophylactic and therapeutic interventions. This paper presents some insights and comments on the possible impact of exogenous fermented food microbes on the gut homeostasis. We shed light on the similar features shared by both fermented food microbes and probiotics. In particular, the key role of microbial strains as part of food ecosystems for health and diseases is discussed through the prism of fermented dairy products and gut inflammation. PMID- 25816751 TI - HSF1 transcriptional activity is modulated by IER5 and PP2A/B55. AB - Heat shock factor 1 (HSF1) is the master transcriptional regulator of chaperone genes. HSF1 regulates the expression of the immediate-early response gene IER5, which encodes a protein that has roles in the stress response and cell proliferation. Here, we have shown that IER5 interacts with protein phosphatase 2A (PP2A) and its B55 regulatory subunits. Expression of IER5 and B55 in cells leads to HSF1 dephosphorylation and activation of HSF1 target genes. The B55 subunits directly bind to HSF1. These results suggest that IER5 functions as a positive feedback regulator of HSF1 and that this process involves PP2A/B55 and HSF1 dephosphorylation. PMID- 25816752 TI - DAMPs activating innate immune responses in sepsis. AB - Sepsis refers to the deleterious and non-resolving systemic inflammatory response of the host to microbial infection and is the leading cause of death in intensive care units. The pathogenesis of sepsis is highly complex. It is principally attributable to dysregulation of the innate immune system. Damage-associated molecular patterns (DAMPs) are actively secreted by innate immune cells and/or released passively by injured or damaged cells in response to infection or injury. In the present review, we highlight emerging evidence that supports the notion that extracellular DAMPs act as crucial proinflammatory danger signals. Furthermore, we discuss the potential of a wide array of DAMPs as therapeutic targets in sepsis. PMID- 25816750 TI - Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle. AB - PKD-mediated phosphorylation of class IIa HDACs frees the MEF2 transcription factor to activate genes that govern muscle differentiation and growth. Studies of the regulation and function of this signaling axis have involved MC1568 and Go 6976, which are small molecule inhibitors of class IIa HDAC and PKD catalytic activity, respectively. We describe unanticipated effects of these compounds. MC1568 failed to inhibit class IIa HDAC catalytic activity in vitro, and exerted divergent effects on skeletal muscle differentiation compared to a bona fide inhibitor of these HDACs. In cardiomyocytes, Go-6976 triggered calcium signaling and activated stress-inducible kinases. Based on these findings, caution is warranted when employing MC1568 and Go-6976 as pharmacological tool compounds to assess functions of class IIa HDACs and PKD. PMID- 25816753 TI - An SCD gene from the Mollusca and its upregulation in carotenoid-enriched scallops. AB - Carotenoids are a diverse group of red, orange, and yellow pigments that act as vitamin A precursors and antioxidants. Animals can only obtain carotenoids through their diets. Amongst the carotenoids identified in nature, over one third are of marine origin, but current research on carotenoid absorption in marine species is limited. Bivalves possess an adductor muscle, which is normally white in scallops. However, a new variety of Yesso scallop (Patinopecten yessoensis), the 'Haida golden scallop', can be distinguished by its adductor muscle's orange colour, which is caused by carotenoid accumulation. Studying the genes related to carotenoid accumulation in this scallop could benefit our understanding of the mechanisms underlying carotenoid absorption in marine organisms, and it could further improve scallop breeding for carotenoid content. Stearoyl-CoA desaturase (SCD) is the rate-limiting enzyme in the production of monounsaturated fatty acids, which enhance carotenoid absorption. Here, the full-length cDNA and genomic DNA sequences of the SCD gene from the Yesso scallop (PySCD) were obtained. The PySCD gene consisted of four exons and three introns, and it contained a 990-bp open reading frame encoding 329 amino acids. It was ubiquitously expressed in adult tissues, embryos and larvae of both white Yesso scallops and 'Haida golden' scallops. Although the expression pattern of PySCD in both types of scallops was similar, significantly more PySCD transcripts were detected in the 'Haida golden' scallops than in the white scallops. Elevated PySCD expression was found in tissues including the adductor muscle, digestive gland, and gonad, as well as in veliger larvae. This study represents the first characterisation of an SCD gene from the Mollusca. Our data imply that PySCD functions in multiple biological processes, and it might be involved in carotenoid accumulation. PMID- 25816754 TI - Peripheral expression of hepcidin gene in Egyptian beta-thalassemia major. AB - Iron overload is the major cause of morbidity and mortality in transfusion dependent beta-thalassemia major patients. There is a sophisticated balance of body iron metabolism of storage and transport which is regulated by several factors including the peptide hepcidin. Hepcidin is the main iron regulatory molecule; it is secreted mainly by the liver and other tissues including monocytes and lymphocytes. Expression of hepcidin in such cells is unclear and has been studied in few reports with controverted result. Peripheral expression of hepcidin was measured using quantitative real time PCR (qRT-PCR) in 50 beta thalassemia major patients, in addition to 20 healthy volunteers as a control group. Hepcidin levels in beta-thalassemia major patients showed statistically significant decrease in comparison to the control group, and was correlated to cardiac iron stores (T2*). However, hepcidin level was not different among the patients according to the HCV status or whether splenectomized or not. In conclusion; peripheral expression of hepcidin, in iron overloaded beta thalassemia major patients, is a reflection of hepatic expression. It can be used as a molecular predictor for the severity of cardiac iron overload and can be used as a future target for therapy in beta-thalassemia major patients. PMID- 25816755 TI - Impact of interviewers' supportive comments and children's reluctance to cooperate during sexual abuse disclosure. AB - In the field of child sexual abuse (CSA) disclosure, many studies have been conducted on the impact of interviewers' questioning style, but few have examined the impact of interviewers' supportive comments on children's cooperative and reluctant disclosure of substantive details. This field study used a sample of children ranging from 4 to 13 years of age who have all disclosed CSA. The first objective was to examine if the interviewer's and the child's comments during CSA interviews would vary as a function of the use of the National Institute of Child Health and Human Development (NICHD) Protocol. The second objective was to identify the strongest correlates of the proportion of details disclosed by the children during forensic interviews. A total of 90 matched NICHD Protocol and non Protocol interviews done by the same interviewers were audio-taped, transcribed, and coded using verbal subscales. The goal was to explore if differences exist between the interviewers' supportive and non-supportive comments as well as children's cooperative and reluctant statements during investigative interviews conducted prior to or after the NICHD Protocol training. Results of a MANCOVA showed that the use of the NICHD Protocol had no influence on interviewers' and children's demeanors. A hierarchical multiple regression analysis controlling for relevant variables (e.g., child's age and NICHD Protocol) showed that children's reluctance and interviewers' non-support were associated with a lesser proportion of details. Overall, these results indicate that in order to promote detailed disclosure of CSA, interviewers should decrease their non-supportive comments and learn to deal more effectively with children's reluctance during forensic interviews. As such, protocols and training should encourage investigative interviewers to devote more time identifying early signs of children's verbal reluctance and to understand the negative impact of non-supportive comments on the disclosure of substantive details. PMID- 25816757 TI - Improving in vitro maturation and pregnancy outcome in cattle using a novel oocyte shipping and maturation system not requiring a CO2 gas phase. AB - The present work evaluated the benefit of a novel shipping and maturation medium (SMM) not requiring a CO2 gas for maturation and subsequent embryonic development of slaughterhouse and ovum pickup (OPU) bovine cumulus-oocyte complexes (COCs). Four experiments were conducted. In experiment 1, COCs were maturated for 18 hours in SMM and then incubated for 6 hours in, or 24 hours in a conventional system (control). Experiment 2 compared maturation for 24 hours in SMM versus 24 hours in the control. Experiment 3 compared three different incubation temperatures (37 degrees C, 38 degrees C, and 38.5 degrees C) for COCs maturation in SMM. In experiment 4, COCs obtained from 166 OPU sessions (representing two dairy and two beef breeds) in two locations (Wisconsin and California) were matured in SMM or control and evaluated relative to embryo production and pregnancy rates. Frozen semen was used for all experiments. The results for experiment 1 showed that the blastocyst rate and total embryo production rate (TE, Day-7 morulae plus all blastocysts) were higher for SMM than those in the control. However, no differences were observed for cleavage rate or blastocyst stage. In experiment 2, the blastocyst rate and TE were higher for SMM than those in the control; however, there was no difference for cleavage rate, total cell number, blastocyst stage. In experiment 3, the cleavage rate was similar, but the blastocyst rate and TE were greater for 38.5 degrees C than those for 38.0 degrees C and 37.5 degrees C. For experiment 4, Wisconsin OPU derived COCs had a greater cleavage rate, blastocyst rate, TE, and blastocyst stage for SMM versus control. There were no breed effects. For the California trial, OPU-derived COCs matured in SMM had similar cleavage and pregnancy rates at Day 35 but greater blastocyst rates and transferred embryos per session than the control, which resulted in 2.2 more pregnancies per OPU session. Holstein COCs had superior embryonic development but similar pregnancy compared with Jersey. We conclude that COCs matured in SMM had greater oocyte competence than the control. Also, maturation at 38.5 degrees C in SMM was optimal for embryonic development. In summary, SMM resulted in greater embryonic development, similar pregnancy rates, but higher pregnancies per OPU session than the conventional maturation system. PMID- 25816756 TI - Sexual abuse, residential schooling and probable pathological gambling among Indigenous Peoples. AB - Sexual abuse leads to short-term and long-lasting pervasive outcomes, including addictions. Among Indigenous Peoples, sexual abuse experienced in the context of residential schooling may have led to unresolved grief that is contributing to social problems, such as pathological (disordered) gambling. The aim of this study is to investigate the link between child sexual abuse, residential schooling and probable pathological gambling. The participants were 358 Indigenous persons (54.2% women) aged between 18 and 87 years, from two communities and two semi-urban centers in Quebec (Canada). Probable pathological gambling was evaluated using the South Oaks Gambling Screen (SOGS), and sexual abuse and residential schooling were assessed with dichotomous questions (yes/no). The results indicate an 8.7% past-year prevalence rate of pathological gambling problems among participants, which is high compared with the general Canadian population. Moreover, 35.4% were sexually abused, while 28.1% reported having been schooled in a residential setting. The results of a logistic regression also indicate that experiences of child sexual abuse and residential schooling are associated with probable pathological gambling among Indigenous Peoples. These findings underscore the importance of using an ecological approach when treating gambling, to address childhood traumas alongside current addiction problems. PMID- 25816758 TI - Electride support boosts nitrogen dissociation over ruthenium catalyst and shifts the bottleneck in ammonia synthesis. AB - Novel approaches to efficient ammonia synthesis at an ambient pressure are actively sought out so as to reduce the cost of ammonia production and to allow for compact production facilities. It is accepted that the key is the development of a high-performance catalyst that significantly enhances dissociation of the nitrogen-nitrogen triple bond, which is generally considered a rate-determining step. Here we examine kinetics of nitrogen and hydrogen isotope exchange and hydrogen adsorption/desorption reactions for a recently discovered efficient catalyst for ammonia synthesis--ruthenium-loaded 12CaO.7Al2O3 electride (Ru/C12A7:e(-))--and find that the rate controlling step of ammonia synthesis over Ru/C12A7:e(-) is not dissociation of the nitrogen-nitrogen triple bond but the subsequent formation of N-Hn species. A mechanism of ammonia synthesis involving reversible storage and release of hydrogen atoms on the Ru/C12A7:e(-) surface is proposed on the basis of observed hydrogen absorption/desorption kinetics. PMID- 25816759 TI - Depressive and anxiety symptoms and social support are independently associated with disease-specific quality of life in Colombian patients with rheumatoid arthritis. AB - OBJECTIVE: To examine the relationship between disease-specific Quality of Life (QOL) and socio-demographic, medical, and psychosocial factors in Colombian patients with Rheumatoid Arthritis (RA). METHODS: One hundred and three RA patients recruited from ambulatory centers in Neiva, Colombia were administered the Disease Activity Scale 28 (DAS-28), QOL-RA, Zung Self-Rating Depression Scale, State-Trait Anxiety Inventory (STAI), Interpersonal Support Evaluation List-12 (ISEL-12), and Symptom Checklist-90 Revised (SCL-90R). RESULTS: Lower QOL RA was associated with lower socio-economic status (SES; r=0.26, p<0.01), higher likelihood of using opioids (t=-2.51, p<0.05), higher likelihood of comorbid pulmonary disease (t=-2.22, p<0.05), and lower ISEL-12 sub-scales (r's=0.41-0.31, p's<0.001). Lower QOL-RA was associated with higher DAS-28 (r=-0.28, p<0.01), Visual Analog Scale (VAS; r=-0.35, p<0.001), Zung Depression (r=-0.72, p <0.001), STAI-State (r=-0.66, p<0.001), STAI-Trait (r=-0.70, p<0.001), SCL-90R Global Severity Index (r=-0.50, p<0.001), SCL-90R Positive Symptom Total (r=-0.57, p<0.001), and all SCL-90R sub-scales (r's=-0.54--0.21, p's<0.01). A multivariate linear regression model indicated that SES (B=2.77, p<0.05), Zung Depression (B= 0.53, p<0.001), STAI-State (B=-0.26, p<0.05), and ISEL-12 Belonging (B=1.15, p<0.01) were independently associated with QOL-RA, controlling for significant associations. CONCLUSIONS: More depressive and anxiety symptoms were independently associated with lower disease-specific QOL, while higher perceptions of having people to do activities with (belonging social support) and higher SES were independently associated with higher disease-specific QOL. Psychosocial factors impact QOL in RA above and beyond disease activity. Additional research into the benefits of psychosocial assessment of RA patients and provision of comprehensive care to improve QOL is warranted. PMID- 25816760 TI - The bacteriocin AS-48 requires dimer dissociation followed by hydrophobic interactions with the membrane for antibacterial activity. AB - The molecular mechanism underlining the antibacterial activity of the bacteriocin AS-48 is not known, and two different and opposite alternatives have been proposed. Available data suggested that the interaction of positively charged amino acids of AS-48 with the membrane would produce membrane destabilization and disruption. Alternatively, it has been proposed that AS-48 activity could rely on the effective insertion of the bacteriocin into the membrane. The biological and structural properties of the AS-48G13K/L40K double mutant were investigated to shed light on this subject. Compared with the wild type, the mutant protein suffered an important reduction in the antibacterial activity. Biochemical and structural studies of AS-48G13K/L40K mutant suggest the basis of its decreased antimicrobial activity. Lipid cosedimentation assays showed that the membrane affinity of AS-48G13K/L40K is 12-fold lower than that observed for the wild type. L40K mutation is responsible for this reduced membrane affinity and thus, hydrophobic interactions are involved in membrane association. Furthermore, the high-resolution crystal structure of AS-48G13K/L40K, together with the study of its dimeric character in solution showed that G13K stabilizes the inactive water soluble dimer, which displays a reduced dipole moment. Our data suggest that the cumulative effect of these three affected properties reduces AS-48 activity, and point out that the bactericidal effect is achieved by the electrostatically driven approach of the inactive water-soluble dimer towards the membrane, followed by the dissociation and insertion of the protein into the lipid bilayer. PMID- 25816761 TI - Retroviral proteases and their roles in virion maturation. AB - Proteolytic processing of viral polyproteins is essential for retrovirus infectivity. Retroviral proteases (PR) become activated during or after assembly of the immature, non-infectious virion. They cleave viral polyproteins at specific sites, inducing major structural rearrangements termed maturation. Maturation converts retroviral enzymes into their functional form, transforms the immature shell into a metastable state primed for early replication events, and enhances viral entry competence. Not only cleavage at all PR recognition sites, but also an ordered sequence of cleavages is crucial. Proteolysis is tightly regulated, but the triggering mechanisms and kinetics and pathway of morphological transitions remain enigmatic. Here, we outline PR structures and substrate specificities focusing on HIV PR as a therapeutic target. We discuss design and clinical success of HIV PR inhibitors, as well as resistance development towards these drugs. Finally, we summarize data elucidating the role of proteolysis in maturation and highlight unsolved questions regarding retroviral maturation. PMID- 25816763 TI - Plant virus directed fabrication of nanoscale materials and devices. AB - Bottom-up self-assembly methods in which individual molecular components self organize to form functional nanoscale patterns are of long-standing interest in the field of materials sciences. Such self-assembly processes are the hallmark of biology where complex macromolecules with defined functions assemble from smaller molecular components. In particular, plant virus-derived nanoparticles (PVNs) have drawn considerable attention for their unique self-assembly architectures and functionalities that can be harnessed to produce new materials for industrial and biomedical applications. In particular, PVNs provide simple systems to model and assemble nanoscale particles of uniform size and shape that can be modified through molecularly defined chemical and genetic alterations. Furthermore, PVNs bring the added potential to "farm" such bio-nanomaterials on an industrial scale, providing a renewable and environmentally sustainable means for the production of nano-materials. This review outlines the fabrication and application of several PVNs for a range of uses that include energy storage, catalysis, and threat detection. PMID- 25816762 TI - Innate immune recognition of DNA: A recent history. AB - Innate immune DNA sensing underpins many physiological and pathological responses to DNA, including anti-viral immunity to DNA viruses. Although it has been appreciated for many years that cytosolic DNA can evoke a type I interferon response, it is only within the past decade that the cellular mechanisms responsible for such a response have been defined. Here we review the discoveries that led to an appreciation of the existence of cytosolic DNA sensor proteins, and discuss two key such sensors, cGAS and IFI16, in detail. DNA sensors operate via STING, a protein shown to have a central role in controlling altered gene induction in response to DNA in vivo, and as such to be central to a rapidly expanding list of both protective and harmful responses to DNA. We also discuss recent insights into how and when DNA stimulates innate immunity, and highlight current outstanding questions in the DNA sensing field. PMID- 25816764 TI - Ferret models of viral pathogenesis. AB - Emerging and well-known viral diseases remain one the most important global public health threats. A better understanding of their pathogenesis and mechanisms of transmission requires animal models that accurately reproduce these aspects of the disease. Here we review the role of ferrets as an animal model for the pathogenesis of different respiratory viruses with an emphasis on influenza and paramyxoviruses. We will describe the anatomic and physiologic characteristics that contribute to the natural susceptibility of ferrets to these viruses, and provide an overview of the approaches available to analyze their immune responses. Recent insights gained using this model will be highlighted, including the development of new prophylactic and therapeutic approaches. To provide decision criteria for the use of this animal model, its strengths and limitations will be discussed. PMID- 25816765 TI - Insulin use and risk of diabetic macular edema in diabetes mellitus: a systemic review and meta-analysis of observational studies. AB - BACKGROUND: Diabetes mellitus is a common and serious disorder. A search of the literature reveals no comprehensive quantitative assessment of the association between insulin use and incidence of diabetic macular edema. Therefore, we performed a meta-analysis of observational studies to evaluate the effect of insulin use on the risk of developing macular edema. MATERIAL/METHODS: Comparative studies published until May 2014 were searched through a comprehensive search of the Medline, Embase, and the Cochrane Library electronic databases. A systematic review and quantitative analysis of comparative studies reporting the effect of insulin use on the incidence of macular edema was performed. All analyses were performed using the Review Manager (RevMan) v.5 (Nordic Cochrane Centre, Copenhagen, Denmark). RESULTS: A total of 202 905 individuals were included in the present meta-analysis. In a random-effects meta analysis, the use of insulin was found to be associated with increased risk of macular edema (RR, 3.416; 95% CI, 2.417-4.829; I2, 86.6%). Analysis that just included high-quality studies showed that insulin use increased the risk of macular edema (RR, 2.728; 95% CI, 1.881-3.955; I2=77.7%). In cohort studies (RR, 4.509; 95% CI, 3.100-6.559; I2, 77.7%) but not in case-control studies (RR, 1.455; 95% CI, 0.520 to 4.066; I2, 95.9%), increased incidence of macular edema was observed. CONCLUSIONS: The results of this meta-analysis of observational studies demonstrate that insulin use is a risk factor for diabetic macular edema. However, available data are still sparse, and in-depth analyses of the assessed associations in the context of additional longitudinal studies are highly desirable to enable more precise estimates and a better understanding of the role of insulin use in incidence of diabetic macular edema. PMID- 25816766 TI - Cognitive-behavioural therapy for outpatients with eating disorders: effectiveness for a transdiagnostic group in a routine clinical setting. AB - Whilst there is a growing evidence to support the impact of cognitive-behavioural therapy (CBT) in the treatment of adults with eating disorders, much of this evidence comes from tightly controlled efficacy trials. This study aimed to add to the evidence regarding the effectiveness of CBT when delivered in a routine clinical setting. The participants were 203 adults presenting with a range of eating disorder diagnoses, who were offered CBT in an out-patient community eating disorders service in the UK. Patients completed measures of eating disorder pathology at the start of treatment, following the sixth session, and at the end of treatment. Symptoms of anxiety, depression, and psychosocial functioning were measured pre- and post-treatment. Approximately 55% of patients completed treatment, and there were no factors that predicted attrition. There were significant improvements in eating disorder psychopathology, anxiety, depression and general functioning, with particular changes in eating attitudes in the early part of therapy. Effect sizes were medium to large for both completer and intention to treat analyses. These findings confirm that evidence based forms of CBT can be delivered with strong outcomes in routine clinical settings. Clinicians should be encouraged to deliver evidence-based treatments when working in these settings. PMID- 25816767 TI - Differentiation of a free-living alga into forms with ecto- and endosymbiotic associations with heterotrophic organisms in a 5-year microcosm culture. AB - The ecological mechanisms underlying the diversification of autotrophic species into endosymbiotic lifestyles and the ways in which the evolution of endosymbiotic species is ecologically and evolutionarily affected by sister lineages/lines that are adapted to extra-host environments remain unclear. In this paper, we investigated a differentiation process of algal species in which an endosymbiotic type was differentiated phenotypically from a free-living ancestral clone, by using an experimental model called the CET microcosm, which contains a green alga (Micractinium sp.), a bacterium (Escherichia coli), and a ciliate (Tetrahymena thermophila) cultured together without an external resource supply for over 5 years. We then analyzed the algal diversification process by comparing algal phenotypic properties regarding cell-aggregate formation and their effects on the survival of Tetrahymena (using a clone isolated on day 2668) in the absence of bacteria. We examined 13 Micractinium clones, including both ancestral and derived clones isolated from long-term (day 1819-1847) CET microcosm cultures. The results revealed that the free-living ancestral algal strain diversified in sympatry into an aggregate-forming type that associates with E. coli, and a non-aggregate-forming type that associates with Tetrahymena. Furthermore, a competition experiment revealed that the endosymbiotic (non aggregate-forming) type was less adapted to the extracellular environment than the aggregate-forming type. This result suggests that severe competition with a nonendosymbiotic sister line in the extra-host environment favors the host benefiting phenotype in an endosymbiotic line, because such symbionts can enhance the longevity of the host, thereby enabling the survival and reproduction of the symbiont within the host. PMID- 25816768 TI - Eco-friendly copper recovery process from waste printed circuit boards using Fe3+/Fe2+ redox system. AB - The present study aimed at developing an original and environmentally friendly process for the recovery of copper from waste printed circuit boards (WPCBs) by chemical dissolution with Fe(3+) combined with the simultaneous electrowinning of copper and oxidant regeneration. The recovery of copper was achieved in an original set-up consisting of a three chamber electrochemical reactor (ER) connected in series with a chemical reactor (CR) equipped with a perforated rotating drum. Several experiments were performed in order to identify the optimal flow rate for the dissolution of copper in the CR and to ensure the lowest energy consumption for copper electrodeposition in the ER. The optimal hydrodynamic conditions were provided at 400 mL/min, leading to the 75% dissolution of metals and to a low specific energy consumption of 1.59 kW h/kg Cu for the electrodeposition process. In most experiments, the copper content of the obtained cathodic deposits was over 99.9%. PMID- 25816769 TI - Solar assisted alkali pretreatment of garden biomass: Effects on lignocellulose degradation, enzymatic hydrolysis, crystallinity and ultra-structural changes in lignocellulose. AB - A comprehensive study was carried out to assess the effectiveness of solar assisted alkali pretreatment (SAAP) on garden biomass (GB). The pretreatment efficiency was assessed based on lignocellulose degradation, conversion of cellulose into reducing sugars, changes in the ultra-structure and functional groups of lignocellulose and impact on the crystallinity of cellulose, etc. SAAP was found to be efficient for the removal of lignin and hemicellulose that facilitated enzymatic hydrolysis of cellulose. FTIR and XRD studies provided details on the effectiveness of SAAP on lignocellulosic moiety and crystallinity of cellulose. Scanning electron microscopic analysis showed ultra-structural disturbances in the microfibrils of GB as a result of pretreatment. The mass balance closer of 97.87% after pretreatment confirmed the reliability of SAAP pretreatment. Based on the results, it is concluded that SAAP is not only an efficient means of pretreatment but also economical as it involved no energy expenditure for heat generation during pretreatment. PMID- 25816770 TI - Carbon pools and flows during lab-scale degradation of old landfilled waste under different oxygen and water regimes. AB - Landfill aeration has been proven to accelerate the degradation of organic matter in landfills in comparison to anaerobic decomposition. The present study aims to evaluate pools of organic matter decomposing under aerobic and anaerobic conditions using landfill simulation reactors (LSR) filled with 40 year old waste from a former MSW landfill. The LSR were operated for 27 months, whereby the waste in one pair was kept under anaerobic conditions and the four other LSRs were aerated. Two of the aerated LSR were run with leachate recirculation and water addition and two without. The organic carbon in the solid waste was characterized at the beginning and at the end of the experiments and major carbon flows (e.g. TOC in leachate, gaseous CO2 and CH4) were monitored during operation. After the termination of the experiments, the waste from the anaerobic LSRs exhibited a long-term gas production potential of more than 20 NL kg(-1) dry waste, which corresponded to the mineralization of around 12% of the initial TOC (67 g kg(-1) dry waste). Compared to that, aeration led to threefold decrease in TOC (32-36% of the initial TOC were mineralized), without apparent differences in carbon discharge between the aerobic set ups with and without water addition. Based on the investigation of the carbon pools it could be demonstrated that a bit more than 10% of the initially present organic carbon was transformed into more recalcitrant forms, presumably due to the formation of humic substances. The source of anaerobic degradation could be identified mainly as cellulose which played a minor role during aerobic degradation in the experiment. PMID- 25816771 TI - Thermodynamic analysis of the disorder-to-alpha-helical transition of 18.5-kDa myelin basic protein reveals an equilibrium intermediate representing the most compact conformation. AB - The intrinsically disordered, 18.5-kDa isoform of myelin basic protein (MBP) is a peripheral membrane protein that is essential to proper myelin formation in the central nervous system. MBP acts in oligodendrocytes both to adjoin membrane leaflets to each other in forming myelin and as a hub in numerous protein-protein and protein-membrane interaction networks. Like many intrinsically disordered proteins (IDPs), MBP multifunctionality arises from its high conformational plasticity and its ability to undergo reversible disorder-to-order transitions. One such transition is the disorder-to-alpha-helical conformational change that is induced upon MBP-membrane binding. Here, we have investigated the disorder-to alpha-helical transition of MBP-derived alpha-peptides and the full-length 18.5 kDa protein. This transition was induced through titration of the membrane mimetic solvent trifluoroethanol into both protein and peptide solutions, and conformational change was monitored using circular dichroism spectroscopy, 1 anilinonaphthalene-8-sulfonic acid binding, tryptophan fluorescence quenching, and Forster (fluorescence) resonance energy transfer measurements. The data suggest that the disorder-to-alpha-helical transition of MBP follows a 3-state model: disordered<->intermediate<->alpha-helical, with each of the identified equilibrium states likely representing a conformational ensemble. The disordered state is characterized by slight compaction with little regular secondary structure, whereas the intermediate is also disordered but globally more compact. Surprisingly, the alpha-helical conformation is less compact than the intermediate. This study suggests that multifunctionality in MBP could arise from differences in the population of energetically distinct ensembles under different conditions and also provides an example of an IDP that undergoes cooperative global conformation change. PMID- 25816772 TI - A combined NMR and computational approach to investigate peptide binding to a designed Armadillo repeat protein. AB - The specific recognition of peptide sequences by proteins plays an important role both in biology and in diagnostic applications. Here we characterize the relatively weak binding of the peptide neurotensin (NT) to the previously developed Armadillo repeat protein VG_328 by a multidisciplinary approach based on solution NMR spectroscopy, mutational studies, and molecular dynamics (MD) simulations, totaling 20MUs for all MD runs. We describe assignment challenges arising from the repetitive nature of the protein sequence, and we present novel approaches to address them. Partial assignments obtained for VG_328 in combination with chemical shift perturbations allowed us to identify the repeats not involved in binding. Their subsequent elimination resulted in a reduced-size binder with very similar affinity for NT, for which near-complete backbone assignments were achieved. A binding mode suggested by automatic docking and further validated by explicit solvent MD simulations is consistent with paramagnetic relaxation enhancement data collected using spin-labeled NT. Favorable intermolecular interactions are observed in the MD simulations for the residues that were previously shown to contribute to binding in an Ala scan of NT. We further characterized the role of residues within the N-cap for protein stability and peptide binding. Our multidisciplinary approach demonstrates that an initial low-resolution picture for a low-micromolar-peptide binder can be refined through the combination of NMR, protein design, docking, and MD simulations to establish its binding mode, even in the absence of crystallographic data, thereby providing valuable information for further design. PMID- 25816773 TI - Key residues of S. flexneri OmpA mediate infection by bacteriophage Sf6. AB - Many viruses, including bacteriophage, have the inherent ability to utilize several types of proteinaceous receptors as an attachment mechanism to infect cells, yet the molecular mechanisms that drive receptor binding have not been elucidated. Using bacteriophage Sf6 and its host, Shigella flexneri, we investigated how Sf6 utilizes outer membrane protein A (OmpA) for infection. Specifically, we identified that surface loops of OmpA mediate Shigella infection. We further characterized which residues in the surface loops are responsible for Sf6 binding and productive infection using a combination of in vivo and in vitro approaches including site-directed mutagenesis, phage plaque assays, circular dichroism spectroscopy, and in vitro genome ejection assays. Our data indicate that Sf6 can productively interact with other bacterial OmpAs as long as they share homology in loops 2 and 4, suggesting that these loops may determine host specificity. Our data provide a model in which Sf6 interacts with OmpA using the surface of the protein and new insights into viral attachment through binding to membrane protein receptors. PMID- 25816774 TI - Nucleic acid recognition orchestrates the anti-viral response to retroviruses. AB - Intrinsic restriction factors and viral nucleic acid sensors are important for the anti-viral response. Here, we show how upstream sensing of retroviral reverse transcripts integrates with the downstream effector APOBEC3, an IFN-induced cytidine deaminase that introduces lethal mutations during retroviral reverse transcription. Using a murine leukemia virus (MLV) variant with an unstable capsid that induces a strong IFNbeta antiviral response, we identify three sensors, IFI203, DDX41, and cGAS, required for MLV nucleic acid recognition. These sensors then signal using the adaptor STING, leading to increased production of IFNbeta and other targets downstream of the transcription factor IRF3. Using knockout and mutant mice, we show that APOBEC3 limits the levels of reverse transcripts that trigger cytosolic sensing, and that nucleic acid sensing in vivo increases expression of IFN-regulated restriction factors like APOBEC3 that in turn reduce viral load. These studies underscore the importance of the multiple layers of protection afforded by host factors. PMID- 25816775 TI - Autophagy mediates tolerance to Staphylococcus aureus alpha-toxin. AB - Resistance and tolerance are two defense strategies employed by the host against microbial threats. Autophagy-mediated degradation of bacteria has been extensively described as a major resistance mechanism. Here we find that the dominant function of autophagy proteins during infections with the epidemic community-associated methicillin-resistant Staphylococcus aureus USA300 is to mediate tolerance rather than resistance. Atg16L1 hypomorphic mice (Atg16L1(HM)), which have reduced autophagy, were highly susceptible to lethality in both sepsis and pneumonia models of USA300 infection. Autophagy confers protection by limiting the damage caused by alpha-toxin, particularly to endothelial cells. Remarkably, Atg16L1(HM) mice display enhanced survival rather than susceptibility upon infection with alpha-toxin-deficient S. aureus. These results identify an essential role for autophagy in tolerance to Staphylococcal disease and highlight how a single virulence factor encoded by a pathogen can determine whether a given host factor promotes tolerance or resistance. PMID- 25816776 TI - RNase L activates the NLRP3 inflammasome during viral infections. AB - The NLRP3 inflammasome assembles in response to danger signals, triggering self cleavage of procaspase-1 and production of the proinflammatory cytokine IL-1beta. Although virus infection activates the NLRP3 inflammasome, the underlying events remain incompletely understood. We report that virus activation of the NLRP3 inflammasome involves the 2',5'-oligoadenylate (2-5A) synthetase(OAS)/RNase L system, a component of the interferon-induced antiviral response that senses double-stranded RNA and activates endoribonuclease RNase L to cleave viral and cellular RNAs. The absence of RNase L reduces IL-1beta production in influenza A virus-infected mice. RNA cleavage products generated by RNase L enhance IL-1beta production but require the presence of 2',3'-cyclic phosphorylated termini characteristic of RNase L activity. Additionally, these cleavage products stimulate NLRP3 complex formation with the DExD/H-box helicase, DHX33, and mitochondrial adaptor protein, MAVS, which are each required for effective NLRP3 inflammasome activation. Thus, RNA cleavage events catalyzed by RNase L are required for optimal inflammasome activation during viral infections. PMID- 25816777 TI - E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells. AB - The fast proliferation of cancer cells requires reprogramming of its energy metabolism with aerobic glycolysis as a major energy source. Sirt6, a class III histone deacetylase, has been shown to down regulate glycolysis by inhibiting the expression of several key glycolytic genes. Based on the published study on the metabolic phenotype of E2F1 -/- mice and SIRT6 -/- mice, we hypothesize that E2F1 enhances glycolysis and inhibits the expression of Sirt6. Indeed, over-expressing of E2F1, but not its DNA binding deficient mutant, significantly enhanced glucose uptake and lactate production in bladder and prostate cancer cell lines. E2F1 over-expression also suppressed Sirt6 expression and function. Moreover, E2F1 directly bound to Sirt6 promoter and suppressed Sirt6 promoter activity under both normoxic and hypoxic culture conditions. E2F1 siRNA blocked the up regulation of E2F1 under hypoxia, increased Sirt6 expression and decreased glycolysis compared to those of scrambled siRNA transected cells. Furthermore, HDAC1 deacetylated E2F1 and diminished its transcription suppression of Sirt6 promoter. Treatment with the HDAC inhibitor, trichostatin A (TSA), suppressed Sirt6 promoter activity with increased binding of acetylated E2F1 to Sirt6 promoter. Mutating the E2F1 binding site on the proximal Sirt6 promoter abolished the suppression of Sirt6 transcription by TSA. These data indicate a novel oncogenic role of E2F1, i.e. enhancing glycolysis by suppressing Sirt6 transcription. PMID- 25816779 TI - Proteinase K and the structure of PrPSc: The good, the bad and the ugly. AB - Infectious proteins (prions) are, ironically, defined by their resistance to proteolytic digestion. A defining characteristic of the transmissible isoform of the prion protein (PrP(Sc)) is its partial resistance to proteinase K (PK) digestion. Diagnosis of prion disease typically relies upon immunodetection of PK digested PrP(Sc) by Western blot, ELISA or immunohistochemical detection. PK digestion has also been used to detect differences in prion strains. Thus, PK has been a crucial tool to detect and, thereby, control the spread of prions. PK has also been used as a tool to probe the structure of PrP(Sc). Mass spectrometry and antibodies have been used to identify PK cleavage sites in PrP(Sc). These results have been used to identify the more accessible, flexible stretches connecting the beta-strand components in PrP(Sc). These data, combined with physical constraints imposed by spectroscopic results, were used to propose a qualitative model for the structure of PrP(Sc). Assuming that PrP(Sc) is a four rung beta-solenoid, we have threaded the PrP sequence to satisfy the PK proteolysis data and other experimental constraints. PMID- 25816780 TI - Using bioluminescence imaging in glioma research. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumour and has the worst prognosis. Over the last decade, the use of bioluminescence imaging technology has rapidly become widespread to further understand the mechanisms that drive GBM development and progression. Pre-clinical evaluation and optimisation of therapeutic efficacy in GBM research has also utilised this simple non-invasive technology. Here we summarise recent advances made in glioma biology and therapeutic intervention using bioluminescence imaging. This review also describes the current knowledge regarding the use of luciferase-based reporters in examining the role of specific cancer signalling cascades that promote glioma progression. PMID- 25816778 TI - Usefulness of N-terminal Pro-brain Natriuretic Peptide and Myocardial Perfusion in Asymptomatic Adults (from the Multi-Ethnic Study of Atherosclerosis). AB - This study sought to investigate the relation between myocardial perfusion and N terminal pro-brain natriuretic peptide (NT-proBNP) in asymptomatic adults without overt coronary artery disease. NT-proBNP is a cardiac neurohormone secreted from the ventricles in response to ventricular volume expansion and pressure overload and may also be elevated in the setting of reduced myocardial perfusion. We hypothesized that reduced myocardial perfusion reserve (MPR) would be associated with elevated NT-proBNP in participants free of overt cardiovascular disease. MPR was measured by cardiac magnetic resonance, before and after adenosine infusion, in 184 MESA participants (mean age 60 +/- 10.4, 58% white, 42% Hispanic, 44% women) without overt cardiovascular disease. MPR was modeled as hyperemic myocardial blood flow (MBF) adjusted for MBF at rest. A linear regression analysis, adjusted for demographics, established cardiovascular risk factors, left ventricular mass, coronary calcium score, body mass index, and medications, was used to determine the association between MPR and NT-proBNP. Participants with low hyperemic MBF were more likely to be older, male, diabetic, and have higher blood pressure and higher coronary artery calcium score. Mean hyperemic MBF was 3.04 +/- 0.829 ml/min/g. MPR was inversely associated with NT-proBNP levels. In a fully adjusted model, every 1-SD decrement in MPR was associated with a 21% increment in NT-proBNP (p = 0.04). In conclusion, MPR is inversely associated with NT-proBNP level in this cross-sectional study of asymptomatic adults free of overt coronary artery disease, suggesting that higher NT-proBNP levels may reflect subclinical myocardial microvascular dysfunction. PMID- 25816781 TI - Three-dimensional conformal radiation therapy for inoperable massive hepatocellular carcinoma in six dogs. AB - OBJECTIVES: To evaluate the activity and tolerability of three-dimensional conformal radiation therapy (3D-CRT) in dogs with massive hepatocellular carcinoma. MATERIALS AND METHODS: Six dogs with massive hepatocellular carcinoma that were ineligible for surgical resection or with owners who declined surgical resection, and underwent 3D-CRT were retrospectively reviewed. 6 to 10 Gy per fraction was prescribed at isocentre of planning target volume to a total dose of 18 to 42 Gy with 1 to 2 fractions per week for a total of 3 to 7 fractions. Follow-up examinations included physical examination, contrast-enhanced CT scan and blood analysis (complete blood count, electrolytes and serum biochemical panel). RESULTS: The median follow-up time after 3D-CRT was 534 (range, 281 to 1057) days. An objective response was observed in five of six cases. Radiation induced liver disease developed in one dog but was asymptomatic and reversible. Toxicity was not noted in any other dog. CLINICAL SIGNIFICANCE: 3D-CRT appears to be a viable treatment option for dogs with inoperable massive hepatocellular carcinoma. PMID- 25816782 TI - Structural orientation dependent sub-lamellar bone mechanics. AB - The lamellar unit is a critical component in defining the overall mechanical properties of bone. In this paper, micro-beams of bone with dimensions comparable to the lamellar unit were fabricated using focused ion beam (FIB) microscopy and mechanically tested in bending to failure using atomic force microscopy (AFM). A variation in the mechanical properties, including elastic modulus, strength and work to fracture of the micro-beams was observed and related to the collagen fibril orientation inferred from back-scattered scanning electron microscopy (SEM) imaging. Established mechanical models were further applied to describe the relationship between collagen fibril orientation and mechanical behaviour of the lamellar unit. Our results highlight the ability to measure mechanical properties of discrete bone volumes directly and correlate with structural orientation of collagen fibrils. PMID- 25816783 TI - Calculation and comparison of xenon and samarium reactivities of the HEU, LEU core in the low power research reactor. AB - Comparative studies for the conversion of the fuel from HEU to LEU in the Miniature Neutron Source Reactor (MNSR) have been performed using the MCNP4C and GETERA codes. The precise calculations of (135)Xe and (149)Sm concentrations and reactivities were carried out and compared during the MNSR operation time and after shutdown for the existing HEU fuel (UAl4-Al, 90% enriched) and the potential LEU fuels (U3Si2-Al, U3Si-Al, U9Mo-Al, 19.75% enriched and UO2, 12.6% enriched) in this paper using the MCNP4C and GETERA codes. It was found that the (135)Xe and (149)Sm reactivities did not reach their equilibrium reactivities during the daily operating time of the reactor. The (149)Sm reactivities could be neglected compared to (135)Xe reactivities during the reactor operating time and after shutdown. The calculations for the UAl4-Al produced the highest (135)Xe reactivity in all the studied fuel group during the reactor operation (0.39 mk) and after the reactor shutdown (0.735 mk), It followed by U3Si-Al (0.34 mk, 0.653 mk), U3Si2-Al (0.33 mk, 0.634 mk), U9Mo-Al (0.3 mk, 0.568 mk) and UO2 (0.24 mk, 0.448 mk) fuels, respectively. Finally, the results showed that the UO2 was the best candidate for fuel conversion to LEU in the MNSR since it gave the lowest (135)Xe reactivity during the reactor operation and after shutdown. PMID- 25816784 TI - Kamakahi vs ASRM and the future of compensation for human eggs. AB - A recent lawsuit that alleges that the American Society for Reproductive Medicine (ASRM) engages in price-fixing by capping the amount of compensation paid for human oocytes has several critical ethical and policy implications that have received relatively little attention. ASRM has argued that ceilings on donor compensation prevent enticement, exploitation, and oocyte commodification. Critics counter that low donor compensation decreases supply, because fewer women are then interested in donating, which then increases prices for the service that physicians, not donors, accrue, and that ethical goals can be better achieved through enhanced informed consent, hiring egg donor advocates, and better counseling and screening. Yet, if compensation caps are removed, questions emerge concerning what the oocyte market would then look like. Informed consent is an imperfect process. Beyond the legal and economic questions of whether ASRM violates the Sherman Anti-trust Act also lie crucial questions of whether human eggs should be viewed as other products. We argue that human eggs differ from other factory-produced goods and should command moral respect. Although eggs (or embryos) are not equivalent to human beings, they deserve special consideration, because of their potential for human life, and thus have a different moral status. ASRM's current guidelines appear to address, even if imperfectly, ethical challenges that are related to egg procurement for infertility treatment. Given public concerns about oocyte commodification and ASRM's wariness of government regulations, existing guidelines may represent a compromise by aiding patients who seek eggs, while simultaneously trying to avoid undue influence, exploitation, and eugenics. Although the ultimate outcome of this lawsuit remains unclear, policy makers, providers, lawyers, judges, and others should attend seriously to these issues. Alternatives to current ASRM guidelines may be possible (eg, raising the current caps to, say, $12,000 or $15,000, potentially increasing donation, while still avoiding certain ethical difficulties) and warrant close consideration. These complex conflicting ethical issues deserve more attention than they have received because they affect key aspects of clinical practice and the lives of countless patients. PMID- 25816785 TI - Which twin is which? A proposed solution for the labeling of twins at birth. PMID- 25816786 TI - US health care system: we can do better. AB - In this review, South Atlantic Association of Obstetricians and Gynecologists President N. Donald Diebel examines a brief history of health care in the United States and shares his thoughts about questions raised in his 2015 presidential address: How can the enormous advances in medical science be extended to everyone and not just some? What are the obstacles or impediments to this task? How can they be overcome? PMID- 25816787 TI - Survey of American obstetricians regarding group B streptococcus: opinions and practice patterns. AB - OBJECTIVE: The objective of the study was to evaluate attitudes and practice patterns of obstetricians related to screening for group B streptococcal colonization and providing intrapartum antibiotic prophylaxis against early-onset neonatal infections with group B streptococcus. STUDY DESIGN: We mailed a survey to 546 members of the American College of Obstetricians and Gynecologists, including members of the Collaborative Ambulatory Research Network and non Collaborative Ambulatory Research Network members. Stratified random selection was used to generate samples from both of these groups. RESULTS: The survey response rate was 60% for Collaborative Ambulatory Research Network members and 42% for non-Collaborative Ambulatory Research Network members. Of the 206 respondents who reported providing prenatal care, 97% collect screening samples at 35-37 weeks' gestational age. Anatomic sites used to collect samples were more variable: 62% include lower vagina and rectum, 26% include lower vagina and perianal skin but not rectum, and 5% include neither the perianal skin nor the rectum. First-line agents for intrapartum antibiotic prophylaxis were penicillin (71%), ampicillin (27%), and cefazolin (2%). For patients reporting a nonanaphylactic penicillin allergy, drugs used for intrapartum antibiotic prophylaxis were more varied: cefazolin (51%), clindamycin (36%), vancomycin (8%), and erythromycin (5%). For patients undergoing a labor induction starting with a cervical ripening agent, less than 40% typically give the first dose of intrapartum antibiotic prophylaxis before or at the time of cervical ripening agent administration, and 15% wait until the patient reaches the active phase of labor. CONCLUSION: Gaps in knowledge and reported practice related to the prevention of early-onset neonatal group B streptococcus infections were similar to gaps in implementation of guidelines demonstrated in past studies. New approaches to improve implementation are warranted. PMID- 25816788 TI - Role of Endoplasmic reticulum apoptotic pathway in testicular Sertoli cells injury induced by Carbon disulfide. AB - The exposure of Carbon disulfide (CS2) is associated with germ cell injury and male infertility in animals and humans. However, the molecular mechanism is currently unknown. This study show here that CS2-induced Sertoli cells injury via Endoplasmic reticulum (ER) apoptotic pathway. SD male rats were exposed to doses of CS2 (0, 50, 250, 1250mgm(-3)) for 4weeks. After treatment, loose structures of seminiferous tubules and disordered cell arrangements were observed by light microscopy. Ultrastructural lesions, deformed chromatins and vacuoles formed from swollen ER were observed by electron microscopy. After primary culture of Sertoli cells, a dose-dependent increased apoptosis were found. The increased activity of Caspase 3, accumulation of intracellular Ca(2+), up-regulation of mRNA and protein expressions of ER apoptotic relative molecules (Calpain 2, Cleaved Caspase 12, GRP78 and CHOP) were also found in this study. Altogether, our findings indicated that ER apoptotic pathway played an important role in CS2 induced Sertoli cell impairment. PMID- 25816789 TI - A response strategy predicts acquisition of schedule-induced polydipsia in rats. AB - Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phenotypic learning traits representative of neural circuitry that underlies SIP and hypothesized that rats that are response-learners will be more susceptible in developing compulsive water drinking. Using the Y-maze, the rats were characterized as either place- or response-learners. They were exposed to the SIP protocol for a period of 21days. Subsequent histological staining for FosB/DeltaFosB examined neuronal activation associated with SIP in several brain regions. The rats with a preference for a response-learning strategy were more likely to develop SIP than the rats using a place-learning strategy. Furthermore amphetamine sensitization, observed to increase SIP, also shifted learning strategy to a response-learning strategy. No differences were observed in FosB/DeltaFosB expression between SIP and non-SIP rats in the dorsolateral striatum (DLS) and CA1 region of the hippocampus. However, SIP rats had greater FosB/DeltaFosB expression in prefrontal cortex regions. The rats that develop SIP have a preference for response-learning strategies and increased neuronal activation in frontal cortical regions associated with habit formation and compulsion. PMID- 25816790 TI - Drugs of abuse and Parkinson's disease. AB - The term "drug of abuse" is highly contextual. What constitutes a drug of abuse for one population of patients does not for another. It is therefore important to examine the needs of the patient population to properly assess the status of drugs of abuse. The focus of this article is on the bidirectional relationship between patients and drug abuse. In this paper we will introduce the dopaminergic systems of the brain in Parkinson's and the influence of antiparkinsonian drugs upon them before discussing this synergy of condition and medication as fertile ground for drug abuse. We will then examine the relationship between drugs of abuse and Parkinson's, both beneficial and deleterious. In summary we will draw the different strands together and speculate on the future merit of current drugs of abuse as treatments for Parkinson's disease. PMID- 25816791 TI - Serotonin transporter availability may moderate the association between perceiving stress and depressive tendencies - A SPECT with 5-HTTLPR genotyping study. AB - It was found that serotonin transporter (SERT) gene (5-HTTLPR) polymorphism may moderate the association between perceiving stress and depressive tendency. Although SERT availability in the central nervous system could be associated with 5-HTTLPR polymorphism, whether SERT availability moderates the association between stress and depressive tendency is unclear. This study aimed to investigate whether there is a SERT availability*environmental stress interaction effect, as well as a gene-by-environmental (G*E) interaction effect, using single photon emission computed tomography (SPECT) with a serotonin transporter radiotracer, [(123)I]ADAM. 87 healthy volunteers were enrolled. The SERT availability was approximated using SPECT with [(123)I]ADAM. Stress and depressive tendencies were measured by the Recent Life Change Questionnaire (RLCQ) and the Taiwanese Depression Questionnaire (TDQ), respectively. A significant interaction of sex*RLCQ*thalamic SERT availability on the TDQ was found, and this effect was robust after controlling for the effect of the SS genotype. The interaction of RLCQ*thalamic SERT availability on the TDQ was significant among males. In particular, a significant association between RLCQ and TDQ (Spearman correlation, rho=0.64, p<0.01) was found among male subjects with a lower level of thalamic SERT availability. SERT availability may play a role in depressive tendency when under perceived stress among healthy individuals, independent of G*E. This finding provides new evidence that confirms the role of the serotonergic system in the association between stress and depression. Males with lower levels of SERT availability may be more vulnerable to the effects of negative life events. PMID- 25816792 TI - The changing donor landscape of health sector aid to Vietnam: a qualitative case study. AB - The study objective was to identify how donors and government agencies in Vietnam responded to donor proliferation in health sector aid between 1995 and 2012. Interviews were conducted with key informants from donor agencies, central government, and civil society in Hanoi in 2012 (n = 34 interviews), identified through OECD Creditor Reporting System data, internet research, and snowball sampling. Interview transcripts were coded for key themes using the constant comparative method. Documentary materials were used in triangulation and validation of key informant accounts. The study identified a timeline of key events and key themes. The number of donors providing health sector aid to Vietnam increased sharply during the late 1990s and early 2000s, then leveled off and declined between 2008 and 2012. Reasons for donor entry included Vietnam's health needs, perceptions of health as less politically sensitive, and donor interests in facilitating market access. Reasons for donor withdrawal included Vietnam's achievement of middle-income status, the global financial crisis, and donors' shifting global priorities. Key themes included high competition among donors, strategic actions by government to increase its control over aid, and the multiplicity of government units involved with health sector aid. The study concludes that central government and donor agencies in Vietnam responded to donor proliferation in health sector aid by endorsing aid effectiveness policies but implementing these policies inconsistently in practice. Whereas previous literature has emphasized donor proliferation's transaction costs, this study finds that the benefits of a large number of less coordinated donors may outweigh the increased administrative costs under certain conditions. In Vietnam, these conditions included relatively high capacity within government, low government dependence on aid, and government interest in receiving diverse donor recommendations. Vietnam's experience of donor proliferation followed by donor withdrawal illustrates a trajectory that other countries may experience as they transition from low-to middle-income status. PMID- 25816793 TI - Recovery performance and factors that classify young fallers and non-fallers in Parkinson's disease. AB - Postural instability is a major problem for Parkinson's disease patients (PDs). Identifying the causes of postural instability at a young age would contribute to the development of adequate training interventions aiming to reduce falls. The purpose of this study was to investigate the effect of muscle strength and balance ability on dynamic stability control after simulated disturbances and to develop an applicable tool able to classify young PDs into fallers and non fallers. Twenty-five young PDs (12 fallers, 13 non-fallers, 48+/-5 yrs.) and 14 healthy controls participated in the study. Dynamic stability was examined during simulated forward falls. Muscle strength was assessed by isometric maximal plantarflexion and knee extension contractions. Balance ability was evaluated by measuring the anterior and posterior limits of stability (LoS). The fallers showed lower recovery performance in forward falls and lower muscle strength compared to controls. Muscle strength and anterior LoS were significantly associated to stability performance. These two factors could correctly classify 90% of PD fallers, establishing an accurate assessment tool to predict the falling risk in young PDs. Furthermore, muscle strength partly explained recovery performance; therefore, we can argue that young PDs with an increased falling risk may benefit from leg-extensors strengthening and stability training. PMID- 25816795 TI - Team activity recognition in Association Football using a Bag-of-Words-based method. AB - In this paper, a new methodology is used to perform team activity recognition and analysis in Association Football. It is based on pattern recognition and machine learning techniques. In particular, a strategy based on the Bag-of-Words (BoW) technique is used to characterize short Football video clips that are used to explain the team's performance and to train advanced classifiers in automatic recognition of team activities. In addition to the neural network-based classifier, three more classifier families are tested: the k-Nearest Neighbor, the Support Vector Machine and the Random Forest. The results obtained show that the proposed methodology is able to explain the most common movements of a team and to perform the team activity recognition task with high accuracy when classifying three Football actions: Ball Possession, Quick Attack and Set Piece. Random Forest is the classifier obtaining the best classification results. PMID- 25816794 TI - Visual contribution to human standing balance during support surface tilts. AB - Visual position and velocity cues improve human standing balance, reducing sway responses to external disturbances and sway variability. Previous work suggested that human balancing is based on sensory estimates of external disturbances and their compensation using feedback mechanisms (Disturbance Estimation and Compensation, DEC model). This study investigates the visual effects on sway responses to pseudo-random support surface tilts, assuming that improvements result from lowering the velocity threshold in a tilt estimate and the position threshold in an estimate of the gravity disturbance. Center of mass (COM) sway was measured with four different tilt amplitudes, separating the effect of visual cues across the conditions 'Eyes closed' (no visual cues), '4Hz stroboscopic illumination' (visual position cues), and 'continuous illumination' (visual position and velocity cues). In a model based approach, parameters of disturbance estimators were identified. The model reproduced experimental results and showed a specific reduction of the position and velocity threshold when adding visual position and velocity cues, respectively. Sway variability was analyzed to explore a hypothesized relation between estimator thresholds and internal noise. Results suggest that adding the visual cues reduces the contribution of vestibular noise, thereby reducing sway variability and allowing for lower thresholds, which improves the disturbance compensation. PMID- 25816796 TI - Abdominal compartment syndrome and open abdomen management with negative pressure devices. AB - BACKGROUND: Abdominal compartment syndrome (ACS) is defined as an increase of intra-abdominal pressure (IAH) to values higher than 20 mmHg, associated with reduced perfusion and organ dysfunction. MATERIALS AND METHODS: There is a classification of open abdomen which stratifies patients according to the natural history of improvement or clinical deterioration. The aim of treatment is to maintain the open abdomen at the lowest level and to prevent progression to a more complex level. DISCUSSION: Surgical treatment essentially consists in abdominal decompression by leaving the abdomen open. Analysis of the literature shows that negative pressure increases the rate of primary fascial closure; entero-cutaneous fistulas are seen in a minority of cases, without seeming consequence of the application of the dressing. Open abdomen management consists of three treatment stages: acute (24-48 hours), intermediate (from 48 hours to 10 days) and late or reconstruction (from 10 days to the final closure). CONCLUSION: It's important to recognize patients at risk of IAH and the first signs of ACS and intervene early with abdominal decompression if this will establish itself. Management of the open abdomen is now facilitated by negative pressure devices, which positively affect the morbidity and mortality of patients with ACS. PMID- 25816797 TI - Aggression proneness: Transdiagnostic processes involving negative valence and cognitive systems. AB - Aggressive behavior is observed in persons with various mental health problems and has been studied from the perspectives of neuroscience and psychophysiology. The present research reviews some of the extant experimental literature to help clarify the interplay between domains of functioning implicated in aggression proneness. We then convey a process-oriented model that elucidates how the interplay of the Negative Valence and Cognitive System domains of NIMH's Research Domain Criteria (RDoC) helps explain aggression proneness, particularly reactive aggression. Finally, we report on a study involving event-related potential (ERP) indices of emotional and inhibitory control processing during an emotional linguistic go/no-go task among 67 individuals with histories of violence and criminal offending (30% female, 44% African-American) who reported on their aggressive tendencies using the Buss-Perry Aggression Questionnaire. Results provide evidence that tendencies toward angry and aggressive behavior relate to reduced inhibitory control processing (no-go P3) specifically during relevant threat-word blocks, suggesting deterioration of cognitive control by acute or sustained threat sensitivity. These findings highlight the value of ERP methodologies for clarifying the interplay of Negative Valence and Cognitive System processes in aggression proneness. PMID- 25816798 TI - Autophagy in axonal degeneration in glaucomatous optic neuropathy. AB - The role of autophagy in retinal ganglion cell (RGC) death is still controversial. Several studies focused on RGC body death, although the axonal degeneration pathway in the optic nerve has not been well documented in spite of evidence that the mechanisms of degeneration of neuronal cell bodies and their axons differ. Axonal degeneration of RGCs is a hallmark of glaucoma, and a pattern of localized retinal nerve fiber layer defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. As models of preceding axonal degeneration, both the tumor necrosis factor (TNF) injection model and hypertensive glaucoma model may be useful in understanding the mechanism of axonal degeneration of RGCs, and the concept of axonal protection can be an attractive approach to the prevention of neurodegenerative optic nerve disease. Since mitochondria play crucial roles in glaucomatous optic neuropathy and can themselves serve as a part of the autophagosome, it seems that mitochondrial function may alter autophagy machinery. Like other neurodegenerative diseases, optic nerve degeneration may exhibit autophagic flux impairment resulting from elevated intraocular pressure, TNF, traumatic injury, ischemia, oxidative stress, and aging. As a model of aging, we used senescence accelerated mice to provide new insights. In this review, we attempt to describe the relationship between autophagy and recently reported noteworthy factors including Nmnat, ROCK, and SIRT1 in the degeneration of RGCs and their axons and propose possible mechanisms of axonal protection via modulation of autophagy machinery. PMID- 25816801 TI - Do hypnozoites cause relapse in malaria? AB - The concept that hypnozoites give rise to relapses in Plasmodium vivax and Plasmodium ovale malaria has become dogma. However, it is evident from particular contemporary research findings that hypnozoites are not necessarily the origin of all relapse-like recurrences of malaria caused by these parasites. This is the core opinion presented, and I discuss it fully. The hypnozoite theory of relapse needs to be re-evaluated in view of the recent, increased focus on P. vivax and liver stages of Plasmodium. Hypnozoites have also assumed a new significance because they might, by facilitating ongoing transmission, be a threat to the current (post-2007) goal of eliminating malaria globally. I have suggested some new research directions for finding putative nonhypnozoite sources of recurrent malaria. PMID- 25816800 TI - Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming. AB - High mobility group box-1 (HMGB1) is an endogenous danger signal or alarmin that mediates activation of the innate immune response including chemotaxis and pro inflammatory cytokine release. HMGB1 has been implicated in the pathophysiology of several neuroinflammatory conditions including ischemia, traumatic brain injury, seizure and chronic ethanol use. In the present review, the unique structural and functional properties of HMGB1 will be explored including its affinity for multiple pattern recognition receptors (TLR2/TLR4), redox sensitivity and adjuvant-like properties. In light of recent evidence suggesting that HMGB1 may also mediate stress-induced sensitization of neuroinflammatory responses, mechanisms of HMGB1 action in neuroinflammatory priming are explored. A model of neuroinflammatory priming is developed wherein glucocorticoids induce synthesis and release of HMGB1 from microglia, which signals through TLR2/TLR4, thereby priming the NLRP3 inflammasome. We propose that if GCs reach a critical threshold as during a fight/flight response, they may thus function as an alarmin by inducing HMGB1, thereby preparing an organism's innate immune system (NLRP3 inflammasome priming) for subsequent immune challenges such as injury, trauma or infection, which are more likely to occur during a fight/flight response. In doing so, GCs may confer a significant survival advantage by enhancing the central innate immune and sickness response to immune challenges. PMID- 25816799 TI - Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. AB - Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model. Pregnant rhesus monkeys were injected with a modified form of the viral mimic polyI:C (poly ICLC) or saline at the end of the first trimester. Brain tissue was collected from the offspring at 3.5 years and blocks of dorsolateral prefrontal cortex (BA46) were used to analyze neuronal dendritic morphology and spine density using the Golgi-Cox impregnation method. For each case, 10 layer III pyramidal cells were traced in their entirety, including all apical, oblique and basal dendrites, and their spines. We further analyzed somal size and apical dendrite trunk morphology in 30 cells per case over a 30 MUm section located 100+/-10 MUm from the soma. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter and exhibited a greater number of oblique dendrites. These data provide the first evidence that prenatal exposure to MIA alters dendritic morphology in a nonhuman primate MIA model, which may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders related to maternal infection. PMID- 25816802 TI - Gabapentin as an adjuvant for postoperative pain management in dogs undergoing mastectomy. AB - This study aimed to evaluate the analgesic efficacy of gabapentin as an adjuvant for postoperative pain management in dogs. Twenty dogs undergoing mastectomy were randomized to receive perioperative oral placebo or gabapentin (10 mg/kg). All dogs were premedicated with intramuscular acepromazine (0.03 mg/kg) and morphine (0.3 mg/ kg). Anesthesia was induced with propofol (4 mg/kg) intravenously and maintained with isoflurane. Intravenous meloxicam (0.2 mg/kg) was administered preoperatively. Postoperative analgesia was evaluated for 72 hr. Rescue analgesia was provided with intramuscular morphine (0.5 mg/kg). Dogs in the Placebo group received significantly more morphine doses than the Gabapentin group (P=0.021), despite no significant differences in pain scores. Perioperative gabapentin reduced the postoperative morphine requirements in dogs after mastectomy. PMID- 25816803 TI - Immunohistochemistry and molecular epidemiology of avian paramyxovirus 1 from formalin-fixed and paraffin-embedded sections of Japanese doves (Columba livia) affected with neurological signs. AB - Four doves (Nos. 1-4 birds) affected with neurological signs (ataxia, circling and torticollis) were investigated pathologically and microbiologically. Viral isolation was tried from the tracheal and cloacal swabs of all 4 birds and from liver, spleen, kidney, heart, lung and brain of Nos. 1 and 2 birds. No viruses were isolated from 4 birds, but they had high serum antibody titers against avian paramyxovirus 1 (APMV-1). Histologically, they had the characteristic histological changes of pigeon APMV-1 infection; nonpurulent encephalitis and interstitial nephritis. Immununohistochemically, APMV-1 antigens were detected in the necrotic renal tubular epithelial cells of 1 bird of them (No. 3 bird). Detection of APMV-1 ribonucleic acid (RNA) from formalin-fixed and paraffin embedded (FFPE) sections was attempted by reverse transcription-polymerase chain reaction (RT-PCR). Sequencing the RT-PCR product showed the virus RNA belonged to the same APMV-1 genotype (VI) as the strains isolated from the world previous cases of pigeon APMV-1 infection. The RT-PCR of FFPE sections and sequencing of RT-PCR products are useful for molecular epidemiology of the virus when viral isolation from fresh samples is unsuccessful. PMID- 25816804 TI - Pediatric dermatology training during residency: a survey of the 2014 graduating residents. AB - BACKGROUND: Knowledge of pediatric dermatology is considered a core competency of dermatology training and should be expected of all practicing dermatologists. While the numbers of both pediatric dermatology fellowships and board certified pediatric dermatologists in the workforce have increased over the years, recent reports suggest that there is a gap in pediatric dermatology education during dermatology residency. The goal of this study is to assess the current state of pediatric education during residency, as well as the clinical experience, satisfaction and expectations of graduating dermatology residents. METHODS: A 31 question self-report survey was distributed electronically to 294 third-year dermatology residents with questions pertaining to demographics, didactic education, resident experience in pediatric dermatology training, satisfaction with pediatric training and future plans. RESULTS: One hundred and twenty-three residents responded (41.8% response rate) representing approximately 29.1% of the total number of graduating residents. 69 (56.1%) residents reported academic time specifically devoted to pediatric dermatology, the majority (79.7%) of which was led by pediatric dermatologists. 82% of residents reported dedicated pediatric dermatology clinics at their program. 86.8% of respondents felt that their training in pediatric dermatology will allow them to confidently see pediatric dermatology patients in practice. CONCLUSIONS: This survey highlights a promising state of pediatric dermatology training among current graduating dermatology residents. The majority of current graduating dermatology residents are satisfied with their pediatric dermatology education, feel confident treating pediatric patients, and plan to see pediatric patients in clinical practice. PMID- 25816805 TI - n-3 polyunsaturated fatty acids and adiponectin in patients with end-stage renal disease. AB - BACKGROUND AND AIM: In subjects without kidney disease, adiponectin appears to have anti-inflammatory, anti-diabetic, and anti-atherogenic effects. n-3 polyunsaturated fatty acids (PUFA) from seafood have several beneficial effects in patients with endstage renal disease (ESRD) and the aim of the present study was to assess the effect of n-3 PUFA supplementation on plasma adiponectin levels in ESRD patients. METHODS: In a double blinded intervention trial, 162 ESRD patients (mean age 67 years A +/- 13, 56 women and 106 men) undergoing chronic hemodialysis were randomized to 1.7 g n-3 PUFA daily or placebo for 3 months. Adiponectin, plasma lipids and lipoproteins were measured at baseline and after the intervention period. RESULTS: At baseline, adiponectin was positively correlated to HDL-cholesterol (r = 0.55, p < 0.001) and inversely correlated to plasma triglycerides, body mass index (BMI) and high sensitive C-reactive protein (Hs-CRP) (r = -0.32, p < 0.01, r = -0.43, p < 0.01, and r = -0.21, p < 0.01, respectively). Furthermore, adiponectin was inversely correlated to the plasma levels of the two major n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (r = -0.19, p < 0.001, and r = -0.30, p < 0.001, respectively). Baseline plasma adiponectin levels were high in both groups but after 3 months of supplementation no significant change was observed in the groups. Thus, n-3 PUFA supplementation did not change adiponectin levels. CONCLUSION: We found an elevated plasma adiponectin level, which was inversely associated with plasma levels of DHA and EPA at baseline. Supplementation with n-3 PUFAs for 3 months did not change adiponectin levels. The negative result in this study may be related to a relatively low dose and future studies with higher dose and longer duration are needed to explore this mechanism. PMID- 25816806 TI - Pharmacokinetics and pharmacodynamics of pegloticase in patients with end-stage renal failure receiving hemodialysis. AB - AIMS: Phase 3 trial data indicate that treatment of chronic tophaceous gout with pegloticase, a recombinant uricase conjugated to polyethylene glycol, does not reduce estimated glomerular filtration rate in chronic kidney disease (CKD) patients and that pegloticase therapeutics are independent of CKD stages 1 - 4. We determined the pharmacokinetics/pharmacodynamics of pegloticase after a single dose in non-gout subjects with stage 5 CKD receiving hemodialysis. METHODS: In this open-label phase 1 study, 12 subjects received a single intravenous dose of pegloticase 8 mg 3 hours prior to hemodialysis. Blood samples for determination of serum pegloticase concentrations and serum uric acid (SUA) levels were collected immediately predose and at regular intervals before, during, and after hemodialysis. RESULTS: Mean serum pegloticase concentrations remained stable and were unaffected by dialysis sessions. Mean SUA fell to undetectable levels within 3 hours and remained undetected for up to 72 hours postdose. CONCLUSION: Our findings indicate no significant effect of hemodialysis on either the stability of serum pegloticase concentrations after a single dose or the capacity of pegloticase to lower SUA. No new safety signals were detected. Administration of pegloticase in patients with comorbid chronic tophaceous gout and endstage renal failure requiring hemodialysis appears feasible. PMID- 25816807 TI - Risk factors associated with efficacy outcomes in kidney transplantation: analysis of a contemporary cohort of patients from the A2309 trial. AB - A multivariate analysis of risk factors for a composite endpoint of treated biopsy proven acute rejection (BPAR), graft loss, death, or loss to follow-up was undertaken in a cohort of 833 de novo kidney transplants from an international trial (A2309). Patients were randomized to everolimus (trough concentration 3-8 ng/mL or 6-12 ng/mL) with reduced cyclosporine or to mycophenolic acid (MPA) with standard cyclosporine. Cox proportional hazard modeling, incorporating a range of recipient, donor, and transplant variables, showed that treatment group (i.e., randomization to either everolimus 3-8 ng/mL or 6-12 ng/mL vs. MPA) showed no significant association with risk of the composite efficacy endpoint at either month 12 or month 24 (significance level 0.05). At month 12, Cox proportional hazard modeling showed that black race (hazard ratio (HR) 1.68; 95% confidence interval (CI) 1.08, 2.60; p=0.021), increasing donor age in years (HR 1.01; 95% CI 1.00, 1.03; p=0.022), and delayed graft function (DGF; yes vs. no, HR 2.75; 95% CI 1.82, 4.16; p< 0.001) predicted higher risk of the composite endpoint; female gender (female vs. male HR 0.67; 95% CI 0.48, 0.93; p=0.017), and < 3 HLA mismatches (HR 0.70; 95% CI 0.50, 0.99; p=0.049) were associated with reduced risk. At month 24, increasing recipient age in years (HR 0.99; 95% CI 0.98, 0.99; p=0.028), black recipient race (HR 1.62; 95% CI 1.09, 2.42; p=0.018), increasing donor age in years (HR 1.01; 95% CI 1.00, 1.02; p=0.008) and delayed graft function (DGF) (HR 2.60; 95% CI 1.78, 3.82; p<0.001) were predictive of risk. These findings show that, independently from type of immunosuppression, organ quality (expressed by DGF), donor age and recipient age, race and gender appear to be the main determinants of efficacy within 2 years after kidney transplantation. PMID- 25816809 TI - Neonatal atypical hemolytic uremic syndrome from a factor H mutation treated with eculizumab. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) results from an inherited dysregulation of the alternative complement pathway leading to thrombotic microangiopathy consisting of hemolytic anemia, thrombocytopenia, and renal injury. The complement inhibitor eculizumab is an approved treatment, but its reported use in neonates - who have an inherently high risk of infection - is limited. CASE DIAGNOSIS/TREATMENT: A 28-day-old female presented with gross hematuria and hypertension. aHUS was suspected based on anemia with schistocytes, thrombocytopenia, low C3, and acute kidney injury requiring peritoneal dialysis. A septic work-up initiated on day 2 for hypothermia and respiratory failure was negative. There was no improvement after 6 days of plasma therapy. Despite being < 6 weeks old she was vaccinated with pneumococcal-13 conjugate, meningococcal (groups C and Y) polysaccharide, and Haemophilus b tetanus toxoid conjugate vaccines and started on penicillin prophylaxis. After 1 dose of eculizumab 300 mg, dialysis was discontinued and her hematological parameters improved. Genetic testing revealed a complement factor H mutation. After 11 months of follow-up, she remains on eculizumab and penicillin without recurrence of aHUS or any infectious complications. CONCLUSIONS: Eculizumab is a safe and effective treatment option for aHUS even in neonates at high risk for infection. PMID- 25816808 TI - Prevalence and predictors of aortic dilation as a novel cardiovascular complication in children with end-stage renal disease. AB - BACKGROUND: Cardiovascular disease is the leading cause of death in children with end-stage renal disease (ESRD). Isolated aortic dilation (AD) is rare in children. We aimed to determine the prevalence and the risk factors for AD in children with ESRD. METHODS AND STUDY DESIGN: We reviewed records of all ESRD patients followed mat our institution from January 2007 to October 2012. AD was defined as Z-score > 2 in the dimension of at least one of the following echocardiographic aortic parameters: annulus, root at the sinus, sino-tubular junction, or ascending aorta. RESULTS: The records of 78 patients on dialysis and 19 kidney transplant recipients were available. 30 patients (30.9%) had AD. Multivariate analysis revealed independent associations of AD with body mass index (BMI) Z-score (OR = 0.52, 95% confidence interval (CI): 0.35 - 0.78) and ESRD secondary to glomerular disease (OR = 4.58, 95% CI: 1.45 - 14.46). We developed a classification and regression tree (CART) model to identify patients at low vs. high AD risk. Our model classified 62 patients of the cohort (64%) to be high- or lowrisk, with a positive predictive value of 89% and a negative predictive value of 100%. CONCLUSION: Our data suggest that AD, as a possible marker of aortopathy and early aneurysm formation, is a novel and prevalent cardiovascular complication in ESRD children. Glomerular disease and low BMI Zscore appear to be potent predictors. CART modeling helps identify high-risk children, potentially guiding decisions regarding targeted echocardiographic evaluations. PMID- 25816810 TI - Description of Octadecabacter temperatus sp. nov., isolated from the southern North Sea, emended descriptions of the genus Octadecabacter and its species and reclassification of Octadecabacter jejudonensisPark and Yoon 2014 as Pseudooctadecabacter jejudonensis gen. nov., comb. nov. AB - A heterotrophic, Gram-negative, aerobic bacterium, designated strain SB1T, was isolated from surface water of the southern North Sea. Comparison of 16S rRNA gene sequences revealed that strain SB1T is affiliated to the genus Octadecabacter within the marine Roseobacter clade (family Rhodobacteraceae), with Octadecabacter antarcticus as the closest described species (98.2 % sequence similarity to the type strain). DNA-DNA hybridization indicated that SB1T represents a distinct species within this genus. On marine agar, strain SB1T formed beige, circular and convex colonies. Cells were irregular, motile rods. Growth occurred between 4 and 25 degrees C and was optimal at 20 degrees C, and at pH 7-9 (optimum pH 7.5-8.5) and NaCl concentrations between 1 and 6 % (optimum 2-4 %). The DNA G+C content of SB1T was 54.7 mol%. The fatty acids (>1 %) comprised 10 : 0 3-OH, 12 : 1 3-OH, 16 : 1omega7c, 16 : 0, 18 : 2omega7,12, 18 : 1omega7c, 18 : 0 and 11-methyl 18 : 1omega7c. The sole respiratory lipoquinone was ubiquinone Q-10 and the polar lipid pattern indicated the presence of the phospholipids phosphatidylglycerol and phosphatidylcholine, as well as unidentified aminolipid AL1, phospholipids PL1 and PL3 and lipids L1, L2 and L4. On the basis of phylogenetic and phenotypic differences, strain SB1T represents a novel species in the genus Octadecabacter, for which we propose the name Octadecabacter temperatus sp. nov. The type strain is SB1T ( = DSM 26878T = LMG 27946T). Furthermore, our results suggest the reclassification of Octadecabacter jejudonensis as the type species of a new genus, Pseudooctadecabacter gen. nov., as Pseudooctadecabacter jejudonensis comb. nov. (type strain SSK2-1T = KCTC 32535T = CECT 8397T). Finally, emended descriptions of the genus Octadecabacter and its species Octadecabacter antarcticus and Octadecabacter arcticus are also provided. PMID- 25816811 TI - Anticoagulation reversal in the era of the non-vitamin K oral anticoagulants. AB - In recent years, non-vitamin K oral anticoagulants (NOACs) have emerged as an alternative to warfarin for the prevention and treatment of thrombo-embolic disease. Large randomized trials have demonstrated that these agents, which act by directly targeting thrombin (dabigatran) and factor Xa (rivaroxaban, apixaban, and edoxaban), are at least as effective as warfarin, with lower rates of bleeding and fewer interactions with food and drugs. In addition, NOACs have a more predictable anticoagulant effect, allowing a fixed dose regimen and obviating the need for routine anticoagulation monitoring. Since the introduction of NOACs, one of the major concerns for clinicians has been the lack of specific agents to reverse their anticoagulant effect in case of life-threatening haemorrhagic complications or emergency surgery, which have limited their use in patients deemed at a higher risk of bleeding. New specific antidotes (e.g. idarucizumab, andexanet alfa, and ciraparantag) show promising data, and may soon become available for clinical use. In this article, we review the pharmacology of these agents, the incidence and outcomes of haemorrhagic complications, the available strategies for anticoagulation reversal, and the more recent advances for the development of specific antidotes. PMID- 25816812 TI - Standardizing the D-dimer Assay: Proposing the D-dimer International Managed Ratio. PMID- 25816813 TI - Indiana declares health emergency in response to HIV outbreak. PMID- 25816814 TI - Measuring Public Support for Prisoner Reentry Options. AB - Few topics have been discussed more extensively or feverishly within correctional academic and professional circles in the past few decades than prisoner reentry. Although program and policy evaluations have been conducted, a lack of public support for prisoner reentry initiatives could undermine the sustainability of prisoner reentry as a large-scale movement. Interestingly, no multivariate, explanatory analyses of the correlates of support for prisoner reentry policies could be found in the literature. This omission is due in part to the absence of clear psychometric measures to assess support. The current study examines the data obtained from a sample of residents in a Midwestern state to determine the dimensionality of support for prisoner reentry interventions using both exploratory factor analysis (EFA) and ordinary least squares (OLS) regression. Specifically, our expectation is that the following three-factor structure will be identified: (a) support for transitional programs aimed at building skills and knowledge to handle the obstacles of the prison-to-community transitional process, (b) support for post-release transitional housing units, and (c) opposition to denying offenders housing opportunities. Our results support a three-factor model. The implications of these findings for future research are discussed. PMID- 25816816 TI - Higher incentives can impair performance: neural evidence on reinforcement and rationality. AB - Standard economic thinking postulates that increased monetary incentives should increase performance. Human decision makers, however, frequently focus on past performance, a form of reinforcement learning occasionally at odds with rational decision making. We used an incentivized belief-updating task from economics to investigate this conflict through measurements of neural correlates of reward processing. We found that higher incentives fail to improve performance when immediate feedback on decision outcomes is provided. Subsequent analysis of the feedback-related negativity, an early event-related potential following feedback, revealed the mechanism behind this paradoxical effect. As incentives increase, the win/lose feedback becomes more prominent, leading to an increased reliance on reinforcement and more errors. This mechanism is relevant for economic decision making and the debate on performance-based payment. PMID- 25816815 TI - Susceptibility to social pressure following ventromedial prefrontal cortex damage. AB - Social pressure influences human behavior including risk taking, but the psychological and neural underpinnings of this process are not well understood. We used the human lesion method to probe the role of ventromedial prefrontal cortex (vmPFC) in resisting adverse social pressure in the presence of risk. Thirty-seven participants (11 with vmPFC damage, 12 with brain damage outside the vmPFC and 14 without brain damage) were tested in driving simulator scenarios requiring left-turn decisions across oncoming traffic with varying time gaps between the oncoming vehicles. Social pressure was applied by a virtual driver who honked aggressively from behind. Participants with vmPFC damage were more likely to select smaller and potentially unsafe gaps under social pressure, while gap selection by the comparison groups did not change under social pressure. Participants with vmPFC damage also showed prolonged elevated skin conductance responses (SCR) under social pressure. Comparison groups showed similar initial elevated SCR, which then declined prior to making left-turn decisions. The findings suggest that the vmPFC plays an important role in resisting explicit and immediately present social pressure with potentially negative consequences. The vmPFC appears to contribute to the regulation of emotional responses and the modulation of decision making to optimize long-term outcomes. PMID- 25816817 TI - Spirometer Replacement and Serial Lung Function Measurements in Population Studies: Results From the SAPALDIA Study. AB - The Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), a population cohort study, used heated-wire spirometers in 1991 and 2002 and then ultrasonic spirometers in 2010 revealing measurement bias in healthy never smokers. To provide a practical method to control for measurement bias given the replacement of spirometer in long-term population studies, we built spirometer-specific reference equations from healthy never smokers participating in 1991, 2002, and 2010 to derive individualized corrections terms. We compared yearly lung function decline without corrections terms with fixed terms that were obtained from a quasi-experimental study and individualized terms. Compared with baseline reference equations, spirometer-specific reference equations predicted lower lung function. The mean measurement bias increased with age and height. The decline in forced expiratory volume in 1 second during the reference period of 1991-2002 was 31.5 (standard deviation (SD), 28.7) mL/year while, after spirometer replacement, uncorrected, corrected by fixed term, and individualized term, the declines were 47.0 (SD, 30.1), 40.4 (SD, 30.1), and 30.4 (SD, 29.9) mL/year, respectively. In healthy never smokers, ultrasonic spirometers record lower lung function values than heated-wire spirometers. This measurement bias is sizeable enough to be relevant for researchers and clinicians. Future reference equations should account for not only anthropometric variables but also spirometer type. We provide a novel method to address spirometer replacement in cohort studies. PMID- 25816818 TI - Hypothetical exposure limits for oil-based metalworking fluids and cardiovascular mortality in a cohort of autoworkers: structural accelerated failure time models in a public health framework. AB - Occupational exposure to aerosolized particles of oil-based metalworking fluid was recently linked to deaths from ischemic heart disease. The current recommended exposure limits might be insufficient. Studying cardiovascular mortality is challenging because symptoms can induce sicker workers to reduce their exposure, causing healthy-worker survivor bias. G-estimation of accelerated failure time models reduces this bias and permits comparison of multiple exposure interventions. Michigan autoworkers from the United AutoWorkers-General Motors cohort (n = 38,666) were followed from 1941 through 1994. Separate binary variables indicated whether annual exposure exceeded a series of potential limits. Separate g-estimation analyses for each limit yielded the total number of life-years that could have been saved among persons who died from specific cardiovascular causes by enforcing that exposure limit. Banning oil-based fluids would have saved an estimated 4,003 (95% confidence interval: 2,200, 5,807) life years among those who died of ischemic heart disease. Estimates for cardiovascular disease overall, acute myocardial infarction, and cerebrovascular disease were 3,500 (95% confidence interval: 1,350, 5,651), 2,932 (95% confidence interval: 1,587, 4,277), and 917 (95% confidence interval: -80, 1,913) life years, respectively. A limit of 0.01 mg/m(3) would have had a similar impact on cerebrovascular disease but one only half as great on ischemic heart disease. Analyses suggest that limiting exposure to metalworking fluids could have saved many life-years lost to cardiovascular diseases in this cohort. PMID- 25816820 TI - Environmental factors that affect the Fukuda stepping test in normal participants. AB - BACKGROUND: The Fukuda stepping test is commonly used to assess peripheral vestibular function. It has, however, been suggested that its maximal sensitivity and specificity are 70 per cent and 50 per cent, respectively. This study was undertaken to evaluate environmental factors that may influence the reliability of this assessment and hence to 'sharpen' its use in a clinical setting. METHODS: Forty-four participants aged between 20 and 43 years were asked to perform the Fukuda stepping test in both a standard clinic room and a soundproofed room under the following conditions in a randomised order: on the floor versus on foam; with and without a sound-localising source; and with and without ear defenders. RESULTS: Significant differences in the extent of rotation were found when comparing the results obtained in several settings, including standing on the floor in a standard room versus a soundproofed room (p = 0.036), and standing on foam in a standard room versus a soundproofed room (p = 0.015). CONCLUSION: Our results suggest that certain alterations to the test environment may improve the sensitivity of this clinical examination. PMID- 25816821 TI - Use of value of information in UK health technology assessments. AB - OBJECTIVES: The aim of this study was to identify and critically appraise the use of Value of Information (VOI) analyses undertaken as part of health technology assessment (HTA) reports in England and Wales. METHODS: A systematic review of National Institute for Health Research (NIHR) funded HTA reports published between 2004 and 2013 identified the use of VOI methods and key analytical details in terms of: (i) types of VOI methodology used; (ii) parameters and key assumptions; and (iii) conclusions drawn in terms of the need for further research. RESULTS: A total of 512 HTA reports were published during the relevant timeframe. Of these, 203 reported systematic review and economic modeling studies and 25 of these had used VOI method(s). Over half of the twenty-five studies (n = 13) conducted both EVPI (Expected Value of Perfect Information) and EVPPI (Expected Value of Partial Perfect Information) analyses. Eight studies conducted EVPI analysis, three studies conducted EVPI, EVPPI, and EVSI (Expected Value of Sampling Information) analyses and one study conducted EVSI analysis only. The level of detail reporting the methods used to conduct the VOI analyses varied. CONCLUSIONS: This review has shown that the frequency of the use of VOI methods is increasing at a slower pace compared with the published volume of HTA reports. This review also suggests that analysts reporting VOI method(s) in HTA reports should aim to describe the method(s) in sufficient detail to enable and encourage decision-makers guiding research prioritization decisions to use the potentially valuable outputs from quantitative VOI analyses. PMID- 25816819 TI - Invited commentary: Estimating population impact in the presence of competing events. AB - The formal approach in the field of causal inference has enabled epidemiologists to clarify several complications that arise when estimating the effect of an intervention on a health outcome of interest. When the outcome is a failure time or longitudinal process, researchers must often deal with competing events. In this issue of the Journal, Picciotto et al. (Am J Epidemiol. 2015;181(8):563-570) use structural nested failure time models to assess potential population effects of hypothetical interventions and censor competing events. In the present commentary, we discuss 2 interpretations that result from treating competing events as censored observations and how they relate to measures of public health impact. We also comment on 2 alternative approaches for handling competing events: an inverse probability weighting estimator of the survivor average causal effect and the parametric g-formula, which can be used to estimate a functional of the subdistribution of the event of interest. We argue that careful consideration of the tradeoff between the interpretation of the parameters from each approach and the assumptions required to estimate these parameters should guide researchers on the various ways to handle competing events in epidemiologic research. PMID- 25816822 TI - Early dialogue with health technology assessment bodies: a European perspective. AB - INTRODUCTION: Evidence requirements may differ across HTA bodies, and so pharmaceutical companies must plan to synergize their evidence generation strategy, across global regulatory and HTA bodies. Until recently, companies had no official platform to discuss the clinical development of a drug with HTA bodies; however, this is changing. OBJECTIVES: To achieve broad usage in the EU, products must achieve both regulatory and reimbursement approval, the latter of which is based on HTA appraisal in many markets. The objective of this study is to present and evaluate the different options available for early HTA consultation (during drug development/Phase III) in the major European markets from the industry perspective. METHODS: An exploratory (nonsystematic) literature review was performed to identify the European markets offering early HTA consultations, and each process was analyzed using a set of predefined metrics that are relevant to industry (the ability to consult with the regulatory body in parallel, consultation fees, length of consultation meeting, language of consultation meeting, maximum number of pharmaceutical company employees attending, procedural timelines, nature of data for which consultative advice can be sought, the output of the process, and the ability to involve external experts). RESULTS: Four different types of early HTA consultation processes were identified across the major European HTA markets. The nature of these processes varied in terms of the types and number of questions that can be addressed, the length of the meeting, the reporting output, and the ability to involve external experts. CONCLUSIONS: The availability of various options for early HTA consultation may help to avoid a mismatch between the evidence generated by means of a product's clinical development program, and the evidence expected by HTA bodies and payers, which can facilitate the pricing and reimbursement process upon a product's market authorization. PMID- 25816823 TI - Revealing and acknowledging value judgments in health technology assessment. AB - BACKGROUND: Although value issues are increasingly addressed in health technology assessment (HTA) reports, HTA is still seen as a scientific endeavor and sometimes contrasted with value judgments, which are considered arbitrary and unscientific. This article aims at illustrating how numerous value judgments are at play in the HTA process, and why it is important to acknowledge and address value judgments. METHODS: A panel of experts involved in HTA, including ethicists, scrutinized the HTA process with regard to implicit value judgments. It was analyzed whether these value judgments undermine the accountability of HTA results. The final results were obtained after several rounds of deliberation. RESULTS: Value judgments are identified before the assessment when identifying and selecting health technologies to assess, and as part of assessment. They are at play in the processes of deciding on how to select, frame, present, summarize or synthesize information in systematic reviews. Also, in economic analysis, value judgments are ubiquitous. Addressing the ethical, legal, and social issues of a given health technology involves moral, legal, and social value judgments by definition. So do the appraisal and the decision-making process. CONCLUSIONS: HTA by and large is a process of value judgments. However, the preponderance of value judgments does not render HTA biased or flawed. On the contrary they are basic elements of the HTA process. Acknowledging and explicitly addressing value judgments may improve the accountability of HTA. PMID- 25816824 TI - HTA and its legal issues: a framework for identifying legal issues in health technology assessment. AB - OBJECTIVES: Legal analysis can highlight important issues that are relevant when deciding whether a medical technology should be implemented or reimbursed. Literature and studies show that even though the law is an acknowledged part of health technology assessment (HTA), legal issues are rarely considered in practice. One reason for this may be the lack of knowledge about the diversity of legal issues that are relevant for HTA. Therefore, this contribution aims primarily to identify and then explain the relevant legal issues in HTA. This study offers a framework for identifying the legal issues in HTAs in different jurisdictions and provides a basis for further research. METHODS: After extensive literature search, the authors review Swiss health law to identify legal issues that are relevant to HTA. The authors then categorize these legal issues using a framework with an inside and outside perspective. Finally, they explain a selection of these legal issues with several examples. RESULTS: This study reveals numerous legal issues that are relevant for HTA and underlines the necessity of incorporating legal analysis in HTAs. The suggested perspectival framework in this study provides a basis to structure the legal analysis. The identified legal issues are relevant in other countries and the perspectival framework is transferable to other jurisdictions. CONCLUSIONS: The article underlines the importance of in-depth discussion about the role of law in HTA. It provides a structured overview of the legal issues in HTA and suggests a development of more concrete instruments toward a standardized legal technology assessment. PMID- 25816825 TI - Health technology assessment and evidence-based policy making: Queensland Department of Health experience. AB - BACKGROUND: Evidence-based policy making is increasingly used for better resource allocation. Queensland Department of Health has developed a new model to introduce innovative health technologies through a health technology assessment (HTA) program. STRUCTURE: A state-wide committee and several sub-committees at health service district level were established to oversee the HTA program and to monitor the uptake of technologies. The committees are supported by a multidisciplinary secretariat comprising staff with key HTA skills. PROCESS: The process starts with HTA applications, which are then shortlisted according to prespecified criteria. A due diligence process adopting a rapid evidence assessment approach is used to evaluate the applications. Based on the assessment, recommendations are made using a deliberative decision-making process guided by well-recognized tools. With positive recommendation, a technology is piloted in constrained local setting before its system-wide diffusion. OUTCOME: The HTA program has assisted health administrators in prioritizing their health technology agendas. It has gained trust and wide support from policy makers and is increasingly used to support funding allocations, indicating the increasing awareness of and confidence in the program. CONCLUSIONS: The HTA program is a valuable process to assist evidence-based policy development and to guide better resource allocation. PMID- 25816826 TI - Belgian guidelines for economic evaluations: second edition. AB - OBJECTIVES: The aim of this study was to present the updated methodological guidelines for economic evaluations of healthcare interventions (drugs, medical devices, and other interventions) in Belgium. METHODS: The update of the guidelines was performed by three Belgian health economists following feedback from users of the former guidelines and personal experience. The updated guidelines were discussed with a multidisciplinary team consisting of other health economists, assessors of reimbursement request files, representatives of Belgian databases and representatives of the drugs and medical devices industry. The final document was validated by three external validators that were not involved in the previous discussions. RESULTS: The guidelines give methodological guidance for the following components of an economic evaluation: literature review, perspective of the evaluation, definition of the target population, choice of the comparator, analytic technique and study design, calculation of costs, valuation of outcomes, definition of the time horizon, modeling, handling uncertainty and discounting. We present a reference case that can be considered as the minimal requirement for Belgian economic evaluations of health interventions. CONCLUSIONS: These guidelines will improve the methodological quality, transparency and uniformity of the economic evaluations performed in Belgium. The guidelines will also provide support to the researchers and assessors performing or evaluating economic evaluations. PMID- 25816827 TI - Understanding and anticipating lag-time bias in cost-effectiveness studies: the role of time in cost-effectiveness analysis. AB - BACKGROUND: Timely provision of information on the cost-effectiveness of innovations in health care becomes more and more important, resulting in increasing pressure on researchers to provide proof of cost-effectiveness in a short time frame. However, most of these innovations require considerable time and effort to optimally implement leading to a biased "steady state" cost effectiveness outcome. As decision makers in health care predominantly have a short-term focus, the discrepancy between short-term study outcomes and long-term cost-effectiveness may very well lead to misguided decisions about the adoption of innovations in health care. METHODS: Factors such as learning effects, capacity constraints, and delayed time to benefit are all related to a short-run timeframe and result in inefficiencies during the implementation of an innovation. These factors and the mechanisms by which they influence the cost effectiveness outcome are explained for three different types of healthcare innovations. RESULTS: As standard cost-effectiveness analysis assumes costs and effects to behave constant and representative for an innovation's entire economic lifetime, resulting cost-effectiveness outcomes might give a biased, and often overly pessimistic, reflection of the actual cost-effectiveness of an innovation. This is further amplified by the fact that short-run inefficiencies are most prevalent and impactful during an innovation's earliest stage of operation. CONCLUSIONS: This study advocates to carefully take into account the different factors contributing to lag-time bias in the design and analysis of cost effectiveness studies, and to communicate potential biases due to short-run inefficiencies to all stakeholders involved in the decision making process. PMID- 25816828 TI - Differences in evaluating health technology assessment knowledge translation by researchers and policy makers in China. AB - OBJECTIVES: The aim of this study was to examine the gaps between researchers and policy makers in perceptions and influencing factors of knowledge translation (KT) of health technology assessment (HTA) in China. METHODS: A sample of 382 HTA researchers and 112 policy makers in China were surveyed using structured questionnaires. The questionnaires contained two sections: perceptions of HTA research and assessments of six-stage KT activities. Wilcoxon rank sum test was applied to compare the differences in these two sections between HTA researchers and policy makers. Multivariate linear regression was performed to explore KT determinants of HTA for researchers and policy makers separately. RESULTS: Policy makers and researchers differed in their perceptions of HTA research in all items except collaboration in research development and presentation of evidence in easy to-understand language. Significant differences in KT activities existed in all the six stages except academic translation. Regarding KT determinants, close contact between research unit and policy-making department, relevance of HTA to policy making, and importance of HTA on policy making were considered facilitators by both groups. For researchers, practicality of HTA report and presentation of evidence in easy-to-understand language can facilitate KT. Policy makers, on the other hand, considered an overly pedantic nature of HTA research as an obstacle to effective KT. CONCLUSIONS: Substantial gaps existed between HTA researchers and policy makers regarding the perceptions of HTA research and KT activities. There are also some differences in KT determinants by these two groups. Enhancing collaboration, promoting practicality and policy relevance of HTA research, and making HTA findings easily understood are likely to further the KT of HTA evidence. PMID- 25816829 TI - Advancing palliative care in the Uganda health system: an evidence-based policy brief. AB - OBJECTIVES: This paper describes the development and findings for a policy brief on "Advancing the Integration of Palliative Care into the National Health System" and the subsequent use of this report. METHODS: Key stakeholders involved with palliative care helped identify the problem and potential policy solutions to scale up these services within the health system. A working group of national stakeholder representatives and external reviewers commented on and contributed to successive drafts of the report. Research describing the problem, policy options and implementation considerations was identified by reviewing government documents, routinely collected data, electronic literature searches, contact with key informants, and reviewing the reference lists of relevant documents that were retrieved. RESULTS: The palliative burden is not only high but increasing due to the rise in population and life expectancy. A few options for holistic, supportive care include: Home-based care increases chances of a peaceful death for the terminally ill surrounded by their loved ones; supporting informal caregivers improves their quality of life and discharge planning reduces unscheduled admissions and has the potential to free up capacity for acute care services. A combination of strategies is needed to effectively implement the proposed options as discussed further in this article. CONCLUSIONS: The policy brief report was used as a background document for two stakeholder dialogues whose main outcome was that a comprehensive national palliative care policy should be instituted to include all the options, which need to be integrated within the public health system. A draft policy is now in process. PMID- 25816830 TI - Developing a prioritized list of innovative technologies: the Spanish experience. AB - OBJECTIVES: Selecting technologies for formal assessment poses a great challenge to health technology assessment agencies. This study aims to contribute to the creation of a reference framework for the identification, filtering, and prioritization of new and emerging technologies which could be demanded in clinical practice within the next 1-2 years. METHODS: Technologies were identified using a prevalidated systematic Medline strategy. They were classified by medical specialty and then sent to selected professionals belonging to the medical units or areas responsible for their application, until there was a minimum of three participants per health care setting. A self-administered questionnaire was drawn up and health professionals were asked to: (1) assess the degree of innovation of the technologies, and (11) score their foreseeable clinical impact on the basis of predefined prioritization criteria (n = 4). Intra rater reliability was analyzed using the intraclass correlation coefficient (ICC). RESULTS: The Medline search yielded 246 potentially relevant technologies. When analyzed by health care area or unit, sixty-eight were deemed to be high impact innovative technologies (median score >6), with ICCs ranging from 0.03 to 0.83. The final list resulting from the aggregate analysis comprised fifty-one technologies. CONCLUSIONS: This study constitutes an innovative contribution to horizon scanning, providing a systematic and reproducible basis for the identification and selection of relevant new and emerging technologies based on the views and values of health professionals involved in their use. In our opinion, the current proposal could be helpful and useful to many other organizations worldwide, serving to complement already existing strategies. PMID- 25816831 TI - Can L-Cysteine and Vitamin D Rescue Vitamin D and Vitamin D Binding Protein Levels in Blood Plasma of African American Type 2 Diabetic Patients? AB - AIMS: Vitamin D (VD) deficiency has become a worldwide epidemic, particularly affecting African Americans (AA). VD deficiency has been implicated in the excessive rate of complications associated with diabetes in AA. Blood levels of VD binding protein (VDBP) and glutathione (GSH) are lower in AA compared with those in Caucasians. This study tested the hypothesis that lower GSH levels are linked to VDBP and VD deficiency in AA-type 2 diabetic (AA-T2D) patients. Blood was analyzed from T2D and nondiabetic subjects (N). Experiments examining GSH deficiency and l-cysteine (LC) supplementation were performed using THP-1 monocytes. RESULTS: Plasma levels of LC, GSH, VDBP, and VD were significantly lower in AA-T2D compared with age-matched AA-N or Caucasian-T2D. Lower levels of LC and GSH showed a significant positive correlation with lower VDBP and VD levels in AA-T2D. GSH deficiency investigated using an antisense approach depleted VDBP/vitamin D receptor (VDR); LC supplementation caused significant upregulation of GSH and of VDBP/VDR, while supplementation with VD+LC caused a significantly greater GSH and VDBP/VDR upregulation compared with that of VD alone in monocytes. INNOVATION AND CONCLUSION: The reported observations suggest that VD deficiency may be linked to GSH and LC status and lead to a novel hypothesis that supplementation with LC in combination with VD will be effective in increasing VD levels and reducing health disparities in AA. PMID- 25816832 TI - Calibration and standardisation of graded optic nerve injuries in rats. AB - OBJECTIVES: To calibrate and standardise an animal model of graded optic nerve injury (ONI) in rats to facilitate future inter-laboratory data comparisons, focussing on quantification of injury intensity, injury severity, and the correlation between them. METHODS: A pair of cross-action forceps or a pair of artery clips was used to induce optic nerve (ON) crush injuries. A lever principle and a simplified method were used to measure the crushing force. The simplified method directly measured weights as an external force exerted on the tip of the forceps or clips, which was just sufficient to maintain a gap and was equivalent to the closing (crush) force. The impulse and averaged impulse were explored as physical quantities to compare injury intensities. Graded ONIs were made by crushing the ON for 3, 6, 12, 30 or 60 seconds by the cross-action forceps, or 5, 10 or 15 seconds by the artery clips. The injury severity was evaluated by counting surviving retinal ganglion cell (RGC) through applied FluoroGold to the superior colliculus and lateral geniculate body before ON crush, intact RGC counting by applied FluoroGold after ON crush, and ON axon counting. RESULTS: Similar results were obtained by the lever principle method and the simplified method. The crushing force of the cross-action forceps and the artery clips was 148.0 gram force (gf) and 32.4 gf, respectively. The graded ONI animal models were successfully created in rats without retinal ischaemia post trauma. The averaged impulse produced by the artery clips for 15 seconds was equal to that produced by a 3-second crush of the cross-action forceps. The correlation between injury intensity and injury severity was fitted for a power function. DISCUSSION: Our results provide a simplified and effective means to quantify and analyse data from ON crush studies compared with previously reported animal models. PMID- 25816833 TI - Imaging of perianal fistulizing Crohn's disease. AB - Perianal fistula is a complication of Crohn's disease that carries a high morbidity. It is a channel that develops between the lower rectum, anal canal and perianal or perineal skin. The development of perianal fistulas typically connotes a more aggressive disease phenotype and may warrant escalation of treatment to prevent poor outcomes over time. Based on fistula anatomy, debris can form inside these tracts and cause occlusion, which subsequently leads to abscess formation, fever and malaise. The clinical presentation is often with complaints of pain, continuous rectal drainage of fecal matter as well as malodorous discharge. Considering that the presence of fistulas often indicates refractory and aggressive disease, early identification of its presence is important. Some patients may not have the classic symptoms of fistulizing disease at presentation and others may have significant scarring and/or pain from previous fistulizing episodes, which can make an accurate assessment on physical exam alone problematic. As a result, utilizing diagnostic imaging is the best means of identifying the early signs of perianal fistulas or abscess formation in these patients. Several imaging modalities exist which can be used for diagnosis and management. Endoscopic ultrasound and pelvic MRI are considered the most useful in establishing the diagnosis. However, a combination of multiple imaging modalities and/or examination under anesthesia is probably the most ideal. Incomplete characterization of the fistula tract(s) extent or the presence of abscess carries a high morbidity and far-reaching personal expense for the patient - promoting worsening of the disease. PMID- 25816834 TI - Effect of movement kinematics on the cyclic fatigue resistance of nickel-titanium instruments. AB - AIM: To compare the cyclic fatigue resistance of new generation OneShape and WaveOne instruments when used with different kinematics. METHODOLOGY: An artificial canal, made of stainless steel with an inner diameter of 1.5 mm, a 60 degrees angle of curvature and a curvature radius of 3 mm, was used for cyclic fatigue test of new generation OneShape and WaveOne instruments. Groups were as follows (n = 20): 150 degrees -30 degrees , 210 degrees -30 degrees , 360 degrees -30 degrees and continuous rotation. The time to fracture was recorded in seconds, and the data were analysed statistically using a two-way anova and LSD tests (P = 0.05). RESULTS: Cyclic fatigue resistance was significantly affected by the movement kinematics (P < 0.001). The cyclic fatigue resistance of the new generation OneShape instruments increased significantly when operated in various reciprocation motions (150 degrees CW-30 degrees CCW, 210 degrees CW-30 degrees CCW and 360 degrees CW-30 degrees CCW) compared with the continuous rotation mode. New generation OneShape instruments had significantly more resistance to fracture under cyclic loading than WaveOne instruments (P < 0.001). CONCLUSIONS: When using new generation OneShape and WaveOne instruments, all the reciprocating motions (150 degrees CW-30 degrees CCW, 210 degrees CW-30 degrees CCW and 360 degrees CW-30 degrees CCW) resulted in extended fatigue life when compared with continuous rotation. PMID- 25816835 TI - Mucosal leishmaniasis mimicking squamous cell carcinoma in a liver transplant recipient. AB - Organ transplant recipients living in endemic regions are at increased risk of Leishmania infections. Visceral leishmaniasis is the most common kind of presentation in the Mediterranean basin. Rarely, Leishmania infantum may cause localized mucosal disease. We present the first case, to our knowledge, of a liver transplant recipient with localized mucosal leishmaniasis. Twenty-two years after transplantation, a painless, very slow growing ulcer appeared on the inner side of the patient's upper lip. A biopsy performed in the community hospital showed non-specific chronic inflammation without neoplastic signs. Because of a high suspicion of malignancy, the patient was transferred to the referral hospital to consider complete excision. The excisional biopsy revealed a granulomatous inflammatory reaction together with intracellular Leishmania amastigotes within macrophages. Leishmaniasis was confirmed by the nested polymerase chain reaction assay. The clinical and laboratory findings did not suggest visceral involvement. The patient received meglumine antimoniate for 21 days without relevant adverse effects. PMID- 25816836 TI - Rapid enzyme analysis as a diagnostic tool for wound infection: Comparison between clinical judgment, microbiological analysis, and enzyme analysis. AB - In clinical practice, diagnosis of wound infection is based on the classical clinical signs of infection. When infection is suspected, wounds are often swabbed for microbiological culturing. These methods are not accurate (clinical judgment in chronic wounds) or provide results after several days (wound swab). Therefore, there is an urgent need for an easy-to-use diagnostic tool for fast detection of wound infection, especially in chronic wounds. This study determined the diagnostic properties of the enzymes myeloperoxidase, human neutrophil elastase (HNE), lysozyme and cathepsin-G in detecting wound infection when compared to wound swabs. Both chronic and acute wounds of 81 patients were assessed through clinical judgment, enzyme analysis and wound swab. Three promising enzyme models for detecting wound infection were identified. A positive test was defined as: at least one enzyme positive after 30 minutes (model 1), lysozyme and HNE positive after 30 minutes (model 2), myeloperoxidase positive after 5 minutes, and HNE or lysozyme positive after 30 minutes (model 3). All models were significant (p<=0.001). There was no correlation between clinical judgment and wound swab, indicating the need for novel diagnostic systems. Enzyme analysis is fast, easy to use and superior to clinical judgment when compared to wound swabs. PMID- 25816837 TI - Fall in population-based mortality from coronary heart disease negated in people with diabetes mellitus: data from England. AB - AIMS: Mortality rates for coronary heart disease (CHD) have declined substantially in developed countries. Diabetes mellitus is an important risk factor for CHD; its prevalence is increasing. We aimed to compare trends in population-based mortality for CHD without diabetes on the death certificate with trends for CHD with diabetes on the same certificate. METHODS: Analysis of an all England dataset with multiple-cause coded mortality records from 1995 to 2010. Analysis of a similar dataset for Oxford, because it has the longest run of multiple-cause coded mortality in England, from 1979. Age-specific and age standardized mortality rates were calculated. RESULTS: In the all-England dataset, there were 1 772 760 deaths with CHD and no mention of diabetes; and 173 184 deaths with CHD and diabetes on the same death certificate. Of deaths with CHD without a mention of diabetes, rates per million men fell by more than half from 2843 (95% confidence interval: 2822-2862) in 1995 to 1379 (1366-1391) in 2010; and those in women halved from 1324 (1314-1336) to 628 (621-635). Of deaths with CHD and diabetes, rates per million men increased from 194 (188-200) to 215 (210-220); and those for women fell, but only very slightly, from 114 (111-118) to 101 (98-104). The longer run in Oxford, from 1979, showed that rates in men and women without diabetes had fallen by two-thirds; but that rates for CHD with diabetes had not fallen. CONCLUSIONS: The fall in mortality from CHD without diabetes has been spectacular. There has been no comparable fall in mortality from CHD with diabetes. PMID- 25816838 TI - Testing the interactive effects of carotenoids and polyunsaturated fatty acids on ejaculate traits in the guppy Poecilia reticulata (Pisces: Poeciliidae). AB - Using the polyandrous livebearing guppy Poecilia reticulata, this study revealed no main effects of carotenoids in the diet on ejaculate traits, but significant main effects of polyunsaturated fatty acids (PUFAs) on sperm viability and weak but significant interacting effects of both nutrients on sperm length. Collectively, these findings not only add evidence that PUFAs are critical determinants of sperm quality, but also provide tentative evidence that for some traits these effects may be moderated by carotenoid intake. PMID- 25816839 TI - Effects of feeding fatty acid calcium and the interaction of forage quality on production performance and biochemical indexes in early lactation cow. AB - Multiparous early lactation Holstein cows (n = 16) were used in a randomized complete block design to determine the effects of feeding fatty acid calcium and the interaction of forage quality on production performance and biochemical indexes in early lactation cow. Treatments were as follows: (i) feeding low quality forage without supplying fatty acid calcium (Diet A), (ii) feeding low quality forage with supplying 400 g fatty acid calcium (Diet B), (iii) feeding high-quality forage without supplying fatty acid calcium (Diet C) and (iv) feeding high-quality forage with supplying 400 g fatty acid calcium. This experiment consisted 30 days. The milk and blood samples were collected in the last day of the trail. Intakes were recorded in the last 2 days of the trail. Supplementation of fatty acid calcium decreased significantly dry matter intake (DMI) (p < 0.01). Addition fatty acid calcium decreased milk protein percentage (p < 0.01) and milk SNF percentage (p < 0.01), but increased MUN (p < 0.05). Supplemented fatty acid decreased concentration of blood BHBA (p < 0.05), but increased TG, NEFA, glucagon, GLP-1, CCK, leptin, ApoA-IV, serotonin and MSH concentration in blood, the CCK concentration and feed intake showed a significant negative correlation (p < 0.05). PMID- 25816840 TI - Allele-specific PCR is a powerful tool for the detection of the MYD88 L265P mutation in diffuse large B cell lymphoma and decalcified bone marrow samples. PMID- 25816841 TI - Prognostic implications of pathologically determined tumour volume in glottic carcinomas treated by transoral laser microsurgery. AB - OBJECTIVES: The TNM classification system for squamous cell carcinoma (SCC) of the head and neck neglects to incorporate volumetric analysis of the primary tumour. Tumour volume (TV) has been implicated prognostically in laryngeal SCC treated by primary radiotherapy (RT), but data for patients treated surgically are lacking. We evaluated such for glottic SCCs resected by transoral laser microsurgery (TLM). DESIGN: Retrospective cohort study utilising TVs calculated as the product of tumour resection dimensions and time-to-event analyses using the Kaplan-Meier method. The prognostic ability of variables was estimated using log-rank statistics, univariate Cox regression and receiver-operating characteristics analysis where appropriate. SETTING: Tertiary referral head and neck cancer centre. PARTICIPANTS: Patients undergoing primary TLM for glottic SCC with curative intent (2007-2011) with at least 12 months follow-up data. MAIN OUTCOME MEASURES: Prognostic impact of TV on local control (LC), overall survival (OS) and disease-specific survival (DSS). RESULTS: Eligible patients (n = 129) had a median follow-up of 40 months (range 14-79 months). Median TV for all cases was 300 mm(3) (range 2-19800 mm(3)). Three-year LC, OS and DSS were 92%, 92% and 98%, respectively. Tumour volume was not a significant predictor of any oncological outcome measure. Otherwise, a significant influence of pT stage on DSS was observed and of age on OS. CONCLUSIONS: In contrast to laryngeal SCC treated by RT, TV does not appear to portend oncological outcome in glottic SCC managed specifically by TLM and consequently does not warrant incorporation into current prognostic models for such patients. PMID- 25816843 TI - Treating substance use disorders in patients with hepatitis C. PMID- 25816844 TI - Optimization of low-temperature blanching combined with calcium treatment to inactivate Escherichia coli O157:H7 on fresh-cut spinach. AB - AIMS: To develop a mild blanching method with calcium salts to ensure microbiological safety and quality of fresh-cut spinach. METHODS AND RESULTS: The antimicrobial efficacy of eight calcium salts was evaluated on Escherichia coli O157:H7 at 45-65 degrees C and calcium hydroxide (Ca(OH)2 ) showed the greatest synergistic antimicrobial effect with heat. Combinations of low temperature treatments (45, 55, 65 degrees C), time (20, 40, 60 s) and Ca(OH)2 (0.25, 0.50, 0.75%) were applied for E. coli O157:H7 disinfection on fresh-cut spinach to develop a predictive model using a Box-Behnken experimental design. A suitable quadratic model was produced (R(2) = 0.98, P < 0.001) and the optimum condition (64.9 degrees C with 0.52% Ca(OH)2 for 42.4 s) was drawn by reducing 6.6 log CFU g(-1) of E. coli O157:H7 on fresh-cut spinach. Blanching at 61.9 degrees C with 0.52% Ca(OH)2 for 41.7 s can inactivate E. coli O157:H7 on spinach by 5.4 log CFU g(-1) . The new method was comparable to the CDC recommendation for safe spinach cooking (71.1 degrees C, 15 s; 5.0 log CFU g(-1) reduction) with lower levels of weight loss of the spinach (P < 0.05). CONCLUSIONS: This study suggests an efficient spinach blanching method for E. coli O157:H7 disinfection. SIGNIFICANCE AND IMPACT OF THE STUDY: This blanching method will enhance microbiological safety of fresh-cut produce while minimizing the use of energy and chemicals. PMID- 25816842 TI - Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons. AB - The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons. PMID- 25816846 TI - Levothyroxine Poisoning - Symptoms and Clinical Outcome. AB - Levothyroxine (LT), T4, poisoning is rarely associated with a severe outcome. However, cases with significant complications have been reported. The aim of this study was to identify factors associated with symptoms of poisoning including late-onset symptoms. All enquiries to the Danish Poison Information Centre (DPIC) concerning LT poisoning between March 2007 and September 2012 were reviewed and the following parameters were recorded: age, dose, time from ingestion, multiple drug intake and symptoms. To evaluate the frequency of late-onset symptoms, a subgroup of patients without initial symptoms were contacted. A total of 181 patients were registered (112 children). Ingested LT dose ranged from 10 to 9000 mcg (median 275 mcg). A total of 29 of 181 (16%) patients were symptomatic at the time of enquiry, and there was no difference in ingested LT dose between asymptomatic and symptomatic patients, neither in children nor in adults (age 16 92 years) (p < 0.68 and p < 0.47, respectively). In total, 153 of 181 (85%) patients did not have symptoms of poisoning at the time of enquiry; however, in 9 of 21 (43%) patients, we were able to contact, late-onset symptoms existed. In none of the cases, hospital contact was needed and there were no reports of long term sequelae. Acute LT poisoning often follows a benign course. The occurrence of symptoms appears not to be dose dependent. Late-onset symptoms seem to be common. However, all symptoms resolved spontaneously without need of medical care. PMID- 25816847 TI - Does lower lifetime fluoridation exposure explain why people outside capital cities have poor clinical oral health? AB - BACKGROUND: Australians outside state capital cities have greater caries experience than their counterparts in capital cities. We hypothesized that differing water fluoridation exposure was associated with this disparity. METHODS: Data were the 2004-06 Australian National Survey of Adult Oral Health. Examiners measured participant decayed, missing and filled teeth and DMFT Index, and lifetime fluoridation exposure was quantified. Multivariable linear regression models estimated differences in caries experience between capital city residents and others, with and without adjustment for fluoridation exposure. RESULTS: There was greater mean lifetime fluoridation exposure in state capital cities (59.1%, 95% confidence interval = 56.9, 61.4) than outside capital cities (42.3, confidence interval = 36.9, 47.6). People located outside capital city areas had differing sociodemographic characteristics and dental visiting patterns, and a higher mean DMFT (capital cities = 12.9, non-capital cities = 14.3, p = 0.02), than people from capital cities. After adjustment for sociodemographic characteristics and dental visits, DMFT of people living in capital cities was less than non-capital city residents (regression coefficient = 0.8, p = 0.01). The disparity was no longer statistically significant (regression coefficient = 0.6, p = 0.09) after additional adjustment for fluoridation exposure. PMID- 25816845 TI - Early hemostatic responses to trauma identified with hierarchical clustering analysis. AB - BACKGROUND: Trauma-induced coagulopathy is a complex multifactorial hemostatic response that is poorly understood. OBJECTIVES: To identify distinct hemostatic responses to trauma and identify key components of the hemostatic system that vary between responses. PATIENTS/METHODS: A cross-sectional observational study of adult trauma patients at an urban level I trauma center emergency department was performed. Hierarchical clustering analysis was used to identify distinct clusters of similar subjects according to vital signs, injury/shock severity, and comprehensive assessment of coagulation, clot formation, platelet function, and thrombin generation. RESULTS: Among 84 total trauma patients included in the model, three distinct trauma clusters were identified. Cluster 1 (N = 57) showed platelet activation, preserved peak thrombin generation, plasma coagulation dysfunction, a moderately decreased fibrinogen concentration and normal clot formation relative to healthy controls. Cluster 2 (N = 18) showed platelet activation, preserved peak thrombin generation, and a preserved fibrinogen concentration with normal clot formation. Cluster 3 (N = 9) was the most severely injured and shocked, and showed a strong inflammatory and bleeding phenotype. Platelet dysfunction, thrombin inhibition, plasma coagulation dysfunction and a decreased fibrinogen concentration were present in this cluster. Fibrinolytic activation was present in all clusters, but was particularly increased in cluster 3. Trauma clusters were most noticeably different in their relative fibrinogen concentration, peak thrombin generation, and platelet-induced clot contraction. CONCLUSIONS: Hierarchical clustering analysis identified three distinct hemostatic responses to trauma. Further insights into the underlying hemostatic mechanisms responsible for these responses are needed. PMID- 25816848 TI - Successful stem cell transplantation in a patient with primary cutaneous aggressive cytotoxic epidermotropic CD8+ T-cell lymphoma. PMID- 25816849 TI - Epidural analgesia with amide local anesthetics, bupivacaine, and ropivacaine in combination with fentanyl for labor pain relief: a meta-analysis. AB - BACKGROUND: The study compares the effectiveness of bupivacaine and fentanyl (BUPI-FEN) and ropivacaine and fentanyl (ROPI-EFN) in epidural analgesia for labor pain through a meta-analysis of relevant randomized clinical trials. MATERIAL AND METHODS: Multiple electronic databases were searched using appropriate MeSH terms and keywords for original English language research papers published between 1990 and March 2014. Meta-analyses results were based on the mean differences between the groups as well as odds ratios where appropriate. Statistical heterogeneity amongst the included studies was tested by I^2 index. RESULTS: Nine studies that met the inclusion criteria were selected for analysis which consisted of 556 parturient patients. The duration of the second stage of labor was significantly shorter in the BUPI-FEN group by a mean of -6.87 (-10.98, -2.77; P<0.002). On the other hand, the ROPI-FEN group had a significantly lower incidence of motor blockade by a mean of 0.31 (0.18, 0.51; P<0.00001). A positive relationship between the amide local anesthetic concentration and the number of women having motor blockade was observed, but a negative relationship between fentanyl concentration and the number of women experiencing a motor block. Moreover, a positive correlation was found between the concentration of ropivacaine and the incidence of instrumental delivery and between the concentration of bupivacaine and the incidence of cesarean delivery. CONCLUSIONS: In combination with fentanyl, bupivacaine and ropivacaine exhibit comparable efficacy and safety. However, BUP-FEN analgesia led to a shortened second-stage labor and ROPI-FEN resulted in a significantly lower incidence of motor block. PMID- 25816850 TI - Genetic diversity and QTL mapping of thermostability of limit dextrinase in barley. AB - Limit dextrinase (LD) is an essential amylolytic enzyme for the complete degradation of starch, and it is closely associated with malt quality. A survey of 51 cultivated barley and 40 Tibetan wild barley genotypes showed a wide genetic diversity of LD activity and LD thermostability. Compared with cultivated barley, Tibetan wild barley showed lower LD activity and higher LD thermostability. A doubled haploid population composed of 496 DArT and 28 microsatellite markers was used for mapping Quantitative Trait Loci (QTLs). Parental line Yerong showed low LD activity and high LD thermostability, but Franklin exhibited high LD activity and low LD thermostability. Three QTLs associated with thermostable LD were identified. The major QTL is close to the LD gene on chromosome 7H. The two minor QTLs colocalized with previously reported QTLs determining malt-extract and diastatic power on chromosomes 1H and 2H, respectively. These QTLs may be useful for a better understanding of the genetic control of LD activity and LD thermostability in barley. PMID- 25816852 TI - Drought-related tree mortality: addressing the gaps in understanding and prediction. AB - Increased tree mortality during and after drought has become a research focus in recent years. This focus has been driven by: the realisation that drought-related tree mortality is more widespread than previously thought; the predicted increase in the frequency of climate extremes this century; and the recognition that current vegetation models do not predict drought-related tree mortality and forest dieback well despite the large potential effects of these processes on species composition and biogeochemical cycling. To date, the emphasis has been on understanding the causal mechanisms of drought-related tree mortality, and on mechanistic models of plant function and vegetation dynamics, but a consensus on those mechanisms has yet to emerge. In order to generate new hypotheses and to help advance the modelling of vegetation dynamics in the face of incomplete mechanistic understanding, we suggest that general patterns should be distilled from the diverse and as-yet inconclusive results of existing studies, and more use should be made of optimisation and probabilistic modelling approaches that have been successfully applied elsewhere in plant ecology. The outcome should inform new empirical studies of tree mortality, help improve its prediction and reduce model complexity. PMID- 25816851 TI - Predicting the extent of metabolism using in vitro permeability rate measurements and in silico permeability rate predictions. AB - The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metabolism and solubility of a drug. However, defining the extent of metabolism relies upon clinical data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, we aimed to determine if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metabolism, to determine a reference compound representing the permeability rate above which compounds would be expected to be extensively metabolized, and to predict the major route of elimination of compounds in a two tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calculated using ADMET Predictor or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compounds was analyzed with receiver operating characteristic curves. Compounds that yielded the highest sensitivity-specificity average were selected as permeability rate reference standards. The major route of elimination of poorly permeable drugs was predicted by our previously published model, and the accuracies and predictive values were calculated. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metabolism of compounds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Caco-2 and MDCK, respectively, while theophylline predicted greater than 80% of extensively and poorly metabolized drugs correctly in PAMPA. A two tier approach predicting elimination route predicts 72 +/- 9%, 49 +/- 10%, and 66 +/- 7% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is predicted in silico and 74 +/- 7%, 85 +/- 2%, and 73 +/- 8% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is determined in vitro. PMID- 25816853 TI - New insights into the phase diagram of a magnetic perovskite, LaCo1/3Mn2/3O3. AB - We report the crystal structure of the orthorhombic perovskite LaCo1/3Mn2/3O3 as determined by neutron diffraction from 5-300 K. A high-temperature x-ray diffraction study is also reported from 290-900 K. At temperatures above 570 K, LaCo1/3Mn2/3O3 transforms to a rhombohedral structure with space group R3c. This rhombohedral phase is also observed in the material at high pressure and the crystal structure has been determined by in situ neutron diffraction at 4.7 GPa. Finally, the ferromagnetic behaviour has been determined by magnetometry and the magnetic structure has been determined using low temperature neutron diffraction at ambient pressure. PMID- 25816854 TI - Is it possible to limit the use of CT scanning in acute diverticular disease without compromising outcomes? A preliminary experience. AB - The aim of our study was to determine whether the use of CT scanning in the assessment of acute diverticulitis can be reduced without a negative effect on outcome. Our series consisted of 93 out of 100 patients with acute diverticulitis admitted to the Emergency Room of our institution in the period from February 2012 to March 2013.The Hinchey classification system was used to stage disease based on findings on ultrasound (US) examination and/or computed tomography (CT) scanning. We compared the patients' Hinchey stage (HS) on admission and 72 hours later. Types of treatment were defined as emergency or delayed intervention (operative approaches (OA); ultrasound-guided percutaneous drainage (UPD), and surgery. The borderline between conservative and surgical management was identified. In patients with a HS 15 was defined as major trauma. Inter-rater reliability of new injury severity scoring system was expressed as intra-class correlation coefficient with 95% confidence intervals. RESULTS: There were 125 major and 303 minor traumas. The intra-class correlation coefficient was 0.83 (95% confidence intervals 0.58-0.94) for major trauma and intra-class correlation coefficient was 0.96 (95% confidence intervals 0.89-0.98) for minor trauma. Traffic (37%) and fall (31%) accidents were the leading mechanisms of injury. Elderly (aged ?65 years) were at an increased risk of fall accidents (p<0.001). The overall 3 month mortality rate was 10.3% (2% for new injury severity scoring system 16-24, 39% for new injury severity scoring system 25-40 and 68% for new injury severity scoring system >40). A higher new injury severity scoring system score (p<0.001), higher age (p<0.001), shock at admission (p<0.001), intensive care unit stay (p<0.004) and administration of massive red blood cell transfusion (p<0.048) were associated with mortality. Thirty-three patients underwent forensic autopsy and were tested positive for one or multiple drugs in 52% and 33%, respectively. CONCLUSIONS: The high prevalence of detected drugs among those undergoing forensic toxicological examination suggests that toxicology screening should be integrated into all red trauma alarm admissions, which may have implications on prevention of future trauma morbidity and mortality. PMID- 25816860 TI - Reduction in pedometer-determined physical activity in the adult Danish population from 2007 to 2012. AB - AIMS: To examine the development in pedometer-determined physical activity from 2007-2008 to 2011-2012 in the adult Danish population. METHODS: The study population comprised two random samples of 18-75-year-old individuals who took part in cross-sectional studies in 2007-2008 (n=224) and 2011-2012 (n=1515). Pedometer data (sealed Yamax SW 200) were obtained for seven consecutive days. Data for 1624 participants (48.2% men) were included in the analysis. An overall step-defined activity level was examined based on a graduated step index (sedentary, low active, somewhat active, active, highly active). The pedometer determined outcomes were analysed using regression models. RESULTS: A borderline significant decline (p=0.077) from 8788 to 8341 steps/day (-446 (95% confidence intervals -50, 943)) was found between 2007-2008 and 2011-2012. Furthermore, a 23.7% (95% confidence intervals -41.7%, -0.1%) lower overall step-defined activity level was observed in 2011-2012 compared to 2007-2008. These changes were primarily due to a reduced level of activity among women. The proportion of individuals taking ?10,000 steps/day decreased non-significantly from 34.8% to 29.3%, whereas the proportion taking <5000 steps/day did not differ between survey periods. CONCLUSIONS: This nationally representative survey suggests an overall reduction in the physical activity level among Danish adults. The reduction was due to a shift in the population distribution from higher to lower levels of activity. If this shift is true, it is worrying from a public health perspective. Our study result needs, however, to be confirmed by other population studies. PMID- 25816861 TI - Sickness absence and subsequent disposable income: A population-based cohort study. AB - AIMS: Studies show a negative association between an absence from work due to disease of injury (sickness absence (SA)) and subsequent earnings; however, little is known about the association between SA and an individuals' subsequent overall economic welfare. Our primary objective was to evaluate individuals' disposable income (DI) following a spell of SA. Our secondary objective was to examine if the potential association between SA and DI differs, depending on the diagnosis given to that sickness or the duration of the SA spell. METHODS: We used a cohort based on a linked individual register database that includes all individuals living in Sweden from 2001 to 2005, aged 30-54. DI was measured 2-6 years after a spell of SA and compared with a propensity score-matched reference group (individuals without SA in 2005). Each year of follow-up during 2007-2011 was estimated by linear regression for three different forms of exposure: SA (yes/no), diagnosis specific (cancer, circulatory, injuries, musculoskeletal or mental illnesses), and by duration of the SA spell (15-29, 30-89, 90-179 or > 179 days). RESULTS: Individuals with SA during 2005 had 4% lower disposable income in subsequent years than the reference group. Our results were similar across diagnoses, except for mental diagnoses, where disposable income was 7-10% lower than the reference group; and for cancer, where we found only a marginal difference among those with SA and the reference group. Furthermore, DI was negatively associated with the SA spell duration. CONCLUSIONS: SA was associated with lower subsequent DI, 2-6 years after a SA spell, especially after a mental illness diagnosis and if the SA was for longer spells. PMID- 25816863 TI - How well do parental and peer relationships in adolescence predict health in adulthood? AB - AIM: Although health effects of social relationships are well-researched, long term health consequences of adolescent family as well as peer relationships are poorly understood. The aim of the study was to explore the prospective importance of parental and peer social relationships in adolescence on internalising and functional somatic symptoms in adulthood. METHODS: Data were drawn from four waves of the Northern Swedish Cohort Study, response rate 94.3%, N=1001. Outcome variables were internalising and functional somatic symptoms at the ages of 21, 30 and 42. Relationship variables at age 16 were poor parental contact and three indicators of poor peer relationships. Associations were assessed in multivariate ordinal logistic regressions with adjustment for confounders and baseline health. RESULTS: Results show that the main relationships-related predictors of adult internalising symptoms were self-rated poor peer relationships in terms of spending time alone during after-school hours and poor parental relationship. Functional somatic symptoms on the other hand were most strongly associated with poor parental contact and not being happy with classmates at age 16. CONCLUSIONS: The quality of parental and peer relationships in adolescence predicts adult mental and functional somatic health as much as 26 years later, even when accounting for confounders and adolescent symptomatology. This study extends past research by exploring how both adolescent parental and peer relationships (self reported as well as teacher reported) predict adult self-reported health. PMID- 25816862 TI - Barriers and facilitators for implementation of a return-to-work intervention for sickness absence beneficiaries with mental health problems: Results from three Danish municipalities. AB - AIMS: Evidence for the effectiveness of return-to-work (RTW) interventions aimed at sickness absence beneficiaries with mental health problems (MHPs) is still relatively sparse and mostly inconclusive. This may in part reflect the varying settings and inconsistent implementations associated with the interventions. The aim of this paper is to identify barriers and facilitators for the implementation of a coordinated and tailored RTW-intervention implemented at three different sites. METHODS: We used qualitative and quantitative data to assess the implementation according to process evaluation guidelines. Data sources were individual and group interviews, observations, national registers, and documents used in the intervention. RESULTS: The quality of the implementation varied greatly across the three settings. Barriers included lack of skills to assess MHPs according to the inclusion criteria, different interpretations of sickness absence legislation among stakeholders, competing rehabilitation alternatives, and lack of managerial support for the intervention. An important facilitator was the motivation and availability of resources to solve disagreements through extensive communication. CONCLUSIONS: The different settings presented various barriers and facilitators, which resulted in different versions of the intervention. A higher degree of user involvement in the design and development phase is likely to improve the implementation quality of future interventions. PMID- 25816864 TI - Functional performance in older adults with hearing loss: Application of the International Classification of Functioning brief core set for hearing loss: A pilot study. AB - OBJECTIVES: The beta version of the International Classification of Functioning, Disability, and Health (ICF) brief core set for hearing loss in adults was developed and recommended to be validated through the audiologic rehabilitation clinical practice. The aims of this pilot study were to validate the ICF brief core set by examining the dimensions of hearing performance measures used in a standard care university clinic specializing in amplification, and seeing if those dimensions support the structure provided by the core set. DESIGN: ICF linking, classification, and qualifier coding procedures were applied on a data set identified from clinical records and two paper-pencil questionnaires; and completed by consensus of two experienced audiologists. STUDY SAMPLE: Forty-nine participants were recruited from an out-patient population at an audiology clinic. RESULTS: Eighteen of 27 items from the brief core set were able to be linked and validated. Four factors were identified, and confirmed the structure of ICF concept: Auditory function, Other functions, Activities/contextual interaction, and Third-party disability. Further, three predictors significantly discriminated performance in 28 participants: the use of hearing assistive devices, speech-reading, and active social life. CONCLUSIONS: The ICF brief core set is a valuable tool for use in audiologic rehabilitation clinical practice and research design. PMID- 25816865 TI - A process evaluation of implementing a vocational enablement protocol for employees with hearing difficulties in clinical practice. AB - OBJECTIVE: A multidisciplinary vocational rehabilitation programme, the Vocational Enablement Protocol (VEP) was developed to address the specific needs of employees with hearing difficulties. In the current study we evaluated the process of implementing the VEP in audiologic care among employees with hearing impairment. DESIGN: In conjunction with a randomized controlled trial, we collected and analysed data on seven process parameters: recruitment, reach, fidelity, dose delivered, dose received and implemented, satisfaction, and perceived benefit. STUDY SAMPLE: Sixty-six employees with hearing impairment participated in the VEP. The multidisciplinary team providing the VEP comprised six professionals. RESULTS: The professionals performed the VEP according to the protocol. Of the recommendations delivered by the professionals, 31% were perceived as implemented by the employees. Compliance rate was highest for hearing-aid uptake (51%). Both employees and professionals were highly satisfied with the VEP. Participants rated good perceived benefit from it. CONCLUSIONS: Our results indicate that the VEP could be a useful treatment for employees with hearing difficulties from a process evaluation perspective. Implementation research in the audiological setting should be encouraged in order to further provide insight into parameters facilitating or hindering successful implementation of an intervention and to improve its quality and efficacy. PMID- 25816866 TI - Hearing aid and cochlear implant use in children with hearing loss at three years of age: Predictors of use and predictors of changes in use. AB - OBJECTIVE: To examine usage patterns of hearing aids and cochlear implants in children up to three years of age, how usage changes longitudinally, and factors associated with device usage. DESIGN: Parent report and Parent's Evaluation of Aural/oral Performance of Children (PEACH) data were obtained at six and twelve months after hearing-aid fitting or cochlear implant switch-on, and again at three years of age. The effect of device use on auditory functional performance was investigated using the PEACH questionnaire. STUDY SAMPLE: Four hundred and thirteen participants from the Longitudinal Outcomes of Children with Hearing Impairment (LOCHI) study were included for analysis. RESULTS: For users of hearing aids, higher usage at three years was associated with higher maternal education, and more severe hearing loss. For users of cochlear implants, higher usage was associated with higher maternal education and the absence of additional disabilities. Higher PEACH scores were associated with higher usage scores. After allowing for the effects of demographic characteristics, device use was not a significant predictor of functional performance. CONCLUSIONS: Sixty-two percent of children achieved consistent use (> 75% of waking hours) within the first year of receiving a hearing aid or a cochlear implant, and 71% by three years of age. PMID- 25816867 TI - Do family-oriented interventions reduce poststroke depression? A systematic review and recommendations for practice. AB - INTRODUCTION: Up to half of all stroke survivors become depressed. Poststroke depression (PSD) negatively impacts on quality of life and rehabilitation outcomes and increases risk of mortality. Depression is also common in carers, leading to poorer outcomes in survivors. Few stroke patients receive adequate care to support prevention and management of PSD. We aimed to systematically review the evidence regarding the effectiveness of family-oriented interventions to prevent and manage depression after stroke and identify components of effective interventions. METHODS: A systematic review was conducted, adhering to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Eight databases were searched, and relevant journals and reference lists were hand searched. Abstracts were screened for relevance and two authors independently assessed selected full texts against inclusion criteria. Studies were included if they (1) engaged stroke patients and their informal/family caregivers; (2) measured changes in depression due to an intervention; and (3) were available in English. RESULTS: Twenty-five of 2741 identified citations met the inclusion criteria. Five studies demonstrated significant reductions in depression. Commonalities across effective studies included the delivery of interventions that were structured and multicomponent, actively engaged patients and families, coordinated care, and were initiated soon after a stroke. CONCLUSION: Family-oriented stroke rehabilitation may reduce depression in stroke survivors and their family caregivers. More research is required to clarify the effectiveness, feasibility, and acceptability of working with families and patients living with or who may be at risk of PSD. PMID- 25816869 TI - Relationship between social interaction bids and language in late talking children. AB - PURPOSE: The aim of this paper is to explore the relationship between language development and the frequency of social interaction (SI) behaviours during language acquisition in late-talking (LT) children who exhibit delays in expressive vocabulary development but have age-appropriate cognitive skills. METHOD: The research consists of a longitudinal study with a first test followed by two re-tests 5 months apart, in which LT children were compared to 5-months younger typically-developing (TD) children. RESULT: Data showed that LT children performed significantly fewer initiation of SI behaviours, but no differences between groups in responding to SI behaviours were observed. Furthermore, LT children who have lower language comprehension scores initiate social interaction more frequently. CONCLUSION: The results showed that LT children seem to be less active in starting social interaction and participation, but, once they get involved, they respond similarly to TD children of comparable expressive language competence. Additionally, the correlation pattern between the frequency of SI behaviours and language functions showed that LT toddlers with more prominent receptive language delay are more interested in initiating interaction with their partner, thus suggesting that they need a partner's "scaffolding" to overcome this lack. PMID- 25816870 TI - Special focus on nanoscale regeneration. PMID- 25816868 TI - A multi-centre audit of epistaxis management in England: is there a case for a national review of practice? AB - OBJECTIVE: The ENT-UK Clinical Audit and Practice Advisory Group initiated a pilot audit to investigate variance in epistaxis management between six units nationwide. METHOD: All patients with a diagnosis of epistaxis who were admitted for in-patient care at six ENT departments between November 2011 and February 2012 were prospectively enrolled. RESULTS: A total of 166 patients were included in the study. Variance was demonstrated between the six units in a number of the key outcome areas. Twenty-eight per cent of patients were identified as eligible for operative intervention for epistaxis in one unit, compared with only 12.5 per cent in another. CONCLUSION: There are measurable, patient-relevant outcomes to assess epistaxis management and these can highlight areas of potential improvement. This pilot audit gives a snapshot of modern practice, which shows variance between the six units assessed. A national audit may allow us to improve patient experience and maximise efficiency in delivering emergency care in our most common patient encounter. PMID- 25816871 TI - Receptor clustering control and associated force sensing by surface patterning: when force matters. PMID- 25816872 TI - Seeking the right context for evaluating nanomedicine: from tissue models in petri dishes to microfluidic organs-on-a-chip. PMID- 25816873 TI - Multiple facets for extracellular matrix mimicking in regenerative medicine. PMID- 25816874 TI - The influence of anisotropic nano- to micro-topography on in vitro and in vivo osteogenesis. AB - AIM: Topographically modified substrates are increasingly used in tissue engineering to enhance biomimicry. The overarching hypothesis is that topographical cues will control cellular response at the cell-substrate interface. MATERIALS & METHODS: The influence of anisotropically ordered poly(lactic-co-glycolic acid) substrates (constant groove width of ~1860 nm; constant line width of ~2220 nm; variable groove depth of ~35, 306 and 2046 nm) on in vitro and in vivo osteogenesis were assessed. RESULTS & DISCUSSION: We demonstrate that substrates with groove depths of approximately 306 and 2046 nm promote osteoblast alignment parallel to underlined topography in vitro. However, none of the topographies assessed promoted directional osteogenesis in vivo. CONCLUSION: 2D imprinting technologies are useful tools for in vitro cell phenotype maintenance. PMID- 25816876 TI - Human mesenchymal stem cell behavior on femtosecond laser-textured Ti-6Al-4V surfaces. AB - AIM: The aim of the present work was to investigate ultrafast laser surface texturing as a surface treatment of Ti-6Al-4V alloy dental and orthopedic implants to improve osteoblastic commitment of human mesenchymal stem cells (hMSCs). MATERIALS & METHODS: Surface texturing was carried out by direct writing with an Yb:KYW chirped-pulse regenerative amplification laser system with a central wavelength of 1030 nm and a pulse duration of 500 fs. The surface topography and chemical composition were investigated by scanning electron microscopy and x-ray photoelectron spectroscopy, respectively. Three types of surface textures with potential interest to improve implant osseointegration can be produced by this method: laser-induced periodic surface structures (LIPSSs); nanopillars (NPs); and microcolumns covered with LIPSSs, forming a bimodal roughness distribution. The potential of the laser treatment in improving hMSC differentiation was assessed by in vitro study of hMSCs spreading, adhesion, elongation and differentiation using epifluorescence microscopy at different times after cell seeding, after specific stainings and immunostainings. RESULTS: Cell area and focal adhesion area were lower on the laser-textured surfaces than on a polished reference surface. Obviously, the laser-textured surfaces have an impact on cell shape. Osteoblastic commitment was observed independently of the surface topography after 2 weeks of cell seeding. When the cells were cultured (after 4 weeks of seeding) in osteogenic medium, LIPSS- and NP- textured surfaces enhanced matrix mineralization and bone-like nodule formation as compared with polished and microcolumn-textured surfaces. CONCLUSION: The present work shows that surface nanotextures consisting of LIPSSs and NPs can, potentially, improve hMSC differentiation into an osteoblastic lineage. PMID- 25816875 TI - Antibacterial and osteogenic stem cell differentiation properties of photoinduced TiO2 nanoparticle-decorated TiO2 nanotubes. AB - AIM: To improve the antibacterial and mammalian cell compatibility properties of titania nanotubes (TNTs) anodized into titanium (Ti). MATERIALS & METHODS: 3-8-nm TiO2 nanoparticles were decorated on the surface and inside TNT (TNT-TiO2) through a hydrothermal method. After UV light treatment, two types of oral bacteria and stem cells were cultured on the samples to determine antibacterial and compatibility properties. RESULTS: TiO2 nanoparticles increased the surface area and photocatalysis of TNTs. Based on the photocatalysis effect and prolonged photo-induced wettability, the numbers of Streptococcus mutans and Porphyromonas gingivalis were lower on the surface of TNT-TiO2 than pure Ti and TNTs after the first 7 days. Specifically, for S. mutans, the glycosytransferase (gtf) genes were downregulated 0.1-0.2-fold on TNT-TiO2. Due to the different topography and high surface energy of TNT-TiO2, stem cells also showed improved osteogenic functions on TNT-TiO2. CONCLUSION: In this study, we demonstrated for the first time improved antibacterial properties and, at the same time, greater stem cell osteogenic capacity when decorating TNTs with nanosized TiO2 particles, which may significantly improve orthopedic and dental implant efficacy. PMID- 25816877 TI - Comparative bone tissue integration of nanostructured and microroughened dental implants. AB - AIM: The aim was to compare osteointegration of nanostructured implants to a microsurface widely used for titanium dental implants. MATERIALS & METHODS: Commercial titanium dental implants with smooth or microroughened surfaces were nanostructured. Implants were inserted into the femoral condyles of rabbits. After 2 and 4 weeks, histomorphometry calculation was performed. RESULTS: Nanotubes measuring 60 nm in diameter were observed on both S-NANO (roughness: 0.05 MUm) and R-NANO (roughness: 0.40 MUm) surfaces. The MICRO surface exhibited typical random cavities (roughness: 2.09 MUm). At 4 weeks, bone-to-implant contact values were significantly higher for the R-NANO than for the MICRO surface while no differences were observed at 2 weeks. CONCLUSION: Overall, this study shows that the nanostructured surfaces improved osteointegration similar or higher than the MICRO. PMID- 25816878 TI - Active implant combining human stem cell microtissues and growth factors for bone regenerative nanomedicine. AB - AIMS: Mesenchymal stem cells (MSCs) from adult bone marrow provide an exciting and promising stem cell population for the repair of bone in skeletal diseases. Here, we describe a new generation of collagen nanofiber implant functionalized with growth factor BMP-7 nanoreservoirs and equipped with human MSC microtissues (MTs) for regenerative nanomedicine. MATERIALS & METHODS: By using a 3D nanofibrous collagen membrane and by adding MTs rather than single cells, we optimize the microenvironment for cell colonization, differentiation and growth. RESULTS & CONCLUSION: Furthermore, in this study, we have shown that by combining BMP-7 with these MSC MTs in this double 3D environment, we further accelerate bone growth in vivo. The strategy described here should enhance the efficiency of therapeutic implants compared with current simplistic approaches used in the clinic today based on collagen implants soaked in bone morphogenic proteins. PMID- 25816879 TI - Fibrin-based microsphere reservoirs for delivery of neurotrophic factors to the brain. AB - AIM: The in vivo therapeutic potential of neurotrophic factors to modify neuronal dysfunctions is limited by their short half-life. A biomaterials-based intervention, which protects these factors and allows a controlled release, is required. MATERIALS & METHODS: Hollow fibrin microspheres were fabricated by charge manipulation using polystyrene templates and were loaded with NGF. Bioactivity of released NGF was demonstrated by neuronal outgrowth assay in PC-12 cells followed by in vivo assessment for NGF release and host response. RESULTS: Fibrin-based hollow spheres showed high loading efficiency (>80%). Neurotrophin encapsulation into the microspheres did not alter its bioactivity and controlled release of NGF was observed in the in vivo study. CONCLUSION: Fibrin hollow microspheres act as a suitable delivery platform for neurotrophic factors with tunable loading efficiency and maintaining their bioactive form after release in vivo. PMID- 25816880 TI - In vitro and in vivo evaluation of the inflammatory potential of various nanoporous hydroxyapatite biomaterials. AB - AIM: To discriminate the most important physicochemical parameters for bone reconstruction, the inflammatory potential of seven nanoporous hydroxyapatite powders synthesized by hard or soft templating was evaluated both in vitro and in vivo. MATERIALS & METHODS: After physical and chemical characterization of the powders, we studied the production of inflammatory mediators by human primary monocytes after 4 and 24 h in contact with powders, and the host response after 2 weeks implantation in a mouse critical size defect model. RESULTS: In vitro results highlighted increases in the secretion of TNF-alpha, IL-1, -8, -10 and proMMP-2 and -9 and decreases in the secretion of IL-6 only for powders prepared by hard templating. In vivo observations confirmed an extensive inflammatory tissue reaction and a strong resorption for the most inflammatory powder in vitro. CONCLUSION: These findings highlight that the most critical physicochemical parameters for these nanoporous hydroxyapatite are, the crystallinity that controls dissolution potential, the specific surface area and the size and shape of crystallites. PMID- 25816882 TI - Cell migration within confined sandwich-like nanoenvironments. AB - AIM: We introduced sandwich-like culture as a tool to engineer the cellular nanoenvironment by tuning protein presentation and activation of dorsal and ventral receptors. We aim at studying cell migration under more similar conditions to the 3D physiological one. MATERIALS & METHODS: We have investigated different nanoenvironments by changing the protein coating and using materials that adsorb proteins in different conformation, seeking to show their specific role in cell migration. RESULTS: Cell migration within sandwich cultures greatly differs from 2D cultures, shares some similarities with migration within 3D environments and is highly dependent on the protein nanoenvironment. Beyond differences in cell morphology and migration, dorsal stimulation promotes cell remodeling of the extracellular matrix over simple ventral receptor activation in traditional 2D cultures. CONCLUSION: Local(nano) stimulation of dorsal and ventral receptors within sandwich cultures alter cell migration in comparison to standard 2D environments. PMID- 25816881 TI - Electrodeposited gels prepared from protein alloys. AB - AIM: Silk-tropoelastin alloys, composed of recombinant human tropoelastin and regenerated Bombyx mori silk fibroin, are an emerging, versatile class of biomaterials endowed with tunable combinations of physical and biological properties. Electrodeposition of these alloys provides a programmable means to assemble functional gels with both spatial and temporal controllability. MATERIALS & METHODS: Tropoelastin-modified silk was prepared by enzymatic coupling between tyrosine residues. Hydrogel coatings were electrodeposited using two wire electrodes. RESULTS & DISCUSSION: Mechanical characterization and in vitro cell culture revealed enhanced adhesive capability and cellular response of these alloy gels as compared with electrogelled silk alone. CONCLUSION: These electro-depositable silk-tropoelastin alloys constitute a suitable coating material for nanoparticle-based drug carriers and offer a novel opportunity for on-demand encapsulation/release of nanomedicine. PMID- 25816883 TI - Regulation of stem cell fate by nanomaterial substrates. AB - Stem cells are increasingly studied because of their potential to underpin a range of novel therapies, including regenerative strategies, cell type-specific therapy and tissue repair, among others. Bionanomaterials can mimic the stem cell environment and modulate stem cell differentiation and proliferation. New advances in these fields are presented in this review. This work highlights the importance of topography and elasticity of the nano-/micro-environment, or niche, for the initiation and induction of stem cell differentiation and proliferation. PMID- 25816884 TI - Responsive cell-material interfaces. AB - Major design aspects for novel biomaterials are driven by the desire to mimic more varied and complex properties of a natural cellular environment with man made materials. The development of stimulus responsive materials makes considerable contributions to the effort to incorporate dynamic and reversible elements into a biomaterial. This is particularly challenging for cell-material interactions that occur at an interface (biointerfaces); however, the design of responsive biointerfaces also presents opportunities in a variety of applications in biomedical research and regenerative medicine. This review will identify the requirements imposed on a responsive biointerface and use recent examples to demonstrate how some of these requirements have been met. Finally, the next steps in the development of more complex biomaterial interfaces, including multiple stimuli-responsive surfaces, surfaces of 3D objects and interactive biointerfaces will be discussed. PMID- 25816885 TI - Integrating mechanical and biological control of cell proliferation through bioinspired multieffector materials. AB - In nature, cells respond to complex mechanical and biological stimuli whose understanding is required for tissue construction in regenerative medicine. However, the full replication of such bimodal effector networks is far to be reached. Engineering substrate roughness and architecture allows regulating cell adhesion, positioning, proliferation, differentiation and survival, and the external supply of soluble protein factors (mainly growth factors and hormones) has been long applied to promote growth and differentiation. Further, bioinspired scaffolds are progressively engineered as reservoirs for the in situ sustained release of soluble protein factors from functional topographies. We review here how research progresses toward the design of integrative, holistic scaffold platforms based on the exploration of individual mechanical and biological effectors and their further combination. PMID- 25816886 TI - Chemotherapy with or without plasmapheresis in acute renal failure due to multiple myeloma: a meta-analysis. AB - BACKGROUND/AIM: The clinical benefits of plasmapheresis in the management of multiple myeloma-induced acute renal failure remain controversial. In this study, we conducted a meta-analysis to quantitatively evaluate the clinical efficacy of chemotherapy with or without plasmapheresis in the treatment of multiple myeloma patients with renal failure. METHODS: Randomized controlled trials evaluating clinical efficacy of plasmapheresis were identified by searching PubMed (from 1980 to November 2013) and EMBASE (from 1980 to November 2013). Outcomes subjected to meta-analysis were 6-month survival and dialysis-dependent rate. RESULTS: Three randomized controlled studies were selected for meta-analysis. A total of 63 patients received chemotherapy only and 84 patients were given both chemotherapy and plasmapheresis. No difference was observed in 6-month survival rate between plasmapheresis and control group (75% vs. 66.7%; risk ratio, 0.92; 95% CI, 0.76 - 1.11; p = 0.39). 6-month dialysis-dependent ratio was significantly lower in patients treated with both chemotherapy and plasmapheresis than chemotherapy only (15.6% vs. 37.2%; risk ratio, 2.02; 95% CI, 1.03 - 3.96; p = 0.04). CONCLUSION: Our meta-analysis results showed that plasmapheresis used as an adjunct to chemotherapy had a benefit in the management of dialysisdependent multiple myeloma patients with renal failure. PMID- 25816887 TI - Appraisals to affect: Testing the integrative cognitive model of bipolar disorder. AB - OBJECTIVE: Cognitive models have suggested that extreme appraisals of affective states and maladaptive affect regulation strategies are important in the development of bipolar symptomatology. Little is known about the pathway by which these appraisals and behaviours interact in the formation of activated and depressed affective states. This study tested the predictions that (1) ascent behaviours mediate the relationship between positive appraisals of activated mood and activation; and (2) descent behaviours mediate the relationship between negative appraisals of activated mood and depression. METHOD: A total of 52 individuals with a DSM-IV diagnosis of bipolar I or II disorder (confirmed by structured interview) completed biweekly assessments of affect regulation behaviours and mood for 4 weeks. Positive and negative appraisals of affective states were assessed at baseline through the Hypomanic Attitudes and Positive Prediction Inventory. Multilevel mediation analysis was used to explore the data. RESULTS: Ascent behaviours partially mediated the relationship between positive appraisals of activated mood and activation. Descent behaviours, but not negative appraisals of activated mood, predicted levels of depression indicating the absence of a mediation effect. CONCLUSION: The results suggest that positive appraisals of activated mood can escalate activation in individuals with bipolar disorder. Such appraisals may be inherently rewarding and reinforcing directly elevating levels of activation, whilst increasing individuals' use of ascent behaviours. The results are consistent with the view that appraisals and behaviours should be targeted during cognitive behavioural therapy for bipolar disorder. PRACTITIONER POINTS: It may be beneficial to target positive appraisals of activated mood in cognitive behavioural therapy for mania. Cognitive behavioural therapists may also wish to focus on identifying and targeting individuals' use of ascent behaviours to reduce highly activated states. PMID- 25816888 TI - Fixed combination of insulin and a glucagon-like peptide-1 analog for the treatment of type 2 diabetes, exemplified by insulin degludec and liraglutide. AB - Insulin therapy in the management of Type 2 diabetes is often postponed and/or not adequately intensified to maintain glycemic control because of the risk of weight gain and hypoglycemia. A fixed combination of the long-acting insulin degludec and liraglutide has recently been accepted by the EMA for the management of Type 2 diabetes. The incentive for this combination is to exploit the advantages of each of the drugs while counterbalancing the side effects. Insulin degludec effectively reduces fasting plasma glucose, but carries the risk of hypoglycemia and body weight gain. Liraglutide, on the other hand, exerts glycemic control with a minimal risk of hypoglycemia and, at the same time, reduces appetite and body weight. PMID- 25816889 TI - Mycobacterium abscessus pulmonary infection complicated with vertebral osteomyelitis in a heart transplant recipient: case report and literature review. AB - Infections produced by Mycobacterium abscessus are emerging in immunosuppressed patients, such as solid organ transplant recipients. We report the first case, to our knowledge, of a vertebral osteomyelitis caused by M. abscessus in a heart transplant recipient, and review the risk factors, manifestations, and therapeutic approaches to this uncommon disease. PMID- 25816890 TI - SENP1 regulates cell migration and invasion in neuroblastoma. AB - Neuroblastoma (NB) is an embryonic solid tumor derived from precursor cells of the sympathetic nervous system, and accounts for 11% of childhood cancers and around 15% of cancer deaths in children. SUMOylation and deSUMOylation are dynamic mechanisms regulating a spectrum of protein activities. The SUMO proteases (SENP) remove SUMO conjugate from proteins, and their expression is deregulated in diverse cancers. However, nothing is known about the role of SENPs in NBL. In the present study, we found that SENP1 expression was significantly high in metastatic NB tissues compared with primary NB tissues. Overexpression of SENP1 promoted NB cells migration and invasion. Inhibition of SENP1 could significantly suppress NB cell migration and invasion. Moreover, we found that SENP1 could regulate the expression of CDH1, MMP9, and MMP2. In summary, the data presented here indicate a significant role of SENP1 in the regulation of cell migration and invasion in NB and suppress SENP1 expression as promising candidates for novel treatment strategies of NB. PMID- 25816891 TI - Approach to assessing the economic impact of insulin-related hypoglycaemia using the novel Local Impact of Hypoglycaemia Tool. AB - AIM: To provide estimates of the costs of severe and non-severe insulin-related hypoglycaemia in the UK using the Local Impact of Hypoglycaemia Tool. METHODS: Rates of hypoglycaemia were extracted from the UK Hypoglycaemia Study Group observational study. The costs of severe and non-severe hypoglycaemic episodes in insulin-treated adults with Type 1 and Type 2 diabetes were estimated from UK data sources. The rates and costs were then applied to specific populations to give an estimate of the cost of insulin-related hypoglycaemia for the UK, a specific locality, or a user-defined population. User-specific rates and costs could also be applied. RESULTS: The estimated cost of a hypoglycaemic episode can range from as much as L2,152 for severe episodes (for which the patient is admitted to hospital) to as little as L1.67 for non-severe episodes. With a UK population of 64.1 million, the total estimated cost of managing insulin-related hypoglycaemia is L468.0 m per year (L295.9 m for severe episodes, L172.1 m for non-severe episodes). On a local health economy level, using a hypothetical general population of 100 000, the total cost of managing insulin-related hypoglycaemia is estimated to be L730,052 per year (L461,658 for severe and L268,394 for non-severe episodes). CONCLUSIONS: The Local Impact of Hypoglycaemia Tool highlights the economic burden of insulin-related hypoglycaemia. Non-severe episodes are often overlooked because of their low individual cost, but their high frequency makes the cumulative cost substantial. The Local Impact of Hypoglycaemia Tool also shows clinicians and budget-holders the economic impact of lower rates of hypoglycaemia. PMID- 25816893 TI - Treatment of venous leg ulcers with ultrasound-guided foam sclerotherapy: Healing, long-term recurrence and quality of life evaluation. AB - Venous leg ulcers (VLU) generally have slow healing rates (HR) and frequent recurrence rates (RR). The underlying etiology is venous hypertension. The present observational cohort study was to determine healing and RR in VLU treated with ultrasound-guided foam sclerotherapy (UGFS). One hundred and eighty VLU were treated with polidocanol microfoam monthly under ultrasound control. Median follow-up was 30 months (range: 17-40). One hundred seventy-two (95.6%) ulcers healed during the study. The overall twenty-four week HR was 79.4% and was significantly higher (95.1%) in patients with isolated great saphenous vein incompetence than in those with great saphenous vein plus perforator (91.7%) or exclusive perforator incompetence (78.9%) (p < 0.01). Patients without deep vein incompetence had a significantly higher 6-month HR (89.8%) than those with (67.4%) (p < 0.01). Multivariate analysis identified the following independent risk factors: chronicity > 12 months (OR 7.69), area > 6 cm(2) (OR 4.24), lipodermatoesclerosis (OR 12.22), history of > 3 previous ulcers (OR 5.57) and history of deep vein thrombosis (OR 6.18). One, two and three year ulcer RR were 8.1%, 14.9%, and 20.8%, respectively. Isolated perforator incompetence and previous history of venous surgery were significantly (p = 0.03) associated with a higher RR. VLU treated with microfoam sclerotherapy are associated with high HR and low mid-term RR. PMID- 25816892 TI - Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop. AB - We have previously reported that an adaptor protein CRK, including CRK-I and CRK II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues. PMID- 25816895 TI - Conservative management of a traumatic superficial temporal artery aneurysm. PMID- 25816894 TI - (1)H-NMR screening for the high-throughput determination of genotype and environmental effects on the content of asparagine in wheat grain. AB - Free asparagine in cereals is known to be the precursor of acrylamide, a neurotoxic and carcinogenic product formed during cooking processes. Thus, the development of crops with lower asparagine is of considerable interest to growers and the food industry. In this study, we describe the development and application of a rapid (1)H-NMR-based analysis of cereal flour, that is, suitable for quantifying asparagine levels, and hence acrylamide-forming potential, across large numbers of samples. The screen was applied to flour samples from 150 bread wheats grown at a single site in 2005, providing the largest sample set to date. Additionally, screening of 26 selected cultivars grown for two further years in the same location and in three additional European locations in the third year (2007) provided six widely different environments to allow estimation of the environmental (E) and G x E effects on asparagine levels. Asparagine concentrations in the 150 genotypes ranged from 0.32 to 1.56 mg/g dry matter in wholemeal wheat flours. Asparagine levels were correlated with plant height and therefore, due to recent breeding activities to produce semi-dwarf varieties, a negative relationship with the year of registration of the cultivar was also observed. The multisite study indicated that only 13% of the observed variation in asparagine levels was heritable, whilst the environmental contribution was 36% and the GxE component was 43%. Thus, compared to some other phenotypic traits, breeding for low asparagine wheats presents a difficult challenge. PMID- 25816896 TI - Correlation between salivary and serum oxidized LDL levels: a pilot study on overweight/obese subjects. AB - BACKGROUND: Saliva contains a variety of substances and could be functionally equivalent to serum in reflecting the physiological state of the body, including metabolic variations. Salivary samples are non-invasive, safe, and easier to handle than serum. Oxidized LDL cholesterol (oxLDL) is an additional cardiovascular risk factor playing an important role in atheromatous plaque formation; overweight/obese subjects present an increase in oxLDL concentrations. The aims of the study were to assess oxLDL salivary levels, if detectable, and to verify their possible correlation with serum in overweight/obese subjects. METHODS: Thirty-five consecutive overweight/obese subjects and 10 normal weight controls were enrolled. Serum and salivary oxLDL levels were measured by a commercial enzyme-linked-immunosorbent assay (ELISA method). RESULTS: oxLDL levels were detectable in salivary samples and correlated (P = 0.001) with serum levels. Overweight/obese subjects showed serum and salivary oxLDL levels higher than controls (P = 0.000 and P = 0.022, respectively). CONCLUSIONS: Our study showed the presence of oxLDL in salivary samples and highlighted a correlation between salivary oxLDL levels and their counterpart in serum. Moreover, salivary oxLDL levels were higher in overweight/obese subjects than in controls. Therefore, a salivary sample could be functionally equivalent to serum in monitoring cardiovascular risk in overweight/obese subjects. PMID- 25816898 TI - Flavor of fresh blueberry juice and the comparison to amount of sugars, acids, anthocyanidins, and physicochemical measurements. AB - Six cultivars of southern highbush (SHB) and rabbiteye (RE) blueberry samples were harvested on 2 different dates. Each treatment combination was pressed 2 times for repeated measures. Fresh juice was characterized for 18 flavor/taste/feeling factor attributes by a descriptive flavor panel. Each sample was measured for sugars, acids, anthocyanidins, Folin-Ciocalteu, soluble solids (BRIX), titratable acidity (TA), and antioxidant capacity (ORACFL ). Flavors were correlated with the composition and physicochemical data. Blueberry flavor correlated with 3 parameters, and negatively correlated with 2. Strawberry correlated with oxalic acid and negatively correlated with sucrose and quinic acid. Sweet aroma correlated with oxalic and citric acid, but negatively correlated with sucrose, quinic, and total acids. Sweet taste correlated with 11 parameters, including the anthocyanidins; and negatively correlated with 3 parameters. Neither bitter nor astringent correlated with any of the antioxidant parameters, but both correlated with total acids. Sour correlated with total acids and TA, while negatively correlating with pH and BRIX:TA. Throat burn correlated with total acids and TA. Principal component analysis negatively related blueberry, sweet aroma, and sweet to sour, bitter, astringent, tongue tingle, and tongue numbness. The information in this component was related to pH, TA, and BRIX:TA ratio. Another principal component related the nonblueberry fruit flavors to BRIX. This PC, also divided the SHB berries from the RE. This work shows that the impact of juice composition on flavor is very complicated and that estimating flavor with physicochemical parameters is complicated by the composition of the juice. PMID- 25816897 TI - Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. AB - BACKGROUND AND PURPOSE: Transient receptor potential canonical (TRPC) channels play important roles in a broad array of physiological functions and are involved in various diseases. However, due to a lack of potent subtype-specific inhibitors the exact roles of TRPC channels in physiological and pathophysiological conditions have not been elucidated. EXPERIMENTAL APPROACH: Using fluorescence membrane potential and Ca(2+) assays and electrophysiological recordings, we characterized new 2-aminobenzimidazole-based small molecule inhibitors of TRPC4 and TRPC5 channels identified from cell-based fluorescence high-throughput screening. KEY RESULTS: The original compound, M084, was a potent inhibitor of both TRPC4 and TRPC5, but was also a weak inhibitor of TRPC3. Structural modifications of the lead compound resulted in the identification of analogues with improved potency and selectivity for TRPC4 and TRPC5 channels. The aminobenzimidazole derivatives rapidly inhibited the TRPC4- and TRPC5-mediated currents when applied from the extracellular side and this inhibition was independent of the mode of activation of these channels. The compounds effectively blocked the plateau potential mediated by TRPC4-containing channels in mouse lateral septal neurons, but did not affect the activity of heterologously expressed TRPA1, TRPM8, TRPV1 or TRPV3 channels or that of the native voltage-gated Na(+) , K(+) and Ca(2) (+) channels in dissociated neurons. CONCLUSIONS AND IMPLICATIONS: The TRPC4/C5-selective inhibitors developed here represent novel and useful pharmaceutical tools for investigation of physiological and pathophysiological functions of TRPC4/C5 channels. PMID- 25816899 TI - Effects of partial replacement of barley grain with beet pulp on performance, ruminal fermentation and plasma concentration of metabolites in transition dairy cows. AB - The objective of this study was to determine the effect of partial replacement of barley grain with beet pulp (BP) on dry matter intake (DMI), ruminal fermentation, plasma concentration of metabolites and milk yield of transition dairy cows. Twenty-four multiparous Holstein cows [735 +/- 26 kg of body weights and 3.5 +/- 0.05 of body condition score (BCS)] were used in a randomized complete block design. Cows were assigned randomly on day 28 relative to expected parturition date to one of three treatments containing (i) 0% BP, (ii) 25% BP or (iii) 50% BP substituted for barley grain on a DM basis. During the pre-partum period, DMI and energy intake were greater (P < 0.01) in cows fed the BP diet compared with cows fed the barley grain diet. During the post-partum period, substituting BP for barley grain caused a response in DMI and energy intake, with the highest amount for the 25% BP diet and lowest for the 50% BP diet (P < 0.01). Milk yield was lowest (P < 0.01) for 50% BP diet than the other treatments. During the post-partum period, cows fed the 50% BP diets had greater rumen pH, molar proportion of butyrate and acetate: propionate ratio (P < 0.01) in the rumen compared with cows fed the 0% BP diets. In addition, cows fed the BP diets had greater (P < 0.01) plasma beta-hydroxybutyrate and lower plasma glucose (P < 0.05) and blood urinary nitrogen (BUN) (P < 0.01) concentrations than cows fed the barley grain diets. Results showed that substituting BP for barley grain was effective in increasing DMI, but it did not have a significant effect on net energy balance during the post-partum period. However, replacing BP for barley grain at 50% had adverse effects on DMI, milk yield and metabolic status, as indicated by key blood metabolite concentrations. PMID- 25816900 TI - Treatment of Langerhans cell histiocytosis: it is time to learn from the past. PMID- 25816901 TI - Providing an extended use of an otological-specific outcome instrument to derive cost-effectiveness estimates of treatment. AB - OBJECTIVES: Although quality-adjusted life years (QALYs) are increasingly being used by decision-makers to make comparisons of cost-effectiveness, there are no otological-specific outcome measures that fit within this QALY framework. This study had two main objectives. The first was to provide a means to derive QALYs from a condition-specific otological instrument (Cambridge Otology Quality of Life, COQOL), and the second was to assess the convergent validity, or degree of correlation, between the COQOL and SF-6D, an established QALY instrument. DESIGN: Longitudinal cohort study designed to assess the convergent validity between SF 6D and COQOL and to generate a mapping function to enable SF-6D values to be predicted from the COQOL responses. SETTING: Cambridge University Hospital, UK. PARTICIPANTS: A total of 207 patients attending a routine outpatient general otology clinic. MAIN OUTCOME MEASURES: SF-6D and the COQOL instrument completed at baseline and again 3 months later. RESULTS: Convergent validity was demonstrated with mean SF-6D values decreasing linearly with increasing severity on the COQOL instrument. Overall, the correlation between the COQOL scores and the SF-6D values was moderate and statistically significant (r = 0.490, P = <0.001). A simple mapping model based on an ordinary least squares (OLS) regression function predicted SF-6D values from the COQOL data with a reasonable degree of accuracy. Further validation using the follow-up 3-month data confirmed the prediction power of this mapping model. CONCLUSIONS: This study provides a method for estimating QALYs from condition-specific COQOL data and provides the opportunity for the cost-effectiveness of otological treatment to be measured and placed within the national QALY framework. PMID- 25816903 TI - Men living with long-term conditions: exploring gender and improving social care. AB - Disabled men have traditionally been seen as incomplete men or as entirely gender less. Research which has looked at the intersection of disability and male gender has largely treated disabled men as a homogeneous group with little reference to, for example, impairment-related differences. The ongoing move towards self directed, personalised social care in England suggests that support needs relating to gender may be taken more seriously. A qualitative study with 20 men with Duchenne muscular dystrophy in England in 2013 explored the men's experiences of the organisation and delivery of social care as it pertained to their sense of being men. Our main finding was that social care in its broadest sense did little to support a positive sense of masculinity or male gender. More often than not the organisation and delivery of social care people de-gendered or emasculated many of the men who took part in the study. Our paper speaks to the need to explore impairment-specific issues for disabled men; to deliver a more person-centred approach to social care which recognises the importance of the social and sexual lives of disabled men; and to create ways in which men can support and empower each other to assert essential human rights relating to independence, dignity and liberty. PMID- 25816904 TI - Is Pornography Use Associated with Sexual Difficulties and Dysfunctions among Younger Heterosexual Men? AB - INTRODUCTION: Recent epidemiological studies reported high prevalence rates of erectile dysfunction (ED) among younger heterosexual men (<=40). It has been suggested that this "epidemic" of ED is related to increased pornography use. However, empirical evidence for such association is currently lacking. AIM: This study analyzes associations between pornography use and sexual health disturbances among younger heterosexual men using four large-scale online samples from three European countries. METHODS: The analyses were carried out using a 2011 cross-sectional online study of Croatian, Norwegian, and Portuguese men (Study 1; N = 2,737) and a 2014 cross-sectional online study of Croatian men (Study 2; N = 1,211). Chi-square test and multivariate logistic regression were used to explore the associations between pornography use and sexual difficulties. MAIN OUTCOME MEASURES: In Study 1, erectile difficulties, inability to reach orgasm, and a lack of sexual desire were measured using the Global Study of Sexual Attitudes and Behavior indicators. In Study 2, ED was measured with the abridged International Index of Erectile Function (IIEF-5). Delayed ejaculation and a decrease of sexual desire were assessed with one-item indicators. RESULTS: In Study 1, only the relationship between pornography use and ED among Croatian men was statistically significant (chi(2) [2] = 18.76, P < 0.01). The association was small and inconsistent. Compared with infrequent use of pornography, moderate but not high frequency of pornography use increased the odds of reporting ED (adjusted odds ratio = 0.53, P < 0.01). In Study 2, no significant associations both between either the frequency or the recent dynamics of pornography use and male sexual dysfunctions were observed. CONCLUSION: We found little evidence of the association between pornography use and male sexual health disturbances. Contrary to raising public concerns, pornography does not seem to be a significant risk factor for younger men's desire, erectile, or orgasmic difficulties. PMID- 25816905 TI - Medical photography: it has never been so easy and yet so complex. PMID- 25816906 TI - Constipation during acute hospitalisation: vigilance critical for all patients at high risk. PMID- 25816907 TI - Women's toileting behaviours: an online survey of female advanced practice providers. PMID- 25816902 TI - d-amino acid oxidase knockout (Dao(-/-) ) mice show enhanced short-term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption. AB - d-amino acid oxidase (DAO, DAAO) is an enzyme that degrades d-serine, the primary endogenous co-agonist of the synaptic N-methyl-d-aspartate receptor. Convergent evidence implicates DAO in the pathophysiology and potential treatment of schizophrenia. To better understand the functional role of DAO, we characterized the behaviour of the first genetically engineered Dao knockout (Dao(-/-) ) mouse. Our primary objective was to assess both spatial and non-spatial short-term memory performance. Relative to wildtype (Dao(+/+) ) littermate controls, Dao(-/ ) mice demonstrated enhanced spatial recognition memory performance, improved odour recognition memory performance, and enhanced spontaneous alternation in the T-maze. In addition, Dao(-/-) mice displayed increased anxiety-like behaviour in five tests of approach/avoidance conflict: the open field test, elevated plus maze, successive alleys, light/dark box and novelty-suppressed feeding. Despite evidence of a reciprocal relationship between anxiety and sleep and circadian function in rodents, we found no evidence of sleep or circadian rhythm disruption in Dao(-/-) mice. Overall, our observations are consistent with, and extend, findings in the natural mutant ddY/Dao(-) line. These data add to a growing body of preclinical evidence linking the inhibition, inactivation or deletion of DAO with enhanced cognitive performance. Our results have implications for the development of DAO inhibitors as therapeutic agents. PMID- 25816908 TI - Improving the odds: ezetimibe and cardiovascular disease. AB - The beauty of science is that well-conducted experiments provide answers to questions which were posed in times of greater ignorance. Cardiovascular disease (CVD) is the leading cause of death worldwide and will be for some time. Cholesterol is a critical player which drives the underlying pathophysiological process of atherosclerosis. Statins are the first line treatment for lipids in CVD given their ability to low-density lipoprotein cholesterol (LDL-C) by up to 50%, and their proven benefits in both primary and secondary intervention . Despite the unprecedented efficacy of statins, additional treatments are sought to potentially reduce the residual risk that remains despite statin treatment such as that associated with reduced high-density lipoprotein cholesterol levels (HDL-C) or triglycerides . In the last 5 years, several trials have reported on their potential additional benefit beyond statin therapy. These include omega-3 fatty acids in patients with prediabetes or diabetes , fibrates in diabetes , nicotinic acid/niacin in cardiovascular disease and cholesterol ester transfer protein inhibitors in cardiovascular disease . Despite their promise, none of these treatments were able to demonstrate benefit beyond baseline statin therapy when compared with placebo . The idea that benefit beyond statin treatment may be an unachievable goal has dogged the medical community working on CVD prevention. The phrase, 'Statins for atherosclerosis - as good as it gets?' was coined in 2005 and has rung true up until now . PMID- 25816909 TI - Complex clinical reasoning in the critical care unit - difficulties, pitfalls and adaptive strategies. AB - Diagnostic error has implications for both clinical outcome and resource utilisation, and may often be traced to impaired data gathering, processing or synthesis because of the influence of cognitive bias. Factors inherent to the intensive/acute care environment afford multiple additional opportunities for such errors to occur. This article illustrates many of these with reference to a case encountered on our intensive care unit. Strategies to improve completeness of data gathering, processing and synthesis in the acute care environment are critically appraised in the context of early detection and amelioration of cognitive bias. These include reflection, targeted simulation training and the integration of social media and IT based aids in complex diagnostic processes. A framework which can be quickly and easily employed in a variety of clinical environments is then presented. PMID- 25816910 TI - Hispanic parents' experiences of the process of caring for a child undergoing routine surgery: a focus on pain and pain management. AB - PURPOSE: The purpose was to understand the processes Hispanic parents undergo in managing postoperative care of children after routine surgical procedures. DESIGN AND METHODS: Sixty parents of children undergoing outpatient surgery were interviewed. Data were analyzed using grounded theory methodology. RESULTS: Parents experienced five subprocesses that comprised the overall process of caring for a child after routine surgery: (a) becoming informed; (b) preparing; (c) seeking reassurance; (d) communicating with one's child; and (e) making pain management decisions. PRACTICE IMPLICATIONS: Addressing cultural factors related to pain management in underserved families may instill greater confidence in managing pain. PMID- 25816911 TI - Testing cognitive predictors of individual differences in the sexual psychophysiological responses of sexually functional women. AB - The literature on sexual responses shows a large and not fully understood between women variance in sexual responses and in strength of coherence between physiological and subjective sexual responses. This study investigated cognitive factors theorized to be associated with sexual responses that could explain such variance. Specifically, we investigated the predictive value of sexual excitation/inhibition and sexual schemas on sexual response and coherence. Vaginal photoplethysmography and continuous subjective sexual arousal were collected from 29 young women while they watched a control/erotic video sequence. Hierarchical linear modeling revealed that high sexual excitation and schemas related to passion and romance were related to higher coherence. These findings support the notion that cognitive factors that enhance sexual arousal contribute to the large variation seen in the coherence of sexual response as measured in the laboratory. PMID- 25816913 TI - Dietary phenolic compounds selectively inhibit the individual subunits of maltase glucoamylase and sucrase-isomaltase with the potential of modulating glucose release. AB - In this study, it was hypothesized that dietary phenolic compounds selectively inhibit the individual C- and N-terminal (Ct, Nt) subunits of the two small intestinal alpha-glucosidases, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI), for a modulated glycemic carbohydrate digestion. The inhibition by chlorogenic acid, caffeic acid, gallic acid, (+)-catechin, and (-) epigallocatechin gallate (EGCG) on individual recombinant human Nt-MGAM and Nt-SI and on mouse Ct-MGAM and Ct-SI was assayed using maltose as the substrate. Inhibition constants, inhibition mechanisms, and IC50 values for each combination of phenolic compound and enzymatic subunit were determined. EGCG and chlorogenic acid were found to be more potent inhibitors for selectively inhibiting the two subunits with highest activity, Ct-MGAM and Ct-SI. All compounds displayed noncompetitive type inhibition. Inhibition of fast-digesting Ct-MGAM and Ct-SI by EGCG and chlorogenic acid could lead to a slow, but complete, digestion of starch for improved glycemic response of starchy foods with potential health benefit. PMID- 25816912 TI - Novel kappa-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation. AB - AIM: To characterize the pharmacological profiles of a novel kappa-opioid receptor agonist MB-1C-OH. METHODS: [(3)H]diprenorphine binding and [(35)S]GTPgammaS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. RESULTS: In [(3)H]diprenorphine binding assay, MB-1C-OH did not bind to MU- and delta-opioid receptors at the concentration of 100 MUmol/L, but showed a high affinity for kappa-opioid receptor (Ki=35 nmol/L). In [(35)S]GTPgammaS binding assay, the compound had an Emax of 98% and an EC50 of 16.7 nmol/L for kappa-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED50=0.39 mg/kg), which was antagonized by pretreatment with a selective kappa-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED50=0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical kappa agonist (-)U50,488H. CONCLUSION: MB-1C-OH is a novel kappa-opioid receptor agonist that produces potent antinociception causing less sedation and depression. PMID- 25816914 TI - PEGylated Fmoc-Amino Acid Conjugates as Effective Nanocarriers for Improved Drug Delivery. AB - A structure-activity relationship (SAR) study was conducted using a series of PEGylated Fmoc-amino acid conjugates (PFA) as a simple model to gain more insight into carrier-drug interaction. Among the eight PEG2000-Fmoc conjugates with different neighboring structures of Fmoc motif, PEG2000-Fmoc-Lys (Cbz) (PFA2) based nanomicelles exhibited the smallest particle size distribution, lowest critical micelle concentration (CMC) value, and highest loading capacity with paclitaxel (PTX). These biophysical properties were largely attributed to the strengthened carrier-carrier and carrier-drug interaction, including pi-pi stacking, hydrophobic, and hydrogen bonding interaction, as confirmed by fluorescence quenching and (13)C NMR study. In vitro and in vivo evaluation further demonstrated the effectiveness of PFA2 as a nanocarrier for efficient delivery of PTX to achieve improved antitumor activity. Importantly, PFA2 was also effective in formulating eight other model drugs of diverse structures, indicating a broad application potential. This work may shed insights into the molecular basis for the structural optimization of nanocarriers for improved delivery efficacy. PMID- 25816915 TI - Plastic expression of heterochrony quantitative trait loci (hQTLs) for leaf growth in the common bean (Phaseolus vulgaris). AB - Heterochrony, that is, evolutionary changes in the relative timing of developmental events and processes, has emerged as a key concept that links evolution and development. Genes associated with heterochrony encode molecular components of developmental timing mechanisms. However, our understanding of how heterochrony genes alter the expression of heterochrony in response to environmental changes remains very limited. We applied functional mapping to find quantitative trait loci (QTLs) responsible for growth trajectories of leaf area and leaf mass in the common bean (Phaseolus vulgaris) grown in two contrasting environments. We identified three major QTLs pleiotropically expressed under the two environments. Further characterization of the temporal pattern of these QTLs indicates that they are heterochrony QTLs (hQTLs) in terms of their role in influencing four heterochronic parameters: the timing of the inflection point, the timing of maximum acceleration and deceleration, and the duration of linear growth. The pattern of gene action by the hQTLs on each parameter was unique, being environmentally dependent and varying between two allometrically related leaf growth traits. These results provide new insights into the complexity of genetic mechanisms that control trait formation in plants and provide novel findings that will be of use in studying the evolutionary trends. PMID- 25816917 TI - Clinical Evaluation of Coronary In-Stent Restenosis Using Dual-Source Computed Tomography. AB - OBJECTIVE: To explore the feasibility of dual-source computed tomography (DSCT) in the evaluation of coronary in-stent restenosis (ISR) by comparing the results of DSCT and selective coronary angiography (CAG). METHODS: In-stent restenosis examination results from DSCT were compared with those obtained using CAG. RESULTS: Among 173 stents studied, 156 yielded good quality images when evaluated with DSCT. CAG identified 38 ISR cases, while DSCT found 40. Among the 112 stents in the study with an inner diameter >=3.0 mm, CAG identified 29 as having ISR, while DSCT reported the same finding in 30; among the 44 stents with inner diameter <3.0 mm, CAG identified ISR in 9, while DSCT found ISR in 10. CONCLUSIONS: Stent inner diameter is a key factor influencing the imaging of the stent lumen. DSCT demonstrated a higher negative predictive value in ISR assessment, suggesting that it could replace CAG for assessing the patency of stents with a larger inner diameter (>=3 mm). PMID- 25816918 TI - Quality of Life after Endoluminal Loco-Regional Resection (ELRR) by Transanal Endoscopic Microsurgery (TEM). AB - AIM: Endoluminal Loco-Regional Resection (ELRR) by Transanal Endoscopic Microsurgery (TEM) may be considered a valid alternative surgical treatment in patients with rectal cancer. Aim of this study is to evaluate the short and medium term Quality of Life (QoL) from prospectively collected data in patients who underwent ELRR by TEM. MATERIAL OF STUDY: From May 2010 to June 2013, 31 patients with iT1-iT2-iT3N0 rectal cancer were enrolled in this study. Patients with T1 rectal cancer underwent ELRR by TEM. Patients with iT2-iT3 rectal cancer underwent neoadjuvant radio-chemoterapy (n-RCT) before surgery. QoL was evaluated by EORTC QLQ-C30 and QLQ-CR38 questionnaires before surgery and 1, 6, and 12 months after surgery. RESULTS: Mean distance from the anal verge was 5.4 cm (range 1-10). Mean operative time was 145.8 minutes (range 60-300). Pathological staging was as follows: pT0N0 (6), pT1N0 (18), pT2N0 (7). At 1 month after surgery, in QLQC30 questionnaire, significant worsening was observed in Global Health Status (p=0.0028), Physical Functioning (p=0.0016), Role Functioning (p=0.0004), Fatigue (p=0.0024), Pain (p=0.0003) and Dyspnoea (p=0.0192). In QLQCR38 questionnaire significant worsening at 1 month was observed in Defecation Problems (p=0.0005) and Weight Loss (p=0.0008). At six and twelve months after surgery, no significant differences were observed in QLQ-C30 and in QLQCR38 questionnaires. DISCUSSION: QoL evaluation showed worsening results at 1 month after ELRR by TEM, in QLQ-C30 and in QLQCR38 questionnaires. CONCLUSIONS: At 6 and 12 months after surgery, no significant differences in QoL as compared to preoperative status were observed. PMID- 25816920 TI - Effect of the variation of the electronic density of states of zirconium and tungsten on their respective thermal conductivity evolution with temperature. AB - The thermal conductivity of zirconium and tungsten above 500 K is calculated with atomistic simulations using a combination of empirical potentials molecular dynamics and density functional theory calculations. The thermal conductivity is calculated in the framework of Kubo-Greenwood theory. The obtained values are in quantitative agreement with experiments. The fact that the conductivity of Zr increases with temperature while that of tungsten is essentially constant is reproduced by the calculations. The evolution with temperature of the electronic density of states of these two pseudo-gap metals proves to explain the observed variations of the conductivity. PMID- 25816919 TI - Angioimmunoblastic T-cell lymphoma with coexisting plasma cell myeloma: a case report and review of the literature. AB - Angioimmunoblastic T-cell lymphoma (AITL) is recognized as a distinct clinicopathological subtype of peripheral T-cell lymphomas. Its clinical features include generalized lymphadenopathy, constitutional symptoms, and autoimmune related findings, such as hemolytic anemia. Pathologically, AITL is characterized by a polymorphous infiltrate in lymph nodes with prominent proliferation of high endothelial venules and follicular dendritic cells. We present an 80-year-old Chinese man with generalized lymphadenopathy and pulmonary infection, diagnosed as AITL based on the distinctive pathological findings and T-cell receptor gamma (TCR-gamma) gene rearrangement analysis of lymph nodes. Importantly, the patient suffered from a coexisting plasma cell myeloma, as judged by monoclonal immunoglobulin in the serum, immature plasma cells, and rearrangement of the immunoglobulin heavy-chain (IgH) gene in the bone marrow. The patient received two courses of the chemotherapy but died of pneumonia 6 months after diagnosis. AITL can be accompanied by polyclonal or clonal proliferation of B lymphocytes; however, AITL are rarely associated with plasma cell proliferation. In fact, 14 AITL cases with plasma cell proliferation have been reported in the literature, but none of them manifested the infiltration of monoclonal immature plasma cells in the bone marrow. To the best of our knowledge, this is the first report of newly diagnosed, concurrent AITL and plasma cell myeloma, providing the evidence for the interplay between malignant T cells and plasma cell proliferation. A review of the literature has also supported a relationship between AITL and plasma cell proliferation. Awareness of this relationship is important for correct diagnosis and appropriate treatment of AITL. PMID- 25816921 TI - Using a personalized DVD to prescribe an exercise program to older people post hip fracture enhances adherence to the exercises - A feasibility study. AB - Optimum recovery from hip fracture has been linked to the provision of effective rehabilitation, but levels of adherence vary among older patients. In this feasibility study a novel personalized DVD was designed for four participants, which delivered a 5 week tailored home exercise program (HEP), with the participant being videoed completing their exercises. Treatment fidelity of the DVD HEP was evaluated, including participants' perceptions of and response to the DVD-HEP, which was explored using diaries and interviews and analyzed thematically. Secondary outcome measures including exercise adherence and self efficacy for exercise were analyzed using descriptive statistics. Levels of adherence to the HEP were 1.2-3.5 times more than the minimum prescribed dose and participants demonstrated higher levels of self-efficacy for exercise. Adherence was found to be enhanced by physical improvement, positive self-reflection about engagement in the DVD-HEP, the format of the DVD, and increased self-efficacy. Personalized DVDs may be a feasible method of promoting adherence to home exercise programs among older patients. PMID- 25816922 TI - An original case of Francisella tularensis subsp. holarctica bacteremia after a near-drowning accident. AB - We report the first case of Francisella tularensis subsp. holarctica bacteremia after water contamination in France. A 75-year-old man developed septic pneumonic tularemia after a near-drowning accident. We highlight the need for a longer incubation time for isolation of F. tularensis from blood cultures. PMID- 25816924 TI - New reports from the NIOSH health hazard evaluation program. PMID- 25816923 TI - Occupational and non-occupational factors associated with work-related injuries among construction workers in the USA. AB - BACKGROUND: Many factors contribute to occupational injuries. However, these factors have been compartmentalized and isolated in most studies. OBJECTIVE: To examine the relationship between work-related injuries and multiple occupational and non-occupational factors among construction workers in the USA. METHODS: Data from the 1988-2000 National Longitudinal Survey of Youth, 1979 cohort (N = 12,686) were analyzed. Job exposures and health behaviors were examined and used as independent variables in four multivariate logistic regression models to identify associations with occupational injuries. RESULTS: After controlling for demographic variables, occupational injuries were 18% (95% CI: 1.04-1.34) more likely in construction than in non-construction. Blue-collar occupations, job physical efforts, multiple jobs, and long working hours accounted for the escalated risk in construction. Smoking, obesity/overweight, and cocaine use significantly increased the risk of work-related injury when demographics and occupational factors were held constant. CONCLUSIONS: Workplace injuries are better explained by simultaneously examining occupational and non-occupational characteristics. PMID- 25816925 TI - Haemodynamic and electrophysiological markers of pragmatic language comprehension in schizophrenia. AB - OBJECTIVES: The present study aimed at investigating neurophysiological markers of language perception in schizophrenia using simultaneous near-infrared spectroscopy (NIRS) and event-related potentials (ERPs), which have been proven to be useful for studying language processing abilities in psychiatric patients. The study shall help to integrate previous findings from ERP and fMRI studies on figurative language comprehension in schizophrenia and elucidate how electrophysiological and haemodynamic markers of language processing are related. METHODS: Twenty-two healthy subjects and 22 schizophrenia patients judged 120 sentences regarding their meaningfulness. Phrases were literal, metaphoric, or meaningless. EEG-fNIRS signals were recorded throughout the entire experiment. RESULTS: Schizophrenia patients showed deficient and delayed sentence comprehension. Both the early N400 and left-hemispheric activation during language comprehension were altered in patients. Correlation analyses showed that metaphor-related ERPs were strongly linked to haemodynamic cortical activity in healthy subjects, but not in patients. CONCLUSIONS: Our results indicate group differences in cortical electrophysiological and haemodynamic activation that represent rather general impairments in the processing of complex language. Simultaneous EEG/NIRS applications are useful to depict these neural markers and to investigate their relationship. Future studies are needed to clarify the nature of respective anomalies and their potential as putative neural markers in schizophrenia research. PMID- 25816926 TI - Far-lateral approach assisted by multimodal neuronavigation and electrophysiological monitoring technique for complex clival tumor. AB - Large clival meningiomas are a major surgical challenge with risks to life and permanent deficit. A 65-year-old man with a meningioma anterior to the medulla oblongata with brain stem compression was operated with far-lateral approach assisted by multimodal neuronavigation and neurophysiological monitoring techniques. Total resection of the tumor was achieved with no intra- or post operative complications. This case illustrates the benefits obtained by a multimodal approach. PMID- 25816927 TI - Atomic Resolution of Calcium and Oxygen Sublattices of Calcite in Ambient Conditions by Atomic Force Microscopy Using qPlus Sensors with Sapphire Tips. AB - Characterization and imaging at the atomic scale with atomic force microscopy in biocompatible environments is an ongoing challenge. We demonstrate atomically resolved imaging of the calcite (1014) surface plane using stiff quartz cantilevers ("qPlus sensors", stiffness k = 1280 N/m) equipped with sapphire tips in ambient conditions without any surface preparation. With 10 atoms in one surface unit cell, calcite has a highly complex surface structure comprising three different chemical elements (Ca, C, and O). We obtain true atomic resolution of calcite in air at relative humidity ranging from 20% to 40%, imaging atomic steps and single atomic defects. We observe a great durability of sapphire tips with their Mohs hardness of 9, only one step below diamond. Depending on the state of the sapphire tip, we resolve either the calcium or the oxygen sublattice. We determine the tip termination by comparing the experimental images with simulations and discuss the possibility of chemical tip identification in air. The main challenges for imaging arise from the presence of water layers, which form on almost all surfaces and have the potential to dissolve the crystal surface. Frequency shift versus distance spectra show the presence of at least three ordered hydration layers. The measured height of the first hydration layer corresponds well to X-ray diffraction data and molecular dynamic simulations, namely, ~220 pm. For the following hydration layers we measure ~380 pm for the second and third layer, ending up in a total hydration layer thickness of at least 1 nm. Understanding the influence of water layers and their structure is important for surface segregation, surface reactions including reconstructions, healing of defects, and corrosion. PMID- 25816928 TI - Sphenopalatine foramen: endoscopic approach with bony landmarks. AB - OBJECTIVE: To establish whether nasal bony landmarks on computed tomography could be utilised reliably in endoscopic approaches to the sphenopalatine foramen. METHODS: A prospective analysis of 102 consecutive helical computed tomography scans of the paranasal sinuses was carried out by 2 senior ENT surgeons. Distances from the sphenopalatine foramen to endoscopically palpable bony landmarks were measured. RESULTS: There were a total of 102 patients (45 females and 57 males), with a mean age of 62 years. The mean distance from the posterior fontanelle to the sphenopalatine foramen was 14.1 mm (standard deviation = 2.13). The average vertical distance of the sphenopalatine foramen opening from the bony attachment of the inferior turbinate was 14.13 mm. There were no statistically significant differences between any of these measurements (foramen width p-value = 0.714, distance from fontanelle p-value = 0.43 and distance from inferior turbinate p-value = 0.48). CONCLUSION: Determination of reliable bony landmarks is clinically useful in endoscopic surgery and can aid identification of the sphenopalatine foramen. The inferior turbinate concha and posterior fontanelle may be used as reliable computed tomography landmarks for endoscopic approaches to the sphenopalatine foramen. PMID- 25816929 TI - Expression of endothelin-1 and endothelin-1 receptor A in canine mammary tumours. AB - Endothelins and their receptors have been implicated in numerous diseases and have recently emerged as relevant players in a variety of malignancies. Tumours overexpress the Endothelin-1 (ET-1) and the Endothelin-A receptors (ETAR) and their interaction enhances tumour growth and metastasis by promoting tumour cell survival, proliferation and angiogenesis. In this study we have evaluated the expression of ET-1 and ETAR in 50 canine mammary tumours, compared to normal controls. Results demonstrated a progressive increase in ET-1 and ETAR expression from benign tumour to grade 1 and to grade 2 malignant mammary tumours with a decrease of expression in grade 3 carcinomas. Co-localization of ET-1 and ETAR was observed in benign mammary tumours and in G1 and G2 carcinomas, while absent in G3 carcinomas. Concluding, ET-1/ETAR can be considered reliable markers for evaluating malignancy of canine mammary tumours and could have importance for the development of specific anticancer therapies. PMID- 25816930 TI - Characterization of GM-CSF-inhibitory factor and Uracil DNA glycosylase encoding genes from camel pseudocowpoxvirus. AB - The present study describes the PCR amplification of GM-CSF-inhibitory factor (GIF) and Uracil DNA glycosylase (UDG) encoding genes of pseudocowpoxvirus (PCPV) from the Indian Dromedaries (Camelus dromedarius) infected with contagious ecthyma using the primers based on the corresponding gene sequences of human PCPV and reindeer PCPV, respectively. The length of GIF gene of PCPV obtained from camel is 795 bp and due to the addition of one cytosine residue at position 374 and one adenine residue at position 516, the open reading frame (ORF) got altered, resulting in the production of truncated polypeptide. The ORF of UDG encoding gene of camel PCPV is 696 bp encoding a polypeptide of 26.0 kDa. Comparison of amino acid sequence homologies of GIF and UDG of camel PCPV revealed that the camel PCPV is closer to ORFV and PCPV (reference stains of both human and reindeer), respectively. PMID- 25816931 TI - Preoperative ultra-rapid opiate detoxification for the treatment of post operative surgical pain. AB - Over the past two decades, the prescription of high dose opiate therapy has continued to accelerate in an attempt to treat patients with chronic pain. This presents a substantial challenge when patients on high dose opiate therapy require surgery, as opiate pain relief is a cornerstone of postoperative pain management. These patients have exceptionally challenging pain to control. This is likely due to downregulation of existing opiate receptors and the reluctance of clinicians to increase doses of opiates to exceptionally high levels to facilitate pain relief. We hypothesize that using the method of ultra-rapid opiate detoxification (UROD), it would be possible to rapidly increase the number of opiate receptors and return patients to a more naive state, which would be susceptible to exogenous opiate administration. Validation of this hypothesis is supported by two mechanisms, the first of which are reports of patients that underwent UROD for opiate addition that subsequently suffer respiratory arrests when beginning to rapidly abuse opiates shortly after treatment. Additionally there are data demonstrating the tapering of opiate therapy prior to elective surgery results in better pain control. In conclusion, we hypothesize that patients on chronic high dose opiates could obtain substantially better pain relief if they underwent UROD prior to surgery. This technique could be administered shortly before surgery and may dramatically improve the patients' recoveries. PMID- 25816932 TI - Mortality patterns among recipients of autologous hematopoietic stem cell transplantation for lymphoma and myeloma in the past three decades. AB - BACKGROUND: Understanding the mortality patterns of patients with lymphoma and myeloma, who have undergone autologous hematopoietic stem cell transplantation (ASCT) might identify improvement opportunities. PATIENTS AND METHODS: The present retrospective study included patients with lymphoma and myeloma, aged >= 18 years, who had undergone ASCT from 1983 to 2010 at the University of Nebraska Medical Center. Of the 2284 patients, 972 had died within first 5 years after ASCT. The patients were divided into 3 cohorts according to the time of transplantation: 1983 to 1990 (cohort I), 1991 to 2000 (cohort II), and 2001 to 2010 (cohort III). Using Cox proportional hazards regression analysis, the risk of cause-specific mortality was compared across the 3 cohorts. RESULTS: Of a total of 1215 deaths, 972 (80%) occurred within the first 5 years after ASCT. Disease relapse (73.4%), organ failure (7.8%), infection (4.7%), and secondary malignancy (4.2%) accounted for most of the deaths. The risk of death from infection (P < .0001), but not from relapse (P = .26), organ failure (P = .68), or secondary malignancy (P = .15), had declined in the more recent cohorts. CONCLUSION: The 5-year overall survival of patients undergoing ASCT has improved significantly owing to a decline in infectious mortality. Our results highlight that the mortality from relapse remains the most common cause of death, warranting investigation of different strategies to reduce the incidence of relapse and improve the therapy for relapse after ASCT. PMID- 25816933 TI - Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis--A Systematic Review of Prospective Studies. AB - Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis. PMID- 25816934 TI - A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma. AB - INTRODUCTION: Overexpression of cyclin D1 is a hallmark feature of mantle cell lymphoma (MCL). Many of the oncogenic effects of cyclin D1 are mediated through cyclin-dependent kinases (CDKs). P276-00 is a potent small molecule inhibitor of CDK4-D1, CDK1-B, and CDK9-T, with promising activity in preclinical models. In phase I studies of P276-00 in patients with refractory solid neoplasms, it was well-tolerated with a mild trend toward single-agent efficacy. PATIENTS AND METHODS: A phase II study of P276-00 was conducted in patients with relapsed or refractory MCL at the recommended dose of 185 mg/m(2)/day from days 1 to 5 of a 21-day cycle. Thirteen patients were enrolled in the present study. RESULTS: Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE), and 1 patient died. Also, 11 patients (84.6%) experienced a treatment-emergent AE deemed related to P276-00. Of the 13 patients, 9 (69.2%) received >= 2 cycles of treatment, which was the predefined threshold to be evaluable for efficacy. Treatment was discontinued early in 2 patients because of AEs (1 of which was attributed to P276-00 administration) and in 2 patients because of disease progression. Finally, 2 patients experienced stable disease for an estimated median duration of 60.5 days (range, 58-63 days). The estimated median time to progression for the predefined efficacy population was 43 days (range, 38-58 days). CONCLUSION: Given the results observed in the present study, if evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease. PMID- 25816948 TI - Lessons learned from a thorny case. PMID- 25816944 TI - Changes in research on language barriers in health care since 2003: A cross sectional review study. AB - BACKGROUND: Understanding how to mitigate language barriers is becoming increasingly important for health care providers around the world. Language barriers adversely affect patients in their access to health services; comprehension and adherence; quality of care; and patient and provider satisfaction. In 2003, the United States (US) government made a major change in national policy guidance that significantly affected limited English proficient patients' ability to access language services. OBJECTIVE: The objectives of this paper are to describe the state of the language barriers literature inside and outside the US since 2003 and to compare the research that was conducted before and after a national policy change occurred in the US. We hypothesize that language barrier research would increase inside and outside the US but that the increase in research would be larger inside the US in response to this national policy change. METHODS: We reviewed the research literature on language barriers in health care and conducted a cross sectional analysis by tabulating frequencies for geographic location, language group, methodology, research focus and specialty and compared the literature before and after 2003. RESULTS: Our sample included 136 studies prior to 2003 and 426 studies from 2003 to 2010. In the 2003 2010 time period there was a new interest in studying the providers' perspective instead of or in addition to the patients' perspective. The methods remained similar between periods with greater than 60% of studies being descriptive and 12% being interventions. CONCLUSIONS: There was an increase in research on language barriers inside and outside the US and we believe this was larger due to the change in the national policy. We suggest that researchers worldwide should move away from simply documenting the existence of language barriers and should begin to focus their research on documenting how language concordant care influences patient outcomes, providing evidence for interventions that mitigate language barriers, and evaluating the cost effectiveness of providing language concordant care to patients with language barriers. We think this is possible if funding agencies around the world begin to request proposals for these types of research studies. Together, we can begin document meaningful ways to provide high quality health care to patients with language barriers. PMID- 25816949 TI - Memorial for Michael Davidson, MD. PMID- 25816950 TI - Is open surgery for iatrogenic esophageal perforation now a surgical relic, like bloodletting and trepanation? PMID- 25816951 TI - Perioperative endothelin-1 levels: Searching for the hidden fingerprint of nonocclusive mesenteric ischemia. PMID- 25816952 TI - Off-pump hepatic to azygos connection via thoracotomy for relief of fistulas after a Kawashima procedure: Ten-year results. AB - OBJECTIVES: An almost universal incidence of developing pulmonary arteriovenous fistulas after the Kawashima operation has been reported. Exclusion of the hepatic venous flow from the pulmonary circulation causes the development of these malformations. Redirection of hepatic venous flow to the pulmonary circulation mostly leads to the regression of the arteriovenous fistulas. METHODS: We analyzed 11 patients with arteriovenous fistulas that developed after the Kawashima operation. The hepatic-to-azygos shunts were performed with an off pump technique through a lateral thoracotomy in all but one. Operative and postoperative data were retrospectively collected. RESULTS: No intraoperative complications occurred, and no patient died in the hospital. Up to 10-year follow up showed a significant postoperative improvement of patients' oxygen saturation and New York Heart Association class. Apart from 2 re-thoracotomies for bleeding in 1 patient, no complications occurred and no patient died during follow-up. Two other patients underwent reoperation for an undiagnosed additional hepatic vein. The improvement of patients' oxygen saturation and New York Heart Association class persisted during the follow-up period. CONCLUSIONS: The surgical connection can be performed safely with an off-pump technique that avoids the risks related to extracorporeal circulation and circulatory arrest. The results at 10 years follow-up confirmed the efficacy and safety of the surgical technique described. PMID- 25816953 TI - Now that reimbursement for readmission to the hospital is threatened, we are finally focused on readmissions after esophagectomy. PMID- 25816954 TI - Does preoperative carotid stenosis screening reduce perioperative stroke in patients undergoing coronary artery bypass grafting? AB - A number of institutions routinely perform carotid artery ultrasound screening before coronary artery bypass grafting (CABG) to identify carotid artery disease requiring revascularization before or during CABG, with the expectation of reducing perioperative neurologic events. The assumptions are that carotid disease is causally related to perioperative stroke and that prophylactic carotid revascularization decreases the risk of post-CABG neurologic events. Although carotid artery stenosis is a known risk factor for perioperative stroke in patients undergoing CABG, it might be a surrogate marker for diffuse atherosclerotic disease rather than a direct etiologic factor. Moreover, the benefit of prophylactic carotid revascularization in patients with asymptomatic unilateral carotid disease is uncertain. Therefore, we have reviewed the literature for evidence that preoperative carotid artery screening, by identifying patients with significant carotid artery stenosis and altering their management, reduces perioperative neurologic events in those undergoing CABG. PMID- 25816955 TI - Aortic cannulation system for minimally invasive mitral valve surgery. PMID- 25816956 TI - The elephant trunk is freezing: The Hannover experience. AB - BACKGROUND: The "elephant trunk" (ET) technique traditionally has been performed to treat complex aortic diseases involving the aortic arch and the descending aorta. Despite the fact that, in recent years, the "frozen elephant trunk" (FET) technique has been used increasingly for such pathologies, discussion is still ongoing in the surgical community regarding which of the 2 techniques is better. We compared our results using the classic ET versus the FET technique. METHODS: From August 2001 to March 2013, a total of 277 patients underwent total aortic arch replacement and either ET (group A) or FET (group B) implantation. In group A, 97 patients (59 men; age 59.7 +/- 12.7 years; 44.3% with aneurysm; 55.6% with dissection [48.45% acute]) underwent an ET procedure; 21.64% were reoperations. In group B, 180 patients underwent an FET procedure (126 men; age 59.8 +/- 13.2 years; 34.4% with aneurysm; 63.3% with dissection [35% acute]); 30% were reoperations. RESULTS: In group A, in-hospital mortality was 24.7%; postoperative stroke rate was 12.4%. During follow-up, 27.8% underwent a second-stage procedure. In group B, in-hospital mortality was 12.2%; postoperative stroke rate was 13.3%. During follow-up, 27.7% patients underwent further interventions in the downstream aorta. CONCLUSIONS: In selected patients with combined aortic arch and descending aortic aneurysms limited to the proximal descending aorta, the FET approach potentially allows for single-stage therapy, whereas a second-stage operation is inevitable with the classic ET approach. Moreover, owing to the availability of prefabricated, easy-to-use, FET, hybrid prostheses that result in significantly better outcomes in patients who have acute aortic dissection, type A, and if necessary, and provide an ideal "landing zone" for future endovascular completion, the classic ET procedure is "freezing," in the sense that it is being replaced by the FET approach. PMID- 25816957 TI - SCAI/AATS/ACC/STS operator and institutional requirements for transcatheter valve repair and replacement, part III: Pulmonic valve. PMID- 25816958 TI - The mesothelioma enigma. PMID- 25816959 TI - An unusual presentation of esophageal metastasis from breast cancer. PMID- 25816960 TI - Conventional versus frozen elephant trunk for complex aortic arch pathology: What should we be doing now? PMID- 25816961 TI - Early stenosis of an aortic porcine bioprosthesis due to thrombosis: Case report and literature review. PMID- 25816962 TI - Squeezing into a narrow market. PMID- 25816963 TI - Conventional bronchoscopy for evaluation of the solitary pulmonary nodule: Beneficial for a select few patients, or are we still "looking for a needle in a haystack"? PMID- 25816964 TI - Considering what we know, diagnostic yield and postoperative mortality associated with surgical lung biopsy for evaluation of interstitial lung diseases are good ... we think .... PMID- 25816965 TI - Does chance truly favor the prepared mind? PMID- 25816966 TI - Prediction methods of skin burn for performance evaluation of thermal protective clothing. AB - Most test methods use skin burn prediction to evaluate the thermal protective performance of clothing. In this paper, we reviewed different burn prediction methods used in clothing evaluation. The empirical criterion and the mathematical model were analyzed in detail as well as their relationship and limitations. Using an empirical criterion, the onset of skin burn is determined by the accumulated skin surface energy in certain periods. On the other hand, the mathematical model, which indicates denatured collagen, is more complex, which involves a heat transfer model and a burn model. Further studies should be conducted to examine the situations where the prediction methods are derived. New technologies may be used in the future to explore precise or suitable prediction methods for both flash fire tests and increasingly lower-intensity tests. PMID- 25816968 TI - Fractional order fuzzy control of hybrid power system with renewable generation using chaotic PSO. AB - This paper investigates the operation of a hybrid power system through a novel fuzzy control scheme. The hybrid power system employs various autonomous generation systems like wind turbine, solar photovoltaic, diesel engine, fuel cell, aqua electrolyzer etc. Other energy storage devices like the battery, flywheel and ultra-capacitor are also present in the network. A novel fractional order (FO) fuzzy control scheme is employed and its parameters are tuned with a particle swarm optimization (PSO) algorithm augmented with two chaotic maps for achieving an improved performance. This FO fuzzy controller shows better performance over the classical PID, and the integer order fuzzy PID controller in both linear and nonlinear operating regimes. The FO fuzzy controller also shows stronger robustness properties against system parameter variation and rate constraint nonlinearity, than that with the other controller structures. The robustness is a highly desirable property in such a scenario since many components of the hybrid power system may be switched on/off or may run at lower/higher power output, at different time instants. PMID- 25816967 TI - Home fire safety education for parents of newborns. AB - In children under 1 year of age, the proportion of unintentional burns increases with infant age and mobility. Infants are not able to avoid burns and are dependent on parental or adult help. Treatment of burns in young children is expensive in terms of the life-long costs. The purpose of this study was to examine changes in home fire safety (HFS) knowledge and practices over time for parents of newborn children and expecting parents. HFS knowledge of 103 parents was assessed at baseline, immediately after watching a DVD on HFS (recall), and at 2-week follow-up (retention). In addition, the United States Fire Administration (USFA)/Federal Emergency Management Agency (FEMA) Home Safety Checklist which examines HFS practices in the homes was administered. Seventy percent of the participants were Caucasian, 65% were married, and 81% were first time parents. HFS knowledge increased significantly from baseline to recall (45+/ 12% vs. 87+/-17% correct responses, p<0.0001), but declined to 75+/-18% correct at retention. That is, an individual's baseline scores nearly doubled at recall (42+/-11% change in baseline score), but only increased by 67% at retention (30+/ 15% change in baseline score). For a subsample of parents who completed the USFA Checklist (n=22), the mean percentage of advocated practices followed was 71+/ 11% (range: 40-89%). Using DVDs was an effective educational modality for increasing HFS knowledge. This addressed an important problem of decreasing burns in infants through increasing parent knowledge and HFS practices using a short, inexpensive DVD. PMID- 25816969 TI - Reduced HLA Class II antibody response to proteasome inhibition in heart transplantation. PMID- 25816970 TI - Differential kinetics at PK/PEPCK branch point in the cestode, Raillietina echinobothrida. AB - Pyruvate kinase (PK; EC 2.7.1.40) and phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) are essential regulatory enzymes of glucose oxidation in helminths, the PK/PEPCK branch point being the first divergent step between carbohydrate catabolism of the parasites and their hosts. Recently, PEPCK from the cestode parasite, Raillietina echinobothrida, has been purified and characterized. In order to find out the differential kinetics, if any, at PK/PEPCK branch point in the parasite, in this study, we purified and characterized the parasite PK and compared it with the parasite PEPCK. The purified PK displayed standard Michaelis Menten kinetics with Kmapp of 77.8 uM for its substrate PEP, whereas the Kmapp was 46.9 uM for PEPCK. PEP exhibited differential kinetics at PK/PEPCK branch point of the parasite and behaved as a homotropic effector for PEPCK, but not for PK. The inhibitory constant (Ki) for genistein and daidzein (phytochemicals from Flemingia vestita) was determined and discussed. From these results, we hypothesize that PK/PEPCK branch point is a probable site for anthelmintic action. PMID- 25816971 TI - In vivo viability of Echinococcus multilocularis eggs in a rodent model after different thermo-treatments. AB - Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a serious and emerging zoonotic disease in many parts of the northern hemisphere. Humans but also primates and other accidental hosts can acquire the infection by the ingestion of eggs excreted by the carnivore definitive hosts, e.g. after hand contact with egg-contaminated environments or by consumption of contaminated food or beverages. The goal of this study was to develop a sensitive in vivo method to determine the viability of E. multilocularis eggs and to establish suitable conditions (optimal temperature, exposure time and humidity) for their (prophylactic) inactivation. The sensitivity of a rodent model was evaluated and, conclusively, C57Bl/6 mice were most susceptible to subcutaneous inoculation of small numbers of sodium hypochlorite-resistant oncospheres, even more than to oral inoculation of mature eggs. In the second part of the study, various combinations of exposure temperature (between 45 degrees C and 80 degrees C), times (between 30 min and 180 min) and relative humidity (70% vs. suspended in water) were tested. After heat treatment in an incubator, the sodium hypochlorite resistance test was used to assess in vitro egg viability at the time of inoculation. Subsequently, the infectivity of the oncospheres was evaluated by subcutaneous inoculation in mice. Eggs exposed to increasing temperatures were more resistant to heat if suspended in water as compared to eggs exposed on a filter paper at 70% relative humidity. As survival of eggs in water droplets on the vegetables cannot be excluded, further experiments were performed with eggs suspended in water only. Eggs were infectious after heat exposure at 65 degrees C for up to 120 min, however, no echinococcosis developed after treatment of the eggs at 65 degrees C for 180 min or at 70, 75 and 80 degrees C for 7.5, 15 or 30 min. PMID- 25816972 TI - Identification of putative genes involved in parasitism in the anchor worm, Lernaea cyprinacea by de novo transcriptome analysis. AB - There is little information on the genome sequence of Lernaea cyprinacea a major ectoparasite of freshwater fish throughout the world. We subjected the L. cyprinacea transcriptome (adult and free living stages) to Illumina HiSeq 2000 sequencing. We obtained a total of 31,671,751 (31.67 millions) reads for the adult parasitic stage and 33,840,446 (33.84 millions) for the free living stage. The reads were assembled into 50,792 contigs for the adult stage and 69,378 for the free living stage. Using the pfam database, 41.91% of the transcriptome was annotated. The transcriptome was mined for genes associated with parasitism. To examine gene expression changes associated with the parasitism of L. cyprinacea during the transit from the free living to parasitic stage, we studied the differentially expressed transcripts between the two stages. The microsatellite markers were also identified (9,843 for adult stage; 16,813 for free living stages) and this would facilitate population genetic studies in various geographical isolates of Lernaea. Our data provides the most comprehensive sequence resource available for L. cyprinacea and demonstrates that Illumina sequencing allows de novo transcriptome assembly and gene expression analysis in a species lacking genome information. The data could open new avenues for a wide array of genetic, evolutionary, biological, ecological, epidemiological studies, and a solid foundation for the development of novel interventions against L. cyprinacea. PMID- 25816974 TI - The laminated layer: Recent advances and insights into Echinococcus biology and evolution. AB - The laminated layer is the unique mucin-based extracellular matrix that protects Echinococcus larvae, and thus to an important extent, shapes host-parasite relationships in the larval echinococcoses. In 2011, we published twin reviews summarizing what was known about this structure. Since then, important advances have been made. Complete genomes and some RNAseq data are now available for E. multilocularis and E. granulosus, leading to the inference that the E. multilocularis LL is probably formed by a single type of mucin backbone, while a second apomucin subfamily additionally contributes to the E. granulosus LL. Previously suspected differences between E. granulosus and E. multilocularis in mucin glycan size have been confirmed and pinned down to the virtual absence of Galbeta1-3 chains in E. multilocularis. The LL carbohydrates from both species have been found to interact selectively with the Kupffer cell receptor expressed in rodent liver macrophages, highlighting the ancestral adaptations to rodents as intermediate hosts and to the liver as infection site. Finally, LL particles have been shown to possess carbohydrate-independent mechanisms profoundly conditioning non-liver-specific dendritic cells and macrophages. These advances are discussed in an integrated way, and in the context of the newly determined phylogeny of Echinococcus and its taenid relatives. PMID- 25816973 TI - A protein extract and a cysteine protease inhibitor enriched fraction from Jatropha curcas seed cake have in vitro anti-Toxoplasma gondii activity. AB - Toxoplasma gondii is a parasite of great medical and veterinary importance that has worldwide distribution and causes toxoplasmosis. There are few treatments available for toxoplasmosis and the search for plant extracts and compounds with anti-Toxoplasma activity is of utmost importance for the discovery of new active drugs. The objective of this study was to investigate the action of a protein extract and a protease inhibitor enriched fraction from J. curcas seed cake on developing tachyzoites of T. gondii-infected Vero cells. The protein extract (JcCE) was obtained after solubilization of the J. curcas seed cake with 100 mM sodium borate buffer, pH 10, centrifugation and dialysis of the resulting supernatant with the extracting buffer. JcCE was used for the in vitro assays of anti-Toxoplasma activity at 0.01, 0.1, 0.5, 1.5, 3.0 and 5.0 mg/ml concentration for 24 h. The results showed that JcCE reduced the percentage of infection and the number of intracellular parasites, but had no effect on the morphology of Vero cells up to 3.0 mg/mL. The cysteine protease inhibitor enriched fraction, which was obtained after chromatography of JcCE on Sephadex G-75 and presented a unique protein band following SDS-PAGE, reduced both the number of T. gondii infected cells and intracellular parasites. These results suggest that both JcCE and the cysteine protease inhibitor enriched fraction interfere with the intracellular growth of T. gondii. PMID- 25816975 TI - The innate resistance of Trypanosoma copemani to human serum. AB - Trypanosoma copemani is known to be infective to a variety of Australian marsupials. Characterisation of this parasite revealed the presence of stercorarian-like life-cycle stages in culture, which are similar to T. rangeli and T. cruzi. The blood incubation infectivity test (BIIT) was adapted and used to determine if T. copemani, like T. cruzi and T. rangeli, has the potential to grow in the presence of human serum. To eliminate any effects of anticoagulants on the complement system and on human high density lipoprotein (HDL), only fresh whole human blood was used. Trypanosoma copemani was observed by microscopy in all human blood cultures from day 5 to day 19 post inoculation (PI). The mechanism for normal human serum (NHS) resistance in T. copemani is not known. The results of this study show that at least one native Australian trypanosome species may have the potential to be infective for humans. PMID- 25816976 TI - Development of novel valerolactam-benzimidazole hybrids anthelmintic derivatives: Diffusion and biotransformation studies in helminth parasites. AB - In the search for new anthelmintics able to overcome the resistance problem against all available drugs in livestock, the synthesis of novel valerolactam benzimidazole hybrid compounds was reported. This allowed us to obtain these in vitro and in vivo bioactive compounds using Nippostrongylus brasiliensis rat model by integrating physiology-based assays and ex vivo diffusion studies. In order to further study those novel hybrid molecules, Haemonchus contortus (a sheep gastrointestinal nematode of interest) and Mesocestoides vogae tetrathyridia (a useful system to study the efficacy of anthelmintic drugs against cestoda) were used as parasite models to compare the ex vivo patterns of diffusion and biotransformation of benzimidazoles and their valerolactam benzimidazole hybrid derivatives. On average, a nine-fold higher intraparasitic concentration of compounds was found in M. vogae compared with H.contortus, with similarities regarding the order of entry of compounds, highlighting febendazole (FEB) and its hybrid compound 10, while valerolactam compound 2 practically did not penetrate the parasites. Interestingly, sulphoxidation drug metabolism was observed and measured, revealing percentages of oxidation of 8.2% and 14.5% for albendazole (ABZ) and febendazole respectively in M. vogae, while this effect was more relevant in H. contortus parasite. More importantly, significant differences were observed between anthelmintic-susceptible adult parasites (Hc S) and those from sheep farms (Hc U). In fact, the percentages of oxidation of FEB and the hybrid compound 8 were higher in Hc U (25.5%, 54.1%, respectively) than in Hc S (8.8%, 38.2%). Interestingly, sulphoxidation of hybrid compound 10 was neither observed in M. vogae nor in H. contortus parasites, suggesting that increased drug metabolism (oxidation reactions) could not be used by these parasites as a defense mechanism against this novel drug. PMID- 25816977 TI - Rhombencephalosynapsis. PMID- 25816978 TI - Metal tolerance in emerging clinically relevant multidrug-resistant Salmonella enterica serotype 4,[5],12:i:- clones circulating in Europe. AB - The occurrence of acquired metal tolerance genes in emerging MDR Salmonella enterica serotype 4,[5],12:i:- clones was assessed and their associated platforms and tolerance phenotype were characterised. Salmonella 4,[5],12:i:- from different sources belonging to European, Spanish and Southern European clones were studied. Screening for copper (pcoA-pcoD/tcrB), silver/copper (silA-silE), mercury (merA), arsenic (arsB) and tellurite (terF) tolerance genes was performed by PCR/sequencing. CuSO(4)/AgNO(3) MICs were determined in aerobic/anaerobic atmospheres by agar dilution. Conjugation assays, genomic location and plasmid analysis were performed by standard procedures. Most isolates from European (98%) and Spanish (74%) clones carried silA-silE, contrasting with the Southern European clone (26%). merA/62% (European and Spanish clones) and pcoA-pcoD/50% (European clone) were also detected. merA+/-pco+sil were chromosomally located in the European clone, whereas in Spanish and Southern European clones sil+/-merA were within plasmids, both with antibiotic resistance genes. The pcoA-pcoD/silA silE(+) isolates showed higher MICCuSO(4) in anaerobiosis than those without these genes (MIC(50)=24-28 vs. 2 mM). Different MICAgNO(3) of silA-silE(+) (MIC(50)=0.25 mM) and silA-silE(-)(MIC(50)=0.16 mM) isolates were observed in both atmospheres, with an MIC increment after prior exposure to silver (>3 vs. 0.08-0.125 mM) in aerobiosis. A high frequency of copper and silver tolerance, particularly among the two major Salmonella 4,[5],12:i:- MDR clones (European/Spanish) circulating in Europe and causing human infections, might facilitate adaptation/expansion of these strains in metal-contaminated environments, particularly copper in anaerobiosis. Furthermore, metal toxic concentrations in food-animal environments can contribute to persistence of genetic platforms carrying metal/antibiotic resistance genes in this foodborne zoonotic pathogen. PMID- 25816979 TI - Nanotechnology approaches for antibacterial drug delivery: Preparation and microbiological evaluation of fusogenic liposomes carrying fusidic acid. AB - Many antibacterial drugs have some difficulty passing through the bacterial cell membrane, especially if they have a high molecular weight or large spatial structure. Consequently, intrinsic resistance is shown by some bacterial strains. Reduced cell membrane permeability is one of the mechanisms of resistance known for fusidic acid (FUS), a bacteriostatic steroidal compound with activity limited to Gram-positive bacteria. Moreover, the lipophilic character of FUS has been shown to cause drug retention inside the bilayers of cell membranes, preventing its diffusion towards target sites inside the cytoplasm. Targeting antimicrobial agents by means of liposomes may be a valid strategy in the treatment of infections refractory to conventional routes of antimicrobial treatment. On this basis, loading of FUS in fusogenic liposomes (FLs) was planned in this study. Fusogenic small unilamellar vesicles loaded with FUS were produced to evaluate their influence on improving the cell penetration and antibacterial activity of the antibiotic. The produced carriers were technologically characterised and were subjected to an in vitro microbiological assay against several strains of Gram negative and Gram-positive bacteria. The experimental results showed that encapsulating FUS in a liposomal carrier can improve antimicrobial efficacy and reduce the effective concentration required, probably through putative mechanisms of increased diffusion through the bacterial cell membrane. In fact, whilst free FUS was active only on the tested Gram-positive strains, incubation of FUS-loaded FLs exhibited growth inhibitory activity both against Gram-positive and Gram negative strains. The lowest MICs were obtained against Staphylococcus epidermidis (<=0.15 MUg/mL) and Acinetobacter baumannii (37.5 MUg/mL) clinical strains. PMID- 25816980 TI - [Blood glucose control and mortality in type 1 diabetes]. PMID- 25816981 TI - Hodgkin's lymphoma of the thyroid in a woman with autoimmune thyroiditis. PMID- 25816982 TI - Randomized clinical trial of nutritional counseling for malnourished hospital patients. AB - INTRODUCTION: Malnutrition is associated with an increased risk of mortality and morbidity, longer hospital stays and general loss of quality of life. The aim of this study is to assess the impact of dietary counseling for malnourished hospital patients. PATIENTS AND METHODS: Prospective, randomized, open-label study of 106 hospital patients with malnutrition (54 in the control group and 52 in the intervention group). The intervention group received dietary counseling, and the control group underwent standard treatment. We determined the patients' nutritional state (body mass index, laboratory parameters, malnutrition universal screening tool), degree of dependence (Barthel index), quality of life (SF-12), degree of satisfaction (CSQ-8), the number and length of readmissions and mortality. RESULTS: The patients who underwent the "intervention" increased their weight at 6 months, while the controls lost weight (difference in body mass index, 2.14kg/m(2); p<.001). The intervention group had better results when compared with the control group in the Malnutrition Universal Screening Tool scores (difference, -1.29; p<.001), Barthel index (difference, 7.49; p=.025), SF 12 (difference, 13.72; p<.001) and CSQ-8 (difference, 4.34, p<.001) and required fewer readmissions (difference, -0.37; p=.04) and shorter stays for readmissions (difference, -6.75; p=.035). Mortality and laboratory parameters were similar for the 2 groups. CONCLUSIONS: Nutritional counseling improved the patients' nutritional state, quality of life and degree of dependence and decreased the number of hospital readmissions. PMID- 25816983 TI - Telmisartan attenuated LPS-induced neuroinflammation in human IMR-32 neuronal cell line via SARM in AT1R independent mechanism. AB - AIM: The aim of this study was to find the protective role of Telmisartan (TS) in LPS intoxicated neuronal cells and elucidate the possible neuroprotective mechanism of action. MAIN METHODS: TLR4 and AT1R specific primers were designed and used in rtPCR to confirm the receptor expression in IMR-32 and Neuro2A cell lines. The protective effect of TS was assayed by MTT assay. The mechanism of action of TS was elucidated by assessing the expression and activation of TLR4 specific adaptor proteins SARM and MyD88, phosphorylated NFkappaB, PPARgamma, MAPK p38, c-JNK, ERK by Western blotting. Selective PPARgamma antagonist GW9662 was used to confirm the link between PPARgamma activation and TLR4 mediated NFkappaB inflammatory mechanisms. The pro-inflammatory cytokines TNFalpha, IL1beta, and IL-6 and anti-inflammatory cytokine IL10 release were measured by ELISA. KEY FINDINGS: IMR-32 cells expressed TLR4 receptor and Neuro2A cells expressed both AT1R and TLR4 receptors. TS significantly protected both the cell lines from LPS intoxication. TS significantly suppressed the TLR4 mediated inflammatory response by PPARgamma and SARM protein activation and the effect was reversed significantly by selective PPARgamma antagonist GW9662, confirming the existence of link between PPARgamma activation and TLR4 mediated inflammation via SARM. SIGNIFICANCE: LPS intoxicated human neuronal IMR-32 cells can be a good in vitro model to study inflammatory mediated neurodegeneration due to TLR4 receptor expression. Our study strongly recommends that the PPARgamma activating pleiotropic effect of TS is responsible for the protective effect in LPS induced TLR4 mediated inflammation via SARM adaptor protein in the IMR-32 cell line. PMID- 25816984 TI - Interaction of oridonin with human serum albumin by isothermal titration calorimetry and spectroscopic techniques. AB - Oridonin has been traditionally and widely used for treatment of various human diseases due to its uniquely biological, pharmacological and physiological functions. In this study, the interaction between oridonin and human serum albumin (HSA) was investigated using isothermal titration calorimetry (ITC), in combination with fluorescence spectroscopy and UV-vis absorption spectroscopy. We found that the hydrogen bond and van der Waals force are the major binding forces in the binding of oridonin to HSA. The binding of oridonin to HSA is driven by favorable enthalpy and unfavorable entropy. Oridonin can quench the fluorescence of HSA through a static quenching mechanism. The binding constant between oridonin and HSA is moderate and the equilibrium fraction of unbound oridonin f(u) > 60%. Binding site I is found to be the primary binding site for oridonin. Additionally, oridonin may induce conformational changes of HSA and affect its biological function as the carrier protein. The results of the current study suggest that oridonin can be stored and transported from the circulatory system to reach its target organ to provide its therapeutic effects. But its side-effect in the clinics cannot be overlook. The study provides an accurate and full basic data for clarifying the binding mechanism of oridonin with HSA and is helpful for understanding its effect on protein function during the blood transportation process and its biological activity in vivo. PMID- 25816985 TI - The traditional use of plants to manage candidiasis and related infections in Venda, South Africa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper presents results of an ethnobotanical survey of medicinal plants used for the management of candidiasis and related fungal infections in the Venda area, South Africa. MATERIALS AND METHODS: Ethnobotanical data about the uses of plants were gathered from eleven rural traditional healers using semi-structured interviews. RESULTS: A total of 45 species belonging to 24 different families were identified, of which the dominant family was the Fabaceae with 13 species (28.9%) followed by the Asteraceae and Solanaceae with 3 species each (6.7 %). A total of 28 of these plant species (62.2%) have been shown to have anticandidal activity and 14 species (31%) have been recorded for antifungal uses in the literature. Amongst the 45 species recorded, 51% were trees, 33% were shrubs, and 16% were herbs. The most widely used plant species were Acacia caffra, Clerodendrum glabrum, Croton gratissimus, Elaeodendron transvaalense, Faurea saligna, Hippocratea longipetiolata, Osyris lanceolata, Richardia brasiliensis, Schkuhria pinnata, Schotia brachypetala, Spilanthes acmella, Strychnos potatorum, Vangueria infausta subsp. infausta and Withania somnifera. The plant parts mostly used in the therapeutic preparations were roots (27.7%), bark (23.2%), and a combination of roots, bark (18.7%) and leaves (14.3%). Decoctions (44.4%), infusions (20%), macerations (17.7%), burning (11.4%) and paste (6.5%) were used. Most of the herbal remedies were administered orally. The main factors threatening the conservation status of these plants are unsustainable methods of harvesting, logging for firewood, building materials and crafts. CONCLUSION: The Venda area is rich in plant diversity and local indigenous knowledge of medicinal plants can play an important role as a model for low cost primary health care. Further studies are in progress to validate the indigenous plants recorded as traditional remedies in this area. PMID- 25816986 TI - More than just immune evasion: Hijacking complement by Plasmodium falciparum. AB - Malaria remains one of the world's deadliest diseases. Plasmodium falciparum is responsible for the most severe and lethal form of human malaria. P. falciparum's life cycle involves two obligate hosts: human and mosquito. From initial entry into these hosts, malaria parasites face the onslaught of the first line of host defence, the complement system. In this review, we discuss the complex interaction between complement and malaria infection in terms of hosts immune responses, parasite survival and pathogenesis of severe forms of malaria. We will focus on the role of complement receptor 1 and its associated polymorphisms in malaria immune complex clearance, as a mediator of parasite rosetting and as an entry receptor for P. falciparum invasion. Complement evasion strategies of P. falciparum parasites will also be highlighted. The sexual forms of the malaria parasites recruit the soluble human complement regulator Factor H to evade complement-mediated killing within the mosquito host. A novel evasion strategy is the deployment of parasite organelles to divert complement attack from infective blood stage parasites. Finally we outline the future challenge to understand the implications of these exploitation mechanisms in the interplay between successful infection of the host and pathogenesis observed in severe malaria. PMID- 25816989 TI - Comment on "Biodegradation of perfluorooctanesulfonate (PFOS) as an emerging contaminant". PMID- 25816988 TI - MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation. AB - Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1 TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer. PMID- 25816990 TI - Impact of full field digital mammography on the classification and mammographic characteristics of interval breast cancers. AB - OBJECTIVE: Full field digital mammography (FFDM) is increasingly replacing screen film mammography (SFM) in breast screening programs. Interval breast cancers are an issue in all screening programs and the purpose of our study is to assess the impact of FFDM on the classification of interval breast cancers at independent blind review and to compare the mammographic features of interval cancers at FFDM and SFM. MATERIALS AND METHODS: This study included 138 cases of interval breast cancer, 76 following an FFDM screening examination and 62 following screening with SFM. The prior screening mammogram was assessed by each of five consultant breast radiologists who were blinded to the site of subsequent cancer. Subsequent review of the diagnostic mammogram was performed and cases were classified as missed, minimal signs, occult or true interval. Mammographic features of the interval cancer at diagnosis and any abnormality identified on the prior screening mammogram were recorded. RESULTS: The percentages of cancers classified as missed at FFDM and SFM did not differ significantly, 10.5% (8 of 76) at FFDM and 8.1% (5 of 62) at SFM (p=.77). There were significantly less interval cancers presenting as microcalcifications (alone or in association with another abnormality) following screening with FFDM, 16% (12 of 76) than following a SFM examination, 32% (20 of 62) (p=.02). CONCLUSION: Interval breast cancers continue to pose a problem at FFDM. The switch to FFDM has changed the mammographic presentation of interval breast cancer, with less interval cancers presenting in association with microcalcifications. PMID- 25816987 TI - The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. AB - Sonic hedgehog (Shh) signaling is critical in development and oncogenesis, but the mechanisms regulating this pathway remain unclear. Although protein phosphorylation clearly affects Shh signaling, little is known about phosphatases governing the pathway. Here, we conducted a small hairpin RNA (shRNA) screen of the phosphatome and identified Eya1 as a positive regulator of Shh signaling. We find that the catalytically active phosphatase Eya1 cooperates with the DNA binding protein Six1 to promote gene induction in response to Shh and that Eya1/Six1 together regulate Gli transcriptional activators. We show that Eya1, which is mutated in a human deafness disorder, branchio-oto-renal syndrome, is critical for Shh-dependent hindbrain growth and development. Moreover, Eya1 drives the growth of medulloblastoma, a Shh-dependent hindbrain tumor. Together, these results identify Eya1 and Six1 as key components of the Shh transcriptional network in normal development and in oncogenesis. PMID- 25816991 TI - Noninvasive method for mapping CVR in moyamoya disease using ASL-MRI. AB - PURPOSE: To project a noninvasive method for mapping cerebrovascular reserve (CVR) in moyamoya disease (MMD) using ASL-MRI. METHODS: 16 MMD patients underwent cerebral blood flow (CBF) examinations by standard ASL-MRI, pulse-wave synchronized ASL-MRI (pulsy ASL-MRI) which tagged the arterial blood coincident with a peak of a pulse wave, and single photon emission computed tomography (SPECT) imagings with iodine-123-N-isopropyl-p-iodoamphetamine in the resting (rest-IMP) and after acetazolamide challenge (ACZ-IMP). Hemispheric 32-sided cerebral blood flow (CBF) values were measured with normalized CBF maps created from standard ASL-MRI (standard-ASL value), pulsy ASL-MRI (pulsy-ASL value), rest IMP (rest-IMP value), and ACZ-IMP (ACZ-IMP value). CVR based on rest-IMP and ACZ IMP values (IMP-CVR) was calculated. ASL-CVR was also calculated on the basis of corrected standard-ASL values and pulsy-ASL values, which were adjusted to the ACZ-IMP values and rest-IMP values, respectively, by the least-squares method. We assessed the relationships between rest-IMP values and pulsy-ASL values, ACZ-IMP values and standard-ASL values, and IMP-CVR and ASL-CVR. RESULTS: Significant relationships were observed between rest-IMP values and pulsy-ASL values (correlation coefficient (r=0.557, p<0.01)), ACZ-IMP values and standard-ASL values (r=0.825, p<0.01), and IMP-CVR and ASL-CVR (r=0.736, p<0.01). CONCLUSIONS: ASL-MRI is equivalent to SPECT and that it might serve as a noninvasive method for mapping CVR in MMD. PMID- 25816992 TI - Good interrater reliability of a new grading system in detecting traumatic bone marrow lesions in the knee by dual energy CT virtual non-calcium images. AB - OBJECTIVE: To evaluate the capacity of dual-energy computed tomography (DECT) virtual non-calcium (VNCa) images in detecting post-traumatic bone marrow lesions (BMLs) in the knee with a new grading system. METHODS: DECT and magnetic resonance (MR) imaging were used to examine acute trauma of the knee in 32 patients. VNCa images were generated by dual-energy subtraction of calcium, and the lower end of the femur and upper end of the tibia each were divided into six regions for grading of bone marrow by two musculoskeletal radiologists using a four-grading system (Grade 4, very obvious lesions; Grade 3, relatively obvious lesions; Grade 2, slight or suspicious lesion on VNCa image and mild lesion on MR image; Grade 1, normal bone marrow). CT values were obtained in the BMLs. MR images were used as the reference standard. Grade 3-4 bone marrow was regarded as a positive result to evaluate the performance of VNCa images in detecting traumatic BMLs in the knee, and receiver operating characteristic (ROC) curve analysis of VNCa images for detection of knee BMLs was performed based on CT value of the bone marrow. RESULTS: Bone marrow rating by the two radiologists showed very good consistency (kappa=0.850 and 0.869 for VNCa and MR images, respectively). VNCa and MR images had good consistency (kappa=0.799 for lower end of the femur; kappa=0.659 for upper end of the tibia). When Grade 3-4 bone marrow was regarded as a positive result, the sensitivity, specificity, positive predictive value, and negative predictive value of VNCa images for detection of BMLs in the lower end of the femur were 73.5%, 98.6%, 94.7%, and 91.6%, respectively, and the values in the upper end of the tibia were 91.0%, 100.0%, 100.0%, and 95.4%, respectively. The CT values of bone marrow were (-52.5 +/- 31.3) HU in positive area and (-91.2 +/- 16.9) HU in negative area for the lower end of the femur, and those were (-51.3 +/- 30.2) HU in positive area and (-104.7 +/- 17.5) HU in negative area for the upper end of the tibia (all p values<0.0001). The areas under the ROC curve of VNCa images for detection of BMLs were 0.875 for the lower end of the femur and 0.939 for the upper end of the tibia. CONCLUSION: Good interrater reliability of this new grading system in detecting traumatic BMLs in the knee by VNCa images of DECT can be obtained with good diagnostic predictive values. PMID- 25816994 TI - Characterization of hepatocellular carcinoma (HCC) lesions using a novel CT-based volume perfusion (VPCT) technique. AB - OBJECTIVE: To characterize hepatocellular carcinoma (HCC) in terms of perfusion parameters using volume perfusion CT (VPCT) and two different calculation methods, compare their results, look for interobserver agreement of measurements and correlation between tumor arterialization and lesion size. MATERIAL AND METHODS: This study was part of a prospective monitoring study in patients with HCC undergoing TACE, which was approved by the local Institutional Review Board. 79 HCC-patients (mean age, 64.7) with liver cirrhosis were enrolled. VPCT was performed for 40s covering the involved liver (80 kV, 100/120 mAs) using 64 mm * 0.6 mm collimation, 26 consecutive volume measurements, 50 mL iodinated contrast IV and 5 mL/s flow rate. Mean/maximum blood flow (BF; ml/100mL/min), blood volume (BV) and k-trans were determined both with the maximum slope+Patlak vs. deconvolution method. Additionally, the portal venous liver perfusion (PVP), the arterial liver perfusion (ALP) and the hepatic perfusion index (HPI) were determined for each tumor including size measurements. Interobserver agreement for all perfusion parameters was calculated using intraclass correlation coefficients (ICC). RESULTS: The max. slope+Patlak method yielded: BFmean/max=37.8/57 mL/100g-tissue/', BVmean/max=9.8/11.1 mL/100g-tissue, k-trans mean/max=34.4/44.5 mL/100g-tissue/'. For the deconvolution method BFmean/max, BVmean/max and, k-trans-mean/max were 68.3/106.1 mL/100g-tissue/', 12.6/15.5 mL/100g-tissue and 24/33.8 mL/100g-tissue/'. Mean ALP, PVP, HPI and size were 53.7 mL/100g-tissue/', 2.4 mL/100g-tissue/', 96.4 and 3.5 cm, respectively. Interobserver agreement measured with intraclass coefficient correlation (ICC) was very good for all perfusion parameters (>= 0.99). Best correlation between calculation methods was achieved for measurements of BF, while BV and k-trans values were less correlated. There was no relationship between HPI and lesion size. CONCLUSION: VPCT can measure tumor volume perfusion non-invasively and enables quantification of the degree of HCC arterialization. Results are dependent on the technique used with best inter-method correlation for BF. Tumor HPI did not proved size-dependent. PMID- 25816993 TI - 18F-FDG-PET/CT parameters as imaging biomarkers in oral cavity squamous cell carcinoma, is visual analysis of PET and contrast enhanced CT better than the numbers? AB - PURPOSE: This study was designed to seek associations between positron emission tomography/computed tomography (PET/CT) parameters, contrast enhanced neck computed tomography (CECT) and pathological findings, and to determine the potential prognostic value of PET/CT and CECT parameters in oral cavity squamous cell carcinoma (OCSCC). MATERIALS AND METHOD: 36 OCSCC patients underwent staging PET/CT and 30/36 of patients had CECT. PET/CT parameters were measured for the primary tumor and the hottest involved node, including maximum, mean, and peak standardized uptake values (SUV max, SUV mean, and SUV peak), metabolic tumor volume (MTV), total lesion glycolysis (TLG), standardized added metabolic activity (SAM), and normalized standardized added metabolic activity (N SAM). Qualitative assessment of PET/CT and CECT were also performed. Pathological outcomes included: perineural invasion, lymphovascular invasion, nodal extracapsular spread, grade, pathologic T and N stages. Multivariable logistic regression models were fit for each parameter and outcome adjusting for potentially confounding variables. Multivariable Cox proportional hazards models were used for progression free survival (PFS), locoregional recurrence free survival (LRFS), overall survival (OS) and distant metastasis free survival (DMFS). RESULTS: In multivariable analysis, patients with high (>= median) tumor SUV max (OR 6.3), SUV mean (OR 6.3), MTV (OR 19.0), TLG (OR 19.0), SAM (OR 11.7) and N SAM (OR 19.0) had high pathological T-stage (T3/T4) (p<0.05). Ring/heterogeneous pattern on CECT qualitative assessment was associated with worse DMFS and OS. CONCLUSION: High PET/CT parameters were associated with pathologically advanced T stage (T3/T4). Qualitative assessment of CECT has prognostic value. PET/CT parameters did not predict clinical outcome. PMID- 25816995 TI - Granulomatosis with polyangiitis and intravenous immunoglobulins: a case series and review of the literature. AB - Granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing small-vessel vasculitis, belonging to the group of anti-neutrophil cytoplasm antibody vasculitis. The therapeutic strategy includes, in most cases, corticosteroids associated, at least in severe forms of the disease, with immunosuppressive agents: cyclophosphamide and rituximab to induce remission, methotrexate, azathioprine and mycophenolate mofetil to prevent relapses. Intravenous immunoglobulins represent an alternative adjuvant therapy. We described 5 cases of patients with granulomatosis with polyangiitis treated with monthly high-dose intravenous immunoglobulins (500mg/kg/daily for 3 consecutive days for 9months). No patients experienced adverse reactions, and 4 patients (80%) achieved a complete remission after 9 courses of this therapy, which was maintained also 3months later, although we are unable to determine whether improvement in outcomes was a direct result of the IVIG. We also discussed the beneficial effects of intravenous immunoglobulins in patients suffering from granulomatosis with polyangiitis, reporting the previously published data. PMID- 25816996 TI - Molecular simulations of hevein/(GlcNAc)3 complex with weakened OH/O and CH/pi hydrogen bonds: implications for their role in complex stabilization. AB - Carbohydrate-protein complexes are often characterized by interactions via aromatic amino acid residues. Several mechanisms have been proposed to explain these stacking-like interactions between pyranose sugars and aromatic moieties. The physical basis of these interactions is being explained as either dispersion CH/pi or hydrophobic. In order to elucidate the nature of these interactions, we performed a series of molecular dynamics simulation of hevein domain (HEV32) in complex with (beta-D-GlcNAc)3. Selected OH/O and CH/pi hydrogen bonds involved in carbohydrate recognition were artificially weakened in 100 ns molecular dynamics simulations. Separate weakening of either OH/O or CH/pi hydrogen bonds was not sufficient to destabilize the complex. This indicates that other effects, not solely CH/pi dispersion interactions, contribute significantly to the stability of the complex. Significant destabilization of complexes was reached only by simultaneous weakening of OH/O and CH/pi hydrogen bonds. This also shows that classical hydrogen bonds and CH/pi interactions are working in concert to stabilize this carbohydrate-protein test case. PMID- 25816997 TI - Structure elucidation of the capsular polysaccharide of Acinetobacter baumannii AB5075 having the KL25 capsule biosynthesis locus. AB - Capsular polysaccharide was isolated by the phenol-water extraction of Acinetobacter baumannii AB5075 and studied by 1D and 2D (1)H and (13)C NMR spectroscopy. The following structure of the linear trisaccharide repeating unit was established: -> 3)-beta-D-ManpNAcA-(1 -> 4)-beta-D-ManpNAcA-(1 -> 3)-alpha-D QuipNAc4NR-(1 -> where R indicates (S)-3-hydroxybutanoyl or acetyl in the ratio ~ 2.5:1. The genes in the polysaccharide biosynthesis locus designated KL25 are appropriate to the established CPS structure. PMID- 25816998 TI - Trancriptomic approach reveals the molecular diversity of Hottentotta conspersus (Buthidae) venom. AB - Scorpion venom consists of a complex mixture of molecules including biologically active compounds. Because of their high potency and selectivity, toxins have medical applicability. In the last decades, scorpion toxins have thus gained considerable interest among scientist in the fields of pharmacology, biophysics and neurobiology. Identification of scorpion venom peptides and toxins can be achieved based on transcriptome approaches. We constructed the first cDNA library and Expressed Sequence Tag (EST) study to explore the transcriptomic composition of the telson from the southern African scorpion Hottentotta conspersus, belonging to the family Buthidae. We obtained 21 new venom-related sequences (8 contigs and 16 singlets) from a total of 98 ESTs analyzed, including putative neurotoxins (chloride, potassium, sodium and calcium channel toxins), bradykinin potentiating peptides and other venom peptides without established function. These novel toxin-related sequences might serve as basis for further research both of pharmaceutical and phylogenetic nature. PMID- 25816999 TI - Heat treatment and the use of additives to improve the stability of paralytic shellfish poisoning toxins in shellfish tissue reference materials for internal quality control and proficiency testing. AB - The need for homogenous reference materials stable for paralytic shellfish toxins is vital for the monitoring and quality assurance of these potent neurotoxins in shellfish. Two stabilisation techniques were investigated, heat treatment through autoclaving and the addition of preserving additives into the tissue matrix. Short and long-term stability experiments as well as homogeneity determination were conducted on materials prepared by both techniques in comparison with an untreated control using two LC-FLD methods. Both techniques improved the stability of the matrix and the PSP toxins present compared to the controls. A material was prepared using the combined techniques of heat treatment followed by spiking with additives and data is presented from this optimised reference material as used over a two year period in the Irish national monitoring program and in a development exercise as part of a proficiency testing scheme operated by QUASIMEME (Quality Assurance of Information for Marine Environmental Monitoring in Europe) since 2011. The results were indicative of the long-term stability of the material as evidenced through consistent assigned values in the case of the proficiency testing scheme and a low relative standard deviation of 10.5% for total toxicity data generated over 24 months. PMID- 25817000 TI - General characterization of Tityus fasciolatus scorpion venom. Molecular identification of toxins and localization of linear B-cell epitopes. AB - This communication describes the general characteristics of the venom from the Brazilian scorpion Tityus fasciolatus, which is an endemic species found in the central Brazil (States of Goias and Minas Gerais), being responsible for sting accidents in this area. The soluble venom obtained from this scorpion is toxic to mice being the LD50 is 2.984 mg/kg (subcutaneally). SDS-PAGE of the soluble venom resulted in 10 fractions ranged in size from 6 to 10-80 kDa. Sheep were employed for anti-T. fasciolatus venom serum production. Western blotting analysis showed that most of these venom proteins are immunogenic. T. fasciolatus anti-venom revealed consistent cross-reactivity with venom antigens from Tityus serrulatus. Using known primers for T. serrulatus toxins, we have identified three toxins sequences from T. fasciolatus venom. Linear epitopes of these toxins were localized and fifty-five overlapping pentadecapeptides covering complete amino acid sequence of the three toxins were synthesized in cellulose membrane (spot synthesis technique). The epitopes were located on the 3D structures and some important residues for structure/function were identified. PMID- 25817001 TI - Elucidation of procoagulant mechanism and pathophysiological significance of a new prothrombin activating metalloprotease purified from Daboia russelii russelii venom. AB - The procoagulant proteases present in Russell's Viper venom (RVV) are responsible for promoting consumption coagulopathy in victims. In this study, a procoagulant metalloprotease (Rusviprotease) possessing prothrombin activating and alpha fibrinogenase properties has been purified and characterized from RVV. Rusviprotease is a 26.8 kDa glycoprotein which also exists in other multimeric forms. The peptide mass fingerprinting and secondary structure analyses of Rusviprotease revealed its similarity with snake venom prothrombin activators and metalloproteases. Similar to group A prothrombin activators, Rusviprotease cleaved prothrombin independent of any co-factor requirement generating meizothrombin which is further cleaved to form thrombin. The Km and Vmax values of Rusviprotease towards prothrombin were determined to be 1.73 MUM, and 153.5 nM thrombin generated/min/MUmoles of Rusviprotease, respectively. The Km and Vmax values of Rusviprotease towards fibrinogen were calculated to be 3.14 MUM and 78.7 nmol/min, respectively. Spectrofluorometric study provided the evidence of interaction between Rusviprotease and factor Xa with a Kd value of 6.64 nM. This interaction augmented the prothrombin activating property of the factor Xa prothrombinase-Rusviprotease complex by 2.5 fold. Intravenous injection of Rusviprotease to BALB/c mice (0.1 mg/kg) resulted in in vivo defibrinogenation rendering the blood incoagulable. In conclusion, Rusviprotease is the first example of a prothrombin activator with fibrinogenolytic property purified from Daboia russelii russelii venom. PMID- 25817002 TI - Toxalbumin exposures: 12 years' experience of U.S. poison centers. AB - BACKGROUND: Toxalbumins are natural plant toxins purported to be highly toxic. The purpose was to evaluate toxalbumin exposures reported to U.S. poison centers to determine plants involved and their toxicities. METHODS: A retrospective review of National Poison Data System data on acute toxalbumin exposures with known outcomes from 2000 through 2011 was performed. RESULTS: There were 1164 exposures. The majority involved one route (1135; 97.5%), mostly ingestions (904; 79.7%) or dermal (166; 14.3%). Most patients developed no effects (694; 59.6%) or minor effects (374; 32.1%). Moderate or major effects occurred in 8.3% with 66.6% ingestions and 23.9% dermal. There were no deaths. Exposures to the plants Ricinus communis and Robinia pseudoacacia were most common (33.8% and 32.9%, respectively), with gastrointestinal effects from R. communis (vomiting 19.6%, diarrhea 8.9%, nausea 7.9%) and dermal effects from R. pseudoacacia (puncture 28.7%, dermal irritation/pain 27.9%, and edema 13.3%). CONCLUSIONS: While toxalbumin plant exposures were generally well-tolerated, continued evaluation of risk is warranted since plants were primarily identified by the public. Major effects occurred in under 1% of cases overall, and not at all following unintentional ingestions. These findings should help allay concerns that unintentional ingestions of toxalbumin plants by young children will cause serious toxicity and possibly death. PMID- 25817003 TI - Detection of human exposure to saxitoxin and neosaxitoxin in urine by online solid phase extraction-liquid chromatography-tandem mass spectrometry. AB - Saxitoxin (STX) and neosaxitoxin (NEO) are potent neurotoxins that cause paralytic shellfish poisoning (PSP). PSP typically occurs through the ingestion of bivalve shellfish that have consumed toxin producing dinoflagellates. Due to initial presentation of symptoms being nonspecific, a clinical measurement is needed to confirm exposure to these toxins. Our group has developed an online solid phase extraction hydrophilic interaction liquid chromatography (HILIC) method for the analysis of STX and NEO in human urine with tandem mass spectrometry. A unique feature of this online method is the incorporation of a new synthetic (15)N4-STX labeled internal standard used for quantitation. Manual sample preparation time was reduced by approximately 70% for 98 urine samples as compared to a previously reported method. The lowest reportable limit for STX was improved from 5.0 ng/mL to 1.01 ng/mL and from 10.0 ng/mL to 2.62 ng/mL for NEO. Three analysts validated the method with 20 calibration curves total over 30 days with precision and accuracy within +/-15% for all QCs. This new online method rapidly identifies STX and NEO exposure with improved sensitivity, which can facilitate the work of public health authorities to confirm the cases of PSP, complementing the many shellfish monitoring programs worldwide. PMID- 25817004 TI - A tyrosine-containing analog of mu-conotoxin GIIIA as ligand in the receptor binding assay for paralytic shellfish poisons. AB - Development of novel analytical tools to detect marine biotoxins has been warranted in view of the apparent global pervasiveness of algal-derived shellfish poisoning, and the limitations of existing methods. Here, we describe the initial phase in the development and evaluation of a tyrosine-containing analog of MU conotoxin (MU-CTX) GIIIA as an alternative to saxitoxin (STX) in a receptor binding assay (RBA) for paralytic shellfish poisons. The peptide analog was synthesized and characterized for structure and bioactivity. The major product of oxidation elicited paralytic symptoms in mice at a minimum dose of 1.31 mg kg(-1) (i.p.). Mass spectrometry analysis of the bioactive peptide gave a molecular mass of 2637.52 Da that was close to the predicted value. Iodination via chloramine-T produced non-, mono- and di-iodinated peptides (respectively, NIP, MIP and DIP). Competition assays against (3)H-STX revealed higher Ki and EC50 (P < 0.0001, ANOVA) indicating reduced affinity for the receptor, and limited displacement of receptor-bound STX. However, subsequent use of MIP may extend the application of RBA to detect small changes in toxin levels owing to its likely enhanced displacement by STX. This may be useful in analyzing samples with toxicities near the regulatory limit, or in establishing baseline values in high risk environments. PMID- 25817005 TI - Insight into alteration of gut microbiota in Clostridium difficile infection and asymptomatic C. difficile colonization. AB - Clostridium difficile is well recognized as the common pathogen of nosocomial diarrhea, meanwhile, asymptomatic colonization with C. difficile in part of the population has also drawn public attention. Although gut microbiota is known to play an important role in the pathogenesis of C. difficile infection (CDI), whether there is any alteration of gut microbial composition in asymptomatic C. difficile carriers hasn't been clearly described. The purpose of this study was to explore the differences in gut microbiome among CDI patients, asymptomatic C. difficile carriers and healthy individuals. We performed fecal microbiota analysis on the samples of eight CDI patients, eight asymptomatic C. difficile carriers and nine healthy subjects using 16S rRNA gene pyrosequencing. CDI patients and asymptomatic carriers showed reduced microbial richness and diversity compared with healthy subjects, accompanied with a paucity of phylum Bacteroidetes and Firmicutes as well as an overabundance of Proteobacteria. Some normally commensal bacteria, especially butyrate producers, were significantly depleted in CDI patients and asymptomatic carriers. Furthermore, the differences observed in microbial community structure between CDI patients and asymptomatic carriers suggested that the gut microbiota may be a potential factor of disease state for CDI. Our study demonstrates the characterization and diversity of gut microbiota in CDI and asymptomatic C. difficile colonization, which will provide new ideas for surveillance of the disease state and development of microbiota targeted agents for CDI prevention and treatment. PMID- 25817006 TI - Literature Synthesis: Patient Aggression Risk Assessment Tools in the Emergency Department. PMID- 25817007 TI - The Portuguese emergency medical system. PMID- 25817008 TI - Combinatorial gene construct and non-viral delivery for anti-obesity in diet induced obese mice. AB - The combinatorial peptidergic therapy of islet amyloid polypeptide (IAPP) and leptin (LEP) analogues was once an optimistic option in treating obese animals and patients. However, the need for frequent administrations and its negative side effects prevent it from being a viable choice. Here, we developed a combinatorial gene therapy of IAPP and LEP, where two genes are inserted into a single plasmid with self-cleaving furin and 2A sites to treat diet-induced obese (DIO) mice. The developed plasmid DNA (pDNA) individually produced both IAPP and LEP peptides in vitro and in vivo. The pDNA was delivered with a non-viral polymeric carrier, and its once-a-week administrations demonstrated a synergistic loss of body weight and significant reductions of fat mass, blood glucose, and lipid levels in DIO mice. The results suggest that the combinatorial gene therapy would have higher potential than the peptidergic approach for future translation due to its improved practicability. PMID- 25817009 TI - Correlation Between the Dynamic Postoperative Visual Outcome and the Restoration of Foveal Microstructures After Macular Hole Surgery. AB - PURPOSE: To analyze the long-term dynamic healing process of outer retinal changes for 1 year in patients who underwent a standard vitrectomy procedure for idiopathic macular hole (MH) repair. DESIGN: Retrospective, consecutive, observational case series. METHODS: Data were collected on 60 eyes of 56 patients (30 women, 26 men) that underwent successful pars plana vitrectomy (PPV) and internal limiting membrane (ILM) peeling for idiopathic MH from January 2011 to December 2012. The age distribution ranged from 56 to 85 years (mean: 64 years). Forty eyes underwent combined phacoemulsification, PPV, ILM peeling, and intraocular lens implantation; 20 preoperative pseudophakic eyes underwent PPV and ILM peeling only. The main outcome measures included logMAR best-corrected visual acuity (BCVA) and macular microstructures determined by spectral-domain optical coherence tomography performed pre- and postoperatively during follow-up visits at 1, 3, 6, 9, and 12 months. RESULTS: One month after surgery, 24 eyes (40%) showed normal external limiting membrane (ELM), 36 eyes (60%) showed normal ELM at 3 months, and 54 eyes (90%) showed normal ELM 12 months after surgery. Six eyes (10%) revealed a continuous ellipsoid zone (EZ) at 1 month, 18 eyes (30%) at 3 months, and 48 eyes (80%) at 12 months postoperatively. There were no eyes with a disrupted ELM in the presence of an intact EZ line. The eyes with intact ELM and/or intact EZ line showed better BCVA than eyes with defects in ELM or EZ line. On the contrary, glial cell presentation is significantly associated with worse postoperative BCVA. However, the presence of foveal cystoid change is not significantly associated with postoperative BCVA. CONCLUSIONS: The ELM and EZ line at the fovea recovered and the presence of glial cells and cystoid space resolved gradually after surgery. The postoperative visual acuity was correlated with resolved glial cells and a restored ELM and EZ line. PMID- 25817011 TI - Mentor-guided self-directed learning affects resident practice. AB - OBJECTIVE: Self-directed learning (SDL) can be as effective as instructor-led training. It employs less instructional resources and is potentially a more efficient educational approach. Although SDL is encouraged among residents in our surgical training program via 24-hour access to surgical task trainers and online modules, residents report that they seldom practice. We hypothesized that a mentor-guided SDL approach would improve practice habits among our residents. DESIGN: From 2011 to 2013, 12 postgraduate year (PGY)-2 general surgery residents participated in a 6-week minimally invasive surgery (MIS) rotation. At the start of the rotation, residents were asked to practice laparoscopic skills until they reached peak performance in at least 3 consecutive attempts at a task (individual proficiency). SETTING: Trainees met with the staff surgeon at weeks 3 and 6 to evaluate progress and review a graph of their individual learning curve. All trainees subsequently completed a survey addressing their practice habits and suggestions for improvement of the curriculum. RESULTS: By the end of the rotation, 100% of participants improved in all practiced tasks (p < 0.05), and each reported that they practiced more in this rotation than during rotations without mentor-guided SDL. Additionally, 6 (50%) residents reported that their skill level had improved relative to their peers. Some residents (n = 3) felt that the curriculum could be improved by including task-specific goals and additional practice sessions with the staff surgeon. CONCLUSIONS: Mentor-guided SDL stimulated surgical residents to practice with greater frequency. This repeated deliberate practice led to significantly improved MIS skills without significantly increasing the need for faculty-led instruction. Some residents preferred more discrete goal setting and increased mentor guidance. PMID- 25817010 TI - Cervical cancer screening in Europe: Quality assurance and organisation of programmes. AB - BACKGROUND: Cervical screening programmes have reduced cervical cancer incidence and mortality but the level of success is highly variable between countries. Organisation of programmes is essential for equity and cost-effectiveness. However, there are differences in effectiveness, also among organised programmes. In order to identify the key organisational components that determine effectiveness, we performed a Europe-wide survey on the current status of organisation and organised quality assurance (QA) measures in cervical cancer prevention programmes, as well as organisation-associated costs. METHODS: A comprehensive questionnaire was developed through systematic review of literature and existing guidelines. The survey was sent to programme organisers, Ministries of Health and experts in 34 European Union (EU) and European Free Trade Agreement (EFTA) countries. Detailed aspects of programme organisation, quality assurance, monitoring, evaluation and corresponding line-item costs were recorded. Documentation of programme guidelines, protocols and publications was requested. RESULTS: Twenty-nine of 34 countries responded. The results showed that organised efforts for QA, monitoring and evaluation were carried out to a differing extent and were not standardised, making it difficult to compare the cost-effectiveness of organisation and QA strategies. Most countries found it hard to estimate the costs associated with launching and operating the organised programme. CONCLUSIONS: To our knowledge, this is the first questionnaire to request detailed information on the actual organisation and QA of programmes. The results of this survey can be used as a basis for further development of standardised guidelines on organisation and QA of cervical cancer screening programmes in Europe. PMID- 25817012 TI - The role of nontechnical skills in simulated trauma resuscitation. AB - OBJECTIVE: Trauma team training provides instruction on crisis management through debriefing and discussion of teamwork and leadership skills during simulated trauma scenarios. The effects of team leader's nontechnical skills (NTSs) on technical performance have not been thoroughly studied. We hypothesized that team's and team leader's NTSs correlate with technical performance of clinical tasks. DESIGN: Retrospective cohort study. SETTING: Brigham and Women's Hospital, STRATUS Center for Surgical Simulation PARTICIPANTS: A total of 20 teams composed of surgical residents, emergency medicine residents, emergency department nurses, and emergency services assistants underwent 2 separate, high-fidelity, simulated trauma scenarios. Each trauma scenario was recorded on video for analysis and divided into 4 consecutive sections. For each section, 2 raters used the Non Technical Skills for Surgeons framework to assess NTSs of the team. To evaluate the entire team's NTS, 2 additional raters used the Modified Non-Technical Skills Scale for Trauma system. Clinical performance measures including adherence to guidelines and time to perform critical tasks were measured independently. RESULTS: NTSs performance by both teams and team leaders in all NTS categories decreased from the beginning to the end of the scenario (all p < 0.05). There was significant correlation between team's and team leader's cognitive skills and critical task performance, with correlation coefficients between 0.351 and 0.478 (p < 0.05). The NTS performance of the team leader highly correlated with that of the entire team, with correlation coefficients between 0.602 and 0.785 (p < 0.001). CONCLUSIONS: The NTSs of trauma teams and team leaders deteriorate as clinical scenarios progress, and the performance of team leaders and teams is highly correlated. Cognitive NTS scores correlate with critical task performance. Increased attention to NTSs during trauma team training may lead to sustained performance throughout trauma scenarios. Decision making and situation awareness skills are critical for both team leaders and teams and should be specifically addressed to improve performance. PMID- 25817013 TI - A systematic approach to developing a global surgery elective. AB - BACKGROUND: Interest in global health has been increasing for years among American residents and medical students. Many residency programs have developed global health tracks or electives in response to this need. OBJECTIVES: Our goal was to create a global surgery elective based on a synergistic partnership between our institution and a hospital in the developing world. DESIGN: We created a business plan and 1-year schedule for researching potential sites and completing a pilot rotation at our selected hospital. SETTING: We administered a survey to general surgery residents at the University of Cincinnati and visited medical facilities in Sierra Leone, Cameroon, and Malawi. PARTICIPANTS: The survey was given to all general surgery residents. A resident and a faculty member executed the fact-finding trip as well as the pilot rotation. RESULTS: Our general surgery residents view an international elective as integral to residency training and would participate in such an elective. After investigating 6 hospitals in sub-Saharan Africa, we conducted a pilot rotation at our selected hospital and gained the necessary information to organize a curriculum. We will begin sending senior residents for 8-week rotations in the coming academic year. CONCLUSIONS: By systematically approaching the process of creating a global surgery elective, we were able to gain considerable insight into choosing a location and organizing the elective. PMID- 25817014 TI - Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome. AB - Robinow syndrome (RS) is a phenotypically and genetically heterogeneous condition that can be caused by mutations in genes encoding components of the non-canonical Wnt signaling pathway. In contrast, germline mutations that act to increase canonical Wnt signaling lead to distinctive osteosclerotic phenotypes. Here, we identified de novo frameshift mutations in DVL1, a mediator of both canonical and non-canonical Wnt signaling, as the cause of RS-OS, an RS subtype involving osteosclerosis, in three unrelated individuals. The mutations all delete the DVL1 C terminus and replace it, in each instance, with a novel, highly basic sequence. We showed the presence of mutant transcript in fibroblasts from one individual with RS-OS and demonstrated unimpaired protein stability with transfected GFP tagged constructs bearing a frameshift mutation. In vitro TOPFlash assays, in apparent contradiction to the osteosclerotic phenotype, revealed that the mutant allele was less active than the wild-type allele in the canonical Wnt signaling pathway. However, when the mutant and wild-type alleles were co-expressed, canonical Wnt activity was 2-fold higher than that in the wild-type construct alone. This work establishes that DVL1 mutations cause a specific RS subtype, RS OS, and that the osteosclerosis associated with this subtype might be the result of an interaction between the wild-type and mutant alleles and thus lead to elevated canonical Wnt signaling. PMID- 25817015 TI - Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. AB - Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies-heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase (AARS) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS, and the single affected child is homozygous for p.Arg751Gly AARS. The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations. PMID- 25817016 TI - DVL1 frameshift mutations clustering in the penultimate exon cause autosomal dominant Robinow syndrome. AB - Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical signaling gene WNT5A underlie a subset of autosomal-dominant Robinow syndrome (DRS) cases, but most individuals with DRS remain without a molecular diagnosis. We performed whole-exome sequencing in four unrelated DRS-affected individuals without coding mutations in WNT5A and found heterozygous DVL1 exon 14 mutations in three of them. Targeted Sanger sequencing in additional subjects with DRS uncovered DVL1 exon 14 mutations in five individuals, including a pair of monozygotic twins. In total, six distinct frameshift mutations were found in eight subjects, and all were heterozygous truncating variants within the penultimate exon of DVL1. In five families in which samples from unaffected parents were available, the variants were demonstrated to represent de novo mutations. All variant alleles are predicted to result in a premature termination codon within the last exon, escape nonsense-mediated decay (NMD), and most likely generate a C-terminally truncated protein with a distinct -1 reading-frame terminus. Study of the transcripts extracted from affected subjects' leukocytes confirmed expression of both wild-type and variant alleles, supporting the hypothesis that mutant mRNA escapes NMD. Genomic variants identified in our study suggest that truncation of the C-terminal domain of DVL1, a protein hypothesized to have a downstream role in the Wnt-5a non-canonical pathway, is a common cause of DRS. PMID- 25817019 TI - Carbohydrate catabolic diversity of bifidobacteria and lactobacilli of human origin. AB - Because increased proportions of particular commensal bacteria such as bifidobacteria and lactobacilli have been linked to human health through a variety of mechanisms, there is corresponding interest in identifying carbohydrates that promote growth and metabolic activity of these bacteria. We evaluated the ability of 20 carbohydrates, including several commercially available carbohydrates that are sold as prebiotic ingredients, to support growth of 32 human-derived isolates belonging to the genera Bifidobacterium and Lactobacillus, including those isolated from healthy elderly subjects. In general, bifidobacterial strains were shown to display more diverse carbohydrate utilization profiles compared to the tested Lactobacillus species, with several bifidobacterial strains capable of metabolizing xylo-oligosaccharide (XOS), arabinoxylan, maltodextrin, galactan and carbohydrates containing fructo oligosaccharide (FOS) components. In contrast, maltodextrin, galactan, arabinogalactan and galactomannan did not support robust growth (>=0.8 OD600 nm) of any of the Lactobacillus strains assessed. Carbohydrate fermentation was variable among strains tested of the same species for both genera. This study advances our knowledge of polysaccharide utilization by human gut commensals, and provides information for the rational design of selective prebiotic food ingredients. PMID- 25817018 TI - Mutations in TUBGCP4 alter microtubule organization via the gamma-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy. AB - We have identified TUBGCP4 variants in individuals with autosomal-recessive microcephaly and chorioretinopathy. Whole-exome sequencing performed on one family with two affected siblings and independently on another family with one affected child revealed compound-heterozygous mutations in TUBGCP4. Subsequent Sanger sequencing was performed on a panel of individuals from 12 French families affected by microcephaly and ophthalmic manifestations, and one other individual was identified with compound-heterozygous mutations in TUBGCP4. One synonymous variant was common to all three families and was shown to induce exon skipping; the other mutations were frameshift mutations and a deletion. TUBGCP4 encodes gamma-tubulin complex protein 4, a component belonging to the gamma-tubulin ring complex (gamma-TuRC) and known to regulate the nucleation and organization of microtubules. Functional analysis of individual fibroblasts disclosed reduced levels of the gamma-TuRC, altered nucleation and organization of microtubules, abnormal nuclear shape, and aneuploidy. Moreover, zebrafish treated with morpholinos against tubgcp4 were found to have reduced head volume and eye developmental anomalies with chorioretinal dysplasia. In summary, the identification of TUBGCP4 mutations in individuals with microcephaly and a spectrum of anomalies in eye development, particularly photoreceptor anomalies, provides evidence of an important role for the gamma-TuRC in brain and eye development. PMID- 25817020 TI - Acute and sub-chronic toxicity of glucose-cysteine Maillard reaction products in Sprague-Dawley rats. AB - Maillard reaction products (MRPs) derived from glucose-cysteine reactions have excellent anti-browning ability. However, there is a lack of information about their acute and sub-chronic toxicities. To our knowledge, the present study is the first to evaluate the acute and sub-chronic toxicities of MRPs in experimental animals. Acute toxicity testing and analysis by Horn's method showed that the median lethal oral dose (LD50) of MRPs in rats was 6.81 g/kg body weight. The sub-chronic toxicity test involved feeding rats with diet containing 0, 0.43, 0.85, or 1.70% (w/w) MRPs for 90 days. These treatments did not affect mortality, gross pathology, histology, hematology, or blood chemistry, and there were no dose-dependent changes in feed consumption. Based on these results, the dietary no-observed-adverse-effect level (NOAEL) for 90-day exposure was 1.29 and 1.51 g MRPs/kg body weight/day for male and female rats, respectively. PMID- 25817021 TI - RIFM fragrance ingredient safety assessment, alpha-Irone, CAS registry number 79 69-6. PMID- 25817023 TI - Current models of the marmoset brain. AB - Since the availability of the common marmoset monkey as a primate model in neuroscience research has recently increased, much effort has been made to develop a reliable guide of the brain structures of this species. In this article, we review the development of the marmoset brain atlas and discuss a newly developed brain model, which was reconstructed from histological sections under volume-rendering technology. This kind of brain model allows virtual sections to be constructed on any axis, with nomenclatural annotations to structures in situ. This model is also applicable for the identification of structures revealed in magnetic resonance imaging studies. The brain model is accessible at the following web address: http://brainatlas.brain.riken.jp/marmoset/modules/xoonips/listitem.php?index_id=6 . PMID- 25817022 TI - RIFM fragrance ingredient safety assessment, allyl (cyclohexyloxy)acetate, CAS registry number 68901-15-5. PMID- 25817017 TI - A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. AB - We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 * 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRbeta1 and HLA-DQalpha1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(*)04. An omnibus test on polymorphic amino acid positions highlighted DRbeta1 13 (p = 4.08 * 10(-43)) and HLA-DQalpha1 47 (p = 4.02 * 10(-46)), 56, and 76 (both p = 1.84 * 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 * 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 * 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 * 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. PMID- 25817025 TI - Thermogravimetric analysis of the behavior of sub-bituminous coal and cellulosic ethanol residue during co-combustion. AB - The influence of the addition of cellulosic ethanol residue (CER) on the combustion of Indonesian sub-bituminous coal was analyzed by non isothermal thermo-gravimetric analysis (TGA). The effect of blends ratio (5%, 10%, 15% and 20%), interaction mechanism, and heating rate (5 degrees C/min, 10 degrees C/min, 15 degrees C/min, 20 degrees C/min) on the combustion process was studied. The results show that the increase of the blending ratio allows to achieve the increase of the combustibility index from 7.49E-08 to 5.26E-07 at the blending ratio of 20%. Two types of non-isothermal kinetic analysis methods (Ozawa-Flynn Wall and Vyazovkin) were also applied. Results indicate that the activation energy of the blends decreases with increasing the conversion rate. In particular, the blending ratio of 20% confirms to have the better combustion performance, with the average value of the activation energy equal to 41.10 kJ/mol obtained by Ozawa-Flynn-Wall model and 31.17 kJ/mol obtained by Vyazovkin model. PMID- 25817024 TI - Urinary bromophenol glucuronide and sulfate conjugates: Potential human exposure molecular markers for polybrominated diphenyl ethers. AB - One possible source of urinary bromophenol (BP) glucuronide and sulfate conjugates in mammalian animal models and humans is polybromodiphenyl ethers (PBDEs), a group of additive flame-retardants found ubiquitously in the environment. In order to study the correlation between levels of PBDEs in human blood plasma and those of the corresponding BP-conjugates in human urine, concentrations of 17 BDE congeners, 22 OH-BDE and 13 MeO-BDE metabolites, and 3 BPs in plasma collected from 100 voluntary donors in Hong Kong were measured by gas chromatograph tandem mass spectrometry (GC-MS). Geometric mean concentration of SigmaPBDEs, SigmaOH-BDEs, SigmaMeO-BDEs and SigmaBPs in human plasma were 4.45 ng g(-1) lw, 1.88 ng g(-1) lw, 0.42 ng g(-1) lw and 1.59 ng g(-1) lw respectively. Concentrations of glucuronide and sulfate conjugates of 2,4 dibromophenol (2,4-DBP) and 2,4,6-tribromophenol (2,4,6-TBP) in paired samples of urine were determined by liquid chromatography tandem triple quadrupole mass spectrometry (LC-MS/MS). BP-conjugates were found in all of the parallel urine samples, in the range of 0.08-106.49 MUg g(-1)-creatinine. Correlations among plasma concentrations of SigmaPBDEs/SigmaOH-BDEs/SigmaMeO-BDEs/SigmaBPs and BP conjugates in urine were evaluated by multivariate regression and Pearson product correlation analyses. These urinary BP-conjugates were positively correlated with SigmaPBDEs in blood plasma, but were either not or negatively correlated with other organobromine compounds in blood plasma. Stronger correlations (Pearson's r as great as 0.881) were observed between concentrations of BDE congeners having the same number and pattern of bromine substitution on their phenyl rings in blood plasma and their corresponding BP-conjugates in urine. PMID- 25817026 TI - Microbial structures and community functions of anaerobic sludge in six full scale wastewater treatment plants as revealed by 454 high-throughput pyrosequencing. AB - The microbial communities and abundance in anaerobic sludge from 4 industrial and 2 municipal wastewater treatment plants were investigated using 454 pyrosequencing technology in this study. A total of 5482-8692 high-quality reads of 16S rRNA V3-V5 regions were obtained. Taxonomic analysis using QIIME and RDP classifier found that Proteobacteria, Bacteroidetes, Chloroflexi and Firmicutes were the most abundant phyla in these samples. Furthermore, real-time PCR was used to validate the absolute abundance of these 16S rRNAs and some functional genes, including total bacteria, anammox bacteria, NOB (Nitrobacter, Nitrospira), AOA amoA, AOB amoA, nosZ, nirS, nirK, narG, napA, nrfA, mcrA and dsrA. Multivariate linear regression analysis indicated that AOA might be mixotrophic. Finally, redundancy analysis was used to reveal the relationships between operation parameters and microbial communities. Results showed that the coexistence of anammox, denitrification and DNRA could be useful for the simultaneous removal of nitrogen and organic matter. PMID- 25817027 TI - Influence of headspace flushing on methane production in Biochemical Methane Potential (BMP) tests. AB - The influence of headspace flushing on the specific methane (CH4) production of blank samples with just inoculum in Biochemical Methane Potential (BMP) tests was studied. The three most common ways were applied: flushing with nitrogen (N2) gas, flushing with a mixture of N2 and CO2 (80/20 v/v), and no flushing. The results revealed that removing the oxygen is crucial to avoid aerobic respiration, which caused both hindered activity of methanogens and loss of methane potential. Furthermore it was demonstrated that 20% of CO2 in the flush gas increased significantly the methane production by over 20% compared to the flushing with pure N2. In order to mimic the same headspace conditions as in full scale treatment plants, using a flush gas with a similar CO2 concentration as the expected biogas is suggested. PMID- 25817028 TI - Microbial-chemical indicator for anaerobic digester performance assessment in full-scale wastewater treatment plants for biogas production. AB - Anaerobic digestion was introduced into wastewater treatment plants several years ago, but anaerobic digestion performance has not yet been achieved. The variability of the microbial community in digesters is poorly understood, and despite the crucial role of anaerobic digestion reactors, the microbial equilibrium that yields the best performance in these reactors has only recently been hypothesised. In this study, two full-scale continuous anaerobic reactors, placed in Torino's main wastewater treatment plant in northern Italy, were followed to develop a summary indicator for measuring anaerobic digestion performance. A total of 100 sludge samples were collected. The samples were characterised chemically and physically, and microbial groups were quantified by qRT-PCR. A chemical biological performance index strictly correlated to specific biogas production (rho=0.739, p<0.01) is proposed. This approach will produce new management tools for anaerobic digestion in wastewater treatment plants. PMID- 25817029 TI - Survival and activity of individual bioaugmentation strains. AB - Successful application of bioaugmentation for enhanced degradation of environmental pollutants is often limited by the lack of methods to monitor the survival and activity of individual bioaugmentation strains. However, recent advancements in sequencing technologies and molecular techniques now allow us to address these limitations. Here a complementing set of general applicable molecular methods are presented that provides detailed information on the performance of individual bioaugmentation strains under in situ conditions. The approach involves genome sequencing to establish highly specific qPCR and RT-qPCR tools for cell enumerations and expression of involved genes, stable isotope probing to follow growth on the target compounds and GFP-tagging to visualize the bioaugmentation strains directly in samples, all in combination with removal studies of the target compounds. The concept of the approach is demonstrated through a case study involving degradation of aromatic hydrocarbons in activated sludge augmented with the bioaugmentation strain Pseudomonas monteilii SB3078. PMID- 25817030 TI - Blending municipal solid waste with corn stover for sugar production using ionic liquid process. AB - Municipal solid waste (MSW) represents an attractive cellulosic resource for sustainable fuel production. However, its heterogeneity is the major barrier to efficient conversion to biofuels. MSW paper mix was generated and blended with corn stover (CS). It has been shown that both of them can be efficiently pretreated in certain ionic liquids (ILs) with high yields of fermentable sugars. After pretreatment in 1-ethyl-3-methylimidazolium acetate ([C2C1Im][OAc]), over 80% glucose has been released with enzymatic saccharification. We have also applied an enzyme-free process by adding mineral acid and water directly into the IL/biomass slurry to induce hydrolysis. With the acidolysis process in 1-ethyl-3 methylimidazolium chloride ([C2C1Im]Cl), up to 80% glucose and 90% xylose are released. There is a correlation between the viscosity profile and hydrolysis efficiency; low viscosity of the hydrolysate generally corresponds to high sugar yields. Overall, the results indicate the feasibility of incorporating MSW as a robust blending agent for biorefineries. PMID- 25817032 TI - Hydrogen fermentation of food waste by alkali-shock pretreatment: microbial community analysis and limitation of continuous operation. AB - In the study, at first, batch tests were performed to investigate the effect of alkali-shock on H2 production from food waste (FW). After alkali-pretreatment of FW at pH 9.0-13.0, the FW was cultivated under mesophilic condition at pH 6.0 for 30 h without external inoculum addition. The amount of H2 production from FW pretreated at pH 11.0 and 12.0 was higher than that achieved in other pretreatment pH. The main metabolite was butyrate, and Clostridium were dominant at pH 11.0 and 12.0. Meanwhile, lactate was the main metabolite with Enterococcus and Streptococcus being the dominant genus at other pretreatment pH. When the batch process was switched to a continuous mode, H2 production was significantly dropped due to the increased activity of H2-consumers. The reliability of alkali pretreatment at pH 11.0 was proven by repeating the scale-up batch process, recording 1.57+/-0.11 mol H2/mol hexose(added) (17+/-2LH2/kg FW) and 4.39+/ 0.32LH2/L/d. PMID- 25817031 TI - Combined effect of erythromycin, tetracycline and sulfamethoxazole on performance of anaerobic sequencing batch reactors. AB - The combined effects of erythromycin-tetracycline-sulfamethoxazole (ETS) and sulfamethoxazole-tetracycline (ST) antibiotics on the performance of anaerobic sequencing batch reactors were studied. A control reactor was fed with wastewater that was free of antibiotics, while two additional reactors were fed with ETS and ST. The way in which the ETS and ST mixtures impact COD removal, VFA production, antibiotic degradation, biogas production and composition were investigated. The effects of the ETS mixtures were different from the ST mixtures, erythromycin can have an antagonistic effect on sulfamethoxazole and tetracycline. The anaerobic pre-treatment of these antibiotics can represent a suitable alternative to the use of chemical treatments for concentrations at 10 mg/L of S and 1 mg/L of T; 2 mg/L of E, 2 mg/L of T and 20 mg/L of S for the ST and ETS reactors respectively, which corresponds to min 70% COD removal efficiency. PMID- 25817033 TI - Using a combined hydrolysis factor to optimize high titer ethanol production from sulfite-pretreated poplar without detoxification. AB - Sulfite pretreatment to overcome the recalcitrance of lignocelluloses (SPORL) was applied to poplar NE222 chips in a range of chemical loadings, temperatures, and times. The combined hydrolysis factor (CHF) as a pretreatment severity accurately predicted xylan dissolution by SPORL. Good correlations between CHF and pretreated solids enzymatic digestibility, sugar yield, and the formations of furfural and acetic acid were obtained. Therefore, CHF was used to balance sugar yield with the formation of fermentation inhibitors for high titer ethanol production without detoxification. The results indicated that optimal sugar yield can be achieved at CHF=3.1, however, fermentation using un-detoxified whole slurries of NE222 pretreated at different severities by SPORL indicated CHF~2 produced best results. An ethanol titer of 41 g/L was achieved at total solids of approximately 20 wt% without detoxification with a low cellulase loading of 15 FPU/g glucan (27 mL/kg untreated wood). PMID- 25817034 TI - Application of acid mine drainage for coagulation/flocculation of microalgal biomass. AB - A novel application of acid mine drainage (AMD) for biomass recovery of two morphologically different microalgae species with respect to AMD dosage, microalgal cell density and pH of medium was investigated. Optimal flocculation of Scenedesmus obliquus and Chlorella vulgaris occurred with 10% dosage of AMD at an initial pH 9 for both 0.5 and 1.0 g/L cell density. The flocculation efficiency was 89% for S. obliquus and 93% for C. vulgaris. Zeta potential (ZP) was increased from -10.66 to 1.77 and -13.19 to 1.33 for S. obliquus and C. vulgaris, respectively. Scanning electron microscope with energy-dispersive X-ray of the microalgae floc confirmed the sweeping floc formation mechanism upon the addition of AMD. Application of AMD for the recovery of microalgae biomass is a cost-effective method, which might further allow reuse of flocculated medium for algal cultivation, thereby contributing to the economic production of biofuel from microalgal biomass. PMID- 25817036 TI - Simultaneous treatment (cell disruption and lipid extraction) of wet microalgae using hydrodynamic cavitation for enhancing the lipid yield. AB - Simultaneous treatment (combining with cell disruption and lipid extraction) using hydrodynamic cavitation (HC) was applied to Nannochloropsis salina to demonstrate a simple and integrated way to produce oil from wet microalgae. A high lipid yield from the HC (25.9-99.0%) was observed compared with autoclave (16.2-66.5%) and ultrasonication (5.4-26.9%) in terms of the specific energy input (500-10,000 kJ/kg). The optimal conditions for the simultaneous treatment were established using a statistical approach. The efficiency of the simultaneous method was also demonstrated by comparing each separate treatment. The maximum lipid yield (predicted: 45.9% and experimental: 45.5%) was obtained using 0.89% sulfuric acid with a cavitation number of 1.17 for a reaction time of 25.05 min via response surface methodology. Considering its comparable extractability, energy-efficiency, and potential for scale-up, HC may be a promising method to achieve industrial-scale microalgae operation. PMID- 25817035 TI - Control of CO2 input conditions during outdoor culture of Chlorella vulgaris in bubble column photobioreactors. AB - A study on the optimization of CO2 usage during outdoor microalgae cultivation in order to further maximize the CO2 to biomass conversion efficiency is presented. A constant supply of CO2 was found to be non-essential for culturing microalgae outdoors in 80 L (8 L*10 sets) bubble columns. Among the different CO2 input conditions that were studied, 2% CO2 with intermittent supply and 2%+4% CO2 alternation did not affect the algal growth as compared to having a constant supply of 2% CO2. However, during both input conditions, the CO2 to biomass conversion efficiency was doubled while the amount of CO2 used was reduced by 50%. The algal biomass obtained was found to have a higher carbohydrate yield but a lower protein yield as compared to previously published studies. The findings from this study could be applied for large-scale microalgae production so as to minimize cultivation and energy costs. PMID- 25817037 TI - An agent-based model of dialect evolution in killer whales. AB - The killer whale is one of the few animal species with vocal dialects that arise from socially learned group-specific call repertoires. We describe a new agent based model of killer whale populations and test a set of vocal-learning rules to assess which mechanisms may lead to the formation of dialect groupings observed in the wild. We tested a null model with genetic transmission and no learning, and ten models with learning rules that differ by template source (mother or matriline), variation type (random errors or innovations) and type of call change (no divergence from kin vs. divergence from kin). The null model without vocal learning did not produce the pattern of group-specific call repertoires we observe in nature. Learning from either mother alone or the entire matriline with calls changing by random errors produced a graded distribution of the call phenotype, without the discrete call types observed in nature. Introducing occasional innovation or random error proportional to matriline variance yielded more or less discrete and stable call types. A tendency to diverge from the calls of related matrilines provided fast divergence of loose call clusters. A pattern resembling the dialect diversity observed in the wild arose only when rules were applied in combinations and similar outputs could arise from different learning rules and their combinations. Our results emphasize the lack of information on quantitative features of wild killer whale dialects and reveal a set of testable questions that can draw insights into the cultural evolution of killer whale dialects. PMID- 25817038 TI - Spatial sorting and range shifts: consequences for evolutionary potential and genetic signature of a dispersal trait. AB - Species are shifting their ranges under climate change, with genetic and evolutionary consequences. As a result, the spatial distribution of genetic diversity in a species' range can show a signature of range expansion. This genetic signature takes time to decay after the range stops expanding and it is important to take that lag time into account when interpreting contemporary spatial patterns of genetic diversity. In addition, the return to spatial equilibrium on an ecologically relevant timescale will depend on migration of genetic diversity across the species' range. However, during a range shift alleles may go extinct at the retracting range margin due to spatial sorting. Here we studied the spatial pattern of genotypes that differ in dispersal rate across the species range before, during and after a range shift, assessed the effect of range retraction on this pattern, and quantified the duration of the ephemeral genetic signature of range expansion for this trait. We performed simulation experiments with an individual-based metapopulation model under several contemporary climate change scenarios. The results show an increase of the number of individuals with high dispersal rate. If the temperature increased long enough the allele coding for low dispersal rate would go extinct. The duration of the genetic signature of range expansion after stabilisation of the species' distribution lasted up to 1200 generations after a temperature increase for 60 years at the contemporary rate. This depended on the total displacement of the climate optimum, as the product of the rate of temperature increase and its duration. So genetic data collected in the field do not necessarily reflect current selection pressures but can be affected by historic changes in species distribution, long after the establishment of the current species' range. Return to equilibrium patterns may be hampered by loss of evolutionary potential during range shift. PMID- 25817039 TI - Expression of human and mouse adenine nucleotide translocase (ANT) isoform genes in adipogenesis. AB - Adenine nucleotide translocases (ANTs) are mitochondrial proteins encoded by nuclear DNA that catalyze the exchange of ATP generated in the mitochondria for ADP produced in cytosol. There are four ANT isoforms in humans (hANT1-4) and three in mice (mANT1, mANT2 and mANT4), all encoded by distinct genes. The aim of this study was to quantify expression of ANT isoform genes during the adipogenesis of mouse 3T3-L1 and human Simpson-Golabi-Behmel syndrome (SGBS) derived preadipocytes. We also studied the effects of the adipogenesis regulators, insulin and rosiglitazone, on ANT isoform expression in differentiated adipocytes and examined the expression of ANT isoforms in subcutaneous and visceral white adipose tissue (WAT) from mice and humans. We found that adipogenesis was associated with an increase in the expression of ANT isoforms, specifically mANT2 in mouse 3T3-L1 cells and hANT3 in human SGBS cells. These changes could be involved in the increases in oxidative metabolism and decreases in lactate production observed during differentiation. Insulin and rosiglitazone induced mANT2 gene expression in mature 3T3-L1 cells and hANT2 and hANT3 gene expression in SGBS adipocytes. Furthermore, human WAT expressed greater amounts of hANT3 than hANT2, and the expression of both of these isoforms was greater in subcutaneous WAT than in visceral WAT. Finally, inhibition of ANT activity by atractyloside or bongkrekic acid impaired proper adipocyte differentiation. These results suggest that changes in the expression of ANT isoforms may be involved in adipogenesis in both human and mouse WAT. PMID- 25817040 TI - Human enhancer of filamentation 1-induced colorectal cancer cell migration: Role of serine phosphorylation and interaction with the breast cancer anti-estrogen resistance 3 protein. AB - Human enhancer of filamentation 1 (HEF1) is a member of the p130Cas family of docking proteins involved in integrin-mediated cytoskeleton reorganization associated with cell migration. Elevated expression of HEF1 promotes invasion and metastasis in multiple cancer cell types. To date, little is known on its role in CRC tumor progression. HEF1 is phosphorylated on several Ser/Thr residues but the effects of these post-translational modifications on the functions of HEF1 are poorly understood. In this manuscript, we investigated the role of HEF1 in migration of colorectal adeno-carcinoma cells. First, we showed that overexpression of HEF1 in colo-carcinoma cell line HCT116 increases cell migration. Moreover, in these cells, HEF1 increases Src-mediated phosphorylation of FAK on Tyr-861 and 925. We then showed that HEF1 mutation on Ser-369 enhances HEF1-induced migration and FAK phosphorylation as a result of protein stabilization. We also, for the first time characterized a functional mutation of HEF1 on Arg-367 which mimics the effect of Ser-369 to Ala mutation. Finally through mass spectrometry experiments, we identified BCAR3 as an essential interactor and mediator of HEF1-induced migration. We demonstrated that single amino acid mutations that prevent formation of the HEF1-BCAR3 complex impair HEF1 mediated migration. Therefore, amino-acid substitutions that impede Ser-369 phosphorylation stabilize HEF1 which increases the migration of CRC cells and this latter effect requires the interaction of HEF1 with the NSP family adaptor protein BCAR3. Collectively, these data reveal the importance of HEF1 expression level in cancer cell motility and then support the utilization of HEF1 as a biomarker of tumor progression. PMID- 25817041 TI - Activation of OR1A1 suppresses PPAR-gamma expression by inducing HES-1 in cultured hepatocytes. AB - Olfactory receptors (ORs) comprise the largest G protein-coupled receptor gene superfamily. Recent studies indicate that ORs are also expressed in non-olfactory organs, including metabolically active tissues, although their biological functions in these tissues are largely unknown. In this study, OR1A1 expression was detected in HepG2 liver cells. OR1A1 activation by (-)-carvone, a known OR1A1 ligand, increased the cyclic adenosine monophosphate (cAMP), but not intracellular Ca(2+) concentration, thereby inducing protein kinase A (PKA) activity with subsequent phosphorylation of cAMP response element-binding protein (CREB) and upregulation of the CREB-responsive gene hairy and enhancer of split (HES)-1, a corepressor of peroxisome proliferator-activated receptor-gamma (PPAR gamma) in hepatocytes. In (-)-carvone-stimulated cells, the repression of PPAR gamma reduced the expression of the target gene, mitochondrial glycerol-3 phosphate acyltransferase, which encodes a key enzyme involved in triglyceride synthesis. Intracellular triglyceride level and lipid accumulation were reduced in cells stimulated with (-)-carvone, effects that were diminished following the loss of OR1A1 function. These results indicate that OR1A1 may function as a non redundant receptor in hepatocytes that regulates the PKA-CREB-HES-1 signaling axis and thereby modulates hepatic triglyceride metabolism. PMID- 25817042 TI - Prevalence and characterization of Salmonella isolated from chicken meat in Turkey. AB - This study was conducted in a Turkish province to investigate the presence of Salmonella spp. in 150 chicken meat samples using 2 phenotyping techniques: classic culture technique (CCT) and immunomagnetic separation (IMS). For the confirmation of the isolates at molecular levels, invA gene was detected in these isolates. The presence of invA, class 1 (Cls1) integrons, and integrase (Int1) genes was demonstrated by PCR assay; and the resistance of the isolated Salmonella spp. strains to antibiotics was determined by disk diffusion test. All the cultural and PCR results were evaluated together; Salmonella spp. were detected in a total of 64 (42.66%) chicken meat samples. Contamination rate was higher in carcasses (53.33%, n = 75) than in meat pieces (32%, n = 75). When results of standard culture were compared with IMS technique, IMS (n = 54) showed a clear superiority over the CCT (n = 38). A very high resistance rate (>= 89.28%) to vancomycin, tetracycline, streptomycin, or nalidixic acid was found. Trimethoprim-sulfamethoxazole resistance was present in 32.14%. Relatively lower incidence of resistance (<= 8.33%) to gentamicin, chloramphenicol, ampicillin, and ceftriaxone was observed. Concurrent resistance to at least 4 antibiotics was detected in 92.85% of the isolates. Cls1 integrons and Int1 were positive in 80.95% and 95.23% of the isolates, respectively. However, Int1 alone was detected in 15.47% (n = 13). In conclusion, the high prevalence of Salmonella spp. in chicken meat may pose a potential public health risk, and the presence of antibiotic-resistant Salmonella spp. isolate together with Cls1 integron and/or integrase might play an important role in horizontal antibiotic gene transfer. PMID- 25817043 TI - Meta-chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice. AB - BACKGROUND AND PURPOSE: Most forms of human obesity are characterized by impaired leptin sensitivity and, therefore, the effectiveness of anti-obesity leptin therapy in these leptin-resistant obese patients is marginal. Hence, the development of strategies to increase leptin sensitivity is of high priority in the field of obesity research. EXPERIMENTAL APPROACH: We first examined the effects of co-administration of leptin and meta-chlorophenylpiperazine (mCPP), an agonist of 5-HT2C and 5-HT1B receptors, on energy balance in leptin-resistant diet-induced obese (DIO) mice. We further assessed leptin-induced phosphorylation of the STAT-3 (pSTAT3) in various brain regions of DIO mice pretreated with mCPP or in mice genetically lacking 5-HT2C receptors. RESULTS: Co-administration of mCPP with leptin had an additive effect on reducing body weight in DIO mice. Furthermore, mCPP pretreatment in DIO mice enhanced leptin-induced pSTAT3 in the arcuate nucleus, the ventromedial hypothalamic nucleus, and the ventral premammillary nucleus. Finally, deletion of 5-HT2C receptors significantly blunted leptin-induced pSTAT3 in these same hypothalamic regions. CONCLUSIONS AND IMPLICATIONS: Our study provides evidence that drugs, which activate 5-HT2C receptors, could function as leptin sensitizers and be used in combination with leptin to provide additional weight loss in DIO. PMID- 25817044 TI - Immunogenicity of virosomal adjuvanted trivalent influenza vaccination in allogeneic stem cell transplant recipients. AB - BACKGROUND: Influenza vaccination is generally recommended to hematopoietic stem cell transplant (HSCT) recipients. However, the seasonal subunit vaccination response is frequently suboptimal, and alternate more efficient vaccination systems must be examined. We compared the immunogenicity of an adjuvanted virosomal influenza and subunit vaccine in HSCT recipients. METHODS: The immunogenicity after a single dose (0.5 mL) of adjuvanted trivalent virosomal vaccination was evaluated in a study cohort of 21 HSCT recipients and compared to a control cohort of 30 HSCT recipients who received a single dose (0.5 mL) of non adjuvanted seasonal trivalent subunit vaccination over 4 seasons from 2010 to 2014. Whole blood interferon-gamma (IFN-gamma) release assays were tested, both before and 30 days after vaccination, in response to influenza pandemic (pdm) H1N1, H3N2, and B antigens. HLA-A*02 dextramers, to gauge for the absolute number of antigen-specific CD8(+) T-cells, and pdm 2009 hemagglutinin inhibition (HI) assays, to test for neutralizing antibodies, were used as immunological readouts. RESULTS: The pdm HI titers were poor in both cohorts with only 23% (5/21) after virosomal vaccination and 13.3% (4/30) in the seasonal vaccine cohort having protective titers (>=40). The delta change of IFN-gamma production in response to influenza pdm H1N1 (P = 0.005) and influenza B antigens (P = 0.01) were significantly elevated in blood from individuals who received the virosomal as compared to the seasonal vaccine. The IFN-gamma response to pdm H1N1 was stronger (P < 0.001), as compared to seasonal vaccination, in patients vaccinated >6 month post HSCT. We detected a significant increase in the frequency of matrix 1 (GILGFVTL) dextramer-specific CD8(+) T-cells after the virosomal vaccine (P = 0.01). No differences were seen in the hemagglutinin-specific CD8(+) T-cells between the 2 cohorts. CONCLUSION: Vaccination using a virosomal delivery system is beneficial in eliciting robust cellular immune responses to pdm H1N1 influenza in SCT recipients. PMID- 25817045 TI - Nulliparous pregnant women's narratives of imminent childbirth before and after internet-based cognitive behavioural therapy for severe fear of childbirth: a qualitative study. AB - OBJECTIVE: To describe the expectations concerning imminent childbirth before and after 8 weeks of internet-based cognitive behavioural therapy (ICBT) among nulliparous pregnant women with severe fear of childbirth. DESIGN: Qualitative study of nulliparous pregnant women's narratives before and after CBT. SETTING: The first ICBT programme for treating severe fear of childbirth. SAMPLE: Fifteen nulliparous pregnant Swedish women with severe fear of childbirth participating in an ICBT self-help programme. METHODS: Semi-structured open-ended questions over the internet before and after 8 weeks of ICBT. The data were analysed using thematic analysis. MAIN OUTCOME MEASURES: The participants' narratives pertaining to five different situations during labour and delivery before and after ICBT. RESULTS: After therapy, participants described a more realistic attitude towards imminent childbirth, more self-confidence and more active coping strategies. They perceived their partners and the staff as more supportive. They were more aware of the approaching meeting with their baby when giving birth. CONCLUSIONS: Following the ICBT programme, participants changed their attitude towards imminent childbirth from negative to more positive. This was manifested in positive and more realistic expectations regarding themselves, their partner and the staff that would look after them. PMID- 25817046 TI - Pazopanib can preserve cosmetic quality of life even in end-stage angiosarcoma. PMID- 25817047 TI - Comparison of two classification systems in predicting the outcome of diabetic foot ulcers: the Wagner grade and the Saint Elian Wound score systems. AB - The aim of the study was to compare two systems of classification in a consecutive population with diabetic foot ulcers: the Wagner grade and the Saint Elian Wound Score System (SEWSS). Sociodemographic information, patient-related and ulcer-related data at first presentation was recorded, and the patients were followed up until wound healing or accepting major amputation or for 24 weeks. One hundred eighty-six patients were included in the study, of which 172 patients were completely followed up. Among the remaining 172 patients, 53.5% (n = 92) were healed without minor amputation, 32% (n = 55) were healed with minor amputation, 9.3% (n = 16) were not healed at study termination, 3.5% (n = 6) died and 1.7% (n = 3) underwent major amputation. The median healing time for Wagner 1, Wagner 2, Wagner 3, and Wagner 4 were 23, 50, 54, 119 days, respectively. The log-rank test showed significant differences in healing time for Wagner 1, Wagner 2, Wagner 3, and Wagner 4; The median healing time for SEWSS I, SEWSS II and SEWSS III were 12, 51, and 150 days, respectively. The log-rank test showed significant differences in healing time for SEWSS I, SEWSS II and SEWSS III. Cox regression analysis showed a decreasing probability of healing with or without minor amputation with a higher SEWSS value, an increase in the SEWSS by one score reduced the probability for healing by 24%. ROC analysis showed Wagner 3 and a cut-point 17 of SEWSS had the highest Youden's index. Both the Wagner grade and SEWSS system were associated with the ulcer healing time for the patients with active DFUs. The SEWSS score makes it a better prediction tool of DFU outcome synthetically. PMID- 25817048 TI - Evolving minimum standards in responsible international sperm donor offspring quota. AB - An international working group was established with the aim of making recommendations on the number of offspring for a sperm donor that should be allowable in cases of international use of his sperm. Considerations from genetic, psychosocial, operational and ethical points of view were debated. For these considerations, it was assumed that current developments in genetic testing and Internet possibilities mean that, now, all donors are potentially identifiable by their offspring, so no distinction was made between anonymous and non-anonymous donation. Genetic considerations did not lead to restrictive limits (indicating that up to 200 offspring or more per donor may be acceptable except in isolated social-minority situations). Psychosocial considerations on the other hand led to proposals of rather restrictive limits (10 families per donor or less). Operational and ethical considerations did not lead to more or less concrete limits per donor, but seemed to lie in-between those resulting from the aforementioned ways of viewing the issue. In the end, no unifying agreed figure could be reached; however the consensus was that the number should never exceed 100 families. The conclusions of the group are summarized in three recommendations. PMID- 25817049 TI - Treatment of Langerhans cell histiocytosis: it is time to learn from the past: response to Minkov and Rodriguez-Galindo. PMID- 25817050 TI - The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus. AB - AIMS: To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. METHODS: Clinical inputs sourced from a head-to head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. RESULTS: The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of L1246 (95% CI: L613; L1637). This resulted in an ICER point estimate of L2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of L20,000 per QALY. CONCLUSIONS: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy. PMID- 25817051 TI - Acrylamide induces mitochondrial dysfunction and apoptosis in BV-2 microglial cells. AB - Acrylamide (ACR), a potent neurotoxin, can be produced during food processing at high temperature. This study examined the redox-dependent apoptotic and inflammatory responses of ACR in an immortalized mouse microglia cell line BV2. The exposure of BV2 cells to ACR reduced cell viability and induced apoptosis in a concentration-dependent manner. ACR impaired cell energy metabolism by decreasing mitochondrial respiration, anaerobic glycolysis, and lowering expression of the complex I, III, and IV subunits. Mitochondrial dysfunction was associated with a decrease of the mitochondrial membrane potential and the Bcl 2/Bax ratio, thus resulting in activation of the mitochondrion-driven apoptotic signaling. This was accompanied by (a) the modulation of redox-sensitive signaling, suppressed Akt activation and increased JNK and p38 activation, and (b) increased expression of NFkappaB and downstream inducible nitric oxide synthase (iNOS) and nitric oxide generation, thus supporting indirectly a proinflammatory effect of ACR. Nrf2 expression was also increased but not its translocation to the nucleus. Expectedly, the electrophilic attack of ACR on GSH resulted in substantial loss of GSH with a minor GSSG formation. These changes in the cell's redox status elicited by ACR resulted in increased H2O2 formation. The changes in mitochondrial functionality and complex subunit expression caused by ACR were reversed by N-acetyl-L-cysteine (NAC). Likewise, NAC restored the cell's redox status by increasing GSH levels with concomitant attenuation of H2O2 generation; these effects resulted in decreased apoptotic cell death and inflammatory responses. ACR-mediated mitochondrial dysfunction along with a more oxidized redox status seems to be critical events leading to activation of the intrinsic apoptotic pathway and inflammatory responses. PMID- 25817052 TI - Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review. AB - Mesenchymal stem cells (MSC) are widely studied for their immunomodulatory properties. Data from in vitro and pre-clinical models demonstrate that MSC suppress activated immune cells and ameliorate the severity of experimental immune disease. In complex human studies, the immunomodulatory efficacy of MSC therapy is not well established. We conducted a systematic review of clinical studies which used MSC with the purpose of immunomodulation and included at least 10 patients to investigate the efficacy of MSC therapy. Sixty-two studies comprising 10 different immune disorders were included in the analysis, of which 18 studies represented controlled trials. Although several of the studies reported an amelioration of disease severity, other studies failed to observe a beneficial effect of MSC. The low number of randomized controlled trials, small number of studies per disease category and limited immunological readout parameters made it difficult to draw a definitive conclusion on the efficacy of MSC immune therapy. PMID- 25817053 TI - Humanitarian obstetric care for refugees of the Syrian war. The first 6 months of experience of Gynecologie Sans Frontieres in Zaatari Refugee Camp (Jordan). AB - OBJECTIVE: To report the first 6 months of experience of a nongovernmental organization-managed obstetric care unit in a war refugee camp, with problems encountered and solutions implemented. DESIGN: Prospective observational study of the maternity activity of Gynecologie Sans Frontieres (GSF). SETTING: GSF's maternity unit, in Zaatari camp (Jordan). POPULATION: All pregnant women among Syrian refugees who came to the unit for delivery. METHODS: The GSF's maternity unit is a light structure built with three tents, permitting low-risk pregnancy care and childbirth. Emergency cesarean deliveries were performed in the Moroccan army field hospital. High-risk pregnancies were transferred to Al Mafraq or Amman Hospital (Jordan) after assessment. MAIN OUTCOME MEASURES: Delivery characteristics, indications for referral. RESULTS: From September 2012 to February 2013, 371 women attended the unit and 299 delivered in it. Delivery rates increased from 5/month to 112/month over the period. Mean gestational age at birth was 39(+3) gestational weeks (SD = 1.9). Median birthweight was 3100 g (25-75% interquartile range 2840-3430 g). Spontaneous vaginal deliveries were dominant and the major maternal complication was postpartum hemorrhage (n = 13). Eighty-two women were referred to Al Mafraq or Amman hospitals, mainly for preterm labor (32%) and congenital malformations (11%). We managed one case of stillbirth. Maternal mortality did not occur. CONCLUSIONS: Despite the difficulties of war, high-risk pregnant women were properly identified, permitting referrals when required. Cooperation with other nongovernmental organizations, including the United Nations High Commissioner for Refugees, was essential for the management of situations at risk of complications and to contain perinatal and maternal mortality. PMID- 25817055 TI - A cross-cultural investigation of attachment style, catastrophizing, negative pain beliefs, and symptom severity in irritable bowel syndrome. AB - BACKGROUND: Little information exists regarding whether psychosocial variables in irritable bowel syndrome (IBS) vary by geographic location. Adult attachment is an important psychological concept rooted in childhood relationship experience that has not been previously studied in IBS. Catastrophizing and negative pain beliefs have been described in IBS and may be affected by attachment. AIMS: In this cross-cultural study, we determined: (i) whether attachment differs between IBS patients and controls, (ii) whether geographic location has a significant effect on attachment style, catastrophizing and negative pain beliefs, and (iii) how all three variables correlate with IBS symptom severity. METHODS: 463 IBS patients, with moderate to severe symptom scores, and 192 healthy controls completed validated questionnaires about attachment, catastrophizing, negative pain beliefs and IBS-SSS in nine locations, USA (New York, Los Angeles), Mexico, Italy (Rome, Bari), Romania, Iran, India, and China. KEY RESULTS: Attachment anxiety and avoidance scores were significantly higher in IBS patients than in controls (p < 0.001). This was particularly true for the fearful-avoidant attachment category, especially in China and Romania. Path analysis showed that attachment anxiety and avoidance had indirect effects on IBS-SSS through catastrophizing (p < 0.0001) and negative pain beliefs (p = 0.005). All three psychosocial measures varied significantly depending on location. CONCLUSIONS & INFERENCES: In the IBS population studied, attachment style was significantly different in IBS compared to a control population. Geographic differences in attachment, catastrophizing and negative pain beliefs were documented and their correlation with symptom severity and thus, research of psychosocial variables in IBS should take into account the location of the population studied. PMID- 25817054 TI - HIV, opiates, and enteric neuron dysfunction. AB - Human immune deficient virus (HIV) is an immunosuppressive virus that targets CD4(+) T-lymphocytes. HIV infections cause increased susceptibility to opportunistic infections and cancer. HIV infection can also alter central nervous system (CNS) function causing cognitive impairment. HIV does not infect neurons but it does infect astrocytes and microglia in the CNS. HIV can also infect enteric glia initiating an intestinal inflammatory response which causes enteric neural injury and gut dysfunction. Part of the inflammatory response is HIV induced production of proteins including, Transactivator of transcription (Tat) which contribute to neuronal injury after release from HIV infected glial cells. A risk factor for HIV infection is intravenous drug use with contaminated needles and chronic opiate use can exacerbate neural injury in the nervous system. While most research focuses on the actions of Tat and other HIV related proteins and opiates on the brain, recent data indicate that Tat can cause intestinal inflammation and disruption of enteric neuron function, including alteration of Na(+) channel activity and action potential generation. A paper published in this issue of Neurogastroenterology and Motility extends these findings by identifying an interaction between Tat and morphine on enteric neuron Na(+) channels and on intestinal motility in vivo using a Tat expressing transgenic mouse model. These new data show that Tat protein can enhance the inhibitory actions of morphine on action potential generation and propulsive motility. These findings are important to our understanding of how HIV causes diarrhea in infected patients and for the use of opioid drugs to treat HIV-induced diarrhea. PMID- 25817056 TI - Modulation of intestinal afferent nerve sensitivity to inflammatory mediators following systemic endotoxin in mice. AB - BACKGROUND: Endotoxin exposure may be followed by visceral hypersensitvity but potential mechanisms are not fully explored. We aimed to test the hypothesis that mast cells and the cyclooxygenase pathway (COX) mediate modulation of afferent nerve sensitivity following systemic endotoxin. METHODS: C57Bl6 mice received endotoxin injection i.p. to induce systemic inflammation. Control animals received normal saline. Extracellular multi-unit afferent nerve discharge was recorded from jejunal mesenteric nerves in vitro. Afferent nerve response to 5 hydroxytryptamine (5-HT, 250 MUmol/L), bradykinin (BK, 0.5 MUmol/L), and to mechanical ramp distension of the intestinal lumen from 0 to 60 cmH2O were recorded 2 h following endotoxin administration. KEY RESULTS: Following endotoxin administration peak afferent discharge to 5-HT and BK was increased compared to controls (p < 0.05). Pre-perfusion with the mast cell stabilizer Doxantrazole (10(-4) M), or the cyclooxygenase inhibitor Naproxen inhibited the increased response to 5-HT and BK (p < 0.05 vs endotoxin pretreatment). Mechanosensitivity during luminal ramp distension from 10 to 60 cmH2O was increased following endotoxin pretreatment compared to controls (p < 0.05). This increase in sensitivity following endotoxin was no longer observed after Doxantrazole or Naproxen administration for pressures from 10 to 30 cmH2O (p < 0.05). Selective COX-2 inhibition by NS398 (10 MUM) but not COX-1 inhibition by SC560 (300 MUM) reduced increased afferent discharge in endotoxin pretreated animals to 5-HT, BK and mechanical ramp distension from 10 to 40 cmH2O (all p < 0.05). CONCLUSIONS & INFERENCES: Systemic endotoxin sensitizes mesenteric afferent nerve fibers to 5 HT, BK and mechanical stimuli. The underlying mechanism responsible for this sensitization seems to involve mast cells and the COX-2 pathway. PMID- 25817057 TI - Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study. AB - BACKGROUND: The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL). METHODS: Prospective case-control study in secondary care GI clinics over 2 years. JHS was assessed by the first author prior to consultation in 641 consecutive new patients. Diagnosis of FGID (cases, n = 336) or organic disorders (controls, n = 305) was established blind to JHS status. JHS prevalence was compared in cases (FGID patients) and controls (organic disorders patients). Extra-intestinal comorbidity and QOL were compared in FGID patients with and without JHS. KEY RESULTS: JHS prevalence was higher in FGID compared to organic GI disorders (39.0% vs 27.5%, ORadj: 1.51, CI: 1.07-2.12, p = 0.02), and particularly associated with functional gastroduodenal disorders (44.1%, ORadj: 2.08, CI: 1.25 3.46, p = 0.005), specifically postprandial distress syndrome (51%, ORadj: 1.99, CI: 1.06-3.76, p = 0.03). FGID patients with JHS had increased chronic pain (23.2% vs 11.9%, p = 0.01), fibromyalgia (10.5% vs 3.1%, p = 0.01), somatization scores (13 vs 10, p < 0.001), urinary autonomic scores (30.5 vs 20.7, p = 0.03), and worse pain-related QOL scores (45.0 vs 63.5, p = 0.004). CONCLUSIONS & INFERENCES: JHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL. Further research is required to understand the pathophysiological basis of this association. PMID- 25817058 TI - Obituary: Lionel Bueno: 1945-2015. PMID- 25817059 TI - Corrigendum: OM14 is a mitochondrial receptor for cytosolic ribosomes that supports co-translational import into mitochondria. PMID- 25817060 TI - Molecular cloning and transgenic characterization of the genes encoding chalcone synthase and chalcone isomerase from the Tibetan herbal plant Mirabilis himalaica. AB - Mirabilis himalaica is an endangered medicinal plant species in the Tibetan Plateau. The two genes respectively encoding chalcone synthase (MhCHS) and chalcone isomerase (MhCHI) were isolated and characterized from M. himalaica. The sequence analysis revealed that the two genes were similar with their corresponding homologous genes in other plants. The tissue profiles showed that both MhCHS and MhCHI had higher expression levels in roots than in stems and leaves. Transgenic hairy root cultures respectively with overexpressing MhCHS and MhCHI were established. The genomic PCR detection confirmed the authority of transgenic hairy root lines, in which either MhCHS or MhCHI expression levels were much higher than that in non-transgenic hairy root line. Finally, the HPLC detection results demonstrated that the rotenoid contents in MhCHS/MhCHI transformed hairy root lines were enhanced. This study provided two candidate genes that could be used to genetic engineering rotenoid biosynthesis in M. himalaica and an alternative method to produce rotenoid using transgenic hairy root cultures. PMID- 25817061 TI - Clinical presentation in insulinoma predicts histopathological tumour characteristics. AB - BACKGROUND: Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72-h fast. However, the prognostic value of parameters in the standardized 72-h fast on histopathological tumour criteria and clinical presentation has not been examined. METHODS: In thirty-three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki-67 index. Cut-off values for classical grading (G(clas)) were set at G1(clas) <= 2%, G2(clas) 3-20% & G3(clas) >20% and for modified grading (G(mod)) at G1(mod) <5%, G2(mod) 5-20% & G3(mod) >20%. RESULTS: When G(mod) criteria were applied, the initial blood glucose was lower in GII/III(mod) patients compared to GI(mod) (2.8 +/- 0.8 vs 3.8 +/- 1.3 mmol/l; P = 0.046). Basal and end of fast levels of insulin (basal insulin 71 +/- 61 vs 20 +/- 16 mU/l; P < 0.001; end of fast insulin 77 +/- 51 vs 21 +/- 20 mU/l; P < 0.001) and c-peptide (basal c-peptide 5.4 +/- 2.4 vs 2.7 +/- 1.6 MUg/l; P = 0.004; end of fast c-peptide 5.3 +/- 2.4 vs 2.5 +/- 1.4 MUg/l; P = 0.001) were significantly higher in GII/III(mod) than in GI(mod). No differences between the groups were observed when G(clas) criteria were applied. Additionally, close correlations were observed between insulin concentration, Ki-67 index and tumour size. CONCLUSION: This study shows an impact of histopathological tumour characteristics in patients suffering from an insulinoma on clinical presentation during a standardized 72-h fast. Lower initial blood glucose levels and higher concentrations of insulin and c-peptide are associated with worse tumour grading and larger tumour size. PMID- 25817062 TI - Effects of balloon inflation and cough trick methods on easing pain in children during the drawing of venous blood samples: a randomized controlled trial. AB - PURPOSE: The purpose was to determine the effects of the balloon inflation and cough trick methods on easing pain in children during the drawing of venous blood samples. DESIGN AND METHODS: In this prospective randomized controlled study, 9- to 12-year-old children in the intervention groups were asked to cough or inflate balloons during the venipuncture procedure. The Faces Pain Scale-Revised was used to assess pain intensity. RESULTS: Pain intensity significantly differed between the control (n = 44) and intervention groups (balloon inflation [n = 44] and cough trick [n = 44], p < .001). PRACTICE IMPLICATIONS: Coughing and inflating balloons during venipuncture do not require preparation and are time saving, easy, accessible, and effective in reducing pain. PMID- 25817063 TI - Effect of Megasphaera elsdenii NCIMB 41125 dosing on rumen development, volatile fatty acid production and blood beta-hydroxybutyrate in neonatal dairy calves. AB - Thirty calves were randomly assigned to two treatments and fed until weaning [42 days (d) of age]. Treatments were a control group (n = 15), which did not receive Megasphaera elsdenii (Me0) and a M. elsdenii group, which received a 50-ml oral dose of M. elsdenii NCIMB 41125 (10(8) CFU/ml) at day 14 day of age (Me14). Calves were given colostrum for the first 3 day followed by limited whole milk feeding. A commercial calf starter was offered ad libitum starting at day 4 until the end of the study. Fresh water was available throughout the study. Feed intake and growth were measured. Blood samples were collected via jugular venipuncture to determine beta-hydroxybutyrate (BHBA) concentrations. Fourteen male calves (seven per group) were euthanised on day 42 and digestive tracts harvested. Reticulo-rumen weight was determined and rumen tissue samples collected from the cranial and caudal sacs of the ventral and dorsal portions of the rumen for measurements of papillae length, papillae width and rumen wall thickness. Dosing with M. elsdenii NCIMB 41125 improved starter dry matter intake (DMI), weaning body weight (BW) and tended to improve average daily gain. Calves in Me14 group had greater plasma BHBA concentration than Me0-calves during the last 3 weeks of the trial and had at day 42 greater reticulo-rumen weight, papillae width and papillae density compared to Me0. No differences in rumen wall thickness or papillae length were observed between the two groups. Total volatile fatty acids, acetate and propionate production did not differ between treatments, but butyrate production was greater in Me14 than Me0. Dosing M. elsdenii NCIMB 41125 showed benefit for calves with improved feed intake and rumen development suggesting increased epithelium metabolism and improved absorption of digestive end products. PMID- 25817064 TI - Pupil size reveals preparatory processes in the generation of pro-saccades and anti-saccades. AB - The ability to generate flexible behaviors to accommodate changing goals in response to identical sensory stimuli is a signature that is inherited in humans and higher-level animals. In the oculomotor system, this function has often been examined with the anti-saccade task, in which subjects are instructed, prior to stimulus appearance, to either automatically look at the peripheral stimulus (pro saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti-saccade). Distinct neural preparatory activity between the pro-saccade and anti-saccade conditions has been well documented, particularly in the superior colliculus (SC) and the frontal eye field (FEF), and this has shown higher inhibition-related fixation activity in preparation for anti-saccades than in preparation for pro-saccades. Moreover, the level of preparatory activity related to motor preparation is negatively correlated with reaction times. We hypothesised that preparatory signals may be reflected in pupil size through a link between the SC and the pupil control circuitry. Here, we examined human pupil dynamics during saccade preparation prior to the execution of pro-saccades and anti-saccades. Pupil size was larger in preparation for correct anti-saccades than in preparation for correct pro saccades and erroneous pro-saccades made in the anti-saccade condition. Furthermore, larger pupil dilation prior to stimulus appearance accompanied saccades with faster reaction times, with a trial-by-trial correlation between dilation size and anti-saccade reaction times. Overall, our results demonstrate that pupil size is modulated by saccade preparation, and neural activity in the SC, together with the FEF, supports these findings, providing unique insights into the neural substrate coordinating cognitive processing and pupil diameter. PMID- 25817065 TI - Supporting people with dementia to walkabout safely outdoors: development of a structured model of assessment. AB - People with dementia while missing are at risk of harm including death. Yet, welfare concerns arise when freedom to walkabout outdoors is restricted and in particular, getting lost is a risk factor for admission to long-term care. Accurate methods of assessing the risks posed to community-dwelling people with dementia from getting lost are needed to ensure intervention is proportionate. Currently available assessment tools focus upon the identification of dementia related changes in a person's walking behaviour, traditionally referred to as 'wandering'. 'Wandering' and getting lost are conceptually distinct; measures of 'wandering' are not sufficient to support the assessment of risk while walking outdoors. The objective of this study was to develop an assessment schedule that can evaluate safety in community-dwelling people with dementia who walkabout outdoors. A structured assessment schedule was generated from research on the aetiology of getting lost, a review of existing assessment tools, an observational study of incidents of getting lost and qualitative data from families experiencing this issue. A content validity study was then undertaken with a panel of 17 health and social care practitioners and researchers in the field. A schedule of 7 domains and 38 items was generated, 33 of which were deemed valid by the expert panel. Panel feedback suggests the schedule needs to be used flexibly to reflect an individual's unique living circumstances. Reflecting the complex aetiology of getting lost, considerable challenges exist when assessing risk in this field. The implications of this study for practitioners are discussed with reference to the merits of narrative and structured models of assessment, and the balance between objective safety and subjective well-being that is required when making decisions about intervention. The direction of further research is examined as a means of supporting professional assessment of this complex issue. PMID- 25817066 TI - Outcome of Vaginoplasty in Male-to-Female Transgenders: A Systematic Review of Surgical Techniques. AB - INTRODUCTION: Gender reassignment surgery is the keystone of the treatment of transgender patients. For male-to-female transgenders, this involves the creation of a neovagina. Many surgical methods for vaginoplasty have been opted. The penile skin inversion technique is the method of choice for most gender surgeons. However, the optimal surgical technique for vaginoplasty in transgender women has not yet been identified, as outcomes of the different techniques have never been compared. AIM: With this systematic review, we aim to give a detailed overview of the published outcomes of all currently available techniques for vaginoplasty in male-to-female transgenders. METHODS: A PubMed and EMBASE search for relevant publications (1995-present), which provided data on the outcome of techniques for vaginoplasty in male-to-female transgender patients. MAIN OUTCOME MEASURES: Main outcome measures are complications, neovaginal depth and width, sexual function, patient satisfaction, and improvement in quality of life (QoL). RESULTS: Twenty six studies satisfied the inclusion criteria. The majority of these studies were retrospective case series of low to intermediate quality. Outcome of the penile skin inversion technique was reported in 1,461 patients, bowel vaginoplasty in 102 patients. Neovaginal stenosis was the most frequent complication in both techniques. Sexual function and patient satisfaction were overall acceptable, but many different outcome measures were used. QoL was only reported in one study. Comparison between techniques was difficult due to the lack of standardization. CONCLUSIONS: The penile skin inversion technique is the most researched surgical procedure. Outcome of bowel vaginoplasty has been reported less frequently but does not seem to be inferior. The available literature is heterogeneous in patient groups, surgical procedure, outcome measurement tools, and follow-up. Standardized protocols and prospective study designs are mandatory for correct interpretation and comparability of data. PMID- 25817067 TI - Aversive event unpredictability causes stress-induced hypoalgesia. AB - Temporal predictability, or knowing when a noxious stimulus will occur, has been implicated in stress-induced hypoalgesia, but the contribution of event predictability, or knowing what the stimulus will be, remains poorly understood. To address this issue, we examined the effects of event predictability on pain intensity ratings and nociceptive flexion reflex responses. Participants repeatedly experienced five intensities of electrocutaneous stimulation, ranging from nonpainful to extremely painful, delivered either randomly (unpredictability group) or blocked (predictability group) with no cues provided. Unpredictable shocks produced the lowest pain ratings while evoking the highest flexion reflex responses. Moreover, anticipatory heart rate data indicated that unpredictable trials were the most physiologically arousing. Our findings show that uncertainty about the upcoming stimulus intensity is stressful and unpleasant, thereby causing hypoalgesia and reflex potentiation. PMID- 25817068 TI - Degradation of Curcumin: From Mechanism to Biological Implications. AB - Curcumin is the main bioactive ingredient in turmeric extract and widely consumed as part of the spice mix curry or as a dietary supplement. Turmeric has a long history of therapeutic application in traditional Asian medicine. Biomedical studies conducted in the past two decades have identified a large number of cellular targets and effects of curcumin. In vitro curcumin rapidly degrades in an autoxidative transformation to diverse chemical species, the formation of which has only recently been appreciated. This paper discusses how the degradation and metabolism of curcumin, through products and their mechanism of formation, provide a basis for the interpretation of preclinical data and clinical studies. It is suggested that the previously unrecognized diversity of its degradation products could be an important factor in explaining the polypharmacology of curcumin. PMID- 25817069 TI - The combined effects of maternal depression and excess weight on neonatal outcomes. AB - OBJECTIVE: Maternal overweight/obesity and depression are among the most prevalent pregnancy complications, and although individually they are associated with poor pregnancy outcomes, their combined effects are unknown. Owing to this, the objective of this study was to determine the prevalences and the individual and combined effects of depression and overweight/obesity on neonatal outcomes. METHODS: A retrospective cohort study of all singleton hospital births at >20 weeks gestation in Ontario, Canada (April 2007 to March 2010) was conducted. The primary outcome measure was a composite neonatal outcome, which included: stillbirth, neonatal death, preterm birth, birth weight <2500 g, <5% or >95%, admission to a neonatal special care unit, or a 5-min Apgar score <7. RESULTS: Among the 70,605 included women, 49.7% had a healthy pre-pregnancy BMI, whereas 50.3% were overweight/obese; depression was reported in 5.0% and 6.2%, respectively. Individually, depression and excess pre-pregnancy weight were associated with an increased risk of adverse neonatal outcomes, but the highest risk was seen when they were both present (16% of non-depressed healthy weight pregnant women, 19% of depressed healthy weight women, 20% of non-depressed overweight/obese women and 24% of depressed overweight/obese women). These higher risks of adverse neonatal outcomes persisted after accounting for potential confounding variables, such as maternal age, education and pre-existing health problems (adjusted odds ratio (OR) 1.22, 95% confidence interval (CI) 1.13-1.33, adjusted OR 1.23, 95% CI 1.18-1.28 and adjusted OR 1.42, 95% CI 1.31-1.54, in the last three groups above, respectively, relative to non-depressed healthy weight women). There was no significant interaction between weight category and depression (P=0.2956). CONCLUSIONS: When dually present, maternal overweight/obesity and depression combined have the greatest impact on the risk of adverse neonatal outcomes. Our findings have important public health implications given the exorbitant proportions of both of these risk factors. PMID- 25817070 TI - miR-20a regulates adipocyte differentiation by targeting lysine-specific demethylase 6b and transforming growth factor-beta signaling. AB - BACKGROUND: Several types of microRNAs (miRNAs) have recently been defined as important regulators in adipocyte differentiation, the role of other miRNAs in the processes and the mechanisms involved remain to be explored. METHODS: miR-20a expression was quantified in primary cultured marrow stromal cells and adipogenic cell lines after adipogenic treatment. Effects of miR-20a on adipocyte differentiation were studied following supplementing or depleting miR-20a in murine 3T3-L1 preadipocytes, ST2 stromal cells and C3H10T1/2 mesenchymal cells. Bioinformatics prediction of miRNA targets was performed, and potential targets of miR-20a were verified by using dual luciferase activity assays. Gain-of function and loss-of-function studies were performed to examine the effects of the target genes on adipocyte differentiation. RESULTS: miR-20a was induced in primary cultured marrow stromal cells and established adipogenic lines after adipogenic treatment. Supplementing miR-20a activity suppressed the growth of 3T3 L1 preadipocytes and induced 3T3-L1, ST2 and C3H10T1/2 cells to differentiate into mature adipocytes, along with the induction of adipocyte-specific transcription factors peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer binding protein-alpha (C/EBPalpha), C/EBPbeta and the marker gene adipocyte protein 2 (aP2). Conversely, inhibition of the endogenous miR-20a repressed 3T3-L1, ST2 and C3H10T1/2 cells to fully differentiate. Transforming growth factor-beta receptor II (Tgfbr2) and lysine-specific demethylase 6b (Kdm6b) were shown to be direct targets of miR-20a. Supplementing miR-20a activity in ST2 reduced levels of KDM6B and TGFBR2 proteins, while suppression of endogenous miR-20a increased KDM6B and TGFBR2. While TGF-beta signaling is a well-documented inhibitor of adipogenesis, the effects of Kdm6b on adipocyte formation need to be clarified. We demonstrated that overexpression of Kdm6b inhibited, while knockdown of Kdm6b promoted the differentiation of the ST2 cells into mature adipocytes. CONCLUSION: The present work provides evidence that mouse miR-20a promotes adipocyte progenitor cells to differentiate and this function may depend upon its inhibitory effects on Kdm6b and TGF-beta signaling. PMID- 25817071 TI - Sex-biased gene expression in dioecious garden asparagus (Asparagus officinalis). AB - Sex chromosomes have evolved independently in phylogenetically diverse flowering plant lineages. The genes governing sex determination in dioecious species remain unknown, but theory predicts that the linkage of genes influencing male and female function will spur the origin and early evolution of sex chromosomes. For example, in an XY system, the origin of an active Y may be spurred by the linkage of female suppressing and male promoting genes. Garden asparagus (Asparagus officinalis) serves as a model for plant sex chromosome evolution, given that it has recently evolved an XX/XY sex chromosome system. In order to elucidate the molecular basis of gender differences and sex determination, we used RNA sequencing (RNA-Seq) to identify differentially expressed genes between female (XX), male (XY) and supermale (YY) individuals. We identified 570 differentially expressed genes, and showed that significantly more genes exhibited male-biased than female-biased expression in garden asparagus. In the context of anther development, we identified genes involved in pollen microspore and tapetum development that were specifically expressed in males and supermales. Comparative analysis of genes in the Arabidopsis thaliana, Zea mays and Oryza sativa anther development pathways shows that anther sterility in females probably occurs through interruption of tapetum development before microspore meiosis. PMID- 25817072 TI - Rapid and Persistent Delivery of Antigen by Lymph Node Targeting PRINT Nanoparticle Vaccine Carrier To Promote Humoral Immunity. AB - Nanoparticle delivery of subunit vaccines may increase vaccine efficacy, leading to a wide variety of safe and effective vaccines beyond those available through dosing inactivated or live, attenuated whole pathogens. Here we present a versatile vaccine delivery platform based on PRINT hydrogels made of biocompatible hydroxy-poly(ethylene glycol) (PEG) that is able to activate the complement system by the alternative pathway. These lymph node targeting nanoparticles (NPs) promote the immunogenicity of a model antigen, ovalbumin, showing comparable adjuvant effect to alum. We demonstrate that an antigen specific humoral response is correlated with antigen delivery to the draining lymph nodes, in particular, B cell rich regions of the lymph nodes. 80 * 180 nm cylindrical NPs were able to sustain prolonged antigen presentation to antigen presenting cells (APCs) and elicit a stronger immune response than nondraining 1 * 1 MUm NPs or rapidly clearing soluble antigen. The 80 * 180 nm NPs also show high levels of uptake by key APCs and efficiently stimulate CD4(+) helper T cell proliferation in vivo, further promoting antibody production. These features together produce a significant humoral immune response, superior to that produced by free antigen alone. The simplicity of the chemistries used in antigen conjugation to PRINT NPs confers versatility to this antigen delivery platform, allowing for potential application to many infectious diseases. PMID- 25817073 TI - BRAF V600 point mutation is not present in relapsing meningioma. PMID- 25817074 TI - Evolution to malignancy: A genetic stepwise study of tumor suppressor genes loss in a recurrent meningioma. PMID- 25817075 TI - Multinucleated giant cell granulomatous reaction to psammomatous calcifications in inflammatory (calcified fibrous) pseudotumor of CNS. PMID- 25817076 TI - Myopathic changes in patients with elastofibroma dorsi. PMID- 25817077 TI - The Effect of Habitual Physical Training on Left Ventricular Function During Exercise Assessed by Three-Dimensional Echocardiography. AB - BACKGROUND: Stroke volume (SV) in trained athletes continuously increases with progressive exercise intensity. We studied whether physical training affected left ventricle (LV) function response to exercise using 3D echocardiography and tissue Doppler imaging (TDI). METHODS: Eleven male university athletes and 12 male university nonathletes were enrolled in this study. After baseline data were collected, subjects performed a symptom-limited supine bicycle ergometer exercise test. Initial workload was 25 Watts (W) and increased 25 W every 3 minutes. At rest and every exercise stage, LV end-systolic and diastolic volume index (LVEDVI and LVESVI), SV index (SVI), cardiac index (CI), LV ejection fraction (LVEF), and early lateral mitral flow velocity (Ea) were evaluated. Heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) were continuously recorded. RESULTS: Nonathletes showed a slow increase in CI, and SVI reached a plateau value at a HR of 90 beats per minute (bpm). In contrast, CI and SVI increased progressively and continuously in athletes. Both CI and SVI were significantly higher in athletes than in nonathletes at HRs of 100, 110, and 120 bpm. LVEDVI kept increasing in athletes while it plateaued in nonathletes. In contrast, LVESV decreased continuously during exercise in both groups. There was no significant difference in LVEF, Ea, SBP, or DBP at rest and during exercise between the two groups. CONCLUSION: LV responses to exercise in athletes were different from those of in nonathletes; thus, habitual physical training may play an important role in the increase in both SVI and CI in young individuals. PMID- 25817078 TI - Perception of students' intelligence malleability and potential for future success: Unfavourable beliefs towards girls. AB - BACKGROUND: Endorsing an entity theory of intelligence has negative effects on students' academic trajectories. Research focused on students' personal theories of intelligence has shown that girls are more likely than boys to hold an entity theory of intelligence. However, no study has examined the possibility of a gender stereotype basis for this belief. AIMS: We examined whether secondary school students are knowledgeable about others' beliefs describing female students' intelligence as less malleable than male students' intelligence. SAMPLE AND METHOD: A sample of 85 French ninth graders were asked to rate to what extent others perceived: (1) female or male students' intelligence as malleable and fixed; (2) female or male students as making efforts for their current achievement; and (3) female or male students as having potential for future success. RESULTS: Participants reported that others perceived girls' intelligence as less malleable than boys' intelligence. Moreover, the relationship between current efforts and potential for future achievement depended on the target's gender. The more hardworking a female student was perceived to be in school, the less she was considered to have potential to succeed in the future, whereas such a link was not observed for a male student. CONCLUSIONS: Secondary school students seem to be knowledgeable about a gender stereotype regarding intelligence and potential for academic success which is unfavourable for female students. Implications for students' academic trajectories are discussed. PMID- 25817079 TI - A modified pathway of perineal packing in patients requiring surgery for perineal fistulas with extensive perineal involvement. AB - AIM: To describe a method to manage complex perianal fistulas with extensive perineal involvement, allowing avoidance of exposure of wide wounds and repeated procedures. MATERIAL OF STUDY: All patients presenting with perianal fistulas extensively spreading to the perineum requiring surgery between January 2010 and December 2012 were enrolled in the present study. Diabetic patients and those with active abdominal Crohn's disease (CD) were ruled out from evaluation. After clinical and radiological assessment, patients underwent exploration under anaesthesia, and the conventional procedures were completed with at least one wide perineal fistulotomy, managed with "perineal packing" with gauzes. Patients were followed-up for complications and healing of fistulas. RESULTS: Eight patients (3 males, mean age 38 +/- 5.1 years) were enrolled in the present study. Four patients had CD, two had Hidradenitis suppurativa, and two had idiopathic fistula-in-ano. All but two patients were not required to stay overnight. Gauzes were removed in outpatient settings. One patient had bleeding requiring coagulation with electroscalpel. One patient needed to receive analgesics and four wore pads in the maturation period. No sepsis was observed. Mean time to healing was 21.5 +/- 3.2 days; mean time off-work was 2 +/- 1.3 days. Patients reported no significant impairment of leisure activities. No recurrences were observed at a mean follow-up of 16.4 +/- 2.1 months. Major complications were not observed. DISCUSSION: All patients achieved complete healing of the perineal tracks, without significant impairment of social function and need for further surgical treatments. Patients were safely discharged and promptly returned to work or leisure activities. CONCLUSIONS: Our data suggest that the procedure is safe and effective in selected patients with extensive perineal involvement. PMID- 25817080 TI - Magnetostriction and ferroelectric state in AgCrS2. AB - The band structure calculations in the GGA+U approximation show the presence of additional lattice distortions in the magnetically ordered phase of AgCrS2. The magnetostriction leads to the formation of long and short Cr-Cr bonds in the case when the respective Cr ions have the same or opposite spin projections. These changes in the Cr lattice are accompanied by distortions of the CrS6 octahedra, which in turn lead to the development of spontaneous electric polarization. PMID- 25817081 TI - Chronic lupus peritonitis is characterized by the ascites with a large content of interleukin-6. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease and can cause multi organ damage. Peritoneal involvement, also called lupus peritonitis, is a rare but sometimes fatal manifestation. Deposition of immune complexes consisting of immunoglobulin G and complement is considered to be involved in the pathogenesis of lupus peritonitis; however, it remains unknown whether inflammatory cytokines contribute to the pathology of this manifestation. Here we present two patients with treatment-resistant lupus peritonitis: a 37-year-old woman with a 26-year history of SLE who had been treated with prednisolone and cyclophosphamide followed by azathioprine and a 65-year-old woman with a 33-year history of SLE who had been treated with prednisolone alone. Both patients were admitted to our department because of abdominal distention. Computed tomography scans showed massive ascites. Ascitic fluid examinations of both patients showed leukocytosis with no evidence of malignancy or infection. After eliminating other causes for ascites, they were diagnosed with lupus peritonitis. Despite the intensified immunosuppressive therapy, they died of uncontrolled peritonitis several months after admission. Examinations of the ascites at admission also revealed a large content of interleukin (IL)-6, compared with other inflammatory cytokines, IL 1beta and tumor necrosis factor-alpha. In fact, the ascitic IL-6 levels of these two patients were 12,389 pg/mL and 5,486 pg/mL, much higher than their serum IL-6 levels of 36 pg/mL and 140 pg/mL, respectively. We therefore suggest that IL-6 may contribute to the pathogenesis of lupus peritonitis and that the inhibition of IL-6 signaling may provide a novel therapeutic strategy for lupus peritonitis. PMID- 25817082 TI - Diabetic pregnancy outcomes in mothers treated with basal insulin lispro protamine suspension or NPH insulin: a multicenter retrospective Italian study. AB - OBJECTIVE: The aim of this study was to study the efficacy and safety of long acting insulin analog insulin lispro protamine suspension (ILPS) in diabetic pregnant women. METHODS: In a multicenter observational retrospective study, we evaluated pregnancy outcome in 119 women affected by type 1 diabetes and 814 with gestational diabetes (GDM) treated during pregnancy with ILPS, compared with a control group treated with neutral protamine hagedorn (NPH) insulin. RESULTS: Among type 1 diabetic patients, fasting blood glucose at the end of pregnancy was significantly lower in ILPS-treated than in NPH-treated patients. HbA1c levels across pregnancy did not differ between groups. Caesarean section and preterm delivery rates were significantly lower in the ILPS-women. Fetal outcomes were similar in the ILPS and NPH groups. Among GDM women, fasting blood glucose at the end of pregnancy was significantly lower in ILPS-treated than in NPH-treated patients. Duration of gestation was significantly longer, caesarian section and preterm delivery rates were lower in the ILPS-treated group. In addition, there were significantly fewer babies with an excessive ponderal index or neonatal hypoglycemic episodes in the ILPS group than in the NPH group. CONCLUSIONS: Association of ILPS with rapid-acting analogs in pregnancy is safe in terms of maternal and fetal outcomes. PMID- 25817083 TI - Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress. AB - Autophagy plays a key role in the maintenance of cellular homeostasis, and autophagy deregulation gives rise to severe disorders. Many of the signaling pathways regulating autophagy under stress conditions are still poorly understood. Using a model of proteasome stress in rat hippocampus, we have characterized the functional crosstalk between the ubiquitin proteasome system and the autophagy-lysosome pathway, identifying also age-related modifications in the crosstalk between both proteolytic systems. Under proteasome inhibition, both autophagy activation and resolution were efficiently induced in young but not in aged rats, leading to restoration of protein homeostasis only in young pyramidal neurons. Importantly, proteasome stress inhibited glycogen synthase kinase-3beta in young but activated in aged rats. This age-related difference could be because of a dysfunction in the signaling pathway of the insulin growth factor-1 under stress situations. Present data highlight the potential role of glycogen synthase kinase-3beta in the coordination of both proteolytic systems under stress situation, representing a key molecular target to sort out this deleterious effect. PMID- 25817084 TI - Sporadically second localization of cerebellar hemangioblastoma in sella turcica mimicking a meningioma with no associated von Hippel-Lindau disease. AB - A 72-year-old man presented with a gradual bilateral decrease in visual acuity. Imaging showed lesion in the sella turcica diagnosed as meningioma but proving secondarily to be a hemangioblastoma. His neurosurgical history included a resection of a cerebellar hemangioblastoma 30 years ago. To our knowledge, such a hemangioblastoma second localization from the infratentorial to supratentorial has not been reported in the literature for patients not presenting with von Hippel-Lindau disease. PMID- 25817085 TI - ["Big data"; application and use for the health system]. PMID- 25817086 TI - [Subcutaneous drug administration in palliative care]. AB - OBJECTIVE: Develop a guide that compiles all the information available in the literature for healthcare staff on the administration of drugs subcutaneously in palliative care patients of the Hospital Unit of home. METHOD: It is designed a summary table of drugs likely to be administered subcutaneously in palliative care patients through the revision of the technical reports of the manufacturers and other literature published by scientific organizations, in addition to the literature search on Pubmed(r) and Micromedex(r). RESULTS: We have reviewed 65 drugs and a guide has been developed of recommendations depending on whether there is information of his administration by subcutaneous or, if on the contrary, its use is contraindicated. CONCLUSIONS: Although mainly manufacturers laboratories do not have data, information collected in this guide will allow the management of the subcutaneous route of some of the most commonly used medications in palliative care. PMID- 25817087 TI - Indirect comparison for Anti-TNF drugs in moderate to severe ulcerative colitis. AB - OBJECTIVE: To compare the relative efficacy of infliximab, adalimumab and golimumab through adjusted indirect treatment comparisons (ITCs). METHODS: An exhaustive search was performed until October 2013. Databases consulted were MEDLINE, EMBASE, the Cochrane Library, the Centre for Reviews and Dissemination and the Web of Science. Randomized control trials (RCTs) comparing the efficacy of infliximab, adalimumab or golimumab versus placebo, in terms of clinical remission, clinical response and mucosal healing, were included. In the case that more than one RCT fulfilled the inclusion criteria for the same drug, a metanalysis was undertaken using a fixed effects model. ITCs were carried out using the method proposed by Bucher et al. RESULTS: 6 RCTs published in 5 papers were included: 2 for infliximab (ACT 1 and ACT 2), 2 for adalimumab (ULTRA 1 y ULTRA 2) and 2 for golimumab (PURSUIT-SC y PURSUIT-M).In these RTCs, each biological agent was superior in efficacy to placebo. The results of the adjusted ITC are the following. In relation to the clinical remission, in the induction and maintenance period, there are no statistically significant differences between the three anti-TNF drugs. In relation to the clinical response and mucosal healing, in the induction period, there are statistically significant differences between infliximab and adalimumab. CONCLUSION: In view of the results obtained, infliximab, adalimumab and golimumab appear to be similarly effective therapeutic alternatives. Therefore, other considerations such as safety, tolerance and cost-effectiveness should be taken into account in order to select the most appropriate treatment. PMID- 25817088 TI - [Use of valproic acid in long stay units of psychiatry]. AB - OBJECTIVE: Valproic acid is often used in psychiatry to treat schizophrenia and other conditions outside of indication ("off-label"). However, its effectiveness has not been sufficiently demonstrated and its use is not exempt of adverse effects. This study's main objective is to determine the frequency of use of valproic acid in approved indications and the "off-label" use in psychiatric patients. METHODS: A cross-sectional study on July 7, 2014 with a sample of 167 patients residents in a psychiatric center was designed. Demographics, valproic acid treatment, posology and associated drug treatment, monitoring safety parameters, interactions and valproic acid concentrations. RESULTS: Valproic acid is prescribed in 1 of 3 patients of the center. It was used in the approved indications in 8 (15%) of the 53 patients analyzed: 5 (9%) of them with bipolar disorder and 3 (6%) diagnosed with epilepsy. Other 5 patients (9%) were included in the extended schizoaffective disorder indication. 76% (40) of the evaluated patients were prescribed valproic acid off-label. The mean dose of valproic acid was 1.26 Defined Daily Dose / patient / day. An average of 6 drugs associated with valproic acid was found. 18% of patients had thrombocytopenia. CONCLUSIONS: Valproic acid is often used off-label in psychiatric patients. It should be assessed the benefit-risk in this population. PMID- 25817089 TI - [Designing a software for drug management in special situations at a hospital's drug administration service]. AB - OBJECTIVE: to describe the features of a computer program for management of drugs in special situations (off-label and compassionate use) in a Department of Hospital Pharmacy (PD). To describe the methodology followed for its implementation in the Medical Services. To evaluate their use after 2 years of practice. METHOD: the design was carried out by pharmacists of the PD. The stages of the process were: selection of a software development company, establishment of a working group, selection of a development platform, design of an interactive Viewer, definition of functionality and data processing, creation of databases, connection, installation and configuration, application testing and improvements development. A directed sequential strategy was used for implementation in the Medical Services. The program's utility and experience of use were evaluated after 2 years. RESULTS: a multidisciplinary working group was formed and developed Pk_Usos(r). The program works in web environment with a common viewer for all users enabling real time checking of the request files' status and that adapts to the management of medications in special situations procedure. Pk_Usos(r) was introduced first in the Oncology Department, with 15 oncologists as users of the program. 343 patients had 384 treatment requests managed, of which 363 are authorized throughout two years. CONCLUSIONS: PK_Usos(r) is the first software designed for the management of drugs in special situations in the PD. It is a dynamic and efficient tool for all professionals involved in the process by optimization of times. PMID- 25817090 TI - [Adherence in patients with chronic treatment: data of "adherence day 2013"]. AB - OBJETIVE: The primary objective of this study was to evaluate the adherence level in chronic conditions patients during "The Adherence Day" celebrated on November 15, 2013. METHODS: We performed a transversal, observational and multicenter study at 43 Spanish hospitals, in order to estimate adherence in chronic treatments. We used the validated questionnaires Haynes- Sackett and Morisky- Green to measure medication adherence; but also a visual analogue scale and questions related with treatment complexity and selective adherence were applied. We performed a descriptive analysis and the closeness of agreement between questionnaires results. RESULTS: A total of 723 surveys were collected especially among outpatients. 43% of the participants were women, with a median age of 51 and taking 3 drugs per day. 10.8% of the patients reported to have difficulty taking their pills according to Haynes- Sackett test. However, depending on Morisky- Green questionnaire, 56.4% of the participants were totally compliant; but considering only the question about forgetfulness, more were adherents (77%). 71% of the patients considered their compliance level as good (more than 8) according to visual analogue scale. And 11% presented a selective adherence, no taking equally well all the medications. The closeness of agreement between questionnaires and Morisky- Green test, as gold standard, was poor for Haynes- Sackett and weak for visual analogue scale. CONCLUSIONS: In our study only 56% of the patients with chronic treatment had a perfect adherence. PMID- 25817091 TI - [Biosimilars, the journey has begun]. AB - According to the European Medicine Agency, a "biosimilar" is a biological medicinal product that contains a version of the active substance of an original biological medicinal product (reference or innovative medicinal product) that has been authorized in the European Economic Area. The similarity to the reference medicinal product in terms of quality, biological activity, safety and efficacy needs to be set on a comprehensive comparability basis. The generic standard approach (demonstration of bioequivalence with a reference medicinal product by appropriate bioavailability studies), which is applicable to a wide range of chemically derived medicinal products, is not sufficient to prove the similarity of biotechnology derived products due to their structural complexity. Furthermore, these biopharmaceuticals products, in comparison with the conventional ones, show a greater ability to activate the immune response. The evaluation of biosimilar medicines for authorisation purposes by the European Medicine Agency does not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine. Substitution policies are, therefore, within the remit of the EU member states. In order to support pharmacovigilance monitoring, all appropriate measures should be taken to clearly identify any biological medicinal product with due regard to its brand name and batch number. The situation of the European Community and the regulatory framework have been developed since the first applications (growth hormone), almost a decade ago, until the recent advent (monoclonal antibodies). The introduction to the market of biosimilars have positive effects on competition by improving access to biological therapies. PMID- 25817092 TI - [Interstitial lung disease induced by raltitrexed-oxaliplatin based chemotherapy for colorectal cancer: a case report]. PMID- 25817093 TI - [Some questions about abiraterone, breakfast and public funding]. PMID- 25817094 TI - [Drug use in off-label dosage regimes]. PMID- 25817095 TI - Internal and external atomic steps in graphite exhibit dramatically different physical and chemical properties. AB - We report on the physical and chemical properties of atomic steps on the surface of highly oriented pyrolytic graphite (HOPG) investigated using atomic force microscopy. Two types of step edges are identified: internal (formed during crystal growth) and external (formed by mechanical cleavage of bulk HOPG). The external steps exhibit higher friction than the internal steps due to the broken bonds of the exposed edge C atoms, while carbon atoms in the internal steps are not exposed. The reactivity of the atomic steps is manifested in a variety of ways, including the preferential attachment of Pt nanoparticles deposited on HOPG when using atomic layer deposition and KOH clusters formed during drop casting from aqueous solutions. These phenomena imply that only external atomic steps can be used for selective electrodeposition for nanoscale electronic devices. PMID- 25817096 TI - Apelin inhibits the activation of the nucleotide-binding domain and the leucine rich, repeat-containing family, pyrin-containing 3 (NLRP3) inflammasome and ameliorates insulin resistance in severely burned rats. AB - BACKGROUND: Hyperglycemia with insulin resistance remains a challenging problem in severely burned patients. Recent studies indicated the involvement of the nucleotide-binding domain and the leucine-rich, repeat-containing family, pyrin containing 3 (NLRP3) inflammasome in insulin resistance and a beneficial role of apelin in insulin resistance. Our aim was to investigate whether apelin inhibits the activation of the NLRP3 inflammasome and ameliorates insulin resistance in severely burned rats. METHODS: Male Wistar rats were subjected to a full thickness burn injury comprising 40% of the total body surface area and were randomized to receive apelin, N(G)-methyl-L-arginine acetate salt (L-NMMA), and apelin plus treatments with L-NMMA. The following outcome measurements were assessed: apelin/APJ mRNA expression in white adipose tissue (WAT) and muscles, plasma apelin level, and activation of the NLRP3 inflammasome in WAT, Interleukin 1 beta, interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 levels in plasma, insulin resistance, survival rates, and endothelial nitric oxide synthase phosphorylation in soleus muscles. RESULTS: Severe burn induced a decreased expression of apelin/APJ mRNA in soleus muscles and a decrease in plasma apelin levels. Burn injury with apelin treatment restored plasma apelin level, inhibited NLRP3 inflammasome activity in WAT, and decreased inflammatory cytokine levels in plasma. Rats treated with apelin also showed improved insulin sensitivity and decreased mortality, accompanied by a remarkable induction of endothelial nitric oxide synthase phosphorylation in soleus muscle. Furthermore, the aforementioned effects of apelin were inhibited in part by treatment with L-NMMA. CONCLUSION: Apelin inhibits the activation of NLRP3 inflammasome, attenuates systemic inflammatory response, ameliorates insulin resistance, and promotes survival after severe burn, in part through an endothelial nitric oxide synthase-dependent pathway. PMID- 25817097 TI - Contraction of abdominal wall muscles influences size and occurrence of incisional hernia. AB - BACKGROUND: Incisional hernias are a complication in 10% of all open abdominal operations and can result in substantial morbidity. The purpose of this study was to determine whether inhibiting abdominal muscle contraction influences incisional hernia formation during the fascial healing after laparotomy. We hypothesized that decreasing the deformation of the abdominal musculature would decrease the size or occurrence of an incisional hernia. METHODS: Using an established rat model for incisional hernia, a laparotomy through the linea alba was closed with 1 mid-incision, fast-absorbing suture. Three groups were compared: a sham group (sham; n = 6) received no laparotomy, and the saline hernia (SH; n = 6) and Botox hernia (BH; n = 6) groups were treated once with equal volumes of saline or botulinum toxin (Botox, Allergan) before the incomplete laparotomy closure. On postoperative day 14, the abdominal wall was examined for herniation and adhesions, and contractile forces were measured for abdominal wall muscles. RESULTS: No hernias developed in the sham rats. Rostral hernias developed in all SH and BH rats. Caudal hernias developed in all SH rats, but in only 50% of the BH rats. Rostral hernias in the BH group were 35% shorter and 43% narrower compared with those in the SH group (P < .05). The BH group had weaker abdominal muscles compared with the sham and SH groups (P < .05). CONCLUSION: In our rat model, partial paralysis of abdominal muscles decreases the number and size of incisional hernias. These results suggest that contractions of the abdominal wall muscle play a role in the pathophysiology of the formation of incisional hernias. PMID- 25817098 TI - Program directors' criteria for selection into urology residency. AB - OBJECTIVE: To investigate urology residency program directors' criteria for resident selection. METHODS: In 2014, the urology residency program directors were surveyed using an email questionnaire. The generated questionnaire included the following 3 components: (1) assessing the factors used in selecting applicants for interviewing and matching, (2) rating the factors resulting in a negative decision for applicants for interviewing and matching, and (3) investigating the factors that gave applicants special attention or consideration from program directors. Analysis of variance testing and post hoc Student t tests were used to assess for differences in the mean importance score of the factors. RESULTS: Urology reference letters and United States Medical Licensing Examination (USMLE) scores were ranked as the most important factors for applicant selection. A USMLE Step 1 score <=220 and a USMLE Step 2 score <=220 were the most deleterious factors to applicants, with a previous match failure being no less deleterious to an applicant than a USMLE Step 1 or 2 score <=220. Program directors gave special attention or consideration to gender (25%), minority status (36.8%), being from the same medical school as the program director (61.8%), completing an away rotation at the program director's institution (86.8%), being a child of an academic urologist (47.4%), and being a child of an academic nonurologic physician (15.8%). CONCLUSION: Although program directors consider a variety of factors during the residency selection process, USMLE performance, urology references, and completing an away rotation at the program directors' institution appear to be the most important factors to program directors during the residency selection process. PMID- 25817099 TI - Editorial comment. PMID- 25817100 TI - Reply: To PMID 25817098. PMID- 25817101 TI - Prospective multi-institutional study analyzing pain perception of flexible and rigid cystoscopy in men. AB - OBJECTIVE: To evaluate pain perception in men undergoing flexible or rigid diagnostic cystoscopy. METHODS: This is a prospective multi-institutional analysis of men undergoing cystoscopy in 4 European departments of urology. Pain perception was assessed with an 11-point numeric rating scale. Pain categories were as follows: no (0 points), mild (1-3), moderate (4-6), and severe pain (7 10). Assessment of pain was before, during cystoscopy, and at days 1, 4, and 7 of follow-up. RESULTS: A total of 300 cystoscopies were analyzed (150 rigid and 150 flexible). Men undergoing flexible cystoscopy were more frequently free of pain (58.7% vs 24%; P <.0001). Mild pain (54% vs 30.7%; P <.0001) and moderate pain (18.7% vs 9.3%; P = .02) were more common with rigid devices. No significant differences were prevalent in severe pain perception (3.3% vs 1.3%; P = .25). Patients, who had previous experience with cystoscopy reported similar pain levels as patients naive to cystoscopy, regardless if rigid (P = .92) or flexible (P = .26) devices were used. Pain decreased to the baseline during the 1-week follow-up after both, flexible and rigid cystoscopy. In multivariate regression analyses, rigid cystoscopy was an independent predictor for not being pain free (odds ratio [OR] = 0.15; confidence interval [CI] = 0.08-0.28; P <.0001), for experiencing mild pain (OR = 2.57; CI = 1.57-4.19; P <.0001), and for moderate pain (OR = 2.39; CI = 1.13-5.07; P = .02). Severe pain was seldom with both devices, and thus, no statistical difference was found. CONCLUSION: Flexible diagnostic cystoscopy caused less pain than rigid cystoscopy in men. Patient's previous experience with cystoscopy did not influence pain sensation. The type of cystoscope itself was identified as an independent risk factor of pain perception. PMID- 25817103 TI - Testosterone replacement therapy and the internet: an assessment of providers' health-related web site information content. AB - OBJECTIVE: To compare how providers of testosterone replacement therapy (TRT) in large metropolitan cities promote androgen replacement on their patient-oriented Web sites. MATERIALS AND METHODS: TRT provider Web sites were identified using Google search and the terms "Testosterone replacement" and the name of the 5 most populous US cities. These Web sites were assessed for (1) type or specialty of medical provider, (2) discussion of the benefits and risks of TRT, and (3) industry affiliations. RESULTS: In total, 75 Web sites were evaluated. Twenty seven of the 75 clinics (36%) were directed by nonphysicians, 35 (47%) were overseen by nonurology or nonendocrine physicians, and only 13 (17%) were specialist managed. Fourteen of 75 (18.6%) Web sites disclosed industry relationships. Ninety-five percent of Web sites promoted the benefits of TRT including improved sex drive, cognitive improvement, increased muscle strength, and/or improved energy. Only 20 of 75 Web sites (26.6%) described any side effect of TRT. Web sites directed by specialists were twice as likely to discuss risks of TRT compared with nonspecialist providers (41% vs 20%; odds ratio = 2.77; P <.01). Nine of 75 (12%) of all Web sites actually refuted that TRT was associated with significant side effects. CONCLUSION: Urologists and endocrinologists are in the minority of providers promoting TRT on the Internet. Specialists are more likely to discuss risks associated with TRT although the majority of surveyed Web sites that promote TRT do not mention treatment risks. There is substantial variability in quality and quantity of information on provider Web sites, which may contribute to misinformation regarding this prevalent health issue. PMID- 25817104 TI - Outcomes of microsurgical vasovasostomy for vasectomy reversal: a meta-analysis and systematic review. AB - OBJECTIVE: To perform a systematic review and meta-analysis of the published literature evaluating vasovasostomy for vasectomy reversal outcomes. METHODS: We conducted a review of English language articles describing results of microscopic vasovasostomy for vasectomy reversal. Two reviewers independently examined the studies for eligibility and evaluated data from each study. Meta-analysis was performed using a random effects model. RESULTS: Thirty-one studies with 6633 patients met inclusion criteria. Mean patient age at time of vasectomy reversal was 38.9 years with a mean obstructive interval of 7.2 years. The mean postprocedure patency and pregnancy rates weighted by sample size were 89.4% and 73.0%, respectively. A meta-analysis comparing an obstructive interval (OI) of <10 years to an OI of at least 10 years duration produced a pooled incidence ratios (IR; meta-IR) of 1.17 (95% confidence interval [CI], 1.09-1.25) for patency and 1.24 (95% CI, 1.12-1.38) for pregnancy. Incidence of patency for modified 1-layer technique was similar to that after a 2-layer procedure with a meta-IR of 1.04 (95% CI, 1.00-1.08). Because of a small number of relevant studies, a meta-analysis for other predictors of success such as sperm granuloma, quality of vasal fluid, and female factors was not feasible. CONCLUSION: We found no statistically significant difference in vasovasostomy outcomes when comparing the impact of single vs multilayer anastomoses. Patients with an OI <10 years showed higher patency and pregnancy rates compared with those with an OI >=10 years. Uniform definitions of patency are necessary to characterize success and standardize outcome reporting. PMID- 25817102 TI - Retrospective review of serum and urinary lithogenic risk factors in patients with osteoporosis and osteopenia. AB - OBJECTIVE: To analyze differences in bone remodeling markers, lithogenic factors and bone densitometry among the 3 groups of patients (controls, patients with relapsing calcium renal lithiasis, and patients with loss of bone mineral density without lithiasis). MATERIAL AND METHODS: This is a cross-sectional study including 203 patients who were divided in 3 groups: group 1 (controls), group 2 (patients with relapsing calcium renal lithiasis), and group 3 (patients with osteopenia and/or osteoporosis in the lumbar spine or hip). Bone densitometry, calcium-phosphorous and bone metabolism analysis, and analysis of lithogenic risk factors in fasting urine samples and 24-hour urine samples were performed. Statistical analysis was performed with SPSS 17.0. A P <=.05 was considered statistically significant. RESULTS: Patients in group 2 presented greater calcium excretion and a lower citrate excretion in 24-hour urine samples as compared with the other 2 groups. The proportion of hypercalciuria and hypocitraturia was higher in group 2. In addition, patients in group 2 presented a lower loss of bone mineral density as well as altered bone remodeling markers as compared with those in group 1. Patients in group 3 also presented alterations in urine calcium and citrate excretion with respect to the control group, with elevated fasting calcium and citrate levels and calcium-to-citrateratio. CONCLUSION: Lithogenic risk factors are altered in patients with osteopenia and/or osteoporosis without renal lithiasis although to a lesser extent than patients with calcium renal lithiasis. PMID- 25817105 TI - Reassessing the role of subclinical varicocele in infertile men with impaired semen quality: a prospective study. AB - OBJECTIVE: To evaluate the seminal, hormonal, and spontaneous pregnancy outcome after percutaneous embolization of the internal spermatic vein in infertile men with left-sided subclinical varicocele and one or more abnormal semen parameters. METHODS: A total of 218 patients underwent percutaneous embolization, and 119 patients were included as the observation group. All patients were followed up prospectively for 39.4 +/- 6.5 months. Semen parameters and hormonal levels were evaluated before any procedure and 6 months after. RESULTS: Significant improvement in the mean sperm concentration, total motility, and lower follicle stimulating hormone levels was noted in those who underwent varicocele embolization as compared with those not treated. After 39.4 +/- 6.5 months, pregnancy rates were 46.3% for the treated group and 11.8% for the control group (P = .011). CONCLUSION: In infertile men, small varicoceles, even subclinical ones, should be identified and treated. PMID- 25817106 TI - Usefulness of 2010 world health organization reference values for determining indications for varicocelectomy. AB - OBJECTIVE: To investigate the impact of 2010 World Health Organization (WHO) reference values in patients who underwent microsurgical varicocelectomy. METHODS: This retrospective cohort study included 206 men who underwent microsurgical varicocelectomy for a clinical varicocele with at least 1 abnormal semen parameter according to the 1999 WHO criteria. The preoperative semen analysis findings were reclassified according to the 2010 WHO criteria, and an improved seminal result after varicocelectomy was defined as a >=20% increase in sperm count or motility. RESULTS: Semen results of 114 men (55.3%) were reclassified as being above the reference values according to the 2010 WHO criteria. Among those with below reference values, 79.3% and 34.8% showed improved sperm counts and motility, respectively. However, in patients whose semen results converted to normal, 47.4% and 20.2% showed improved sperm counts and motility, respectively. Among those whose semen results were normal on the 2010 criteria, 58.8% showed improved sperm count or motility after microsurgical varicocelectomy. CONCLUSION: More than half of the patients whose semen results converted to normal on the 2010 WHO criteria showed improved seminal results after microsurgical varicocelectomy. It is necessary to reconsider the 2010 WHO criteria when determining the surgical indication for microsurgical varicocelectomy. PMID- 25817107 TI - Efficacy of Dapoxetine for the treatment of premature ejaculation: a meta analysis of randomized clinical trials on intravaginal ejaculatory latency time, patient-reported outcomes, and adverse events. AB - OBJECTIVE: To evaluate the efficacy of dapoxetine in the treatment of premature ejaculation (PE) with a meta-analysis method. METHOD: We looked for randomized controlled trials (RCTs) from MEDLINE, EMBASE, Cochrane library, "International Standard Randomized Controlled Trial Number Register," and "ClinicalTrials.gov," which reported efficacy of dapoxetine for PE. Two reviewers searched and examined the RCTs independently. The meta-analysis was performed by RevMan5.0 software. RESULTS: We included 5 RCTs comparing dapoxetine with placebo. Dapoxetine was more effective than placebo for intravaginal ejaculatory latency time (weighted mean difference = 1.47; 95% confidence interval [CI] = 1.22-1.71; P <.00001). For the 4 patient-reported outcomes, dapoxetine was also more effective (for clinical global impression of change, odds ratio [OR] = 3.19; 95% CI, 2.47-4.11; P <.00001; for composite patient-reported outcomes criteria for clinical benefit, OR = 2.29; 95% CI, 1.74-3.00; P <.00001; for satisfaction with sexual intercourse, OR = 1.89; 95% CI, 1.68-2.12; P <.00001; for decrease in personal distress related to ejaculation, OR = 0.72; 95% CI, 0.57-0.90; P <.00001). CONCLUSION: Dapoxetine is effective and well tolerated for either lifelong or acquired PE. But the long-term benefits and safety remain to be investigated. PMID- 25817108 TI - Prospective randomized comparison between cold and warm ischemia in patients with renal insufficiency undergoing partial nephrectomy. AB - OBJECTIVE: To compare between the effects of cold and warm ischemia on the risk of deterioration of renal insufficiency in patients with T1 renal tumor managed by partial nephrectomy. METHODS: This prospective randomized study was performed on 120 patients with chronic kidney disease, all having T1 renal tumors. Renal function was estimated by estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease formula. Patients were randomly divided into 2 groups: in group A, warm ischemia was used, and in group B, cold ischemia was used. All patients were treated by open partial nephrectomy. Patients were followed up for 2 years. The primary outcome of the study was eGFR at 2 years. Secondary outcomes were tumor recurrence, loss of follow-up, or patient death. RESULTS: Mean age of patients was 60.7 +/- 5.3 years. Associated chronic disease (diabetes and/or hypertension) was present in 93 patients. Worsening of renal insufficiency occurred within 1 month of surgery in 38 patients (27 in group A and 11 in group B). At 3 months follow-up, 21 of these 38 patients returned to their baseline eGFR. Warm ischemia rendered patients more prone to a decrease in eGFR after partial nephrectomy, with relative risk of 1.34 and 2 times at 3 months and 2 years of follow-up, respectively. CONCLUSION: Warm ischemia increases the risk of deterioration of renal functions in patients with renal insufficiency undergoing open partial nephrectomy for renal tumors. PMID- 25817109 TI - Editorial comment. PMID- 25817110 TI - Association of distance to treatment facility on quality and survival outcomes after radical cystectomy for bladder cancer. AB - OBJECTIVE: To examine the association of travel distance on quality and survival outcome measures for bladder cancer patients undergoing radical cystectomy for urothelial carcinoma. METHODS: Four hundred eight patients who underwent radical cystectomy for bladder cancer at a single institution from 2007 to 2013 were included. Multivariate logistic regression was used to determine the association of distance from treatment facility with 90-day mortality and quality-of-care endpoints including neoadjuvant chemotherapy use and time to cystectomy. Survival was assessed by multivariate Cox regression. RESULTS: Fifty-seven percent of patients lived within 50 miles of the treatment facility. There was no difference in time to cystectomy or the utilization of neoadjuvant chemotherapy between patients in different distance groups. On multivariate analysis, distance to treatment facility was the only predictor of 90-day mortality (odds ratio, 11.20; 95% confidence interval, 2.27-55.43; P = .003, for patients traveling >150 vs <50 miles). Although there was no difference in recurrence and cancer-specific survival between distance groups, greater distance was associated with worse overall survival on multivariate analysis (hazard ratio, 1.59; 95% confidence interval, 0.99-2.56; P = .05, for patients traveling >150 vs <50 miles). CONCLUSION: Distance to treatment facility did not impact quality measures including time to cystectomy or use of neoadjuvant chemotherapy, and there was no difference in cancer-specific mortality between distance groups. There was a detrimental association of increased travel distance with 90-day mortality, which could reflect disparities in access to care after cystectomy. PMID- 25817112 TI - Editorial comment. PMID- 25817111 TI - Videourodynamic evaluation of intracorporeally reconstructed orthotopic U-shaped ileal neobladders. AB - OBJECTIVE: To study the functional outcomes of 30 patients who had previously undergone laparoscopic radical cystectomy with intracorporeal orthotopic ileal neobladder reconstruction using videourodynamic (VUDM) assessment 180 days postoperatively. METHODS: Between November 2010 and December 2013, 30 male patients had undergone laparoscopic radical cystectomy with bilateral standard pelvic lymphadenectomy and pure laparoscopic orthotopic ileal U-shaped neobladder diversion. The demographic data were as follows: median age, 67 years (range, 62 79); body mass index, 22.3 kg/m(2) (range, 16-26.1 kg/m(2)); and mean American Society of Anesthesiologists score 2.2 (range, 1-3). Functional outcomes were assessed performing a standard VUDM study combined with perineal floor electromyography 180 days postoperatively. RESULTS: VUDM evaluations showed good functional outcomes of the reservoirs. Mean maximal neobladder capacity was 287 mL (range, 210-335 mL). Residual peristaltic activity was observed in all the individuals evaluated; however, only 9 of 30 individuals (30%) displayed severe peristaltic activity. Six of these 9 individuals (66.6%) experienced urinary leakage during these contractions. Mean postvoid residual volume was 44 mL (range, 0-105 mL), and peak flow rate was 13.9 mL/s (range, 9.7-29.2 mL/s). The Valsalva maneuver was positive in 5 of 30 subjects (17%). Bladder morphology assessed during contrast cystography showed the desired U-shape in all cases. Ureteral reflux was observed in 7 of 30 individuals (23.3%). CONCLUSION: Based on VUDM, our study shows that U-shaped ileal neobladders achieved by a totally laparoscopic approach obtained good functional outcomes. These findings support the evidence that a minimally invasive approach does not impose technical limitations that negatively impact the surgical results. PMID- 25817113 TI - Reply: To PMID 25817111. PMID- 25817114 TI - Association between surgeon and hospital characteristics and lymph node counts from radical prostatectomy and pelvic lymph node dissection. AB - OBJECTIVE: To assess whether surgical approach and hospital characteristics independently determine the number of lymph nodes (LNs) removed from prostate cancer patients undergoing radical prostatectomy (RP) and pelvic LN dissection (PLND). METHODS: Using the National Cancer Database, we identified all surgically treated patients diagnosed with pretreatment intermediate- or high-risk prostate cancer from 2010 to 2011. The primary outcome was the number of LNs retrieved at the time of RP. Generalized estimating equations were used to assess for differences in the adjusted number of LNs retrieved after accounting for patient and hospital characteristics and surgical approach. RESULTS: Overall, 35,876 patients were diagnosed with intermediate-risk (61.2%) and high-risk (38.8%) prostate cancer and underwent RP and PLND.On multivariate analysis, open RP and high-volume and academic hospitals were independently associated with greater LN counts compared with robotic-assisted RP and medium or low and community hospitals, respectively (all P <.001). After adjusting for patient and hospital variables, higher adjusted LN counts were observed for open RP compared with robotic-assisted RP (7.1 vs 6.1; P <.001). Adjusted counts were also higher for high-volume hospitals compared with medium- or low-volume hospitals (7.8 vs 5.9; P <.001), and academic compared with community hospitals (7.3 vs 5.6; P <.001). CONCLUSION: Among patients with aggressive prostate cancer treated with RP and PLND, retrieval of LN counts varied by surgical approach and hospital characteristics. PMID- 25817115 TI - Metabolic disorders in Turkish children with urolithiasis. AB - OBJECTIVE: To review metabolic disorders in Turkish children with urinary tract stone disease. MATERIALS AND METHODS: The medical records of 308 pediatric patients with the diagnosis of urolithiasis between 1996 and 2008, whose disease progression was followed in a single tertiary-care center, were reviewed retrospectively. Two hundred forty-eight patients whose metabolic analyses were performed were included in the study. RESULTS: Of the 248 patients participating in the study, 142 (57%) were men and 106 (43%) were women. The median age of the patients was 48 months (minimum-maximum, 2-180 months). Seventy-six percent of the patients had metabolic disorders. Of all patients, 44% had 1, 23% had 2, and 7% had 3 metabolic disorders. Hypercalciuria, hypocitraturia, hyperoxaluria, hyperuricosuria, and cystinuria were detected in 41%, 39%, 22%, 9%, and 4% of the patients, respectively. The rate of multiple stone formation, infection, and recurrence was significantly higher in the 0-2 years age group (P = .030, P = .001, P = .019, respectively). The median age of patients was greater (P = .001) in patients with hyperoxaluria in comparison with other metabolic disorders. Compared with other metabolic disorders, multiple stones and recurrence were more frequent in patients with cystinuria (P = .022 and P = .008, respectively). The size of the stones was greater in patients with hyperuricosuria in comparison with other metabolic disorders (P = .009). CONCLUSION: The majority of children with urinary tract stone disease exhibited >=1 metabolic risk factors. Metabolic risk factors should be evaluated in all children with urinary stone disease to provide appropriate treatment. PMID- 25817116 TI - Inflammatory myofibroblastic tumor of the bladder masquerading as eosinophilic cystitis: case report and review of the literature. AB - A 9-year-old boy presented with gross hematuria of 2 days duration. Cystoscopic evaluation revealed an anterior bladder mass. Pathology was consistent with eosinophilic cystitis, and a steroid regimen was initiated accordingly, but no improvement ensued. Concern for alternate malignant pathology led to open resection and the ultimate diagnosis of inflammatory myofibroblastic tumor of the bladder. Inflammatory myofibroblastic tumor is a rare tumor of the bladder in children and to our knowledge has not previously been associated with a misleading eosinophil-rich mucosal inflammatory response. PMID- 25817117 TI - Novel use of an osmotic self-inflating tissue expander for hypospadias revision surgery. AB - We describe the successful use of an osmotic self-inflating tissue expander for complex pediatric hypospadias repair. A 5-year-old boy, who had undergone previous hypospadias repair and subsequent fistula repair, presented with significant rotation of the penile shaft, with extensive scar tissue but insufficient native penile shaft skin for redo surgery. A 15 * 6 mm Osmed self inflating cylindrical expander was used to allow excision of scar tissue and cover with expanded native skin. An excellent cosmetic and functional outcome was achieved at clinic review, 18 months postoperatively. The use of self-inflating tissue expanders offers a novel technique to achieve adequate native skin in the management of complex pediatric hypospadias. PMID- 25817118 TI - Pelvic radiation is associated with urinary fistulae repair failure and need for permanent urinary diversion. AB - OBJECTIVE: To review our experience with nonmuscle flap repairs of enterourinary fistulae (EUF) and urinary cutaneous fistulae (UCF). EUF and UCF can be treated either with temporary urinary diversion allowing for healing by secondary intention or primary closure of the defect using an interposing omental, sliding, or muscle flap. Even after successful fistula repair, permanent urinary diversion can be required because of persistent urinary incontinence. MATERIALS AND METHODS: We reviewed 86 patients who underwent treatment of EUF or UCF at Washington University between the years 1998 and 2013. Of these, 39 patients underwent fistula repair, whereas 47 patients underwent either surgical or nonsurgical urinary diversion. Outcomes measured included postoperative fistula closure, need for permanent urinary diversion, and urinary incontinence. RESULTS: The mean age in our series was 59 years (21-87 years) at the time of surgery, with median follow-up of 20 months (1-137 months). Among patients who underwent surgical repair, radiation was associated with higher rates of repair failure (P = .0002), postsurgical incontinence (P <.0001), and the need for permanent urinary diversion (P = .0076). At the time of final follow-up, 32 of the 44 radiated patients had required permanent diversion (72%) compared with 3 of the 42 nonradiated patients (7%; P <.0001). CONCLUSION: Patients who undergo pelvic radiation before EUF and UCF repairs are at higher risk for developing repair failure and postsurgical incontinence. Many patients eventually require permanent urinary diversion. Therefore, EUF and UCF repairs in radiated patients should be undertaken with caution, and patients should be counseled about the possibility of urinary diversion as primary therapy. PMID- 25817119 TI - Editorial comment. PMID- 25817120 TI - Reply: To PMID 25817118. PMID- 25817121 TI - The impact of resident involvement in male one-stage anterior urethroplasties. AB - OBJECTIVE: To assess the effect of resident involvement in male anterior urethroplasties with regard to perioperative and postoperative outcomes using a large multi-institutional prospectively collected database. METHODS: Relying on the American College of Surgeons National Surgical Quality Improvement Program Participant User Files (2005-2012), we extracted all entries with Current Procedural Terminology coding for male one-stage anterior urethroplasty in men (54,310). Cases with missing entries on resident involvement were excluded. Descriptive and logistic regression analyses were constructed to assess the impact of trainee involvement (attending only vs resident) on perioperative and postoperative outcomes. Prolonged operative time (pOT) was defined as operative time >75th percentile (>204 minutes). RESULTS: A total of 235 one-stage urethroplasties were performed during the study period, for which resident involvement was available. Resident involvement was significantly associated with younger patient age (P = .011) and patients with a pre-existing diabetic condition (P = .047). In univariate analyses, the rate of pOT was significantly higher in the resident involvement group (P = .027). In multivariate models, resident involvement was an independent predictor of pOT (odds ratio, 2.4; 95% confidence interval, 1.3-9.7; P = .035). There were no differences in 30-day postoperative complications, length of hospital stay, or readmissions. Limitations of the study include inability to adjust for case complexity and type of reconstruction. CONCLUSION: Resident involvement is associated with pOT for anterior urethral strictures. However, it does not adversely affect complication rates or the length of hospital stay. PMID- 25817122 TI - Two-sided dorsal plus ventral oral graft bulbar urethroplasty: long-term results and predictive factors. AB - OBJECTIVE: To evaluate long-term outcomes of the 2-sided dorsal plus ventral oral graft (DVOG) urethroplasty by preserving the narrow urethral plate in tight bulbar strictures and investigate which factors might influence long-term outcomes. METHODS: This is a single-center retrospective study of 166 patients who underwent DVOG urethroplasty for tight bulbar strictures by a single surgeon (E.P.) between 2002 and 2013. The strictured urethra was opened ventrally; the exposed urethral plate was incised in the midline and augmented dorsally and ventrally using 2 oral grafts. Outcome was considered a failure when any postoperative instrumentation was needed. According to stricture length, patients were classified in 3 groups as follows: <=1.5 cm (group 1), >1.5 and <=3.9 cm (group 2), and >=4 cm (group 3). Time to failure was analyzed using Kaplan-Meier estimates and Cox regression. RESULTS: Median follow-up was 47 months (interquartile range, 33-95.5 months). Of the 166 patients, 149 (89.8%) were successful and 17 (10.2%) were failures. Most of the failures (90%) were observed during the first 5 years of follow-up; afterward, the success rate remained stable. The stricture length was a significant predictor of surgical outcome (odds ratio, 1.743 per cm; confidence interval, 1.2-2.5; P <.001); patients with a urethral stricture >=4 cm presented a higher risk of late failure. Age, stricture etiology, and previous treatment were not significant predictors of surgical outcome. CONCLUSION: With long-term follow-up, the treatment of tight bulbar strictures using a 2-sided DVOG urethroplasty showed a high success rate. The stricture length is an independent predictor of failure. PMID- 25817123 TI - Calibration of a novel, laparoscopic, 12-mm, ultrasound, image-guided, high intensity focused ultrasound probe for ablation of renal neoplasms. AB - OBJECTIVE: To calibrate a 12-mm high-intensity focused ultrasound (HIFU) probe to produce histologically verifiable complete tissue necrosis through thermal energy delivery while maintaining safety in ablation of porcine renal tissue. METHODS: The study was approved by the animal research committee at our institution. A HIFU probe on a fixed arm was introduced, and ablation was subsequently carried out robotically (under computer control) at 2 planned locations within each kidney at varying energy levels. After 4 days of survival, kidneys were retrieved and pathologic analysis of the lesions was carried out for necrotic volume. Planned volume was compared with pathologic necrotic volume. RESULTS: A series of optimizations were carried out as the experiment progressed. Near optimal ablation zone dimensions with complete cell death were achieved when the energy density was between 400 and 460 calories/cm(3). Pathologic analysis demonstrated the average ratio of necrotic zone volume to planned zone volume was 1.0 (standard deviation, 0.18) in the 7 lesions with energy density between 400 and 460 calories/cm(3). All animals survived the surgeries, and no device-related complications were identified during the study. No acute renal failure was identified in analysis of the blood work. CONCLUSION: A novel 12-mm laparoscopic HIFU probe was successfully calibrated for the ablation of porcine renal tissue. The safety profile of the Sonatherm probe was found to be excellent with no complications identified. PMID- 25817124 TI - Transition of urologic patients from pediatric to adult care: a preliminary assessment of readiness in spina bifida patients. AB - OBJECTIVE: To assess the awareness and readiness of both spina bifida patients and parents regarding the transition process before transitioning, with a secondary aim that included identifying potential factors associated with successful transition. METHODS: All children aged >=14 years requiring long-term care were prospectively enrolled. Questions designed by pediatric and adult urologists and an adolescent health specialist addressing the awareness of long term follow-up and the desire to learn more about transitioning were administered by nursing staff at regularly scheduled clinic appointments. All spina bifida patients evaluated in the past 5 years were identified, and clinical factors associated with transitioning were compared. Statistical analysis using the Fisher exact test and the chi-square test were used to compare patients' and parents' responses and categorical variables between patients transitioned and those eligible. P <.05 was considered significant. RESULTS: A total of 33 surveys were prospectively collected. Twenty-two percent of parents and 40% of patients said they never wanted to transition (P = .28). Parents had thought about transitioning more than the patients (88.9% and 40%, respectively; P = .002). Of the 97 patients eligible for transition, 34% had a transition plan. The only significant predictor of transitioning to adult care was a previous history of stones (P = .03). CONCLUSION: Transitioning to adult urologic care is a necessity for many, and parents are significantly more aware of transitioning than the patient. Acknowledging and understanding the concerns of patients and families will help optimize the transition to adult urologic care. PMID- 25817125 TI - Re: Stewart et al.: stone size limits the use of hounsfield units for prediction of calcium oxalate stone composition (Urology 2015;85:292-295). PMID- 25817126 TI - Penile cancer in a man with netherton syndrome. AB - Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect (trichorrhexis invaginata or bamboo hair), and severe atopic manifestations including atopic dermatitis and hay fever with high serum immunoglobulin E levels and hypereosinophilia. NS is caused by loss-of-function mutations in serine protease inhibitor of Kazal-type 5 (SPINK5) encoding lympho-epithelial Kazal-type-related inhibitor (LEKTI) expressed in the stratified epithelia. We report the first case of penile squamous cell carcinoma in a patient with NS. PMID- 25817127 TI - Cavernosal hematoma mimicking priapism. AB - We present a case of corpus cavernosum hematoma mimicking priapism. A 42-year-old man presented to the emergency room with penile pain and partial erection. Examination revealed partial erection and palpable space-occupying lesion of the corpus cavernosum without lymphadenopathy. Malignant workup was negative. Imaging assisted in diagnosis of unilateral hematoma of the corpus cavernosum. The lesion spontaneously resolved without the need for intervention. PMID- 25817128 TI - Acute Fibrinous Organizing Pneumonia: A Case Report and Literature Review. AB - Acute fibrinous organizing pneumonia (AFOP) is a distinct histopathologic pattern of lung injury with the hallmark feature of intra-alveolar fibrin deposits with associated organizing pneumonia, type II pneumocyte hyperplasia, and a patchy lymphohistiocytic proliferation. We describe the case of a previously healthy 47 year-old man who presented with a 4-day history of worsening dyspnea, cough, and nocturnal fevers and miliary nodules on chest imaging. Subsequently, there was an indication of AFOP when he underwent open lung biopsy. AFOP has been associated with a variety of underlying conditions including rheumatologic diseases, medications, and infections, and several cases were idiopathic. This case highlights the importance for radiologists to be aware of this uncommon pattern of lung injury and to consider it in the differential when encountering bilateral miliary infiltrates on chest imaging. PMID- 25817129 TI - The effectiveness of a new method using an extra-alveolar hemostatic agent after dental extractions in older patients on oral anticoagulation treatment: an intrapatient study. AB - OBJECTIVE: The present study aimed to evaluate the effectiveness of a new adhesive agent, HemCon Dental Dressing (HDD), in patients receiving oral anticoagulant treatment (OAT), who were undergoing nonsurgical tooth extractions without interruption or reduction of OAT, compared with that of a common local hemostatic agent. STUDY DESIGN: Twenty patients on OAT with an international normalized ratio (INR) ranging between 1.6 and 3.5 were recruited. In the same session, each patient was subjected to the extraction of two teeth: In the test site the HDD was applied, and in the control site, a common hemostatic sponge (CollaPlug, Zimmer Dental) was used. RESULTS: The mean application time was significantly lower in the test group than in the control group, and this difference is statistically significant. The mean postoperative pain was significantly lower in the test group than in the control group the morning after surgery and at the time of suture removal. Post-extraction socket healing was significantly better in the test group than in the control group. CONCLUSIONS: Tooth extraction in patients receiving OAT and have an INR lower than 3.5 is a safe procedure without discontinuation of the OA regimen. The HDD seems to reduce postoperative side effects and obtain rapid soft tissue healing. PMID- 25817130 TI - Site-specific acetaldehyde production and microbial colonization in relation to oral squamous cell carcinoma and oral lichenoid disease. PMID- 25817131 TI - Treating maxillofacial trauma for over half a century: how can we interpret the changing patterns in etiology and management? AB - OBJECTIVE: The aim of this study was to reveal the changes in the etiology and treatment of maxillofacial fractures in Greece over the period of the last 53 years. STUDY DESIGN: A patient-oriented retrospective review of clinical and epidemiologic data was performed to include all patients with maxillofacial fractures treated in the Oral and Maxillofacial Surgery Department of KAT General Hospital of Athens. We reviewed the causes of these injuries, their sites, and treatments (outcome variables) over the last 28 years and compared the results with those of a similar study from the same Department from 1960 to 1984 (predictor variable). RESULTS: The zygomatic complex was the most frequent fracture site in the recent years, whereas the condyle and symphysis were the most common ones in the early period. We observed a remarkable increase of injuries from interpersonal violence (P < .0001) and a divergence from conservative treatment (P < .001) with time. CONCLUSIONS: Universal agreement exists on the rapidly rising prevalence of facial fractures in the developed countries as a result of physical violence, and the present study confirmed this conclusion. Throughout the last 50 years, there has been a constant tendency of surgeons to adopt the concept of open reduction and internal fixation. PMID- 25817133 TI - Adaptive immunity to suffering. PMID- 25817132 TI - Iron, inflammation and atherosclerosis risk in men vs. perimenopausal women. AB - OBJECTIVE: Age at first atherosclerotic event is typically older for women vs. men; monthly iron loss has been postulated to contribute to this advantage. We investigated the relationship between an MRI-based arterial wall biomarker and the serum inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) in perimenopausal women vs. men. METHODS AND RESULTS: Women without evident atherosclerotic disease were prospectively enrolled and observed over 24 months of menopause transition, indicated by hormone levels and reduction in median number of menstrual cycles from 4 [3-6] per year to 0 [0-1] per year (P < 0.01). Higher hsCRP predicted shorter carotid artery wall T2* in women entering the menopause transition (r = -0.3139, P = 0.0014); this relationship weakened after 24 months of perimenopause in women (r = -0.1718, P = 0.0859) and was not significant in a cohort of men matched for age and cardiovascular risk category (r = -0.0310, P = 0.8362). Serum ferritin increased from baseline to 24-month follow-up during women's menopause transition (37 [20-79] to 67 [36-97] ng/mL, P < 0.01), but still remained lower compared to men (111 [45-220] ng/mL, P < 0.01). Circulating ferritin levels correlated with arterial wall T2* values in women at baseline (r = -0.3163, P = 0.0013) but not in women after 24 months (r = -0.0730, P = 0.4684) of menopause transition nor in men (r = 0.0862, P = 0.5644). CONCLUSIONS: An arterial wall iron-based imaging biomarker reflects degree of systemic inflammation in younger women, whereas this relationship is lost as women transition through menopause to become more similar to men. Iron homeostasis and inflammation in the arterial wall microenvironment warrants further investigation as a potential early target for interventions that mitigate atherosclerosis risk. PMID- 25817134 TI - A mimic of anterior wall myocardial infarction. PMID- 25817135 TI - Elevated Excitatory Input to the Nucleus Accumbens in Schizophrenia: A Postmortem Ultrastructural Study. AB - The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ. PMID- 25817136 TI - Multi-state modelling of repeated hospitalisation and death in patients with heart failure: The use of large administrative databases in clinical epidemiology. AB - In chronic diseases like heart failure (HF), the disease course and associated clinical event histories for the patient population vary widely. To improve understanding of the prognosis of patients and enable health care providers to assess and manage resources, we wish to jointly model disease progression, mortality and their relation with patient characteristics. We show how episodes of hospitalisation for disease-related events, obtained from administrative data, can be used as a surrogate for disease status. We propose flexible multi-state models for serial hospital admissions and death in HF patients, that are able to accommodate important features of disease progression, such as multiple ordered events and competing risks. Fully parametric and semi-parametric semi-Markov models are implemented using freely available software in R. The models were applied to a dataset from the administrative data bank of the Lombardia region in Northern Italy, which included 15,298 patients who had a first hospitalisation ending in 2006 and 4 years of follow-up thereafter. This provided estimates of the associations of age and gender with rates of hospital admission and length of stay in hospital, and estimates of the expected total time spent in hospital over five years. For example, older patients and men were readmitted more frequently, though the total time in hospital was roughly constant with age. We also discuss the relative merits of parametric and semi-parametric multi-state models, and model assessment and comparison. PMID- 25817137 TI - The health coaches from Dunkin' Donuts. PMID- 25817138 TI - Editorial comment. PMID- 25817139 TI - Long-term bladder function after ureterocele decompression in children. AB - PURPOSE: There is limited knowledge of long-term bladder function after ureterocele decompression. We studied bladder function in patients who underwent surgery in childhood for duplex system ureteroceles. MATERIALS AND METHODS: Toilet trained children treated for duplex system ureteroceles between 1990 and 2010 were included in study. We evaluated voiding dysfunction by the valid DVSS questionnaire and noninvasive studies, including uroflowmetry, electromyogram and post-void residual urine measurement. Urodynamics were done only in patients with abnormal DVSS or abnormal noninvasive studies. Patients were divided into group 1 ureterocele decompression (endoscopic incision), upper pole partial nephrectomy and ureteropelvic anastomosis, and group 2-primary or secondary bladder surgery (ureterocelectomy, ureterovesical reimplantation and bladder floor reconstruction). RESULTS: Of 62 operated patients 17 were lost to followup and 45 were fully studied at a mean followup of 9.5 years (range 3 to 20). Initial surgery was done at mean age of 5.1 months (range 6 days to 48 months). In the 33 group 1 patients, of whom 70% underwent endoscopic incision, the mean DVSS score was 1.5 (range 0 to 6), 7 patients (22%) had abnormal uroflowmetry or significant post-void residual urine and none had abnormal DVSS results. In the 12 patients in group 2 the mean DVSS score was 4 (range 0 to 11), 8 patients (66%) had abnormal uroflowmetry and significant post-void residual urine, and 3 had abnormal DVSS findings (p = 0.036). All group 2 patients underwent bladder surgery after decompression, including endoscopic incision in 2 and upper pole partial nephrectomy in 1. Only 1 child needed clean intermittent catheterization at age 3 years for hypocontractile megacystis and repeat febrile urinary tract infections. CONCLUSIONS: Ureterocele decompression alone in early childhood does not lead to major bladder dysfunction at long-term evaluation. Even if secondary bladder surgery is needed, significant bladder dysfunction is rare. PMID- 25817140 TI - National practice patterns and outcomes of pediatric nephrectomy: comparison between urology and general surgery. AB - PURPOSE: In adults nephrectomy is under the purview of urologists, but pediatric urologists and pediatric general surgeons perform extirpative renal surgery in children. We compared the contemporary performance and outcome of all-cause nephrectomy at pediatric hospitals as performed by pediatric urologists and pediatric general surgeons. MATERIALS AND METHODS: We queried the Pediatric Health Information System to identify patients 0 to 18 years old who were treated with nephrectomy between 2004 and 2013 by pediatric urologists and pediatric general surgeons. Data points included age, gender, severity level, mortality risk, complications and length of stay. Patients were compared by APR DRG codes 442 (kidney and urinary tract procedures for malignancy) and 443 (kidney and urinary tract procedures for nonmalignancy). RESULTS: Pediatric urologists performed more all-cause nephrectomies. While pediatric urologists were more likely to operate on patients with benign renal disease, pediatric general surgeons were more likely to operate on children with malignancy. Patients on whom pediatric general surgeons operated had a higher average severity level and were at greater risk for mortality. After controlling for differences patients without malignancy operated on by pediatric urologists had a shorter length of stay, and fewer medical and surgical complications. There was no difference in length of stay, or medical or surgical complications in patients with malignancy. CONCLUSIONS: Overall compared to pediatric general surgeons more nephrectomies are performed by pediatric urologists. Short-term outcomes, including length of stay and complication rates, appear better in this data set in patients without malignancy who undergo nephrectomy by pediatric urologists but there is no difference in outcomes when nephrectomy is performed for malignancy. PMID- 25817141 TI - Editorial comment. PMID- 25817143 TI - Editorial comment. PMID- 25817142 TI - Antibiotic prophylaxis for prevention of febrile urinary tract infections in children with vesicoureteral reflux: a meta-analysis of randomized, controlled trials comparing dilated to nondilated vesicoureteral reflux. AB - PURPOSE: The followup and treatment of children with vesicoureteral reflux has been debated for many years. Antibiotic prophylaxis has a role for preventing urinary tract infection in these children. Recent studies and guidelines suggested that prophylaxis has little or no role in preventing urinary tract infection in those children, especially those with low grades (I and II) of reflux. MATERIALS AND METHODS: We analyzed all published randomized, controlled trials comparing antibiotic prophylaxis vs no prophylaxis or placebo in children with vesicoureteral reflux. The children were divided into those with nondilated (grades I and II) and dilated (grades III and IV) vesicoureteral reflux. After data were analyzed the RIVUR study was published and, therefore, it was added to the analyzed data. RESULTS: After analyzing the first published studies we found that antibiotic prophylaxis would be beneficial only in children with high grade vesicoureteral reflux. With the addition of the data in the RIVUR study these results changed. The new pooled data support antibiotic prophylaxis in all children with vesicoureteral reflux. CONCLUSIONS: Vesicoureteral reflux management is still controversial. In contrast to recently published studies and guidelines, this meta-analysis supports antibiotic prophylaxis in all children with vesicoureteral reflux regardless of reflux grade. More studies are needed to support this finding. PMID- 25817144 TI - Editorial comment. PMID- 25817145 TI - Editorial comment. PMID- 25817147 TI - Editorial comment. PMID- 25817149 TI - Categorization of bladder dynamics and treatment after fetal myelomeningocele repair: first 50 cases prospectively assessed. AB - PURPOSE: We categorized bladder patterns and principles of treatment applied to patients who underwent myelomeningocele repair during gestation in a prospective urological assessment. MATERIALS AND METHODS: We performed urinary tract ultrasound, voiding cystourethrogram and urodynamic evaluation. We then categorized patients into 4 patterns, including normal, high risk (overactive bladder with detrusor leak point pressure greater than 40 cm H2O and high filling pressure also greater than 40 cm H2O), incontinent and underactive bladder. RESULTS: A total of 51 patients were enrolled in study at the first medical appointment. Urodynamic evaluation was done in 48 of these patients as the initial investigation, enabling attribution of a bladder pattern. The high risk pattern was found in 27 patients (56.2%), 18 were incontinent and 1 had an underactive bladder. Only 2 patients (4.2%) in this series had a normal bladder. CONCLUSIONS: Of patients who underwent myelomeningocele closure during gestation 93.7% had significant lower urinary tract dysfunction consisting of high bladder pressure or incontinence. These data reinforce the absolute need to follow these patients closely. The potential benefits of fetal surgery in the urinary tract remain to be proved. PMID- 25817150 TI - Tunneled buccal mucosa tube grafts for repair of proximal hypospadias. AB - PURPOSE: Buccal mucosa is the favored graft material for patients with long urethral defects and a paucity of skin. Since 2007, we have used the novel tunneled buccal mucosa tube graft urethroplasty technique in these patients. We describe this operative technique and report our surgical and functional outcomes. MATERIALS AND METHODS: Between 2007 and 2013, 37 males with proximal hypospadias underwent tunneled buccal mucosa tube graft urethroplasty. After the penile shaft was optimized at a prior stage a free buccal graft was tubularized and tunneled under the intact ventral shaft skin and into the glans. We retrospectively reviewed all charts to report our results. We assessed uroflowmetry and bladder ultrasound for post-void residual urine. RESULTS: The overall complications rate in 34 patients with more than 1-year followup was 32% (11), including fistula in 5, proximal stricture in 4 and meatal stenosis in 2. In the first 10 patients a total of 7 complications (70%) developed but there were only 4 complications in the next 24 (16%). Surgeon experience was the only significant predictor of complications (p = 0.003). We obtained uroflow and post void residual urine data on 13 of 37 patients, of whom 9 achieved a normal flow pattern and post-void residual urine, and 4 had a blunted flow pattern. CONCLUSIONS: The novel technique of the tunneled buccal mucosa tube graft in patients with proximal hypospadias represents a good alternative for a long urethroplasty in patients with a paucity of skin. After the learning curve plateaus the rate and degree of complications decrease. Furthermore, voiding function is adequate, as assessed by uroflow studies and post-void residual urine measurement. PMID- 25817151 TI - Objective long-term evaluation after bladder autoaugmentation with rectus muscle backing. AB - PURPOSE: Bladder autoaugmentation with rectus muscle backing is an efficient surgical technique for bladder augmentation. We evaluated long-term outcomes to determine the value of this procedure. MATERIALS AND METHODS: Between August 1999 and June 2004 autoaugmentation was performed in 16 girls and 7 boys 4 to 13 years old (median age 8). The indication was neurogenic bladder with small capacity and poor compliance due to myelomeningocele in 18 patients, tethered cord in 3 and sacral agenesis in 2. Detrusorectomy usually involved the whole upper half of the bladder. The prolapsed bladder urothelium was hitched to the 2 rectus muscles to prevent retraction and provide easier bladder emptying with voluntary muscle contractions. RESULTS: At the median early followup of 27 months (range 9 to 49) bladder volume had increased significantly in all 23 patients (median 338 ml, range 190 to 462). At the current median long-term followup of 134 months (range 94 to 159) bladder volume continued to be significant compared to median bladder capacity preoperatively (median 419 ml, range 296 to 552). Voluntary voiding was achieved in 14 patients without post-void residual urine. Nine patients used clean intermittent catheterization, of whom only 4 could not empty the bladder voluntarily and relied only on clean intermittent catheterization. CONCLUSIONS: Detrusorectomy with a rectus muscle hitch and backing is a minimally invasive, completely extraperitoneal, simple and safe procedure. However, the technique is indicated only in select cases without anterior abdominal wall anomalies. PMID- 25817152 TI - Adolescent and adult outcomes in women following childhood vaginal reconstruction for cloacal anomaly. AB - PURPOSE: We examined outcomes in female adolescents and women who underwent vaginoplasty in childhood during genitourinary reconstruction for cloacal anomalies. MATERIALS AND METHODS: We retrospectively reviewed the medical notes on girls and women attending an adult specialist center for genitourinary anomalies. Data were collected on vaginal reconstruction, menstruation, sexual and reproductive function, and urological and gastroenterological outcomes. RESULTS: We identified 19 patients with a mean age of 22 years (range 13 to 35), of whom 16 (84%) underwent vaginoplasty in the first year of life. Nine of these 16 patients (56%) had required 1 (7) or 2 (2) further vaginal reconstructions to facilitate menstruation or sexual activity. The remaining 7 patients (44%) required no further vaginal reconstruction. Nine of the 19 patients (47%) had associated mullerian anomalies, obstructed menstruation developed in 5 (26%) and 1 required hemihysterectomy. Eight patients were sexually active, of whom 1 experienced difficult penetration. Three patients attempted to conceive, including 1 with a complex preterm delivery and 2 undergoing fertility treatment. Of the patients 74% underwent further reconstruction of the renal tract and 36% had an enteric stoma. CONCLUSIONS: This study confirms the complexity of vaginal reconstruction in this group with a notable vaginoplasty revision rate. Mullerian anomalies were identified in almost half of the patients, a higher incidence than previously reported, and in a quarter obstructed menstruation developed in puberty. A specialist team with gynecologic input should treat patients with cloacal anomalies. Outcome data are sparse. There remains a need for well planned, prospective cohort studies that include assessments of psychological, sexual and reproductive outcomes. PMID- 25817153 TI - Editorial comment. PMID- 25817154 TI - Editorial comment. PMID- 25817155 TI - Editorial comment. PMID- 25817156 TI - Editorial comment. PMID- 25817157 TI - Imaging after urinary tract infection in older children and adolescents. AB - PURPOSE: There are few guidelines and little data on imaging after urinary tract infections in older children. We determined the clinical yield of renal and bladder ultrasound, and voiding cystourethrogram in older children and adolescents after urinary tract infection. MATERIALS AND METHODS: We analyzed findings on voiding cystourethrogram, and renal and bladder ultrasound as well as the clinical history of patients who underwent the 2 studies on the same day between January 2006 and December 2010. We selected for study patients 5 to 18 years old who underwent imaging for urinary tract infection. Those with prior postnatal genitourinary imaging or prenatal hydronephrosis were excluded from analysis. RESULTS: We identified a cohort of 153 patients, of whom 74% were 5 to 8 years old, 21% were 8 to 12 years old and 5% were 12 to 18 years old. Of the patients 77% were female, 78% had a febrile urinary tract infection history and 55% had a history of recurrent urinary tract infections. Renal and bladder ultrasound findings revealed hydronephrosis in 7.8% of patients, ureteral dilatation in 3.9%, renal parenchymal findings in 20% and bladder findings in 12%. No patient had moderate or greater hydronephrosis. Voiding cystourethrogram showed vesicoureteral reflux in 34% of cases and bladder or urethral anomalies in 12%. Reflux was grade I, II-III and greater than III in 5.9%, 26% and 2% of patients, respectively. For any voiding cystourethrogram abnormality the sensitivity and specificity of any renal and bladder ultrasound abnormality were 0.49 (95% CI 0.37-0.62) and 0.76 (95% CI 0.66-0.84), respectively. Positive and negative predictive values were 0.58 (95% CI 0.44-0.71) and 0.69 (0.59-0.77), respectively. CONCLUSIONS: In older children with a history of urinary tract infection the imaging yield is significant. However, imaging revealed high grade hydronephrosis or high grade vesicoureteral reflux in few patients. Renal ultrasound is not reliable for predicting voiding cystourethrogram findings such as vesicoureteral reflux. PMID- 25817158 TI - Editorial comment. PMID- 25817160 TI - Congenital adrenal hyperplasia: current surgical management at academic medical centers in the United States. AB - PURPOSE: Controversy exists on the necessity for and timing of genitoplasty in girls with congenital adrenal hyperplasia. Our knowledge of surgical preferences is limited to retrospective series from single institutions and physician surveys, which suggest a high rate of early reconstruction. We evaluated current surgical treatment for congenital adrenal hyperplasia at academic centers. MATERIALS AND METHODS: We queried the Faculty Practice Solutions Center database to identify all female patients younger than 18 years with a diagnosis of congenital adrenal hyperplasia between 2009 and 2012. Procedures were identified by CPT codes for vaginoplasty, clitoroplasty and other genital procedures. Reconstruction type, age at surgery and surgeon volume were analyzed. RESULTS: We identified 2,614 females in the database with a diagnosis of congenital adrenal hyperplasia who were seen at a total of 60 institutions. Of infants younger than 12 months between 2009 and 2011 as few as 18% proceeded to surgery within a 1 to 4-year followup. Of those referred to a pediatric urologist 46% proceeded to surgery. Of patients who underwent surgery before age 2 years clitoroplasty and vaginoplasty were performed in 73% and 89%, respectively, while 68% were treated with a combined procedure. A medium or high volume surgeon was involved in 63% of cases. CONCLUSIONS: Many patients with congenital adrenal hyperplasia in the database did not proceed to early reconstructive surgery. Of those referred to surgeons, who were possibly the most virilized patients, about half proceeded to early surgery and almost all underwent vaginoplasty as a component of surgery. About two-thirds of the procedures were performed by medium or high volume surgeons, indicative of the surgical centralization of disorders of sexual development. PMID- 25817161 TI - Editorial comment. PMID- 25817162 TI - Development and evaluation of a palliative care curriculum for cystic fibrosis healthcare providers. AB - BACKGROUND: Primary palliative care refers to basic skills that all healthcare providers can employ to improve quality of life for patients at any stage of disease. Training in these core skills is not commonly provided to clinicians caring for cystic fibrosis (CF) patients. The objective of this study was to assess change in comfort with core skills among care team members after participation in CF-specific palliative care training focused on management of burdensome symptoms and difficult conversations. METHODS: A qualitative needs assessment was performed to inform the development of an 18-hour curriculum tailored to the chronicity and complexity of CF care. A 32-question pre- and post course survey assessed CF provider comfort with the targeted palliative care skills in 5 domains using a 5-point Likert scale (1=very uncomfortable, 3=neutral, 5=very comfortable). RESULTS: Among course participants (n=16), mean overall comfort score increased by 0.9, from 3 (neutral) to 3.9 (comfortable) (p<0.001). Mean comfort level increased significantly (range 0.8 to 1.4) in each skill domain: use of supportive care resources, pain management, non-pain symptom management, communication, and psychosocial skills. CONCLUSIONS: CF-specific palliative care training was well received by participants and significantly improved self-assessed comfort with core skills. PMID- 25817163 TI - N-Formyl peptides drive mitochondrial damage associated molecular pattern induced neutrophil activation through ERK1/2 and P38 MAP kinase signalling pathways. AB - Traumatic injury results in a systemic inflammatory response syndrome (SIRS), a phenomenon characterised by the release of pro-inflammatory cytokines into the circulation and immune cell activation. Released from necrotic cells as a result of tissue damage, damage associated molecular patterns (DAMPs) are thought to initiate the SIRS response by activating circulating immune cells through surface expressed pathogen recognition receptors. Neutrophils, the most abundant leucocyte in human circulation, are heavily implicated in the initial immune response to traumatic injury and have been shown to elicit a robust functional response to DAMP stimulation. Here, we confirm that mitochondrial DAMPs (mtDAMPs) are potent activators of human neutrophils and show for the first time that signalling through the mitogen-activated-protein-kinases p38 and extracellular signal-related-kinase 1/2 (ERK1/2) is essential for this response. At 40 and/or 100 MUg/ml, mtDAMPs activated human neutrophils, indicated by a significant reduction in the surface expression of L-selectin, and triggered a number of functional responses from both resting and tumour necrosis factor-alpha primed neutrophils, which included reactive oxygen species (ROS) generation, degranulation, secretion of interleukin-8 and activation of p38 and ERK1/2 MAPKs. Pre-treatment of neutrophils with Cyclosporin H, a selective inhibitor of formyl peptide receptor-1 (FPR-1), significantly inhibited mtDAMP-induced L-selectin shedding as well as p38 and ERK1/2 activation, suggesting that N-formyl peptides are the main constituents driving mtDAMP-induced neutrophil activation. Indeed, no evidence of L-selectin shedding or p38 and ERK1/2 activation was observed in neutrophils challenged with mitochondrial DNA alone. Interestingly, pharmacological inhibition of p38 or ERK1/2 either alone or in combination significantly inhibited L-selectin shedding and IL-8 secretion by mtDAMP challenged neutrophils, revealing for the first time that MAPK activation is required for mtDAMP-induced neutrophil activation and function. Our findings demonstrate that signalling through FPR-1 and activation of p38 and ERK1/2 MAPKs are key events in mtDAMP-induced neutrophil activation. Gaining an understanding of the signalling pathways involved in mtDAMP-induced neutrophil activation may assist in the development of future therapeutic strategies aimed at targeting the SIRS response to improve the outcome of the hospitalised trauma patient. Reducing the severity of the inflammatory response may realise substantial benefits for the severely injured trauma patient. PMID- 25817164 TI - Family members' experience of providing support for young people with traumatic physical injury during the acute hospital phase of care: A qualitative study. AB - PURPOSE: The aim of this study was to explore how family members perceive and support young people with traumatic physical injury during the acute phase of hospital care. METHODS: This study forms part of the qualitative explanatory follow-up phase of a mixed methods study. The paper reports on family members' experiences of providing support to young people 16-24 years admitted with major traumatic injury to an Australian Level 1 Trauma Centre. Semi-structured in-depth interviews with family members were conducted and transcribed verbatim. Data were managed using NVivo software, and thematically analysed. FINDINGS: Family support was determined by how family members perceived the injury. Driven by a need to protect the injured young person, family members sought to control potential emotional impacts of injury, creating a buffer between the young person and other people including healthcare professionals. Family members safeguarded the psychological well-being of the young person, in an attempt to facilitate their transition back to independence. CONCLUSION: This study identifies iterative changes in family relationships and emotional and practical support provided by family members during the initial injury trajectory, extending understandings of the broader burden of injury. Key elements of family stress theory offer a useful framework for the development of anticipatory guidance for clinicians that are responsive to the emotional needs of patients and families, supporting the need for a family-centred care approach to managing major traumatic injury in young people. PMID- 25817165 TI - Penetrating cardiac injury: consider direct exploration and "finger haemostasis", and remember to screen for intra-cardiac injury after a successful repair. PMID- 25817166 TI - Prolonged dysphonia as a complication of interscalene block. AB - The interscalene block (ISB) of the brachial plexus is a common technique for anaesthesia and the treatment of postoperative pain in shoulder surgery. Despite the well-known advantages of this technique, it is not without risks that need to be identified and taken into account. The most frequent complications associated with it are of a neurological nature and most are transient. It has been shown that the use of nerve stimulation does not guarantee a safe block. Ultrasound guidance now makes it possible to visualise potentially dangerous structures, thus allowing us to reduce the risk of associated complications. We present the case of a patient with transient dysphonia secondary to recurrent laryngeal nerve palsy. We also discuss briefly the most common complications associated with the technique. PMID- 25817168 TI - Commentary: Tobacco consumption and body weight: Mendelian randomization across a range of exposure. PMID- 25817167 TI - Sternal fracture in the age of pan-scan. AB - STUDY OBJECTIVE: Widespread chest CT use in trauma evaluation may increase the diagnosis of minor sternal fracture (SF), making former teaching about SF obsolete. We sought to determine: (1) the frequency with which SF patients are diagnosed by CXR versus chest CT under current imaging protocols, (2) the frequency of surgical procedures related to SF diagnosis, (3) SF patient mortality and hospital length of stay comparing patients with isolated sternal fracture (ISF) and sternal fracture with other thoracic injury (SFOTI), and (4) the frequency and yield of cardiac contusion (CC) workups in SF patients. METHODS: We analyzed charts and data of all SF patients enrolled from January 2009 to May 2013 in the NEXUS Chest and NEXUS Chest CT studies, two multi-centre observational cohorts of blunt trauma patients who received chest imaging for trauma evaluation. RESULTS: Of the 14,553 patients in the NEXUS Chest and Chest CT cohorts, 292 (2.0%) were diagnosed with SF, and 94% of SF were visible on chest CT only. Only one patient (0.4%) had a surgical procedure related to SF diagnosis. Cardiac contusion was diagnosed in 7 (2.4%) of SF patients. SF patient mortality was low (3.8%) and not significantly different than the mortality of patients without SF (3.1%) [mean difference 0.7%; 95% confidence interval (CI) 1.0 to 3.5%]. Only 2 SF patient deaths (0.7%) were attributed to a cardiac cause. SFOTI patients had longer hospital stays but similar mortality to patients with ISF (mean difference 0.8%; 95% CI -4.7% to 12.0). CONCLUSIONS: Most SF are seen on CT only and the vast majority are clinically insignificant with no change in treatment and low associated mortality. Workup for CC in SF patients is a low yield practice. SF diagnostic and management guidelines should be updated to reflect modern CT-driven trauma evaluation protocols. PMID- 25817169 TI - Hypertrichosis pinnae auris may enhance the hearing power of an individual. AB - In this correspondence, we hypothesize that the hypertrichosis pinnae auris might influence the hearing power of an individual. It is a well established fact that the inner cells of the ears acts as sensory cells which respond to the incoming sound vibrations. The occurrence and degree of hairiness have been reported to increase with advancing age; therefore, we theorize that there might be the presence of the sensory activity in the hairs present on the outer area of the ear, which would enhance the hearing ability of the individuals. PMID- 25817170 TI - Osmolyte mixtures have different effects than individual osmolytes on protein folding and functional activity. AB - Osmolytes are small organic molecules accumulated by organisms under stress conditions to protect macromolecular structure and function. In the present study, we have investigated the effect of several binary osmolyte mixtures on the protein folding/stability and function of RNase-A. For this, we have measured DeltaGD(o) (Gibbs free energy change at 25 degrees C) and specific activity of RNase-A mediated hydrolysis of cytidine 2'-3' cyclic monophosphate in the presence and absence of individual and osmolyte mixtures. It was found that the osmolyte mixtures have different effect on protein stability and function than that of individual osmolytes. Refolding studies of RNase-A in the presence of osmolyte mixtures and individual osmolytes also revealed that osmolyte mixtures have a poor refolding efficiency relative to the individual osmolytes. PMID- 25817171 TI - Effects of exercise on the nephron of Goto-Kakizaki rats: morphological, and advanced glycation end-products and inducible nitric oxide synthase immunohistochemical analyses. AB - The current study aimed to examine how exercise affects morphology of the nephron, and localization of advanced glycation end-products (AGEs) and inducible nitric oxide synthase (iNOS) immunoreactivity in diabetic Goto-Kakizaki rats. Four groups of male rats were studied. WIS SED (Wistar rats; sedentary) group served as a control. Other groups were WIS EX (Wistar rats; exercise), GK SED (Goto-Kakizaki diabetic rats; sedentary) and GK EX (Goto-Kakizaki diabetic rats; exercise) groups. The rats in EX groups were subjected to 15weeks of treadmill running at a speed of 15m/min for a total of 30minutes, three times a week. Changes in the structure of renal corpuscles and in the distribution of AGEs- and iNOS-immunoreactive cells of the uriniferous tubules were evaluated. Every parameter of GK EX was significantly different from that of GK SED (area of Bowman's capsules: p<0.001, area of glomeruli: p<0.05 and the occupancy of a glomerulus: p<0.05). These findings suggest that exercise may ameliorate glomerular filtration rate (GFR). The localizations of AGEs and iNOS immunostaining in the uriniferous tubules were similar in each group. Immunohistochemical assays revealed that the number of the AGEs and iNOS immunopositive cells of the proximal tubule of cortico-deep layer in EX groups were markedly greater than those in SED groups and that iNOS expression in GK EX was significantly higher than GK SED (p<0.05). Exercise seems to normalize the GFR and glomerular filtrate absorption from the uriniferous tubules in Goto Kakizaki diabetic rats with the recovered shape of renal corpuscles and may be involved in the absorption and catabolization of AGEs with iNOS-related reactions for reabsorption. PMID- 25817172 TI - Changes in vision related quality of life in patients with diabetic macular edema: ranibizumab or laser treatment? AB - PURPOSE: To compare the changes in vision related quality of life (VR-QoL) in patients with diabetic macular edema (DME) undergoing intravitreal ranibizumab (IVR) injection or focal/grid laser. MATERIAL AND METHODS: In this prospective study, 70 patients with clinically significant macular edema (CSME) were randomized to undergo IVR injection (n=35) and focal/grid laser (n=35). If necessary, the laser or ranibizumab injections were repeated. Distance and near visual acuities, central retinal thickness (CRT) and The 25-item Visual Function Questionnaire (VFQ-25) were used to measure the effectiveness of treatments and VR-QoL before and after 6 months following IVR or laser treatment. RESULTS: The demographic and clinical findings before the treatments were similar in both main groups. The improvements in distance and near visual acuities were higher in IVR group than the laser group (p<0.01). The reduction in CRT in IVR group was higher than that in laser treatment group (p<0.01). In both groups, the VFQ-25 composite score tended to improve from baseline to 6 months. And at 6th month, the changes in composite score were significantly higher in IVR group than in laser group (p<0.05). The improvements in overall composite scores were 6.3 points for the IVR group compared with 3.0 points in the laser group. Patients treated with IVR and laser had large improvements in composite scores, general vision, near and distance visual acuities in VFQ-25 at 6 months, in comparison with baseline scores, and also mental health subscale in IVR group. CONCLUSION: Our study revealed that IVR improved not only visual acuity or CRT, but also vision related quality of life more than laser treatment in DME. And these patient-reported outcomes may play an important role in the treatment choice in DME for clinicians. PMID- 25817173 TI - Soluble receptor for advanced glycation end products and insulin resistance during development of type 2 diabetes mellitus. PMID- 25817174 TI - Protuberance or fossa on the lateral surface of the mandible in primates. AB - In order to clarify the morphological characteristics and function of the protuberance and/or fossa on the lateral surface of the mandible, we examined 778 mandibles of 9 genera, 19 species of non-human primates. Both protuberance and fossa were found in Macaca, Chlorocebus, and Cercocebus at frequencies ranging from 0% to 60%. The protuberance was composed of compact bone and was similar to the mandibular torus in humans. A well-developed protuberance extended from the fourth premolar to third molar region, and was situated at the central part of the mandibular body, or continued on the oblique line. Sometimes the protuberance localized on the mandibular base. A deep and large fossa was found in all individuals of Papio, Theropithecus, and Mandrillus, and the bone width was thin in the center of the fossa. The fossa extended from the third premolar to the second molar region, and the deepest area was the first molar region. In Macaca, Chlorocebus, and Cercocebus, the curvature of the external table of the mandible created a fossa. In Colobus, and Hylobates, the external surface of the mandible looked concave because of the thickened mandibular base. These concavo-convex structures have some biological functions and represent an adaptive change for mastication. PMID- 25817175 TI - [Idiopathic facial paralysis in children]. AB - BACKGROUND: Idiopathic facial palsy is the most common cause of facial nerve palsy in children. Controversy exists regarding treatment options. The objectives of this study were to review the epidemiological and clinical characteristics as well as the outcome of idiopathic facial palsy in children to suggest appropriate treatment. PATIENTS AND METHODS: A retrospective study was conducted on children with a diagnosis of idiopathic facial palsy from 2007 to 2012. RESULTS: A total of 37 cases (13 males, 24 females) with a mean age of 13.9 years were included in this analysis. The mean duration between onset of Bell's palsy and consultation was 3 days. Of these patients, 78.3% had moderately severe (grade IV) or severe paralysis (grade V on the House and Brackmann grading). Twenty-seven patients were treated in an outpatient context, three patients were hospitalized, and seven patients were treated as outpatients and subsequently hospitalized. All patients received corticosteroids. Eight of them also received antiviral treatment. The complete recovery rate was 94.6% (35/37). The duration of complete recovery was 7.4 weeks. DISCUSSION: Children with idiopathic facial palsy have a very good prognosis. The complete recovery rate exceeds 90%. However, controversy exists regarding treatment options. High-quality studies have been conducted on adult populations. Medical treatment based on corticosteroids alone or combined with antiviral treatment is certainly effective in improving facial function outcomes in adults. In children, the recommendation for prescription of steroids and antiviral drugs based on adult treatment appears to be justified. CONCLUSION: Randomized controlled trials in the pediatric population are recommended to define a strategy for management of idiopathic facial paralysis. PMID- 25817176 TI - [Classic Kaposi sarcoma]. PMID- 25817177 TI - Resilience and corpus callosum microstructure in adolescence. AB - BACKGROUND: Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress resilient adolescents. METHOD: Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography. RESULTS: Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups. CONCLUSION: High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure. PMID- 25817178 TI - Irbesartan attenuates production of high-mobility group box 1 in response to lipopolysaccharide via downregulation of interferon-beta production. AB - High-mobility group box 1 (HMGB1) is suggested to participate in development of local and systemic inflammatory disorders. Irbesartan (IRB), an angiotensin II type1 receptor blocker, is widely used for treatment of hypertension, especially in patients with diabetic nephropathy. The effect of IRB on lipopolysaccharide (LPS)-induced HMGB1 and nitric oxide (NO) production was examined using RAW 264.7 macrophage-like cells. IRB inhibited LPS-induced HMGB1 production. IRB also reduced LPS-induced expression of an inducible NO synthase, and inhibited LPS induced NO production. The expression levels of IFN-beta protein and mRNA, which is a key molecule in MyD88-independent pathway of LPS signaling, were exclusively inhibited by IRB. Peroxisome proliferator-activated receptor-gamma and angiotensin II type 1 receptor were not involved in the inhibitory action of IRB on LPS-induced HMGB1 and NO production. Collectively, IRB was suggested to inhibit LPS-induced HMGB1 production via downregulation of IFN-beta production in the MyD88-independent pathway. PMID- 25817179 TI - [Feedback of ultrasound and RMI in the staging of endometrial carcinoma in early stage]. AB - OBJECTIVES: Endometrial cancer is the most common gynecological cancer in France. The therapeutic management is based on preoperative staging. The recommended imaging examination remains the MRI. This is to evaluate ultrasound and MRI in the staging for localized cancers. METHODS: This is a retrospective observational study, conducted from July 2012 to July 2014, at the University Hospital of Nancy, on all patients care for endometrial cancer stage I, who underwent a pelvic ultrasound and MRI for the assessment of myometrial infiltration. RESULTS: Twenty-nine patients were included with a mean age of 69 years and a BMI of 30 kg/m(2). Using ultrasound, we have a sensitivity of 58%, a specificity of 100%, a positive predictive value (PPV) of 100%, a negative predictive value (NPV) of 70% and an accuracy of 75%. Using MRI, we have a sensitivity of 83%, a specificity of 100%, a PPV of 83%, a VPN of 88%, and an accuracy of 86%. CONCLUSION: Transvaginal sonography should be performed before post-menopausal bleeding. It remains possible in the staging of localized cancers. PMID- 25817180 TI - [Labor duration: from normality to dystocia]. AB - "Normal" labor has been surprisingly little studied in the past 60 years even though it is a central axis in obstetrics. Standards were proposed 60 years ago by Emmanuel Friedman and adopted by many countries to become then, driven from Dublin school, the conditions allowing the management of labor: rupture of membranes and oxytocin with, in case of failure for dynamic dystocia, cesarean. Recent data have suggested that labor duration had changed since the 1960s. Changes in women's characteristics and in obstetric practice especially with the widespread use of oxytocin and realization of epidural may have an impact on labor duration. Current studies suggest that it may be possible to authorize longer labor duration without significant increase in maternal or neonatal morbidity. However, it is premature to change practices following the latest American recommendations without prior studies. PMID- 25817181 TI - [Elective single embryo transfer policy at 48/72 h: which results after fresh transfers and frozen/thawed transfers?]. AB - OBJECTIVES: To evaluate our elective single embryo transfer policy performed at 48/72h and define predictive factors of pregnancy after frozen/thawed embryo transfer. METHODS: Analysis of 289 elective single embryo transfers (eSET) performed in a selected population in the ART center of Marseille University Hospital from January 2005 to December 2011, as well as the 325 following frozen/thawed embryo transfers performed in this population between May 2005 and December 2012. RESULTS: Cumulative pregnancy rate/oocyte retrieval was of 62.6%; 45% of the couples obtained the birth of at least one child. During this studied period, cumulative pregnancy and delivery rates in the whole population remained stable while multiple delivery rate/delivery clearly decreased. Elective single embryo after frozen/thawed transfer gave satisfying results (24.6% pregnancy/transfer) only in the lack of lysis or in case of mild lysis (1-25%) of the transferred embryo. CONCLUSION: The implementation of an eSET policy gives satisfying results, depending largely on embryo quality. By proposing eSET to a well-targeted population, chosen both on clinical and biological criteria, a clear reduction of cumulative multiple delivery rate/delivery was obtained in our center over this period, without any global decrease of cumulative pregnancy rate/attempt. Embryo quality is a major factor of success, especially in frozen/thawed cycles. The elective single embryo frozen/thawed transfer should be carried out only if embryo lysis after thawing does not exceed 25%. PMID- 25817182 TI - Oral health of children with type 1 diabetes mellitus: A systematic review. AB - AIM: This systematic review investigated the oral health status of children with type 1 diabetes. METHODS: A systematic search was conducted using PubMed/Medline, Web of Knowledge, SCOPUS and EMBASE. The search included all studies published from inception of database to January 2014. A total of 1179 abstracts were analyzed for selection in 2 phases. The first phase selection was based on the title and abstracts alone. The selected abstracts were then included for second phase, where full articles were obtained. The selection was carried out by 2 independent reviewers (Kappa value=0.809). Only 37 articles were included for final analysis in this review. RESULTS: There is conflicting evidence in the caries experience between children with type 1 diabetes and healthy children. For periodontal health, most studies reported significantly greater plaque accumulation and higher gingival index in children with type 1 diabetes. Cohort studies reported no significant differences in perioodontal parameters over time. CONCLUSIONS: There is conflicting evidence regarding the caries experience of children with type 1 diabetes, but they exhibit poorer periodontal health status with greater plaque accumulation compared to healthy children. Further studies are warranted to assess the oral health status of children with type 1 diabetes. PMID- 25817183 TI - Topical Administration of Tranexamic Acid Plus Diluted-Epinephrine in Primary Total Knee Arthroplasty: A Randomized Double-Blinded Controlled Trial. AB - The aim of this trial was to evaluate the efficacy and safety of intra-articular administration of tranexamic acid (TXA) plus diluted-epinephrine (DEP) on perioperative blood loss and transfusion in primary unilateral total knee arthroplasty (TKA) without drainage. One hundred patients scheduled to undergo TKA were randomized into two groups: 50 patients received intra-articular 3g TXA plus 0.25mg DEP (1:200,000), and 50 patients received 3g topical TXA alone. The results showed that topical combined administration significantly reduced total blood loss (P=0.006), hidden blood loss (P=0.000) and transfusion rate (0% vs. 4%), without increasing the risk of thromboembolic and hemodynamic complications (P>0.05). Therefore, topical TXA plus DEP was effective and safe in reducing blood loss and transfusion following TKA, without substantial complications. PMID- 25817184 TI - Intraoperative Purulence Is Not Reliable for Diagnosing Periprosthetic Joint Infection. AB - Purulence, defined as presence of pus, is based on subjective interpretation yet has been considered a definite sign of periprosthetic joint infection (PJI). 583 patients undergoing revision arthroplasty due to presumed PJI were retrospectively studied. PJI definition was independent of purulence, based on the definition of Musculoskeletal Infection Society recently modified by International Consensus Group on PJI. 498 patients fulfilled the criteria for definite PJI and 59 patients were deemed as aseptic. Purulence had sensitivity, specificity, positive and negative predictive values of 0.82, 0.32, 0.91, and 0.17, respectively. Purulence was not correlated with higher culture positivity yet was associated with higher synovial WBC counts (mean of 34.8 versus 5.2*10(3)/MUL in patients without purulence [P<0.001]). In the absence of objective definition for purulence and in light of its inadequate test characteristics compared to a multi-criteria definition, purulence cannot serve as a single absolute diagnostic criterion for PJI. LEVEL OF EVIDENCE: Level I, Diagnostic Studies. PMID- 25817185 TI - Postoperative Coronal Alignment After Total Knee Arthroplasty: Does Tailoring the Femoral Valgus Cut Angle Really Matter? AB - Postoperative alignment was measured in 80 TKA divided into 2 groups. Knees in the tailored group (n=40) were performed with a personalized valgus cut angle (VCA) based on preoperative hip-to-ankle (HTA) radiographs. The fixed group knees (n=40) were performed utilizing a 4 degrees VCA in valgus knees and obese patients, and 5 degrees in neutral and varus knees. There was no significant difference between groups in average preoperative mechanical alignment or average severity of preoperative deformity. There was no statistically significant difference between groups in postoperative mechanical alignment (tailored: 2.6 degrees ; fixed: 1.3 degrees ; P=0.08) or severity of residual deformity (tailored: 3.5 degrees ; fixed: 2.6 degrees ; P=0.10). Accuracy of the tibial cut angle (TCA) and severity of the preoperative deformity were strong independent predictors of postoperative alignment (R(2)=58% and R(2)=33%, respectively). PMID- 25817186 TI - Bacterial Contamination in Tips of Electrocautery Devices During Total Hip Arthroplasty. AB - Surgical equipment can become contaminated during surgery. It is unknown if electrocautery tips can become contaminated in clean orthopedic procedures despite the produced heat. Therefore, we conducted a prospective study to address this concern. The tips from 25 primary and 25 aseptic revision THAs were collected and an additional 5 sterile tips served as negative controls. Aerobic and anaerobic cultures were incubated for a minimum of 3 days. There were 3 positive cultures (6%); one in primary THA (4%) with Lactobacillus and Enterococcus faecalis; two among revisions (8%), one with E. faecalis and another one with alpha hemolytic streptococci and coagulase negative Staphylococcus. The mean exposure time of the contaminated tips was 132.3 minutes. Patients were followed for 90 days postoperatively and none of them developed surgical site infection. This is the first study to demonstrate that electrosurgical devices can become contaminated during THA in laminar flow equipped operating rooms. PMID- 25817187 TI - Corrosion and Fretting of a Modular Hip System: A Retrieval Analysis of 60 Rejuvenate Stems. AB - Femoral stems with dual-taper modularity were introduced to allow independent control of length, offset, and version. Corrosion and fretting related to micromotion at the neck-stem junction are thought to stimulate an adverse local tissue reaction (ALTR). Analysis of 60 consecutively retrieved modular-neck stem implants (Rejuvenate, Stryker) revised primarily for ALTR was done to determine the variables influencing corrosion and fretting patterns at the neck-stem interface. Taper damage evaluation was performed with stereomicrocopic analysis with two observers. Evidence of fretting and corrosion was seen at the neck-stem taper in all implants, including three implants revised for periprosthetic fractures within four weeks of the index surgery indicating that this process starts early. Femoral stems paired with the long overall neck lengths had significantly higher corrosion scores. Correlation of the corrosion severity at particular locations with the length of implantation suggests that the neck-stem junction experiences cyclic cantilever bending in vivo. The positive correlation between the length of implantation and fretting/corrosion scores bodes poorly for patients who still have this implant. Scanning electron microscopy on a subset of specimens was also performed to evaluate the black corrosion material. We strongly urge frequent follow-up exams for every patient with this particular modular hip stem. PMID- 25817188 TI - Variations In Good Patient Reported Outcomes After Total Knee Arthroplasty. AB - This study identifies optimal OKS values that discriminate post-operative (TKA) patient satisfaction and determines the variation in threshold values by patient characteristics and expectations. It is the first to identify patient improvement using measures (PoPC) that account for patient's pre-operative symptom severity. Of 365 primary TKA patients from a London district general hospital 84% were satisfied at 12 and 24 months. Whilst the overall OKS thresholds (follow-up, change, PoPC) were stable at 12 months (31, 11, 39.7%) and 24 months (35, 12, 38.9%), patients who were older (>=75years), were underweight/normal (BMI<25), had pre-operative symptom severity (OKS<=15) and expected no pain post-surgery, required a greater (potential) improvement to be classed as satisfied. When reporting good patient outcomes, cohorts should be stratified accordingly. PMID- 25817189 TI - All-arthroscopic suprapectoral versus open subpectoral tenodesis of the long head of the biceps brachii. AB - BACKGROUND: Pathologic changes of the long head of the biceps tendon are a recognized source of shoulder pain in adults that can be treated with tenotomy or tenodesis when nonoperative measures are not effective. It is not clear whether arthroscopic or open biceps tenodesis has a clinical advantage. HYPOTHESIS: Pain relief and shoulder function after all-arthroscopic suprapectoral biceps tenodesis are similar to outcomes after an open subpectoral tenodesis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A prospective database was reviewed for patients undergoing an all-arthroscopic suprapectoral or open subpectoral biceps tenodesis. Adult patients with a minimum 18-month follow-up were included. Patients undergoing a concomitant rotator cuff or labral repair were excluded. The groups were matched to age within 3 years, sex, and time to follow-up within 3 months. Pain improvement, development of a "Popeye" deformity, muscle cramping, postoperative American Shoulder and Elbow Surgeons scores, satisfaction scores, and complications were evaluated. RESULTS: Forty-six patients (23 all-arthroscopic, 23 open) with an average age of 57.2 years (range, 45-70 years) were evaluated at a mean follow-up of 30.1 months (range, 21.1-44.9 months). No patients in either group developed a Popeye deformity or complained of arm cramping. There was no significant difference in mean American Shoulder and Elbow Surgeons scores between the open and all-arthroscopic groups (92.3 vs 88.9; P=.42); similarly, there was no significant difference in patient satisfaction scores between the groups (8.9 vs 9.1; P=.73). Eighteen patients (78.3%) in the arthroscopic cohort and 16 (69.6%) in the open cohort fully returned to athletic activity (P=.50). Eight patients (34.8%) in the arthroscopic group and 10 (39.1%) in the open group reported pain at night or with heavy activities. There were no complications in the all-arthroscopic group. There were 2 complications in the open group that resolved by final follow-up. CONCLUSION: Biceps tenodesis remains a reliable treatment for pathologic abnormality of the long head of the biceps. Patients undergoing an all-arthroscopic suprapectoral tenodesis in the distal aspect or distal to the bicipital groove showed similar pain relief and clinical outcomes as compared with patients undergoing open subpectoral tenodesis. Open subpectoral biceps tenodesis may carry a higher complication risk secondary to a more invasive technique. PMID- 25817190 TI - Fresh osteochondral allografts in the knee: comparison of primary transplantation versus transplantation after failure of previous subchondral marrow stimulation. AB - BACKGROUND: In most treatment algorithms, osteochondral allograft (OCA) transplantation is regarded as an alternative salvage procedure when other, previous reparative treatments have failed. PURPOSE: To compare the outcomes of a retrospective matched-pair cohort of (1) primary OCA transplantation and (2) OCA transplantation after failure of previous subchondral marrow stimulation. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: An OCA database was used to identify 46 knees that had OCA transplantation performed as a primary treatment (group 1) and 46 knees that underwent OCA transplantation after failure of previous subchondral marrow stimulation (group 2). All patients had a minimum of 2 years' follow-up. Patients in each group were matched for age (+/-5 years), diagnosis (osteochondral lesion, degenerative chondral lesion, traumatic chondral injury), and graft size (small, <5 cm2; medium, 5-10 cm2; large, >10 cm2). The groups had similar body mass indexes, sex distributions, and graft locations (femoral condyle, patella, and trochlea. The number and type of further surgeries after the OCA transplantation were assessed; failure was defined as any reoperation resulting in removal of the graft. Functional outcomes were evaluated by use of the modified Merle d'Aubigne-Postel (18-point) scale, International Knee Documentation Committee (IKDC) subjective knee evaluation form, Knee injury and Osteoarthritis Outcomes Score (KOOS), and the Knee Society function (KS-F) scale. Patient satisfaction, according to a 5-point scale from "extremely satisfied" to "dissatisfied," was recorded at the latest follow-up. RESULTS: Eleven of 46 knees (24%) in group 1 had reoperations, compared with 20 of 46 knees (44%) in group 2 (P = .04). The OCA was classified as a failure in 5 knees (11%) in group 1 and 7 knees (15%) in group 2 (P = .53). At 10 years of follow up, survivorship of the graft was 87.4% and 86% in groups 1 and 2, respectively. Both groups showed improvement in pain and function on all subjective scores from preoperatively to the latest follow-up (all P < .001). Results showed that 87% of patients in group 1 and 97% in group 2 were "satisfied" or "extremely satisfied" with the OCA transplantation. CONCLUSION: Favorable results were shown in both groups with significant improvement of functional scores and excellent survivorship. Despite the higher reoperation rate in the previously treated group, previous subchondral marrow stimulation did not adversely affect the survivorship and functional outcome of OCA transplantation. PMID- 25817191 TI - The adventures of a rogue cell. PMID- 25817192 TI - The curious incident of the translational dog that didn't bark. AB - There is a general assumption that it is now time for more translational research and less basic research. Science policy leaders have sent mixed signals and the community has responded by submitting more grant applications focused on translational or applied research. Nothing could be more treacherous, because to develop innovative therapies we must more fully understand the complexities of biology, a goal requiring more, not less, basic science. PMID- 25817194 TI - Breast cancer, heart disease, and whispering "fire" in a public theater. PMID- 25817193 TI - Serum lipids, lipoproteins, and risk of breast cancer: a nested case-control study using multiple time points. AB - BACKGROUND: There is strong evidence that breast cancer risk is influenced by environmental factors. Blood lipid and lipoprotein levels are also influenced by environmental factors and are associated with some breast cancer risk factors. We examined whether serial measures of serum lipids and lipoproteins were associated with breast cancer risk. METHODS: We carried out a nested case-control study within a randomized long-term dietary intervention trial with 4690 women with extensive mammographic density followed for an average of 10 years for breast cancer incidence. We measured lipids in an average of 4.2 blood samples for 279 invasive breast cancer case subjects and 558 matched control subjects. We calculated subaverages of lipids for each subject based on menopausal status and use of hormone replacement therapy (HRT) at blood collection and analyzed their association with breast cancer using generalized estimating equations. All statistical tests were two-sided. RESULTS: High-density lipoprotein-cholesterol (HDL-C) (P = .05) and apoA1 (P = .02) levels were positively associated with breast cancer risk (75(th) vs 25(th) percentile: HDL-C, 23% higher; apoA1, 28% higher) and non-HDL-C (P = .03) and apoB (P = .01) levels were negatively associated (75(th) vs 25(th) percentile: non-HDL-C, 19% lower; apoB, 22% lower). These associations were observed only when lipids were measured when HRT was not used. Total cholesterol and triglyceride levels were not statistically significantly associated with breast cancer risk. CONCLUSIONS: These results demonstrate that serum lipids are associated with breast cancer risk in women with extensive mammographic density. The possibility that interventions for heart disease prevention, which aim to reduce non-HDL-C or raise HDL-C, may have effects on breast cancer risk merits examination. PMID- 25817195 TI - Induction of apoptosis by parthenolide in human oral cancer cell lines and tumor xenografts. AB - OBJECTIVES: Parthenolide (PTL), a representative sesquiterpene lactone that is responsible for medicinal properties of the feverfew, is known to modulate diverse intracellular signaling pathways, thereby exerting the tumor growth inhibitory effects. In this study, authors attempted to examine the pro-apoptotic effects and possible biochemical mechanisms of PTL in human oral cancer cell lines and tumor xenografts. MATERIAL AND METHODS: The apoptotic effects and related molecular mechanisms of PTL on oral cancer were evaluated using cell viability assay, MTS assay, DAPI staining, western blot analysis, reverse transcriptase-polymerase chain reaction, small interfering RNA transfection and nude mouse xenograft assay. RESULTS: PTL treatment increased the cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP), and the nuclear fragmentation in a concentration- or time-dependent manner. PTL treatment increased Bim protein expression by enhancing the Bim mRNA expression as well as stabilizing Bim protein level. PTL treatment also induced the translocation of cytosolic Bim into the mitochondria and, more importantly, PTL-induced apoptosis was significantly attenuated, when the Bim expression was knockdown by siRNA transfection. PTL treatment also induced death receptor 5 (DR5) protein expression and this event was closely correlated with an increase in the cleavage of caspase-8 and formation of truncation of Bid (t-Bid). Finally, PTL shrunk tumor size and volume resulting from apoptotic cell death by increasing Bim and DR5 whereas there were no abnormal histopathological findings in normal organs. CONCLUSION: This study proposes that PTL is a strong apoptotic inducer that deserves the further investigations for potential chemotherapeutic agent of human oral cancers. PMID- 25817196 TI - Effects of dispersal on total biomass in a patchy, heterogeneous system: Analysis and experiment. AB - An intriguing recent result from mathematics is that a population diffusing at an intermediate rate in an environment in which resources vary spatially will reach a higher total equilibrium biomass than the population in an environment in which the same total resources are distributed homogeneously. We extended the current mathematical theory to apply to logistic growth and also showed that the result applies to patchy systems with dispersal among patches, both for continuous and discrete time. This allowed us to make specific predictions, through simulations, concerning the biomass dynamics, which were verified by a laboratory experiment. The experiment was a study of biomass growth of duckweed (Lemna minor Linn.), where the resources (nutrients added to water) were distributed homogeneously among a discrete series of water-filled containers in one treatment, and distributed heterogeneously in another treatment. The experimental results showed that total biomass peaked at an intermediate, relatively low, diffusion rate, higher than the total carrying capacity of the system and agreeing with the simulation model. The implications of the experiment to dynamics of source, sink, and pseudo-sink dynamics are discussed. PMID- 25817197 TI - Genomic architecture of asthma differs by sex. AB - Asthma comprised of highly heterogeneous subphenotypes resulting from complex interplay between genetic and environmental stimuli. While much focus has been placed on extrinsic environmental stimuli, intrinsic environment such as sex can interact with genes to influence asthma risk. However, few studies have examined sex-specific genetic effects. The overall objective of this study was to evaluate if sex-based differences exist in genomic associations with asthma. We tested 411 asthmatics and 297 controls for presence of interactions and sex-stratified effects in 51 genes using both SNP and gene expression data. Logistic regression was used to test for association. Over half (55%) of the genetic variants identified in sex-specific analyses were not identified in the sex-combined analysis. Further, sex-stratified genetic analyses identified associations with significantly higher median effect sizes than sex-combined analysis for girls (p value=6.5E-15) and for boys (p-value=1.0E-7). When gene expression data were analyzed to identify genes that were differentially expressed in asthma versus non-asthma, nearly one third (31%) of the probes identified in the sex-specific analyses were not identified in the sex-combined analysis. Both genetic and gene expression data suggest that the biologic underpinnings for asthma may differ by sex. Failure to recognize sex interactions in asthma greatly decreases the ability to detect significant genomic variation and may result in significant misrepresentation of genes and pathways important in asthma in different environments. PMID- 25817198 TI - Properties of the indole ring in metal complexes. A comparison with the phenol ring. AB - Tryptophan (Trp), an essential amino acid, has an indole ring with a high electron density and is frequently seen at the proximal position of the metal site in metalloproteins. For example, the indole ring of Trp has been reported to interact weakly with Cu(I) in a Cu chaperone CusF. Another aromatic amino acid, tyrosine (Tyr), has a phenol ring, which is an important metal binding site in various metalloproteins. Although the structures of the aromatic rings are different, they both have a weakly acidic moiety and perform some similar roles in biological systems, such as radical formation and electron transfer. In this review, we focus on these and other properties of the indole and phenol rings in metal-containing systems. PMID- 25817199 TI - Expression and regulation of scavenger receptor class B type 1 in the rat ovary and uterus during the estrous cycle. AB - Scavenger receptor class B type 1 (SR-B1) preferentially mediates the selective uptake of high density lipoprotein-cholesterol ester and the delivery of cholesterol for steroidogenesis. Although multiple analyses have investigated the function of SR-B1 in the liver, adrenal and ovary, its expression in rat ovary and uterus during the estrous cycle is lacking. In the present study, real-time PCR, western blot and immunohistochemistry (IHC) were used to investigate SR-B1 expression in the rat ovary and uterus during the estrous cycle. The results demonstrated that ovarian SR-B1 expression was in a stage-dependent manner, continuously increased from proestrus and kept elevated during metoestrus, while uterine SR-B1 expression decreased from proestrus to diestrus. To determine whether ovarian and uterine SR-B1 expression were affected by sex steroid hormones, immature rats were treated with 17 beta-estradiol (E2), progesterone (P4), or their antagonists from postnatal days 24-26. Results showed that the levels of SR-B1 mRNA and protein were significantly up-regulated by E2 in both the ovary and uterus. IHC results showed that SR-B1 was primarily localized in the oocytes, theca internal cells (T-I) of follicles, interstitial cells (IC) as well as corpus luteum (CL), but not granulosa cells (GC) in the ovary during the estrous cycle. Uterine SR-B1 was highly expressed in the endometrial luminal epithelial cells (LEC) and glandular epithelial cells (GEC) as well as in the circular muscle (CM) cells, and weak staining in stromal cells (SC) through estrous cycle. Taken together, SR-B1 expression in the ovary and uterus across the estrous cycle demonstrate that SR-B1 may be involved in uterine function, follicular development as well as luteal function. PMID- 25817200 TI - Comparison of airway intubation devices when using a biohazard suit: a feasibility study. AB - OBJECTIVES: We set out to compare emergency medicine residents' intubating times and success rates for direct laryngoscopy (DL), GlideScope-assisted intubation (GS), and the Supraglottic Airway Laryngopharyngeal Tube (SALT) airway with and without biohazard gear. METHODS: Each resident passed through 2 sets of 3 testing stations (DL, GS, SALT) in succession, intubating Laerdal mannequin heads with the 3 modalities after randomization to start with or without biohazard gear. RESULTS: Thirty-seven residents participated, and 27 were male (73%); 14 (37.8%) had prior experience intubating in biohazard suits. There was a statistically significant difference in those who had prior intubation experience between DL (37, 100%), GS (32, 86.5%), and SALT (12, 32.4%) (P < .001) and in median time to intubation (48 seconds, no suit; 57 seconds, with suits) (P = .03). There was no statistically significant difference between the overall times to intubate for the 3 devices. First-pass success was highest for DL (91.2%, no suit; 83.7%, suit) followed by GS (89%, no suit; 78.3%, suit) and SALT (51%, no suit; 67.6%, suit). CONCLUSION: A minority of participants had prior experience intubating in biohazard suits. Use of biohazard suits extends time to successful intubation. There was no difference in time to intubation for the 3 devices, but first-pass success was highest for DL (with or without biohazard gear). PMID- 25817201 TI - Intracranial hematoma and midline shift detected by transcranial color-coded duplex sonography. PMID- 25817202 TI - The utility of transvaginal ultrasound in the ED evaluation of complications of first trimester pregnancy. AB - BACKGROUND: For patients with early intrauterine pregnancy (IUP), the sonographic signs of the gestation may be below the resolution of transabdominal ultrasound (TAU); however, it may be identified by transvaginal ultrasound (TVU). We sought to determine how often TVU performed in the emergency department (ED) reveals a viable IUP after a nondiagnostic ED TAU and the impact of ED TVU on patient length of stay (LOS). METHODS: This was a retrospective cohort study of women presenting to our ED with complications of early pregnancy from January 1, 2007 to February 28, 2009 in a single urban adult ED. Abstractors recorded clinical and imaging data in a database. Patient imaging modality and results were recorded and compared with respect to ultrasound (US) findings and LOS. RESULTS: Of 2429 subjects identified, 795 required TVU as part of their care. Emergency department TVU was performed in 528 patients, and 267 went to radiology (RAD). Emergency department TVU identified a viable IUP in 261 patients (49.6%). Patients having initial ED US had shorter LOS than patients with initial RAD US (median 4.0 vs 6.0 hours; P < .001). Emergency department LOS was shorter for women who had ED TVU performed compared with those sent for RAD TVU regardless of the findings of the US (median 4.9 vs 6.7 hours; P < .001). There was no increased LOS for patients who needed further RAD US after an indeterminate ED TVU (7.0 vs 7.1 hours; P = .43). There was no difference in LOS for those who had a viable IUP confirmed on ED TAU vs ED (median 3.1 vs 3.2 hours, respectively; P < .32). CONCLUSION: When an ED TVU was performed, a viable IUP was detected 49.6% of the time. Emergency department LOS was significantly shorter for women who received ED TVU after indeterminate ED TAU compared with those sent to RAD for TVU, with more marked time savings among those with live IUP diagnosed on ED TVU. For patients who do not receive a definitive diagnosis of IUP on ED TVU, this approach does not result in increased LOS. PMID- 25817204 TI - Lipoprotein-induced phenoloxidase-activity in tarantula hemocyanin. AB - Phenoloxidases play vital roles in invertebrate innate immune reactions, wound closure and sclerotization processes in arthropods. In chelicerates, where phenoloxidases are lacking, phenoloxidase-activity can be induced in the oxygen carrier hemocyanin in vitro by proteolytic cleavage, incubation with the artificial inducer SDS, or lipids. The role of protein-protein interaction has up to now received little attention. This is remarkable, as lipoproteins - complexes of proteins and lipids - are present at high concentrations in arthropod hemolymph. We characterized the three lipoproteins present in tarantula hemolymph, two high-density lipoproteins and one very high-density lipoprotein, and show that the two high-density lipoproteins have distinct structures: the more abundant high-density lipoprotein is an ellipsoid particle with axes of ~22.5 nm and ~16.8 nm, respectively. The second high-density lipoprotein, present only in trace amount, is a large discoidal lipoprotein with a diameter of ~38.4 nm and an on-edge thickness of ~7.1 nm. We further demonstrate that the interaction between lipoproteins and hemocyanin induces phenoloxidase activity in hemocyanin, and propose that this activation is due to protein-protein interaction rather than protein-lipid interaction, as neither lipid micelles nor lipid monomers were found to be activating. Activation was strongest in the presence of high-density lipoproteins; very high-density lipoproteins were found to be non-activating. This is the first time that the ability of lipoproteins to induce phenoloxidase activity of hemocyanin has been demonstrated, thus adding novel aspects to the function of lipoproteins apart from their known role in nutrient supply. PMID- 25817203 TI - Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. AB - Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI 463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification. PMID- 25817205 TI - The MARK-AGE phenotypic database: Structure and strategy. AB - In the context of the MARK-AGE study, anthropometric, clinical and social data as well as samples of venous blood, buccal mucosal cells and urine were systematically collected from 3337 volunteers. Information from about 500 standardised questions and about 500 analysed biomarkers needed to be documented per individual. On the one hand handling with such a vast amount of data necessitates the use of appropriate informatics tools and the establishment of a database. On the other hand personal information on subjects obtained as a result of such studies has, of course, to be kept confidential, and therefore the investigators must ensure that the subjects' anonymity will be maintained. Such secrecy obligation implies a well-designed and secure system for data storage. In order to fulfil the demands of the MARK-AGE study we established a phenotypic database for storing information on the study subjects by using a doubly coded system. PMID- 25817206 TI - MARK-AGE standard operating procedures (SOPs): A successful effort. AB - Within the MARK-AGE project, a population study (3337 subjects) was conducted to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any single marker. The MARK-AGE project involves 14 European countries and a total of 26 research centres. In such a study, standard operating procedures (SOPs) are an essential task, which are binding for all MARK-AGE Beneficiaries. The SOPs cover all aspects of subject's recruitment, collection, shipment and distribution of biological samples (blood and its components, buccal mucosa cells or BMC and urine) as well as the anthropometric measurements and questionnaires. PMID- 25817207 TI - Physical activity and subjective well-being: the role of time. AB - This study examines the role of time in explaining the effect of physical activity on subjective well-being. Specifically, it looks at the composite structure of time needed for participation in a time-efficient fitness programme and how different time components affect satisfaction with health, leisure time, fitness, body and look. This quasi-experimental study consisted of three stages: (i) physical entry test and pre-survey, (ii) training intervention (30 min; performed twice a week over a 4-week period) and (iii) exit test and post-survey. A total of N = 10 481 individuals participated across 316 German fitness centres. Regression results show that total time spent significantly increases satisfaction with health and fitness. Time spent on approach and parking reduces satisfaction with leisure time, while time spent on wellness and showering increases it. Spending time in the bistro increases satisfaction with health and fitness. Time spent on the actual fitness training has no significant effect on either satisfaction measure. The findings indicate that it is important to consider the composite structure of time needed for physical activity because other activities matter more than the actual time spent on exercising. Public health policies and policy makers should therefore support such time-efficient programmes. PMID- 25817208 TI - Multiple anthropometric measures in relation to incidence of diabetes: a Swedish population-based cohort study. AB - BACKGROUND: Obesity is the major modifiable risk factor for diabetes. This study investigated the incidence of diabetes in relation to multiple anthropometric measures. METHODS: Body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), waist-hip ratio (WHR) and body fat percentage (BF %) were measured among 26,604 subjects (aged 45-73 years) without history of diabetes from the Malmo Diet and Cancer cohort. RESULTS: During 14 years of follow-up, 2935 subjects (1519 men, 1416 women) were diagnosed with diabetes. In men, incidence of diabetes was 24.1 and 4.0 per 1000 person-years comparing the fourth vs. first quartile of WHtR. The multivariate adjusted hazard ratios (HR; fourth vs first quartile) were 6.00 [95% confidence interval (CI): 5.02-7.16) for WHtR, 5.95 (CI: 4.96-7.14) for WC, 5.19 (CI: 4.38-6.15) for BMI, 4.71 (CI: 3.96-5.60) for WHR and 3.21 (CI: 2.75-3.76] for BF%. For women, incidence of diabetes was 15.1 and 1.4 per 1000 person-years for fourth vs first quartile of WHtR (HR: 10.19, CI: 8.10 12.82). HR was 9.16 (CI: 7.40-11.33) for WC, 6.42 (CI: 5.27-7.81) for BMI, 6.75 (CI: 5.52-8.25) for WHR and 5.39 (CI: 4.42-6.57) for BF%. Model discrimination was marginally increased when WC, WHtR or WHR was used in combination with BMI. CONCLUSION: All measures of obesity were associated with substantially increased incidence of diabetes. Abdominal obesity was associated with higher incidence rates in men than in women, but in terms of relative risks the relationships were stronger in women. The combination of BMI and abdominal obesity measures had stronger association with diabetes than BMI alone. PMID- 25817209 TI - Impact of living alone on institutionalization and mortality: a population-based longitudinal study. AB - BACKGROUND: Living alone is common among elderly people in Western countries, and studies on its relationship with institutionalization and all-cause mortality have shown inconsistent results. We investigated that the impact of living alone on institutionalization and mortality in a population-based cohort of elderly people. METHODS: Data originate from the Swedish National study on Aging and Care Kungsholmen. Participants aged >=66 years and living at home (n = 2404) at baseline underwent interviews and clinical examination. Data on living arrangements were collected in interviews. All participants were followed for 6 years; survival status and admission into institutions were tracked continuously through administrative registers from 2001 to 2007. Data were analysed using Cox proportional hazard models, competing risk regressions and Laplace regressions with adjustment for potential confounders. RESULTS: Of the 2404 participants, 1464 (60.9%) lived alone at baseline. During the follow-up, 711 (29.6%) participants died, and 185 (15.0%) were institutionalized. In the multi-adjusted Cox model, the hazard ratio (HR) of mortality in those living alone was 1.35 (95% confidence interval [CI] 1.18 to 1.54), especially among men (HR = 1.44, 95% CI 1.18 to 1.76). Living alone shortened survival by 0.6 years and was associated with the risk of institutionalization (HR = 1.74, 95% CI 1.10 to 2.77) after taking death into account as a competing risk. CONCLUSIONS: Living alone is associated with elevated mortality, especially among men and an increased risk of institutionalization. Over a 6-year period, living alone was related to a half year reduction in survival among elderly people in Sweden. PMID- 25817210 TI - Identification and elimination of metabolic bottlenecks in the quinone modification pathway for enhanced coenzyme Q10 production in Rhodobacter sphaeroides. AB - In this report, UbiE and UbiH in the quinone modification pathway (QMP) were identified in addition to UbiG as bottleneck enzymes in the CoQ10 biosynthesis by Rhodobacter sphaeroides. The CoQ10 content was enhanced after co-overexpression of UbiE and UbiG, however, accompanied by the accumulation of the intermediate 10P-MMBQ. UbiH was then co-overexpressed to pull the metabolic flux towards downstream, resulting in an elevated CoQ10 productivity and decreased biomass. On the other hand, the expression levels of UbiE and UbiG were tuned to eliminate the intermediate accumulation, however at the sacrifice of productivity. To alleviate the detrimental effect on either productivity or cell growth, we tried to fuse UbiG with UbiE and localize them onto the membrane to elevate intermediate conversion. By fusing UbiE and UbiG to pufX, CoQ10 was accumulated to 108.51+/-2.76mg/L with a biomass of 12.2+/-0.9g/L. At last, we combined the optimized QMP and the previously engineered 2-methyl-d-erythritol-4-phosphate pathway (MEP) to further boost CoQ10 biosynthesis, resulting in a strain with 138+/-2.64mg/L CoQ10 production. PMID- 25817211 TI - Review: Properties of sperm and seminal fluid, informed by research on reproduction and contraception. AB - Forensic DNA testing is grounded in molecular biology and population genetics. The technologies that were the basis of restriction length polymorphism testing (RFLP) have given way to PCR based technologies. While PCR has been the pillar of short tandem repeat (STR) methods and will continue to be used as DNA sequencing and analysis of single nucleotide polymorphisms (SNPs) are introduced into human identification, the molecular biology techniques in use today represent significant advances since the introduction of STR testing. Large forensic laboratories with dedicated research teams and forensic laboratories which are part of academic institutions have the resources to keep track of advances which can then be considered for further research or incorporated into current testing methods. However, many laboratories have limited ability to keep up with research advances outside of the immediate area of forensic science and may not have access to a large university library systems. This review focuses on filling this gap with respect to areas of research that intersect with selected methods used in forensic biology. The review summarizes information collected from several areas of the scientific literature where advances in molecular biology have produced information relevant to DNA analysis of sexual assault evidence and methods used in presumptive and confirmatory identification of semen. Older information from the literature is also included where this information may not be commonly known and is relevant to current methods. The topics selected highlight (1) information from applications of proteomics to sperm biology and human reproduction, (2) seminal fluid proteins and prostate cancer diagnostics, (3) developmental biology of sperm from the fertility literature and (4) areas where methods are common to forensic analysis and research in contraceptive use and monitoring. Information and progress made in these areas coincide with the research interests of forensic biology and cross-talk between these disciplines may benefit both. PMID- 25817212 TI - Micro-computed Tomographic Assessment on the Effect of ProTaper Next and Twisted File Adaptive Systems on Dentinal Cracks. AB - INTRODUCTION: The aim of the present study was to evaluate the frequency of dentinal microcracks observed after root canal preparation with ProTaper Next (PTN; Dentsply Maillefer, Ballaigues, Switzerland) and Twisted File Adaptive (TFA; SybronEndo, Orange, CA) systems through micro-computed tomographic analysis. METHODS: Twenty moderately curved mesial roots of mandibular molars presenting a type II Vertucci canal configuration were randomly assigned to 2 experimental groups (n = 10) according to the system used for the root canal preparation: PTN or TFA systems. The specimens were scanned through high resolution micro-computed tomographic imaging before and after root canal preparation. Afterward, pre- and postoperative cross-sectional images of the mesial roots (N = 25,820) were screened to identify the presence of dentinal defects. RESULTS: Dentinal microcracks were observed in 38.72% (n = 5150) and 30.27% (n = 3790) of the cross-sectional images in the PTN and TFA groups, respectively. All dentinal defects identified in the postoperative scans were already present in the corresponding preoperative images. CONCLUSIONS: Root canal preparation with PTN and TFA systems did not induce the formation of new dentinal microcracks. PMID- 25817213 TI - Effect of Time Lapse between Endodontic and Periodontal Therapies on the Healing of Concurrent Endodontic-Periodontal Lesions without Communication: A Prospective Randomized Clinical Trial. AB - INTRODUCTION: The aim of this prospective randomized clinical trial was to evaluate the effect of a time lapse between endodontic treatment and nonsurgical periodontal treatment on periodontal healing of concurrent endodontic-periodontal lesions without communication. METHODS: Thirty-one patients were randomly divided into 2 groups: group 1: endodontic treatment and scaling and root planning (SRP) were performed simultaneously and group 2: SRP was performed 3 months after endodontic treatment. Both groups were followed for 3 and 6 months after SRP. Primary outcome variables were the probing depth, clinical attachment level, and periapical index score. RESULTS: Both the groups showed a significant improvement in all the clinical parameters evaluated after the completion of endodontic and periodontal treatment (P < .05). No statistically significant difference in improvement was observed between the 2 groups at 3 and 6 months after SRP (P > .05). Periodontal healing responses were comparable in the 2 groups, with no apparent detriment resulting from simultaneous treatment. Improvements in periodontal parameters that were achieved in 6 months in group 2 were achieved only in 3 months in group 1 (P > .05). CONCLUSIONS: Nonsurgical periodontal treatment may be performed simultaneously with endodontic treatment in the management of concurrent endodontic-periodontal lesions without communication, and an observation period after endodontic treatment may not be required. PMID- 25817214 TI - PEP-1-FK506BP inhibits alkali burn-induced corneal inflammation on the rat model of corneal alkali injury. AB - FK506 binding protein 12 (FK506BP) is a small peptide with a single FK506BP domain that is involved in suppression of immune response and reactive oxygen species. FK506BP has emerged as a potential drug target for several inflammatory diseases. Here, we examined the protective effects of directly applied cell permeable FK506BP (PEP-1-FK506BP) on corneal alkali burn injury (CAI). In the cornea, there was a significant decrease in the number of cells expressing pro inflammation, apoptotic, and angiogenic factors such as TNF-alpha, COX-2, and VEGF. Both corneal opacity and corneal neovascularization (CNV) were significantly decreased in the PEP-1-FK506BP treated group. Our results showed that PEP-1-FK506BP can significantly inhibit alkali burn-induced corneal inflammation in rats, possibly by accelerating corneal wound healing and by reducing the production of angiogenic factors and inflammatory cytokines. These results suggest that PEP-1-FK506BP may be a potential therapeutic agent for CAI. PMID- 25817215 TI - Fluorescent and Bioluminescent Nanoprobes for In Vitro and In Vivo Detection of Matrix Metalloproteinase Activity. AB - Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade the extracellular matrix (ECM) and regulate the extracellular microenvironment. Despite the significant role that MMP activity plays in cell-cell and cell-ECM interactions, migration, and differentiation, analyses of MMPs in vitro and in vivo have relied upon their abundance using conventional immunoassays, rather than their enzymatic activities. To resolve this issue, diverse nanoprobes have emerged and proven useful as effective activity-based detection tools. Here, we review the recent advances in luminescent nanoprobes and their applications in in vitro diagnosis and in vivo imaging of MMP activity. Nanoprobes with the purpose of sensing MMP activity consist of recognition and detection units, which include MMP-specific substrates and luminescent (fluorescent or bioluminescent) nanoparticles, respectively. With further research into improvement of the optical performance, it is anticipated that luminescent nanoprobes will have great potential for the study of the functional roles of proteases in cancer biology and nanomedicine. PMID- 25817216 TI - Treatment: special conditions: co-existing vascular disease: stroke. PMID- 25817217 TI - Rationale for a single-pill combination of perindopril arginine and amlodipine besylate. AB - A systematic review identified 86 outcome-based clinical trials involving perindopril, amlodipine, or other antihypertensive drugs. In fixed-effects meta analyses of 11 clinical trials (90,208 subjects), amlodipine was associated with a significant 24% increase in heart failure, but a significant decrease in death, cardiovascular death, stroke, coronary heart disease, and first major cardiovascular adverse event. In five clinical trials (52,565 subjects), perindopril was associated with a significant reduction in all six cardiovascular endpoints. Network and Bayesian meta-analyses suggested that (with the exception of amlodipine and heart failure), each agent was at least as effective as an initial diuretic to prevent these events. Short-term trials have demonstrated that the combination of perindopril and amlodipine is safe and effective, with statistically greater lowering of blood pressure than either agent alone and a potential synergistic effect on pedal edema. The single-pill combination of perindopril and amlodipine may be a useful addition to the antihypertensive armamentarium. PMID- 25817218 TI - Antibacterial behaviour of Vitex negundo extract assisted ZnO nanoparticles against pathogenic bacteria. AB - The biological routes are advantageous over the chemical and physical ones as unlike. These, the biological synthesis protocol occurs at ambient conditions, are cheap, non-toxic and eco-friendly. This research describes the synthesis of zinc oxide nanoparticles (ZnO NPs) using Vitex negundo plant extract with zinc nitrate hexahydrate as precursor. Biomolecules present in plant extract can be used to hydrolyze metal ions into metal oxide NPs in a single-step green synthesis. The hydrolyzing agents involved the various water soluble plant metabolites such as flavonoid, alkaloids, flavone, phenolic compounds, terpenoids and co-enzymes. Presence of isoorientin (flavone) in V. negundo plant extract is mainly responsible for the formation of ZnO NPs. The prepared ZnO NPs were calcinated at 450 degrees C and were confirmed by XRD, FT-IR, UV-visible, SEM with EDX and DLS analysis. The biological application of antibacterial activity was done by gram positive and gram negative bacteria. PMID- 25817219 TI - Characterization of novel entecavir resistance mutations. AB - BACKGROUND & AIMS: Entecavir (ETV) is approved for the treatment of chronic hepatitis B virus (HBV) infections, but the virus can acquire resistance to the drug. This requires lamivudine resistance mutations (LAMr) and at least one additional mutation. Here, we characterized two novel mutations, rtI163V and rtA186T, associated with viral breakthrough (VBT) in an ETV-refractory patient. METHODS: HBV from an ETV-refractory patient was sequenced, and newly identified mutations were inserted into a replication-competent clone by mutagenesis. Clones were analyzed for replication efficacy and susceptibility to ETV in vitro. Chimeric mice with human hepatocytes were inoculated with the patient's serum at VBT, and monitored for viral mutation pattern using a next-generation sequencing approach. RESULTS: RtI163V and rtA186T mutations were detected together with LAMr (rtL180M and rtM204V) at VBT. RtA186T plus LAMr reduced susceptibility to ETV more than 111.1-fold compared with the wild-type clone, while rtI163V plus LAMr resulted in a 20.4-fold reduction. RtA186T significantly reduced viral replication efficacy, while the rtI163V mutation rescued it. Interestingly, the viral mutation pattern in the chimeric mice indicated dominant (or selective) proliferation of a clone containing rtI163V and rtA186T mutations plus LAMr under ETV treatment. Three-dimensional docking simulation indicated that rtA186T reduced the binding affinity of the HBV polymerase to ETV. CONCLUSIONS: VBT in this ETV-refractory patient is attributable to the novel ETV resistance mutations rtI163V and rtA186T. RtA186T was apparently responsible for ETV resistance but the selection of a clone with the double mutation plus LAMr suggests that rtI163V is required to sustain viral fitness. PMID- 25817220 TI - Combining qualitative and quantitative imaging evaluation for the assessment of genomic DNA integrity: The SPIDIA experience. AB - In this note, we present an ad hoc procedure that combines qualitative (visual evaluation) and quantitative (ImageJ software) evaluations of Pulsed-Field Gel Electrophoresis (PFGE) images to assess the genomic DNA (gDNA) integrity of analyzed samples. This procedure could be suitable for the analysis of a large number of images by taking into consideration both the expertise of researchers and the objectiveness of the software. We applied this procedure on the first SPIDIA DNA External Quality Assessment (EQA) samples. Results show that the classification obtained by this ad hoc procedure allows a more accurate evaluation of gDNA integrity with respect to a single approach. PMID- 25817221 TI - Apportioning sources of organic matter in streambed sediments: an integrated molecular and compound-specific stable isotope approach. AB - We present a novel application for quantitatively apportioning sources of organic matter in streambed sediments via a coupled molecular and compound-specific isotope analysis (CSIA) of long-chain leaf wax n-alkane biomarkers using a Bayesian mixing model. Leaf wax extracts of 13 plant species were collected from across two environments (aquatic and terrestrial) and four plant functional types (trees, herbaceous perennials, and C3 and C4 graminoids) from the agricultural River Wensum catchment, UK. Seven isotopic (delta13C27, delta13C29, delta13C31, delta13C27-31, delta2H27, delta2H29, and delta2H27-29) and two n-alkane ratio (average chain length (ACL), carbon preference index (CPI)) fingerprints were derived, which successfully differentiated 93% of individual plant specimens by plant functional type. The delta2H values were the strongest discriminators of plants originating from different functional groups, with trees (delta2H27-29= 2080/00 to -1640/00) and C3 graminoids (delta2H27-29=-2590/00 to -2210/00) providing the largest contrasts. The delta13C values provided strong discrimination between C3 (delta13C27-31=-37.50/00 to -33.80/00) and C4 (delta13C27-31=-23.50/00 to -23.10/00) plants, but neither delta13C nor delta2H values could uniquely differentiate aquatic and terrestrial species, emphasizing a stronger plant physiological/biochemical rather than environmental control over isotopic differences. ACL and CPI complemented isotopic discrimination, with significantly longer chain lengths recorded for trees and terrestrial plants compared with herbaceous perennials and aquatic species, respectively. Application of a comprehensive Bayesian mixing model for 18 streambed sediments collected between September 2013 and March 2014 revealed considerable temporal variability in the apportionment of organic matter sources. Median organic matter contributions ranged from 22% to 52% for trees, 29% to 50% for herbaceous perennials, 17% to 34% for C3 graminoids and 3% to 7% for C4 graminoids. The results presented here clearly demonstrate the effectiveness of an integrated molecular and stable isotope analysis for quantitatively apportioning, with uncertainty, plant-specific organic matter contributions to streambed sediments via a Bayesian mixing model approach. PMID- 25817222 TI - Kidney biopsy findings in primary Sjogren syndrome. AB - BACKGROUND: Renal involvement is rare in primary Sjogren syndrome (PSS). In this study, we examined renal biopsy findings in patients with PSS and correlated them with their clinical and renal findings. METHODS: Twenty-five patients with PSS who underwent renal biopsies from two renal units in Scotland between 1978 and 2013 were identified from renal biopsy database. We examined the renal morphologic, clinical and renal findings at the time of renal biopsy, renal and patient outcomes. RESULTS: The diagnosis of PSS preceded renal biopsy in 18/25 patients. In this group, the median duration of the disease was 5.5 years. Significant proteinuria, combined microscopic haematuria and proteinuria and reduced renal excretory function were found in 76, 56 and 84% of patients, respectively. The 3-year actuarial patient survival was significantly lower in patients with glomerulonephritis as compared with tubulointerstitial nephritis (66 versus 100%, P = 0.02). There was no difference in 3-year actuarial renal survival between these two groups (92 versus 92%, P = 1.0). CONCLUSIONS: Renal biopsy is rare in PSS and often reveals diverse pathological findings. Glomerulonephritis, as compared with tubulointerstitial nephritis, is associated with higher early mortality. Further studies are needed to evaluate the utility of renal biopsy and its impact on disease management. PMID- 25817223 TI - Circulating Wnt/beta-catenin signalling inhibitors and uraemic vascular calcifications. AB - BACKGROUND: The process of vascular calcification has been associated with the canonical Wnt/beta-catenin signalling pathway in cell cultures and animal studies. The relationship between circulating Wnt/beta-catenin inhibitors and vascular calcification in dialysis patients is unknown. The aim of this study was to investigate the associations between serum dickkopf-1 (Dkk-1) and sclerostin, two circulating inhibitors of the Wnt/beta-catenin signalling pathway, and the severity of aortic calcification (AoC) and cardiovascular outcomes in dialysis patients. METHODS: This was a prospective observational cohort study. One hundred and twenty-five patients on maintenance haemodialysis participated in the study. Serum levels of Dkk-1 and sclerostin were measured. AoC scores were calculated from plain films of both posterior-anterior and lateral views. The patients were followed up for 2 years or until death or withdrawal. RESULTS: The circulating sclerostin level was inversely associated with the severity of AoC (P = 0.035) and indicators of the bone turnover rate including serum alkaline phosphatase (ALP) (r = -0.235, P = 0.008) and intact parathyroid hormone (r = -0.523, P < 0.001). Furthermore, Cox regression analysis indicated that the patients with high circulating sclerostin levels were less likely to experience future cardiovascular events [1 pmol/L sclerostin increase, hazard ratio 0.982 (95% CI, 0.967-0.996), P = 0.015] after adjusting for a propensity score. In contrast, serum Dkk-1 was not associated with AoC and clinical outcomes. CONCLUSIONS: In long-term haemodialysis patients, circulating sclerostin but not Dkk-1 is inversely associated with AoCs and future cardiovascular events. Our findings suggest that sclerostin, as a bone-related protein, might act as a communicator between uraemic bone and vasculature. PMID- 25817224 TI - Refining the definition of clinically important mineral and bone disorder in hemodialysis patients. AB - BACKGROUND: It is important to identify an easily defined subset of patients at increased risk of adverse clinical outcomes associated with mineral and bone disorder (MBD) biomarkers (parathyroid hormone, calcium and phosphate). METHODS: Observational cohort study of 26 221 prevalent hemodialysis patients in Davita clinics as of 31 August 2005 and followed up until 31 December 2006 (16 months). Predictors were 12 possible definitions of 'clinically important' MBD based on all 3 biomarkers, and 18 alternative definitions based on only 1 or 2 biomarkers. Events were death alone and a composite of cardiovascular hospitalization or death. Excess events were calculated based on a multivariate Cox model using 5224 patients in target for all MBD biomarkers and applied to 20 997 patients out of target for at least one biomarker. Excess events attributable to MBD were estimated by subtracting the multivariate model-derived predicted number from the actual number. Outcomes were the proportion of excess events attributable to MBD captured by each definition (threshold >=70%) and the reduction in the population size considered to have clinically important MBD (threshold >=30%). The excess fraction was excess events divided by actual events. RESULTS: Patients with more biochemical markers out of target tended to be younger, black and have longer times since starting dialysis. The excess fraction associated with MBD ranged from ~10 to 26% depending on the clinical endpoint and definition. The only definition to meet the thresholds required at least two of the three MBD biomarkers to be out of target (high or low). It captured 82% of excess composite endpoints and 74% of excess deaths and reduced the at-risk population by 46%. CONCLUSIONS: Patients with at least two of three MBD biomarkers out of target represent a subgroup of patients at elevated risk of adverse clinical events. PMID- 25817225 TI - Urinary creatinine excretion, measured glomerular filtration rate and CKD outcomes. AB - BACKGROUND: Muscle wasting predicts mortality in patients with end-stage renal disease (ESRD), but its role in the progression of chronic kidney disease (CKD) is uncertain. We studied CKD outcomes associated with low muscle mass, assessed by urinary creatinine excretion (UCr). METHODS: The NephroTest cohort included 1429 patients with CKD stages 1-4 and both measured glomerular filtration rate (mGFR) (by (51)Cr-EDTA) and estimated glomerular filtration rate (eGFR) (by CKD Epidemiology Collaboration equation). We used cause-specific Cox models to estimate hazard ratios (HRs) for the competing risks of ESRD and death associated with gender-specific UCr quartiles. RESULTS: UCr was 13.6 +/- 3.2 mmol/24 h (0.17 +/- 0.05 mmol/kg/24 h) in men and 9.2 +/- 2.1 (0.14 +/- 0.05) in women. It was positively associated with mGFR, but not with eGFR. Over a median follow-up of 3.6 (2.1-5.8) years, 229 patients developed ESRD and 113 patients died before ESRD. Compared with patients in the highest UCr quartile, those in the lowest quartile had a higher crude HR (95% confidence interval) for pre-ESRD death: 4.3 (2.4-7.7), which was weakened, but remained statistically significant, independent of demographics, mGFR and several other factors: 2.1 (1.04-4.3). Their crude ESRD risk was not higher: HR: 0.95 (0.65-1.4), and even tended to be lower after adjusting for mGFR and log-proteinuria: HR: 0.70 (0.45-1.1). Adjustment for eGFR instead of mGFR reversed this relationship: HR: 1.7 (1.1 2.7). CONCLUSIONS: In early stage CKD, low UCr is associated with higher risk for mortality, but not for ESRD. Using creatinine-based equation to adjust for GFR may bias the relationship of UCr with ESRD risk. PMID- 25817227 TI - Should age be a factor for initiating post-cardiac arrest care or for temperature management strategies? PMID- 25817228 TI - Electric foot shock stress adaptation: Does it exist or not? AB - Stress adaptation is a protective phenomenon against repeated stress exposure and is characterized by a decreased responsiveness to a repeated stress stimulus. The adaptation is associated with a complex cascade of events, including the changes in behavior, neurotransmitter and gene expression levels. The non-adaptation or maladaptation to stress may underlie the affective disorders, such as anxiety, depression and post-traumatic stress disorder (PTSD). Electric foot shock is a complex stressor, which includes both physical and emotional components. Unlike immobilization, restraint and cold immersion stress, the phenomenon of stress adaptation is not very well defined in response to electric foot shock. A number of preclinical studies have reported the development of adaptation to electric foot shock stress. However, evidence also reveals the non-adaptive behavior in response to foot shocks. The distinct adaptive/non-adaptive responses may be possibly influenced by the type, intensity, and duration of the stress. The present review discusses the existence or non-existence of adaptation to electric foot shock stress along with possible mechanism. PMID- 25817226 TI - Longitudinal changes in hematocrit in hypertensive chronic kidney disease: results from the African-American Study of Kidney Disease and Hypertension (AASK). AB - BACKGROUND: Anemia is common in chronic kidney disease (CKD) and associated with poor outcomes. In cross-sectional studies, lower estimated glomerular filtration rate (eGFR) has been associated with increased risk for anemia. The aim of this study was to determine how hematocrit changes as eGFR declines and what factors impact this longitudinal association. METHODS: We followed 1094 African-Americans with hypertensive nephropathy who participated in the African-American Study of Kidney Disease and Hypertension. Mixed effects models were used to determine longitudinal change in hematocrit as a function of eGFR. Interaction terms were used to assess for differential effects of age, gender, baseline eGFR, baseline proteinuria, malnutrition and inflammation on eGFR-associated declines in hematocrit. In sensitivity analyses, models were run using iGFR (by renal clearance of I(125) iothalamate) in place of eGFR. RESULTS: At baseline, mean hematocrit was 39% and 441 (40%) individuals had anemia. The longitudinal relationship between eGFR and hematocrit differed by baseline eGFR and was steeper when baseline eGFR was <45 mL/min/1.73 m(2). For example, the absolute decline in hematocrit per 10 mL/min/1.73 m(2) decline in longitudinal eGFR was 3.7, -1.3 and -0.5% for baseline eGFR values of 20, 40 and 60 mL/min/1.73 m(2), respectively (P < 0.001 comparing the longitudinal association between baseline eGFR = 40 or 60 versus baseline eGFR = 20 mL/min/1.73 m(2)). Similarly, male sex, younger age (<65 years) and higher baseline proteinuria (protein-to-creatinine ratio >0.22) were associated with greater hematocrit declines per unit decrease in longitudinal eGFR compared with female sex, older age and low baseline proteinuria, respectively (P-interaction <0.05 for each comparison). The longitudinal eGFR-hematocrit association did not differ by body mass index, serum albumin or C-reactive protein. CONCLUSIONS: Men, younger individuals and those with low baseline eGFR (<45 mL/min/1.73 m(2)) or baseline proteinuria are particularly at risk for eGFR-related declines in hematocrit. PMID- 25817229 TI - Epigenetic regulation of protein tyrosine phosphatase PTPN12 in triple-negative breast cancer. AB - AIMS: The present study showed that the expression of PTPN12 is epigenetically regulated. 5-Azacytidine (5-Azac), a DNA hypomethylating agent, significantly increased the expression of PTPN12 at low concentrations (1MUM and 2.5MUM) and decreased the expression of PTPN12 at 5MUM in the MDA-MB-231 and BT-549 triple negative breast cancer cell lines. MAIN METHODS: Human MCF-7, MDA-MB-231 and BT 549 cells were exposed to different concentrations of 5-Azac for 24 and 48h. RT PCR was performed to determine the mRNA expression of PTPN12, E-cadherin and miRNA-124. Western blotting was performed to assess the protein expression of various proteins, including PTPN12, E-cadherin, DNMT and PARP. KEY FINDINGS: 5 Azac, a DNA hypomethylating agent, significantly increased the expression of PTPN12 at low concentrations (1MUM and 2.5MUM) and decreased PTPN12 expression at 5MUM. We provide the first evidence that PTPN12 expression is epigenetically regulated and that it is up-regulated at a lower dose of a DNMT1 inhibitor in MDA MB-231 and BT-549 cells. Interestingly, the levels of miRNA-124 were increased only at 5MUM, the concentration at which PTPN12 expression was suppressed. SIGNIFICANCE: To the best of our knowledge, this is the first report that highlights the therapeutic potential of low-dose 5-Azac for the treatment of TNBC. Therefore, 5-Azac, an agent that has already been tested in acute myeloid leukemia, may be more effective at lower doses for the treatment of triple negative breast cancer. PMID- 25817230 TI - High-dose pentazocine antagonizes the antinociception induced by high-dose morphine. AB - AIMS: To investigate the effects of high doses of pentazocine on antinociception induced by a high dose of morphine and the role of the kappa-opioid receptors (KORs) in these effects in mice. MAIN METHODS: Sixty-six C57BL/6J mice were pretreated with a KOR antagonist, nor-binaltorphimine (nor-BNI) (10mg.kg(-1)), or a normal saline placebo. All the mice received a subcutaneous injection of morphine (10mg.kg(-1)) 120min later and different doses of pentazocine (3, 10, 30, 56, 100mg.kg(-1)) or a normal saline placebo. A tail pressure test, hot plate test and tail flick test were performed before and at 30, 60, 90 and 120min after the injection of morphine. KEY FINDINGS: The tail pressure test, hot plate test and tail flick test showed that pentazocine at doses of 10 to 100mg.kg(-1), but not at 3mg.kg(-1), had significant antagonizing effects on the antinociception induced by high-dose morphine to mechanical and thermal pain, and nor-BNI did not affect antinociception in combination with pentazocine at 10 to 100mg.kg(-1) and morphine at 10mg.kg(-1). SIGNIFICANCE: High-doses of pentazocine antagonize the antinociception induced by a high-dose of morphine in a dose-dependent manner, and this antagonistic effect is not associated with the activation of KORs. PMID- 25817231 TI - Evaluation of serum midkine as a biomarker in differentiated thyroid cancer. AB - AIMS: Midkine is a multifunctional cytokine identified to be a promising cancer biomarker. We aimed to prospectively investigate serum midkine as a diagnostic and prognostic biomarker in differentiated thyroid cancer (DTC). MAIN METHODS: 162 patients with thyroid nodules participated in the surgical cohort (post surgical pathology proved 70 cases with DTC and 92 cases with benign thyroid nodules), 75 healthy subjects served as control. Diagnostic values of pre surgical midkine and thyroglobulin for DTC were conducted by receiver operating characteristic (ROC) curves. 214 DTC patients participated in the (131)I treatment cohort. Prognostic values of pre-(131)I-ablative midkine and thyroglobulin to predict (131)I-avid metastases were performed by ROC curves. Metastasis-free survival was analyzed by the Kaplan-Meier method. KEY FINDINGS: Much better diagnostic capability of midkine than thyroglobulin was shown to differentiate DTC from benign thyroid nodules, with cut-off midkine value of 323.12pg/ml and diagnostic accuracy of 75.31%. Nearly similar diagnostic capabilities of midkine and thyroglobulin were shown to distinguish DTC from normal participants. Pre-(131)I-ablative thyroglobulin demonstrated perfect ability to predict metastases, with cut-off value and diagnostic accuracy of 19.50ng/ml and 96.73%. Midkine also performed well with a cut-off value and diagnostic accuracy of 504.71pg/ml and 89.25%. DTC patients with midkine or thyroglobulin levels higher than those of thresholds (500pg/ml or 20ng/ml) showed a significantly worse (131)I-avid metastasis-free survival by the Kaplan-Meier method (P<0.01). SIGNIFICANCE: Our results show that midkine is as good as or even better than thyroglobulin to screen patients with thyroid nodules for DTC before surgery, and to predict whether metastases exist before the first (131)I ablative therapy. PMID- 25817232 TI - Protective effects of phosphatidylcholine on oxaliplatin-induced neuropathy in rats. AB - AIMS: The present study was designed to investigate the therapeutic potential of phosphatidylcholine (PC) on oxaliplatin-induced peripheral neuropathy. MAIN METHODS: Male Sprague-Dawley rats were randomly divided into three groups: the control group, the oxaliplatin group (4mg/kg, twice per week for 4weeks) and the oxaliplatin+PC (300mg/kg) group. To evaluate the effect of PC, we examined the thermal nociceptive threshold changes in oxaliplatin-induced peripheral neuropathy by conducting paw pressure, hot-plate and tail-flick tests. Additional experiments on the degree of oxidative stress in the sciatic nerves were performed by measuring the level of MDA, total glutathione (GSH), glutathione peroxidase (GPx) activity and superoxide dismutase (SOD) activity. We also used histopathological and immunohistochemical methods to observe neuronal damage and glial activation. KEY FINDINGS: PC attenuated oxidative stress by increasing antioxidant levels. In histopathological evaluation, the PC administrated group maintained normal morphologic appearance of sciatic nerves, similar to the control group. In spinal cords, however, no significant difference between the oxaliplatin-alone group and the oxaliplatin+PC group was observed. In the immunohistochemical evaluation, PC administration ameliorated oxaliplatin-induced microglial activation. SIGNIFICANCE: It is suggested that PC has a therapeutic potential against oxaliplatin-induced peripheral neuropathy due to its antioxidant property and modulation of microglial activities. PMID- 25817233 TI - AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells. AB - AIM: It is well known that lipid accumulation and inflammation are two important steps in pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD). However, fewer studies have explored the direct relationship between lipid accumulation and inflammation in early NAFLD. Tumor necrosis factor alpha (TNF alpha) is one of the classical inflammatory cytokines. AMP-activated protein kinase (AMPK) is known as a critical regulator of energy homeostasis in metabolic processes. This study aims to investigate the role of TNF-alpha on lipid deposition of HepG2 cells and examine the modification of AMPK pathway. MAIN METHODS: TNF-alpha was added in HepG2 cells and lipid accumulation was analyzed by Oil Red O staining and quantitative test of triglyceride (TG). The expressions of phosphorylated AMPK and its pathway (including mTOR and SREBP-1) were determined. Furthermore, an AMPK agonist (metformin or AICAR) or antagonist (compound C) was co-administrated with TNF-alpha in HepG2 cells to investigate its effect on TNF-alpha induced lipid deposition. KEY FINDINGS: A significant increment of TG content in HepG2 cells was observed after TNF-alpha treatment. Meanwhile, substantially suppressed AMPK and ACC phosphorylation, enhanced mTOR and p70S6K phosphorylation, and increased protein expression of FAS and SREBP-1 were found. Co-treatment with metformin or AICAR decreased the TNF-alpha-induced intracellular TG, accompanied by significantly enhanced AMPK and ACC phosphorylation, suppressed mTOR and p70S6K phosphorylation, and reduced SREBP-1 and FAS expressions. On the contrary, while co-incubated with compound C, AMPK and ACC phosphorylation were suppressed and the inhibitory effect of metformin on HepG2 cell lipid deposition was also attenuated. SIGNIFICANCE: Our results suggest that TNF-alpha directly induces lipid accumulation in HepG2 cells, at least in part, through the inhibition of AMPK/mTOR/SREBP-1 pathway. PMID- 25817234 TI - Puerarin suppresses high glucose-induced MCP-1 expression via modulating histone methylation in cultured endothelial cells. AB - AIMS: Hyperglycemia is commonly associated with microcirculation dysfunction. The purpose of the present study was to investigate the epigenetic mechanism involved in the repression of monocyte chemoattractant protein-1 (MCP-1) expression by puerarin under high glucose (25mM) condition. MAIN METHODS: MCP-1 gene expression was measured by Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the histone 3 lysine 4 methylation (H3K4me) and lysine 9 methylation (H3K9me) were evaluated using chromatin immunoprecipitation assay. KEY FINDINGS: Puerarin significantly inhibited high glucose-induced upregulation of H3K4 di- and tri methylation (H3K4me2/3) on the MCP-1 gene promotor. Additionally, the enrichment of H3K4 histone methyltransferases including MLL, menin and SET7 on the MCP-1 promotor was increased, while the demethylase LSD1 was decreased in EA.hy926 cells following exposure to high glucose. The changes of the above enzymes were reversed by puerarin treatment. The mRNA expression of MCP-1 was increased by LSD1 blockage, while was decreased by MLL3 blockage. SIGNIFICANCE: Our findings suggested that puerarin plays a critical role in transcriptional repression of high glucose-induced MCP-1 gene expression, at least in part due to alteration of H3K4me2/3 methylation, thus possesses a therapeutic potential in diabetes-induced vascular injuries. PMID- 25817235 TI - Prenatal zinc prevents communication impairments and BDNF disturbance in a rat model of autism induced by prenatal lipopolysaccharide exposure. AB - Aims: Previous investigations by our group have shown that prenatal exposure to lipopolysaccharide (LPS),which mimics infections by Gram-negative bacteria, induced autistic-like behavior. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism.We selected zinc as the prenatal treatment to prevent or ease the impairments induced by LPS because LPS induces hypozincaemia.Materials and methods:We evaluated the effects of LPS and zinc on female reproductive performance. Communication,which is impaired in autism,was tested in pups by ultrasonic vocalizations. Plasma levels of brain-derived neurotrophic factor (BDNF) were determined because it has been considered an autism important biomarker.Key findings: Prenatal LPS exposure reduced offspring number and treatment with zinc prevented this reduction.Moreover, pups that were prenatally exposed to LPS spent longer periods without calling their mothers, and posttreatment with zinc prevented this impairment induced by LPS to the same levels as controls. Prenatal LPS also increased BDNF levels in adult offspring, and posttreatment with zinc reduced the elevation of BDNF to the same levels as controls.Significance: BDNF hyperactivity was also found in several studies of autistic patients. Together with our previous studies, our model of prenatal LPS induced autistic-like behavioral, brain, and immune disturbances. This suggests that it is a valid rat model of autism. Prenatal zinc prevented reproductive, communication, and BDNF impairments.The present study revealed a potential beneficial effect of prenatal zinc administration for the prevention of autism with regard to the BDNF pathway. PMID- 25817236 TI - Feasibility of including green tea products for an analytically verified dietary supplement database. AB - The Dietary Supplement Ingredient Database (DSID) is a federally funded, publicly accessible dietary supplement database that currently contains analytically derived information on micronutrients in selected adult and children's multivitamin and mineral (MVM) supplements. Other constituents in dietary supplement products such as botanicals are also of interest and thus are being considered for inclusion in the DSID. Thirty-eight constituents, mainly botanicals were identified and prioritized by a federal interagency committee. Green tea was selected from this list as the botanical for expansion of the DSID. This article describes the process for prioritizing dietary ingredients in the DSID. It also discusses the criteria for inclusion of these ingredients, and the approach for selecting and testing products for the green tea pilot study. PMID- 25817237 TI - Detection and preliminary physico-chemical properties of antimicrobial components in the native excretions/secretions of three species of Chrysomya (Diptera, Calliphoridae) in Brazil. AB - Antibiotic-resistant bacteria in hospitals and communities increasingly threaten public health in Brazil and the rest of the World. There is an urgent need for additional antimicrobial drugs. Calliphorid blowfly larvae are a rich source of antimicrobial factors but the potential of Neotropical species has been neglected. This preliminary study evaluates the antimicrobial activity of the native excretions/secretions of larvae of three species of Brazilian calliphorids, Chrysomya megacephala, Chrysomya albiceps and Chrysomya putoria. Native excretions/secretions were collected from third instar larvae, sterile filtered and tested for antibacterial activity against Staphylococcus aureus 9518, Escherichia coli K12 4401 and Serratia marcescens 365. Turbidometric assays were made in micro-plates, using an ELISA reader, with readings taken up to 22 h. Bacterial suspensions at the start and end of each experiment were also serially diluted, spread on nutrient agar plates and then colony forming units counted. The physico-chemical characteristics of the native excretions/secretions were also tested by freezing/thawing, boiling, and protease digestion. The native excretions/secretions of larvae from these three Chrysomya species significantly inhibited bacterial growth. Therefore, Brazilian calliphorid flies could potentially provide new classes of antibiotics. PMID- 25817238 TI - Detection of Mayaro virus infections during a dengue outbreak in Mato Grosso, Brazil. AB - Arboviruses are common agents of human febrile illness worldwide. In dengue endemic areas illness due to other arboviruses have been misdiagnosed as dengue based only on clinical-epidemiological data. In this study we investigated the presence of Brazilian arboviruses in sera of 200 patients presenting acute febrile illness, during a dengue outbreak in Sinop, MT, Brazil. The results showed that 38 samples were positive to Dengue virus (DENV) type 1, two samples to DENV type 4, and six to Mayaro virus. These results indicate that arboviruses others than DENV are circulating in Sinop and the surrounding region, which are going undiagnosed. In addition, molecular and evolutionary analyses indicate that two MAYV genotypes are co-circulating in Mato Grosso, Brazil. Thus, a strong surveillance program must be implemented to evaluate and monitor the distribution and the true importance of non-dengue arboviruses in the etiology of acute febrile illnesses. PMID- 25817239 TI - Desymmetrization of myo-inositol derivatives by lanthanide catalyzed phosphitylation with C2-symmetric phosphites. AB - Desymmetrization by phosphorylation represents a promising method with potential impact in many different areas of research. C2-Symmetric phosphoramidites have been used to desymmetrize myo-inositol derivatives by functionalization at different positions. With this method, 1:1 mixtures of diastereomers are obtained that can be separated subsequently. In this work, activation of a C2-symmetric phosphoramidite is achieved by addition of pentafluorophenol (PFP) and leads to a reactive PFP phosphite, which can then be coupled to protected myo-inositol derivatives with reactive OH groups at the 1, 3, 4 and 6 positions. This strategy enhances the diastereoselectivity of the coupling reaction with a preference towards phosphitylation at position 6 (up to 3:1) or position 3 (up to 2:1). The concept of attenuative activation of phosphoramidites via in situ generated pentafluorophenol phosphite triesters is thus proven in these studies. It is further shown that Lewis-Acid catalysis enhances the rate of phosphite triester coupling without affecting the diastereoselectivity. This novel strategy improves access to different phosphorylated myo-inositol derivatives and will thus enable further studies into the function of these important intracellular second messengers. PMID- 25817240 TI - Design, synthesis and biological evaluation of N-phenylthieno[2,3-d]pyrimidin-4 amines as inhibitors of FGFR1. AB - Fibroblast grow factor receptor 1 (FGFR1) is an important anti-cancer target that plays crucial role in oncogenesis and oncogenic angiogenesis. The structure activity relationship (SAR) of N-phenylthieno[2,3-d]pyrimidin-4-amines was investigated. Binding of active compounds with FGFR1 kinase was analyzed by molecular modeling studies. Selected active thieno[2,3-d]pyrimidines were tested for selectivity and antiproliferative activity. The most active compounds, 3-({6 phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol and 3-({5-phenylthieno[2,3 d]pyrimidin-4-yl}amino)phenol have IC50 0.16 and 0.18 MUM, respectively. The results presented here may help to identify new thienopyrimidines with optimized cell growth inhibitory activity which may be further used as anticancer agents. PMID- 25817241 TI - Updating the emotional content of working memory in social anxiety. AB - BACKGROUND AND OBJECTIVES: Cognitive accounts suggest that information processing biases have an important role in the etiology and maintenance of social anxiety (SA). Empirical evidence support this notion has been established in variety of cognitive domains. Yet, it is still not known how social anxious individuals process emotional content in working memory (WM). Maladaptive WM updating may influence emotion regulation and anxiety during social situations in SA. Thus, the aim of the present study was to explore biases when updating emotional content in SA. METHODS: 31 participants with high SA and 34 control participants performed an emotional 2-back task. Biases were assessed by intrusion cost in reaction times, which reflects the conflict between the inhibition of irrelevant content and the activation of relevant content. RESULTS: Results revealed a diminished intrusion cost in reaction times for irrelevant positive content in the high, but not in the low SA group. No differences were found for negative or neutral content. LIMITATIONS: In the present study we used an analogue sample of students with high SA rather than a true clinical sample. Further research is needed to examine WM updating in clinical population. CONCLUSIONS: These findings suggest that individuals with SA are better at inhibiting irrelevant positive information, a maladaptive cognitive bias that may prevent positive feedback from entering the cognitive system. This cognitive bias in WM may play a role in the etiology and maintenance of SA. PMID- 25817242 TI - Subjective competence breeds overconfidence in errors in psychosis. A hubris account of paranoia. AB - BACKGROUND AND OBJECTIVES: Overconfidence in errors is a well-replicated cognitive bias in psychosis. However, prior studies have sometimes failed to find differences between patients and controls for more difficult tasks. We pursued the hypothesis that overconfidence in errors is exaggerated in participants with a liability to psychosis relative to controls only when they feel competent in the respective topic and/or deem the question easy. Whereas subjective competence likely enhances confidence in those with low psychosis liability as well, we still expected to find more 'residual' caution in the latter group. METHODS: We adopted a psychometric high-risk approach to circumvent the confounding influence of treatment. A total of 2321 individuals from the general population were administered a task modeled after the "Who wants to be a millionaire" quiz. Participants were requested to endorse one out of four response options, graded for confidence, and were asked to provide ratings regarding subjective competence for the knowledge domain as well as the subjective difficulty of each item. RESULTS: In line with our assumption, overconfidence in errors was increased overall in participants scoring high on the Paranoia Checklist core paranoia subscale (2 SD above the mean). This pattern of results was particularly prominent for items for which participants considered themselves competent and which they rated as easy. LIMITATIONS: Results need to be replicated in a clinical sample. DISCUSSION: In support of our hypothesis, subjective competence and task difficulty moderate overconfidence in errors in psychosis. Trainings that teach patients the fallibility of human cognition may help reduce delusional ideation. PMID- 25817243 TI - Multilevel multidimensional item response model with a multilevel latent covariate. AB - In a pre-test-post-test cluster randomized trial, one of the methods commonly used to detect an intervention effect involves controlling pre-test scores and other related covariates while estimating an intervention effect at post-test. In many applications in education, the total post-test and pre-test scores, ignoring measurement error, are used as response variable and covariate, respectively, to estimate the intervention effect. However, these test scores are frequently subject to measurement error, and statistical inferences based on the model ignoring measurement error can yield a biased estimate of the intervention effect. When multiple domains exist in test data, it is sometimes more informative to detect the intervention effect for each domain than for the entire test. This paper presents applications of the multilevel multidimensional item response model with measurement error adjustments in a response variable and a covariate to estimate the intervention effect for each domain. PMID- 25817244 TI - Interaction effect of whole wheat feeding and mannanoligosaccharides supplementation on growth performance, haematological indices and caecal microbiota of cockerel chicks. AB - The interaction effect of whole wheat feeding and mannanoligosaccharides supplementation on growth performance, haematological indices and caecal microbiota of cockerel chicks were investigated using 250-day-old cockerel chicks previously reared for 7 days pre-experimental period. Birds were fed with commercial chick mash during the pre-experimental period. At the expiration of this period, 192 chicks were selected on weight equalization basis and assigned into 24 pens. Each treatment consisted of six pens, while each pen housed eight birds. Four wheat-soya bean-based experimental diets were formulated in a 2 * 2 factorial arrangement of diets having two wheat forms (ground and whole wheat grain) each supplemented or not with 1 g/kg MOS/kg feed. Whole wheat feeding (irrespective of MOS supplementation) showed reduced (p < 0.05) feed intake. Birds fed whole wheat diet supplemented with MOS recorded the highest (p < 0.01) final live weight, weight gain and the best (p < 0.05) feed conversion ratio. Haemoglobin concentration, packed cell volume and red blood cell count of the chicks were not affected (p > 0.05) by dietary treatment. However, dietary supplementation with MOS resulted in increased (p < 0.05) WBC counts. The caecum content of chicks fed with MOS-supplemented whole wheat diets recorded the least (p < 0.01) salmonella counts. In conclusion, combination of whole wheat feeding and MOS supplementation showed improved growth performance, gut microbiota and indications of improved health status of cockerel chicks. PMID- 25817245 TI - Serodiagnosis of Toxoplasma gondii infection in farm animals (horses, swine, and sheep) by enzyme-linked immunosorbent assay using chimeric antigens. AB - Toxoplasma gondii infects all warm-blooded animals including humans, causing serious public health problems and great economic loss in the animal husbandry. Commonly used serological tests for diagnosis of toxoplasmosis involve preparation of whole Toxoplasma lysate antigen (TLA) from tachyzoites. The production of this antigen is associated with high costs and lengthy preparation and the possibility of staff infection. There are also some difficulties in the standardization of such tests. One approach in order to improve the diagnosis of T. gondii infection is to use recombinant chimeric antigens in place of the TLA, which was confirmed by studies in the serodiagnosis of toxoplasmosis in humans. In this paper, we assess, for the first time, the diagnostic utility of five T. gondii recombinant chimeric antigens (MIC1-MAG1-SAG1S, SAG1L-MIC1-MAG1, SAG2-GRA1 ROP1S, SAG2-GRA1-ROP1L, and GRA1-GRA2-GRA6) in immunoglobulin G (IgG) enzyme linked immunosorbent assays (IgG ELISAs) with sera from three different groups of livestock animals (horses, pigs, and sheep). The reactivity of individual chimeric antigens was analyzed in relation to the results obtained in IgG ELISAs based on a mixture of three antigens (M1: rSAG1+rMIC1+rMAG1, M2: rSAG2+rGRA1+rROP1, and M3: rGRA1+rGRA2+rGRA6) and referenced to TLA. All chimeric antigens were characterized by high specificity (100%), and the sensitivity of the IgG ELISAs based on chimeric antigens was variable (between 28.4% and 100%) and mainly dependent on the animal species. The chimeric antigens were generally more reactive than mixtures of three antigens. The most effective for the diagnosis of toxoplasmosis was SAG2-GRA1-ROP1L, which can detect specific anti-T. gondii antibodies in 100%, 93.8%, and 100% of positive serum samples from horses, pigs, and sheep, respectively. The present study shows that recombinant chimeric antigens can be successfully used to diagnose T. gondii infection in farm animals, and can replace the commonly used TLA. PMID- 25817246 TI - Cutaneous wound healing in aging small mammals: a systematic review. AB - As the elderly population grows, so do the clinical and socioeconomic burdens of nonhealing cutaneous wounds, the majority of which are seen among persons over 60 years of age. Human studies on how aging effects wound healing will always be the gold standard, but studies have ethical and practical hurdles. Choosing an animal model is dictated by costs and animal lifespan that preclude large animal use. Here, we review the current literature on how aging effects cutaneous wound healing in small animal models and, when possible, compare healing across studies. Using a literature search of MEDLINE/PubMed databases, studies were limited to those that utilized full-thickness wounds and compared the wound healing parameters of wound closure, reepithelialization, granulation tissue fill, and tensile strength between young and aged cohorts. Overall, wound closure, reepithelialization, and granulation tissue fill were delayed or decreased with aging across different strains of mice and rats. Aging in mice was associated with lower tensile strength early in the wound healing process, but greater tensile strength later in the wound healing process. Similarly, aging in rats was associated with lower tensile strength early in the wound healing process, but no significant tensile strength difference between young and old rats later in healing wounds. From studies in New Zealand White rabbits, we found that reepithelialization and granulation tissue fill were delayed or decreased overall with aging. While similarities and differences in key wound healing parameters were noted between different strains and species, the comparability across the studies was highly questionable, highlighted by wide variability in experimental design and reporting. In future studies, standardized experimental design and reporting would help to establish comparable study groups, and advance the overall knowledge base, facilitating the translatability of animal data to the human clinical condition. PMID- 25817247 TI - Effective biosynthesis of ethyl (R)-4-chloro-3-hydroxybutanoate by supplementation of l-glutamine, d-xylose and beta-cyclodextrin in n-butyl acetate water media. AB - To avoid adding NAD(+) and effectively transform ethyl 4-chloro-3-oxobutanoate, the mixture of l-glutamine (200mM) and d-xylose (250mM) was added into in n-butyl acetate-water (10:90, v/v) biphasic system instead of NAD(+) for increasing the biocatalytic efficiency. To further improve the synthesis of optically pure ethyl (R)-4-chloro-3-hydroxybutanoate (>99% ee), beta-cyclodextrin was also added into this reaction media, and ethyl (R)-4-chloro-3-hydroxybutanoate (>99% ee) could be effectively synthesized from 800mM ethyl 4-chloro-3-oxobutanoate in the yield of 100% by whole-cells of recombinant E. coli CCZU-A13. Finally, the possible mechanism for improving the reductase activity by supplementation of l-glutamine, d-xylose and beta-CD was proposed. In conclusion, this strategy has high potential for the effective biosynthesis of ethyl (R)-4-chloro-3-hydroxybutanoate (>99% ee). PMID- 25817249 TI - Can FreeSurfer Compete with Manual Volumetric Measurements in Alzheimer's Disease? AB - Alzheimer's disease-related pathology results in tremendous structural and functional changes in the brain. These morphological changes might lead to a less precise performance of automated brain segmentation techniques in AD-patients, which in turn could possibly lead to false allocations of gray matter, white matter or cerebrospinal fluid. FreeSurfer has been shown to operate as an accurate and reliable instrument to measure cortical thickness and volume of neuroanatomical structures. Considering the principal role of FreeSurfer in the imaging field of AD, the present study aims to investigate the robustness of FreeSurfer to capture morphological changes in the brain against varying processing variables in comparison to manual measurements (the gold standard). T1 weighted MRI scan data were used pertaining to a sample of 53 individuals (18 healthy participants, 18 patients with mild cognitive impairment, and 18 patients with mild AD). Data were analyzed with different FreeSurfer versions (v4.3.1, v4.5.0, v5.0.0, v5.1.0), on a custom-built cluster (LINUX) and a Macintosh (UNIX) workstation. Group differences across versions and workstations were most consistent for both the hippocampus and posterior cingulate, regions known to be affected in the earliest stages of the disease. The results showed that later versions of FreeSurfer were more sensitive to identify group differences and corresponded best with the results of gold standard manual volumetric methods. In conclusion, later versions of FreeSurfer were more accurate than earlier versions, especially in medial temporal and posterior parietal regions. This development is very promising for future applications of FreeSurfer in research studies and encourages the future role of FreeSurfer output as a candidate marker in clinical practice. PMID- 25817248 TI - Lyophilization conditions for the storage of monooxygenases. AB - Cyclohexanone monooxygenase (CHMO) was used as a model enzyme to find suitable freeze-drying conditions for long-term storage of an isolated monooxygenase. CHMO is a Baeyer-Villiger monooxygenase (BVMO) known for its ability to catalyze a large number of oxidation reactions. With a focus on establishing the optimal formulation, additives were tested for enzyme stabilization during and after lyophilization. The results were successfully transferred to two other monooxygenases, namely the BVMO cyclopentadecanone monooxygenase (CPDMO) and a cytochrome P450 monooxygenase, P450 BM3. In the absence of a lyoprotectant, lyophilized P450 BM3 is almost completely inactivated, while the lyophilized BVMOs quickly lost activity when stored at 50 degrees C. Lyophilization in the presence of 2% (w/v) sucrose was found to be the best formulation to preserve activity and protect against inactivation when stored as lyophilizate at 50 degrees C. PMID- 25817250 TI - Therapeutic Approaches to ModulatingGlutathione Levels as a Pharmacological strategy in Alzheimer's Disease. AB - Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD).The main endogenousantioxidant,glutathione (GSH),has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteineHowever, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacyto elevatedepleted GSH levels in several in vivo and in vitro models of disease.It has beensuggestedthat the decline in GSH levels in AD, may be associated with down regulation ofGSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulatedby non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor gamma-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves asa crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH,andthe administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD. PMID- 25817251 TI - Childhood and Adulthood Rural Residence Increases the Risk of Dementia: NEDICES Study. AB - OBJECTIVE: This research aims to determine whether residence (rural vs. urban) at different life stages (childhood, adulthood, and late life) is associated with increased risk of incident dementia in a population-based cohort of older Spaniards. METHODS: In this prospective study, 2,711 participants aged 65 years and older were assessed at baseline and 3 years later. All cases of incident dementia were diagnosed using DSM-IV criteria. The relationship between residence and the relative risk of dementia was analysed using Cox's regression models. Demographics, comorbidity index, consumption (tobacco / alcohol) and doubtful dementia diagnosis were considered as possible confounders. RESULTS: At the three year follow-up, 91 cases of dementia were detected. Lower education and occupational attainment were associated with a higher incidence of dementia three years later. Rural residence in adulthood was associated with a significantly higher risk of dementia at the follow-up. Childhood rural residence revealed a marked trend for risk of dementia (p = 0.08), but it was nonsignificant in later life. The risk of dementia was considerably higher for the rural/low-education group than for the urban/high-education group, for both childhood and adulthood residence. Finally, people from areas with the lowest socio- economic status Arevalo (rural, blue-collar) and Margaritas (urban, blue-collar) showed higher risk of dementia than people from Lista (urban, mixed white/blue collar). CONCLUSION: In this cohort, early and mid-life stages rural residence was a risk factor for dementia, but not later-life rural residence. The rural residence effect was noticeably higher in people with a lower educational level. PMID- 25817252 TI - Natural AD-Like Neuropathology in Octodon degus: Impaired Burrowing and Neuroinflammation. AB - Alzheimer's disease (AD) is the most common cause of dementia, affecting more than 36 million people worldwide. Octodon degus, a South American rodent, has been found to spontaneously develop neuropathological signs of AD, including amyloid-beta (Abeta) and tau deposits, as well as a decline in cognition with age. Firstly, the present work introduces a novel behavioral assessment for O. degus - the burrowing test - which appears to be a useful tool for detecting neurodegeneration in the O. degus model for AD. Such characterization has potentially wide-ranging implications, because many of these changes in species typical behaviors are reminiscent of the impairments in activities of daily living (ADL), so characteristic of human AD. Furthermore, the present work characterizes the AD-like neuropathology in O. degus from a gene expression point of view, revealing a number of previously unreported AD biomarkers, which are found in human AD: amyloid precursor protein (APP), apolipoprotein E (ApoE), oxidative stress-related genes from the NFE2L2 and PPAR pathway, as well as pro inflammatory cytokines and complement proteins, in agreement with the known link between neurodegeneration and neuroinflammation. In summary, the present results confirm a natural neuropathology in O. degus with similar characteristics to AD at behavioral, cellular and molecular levels. These characteristics put O. degus in a singular position as a natural rodent model for research into AD pathogenesis and therapeutics against AD. PMID- 25817253 TI - VEGF Mediates ApoE4-Induced Neovascularization and Synaptic Pathology in the Choroid and Retina. AB - Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. Recent findings suggest that retina of apoE4 mice have synaptic and functional impairments. We presently investigated the effects of apoE4 on retinal and choroidal vasculature and the possible role of VEGF in these effects. There were no histological differences between the retinal and choroidal vasculatures of naive apoE3 and apoE4 mice. In contrast, laserdriven choroidal injury induced higher levels of choroidal neovascularization (CNV) in apoE4 than in apoE3 mice. These effects were associated with an inflammatory response and with activation of the Muller cells and asrocytic markers gluthatione synthetase and GFAP, all of which were more pronounced in the apoE4 mice. CNV also induced a transient increase in the levels of the synaptic markers synaptophysin and PSD95 which were however similar in the apoE4 and apoE3 naive mice. Retinal and choroidal VEGF and apoE levels were lower in naive apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in VEGF following injury. Retinal and choroidal VEGF and apoE levels were lower in naive apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in VEGF following injury. PMID- 25817255 TI - Running Exercise Reduces Myelinated Fiber Loss in the Dentate Gyrus of the Hippocampus in APP/PS1 Transgenic Mice. AB - To investigate the effect of running exercise on myelinated fibers in the dentate gyrus (DG) of the hippocampus during Alzheimer's disease (AD), 6-month-old male APP/PS1 transgenic mice were randomly assigned to control or running groups. The running group mice were subjected to a running protocol for four months. The behaviors of the mice from both group mice were then assessed using the Morris water maze, and the total volume of the DG and the related quantitative parameters with characteristics of the myelinated nerve fiber and the myelin sheath in the DG were investigated using unbiased stereological techniques and electron microscopy. Learning and spatial memory performances were both significantly increased in the running group compared with the control group. There was no significant difference in the gratio of the myelinated axons between the two groups. However, the DG volume, the myelinated fiber length and volume in the DG, and the myelin sheath volume and thickness in the DG were all significantly increased in the running group mice compared with the control group mice. These results indicated that running exercise was able to prevent DG atrophy and delay the progression of the myelinated fiber loss and the demyelination of the myelin sheaths in the DG in an AD mouse model, which may underlie the running-induced improvement in learning and spatial memory. Taken together, these results demonstrated that running exercise could delay the progression of AD. PMID- 25817256 TI - 4Abeta1-15-Derived Monoclonal Antibody Reduces More Abeta Burdens and Neuroinflammation than Homologous Vaccine in APP/PS1 Mice. AB - The common pathological hallmark of Alzheimer's disease (AD) is beta-amyloid plaque deposition. The ideal therapy would reduce the Abeta burden with a low inflammatory immune response. Passive immunotherapy is an advanced treatment that dramatically reduces brain Abeta pathologies in AD animal models. The objective of our study was to observe the effects of 5C8H5, a novel monoclonal antibody derived from 4Abeta1-15, on brain Abeta pathology in an APP/PS1 mouse model of AD. Six-month-old transgenic mice were administered 5C8H5, 4Abeta1-15 or IgG, and same-aged wild-type untreated C57Bl/6J mice were employed as controls. Inflammatory factors and Abeta40/42 levels were detected by ELISA, while Abeta plaques, microglial cell activation, microhemorrhages and neurogenesis were evaluated by immunohistochemical staining. Compared with 4Abeta1-15-treated mice, the mice in the 5C8H5 group induced more Abeta clearance with less microglial cell activation in a niche of Th2-polarized immune response. The levels of proinflammatory factors, including IL-1beta, IL-6, TNF-alpha and IFN-gamma, were significantly decreased in the CNS, while the level of antiinflammatory IL-4 was increased. Moreover, the mice in the 5C8H5 group induced more neurogenesis without microhemorrhage exacerbation and thereby performed better in behavioral assays than did the 4Abeta1-15 group. In conclusion, the novel monoclonal antibody induces more Abeta clearance and less microglial cell activation in the absence of inflammation, accompanied by an increased Th2-polarized immune response, which makes it a more promising therapeutic strategy. These data provide evidence that passive immunity could alleviate pathologic Abeta alterations by modulating inflammation and should be pursued further for the treatment of AD. PMID- 25817254 TI - Oxidant/Antioxidant imbalance and the risk of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia characterized by progressive loss of memory and other cognitive functions among older people. Senile plaques and neurofibrillary tangles are the most hallmarks lesions in the brain of AD in addition to neurons loss. Accumulating evidence has shown that oxidative stress-induced damage may play an important role in the initiation and progression of AD pathogenesis. Redox impairment occurs when there is an imbalance between the production and quenching of free radicals from oxygen species. These reactive oxygen species augment the formation and aggregation of amyloid-beta and tau protein hyperphosphorylation and vice versa. Currently, there is no available treatments can modify the disease. However, wide varieties of antioxidants show promise to delay or prevent the symptoms of AD and may help in treating the disease. In this review, the role of oxidative stress in AD pathogenesis and the common used antioxidant therapies for AD will summarize. PMID- 25817257 TI - Carotid and vertebral arterial variations in Alzheimer's disease. AB - The effects of carotid and vertebral arterial morphological variations on cognitive function impairment remain unclear. We investigated the association between extracranial carotid and vertebral arterial variations and the risk of Alzheimer's disease (AD). A prospective study with a 5-year followup was conducted from July 2008 to June 2013. A total of 1741 subjects (50 years of age and older) were examined for carotid and vertebral arterial variations using computed tomography angiography (CTA) and completed the study follow-up. Variations of the carotid and vertebral arteries were classified as tortuosity, kinking and coiling, according to the Weibel and Fields criteria. Cognitive function was assessed using the Mini-Mental State Examination and the Activities of Daily Living scale. We analyzed the association between arterial variations and the risk of AD by using multivariate Cox proportional-hazards models. The prevalence of carotid arterial variations was 38.4%, and the prevalence of vertebral arterial variations was 86.6%. Among the 1741 subjects who completed the study follow-up, 134 AD cases were detected. The subjects diagnosed with AD displayed greater kinking and coiling in the carotid artery (P<0.01) and vertebral artery (P<0.05) than the subjects without AD. After adjusting for potential confounders, kinking and coiling (hazard ratio [HR]=1.93, 95% confidence interval [CI], 1.37 to 2.86, P<0.01) in the carotid artery were significantly associated with AD. Additionally, after adjusting for potential confounders, kinking and coiling (HR=1.73, 95% CI, 1.25 to 2.31, P<0.01) in the vertebral artery were significantly associated with the risk of AD. We determined that age, hypertension and smoking status were significant predictors of AD in the multivariable models with carotid and vertebral arterial variation. The results of the current study indicate that severe carotid and vertebral arterial variations are associated with a significantly increased risk of AD. Further investigation into the association between these variations and AD would be useful for preventing AD. PMID- 25817258 TI - Generic immunosuppression in transplantation: current evidence and controversial issues. AB - The overall success of organ transplantation in the 21st century has been predicated, in part, on the use of newer, more potent, and selective immunosuppressive agents. However, the high cost of lifelong immunosuppression represents a financial burden for many patients. In the past 15 years, regulatory agencies in Europe and America have approved several generic immunosuppressants. One concern is whether the conversion between innovator and generic immunosuppressants will prove to be problematic. This manuscript aims to compare and contrast the bioequivalence requirements among regulatory authorities in the USA, Europe, and Canada, evaluate published studies of generic immunosuppressants in transplant recipients, summarize consensus statements made by transplant organizations and discuss how to engage patients in discussion regarding the choice between innovator and generic immunosuppressants. PMID- 25817259 TI - Differential cytokine expression detected by protein microarray screening in peripheral blood of patients with refractory Graves' disease. AB - OBJECTIVE: The prognosis of Graves' disease (GD) varies among patients. However, the immune pathogenesis of refractory GD is still unknown. The aim of this study was to explore the cytokine expression profile associated with refractory GD. METHODS: Preliminary cytokine protein microarray screening was performed to detect differentially expressed cytokines in the plasma of four patients with refractory GD and four patients with stable GD. Some differentially expressed cytokines were then validated in plasma by enzyme-linked immunosorbent assay (ELISA) and in peripheral blood mononuclear cells (PBMCs) by quantitative real time polymerase chain reaction (qRT-PCR) on another independent set of samples. RESULTS: We found that 21 cytokines were differentially expressed between patients with intractable GD and those in remission, including 18 upregulated and 3 downregulated cytokines with a fold change >1.30 and <0.77, respectively. Intractability-related elevation of three cytokines (IL-4, IL-6 and IL-10) was validated by ELISA in plasma on another GD cohort with 30 patients in recurrence and 14 in remission (t-test, P = 0.035, 0.033 and 0.041, respectively). Furthermore, mRNA expression of IL-4, IL-6 and IL-10 in PBMCs, detected by qRT PCR, was significantly elevated in patients with refractory GD compared with those in remission (P = 0.039, 0.047 and 0.042, respectively). CONCLUSION: The severity of GD is associated with the aberrant expression and secretion of several cytokines that may serve as potential biomarkers and predictors for disease prognosis. Targeting these cytokines or their receptors may also lead to a novel therapeutic intervention for GD. PMID- 25817261 TI - Preparative separation and purification of fumigaclavine C from fermented mycelia of Aspergillus fumigatus CY018 by macroporous adsorption resin. AB - In this work, the separation and purification of fumigaclavine C (FC), an ergot alkaloid with strong anti-inflammatory activity from fermented mycelia of Aspergillus fumigatus was systematically evaluated. Among the eight tested resins, the non-polar resin D101 displayed the best adsorption and desorption based on of static adsorption and desorption tests. Adsorption isotherms were constructed on D101 resin and fitted well to the Freundlich model. Dynamic adsorption and desorption tests on a column packed with D101 resin have been investigated for optimization of chromatographic parameters. Under optimized conditions, the contents of FC increased from 7.32% (w/w) in the crude extract to 67.54% in the final product with a recovery yield of 90.35% (w/w) via one run. Furthermore, a lab scale-up separation was carried out, in which the FC content and recovery yield were 65.83% and 90.13%, respectively. These results demonstrated that this adsorption-desorption strategy by using D101 resin was simple and efficient, thus showing potential for large scale purification and preparation of FC in the future. PMID- 25817262 TI - Selective microemulsion liquid chromatography analysis of dopamine receptor antagonist LE300 and its N-methyl metabolite in mouse sera by using a monolithic silica column. AB - A highly selective, sensitive, and rapid microemulsion liquid chromatography (MELC) method was developed and validated for the simultaneous determination of a novel type of dopamine receptor antagonist LE300 and its N-methyl metabolite in mouse sera. LE300, its N-methyl metabolite, and pindolol (an internal standard) were detected using excitation and emission wavelengths of 275 and 340 nm, respectively. HPLC analysis by using a monolithic column was performed by directly injecting the sample after appropriate dilution with the microemulsion mobile phase. The chromatographic behaviour of these compounds was studied to demonstrate their chromatographic efficiency, retention, and peak symmetry. The MELC method was validated for its specificity, linearity, accuracy, precision, robustness and stability. An experimental design was used during validation to evaluate method robustness. The calibration curves in serum showed excellent linearity (r=0.997) over concentrations ranging from 10 to 400 ngmL(-1) for LE300 and 15 to 500 ngmL(-1) for its N-methyl metabolite. The mean relative standard deviation (RSD) of the results of inter- and intra-day precision and accuracy of LE300 and its N-methyl metabolite were <=5%. The overall recoveries of LE300 and its N-methyl metabolite from mouse sera were in the range 97.9-101.5% with %RSD ranging from 0.98% to 3.63%, which were in line with ICH guidelines. The assay was successfully applied in a pharmacokinetic study. PMID- 25817260 TI - The C-terminal peptide plays a role in the formation of an intermediate form during the transition between xanthine dehydrogenase and xanthine oxidase. AB - Mammalian xanthine oxidoreductase can exist in both dehydrogenase and oxidase forms. Conversion between the two is implicated in such diverse processes as lactation, anti-bacterial activity, reperfusion injury and a growing number of diseases. We have constructed a variant of the rat liver enzyme that lacks the carboxy-terminal amino acids 1316-1331; it appears to assume an intermediate form, exhibiting a mixture of dehydrogenase and oxidase activities. The purified variant protein retained ~ 50-70% of oxidase activity even after prolonged dithiothreitol treatment, supporting a previous prediction that the C-terminal region plays a role in the dehydrogenase to oxidase conversion. In the crystal structure of the protein variant, most of the enzyme stays in an oxidase conformation. After 15 min of incubation with a high concentration of NADH, however, the corresponding X-ray structures showed a dehydrogenase-type conformation. On the other hand, disulfide formation between Cys535 and Cys992, which can clearly be seen in the electron density map of the crystal structure of the variant after removal of dithiothreitol, goes in parallel with the complete conversion to oxidase, resulting in structural changes identical to those observed upon proteolytic cleavage of the linker peptide. These results indicate that the dehydrogenase-oxidase transformation occurs rather readily and the insertion of the C-terminal peptide into the active site cavity of its subunit stabilizes the dehydrogenase form. We propose that the intermediate form can be generated (e.g. in endothelial cells) upon interaction of the C-terminal peptide portion of the enzyme with other proteins or the cell membrane. DATABASE: Coordinate sets and structure factors for the four crystal structures reported in the present study have been deposited in the Protein Data Bank under the identification numbers 4YRW, 4YTZ, 4YSW, and 4YTY. PMID- 25817264 TI - Evaluation of dermal extracellular matrix and epidermal-dermal junction modifications using matrix-assisted laser desorption/ionization mass spectrometric imaging, in vivo reflectance confocal microscopy, echography, and histology: effect of age and peptide applications. AB - This study was conducted to establish a new methodology for evaluating elements of dermal extracellular matrix (ECM), of epidermal-dermal junction (EDJ), and effects of molecules which can modulate their synthesis. This methodology is based on matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI). In vivo reflectance confocal microscopy (in vivo RCM) and echography were also used. Using immunohistochemistry methods on explants, age-related modification data were obtained for selected dermal ECM and EDJ proteins (collagen I, collagen IV, collagen VII, collagen XVII, nidogen I, decorin/decorunt) and used as reference for MALDI-MSI studies. A methodology was developed with MALDI-MSI to map epidermis and dermis proteins. Then MALDI-MSI was used to study age modifications. In vivo RCM and high-frequency ultrasounds were used to evaluate ECM and EDJ undulation modifications caused by aging. Anti-aging molecule evaluations were performed with a blend of palmitoyl oligopeptide and palmitoyl tetrapeptide-7. Immunohistochemistry studies demonstrated that the selected proteins were found to be less abundant in aged group explants vs. young group except for decorin. MALDI-MSI studies correlated the results obtained for decorin. In vivo RCM measurements indicated a decrease of EDJ undulation depth with age and ECM modifications in the upper part of dermis. Echography demonstrated that the peptide blend reduced subepidermal low-echogenic band thickness and improved its density. In vivo RCM studies indicated that the peptides improved the ECM structure vs. placebo. This preliminary MALDI-MSI study raised some technical difficulties that were overcome. Further studies will be conducted to identify more proteins and to demonstrate the interest of this method for cosmetic evaluations. PMID- 25817265 TI - Practical experience of biologics for treatment of very severe psoriasis: a retrospective case cohort study of patients with a baseline Psoriasis Area and Severity Index greater than 20. PMID- 25817263 TI - Capturing and identification of differentially expressed fucome by a gel free and label free approach. AB - This research reports a proof-of-concept that describes an instrumental approach that is gel free and label free at both the separation and mass spectrometry ends for the capturing and identification of differentially expressed proteins (DEPs) in diseases, e.g., cancers. The research consists of subjecting/processing equalized and non-equalized (i.e., untreated) disease-free and hepatocellular carcinoma (HCC) human sera via a multicolumn platform for capturing/fractionating human serum fucome. The equalization was performed via the combinatorial peptide ligand library (CPLL) beads technology that ensured narrowing the protein concentration range, thus allowing the detection of low abundance proteins. The equalized and non-equalized disease-free and HCC sera were first fractionated online onto two lectin columns specific to fucose, namely Aleuria aurantia lectin (AAL) and Lotus tetragonolobus agglutinin (LTA) followed by the online fractionation of the lectin captured fucome by reversed phase chromatography. The online desalted fractions were first subjected to trypsinolysis and then to liquid chromatography-mass spectrometry (LC-MS/MS) analysis. In comparison with untreated serum, the CPLL treated serum is superior in terms of the total number of identified DEPs, which reflected an increased number of DEPs in a wide abundance range. The DEPs in HCC serum were found to be 70 and 40 in both LTA and AAL fractions for the serum treated by CPLL and untreated serum, respectively. In addition, the platform combined with the CPLL treatment was accomplished with virtually no sample loss and dilution as well as with no experimental biases and sample labeling when comparing the diseased-free and cancer sera using LC-MS/MS. PMID- 25817266 TI - Regulation of the endothelial apelin/APJ system by hemodynamic fluid flow. AB - Although the apelin/APJ system is abundantly expressed in vascular endothelial cells (EC), it has not yet been considered to be regulated by fluid flow. The aim of this study was to explore the influence of shear stress on the expression of apelin/APJ in human EC. Therefore, gene and protein expression were assessed after flow exposure; cell supernatants were collected for measurements of NO and apelin; APJ or apelin knockdown were performed using siRNA. Our data show that gene and protein expression of apelin and APJ are modulated by fluid flow depending on the magnitude of shear stress. Moreover, apelin-12 activated NO production via PI3K/Akt signaling in human EC. In contrast, apelin-13 additionally activated Erk1/2 phosphorylation and enhanced EC proliferation. Knockdown of APJ inhibited phosphorylation of PI3K and impaired flow-induced eNOS and PECAM-1 expression. Knockdown of apelin had no influence on flow-induced APJ and PECAM-1 expression, but derogated eNOS expression under static and flow conditions. The present study reveals a flow-mediated adjustment of the apelin/APJ system in human EC in which APJ expression is induced by shear stress independently of its ligand. Furthermore, apelin-12 signaling is an essential regulatory element in endothelial NO synthesis. PMID- 25817267 TI - Red blood cells alloimmunization and autoimmunization among transfusion-dependent beta-thalassemia patients in Alexandria province, Egypt. AB - BACKGROUND: Beta thalassemia is considered a severe, progressive anemia, which needs regular transfusions for life expectancy. One of the most important complications of regular blood transfusions is autoimmunization and alloimmunization, which increases the need for transfusion. This study was performed to investigate the frequency of auto- and allo-antibodies in beta thalassemia patients in Alexandria, Egypt. MATERIALS AND METHODS: Blood samples of fourteen beta thalassemia patients were collected and tested for autosensitization with direct antiglobulin test (DAT). The positive DAT blood sample undergone antibody elution then identification. Plasma of the patients were also investigated for allosensitization by testing against cell panel reagents. RESULTS: DAT was positive in 45% of the patients. Eluted antibodies were identified in 6 cases of 10, they were Kp(b) and Lu(b), and one positive test was unidentified. Alloantibodies were detected in 42.5% of the cases. The identified antibodies were anti-D (4.76%), anti-c (4.76%), anti-K (4.76%), anti Kp(a) (9.52%), anti-Kp(b) (19.05%), anti-Lu(a) (9.52%), anti-Lu(b) (19.05%), and anti-Bg(a) (4.76%). A total 23.81% of the alloantibodies were unidentified. DISCUSSION: This study observes that autoimmunization and alloimmunization were more frequent among poly transfused beta thalassemia Egyptian patients. The presence of these clinically significant alloantibodies is a bad indicator for situation of blood transfusion. There is need for use an effective strategies to provide a safe blood for those patients by using leukodepleted blood and more compatible blood with extended phenotyping. PMID- 25817268 TI - Extended platelet concentrate storage/practice - A model based on the rationalized microbial monitoring. PMID- 25817269 TI - The effect of health education on Taiwanese hypertensive patients' knowledge and cognition of stroke. AB - BACKGROUND: Hypertension is a risk factor for stroke. Increasing patient knowledge and cognition about stroke among hypertensive patients is essential. AIMS: To explore the effect of a health education intervention on the knowledge and cognition of stroke in hypertensive patients. METHODS: A quasi-experimental design was used with 103 patients with hypertension. The sample was recruited from a cardiologist's outpatient office at a medical center in Kaohsiung city, southern Taiwan. Half the patients (experimental group, n = 52) received health education, whereas the others received only conventional general outpatient care (control group, n = 51). All patients underwent a pretest followed by posttests at 4 and 8 weeks after the intervention. A stroke knowledge scale and stroke cognition scale were used for data collection. RESULTS: The experimental group scored significantly higher than the control group in level of knowledge and cognition of stroke. DISCUSSION: This study supports that a health education CD ROM and printed information provided in the outpatient clinical improves knowledge of and cognition of stroke among hypertensive patients. IMPLICATIONS FOR PRACTICE: In outpatient clinical practice, nurses can help improve patients' knowledge and cognition of the risks of stroke by playing the health education CD ROM and providing printed information during the patients' wait time before appointments. CONCLUSIONS: Further studies with a longer follow-up (6 months or 1 year) are needed to evaluate the long-term effects of health education on stroke knowledge and cognition among patients with hypertension. LINKING EVIDENCE TO ACTION: An outpatient health education program using a CD-ROM and printed information for hypertensive patients can improve the patients' knowledge and cognition of stroke. PMID- 25817270 TI - Corrigendum: Annexin A2 promotes phagophore assembly by enhancing Atg16+ vesicle biogenesis and homotypic fusion. PMID- 25817271 TI - In silico analysis of human Toll-like receptor 7 ligand binding domain. AB - Toll-like receptors recognizing pathogen-associated molecular patterns are preface actors for innate immunity. Among them TLR7 is a transmembrane protein playing very crucial role in the signaling pathways involved in innate immunity by recognizing viral ssRNA and specific small molecule agonists. The unavailability of experimental 3D structure of this receptor till date hampers the focused exploration of TLR7 interaction with its ligands. However, several proteins possessing high homology domain enabled us to construct a reliable 3D model of hTLR7 ECD, which was employed to generate the homodimer model using protein-protein docking strategy. Further molecular docking studies between developed homodimer model and ligands were performed to explore the most preferred site of hTLR7 ECD interacting with ligands. The comparative analysis of docking energies and protein-ligand interactions of all the ligands revealed resiquimod as the prominent agonist. Furthermore, molecular interactions between protein-ligand complexes suggested LRR15 and LRR16 region of hTLR7 ECD as the most preferential site for ligand binding. The Ser434 and Gly437 of LRR15 region of hTLR7 were found to be conserved with Drosophila Toll protein. The obtained complex model may lead to a better understanding of TLR7 functioning along with its inheritance from invertebrates to mammals. PMID- 25817272 TI - Biomass allocation and long-term growth patterns of temperate lianas in comparison with trees. AB - The host-dependent support habit of lianas is generally interpreted as a strategy designed to reduce resource investment in mechanical tissues; this allows preferential allocation to leaf and stem extension, thereby enhancing productivity and competitive abilities. However, this hypothesis has not been rigorously tested. We examined the aboveground allometries regarding biomass allocation (leaf mass and current-year stem mass (approximated as biomass allocated to extension growth) vs total aboveground mass) and long-term apparent growth patterns (height and aboveground mass vs age, i.e. numbers of growth rings) for nine deciduous liana species in Japan. Lianas had, on average, three- and five-fold greater leaf and current-year stem mass, respectively, than trees for a given aboveground mass, whereas the time course to reach the forest canopy was comparable and biomass accumulation during that period was only one-tenth that of co-occurring canopy trees. The balance between the lengths of yearly stem extension and existing older stems indicated that lianas lost c. 75% of stem length during growth to the canopy, which is probably a consequence of the host dependent growth. Our observations suggest that, although lianas rely on hosts mechanically, allowing for short-term vigorous growth, this habit requires a large cost and could limit plant growth over protracted periods. PMID- 25817273 TI - Quantum phase transitions and string orders in the spin-1/2 Heisenberg-Ising alternating chain with Dzyaloshinskii-Moriya interaction. AB - Quantum phase transitions (QPTs) and the ground-state phase diagram of the spin 1/2 Heisenberg-Ising alternating chain (HIAC) with uniform Dzyaloshinskii-Moriya (DM) interaction are investigated by a matrix-product-state (MPS) method. By calculating the odd- and even-string order parameters, we recognize two kinds of Haldane phases, i.e. the odd- and even-Haldane phases. Furthermore, doubly degenerate entanglement spectra on odd and even bonds are observed in odd- and even-Haldane phases, respectively. A rich phase diagram including four different phases, i.e. an antiferromagnetic (AF), AF stripe, odd- and even-Haldane phases, is obtained. These phases are found to be separated by continuous QPTs: the topological QPT between the odd- and even-Haldane phases is verified to be continuous and corresponds to conformal field theory with central charge c = 1; while the rest of the phase transitions in the phase diagram are found to be c = 1/2. We also revisit, with our MPS method, the exactly solvable case of HIAC model with DM interactions only on odd bonds and find that the even-Haldane phase disappears, but the other three phases, i.e. the AF, AF stripe and odd-Haldane phases, still remain in the phase diagram. We exhibit the evolution of the even Haldane phase by tuning the DM interactions on the even bonds gradually. PMID- 25817274 TI - Investigation of Recessive Effects in Schizophrenia Using Next-Generation Exome Sequence Data. AB - A number of gene-wise approaches to analysis were applied to whole exome sequence data from 2545 Swedish schizophrenia cases with 2545 matched controls. A weighted burden test was used to detect dominant and additive effects. Recessive effects were investigated by testing whether there was an excess of cases bearing two or more rare, functional variants or whether there was an excess of cases in which both phased haplotypes carried at least one rare, functional variant. Counts for cases were compared with controls and also with the expectation under Hardy Weinberg equilibrium. Analyses were performed using the SCOREASSOC program. No gene produced statistically significant results although COMT was highly ranked by the weighted burden test and within it the Ala72Ser polymorphism rs6267 had an uncorrected p value of 0.00003. A number of spurious results were generated, some apparently due to miscalling of homozygotes and others due to a failure to eradicate the effects of linkage disequilibrium between variants. These problems were not marked when using phased haplotypes but this method failed to produce any significant or suggestive findings. If there are exonic variants with recessive effects on the risk of schizophrenia, then the methods used were unable to detect them. PMID- 25817276 TI - Verification of glycemic profiles using continuous glucose monitoring: cases with steroid use, liver cirrhosis, enteral nutrition, or late dumping syndrome. AB - Glycemic control is often difficult to achieve in patients with diabetes, especially in the presence of comorbid diseases or conditions such as steroid-use or liver cirrhosis, or in patients receiving enteral nutrition. Moreover, reactive hypoglycemia due to late dumping syndrome in people having undergone gastrectomy is also a matter of concern. Empirically and theoretically, the typical glycemic profiles associated with these conditions have been determined; however, what actually happens during a 24-h span is still somewhat obscure. In order to verify and provide information about the 24-h glycemic profiles associated with these conditions, 8 patients with the 4 above-mentioned conditions were monitored using a continuous glucose monitoring system (CGMS). For all 8 patients, CGMS provided detailed information regarding the 24-h glycemic profiles. The CGM results showed typical glycemic patterns for each condition, and we were moreover able to observe the effects of various practical treatments. Based on these cases, we conclude that the CGMS is highly useful for determining the glycemic patterns of patients with the aforementioned conditions in a practical setting; and this system may be used to monitor the treatment success of such cases. PMID- 25817275 TI - Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing. AB - In this study, we show that several microtubule-destabilizing agents used for decades for treatment of cancer and other diseases also sensitize cancer cells to oncolytic rhabdoviruses and improve therapeutic outcomes in resistant murine cancer models. Drug-induced microtubule destabilization leads to superior viral spread in cancer cells by disrupting type I IFN mRNA translation, leading to decreased IFN protein expression and secretion. Furthermore, microtubule destabilizing agents specifically promote cancer cell death following stimulation by a subset of infection-induced cytokines, thereby increasing viral bystander effects. This study reveals a previously unappreciated role for microtubule structures in the regulation of the innate cellular antiviral response and demonstrates that unexpected combinations of approved chemotherapeutics and biological agents can lead to improved therapeutic outcomes. PMID- 25817277 TI - A review of the pathomechanism of forward slippage in pediatric spondylolysis: the Tokushima theory of growth plate slippage. AB - Spondylolysis is a stress fracture of the pars interarticularis, which in some cases progresses to spondylolisthesis (forward slippage of the vertebral body). This slip progression is prevalent in children and occurs very rarely after spinal maturation. The pathomechanism and predilection for children remains controversial despite considerable clinical and basic research into the disorder over the last three decades. Here we review the pathomechanism of spondylolytic spondylolisthesis in children and adolescents, and specifically the Tokushima theory of growth plate slippage developed from our extensive research findings. Clinically, we have observed the slippage site near the growth plate on MRI; then, using fresh cadaveric spines, we found the weakest link against forward shear loading was the growth plate. We subsequently developed an immature rat model showing forward slippage after growth plate injury. Moreover, finite element analysis of the pediatric spine clearly showed increased mechanical stress at the growth plate in the spondylolytic pediatric spine model compared with the intact pediatric spine. Thus, spondylolysis progresses to spondylolisthesis (forward slippage) in children and adolescents with the growth plate as the site of the slippage. Repetitive mechanical loading on to the growth plate may serve to separate the growth plate and subsequently progress to spondylolisthesis. PMID- 25817278 TI - Epigenetic regulation of mammalian sex determination. AB - Epigenetics is the study of changes in gene function that cannot be explained by changes in DNA sequence. A mammalian body contains more than two-hundred different types of cells, all derived from a single fertilized egg. Epigenetic gene regulation mechanisms essentially contribute to various processes of mammalian development. The essence of epigenetic regulation is the modulation of gene activity through changes in chromatin structure. DNA methylation and histone modifications are the major epigenetic mechanisms. Sex determination is the process of establishing a gender. Sry, the sex-determining gene in therian mammals, initiates testis differentiation. Recent studies have provided evidence that epigenetic mechanisms contribute to Sry regulation. PMID- 25817279 TI - Recent progress in the development of genetically encoded Ca2+ indicators. AB - Genetically encoded calcium indicators (GECIs) are powerful tools to monitor the dynamics of calcium ion (Ca(2+)) in living cells and organisms. With the help of GFP technology and DNA engineering, a dozen sets of GECIs have been developed so far. Their application has been widely extended into the analysis at the subcellular local, single and population of cell. In the past decades, GECIs have been dramatically improved in their performance and are becoming more and more useful for live imaging. In this review, the progress in the development of GECIs is discussed by introducing the history and emerging GECIs, which would help the selection of the appropriate GECI for a given application. PMID- 25817280 TI - Neuroimaging in autism spectrum disorders: 1H-MRS and NIRS study. AB - Using proton magnetic resonance spectroscopy ((1)H-MRS), we measured chemical metabolites in the left amygdala and the bilateral orbito-frontal cortex (OFC) in children with autism spectrum disorders (ASD). The concentrations of N acetylaspartate (NAA) in these regions of ASD were significantly decreased compared to those in the control group. In the autistic patients, the NAA concentrations in these regions correlated with their social quotient. These findings suggest the presence of neuronal dysfunction in the amygdala and OFC in ASD. Dysfunction in the amygdala and OFC may contribute to the pathogenesis of ASD. We performed a near-infrared spectroscopy (NIRS) study to evaluate the mirror neuron system in children with ASD. The concentrations of oxygenated hemoglobin (oxy-Hb) were measured with frontal probes using a 34-channel NIRS machine while the subjects imitated emotional facial expressions. The increments in the concentration of oxy-Hb in the pars opercularis of the inferior frontal gyrus in autistic subjects were significantly lower than those in the controls. However, the concentrations of oxy-Hb in this area were significantly elevated in autistic subjects after they were trained to imitate emotional facial expressions. The results suggest that mirror neurons could be activated by repeated imitation in children with ASD. PMID- 25817281 TI - Clinical role of Foxp3+ regulatory T cell in Living donor related liver transplantation for prediction of life-threatening complications. AB - PURPOSES: It is no doubt that regulatory T cells (Foxp3(+)CD4(+)CD25(+)T cells: Treg) play important roles in transplant immunity. We investigated the significance of Treg expression in acute stage of living donorrelated liver transplantation (LDLT) for the possibility of the sensitive marker for immunological state and homeostatic stress after liver transplantation. METHODS: Peripheral blood was drawn from 5 recipients of LDLT preoperatively and on post operative 1, 4, 7, and 14 days. The peripheral blood mononuclear cells (PBMCs) were stained with CD4, CD25, Foxp3, and were analyzed with FACScan. This data was compared with clinical output of LDLT. RESULT: The populations of Treg were significantly decreased in all patients on day 1 after LDLT and significantly increased in patients who had early postoperative complications compared with patients who had no complications. CONCLUSIONS: The population of Treg in peripheral blood may reflect the surgical stress such as life-threatening complications after LDLT. PMID- 25817282 TI - Impact of newly developed, next-generation artificial endocrine pancreas. AB - BACKGROUND: Recent studies have shown that strict perioperative blood glucose management may reduce mortality and morbidity in critically ill adult patients. The purpose of this study was to assess the accuracy and efficacy of the intraoperative application of a newly developed, next-generation artificial endocrine pancreas (STG-55, Nikkiso Co., Ltd., Tokyo, Japan). METHODS: Twenty patients scheduled to undergo surgery were enrolled in this study. The STG-55 is designed to be more user-friendly than its conventional counterpart (STG-22) while maintaining the latter's fundamental functions, such as a closed-loop system using algorithms for insulin and glucose infusion. After anesthetic induction, a 20G intravenous catheter was inserted into a peripheral forearm vein and connected to a continuous blood glucose monitor. The resultant 105 scores for paired blood glucose values were compared by Bland-Altman analysis. RESULTS: Stable blood glucose values were maintained automatically, and there were no complications related to use of the STG-55. A close correlation (r=0.96) was observed between continuous glucose measurements using the STG-55 and conventional intermittent glucose measurements. The difficulty of manipulation using this system was decreased by improved preparation procedures. CONCLUSION: The glycemic control system using the STG-55 could provide an alternative way to achieve effective and safe perioperative glycemic control. PMID- 25817283 TI - Distribution and toxicity evaluation of ZnO dispersion nanoparticles in single intravenously exposed mice. AB - ZnO nanoparticles (NPs) have been widely used in various commercial products. Application of ZnO NPs is expected to apply to cancer diagnosis and therapy, used as drug delivery carriers. In the present study, the lethal dose 50 (LD50) of intravenously administered ZnO NPs (0.3 mg/kg) was calculated in mice. Blood kinetics and tissue distribution of a toxic dose of ZnO NPs (0.2 mg/kg, 0.05 mg/kg) were investigated after intravenous exposure. In addition, 8-hydroxy-2' deoxyguanosine (8-OHdG) was evaluated. Following the injection, ZnO NPs were rapidly removed from the blood and distributed to organs. Pulmonary emphysema was observed pathologically study in mice at 3 days after the 0.2 mg/kg dose and at 6 days after the 0.05 mg/kg dose. ZnO NPs were mainly accumulated in the lung and spleen within 60 min. From the long-term tissue distribution study, the liver showed peak concentration at 6 days, and spleen peaked at 1 day. The lungs kept high levels until 6 days. Tissue distribution and pathological study showed that the spleen, liver, and lungs are target organs for ZnO NPs. Accumulation in the liver and spleen may be due to the phagocytosis by macrophages. A dose-dependent increase in 8-OHdG was observed in mice treated with ZnO NPs. This study is the first to show information on kinetics and target organs following intravenous ZnO injection. PMID- 25817284 TI - Prefrontal activation during two Japanese Stroop tasks revealed with multi channel near-infrared spectroscopy. AB - The Stroop task is sometimes used in psychiatric research to elicit prefrontal activity, which presumably reflects cognitive functioning. Although there are two Stroop tasks (Kana script and Kanji script) in Japan, it is unclear whether these tasks elicit the same hemoglobin changes. Moreover, it is unclear whether psychological conditions or characteristics influence hemoglobin changes in the Japanese Stroop task. The aim of this study was to clarify whether hemoglobin changes elicited by the two Japanese Stroop tasks accurately reflected cognitive functioning. Hemoglobin changes were measured with multi-channel near-infrared spectroscopy (NIRS) in 100 healthy Japanese participants performing two Japanese Stroop tasks. The Beck-Depression Inventory (BDI), State-Trait-Anxiety Inventory (STAI), and Maudsley Obsessive Compulsive Inventory (MOCI) were administered to participants to identify psychological conditions or personality characteristics. Compared with the Kanji task, the Kana task produced a greater Stroop effect and a larger increase in oxyhemoglobin (oxy-Hb) concentration. Moreover there were no significant correlations between oxy-Hb concentration and BDI, STAI-trait, STAI state, or MOCI scores. Therefore we found that a participant's psychological conditions or characteristics did not influence the hemodynamic changes during either task. These data suggest the Kana Stroop task is more useful than the Kanji Stroop task for NIRS studies in psychiatric research. PMID- 25817285 TI - Gender differences of the influential factors on the mental health condition of teachers in the A university. AB - The purpose of this research was to investigate the gender differences of the influential factors on the mental health condition among university teachers in the A university in Japan. A questionnaire survey was mailed to 924 university teachers in Japan, with a survey return rate of 43.8% (N=405). The General Health Questionnaire 28 (GHQ-28), Multidimensional Scale of Perceived Social Support (MSPSS), the Japanese version of the Brief Coping Orientation to Problems Experienced (COPE) and the Work Situation Questionnaire (WSQ) developed by the authors were administered to subjects. The GHQ-28 total score and all of sub score of the woman was significantly higher than men. In the correlated factor of mental health, level of job satisfaction and job control, social support of significant others was observed in the both sexes. However, gender differences was observed in the coping style. Some copings including self-distraction and self-blame were related to the men, but the woman was related to the substance use. University teachers had some gender differences in the factors affecting their mental health condition. In order to improve university teacher's mental health condition, it is necessary to increase their level of job satisfaction and feeling of job control in the workplace. Especially, it was considered women's coping using substance use was important. PMID- 25817286 TI - Relationship between physique and food avoidance in infants: a study conducted in a community setting in Japan. AB - The relationship between food avoidance during infancy and the growth of Japanese infants in a community health setting has not been well evaluated. In order to assess the growth of infants who avoided either of the three major allergen foods in Japan, eggs, milk or wheat, we employed the results of 4 physical checkups recorded in maternity passbooks and administrated a questionnaire on allergic diseases, height and weight at birth to the guardians of 1,132 infants at the age of 3.5 years. Data was obtained from 890 subjects (78.6%) and 662 subjects (58.5%) who met the inclusion criteria were analyzed. The height, weight and body mass index percentile scores of each subject were calculated. Subjects who avoided either of the three foods at 3.5 years had lower weight percentile scores at 1.5 years, lower height and weight percentile scores at 3.5 years, and lower weight growth rates, compared with the subjects who did not avoid any of the three foods at 3.5 years (P=0.02, 0.03, 0.03, 0.01). The results suggested that there was a negative relationship between physique and food avoidance in infants, and that physical and nutritional assessments are important for food avoiders. PMID- 25817287 TI - Wakame (Undaria pinnatifida ) modulates hyperphosphatemia in a rat model of chronic renal failure. AB - In chronic renal failure, inorganic phosphate (Pi) retention speeds up the progression to end-stage renal disease. The current therapy for hyperphosphatemia in patients with chronic renal failure consists of dietary Pi restriction combined with administration of Pi binders, but each therapy has practical problems. Thus, the discovery of foods or nutrients that inhibit Pi absorption may be useful for the treatment of hyperphosphatemia. In the present study, we investigated whether wakame (Undaria pinnatifida) is a useful food for the prevention of hyperphosphatemia in a rat model of renal failure. Feeding a diet containing 5% wakame significantly decreased plasma and urinary Pi levels and increased the amount of fecal Pi. In addition, wakame significantly reduced plasma blood urea nitrogen and plasma Pi levels in 5/6 nephrectomized rats fed a high-Pi diet. Biochemical analyses showed that the reduction of intestinal Pi absorption is the main reason for the decrease in plasma Pi levels in rats fed a diet containing wakame. In addition, feeding alginic acid and fucoidan, major components of wakame fiber, was effective in reducing plasma Pi levels in normal rats. Finally, we concluded that wakame may be a useful food for the prevention of hyperphosphatemia in rodents. PMID- 25817289 TI - Rice bran extract containing acylated steryl glucoside fraction decreases elevated blood LDL cholesterol level in obese Japanese men. AB - People who frequently consume whole grains show a lower incidence of arteriosclerotic disease than people who consume primarily refined grains. We examined whether or not rice bran extract containing the acylated steryl glucosides (ASG) fraction decreases blood LDL cholesterol levels in obese Japanese men with high blood levels of LDL cholesterol. The study utilized a randomized, double-blind design. A total of 51 subjects were randomly allocated to either a rice bran extract containing ASG fraction (RB-ASG) group or a placebo group. Subjects in the RB-ASG group received 30-50 mg/day of RB-ASG, and the placebo group took 9 capsules/day for 12 weeks. Before and after intake, height, weight, body fat percentage, systolic and diastolic blood pressure were measured, blood was collected, and visceral fat area, subcutaneous fat area, and abdominal circumference were determined based on umbilical computed tomography. Percentage decreases in blood LDL cholesterol, non-HDL cholesterol, LDL/HDL ratio, abdominal circumference and subcutaneous fat area were significantly better in the RB-ASG group than in the placebo group. These findings suggest that RB-ASG fraction may reduce blood LDL cholesterol levels and the risk of arteriosclerosis in obese Japanese men with high LDL cholesterol levels. PMID- 25817288 TI - Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells. AB - VEGF-targeting anti-angiogenic drugs have enabled significant advances in cancer therapy. However, acquired resistance to VEGF-targeting drugs occurs, leading to disease progression. How tumors become the resistance remains fully uncertain. One of possible mechanisms for the resistance may be the direct effect of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGF-R). We investigated here the direct effect of chronic VEGF inhibition on phenotype changes in cancer cells. To chronically inhibit cancer cell-derived VEGF, human colon cancer HCT116 cells were chronically exposed (3 months) to anti-VEGF neutralizing monoclonal antibody (HCT/mAb cells, blockade of VEGF alone) or VEGF-R tyrosine kinase inhibitor foretinib (HCT/fore cells, blockade of all VEGF family). HCT/mAb cells redundantly increased VEGF family member (VEGF, PlGF, VEGF-B, VEGF-R1 and VEGF R2) and induced a resistance to hypoxia-induced apoptosis. By contrast, HCT/fore cells did not show the redundant increase in VEGF family member, but significantly increased a VEGF-independent pro-angiogenic factor FGF-2. HCT/fore cells showed increased migration and invasion activities in addition to a resistance to hypoxia-induced apoptosis. The resistance to apoptosis was significantly suppressed by inhibition of hypoxia-inducible factor-1alpha in HCT/mAb cells, but not in HCT/fore cells. These findings suggest that chronic inhibition of VEGF/VEGF-R accelerates malignant phenotypes of colon cancer cells. J. Med. Invest. 62: 75-79, February, 2015. PMID- 25817290 TI - Case of adult-onset Coats' disease with epiretinal membrane treated with 25-gauge pars plana vitrectomy. AB - We describe a case of untreated adult-onset Coats' disease with a proliferative epiretinal membrane (ERM) treated successfully with 25-gauge pars plana vitrectomy (25GPPV). A 26-year-old man presented with a 3-week history of decreased vision in his left eye. At the initial examination, the decimal best corrected visual acuity (BCVA) was 0.7 in the left eye. Ophthalmoscopy revealed the typical appearance of Stage 2A Coats' disease but with a proliferative ERM in the posterior pole. The patient received 2 monthly intravitreal injections of 2.5 mg bevacizumab, 5 laser photocoagulations to the area of telangiectasia, and 1 session of cryoretinopexy. Nine months after the initial visit, a traction by the ERM on the parafoveal area developed causing macular edema which reduced the BCVA to 0.3. He underwent 25GPPV with the removal of the ERM. In addition, the peripheral telangiectasia was treated intraoperatively with both laser photocoagulation and cryoretinopexy. Postoperatively, the traction to the parafoveal area was released and the BCVA improved to 0.6 which remained stable during the follow-up period of 13 months. We conclude that 25GPPV combined with ERM peeling, laser photocoagulation, and cryoretinopexy can be effective for adult-onset Coats' disease associated with an ERM. PMID- 25817291 TI - Huge splenic epidermoid cyst with elevation of serum CA19-9 level. AB - A 30-year-old female was referred to our hospital for further examination of liver dysfunction. A huge, soft mass was noted in her left upper quadrant on physical examination. Abdominal ultrasonography and computed tomography revealed a huge cystic tumor of 20 cm in the hilus of the spleen. Serum CA19-9 was 491 U/ml, and splenectomy was performed under suspicion of a malignant cystic tumor. The inner surface of the cyst was lined by squamous epithelial cells that were immunohistochemically positive for CA19-9. Serum CA19-9 level was normalized after the surgery. Our case of a very rare, huge epidermoid cyst of the spleen suggests that measurement of the serum CA19-9 level is useful for evaluating therapeutic efficacy of a splenic epidermoid cyst. PMID- 25817292 TI - Transient severe hypotension with once-weekly subcutaneous injection of teriparatide in osteoporotic patient: a case report and insight for the drug interaction between hypotensive agents and teriparatide. AB - Teriparatide, a recombinant form of parathyroid hormone, were well recognized as a useful option for the treatment of the osteoporosis. Although some side effects of teriparatide include headache, nausea, dizziness, and limb pain were reported. Here we present a 80-year-old woman of transient asymptomatic hypotension with once-weekly subcutaneous injection of teriparatide for the treatment of osteoporosis with hypertension disease as acute-phase reactions. Systolic blood pressure decreased in both 30 min and 60 min after injection compared with before injection. Heart rate increased with passage of time. Statistically significant were observed among before, 30 min, 60 min after injection of teriparatide. Slight nausea was seen as subjective symptoms with the first and second injection after 30 min. This case indicates careful attention, at least 1 hr, was recommended with weekly subcutaneous injections of teriparatide in the treatment for osoteoproteic patient with hypertension decreases. This is a first report, to the best of our knowledge, to demonstrate the transient asymptomatic hypotension after once-weekly injection of teriparatide with hypertension disease. Transient hypotension occurred after injection of teriparatide during the treatment period and was asymptomatic except for the first 2 injections. PMID- 25817293 TI - Salmonella osteomyelitis of the distal radius in a healthy young adult patient: report of a rare case and literature review. AB - Salmonella osteomyelitis of the radius in a healthy individual is very rare. We present such a case involving the distal radius of a healthy 23-year-old man without underlying disease or possible episode. He had right wrist pain for approximately 3 years, and osteolytic lesion was seen in the right distal radius. He underwent surgical treatment, and salmonella was isolated from pus in the lesion. Postoperative antibiotics successfully treated his infection. He had no sign of recurrence, but the point of entry for infection remains unknown. PMID- 25817294 TI - Percutaneous endoscopic lumbar discectomy for a huge herniated disc causing acute cauda equina syndrome: a case report. AB - Microsurgery for lumbar disc herniation that requires surgical intervention has been well described. The methods vary from traditional open discectomy to minimally invasive techniques. All need adequate preanesthetic preparation of patients as general anesthesia is required for the procedure, and nerve monitoring is necessary to prevent iatrogenic nerve injury. Conventional surgical techniques sometimes require the removal of the corresponding lamina to assess the nerve root and herniated disc, and this may increase the risk for posterior instability of the vertebral body. Should this occur, fusion surgery may be needed, further increasing morbidity and cost. We present here a case of lumbar herniated disc fragments causing acute cauda equina syndrome that were endoscopically resected through a transforaminal approach in an awake patient under local anesthesia. Percutaneous endoscopic discectomy under local anesthesia proved to be a better alternative to open back surgery as it made immediate intervention possible, was associated with fewer perioperative complications and morbidity, minimized soft tissue damage, and allowed early rehabilitation with a better outcome and greater patient satisfaction. In addition to these advantages, percutaneous endoscopic discectomy protects other approaches that may be needed in subsequent surgeries, whether open or minimally invasive. PMID- 25817295 TI - Household endotoxin exposure and increased risk of diabetes in older adults. PMID- 25817296 TI - Prognostic roles of absolute monocyte and absolute lymphocyte counts in patients with advanced-stage follicular lymphoma in the rituximab era: an analysis from the FOLL05 trial of the Fondazione Italiana Linfomi. AB - Recently, in an attempt to improve the discrimination power of the international prognostic index (IPI), patients with diffuse large B-cell lymphoma were evaluated to determine the prognostic roles of peripheral blood absolute monocyte count (AMC) and absolute lymphocyte count (ALC). Here, we analysed data of 428 patients with follicular lymphoma (FL) enrolled in a prospective, randomized trial (FOLL05 study) conducted by Fondazione Italiana Linfomi, to assess the impact of AMC and ALC on progression-free survival (PFS). All patients had been treated with one of three treatment combinations: (i) rituximab (R) plus cyclophosphamide, vincristine and prednisone; (ii) R plus cyclophosphamide, doxorubicin, vincristine and prednisone or (iii) R plus mitoxantrone and fludarabine. We showed that only AMC was a powerful predictor of PFS, and possibly overall survival, in patients with FL treated with combination chemotherapy regimens that contained R. The AMC can be used alone as a novel, simple factor that can predict survival outcome in patients with FL, independent of the immunochemotherapy regimen. It may therefore be widely used by clinicians, due to its simplicity and broad applicability. Additionally, it can be combined with other factors that determine the IPI or FLIPI, to increase the discriminating ability of these indices. PMID- 25817297 TI - From admission to discharge in mental health services: a qualitative analysis of service user involvement. AB - BACKGROUND: User involvement and recovery are now widely used terms within the mental health policy, research and practice discourse. However, there is a question mark about the impact these ideas have in everyday practice. Of interest is the degree of involvement in key transitions of care. In particular, admission to and discharge from acute inpatient mental health wards. OBJECTIVE: To explore the nature of service user involvement in the admission and discharge process into and out of acute inpatient mental health care. DESIGN: A qualitative study using focus groups. SETTING AND PARTICIPANTS: One acute, inpatient mental health ward was the focus of the study. Seven uniprofessional focus group interviews were conducted with ward staff, community staff and service users (total number of participants = 52). Conventional, thematic qualitative techniques were used to analyse the data. RESULTS: The data analysed and presented in this article relate to the loss of the service user voice at the key transition points into and out of acute inpatient care. Due to the lack of resources (inpatient beds and community care follow-up), the role service users could play was diminished. In their narratives, clinical staff associated the person with the process and used language which dehumanized the individual. CONCLUSION: Service users experience numerous care transitions into and out of hospital. As there is the potential for these encounters to have a lasting negative effect, the importance of ensuring service users have a voice in what is happening to them is crucial. PMID- 25817298 TI - GBD-2010 overestimates deaths from road injuries in OECD countries: new methods perform poorly. AB - BACKGROUND: We assessed the quality of Global Burden of Disease-2010 (GBD-2010) estimates of road injury deaths by comparing with government statistics for Organisation for Economic Co-operation and Development (OECD) countries that report to the International Road Traffic Accident Database (IRTAD). METHODS: We obtained tabulated data for 25 OECD countries that report to IRTAD and also report vital registration (VR) data to WHO. We collated VR deaths corresponding to the GBD-2010 road injury definition and estimated 'traffic', 'non-traffic' and 'unspecified whether traffic or non-traffic' components. We estimated national road injury deaths by redistributing partially specified causes of death, as was done by GBD until this was replaced by more complex methods in GBD-2010. RESULTS: GBD-2010 estimates of road injury deaths exceeded IRTAD by 45% overall. IRTAD values fell below the GBD-2010 95% uncertainty interval in all but three countries. Mismatch of conceptual scope accounted for about 8% of this discrepancy, 5% was because GBD-2010 included cases other than road traffic and 3% because GBD-2010 (unlike IRTAD) includes deaths >30 days after injury. Pro rata distribution of partially specified causes in VR data gave estimates that were 18% higher than IRTAD but closer than GBD-2010 estimates for all but two countries. Cases in VR data specified as road injury gave estimates closer to IRTAD. CONCLUSIONS: GBD-2010 road injury mortality estimates are substantially higher than the road death toll in OECD countries. The discrepancy is not explained by wider scope of the GBD road injury construct nor by undercounting by IRTAD. GBD-2010 likely attributed substantially more deaths with partially specified causes to road injuries than is appropriate. PMID- 25817299 TI - Use of perioperative hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasty and association with adverse outcomes: a retrospective population based analysis. AB - OBJECTIVE: To determine whether the perioperative use of hydroxyethyl starch 6% and albumin 5% in elective joint arthroplasties are associated with an increased risk for perioperative complications. DESIGN: Retrospective cohort study of population based data between 2006 and 2013. SETTING: Data from 510 different hospitals across the United States participating in the Premier Perspective database. PARTICIPANTS: 1,051,441 patients undergoing elective total hip and knee arthroplasties. EXPOSURES: Perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5%, or neither. MAIN OUTCOME MEASURES: Acute renal failure and thromboembolic, cardiac, and pulmonary complications. RESULTS: Compared with patients who received neither colloid, perioperative fluid resuscitation with hydroxyethyl starch 6% or albumin 5% was associated with an increased risk of acute renal failure (odds ratios 1.23 (95% confidence interval 1.13 to 1.34) and 1.56 (1.36 to 1.78), respectively) and most other complications. A recent decrease in hydroxyethyl starch 6% use was noted, whereas that of albumin 5% increased. CONCLUSIONS: Similar to studies in critically ill patients, we showed that use of hydroxyethyl starch 6% was associated with an increased risk of acute renal failure and other complications in the elective perioperative orthopedic setting. This increased risk also applied to albumin 5%. These findings raise questions regarding the widespread use of these colloids in elective joint arthroplasty procedures. PMID- 25817300 TI - Genetic association of interleukin-2, interleukin-4, interleukin-6, transforming growth factor-beta, tumour necrosis factor-alpha and blood concentrations of calcineurin inhibitors in Turkish renal transplant patients. AB - Cytokines are essential for the control of the immune response as most of the immunosuppressive drugs target cytokine production or their action. The calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus are immunosuppressive drugs widely used after renal transplantation to prevent allograft rejection. They are characterized by large interindividual variability in their pharmacokinetics; therefore, monitoring their blood concentrations is important to predict their optimal dosage following transplantation. Calcineurin inhibitors inhibit the phosphatase activity of calcineurin, thereby suppressing the production of other cytokines such as transforming growth factor (TGF-beta), tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-2, and IL-4. The aim of this study was to investigate the relationship between polymorphisms of cytokines and blood concentrations of CNIs in renal transplant patients. The study included 53 CsA-treated renal transplant patients and 37 tacrolimus-treated renal transplant patients. Cytokine polymorphisms were analysed using polymerase chain reaction (PCR) sequence-specific primers with the cytokine CTS-PCR-sequence specific primers Tray Kit; University of Heidelberg. Blood concentrations of CNIs were determined with Cloned Enzyme Donor Immunoassay (CEDIA) method. Patients with TC genotype of TGF-beta at codon 10 had lower CsA blood concentrations than the TT and CC genotypes (P = 0.005) at 1 month in CsA treatment group. The ratio of blood concentration/dose of CsA for patients with TGF-beta1-codon 10 TC genotype was lower than for patients with TT, CC genotypes, and the dose given to these patients was higher in the first month (P = 0.046). The ratio of blood concentration/dose of CsA for patients with IL-2-330 GG genotype was higher than for patients with GT, TT genotypes, and the dose given to these patients was lower at first month and sixth months (P = 0.043, P = 0.035 respectively). The tacrolimus blood concentrations were significantly higher in patients with the genotype GG of IL-2-330 (P = 0.012) at the third month. Patients who had the TC genotype TGF-beta codon 10 had lower CsA blood concentrations and this group had higher acute rejection (P = 0.033). These results suggest that the genotyping for TGF-beta-codon 10, IL-2-330 and IL-6-174 polymorphisms may help individualized immunosuppressive dosage regiments. PMID- 25817301 TI - More similarities than differences between men and women with irritable bowel syndrome. AB - BACKGROUND: Differences regarding symptoms, coping abilities, and quality of life (QOL) between men and women with irritable bowel syndrome (IBS) have been reported but data are sparse and sometimes conflicting. The aim of present study was to investigate gender differences in gastrointestinal, extra-intestinal, and psychological symptoms, and sense of coherence (SOC) and QOL in a large group of patients diagnosed with IBS. METHODS: We analyzed questionnaire data from 557 patients (152 men) diagnosed with IBS consecutively included in studies at an outpatient clinic for functional bowel disorders between 2002 and 2010. Following questionnaires were included: IBS severity scoring system (IBS-SSS), Hospital Anxiety and Depression Scale (HAD), IBSQOL Scale, Visceral Sensitivity Index (VSI), SOC Scale, Bristol Stool Form Scale (BSFS), and Patient Health Questionnaire (PHQ-15). KEY RESULTS: Women had harder stools (FDR-adjusted p value: q = 0.033), more severe bloating (q = 0.020), higher symptom severity (q = 0.042), higher total somatic symptom burden (q = 0.035), lower SOC (q = 0.042), and lower QOL. Women rated more general anxiety (q = 0.017) and gastrointestinal specific anxiety (q = 0.042), but there were no group differences in depression, pain, stool frequency, impact on daily life, dissatisfaction with bowel habit, or extra-colonic symptoms. The differences found were small (effect sizes: r < 0.3). CONCLUSIONS & INFERENCES: In this study, we demonstrated more similarities than differences between men and women with IBS. The largest difference were seen for QOL which might reflect certain structural stressors to which women in general are more exposed than men. PMID- 25817302 TI - Expression of genes of the cardiac and renal renin-angiotensin systems in preterm piglets: is this system a suitable target for therapeutic intervention? AB - OBJECTIVES: The newborn circulating, cardiac and renal renin-angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets. METHODS: Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R). RESULTS: All the genes studied were expressed in the kidney; neither renin nor AT2R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT1R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT2R mRNA abundance was highest in GC treated preterm piglets, and the AT1R/AT2R ratio was increased at term. CONCLUSIONS: Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT1R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs. PMID- 25817303 TI - Electrophilic Aromatic Deuteration of Lignans: Mostly Reliable but Occasionally Aberrant Selectivities. AB - Lignans are a ubiquitous group of natural products of plant or mammalian origin. In the human diet, especially in fiber-rich foods, there are measurable amounts of lignans. Lignan intake is associated with a reduced risk of a range of chronic Western diseases, and in studying these compounds and their biological activity, authentic stable isotope labeled analogues are needed. This review summarizes the reported labeling methods and discusses the selectivity and reactivity in the electrophilic aromatic deuteration of lignans where recently a number of unexpected selectivities or nonselectivities have been encountered. PMID- 25817304 TI - Infiltrating hybrid mesenchymal tumor of skeletal muscle showing lipomatous, hemangiomatous, leiomyomatous and osseous features - An unusual soft tissue tumor providing insight into the pathogenesis of lipoma variants. AB - Infiltrating angiolipoma and osteolipoma of the hand are rare. A 40-year-old man presented with slowly enlarging swelling of his right hand for two and half years without functional deficit but it became painful with slight limitation of movement for the past few months. Plain radiograph showed a large soft tissue swelling with specks of calcifications. Ultrasonography and magnetic resonance imaging revealed an infiltrative mass in the right palm deep to the flexor tendons. As biopsy suggested infiltrative angiolipoma of skeletal muscle, debulking of the tumor was performed. The tumor showed coexistence of all four mesenchymal elements, fat, blood vessel, smooth muscle and bone in various combinations in the form of angiolipomatous, osteolipomatous, ossified intramuscular hemangiomatous, myolipomatous and angiomyolipomatous patterns throughout the entire tumor. Small meningothelial-like whorls of spindle cells were focally seen, some showed intramembranous ossification forming small woven bony spicules in their centers. There were no atypical cells or lipoblasts. Staining for CDK4, MDM2, p16, HMB45 and Melan A was negative. The diagnosis was "infiltrating hybrid mesenchymal tumor of skeletal muscle showing lipomatous, hemangiomatous, leiomyomatous and osseous features". The fairly even admixture of the various components supports the neoplastic participation of each individual element. Hybrid mesenchymal tumor most probably originates from multipotent neoplastic cells showing multidirectional differentiation. PMID- 25817305 TI - Bisphosphonate-associated peri-implant fractures: a new clinical entity? A series of 10 patients with 11 fractures. AB - BACKGROUND AND PURPOSE: The current definition of atypical femoral fractures (AFFs) associated with bisphosphonate use includes only de novo fractures. However, in recent years reports of bisphosphonate-associated periprosthetic fractures involving stemmed arthroplasty implants have emerged. In a case series of peri-implant fractures in femurs with plate/screw constructs, we aimed to assess similarities with classical AFFs and how their location may have implications for the pathogenesis and management of AFFs. PATIENTS AND METHODS: We retrospectively identified 10 patients with 11 peri-implant fractures. RESULTS: The patients were ambulant women, mean age 80 (70-92) years. Mean duration of bisphosphonate use was 5 (1-10) years. The peri-implant fractures were sustained an average of 4 years (6 months to 9 years) from the time of index surgery. They were all associated with low-energy mechanisms. 8 fractures occurred near the tip of a plate, while 3 traversed the penultimate screwhole of a plate. The peri-implant fractures showed clinical and radiological features of atypicality such as lateral cortical thickening, simple fracture pattern, and lack of comminution. The patients underwent revision surgery, with bone grafting used in all but 1 case. Radiological union was evident after 2-4 months. INTERPRETATION: Atypical peri-implant fractures of the femur associated with bisphosphonate use may be a new entity. Stress lesions and atypical fractures may tend to develop over stress risers along the operated femur. This finding has implications for the pathogenesis and clinical management of AFFs. PMID- 25817306 TI - Significant Reduction in Mitral Regurgitation Volume Is the Main Contributor for Increase in Systolic Forward Flow in Patients with Functional Mitral Regurgitation after Transcatheter Aortic Valve Replacement: Hemodynamic Analysis Using Echocardiography. AB - BACKGROUND: Reduction in mitral regurgitation (MR) after transcatheter aortic valve replacement (TAVR) has previously been reported. However, the hemodynamic effects of TAVR in patients with MR have not been previously evaluated. METHODS: We analyzed 571 patients who underwent TAVR from December 2010 to December 2013. We studied 20 patients with moderate or severe preprocedural functional mitral regurgitation (FMR) who also had a follow-up transthoracic echocardiography (TTE) examination between 90 and 360 days (median 213 days) after TAVR (Significant FMR Group). We also studied age- and gender-matched 20 patients with mild or lesser MR (Nonsignificant MR Group). Left ventricular functional measurements were assessed using echocardiography before and after TAVR. Left ventricular outflow tract stroke volume measurements using pulsed-wave Doppler (SVLVOT ) were calculated as a representative of systolic forward flow, and stroke volume by the Simpson's method (SVSimpson ) was calculated as a parameter of degree of LV contraction. RESULTS: MR grade improved in 22 of 40 patients after TAVR. In both groups, BNP level decreased, left ventricular ejection fraction increased, and SVLVOT increased after TAVR. SVSimpson increased in the Nonsignificant MR Group and remained unchanged in the Significant FMR Group. Vena contracta width of MR (MRVC) decreased in the Significant FMR Group. Using multivariable analysis in the Significant FMR Group, the increase in SVLVOT significantly correlated with the decrease in MRVC (P < 0.05). CONCLUSIONS: SVLVOT increased significantly after TAVR in patients with FMR. In these patients, increase in SVLVOT after TAVR was associated with decrease in severity of MR. PMID- 25817307 TI - Corrigendum. PMID- 25817308 TI - [Benefits of using the cutometer to evaluate the effectiveness of skin treatments in plastic and maxillofacial surgery]. AB - INTRODUCTION: Evaluating skin properties is often too subjective. Using the cutometer allows one to take objective measures of certain mechanic properties of the skin such as visco-elasticity. The aim of this article is to evaluate through a review of existing literature the advantages and the limits of the cutometer and to propose an improvement. MATERIAL AND METHODS: The selection of articles has been conducted with the PubMed database in order to identify all publications concerning the cutometer up until September 2013. The analysis criteria were: (1) quantitative distribution of articles from the first publication until today; (2) qualitative distribution over the various medical fields. The articles have been organized in 3 groups: medical, surgical and burns; (3) list of biases in the interpretation of results and limits of this measuring tool. RESULTS: One hundred and twenty-nine publications have been included. The first article regarding the cutometer was published in 1994. We observe an increase in the number of publications after 2005. Most of the articles were published in medical journals of dermatology or cosmetology (83%), only 9% of articles have been published in burn study journals and 8% in surgical journals. The pressure applied by the experimenter constitutes the main measure bias. DISCUSSION: The use of an external device maintaining the probe with an invariable pressure corresponding to its own weight enables more reliable results all the while limiting the inter- and intra-individual variability. PMID- 25817309 TI - Contamination of the southern Baltic Sea waters by the residues of selected pharmaceuticals: Method development and field studies. AB - In this study the occurrence of thirteen pharmaceuticals in seawaters collected from southern Baltic Sea was evaluated for the first time. It was performed by applying newly developed analytical procedure. The method was characterized in terms of its basic validation parameters as well as matrix effects, extraction efficiency and absolute recovery. The results were expressed as result +/- expanded uncertainty, which was estimated according to the Guide to the Expression of Uncertainty in Measurement. Additionally, in order to verify the influence of variable parameters of the analyzed samples on method performance parameters, chemometric analysis was carried out. The obtained results revealed that residues of pharmaceuticals were present in seawaters at a concentration level of ng L(-1). Trimethoprim, sulfamethoxazole and enrofloxacin were most frequently detected compounds. The highest concentration was determined for ketoprofen (135.0 +/- 10.9 ng L(-1)). Marine pollution potential hotspots were found in enclosed or semi-enclosed bodies of water. PMID- 25817310 TI - Applications of biological tools or biomarkers in aquatic biota: A case study of the Tamar estuary, South West England. AB - Biological systems are the ultimate recipients of pollutant-induced damage. Consequently, our traditional reliance on analytical tools is not enough to assess ecosystem health. Biological responses or biomarkers are therefore also considered to be important tools for environmental hazard and risk assessments. Due to historical mining, other anthropogenic activities, and its conservational importance (e.g. NATURA sites, SACs), the Tamar estuary in South West England is an ideal environment in which to examine applications of such biological tools. This review presents a thorough and critical evaluation of the different biological tools used in the Tamar estuary thus far, while also discussing future perspectives for biomarker studies from a global perspective. In particular, we focus on the challenges which hinder applications of biological tools from being more readily incorporated into regulatory frameworks, with the aim of enabling both policymakers and primary stakeholders to maximise the environmental relevance and regulatory usefulness of such tools. PMID- 25817311 TI - Effects of light pollution on the emergent fauna of shallow marine ecosystems: Amphipods as a case study. AB - Light pollution from coastal urban development is a widespread and increasing threat to biodiversity. Many amphipod species migrate between the benthos and the pelagic environment and light seems is a main ecological factor which regulates migration. We explore the effect of artificial lighting on amphipod assemblages using two kind of lights, LED and halogen, and control traps in shallow waters of the Great Barrier Reef. Both types of artificial light traps showed a significantly higher abundance of individuals for all species in comparison to control traps. LED lights showed a stronger effect over the amphipod assemblages, with these traps collecting a higher number of individuals and differing species composition, with some species showing a specific attraction to LED light. As emergent amphipods are a key ecological group in the shallow water environment, the impact of artificial light can affect the broader functioning of the ecosystem. PMID- 25817312 TI - Impact of industrial pollution on recent dinoflagellate cysts in Izmir Bay (Eastern Aegean). AB - The spatial distribution of dinoflagellate cysts was studied to understand the impact of industrial pollution on the surface sediment of Izmir Bay, Turkey. Forty two dinoflagellate cyst morphotypes belonging to 12 genera were identified and qualified at 12 sampling points. The cyst of Gymnodinium nolleri dominated the bay and had the highest abundance in most of the stations, following Spiniferites bulloideus and Lingulodinium machaerophorum. The highest cyst concentration was recorded in the inner part of the bay. Cyst concentration ranged between 384 and 9944 cyst g(-1) dry weight of sediment in the sampling area. Sediment metal concentrations were determined. Heavy metal levels in Izmir Inner Bay were higher than the Middle and Outer Bay. L. machaerophorum, Dubridinium caperatum and Polykrikos kofoidii showed significant positive correlation with some metals (Cd, Pb, Cu, Zn) and organic carbon content. However, there was no significant correlation between dinoflagellate cyst abundance and sediment type. PMID- 25817314 TI - Development of bioelectrocatalytic activity stimulates mixed-culture reduction of glycerol in a bioelectrochemical system. AB - In a microbial bioelectrochemical system (BES), organic substrate such as glycerol can be reductively converted to 1,3-propanediol (1,3-PDO) by a mixed population biofilm growing on the cathode. Here, we show that 1,3-PDO yields positively correlated to the electrons supplied, increasing from 0.27 +/- 0.13 to 0.57 +/- 0.09 mol PDO mol(-1) glycerol when the cathodic current switched from 1 A m(-2) to 10 A m(-2) . Electrochemical measurements with linear sweep voltammetry (LSV) demonstrated that the biofilm was bioelectrocatalytically active and that the cathodic current was greatly enhanced only in the presence of both biofilm and glycerol, with an onset potential of -0.46 V. This indicates that glycerol or its degradation products effectively served as cathodic electron acceptor. During long-term operation (> 150 days), however, the yield decreased gradually to 0.13 +/- 0.02 mol PDO mol(-1) glycerol, and the current-product correlation disappeared. The onset potentials for cathodic current decreased to 0.58 V in the LSV tests at this stage, irrespective of the presence or absence of glycerol, with electrons from the cathode almost exclusively used for hydrogen evolution (accounted for 99.9% and 89.5% of the electrons transferred at glycerol and glycerol-free conditions respectively). Community analysis evidenced a decreasing relative abundance of Citrobacter in the biofilm, indicating a community succession leading to cathode independent processes relative to the glycerol. It is thus shown here that in processes where substrate conversion can occur independently of the electrode, electroactive microorganisms can be outcompeted and effectively disconnected from the substrate. PMID- 25817313 TI - Fast growth involves high dependence on stored resources in seedlings of Mediterranean evergreen trees. AB - BACKGROUND AND AIMS: The carbon (C) and nitrogen (N) needed for plant growth can come either from soil N and current photosynthesis or through remobilization of stored resources. The contribution of remobilization to new organ growth on a whole-plant basis is quite well known in deciduous woody plants and evergreen conifers, but this information is very limited in broadleaf evergreen trees. This study compares the contribution of remobilized C and N to the construction of new organs in spring, and assesses the importance of different organs as C and N sources in 1-year-old potted seedlings of four ecologically distinct evergreen Mediterranean trees, namely Quercus ilex, Q. coccifera, Olea europaea and Pinus hapelensis. METHODS: Dual (13)C and (15)N isotope labelling was used to unravel the contribution of currently taken up and stored C and N to new growth. Stored C was labelled under simulated winter conditions. Soil N was labelled with the fertilization during the spring growth. KEY RESULTS: Oaks allocated most C assimilated under simulated winter conditions to coarse roots, while O. europaea and P. halepensis allocated it to the leaves. Remobilization was the main N source (>74 %) for new fine-root growth in early spring, but by mid-spring soil supplied most of the N required for new growth (>64 %). Current photosynthesis supplied >60 % of the C in new fine roots by mid-spring in most species. Across species, the proportion of remobilized C and N in new shoots increased with the relative growth rate. Quercus species, the slowest growing trees, primarily used currently acquired resources, while P. halepensis, the fastest growing species, mainly used reserves. Increases in the amount of stored N increased N remobilization, which fostered absolute growth both within and across species. Old leaves were major sources of remobilized C and N, but stems and roots also supplied considerable amounts of both in all species except in P. halepensis, which mainly relied on foliage formed in the previous growing season to supply stored resources. CONCLUSIONS: Seedlings of Mediterranean evergreen trees have distinct C and N storage physiologies, with relative growth rate driving the contribution of remobilized resources to new growth. These differences may reduce competition and facilitate species coexistence. PMID- 25817315 TI - Is the noun ending a cue to grammatical gender processing? An ERP study on sentences in Italian. AB - Gender-to-ending consistency has been shown to influence grammatical gender retrieval in isolated word presentation. Notwithstanding the wealth of evidence, the exact role and the time course of processing of this distributional information remain unclear. This ERP study investigated if and when the brain detects gender-to-ending consistency in sentences containing Italian determiner noun pairs. Determiners either agreed or disagreed in gender with the nouns whose endings were reliable or misleading cues to gender (transparent and irregular nouns). Transparent nouns elicited an increased frontal negativity and a late posterior positivity compared to irregular nouns (350-950 ms), suggesting that the system is sensitive to gender-to-ending consistency from relatively early stages of processing. Gender agreement violations evoked a similar LAN-P600 pattern for both types of nouns. The present findings provide evidence for an early detection of reliable gender-related endings during sentence reading. PMID- 25817316 TI - Stretch-induced changes in tension generation process and stiffness are not accompanied by alterations in muscle architecture of the middle and distal portions of the two gastrocnemii. AB - The study aimed to evaluate the stretch-induced changes in muscle architecture in different portions of the gastrocnemius medialis (GM) and lateralis (GL) muscles. The reliability and sensitivity of the measurements were also assessed. Fascicle length (FL) and pennation angle (PA) were calculated in the middle and distal portions of GM and GL at 0 degrees , 10 degrees and 20 degrees of ankle dorsiflexion. At the same angles, passive torque (Tpass), peak torque (pT) and myotendinous junction displacement of GM were determined. Stiffness was calculated at muscle-tendon unit (MTU), muscle and tendon level. After static stretching administration, Tpass, pT and MTU stiffness decreased by 22%, 12% and 16%, respectively (p<0.05). Muscle and tendon stiffness decreased by 15% and 16% (p<0.05). Nevertheless, no changes in FL and PA occurred. The reliability of the approach was always very high (intraclass correlation coefficient>0.90), with an adequate level of sensitivity. pT after static stretching was related to decreases in MTU, muscle and tendon stiffness, but not to alterations in muscle architecture. PMID- 25817317 TI - Regular theta-firing neurons in the nucleus incertus during sustained hippocampal activation. AB - This paper describes the existence of theta-coupled neuronal activity in the nucleus incertus (NI). Theta rhythm is relevant for cognitive processes such as spatial navigation and memory processing, and can be recorded in a number of structures related to the hippocampal activation including the NI. Strong evidence supports the role of this tegmental nucleus in neural circuits integrating behavioural activation with the hippocampal theta rhythm. Theta oscillations have been recorded in the local field potential of the NI, highly coupled to the hippocampal waves, although no rhythmical activity has been reported in neurons of this nucleus. The present work analyses the neuronal activity in the NI in conditions leading to sustained hippocampal theta in the urethane-anaesthetised rat, in order to test whether such activation elicits a differential firing pattern. Wavelet analysis has been used to better define the neuronal activity already described in the nucleus, i.e., non-rhythmical neurons firing at theta frequency (type I neurons) and fast-firing rhythmical neurons (type II). However, the most remarkable finding was that sustained stimulation activated regular-theta neurons (type III), which were almost silent in baseline conditions and have not previously been reported. Thus, we describe the electrophysiological properties of type III neurons, focusing on their coupling to the hippocampal theta. Their spike rate, regularity and phase locking to the oscillations increased at the beginning of the stimulation, suggesting a role in the activation or reset of the oscillation. Further research is needed to address the specific contribution of these neurons to the entire circuit. PMID- 25817318 TI - A window into new drug development for urologic oncology. Part II: Bench-to bedside research improves survival in urologic cancer, and the discovery of better biomarkers can help predict patient response, toxicity, and resistance to therapy. PMID- 25817319 TI - Live surgical demonstrations: An endangered species. AB - Despite the increasing controversy surrounding live surgical demonstrations, they remain an incredibly valuable tool for urologic education. Live surgery is the most effective means to demonstrate certain surgical techniques and intraoperative decision making. The many potential benefits far outweigh the potential concerns when live surgical events are performed in a thoughtful regulatory framework. Appropriate patient and surgeon selection is integral to successful live surgical events. Under these circumstances, live surgery should remain safe for the patient and instructive for the urologist. PMID- 25817320 TI - Zolpidem and eszopiclone prime alpha1beta2gamma2 GABAA receptors for longer duration of activity. AB - BACKGROUND AND PURPOSE: GABAA receptors mediate neuronal inhibition in the brain. They are the primary targets for benzodiazepines, which are widely used to treat neurological disorders including anxiety, epilepsy and insomnia. The mechanism by which benzodiazepines enhance GABAA receptor activity has been extensively studied, but there is little mechanistic information on how non-benzodiazepine drugs that bind to the same site exert their effects. Eszopiclone and zolpidem are two non-benzodiazepine drugs for which no mechanism of action has yet been proposed, despite their clinical importance as sleeping aids. Here we investigate how both drugs enhance the activity of alpha1beta2gamma2 GABAA receptors. EXPERIMENTAL APPROACH: We used rapid ligand application onto macropatches and single-channel kinetic analysis to assess rates of current deactivation. We also studied synaptic currents in primary neuronal cultures and in heterosynapses, whereby native GABAergic nerve terminals form synapses with HEK293 cells expressing alpha1beta2gamma2 GABAA receptors. Drug binding and modulation was quantified with the aid of an activation mechanism. KEY RESULTS: At the single channel level, the drugs prolonged the duration of receptor activation, with similar KD values of ~80 nM. Channel activation was prolonged primarily by increasing the equilibrium constant between two connected shut states that precede channel opening. CONCLUSIONS AND IMPLICATIONS: As the derived mechanism successfully simulated the effects of eszopiclone and zolpidem on ensemble currents, we propose it as the definitive mechanism accounting for the effects of both drugs. Importantly, eszopiclone and zolpidem enhanced GABAA receptor currents via a mechanism that differs from that proposed for benzodiazepines. PMID- 25817321 TI - Lionel Bueno, PhD, July 9, 1945-January 24, 2015. PMID- 25817322 TI - The association between the severity of poststroke depression and clinical outcomes after first-onset stroke in Korean patients. AB - OBJECTIVE: The purpose of the present study is to evaluate the association between poststroke depression (PSD) and clinical outcomes in first-onset stroke patients who are undergoing a rehabilitation program. METHODS: The present study included 180 inpatients that were recruited consecutively and followed up over a 6-month observational period. Poststroke depression was diagnosed using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Symptoms of depression and clinical outcomes were assessed using the Beck Depression Inventory, the modified Barthel Index (MBI) and the Mini Mental State Examination (MMSE). All patients were assessed at baseline and at the end of the 6-month observational period. RESULTS: Of the 180 patients, 127 (70.6%) were diagnosed with minimal-to-mild depression (MMD), and 53 (29.4%) were diagnosed with moderate-to-severe depression (MSD). The mean change in MBI scores from baseline to 6 months was significantly higher (P=.029) in the MMD group (23.8) than in the MSD group (8.6). The odds ratio for an unfavorable outcome (MBI score <60) in patients with MSD was approximately 3.5 in relation to patients with MMD. The mean change in MMSE score (4.4 versus 7.4) was not significantly different between the MMD and MSD groups. CONCLUSION: The present findings suggest that the severity of PSD may be associated with clinical outcomes in Korean patients 6 months after a first-onset stroke. Our data agree with previous findings, which indicate that clinicians should carefully evaluate symptoms of depression in stroke patients during routine clinical practice. The methodological shortcomings of the present study may require further studies with adequate power and improved design to clarify the association between PSD and clinical outcomes following stroke. PMID- 25817323 TI - Therapist-supervised hand therapy versus home therapy with therapist instruction following distal radius fracture. AB - PURPOSE: To investigate whether there was a difference in Patient-Rated Wrist Hand Evaluation (PRWHE) scores between patients with and without comorbidities who receive regular supervised therapy provided by a certified hand therapist (CHT) compared with patients who were provided with a home exercise program and were regularly monitored. METHODS: Fifty patients with a diagnosis of distal radius fractures and volar plate fixation were enrolled in a prospective, randomized clinical trial comparing those who received therapy under the supervision of a CHT with those enrolled in a home exercise program that was instructed and monitored by a CHT. The primary outcome measure (PRWHE) and secondary outcome measures, total arc of motion for wrist flexion and extension, supination and pronation, and grip strength, were assessed at 12 weeks. The primary outcome measure for both groups was also gathered at 6 months. RESULTS: There were no statistically significant differences between the final scores of the PRWHE, wrist or forearm motion, pain, or grip strength between groups. Effect size calculations revealed that both groups experienced a large effect size for all outcomes. CONCLUSIONS: Supervised clinic-based therapy is equally beneficial for patients without complications. Clinic-based therapy may be preferable for patients with noteworthy complications after a distal radius fracture with volar plate fixation. Patients with decreased finger motion and various comorbidities may benefit from therapy provided in a clinic under the supervision of a certified hand therapist. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 25817324 TI - Editorial overview: genome studies and molecular genetics: data-driven approaches to genotype-to-phenotype studies in crops. PMID- 25817325 TI - Fetal growth trajectory and risk for eczema in a Saudi population. AB - BACKGROUND: Recent studies in Western cohorts have identified associations between increasing fetal abdominal circumference (AC) during mid-pregnancy and increased risk for eczema and atopy. We sought to replicate these findings in a Saudi population where antenatal environmental exposures are different compared with Western countries. METHODS: A Saudi birth cohort was recruited to relate maternal dietary intake and fetal growth to wheeze, eczema, and rhinitis in the first 2 yrs. Fetal size was determined from routine ultrasound scan measurements in the second and third trimesters and birthweight was noted. Parent-reported outcomes during the first 2 yrs were acquired by telephone-administered questionnaire. RESULTS: There were 1076 mothers recruited. AC was determined in 562 for the second, in 632 for the third, and in 281 for both second and third trimesters. A history of eczema was determined in 814 children at 2 yrs of age. There was an inverse relationship between change in abdominal circumference between the second and third trimesters for eczema (OR 0.66 per z score increase in AC [95% CI 0.49, 0.89]), and the quartile with the greatest faltering growth were at increased risk compared with other groups (p <= 0.045). Change in fetal size between the third trimester and birth was not associated with altered eczema risk. There were no associations between fetal growth and wheeze at the age of 2 yrs. CONCLUSIONS: Our findings contrast observations made in Western populations but nonetheless suggest that factors associated with changing fetal growth trajectory in the second half of pregnancy are also relevant to atopy development on the global setting. PMID- 25817326 TI - Basal functional status predicts functional recovery in critically ill patients with multiple-organ failure. AB - PURPOSE: We aimed to investigate the effect of baseline demographic, clinical, and functional characteristics of intensive care unit (ICU) patients with multiple-organ failure (MOF) on their functional recovery at 6 and 12 months posthospitalization. MATERIALS AND METHODS: A total of 545 consecutively admitted adult patients with MOF during on admission were included in the study. Patients' functional status was prospectively assessed and compared with the baseline status and at 6 and 12 months postdischarge, using the Modified Rankin Scale and the Glasgow Outcome Scale Extended. Severity of disease on admission was assessed using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II. RESULTS: A total of 266 patients were followed up. Functional status among MOF survivors improved between the 6th and 12th month postdischarge from the ICU. Higher functional status before admission, lower severity scores on admission, and younger age positively affected the improvement in functional status after ICU discharge. CONCLUSIONS: The level of functional status befre ICU admission should be considered not only in research studies looking a long-term outcomes from ICU but also in the clinical care planning of critically ill patients during and after their ICU admission. PMID- 25817327 TI - Biocalorimetry. PMID- 25817328 TI - Prognostic impact of B-cell lymphoma 6 in primary CNS lymphoma. AB - BACKGROUND: We investigated the prognostic significance of B-cell differentiation status and common B-cell differentiation markers in a post hoc analysis of 119 patients with primary CNS lymphoma (PCNSL) homogeneously receiving high-dose methotrexate (HDMTX)-based chemotherapy within the prospective G-PCNSL-SG1 trial. METHODS: We evaluated protein expression of B-cell lymphoma 2 (BCL2), BCL6, CD10, and multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) by immunohistochemistry and analyzed the association with survival. RESULTS: The median follow-up of all patients was 67.5 months. Median progression-free survival (PFS) was 10.61 months (95% CI: 4.23-17.00). Median overall survival (OS) was 28.85 months (95% CI: 17.96-39.73). Eighty-nine tumors expressed BCL2 (92.7%), 24 (20.5%) expressed CD10, 60 (54.1%) expressed BCL6, and 87 (79.0%) expressed MUM1/IRF4. On the basis of the Hans algorithm, 80 tumors (73.4%) were classified to the non-germinal center B group, suggesting a post-germinal center origin of PCNSL. Expression of BCL6 (cutoff point 30%), but none of the other markers, was associated with shorter PFS (P = .047) and OS (P = .035). On multivariate analysis, BCL6 expression was associated with shorter PFS (hazard ratio: 1.95, 95% CI: 1.22-3.12, P = .005) but not OS (hazard ratio: 1.85, 95% CI: 0.71-4.80, P = .21). Classification according to Hans algorithm and expression status of the single B-cell markers BCL2, CD10, and MUM1/IRF4 did not correlate with prognosis. CONCLUSION: The findings are limited by the fact that only 23% of all G-PCNSL-SG1 patients could be included in the analysis. If validated in an independent cohort, BCL6 may assume clinical relevance as an unfavorable prognostic biomarker in PCNSL. PMID- 25817329 TI - Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice. AB - OBJECTIVE: Activated factor X (FXa) plays a key role in the coagulation cascade, whereas accumulating evidence suggests that it also contributes to the pathophysiology of chronic inflammation on the vasculature. In this study, we assessed the hypothesis that rivaroxaban (Riv), a direct FXa inhibitor, inhibits atherogenesis by reducing macrophage activation. METHODS AND RESULTS: Expression levels of PAR-1 and PAR-2, receptors for FXa, increased in the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice compared with wild-type mice (P < 0.01, P < 0.05, respectively). Administration of Riv (5 mg/kg/day) for 20 weeks to 8-week-old ApoE(-/-) mice reduced atherosclerotic lesion progression in the aortic arch as determined by en-face Sudan IV staining compared with the non treated group (P < 0.05) without alteration of plasma lipid levels and blood pressure. Histological analyses demonstrated that Riv significantly decreased lipid deposition, collagen loss, macrophage accumulation and matrix metallopeptidase-9 (MMP-9) expression in atherosclerotic plaques in the aortic root. Quantitative RT-PCR analyses using abdominal aorta revealed that Riv significantly reduced mRNA expression of inflammatory molecules, such as MMP-9, tumor necrosis factor-alpha (TNF-alpha). In vitro experiments using mouse peritoneal macrophages or murine macrophage cell line RAW264.7 demonstrated that FXa increased mRNA expression of inflammatory molecules (e.g., interleukin (IL) 1beta and TNF-alpha), which was blocked in the presence of Riv. CONCLUSIONS: Riv attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice, at least in part by inhibiting pro-inflammatory activation of macrophages. These results indicate that Riv may be particularly beneficial for the management of atherosclerotic diseases, in addition to its antithrombotic activity. PMID- 25817331 TI - Enhancing bull sexual behavior using estrus-specific molecules identified in cow urine. AB - Deficiencies in bull mating behavior have implications for bovine artificial insemination activities. The aim of this study was to identify the compounds present in fluids emitted by cows during estrus, which could enhance bull libido. Chemical analysis of urine samples from cows led to the characterization of molecules varying specifically at the preestrous and estrous stages. The synthetic counterpart molecules (1,2-dichloroethylene, squalene, coumarin, 2 butanone, oleic acid) were used to investigate the biological effects on male sexual behavior and sperm production. When presented to males, 2-butanone and oleic acid synthetic molecules significantly lowered mounting reaction time and ejaculation time (-33% and 21% after 2-butanone inhalation, respectively, P < 0.05). The "squalene +1,2-dichloroethylene" combination induced a 9% increase of sperm quantity (P < 0.05). This study suggests that the identified estrous specific molecules could be part of the chemical signals involved in male and female mating behavior and may be used for a wide range of applications. The identification of these molecules may have implications for the cattle breeding industry. PMID- 25817330 TI - Genetics of cardiovascular disease: Importance of sex and ethnicity. AB - Sex differences in incidence and prevalence of and morbidity and mortality from cardiovascular disease are well documented. However, many studies examining the genetic basis for cardiovascular disease fail to consider sex as a variable in the study design, in part, because there is an inherent difficulty in studying the contribution of the sex chromosomes in women due to X chromosome inactivation. This paper will provide general background on the X and Y chromosomes (including gene content, the pseudoautosomal regions, and X chromosome inactivation), discuss how sex chromosomes have been ignored in Genome wide Association Studies (GWAS) of cardiovascular diseases, and discuss genetics influencing development of cardiovascular risk factors and atherosclerosis with particular attention to carotid intima-medial thickness, and coronary arterial calcification based on sex-specific studies. In addition, a brief discussion of how ethnicity and hormonal status act as confounding variables in sex-based analysis will be considered along with methods for statistical analysis to account for sex in cardiovascular disease. PMID- 25817332 TI - Biomechanical properties of murine meniscus surface via AFM-based nanoindentation. AB - This study aimed to quantify the biomechanical properties of murine meniscus surface. Atomic force microscopy (AFM)-based nanoindentation was performed on the central region, proximal side of menisci from 6- to 24-week old male C57BL/6 mice using microspherical tips (Rtip~5um) in PBS. A unique, linear correlation between indentation depth, D, and response force, F, was found on menisci from all age groups. This non-Hertzian behavior is likely due to the dominance of tensile resistance by the collagen fibril bundles on meniscus surface that are mostly aligned along the circumferential direction. The indentation resistance was calculated as both the effective modulus, Eind, via the isotropic Hertz model, and the effective stiffness, Sind = dF/dD. Values of Sind and Eind were found to depend on indentation rate, suggesting the existence of poro-viscoelasticity. These values do not significantly vary with anatomical sites, lateral versus medial compartments, or mouse age. In addition, Eind of meniscus surface (e.g., 6.1+/-0.8MPa for 12 weeks of age, mean+/-SEM, n=13) was found to be significantly higher than those of meniscus surfaces in other species, and of murine articular cartilage surface (1.4+/-0.1MPa, n=6). In summary, these results provided the first direct mechanical knowledge of murine knee meniscus tissues. We expect this understanding to serve as a mechanics-based benchmark for further probing the developmental biology and osteoarthritis symptoms of meniscus in various murine models. PMID- 25817333 TI - Engineering meniscus structure and function via multi-layered mesenchymal stem cell-seeded nanofibrous scaffolds. AB - Despite advances in tissue engineering for the knee meniscus, it remains a challenge to match the complex macroscopic and microscopic structural features of native tissue, including the circumferentially and radially aligned collagen bundles essential for mechanical function. To mimic this structural hierarchy, this study developed multi-lamellar mesenchymal stem cell (MSC)-seeded nanofibrous constructs. Bovine MSCs were seeded onto nanofibrous scaffolds comprised of poly(epsilon-caprolactone) with fibers aligned in a single direction (0 degrees or 90 degrees to the scaffold long axis) or circumferentially aligned (C). Multi-layer groups (0 degrees /0 degrees /0 degrees , 90 degrees /90 degrees /90 degrees , 0 degrees /90 degrees /0 degrees , 90 degrees /0 degrees /90 degrees , and C/C/C) were created and cultured for a total of 6 weeks under conditions favoring fibrocartilaginous tissue formation. Tensile testing showed that 0 degrees and C single layer constructs had stiffness values several fold higher than 90 degrees constructs. For multi-layer groups, the stiffness of 0 degrees /0 degrees /0 degrees constructs was higher than all other groups, while 90 degrees /90 degrees /90 degrees constructs had the lowest values. Data for collagen content showed a general positive interactive effect for multi-layers relative to single layer constructs, while a positive interaction for stiffness was found only for the C/C/C group. Collagen content and cell infiltration occurred independent of scaffold alignment, and newly formed collagenous matrix followed the scaffold fiber direction. Structural hierarchies within multi lamellar constructs dictated biomechanical properties, and only the C/C/C constructs with non-orthogonal alignment within layers featured positive mechanical reinforcement as a consequence of the layered construction. These multi-layer constructs may serve as functional substitutes for the meniscus as well as test beds to understand the complex mechanical principles that enable meniscus function. PMID- 25817334 TI - A model of Stokesian peristalsis and vesicle transport in a three-dimensional closed cavity. AB - The complexity of the mechanics involved in the mammalian reproductive process is evident. Neither an ovum nor an embryo is self-propelled, but move through the oviduct or uterus due to the peristaltic action of the tube walls, imposed pressure gradients, and perhaps ciliary motion. Here we use the method of regularized Stokeslets to model the transport of an ovum or an embryo within a peristaltic tube. We represent the ovum or the embryo as a spherical vesicle of finite volume - not a massless point particle. The outer membrane of the neutrally buoyant vesicle is discretized by nodes that are joined by a network of springs. The elastic moduli of these springs are chosen large enough so that a spherical shape is maintained. For simplicity, here we choose an axisymmetric tube where the geometry of the two-dimensional cross-section along the tube axis reflects that of the sagittal cross-section of the uterine cavity. Although the tube motion is axisymmetric, the presence of the vesicle within the tube requires a fully three-dimensional model. As was found in Yaniv et al. (2009, 2012) for a 2D closed channel, we find that the flow dynamics in a 3D peristaltic tube are strongly influenced by the closed end and the manner in which the peristaltic wave damps out towards the closure. In addition, we demonstrate that the trajectory of a vesicle of finite volume can greatly differ from the trajectory of a massless fluid particle initially placed at the vesicle's centroid. PMID- 25817335 TI - Nucleotide-binding oligomerization domain-2 (NOD2) regulates type-1 cytokine responses to Mycobacterium avium but is not required for host control of infection. AB - Nucleotide-binding oligomerization domain-2 (NOD2) is an innate immune receptor that recognizes peptidoglycan-derived muramyl dipeptide from intracellular bacteria and triggers proinflammatory signals. In this study, we sought to evaluate the role played by this receptor during early and late stages of infection with Mycobacterium avium in mice. We demonstrated that NOD2 knockout (KO) animals were able to control M. avium infection similarly to wild-type mice at all time points studied, even though IL-12 and TNF-alpha production was impaired in NOD2-deficient macrophages. At 100 days following infection with this bacterium, but not at 30 days post-infection, NOD2-deficient mice showed significantly diminished production of IFN-gamma, as confirmed by reduced accumulation of IFN-gamma and IL-12 mRNA in the spleens of KO mice. Additionally, a reduction in the size and in the number of lymphocytes/granulocytes of hepatic granulomas from NOD2 KO animals was observed only during late time points of M. avium infection. Taken together, these data demonstrate that NOD2 regulates type 1 cytokine responses to M. avium but is not required for the control of infection with this bacterium in vivo. PMID- 25817336 TI - Sensing with Advanced Computing Technology: Fin Field-Effect Transistors with High-k Gate Stack on Bulk Silicon. AB - Field-effect transistors (FETs) form an established technology for sensing applications. However, recent advancements and use of high-performance multigate metal-oxide semiconductor FETs (double-gate, FinFET, trigate, gate-all-around) in computing technology, instead of bulk MOSFETs, raise new opportunities and questions about the most suitable device architectures for sensing integrated circuits. In this work, we propose pH and ion sensors exploiting FinFETs fabricated on bulk silicon by a fully CMOS compatible approach, as an alternative to the widely investigated silicon nanowires on silicon-on-insulator substrates. We also provide an analytical insight of the concept of sensitivity for the electronic integration of sensors. N-channel fully depleted FinFETs with critical dimensions on the order of 20 nm and HfO2 as a high-k gate insulator have been developed and characterized, showing excellent electrical properties, subthreshold swing, SS ~ 70 mV/dec, and on-to-off current ratio, Ion/Ioff ~ 10(6), at room temperature. The same FinFET architecture is validated as a highly sensitive, stable, and reproducible pH sensor. An intrinsic sensitivity close to the Nernst limit, S = 57 mV/pH, is achieved. The pH response in terms of output current reaches Sout = 60%. Long-term measurements have been performed over 4.5 days with a resulting drift in time deltaVth/deltat = 0.10 mV/h. Finally, we show the capability to reproduce experimental data with an extended three-dimensional commercial finite element analysis simulator, in both dry and wet environments, which is useful for future advanced sensor design and optimization. PMID- 25817337 TI - Delivery strategies to enhance oral vaccination against enteric infections. AB - While the majority of human pathogens infect the body through mucosal sites, most licensed vaccines are injectable. In fact the only mucosal vaccine that has been widely used globally for infant and childhood vaccination programs is the oral polio vaccine (OPV) developed by Albert Sabin in the 1950s. While oral vaccines against Cholera, rotavirus and Salmonella typhi have also been licensed, the development of additional non-living oral vaccines against these and other enteric pathogens has been slow and challenging. Mucosal vaccines can elicit protective immunity at the gut mucosa, in part via antigen-specific secretory immunoglobulin A (SIgA). However, despite their advantages over the injectable route, oral vaccines face many hurdles. A key challenge lies in design of delivery strategies that can protect antigens from degradation in the stomach and intestine, incorporate appropriate immune-stimulatory adjuvants and control release at the appropriate gastrointestinal site. A number of systems including micro and nanoparticles, lipid-based strategies and enteric capsules have significant potential either alone or in advanced combined formulations to enhance intestinal immune responses. In this review we will outline the opportunities, challenges and potential delivery solutions to facilitate the development of improved oral vaccines for infectious enteric diseases. PMID- 25817338 TI - Use of the new Airtraq "Airtraq AVANT" in clinical settings. PMID- 25817339 TI - rPSGL-1-Ig, a recombinant PSGL-1-Ig fusion protein, ameliorates LPS-induced acute lung injury in mice by inhibiting neutrophil migration. AB - The binding of selectin to P—selectin glycoprotein ligand—1 (PSGL—1) mediates the tethering and rolling of leukocytes on the endothelium during leukocyte migration and inflammation. Recombinant human PSGL—1—Ig fusion protein (rPSGL—1—Ig) is a widely used selectin inhibitor that prevents neutrophil entry into inflamed or reperfused tissues. We hypothesized that rPSGL—1—Ig could be used to as a drug for the treatment of acute lung injury (ALI). We induced murine ALI by injecting mice with lipopolysaccharide (LPS) and then treated the mice with rPSGL—1—Ig. We determined the lung injury index, wet/dry ratio, and inflammatory cytokine level in differentially treated mice. The symptoms of LPS—induced lung injury were alleviated by rPSGL—1—Ig treatment. The histopathological index of LPS—induced lung injury improved after rPSGL—1—Ig treatment. rPSGL—1—Ig treatment also reduced the recruitment of inflammatory cells, including neutrophils, into the lung, as well as reducing the level of inflammatory cytokines. These data suggest that rPSGL—1—Ig protein has a therapeutic effect on LPS—induced lung injury. PMID- 25817340 TI - RANKL inhibits cell proliferation by regulating MALAT1 expression in a human osteoblastic cell line hFOB 1.19. AB - Receptor activator of NF—κB ligand (RANKL), a TNF—related protein, is a key factor regulating bone metabolism. It has been well known that RANKL—mediated signaling regulates the formation, activation and survival of osteoclast in normal bone modeling and remodeling, and also plays an important role in a variety of pathologic conditions. However, there is no direct evidence about the effect of RANKL on osteoblast. Herein, we investigated whether RANKL had effect on cell proliferation in a normal human fetal osteoblastic cell line hFOB 1.19. MTT assay showed that RANKL inhibited hFOB 1.19 cells growth in a dose—dependent and time—dependent manner. Importantly, we found that RANKL induced the expression of a lncRNA, MALAT1, for the first time. Knockdown of RANK by siRNA blocked the induction of MALAT1 by RANKL. By infection with MALAT1 siRNA, MALAT1 knockdown reversed RANKL—induced cells growth inhibition and cell cycle arrest. In addition, MALAT1 also regulated OPG expression in hFOB 1.19 cells. In conclusion, RANKL, binding to its receptor RANK, inhibited cell proliferation via MALAT1 upregulation in osteoblast cells in vitro. PMID- 25817341 TI - The cultivation of bone marrow mesenchymal stem cells derived from patients with high altitude polycythemia. AB - The aim of this study was to isolate and culture bone marrow mesenchymal stem cells (MSCs) from patients with high altitude polycythemia (HAPC) in order to provide a foundation for further exploration of their biological characteristics. MSCs were isolated and cultured from 10 HAPC patients and 10 healthy controls by using a density gradient centrifugation and an adherent screening method. The morphous of MSCs were observed under an inverted microscope, and its surface antigens were determined using flow cytometry. The growth of the MSCs was also detected to evaluate its proliferation. Bone marrow mononuclear cells were isolated from the bone marrow using a density gradient centrifugation, and they were cultured in vitro. The bone marrow MSCs were successfully isolated and cultured, which presented as fusiform and adherent cells. The MSCs in both groups expressed CD90,CD44,CD29,CD105, CD106, CD146, CD166,Stro—1 and CD13, but they did not express CD45, CD4,CD8,CD19,CD20,CD80,CD14,CD3,CD34 or HLA—DR (P>0.05). The bone marrow MSCs from HAPC patients had a higher proliferation than the bone marrow MSCs from the healthy controls (P<0.01). The bone marrow MSCs from HAPC patients can be effectively cultured in vitro. PMID- 25817342 TI - Forced expression of PDX-1 gene makes hepatoma cells to acquire glucose responsive insulin secretion while maintaining hepatic characteristic. AB - Evidence shows that forced expression of the PDX1 gene converts hepatoma cells, mouse liver epithelial cells (MLECs) and HepaRG cells, into insulin—producing cells, β—cells, or islets of Langerhans. However, no reports have investigated the characteristics of mouse or human hepatocytes introduced with the PDX1 gene over prolonged observation periods. In this study, we immunohistologically and molecularly investigated the alternative processes induced by PDX1 gene introduction in mouse and human hepatocytes over prolonged observation periods using immunocytochemistry, immunofluorescence, polymerase chain reaction (PCR), Western blotting, and flow cytometry (FCM) analysis. Immunocytochemical and immunofluorescent observations showed that MLECs and HepaRG cells on 2 and 21 days after introduction of the PDX1 gene comprised cells double—positive for insulin and albumin. Additionally, they showed MAFA expression and glucose—responsive insulin secretion with glucokinase expression. However mouse embryonic fibroblasts introduced with PDX1—GFP could not acquire glucose—responsive insulin secretion and glucokinase expression. Subsequently, we hypothesized that the number of albumin—positive MLECs and HepaRG cells would decrease after introduction of PDX1 due to the conversion of MLECs and HepaRG cells into insulin—producing cells. However, FCM analysis indicated that the number of albumin—positive MLECs and HepaRG cells was not altered by the introduction of PDX1. We thought that MLECs and HepaRG cells introduced with the PDX1 gene could acquire a functional insulin secretory capacity without conversion to β—cells, or islets of Langerhans, and the acquisition could need glucokinase expression. PMID- 25817343 TI - Insulin over expression induces heart abnormalities via reactive oxygen species regulation, might be step towards cardiac hypertrophy. AB - Insulin is known to regulate blood—glucose level and promote its utilization as an energy source in cardiac tissues under normal physiological conditions as well as stimulates signaling pathways that involved cell growth and proliferation. Although recently insulin generated free radicals via NAD(P)H has been documented but the molecular mechanism is still under investigation. The aim of present study is to elucidate the reactive oxygen species (ROS) dependent possible role of insulin in cardiac abnormalities, including hypertrophy by regulation of antioxidants enzyme (SOD) activity. In the current study, 60 cardiac patients and 50 healthy individuals as well as the rat model with insulin administration were under investigation. Oxidant, anti—oxidant biochemical assays, hypertrophic marker expression via immunobloting and histopathology were performed. We observed statistically significant elevation of the reactive oxygen species level in the serum of patients as well as in the insulin administrated rat model, a mild expression of cardiac marker in experimental models along with abnormal histopathology of hearts. However, super oxide dismutase free radical scavenger activity was down regulated upon insulin treatment compared to control rats. Conclusively, the present study showed that over expression of insulin might stimulate cardiac hypertrophic signal via up regulation of free radicals and down regulation of antioxidants enzymes including SOD activity. PMID- 25817344 TI - Enhanced growth and osteogenic differentiation of Induced Pluripotent Stem cells by Extremely Low-Frequency Electromagnetic Field. AB - It is accepted that induced pluripotent stem cells (iPSCs) have a great osteogenic potential differentiation, in the present study, we tried to improve this potentials using mechanical and biological stimulation. To achieve this goal, the influence of prolonged pulsed extremely low frequency electromagnetic field (ELF—EMF) (50 Hz and 1.5 mT) was investigated on cultured iPSCs. After evaluation of iPSCs biological behavior under radiation using MTT assay, osteogenic differentiation of stem cells was investigated via common important osteogenic markers such as alkaline phosphatase (ALP) activity, calcium mineral deposition and important bone—related genes. MTT result showed that proliferation rate of iPSCs significantly increased followed by stimulate with ELF—EMF. Osteogenic differentiation characterization demonstrated that potential of stem cells also was significantly increased while these cells cultured under both ELF—EMF and osteogenic medium (OM) in comparison to cultured under ELF—EMF or OM alone. According to the results, concluded that combination of OM and ELF—EMF can be a great supplement for bone differentiation of stem cells and appropriate candidate for use in the treatment of bone defects and osteoporosis patients by accelerating healing process. PMID- 25817345 TI - Knockdown of Pim-3 suppresses the tumorigenicity of glioblastoma by regulating cell cycle and apoptosis. AB - Products of the Pim (the proviral integration site for the Moloney murine leukemia virus) family of proto—oncogenes possess serine/threonine kinase activity and belong to the Ca2+/calmodulin—dependent protein kinase group. Pim—3, a member of the Pim family is closely linked to the development of a variety of tumors. However, the role of Pim—3 in human glioblastoma remains unknown. In this study, we elucidated the role of Pim—3 in the growth and apoptosis of glioblastoma cells. Western blotting was used for determination of protein levels, and shRNA was used for Pim—3 knockdown. The MTT assay was used to evaluate cell proliferation and flow cytometry was used to determine cell cycle status and the number of apoptotic cells. A mouse xenograft model was established by injecting nude mice with Pim—3—depleted glioblastoma cells in order to determine tumor growth in vivo. We demonstrated that Pim—3 was highly expressed in human glioblastoma cell lines. We also found that knockdown of Pim—3 by specific shRNA slowed decreased proliferation, induced cell cycle arrest in the G0/G1 phase, and increased apoptosis in glioblastoma cells. Pim—3 knockdown potently inhibited the growth of subcutaneously implanted glioblastoma cells in vivo. We further revealed that Pim—3 knockdown induced growth inhibition by reducing the levels of the anti—apoptotic protein Bcl—xl and cell cycle regulatory proteins, including cyclin D1 and Cdc25C, and increasing the levels of the pro—apoptotic protein Bax. PMID- 25817346 TI - Effects of down-regulated steroidogenic factor-1 on ACTH and potassium chloride induced steroid synthesis in H295R cells. AB - The prevalence of adrenal diseases in the cortex is more common than that in the medulla in the form of hormone disorder or neoplasm. Steroidogenic factor—1 (SF—1) is important in regulating aldosterone synthase (CYP11B2) and cortisol synthase (CYP11B1). SF—1 is increased in aldosterone—producing adenoma (APA) and cortisol—producing adenoma (CPA). Overexpression of SF—1 has been extensively studied, but the available in—depth information regarding the effects of downregulated SF—1 on CYP11B2/CYP11B1 and their regulators is limited. In this paper, we attempted to investigate the effects of downregulated SF—1 on aldosterone to adrenocorticotropic hormone (ACTH) and potassium chloride (KCl) stimulation and those on cortisol to ACTH stimulation through RNA interference in acute and chronic phases. Downregulated SF—1 decreased the sensitivity of aldosterone to ACTH/KCl and that of cortisol to ACTH stimulation. This study provides new insights into the influence of SF—1 on adrenocortical diseases by considering the effects of SF—1 on regulation. PMID- 25817347 TI - Polymorphism of the LIG3 gene in keratoconus and Fuchs endothelial corneal dystrophy. AB - The product of the LIG3 gene encodes DNA ligase III, which is involved in the repair of oxidatively damaged DNA in the base excision repair pathway. We hypothesized that polymorphism in this gene may change susceptibility to oxidative stress and predispose individuals to the development of keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Therefore, we investigated the association between genotypes and haplotypes of the g.29661G>A polymorphism (rs1003918) and the g.29059C>T polymorphism (rs1052536) of the LIG3 gene and the occurrence of KC and FECD in patients with FECD (258 individuals) or KC (283) and ethnically matched controls (300). The A/A genotype and the A allele of the g.29661G>A polymorphism were associated with increased occurrence of KC, while the G allele of this polymorphism was positively correlated with a decreased occurrence of this disease. The T/C genotype of the g.29059C>T polymorphism was associated with decreased FECD occurrence. In addition, the AT haplotype was associated with increased occurrence of KC and FECD, while the GT haplotype was associated with decreased occurrence of these diseases. The g.29661G>A and g.29059C>T polymorphisms may play a role in the KC and FECD pathogenesis and can be considered as markers in these diseases. PMID- 25817348 TI - The relationship between MMP-9 promoterpolymorphism and IVF outcome. AB - Angiogenesis, invasion and decidualization play an important role in implantation and embryo development. Matrix metalloproteinases (MMPs) are crucial for the degradation/remodeling of the extracellular matrix, and are involved in spiral artery formation and invasion of endometrium during implantation. A functional single—nucleotide polymorphism (SNP) in the MMP9 promoter, —1562C/T, is known to influence gene expression in allele—specific manner. The present study evaluated the association between maternal genotype of SNP —1562C/T of MMP9 and in vitro fertilization and embryo transfer (IVF—ET) outcome in infertile women. This case-control study was comprised of infertile patients (n= 123) and women having one healthy child as controls (n= 147). Genotyping for SNP—1562C/T was performed by PCR/RFLP. Allele and genotype distribution did not differ significantly between patients and controls (P>0.05). The MMP9 genotype frequencies amongst the 123 cases were C/C=73.17%, C/T=24.40% and T/T=2.43%; the C and T allele frequencies were 85.36% and 14.63%, respectively. The MMP9 genotype frequencies amongst the 147 controls were C/C=73.46%, C/T=20.40% and T/T=6.12%; the C and T allele frequencies were 83.67% and 16.32%, respectively. In conclusion, the results of this study indicate that SNP —1562C/T of MMP9 may not be associated with IVF—ET outcome in this population. PMID- 25817349 TI - In vitro protective effect of atorvastatin against ionizing radiation induced genotoxicity in human lymphocytes. AB - Atorvastatin (AT) is widely used as a medication for treatment of hypercholesterolemia. Recent studies showed that AT enhanced cell toxicity induced by ionizing radiation in cancerous cells. In this study, the radioprotective effect of AT was investigated against genotoxicity induced by ionizing radiation in human blood lymphocytes. Peripheral blood samples were collected from human volunteers and incubated with AT at different concentrations (0.05, 0.1, 1, or 10 MUM) for two hours. The whole blood was exposed to X-ray at dose 1.5 Gy. Lymphocytes were cultured with mitogenic stimulation to determine the micronuclei in cytokinesis blocked binucleated lymphocyte. AT exhibited a significant decreasing in the frequency of micronuclei in human lymphocytes exposed to ionizing radiation, as compared to with similarly irradiated lymphocytes without AT treatment. The maximum protection and higher decreasing in frequency of micronuclei was observed at 10 MUM of AT (68% decrease), providing maximal protection against ionizing radiation. This data is promising for protection human normal cells from the genetic damage induced by ionizing irradiation. PMID- 25817350 TI - Effects of periodontal therapy on white blood cell count and levels of transforming growth factor beta in serum of subjects with severe periodontitis. AB - This study aimed to investigate the effects of nonsurgical periodontal therapy on white blood cell (WBC) count and levels of transforming growth factor beta (TGF—β) in serum from subjects with severe periodontitis. Serum from 28 subjects with periodontitis (mean age: 34.36+/-6.24; 32% men) and 27 healthy controls (mean age: 33.18+/-6.42; 33% men) were collected prior to therapy. Blood samples were obtained from 23 subjects who completed therapy (9—12 months). A well—controlled periodontal treatment protocol was established in three stages: mechanical periodontal therapy (scaling and root planning), reinstrumentation of dental sites, and supportive periodontal therapy. Periodontal and systemic parameters such as the total number of WBCs and TGF—β levels, accessed by enzyme—linked immunosorbent assay (ELISA), were included. After therapy, all clinical periodontal parameters decreased (p<0.0001). There were no statistical differences in WBC count between experimental and control groups before or after therapy. However, after therapy, the mean value of lymphocytes in patients with localized aggressive periodontitis (LAgP) was statistically higher than that of patients with generalized chronic periodontitis (GCP) (p<0.0357). Additionally, TGF—β levels in LAgP and GCP patients were higher compared to controls before therapy (p<0.05 and p<0.01, respectively). In LAgP patients, periodontal therapy was associated with increased number of lymphocytes. PMID- 25817351 TI - Correlations between extent of X-ray infiltration and levels of serum C-reactive protein in adult non-severe community-acquired pneumonia. AB - Pneumonia cases can vary in both severity and chest X-ray findings. Elevated C reactive protein (CRP) levels may be an indicator of disease severity. We retrospectively evaluated factors correlated with the extent of chest X-ray infiltration both in community-acquired pneumonia (CAP) and a subgroup of cases with pneumococcal pneumonia. In a clinical study that evaluated the efficacy of sitafloxacin, 137 patients with CAP had been previously enrolled. In our study, 75 patients with pneumococcal pneumonia were identified among these 137 CAP patients. The extent of chest X-ray infiltration was scored and correlations with age, sex, body temperature, white blood cell (WBC) count, and CRP levels were analyzed using multivariate analysis with logistic regression. Significant correlations were observed between the extent of chest X-ray infiltration and CRP levels in both CAP and pneumococcal pneumonia. Our data indicates that CRP is a valuable and informative resource that could reflect the severity of pneumonia in cases of both CAP and pneumococcal pneumonia. PMID- 25817353 TI - Serum antimicrobial concentrations for surgical antimicrobial prophylaxis in radical nephrectomy and radical prostatectomy. AB - To evaluate the current methods of surgical antimicrobial prophylaxis from the viewpoint of pharmacokinetics for patients undergo urologic surgery, this study was designed to measure the serum concentrations of two different prophylactic antimicrobial agents in different types of urologic surgery. This prospective study included 39 patients with prostate cancer, renal pelvic cancer, ureteral cancer or renal cancer treated by radical surgery from August 2005 to March 2006. Blood samples were taken intraoperatively at 30 min and 180 min after the beginning of the first administration. The half-life of the beta phase of cefazolin is 2.46 h and that of piperacillin is 0.7 h according to their manufacturers. The average serum concentration of cefazolin at 30 min was 144 MUg/mL in the prostatectomy group and 175 MUg/mL in the nephrectomy group. At 180 min, the average concentration of cefazolin was 37 MUg/mL in prostatectomy group and 59 MUg/mL in the nephrectomy group. The average concentration of piperacillin at 30 min was 134 MUg/mL in the prostatectomy group and 137 MUg/mL in the nephrectomy group. At 180 min, the average concentration of piperacillin was 10 MUg/mL in the prostatectomy group and 22 MUg/mL in the nephrectomy group. Thus, the concentration at 180 min after the beginning of infusion was different according to the half-life of each antimicrobial agent. Therefore, up-to-date guidelines for surgical antimicrobial prophylaxis that deal with additional types of intraoperative prophylaxis should be consulted if the operation exceeds two half-lives of the prophylactic antimicrobial agents used in real-life clinical practice. PMID- 25817352 TI - Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens' antibacterial susceptibility. AB - The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents. Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S. pneumoniae were 1.1% and 0.0%, respectively. Among H. influenzae, 17.6% of them were found to be beta-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be beta-lactamase-non-producing ABPC-resistant and 11.0% to be beta-lactamase producing ABPC-resistant strains. Extended spectrum beta-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo beta-lactamase were 2.9% and 0.6%, respectively. Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis. PMID- 25817354 TI - A Transcriptional Map of the Renal Tubule: Linking Structure to Function. PMID- 25817356 TI - Co-occurrence of anxiety and depressive-like behaviors following adolescent social isolation in male mice; possible role of nitrergic system. AB - Approximately more than 50% of patients with depression have the co-occurrence of anxiety, which complicates the treatment of disease. Recently, social isolation stress (SIS) paradigm has been suggested as an animal model to investigate the underlying mechanism involved in depression-anxiety co-occurrence. In this study, applying six weeks of SIS to adolescent mice, we tested whether nitrergic system plays a role in co-occurrence of depression and anxiety. In this study, comparisons between socially and isolated conditioned (SC and IC) animals showed that SIS induces behaviors relevant to depression and anxiety in IC mice and in addition, nitrergic system is involved in mediating the negative outcomes of SIS. Administration of subeffective doses of aminoguanidine (a specific inducible nitric oxide synthase inhibitor or iNOS, 50mg/kg) and L-NAME (non-specific inhibitor of NOS, 10mg/kg) significantly reversed the negative effects of SIS on behavioral profile as well as nitrite levels in the cortex of IC mice, Although administration of subeffective dose of 7-nitroindazole (a specific neuronal NOS inhibitor, 25mg/kg) decreased the nitrite levels in the hippocampus, but had no effect on depressant and anxiogenic effects of SIS. Results of this study confirmed that SIS is an appropriate animal model to investigate the potential mechanisms in depression-anxiety co-occurrence. We also showed that nitrergic system has contributed to co-occurrence of depression and anxiety in IC mice as an underlying mechanism. PMID- 25817355 TI - Deep Sequencing in Microdissected Renal Tubules Identifies Nephron Segment Specific Transcriptomes. AB - The function of each renal tubule segment depends on the genes expressed therein. High-throughput methods used for global profiling of gene expression in unique cell types have shown low sensitivity and high false positivity, thereby limiting the usefulness of these methods in transcriptomic research. However, deep sequencing of RNA species (RNA-seq) achieves highly sensitive and quantitative transcriptomic profiling by sequencing RNAs in a massive, parallel manner. Here, we used RNA-seq coupled with classic renal tubule microdissection to comprehensively profile gene expression in each of 14 renal tubule segments from the proximal tubule through the inner medullary collecting duct of rat kidneys. Polyadenylated mRNAs were captured by oligo-dT primers and processed into adapter ligated cDNA libraries that were sequenced using an Illumina platform. Transcriptomes were identified to a median depth of 8261 genes in microdissected renal tubule samples (105 replicates in total) and glomeruli (5 replicates). Manual microdissection allowed a high degree of sample purity, which was evidenced by the observed distributions of well established cell-specific markers. The main product of this work is an extensive database of gene expression along the nephron provided as a publicly accessible webpage (https://helixweb.nih.gov/ESBL/Database/NephronRNAseq/index.html). The data also provide genome-wide maps of alternative exon usage and polyadenylation sites in the kidney. We illustrate the use of the data by profiling transcription factor expression along the renal tubule and mapping metabolic pathways. PMID- 25817357 TI - The influence of the new enkephalin derivative, cyclo[N(epsilon),N(beta)-carbonyl d-Lys(2),Dap(5)] enkephalinamide (cUENK6), on reinstatement of ethanol-induced conditioned place preference in rats. AB - The aim of the present study was to determine whether a new cyclic analog of enkephalin, cyclo[N(epsilon),N(beta)-carbonyl-d-Lys(2),Dap(5)] enkephalinamide (cUENK6), a preferential MU-(MORs), and, to a lower extent, a delta-opioid receptor (DORs) agonist in vitro, could reinstate ethanol-induced conditioned place preference (CPP). In our work, male Wistar rats were first conditioned either with ethanol (10% w/v, 0.5g/kg, intraperitoneally (i.p.)) or 0.9% NaCl in a biased CPP procedure. The intracerebroventricular (i.c.v.) administration of DORs antagonist (naltrindole, 2.5 and 5nmol) or MORs antagonist (beta funaltrexamine, 5 and 10nmol), but not the kappa opioid receptor (KORs) antagonist (norbinaltorphimine, 5 and 10nmol) was then administered and inhibited the expression of ethanol-induced CPP. After the extinction session, i.c.v. administration of cUENK6 at the dose of 0.125, 0.25 and 0.5nmol occurred, and was found to reinstate the ethanol-induced CPP similar to that of the priming injection of ethanol. However, the reinstated effect of cUENK6 (0.25nmol) was strongly abolished by administration of naltrindole and, to lesser extent, by beta-funaltrexamine. Furthermore, the preferential MORs agonist-morphine (13nmol, i.c.v.) and the DORs agonist-[Leu(5)]-enkephalin (2.7 and 5.4nmol, i.c.v.) also reinstated the ethanol-induced CPP. cUENK6 given alone at the dose of 0.25nmol before the testing phase had no effect in animals that received 0.9% NaCl during the conditioning phase and also did not influence their locomotor activity. These data suggest that the effects of cUENK6 did not have an impact on the results obtained in the reinstatement procedure of CPP. Overall, the data support the idea that both MORs and DORs are normally involved in the expression and reinstatement of ethanol conditioned seeking behavior - as indexed by CPP in rats. PMID- 25817358 TI - Variation in complement protein C1q is not a major contributor to cognitive impairment in Parkinson's disease. AB - Traditional dogma regarding the brain as an immune exempt organ has changed in recent years. New research has highlighted the role of the classical complement cascade in both synaptic elimination and function, driven largely by the role of the pathway initiating protein C1q. Given the links between C1q and cognitive function we assessed the genetic variability of the C1q encoding genes: C1QA, C1QB and C1QC between PD patients and matched controls. Despite a strong link between C1Q/cognitive decline and PD/cognitive decline we were unable to find a link between common C1Q variation and PD. We conclude that common C1Q-A/B/C genetic variation is unlikely to contribute to cognitive decline or the missing heritability in PD. PMID- 25817359 TI - Effects of task repetition on event-related potentials in somatosensory Go/No-go paradigm. AB - We investigated the effects of task repetition on the N140 and P300 components of event-related potentials (ERPs) in somatosensory Go/No-go paradigms. A Go or No go stimulus was presented to the second or fifth digit of the left hand, respectively, at the same probability, and subjects had to respond by pushing a button with their right thumb as quickly as possible only after the presentation of a Go stimulus. The condition comprised seven sessions of recordings, and subjects were allowed to relax for five minutes after one session. The behavioral data for the reaction time (RT), standard deviation of RT, and error rates showed the absence of an effect by task repetition. In ERP waveforms, the amplitudes of N140 and P300 decreased with task repetition, and the latency of P300 was delayed by task repetition. There was no significant effect of task repetition on the peak latency of N140. Changes in amplitude and latency values in N140 and P300 during Go/No-go paradigms reflected changes in the neural activation of response execution and inhibition processing with task repetition. PMID- 25817360 TI - Decreased resting-state connections within the visuospatial attention-related network in advanced aging. AB - Advanced aging is accompanied by a decline in visuospatial attention. Previous neuroimaging and electrophysiological studies have demonstrated dysfunction in specific brain areas related to visuospatial attention. However, it is still unclear how the functional connectivity between brain regions causes the decline of visuospatial attention. Here, we combined task and rest functional magnetic resonance imaging (fMRI) to investigate the age-dependent alterations of resting state functional connectivity within the task-related network. Twenty-three young subjects and nineteen elderly subjects participated in this study, and a modified Posner paradigm was used to define the region of interest (ROI). Our results showed that a marked reduction in the number of connections occurred with age, but this effect was not uniform throughout the brain: while there was a significant loss of communication in the anterior portion of the brain and between the anterior and posterior cerebral cortices, communication in the posterior portion of the brain was preserved. Moreover, the older adults exhibited weakened resting-state functional connectivity between the supplementary motor area and left anterior insular cortex. These findings suggest that, the disrupted functional connectivity of the brain network for visuospatial attention that occurs during normal aging may underlie the decline in cognitive performance. PMID- 25817361 TI - BDNF genotype influence the efficacy of rTMS in stroke patients. AB - Brain-derived neurotrophic factor (BDNF) genotype can influence neural response to repetitive transcranial magnetic stimulation (rTMS) in normal individuals. In this study we established personalized stimulus intensity of facilitatory rTMS according to BDNF genotype in stroke patients. Twenty-two chronic stroke patients were enrolled. All patients underwent three different sessions of rTMS over the ipsilesional M1 in randomized order with a washout period exceeding 24h: first condition, high-frequency rTMS with sub-threshold intensity; second condition, high-frequency rTMS with supra-threshold intensity; third condition, sham rTMS. Cortical excitability in the affected hemisphere was assessed with motor evoked potentials (MEPs) before and after stimulation. Data were analyzed according to BDNF genotype. Six [27.3%] and 16 [72.7%] participants were classified in the Val/Val group and Met allele group, respectively. In each group, significant increases were observed in the amplitude of MEPs after the stimulation in the first and second conditions (p<0.05), but not in the third condition. However, a significantly higher increase of amplitude of MEPs was observed between the first and second conditions in only the Val/Val group (p<0.05). BDNF genotype and stimulus intensity should be considered when high-frequency rTMS is used for the modulation of cortical excitability in patients with chronic stroke. PMID- 25817362 TI - Molecular composition and expression pattern of the extracellular matrix in a mossy fiber-generating precerebellar nucleus of rat, the prepositus hypoglossi. AB - The prepositus hypoglossi nucleus (PHN) is a mossy fiber-generating precerebellar nucleus of the brainstem, regarded as one of the neural integrators of the vestibulo-ocular reflex. The aim of the present work is to reveal the distribution of various molecular components of the extracellular matrix (ECM) in the prepositus hypoglossi nucleus by using histochemical and immunohistochemical methods. Our most characteristic finding was the accumulation of the ECM as perineuronal net (PNN) and axonal coat and we detected conspicuous differences between the magnocellular (PHNm) and parvocellular (PHNp) divisions of the PHN. PNNs were well developed in the PHNm, whereas the pericellular positivity was almost absent in the PHNp, here a diffuse ECM was observed. In the PHNm the perineuronal net explored the most intense staining with the aggrecan, and tenascin-R antibodies followed by the hyaluronan, then least with reactions for chondroitin sulfate-based proteoglycan components and HAPLN1 link protein reactions, but PNNs were not observed with the versican, neurocan, and brevican staining. We hypothesized that the difference in the ECM organization of the two subnuclei is associated with their different connections, cytoarchitecture, physiological properties and with their different functions in the vestibular system. PMID- 25817363 TI - Optoactivation of parvalbumin neurons in the spinal dorsal horn evokes GABA release that is regulated by presynaptic GABAB receptors. AB - Among heterogeneous neural cells in the spinal dorsal horn, parvalbumin (PV) positive neurons are one subtype of GABA (gamma-aminobutyric acid)-containing interneurons. Using an optogenetic approach, we expressed blue light-sensitive cation channel channelrhodopsin-2 (ChR2) via a viral vector on PV neurons in the spinal dorsal horn. Combined with in vitro whole-cell recordings, we activated ChR2 expressed on PV neurons by blue light and recorded GABAA receptor-mediated light-evoked inhibitory postsynaptic currents (L-IPSCs). The L-IPSCs were action potential-dependent and abolished by the GABAA receptor antagonist picrotoxin, indicating a synchronic GABA release from presynaptic terminals. Activation of GABAB receptors (the metabotropic receptors of GABA) on presynaptic terminals by a putative agonist, baclofen, depressed the amplitude of L-IPSCs. This depression was largely occluded by pretreatment with the highly selective Cav2.1 (P/Q-type) Ca(2+) channel blocker omega-agatoxin IVA. N-type Ca(2+) channel blocker omega conotoxin GVIA showed less effects on either L-IPSCs or baclofen depression. We conclude that optoactivation of PV-ChR2 neurons in the spinal dorsal horn induces GABA release from presynaptic terminals, which is modulated by presynaptic GABAB receptors that are coupled to P/Q-type Ca(2+) channels. Importantly, our studies provide a simple and reliable optogenetic approach to study dorsal horn neural circuits. PMID- 25817364 TI - Is the 1254T>C polymorphism in the DMT1 gene associated with Parkinson's disease? AB - Parkinson's disease (PD) is a late-onset neurodegenerative disorder with both familial and sporadic presentation. The main pathological characteristic of PD is the death of dopaminergic neurons in the substantia nigra (SN) pars compacta. PD is the second most common neurodegenerative disease worldwide, after Alzheimer's disease. Recent studies have suggested increased levels of iron and iron-binding proteins in the brains of patients with PD. Divalent metal transporter 1 (DMT1) is one protein responsible for iron transport. Postmortem studies have shown an important increase in DMT1 levels in the SN of patients with PD. Our aim is to determine whether there is an association between DMT1 polymorphisms and PD. We analyzed two single nucleotide polymorphisms (1254T>C and IVS4+44C>A) in the DMT1 gene in patients with 97 Parkinson's disease and in 100 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). No association was found between the IVS4+44C>A polymorphism and PD, but the TT genotype and T allele of the 1254T>C polymorphism in the DMT1 gene were associated with PD (P=0.002 and P=0.012, respectively). In contrast to a previous study, our results suggest that the TT genotype and T allele of the 1254T>C polymorphism may be a risk factor for PD. PMID- 25817365 TI - NMR metabonomics of cerebrospinal fluid distinguishes between Parkinson's disease and controls. AB - This study assesses if nuclear magnetic resonance (NMR) metabonomics can discriminate between Parkinson's disease (PD) patients and control subjects, and consequently identify metabolic markers for the disease. One-dimensional (1)H NMR spectroscopy was used for quantitative analysis of metabolites in the cerebrospinal fluid (CSF) from 10 PD patients and 10 control individuals, together with uni- and multivariate statistical analysis to discriminate between the groups and to identify significantly altered metabolite concentrations. In total 60 metabolites were identified and of those 38 were quantified in all CSF samples. An overall lowering of metabolite content was observed in PD patients compared to control subjects (fold change of 0.85+/-0.30). Multivariate statistics reveal significant changes (|w*|>0.2) among nine metabolites (alanine, creatinine, dimethylamine, glucose, lactate, mannose, phenylalanine, 3 hydroxyisobutyric acid and 3-hydroxyisovaleric acid). Three of these (alanine, creatinine and mannose) are identified as significantly changed also by univariate statistics (p<0.00132, Bonferroni corrected). Panels with all or a selected set of these metabolites were successfully used for discriminating between the two groups. In conclusion, NMR metabonomics can readily determine metabolite concentrations in CSF, identify putative biomarkers that distinguish between the PD patients and control subjects, and thus potentially become a tool for diagnostic purposes. PMID- 25817366 TI - Excitability changes in the left primary motor cortex innervating the hand muscles induced during speech about hand or leg movements. AB - In the present study, we used transcranial magnetic stimulation (TMS) to investigate the changes in the excitability of the left primary motor cortex (M1) innervating the hand muscles and in short-interval intracortical inhibition (SICI) during speech describing hand or leg movements. In experiment 1, we investigated the effects of the contents of speech on the amplitude of the motor evoked potentials (MEPs) induced during reading aloud and silent reading. In experiment 2, we repeated experiment 1 with an additional condition, the non vocal oral movement (No-Voc OM) condition, and investigated the change in SICI induced in each condition using the paired TMS paradigm. The MEP observed in the reading aloud and No-Voc OM conditions exhibited significantly greater amplitudes than those seen in the silent reading conditions, irrespective of the content of the sentences spoken by the subjects or the timing of the TMS. There were no significant differences in SICI between the experimental conditions. Our findings suggest that the increased excitability of the left M1 hand area detected during speech was mainly caused by speech-related oral movements and the activation of language processing-related brain functions. The increased left M1 excitability was probably also mediated by neural mechanisms other than reduced SICI; i.e., disinhibition. PMID- 25817367 TI - Ameliorative effect of gastrodin on 3,3'-iminodipropionitrile-induced memory impairment in rats. AB - 3,3'-Iminodipropionitrile (IDPN), one of the nitrile derivatives inducing neurotoxicity, causes the dyskinetic syndrome and cognitive impairment. Gastrodin is widely used to treat neurological disorders and showed to improve cognitive functions. The present study aimed to determine whether treatment with gastrodin can attenuate IDPN-induced impairment of memory consolidation in the passive avoidance (PA) task, and to explore the possible neural mechanisms. Our results showed that intragastric administration of gastrodin (200mg/kg) reversed the IDPN induced impairment of memory consolidation as indicated by the prolonged retention latency in the PA task. Furthermore, gastrodin reverted IDPN-induced reduction of serotonin (5-HT) and elevation of serotonin turnover ratio. Gastrodin treatment prevented the increase of serotonin transporter (SERT) and the decrease of serotonin 1A (5-HT1A) receptor expression in the hippocampus of IDPN-treated rats. These results suggest that long-term gastrodin treatment could represent a novel pharmacological strategy for IDPN-induced memory impairment, as well that its protective effect is mediated through normalization of the serotoninergic system. PMID- 25817368 TI - Reinvestigation of cochlear pathology in circling mice. AB - The main causes of early hearing deficit in circling mice have been reported to be early degeneration of the organ of Corti and deterioration of spiral ganglion neurons. As an exact cochlear pathology is essential to explain our previous results regarding the auditory brainstem circuits of developing circling mice, we reinvestigated the cochlear pathology in developing circling mice (14, 22, and 38 days old). It has been reported that the organ of Corti in circling mice completely degenerates as early as postnatal day (P) 21 and that circling mice are deaf by P18. Although we confirmed that circling mice were deaf at P15 and that hair bundles of outer hair cells were defective at P18, complete degeneration of the organ of Corti was not observed by P38 in circling mice. At P22, the type I cell-like spiral ganglion cell density in circling mice was reduced to 78% of that of control mice (ICR mice), but it was not significantly different from that of other control mice (heterozygous (+/cir) mice, littermates of circling mice) that could hear at P22. Our data suggest that other factors, such as absence of neurotransmitter release from inner hair cells, should be considered to explain the early hearing deficit observed at P15 in circling mice. PMID- 25817369 TI - The risk of osteoporosis in patients with liver cirrhosis: a meta-analysis of literature studies. AB - OBJECTIVE: Data about the association between cirrhosis and osteoporosis are contrasting. Thus, we have performed a meta-analysis of literature studies on this topic. DESIGN: MEDLINE, Cochrane library, EMBASE, Scopus and Web of Science databases have been searched to retrieve all articles of interest. Data on prevalence of osteoporosis, bone mineral density (BMD) and bone turnover laboratory parameters were compared among cirrhotic patients and control subjects without cirrhosis. PATIENTS: Studies on patients with liver cirrhosis screened for the presence of osteoporosis were included. RESULTS: Six case-control studies (372 cirrhotic patients and 1579 controls) were included. The prevalence of osteoporosis was higher in cirrhotic patients than in controls (34.7% vs 12.8%, OR: 2.52, 95%CI: 1.11, 5.69; P = 0.03, I(2) = 81%; P = 0.005). Accordingly, a reduced lumbar spine BMD (MD: -0.13, 95%CI: -0.24, -0.02; P = 0.02, I(2) = 93%; P < 0.00001) and z-score (MD: -1.06, 95%CI: -1.79, -0.34; P = 0.004, I(2) = 95%; P < 0.00001) were found in cirrhotic patients as compared with controls. In contrast, no significant differences were reported in femoral neck BMD and z score. Interestingly, bone turnover laboratory parameters widely confirmed these results showing higher levels of ALP and D-Pyr, accompanied by reduced levels of IGF-1, PTH and 25-OH-D in cirrhotic patients as compared with controls. CONCLUSIONS: Despite the high heterogeneity among studies, data showed an increased prevalence of osteoporosis in patients with cirrhosis. This information suggests the need of an accurate screening of bone mineral density in patients with liver cirrhosis to plan an adequate osteoporosis management. PMID- 25817370 TI - Categorization training increases the perceptual separability of novel dimensions. AB - Perceptual separability is a foundational concept in cognitive psychology. A variety of research questions in perception - particularly those dealing with notions such as "independence," "invariance," "holism," and "configurality" - can be characterized as special cases of the problem of perceptual separability. Furthermore, many cognitive mechanisms are applied differently to perceptually separable dimensions than to non-separable dimensions. Despite the importance of dimensional separability, surprisingly little is known about its origins. Previous research suggests that categorization training can lead to learning of novel dimensions, but it is not known whether the separability of such dimensions also increases with training. Here, we report evidence that training in a categorization task increases perceptual separability of the category-relevant dimension according to a variety of tests from general recognition theory (GRT). In Experiment 1, participants who received pre-training in a categorization task showed reduced Garner interference effects and reduced violations of marginal invariance, compared to participants who did not receive such pre-training. Both of these tests are theoretically related to violations of perceptual separability. In Experiment 2, participants who received pre-training in a categorization task showed reduced violations of perceptual separability according to a model-based analysis of data using GRT. These results are at odds with the common assumption that separability and independence are fixed, hardwired characteristics of features and dimensions. PMID- 25817371 TI - The role of YY1 in oncogenesis and its potential as a drug target in cancer therapies. AB - Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications. Recent studies reveal a proliferative role of YY1 in oncogenesis. Consistently, YY1 overexpression has been observed in various human malignancies and its levels correlate with poor prognoses of many types of cancers. In this review, we focus on the signaling pathways and regulatory proteins that YY1 modulates to promote tumor cell growth, proliferation, migration and metastasis. We also discuss the signals and molecules that regulate YY1 expression and function in cancer-related context. Based on the expression feature and regulatory activities in tumor cells, YY1 possesses a great potential as a biomarker for many cancers and can serve as a therapeutic target clinically to impede cancer development and progression or sensitize cancer cells to anticancer drugs. PMID- 25817372 TI - Identification of VEGFR2-binding peptides using high throughput bacterial display methods and functional assessment. AB - The signal transduction pathway initiated by vascular endothelial growth factor vascular endothelial growth factor receptor 2 (VEGF-VEGFR2) plays an important role in the angiogenesis of tumors. The effective antagonists of VEGFR2 would behave as potent drugs for the treatment of malignant cancers. In our study, specific binding peptides with high affinity to VEGFR2 were obtained through bacterial display technology. Conserved motif (FF/YEXWGVK) among those peptide sequences was discovered. One of the selected peptides, VRBP1 (YDGNSFYEMWGVKPASES) was identified by screening the biased bacterial peptide library and its physiochemical feature was further characterized. The results of surface plasmon resonance (SPR) assay indicated that the dissociation constant (KD) value of VRBP1 was 228.3 nM and this peptide competed with VEGF binding to VEGFR2. Particles conjugated with VRBP1 could recognize the human umbilical vein endothelial cells (HUVEC) which express VEGFR2 on the surface. Further therapeutic effect of VRBP1 was examined by in vivo experiments. VRBP1 could result in a significant decrease in tumor size of H460 xenografts. The results from the immunohistochemical assay showed that CD31 positive signals in VRBP1 treated group were fewer than those in the control ones. These data highlighted the potential of VEGFR2-binding peptides as effective molecules for cancer diagnosis and therapy. PMID- 25817373 TI - Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial. AB - BACKGROUND: Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. METHODS: We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. FINDINGS: Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0.0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0.0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421.4 [95% CI 249.7 711.3] and 820.5 [598.9-1124.0], respectively; p<0.0001) and day 28 (682.7 [424.3 1098.5] and 1305.7 [970.1-1757.2], respectively; p<0.0001). T-cell responses peaked at day 14 at a median of 465.0 spot-forming cells (IQR 180.0-1202.5) in participants in the low-dose group and 765.0 cells (400.0-1460.0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. INTERPRETATION: Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. FUNDING: China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. PMID- 25817375 TI - An updated Ebola vaccine: immunogenic, but will it protect? PMID- 25817376 TI - Gestational hypertension before term: observe or deliver? PMID- 25817374 TI - Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial. AB - BACKGROUND: There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS: We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS: Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1.1%) of 352 women allocated to immediate delivery versus 11 (3.1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0.36, 95% CI 0.12-1.11; p=0.069). Respiratory distress syndrome was diagnosed in 20 (5.7%) of 352 neonates in the immediate delivery group versus six (1.7%) of 351 neonates in the expectant monitoring group (RR 3.3, 95% CI 1.4-8.2; p=0.005). No maternal or perinatal deaths occurred. INTERPRETATION: For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING: ZonMw. PMID- 25817377 TI - Highlights of carotenoid research from the 17th International Carotenoid Symposium. PMID- 25817379 TI - How the ACR Works-The Chapters' Vital Role. PMID- 25817378 TI - Tolerance of human embryonic stem cell derived islet progenitor cells to vitrification-relevant solutions. AB - We have previously shown that human embryonic stem cell derived islet progenitors (hESC-IPs), encapsulated inside an immunoprotective device, mature in vivo and ameliorate diabetes in mice. The ability to cryopreserve hESC-IPs preloaded in these devices would enhance consistency and portability, but traditional 'slow freezing' methods did not work well for cells encapsulated in the device. Vitrification is an attractive alternative cryopreservation approach. To assess the tolerance of hESC-IPs to vitrification relevant conditions, we here are reporting cell survival following excursions in tonicity, exposure to fifteen 40% v/v combinations of 4 cryoprotectants, and varied methods for addition and elution. We find that 78% survival is achieved using a protocol in which cells are abruptly (in one step) exposed to a solution containing 10% v/v each dimethyl sulfoxide, propylene glycol, ethylene glycol, and glycerol on ice, and eluted step-wise with DPBS+0.5M sucrose at 37 degrees C. Importantly, the hESC-IPs also maintain expression of the critical islet progenitor markers PDX-1, NKX6.1, NGN3 and NEURO-D1. Thus, hESC-IPs exhibit robust tolerance to exposure to vitrification solutions in relevant conditions. PMID- 25817380 TI - The 2014 Moreton Lecture: A Rebuttal. PMID- 25817381 TI - Radiology Is a Team Sport. PMID- 25817382 TI - Best practices for evaluating and tracking protective garments. PMID- 25817383 TI - X-ray computed tomography system for laboratory small-object imaging: Enhanced tomography solutions. AB - A portable X-ray tomography system has been installed and actually being tested at our medical imaging laboratory. This tomography system employs a combination of scintillator screen and CCD camera as image detector. The limit of spatial resolution of 290 MUm of this imaging system is determined by the establishment of its modulation transfer function (MTF). In this work, we present attempts to address some issues such as limited resolution and low contrast through the development of affordable post-acquisition solutions based on the application of super-resolution method (projection onto convex sets, POCS) to create new projections set enabling the reconstruction of an improved 3D image in terms of contrast, resolution and noise. In addition to small-object examination, this tomography system is used for hands-on training activities involving students and scientists. PMID- 25817384 TI - A novel data-driven algorithm to reveal and track the ribosome heterogeneity in single molecule studies. AB - The unique advantage of the single molecule approach is to reveal the inhomogeneous subpopulations in an ensemble. For example, smFRET (single molecule fluorescence resonance energy transfer) can identify multiple subpopulations based on the FRET efficiency histograms. However, identifying multiple FRET states with overlapping average values remains challenging. Here, we report a new concept and method to analyze the single molecule FRET data of a ribosome system. The main results are as follows: 1. based on a hierarchic concept, multiple ribosome subpopulations are identified. 2. The subpopulations are self-identified via the cross-correlation analysis of the FRET histogram profiles. The dynamic heterogeneity is tracked after 2 min intervals on the same ribosomes individually. 3. The major ribosome subpopulations exchange with each other with a certain pattern, indicating some correlations among the motions of the tRNAs and the ribosomal components. Experiments under the conditions of 20% glycerol or 1mM viomycin supported this conclusion. PMID- 25817385 TI - A prospective study comparing ultrapulse CO2 laser and trichloroacetic acid in treatment of Xanthelasma palpebrarum. AB - BACKGROUND: Xanthelasma Palpebrarum is a type of xanthoma which presents as cosmetic concern. OBJECTIVE: To compare the efficacy of 30% TCA and UpCO2 laser in XP. METHODS AND MATERIALS: Fifty patients with XP were categorized clinically into three groups. Patients in each group were alternately allocated to 30% TCA (Group A) and laser (Group B). TCA was applied weekly (maximum: 12 sessions), and laser sessions were given monthly (maximum: three sessions). The primary outcome measures were total patients cured, the number of sessions, and mean VAS at the end of treatment. The secondary outcome measures were total duration of treatment, side effects, and recurrence in follow-up (6 months) (P < 0.05 significant). RESULTS: In Group A, 14 of 25 and in Group B, 25 of 25 patients achieved complete cure (P < 0.05). The mean VAS was lower for Group A (patient: 4.56 vs. 5.36; physician: 4.64 vs. 5.44) [P < 0.05] with significant difference only for group III patients. Mean number of sessions was less with laser group (1.56 vs. 9.74), except in group I. There was no significant difference in pigmentary changes and recurrence. CONCLUSION: For clinically mild lesions, both TCA and laser are good options, but laser is a better option for severe lesions. Recurrence is a concern with both modalities. PMID- 25817386 TI - Solution structure of the Atg1 complex: implications for the architecture of the phagophore assembly site. AB - The biogenesis of autophagosomes commences at the phagophore assembly site (PAS), a protein-vesicle ultrastructure that is organized by the Atg1 complex. The Atg1 complex consists of the Atg1 protein kinase, the intrinsically disordered region rich Atg13, and the dimeric double crescent-shaped Atg17-Atg31-Atg29 subcomplex. We show that the PAS contains a relatively uniform ~28 copies of Atg17, and upon autophagy induction, similar numbers of Atg1 and Atg13 molecules. We then apply ensemble refinement of small-angle X-ray scattering to determine the solution structures of the Atg1-Atg13 and Atg17-Atg31-Atg29 subcomplexes and the Atg1 complex, using a trimmed minipentamer tractable to biophysical studies. We observe tetramers of Atg1 pentamers that assemble via Atg17-Atg31-Atg29. This leads to a model for the higher organization of the Atg1 complex in PAS scaffolding. PMID- 25817387 TI - Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis. AB - The Chinese herb Dichroa febrifuga has traditionally treated malaria-associated fever. Its active component febrifugine (FF) and derivatives such as halofuginone (HF) are potent anti-malarials. Here, we show that FF-based derivatives arrest parasite growth by direct interaction with and inhibition of the protein translation enzyme prolyl-tRNA synthetase (PRS). Dual administration of inhibitors that target different tRNA synthetases suggests high utility of these drug targets. We reveal the ternary complex structure of PRS-HF and adenosine 5' (beta,gamma-imido)triphosphate where the latter facilitates HF integration into the PRS active site. Structural analyses also highlight spaces within the PRS architecture for HF derivatization of its quinazolinone, but not piperidine, moiety. We also show a remarkable ability of HF to kill the related human parasite Toxoplasma gondii, suggesting wider HF efficacy against parasitic PRSs. Hence, our cell-, enzyme-, and structure-based data on FF-based inhibitors strengthen the case for their inclusion in anti-malarial and anti-toxoplasmosis drug development efforts. PMID- 25817389 TI - Prostate carcinoma in liver transplant recipients: Think about it! AB - OBJECTIVES: To analyze retrospectively our series of prostate cancer (PC) in liver transplant recipients (LTRs) given an increase in frequency in an aging recipient population when no studies were reported in literature. METHODS: We conducted a retrospective analysis of LTRs in a single institution. After liver transplantation, all patients were followed up in our institution with an annual digital rectal examination by a urologist and prostate-specific antigen measurement after the age of 50 years. RESULTS: Between 1995 and 2013, among 361 male LTRs, 12 (3.3%) had PC. The mean age at diagnosis was 62.8 years, and the time lapse between liver transplantation and diagnosis was 55.7 months. The median initial prostate-specific antigen level was 7.4ng/ml. In total, 9 patients underwent radical prostatectomy. Histological findings showed 5 pT2 and 4 pT3 cancers. A patient showed invasion in the lymph nodes and was treated with hormonotherapy. Another patient had a biochemical recurrence at 10 months and underwent salvage radiotherapy. After 32.9 months of follow-up, no other patients showed any recurrence. Moreover, 1 patient was treated by radiohormonotherapy for high-risk PC with no recurrence at 65 months, and 1 patient was treated with high intensity focal ultrasound. There was 1 patient with metastatic disease who received hormonotherapy and died 5 months after diagnosis. CONCLUSION: Our incidence of intermediate- and high-risk PCs in LTRs was slightly higher than in the general population. In the absence of any recommendations, individual screening should be proposed to LTRs. The treatment of choice remains surgery or radiotherapy to ensure a good carcinologic control. PMID- 25817388 TI - Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by alpha2 noradrenergic receptors within the locus coeruleus. AB - Long-term l-DOPA use for Parkinson's disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as l-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the alpha2-adrenoceptors (alpha2R) in l DOPA's therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic alpha2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and l-DOPA's therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of alpha2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic l-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with l-DOPA's antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate l-DOPA's antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that alpha2R play an important modulatory role in l-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target. PMID- 25817390 TI - Rebamipide suppresses TNF-alpha mediated inflammation in vitro and attenuates the severity of dermatitis in mice. AB - Rebamipide is a routine drug for the treatment of gastritis in a clinical setting. Recently, it has been shown to protect against various inflammatory diseases, and has provided a potential therapy for these diseases. However, whether rebamipide has a role in dermatitis remains to be elucidated. Here, we found that rebamipide alleviated the inflammatory reaction induced by tumor necrosis factor-alpha in RAW264.7, a stable macrophage cell line. Furthermore, rebamipide treatment repressed activation of nuclear factor-kappaB signaling, a well-established inflammatory signaling pathway. Moreover, an oxazolone-induced dermatitis mouse model was established to investigate the role of rebamipide in vivo. PBS control group exhibited typical skin inflammation, whereas treatment with rebamipide remarkably attenuated a dermatitis phenotype in this mouse model. The protective role of rebamipide in dermatitis in vivo was probably due to its inhibition of nuclear factor-kappaB signaling. Collectively, rebamipide may represent a promising molecular target for the prevention and treatment of inflammatory skin diseases. PMID- 25817391 TI - Impact of Incremental Perfusion Loss on Oxygen Transport in a Capillary Network Mathematical Model. AB - OBJECTIVES: To quantify how incremental capillary PL, such as that seen in experimental models of sepsis, affects tissue oxygenation using a computation model of oxygen transport. METHODS: A computational model was applied to capillary networks with dimensions 84 * 168 * 342 (NI) and 70 * 157 * 268 (NII) MUm, reconstructed in vivo from rat skeletal muscle. FCD loss was applied incrementally up to ~40% and combined with high tissue oxygen consumption to simulate severe sepsis. RESULTS: A loss of ~40% FCD loss decreased median tissue PO2 to 22.9 and 20.1 mmHg in NI and NII compared to 28.1 and 27.5 mmHg under resting conditions. Increasing RBC SR to baseline levels returned tissue PO2 to within 5% of baseline. HC combined with a 40% FCD loss, resulted in tissue anoxia in both network volumes and median tissue PO2 of 11.5 and 8.9 mmHg in NI and NII respectively; median tissue PO2 was recovered to baseline levels by increasing total SR 3-4 fold. CONCLUSIONS: These results suggest a substantial increase in total SR is required in order to compensate for impaired oxygen delivery as a result of loss of capillary perfusion and increased oxygen consumption during sepsis. PMID- 25817392 TI - ABCA3 protects alveolar epithelial cells against free cholesterol induced cell death. AB - Diffuse parenchymal lung diseases (DPLDs) are characterized by chronic inflammation and fibrotic remodeling of the interstitial tissue. A small fraction of DPLD cases can be genetically defined by mutations in certain genes, with ABCA3 being the gene most commonly affected. However, the pathomechanisms underlying ABCA3-induced DPLD are far from clear. To investigate whether ABCA3 plays a role in cellular cholesterol homeostasis, phospholipids, free cholesterol, and cholesteryl esters were quantified in cells stably expressing ABCA3 using mass spectrometry. Cellular free cholesterol and lipid droplets were visualized by filipin or oil red staining, respectively. Expression of SREBP regulated genes was measured using qPCR. Cell viability was assessed using the XTT assay. We found that wild type ABCA3 reduces cellular free cholesterol levels, induces the SREBP pathway, and renders cells more resistant to loading with exogenous cholesterol. Moreover, ABCA3 mutations found in patients with DPLD interfere with this protective effect of ABCA3, resulting in free cholesterol induced cell death. We conclude that ABCA3 plays a previously unrecognized role in the regulation of cellular cholesterol levels. Accumulation of free cholesterol as a result of a loss of ABCA3 export function represents a novel pathomechanism in ABCA3-induced DPLD. PMID- 25817393 TI - [Approach to a respiratory syncytial virus outbreak related to medical care in hematology]. PMID- 25817394 TI - Long-term controlled delivery of rhBMP-2 from collagen-hydroxyapatite scaffolds for superior bone tissue regeneration. AB - The clinical utilization of recombinant human bone morphogenetic protein 2 (rhBMP 2) delivery systems for bone regeneration has been associated with very severe side effects, which are due to the non-controlled and non-targeted delivery of the growth factor from its collagen sponge carrier post-implantation which necessitates supraphysiological doses. However, rhBMP-2 presents outstanding regenerative properties and thus there is an unmet need for a biocompatible, fully resorbable delivery system for the controlled, targeted release of this protein. With this in mind, the purpose of this work was to design and develop a delivery system to release low rhBMP-2 doses from a collagen-hydroxyapatite (CHA) scaffold which had previously been optimized for bone regeneration and recently demonstrated significant healing in vivo. In order to enhance the potential for clinical translation by minimizing the design complexity and thus upscaling and regulatory hurdles of the device, a microparticle and chemical functionalization free approach was chosen to fulfill this aim. RhBMP-2 was combined with a CHA scaffold using a lyophilization fabrication process to produce a highly porous CHA scaffold supporting the controlled release of the protein over the course of 21days while maintaining in vitro bioactivity as demonstrated by enhanced alkaline phosphatase activity and calcium production by preosteoblasts cultured on the scaffold. When implanted in vivo, these materials demonstrated increased levels of healing of critical-sized rat calvarial defects 8weeks post implantation compared to an empty defect and unloaded CHA scaffold, without eliciting bone anomalies or adjacent bone resorption. These results demonstrate that it is possible to achieve bone regeneration using 30 times less rhBMP-2 than INFUSE(r), the current clinical gold standard; thus, this work represents the first step of the development of a rhBMP-2 eluting material with immense clinical potential. PMID- 25817395 TI - Subtelomeric 6p25 deletion/duplication: Report of a patient with new clinical findings and genotype-phenotype correlations. AB - The 6p terminal deletions are rare and present variability of clinical features, which increases the importance of reporting additional cases in order to better characterize genotype-phenotype correlations. We report a 12-year-old girl with a de novo deletion in 6p25.1-pter characterized by high-resolution karyotyping and FISH. Further analysis using oligonucleotide array-CGH revealed a 5.06 Mb 6p25.1 pter deletion associated with a contiguous 1 Mb 6p25.1 duplication. The patient presented normal growth, developmental delay, frontal bossing, severe hypertelorism, corectopia, wide and depressed nasal bridge, mild learning disability, hearing loss and diffuse leukopathy. Additionaly, she presented peculiar phenotypic features reported herein for the first time in 6p25 deletion syndrome: cerebrospinal fluid fistula and bones resembling those seen in 3-M syndrome. The distinctive phenotype of the 6p25 deletion syndrome has been mainly correlated with the FOXC1 and FOXF2 genes deletions, both related mainly to eye development. We also consider the SERPINB6 as a candidate for sensorineural hearing loss and TUBB2A as a candidate for our patient's skeletal features. In addition, as our patient had a duplication including NRN1, a gene related with neurodevelopment, synaptic plasticity and cognitive dysfunction in schizophrenia, we suggest that this gene could be associated with her white matter abnormalities and neurocognitive phenotype. PMID- 25817396 TI - A surgeon's reflections on love. PMID- 25817397 TI - Does surgery residency prepare residents to work at critical access hospitals? AB - BACKGROUND: Operations performed by surgeons working at Critical Access Hospitals (CAHs) and surgery residents have not been compared. METHODS: Procedure codes logged by general surgery residents graduating from our institution in 2013 and 2014 were obtained. Procedure codes were obtained for all CAHs in our state for 2012 to 2013. Clinically relevant categories were compared among residents and general surgeons at CAHs. RESULTS: A total of 34,246 procedures logged by general surgeons at CAHs were compared with 31,977 procedures logged by surgery residents. Endoscopy comprised 56.1% of cases done by general surgeons versus 9.1% of cases by residents (P < .001). Excluding endoscopy, rural surgeons had higher percentages in hernia, skin/soft tissue, cholecystectomy/common bile duct, rectal/anal, and breast cases. Residents who completed a rural surgery rotation had higher numbers in small/large bowel, hernia, breast, and endoscopy. CONCLUSIONS: Surgery residency provides less exposure to endoscopy compared with a general surgery practice at CAHs. A rural rotation increases endoscopic exposure. PMID- 25817398 TI - Mannoproteins from yeast and hyphal form of Candida albicans considerably differ in mannan and protein content. AB - Significant differences in carbohydrate composition of mannoproteins obtained from yeast and hyphal cell walls of Candida albicans (serotypes A and B) were found. Yeast mannoproteins from both serotypes consisted up to 46% of mannan while the same parts from hyphal cells contained only about 14% of mannan. Another difference was in protein content, 47-53% for yeasts, 3-4.5% for hyphae, respectively. Moreover, HPLC profiles of yeast mannoproteins were more complex compared to those of hyphal form. Subsequently, mannans were prepared from yeast and hyphal mannoproteins using cetavlon fractionation. Mannans from both yeast serotypes contained higher amounts of mannose (91.4% serotype A; 92.8% serotype B) than mannans from hyphae (66.4% serotype A; 76.3% serotype B). Unlike mannans from serotype B, mannans from serotype A contained beta-(1 -> 2)-linked mannopyranosyl units in acid-stable moiety. Further, hyphal mannans were less branched than yeast mannans. The shift from yeast to hyphal form probably led to simplification of mannan structure. PMID- 25817399 TI - Decellularization technology in CNS tissue repair. AB - Decellularization methodologies have been successfully used in a variety of tissue engineering and regenerative technologies and methods of decellularization have been developed for target tissues and organs of interest. The technology to promote regeneration and functional recovery in the CNS, including brain and spinal cord, has, however, made slow progress mainly because the intrinsic regenerative potential of the CNS is regarded as low. To date, currently available therapies have been unable to provide significant functional recovery and successful therapies, which could provide functional restoration to the injured brain and spinal cord are controversial. In this review, the authors provide a critical analysis, comparing the advantages and limitations of the major decellularization methods and considering the effects of these methods upon the biologic scaffold material. The authors also review studies that supplement decellularized grafts with exogenous factors, such as stem cells and growth factors, to both promote and enhance regeneration through decellularized allografts. PMID- 25817400 TI - Protective effects of resveratrol on the inhibition of hippocampal neurogenesis induced by ethanol during early postnatal life. AB - Ethanol (EtOH) exposure during early postnatal life triggers obvious neurotoxic effects on the developing hippocampus and results in long-term effects on hippocampal neurogenesis. Resveratrol (RSV) has been demonstrated to exert potential neuroprotective effects by promoting hippocampal neurogenesis. However, the effects of RSV on the EtOH-mediated impairment of hippocampal neurogenesis remain undetermined. Thus, mice were pretreated with RSV and were later exposed to EtOH to evaluate its protective effects on EtOH-mediated toxicity during hippocampal development. The results indicated that a brief exposure of EtOH on postnatal day 7 resulted in a significant impairment in hippocampal neurogenesis and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by pretreatment with RSV. Furthermore, EtOH exposure resulted in a reduction in spine density on the granular neurons of the dentate gyrus (DG), and the spines exhibited a less mature morphological phenotype characterized by a higher proportion of stubby spines and a lower proportion of mushroom spines. However, RSV treatment effectively reversed these responses. We further confirmed that RSV treatment reversed the EtOH-induced down-regulation of hippocampal pERK and Hes1 protein levels, which may be related to the proliferation and maintenance of NPCs. Furthermore, EtOH exposure in the C17.2 NPCs also diminished cell proliferation and activated apoptosis, which could be reversed by pretreatment of RSV. Overall, our results suggest that RSV pretreatment protects against EtOH-induced defects in neurogenesis in postnatal mice and may thus play a critical role in preventing EtOH-mediated toxicity in the developing hippocampus. PMID- 25817401 TI - Therapeutic effect of post-exposure treatment with antiserum on severe fever with thrombocytopenia syndrome (SFTS) in a mouse model of SFTS virus infection. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease that is endemic in China, Korea and Japan. No effective vaccine or specific treatment for SFTS is currently available. Here, we used a mouse model to examine the effects of ribavirin, site-1 protease inhibitor PF-429242, steroids, and combination of minocycline and ciprofloxacin (MC) on SFTS infection. The antiserum from a patient who recovered from SFTS was also examined for its effect on mice. Administration of antiserum completely protected mice against lethal infection with SFTSV. It could also protect mice from showing clinical signs of the disease due to non-lethal infection. MC-treatment resulted in prolonged survival times during lethal infection. Although other agents had no significant protective effects, they did not provide detrimental effects that could lead to progression of the disease in mice. Our results suggest that antiserum treatment may be clinically useful for post-exposure prophylaxis against SFTSV infection. PMID- 25817402 TI - Effect of time at temperature on wild poliovirus titers in stool specimens. AB - BACKGROUND: The effect of transport temperature on the viability of poliovirus in stool specimens from paralyzed cases has not been tested. Quality assurance of programmatic indicators will be necessary in the final phase of polio eradication. OBJECTIVE: To estimate the effect of time at elevated temperatures on wild poliovirus titers in stool specimens. METHODS: We exposed aliquots of pooled wild poliovirus type 1 specimens to elevated temperatures (27 degrees C, 31 degrees C, and 35 degrees C) for varying time periods up to 14 days. We determined the virus titer of these aliquots and created decay curves at each temperature to estimate the relationship between time at temperature and virus titer. RESULTS: We found significantly different slopes of decay at each temperature. The negative slopes increased as the temperature increased. CONCLUSIONS: While poliovirus in stool remains relatively stable at moderately elevated temperature, transport at higher temperatures could impact sample integrity and virus isolation results. PMID- 25817403 TI - A single NS2 mutation of K86R promotes PR8 vaccine donor virus growth in Vero cells. AB - Vaccination is the most effective way to prevent and control infection by influenza viruses, and a cell-culture-based vaccine production system is preferred as the future choice for the large-scale production of influenza vaccines. As one of the WHO-recommended cell lines for producing influenza vaccines, Vero cells do not efficiently support the growth of the current influenza A virus vaccine donor strain, the A/Puerto Rico/8/1934 (PR8) virus. In this study, a single mutation of K86R in the NS2 protein can sufficiently render the high-yielding property to the PR8 virus in Vero cells. Further analysis showed that the later steps in the virus replication cycle were accelerated by NS2(K86R) mutation, which may relate to an enhanced interaction between NS2(K86R) and the components of host factor F1Fo-ATPase, FoB and F1beta. Because the NS2(K86R) mutation does not increase PR8 virulence in either mice or embryonated eggs, the PR8-NS2(K86R) virus could serve as a promising vaccine donor strain in Vero cells. PMID- 25817404 TI - Potential linkage between compound microsatellites and recombination in geminiviruses: Evidence from comparative analysis. AB - The compound microsatellites consist of two or more individual microsatellites, originate from mutation or imperfection in simple repeat sequences. The reports on systematic analysis of the occurrence, size and density of compound microsatellite (cSSR) types are very rare. Our study indicates that cSSRs are clustered at specific regions in the begomovirus genomes. cSSRs were overrepresented in majority of begomovirus genomes indicating that they might have some functional significance. Further, non-random distribution pattern of cSSR in begomovirus genomes was significantly correlated with the recombination breakpoint positions in the genome. The analysis of cSSR regions in the viral genome indicates the presence of stem loop (hairpin) secondary structure. The significance of these findings in biology of geminiviruses is discussed based on our present understanding of recombination and repetitive DNA. To our knowledge, this is the first analysis suggesting the possible association between recombination and microsatellites in any viral genome. PMID- 25817406 TI - Circadian cortisol and fatigue severity in relapsing-remitting multiple sclerosis. AB - Cortisol is a key regulator of the immune system, energy metabolism, and stress, yet its relevance to fatigue experienced by people with relapsing-remitting multiple sclerosis (RRMS) remains uncertain. We examined cortisol secretory activity in RRMS and its association with fatigue severity between-individuals and within-individuals (day-to-day) using a case-control ecological momentary assessment design. While undergoing usual daily routines, 38 people with RRMS and 38 healthy control participants provided saliva samples at strategic time-points over 4 consecutive weekdays to measure the cortisol awakening response (CAR; 0, 30, and 45 min after awakening) and the diurnal cortisol slope (DCS; 6 quasi random samples provided between 1000 h and 2000 h). Recalled fatigue was measured at baseline, and daily fatigue was measured as the mean average of momentary fatigue ratings provided alongside each DCS sample. Multilevel modeling found CAR output was greater in RRMS than controls, and recalled fatigue in RRMS was associated with both lower waking cortisol level and larger awakening response. Day-to-day, the CAR was not associated with same-day fatigue levels in RRMS. Cortisol appears to have a role in fatigue experienced in RRMS, but whether it is a causal factor remains unclear. PMID- 25817405 TI - Pathogenicity and pathogenesis of a United States porcine deltacoronavirus cell culture isolate in 5-day-old neonatal piglets. AB - Porcine deltacoronavirus (PDCoV) was first identified in Hong Kong in 2009-2010 and reported in United States swine for the first time in February 2014. However, diagnostic tools other than polymerase chain reaction for PDCoV detection were lacking and Koch's postulates had not been fulfilled to confirm the pathogenic potential of PDCoV. In the present study, PDCoV peptide-specific rabbit antisera were developed and used in immunofluorescence and immunohistochemistry assays to assist PDCoV diagnostics. The pathogenicity and pathogenesis of PDCoV was investigated following orogastric inoculation of 5-day-old piglets with a plaque purified PDCoV cell culture isolate (3 * 10(4) TCID50 per pig). The PDCoV inoculated piglets developed mild to moderate diarrhea, shed increasing amount of virus in rectal swabs from 2 to 7 days post inoculation, and developed macroscopic and microscopic lesions in small intestines with viral antigen confirmed by immunohistochemistry staining. This study experimentally confirmed PDCoV pathogenicity and characterized PDCoV pathogenesis in neonatal piglets. PMID- 25817408 TI - Carbapenem-resistant Klebsiella pneumoniae meningitis: A case report. PMID- 25817407 TI - Expression quantitative trait loci (eQTLs) in microRNA genes are enriched for schizophrenia and bipolar disorder association signals. AB - BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) have substantial negative impact on the quality of human life. Both, microRNA (miRNA) expression profiling in SZ and BD postmortem brains [and genome-wide association studies (GWAS)] have implicated miRNAs in disease etiology. Here, we aim to determine whether significant GWAS signals observed in the Psychiatric Genetic Consortium (PGC) are enriched for miRNAs. METHOD: A two-stage approach was used to determine whether association signals from PGC affect miRNAs: (i) statistical assessment of enrichment using a Simes test and sum of squares test (SST) and (ii) biological evidence that quantitative trait loci (eQTL) mapping to known miRNA genes affect their expression in an independent sample of 78 postmortem brains from the Stanley Medical Research Institute. RESULTS: A total of 2567 independent single nucleotide polymorphisms (SNPs) (R2 > 0.8) were mapped locally, within 1 Mb, to all known miRNAs (miRBase v. 21). We show robust enrichment for SZ- and BD related SNPs with miRNAs using Simes (SZ: p <= 0.0023, BD: p <= 0.038), which remained significant after adjusting for background inflation in SZ (empirical p = 0.018) and approached significance in BD (empirical p = 0.07). At a false discovery rate of 10%, we identified a total of 32 eQTLs to influence miRNA expression; 11 of these overlapped with BD. CONCLUSIONS: Our approach of integrating PGC findings with eQTL results can be used to generate specific hypotheses regarding the role of miRNAs in SZ and BD. PMID- 25817410 TI - A parallel algorithm for solving the n-queens problem based on inspired computational model. AB - DNA computing provides a promising method to solve the computationally intractable problems. The n-queens problem is a well-known NP-hard problem, which arranges n queens on an n * n board in different rows, columns and diagonals in order to avoid queens attack each other. In this paper, we present a novel parallel DNA algorithm for solving the n-queens problem using DNA molecular operations based on a biologically inspired computational model. For the n-queens problem, we reasonably design flexible length DNA strands representing elements of the allocation matrix, take appropriate biologic manipulations and get the solutions of the n-queens problem in proper length and O(n(2)) time complexity. We extend the application of DNA molecular operations, simultaneity simplify the complexity of the computation and simulate to verify the feasibility of the DNA algorithm. PMID- 25817409 TI - Oral two-generation reproduction toxicity study with NM-200 synthetic amorphous silica in Wistar rats. AB - Synthetic amorphous silica (SAS) like NM-200 is used in a wide variety of technological applications and consumer products. Although SAS has been widely investigated the available reproductive toxicity studies are old and do not cover all requirements of current OECD Guidelines. As part of a CEFIC-LRI project, NM 200 was tested in a two-generation reproduction toxicity study according to OECD guideline 416. Male and female rats were treated by oral gavage with NM-200 at dose levels of 0, 100, 300 and 1000mg/kg bw/day for two generations. Body weight and food consumption were measured throughout the study. Reproductive and developmental parameters were measured and at sacrifice (reproductive) organs and tissues were sampled for histopathological analysis. Oral administration of NM 200 up to 1000mg/kg bw/day had no adverse effects on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations. The NOAEL was 1000mg/kg body weight per day. PMID- 25817411 TI - Free and bound volatile chemicals in mulberry (Morus atropurpurea Roxb.). AB - Mulberry (Morus atropurpurea Roxb.) is a popular and desirable fruit that is widely cultivated in China. Despite its popularity, the free volatile chemicals and glycosidically bound volatiles (GBVs) of mulberry have been minimally studied. To this end, we have investigated these compounds in 4 mulberry cultivars via solid phase extraction (SPE) and headspace solid phase microextraction with gas chromatography-mass spectrometry (HS-SPME-GC-MS). A total of 55 free volatile chemicals and 57 GBVs were identified and quantified. In 3 of the cultivars ("YFS," "T10," and "D10"), the GBVs were found in higher amounts than their free counterparts, corresponding to a ratio of 1.2 to 1.8. The characteristic aromas were determined by their odor activity values (OAVs) and by generating an aroma series (AS). A total of 20 volatile compounds had OAVs >= 1.0. In particular, ethyl butanoate, hexanal, (Z)-3-hexenal (E)-2-hexenal, (E)-2 nonenal, and eugenol had relatively high OAVs and were considered to be the key aromas contributing to the mulberry flavor. Consequently, mulberry was characterized by a variety of herbaceous scents having a background of sweet, spicy, fruity, and floral notes. The free volatiles exhibited strong herbaceous notes, whereas the GBVs were responsible for the sweet and spicy qualities of the fruit. Based on our results, 2 cultivars ("YFS" and "D10") are proposed to be good candidates suitable for the further development of mulberry-based food products due to their complex and desirable aromas. PMID- 25817412 TI - Differential regulation of dehydrin expression and trehalose levels in Cardinal table grape skin by low temperature and high CO2. AB - Dehydrins and trehalose are multifunctional protective biomolecules that play a role in counteracting cellular damage during dehydrative stresses. In this paper, we studied dehydrin isoform patterns, dehydrin gene expression and trehalose levels in the skin of Cardinal (Vitis vinifera L.) table grapes, along with their regulation by different cold postharvest storage conditions. Immunoanalysis with K-segment antibody recognizes four constitutive dehydrins (from 17 to 44 kDa) that are tightly regulated by low temperature and high CO2. Phosphatase treatment showed that DHN44 and DHN22 isoforms are phosphorylated polypeptides, while MALDI TOF MS and MS/MS analysis suggested that 44 kDa polypeptide may be a dehydrin homodimer. At the transcriptional level, dehydrins are also regulated by low temperature and high CO2, showing a fairly good correlation with their mRNA levels. Trehalose was quantified by high performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD), revealing a progressive increase of this metabolite throughout storage at 0 degrees C and the sudden transitory increases in short-term high CO2-treated fruit. We propose that the constitutive presence and up-regulation of dehydrins and trehalose during low temperature postharvest storage could be positively correlated with the relative chilling tolerance of table grapes and the adaptive responses activated by high CO2 levels to preserve cell water status and to counteract the disruption of physiological processes during cold storage. PMID- 25817413 TI - MAP kinase phosphatase 1 harbors a novel PTS1 and is targeted to peroxisomes following stress treatments. AB - In Arabidopsis thaliana, twenty mitogen-activated protein kinases (MAPKs/MPKs) are regulated by five MAP kinase phosphatases (MKPs). Arabidopsis MKP1 has an important role in biotic, abiotic and genotoxic stresses and has been shown to interact with and negatively regulate specifically MPK3 and MPK6. MKP1 has been reported to have a role in negative regulation of reactive oxygen species (ROS) and salicylic acid (SA) production. As essential organelles involved in production of ROS and SA, peroxisomes could possibly be an important compartment for MKP1 activity, however MKP1 was previously reported to be cytosolic. By screening Arabidopsis protein phosphatases for peroxisomal targeting signal 1 (PTS1), we identified MKP1 as a putative peroxisomal protein. Arabidopsis MKP1 was found to harbor a non-canonical PTS1-like tripeptide (Ser-Ala-Leu>) that is conserved in MKP1 orthologs. We show experimentally that the C-terminal Ser-Ala Leu> can function as a novel PTS1, and alanine in position -2, adds more relaxation to the plant PTS1 motif. The full-length MKP1 remained in the cytosol when transiently expressed in Arabidopsis mesophyll protoplasts under standard conditions. When different biotic and abiotic stresses were applied to mesophyll protoplasts, the full length protein changed its targeting to unidentified organelle-like structures that subsequently fused with peroxisomes. Our results identify MKP1 as a protein dually targeted to cytosol and peroxisomes. The finding that MKP1 targets peroxisomes by a non-canonical PTS1 under stressful conditions highlights the complexity of peroxisomal targeting mechanism. PMID- 25817414 TI - Spikelet-specific variation in ethylene production and constitutive expression of ethylene receptors and signal transducers during grain filling of compact- and lax-panicle rice (Oryza sativa) cultivars. AB - Grain yields in modern super rice cultivars do not always meet the expectations because many spikelets are located on secondary branches in closely packed homogeneous distribution in these plants, and they do not fill properly. The factors limiting grain filling of such spikelets, especially in the lower panicle branches, are elusive. Two long-duration rice cultivars differing in panicle density, Mahalaxmi (compact) and Upahar (lax), were cultivated in an open field plot. Grain filling, ethylene production and constitutive expression of ethylene receptors and ethylene signal transducers in apical and basal spikelets of the panicle were compared during the early post-anthesis stage, which is the most critical period for grain development. In another experiment, a similar assessment was made for the medium-duration cultivars compact-panicle OR-1918 and lax-panicle Lalat. Grain weight of the apical spikelets was always higher than that of the basal spikelets. This gradient of grain weight was wide in the compact-panicle cultivars and narrow in the lax-panicle cultivars. Compared to apical spikelets, the basal spikelets produced more ethylene at anthesis and retained the capacity for post-anthesis expression of ethylene receptors and ethylene signal transducers longer. High ethylene production enhanced the expression of the RSR1 gene, but reduced expression of the GBSS1 gene. Ethylene inhibited the partitioning of assimilates of developing grains resulting in low starch biosynthesis and high accumulation of soluble carbohydrates. It is concluded that an increase in grain/spikelet density in rice panicles reduces apical dominance to the detriment of grain filling by production of ethylene and/or enhanced perception of the ethylene signal. Ethylene could be a second messenger for apical dominance in grain filling. The manipulation of the ethylene signal would possibly improve rice grain yield. PMID- 25817415 TI - Molecular cloning of the BLADE-ON-PETIOLE gene and expression analyses during nodule development in Lupinus luteus. AB - The BLADE-ON-PETIOLE (BOP) genes have been recently shown to play an essential role in many physiological processes, including embryogenesis, meristem determinacy, leaf patterning and nodule development. In our research we used Lupinus luteus, a plant with great agronomic potential due to its high protein content and nitrogen fixation ability. In this work, LlBOP in L. luteus was identified for the first time and its expression during nodule development was analyzed. The high expression levels of LlBOP and LlLbI (LEGHEMOGLOBIN), essential to nitrogen-fixing symbiosis, were noted in the developing root nodules and were correlated with the occurrence of leghemoglobin. All of these data indicate that LlBOP is an important regulator of root nodule formation and functioning in L. luteus. PMID- 25817416 TI - Pre-implementation studies of a workforce planning tool for nurse staffing and human resource management in university hospitals. AB - AIM: To investigate the reliability, validity and feasibility of the RAFAELA workforce planning system (including the Oulu patient classification system - OPCq), before deciding on implementation in Dutch hospitals. BACKGROUND: The complexity of care, budgetary restraints and demand for high-quality patient care have ignited the need for transparent hospital workforce planning. METHODS: Nurses from 12 wards of two university hospitals were trained to test the reliability of the OPCq by investigating the absolute agreement of nursing care intensity (NCI) measurements among nurses. Validity was tested by assessing whether optimal NCI/nurse ratio, as calculated by a regression analysis in RAFAELA, was realistic. System feasibility was investigated through a questionnaire among all nurses involved. RESULTS: Almost 67 000 NCI measurements were performed between December 2013 and June 2014. Agreement using the OPCq varied between 38% and 91%. For only 1 in 12 wards was the optimal NCI area calculated judged as valid. Although the majority of respondents was positive about the applicability and user-friendliness, RAFAELA was not accepted as useful workforce planning system. CONCLUSION AND IMPLICATIONS FOR NURSING MANAGEMENT: Nurses' performance using the RAFAELA system did not warrant its implementation. Hospital managers should first focus on enlarging the readiness of nurses regarding the implementation of a workforce planning system. PMID- 25817417 TI - Nutritional approaches to ameliorate pulmonary hypertension in broiler chickens. AB - This article reviews recent nutritional approaches for counteracting the development of pulmonary hypertension syndrome (PHS; ascites) in broiler chickens especially when they are reared at high altitudes. High altitudes impose the sustained stress of hypobaric hypoxia, which reduces the availability of atmospheric oxygen to red blood cells passing through the lungs, thereby causing systemic arterial hypoxaemia (undersaturation of haemoglobin with oxygen), pulmonary arterial hypertension and PHS/ascites in susceptible broilers. Proper nutritional strategies are needed to reduce metabolic activity and prevent the development of ascites especially when modern broilers are reared in regions where the existing altitudes limit the availability of atmospheric oxygen. This article also addresses controversies with regard to broiler nutrition in relation to PHS. For example, the catabolism of protein from feed ingredients incurs increased oxygen consumption, suggesting that feeding reduced-protein diets to broiler chickens may result in reduced PHS incidences. However, experimental and field data indicate that feeding reduced-protein diets to broilers subjected to hypobaric hypoxia increases the development of PHS. Controversies on the nutrition of unsaturated fat in relation to PHS are also discussed. In conclusion, hypoxia, acidosis, vasoconstriction and enhanced metabolic rate are triggers of PHS. Feeding reduced-protein diets might promote the susceptibility of broilers to PHS by decreased dietary intake of arginine, decreased uric acid production and increased lipogenesis. Feeding high-protein diets, dietary arginine supplementation, partial substitution of sodium bicarbonate for sodium chloride, feeding low-fat diets and effective feed restriction programmes can be considered as nutritional approaches to prevent PHS. PMID- 25817418 TI - A 13-year retrospective study evaluating the efficacy of using air-fluidised beds for toxic epidermal necrolysis patients. AB - OBJECTIVES: Toxic epidermal necrolysis (TEN) is a potentially life-threatening dermatological disease involving large areas of skin loss with systemic symptoms. This study evaluated the efficacy of air-fluidised bed therapy for TEN patients. METHODS: Of 27 people with TEN, 11 used air-fluidised beds (the air-fluidised group) and 16 used standard beds (the control group). Days to complete re epithelialisation, re-epithelialisation rate, incidence of complications, mortality, pain measured by visual analogue score and the incidence of cutaneous infection were compared in these groups. RESULTS: The mean body surface area of involvement was 77.0 +/- 11.8% and baseline mean severity-of-illness score for TEN (SCORTEN) was 2.81 +/- 1.08. The re-epithelialisation rate in the air fluidised group was 100% but was only 56.3% in the control group (P < 0.05). There was a significant difference in the time taken to complete re epithelialisation between the air-fluidised group (13 days [95% CI: 9.0-17.0]) and the control group (21 days [16.5-25.5], P < 0.05). Furthermore, the incidence of complications was 18% in the air-fluidised group versus 75% in the control group, including fewer cutaneous infections (P < 0.05). There was a significant reduction in pain among the air-fluidised group compared with the control group (P < 0.05). There were no deaths in the air-fluidised group while 19% of the control group died. CONCLUSION: Air-fluidised beds can reduce the time to complete re-epithelialisation, relieve pain and increase the re-epithelialisation rate of TEN patients, but there was no significant difference between them in mortality rate in our study. PMID- 25817419 TI - Improving Chronic Diseases Management Through the Development of an Evidence Based Resource. AB - OBJECTIVE: There is a large gap between evidence and practice within health care, particularly within the field of chronic disease. To reduce this gap and improve the management of chronic disease, a collaborative partnership between two schools within a large university and two industry partners (a large regional rural hospital and a rural community health center) in rural Victoria, Australia, was developed. The aim of the collaboration was to promote the development of translation science and the implementation of evidence-based health care in chronic disease with a specific focus on developing evidence-based resources that are easily accessed by clinicians. METHODS: A working group consisting of members of the collaborating organizations and an internationally renowned expert reference group was formed. The group acted as a steering committee and was tasked with developing a taxonomy of the resources. In addition, a peer review process of all resources was established. A corresponding reference group consisting of researchers and clinicians who are clinical experts in various fields was involved in the review process. The resources developed by the group include evidence summaries and recommended practices made available on a web based database, which can be accessed via subscription by clinicians and researchers worldwide. RESULTS: As of mid-2014, there were 109 new evidence summaries and 25 recommended practices detailing the best available evidence on topics related to chronic disease management including asthma, diabetes, heart failure, dementia, and others. Training sessions and a newsletter were developed for clinicians within the node to enable them to use the content effectively. LINKING EVIDENCE TO ACTION: This paper describes the processes involved in the successful development of the collaborative partnership and its evolution into producing a valuable resource for the translation of evidence into practice in the areas of chronic disease management. The resource developed is being used by clinicians to inform practice and support their clinical decision making. PMID- 25817420 TI - Tumor Necrosis Factor-alpha, Interleukins-12(p40), 6, and 10 levels in cerebrospinal fluid and outcome prediction in Ossimi sheep with encephalitic listeriosis. AB - Encephalitic listeriosis in sheep is a life-threatening disease. However, little is known about the cytokine response and their predictive value in this disease. The aim of present study was to assess the prognostic significance of Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-12(p40) (IL-12 p40), Interleukin-6 (IL-6), and Interleukin 10 (IL-10) levels in cerebrospinal fluid (CSF) in sheep with encephalitic listeriosis. Fifty-nine ewes in 14 flocks were diagnosed clinically as having listeriosis. CSF was collected and subjected to bacteriological examination and estimation of selected cytokines. Twenty-eight ewes were confirmed to be infected with Listeria monocytogenes. Based on antimicrobial sensitivity test, sheep were treated and the outcome was recorded as survivors (n=10) and non-survivors (n=18). Cutoff points for CSF cytokines were determined by Receiver operating characteristic analysis (ROC). Association between levels of CSF cytokines and outcome of listeriosis was assessed by logistic regression. TNF-alpha, IL-6 and IL-12(p40) levels as well as TNF alpha/IL-10 ratio were significantly higher in non-survivors than survivors (p=0.002, 0.0021, 0.0033, and 0.001, respectively). However, IL-10 level was significantly lower in non-survivors than survivors (p=0.0058). ROC analysis revealed that IL-6 and TNF-alpha/IL-10 ratio had the highest AUC values (0.98, 0.984, respectively). Final multivariate logistic regression model showed that TNF-alpha/IL-10 ratio was the only variable that has predictive value for mortality in diseased sheep (p: 0.001; OR: 7.2; 95% CI: 5.7-9.8). TNF-alpha showed a positive correlation with IL-12beta (r=0.917) and IL-6 (r=0.965). IL-12 (p40) showed also a positive correlation with IL-6 (r=0.906). However, IL-10 showed a negative correlation with TNF-alpha (r=-0.915), IL-12(p40) (r=-0.790), and IL-6 (r=-0.902). In conclusion, TNF-alpha/IL-10 ratio may provide predictive information about outcome of encephalitic listeriosis in sheep. PMID- 25817421 TI - Catalytic gasification of oil-extracted residue biomass of Botryococcus braunii. AB - Catalytic gasification of the oil-extracted residue biomass of Botryococcus braunii was demonstrated in a laboratory-scale continuous feeding dual bed reactor. Steam gasification at 1023 K over Ni-Fe/Mg/Al catalyst can completely reform tar derived from pyrolysis of the residue biomass into C1 gases and hydrogen, and has achieved 91%-C conversion to gaseous product (CO+CO2+CH4). Composition of product gas has higher contents of CO and H2 with their ratio (H2/CO) of around 2.4 which is slightly H2-rich syngas. Maximum hydrogen yield of 74.7 mmol g-biomass(-1) obtained in this work is much higher than that from gasification of other algal biomass reported in literature. The residue biomass of B. braunii can be a superior renewable source of syngas or hydrogen. PMID- 25817422 TI - An integrated process for microalgae harvesting and cell disruption by the use of ferric ions. AB - In this study, a simultaneous process of harvesting biomass and extracting crude bio-oil was attempted from wet microalgae biomass using FeCl3 and Fe2(SO4)3 as both coagulant and cell-disrupting agent. A culture solution of Chlorella sp. KR 1 was firstly concentrated to 20 g/L and then proceeded for cell disruption with the addition of H2O2. Optimal dosage were 560 and 1060 mg/L for FeCl3 and Fe2(SO4)3, showing harvesting efficiencies of more than 99%. Optimal extraction conditions were identified via the response surface method (RSM), and the extraction yield was almost the same at 120 degrees C for both iron salts but FAME compositions after transesterification was found to be quite different. Given iron salts were a reference coagulant in water treatment in general and microalgae harvesting in particular, the present approach of using it for harvesting and oil-extraction in a simultaneous manner can serve as a practical route for the microalgae-derived biodiesel production. PMID- 25817423 TI - How does a physician's accurate understanding of a cancer patient's unmet needs contribute to patient perception of physician empathy? AB - OBJECTIVE: Unmet supportive care needs of patients decrease patient perception of physician empathy (PE). We explored whether the accurate physician understanding of a given patient's unmet needs (AU), could buffer the adverse effect of these unmet needs on PE. METHODS: In a cross-sectional design, 28 physicians and 201 metastatic cancer patients independently assessed the unmet supportive care needs of patients. AU was calculated as the sum of items for which physicians correctly rated the level of patient needs. PE and covariates were assessed using self reported questionnaires. Multilevel analyses were carried out. RESULTS: AU did not directly affect PE but acted as a moderator. When patients were highly expressive and when physicians perceived poor rapport with the patient, a high AU moderated the adverse effect of patient unmet needs on PE. CONCLUSION: Physician AU has the power to protect the doctor-patient relationship in spite of high patient unmet needs, but only in certain conditions. PRACTICE IMPLICATIONS: Physicians should be encouraged toward AU but warned that high rapport and patient low emotional expression may impede an accurate reading of patients. In this latter case, they should request a formal assessment of their patients' needs. PMID- 25817424 TI - Using the Patient Centered Observation Form: Evaluation of an online training program. AB - OBJECTIVE: The Patient Centered Observation Form (PCOF) helps trainees identify and describe specific communication skills and enhance self-awareness about skill use. We studied the effectiveness and ease of use of the Improving Communication Assessment Program (ICAP), an online module that prepares trainees to use the PCOF. METHODS: Students, residents and medical educators viewed two videos (common and better skill use) of the same interaction and rated each video using the PCOF. Video sequence was randomized. We assessed agreement with experts, ease of use, concepts learned, and areas of confusion. RESULTS: Trainees (211) achieved strong agreement (.83) with experts and were highly satisfied (mean 4.18 out of 5). Viewing the common video first produced higher agreement (.87 vs .79; ES=.4) with experts and greater satisfaction (4.36 vs 4.02, ES .4) than viewing the better video first. Trainees reported diverse areas of learning and minimal confusion. CONCLUSION: ICAP training to use the PCOF may facilitate teaching and assessment of communication skills and enrich training through peer observation and feedback. We offer several educational strategies. PRACTICE IMPLICATIONS: Learning to use the PCOF via the ICAP module may accelerate communication training for medical students, residents, medical educators and practicing clinicians. PMID- 25817426 TI - Optimization of medium components and physicochemical parameters to simultaneously enhance microbial growth and production of lypolitic enzymes by Stenotrophomonas sp. AB - The optimization of lipase and esterase production (LP and EP) and bacterial growth (BG) of a Stenotrophomonas sp. strain was developed. For this purpose, the effect of five different medium components and three physicochemical parameters were evaluated using a Plackett-Burman statistical design. Among eight variables, stirring speed, pH, and peptone concentration were found to be the most effective factors on the three responses under evaluation. An optimization study applying Box-Behnken response surface methodology was used to study the interactive effects of the three selected variables on LP/EP and microorganism growth. Predicted models were found to be significant with high regression coefficients (90%-99%). By using the desirability function approach, the optimum condition applying simultaneous optimization of the three responses under study resulted to be: stirring speed of 100 rpm, pH of 7.5, and a peptone concentration of 10 g/L, with a desirability value of 0.977. Under these optimal conditions, it is possible to achieve in the optimized medium a 15-fold increase in esterase productivity, a 117-fold increase in lipase production, and a 9-log CFU/mL increase in BG, compared with the basal medium without agitation. PMID- 25817425 TI - Validation of the short-form Health Literacy Scale in patients with stroke. AB - OBJECTIVE: We aimed to validate a Mandarin version of the short-form Health Literacy Scale (SHEAL) in patients with stroke. METHODS: Each patient with stroke was interviewed with the SHEAL. The Public Stroke Knowledge Quiz (PSKQ) was administered as a criterion for examining the convergent validity of the SHEAL. The discriminative validity of the SHEAL was determined with age and education level as independent grouping variables. RESULTS: A total of 87 patients with stroke volunteered to participate in this prospective study. The SHEAL demonstrated sufficient internal consistency reliability (alpha=0.82) and high correlation with the PSKQ (r=0.62). The SHEAL scores between different age groups and education level groups were significantly different. The SHEAL, however, showed a notable ceiling effect (24.1% of the participants), indicating that the SHEAL cannot differentiate level of health literacy between individuals with high health literacy. CONCLUSION: The internal consistency reliability, convergent validity, and discriminative validity of the SHEAL were adequate. However, the internal consistency reliability and ceiling effect of the SHEAL need to be improved. PRACTICE IMPLICATIONS: The SHEAL has shown its potential for assessing the health literacy of patients with stroke for research purposes. For clinical usage, however, the SHEAL should be used with caution. PMID- 25817427 TI - Environmental metabolomics reveal geographic variation in aerobic metabolism and metabolic substrates in Mongolian gerbils (Meriones unguiculatus). AB - Mongolian gerbils (Meriones unguiculatus) have a large-scale distribution in northern China. Geographic physiological variations which related to energy and water metabolism are critical to animals' local adaptation and distribution. However, the underlying biochemical mechanism of such variation and its role in adaptation remains largely unknown. We used GC-MS metabolomics approach to investigate the biochemical adaptation of Mongolian gerbils from xeric (desert), transition (desert steppe) and mesic (typical steppe) environments. Gerbils in desert population had lower resting metabolic rate (RMR) and total evaporative water loss (TEWL) than mesic population. Serum metabolomics revealed that concentrations of five tricarboxylic acid cycle intermediates (citrate, cis aconitate, alpha-ketoglutarate, fumarate and malate) were lower in desert population than mesic population. Gastrocnemius metabolomics and citrate synthase activity analysis showed a lower concentration of citrate and lower citrate synthase activity in desert population. These findings suggest that desert dwelling gerbils decrease RMR and TEWL via down-regulation of aerobic respiration. Gastrocnemius metabolomics also revealed that there were higher concentrations of glucose and glycolytic intermediates, but lower concentrations of lipids, amino acids and urea in desert population than mesic population. This geographic variation in metabolic substrates may enhance metabolic water production per oxygen molecule for desert population while constraining aerobic respiration to reduce RMR and TEWL. PMID- 25817428 TI - Social media in travel medicine: a review. AB - The use of social media is widespread and provides new opportunities for healthcare professionals and healthcare organisations to interact with patients, the public, policy makers, and each other. Social media offers the possibility of providing users with up-to-date information when, where, and how they want it, but it also brings with it some challenges. With increasing use of social media, there is potential to change the way travel medicine is delivered; practitioners should consider how to exploit the benefits in their practice, and not be afraid to experiment. However they need to be cognizant of the potential pitfalls. The information exchanged requires careful application as it may not always achieve the desired outcome, it needs to be monitored for quality, accuracy, and reliability, and confidentiality and privacy must be maintained. Most importantly, as social media becomes more sophisticated and widely adopted in the healthcare arena, further evaluation and research is required to understand its impact and its application to travel medicine. PMID- 25817429 TI - Vector-borne infections in the Caribbean - exceptional Haiti. PMID- 25817430 TI - Apropos - the efficacy of repellents against Aedes, Anopheles, Culex and Ixodes spp. A literature review. PMID- 25817431 TI - Editorial Comment. PMID- 25817433 TI - Genome-wide patterns of differentiation and spatially varying selection between postglacial recolonization lineages of Populus alba (Salicaceae), a widespread forest tree. AB - Studying the divergence continuum in plants is relevant to fundamental and applied biology because of the potential to reveal functionally important genetic variation. In this context, whole-genome sequencing (WGS) provides the necessary rigour for uncovering footprints of selection. We resequenced populations of two divergent phylogeographic lineages of Populus alba (n = 48), thoroughly characterized by microsatellites (n = 317), and scanned their genomes for regions of unusually high allelic differentiation and reduced diversity using > 1.7 million single nucleotide polymorphisms (SNPs) from WGS. Results were confirmed by Sanger sequencing. On average, 9134 high-differentiation (>= 4 standard deviations) outlier SNPs were uncovered between populations, 848 of which were shared by >= three replicate comparisons. Annotation revealed that 545 of these were located in 437 predicted genes. Twelve percent of differentiation outlier genome regions exhibited significantly reduced genetic diversity. Gene ontology (GO) searches were successful for 327 high-differentiation genes, and these were enriched for 63 GO terms. Our results provide a snapshot of the roles of 'hard selective sweeps' vs divergent selection of standing genetic variation in distinct postglacial recolonization lineages of P. alba. Thus, this study adds to our understanding of the mechanisms responsible for the origin of functionally relevant variation in temperate trees. PMID- 25817434 TI - On the nature of magnetic state in the spinel Co2SnO4. AB - In the spinel Co2SnO4, coexistence of ferrimagnetic ordering below T(N) ? 41 K followed by a spin glass state below T(SG) ? 39 K was proposed recently based on the temperature dependence of magnetization M(T) data. Here new measurements of the temperature dependence of the specific heat C(P)(T), ac-susceptibilities chi'(T) and chi"(T) measured at frequencies between 0.51 and 1.2 kHz, and the hysteresis loop parameters (coercivity H(C)(T) and remanence M(R)(T)) in two differently prepared samples of Co2SnO4 are reported. The presence of the Co(2+) and Sn(4+) states is confirmed by x-ray photoelectron spectroscopy (XPS) yielding the structure: Co2SnO4 = [Co(2+)][Co(2+)Sn(4+)]O4. The data of C(P) versus T shows only an inflection near 39 K characteristic of spin-glass ordering. The analysis of the frequency dependence of ac-magnetic susceptibility data near 39 K using the Vogel-Fulcher law and the power-law of the critical slowing-down suggests the presence of spin clusters in the system which is close to a spin glass state. With a decrease in temperature below 39 K, the temperature dependence of the coercivity H(C) and remanence M(R) for the zero-field cooled samples show both H(C) and M(R) reaching their peak magnitudes near 25 K, then decreasing with decreasing T and becoming negligible below 15 K. The plot of C(P)/T versus T also yields a weak inflection near 15 K. This temperature dependence of H(C) and remanence M(R) is likely associated with the different magnitudes of the magnetic moments of Co(2+) ions on the 'A' and 'B' sites and their different temperature dependence. PMID- 25817432 TI - Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control. AB - DNA replication stress is a source of genomic instability. Here we identify changed mutation rate 1 (Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that Cmr1--together with Mrc1/Claspin, Pph3, the chaperonin containing TCP1 (CCT) and 25 other proteins- define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to Cmr1, its human orthologue WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that Cmr1/WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins. PMID- 25817435 TI - Corrigendum: New loci and coding variants confer risk for age-related macular degeneration in East Asians. PMID- 25817436 TI - Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant. AB - Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25.7%) and 46 patients developed a life-threatening bleeding episode (9.4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67.1% for only 17.1% for patients with life-threatening bleeding (P < 0.001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development. PMID- 25817437 TI - ERAP1 variants are associated with ankylosing spondylitis in East Asian population: a new Chinese case-control study and meta-analysis of published series. AB - Endoplasmic reticulum aminopeptidase 1 (ERAP1) has been confirmed to be associated with ankylosing spondylitis (AS) in Caucasian. However, whether they are associated with AS in East Asian population remains unidentified. We investigated this relationship by a new Chinese case-control study and a meta analysis of published series. 368 cases and 460 controls were recruited in the Chinese case-control study. Genotyping was completed using the chip-based matrix assisted laser desorption ionization time-of-flight mass spectrometry. Allelic associations were analysed using contingency tables. In the meta-analysis, up to 2748 cases and 2774 controls from seven different studies and the new Chinese study were combined using Review Manager software version 5.1.1. Mantel-Haenszel or Inverse Variance test was used to calculate fixed or random-effects pooled ORs. In the new Chinese study, strong association with AS was observed for marker rs10050860, rs27434 and rs1065407 at P value of <0.001. Moderate association was observed for rs30187 at P value of <0.01, while no association was observed for rs27044 (P = 0.37) and rs2287987 (P = 0.23). The meta-analysis showed that rs27037 and rs30187 were strongly associated with AS (P < 0.00001). Significant association was also observed for rs27434 (P = 0.001). No association was shown for rs27044 (P = 0.70). We concluded that ERAP1 variants are associated with AS in East Asian population, indicating a common pathogenic mechanism for AS in East Asians and Caucasians. PMID- 25817438 TI - Prevalence of irritable bowel syndrome in caregivers of patients with chronic diseases. AB - BACKGROUND: Caregivers are an at-risk population for psychic and physical diseases such as irritable bowel syndrome (IBS). However, it is not known whether providing care for the chronically ill patient can be considered a risk factor for developing IBS. In this study, our aim was to evaluate the prevalence of IBS according to the Rome II criteria in a group of caregivers. METHODS: A cross sectional study was conducted through an evaluation of caregivers of chronically ill patients. Subjects completed questionnaires including the Rome II Modular Questionnaire, the Hospital Anxiety and Depression Scale, the Zarit Caregiver Burden Interview (ZCBI) (an instrument for evaluating the burden experienced by caregivers), and the irritable bowel syndrome quality of life (IBS-QoL) questionnaire. KEY RESULTS: Ninety-six primary caregivers (mean age was 43.6 +/- 13.7 years and 87% were women) were evaluated. The mean length of time providing care was 37.6 months (3-288 months). Forty-seven caregivers (49%) presented with IBS. The caregivers with IBS had higher scores in the global ZCBI score (47 +/- 8 vs 28 +/- 8, p = 0.001) and on the anxiety and depression scale (p = 0.001) than those that did not have IBS. A total of 72% were diagnosed with caregiver stress syndrome; 42 of them had IBS according to the Rome II questionnaire (60% vs 18%, p = 0.001, relative risk 3.28, 95% CI: 1.4-7.4). CONCLUSIONS & INFERENCES: Caregivers of chronically ill patients have a high prevalence of IBS, which is associated with depression, anxiety, and poor QoL. PMID- 25817440 TI - [Psoriasis: treatment in special circumstances and biosimilars]. PMID- 25817439 TI - Trichoharzianol, a new antifungal from Trichoderma harzianum F031. AB - A new decalin derivative, trichoharzianol (1), together with three known compounds, eujavanicol A (2), 5-hydroxy-3-hydroxymethyl-2-methyl-7 methoxychromone (3), and 4,6-dihydroxy-5-methylphthalide (4), were isolated from Trichoderma harzianum F031. For the first time, compounds 2-4 were reported from the Trichoderma species. Their structures were characterized by spectroscopic methods. Trichoharzianol (1) showed the highest antifungal activity against Colletotrichum gloeosporioides, with a minimum inhibitory concentration (MIC) of 128 MUg/mL. PMID- 25817441 TI - The emotional body and time perception. AB - We examined the effects of emotional bodily expressions on the perception of time. Participants were shown bodily expressions of fear, happiness and sadness in a temporal bisection task featuring different stimulus duration ranges. Stimulus durations were judged to be longer for bodily expressions of fear than for those of sadness, whereas no significant difference was observed between sad and happy postures. In addition, the magnitude of the lengthening effect of fearful versus sad postures increased with duration range. These results suggest that the perception of fearful bodily expressions increases the level of arousal which, in turn, speeds up the internal clock system underlying the representation of time. The effect of bodily expressions on time perception is thus consistent with findings for other highly arousing emotional stimuli, such as emotional facial expressions. PMID- 25817442 TI - Loperamide toxicokinetics: serum concentrations in the overdose setting. PMID- 25817443 TI - Instability of a dinucleotide repeat in the 3'-untranslated region (UTR) of the microsomal prostaglandin E synthase-1 (mPGES-1) gene in microsatellite instability-high (MSI-H) colorectal carcinoma. AB - DNA mismatch-repair gene mutations, with consequent loss of functional protein expression, result in microsatellite instability (MSI). Microsatellite sequences are found in coding regions and in regulatory regions of genes (i.e., 5'-UTRs and 3'-UTRs). In addition to being a surrogate marker of defective mismatch repair, deletion or insertion microsatellite sequences can dysregulate gene expression in MSI-H (microsatellite instability-high) tumors. The microsomal prostaglandin E synthase-1 (mPGES-1) gene product, mPGES-1, participates in prostaglandin E2 (PGE2) production. Moreover, mPGES-1 is often overexpressed in human colorectal tumors, and is thought to contribute to progression of these tumors. Here we identified a dinucleotide repeat, (GT)24, in the mPGES-1 gene 3' untranslated region (3'-UTR), and analyzed its mutation frequencies in MSI-H and microsatellite stable (MSS) tumors. The (GT)24 repeat exhibited instability in all MSI-H tumors examined (14), but not in any of the MSS tumors (13). In most cases, (GT)24 repeat instability resulted in insertion of additional GT units. We also determined mPGES-1 mRNA levels in MSI-H and MSS colorectal cancer cell lines. Three of four previously designated "MSI-H" cell lines showed higher mPGES 1 mRNA levels compared to MSS cell lines; correlations between elevated mPGES-1 mRNA levels and microsatellite (GT)24 repeat characteristics are present for all six cell lines. Our results demonstrate that mPGES-1 is a target gene of defective mismatch repair in human colorectal cancer, with functional consequence. PMID- 25817445 TI - Renal function and dapagliflozin in routine clinical practice. PMID- 25817446 TI - [Molecular diagnosis of Parapoxvirus infection]. PMID- 25817444 TI - Anti-androgen enzalutamide enhances prostate cancer neuroendocrine (NE) differentiation via altering the infiltrated mast cells -> androgen receptor (AR) -> miRNA32 signals. AB - The recently developed anti-androgen enzalutamide also known as (MDV3100) has the advantage to prolong by 4.8 months the survival of castration resistant prostate cancer (CRPC) patients. However, the mechanisms behind the potential side effects involving the induction of the prostate cancer (PCa) neuroendocrine (NE) differentiation remain unclear. Here we found PCa cells could recruit more mast cells than normal prostate epithelial cells, and enzalutamide (or casodex) treatment could further increase such recruitment that resulted in promoting the PCa NE differentiation. Mechanism dissection found infiltrated mast cells could function through positive feedback to enhance PCa to recruit more mast cells via modulation of the androgen receptor (AR) -> cytokines IL8 signals, and interruption by AR-siRNA or neutralizing anti-IL8 antibody could partially reverse the recruitment of mast cells. Importantly, targeting the PCa androgens/AR signals with AR-siRNA or enzalutamide (or casodex) also increased PCa NE differentiation via modulation of the miRNA32 expression, and adding miRNA32 inhibitor reversed the AR-siRNA- or enzalutamide-enhanced NE differentiation. Together, these results not only identified a new signal via infiltrated mast cells -> PCa AR -> miRNA32 to increase PCa NE differentiation, it also pointed out the potential unwanted side effects of enzalutamide (or casodex) to increase PCa NE differentiation. Targeting these newly identified signals, including AR, IL8, or miRNA32, may help us to better suppress PCa NE differentiation that is induced during ADT with anti-androgen enzalutamide (or casodex) treatment. PMID- 25817447 TI - [Recommendations regarding diagnosis and treatment of transthyretin familial amyloid polyneuropathy.Grupo de Estudio y Tratamiento de la Polineuropatia Amiloidotica Familiar por Transtiretina (GETPAF-TTR)]. PMID- 25817448 TI - [Fever induced by hydroxycarbamide]. PMID- 25817449 TI - [New agents for hypercholesterolemia]. AB - An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage. PMID- 25817450 TI - [Pellagra]. PMID- 25817452 TI - [Neuralgic amyotrophy associated to hepatitis E virus infection]. PMID- 25817451 TI - [Central nervous system relapse in diffuse large B cell lymphoma: Risk factors]. AB - Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25-30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary. PMID- 25817453 TI - [Methoxetamine-associated emergencies. First Spanish descriptions of this new drug]. PMID- 25817454 TI - [PAPRICA-2 study: Role of precipitating factor of an acute heart failure episode on intermediate term prognosis]. AB - OBJECTIVE: To evaluate the precipitating factors (PF) associated with acute heart failure and their association with medium-term prognosis. PATIENTS AND METHODS: Multipurpose prospective study from the EAHFE Registry. We included as PF: infection, rapid atrial fibrillation (RAF), anaemia, hypertensive crisis, non adherence to diet or drug therapy and non-ST-segment-elevation acute coronary syndrome (NSTEACS). Patients without PF were control group. Hazard ratios (HR) crudes and adjusted for reconsultations and mortality at 90 days were calculated. RESULTS: 3535 patients were included: 28% without and 72% with PF. Patients with RAF (HR 0.67; 95%CI 0.50-0.89) and hypertensive crisis (HR 0.45; 95%CI 0.28-0.72) had less mortality and patients with NSTEACS (HR 1.79; 95%CI 1.19-2.70) had more mortality. Reconsultation was fewer in patients with infection (HR 0.74; 95%CI 0.64-0.85), RAF (HR 0.69; 95%CI 0.58-0.83) and hypertensive crisis (HR 0.71; 95%CI 0.55-0.91). These differences were maintained in all the adjusted models except for hypertensive crisis. CONCLUSIONS: One PF is identified in 3 out of 4 patients and it may influence medium-term prognosis. At 90 days, NSTEACS and RAF were associated with more and less mortality respectively, and RAF and infection with less probability of reconsultation. PMID- 25817455 TI - Clinical impact of model-based type iterative reconstruction with fast reconstruction time on image quality of low-dose screening chest CT. AB - BACKGROUND: Model-based type iterative reconstruction algorithms with fast reconstruction times are now available. The clinical feasibility of their reconstruction has not been evaluated adequately. PURPOSE: To investigate the effects of model-based type iterative reconstruction, i.e. iterative model reconstruction (IMR), with fast reconstruction time on the qualitative and quantitative image quality at low-dose chest computed tomography (CT). MATERIAL AND METHODS: Thirty-one patients undergoing low-dose screening chest CT were enrolled. Images were reconstructed using filtered back projection (FBP), hybrid iterative reconstruction (HIR), and IMR algorithms. The CT attenuation and image noise for all reconstructions were calculated at the lung apex, middle, and base. Using a 4-point scale, two reviewers visually evaluated the image quality with respect to vessel sharpness, streak artifact, the mediastinum, and the overall image quality of each reconstruction method. RESULTS: The mean estimated effective dose was 1.0 +/- 0.3 mSv. There was no significant difference in the CT attenuation among the three reconstructions. The mean image noise of FBP, HIR, and IMR images was 124.3 +/- 57.3, 34.8 +/- 10.2, and 22.9 +/- 5.8 HU, respectively. There were significant differences for all comparison combinations among the three methods (P < 0.01). The best subjective overall image quality for the lung and mediastinum was obtained with IMR (P < 0.01). The reconstruction time for IMR was within 3 min in all cases. CONCLUSION: At low-dose chest CT, IMR can improve the qualitative and quantitative visualization of both lung and mediastinal structures especially in the lung apex at a clinically acceptable reconstruction time. Its application may improve diagnostic performance. PMID- 25817456 TI - Carbon stable-isotope tracking in breath for comparative studies of fuel use. AB - Almost half a century ago, researchers demonstrated that the ratio of stable carbon isotopes in exhaled breath of rats and humans could reveal the oxidation of labeled substrates in vivo, opening a new chapter in the study of fuel use, the fate of ingested substrates, and aerobic metabolism. Until recently, the combined use of respirometry and stable-isotope tracer techniques had not been broadly employed to study fuel use in other animal groups. In this review, we summarize the history of this approach in human and animal research and define best practices that maximize its utility. We also summarize several case studies that use stable-isotope measurements of breath to explore the limits of aerobic metabolism and substrate turnover among several species and various physiological states. We highlight the importance of a comparative approach in revealing the profound effects that phylogeny, ecology, and behavior can have in shaping aerobic metabolism and energetics as well as the fundamental biological principles that underlie fuel use and metabolic function across taxa. New analytical equipment and refinement of methodology make the combined use of respirometry and stable-isotope tracer techniques simpler to perform, less costly, and more field ready than ever before. PMID- 25817457 TI - Colloid solutions in the perioperative setting. PMID- 25817458 TI - Percutaneous transhepatic cholangiography and intraductal radiofrequency ablation combined with biliary stent placement for malignant biliary obstruction. AB - PURPOSE: To determine the safety and feasibility of percutaneous transhepatic cholangiography (PTC) and intraductal radiofrequency (RF) ablation combined with biliary stent placement for malignant biliary obstruction. MATERIALS AND METHODS: Data from patients with unresectable malignant biliary obstruction who underwent PTC, intraductal RF ablation, and biliary stent placement (n = 12) or PTC and biliary stent placement only (control group; n = 14) were reviewed. Postoperative complications, jaundice remission, and stent patency were assessed. RESULTS: All procedures were successful. No severe complications (eg, biliary bleeding, perforation) occurred. Two experimental group patients developed cholangitis, which resolved with conservative treatment. The 1-week jaundice remission and 3 month stent patency rates were similar in both groups, but the 6-month stent patency rate was higher in the experimental group (P < .05). In the experimental group, one death occurred as a result of gastrointestinal hemorrhage (unrelated to stent placement) by 3 months, and there were two cases of recurrent jaundice by 6 months. The latter two patients underwent repeat PTC, ablation, and stent placement. In the control group, one death occurred as a result of hepatic failure caused by progressive jaundice at 3 months, and another death resulted from disseminated intravascular coagulation caused by jaundice recurrence at 138 days after stent placement. In addition, seven patients developed jaundice recurrence (50-151 d after stent placement). PTC and repeat stent placement were performed in these patients. CONCLUSIONS: Percutaneous transhepatic cholangiography and intraductal RF ablation combined with biliary stent placement for malignant biliary obstruction is safe and feasible and effectively prolongs stent patency time. PMID- 25817459 TI - Selection and molecular characterization of cellulolytic-xylanolytic fungi from surface soil-biomass mixtures from Black Belt sites. AB - Plant biomass is an abundant renewable natural resource that can be transformed into chemical feedstocks. Enzymes used in saccharification of lignocellulosic biomass are a major part of biofuel production costs. A cocktail of cellulolytic and xylanolytic enzymes are required for optimal saccharification of biomass. Accordingly, thirty-two fungal pure cultures were obtained from surface soil biomass mixtures collected from Black Belt sites in Alabama by culturing on lignocellulosic biomass medium. The fungal strains were screened for the coproduction of cellulolytic and xylanolytic enzymes. Strains that displayed promising levels of cellulolytic and xylanolytic enzymes were characterized by molecular analysis of DNA sequences from the large subunit and internal transcribed spacer (ITS) of their ribosomal RNA gene. Nucleotide sequence analysis revealed that two most promising isolates FS22A and FS5A were most similar to Penicillium janthinellum and Trichoderma virens. Production dynamics of cellulolytic and xylanolytic enzymes from these two strains were explored in submerged fermentation. Volumetric productivity after 120 h incubation was 121.08 units/L/h and 348 units/L/h for the filter paper cellulase and xylanase of strain FS22A, and 90.83 units/L/h and 359 units/L/h, respectively for strain FS5A. Assays with 10 times dilution of enzymes revealed that the activities were much higher than that observed in the crude culture supernatant. Additionally, both FS22A and FS5A also produced amylase in lignocellulose medium. The enzyme profiles of these strains and their activities suggest potential applications in cost effective biomass conversion and biodegradation. PMID- 25817460 TI - Effect of asthma on falling into poverty: the overlooked costs of illness. AB - BACKGROUND: Studies on the indirect costs of asthma have taken a narrow view of how the condition affects the living standards of patients by examining only the association with employment and income. OBJECTIVE: To build on the current cost of-illness literature and identify whether having asthma is associated with an increased risk of poverty, thus giving a more complete picture of the costs of asthma to individuals and society. METHODS: Longitudinal analysis of the nationally representative Household Income and Labour Dynamics in Australian survey to estimate the relative risk of income poverty, multidimensional poverty, and long-term multidimensional poverty between 2007 and 2012 and population attributable risk method to estimate the proportion of poverty between 2007 and 2012 directly attributable to asthma. RESULTS: No significant difference was found in the risk of falling into income poverty between those with and without asthma (P = .07). Having asthma increased the risk of falling into multidimensional poverty by 1.35 (95% confidence interval [CI], 1.01-1.83) and the risk of falling into chronic multidimensional poverty by 2.22 (95% CI, 1.20 4.10). Between 2007 and 2012, a total of 5.2% of income poverty cases (95% CI, 5.1%-5.4%), 7.8% of multidimensional poverty cases (95% CI, 7.7%-8.0%), and 19.6% of chronic multidimensional poverty cases (95% CI, 19.2%-20.0%) can be attributed to asthma. CONCLUSION: Asthma is associated with an increased risk of falling into poverty. This should be taken into consideration when considering the suitability of different treatment options for patients with asthma. PMID- 25817461 TI - Phytobezoar-induced small bowel obstruction associated with a concomitant gastric phytobezoar and ulcer in an elderly woman. AB - Bezoars are aggregates of indigested foreign material that accumulate in the gastroenteric tract, expecially in the stomach and in the narrowest points of the small bowel. They often occur in subjects who follow a diet rich in fruit and vegetables and in those one who previously underwent gastric resective surgery for peptic ulcer. Bezoar formation has even been observed in case of reduced gastric motility and secretion due to diabetes, hypothyroidism, pernicious anemia, myotonic syndromes, and Guillain-Barre syndrome. As they are an uncommon cause of small bowel obstruction, phytobezoars are often not considered in the differential diagnosis of occlusive intestinal syndromes and so frequently come as an intraoperative finding. A consequence of this missed diagnosis in the preoperative period is an unnecessary diagnostic delay that can significantly increase morbidity and mortality. This case report illustrates the need to include phytobezoars in the preoperative diagnostic workout of intestinal obstruction in order to rule out the presence of multiple bezoars and prevent recurrent obstruction. Now that phytobezoars are becoming a less infrequent cause of small bowel obstruction than previously thought, such a diagnostic possibility should always be considered. PMID- 25817462 TI - Dimorphism in genes encoding sexual-stage proteins of Plasmodium ovale curtisi and Plasmodium ovale wallikeri. AB - Plasmodium ovale curtisi and Plasmodium ovale wallikeri are distinct species of malaria parasite which are sympatric throughout the tropics, except for the Americas. Despite this complete overlap in geographic range, these two species do not recombine. Although morphologically very similar, the two taxa must possess distinct characters which prevent recombination between them. We hypothesised that proteins required for sexual reproduction have sufficiently diverged between the two species to prevent recombination in any mosquito blood meal in which gametocytes of both species are ingested. In order to investigate possible barriers to inter-species mating between P. ovale curtisi and P. ovale wallikeri, homologues of genes encoding sexual stage proteins in other plasmodia were identified and compared between the two species. Database searches with motifs for 6-cysteine, Limulus Coagulation factor C domain-containing proteins and other relevant sexual stage proteins in the genus Plasmodium were performed in the available P. ovale curtisi partial genome database (Wellcome Trust Sanger Institute, UK). Sequence fragments obtained were used as the basis for PCR walking along each gene of interest in reference isolates of both P. ovale curtisi and P. ovale wallikeri. Sequence alignment of the homologues of each gene in each species showed complete dimorphism across all isolates. In conclusion, substantial divergence between sexual stage proteins in the two P. ovale spp. was observed, providing further evidence that these do not recombine in nature. Incompatibility of proteins involved in sexual development and fertilisation thus remains a plausible explanation for the observed lack of natural recombination between P. ovale curtisi and P. ovale wallikeri. PMID- 25817463 TI - Paternal antigen-specific proliferating regulatory T cells are increased in uterine-draining lymph nodes just before implantation and in pregnant uterus just after implantation by seminal plasma-priming in allogeneic mouse pregnancy. AB - Paternal antigen-specific regulatory T (PA-specific Treg) cells play an important role in feto-maternal tolerance. To detect the PA-specific Tregs, female BALB/c mice were mated with male DBA/2 mice. Mls Ia antigen on DBA/2 mice is recognized by the T-cell receptor Vbeta6; thus, CD4(+)Foxp3(+)Vbeta6(+) cells are recognized as PA-specific Treg cells. CD4(+)CD25(+)Vbeta6(+) cells effectively suppressed the allo-reactive proliferation of lymphocytes compared with that of CD4(+)CD25(+)Vbeta6(-) cells. Vbeta6(+) PA-specific Treg cells expressed CCR4 and CCR5 on their surface. The frequency of Ki67(+) PA-specific Treg cells among Treg cells was significantly increased in draining lymph nodes on day 3.5 post-coitus (pc; 6.8+/-1.1%, p<0.05) and day 5.5 pc (7.2+/-1.1%, p<0.05) in allogeneic pregnant mice compared with that in nonpregnant mice (2.7+/-0.2%). The frequency of Ki67(+) PA-specific Treg cells in the uterus increased significantly after day 5.5 pc in allogeneic pregnant mice compared with that in nonpregnant mice (8.8+/ 2.8% vs. 1.2+/-1.3%, p<0.05). However, Ki67(-)PA-specific Tregs did not change during pregnancy. To analyze the role of seminal fluid or sperm in Treg expansion, female BALB/c mice were mated with vasectomized DBA/2 male mice (VAS) or seminal vesicle-excised DBA/2 male mice (SVX). The frequency of Ki67(+) PA specific Treg cells did not increase in draining lymph nodes or uterus in BALB/c*DBA/2 (SVX) allogeneic mating mice. These findings suggest that the priming by seminal fluid is important for the induction of proliferating PA specific Tregs in uterine-draining lymph nodes just before implantation and pregnant uterus after implantation, resulting in successful implantation and the maintenance of allogeneic pregnancy. PMID- 25817465 TI - Only humans have human placentas: molecular differences between mice and humans. AB - The placenta is one of the organs with the highest evolutionary diversity among animal species. In consequence, an animal model that reflects human placentation exactly does not exist. However, the mouse is the most frequently used animal model for placenta and pregnancy research. It possesses a hemochorial placenta, which is similar, but also different from the human placenta. The question whether the similarities are sufficient for the achievement of useful results with regard to human pregnancy was debated recently at the 11th Congress of the European Society for Reproductive Immunology (Budapest, Hungary). Here, we discuss the molecular features of the human placenta that are restricted to primates or even to humans. Many of the primate-specific genetic novelties, e.g., the large microRNA cluster on chromosome 19, have been detected during the last 10-15 years and could not be referred to in earlier discussions. Now, in the light of recent findings and a better understanding of interspecies differences, we conclude that the mouse model is often overvalued. Owing to the increasing number of known human-specific factors in human placentation we consider that many aspects of human placentation can only be understood on the basis of experiments on human cells and tissues in combination with data collections from human subject studies. PMID- 25817464 TI - Stimulation of the JAK/STAT pathway by LIF and OSM in the human granulosa cell line COV434. AB - The development of the follicle and competent oocyte is highly coordinated, requiring interplay among several systems. These implicate endocrine, immune, and metabolic signals, intrafollicular paracrine factors from theca, mural, and cumulus granulosa cells, and the oocyte itself. Granulosa cells play a key role in their interaction. COV434 is one of the few human granulosa cell lines that can be used as an in vitro model for ovarian research. We aimed to evaluate the possible activation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway by IL-6-type cytokines leukemia inhibitory factor (LIF) and oncostatin M (OSM) in COV434 cells. Expression of GP130 (glycoprotein 130), STAT3 (signal transducer and activators of transcription 3), PIAS3 (protein inhibitor of activated STAT 3), and SOCS3 (suppressor of cytokine signaling 3) genes after stimulation with LIF or OSM was assessed using RT-qPCR (real-time PCR). GP130 transcripts were significantly upregulated after incubation with LIF or OSM for 24h. Expression of the STAT3 gene was stimulated only after incubation with LIF, but not OSM. SOCS3 showed significant upregulation for all time periods and the levels of PIAS3 were initially down- and after 24h upregulated. Furthermore, the major signaling components of the JAK/STAT pathway, GP130 and STAT3, and the kinase activation patterns of STAT3, were examined at protein level. We found constitutive protein expression for GP130, STAT3, pSTAT3(ser727) and upregulation of pSTAT3(tyr705) by LIF and OSM. Our results demonstrate the activation of the JAK/STAT pathway by LIF and OSM in human granulosa cells. PMID- 25817466 TI - The relationship between seizure onset zone and ictal tachycardia: An intracranial EEG study. AB - OBJECTIVES: Seizures are often accompanied by ictal tachycardia, which, when pronounced, is one of the cardiac arrhythmias associated with sudden unexpected death in epilepsy (SUDEP). We examined the relationship between the lateralization and localization of seizure onset and development of ictal tachycardia. METHODS: We identified patients who underwent bi-hemispheric intracranial EEG recording over a period of 18 months. Two to four consecutive seizures were reviewed for each patient. RESULTS: Fifty-seizures from 19 consecutive patients were analyzed. Forty seizures (80%) developed tachycardia (>20% increase from baseline), but laterality at seizure onset did not predict its occurrence (p=0.168). Bi-laterality at ictal onset was associated with early ictal tachycardia (<10s) (p=0.0208). Seizures out of sleep developed tachycardia faster (mean 19.7s vs. 68.2s, p=0.0067), but the state of alertness was not predictive of the development of tachycardia within 10s of seizure onset. Temporal and/or orbito-frontal lobe involvement was associated with tachycardia when compared to any other lobar combinations at ictal onset (p=0.0073). CONCLUSION: Laterality at seizure onset does not predict the occurrence of ictal tachycardia. Involvement of the temporal and orbito-frontal cortex, spread to the contralateral hemisphere and state of alertness, may define the degree and rate of autonomic changes. SIGNIFICANCE: Our results help clarify the autonomic control during seizures and offer potential use for future studies in SUDEP risk and automatic seizure detection. PMID- 25817467 TI - Angle closure secondary to the use of lorazepam in patient with myopia magna. AB - CASE REPORT: Myopic magna with narrow anterior chamber that presented with a secondary angle closure due to lorazepam. DISCUSSION: Angle closure usually occurs in predisposed patients and is triggered by precipitating factors. Many drugs routinely used in clinical practice could act as a factor responsible for the secondary angle closure. PMID- 25817468 TI - [Genetic analysis results of patients with a retinoblastoma refractory to systemic chemotherapy]. AB - OBJECTIVE: To analyze the genetic alterations identified in the RB1 gene in retinoblastoma patients who do not respond to systemic chemotherapy. METHODS: A genetic analysis was performed on 115 patients with retinoblastoma, 40 of whom had received systemic chemotherapy, and 29 of them had bilateral disease. Descriptive and retrospective study. Non-responders were considered as patients who are finally enucleated. RESULTS: Patients with deletion type mutations are those with less preservation of the eyeball (Pearson Chi-square, P=.055). Patients with an impaired nonsense-frameshift type are more likely to preserve the eyeball. Of the 3 patients who had undergone bilateral enucleation, 2 of them had deletions and one missense alteration. Survival analysis (Kaplan-Meier curve) shows that patients with deletion type mutations are more resistance to chemotherapy, are suffering higher rates of enucleation, and for a shorter period of time (log rank [Mantel-Cox] with a significance level of P=.053), which are also associated with increased rate of being bilateral. CONCLUSIONS: Patients with a genotype show increased resistance to chemotherapy should be evaluated more closely and treated with various therapeutic weapons early. Patients that have deletions in the RB1 gene are at increased risk of chemoresistance. It is likely that other genetic alterations other than RB1 gene may be related to tumor aggressiveness and treatment resistance. PMID- 25817469 TI - Mean platelet volume increased in children with asthma. PMID- 25817471 TI - Treatment with misoprostol by midwives is safe and effective. PMID- 25817470 TI - Interleukin-2 treatment reverses effects of cAMP-responsive element modulator alpha-over-expressing T cells in autoimmune-prone mice. AB - Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are often characterized by a failure of self-tolerance and result in an uncontrolled activation of B cells and effector T cells. Interleukin (IL)-2 critically maintains homeostasis of regulatory T cells (T(reg)) and effector T cells in the periphery. Previously, we identified the cAMP-responsive element modulator alpha (CREMalpha) as a major factor responsible for decreased IL-2 production in T cells from SLE patients. Additionally, using a transgenic mouse that specifically over-expresses CREMalpha in T cells (CD2CREMalphatg), we provided in-vivo evidence that CREMalpha indeed suppresses IL-2 production. To analyse the effects of CREMalpha in an autoimmune prone mouse model we introduced a Fas mutation in the CD2CREMalphatg mice (FVB/Fas(-/-) CD2CREMalphatg). Overexpression of CREMalpha strongly accelerated the lymphadenopathy and splenomegaly in the FVB/Fas(-/-) mice. This was accompanied by a massive expansion of double-negative (DN) T cells, enhanced numbers of interferon (IFN)-gamma-producing T cells and reduced percentages of T(regs). Treatment of FVB/Fas(-/-) CD2CREMalphatg mice with IL-2 restored the percentage of T(regs) and reversed increased IFN-gamma production, but did not affect the number of DNTs. Our data indicate that CREMalpha contributes to the failure of tolerance in SLE by favouring effector T cells and decreasing regulatory T cells, partially mediated by repression of IL-2 in vivo. PMID- 25817472 TI - Comparison of treatment of incomplete abortion with misoprostol by physicians and midwives at district level in Uganda: a randomised controlled equivalence trial. AB - BACKGROUND: Misoprostol is established for the treatment of incomplete abortion but has not been systematically assessed when provided by midwives at district level in a low-resource setting. We investigated the effectiveness and safety of midwives diagnosing and treating incomplete abortion with misoprostol, compared with physicians. METHODS: We did a multicentre randomised controlled equivalence trial at district level at six facilities in Uganda. Eligibility criteria were women with signs of incomplete abortion. We randomly allocated women with first trimester incomplete abortion to clinical assessment and treatment with misoprostol either by a physician or a midwife. The randomisation (1:1) was done in blocks of 12 and was stratified for study site. Primary outcome was complete abortion not needing surgical intervention within 14-28 days after initial treatment. The study was not masked. Analysis of the primary outcome was done on the per-protocol population with a generalised linear-mixed effects model. The predefined equivalence range was -4% to 4%. The trial was registered at ClinicalTrials.gov, number NCT01844024. FINDINGS: From April 30, 2013, to July 21, 2014, 1108 women were assessed for eligibility. 1010 women were randomly assigned to each group (506 to midwife group and 504 to physician group). 955 women (472 in the midwife group and 483 in the physician group) were included in the per-protocol analysis. 452 (95.8%) of women in the midwife group had complete abortion and 467 (96.7%) in the physician group. The model-based risk difference for midwife versus physician group was -0.8% (95% CI -2.9 to 1.4), falling within the predefined equivalence range (-4% to 4%). The overall proportion of women with incomplete abortion was 3.8% (36/955), similarly distributed between the two groups (4.2% [20/472] in the midwife group, 3.3% [16/483] in the physician group). No serious adverse events were recorded. INTERPRETATION: Diagnosis and treatment of incomplete abortion with misoprostol by midwives is equally safe and effective as when provided by physicians, in a low-resource setting. Scaling up midwives' involvement in treatment of incomplete abortion with misoprostol at district level would increase access to safe post-abortion care. FUNDING: The Swedish Research Council, Karolinska Institutet, and Dalarna University. PMID- 25817473 TI - Correlation between injury pattern and Finite Element analysis in biomechanical reconstructions of Traumatic Brain Injuries. AB - At present, Finite Element (FE) analyses are often used as a tool to better understand the mechanisms of head injury. Previously, these models have been compared to cadaver experiments, with the next step under development being accident reconstructions. Thus far, the main focus has been on deriving an injury threshold and little effort has been put into correlating the documented injury location with the response displayed by the FE model. Therefore, the purpose of this study was to introduce a novel image correlation method that compares the response of the FE model with medical images. The injuries shown on the medical images were compared to the strain pattern in the FE model and evaluated by two indices; the Overlap Index (OI) and the Location Index (LI). As the name suggests, OI measures the area which indicates both injury in the medical images and high strain values in the FE images. LI evaluates the difference in center of mass in the medical and FE images. A perfect match would give an OI and LI equal to 1. This method was applied to three bicycle accident reconstructions. The reconstructions gave an average OI between 0.01 and 0.19 for the three cases and between 0.39 and 0.88 for LI. Performing injury reconstructions are a challenge as the information from the accidents often is uncertain. The suggested method evaluates the response in an objective way which can be used in future injury reconstruction studies. PMID- 25817474 TI - A continuous fiber distribution material model for human cervical tissue. AB - The uterine cervix during pregnancy is the vital mechanical barrier which resists compressive and tensile loads generated from a growing fetus. Premature cervical remodeling and softening is hypothesized to result in the shortening of the cervix, which is known to increase a woman's risk of preterm birth. To understand the role of cervical material properties in preventing preterm birth, we derive a cervical material model based on previous mechanical, biochemical and histological experiments conducted on nonpregnant and pregnant human hysterectomy cervical tissue samples. In this study we present a three-dimensional fiber composite model that captures the equilibrium material behavior of the tissue in tension and compression. Cervical tissue is modeled as a fibrous composite material, where a single family of preferentially aligned and continuously distributed collagen fibers are embedded in a compressible neo-Hookean ground substance. The total stress in the collagen solid network is calculated by integrating the fiber stresses. The shape of the fiber distribution is described by an ellipsoid where semi-principal axis lengths are fit to optical coherence tomography measurements. The composite material model is fit to averaged mechanical testing data from uni-axial compression and tension experiments, and averaged material parameters are reported for nonpregnant and term pregnant human cervical tissue. The model is then evaluated by investigating the stress and strain state of a uniform thick-walled cylinder under a compressive stress with collagen fibers preferentially aligned in the circumferential direction. This material modeling framework for the equilibrium behavior of human cervical tissue serves as a basis to determine the role of preferentially-aligned cervical collagen fibers in preventing cervical deformation during pregnancy. PMID- 25817475 TI - Zero- vs. one-dimensional, parametric vs. non-parametric, and confidence interval vs. hypothesis testing procedures in one-dimensional biomechanical trajectory analysis. AB - Biomechanical processes are often manifested as one-dimensional (1D) trajectories. It has been shown that 1D confidence intervals (CIs) are biased when based on 0D statistical procedures, and the non-parametric 1D bootstrap CI has emerged in the Biomechanics literature as a viable solution. The primary purpose of this paper was to clarify that, for 1D biomechanics datasets, the distinction between 0D and 1D methods is much more important than the distinction between parametric and non-parametric procedures. A secondary purpose was to demonstrate that a parametric equivalent to the 1D bootstrap exists in the form of a random field theory (RFT) correction for multiple comparisons. To emphasize these points we analyzed six datasets consisting of force and kinematic trajectories in one-sample, paired, two-sample and regression designs. Results showed, first, that the 1D bootstrap and other 1D non-parametric CIs were qualitatively identical to RFT CIs, and all were very different from 0D CIs. Second, 1D parametric and 1D non-parametric hypothesis testing results were qualitatively identical for all six datasets. Last, we highlight the limitations of 1D CIs by demonstrating that they are complex, design-dependent, and thus non generalizable. These results suggest that (i) analyses of 1D data based on 0D models of randomness are generally biased unless one explicitly identifies 0D variables before the experiment, and (ii) parametric and non-parametric 1D hypothesis testing provide an unambiguous framework for analysis when one's hypothesis explicitly or implicitly pertains to whole 1D trajectories. PMID- 25817476 TI - Patterns of frequency distribution of woody plant heights: a response to Scheffer et al. PMID- 25817477 TI - Development of a sensitive, accurate and robust liquid chromatography/mass spectrometric method for profiling of angiotensin peptides in plasma and its application for atherosclerotic mice. AB - Quantification of angiotensin (Ang) peptides in biological matrices is a challenge due to their low picomolar (pM) concentration and poor analytical performance of current methods. This work aimed to select an optimal strategy for liquid chromatography/mass spectrometry (LC/MS) quantification of major angiotensins in plasma of wild type and atherosclerotic mice. Optimal LC/MS set up for Ang quantification was chosen, based on analytical performance, from: nanoflow/orbitrap, nanoflow/triple quadrupole and preconcentration nanoflow/triple quadrupole. The best LC/MS configuration (preconcentration nanoflow/triple quadrupole) was validated and used for measurement of angiotensins (Ang I, II, III, IV and (1-7)) in plasma of 6-month-old atherosclerotic apolipoprotein E/LDL receptor double knock-outs (ApoE/LDLR (--/- )) and wild type C57BL/6J (WT) mice. The method established for Ang quantification was selective, accurate and highly sensitive with LLOQ of 5pgmL( 1). The peak area intra-day precisions for Ang II and Ang-(1-7) were in the range 3.0-5.1 and 3.5-5.8, respectively, with corresponding accuracy of 95.4-103.5% and 95.6-106.3%. Plasma angiotensin profile was substantially modified in ApoE/LDLR knock-out mice with increase in concentration of Ang II from 37.6+/-21.3pgmL(-1) in WT to 200.2+/-47.6pgmL(-1). Concentrations of Ang I, III and IV were also increased 3-10 fold in ApoE/LDLR (--/--) mice while that of Ang-(1-7) was unchanged. We conclude that the method developed could be effectively used for accurate, comprehensive profiling of angiotensin peptides in mouse plasma. We identified substantial changes in renin-angiotensin system in a genetic mouse model of atherosclerosis consistent with the overactivation of angiotensin converting enzyme (ACE) and the impairment of ACE2. PMID- 25817478 TI - Selective removal of carbon dioxide contained in the effluent from ion chromatography suppressors using a new non-vacuum device. AB - In this paper, a new CO2 gas removal device optimized to selectively remove CO2 gas contained in the effluent from suppressors used in ion chromatography (IC) under non-vacuum conditions is described. This device consists of a closed vessel equipped with gas permeable tubing (GPT) and a CO2 adsorbent. During operation, the CO2 adsorbent adsorbs CO2 gas in the vessel, creating CO2 partial pressure difference between the inside of the GPT and the vessel. The CO2 gas contained in the effluent being pumped into the GPT is selectively removed from the effluent based on the diffusion of the CO2 associated with the CO2 partial pressure difference. The purpose of this study is to optimize the IC operating conditions with the aim of selectively removing HCO3(-) (CO3(2-)) contained in the effluent and reducing the electrical conductivity of the effluent under non-vacuum conditions. The electrical conductivity of the effluent and the signal intensity of the water dip is decreased by approximately 25 MUS/cm (from 30 to 5 MUS/cm) and by approximately twentieth, respectively, using the optimized CO2 remover. In addition, the anion detection limit achieved in IC instruments with a CO2 remover is on the order of a few ppb. PMID- 25817481 TI - On-demand doping of graphene by stamping with a chemically functionalized rubber lens. AB - A customized graphene doping method was developed involving stamping using a chemically functionalized rubber lens as a novel design strategy for fabricating advanced two-dimensional (2D) materials-based electronic devices. Our stamping strategy enables deterministic control over the doping level and the spatial pattern of the doping on graphene. The dopants introduced onto graphene were locally and continuously controlled by directly stamping dopants using a chemically functionalized hemispherical rubber lens onto the graphene. The rubber lens was functionalized using two different dopants: poly(ethylene imine) to achieve n-type doping and bis(trifluoromethanesulfonyl)amine to achieve p-type doping. The graphene doping was systematically controlled by varying both the contact area (between the rubber lens and the graphene) and the contact time. Graphene doping using a stamp with a chemically functionalized rubber lens was confirmed by both Raman spectroscopy and charge transport measurements. We theoretically modeled the conductance properties of the spatially doped graphene using the effective medium theory and found excellent agreement with the experimental results. Finally, complementary inverters were successfully demonstrated by connecting n-type and p-type graphene transistors fabricated using the stamping doping method. We believe that this versatile doping method for controlling charge transport in graphene will further promote graphene electronic device applications. The doping method introduced in this paper may also be applied to other emergent 2D materials to tightly modulate the electrical properties in advanced electronic devices. PMID- 25817480 TI - Analysis of tandem E-box motifs within human Complement receptor 2 (CR2/CD21) promoter reveals cell specific roles for RP58, E2A, USF and localized chromatin accessibility. AB - Complement receptor 2 (CR2/CD21) plays an important role in the generation of normal B cell immune responses. As transcription appears to be the prime mechanism via which surface CR2/CD21 expression is controlled, understanding transcriptional regulation of this gene will have broader implications to B cell biology. Here we report opposing, cell-context specific control of CR2/CD21 promoter activity by tandem E-box elements, spaced 22 bp apart and within 70 bp of the transcription initiation site. We have identified E2A and USF transcription factors as binding to the distal and proximal E-box sites respectively in CR2-positive B-cells, at a site that is hypersensitive to restriction enzyme digestion compared to non-expressing K562 cells. However, additional unidentified proteins have also been found to bind these functionally important elements. By utilizing a proteomics approach we have identified a repressor protein, RP58, binding the distal E-box motif. Co-transfection experiments using RP58 overexpression constructs demonstrated a specific 10-fold repression of CR2/CD21 transcriptional activity mediated through the distal E-box repressor element. Taken together, our results indicate that repression of the CR2/CD21 promoter can occur through one of the E-box motifs via recruitment of RP58 and other factors to bring about a silenced chromatin context within CR2/CD21 non-expressing cells. PMID- 25817482 TI - See it, grab it, or STOP! Relationships between trait impulsivity, attentional bias for pictorial food cues and associated response inhibition following in-vivo food cue exposure. AB - Impulsivity is associated with appetitive behaviour such as heightened sensitivity to cues of reward. Impulsivity may thus confer a vulnerability to weight gain by virtue of over-responsiveness to rewarding appetitive cues. This vulnerability should be detectable as heightened cognitive and behavioural responsiveness to food cues, namely, an attentional bias to food-stimuli, subjective wanting, and loss of inhibitory control. We examined this proposition by measuring reactions to acute, in-vivo, food-cue exposure in low-impulsive and high-impulsive individuals. We expected that high-impulsive individuals would: (1) show a greater attentional bias towards pictorial food cues presented after in-vivo food cue exposure; (2) show a greater appetitive reaction to high-calorie snack foods; and (3) show poorer inhibitory control after in vivo exposure compared to control. Fifty female participants (25 yr +/- 1.1; 24 kg/m2 +/- 0.6) randomly allocated to either a high-calorie food-cue exposure or food-neutral control condition subsequently completed a food-cue visual probe reaction time task, subjective ratings of appetitive state and the Stop-Signal task. A significant Group-by-Duration interaction indicated that high-impulsives show slowed disengagement (longer RTs for 2000 ms duration) of pictorial food stimuli compared to their low-impulsive counterparts. Conversely, the low impulsive group show greater attentional bias than the high impulsive group (faster RTs) at the 500 ms duration, indicating speeded detection of pictorial food cues. High impulsives showed poorer response inhibition compared to low-impulsives following in-vivo food-cue exposure. Impulsivity did not significantly moderate the effect of in-vivo cue-exposure on desire-to-eat ratings. The evidence we obtained regarding inhibitory control following in vivo food cue exposure suggests that high-impulsive individuals may be prone to overeat when their reward systems are activated, a hypothesis that requires further confirmation. PMID- 25817483 TI - Automatic approach/avoidance tendencies towards food and the course of anorexia nervosa. AB - OBJECTIVE: The aim of the present study was to investigate the role of automatic approach/avoidance tendencies for food in Anorexia Nervosa (AN). We used a longitudinal approach and tested whether a reduction in eating disorder symptoms is associated with enhanced approach tendencies towards food and whether approach tendencies towards food at baseline are predictive for treatment outcome after one year follow up. METHOD: The Affective Simon Task-manikin version (AST manikin) was administered to measure automatic approach/avoidance tendencies towards high-caloric and low-caloric food in young AN patients. Percentage underweight and eating disorder symptoms as indexed by the EDE-Q were determined both during baseline and at one year follow up. RESULTS: At baseline anorexia patients showed an approach tendency for low caloric food, but not for high caloric food, whereas at 1 year follow up, they have an approach tendency for both high and low caloric food. Change in approach bias was neither associated with change in underweight nor with change in eating disorder symptoms. Strength of approach/avoidance tendencies was not predictive for percentage underweight. DISCUSSION: Although approach tendencies increased after one year, approach tendencies were neither associated with concurrent change in eating disorder symptoms nor predictive for treatment success as indexed by EDE-Q. This implicates that, so far, there is no reason to add a method designed to directly target approach/avoidance tendencies to the conventional approach to treat patients with a method designed to influence the more deliberate processes in AN. PMID- 25817484 TI - A licence to vape: Is it time to trial of a nicotine licensing scheme to allow Australian adults controlled access to electronic cigarettes devices and refill solutions containing nicotine? AB - Australia has some of the most restrictive laws concerning use of nicotine in e cigarettes. The only current legal option for Australians to legally possess and use nicotine for vaping is with a medical prescription and domestic supply is limited to compounding pharmacies that prepare medicines for specific patients. An alternative regulatory option that could be implemented under current drugs and poisons regulations is a 'nicotine licensing' scheme utilising current provisions for 'dangerous poisons'. This commentary discusses how such a scheme could be used to trial access to nicotine solutions for vaping outside of a 'medicines framework' in Australia. PMID- 25817485 TI - [The tip of the iceberg: cutaneous manifestations of paediatric diseases with neurological involvement]. AB - INTRODUCTION: Some cutaneous lesions might be the first clinical manifestation of diseases with systemic involvement. This article aims to review the relevant dermatological semiology for the concerning diseases with neurological involvement in childhood. MATERIAL AND METHODS: Review of the related literature indexed to MedLine published in the last twelve years. RESULTS: The main relevant nosologic groups include the genodermatosis (namely neurocutaneous syndromes), pigmentary, vascular and endocrine disorders, congenital enzymatic deficiencies and occult spinal dysraphisms. DISCUSSION: The recognition of specific cutaneous signs is important once may enable a much earlier diagnosis. PMID- 25817486 TI - Osteoarthritis. AB - Osteoarthritis is nowadays one of the most frequent chronic diseases and, with the increase in life expectancy, both its prevalence and incidence is expected to rise. This condition is progressive and leads to functional decline and loss in quality of life, with important health care and society costs. A review of relevant and recent literature on osteoarthritis was performed in PubMed. The purpose of this study is to understand important aspects about osteoarthritis estimates, burden of disease, pathophysiology, risk factors, diagnosis and treatment. PMID- 25817479 TI - Decoding mechanisms by which silent codon changes influence protein biogenesis and function. AB - SCOPE: Synonymous codon usage has been a focus of investigation since the discovery of the genetic code and its redundancy. The occurrences of synonymous codons vary between species and within genes of the same genome, known as codon usage bias. Today, bioinformatics and experimental data allow us to compose a global view of the mechanisms by which the redundancy of the genetic code contributes to the complexity of biological systems from affecting survival in prokaryotes, to fine tuning the structure and function of proteins in higher eukaryotes. Studies analyzing the consequences of synonymous codon changes in different organisms have revealed that they impact nucleic acid stability, protein levels, structure and function without altering amino acid sequence. As such, synonymous mutations inevitably contribute to the pathogenesis of complex human diseases. Yet, fundamental questions remain unresolved regarding the impact of silent mutations in human disorders. In the present review we describe developments in this area concentrating on mechanisms by which synonymous mutations may affect protein function and human health. PURPOSE: This synopsis illustrates the significance of synonymous mutations in disease pathogenesis. We review the different steps of gene expression affected by silent mutations, and assess the benefits and possible harmful effects of codon optimization applied in the development of therapeutic biologics. PHYSIOLOGICAL AND MEDICAL RELEVANCE: Understanding mechanisms by which synonymous mutations contribute to complex diseases such as cancer, neurodegeneration and genetic disorders, including the limitations of codon-optimized biologics, provides insight concerning interpretation of silent variants and future molecular therapies. PMID- 25817487 TI - [Nephrocalcinosis and subcutaneous fat necrosis]. AB - Subcutaneous fat necrosis of the newborn is an uncommon, transient and self healing panniculits. This entity generally follows an uncomplicated course, however there are rare and important complications. The authors present a case of a newborn with subcutaneous fat necrosis complicated by hypercalcemia and nephrocalcinosis. The pathogenesis of hypercalcemia is not fully understood and the nephrocalcinosis can evolve to chronic kidney disease. Clinicians should be aware of subcutaneous fat necrosis as a possible risk factor for hypercalcemia and patients should have serial serum and urinary calcium determinations for up to 6 months after the appearance of the skin lesions. The early diagnosis and prompt treatment of hypercalcemia are essential to prevent severe complications. PMID- 25817488 TI - Thank you, reviewers of Acta Medica Portuguesa. PMID- 25817489 TI - [The national health service: dream and reality]. PMID- 25817490 TI - [Clinical semiology at the technology age: the new cardiology]. PMID- 25817491 TI - Cure of hepatitis C. PMID- 25817492 TI - [Analysis of the Cochrane Review: thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev. 2014,1: CD002783]. AB - The standard treatment for acute deep vein thrombosis (DVT) targets to reduce immediate complications, however thrombolysis could reduce the long-term complications of post-thrombotic syndrome in the affected limb. This systematic review aimed to assess the effects of thrombolytic therapy and anticoagulation versus anticoagulation in people with deep vein thrombosis of the lower limb through the effects on pulmonary embolism, recurrent deep vein thrombosis, major bleeding, post-thrombotic complications, venous patency and venous function. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last search in April 2013) and CENTRAL (2013, Issue 4). A total of 17 randomised controlled trials (RCTs) and 1103 participants were included. In the experimental group receiving thrombolysis, complete clot lysis occurred more frequently and there was greater improvement in venous patency. The incidence of post-thrombotic syndrome decreased by a 1/3 and venous ulcers were less frequent. There were more bleeding complications and 3 strokes occurred in less recent studies, yet there seemed to be no significant effect on mortality. Data on the occurrence of pulmonary embolism and recurrent deep vein thrombosis were inconclusive. There are advantages to thrombolysis, yet the application of rigorous criteria is warranted to reduce bleeding complications. Catheter directed thrombolysis is the current preferred method, as opposed to systemic thrombolysis in the past, and other studies comparing these procedures show that results are similar. PMID- 25817493 TI - Etiological agents and antimicrobial susceptibility in hospitalized children with acute pyelonephritis. AB - INTRODUCTION: Antibiotic resistance driven by antibiotic use remains a major public health and professional concern. Our aim was to know the local prevalence of uropathogens and their antimicrobial susceptibility profile in acute pyelonephritis. MATERIAL AND METHODS: A prospective study of patients admitted in a level III Pediatric Department ward with acute pyelonephritis from 1994 to 2012 was performed in Northern Portugal. Etiological agents and their antimicrobial sensitivity profile were evaluated in four timed periods (G1: 1994-97; G2: 2002; G3: 2007; G4: 2012). RESULTS: We evaluated 581 patients, 66% female with median age 22 months. Escherichia coli was the leading uropathogen and its prevalence remained stable during the last 18 years. It showed an increased sensitivity to amoxicillin-clavulanate from 71% in G1 to 81.5% in G4 (p = 0.001) and a decreased resistance rate from 8.7% in G1 to 2.8% in G4 (p = 0.008). Its sensitivity to 2nd and 3rd generation cephalosporin was more than 90% (p = ns) and more than 95% to nitrofurantoin (p = ns). Resistance rate of cotrimoxazole increased from 22% to 26% (p = 0.008). DISCUSSION: Escherichia coli remains the main uropathogen responsible for acute pyelonephritis, reason why its antimicrobial sensitivity profile will determine the empirical therapeutic choice. CONCLUSIONS: Amoxicillin clavulanate remains a good first-line choice for empirical treatment of acute pyelonephritis in our inpatient health care. PMID- 25817494 TI - [Problems identified in the package leaflets of the Portuguese non-generic medicines]. AB - INTRODUCTION: All medicines for human use are marketed with a package leaflet. Every package leaflet must contain an initial list mentioning all sections of the document in accordance to the European template Quality Review of Documents, being not to extensive, i.e. comprising approximately 1500 words. The so-called mixed leaflets contain information about medicines with more than one strength/ pharmaceutical form, and only exceptionally are authorized. In this context, the objectives of the present study comprised the identification of issues in all package leaflets of Portuguese non-generic medicines: 1. to confirm the presence of an initial list, 2. to quantify the number of mixed leaflets, and 3. to evaluate their length (in number of pages). MATERIAL AND METHODS: Consultation of the leaflets, in a public database (Infomed), according to the classification of the National Prescribing Guide (1st trimester 2012). The data collected was subject to quality control and statistical analysis. RESULTS: Identification of 2729 package leaflets, representing 3080 medicines. A total of 2042 leaflets were evaluated, with 181 (8.9%) missing the initial list and 351 (17.2%) being mixed. The average number of pages was 6.9 (SD=2.6), the minimum = 2 and the maximum = 26. DISCUSSION: In some cases, readability and comprehension of some Portuguese leaflets might be compromised since: 1) some leaflets did not contain an initial list, 2) were classified as mixed leaflets, and/or 3) were classified as too extensive. CONCLUSION: Regulatory authorities and marketing authorization holders might need to take into consideration these issues during the development and approval of package leaflets. PMID- 25817495 TI - [Gestational diabetes and the new screening test's impact]. AB - INTRODUCTION: In 2011, a new screening test for gestational diabetes was introduced which allowed an earlier and larger diagnosis with the goal of reducing maternal and perinatal complications. The aim of our study was to evaluate the prevalence of gestational diabetes, compare maternal and perinatal outcomes with the previous and present screening tests and analyze postpartum screening results. MATERIAL AND METHODS: Retrospective study of women with singletons and gestational diabetes diagnosed during 2009 (n = 223) and 2012 (n = 237), at Maternidade Dr. Alfredo da Costa, Portugal. Analysis of clinical charts and assessment of demographic data, medical and obstetric history, weight gain during pregnancy, gestational age at diagnosis, treatment regimens, neonatal outcomes and postpartum screening results, followed by comparison of these variables between the years of 2009 and 2012. RESULTS: In 2012, there was an increased gestational diabetes prevalence, lower weight gain during pregnancy (p < 0.001), more frequent use of pharmacological therapy (p < 0.001) and more diagnosed cases during first and second trimester (p < 0.001). As for neonatal outcomes, in this group, the medium weight at birth was significantly lower (p = 0.001) with a decrease of newborns great for gestational age (p = 0.002). Postpartum screening rate was similar among both groups but in 2012 there was an increase of normal results and a decrease of impaired fasting glucose. DISCUSSION: Tighter criteria of the current screening test resulted in reduction of the majority of gestational diabetes complications but raised new questions. CONCLUSION: The introduction of the current screening test resulted in an increased prevalence, earlier diagnosis and reduction of macrosomia. PMID- 25817496 TI - [FATA Study: prevalence of atrial fibrillation and antithrombotic therapy in primary health care in a northern city of Portugal]. AB - INTRODUCTION: Atrial fibrillation is the most prevalent sustained arrhythmia. The efficacy of oral anticoagulation has been proved in prevention stroke in these patients. However, this seems to be an underutilized treatment. OBJECTIVES: to determine the prevalence of known atrial fibrillation in a Primary Health Care population; to identify major comorbidities, current antithrombotic therapy and evaluate their suitability according to the European Society of Cardiology guidelines. MATERIAL AND METHODS: Observational cross-sectional analytical study. POPULATION: all patients aged 30 or above, enrolled in eight Family Health Units of Vila Nova de Gaia and diagnosed with atrial fibrillation. RESULTS: Prevalence of atrial fibrillation was 1.29% (n = 940), being higher in males (p = 0.01) and increasing with age (p < 0.001). The most common comorbidities were hypertension (76.4%), heart failure (32.0%) and diabetes mellitus (28.2%). A total of 52% was performing anticoagulant therapy, 29% antiplatelet agents and 4% both therapies. Of those with low thrombotic risk, 63.6% was wrongly performing some kind of antithrombotic therapy; among patients with high risk or valvular disease 56.8% was properly undergoing anticoagulant therapy. CONCLUSION: The prevalence of atrial fibrillation as well as the frequency of the main comorbidities associated with it are in line with the majority of studies. Although most patients are undergoing oral anticoagulation, only 56.8% of those with atrial fibrillation was performing adequate antithrombotic therapy as recommended by the European Society of Cardiology guidelines, which denote a marked underutilization of this treatment. PMID- 25817497 TI - [Psychiatric comorbidities associated with headaches: the experience of the liaison consultation]. AB - INTRODUCTION: The comorbidity between headaches and psychiatric disorders is common and may be explained by different mechanisms in terms of uni or bi directional models, or sharing of genetic and environmental risk factors relating to development of both clinical conditions. The presence of this comorbidity has important implications for patients with headaches and for patients with psychiatric disorders, worsens the clinical situation, increases the risk of chronicity, the pain intensity and the rate of treatment failure. MATERIAL AND METHODS: The authors performed a descriptive, retrospective study of prevalence, involving 250 patients seen in Psychiatry - Headaches liaison consultation, over a period of 3 years, from July 1, 2011 to July 1, 2013. The authors undertook the analysis of the clinical records, in respect to sociodemographic and clinical data, neurological and psychiatric diagnosis and prescribed therapy. RESULTS AND DISCUSSION: During this period were made 689 liaison consultations, with a prevalence of female patients (84%) and a mean age of 47 years. The tension type headache (60.8%), migraine (24.8%) and headache attributed to psychiatric disorders (7.2%) were the most prevalent types of headaches. Mood disorders (62%) and neurotic stress related disorders (39.2%) were the most frequent psychiatric diagnoses. The therapeutic intervention in these cases emphasizes the multidisciplinary approach with the collaboration of Neurologist and Psychiatrist, based in psychoeducation, cognitive-behavioral intervention and psychopharmacological treatment. CONCLUSION: Given the complexity of the clinical picture in cases of comorbidity, the experience of psychiatry liaison consultation and multidisciplinary intervention has proved particularly valuable in treating these patients, configuring itself as the proper treatment of this comorbidity. PMID- 25817498 TI - Prevalence of autonomic dysfunction in patients with multiple sclerosis. AB - BACKGROUND: Autonomic nervous system dysfunction is commonly seen in multiple sclerosis patients and should be explored in the routine evaluation. Composite Autonomic Symptom Score questionnaire was validated as a self-assessment instrument of autonomic symptoms. OBJECTIVES: Determine the frequency of autonomic symptoms in multiple sclerosis patients through a Portuguese version of Composite Autonomic Symptom Score; compare questionnaire results between patients and a control group; assess the feasibility of this questionnaire application in multiple sclerosis Portuguese patients. MATERIAL AND METHODS: This case-control study used a Portuguese translated version of Composite Autonomic Symptom Score to determine the frequency of autonomic symptoms in multiple sclerosis patients. RESULTS: One-hundred and three relapsing-remitting multiple sclerosis patients - median age 41 years, median disease duration 6 years, median EDSS score 1 - and 80 healthy subjects were included. Alterations in autonomic function were reported in 97.1% of the cases, with statistical significance in orthostatic intolerance and gastrointestinal domain scores. Nevertheless, the difference between multiple sclerosis patients (41.7%) without confounding factors that could interfere with autonomic dysfunction (i.e. comorbidities or medications) and controls showed no statistical significance. DISCUSSION: Our results may be related to the short disease duration, young age and lowdisability status of our patients unaffected by confounding factors. The questionnaire was not designed specifically for multiple sclerosis and it may not be as sensible to early autonomic symptoms as to more severe manifestations. CONCLUSIONS: Further studies are needed to achieve more robust results, validate this questionnaire and assess its application in multiple sclerosis patients in Portugal. PMID- 25817499 TI - [Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: genotype phenotype correlation]. AB - INTRODUCTION: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is one of the most frequent inborn conditions. It is caused by distinct mutations in the CYP21A2 gene and in the majority of cases the disease's severity correlates with CYP21A2 allelic variation Our aim was to describe the mutational spectrum of CYP21A2 and evaluate genotype-phenotype correlation in a cohort of portuguese patients with 21-hydroxylase deficiency. MATERIAL AND METHODS: Retrospective study of 22 patients with clinical diagnosis of 21-hydroxylase deficiency. Molecular analysis of CYP21A2 was performed and genotype-phenotype correlation was then established. RESULTS: Genotyping was performed in 22 unrelated patients: 5 with classic salt-wasting (average age of diagnosis 10,2 days; minimum 1, maximum 20 days), 7 with classic simple virilizing (average age of diagnosis 3,5 years; minimum 0 days, maximum 7 years) and 10 with nonclassical form (average age of diagnosis 5,7 years; minimum 4 years, maximum 8 years). The most frequent genetic defects in the classic forms were I2 splice (24%) and I172N (24%), followed by Q318X (16%) and gene deletions (16%) and in the nonclassical form, the V281L (80%). The overall concordance between genotype and phenotype was 81,8%. Genotype accurately predicted phenotype in 83,3%, 100% and 90% of patients with classic salt-wasting, classic simple virilizing and nonclassical mutations, respectively. DISCUSSION: The frequency of genetic defects in our patients was comparable to similar studies. In most cases there was a good correlation between genotype and phenotype. CONCLUSIONS: Molecular analysis of CYP21A2 provides useful information in terms of prediction of disease severity, genetic and prenatal counseling. PMID- 25817500 TI - Efficacy and safety of percutaneous radiofrequency thermal ablation in the treatment of lung cancer lesions. AB - INTRODUCTION: In this study, we reviewed a clinical series composed by all malignant lung lesions submitted to computed tomography-guided percutaneous thermal radiofrequency ablation, in our hospital, a rather recent technique that has been gaining scientific recognition. MATERIAL AND METHODS: For data purposes, all radiofrequency ablation and corresponding clinical records were retrospectively analysed. A computed tomography scan was performed before and after each procedure to evaluate the tumour's features, and at a second step to assess results and complications. The frequency of local recurrence and disease progression were determined based on imaging follow-up. Kaplan-Meier analysis was used to estimate survival. Univariate analysis recognized clinical and pathological factors affecting survival. These were also tested by multivariate analysis. RESULTS: A total of 28 malignant lung lesions, 20 primary and 8 metastatic, from 28 patients (78.6% male; mean age 62 +/- 17 years old), were submitted to computed tomography-guided radiofrequency ablation between January 2004 and July 2010. Total necrosis was achieved in 74.1% of the lesions. Immediate radiofrequency ablation-related complications were observed in half of the procedures. Among major complications, death occurred in one patient only. Median overall survival was 43.0 months for a mean 2-years follow-up.Median progression-free survival was 31.6 months. Lesion's size smaller than 35 mm, stage III disease by the TNM classification and previous treatment attempts were significantly associated with better outcomes. Disease-related mortality was 46.4%. DISCUSSION: This procedure proved to be efficient to treat lung cancerous lesions, with a low-rate of major complications. CONCLUSIONS: Computed tomography guided percutaneous radiofrequency ablation is a minimally invasive procedure that appears to be valuable in the treatment of lung cancer lesions. PMID- 25817501 TI - Effects of local anesthetic on the time between analgesic boluses and the duration of labor in patient-controlled epidural analgesia: prospective study of two ultra-low dose regimens of ropivacaine and sufentanil. AB - BACKGROUND: Patient-controlled epidural analgesia with low concentrations of anesthetics is effective in reducing labor pain. The aim of this study was to assess and compare two ultra-low dose regimens of ropivacaine and sufentanil (0.1% ropivacaine plus 0.5 MUg.ml-1 sufentanil vs. 0.06% ropivacaine plus 0.5 MUg.ml-1 sufentanil) on the intervals between boluses and the duration of labor. MATERIAL AND METHODS: In this non-randomized prospective study, conducted between January and July 2010, two groups of parturients received patient-controlled epidural analgesia: Group I (n = 58; 1 mg.ml-1 ropivacaine + 0.5 MUg.ml-1 sufentanil) and Group II (n = 57; 0.6 mg.ml-1 ropivacaine + 0.5 MUg.ml-1 sufentanil). Rescue doses of ropivacaine at the concentration of the assigned group without sufentanil were administered as necessary. Pain, local anesthetic requirements, neuraxial blockade characteristics, labor and neonatal outcomes, and maternal satisfaction were recorded. RESULTS: The ropivacaine dose was greater in Group I (9.5 [7.7-12.7] mg.h-1 vs. 6.1 [5.1-9.8 mg.h-1], p < 0.001). A time increase between each bolus was observed in Group I (beta = 32.61 min, 95% CI [25.39; 39.82], p < 0.001), whereas a time decrease was observed in Group II (beta = -1.40 min, 95% CI [-2.44; -0.36], p = 0.009). The duration of the second stage of labor in Group I was significantly longer than that in Group II (78 min vs. 65 min, p < 0.001). CONCLUSIONS: Parturients receiving 0.06% ropivacaine exhibited less evidence of cumulative effects and exhibited faster second stage progression than those who received 0.1% ropivacaine. PMID- 25817502 TI - [Weight control attempts among Portuguese adults: prevalence, motives and behavioral strategies]. AB - INTRODUCTION: In Portugal, there are no representative data on how many people are actively trying to control their weight and which strategies and motives underlie those attempts. The aim of this study was to estimate the prevalence of weight loss/maintenance attempts and to identify the associated behavioral strategies and motives, in a representative sample of Portuguese adults. MATERIAL AND METHODS: Cross-sectional study with a sample of 1098 Portuguese adults. Sociodemographic information, anthropometric data and weight loss/maintenance strategies and motives were assessed by telephone interview. RESULTS: About 44% of Portuguese adults (53% women and 35% men) are actively trying to control their weight. About 22% of women with normal weight are trying to lose weight while 53% of men and 34% of women with excess weight are not trying to manage their weight. About 49% of men with higher educational level are trying to control their weight, which compares to 32% among the least educated men. The most frequently used strategy to manage weight is regular vegetable consumption and the motives most frequently reported were improving health/preventing diseases and improving wellbeing. DISCUSSION AND CONCLUSION: More than half of Portuguese women and about one-third of men are actively trying to control their weight, using behavioral strategies which are generally consistent with public health recommendations. The predominant motives are related to improving health and wellbeing. This study contributes to understanding weight management in Portugal, and could be useful in the development of obesity prevention strategies that match the population profile. PMID- 25817504 TI - [Diabetic eye disease]. AB - Diabetes mellitus is a chronic metabolic disease characterized by sustained hyperglycemia leading to macro and microvascular complications. The eye is one of the main organs affected by this disease, being diabetic retinopathy the most well-known microvascular complication and the leading cause of blindness in the working age population. However, diabetic ocular disease is not only characterized by diabetic retinopathy. Other important ocular manifestations of diabetes mellitus include cataract, glaucoma, ischemic optic neuropathy, cranial nerve palsies and recurrent corneal erosion syndrome. Here, we emphasize diabetic retinopathy as the most important and characteristic complication of diabetes mellitus, but also review less well-known complications with the aim to alert and sensitize non-ophthalmologist clinicians that treat diabetic individuals, in order to promote an early diagnosis and treatment of the sight-threatening complications of diabetes. PMID- 25817503 TI - [Evaluation of hearing in patients with multiresistant tuberculosis]. AB - INTRODUCTION: Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis constitute a major threat to worldwide tuberculosis control. The treatment demands the use of a therapeutic regimen in second-line drugs for a minimum period of 20 months, which includes aminoglycosides over a period of about eight months. These are associated with permanent cochleovestibular changes. MATERIAL AND METHODS: This cross-sectional study aims to evaluate the auditory function in individuals who completed treatment for multidrug-resistant tuberculosis (with scheme that included aminoglycosides) at the Center of Regional Reference for multidrug-resistant tuberculosis located in the North of Portugal, between the years 2009 and 2012. Patients who met the inclusion criteria were submitted to tonal and vocal audiograms, otoacoustic emissions at 2000-5000 Hz frequencies, and a tympanogram. RESULTS: Between 2009 and 2012, 27 patients were referred to the Centre of Regional Reference for multidrug resistant tuberculosis, in the North Region of Portugal, resulting in five deaths. Of the 22 individuals invited, 11 attended. These were aged between 31 and 59 years (41 +/- 10). Amikacin was used in 80% of patients. Six patients (60%) had sensorineural hearing loss. DISCUSSION/CONCLUSION: The results of this study suggest the need for a more frequent audiological monitoring in patients with multidrug-resistant tuberculosis treated with aminoglycosides allowing early detect hearing loss. PMID- 25817505 TI - A rare abdomino-pelvic tumor: paraganglioma. AB - Paragangliomas are rare tumors, with a reported incidence of 2-8 per million. They are chromaffin cell tumors that develop from the neural crest cells and may be divided in tumors derived from the parasympathetic or sympathetic ganglia. We report a case a of a 32-year-old nulliparous woman, referred to our Infertility Clinic. Abdomino-pelvic ultrasound identified a large abdominopelvic tumor, without ovarian origin (both ovaries were identified and had normal morphology). Magnetic Resonance Imaging suggested a right adnexal multicystic, vascularized mass close to iliac vessels and questioning an ovarian origin. At exploratory laparotomy, a 10 cm encapsulated and vascularized mass was found beginning just below right renal artery and extending to the level of the broad ligament. This mass was totally excised and histopathology was consistent with Paraganglioma. PMID- 25817506 TI - [Primary meningococcal septic arthritis in a two month old infant]. AB - Meningococcal septic arthritis, ocurring without signs of sepsis, is rare, including at pediatric age. The confinement of infection to a single articulation (monoarticular form) is even rarer in infections by Neisseria spp. We discuss the case of a two month-old caucasian girl, presenting with fever and persistent crying during nappy change. Absence of clinical sepsis was notable. She had had no previous anti-meningococcal immunizations. The ultrasound of the left hip revealed the presence of intra-articular fluid. Culture of the purulent sample after drainage by arthrotomy produced Neisseria meningitidis. She had a good clinical response to the antibiotics. Follow-up showed no sequels. Albeit a rare entity, primary meningococcal arthritis is a mandatory differential diagnosis concerning a feverish child with articular complaints. PMID- 25817507 TI - Secondary rhinoplasty using the technique of Turkish Delight: a case report and a brief review of the literature. AB - Rhinoplasty is a demanding task, especially when augmentation of the nasal contour is required. Autologous cartilage grafts are challenging. Contour and alignment of the graft are difficult goals. It is presented a case of a successfully nasal dorsum augmentation in a secondary rhinoplasty with the Turkish Delight technique and a brief review of literature. A 33-years-old female, with history of complete unilateral cleft nasal deformity on the right, and severe nasal deformity, previously submitted to other procedures, was referred to our Center. As she presented a visible cartilage graft, it was decided to perform the Turkish Delight technique. The autograft was effective for increasing of the nasal dorsum, at four years post-operative. There was no evidence of extrusion. The patient is satisfied with the result. The technique is effective in the reconstruction of complex dimorphism of the nasal dorsum, particularly in secondary rhinoplasty. PMID- 25817508 TI - [Oral lipoma]. PMID- 25817509 TI - Pneumoperitoneum, pneumomediastinum and subcutaneous emphysema following diagnostic colonoscopy. PMID- 25817510 TI - [Bacteriuria and leukocyturia in pediatric urinary tract infections: a comment on the national guideline]. PMID- 25817511 TI - [Loneliness and mental health]. PMID- 25817512 TI - A Peruvian family with a novel PARK2 mutation: Clinical and pathological characteristics. AB - BACKGROUND: Mutations in PARK2 result in autosomal recessive young onset Parkinson's disease (YOPD). Although there have been a number of reports on the clinical characteristics of PARK2-related PD, there is limited information available on the associated neuropathologic changes. DESIGN: We describe the clinical and pathological characteristics of a Peruvian family with YOPD. The proband and one unaffected sibling were screened for PARK2 dosage and point mutations. One affected sibling had detailed neuropathologic examination. SETTING: Instituto Nacional de Ciencias Neurologicas (INCN) in Lima, Peru. RESULTS: The proband and two of her four siblings developed YOPD and both parents were unaffected. The clinical course has been characterized by akinetic-rigid parkinsonism predominantly affecting the lower limbs and dyskinesias. Analysis of PARK2 showed that the proband is compound heterozygous for a novel acceptor splice site mutation in intron 5 (IVS5-1G>A) and an exon 7 deletion. Neuropathologic assessment of an affected sibling revealed severe neuronal loss in the substantia nigra (SN) and loss of tyrosine hydroxylase immunopositive fibers in the striatum. No Lewy body pathology was observed using standard histology or immunohistochemistry for alpha-synuclein. CONCLUSIONS: Consistent with most neuropathologic reports of patients with PARK2 mutations, we did not observe Lewy body inclusions, despite marked SN degeneration and severe dopaminergic denervation of the striatum. These data describe a novel splice site mutation and further extend the clinicopathological characterization of PARK2 associated PD. PMID- 25817513 TI - Genetic markers of Restless Legs Syndrome in Parkinson disease. AB - INTRODUCTION: Several studies proposed that Restless Legs Syndrome (RLS) and Parkinson disease (PD) may be clinically and/or etiologically related. To examine this hypothesis, we aimed to determine whether the known RLS genetic markers may be associated with PD risk, as well as with PD subtype. METHODS: Two case-control cohorts from Tel-Aviv and New-York, including 1133 PD patients and 867 controls were genotyped for four RLS-related SNPs in the genes MEIS1, BTBD9, PTPRD and MAP2K5/SKOR1. The association between genotype, PD risk and phenotype was tested using multivariate regression models. RESULTS: None of the tested SNPs was significantly associated with PD risk, neither in any individual cohort nor in the combined analysis after correction for multiple comparisons. The MAP2K5/SKOR1 marker rs12593813 was associated with higher frequency of tremor in the Tel-Aviv cohort (61.0% vs. 46.5%, p = 0.001, dominant model). However, the risk allele for tremor in this gene has been associated with reduced RLS risk. Moreover, this association did not replicate in Tremor-dominant PD patients from New-York. CONCLUSION: RLS genetic risk markers are not associated with increased PD risk or subtype in the current study. Together with previous genetic, neuropathological and epidemiologic studies, our results further strengthen the notion that RLS and PD are likely to be distinct entities. PMID- 25817515 TI - Parkinson disease: alpha-synuclein mutational screening and new clinical insight into the p.E46K mutation. AB - BACKGROUND: Amongst Parkinson's disease-causing genetic factors, missense mutations and genomic multiplications in the gene encoding alpha-synuclein are well established causes of the disease, although genetic data in populations with a high degree of admixture, such as the Brazilian one, are still scarce. METHODS: In this study, we conducted a molecular screening of alpha-synuclein point mutations and copy number variation in the largest cohort of Brazilian patients with Parkinson's disease (n = 549) and also in twelve Portuguese and one Bolivian immigrants. Genomic DNA was isolated from peripheral blood leukocytes or saliva, and the mutational screening was performed by quantitative and qualitative real time PCR. RESULTS: The only alteration identified was the p.E46K mutation in a 60 year-old man, born in Bolivia, with a familial history of autosomal dominant Parkinson's disease. This is the second family ever reported, in which this rare pathogenic mutation is segregating. The same mutation was firstly described ten years ago in a Spanish family with a neurodegenerative syndrome combining parkinsonism, dementia and visual hallucinations. The clinical condition of our proband reveals a less aggressive phenotype than previously described and reinforces that marked phenotypic heterogeneity is common among patients with Parkinson's disease, even among those carriers sharing the same mutation. CONCLUSION: Our findings add new insight into the preexisting information about alpha-synuclein p.E46K, improving our understanding about the endophenotypes associated to this mutation and corroborate that missense alterations and multiplications in alpha-synuclein are uncommon among Brazilian patients with Parkinson's disease. PMID- 25817514 TI - Morphologic changes in the mesolimbic pathway in Parkinson's disease motor subtypes. AB - BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder associated with gray matter atrophy. Cortical atrophy patterns may further help distinguish between PD motor subtypes. Comparable differences in subcortical volumes have not been found. METHODS: Twenty-one cognitively intact and treated PD patients, including 12 tremor dominant (TD) subtype, Nine postural instability gait dominant (PIGD) subtype, and 20 matched healthy control subjects underwent 3.0 T high-resolution structural MRI scanning. Subcortical volumetric analysis was performed using FreeSurfer and shape analysis was performed with FIRST to assess for differences between PD patients and controls and between PD subtypes. RESULTS: No significant differences in subcortical volumes were found between motor PD subtypes, but comparing grouped PD patients with controls revealed a significant increase in hippocampal volume in PD patients (p = 0.03). A significant shape difference was detected in the right nucleus accumbens (NAcc) between PD and controls and between motor subtypes. Shape differences were driven by positive deviations in the TD subtype. Correlation analysis revealed a trend between hippocampal volume and decreasing MDS-UPDRS (p = 0.06). CONCLUSION: While no significant differences in subcortical volumes between PD motor subtypes were found, increased hippocampal volumes were observed in PD patients compared to controls. Right NAcc shape differences in PD patients were driven by changes in the TD subtype. These unexpected findings may be related to the effects of chronic dopaminergic replacement on the mesolimbic pathway. Further studies are needed to replicate and determine the clinical significance of such morphologic changes. PMID- 25817516 TI - Conservative management of a post-traumatic pseudoaneurysm of the artery of cervical enlargement-anterior spinal artery junction. AB - A 22-year-old man suffered severe sudden onset head and neck pain after being pushed from behind during an assault. Physical examination was normal. Cervical MRI demonstrated an intradural hematoma, anterior to the cord, between C2-4. Subsequent contrast enhanced MR angiography and digital subtraction vertebral angiography confirmed that the cause of the hemorrhage was a fusiform (presumed dissecting) pseudoaneurysm of the artery of the cervical enlargement at its junction with the anterior spinal artery. The aneurysm was managed conservatively. Follow-up angiography demonstrated that the aneurysm had spontaneously thrombosed within 10 days and remained occluded at 2 months. The patient remained occluded at 6 months following the initial injury. Anterior spinal aneurysms represent a management dilemma and options are discussed. PMID- 25817517 TI - Exercise stress testing after stroke or transient ischemic attack: a scoping review. AB - OBJECTIVE: To provide insight into exercise stress testing after stroke or transient ischemic attack (TIA) in terms of feasibility, safety, and protocols used. DATA SOURCES: PubMed, Embase, CINAHL, and Web of Science were searched for relevant studies published from inception to March 2014, and reference lists were hand searched. STUDY SELECTION: To be included in the review, the articles needed to include participants diagnosed with stroke or TIA and have any form of test to assess exercise capacity. DATA EXTRACTION: The scoping review methodology does not include critical appraisal of the literature but was chosen to reflect all aspects of exercise stress testing after stroke or TIA. Two reviewers performed screening for eligible studies independently, and 1 reviewer extracted the data. DATA SYNTHESIS: We found a total of 112 studies involving 5008 participants describing symptom-limited (n=103), submaximal (n=9), and field (n=6) exercise stress test protocols. Some of the studies reported on data from >1 protocol. Metabolic analysis was included in 87% of the studies involving symptom-limited tests, 40% of submaximal studies, and 29% of field tests. Monitoring of blood pressure, perceived exertion, and electrocardiographic responses was done in 54%, 42%, and 95% of all studies, respectively. A mere 10% of all studies reported on electrocardiographic abnormalities detected during testing. No serious adverse events were reported. CONCLUSIONS: Symptom-limited exercise stress testing appears to be safe in patients with stroke or TIA and provides a more valid measure of exercise capacity than submaximal and field tests. The level of disability may compromise feasibility, and test modality should be chosen carefully to optimize test results. PMID- 25817518 TI - Laparoscopic hysterectomy with morcellation vs abdominal hysterectomy for presumed fibroid tumors in premenopausal women: a decision analysis. AB - OBJECTIVE: The purpose of this study was to model outcomes in laparoscopic hysterectomy with morcellation compared with abdominal hysterectomy for the presumed fibroid uterus and to examine short- and long-term complications and death. STUDY DESIGN: A decision tree was constructed to compare outcomes for a hypothetical cohort of 100,000 premenopausal women who underwent hysterectomy for presumed fibroid tumors over a 5-year time horizon. Parameter and quality-of-life utility estimates were determined from published literature for postoperative complications, leiomyosarcoma incidence, death related to leiomyosarcoma, and procedure-related death. RESULTS: The decision-tree analysis predicted fewer overall deaths with laparoscopic hysterectomy compared with abdominal hysterectomy (98 vs 103 per 100,000). Although there were more deaths from leiomyosarcoma after laparoscopic hysterectomy (86 vs 71 per 100,000), there were more hysterectomy-related deaths with abdominal hysterectomy (32 vs 12 per 100,000). The laparoscopic group had lower rates of transfusion (2400 vs 4700 per 100,000), wound infection (1500 vs 6300 per 100,000), venous thromboembolism (690 vs 840 per 100,000) and incisional hernia (710 vs 8800 per 100,000), but a higher rate of vaginal cuff dehiscence (640 vs 290 per 100,000). Laparoscopic hysterectomy resulted in more quality-adjusted life years (499,171 vs 490,711 over 5 years). CONCLUSION: The risk of leiomyosarcoma morcellation is balanced by procedure-related complications that are associated with laparotomy, including death. This analysis provides patients and surgeons with estimates of risk and benefit on which patient-centered decisions can be made. PMID- 25817519 TI - A prediction model for periodontal disease: modelling and validation from a National Survey of 4061 Taiwanese adults. AB - AIMS: The aim of this study was to predict periodontal disease (PD) with demographical features, oral health behaviour, and clinical correlates based on a national survey of periodontal disease in Taiwan. MATERIALS AND METHODS: A total of 4061 subjects who were enrolled in a cross-sectional nationwide survey on periodontal conditions of residents aged 18 years or older in Taiwan between 2007 and 2008 were included. The community periodontal index (CPI) was used to measure the periodontal status at the subject and sextant levels. Information on demographical features and other relevant predictive factors for PD was collected using a questionnaire. RESULTS: In our study population, 56.2% of subjects had CPI grades >=3. Periodontitis, as defined by CPI >=3, was best predicted by a model including age, gender, education, brushing frequency, mobile teeth, gingival bleeding, smoking, and BMI. The area under the curve (AUC) for the final prediction model was 0.712 (0.690-0.734). The AUC was 0.702 (0.665-0.740) according to cross-validation. CONCLUSIONS: A prediction model for PD using information obtained from questionnaires was developed. The feasibility of its application to risk stratification of PD should be considered with regard to community-based screening for asymptomatic PD. PMID- 25817520 TI - Frequency and profile of Parkinson's disease prodromi in patients with malignant melanoma. AB - OBJECTIVE: The results of register studies suggest an association between Parkinson's disease (PD) and melanoma. We studied the frequency and profile of early markers of PD in patients with malignant melanoma. METHODS: 100 participants were enrolled in a prospective observational study, of whom 65 had a history of high-risk cutaneous (n=53) or uveal (n=12) melanoma (31 women; age, 61.2+/-14.9 years) and another 35 served as control participants (19 women; 54.6+/-20.5 years). Participants underwent assessments of motor function (Unified PD Rating Scale; keyboard tapping test), olfactory function, colour vision, depressive symptoms, the Non-Motor Symptoms Questionnaire, and transcranial brain sonography. Raters were blinded to the diagnosis and clinical data of study participants. RESULTS: Patients with melanoma showed increased frequency of substantia nigra hyperechogenicity and prodromal motor and non-motor features of PD, especially asymmetric motor slowing and apathy. Hyposmia and colour vision disturbance were, however, infrequent. Larger echogenicity of substantia nigra correlated with lower serum iron in patients with melanoma, similar to previously reported findings in PD, and independently from the earlier findings, with lighter skin pigmentation. Substantia nigra hyperechogenicity, combined with motor asymmetry or hyposmia, was present at baseline in all participants with mild or definite parkinsonism diagnosed after 1 year. Parkinsonism was specifically related to melanoma location at the sun-exposed skin of the head or neck. CONCLUSIONS: History of melanoma was associated with increased prevalence of prodromal markers of PD. Their predictive value needs to be established in long-term investigations. The similarity of serum iron characteristics found in patients with melanoma and PD deserves further research. PMID- 25817521 TI - Psychosocial correlates, psychological distress, and quality of life in patients with medically unexplained symptoms: a primary care study in Karachi, Pakistan. AB - OBJECTIVE: To examine the psychosocial correlates and association of psychological distress and quality of life (QOL) in patients with medically unexplained symptoms (MUS) compared to those with medically explained symptoms (MES) in a primary care setting in Karachi, Pakistan. METHODS: A cross-sectional study of 472 patients attending GP clinics between March and August 2009 in Karachi. Participants completed questionnaires to assess demographic details, somatic symptoms, anxiety, depression, and QOL. The patients' GP recorded whether the presenting complaint was medically unexplained or medically explained. RESULTS: MUS subjects in our study were more educated, had better social support and fewer financial problems, were less depressed and had a better QOL than subjects who had medically explained symptoms (non-MUS). Both groups (MUS and non MUS) were comparable in terms of anxiety and number of somatic symptoms, but non MUS subjects were more depressed than the MUS group. In a regression analysis, the number of somatic symptoms and lower levels of anxiety predicted poorer QOL in this sample. Whether these symptoms were medically explained (or not) did not seem to contribute significantly to the QOL. CONCLUSION: Our findings confirm that even in the developing world, patients with MUS are common among primary care attendees. However, patients with MUS in urban Karachi, Pakistan may differ from Western MUS subjects in the role of stress, support, and anxiety in their presentation, and may be reflective of a conceptually different group of difficulties. PMID- 25817522 TI - Depression and CD4 cell count among patients with HIV in a Nigerian University Teaching Hospital. AB - OBJECTIVE: Depression is common in people living with HIV/AIDS and there is some evidence that depressive symptoms may have adverse effects on immune functioning. The purpose of this study was to determine the prevalence of current depressive disorder in patients with HIV/AIDS and its association with CD4 cell count. METHODS: A consecutive sample of 310 patients with HIV/AIDS attending Out-patient clinic in Ahmadu Bello University Teaching Hospital (A.B.U.T.H.), Zaria, Nigeria was assessed. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to screen for depressive symptoms, and the Schedule for Clinical Assessment in Neuropsychiatry (SCAN) was used to confirm the diagnosis of current depressive disorder. The CD4 cell counts of participants with depressive disorder were compared with those of participants without depressive disorder. Multiple regression analysis was conducted to identify socio-demographic and disease related factors associated with depression. RESULTS: Among the 310 HIV-infected participants assessed for depression, 14.2% had current depressive disorder. Adjusting for age, gender, education, occupation, and marital status, patients with CD4 counts < 150 cells/MUl were more likely to be depressed. CONCLUSION: Depression is common among HIV-infected persons in Nigeria and is associated with low CD4 cell counts. The screening and treatment of mental health problems such as depression should be considered an integral component of HIV care and support. PMID- 25817523 TI - Depressive symptoms and type 2 diabetes mellitus in rural appalachia: an 18-month follow-up study. AB - OBJECTIVE: Despite high rates of diabetes and depression in rural areas, limited data exists to document patterns and predictors of depressive symptoms in rural patients with type 2 diabetes (T2DM). The purpose of this study was to assess the rates and predictors of co-morbid depressive symptoms over an 18-month period in a cohort of rural Appalachian adults with T2DM. METHODS: N = 100 adult T2DM patients were recruited from family medicine and endocrinology practices located in the rural Appalachian counties of southeastern Ohio and West Virginia. Data were collected using a longitudinal observational survey design. RESULTS: The sample consisted of predominantly White (93%) females (62%) who were married (71%), completed high school or less (48%), and had a mean age of 60 years (SD 11). Mean BDI score was 14.0 (SD 12) with 27% scoring in the moderate/severe range for depressive symptoms. A majority of patients (77%) reported depressive symptoms, at both time points, with 88% of these reporting consistent depressive symptoms in the year prior to study follow-up. Patients with depressive symptoms at Time 1 and Time 2 did not differ from other groups in the number of treatment strategies or medications used. Predictors of depressive symptoms in this group were increased diabetes treatment complexity (OR = 2.3), lack of home ownership (OR = 11.4), and decreased satisfaction with antidepressant medications (OR = 2.0; chi(2) = 28.9, p < .0001). CONCLUSIONS: Rural T2DM patients reported high rates of repeated depressive symptoms without corresponding rates of depression treatment. These patients may benefit from close monitoring and ongoing adjustment of their treatment for depression and diabetes by primary care providers. PMID- 25817524 TI - Understanding preventive health screening services use in persons with serious mental illness: how does integrated behavioral health primary care compare? AB - OBJECTIVE: People with serious mental illness have reduced life expectancy, in large part due to reduced access to medical services and underutilization of preventive health services. This is a cross-sectional study that compared preventive services use in an integrated behavioral health primary care clinic (IBHPC) with two existing community mental health programs. METHODS: Participants completed questionnaires about preventive health services use that contained 33 questions about demographic clinical information, and use of preventive health services, from October 2010 to December 2012. Services examined included mammogram, Papanicolaou Test, prostate specific antigen, digital rectal exam, fecal occult blood test, and flexible sigmoidoscopy or colonoscopy; blood pressure, height and weight, cholesterol, and blood sugar for diabetes; and influenza immunization, Hepatitis C Virus (HCV), and Human Immunodeficiency Virus (HIV) antibodies. A health service utilization score was developed and used as primary outcome for data analyses. RESULTS: In the multivariate analyses female gender (p < 0.05), race/ethnicity (p = 0.01 for Asian, p = 0.04 for Hispanic/Latino, both compared to White), program type (p < 0.001), and having a primary care provider (p < 0.001) were significant predictors of higher services use. IBHPC was associated with higher overall service utilization compared to one community mental health program (p < 0.001) but was similar when compared another (p = 0.34). There was high variability in use of individual services among the clinical programs. CONCLUSION: More studies are needed to examine the effectiveness of integrated care in improving use of health screening services. Characteristics of the clinic in relation to use of preventive services deserve further study. PMID- 25817525 TI - Religious involvement, suicidal ideation and behavior in mainland China. AB - OBJECTIVE: Little is known about relations between religious involvement and suicidal behaviors in mainland China. This study aims to examine the association between religious involvement and suicidal ideation, planning, and attempts within a general community population controlling for socio-demographic, physical, and mental health factors. METHOD: Data were examined from a population based sample of 2,769 community-dwelling adults in the province of Ningxia China, where nearly 40% are Muslim, 11% other religious affiliations, and 49% no religion. Four separate logistic regression models examined correlations between religious involvement and self-reported suicidal thoughts, plans, and attempts. Analyses were also stratified by Muslim affiliation (n = 1103) and no religion (n = 1,366). RESULTS: Bivariate analyses in the overall sample demonstrated that higher personal religiosity scores (chi(2) = 6.8, p < 0.01) and total religiosity scores (chi(2) = 5.1, p < 0.05) were positively correlated with developing a suicidal plan, which disappeared after controlling for demographic characteristics. Otherwise, no significant correlations were found between any religious characteristic and suicidal ideation, plan, or attempt in either Muslims or those with no religion. CONCLUSIONS: In contrast to most previous studies, religious involvement plays less of a role in suicidal behaviors in at least one province of mainland China. PMID- 25817526 TI - Neurochemical alterations associated with borderline personality disorder. AB - In neuroimaging on borderline personality disorder, prior studies focused on the hippocampus and amygdala, as mentioned above. However, no study investigated whether there were neurochemical changes in the patients with borderline personality disorder. Therefore, in the present study, we aimed to investigate neurochemical change of patients diagnosed with borderline disorder and hypothesized that neurochemicals would change in the hippocampus region of these patients. Seventeen patients and the same number of healthy control subjects were analyzed by using a 1.5 Tesla GE Signa Imaging System. N-acetylaspartate (NAA), choline compounds (CHO), and creatine (CRE) values of hippocampal region were measured. The mean NAA/CRE ratio in the hippocampus region was significantly reduced in the patients with borderline personality disorder compared to that of healthy control subjects, In addition, NAA/CHO ratio of the patients with borderline personality disorder was also significantly reduced when compared to that of healthy subjects. There was no difference in the ratio of CHO/CRE. In summary, we present evidence for reduced NAA in the patients with borderline personality disorder. PMID- 25817527 TI - Current and future trends in electronic cigarette use. AB - The controversy regarding the use of electronic cigarettes as a possible modality for smoking cessation has grown in recent years. Epidemiologic surveys indicate that usage rates in both adults and adolescents have increased substantially as the popularity of these devices continues to rise. At present, there is a small but growing body of evidence studying the possible role that these "e-cigarettes" may have as a nicotine replacement tool. Much of the existing data are from observational studies and surveys which track the epidemiologic and demographic trends of e-cigarette users. More recently-published articles have begun to utilize randomized, experimental designs to directly compare the efficacy of e cigarettes to active and passive controls in outcome measures such as conventional cigarette quit rates and time to relapse. Barriers to widespread adoption of e-cigarette use as a smoking cessation modality include a lack of long-term safety and toxicology data, a lack of standardization of devices, and a debate regarding whether devices can be marketed for both social nicotine use, as well as nicotine replacement. A possible role of e-cigarettes that has not yet been explored is in the primary prevention of conventional cigarette use among young adults that are smoking-naive. PMID- 25817529 TI - Quantitative Ultrasonic Nakagami Imaging of Neck Fibrosis After Head and Neck Radiation Therapy. AB - PURPOSE: To investigate the feasibility of ultrasound Nakagami imaging to quantitatively assess radiation-induced neck fibrosis, a common sequela of radiation therapy (RT) to the head and neck. METHODS AND MATERIALS: In a pilot study, 40 study participants were enrolled and classified into 3 subgroups: (1) a control group of 12 healthy volunteers; (2) an asymptomatic group of 11 patients who had received intensity modulated RT for head and neck cancer and had experienced no neck fibrosis; and (3) a symptomatic group of 17 post-RT patients with neck fibrosis. Each study participant underwent 1 ultrasound study in which scans were performed in the longitudinal orientation of the bilateral neck. Three Nakagami parameters were calculated to quantify radiation-induced tissue injury: Nakagami probability distribution function, shape, and scaling parameters. Physician-based assessments of the neck fibrosis were performed according to the Radiation Therapy Oncology Group late morbidity scoring scheme, and patient-based fibrosis assessments were rated based on symptoms such as pain and stiffness. RESULTS: Major discrepancies existed between physician-based and patient-based assessments of radiation-induced fibrosis. Significant differences in all Nakagami parameters were observed between the control group and 2 post-RT groups. Moreover, significant differences in Nakagami shape and scaling parameters were observed among asymptomatic and symptomatic groups. Compared with the control group, the average Nakagami shape parameter value increased by 32.1% (P<.001), and the average Nakagami scaling parameter increased by 55.7% (P<.001) for the asymptomatic group, whereas the Nakagami shape parameter increased by 74.1% (P<.001) and the Nakagami scaling parameter increased by 83.5% (P<.001) for the symptomatic group. CONCLUSIONS: Ultrasonic Nakagami imaging is a potential quantitative tool to characterize radiation-induced asymptomatic and symptomatic neck fibrosis. PMID- 25817530 TI - Mapping (15)O production rate for proton therapy verification. AB - PURPOSE: This work was a proof-of-principle study for the evaluation of oxygen-15 ((15)O) production as an imaging target through the use of positron emission tomography (PET), to improve verification of proton treatment plans and to study the effects of perfusion. METHODS AND MATERIALS: Dynamic PET measurements of irradiation-produced isotopes were made for a phantom and rabbit thigh muscles. The rabbit muscle was irradiated and imaged under both live and dead conditions. A differential equation was fitted to phantom and in vivo data, yielding estimates of (15)O production and clearance rates, which were compared to live versus dead rates for the rabbit and to Monte Carlo predictions. RESULTS: PET clearance rates agreed with decay constants of the dominant radionuclide species in 3 different phantom materials. In 2 oxygen-rich materials, the ratio of (15)O production rates agreed with the expected ratio. In the dead rabbit thighs, the dynamic PET concentration histories were accurately described using (15)O decay constant, whereas the live thigh activity decayed faster. Most importantly, the (15)O production rates agreed within 2% (P>.5) between conditions. CONCLUSIONS: We developed a new method for quantitative measurement of (15)O production and clearance rates in the period immediately following proton therapy. Measurements in the phantom and rabbits were well described in terms of (15)O production and clearance rates, plus a correction for other isotopes. These proof-of-principle results support the feasibility of detailed verification of proton therapy treatment delivery. In addition, (15)O clearance rates may be useful in monitoring permeability changes due to therapy. PMID- 25817532 TI - A systematic study of temperature sensitive liposomal delivery of doxorubicin using a mathematical model. AB - BACKGROUND: Temperature-sensitive liposomes (TSL) in combination with hyperthermia (HT) exposure have emerged as a potentially attractive option to achieve therapeutic drug concentration at targeted tumour site while reducing adverse side effects associated with systemic administration of anticancer drugs. The aim of this study is to elucidate the interplay among different kinetic steps by means of computational modelling. METHODS: A multi-compartment model for TSL mediated delivery of doxorubicin (DOX) is developed, which incorporates descriptions of the pharmacokinetics of TSL and DOX, and their accumulation in tumour tissue following intravascular triggered release. By examining dynamic interactions among TSL properties, tumour physiological properties and treatment regimen, peak intracellular DOX concentration is predicted for continuous and pulse HT exposures. RESULTS: Drug release rate from TSL has a saturable effect on peak intracellular drug concentration, and no further gain could be achieved for release rates greater than 0.1018 s(-1). A similar effect has also been found for heating duration, such that for a given bolus injection, peak intracellular drug concentration reaches its maximum and then levels off after HT duration of 2h. These results suggest that both TSL release rate and HT duration can be optimised in accordance with other parameters, e.g. clearance rate of TSL and administration mode, in order to achieve a desirable level of intracellular drug concentration. However, prolonged heating is not effective for resistant tumour cells with overexpression of ABC (ATP-binding cassette) transporter proteins. CONCLUSIONS: The results obtained in this study can be used to guide the design and optimisation of TSL parameters and treatment regimens. PMID- 25817531 TI - Clinical validation of 4-dimensional computed tomography ventilation with pulmonary function test data. AB - PURPOSE: A new form of functional imaging has been proposed in the form of 4 dimensional computed tomography (4DCT) ventilation. Because 4DCTs are acquired as part of routine care for lung cancer patients, calculating ventilation maps from 4DCTs provides spatial lung function information without added dosimetric or monetary cost to the patient. Before 4DCT-ventilation is implemented it needs to be clinically validated. Pulmonary function tests (PFTs) provide a clinically established way of evaluating lung function. The purpose of our work was to perform a clinical validation by comparing 4DCT-ventilation metrics with PFT data. METHODS AND MATERIALS: Ninety-eight lung cancer patients with pretreatment 4DCT and PFT data were included in the study. Pulmonary function test metrics used to diagnose obstructive lung disease were recorded: forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity. Four-dimensional CT data sets and spatial registration were used to compute 4DCT-ventilation images using a density change-based and a Jacobian-based model. The ventilation maps were reduced to single metrics intended to reflect the degree of ventilation obstruction. Specifically, we computed the coefficient of variation (SD/mean), ventilation V20 (volume of lung <=20% ventilation), and correlated the ventilation metrics with PFT data. Regression analysis was used to determine whether 4DCT ventilation data could predict for normal versus abnormal lung function using PFT thresholds. RESULTS: Correlation coefficients comparing 4DCT ventilation with PFT data ranged from 0.63 to 0.72, with the best agreement between FEV1 and coefficient of variation. Four-dimensional CT ventilation metrics were able to significantly delineate between clinically normal versus abnormal PFT results. CONCLUSIONS: Validation of 4DCT ventilation with clinically relevant metrics is essential. We demonstrate good global agreement between PFTs and 4DCT-ventilation, indicating that 4DCT-ventilation provides a reliable assessment of lung function. Four-dimensional CT ventilation enables exciting opportunities to assess lung function and create functional avoidance radiation therapy plans. The present work provides supporting evidence for the integration of 4DCT-ventilation into clinical trials. PMID- 25817533 TI - Median prior constrained TV algorithm for sparse view low-dose CT reconstruction. AB - It is known that lowering the X-ray tube current (mAs) or tube voltage (kVp) and simultaneously reducing the total number of X-ray views (sparse view) is an effective means to achieve low-dose in computed tomography (CT) scan. However, the associated image quality by the conventional filtered back-projection (FBP) usually degrades due to the excessive quantum noise. Although sparse-view CT reconstruction algorithm via total variation (TV), in the scanning protocol of reducing X-ray tube current, has been demonstrated to be able to result in significant radiation dose reduction while maintain image quality, noticeable patchy artifacts still exist in reconstructed images. In this study, to address the problem of patchy artifacts, we proposed a median prior constrained TV regularization to retain the image quality by introducing an auxiliary vector m in register with the object. Specifically, the approximate action of m is to draw, in each iteration, an object voxel toward its own local median, aiming to improve low-dose image quality with sparse-view projection measurements. Subsequently, an alternating optimization algorithm is adopted to optimize the associative objective function. We refer to the median prior constrained TV regularization as "TV_MP" for simplicity. Experimental results on digital phantoms and clinical phantom demonstrated that the proposed TV_MP with appropriate control parameters can not only ensure a higher signal to noise ratio (SNR) of the reconstructed image, but also its resolution compared with the original TV method. PMID- 25817534 TI - Automatic detection of atrial fibrillation using stationary wavelet transform and support vector machine. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, and a major public health burden associated with significant morbidity and mortality. Automatic detection of AF could substantially help in early diagnosis, management and consequently prevention of the complications associated with chronic AF. In this paper, we propose a novel method for automatic AF detection. METHOD: Stationary wavelet transform and support vector machine have been employed to detect AF episodes. The proposed method eliminates the need for P-peak or R-Peak detection (a pre-processing step required by many existing algorithms), and hence its performance (sensitivity, specificity) does not depend on the performance of beat detection. The proposed method has been compared with those of the existing methods in terms of various measures including performance, transition time (detection delay associated with transitioning from a non-AF to AF episode), and computation time (using MIT-BIH Atrial Fibrillation database). RESULTS: Results of a stratified 2-fold cross-validation reveals that the area under the Receiver Operative Characteristics (ROC) curve of the proposed method is 99.5%. Moreover, the method maintains its high accuracy regardless of the choice of the parameters' values and even for data segments as short as 10s. Using the optimal values of the parameters, the method achieves sensitivity and specificity of 97.0% and 97.1%, respectively. DISCUSSION: The proposed AF detection method has high sensitivity and specificity, and holds several interesting properties which make it a suitable choice for practical applications. PMID- 25817535 TI - Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. AB - Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans. PMID- 25817536 TI - Lack of sterol regulatory element binding factor-1c imposes glial Fatty Acid utilization leading to peripheral neuropathy. AB - Myelin is a membrane characterized by high lipid content to facilitate impulse propagation. Changes in myelin fatty acid (FA) composition have been associated with peripheral neuropathy, but the specific role of peripheral nerve FA synthesis in myelin formation and function is poorly understood. We have found that mice lacking sterol regulatory element-binding factor-1c (Srebf1c) have blunted peripheral nerve FA synthesis that results in development of peripheral neuropathy. Srebf1c-null mice develop Remak bundle alterations and hypermyelination of small-caliber fibers that impair nerve function. Peripheral nerves lacking Srebf1c show decreased FA synthesis and glycolytic flux, but increased FA catabolism and mitochondrial function. These metabolic alterations are the result of local accumulation of two endogenous peroxisome proliferator activated receptor-alpha (Pparalpha) ligands, 1-palmitoyl-2-oleyl-sn-glycerol-3 phosphatidylcholine and 1-stearoyl-2-oleyl-sn-glycerol-3-phosphatidylcholine. Treatment with a Pparalpha antagonist rescues the neuropathy of Srebf1c-null mice. These findings reveal the importance of peripheral nerve FA synthesis to sustain myelin structure and function. PMID- 25817538 TI - Factors influencing individual variability in high fat diet-induced weight gain in out-bred MF1 mice. AB - Easy access to high-energy palatable foods has been suggested to have contributed to the world-wide obesity epidemic. However, within these 'obesogenic' environments many people manage to remain lean. Mice also show variability in their weight gain responses to high-fat diet (HFD) feeding and their weight loss responses to calorically restricted (CR) feeding. In this study we investigated which factors contribute to determining susceptibility to HFD-induced obesity in mice, and whether the responses in weight gain on HFD are correlated with the responses to CR. One-hundred twenty four mice were exposed to 30% CR for 28days followed by a 14day recovery period, and subsequent exposure to 60% HFD for 28days. Responses in various metabolic factors were measured before and after each exposure (body mass; BM, body composition, food intake; FI, resting metabolic rate; RMR, physical activity, body temperature and glucose tolerance; GT). Weight changes on HFD ranged from -1 to 26%, equivalent to -0.2g to 10.5g in absolute mass. Multiple regression models showed that fat free mass (FFM) of the mice before exposure to HFD predicted 12% of the variability in weight gain on HFD (p<0.001). Also, FI during the first week of HFD feeding predicted 20% of the variability in BM and fat mass (FM) gain 4weeks later. These data may point to a role for the reward system in driving individual differences in FI and weight gain. Weight gain on the HFD was significantly negatively correlated to weight loss on CR, indicating that animals that are poor at defending against weight gain on HFD, were also poor at defending against CR-induced weight loss. Changes in FM and FFM in response to HFD or CR were not correlated however. PMID- 25817537 TI - Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice. AB - Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro-inflammatory cytokines interleukin 1beta (IL-1beta) and interleukin 18 (IL-18) via activation of caspase-1/11. Previously, it was shown that complete caspase-1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage-specific caspase-1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase-1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase-1/11 activation to atherosclerosis development, Ldlr(-/-) mice received a transplant (tp) of wild-type (WT) or caspase-1/11(-/-) bone marrow, to create WT-tp mice and caspase-1/11(-/-) -tp mice, and fed a high-fat, high-cholesterol diet for 12 weeks. Our results showed an increase in anti inflammatory blood leukocytes in caspase-1/11(-/-) -tp mice compared with WT-tp mice, as indicated by a decreased level of Ly6C(high) monocytes and an increased level of Ly6C(low) monocytes. In line with our hypothesis, hematopoietic deletion of caspase-1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase-1/11(-/ ) -tp mice. Our data indicate that hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression. PMID- 25817539 TI - Stereotaxic atlas of the goat brain for an accurate approach to the hypothalamic nuclei. AB - While the external acoustic meatus of mice, rats and cats are at right angles to the side of the head, they are angled forward in ruminants. Because of this, the coordinates of stereotaxic atlases created using the same methods as for small animals were not suitable for practical use and made it very difficult to place electrodes in hypothalamic nuclei. The aim of this study was to produce a highly accurate stereotaxic atlas for goats that enables precise placement of electrodes in the hypothalamic nuclei. A method of fixing the head in place so as to maintain the basis cranii interna in a horizontal position was established allowing right angled three dimensional axes to be superimposed in the brains of Japanese Saanen goats. This research attempted to establish a new landmark alternative to the external acoustic meatus. The new landmark is the extremitas posterior clivus presphenoidale (EPCP) at the base of cranial bone. This landmark can easily be visualized through lateral radiography. This enabled the AP (anterior-posterior) and H (height) coordinates of the position to be fixed at 30 and 5, respectively. The A30 and H5 coordinates of the serial frontal, sagittal, and horizontal stereotaxic atlases in the present experiment were set to coincide with the position of the EPCP. In order to clarify whether the deviation of the stereotaxic brain coordinates due to inconsistent immobilization the goat's head was eliminated, the AP and H coordinates of the extremitas anterior fossa hypophysialis and the extremitas posterior fossa hypophysialis were measured using the corrected axes. In the three dimensional stereotaxic atlas created using the new landmark, it became possible to approach the hypothalamic nuclei of goats accurately. This method significantly differentiates the stereotaxic atlas from its predecessors. PMID- 25817540 TI - The clinical characteristics and prognosis of IGH deletion in multiple myeloma. AB - OBJECTIVE: To analyze the frequency, clinical characteristics, and prognosis of IGH deletion in multiple myeloma (MM). METHODS: A total of 310 consecutive patients with multiple myeloma were analyzed. Among them 251 patients were newly diagnosed and 59 patients were previously treated, fluorescence in situ hybridization (FISH) with IGH break apart probes were done for each case. Patterns of IGH deletion, response rate, overall survival, and progression free survival were analyzed. RESULTS: Several patterns of IGH deletion were identified, including monoallelic deletion of whole locus of IGH, monoallelic deletion of 3' IGH, monoallelic deletion of 5' IGH, biallelic deletion of 3' IGH deletion, and complicated deletions with various types. The incidence rate of IGH deletion was 22.7% (57/251) in newly diagnosed patients and 27.2% (16/59) in previously treated patients, no significant difference was found between the two groups (p=0.375). IGH deletion was associated with kappa light chain M component (p<0.001), 13q deletion (p=0.006), and absence of t(4; 14)(p=0.033). In the cases with 13q deletion, the frequency of IGH deletion is 3.5% (1/28) in patients with t(4;14) and 40.5% (32/79) in patients without t(4;14), significant difference was found (p=0.006). We further analyzed the response rates of patients with IGH deletion who received a uniform induction regimen of PAD composing of bortezomib, epirubicin, and dexamethasone. Overall response rate (ORR) in patients with IGH deletion was better than that in patients without IGH deletion (87.5 vs. 73.6%, p<0.001), while no significant difference was found in survival analysis, either OS or PFS (p=0.158 and p=0.177, respectively). CONCLUSION: IGH deletion is frequent in multiple myeloma, the incidence rate was higher in patients with 13q deletion and without t(4;14). Patients with IGH deletion had better ORR to PAD induction therapy, while it has no influence on the prognosis of multiple myeloma. PMID- 25817541 TI - The Validation and Reliability of the Chinese Version of the Speech Handicap Index for Patients With Oral and Oropharyngeal Cancer. AB - OBJECTIVES: The purpose of this study was to investigate the validity and reliability of the translated Chinese version of the Speech Handicap Index (SHI) questionnaire for Chinese-speaking patients with oral and oropharyngeal cancer. METHODS: The original English version of the SHI was translated into Chinese. Forty-two consecutive patients with oral and oropharyngeal cancer were included in the study. All subjects were asked to complete the Chinese version of the SHI and the University of Washington Quality of Life Questionnaire (UWQOL V.04). Fifteen patients were randomly retested on both questionnaires 2 weeks later. The internal consistency, test-retest reliability, construct validity, and group validity of the Chinese version of the SHI were tested using Cronbach alpha, Spearman correlation coefficient (r), and Mann-Whitney U tests. Descriptive and bivariate statistics were computed, and the P value was set to 0.05. RESULTS: The Cronbach alpha for the total SHI, the speech domain, and the psychosocial domain were 0.96, 0.90, and 0.92, respectively. The test-retest reliability scores for the total SHI, the speech domain, the psychosocial domain, and the overall question were 0.94, 0.97, 0.90, and 0.83, respectively. To measure construct validity, Spearman correlation coefficients between different items of the SHI and the UWQOL were all >0.4, which signified a moderate to significant correlation. There were significant differences between patient groups when divided by age, clinical stage, educational level, radiotherapy, and reconstruction, on all or on parts of the various SHI domains. CONCLUSIONS: The Chinese version of the SHI is a valid and reliable tool for the speech assessment of patients with oral and oropharyngeal cancer. PMID- 25817543 TI - The let-7g microRNA promotes follicular granulosa cell apoptosis by targeting transforming growth factor-beta type 1 receptor. AB - The intronic microRNA let-7g controls cell differentiation and proliferation during angiogenesis and oncogenesis. Here, we demonstrate that let-7g regulates granulosa cell (GC) apoptosis and follicular atresia in the pig ovary. Bioinformatics analyses and luciferase reporter assays showed that transforming growth factor-beta type 1 receptor (TGFBR1) is a let-7g target. Overexpression of let-7g induced apoptosis of porcine GCs in vitro and repressed the mRNA and protein levels of TGFBR1, as well as the level of phosphorylated SMAD3 (p-SMAD3) protein. RNA interference-mediated knockdown of TGFBR1 and inhibitor LY2157299 mediated blocking of TGFBR1 significantly increased the rate of apoptosis of GCs and Caspase-3 activity. In addition, treatment of porcine GCs with TGF-beta1 reduced the level of let-7g and increased the levels of the TGFBR1 mRNA and proteins significantly. Overall, these results demonstrate that let-7g regulates the apoptosis of GCs in the pig ovary by targeting TGFBR1 and down-regulating the TGF-beta signaling pathway. PMID- 25817544 TI - Sixteenth conference on the adrenal cortex (Adrenal 2014), Chicago, Illinois, June 17-20, 2014. PMID- 25817542 TI - Childhood obesity, bone development, and cardiometabolic risk factors. AB - Osteoporosis and obesity are both major public health concerns. It has long been considered that these are distinct disorders rarely found in the same individual; however, emerging evidence supports an important interaction between adipose tissue and the skeleton. Whereas overweight per se may augment bone strength, animal studies suggest that the metabolic impairment that accompanies obesity is detrimental to bone. Obesity during childhood, a critical time for bone development, likely has profound and lasting effects on bone strength and fracture risk. This notion has received little attention in children and results are mixed, with studies reporting that bone strength development is enhanced or impaired by obesity. Whether obesity is a risk factor for osteoporosis or childhood bone health, in general, remains an important clinical question. Here, we will focus on clarifying the controversial relationships between childhood obesity and bone strength development, and provide insights into potential mechanisms that may regulate the effect of excess adiposity on bone. PMID- 25817545 TI - A brief glimpse over the horizon for type 1 diabetes nanotherapeutics. AB - The pace at which nanotherapeutic technology for human disease is evolving has accelerated exponentially over the past five years. Most of the technology is centered on drug delivery which, in some instances, offers tunable control of drug release. Emerging technologies have resulted in improvements in tissue and cell targeting while others are at the initial stages of pairing drug release and drug release kinetics with microenvironmental stimuli or changes in homeostasis. Nanotherapeutics has only recently been adopted for consideration as a prophylaxis/treatment approach in autoimmunity. Herein, we summarize the current state-of-the art of nanotherapeutics specifically for type 1 diabetes mellitus and offer our view over the horizon of where we envisage this modality evolving towards. PMID- 25817546 TI - UV-B induction of the E3 ligase ARIADNE12 depends on CONSTITUTIVELY PHOTOMORPHOGENIC 1. AB - The UV-B inducible ARIADNE12 (ARI12) gene of Arabidopsis thaliana is a member of the RING-between-RING (RBR) family of E3 ubiquitin ligases for which a novel ubiquitination mechanism was identified in mammalian homologs. This RING-HECT hybrid mechanism needs a conserved cysteine which is replaced by serine in ARI12 and might affect the E3 ubiquitin ligase activity. We have shown that under photomorphogenic UV-B, ARI12 is a downstream target of the classical ultraviolet B (UV-B) UV Resistance Locus 8 (UVR8) pathway. However, under high fluence rate of UV-B ARI12 was induced independently of UVR8 and the UV-A/blue light and red/far-red photoreceptors. A key component of several light signaling pathways is Constitutively Photomorphogenic 1 (COP1). Upon UV-B COP1 is trapped in the nucleus through interaction with UVR8 permitting the activation of genes that regulate the biosynthesis of UV-B protective metabolites and growth adaptations. To clarify the role of COP1 in the regulation of ARI12 mRNA expression and ARI12 protein stability, localization and interaction with COP1 was assessed with and without UV-B. We found that COP1 controls ARI12 in white light, low and high fluence rate of UV-B. Furthermore we show that ARI12 is indeed an E3 ubiquitin ligase which is mono-ubiquitinated, a prerequisite for the RING-HECT hybrid mechanism. Finally, genetic analyses with transgenes expressing a genomic pmARI12:ARI12-GFP construct confirm the epistatic interaction between COP1 and ARI12 in growth responses to high fluence rate UV-B. PMID- 25817547 TI - A Hybrid PSO-DEFS Based Feature Selection for the Identification of Diabetic Retinopathy. AB - Diabetic Retinopathy (DR) is an eye disease, which may cause blindness by the upsurge of insulin in blood. The major cause of visual loss in diabetic patient is macular edema. To diagnose and follow up Diabetic Macular Edema (DME), a powerful Optical Coherence Tomography (OCT) technique is used for the clinical assessment. Many existing methods found out the DME affected patients by estimating the fovea thickness. These methods have the issues of lower accuracy and higher time complexity. In order to overwhelm the above limitations, a hybrid approaches based DR detection is introduced in the proposed work. At first, the input image is preprocessed using green channel extraction and median filter. Subsequently, the features are extracted by gradient-based features like Histogram of Oriented Gradient (HOG) with Complete Local Binary Pattern (CLBP). The texture features are concentrated with various rotations to calculate the edges. We present a hybrid feature selection that combines the Particle Swarm Optimization (PSO) and Differential Evolution Feature Selection (DEFS) for minimizing the time complexity. A binary Support Vector Machine (SVM) classifier categorizes the 13 normal and 75 abnormal images from 60 patients. Finally, the patients affected by DR are further classified by Multi-Layer Perceptron (MLP). The experimental results exhibit better performance of accuracy, sensitivity, and specificity than the existing methods. PMID- 25817548 TI - The electrical interplay between proteins and lipids in membranes. AB - All molecular interactions that are relevant to cellular and molecular structures are electrical in nature but manifest in a rich variety of forms that each has its own range and influences on the net effect of how molecular species interact. This article outlines how electrical interactions between the protein and lipid membrane components underlie many of the activities of membrane function. Particular emphasis is placed on spatially localised behaviour in membranes involving modulation of protein activity and microdomain structure. The interactions between membrane lipids and membrane proteins together with their role within cell biology represent an enormous body of work. Broad conclusions are not easy given the complexities of the various systems and even consensus with model membrane systems containing two or three lipid types is difficult. By defining two types of broad lipid-protein interaction, respectively Type I as specific and Type II as more non-specific and focussing on the electrical interactions mostly in the extra-membrane regions it is possible to assemble broad rules or a consensus of the dominant features of the interplay between these two fundamentally important classes of membrane component. This article is part of a special issue entitled: Lipid-protein interactions. PMID- 25817549 TI - Molecular dynamics simulations of GPCR-cholesterol interaction: An emerging paradigm. AB - G protein-coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across cell membranes and represent major targets in the development of novel drug candidates. Membrane cholesterol plays an important role in GPCR structure and function. Molecular dynamics simulations have been successful in exploring the effect of cholesterol on the receptor and a general consensus molecular view is emerging. We review here recent molecular dynamics studies at multiple resolutions highlighting the main features of cholesterol GPCR interaction. Several cholesterol interaction sites have been identified on the receptor that are reminiscent of nonannular sites. These cholesterol hot spots are highly dynamic and have a microsecond time scale of exchange with the bulk lipids. A few consensus sites (such as the CRAC site) have been identified that correspond to higher cholesterol interaction. Interestingly, high plasticity is observed in the modes of cholesterol interaction and several sites have been suggested to have high cholesterol occupancy. We therefore believe that these cholesterol hot-spots are indicative of 'high occupancy sites' rather than 'binding sites'. The results suggest that the energy landscape of cholesterol association with GPCRs corresponds to a series of shallow minima interconnected by low barriers. These specific interactions, along with general membrane effects, have been observed to modulate GPCR organization. Membrane cholesterol effects on receptor structure and organization, that in turn influences receptor cross-talk and drug efficacy, represent a new frontier in GPCR research. This article is part of a Special Issue entitled: Lipid-protein interactions. Guest Editors: Amitabha Chattopadhyay and Jean-Marie Ruysschaert. PMID- 25817550 TI - Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay. AB - Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8MUm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0MUm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non linear dose response curves. PMID- 25817551 TI - [The Ebola virus and nursing student safety: experience of institutional cooperation in simulation training]. PMID- 25817552 TI - Hospital costs associated with nosocomial infections in a pediatric intensive care unit. AB - OBJECTIVE: To estimate the additional cost attributable to nosocomial infection (NI) in a pediatric intensive care unit (PICU) and related factors. METHODS: A prospective cohort study was conducted in all children admitted to the PICU of a tertiary-care pediatric hospital between 2008 and 2009. Descriptive and bivariate analyses were conducted of total direct costs due to PICU stay and medical procedures in patients with and without NI. A log-linear regression model was performed to determine the factors associated with higher total cost. RESULTS: A total of 443 patients were studied and the prevalence of NI was 11.3%. The difference in the median total cost was ?30,791.4 per patient between groups with and without NI. The median cost of PICU length of stay in patients with NI was almost eight times higher than the median cost of patients without NI. In patients with NI, the highest costs related to medical procedures were associated with antibiotics, enteral and parenteral feeding, and imaging tests. In the multivariate model, the factors associated with higher cost were infection, the performance of cardiovascular surgery, urgent admission, a higher pediatric risk mortality score, and the presence of immunosuppression. By contrast, older children and those with surgical admission generated lower cost. CONCLUSIONS: NI was associated with an increase in total cost, which implies that the prevention of these infections through specific interventions could be cost-effective and would help to increase the safety of healthcare systems. PMID- 25817553 TI - Coronary CT angiography for chest pain in pseudoxanthoma elasticum and cardiac intervention management. AB - We describe the case of a rare cause of severe coronary artery disease in a young woman without cardiovascular risk factors. Cardiac CT played an important role in diagnosis and cardiac management including coronary intervention. PMID- 25817554 TI - Phosphate and arsenate removal efficiency by thermostable ferritin enzyme from Pyrococcus furiosus using radioisotopes. AB - Oxo-anion binding properties of the thermostable enzyme ferritin from Pyrococcus furiosus were characterized with radiography. Radioisotopes (32)P and (76)As present as oxoanions were used to measure the extent and the rate of their absorption by the ferritin. Thermostable ferritin proved to be an excellent system for rapid phosphate and arsenate removal from aqueous solutions down to residual concentrations at the picomolar level. These very low concentrations make thermostable ferritin a potential tool to considerably mitigate industrial biofouling by phosphate limitation or to remove arsenate from drinking water. PMID- 25817555 TI - UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice. AB - Irinotecan is a major drug in the treatment of advanced colorectal cancer. Its active form is the SN38 metabolite, which is cleared by the biliary route after glucuronidation by uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). UGT1A1 activity exhibits a wide intersubject variability, in part related to UGT1A1 gene polymorphisms. The present review on the impact of the deficient UGT1A1*28 variant on irinotecan efficacy and toxicity was produced by a French joint workgroup comprising the Group of Clinical Onco-pharmacology (GPCO Unicancer) and the National Pharmacogenetics Network (RNPGx). It clearly emerges that for irinotecan doses at least equal to 180 mg/m(2) , patients homozygous for the UGT1A1*28 allele are at increased risk of developing hematological and/or digestive toxicities. Irinotecan dose reduction is thus recommended in homozygous *28/*28 patients. In addition, this personalized medicine strategy aims to secure high-dose irinotecan administration (>=240 mg/m(2) ) that have proven to be safe in homozygous *1/*1 patients only. The clinical relevance of this test is discussed in terms of treatment efficacy improvement, as increasing the irinotecan dose appears to be safe in patients not bearing a deficient allele. Best execution practices, cost-effectiveness, and result interpretation are discussed with the aim of facilitating the implementation of this analysis in clinical practice. The existence of networks of laboratories performing this test in routine hospital treatment, as in France, offers the prospect of widespread screening, thus guaranteeing equal access to safe treatment and optimized therapy for patients receiving irinotecan-based therapy in advanced colorectal cancer. PMID- 25817556 TI - Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study. AB - Factor XI (FXI)-deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high-risk situations, especially when FXI levels are below 20 IU dL(-1) . HEMOLEVEN is a human plasma derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI-deficient patients in 13 French centres in a 3-year postmarketing study. Forty-four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months-91 years). Basal FXI levels were <1 to 51 IU dL(-1) (median: 5.5); 29 patients were severely FXI-deficient (<20 IU dL(-1) ). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis. PMID- 25817557 TI - Pivotal preclinical trial of the spheroid reservoir bioartificial liver. AB - BACKGROUND & AIMS: The neuroprotective effect of the spheroid reservoir bioartificial liver (SRBAL) was evaluated in a porcine model of drug-overdose acute liver failure (ALF). METHODS: Healthy pigs were randomized into three groups (standard therapy (ST) alone, ST+No-cell device, ST+SRBAL device) before placement of an implantable intracranial pressure (ICP) monitor and a tunneled central venous catheter. One week later, pigs received bolus infusion of the hepatotoxin D-galactosamine and were followed for up to 90h. RESULTS: At 48h, all animals had developed encephalopathy and biochemical changes confirming ALF; extracorporeal treatment was initiated and pigs were observed up to 90h after drug infusion. Pigs treated with the SRBAL, loaded with porcine hepatocyte spheroids, had improved survival (83%, n=6) compared to ST alone (0%, n=6, p=0.003) and No-cell device therapy (17%, n=6, p=0.02). Ammonia detoxification, peak levels of serum ammonia and peak ICP, and pig survival were influenced by hepatocyte cell dose, membrane pore size and duration of SRBAL treatment. Hepatocyte spheroids remained highly functional with no decline in mean oxygen consumption from initiation to completion of treatment. CONCLUSIONS: The SRBAL improved survival in an allogeneic model of drug-overdose ALF. Survival correlated with ammonia detoxification and ICP lowering indicating that hepatocyte spheroids prevented the cerebral manifestations of ALF (brain swelling, herniation, death). Further investigation of SRBAL therapy in a clinical setting is warranted. PMID- 25817558 TI - MicroRNA-221 governs tumor suppressor HDAC6 to potentiate malignant progression of liver cancer. AB - BACKGROUND & AIMS: Most common reason behind changes in histone deacetylase (HDAC) function is its overexpression in cancer. However, among HDACs in liver cancer, HDAC6 is uniquely endowed with a tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered. METHODS: Microarray profiling and target prediction programs were used to identify miRNAs targeting HDAC6. A series of inhibitors, activators and siRNAs was introduced to validate regulatory mechanisms for microRNA-221-3p (miR-221) governing HDAC6 in hepatocarcinogenesis. RESULTS: Comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs that are significantly upregulated in hepatocellular carcinoma (HCC). While miR-221 was identified as a suppressor of HDAC6 by ectopic expression of miRNA mimics in Dicer knockdown cells, targeted disruption of miR-221 repressed cancer cell growth through derepressing HDAC6 expression. Suppression of HDAC6 via miR-221 was induced by JNK/c-Jun signaling in liver cancer cells but not in normal hepatic cells. Additionally, cytokine induced NF-kappaBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in HCC cells. HCC tissues derived from chemical-induced rat and H ras12V transgenic mice liver cancer models validated that JNK/c-Jun activation and NF-kappaBp65 nuclear translocation are essential for the transcription of miR 221 leading to repression of HDAC6 in HCC. CONCLUSIONS: Our findings suggest that the functional loss or suppression of the tumor suppressor HDAC6 is caused by induction of miR-221 through coordinated JNK/c-Jun- and NF-kappaB-signaling pathways during liver tumorigenesis, providing a novel target for the molecular treatment of liver malignancies. PMID- 25817559 TI - Racial variation in the clinical and economic burden of skeletal-related events among elderly men with stage IV metastatic prostate cancer. AB - Prostate cancer (PCa) outcomes vary widely among African American (AA) and non Hispanic White (NHW) men. The authors investigated racial variation in the incidence of skeletal-related events (SREs) and SRE-related healthcare costs among AA and NHW men, a topic that has received limited attention in the literature. AA and NHW men diagnosed with metastatic PCa were identified from the linked Surveillance, Epidemiology and End Results-Medicare dataset. The sample included 6455 men with metastatic PCa, including 5420 NHW men and 1035 AA men. Approximately 16% experienced SREs during follow-up. AA men were less likely to experience SREs compared with NHW men, controlling for individual characteristics (adjusted odds ratio: 0.79; 95% CI: 0.66- 0.94). The SRE-specific costs were US$35,725 (US$22,190-US$49,260) among AA men and US$25,896 (US$21,669-US$30,123) among NHW men. Although AA men were less likely to experience SREs, there were substantial costs attributable to the treatment of SREs among AA men. PMID- 25817560 TI - Late open conversion after endovascular abdominal aortic aneurysm repair. AB - OBJECTIVE: This study determined the incidence, the surgical details, and the outcome of late open conversion after failed endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm. METHODS: A review of English-language medical literature from 1991 to 2014 was conducted using the PubMed and EMBASE databases to find all studies involving late conversion after EVAR for abdominal aortic aneurysm. The search identified 26 articles encompassing 641 patients (84% men; median age, 73.5 years). RESULTS: Mean interval from the initial implantation was 38.5 +/- 10.7 months. The cumulative single-center open conversion rate was 3.7%. The indications for late open conversion included endoleak in 62.4%, infection in 9.5%, migration in 5.5%, and thrombosis in 6.7%. Operations were urgent in 22.5% of the patients. The 30-day mortality was 9.1%. Mortality rates were different between elective (3.2%) and nonelective patients (29.2%). Five aneurysm-related deaths (1.5%) and two graft infections (0.6%) occurred during a median follow-up of 26.4 months (range, 5-50.2 months). CONCLUSIONS: The number of patients with failed EVAR and without further options for endovascular salvage is growing. Endoleak remains the most important weakness of EVAR as the leading cause of late open conversion. Such procedures, although technically demanding, are associated with relatively low mortality rates when performed electively. Open repair still represents a valuable solution for many patients with failed EVAR. PMID- 25817561 TI - Endovascular longitudinal fenestration and stent graft placement for treatment of aneurysms developing after chronic type B aortic dissection. AB - The thickened intimal flap present in cases of chronic aortic dissection can present a challenge to attempts at endovascular stent graft treatment performed for subsequent aneurysmal degeneration by precluding adequate landing zones for the endograft and by constraining the endograft from full expansion. In this report we describe our technique and outcome for longitudinal endovascular fenestration of chronic aortic dissection flaps to facilitate endovascular stent graft treatment for thoracic aortic aneurysms developing after aortic dissection. PMID- 25817563 TI - Total and inorganic arsenic in Iranian rice. AB - It is well known that arsenic (As) exposure, particularly to inorganic species (i As), has adverse effects on humans. Nowadays, the European Union (EU) has still not regulated the maximum residue limit of As in commercial samples of rice and rice-based products, although it is actively working on the topic. The European Food Safety Authority (EFSA) is collecting data on total arsenic (t-As) and i-As from different rice-producing regions not only from EU countries but also from other parts of the world to finally set up this maximum threshold. As Iran is a rice-producing country, the aim of this work was to evaluate the contents of t-As and i-As in 15 samples of Iranian white, nonorganic, and aromatic rice collected from the most important rice-producing regions of the country. The means of t-As and i-As were 120 and 82 MUg/kg, respectively. The experimental i-As mean in Iranian rice was below the Chinese standard for the i-As in rice, 150 MUg/kg, and the Food and Agriculture Organization of the United Nations (FAO) limit, 200 MUg/kg. Therefore, Iranian rice seems to have reasonable low i-As content and it is safe to be marketed in any market, including China and the EU. PMID- 25817562 TI - Symptomatic Renal Artery Stenosis and Infra-renal AAA. AB - OBJECTIVES: To identify evidence to guide the vascular surgeon as to the relevance of renal artery stenting in a patient with symptomatic renal artery stenosis undergoing elective endovascular aortic aneurysm repair (EVAR). METHODS: A comprehensive literature search of MEDLINE was performed without time limits. The following terms were used in the first instance: renal artery stenting and renal artery stenosis, and any other analogous terms identified during the search. Selection criteria were set to randomised control trials. RESULTS: Despite several large, randomised controlled trials investigating renal artery stenting against medical treatment alone in symptomatic renal artery stenosis, there has been no significant benefit identified in terms of improvement in renal function, control of blood pressure, or need for dialysis. The stented populations were also more likely to suffer from complications caused by the procedure such as bleeding, cholesterol embolisation and flash pulmonary oedema. CONCLUSION: There is no evidence for the use of renal artery stenting over optimal medical management in the treatment of patients with symptomatic atherosclerotic renal artery stenosis, irrelevant of the degree of stenosis. In the setting of EVAR, prevention of deterioration of renal function should be with involvement of the renal physicians, adequate hydration, and use of minimal contrast agent. Repair should be undertaken in centres with access to 24-hour haemofiltration services. PMID- 25817564 TI - Total Masquerading Bundle Branch Block. AB - We report a case of 82-year-old female with total masquerading bundle branch block. We discuss the problems with ECG analysis. PMID- 25817565 TI - Change of a conserved amino acid in the MYC2 and MYC3 transcription factors leads to release of JAZ repression and increased activity. AB - The bHLH transcription factor MYC2, together with its paralogues MYC3 and MYC4, is a master regulator of the response to the jasmonate (JA) hormone in Arabidopsis (Arabidopsis thaliana). In the absence of JA, JASMONATE ZIM (JAZ) proteins interact with the MYC proteins to block their activity. Understanding of the mechanism and specificity of this interaction is key to unravel JA signalling. We generated mutant MYC proteins and assessed their activity and the specificity of their interaction with the 12 Arabidopsis JAZ proteins. We show that the D94N mutation present in the atr2D allele of MYC3 abolishes the interaction between MYC3 and most JAZ proteins. The same effect is observed when the corresponding conserved Asp (D105) was mutated in MYC2. Accordingly, MYC2(D105N) activated target genes in the presence of JAZ proteins, in contrast to wild-type MYC2. JAZ1 and JAZ10 were the only JAZ proteins still showing interaction with the mutant MYC proteins, due to a second MYC interaction domain, besides the classical Jas domain. Our results visualize the divergence among JAZ proteins in their interaction with MYC proteins. Ultimately, the transferability of the Asp-to-Asn amino acid change might facilitate the design of hyperactive transcription factors for plant engineering. PMID- 25817566 TI - Accounting for biodiversity in the dairy industry. AB - Biodiversity is an essential part of properly functioning ecosystems, yet the loss of biodiversity currently occurs at rates unparalleled in the modern era. One of the major causes of this phenomenon is habitat loss and modification as a result of intensified agricultural practices. This paper provides a starting point for considering biodiversity within dairy production, and, although focusing primarily on the United States, findings are applicable broadly. Biodiversity definitions and assessments (e.g., indicators, tools) are proposed and reviewed. Although no single indicator or tool currently meets all the needs of comprehensive assessment, many sustainable practices are readily adoptable as ways to conserve and promote biodiversity. These practices, as well as potential funding opportunities are identified. Given the state of uncertainty in addressing the complex nature of biodiversity assessments, the adoption of generally sustainable environmental practices may be the best currently available option for protecting biodiversity on dairy lands. PMID- 25817567 TI - The future of diabetes. PMID- 25817568 TI - Clinical and image improvement of Raynaud's phenomenon after botulinum toxin type A treatment. AB - Raynaud's phenomenon is often accompanied by pain, digital ulceration and compromised daily activities. Pharmacological therapy or sympathectomies have been administered to diminish these symptoms but existing treatments are not invariably efficacious. A recent case series has described the use of botulinum toxin type A in the treatment of Raynaud's phenomenon. We report two patients with severe or mild Raynaud's phenomenon who were injected with BTX-A; both of whom experienced clinical and image improvement after treatment. PMID- 25817569 TI - Teaching Systematic Searching in a Baccalaureate Nursing Research Course. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 25817570 TI - Primary decompressive craniectomy for poor-grade middle cerebral artery aneurysms with associated intracerebral hemorrhage. AB - OBJECTIVE: Aggressive surgery seems mandatory for poor-grade middle cerebral artery (MCA) aneurysm with associated intracerebral hemorrhage (ICH). However, primary decompressive craniectomy (DC) is controversial. We performed a case control study to define the role of primary DC. MATERIALS AND METHODS: We analyzed data from the two cohorts: a multicenter prospective poor-grade aSAH registry study (AMPAS); and the National Clinical Research Center for Neurological Diseases (NCRC-ND) database of poor-grade patients. Outcome was assessed by modified Rankin Scale (mRS) and was dichotomized into favorable (mRS 0-3) and unfavorable outcome (mRS 4-6). We compared major complication rates, mortality and outcomes between primary DC and control groups. RESULTS: Twenty four patients with primary DC were included in the study group. Fourteen patients without DC were included in the control group. Patients with younger age and lower Glasgow coma score (GCS) more often underwent primary DC. Major complications did not differ between the two groups. Fourteen (58%) patients had a favorable outcome, and the mortality was 29%. Primary DC appeared to have lower in-hospital mortality and have better outcome. Adjusting for age and admission GCS, primary DC was not significantly associated with decreased mortality and improved outcomes. CONCLUSIONS: Although primary DC does not increase postoperative complication and mortality risk, current results showed primary DC does not seem to be significantly associated with improved outcomes. However, more than one half of patients most benefit from primary DC. Further prospective controlled studies are warranted to clarify the issue. PMID- 25817571 TI - Sinking skin flap syndrome and paradoxical herniation secondary to lumbar drainage. AB - OBJECTIVE: Decompressive craniectomy (DC) has been regaining popularity in the field of neurosurgery because it can alleviate intracranial hypertension and brain swelling. Lumbar drainage (LD) is affective in managing numerous neurosurgical circumstances such as aneurysmal subarachnoid hemorrhage, refractory intracranial hypertension, cerebrospinal fluid (CSF) leakage and intraoperative brain relaxation. Sinking skin flap syndrome (SSFS) or paradoxical herniation (PH) is a rare complication and sporadically occurs in patients after DC. Hereby, we report for the first time that DC patients with LD can progress to SSFS or PH. We also evaluated the risk factors for the incidence of SSFS in DC patients with LD. METHODS: We retrospectively assessed 37 patients who underwent DC and LD for cerebrovascular diseases from the First Hospital of Jilin University between January, 2007 and December, 2012. RESULTS: Nine (4 male and 5 female) of 37 patients experienced SSFS or PH following LD. At the last follow-up (mean 9 months, range 6-12 months), eight patients recovered completely due to timely conservative management and one patient died from PH. The mortality rate was 11% (1/9) from the complications of PH or SSFS. Further statistical analysis revealed that mean daily CSF volume was a risk factor for the incidence of SSFS in DC patients with LD. CONCLUSIONS: SSFS or PH can be identified in DC patients following LD. Patients that undergo DC and LD should be monitored more intensively. Most patients can completely recover with timely conservative management, bed rest, Trendelenburg position, sufficient intravenous fluid, and temporary clipping of the catheter. PMID- 25817572 TI - Differential regulation of TROP2 release by PKC isoforms through vesicles and ADAM17. AB - TROP2, a cancer cell surface protein with both pro-oncogenic and anti-oncogenic properties is cleaved by ADAM17. ADAM17 dependent cleavage requires novel PKC activity which is blocked by the ADAM10/ADAM17 inhibitor GW64 as well as by the PKC inhibitor Bim-1. Full length TROP2 release is induced by classical PKC activation and blocked by Go6979, without affecting ADAM17 dependent TROP2 cleavage. Full length TROP2 is released in ectosomes, as inhibition of endocytosis did not prevent release. Inhibition of the atypical PKC isoform PKCzeta stimulated metalloproteinase dependent N-terminal alternative TROP2 cleavage. The resulting alternative TROP2 cleavage product remains membrane associated via a disulphide bond, but is released in microvesicles with an average size of 107nm. Inhibition of endocytosis following PKCzeta inhibition prevented alternative cleavage and release of TROP2, suggesting that these events require endocytic uptake and exosomal release of the corresponding microvesicles. The alternative TROP2 cleavage product was also found in PC3 cell lysates following deglycosylation, and may represent a novel biomarker in prostate cancer. PMID- 25817573 TI - Neuropeptide Y receptor mediates activation of ERK1/2 via transactivation of the IGF receptor. AB - Neuropeptide Y binds to G-protein coupled receptors whose action results in inhibition of adenylyl cyclase activity. Using HEK293 cells stably expressing the native neuropeptide Y Y1 receptors, we found that the NPY agonist elicits a transient phosphorylation of the extracellular signal-regulated kinases (ERK1/2). We first show that ERK1/2 activation following Y1 receptor stimulation is dependent on heterotrimeric Gi/o since it is completely inhibited by pre treatment with pertussis toxin. In addition, ERK1/2 activation is internalization independent since mutant Y1 receptors unable to recruit beta-arrestins, can still activate ERK signaling to the same extent as wild-type receptors. We next show that this activation of the MAPK pathway is inhibited by the MEK inhibitor U0126, is not dependent on calcium signaling at the Y1 receptor (no effect upon inhibition of phospholipase C, protein kinase C or protein kinase D) but instead dependent on Gbeta/gamma and associated signaling pathways that activate PI3 kinase. Although inhibition of the epidermal-growth factor receptor tyrosine kinase did not influence NPY-induced ERK1/2 activation, we show that the inhibition of insulin growth factor receptor IGFR by AG1024 completely blocks activation of ERK1/2 by the Y1 receptor. This Gbeta/gamma-PI3K-AG1024-sensitive pathway does not involve activation of IGFR through the release of a soluble ligand by metalloproteinases since it is not affected by the metalloproteinase inhibitor marimastat. Finally, we found that a similar pathway, sensitive to wortmannin-AG1024 but insensitive to marimastat, is implicated in activation of ERK signaling in HEK293 cells by endogenously expressed GPCRs coupled to Gq protein (muscarinic M3 receptors) or coupled to Gs-protein (endothelin ETB receptors). Our analysis is the first to show that beta-arrestin recruitment to the NPY Y1 receptor is not necessary for MAPK activation by this receptor but that transactivation of the IGFR receptor is required. PMID- 25817574 TI - GW5074 and PP2 kinase inhibitors implicate nontraditional c-Raf and Lyn function as drivers of retinoic acid-induced maturation. AB - The multivariate nature of cancer necessitates multi-targeted therapy, and kinase inhibitors account for a vast majority of approved cancer therapeutics. While acute promyelocytic leukemia (APL) patients are highly responsive to retinoic acid (RA) therapy, kinase inhibitors have been gaining momentum as co-treatments with RA for non-APL acute myeloid leukemia (AML) differentiation therapies, especially as a means to treat relapsed or refractory AML patients. In this study GW5074 (a c-Raf inhibitor) and PP2 (a Src-family kinase inhibitor) enhanced RA induced maturation of t(15;17)-negative myeloblastic leukemia cells and rescued response in RA-resistant cells. PD98059 (a MEK inhibitor) and Akti-1/2 (an Akt inhibitor) were less effective, but did tend to promote maturation-uncoupled G1/G0 arrest, while wortmannin (a PI3K inhibitor) did not enhance differentiation surface marker expression or growth arrest. PD98059 and Akti-1/2 did not enhance differentiation markers and have potential, antagonistic off-targets effects on the aryl hydrocarbon receptor (AhR), but neither could the AhR agonist 6 formylindolo(3,2-b)carbazole (FICZ) rescue differentiation events in the RA resistant cells. GW5074 rescued early CD38 expression in RA-resistant cells exhibiting an early block in differentiation before CD38 expression, while for RA resistant cells with differentiation blocked later, PP2 rescued the later differentiation marker CD11b; but surprisingly, the combination of the two was not synergistic. Kinases c-Raf, Src-family kinases Lyn and Fgr, and PI3K display highly correlated signaling changes during RA treatment, while activation of traditional downstream targets (Akt, MEK/ERK), and even the surface marker CD38, were poorly correlated with c-Raf or Lyn during differentiation. This suggests that an interrelated kinase module involving c-Raf, PI3K, Lyn and perhaps Fgr functions in a nontraditional way during RA-induced maturation or during rescue of RA induction therapy using inhibitor co-treatment in RA-resistant leukemia cells. PMID- 25817575 TI - Neurokinin-1 activation affects EGFR related signal transduction in triple negative breast cancer. AB - Breast cancers bear overexpression of neurokinin-1 (NK-1). The aim of this study was to investigate the relationship between NK-1 and EGFR in triple negative breast cancers (TNBCs). Immunohistochemistry was performed to investigate NK-1 and EGFR expressions in TNBCs. [Sar(9), ?Met(O2)(11)] substance P (SMSP) was used to activate NK-1 in two TNBC cell lines, MDA-MB-231 and MDA-MB-468. L-733060 and siRNA against NK-1 were used to inhibit NK-1. The in vitro regulatory effect of NK-1 was determined using CCK-8 proliferation assay. The effects of NK-1 activation and inhibition on EGFR and its downstreaming pathway were analyzed using western blot and real-time quantitative PCR. We found that the proportion of EGFR positive cases was increased with the increasement of NK-1 levels. SMSP could promote the proliferation of TNBC cells, while L-733060 and siRNA could inhibit cell proliferation and induce apoptosis. Moreover, SMSP could enhance expressions of phosphorylation (p)-EGFR and EGFR, and activate p-Akt and p-Erk. NK1-siRNA could decrease p-EGFR, p-Akt and p-Erk. In the presence of cetuximab (0.2mg/mL), SMSP still could stimulate cell proliferation, and activate p-EGFR. However, in the presence of erlotinib (10MUM), SMSP could not stimulate cell proliferation and could not activate p-EGFR. Our study showed the interaction between NK-1 and EGFR in TNBCs. These results suggested that NK-1 may regulate TNBC proliferation through EGFR phosphorylation, and the curative effect of EGFR monoclonal antibodies may be affected by NK-1 activation. PMID- 25817576 TI - Temporal Influence of Heart Failure Hospitalizations Prior to Implantable Cardioverter Defibrillator or Cardiac Resynchronization Therapy With Defibrillator on Subsequent Outcome in Mild Heart Failure Patients (from MADIT CRT). AB - The temporal effect of heart failure (HF) hospitalization occurring at different time periods before implantation has not yet been studied in detail. The aim of the present study was to investigate the potential association between time from last HF hospitalization to device implantation and effects on subsequent outcomes and benefit from cardiac resynchronization therapy with a defibrillator (CRT-D). Multivariate Cox models were used to determine the temporal influence of previous HF hospitalization on the end point of HF or death within all left bundle branch block implantable cardioverter-defibrillator (ICD) and CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) trial (n = 1,250) and to evaluate the clinical benefit of CRT-D implantation, comparing CRT-D patients with ICD patients within each previous HF hospitalization group. The patients with previous HF hospitalization <=12 months before device implantation had the greatest incidence of HF or death during 4-year follow-up (31%), while those with previous HF hospitalization >12 months and those with no previous HF hospitalization had similar lower rates of HF or death (22% and 24%, respectively). All patients treated with CRT-D derived significant clinical benefit compared with their ICD counterparts, regardless of time of previous hospitalization (hazard ratios 0.38 [no previous hospitalization], 0.49 (<=12 months), and 0.45 (>12 months); p for interaction = 0.67). In conclusion, in the present study of patients with mild HF with prolonged QRS intervals and LBBB, a previous HF hospitalization <=12 months was associated with increased risk for HF or death compared with >12 months and no previous HF hospitalizations. The clinical benefit of CRT-D was evident in all patients regardless of time from last HF hospitalization to implantation compared with ICD only. PMID- 25817577 TI - Assessment of antimicrobial utilization metrics: days of therapy versus defined daily doses and pharmacy dispensing records versus nursing administration data. AB - OBJECTIVE: To compare antimicrobial utilization data derived from pharmacy dispensing records and nursing administration record data by 2 commonly used units of measure. DESIGN, PARTICIPANTS, AND METHODS: Data from nursing administration records and pharmacy dispensing records were obtained for 32 medical wards. From nursing and pharmacy data, defined daily doses (DDD) were calculated, and from the nursing data, days of therapy were derived. Direct comparison of total antimicrobial use was performed by graphical analysis and linear regression. Slope of trend line was used to quantify the difference between pairs of measures. Bland-Altman plots were constructed to determine constant and proportional bias. At the level of individual agents, difference between pairs of measures was calculated and presented graphically and the average (95% CI) for the difference between measures was determined. RESULTS: Nursing administration record-derived DDD were on average 23% lower than corresponding rates of pharmacy dispensing record-derived DDD. The difference between rates of utilization by days of therapy vs DDD from the same source (nursing) was relatively small. Results from analysis of different individual agents were highly variable with wide 95% CIs. CONCLUSIONS: In our setting, we found clinically relevant differences in antimicrobial utilization associated with data from different sources. This outweighed the importance of the metric (DDD or days of therapy). However, measurement of use of individual agents was highly variable and sensitive to both metric unit and data sources. PMID- 25817578 TI - Effects of different forms and origins of oilseeds on dynamics of ruminal biohydrogenation of long-chain fatty acids in vitro. AB - Dietary unsaturated fatty acids (FA) are intensively hydrogenated in the rumen, resulting in reduced amount of poly-unsaturated fatty acids (PUFA) and accumulation of several biohydrogenation (BH) products. In this study, BH of PUFA originating from different oilseeds (linseed, soya beans, sunflower seed and rapeseed) present in crushed oilseeds or their free oils were assessed in vitro. The assay substrates were incubated in buffered rumen fluid for 0, 6, 12 and 24 h. After incubation, the FA pattern of the incubated samples was analysed using gas chromatography. Biohydrogenation is defined as disappearance of double bonds (DB) calculated from the contents of unsaturated FA. After 24-h incubation, the DB contents of all oilseeds were reduced (p < 0.001) by 40-60%. The reduction was higher (p < 0.001) for the crushed form compared with the oil form. In addition, linseed and sunflower seed known as oilseeds with high contents of linolenic acid C18:3 c9,12,15 (LNA) and linoleic acid C18:2 c9,12 (LA), respectively, showed a higher (p < 0.001) accumulation of the BH intermediates conjugated linoleic acid (CLA, isomer C18:2 c9t11) and vaccenic acid (C18:1 t11) for the crushed form, when compared with the oil. These results suggest an inherent effect of the physical form of the assay oilseeds on in vitro BH. Changes in FA pattern during BH in vitro can be attributed to both source and physical form of the assay oilseeds. However, further investigations are warranted to ensure whether the observed in vitro effects on ruminal BH can be confirmed in vivo. PMID- 25817579 TI - Ceftaroline fosamil as first-line versus second-line treatment for acute bacterial skin and skin structure infections (ABSSSI) or community-acquired bacterial pneumonia (CABP). AB - The Clinical Assessment Program and Teflaro((r)) Utilization Registry (CAPTURE) is a multicenter registry study of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP) patients treated with ceftaroline fosamil in the US. Data for this analysis were collected between August 2011 and February 2013 at US study centres by randomly ordered chart review. Clinical success rates among ABSSSI patients were >81% when ceftaroline fosamil was used as first- or second-line therapy, including monotherapy and concurrent therapy. Among CABP patients, clinical success rates were >77% among first-line and second-line patients and patients who received first-line concurrent therapy or second line monotherapy or concurrent therapy. For CABP patients treated with ceftaroline fosamil as first-line monotherapy, the clinical success rate was 70%. Ceftaroline fosamil is an effective treatment option for patients with ABSSSI or CABP with similar clinical success rates when used as first-line or second-line treatment. PMID- 25817584 TI - Phylogenetic Characterization of Phosphatase-Expressing Bacterial Communities in Baltic Sea Sediments. AB - Phosphate release from sediments hampers the remediation of aquatic systems from a eutrophic state. Microbial phosphatases in sediments release phosphorus during organic matter degradation. Despite the important role of phosphatase-expressing bacteria, the identity of these bacteria in sediments is largely unknown. We herein presented a culture-independent method to phylogenetically characterize phosphatase-expressing bacteria in sediments. We labeled whole-cell extracts of Baltic Sea sediments with an artificial phosphatase substrate and sorted phosphatase-expressing cells with a flow cytometer. Their phylogenetic affiliation was determined by Denaturing Gradient Gel Electrophoresis. The phosphatase-expressing bacterial community coarsely reflected the whole-cell bacterial community, with a similar dominance of Alphaproteobacteria. PMID- 25817583 TI - Tackling antibiotic resistance: the environmental framework. AB - Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment. PMID- 25817585 TI - Diversity Profile of Microbes Associated with Anaerobic Sulfur Oxidation in an Upflow Anaerobic Sludge Blanket Reactor Treating Municipal Sewage. AB - We herein analyzed the diversity of microbes involved in anaerobic sulfur oxidation in an upflow anaerobic sludge blanket (UASB) reactor used for treating municipal sewage under low-temperature conditions. Anaerobic sulfur oxidation occurred in the absence of oxygen, with nitrite and nitrate as electron acceptors; however, reactor performance parameters demonstrated that anaerobic conditions were maintained. In order to gain insights into the underlying basis of anaerobic sulfur oxidation, the microbial diversity that exists in the UASB sludge was analyzed comprehensively to determine their identities and contribution to sulfur oxidation. Sludge samples were collected from the UASB reactor over a period of 2 years and used for bacterial 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) and next-generation sequencing analyses. T-RFLP and sequencing results both showed that microbial community patterns changed markedly from day 537 onwards. Bacteria belonging to the genus Desulforhabdus within the phylum Proteobacteria and uncultured bacteria within the phylum Fusobacteria were the main groups observed during the period of anaerobic sulfur oxidation. Their abundance correlated with temperature, suggesting that these bacterial groups played roles in anaerobic sulfur oxidation in UASB reactors. PMID- 25817586 TI - An allosteric photoredox catalyst inspired by photosynthetic machinery. AB - Biological photosynthetic machinery allosterically regulate light harvesting via conformational and electronic changes at the antenna protein complexes as a response to specific chemical inputs. Fundamental limitations in current approaches to regulating inorganic light-harvesting mimics prevent their use in catalysis. Here we show that a light-harvesting antenna/reaction centre mimic can be regulated by utilizing a coordination framework incorporating antenna hemilabile ligands and assembled via a high-yielding, modular approach. As in nature, allosteric regulation is afforded by coupling the conformational changes to the disruptions in the electrochemical landscape of the framework upon recognition of specific coordinating analytes. The hemilabile ligands enable switching using remarkably mild and redox-inactive inputs, allowing one to regulate the photoredox catalytic activity of the photosynthetic mimic reversibly and in situ. Thus, we demonstrate that bioinspired regulatory mechanisms can be applied to inorganic light-harvesting arrays displaying switchable catalytic properties and with potential uses in solar energy conversion and photonic devices. PMID- 25817587 TI - Correlation between 'ACKR1/DARC null' polymorphism and benign neutropenia in Yemenite Jews. PMID- 25817588 TI - Novel hybrid nocodazole analogues as tubulin polymerization inhibitors and their antiproliferative activity. AB - We describe the design, synthesis and SAR profiling of a series of novel combretastatin-nocodazole conjugates as potential anticancer agents. The thiophene ring in the nocodazole moiety was replaced by a substituted phenyl ring from the combretastatin moiety to design novel hybrid analogues. The hydroxyl group at the ortho position in compounds 2, 3 and 4 was used as the conformationally locking tool by anticipated six-membered hydrogen bonding. The bioactivity profiles of all compounds as tubulin polymerization inhibitors and as antiproliferative agents against the A-549 human lung cancer cell line were investigated Compounds 1 and 4 showed MUM IC50 values in both assays. PMID- 25817589 TI - Rho-associated kinase signaling is required for osteopontin-induced cell invasion through inactivating cofilin in human non-small cell lung cancer cell lines. AB - Osteopontin (OPN) is involved in tumor progression such as invasion and metastasis, and poor prognosis of lung cancer. However, how OPN affects the invasive behavior of lung cancer is not well defined. Here, we examined the underlying molecular mechanism of OPN-induced invasion in human non-small cell lung cancer (NSCLC) cell lines including A549 cells. OPN markedly increased the phosphorylation of LIM kinase 1 and 2 (LIMK1/2), and cofilin without affecting their total forms. The expression of Rho-associated kinase 1 (ROCK1), but not p21 activated kinase 1 and 2 (PAK1/2), was increased by OPN treatment as an upstream effector of LIMK/cofilin. The phosphorylation of cofilin by OPN was suppressed when cells were pretreated with ROCK inhibitor Y27632 by Western blot. Moreover, it verified that OPN inactivated cofilin through ROCK signaling in other NSCLC cell lines. OPN induced the phosphorylation of FAK and AKT. FAK inhibitor FAKi-14 and PI3K inhibitor wortmannin decreased the expressions of ROCK1, and phosphorylation of LIMK1/2 and cofilin. OPN caused a significant increase in the lamellipodia formation and cell invasion, and these are suppressed by FAK inhibitor FAKi-14, PI3K inhibitor wortmannin and ROCK inhibitor Y27632. Taken together, these results suggest that OPN triggers ROCK signaling mediated by FAK/PI3K/AKT pathway, which in turn induces the lamellipodia formation to allow the invasion of lung cancer cells through inactivating cofilin. PMID- 25817590 TI - Crystal structure of the most catalytically effective carbonic anhydrase enzyme known, SazCA from the thermophilic bacterium Sulfurihydrogenibium azorense. AB - Two thermostable alpha-carbonic anhydrases (alpha-CAs) isolated from thermophilic Sulfurihydrogenibium spp., namely SspCA (from S. yellowstonensis) and SazCA (from S. azorense), were shown in a previous work to possess interesting complementary properties. SspCA was shown to have an exceptional thermal stability, whereas SazCA demonstrated to be the most active alpha-CA known to date for the CO2 hydration reaction. Here we report the crystallographic structure of SazCA and the identification of the structural features responsible for its high catalytic activity, by comparing it with SspCA structure. These data are of relevance for the design of engineered proteins showing higher stability and catalytic activity than other alpha-CAs known to date. PMID- 25817591 TI - (+)- and (-)-liriodenol, a pair of novel enantiomeric lignans from Liriodendron hybrid. AB - (+)- and (-)-liriodenol, a pair of unprecedented enantiomeric lignans bearing a 1,1-disubstituted olefinic group, were isolated from the barks of Liriodendron hybrid. The structure and relative configurations were determined by comprehensive analysis of MS and NMR spectroscopy. The cytotoxicity of these three lignans ((+/-)-, (+)-, and (-)-liriodenol) was evaluated in vitro against four selected human tumor cell lines, where (+)-liriodenol showed more significant cytotoxic effects than the (+/-)- and (-)-liriodenol enantiomers. PMID- 25817593 TI - Memorial for Michael Davidson, MD. PMID- 25817592 TI - Molecular characterization of epithelioid haemangioendotheliomas identifies novel WWTR1-CAMTA1 fusion variants. AB - AIMS: Epithelioid haemangioendothelioma (EHE) is a malignant vascular neoplasm. Subsets have been characterized previously by translocations resulting in either WWTR1-CAMTA1 or YAP1-TFE3 fusion. We sought to develop molecular and immunohistochemical (IHC) assays to aid in the diagnosis and characterization of EHE. METHODS AND RESULTS: Fifty-two formalin-fixed, paraffin-embedded (FFPE) cases diagnosed between 2002 and 2014 were retrieved from the pathology files of our institutions. Reverse transcription-polymerase chain reaction (RT-PCR) assays were optimized to detect WWTR1-CAMTA1 and YAP1-TFE3 fusion transcripts in FFPE tissue and transcription factor E3 (TFE3) protein accumulation was examined by immunohistochemistry (IHC). RNA was extracted from 33 adequate samples, with more recent cases providing a greater yield of high quality RNA. Fourteen of 18 informative cases were positive for WWTR1-CAMTA1 fusion transcripts, four of which showed higher-grade cytological features termed by some as 'malignant EHE'. Novel in-frame fusion transcripts were identified in four cases by direct sequencing. IHC revealed variable nuclear TFE3 staining in six of 17 cases; three with patchy staining showed WWTR1-CAMTA1 fusion. One of 18 informative cases was positive for YAP1-TFE3 fusion and showed strong nuclear TFE3 staining by IHC. CONCLUSIONS: This study confirms the high incidence of WWTR1-CAMTA1 and YAP1-TFE3 rearrangements in EHE and indicates that the staining pattern for TFE3 IHC is critical for specificity. PMID- 25817594 TI - Linear spin wave theory for single-Q incommensurate magnetic structures. AB - Linear spin wave theory provides the leading term in the calculation of the excitation spectra of long-range ordered magnetic systems as a function of 1/?S. This term is acquired using the Holstein-Primakoff approximation of the spin operator and valid for small deltaS fluctuations of the ordered moment. We propose an algorithm that allows magnetic ground states with general moment directions and single-Q incommensurate ordering wave vector using a local coordinate transformation for every spin and a rotating coordinate transformation for the incommensurability. Finally we show, how our model can determine the spin wave spectrum of the magnetic C-site langasites with incommensurate order. PMID- 25817595 TI - Efficacy of topical 0.1% adapalene gel for use in the treatment of childhood acanthosis nigricans: a pilot study. PMID- 25817596 TI - The effect of CO2 laser treatment on skin tissue. AB - BACKGROUND/OBJECTIVE: The aim of this study was to evaluate the effects of multiple pulses on the depth of injury caused by CO2 laser in an in vivo rat model. METHODS: A 10 600-nm CO2 laser was applied to rat skin, with one side of the rat dorsal skin being exposed, leaving the other side as a control. RESULTS: All of the various laser pulses tested led to gradual loss of epidermal thickness as well as a dramatic increase in thermal damage depth. Collagen coagulation was most effective with ten pulses of CO2 laser, while the strength of irradiated skin tissue increased as the influence of the laser increased. CONCLUSION: Fundamental laser-skin interaction effects were studied using a CO2 laser. The photodamaged areas obtained from laser interaction were recorded via couple charge device video camera and analyzed via ImageJ software. Photodamage induced by CO2 laser is due to photothermal effects, which involve burning and vaporizing mechanisms to ablate the epidermis layer. The burning area literally expands and penetrates deep into the dermis layer, subsequently causing collagen coagulation. This fundamental study shows in detail the effect of CO2 laser interaction with skin. The CO2 attributed severe burning, producing deep coagulation, and induced strength to treated skin. PMID- 25817597 TI - Cognition and Emotion to respond. PMID- 25817598 TI - Application of Differential Colorimetry To Evaluate Anthocyanin-Flavonol-Flavanol Ternary Copigmentation Interactions in Model Solutions. AB - The combined effect of anthocyanin-flavanol-flavonol ternary interactions on the colorimetric and chemical stability of malvidin-3-glucoside has been studied. Model solutions with fixed malvidin-3-glucoside/(+)-catechin ratio (MC) and variable quercetin-3-beta-d-glucoside concentration (MC+Q) and solutions with fixed malvidin-3-glucoside/quercetin-3-beta-d-glucoside ratio (MQ) and variable (+)-catechin concentration (MQ+C) were tested at levels closer to those existing in wines. Color variations during storage were evaluated by differential colorimetry. Changes in the anthocyanin concentration were monitored by HPLC-DAD. CIELAB color-difference formulas were demonstrated to be of practical interest to assess the stronger and more stable interaction of quercetin-3-beta-d-glucoside with MC binary mixture than (+)-catechin with MQ mixture. The results imply that MC+Q ternary solutions kept their intensity and bluish tonalities for a longer time in comparison to MQ+C solutions. The stability of malvidin-3-glucoside improves when the concentration of quercetin-3-beta-d-glucoside increases in MC+Q mixtures, whereas the addition of (+)-catechin in MQ+C mixtures resulted in an opposite effect. PMID- 25817599 TI - Identification of reference microRNAs for quantitative expression analysis in porcine peripheral blood mononuclear cells treated with polyinosinic polycytidylic acid. AB - Peripheral blood mononuclear cells (PBMCs) are clinically important cells. Detection of microRNAs (miRNAs) expression in PBMCs can be useful for miRNA biomarker discovery for various diseases. Quantitative real-time PCR (qRT-PCR) has become an important method used for measuring miRNAs expression. However, the reliability of qRT-PCR data critically depends on proper selection of reference genes. Here, we performed qRT-PCR to quantify the expression levels of nine miRNAs (Ssc-miR-16, Hsa-miR-25, Ssc-miR-34a, Hsa-miR-93, Bta-miR-92b, Ssc-miR 103, Ssc-miR-106a, Ssc-miR-128 and Ssc-miR-107) and one small nuclear RNA (U6) in PBMCs treated with polyinosinic-polycytidylic acid [poly (I:C)] that widely used for simulating viral infection. We used the four statistical algorithms (GeNorm 3.5, NormFinder, BestKeeper and comparative ? Ct method) to evaluate gene expression stability and observed that Ssc-miR-34a was the best single reference gene and the pair of Ssc-miR-107 and Ssc-miR-103 was the best combination of reference miRNAs for porcine PBMCs treated with poly (I:C). Our study shows the first evidence of careful selection of reference miRNAs in porcine PBMCs and maybe helpful for discovering miRNA biomarkers for double-stranded RNA-induced disease. PMID- 25817600 TI - Graphene oxide stabilized by PLA-PEG copolymers for the controlled delivery of paclitaxel. AB - PURPOSE: To investigate the application of water-dispersible poly(lactide) poly(ethylene glycol) (PLA-PEG) copolymers for the stabilization of graphene oxide (GO) aqueous dispersions and the feasibility of using the PLA-PEG stabilized GO as a delivery system for the potent anticancer agent paclitaxel. METHODS: A modified Staudenmaier method was applied to synthesize graphene oxide (GO). Diblock PLA-PEG copolymers were synthesized by ring-opening polymerization of dl-lactide in the presence of monomethoxy-poly(ethylene glycol) (mPEG). Probe sonication in the presence of PLA-PEG copolymers was applied in order to reduce the hydrodynamic diameter of GO to the nano-size range according to dynamic light scattering (DLS) and obtain nano-graphene oxide (NGO) composites with PLA-PEG. The composites were characterized by atomic force microscopy (AFM), thermogravimetric analysis (TGA), and DLS. The colloidal stability of the composites was evaluated by recording the size of the composite particles with time and the resistance of composites to aggregation induced by increasing concentrations of NaCl. The composites were loaded with paclitaxel and the in vitro release profile was determined. The cytotoxicity of composites against A549 human lung cancer cells in culture was evaluated by flow cytometry. The uptake of FITC-labeled NGO/PLA-PEG by A549 cells was also estimated with flow cytometry and visualized with fluorescence microscopy. RESULTS: The average hydrodynamic diameter of NGO/PLA-PEG according to DLS ranged between 455 and 534 nm, depending on the molecular weight and proportion of PLA-PEG in the composites. NGO/PLA-PEG exhibited high colloidal stability on storage and in the presence of high concentrations of NaCl (far exceeding physiological concentrations). Paclitaxel was effectively loaded in the composites and released by a highly sustained fashion. Drug release could be regulated by the molecular weight of the PLA-PEG copolymer and its proportion in the composite. The paclitaxel-loaded composites exhibited cytotoxicity against A549 cancer cells which increased with incubation time, in conjunction with the increasing with time uptake of composites by the cancer cells. CONCLUSION: Graphene oxide aqueous dispersions were effectively stabilized by water-dispersible, biocompatible and biodegradable PLA-PEG copolymers. The graphene oxide/PLA-PEG composites exhibited satisfactory paclitaxel loading capacity and sustained in vitro drug release. The paclitaxel loaded composites could enter the A549 cancer cells and exert cytotoxicity. The results justify further investigation of the suitability of PLA-PEG stabilized graphene oxide for the controlled delivery of paclitaxel. PMID- 25817601 TI - Does increased adherence to medications change health care financial burdens for adults with diabetes? AB - BACKGROUND: The aim of the present study was to investigate increased out-of pocket drug costs and financial burdens of achieving adherence to oral antidiabetic medications and medications for prevalent comorbidities. METHODS: Concurrent adherence to medications, out-of-pocket drug costs, and financial burdens were measured among non-elderly adults with diabetes in the Medical Expenditure Panel Survey. "Financial burden" was defined as spending on health care exceeding 10% of family income. This study simulated the increased out-of pocket drug costs and financial burdens that would result if non-adherent adults in our sample had obtained sufficient medications to be adherent. For each adult, for all therapeutic classes in which they were non-adherent, we calculated the additional days supplied required to become adherent, as well as out-of-pocket spending on these additional days supplied. RESULTS: Approximately one-quarter adhered to all required medications. Among non-adherent adults with employer sponsored insurance and public insurance, the mean annual out-of-pocket drug costs of achieving adherence were US$171 and US$68, respectively, which was generally affordable. However, 35.6% of the uninsured lived in families that spent 10% or more of their income on health care. Mean simulated additional out of-pocket drug costs of achieving adherence were US$310 for the uninsured. These additional drug costs would increase those spending 10% or more of income to 39.6% of the uninsured. CONCLUSIONS: Efforts to reduce the costs faced by the uninsured and insured will make adherence more affordable and, therefore, more attainable for some adults with diabetes. PMID- 25817604 TI - ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affect renal function in patients with rheumatoid arthritis. AB - BACKGROUND: This study aimed to evaluate the blood exposure of and clinical responses to tacrolimus based on genetic variants of CYP3A5 and ABCB1 in patients with rheumatoid arthritis. METHODS: Seventy rheumatoid arthritis patients treated with oral tacrolimus once daily were enrolled. Blood concentrations of tacrolimus and its major metabolite 13-O-demethylate at 12h after dosing were determined. The relationships between the tacrolimus pharmacokinetics and efficacy, renal function, and CYP3A5 and ABCB1 genotypes were evaluated. RESULTS: Dose-normalized blood concentration of tacrolimus was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. A lower metabolic ratio of 13-O demethylate to tacrolimus was observed in the CYP3A5*3/*3 group. The ABCB1 3435TT group had higher dose-normalized blood concentrations of tacrolimus and 13-O demethylate. The blood tacrolimus concentration was inversely correlated with the estimated glomerular filtration rate (eGFR). ABCB1 C3435T but not CYP3A5 genotype had decreased eGFR. Patients lacking the CYP3A5*3 allele had a higher incidence of tacrolimus withdrawal. CONCLUSION: CYP3A5*3 increased the blood exposure of tacrolimus through its metabolic reduction. ABCB1 C3435T led to a higher blood exposure of tacrolimus and its major metabolite. The ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affected renal function in rheumatoid arthritis patients. PMID- 25817605 TI - Glycated albumin as a diagnostic tool for diabetes in a general Japanese population. AB - OBJECTIVE: Diabetes mellitus is a major cause of cardiovascular, kidney, neurologic, and eye diseases, and may be preventable in some cases by lifestyle modification. Screening tests for diabetes mellitus include fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Our objective was to evaluate the utility of plasma glycated albumin (GA) in the diagnosis of diabetes mellitus. DESIGN AND METHODS: A cross-sectional, community-based population study of 908 non-diabetic Japanese residents was conducted. Of these subjects, 176 with FPG value between 5.5 and 6.9mmol/l, and an HbA1c level of <6.5% received an oral glucose tolerance test (OGTT). RESULTS: The OGTT results were used for the diagnosis of diabetes mellitus using World Health Organization criteria. Receiver operating characteristic (ROC) analyses demonstrated that optimal threshold values for the diagnosis of diabetes in this population were 15.2% for GA and 5.9% for HbA1c, respectively. Using these cutoff levels, the sensitivity of GA at 62.1% for detecting diabetes was the same as that of HbA1c. However the specificity for GA for detecting diabetes was 61.9%, while for HbA1c it was higher at 66.7%. CONCLUSIONS: Our results indicate that the measurement of glycated albumin may serve as a useful screening test for diabetes in a general Japanese population. PMID- 25817606 TI - Glove use among hairdressers: difficulties in the correct use of gloves among hairdressers and the effect of education. AB - BACKGROUND: Hand eczema is frequent among Danish hairdressers, and they are advised to use gloves as protection. However, studies indicate that a significant proportion use gloves inappropriately. OBJECTIVES: To determine whether hairdressers and apprentices use protective gloves in the correct way, and to determine whether a demonstration of correct use could cause an improvement. METHODS: Forty-three hairdressers and apprentices were asked to perform a hair wash while wearing gloves. The shampoo used was contaminated with an ultraviolet (UV) trace material. Two rounds of hair washing were carried out by each person, interrupted by a demonstration of how to use gloves correctly. Photographs were taken to compare UV contamination before and after the demonstration. RESULTS: All of the participants (100%) had their hands contaminated during the first round; the area ranged between 0.02 and 101.37 cm(2) (median 3.62 cm(2)). In the second round, 55.8% were contaminated (range 0.00-3.08 cm(2) ; median 0.01 cm(2)). The reduction in contaminated skin areas was statistically significant (p < 0.001), proving an effect of the glove demonstration. There were no significant differences between hairdressers and apprentices. CONCLUSIONS: Hairdressers and apprentices lack knowledge on how to handle gloves correctly. A short demonstration of correct glove use made a significant difference in the skin protection provided by gloves. PMID- 25817607 TI - Oral microbiota change, tooth decay and hemorrhoidal disease. PMID- 25817608 TI - Fabrication of TiO2-SiO2 bioceramic coatings on Ti alloy and its synergetic effect on biocompatibility and corrosion resistance. AB - Most of the research work focussed on fabricating an implant material with an ideal combination of potential bioactivity on the surface and striking mechanical property of bulk in one elementary operation. Interwoven with above concept, SiO2 incorporated nanostructured titania coatings were fabricated on Ti alloy by anodization using sodium silico fluoride electrolyte (SSF). The coatings were characterized by SEM, EDS, AFM, XRD and AT-FTIR techniques. The bioactivity and biocompatibility of the anodic coatings were also investigated. The AT-FTIR, EDS and XRD studies confirm the incorporation of SiO2 into TiO2 coating was confirmed by EDS, XRD and AT-FTIR techniques. The coating formed at the optimum conditions displays a dome like structure with nano flake morphology with maximum mechanical and anticorrosion properties. AFM analysis inferred that the surface roughness of the ceramic coating is higher compared to the pure titania. The SBF test and cell adhesion results predicted that SiO2 incorporated TiO2 coating is superior in their bioactivity compared to TiO2 coating. PMID- 25817609 TI - Micro-scale testing and micromechanical modelling for high cycle fatigue of CoCr stent material. AB - This paper presents a framework of experimental testing and crystal plasticity micromechanics for high cycle fatigue (HCF) of micro-scale L605 CoCr stent material. Micro-scale specimens, representative of stent struts, are manufactured via laser micro-machining and electro-polishing from biomedical grade CoCr alloy foil. Crystal plasticity models of the micro-specimens are developed using a length scale-dependent, strain-gradient constitutive model and a phenomenological (power-law) constitutive model, calibrated from monotonic and cyclic plasticity test data. Experimental microstructural characterisation of the grain morphology and precipitate distributions is used as input for the polycrystalline finite element (FE) morphologies. Two microstructure-sensitive fatigue indicator parameters are applied, using local and non-local (grain-averaged) implementations, for the phenomenological and length scale-dependent models, respectively, to predict fatigue crack initiation (FCI) in the HCF experiments. PMID- 25817611 TI - Erratum. PMID- 25817610 TI - Outcome of renal transplantation in patients with type 2 diabetic nephropathy: a single-center experience. AB - BACKGROUND: Renal transplantation has been established as a treatment for end stage renal disease (ESRD) due to diabetic nephropathy. However, few studies have focused on the outcome after renal transplantation in patients with ESRD and type 2 diabetic nephropathy. To investigate the effect of renal transplantation on ESRD with type 2 diabetic nephropathy, we retrospectively analyzed patients who received renal transplantation at our facility. This study aimed to compare the outcome of renal transplantation for type 2 diabetic nephropathy with that for nondiabetic nephropathy. METHODS: We studied 290 adult patients, including 65 with type 2 diabetic nephropathy (DM group) and 225 with nondiabetic nephropathy (NDM group), who underwent living-donor renal transplantation at our facility from February 2008 to March 2013. We compared the 2 groups retrospectively. RESULTS: In the DM and NDM groups, the 5-year patient survival rates were 96.6% and 98.7%, and the 5-year graft survival rates were 96.8% and 98.0%, respectively, with no significant differences between the groups. There were no significant differences in the rates of surgical complications, rejection, and infection. The cumulative incidence of postoperative cardiovascular events was higher in the DM group than in the NDM group (8.5% vs 0.49% at 5 years; P = .002). CONCLUSIONS: Patient and graft survival rates after renal transplantation for type 2 diabetic nephropathy are not inferior to those for recipients without diabetic nephropathy. Considering the poor prognosis of patients with diabetic nephropathy on dialysis, renal transplantation can provide significant benefits for these patients. PMID- 25817615 TI - Correlation between Sleep Duration and Risk of Stroke. AB - Modern lifestyle and job requirements have changed the sleep habits of most of the adult population. Various population-based studies have associated an increase in mortality with either shortened sleep or long sleep duration. Thus a U-shaped relationship between sleep duration and all-cause mortality in both men and women has been suggested. Several studies have found an association between sleep duration and risk of cardiovascular diseases also. Efforts to understand the etiology of stroke have indicated an association between sleep and stroke too. Obstructive sleep apnea, a sleep-related disorder, has been reported to significantly increase the risk of stroke. Moreover, many studies have shown that both short and long sleep durations are related to increased likelihood of diabetes and hypertension, which themselves are risk factors for stroke. Therefore, this review focuses on the correlation between sleep duration and risk of stroke based on the experimental and epidemiologic studies. Although a few experimental studies have reported that partial sleep deprivation may reduce stroke incidence and severity, yet, most experimental and observational studies have indicated a strong association between short/long sleep durations and higher risk of stroke. PMID- 25817614 TI - Vertebrobasilar ectasia in patients with lacunar stroke: the secondary prevention of small subcortical strokes trial. AB - BACKGROUND: The clinical implications of vertebrobasilar ectasia (VBE) in patients with cerebral small-artery disease are not well defined. We investigated whether VBE is associated with recurrent stroke, major hemorrhage, and death in a large cohort of patients with recent lacunar stroke. METHODS: Maximum diameters of the vertebral and basilar arteries were measured by magnetic resonance angiography and computed tomographic angiography in 2621 participants in the Secondary Prevention of Small Subcortical Strokes trial. VBE was defined a priori as basilar artery greater than 4.5 mm and/or vertebral artery greater than 4.0 mm. Patient characteristics and risks of stroke recurrence and mortality during follow-up (median, 3.5 years) were compared between patients with and without VBE. RESULTS: VBE affecting 1 or more arteries was present in 200 (7.6%) patients. Patient features independently associated with VBE were increasing age, male sex, white race ethnicity, hypertension, and higher baseline diastolic blood pressure. Baseline systolic blood pressure was inversely associated with VBE. After adjustment for other risk factors, VBE was not predictive of recurrent stroke (hazard ratio [HR], 1.3; 95% confidence interval [CI], .85-1.9) or major hemorrhage (HR, 1.5; CI, .94-2.6), but was of death (HR, 1.7; CI, 1.1-2.7). CONCLUSIONS: In this large well-characterized cohort of patients with recent lacunar stroke, VBE was predictive of death but not of recurrent stroke or major hemorrhage. In these exploratory analyses, the frequency of VBE was directly related to diastolic blood pressure but inversely related to systolic blood pressure. PMID- 25817616 TI - Clinical study of 46 patients with lateral medullary infarction. AB - BACKGROUND: Lateral medullary infarction (LMI) exhibits a variety of clinical features. Various bulbar symptoms can occur in LMI. METHODS: Neuroradiologic findings of 46 LMI patients were examined. Their infarcts were categorized into the rostral, middle, and caudal groups and were further subdivided into the anteromedial, anterolateral, lateral (L), and posterior regions. RESULTS: The middle medulla was the most common site (27 patients). Most lesions affected the L region alone (25 patients). Dysarthria and facial palsy occurred significantly more frequently in the rostral group than those in the caudal group. Severe truncal ataxia was significantly more common in the caudal group than that in the rostral group. Twenty-five of the 28 patients with severe truncal ataxia displayed vestibular symptoms; otherwise, the other 3 patients showed absence of vestibular symptoms. Soft palate paralysis occurred at a significantly high frequency in the patients with dysphagia and hoarseness compared with the patients without these 2 symptoms. Segmental sensory disturbance occurred in 5 patients, 4 of whom exhibited atypical patterns. CONCLUSIONS: The results of our comparisons between the rostral and caudal groups were consistent with those of previous studies. The presence of severe truncal ataxia without vestibular symptoms in LMI was atypical. An analysis of the bulbar symptoms indicated that the extent to which soft palate paralysis contributed to dysphagia was associated with the severity of ischemia in the nucleus ambiguus. The present study showed variability in clinical features of LMI, which was related to differences in the severity and the extent of ischemia in the lateral medulla. PMID- 25817617 TI - Neurologic symptom severity after a recent noncardioembolic stroke and recurrent vascular risk. AB - BACKGROUND: There is a well-established relation of symptom severity with functional status and mortality after an index stroke. However, little is known about the impact of symptom severity of a recent index stroke on risk of recurrent vascular events. METHODS: We reviewed the data set of a multicenter trial involving 3680 recent noncardioembolic stroke patients aged 35 years or older and followed for 2 years. Independent associations of stroke severity (as measured by National Institutes of Health Stroke Scale [NIHSS] score) with recurrent stroke (primary outcome) and stroke/coronary heart disease (CHD)/vascular death (secondary outcome) were analyzed. NIHSS score was analyzed as a dichotomous (<4 versus >=4) and a continuous variable. RESULTS: Among study subjects, 550 (15%) had NIHSS scores of 4 or more (overall scores ranged from 0 to 18, median score was 1 [25th-75th percentile 0-2]). NIHSS was measured at a median of 35 days after the index stroke. After adjusting for multiple covariates, NIHSS of 4 or more was independently linked to a higher risk of recurrent stroke (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.01 1.84) and risk of stroke/CHD/vascular death (HR, 1.32; 95% CI, 1.07-1.64). Analysis of NIHSS score as a continuous variable also showed a higher risk of recurrent stroke (HR, 1.06; 95% CI, 1.00-1.12) and stroke/CHD/vascular death (HR, 1.05; 95% CI, 1.01-1.09) with increasing index stroke symptom severity. CONCLUSIONS: Greater residual symptom severity after a recent stroke is associated with higher risk of recurrent vascular events. Future studies are needed to confirm this relationship and to clarify its underlying mechanisms. PMID- 25817618 TI - Frequency of new pulmonary neoplasm incidentally detected by computed tomography angiography in acute stroke patients-a single-center study. AB - BACKGROUND: Incidental findings of suspect lung opacities are common in computed tomography (CT)-based thorax examinations, especially in high-risk patients, such as stroke patients. Screening with CT of the thorax has detected lung cancer in approximately .31%-1.20% of high-risk populations. The aim of the present study was to report the frequency of suspect lung opacities on routine acute stroke imaging. METHODS: Seven hundred and fifty-seven consecutive stroke patients evaluated for intravenous thrombolysis treatment within 4.5 hours of symptom debut, from June 2009 to December 2011, were included in a prospective registry on which this analysis was based. On admission, CT angiography from the aortic arch to vertex was performed, including the lung apices, corresponding to 1/3 of the total lung volume. A senior neuroradiologist reviewed all scans registering suspect lung opacities, which subsequently were characterized as either malignant, presumed malignant, presumed benign or benign, based on radiologic parameters of malignancy, positron emission tomography scan, histology, and clinical features. RESULTS: Suspect lung opacities appeared on the CT angiography in 20 patients (2.6%). Five suspect lung opacities were categorized as malignant and 3 suspect lung opacities were categorized as presumed malignant. This corresponds to an incidence of 1.1% (8 of 750). CONCLUSIONS: Malignant lung opacities were found in approximately 1% of this high-risk population, whereas our findings do not support full CT of the thorax as routine on stroke patients. PMID- 25817619 TI - Can the Montreal Cognitive Assessment predict discharge destination in a stroke population in the hospital? AB - BACKGROUND: To decide on an appropriate discharge destination for stroke survivors from hospital, factors such as activities of daily living and age are often taken into account as predictors. Cognition has been found to support the decision whether to send a patient home or to a dependent living situation. The Montreal Cognitive Assessment (MOCA) has been proven to be a suitable cognitive screening instrument in the acute phase after stroke. However, its predictive value in the determination of discharge destination is unknown. The aim of the present study was to examine whether cognitive functioning, as measured with the MOCA, in the acute phase after stroke could predict discharge destination. METHODS: The study involved 211 patients with a first-ever cerebral stroke within the first week after stroke. Demographic and stroke-specific data, cognitive functioning (MOCA), and level of functional disability (Barthel Index [BI]) were collected. Multivariate logistic regression analyses were used to predict discharge destination (dependent versus independent living situation). RESULTS: Both age (B = -.05; P < .01) and BI score (B = .33; P < .001) were found to be significantly related to discharge destination with explained variance of 43%. Adding MOCA score as a predictor variable to the model resulted in a nonsignificant improvement of the model, explaining 44% of the variance. CONCLUSIONS: Cognitive functioning, as measured by a single screening instrument such as the MOCA, in the acute phase after stroke is not predictive for discharge destination. PMID- 25817620 TI - Significant Association between Carotid Artery Kinking and Leukoaraiosis in Middle-Aged and Elderly Chinese Patients. AB - BACKGROUND: Leukoaraiosis (LA) and carotid artery morphologic variations are 2 common imaging manifestations. The purpose of this study was to determine whether carotid artery morphologic variations are correlated with LA. METHODS: A total of 702 patients, aged 50 years or older, admitted to our hospital from November 1, 2013, to January 30, 2014, were prospectively enrolled in this study. All participants underwent magnetic resonance imaging to assess the presence and severity of LA. Carotid artery morphologic variations were classified into tortuosity, kinking, and coiling by computed tomography angiography. Logistic regression analyses were performed to examine the relationship between carotid artery morphologic variations, its components, and LA. RESULTS: The frequency of hemisphere with LA and carotid artery with carotid artery morphologic variations was 49.9% and 70.3% in the cohort, respectively. Carotid kinking was associated with an increased risk of ipsilateral LA after multivariable adjustment (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.57-3.36 for left side; OR, 2.51; 95% CI: 1.68-3.74 for right side), whereas carotid tortuosity and coiling were not related to LA. Moreover, the prevalence of carotid kinking gradually increased with advancing grades of ipsilateral LA. CONCLUSIONS: The present study demonstrated that carotid artery kinking may be associated with an increased risk of LA in middle-aged and elderly Chinese patients. Further prospective studies are needed to confirm these findings. PMID- 25817621 TI - Isolated Unilateral Ptosis due to Paramedian Midbrain Infarction. AB - A 59-year-old man who had hypertension, dyslipidemia, diabetes mellitus, and left eye glaucoma developed sudden vertigo and left ptosis; he did not notice diplopia. He visited our hospital on day 3 after onset and neurologic examination showed left ptosis. His left visual acuity was counting fingers, and the light reflex was sluggish owing to glaucoma. Pupil sizes were equal, and eye movements and the lower lid were unremarkable. Magnetic resonance images revealed an acute infarction of the left paramedian midbrain. We considered that selective damage to the oculomotor fascicles innervating the left levator palpebrae superioris caused ipsilateral ptosis. As the fascicles for this ocular muscle run in the small area adjacent to those for the medial rectus, inferior rectus and superior rectus muscles, this is an extremely rare case of midbrain infarction presenting with isolated unilateral ptosis. PMID- 25817622 TI - Prediction of cerebrovascular reserve capacity by computed tomography perfusion using 320-row computed tomography. AB - BACKGROUND: Acetazolamide loading has been the "gold standard" for evaluating cerebrovascular reserve capacity (CVRC). However, life-threatening side effects of acetazolamide have recently been reported. The aim of the study was to identify alternative methods for evaluating CVRC. METHODS: We reviewed 6 patients who underwent both computed tomography perfusion (CTP) imaging and xenon CT (XeCT) imaging with and without acetazolamide loading during the same periods. The data were obtained as volume data using 320-row CT and applied to the automated region of interest-determining software and converted to standardized images. Correlations between CVRC and CTP parameters were analyzed by Pearson correlation coefficient analysis, and simple regression was used to assess the relationship between the data. When statistically significant, correlation between CVRC and any CTP data is identified, and cutoff points for CVRC 30% and 10% were calculated with receiver operating characteristic curves. RESULTS: Of 4 CTP parameters evaluated, statistically significant correlations were observed between time to peak (TTP) by CTP and CVRC (P < .0001, r = -.7228) calculated from XeCT. The regression line using CVRC as outcome variable (y) and using TTP as predictor variable (x) was y = -9.062x + 140.1. The cutoff value for the TTP for CVRC less than 10% was 12.56 seconds (sensitivity of 86% and specificity of 85%) and that for CVRC less than 30% was 9.34 seconds (sensitivity of 77% and specificity of 96%). CONCLUSIONS: TTP calculated from CTP data correlated well with the CVRC calculated from XeCT data. These results suggest that TTP calculated from CTP could be used to estimate CVRC in patients with occlusive cardiovascular disease. PMID- 25817623 TI - Genetic Analysis of RNF213 c.14576G>A Variant in Nonatherosclerotic Quasi Moyamoya Disease. AB - BACKGROUND: Quasi-moyamoya disease (MMD) and MMD (definite MMD) have similar cerebral angiographic features, but whether these related diseases have similar etiology or genetic background remains unclear. Recently, we have reported that the recently identified MMD susceptibility gene variant RNF213 c.14576G>A (rs112735431) was associated with atherosclerotic intracranial major artery stenosis/occlusion. The present study investigated the occurrence of RNF213 c.14576G>A in patients with nonatherosclerotic quasi-MMD. METHODS: This study was a 2-hospital-based case-control study conducted at the Department of Neurosurgery, The University of Tokyo Hospital and Kanto Neurosurgical Hospital. A total of 87 Japanese patients who agreed to participate in this study were enrolled among both new and revisiting outpatients from October 2011 to December 2013 as follows: 78 patients with definite MMD and 9 patients with nonatherosclerotic quasi-MMD. RESULTS: The 9 patients with nonatherosclerotic quasi-MMD included 3 patients with previous irradiation, 2 with hyperthyroidism, 1 with Turner syndrome, 1 with meningitis, 1 with Behcet disease, and 1 with idiopathic pachymeningitis. The 78 patients with definite MMD included 66 patients (84.6%) with the c.14576G>A variant (64 heterozygotes and 2 homozygous). In contrast, no patients with nonatherosclerotic quasi-MMD had the variant. CONCLUSIONS: Nonatherosclerotic quasi-MMD did not have RNF213 c.14576G>A variant. Moyamoya disease and related diseases might be classified by genetic analysis of the RNF213 c.14576G>A genotype. Further larger studies are required to confirm the present findings. PMID- 25817624 TI - Early relapsing calcified cerebral embolism. AB - Calcified cerebral emboli are rarely reported, but may be recurrent and devastating. Misdiagnosis at interpretation of initial brain computed tomography (CT) scan may occur in up to 27% of cases. The purpose of this case report was to describe clinical, CT, and CT angiography findings in a 79-year-old woman undergoing early recurrent stroke from calcified cerebral embolism. Neuroradiology should not overlook calcified cerebral embolism, and this confirms the role of CT in the assessment of stroke. PMID- 25817625 TI - Serum uric acid is neuroprotective in Chinese patients with acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator. AB - BACKGROUND: Exogenous uric acid (UA) is a neuroprotective antioxidant that reinforces the benefits of intravenous recombinant tissue plasminogen activator thrombolysis in animal thromboembolic stroke. However, whether serum uric acid (SUA) also increases the benefits of thrombolysis in Chinese patients with acute ischemic stroke (AIS) has yet to be fully defined. METHODS: A total of 216 consecutive AIS patients of Chinese origin treated with intravenous thrombolysis were enrolled in a prospective stroke registry. Demographic and clinical characteristics, conventional risk factors, important laboratory data, and neurologic course were prospectively recorded. Functional outcomes were assessed with the modified Rankin Scale (mRS) score on day 90 by telephone calls. Receiver operating characteristic curves and binary logistic regression models were used to examine the performance of SUA in predicting excellent outcomes (mRS, 0-1). RESULTS: SUA levels were significantly higher in patients with excellent outcomes than those in patients with poor outcomes (331.46 +/- 103.39 versus 277.69 +/- 105.62, P = .008). SUA had a modest power for predicting excellent outcomes as suggested by area under the curve of .665 +/- .052, P = .003. In multivariate models, increased SUA levels (adjusted odds ratio, 1.005; 95% confidence interval, 1.002-1.009; P = .033) were associated with excellent outcomes independently of the effect of possible confounders. Spearman correlation tests indicated that there was an inverse correlation between SUA levels and stroke severity. CONCLUSIONS: Increased SUA levels are associated with excellent outcomes in Chinese patients with AIS treated with intravenous thrombolysis, giving additional support to administration of exogenous UA as an adjuvant to thrombolysis. PMID- 25817627 TI - Transient Neurologic Deficits: Can Transient Ischemic Attacks Be Discriminated from Migraine Aura without Headache? AB - BACKGROUND: Transient neurologic deficits (TNDs) are often considered first to be transient ischemic attacks (TIAs) but TND with normal brain imaging is also characteristic of other prevalent conditions like migraine aura leading to potential confusion. We aimed to determine if migraine aura with headache (MA) and migraine aura without headache (MAWH) can be distinguished from TIA on clinical or paraclinical ground using validated international criteria. METHODS: Clinical and paraclinical data from 32 patients with TIA were compared with 32 patients with MAWH and 32 with MA. Participants underwent a thorough evaluation including standardized clinical examination, laboratory testing, magnetic resonance imaging of the brain, cardiovascular work-up, and electroencephalogram. RESULTS: Patient with TIA were significantly older (65.41 +/- 16.93 years) than patients with MAWH (50.41 +/- 19.69, P = .002) or MA (40.56 +/- 11.72, P = .00001), and were mostly male (male:female = .82) compared with the 2 other groups. History of stroke, high blood pressure, and dyslipidemia were significantly more frequent in patients with TIA. Visual deficits occurred in 63% of patients with MAWH, 41% for patients with MA, and 10% for patients with TIA. In patients with TIA, the TND was inaugural in 94% of cases, conversely to MAWH and MA in which TND was inaugural in only 19% and 38%, respectively (P <= .0001). CONCLUSIONS: Despite some sociodemographic, clinical, and paraclinical differences in the presentation of these TND, there is no feature accurately distinguishing between TIA and TND associated with migrainous phenomena when validated actual criteria are used, leading to probable confusion in most studies. There is a need to develop reliable criteria and/or tests for this purpose. PMID- 25817626 TI - Stroke Awareness Is Worse among the Old and Poorly Educated: A Population-Based Survey. AB - BACKGROUND: This article surveys a representative sample of adults to assess their knowledge of stroke, its vascular risk factors and warning symptoms, illness perception, and attitude toward strokes. METHODS: A representative sample of the region population was selected using a double randomization design. Previously trained medical students carried out face-to-face interviews using a structured questionnaire with open- and closed-ended questions. RESULTS: In all, 2411 subjects were interviewed. Seventy-three percent reported at least 1 correct warning sign of stroke, whereas only 12.2% reported 3. The most frequently mentioned were sudden weakness, dizziness, and headache. Only 59.2% named at least 1 correct risk factor for stroke. Smoking and hypertension were mainly named. Forty percent of the respondents demonstrated adequate knowledge of stroke. Tellingly, prevalence of adequate knowledge was significantly lower in subjects with previous stroke (29.3% [95% confidence interval {CI}, 19.7-40.3], P = .049), hypertension (35.0% [95% CI, 31.1-39.1], P = .009), diabetes (31.9% [95% CI, 25.9-38.3], P = .011), hypercholesterolemia (35.8% [95% CI, 31.8-39.9], P = .03), and obesity (28.2% [95% CI, 23.8-33.0], P < .001). Illness perception was generally correct. In the final logistic regression model, younger age, urban area of residence, higher educational level, higher family income, normal pressure, normal weight, and family history of stroke were associated with adequate knowledge of stroke. CONCLUSIONS: Basic knowledge of stroke is insufficient among the general population of Extremadura. There is a discrepancy between theoretical stroke knowledge and illness perception. These findings have implications for public health initiatives for stroke. PMID- 25817628 TI - Detection of basilar artery dissection by ultrasound. AB - We report a case of a 45-year-old woman with unusual headache 1 week before admission. After cerebrovascular ultrasound, a basilar artery dissection was supposed despite the normal neurologic, cerebrospinal fluid, and computed tomography findings. On a follow-up color-coded duplex sonography (1 month after the onset), reperfusion was detected in the vertebral and basilar arteries, but residual high-grade stenosis of the basilar artery was also present. PMID- 25817629 TI - Detectability of ischemic lesions on diffusion-weighted imaging is biphasic after transient ischemic attack. AB - BACKGROUND: Experimental studies of transient focal ischemia indicate biphasic detectability of lesions by diffusion-weighted imaging (DWI); poorly detectable phase exists at 1-12 hours after reperfusion. The present study aimed to clarify whether poorly detectable phase also exists in DWI of transient ischemic attack (TIA) patients. METHODS: A retrospective study was conducted in 144 consecutive TIA patients who underwent magnetic resonance imaging (MRI) within 2 weeks after carotid TIA. Patients were classified into 9 groups according to time from disappearance of TIA symptoms to DWI: intraischemic period, 0-1 hour, 1-12 hours, 12-24 hours, 1-2 days, 2-3 days, 3-7 days, 7-10 days, and 10-14 days after the end of TIA. RESULTS: Lesions were detected in 33 of 144 patients (22.9%). The frequency of positive lesions was 20% in the intraischemic period and 30.8% at 0 1 hour after the end of TIA; it markedly decreased to 8.7% at 1-12 hours after end of TIA. Thereafter, it increased to 21.7%, 30.8%, 36.4%, 37.0%, 38.5%, and 30% at 12-24 hours, 1-2 days, 2-3 days, 3-7 days, 7-10 days, and 10-14 days after the end of TIA, respectively. In 7 patients, MRI was repeated twice, at 1-12 hours and then at 5-13 days after the end of TIA. Lesions were never detected on the first MRI but were clearly demonstrated in 4 of 7 patients on the second MRI. CONCLUSIONS: The detectability of ischemic lesions may be biphasic after TIA as indicated by experimental studies. PMID- 25817630 TI - Does airway hyperresponsiveness monitoring lead to improved asthma control? AB - The current guidelines recommend an approach to asthma management based on asthma control, rather than asthma severity. Although several specific questionnaires have been developed and control criteria have been established based on clinical guidelines, the evaluation of asthma control is still not optimal. In general, these indicators provide adequate assessment of current control, but they are more limited when estimating future risk. There is much evidence demonstrating the persistence of airway inflammation and airway hyperresponsiveness (AHR) in patients with total control. Therefore, the objective of this review was to analyse the possible role of AHR monitoring as an instrument for assessing asthma control. We will evaluate its capacity as an indicator for future risk, both for estimating the possibility of clinical deterioration and loss of lung function or exacerbations. Furthermore, its relationship with inhaled corticosteroid treatment will be analysed, while emphasizing its capacity for predicting response and adjusting dosage, as well as information about the capability of AHR for monitoring treatment. Last of all, we will discuss the main limitations and emerging opportunities of AHR as an assessment instrument for asthma control. PMID- 25817631 TI - Concordance between 11C-PIB-PET and clinical diagnosis in a memory clinic. AB - INTRODUCTION: Today, ligands that bind to fibrillar beta-amyloid are detectable by Positron Emission Tomography (PET) allowing for in vivo visualization for Abeta burden. However, amyloid plaques detection per se does not establish Alzheimer's Disease diagnosis. In this sense, the utility of amyloid imaging to improve clinical diagnosis was settled only for specific clinical scenarios and few studies have assessed amyloid molecular neuroimaging in a broader clinical setting. The aim of this study is to determine the frequency of PiB amyloid findings in different diagnostic syndromes grouped into high and low probability pre- test categories, taking into account pre-test clinical assumption of the presence of AD related pathology. METHODS: 144 patients were assigned into categories of high or low pretest probability according to clinical suspicion of AD pathology. The high probability group included: amnestic Mild Cognitive Impairment (MCI), amnestic and other domains MCI, Dementia of Alzheimer's Type (DAT), Posterior Cortical Atrophy (PCA), logopenic Primary Progressive Aphasia (PPA), Cerebral Amyloid Angiopathy and mixed dementia. The low assumption group included: normal controls, non-amnestic MCI, non-logopenic PPA and Frontotemporal Dementia (FTD). RESULTS: Only normal controls and DAT patients (typical and atypical presentation) were the most consistent across clinical and molecular diagnostics. MCI, non-logopenic PPA and FTD were the syndromic diagnoses that most discrepancies were found. DISCUSSION: This study demonstrates that detecting in vivo amyloid plaques by molecular imaging is considerably frequent in most of the dementia syndromes and shows that there are frequent discordance between molecular diagnosis and clinical assumption. PMID- 25817632 TI - Abdominal desmoid tumors. A new reconstructive approach. AB - INTRODUCTION: Desmoid tumors are rare soft tissue tumors derived from musculoaponeurotic structures of the abdominal wall musculature. Although they are considered benign tumors because they don't metastasize to other parts of the body, they are clinically considered as malignant for their high tendency on infiltrative growth with local invasion and trend to recurrence after local excision. Several reconstructive techniques are proposed in the literature. METHODS: Nine female patients with abdominal desmoid tumors underwent the removal of a mass of tissue running from the skin to peritoneum near the tumor with a safety margin in macroscopically normal tissue at least of 5 centimeters from the edge of the tumor. After wide excision, a polypropylene mesh was placed in the rear muscular pocket without anchoring suture (sliding mesh sutureless hernioplasty) RESULTS: No patients had perioperative complications or abdominal wall weakness or an incisional hernia in the following 5 years. CONCLUSIONS: We consider this technique of abdominal wall reconstruction after desmoid tumor removal a simple procedure that reduces relapsing events and recurrences of abdominal hernia, reducing tension and pain caused by the traditional suture repair technique. LEVEL OF EVIDENCE: IV. PMID- 25817633 TI - Confusion surrounds UK policy on open access publishing, review finds. PMID- 25817635 TI - Preparation of zwitterionically charged nanocrystals by surface TEMPO-mediated oxidation and partial deacetylation of alpha-chitin. AB - Zwitterionic nanocrystals were prepared by TEMPO-mediated oxidation, partial deacetylation, and subsequent mechanical disintegration of alpha-chitin. The pH dependence of the morphology, transparency, and viscosity of the nanocrystals were evaluated. After those reactions, the carboxylate and amino group contents of the chitin derivative were 0.45 and 1.26 mmol/g, respectively. After mechanical treatment, the water dispersion consisted of nanocrystals approximately 250 nm long and 10nm thick. Under acidic and basic conditions, the water dispersions were highly transparent. On the other hand, under neutral conditions, the dispersion was turbid due to the ionic interaction between the cationic and anionic groups on the nanocrystal surface. Although the surface zwitterionic nanocrystals collected from acidic and basic dispersion were randomly oriented due to electrostatic repulsions, nanocrystals formed aggregates in neutral water due to the cationic and anionic interaction between them. Nanocrystals in neutral water had higher viscosity than those in acidic and basic water, since ionic interaction caused nanocrystal networks to form in water. PMID- 25817634 TI - Use of synchrotron medical microbeam irradiation to investigate radiation-induced bystander and abscopal effects in vivo. AB - The question of whether bystander and abscopal effects are the same is unclear. Our experimental system enables us to address this question by allowing irradiated organisms to partner with unexposed individuals. Organs from both animals and appropriate sham and scatter dose controls are tested for expression of several endpoints such as calcium flux, role of 5HT, reporter assay cell death and proteomic profile. The results show that membrane related functions of calcium and 5HT are critical for true bystander effect expression. Our original inter-animal experiments used fish species whole body irradiated with low doses of X-rays, which prevented us from addressing the abscopal effect question. Data which are much more relevant in radiotherapy are now available for rats which received high dose local irradiation to the implanted right brain glioma. The data were generated using quasi-parallel microbeams at the biomedical beamline at the European Synchrotron Radiation Facility in Grenoble France. This means we can directly compare abscopal and "true" bystander effects in a rodent tumour model. Analysis of right brain hemisphere, left brain and urinary bladder in the directly irradiated animals and their unirradiated partners strongly suggests that bystander effects (in partner animals) are not the same as abscopal effects (in the irradiated animal). Furthermore, the presence of a tumour in the right brain alters the magnitude of both abscopal and bystander effects in the tissues from the directly irradiated animal and in the unirradiated partners which did not contain tumours, meaning the type of signal was different. PMID- 25817636 TI - The stability and degradation kinetics of Sulforaphene in microcapsules based on several biopolymers via spray drying. AB - Sulforaphene (SFE) was extracted from the radish seeds and the purity of SFE extracted by our laboratory was 95%. It is well known that SFE can prevent cancers. It is also known that SFE is unstable to heat. To overcome the problem, SFE microcapsules using natural biopolymers were prepared by spray drying. The results indicated that SFE microcapsules using hydroxypropyl-beta-cyclodextrin (HP-beta-CD), maltodextrin (MD) and isolated soybean protein (SPI) as wall materials could effectively improve its stability against heat, especially SFE loaded HP-beta-CD and MD microcapsules. The amount of SFE in the microcapsules was found 20% higher than that of the non-encapsulated SFE under 90 degrees C in 168 h. Our finding suggested that the rate of degradation of the non-encapsulated and encapsulated SFE with HP-beta-CD, MD and SPI followed the first-order kinetics. The speed of the degradation of the encapsulated SFE in biopolymers increased from SFE with HP-beta-CD, to SFE with MD, and to SFE-SPI. The non encapsulated SFE degrades fastest. PMID- 25817637 TI - Glow discharge electrolysis plasma initiated preparation of temperature/pH dual sensitivity reed hemicellulose-based hydrogels. AB - The temperature/pH dual sensitivity reed hemicellulose-based hydrogels have been prepared through glow discharge electrolysis plasma (GDEP). The effect of different discharge voltages on the temperature and pH response performance of reed hemicellulose-based hydrogels was inspected, and the formation mechanism, deswelling behaviors of reed hemicellulose-based hydrogels were also discussed. At the same time, infrared spectroscopy (FT-IR), scanning differential thermal analysis (DSC) and scanning electron microscope (SEM) were adopted to characterize the structure, phase transformation behaviors and microstructure of hydrogels. It turned out to be that all reed hemicellulose-based hydrogels had a double sensitivity to temperature and pH, and their phase transition temperatures were all approximately 33 degrees C, as well as the deswelling dynamics met the first model. In addition, the hydrogel (TPRH-3), under discharge voltage 600 V, was more sensitive to temperature and pH and had higher deswelling ratio. PMID- 25817638 TI - Chitosan nanofibers fabricated by combined ultrasonic atomization and freeze casting. AB - Aligned chitosan nanofibers exhibiting diameters smaller than 100 nm were easily prepared by combining ultrasonic atomization with freeze casting. A major advantage of this approach is the use of distilled water as main solvent. Scanning electron microscopy demonstrated that fiber diameter and morphology mainly depended on the atomizing tools, freezing temperature, and chitosan solution viscosity. Minimum diameter and uniform orientation were achieved using an electric flosser as an atomizing tool, liquid nitrogen as a coolant, 0.4 wt% aqueous chitosan solution (molecular weight = 22 kDa), and a small amount of lactic acid as solvent at 0 degrees C. The resulting chitosan nanofibers may find application in biomedical and food engineering. Moreover, this new technology may be applicable to other natural and synthetic water-soluble polymers. PMID- 25817639 TI - Low molecular weight heparin mediating targeting of lymph node metastasis based on nanoliposome and enzyme-substrate interaction. AB - The aim of our study is to develop a new function of low molecular weight heparin (LMWHEP) for targeting tumor metastatic lymph node based on LMWHEP-modified nanoliposome and LMWHEP-heparanase (HPA) interaction (LMWHEP-HPA). At First, LMWHEP-modified nanoliposomes (LMWHEP-LPs) were prepared by the electrostatic attraction and the physiochemical properties were evaluated. Then the effects of LMWHEP-HPA on the stability and drug release were investigated. In addition, the cellular uptake of LMWHEP-LPs was studied by using Hela, MCF-7, L929 and RAW264.7 cells. Finally, the targeting ability as well as the tissue distribution was examined in the mice model bearing Hela tumor lymph node metastasis. LMWHEP-LPs prepared had suitable physicochemical properties. The effect results of LMWHEP HPA showed that LMWHEP coated on the surface of nanoliposome could be degraded by HPA. Compared with the unmodified-nanoliposome, the LMWHEP modification could improve the cellular uptake and increase the targeting ability to the metastatic lymph nodes according to LMWHEP-HPA. This study demonstrates LMWHEP is a highly promising polymer material for the targeting of tumor lymph node metastasis. PMID- 25817640 TI - Extraction of a soluble polysaccharide from Auricularia polytricha and evaluation of its anti-hypercholesterolemic effect in rats. AB - Mushroom extracts are a new source of supplements for health and pharmaceutical due to their bioactivities. This study was to optimize the extraction parameters of a soluble polysaccharide from Auricularia polytricha (SPAP) by response surface methodology. The practical optimum parameters were an extraction time of 4h, an extraction temperature of 95 degrees C and a ratio of water to fruiting bodies of 28 mL/g, and the highest extraction rate was 19.77%. In vivo, male Sprague-Dawley (SD) rats were diet-induced hypercholesterolemic models and oral administration of SPAP to evaluate anti-hypercholesterolemic effects. The results showed that SPAP decreased the serum concentrations of blood lipid, made them close to the normal level. The total cholesterol in the SPAP consumption groups was significantly decreased 34.6 +/- 7.6% and 33.3 +/- 7.9% with dose of 4.5 and 9.0mg/kg BW in the 29th day. This study suggested that SPAP was a suitable natural agent and may be applied in therapy. PMID- 25817641 TI - Optimized synthesis of O-carboxymethyl-N,N,N-trimethyl chitosan. AB - We present here the synthesis of a highly O-carboxymethylated chitosan derivative. First, an improved protocol for the two-step synthesis of N-trimethyl chitosan (TMC) from chitosan was developed, yielding a maximum degree of quaternization (DQ) of up to 46.6%. Successively, the chitosan derivative O carboxymethyl-N-trimethyl chitosan (CMTMC) was synthesized from the TMC obtained by applying an optimized synthesis pathway. In contrast to previous reports, the optimized protocol was shown to yield very high rates (>85%) of O carboxymethylation of CMTMC, as shown by (1)H NMR and heteronuclear single quantum correlation ((1)H-(13)C HSQC). Finally, in vitro cytocompatibility (viability >80%) of the polymer was demonstrated using human fibroblasts. PMID- 25817642 TI - Preparation of arginine modified PEI-conjugated chitosan copolymer for DNA delivery. AB - Polyethylenimine-conjugated chitosan (CS-PEI) and arginine modified polyethylenimine-conjugated chitosan (CS-PEI-Arg) were prepared, and the copolymers were characterized by FTIR, (1)H NMR, and XRD. The properties of these copolymers like plasmid DNA (pDNA) binding capacity, complexes' size and zeta potential, cytotoxicity and transfection efficiency were also evaluated. The results show that CS-PEI-Arg derivatives can bind pDNA thoroughly, and form complexes with sizes about 170 nm. Cytotoxicity assay in HepG2 and 293T cells show that CS-PEI-Arg has lower cytotoxicity compared with CS-PEI, which is similar to CS and far below that of PEI. In vitro luciferase assay show that CS PEI-Arg has better transfection efficiency than CS-PEI, which is superior to that of PEI. The best transfection efficiency of CS-PEI-Arg (N/P = 50) is 2.3-fold, 4.2-fold of those of CS-PEI (N/P = 20) and PEI's (N/P = 10) efficiency respectively. These results display that CS-PEI-Arg is a promising candidate as an efficient gene vector. PMID- 25817643 TI - Cellulose nanocrystal isolation from tomato peels and assembled nanofibers. AB - Pure cellulose has been successfully isolated from tomato peels by either acidified sodium chlorite or chlorine-free alkaline peroxide routes, at 10.2 13.1% yields. Negatively charged (zeta = -52.4 mV, 0.48 at% S content) and flat spindle shaped (41:2:1 length:width:thickness) cellulose nanocrystals (CNCs) were isolated at a 15.7% yield via sulfuric acid hydrolysis (64% H2SO4, 8.75 mL/g, 45 degrees C, 30 min). CNCs could be facilely assembled from dilute aqueous suspensions into highly crystalline (80.8%) cellulose Ibeta fibrous mass containing mostly sub-micron fibers (phi = 260 nm) and few interconnected nanofibers (phi = 38 nm), with 21.7 m(2)/g specific surface and 0.049 m(3)/g pore volume. More uniformly nanofibers with average 42 nm width and significantly improved specific surface area (101.8m(2)/g), mesoporosity and pore volume (0.4m(3)/g) could be assembled from CNCs in 1:1 v/v tert-butanol/water mixture. PMID- 25817645 TI - Impact of single and dual modifications on physicochemical properties of japonica and indica rice starches. AB - The japonica (JR) and indica (IR) rice starches were modified by acetylation, hydroxypropylation, cross-linking, and dual modification (cross-linked acetylation and cross-linked hydroxypropylation) and the effects of single and dual chemical modifications of JR and WR on the physicochemical properties were investigated. The JR had a greater substitution degree of acetyl or hydroxypropyl groups than IR. The dual-modified JR showed broader gelatinization temperature range than corresponding single-modified starches, but narrower it in IR. The dual-modified JR and IR showed higher pasting temperature and lower breakdown than their corresponding single-modified starches. The dual modification with JR and IR induced significant increase in gel hardness as compared to the corresponding unmodified and single-modified starches. The dual-modified JR had a greater hardness, gumminess, and chewiness than the dual-modified IR. The different impact of single and dual modification with JR and IR on the physicochemical properties could be due to the differences in the location and distribution of substituent groups on the starch molecules. PMID- 25817644 TI - A bioactive film based on cashew gum polysaccharide for wound dressing applications. AB - This work presents the development of a new bioactive material for wound therapeutics which may play a dual role of modulate metallo proteinases activity while prevents infection blocking out pathogenic microorganisms and foreign materials. A CGP/PVA film was activated by covalent immobilization of trypsin. Results from biocompatibility test revealed that PDL fibroblasts grown on the surface of CGP/PVA and the high amount of viable cells proved absence of cytotoxicity. Trypsin immobilized onto CGP/PVA film remained 100% active after 28 days stored dried at room temperature. In addition, CGP/PVA-trypsin film could be used for 9 cycles of storage/use without loss of activity. After immobilization, trypsin retained its collagenolytic activity, indicating this material as a promising material for wound dressing applications. PMID- 25817646 TI - Water-soluble aminocurdlan derivatives by chemoselective azide reduction using NaBH4. AB - Water-solubility can often enhance the utility of polysaccharide derivatives, for example in pharmaceutical and biomedical applications. Synthesis of water-soluble aminopolysaccharides, particularly those bearing other sensitive functional groups, can be a challenging endeavor. Curdlan is a bioactive beta-1,3-glucan with considerable promise for biomedical applications. Aminocurdlans are intriguing target molecules for study of, for example, their interactions with the proteins that form tight junctions between enterocytes. Herein we report the preparation of two water-soluble 6-aminocurdlans starting from 6-bromo-6 deoxycurdlan. The 6-bromide was first displaced by nucleophilic substitution with sodium azide in dimethyl sulfoxide. The O-2 groups were acylated with hydrophilic oligo (ethylene oxide) esters, so as to enhance aqueous solubility. The resultant 6-azido-6-deoxy-2,4-di-O-trioxadecanoylcurdlan was then treated with excess sodium borohydride to reduce the azide; unexpectedly, the water-soluble product proved to be the amide, 6-trioxadecanamido-6-deoxycurdlan. Regioselectivity and degree of substitution (DS) of those derivatives were characterized by means of (1)H NMR, (13)C NMR and FTIR-spectroscopy, elemental analysis, and titration. Alternatively, direct borohydride reduction of the parent 6-azido-6-deoxycurdlan afforded 6-amino-6-deoxycurdlan that was also water-soluble. PMID- 25817647 TI - Purification, characterization and neuroprotective effects of a polysaccharide from Gynostemma pentaphyllum. AB - In the present study, we investigated the neuroprotective effects of GPP1, a purified polysaccharide from Gynostemma pentaphyllum, on Abeta (25-35)-induced neuronal toxicity and explore its potential mechanisms in PC12 cells. The results showed pretreatment with GPP1 prior to Abeta (25-35) exposure significantly protected PC12 cells from Abeta (25-35)-induced cell death, lactate dehydrogenase (LDH) release, DNA damage, intracellular free calcium concentration ([Ca(2+)]i) influx, mitochondrial dysfunction and mitochondrial cytochrome c (Cyt-C) release. In addition, pretreatment with GPP1 also protected PC12 cells against Abeta (25 35)-induced the accumulation of reactive oxygen species (ROS) and lipid peroxidation product MDA, the reduction in glutathione (GSH) level and superoxide dismutase (SOD) activity, the increased Bax/Bcl-2 protein expression ratio and caspase-3 activation. Our findings suggest that GPP1 exerts a neuroprotective effect against Abeta (25-35)-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and suppressing the mitochondrial apoptotic pathway. PMID- 25817648 TI - Structural modification and characterisation of a sugary maize soluble starch particle after double enzyme treatment. AB - Sugary maize soluble starch particles were modified by using a combined beta amylase and transglucosidase reaction, and their molecular fine structure and susceptibility to digestive enzymes were investigated. After the dual enzyme treatment, the molecular weight of starch particle decreased from 2.08 * 10(7) to 0.96 * 10(7)g/mol accompanied by the appearance of DP 2-5 chains and the degradation of DP > 12 chains, and the percentage of alpha-1,6 linkages increased from 8.1 to 21.7%. The digestion behaviour of enzyme-treated starch was correlated with the quantity of shorter chains and increased alpha-1,6 linkages. The data revealed that maize soluble starches subjected to a combined beta amylase and transglucosidase treatment for 60 min or greater, produced novel, highly branched nano-particles with slow digestion and resistance characteristics, which could be used as a potential delivery carrier for functional food components. PMID- 25817649 TI - Crystallization and chain reorganization of debranched rice starches in relation to resistant starch formation. AB - The effects of chain distribution, concentration, temperature and hydrothermal treatments on the recrystallization behavior and formation of resistant starch (RS) were investigated. Waxy and normal rice starches were debranched at 10 and 21% w/w solid concentrations, incubated at 25 or 50 degrees C, and further subjected to annealing or heat moisture treatment (HMT) to enhance RS formation. The crystallization at 25 degrees C favored the formation of the B-type structure, whereas crystallization at 50 degrees C led to the A-type structure with a higher melting temperature (100-120 degrees C) and a higher RS content (52%). All incubated samples showed an increase in RS content after subsequent hydrothermal treatments. The sample incubated at a high temperature contained the highest RS content (74.5%) after HMT with larger/perfect crystallites. These results suggested that the RS formation could be manipulated by crystallization conditions and improved by hydrothermal treatments which are dependent on the initial crystalline perfection. PMID- 25817650 TI - Biodegradation of starch films: the roles of molecular and crystalline structure. AB - The influences of molecular, crystalline and granular structures on the biodegradability of compression-molded starch films were investigated. Fungal alpha-amylase was used as model degradation agent. The substrates comprised varied starch structures obtained by different degrees of acid hydrolysis, different granular sizes using size fractionation, and different degrees of crystallinity by aging for different times (up to 14 days). Two stages are identified for unretrograded films by fitting degradation data using first-order kinetics. Starch films containing larger molecules were degraded faster, but the rate coefficient was independent of the granule size. Retrograded films were degraded much slower than unretrograded ones, with a similar rate coefficient to that in the second stage of unretrograded films. Although initially the smaller molecules or the easily accessible starch chains on the amorphous film surface were degraded faster, the more ordered structure (resistant starch) formed from retrogradation, either before or during enzymatic degradation, strongly inhibits film biodegradation. PMID- 25817651 TI - Fabrication of cyclodextrins-procainamide supramolecular self-assembly: shape shifting of nanosheet into microtubular structure. AB - Encapsulation behavior of alpha- and beta-cyclodextrins (alpha-CD, beta-CD) with procainamide hydrochloride (PCA) has been investigated by absorption, fluorescence, time-resolved fluorescence, proton nuclear magnetic resonance spectroscopy, scanning electron microscope, Fourier transform-infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction techniques. Spectral results revealed that PCA forms 1:2 drug-CD2 inclusion complexes with CDs. Novel supramolecular self-assemblies have been fabricated by inclusion complexation of PCA with alpha-CD/beta-CD and characterized by transmission electron microscope and micro-Raman imaging. The obtained results from transmission electron microscope indicated that PCA/alpha-CD complex could form nano-sized particles. However, when the macrocyclic ring with six glucose units was switched into seven glucose units, the resultant PCA/beta-CD complex could be self-assembled to micro-sized tubular structures. Shape-shifting of 2D nanosheet into 1D microtube by simple rolling mechanism was analyzed. Thermodynamic parameters of inclusion process were determined by Parameter Method 3 calculations. PMID- 25817652 TI - High concentration honey chitosan electrospun nanofibers: biocompatibility and antibacterial effects. AB - Honey nanofibers represent an attractive formulation with unique medicinal and wound healing advantages. Nanofibers with honey concentrations of <10% were prepared, however, there is a need to prepare nanofibers with higher honey concentrations to increase the antibacterial and wound healing effects. In this work, chitosan and honey (H) were cospun with polyvinyl alcohol (P) allowing the fabrication of nanofibers with high honey concentrations up to 40% and high chitosan concentrations up to 5.5% of the total weight of the fibers using biocompatible solvents (1% acetic acid). The fabricated nanofibers were further chemically crosslinked, by exposure to glutaraldehyde vapor, and physically crosslinked by heating and freezing/thawing. The new HP-chitosan nanofibers showed pronounced antibacterial activity against Staphylococcus aureus but weak antibacterial activity against Escherichia coli. The developed HP-chitosan nanofibers revealed no cytotoxicity effects on cultured fibroblasts. In conclusion, biocompatible, antimicrobial crosslinked honey/polyvinyl alcohol/chitosan nanofibers were developed which hold potential as effective wound dressing. PMID- 25817653 TI - Coating cortical bone allografts with periosteum-mimetic scaffolds made of chitosan, trimethyl chitosan, and heparin. AB - Bone allografts have very limited healing leading to high rates of failure from non-union, fracture, and infection. The limited healing of bone allografts is due in large part to devitalization and removal of the periosteum, which removes osteogenic cells and osteoinductive signals. Here we report techniques for directly coating cortical bone with tissue scaffolds, and evaluate the scaffolds' capacity to support osteoprogenitor cells. Three types of coatings are investigated: N,N,N-trimethyl chitosan-heparin polyelectrolyte multilayers, freeze-dried porous chitosan foam coatings, and electrospun chitosan nanofibers. The freeze-dried and electrospun scaffolds are also further modified with polyelectrolyte multilayers. All of the scaffolds are durable to subsequent aqueous processing, and are cytocompatible with adipose-derived stem cells. Alkaline phosphatase and receptor activator of nuclear factor kappa-B ligand expression at days 7 and 21 suggest that these scaffolds support an osteoprogenitor phenotype. These scaffolds could serve as periosteum mimics, deliver osteoprogenitor cells, and improve bone allograft healing. PMID- 25817654 TI - Pasting properties of heat-moisture treated canna starches using different plasticizers during treatment. AB - Different plasticizers (propanol, propylene glycol, glycerol, erythritol, xylitol and sorbitol) were used for plasticizing canna starch during heat-moisture treatment (HMT). Pasting properties of the modified starches were determined and compared with those of native starch and of HMT starch using water as a plasticizer. Canna starch was soaked in 5% (w/w) plasticizer solutions and adjusted to 25% moisture content before heating at 100 degrees C for 1h. The least change in paste viscosity was found when water was used as a plasticizer. Viscosity of the modified starches decreased as the molecular weight of plasticizers decreased. Plasticizer content in starch granules increased with decreasing molecular weight of the plasticizer, as well as with increased soaking time (from 10 min to 4 and 24h). However, pasting profiles of HMT starches prepared by soaking for 4h were comparable to those soaked for 24h, indicating that there was an effective limit of plasticizers. The plasticizer content in starch granules played a greater role in HMT than the number of hydroxyl groups. PMID- 25817655 TI - Characteristics of starch-based films with different amylose contents plasticised by 1-ethyl-3-methylimidazolium acetate. AB - Starch-based films plasticised by an ionic liquid, 1-ethyl-3-methylimidazolium acetate ([Emim][OAc]), were prepared by a simple compression moulding process, facilitated by the strong plasticisation effect of [Emim][OAc]. The effects of amylose content of starch (regular vs. high-amylose maize) and relative humidity (RH) during ageing of the samples on a range of structural and material characteristics were investigated. Surprisingly, plasticisation by [Emim][OAc] made the effect of amylose content insignificant, contrary to most previous studies when other plasticisers were used. In other words, [Emim][OAc] changed the underlying mechanism responsible for mechanical properties from the entanglement of starch macromolecules (mainly amylose), which has been reported as a main responsible factor previously. The crystallinity of the plasticised starch samples was low and thus was unlikely to have a major contribution to the material characteristics, although the amylose content impacted on the crystalline structure and the mobility of amorphous parts in the samples to some extent. Therefore, RH conditioning and thus the sample water content was the major factor influencing the mechanical properties, glass transition temperature, and electrical conductivity of the starch films. This suggests the potential application of ionic liquid-plasticised starch materials in areas where the control of properties by environmental RH is desired. PMID- 25817656 TI - Significance of thermal transitions on starch digestibility and firming kinetics of restricted water mixed flour bread matrices. AB - The impact of wheat (WT) flour replacement up to 45% (weight basis) by incorporation of ternary blends of teff (T), green pea (GP) and buckwheat (BW) flours on the thermal profiles of quaternary blended dough matrices have been investigated by simulating baking, cooling, and storage in differential scanning calorimeter (DSC) pans. Endothermal transitions related to suitable patterns for low and slow starch hydrolysis, softer crumb and retarded firming kinetics in blended breads include delayed temperatures for starch gelatinization, and for the dissociation of amylose-lipid complex. In addition, (a) higher stability for the amylose-lipid inclusion complex, (b) lower energy for starch gelatinization, (c) lower limiting melting enthalpy and (d) slower rate for amylopectin retrogradation meet thermal requirements for achieving suitable textural and starch digestibility features in blended breads, fulfilled by adding T/GP/BW to replace 45% of WT flour in blended dough formulations. PMID- 25817657 TI - Impact of hydrolysis conditions on the detection of mannuronic to guluronic acid ratio in alginate and its derivatives. AB - Alginate is a linear and acidic polysaccharide, composed of (1 -> 4) linked beta D-mannuronic acid (ManA) and alpha-L-guluronic acid (GulA). The ratio of ManA to GulA (M/G) is one of the most important factors for the application of alginate and its derivatives in various areas. In this work, a robust and accurate method was developed to analyze M/G using high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). The impact of hydrolysis conditions on the release patterns of ManA and GulA from alginate and its derivatives was investigated. The release patterns of ManA and GulA need to be considered separately to obtain an accurate M/G. Several hydrolysis conditions were established that released ManA and GulA completely and maintained these saccharide residues intact. The proper M/G of alginates from different sources and its derivatives could then be calculated by integration of the corresponding ManA and GulA peaks. PMID- 25817659 TI - Rheological properties of wheat starch influenced by amylose lysophosphatidylcholine complexation at different gelation phases. AB - Amylose is able to form helical inclusion complexes with lysophosphatidylcholine (LPC). This complexation influences the functional and rheological properties of wheat starch; however it is well known that the formation of these complexes lead the starchy systems to a slower enzymatic hydrolysis. Based on this, to benefit from both the structuring properties of starch and also lower digestibility of the inclusion complexes, the objective of this study is the formation of amylose LPC inclusion complexes while developing a firm network providing the desired functional properties in a starchy system. To investigate the influence of amylose-LPC complex formation at different stages of starch gelation on the viscosity behavior of wheat starch, 3% (w/w) LPC was added at three different points of the viscosity profile, obtained by rapid visco analyzer (RVA). LPC addition at all points affected the gelation behavior of wheat starch as compared with the reference. LPC addition at half-peak and peak of the viscosity profile resulted in a viscosity increase during cooling. Measuring the dynamic rheological properties of the freshly prepared gelatinized samples showed a decrease of storage modulus (G') and loss modulus (G") in the presence of LPC. During storage, in the presence of LPC, a lower elasticity was observed which indicates a lower rate of amylose retrogradation due to complexation with LPC. PMID- 25817658 TI - Immunomodulating and antioxidant effects of polysaccharide conjugates from the fruits of Ziziphus Jujube on Chronic Fatigue Syndrome rats. AB - To detect the treatment effect of the fruits of Ziziphus Jujube in Chronic Fatigue Syndrome (CFS). Jujube polysaccharide conjugates (JPC) were isolated from the fruits of Z. Jujube. General physicochemical properties of JPC were analyzed. A four-week rats CFS model was established and JPC were orally administrated, the behavior experiments were conducted after CFS. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and the levels of malondialdehyde (MDA) in serum were elevated and T lymphocyte proliferation, CD4(+)/CD8(+) ratio and natural killer (NK) cells activity were analyzed. JPC markedly improved behaviors of CFS rats, also decreased MDA levels in serum, and elevated T lymphocyte proliferation, CD4(+)/CD8(+) ratio and natural killer (NK) cells activities. This suggests that JPC can improve the immune system and antioxidant activity of CFS rats and might be regarded as a biological response modifier. PMID- 25817660 TI - Bio-based polyurethane reinforced with cellulose nanofibers: a comprehensive investigation on the effect of interface. AB - Novel bio-based polyurethane (PU) nanocomposites composed of cellulose nanofiller extracted from the rachis of date palm tree and polycaprolactone (PCL) diol based PU were prepared by casting/evaporation. Two types of nanofiber were used: cellulose nanofibrils (CNFs) and cellulose nanocrystals (CNCs). The mechanical and thermal properties of the nanocomposite films were studied by DMA, DSC, and tensile tests and the morphology was investigated by SEM. Bionanocomposites presented good mechanical properties in comparison to neat PU. While comparing both nanofillers, the improvement in mechanical and thermal properties was more pronounced for the nanocomposites based on CNF which could be explained, not only by the higher aspect ratio of CNF, but also by their better dispersion in the PU matrix. Calculation of the solubility parameters of the nanofiller surface polymers and of the PU segments portend a better interfacial adhesion for CNF based nanocomposites compared to CNC. PMID- 25817661 TI - High throughput exopolysaccharide screening platform: from strain cultivation to monosaccharide composition and carbohydrate fingerprinting in one day. AB - Microbial exopolysaccharides (EPS) are multifunctional biogenic polymers, which exist in highly diverse chemical structures. To facilitate a fast determination of the carbohydrate composition of novel isolated strains or modified EPS variants a fast screening and analytical method is required. The platform as realized and described in this article is based on the fast carbohydrate analysis via liquid chromatography coupled with ultra violet and electrospray ionization ion trap detection in 96-well format to detect different sugars, sugar derivatives and substituents such as pyruvate. Monosaccharide analysis from hydrolyzed polysaccharides was validated successfully by 16 commercially available polymers with known structure. The method is sensitive enough to distinguish various types of sphingans which solely differ in small alterations in the monomer composition. Even a quantitative detection of single monomers as present in complex plant polysaccharides like karaya gum, with the lowest recovery, was in accordance with literature. Furthermore, 94 bacterial strains for the validation of the screening platform were completely analyzed and 41 EPS producing strains were efficiently identified. Using the method a carbohydrate fingerprint of the strains was obtained even allowing a very fast differentiation between strains belonging to the same species. This method can become a valuable tool not only in the fast analysis of strain isolates but also in the targeted screening for polysaccharides containing special rare sugars as well in the screening of strain libraries from genetic engineering for altered structures. PMID- 25817662 TI - Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake. AB - The poor stability of solid lipid nanoparticles (SLN) under acidic condition resulted in large aggregation in gastric environment, limiting their application as oral delivery systems. In this study, a series of SLN was prepared to investigate the effects of surfactant/cosurfactant and chitosan coating on their physicochemical properties as well as cellular uptake. SLN was prepared from Compritol 888 ATO using a low-energy method combining the solvent-diffusion and hot homogenization technique. Poloxamer 188 and polyethylene glycol (PEG) were effective emulsifiers to produce SLN with better physicochemical properties than SLN control. Chitosan-coated SLN exhibited the best stability under acidic condition by forming a thick layer around the lipid core, as clearly observed by transmission electron microscope. The intermolecular interactions in different formulations were monitored by Fourier transform infrared spectroscopy. Chitosan coating also significantly improved the mucoadhesive property of SLN as determined by Quartz Crystal Microbalance. In vitro drug delivery assays, cytotoxicity, and cellular uptake of SLN were studied by incorporating coumarin 6 as a fluorescence probe. Overall, chitosan-coated SLN was superior to other formulations and held promising features for its application as a potential oral drug delivery system for hydrophobic drugs. PMID- 25817663 TI - Influence of alkali metal cations on the thermal, mechanical and morphological properties of rectorite/chitosan bio-nanocomposite films. AB - The main theme of this work is to study the influence of ion-exchangeable alkali metal cations, such as: Li(+), Na(+), K(+), and Cs(+) on the thermal, mechanical and morphological properties. In this regard, a set of rectorite/chitosan (REC CS) bio-nanocomposite films (BNCFs) was prepared by facile reaction of chitosan with ion-exchanged REC clay. The microstructure and morphology of BNCFs were investigated with XRD, TEM, SEM and AFM. Thermal and tensile properties of BNCFs were also investigated. As revealed from TEM and XRD results, the BNCFs featured a mixed morphology. Some intercalated clay sheets, together with nano-sized clay tactoids were obtained in LiREC/CS, NaREC/CS and KREC/CS of the BNCFs. From fractured surface study, via SEM, it was observed that the dispersion of chitosan polymer attaches to (and covers) the clay platelets. FTIR confirmed strong hydrogen bonds between clay and chitosan polymer. In addition, the thermal stabilities significantly varied when alkali metal cations varied from Li(+) to Cs(+). The BNCFs featured high tensile strengths (up to 84 MPa) and tensile moduli (up to 45 GPa). After evaluating these properties of BNCFs, we came to conclusion that these bio-nano composites can be used for packaging applications. PMID- 25817664 TI - Liquid phase adsorption behavior of inulin-type fructan onto activated charcoal. AB - This study describes liquid phase adsorption characteristics of inulin-type fructan onto activated charcoal. Batch mode experiments were conducted to study the effects of pH, contact time, temperature and initial concentration of inulin. Nearly neutral solution (pH 6-8) was favorable to the adsorption and the equilibrium was attained after 40 min with the maximum adsorption Qmax 0.182 g/g (adsorbate/adsorbent) at 298 K. The experimental data analysis indicated that the adsorption process fitted well with the pseudo-second-order kinetic model (R(2) = 1) and Langmuir isotherms model (R(2) > 0.99). Thermodynamic parameters revealed that the adsorption process was spontaneous and exothermic with a physical nature. Inulin desorption could reach 95.9% using 50% ethanol solution and activated charcoal could be reused without significant losses in adsorption capacity. These results are of practical significance for the application of activated charcoal in the production and purification of inulin-type fructan. PMID- 25817665 TI - Development and evaluation of gel-forming ocular films based on xyloglucan. AB - This study aims at application of xyloglucan, polysaccharide polymer as novel film forming agent for ocular delivery of ciprofloxacin. Ciprofloxacin ocular films were prepared by the solvent casting method using xuloglucan (2%). The prepared formulations were evaluated for thickness, percentage drug content, surface pH, swelling, mechanical strength and in vitro drug release. The films were found to be of uniform thickness (0.20 +/- 0.07 MUm). The % drug content in the films was found to be 95.45 +/- 0.25%. The cumulative % drug releases from the formulation was 98.85 at the end of 24h. The formulations followed the anomalous transport release mechanism. Ocular irritancy study reveals safety of formulation to ocular mucosa. Thus, this study suggests that xyloglucan can act as a potential film forming polymer for ocular delivery of a ciprofloxacin. PMID- 25817666 TI - Multiscale characterization of arabinoxylan and beta-glucan composite films. AB - Composite films made with Arabinoxylans (AXs) (with high, middle and low level of substitution by arabinose) and (1 -> 3)(1 -> 4)-beta-D-glucans (BGs) extracted from cereal cell walls have been prepared and analyzed using microscopy (SEM and LSCFM), DSC, mechanical tests and TD-NMR spectroscopy. The objectives were to correlate molecular and physico-chemical properties of films with mechanical and hydration properties of wheat cell walls. A phase separation phenomenon was observed for films made with highly substituted AXs and BGs at a ratio AX/BG of 60/40. This phase separation was correlated with lower dipolar interactions between polysaccharide chains and a decrease of ultimate strain and stress of films. Highly substituted AX and BG composite films exhibited very weak mechanical properties in agreement with weaker interactions between the polymer chains. This effect was supported by NMR results showing that interactions between AXs and BGs decreased with increased substitution of AXs in composite films. Lower dipolar interactions between polysaccharides favored the water mobility in relation with a higher specific surface area of polysaccharides in films but also higher distances between polysaccharide chains so larger nanopores in composite films made within highly substituted AXs. These multiscale characterizations agreed with the structural changes observed in wheat grain during its development. PMID- 25817668 TI - Carboxymethylcellulose (CMC) formed nanogels with branched poly(ethyleneimine) (bPEI) for inhibition of cytotoxicity in human MSCs as a gene delivery vehicles. AB - Specific vehicles are necessary for safe and efficient gene transfection into cells. Nano-type hydrogels (nanogel) comprising carboxymethylcellulose (CMC) complexed with branched type cationic poly(ethleneimine) (bPEI) were used as gene delivery vehicles. When complexes of CMC and bPEI were used in vitro, CMC showed nano-gel type properties, as shown by the results of a viscosity test, and bPEI showed low cytotoxicity comparing to bPEI alone. Together, these properties are shown to maintain high gene transfection efficiency. In viability experiments using three types of adult stem cells, cell viability varied depending on the branch form of PEI and whether or not it is in a complex with CMC. The gene delivery efficacy showed that the CMC nanogel complexed with bPEI (CMC-bPEI) showed more uptaking and gene transfection ability in hMSCs comparing to bPEI alone. In osteogenesis, the CMC-bPEI complexed with OSX pDNA showed more easy internalization than bPEI alone complexed with OSX pDNA in hMSCs. Specific genes and proteins related in osteogenic differentiation were expressed in hMSCs when the CMC-bPEI complexed with OSX pDNA was used. PMID- 25817667 TI - Removal of cadmium from aqueous solution using low molecular weight chitosan derivative. AB - A 2(3) factorial design was used to examine the sorption of Cd(2+) onto cross linked low molecular weight chitosan pyruvic acid derivative. Three factors and two levels of solution pH (A) (6.0 or 10.0), temperature (B) (45 or 70 degrees C) and Cd(II) concentration (C) (1 or 3 mg/L) were considered. Batch mode system was employed with 0.05 g of the sorbent and 25 mL of Cd(II) solution. The efficiency of cadmium removal during an exposition time of 4h was then evaluated. The factors and their interaction effect on the cadmium removal efficiency followed the order: Cd(II) concentration > solution pH > interaction between solution pH and Cd(II) concentration>interaction between solution pH, temperature and Cd(II) concentration. Langmuir isotherm model was the best isotherm model. The Pseudo second order fitted well the kinetic data. The thermodynamic studies revealed the nature of the cadmium sorption. PMID- 25817670 TI - Morphological, physicochemical, and viscoelastic properties of sonicated corn starch. AB - In the present work, different parameters of ultrasound treatment were studied for physical modification of corn starch. The results revealed that the influence of sonication strongly depends on temperature (25-65 degrees C) and exposure time (5-15 min), while concentration (10-20% w/w) and ultrasound amplitude (50 and 100%) have little influence on functional and rheological properties. SEM micrographs demonstrated the damage induced by ultrasound on starch granules' surface. The solubility, swelling power, and gel clarity were increased. Ultrasonication decreased the gelatinisation enthalpy and temperature range while the X-ray pattern and crystallinity remained almost unchanged, except for samples treated at onset temperature as measured by DSC. The pseudoplasticity and consistency coefficient decreased; also, apparent viscosity diminished prominently. The pasting behaviour of samples was altered without any clear change in gel strength characterised by loss factor. The results of the present work provide further insight into the mode of action of ultrasound on modifying corn starch granules. PMID- 25817669 TI - Arabinan-rich pectic polysaccharides from buriti (Mauritia flexuosa): an Amazonian edible palm fruit. AB - Primary cell wall polysaccharides from aqueous extract of buriti fruit pulp (Mauritia flexuosa, an exotic tropical palm) were isolated and characterized. After freeze-thaw and alpha-amylase treatments, extracted polysaccharides were purified by sequential ultrafiltration through membranes. Two homogeneous fractions were obtained, SBW-100R and SBW-30R (Mw of 126 kDa and 20 kDa, respectively). Monosaccharide composition, methylation and (13)C NMR analysis showed that fraction SBW-100R contained a (1 -> 5)-linked arabinan, branched at O 3 and O-2 positions, linked to a type I rhamnogalacturonan. Low amounts of these polymers were also present in fraction SBW-30R according to (13)C NMR analysis and monosaccharide composition. However, a high methyl esterified homogalacturonan (HG) was present in higher proportions. These results reinforce previous findings present in literature data which indicate that pectic polysaccharides are found in high amounts in primary cell walls of palms, which are commelinid monocotyledons. PMID- 25817671 TI - Cellulose-silica aerogels. AB - Aerogels based on interpenetrated cellulose-silica networks were prepared and characterised. Wet coagulated cellulose was impregnated with silica phase, polyethoxydisiloxane, using two methods: (i) molecular diffusion and (ii) forced flow induced by pressure difference. The latter allowed an enormous decrease in the impregnation times, by almost three orders of magnitude, for a sample with the same geometry. In both cases, nanostructured silica gel was in situ formed inside cellulose matrix. Nitrogen adsorption analysis revealed an almost threefold increase in pores specific surface area, from cellulose aerogel alone to organic-inorganic composite. Morphology, thermal conductivity and mechanical properties under uniaxial compression were investigated. Thermal conductivity of composite aerogels was lower than that of cellulose aerogel due to the formation of superinsulating mesoporous silica inside cellulose pores. Furthermore, composite aerogels were stiffer than each of reference aerogels. PMID- 25817672 TI - Preparation and properties of a hydrogel of maleated poly(vinyl alcohol) (PVAM) grafted with cassava starch. AB - A novel pH-sensitive graft copolymer (PVAM-g-CSt) was synthesized from maleated poly(vinyl alcohol) (PVAM) and cassava starch (CSt) through a grafting reaction using potassium persulfate as a thermal initiator. The chemical structure of the PVAM-g-CSt was revealed by FTIR and ether linkage of the graft copolymer was observed at 1089 cm(-1). The degree of grafting of the copolymer was found to range between 40 and 82%, depending on the PVAM/CSt ratio. The highest tensile strength was found at a ratio of 9:1 PVAM/CSt. In addition, the swelling ratio in water increased with increasing proportions of CSt in the PVAM-g-CSt due to the decrease in the degree of grafting. The resulting hydrogel exhibits good pH sensitivity in different pH mediums. The graft copolymer easily degraded in natural soil, especially at high proportions of CSt in the blend. PMID- 25817673 TI - High quality fluorescent cellulose nanofibers from endemic rice husk: isolation and characterization. AB - Cellulose nanofibers (CNFs) with high crystallinity and purity were isolated from two endemic rice husk varieties using a hydrothermal approach followed by acid alkali treatments and mechanical disruption. The CNFs isolated had a mean diameter of ~ 35 nm. The TGA and DTG profiles showed good thermostability of the CNFs. The CNFs also showed a prominent photoluminescence peak at 404 nm with high quantum yield (~ 58%). This is the first report on the native fluorescence property of nanocellulose in absence of any conjugated fluorescence molecule/dye. The CNFs further demonstrated appreciable hemocompatibility in the hemolysis test, exhibiting its potential for biomedical applications. PMID- 25817674 TI - Preparation of agar nanospheres: comparison of response surface and artificial neural network modeling by a genetic algorithm approach. AB - Multivariate nature of drug loaded nanospheres manufacturing in term of multiplicity of involved factors makes it a time consuming and expensive process. In this study genetic algorithm (GA) and artificial neural network (ANN), two tools inspired by natural process, were employed to optimize and simulate the manufacturing process of agar nanospheres. The efficiency of GA was evaluated against the response surface methodology (RSM). The studied responses included particle size, poly dispersity index, zeta potential, drug loading and release efficiency. GA predicted greater extremum values for response factors compared to RSM. However, real values showed some deviations from predicted data. Appropriate agreement was found between ANN model predicted and real values for all five response factors with high correlation coefficients. GA was more successful than RSM in optimization and along with ANN were efficient tools in optimizing and modeling the fabrication process of drug loaded in agar nanospheres. PMID- 25817675 TI - Structural alterations, pore generation, and deacetylation of alpha- and beta chitin submitted to steam explosion. AB - The purpose of this study was to use an environmentally friendly steam explosion method to achieve alpha- and beta-chitin structural alterations, pore generation, and deacetylation, enhancing the degree of deacetylation (DD) in chitin and extending its applications. The samples of alpha- and beta-chitin possessing various moisture contents that were exploded at 9 kg/cm(2) exhibited higher DDs, lower densities, lower crystallinity and more porous structures compared to unexploded chitin. After explosion, beta-chitin exhibited a larger expansion ratio, lower crystallinity and contained a larger proportion of small-sized particles compared to alpha-chitin. The highest DD values of exploded alpha- and beta-chitin with 75% moisture content were 42.9% and 43.7%, respectively. The exploded chitin samples with lower moisture content exhibited lower DDs, densities, crystallinity indices, smaller particle sizes, and higher expansion ratios than the chitin samples with higher moisture content. The chitin samples with lower moisture content also contained larger and more numerous pores. PMID- 25817676 TI - Multi-wavelength colorimetric determination of large-ring cyclodextrin content for the cyclization activity of 4-alpha-glucanotransferase. AB - Large-ring cyclodextrins (LR-CDs) have a number of intriguing properties for potential use in pharmaceutical and food industry. To date, no colorimetric method has been reported for LR-CD content quantification. In this study, triple wavelength colorimetry (TWC) and orthogonal-function spectrophotometry (OFS) have been successfully applied to determine ingredient concentrations in a mixture of amylose and LR-CDs. Both TWC and OFS yielded precise amylose content data in good agreement with expected values. For quantification of LR-CD content, OFS provided a higher accuracy than TWC, which resulted in a slight over-determination. As a comparison, single-wavelength colorimetry performed at the corresponding absorption maximum led to a significant over-determination of both amylose and LR CD contents. The validity of TWC and OFS allowed their application for discriminative detection of the cyclization and total activity of a 4-alpha glucanotransferase (4 alphaGTase) from Thermus aquaticus regarding the synthesis of LR-CDs and the conversion of amylose to small molecules, respectively. High pressure size exclusion chromatography analysis of the post-reaction mixtures following 4 alphaGTase-catalyzed conversion of amylose revealed the presence of linear malto-oligosaccharides in the LR-CD fraction. By introduction of a correction factor, the interference caused by linear malto-oligosaccharides was eliminated for a more accurate determination of LR-CD cyclization activity. PMID- 25817677 TI - Self-healable hydrogel on tumor cell as drug delivery system for localized and effective therapy. AB - A self-healable chitosan(CS)/polyvinyl alcohol (PVA) hydrogel as an injectable drug carrier was first prepared in situ on tumor cells for effective and localized therapy. PVA molecules have a synergistic effect on the formation and maintenance of 3D network conformation of hydrogel. The hydrogel shows good biocompatibility and could be easily and rapidly formed. When loaded with fluorouracil (5-FU), the hydrogel possessed good drug retention ability at pH 7.4, which can prevent the loss of drug to normal cells and reduce the side effect. As well, the hydrogel shows continuous and controllable drug release, with the final cumulative releasing amount of 84.8% at pH 5.0. Therefore, the hydrogel not only could maintain a higher 5-FU concentration around tumor cells to enhance the antitumor effect, but also can achieve pH sensitive controllable drug release at the lesion site. Meantime, the attractive self-healing ability of the CS/PVA hydrogel is first revealed in this study, which contributes to the regeneration of its integral network from the broken fragments. The CS/PVA hydrogel may hold promise for better applications in anti-tumor therapy. PMID- 25817678 TI - Impregnation of silver nanoparticles into polysaccharide substrates and their properties. AB - A method to impregnate silver nanoparticles (AgNPs) into different polysaccharides substrates (cellulose powder (CP), microcrystalline cellulose (MCC), carboxymethyl cellulose (CMC) and chitosan (Chit)) by using glucose as reducing agent, is presented. X-ray diffraction analyses of polysaccharides coated with AgNPs showed the formation of silver particle sizes in the range of 3.7-5.6 nm and have almost spherical shape. The entire prepared composite shows antimicrobial effect. The antibacterial activity of polysaccharides loaded with silver nanoparticles was evaluated against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) bacteria. The results suggest excellent antibacterial activity. PMID- 25817679 TI - Monitoring and preparation of neoagaro- and agaro-oligosaccharide products by high performance anion exchange chromatography systems. AB - A series of neoagaro-oligosaccharides (NAOS) were prepared by beta-agarase digestion and agaro-oligosaccharides (AOS) by HCl hydrolysis from agarose with defined quantity and degree of polymerization (DP). Chain-length distribution in the crude product mixtures were monitored by two high performance anion exchange chromatography systems coupled with a pulsed amperometric detector. Method 1 utilized two separation columns: a CarboPac(TM) PA1 and a CarboPac(TM) PA100 connected in series and method 2 used the PA100 alone. Method 1 resolved the product in size ranges consisting of DP 1-46 for NAOS and DP 1-32 for AOS. Method 2 clearly resolved saccharide product sizes within DP 26. The optimized system utilizing a semi-preparative CarboPac(TM) PA100 column was connected with a fraction collector to isolate and quantify individually separated products. This study established systems for the preparation and qualitative and quantitative measurements as well as for the isolation of various sizes of oligomers generated from agarose. PMID- 25817680 TI - Hydrodynamic characterisation of chitosan and its interaction with two polyanions: DNA and xanthan. AB - Chitosan, a soluble polycationic derivative of insoluble chitin, has been widely considered for use in the food, cosmetic and pharmaceutical industries. Commercial ("C") and in-house laboratory ("L") prepared chitosan samples extracted from crustaceous shells with different molecular weight and degrees of acetylation (25% and 15%) were compared with regards to (i) weight-average molecular weight (Mw); (ii) sedimentation coefficient (s(o)(20,w)) distribution, and (iii) intrinsic viscosity ([eta]). These parameters were estimated using a combination of analytical ultracentrifugation (AUC), size exclusion chromatography coupled to multi-angle laser light scattering (SEC-MALS) and differential pressure viscometry. Polydisperse distributions were seen from sedimentation coefficient distributions and elution profiles from SEC-MALS. Mw values obtained for each sample by sedimentation equilibrium measurements were in excellent agreement with those obtained from SEC-MALS. Mark-Houwink-Kuhn-Sakurada (MHKS) and Wales van Holde analyses of the data all suggest a semi-flexible conformation. The principle of co-sedimentation was then used to monitor the interactions of the two different molecular weights of L chitosans with two polyanions, DNA and xanthan (another double helical high molecular weight molecule). Interactions were clearly observed and then quantified from the changes in the sedimentation coefficient distribution of the mixture compared to unmixed controls using sedimentation velocity. The interactions appeared to show a strong dependence on molecular weight. The relevance of this for DNA condensation applications is indicated. PMID- 25817681 TI - Engineered pigments based on iridescent cellulose nanocrystal films. AB - A simple method to produce biobased iridescent pigments from cellulose nanocrystal (CNC) films is reported. The process consists of forming nanostructured films from a CNC liquid-crystalline suspension and an appropriate dry grinding. The features of the iridescent pigments are described; they have a flake-like morphology with a thickness of 25 MUm. However, because of the presence of sulfate groups, thermal degradation and high redispersion in water occur, which affect the iridescent property of these biobased pigments. To overcome such limitations, two post-treatments are proposed. The sulfate ester groups are removed from the iridescent pigments with vacuum overdrying. The mass loss of iridescent pigment in water is reduced with an increase of the ionic strength in the aqueous medium by NaCl addition. These post-treatments have proven to be efficient and engineered pigments based on CNC films can be used to add anticounterfeiting features to packaging manufactured by classical paper techniques or extrusion. PMID- 25817682 TI - Chemical structure and anticoagulant activity of highly pyruvylated sulfated galactans from tropical green seaweeds of the order Bryopsidales. AB - Sulfated and pyruvylated galactans were isolated from three tropical species of the Bryopsidales, Penicillus capitatus, Udotea flabellum, and Halimeda opuntia. They represent the only important sulfated polysaccharides present in the cell walls of these highly calcified seaweeds of the suborder Halimedineae. Their structural features were studied by chemical analyses and NMR spectroscopy. Their backbone comprises 3-, 6-, and 3,6-linkages, constituted by major amounts of 3 linked 4,6-O-(1'-carboxy)ethylidene-d-galactopyranose units in part sulfated on C 2. Sulfation on C-2 was not found in galactans from other seaweeds of this order. In addition, a complex sulfation pattern, comprising also 4-, 6-, and 4,6 disulfated galactose units was found. A fraction from P. capitatus, F1, showed a moderate anticoagulant activity, evaluated by general coagulation tests and also kinetics of fibrin formation was assayed. Besides, preliminary results suggest that one of the possible mechanisms involved is direct thrombin inhibition. PMID- 25817683 TI - Bacterial cellulose membrane produced by Acetobacter sp. A10 for burn wound dressing applications. AB - Bacteria cellulose membranes (BCM) are used for wound dressings, bone grafts, tissue engineering, artificial vessels, and dental implants because of their high tensile strength, crystallinity and water holding ability. In this study, the effects of BCM application for 15 days on healing of burn wounds were investigated based on evaluation of skin regeneration and angiogenesis in burn injury skin of Sprague-Dawley (SD) rats. BCM showed a randomly organized fibrils network, 12.13 MPa tensile strength, 12.53% strain, 17.63% crystallinity, 90.2% gel fraction and 112.14 g * m(2)/h highest water vapor transmission rate (WVTR) although their swelling ratio was enhanced to 350% within 24h. In SD rats with burned skin, the skin severity score was lower in the BCM treated group than the gauze (GZ) group at all time points, while the epidermis and dermis thickness and number of blood vessels was greater in the BCM treated group. Furthermore, a significant decrease in the number of infiltrated mast cells and in vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) expression was observed in the BCM treated group at day 10 and 15. Moreover, a significant high level in collagen expression was observed in the BCM treated group at day 5 compared with GZ treated group, while low level was detected in the same group at day 10 and 15. However, the level of metabolic enzymes representing liver and kidney toxicity in the serum of BCM treated rats was maintained at levels consistent with GZ treated rats. Overall, BCM may accelerate the process of wound healing in burn injury skin of SD rats through regulation of angiogenesis and connective tissue formation as well as not induce any specific toxicity against the liver and kidney. PMID- 25817685 TI - In situ forming hydrogels of hyaluronic acid and inulin derivatives for cartilage regeneration. AB - An in situ forming hydrogel obtained by crosslinking of amino functionalized hyaluronic acid derivatives with divinylsulfone functionalized inulin (INU-DV) has been here designed and characterized. In particular two hyaluronic acid derivatives bearing respectively a pendant ethylenediamino (EDA) portion (HA-EDA) and both EDA and octadecyl pendant groups (HA-EDA-C18) were crosslinked through an azo-Michael reaction with INU-DV. Gelation time and consumption of DV portions have been evaluated on hydrogel obtained using HA-EDA and HA-EDA-C18 derivatives with a concentration of 3% w/v and a ratio 80/20 w/w respect to the crosslinker INU-DV. The presence of pendant C18 chains improves mechanical performances of hydrogels and decreases the susceptibility to hyaluronidase hydrolysis. Bovine chondrocytes, encapsulated during crosslinking, sufficiently survive and efficiently proliferate until 28 days of analysis. PMID- 25817684 TI - Combinatorial one-pot chemoenzymatic synthesis of heparin. AB - Contamination in heparin batches during early 2008 has resulted in a significant effort to develop a safer bioengineered heparin using bacterial capsular polysaccharide heparosan and recombinant enzymes derived from the heparin/heparan sulfate biosynthetic pathway. This requires controlled chemical N-deacetylation/N sulfonation of heparosan followed by epimerization of most of its glucuronic acid residues to iduronic acid and O-sulfation of the C2 position of iduronic acid and the C3 and C6 positions of the glucosamine residues. A combinatorial study of multi-enzyme, one-pot, in vitro biocatalytic synthesis, carried out in tandem with sensitive analytical techniques, reveals controlled structural changes leading to heparin products similar to animal-derived heparin active pharmaceutical ingredients. Liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy analysis confirms an abundance of heparin's characteristic trisulfated disaccharide, as well as 3-O-sulfo containing residues critical for heparin binding to antithrombin III and its anticoagulant activity. The bioengineered heparins prepared using this simplified one-pot chemoenzymatic synthesis also show in vitro anticoagulant activity. PMID- 25817686 TI - Impact of amylose content on starch physicochemical properties in transgenic sweet potato. AB - The intrinsic relationship between amylose content and starch physicochemical properties was studied using six representative starch samples (amylose content 0 65%) produced from transgenic sweet potato (cultivar Xushu22). The transgenic lines (waxy and high-amylose) and wild-type (WT) sweet potatoes were analyzed for amylose content, particle size and chain length distribution, X-ray diffraction analysis, thermal characteristics, pasting and rheological property. Compared to the WT starch, the waxy and high-amylose starches showed larger average granule sizes and had fewer short chains and more medium and long chains. X-ray diffractogram analysis revealed that high-amylose starches show a type-B crystal form with a markedly decreased degree of crystallinity in contrast to the type-A crystal form of the WT and waxy starches. In the high-amylose sweet potato starches, the rise of setback value and the reduction of breakdown value led to the high shear resistance as indicated by the higher G', G", and tandelta from the oscillation test. DeltaH was not found to be decreased with the reduction of crystallinity. The shear stress resistance of starch gel after gelatinization was also enhanced as amylose content increased. Principal component analysis also confirmed that the amylose content greatly influenced the starch structure and properties, e.g., storage modulus, setback value, and average chain length. Thus, our study not only shed light on how amylose content affects starch properties but also identified novel starches that are available for various applications. PMID- 25817687 TI - Polysaccharides from Smilax glabra inhibit the pro-inflammatory mediators via ERK1/2 and JNK pathways in LPS-induced RAW264.7 cells. AB - The rhizomes of Smilax glabra have been used as both food and folk medicine in many countries for a long time. However, little research has been reported on polysaccharides of S. glabra. In the present study, two polysaccharide fractions, SGP-1 and SGP-2, were isolated from the rhizomes of S. glabra with the number average molecular weights of 1.72 * 10(2)kDa and 1.31 * 10(2)kDa, and the weight average molecular weights of 1.31 * 10(5)kDa and 1.18 * 10(5)kDa, respectively, and their mainly monosaccharide compositions were both galactose and rhamnose (2.5:1). Both SGP-1 and SGP-2 significantly suppressed the release of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) from LPS-induced RAW 264.7 cells, as well as the mRNA expression of inducible nitric oxide synthase (iNOS), TNF-alpha and IL-6. Additionally, SGP-1 and SGP-2 repressed the extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK). These findings strongly suggested polysaccharides were also the anti-inflammatory active ingredient for S. glabra, and the potential of SGP-1 and SGP-2 as the anti-inflammatory agents. PMID- 25817688 TI - Amylose and amylopectin branch chain reactivity in a model derivatization system. AB - The impact of starch granule structure on amylose (AM) and amylopectin (AP) chain reactivities was investigated over a 24h period in a model reaction system utilizing a fluorescent probe [DTAF, 5-(4,6-dichlorotriazinyl)aminofluorescein] as a reagent. For various reaction time intervals (0.5, 4, 12, or 24h), molecular reactivities of debranched starch derivatives were assessed via size-exclusion chromatography equipped with refractive index and fluorescence detection. For all starch chain fractions, the initial rate of derivatization (0-0.5h) was rapid, but decreased thereafter. Starch chain reactivities followed the general order: AP long chains ? AM, AP medium chains>AP short chains, though both AM and AP long chain reactivities were somewhat impacted by the high relative reactivity of starch chains eluting in the AM/AP long chain boundary region. Varied starch chain reactivities were attributed to their relative locale within the granule, corroborating the impact of granule architecture on molecular-level reaction patterns of starch chains. PMID- 25817689 TI - Derivatization patterns among starch chain populations assessed by ion-exchange chromatography: a model system approach. AB - Reaction patterns of wheat starch derivatized with a fluorescent probe (model reaction system) were investigated over the course of a reaction period (0.5, 4, 12, or 24h). Debranched derivatives were fractionated into three populations (Unbound, Bound-1, Bound-2) based on charge density via anion-exchange chromatography, with each ion-exchanged fraction further analyzed by size exclusion chromatography (refractive index [RI] and fluorescence [FL] detection) to assess proportions and patterns of reaction on amylose (AM) and amylopectin (AP) long (LC), medium (MC), and short (SC) branch chains. Approximately 11-12% of the total chains accounted for 63-75% of the FL recovered in the two bound fractions. FL peaks representing AM, AP-LC, AP-MC, AP-SC, and intermediate material (eluted with AM based on molecular size, but reacted more akin to AP-LC) were monitored over the reaction period. Fractionation behaviors varied amongst starch chains, attributable to the impact of the granule structure on molecular reaction patterns. PMID- 25817690 TI - Composition, structure, physicochemical properties, and modifications of cassava starch. AB - Cassava is highly tolerant to harsh climatic conditions and has great productivity on marginal lands. The supply of cassava starch, the major component of the root, is thus sustainable and cheap. This review summarizes the current knowledge of the composition, physical and chemical structures, physicochemical properties, nutritional quality, and modifications of cassava starch. Research opportunities to better understand this starch are provided. PMID- 25817695 TI - Peroxiredoxin 1 protects the pea aphid Acyrthosiphon pisum from oxidative stress induced by Micrococcus luteus infection. AB - Reactive oxygen species (ROSs) are generated in organisms in response to infections caused by invading microbes. However, excessive ROSs will inflict oxidative damage on the host. Peroxiredoxins (Prxs) are antioxidative enzymes that may eliminate ROSs efficiently. In this study, ApPrx1 from the pea aphid Acyrthosiphon pisum was cloned, and its function was investigated in vitro and in vivo. In the presence of DTT, recombinant ApPrx1 protein from Escherichia coli showed antioxidative activity by eliminating H2O2 effectively. The H2O2 levels were significantly higher in Micrococcus luteus-infected aphids than in uninfected aphids, and ApPrx1 expression was remarkably up-regulated when the aphids were infected with M. luteus or injected with H2O2. When ApPrx1 expression was reduced by dsRNA injection, the survival of the aphids decreased significantly after M. luteus infection. Knockdown of ApPrx1 decreased M. luteus loads inside the aphids 48h post-infection. While under infection conditions, the H2O2 levels were much higher in ApPrx1 knockdown aphids than in dsGFP-injected aphids, indicating that the decreased survival of the aphids was caused by increased oxidative stress. Taken together, our results reveal that ApPrx1 plays a protective role in oxidative stress caused by bacterial infection. PMID- 25817696 TI - Molecular cloning and characterization of l-methionine gamma-lyase from Streptomyces avermitilis. AB - A pyridoxal 5'-phosphate-dependent methionine gamma-lyase (MGL) was cloned from Streptomyces avermitilis catalyzed the degradation of methionine to alpha ketobutyrate, methanethiol, and ammonia. The sav7062 gene (1,242 bp) was corresponded to 413 amino acid residues with a molecular mass of 42,994 Da. The deduced amino acid sequence showed a high degree of similarity to those of other MGL enzymes. The sav7062 gene was overexpressed in Escherichia coli. The enzyme was purified to homogeneity and exhibited the MGL catalytic activities. We cloned the enzyme that has the MGL activity in Streptomyces for the first time. PMID- 25817697 TI - Partial inhibition of differentiation associated with elevated protein levels of pluripotency factors in mouse embryonic stem cells expressing exogenous EGAM1N homeoprotein. AB - We previously reported that transcripts encoding the homeoprotein EGAM1N are expressed in preimplantation mouse embryos and embryonic stem (ES) cells, and the exogenous expression of EGAM1N inhibits the differentiation of ES cells. In order to clarify the relationship between the inhibition of differentiation and EGAM1N, we generated mouse MG1.19 ES cells stably expressing EGAM1N. Control transfectants with an empty vector formed relatively flattened cell colonies similar to those observed in parental MG1.19 cells. In contrast, Egam1n transfectants formed tightly aggregated cell colonies with increased localization of CDH1 at cell-to-cell interfaces. The protein levels of pluripotency factors, including TBX3 and SOX2, were also increased. The expression of Tbx3 transcripts was induced, although the level of Sox2 transcripts was almost unchanged. The expression of EGAM1N resulted in no obvious changes in the expression of genes encoding receptors, protein kinases, transcription factors, and their encoded proteins involved in the LIF-STAT3 signaling pathway. Alkaline phosphatase activity, a marker for the undifferentiated state, in Egam1n transfectants was exhibited in a clonal proliferation assay. When differentiation of Egam1n transfectants was induced, progression was prevented with increases in transcript levels of Pou5f1, Sox2, Nanog, Klf4, Tbx3, and their encoded proteins. However, Egam1n transfectants formed relatively flattened-cell layers as observed in the control, indicating that the expression of EGAM1N could not maintain LIF independent self-renewal of ES cells. Overall, we suggest that expression of EGAM1N could inhibit differentiation, at least in part, by elevating the protein levels of pluripotency factors in MG1.19 ES cells. PMID- 25817698 TI - Endoscopic resection of giant esophageal leiomyoma through the submucosal tunnel technique. PMID- 25817699 TI - Positive association between serum thymic stromal lymphopoietin and anti citrullinated peptide antibodies in patients with rheumatoid arthritis. AB - Thymic stromal lymphopoietin (TSLP) has been suggested recently to play an important role in the pathophysiology of rheumatoid arthritis (RA). However, there is little information on serum TSLP concentrations in RA and its clinical significance. The present study investigated whether serum TSLP concentrations were affected in patients with RA. Using an enzyme-linked immunosorbent assay (ELISA), we measured TSLP concentrations in the serum obtained from 100 patients with RA, 60 patients with osteoarthritis (OA) and 34 healthy volunteers. We also investigated the correlation between serum TSLP concentrations and clinical parameters of disease activity in RA [disease activity score using 28 joint counts (DAS28)-C-reactive protein (CRP), DAS28-erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI]), patient's/-physician's Visual Analogue Scale (VAS), swollen joints count, tender joints count, CRP, ESR and matrix metalloproteinase-3 (MMP-3) concentrations]. In addition, we investigated the correlation between serum TSLP concentrations and anti-citrullinated peptide antibody (ACPA) and serum tumour necrosis factor (TNF)-alpha. Serum TSLP levels in patients with RA were significantly higher than those in patients with OA and in healthy volunteers. Interestingly, serum TSLP concentrations were correlated significantly with ACPA titres, but not with other clinical parameters. There was a significant increase in serum TSLP concentrations in patients with RA, which was correlated positively with serum ACPA titres. These findings suggest that in patients with RA, TSLP may play a role in ACPA production by B cells. PMID- 25817700 TI - Role of atopy patch test for diagnosis of food allergy-related gastrointestinal symptoms in children. AB - BACKGROUND: Double-blind, placebo-controlled food challenge is the gold standard for diagnosing food allergy. However, it is a time-consuming procedure and requires onsite medical supervision and resuscitating medicines and devices on hand. The objective of this study was to compare the atopy patch test (APT) with the oral food challenge test (OFC) in children with suspected food allergy related gastrointestinal (GI) symptoms. METHODS: A prospective self-controlled study enrolled children with a history of suspected food allergy-related GI symptoms. Skin prick test (SPT) and APT using lyophilized and commercial allergen extracts for cow's milk, egg, wheat, soy, and shrimp were evaluated, and OFC was performed. RESULTS: Thirty-nine patients (25 boys, median age 2.4 yrs) with 76 events of suspected food allergy-related GI symptoms were enrolled. SPT was positive in 11/76 events (14.5%). Sensitivity, specificity, predictive values, and likelihood ratio were calculated related to the food challenge outcome. Of 41 OFC, 30 (73.2%) were positive. APT using lyophilized allergen extracts yielded high sensitivity (80%) and high positive predictive value (85.7%). APT using commercial allergen extracts yielded low sensitivity (30%) but high specificity (90%). The negative predictive value of APT using lyophilized and commercial allergen extracts was 53.8% and 32.2%, respectively. All cases with positive APT using lyophilized allergen extracts together with positive SPT also had positive OFC. CONCLUSION: In contrast to commercial extracts, APT with lyophilized allergen extracts is reliable, safe, and maybe useful for the diagnosis of suspected food allergy-related GI symptoms in children. OFC is still needed in most of the cases. PMID- 25817701 TI - The impact of ACE gene I/D polymorphism on plasma glucose and lipid concentrations in schizophrenia patients. PMID- 25817703 TI - Molecular diagnostic testing for common stool pathogens. PMID- 25817704 TI - Highly stable and luminescent layered hybrid materials for sensitive detection of TNT explosives. AB - Self-assembly is an effective way to fabricate optical molecular materials. However, this strategy usually changes the nanoenvironment surrounding fluorescence molecules, yielding low luminescence efficiency. Herein, we report the intercalation of a ruthenium polypyridine (Ru) complex into the interlayer galleries of layered double hydroxides (LDHs), forming a Ru/LDH hybrid. The Ru complex exists as an ordered monolayer state, and the hybrid exhibits high thermal and photo stability. Its luminescence efficiency and lifetime are increased by ~1.7 and ~1 times, respectively, compared to those of free molecules. We constructed a Ru/LDH sensing platform based on a fluorescence quenching effect for highly sensitive detection of TNT with a detection limit of 4.4 MUM. PMID- 25817702 TI - Longitudinal changes in diffusion properties in white matter pathways of children with tuberous sclerosis complex. AB - BACKGROUND: Abnormal white matter development in patients with tuberous sclerosis complex, a multisystem hamartomatous disorder caused by aberrant neural proliferation and axonal maturation, may be associated with poorer neurocognitive outcomes. The purpose of this study is to identify predictors of longitudinal changes in diffusion properties of white matter tracts in patients with tuberous sclerosis complex. METHODS: Diffusion magnetic resonance imaging was carried out in 17 subjects with tuberous sclerosis complex (mean age, 7.2 +/- 4.4 years) with at least two magnetic resonance imaging scans (mean number of days between scans, 419.4 +/- 105.4). There were 10 males; 5 of 17 had autism spectrum disorder and 10 of 17 had epilepsy. Regions of interest were placed to delineate the internal capsule/corona radiata, cingulum, and corpus callosum. The outcomes were mean change in apparent diffusion coefficient and fractional anisotropy. Data were analyzed using Pearson's correlation and multiple linear regression analyses. RESULTS: Gender was a significant predictor of mean change in apparent diffusion coefficient in the left internal capsule, right and left cingulum bundles, and corpus callosum and a significant predictor of mean change in fractional anisotropy in the corpus callosum. Epilepsy was a significant predictor of mean change in apparent diffusion coefficient in the left internal capsule. Autism spectrum disorder was not predictive of diffusion changes in any of the studied pathways. CONCLUSION: Clinical variables, including gender and epilepsy, have an effect on the development of white matter pathways. These variables should be taken into consideration when counseling tuberous sclerosis complex patients and in future imaging studies in this population. PMID- 25817705 TI - Surface molecularly imprinted silica for selective solid-phase extraction of biochanin A, daidzein and genistein from urine samples. AB - Selective molecularly imprinted silica polymer (SiO2MIP) for extraction of biochanin A, daidzein and genistein was synthesized using the surface molecular imprinting technique with the silica gel as a support. Biochanin A (BCA) was used as a template, 3-aminopropyltriethoxysilane (APTES) as a functional monomer, and tetraethoxysilicane (TEOS) as a cross-linker. Non-imprinted polymer with the sol gel process (SiO2NIP) was also prepared for comparison. The synthesized polymers were characterized by Fourier transform infrared spectrometry (FTIR), scanning electron microscopy (SEM) and a standard Brunauer-Emett-Teller (BET) and Barret Joyner-Halenda (BJH) analysis. The obtained results indicated the structural differences between imprinted and non-imprinted polymers. Finally, the SiO2MIP and SiO2NIP were adopted as the adsorbents of solid phase extraction for isolation and preconcentration of biochanin A and its structural analogues daidzein and genistein from aqueous and urine samples. The performance analysis revealed that SiO2MIP displayed better affinity to the three investigated isoflavones compared with SiO2NIP. The recoveries of spiked samples for studied analytes ranged from 65.7% to 102.6% for molecularly imprinted silica polymer and 8.9-16.0% for non-imprinted sorbents. PMID- 25817706 TI - Evaluation and characterization of axial distribution in expanded bed: II. Liquid mixing and local effective axial dispersion. AB - Expanded bed adsorption (EBA) is a promising technology to capture proteins directly from unclarified feedstock. In order to better understand liquid mixing along the bed height in expanded beds, an in-bed sampling method was used to measure residence time distribution at different bed heights. A 2cm diameter nozzle column was tested with agarose raw beads (3% crosslinked agarose containing tungsten carbide). Two settled bed heights (11.5 and 23.1cm) with different expansion factors (1.4-2.6) were investigated and the number of theoretical plates (N), the height equivalent of theoretical plate (HETP) and the local effective axial dispersion coefficient (Dax) were calculated for each bed height-defined zone. The effects of expansion factor, settled bed height and mobile phase were evaluated. The results showed that N increased with the increase of expansion factors, but Dax was unaffected under fixed bed heights. Dax and HETP were found similar as a function of relative bed height for two settled bed heights tested. Higher mobile phase viscosity resulted in stronger axial dispersion. In addition, the local effective Dax under the expansion factor near 2.0 had a different profile which showed minimum values at 0.6-0.8 relative bed height, and the potential mechanism was discussed. These results would be useful for the characterization of axial dispersion and modeling protein adsorption in expanded beds under varying operation conditions. PMID- 25817707 TI - Effects of substitution groups of glutamide-derived molecular gels on molecular shape recognition. AB - We have reported that self-assembling glutamide lipid-grafted porous silica particles show high selectivity towards polycyclic aromatic hydrocarbons (PAHs) and bio-molecules. This enhancement of molecular recognition is brought about by the formation of a highly ordered structure in the glutamide lipid through intermolecular hydrogen bonding. To utilise, for selective separations, the highly oriented structure of glutamide lipids on the silica surface, in this study, we synthesised four glutamide lipids with different substitution groups and studied the separation behaviours of the glutamide lipid-grafted porous silica particles as reversed phase high-performance liquid chromatography (RP HPLC) stationary phases. According to the HPLC studies, the functional group substitutions and the spacer group connecting the glutamide moiety and silica surface had a noticeable effect on the retention behaviours. Particularly, glutamide lipids with a long spacer group (C10) showed a higher selectivity towards positional (o-/m-/p-terphenyl) and geometrical (cis-/trans-stilbene) isomers. Differential scanning calorimetric and Fourier transform infrared spectroscopic studies suggested that the long spacer group induced the assembled structure of the glutamide lipid on the silica surface. Interestingly, the glutamide lipids with dodecyl groups and benzyl groups showed reverse elution orders towards the length to breadth ratio of PAHs. PMID- 25817708 TI - Factors affecting measurement of channel thickness in asymmetrical flow field flow fractionation. AB - Asymmetrical flow field-flow fractionation (AF4) has been considered to be a useful tool for simultaneous separation and characterization of polydisperse macromolecules or colloidal nanoparticles. AF4 analysis requires the knowledge of the channel thickness (w), which is usually measured by injecting a standard with known diffusion coefficient (D) or hydrodynamic diameter (dh). An accurate w determination is a challenge due to its uncertainties arising from the membrane's compressibility, which may vary with experimental condition. In the present study, influence of factors including the size and type of the standard on the measurement of w was systematically investigated. The results revealed that steric effect and the particles-membrane interaction by van der Waals or electrostatic force may result in an error in w measurement. PMID- 25817709 TI - A new anion-exchange/hydrophobic monolith as stationary phase for nano liquid chromatography of small organic molecules and inorganic anions. AB - In this study, an anion-exchange/hydrophobic polymethacrylate-based stationary phase was prepared for nano-liquid chromatography of small organic molecules and inorganic anions. The stationary phase was synthesized by in situ polymerization of 3-chloro-2-hydroxypropylmethacrylate and ethylene dimethacrylate inside silanized 100 MUm i.d. fused silica capillary. The porogen mixture consisted of toluene and dodecanol. The pore size distrubution profiles of the resulting monolith were determined by mercury intrusion porosimetry and the morphology of the prepared monolith was investigated by scanning electron microscope. Good permeability, stability and column efficiency were observed on the monolithic column with nano flow. The produced monolithic column, which contains reactive chloro groups, was then modified by reaction with N,N-dimethyl-N-dodecylamine to obtain an anion-exchange/hydrophobic monolithic stationary phase. The functionalized monolith contained ionizable amine groups and hydrophobic groups that are useful of anion-exchange/hydrophobic mixed-mode chromatography. The final monolithic column performance with respect to anion-exchange and hydrophobic interactions was assesed by the separation of alkylbenzene derivatives, phenolic compounds and inorganic anions, respectively. Theoretical plate numbers up to 23,000 plates/m were successfully achieved in the separation of inorganic anions. PMID- 25817710 TI - Amygdala signals subjective appetitiveness and aversiveness of mixed gambles. AB - People are more sensitive to losses than to equivalent gains when making financial decisions. We used functional magnetic resonance imaging (fMRI) to illuminate how the amygdala contributes to loss aversion. The blood oxygen level dependent (BOLD) response of the amygdala was mapped while healthy individuals were responding to 50/50 gambles with varying potential gain and loss amounts. Overall, subjects demanded twice as high potential gain as loss to accept a gamble. The individual level of loss aversion was expressed by the decision boundary, i.e., the gain-loss ratio at which subjects accepted and rejected gambles with equal probability. Amygdala activity increased the more the gain loss ratio deviated from the individual decision boundary showing that the amygdala codes action value. This response pattern was more strongly expressed in loss aversive individuals, linking amygdala activity with individual differences in loss aversion. Together, the results show that the amygdala signals subjective appetitiveness or aversiveness of gain-loss ratios at the time of choice. PMID- 25817712 TI - Pseudogenization of CCL14 in the Ochotonidae (pika) family. AB - The interaction between chemokines and their receptors is crucial for inflammatory cell trafficking. CCL14 binds with high affinity to CCR5. In leporids, CCR5 underwent gene conversion with CCR2. The study of CCR5 ligands in leporid species showed that CCL8 is pseudogenized, while CCL3, CCL4 and CCL5 are functional. Here, we study the evolution of CCL14 in mammals with emphasis in the order Lagomorpha. By employing maximum likelihood methods we detected six sites under positive selection. Some of these sites are located in regions crucial for CCL14 activation and binding to receptors. Sequencing of CCL14 in Ochotona species showed that O. princeps, O. pallasi, O. alpina and O. turuchanensis have a mutation at the start codon (Met > Thr), while O. hoffmanni, O. mantchurica, O. dauurica and O. rufescens present the mammalian conserved Met. Ochotona hyperborea has the two alleles. In O. pusilla, CCL14 is a pseudogene due to a seven base pair insertion. Like CCL3, CCL4 and CCL5, CCL14 is functional in all leporids but in the Ochotonidae family it underwent a pseudogenization process. This suggests that CCL14 has an important biological role in other mammals by evolving under positive selection that has been lost in Ochotonidae (subgenera Pika and Lagotona). PMID- 25817711 TI - Type 2 diabetes alters bone and marrow blood flow and vascular control mechanisms in the ZDF rat. AB - Bone health and cardiovascular function are compromised in individuals with type 2 diabetes mellitus (T2DM). The purpose of this study was to determine whether skeletal vascular control mechanisms are altered during the progression of T2DM in Zucker diabetic fatty (ZDF) rats. Responses of the principal nutrient artery (PNA) of the femur from obese ZDF rats with prediabetes, short-term diabetes, and long-term diabetes to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilation and potassium chloride, norepinephrine (NE), and a myogenic vasoconstrictor were determined in vitro. Few changes in the PNA vasomotor responses occurred for the prediabetic and short-term diabetic conditions. Endothelium-dependent and -independent vasodilation were reduced, and NE and myogenic vasoconstriction were increased in obese ZDF rats with long-term diabetes relative to lean age-matched controls. Differences in endothelium dependent vasodilation of the femoral PNA between ZDF rats and controls were abolished by the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester. The passive pressure-diameter response of the femoral PNA was also lower across a range of intraluminal pressures with long-term T2DM. Regional bone and marrow perfusion and vascular conductance, measured in vivo using radiolabeled microspheres, were lower in obese ZDF rats with long-term diabetes. These findings indicate that the profound impairment of the bone circulation may contribute to the osteopenia found to occur in long bones during chronic T2DM. PMID- 25817713 TI - Evaluation of Demons- and FEM-Based Registration Algorithms for Lung Cancer. AB - We evaluated and compared the accuracy of 2 deformable image registration algorithms in 4-dimensional computed tomography images for patients with lung cancer. Ten patients with non-small cell lung cancer or small cell lung cancer were enrolled in this institutional review board-approved study. The displacement vector fields relative to a specific reference image were calculated by using the diffeomorphic demons (DD) algorithm and the finite element method (FEM)-based algorithm. The registration accuracy was evaluated by using normalized mutual information (NMI), the sum of squared intensity difference (SSD), modified Hausdorff distance (dH_M), and ratio of gross tumor volume (rGTV) difference between reference image and deformed phase image. We also compared the registration speed of the 2 algorithms. Of all patients, the FEM-based algorithm showed stronger ability in aligning 2 images than the DD algorithm. The means (+/ standard deviation) of NMI were 0.86 (+/-0.05) and 0.90 (+/-0.05) using the DD algorithm and the FEM-based algorithm, respectively. The means of SSD were 0.006 (+/-0.003) and 0.003 (+/-0.002) using the DD algorithm and the FEM-based algorithm, respectively. The means of dH_M were 0.04 (+/-0.02) and 0.03 (+/-0.03) using the DD algorithm and the FEM-based algorithm, respectively. The means of rGTV were 3.9% (+/-1.01%) and 2.9% (+/-1.1%) using the DD algorithm and the FEM based algorithm, respectively. However, the FEM-based algorithm costs a longer time than the DD algorithm, with the average running time of 31.4 minutes compared to 21.9 minutes for all patients. The preliminary results showed that the FEM-based algorithm was more accurate than the DD algorithm while compromised with the registration speed. PMID- 25817714 TI - Acute retinal injury and the relationship between nerve growth factor, Notch1 transcription and short-lived dedifferentiation transient changes of mammalian Muller cells. AB - Our aim is to define related molecular events on how dormant Muller glia cells re enter the cell cycle, proliferate and produce new retinal neurons from initial injury to glial scar formation. Sodium iodate (NaIO3) was used to induce acute retinal injury. Long-Evans rats were administered with NaIO3 or phosphate buffered saline by intraperitoneal injection. The proliferation, dedifferentiation and neurogenesis of Muller cells were analyzed by double labeled fluorescence immunohistochemistry with primary antibodies - against Muller cells and specific cell markers. Possible molecules that limit the regenerative potential of Muller cells were also determined by immunofluorescence staining, quantitative RT-PCR, protein array, ELISA and Western blot. In the first 3-7days after NaIO3 administration, Muller cells were activated and underwent a fate switch, including transient proliferation, dedifferentiation and neurogenesis. Nerve growth factor (NGF) signaling concomitantly increased with the downregulation of p27(Kip1) in Muller cells, which may promote Muller cells to re-enter the cell cycle. The transient increase of NGF signaling and the transient decrease of Notch signaling inhibited Hes1, which might enhance the neuronal differentiation of dedifferentiated Muller cells and suppress gliosis. Upregulated Notch and decreased NGF expressions limit dedifferentiation and neurogenesis, but induces retinal Muller cell gliosis at a later stage. We conclude that transient NGF upregulation and Notch1 downregulation may activate the transient proliferation, dedifferentiation and neurogenesis of Muller cells during NaIO3-induced acute retinal injury; which could be a therapeutic target for overcoming Muller cell gliosis. Such therapy could be potentially used for treating retinal-related diseases. PMID- 25817715 TI - On-Off asymmetry in the perception of blur. AB - Natural images appear blurred when imperfect lens focus reduces contrast energy at higher spatial frequencies. Here, we present evidence that perceived blur also depends on asymmetries between On (positive contrast polarities) and Off (negative contrast polarities) image signals. Psychophysical matching experiments involving natural and artificial stimuli suggest that attenuating Off signals at high spatial frequencies results in increased perceptual blur relative to similar attenuations of On signals. Results support the notion that Off image signals play an important role in blur perception. PMID- 25817716 TI - Blur adaptation: contrast sensitivity changes and stimulus extent. AB - A prolonged exposure to foveal defocus is well known to affect the visual functions in the fovea. However, the effects of peripheral blur adaptation on foveal vision, or vice versa, are still unclear. In this study, we therefore examined the changes in contrast sensitivity function from baseline, following blur adaptation to small as well as laterally extended stimuli in four subjects. The small field stimulus (7.5 degrees visual field) was a 30min video of forest scenery projected on a screen and the large field stimulus consisted of 7-tiles of the 7.5 degrees stimulus stacked horizontally. Both stimuli were used for adaptation with optical blur (+2.00D trial lens) as well as for clear control conditions. After small field blur adaptation foveal contrast sensitivity improved in the mid spatial frequency region. However, these changes neither spread to the periphery nor occurred for the large field blur adaptation. To conclude, visual performance after adaptation is dependent on the lateral extent of the adaptation stimulus. PMID- 25817718 TI - Contribution of HIV-Tat protein to HIV-sequelae. PMID- 25817717 TI - Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies. AB - OBJECTIVES: Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-beta signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate. METHODS: The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus host-disease (cGvHD). Doses of 0.1-3 mg/kg twice a day for riociguat and of 3-10 mg/kg twice a day for sildenafil were used. RESULT: Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat. CONCLUSIONS: These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting. PMID- 25817719 TI - Placental deposition of C-reactive protein is a common feature of human pregnancy. AB - This study examined the occurrence of placental C-reactive protein (CRP) in normal pregnancy with term delivery, spontaneous preterm delivery (sPTD), preeclampsia, and miscarriage. CRP immunoreactivity was detected in the syncytiotrophoblast. The immunopositive rate was significantly higher in sPTD than preeclampsia. The CRP immunopositive rate was also higher in acute chorioamnionitis than those without and showed a good correlation with the maternal serum CRP concentration. CRP mRNA expression was not detected in human and mouse placentas or choriocarcinoma cells. CRP may play a role in the pathological and physiological states of pregnancy. PMID- 25817720 TI - [Arrhythomgenic right ventricular dysplasia and sudden death: An autopsy and histological study]. AB - Arrhythmogenic right ventricular dysplasia (ARVD) is cardiomyopathy where normal myocardial tissue is replaced with fibrofatty tissue. Histological examination performed on myocardial biopsy or on autopsy samples are used to confirm the diagnosis. However, in many cases, the diagnosis cannot be made on a simple macroscopic and histological study and requires genetic analysis and molecular biology. In this work, we propose to describe the main macroscopic and histological findings of ARVD through the study of an autopsy series. We report 12 autopsy cases of sudden death in ARVD collected in the Department of Forensic Medicine of the University Hospital Fattouma Bourguiba Monastir (Tunisia) during a period of 20years. Microscopic examination was performed on 5microns thick histological sections. All slides were reviewed by two operators in a double blind (physician pathologist, pathologist) and in each, the percentage of adipose tissue, fibrosis and infarction in the right ventricle, left ventricle and interventricular septum, the presence or absence of inflammatory infiltrate, the presence or absence of signs of degeneration of myocytes were noticed. ARVD was found in 12 cases (1.8% of sudden cardiac death). The age ranged between 13 and 67years (mean age: 45.3years). The death occurred in half of the cases during exercise. Macroscopic examination of the RV showed the presence of a wall thinning (thickness<3mm) in 9 cases. Histological study highlight RV adipose infiltration in all cases with a percentage between 15% and 60%, fibrotic lesions were observed in only 9 cases with an average percentage of 10.25% and signs of degeneration of myocytes were noted in 10 cases. In concordance with what has been reported in the literature, there is still no consensus regarding the criteria to be adopted to pose with certainty the diagnosis of ARVD and the presence of adipose tissue remains the criterion more suggestive. PMID- 25817721 TI - Quantitative assessment of distance to collection point and improved sorting information on source separation of household waste. AB - The present study measures the participation of households in a source separation scheme and, in particular, if the household's application of the scheme improved after two interventions: (a) shorter distance to the drop-off point and (b) easy access to correct sorting information. The effect of these interventions was quantified and, as far as possible, isolated from other factors that can influence the recycling behaviour. The study was based on households located in an urban residential area in Sweden, where waste composition studies were performed before and after the interventions by manual sorting (pick analysis). Statistical analyses of the results indicated a significant decrease (28%) of packaging and newsprint in the residual waste after establishing a property close collection system (intervention (a)), as well as significant decrease (70%) of the miss-sorted fraction in bags intended for food waste after new information stickers were introduced (intervention (b)). Providing a property close collection system to collect more waste fractions as well as finding new communication channels for information about sorting can be used as tools to increase the source separation ratio. This contribution also highlights the need to evaluate the effects of different types of information and communication concerning sorting instructions in a property close collection system. PMID- 25817723 TI - Reviewers: the ultimate resource for scientific publishing. PMID- 25817722 TI - Characterization of fine fraction mined from two Finnish landfills. AB - A fine fraction (FF) was mined from two Finnish municipal solid waste (MSW) landfills in Kuopio (1- to 10-year-old, referred as new landfill) and Lohja (24- to 40-year-old, referred as old landfill) in order to characterize FF. In Kuopio the FF (<20mm) was on average 45+/-7% of the content of landfill and in Lohja 58+/-11%. Sieving showed that 86.5+/-5.7% of the FF was smaller than 11.2mm and the fraction resembled soil. The total solids (TS) content was 46-82%, being lower in the bottom layers compared to the middle layers. The organic matter content (measured as volatile solids, VS) and the biochemical methane potential (BMP) of FF were lower in the old landfill (VS/TS 12.8+/-7.1% and BMP 5.8+/-3.4 m(3)CH4/t TS) than in the new landfill (VS/TS 21.3+/-4.3% and BMP 14.4+/-9.9 m(3)CH4/t TS), and both were lower compared with fresh MSW. In the Kuopio landfill materials were also mechanically sieved in the full scale plant in two size fraction <30 mm (VS/TS 31.1% and 32.9 m(3)CH4/t TS) and 30-70 mm (VS/TS 50.8% and BMP 78.5m(3)CH4/t TS). The nitrogen (3.5+/-2.0 g/kg TS), phosphorus (<1.0-1.5 g/kg TS) and soluble chemical oxygen demand (COD) (2.77+/-1.77 kg/t TS) contents were low in all samples. Since FF is major fraction of the content of landfill, the characterization of FF is important to find possible methods for using or disposing FF mined from landfills. PMID- 25817726 TI - Zoledronic acid therapy for recurrent giant cell tumor of the C2 vertebra in an adolescent. PMID- 25817727 TI - Aneurysmal bone cyst of the cervical spine. PMID- 25817725 TI - Hepatitis C virus core protein induces epithelial-mesenchymal transition in human hepatocytes by upregulating E12/E47 levels. AB - Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), an essential component of cancer progression to more aggressive phenotypes characterized by tumor dedifferentiation, infiltration, and metastasis. However, the underlying mechanism for E-cadherin downregulation in hepatitis C virus (HCV) associated hepatocellular carcinoma (HCC) is still unclear. In this study, we found that ectopic expression of HCV core protein or infection with HCV in human hepatocytes upregulated the levels of the transcriptional repressors, E12 and E47, resulting in inactivation of the E-cadherin promoter, containing E-box motifs, and subsequent repression of its expression. E12/E47 knock-down almost completely abolished the potential of HCV core protein to repress E-cadherin expression. HCV core protein inhibited ubiquitin-dependent proteasomal degradation of E12/E47 without affecting their expression at the transcriptional level. E12/E47 upregulation ultimately led to EMT in human hepatocytes, as demonstrated by morphological changes, altered expression levels of EMT markers, including E-cadherin, plakoglobin, and fibronectin, and increased capacity for cell detachment and migration. In conclusion, HCV core protein represses E cadherin expression by upregulating E12/E47 levels to induce EMT in HCV associated HCC. PMID- 25817724 TI - Centromere pairing--tethering partner chromosomes in meiosis I. AB - In meiosis, homologous chromosomes face the obstacle of finding, holding onto and segregating away from their partner chromosome. There is increasing evidence, in a diverse range of organisms, that centromere-centromere interactions that occur in late prophase are an important mechanism in ensuring segregation fidelity. Centromere pairing appears to initiate when homologous chromosomes synapse in meiotic prophase. Structural proteins of the synaptonemal complex have been shown to help mediate centromere pairing, but how the structure that maintains centromere pairing differs from the structure of the synaptonemal complex along the chromosomal arms remains unknown. When the synaptonemal complex proteins disassemble from the chromosome arms in late prophase, some of these synaptonemal complex components persist at the centromeres. In yeast and Drosophila these centromere-pairing behaviors promote the proper segregation of chromosome partners that have failed to become linked by chiasmata. Recent studies of mouse spermatocytes have described centromere pairing behaviors that are similar in several respects to what has been described in the fly and yeast systems. In humans, chromosomes that fail to experience crossovers in meiosis are error-prone and are a major source of aneuploidy. The finding that centromere pairing is a conserved phenomenon raises the possibility that it may play a role in promoting the segregation fidelity of non-exchange chromosome pairs in humans. PMID- 25817728 TI - Cone-beam computed tomography evaluation of the soft tissue thickness and greater palatine foramen location in the palate. AB - AIM: The aim of this study was to evaluate the palatal mucosa thickness and greater palatine foramen location using cone-beam computerized tomography (CBCT). MATERIALS AND METHODS: Cone-beam computerized tomography images of 345 patients were measured. The relationship between palate vault depth and angle between the alveolar bone and palatal plane (PA) was evaluated. Differences in the palatal mucosal thickness according to age, gender and tooth site were evaluated. RESULTS: The mean palatal mucosal thickness from the second molar to the canine teeth were 3.7, 3.3, 3.7, 3 and 3 mm, respectively. The palatal mucosal thickness at the second molar and second premolar was statistically different from those at other zones. There was no correlation between the palatal junction angle and the palatal depth. Greater palatine foramen was observed at the level of third molar tooth, between third and second molar, second molar 63%, 31% and 6% in men and 56%, 36% and 8% in women respectively. CONCLUSIONS: The second premolar to second molar zone was considered a suitable graft site based on the mean palatal mucosal thickness. PMID- 25817730 TI - Adenosine induces apoptosis through TNFR1/RIPK1/P38 axis in colon cancer cells. AB - Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy. PMID- 25817729 TI - Dry eye modulates the expression of toll-like receptors on the ocular surface. AB - We aimed to determine if toll-like receptor (TLR) expression is modulated in response to dry eye-associated conditions and in dry eye syndrome (DES). Primary human corneal epithelial cells (HCEC), an SV40 HCEC cell line or a normal human conjunctival epithelial cell line (IOBA-NHC) were cultured under hyperosmolar stress (HOS) (400-500 mOsm/kg) or with DES associated cytokines (IL-1alpha/beta, TNFalpha or TGFbeta) at concentrations ranging from 1 to 1000 ng/ml for up to 24 h. Epithelial cells were harvested from a human cornea organ culture model following 24 h of desiccation. Conjunctival impression cytology samples were harvested from subjects with DES and age and gender-matched normal subjects. TLR4, TLR5 or TLR9 mRNA or protein was examined by quantitative RT-PCR, western blotting or flow cytometry. TLR functionality was evaluated in terms of addition of TLR agonists and quantitation of secreted inflammatory cytokines by the use of ELISA and Luminex assays. In SV40 HCEC, HOS significantly increased TLR4 by 8.18 fold, decreased TLR9 by 0.58 fold, but had no effect on TLR5 mRNA expression. TLR4 and TLR9 protein were decreased by 67.7% and 72% respectively. TLR4 mRNA was also significantly up-regulated by up to 9.70 and 3.36 fold in primary HCEC and IOBA-NHC respectively. DES associated cytokines had no effect on TLR4, TLR5 and TLR9 expression. In response to desiccation, TLR4 and TLR5 mRNA were significantly up-regulated by 4.81 and 2.51 fold respectively, while TLR9 mRNA was down-regulated by 0.86 fold in HCEC. A similar trend for TLR4 and TLR9 protein was observed. TLR9 mRNA was significantly down-regulated by almost 59.5% in DES subjects. In conclusion, changes in TLR expression occur in dry eye and could have an important role in ocular surface susceptibility to inflammation and infection. PMID- 25817731 TI - In-vitro and in-vivo imaging of MMP activity in cartilage and joint injury. AB - Non-destructive detection of cartilage-degrading activities represents an advance in osteoarthritis (OA) research, with implications in studies of OA pathogenesis, progression, and intervention strategies. Matrix metalloproteinases (MMPs) are principal cartilage degrading enzymes that contribute to OA pathogenesis. MMPSense750 is an in-vivo fluorimetric imaging probe with the potential to continuously and non-invasively trace real-time MMP activities, but its use in OA related research has not been reported. Our objective is to detect and characterize the early degradation activities shortly after cartilage or joint injury with MMPSense750. We determined the appropriate concentration, assay time, and linear range using various concentrations of recombinant MMPs as standards. We then quantified MMP activity from cartilage explants subjected to either mechanical injury or inflammatory cytokine treatment in-vitro. Finally, we performed in-vivo MMP imaging of a mouse model of post-traumatic OA. Our in-vitro results showed that the optimal assay time was highly dependent on the MMP enzyme. In cartilage explant culture media, mechanical impact or cytokine treatment increased MMP activity. Injured knees of mice showed significantly higher fluorescent signal than uninjured knees. We conclude that MMPSense750 detects human MMP activities and can be used for in-vitro study with cartilage, as well as in-vivo studies of knee injury, and can offering real-time insight into the degradative processes that occurring within the joint before structural changes become evident radiographically. PMID- 25817732 TI - Improving vascularization of engineered bone through the generation of pro angiogenic effects in co-culture systems. AB - One of the major problems with bone tissue engineering is the development of a rapid vascularization after implantation to supply the growing osteoblast cells with the nutrients to grow and survive as well as to remove waste products. It has been demonstrated that capillary-like structures produced in vitro will anastomose rapidly after implantation and become functioning blood vessels. For this reason, in recent years many studies have examined a variety of human osteoblast and endothelial cell co-culture systems in order to distribute osteoblasts on all parts of the bone scaffold and at the same time provide conditions for the endothelial cells to migrate to form a network of capillary like structures throughout the osteoblast-colonized scaffold. The movement and proliferation of endothelial cells to form capillary-like structures is known as angiogenesis and is dependent on a variety of pro-angiogenic factors. This review summarizes human 2- and 3-D co-culture models to date, the types and origins of cells used in the co-cultures and the proangiogenic factors that have been identified in the co-culture models. PMID- 25817733 TI - Healthcare resource use in patients of the Australian Transition Care Program. AB - OBJECTIVE: The aim of the present study was to describe, from the perspective of the healthcare funder, the cost components of the Australian Transition Care Program (TCP) and the healthcare resource use and costs for a group of transition care clients over a 6-month period following admission to the program. METHODS: A prospective cohort observational study of 351 consenting patients entering community-based transition care at six sites in two states in Australia from November 2009 to September 2010 was performed. Patients were followed up 6 months after admission to the TCP to ascertain current living status and hospital re admissions over the follow-up period. Cost data were collected by transition care teams and from administrative data (hospital and Medicare records). RESULTS: The TCP provides a range of services with most costs attributed to provision of personal care support, case management, physiotherapy and occupational therapy. Most healthcare costs up to 6 months after transition care admission were incurred from the hospital admission leading to transition care and from re admissions. Orthopaedic conditions incurred the highest costs, with many of these for elective procedures and others resulting from falls. Hospital re-admission rates in the present study were 10% lower than in a previous evaluation ofthe TCP. Over 6 months, approximately 40% of patients in the study were re-admitted to hospital at an average cost of A$7038. CONCLUSIONS: Although the cost of the TCP is relatively high, it may have some impact on reducing hospital re admissions and preventing or delaying residential care admissions. PMID- 25817734 TI - Estimating kidney function and use of oral antidiabetic drugs in elderly. AB - The prevalence of diabetes mellitus (DM) and renal impairment rises with age making regular estimation of glomerular filtration rate (eGFR) in older diabetics necessary. This study investigated the differences among available estimating equations in assessing eGFR in older diabetics and examined the use of oral antidiabetic drugs (OADs) in relation to renal function. Patients with DM were participants of the Berlin Initiative Study (BIS), a population-based cohort study initiated in 2009 in Berlin, Germany, to evaluate kidney function in people >=70 years. GFR was estimated with the creatinine-based CKD-EPICREA (Chronic Kidney Disease Epidemiology Collaboration), the MDRD (Modification of Diet in Renal Diseases) and the BIS1 equation and was directly measured (mGFR) with iohexol clearance as a gold standard in a subgroup (n = 137). Creatinine clearance was estimated with the Cockcroft-Gault equation (CrCl). DM prevalence was 26% (539 of 2070 overall participants). The antidiabetic drugs most commonly used among OAD patients were metformin (67%), glimepiride (27%) and glibenclamide (14%). Three of ten metformin patients had a CrCl <60 mL/min. Compared to mGFR, the mean differences of filtration rates calculated by MDRD, CKD-EPICREA and BIS1 were +8.9, +6.7 and -1.8 mL/min/1.73 m(2) , respectively. Summing up, many patients with a CrCl <60 mL/min received metformin, although this represents a contraindication in Germany. Glibenclamide was commonly used despite its classification as potentially inappropriate medication in older adults. Finally, BIS1 performed better in estimating GFR in older diabetics than MDRD or CKD EPICREA . PMID- 25817736 TI - Providing perspective for interpreting cardiovascular mortality risks associated with ozone exposures. AB - When identifying standards for air pollutants based on uncertain evidence, both science and policy judgments play critical roles. Consequently, critical contextual factors are important for understanding the strengths, limitations, and appropriate interpretation of available science, and potential benefits of risk mitigation alternatives. These factors include the relative magnitude and certainty of the risks posed by various factors and the impacts of other risk factors on air pollutant epidemiology study findings. This commentary explores ozone's status as a risk factor for cardiovascular mortality in contrast with decades of strong and consistent evidence for other established risk factors. By comparison, the ozone evidence is less conclusive, more heterogeneous, and subject to substantial uncertainty; ozone's potential effects, if any, are small and challenging to discern. Moreover, the absence of a demonstrated causal relationship calls into question efforts to quantify cardiovascular mortality risks attributed to ozone exposures on a population level and highlights the need to explicitly acknowledge this uncertainty if such calculations are performed. These concerns are relevant for other similar policy contexts - where multiple established risk factors contribute to the health impact of interest; exposure effect associations are relatively small, weak, and uncertain; and a causal relationship has not been clearly established. PMID- 25817735 TI - Opinion on environmental risks and indirect health effects of mercury from dental amalgam. PMID- 25817737 TI - The surgical management of metastatic spinal tumors based on an Epidural Spinal Cord Compression (ESCC) scale. AB - BACKGROUND CONTEXT: There have been no previous studies looking at the outcome of surgical decompression (+/-stabilization) for various grades of epidural spinal cord compression (ESCC) due to spinal metastases. PURPOSE: The aim of this study was to determine the outcome of surgical treatment in patients with ESCC using the Bilsky six-point scale. STUDY DESIGN/SETTING: This was a retrospective cohort review of prospectively collected data. PATIENT SAMPLE: A consecutive series of 101 patients managed over the period of 3 years for ESCC due to spinal metastases in a tertiary spine surgery referral unit were included. METHODS: Data on age, gender, revised Tokuhashi score, preoperative Frankel grade, tumor histology, magnetic resonance imaging scan-based Bilsky cord compression grade, postoperative Frankel grade at last follow-up, complications, and survivorship were collected. OUTCOME MEASURES: Frankel grading system for function was used to evaluate the patient's preoperative and postoperative neurologic status. Patient survival and postoperative complications were also collected. RESULTS: Average patient age was 64.7 years (13-88 years): 62 males and 39 females. Mean follow-up was 7.3 months (3-23.3 months). Most primary tumors were in prostate, breast, renal, lung, and the blood dyscrasias. Within the lower grade of compression (Group 1; Bilsky Grades 0,1a, 1b, and 1c; n=40), 29 patients (72.5%) had no improvement in Frankel grade, seven patients (17.5%) improved, whereas four patients (10%) deteriorated neurologically after surgery. Within the higher compression grade (Group 2; Bilsky Grades 2 and 3; n=61), 37 patients (60%) did not experience neurologic change, 20 (33%) improved, whereas neurology worsened in four patients (7%). When compared with Group 2 patients, Group 1 patients had better preoperative Frankel scores but a greater number of patients in Group 2 improved their Frankel scores significantly postoperatively. The mean revised Tokuhashi score for Groups 1 and 2 was 10 and 9.1, respectively (p=.1). The complication rate for Groups 1 and 2 was 25% and 42.6%, respectively (p=.052). Survival analysis showed no difference between the groups (Group 1: median 376 days [12-1052]; Group 2: median 326 days [12-979]; p=.62). CONCLUSIONS: Surgery can achieve improvements in neurology even in higher grades of cord compression. There is a trend toward more complications and worse survival with spinal surgery in patients with higher grades of compression. PMID- 25817738 TI - Unusual metastasis of papillary thyroid carcinoma: lumbar vertebrae. PMID- 25817739 TI - The influence of facet joint orientation and tropism on the stress at the adjacent segment after lumbar fusion surgery: a biomechanical analysis. AB - BACKGROUND CONTEXT: Facet joint orientation and tropism influence the biomechanics of the corresponding segment. Therefore, the sagittal orientation or tropism of the facet joint adjacent to the fusion segment seems a potential risk factor for adjacent segment degeneration. However, there have been no biomechanical studies regarding this issue. PURPOSE: To investigate the association between adjacent facet orientation and facet tropism and stress in adjacent disc/facet joints using finite element (FE) analysis. STUDY DESIGN: An FE analysis. METHODS: Four intact (F50, F55, F60, and FT [facet tropism]) and matched L3-L4 fusion (F50, F55, F60, and FT fusion) models with different facet joint orientation (50 degrees , 55 degrees , 60 degrees relative to the coronal plane, and facet tropism, respectively) at both L2-L3 facet joints were simulated. In each model, intradiscal pressures and facet contact force at the L2 L3 segment were investigated under pure moments and anterior shear force. RESULTS: Compared with the matched-intact model, the F60 fusion model yielded the highest and largest percentage increase of intradiscal pressure at the L2-L3 segment under flexion, torsion moment, and anterior shear force among the F50, F55, and F60 fusion models. F60 fusion model also demonstrated the largest facet contact force under torsion moment among the F50, F55, and F60 fusion models. In all conditions tested, the FT fusion model demonstrated the highest intradiscal pressure and facet contact force of all the models. CONCLUSIONS: Facet joint orientation and tropism at the adjacent segment influences the overstress of the adjacent segment, especially under the clinical circumstance of increased anterior shear force. PMID- 25817740 TI - Myocardial perfusion imaging using contrast echocardiography. AB - Microbubbles are an excellent intravascular tracer, and both the rate of myocardial opacification (analogous to coronary microvascular perfusion) and contrast intensity (analogous to myocardial blood volume) provide unique insights into myocardial perfusion. A strong evidence base has been accumulated to show comparability with nuclear perfusion imaging and incremental diagnostic and prognostic value relative to wall motion analysis. This technique also provides the possibility to measure myocardial perfusion at the bedside. Despite all of these advantages, the technique is complicated, technically challenging, and has failed to scale legislative and financial hurdles. The development of targeted imaging and therapeutic interventions will hopefully rekindle interest in this interesting modality. PMID- 25817741 TI - High-Frequency Anterior Thalamus Stimulation Interrupts Cortical Midline Theta Rhythm During Drowsiness in an Epileptic Patient. PMID- 25817742 TI - Paul Tessier facial reconstruction in 1970 Iran, a series of post-noma defects. AB - BACKGROUND: Paul Tessier was a pioneering plastic surgeon who founded craniofacial surgery and had an international influence in the field of reconstructive surgery. We reviewed his techniques in the reconstruction of post noma defects in Iran in the late 1970s. PATIENTS AND METHODS: We studied a series of 23 patients operated on by Tessier from 1974 to 1978 in Iran (property of Association Francaise des Chirurgiens de la Face). They all suffered from noma in childhood with major facial defects. RESULTS: Ten suffered from simple lip and cheek defects, nine also from nose defects and four from extensive facial defects. Abbe flaps were used in 15 patients to reconstruct the lips completed by commissuroplasty in six patients. Nose defects were reconstructed with nasofrontal flaps (ten cases). The outer cheek was reconstructed with a rotation flap (four cases), or with a frontotemporal flap (six cases). The inner cheek was reconstructed using a Barron-Tessier myocutaneous flap (ten cases). Of the 23 patients, partial flap necrosis occurred in five cases. CONCLUSIONS: Tessier was a pioneering plastic surgeon who used local flaps to reconstruct these important facial defects. He had a high rate of success, although nowadays local flaps are commonly replaced by free flaps. PMID- 25817743 TI - Endoscopic retrograde cholangiopancreatography-associated AmpC Escherichia coli outbreak. AB - BACKGROUND: We identified an outbreak of AmpC-producing Escherichia coli infections resistant to third-generation cephalosporins and carbapenems (CR) among 7 patients who had undergone endoscopic retrograde cholangiopancreatography at hospital A during November 2012-August 2013. Gene sequencing revealed a shared novel mutation in a bla CMY gene and a distinctive fumC/ fimH typing profile. OBJECTIVE: To determine the extent and epidemiologic characteristics of the outbreak, identify potential sources of transmission, design and implement infection control measures, and determine the association between the CR E. coli and AmpC E. coli circulating at hospital A. METHODS: We reviewed laboratory, medical, and endoscopy reports, and endoscope reprocessing procedures. We obtained cultures from endoscopes after reprocessing as well as environmental samples and conducted pulsed-field gel electrophoresis and gene sequencing on phenotypic AmpC isolates from patients and endoscopes. Cases were those infected with phenotypic AmpC isolates (both carbapenem-susceptible and CR) and identical bla CMY-2, fumC, and fimH alleles or related pulsed-field gel electrophoresis patterns. RESULTS: Thirty-five of 49 AmpC E. coli tested met the case definition, including all CR isolates. All cases had complicated biliary disease and had undergone at least 1 endoscopic retrograde cholangiopancreatography at hospital A. Mortality at 30 days was 16% for all patients and 56% for CR patients. Two of 8 reprocessed endoscopic retrograde cholangiopancreatography scopes harbored AmpC that matched case isolates by pulsed-field gel electrophoresis. Environmental cultures were negative. No breaches in infection control were identified. Endoscopic reprocessing exceeded manufacturer's recommended cleaning guidelines. CONCLUSION: Recommended reprocessing guidelines are not sufficient. PMID- 25817744 TI - Group Cognitive-Behavioral Therapy for Anxiety Disorders With Personality Disorders in Day Clinic Setting. AB - PURPOSE: Short-term group cognitive-behavioral therapy (GCBT) with weekly homogeneous group sessions for treating specific anxiety disorders is relatively well developed and recognized. However, 12 weeks of intensive daily therapy for mixed anxiety and personality disorders is not. The current article aims to fill this gap by presenting the method of intensive transdiagnostic GCBT for anxiety disorders with comorbid personality disorders in a day hospital setting. Preliminary studies showed that participants exhibited significant improvement during this type of treatment. CONCLUSIONS: This article reviews the advantages of group therapy that is transdiagnostic over the homogeneous group and individual therapy formats. PRACTICE IMPLICATIONS: The detailed description of the current therapeutical program may facilitate the development of similar programs in day clinic settings. PMID- 25817745 TI - Staging for endometrial cancer: The controversy around lymphadenectomy - Can this be resolved? AB - Endometrial cancer remains the most common malignancy of the female genital tract. Lymph node metastasis is one of the most important prognostic factors, and stratification into pelvic lymph node invasion (stage IIIC1) and para-aortic lymph node invasion (stage IIIC2) improved the predictive value of the 2009 International Federation of Gynecology and Obstetrics (FIGO) classification. Radiological examination methods such as magnetic resonance imaging and positron emission tomography-computed tomography do not have good-enough sensitivity to avoid lymphadenectomy for the assessment of lymph node invasion. Prediction scores are becoming increasingly valuable to exclude lymph node metastasis in low risk groups, and biomarkers could help to identify patients with high-risk lymph node metastatic probability. The therapeutic role of lymph node dissection remains a matter of debate. Several end points can be considered to evaluate the opportunity of lymphadenectomy in endometrial cancer. First, we compare survival according to the realization, the extent, and the numbers of nodes removed during lymphadenectomy. Second, we assess the opportunity of lymphadenectomy in order to tailor adjuvant treatment modalities. Third, we analyze the surgical complication rate after pelvic lymphadenectomy. PMID- 25817746 TI - Severe camptodactyly: A systematic surgeon and therapist collaboration. AB - INTRODUCTION: Although common, the treatment of camptodactyly is controversial. PURPOSE: Our purpose is to delineate a logical stepwise treatment plan based on corresponding components of the pre-operative and intraoperative evaluation of camptodactyly. In addition, describe structure rehabilitation plan utilizing the same stepwise evaluation. METHODS: With the use of a retrospective cohort study design, we reviewed 18 consecutively operated digits in twelve patients with camptodactyly affecting the proximal interphalangeal (PIP) joint. There were five girls and eight boys, averaging eight years of age (range: 9 months to 15 years) at surgery. RESULTS: Surgery corrected flexion contractures with mean post operative flexion contracture of 3 degrees (range 0-25 degrees ) at mean follow up of 11 months (range 3-32 months). 15 of 18 digits achieved full active PIP extension. DISCUSSION: By employing a detailed clinical assessment to guide surgical treatment followed by focused therapy, we have markedly improved flexion contractures in digits with moderate to severe camptodactyly. CONCLUSIONS: Hand therapy is essential to maintain and further surgical improvement of passive extension and to regain active extension following surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25817747 TI - Bariatric surgery for nonalcoholic fatty liver disease in adolescents with severe obesity. PMID- 25817748 TI - Polyester tape scapulopexy for chronic upper extremity brachial plexus injury. AB - PURPOSE: To report the results of scapular stabilization for winging in patients with chronic upper brachial plexus injury. METHODS: Eight patients, mean age 36 years, who had a winged scapula after successful restoration of major shoulder function by nerve transfer underwent scapular stabilization to the ribcage using polyester tape. The follow-up period ranged from 24 to 40 months (mean, 38 mo). Data collection included radiographic analysis, active range of motion measurement, University of California Los Angeles shoulder score, and visual analog scale pain score. RESULTS: All patients had clinical improvement with resolution of scapular winging. Five patients had no winging and 3 had mild winging after the surgery. Mean active forward flexion increased from 101 degrees preoperatively to 127 degrees postoperatively. Mean active shoulder abduction increased from 91 degrees preoperatively to 121 degrees postoperatively. Mean University of California Los Angeles shoulder score improved from 17 to 27 and mean visual analog scale pain score improved from 6.1 to 0.7. In addition, mean lateral deviated angle increased from 4 degrees from neutral preoperatively to 9 degrees at the last follow-up. All patients reported satisfaction with postoperative appearance. CONCLUSIONS: Outcomes of polyester tape scapulopexy in the short to intermediate term were favorable in terms of improved appearance, upper extremity function, and pain reduction in patients with winged scapula resulting from chronic upper brachial plexus injury, and with successful restoration of shoulder motion by previous nerve transfers. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25817749 TI - Flexor digitorum profundus laceration in association with closed middle phalangeal fracture: case report. AB - We report a patient with a flexor digitorum profundus laceration caused by the volarly displaced proximal fragment of a middle phalangeal fracture. Awareness of this association may allow timely recognition and appropriate treatment. PMID- 25817750 TI - Anteriorly positioned ulnar nerve at the elbow: a rare anatomical event: case report. AB - Two patients with an anteriorly positioned ulnar nerve at the elbow, identified during cubital tunnel release, are presented. Upon encountering an empty cubital tunnel, additional dissection found the ulnar nerve to course posterior to and to penetrate through the intermuscular septum 3 to 5 cm proximal to the medial epicondyle. It then ran anterior to the pronator-flexor mass before entering the forearm between the ulnar and the humeral heads of the flexor carpi ulnaris. Although a rare anatomical anomaly, an anteriorly positioned ulnar nerve is potentially an underreported finding. In individuals with cubital tunnel syndrome, diagnosis and surgical treatment may be negatively affected if the surgeon fails to recognize the aberrant anatomy. Upper extremity surgeons should also be mindful of this rare anomaly when performing elbow arthroscopy or medial epicondyle release to prevent inadvertent injury to the nerve. PMID- 25817751 TI - Within-session reliability and smallest real difference of muscle strength following nerve transfers in patients with brachial plexus injuries. AB - PURPOSE: To quantify the smallest real difference (SRD) of muscle strength in patients with brachial plexus injuries (BPI) after nerve transfer. METHODS: This study enrolled 16 patients with BPI who had C5-C6 and C5-C7 root injuries and who received nerve transfer of the spinal accessory nerve to the suprascapular nerve and fascicles of the ulnar nerve to the branch of the musculocutaneous nerve that innervates the biceps muscle. The quantitative peak strength of the shoulder abductor, external rotator, and elbow flexor in both arms were measured by the hand-held dynamometer. The SRD of each muscle was determined from the values of the intraclass correlation coefficient and standard error of measurement. RESULTS: In the involved arm, peak strength ranged from 18% of the noninvolved (shoulder external rotator) to 40% of the noninvolved (shoulder abductor). The intraclass coefficient for within-session reliability revealed good to excellent reliability for muscles, ranging from 0.86 to 0.99 and 0.87 to 0.91 in the involved and noninvolved arms, respectively. The SRD values were low for the shoulder external rotator (2.6 kg) and high for the elbow flexor (3.3 kg). CONCLUSIONS: The hand-held dynamometer is a device with good to excellent reliability for measuring the objective strength of patients with BPI in a single session. The SRD values established in the current study are more applicable for patients achieving a Medical Research Council grading of 3 or higher and can be used to detect real changes occurring after intervention, which can thereby differentiate real changes from changes that could be attributed to random variation in the measurements. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnosis II. PMID- 25817752 TI - Sildenafil as a therapeutic option for digital ischemic ulceration: case report. AB - We report the case of a 37-year-old woman who developed critical upper limb ischemia caused by a cervical rib. Because the malformation was initially undiagnosed, a vascular bypass was performed, and failure occurred. Following a 6 month therapy with sildenafil, revascularization of the arm was successful and amputation was avoided. A 6-year follow-up shows a rich collateral network at the compression site and normal values of digital plethysmography. Because hand surgeons often see patients with digital ulcerations and other manifestations of peripheral vascular pathology, therapy of ischemia with sildenafil could be an effective treatment option in patients not responding to classic drugs. PMID- 25817753 TI - The effect of barbed suture tendon repair on work of flexion. AB - PURPOSE: To compare the work of flexion, ultimate strength, and gap resistance of a conventional 4-strand tendon repair to a knotless barbed-suture 4-strand tendon repair. METHODS: Tendon repairs were performed on 16 cadaver flexor digitorum profundus tendons using either a 4-strand double Kessler repair or a similar but knotless 4-strand repair with a unidirectional barbed suture. Work of flexion, gap resistance during cyclical loading, and ultimate strength of both techniques were determined and their means compared. RESULTS: There was no difference in mean maximum load and gap formation between the 2 techniques. Work of flexion was higher for the barbed-suture repair group compared with the traditional repair group (39 N.mm vs 31 N.mm). CONCLUSIONS: The higher work of flexion in the barbed suture group suggests that barbed suture may negatively affect tendon gliding within the flexor tendon sheath. CLINICAL RELEVANCE: Knotless barbed-suture tendon repair leads to increased work of flexion compared with traditional flexor tendon repairs, which may result in an increased rupture incidence. PMID- 25817754 TI - Pain in children following microsurgical reconstruction for obstetrical brachial plexus palsy. AB - PURPOSE: To determine the prevalence and characteristics of pain experienced by children who have had microsurgical reconstruction for obstetrical brachial plexus palsy (OBPP). METHODS: A prospective case series study was conducted of 65 children aged 6 to 18 years with a diagnosis of OBPP and who had microsurgery at less than 12 months of age with nerve grafting or transfer. A total of 28 patients (43%) had upper OBPP and 37 (57%) had total OBPP. We evaluated pain using the Faces Pain Scale-Revised and the Adolescent Pediatric Pain Tool. Sensory symptoms in the affected limb were also collected. Mean age was 11.0 +/- 3.3 years. RESULTS: We evaluated 65 children. The point prevalence of pain (pain at the time of assessment) was 25%. The reported lifetime prevalence of pain (experienced anytime during life) was 66%. A total of 71% reported that the affected extremity felt different at least once in their lifetime. Average intensity of those with pain (n = 43) was 40 +/- 19 mm on a 100-mm visual analog scale. Seventy percent of children reported that symptoms occurred every day or at least once a week. Anatomical distribution of pain was throughout the affected upper extremity irrespective of the severity of injury, with the exception of children with upper plexus injuries who did not report pain in their hand. Words typically used to describe neuropathic or musculoskeletal symptoms were chosen by the children to represent their pain. CONCLUSIONS: Children with OBPP who had microsurgical reconstruction commonly reported pain. These symptoms were typically frequent but were episodic and low in intensity. The descriptions of the type of pain include terms typical of both neuropathic and musculoskeletal origins. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 25817755 TI - Increased pain catastrophizing associated with lower pain relief during spinal cord stimulation: results from a large post-market study. AB - BACKGROUND: Pain catastrophizing is a negative cognitive distortion to actual or anticipated pain. Our aim was to determine if greater catastrophizing has a deleterious relationship with pain intensity and efficacy outcomes in patients receiving SCS. METHODS: As part of an ongoing Institutional Review Board approved, multi-site, single arm post-market study, 386 patients were implanted with an Eon MiniTM SCS system and had follow-up visits at 3, 6, and 12 months post-implant. Outcomes collected during the study included, but were not limited to pain intensity using the numeric rating scale (NRS), patient reported pain relief (PRP), satisfaction with their SCS system, quality of life (QOL), pain catastrophizing scale (PCS) and state-trait anxiety index (STAI). RESULTS: NRS scores were associated with higher PCS scores at six months (r = 0.50, p < 0.001). The PCS was a strong predictor of the NRS when controlled for known confounders. Patients with PCS >=30 at 6-months post-implant had a lower six month PRP (p < 0.001) and were five times more likely to report dissatisfaction with their SCS device (p < 0.001, OR = 5.46, 95% CI: 2.51-6.35). Additionally, at six months, those who were clinically catastrophizing were three times more likely to report deterioration in QOL (p < 0.002, OR = 3.12, 95% CI: 1.62-5.51). These findings were similar at the 12 months follow visit. CONCLUSIONS: Our results indicate that patients with greater catastrophizing, post-implant, were more likely to report higher pain intensity and lower pain relief, quality of life and satisfaction with SCS. These results indicate that associations between pain intensity and pain-related mental health may contribute to influence the overall efficacy of SCS. PMID- 25817756 TI - Elimination of drugs of abuse and their toxicity from natural waters by photo Fenton treatment. AB - This paper investigates the elimination of drugs of abuse from six different chemical classes and their metabolites in natural fluvial waters (nearby the output of a sewage system). Mineralization of these substances and toxicological characterization before and after treatment by a heterogeneous photo-Fenton system has been evaluated. This advanced oxidation technology was able to significantly reduce the concentration of the drugs of abuse in all the tested conditions (different hydrogen peroxide and catalyst loadings). However, toxicological analyses measured as inhibition of fern spore mitochondrial activity, showed only a complete elimination of acute and chronic toxicity when a higher solid catalyst loading was used (0.6 g/L). A lower catalyst loading of 0.2 g/L was not enough for toxicity elimination. These results evidence the need for combining toxicological tests and chemical analyses in order to establish the effectiveness of the water treatment technologies based on advanced oxidation processes. PMID- 25817757 TI - Developmental effects of parental exposure to soil contaminated with urban metals. AB - Soil is a highly complex material, and because of rapid population growth, intense industrial activity and petrochemical development, it has suffered from contamination with substances of various origins. These environmental contaminants may have detrimental effects on human health, particularly during development. Due to the ability to transmit contaminants to the fetus, evaluating the effects of exposure of pregnant women on the psychomotor development of their offspring is of particular interest. Therefore, this study aimed to investigate the effects of exposure of female rats to an urban soil influenced by the dispersion of air contaminants during periods of pre-pregnancy, pregnancy and lactation on offspring development. Using physiological, behavioral and hematological parameters, deleterious effects on offspring were assessed. In behavioral parameters, parental exposure during pregnancy and lactation resulted in no significant differences in the evaluated parameters when compared to the control group. In contrast, pups from the pre-pregnancy group displayed decreased locomotor and exploratory activity in addition to increased levels of anxiety. Furthermore, offspring of rats exposed to contaminated urban soil during pre pregnancy demonstrated significant changes in weight gain and development length and a reduction in the number of platelets compared to controls. Significantly, pups born to mothers exposed to contaminated urban soil during the pregnancy displayed changes in birth weight, weight gain during the growth, development length, incisor eruption and opening of the ears in addition to a reduction in their physical performance and a change in the number of lymphocytes. These results clearly show the negative influence of parental exposure to contaminated urban soil on the general development of the rats during the periods studied. These data indicate that developing organisms are highly sensitive to external factors. Further, they demonstrate the utility of these various biomarkers for identifying and displaying toxic effects of exposure to contaminated soils. PMID- 25817758 TI - Inactivation of adenovirus, reovirus and bacteriophages in fecal sludge by pH and ammonia. AB - The aim of this study was to evaluate the inactivation of adenovirus, reovirus and bacteriophages (MS2, PhiX174, 28B) in a fecal sludge. We conducted two experiments. In the first, we tested different compositions of the fecal sludge by mixing different amounts of water, feces and urine, totaling nine combinations which were kept at temperatures between 10 and 28 degrees C. In the second study, urea was added to the mixtures, which were kept at temperatures from 5 to 33 degrees C. The inactivation was based on a combination of temperature, pH and uncharged ammonia concentration. The increase in pH and ammonia was provided mainly by urine content (Experiment 1) and by urine and added urea (Experiment 2). The inactivation of bacteriophages was slower than the AdV and ReV. At 23 degrees C and 28 degrees , reasonable treatment times were obtained when pH was higher than 8.9 and NH3 concentrations were higher than 35 and 55 mM respectively. With those conditions, the maximum time for a 3 log reduction in viruses, according to this study, would be 35 days (23 degrees C) and 21 days (28 degrees C). However, in most applications where helminth eggs are present, the treatment time and NH3 for sanitization will be the scaling criteria, as they are more persistent. Concerning the sanitization of effluents from latrines, vacuum toilets or dry toilets in developing countries with tropical and sub-tropical climates, the use of intrinsic ammonia combined with high pH can be effective in producing a safe and highly valuable liquid that can be used as a fertilizer. In the case of the fecal sludge with very intrinsic ammonia concentration (<20 mM), sanitization could still be achieved by the addition of urea. PMID- 25817759 TI - Degradation of chloroacetanilide herbicides and bacterial community composition in lab-scale wetlands. AB - Degradation of chloroacetanilide herbicides rac-metolachlor, acetochlor, and alachlor, as well as associated bacterial populations, were evaluated in vertical upflow wetland columns using a combination of hydrochemical and herbicide analyses, and DNA-based approaches. Mass dissipation of chloroacetanilides, continuously supplied at 1.8-1.9 MUM for 112 days, mainly occurred in the rhizosphere zone under nitrate and sulphate-reducing conditions, and averaged 61+/-14%, 52+/-12% and 29+/-19% for acetochlor, alachlor and rac-metolachlor, respectively. Metolachlor enantiomer fractions of 0.494+/-0.009 in the oxic zone and 0.480+/-0.005 in the rhizosphere zone indicated preferential biodegradation of the S-enantiomer. Chloroacetanilide ethane sulfonic acid and oxanilic acid degradates were detected at low concentrations only (0.5 nM), suggesting extensive degradation and the operation of yet unknown pathways for chloroacetanilide degradation. Hydrochemical parameters and oxygen concentration were major drivers of bacterial composition, whereas exposure to chloroacetanilides had no detectable impact. Taken together, the results underline the importance of anaerobic degradation of chloroacetanilides in wetlands, and highlight the potential of complementary chemical and biological approaches to characterise processes involved in the environmental dissipation of chloroacetanilides. PMID- 25817760 TI - The anticancer drug metabolites endoxifen and 4-hydroxy-tamoxifen induce toxic effects on Daphnia pulex in a two-generation study. AB - Although pharmaceutical metabolites are found in the aquatic environment, their toxicity on living organisms is poorly studied in general. Endoxifen and 4 hydroxy-tamoxifen (4OHTam) are two metabolites of the widely used anticancer drug tamoxifen for the prevention and treatment of breast cancers. Both metabolites have a high pharmacological potency in vertebrates, attributing prodrug characteristics to tamoxifen. Tamoxifen and its metabolites are body-excreted by patients, and the parent compound is found in sewage treatment plan effluents and natural waters. The toxicity of these potent metabolites on non-target aquatic species is unknown, which forces environmental risk assessors to predict their toxicity on aquatic species using knowledge on the parent compounds. Therefore, the aim of this study was to assess the sensitivity of two generations of the freshwater microcrustacean Daphnia pulex towards 4OHTam and endoxifen. Two chronic tests of 4OHTam and endoxifen were run in parallel and several endpoints were assessed. The results show that the metabolites 4OHTam and endoxifen induced reproductive and survival effects. For both metabolites, the sensitivity of D. pulex increased in the second generation. The intrinsic rate of natural increase (r) decreased with increasing 4OHTam and endoxifen concentrations. The No Observed Effect Concentrations (NOECs) calculated for the reproduction of the second generation exposed to 4OHTam and endoxifen were <1.8 and 4.3 MUg/L, respectively, whereas the NOECs that were calculated for the intrinsic rate of natural increase were <1.8 and 0.4 MUg/L, respectively. Our study raises questions about prodrug and active metabolites in environmental toxicology assessments of pharmaceuticals. Our findings also emphasize the importance of performing long-term experiments and considering multi-endpoints instead of the standard reproduction outcome. PMID- 25817761 TI - Emission factor estimation of ca. 160 emerging organic microcontaminants by inverse modeling in a Mediterranean river basin (Llobregat, NE Spain). AB - Starting from measured river concentrations, emission factors of 158 organic compounds out of 199 analyzed belonging to different groups of priority and emerging contaminants [pesticides (25), pharmaceuticals and hormones (81), perfluoroalkyl substances (PFASs) (18), industrial compounds (12), drugs of abuse (8) and personal care products (14)] have been estimated by inverse modeling. The Llobregat river was taken as case study representative of Mediterranean rivers. Industrial compounds and pharmaceuticals are the dominant groups (range of 10(4) mg.1000 inhab(-1).d(-1)). Personal care products, pesticides, PFASs and illegal drugs showed a load approximately one order of magnitude smaller. Considered on a single compound basis industrial compounds still dominate (range of ca. 10(3) mg.1000 inhab(-1).d(-1)) over other classes. Generally, the results are within the range when compared to previously published estimations for other river basins. River attenuation expressed as the percentage fraction of microcontaminants eliminated was quantified. On average they were around 60-70% of the amount discharged for all classes, except for PFASs, that are poorly eliminated (ca. 20% on average). Uncertainties associated with the calculated emissions have been estimated by Monte-Carlo methods (15,000 runs) and typically show coefficients of variation of ca. 120%. Sensitivities associated with the various variables involved in the calculations (river discharge, river length, concentration, elimination constant, hydraulic travel time and river velocity) have been assessed as well. For the intervals chosen for the different variables, all show sensitivities exceeding unity (1.14 to 3.43), tending to amplify the variation of the emission. River velocity and basin length showed the highest sensitivity value. Even considering the limitations of the approach used, inverse modeling can provide a useful tool for management purposes facilitating the quantification of release rates of chemicals into the aquatic environment. PMID- 25817762 TI - Arsenic speciation driving risk based corrective action. AB - The toxicity of arsenic depends on a number of factors including its valence state. The more potent trivalent arsenic [arsenite (As3+)] inhibits a large number of cellular enzymatic pathways involved in energy production, while the less toxic pentavalent arsenic [arsenate (As5+)] interferes with phosphate metabolism, phosphoproteins and ATP formation (uncoupling of oxidative phosphorylation). Environmental risk based corrective action for arsenic contamination utilizes data derived from arsenite studies of toxicity to be conservative. However, depending upon environmental conditions, the arsenate species may predominate substantially, especially in well aerated surface soils. Analyses of soil concentrations of arsenic species at two sites in northeastern Texas historically contaminated with arsenical pesticides yielded mean arsenate concentrations above 90% of total arsenic with the majority of the remainder being the trivalent arsenite species. Ecological risk assessments based on the concentration of the trivalent arsenite species will lead to restrictive remediation requirements that do not adequately reflect the level of risk associated with the predominate species of arsenic found in the soil. The greater concentration of the pentavalent arsenate species in soils would be the more appropriate species to monitor remediation at sites that contain high arsenate to arsenite ratios. PMID- 25817763 TI - Patterns and predictability in the intra-annual organic carbon variability across the boreal and hemiboreal landscape. AB - Factors affecting total organic carbon (TOC) concentrations in 215 watercourses across Sweden were investigated using parameter parsimonious regression approaches to explain spatial and temporal variabilities of the TOC water quality responses. We systematically quantified the effects of discharge, seasonality, and long-term trend as factors controlling intra-annual (among year) and inter annual (within year) variabilities of TOC by evaluating the spatial variability in model coefficients and catchment characteristics (e.g. land cover, retention time, soil type). Catchment area (0.18-47,000 km2) and land cover types (forests, agriculture and alpine terrain) are typical for the boreal and hemiboreal zones across Fennoscandia. Watercourses had at least 6 years of monthly water quality observations between 1990 and 2010. Statistically significant models (p<0.05) describing variation of TOC in streamflow were identified in 209 of 215 watercourses with a mean Nash-Sutcliffe efficiency index of 0.44. Increasing long term trends were observed in 149 (70%) of the watercourses, and intra-annual variation in TOC far exceeded inter-annual variation. The average influences of the discharge and seasonality terms on intra-annual variations in daily TOC concentration were 1.4 and 1.3 mg l(-1) (13 and 12% of the mean annual TOC), respectively. The average increase in TOC was 0.17 mg l(-1)year(-1) (1.6% year( 1)). Multivariate regression with over 90 different catchment characteristics explained 21% of the spatial variation in the linear trend coefficient, less than 20% of the variation in the discharge coefficient and 73% of the spatial variation in mean TOC. Specific discharge, water residence time, the variance of daily precipitation, and lake area, explained 45% of the spatial variation in the amplitude of the TOC seasonality. Because the main drivers of temporal variability in TOC are seasonality and discharge, first-order estimates of the influences of climatic variability and change on TOC concentration should be predictable if the studied catchments continue to respond similarly. PMID- 25817764 TI - Legacy and emerging organic pollutants in liver and plasma of long-finned pilot whales (Globicephala melas) from waters surrounding the Faroe Islands. AB - Concentrations of PCBs, organochlorine pesticides (OCPs), brominated flame retardants and a suite of relevant metabolites of these POPs, in all 175 different compounds, were determined in liver and plasma of traditionally hunted pilot whales (n=14 males and n=13 females of different age groups) from the Faroe Islands. The main objectives of this study were to determine differences in the presence and concentrations of the compounds in the liver and plasma, how they depend on developmental stage (calves, sub adults, and adult females), and to assess maternal transfer of the compounds to suckling calves. Generally, the lipid weight (lw) concentrations of quantified POPs in the liver and plasma of pilot whales were positively correlated, and lw concentrations of most POPs did not differ between these matrices. However, concentrations of some individual POPs differed significantly (p<0.05) between plasma and liver; CB-153 (p=0.044), CB-174 (p=0.027) and BDE-47 (p=0.017) were higher in plasma than in liver, whereas p,p'-DDE (p=0.004) and HCB (p<0.001) were higher in liver than in plasma. POP concentrations differed between age/gender groups with lower levels in adult females than in juveniles. The relative distribution of compounds also differed between the age groups, due to the influence of the maternal transfer of the compounds. The results indicated that larger, more hydrophobic POPs were transferred to the offspring less efficiently than smaller or less lipid soluble compounds. Very low levels of both OH- and/or MeSO2-PCB and PBDE metabolites were found in all age groups, with no significant (p>0.05) differences between the groups, strongly suggesting a very low metabolic capacity for their formation in pilot whales. The lack of difference in the metabolite concentrations between the age groups also indicates less maternal transfer of these contaminant groups compared to the precursor compounds. PMID- 25817765 TI - Vaginal Burn from Alkaline Battery in an 8-Year-Old. AB - BACKGROUND: Life-threatening injury from battery ingestion has mandated changes in the manufacture of battery-operated devices. Whilst esophageal burns are commonly publicized, there is scarce literature on vaginal burns and their potential morbidity. CASE: An 8-year-old girl presented with self-report of a "fluffy toy" per vagina. Under general anesthesia, her vagina was examined and the mucosa appeared coated in a "blue fur." It was soon identified as corrosive damage from an alkaline button battery. Fistula and rectal injury were excluded. Symptomatic relief was achieved with the use of estradiol lidocaine intravaginal concoction following removal. SUMMARY AND CONCLUSIONS: Optimal management of a vaginal foreign body relies upon clinical suspicion, familiarity with prepubertal vaginal instrumentation, and expeditious removal of inserted batteries to avoid serious morbidity. PMID- 25817766 TI - Nearly Normal Congenital Cervical Fragmentation: A Hard-To-Diagnose and Successful End-To-End Anastomosis. AB - BACKGROUND: Congenital cervical fragmentation is a very rare genital tract malformation that usually presents in adolescence with primary amenorrhea and cyclic, monthly, lower abdominal pain. We report a nearly normal case of congenital cervical fragmentation and successful end-to-end anastomosis. CASE: A 15-year-old girl presented with primary amenorrhea with cyclic, monthly lower abdominal pain lasting for 15 months without any abnormal imaging findings (pelvic CT scan, ultrasonography, and hysteroscopy). Misdiagnosis and appendectomy was performed at the time of the initial lower abdominal pain. Diagnostic combined hysteroscopy and laparoscopy were performed in our hospital, and cervical fragmentation was diagnosed. A converted laparotomy end-to-end anastomosis was performed successfully, and regular menstruation was restored after the operation. SUMMARY AND CONCLUSION: The malformation of nearly normal congenital cervical fragmentation is existent and hard to diagnose. As long as the patient has persistent primary amenorrhea with cyclic, monthly lower abdominal pain, even if no abnormal findings on imaging, obstructive malformation of the reproductive duct should be the primary suspicion. Diagnosis and treatment should occur as early as possible to preserve the patient's fertility. End-to-end anastomosis is the best method for this type of patient. PMID- 25817767 TI - Asymmetrical Ovarian Enlargement: Caught Timely Before the Cut! AB - BACKGROUND: Van Wyk-Grumbach syndrome is a rare complication of prolonged untreated primary hypothyroidism characterized by precocious puberty and enlarged multicystic ovaries. High index of suspicion and timely diagnosis can prevent unnecessary surgical procedures because this condition can be reversed with thyroid hormone supplementation. CASE: A 12-year-old girl underwent abdominal ultrasonography for recurrent abdominal pain, which showed bilateral asymmetrical enlargement of ovaries. Ovarian tumor markers were negative. Subsequent evaluation revealed severe hypothyroidism. Patient was started on levothyroxine and both ovaries showed regression to normal volume within 1 year of normalizing thyroid function tests. SUMMARY AND CONCLUSION: Prompt and adequate medical management with levothyroxine can completely reverse ovarian enlargement associated with hypothyroidism. PMID- 25817769 TI - Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: study of 6-substituted pyridine-3-boronic acid derivatives. AB - In response to the extensive use of antibiotics, bacteria have evolved numerous mechanisms of defense against antimicrobial agents. Among them, extrusion of the antimicrobial agents outside the bacterial cell through efflux pumps is a major cause of concern. At first limited to one or few structurally-related antibiotics, bacterial resistance have then progressed towards cross-resistance between different classes of antibiotics, leading to multidrug-resistant microorganisms. Emergence of these pathogens requires development of novel therapeutic strategies and inhibition of efflux pumps appears to be a promising strategy that could restore the potency of existing antibiotics. NorA is the most studied chromosomal efflux pump of Staphylococcus aureus; it is known to be implied in resistance of Methicillin-resistant S. aureus (MRSA) strains against a wide range of unrelated substrates, including hydrophilic fluoroquinolones. Starting from 6-benzyloxypyridine-3-boronic acid I that we previously identified as a potential inhibitor of the NorA efflux pump against the NorA-overexpressing S. aureus 1199B strain (SA1199B), we describe here the synthesis and biological evaluation of a series of 6-(aryl)alkoxypyridine-3-boronic acids. 6-(3 Phenylpropoxy)pyridine-3-boronic acid 3i and 6-(4-phenylbutoxy)pyridine-3-boronic acid 3j were found to potentiate ciprofloxacin activity by a 4-fold increase compared to the parent compound I. In addition, it has been shown that both compounds promote Ethidium Bromide (EtBr) accumulation in SA1199B, thus corroborating their potential mode of action as NorA inhibitors. PMID- 25817768 TI - [Identification of variants in LMF1 gene associated with primary hypertriglyceridemia]. AB - The majority of severe primary hypertriglyceridemia (HTG) are diagnosed in adults, and their molecular bases have not yet been fully defined. The promoter, coding regions and intron-exon boundaries of LMF1 were sequenced in 112 patients with severe primary hipertrigliceridemia (defined as TG above 500mg/dl). Five patients (4.46%) were carriers of four rare variants in the LMF1 gene associated with HTG, which participate in lipoprotein lipase (LpL) function. Also, we have identified two common variants, c.194-28 T>G and c.729+18C>G that were associated with HTG, with a different allelic frequency to that observed in the general population. A bioinformatic analysis of all found variants was conducted, defining the following as potentially harmful: p.Arg364Gln, p.Arg451Trp, p.Pro562Arg and p.Leu85Leu. Our results suggest that LMF1 mutations are involved in a substantial proportion of cases with severe HTG, putting together the moderate-aggressive effect of rare mutations with polymorphisms classically associated with this disease. PMID- 25817771 TI - PEGylation of the peptide Bac7(1-35) reduces renal clearance while retaining antibacterial activity and bacterial cell penetration capacity. AB - The proline-rich antibacterial peptide Bac7(1-35) protects mice against Salmonella typhimurium infection, despite its rapid clearance. To overcome this problem the peptide was linked to a polyethylene glycol (PEG) molecule either via a cleavable ester bond or via a non-hydrolysable amide bond. Both the PEGylated conjugates retained most of the in vitro activity against S. typhimurium. In addition, the ester bond was cleaved in human serum or plasma, releasing a carboxymethyl derivative of Bac7(1-35) which accounts for a higher activity of this peptide with relative to the other, non-hydrolysable form. Both PEGylated peptides maintained the capacity of the unconjugated form to kill bacteria without permeabilizing the bacterial membranes, by penetrating into cells. They exploited the same transporter as unmodified Bac7(1-35), suggesting it has the capacity to internalize quite sizeable cargo if this is linked to Bac7 fragment. PEGylation allows the peptide to have a wide distribution in mice, and a slow renal clearance, indicating that this strategy would improve the bioavailability of Bac7, and in principle of other antimicrobial peptides. This can be an equally important issue to reducing cytotoxicity for therapeutic use of these antibacterials. PMID- 25817770 TI - Synthesis of diethyl 4-substituted-2,6-dimethyl-1,4-dihydropyridine-3,5 dicarboxylates as a new series of inhibitors against yeast alpha-glucosidase. AB - 1,4-Dihydropyridine-3,5-dicarboxylate derivatives (1-25) were synthesized in high yields via Hantzsch reaction and evaluated for their alpha-glucosidase inhibitory activity. Compounds 1, 2, 6-8, 11, 13-15, and 23-25 showed a potent inhibitory activity against yeast alpha-glucosidase with IC50 values in the range of 35.0 273.7 MUM, when compared with the standard drug acarbose (IC50 = 937 +/- 1.60 MUM). Their structures were characterized by different spectroscopic techniques. The kinetics, selectivity, and toxicity studies on these compounds were also carried out. The kinetic studies on most active compounds 14 and 25 determined their modes of inhibition and dissociation constants Ki. Compound 14 was found to be a non-competitive inhibitor with Ki = 25.0 +/- 0.06, while compound 25 was identified as a competitive inhibitor with Ki = 66.0 +/- 0.07 MUM. PMID- 25817772 TI - Design, synthesis, and biological evaluation of benzoselenazole-stilbene hybrids as multi-target-directed anti-cancer agents. AB - To identify novel multi-target-directed drug candidates for the treatment of cancer, a series of benzoselenazole-stilbene hybrids were synthesised by combining the pharmacophores of resveratrol and ebselen. The biological assay indicated that all of the hybrids exhibited antiproliferative activities against four human cancer cell lines and demonstrated good TrxR inhibitory activities. The mechanism of cell apoptosis was investigated in G2/M cell cycle arrest induced by compound 6e and the apoptosis of the human liver carcinoma Bel-7402 cell line. The significant increase in intracellular ROS confirmed that compound 6e was capable of causing oxidative stress-induced apoptosis in cancer cells. Our results support the potential of compound 6e as a candidate for further studies examining the development of novel drugs for cancer treatment. PMID- 25817773 TI - Synthesis and in vitro antiplasmodial evaluation of 7-chloroquinoline-chalcone and 7-chloroquinoline-ferrocenylchalcone conjugates. AB - The manuscript describes the synthesis of novel amide tethered 7-chloroquinoline chalcone and 7-chloroquinoline-ferrocenylchalcone bifunctional hybrids and their evaluation as antimalarial agents against W2 resistant strain of Plasmodium falciparum. The antiplasmodial activity of 7-chloroquinoline-ferrocenylchalcones was found to be less than their corresponding simple chalcone conjugates. The presence of a methoxy substituent at para position of ring B on chalcones and longer alkyl chain length markedly improved the antiplasmodial profiles of the synthesized scaffolds with the most potent of the test compound exhibiting an IC50 value of 17.8 nM. PMID- 25817774 TI - Synthesis of heterocycle-modified betulinic acid derivatives as antitumor agents. AB - A series of novel heterocycle-modified betulinic acid (BA) derivatives were synthesized and investigated for their activity against the growth of eight non drug resistant and one multidrug-resistant tumor cell line using a sulforhodamine B (SRB) assay. The most active compound 17 showed an average IC50 1.19 MUM, which was about 20 times more potent than the lead compound BA. It is amazing that for most synthetic saturated N-heterocycle derivatives, MCF-7/ADR was the most sensitive tumor cells, especially 17 showed the most potent antitumor activity (IC50 = 0.33 MUM) on this multidrug-resistant tumor cell line, that was 117 times more potent than BA. Most of the tested compounds displayed less toxic on human fibroblasts (HAF) in comparison with the tumor cell lines. The cytometry and transwell migration assays were used to test the ability of 17 to induce apoptosis and inhibit metastasis on tumor cell lines respectively. PMID- 25817775 TI - Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFbeta/Smad inhibitors. AB - Targeting TGFbeta/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4 dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. through induction of TGFbeta receptor type II degradation. In the present work, >40 rationally designed, novel DHPs were synthesized and evaluated for TGFbeta inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4"-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are (R)-configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r(2) = 0.93) with a good predictive power (r(2)pred = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGFbeta inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands (e.g., lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies in vivo. PMID- 25817776 TI - The economics of adalimumab for ulcerative colitis. AB - Ulcerative colitis is a chronic inflammatory disease, characterized by diffuse mucosal inflammation in the colon. Adalimumab, as a TNF-alpha blocker, offers a safe and efficacious treatment option for patients with moderate to severe ulcerative colitis and refractory or intolerant to conventional medications; however, its cost-effectiveness profile has not yet been well established. Future economic evaluations should choose appropriate comparators in the context of target-reimbursement decision making and focus on cost-effectiveness over a long time horizon. PMID- 25817778 TI - Assessment of protein modifications in liver of rats under chronic treatment with paracetamol (acetaminophen) using two complementary mass spectrometry-based metabolomic approaches. AB - Liver protein can be altered under paracetamol (APAP) treatment. APAP-protein adducts and other protein modifications (oxidation/nitration, expression) play a role in hepatotoxicity induced by acute overdoses, but it is unknown whether liver protein modifications occur during long-term treatment with non-toxic doses of APAP. We quantified APAP-protein adducts and assessed other protein modifications in the liver from rats under chronic (17 days) treatment with two APAP doses (0.5% or 1% of APAP in the diet w/w). A targeted metabolomic method was validated and used to quantify APAP-protein adducts as APAP-cysteine adducts following proteolytic hydrolysis. The limit of detection was found to be 7ng APAP cysteine/mL hydrolysate i.e. an APAP-Cys to tyrosine ratio of 0.0160/00. Other protein modifications were assessed on the same protein hydrolysate by untargeted metabolomics including a new strategy to process the data and identify discriminant molecules. These two complementary mass spectrometry (MS)-based metabolic approaches enabled the assessment of a wide range of protein modifications induced by chronic treatment with APAP. BIOLOGICAL SIGNIFICANCE: APAP-protein adducts were detected even in the absence of glutathione depletion and hepatotoxicity, i.e. in the 0.5% APAP group, and increased by 218% in the 1% APAP group compared to the 0.5% APAP group. At the same time, the untargeted metabolomic method revealed a decrease in the binding of cysteine, cysteinyl glycine and GSH to thiol groups of protein cysteine residues, an increase in the oxidation of tryptophan and proline residues and a modification in protein expression. This wide range of modifications in liver proteins occurred in rats under chronic treatment with APAP that did not induce hepatotoxicity. PMID- 25817777 TI - Assessment of affective and somatic signs of ethanol withdrawal in C57BL/6J mice using a short-term ethanol treatment. AB - Alcohol is one of the most prevalent addictive substances in the world. Withdrawal symptoms result from abrupt cessation of alcohol consumption in habitual drinkers. The emergence of both affective and physical symptoms produces a state that promotes relapse. Mice provide a preclinical model that could be used to study alcohol dependence and withdrawal while controlling for both genetic and environmental variables. The use of a liquid ethanol diet offers a reliable method for the induction of alcohol dependence in mice, but this approach is impractical when conducting high-throughput pharmacological screens or when comparing multiple strains of genetically engineered mice. The goal of this study was to compare withdrawal-associated behaviors in mice chronically treated with a liquid ethanol diet vs. mice treated with a short-term ethanol treatment that consisted of daily ethanol injections containing the alcohol dehydrogenase inhibitor, 4-methylpyrazole. Twenty-four hours after ethanol treatment, mice were tested in the open field arena, the elevated plus maze, the marble burying test, or for changes in somatic signs during spontaneous ethanol withdrawal. Anxiety-like and compulsive-like behaviors, as well as physical signs, were all significantly elevated in mice undergoing withdrawal, regardless of the route of ethanol administration. Therefore, a short-term ethanol treatment can be utilized as a screening tool for testing genetic and pharmacological agents before investing in a more time-consuming ethanol treatment. PMID- 25817779 TI - Interleukin-8 -251A/T gene polymorphism and lung cancer susceptibility: a meta analysis. AB - Many studies have examined the association between the interleukin-8 -251T/A (rs4073) gene polymorphism and lung cancer risk in various populations, but the results have been inconsistent. In this meta-analysis, PubMed was searched for case-control studies published through 01 December 2013. The data were extracted, and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. We assessed six published studies on the association between the interleukin-8 251T/A polymorphism and lung cancer risk. The included studies yielded a total of 3265 lung cancer cases and 3607 controls. For the homozygous A/A and A allele carriers (T/A + A/A), the pooled ORs for all studies combining 3265 cases and 3607 controls were 1.03 (95% CI = 0.92-1.14; P = 0.235 for heterogeneity) and 1.07 (95% CI = 0.96-1.19; P = 0.245 for heterogeneity) when compared with the homozygous wild-type genotype (T/T). When the analysis was stratified by ethnicity, significant risks were found among Asians for both the A allele carriers and the homozygous A/A individuals. However, no significant associations were found in non-Asian populations using any of the genetic models. This meta analysis suggests that the interleukin-8 -251A allele confer an increased risk for the development of lung cancer among Asians. PMID- 25817780 TI - Factors contributing to poor treatment outcomes in childhood atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic relapsing inflammatory disease of the skin and is the most common paediatric dermatological condition. While no cure is available, it can be treated effectively if adherence to a therapeutic plan is maintained. Poor adherence to treatment is common in AD and can lead to treatment failure, which has significant impacts on the patient, family and society. A comprehensive literature search was conducted to identify factors that contribute to poor treatment adherence in childhood AD and to identify possible strategies to remedy these. Identified factors leading to poor treatment adherence include: complexity of treatment regimen, lack of knowledge, impaired quality of life, dissatisfaction with treatment strategies, infrequent follow up, corticosteroid phobia and the use of complementary and alternative medicine. Effective strategies to increase treatment adherence include: caregiver education and utilisation of education adjuncts, optimisation of the patient/caregiver clinician relationship, early and frequent follow up and improvement of patient and caregiver quality of life. PMID- 25817781 TI - Using Ultrasonic Transient Elastometry (FibroScan) to Predict Esophageal Varices in Patients with Viral Liver Cirrhosis. AB - The correlation between liver stiffness (LS), measured by ultrasonic transient elastometry (FibroScan), and the presence and severity of esophageal varices (EV) in patients with viral cirrhosis of the liver has not been well documented to date. The study described here investigated the value of using FibroScan to predict EV. Patients with cirrhosis (200 patients: 167 cases caused by hepatitis B virus and 33 cases caused by hepatitis C virus) underwent both upper gastrointestinal endoscopy and FibroScan. Demographic, clinical, biochemical and endoscopic data and FibroScan-obtained LS parameters were collected. The mean LS value in patients with EV (33.2 kPa) was significantly higher than the mean LS value in patients without EV (18.6 kPa) (p < 0.05). The mean LS value in patients with grade 2 and 3 EV (38.3 kPa) was significantly higher than that in patients with grade 1 EV (24.8 kPa) (p < 0.05). Overall, FibroScan was 86.4% sensitive and 72.2% specific in predicting the presence of EV, with an area under the receiver operating characteristic curve (AUROC) of 0.84. The sensitivity and specificity for the patients with grade 2 or 3 EV were 84% and 73% (AUROC = 0.86). When FibroScan was combined with platelet count, the overall sensitivity and specificity of prediction increased to 84% and 80% (AUROC = 0.88), respectively, and 84% and 75% (AUROC = 0.89), respectively, in patients with grade 2 and 3 EV. FibroScan alone or combined with platelet count might predict the presence and severity of EV in patients with hepatitis B or C-related viral cirrhosis. PMID- 25817782 TI - Temporal compounding: a novel implementation and its impact on quality and diagnostic value in echocardiography. AB - Temporal compounding can be used to suppress acoustic noise in transthoracic cardiac ultrasound by spatially averaging partially decorrelated images acquired over consecutive cardiac cycles. However, the reliable spatial and temporal alignment of the corresponding frames in consecutive cardiac cycles is vital for effective implementation of temporal compounding. This study introduces a novel, efficient, accurate and robust technique for the spatiotemporal alignment of consecutive cardiac cycles with variable temporal characteristics. Furthermore, optimal acquisition parameters, such as the number of consecutive cardiac cycles used, are derived. The effect of the proposed implementation of temporal compounding on cardiac ultrasound images is quantitatively assessed (32 clinical data sets providing a representative range of image qualities and diagnostic values) using measures such as tissue signal-to-noise ratio, chamber signal-to noise ratio, tissue/chamber contrast and detectability index, as well as a range of clinical measurements, such as chamber diameter and wall thickness, performed during routine echocardiographic examinations. Temporal compounding (as implemented) consistently improved the image quality and diagnostic value of the processed images, when compared with the original data by: (i) increasing tissue and cavity signal-to-noise ratios as well as tissue/cavity detectability index, (ii) improving the corresponding clinical measurement repeatability and inter operator measurement agreement, while (iii) reducing the number of omitted measurements caused by data corruption. PMID- 25817783 TI - The longevity in the yeast Saccharomyces cerevisiae: A comparison of two approaches for assessment the lifespan. AB - Longevity of the selected "longevity mutants" of yeast was studied using two methods. The standard method was based on counting the number of daughter cells produced. Modification of that method allowed for establishing the length of life expressed in units of time. It appeared that all the studied "deletion longevity mutants" showed a statistically meaningful increase in the number of daughters produced (replicative lifespan), whereas only one of the mutants, previously regarded as "short lived", showed a meaningful increase in the time of life. The analysis of the available data shows that the time of life of most yeast strains is similar irrespective of their genetic background and mutations, which suggests a quasi-programmed nature of yeast death. PMID- 25817784 TI - Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12. AB - Besides its function in transport of fatty acids into mitochondria in order to provide substrates for beta-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 MUM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA interference for sir-2.1, a candidate genes mediating the effects of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for gamma butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. PMID- 25817785 TI - LPS-miR-34a-CCL22 axis contributes to regulatory T cell recruitment in periapical lesions. AB - Regulatory T cells (Tregs) have been shown to regulate the immune response and to control the defense against infection in periapical lesions, but the underlying mechanisms by which Tregs are recruited to these lesions remain unknown. Here we demonstrate that expression of the gene encoding CCL22 (also known as macrophage derived chemokine), the major chemoattractant that recruits Tregs, is upregulated in periapical tissue during the progression of experimental periapical lesions; this upregulation positively correlated with the number of Tregs that accumulated in the lesions. In terms of mechanism, we determined that lipopolysaccharide (LPS) up-regulates Ccl22 expression in macrophages by suppressing miR-34a. These findings suggest that the LPS-miR-34a-CCL22 axis may contribute to the recruitment of Tregs in periapical lesions, providing a potential therapeutic target for controlling this disease. PMID- 25817786 TI - Slp2-a inactivates ezrin by recruiting protein phosphatase 1 to the plasma membrane. AB - Synaptotagmin-like protein 2-a (Slp2-a) was originally described as a membrane trafficking protein that consists of a Slp homology domain (SHD), a linker domain, and tandem C2 domains (named the C2A domain and C2B domain). Slp2-a mediates docking of Rab27-bearing vesicles to the plasma membrane through simultaneous interaction with Rab27 and phospholipids in the plasma membrane. We have recently reported that Slp2-a regulates renal epithelial cell size through interaction with Rap1GAP2 via the C2B domain independently of Rab27 and demonstrated the presence of excess activation of ezrin, a membrane-cytoskeleton linker and signal transducer, in Slp2-a-knockdown Madin-Darby canine kidney II (MDCK II) cells. However, the precise mechanism of ezrin inactivation by Slp2-a in cell size control has remained largely unknown. In this study, we investigated the functional relationship between Slp2-a and ezrin in MDCK II cells. The results showed that activation of ezrin in control MDCK II cells either pharmacologically or by overexpression of a constitutively active ezrin mutant caused an increase in cell size, whereas inactivation of ezrin in Slp2-a knockdown cells by a specific ezrin inhibitor restored them to their normal cell size. We also found that Slp2-a interacts via its previously uncharacterized linker domain with protein phosphatase 1beta (PP1beta), which inactivates ezrin, and that the interaction is required for the plasma membrane localization of PP1beta. These results indicate that Slp2-a inactivates ezrin by recruiting PP1 to the plasma membrane. PMID- 25817787 TI - USP22 acts as an oncogene by regulating the stability of cyclooxygenase-2 in non small cell lung cancer. AB - The histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is an epigenetic modifier and an oncogene that is upregulated in many types of cancer. In non-small cell lung cancer (NSCLC), aberrant expression of USP22 is a predictor of poor survival, as is high expression of cyclooxygenase-2 (COX-2). Despite its oncogenic role, few substrates of USP22 have been identified and its mechanism of action in cancer remains unclear. Here, we identified COX-2 as a direct substrate of USP22 and showed that its levels are modulated by USP22 mediated deubiquitination. Silencing of USP22 downregulated COX-2, decreased its half-life, and inhibited lung carcinoma cell proliferation by directly interacting with and modulating the stability and activity of COX-2 through the regulation of its ubiquitination status. The findings of the present study suggest a potential mechanism underlying the oncogenic role of USP22 mediated by the modulation of the stability and activity of COX-2. PMID- 25817788 TI - Functional magnetic resonance imaging reveals abnormal brain connectivity in EGR3 gene transfected rat model of schizophrenia. AB - Schizophrenia is characterized by the disorder of "social brain". However, the alternation of connectivity density in brain areas of schizophrenia patients remains largely unknown. In this study, we successfully created a rat model of schizophrenia by the transfection of EGR3 gene into rat brain. We then investigated the connectivity density of schizophrenia susceptible regions in rat brain using functional magnetic resonance imaging (fMRI) in combination with multivariate Granger causality (GC) model. We found that the average signal strength in prefrontal lobe and hippocampus of schizophrenia model group was significantly higher than the control group. Bidirectional Granger causality connection was observed between hippocampus and thalamic in schizophrenia model group. Both connectivity density and Granger causality connection were changed in prefrontal lobe, hippocampus and thalamus after risperidone treatment. Our results indicated that fMRI in combination with GC connection analysis may be used as an important method in diagnosis of schizophrenia and evaluation the effect of antipsychotic treatment. These findings support the connectivity disorder hypothesis of schizophrenia and increase our understanding of the neural mechanisms of schizophrenia. PMID- 25817789 TI - A novel major facilitator transporter TrSTR1 is essential for pentose utilization and involved in xylanase induction in Trichoderma reesei. AB - Trichoderma reesei (teleomorph Hypocrea jecorina) is an industrially important filamentous fungus for glycoside hydrolases production, with its xylanolytic enzymes widely applied in many areas. However, the molecular mechanisms underlying xylanase expression are still insufficiently understood. In particular, the effect of sugar transporter on the induction of xylanase expression is unclear. In this work, we identified a novel major facilitator transporter TrSTR1 that is capable of transporting xylose by using a xylose utilization system in Saccharomyces cerevisiae. In T. reesei, TrSTR1 is essential for the utilization of d-xylose, l-arabinose, and even their downstream metabolites D-xylitol and L-arabitol. TrSTR1 is also involved in the induction of xylanase expression since both the xylanase activity and extracellular protein concentration in the Tu6?str1 strain were decreased, which further confirmed by a qRT-PCR analysis of the transcript levels of the key transcriptional regulators. Our observations provide new insights into connections between pentose utilization and xylanase production in T. reesei. PMID- 25817790 TI - Microvesicles released constitutively from prostate cancer cells differ biochemically and functionally to stimulated microvesicles released through sublytic C5b-9. AB - We have classified microvesicles into two subtypes: larger MVs released upon stimulation of prostate cancer cells, sMVs, and smaller cMVs, released constitutively. cMVs are released as part of cell metabolism and sMVs, released at 10-fold higher levels, produced upon activation, including sublytic C5b-9. From electron microscopy, nanosight tracking analysis, dynamic light scattering and flow cytometry, cMVs (194-210 nm in diameter) are smaller than sMVs (333-385 nm). Furthermore, using a Quartz Crystal Microbalance measuring changes in resonant frequency (Deltaf) that equate to mass deposited on a sensor, an sMV and a cMV are estimated at 0.267 and 0.241 pg, respectively. sMVs carry more calcium and protein, express higher levels of lipid rafts, GPI-anchored CD55 and phosphatidylserine including deposited C5b-9 compared to cMVs. This may allude to biological differences such as increased bound C4BP on sMVs inhibiting complement more effectively. PMID- 25817791 TI - Dihydrolipoic but not alpha-lipoic acid affects susceptibility of eukaryotic cells to bacterial invasion. AB - Sensitivity of eukaryotic cells to facultative pathogens can depend on physiological state of host cells. Previously we have shown that pretreatment of HeLa cells with N-acetylcysteine (NAC) makes the cells 2-3-fold more sensitive to invasion by the wild-type Serratia grimesii and recombinant Escherichia coli expressing gene of actin-specific metalloprotease grimelysin [1]. To evaluate the impact of chemically different antioxidants, in the present work we studied the effects of alpha-Lipoic acid (LA) and dihydrolipoic acid (DHLA) on efficiency of S. grimesii and recombinant E. coli expressing grimelysin gene to penetrate into HeLa and CaCo cells. Similarly to the effect of NAC, pretreatment of HeLa and CaCo cells with 0.6 or 1.25 mM DHLA increased the entry of grimelysin producing bacteria by a factor of 2.5 and 3 for the wild-type S. grimesii and recombinant E. coli, respectively. In contrast, pretreatment of the cells with 0.6 or 1.25 mM LA did not affect the bacteria uptake. The increased invasion of HeLa and CaCo cells correlated with the enhanced expression of E-cadherin and beta-catenin genes, whereas expression of these genes in the LA-treated cells was not changed. Comparison of these results suggests that it is sulfhydryl group of DHLA that promotes efficient modification of cell properties assisting bacterial uptake. We assume that the NAC- and DHLA-induced stimulation of the E-cadherin-catenin pathway contributes to the increased internalization of the grimelysin producing bacteria within transformed cells. PMID- 25817792 TI - Lack of non-hematopoietic SIRPalpha signaling disturbs the splenic marginal zone architecture resulting in accumulation and displacement of marginal zone B cells. AB - Signal regulatory protein alpha (SIRPalpha) is an immunoglobulin super family protein predominantly expressed by myeloid but not lymphoid cells, and its role in lymphocyte homeostasis and function is still to be revealed. We demonstrate that mice bearing a mutant SIRPalpha lacking the cytoplasmic signaling domain (SIRPalpha MT) had an increased amount of splenic marginal zone (MZ) B cells compared to wild-type controls. Immunohistochemical analysis revealed an increased localization of MZB cells into B cell follicular areas of the white pulp in SIRPalpha MT spleens. However, we found no signs of an increased MZB cell activation level in MT mice. The immune response to T-independent antigens in vivo was slightly increased in SIRPalpha MT mice while sorted MZB from these mice responded normally to LPS in vitro. Bone marrow reconstitution experiments demonstrated that the MZB cell phenotype of SIRPalpha MT mice was due to lack of SIRPalpha signaling in non-hematopoietic cells. In contrast, MZ retention of MZ macrophages required hematopoietic SIRPalpha, while normal distribution of metallophilic macrophages required non-hematopoietic SIRPalpha signaling. In summary, these data identified SIRPalpha signaling in non-hematopoietic cells to play an important role in regulating the numbers and positioning MZB cell in the spleen. PMID- 25817793 TI - Roles of hepatic glucokinase in intertissue metabolic communication: Examination of novel liver-specific glucokinase knockout mice. AB - Glucokinase is expressed principally in pancreatic beta-cells and hepatocytes, and catalyzes the phosphorylation of glucose to glucose-6-phosphate, a rate limiting step of glycolysis. To better understand the roles of hepatic glucokinase, we generated Gck knockout mice by ablating liver-specific exon 1b. The knockout mice exhibited impaired glucose tolerance, decreased hepatic glycogen content, and reduced Pklr and Fas gene expression in the liver, indicating that hepatic glucokinase plays important roles in glucose metabolism. It has also been reported that hepatic glucokinase regulates the expression of thermogenesis-related genes in brown adipose tissue (BAT) and insulin secretion in response to glucose. However, the liver-specific Gck knockout mice displayed neither altered expression of thermogenesis-related genes in BAT nor impaired insulin secretion by beta-cells under a normal chow diet. These results suggest that chronic suppression of hepatic glucokinase has a small influence on intertissue (liver-to-BAT as well as liver-to-beta-cell) metabolic communication. PMID- 25817794 TI - miR-340 inhibits glioblastoma cell proliferation by suppressing CDK6, cyclin-D1 and cyclin-D2. AB - Glioblastoma development is often associated with alteration in the activity and expression of cell cycle regulators, such as cyclin-dependent kinases (CKDs) and cyclins, resulting in aberrant cell proliferation. Recent studies have highlighted the pivotal roles of miRNAs in controlling the development and growth of glioblastoma. Here, we provide evidence for a function of miR-340 in the inhibition of glioblastoma cell proliferation. We found that miR-340 is downregulated in human glioblastoma tissue samples and several established glioblastoma cell lines. Proliferation and neurosphere formation assays revealed that miR-340 plays an oncosuppressive role in glioblastoma, and that its ectopic expression causes significant defect in glioblastoma cell growth. Further, using bioinformatics, luciferase assay and western blot, we found that miR-340 specifically targets the 3'UTRs of CDK6, cyclin-D1 and cyclin-D2, leading to the arrest of glioblastoma cells in the G0/G1 cell cycle phase. Confirming these results, we found that re-introducing CDK6, cyclin-D1 or cyclin-D2 expression partially, but significantly, rescues cells from the suppression of cell proliferation and cell cycle arrest mediated by miR-340. Collectively, our results demonstrate that miR-340 plays a tumor-suppressive role in glioblastoma and may be useful as a diagnostic biomarker and/or a therapeutic avenue for glioblastoma. PMID- 25817796 TI - Geographic bias in citation rates of conservation research. AB - We investigated whether the impact of conservation science is greater for research conducted in countries with more pressing conservation problems. We quantified research impact for 231 countries based on 2 citation metrics (mean cites per paper and h index) and fitted models predicting research impact based on number of threatened bird and mammal species (as a measure of conservation importance of a country) and a range of demographic variables. Citation rates of conservation research increased as a country's conservation need increased and as human population, quality of governance, and wealth increased. Even after accounting for these factors, citation rates among regions and countries within regions varied significantly. The conservation research community needs to consider ways to begin addressing the entrenched disadvantages some countries have when it comes to initiating projects and producing high-quality research. PMID- 25817797 TI - Genetic heteroscedasticity of teat count in pigs. AB - The genetic improvement in pig litter size has been substantial. The number of teats on the sow must thus increase as well to meet the needs of the piglets, because each piglet needs access to its own teat. We applied a genetic heterogeneity model to teat counts in pigs, and estimated a medium heritability for teat counts (0.35), but found a low heritability for residual variance (0.06), indicating that selection for reduced residual variance might have a limited effect. A numerically positive correlation (0.8) was estimated between the breeding values for the mean and the residual variance. However, because of the low heritability of the residual variance, the residual variance will probably increase very slowly with the mean. PMID- 25817795 TI - Identification of Helicobacter pylori VacA in human lung and its effects on lung cells. AB - OBJECTIVE: Prior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells. METHODS: The presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex((r)) Assays. RESULTS: VacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin 8 and interleukin-6 were the primary secretory products induced by VacA. CONCLUSIONS: H. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells. PMID- 25817798 TI - Geographic Variation in Zygomaxillary Suture Morphology and its Use in Ancestry Estimation. AB - Angled/curved zygomaxillary suture coding is widely employed in cranial assessments of ancestry. However, the efficacy of this method has not been extensively evaluated across diverse populations. In this study, zygomaxillary suture morphology was assessed on a total of 411 human crania from six populations (European, Native American, African, Asian, Arctic Circle, and Aboriginal Australian) using a novel 3D coordinate landmark method. Our results indicate a predominance of angled sutures among native peoples of the Arctic and North America (85-86%), a prevalence of curved sutures among Africans and Aboriginal Australians (77-81%), and essentially equal proportions of both configurations in Asians and Europeans (50-56%). Statistically, angled/curved coding generally discriminates poorly between groups, except when populations with antithetically high frequencies of the two configurations (e.g., African vs. Native American) are compared. Moreover, comparisons across previous studies reveal conflicting frequencies for many populations, further suggesting limited utility of this trait in ancestry estimation. PMID- 25817799 TI - Second malignancies following treatment of chronic myeloid leukaemia in the tyrosine kinase inhibitor era. AB - Given that tyrosine kinase inhibitors (TKIs) have dramatically improved the survival of patients with chronic myeloid leukaemia (CML), we were interested in examining the possible risk of long-term adverse events, such as the emergence of other neoplasms. Therefore, we studied the development of second malignancies in 868 patients diagnosed with CML between 2002 and 2011 using the Swedish CML register, cross-linked to the Swedish Cancer register. With a median follow-up of 3.7 (range 0-9.9) years, 65 (7.5%) patients developed 75 second malignancies (non haematological), 52 of which were of the invasive type. Compared to expected rates in the background population, the risk of second malignancies was higher in the CML cohort, with a standardized incidence ratio (SIR) of 1.52 (95% CI 1.13 1.99). The SIR before and after the second year following diagnosis of CML was 1.58 and 1.47, respectively. Among specific cancer types, gastrointestinal and nose and throat cancer were significantly increased. Founded on a population based material, our results indicate that CML patients treated in the TKI era are at an increased risk of developing a second malignancy, with indications that this risk may more likely be linked to CML itself rather than to the TKI treatment. PMID- 25817800 TI - Association between FokI, ApaI and TaqI RFLP polymorphisms in VDR gene and Hashimoto's thyroiditis: preliminary data from female patients in Serbia. AB - Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disorder caused by an interaction between genes and environmental triggers. Intrathyroid lymphocytic infiltration may lead to progressive destruction of thyroid tissue and consequently to hypothyroidism. Many studies in different populations have shown association between vitamin D receptor (VDR) gene polymorphisms and various autoimmune diseases, including HT. The study included 44 female patients (mean age +/- standard deviation 38 +/- 5.4) with Hashimoto's thyroiditis and 32 healthy age-matched, sex-matched and geographically matched controls without personal history of autoimmune and endocrine diseases. Genomic DNA was isolated from peripheral blood-EDTA, and the target VDR gene was genotyped by PCR-RFLP technique after VDR-FokI (rs2228570), VDR-ApaI (rs7975232) and VDR-TaqI (rs731236) restriction enzymes digestion. We used spss 20.0 integrated software for data analysis and found a significant difference in the genotype distribution of VDR-FokI polymorphism between patients with HT and controls (P = 0.009). For ApaI and TaqI, we observed a higher frequency of variant allele in patients with HT, which was not significantly different compared to control women (P > 0.05). The current first and preliminary results identified the association between VDR FokI gene polymorphism and Hashimoto's thyroiditis in Serbian population. Results need to be supported by further investigations that define haplotype patterns for VDR gene polymorphisms in a larger group of HT patients of both sexes. PMID- 25817801 TI - Effects of genetic variants in the promoter region of the bovine adiponectin (ADIPOQ) gene on marbling of Hanwoo beef cattle. AB - This study aimed to verify genetic effects of the bovine adiponectin (ADIPOQ) gene on carcass traits of Hanwoo cattle. The measured carcass traits were marbling score (MAR), backfat thickness (BFT), loineye area (LEA), and carcass weight (CAW). Selection of primers was based on the bovine ADIPOQ sequence, and the analysis amplified approximately 267 and 333 bp genomic segments, including 67 bp of insertions in the promoter region. Sequencing analysis confirmed genetic variants (g.81966235C>T, g.81966377T>C, and g.81966364D>I) that showed significant effects on MAR. The present results suggest that the identified SNPs are useful genetic markers for the improvement of carcass traits in Hanwoo cattle. PMID- 25817802 TI - Effect of an allostatic modulator on stress blood indicators and meat quality of commercial young bulls in Mexico. AB - To assess the effect of an allostatic modulator (AM) on stress blood indicators and meat quality traits, the feed of 80 non-castrated 18-20 month-old bulls was supplemented with 10 g/day of an AM for 30 days before slaughter. Another 80 bulls served as control animals. The AM was comprised of ascorbic acid, acetoxybenzoic acid and sodium and potassium chloride. Blood samples were taken at slaughter for analyses of hematocrit value, erythrocyte and leukocyte counts, and glucose, lactate and cortisol concentrations. Post-mortem measures of meat color and pH were made at 24h and color, shear force and cooking loss on meat from 20 animals at 28 days. The AM supplementation resulted in lower hematocrit value, erythrocyte count and glucose level (P<0.05), higher a* (P<0.0001) and b* (P<0.0001) at 24h and lower b* (P<0.05) at 28 days. Thus AM treatment improved some stress blood indicators and meat color and therefore merits further investigation. PMID- 25817803 TI - Carcass parameters and meat quality in meat-goat kids finished on chicory, birdsfoot trefoil, or red clover pastures. AB - This study was conducted during the 2009 and 2010 grazing seasons to assess carcass parameters and chevon (goat meat) quality when meat-goat kids (n=72) were finished on pastures of red clover (Trifolium pratense L.; RCL), birdsfoot trefoil (Lotus corniculatus L.; BFT), or chicory (Cichorium intybus L.; CHIC). Final live weight (P<0.05) and carcass weight (P=0.10) were greater when goats were finished on RCL compared to CHIC with BFT being intermediate. Ribeye area, backfat thickness, body wall thickness, internal fat score, and leg score were not different (P>0.10) among treatments when adjusted for the covariate of carcass weight. Finishing meat-goat kids on RCL, BFT, or CHIC impacted concentrations of fatty acids (FAs) 18:1 trans-10, 18:1 cis-11, 18:2, 18:3 polyunsaturated fatty acids (PUFAs), omega-6, omega-3, and PUFA:saturated fatty acid ratio in longissimus lumborum samples. Finishing meat-goat kids on CHIC, RCL, or BFT pastures produced carcass weights acceptable for most ethnic markets in the USA. PMID- 25817804 TI - Improvement of dissolution rate of indomethacin by inkjet printing. AB - The aim of this study was to prepare printable inks of the poorly water soluble drug indomethacin (IMC), fabricate printed systems with flexible doses and investigate the effect of ink excipients on the printability, dissolution rate and the solid state properties of the drug. A piezoelectric inkjet printer was used to print 1*1cm(2) squares onto a paper substrate and an impermeable transparency film. l-arginine (ARG) and polyvinylpyrrolidone (PVP) were used as additional formulation excipients. Accurately dosed samples were generated as a result of the ink and droplet formation optimization. Increased dissolution rate was obtained for all formulations. The formulation with IMC and ARG printed on transparency film resulted in a co-amorphous system. The solid state characteristics of the printed drug on porous paper substrates were not possible to determine due to strong interference from the spectra of the carrier substrate. Yet, the samples retained their yellow color after 6months of storage at room temperature and after drying at elevated temperature in a vacuum oven. This suggests that the samples remained either in a dissolved or an amorphous form. Based on the results from this study a formulation guidance for inkjet printing of poorly soluble drugs is also proposed. PMID- 25817806 TI - Synergistic mosquito-repellent activity of Curcuma longa, Pogostemon heyneanus and Zanthoxylum limonella essential oils. AB - Mosquito repellents play an important role in preventing man-mosquito contact. In the present study, we evaluated the synergistic mosquito-repellent activity of Curcuma longa, Pogostemon heyneanus and Zanthoxylum limonella essential oils. The mosquito repellent efficacies of three essential oils were evaluated separately and in combination under laboratory and field conditions. N,N Diethylphenylacetamide (DEPA) and dimethylphthalate (DMP) were used for comparison of the protection time of the mixture of essential oils. At an optimum concentration of 20%, the essential oils of C. longa, Z. limonella and P. heyneanus provided complete protection times (CPTs) of 96.2, 91.4 and 123.4 min, respectively, against Aedes albopictus mosquitoes in the laboratory. The 1:1:2 mixture of the essential oils provided 329.4 and 391.0 min of CPT in the laboratory and field trials, respectively. The percent increases in CPTs for the essential oil mixture were 30 for DMP and 55 for N,N-diethylphenylacetamide (DEPA). The synergistic repellent activity of the essential oils used in the present study might be useful for developing safer alternatives to synthetic repellents for personal protection against mosquitoes. PMID- 25817807 TI - Validation study on how to avoid microbial contamination during pharmaceutical production. AB - Every person involved in pharmaceutical product manufacturing has the responsibility to assure the quality of the product being produced. The aim of this paper is to validate quality assurance throughout the process of manufacturing pharmaceutical products. Additionally, within aseptic manufacturing, certain monitoring and information needs to be collected on a routine basis to continually assess the state of control of the complete operation. The basis for assessing the state of control is to have rigorous and defined information flow processes. Once the information is collected, quality assurance involves the ability to assess, evaluate, and make appropriate decisions to ensure the product has the required safety, identity, strength, quality, and purity. Quality assurance study is the process of bringing all of the information together, evaluating the information, making decisions, refining systems, and applying process knowledge. This process begins in the early stages of drug development when not a lot of specific process information about the process is known, but it is important to allow for development to progress, building knowledge about process. However, even in early development, sterility assurance requirements should be largely the same at all stages of development and routine commercial manufacturing. PMID- 25817805 TI - Prevalence of Panton-Valentine leukocidin-positive methicillin-susceptible Staphylococcus aureus infections in a Saudi Arabian hospital. AB - Panton-Valentine leukocidin (PVL) is a two-component toxin associated with the toxicity and virulence of Staphylococcus aureus. The presence of PVL is well documented in community-acquired methicillin-resistant S. aureus (CA-MRSA) and is observed in methicillin-susceptible S. aureus (MSSA) with variable prevalence. We assessed the prevalence of PVL in a sample of 93 MSSA patients in a healthcare facility in Eastern Saudi Arabia using real-time PCR for lukSF-PV genes. The presence or absence of PVL was correlated with age, gender, hospitalization status, infection site and antibiotic resistance. PVL was detected in 28 (30%) patient samples. PVL was associated with a greater likelihood of resistance to trimethoprim-sulfamethoxazole (a resistance of 39.2% of PVL-positive isolates compared to 6.1% of PVL-negative isolates) (p < 0.0007). These results suggest a significant prevalence of PVL expression in MSSA strains in the study population and call for monitoring of and surveillance programs for PVL status and the selection of appropriate antibiotic treatments. PMID- 25817808 TI - Investigation of a sterilization system using active oxygen species generated by ultraviolet irradiation. AB - We have been investigating an advanced sterilization system that employs active oxygen species (AOS). We designed the sterilization equipment, including an evacuation system, which generates AOS from pure oxygen gas using ultraviolet irradiation, in order to study the conditions necessary for sterilization in the system's chamber. Using Geobachillus stearothermophilus spores (10(6) CFU) in a sterile bag as a biological indicator (BI) in the chamber of the AOS sterilization apparatus, we examined the viability of the BI as a function of exposure time, assessing the role of the decompression level in the sterilization performance. We found that the survival curves showed exponential reduction, and that the decompression level did not exert a significant influence on the survival curve. Subsequently, we investigated the sterilization effect as influenced by the spatial and environmental temperature variation throughout the chamber, and found that the sterilization effect varied with position, due to the varying environmental temperature in the respective areas. We confirmed that temperature is one of the most important factors influencing sterilization in the chamber, and estimated the temperature effect on the distribution of atomic oxygen concentration, using the quartz crystal microbalance (QCM) method with fluorocarbon thin film prepared by radio frequency sputtering. PMID- 25817809 TI - Antibacterial susceptibility of enterobacteriaceae isolated from raw horsemeat isolated for human consumption (basashi). AB - Drug susceptibility testing was carried out using 14 antibiotics in order to identify trends in the antibiotic tolerance of 142 strains of Enterobacteriaceae isolated from horsemeat commercially available for raw consumption (basashi). A comparison of the sensitivity to the 14 antibiotics using the 90% MIC (minimum inhibitory concentration) values (MIC90) showed the strongest tolerance to ampicillin (ABPC) at a concentration of > 128 MUg/mL, followed by that to fosfomycin (FOM) at a concentration of 128 MUg/mL. When the sensitivity to these antibiotics was examined for each individual genus of tested bacteria, Hafnia spp. exhibited relative tolerance to ceftazidime (CAZ) and ceftriaxone (CTRX) at a concentration of 4 MUg/mL and 2 MUg/mL, respectively, which was high in comparison to that observed for the other strains. Furthermore, Raoultella spp. and Serratia spp. were found to be highly resistant to tetracycline (TC) at a concentration of 128 MUg/mL and 64 MUg/mL, respectively. Of the 142 strains of test bacteria, 140 (98.6%) demonstrated resistance to ABPC, with the exception of Hafnia alvei and Klebsiella pneumonia. In addition, a total of eight strains (5.6%), seven Serratia marcescens strains and one Raoultella terrigena strain, were found to be resistant to TC. Furthermore, one strain of Citrobacter freundii exhibited resistance to nalidixic acid (NA), while another displayed resistance to ofloxacin (OFLX) (0.7% each), and one strain (0.7%) each of Enterobacter cloacae, Serratia marcescens and Citrobacter youngae demonstrated resistance to fosfomycin (FOM), streptomycin (SM) and kanamycin (KM), respectively. A single strain of C. freundii was found to be resistant to three antibiotics, ABPC, NA and OFLX. Resistance to two antibiotics was confirmed in 11 strains, including seven strains of S. marcescens and one strain of R. terrigena (a total of eight strains) resistant to ABPC and TC, and one strain each of C. youngae, S. marcescens and E. cloacae resistant to ABPC and KM, ABPC and SM, and ABPC and FOM, respectively. In addition, 128 strains were resistant to the single antibiotic of ABPC alone. Of the 140 strains demonstrating antibiotic resistance, 137 (97.9%) retained the conjugative R-plasmid transfer factor, excluding three strains of S. marcescens. All transfer factors were ABPC and retained by a high proportion of the bacterial groups, with one strain (100%) being resistant to three antibiotics, nine (81.8%) of the 11 strains being resistant to two antibiotics, and 127 (99.2%) of the 128 strains being resistant to a single antibiotic. In addition, we examined ESBL productivity in the 140 strains of bacteria demonstrating drug tolerance; however, no strains exhibited this characteristic. Therefore, further observation is required to ascertain trends in antibiotic-tolerant bacteria. PMID- 25817810 TI - Effect of polyphenols on reactive oxygen species production and cell growth of human dermal fibroblasts after irradiation with ultraviolet-A light. AB - Ultraviolet-A (UV-A) can damage microbes by generating reactive oxygen species (ROS), singlet oxygen, superoxides, hydrogen peroxide and hydroxyl radicals. These species readily react with lipids, proteins, DNA and other constituents of cells, leading to oxidative deterioration and the eventual death of the microbe. However, the oxidative ability of these reactive species also harms the viability of mammalian cells such as fibroblasts and keratinocytes, as they cause both acute and chronic damage, photo-aging, and photo-carcinogenesis. This study describes a UV-A treatment that does not affect the viability or growth of human neonate dermal fibroblasts, as determined by examining the post-irradiation cell density after the addition of polyphenols as antioxidants. The results demonstrate the possible wide applicability of UV-A sterilization. The potency of polyphenols for attenuating UV-A-induced ROS generation in cells was tested using (+)-catechin hydrate, (-)- epigallocatechin gallate hydrate, morin hydrate, quercetin hydrate and resveratrol. The lowest concentration of polyphenols required to reduce ROS by 50% in cells upon exposure to a dose of 15 J cm(-2) was determined and defined as its IC50. Pre-treatment with morin hydrate at its IC50 allowed cells irradiated with 5.0 J cm(-2) UV-A to recover to the level of the specific growth rate of cells incubated without UV-A irradiation. However, the growth rate of cells exposed to 15 J cm(-2) UV-A irradiation was scarcely influenced by co-incubation with morin hydrate; this dose of UV-A also suppressed cell growth completely in the absence of morin hydrate, although co-incubation resulted in no decrease in cell viability. This study demonstrates the potential of polyphenols for protecting both the viability of cells and their ability to proliferate from damage caused by UV-A-irradiation. PMID- 25817811 TI - Bioremediation of bisphenol-A polluted soil by Sphingomonas bisphenolicum AO1 and the microbial community existing in the soil. AB - Bisphenol A (BPA, 2,2'-Bis (4-hydroxyphenyl) propane) is an artificial pollutant that is easily detected in soil and water environments. BPA decomposition and removal from the environment is relatively difficult due to its stability. This study evaluated the BPA decomposition and removal activities of the microbial community existing in the soil with or without Sphingomonas bisphenolicum AO1, and revealed the toxic effects of BPA towards the microbial community. The microbial community in soil was able to degrade BPA at 1.0 mg.g(-1) soil or lower, although its degradation was slow. On the other hand, BPA at more than 10 mg.g(-1) soil was not only degraded by the microbial community but also decreased its diversity, suggesting that BPA is harmful to many microorganisms. PCR-TTGE analysis and the cloned 16S rRNA gene sequence analysis indicated that Sphingomonadales, Xanthomonadales, Burkholderiales and Pseudomonadales in the microbial community might independently or cooperatively degrade BPA. On the other hand, supplementation with strain AO1 was able to significantly improve the BPA decomposition activity of the microbial community in soil even at 10 mg BPA.g(-1) soil, although BPA at 100 mg.g(-1) soil overwhelmed the BPA decomposition activity of strain AO1. Furthermore, it was also concluded that strain AO1 could not inhabit BPA purified soil after decomposition of BPA by strain AO1 and the soil microbial community, suggesting that the application of strain AO1 could be a low-burden method for the decomposition and removal of BPA from the natural environment. PMID- 25817812 TI - Antimicrobial activity and stability of weakly acidified chlorous acid water. AB - The antimicrobial activity of weakly acidified chlorous acid water (WACAW) against Staphylococcus aureus, non-pathogenic Escherichia coli, enterohemorrhagic E. coli (EHEC O157:H7), Candida albicans, and spore-forming Bacillus and Paenibacillus species was evaluated in vitro. The antiviral activity was also examined using feline calicivirus (FCV). Diluted WACAW (>100 ppm) effectively reduced the number of non-spore-forming bacteria (>4 log10 CFU reductions) within 5 min. Treatment with this sanitizer at 400 ppm for 30 min achieved>5 log10 CFU reductions in spore-forming Bacillus and Paenibacillus species while an equivalent concentration of sodium hypochlorite (NaClO) resulted in only a 0.98 and 2.72 log10 CFU reduction, respectively. The effect of this sanitizer against FCV was equivalent to that of NaClO. Immersion in WACAW (400 ppm) achieved >4 and 2.26 log10 CFU reductions in Campylobacter jejuni and EHEC, respectively, on artificially contaminated broiler carcass pieces. Finally, theantimicrobial activity of this sanitizer was shown to be maintained for at least 28 d when in contact with nonwoven fabric (100% cotton). This study showed that pH control of chlorous acid is expected to modify its antimicrobial activity and stability. WACAW is expected to have applications in various settings such as the food processing and healthcare industries. PMID- 25817813 TI - Development of a new technique using glass beads for dry dispersion of airborne fungal spores. AB - To evaluate the removal of airborne microbes by air cleaners, a technique for generating airborne fungal spores in the dry state in a test chamber (dry dispersion) become necessary. The Society of Indoor Environment Japan (SIEJ) published SIEJ Standard Method No. 20110001 (SIEJ standard),in which an aerial ultrasonic oscillator was used as the device for dry dispersion. However, a more versatile apparatus is also necessary from a practical point of view. Therefore, we developed a new device using glass beads for the dispersion. Glass beads and a fungal sheet containing spores of Wallemia sebi were set in a midget impinger, which was connected to a compressor and a compact test chamber (1 m(3)). Air was blown into the impinger from the compressor. The spores on the fungal sheet were released by impingement of the glass beads when the beads were induced to float by the air blown into the impinger, and the spores were introduced to the chamber by the airflow. This newly developed technique can be used in a compact chamber system and could be applicable as an improved method for generating airborne fungal spores in the dry state in the SIEJ standard. PMID- 25817815 TI - Expression of gyrB and 16S ribosomal RNA genes as indicators of growth and physiological activities of Legionella pneumophila. AB - To determine whether the DNA gyrase (gyrB) and 16S ribosomal RNA (16S rRNA) genes can be used as indicators of the biological activities of Legionella pneumophila, the expression levels were estimated. The ratio of mRNA/DNA in gyrB was 0.7 in mid log phase and decreased drastically after the log phase. For 16S rRNA, the ratio was highest in mid log phase (7.0*10(3)), and the value that was about 10% of that in the log phase was maintained for six days. The rRNA may be vital in the resting or active but nonculturable cells that are not growing but physiologically active. The expression levels of gyrB mRNA and 16S rRNA can be used as indicators of the growth activity and the physiological activity of L. pneumophila, respectively. Therefore, by measurement of these indicators, we can evaluate the activities of Legionella cells in various environments. PMID- 25817814 TI - Effects of oakmoss and its components on Acanthamoeba castellanii ATCC 30234 and the uptake of Legionella pneumophila JCM 7571 (ATCC 33152) into A. castellanii. AB - Acanthamoeba castellanii, a ubiquitous organism in water environments, is pathogenic toward humans and also is a host for bacteria of the genus Legionella, a causative agent of legionellosis. Oakmoss, a natural fragrance ingredient, and its components are antibacterial agents specifically against the genus Legionella. In the present study, oakmoss and its components were investigated for their amoebicidal activity against A. castellanii ATCC 30234 and the inhibitory effect on the uptake of L. pneumophila JCM 7571 (ATCC 33152) into A. castellanii. The oakmoss and its components 3-hydroxy-5-methylphenyl 2,4 dihydroxy-6-methylbenzoate(5), and 6,8-dihydroxy-3-pentyl-1H-isochromen-1-one (12) exhibited high amoebicidal activity (IC50 values; 10.5 +/- 2.3, 16.3 +/- 4.0 and 17.5 +/- 2.8 MUg/mL, respectively) after 48 h of treatment, which were equivalent to that of the reference compound, chlorhexidine gluconate. Pretreatment of L. pneumophila with sub-minimal inhibitory concentration of oakmoss, compound 5, 3-hydroxy-5-methylphenyl 2-hydroxy-4-methoxy-6 methylbenzoate (10) and 8-(2,4-dihydroxy-6-pentylphenoxy)-6-hydroxy-3-pentyl-1H isochromen-1-one (14) obviously reduced the uptake of L. pneumophila into A.castellanii (p < 0.05).The inhibitory effect of compound 5 on the uptake of L. pneumophila was almost equivalent to that of ampicillin used as a reference. Thus, the oakmoss and its components were considered to be good candidates for disinfectants against not only genus Legionella but also A. castellanii. PMID- 25817816 TI - Detection of Legionella species in environmental water by the quantitative PCR method in combination with ethidium monoazide treatment. AB - We detected Legionella species in 111 bath water samples and 95 cooling tower water samples by using a combination of conventional plate culture, quantitative polymerase chain reaction (qPCR) and qPCR combined with ethidium monoazide treatment (EMA-qPCR) methods. In the case of bath water samples, Legionella spp. were detected in 30 samples by plate culture, in 85 samples by qPCR, and in 49 samples by EMA-qPCR. Of 81 samples determined to be Legionella-negative by plate culture, 56 and 23 samples were positive by qPCR and EMA-qPCR, respectively. Therefore, EMA treatment decreased the number of Legionella-positive bath water samples detected by qPCR. In contrast, EMA treatment had no effect on cooling tower water samples. We therefore expect that EMA-qPCR is a useful method for the rapid detection of viable Legionella spp. from bath water samples. PMID- 25817818 TI - Magnon Hall effect on the Lieb lattice. AB - Ferromagnetic insulators without inversion symmetry may show magnon Hall effect (MHE) in the presence of a temperature gradient due to the existence of Dzyaloshinskii-Moriya interaction (DMI). In this theoretical study, we investigate MHE on a lattice with inversion symmetry, namely the Lieb lattice, where the DMI is introduced by adding an external electric field. We show the nontrivial topology of this model by examining the existence of edge states and computing the topological phase diagram characterized by the Chern numbers of different bands. Together with the topological phase diagram, we can further determine the sign and magnitude of the transverse thermal conductivity. The impact of the flat band possessed by this model on the thermal conductivity is discussed by computing the Berry curvature analytically. PMID- 25817817 TI - Reference values of spirometry for Finnish adults. AB - BACKGROUND: Diagnostic assessment of lung function necessitates up-to-date reference values. The aim of this study was to estimate reference values for spirometry for the Finnish population between 18 and 80 years and to compare them with the existing Finnish, European and the recently published global GLI2012 reference values. METHODS: Spirometry was performed for 1380 adults in the population-based FinEsS studies and for 662 healthy non-smoking volunteer adults. Detailed predefined questionnaire screening of diseases and symptoms, and quality control of spirometry yielded a sample of 1000 native Finns (387 men) healthy non smokers aged 18-83 years. Sex-specific reference values, which are estimated using the GAMLSS method and adjusted for age and height, are provided. RESULTS: The predicted values for lung volumes are larger than those obtained by GLI2012 prediction for the Caucasian subgroup for forced vital capacity (FVC) by an average 6.2% and 5.1% and forced expiratory volume in 1 s (FEV1) by an average 4.2% and 3.0% in men and women, respectively. GLI2012 slightly overestimated the ratio FEV1/FVC with an age-dependent trend. Most reference equations from other European countries, with the exception of the Swiss SAPALDIA study, showed an underestimation of FVC and FEV1 to varying degrees, and a slight overestimation of FEV1/FVC. CONCLUSION: This study offers up-to-date reference values of spirometry for native Finns with a wide age range. The GLI2012 predictions seem not to be suitable for clinical use for native Finns due to underestimation of lung volumes. PMID- 25817819 TI - Rabbit syndrome because of topical minoxidil foam. PMID- 25817820 TI - "Fury, us": Anger as a basis for new group self-categories. AB - We tested the hypothesis that shared emotions, notably anger, influence the formation of new self-categories. We first measured participants' (N = 89) emotional reactions to a proposal to make university assessment tougher before providing feedback about the reactions of eight other co-present individuals. This feedback always contained information about the other individuals' attitudes to the proposals (four opposed and four not opposed) and in the experimental condition emotion information (of those opposed, two were angry, two were sad). Participants self-categorised more with, and preferred to work with, angry rather than sad targets, but only when participants' own anger was high. These findings support the idea that emotions are a potent determinant of self-categorisation, even in the absence of existing, available self-categories. PMID- 25817821 TI - An outbreak of hepatitis E in an urban area of Bangladesh. AB - We investigated an outbreak of jaundice in urban Bangladesh in 2010 to examine the cause and risk factors and assess the diagnostic utility of commercial assays. We classified municipal residents reporting jaundice during the preceding 4 weeks as probable hepatitis E cases and their neighbours without jaundice in the previous 6 months as probable controls. We tested the sera collected from probable cases and probable controls for IgM anti-hepatitis E virus (HEV), and the IgM-negative sera for IgG anti-HEV using a commercial assay locally. We retested the IgM-positive sera for both IgM and IgG anti-HEV using another assay at the Centre for Disease Control and Prevention (CDC), USA. Probable cases positive for IgM anti-HEV were confirmed cases; probable controls negative for both IgM and IgG anti-HEV were confirmed controls. We explored the local water supply and sanitation infrastructure and tested for bacterial concentration of water samples. Probable cases were more likely than probable controls to drink tap water (adjusted odds ratio: 3.4; 95% CI: 1.2-9.2). Fifty-eight percentage (36/62) of the case sera were IgM anti-HEV positive; and 75% of the IgM-positive samples were confirmed positive on retesting with another assay at CDC. Compared to confirmed controls, cases confirmed using either or both assays also identified drinking tap water as the risk factor. Two tap water samples had detectable thermotolerant coliforms. Research exploring decentralized water treatment technologies for sustainable safe water might prevent HEV transmission in resource-poor cities. Detection of serological markers in a majority of probable cases implied that available diagnostic assays could adequately identify HEV infection during outbreaks. PMID- 25817822 TI - Clinicopathological significance of ARID1B in breast invasive ductal carcinoma. AB - AIMS: Identification of prognostic and predictive biomarkers for breast cancer is essential to better stratify patients for treatment and evaluate patient outcome. AT-rich interactive domain-containing protein 1B (ARID1B) is implicated in cell proliferation, but its role in tumorigenesis remains unclear. METHODS AND RESULTS: Immunohistochemical analysis of ARID1B expression using breast cancer tissue microarrays containing 156 breast invasive ductal carcinoma patient samples and subsequent statistical data analysis based on ARID1B immunoreactivity score were performed to examine the correlation between clinicopathological parameters in breast cancer and ARID1B expression. In-vitro assays were also performed to study the role of ARID1B in cell cycle progression. Univariate analysis revealed that high ARID1B expression is correlated closely with histological grade (P = 0.045) and size (P = 0.043) of invasive breast cancer. These findings were confirmed by multivariate analysis. Notably, increased ARID1B expression was frequently detected in the aggressive triple-negative breast cancer subtypes (P = 0.039) and associated with decreased 5-year disease-free survival rate. Lastly, MDA-MB-231 cells with reduced ARID1B activity displayed a delay in G1 to S phase cell cycle transition and consequently showed a decrease in cell proliferation compared with controls (P < 0.001). CONCLUSIONS: ARID1B potentially serves as a valuable prognostic and predictive biomarker as well as a therapeutic target in breast cancer. PMID- 25817823 TI - Ability of Kocuria varians LTH 1540 To Degrade Putrescine: Identification and Characterization of a Novel Amine Oxidase. AB - This work describes the identification and characterization of an amine oxidase from Kocuria varians LTH 1540 (syn. Micrococcus varians) primarily acting on putrescine. Data from MALDI-TOF MS/MS and the identification of Delta(1) pyrroline as degradation product from putrescine indicate that the enzyme is a flavin-dependent putrescine oxidase (PuO). Properties of partially purified enzyme have been determined. The enzyme oxidizes diamines, putrescine and cadaverine, and, to a lesser extent, polyamines, such as spermidine, but not monoamines. The kinetic constants (Km and Vmax) for the two major substrates were 94 +/- 10 MUM and 2.3 +/- 0.1 MUmol/min.mg for putrescine and 75 +/- 5 MUM and 0.15 +/- 0.02 MUmol/min.mg for cadaverine. Optimal temperature and pH were 45 degrees C and 8.5, respectively. Enzyme was stable until 50 degrees C. K. varians PuO is sensitive to human flavin-dependent amine oxidase inhibitors and carboxyl-modifying compounds. The new enzyme has been isolated from a bacterial starter used in the manufacture of fermented meat. One of the problems of fermented foods or beverages is the presence of toxic biogenic amines produced by bacteria. The importance of this works lies in the description of a new enzyme able to degrade two of the most abundant biogenic amines (putrescine and cadaverine), the use of which could be envisaged to diminish biogenic amines content in foods in the future. PMID- 25817824 TI - beta2-Glycoprotein I-Dependent Anti-Cardiolipin Antibodies Associated With Periodontitis in Patients With Systemic Lupus Erythematosus. AB - BACKGROUND: It was reported that patients with systemic lupus erythematosus (SLE) exhibited increased levels of anticardiolipin (anti-CL) antibodies, a class of antiphospholipid antibodies associated with thrombosis. beta2-glycoprotein I (beta2GPI) has been considered as the actual target antigen for anti-CL antibodies. This study investigates the association of periodontal infection with anti-CL antibodies in patients with SLE. METHODS: Fifty-three SLE female patients and 56 healthy female volunteers were recruited in this case-control study. All participants received periodontal examinations. The presence of Porphyromonas gingivalis and Treponema denticola in saliva and plaque samples was detected by polymerase chain reaction. Levels of serum anti-CL and anti-beta2GPI antibodies were examined using enzyme-linked immunosorbent assay. RESULTS: Patients with SLE exhibited more periodontal attachment loss and increased titers of serum anti-CL and anti-beta2GPI antibodies compared with healthy controls. Patients with active SLE who harbored P. gingivalis or P. gingivalis together with T. denticola intraorally exhibited significantly higher anti-CL and anti-beta2GPI antibodies than those without these bacteria. Anti-CL and anti-beta2GPI antibody levels correlated positively with clinical attachment level. Furthermore, increased anti beta2GPI antibody levels were significantly associated with C-reactive protein and erythrocyte sedimentation rate. CONCLUSIONS: Elevated anti-CL and anti beta2GPI antibody levels were associated with periodontopathic bacteria and periodontal breakdown in patients with SLE. Periodontitis might be a modifiable risk factor for SLE. PMID- 25817826 TI - Acute pancreatitis and aseptic meningitis: Rare complications of Salmonella paratyphi infection. PMID- 25817825 TI - Nanoemulsion-based mucosal adjuvant induces apoptosis in human epithelial cells. AB - Nanoemulsions (NEs) are adjuvants that enhance antigen penetration of the nasal mucosa, increase cellular uptake of antigens by both epithelial and dendritic cells, and promote the migration of antigen-loaded dendritic cells to regional lymph nodes within 24-h of vaccine administration. The objective of this study was to elucidate cell death caused by W805EC NE and identify caspases and genes associated with death pathways. Consistent with this aim, we show that exposure of human epithelial cells (EC), both RPMI 2650 and FaDu, to NE results in the activation of caspases (1, 3/7, 6, 8, and 9) and the expression of genes involved in apoptotic as well as authophagy and necrosis pathways. Interestingly, the NE activates caspase 8 which promotes "immunogenic apoptosis". The rescue assay was employed to investigate the fate of RPMI 2650 cells treated with W805EC NE. After four-hour treatment with as little as 0.03% of NE no cells were rescued at 72h. Remarkably, immediately after four-hour treatment, the cells morphologically resembled untreated cells and most of the cells were alive. Altogether, these results suggest that NE induces death of human ECs through multiple pathways. Epithelial cell death caused by W805EC may have further implications on antigen uptake, processing, and presentation by DC's. PMID- 25817827 TI - Correlation between peritoneal lavage cytology and tumour stage in patients with colorectal cancer. AB - BACKGROUND AND STUDY AIMS: Complete surgical removal of the involved bowel segment in colorectal cancer is the most effective primary treatment. The main prognostic factors for colorectal cancer are penetration of the tumour into different layers of the bowel wall and regional lymph node involvement. Positive lavage cytology has been used to predict peritoneal recurrence, but its effectiveness remains controversial. This study was conducted to assess the prevalence of positive peritoneal lavage cytology in correlation with the tumour stage in patients with colorectal cancer. PATIENTS AND METHODS: This prospective cross-sectional study was performed on 20 patients with different cases of colorectal cancer attending the colorectal unit and emergency department of the Kasr Al Ainy Hospital, Cairo University Hospitals, from March 2012 to March 2013. RESULTS: The patients' gender did not influence the peritoneal lavage cytology results (p = 0.062); there is no significant correlation between the TNM staging system and cytology in patients with colorectal cancer (p = 0.253). CONCLUSION: Although there is a positive linear correlation between the tumour stage and positive peritoneal lavage cytology, it did not reach a statistically significant level. In addition, the greater the depth of invasion, the higher the lavage cytology rate. However, this trend was not statistically significant. PMID- 25817830 TI - New approaches to wound healing for diabetes. PMID- 25817829 TI - Corrigendum: Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. PMID- 25817828 TI - Local estrogen metabolism in epithelial ovarian cancer suggests novel targets for therapy. AB - Epithelial ovarian cancer (EOC) accounts for about 90% of malignant ovarian tumors, and estrogen is often implicated in disease progression. We therefore compared the potential for gating of estrogen action via pre-receptor metabolism in normal human ovarian surface epithelium (OSE), EOC and selected EOC cell lines (SKOV3 and PEO1). Steroid sulphatase (STS), estrogen sulfotransferase (EST), 17beta-hydroxysteroid dehydrogenases 2 (17BHSD2) and 5 (17BHSD5) mRNAs, proteins and enzymatic activities were all detectable in primary cell cultures of OSE and EOC, whereas aromatase and 17BHSD1 expression was negligible. qRT-PCR assay on total mRNA revealed significantly higher EST mRNA expression in OSE compared to EOC (P<0.05). Radioenzymatic measurements confirmed reduced sulfoconjugation (neutralization) of free estrogen in EOC relative to OSE. OSE cells were more effective at converting free [(3)H]-E1 to [(3)H]-E1S or [(3)H]-E2S, while EOC cell lines mainly converted [(3)H]-E1 to [(3)H]-E2 with minimal formation of [(3)H]-E1S or [(3)H]-E2S. IL1alpha treatment suppressed EST (P<0.01) and 17BHSD2 (P<0.001) mRNA levels in OSE and stimulated STS mRNA levels (P<0.001) in cancer (SKOV3) cells. These results show that estrogen is differentially metabolized in OSE and EOC cells, with E2 'activation' from conjugated estrogen predominating in EOC. Inflammatory cytokines may further augment the local production of E2 by stimulating STS and suppressing EST. We conclude that local estrogen metabolism may be a target for EOC treatment. PMID- 25817831 TI - Decrease in the rate of sensitization and clinical allergy to natural rubber latex. AB - BACKGROUND: In the 1980s, a striking increase in natural rubber latex (NRL) allergy was seen. Since then, many measures have been taken to prevent NRL allergy. OBJECTIVES: To investigate changes in the prevalence of NRL sensitization/clinical NRL allergy over time from 2002 to 2013. METHODS: All patients prick tested for NRL at the Department of Dermatology and Allergy Centre, Odense University Hospital were included in this study (n = 8580). In NRL sensitized patients, the clinical relevance was evaluated for NRL. Furthermore, concomitant positive prick test results for birch pollen were recorded, together with food-related symptoms and sensitization in a subgroup of patients. RESULTS: The prevalence of NRL sensitization declined from 6.1% in 2002-2005 to 1.9% in 2006-2009, and then to 1.2% in 2010-2013 (p < 0.0001). The prevalence of clinical NRL allergy declined from 1.3% in 2002-2005 to 0.5-0.6% in 2006-2013 (p < 0.004). Among the NRL-sensitized patients, 64% had a concomitant positive prick test reaction to birch pollen, and 52% had a history of reaction to oral intake of related fruits or vegetables. CONCLUSION: Our study showed a statistically significant decline in the number of patients sensitized/clinically allergic to NRL. Many of the NRL-sensitized patients without clinical allergy to NRL had concomitant birch pollen sensitization, and reported food-related symptoms. PMID- 25817832 TI - Monomethyl ethers of 4,5-dihydroxypipecolic acid from Petaladenium urceoliferum: Enigmatic chemistry of an enigmatic legume. AB - Leaves of Petaladenium (Leguminosae), an Amazonian monospecific genus recently revealed as a member of the Amburaneae clade among the earliest-diverging papilionoid legumes, were found to accumulate three monomethyl ethers of 4,5 dihydroxypipecolic acids. These were characterised by spectroscopic means as the (2S,4S,5R) and (2S,4R,5S) epimers of 5-hydroxy-4-methoxypipecolic acid and (2S,4R,5R)-4-hydroxy-5-methoxypipecolic acid. These compounds were not detected in any other genera in the Amburaneae clade or the wider Angylocalyceae Dipterygeae-Amburaneae (ADA) clade of papilionoid legumes. Hydroxypipecolic acids, however, were detected in leaves of Myrocarpus and Myroxylon (sister genera in the Amburaneae clade), Angylocalyx and Xanthocercis (sister genera in the Angylocalyceae clade) and Monopteryx (Dipterygeae clade), and were also present in Petaladenium. Iminosugars, known to be accumulated by all four genera in the Angylocalyceae clade (Alexa, Angylocalyx, Castanospermum and Xanthocercis), were found to be characteristic of this group within the ADA clade. PMID- 25817833 TI - Cytotoxic indole alkaloids from the fruits of Melodinus cochinchinensis. AB - Eight indole alkaloids, melosines A-H, together with 13 known alkaloids, were isolated from the fruits of Melodinus cochinchinensis. The structure elucidation of isolated secondary metabolites was based on comprehensive spectroscopic data analysis. Melosine B showed moderate cytotoxic activity against five human cancer cell lines, HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 1.6 to 8.1MUM. PMID- 25817834 TI - Ganoderma pfeifferi--A European relative of Ganoderma lucidum. AB - In contrast to well-studied and broadly used Ganoderma species, such as Ganoderma lucidum and Ganoderma applanatum, knowledge regarding Ganoderma pfeifferi is very limited. Herein is an overview of the phytochemistry, biological activities and possible applications of this mushroom species. In addition to triterpenoids and polysaccharides, G. pfeifferi contains unique sesquiterpenoids and other small molecular weight compounds. Some of these compounds exhibit remarkable antimicrobial activities in vitro and in vivo against multi-resistant bacteria, such as MRSA. Antiviral properties, UV-protection abilities and other activities are also known. Potential issues arising from the conversion of research results into practical applications are discussed. PMID- 25817835 TI - Absolute configurations of phytotoxins seiricardine A and inuloxin A obtained by chiroptical studies. AB - The absolute configuration (AC) of the plant phytotoxin inuloxin A, produced by Inula viscosa, and of the fungal phytotoxin seiricardine A, obtained from Seiridium fungi, pathogen for cypress, has been determined by experimental measurements and theoretical simulations of chiroptical properties of three related methods, namely, Optical Rotatory Dispersion (ORD), Electronic Circular Dichroism (ECD), and Vibrational Circular Dichroism (VCD). Computational prediction by Density Functional Theory (DFT) of VCD spectra and by Time dependent DFT (TDDFT) of ORD and ECD spectra allowed to assign (7R,8R,10S) AC to naturally occurring (+)-inuloxin A. In the case of compound (-)-seiricardine A, which lacks useful for the analysis UV-Vis absorption, and thus provides a hardly detectable ECD spectrum and quite low ORD values, an introduction of a suitable chromophore by chemical derivatization was performed. The corresponding derivative, 2-O-p-bromobenzoate ester, gave rise to an intense ECD spectrum and higher ORD and VCD values. The comparison of computed spectra with the experimental ones allowed to assign (1S,2R,3aS,4S,5R,7aS) AC to (-)-2-O-p bromobenzoate ester of seiricardine A and then to (-)-seiricardine A. This study further supports a recent trend of concerted application of more than a single chiroptical technique toward an unambiguous assignment of AC of flexible and complex natural products. Moreover, the use of chemical derivatization, with insertion of suitable chromophoric moieties has allowed to treat also UV-Vis transparent molecules by ECD and ORD spectroscopies. PMID- 25817836 TI - Bioactive maca (Lepidium meyenii) alkamides are a result of traditional Andean postharvest drying practices. AB - Maca, Lepidium meyenii Walpers (Brassicaceae), is an annual herbaceous plant native to the high plateaus of the Peruvian central Andes. Its underground storage hypocotyls have been a traditional medicinal agent and dietary staple since pre-Columbian times. Reported properties include energizing and fertility enhancing effects. Published reports have focused on the benzylalkamides (macamides) present in dry hypocotyls as one of the main bioactive components. Macamides are secondary amides formed by benzylamine and a fatty acid moiety, with varying hydrocarbon chain lengths and degree of unsaturation. Although it has been assumed that they are usually present in fresh undamaged tissues, analyses show them to be essentially absent from them. However, hypocotyls dried by traditional Andean postharvest practices or industrial oven drying contain up to 800MUgg(-1) dry wt (2.3MUmolg(-1) dry wt) of macamides. In this study, the generation of macamides and their putative precursors were studied during nine week traditional drying trials at 4200m altitude and in ovens under laboratory conditions. Freeze-thaw cycles in the open field during drying result in tissue maceration and release of free fatty acids from storage and membrane lipids up to levels of 1200MUgg(-1) dry wt (4.3MUmolg(-1) dry wt). Endogenous metabolism of the isothiocyanates generated from glucosinolate hydrolysis during drying results in maximal benzylamine values of 4300MUgg(-1) dry wt (40.2MUmolg(-1) dry wt). Pearson correlation coefficients of the accumulation profiles of benzylamine and free fatty acid to that of macamides showed good values of 0.898 and 0.934, respectively, suggesting that both provide sufficient substrate for amide synthesis during the drying process. PMID- 25817837 TI - Myositis with endomysial cell invasion indicates inclusion body myositis even if other criteria are not fulfilled. AB - The objective of this study was to investigate if patients with endomysial mononuclear cell infiltrates invading non-necrotic fibers have a disease course consistent with inclusion body myositis (IBM), irrespective of other histopathological and clinical characteristics. All patients with a muscle biopsy showing endomysial inflammation with invasion of non-necrotic muscle fibers during the period 1979-2006 in two tertiary neuromuscular referral centers were classified into three groups: 1) patients whose biopsies also showed rimmed vacuoles; 2) patients whose biopsies showed no vacuoles but fulfilled clinical criteria for IBM, and 3) patients whose biopsies showed no vacuoles, and also did not fulfill clinical criteria for IBM (unclassified patients). These groups were compared with regard to age, gender, clinical features, and disease course including response to immunosuppressive treatment. Eighty-one individuals (41 men) were included. Rimmed vacuoles were found in 49 patients (60.5%). Fourteen patients (17.3%) fulfilled clinical criteria for IBM and 18 patients (22.2%) were unclassified at presentation. At follow up (mean duration 9 years) three women remained unclassified (4%). There were no differences in disease course or effect of treatment between the three groups. Men had more often rimmed vacuoles than women (73% vs 48%; p = 0.018), and women more often than men were unclassified. Women tended to show more often temporary improvement if treated (p = 0.07), but none had sustained improvement. In conclusion, patients with a muscle biopsy showing endomysial cell infiltration with invasion of non-necrotic muscle fibers most probably have IBM, regardless of clinical and other pathological features. Women lack typical features more often than men. PMID- 25817838 TI - A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human. AB - Mutations in the microtubule-associated protein doublecortin (DCX) cause type I (X-linked or XLIS) lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in females, with defects in neuron migration during development affecting cortical lamination. We found that besides its well-established expression in migrating neurons of the brain, doublecortin (Dcx in mice) is also expressed in motor neurons and skeletal muscle in embryonic neuromuscular junctions (NMJs), raising the possibility of a role in synaptogenesis. Studies with whole-mount preparations of embryonic mouse diaphragm revealed that loss of Dcx leads to abnormal presynaptic arborization and a significantly increased incidence of short axonal extensions beyond innervated acetylcholine receptor (AChR) clusters in the developing NMJ. This phenotype, albeit relatively mild, suggests that Dcx contributes to a stop/stabilizing signal at the synapse, which normally limits further axonal growth following establishment of synaptic contact with the postsynaptic element. Importantly, we also identified abnormal and denervated NMJs in a muscle biopsy from a 16-year-old female patient with SBH, showing both profound presynaptic and postsynaptic morphological defects. Overall, these combined results point to a critical role of doublecortin in the formation of the NMJ. PMID- 25817839 TI - Congenital autophagic vacuolar myopathy is allelic to X-linked myopathy with excessive autophagy. PMID- 25817841 TI - Brain-derived neurotrophic factor: Regulation, effects, and potential clinical relevance. PMID- 25817840 TI - Why acute unilateral vestibular cortex lesions mostly manifest without vertigo. AB - OBJECTIVES: The aim of the current study was, first, to determine the critical causative vestibular areas that in exceptional cases manifest with transient vertigo or dizziness in acute strokes of the middle cerebral artery, and second, to try to explain why in most cases unilateral lesions of these areas manifest without vertigo. METHODS: We determined the ischemic areas of the 10 published cases by overlapping the CT/MRI lesions and attributed them to the temporoparietal vestibular network. RESULTS: These overlap areas were located either in the posterior retroinsular cortex (n = 8), i.e., the parieto-insular vestibular cortex, or the separate parietal vestibular cortex (n = 2). CONCLUSION: Thus, rare vestibular cortical vertigo is mostly elicited by acute lesions of the core region of the retroinsular vestibular network. However, the more interesting question is related to the lack of cortical vertigo when this area is affected. We propose a concept to explain how the unaffected opposite hemisphere can suppress vertigo. This is based on visual-vestibular interaction for motion perception and orientation. It is the hemisphere in which vestibular and visual inputs are in agreement, which is the more reliable and determines the global perception of body orientation and motion. PMID- 25817842 TI - Full medical support for intracerebral hemorrhage. AB - OBJECTIVE: This study tested the hypothesis that patients without placement of new do-not-resuscitate (DNR) orders during the first 5 days after intracerebral hemorrhage (ICH) have lower 30-day mortality than predicted by the ICH Score without an increase in severe disability at 90 days. METHODS: This was a prospective, multicenter, observational cohort study at 4 academic medical centers and one community hospital. Adults (18 years or older) with nontraumatic spontaneous ICH, Glasgow Coma Scale score of 12 or less, who did not have preexisting DNR orders were included. RESULTS: One hundred nine subjects were enrolled. Mean age was 62 years; median Glasgow Coma Scale score was 7, and mean hematoma volume was 39 cm(3). Based on ICH Score prediction, the expected overall 30-day mortality rate was 50%. Observed mortality was substantially lower at 20.2%, absolute average difference 29.8% (95% confidence interval: 21.5%-37.7%). At 90 days, 27.1% had died, 21.5% had a modified Rankin Scale score = 5 (severe disability). A good outcome (modified Rankin Scale score 0-3) was achieved by 29.9% and an additional 21.5% fell into the moderately severe disability range (modified Rankin Scale score = 4). CONCLUSIONS: Avoidance of early DNR orders along with guideline concordant ICH care results in substantially lower mortality than predicted. The observed functional outcomes in this study provide clinicians and families with data to determine the appropriate goals of treatment based on patients' wishes. PMID- 25817843 TI - Copy number variations in cryptogenic cerebral palsy. AB - OBJECTIVE: To determine the prevalence and characteristics of copy number variations (CNVs) in children with cerebral palsy (CP) of unknown etiology, comprising approximately 20% of the CP population. METHODS: Fifty-two participants (age 10.5 +/- 7.8 years; Gross Motor Function Classification System scale 2.8 +/- 1.3) with nonprogressive pyramidal and/or extrapyramidal signs since infancy and no identified etiology were enrolled. Individuals with evidence of acquired causes were excluded. Participants underwent neurologic and clinical genetic examinations before the genomic testing. Chromosomal microarray analysis to detect CNVs was performed using the Affymetrix platform. CNVs identified were classified as pathogenic, likely pathogenic, likely benign, or benign. Only pathogenic and likely pathogenic CNVs were defined as clinically significant. RESULTS: Thirty-nine CNVs were found in 25 of 52 participants (48%). Sixteen participants (31%) had clinically significant CNVs: 10 pathogenic and 6 likely pathogenic, of which 7 were not previously associated with motor disability. Nine participants had likely benign CNVs. Clinically significant CNVs were more frequently de novo (12/16; p < 0.001) including in 5 of 8 individuals who had a first- or second-degree relative with a major neurologic disorder. Dysmorphic features and nonmotor comorbidities were more prevalent in individuals with clinically significant CNVs (p < 0.05 for both). CONCLUSION: CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology. PMID- 25817844 TI - Polymorphisms at 17 Y-STR loci in Botswana populations. AB - Seventeen Y-chromosomal short tandem repeats (YSTRs)-DYS19, DYS389I, DYS389II, DYS385a/b, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, and Y-GATA-H4-were analyzed in 252 unrelated male individuals from Botswana. A total of 238 unique haplotypes were identified. The discrimination capacity (DC) was 0.9444 whereas the haplotype diversity (HD) was 0.9990. A database search of the 238 unique haplotypes in the Y chromosome haplogroup database (YHRD) yielded three African American, six Sub-Saharan African, and two admixed South American matches. Five additional African-American matches were detected in the Applied Biosystems Y-STR database. RST, multi dimensional scaling (MDS) and AMOVA were used to investigate population differentiation in Sub-Saharan Africa and in Botswana. The populations in Sub Saharan Africa were found to be heterogeneous, with Botswana showing significant differences from its neighbors. No geographic regional or ethnic differentiation was observed within Botswana. Regional and ethnic variation can be useful in forensic working hypotheses. PMID- 25817845 TI - Coupled numerical analysis to investigate the heating mechanism of ultrasonic imprint lithography. AB - Ultrasonic imprint lithography (UIL) is a micropattern replication technology on thermoplastic polymers using ultrasonic vibration energy. The UIL process involves three steps: (i) microscale vibration from an ultrasonic horn causes repetitive deformation of a polymer surface, (ii) the polymer surface is locally softened by repetitive deformation and friction, and (iii) micro/nanoscale patterns engraved on the horn or the mold are replicated on the softened substrate. To replicate micro/nano patterns with high accuracy, the effects of various processing conditions should be investigated, and so far, these have been studied experimentally. In this study, coupled numerical analysis was performed using finite element simulation to investigate the heating mechanism of the UIL process, by joining transient structural analysis and heat transfer analysis. The effect of imprinting conditions on the heating capability was investigated using the proposed coupled simulation. The differences between direct and indirect imprinting are also discussed in terms of heating mechanism, and compared with experiments. PMID- 25817846 TI - "Brain Death" and dead donor rule. Discussion and proposals on the thesis of Truog. AB - The introduction in 1968 by the "ad hoc" Harvard committee of the concept of "Brain Death" gave birth to the worldwide diffusion of organ transplantation. Recently "Total Brain Failure" has been proposed as preferred term, instead of "Brain Death", by the President's Council on Bioethics. The concepts of "brain death" and of "dead donor rule" remain the ethical and moral support of organ transplantation. However both criteria has been questioned , either separately or all together , by many authors and particularly by Dr. Robert D. Truog. PMID- 25817848 TI - Markers of automaticity in sleep-associated consolidation of novel words. AB - Two experiments investigated effects of sleep on consolidation and integration of novel form-meaning mappings using size congruity and semantic distance paradigms. Both paradigms have been used in previous studies to measure automatic access to word meanings. When participants compare semantic or physical font size of written word-pairs (e.g. BEE-COW), judgments are typically faster if relative sizes are congruent across both dimensions. Semantic distance effects are also found for wellestablished words, with semantic size judgements faster for pairs that differ substantially on this dimension. English-speaking participants learned novel form-meaning mappings with Mandarin (Experiment 1) or Malay (Experiment 2) words and were tested following overnight sleep or a similar duration awake. Judgements on English words controlled for circadian effects. The sleep group demonstrated selective stronger size congruity and semantic distance effects for novel word-pairs. This benefit occurred in Experiment 1 for semantic size comparisons of novel words, and in Experiment 2 on comparisons where novel pairs had large distances and font differences (for congruity effects) or in congruent trials (for semantic distance effects). Conversely, these effects were equivalent across sleep and wake for English words. Experiment 2 included polysomnography data and revealed that changes in the strength of semantic distance and congruity effects were positively correlated with slow-wave sleep and sleep spindles respectively. These findings support systems consolidation accounts of declarative learning and suggest that sleep plays an active role in integrating new words with existing knowledge, resulting in increased automatic access of the acquired knowledge. PMID- 25817847 TI - Perceptual and motor laterality effects in pianists during music sight-reading. AB - Forty-six right-handed pianists were tested in a music sight-reading task in which they had to perform on a keyboard. Stimuli were single notes or single triads (chords) presented tachistoscopically in the left or right visual field in form of musical notation or verbal labels. Left-hand, right-hand or two-hands performance was required. Results showed, besides the expected Simon effect producing faster responses for stimuli to be performed with the hand ipsilateral to the side of presentation, a complex pattern of laterality which depended primarily upon the requested motor output. A tendency in favor of the left hemisphere (right visual field, RVF) was observed, this asymmetry being significant only in the single-hand tasks. On the contrary, in the two-hands task an opposite asymmetry was observed with musical notation. Moreover, a strong unexpected role of the bass clef was observed, which penalized left hand performance in particular with LVF stimuli. This effect even overcame the Simon effect, suggesting the presence of a bias in favor of the left hemisphere in musical transposition. Results point to a variegated pattern of hemispheric asymmetries in music sight-reading which depend on both stimulus coding and motor output type (e.g. two- or single-hand performance). A RH asymmetry was observed during two-hands playing with musical notation. Conversely, playing with one hand seems more leftward lateralized. This pattern of asymmetry would reflect a LH ability in simple "core" music reading together with a RH ability in the coordination of simultaneous responses by the two hands. PMID- 25817849 TI - Low incidence of early postoperative cerebral edema after coronary artery bypass grafting. AB - OBJECTIVE: Using magnetic resonance imaging, the authors studied the influence of a single high dose of intraoperative dexamethasone on the severity of cerebral edema that can occur early after coronary artery bypass grafting (CABG). It was hypothesized that high-dose intraoperative dexamethasone reduces cerebral edema after CABG. DESIGN: Secondary analysis in a subset of participants of the Dexamethasone for Cardiac Surgery (DECS) trial. The DECS trial was a multicenter, randomized, double-blind, placebo-controlled trial in 4,494 cardiac surgery patients, which studied the effect of high-dose dexamethasone on mortality and major complications after cardiac surgery. SETTING: A large university hospital in The Netherlands. PARTICIPANTS: Twenty adult patients who underwent CABG with cardiopulmonary bypass (CPB) between March and November 2011. INTERVENTIONS: Participants received a single intravenous dose of dexamethasone, 1 mg/kg, or placebo, at induction of anesthesia. MEASUREMENTS AND MAIN RESULTS: Patients underwent magnetic resonance imaging scanning immediately after surgery. The primary outcome was the severity of cerebral edema. Data from 18 patients (9 in each group, median age 69 years in both groups) could be analyzed. Patients in the dexamethasone group were (median, interquartile range 66 (53-99) minutes on cardiopulmonary bypass v 95 (81-105) minutes in the placebo group (p = 0.11). Only 1 patient in the dexamethasone group had slight cerebral edema (0% v 11%, p = 1.00), and edema severity did not differ between groups (p = 1.00). CONCLUSIONS: Relevant degrees of early postoperative cerebral edema were not observed. The present study findings strongly contrasted with older studies showing cerebral edema early after CABG in most patients. PMID- 25817851 TI - [Cannabis-induced pancreatitis]. PMID- 25817850 TI - Synovial fluid and plasma n3 long chain polyunsaturated fatty acids in patients with inflammatory arthritis. AB - Relationships between n-3 long chain polyunsaturated fatty acids (LC-PUFA) in plasma and synovial fluid (SF) were examined in 36 patients with knee effusion within the context of a variety of rheumatic diagnoses and various stated fish oil (FO) intakes (from 0 to 30mL of standard FO daily) of variable duration. In a sub-group of patients, correlations between PUFA in SF mononuclear cells (MNC) and cell-free supernatants of SF and between SF MNC and peripheral blood (PB) MNC were examined. Correlations were also sought between clinical data (stated FO intake, pain score) and n-3 LC-PUFA. Correlations between plasma n-3 LC-PUFA and SF n-3 LC-PUFA were very strong (r(2)>0.9, p<0.001). The LC-PUFA profiles of SF supernatants differed from those of MNC. PUFA profiles in PB MNC and SF MNC were similar, except for a higher proportion of DHA in the latter. Positive correlations were observed between stated intakes of FO and EPA in plasma and SF (for both r=0.37, p=0.02) and DHA in plasma (r=0.37, p=0.02) and SF (r=0.36, p=0.03). n-3 LC-PUFA in plasma and SF correlated inversely with pain score (plasma r(2)=0.16, p<0.02; SF r(2) 0.32, p=0.001). In conclusion, plasma n-3 LC PUFA is a strong indicator of SF n-3 LC-PUFA status across a broad range of rheumatic diagnoses and FO intakes. Higher n-3 LC-PUFA in plasma and SF were associated with lesser pain experience. PMID- 25817852 TI - [Eczematous lesions and acquired ichthyosis as a presenting finding of CD30+ anaplastic large cell lymphoma]. PMID- 25817853 TI - [Use of COPD-6 Vitalograph in Primary Care as tool for smoking cessation]. AB - OBJECTIVES: PRIMARY OBJECTIVE: To assess the evolution of smoking cessation process after using a COPD-6 Vitalograph in smokers that came to a primary care practice (PCP) during a three year period (March 2011- February 2013). SECONDARY OBJECTIVES: To assess if there are any new COPD diagnoses and to compare the smoking cessation outcomes to those of a specific smoking cessation practice (SSCP) from another healthcare centre. METHODOLOGY: Two devices were used: Vitalograph (electronic device measuring the lung function) and the CO-oximeter, in 176 patients (active search of smokers). VARIABLES: tobacco pack-years, tobacco dependence (shortened Fagerstrom test), CO in exhaled breath (in parts per million-ppm), personal history of COPD or cardiovascular disease (CVD). The patients performed three forced exhalations and the Vitalograph registered the lung function (FEV1, FEV6, FEV1/FEV6) and the estimated lung age (ELA). Patient attitude was assessed (phases: pre-contemplation, contemplation, preparation) before and after the test, informing them of the outcomes. Patient progress in the smoking cessation process was also recorded. RESULTS: A total of 176 smokers were studied in PCP and 33 in SSCP. PCP/SSCP: age: 45.9/51.6 years old (p=042); pack-years 25.5/39.3 (p=0001); patients who quit smoking and used medicines for it 2/9. In PCP: age-ELA 45.9/57.4 (p=0.000). In SSCP: age-ELA 51.6/74.3 (p=000). Smoking habit evolution PCP/SSCP: cessation 24.5%/48.5% (p=004). Difference 24%. CI difference (6.4-42.8%). In PCP new COPD diagnosis in 6 smokers. CONCLUSIONS: COPD-6 Vitalograph is a fast and easy to use tool in day-to-day practice. The percentage of smoking cessation is better in SSCP, although a high smoking cessation rate was obtained in PCP (active search). PMID- 25817854 TI - [A way of helping "Mr. Minotaur" and "Ms. Ariadne" to exit from the multiple morbidity labyrinth: the "master problems"]. AB - Multiple morbidity seems to be "infinite" and so is not easy to make useful decisions. A new concept is introduced: the "master problems", as a qualitative method to facilitate the exit from this maze of multiple morbidity. Metaphors from the art world have been used to teach this concept. These "master problems" generally remain hidden and can only "unravel" between the interstices of multiple morbidity, when the details of the system that defines the problem are explained. A problem with "energy" or a "master problem" is complex, multiple and dramatic or theatrical--everything in the clinical history history make us look into that particular question. It is what gives us a blow to the stomach, which causes our hearts to beat faster, that moves us on many levels, which has a high "density of emotions", human elements, social symbols, and opens solutions in a patient. PMID- 25817855 TI - Glutamate Signaling in Synaptogenesis and NMDA Receptors as Potential Therapeutic Targets for Psychiatric Disorders. AB - Glutamate, a major excitatory neurotransmitter, plays important roles in synaptic plasticity, such as long-term potentiation (LTP) and new synapse formation. Growing evidence suggests that glutamate signaling is involved in the neurobiology of psychiatric disorders, including schizophrenia, major depressive disorder (MDD) and bipolar disorder (BP). Postmortem brain studies demonstrated altered spine density in brains from patients with these psychiatric disorders, indicating that remodeled neuronal circuits may contribute to the pathobiology of these psychiatric diseases. Drugs targeting the glutamate system have typically attracted attention as they show efficacy in animal studies and potential therapeutic effects in the clinical setting. In particular, the Nmethyl- D aspartate (NMDA) receptor antagonist, ketamine exerts a rapid and robust antidepressant effect in treatment-resistant patients with MDD and BP, whereas conventional antidepressants require several weeks for therapeutic onset. Animal studies showed that ketamine induced rapid synaptogenesis, suggestive of synaptic plasticity via NMDA receptor signaling being an essential event in the treatment of depression. Therefore, drugs modulating glutamate signaling could also be potential therapeutic drugs for psychiatric disorders. First, we summarize the role of glutamate signaling on dendritic spine formation, maintenance and remodeling. Then, we discuss the abnormalities identified in dendritic spine and glutamate signaling from postmortem brain studies and animal models of psychiatric disorders. Finally, we review the potential benefits of drugs acting on the NMDA receptor in clinical and animal models of psychiatric disorders. PMID- 25817856 TI - Improvement of learning and increase in dopamine level in the frontal cortex by methylphenidate in mice lacking dopamine transporter. AB - The symptoms of attention-deficit/hyperactivity disorder (ADHD) are characterized by inattention and hyperactivity-impulsivity. It is a common childhood neurodevelopmental disorder that often persists into adulthood. Improvements in ADHD symptoms using psychostimulants have been recognized as a paradoxical calming effect. The psychostimulant methylphenidate (MPH) is currently used as the first-line medication for the management of ADHD. Recent studies have drawn attention to altered dopamine-mediated neurotransmission in ADHD, particularly reuptake by the dopamine transporter (DAT). This hypothesis is supported by the observation that DAT knockout mice exhibit marked hyperactivity that is responsive to acute MPH treatment. However, other behaviors relevant to ADHD have not been fully clarified. In the present study, we observed learning impairment in shuttle-box avoidance behavior together with hyperactivity in a novel environment in DAT knockout mice. Methylphenidate normalized these behaviors and enhanced escape activity in the tail suspension test. Interestingly, the effective dose of MPH increased extracellular dopamine in the prefrontal cortex but not striatum, suggesting an important role for changes in prefrontal dopamine in ADHD. Research that uses rodent models such as DAT knockout mice may be useful for elucidating the pathophysiology of ADHD. PMID- 25817858 TI - Possible involvement of muscarinic receptors in psychiatric disorders: a focus on schizophrenia and mood disorders. AB - A considerable body of data supports a role for the central cholinergic system in the aetiologies of schizophrenia and mood disorders. There have been breakthroughs in gaining structural data on muscarinic receptors (CHRMs), understanding their role in CNS functioning and in synthesising drugs that can specifically target each of the 5 CHRMs. This means it is opportune to consider the role of specific CHRMs in the pathophysiologies of schizophrenia and mood disorders. This review will focus on data suggesting changes in levels of CHRM1 and CHRM4 implicate these receptors in the pathophysiology of schizophrenia whereas data suggest a role for CHRM2 in mood disorders. There will be a selected reference to recent developments in understanding the roles of CHRM1, 2 and 4 in CNS function and how these predict mechanisms by which these receptors could induce the symptoms prevalent in schizophrenia and mood disorders. Finally, there will be comments on the potential advantages and problems in targeting CHRM1 and CHRM4 to treat the symptoms of schizophrenia and CHRM2 to treat the symptom of depression. PMID- 25817857 TI - Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801. AB - Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 MUg/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK 801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner. PMID- 25817859 TI - Region-specific dendritic spine loss of pyramidal neurons in dopamine transporter knockout mice. AB - Dopamine transporter (DAT) knockout (KO) mice show numerous behavioral alterations, including hyperlocomotion, cognitive deficits, impulsivity and impairment of prepulse inhibition of the startle reflex (PPI), phenotypes that may be relevant to frontostriatal disorders such as schizophrenia. Dendritic spine changes of pyramidal neurons in the dorsolateral prefrontal cortex (DLPFC) are among the most replicated of findings in postmortem studies of schizophrenia. The mechanisms that account for dendritic changes in the DLPFC in schizophrenia are unclear. Here, we report basal spine density of pyramidal neurons in the medial prefrontal cortex (mPFC), the motor cortex, the CA1 region of the hippocampus, and the basolateral amygdala in DAT KO mice. Pyramidal neurons were visualized using DAT KO mice crossbred with a Thy1-GFP transgenic mouse line. We observed a significant decrease in spine density of pyramidal neurons in the mPFC and the CA1 region of the hippocampus in DAT KO mice compared to that in WT mice. On the other hand, no difference was observed in spine density of pyramidal neurons in the motor cortex or the basolateral amygdala between DAT genotypes. These results suggest that decreased spine density could cause hypofunction of the mPFC and the hippocampus, and contribute to the behavioral abnormalities observed in DAT KO mice, including cognitive deficits. This might suggest that aberrant dopaminergic signaling may trigger dystrophic changes in dendrites of hippocampal and prefrontocortical pyramidal neurons in schizophrenia. PMID- 25817861 TI - The Piccolo Intronic Single Nucleotide Polymorphism rs13438494 Regulates Dopamine and Serotonin Uptake and Shows Associations with Dependence-Like Behavior in Genomic Association Study. AB - Piccolo (PCLO) inhibits methamphetamine-induced neuropharmacological effects via modulation of dopamine (DA) uptake and regulation of the transport of synaptic vesicles in neuronal cells. Clinical studies have recently suggested that the single nucleotide polymorphism (SNP) rs13438494 in the intron 24 of the PCLO gene is associated with psychiatric disorder, in the meta-analysis of GWAS. Therefore, in this study, we attempted to evaluate the possible role of the PCLO SNP in the mechanisms of uptake of monoamines. To characterize rs13438494 in the PCLO gene, we constructed plasmids carrying either the C or A allele of the SNP and transiently transfected them into SH-SY5Y cells to analyze genetic effects on the splicing of PCLO mRNA. The C and A allele constructs produced different composition of the transcripts, indicating that the intronic SNP does affect the splicing pattern. We also transfected DA and serotonin (5-hydroxytryptamine; 5- HT) transporters into cells and analyzed their uptakes to elucidate the association to psychiatric disorders. In the cells transfected with the C allele, both the DA and 5-HT uptake were enhanced compared to the A allele. We also conducted a clinical study, in order to clarify the genetic associations. PCLO rs13438494 exhibits a relationship with the symptoms of drug dependence or related parameters, such as the age of first exposure to methamphetamine, eating disorders, tobacco dependence and fentanyl requirement. Our findings suggest that rs13438494 is associated with drug abuse and contributes to the pathogenesis of psychiatric disorders via modulation of neurotransmitter turnover. PMID- 25817862 TI - IL-5 production by resident mucosal allergen-specific T cells in an explant model of allergic rhinitis. AB - BACKGROUND: Seasonal allergic rhinitis is a chronic inflammation in the nasal mucosa triggered by inhaled aeroallergens. The inflammatory reaction is controlled by allergen-specific T cells, but where and how these T cells become activated is not fully understood. OBJECTIVES: We wanted to determine whether allergen-specific T-helper (Th) 2 cells are residing in the nasal mucosa under steady-state conditions outside of the pollen season and, if so, whether these cells are activated locally in response to allergen challenge. METHODS: Mucosal biopsies from the lower turbinate were obtained out of season from patients with either birch- or grass-pollen-allergic rhinitis and from healthy controls. Cultured explant samples were challenged with relevant pollen extract or with a mix of overlapping 20-mer peptides derived from the sequence of the major birch allergen, Betula verrucosa (Bet v) 1. After 24 h, culture medium was harvested for multiplex cytokine and tryptase analysis. RESULTS: Significant amounts of interleukin (IL)-5 were secreted from resident cells in response to ex vivo allergen challenge in the allergic group only. No increase was observed for the other cytokines measured. Production of IL-5 in response to both extract and the Bet v1-derived peptide mix strongly suggested that T cells were a major source of IL-5. CONCLUSION: Our explant model indicated that local presentation of antigen to resident allergen-specific Th2 cells is the early event in the pathogenesis of allergic rhinitis. These findings identify possible cellular targets for anti inflammatory treatment. PMID- 25817860 TI - Specific Roles of NMDA Receptor Subunits in Mental Disorders. AB - N-methyl-D-aspartate (NMDA) receptor plays important roles in learning and memory. NMDA receptors are a tetramer that consists of two glycine-binding subunits GluN1, two glutamate-binding subunits (i.e., GluN2A, GluN2B, GluN2C, and GluN2D), a combination of a GluN2 subunit and glycine-binding GluN3 subunit (i.e., GluN3A or GluN3B), or two GluN3 subunits. Recent studies revealed that the specific expression and distribution of each subunit are deeply involved in neural excitability, plasticity, and synaptic deficits. The present article summarizes reports on the dysfunction of NMDA receptors and responsible subunits in various neurological and psychiatric disorders, including schizophrenia, autoimmune-induced glutamatergic receptor dysfunction, mood disorders, and autism. A key role for the GluN2D subunit in NMDA receptor antagonist-induced psychosis has been recently revealed. PMID- 25817864 TI - Dietary I(-) absorption: expression and regulation of the Na(+)/I(-) symporter in the intestine. AB - Thyroid hormones are critical for the normal development, growth, and functional maturation of several tissues, including the central nervous system. Iodine is an essential constituent of the thyroid hormones, the only iodine-containing molecules in vertebrates. Dietary iodide (I(-)) absorption in the gastrointestinal tract is the first step in I(-) metabolism, as the diet is the only source of I(-) for land-dwelling vertebrates. The Na(+)/I(-) symporter (NIS), an integral plasma membrane glycoprotein located in the brush border of enterocytes, constitutes a central component of the I(-) absorption system in the small intestine. In this chapter, we review the most recent research on structure/function relations in NIS and the protein's I(-) transport mechanism and stoichiometry, with a special focus on the tissue distribution and hormonal regulation of NIS, as well as the role of NIS in mediating I(-) homeostasis. We further discuss recent findings concerning the autoregulatory effect of I(-) on I(-) metabolism in enterocytes: high intracellular I(-) concentrations in enterocytes decrease NIS-mediated uptake of I(-) through a complex array of posttranscriptional mechanisms, e.g., downregulation of NIS expression at the plasma membrane, increased NIS protein degradation, and reduction of NIS mRNA stability leading to decreased NIS mRNA levels. Since the molecular identification of NIS, great progress has been made not only in understanding the role of NIS in I(-) homeostasis but also in developing protocols for NIS-mediated imaging and treatment of various diseases. PMID- 25817863 TI - Dying With Carolyn: Using Simulation to Improve Communication Skills of Unregulated Care Providers Working in Long-Term Care. AB - This article examines the development, implementation, and evaluation of a pilot project utilizing high-fidelity simulation (HFS) to improve frontline staff members' confidence and skills to communicate about death and dying in long-term care homes. The target group was unregulated care providers who provide palliative care for residents and their families. Eighteen participants engaged in the educational intervention and evaluation. Results supported the effectiveness of HFS as an educational tool for unregulated health care providers. Quantitative data showed statistically significant improvements in participants' self-efficacy scores related to communicating about death and dying and end-of-life care. Qualitative data indicated that the experience was a valuable learning opportunity and helped participants develop insights into their own values, beliefs, and fears providing end-of-life care. HFS is therefore recommended as an innovative training strategy to improve palliative care communication in long-term care homes. PMID- 25817865 TI - Apical iodide efflux in thyroid. AB - Thyroid follicular epithelial cells produce thyroxine (T4) and its physiologically active derivative, 3,3',5-triiodothyronine (T3), hormones that regulate critical developmental and metabolic functions. In order for the thyroid to form hormone precursor, iodide, the defining element in thyroid hormone, must cross both blood-facing and luminal sides of the follicular epithelium. The pathway for uptake from blood is well understood, but the mechanism(s) that enable iodide to cross the luminally facing apical membrane remain obscure. This chapter considers the physiological properties of several molecularly characterized anion transport proteins, all of which potentially contribute to the overall mechanism of apical iodide efflux. PMID- 25817868 TI - Control of ENaC-mediated sodium reabsorption in the distal nephron by Bradykinin. AB - Kinins, such as Bradykinin (BK), are peptide hormones of the kallikrein-kinin system. Apart from being a vasodilator, BK also increases urinary sodium excretion to reduce systemic blood pressure. It is becoming appreciated that BK modulates function of the epithelial Na(+) channel in the distal part of the renal nephron to affect tubular sodium reabsorption. In this chapter, we outline the molecular details, as well as discuss the physiological relevance of this regulation for the whole organism sodium homeostasis and setting chronic blood pressure. PMID- 25817866 TI - The sodium/multivitamin transporter: a multipotent system with therapeutic implications. AB - The Na(+)/multivitamin transporter (SMVT) is a member of the solute:sodium symporter family that catalyzes the Na(+)-dependent uptake of the structurally diverse water-soluble vitamins pantothenic acid (vitamin B5) and biotin (vitamin H), alpha-lipoic acid-a vitamin-like substance with strong antioxidant properties and iodide. The organic substrates of SMVT play central roles in the cellular metabolism and are, therefore, essential for normal human health and development. For example, biotin deficiency leads to growth retardation, dermatological disorders, and neurological disorders. Animal studies have shown that biotin deficiency during pregnancy is directly correlated to embryonic growth retardation, congenital malformation, and death of the embryo. This chapter focuses on the structural and functional features of the human isoform of SMVT (hSMVT); the discovery of which was greatly facilitated by the cloning and expression of hSMVT in tractable expression systems. Special emphasis will be given to mechanistic implications of the transport process of hSMVT that will inform our understanding of the molecular determinants of hSMVT-mediated transport in dynamic context to alleviate the development and optimization of hSMVT as a multipotent platform for drug delivery. PMID- 25817867 TI - Regulation of alphaENaC transcription. AB - Aldosterone is a major regulator of Na(+) absorption and acts primarily by controlling the epithelial Na(+) channel (ENaC) function at multiple levels including transcription. ENaC consists of alpha, beta, and gamma subunits. In the classical model, aldosterone enhances transcription primarily by activating mineralocorticoid receptor (MR). However, how aldosterone induces chromatin alternation and thus leads to gene activation or repression remains largely unknown. Emerging evidence suggests that Dot1a-Af9 complex plays an important role in repression of alphaENaC by directly binding and modulating targeted histone H3 K79 hypermethylation at the specific subregions of alphaENaC promoter. Aldosterone impairs Dot1a-Af9 formation by decreasing expression of Dot1a and Af9 and by inducing Sgk1, which, in turn, phosphorylates Af9 at S435 to weaken Dot1a Af9 interaction. MR counterbalances Dot1a-Af9 action by competing with Dot1a for binding Af9. Af17 derepresses alphaENaC by competitively interacting with Dot1a and facilitating Dot1a nuclear export. Consistently, MR(-/-) mice have impaired ENaC expression at day 5 after birth, which may contribute to progressive development of pseudohypoaldosteronism type 1 in a later stage. Af17(-/-) mice have decreased ENaC expression, renal Na(+) retention, and blood pressure. In contrast, Dot1l(AC) mice have increased alphaENaC expression, despite a 20% reduction of the principal cells. This chapter reviews these findings linking aldosterone action to ENaC transcription through chromatin modification. Future direction toward the understanding the role of Dot1a-Af9 complex beyond ENaC regulation, in particular, in renal fibrosis is also briefly discussed. PMID- 25817870 TI - Pharmacological regulation of the cholesterol transport machinery in steroidogenic cells of the testis. AB - Reduced serum testosterone (T), or hypogonadism, is estimated to affect about 5 million American men, including both aging and young men. Low serum T has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass and bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Administering exogenous T, known as T replacement therapy (TRT), reverses many of the symptoms of low T levels. However, this treatment can result in luteinizing hormone suppression which, in turn, can lead to reduced sperm numbers and infertility, making TRT inappropriate for men who wish to father children. Additionally, TRT may result in supraphysiologic T levels, skin irritation, and T transfer to others upon contact; and there may be increased risk of prostate cancer and cardiovascular disease, particularly in aging men. Therefore, the development of alternate therapies for treating hypogonadism would be highly desirable. To do so requires greater understanding of the series of steps leading to T formation and how they are regulated, and the identification of key steps that are amenable to pharmacological modulation so as to induce T production. We review herein our current understanding of mechanisms underlying the pharmacological induction of T formation in hypogonadal testis. PMID- 25817871 TI - Insulin transport into the brain and cerebrospinal fluid. AB - The pancreatic hormone insulin plays a well-described role in the periphery, based principally on its ability to lower circulating glucose levels via activation of glucose transporters. However, insulin also acts within the central nervous system (CNS) to alter a number of physiological outcomes ranging from energy balance and glucose homeostasis to cognitive performance. Insulin is transported into the CNS by a saturable receptor-mediated process that is proposed to be dependent on the insulin receptor. Transport of insulin into the brain is dependent on numerous factors including diet, glycemia, a diabetic state and notably, obesity. Obesity leads to a marked decrease in insulin transport from the periphery into the CNS and the biological basis of this reduction of transport remains unresolved. Despite decades of research into the effects of central insulin on a wide range of physiological functions and its transport from the periphery to the CNS, numerous questions remain unanswered including which receptor is responsible for transport and the precise mechanisms of action of insulin within the brain. PMID- 25817872 TI - Regulation of hormone-sensitive renal phosphate transport. AB - Phosphate is essential for growth and maintenance of the skeleton and for generating high-energy phosphate compounds. Evolutionary adaptation to high dietary phosphorous in humans and other terrestrial vertebrates involves regulated mechanisms assuring the efficient renal elimination of excess phosphate. These mechanisms prominently include PTH, FGF23, and Vitamin D, which directly and indirectly regulate phosphate transport. Disordered phosphate homeostasis is associated with pathologies ranging from kidney stones to kidney failure. Chronic kidney disease results in hyperphosphatemia, an elevated calcium*phosphate product with considerable morbidity and mortality, mostly associated with adverse cardiovascular events. This chapter highlights recent findings and insights regarding the hormonal regulation of renal phosphate transport along with imbalances of phosphate balance due to acquired or inherited diseases states. PMID- 25817873 TI - Regulation of aquaporins by vasopressin in the kidney. AB - Vasopressin is the main hormone that regulates water conservation in mammals and one of its major targets is the principal cells in the renal collecting duct. Vasopressin increases the apical water permeability of principal cells, mediated by apical accumulation of aquaporin-2 (AQP2), a water channel protein, thus facilitating water reabsorption by the kidney. The mechanisms underlying the accumulation of AQP2 in response to vasopressin include vesicular trafficking from intracellular storage vesicles expressing AQP2 within several tens of minutes (short-term regulation) and protein expression of AQP2 over a period of hours to days (long-term regulation). This chapter reviews vasopressin signaling in the kidney, focusing on the molecular mechanisms of short- and long-term regulations of AQP2 expression. PMID- 25817874 TI - The structure and function of the dopamine transporter and its role in CNS diseases. AB - In this chapter, we explore the basic science of the dopamine transporter (DAT), an integral component of a system that regulates dopamine homeostasis. Dopamine is a key neurotransmitter for several brain functions including locomotor control and reward systems. The transporter structure, function, mechanism of action, localization, and distribution, in addition to gene regulation, are discussed. Over many years, a wealth of information concerning the DAT has been accrued and has led to increased interest in the role of the DAT in a plethora of central nervous system diseases. These DAT characteristics are explored in relation to a range of neurological and neuropsychiatric diseases, with a particular focus on the genetics of the DAT. In addition, we discuss the pharmacology of the DAT and how this relates to disease and addiction. PMID- 25817869 TI - Inhibition of ENaC by endothelin-1. AB - The amiloride-sensitive epithelial Na(+) channel (ENaC) is a key player in the regulation of Na(+) homeostasis. Its functional activity is under continuous control by a variety of signaling molecules, including bioactive peptides of endothelin family. Since ENaC dysfunction is causative for disturbances in total body Na(+) levels associated with the abnormal regulation of blood volume, blood pressure, and lung fluid balance, uncovering the molecular mechanisms of inhibitory modulation or inappropriate activation of ENaC is crucial for the successful treatment of a variety of human diseases including hypertension. The precise regulation of ENaC is particularly important for normal Na(+) and fluid homeostasis in organs where endothelins are known to act: the kidneys, lung, and colon. Inhibition of ENaC by endothelin-1 (ET-1) has been established in renal cells, and several molecular mechanisms of inhibition of ENaC by ET-1 are proposed and will be reviewed in this chapter. PMID- 25817875 TI - Regulation of the norepinephrine transporter by endothelins: a potential therapeutic target. AB - Neuronal norepinephrine (NE) uptake is a crucial step in noradrenergic neurotransmission that regulates NE concentration in the synaptic cleft. It is a key mechanism mediated by the NE transporter (NET) which takes the neurotransmitter into the presynaptic neuron terminal or the adrenal medulla chromaffin cell. The activity of NET is short and long terms modulated by phosphorylation mediated by protein kinases A, C, and G and calcium-calmodulin dependent protein kinase, whereas the transporter availability at the cell surface is regulated by glycosylation. Several neuropeptides like angiotensins II, III, and 1-7, bradykinin, natriuretic peptides, as well as endothelins (ETs) regulate a wide variety of biological effects, including noradrenergic transmission and in particular neuronal NE uptake. Diverse reports, including studies from our laboratory, show that ETs differentially modulate the activity and expression of NET not only in normal conditions but also in diverse cardiovascular diseases such as congestive heart failure and hypertension. Current literature supports a key role for the interaction between ETs and NE in maintaining neurotransmission homeostasis and further suggests that this interaction may represent a potential therapeutic target for various diseases, particularly hypertension. PMID- 25817876 TI - Vitamin D-enhanced duodenal calcium transport. AB - For humans and rodents, duodenum is a very important site of calcium absorption since it is exposed to ionized calcium released from dietary complexes by gastric acid. Calcium traverses the duodenal epithelium via both transcellular and paracellular pathways in a vitamin D-dependent manner. After binding to the nuclear vitamin D receptor, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] upregulates the expression of several calcium transporter genes, e.g., TRPV5/6, calbindin D9k, plasma membrane Ca(2+)-ATPase1b, and NCX1, thereby enhancing the transcellular calcium transport. This action has been reported to be under the regulation of parathyroid-kidney-intestinal and bone-kidney-intestinal axes, in which the plasma calcium and fibroblast growth factor-23 act as negative feedback regulators, respectively. 1,25(OH)2D3 also modulates the expression of tight junction-related genes and convective water flow, presumably to increase the paracellular calcium permeability and solvent drag-induced calcium transport. However, vitamin D-independent calcium absorption does exist and plays an important role in calcium homeostasis under certain conditions, particularly in neonatal period, pregnancy, and lactation as well as in naturally vitamin D impoverished subterranean mammals. PMID- 25817877 TI - Endocannabinoid transport revisited. AB - Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the endocannabinoid system which plays a major role in health and disease. The primary endocannabinoids are anandamide (AEA, N-arachidonoylethanolamine) and 2 arachidonoyl glycerol. While their biosynthesis and metabolism have been studied in detail, it remains unclear how endocannabinoids are transported across the cell membrane. In this review, we critically discuss the different models of endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed. A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration. We conclude that novel and more specific probes will be essential to identify the missing targets involved in endocannabinoid membrane transport. PMID- 25817878 TI - Adenosine transporters and receptors: key elements for retinal function and neuroprotection. AB - Adenosine is an important neuroactive substance in the central nervous system, including in the retina where subclasses of adenosine receptors and transporters are expressed since early stages of development. Here, we review some evidence showing that adenosine plays important functions in the mature as well as in the developing tissue. Adenosine transporters are divided into equilibrative and concentrative, and the major transporter subtype present in the retina is the ENT1. This transporter is responsible for a bidirectional transport of adenosine and the uptake or release of this nucleoside appears to be regulated by different signaling pathways that are also controlled by activation of adenosine receptors. Adenosine receptors are also key players in retina physiology regulating a variety of functions in the mature and developing tissue. Regulation of excitatory neurotransmitter release and neuroprotection are the main functions played be adenosine in the mature tissue, while regulation of cell survival and neurogenesis are some of the functions played by adenosine in developing retina. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosine-related drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. PMID- 25817879 TI - Hormones and transport systems. Preface. PMID- 25817880 TI - Emotional Experiences Among Siblings of Children With Rare Disorders. AB - OBJECTIVE: This research aimed to provide new knowledge about the emotional experiences of siblings of children with rare disorders. METHODS: Qualitative thematic analysis was conducted based on videotapes of 11 support groups for 58 siblings aged 7-17 years (Mage = 11.4 years, SD = 2.4) of children with rare disorders. RESULTS: Participants described contradictory emotions in three main contexts: (1) implications of the disorder (knowledge, medical issues, prognosis); (2) consequences for family life (practical implications, limitations of the child with disorder, perspectives on the sibling relationship); and (3) consequences for social life (reflections about (ab)normality, reactions from others). Passive coping strategies were frequently described relative to active coping strategies. An emerging dilemma for participants was hiding versus sharing emotional experiences. CONCLUSIONS: Siblings' emotional experiences are characterized by diverse and contradictory feelings. Interventions to promote emotional health in siblings of children with rare disorder should address this complexity. PMID- 25817881 TI - Topical Review: Theoretical Frameworks in Pediatric Adherence-Promotion Interventions: Research Findings and Methodological Implications. AB - OBJECTIVE: To summarize the guiding theoretical frameworks included in pediatric adherence-promotion interventions and characterize targeted domains using the theoretical domains framework (TDF), a standardized system developed by adult behavior change researchers. METHODS: A systematic review of PubMed, PsycINFO, and CINAHL databases identified 47 articles describing pediatric adherence promotion interventions. Data extraction was completed independently by two authors. Targeted intervention domains were classified using the TDF. RESULTS: The majority of interventions did not cite a guiding theoretical framework or cited multiple theories with overlapping domains. The TDF was a reliable categorization system and suggested that pediatric adherence-promotion interventions most commonly target knowledge, skills, and social influences. CONCLUSIONS: Pediatric adherence-promotion interventions draw from a variety of theories and lack a consistent language for describing targeted domains. The adapted TDF proposed here is one method of reducing variability in intervention development and reporting and may facilitate efforts to identify the processes that improve adherence. PMID- 25817882 TI - Changes in hippocampal orexin 1 receptor expression involved in tooth pain induced learning and memory impairment in rats. AB - Orexin 1 receptor signaling plays a significant role in pain as well as learning and memory processes. This study was conducted to assess the changes in orexin 1 receptor expression levels in hippocampus following learning and memory impairment induced by tooth inflammatory pulpal pain. Adult male Wistar rats received intradental injection of 100 ug capsaicin to induce pulpal pain. After recording the pain scores, spatial learning and memory were assessed using Morris Water Maze test. The hippocampal levels of orexin 1 receptor mRNA and protein were determined by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting respectively. The data showed that capsaicin induced tooth inflammatory pulpal pain was correlated with learning and memory impairment. Intra-hippocampal injection of orexin A inhibited pain-induced learning and memory impairment. However, orexin 1 receptor antagonist, SB-334867, had no effect on learning and memory impairment. Moreover, capsaicin-induced pain significantly decreased hippocampal orexin 1 receptor mRNA and protein levels. Meanwhile, reversed changes took place in the ibuprofen-pretreated group (p < 0.05). It seems that decrease in orexin 1 receptor density and signaling could be involved in tooth pain-induced learning and memory impairment. PMID- 25817883 TI - Accuracy and patient-centered outcome variables in guided implant surgery: a RCT comparing immediate with delayed loading. AB - AIM: To assess the accuracy and patient-centered outcome of a novel guided surgery system for placing implants in an edentulous maxilla. MATERIAL AND METHODS: Fifteen consecutive patients with sufficient bone to place six implants in the maxilla were randomly assigned to the immediate loading (with delivery of the final prosthesis within 24 h) or the delayed loading treatment group. Accuracy was assessed by matching the planning CT with a postoperative CBCT. Patient-centered outcome measures were the Dutch version of the McGill Pain Questionnaire (MPQ-DLV), the health-related quality of life instrument (HRQOL), visual analog scales (VAS), the duration of the procedure, and the analgesic doses taken each day. RESULTS: A mean deviation was found at the entry point of 0.9 mm (range: 0.1-4.5, median 0.8) and of 1.2 mm (range: 0.2-4.9, median 1.1) at the apex, and an angular deviation of 2.7 degrees (range: 0.0-6.6 degrees , median 2.3) was observed. The mean vertical deviation was 0.5 mm (range: 0.0-3.2, median 0.4), and in a horizontal direction, this was 0.7 mm (range: 0.1-3.1, median 0.6). The mean deviation in mesio-distal direction was 0.5 mm (range: 0.0 2.3, median 0.4) and in bucco-lingual direction 0.5 mm +/- 0.4 (range: 0.0-2.2, median 0.3). No statistical differences could be shown between treatment groups on pain response (MPQ-DLV), treatment perception (VAS), number or kind of pain killers, or for the HRQOLI instrument. CONCLUSION: The accuracy of a novel CT based guide is comparable to the accuracy data of other systems. Within the limitations of this study, no difference could be found in patient-centered outcome variables after immediate or delayed loading. PMID- 25817884 TI - Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. AB - STUDY OBJECTIVE: We assess and compare the analgesic efficacy and safety of subdissociative intravenous-dose ketamine with morphine in emergency department (ED) patients. METHODS: This was a prospective, randomized, double-blind trial evaluating ED patients aged 18 to 55 years and experiencing moderate to severe acute abdominal, flank, or musculoskeletal pain, defined as a numeric rating scale score greater than or equal to 5. Patients were randomized to receive ketamine at 0.3 mg/kg or morphine at 0.1 mg/kg by intravenous push during 3 to 5 minutes. Evaluations occurred at 15, 30, 60, 90, and 120 minutes. Primary outcome was reduction in pain at 30 minutes. Secondary outcome was the incidence of rescue analgesia at 30 and 60 minutes. RESULTS: Forty-five patients per group were enrolled in the study. The primary change in mean pain scores was not significantly different in the ketamine and morphine groups: 8.6 versus 8.5 at baseline (mean difference 0.1; 95% confidence interval -0.46 to 0.77) and 4.1 versus 3.9 at 30 minutes (mean difference 0.2; 95% confidence interval -1.19 to 1.46; P=.97). There was no difference in the incidence of rescue fentanyl analgesia at 30 or 60 minutes. No statistically significant or clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. Patients in the ketamine group reported increased minor adverse effects at 15 minutes post-drug administration. CONCLUSION: Subdissociative intravenous ketamine administered at 0.3 mg/kg provides analgesic effectiveness and apparent safety comparable to that of intravenous morphine for short-term treatment of acute pain in the ED. PMID- 25817885 TI - ANO1 taking center stage: blood pressure regulation in SHRs. PMID- 25817886 TI - Screening breeding sites of the common toad (Bufo bufo) in England and Wales for evidence of endocrine disrupting activity. AB - Anuran amphibians are often present in agricultural landscapes and may therefore be exposed to chemicals in surface waters used for breeding. We used passive accumulation devices (SPMD and POCIS) to sample contaminants from nine breeding sites of the Common toad (Bufo bufo) across England and Wales, measuring endocrine activity of the extracts in a recombinant yeast androgen screen (YAS) and yeast estrogen screen (YES) and an in vitro vitellogenin induction screen in primary culture of Xenopus laevis hepatocytes. We also assessed hatching, growth, survival, and development in caged larvae in situ, and sampled metamorphs for gonadal histopathology. None of the SPMD extracts exhibited estrogen receptor or androgen receptor agonist activity, while POCIS extracts from two sites in west central England exhibited concentration-dependent androgenic activity in the YAS. Three sites exhibited significant estrogenic activity in both the YES and the Xenopus hepatocyte. Hatching rates varied widely among sites, but there was no consistent correlation between hatching rate and intensity of agricultural activity, predicted concentrations of agrochemicals, or endocrine activity measured in YES/YAS assays. While a small number of intersex individuals were observed, their incidence could not be associated with predicted pesticide exposure or endocrine activitity measured in the in vitro screens. There were no significant differences in sex ratio, as determined by gonadal histomorphology among the study sites, and no significant correlation was observed between proportion of males and predicted exposure to agrochemicals. However, a negative correlation did become apparent in later sampling periods between proportion of males and estrogenic activity of the POCIS sample, as measured in the YES. Our results suggest that larval and adult amphibians may be exposed to endocrine disrupting chemicals in breeding ponds, albeit at low concentrations, and that chemical contaminants other than plant protection products may contribute to endocrine activity of surface waters in the agricultural landscape. PMID- 25817887 TI - Left Ventricular Retraining and Late Arterial Switch for D-Transposition of the Great Arteries. AB - BACKGROUND: For many decades, patients with d-transposition of the great arteries underwent an atrial switch procedure. Although many of these patients have continued to do well, a subset experience profound right ventricular failure. Some may be candidates for left ventricular (LV) retraining and late arterial switch. The purpose of this study was to review our experience with LV retraining and late arterial switch. METHODS: This was a retrospective review of 32 patients with d-transposition. Thirty patients underwent a previous atrial switch and subsequently experienced right ventricular failure, whereas 2 presented late (8 months and 6 years) without previous intervention. The median age at the time of enrollment in this program was 15 years. Seven patients proceeded directly to late arterial switch owing to systemic LV pressures. The remaining 25 underwent a pulmonary artery band for LV retraining. RESULTS: Twenty of the 32 (63%) patients enrolled in this program were able to undergo a late arterial switch. There were 2 operative mortalities (10%). Two additional patients survived surgery but died in the early outpatient time period. There has been no late mortality after the arterial switch with a median follow-up of 5 years. Twelve patients underwent one or more pulmonary artery band procedures without evidence of effective LV retraining. There have been 2 early and 3 late (42%) deaths in this subgroup. CONCLUSIONS: The outcomes after arterial switch are encouraging and suggest that LV retraining and late arterial switch provide a viable option for this complex group of patients. PMID- 25817888 TI - SCAI/AATS/ACC/STS Operator and Institutional Requirements for Transcatheter Valve Repair and Replacement, Part III: Pulmonic Valve. PMID- 25817889 TI - Antioxidants and NOS inhibitors selectively targets manganese-induced cell volume via Na-K-Cl cotransporter-1 in astrocytes. AB - Manganese has shown to be involved in astrocyte swelling. Several factors such as transporters, exchangers and ion channels are attributed to astrocyte swelling as a result in the deregulation of cell volume. Products of oxidation and nitration have been implied to be involved in the pathophysiology of swelling; however, the direct link and mechanism of manganese induced astrocyte swelling has not been fully elucidated. In the current study, we used rat primary astrocyte cultures to investigate the activation of Na-K-Cl cotransporter-1 (NKCC1) a downstream mechanism for free radical induced astrocyte swelling as a result of manganese toxicity. Our results showed manganese, oxidants and NO donors as potent inducer of oxidation and nitration of NKCC1. Our results further confirmed that manganese (50 MUM) increased the total protein, phosphorylation and activity of NKCC1 as well as cell volume (p < 0.05 vs. control). NKCC1 inhibitor (bumetanide), NKCC1 siRNA, antioxidants; DMTU, MnTBAP, tempol, catalase and Vit-E, NOS inhibitor; L NAME, peroxinitrite scavenger; uric acid all significantly reversed the effects of NKCC1 activation (p < 0.05). From the current investigation we infer that manganese or oxidants and NO induced activation, oxidation/nitration of NKCC1 play an important role in the astrocyte swelling. PMID- 25817890 TI - Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations--different outcome? AB - We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta. PMID- 25817891 TI - Voltage-gated calcium channels: Determinants of channel function and modulation by inorganic cations. AB - Voltage-gated calcium channels (VGCCs) represent a key link between electrical signals and non-electrical processes, such as contraction, secretion and transcription. Evolved to achieve high rates of Ca(2+)-selective flux, they possess an elaborate mechanism for selection of Ca(2+) over foreign ions. It has been convincingly linked to competitive binding in the pore, but the fundamental question of how this is reconcilable with high rates of Ca(2+) transfer remains unanswered. By virtue of their similarity to Ca(2+), polyvalent cations can interfere with the function of VGCCs and have proven instrumental in probing the mechanisms underlying selective permeation. Recent emergence of crystallographic data on a set of Ca(2+)-selective model channels provides a structural framework for permeation in VGCCs, and warrants a reconsideration of their diverse modulation by polyvalent cations, which can be roughly separated into three general mechanisms: (I) long-range interactions with charged regions on the surface, affecting the local potential sensed by the channel or influencing voltage-sensor movement by repulsive forces (electrostatic effects), (II) short range interactions with sites in the ion-conducting pathway, leading to physical obstruction of the channel (pore block), and in some cases (III) short-range interactions with extracellular binding sites, leading to non-electrostatic modifications of channel gating (allosteric effects). These effects, together with the underlying molecular modifications, provide valuable insights into the function of VGCCs, and have important physiological and pathophysiological implications. Allosteric suppression of some of the pore-forming Cavalpha1 subunits (Cav2.3, Cav3.2) by Zn(2+) and Cu(2+) may play a major role for the regulation of excitability by endogenous transition metal ions. The fact that these ions can often traverse VGCCs can contribute to the detrimental intracellular accumulation of metal ions following excessive release of endogenous Cu(2+) and Zn(2+) or exposure to non-physiological toxic metal ions. PMID- 25817892 TI - Proteasome activity is important for replication recovery, CHK1 phosphorylation and prevention of G2 arrest after low-dose formaldehyde. AB - Formaldehyde (FA) is a human carcinogen with numerous sources of environmental and occupational exposures. This reactive aldehyde is also produced endogenously during metabolism of drugs and other processes. DNA-protein crosslinks (DPCs) are considered to be the main genotoxic lesions for FA. Accumulating evidence suggests that DPC repair in high eukaryotes involves proteolysis of crosslinked proteins. Here, we examined a role of the main cellular proteolytic machinery proteasomes in toxic responses of human lung cells to low FA doses. We found that transient inhibition of proteasome activity increased cytotoxicity and diminished clonogenic viability of FA-treated cells. Proteasome inactivation exacerbated suppressive effects of FA on DNA replication and increased the levels of the genotoxic stress marker gamma-H2AX in normal human cells. A transient loss of proteasome activity in FA-exposed cells also caused delayed perturbations of cell cycle, which included G2 arrest and a depletion of S-phase populations at FA doses that had no effects in control cells. Proteasome activity diminished p53 Ser15 phosphorylation but was important for FA-induced CHK1 phosphorylation, which is a biochemical marker of DPC proteolysis in replicating cells. Unlike FA, proteasome inhibition had no effect on cell survival and CHK1 phosphorylation by the non-DPC replication stressor hydroxyurea. Overall, we obtained evidence for the importance of proteasomes in protection of human cells against biologically relevant doses of FA. Biochemically, our findings indicate the involvement of proteasomes in proteolytic repair of DPC, which removes replication blockage by these highly bulky lesions. PMID- 25817893 TI - Genotoxic effect of ethacrynic acid and impact of antioxidants. AB - It is known that ethacrynic acid (EA) decreases the intracellular levels of glutathione. Whether the anticipated oxidative stress affects the structural integrity of DNA is unknown. Therefore, DNA damage was assessed in EA-treated HCT116 cells, and the impact of several antioxidants was also determined. EA caused both concentration-dependent and time-dependent DNA damage that eventually resulted in cell death. Unexpectedly, the DNA damage caused by EA was intensified by either ascorbic acid or trolox. In contrast, EA-induced DNA damage was reduced by N-acetylcysteine and by the iron chelator, deferoxamine. In elucidating the DNA damage, it was determined that EA increased the production of reactive oxygen species, which was inhibited by N-acetylcysteine and deferoxamine but not by ascorbic acid and trolox. Also, EA decreased glutathione levels, which were inhibited by N-acetylcysteine. But, ascorbic acid, trolox, and deferoxamine neither inhibited nor enhanced the capacity of EA to decrease glutathione. Interestingly, the glutathione synthesis inhibitor, buthionine sulfoxime, lowered glutathione to a similar degree as EA, but no noticeable DNA damage was found. Nevertheless, buthionine sulfoxime potentiated the glutathione-lowering effect of EA and intensified the DNA damage caused by EA. Additionally, in examining redox sensitive stress gene expression, it was found that EA increased HO-1, GADD153, and p21mRNA expression, in association with increased nuclear localization of Nrf 2 and p53 proteins. In contrast to ascorbic acid, trolox, and deferoxamine, N acetylcysteine suppressed the EA-induced upregulation of GADD153, although not of HO-1. Overall, it is concluded that EA has genotoxic properties that can be amplified by certain antioxidants. PMID- 25817894 TI - Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone. AB - Mephedrone is a new designer drug of abuse. We have investigated the neurochemical/enzymatic changes after mephedrone administration to adolescent rats (3*25 mg/kg, s.c. in a day, with a 2 h interval between doses, for two days) at high ambient temperature (26+/-2 degrees C), a schedule that intends to model human recreational abuse. In addition, we have studied the effect of mephedrone in spatial learning and memory. The drug caused a transient decrease in weight gain. After the first dose, animals showed hypothermia but, after the subsequent doses, temperature raised over the values of saline-treated group. We observed the development of tolerance to these thermoregulatory effects of mephedrone. Mephedrone induced a reduction of the densities of dopamine (30% in the frontal cortex) and serotonin (40% in the frontal cortex and the hippocampus and 48% in the striatum) transporters without microgliosis. These deficits were also accompanied by a parallel decrease in the expression of tyrosine hydroxylase and tryptophan hydroxylase 2. These changes matched with a down-regulation of D2 dopamine receptors in the striatum. Mephedrone also induced an oxidative stress evidenced by an increase of lipid peroxidation in the frontal cortex, and accompanied by a rise in glutathione peroxidase levels in all studied brain areas. Drug-treated animals displayed an impairment of the reference memory in the Morris water maze one week beyond the cessation of drug exposure, while the spatial learning process seems to be preserved. These findings raise concerns about the neuronal long-term effects of mephedrone. PMID- 25817895 TI - Percutaneous endoscopic debridement and washout of a bilateral, loculated, hepatic abscess: a minimally invasive approach to a high-risk surgical situation. PMID- 25817896 TI - Adenoma detection rate varies greatly during colonoscopy training. AB - BACKGROUND: The adenoma detection rate (ADR) is considered the most important quality indicator for colonoscopy and varies widely among colonoscopists. It is unknown whether the ADR of gastroenterology consultants can already be predicted during their colonoscopy training. OBJECTIVE: To evaluate the ADR of fellows in gastroenterology and evaluate whether this predicts their ADR as gastroenterology consultants. DESIGN: Retrospective observational study. SETTING: Academic and regional centers. PATIENTS: Symptomatic patients undergoing colonoscopy. MAIN OUTCOME MEASUREMENTS: The variance in ADR among 7 gastroenterology fellows during their training (between May 2004 and March 2012) and of the same fellows after they registered as consultants (between October 2011 and April 2014) was evaluated. Multivariate logistic regression was performed to compare the highest detector (endoscopist with highest ADR) with the individual fellows and to evaluate whether an ADR of 20% or higher during the training was predictive of a high ADR as a consultant. RESULTS: During training, ADRs ranged from 14% to 36% (P < .001). Compared with the highest detector, the OR for detecting an adenoma ranged from 0.64 (95% CI, 0.40-1.03) to 0.29 (95% CI, 0.17-0.48). After registration, ADR ranged from 19.8% to 40.2% (P = .066). Compared with the highest detector during consultancy, the OR ranged from 0.64 (95% CI, 0.34-1.21) to 0.26 (95% CI, 0.13-0.52). Only 2 fellows significantly improved their ADR after completing their training. An ADR lower than 20% during training was associated with a lower ADR as a consultant (OR 0.51; 95% CI, 0.30-0.87). LIMITATIONS: Retrospective study. CONCLUSIONS: Variance in ADR is already present during the endoscopy training of gastroenterology fellows. Most fellows do not improve their ADR after completing their training. These findings suggest that the ADR can be predicted during colonoscopy training, and we suggest that feedback and benchmarking should be implemented early during training of fellows in an effort to improve ADR in future daily practice as a consultant. PMID- 25817897 TI - Recurrent intestinal metaplasia after radiofrequency ablation for Barrett's esophagus: endoscopic findings and anatomic location. AB - BACKGROUND: Radiofrequency ablation (RFA) is a safe and effective treatment for Barrett's esophagus (BE) that results in high rates of complete eradication of intestinal metaplasia (CEIM). However, recurrence is common after CEIM, and surveillance endoscopy is recommended. Neither the anatomic location nor the endoscopic appearance of these recurrences is well-described. OBJECTIVE: Describe the location of histologic specimens positive for recurrence after CEIM and the testing performance of endoscopic findings for the histopathologic detection of recurrence. DESIGN: Retrospective cohort. SETTING: Single referral center. PATIENTS: A total of 198 patients with BE with at least 2 surveillance endoscopies after CEIM. INTERVENTIONS: RFA, EMR, surveillance endoscopy. MAIN OUTCOME MEASUREMENTS: The anatomic location and histologic grade of recurrence. RESULTS: In a mean 3.0 years of follow-up, 32 (16.2%; 95% confidence interval [CI], 11.0%-22.0%) patients had recurrence of disease, 5 (2.5%; 95% CI, 0.3% 4.7%) of whom progressed beyond their worst before-treatment histology. Recurrence was most common at or near the gastroesophageal junction (GEJ). Recurrence>1 cm proximal to the GEJ always was accompanied by endoscopic findings, and random biopsies in these areas detected no additional cases. The sensitivity of any esophageal sign under high-definition white light or narrow band imaging for recurrence was 59.4% (42.4%, 76.4%), and the specificity was 80.6% (77.2%, 84.0%). LIMITATIONS: Single-center study. CONCLUSION: Recurrent intestinal metaplasia often is not visible to the endoscopist and is most common near the GEJ. Random biopsies>1 cm above the GEJ had no yield for recurrence. In addition to biopsy of prior EMR sites and of suspicious lesions, random biopsies oversampling the GEJ are recommended. PMID- 25817899 TI - Nano-sized Mn3O4 and beta-MnOOH from the decomposition of beta-cyclodextrin-Mn: 1. Synthesis and characterization. AB - Nano-sized Mn oxides contain Mn3O4 and beta-MnOOH have been prepared by a simple and high-yield method using beta-cyclodextrin as a ligand for Mn ions, and decomposition of this Mn complex. Scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy and X-ray diffraction spectroscopy have been used to characterize morphologies and the phases of these prepared nano-sized Mn oxides. PMID- 25817898 TI - Steap4 attenuates high glucose and S100B-induced effects in mesangial cells. AB - Six-transmembrane epithelial antigen of prostate 4 (Steap4)-knockout mice develop hyperglycaemia and inflammation whereas Steap4 overexpression attenuates atherosclerosis in diabetic mice. Thus, we studied the roles of Steap4 in high glucose (HG, 27.5 mM) or S100B (1 MUM, a ligand for the receptor for advanced glycation end-product or RAGE)-induced effects in mouse mesangial (MES13) cells. We found that HG-induced Steap4 protein expression was dependent on S100B. HG increased cell membrane, but not cytosolic, Steap4 protein expression. HG increased protein-protein interaction between Steap4 and S100B, which was confirmed by mass spectrometry of immunoprecipitated S100B. SP600125, LY294002 and AG490 attenuated S100B-induced Steap4 protein expression or gene transcriptional activity. A mutation in signal transducer and activator of transcription 3 (Stat3) site 2 of the Steap4 promoter constructs resulted in a marked decrease in HG or S100B-induced activation of Steap4 gene transcription. Overexpression of Steap4 attenuates HG or S100B-induced collagen IV, fibronectin and cyclooxygenase 2 protein expression. Overexpression of Steap4 attenuates HG or S100B-induced transforming growth factor-beta (TGF-beta). Moreover, overexpression of Steap4 attenuates S100B-induced signalling. Finally, overexpressing Steap4 attenuated renal expression of fibronectin, S100B, TGF beta, type IV collagen, p-Akt, p-extracellular signal regulated kinase 1/2 and p Stat3 in streptozotocin-diabetic mice. Thus, overexpression of Steap4 attenuated HG or S100B-induced effects in MES13 cells and attenuated some of S100B-induced effects in diabetic mouse kidneys. PMID- 25817900 TI - Genetic counseling for a three-generation Chinese family with Waardenburg syndrome type II associated with a rare SOX10 mutation. AB - OBJECTIVE: Waardenburg syndrome is clinically and genetically heterogeneous. The SOX10 mutation related with Waardenburg syndrome type II is rare in Chinese. This study aimed to uncover the genetic causes of Waardenburg syndrome type II in a three-generation family to improve genetic counseling. METHODS: Complete clinical and molecular evaluations were conducted in a three-generation Han Chinese family with Waardenburg syndrome type II. Targeted genetic counseling was provided to this family. RESULTS: We identified a rare heterozygous dominant mutation c.621C>A (p.Y207X) in SOX10 gene in this family. The premature termination codon occurs in exon 4, 27 residues downstream of the carboxyl end of the high mobility group box. Bioinformatics prediction suggested this variant to be disease causing, probably due to nonsense-mediated mRNA decay. Useful genetic counseling was given to the family for prenatal guidance. CONCLUSION: Identification of a rare dominant heterozygous SOX10 mutation c.621C>A in this family provided an efficient way to understand the causes of Waardenburg syndrome type II and improved genetic counseling. PMID- 25817901 TI - Arterial flow waveforms, vascular tone, and chronic fatigue: a case report. AB - We present the case of a patient with chronic fatigue secondary to Postural Orthostatic Tachycardia Syndrome (POTS) who had distinctive abnormalities in his arterial waveform morphology as assessed by pulse oximetry. Moreover, the patient's arterial waveform changed markedly from being supine to upright, suggesting that arterial flow patterns may be abnormal in our patient. Analysis of the waveform suggested a positional hypovolemia as the cause of his orthostatic intolerance. We review general aspects of arterial flow waveform analysis pertinent to health care providers and discuss the pathophysiology of POTS. PMID- 25817902 TI - Volume of carotid bodies and cardiac autonomic function in patients with essential hypertension. AB - PURPOSE: Determination of the relationship between the estimated total volume of the carotid bodies (VrCB+lCB), assessed by computed tomography angiography (CTA), and the autonomic cardiac function in patients with essential hypertension (EH). MATERIALS AND METHODS: The study included 69 patients with diagnosed and pharmacologically treated EH. The estimated volume of each carotid body (CB) was evaluated on the basis of scans obtained in the CTA of carotid arteries, using the following formula: 4/3*pi*half of transverse dimension of CB in axial projection*half of longitudinal dimension of CB in the axial projection*half of craniocaudal dimension of CB in the sagittal/coronal projection. Cardiac autonomic function was assessed using time domain analysis of heart rate variability (HRV). RESULTS: The mean values of SDNNi, rMSSD and pNN50 at 24-h monitoring, during daily activity and during night rest, were significantly lower in patients with hypertension with the values of VrCB+lCB>=median compared to the group of hypertensive patients with the values of VrCB+lCB=median, the mean values of SDNN were lower during daily activity. Based on the regression analysis, it was found out that the higher values of VrCB+lCB are an independent risk factor in HRV reduction (expressed as a reduction in the rMSSD). CONCLUSION: In patients with EH, a relationship between the volume of CB, assessed by CTA of carotid arteries, and autonomic cardiac function seems to be probable. PMID- 25817903 TI - Treatment of type B periprosthetic femur fractures with curved non-locking plate with eccentric holes: Retrospective study of 43 patients with minimum 1-year follow-up. AB - INTRODUCTION: Periprosthetic femur fracture (PFF) is a serious complication after total hip arthroplasty that can be treated using different internal fixation devices. However, the outcomes with curved non-locking plates with eccentric holes in this indication have not been reported previously. The objectives of this study were to determine: (1) the union rate; (2) the complication rate; (3) autonomy in a group of patients with a Vancouver type B PFF who were treated with this plate. HYPOTHESIS: Use of this plate results in a high union rate with minimal mechanical complications. MATERIALS AND METHODS: Forty-three patients with a mean age of 79 years +/- 13 (41-98) who had undergone fixation of Vancouver type B PFF with this plate between 2002 and 2007 were included in the study. The time to union and Parker Mobility Score were evaluated. The revision free survival (all causes) was calculated using Kaplan-Meier analysis. The average follow-up was 42 months +/- 20 (16-90). RESULTS: Union was obtained in all patients in a mean of 2.4 months +/- 0.6 (2-4). One patient had varus malunion of the femur. The Parker Mobility Score decreased from 5.93 +/- 1.94 (2 9) to 4.93 +/- 1.8 (1-9) (P = 0.01). Two patients required a surgical revision: one for an infection after 4.5 years and one for stem loosening. The survival of the femoral stem 5 years after fracture fixation was 83.3% +/- 12.6%. CONCLUSION: Use of a curved plate with eccentric holes for treating type B PFF led to a high union rate and a low number of fixation-related complications. However, PFF remains a serious complication of hip arthroplasty that is accompanied by high morbidity and mortality rates. PMID- 25817904 TI - Degenerative facet joint changes in lumbar percutaneous pedicle screw fixation without fusion. AB - BACKGROUND: Aim of the study was to evaluate degenerative lumbar facet-joints changes after percutaneous pedicle screw fixation (PPSF) in the treatment of lumbar fractures. MATERIALS AND METHODS: Thirty patients underwent short PPSF without fusion. CT-scan was performed in the pre- and post-operative time at four, eight and 12 months. The six zygapophyseal joints adjacent the fracture's level were evaluated. RESULTS: At four months patients showed no differences between pre- and post-operative joint radiographic aspect. At eight and 12 months, CT-scan demonstrated a progressive degeneration only in the middle joints respectively in 21.42% and in 76.92% of the cases. All 10 disrupted facet joints showed progressive degenerative changes at eight and 12 months. CONCLUSION: Lumbar percutaneous fixation without fusion induces little degenerations essentially collocated in the middle joints close to fracture level at eight and 12 months. In the proximal and distal joints adjacent the screws degenerative changes can be seen only when associated to pedicle-screw encroachment. PMID- 25817905 TI - Interest of including trauma photography in the picture archiving and communication system of a teaching hospital. AB - Digital imaging is a daily practice in traumatology. Such photographs should remain confidential. However, there is a need for objectivity concerning the circumstances and clinical follow-up for trauma patients. This paper describes how to conserve these photographs within the picture archiving and communication system (PACS) safely as regards identity and confidentiality. A computer converts the photographs into DICOM files. The DICOM image is associated to a reconciliation layer, validated by the physician in charge, and then included in the hospital PACS. This improves transmission from one medical team to another, both initially and after the accident if an expert medical opinion is required. The literature has demonstrated the value of photographs in modern medicine, but the technical and legal challenges are many. They enhance the computerized medical records. Identification, confidentiality and integration in the PACS are obstacles that we have now overcome. PMID- 25817906 TI - Bilateral internal hemipelvectomy for osteosarcoma in a pediatric patient previously treated for rhabdomyosarcoma. AB - The surgical treatment of malignant bone tumors involving the pelvis represents a great challenge in terms of local control. Internal hemipelvectomy is a major surgical procedure that involves the resection of the entire hemipelvis or of a portion of the hemipelvis with preservation of the ipsilateral extremity. The need for a bilateral internal hemipelvectomy is an extraordinary situation. We describe the case of an 11-year-old girl with a primary diagnosis of rhabdomyosarcoma of the bladder at the age of two years who subsequently developed a right pelvis osteosarcoma at the age of six years and a left pelvis osteosarcoma at the age of nine years. She ultimately underwent sequential bilateral internal hemipelvectomies and she postoperatively ambulates without an assist device. PMID- 25817907 TI - The influence of obesity on primary total hip arthroplasty outcomes: A meta analysis of prospective cohort studies. AB - BACKGROUND: Whether or not, obesity negatively influencing the outcomes of primary total hip arthroplasty (THA) remains a controversial issue. Though observational studies focused on this topic, the reported conclusions remain inconsistent. Therefore, we performed a meta-analysis of prospective cohort studies to evaluate if obesity negatively affects: (1) the overall complication rate (incidence of dislocation, deep infection and osteolysis); (2) functional outcome; (3) operative time and stay duration in hospital for the primary THA. METHODS: We searched the PubMed, Embase, Web of Science, and the Cochrane Library until July 2014 to identify the eligible prospective studies. The Newcastle Ottawa Scale (NOS) was used for quality assessment of the included studies. We extracted and pooled the data. As for continuous data, mean difference (MD) was calculated; for dichotomous variables, we calculated a weighted relative risk (RR) with its 95% confidence interval. Heterogeneity was evaluated using I(2) statistics. P <= 0.05 was thought to be significant. RESULTS: Fifteen studies were eligible for data extraction, which involved 11,271 total hip arthroplasties. The pooled data of complication rate demonstrated that obese patients suffered higher rates of complication (RR: 1.68, 95% CI 1.23 to 2.30, P = 0.0004), dislocation (RR: 2.08, 95% CI 1.54 to 2.81, P < 0.0001) and deep infection (RR: 2.92, 95% CI 0.74 to 11.49, P = 0.13). For the functional result, obese patients acquired relatively lower Harris Hip Score than non-obese patients (MD: -2.75, 95% CI -4.77 to -0.6), no difference was found regarding Oxford Hip Score (MD: -0.46, 95% CI -2.18 to 1.26, P = 0.60). Obese patients compared to non obese patients showed an increase duration of operation (MD: 10.67, 95% CI 3.00 to 18.35, P = 0.006). However, no significant difference was found in the length of stay in hospital between obese and non-obese patients (MD: -0.16, 95% CI -0.34 to 0.02, P = 0.08). CONCLUSIONS: This meta-analysis of prospective cohort studies demonstrates that obesity negatively influences the overall complication rate, dislocation rate, functional outcome and operative time of primary total hip arthroplasty. PMID- 25817908 TI - Return to sports after autogenous osteochondral mosaicplasty of the femoral condyles: 25 cases at a mean follow-up of 9 years. AB - INTRODUCTION: Autogenous osteochondral mosaicplasty is the most common cartilage restoration technique in standard clinical practice. The purpose of this study was to evaluate the return to sports 9 years after mosaicplasty of the femoral condyles. HYPOTHESIS: The long-term results of an osteochondral autograft show that patients can regain their pre-injury activity level. MATERIAL AND METHODS: This study is based on a series of 25 patients with a mean age of 28.9 years (range, 16-44 years) who had stage 3 or 4 chondral lesions of the femoral condyles (according to the ICRS or ICRS-OCD scores). The origin of the lesion was osteochondritis dissecans (13 knees), osteochondral fracture sequelae (ten knees), or aseptic osteonecrosis (two knees). The average size of the lesion was 2.11 +/- 0.9 cm(2). Ten patients (40%) had an associated procedure during the osteochondral autograft. The patients were assessed clinically (IKDC and Lysholm Tegner scores) and radiographically by a reviewer independent of the team of operators. RESULTS: All patients were re-examined at a mean follow-up of 9 years (range, 6-15 years), with 84% satisfied or very satisfied with the procedure. The average IKDC was 74.5 +/- 18.5 points. The average Lysholm score was 87.3 +/- 11.6 points. The average Tegner score ranged from 6.35 +/- 1.53 points prior to surgery to 5.60 +/- 1.64 points after surgery (P = 0.001). The average loss was 0.64 points for patients whose presurgery Tegner score was greater than or equal to 7 (P = 0.019) and 0.3 points if lower than 7. The radiologic evaluation of 21 patients showed complete osteointegration of the grafts in 90% of cases. CONCLUSION: The results of the femoral condyle mosaic autografts are satisfactory, a mean of 9 years after surgery. The most active patients lowered their activity level while the more sedentary did not have to adapt their lifestyle. PMID- 25817909 TI - Can the simple clinical score usefully predict the mortality risk and length of stay for a recently admitted patient? AB - OBJECTIVES: The aim of the present study was to determine whether an aggregate simple clinical score (SCS) has a role in predicting the imminent mortality and in-hospital length of stay (LOS) of newly admitted, acutely unwell General Medical in-patients. METHODS: Data were collected prospectively from adult patients admitted through an Acute Medical Unit between February and August 2013. Using logistic regression analysis before and after adjustment for age, the SCS was assessed for its association with LOS and mortality, including 30-day mortality, just for those patients for full resuscitation. Changes in sensitivity and specificity after adding SCS to age as a predictor, as well as the change in the net reclassification index, were determined using the predicted probabilities from the logistic regression models. RESULTS: The SCS was superior to age in predicting mortality of any patient within 30 days. It did not assist in predicting 30-day mortality for those patients who were for full resuscitation. The ability of the SCS to predict long stay (> 72h) remained relatively low (64%) and was inferior to published rates achieved by bedside clinician assessment (74% 82%). CONCLUSION: There was no useful prospective role for the SCS in predicting LOS and mortality of in-patients newly admitted to a General Medicine service. PMID- 25817910 TI - Molecular basis of the inhibition of the fast inactivation of voltage-gated sodium channel Nav1.5 by tarantula toxin Jingzhaotoxin-II. AB - Jingzhaotoxin-II (JZTX-II) is a 32-residue peptide from the Chinese tarantula Chilobrachys jingzhao venom, and preferentially inhibits the fast inactivation of the voltage-gated sodium channels (VGSCs) in rat cardiac myocytes. In the present study, we elucidated the action mechanism of JZTX-II inhibiting hNav1.5, a VGSC subtype mainly distributed in human cardiac myocytes. Among the four VGSC subtypes tested, hNav1.5 was the most sensitive to JZTX-II (EC50=125+/-4nM). Although JZTX-II had little or no effect on steady-state inactivation of the residual currents conducted by hNav1.5, it caused a 10mV hyperpolarized shift of activation. Moreover, JZTX-II increased the recovery rate of hNav1.5 channels, which should lead to a shorter transition from the inactivation to closed state. JZTX-II dissociated from toxin-channel complex via extreme depolarization and subsequently rebound to the channel upon repolarization. Mutagenesis analyses showed that the domain IV (DIV) voltage-sensor domain (VSD) was critical for JZTX II binding to hNav1.5 and some mutations located in S1-S2 and S3-S4 extracellular loops of hNav1.5 DIV additively reduced the toxin sensitivity of hNav1.5. Our data identified the mechanism underlying JZTX-II inhibiting hNav1.5, similar to scorpion alpha-toxins, involving binding to neurotoxin receptor site 3. PMID- 25817911 TI - An extraordinary relationship involving MIF-1 and other peptides. AB - In commemoration of Abba J. Kastin's exceptional service as the founding editor for the international journal Peptides, I review our collaborative work on how neuropeptides are involved in depression and other neuropsychiatric behavior. A special focus is on MIF-1 (prolyl-leucyl-glycinamide) that was discovered in the Kastin laboratory and shown effective to treat human depression with greater efficacy and faster onset of action than traditional antidepressants at the time of clinical trial. My personal reflection of the evolving changes of translational research on neuropeptides will hopefully provide some insight to young investigators. PMID- 25817912 TI - Serial 3D imaging mass spectrometry at its tipping point. AB - Since biology is by and large a 3-dimensional phenomenon, it is hardly surprising that 3D imaging has had a significant impact on many challenges in the life sciences. Imaging mass spectrometry (MS) is a spatially resolved label-free analytical technique that recently maturated into a powerful tool for in situ localization of hundreds of molecular species. Serial 3D imaging MS reconstructs 3D molecular images from serial sections imaged with mass spectrometry. As such, it provides a novel 3D imaging modality inheriting the advantages of imaging MS. Serial 3D imaging MS has been steadily developing over the past decade, and many of the technical challenges have been met. Essential tools and protocols were developed, in particular to improve the reproducibility of sample preparation, speed up data acquisition, and enable computationally intensive analysis of the big data generated. As a result, experimental data is starting to emerge that takes advantage of the extra spatial dimension that 3D imaging MS offers. Most studies still focus on method development rather than on exploring specific biological problems. The future success of 3D imaging MS requires it to find its own niche alongside existing 3D imaging modalities through finding applications that benefit from 3D imaging and at the same time utilize the unique chemical sensitivity of imaging mass spectrometry. This perspective critically reviews the challenges encountered during the development of serial-sectioning 3D imaging MS and discusses the steps needed to tip it from being an academic curiosity into a tool of choice for answering biological and medical questions. PMID- 25817913 TI - "ORIF" for displaced intra-articular calcaneal fractures in children. AB - BACKGROUND: Calcaneal fractures in children are rare injuries, and those with displaced intra-articular fracture patterns are found even less frequently. Recent data in the adult literature have suggested operative treatment of displaced intra-articular calcaneal fractures leads to a more favorable outcome. OBJECTIVE: The aim of this study is to analyze the outcomes of displaced intra articular calcaneal fractures in children treated by open reduction and internal fixation. METHODS: Ten displaced intra-articular calcaneal fractures in 10 patients were treated by open reduction and internal fixation. Mean age was 10.2 (6-12 years). According to Sanders' classification, there were 8 patients who had Sanders' Type II fractures, and 2 children sustained Type III fracture. All patients were followed up with a mean 20.3 months (range 6-30). Clinical score according to the (AOFAS) was 95.8 (range 78-100). CONCLUSION: The characteristics of intra-articular calcaneal fractures in children are similar to those in adults and, from our experience, operative treatment of these fractures, to restore calcaneal anatomical alignment yields good short-term results. PMID- 25817914 TI - Microbial and sponge loops modify fish production in phase-shifting coral reefs. AB - Shifts from coral to algae dominance of corals reefs have been correlated to fish biomass loss and increased microbial metabolism. Here we investigated reef benthic and planktonic primary production, benthic dissolved organic carbon (DOC) release and bacterial growth efficiency in the Abrolhos Bank, South Atlantic. Benthic DOC release rates are higher while water column bacterial growth efficiency is lower at impacted reefs. A trophic model based on the benthic and planktonic primary production was able to predict the observed relative fish biomass in healthy reefs. In contrast, in impacted reefs, the observed omnivorous fish biomass is higher, while that of the herbivorous/coralivorous fish is lower than predicted by the primary production-based model. Incorporating recycling of benthic-derived carbon in the model through microbial and sponge loops explains the difference and predicts the relative fish biomass in both reef types. Increased benthic carbon release rates and bacterial carbon metabolism, but decreased bacterial growth efficiency could lead to carbon losses through respiration and account for the uncoupling of benthic and fish production in phase-shifting reefs. Carbon recycling by microbial and sponge loops seems to promote an increase of small-bodied fish productivity in phase-shifting coral reefs. PMID- 25817916 TI - Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade off network meta-analysis. AB - CONTEXT: Erectile dysfunction (ED) is a major health care problem worldwide and phosphodiesterase 5 inhibitors (PDE5Is) are the pharmacological treatment of choice. However, the optimal PDE5I for ED treatment is not known. OBJECTIVE: To investigate trade-offs between efficacy and adverse events for various PDE5Is in treating ED. EVIDENCE ACQUISITION: A review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. Medline, Scopus, reference lists of relevant articles, and systematic reviews were searched. Eligible studies were randomized controlled trials comparing at least one PDE5I for treating ED with placebo or another PDE5I. EVIDENCE SYNTHESIS: We included 82 trials (47 626 patients) for efficacy analysis and 72 trials (20 325 patients) for adverse event analysis. In the trade-off analysis of starting dosages, sildenafil 50mg had the greatest efficacy but also had the highest rate of overall adverse events. Tadalafil 10mg had intermediate efficacy but had the lowest overall rate of all adverse events. Vardenafil 10mg and avanafil 100mg had similar overall adverse events than sildenafil 50mg but a markedly lower global efficacy. Udenafil 100mg had similar global efficacy to that of tadalafil 10mg but its overall adverse event rates were higher. CONCLUSIONS: This is the first trade-off analysis of the different PDE5Is currently available. For individuals who prioritize high efficacy, sildenafil 50mg appears to be the treatment of choice. Men wishing to optimize tolerability should take tadalafil 10mg or switch to udenafil 100mg in the case of insufficient efficacy. PATIENT SUMMARY: For patients with erectile dysfunction who wish to prioritize high efficacy, sildenafil 50mg appears to be the treatment of choice. Men who wish to optimize tolerability should take tadalafil 10mg or switch to udenafil 100mg in the case of insufficient efficacy. PMID- 25817917 TI - Centralization and Quality Control of Elective Surgery Improve Outcome: Aren't We Ethically Obliged to Force the Pace of Creating High-volume Centers? PMID- 25817915 TI - Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. AB - Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2 chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0.02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain. PMID- 25817918 TI - Usability flaws of medication-related alerting functions: A systematic qualitative review. AB - INTRODUCTION: Medication-related alerting functions may include usability flaws that limit their optimal use. A first step on the way to preventing usability flaws is to understand the characteristics of these usability flaws. This systematic qualitative review aims to analyze the type of usability flaws found in medication-related alerting functions. METHOD: Papers were searched via PubMed, Scopus and Ergonomics Abstracts databases, along with references lists. Paper selection, data extraction and data analysis was performed by two to three Human Factors experts. Meaningful semantic units representing instances of usability flaws were the main data extracted. They were analyzed through qualitative methods: categorization following general usability heuristics and through an inductive process for the flaws specific to medication-related alerting functions. MAIN RESULTS: From the 6380 papers initially identified, 26 met all eligibility criteria. The analysis of the papers identified a total of 168 instances of usability flaws that could be classified into 13 categories of usability flaws representing either violations of general usability principles (i.e. they could be found in any system, e.g. guidance and workload issues) or infractions specific to medication-related alerting functions. The latter refer to issues of low signal-to-noise ratio, incomplete content of alerts, transparency, presentation mode and timing, missing alert features, tasks and control distribution. MAIN CONCLUSION: The list of 168 instances of usability flaws of medication-related alerting functions provides a source of knowledge for checking the usability of medication-related alerting functions during their design and evaluation process and ultimately constructs evidence-based usability design principles for these functions. PMID- 25817920 TI - MorphoCol: An ontology-based knowledgebase for the characterisation of clinically significant bacterial colony morphologies. AB - BACKGROUND: One of the major concerns of the biomedical community is the increasing prevalence of antimicrobial resistant microorganisms. Recent findings show that the diversification of colony morphology may be indicative of the expression of virulence factors and increased resistance to antibiotic therapeutics. To transform these findings, and upcoming results, into a valuable clinical decision making tool, colony morphology characterisation should be standardised. Notably, it is important to establish the minimum experimental information necessary to contextualise the environment that originated the colony morphology, and describe the main morphological features associated unambiguously. RESULTS: This paper presents MorphoCol, a new ontology-based tool for the standardised, consistent and machine-interpretable description of the morphology of colonies formed by human pathogenic bacteria. The Colony Morphology Ontology (CMO) is the first controlled vocabulary addressing the specificities of the morphology of clinically significant bacteria, whereas the MorphoCol publicly Web-accessible knowledgebase is an end-user means to search and compare CMO annotated colony morphotypes. Its ultimate aim is to help correlate the morphological alterations manifested by colony-forming bacteria during infection with their response to the antimicrobial treatments administered. CONCLUSIONS: MorphoCol is the first tool to address bacterial colony morphotyping systematically and deliver a free of charge resource to the community. Hopefully, it may introduce interesting features of analysis on pathogenic behaviour and play a significant role in clinical decision making. DATABASE URL: http://morphocol.org. PMID- 25817919 TI - An integrated, ontology-driven approach to constructing observational databases for research. AB - The electronic health record (EHR) contains a diverse set of clinical observations that are captured as part of routine care, but the incomplete, inconsistent, and sometimes incorrect nature of clinical data poses significant impediments for its secondary use in retrospective studies or comparative effectiveness research. In this work, we describe an ontology-driven approach for extracting and analyzing data from the patient record in a longitudinal and continuous manner. We demonstrate how the ontology helps enforce consistent data representation, integrates phenotypes generated through analyses of available clinical data sources, and facilitates subsequent studies to identify clinical predictors for an outcome of interest. Development and evaluation of our approach are described in the context of studying factors that influence intracranial aneurysm (ICA) growth and rupture. We report our experiences in capturing information on 78 individuals with a total of 120 aneurysms. Two example applications related to assessing the relationship between aneurysm size, growth, gene expression modules, and rupture are described. Our work highlights the challenges with respect to data quality, workflow, and analysis of data and its implications toward a learning health system paradigm. PMID- 25817921 TI - Improving diagnostic accuracy using EHR in emergency departments: A simulation based study. AB - It is widely believed that Electronic Health Records (EHR) improve medical decision-making by enabling medical staff to access medical information stored in the system. It remains unclear, however, whether EHR indeed fulfills this claim under the severe time constraints of Emergency Departments (EDs). We assessed whether accessing EHR in an ED actually improves decision-making by clinicians. A simulated ED environment was created at the Israel Center for Medical Simulation (MSR). Four different actors were trained to simulate four specific complaints and behavior and 'consulted' 26 volunteer ED physicians. Each physician treated half of the cases (randomly) with access to EHR, and their medical decisions were compared to those where the physicians had no access to EHR. Comparison of diagnostic accuracy with and without access showed that accessing the EHR led to an increase in the quality of the clinical decisions. Physicians accessing EHR were more highly informed and thus made more accurate decisions. The percentage of correct diagnoses was higher and these physicians were more confident in their diagnoses and made their decisions faster. PMID- 25817922 TI - A computational strategy for altering an enzyme in its cofactor preference to NAD(H) and/or NADP(H). AB - Coenzyme engineering, especially for altered coenzyme specificity, has been a research hotspot for more than a decade. In the present study, a novel computational strategy that enhances the hydrogen-bond interaction between an enzyme and a coenzyme was developed and utilized to alter the coenzyme preference. This novel computational strategy only required the structure of the target enzyme. No other homologous enzymes were needed to achieve alteration in the coenzyme preference of a certain enzyme. Using our novel strategy, Gox2181 was reconstructed from exhibiting complete NADPH preference to exhibiting dual cofactor specificity for NADH and NADPH. Structure-guided Gox2181 mutants were designed in silico and molecular dynamics simulations were performed to evaluate the strength of hydrogen-bond interactions between the enzyme and the coenzyme NADPH. Three Gox2181 mutants displaying high structure stability and structural compatibility to NADH/NADPH were chosen for experimental confirmation. Among the three Gox2181 mutants, Gox2181-Q20R&D43S showed the highest enzymatic activity by utilizing NADPH as its coenzyme, which was even better than the wild-type enzyme. In addition, isothermal titration calorimetry analysis further verified that Gox2181-Q20R&D43S was able to interact with NADPH but the wild-type enzyme could not. This novel computational strategy represents an insightful approach for altering the cofactor preference of target enzymes. PMID- 25817923 TI - Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. AB - STATs can be activated independently of JAKs, most notably by c-Src kinases. In cancer cells, STAT3 and STAT5 activation leads to the increased expression of downstream target genes, leading to increased cell proliferation, cell survival, angiogenesis, and immune system evasion. STAT3 and STAT5 are expressed and activated in head and neck squamous cell carcinoma where they contribute to cell survival and proliferation. STATs can be activated by a number of signal transduction pathways, including the epidermal growth factor receptor (EGFR), nicotinic receptor, interleukin (IL) receptor, and erythropoietin receptor pathways. Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumor progression is a promising strategy for cancer chemoprevention. Several approaches have been used to inhibit STAT3 in the hope of developing an antitumor agent. Although several STAT3-specific agents are promising, none are in clinical development, mostly because of drug delivery and stability issues. PMID- 25817924 TI - The impact of obesity on pediatric procedural sedation-related outcomes: results from the Pediatric Sedation Research Consortium. AB - OBJECTIVES: To evaluate the impact of obesity on adverse events and required interventions during pediatric procedural sedation. METHODS: The Pediatric Sedation Research Consortium database of prospectively collected procedural sedation encounters was queried to identify patients for whom body mass index (BMI) could be calculated. Obesity was defined as BMI >=95th percentile for age and gender. Sedation-related outcomes, adverse events, and therapeutic interventions were compared between obese and nonobese patients. RESULTS: For analysis, 28,792 records were eligible. A total of 5,153 patients (17.9%) were obese; they were predominantly male and older and had a higher median American Society of Anesthesiologists Physical Status classification (P < 0.001). Total adverse events were more common in obese patients (odds ratio [OR] 1.49, 95% confidence interval [1.31, 1.70]). Respiratory events (airway obstruction OR 1.94 [1.54, 2.44], oxygen desaturation OR 1.99 [1.50, 2.63], secretions OR 1.48 [1.01, 2.15], laryngospasm OR 2.30 [1.30, 4.05]), inability to complete the associated procedure (OR 1.96 [1.16, 3.30]), and prolonged recovery (OR 2.66 [1.26, 5.59]) were increased in obese patients. Obese patients more frequently required airway intervention including repositioning, suctioning, jaw thrust, airway adjuncts, and bag-valve-mask ventilation. Multivariate regression analysis demonstrated obesity to be independently associated with minor and moderate but not major adverse events. CONCLUSIONS: Obesity is an independent risk factor for adverse respiratory events during procedural sedation and is associated with an increased frequency of airway interventions, suggesting that additional vigilance and expertise are required when sedating these patients. PMID- 25817925 TI - Active-passive measurements and CFD based modelling for indoor radon dispersion study. AB - Computational fluid dynamics (CFD) play a significant role in indoor pollutant dispersion study. Radon is an indoor pollutant which is radioactive and inert gas in nature. The concentration level and spatial distribution of radon may be affected by the dwelling's ventilation conditions. Present work focus at the study of indoor radon gas distribution via measurement and CFD modeling in naturally ventilated living room. The need of the study is the prediction of activity level and to study the effect of natural ventilation on indoor radon. Two measurement techniques (Passive measurement using pin-hole dosimeters and active measurement using continuous radon monitor (SRM)) were used for the validation purpose of CFD results. The CFD simulation results were compared with the measurement results at 15 points, 3 XY planes at different heights along with the volumetric average concentration. The simulation results found to be comparable with the measurement results. The future scope of these CFD codes is to study the effect of varying inflow rate of air on the radon concentration level and dispersion pattern. PMID- 25817926 TI - Temporal evolution of (36)Cl abundances in the Great Lakes. AB - The observed (36)Cl isotopic abundance in Great Lakes water decreases from west to east, with the highest (36)Cl/Cl ratio of 1332 * 10(-15) in Lake Superior and the lowest (36)Cl/Cl ratio of 151 * 10(-15) in Lake Erie, whereas the (36)Cl concentration ((36)Cl atoms/L) is lowest in Lake Superior and higher in the other Great Lakes. The (36)Cl concentration in Lake Superior is much higher than expected from normal atmospheric deposition over the basin, consistent with deposition of nuclear bomb-produced (36)Cl during 1952-1964. A conservative mass balance model constrained by hydrological parameters and available (36)Cl fluence measurements predicts the (36)Cl abundances in the Great Lakes from 1945 to 2015, in excellent agreement with available data for Lakes Superior, Michigan, and Huron, but the model underestimates (36)Cl abundances for Lakes Erie and Ontario. However, assuming that (36)Cl demonstrates non-conservative behavior and is significantly retained in the drainage basins, a model incorporating a delayed input parameter successfully predicts observed (36)Cl concentrations in all of the Great Lakes. PMID- 25817927 TI - Illustrative cases to support the Cal-VAT guidelines. AB - There is increasing interest in developing more nuanced methods for managing aggression and violence in long-term psychiatric inpatient settings. However, the dearth of controlled studies has, at times, hampered presentation of viable options. Following the publication of guidelines developed in the California State Hospital forensic system, the authors present a group of 7 cases illustrating different approaches to violence management, including pharmacological, psychotherapeutic, and environmental interventions. PMID- 25817928 TI - Quality of life among parents of children with epilepsy: A preliminary research study. AB - PURPOSE: The current preliminary study was based on the principles of positive psychology orientation when examining the multidimensional construct of quality of life (QOL): the physical functioning, psychological functioning, functional state, and social functioning among parents of children with epilepsy. We assessed the contribution of loneliness and personal resources, namely optimism and flexibility, to parents' QOL. METHOD: The study was conducted at a multidisciplinary center for epilepsy in a central hospital in Israel. Forty eight parents agreed to participate in a preliminary research study and completed a battery of self-report questionnaires. RESULTS: Significant negative correlations were found between flexibility and the scores on the four components of QOL (higher scores on the QOL scales indicated lower QOL). Optimism was not found to be associated with the scores on QOL. High levels of loneliness were found to be associated with higher scores on the four components of parents' QOL. Among sociodemographic variables, only the economic situation (due to illness) was linked negatively to the scores on QOL components. Flexibility and economic situation were the significant variables that accounted for the explained variance of total QOL. CONCLUSION: The results of this study highlight the importance of flexibility in effectively managing the stressors that might be associated with childhood epilepsy. These results suggest that psychosocial intervention providing coping strategies for the family might improve QOL. Moreover, a parent's economic situation seems to be an essential part of the psychosocial assessment, and assurance of the optimal utilization of financial rights and facilities may improve their QOL. PMID- 25817929 TI - Nonintravenous midazolam versus intravenous or rectal diazepam for the treatment of early status epilepticus: A systematic review with meta-analysis. AB - BACKGROUND: Prompt treatment of status epilepticus (SE) is associated with better outcomes. Rectal diazepam (DZP) and nonintravenous (non-IV) midazolam (MDZ) are often used in the treatment of early SE instead of intravenous applications. The aim of this review was to determine if nonintravenous MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE seizures in children and adults. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and MEDLINE for randomized controlled trials comparing non-IV MDZ with DZP (by any route) in patients (all ages) with early SE defined either as seizures lasting >5 min or as seizures at arrival in the emergency department. The following outcomes were assessed: clinical seizure cessation within 15 min of drug administration, serious adverse effects, time interval to drug administration, and time from arrival in the emergency department to seizure cessation. Outcomes were assessed using a random-effects Mantel-Haenszel meta-analysis to calculate risk ratio (RR), odds ratio (OR) and mean difference with 95% confidence intervals (95% CIs). RESULTS: Nineteen studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure) were included. One thousand five hundred seventy-three patients were younger than 16 years. For seizure cessation, non-IV MDZ was as effective as DZP (any route) (1933 seizures; RR: 1.03; 95% CIs: 0.98 to 1.08). No difference in adverse effects was found between non-IM MDZ and DZP by any route (1933 seizures; RR: 0.87; 95% CIs: 0.50 to 1.50). Time interval between arrival and seizure cessation was significantly shorter with non-IV MDZ by any route than with DZP by any route (338 seizures; mean difference: -3.67 min; 95% CIs: -5.98 to -1.36); a similar result was found for time from arrival to drug administration (348 seizures; mean difference: -3.56 min; 95% CIs: -5.00 to 2.11). A minimal difference was found for time interval from drug administration to clinical seizure cessation, which was shorter for DZP by any route than for non-IV MDZ by any route (812 seizures; mean difference: 0.56 min; 95% CIs: 0.15 to 0.98 min). Not all studies reported information on time intervals. Comparison by each way of administration failed to find a significant difference in terms of clinical seizure cessation and occurrence of adverse effects. The only exception was the comparison between buccal MDZ and rectal DZP, where MDZ was more effective than rectal DZP in terminating SE but only when results were expressed as OR (769 seizures; OR: 1.78; 95% CIs: 1.11 to 2.85; RR: 1.15; 95% CIs: 0.85 to 1.54). Only one study was entirely conducted in an adult population (21 patients, aged 31 to 69 years), showing no difference in efficacy or time to seizure cessation after drug administration between intranasal MDZ and rectal DZP. CONCLUSIONS: Non-IV MDZ is as effective and safe as intravenous or rectal DZP in terminating early SE in children and probably also in adults. Times from arrival in the emergency department to drug administration and to seizure cessation are shorter with non-IV MDZ than with intravenous or rectal DZP, but this does not necessarily result in higher seizure control. An exception may be the buccal MDZ, which, besides being socially more acceptable and easier to administer, might also have a higher efficacy than rectal DZP in seizure control. This article is part of a Special Issue entitled Status Epilepticus. PMID- 25817930 TI - Optical microscopy with flexible axial capabilities using a vari-focus liquid lens. AB - The axial imaging range of optical microscopy is restricted by its fixed working plane and limited depth of field. In this paper, the axial capabilities of an off the-shelf microscope is improved by inserting a liquid lens, which can be controlled by a driving electrical voltage, into the optical path of the microscope. First, the numerical formulas of the working distance and the magnification with the variation of the focus of the liquid lens are inferred using a ray tracing method and conclusion is obtained that the best position for inserting a liquid lens with consistent magnification is the aperture plane and the rear focal plane of the objective lens. Second, with the liquid lens embedded in the microscope, the numerical relationship between the magnification and the working distance of the proposed flexible-axial-capability microscope and the liquid lens driving voltage is calibrated and fitted using the inferred numerical formulas. Third, techniques including autofocus, extending depth of field and three-dimensional imaging are researched and applied, improving the designed microscope to not only flexibly control its working distance, but also to extend the depth of field near the variable working plane. Experiments show that the presented flexible-axial-capability microscope has a long working distance range of 8 mm, and by calibrating the magnification curve within the working distance range, samples can be observed and measured precisely. The depth of field can be extended to 400 MUm from the variable working plane and is 20 times that of the off-the-shelf microscope. PMID- 25817931 TI - 2011 update Japanese Society for Dialysis Therapy Guidelines of Vascular Access Construction and Repair for Chronic Hemodialysis. PMID- 25817932 TI - Best practice for diabetic patients on hemodialysis 2012. PMID- 25817933 TI - Japanese society for dialysis therapy clinical guideline for "Maintenance hemodialysis: hemodialysis prescriptions". PMID- 25817934 TI - Japanese society for dialysis therapy clinical guideline for "hemodialysis initiation for maintenance hemodialysis". PMID- 25817935 TI - Proposal for the shared decision-making process regarding initiation and continuation of maintenance hemodialysis. PMID- 25817936 TI - Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice. AB - Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase delta molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL. PMID- 25817937 TI - Advanced-stage mycosis fungoides and Sezary syndrome: survival and response to treatment. AB - INTRODUCTION: Mycosis fungoides (MF) is the most common variant of cutaneous T cell lymphomas. Although MF often has an indolent course, patients can progress to, or present with, advanced stage (stage IIB-IVB) MF or with the leukemic variant, Sezary syndrome (SS). PATIENTS AND METHODS: We prospectively evaluated multiple prognostic variables, including demographics, age, TNMB (blood) stage, histologic features, lactate dehydrogenase (LDH), white blood cell counts, and response to treatment, in 168 patients with advanced-stage MF and SS from 2007 to June 2014. Kaplan-Meier estimates were used to determine the median overall survival (OS) and disease-specific survival (DSS). A Cox proportional hazards regression model was used to assess the prognostic factors with univariate and multivariate analyses. RESULTS: We analyzed 140 patients with MF and 28 with SS, whose median survival was 2.47 years. A total of 79 patients (47%) died of any cause. On univariate analysis, age, lymph node stage, and serum LDH level were significant for prognosis. On multivariate analysis, skin and node stage, age, large cell transformation, and LDH level were significantly associated with worse OS. Only N stage and LDH were significant for DSS. Patients who had received biologic response modifiers and histone deacetylase inhibitors first had better survival (2.5 years) than the patients initially treated with multiagent chemotherapy (9 months). CONCLUSION: We found that only a few factors can predict OS and DSS for patients with advanced MF/SS. Also, nonchemotherapy options should be preferred for front-line therapy to improve survival, outcomes, and side effects, including immunosuppression. PMID- 25817939 TI - Rebuilding lives and identities: The role of place in recovery among persons with complex needs. AB - Photo-elicitation interviews (PEIs) were conducted to explore the role of place in recovery - specifically, narrative identity reconstruction - among persons with complex needs. PEIs with 17 formerly homeless adults with co-occurring disorders in New York City produced 243 photos. Content analysis of photos revealed three categories - apartment, neighborhood and people. Two narrative themes - having my own and civic identity - were mapped onto the apartment and neighborhood categories, respectively. Three additional cross-categorical narrative themes were identified: (re)negotiating relationships and boundaries, moving beyond old identities and future possibilities. Housing was central across themes. Understanding of recovery is enhanced when viewed through participant controlled visual methods. PMID- 25817938 TI - Inhibition of cytochrome P450 2B4 by environmentally persistent free radical containing particulate matter. AB - Combustion processes generate particulate matter (PM) that can affect human health. The presence of redox-active metals and aromatic hydrocarbons in the post combustion regions results in the formation of air-stable, environmentally persistent free radicals (EPFRs) on entrained particles. Exposure to EPFRs has been shown to negatively influence pulmonary and cardiovascular functions. Cytochromes P450 (P450/CYP) are endoplasmic reticulum resident proteins that are responsible for the metabolism of foreign compounds. Previously, it was shown that model EPFRs, generated by exposure of silica containing 5% copper oxide (CuO Si) to either dicholorobenzene (DCB230) or 2-monochlorophenol (MCP230) at >= 230 degrees C, inhibited six forms of P450 in rat liver microsomes (Toxicol. Appl. Pharmacol. (2014) 277:200-209). In this study, the inhibition of P450 by MCP230 was examined in more detail by measuring its effect on the rate of metabolism of 7-ethoxy-4-trifluoromethylcoumarin (7EFC) and 7-benzyloxyresorufin (7BRF) by the purified, reconstituted CYP2B4 system. MCP230 inhibited the CYP2B4-mediated metabolism of 7EFC at least 10-fold more potently than non-EPFR controls (CuO-Si, silica, and silica generated from heating silica and MCP at 50 degrees C, so that EPFRs were not formed (MCP50)). The inhibition by EPFRs was specific for the P450 and did not affect the ability of the redox partner, P450 reductase (CPR) from reducing cytochrome c. All of the PM inhibited CYP2B4-mediated metabolism noncompetitively with respect to substrate. When CYP2B4-mediated metabolism of 7EFC was measured as a function of the CPR concentration, the mechanism of inhibition was competitive. EPFRs likely inhibit CYP2B4-mediated substrate metabolism by physically disrupting the CPR.P450 complex. PMID- 25817940 TI - "This place has given me a reason to care": Understanding 'managed alcohol programs' as enabling places in Canada. AB - For several decades, the emphasis on abstinence within homeless support systems has presented significant barriers to care for those who continue to use alcohol or drugs further marginalizing them in terms of housing and health/social services. In response, health care specialists and policymakers have recommended the integration of harm reduction philosophies and interventions into system level responses to end homelessness. Managed alcohol programs (MAPs) have been developed to this end and have demonstrated positive results. While recent studies of MAPs have focused attention on reductions in alcohol related harms few have examined their meaning from the perspective of clients or considered the role of place. In this paper, we utilize the 'enabling places' frameworks to identify the place-bound properties that make a difference in the recovery journeys of clients. Drawing on in-depth interviews with clients from one program we develop a description of MAPs as enabling places that afford the elemental resources for personal recovery. PMID- 25817941 TI - Correction to: 30 years of rabies vaccination with Rabipur: a summary of clinical data and global experience. PMID- 25817942 TI - A simulation study of sample size demonstrated the importance of the number of events per variable to develop prediction models in clustered data. AB - OBJECTIVES: This study aims to investigate the influence of the amount of clustering [intraclass correlation (ICC) = 0%, 5%, or 20%], the number of events per variable (EPV) or candidate predictor (EPV = 5, 10, 20, or 50), and backward variable selection on the performance of prediction models. STUDY DESIGN AND SETTING: Researchers frequently combine data from several centers to develop clinical prediction models. In our simulation study, we developed models from clustered training data using multilevel logistic regression and validated them in external data. RESULTS: The amount of clustering was not meaningfully associated with the models' predictive performance. The median calibration slope of models built in samples with EPV = 5 and strong clustering (ICC = 20%) was 0.71. With EPV = 5 and ICC = 0%, it was 0.72. A higher EPV related to an increased performance: the calibration slope was 0.85 at EPV = 10 and ICC = 20% and 0.96 at EPV = 50 and ICC = 20%. Variable selection sometimes led to a substantial relative bias in the estimated predictor effects (up to 118% at EPV = 5), but this had little influence on the model's performance in our simulations. CONCLUSION: We recommend at least 10 EPV to fit prediction models in clustered data using logistic regression. Up to 50 EPV may be needed when variable selection is performed. PMID- 25817943 TI - In a clinimetric analysis, 3D stereophotogrammetry was found to be reliable and valid for measuring scar volume in clinical research. AB - OBJECTIVES: Volume is an important feature in the evaluation of hypertrophic scars and keloids. Three-dimensional (3D) stereophotogrammetry is a noninvasive technique for the measurement of scar volume. This study evaluated the reliability and validity of 3D stereophotogrammetry for measuring scar volume. STUDY DESIGN AND SETTING: To evaluate reliability, 51 scars were photographed by two observers. Interobserver reliability was assessed by the intraclass correlation coefficient (ICC), and the measurement error was expressed as limits of agreement (LoA). To assess validity, 60 simulated (clay) scars were measured by 3D stereophotogrammetry and subsequently weighed (gold standard). The correlation of volumes obtained by both measures was calculated by a concordance correlation coefficient (CCC), and the measurement error was expressed as a 95% prediction interval. RESULTS: The ICC was 0.99, corresponding to a high correlation of measurements between two observers, although the LoA were relatively wide. The correlation between 3D stereophotogrammetry and the gold standard was also high, with a CCC of 0.97. Again, the plot of the differences and LoA showed moderate agreement for the validity. CONCLUSION: Three-dimensional stereophotogrammetry is suitable for the use in clinical research but not for the follow-up of the individual patient. PMID- 25817944 TI - Directed transport by surface chemical potential gradients for enhancing analyte collection in nanoscale sensors. AB - Nanoscale detectors hold great promise for single molecule detection and the analysis of small volumes of dilute samples. However, the probability of an analyte reaching the nanosensor in a dilute solution is extremely low due to the sensor's small size. Here, we examine the use of a chemical potential gradient along a surface to accelerate analyte capture by nanoscale sensors. Utilizing a simple model for transport induced by surface binding energy gradients, we study the effect of the gradient on the efficiency of collecting nanoparticles and single and double stranded DNA. The results indicate that chemical potential gradients along a surface can lead to an acceleration of analyte capture by several orders of magnitude compared to direct collection from the solution. The improvement in collection is limited to a relatively narrow window of gradient slopes, and its extent strongly depends on the size of the gradient patch. Our model allows the optimization of gradient layouts and sheds light on the fundamental characteristics of chemical potential gradient induced transport. PMID- 25817945 TI - Free dissociable IGF-I: Association with changes in IGFBP-3 proteolysis and insulin sensitivity after surgery. AB - BACKGROUND: Patients receiving a carbohydrate drink (CHO) before major abdominal surgery display improved insulin sensitivity postoperatively and increased proteolysis of IGFBP-3 (IGFBP-3-PA) compared to patients undergoing similar surgery after overnight fasting. AIMS: We hypothesized that serum IGFBP-3-PA increases bioavailability of circulating IGF-I and preserves insulin sensitivity in patients given CHO. DESIGN: Matched control study. METHODS: At Karolinska University Hospital, patients given CHO before major elective abdominal surgery (CHO,n = 8) were compared to patients undergoing similar surgical procedures after overnight fasting (FAST,n = 10). Results from two different techniques for determination of free-dissociable IGF-I (fdIGF-I) were compared with changes in IGFBP-3-PA and insulin sensitivity. RESULTS: Postoperatively, CHO displayed 18% improvement in insulin sensitivity (hyperinsulinemic clamp) and increased IGFBP-3 PA vs. FAST. As determined by IRMA, fdIGF-I increased by 48 +/- 25% in CHO while fdIGF-I decreased by 13 +/- 18% in FAST (p < 0.01 vs. CHO, when corrected for duration of surgery). However, fdIGF-I determined by ultra-filtration decreased similarly in both groups (-22 +/- 8% vs. -25 +/- 8%, p = 0.8) and IGFBP-1 increased similarly in both groups. Patients with less insulin resistance after surgery demonstrated larger increases in fdIGF-I by IRMA (r = 0.58, p < 0.05). Fifty-three % of the variability of the changes in fdIGF-I by IRMA could be explained by changes in IGFBP-3-PA and total IGF-I levels (p < 0.05), while IGFBP 1 did not contribute significantly. CONCLUSION: During conditions when serum IGF I bioavailability is regulated by IGFBP-3 proteolysis, measurements of fdIGF-I by IRMA is of physiological relevance as it correlates with the associated changes in insulin sensitivity. PMID- 25817946 TI - [Blind to reign. The history of Saint Irene: The empress who deprived her own child of sight in order to gain power]. PMID- 25817947 TI - [Descriptive study on basal cell eyelid carcinoma]. AB - OBJECTIVE: To describe a series of cases of basal cell carcinomas of the eyelid. METHODS: A descriptive and retrospective study was conducted by reviewing the medical outcome, histopathological history, and photographic images of 200 patients with basal cell eyelid carcinomas. All were treated in the Herzog Carl Theodor Eye Hospital in Munich, Germany, between 2000 and 2013. RESULTS: In the present study, it was found that females are more affected than males. The mean age of presentation of the tumor occurred at the age of 70 years. In 50% of the cases the tumor was found on the lower lid, especially medially from the center of the lid. The lid margin was involved in 47% of all tumors. The mean diameter was 9.2mm. The recurrence rate after surgery with histologically clear resection margins was 5%. There was a significant relationship between tumor diameter and age. As tumors where located farther away from medial and closer to the lid margin, they became larger. CONCLUSIONS: There is a predominance of women affected by this tumor. This may be related to the fact that the sample was taken from those attending an oculoplastic surgery clinic, where there are generally more women than men attending. The formation of basal cell carcinomas increases with age. The infrequent involvement of the upper lid could be explained by the protection of the the eyebrow. The frequent involvement of the lower lid may be due to the light reflection (total reflection) by the cornea on the lower lid margin. Also chemical and physical effects of the tears may be more harmful on the lower lid. Patients tend to ask for medical help when they are females, younger, when the tumor is closer to the medial canthus or when the tumor is away from the lid margin. PMID- 25817948 TI - [Long-term results of lasik refractive error correction after penetrating keratoplasty in patients with keratoconus]. AB - OBJECTIVE: To evaluate the long term results of Lasik for residual refractive errors (RE) after penetrating keratoplasty (PKP) for keratoconus (KC). DESIGN: Retrospective cohort. METHOD: Records of 14 consecutive patients (19 eyes) who had Lasik after PKP for KC were retrospectively reviewed. In all eyes with refractive stability and suture removed before Lasik, far distance Visual Acuity with (AVCC) and without correction (AVSC), spherical equivalent (EE), refractive (Ast) and keratometric (dK) astigmatism were analyzed pre- and post-operatively before and after one year of follow up. Data were analyzed using Shapiro-Wilk normality test, Student t test and Mann-Whitney test. A P-value of <0,05 was considered statistically significant. RESULTS: The mean follow-up time was 3.16 months for the follow-up before one year postoperative and 5.8 years for the follow-up after one year postoperative. The best spectacle corrected visual acuity of 0,11 LogMAR (DE 0,07) before Lasik remained stable throughout the study. The SE decreased from -2.6 (DE 3.53) to -0,36 D (DE 1.33) (P<.05) for the follow-up before one year postoperative and -1.28 D (DE 1.63) (P=.07) for the follow-up after one year postop. The refractive cylinder was reduced from -3.43 (DE 1.35) preoperative to -1.37 D (DE 1.24) (P<.05) and -3.21 D (DE 2.29) (P=.36) in the long term after one year of follow-up. CONCLUSIONS: Lasik refractive results regress one year after the operation; therefore it is not an effective long-term surgical refractive procedure for residual refractive errors after PKP for KC. PMID- 25817949 TI - Effect of co-management with Internal Medicine on hospital stay in Ophthalmology. AB - OBJECTIVE: Patients admitted to the Department of Ophthalmology (OPH) are of increasing age, comorbidity and complexity, leading to increased consultations/referrals to Internal Medicine (IM). An alternative to consultations/referrals is co-management. The effect of co-management on length of hospital stay was studied in patients admitted to OPH. METHODS: Retrospective observational study was performed that included patients >=14 years old discharged from OPH between 1 January 2009 and 30 June 2013, who were co-managed from May 2011. An analysis was made including age, sex, type of admission, whether it was operated on, administrative weight associated with GRD, total number of discharge diagnoses, Charlson comorbidity index (CCI), mortality, readmissions, and LoS. RESULTS: There were statistically significant differences between the groups in operated patients (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.5 to 3.6), administrative weight (0.1160; 95% CI 0.0738 to 0.1583), and number of diagnoses (0.9, 95% CI 0.5 to 1.3). On adjustment, co management reduced LoS in OPH by 27.8%, 0.5 days (95% CI 0.1 to 1). CONCLUSIONS: Patients admitted to OPH have increasing comorbidity and complexity. Co management is associated with a reduced LoS and costs in OPH, similar to that observed in other surgical services. PMID- 25817951 TI - Intravitreal inyections: What do patients prefer? Analysis of patient's satisfaction and preferences about where to perform intravitreal injection. Author's reply. PMID- 25817950 TI - [Effects of ozurdex on intraocular pressure. A real life clinical practice study]. AB - OBJECTIVE: The dexamethasone biodegradable implant, ozurdex, is approved by the US Food and Drug Administration and by the European Medical Agency for the treatment of intermediate and posterior uveitis, and for the treatment of macular edema following retinal vein occlusion and diabetic macular edema. The aim of this study was to assess the effects of intraocular pressure in a cohort of patients from a real-life clinical practice. METHODS: Retrospective review was performed on the clinical records of patients treated with Ozurdex in Hospital Universitario Cruces in a 6 month period. The following variables were recorded: age, gender, diagnosis and history of glaucoma; intraocular pressure, antihypertensive treatment and macular thickness were recorded before the injection, and in the 1st, 2nd, 4th, and 6th months after the injection. STATISTICAL TESTS: Mann-Whitney U test, Chi square test (with Fisher correction when needed) and Wilcoxon test. The level of statistical significance was set at P<.05. RESULTS: The effects of 75 injections given to 67 patients (35 women: 52%; mean age: 62) were evaluated. Mean intraocular pressure before the injection was 15.9 mmHg and at 1st, 2nd, 4th and 6th months after de injection it was 18.80 (P=.627), 18.84 (P=.494), 17.02 (P=.796) and 15.5 (P=.829), respectively. No statistically significant differences were observed in intraocular pressure measurements at the mentioned follow-up visits between patients with and without a history of glaucoma. CONCLUSIONS: In real-life clinical practice, ozurdex shows an excellent safety profile in terms of intraocular hypertension. Patients with a history of glaucoma may also show this profile, with ozurdex being a good option to treat retinal diseases in these patients. PMID- 25817952 TI - Retinal detachment caused by Arruga suture scleral intrusion. Treatment. AB - CASE REPORT: We present the case of an 81-year-old man with retinal detachment caused by intrusion of an Arruga suture. The encircling buckle was located in the sub-retinal space and caused retinal breaks with retinal detachment DISCUSSION: A pars plana vitrectomy was performed along with intraocular cutting of the Arruga suture with retinal re-attachment. PMID- 25817953 TI - Diagnosis of acute follicular conjunctivitis: A 5-year retrospective analysis in a referral center. AB - OBJECTIVE AND METHODS: A retrospective analysis was performed using the medical records in a referral center in Mexico over a period of 5 years, in order to determine the frequency of acute follicular conjunctivitis. RESULTS AND CONCLUSIONS: A total of 859,986 ophthalmology consultations were given, from which 8,930 were diagnosed with acute follicular conjunctivitis (1.03% of the total). The number of patients diagnosed range between 100 and 200 in the majority of months. In August 2012 an increase was observed with 308 cases, and then decreasing after two months. This study did not demonstrate a highest frequency by month, with exception of year 2012 that showed a peak incidence in the third trimester. PMID- 25817954 TI - Chronic antithrombotic therapy in cataract surgery: How much evidence do we have? PMID- 25817955 TI - Comparative study of keratoconus between Anwar's deep anterior lamellar keratoplasty versus converted penetrating keratoplasty. AB - OBJECTIVE: To compare outcomes between penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) in patients with keratoconus. DESIGN: Retrospective cohort study. METHODS: Data of 90 DALK and 49 procedures from conversion to PK, performed by a single surgeon (R.D.) from 2006 to 2011 were analysed. Outcomes on corrected distance visual acuity (BCVA), astigmatism, time to first refraction, pachymetry, endothelial count cell, and postoperative complications were compared between these groups. RESULTS: The mean age of the patients who underwent DALK and PK was 28.2 and 31.7 years, respectively (P=.17). The mean follow up for DALK and for the PK group was 14.7 and 19.4 months, respectively (P=.13). There was no significant difference between PK and DALK groups in the mean postoperative for: BCVA (LogMAR) (0.17 vs. 0.17; P=.59); refractive astigmatism (-3.19 vs.-3.01 diopters; P=.65), and time for the first subjective refraction (60.5 versus 68 days; P=.50). Main postoperative complications were 8% of endothelial rejection in PK group and 10% of deep stromal vascularization in DALK group. CONCLUSIONS: The only differences in postoperative results between groups were stromal neovascularization in DALK group and endothelial rejection in PK group. DALK should be considered as the first option when keratoplasty is indicated in keratoconus. PMID- 25817956 TI - [Malyugin ring for intraoperative miosis in femtosecond laser phacovitrectomy]. AB - OBJECTIVE: To evaluate the usefulness of the Malyugin ring in poor pupil dilation during phacoemulsification assisted with femtosecond laser with 23 gauge pars plana vitrectomy. METHOD: A 57-year-old female with cataract and vitreous hemorrhage, and poor pupil dilation (5.5mm). The phacoemulsification assisted with femtosecond laser, using Malyugin ring after capsulorrhexis, followed by pars plana vitrectomy, and removing at the end without complications. RESULTS: A successfull intraoperative pupil dilation was achieved without complications, with a final BCVA of 20/40. CONCLUSIONS: The Malyugin ring is an effective alternative in cases with poor pupil dilation in femtophacovitrectomy, preserving the anatomical and functional integrity. PMID- 25817957 TI - Anterior tuberculous scleritis: A diagnostic challenge. AB - CASE REPORT: We present the case of a 26 year-old Pakistani male, who after the presumptive diagnosis of anterior tuberculous scleritis (by an atypical clinical appearance and positive epidemiological link), was diagnosed with pulmonary tuberculosis. DISCUSSION: Nodular anterior scleritis is an uncommon presentation of tuberculosis (TB). It is considered a diagnostic challenge because of the difficulty to extract bacilli from the ocular tissue. However, a detailed medical history and eye examination can be the key to an accurate diagnosis and appropriate treatment of the TB. PMID- 25817958 TI - Comparative study of RetCamRetCam II vs. binocular ophthalmoscopy in a screening program for retinopathy of prematurity. AB - OBJECTIVE: To determine the performance of RetCam vs. binocular ophthalmoscopy (BIO) in a screening program for retinopathy of prematurity (ROP). METHODS: Observational comparative study with prospective data collection. Examinations with RetCam (n=169) were performed on 83 infants included in a screening program for ROP and stored for analysis at a later stage. An experienced ophthalmologist examined the ocular fundus with binocular indirect ophthalmoscopy (BIO). The RetCam images were assessed for the presence of ROP, zone, grade, and presence of plus disease. RetCam and BIO data were compared by visually to estimate sensitivity, specificity, positive (VPP) and negative (VPN) predictive values. RESULTS: ROP disease was detected in 108 eyes with BIO, and in 74 with RetCam. Out of 306 eyes examined with RetCam, false negative results were found in 34 eyes, with no false positives. Sensitivity of RetCam exam vs. BIO was 0.68, and specificity was 0.99. Positive predictive value was 0.93 and negative predictive value was 0.85. All 34 ROP cases not detected with RetCam were in zone III or outer zone II. They were all mild and regressed spontaneously. No threshold ROP was missed with RetCam. CONCLUSION: Binocular indirect ophthalmoscopy is the reference method for the diagnosis of ROP. RetCam may be used as an alternative for ROP screening. PMID- 25817959 TI - [Uveal effusion induced by escitalopram]. AB - CASE REPORT: A 73 year-old woman with depression treated with escitalopram developed acute secondary angle closure glaucoma related to uveal effusion after duplicating the drug dose 3 days before. She evolved favorably once the antidepressant treatment was suspended and a new treatment with topical hypotensive therapy and oral prednisone was used. DISCUSSION: The uveal effusion syndrome associated to medicines is rare; it may be associated with acute myopic shift and acute angle closure glaucoma. The correct diagnosis and discontinuation of the drug lead to the resolution of this nosology. PMID- 25817960 TI - Standardization of the Descemet membrane endothelial keratoplasty technique: Outcomes of the first 450 consecutive cases. AB - OBJECTIVES: To evaluate the clinical outcome of the first 450 consecutive cases after Descemet membrane endothelial keratoplasty (DMEK), as well as the effect of standardization of the technique. MATERIAL AND METHODS: Comparison between 3 groups: Group I: (cases 1-125), as the extended learning curve; Group II: (cases 126-250), transition to technique standardization; Group III: (cases 251-450), surgery with standardized technique. Best corrected visual acuity, endothelial cell density, pachymetry and intra- and postoperative complications were evaluated before, and 1, 3 and 6 months after DMEK. RESULTS: At 6 months after surgery, 79% of eyes reached a best corrected visual acuity of>=0.8 and 43%>=1.0. Mean preoperative endothelial cell density was 2,530+/-220 cells/mm2 and 1,613+/ 495 at 6 months after surgery. Mean pachymetry measured 668+/-92 MUm and 526+/-46 MUm pre- and (6 months) postoperatively, respectively. There were no significant differences in best corrected visual acuity, endothelial cell density and pachymetry between the 3 groups (P > .05). Graft detachment presented in 17.3% of the eyes. The detachment rate declined from 24% to 12%, and the rate of secondary surgeries from 9.6% to 3.5%, from group I to III respectively. CONCLUSIONS: Visual outcomes and endothelial cell density after DMEK are independent of the technique standardization. However, technique standardization may have contributed to a lower graft detachment rate and a relatively low number of secondary interventions required. As such, DMEK may become the first choice of treatment in corneal endothelial disease. PMID- 25817961 TI - Stickler syndrome. Epidemiology of retinal detachment. AB - OBJECTIVE: A review was performed on all patients with Stickler syndrome that had been treated in our Centre since it was diagnosed, in order to evaluate the risk of suffering a retinal detachment (RD). METHODS: A total of 14 patients, diagnosed by clinical criteria, were included. The following variables were evaluated: age, gender, ocular background, follow-up, initial and final visual acuity (VA), optical prescription, prophylactic treatment, surgery and techniques performed. The risk age to suffer a RD, as well as cataracts, was determined by using the Kaplan-Meier survival curve analysis. RESULTS: From a total of 5 men and 9 women, the median initial VA was 0.35, which was the same as the final VA. The median optical prescription was -9.5 D myopia. The median of follow-up was 7 years. Ocular background was 4 RD cases and 2 Lasik surgeries. The operations performed were 8 RD, 12 cataract, 2 glaucoma, 2 macular hole, and one endotropia. The median age of RD was 20 years and cataract 34 years. As regards surgical tecnique, 4 scleral buckle cases, and 4 scleral buckle+pars plana vitrectomy cases were formed. The prophylactic treatments performed were: one scleral buckle case, 4 endolaser photocoagulation, and one cryotherapy. Two of which presented with RD. CONCLUSION: In the series presented, retinal detachment in Stickler syndrome mainly occurs in the second decade of life, with cataracts mainly developing in the fourth decade. PMID- 25817962 TI - [Strabology in the 21st century]. PMID- 25817964 TI - Comparative study of modification of the osmolarity in graft versus host disease. PMID- 25817963 TI - Bilateral acute retinal necrosis due to varicella zoster virus in an elderly patient. AB - CASE REPORT: The case is reported of acute retinal necrosis with bilateral involvement due to Varicella Zoster virus in a 77 year-old man. Polymerase chain reaction (PCR) of aqueous humor was positive for Varicella Zoster virus (VZV). He developed a Kyrieleis' vasculitis a month after the starting treatment, when the PCR analysis was negative. DISCUSSION: PCR is a quick and safe technique, with a high sensitivity and specificity of 97%, useful to diagnose and monitor the viral activity. The intervention must be urgent, due to the dramatically rapid evolution. Oral famciclovir oral is good alternative owing to its bioavailability. PMID- 25817965 TI - [Study of the effect of intravitreal dexamethasone implant in pseudophakic macular edema. Preliminary]. AB - OBJECTIVE: To evaluate the efficacy of intravitreal dexamethasone implant on the treatment of pseudophakic macular edema (PME). MATERIAL AND METHODS: A retrospective, observational, descriptive study was conducted on 4 patients who received an intravitreal injection of dexamethasone implant due to PME in the period from 1st January 2013 to 31st December 2013 in the Hospital Universitario de La Ribera (Alzira, Valencia, Spain). A complete ophthalmic examination was performed on these patients. Best-corrected visual acuity (BCVA), macular thickness), and duration of the effect of the treatment were studied. RESULTS: At baseline, the mean MT was 414MUm. After dexamethasone implant, mean values of MT decreased to 330.25MUm at month one. The mean change from baseline MT was 83.75MUm. The baseline mean BCVA was 0.3 and improved to 0.575 at month one and 3. The mean duration of the effect of the treatment was 3.5 months. CONCLUSIONS: Intravitreal dexamethasone implant is a possible treatment for Irvine-Gass syndrome as it improved visual acuity and reduced the macular thickness of these patients. PMID- 25817966 TI - Uveitis-glaucoma-hyphema syndrome associated with recurrent vitreous hemorrhage. AB - CASE REPORT: A 61-year-old pseudophakic male with recurrent blurred vision episodes associated with uveitis, hyphema, glaucoma and vitreous hemorrhage. Iris transillumination defects and apposition of the optic and iris were found. The patient was diagnosed with Uveitis-Glaucoma-Hyphema (UGH) Syndrome. DISCUSSION: Mechanical irritation of the iris is a consequence of intraocular lens malposition and causes UGH Syndrome. Occasionally it is associated with vitreous hemorrhage. Lens malposition is detected by optical coherence tomography and/or ultrasound biomicroscopy. PMID- 25817967 TI - Study of the relationship between myopia and personality. AB - OBJECTIVE: To study the correlation between the myopic refractive error and certain personality traits, and to determine whether there is a correlation between the degree of myopia and an increased frequency in personality disorders. METHODS: Cross-sectional observational multicenter study conducted on 82 subjects (26 men, 56 women) age over 18 years with myopia (spherical defect <= -0.5 D), with 30 subjects having high myopia (<-6 D). DATA COLLECTED: age and gender, academic level, result in the Neo PI-R personality test, autorefractometry, myopic pathology, and ophthalmological treatment. RESULTS: Correlation (Spearman's) between the magnitude of the spherical defect and the 5 personality traits studied in the total sample was not statistically significant: neuroticism (-0.057; P=.610), extroversion (-0.020; P=.857), openness (-0.032; P=.774), kindness (-0.060; P=.592), and responsibility (-0.034; P=.765). By dividing them into subgroups of low and high significance (t-test), a significant (P=.002) upward trend of the myopic defect with increasing scores on extraversion was found. When comparing high myopic subjects to the non-high myopic ones, there were significant differences between the 2 groups in terms of the associated pathology (P=.001), received treatment (P=.001) and the level of studies (P=.013). There were no differences in the variables of personality: neuroticism (P=.852), extroversion (P=.199), openness (P=.560), kindness (P=.584), and responsibility (P=.722). CONCLUSIONS: A low correlation was found between myopia and personality. There was no difference in the degree of myopia between the groups with different education levels. Subjects with more severe ocular pathology associated with myopia had higher scores in neuroticism, without finding any significant association. PMID- 25817968 TI - [Posterior polymorphous dystrophy, case report and literature review]. AB - CASE REPORT: Posterior Polymorphous Dystrophy (DPP) is a rare posterior corneal dystrophy that is genetically transmitted as autosomal dominant. Corneal structures affected in this dystrophy are Descemet membrane and the endothelium. A case is presented on a 47 years old woman with no relevant history, with typical findings of DPP (vesicular and band lesions at the endothelium and posterior Descemet). DISCUSSION: To our knowledge there are no reported cases of DPP in Latin-American patients in the literature. The clinical manifestations in our patient were found to be very similar to the cases reported in other populations. PMID- 25817969 TI - Large-scale automatic extraction of side effects associated with targeted anticancer drugs from full-text oncological articles. AB - Targeted anticancer drugs such as imatinib, trastuzumab and erlotinib dramatically improved treatment outcomes in cancer patients, however, these innovative agents are often associated with unexpected side effects. The pathophysiological mechanisms underlying these side effects are not well understood. The availability of a comprehensive knowledge base of side effects associated with targeted anticancer drugs has the potential to illuminate complex pathways underlying toxicities induced by these innovative drugs. While side effect association knowledge for targeted drugs exists in multiple heterogeneous data sources, published full-text oncological articles represent an important source of pivotal, investigational, and even failed trials in a variety of patient populations. In this study, we present an automatic process to extract targeted anticancer drug-associated side effects (drug-SE pairs) from a large number of high profile full-text oncological articles. We downloaded 13,855 full text articles from the Journal of Oncology (JCO) published between 1983 and 2013. We developed text classification, relationship extraction, signaling filtering, and signal prioritization algorithms to extract drug-SE pairs from downloaded articles. We extracted a total of 26,264 drug-SE pairs with an average precision of 0.405, a recall of 0.899, and an F1 score of 0.465. We show that side effect knowledge from JCO articles is largely complementary to that from the US Food and Drug Administration (FDA) drug labels. Through integrative correlation analysis, we show that targeted drug-associated side effects positively correlate with their gene targets and disease indications. In conclusion, this unique database that we built from a large number of high-profile oncological articles could facilitate the development of computational models to understand toxic effects associated with targeted anticancer drugs. PMID- 25817970 TI - Cadec: A corpus of adverse drug event annotations. AB - CSIRO Adverse Drug Event Corpus (Cadec) is a new rich annotated corpus of medical forum posts on patient-reported Adverse Drug Events (ADEs). The corpus is sourced from posts on social media, and contains text that is largely written in colloquial language and often deviates from formal English grammar and punctuation rules. Annotations contain mentions of concepts such as drugs, adverse effects, symptoms, and diseases linked to their corresponding concepts in controlled vocabularies, i.e., SNOMED Clinical Terms and MedDRA. The quality of the annotations is ensured by annotation guidelines, multi-stage annotations, measuring inter-annotator agreement, and final review of the annotations by a clinical terminologist. This corpus is useful for studies in the area of information extraction, or more generally text mining, from social media to detect possible adverse drug reactions from direct patient reports. The corpus is publicly available at https://data.csiro.au.(1). PMID- 25817972 TI - Re: dingoes are a major causal factor for the decline and distribution of sheep in Australia. PMID- 25817973 TI - Evaluation of prognostic indicators for canine primary immune-mediated haemolytic anaemia and application of a scoring system for the determination of prognosis. AB - OBJECTIVE: Apply a previously described scoring system retrospectively to cases of canine primary immune-mediated haemolytic anaemia (pIMHA) to determine its accuracy and reliability for the determination of prognosis in Victoria, Australia. METHODS: Retrospective cohort study of 41 dogs diagnosed with pIMHA at the University of Melbourne Veterinary Hospital (UMVH) between August 2006 to December 2012. RESULTS: Of the 41 dogs included, 70.7% were female while 29.3% were male. The overall mortality in this study was 43.9%. The previously described prognostic scoring system when applied to cases of pIMHA in Victoria, Australia, was not found to show statistical significance for prognostification. None of the five prognostic factors were found to be independently significant for prognostification. CONCLUSION: Application of the previously described prognostic scoring system indicated that it may not be reliable for predicting prognoses of dogs with pIMHA in Victoria, Australia. PMID- 25817974 TI - Preoperative factors associated with hypotension in young anaesthetised dogs undergoing elective desexing. AB - OBJECTIVES: Document the proportion of dogs with perioperative hypotension and explore the association of sex, age and body mass and indices of hydration with mean arterial blood pressure (MAP) in two cohorts of young, healthy anaesthetised dogs. METHODS: Dogs were anaesthetised with a standardised protocol. The proportion of dogs with invasively measured MAP <60 mmHg for >=10 min was recorded. The area under the MAP*time curve (MAP-AUC) was calculated for a standard perioperative period. The association of explanatory variables, including sex, age, body mass and indices of hydration (urine specific gravity (USG), packed cell volume and total solids) measured prior to surgery, with the MAP-AUC was explored using regression analysis in the first cohort (n = 71) and externally validated in the second cohort (n = 24). RESULTS: In cohort 1, 35 of 71 dogs (0.49, 95% confidence interval (CI) 0.37-0.61) dogs and 17/24 dogs in cohort 2 (0.71, 95% CI 0.53-0.89) developed hypotension. Regression analysis showed that age and USG were significantly associated with MAP-AUC for cohort 1 (P = 0.0138). There was a positive association of MAP-AUC with age and a negative association with USG. The association of MAP-AUC with USG was supported in cohort 2, with a significant negative association (P = 0.014, r = -0.54) CONCLUSION: The high frequency of hypotension in both cohorts supports blood pressure monitoring during anaesthesia of young, healthy dogs. USG, an index of hydration, appears negatively associated with MAP during anaesthesia, suggesting that subclinical dehydration may contribute to lower MAP during surgical anaesthesia. PMID- 25817975 TI - Addisonian crisis in a dog treated with phenobarbitone. AB - BACKGROUND: A 2-year-old intact female Irish Setter was presented with a 1-week history of anorexia, lethargy, vomiting and diarrhoea. Previous medical therapy included a 3-week treatment with phenobarbitone for suspected idiopathic epilepsy. In humans, phenobarbitone accelerates metabolism of both exogenous and endogenous steroids. CASE REPORT: Based on history, the physical examination showing abnormal mentation and laboratory abnormalities including azotaemia, hyponatraemia and hyperkalaemia, Addisonian crisis was suspected. An adrenocorticotropic hormone stimulation test was performed and confirmed the diagnosis. Treatment with intravenous fluid therapy, glucocorticoids and mineralocorticoids led to a resolution of clinical signs in 3 days. CONCLUSION: To the authors' current knowledge, this is the first reported case of Addisonian crisis in a dog most probably related to phenobarbitone administration. As Addisonian crisis can be life-threatening, clinicians should be aware of this adverse effect of phenobarbitone and use it cautiously in dogs with borderline hypoadrenocorticism. PMID- 25817976 TI - Agreement among three different equine venipuncture sites with regard to measurement of packed cell volume and total solids. AB - The primary objective of this study was to determine the agreement between the packed cell volume (PCV) and total solids (TS) values in blood collected from the jugular vein (JV) in comparison with the cephalic vein (CV) and the transverse facial venous sinus (TFVS) in healthy adult horses. A total of 72 samples were taken from 24 horses. We found high agreement that reflects no clinically relevant differences between the PCV and TS values obtained from the CV or the TFVS in comparison with the JV in standing healthy adult horses. PMID- 25817977 TI - Effect of an anti-gonadotropin-releasing factor vaccine on sexual and aggressive behaviour in male pigs during the finishing period under Australian field conditions. AB - OBJECTIVE: The objective of this study was to evaluate the effectiveness of an anti-gonadotropin-releasing factor vaccine in controlling sexual and aggressive behaviour of male pigs in the late finishing period under Australian field conditions. METHODS: Male pigs from four consecutive batches over a 4-month period were randomly assigned to two groups: an untreated control group (n = 434) or a group treated with Improvac(r) (n = 433). The vaccine was administered at 10 and 16 weeks of age. Pigs were housed under commercial conditions in ecoshelters, a commonly used housing system in Australia in which pigs are kept in large pens often containing >100 animals. The occurrence of sexual and aggressive behaviours was recorded and evaluated after second vaccination until slaughter at 22 weeks of age. RESULTS: Male pigs treated with Improvac demonstrated significant reductions in mounting, fighting, pushing, head butting and tail manipulation when compared with control animals. CONCLUSION: This study confirms that vaccination with Improvac can improve the welfare of entire male pigs by inhibiting sexual and aggressive behaviour. PMID- 25817978 TI - Effect of the route of administration on the mucosal and systemic immune responses to Lawsonia intracellularis vaccine in pigs. AB - In an on-farm study, 40 weaned piglets aged 3 weeks were vaccinated with Lawsonia intracellularis vaccine orally, IM or IP while a fourth group remained unvaccinated. All vaccinated animals showed increased serum levels of L. intracellularis-specific IgG antibodies, but significantly elevated concentrations of specific IgG, IgA and cytokines were generated in ileal mucosal secretions from the orally and IP vaccinated pigs when examined at 17 days after vaccination. PMID- 25817981 TI - Handling the hot potatoes - issues and advocacy update. PMID- 25817982 TI - Evaluation of perioperative complications in open and laparoscopic surgery for renal cell cancer with tumor thrombus involvement using the Clavien-Dindo classification. AB - OBJECTIVE: To identify risk factors for perioperative complications and morbidity in renal cell cancer (RCC) surgery with tumor thrombus invasion (TTI). PATIENTS AND METHODS: Retrospective single-center analysis of 128 patients who underwent open (n = 97) or laparoscopic (n = 31) radical nephrectomy (NT) for RCC between 1999 and 2010. TTI was at Mayo-Level 0, I, II, III, IV in 88, 7, 10, 4, and 19 cases, respectively. Cavotomy was performed in 27, liver mobilisation in 20, and cardiovascular bypass in 17 patients. RESULTS: The rate of any early postoperative complication (PC) by Clavien-Dindo classification was 58.6%, while the severe early PC rate was 29.7%. There was a statistically significant difference in multivariate analysis in the incidence of any early PC and of severe early PC by Charlson score (OR:1.584 (95%CI:1.141-2.199), p = 0.006; OR:3.065 (95%CI:1.218-7.714), p = 0.017) and by tumor thrombus level TNM-UICC 2010 T3a/T3c (OR:10.668 (95%CI:1.266-89.871), p = 0.029; OR:10.502 (95%CI:2.981 36.992), p < 0.001). In pT3a cases open NT was associated with a higher early (57.9% vs. 25.8%) and severe (24.6% vs. 9.7%) PC rate compared to laparoscopic NT. The 30-day mortality rate was 0%. The 90-day mortality rate was 6.3% but 100% cancer-related. In Cox regression analysis tumor thrombus level was not predictive for overall survival. CONCLUSIONS: The strongest risk factor for early and severe PC in patients with TTI is a supradiaphragmatic tumor thrombus. In cases with severe PC, this fact persists when comparing Mayo-Levels II-III and Level IV. In pT3a cases open NT shows a 2-fold higher early PC rate compared to laparoscopic NT. PMID- 25817983 TI - Surgically treated patients with axial and peripheral Ewing's sarcoma family of tumours: A population based study in Finland during 1990-2009. AB - BACKGROUND: The surgical treatment of Ewing's sarcoma family tumours (ESFTs) is challenging especially with axial tumours. The aim of the study was to analyse surgical treatment and outcome in a nationwide, population-based material consisting of surgically treated axial and peripheral ESFTs of bone and soft tissue. METHODS: The data were collected from the Finnish National Cancer Registry and the medical records of patients diagnosed during 1990-2009. Fifty seven patients with surgically treated ESFTs were included, 22 with an axial and 35 with a peripheral primary tumours. The surgical treatment, its complications, survival and prognostic factors were analysed. RESULTS: Fifty-four patients underwent surgery with a curative intent and three underwent de-bulking operations. Bone reconstruction was performed in six patients with an axial and 15 with a peripheral tumour. Positive resection margins were associated with a worse five-year local relapse-free survival (33% vs. 84% for those with resection margins free of tumour cells, p = 0.003). The five-year sarcoma-specific survival was affected only by an axial location of the primary (61% vs. 89% for those with a peripheral tumour, p = 0.031). The late complications were mainly associated with bone reconstruction and more frequent among patients with a peripheral compared to an axial tumour (p = 0.031). CONCLUSIONS: In the treatment of ESFTs, achieving adequate resection margins is crucial to avoid local relapses. Surgical complications are common particularly with bone reconstruction. PMID- 25817984 TI - Plague bacterium as a transformer species in prairie dogs and the grasslands of western North America. AB - Invasive transformer species change the character, condition, form, or nature of ecosystems and deserve considerable attention from conservation scientists. We applied the transformer species concept to the plague bacterium Yersinia pestis in western North America, where the pathogen was introduced around 1900. Y. pestis transforms grassland ecosystems by severely depleting the abundance of prairie dogs (Cynomys spp.) and thereby causing declines in native species abundance and diversity, including threatened and endangered species; altering food web connections; altering the import and export of nutrients; causing a loss of ecosystem resilience to encroaching invasive plants; and modifying prairie dog burrows. Y. pestis poses an important challenge to conservation biologists because it causes trophic-level perturbations that affect the stability of ecosystems. Unfortunately, understanding of the effects of Y. pestis on ecosystems is rudimentary, highlighting an acute need for continued research. PMID- 25817985 TI - How Kinesthetic Motor Imagery works: a predictive-processing theory of visualization in sports and motor expertise. AB - Kinesthetic Motor Imagery (KMI) is an important technique to acquire and refine motor skills. KMI is widely used by professional athletes as an effective way to improve motor performance without overt motor output. Despite this obvious relevance, the functional mechanisms and neural circuits involved in KMI in sports are still poorly understood. In the present article, which aims at bridging the sport sciences and cognitive neurophysiology literatures, we give a brief overview of relevant research in the field of KMI. Furthermore, we develop a theoretical account that relates KMI to predictive motor control theories assuming that it is based on internal activation of anticipatory images of action effects. This mechanism allows improving motor performance solely based on internal emulation of action. In accordance with previous literature, we propose that this emulation mechanism is implemented in brain regions that partially overlap with brain areas involved in overt motor performance including the posterior parietal cortex, the cerebellum, the basal ganglia and the premotor cortex. Finally, we outline one way to test the heuristic value of our theoretical framework for KMI; we suggest that experience with motor performance improves the ability to correctly infer the goals of others, in particular in penalty blocking in soccer. PMID- 25817987 TI - Evaluation of tools used to measure critical thinking development in nursing and midwifery undergraduate students: a systematic review. AB - BACKGROUND: Well developed critical thinking skills are essential for nursing and midwifery practices. The development of students' higher-order cognitive abilities, such as critical thinking, is also well recognised in nursing and midwifery education. Measurement of critical thinking development is important to demonstrate change over time and effectiveness of teaching strategies. OBJECTIVE: To evaluate tools designed to measure critical thinking in nursing and midwifery undergraduate students. DATA SOURCES: The following six databases were searched and resulted in the retrieval of 1191 papers: CINAHL, Ovid Medline, ERIC, Informit, PsycINFO and Scopus. REVIEW METHODS: After screening for inclusion, each paper was evaluated using the Critical Appraisal Skills Programme Tool. Thirty-four studies met the inclusion criteria and quality appraisal. Sixteen different tools that measure critical thinking were reviewed for reliability and validity and extent to which the domains of critical thinking were evident. RESULTS: Sixty percent of studies utilised one of four standardised commercially available measures of critical thinking. Reliability and validity were not consistently reported and there was a variation in reliability across studies that used the same measure. Of the remaining studies using different tools, there was also limited reporting of reliability making it difficult to assess internal consistency and potential applicability of measures across settings. CONCLUSIONS: Discipline specific instruments to measure critical thinking in nursing and midwifery are required, specifically tools that measure the application of critical thinking to practise. Given that critical thinking development occurs over an extended period, measurement needs to be repeated and multiple methods of measurement used over time. PMID- 25817988 TI - The ECG and the pre-participation examination of young athletes. PMID- 25817986 TI - Correlation between pediatrician supply and public health in Japan as evidenced by vaccination coverage in 2010: secondary data analysis. AB - BACKGROUND: In industrialized countries, assessment of the causal effect of physician supply on population health has yielded mixed results. Since the scope of child vaccination is an indicator of preventive health service utilization, this study investigates the correlation between vaccination coverage and pediatrician supply as a reflection of overall pediatric health during a time of increasing pediatrician numbers in Japan. METHODS: Cross-sectional data were collected from publicly available sources for 2010. Dependent variables were vaccination coverage for measles and diphtheria, pertussis, and tetanus (DPT) by region. The primary predictor of interest was number of pediatricians per 10,000 child population (pediatrician density) at the municipality level. Multivariate logistic regression models were used to estimate associations of interest, conditional on a large range of demographic and infrastructure-related factors as covariates, including non-pediatric physician density, total population, per capita income, occupation, unemployment rate, prevalence of single motherhood, number of hospital beds per capita, length of roads, crime rate, accident rate, and metropolitan area code as urban/rural status. The percentage of the population who completed college-level education or higher in 2010 was included in the model as a proxy for education level. RESULTS: Pediatrician density was positively and significantly associated with vaccination coverage for both vaccine series. On average, each unit of pediatrician density increased odds by 1.012 for measles (95% confidence interval, 1.010-1.015) and 1.019 for DPT (95% confidence interval, 1.016-1.022). CONCLUSIONS: Policies increasing pediatrician supply contribute to improved preventive healthcare services utilization, such as immunizations, and presumably improved child health status in Japan. PMID- 25817989 TI - Pulmonary Cryptococcosis in HIV- sero-negative patients: case series from India. AB - Pulmonary cryptococcosis is likely to be misdiagnosed due to relatively non specific clinical and radiological features. It is more frequently associated with immuno-suppressed conditions especially acquired immuno-deficiency syndrome (AIDS) and pulmonary tuberculosis (PTB). Four cases of pulmonary cryptococcosis were diagnosed over a period of eleven years. All patients in this case series were human immune-deficiency virus (HIV)-negative. The predisposing factors in these patients were diabetes mellitus (DM), acute lymphoblastic leukaemia (ALL), post-partum and pregnancy in one each of the patients. Relapse was seen in two cases. All the patients survived due to strict follow-up. Pulmonary cryptococcosis is common in non-AIDS patients and it warrants rapid diagnosis, treatment and follow-up to prevent relapse. PMID- 25817990 TI - Efficacy of squaric acid dibutyl ester in treatment of recalcitrant warts in children. PMID- 25817991 TI - Transforming growth factor-beta3 regulates cell junction restructuring via MAPK mediated mRNA destabilization and Smad-dependent protein degradation of junctional adhesion molecule B (JAM-B). AB - Junctional adhesion molecule-B (JAM-B) is found between Sertoli cells at the blood-testis barrier (BTB) as well as between Sertoli and germ cells at the apical ectoplasmic specializations (ES) in the testis. The expression of JAM-B is tightly regulated to modulate the passage of spermatocytes across the BTB as well as the release of mature spermatozoa from the seminiferous epithelium. Transforming growth factor beta (TGF-beta) family is implicated in the regulation of testicular cell junction dynamics during spermatogenesis. This study aims to investigate the effects of TGF-beta3 on the expression of JAM-B as well as the underlying mechanisms on how TGF-beta3 regulates JAM-B expression to facilitate the disassembly of the BTB and apical ES. Our results revealed that TGF-beta3 suppresses JAM-B at post-transcriptional and post-translational levels. Inhibitor, siRNA knockdown and co-immunoprecipitation have shown that TGF-beta3 induces JAM-B protein degradation via ubiquitin-proteasome pathway. Immunofluorescence staining further confirmed that blockage of ubiquitin proteasome pathway could abrogate TGF-beta3-induced loss of JAM-B at the cell cell interface. siRNA knockdown and immunofluorescence staining also demonstrated that activation of Smad signaling is required for TGF-beta3-induced JAM-B protein degradation. In addition, TGF-beta3 reduces JAM-B mRNA levels, at least in part, via post-transcriptional regulation. mRNA stability assay has confirmed that TGF beta3 promotes the degradation of JAM-B transcript and TGF-beta3-mediated mRNA destabilization requires the activation of ERK1/2 and p54 JNK signal cascades. Taken together, TGF-beta3 significantly downregulates JAM-B expression via post transcriptional and post-translational modulation and results in the disruption of BTB and apical ES. PMID- 25817992 TI - Interactions between Bcl-xl and its inhibitors: Insights into ligand design from molecular dynamics simulation. AB - The Bcl-xl protein is a potential drug target for cancer, and it has a relatively flat and flexible binding pocket. ABT263 is one of the most promising molecules that inhibit Bcl-xl, and it was developed from its precursor ABT737 with suitable substitutions. However, the structural and mechanistic implications of those changes have not yet been reported. Molecular dynamics simulation has revealed that the conformational microstates of the complex of Bcl-xl and ABT263 shows heterogeneity at the binding interface with Bcl-xl in contrast to the precise interactions witnessed in case of ABT737. This occurs because not all the functional groups of ABT263 are able to anchor into the binding pocket simultaneously at the time of complexation; leaving at least one group weakly associated every time. The insight into the mechanism shows that, in spite of such mutual exclusivity, the resultant effect becomes beneficial, i.e., becomes more effective than ABT737. Going against the traditional belief, the calculations also confirm that there is no benefit of reshaping the highly flexible binding pocket to allow the ligand to be comfortably accommodated and avoid conflicting orientations of the functional groups, as the destabilization becomes active from other sources. These structural clues and in-silico tests suggest possible avenues for improving the binding affinity of ABT263 through further in-vitro and in-vivo tests. PMID- 25817993 TI - Phenotypic malignant changes and untargeted lipidomic analysis of long-term exposed prostate cancer cells to endocrine disruptors. AB - Endocrine disruptors (EDs) are a class of environmental toxic molecules able to interfere with the normal hormone metabolism. Numerous studies involve EDs exposure to initiation and development of cancers, including prostate cancer. In this work, three different EDs (aldrin, aroclor 1254 and chlorpyrifos (CPF)) were investigated as potential inducers of a malignant phenotype in DU145 prostate cancer cells after a chronic exposure. Epithelial to mesenchymal transition (EMT) induction, proliferation, migration, colony formation and release of metalloproteinase 2 (MMP-2) were analyzed in 50-day exposed cells to the selected EDs. As a result, aldrin and CPF exposure led to an EMT induction (loss of 16% and 14% of E-cadherin levels, respectively, compared to the unexposed cells). Aroclor and CPF presented an increased migration (134% and 126%, respectively), colony formation (204% and 144%, respectively) and MMP-2 release (137% in both cases) compared to the unexposed cells. An untargeted lipidomic analysis was performed to decipher the lipids involved in the observed transformations. As general results, aldrin exposure showed a global decrease in phospholipids and sphingolipids, and aroclor and CPF showed an increase of certain phospholipids, glycosphingolipids as well as a remarkable increase of some cardiolipin species. Furthermore, the three exposures resulted in an increase of some triglyceride species. In conclusion, some significant changes in lipids were identified and thus we postulate that some lipid compounds and lipid metabolic pathways could be involved in the acquisition of the malignant phenotype in exposed prostate cancer cells to the selected EDs. PMID- 25817994 TI - PqqD is a novel peptide chaperone that forms a ternary complex with the radical S adenosylmethionine protein PqqE in the pyrroloquinoline quinone biosynthetic pathway. AB - Pyrroloquinoline quinone (PQQ) is a product of a ribosomally synthesized and post translationally modified pathway consisting of five conserved genes, pqqA-E. PqqE is a radical S-adenosylmethionine (RS) protein with a C-terminal SPASM domain, and is proposed to catalyze the formation of a carbon-carbon bond between the glutamate and tyrosine side chains of the peptide substrate PqqA. PqqD is a 10 kDa protein with an unknown function, but is essential for PQQ production. Recently, in Klebsiella pneumoniae (Kp), PqqD and PqqE were shown to interact; however, the stoichiometry and KD were not obtained. Here, we show that the PqqE and PqqD interaction transcends species, also occurring in Methylobacterium extorquens AM1 (Me). The stoichiometry of the MePqqD and MePqqE interaction is 1:1 and the KD, determined by surface plasmon resonance spectroscopy (SPR), was found to be ~12 MUm. Moreover, using SPR and isothermal calorimetry techniques, we establish for the first time that MePqqD binds MePqqA tightly (KD ~200 nm). The formation of a ternary MePqqA-D-E complex was captured by native mass spectrometry and the KD for the MePqqAD-MePqqE interaction was found to be ~5 MUm. Finally, using a bioinformatic analysis, we found that PqqD orthologues are associated with the RS-SPASM family of proteins (subtilosin, pyrroloquinoline quinone, anaerobic sulfatase maturating enzyme, and mycofactocin), all of which modify either peptides or proteins. In conclusion, we propose that PqqD is a novel peptide chaperone and that PqqD orthologues may play a similar role in peptide modification pathways that use an RS-SPASM protein. PMID- 25817995 TI - Modulation of Aminoacylation and Editing Properties of Leucyl-tRNA Synthetase by a Conserved Structural Module. AB - A conserved structural module following the KMSKS catalytic loop exhibits alpha alpha-beta-alpha topology in class Ia and Ib aminoacyl-tRNA synthetases. However, the function of this domain has received little attention. Here, we describe the effect this module has on the aminoacylation and editing capacities of leucyl tRNA synthetases (LeuRSs) by characterizing the key residues from various species. Mutation of highly conserved basic residues on the third alpha-helix of this domain impairs the affinity of LeuRS for the anticodon stem of tRNA(Leu), which decreases both aminoacylation and editing activities. Two glycine residues on this alpha-helix contribute to flexibility, leucine activation, and editing of LeuRS from Escherichia coli (EcLeuRS). Acidic residues on the beta-strand enhance the editing activity of EcLeuRS and sense the size of the tRNA(Leu) D-loop. Incorporation of these residues stimulates the tRNA-dependent editing activity of the chimeric minimalist enzyme Mycoplasma mobile LeuRS fused to the connective polypeptide 1 editing domain and leucine-specific domain from EcLeuRS. Together, these results reveal the stem contact-fold to be a functional as well as a structural linker between the catalytic site and the tRNA binding domain. Sequence comparison of the EcLeuRS stem contact-fold domain with editing deficient enzymes suggests that key residues of this module have evolved an adaptive strategy to follow the editing functions of LeuRS. PMID- 25817996 TI - Dimeric c-di-GMP is required for post-translational regulation of alginate production in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic human pathogen that secretes the exopolysaccharide alginate during infection of the respiratory tract of individuals afflicted with cystic fibrosis and chronic obstructive pulmonary disease. Among the proteins required for alginate production, Alg44 has been identified as an inner membrane protein whose bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) binding activity post-translationally regulates alginate secretion. In this study, we report the 1.8 A crystal structure of the cytoplasmic region of Alg44 in complex with dimeric self intercalated c-di-GMP and characterize its dinucleotide-binding site using mutational analysis. The structure shows that the c-di-GMP binding region of Alg44 adopts a PilZ domain fold with a dimerization mode not previously observed for this family of proteins. Calorimetric binding analysis of residues in the c di-GMP binding site demonstrate that mutation of Arg-17 and Arg-95 alters the binding stoichiometry between c-di-GMP and Alg44 from 2:1 to 1:1. Introduction of these mutant alleles on the P. aeruginosa chromosome show that the residues required for binding of dimeric c-di-GMP in vitro are also required for efficient alginate production in vivo. These results suggest that the dimeric form of c-di GMP represents the biologically active signaling molecule needed for the secretion of an important virulence factor produced by P. aeruginosa. PMID- 25817997 TI - Vacuolar SNARE protein transmembrane domains serve as nonspecific membrane anchors with unequal roles in lipid mixing. AB - Membrane fusion is induced by SNARE complexes that are anchored in both fusion partners. SNAREs zipper up from the N to C terminus bringing the two membranes into close apposition. Their transmembrane domains (TMDs) might be mere anchoring devices, deforming bilayers by mechanical force. Structural studies suggested that TMDs might also perturb lipid structure by undergoing conformational transitions or by zipping up into the bilayer. Here, we tested this latter hypothesis, which predicts that the activity of SNAREs should depend on the primary sequence of their TMDs. We replaced the TMDs of all vacuolar SNAREs (Nyv1, Vam3, and Vti1) by a lipid anchor, by a TMD from a protein unrelated to the membrane fusion machinery, or by artificial leucine-valine sequences. Individual exchange of the native SNARE TMDs against an unrelated transmembrane anchor or an artificial leucine-valine sequence yielded normal fusion activities. Fusion activity was also preserved upon pairwise exchange of the TMDs against unrelated peptides, which eliminates the possibility for specific TMD-TMD interactions. Thus, a specific primary sequence or zippering beyond the SNARE domains is not a prerequisite for fusion. Lipid-anchored Vti1 was fully active, and lipid-anchored Nyv1 permitted the reaction to proceed up to hemifusion, and lipid-anchored Vam3 interfered already before hemifusion. The unequal contribution of proteinaceous TMDs on Vam3 and Nyv1 suggests that Q- and R-SNAREs might make different contributions to the hemifusion intermediate and the opening of the fusion pore. Furthermore, our data support the view that SNARE TMDs serve as nonspecific membrane anchors in vacuole fusion. PMID- 25817998 TI - Mechanistic Studies Reveal Similar Catalytic Strategies for Phosphodiester Bond Hydrolysis by Protein-only and RNA-dependent Ribonuclease P. AB - Ribonuclease P (RNase P) is an endonuclease that catalyzes the essential removal of the 5' end of tRNA precursors. Until recently, all identified RNase P enzymes were a ribonucleoprotein with a conserved catalytic RNA component. However, the discovery of protein-only RNase P (PRORP) shifted this paradigm, affording a unique opportunity to compare mechanistic strategies used by naturally evolved protein and RNA-based enzymes that catalyze the same reaction. Here we investigate the enzymatic mechanism of pre-tRNA hydrolysis catalyzed by the NYN (Nedd4-BP1, YacP nuclease) metallonuclease of Arabidopsis thaliana, PRORP1. Multiple and single turnover kinetic data support a mechanism where a step at or before chemistry is rate-limiting and provide a kinetic framework to interpret the results of metal alteration, mutations, and pH dependence. Catalytic activity has a cooperative dependence on the magnesium concentration (nH = 2) under kcat/Km conditions, suggesting that PRORP1 catalysis is optimal with at least two active site metal ions, consistent with the crystal structure. Metal rescue of Asp-to-Ala mutations identified two aspartates important for enhancing metal ion affinity. The single turnover pH dependence of pre-tRNA cleavage revealed a single ionization (pKa ~ 8.7) important for catalysis, consistent with deprotonation of a metal-bound water nucleophile. The pH and metal dependence mirrors that observed for the RNA-based RNase P, suggesting similar catalytic mechanisms. Thus, despite different macromolecular composition, the RNA and protein-based RNase P act as dynamic scaffolds for the binding and positioning of magnesium ions to catalyze phosphodiester bond hydrolysis. PMID- 25817999 TI - Redox Signal-mediated Enhancement of the Temperature Sensitivity of Transient Receptor Potential Melastatin 2 (TRPM2) Elevates Glucose-induced Insulin Secretion from Pancreatic Islets. AB - Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive Ca(2+) permeable cation channel expressed by pancreatic beta cells where channel function is constantly affected by body temperature. We focused on the physiological functions of redox signal-mediated TRPM2 activity at body temperature. H2O2, an important molecule in redox signaling, reduced the temperature threshold for TRPM2 activation in pancreatic beta cells of WT mice but not in TRPM2KO cells. TRPM2-mediated [Ca(2+)]i increases were likely caused by Ca(2+) influx through the plasma membrane because the responses were abolished in the absence of extracellular Ca(2+). In addition, TRPM2 activation downstream from the redox signal plus glucose stimulation enhanced glucose-induced insulin secretion. H2O2 application at 37 degrees C induced [Ca(2+)]i increases not only in WT but also in TRPM2KO beta cells. This was likely due to the effect of H2O2 on KATP channel activity. However, the N-acetylcysteine-sensitive fraction of insulin secretion by WT islets was increased by temperature elevation, and this temperature-dependent enhancement was diminished significantly in TRPM2KO islets. These data suggest that endogenous redox signals in pancreatic beta cells elevate insulin secretion via TRPM2 sensitization and activity at body temperature. The results in this study could provide new therapeutic approaches for the regulation of diabetic conditions by focusing on the physiological function of TRPM2 and redox signals. PMID- 25818000 TI - Effects of concentration and structure on proteoglycan 4 rheology and interaction with hyaluronan. AB - BACKGROUND: The contribution of proteoglycan 4 (PRG4) to synovial fluid and hyaluronan (HA) solution rheology are poorly understood. The effects of PRG4 disulfide-bonded structure on viscosity and viscosity of newly available full length recombinant human PRG4 (rhPRG4) have not previously been reported. OBJECTIVE: This study determined the viscosity of PRG4 and rhPRG4, R/A (reduced and alkylated) PRG4 and rhPRG4, and PRG4 and rhPRG4+HA solutions. METHODS: Steady shear viscosities of 1.5 MDa HA, PRG4 from bovine cartilage explant culture, rhPRG4 and (rh)PRG4+HA solutions were measured with 40 mm parallel plate fixtures. RESULTS: PRG4 demonstrated shear-dependent viscosity at high concentrations, but Newtonian behaviour at low concentrations and when disulfide bonded/multimeric structure was disrupted by R/A. rhPRG4 demonstrated Newtonian behaviour over all concentrations tested and upon R/A. At high HA concentrations, rhPRG4 reduced solution viscosity, suggesting a binding interaction. At low HA concentrations, solution viscosity was increased relative to HA alone, possibly due to self-association of rhPRG4. Effects of PRG4 on HA solution viscosity were dependent on PRG4's disulfide-bonded structure. CONCLUSIONS: The finding that rhPRG4 can increase the viscosity of low concentration HA solutions suggests that supplementation with rhPRG4 may help mitigate the loss in synovial fluid viscosity experienced with decreased HA concentration in osteoarthritis. PMID- 25818001 TI - The manipulation of alcohol-related interpretation biases by means of Cognitive Bias Modification--Interpretation (CBM-I). AB - BACKGROUND AND OBJECTIVES: There is a large body of evidence demonstrating that alcohol abuse and misuse is characterized by alcohol-related interpretation biases (IBs). The present study tested whether alcohol-related IBs can be trained, and whether this has an effect on alcohol-related associations and drinking behavior. A newly developed alcohol Cognitive Bias Modification - Interpretation (CBM-I) training was employed. The potential moderating effect of executive control on CBM-I training effects was tested. METHOD: Participants were hazardously male drinking students. A classical Stroop was used to assess levels of executive control. Half of the sample was trained to interpret ambiguous alcohol-related scenarios in an alcohol-related manner (alcohol training group), whereas the other half was trained to interpret ambiguous alcohol-related scenarios in a neutral manner (neutral training group). A Single Target Implicit Association Test (STIAT) was used to test whether the training would generalize to implicit alcohol-related associations (target words: alcohol, attributes: positive vs. neutral). To test the training's effect on drinking behavior, a bogus taste test and a one week follow-up measure assessing participant's real life drinking behavior were used. RESULTS: The CBM-I training was partly successful: When presented with novel ambiguous alcohol-related scenarios, participants of the alcohol training group interpreted these scenarios as more alcohol-related after the training. However, there was no reduction in alcohol related IBs in the neutral training group. Results of the STIAT demonstrated that both training groups showed stronger positive than neutral alcohol-related associations. However, there were no between-group differences in alcohol-related associations. Moreover, the CBM-I training's effect was not moderated by levels of executive control. Finally, no group differences were found on levels of alcohol consumption (bogus taste test and at one week follow-up). LIMITATIONS: The neutral training might have been operationalized sub-optimally. A multi session training might have resulted in stronger effects. CONCLUSIONS: These findings are the first to show that alcohol-related IBs can be trained. However, the training effect only partly generalized so more research is needed to advance our understanding of alcohol CBM-I effects. PMID- 25818002 TI - Association between IL28B polymorphism, TNFalpha and biomarkers of insulin resistance in chronic hepatitis C-related insulin resistance. AB - TNFalpha has been shown to play a role in hepatitis C virus (HCV)-induced insulin resistance (IR). Polymorphism of the IL28B gene that encodes IFN-lambda 3 may be associated with IR through modulation of TNFalpha. The aim of this study was to investigate the relationship between IL28B rs12979860 genotype, the level of TNFalpha activation and the degree of IR in patients with chronic hepatitis C. One hundred and thirty-three nondiabetic genotype 1 HCV-infected patients with biopsy proven noncirrhotic hepatitis C were investigated for IR (using HOMA index), IL28B rs12979860 genotype and fasting circulating levels of soluble receptor 1 of TNFalpha (sTNFR1) and adipokines: leptin, adiponectin and IL-6. The HOMA-IR was positively correlated with serum levels of leptin (r = 0.35, P < 0.0001) and sTNFR1 (r = 0.35, P < 0.0001) but not with IL-6 or adiponectin. IL28B rs12979860 CC genotype was observed in 35% patients. Genotype CC and nongenotype CC patients were similar in terms of HOMA-IR (means 1.6 +/- 0.9 vs 1.7 +/- 1.4) and had similar circulating levels of sTNFR1 and adipokines. Independent factors associated with IR were ferritin (OR = 1.002, P = 0.02), leptin (OR = 1.06, P = 0.02) and sTNFR1 (OR = 7.9, P = 0.04). This study suggests that in nondiabetic, noncirrhotic, HCV genotype 1-infected patients, there is no relationship between IL28B rs12979860 genotype and HOMA-IR or sTNFR1 level. HCV-related IR may be mediated through TNFalpha independent of IL28B genotype. PMID- 25818004 TI - Are nematodes a missing link in the confounded ecology of the entomopathogen Bacillus thuringiensis? AB - Bacillus thuringiensis, which is well known as an entomopathogen, has been accepted by the public as a safe bioinsecticide. The natural ecology of this bacterium has never been particularly clear, with views ranging from it being an obligate pathogen to an opportunist pathogen that can otherwise exist as a soil saprophyte or a plant endophyte. This confusion has recently led to it being considered as an environmental pathogen that has evolved to occupy a diverse set of environmental niches in which it can thrive without needing a host. A significant driving force behind this classification is the fact that B. thuringiensis is found in high numbers in environments that are not occupied by the insect hosts to which it is pathogenic. It is our opinion that the ubiquitous presence of this bacterium in the environment is the result of a variety of vectoring systems, particularly those that include nematodes. PMID- 25818005 TI - Is disgust sensitive to classical conditioning as indexed by facial electromyography and behavioural responses? AB - Earlier studies provided preliminary support for the role of classical conditioning as a pathway of disgust learning, yet this evidence has been limited to self-report. This study included facial electromyographical (EMG) measurements (corrugator and levator muscles) and a behavioural approach task to assess participants' motivation-to-eat the actual food items (conditioned stimuli, CS). Food items served as CS and film excerpts of a woman vomiting served as unconditioned stimuli (US). Following acquisition the CS+ (neutral CS paired with US disgust) was rated as more disgusting and less positive. Notably, the conditioned response was transferred to the actual food items as evidenced by participants' reported lowered willingness-to-eat. Participants also showed heightened EMG activity in response to the CS+ which seemed driven by the corrugator indexing a global negative affect. These findings suggest that classical conditioning as a pathway of disgust learning can be reliably observed in subjective but not in disgust-specific physiological responding. PMID- 25818003 TI - Identification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis. AB - Chemoresistance is a poor prognostic factor in breast cancer and is a major obstacle to the successful treatment of patients receiving chemotherapy. However, the precise mechanism of resistance remains unclear. In this study, a pair of breast cancer cell lines, MCF-7 and its adriamycin-resistant counterpart MCF 7/ADR was used to examine resistance-dependent cellular responses and to identify potential therapeutic targets. We applied nanoflow liquid chromatography (nLC) and tandem mass tags (TmT) quantitative mass spectrometry to distinguish the differentially expressed proteins (DEPs) between the two cell lines. Bioinformatics analyses were used to identify functionally active proteins and networks. 80 DEPs were identified with either up- or down-regulation. Basing on the human protein-protein interactions (PPI), we have retrieved the associated functional interaction networks for the DEPs and analyzed the biological functions. Six different signaling pathways and most of the DEPs strongly linked to chemoresistance, invasion, metastasis development, proliferation, and apoptosis. The identified proteins in biological networks served to resistant drug and to select critical candidates for validation analyses by western blot. The glucose-6-phosphate dehydrogenase (G6PD), gamma-glutamyl cyclotransferase (GGCT), isocitrate dehydrogenase 1 (NADP+,soluble)(IDH1), isocitrate dehydrogenase 2 (NADP+,mitochondrial) (IDH2) and glutathione S-transferase pi 1(GSTP1), five of the critical components of GSH pathway, contribute to chemoresistance. PMID- 25818006 TI - Differential proteomic and behavioral effects of long-term voluntary exercise in wild-type and APP-overexpressing transgenics. AB - Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer's disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r(2)=.959), but uncorrelated in transgenics (r(2)=.013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics' deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Abeta40 and Abeta42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. beta-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Abeta. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways. PMID- 25818007 TI - Molecular alterations in areas generating fast ripples in an animal model of temporal lobe epilepsy. AB - The molecular basis of epileptogenesis is poorly characterized. Studies in humans and animal models have identified an electrophysiological signature that precedes the onset of epilepsy, which has been termed fast ripples (FRs) based on its frequency. Multiple lines of evidence implicate regions generating FRs in epileptogenesis, and FRs appear to demarcate the seizure onset zone, suggesting a role in ictogenesis as well. We performed gene expression analysis comparing areas of the dentate gyrus that generate FRs to those that do not generate FRs in a well-characterized rat model of epilepsy. We identified a small cohort of genes that are differentially expressed in FR versus non-FR brain tissue and used quantitative PCR to validate some of those that modulate neuronal excitability. Gene expression network analysis demonstrated conservation of gene co-expression between non-FR and FR samples, but examination of gene connectivity revealed changes that were most pronounced in the cm-40 module, which contains several genes associated with synaptic function and the differentially expressed genes Kcna4, Kcnv1, and Npy1r that are down-regulated in FRs. We then demonstrate that the genes within the cm-40 module are regulated by seizure activity and enriched for the targets of the RNA binding protein Elavl4. Our data suggest that seizure activity induces co-expression of genes associated with synaptic transmission and that this pattern is attenuated in areas displaying FRs, implicating the failure of this mechanism in the generation of FRs. PMID- 25818008 TI - GLT1 overexpression in SOD1(G93A) mouse cervical spinal cord does not preserve diaphragm function or extend disease. AB - Amyotrophic lateral sclerosis (ALS) is characterized by relatively rapid degeneration of both upper and lower motor neurons, with death normally occurring 2-5years following diagnosis primarily due to respiratory paralysis resulting from phrenic motor neuron (PhMN) loss and consequent diaphragm denervation. In ALS, cellular abnormalities are not limited to MNs. For example, decreased levels and aberrant functioning of the major central nervous system (CNS) glutamate transporter, GLT1, occur in spinal cord and motor cortex astrocytes of both humans with ALS and in SOD1(G93A) rodents, a widely studied ALS animal model. This results in dysregulation of extracellular glutamate homeostasis and consequent glutamate excitotoxicity, a primary mechanism responsible for MN loss in ALS animal models and in the human disease. Given these observations of GLT1 dysfunction in areas of MN loss, as well as the importance of testing therapeutic strategies for preserving PhMNs in ALS, we evaluated intraspinal delivery of an adeno-associated virus type 8 (AAV8)-Gfa2 vector to the cervical spinal cord ventral horn of SOD1(G93A) ALS mice for focally restoring intraspinal GLT1 expression. AAV8 was specifically injected into the ventral horn bilaterally throughout the cervical enlargement at 110days of age, a clinically-relevant time point coinciding with phenotypic/symptomatic disease onset. Intraspinal delivery of AAV8-Gfa2-GLT1 resulted in robust transduction primarily of GFAP(+) astrocytes that persisted until disease endstage, as well as a 2-3-fold increase in total intraspinal GLT1 protein expression in the ventral horn. Despite this robust level of astrocyte transduction and GLT1 elevation, GLT1 overexpression did not protect PhMNs, preserve histological PhMN innervation of the diaphragm NMJ, or prevent decline in diaphragmatic respiratory function as assessed by phrenic nerve-diaphragm compound muscle action potential (CMAP) recordings compared to control AAV8-Gfa2-eGFP injected mice. In addition, AAV-Gfa2-GLT1 did not delay forelimb disease onset, extend disease duration (i.e. time from either forelimb or hindlimb disease onsets to endstage) or prolong overall animal survival. These findings suggest that focal restoration of GLT1 expression in astrocytes of the cervical spinal cord using AAV delivery is not an effective therapy for ALS. PMID- 25818009 TI - Ser129 phosphorylation of endogenous alpha-synuclein induced by overexpression of polo-like kinases 2 and 3 in nigral dopamine neurons is not detrimental to their survival and function. AB - Phosphorylation of the alpha-synuclein (alpha-syn) protein at Ser129 [P(S129) alpha-syn] was found to be the most abundant form in intracellular inclusions in brains from Parkinson's disease (PD) patients. This finding suggests that P(S129) alpha-syn plays a central role in the pathogenesis of PD. However, it is at present unclear whether P(S129)-alpha-syn is pathogenic driving the neurodegenerative process. Rodent studies using neither the phosphomimics of human alpha-syn nor co-expression of human wild-type alpha-syn and kinases phosphorylating alpha-syn at Ser129 gave consistent results. One major concern in interpreting these findings is that human alpha-syn was expressed above physiological levels inducing neurodegeneration in rat nigral neurons. In order to exclude this confounding factor, we took a different approach and increased the phosphorylation level of endogenous alpha-syn. For this purpose, we took advantage of recombinant adeno-associated viral (rAAV) vectors to deliver polo like kinase (PLK) 2 or PLK3 in the substantia nigra and investigated whether increased levels of P(S129)-alpha-syn compromised the function and survival of nigral dopaminergic neurons. Interestingly, we observed that hyperphosphorylated alpha-syn did not induce nigral dopaminergic cell death, as assessed at 1 and 4months. Furthermore, histological analysis did not show any accumulation of alpha-syn protein or formation of inclusions. Using in vivo microdialysis, we found that the only measurable functional alteration was the depolarisation induced release of dopamine, while the in vivo synthesis rate of DOPA and dopamine baseline release remained unaltered. Taken together, our results suggest that phosphorylation of alpha-syn at Ser129 does not confer a toxic gain of function per se. PMID- 25818013 TI - Prevalence, awareness, treatment and control of arterial hypertension in Astana, Kazakhstan. A cross-sectional study. AB - OBJECTIVE: Very little is known about prevalence of common cardiovascular risk factors in Central Asia. The aim of the study was to assess the prevalence, awareness, treatment and control of arterial hypertension, and factors associated with these indices in a population sample of Astana, the new capital city of Kazakhstan. DESIGN: Cross-sectional study of subjects registered in eight outpatient policlinics in Astana. METHODS: A total of 497 adults (response rate 56%) aged 50-75 years randomly selected from registers of the policlinics were examined. Hypertension was defined as a mean systolic and/or diastolic blood pressure of >=140/90 mm Hg and/or antihypertensive medication use during the last two weeks. Awareness and treatment were based on self-report. Hypertension control was defined as blood pressure <140/90 mm Hg among hypertensive subjects. RESULTS: The overall prevalence of hypertension was 70%. Among hypertensive subjects, 91% were aware of their condition, 77% took antihypertensive medications, and 34% had blood pressure controlled (<140/90 mm Hg). The prevalence of hypertension and its awareness, treatment and control was more common in women, among persons aged 60 years or more and (except control) among those with high body mass index. None of several available socio-economic or lifestyle measures was associated with any of hypertension indices. CONCLUSIONS: The levels of awareness, treatment and control of hypertension were higher than in most Eastern European and Central Asian populations with available data, most likely reflecting high education and large proportion of civil servants in the new capital city. However, even in this privileged population the rates of successful control of hypertension were modest. PMID- 25818015 TI - Impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Hand Hygiene Approach in five intensive care units in three cities of China. AB - OBJECTIVES: To evaluate the impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Hand Hygiene (HH) Approach in three hospitals in three cities of China, and analyze predictors of poor hand hygiene compliance. STUDY DESIGN: A prospective before-after study from May 2009 to December 2010 in five intensive care units members of the INICC in China. METHODS: The study was divided into two periods: a 3-month baseline period and a follow-up period. A Multidimensional HH Approach was implemented, which included the following elements: 1- administrative support, 2- supplies availability, 3- education and training, 4- reminders in the workplace, 5- process surveillance and 6- performance feedback. Observations were done for HH compliance in each ICU, during randomly selected 30-min periods. RESULTS: A total of 2079 opportunities for HH were recorded. Overall HH compliance increased from 51.5% to 80.1% (95% CI 73.2-87.8; P = 0.004). Multivariate analysis indicated that several variables were significantly associated with poor HH compliance: females vs males (64% vs 55%; 95% CI 0.81-0.94; P = 0.0005), nurses vs physicians (64% vs 57%, P = 0.004), among others. CONCLUSIONS: Adherence to HH was increased significantly with the INICC multidimensional approach. Specific programs directed to improve HH in variables found to be predictors of poor HH compliance should be implemented. PMID- 25818014 TI - Social disparities in access to breast and cervical cancer screening by women living in Spain. AB - OBJECTIVES: To describe uptake of breast and cervical cancer screening by women living in Spain, analyse the possible associated social and health factors, and compare uptake rates with those obtained in previous surveys. STUDY DESIGN: Cross sectional study using data from the 2011 Spanish national health survey. METHODS: Uptake of breast cancer screening was analysed by asking women aged 40-69 years whether they had undergone mammography in the previous two years. Uptake of cervical cancer screening was analysed by asking women aged 25-65 years whether they had undergone cervical cytology in the previous three years. Independent variables included sociodemographic characteristics, and variables related to health status and lifestyle. RESULTS: Seventy-two percent of women had undergone mammography in the previous two years. Having private health insurance increased the probability of breast screening uptake four-fold [odds ratio (OR) 3.96, 95% confidence interval (CI) 2.71-5.79], and being an immigrant was a negative predictor for breast screening uptake. Seventy percent of women had undergone cervical cytology in the previous three years. Higher-educated women were more likely to have undergone cervical cancer screening (OR 2.59, 95% CI 1.97-3.40), and obese women and women living in rural areas were less likely to have undergone cervical cancer screening. There have been no relevant improvements in uptake rates of either breast or cervical cancer screening since 2006. CONCLUSION: Uptake of breast and cervical cancer screening could be improved in Spain, and uptake rates have stagnated over recent years. Social disparities have been detected with regard to access to these screening tests, indicating that it is necessary to continue researching and optimizing prevention programmes in order to improve uptake and reduce these disparities. PMID- 25818016 TI - Prevalence and influencing factors of depressive symptoms among women of reproductive age in the rural areas of Hubei, China. AB - OBJECTIVES: Depression is one of the most common mental disorders and a major public health problem in the Chinese population, especially among women. The current study aims to understand prevalence of depression symptoms and provide detailed epidemiological factors associated with depression among reproductive women in rural areas which was paid less attention in previous surveys. STUDY DESIGN: Cross-sectional study. METHODS: Face-to-face household interviews were conducted on 1058 women (age: 15-49 years) in rural areas from July 2012 to August 2012. Questionnaires were used to investigate the influencing factors of depression among women. Pearson's chi(2), logistic regression analysis and structural equation modelling (SEM) were applied to analyze the related factors. RESULTS: The prevalence of depression among women was 30.7% [95% confidence interval (CI): 27.9%-33.5%]. Compared with non-depressed individuals, those with depression were more likely to be short of social support [odd ratio (OR): 0.940, P < 0.001) and have no one to talk with (OR: 0.366, P < 0.001), to be dissatisfied with the house (OR: 2.673, P < 0.001) and economy (OR: 2.268, P < 0.01) of their family, and to have great pressure (OR: 2.099, P < 0.01), negative life events (OR: 1.485, P < 0.05) and physical diseases (OR: 1.364, P < 0.05). Pressure status, social support assessment, and socio-economic status were negatively related to depression (correlation coefficient: -0.57, -0.27 and 0.17). CONCLUSIONS: The high prevalence of depression among reproductive women in rural areas is of particular concern. Factors associated with depression may assist health care administrations to identify and assess high-risk women and target strategies accordingly. PMID- 25818017 TI - Bidecadal North Atlantic ocean circulation variability controlled by timing of volcanic eruptions. AB - While bidecadal climate variability has been evidenced in several North Atlantic paleoclimate records, its drivers remain poorly understood. Here we show that the subset of CMIP5 historical climate simulations that produce such bidecadal variability exhibits a robust synchronization, with a maximum in Atlantic Meridional Overturning Circulation (AMOC) 15 years after the 1963 Agung eruption. The mechanisms at play involve salinity advection from the Arctic and explain the timing of Great Salinity Anomalies observed in the 1970s and the 1990s. Simulations, as well as Greenland and Iceland paleoclimate records, indicate that coherent bidecadal cycles were excited following five Agung-like volcanic eruptions of the last millennium. Climate simulations and a conceptual model reveal that destructive interference caused by the Pinatubo 1991 eruption may have damped the observed decreasing trend of the AMOC in the 2000s. Our results imply a long-lasting climatic impact and predictability following the next Agung like eruption. PMID- 25818018 TI - [Development And Validation Of A Breastfeeding Knowledge And Skills Questionnaire]. AB - INTRODUCTION: Pediatricians play a key role in the onset and duration of breastfeeding. Although it is known that they lack formal education on this subject, there are currently no validated tools available to assess pediatrician knowledge regarding breastfeeding. OBJECTIVE: To develop and validate a Breastfeeding Knowledge and Skills Questionnaire for Pediatricians. MATERIAL AND METHODS: Once the knowledge areas were defined, a representative sample of pediatricians was chosen to carry out the survey. After pilot testing, non discriminating questions were removed. Content validity was assessed by 14 breastfeeding experts, who examined the test, yielding 22 scorable items (maximum score: 26 points). To approach criterion validity, it was hypothesized that a group of pediatricians with a special interest in breastfeeding (1) would obtain better results than pediatricians from a hospital without a maternity ward (2), and the latter would obtain a higher score than the medical residents of Pediatrics training in the same hospital (3). The questionnaire was also evaluated before and after a basic course in breastfeeding. RESULTS: Breastfeeding experts have an index of agreement of >.90 for each item. The 3 groups (n=82) were compared, finding significant differences between group (1) and the rest. Moreover, an improvement was observed in the participants who attended the breastfeeding course (n=31), especially among those with less initial knowledge. Regarding reliability, internal consistency (KR-20=.87), interobserver agreement, and temporal stability were examined, with satisfactory results. CONCLUSIONS: A practical and self-administered tool is presented to assess pediatrician knowledge regarding breastfeeding, with a documented validity and reliability. PMID- 25818019 TI - Genotype-by-environment interactions underlie the expression of pre- and post copulatory sexually selected traits in guppies. AB - The role that genotype-by-environment interactions (GEIs) play in sexual selection has only recently attracted the attention of evolutionary biologists. Yet GEIs can have profound evolutionary implications by compromising the honesty of sexual signals, maintaining high levels of genetic variance underlying their expression and altering the patterns of genetic covariance among fitness traits. In this study, we test for GEIs in a highly sexually dimorphic freshwater fish, the guppy Poecilia reticulata. We conducted an experimental quantitative genetic study in which male offspring arising from a paternal half-sibling breeding design were assigned to differing nutritional 'environments' (either high or low feed levels). We then determined whether the manipulation of diet quantity influenced levels of additive genetic variance and covariance for several highly variable and condition-dependent pre- and post-copulatory sexual traits. In accordance with previous work, we found that dietary limitation had strong phenotypic effects on numerous pre- and post-copulatory sexual traits. We also report evidence for significant GEI for several of these traits, which in some cases (area of iridescence and sperm velocity) reflected a change in the rank order of genotypes across different nutritional environments (i.e. ecological crossover). Furthermore, we show that genetic correlations vary significantly between nutritional environments. Notably, a highly significant negative genetic correlation between iridescent coloration and sperm viability in the high food treatment broke down under dietary restriction. Taken together, these findings are likely to have important evolutionary implications for guppies; ecological crossover may influence sexual signal reliability in unstable (nutritional) environments and contribute towards the extreme levels of polymorphism in sexual traits typically reported for this species. Furthermore, the presence of environment-specific genetic covariance suggests that trade-offs measured in one environment may not be indicative of genetic constraints in others. PMID- 25818020 TI - Progressive Pearling of Barley Kernel: Chemical Characterization of Pearling Fractions and Effect of Their Inclusion on the Nutritional and Technological Properties of Wheat Bread. AB - Two hulled barley varieties have been sequentially pearled for one to eight cycles, each with 5% removal. The derived fractions were analyzed for their bioactive compound content. The dietary fiber (DF) decreased from the external to the internal layers, whereas beta-glucans showed an inverse trend. Deoxynivalenol contamination was concentrated in the outer layers. The total antioxidant activity (TAA) was higher in the 15-25% fractions, which were used to prepare bread. Five mixtures of refined wheat flour, with an increasing replacement of this pearled barley fraction, were compared with a control for the bioactive compound content, as well as for the rheological and physical bread properties. The inclusion of pearled fractions with up to a 10% substitution leads to a clear enhancement of the DF and TAA, with only minor detrimental effects on the physical parameters. Selected byproducts of barley pearling could be proposed as functional ingredients for bakery products rich in DF and TAA. PMID- 25818021 TI - 'Mislabelled' make-up remover wet wipes as a cause of severe, recalcitrant facial eczema. PMID- 25818022 TI - Reduction in the prevalence of carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa in New York City. AB - We compared susceptibilities of Acinetobacter baumannii and Pseudomonas aeruginosa collected during surveillance studies conducted during 2009 and 2013 2014 involving hospitals in New York City. There were significant decreases in the number of carbapenem-resistant A baumannii and P aeruginosa cases during 2013 2014; it appears the institution of effective infection control measures has contributed to this decline. However the number of isolates of A baumannii with OXA-23-type beta-lactamase increased during 2013-2014. PMID- 25818023 TI - Biochemical and microbial contamination of surgical devices: a quantitative analysis. AB - Reusable devices are required to be safety processed prior to patient use, including cleaning and disinfection and sterilization. In developing and testing cleaning processes, it is important to understand the levels of soils typically present on devices after surgical use. Previous soil investigations have focused on microbial contamination levels; less is known about biochemical contamination. In this study, microbial and biochemical contamination on a range of surgical instrumentation after patient use were investigated. Analysis included bacteria levels, total organic carbon, protein, and hemoglobin. The highest levels of soil contamination were caused by protein, in contrast with bacteria levels being a minor component of instrument soiling. This study provides a better understanding of the microbial and biochemical levels of soils that are typically present in used surgical devices. These levels can be used to develop artificial test soils for testing cleaning efficacy under laboratory conditions and to further evaluate patient risks from inadequate cleaning. PMID- 25818025 TI - The two-visual-systems hypothesis and the perspectival features of visual experience. AB - Some critics of the two-visual-systems hypothesis (TVSH) argue that it is incompatible with the fundamentally egocentric nature of visual experience (what we call the 'perspectival account'). The TVSH proposes that the ventral stream, which delivers up our visual experience of the world, works in an allocentric frame of reference, whereas the dorsal stream, which mediates the visual control of action, uses egocentric frames of reference. Given that the TVSH is also committed to the claim that dorsal-stream processing does not contribute to the contents of visual experience, it has been argued that the TVSH cannot account for the egocentric features of our visual experience. This argument, however, rests on a misunderstanding about how the operations mediating action and the operations mediating perception are specified in the TVSH. In this article, we emphasize the importance of the 'outputs' of the two-systems to the specification of their respective operations. We argue that once this point is appreciated, it becomes evident that the TVSH is entirely compatible with a perspectival account of visual experience. PMID- 25818024 TI - Procedure-specific surgical site infection incidence varies widely within certain National Healthcare Safety Network surgery groups. AB - BACKGROUND: The National Healthcare Safety Network (NHSN) classifies surgical procedures into 40 categories. The objective of this study was to determine surgical site infection (SSI) incidence for clinically defined subgroups within 5 heterogeneous NHSN surgery categories. METHODS: This is a retrospective cohort study using the longitudinal State Inpatient Database. We identified 5 groups of surgical procedures (amputation; bile duct, liver or pancreas [BILI]; breast; colon; and hernia) using ICD-9-CM procedure codes in community hospitals in California, Florida, and New York from January 2009-September 2011 in persons aged >=18 years. Each of these 5 categories was classified to more specific surgical procedures within the group. The 90-day SSI rates were calculated using ICD-9-CM diagnosis codes. RESULTS: There were 62,901 amputation surgeries, 33,358 BILI surgeries, 72,058 breast surgeries, 125,689 colon surgeries, and 85,745 hernia surgeries in 349,298 people. The 90-day SSI rates varied significantly within each of the 5 subgroups. Within the BILI category, bile duct, pancreas, and laparoscopic liver procedures had SSI rates of 7.2%, 17.2%, and 2.2%, respectively (P < .0001 for each) compared with open liver procedures (11.1% SSI). CONCLUSION: The 90-day SSI rates varied widely within certain NHSN categories. Risk adjustment for specific surgery type is needed to make valid comparisons between hospitals. PMID- 25818026 TI - The experience and perceptions of men with prostate cancer and their partners of the CONNECT psychosocial intervention: a qualitative exploration. AB - AIM: To explore the experience of prostate cancer survivors and their partners of the CONNECT psychosocial intervention. BACKGROUND: There is a scarcity of evidence relating to interventions to help men and their partners cope with the after affects of prostate cancer treatment. DESIGN: This study employed a qualitative design for in depth exploration through couple interviews. The addition of a short process evaluation questionnaire was used to supplement the qualitative data. METHODS: Semi-structured interviews were conducted between January 2012-October 2012 with a purposive sample of 11 couple dyads who had participated in the CONNECT intervention. Data were analysed using inductive content analysis. Simple descriptive statistics were used to analyse the findings from the questionnaire data. RESULTS: Couples perceived benefits of participating in the intervention to include: opportunities to share experiences, gain validation, obtain information and engage in couple care. The expertise of the professional facilitator and group dynamics were highlighted as factors influencing the success of the intervention. Potential areas for improvement of the intervention were identified as being: further development of the sexual dysfunction component; incorporation of a partner specific session to better address their needs; determination of optimal delivery format and timing; and further tailoring of the components of the intervention. CONCLUSION: Although there were areas that could be further improved, this psychosocial intervention was valued by the participants. The insight gained from this qualitative exploration can be used to make the necessary changes before the intervention can be tested in a large randomised controlled trial. PMID- 25818027 TI - Single-nucleotide polymorphism discovery and validation in high-density SNP array for genetic analysis in European white oaks. AB - An Illumina Infinium SNP genotyping array was constructed for European white oaks. Six individuals of Quercus petraea and Q. robur were considered for SNP discovery using both previously obtained Sanger sequences across 676 gene regions (1371 in vitro SNPs) and Roche 454 technology sequences from 5112 contigs (6542 putative in silico SNPs). The 7913 SNPs were genotyped across the six parental individuals, full-sib progenies (one within each species and two interspecific crosses between Q. petraea and Q. robur) and three natural populations from south western France that included two additional interfertile white oak species (Q. pubescens and Q. pyrenaica). The genotyping success rate in mapping populations was 80.4% overall and 72.4% for polymorphic SNPs. In natural populations, these figures were lower (54.8% and 51.9%, respectively). Illumina genotype clusters with compression (shift of clusters on the normalized x-axis) were detected in ~25% of the successfully genotyped SNPs and may be due to the presence of paralogues. Compressed clusters were significantly more frequent for SNPs showing a priori incorrect Illumina genotypes, suggesting that they should be considered with caution or discarded. Altogether, these results show a high experimental error rate for the Infinium array (between 15% and 20% of SNPs potentially unreliable and 10% when excluding all compressed clusters), and recommendations are proposed when applying this type of high-throughput technique. Finally, results on diversity levels and shared polymorphisms across targeted white oaks and more distant species of the Quercus genus are discussed, and perspectives for future comparative studies are proposed. PMID- 25818030 TI - Predicting Renal Parenchymal Loss after Nephron Sparing Surgery. AB - PURPOSE: We analyze the relationship among various patient, operative and tumor characteristics to determine which factors correlate with renal parenchymal volume loss after nephron sparing surgery using a novel 3-dimensional volume assessment. MATERIALS AND METHODS: We conducted a retrospective review of an institutional database of patients who underwent nephron sparing surgery from 1992 to 2014 for a localized renal mass. Tumors were classified according to the R.E.N.A.L. nephrometry system. Using 3-dimensional reconstruction imaging software, preoperative and postoperative renal parenchymal volume was calculated for the ipsilateral and contralateral kidney. RESULTS: A total of 158 patients were analyzed. Mean patient age was 58.7 years and mean followup was 40.1 months. Mean preoperative tumor volume was 34.0 cc and mean tumor dimension was 3.4 cm. Mean R.E.N.A.L. nephrometry score was 6.2, with 60.1%, 34.2% and 5.7% of tumors classified as low, medium and high complexity, respectively. Mean change in renal parenchymal volume after nephron sparing surgery was -15.3% for the ipsilateral kidney and -6.8% for total kidney volume. On univariate analysis ischemia time, tumor size, R.E.N.A.L. nephrometry score, complexity grouping and the individual nephrometry components of tumor size, percent exophytic, anterior/posterior, depth and tumor proximity to the renal artery or vein were associated with greater renal parenchymal volume loss. On multivariate analysis only ischemia time, tumor size, posterior location and percent exophytic were independently associated with more renal parenchymal volume loss. CONCLUSIONS: Using precise 3 dimensional volumetric analysis we found that ischemia time, tumor size and endophytic/exophytic properties of a localized renal mass are the most important determinants of renal parenchymal volume loss. PMID- 25818031 TI - Efficacy of Mixtures of Magnesium, Citrate and Phytate as Calcium Oxalate Crystallization Inhibitors in Urine. AB - PURPOSE: The main aim of the current study was to evaluate the effectiveness of mixtures of magnesium, citrate and phytate as calcium oxalate crystallization inhibitors. MATERIALS AND METHODS: A turbidimetric assay in synthetic urine was performed to obtain induction times for calcium oxalate crystallization in the absence and presence of different mixtures of inhibitors. The morphology of calcium oxalate crystals in the absence or presence of inhibitors and mixtures of the inhibitors was evaluated in 2 crystallization experiments at low and high calcium oxalate supersaturation. The crystals formed were examined using scanning electron microscopy. RESULTS: Examination of crystallization induction times revealed clear inhibitory effects of magnesium, citrate and phytate on calcium oxalate crystallization, supporting usefulness in the treatment and prevention of calcium oxalate nephrolithiasis. Significant synergistic effects between magnesium and phytate were observed. Scanning electron microscopy images revealed that phytate is a powerful crystal growth inhibitor of calcium oxalate, totally preventing the formation of trihydrate and monohydrate. In addition to crystallization inhibition capacity, citrate and magnesium avoided calcium oxalate crystallization by decreasing its supersaturation. CONCLUSIONS: The synergistic effect between magnesium and phytate on calcium oxalate crystallization suggests that a combination of these 2 compounds may be highly useful as antilithiasis therapy. PMID- 25818028 TI - Nuclear proteins hijacked by mammalian cytoplasmic plus strand RNA viruses. AB - Plus strand RNA viruses that replicate in the cytoplasm face challenges in supporting the numerous biosynthetic functions required for replication and propagation. Most of these viruses are genetically simple and rely heavily on co opting cellular proteins, particularly cellular RNA-binding proteins, into new roles for support of virus infection at the level of virus-specific translation, and building RNA replication complexes. In the course of infectious cycles many nuclear-cytoplasmic shuttling proteins of mostly nuclear distribution are detained in the cytoplasm by viruses and re-purposed for their own gain. Many mammalian viruses hijack a common group of the same factors. This review summarizes recent gains in our knowledge of how cytoplasmic RNA viruses use these co-opted host nuclear factors in new functional roles supporting virus translation and virus RNA replication and common themes employed between different virus groups. PMID- 25818032 TI - Pain during Female Urethral Catheterization: Intraurethral Lubricant Injection versus Catheter Tip Lubrication--A Prospective Randomized Trial. AB - PURPOSE: Urethral lubrication during catheterization can be performed by instilling the gel directly in the urethra or by pouring the gel on the catheter tip. In this study we compared the pain level associated with each technique during female urethral catheterization in the setup of a multichannel urodynamic study. MATERIALS AND METHODS: A total of 94 women with a mean +/- SD age of 55 +/ 14 years who were referred for a multichannel urodynamic study were prospectively randomized into 2 groups according to lubrication technique, including 1) instillation of 5 ml 2% lidocaine gel in the urethra 5 minutes before catheterization or 2) lubrication of the distal part of the catheter with 5 ml 2% lidocaine gel. A visual analog pain scale of 0 to 10 was completed at different time points, including prior to gel instillation (baseline), during gel instillation (group 1), during catheterization, and 5 and 30 minutes after the procedure ended. RESULTS: The study groups did not differ in demographic, clinical or urodynamic parameters. The mean visual analog scale score during catheterization was 2.3 +/- 1.4 and 2.4 +/- 1.6 in groups 1 and 2, respectively (p = 0.71). There was no difference in the reported visual analog scale score at the other checkpoints. The mean recorded visual analog scale score during instillation of the lubricant in the urethra in group 1 was 1.9 +/- 0.9. CONCLUSIONS: The actual act of lubricant instillation in the urethra during catheterization in women causes additional and unnecessary pain. Therefore, it is not recommended. Other than that there is no difference in the urethral pain level between the 2 lubrication techniques. PMID- 25818033 TI - [Male breast cancer: prognostic factors, diagnosis and treatment: a multi institutional survey of 95 cases]. AB - OBJECTIVES: The optimal treatment for male breast cancer is not known because male breast cancer is a rare disease. It represents as little as 0.6% of all breast cancers and less than 1% of human cancers. The aim was to analyze the clinical, histological and therapeutic characteristics of 95 men cared for breast cancer between 2000 and 2010 in four hospitals, and determine predictors of poor prognosis to improve care of male breast cancer. METHODS: This study is a multi institutional survey, retrospective, involving four French institutions: Cancer Institute of the West (ICO), Reunion Island South hospital group, the hospital group of Dax, and the Bergonie Institute. All carcinomas in situ or invasive breast occurred in male patients were included. An analysis of clinical, histological and therapeutic features was performed. Statistical analysis of our study focused on the overall survival of patients and specific method of Kaplan Meier, enabling search for predictors of poor prognosis. RESULTS: The mean age was 65 years. Thirty-seven percent of patients were overweight or obese. It was in 88% of cases of palpable tumor whose average size was 26.29mm. Ninety patients, none had a lesion palpable T0, 44% T1 tumors, 38% T2 tumors, 3% had a T3 tumors, and finally 10% T4 tumors. The histological type was the most common invasive ductal carcinoma (87%). He found a similar proportion of patients with or without lymph node involvement. N+ patients, capsular rupture was observed in 29% of cases. Receptor positivity was found, estrogen in 95% of cases and progesterone in 83% of cases. Additional irradiation was performed in 75% of patients and chemotherapy in 37% of patients. Overall survival was 79.2% at five years and 70.8% at ten years. Age, tumor size and histological capsular rupture are factors that significantly influence the overall survival and specific. CONCLUSION: Male breast cancer is a different pathology of breast cancer in women. The majority of recommendations suggest treating men who are diagnosed with breast cancer, using the guidelines applied to postmenopausal women treatments. There is no study based on male population that has evaluated these treatment modalities in terms of impact on survival. The diagnosis is usually made at later stages, and tumor size is often greater. Histological characteristics also differ. However, the treatment is almost identical. PMID- 25818034 TI - Perioperative care of elderly outpatients. A review. AB - INTRODUCTION: Epidemiological data show a continuous expansion of elderly population in Europe. Older individuals require more medical services relative to their younger counterparts. The aim of this review was to summarize the most recent considerations in regards to preoperative assessment, postoperative outcomes, patient satisfaction and cost-effectiveness analysis of day surgery in the elderly. METHODS: This review considered studies that included older patients who were undergoing day surgery general procedures (such as inguinal hernia repair, excision of breast lump, haemorrhoidectomy). The interventions of interest to this review included selection criteria, perioperative care, management of postoperative pain. RESULTS: According to a large number of studies, old age does not constitute a contraindication for elderly to undergo ambulatory surgery but this population may require more careful intraoperative cardiovascular management. Hospitalization of older patients is frequently associated with postoperative cognitive dysfunction (POCD). Management of postoperative pain in older patients may be complicated by a number of factors, including a higher risk of age- and disease-related changes in physiology and disease-drug and drug-drug interactions. Early studies evaluating approaches to facilitating the recovery process have demonstrated the benefits of multimodal analgesic techniques. CONCLUSIONS: A lot of studies show that even elderly patients can successfully undergo day surgery procedures by implementing evidence based perioperative care programs, minimizing operative duration and tissue trauma and providing a comfortable setting. PMID- 25818035 TI - [Hypereosinophilic syndrome with cardiogenic shock: First Mexican case]. PMID- 25818029 TI - APOBECs and virus restriction. AB - The APOBEC family of single-stranded DNA cytosine deaminases comprises a formidable arm of the vertebrate innate immune system. Pre-vertebrates express a single APOBEC, whereas some mammals produce as many as 11 enzymes. The APOBEC3 subfamily displays both copy number variation and polymorphisms, consistent with ongoing pathogenic pressures. These enzymes restrict the replication of many DNA based parasites, such as exogenous viruses and endogenous transposable elements. APOBEC1 and activation-induced cytosine deaminase (AID) have specialized functions in RNA editing and antibody gene diversification, respectively, whereas APOBEC2 and APOBEC4 appear to have different functions. Nevertheless, the APOBEC family protects against both periodic viral zoonoses as well as exogenous and endogenous parasite replication. This review highlights viral pathogens that are restricted by APOBEC enzymes, but manage to escape through unique mechanisms. The sensitivity of viruses that lack counterdefense measures highlights the need to develop APOBEC-enabling small molecules as a new class of anti-viral drugs. PMID- 25818036 TI - The added value of long-lasting preparedness for the management of a patient with Ebola. PMID- 25818039 TI - One size may not fit all: the debate of universal tumor testing for Lynch syndrome. PMID- 25818037 TI - Dietary patterns and asthma prevalence, incidence and control. AB - BACKGROUND: The increased asthma prevalence in westernized societies has been suggested to be related to environment exposures and lifestyle changes, particularly diet. We aimed to explore the association between dietary patterns and asthma prevalence, incidence and control in a nationally representative population. METHODS: Data from 32,644 adults, 53% female, from the 4th Portuguese National Health Survey were analysed. Prevalence of asthma was 5.3%; 'current asthma', defined by asthma symptoms within previous year, 3.5%; 'current medicated asthma' defined by use of asthma medication within previous year, 3.0%; 'current severe asthma' defined by emergency visit because of asthma within previous year, 1.4%; and 'incident asthma', 0.2%. Dietary patterns (DP) were identified by latent trait models based on dietary intake. Unconditional logistic regression models were performed to analyse association between DP and asthma. Age, gender, education, family income, proxy reporting information, smoking, body mass index and physical activity level were analysed as confounders. RESULTS: Two of the five identified DP were associated with asthma: 'high fat, sugar and salt' DP (positively correlated with pastry, chocolate and sweet desserts, candies, salty snacks, chips, fruit juices, soft drinks and alcoholic beverages consumption at snacks) was associated with asthma prevalence (OR = 1.13, 95% CI = 1.03, 1.24) and current severe asthma (OR = 1.23, 95% CI = 1.03, 1.48), while 'fish, fruit and vegetables' DP (positively correlated with fish, vegetables and fruit intake at meals) was negatively associated with current (OR = 0.84, 95% CI = 0.73, 0.98), and current medicated asthma (OR = 0.84, 95% CI = 0.72, 0.98), after adjustment for confounders. CONCLUSION & CLINICAL RELEVANCE: Our results suggest a protective association between 'fish, vegetables and fruit' DP and current asthma and current medicated asthma, and a detrimental association between 'high fat, sugar and salt' DP and severe asthma prevalence, further supporting the rational for diet and lifestyle intervention studies in asthma based on whole dietary patterns and physical activity. PMID- 25818040 TI - Post-training corticosterone inhibits the return of fear evoked by platform stress and a subthreshold conditioning procedure in Sprague-Dawley rats. AB - The return of fear is an important issue in anxiety disorder research. Each time a fear memory is reactivated, it may further strengthen overactivation of the fear circuit, which may contribute to long-term maintenance of the fear memory. Recent evidence indicates that glucocorticoids may help attenuate pathological fear, but its role in the return of fear is unclear. In the present study, systemic corticosterone (CORT; 25mg/kg) administration 1h after fear conditioning did not impair the consolidation process but significantly suppressed the return of fear evoked by a subthreshold conditioning (SC) procedure and elevated platform (EP) stress. Compared with the SC-induced return of fear, acute stress induced return was state-dependent. In addition, post-training CORT treatment increased the adrenocorticotropic response after EP stress, which indicates that the drug-induced suppression of the return of fear may possibly derive from its regulation effect of the hypothalamic-pituitary-adrenal axis reactivity to stress. These results suggest that post-training CORT administration may help inhibit the return of fear evoked by EP or SC stress. The possible mechanisms involved in the high-dose CORT-induced suppression of the SC- and EP-induced return of fear are discussed. PMID- 25818042 TI - Prognostic indicators for surgical peri-implantitis treatment. AB - OBJECTIVES: Objective of this study was to identify prognostic indicators for the outcome of resective peri-implantitis treatment, by an analysis of the pooled data of two previously conducted randomized controlled trials. MATERIAL AND METHODS: Data of 74 patients with peri-implantitis (187 implants) who had received resective surgical treatment were available. Primary outcome variable was failure of peri-implantitis treatment after 12 months. Multilevel univariable and multiple logistic regression analyses were performed to evaluate the effect of various potentially prognostic indicators on the primary outcome. RESULTS: Peri-implantitis treatment was unsuccessful in 106 implants (57%) and 48 patients (67%) after 12 months. In the multiple regression analysis, the variables "order of inclusion" (P = 0.016) and mean bone loss at baseline (P = 0.030) were significant prognostic indicators for treatment failure. To eliminate the effect of "order of inclusion," post hoc analyses were carried out in a subgroup of patients. The univariable post hoc analysis showed a significant association for smoking (P = 0.015), maximum pocket depth at baseline (P = 0.073), mean bone loss at baseline (P = 0.003), and presence of plaque (P = 0.100). In the multiple regression post hoc analysis, only the variables smoking (P = 0.044) and mean bone loss (P = 0.043) remained statistically significant. CONCLUSIONS: The outcome of surgical peri-implantitis treatment is influenced by the experience of the surgical team with the surgical procedure. The observed learning effect has consequences for clinical practice and for conducting and interpreting clinical trials on peri-implantitis treatment. Other prognostic indicators are amount of peri-implant bone loss at baseline and smoking, and to a lesser extent, probing pocket depth at baseline and presence of plaque during follow-up. Early diagnosis of peri-implantitis and control of behavioral factors are crucial in achieving peri-implantitis treatment success. PMID- 25818043 TI - Evaluating training context competence of use: productive and unproductive models of use. AB - This study discusses an evaluation model carried out in vocational training contexts and draws from a line of studies that have analyzed the processes of meaning construction according to a semiotic and contextual perspective (Freda, 2011; Freda & De Luca Picione, 2014; Salvatore & Freda, 2011; Salvatore & Venuleo, 2008; Valsiner, 2007). The study aims to identify models of use of training contexts (thought of as different ways to give meaning to the relationship between the trainee and the training context), as well as to analyze their relationship with social-demographic variables and course type. An additional aim is to investigate training outcomes to discern any connection existing between models of use and competence of use (e.g. the ability of trainees to participate and benefit from the training setting for their professional development aims). An especially designed ad hoc open-answer questionnaire was administered to 76 trainees in the ex-post impact training phase. We adopted a multi-method analysis methodology (Bolasco, 1999). Data analysis pointed to three models of use: Opaque, Learning, Development. The last one showed a significant association with training outcomes which were effective and useful to hypothesize the development of a competence of use. The results have interesting implications for the design of evaluation programs directed to the sensemaking processes that organize the relationship between the formative self and the training context. PMID- 25818041 TI - Diagnostic yield of genetic testing in epileptic encephalopathy in childhood. AB - OBJECTIVE: Epilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic. METHODS: We included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic. Electronic patient charts were reviewed for clinical features, neuroimaging, biochemical investigations, and molecular genetic investigations including targeted next-generation sequencing of epileptic encephalopathy genes. RESULTS: Genetic causes were identified in 28% of the 110 patients: 7% had inherited metabolic disorders including pyridoxine dependent epilepsy caused by ALDH7A1 mutation, Menkes disease, pyridox(am)ine-5-phosphate oxidase deficiency, cobalamin G deficiency, methylenetetrahydrofolate reductase deficiency, glucose transporter 1 deficiency, glycine encephalopathy, and pyruvate dehydrogenase complex deficiency; 21% had other genetic causes including genetic syndromes, pathogenic copy number variants on array comparative genomic hybridization, and epileptic encephalopathy related to mutations in the SCN1A, SCN2A, SCN8A, KCNQ2, STXBP1, PCDH19, and SLC9A6 genes. Forty-five percent of patients obtained a genetic diagnosis by targeted next-generation sequencing epileptic encephalopathy panels. It is notable that 4.5% of patients had a treatable inherited metabolic disease. SIGNIFICANCE: To the best of our knowledge, this is the first study to combine inherited metabolic disorders and other genetic causes of epileptic encephalopathy. Targeted next-generation sequencing panels increased the genetic diagnostic yield from <10% to >25% in patients with epileptic encephalopathy. PMID- 25818044 TI - Attention to pleasant stimuli in early adolescence predicts alcohol-related problems in mid-adolescence. AB - Attenuated responses to natural rewards have been found to predict subsequent substance use among dependent populations, suggesting that this may be a premorbid risk factor for later problematic substance use. However, research on adolescent risk-taking suggests that exaggerated, rather than blunted, reward responsiveness predicts later substance abuse. Acoustic startle-induced event related potentials (ERP) were recorded in a sample of 11-13 year-olds while they viewed affective pictures, and participants were reassessed four years later regarding alcohol use and experience of alcohol-related problems. Increased attenuation of the amplitude of the P300 component of the ERP during viewing of pleasant pictures, relative to amplitude during neutral pictures (an indicator of increased attention to pleasant pictures), predicted increased likelihood of alcohol-related problems at follow-up. These findings further support research indicating that increased reward responsiveness predicts risky behaviours in adolescence, with anhedonia primarily a consequence of substance dependence. PMID- 25818045 TI - Brightness masking is modulated by disparity structure. AB - The luminance contrast at the borders of a surface strongly influences surface's apparent brightness, as demonstrated by a number of classic visual illusions. Such phenomena are compatible with a propagation mechanism believed to spread contrast information from borders to the interior. This process is disrupted by masking, where the perceived brightness of a target is reduced by the brief presentation of a mask (Paradiso & Nakayama, 1991), but the exact visual stage that this happens remains unclear. In the present study, we examined whether brightness masking occurs at a monocular-, or a binocular-level of the visual hierarchy. We used backward masking, whereby a briefly presented target stimulus is disrupted by a mask coming soon afterwards, to show that brightness masking is affected by binocular stages of the visual processing. We manipulated the 3-D configurations (slant direction) of the target and mask and measured the differential disruption that masking causes on brightness estimation. We found that the masking effect was weaker when stimuli had a different slant. We suggest that brightness masking is partly mediated by mid-level neuronal mechanisms, at a stage where binocular disparity edge structure has been extracted. PMID- 25818046 TI - Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats. AB - The understanding of the intestine contribution to drug biotransformation improved significantly in recent years. However, the sources of inter-individual variability in intestinal drug biotransformation, namely sex-differences, are still elusive. Nevirapine (NVP) is an orally taken anti-HIV drug associated with severe idiosyncratic reactions elicited by toxic metabolites, with women at increased risk. As such, NVP is a good model to assess sex-dimorphic metabolism. The aim of this study was to perform a comparative profiling of NVP biotransformation in rat intestine and liver and evaluate whether or not it is organ- and sex-dependent. Therefore, nevirapine-containing solutions were perfused through the intestine, in a specially designed chamber, or incubated with liver slices, from male and female Wistar rats. The levels of NVP and its Phase I metabolites were quantified by HPLC-UV. Liver incubation experiments yielded the metabolites 2-, 3-, 8-, and 12-OH-NVP, being 12-OH-NVP and 2-OH-NVP the major metabolites in males and females, respectively. Inter-sex differences in the metabolic profile were also detected in the intestine perfusion experiments. Herein, the metabolites 3- and 12-OH-NVP were only found in male rats, whereas 2-OH-NVP levels were higher in females, both in extraluminal (p<0.01) and intraluminal media. The metabolite 8-OH-NVP was not detected in the intraluminal media from either males or females. In this study, important inter sex differences were detected in both organs, providing further clues to the sex dimorphic profile of NVP toxicity. Moreover, an extra-hepatic contribution to NVP biotransformation was observed, strengthening the relevance of the intestinal contribution in the biotransformation of orally taken-drugs. PMID- 25818047 TI - In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish. AB - The brominated flame retardants (BFRs) 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH or DBE-DCBH) and allyl 2,4,6-tribromophenyl ether (ATE or TBP-AE) are alternative BFRs that have been introduced to replace banned BFRs. TBECH is a potential endocrine disrupter in human, chicken and zebrafish and in a recent study we showed that ATE, along with the structurally similar BFR 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE or TBP-DBPE) and its metabolite 2-bromoallyl 2,4,6-tribromophenyl ether (BATE or TBP-BAE) are potential endocrine and neuronal disrupters in human. In this study we analyzed ATE, BATE and DPTE for zebrafish androgen receptor (zAR) modulating properties. In silico analysis with two softwares, Molecular Operating Environment (MOE) and Internal Coordinate Mechanics (ICM), showed that ATE, BATE and DPTE bind to zAR. In vitro AR activation assay revealed that these three BFRs down-regulate 11 ketotestosterone (KT) mediated zAR activation. Exposure to 10 MUM DPTE resulted in reduced hatching success and like TBECH, BATE and DPTE at 10 MUM also had teratogenic properties with 20% and 50% back-bone curvature respectively. Gene transcription analysis in zebrafish embryos as well as in juveniles showed down regulation of the androgen receptor and androgen response genes, which further support that these BFRs are androgen antagonists and potential endocrine disrupting compounds. Genes involved in steroidogenesis were also down-regulated by these BFRs. In view of this, the impact of these BFRs on humans and wildlife needs further analysis. PMID- 25818048 TI - Bis(phenylimidazoselenazolyl) diselenide as an antioxidant compound: An in vitro and in vivo study. AB - The organoselenium compounds have been reported for many biological properties, especially as potent antioxidants. The compound bis(phenylimidazoselenazolyl) diselenide (BPIS) is a novel diaryl diselenide derivative, which shows antinociceptive and anti-inflammatory properties in mice, but whose antioxidant activity has not been studied. The present study aimed to investigate the antioxidant and toxicological potential of BPIS in brain of rats in vitro, and the effect of BPIS against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. BPIS, at low molecular range, reduced lipid peroxidation (LP) and protein carbonyl (PC) content in rat brain homogenates (IC50 values of 1.35 and 0.74 MUM, respectively). BPIS also presented dehydroascorbate reductase like and glutathione-S-transferase-like, as well as DPPH and NO-scavenging activities. Related to togicological assays, BPIS inhibited delta-ALA-D and Na(+), K(+)-ATPase activities in rat brain homogenates and [(3)H]glutamate uptake in synaptosomes in vitro, but these effects were observed at higher concentrations than it had antioxidant effect (IC50 values of 16.41, 26.44 and 3.29 MUM, respectively). In vivo, brains of mice treated with SNP (0.335 MUmol per site; i.c.v.) showed an increase in LP and PC and a reduction in non protein thiol content, however, it was not observed significant alterations in antioxidant enzyme activities. BPIS (10 mg/kg; p.o.) protected against these alterations caused by SNP. In conclusion, the results demonstrated the antioxidant action of BPIS in in vitro assays. Furthermore, BPIS protected against oxidative damage caused by SNP in mouse brain, strengthening the potential antioxidant effect of this compound. PMID- 25818049 TI - No role of beta receptors in cognitive flexibility: Evidence from a task switching paradigm in a randomized controlled trial. AB - There is evidence that noradrenergic coeruleo-cortical projections are involved in different forms of cognitive flexibility. So far, no studies in humans have investigated the involvement of beta receptors on task-switching performance, a well-established measure of cognitive flexibility. The present study investigated whether the administration of propranolol (a central and peripheral beta adrenergic antagonist) affected switching costs (i.e., the increase of reaction time in task-switching trials relative to task-repetition trials). Sixteen healthy adult human subjects performed a global-local task-switching paradigm in a double-blind, within-subjects design study investigating the effects of 80mg of propranolol hydrochloride (a beta1 and beta2 adrenergic receptor antagonist) vs. an oral dose of microcrystalline cellulose (placebo pill). The acute administration of propranolol did not affect the size of switching costs compared to the intake of the neutral placebo. Our results, corroborated by Bayesian inference, suggest that beta receptors do not modulate cognitive flexibility as measured by task-switching performance. PMID- 25818053 TI - Possible predictors for difficult removal of locking plates: A case-control study. AB - INTRODUCTION: Difficult removal of locking plates including less invasive stabilisation systems (LISSs) and locking compression plates (LCPs) sometimes occur. However, investigations of the mechanisms and correlated factors of complicated removal remain scant. This study aims to identify correlated factors for the difficult removal of locking plates and to propose suggestions for decision making regarding implant removal and the prevention of complicated removal. MATERIALS AND METHODS: In total, 308 consecutive patients who underwent LCP/LISS removal from Sep. 2004 to Nov. 2013 were assessed. Using the Mann Whitney U test, we analysed the correlation between difficult removal and the duration between open reduction and internal fixation (ORIF) and implant removal as well as the correlation between difficult removal and the patients' age. Using Chi Square test, we assessed the correlations between complicated removal and the size, location, insertion technique and cortical purchase of the locking head screw (LHS). Correlated factors were separately determined in upper and lower extremities. Rates of difficult removal in different fracture locations were evaluated, and postoperative complications were documented. RESULTS: Of the total 308 patients, thirty-seven had intra-operative difficulties, and six patients experienced postoperative complications. Six out of fifteen patients with peri elbow fractures and five out of seventeen patients with femur fractures suffered difficult removal, while four out of one hundred patients with malleolar fractures had intra-operative difficulties. Difficulties were experienced with 30 of 338 LCPs, 7 of 32 LISSs, 67 of 1533 small-diameter (<= 3.5-mm) LHSs, and 12 of 442 large-diameter (>= 4.5-mm) LHSs. Three LCPs and seventeen small-diameter LHSs were retained. A longer interval between ORIF and removal, younger age and bicortical screws correlated with difficult removal in the upper extremities, and a longer duration before removal, small-diameter LHS and minimally invasive insertion of LHS were predictors in the lower extremities. CONCLUSIONS: Complications occur with LCP/LISS removal, and it should not be a routine procedure. If removal is indicated, performing surgery as soon as radiographs show fracture healing is recommended. Different considerations should apply when making decisions and removing implants from patients with different fracture sites. PMID- 25818051 TI - Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors. AB - Our laboratory previously developed a novel neuropathic and inflammatory facial pain model for mice referred to as the Trigeminal Inflammatory Compression (TIC) model. Rather than inducing whole nerve ischemia and neuronal loss, this injury induces only slight peripheral nerve demyelination triggering long-term mechanical allodynia and cold hypersensitivity on the ipsilateral whisker pad. The aim of the present study is to further characterize the phenotype of the TIC injury model using specific behavioral assays (i.e. light-dark box, open field exploratory activity, and elevated plus maze) to explore pain- and anxiety-like behaviors associated with this model. Our findings determined that the TIC injury produces hypersensitivity 100% of the time after surgery that persists at least 21 weeks post injury (until the animals are euthanized). Three receptive field sensitivity pattern variations in mice with TIC injury are specified. Animals with TIC injury begin displaying anxiety-like behavior in the light-dark box preference and open field exploratory tests at week eight post injury as compared to sham and naive animals. Panic anxiety-like behavior was shown in the elevated plus maze in mice with TIC injury if the test was preceded with acoustic startle. Thus, in addition to mechanical and cold hypersensitivity, the present study identified significant anxiety-like behaviors in mice with TIC injury resembling the clinical symptomatology and psychosocial impairments of patients with chronic facial pain. Overall, the TIC injury model's chronicity, reproducibility, and reliability in producing pain- and anxiety-like behaviors demonstrate its usefulness as a chronic neuropathic facial pain model. PMID- 25818050 TI - Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex. AB - Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin-2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness. PMID- 25818054 TI - Is early hip fracture surgery safe for patients on clopidogrel? Systematic review, meta-analysis and meta-regression. AB - INTRODUCTION: Hip fracture is a common presentation in the elderly population, many of whom will be taking the antiplatelet clopidogrel, which has the potential to increase perioperative bleeding. The aim of this systematic review and meta analysis was to answer the questions: (1) is early hip fracture surgery for patients on clopidogrel associated with worse postoperative outcomes compared to patients not on clopidogrel? (2) is early versus delayed surgery for these patients associated with worse postoperative outcomes? METHODS: A systematic search was conducted of MEDLINE, EMBASE, Cinahl and AMED databases. Results from patients undergoing early surgery on clopidogrel were compared to a control group not taking clopidogrel. In addition, patients taking clopidogrel undergoing early and delayed surgery were compared. RESULTS: For patients taking clopidogrel undergoing early surgery, there was no associated increase in overall mortality (OR 0.89; 95% CI: 0.58-1.38) or 30-day mortality (OR 1.10 95% CI: 0.48-2.54). However, there was an associated increase in blood transfusion (OR 1.41 95% CI: 1.00-1.99). There was an associated decreased length of stay in the early surgery versus delayed surgery group (weighted mean difference -7.09 days (95% CI: -10.14 to -4.04). DISCUSSION: Early surgery appears safe for patients with hip fracture though there may be a small increase in the rate of blood transfusion. However, larger prospective trials are required to confirm these findings. PMID- 25818055 TI - Acute traumatic coagulopathy - Query regarding previous article. PMID- 25818052 TI - Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat. AB - Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A 803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8-60g) and noxious thermal (45 and 48 degrees C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8-60g and 48 degrees C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40-48 degrees C stimuli after systemic administration; significantly inhibited the electrically evoked Adelta-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8-60g and 45-48 degrees C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60g and 45 degrees C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45 degrees C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in osteoarthritic pain. PMID- 25818056 TI - Effect of weather and time on trauma events determined using emergency medical service registry data. AB - INTRODUCTION: Trauma admissions are associated with weather and temporal factors; however, previous study results regarding these factors are contradictory. We hypothesised that weather and temporal factors have different effects on specific trauma events in an emergency medical service (EMS) system. METHODS: EMS data from January 1, 2009, to December 31, 2010, were obtained from the fire department of Taipei City and associated with the local weather data. EMS trauma events were categorised into total trauma, traffic accidents (TAs), motorbike accidents (MBAs), and falls. Hourly data on trauma patients were analysed using the zero-inflated Poisson model. RESULTS: The hourly incidence of total trauma increased with the magnitude of precipitation (incidence rate ratio [IRR]=1.06, 1.09, and 1.11 in light, moderate, and heavy rain, respectively), and this effect was more prominent in fall patients than in patients with other injuries (IRR=1.07, 1.21, and 1.32). However, the hourly incidence of TAs and MBAs was associated only with light rain (IRR=1.11 and 1.06, respectively). An hour of sunshine exposure was associated with an increase in the hourly incidence of all groups, and higher temperatures were associated with an increased hourly incidence of total trauma, TAs, and MBAs, but not falls. The hourly incidence of falls increased only in late fall and winter. Compared with the hourly incidence between 3 am and 7 am, the hourly incidence of all groups plateaued between 7 am and 11 pm and declined from 11 pm to 3 am. During the plateau period, 2 peaks in the incidence of TAs (IRR=5.03 and 5.07, respectively) and MBAs (IRR=5.81 and 5.51, respectively) were observed during 7-11 am and 3-7 pm. The hourly incidence of total trauma, TAs, and MBAs plateaued during workdays, peaked on Fridays, declined on Saturdays, and troughed on Sundays. The incidence of falls increased only on Mondays (IRR=1.09). CONCLUSIONS: Weather and temporal factors had different impacts on the incidence of traffic-related accidents and falls. Therefore, EMS data may have implications in preventing injuries and planning resource use for prehospital trauma rescue. PMID- 25818057 TI - Inter and intra-observer agreement evaluation of the AO and the Tronzo classification systems of fractures of the trochanteric area. AB - INTRODUCTION: We performed an agreement study of the AO and the Tronzo classifications of fractures of the trochanteric area to determine if they allow communication among practitioners with different levels of expertise. MATERIAL AND METHODS: Complete radiographs of 70 patients with trochanteric fractures were classified by nine evaluators (three hip sub-specialists, three orthopaedic surgery residents and three medical interns) using the AO and the Tronzo classifications. After a six-week interval, all cases were presented in a random sequence for repeat evaluation. The Kappa coefficient (k) was used to determine inter- and intra-observer agreement. RESULTS: Inter-observer: considering the main AO fracture types, the agreement was moderate for sub-specialists (k = 0.60 [0.50-0.70]), residents (k = 0.58 [0.48-0.69]) and medical interns (k = 0.56 [0.45-0.69]). Using AO sub-types, all groups achieved fair agreement (sub specialists: k = 0.31 [0.25-0.38]; residents: k = 0.32 [0.26-0.38]; medical interns: k = 0.30 [0.24-0.36]). For the Tronzo classification, sub-specialists (k = 0.56 [0.48-0.65]) and residents (k = 0.47 [0.39-0.55]) obtained moderate agreement; medical interns reached fair agreement (k = 0.33 [0.25-0.41]). Intra observer: considering the main AO fracture types, sub-specialists (k = 0.79 [0.69 0.89]), residents (k = 0.71 [0.60-0.81]) and medical interns (k = 0.70 [0.59 0.82]) obtained substantial agreement. Considering AO sub-types, sub-specialists (k = 0.50 [0.45-0.56]) and medical interns (k = 0.54 [0.48-0.69]) achieved moderate agreement; residents (k = 0.39 [0.33-0.45]) achieved fair agreement. Using the Tronzo classification, all groups obtained substantial agreement (sub specialists: k = 0.66 [0.58-0.74]; residents: k = 0.63 [0.55-0.71]; medical interns: k = 0.68 [0.60-0.76]). CONCLUSION: The AO classification allows an adequate communication when considering the main fracture types; the agreement within sub-types is not satisfactory. The Tronzo classification does not allow reliable communication between medical professionals. PMID- 25818058 TI - Biomechanical comparison of long, short, and extended-short nail construct for femoral intertrochanteric fractures. AB - OBJECTIVES: Short and long cephalomedullary (CM) nails are commonly used construct for fixation of intertrochanteric (IT) fractures. Each of these constructs has its advantages and its shortcomings. The extended-short (ES) CM nail offers a hybrid between long and short nail design that aims to combine their respective benefits. The goals of this study were to (1) biomechanically evaluate and compare construct stiffness for the long, short and ES constructs in the fixation of IT fractures, and to (2) investigate the nature of periprosthetic fractures of constructs implanted with these various designs. METHODS: Eighteen synthetic femora were used to evaluate three types of fracture fixation constructs. Axial compression, bending, and torsional stiffness were reported for both stable and comminuted IT fracture models. All comminuted fracture constructs were loaded to failure in axial compression to measure failure loads and evaluate periprosthetic fracture patterns. RESULTS: Stiffness were similar among constructs with few exceptions. Axial stiffness was significantly higher for the short nail compared to the long nail for the comminuted model (p= 0.020). ES nail constructs exhibited a significantly higher failure load than short nail constructs (p = 0.039). Periprosthetic fractures occurred around the distal interlocking screw in all constructs. CONCLUSIONS: Nail length and position of interlocking screw did not alter the biomechanical properties of the fixation construct in the presented IT fracture model. Periprosthetic fractures generated in this study had similar patterns to those seen clinically. This study also suggests that if a periprosthetic fracture is to occur, there is an increased probability of it happening around the site of the interlocking screw, regardless of nail design. PMID- 25818059 TI - Characterization of patients with cystic fibrosis presenting an indeterminate glucose tolerance (INDET). AB - BACKGROUND: CFRD is preceded and associated with a significantly increased morbidity and mortality. We aimed to characterize a large newly established glucose tolerance subgroup named INDET (indeterminate; 1-h oral glucose tolerance test (OGTT)>11.0 but 2h-OGTT<7.8 mmol/L) in adult patients with cystic fibrosis (CF). METHODS: All CF participants (n=252, >=18 yrs without CFRD) underwent a 2h OGTT with glucose and insulin sample measurements every 30 min. They were then classified as having either normal, impaired, or INDET glucose tolerance, or de novo CFRD. Other clinical characteristics were collected such as the BMI and pulmonary function. RESULTS: All groups were of similar age (P=0.629) and BMI (P=0.813). We found that the INDETs displayed decreased lung function comparable to de novo CFRD. OGTT-derived glucose or insulin secretion/sensitivity parameters cannot fully explain this observation. CONCLUSIONS: Prospective studies are required to establish if the INDET-CF group can identify clinically relevant outcomes. PMID- 25818060 TI - Long-term outcomes from the National Drug Abuse Treatment Clinical Trials Network Prescription Opioid Addiction Treatment Study. AB - BACKGROUND: Despite the growing prevalence of prescription opioid dependence, longitudinal studies have not examined long-term treatment response. The current study examined outcomes over 42 months in the Prescription Opioid Addiction Treatment Study (POATS). METHODS: POATS was a multi-site clinical trial lasting up to 9 months, examining different durations of buprenorphine-naloxone plus standard medical management for prescription opioid dependence, with participants randomized to receive or not receive additional opioid drug counseling. A subset of participants (N=375 of 653) enrolled in a follow-up study. Telephone interviews were administered approximately 18, 30, and 42 months after main-trial enrollment. Comparison of baseline characteristics by follow-up participation suggested few differences. RESULTS: At Month 42, much improvement was seen: 31.7% were abstinent from opioids and not on agonist therapy; 29.4% were receiving opioid agonist therapy, but met no symptom criteria for current opioid dependence; 7.5% were using illicit opioids while on agonist therapy; and the remaining 31.4% were using opioids without agonist therapy. Participants reporting a lifetime history of heroin use at baseline were more likely to meet DSM-IV criteria for opioid dependence at Month 42 (OR=4.56, 95% CI=1.29-16.04, p<.05). Engagement in agonist therapy was associated with a greater likelihood of illicit-opioid abstinence. Eight percent (n=27/338) used heroin for the first time during follow-up; 10.1% reported first-time injection heroin use. CONCLUSIONS: Long-term outcomes for those dependent on prescription opioids demonstrated clear improvement from baseline. However, a subset exhibited a worsening course, by initiating heroin use and/or injection opioid use. PMID- 25818061 TI - Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial. AB - AIM: Bupropion was tested for efficacy to achieve methamphetamine (MA) abstinence in dependent, non-daily users. METHODS: A randomized, double-blind, placebo controlled trial, with 12-week treatment and 4-week follow-up, was conducted with 204 treatment-seeking participants having MA dependence per DSM-IV, who used MA on a less-than-daily basis. 104 were randomized to matched placebo and 100 to bupropion, sustained-release 150mg, twice daily. Participants were seen three times weekly to obtain urine for MA and bupropion assays, study assessments, and thrice weekly, 90-min, group psychotherapy. There was no biomarker for placebo adherence. The primary outcome was achievement of abstinence throughout the last two weeks of treatment; 'success' requiring at least two urine samples during each of Weeks 11 and 12, and all samples MA-negative (<300ng/mL). RESULTS: Bupropion and placebo groups did not differ significantly in the percentage achieving abstinence for the last 2 weeks of treatment (chi-square, p=0.32). Subgroup analysis of participants with lower baseline MA use (<=18 of last 30 days before consent) also revealed no difference in success between groups (p=0.73). Medication adherence per protocol (detectable bupropion, >5ng/mL, in >=50% of urine samples from Study Weeks 1-10 and >=66% of urine samples from Weeks 11 to 12) was achieved by 47% of participants taking bupropion. CONCLUSIONS: These data indicate that bupropion did not increase abstinence in dependent participants who were using MA less-than-daily. Medication non adherence was a limitation in this trial. Psychosocial therapy remains the mainstay of treatment for MA dependence. Further research on subgroups who may respond to bupropion may be warranted. PMID- 25818062 TI - Solid state formulations composed by amphiphilic polymers for delivery of proteins: characterization and stability. AB - Nanocomposite powders composed by polymeric micelles as vehicles for delivery proteins were developed in this work, using insulin as model protein. Results showed that size and polydispersity of micelles were dependent on the amphiphilic polymer used, being all lower than 300 nm, while all the formulations displayed spherical shape and surface charge close to neutrality. Percentages of association efficiency and loading capacity up to 94.15 +/- 3.92 and 8.56 +/- 0.36, respectively, were obtained. X-ray photoelectron spectroscopy (XPS) measurements confirmed that insulin was partially present at the hydrophilic shell of the micelles. Lyophilization did not significantly change the physical characteristics of micelles, further providing easily dispersion when in contact to aqueous medium. The native-like conformation of insulin was maintained at high percentages (around 80%) after lyophilization as indicated by Fourier transform infrared spectroscopy (FTIR) and far-UV circular dichroism (CD). Moreover, Raman spectroscopy did not evidenced significant interactions among the formulation components. The formulations shown to be physically stable upon storage up to 6 months both at room-temperature (20 degrees C) and fridge (4 degrees C), with only a slight loss (maximum of 15%) of the secondary structure of the protein. Among the polymers tested, Pluronic((r)) F127 produced the carrier formulations more promising for delivery of proteins. PMID- 25818063 TI - Novel curcumin-loaded gel-core hyaluosomes with promising burn-wound healing potential: Development, in-vitro appraisal and in-vivo studies. AB - Despite its effectiveness, curcumin (Curc) dermal delivery is handicapped by hydrophobicity, high metabolism and poor skin permeation. In this work, the potential of novel self-assembled nanogels, namely gel-core hyaluosome (GC-HS) to enhance Curc delivery to wound sites, enhance healing rate and decrease scar formation was evaluated. Curc-GC-HS were prepared using film hydration technique and evaluated regarding size, zeta potential (ZP), entrapment efficiency (% EE), and in vitro release. Structure elucidation was performed using light, polarizing and transmission electron microscopy (TEM). In-vivo burn-wound healing potential, skin deposition ability and histological study were evaluated using female Sprague Dawley rats. Curc-GC-HS were compared to conventional transfersomal gel (Curc-T-Pl gel), and other conventional gels. Curc-GC-HS showed nanosize (202.7 +/- 0.66 nm), negative ZP (-33 +/- 2.6 mV) and % EE (96.44 +/- 1.29%). TEM revealed discrete vesicles with characteristic bilayer structure. Polarizing microscopy proposed liquid crystalline consistency. Burn-wound healing study showed that Curc-GC-HS was the only system exhibiting marked improvement at day 7 of treatment. At 11th day, Curc-GC-HS treated wounds showed almost normal skin with no scar confirmed by histological analysis. Curc-GC-HS showed five folds higher skin deposition compared to conventional Curc-T-Pl gel. To conclude, novel gel-core hyaluosomes elaborated are promising nanogels able to increase Curc skin penetration and dermal localization while protecting it against degradation. Future perspective encompasses assessing potential of novel nanocarrier for skin cancer therapy. PMID- 25818064 TI - Controlling protein stability: Mechanisms revealed using formulations of arginine, glycine and guanidinium HCl with three globular proteins. AB - Three distinct interactions between the amino acid arginine and a protein explain arginine's ability to modulate the thermal stability of proteins. Arginine's effect on the protein unfolding behaves like the sum of its constituent parts, glycine and the guanidinium ion. The authors propose that glycine can affect the thermal stability of a protein in two ways: (1) direct interaction with the charged side chains and/or the peptide backbone of the protein which is observed at low concentrations and (2) competition for water between the unfolding protein and the cosolute increasing the energy required to hydrate the unfolding protein. The guanidinium ion acts by (3) direct interaction with apolar regions exposed during unfolding reducing the energy required to hydrate the unfolding protein. PMID- 25818065 TI - Patient-directed music therapy reduces anxiety and sedation exposure in mechanically-ventilated patients: a research critique. AB - This research appraisal, guided by the CASP Randomised Controlled Trial Checklist, critiques a randomised, controlled trial of patient-directed music therapy compared to either noise-cancelling headphones or usual care. This study recruited 373 alert, mechanically-ventilated patients across five intensive care units in the United States. The Music Assessment Tool, administered by a music therapist, facilitated music selection by participants in the intervention group. Anxiety was measured using the VAS-A scale. Sedation exposure was measured by both sedation frequency and by sedation intensity using a daily sedation intensity score. Context for the data was supported by an environmental scan form recording unit activity and by written comments from nurses about the patient's responses to the protocol. Patient-directed music therapy allowed a significant reduction in sedation frequency compared to noise-cancelling headphones and usual care participants. Patient-directed music therapy led to significantly lower anxiety and sedation intensity compared to usual care, but not compared to noise cancelling headphones. This is a robust study with clear aims and a detailed description of research methods and follow-up. While no participants were lost to follow-up, not all were included in the analysis: 37% did not have the minimum of two anxiety assessments for comparison and 23% were not included in sedation analysis. While some participants utilised the intervention or active control for many hours-per-day, half the music therapy participants listened for 12min or less per day and half of the noise-cancelling headphone participants did not appear to use them. While the results suggest that patient-directed music therapy and noise-cancelling headphones may be useful and cost-effective interventions that lead to an overall improvement in anxiety and sedation exposure, these may appeal to a subset of ICU patients. The self-directed use of music therapy and noise-cancelling headphones means these findings may not transfer to sedated or cognitively-impaired patients. PMID- 25818066 TI - Development, diet and dynamism: longitudinal and cross-sectional predictors of gut microbial communities in wild baboons. AB - Gut bacterial communities play essential roles in host biology, but to date we lack information on the forces that shape gut microbiota between hosts and over time in natural populations. Understanding these forces in wild primates provides a valuable comparative context that enriches scientific perspectives on human gut microbiota. To this end, we tested predictors of gut microbial composition in a well-studied population of wild baboons. Using cross-sectional and longitudinal samples collected over 13 years, we found that baboons harbour gut microbiota typical of other omnivorous primates, albeit with an especially high abundance of Bifidobacterium. Similar to previous work in humans and other primates, we found strong effects of both developmental transitions and diet on gut microbial composition. Strikingly, baboon gut microbiota appeared to be highly dynamic such that samples collected from the same individual only a few days apart were as different from each other as samples collected over 10 years apart. Despite the dynamic nature of baboon gut microbiota, we identified a set of core taxa that is common among primates, supporting the hypothesis that microbiota codiversify with their host species. Our analysis identified two tentative enterotypes in adult baboons that differ from those of humans and chimpanzees. PMID- 25818067 TI - Detection of classical Hodgkin lymphoma specific sequence in peripheral blood using a next-generation sequencing approach. AB - We applied a highly sensitive next-generation sequencing method to identify lymphoma-specific immunoglobulin gene segments in classical Hodgkin lymphoma (CHL) at initial diagnosis or recurrence, and assessed the ability of detecting such lymphoma-specific sequences in peripheral blood (PB). Seventeen CHL cases were tested and lymphoma-specific sequences were identified in 12 of the primary tumour biopsies. In 11 of these patients whose paired PB samples were available, tumour-specific clonotypes were detected in PB in eight patients. This data demonstrates the feasibility of detecting circulating tumour-specific sequences, creating an unprecedented opportunity to optimize the future treatment and monitoring strategies for patients with CHL. PMID- 25818068 TI - A decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). AB - The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) 'Nano Task Force' proposes a Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping) that consists of 3 tiers to assign nanomaterials to 4 main groups, to perform sub-grouping within the main groups and to determine and refine specific information needs. The DF4nanoGrouping covers all relevant aspects of a nanomaterial's life cycle and biological pathways, i.e. intrinsic material and system-dependent properties, biopersistence, uptake and biodistribution, cellular and apical toxic effects. Use (including manufacture), release and route of exposure are applied as 'qualifiers' within the DF4nanoGrouping to determine if, e.g. nanomaterials cannot be released from a product matrix, which may justify the waiving of testing. The four main groups encompass (1) soluble nanomaterials, (2) biopersistent high aspect ratio nanomaterials, (3) passive nanomaterials, and (4) active nanomaterials. The DF4nanoGrouping aims to group nanomaterials by their specific mode-of-action that results in an apical toxic effect. This is eventually directed by a nanomaterial's intrinsic properties. However, since the exact correlation of intrinsic material properties and apical toxic effect is not yet established, the DF4nanoGrouping uses the 'functionality' of nanomaterials for grouping rather than relying on intrinsic material properties alone. Such functionalities include system-dependent material properties (such as dissolution rate in biologically relevant media), bio-physical interactions, in vitro effects and release and exposure. The DF4nanoGrouping is a hazard and risk assessment tool that applies modern toxicology and contributes to the sustainable development of nanotechnological products. It ensures that no studies are performed that do not provide crucial data and therefore saves animals and resources. PMID- 25818069 TI - Care related pain in rehabilitation after orthopedic trauma: An exploratory study with qualitative data. AB - OBJECTIVE: Care related pain (CRP) is generally under-estimated and rarely studied in rehabilitation as well as in general medecine. Beliefs about pain influence psychological distress, adjustment to pain and physical disability. In this sense, perceptions of CRP could limit recovery. This exploratory study aims to understand patients' and caregivers' subjective perceptions and beliefs about CRP. PATIENTS AND METHODS: Questionnaires about CRP were submitted to members of the interdisciplinary team of a rehabilitation hospital and to patients with musculoskeletal complaints (cross-sectional design). Twenty patients were also individually interviewed (qualitative data). Four topics were addressed: frequency of CRP, situations and procedures causing CRP, beliefs about CRP and means used to deal with CRP. RESULTS: Seventy-five caregivers and 50 patients replied to the questionnaire. CRP is a very common experience in rehabilitation and it is recognized by both groups. Generally, the situations causing CRP reflect the specificity of rehabilitation (mobilization...) and are similarly perceived by patients and caregivers, with patients considering them as more painful. Beliefs about CRP are clearly different from those usually associated with pain. Both groups point out the utilitarian and the inevitable character of CRP. They differ on that, that patients had a more positive view about CRP. They associate it more often with progress and see it as acceptable at least until a certain limit. They are also able to perceive the richness of means used by physiotherapists to help them coping with CRP. CONCLUSION: Our data may suggest new keys to motivate patient to be active in rehabilitation for example in choosing carefully arguments or words which may fit theirs' beliefs about CRP, or in using various means to manage CRP. Promoting the use of relational competences with chronic pain patients and of a patient-centred approach may also be a concern in training caregivers. PMID- 25818070 TI - Targeted high-resolution ion mobility separation coupled to ultrahigh-resolution mass spectrometry of endocrine disruptors in complex mixtures. AB - Traditional separation and detection of targeted compounds from complex mixtures from environmental matrices requires the use of lengthy prefractionation steps and high-resolution mass analyzers due to the large number of chemical components and their large structural diversity (highly isomeric). In the present work, selected accumulation trapped ion mobility spectrometry (SA-TIMS) is coupled to Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) for direct separation and characterization of targeted endocrine-disrupting compounds (EDC) from a complex environmental matrix in a single analysis. In particular, targeted identification based on high-resolution mobility (R ~ 70-120) and ultrahigh-resolution mass measurements (R > 400 000) of seven commonly targeted EDC and their isobars (e.g., bisphenol A, (Z)- and (E)-diethylstilbestrol, hexestrol, estrone, alpha-estradiol, and 17-ethynylestradiol) is shown from a complex mixture of water-soluble organic matter (e.g., Suwannee River Fulvic Acid Standard II) complemented with reference standard measurements and theoretical calculations (<3% error). PMID- 25818071 TI - Phenotypic plasticity to light and nutrient availability alters functional trait ranking across eight perennial grassland species. AB - Functional traits are often used as species-specific mean trait values in comparative plant ecology or trait-based predictions of ecosystem processes, assuming that interspecific differences are greater than intraspecific trait variation and that trait-based ranking of species is consistent across environments. Although this assumption is increasingly challenged, there is a lack of knowledge regarding to what degree the extent of intraspecific trait variation in response to varying environmental conditions depends on the considered traits and the characteristics of the studied species to evaluate the consequences for trait-based species ranking. We studied functional traits of eight perennial grassland species classified into different functional groups (forbs vs. grasses) and varying in their inherent growth stature (tall vs. small) in a common garden experiment with different environments crossing three levels of nutrient availability and three levels of light availability over 4 months of treatment applications. Grasses and forbs differed in almost all above- and belowground traits, while trait differences related to growth stature were generally small. The traits showing the strongest responses to resource availability were similarly for grasses and forbs those associated with allocation and resource uptake. The strength of trait variation in response to varying resource availability differed among functional groups (grasses > forbs) and species of varying growth stature (small-statured > tall-statured species) in many aboveground traits, but only to a lower extent in belowground traits. These differential responses altered trait-based species ranking in many aboveground traits, such as specific leaf area, tissue nitrogen and carbon concentrations and above-belowground allocation (leaf area ratio and root : shoot ratio) at varying resource supply, while trait-based species ranking was more consistent in belowground traits. Our study shows that species grouping according to functional traits is valid, but trait-based species ranking depends on environmental conditions, thus limiting the applicability of species-specific mean trait values in ecological studies. PMID- 25818072 TI - Physiological, anatomical and transcriptional alterations in a rice mutant leading to enhanced water stress tolerance. AB - Water stress is one of the most severe constraints to crop productivity. Plants display a variety of physiological and biochemical responses both at the cellular and whole organism level upon sensing water stress. Leaf rolling, stomatal closure, deeper root penetration, higher relative water content (RWC) and better osmotic adjustment are some of the mechanisms that plants employ to overcome water stress. In the current study, we report a mutant, enhanced water stress tolerant1 (ewst1) with enhanced water stress tolerance, identified from the ethyl methanesulfonate-induced mutant population of rice variety Nagina22 by field screening followed by withdrawal of irrigation in pots and hydroponics (PEG 6000). Though ewst1 was morphologically similar to the wild type (WT) for 35 of the 38 morphological descriptors (except chalky endosperm/expression of white core, decorticated grain colour and grain weight), it showed enhanced germination in polyethylene glycol-infused medium. It exhibited increase in maximum root length without any significant changes in its root weight, root volume and total root number on crown when compared with the WT under stress in PVC tube experiment. It also showed better performance for various physiological parameters such as RWC, cell membrane stability and chlorophyll concentration upon water stress in a pot experiment. Root anatomy and stomatal microscopic studies revealed changes in the number of xylem and phloem cells, size of central meta-xylem and number of closed stomata in ewst1. Comparative genome-wide transcriptome analysis identified genes related to exocytosis, secondary metabolites, tryptophan biosynthesis, protein phosphorylation and other signalling pathways to be playing a role in enhanced response to water stress in ewst1. The possible involvement of a candidate gene with respect to the observed morpho-physiological and transcriptional changes and its role in stress tolerance are discussed. The mutant identified and characterized in this study will be useful for further dissection of water stress tolerance in rice. PMID- 25818073 TI - Soil microbial community variation correlates most strongly with plant species identity, followed by soil chemistry, spatial location and plant genus. AB - Soil ecologists have debated the relative importance of dispersal limitation and ecological factors in determining the structure of soil microbial communities. Recent evidence suggests that 'everything is not everywhere', and that microbial communities are influenced by both dispersal limitation and ecological factors. However, we still do not understand the relative explanatory power of spatial and ecological factors, including plant species identity and even plant relatedness, for different fractions of the soil microbial community (i.e. bacterial and fungal communities). To ask whether factors such as plant species, soil chemistry, spatial location and plant relatedness influence rhizosphere community composition, we examined field-collected rhizosphere soil of seven congener pairs that occur at Bodega Bay Marine Reserve, CA, USA. We characterized differences in bacterial and fungal communities using terminal-restriction fragment length polymorphism. Plant species identity was the single best statistical predictor of both bacterial and fungal community composition in the root zone. Soil microbial community structure was also correlated with soil chemistry. The third best predictor of bacterial and fungal communities was spatial location, confirming that everything is not everywhere. Variation in microbial community composition was also related to combinations of spatial location, soil chemistry and plant relatedness, suggesting that these factors do not act independently. Plant relatedness explained less of the variation than plant species, soil chemistry, or spatial location. Despite some congeners occupying different habitats and being spatially distant, rhizosphere fungal communities of plant congeners were more similar than expected by chance. Bacterial communities from the same samples were only weakly similar between plant congeners. Thus, plant relatedness might influence soil fungal, more than soil bacterial, community composition. PMID- 25818074 TI - Analysis of population genetic structure and gene flow in an annual plant before and after a rapid evolutionary response to drought. AB - The impact of environmental change on population structure is not well understood. This study aimed to examine the effect of a climate change event on gene flow over space and time in two populations of Brassica rapa that evolved more synchronous flowering times over 5 years of drought in southern California. Using plants grown from seeds collected before and after the drought, we estimated genetic parameters within and between populations and across generations. We expected that with greater temporal opportunity to cross pollinate, due to reduced phenological isolation, these populations would exhibit an increase in gene flow following the drought. We found low but significant FST, but no change in FST or Nm across the drought, in contrast to predictions. Bayesian analysis of these data indicates minor differentiation between the two populations but no noticeable change in structure before and after the shift in flowering times. However, we found high and significant levels of FIS, indicating that inbreeding likely occurred in these populations despite self-incompatibility in B. rapa. In this system, we did not find an impact of climate change on gene flow or population structuring. The contribution of gene flow to adaptive evolution may vary by system, however, and is thus an important parameter to consider in further studies of natural responses to environmental change. PMID- 25818075 TI - Ventricular conduction defects after transcatheter aortic valve implantation: a single-institute analysis. AB - Patients with aortic stenosis tend to develop ventricular conduction problems, which are known adverse events following transcatheter aortic valve implantation (TAVI). Changes in ventricular conduction status after TAVI were analyzed in 195 consecutive patients from a single institute registered in FRANCE2 between February 2010 and June 2012. Among the 195 patients, 29 had a prior pacemaker implantation (+PM) and 6 had acute catastrophic hemodynamics that made a full electrocardiogram (ECG) unavailable. Among the remaining 160, PM was newly required in 28 (17.5%, PM+) but not in 132 (PM-), which included 21 (13.1%) who developed new left bundle branch block (BBB), 12 (7.5%) had right BBB, and 99 (61.9%) had no change. While PM requirement had no correlation with preoperative factors, there was significant association with the development of right BBB with Edwards Sapien/XT (P = 0.003), and new left BBB (P = 0.012) and complete heart block requiring PM with CoreValve (22.6% vs. Edwards Sapien/XT, 7.4%, P = 0.016). Whereas postoperative survival regarding PM status (+PM, PM+, PM-), vascular access, valve size or type showed no difference, delayed heart block (n = 12, Day 2 or later) was associated with poor survival (P = 0.038) compared with the remaining PM+ patients with earlier onset (n = 16, Day 0 or 1). As a result, PM+ patients (n = 28) had significantly longer intensive care unit (ICU) stay and hospitalization than PM- or +PM patients. The results suggest that ventricular conduction problems requiring PM occurred more frequently after TAVI (17.5%) than with usual surgical replacement. Nonetheless, conduction problems failed to influence postoperative survival for up to 3 years on average with use of PM, but therefore did increase medical costs. PMID- 25818076 TI - Cost Effectiveness of Routine Duodenal Biopsy Analysis for Celiac Disease During Endoscopy for Gastroesophageal Reflux. AB - BACKGROUND & AIMS: Some patients with refractory gastroesophageal reflux disease (GERD) actually have undiagnosed celiac disease. These patients often undergo an esophagogastroduodenoscopy (EGD) to determine the etiology and severity of GERD. Performing routine duodenal biopsy analysis during an EGD could identify patients with celiac disease. We evaluated the cost effectiveness of this approach. METHODS: We performed a systematic search of the MEDLINE database to identify publications through March 2014 on patients who underwent a duodenal biopsy analysis during an EGD for GERD. Data collected were used to construct a decision tree to calculate the cost effectiveness of an EGD with and without celiac disease tests. RESULTS: Among 10,000 patients with refractory GERD who underwent an EGD, we predicted a biopsy strategy would detect 70% of patients with celiac disease if the prevalence of celiac disease was 1% in this cohort. Biopsy analysis at the start of the EGD procedure would increase the remaining quality adjusted life years (QALYs) by 0.0032, and increase the lifetime cost by $389/patient. Compared with no biopsy, the biopsy strategy cost $55,692.86/case of celiac disease detected, and $121,875/QALY gained. The incremental cost effectiveness ratio for the biopsy strategy met the threshold of less than $50,000/QALY when 1 of the following parameters was met: when the utility of living with GERD was less than 0.88, when the prevalence of celiac disease in patients with refractory GERD was greater than 1.8%, when biopsy analysis detected celiac disease with more than 98.1% specificity, when the cost of a gluten-free diet was less than $645.85/y, or if the cost of proton pump inhibitor therapy was more than $5874.01/y. CONCLUSIONS: Based on base-case values, it is not cost effective to perform a biopsy analysis to detect celiac disease in patients undergoing an EGD for refractory GERD. However, the approach becomes cost effective when the prevalence of celiac disease in this population is 1.8% or greater. PMID- 25818077 TI - Sendai and Fukuoka Consensus Guidelines Identify Advanced Neoplasia in Patients With Suspected Mucinous Cystic Neoplasms of the Pancreas. AB - BACKGROUND & AIMS: Little is known about whether the 2006 Sendai guidelines or 2012 Fukuoka guidelines are being used to determine the level of risk posed by suspected pancreatic mucinous cystic neoplasms (PCNs). We evaluated whether the guidelines accurately predicted which patients with suspected PCNs, which was based on cross-sectional imaging findings, would be found to have advanced neoplasia in surgery. METHODS: We performed a retrospective study of data collected from 194 patients with cystic lesions of the pancreas, which were assessed by cross-sectional imaging analyses, who underwent surgery for suspected PCNs at the Hospital at the University of Pennsylvania from 2000 through 2008. Imaging data were used to classify patients according to the Sendai guidelines as high risk or low risk and according to the Fukuoka guidelines as high risk, worrisome, or low risk. Pathology analyses of samples collected during surgery were used as the reference. A logistic regression model was created to identify factors associated with advanced neoplasia. The Sendai and Fukuoka guideline criteria were analyzed by univariate and multivariable logistic regression analyses. RESULTS: Advanced neoplasias were found in 36 patients (18.5%; 22 invasive cancers and 14 high-grade dysplasias). The median size of cysts was 33 mm. All patients found to have invasive cancers were accurately assigned to the Sendai guidelines high risk or Fukuoka guidelines high risk groups. However, 3 patients in the Sendai guidelines low risk and 2 patients in the Fukuoka guidelines low risk groups were found to have high-grade dysplasia. The Sendai guidelines identified patients with advanced neoplasia with 91.7% sensitivity, 21.5% specificity, 21% positive predictive value, and 91.9% negative predictive value. A designation of Fukuoka guidelines high risk identified patients with advanced neoplasia with 55.6% sensitivity, 73% specificity, 32% positive predictive value, and 87.9% negative predictive value. Overall, there was no statistically significant difference between the guidelines in predicting which patients had advanced neoplasia. On multivariate analysis, the presence of a mural nodule (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.33-6.27; P = .008), dilated main pancreatic duct >10 mm (OR, 7.44; 95% CI, 2.36-23.52; P = .001), or enhancing solid component (OR, 2.92; 95% CI, 1.16-7.64; P = .02) were associated with detection of advanced neoplasia in pancreatic cysts. CONCLUSION: On the basis of a retrospective analysis, the Sendai and Fukuoka guidelines accurately determine which patients with pancreatic cysts have advanced neoplasia. The guidelines accurately recommended surgical resection for all patients found to have invasive cancer, although some patients with high-grade dysplasia were missed. The updated Fukuoka guidelines are not superior to the Sendai guidelines in identifying neoplasias. Cyst size was not associated with advanced neoplasia. PMID- 25818078 TI - Psychoactive Medications Increase the Risk of Falls and Fall-related Injuries in Hospitalized Patients With Cirrhosis. AB - BACKGROUND & AIMS: Reducing or eliminating falls is a focus of patient safety programs as well as health policy. Falls are tied to hospital reimbursement. However, little is known about the risk of falls among hospitalized patients with cirrhosis or factors that affect risk of falling. METHODS: We conducted a retrospective cohort study of inpatients with cirrhosis from 2010 to 2013 at a liver transplant center. Our primary aim was to determine the clinical factors associated with falls and fall-related injuries for patients with cirrhosis. Our secondary aim was to describe the rate ratio of falls and fall-related injuries among patients with cirrhosis compared with general medical inpatients. RESULTS: During the study period, there were 1749 admissions to the liver service; 55 (3.1%) resulted in falls. Patients who fell were more likely to have received benzodiazepines (50.9% vs 16.7%, P < .0001) and antipsychotic agents (30.9% vs 7.3%, P < .0001). After adjusting for hepatic encephalopathy, the respective odds of a fall after benzodiazepine or antipsychotic exposure were 6.59 (95% confidence interval [CI], 3.76-11.59) and 3.72 (95% CI, 1.90-7.06). The adjusted risk of a fall-related injury was also significantly associated with benzodiazepine and antipsychotic agents, with respective odds ratios of 3.45 (95% CI, 1.39-8.23) and 3.42 (95% CI, 1.09-8.99). Fall-related injuries occurred at a rate of 1.70/1000 patient-days for patients with cirrhosis vs 0.5/1000 patient days for patients in the general medical service. Accordingly, the rate ratio for a fall-related injury among patients with cirrhosis was 3.37 (95% CI, 1.99-5.72; P < .0001). CONCLUSIONS: Psychoactive medications are associated with an increased adjusted risk of falls and fall-related injuries in hospitalized patients with cirrhosis. PMID- 25818079 TI - Pancreatic Duct Drainage for the Treatment of a Huge Pancreatic Cyst Associated With Autoimmune Pancreatitis. PMID- 25818080 TI - A Model to Predict the Severity of Acute Pancreatitis Based on Serum Level of Amylase and Body Mass Index. AB - BACKGROUND & AIMS: Most patients with acute pancreatitis (AP) develop mild disease, but up to 20% develop severe disease. Many clinicians monitor serum levels of amylase and lipase in an attempt to predict the disease course, but this strategy has not been recommended by practice guidelines. We performed a retrospective analysis to determine whether the percentage changes in amylase and lipase were associated with the severity of disease that developed in patients with AP. METHODS: We analyzed data collected from 182 consecutive patients with AP (21 with severe AP) admitted to the Cleveland Clinic from January 2008 through May 2010 (discover cohort). The association between 11 different factors and the severity of AP were assessed by univariable analysis; multivariable models were explored through stepwise selection regression. The percentage change in the serum level of amylase was calculated as follows: ([amylase day 1 - amylase day 2]/amylase day 1) * 100. The percentage change in amylase and body mass index (BMI) were combined to generate a z-score (z = -5.9 + [0.14 * BMI] + [0.01 * percentage change in amylase]), which was converted into a probability distribution called the change in amylase and BMI (CAB) score. The CAB score was validated using the AP database at the University of Pittsburgh Medical Center (140 patients, 35 with severe AP); we calculated p-scores for each patient and estimated the area under the receiver operating characteristics curve values. RESULTS: Univariable analysis identified the percentage change in the serum level of amylase and other factors to be associated significantly with the severity of AP (P = .017). The CAB score was best at identifying patients who developed severe AP, with an area under the receiver operating characteristics curve value of 0.79 in the discovery cohort (95% confidence interval, 0.71-0.87) and 0.731 in the validation cohort (95% confidence interval, 0.61-0.84). CONCLUSIONS: We developed a model to identify patients most likely to develop severe AP based on the percentage changes in serum level of amylase during the first 2 days after admission to the hospital and BMI. PMID- 25818081 TI - In Vitro Fertilization in Women With Inflammatory Bowel Disease Is as Successful as in Women From the General Infertility Population. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) affects women of reproductive age, so there are concerns about its effects on fertility. We investigated the success of in vitro fertilization (IVF) in patients with IBD compared with the general (non-IBD) IVF population. METHODS: We conducted a matched retrospective cohort study of female patients with IBD who underwent IVF from 1998 through 2011 at 2 tertiary care centers. Patients were matched 4:1 to those without IBD (controls). The primary outcome was the cumulative rate of live births after up to 6 cycles of IVF. Secondary outcomes included the proportion of patients who became pregnant and the rate of live births for each cycle. RESULTS: Forty-nine patients with Crohn's disease (CD), 71 patients with ulcerative colitis (UC), 1 patient with IBD-unclassified, and 470 controls underwent IVF during the study period. The cumulative rate of live births was 53% for controls, 69% for patients with UC (P = .08 compared with controls), and 57% for patients with CD (P = .87 compared with controls). The incidence of pregnancy after the first cycle of IVF was similar among controls (40.9%), patients with UC (49.3%; P = .18), and patients with CD (42.9%; P = .79). Similarly, the incidence of live births after the first cycle of IVF was similar among controls (30.2%), patients with UC (33.8%; P = .54), and patients with CD (30.6%; P = .95). CONCLUSIONS: Based on a matched cohort study, infertile women with IBD achieve a rate of live births after IVF that is comparable with those of infertile women without IBD. PMID- 25818082 TI - Elongated Uvula After Esophagogastroduodenoscopy. PMID- 25818083 TI - Severe postoperative wound healing disturbance in a patient with alpha-1 antitrypsin deficiency: the impact of augmentation therapy. AB - Wound healing disturbance is a common complication following surgery, but the underlying cause sometimes remains elusive. A 50-year-old Caucasian male developed an initially misunderstood severe wound healing disturbance following colon and abdominal wall surgery. An untreated alpha-1-antitrypsin (AAT) deficiency in the patient's medical history, known since 20 years and clinically apparent as a mild to moderate chronic obstructive pulmonary disease, was eventually found to be at its origin. Further clinical work-up showed AAT serum levels below 30% of the lower reference value; phenotype testing showed a ZZ phenotype and a biopsy taken from the wound area showed the characteristic, disease-related histological pattern of necrotising panniculitits. Augmentation therapy with plasma AAT was initiated and within a few weeks, rapid and adequate would healing was observed. AAT deficiency is an uncommon but clinically significant, possible cause of wound healing disturbances. An augmentation therapy ought to be considered in affected patients during the perioperative period. PMID- 25818084 TI - Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial. AB - BACKGROUND: The oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC. METHODS: In this single arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160 mg orally once daily on days 4-10 and 18-24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety. RESULTS: Median overall treatment duration with any study drug was 9.9 months (range 0.6-19.6); median treatment duration with regorafenib was 7.7 months (range 0.1-19.5); six patients remained on regorafenib for more than 1 year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications. CONCLUSION: Regorafenib+mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone. PMID- 25818085 TI - Psychosis in primary angiitis of the central nervous system involving bilateral thalami: a case report. AB - OBJECTIVE: To report a case of primary angiitis of the central nervous system (PACNS), a rare inflammatory disease restricted to the central nervous system (CNS), with unusual clinical presentation mimicking schizophrenia. METHOD: Case report. RESULTS: A 45-year-old male presented with alteration of consciousness and confusion. Brain magnetic resonance imaging (MRI) scan showed a mass-like enhancing lesion involving bilateral thalami, and biopsy revealed findings compatible with PACNS. The patient was treated with corticosteroids. Psychotic symptoms crystallized over the initial 2 months after the diagnosis and persisted for over a year. Severity of his symptoms improved with gradual normalization of the radiologic findings and antipsychotic medication. CONCLUSION: Our case highlights the importance of considering PACNS as a differential diagnosis of a tumor-like mass lesion in the CNS and the significance of thalamic involvement in the pathogenesis of psychotic symptoms including delusions and hallucinations. PMID- 25818086 TI - Contrasts in spatial and temporal variability of oxidative capacity and elemental composition in moxibustion, indoor and outdoor environments in Beijing. AB - Moxibustion is a traditional Chinese medicine therapy that burns moxa floss which produces a substantial amount of PM10 into the environment, thus spawning safety concerns about health impacts of the smoke. We compared the oxidative capacity and elemental composition of moxibustion-derived and ambient PM10 in summer and winter to provide a source-, spatial- and temporal-comparison of PM10 biological responses. The PM10 oxidative capacity was 2.04 and 1.45 fold lower, and dose dependent slope gradient was 2.36 and 1.76 fold lower in moxibustion environment than indoor or outdoor. Oxidative damage was highly correlated with iron, cesium, aluminum and cobalt in indoor, but moxibustion environment displayed low associations. The total elemental concentration was also lower in moxibustion environment than indoor (2.28 fold) or outdoor (2.79 fold). The source-to-dose modeling and slope gradient analysis in this study can be used as a model for future source-, spatial- and temporal-related moxibustion safety evaluation studies. PMID- 25818087 TI - Searching for native tree species and respective potential biomarkers for future assessment of pollution effects on the highly diverse Atlantic Forest in SE Brazil. AB - This study summarizes the first effort to search for bioindicator tree species and respective potential biomarkers for future assessment of potential mixed pollution effects on the highly diverse Atlantic Forest in SE-Brazil. Leaves of the three most abundant species inventoried in a phytosociological survey (Croton floribundus, Piptadenia gonoacantha and Astronium graveolens) were collected in four forest remnants during winter and summer (2012). Their potential bioindicator attributes were highlighted using a screening of morphological, chemical and biochemical markers. The leaf surface structure and/or epicuticular wax composition pointed the accumulator properties of C. floribundus and P. gonoacantha. C. floribundus is a candidate for assessing potential accumulation of Cu, Cd, Mn, Ni, S and Zn. P. gonoacantha is a candidate to monitor polycyclic aromatic hydrocarbons. Increased levels of secondary metabolites and decreased antioxidant capacity in leaves of A. graveolens may support its value as a bioindicator for oxidative pollutants by visible dark stipplings. PMID- 25818088 TI - Establishing geochemical background levels of selected trace elements in areas having geochemical anomalies: The case study of the Orbetello lagoon (Tuscany, Italy). AB - The determination of background concentration values (BGVs) in areas, characterised by the presence of natural geochemical anomalies and anthropogenic impact, appears essential for a correct pollution assessment. For this purpose, it is necessary to establish a reliable method for determination of local BGVs. The case of the Orbetello lagoon, a geologically complex area characterized by Tertiary volcanism, is illustrated. The vertical concentration profiles of As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were studied in four sediment cores. Local BGVs were determined considering exclusively samples not affected by anthropogenic influence, recognized by means of multivariate statistics and radiochronological dating ((137)Cs and (210)Pb). Results showed BGVs well-comparable with mean crustal or shale values for most of the considered elements except for Hg (0.87 mg/kg d.w.) and As (16.87 mg/kg d.w.), due to mineralization present in the catchment basin draining into the lagoon. PMID- 25818089 TI - Estimating evaporative vapor generation from automobiles based on parking activities. AB - A new approach is proposed to quantify the evaporative vapor generation based on real parking activity data. As compared to the existing methods, two improvements are applied in this new approach to reduce the uncertainties: First, evaporative vapor generation from diurnal parking events is usually calculated based on estimated average parking duration for the whole fleet, while in this study, vapor generation rate is calculated based on parking activities distribution. Second, rather than using the daily temperature gradient, this study uses hourly temperature observations to derive the hourly incremental vapor generation rates. The parking distribution and hourly incremental vapor generation rates are then adopted with Wade-Reddy's equation to estimate the weighted average evaporative generation. We find that hourly incremental rates can better describe the temporal variations of vapor generation, and the weighted vapor generation rate is 5-8% less than calculation without considering parking activity. PMID- 25818090 TI - Evaluating the efficacy of playground washing to reduce environmental metal exposures. AB - Washing and wet mopping is often advocated as a remedial treatment to limit exposure to lead dust. Here, surface and pre- and post-play wipes were measured to ascertain dust metal exposures (arsenic, cadmium, copper, lead and zinc) following play routines at four playgrounds in the smelter city of Port Pirie, South Australia, which are washed regularly. Although post-play hand wipe metals were 55.9% (95% CI: -0.78, -0.34) lower on wash days, loadings increased ~5.1% (95% CI: 1.2, 11.7) per hour after washing. Despite washing, post-play hand lead exceeded a conservative value of 800 MUg/m(2) within 24 h or sooner, with loadings increasing in proximity to the smelter. Post-play lead loadings were always >1000 MUg/m(2) at the playground closest to smelter. Playground washing results in short-lived exposure reduction and effective treatment requires elimination of smelter emissions. PMID- 25818091 TI - Estimating dry deposition and gas/particle partition coefficients of neutral poly /perfluoroalkyl substances in northern German coast. AB - Dry deposition fluxes of 12 neutral poly-/perfluoroalkyl substances (PFASs) were estimated at Busum located in northern German coast, and their gas/particle partition coefficients were predicted by employing the polyparameter linear free energy relationships (PP-LFERs). The gas deposition flux, particle deposition flux and total (gas + particle) flux of the 12 PFASs during sampling periods were 1088 +/- 611, 189 +/- 75 and 1277 +/- 627 pg/(m(2) d), respectively. The gas deposition of PFASs played a key role during deposition to marine ecosystem. Sensitivity analysis showed that wind speed was the most sensitive parameter for gas deposition fluxes. Good agreements (within 1 log unit) were observed between the measured gas/particle partitioning data of PFASs and the predicted partition coefficients using PP-LFERs, indicating the model can reliably predict the gas/particle partitioning behaviors of atmospheric neutral PFASs. PMID- 25818092 TI - Using foliar and forest floor mercury concentrations to assess spatial patterns of mercury deposition. AB - We evaluated spatial patterns of mercury (Hg) deposition through analysis of foliage and forest floor samples from 45 sites across Adirondack Park, NY. Species-specific differences in foliar Hg were evident with the lowest concentrations found in first-year conifer needles and highest concentrations found in black cherry (Prunus serotina). For foliage and forest floor samples, latitude and longitude were negatively correlated with Hg concentrations, likely because of proximity to emission sources, while elevation was positively correlated with Hg concentrations. Elemental analysis showed moderately strong, positive correlations between Hg and nitrogen concentrations. The spatial pattern of Hg deposition across the Adirondacks is similar to patterns of other contaminants that originate largely from combustion sources such as nitrogen and sulfur. The results of this study suggest foliage can be used to assess spatial patterns of Hg deposition in small regions or areas of varied topography where current Hg deposition models are too coarse to predict deposition accurately. PMID- 25818093 TI - Day-to-day variability of toxic events induced by organic compounds bound to size segregated atmospheric aerosol. AB - This study quantified the temporal variability of concentration of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs), genotoxicity, oxidative DNA damage and dioxin-like activity of the extractable organic matter (EOM) of atmospheric aerosol particles of aerodynamic diameter (dae, MUm) coarse (1 < dae < 10), upper (0.5 < dae < 1) and lower-accumulation (0.17 < dae < 0.5) and ultrafine (<0.17) fractions. The upper accumulation fraction formed most of the aerosol mass for 22 of the 26 study days and contained ~44% of total c-PAHs, while the ultrafine fraction contained only ~11%. DNA adduct levels suggested a crucial contribution of c-PAHs bound to the upper accumulation fraction. The dioxin-like activity was also driven primarily by c-PAH concentrations. In contrast, oxidative DNA damage was not related to c-PAHs, as a negative correlation with c-PAHs was observed. These results suggest that genotoxicity and dioxin-like activity are the major toxic effects of organic compounds bound to size segregated aerosol, while oxidative DNA damage is not induced by EOM. PMID- 25818094 TI - Anesthesia and the developing brain: a way forward for clinical research. AB - It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long-term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome. PMID- 25818095 TI - Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC. AB - INTRODUCTION: Platinum agents can cause the formation of DNA adducts and induce apoptosis to eliminate tumor cells. The aim of the present study was to investigate the influence of genetic variants of MDM2 on chemotherapy-related toxicities and clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We recruited 663 patients with advanced NSCLC who had been treated with first-line platinum-based chemotherapy. Five tagging single nucleotide polymorphisms (SNPs) in MDM2 were genotyped in these patients. The associations of these SNPs with clinical toxicities and outcomes were evaluated using logistic regression and Cox regression analyses. RESULTS: Two SNPs (rs1470383 and rs1690924) showed significant associations with chemotherapy-related toxicities (ie, overall, hematologic, and gastrointestinal toxicity). Compared with the wild genotype AA carriers, patients with the GG genotype of rs1470383 had an increased risk of overall toxicity (odds ratio [OR], 3.28; 95% confidence interval [CI], 1.34-8.02; P = .009) and hematologic toxicity (OR, 4.10; 95% CI, 1.73-9.71; P = .001). Likewise, patients with the AG genotype of rs1690924 showed more sensitivity to gastrointestinal toxicity than did those with the wild-type homozygote GG (OR, 2.32; 95% CI, 1.30-4.14; P = .004). Stratified survival analysis revealed significant associations between rs1470383 genotypes and overall survival in patients without overall or hematologic toxicity (P = .007 and P = .0009, respectively). CONCLUSION: The results of our study suggest that SNPs in MDM2 might be used to predict the toxicities of platinum-based chemotherapy and overall survival in patients with advanced NSCLC. Additional validations of the association are warranted. PMID- 25818096 TI - A fast experimental beam hardening correction method for accurate bone mineral measurements in 3D MUCT imaging system. AB - Bone mineral density plays an important role in the determination of bone strength and fracture risks. Consequently, it is very important to obtain accurate bone mineral density measurements. The microcomputerized tomography system provides 3D information about the architectural properties of bone. Quantitative analysis accuracy is decreased by the presence of artefacts in the reconstructed images, mainly due to beam hardening artefacts (such as cupping artefacts). In this paper, we introduced a new beam hardening correction method based on a postreconstruction technique performed with the use of off-line water and bone linearization curves experimentally calculated aiming to take into account the nonhomogeneity in the scanned animal. In order to evaluate the mass correction rate, calibration line has been carried out to convert the reconstructed linear attenuation coefficient into bone masses. The presented correction method was then applied on a multimaterial cylindrical phantom and on mouse skeleton images. Mass correction rate up to 18% between uncorrected and corrected images were obtained as well as a remarkable improvement of a calculated mouse femur mass has been noticed. Results were also compared to those obtained when using the simple water linearization technique which does not take into account the nonhomogeneity in the object. PMID- 25818097 TI - Insulinaemic and glycaemic responses to a second meal of a fibre- or starch enriched compound feed in healthy horses. AB - This study aimed to investigate the effect of a second meal of a fibre- or starch enriched compound feed on glycaemic and insulinaemic responses in healthy horses. In a cross-over design, horses were fed either a starch-enriched compound feed (SCF) or a fibre-enriched compound feed (FCF). On days of blood collection, test diets were fed in the morning (0800 h, first meal) and a second meal was fed 510 min after the first meal was finished (second meal). Significantly higher glycaemic and insulinaemic responses were associated with SCF compared with FCF. Feeding FCF for the second meal yielded similar moderate glycaemic and insulinaemic responses compared with the first meal. Feeding SCF as a second meal yielded significantly reduced glycaemic and insulinaemic responses from the first meal. In practice, evaluating glycaemic and insulinaemic responses of a single meal may not sufficiently describe the overall impact if more than one meal is fed per day. PMID- 25818098 TI - Control of macaw palm seed germination by the gibberellin/abscisic acid balance. AB - The hormonal mechanisms involved in palm seed germination are not fully understood. To better understand how germination is regulated in Arecaceae, we used macaw palm (Acrocomia aculeata (Jacq.) Lodd. Ex Mart.) seed as a model. Endogenous hormone concentrations, tocopherol and tocotrienol and lipid peroxidation during germination were studied separately in the embryo and endosperm. Evaluations were performed in dry (D), imbibed (I), germinated (G) and non-germinated (NG) seeds treated (+GA3 ) or not treated (control) with gibberellins (GA). With GA3 treatment, seeds germinated faster and to a higher percentage than control seeds. The +GA3 treatment increased total bioactive GA in the embryo during germination relative to the control. Abscisic acid (ABA) concentrations decreased gradually from D to G in both tissues. Embryos of G seeds had a lower ABA content than NG seeds in both treatments. The GA/ABA ratio in the embryo was significantly higher in G than NG seeds. The +GA3 treatment did not significantly affect the GA/ABA ratio in either treatment. Cytokinin content increased from dry to germinated seeds. Jasmonic acid (JA) increased and 1 aminocyclopropane-1-carboylic acid (ACC) decreased after imbibition. In addition, alpha-tocopherol and alpha-tocotrienol decreased, while lipid peroxidation increased in the embryo during germination. We conclude that germination in macaw palm seed involves reductions in ABA content and, consequently, increased GA/ABA in the embryo. Furthermore, the imbibition process generates oxidative stress (as observed by changes in vitamin E and MDA). PMID- 25818099 TI - Rasch modeling and confirmatory factor analysis of the systemizing quotient revised (SQ-R) scale. AB - This study assessed the dimensionality of the Systemizing Quotient-Revised (SQ R), a measure of how strong a person's interest is in systems, using two statistical approaches: Rasch modeling and Confirmatory Factor Analysis (CFA). Participants included N = 675 with an autism spectrum condition (ASC), N = 1369 family members of people with ASC, and N = 2014 typical controls. Data were applied to the Rasch model (Rating Scale) using WINSTEPS. The data fit the Rasch model quite well lending support to the idea that systemizing could be seen as unidimensional. Reliability estimates were .99 for items and .92 for persons. A CFA parceling approach confirmed that a unidimensional model fit the data. There was, however, differential functioning by sex in some of these items. An abbreviated 44-item version of the scale, consisting of items without differential item functioning by sex was developed. This shorter scale also was tested from a Rasch perspective and confirmed through CFA. All measures showed differences on total scale scores between those participants with and without ASC (d = 0.71, p < .005), and between sexes (d = 0.53, p < .005). We conclude that the SQ-R is an appropriate measure of systemizing which can be measured along a single dimension. PMID- 25818100 TI - The mitochondrial division inhibitor mdivi-1 attenuates spinal cord ischemia reperfusion injury both in vitro and in vivo: Involvement of BK channels. AB - Mitochondrial division inhibitor (mdivi-1), a selective inhibitor of a mitochondrial fission protein dynamin-related protein 1 (Drp1), has been shown to exert protective effects in heart and cerebral ischemia-reperfusion models. The present study was designed to investigate the beneficial effects of mdivi-1 against spinal cord ischemia-reperfusion (SCIR) injury and its associated mechanisms. SCIR injury was induced by glutamate treatment in cultured spinal cord neurons and by descending thoracic aorta occlusion for 20 min in rats. We found that mdivi-1 (10 MUM) significantly attenuated glutamate induced neuronal injury and apoptosis in spinal cord neurons. This neuroprotective effect was accompanied by decreased expression of oxidative stress markers, inhibited mitochondrial dysfunction and preserved activities of antioxidant enzymes. In addition, mdivi-1 significantly increased the expression of the large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels, and blocking BK channels by paxilline partly ablated mdivi-1 induced protection. The in vivo experiments showed that mdivi-1 treatment (1 mg/kg) overtly mitigated SCIR injury induced spinal cord edema and neurological dysfunction with no organ-related toxicity in rats. Moreover, mdivi-1 increased the expression of BK channels in spinal cord tissues, and paxilline pretreatment nullified mdivi-1 induced protection after SCIR injury in rats. Thus, mdivi-1 may be an effective therapeutic agent for SCIR injury via activation of BK channels as well as reduction of oxidative stress, mitochondrial dysfunction and neuronal apoptosis. This article is part of a Special Issue entitled SI: Spinal cord injury. PMID- 25818101 TI - Epicardial Fat in Nonalcoholic Fatty Liver Disease: Properties and Relationships With Metabolic Factors, Cardiac Structure, and Cardiac Function. AB - Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance and the metabolic syndrome and might be an important cardiovascular (CV) risk factor. Epicardial adipose tissue (EAT) has been implicated in the pathogenesis of obesity-related CV disease. In an NAFLD population, we investigated EAT thickness and its possible relations to NAFLD and cardiac structure and function. This was an observational study of 57 patients with NAFLD and 48 age-matched controls. Patients with NAFLD had significantly higher body mass index (P < .0001), waist circumference (P < .0001), and high-sensitivity C-reactive protein (P = .005), whereas high-density lipoprotein cholesterol (P = .01) and adiponectin (P = .005) levels were significantly lower. The EAT was not thicker in NAFLD but was positively related to indices of impaired glucose tolerance and inflammation, with diabetes being an independent predictor of EAT thickness (b* = 0.29, P = .04). No relations were found between EAT and cardiac structure and function. In conclusion, this study confirms a pathologic phenotype of NAFLD. Epicardial fat was not significantly related to NAFLD per se, but diabetes, glucose metabolism, and inflammation were closely related to its thickness. PMID- 25818102 TI - Neutrophil to Lymphocyte Ratio and the Extent of Coronary Artery Disease: Results From a Large Cohort Study. AB - The neutrophil to lymphocyte ratio (NLR), an inflammatory biomarker, may be of predictive and prognostic value for cardiovascular (CV) events. We evaluated the relationship of NLR with the prevalence and extent of coronary artery disease (CAD) in consecutive patients undergoing elective or urgent coronary angiography. Our population (n = 3738 patients) was divided into NLR quartiles. Higher NLR was associated with aging and established CV risk factors, previous percutaneous coronary revascularization, acute presentation, and more complex pharmacological therapy. The NLR was related to platelet count, white blood cell count, creatinine, glycemia, uric acid, and C-reactive protein (all P = .001) levels but inversely related to hemoglobin (P < .001), total cholesterol (P = .005), and triglycerides (P < .001) levels. The NLR was associated with multivessel disease (P < .001), anterior descending, right coronary arteries (P < .001) or circumflex branch lesions (P = .01), percentage of stenosis (P < .001), coronary calcification (P < .001), and intracoronary thrombus (P < .001) but inversely with in-stent restenosis (P < .001) and thrombolysis in myocardial infarction flow (P = .04). The NLR was directly related to the prevalence of CAD (P = .001) and severe CAD (P < .001). In patients undergoing coronary angiography, the NLR is independently associated with the prevalence and severity of CAD. PMID- 25818103 TI - Gender Analysis in the Outcomes of a Lifestyle Intervention Among Patients Who Had an Open Heart Surgery. AB - The aim of this study was to evaluate the gender-oriented differences in the outcomes of a lifestyle intervention trial (diet, smoking cessation, and exercise) among patients who had open heart surgery. A randomized, nonblind intervention study was performed on 500 patients who had open heart surgery. Immediately after hospital discharge, 250 patients were randomly allocated lifestyle intervention by receiving oral and written information in the form of a booklet with specific educational information for postoperative rehabilitation. The remaining 250 patients received the regular oral instructions. The applied lifestyle intervention proved to be beneficial only in men as far as quitting smoking (relative risk [RR]: 0.36, confidence interval [CI]: 0.16-0.80; P = .01) and returning to work (RR: 0.35, CI: 0.13-0.92; P = .03) are concerned. For both genders, no significant associations between dietary and physical activity recommendations were observed. CONCLUSION: Lifestyle nursing intervention immediately after open heart surgery had a beneficial effect on men 1 year after the surgery but not on women. Thus, there is a need for gender-specific studies among women. PMID- 25818104 TI - Association Between Platelet to Lymphocyte Ratio and Saphenous Vein Graft Disease. AB - Atherosclerosis plays an important role in saphenous vein graft disease (SVGD). Previous trials showed that inflammatory blood cells play a role in this process. The platelet to lymphocyte ratio (PLR) has been proposed as a novel predictor for cardiovascular risk and indicator of atherosclerosis. The aim of this study was to assess the relationship between SVGD and PLR. A total of 220 patients with SVG were enrolled (n = 87 with SVGD and n = 133 with patent SVG). A >= 50% stenosis within the SVG was defined as clinically significant. Median PLR (P < .001) and mean platelet volume (MPV; P = .043) were significantly higher in patients with SVGD. Also, PLR showed significantly positive correlation with age of SVG (P < .05). Median age of SVGs was also higher in the SVGD group (P = .025). In multivariate logistic regression analyses, the PLR and MPV were independent predictors of SVGD. Using a cutoff level of 106.3, the PLR predicted SVGD with a sensitivity of 87.4% and a specificity of 80.3%. To the best of our knowledge, this study showed, for the first time, that PLR was independently associated with SVGD. Both PLR and MPV might predict SVGD. PMID- 25818105 TI - Transradial Coronary Intervention Versus Coronary Artery Bypass Grafting for Unprotected Left Main and/or Multivessel Disease in Patients With Acute Coronary Syndrome. AB - The overall safety and efficacy of transradial coronary intervention (TRI) versus coronary artery bypass grafting (CABG) for patients with unprotected left main (UPLM) disease and/or multivessel coronary disease (MVD) presenting with acute coronary syndrome (ACS) have not been established. Consecutive patients with ACS undergoing TRI with drug-eluting stent (n = 1431) or CABG (n = 651) for UPLM and/or MVD were included. A propensity-score matching was performed to adjust for differences in baseline characteristics between the 2 cohorts, yielding 524 pairs of matched patients. Median clinical follow-up was 32 months. After propensity score adjustment, no significant difference was observed between the TRI and CABG groups in all-cause mortality (4.0% vs 5.2%; P = .375). Transradial coronary intervention was favored by a significant increase in the incidence of stroke in the CABG group (0.4% vs 1.9%; P = .020), whereas a significantly increased target vessel revascularization rate (16.8% vs 6.3%; P < .0001) observed in the TRI group favored CABG. Composite outcome (death/myocardial infarction/stroke) was comparable between the TRI and the CABG groups (8.0% vs 11.5%; P = .061). Clinical outcomes of TRI on UPLM and/or MVD for patients with ACS are comparable to CABG in composite safety outcomes with the advantage to TRI for avoiding a stroke. PMID- 25818106 TI - Preconditioning With Tauroursodeoxycholic Acid Protects Against Contrast-Induced HK-2 Cell Apoptosis by Inhibiting Endoplasmic Reticulum Stress. AB - To investigate whether tauroursodeoxycholic acid (TUDCA) could attenuate contrast media (CM)-induced renal tubular cell apoptosis by inhibiting endoplasmic reticulum stress (ERS), we exposed HK-2 cells to increasing doses of meglumine diatrizoate (20, 40, and 80 mg I/mL) for 2 to 16 hours, with/without TUDCA preconditioning for 24 hours. Cell viability test, Hoechst 33258 staining, and flow cytometry were used to detect meglumine diatrizoate-induced cell apoptosis, while real-time polymerase chain reaction and Western blot analysis were used to measure the expressions of ERS markers of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), and the apoptosis-related marker of caspase 12. Cell apoptosis and messenger RNA (mRNA) expression of GRP78 (P = .005), ATF4 (P = .01), and caspase 12 (P = .001) were significantly higher in the CM 4 hours group than the control as well as the protein expressions. The TUDCA preconditioning reduced the mRNA expression of GRP78, ATF4, and caspase 12 in the CM 4 hours groups (P = .009, .019, and .003, respectively) as well as the protein expression. In conclusion, TUDCA could protect renal tubular cells from meglumine diatrizoate-induced apoptosis by inhibiting ERS. PMID- 25818107 TI - Efficient vaccine against pandemic influenza: combining DNA vaccination and targeted delivery to MHC class II molecules. AB - There are two major limitations to vaccine preparedness in the event of devastating influenza pandemics: the time needed to generate a vaccine and rapid generation of sufficient amounts. DNA vaccination could represent a solution to these problems, but efficacy needs to be enhanced. In a separate line of research, it has been established that targeting of vaccine molecules to antigen presenting cells enhances immune responses. We have combined the two principles by constructing DNA vaccines that encode bivalent fusion proteins; these target hemagglutinin to MHC class II molecules on antigen-presenting cells. Such DNA vaccines rapidly induce hemagglutinin-specific antibodies and T cell responses in immunized mice. Responses are long-lasting and protect mice against challenge with influenza virus. In a pandemic situation, targeted DNA vaccines could be produced and tested within a month. The novel DNA vaccines could represent a solution to pandemic preparedness in the advent of novel influenza pandemics. PMID- 25818108 TI - Assessing estrogenic activity and reproductive toxicity of organic extracts in WWTP effluents. AB - Trace level organic contaminants might not be completely removed from the municipal wastewater and the safety incurred by them had become a concern. These organic pollutants were extracted from water samples and detected by GC-MS. The estrogenic activity of the organic was tested using Yeast Estrogen Screen to detect the transcriptional activation of the estrogen receptor (ER) and immature mouse uterotrophic bioassays to study reproductive toxicity. The results of GC-MS demonstrated the organic extracts in the municipal wastewater and the WWTP effluents Included two major categories, benzenes and Phthalates. The estrogenic activity of organic extracts from the secondary effluent (SE) and tertiary effluent (TE) was below that of the raw wastewater (RW). Results of uterotrophic bioassay demonstrated that SE would bring some potential hazards on animals while TE was relatively safe. PMID- 25818109 TI - Exposure to bisphenol-A and reproductive hormones among male adults. AB - BACKGROUND: Bisphenol A (BPA) is a suspected human endocrine disruptor which is widely used. METHODS: In order to determine whether urine BPA level is associated with serum reproductive hormone levels among male adults, we carried out a cross sectional study in China. We recruited 592 male workers and collected their urine samples for BPA measurement. We also collected blood samples and examined serum reproductive hormones. We used multiple linear regression and log-binomial model to examine associations between urine BPA level and hormone levels after controlling for age and smoking status. RESULTS: An increased urine BPA level was associated with increased prolactin (p<0.001), estradiol (p<0.001), sex hormone binding globulin level (p=0.001), and a reduced androstenedione (p<0.001) and free androgen index level (p=0.021). Males, whose urine BPA level was in the 2nd, 3rd and highest quartiles, had respectively 1.58, 1.33 and 3.09-fold increased prevalence of having a high prolactin level (>P75 level). The highest quartile of BPA level was associated with 1.63 and 1.50-fold increased prevalence of having a high estradiol and elevated sex hormone-binding globulin level. Males with higher quartile of BPA level had a lower inhibin B level. CONCLUSION: High BPA exposure is associated with increased prolactin, estradiol and sex hormone-binding globulin level in males, and may contribute to male infertility. PMID- 25818110 TI - Fate of psychoactive compounds in wastewater treatment plant and the possibility of their degradation using aquatic plants. AB - In this study we analyzed and characterized 29 psychoactive remedies, illicit drugs and their metabolites in single stages of wastewater treatment plants in the capital city of Slovakia. Psychoactive compounds were present within all stages, and tramadol was detected at a very high concentration (706 ng/L). Significant decreases of codeine, THC-COOH, cocaine and buprenorphine concentration were observed in the biological stage. Consequently, we were interested in the possibility of alternative tertiary post-treatment of effluent water with the following aquatic plants: Cabomba caroliniana, Limnophila sessiliflora, Egeria najas and Iris pseudacorus. The most effective plant for tertiary cleansing was I. pseudacorus which demonstrated the best pharmaceutical removal capacity. After 48 h codeine and citalopram was removed with 87% efficiency. After 96 h were all analyzed compounds were eliminated with efficiencies above 58%. PMID- 25818111 TI - Depressive Symptoms Delayed Quit Attempts and Shortened Abstinence in Young Smokers of the Hong Kong Youth Quitline. AB - INTRODUCTION: Young smokers often report depressive symptoms while receiving smoking cessation counseling. This study examines time patterns in the quitting process among young smokers with or without notable depressive symptoms. METHODS: The quitting trajectories of young smokers aged 12 to 25 (n = 578) who called the Youth Quitline in Hong Kong between March 2006 and May 2011 were recorded and analyzed through multiple telephone sessions over periods of up to 6 months. The time patterns of young smokers who had or did not have notable depressive symptoms were compared using nonparametric Kaplan-Meier methods with log-rank tests. RESULTS: Among young smokers with low levels of nicotine dependence, those who had notable depressive symptoms were less likely to initiate a quit attempt within 28 days after their baseline telephone intervention (probability = .38 vs. .60; P value = .04). Furthermore, young smokers who had notable depressive symptoms were less likely to remain abstinent from smoking for 2 days after starting a quit attempt (probability = .50 vs. .64; P value = .012). Young adults aged 18 or above were more likely to relapse into smoking (adjusted HR = 1.50, 95% CI = 1.01, 2.22). CONCLUSIONS: Depressive symptoms may delay young smokers from initiating quit attempts and shorten their abstinence. A baseline screening process is suggested for identifying youths with co-occurring depressive disorder and nicotine dependence. Further studies should examine a collaborative model of smoking cessation that involves both counselors and physicians in preventing young smokers from rapid relapses after they make quit attempts. PMID- 25818112 TI - [Operative technique: The clitoral transposition]. AB - Female sexual mutilations result in an important physical and mental suffering. A large number of women have been affected and require a global management, including surgical clitoral transposition. This surgical technique is allowing a rapid improvement of clinical symptoms. In this article, we will describe the indications and operative technique of the clitoral transposition. PMID- 25818113 TI - [Maternal and neonatal outcomes of unplanned deliveries]. AB - OBJECTIVES: Know the impact of the unplanned deliveries in a town of medium size, the characteristics of these women and maternal and neonatal risks. MATERIALS AND METHODS: This was a retrospective study conducted between January 2002 and December 2009. Unexpected delivery was defined as any delivery taking place outside of a non-elective way maternity. Each unexpected delivery was matched at nearest delivery of equivalent term, at the CHU maternity, with an onset of spontaneous labour. RESULTS: Ninety-four women gave birth unexpectedly for a total of 48,721 births (incidence of 0.19%). There was a significant difference between cases and controls for parity (1.8 versus 0.9), the lack of follow-up of pregnancy (21.3% versus 1.1%), tobacco (57.4% versus 25.5%), the socio-economic level, the type of feeding (artificial: 61.7% versus 30.6%), the home-hospital distance and obstetric follow-up. We found a significant increase in perinatal mortality (6.4% versus 1%) and stay in Neonatal ICU (19.1% versus 9.2%). The main neonatal morbidity was hypothermia. CONCLUSION: It is difficult to target a population at risk because the type of these women is non-specific. Prevention of unplanned deliveries and their morbidities through information of patients on the grounds of urgent consultation and support of the newborn to limit hypothermia. PMID- 25818114 TI - [Current situation of the education in gynaecology-obstetrics in France]. AB - OBJECTIVES: To get an overview of the education offer for obstetrics trainees in France and to assess their satisfaction and requests regarding these classes and their access. MATERIAL AND METHODS: Two questionnaires were sent over the country between September 2013 and July 2014. The first one was intended to the person in charge of teaching in each university hospital. We asked about the organization of teaching classes and access to simulation workshops. The second one was intended to the local representative of interns of the French association of gynaecology and obstetrics trainees (AGOF). We searched for overall satisfaction and requests concerning these learning classes. RESULTS: Over 28 university hospitals, 19 teachers (67.9 %) and 25 students (89.3 %) responded. Various ways and means of teaching are used throughout the country. Use of simulation workshop has spread in many university hospitals but their types and numbers are still very different among the organizations. Students are globally satisfied by the type, volume and content of their teaching classes. Simulation workshops are really appreciated by trainees and they wish more of them were organized. CONCLUSION: There is a great disparity in the ways of teaching in France. Gathering resources between the different centres may allow trainees to access to the same theoretical education and simulation workshops all over the country. PMID- 25818115 TI - Malakoplakia of the Appendiceal Orifice Mimicking Adenomatous Epithelium. PMID- 25818116 TI - Longitudinal clinical trials with adaptive choice of follow-up time. AB - In longitudinal studies comparing two treatments with a maximum follow-up time there may be interest in examining treatment effects for intermediate follow-up times. One motivation may be to identify the time period with greatest treatment difference when there is a non-monotone treatment effect over time; another motivation may be to make the trial more efficient in terms of time to reach a decision on whether a new treatment is efficacious or not. Here, we test the composite null hypothesis of no difference at any follow-up time versus the alternative that there is a difference at at least one follow-up time. The methods are applicable when a few measurements are taken over time, such as in early longitudinal trials or in ancillary studies. Suppose the test statistic Z(t(k)) will be used to test the hypothesis of no treatment effect at a fixed follow-up time t(k). In this context a common approach is to perform a pilot study on N1 subjects, and evaluate the treatment effect at the fixed time points t1,...,t(K) and choose t* as the value of t(k) for which Z(t(k)) is maximized. Having chosen t* a second trial can be designed. In a setting with group sequential testing we consider several adaptive alternatives to this approach that treat the pilot and second trial as a seamless, combined entity and evaluate Type I error and power characteristics. The adaptive designs we consider typically have improved power over the common, separate trial approach. PMID- 25818117 TI - Programs to increase high school completion: a community guide systematic health equity review. AB - CONTEXT: High school completion (HSC) is an established predictor of long-term morbidity and mortality. U.S. rates of HSC are substantially lower among students from low-income families and most racial/ethnic minority populations than students from high-income families and the non-Hispanic white population. This systematic review assesses the effectiveness of programs to increase HSC and the potential of these programs to improve lifelong health among at-risk students. EVIDENCE ACQUISITION: A search located a meta-analysis (search period 1985 2010/2011) on the effects of programs to increase HSC or General Educational Development (GED) diploma receipt; the meta-analysis was concordant with Community Guide definitions and methodologic standards. Programs were assessed separately for the general student population (152 studies) and students who were parents or pregnant (15 studies). A search for studies published between 2010 and August 2012 located ten more recent studies, which were assessed for consistency with the meta-analysis. Analyses were conducted in 2013. EVIDENCE SYNTHESIS: The review focused on the meta-analysis. Program effectiveness was measured as the increased rate of HSC (or GED receipt) by the intervention group compared with controls. All assessed program types were effective in increasing HSC in the general student population: vocational training, alternative schooling, social emotional skills training, college-oriented programming, mentoring and counseling, supplemental academic services, school and class restructuring, multiservice packages, attendance monitoring and contingencies, community service, and case management. For students who had children or were pregnant, attendance monitoring and multiservice packages were effective. Ten studies published after the search period for the meta-analysis were consistent with its findings. CONCLUSIONS: There is strong evidence that a variety of HSC programs can improve high school or GED completion rates. Because many programs are targeted to high-risk students and communities, they are likely to advance health equity. PMID- 25818118 TI - Associations Between Sildenafil Use and Changes in Days of Hospitalization in a Population With Pulmonary Arterial Hypertension Associated With Connective Tissue Disease. AB - PURPOSE: Pulmonary arterial hypertension (PAH) can be a complication in patients with connective tissue disease (CTD). Although the phosphodiesterase-5 inhibitor sildenafil shows evidence of efficacy and tolerability among patients with PAH associated with CTD in clinical trials, no studies have examined the association between its use and health care resource utilization in clinical practice. The objective of this study was to assess the associations between the use of sildenafil and health care resource utilization, specifically days of hospitalization, in a population with PAH associated with CTD. METHODS: A retrospective, matched, case-control analysis was conducted using data from a commercial claims database. Patients with a claim dated between 2003 and 2009 were selected. Cases and controls were matched on age, sex, and baseline total days of hospitalization. A longitudinal, zero-inflated, negative binomial model was used for analyzing the data after control for age, sex, region, Charlson comorbidity score, and use of PAH-specific medication other than sildenafil. FINDINGS: A total of 420 individuals, 210 cases and 210 controls, were included in the sample. The sample was 85.71% women, and the mean age was 57.6 years. Estimates for variances of an intercept random effect (5.08 * 10(-13)) and for a time-variable random effect (2.84 * 10(-16)) were both essentially zero. Thus a zero-inflated negative binomial model without random effects was used. When individuals were not using sildenafil, each 1-month interval was associated with a 2.8% increase in the mean number of days of hospitalization. In contrast, when individuals were using sildenafil, each 1-month interval was associated with a decrease of 3.3% in days of hospitalization. IMPLICATIONS: In this data analysis of the association between sildenafil use and days of hospitalization among individuals with PAH associated with CTD in a large-scale population, sildenafil use in the treatment of PAH associated with CTD was associated with reduced days of hospitalization during the year after the initiation of treatment. PMID- 25818119 TI - Development of a novel adjuvanted nasal vaccine: C48/80 associated with chitosan nanoparticles as a path to enhance mucosal immunity. AB - In a time in which mucosal vaccines development has been delayed by the lack of safe and effective mucosal adjuvants, the combination of adjuvants has started to be explored as a strategy to obtain potent vaccine formulations. This study describes a novel adjuvant combination as an effective approach for a nasal vaccine - the association of the mast cell activator compound 48/80 with chitosan based nanoparticles. It was hypothesized that mucoadhesive nanoparticles would promote the cellular uptake and prolong the antigen residence time on nasal cavity. Simultaneously, mast cell activation would promote a local microenvironment favorable to the development of an immune response. To test this hypothesis, two different C48/80 loaded nanoparticles (NPs) were prepared: Chitosan-C48/80 NP (Chi-C48/80 NP) and Chitosan/Alginate-C48/80 NP (Chi/Alg C48/80 NP). The potential as a vaccine adjuvant of the two delivery systems was evaluated and directly compared. Both formulations had a mean size near 500nm and a positive charge; however, Chi-C48/80 NP was a more effective adjuvant delivery system when compared with Chi/Alg-C48/80 NP or C48/80 alone. Chi-C48/80 NP activated mast cells at a greater extent, were better internalized by antigen presenting cells than Chi/Alg-C48/80 NP and successfully enhanced the nasal residence time of a model antigen. Superiority of Chi-C48/80 NP as adjuvant was also observed in vivo. Therefore, nasal immunization of mice with Bacillus anthracis protective antigen (PA) adsorbed on Chi-C48/80 NP elicited high levels of serum anti-PA neutralizing antibodies and a more balanced Th1/Th2 profile than C48/80 in solution or Chi/Alg-C48/80 NP. The incorporation of C48/80 within Chi NP also promoted a mucosal immunity greater than all the other adjuvanted groups tested, showing that the combination of a mast cell activator and chitosan NP could be a promising strategy for nasal immunization. PMID- 25818120 TI - Nanoencapsulation of rice bran oil increases its protective effects against UVB radiation-induced skin injury in mice. AB - Excessive UV-B radiation by sunlight produces inflammatory and oxidative damage of skin, which can lead to sunburn, photoaging, and cancer. This study evaluated whether nanoencapsulation improves the protective effects of rice bran oil against UVB radiation-induced skin damage in mice. Lipid-core nanocapsules containing rice bran oil were prepared, and had mean size around 200 nm, negative zeta potential (~-9 mV), and low polydispersity index (<0.20). In order to allow application on the skin, a hydrogel containing the nanoencapsulated rice bran oil was prepared. This formulation was able to prevent ear edema induced by UVB irradiation by 60 +/- 9%, when compared with a hydrogel containing LNC prepared with a mixture of medium chain triglycerides instead of rice bran oil. Protein carbonylation levels (biomarker of oxidative stress) and NF-kappaB nuclear translocation (biomarker of pro-inflammatory and carcinogenesis response) were reduced (81% and 87%, respectively) in animals treated with the hydrogel containing the nanoencapsulated rice bran oil. These in vivo results demonstrate the beneficial effects of nanoencapsulation to improve the protective properties of rice bran oil on skin damage caused by UVB exposure. PMID- 25818121 TI - Outcomes of Video-Assisted Thoracic Surgical Decortication in 274 Patients with Tuberculous Empyema. AB - OBJECTIVE: The present work aimed to retrospectively assess the outcomes associated with decortication by video-assisted thoracic surgery (VATS) in patients with tuberculous empyema. METHODS: Patients (n = 274) who underwent decortication by VATS for surgical management of pleural empyema between January 2000 to 2010 were included. Pre-, intra-, and postoperative characteristics were observed for all patients, which were followed up for 12 months to evaluate surgical outcomes such as postoperative complications and disease recurrence. RESULTS: No patients required conversion to thoracotomy, and no death or postoperative bleeding was reported. The mean operation time was 104.5 +/- 20.4 min, with 271.5 +/- 41.3 ml intraoperative blood loss and median length of hospital stay of 7.2 +/- 3 .4 days. Of the 274 patients, 262 were followed up for 12 months; 26 (9.9%) patients showed complications, including incomplete lung re expansion (11 patients) and persistent air leak (6 patients). While early disease recurrence was observed in 3 (1.1%) patients after surgery, late recurrence was reported for 6 (2.3%) individuals. Interestingly, the complication rate was much higher in patients with chronic empyema (15/34, 44.1%) than in subjects with acute empyema (11/228, 4.8%). CONCLUSIONS: Decortication by VATS decreases postsurgical complications, and results in decreased disease recurrence. This study demonstrated improved outcomes by decortication by VATS, even in patients with stage III tuberculous empyema. PMID- 25818122 TI - Parameterization of an interfacial force field for accurate representation of peptide adsorption free energy on high-density polyethylene. AB - Interfacial force field (IFF) parameters for use with the CHARMM force field have been developed for interactions between peptides and high-density polyethylene (HDPE). Parameterization of the IFF was performed to achieve agreement between experimental and calculated adsorption free energies of small TGTG-X-GTGT host guest peptides (T = threonine, G = glycine, and X = variable amino-acid residue) on HDPE, with +/-0.5 kcal/mol agreement. This IFF parameter set consists of tuned nonbonded parameters (i.e., partial charges and Lennard-Jones parameters) for use with an in-house-modified CHARMM molecular dynamic program that enables the use of an independent set of force field parameters to control molecular behavior at a solid-liquid interface. The R correlation coefficient between the simulated and experimental peptide adsorption free energies increased from 0.00 for the standard CHARMM force field parameters to 0.88 for the tuned IFF parameters. Subsequent studies are planned to apply the tuned IFF parameter set for the simulation of protein adsorption behavior on an HDPE surface for comparison with experimental values of adsorbed protein orientation and conformation. PMID- 25818123 TI - The effects of lycopene on DNA damage and oxidative stress on indomethacin induced gastric ulcer in rats. AB - BACKGROUND AND AIMS: Lycopene, the main antioxidant compound present in tomatoes, has high singlet oxygen- and peroxyl radicals-quenching ability, resulting in protection against oxidative damage in aerobic cell. Indomethacin is a nonsteroidal anti-inflammatory drug, and can promote oxidative damage in gastric tissue. The aim of this study was to investigate the protective effects of lycopene on an indomethacin-induced gastric ulcer model. METHODS: A total of 42 adult male Wistar rats were divided into six groups of seven animals as follows: control, indomethacin, lansoprazole, lycopene 10 mg/kg, lycopene 50 mg/kg and lycopene 100 mg/kg. Gastric ulcers were induced by oral administration of indomethacin, after which the differing doses of lycopene were administered by oral gavage. The efficacy of lycopene was compared with lansoprazole. DNA damage of lymphocytes was measured by comet assay. Activities of superoxide dismutase, catalase and myeloperoxidase, as well as malondialdehyde and glutathione levels were determined in stomach tissue. This tissue was also taken for pathological investigations. The TUNEL method was used to detect apoptotic cells in paraffin sections. RESULTS: The results showed that 100 mg/kg lycopene administration significantly decreased % Tail DNA and Mean Tail Moment in the gastric ulcer group, compared with the other treatment groups. This same dose of lycopene also significantly decreased high malondialdehyde level and myeloperoxidase activity, and increased the activity of antioxidant enzymes (with the exception of catalase) in tissue. Apoptosis rates in the stomachs of the rats correlated with the biochemical and histopathological findings. CONCLUSIONS: These results indicated that lycopene might have a protective effect against indomethacin induced gastric ulcer and oxidative stress in rats. PMID- 25818124 TI - Role of tea tree oil in treatment of acne. PMID- 25818125 TI - David Bruns. PMID- 25818126 TI - A 78-year-old woman with brain metastases. PMID- 25818127 TI - Commentary. PMID- 25818128 TI - Commentary. PMID- 25818129 TI - Have you ever seen a 21-mmol/L serum K+ concentration? PMID- 25818130 TI - A Fatty blood sample. PMID- 25818131 TI - Extreme PCR: a breakthrough innovation for outbreaks? PMID- 25818132 TI - Hemoglobin S. PMID- 25818133 TI - Artist's method: James Abbott McNeill Whistler. PMID- 25818134 TI - Quantitative analysis of phosphoric acid esters in aqueous samples by isotope dilution stir-bar sorptive extraction combined with direct analysis in real time (DART)-Orbitrap mass spectrometry. AB - A novel hyphenated technique, namely the combination of stir bar sorptive extraction (SBSE) with isotope dilution direct analysis in real time (DART) OrbitrapTM mass spectrometry (OT-MS) is presented for the extraction of phosphoric acid alkyl esters (tri- (TnBP), di- (HDBP), and mono-butyl phosphate (H2MBP)) from aqueous samples. First, SBSE of phosphate esters was performed using a TwisterTM coated with 24 MUL of polydimethylsiloxane (PDMS) as the extracting phase. SBSE was optimized for extraction pH, phase ratio (PDMS volume/aqueous phase volume), stirring speed, extraction time and temperature. Then, coupling of SBSE to DART/Orbitrap-MS was achieved by placing the TwisterTM in the middle of an open-ended glass tube between the DART and the OrbitrapTM. The DART mass spectrometric response of phosphate esters was probed using commercially available and synthesized alkyl phosphate ester standards. The positive ion full scan spectra of alkyl phosphate triesters (TnBP) was characterized by the product of self-protonation [M+H](+) and, during collision induced dissociation (CID), the major fragmentation ions corresponded to consecutive loss of alkyl chains. Negative ionization gave abundant [M-H](-) ions for both HDnBP and H2MnBP. TwistersTM coated with PDMS successfully extracted phosphate acid esters (tri-, di- and mono-esters) granted that the analytes are present in the aqueous solution in the neutral form. SBSE/DART/Orbitrap-MS results show a good linearity between the concentrations and relative peak areas for the analytes in the concentration range studied (0.1-750 ng mL(-1)). Reproducibility of this SBSE/DART/Orbitrap-MS method was evaluated in terms of %RSD by extracting a sample of water fortified with the analytes. The %RSDs for TnBP, HDnBP and H2MnBP were 4, 3 and 3% (n=5) using the respective perdeuterated internal standards. Matrix effects were investigated by matrix matched calibration standards using underground water samples (UWS) and river water samples (RWS). Matrix effects were effectively compensated by the addition of the perdeuterated internal standards. The application of this new SBSE/DART/Orbitrap MS method should be very valuable for on-site sampling/monitoring, limiting the transport of large volumes of water samples from the sampling site to the laboratory. PMID- 25818135 TI - Efficient generation of volatile species for cadmium analysis in seafood and rice samples by a modified chemical vapor generation system coupled with atomic fluorescence spectrometry. AB - A vapor generation procedure to determine Cd by atomic fluorescence spectrometry (AFS) has been established. Volatile species of Cd are generated by following reaction of acidified sample containing Fe(II) and L-cysteine (Cys) with sodium tetrahydroborate (NaBH4). The presence of 5 mg L(-1) Fe(II) and 0.05% m/v Cys improves the efficiency of Cd vapor generation substantially about four-fold compared with conventional thiourea and Co(II) system. Three experiments with different mixing sequences and reaction times are designed to study the reaction mechanism. The results document that the stability of Cd(II)-Cys complexes is better than Cys-THB complexes (THB means NaBH4) while the Cys-THB complexes have more contribution to improve the Cd vapor generation efficiency than Cd(II)-Cys complexes. Meanwhile, the adding of Fe(II) can catalyze the Cd vapor generation. Under the optimized conditions, the detection limit of Cd is 0.012 MUg L(-1); relative standard deviations vary between 0.8% and 5.5% for replicate measurements of the standard solution. In the presence of 0.01% DDTC, Cu(II), Pb(II) and Zn(II) have no significant influence up to 5 mg L(-1), 10 mg L(-1)and 10 mg L(-1), respectively. The accuracy of the method is verified through analysis of the certificated reference materials and the proposed method has been applied in the determination of Cd in seafood and rice samples. PMID- 25818136 TI - Sum of ranking differences (SRD) to ensemble multivariate calibration model merits for tuning parameter selection and comparing calibration methods. AB - Most multivariate calibration methods require selection of tuning parameters, such as partial least squares (PLS) or the Tikhonov regularization variant ridge regression (RR). Tuning parameter values determine the direction and magnitude of respective model vectors thereby setting the resultant predication abilities of the model vectors. Simultaneously, tuning parameter values establish the corresponding bias/variance and the underlying selectivity/sensitivity tradeoffs. Selection of the final tuning parameter is often accomplished through some form of cross-validation and the resultant root mean square error of cross-validation (RMSECV) values are evaluated. However, selection of a "good" tuning parameter with this one model evaluation merit is almost impossible. Including additional model merits assists tuning parameter selection to provide better balanced models as well as allowing for a reasonable comparison between calibration methods. Using multiple merits requires decisions to be made on how to combine and weight the merits into an information criterion. An abundance of options are possible. Presented in this paper is the sum of ranking differences (SRD) to ensemble a collection of model evaluation merits varying across tuning parameters. It is shown that the SRD consensus ranking of model tuning parameters allows automatic selection of the final model, or a collection of models if so desired. Essentially, the user's preference for the degree of balance between bias and variance ultimately decides the merits used in SRD and hence, the tuning parameter values ranked lowest by SRD for automatic selection. The SRD process is also shown to allow simultaneous comparison of different calibration methods for a particular data set in conjunction with tuning parameter selection. Because SRD evaluates consistency across multiple merits, decisions on how to combine and weight merits are avoided. To demonstrate the utility of SRD, a near infrared spectral data set and a quantitative structure activity relationship (QSAR) data set are evaluated using PLS and RR. PMID- 25818137 TI - Semiconductor sensor embedded microfluidic chip for protein biomarker detection using a bead-based immunoassay combined with deoxyribonucleic acid strand labeling. AB - Two major issues need to be addressed in applying semiconductor biosensors to detecting proteins in immunoassays. First, the length of the antibody on the sensor surface surpasses the Debye lengths (approximately 1 nm, in normal ionic strength solution), preventing certain specifically bound proteins from being tightly attached to the sensor surface. Therefore, these proteins do not contribute to the sensor's surface potential change. Second, these proteins carry a small charge and can be easily affected by the pH of the surrounding solution. This study proposes a magnetic bead-based immunoassay using a secondary antibody to label negatively charged DNA fragments for signal amplification. An externally imposed magnetic force attaches the analyte tightly to the sensor surface, thereby effectively solving the problem of the analyte protein's distance to the sensor surface surpassing the Debye lengths. In addition, a normal ion intensity buffer can be used without dilution for the proposed method. Experiments revealed that the sensitivity can be improved by using a longer DNA fragment for labeling and smaller magnetic beads as solid support for the antibody. By using a 90 base pair DNA label, the signal was 15 times greater than that without labeling. In addition, by using a 120 nm magnetic bead, a minimum detection limit of 12.5 ng mL(-1) apolipoprotein A1 can be measured. Furthermore, this study integrates a semiconductor sensor with a microfluidic chip. With the help of microvalves and micromixers in the chip, the length of the mixing step for each immunoassay has been reduced from 1h to 20 min, and the sample volume has been reduced from 80 MUL to 10 MUL. In practice, a protein biomarker in a urinary bladder cancer patient's urine was successfully measured using this technique. This study provides a convenient and effective method to measure protein using a semiconductor sensor. PMID- 25818138 TI - Graphene-modified TiO2 nanotube arrays as an adsorbent in micro-solid phase extraction for determination of carbamate pesticides in water samples. AB - Graphene is a good adsorbent for organic pollutants, especially for compounds containing benzene rings. When used in TiO2 nanotube arrays for micro-solid phase extraction (MU-SPE), the combination of graphene's strong adsorptive properties with its good separation capabilities results in excellent sample preconcentration performance. In the present study, graphene-modified TiO2 nanotube arrays were prepared by electrodeposition using a cyclic voltammetric reduction method. Four carbamate pesticides, including metolcarb, carbaryl, isoprocarb, and diethofencarb, were used as model analytes to validate the enrichment properties of the prepared adsorbent in MU-SPE. Factors affecting the enrichment efficiency of the MU-SPE procedure were optimized and included sample pH, elution solvents, salting-out effect, adsorption time and desorption time. Under optimal conditions, graphene-modified TiO2 nanotube arrays exhibited excellent enrichment efficiency for carbamate pesticides. The detection limits of these carbamate pesticides ranged from 2.27 to 3.26 MUg L(-1). The proposed method was validated using four environmental water samples, and yields of pesticides recovered from spiked test samples of the four analytes were in the range of 83.9-108.8%. These results indicate that graphene-modified TiO2 nanotube arrays exhibit good adsorption to the target pollutants, and the method described in this work could be used as a faster and easier alternative procedure for routine analysis of carbamate pesticides in real water samples. PMID- 25818139 TI - Rapid liquid chromatography-tandem mass spectrometry analysis of 4-hydroxynonenal for the assessment of oxidative degradation and safety of vegetable oils. AB - A novel method for the UHPLC-MS/MS analysis of (E)-4-hydroxynonenal (4-HNE) is described. The method is based on derivatization of 4-HNE with pentafluorophenylhydrazine (1) or 4-trifluoromethylphenylhydrazine (2) in acetonitrile in the presence of trifluoroacetic acid as catalyst at room temperature and allows complete analysis of one sample of vegetable oil in only 21 min, including sample preparation and chromatography. The method involving hydrazine 1, implemented in an ion trap instrument with analysis of the transition m/z 337->154 showed LOD=10.9 nM, average accuracy of 101% and precision ranging 2.5-4.0% RSD intra-day (2.7-4.1% RSD inter-day), with 4-HNE standard solutions. Average recovery from lipid matrices was 96.3% from vaseline oil, 91.3% from sweet almond oil and 105.3% from olive oil. The method was tested on the assessment of safety and oxidative degradation of seven samples of dietary oil (soybean, mixed seeds, corn, peanut, sunflower, olive) and six cosmetic-grade oils (avocado, blackcurrant, apricot kernel, echium, sesame, wheat germ) and effectively detected increased 4-HNE levels in response to chemical (Fenton reaction), photochemical, or thermal stress and aging, aimed at mimicking typical oxidation associated with storage or industrial processing. The method is a convenient, cost-effective and reliable tool to assess quality and safety of vegetable oils. PMID- 25818140 TI - Spectrophotometric determination of Rare Earth Elements in aqueous nitric acid solutions for process control. AB - Noninvasive analytical control is of special interest for the complicated and hazardous production processes. On-line monitoring provides a unique opportunity to determine critical concentrations rapidly and without serious risks to operating personnel and the environment. Models for quantitative determination of concentrations of Rare Earth Elements in complex mixtures in nitric acid serve for these purposes. Here, the feasibility of simultaneous determination of cerium, praseodymium, and neodymium using the whole UV-vis spectroscopic range, together with chemometric data processing, is studied. The predictability of two chemometric techniques, partial least squares regression and correlation constrained multivariate curve resolution-alternating least squares are compared. Models' performances are analyzed in out-of-control cases. PMID- 25818141 TI - Single-walled carbon nanotube based transparent immunosensor for detection of a prostate cancer biomarker osteopontin. AB - Osteopontin (OPN) is involved in almost all steps of cancer development, and it is being investigated as a potential biomarker for a diagnosis and prognosis of prostate cancer. Here, we report a label-free, highly sensitive and transparent immunosensor based on single-walled carbon nanotubes (SWCNTs) for detection of OPN. A high density of COOH functionalized SWCNTs was deposited between two gold/indium tin oxide electrodes on a glass substrate by dielectrophoresis. Monoclonal antibodies specific to OPN were covalently immobilized on the SWCNTs. Relative resistance change of the immunosensors was measured as the concentration of OPN in phosphate buffer saline (PBS) and human serum was varied from 1 pg mL( 1) to 1 MUg mL(-1) for different channel lengths of 2, 5, and 10 MUm, showing a highly linear and reproducible behavior (R(2)>97%). These immunosensors were also specific to OPN against another test protein, bovine serum albumin, PBS and human serum, showing that a limit of detection for OPN was 0.3 pg mL(-1). This highly sensitive and transparent immunosensor has a great potential as a simple point-of care test kit for various protein biomarkers. PMID- 25818142 TI - Fluorescence quenching of graphene oxide combined with the site-specific cleavage of restriction endonuclease for deoxyribonucleic acid demethylase activity assay. AB - We report on the development of a sensitive and selective deoxyribonucleic acid (DNA) demethylase (using MBD2 as an example) activity assay by coupling the fluorescence quenching of graphene oxide (GO) with the site-specific cleavage of HpaII endonuclease to improve the selectivity. This approach was developed by designing a single-stranded probe (P1) that carries a binding region to facilitate the interaction with GO, which induces fluorescence quenching of the labeled fluorophore (FAM, 6-carboxyfluorescein), and a sensing region, which contains a hemi-methylated site of 5'-CmCGG-3', to specifically recognize the target (T1, a 32-mer DNA from the promoter region of p53 gene) and hybridize with it to form a P1/T1 duplex. After demethylation with MBD2, the duplex can be specifically cleaved using HpaII, which releases the labeled FAM from the GO surface and results in the recovery of fluorescence. However, this cleavage is blocked by the hemi-methylation of this site. Thus, the magnitude of the recovered fluorescence signal is related to the MBD2 activity, which establishes the basis of the DNA demethylase activity assay. This assay can determine as low as ~(0.05+/-0.01) ng mL(-1) (at a signal/noise of 3) of MBD2 with a linear range of 0.2-300 ng mL(-1) and recognize MBD2 from other possibly coexisting proteins and cancer cell extracts. The advantage of this assay is its ability to avoid false signals and no requirement of bisulfite conversion, PCR amplification, radioisotope labeling, or separation. PMID- 25818143 TI - Sensing for intracellular thiols by water-insoluble two-photon fluorescent probe incorporating nanogel. AB - A novel "turn-on" two-photon fluorescent probe containing a pi-conjugated triarylboron luminogen and a maleimide moiety DMDP-M based on the photo-induced electron transfer (PET) mechanism for biothiol detection was designed and synthesized. By simply loading the hydrophobic DMDP-M on a cross-linked Pluronic((r)) F127 nanogel (CL-F127), a probing system DMDP-M/CL-F127 was established, which shows quick response, high selectivity and sensitivity to cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) in aqueous phase. The DMDP-M/CL-F127 system presented the fastest response to Cys with a rate constant of 0.56 min(-1), and the detection limit to Cys was calculated to be as low as 0.18 MUM. The DMDP-M/CL-F127 system has been successfully applied to the fluorescence imaging of biothiols in NIH/3T3 fibroblasts either with single photon or two-photon excitation because of its high biocompatibility and cell membrane permeability. The present work provides a general, simple and efficient strategy for the application of hydrophobic molecules to sensing biothiols in aqueous phase, and a novel sensing system for intracellular biothiols fitted for both single-photon and two-photon fluorescence imaging. PMID- 25818144 TI - Intrinsic peroxidase-like catalytic activity of nitrogen-doped graphene quantum dots and their application in the colorimetric detection of H2O2 and glucose. AB - In this paper, the highly intrinsic peroxidase-like catalytic activity of nitrogen-doped graphene quantum dots (N-GQDs) is revealed. This activity was greatly dependent on pH, temperature and H2O2 concentration. The experimental results showed that the stable N-GQDs could be used for the detection of H2O2 and glucose over a wide range of pH and temperature, offering a simple, highly selective and sensitive approach for their colorimetric sensing. The linearity between the analyte concentration and absorption ranged from 20 to 1170 MUM for H2O2 and 25 to 375 MUM for glucose with a detection limit of 5.3 MUM for H2O2 and 16 MUM for glucose. This assay was also successfully applied to the detection of glucose concentrations in diluted serum and fruit juice samples. PMID- 25818145 TI - Education and Psychological Distress of Older Chinese: Exploring the Longitudinal Relationship and Its Subgroup Variations. AB - OBJECTIVE: The goal of this study is to examine whether and how education predicts distress for older Chinese and whether this association varies by age, gender, and rural/urban residence. METHOD: The random-effect panel model and Heckman selection model were used to analyze four waves of data with a total sample size of 54,405 from the Chinese Longitudinal Healthy Longevity Survey. RESULTS: We found the following: (a) There is a persistent and negative association between education and distress among older Chinese; (b) education predicts lower levels of distress over time and this is particularly true for males, urban residents, and the young-old; and (c) the effect of education on distress is largely explained by physical health, economic conditions, and a three-dimensional framework of leisure-time activities. DISCUSSION: Our findings strengthen the external validity of the relationship between education and health and suggest the dynamic patterns on the subgroup variations within the association in China. PMID- 25818146 TI - Examining the Risk Factors Associated With Hypertension Among the Elderly in Ghana. AB - OBJECTIVE: This study sought to examine the risk factors associated with hypertension among the elderly in Ghana. We focused on the association between chronic diseases, socioeconomic factors, and being hypertensive. METHOD: Data for the study were drawn from Wave 1 of the 2007/2008 Ghana Study on Global Ageing and Adult Health (SAGE). A binary logit model was used to estimate the effect of other noncommunicable diseases, psychosocial factors, lifestyle factors, and sociocultural and biosocial factors on the elderly being hypertensive. RESULTS: Elderly Ghanaians who had been diagnosed with arthritis, angina, diabetes, and asthma were significantly more likely to be hypertensive. Additionally, those depressed were found to be 1.22 times more likely to be hypertensive. DISCUSSION: Prevention and control of hypertension are complex and demand multistakeholder collaboration including governments, educational institutions, media, food and beverage industry, and a conscious focus on personal lifestyle factors. PMID- 25818147 TI - The Impact of Genetics on Physical Resilience and Successful Aging. AB - OBJECTIVE: To better understand the impact of genetics on resilience and successful aging, we tested a model of successful aging. METHOD: This was a descriptive study with a single interview and blood draw done with residents in a continuing care retirement community. Five genes associated with resilience were included in the model. The hypothesis was tested using structural equation modeling. RESULTS: A total of 116 participants completed the survey. Two SNPs from SLC6A4 (rs25533 and rs1042173) and age were the only variables associated with physical resilience and explained 9% of the variance. Cognitive status, age, and depression were directly associated with successful aging; variance in rs25532 or rs1042173, resilience, and pain were indirectly associated with successful aging through depression. DISCUSSION: Continued research to replicate these findings is needed so as to be able to recognize older adults at risk of low physical resilience and implement appropriate interventions. PMID- 25818148 TI - Endoscopic and Microsurgical Treatment of Sylvian Fissure Arachnoid Cysts Clinical and Radiological Outcome. AB - OBJECTIVE: A Sylvian fissure arachnoid cyst (SAC) is a well-recognized location for an intracranial arachnoid cyst in the pediatric population. For those cysts, which can rupture and be accompanied by a subdural hygroma or hematoma, several treatment modalities have been reported. We report clinical and radiological outcome of fenestration of these cysts by either endoscopy or microsurgery. METHODS: A retrospective review of the database of operative procedures revealed 24 procedures (20 endoscopic and 4 microsurgical procedures) to fenestrate a SAC at university hospitals in Berlin, Germany and Tokyo, Japan. RESULTS: With the applied technique, a reduction of SAC volume of more than 10% was achieved in 83.3% of all patients. The median volume of SACs (n = 24) was significantly reduced from 83.5 mL (range 21-509 mL) preoperatively to 45.5 mL (range 8.4-261 mL; P < 0.01) after 3.5 months and to 29.0 mL (range 0-266 mL; P < 0.01) after 15 months. In children (n = 8) with a ruptured SAC the combined extraaxial volume of a SAC and accompanying hygroma/hematoma was reduced from 166 mL (range 111-291 mL) before surgery to 127 mL (range 87-329 mL) after 2 months and to 77 mL (range 25-140 mL; P < 0.05) after 11 months. Acute clinical symptoms were generally resolved postoperatively; headaches were resolved or improved in 75%. A significant association of resolution or improvement of headaches and volume reduction was demonstrated. CONCLUSIONS: The study demonstrated efficacy in a predominantly endoscopically treated patient cohort with Sylvian fissure arachnoid cysts, as indicated by improvement of clinical symptoms and diminished radiological SAC volume after treatment. PMID- 25818149 TI - Preparation and characterizations of EGDE crosslinked chitosan electrospun membranes. AB - Composite Crosslinked nanofibrous membranes of chitosan, ethylene glycol diglycidyl ether (EGDE) and polyethylene oxide was successfully prepared with bead free morphology via electrospinning technique followed by heat mediated chemical crosslinking. Architectural stability of nanofiber mat in aqueous medium was achieved by chemical crosslinking of only 1% EGDE, and tensile strength tests revealed that increasing EGDE content has considerably enhance the elastic modulus of nanofibers. The structure, morphology and mechanical properties of nanofibers were characterized by Attenuated Total Reflection-Fourier Transform Infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM) and Instron machine, respectively. Skin fibroblasts and endothelial cells showed good attachment, proliferation and viability on crosslinked electrospun membranes. The results indicate a good biocompatibility and non-toxic nature of the resulted membrane. PMID- 25818150 TI - MUCT based assessment of mechanical deformation of designed PTMC scaffolds. AB - BACKGROUND: Advances in rapid-prototyping and 3D printing technologies have enhanced the possibilities in preparing designed architectures for tissue engineering applications. A major advantage in custom designing is the ability to create structures with desired mechanical properties. While the behaviour of a designed scaffold can be simulated using bulk material properties, it is important to verify the behaviour of a printed scaffold at the microstructure level. OBJECTIVE: In this study we present an effective method in validating the mechanical behaviour of designed scaffolds using a MUCT with an in-situ mechanical deformation device. METHODS: The scaffolds were prepared from biodegradable poly(trimethylene carbonate) (PTMC) by stereolithography and images obtained using a high-resolution MUCT with 12.25MUm isometric voxels. The data was processed (filtering, segmentation) and analysed (surface generation, registration) to extract relevant deformation features. RESULTS: The computed local deformation fields, calculated at sub-pore resolutions, displayed expected linear behaviour within the scaffold along the compressions axis. On planes perpendicular to this axis, the deformations varied by 150- 200MUm. CONCLUSIONS: MUCT based imaging with in-situ deformation provides a vital tool in validating the design parameters of printed scaffolds. Deformation fields obtained from micro-tomographic image volumes can serve to corroborate the simulated ideal design with the realized product. PMID- 25818151 TI - Poly(ethylene glycol) grafted polylactide based copolymers for the preparation of PLA-based nanocarriers and hybrid hydrogels. AB - In previous works, poly(D,L-lactide-co-ECL-poly(ethylene glycol) (poly(D,L-La-co alphaPEGECL) amphiphilic graft-copolymers were successfully synthesized according to a copper azide-alkyne cycloaddition (CuAAC) strategy. This paper aims at reporting on the behavior of this amphiphilic copolymer in water, which was not studied in the previous paper. Moreover, the ability of the copolymer to stabilize a PLA nanoparticles aqueous suspension is presented. For this purpose, dynamic light scattering (DLS) and transmission electron microscopy (TEM) are proposed to characterize the nanoparticles in solution. Otherwise, the strategy developed for the synthesis of the amphiphilic copolymers was adapted and extended to the synthesis of PLA-based degradable hydrogel, potentially applicable as drug-loaded degradable polymer implant. PMID- 25818152 TI - Influence of film thickness on the crystalline morphology of a copolyesterurethane comprising crystallizable poly(E-caprolactone) soft segments. AB - BACKGROUND: In this work, a model approach to investigate changes in crystalline morphology during heating/cooling procedures in the context of programming and induction of the shape-memory effect is presented. OBJECTIVE AND METHOD: Atomic force microscopy (AFM) was performed to investigate the variations in poly(E caprolactone) (PCL) crystalline morphology in nm thin films on a silicon substrate and a film with 20 MUm thickness, prepared from a copolyesterurethane (named PDLCL) consisting of crystallizable poly(omega-pentadecalactone) (PPDL) hard segments and crystallizable PCL segments forming switching domains. RESULTS: PCL crystals in switching domains melted/recrystallized repeatedly during heating/cooling cycles between 20 and 70 degrees C, while no evident variation in PPDL crystals forming hard domains was observed. When film thickness was 20 nm, PCL edge-on lamellae were observed, confined in the phase-separated morphology. Flat-on PCL lamellae, which broke out from the previous phase separated morphology, were obtained at a film thickness of 170 nm. In contrast, large PCL spherulites were observed in the 20 MUm thick film. CONCLUSION: PCL crystalline morphology in PDLCL as well as the competition between crystallization and phase separation can be tailored by the film thickness and the substrate. Such AFM investigations on thin films can be a helpful approach for predicting the crystal morphology in micro-/nanoscaled objects. PMID- 25818153 TI - Copper catalyst efficiency for the CuAAC synthesis of a poly(N isopropylacrylamide) conjugated hyaluronan. AB - BACKGROUND: Poly(N-isopropylacrylamide) conjugated hyaluronan (HA-pN), a brush like copolymer system which serves as a polymer vehicle for cellular and drug delivery, has been previously synthesized via the copper catalyzed azide-alkyne reaction (CuAAC) using a combination of copper sulfate and ascorbic acid (CuAsc) as the catalytic system of choice. Bromotris(triphenylphosphine) copper(I) (CuBr(PPh3)3) is an alternative catalytic compound containing a phosphorous ligand which stabilizes copper in the +1 oxidative state in aqueous solvents and can be employed at true catalyst concentrations. OBJECTIVE: CuAsc and CuBr(PPh3)3 were compared for their efficiency; 1) in the synthesis of HA-pN via CuAAC; 2) in producing thermoresponsive compositions and 3) in being extracted from the polymeric compositions. METHODS: The synthesis of the brush copolymer was carried out under strict Schlenk conditions, then characterized by ATR-FTIR, 1H NMR, ICP SFMS, and rheological measurements. RESULTS: CuBr(PPh3)3 catalyzed CuAAC leads to better grafting in water, at a true catalyst concentration, compared to CuAsc. Polymeric solutions exhibited similar traits of increasing mechanical stiffness with rising temperature. Despite purification via chelation and/or dialysis, residual copper was present in similar concentrations in the final polymers. CONCLUSIONS: In the CuAAC driven copolymer synthesis of the HA-pN, CuBr(PPh3)3 is a better catalyst than CuAsc. PMID- 25818154 TI - Preparation of gentamicin dioctyl sulfosuccinate loaded poly(trimethylene carbonate) matrices intended for the treatment of orthopaedic infections. AB - BACKGROUND: Infection is a common problem in trauma and orthopaedic surgery. Antibiotic-loaded biomaterials are used locally to clear infections as an adjunct to systemic antibiotics. Gentamicin-sulphate (GEN-SULPH) is commonly used in antibiotic-loaded biomaterials, although it displays high water solubility resulting in quick diffusion from the carrier. OBJECTIVE: Preparation of a lipophilic derivative of gentamicin to reduce solubility and obtain a slower release. Subsequently, entrapment of this lipophilic gentamicin within poly(trimethylene carbonate) (PTMC) matrices. METHODS: Hydrophobic ion-pairing was used to prepare lipophilic gentamicin (GEN-AOT). The susceptibility of Staphylococcus aureus NCTC 12973 and Staphylococcus epidermidis 103.1 for GEN-AOT was tested and the viability of fibroblasts upon exposure to GEN-AOT was assessed. GEN-AOT was then loaded into PTMC films. RESULTS: GEN-AOT was successfully prepared as confirmed by FTIR-spectroscopy. GEN-AOT was bactericidal for S. epidermidis and S. aureus at 0.5 MUM and 8.5 MUM, respectively. At 1.1 MUM GEN-AOT no reduction in fibroblast viability was observed. At 11 MUM the reduction was ~50% . PTMC discs loaded with GEN-AOT were prepared by compression molding. CONCLUSIONS: Lipophilic GEN-AOT was at least as potent as GEN-SULPH. For S. epidermidis it was even more potent than GEN-SULPH. More than 50% fibroblast cell viability was maintained at bactericidal concentration for both bacterial strains. PMID- 25818155 TI - Preparation and mechanical properties of photo-crosslinked poly(trimethylene carbonate) and nano-hydroxyapatite composites. AB - Composite materials of photo-crosslinked poly(trimethylene carbonate) and nanoscale hydroxyapatite were prepared and their mechanical characteristics for application as orbital floor implants were assessed. The composites were prepared by solvent casting poly(trimethylene carbonate) macromers with varying amounts of nano-hydroxyapatite and subsequent photo-crosslinking. The incorporation of the nano-hydroxyapatite into the composites was examined by thermogravimetric analysis, scanning electron microscopy and gel content measurements. The mechanical properties were investigated by tensile testing and trouser tearing experiments. Our results show that nano-hydroxyapatite particles can readily be incorporated into photo-crosslinked poly(trimethylene carbonate) networks. Compared to the networks without nano-hydroxyapatite, incorporation of 36.3 wt.% of the apatite resulted in an increase of the E modulus, yield strength and tensile strength from 2.2 MPa to 51 MPa, 0.5 to 1.4 N/mm2 and from 1.3 to 3.9 N/mm2, respectively. We found that composites containing 12.4 wt.% nano hydroxyapatite had the highest values of strain at break, toughness and average tear propagation strength (376% , 777 N/mm2 and 3.1 N/mm2, respectively). PMID- 25818156 TI - Rheological, hemostaseological changes during immunetherapy for prevention of HELLP-syndrome in a patient with elevated phospholipid antibodies. AB - OBJECTIVE: Patients with a history of severe obstetric complications in the presence of elevated phospholipid antibodies are at high risk for recurrent obstetric debacle. We report a successful immunologic treatment for prevention of HELLP-Syndrome in subsequent pregnancy in a patient with elevated Phospholipid antibodies, while under rheological and hemostaseological monitoring. METHODS: The patient with prior severe HELLP-Syndrome at term in the presence of reconfirmed elevated phospholipid antibodies in her first pregnancy received pooled immunoglobulins (Sandoglobulin 3 g - Novartis) intravenously for immunological treatment every three weeks in addition to low molecular weight heparin (Clexane 40 mg/d s.c.) and Aspirin (100 mg/d from 2nd trimester) during her subsequent pregnancy. Before each of 10 treatment cycles blood rheological parameters (Red Blood cell {RBC} aggregation stasis E0, low shear E1, RBC - deformability low-, moderate-, and high shear force, plasma viscosity {Pv}), as well as thrombelastometry (ROTEM) and in vitro platelet function (PFA-100) for hemostaseological evaluation was performed. At the same times non-invasive, physical thrombosis screening took place using impedance plethysmography (Filtrass) RESULTS: During pregnancy a constant increase in PV and E1 (>45 S -1) was accompanied by a delayed but continuous increase in RBC deformability beginning at the end of the 2nd trimester. Thrombelastometry revealed a continuous reduction of clot formation time (CFT; extem: 84 to 38 sec) and an increase in maximal clot firmness (MCF; extem: 64 to 78 sec) after TF-induced coagulation activation while MCF and CFT after contact activation (intem) was barely unchanged. Platelet bleeding-time after EPI/Coll stimulation was temporary prolonged by the onset of Aspirin intake (>300 sec) but normalized soon after 20th gestational week, while ADP/Coll stimulation revealed a trend towards prolonged bleeding times at the same time. There was a strong and statistically significant inverse correlation between E1 and TF induced CFT (r =-0.82; p = 0.002) and a positive correlation between E1 and TF induced MCF (r = 0.89; p < 0.001), while the correlation between E1 and contact activated CFT and MCF was weak or absent, respectively. Until GW 38th routine laboratory- (Platelet-count, Haptoglobin, liver enzymes) and clinical findings remained normal, without evidence of HELLP-Syndrome reoccurrence or development of thrombosis. CONCLUSIONS: During immunotherapy in this high risk patient HELLP-Syndrome did not reoccur. The aggregability of RBC was closely related with the formation speed and firmness of clot after TF activated coagulation but not after contact activated coagulation. At the beginning of 3rd trimester RBC aggregation remained dramatically higher as compared to the normal value range of pregnant women found in a large recent trial which may have been an early indicator of imminent HELLP Syndrome. PMID- 25818157 TI - Advanced Functional Polymers in Medicine (AFPM). PMID- 25818158 TI - Cell-based detection of microbial biomaterial contaminations. AB - A major challenge in biomaterial synthesis and functionalization is the prevention of microbial contaminations such as endotoxins (lipopolysaccharides (LPS)). In addition to LPS, which are exclusively expressed by Gram negative bacteria, also other microbial products derived from fungi or Gram positive bacteria can be found as contaminations in research laboratories. Typically, the Limulus amebocyte lysate (LAL)-test is used to determine the endotoxin levels of medical devices. However, this test fails to detect material-bound LPS and other microbial contaminations and, as demonstrated in this study, detects LPS from various bacterial species with different sensitivities.In this work, a cell-based assay using genetically engineered RAW macrophages, which detect not only soluble but also material-bound microbial contaminations is introduced.The sensitivity of this cell-line towards different LPS species and different heat-inactivated microbes was investigated. As proof of principle a soft hydrophobic poly(n-butyl acrylate) network (cPnBA), which may due to adhesive properties strongly bind microbes, was deliberately contaminated with heat-inactivated bacteria. While the LAL-test failed to detect the microbial contamination, the cell-based assay clearly detected material-bound microbial contaminations. Our data demonstrate that a cell-based detection system should routinely be used as supplement to the LAL-test to determine microbial contaminations of biomaterials. PMID- 25818159 TI - Synthesis and characterization of star-shaped oligo(ethylene glycol) with tyrosine derived moieties under variation of their molecular weight. AB - Desamino tyrosine (DAT) and desamino tyrosyl tyrosine (DATT) can be used to functionalize the end groups of water soluble polymers. The phenolic groups may enable physical interactions by pi- pi interaction and hydrogen bonds, which might lead to the formation of a hydrogel by physical crosslinking. However, using star-shaped oligo(ethylene glycols) (sOEG) with a molecular weight of 5 kDa for functionalization with DAT or DATT resulted in the formation of surfactants and not in hydrogels.As the molecular weight of the sOEG polymer chain can have an influence on forming physical cross links, DAT(T)-fuctionalization of sOEGs with higher molecular weight was investigated, the polymers were structurally characterized and for their mechanical properties were evaluated by rheological measurements.Aqueous solutions of DAT(T)-sOEGs with 10 and 20 kDa showed lower storage and loss moduli compared to unfunctionalized sOEGs indicating also the formation of surfactants. Cell-based assays showed that all sOEG solutions did not impair cell viability and were free of endotoxins, which could otherwise induce uncontrolled immune responses.Conclusively, our data suggested that the sOEG solutions have surface active properties without inducing unwanted cellular responses, which is required e.g. in pharmaceutical applications to solubilize hydophobic substances. PMID- 25818160 TI - Modeling of stress relaxation of a semi-crystalline multiblock copolymer and its deformation behavior. AB - Stress relaxation can strongly influence the shape-memory capability of polymers. Recently a modified Maxwell-Wiechert model comprising two Maxwell units and a single spring unit in parallel has been introduced to successfully describe the shape recovery characteristics of amorphous polyether urethanes. In this work we explored whether such a modified Maxwell-Wiechert model is capable to describe the stress relaxation behavior of a semi-crystalline multiblock copolymer named PCL-PIBMD, which consists of crystallizable poly(E-caprolactone) (PCL) segments and crystallizable poly(3S-isobutylmorpholine-2,5-dione) (PIBMD) segments. The stress relaxation behavior of PCL-PIBMD was explored after uniaxial deformation to different strains ranging from 50 to 900% with various strain rates of 1 or 10 or 50 mm.min -1. The modeling results indicated that under the assumption that in PCL-PIBMD both PCL and PIBMD blocks have narrow molecular weight distributions and are arranged in sequence, the two relaxation processes can be related to the amorphous PCL and PIBMD domains and the spring element can be associated to the PIBMD crystalline domains. The first Maxwell unit representing the faster relaxation process characterized by the modulus E1 and the relaxation time tau1 is related to the amorphous PCL domains (which are in the rubbery state), while the second Maxwell unit (E2 ; tau2) represents the behavior of the amorphous PIBMD domains, which are in the glassy state at 50 degrees C. Increasing strain rates resulted in an increase of E1 and a significant reduction in tau1, whereas the elastic modulus as well as the relaxation time related to the amorphous PIBMD domains remained almost constant. When a higher deformation was applied (E >= 200% ) lower values for the elastic moduli of the three model elements were obtained. In general the applied model was also capable to describe the relaxation behavior of PCL-PIBMD at a deformation temperature of 20 degrees C, where additional crystalline PCL domains are existent. The presented approach using a modified Maxwell-Wiechert model to analyze the stress relaxation behavior can be useful to understand the changes in structure-function relation of amorphous as well as semi-crystalline polymers occurring during its uniaxial deformation. PMID- 25818161 TI - Effect of dehydroepiandrosterone add-on therapy on mood, decision making and subsequent relapse of polydrug users. AB - A major problem in the treatment of addiction is predicting and preventing relapse following a rehabilitation program. Recently, in preclinical rodent studies dehydroepiandrosterone (DHEA) was found to markedly improve the resistance to drug reuse. In a double-blind, placebo-controlled study, we examined the effect of DHEA on relapse rates in adult polydrug users taking part in a detoxification program enriched with intensive psychosocial interventions and aftercare. During treatment, participants (79 percent males, mean age 28) consumed DHEA (100 mg/day) or placebo daily for at least 30 days. Of the 121 initial volunteers, 64 participated for at least 1 month. While in treatment, DHEA reduced negative affect on the Positive and Negative Affect Scale (F = 4.25, P = 0.04). Furthermore, in a 16-month follow-up, we found that reuse rates in the DHEA condition were about a third compared with placebo (12 versus 38 percent; chi(2) = 5.03, P = 0.02). DHEA treatment also resulted in an increase in DHEA sulfate (DHEA-S) 1 month following treatment, and the level of DHEA-S predicted relapse in the follow-up assessment. PMID- 25818162 TI - Spinal cord detethering procedures in children: a 5 year retrospective cohort study of the early post-operative course. AB - Tethered spinal cord can cause neurological, orthopaedic and sphincteric problems in children and detethering surgery may prevent or reverse these problems. This 5 year retrospective cohort study aimed to review our experience of detethering surgery at The Children's Hospital at Westmead, Sydney, Australia, particularly examining the early post-operative complications of this procedure. Between 2007 and 2012, 61 children underwent 63 detethering procedures. The median age at detethering surgery was 1.4 years old (interquartile range: 0.7-5.6 years). Fifty five children (90.1%) had lumbosacral procedures, 31 (50.8%) were asymptomatic from tethering, 11 (18.0%) had motor or gait disturbance, 11 (18.0%) sphincteric disturbance, eight (13.1%) lower limb orthopaedic deformities, eight (13.1%) scoliosis, six (9.8%) back or leg pain and two (3.3%) sensory disturbance. The most common tethering pathologies were spinal lipomas in 32 children (52.5%), filum abnormalities in 23 (37.7%), dorsal sinus tracts in eight (13.1%) and diastematomyelia in seven (11.5%). Twenty-six children (42.6%) had either a syrinx or central canal dilatation preoperatively. The most common complications were wound infection and cerebrospinal fluid leak. Six children (9.8%) required reoperation for wound issues and two patients (3.3%) required subsequent reoperation for cord retethering during the study period. There were no deaths and no new neurological deficits. Of the children with the above preoperative deficits, 26.7% were documented to have improvement or resolution of their symptoms post-operatively. The highest rate of improvement occurred in children with motor or gait disturbance (36.4%) or sphincteric disturbance (27.3%). PMID- 25818163 TI - The single nucleotide polymorphism Rs12817488 is associated with Parkinson's disease in the Chinese population. AB - A recent meta-analysis of datasets from five of the published Parkinson's disease (PD) genome-wide association studies implicated the single nucleotide polymorphism (SNP) rs12817488 in coiled-coil domain containing 62 (CCDC62)/huntingtin interacting protein 1 related (HIP1R) as a risk factor for PD. We conducted a case-control study to evaluate the possible association between rs12817488 and PD in Chinese people. All patients (515 PD patients and 518 age and sex-matched controls) were successfully genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. We observed that the rs12817488 polymorphism is associated with PD (p=0.003) and that the genotype and allele frequencies showed a difference between late-onset PD patients and male controls (p=0.025 and p=0.007, respectively). However, there was no difference in the early-onset PD patients and controls. We found a difference in the genotype and allele frequencies between the male PD patients and the male controls (p=0.034 and p=0.017, respectively). However, there was no difference in females. Patients with the A allele were susceptible to PD in both dominant (GA+AA versus GG; odds ratio [OR] 1.365, 95% confidence interval [CI] 1.041-1.788) and recessive (AA versus GG+GA; OR 1.606, 95% CI 1.194-2.158) models. Therefore, our findings support the conclusion that the rs12817488 in CCDC62/HIP1R polymorphism may increase the risk of PD in the Chinese Han population. PMID- 25818164 TI - Pre-existing structural abnormalities of the limbic system in transient global amnesia. AB - This study aimed to investigate the clinical and radiological findings in patients with transient global amnesia and to evaluate structural abnormalities using voxel-based morphometry. The subjects were diagnosed with transient global amnesia. For the voxel-based morphometry analyses, Statistical Parametric Mapping, running on the MATLAB platform (MathWorks, Natick, MA, USA), was employed to analyze the structural differences between patients with transient global amnesia and control subjects. Eighty patients met the inclusion criteria. Twenty-three patients (29%) were men, and 57 patients (71%) were women. There were significantly more women among the transient global amnesia patients compared with the general Korean population. MRI revealed hippocampal cavities in 41 patients (51%), and the incidence of such cavities was significantly different from that of the control subjects (24%). There were no differences in the clinical factors between the patients with and without hippocampal cavities. Diffusion-weighted imaging was performed in 54 patients, and 13 patients (24%) exhibited high signal intensity in the hippocampus. There were also no differences in the clinical factors between the patients with and without high signal intensities in the hippocampus on diffusion-weighted imaging. Twenty-six patients underwent three-dimensional volumetric T1-weighted imaging that produced results suitable for voxel-based morphometry, and these patients presented with gray matter volume reductions in the hippocampus, cingulum, and cerebellum. There were significant structural differences in the limbic structures between patients with transient global amnesia and the control subjects that might have contributed to vulnerability of the memory pathways of the patients with transient global amnesia. PMID- 25818165 TI - Anticancer effect of celastrol on human triple negative breast cancer: possible involvement of oxidative stress, mitochondrial dysfunction, apoptosis and PI3K/Akt pathways. AB - Signaling via the phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is crucial for divergent physiological processes including transcription, translation, cell-cycle progression and apoptosis. The aim of work was to elucidate the anti-cancer effect of celastrol and the signal transduction pathways involved. Cytotoxic effect of celastrol was assessed by MTT assay on human triple negative breast cancer cells (TNBCs) and compared with that of MCF 7. Apoptosis induction was determined by AO/EtBr staining, mitochondrial membrane potential by JC-1, Annexin binding assays and modulation of apoptotic proteins and its effect on PI3K/Akt/mTOR pathway by western blotting. Celastrol induced apoptosis in TNBC cells, were supported by DNA fragmentation, caspase-3 activation and PARP cleavage. Meanwhile, celastrol triggered reactive oxygen species production with collapse of mitochondrial membrane potential, down regulation of Bcl-2 and up-regulation of Bax expression. Celastrol effectively decreased PI3K 110alpha/85alpha enzyme activity, phosphorylation of Akt(ser473) and p70S6K1 and 4E-BP1. Although insulin treatment increased the phosphorylation of Akt(ser473), p70S6K1, 4E-BP1, celastrol abolished the insulin mediated phosphorylation. It clearly indicates that celastrol acts through PI3k/Akt/mTOR axis. We also found that celastrol inhibited the Akt/GSK3beta and Akt/NFkB survival pathway. PI3K/Akt/mTOR inhibitor, PF-04691502 and mTOR inhibitor rapamycin enhanced the apoptosis-inducing effect of celastrol. These data demonstrated that celastrol induces apoptosis in TNBC cells and indicated that apoptosis might be mediated through mitochondrial dysfunction and PI3K/Akt signaling pathway. PMID- 25818166 TI - ZEB2 promotes vasculogenic mimicry by TGF-beta1 induced epithelial-to-mesenchymal transition in hepatocellular carcinoma. AB - AIMS: Zinc finger E-box binding homeobox 2 (ZEB2), an epithelial-mesenchymal transition (EMT) regulator, has been involved in invasion and metastasis of human tumor. Although EMT may be involved in vasculogenic mimicry (VM) formation, no reports describing the relation between ZEB2 and VM are available. We hypothesize that ZEB2 may promote VM formation in hepatocellular carcinoma (HCC). METHODS AND RESULTS: Paraffin-embedded tumor tissue samples from 92 patients were immunostained with anti-ZEB2 antibody. We found that the ZEB2 nuclear expression was significantly associated with VM formation and metastasis. Patients with VM and ZEB2 nuclear expression had a shorter survival period than those without expression. In vitro, ZEB2 overexpression significantly enhanced cell motility, invasiveness, and VM formation of HepG2 cells. ZEB2 upregulation also increased VE-cadherin, Flt-1, and Flk-1 expression and activated MMPs. ZEB2 knockdown inhibited cell motility, invasiveness, and VM formation in Bel7402 cells. ZEB2 knockdown also decreased VE-cadherin, Flt-1, and Flk-1 expression and MMP activity. In addition, EMT in HepG2 cells was induced by TGF-beta1 treatment, and the kinetics of expression of EMT markers and regulators were assessed by Western blot analysis. The expression of ZEB2 increased significantly, and VM formation was promoted. CONCLUSION: ZEB2 can promote VM formation through the EMT pathway. Our findings may represent a novel therapeutic target in HCC. PMID- 25818167 TI - The multifaceted mitochondrion: An attractive candidate for therapeutic strategies. AB - Mitochondria are considered the powerhouse of the cell and disturbances in mitochondrial functions are involved in several disorders such as neurodegeneration and mitochondrial diseases. This review summarizes pharmacological strategies that aim at modifying the number of mitochondria, their dynamics or the mitochondrial quality-control mechanisms, in several pathological instances in which any of these mechanisms are impaired or abnormal. The interplay between different cellular pathways that involve mitochondria in order to respond to stress is highlighted. Such a high mitochondrial plasticity could be exploited for new treatments. PMID- 25818169 TI - Pre-entry student clinical placement demand: can it be met? AB - OBJECTIVES: The Clinical Education Workload Management Initiative (the Initiative) is a unique, multiprofessional, jurisdiction-wide approach and reform process enshrined within an industrial agreement. The Initiative enabled significant investment in allied health clinical education across Queensland public health services to address the workload associated with providing pre entry clinical placements. This paper describes the outcomes of a quality review activity to measure the impact of the Initiative on placement capacity and workload management for five allied health professions. Data related to several key factors impacting on placement supply and demand in addition to qualitative perspectives from workforce surveys are reported. METHODS: Data from a range of quality review actions including collated placement activity data, and workforce and student cohort statistics were appraised. Stakeholder perspectives reported in surveys were analysed for emerging themes. RESULTS: Placement offers showed an upward trend in the context of increased university program and student numbers and in contrast with a downward trend in full-time equivalent (FTE) staffnumbers. Initiative-funded positions were identified as a major factor in individual practitioners taking more students, and staff and managers valued the Initiative funded positions' support before and during placements, in the coordination of placements, and in building partnerships with universities. CONCLUSIONS: The Initiative enabled a co-ordinated response to meeting placement demand and enhanced collaborations between the health and education sectors. Sustaining pre entry student placement provision remains a challenge for the future. PMID- 25818168 TI - GLTSCR2 is an upstream negative regulator of nucleophosmin in cervical cancer. AB - Nucleophosmin (NPM)/B23, a multifunctional nucleolar phosphoprotein, plays an important role in ribosome biogenesis, cell cycle regulation, apoptosis and cancer pathogenesis. The role of NPM in cells is determined by several factors, including total expression level, oligomerization or phosphorylation status, and subcellular localization. In the nucleolus, NPM participates in rRNA maturation to enhance ribosomal biogenesis. Consistent with this finding, NPM expression is increased in rapidly proliferating cells and many types of human cancers. In response to ribosomal stress, NPM is redistributed to the nucleoplasm, where it inactivates mouse double minute 2 homologue to stabilize p53 and inhibit cell cycle progression. These observations indicate that nucleolus-nucleoplasmic mobilization of NPM is one of the key molecular mechanisms that determine the role of NPM within the cell. However, the regulatory molecule(s) that control(s) NPM stability and subcellular localization, crucial to the pluripotency of intercellular NPM, remain(s) unidentified. In this study, we showed that nucleolar protein GLTSCR2/Pict-1 induced nucleoplasmic translocation and enhanced the degradation of NPM via the proteasomal polyubiquitination pathway. In addition, we showed that GLTSCR2 expression decreased the transforming activity of cells mediated by NPM and that the expression of NPM is reciprocally related to that of GLTSCR2 in cervical cancer tissue. In this study, we demonstrated that GLTSCR2 is an upstream negative regulator of NPM. PMID- 25818170 TI - Prevalence of exposure to bovine viral diarrhoea virus (BVDV) and bovine herpesvirus-1 (BoHV-1) in Irish dairy herds. AB - Bovine viral diarrhoea virus (BVDV) and bovine herpesvirus 1 (BoHV-1) are contagious bovine viral agents. The objectives of this study were to use quarterly bulk milk and 'spot' testing of unvaccinated youngstock to establish the national prevalence of exposure to BVDV and/or BoHV-1 in Irish dairy herds. Seasonality of bulk milk ELISA results was also examined. From a geographically representative population of 305 dairy herds, 88% and 80% of herds yielded mean annual positive bulk milk readings for BVDV and BoHV-1, respectively. Of these, 61% were vaccinated against BVDV and 12% against BoHV-1. A total of 2171 serum samples from weanlings having a mean age of 291 days yielded 543 (25%) seropositive for BVDV, and 117 (5.4%) seropositive for BoHV-1. A significant seasonal trend in bulk milk antibody ELISA readings and herd status was recorded for BVDV, with more herds categorised as positive in the latter half of the year. PMID- 25818171 TI - In vivo antitrypanosomal activity of Garcinia hombroniana aqueous extract. AB - The anti-Trypanosoma evansi activity of Garcinia hombroniana (seashore mangosteen) leaves aqueous extract was tested on experimentally infected Sprague Dawley rats. Treatment of infected rats with G. hombroniana extract resulted in a significantly extended post-infection longevity (p < 0.05), compared to the untreated control group. The possible mode of antitrypanosomal effect of the plant extract was also investigated on cultured T. evansi in HMI-9 medium with the addition of 25 ug/ml G. hombroniana aqueous extract. It was observed that the addition of G. hombroniana extract resulted in the inhibition of trypanosomal kinetoplast division, with no significant inhibitory effect on nuclear division. It is concluded from the current study that the aqueous extract of G. hombroniana has a potential antitrypanosomal activity through the inhibition of kinetoplast division, as one of the possible mechanisms of its antitrypanosomal effect. This plant could serve as a possible source of new antitrypanosomal compounds. PMID- 25818172 TI - Enriched environment reduces glioma growth through immune and non-immune mechanisms in mice. AB - Mice exposed to standard (SE) or enriched environment (EE) were transplanted with murine or human glioma cells and differences in tumour development were evaluated. We report that EE exposure affects: (i) tumour size, increasing mice survival; (ii) glioma establishment, proliferation and invasion; (iii) microglia/macrophage (M/Mphi) activation; (iv) natural killer (NK) cell infiltration and activation; and (v) cerebral levels of IL-15 and BDNF. Direct infusion of IL-15 or BDNF in the brain of mice transplanted with glioma significantly reduces tumour growth. We demonstrate that brain infusion of IL-15 increases the frequency of NK cell infiltrating the tumour and that NK cell depletion reduces the efficacy of EE and IL-15 on tumour size and of EE on mice survival. BDNF infusion reduces M/Mphi infiltration and CD68 immunoreactivity in tumour mass and reduces glioma migration inhibiting the small G protein RhoA through the truncated TrkB.T1 receptor. These results suggest alternative approaches for glioma treatment. PMID- 25818173 TI - Rate of evolutionary change in cranial morphology of the marsupial genus Monodelphis is constrained by the availability of additive genetic variation. AB - We tested the hypothesis that the rate of marsupial cranial evolution is dependent on the distribution of genetic variation in multivariate space. To do so, we carried out a genetic analysis of cranial morphological variation in laboratory strains of Monodelphis domestica and used estimates of genetic covariation to analyse the morphological diversification of the Monodelphis brevicaudata species group. We found that within-species genetic variation is concentrated in only a few axes of the morphospace and that this strong genetic covariation influenced the rate of morphological diversification of the brevicaudata group, with between-species divergence occurring fastest when occurring along the genetic line of least resistance. Accounting for the geometric distribution of genetic variation also increased our ability to detect the selective regimen underlying species diversification, with several instances of selection only being detected when genetic covariances were taken into account. Therefore, this work directly links patterns of genetic covariation among traits to macroevolutionary patterns of morphological divergence. Our findings also suggest that the limited distribution of Monodelphis species in morphospace is the result of a complex interplay between the limited dimensionality of available genetic variation and strong stabilizing selection along two major axes of genetic variation. PMID- 25818174 TI - Carotene reactivity in pink grapefruit juice elucidated from model systems and multiresponse modeling. AB - This study was carried out to assess the impact of pink grapefruit juice composition and structure on the degradation kinetics of lycopene and beta carotene using model systems and multiresponse modeling. Carotenes were heated at four temperatures in their native matrix (juice) or were extracted and incorporated in water/ethanol emulsion systems formulated with or without ascorbic acid or naringin. Kinetic analysis showed that the rate constants and activation energy were lower for lycopene than for beta-carotene in the juice, while this trend was inversed in the model system. Multiresponse modeling was used to analyze the role of ascorbic acid and naringin in carotene degradation. Ascorbic acid had a very low impact, while naringin significantly increased the carotene degradation and isomerization rates. We concluded that lycopene was more sensitive to thermal degradation and phytochemical interactions than beta carotene, but this behavior was masked in the fruit juice matrix by better structural protection. PMID- 25818175 TI - Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus. AB - Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of alpha1,alpha2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days. LPS induced an age-related effect in neuronal nitric oxide synthase activity, cyclic guanosine monophosphate, and levels of thiobarbituric acid-reactive substances in rat hippocampus that was linked to changes in alpha2,3-Na,K-ATPase activity, 3-nitrotyrosine proteins, and inducible nitric oxide synthase gene expression. IF induced adaptative cellular stress-response signaling pathways reverting LPS effects in rat hippocampus of young and older rats. The results suggest that IF in both ages would reduce the risk for deficits on brain function and neurodegenerative disorders linked to inflammatory response in the CNS. PMID- 25818176 TI - Visual impairment in an optineurin mouse model of primary open-angle glaucoma. AB - Primary open-angle glaucoma (POAG) is characterized by progressive neurodegeneration of retinal ganglion cells (RGCs). Why RGCs degenerate in low pressure POAG remains poorly understood. To gain mechanistic insights, we developed a novel mouse model based on a mutation in human optineurin associated with hereditary, low-pressure POAG. This mouse improves the design and phenotype of currently available optineurin mice, which showed high global overexpression. Although both 18-month-old optineurin and nontransgenic control mice showed an age-related decrease in healthy axons and RGCs, the expression of mutant optineurin enhanced axonal degeneration and decreased RGC survival. Mouse visual function was determined using visual evoked potentials, which revealed specific visual impairment in contrast sensitivity. The E50K optineurin transgenic mouse described here exhibited clinical features of POAG and may be useful for mechanistic dissection of POAG and therapeutic development. PMID- 25818177 TI - Characterizing human vestibular sensory epithelia for experimental studies: new hair bundles on old tissue and implications for therapeutic interventions in ageing. AB - Balance disequilibrium is a significant contributor to falls in the elderly. The most common cause of balance dysfunction is loss of sensory cells from the vestibular sensory epithelia of the inner ear. However, inaccessibility of inner ear tissue in humans severely restricts possibilities for experimental manipulation to develop therapies to ameliorate this loss. We provide a structural and functional analysis of human vestibular sensory epithelia harvested at trans-labyrinthine surgery. We demonstrate the viability of the tissue and labeling with specific markers of hair cell function and of ion homeostasis in the epithelium. Samples obtained from the oldest patients revealed a significant loss of hair cells across the tissue surface, but we found immature hair bundles present in epithelia harvested from patients >60 years of age. These results suggest that the environment of the human vestibular sensory epithelium could be responsive to stimulation of developmental pathways to enhance hair cell regeneration, as has been demonstrated successfully in the vestibular organs of adult mice. PMID- 25818180 TI - Spatial and temporal variation of body size among early Homo. AB - The estimation of body size among the earliest members of the genus Homo (2.4 1.5Myr [millions of years ago]) is central to interpretations of their biology. It is widely accepted that Homo ergaster possessed increased body size compared with Homo habilis and Homo rudolfensis, and that this may have been a factor involved with the dispersal of Homo out of Africa. The study of taxonomic differences in body size, however, is problematic. Postcranial remains are rarely associated with craniodental fossils, and taxonomic attributions frequently rest upon the size of skeletal elements. Previous body size estimates have been based upon well-preserved specimens with a more reliable species assessment. Since these samples are small (n < 5) and disparate in space and time, little is known about geographical and chronological variation in body size within early Homo. We investigate temporal and spatial variation in body size among fossils of early Homo using a 'taxon-free' approach, considering evidence for size variation from isolated and fragmentary postcranial remains (n = 39). To render the size of disparate fossil elements comparable, we derived new regression equations for common parameters of body size from a globally representative sample of hunter gatherers and applied them to available postcranial measurements from the fossils. The results demonstrate chronological and spatial variation but no simple temporal or geographical trends for the evolution of body size among early Homo. Pronounced body size increases within Africa take place only after hominin populations were established at Dmanisi, suggesting that migrations into Eurasia were not contingent on larger body sizes. The primary evidence for these marked changes among early Homo is based upon material from Koobi Fora after 1.7Myr, indicating regional size variation. The significant body size differences between specimens from Koobi Fora and Olduvai support the cranial evidence for at least two co-existing morphotypes in the Early Pleistocene of eastern Africa. PMID- 25818181 TI - Social anxiety disorder in adolescence: How developmental cognitive neuroscience findings may shape understanding and interventions for psychopathology. AB - Social anxiety disorder represents a debilitating condition that has large adverse effects on the quality of social connections, educational achievement and wellbeing. Age-of-onset data suggests that early adolescence is a developmentally sensitive juncture for the onset of social anxiety. In this review, we highlight the potential of using a developmental cognitive neuroscience approach to understand (i) why there are normative increases in social worries in adolescence and (ii) how adolescence-associated changes may 'bring out' neuro-cognitive risk factors for social anxiety in a subset of individuals during this developmental period. We also speculate on how changes that occur in learning and plasticity may allow for optimal acquisition of more adaptive neurocognitive strategies through external interventions. Hence, for the minority of individuals who require external interventions to target their social fears, this enhanced flexibility could result in more powerful and longer-lasting therapeutic effects. We will review two novel interventions that target information-processing biases and their neural substrates via cognitive training and visual feedback of neural activity measured through functional magnetic resonance imaging. PMID- 25818179 TI - A psychometric systematic review of self-report instruments to identify anxiety in pregnancy. AB - AIMS: To report a systematic review of the psychometric properties of self-report instruments to identify the symptoms of anxiety in pregnancy to help clinicians and researchers select the most suitable instrument. BACKGROUND: Excessive anxiety in pregnancy is associated with adverse birth outcomes, developmental and behavioural problems in infants and postnatal depression. Despite recommendations for routine psychological assessment in pregnancy, the optimal methods to identify anxiety in pregnancy have not been confirmed. DESIGN: Psychometric systematic review. DATA SOURCES: A systematic literature search of the multiple databases (1990-September 2014). REVIEW METHODS: Identification of self-report instruments to measure anxiety in pregnancy using COSMIN guidelines to assess studies reporting a psychometric evaluation of validity and reliability. RESULTS: Thirty-two studies were included. Studies took place in the UK, Australia, Belgium, Canada, Germany, Italy, Scandinavia, Spain and the Netherlands. Seventeen different instruments were identified. Measures of validity were reported in 19 papers and reliability in 16. The overall quality of the papers was rated as fair to excellent using the COSMIN checklist. Only one paper scored excellent in more than one category. CONCLUSION: Many instruments have been adapted for use in different populations to those for which they were designed. The State Trait Anxiety Inventory, Edinburgh Postnatal Depression Scale and the Hospital Anxiety and Depression Scale have been tested more frequently than other instruments, yet require further assessment to confirm their value for use in pregnancy. PMID- 25818182 TI - Neonatal androgenization-induced early endocrine-metabolic and ovary misprogramming in the female rat. AB - AIM: Androgen excess predisposes the organism to develop metabolic-endocrine and reproductive dysfunctions, among them the development of a phenotype resembling that of human Polycystic Ovary Syndrome (PCOS). METHODS: We analyzed the impact of a single neonatal (5day-old) testosterone propionate (TP; s.c. 1.25mg/female pup) dose on: a) several metabolic-endocrine activities and b) ovarian steroidogenic and granulosa cell (GC) functions and also follicular population in juvenile and adult TP and control (CT) rats. KEY FINDINGS: Compared to CT rats, TP animals were characterized by: a) accelerated growth, hyperadiposity and hyperleptinemia, b) very early (pre-weaning age) vaginal opening, c) hyperinsulinemia in adult life, d) dysfunctional ovarian steroidogenesis, e) conserved GC functionality in both juveniles (in vitro) and adults (in vivo), and f) estrous cycles arrested at estrus. Finally, histological studies of the ovaries indicated that in TP (vs. CT) rats: i) primary and antral follicle frequencies were 3- and 15-fold higher and lower, respectively, in juveniles and ii) secondary and atretic follicle frequencies were 3- and 5-fold lower and higher, respectively, in adults. Large cystic images without corpus luteum were observed in the ovaries from adult TP rats only. SIGNIFICANCE: Our results strongly suggest that transient neonatal hyperandrogenemia induced early misprogramming of metabolic-endocrine and ovarian (steroidogenesis/folliculogenesis) functions. Conversely, TP rats preserved their ovary GC endocrine function. Our results further support the high risk of developing ovarian hyperstimulation syndrome for infertile women with transient/chronic hyperandrogenemia (PCOS) subjected to assisted reproductive technologies. PMID- 25818183 TI - Sensitizing osteosarcoma stem cells to doxorubicin-induced apoptosis through retention of doxorubicin and modulation of apoptotic-related proteins. AB - AIMS: Osteosarcoma is the most common pediatric bone malignancy with high propensity to metastasize and relapse. Emerging evidence suggest that osteosarcoma is sustained by a subset of self-renewing cancer stem like cells (CSCs) relying on mechanisms to evade apoptosis and survive in response to drugs induced DNA damage. We proposed to decipher the mechanisms underlying the resistance of CSCs to doxorubicin-induced apoptosis. MAIN METHODS: CSCs were isolated using a sphere-forming assay and tested for sensitivity to doxorubicin induced apoptosis, using MTT cell viability and BrdU proliferation assays, TUNEL staining and caspases 3/7 activity. Bcl-2 family proteins were analyzed by Western blot. Doxorubicin uptake was determined by confocal microscopy and bioluminescence imaging. KEY FINDINGS: We showed that osteosarcoma sphere stem like cells expressed the multidrug-related efflux transporters P-glycoprotein and BCRP and are highly resistant to doxorubicin-induced apoptosis. Conversely after exposure to doxorubicin, these cells displayed an up-regulation of the anti apoptotic proteins Bcl-2 and Bcl-xL with concomitant down-regulation of Bak and decreased caspase 3/7 activity. Inhibition of drug efflux transporters enhanced the cellular uptake of doxorubicin, being encompassed by an up-regulation the pro apoptotic protein Bak and suppression of Bcl-2, favoring the commitment of CSCs towards apoptosis. SIGNIFICANCE: These results seemingly suggest that the high apoptotic threshold of CSCs to doxorubicin-induced cell dead stimuli is mainly dependent on the drug concentration reaching tumor cells that are governed by efflux transporter activity. Therefore, modulation of these transporters may be effective in potentiating the proapoptotic effects of doxorubicin, and emerges as an attractive strategy to sensitize osteosarcoma CSCs to chemotherapy. PMID- 25818184 TI - The role of 17beta-estradiol in the regulation of antioxidant enzymes via the Nrf2-Keap1 pathway in the livers of CBA/H mice. AB - AIMS: We aimed to explore the impact of surgical 17beta-estradiol (E2) deprivation/administration on the expression of antioxidant enzymes with an emphasis on the alteration of the NF-E2-related factor 2/Kelch-like ECH associated protein 1 (Nrf2/Keap1) pathway under physiological conditions in the livers of CBA/H mice of both sexes. MAIN METHODS: Hepatic oxidative stress markers were determined by measuring lipid peroxidation and DNA damage using the comet assay. The expression and activities of two isoforms of superoxide dismutase (Sod-1, Sod-2) and catalase (Cat) were studied using real-time PCR, Western blot and spectrophotometrical analyses. The effect of E2 on Nrf2/Keap1 protein levels and localization was assessed using cytosolic and nuclear fractions. KEY FINDINGS: We demonstrate the E2-mediated repression of the antioxidant enzymes Sod-1, Sod-2 and Cat in the livers of ovariectomized mice treated with E2 and its association with a decreased level of Nrf2/Keap1 proteins in the nucleus. We observed beneficial effects of long-term E2 administration on lipid peroxidation but not on DNA damage in the livers of ovariectomized mice. SIGNIFICANCE: The results of this study may additionally confirm the protective ability of E2 in prolonging the onset of age-related disease in females that ultimately contributes to their longer lifespan. PMID- 25818185 TI - Dihydromyricetin protects endothelial cells from hydrogen peroxide-induced oxidative stress damage by regulating mitochondrial pathways. AB - HEADING AIMS: Dihydromyricetin (DMY) is the most abundant ingredient in vine tea. Here, we investigated the cytoprotective effects and possible mechanisms of DMY on hydrogen peroxide (H2O2)-induced oxidative stress damage in human umbilical vein endothelial cells (HUVECs). MATERIALS AND METHODS: The percentage of cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. We determined the antioxidant properties of DMY by measuring the activity of superoxide dismutase (SOD) and malondialdehyde (MDA). Flow cytometry was used to measure apoptosis in HUVECs that were double stained with Hoechst 33342 and propidium iodide (PI). The generation of intracellular reactive oxygen species (ROS) was measured in 2',7' dichlorofluorescin diacetate (DCFH-DA)-loaded HUVECs using a fluorescent microscope. Moreover, the expression of apoptosis-related proteins was determined by Western blotting. In addition, the release of nitric oxide (NO) was analyzed using a commercial kit. KEY FINDINGS: HUVECs treated with H2O2 had a notable decrease in cell viability that was attenuated when cells were pretreated with DMY (37.5-300MUM). DMY pretreatment significantly attenuated H2O2-induced apoptosis in HUVECs and inhibited intracellular ROS overproduction. Finally, pretreatment of cells with DMY prior to H2O2 exposure resulted in the inhibition of p53 activation, followed by the regulation of the expression of Bcl-2 and Bax, the release of cytochrome c, the cleavage (activation) of caspase-9 and caspase 3, and then the suppression of PARP cleavage in H2O2-induced HUVECs. SIGNIFICANCE: Our study is the first to report that DMY can protect HUVECs from oxidative stress damage, an effect that is mediated by the mitochondrial apoptotic pathways. PMID- 25818186 TI - NSAIDs induce peripheral antinociception by interaction with the adrenergic system. AB - AIMS: We evaluated the role of adrenergic systems on the peripheral antinociception induced by dipyrone and diclofenac. Mainmethods: The rat pawpressure test, inwhich sensitivity is increased by intraplantar injection of prostaglandin E2, was used to examine the peripheral effects of locally administered drugs. KEY FINDINGS: Dipyrone (10, 20 and 40 MUg) and diclofenac (5, 10 and 20 MUg) administered locally into the right paw elicited a dose-dependent antinociceptive effect, which was demonstrated to be local; the injection of drugs into the ipsilateral and contralateral hindpaws demonstrated an effect only in the ipsilateral paw because only the treated paw produced an antinociceptive effect. To test the adrenergic system, we used guanethidine (30 mg/kg) to deplete noradrenalin from noradrenergic vesicles. Guanethidine antagonized the peripheral antinociception induced by diclofenac and dipyrone. Yohimbine (2.5, 5, 10, or 20 MUg/paw) a nonselective alpha2-adrenergic receptor antagonist antagonized the peripheral antinociception induced by diclofenac (20 MUg/paw) and dipyrone (40 MUg/paw). Rauwolscine (Rau; 10, 15, 20 MUg), a selective alpha2C-adrenoreceptor, was able to block the peripheral antinociception induced by NSAIDs. The other specific alpha2A,B and D-adrenoreceptor antagonists (BRL 44480, imiloxan and RX 821002, respectively) did not modify the peripheral antinociception. However, prazosin (0.5, 1, and 2 MUg/paw), an alpha1 receptor antagonist, and propranolol (0.3, 0.6 or 1.2 MUg/paw), a beta-adrenoreceptor antagonist, antagonized the antinociception induced by diclofenac (20 MUg/paw) and dipyrone (40 MUg/paw). SIGNIFICANCE: Dipyrone and diclofenac produce peripheral antinociception, which involves the release of NA and interaction with alpha1, alpha2C and beta adrenoreceptors. PMID- 25818187 TI - The S6K protein family in health and disease. AB - The S6K proteins are mTOR pathway effectors and accumulative evidence suggest that mTOR/S6K signaling contributes to several pathological conditions, such as diabetes, cancer and obesity. The activation of the mTOR/S6K axis stimulates protein synthesis and cell growth. S6K1 has two well-known isoforms, p70-S6K1 and p85-S6K1, generated by alternative translation initiation sites. A third isoform, named p31-S6K1, has been characterized as a truncated type of the protein due to alternative splicing, and reports have shown its important role in cancer. Studies involving S6K2 are scarce. This article aims to review what is new in the literature about these kinases and establish differences regarding their interacting proteins, activation and function, connecting their roles in the homeostasis of the cell and in pathological conditions. PMID- 25818189 TI - Monoacylglycerol lipase inhibitor protects primary cultured neurons against homocysteine-induced impairments in rat caudate nucleus through COX-2 signaling. AB - AIMS: URB602 is a selective inhibitor of monoacylglycerol lipase (MAGL), a serine hydrolase involved in the biological deactivation of the endocannabinoid 2 arachidonoyl glycerol (2-AG). It has been described that URB602 significantly enhances depolarization-induced increases in 2-AG. A high level of homocysteine (Hcy) is a modifiable risk factor for developing Alzheimer's disease (AD). The aim of this study was to investigate the protective effects of URB602 on Hcy induced impairments underlying its cellular and molecular mechanism in primary cultured caudate nucleus (CN) neurons. MAIN METHODS: The expressions of cyclooxygenase-2 (COX-2), ERK1/2, NF-kappaB and IkappaB-alpha as well as cleaved caspase-3 and p-Bcl-2 in Hcy-, URB602 or SR1 (a selective inhibitor of CB1 receptor)-treated primary cultured neurons in CN were measured by immunoblotting technique and neurotoxicity assays were performed by using Hoechst staining. KEY FINDINGS: The MAGL inhibitor URB602 exerted a neuroprotective effect on Hcy induced impairment through suppression of cyclooxygenase-2 (COX-2) elevation and ERK1/2 and NF-kappaB phosphorylation as well as suppressions of IkappaB-alpha degradation in a CB1 receptor-dependent way. Moreover, anti-neuronal impairments of URB602 were mediated by modulating down-regulation of cleaved caspase-3 expression and up-regulation of p-Bcl-2 expression in a CB1 receptor-dependent manner in primary cultured CN neurons. SIGNIFICANCE: These data suggest that the MAGL inhibitor is a promising therapeutic target for some neurodegenerative disorders, such as AD, via the COX-2 signaling pathway. PMID- 25818188 TI - Heterotrimeric G protein-mediated signaling and its non-canonical regulation in the heart. AB - Heterotrimeric guanine nucleotide-binding proteins (G proteins) regulate a multitude of signaling pathways in mammalian cells by transducing signals from G protein-coupled receptors (GPCRs) to effectors, which in turn regulate cellular function. In the myocardium, G protein signaling occurs in all cardiac cell types and is centrally involved in the regulation of heart rate, pump function, and vascular tone and in the response to hemodynamic stress and injury. Perturbations in G protein-mediated signaling are well known to contribute to cardiac hypertrophy, failure, and arrhythmias. Most of the currently used drugs for cardiac and other diseases target GPCR signaling. In the canonical G protein signaling paradigm, G proteins that are located at the cytoplasmic surface of the plasma membrane become activated after an agonist-induced conformational change of GPCRs, which then allows GTP-bound Galpha and free Gbetagamma subunits to activate or inhibit effector proteins. Research over the past two decades has markedly broadened the original paradigm with a GPCR-G protein-effector at the cell surface at its core by revealing novel binding partners and additional subcellular localizations for heterotrimeric G proteins that facilitate many previously unrecognized functional effects. In this review, we focus on non canonical and epigenetic-related mechanisms that regulate heterotrimeric G protein expression, activation, and localization and discuss functional consequences using cardiac examples where possible. Mechanisms reviewed involve microRNAs, histone deacetylases, chaperones, alternative modes of G protein activation, and posttranslational modifications. Some of these newly characterized mechanisms may be further developed into novel strategies for the treatment of cardiac disease and beyond. PMID- 25818190 TI - Chondroprotective effects of a new glucosamine combination in rats: Gene expression, biochemical and histopathological evaluation. AB - AIMS: This study investigates the effect of a new combination of glucosamine hydrochloride, chondroitin sulfate, methylsulfonylmethane, Harpagophytum procumbens root extract (standardized to 3% harpagoside) and bromelain extract (GCMHB) on formalin-induced damage to cartilage tissue in the rat knee joint and evaluates this combination in comparison with another combination of glucosamine hydrochloride, chondroitin sulfate and methylsulfonylmethane (GKM). MATERIALS AND METHODS: Animals in the control group were injected with formalin into the knee joint (FCG). Animals in the GCMHB-500 group were given 500mg/kg GCMHB+formalin, and those in the GKM-500 group were given 500mg/kg GKM+formalin. Finally, a healthy group (HG) was also used. GCMHB and GKM were administered to rats orally once a day for 30days. At the end of this period, the rats were sacrificed and the levels of MDA, NO, 8-OH/Gua, and tGSH in the knee joint tissue were measured. Analysis of IL-1beta and TNF-alpha gene expression was done and the tissue was evaluated histopathologically. KEY FINDINGS: MDA, NO and 8-OH/Gua levels and IL 1beta and TNF-alpha gene expression were significantly lower in the GCMHB-500 group compared to the FCG group, whereas tGSH was significantly higher in the GCMHB-500 group than in the FCG group. No significant difference was found for the IL-1beta, TNF-alpha and oxidant/antioxidant parameters between the GKM and FCG groups. The histopathological analysis showed that GCMHB could prevent damage to the cartilage joint, whereas GKM could not. SIGNIFICANCE: GCMHB may be used clinically by comparing with GKM in the treatment of osteoarthritis. PMID- 25818191 TI - Neuroprotection against 6-OHDA-induced oxidative stress and apoptosis in SH-SY5Y cells by 5,7-Dihydroxychromone: Activation of the Nrf2/ARE pathway. AB - AIMS: The aim of this study was to prove the neuroprotective effect of 5,7 Dihydroxychromone (DHC) through the Nrf2/ARE signaling pathway. To elucidate the mechanism, we investigated whether 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells could be attenuated by DHC via activating the Nrf2/ARE signal and whether DHC could down-regulate 6-OHDA-induced excessive ROS generation MAIN METHODS: To evaluate the neuroprotective effect of DHC against 6 OHDA-induced apoptosis, FACS analysis was performed using PI staining. The inhibitory effect of DHC against 6-OHDA-induced ROS generation was evaluated by DCFH-DA staining assay. Additionally, translocation of Nrf2 to the nucleus and increased Nrf2/ARE binding activity, which subsequently resulted in the up regulation of the Nrf2-dependent antioxidant gene expressions including HO-1, NQO1, and GCLc, were evaluated by Western blotting and EMSA. KEY FINDINGS: Pre treatment of DHC, one of the constituents of Cudrania tricuspidata, significantly protects 6-OHDA-induced neuronal cell death and ROS generation. Also, DHC inhibited the expression of activated caspase-3 and caspase-9 and cleaved PARP in 6-OHDA-induced SH-SY5Y cells. DHC induced the translocation of Nrf2 to the nucleus and increased Nrf2/ARE binding activity which results in the up regulation of the expression of Nrf2-dependent antioxidant genes, including HO-1, NQO1, and GCLc. The addition of Nrf2 siRNA abolished the neuroprotective effect of DHC against 6-OHDA-induced neurotoxicity and the expression of Nrf2-mediated antioxidant genes. SIGNIFICANCE: Activation of Nrf2/ARE signal by DHC exerted neuroprotective effects against 6-OHDA-induced oxidative stress and apoptosis. This finding will give an insight that activating Nrf2/ARE signal could be a new potential therapeutic strategy for neurodegenerative disease. PMID- 25818192 TI - The prevention and treatment of hypoadiponectinemia-associated human diseases by up-regulation of plasma adiponectin. AB - Hypoadiponectinemia is characterized by low plasma adiponectin levels that can be caused by genetic factors, such as single nucleotide polymorphisms (SNPs) and mutations in the adiponectin gene or by visceral fat deposition/obesity. Reports have suggested that hypoadiponectinemia is associated with dyslipidemia, hypertension, hyperuricemia, metabolic syndrome, atherosclerosis, type 2 diabetes mellitus and various cardiovascular diseases. Previous studies have highlighted several potential strategies to up-regulate adiponectin secretion and function, including visceral fat reduction through diet therapy and exercise, administration of exogenous adiponectin, treatment with peroxisome proliferator activating receptor gamma (PPARgamma) agonists (e.g., thiazolidinediones (TZDs)) and ligands (e.g., bezafibrate and fenofibrate) or the blocking of the renin angiotensin system. Likewise, the up-regulation of the expression and stimulation of adiponectin receptors by using adiponectin receptor agonists would be an effective method to treat obesity-related conditions. Notably, adiponectin is an abundantly expressed bioactive protein that also exhibits a wide spectrum of biological properties, such as insulin-sensitizing, anti-diabetic, anti inflammatory and anti-atherosclerotic activities. Although targeting adiponectin and its receptors has been useful for treating diabetes and other metabolic related diseases in experimental studies, current drug development based on adiponectin/adiponectin receptors for clinical applications is scarce, and there is a lack of available clinical trial data. This comprehensive review discusses the strategies that are presently being pursued to harness the potential of adiponectin up-regulation. In addition, we examined the current status of drug development and its potential for clinical applications. PMID- 25818193 TI - Malignant rectal melanoma. Case report. AB - AIM: The aim of this study was to report a case concerning diagnostic and management of Anorectal melanoma. MATERIAL: A 71 years old white man presented in our Institute with anal pain, tenesmus, blooding rectal during the last five months. The ano-rectal examination showed a brownish painful mass in the anal canal. The colonscopy and endoscopy showed a big stenotic mass from anal canal to medium rectum with a diameter of approximately 90 mm. RESULTS: Biopsy of the rectal mass was performed and the histopatological examination showed malignant ephitelioid cells, pigmented melanoma. The patient was treated by abdominoperineal resection with dissection of lymph nodes. Result of histopatological examination was ulcerated Malignant melanoma of the anal canal, growing polypoid with spindle cells and epithelioid infiltrating the mucosa, submucosa and the internal sphincter muscle. Vascular invasion. Subtotal lymph node metastasis in 3 of 17. DISCUSSION: Anorectal melanoma is an uncommon and aggressive disease. The anorectum is the third most common location of malignant melanoma after the skin and retina. Lesions are difficult to diagnose because many are amelanotic and patients present with nonspecific complaints such as anal discomfort or rectal bleeding. After diagnosis, the main treatment available is surgical resection. Sentinel lymph node mapping has an unclear role in its management. Adjuvant therapy has long been recommended; however, there are no strong data to support its use. CONCLUSIONS: There is no convincing evidence to indicate that abdominoperineal resection did not improve the survival rate of patients with malignant rectal melanoma as compared to the wide local excision, while the wide local excision had advantages in lower surgical risk and allowing patients to avoid permanent colostomy. PMID- 25818194 TI - Case report of fatal Mycobacterium tilburgii infection. AB - There are few reports concerning Mycobacterium tilburgii infection in humans because this bacterium is non-cultivatable. Herein, using new molecular techniques, we report the case of an immunocompromised patient with fatal disseminated lymphadenitis that was caused by M. tilburgii.26 years old Caucasian HIV negative female patient presented with abdominal pain. Her clinical assessment revealed disseminated lymphadenitis, that was acid fast bacilli positive. Further molecular evaluation showed the causative agent as M. tilburgii. Despite anti mycobacterial therapy and careful management of intervening complications patient died because of an intraabdominal sepsis. This is the first fatal M. tilburgii infection in the literature. This case points the importance of careful management of patient's immune status and intervening infections besides implementation of effective drug treatment. PMID- 25818195 TI - Diagnostic sensitivity of a rapid antigen test for the detection of Mycoplasma pneumoniae: Comparison with real-time PCR. AB - A rapid antigen kit for the detection of the Mycoplasma pneumoniae ribosomal protein L7/L12 using an immunochromatographic assay, Ribotest Mycoplasma, became available in Japan in 2013. To determine the sensitivity of Ribotest compared with real-time polymerase chain reaction (PCR), we prospectively performed these two tests simultaneously in adolescent and adult patients with community-acquired pneumonia (CAP). In addition, we retrospectively analyzed the theoretical sensitivity of Ribotest using M. pneumoniae PCR-positive specimens from previous studies. In prospective study, 118 CAP cases were enrolled, and 16 cases were diagnosed as M. pneumoniae pneumonia; eight cases were PCR-positive, one case was culture positive, and all cases demonstrated a four-fold increase in antibody titer. Ribotest was positive in 15 cases; five cases were PCR positive and 10 cases were PCR negative. For the PCR was control test, the sensitivity, specificity, and overall agreement with Ribotest were 62.5%, 90.9%, and 88.9%, respectively. In the retrospective study, we used 1110 M. pneumoniae PCR-positive specimens, which are collected from pediatric patients with respiratory tract infection who visited 65 institutions throughout Japan. Using a cut-off level for the Ribotest of 8.3 * 10(4) copy/mL in transport medium, 667 (60.0%) specimens were theoretically positive. In conclusion, our prospective and retrospective results demonstrated that the diagnostic sensitivity of Ribotest compared with PCR was not high, at approximately 60%. Thus, treatment decisions about M. pneumoniae pneumonia should be based on clinical findings such as Japanese Respiratory Society scoring system and not on Ribotest results alone. PMID- 25818196 TI - Comparison of neutrophil infiltration between type 1 and type 2 autoimmune pancreatitis. AB - BACKGROUND: Characteristics of type 2 autoimmune pancreatitis (AIP) is granulocyte epithelial lesions, called idiopathic duct-centric pancreatitis (IDCP). To clarify pathogenesis of IDCP, we investigated mechanism of neutrophil infiltration in type 1 AIP, called lymphoplasmacytic sclerosing pancreatitis (LPSP) and IDCP. METHOD: This study was performed on resected pancreata from patients with alcoholic chronic pancreatitis (ACP, n = 10), LPSP (n = 10) and IDCP (n = 12). The number of neutrophils around the pancreatic ducts was counted. The expression of neutrophils chemoattractants granulocyte chemotactic protein-2 (GCP-2) and interleukin-8 (IL-8) in the pancreatic duct epithelia was examined using immunohistochemistry. The cell staining intensity is scored as negative (0), weak (1), moderate (2) or strong (3). RESULTS: The median number of neutrophils around the interlobular pancreatic ducts was significantly higher in IDCP (15.16; interquartile range [IQR]: 9.74-18.41) than in ACP (2.66; IQR: 1.33 4.33) (P < 0.05) and LPSP (3.16; IQR: 2.74-4.57) (P < 0.01). There was no significant difference in the median number of neutrophils around the intralobular pancreatic ducts among ACP (1.16; IQR: 0.33-3.41), LPSP (3.16; IQR: 0.74-5.5) and IDCP (3.00; IQR: 1.08-7.91). The median score of GCP-2 in the interlobular pancreatic duct epithelia was significantly higher in IDCP (1.5; IQR: 0.25-2) than in ACP (0; IQR: 0-0.75) (P < 0.05) and LPSP (0; IQR: 0-0.75) (P < 0.05). There was no significant difference in the median score of IL-8 in the interlobular pancreatic duct epithelia among ACP (0; IQR: 0-0.75), LPSP (1; IQR: 0-1.75) and IDCP (0.5; IQR: 0-1). CONCLUSIONS: Significantly increased neutrophil infiltration around the interlobular pancreatic duct in IDCP may depend on GCP-2. PMID- 25818197 TI - The relationship between total cellular content of CD203c and cell surface expression on human basophils. PMID- 25818198 TI - Mapping of Post-translational Modifications of Transition Proteins, TP1 and TP2, and Identification of Protein Arginine Methyltransferase 4 and Lysine Methyltransferase 7 as Methyltransferase for TP2. AB - In a unique global chromatin remodeling process during mammalian spermiogenesis, 90% of the nucleosomal histones are replaced by testis-specific transition proteins, TP1, TP2, and TP4. These proteins are further substituted by sperm specific protamines, P1 and P2, to form a highly condensed sperm chromatin. In spermatozoa, a small proportion of chromatin, which ranges from 1 to 10% in mammals, retains the nucleosomal architecture and is implicated to play a role in transgenerational inheritance. However, there is still no mechanistic understanding of the interaction of chromatin machinery with histones and transition proteins, which facilitate this selective histone replacement from chromatin. Here, we report the identification of 16 and 19 novel post translational modifications on rat endogenous transition proteins, TP1 and TP2, respectively, by mass spectrometry. By in vitro assays and mutational analysis, we demonstrate that protein arginine methyltransferase PRMT4 (CARM1) methylates TP2 at Arg(71), Arg(75), and Arg(92) residues, and lysine methyltransferase KMT7 (Set9) methylates TP2 at Lys(88) and Lys(91) residues. Further studies with modification-specific antibodies that recognize TP2K88me1 and TP2R92me1 modifications showed that they appear in elongating to condensing spermatids and predominantly associated with the chromatin-bound TP2. This work establishes the repertoire of post-translational modifications that occur on TP1 and TP2, which may play a significant role in various chromatin-templated events during spermiogenesis and in the establishment of the sperm epigenome. PMID- 25818199 TI - Methylxanthines Increase Expression of the Splicing Factor SRSF2 by Regulating Multiple Post-transcriptional Mechanisms. AB - We have previously reported that the methylxanthine caffeine increases expression of the splicing factor SRSF2, the levels of which are normally controlled by a negative autoregulatory loop. In the present study we have investigated the mechanisms by which methylxanthines induce this aberrant overexpression. RT-PCR analyses suggested little impact of caffeine on SRSF2 total mRNA levels. Instead, caffeine induced changes in the levels of SRSF2 3' UTR splice variants. Although some of these variants were substrates for nonsense-medicated decay (NMD), and could potentially have been stabilized by caffeine-mediated inhibition of NMD, down-regulation of NMD by a genetic approach was not sufficient to reproduce the phenotype. Furthermore, cell-based assays demonstrated that some of the caffeine induced variants were intrinsically more efficiently translated than others; the addition of caffeine increased the translational efficiency of most SRSF2 transcripts. MicroRNA array analyses revealed a significant caffeine-mediated decrease in the expression of two SRSF2-targeting miRs, both of which were shown to repress translation of specific SRSF2 splice variants. These data support a complex model whereby caffeine down-regulates SRSF2-targeting microRNAs, leading to an increase in SRSF2 translation, which in turn induces SRSF2 splicing. SRSF2 splice variants are then stabilized by caffeine-mediated NMD inhibition, breaking the normal negative feedback loop and allowing the aberrant increase in SRSF2 protein levels. These findings highlight the complexity of SRSF2 gene regulation, and suggest ways in which SRSF2 expression may be dysregulated in disease. PMID- 25818200 TI - Effects of post-weaning diet on metabolic parameters and DNA methylation status of the cryptic promoter in the A(vy) allele of viable yellow mice. AB - Mice carrying the A(vy) allele are epigenetic mosaics. If the majority of cells have an active (demethylated) intracisternal A particle (IAP), mice have a yellow coat color and develop adult-onset obesity and diabetes, while mice whose mosaicism predominantly reflects an inactive (methylated) IAP are pseudoagouti (brown) and less prone to metabolic disease. Brown and yellow coat color A(vy)/a post-weaning mice were placed on one of three diets [AIN, and two lower-calorie diets National Institutes of Health (NIH) and methyl-supplemented, NIHMe] to determine whether coat color, weight gain, blood glucose and methylation of hepatic IAP became altered. None of the diets altered A(vy)/a mice coat color. NIHMe did not protect against increasing obesity or the usual onset of hyperglycemia in males. Nor did it promote increased methylation of A(vy) IAP in liver tissue. By contrast, AIN, despite its higher content of fat and carbohydrate and ability to promote greater weight gains than the NIH and NIHMe diets, protected males better against hyperglycemia than either the NIH or NIHMe diets. This diet led to a significantly reduced (~50%; P = .003) average methylation state of all CpG sites within the hepatic IAP for the pseudoagouti mice. On AIN, but not on the other diets, extent of hepatic IAP methylation was negatively correlated (R = 0.97, P <= .001) with body weight of pseudoagouti mice. The findings indicate that post-weaning diet might influence interpretation of studies with A(vy)/a mice because IAP methylation patterns may be malleable in certain organs and influenced by post-weaning diet. PMID- 25818201 TI - Draft genome of Bacillus sp. A053 isolated from the Arctic seawater with antimicrobial activity. AB - Bacillus sp. A053, isolated from the Arctic seawater, shows strong antifungal activity against plant pathogenic fungi. Here, we report the draft sequence of the approximately 4.1-Mbp genome of this strain. To the best of our knowledge, this is the first genome sequence of Bacillus strain isolated from the Arctic seawater with antifungal activity. The genome sequence may provide fundamental molecular information on elucidating the metabolic pathway of antimicrobial compound in this strain. PMID- 25818202 TI - Sepsis in head and neck cancer patients treated with chemotherapy and radiation: Literature review and consensus. AB - The reporting of infection/sepsis in chemo/radiation-treated head and neck cancer patients is sparse and the problem is underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met with the aim of reaching a consensus on a clinical definition and management of infections and sepsis. The Delphi appropriateness method was used for this consensus. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. The paper contains seven clusters of statements about the clinical definition and management of infections and sepsis in head and neck cancer patients, which had a consensus. Furthermore, it offers a review of recent literature in these topics. PMID- 25818203 TI - Establishment of a new anal sphincter injury model in rats based on cardiotoxin. AB - BACKGROUND/PURPOSE: Mainstream models for anal sphincter injury use large animals. We developed a simple and stable anal sphincter injury model in a small animal (i.e., rats) to obtain manometry measurements by using a miniaturized probe and applying cardiotoxin. METHODS: The histological structure of the anal canal was evaluated by using manometry in normal rats (n=40). We damaged the internal and external anal sphincters by locally administering snake poison (cardiotoxin; 20 uM, 100MUL 8 points). We evaluated the anal canal function through manometry measurements (n=5) and examined the histology using hematoxylin eosin staining (at each time point, n=3; total n=15). RESULTS: The manometry parameters and structure of the anal canal of normal rats were similar to those of humans, because rats have resting pressure, rectoanal reflex in the manometry, and an external and internal anal sphincter. After inducing injury, the following findings were observed: rhythmic wave loss and a remarkable reduction in the anal sphincter resting pressure; and local bleeding and advanced infiltration of the inflammatory cells (day 1) and the loss of muscle fibers (day 3). CONCLUSION: This new rat model will contribute to increasing the knowledge on the anal canal. PMID- 25818204 TI - Neurodevelopmental outcome at one year of age in congenital diaphragmatic hernia infants not treated with extracorporeal membrane oxygenation. AB - BACKGROUND: We evaluated the neurodevelopmental (ND) outcome at one year of age for congenital diaphragmatic hernia (CDH) children who have not undergone extracorporeal membrane oxygenation (ECMO) treatment during the neonatal period. MATERIAL AND METHODS: Between 01/2005 and 06/2012, 63 consecutive CDH patients underwent ND assessment using the BSID-III at a median age of 12 months. ND delay was defined by a score of <= 85 in any of the composite scales. Severe impairment was defined as a score of <= 69 in at least one domain. RESULTS: Mean +/- SD cognitive, language, and motor functions were 94 +/- 14, 86 +/- 14, 90 +/- 15, respectively (normal 100 +/- 15, P<0.01 for each). Forty-three-percent scored within the average range for all scales. Forty-four-percent had mild, and 13% had severe delays in at least one domain. Prolonged NICU stay, intubation and O2 requirement, fundoplication, abnormal BAERs, and tracheostomy were associated with lower scores in all domains. Right-sided CDH, male gender, lower 5 min APGAR, pulmonary hypertension, and delayed start of enteral feeding were predictive of lower cognitive and/or language scores. CONCLUSION: At one year of age, a high percentage of CDH children whose illness did not necessitate ECMO have below normal ND scores. Modifiable and non-modifiable factors are significant determinants of adverse outcomes. PMID- 25818205 TI - Pediatric surgical critical care fellowship experience and career paths: Results of a survey of program graduates. AB - PURPOSE: The purpose of this study was to examine motivations, fellowship experiences, and careers of graduates of the 10 accredited pediatric surgical critical care fellowships (PSCCF). METHODS: Queries to PSCCF directors yielded a list of 86 graduates (2003-2013), each of whom received a 23-question survey. RESULTS: Of the 86 graduates contacted, 82 (95.3%) replied. Among graduates who applied, 62 of 74 (83.8%) matched into pediatric surgery (PS) fellowships. On average, the respondents were 33 years old and PGY6 when beginning PSCCF. Half had failed initial attempts to match into PS fellowship. Of the matched respondents, 39 are pediatric surgeons and 21 PS fellows or residents awaiting fellowship. Two additional respondents did not complete fellowship. Among the pediatric surgeons, 13 identified their positions as heavily involved with critical care. The critical care boards pass rate was 94.4% (67/71). Rotations during fellowships were varied, with 74 fellows (90.2%) rotating in the pediatric intensive care unit (ICU), 71 (86.6%) in the neonatal ICU, 54 (65.9%) in the adult surgical ICU, and 36 (43.9%) on the pediatric surgical ward service. CONCLUSIONS: Completion of a PSCCF is highly predictive of a successful PS match. Only a third of PSCCF graduates continue critical care work in a formal fashion after PS fellowship. PMID- 25818206 TI - Hypercoagulability in dogs with blastomycosis. AB - BACKGROUND: Blastomycosis is a potentially fatal fungal disease that most commonly affects humans and dogs. The organism causes systemic inflammation and has a predilection for the lungs. The inflammation might lead to a hypercoagulable state with microemboli in the pulmonary circulation which could contribute to inadequate oxygen exchange in infected dogs. HYPOTHESIS/OBJECTIVES: Dogs with blastomycosis will be hypercoagulable compared with healthy case matched controls. ANIMALS: Client-owned dogs with a diagnosis of blastomycosis (n = 23) and healthy case-matched controls (n = 23). METHODS: Prospective case controlled study of client-owned dogs presented to a veterinary teaching hospital with clinical signs compatible with blastomycosis. Complete blood counts, fibrinogen, PT, aPTT, thromboelastometry (TE), thrombin antithrombin complexes (TAT), and thrombin generation were evaluated. RESULTS: Cases had a leukocytosis compared with controls [mean (SD) 16.6 (7.6) * 10(3)/MUL versus 8.2 (1.8) * 10(3)/MUL, P < .001], hyperfibrinogenemia [median 784 mg/dL, range 329-1,443 versus median 178 mg/dL, range 82-257, P < .001], and increased TAT concentrations [mean (SD) 9.0 (5.7) MUg/L versus 2.0 (2.8) MUg/L, P < .001]. As compared to controls, cases were also hypercoagulable as evaluated by thromboelastometry and had increased in vitro thrombin generation on calibrated automated thrombography. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypercoagulability occurs in dogs with systemic blastomycosis. Additional studies are needed to explore a possible contribution of thrombogenicity to the clinical manifestations of systemic blastomycosis. PMID- 25818207 TI - Plasma vitamin D metabolites and C-reactive protein in stage-stop racing endurance sled dogs. AB - BACKGROUND: Dogs are a unique model for examining the effects of exercise on vitamin D status because of their lack of vitamin D synthesis by UV exposure. In addition, the inflammatory response may be associated with hypovitaminosis D. OBJECTIVES: To investigate the effects of several days of endurance exercise on plasma vitamin D (25-(OH)D3, 24,25-(OH)D3 and 1,25(OH)D3) and serum C-reactive protein (CRP) concentrations in stage-stop racing sled dogs. ANIMALS: 12 racing sled dogs and 8 control dogs. METHODS: Blood was collected before the race and immediately after racing on days 2 and 8. Plasma vitamin D metabolites and serum CRP concentrations were measured. RESULTS: Racing dogs showed a significant increase in 25(OH)D3 on day 2 (P = .027) and day 8 of the race (P < .001), whereas no increases were observed in control dogs. The plasma concentration of 24,25(OH)D3 showed a significant increase by day 8 (P < .001). There were no significant changes in 1,25(OH) D3 concentrations across all time points and groups. Racing dogs had significantly increased CRP concentrations by day 2 (39.3 +/- 30.1 MUg/mL; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Increases in vitamin D metabolites as well as increases in CRP concentrations were observed in racing sled dogs. This finding was contrary to the hypothesis that decreases in vitamin D status in athletes may be related to the acute phase inflammatory response during exercise. In addition, the increased 24,25(OH)D3 concentrations compared to what is observed in other species suggests metabolic variations in dogs that lead to enhanced disposal of vitamin D. PMID- 25818208 TI - Tracheobronchial brush cytology and bronchoalveolar lavage in dogs and cats with chronic cough: 45 cases (2012-2014). AB - BACKGROUND: Animals with chronic cough can have normal bronchoalveolar lavage fluid cytology when small airway disease is absent. Cytology of a tracheobronchial brushing can detect inflammation in larger airways; however, evaluation of this technique has been limited in veterinary medicine. OBJECTIVE: To compare airway brush cytology to bronchoalveolar lavage fluid analysis in dogs and cats with chronic cough. ANIMALS: Forty dogs and five cats undergoing bronchoscopic investigation of chronic cough. METHODS: Prospective study. Bronchoscopy and bronchoalveolar lavage were performed followed by tracheobronchial brushing of central airways. Results of cytologic assessment of BAL fluid and brush cytology were compared for the presence or absence of inflammation and concordance of inflammatory cell type. RESULTS: Brush cytology detected central airway inflammation in 34 of 40 (85%) dogs with inflammatory BAL fluid. However, the type of inflammation reported differed in 23 of 34 dogs. In five cats with inflammation in BAL fluid, brush cytology detected inflammation in four; the type of inflammation was discordant in all cats. CONCLUSIONS AND CLINICAL RELEVANCE: Brush cytology has good agreement with BAL regarding the presence of inflammation, although the type of inflammation detected with the different sampling techniques commonly varies. Brush cytology can provide supplementary information to BAL, and additional studies will provide further information on the role of tracheobronchial brush cytology in the diagnosis and management of respiratory conditions. PMID- 25818209 TI - Co-infections with respiratory viruses in dogs with bacterial pneumonia. AB - BACKGROUND: Bacterial pneumonia (BP) is an inflammation of the lower airways and lung parenchyma secondary to bacterial infection. The pathogenesis of BP in dogs is complex and the role of canine respiratory viruses has not been fully evaluated. OBJECTIVES: The aim of this study was to investigate the occurrence of viral co-infections in dogs with BP and to assess demographic or clinical variables as well as disease severity associated with viral co-infections. ANIMALS: Twenty household dogs with BP caused by opportunistic bacteria and 13 dogs with chronic (>30 days) tracheobronchitis caused by Bordetella bronchiseptica (BBTB). METHODS: Prospective cross-sectional observational study. Diagnosis was confirmed by clinical and laboratory findings, diagnostic imaging, and cytologic and microbiologic analysis of bronchoalveolar lavage or transtracheal wash fluid. Canine parainfluenza virus (CPIV), canine adenovirus, canine herpes virus, canine influenzavirus, canine distemper virus, canine respiratory coronavirus (CRCoV) and canine pneumovirus, as well as B. bronchiseptica and Mycoplasma spp. were analyzed in respiratory samples using PCR assays. RESULTS: CPIV was detected in 7/20 and CRCoV in 1/20 dogs with BP. Respiratory viruses were not detected in dogs with BBTB. There were no significant differences in clinical variables between BP dogs with and without a viral co-infection. CONCLUSION AND CLINICAL IMPORTANCE: Respiratory viruses were found frequently in dogs with BP and may therefore play an important role in the etiology and pathogenesis of BP. Clinical variables and disease severity did not differ between BP dogs with and without viral co-infection. PMID- 25818210 TI - Prevalence and prognostic importance of pulmonary hypertension in dogs with myxomatous mitral valve disease. AB - BACKGROUND: Pulmonary hypertension (PH) is common in dogs with myxomatous mitral valve disease (MMVD) but its effect on clinical outcome has not been investigated. HYPOTHESIS/OBJECTIVES: The presence of PH worsens the outcome in dogs with MMVD. To compare survival times of dogs with MMVD and PH to those without PH. ANIMALS: Two hundred and twelve client-owned dogs. METHODS: Case review study. Medical records of dogs diagnosed with ACVIM stage B2 and C MMVD between January 2010 and December 2011 were retrospectively reviewed. Long-term outcome was determined by telephone interview or from the medical record. End of the observation period was March 2013. PH was identified if tricuspid regurgitation peak velocity was >3 m/s. RESULTS: Two hundred and twelve were identified. Eighty-three dogs (39%) had PH. PH was more commonly identified in stage C compared to B2 (P < .0001). One hundred and five (49.5%) dogs died during the observation period. Median survival time for the entire study population was 567 days (95% CI 512-743). Stage C (P = .003), the presence of PH (P = .009), left atrial to aortic root ratio (LA/Ao) >1.7 (P = .0002), normalized left ventricular end-diastolic diameter (LVEDn) >1.73 (P = .048), and tricuspid regurgitation pressure gradient (TRPG) >55 mmHg (P = .009) were associated with worse outcomes in the univariate analyses. The presence of TRPG >55 mmHg (HR 1.8 95% CI 1-2.9; P = .05) and LA/Ao > 1.7 (HR 2 95% CI 1.2-3.4; P = .01) remained significant predictors of worse outcome in the multivariate analysis. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with MMVD, moderate to severe PH worsens outcome. PMID- 25818211 TI - Clinical severity score system in dogs with degenerative mitral valve disease. AB - BACKGROUND: Several risk factors already have been determined for dogs with degenerative mitral valve disease (DMVD). Risk factors often have been considered in isolation and have not always taken into account additional information provided by the history and physical examination (PE). HYPOTHESIS/OBJECTIVES: Data obtained from history and PE of dogs with DMVD provide prognostic information and can be used for risk stratification. ANIMALS: Client-owned dogs (n = 244) with DMVD recruited from first opinion practice. METHODS: Prospective longitudinal follow-up of dogs with DMVD. History and PE data were obtained at 6 month intervals and analyzed with time-dependent Cox models to derive relative risk of cardiac death. Independent hazard ratios were used to derive a clinical severity score (CSS), the prognostic value of which was evaluated by analyzing the median survival times for different risk groups and ROC analysis. Analysis of the progression of CSS over time also was undertaken. RESULTS: History of cough, exercise intolerance, decreased appetite, breathlessness (difficulty breathing) and syncope with PE findings of heart murmur intensity louder than III/VI and absence of respiratory sinus arrhythmia were independently associated with outcome and allowed development of the CSS. Clinical severity score distinguished groups of dogs with significantly different outcomes. CONCLUSIONS AND CLINICAL IMPORTANCE: Routinely obtained clinical findings allow risk stratification of dogs with DMVD. Results of ancillary diagnostic tests may be complementary to history and PE findings and always should be interpreted in conjunction with these findings. PMID- 25818212 TI - Association of tricuspid annular plane systolic excursion with survival time in Boxer dogs with ventricular arrhythmias. AB - BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) is a useful estimate of right ventricular function in humans. Reference intervals for dogs have been generated, but the value of measuring TAPSE in other diseases, or investigating the association between TAPSE and outcome, is unknown. HYPOTHESIS: TAPSE is lower in Boxer dogs with >=50 VPCs/24 h on Holter than in dogs with fewer ventricular ectopics, and lower TAPSE is associated with a shorter survival time. ANIMALS: Fifty Boxer dogs that presented for investigation of syncope or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) at a veterinary teaching hospital (2004-2011). METHODS: Retrospective study. Clinical records, Holter, and echocardiographic data were reviewed. TAPSE was measured in a blinded manner on stored echocardiographic cine-loops using anatomic M-mode. Outcome information was obtained and death was classified as cardiac or noncardiac. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: TAPSE was lower in Boxers with >=50 VPCs/24 h (13.9 +/- 4.04 mm) than Boxers with <50 VPCs/24 h (16.8 +/- 3.21 mm; P < .001). TAPSE <15.1 mm was associated with shorter cardiac survival time in all dogs (P = .004) and also in dogs without left ventricular dysfunction (P = .035). When controlling for other variables, including ventricular tachycardia on Holter and left ventricular systolic dysfunction, multivariable analysis showed that TAPSE remained an independent predictor of time to cardiac death (HR >4.09, 95%CI 1.15 16.9, P < .029). CONCLUSIONS AND CLINICAL IMPORTANCE: TAPSE offers prognostic value for Boxer dogs, including those with apparently normal systolic function and >=50 VPCs/24 h on Holter analysis. PMID- 25818213 TI - Longitudinal evaluation of serum pancreatic enzymes and ultrasonographic findings in diabetic cats without clinically relevant pancreatitis at diagnosis. AB - BACKGROUND: Cats with diabetes mellitus can have subclinical pancreatitis but prospective studies to confirm this are lacking. Metabolic control of diabetic cats with pancreatitis is difficult. HYPOTHESIS: Subclinical pancreatitis occurs in diabetic cats at the time diabetes is diagnosed or might develop during the follow-up period, hampering diabetic remission. ANIMALS: Thirty cats with newly diagnosed diabetes without clinical signs of pancreatitis on admission. METHODS: Prospective study. On admission and 2 and 6 months later, serum Spec fPL and DGGR lipase were measured and the pancreas underwent ultrasonographic examination. Pancreatitis was suspected if serum markers were increased or >=2 ultrasonographic abnormalities were detected. Cats were treated with insulin glargine and diabetic remission was defined as euglycemia >=4 weeks after discontinuation of insulin. Nonparametric statistical tests were used for analysis. RESULTS: Subclinical pancreatitis at the time of diagnosis was suspected in 33, 50, and 31% of cats based on Spec fPL, DGGR-lipase and ultrasonography, respectively; and in 60% when diagnostic criteria were combined. During the follow-up period, suspected pancreatitis developed in additional 17 30% cats. Only 1 cat had transient clinical signs compatible with pancreatitis. Seventeen of the 30 cats (57%) achieved remission. Frequency of abnormal Spec fPL and DGGR-lipase and abnormal ultrasonographic findings did not differ in cats achieving remission and those who did not. Cats achieving remission had significantly lower Spec fPL at 2 months (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Based on laboratory and ultrasonographic measurements, many cats with diabetes might have pancreatitis, although without clinical signs. Cats with high Spec fPL might have a reduced chance of diabetic remission; however, this topic needs further studies in large cohorts of diabetic cats. PMID- 25818214 TI - Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs. AB - BACKGROUND: Diagnosis of pheochromocytoma (PC) is based on a combination of clinical suspicion, finding an adrenal mass, increased plasma, and urine concentrations of catecholamine metabolites and is finally confirmed with histopathology. In human medicine, it is controversial whether biochemically testing plasma is superior to testing urine. OBJECTIVES: To measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, hypercortisolism (HC), and nonadrenal diseases (NAD) and to determine the test with the best diagnostic performance for dogs with PC. ANIMALS: Seven PC dogs, 10 dogs with HC, 14 dogs with NAD, 10 healthy dogs. METHODS: Prospective diagnostic clinical study. Urine and heparin plasma samples were collected and stored at -80 degrees C before analysis using high-pressure liquid chromatography (HPLC) coupled to electrochemical detection or tandem mass spectrometry were performed. Urinary variables were expressed as ratios to urinary creatinine concentration. RESULTS: Dogs with PC had significantly higher urinary normetanephrine and metanephrine:creatinine ratios and significantly higher plasma-total and free normetanephrine and plasma-free metanephrine concentrations compared to the 3 other groups. There were no overlapping results of urinary normetanephrine concentrations between PC and all other groups, and only one PC dog with a plasma normetanephrine concentration in the range of the dogs with HC and NAD disease. Performances of total and free plasma variables were similar. Overlap of epinephrine and norepinephrine results between the groups was large with both urine and plasma. CONCLUSION AND CLINICAL IMPORTANCE: Measurement of normetanephrine is the preferred biochemical test for PC and urine was superior to plasma. PMID- 25818215 TI - Pharmacokinetics of single-dose rectal zonisamide administration in normal dogs. AB - BACKGROUND: Few medications are available for parental administration to animals with seizures. Rectal administration of medications is often used if the animal cannot be administered oral medications. HYPOTHESIS/OBJECTIVES: To determine the pharmacokinetic differences in zonisamide when administered rectally in either of 2 vehicles and p.o. to dogs. ANIMALS: Eight healthy research dogs. METHODS: Randomized cross-over design. Zonisamide, 10 mg/kg, was administered rectally in polyethylene glycol (PEG-R), rectally in water (H2O-R), and as an oral capsule. Plasma zonisamide concentrations were measured until 72 hours after administration. Zonisamide was quantitated by HPLC and plasma concentration versus time curve data was analyzed by using noncompartmental modeling. RESULTS: Mean maximum plasma zonisamide concentrations (MUg/mL) were significantly higher after oral administration (11.56 +/- 4.04) compared to H2O-R (5.00 +/- 1.83) (P = .004). Disappearance half-life (hours) and mean time to maximum concentration (hours) were not significantly different between methods of administration. Mean relative bioavailability of PEG-R (85 +/- 69%) was significantly higher than that of H2O-R (53 +/- 37%) (P = .039). Dogs tolerated all dosing forms with no evidence of adverse effects. CONCLUSIONS AND CLINICAL IMPORTANCE: The vehicle in which zonisamide is dissolved influences rectal bioavailability, with PEG preferred to H2O-R. Because of the prolonged time to maximum concentration, rectal administration of zonisamide should not be used to treat status epilepticus in dogs. A dose higher than what was used in this study might be necessary, if currently recommended minimum therapeutic concentrations (10 MUg/mL) are to be achieved with a single-dose administration. PMID- 25818216 TI - An open-label phase 1 dose-escalation clinical trial of a single intravenous administration of gemcitabine in dogs with advanced solid tumors. AB - BACKGROUND: A broad range of gemcitabine dosages have been used in dogs. HYPOTHESIS/OBJECTIVES: To determine maximally tolerated dose (MTD), dose-limiting toxicity (DLT), and preliminary antitumor activity of intravenous administration of gemcitabine in dogs with advanced solid tumors. ANIMALS: Twenty-two client owned dogs. METHODS: Dogs with advanced cancer were prospectively enrolled in an open-label Phase 1 study of gemcitabine. Gemcitabine was administered as a 30 minute intravenous bolus starting at 800 mg/m(2), using escalation of 50 mg/m(2) increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing DLT assessed after 1 cycle. Treatment continued until disease progression or unacceptable toxicosis. Additional dogs were enrolled at MTD to better characterize tolerability, and to assess the extent and duration of gemcitabine excretion. RESULTS: Twenty-two dogs were treated at 4 dose levels, ranging from 800 to 950 mg/m(2). Neutropenia was identified as DLT. MTD was 900 mg/m(2). DLT consisting of grade 4 febrile neutropenia was observed at 950 mg/m(2) in 2 dogs. There were no nonhematologic DLTs. Twenty dogs received multiple doses, and none had evidence of severe toxicosis from any of their subsequent treatments. At 900 mg/m(2), 2 complete and 5 partial responses were observed in dogs with measurable tumors. The amount of gemcitabine excreted in urine decreased over time, and was undetectable after the first 24 hours. CONCLUSIONS AND CLINICAL IMPORTANCE: The recommended dose of gemcitabine for future Phase 2 studies is weekly 900 mg/m(2). In chemotherapy-naive dogs with advanced solid tumor this dose level merits further evaluation. PMID- 25818217 TI - Glucocorticoid receptor density and binding affinity in healthy horses and horses with systemic inflammatory response syndrome. AB - BACKGROUND: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in horses with systemic inflammatory response syndrome (SIRS). Peripheral resistance to glucocorticoids has not been investigated in horses. OBJECTIVE: To determine if glucocorticoid receptor (GR) function in horses can be measured using flow cytometry, and to use this information to evaluate HPA axis dynamics. ANIMALS: Eleven healthy adult horses in parts 1 and 2. Ten horses with SIRS and 10 age and sex matched controls in part 3. METHODS: Flow cytometry was used to evaluate GR density and binding affinity (BA) in 3 healthy horses in part 1. In part 2, exogenous ACTH was administered to eight healthy horses. Their cortisol response and GR properties were measured. In part 3, CBC, serum biochemistry, cortisol and ACTH, and GR properties were compared between controls without SIRS (n = 10) and horses with SIRS (n = 10), and between survivors and nonsurvivors (n = 4 and n = 6 respectively). RESULTS: Flow cytometry can be used to measure GR properties in equine PBMCs. No correlation was observed between plasma cortisol concentration and GR density or BA in healthy horses (r = -0.145, P = .428 and r = 0.046, P = .802 respectively). Nonsurvivors with SIRS had significantly decreased GR BA (P = .008). Horses with triglyceride concentration > 28.5 mg/dL had increased odds of nonsurvival (OR=117; 95% CI, 1.94-7,060). GR BA <35.79% was associated with nonsurvival (OR = 30.33; 95% CI, 0.96-960.5). CONCLUSIONS AND CLINICAL IMPORTANCE: Tissue resistance to glucocorticoids contributes to HPA axis dysfunction in adult horses with SIRS. These horses might benefit from treatment with exogenous glucocorticoids. PMID- 25818218 TI - Experimental transmission of Corynebacterium pseudotuberculosis biovar equi in horses by house flies. AB - BACKGROUND: The route of Corynebacterium pseudotuberculosis infection in horses remains undetermined, but transmission by insects is suspected. OBJECTIVES: To investigate house flies (Musca domestica L.) as vectors of C. pseudotuberculosis transmission in horses. ANIMALS: Eight healthy, adult ponies. METHODS: Randomized, controlled, blinded prospective study. Ten wounds were created in the pectoral region where cages for flies were attached. Three ponies were directly inoculated with C. pseudotuberculosis. Four ponies were exposed for 24 hours to 20 hours C. pseudotuberculosis-inoculated flies. One negative control pony was exposed to noninoculated flies. Ponies were examined daily for swelling, heat, pain, and drainage at the inoculation site. Blood was collected weekly for CBC and biochemical analysis, and twice weekly for synergistic hemolysis inhibition titers. RESULTS: Clinical signs of local infection and positive cultures were observed in 7/7 exposed ponies and were absent in the negative control. In exposed ponies, peak serologic titers (1:512 to 1:2,048) were obtained between days 17 and 21. Seroconversion was not observed in the negative control. Neutrophil counts were higher in the positive and fly-exposed groups than in the negative control (P = .002 and P = .005) on day 3 postinoculation. Serum amyloid A concentrations were higher in the positive control than in the negative control and fly-exposed ponies on days 3 (P < .0001) and 7 (P = .0004 and P = .0001). No differences were detected for other biochemical variables. CONCLUSIONS AND CLINICAL IMPORTANCE: House flies can serve as mechanical vectors of C. pseudotuberculosis and can transmit the bacterium to ponies. PMID- 25818219 TI - Serum bile acid concentrations, histopathological features, and short-, and long term survival in horses with hepatic disease. AB - BACKGROUND: Serum bile acid concentrations (SBA) and a histopathological biopsy score [Equine Vet J 35 (2003) 534] are used prognostically in equine hepatic disease. HYPOTHESIS: Histopathologic features and scores, but not SBA, differ between survivors and nonsurvivors and correlate with histopathologic evidence of hepatic inflammation and fibrosis. ANIMALS: Retrospective study. Records (1999 2011) of horses with hepatic disease diagnosed by biopsy and with concurrent measurements of SBA. METHODS: Retrospective cohort study. Biopsies were examined for inflammatory cell infiltration including type and distribution, fibrosis, irreversible cytopathology affecting hepatocytes, hemosiderin, or other pigment deposition and bile duct proliferation. SBA, histopathological findings and a histological score [Equine Vet J 35 (2003) 534] were compared between short- (survival to discharge) and long-term (>6 months) survivors and correlations between SBA and histopathological findings investigated. RESULTS: Of 81 cases 90% survived short-term and 83% long-term. Short-term and long-term nonsurvival were associated with SBA (P = .009; P = .006), overall (P = .001; P = .002) and parenchymal (short-term only; P = .01) inflammation, portal and bridging fibrosis (all P < .001), apoptosis or single cell necrosis (P < .001; P = .008), hemosiderin deposition in hepatocytes (P = .011; P = .028), biliary (both P < .001), vascular (P = .003; P = .045) and endothelial (P < .001; P = .02) hyperplasia, nucleic changes (P = .004; P < .001) and the histopathological score (both P < .001). SBA were significantly and positively correlated with overall (P = .001), parenchymal (P < .001) and portal (P = .004) inflammation and portal (P = .036) and bridging (P = .002) fibrosis. CONCLUSIONS AND CLINICAL IMPORTANCE: SBA, histopathological findings and scores differ between survivors and nonsurvivors. SBA concentrations are associated with inflammation and fibrosis suggesting interference with hepatic function. A histopathological score >2 and, less so, SBA >20 MUmol/L are specific but not sensitive indicators of nonsurvival. PMID- 25818220 TI - Preliminary investigation of the area under the L-lactate concentration-time curve (LACArea) in critically ill equine neonates. AB - BACKGROUND: A variety of measures of L-lactate concentration ([LAC]) in the blood of critically ill neonatal foals have shown utility as prognostic indicators. These measures, evaluating either the severity of hyperlactatemia or the duration of exposure to hyperlactatemia, perform fairly well and have correctly classified 75-80% of foals examined in several studies. The area under the L-lactate concentration versus time curve (LACArea) encompasses both severity and duration of hyperlactatemia and should improve correct classification of patient survival. HYPOTHESIS/OBJECTIVES: LACArea is larger in nonsurviving critically ill neonatal foals. ANIMALS: Forty-nine foals admitted for critical illness to 1 of 4 referral hospitals. METHODS: Whole blood was obtained at admission and 6, 12, 18, and 24 hours after admission for measurement of L-lactate using a handheld lactate meter. LACArea was calculated for: admission-6, 6-12, 12-18, 18-24 hours, and admission-24 hours using the trapezoidal method and summing the 6-hours interval areas to determine total 24 hours area. Differences between survivors and nonsurvivors were determined using robust regression and Kruskal-Wallis testing, P < .05. RESULTS: LACArea was significantly larger in nonsurviving foals (n = 9) than in surviving foals (n = 40) at all time periods examined. CONCLUSIONS AND CLINICAL IMPORTANCE: Differences in LACArea between surviving and nonsurviving critically ill neonatal foals are large and support further investigation of this method as an improved biomarker for survival in critically ill neonatal foals is indicated. PMID- 25818221 TI - Plasma C-reactive protein and haptoglobin concentrations in critically ill neonatal foals. AB - BACKGROUND: Accurate diagnostic markers for sepsis in neonatal foals are needed. Plasma C-reactive protein concentration (p[CRP]) and haptoglobin concentration (p[Hp]) are well-established biomarkers of infection in humans, but studies are lacking in foals. HYPOTHESES: p[CRP]) and p[Hp] are increased in septic foals compared to sick nonseptic and healthy control foals, and are predictive of survival. ANIMALS: Eighty critically ill foals (40 septic, 40 sick nonseptic) and 39 healthy control foals <1 week of age. METHODS: Multicenter, prospective observational clinical study. Venous blood was collected at admission from septic and sick nonseptic foals and from clinically healthy foals at 24 h of age. A diagnosis of sepsis was made based on positive blood culture or a sepsis score >11, and p[CRP] and p[Hp] were measured by using ELISA tests. Data were analyzed by using the Mann-Whitney U-test and forward stepwise multivariable linear regression. P < .05 was considered significant. RESULTS: Plasma [CRP] was positively associated with age, serum globulin, adrenomedullin, and bilirubin concentrations, aspartate aminotransferase activity, glutamyl-transferase activity, band neutrophil count, and rectal temperature, and was increased in foals with toxic neutrophils, enterocolitis, colic, rib fractures and septic arthritis. Surprisingly, p[Hp] was lower in septic foals than in sick nonseptic foals. Neither p[CRP] or p[Hp] was predictive of survival in critically ill foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma [CRP] increases with inflammation in neonatal foals but is not indicative of sepsis. Single time point, admission sampling of p[CRP] and p[Hp] do not appear to be useful biomarkers for sepsis in foals. PMID- 25818222 TI - Quantitative physicochemical analysis of acid-base balance and clinical utility of anion gap and strong ion gap in 806 neonatal calves with diarrhea. AB - BACKGROUND: Acid-base abnormalities in neonatal diarrheic calves can be assessed by using the Henderson-Hasselbalch equation or the simplified strong ion approach which use the anion gap (AG) or the strong ion gap (SIG) to quantify the concentration of unmeasured strong anions such as D-lactate. HYPOTHESIS/OBJECTIVES: To determine and compare the clinical utility of AG and SIG in quantifying the unmeasured strong anion charge in neonatal diarrheic calves, and to examine the associations between biochemical findings and acid base variables by using the simplified strong ion approach. We hypothesized that the SIG provides a more accurate prediction of unmeasured strong anions than the AG. ANIMALS: Eight hundred and six neonatal diarrheic calves admitted to a veterinary teaching hospital. METHODS: Retrospective study utilizing clinicopathologic findings extracted from medical records. RESULTS: Hyperphosphatemia was an important predictor of venous blood pH. Serum inorganic phosphorus and plasma D-lactate concentrations accounted for 58% of the variation in venous blood pH and 77% of the variation in AG and SIG. Plasma D- and total lactate concentrations were slightly better correlated with SIG (rs = -0.69; 0.78) than to AG (rs = 0.63; 0.74). CONCLUSIONS AND CLINICAL IMPORTANCE: Strong ion gap is slightly better at quantifying the unmeasured strong anion concentration in neonatal diarrheic calves than AG. Phosphorus concentrations should be included as part of the calculation of Atot when applying the simplified strong ion approach to acid-base balance to critically ill animals with hyperphosphatemia. PMID- 25818223 TI - Risk factors for the development of hypokalemia in neonatal diarrheic calves. AB - BACKGROUND: Neonatal diarrheic calves have a clear negative potassium balance because of intestinal losses and decreased milk intake but in the presence of acidemia, they usually show normokalemic or hyperkalemic plasma concentrations. OBJECTIVES: To assess whether marked hypokalemia occurs in response to the correction of acidemia and dehydration and to identify factors that are associated with this condition. ANIMALS: Eighty-three calves with a clinical diagnosis of neonatal diarrhea. METHODS: Prospective cohort study. Calves were treated according to a clinical protocol using an oral electrolyte solution and commercially available packages of 8.4% sodium bicarbonate, 0.9% saline and 40% dextrose infusion solutions. RESULTS: The proportion of hypokalemic calves after 24 hours of treatment (19.3%) was twice as great as it was on admission to the hospital. Plasma K(+) after 24 hours of treatment was not significantly correlated to venous blood pH values at the same time but positively correlated to venous blood pH values on admission (r = 0.51, P < .001). Base excess on admission (Odds ratio [OR] = 0.81, 95% confidence interval [CI] = 0.70-0.94), duration of diarrhea (OR = 1.37, 95% CI = 1.05-1.80), milk intake during hospitalization (OR = 0.54, 95% CI = 0.37-0.79) and plasma sodium concentrations after 24 hours (OR = 1.12, 95% CI = 1.01-1.25) were identified to be independently associated (P < .05) with a hypokalemic state after 24 hours of treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Findings of this study suggest that marked depletion of body potassium stores is evident in diarrheic calves that suffered from marked metabolic acidosis, have a low milk intake and a long history of diarrhea. PMID- 25818224 TI - Mannheimia haemolytica in feedlot cattle: prevalence of recovery and associations with antimicrobial use, resistance, and health outcomes. AB - BACKGROUND: Mannheimia haemolytica is an important etiological agent in bovine respiratory disease. OBJECTIVES: Explore risk factors for recovery of susceptible and resistant M. haemolytica in feedlot cattle and explore associations with health outcomes. ANIMALS: Cattle (n = 5,498) from 4 feedlots sampled at arrival and later in feeding period. METHODS: Susceptibility of M. haemolytica isolates tested for 21 antimicrobials. Records of antimicrobial use and health events analyzed using multivariable regression. RESULTS: M. haemolytica recovered from 29% of cattle (1,596/5,498), 13.1% at arrival (95% CI, 12.3-14.1%), and 19.8% at second sampling (95% CI, 18.7-20.9%). Nearly half of study cattle received antimicrobial drugs (AMDs) parenterally, mostly as metaphylactic treatment at arrival. Individual parenteral AMD exposures were associated with decreased recovery of M. haemolytica (OR, 0.2; 95% CI, 0.02-1.2), whereas exposure in penmates was associated with increased recovery (OR, 1.5; 95% CI, 1.05-2.2). Most isolates were pan-susceptible (87.8%; 95% CI, 87.0-89.4%). AMD exposures were not associated with resistance to any single drug. Multiply-resistant isolates were rare (5.9%; 95% CI, 5.1-6.9%), but AMD exposures in pen mates were associated with increased odds of recovering multiply-resistant M. haemolytica (OR, 23.9; 95% CI, 8.4-68.3). Cattle positive for M. haemolytica on arrival were more likely to become ill within 10 days (OR, 1.7; 95% CI, 1.1-2.4). CONCLUSIONS AND CLINICAL IMPORTANCE: Resistance generally was rare in M. haemolytica. Antimicrobial drug exposures in penmates increased the risk of isolating susceptible and multiply resistant M. haemolytica, a finding that could be explained by contagious spread. PMID- 25818225 TI - Evaluation of digital and optical refractometers for assessing failure of transfer of passive immunity in dairy calves. AB - BACKGROUND: Failure of transfer of passive immunity (FTPI) is the underlying predisposing risk factor for most early losses in dairy calves. Refractometers, either optical or digital, can be used to assess FTPI as a part of calf health monitoring program on dairy operations. OBJECTIVES: To evaluate the performance of and differences between digital Brix and optical refractometers for assessing FTPI in dairy calves. ANIMALS: Two hundred Holstein calves from 1 to 11 days of age. METHODS: A cross-sectional study was designed to measure serum IgG concentration by radial immunodiffusion (RID) assay, digital Brix and optical refractometers. The correlation coefficients (r) between the 2 refractometers were plotted against each other and against the measured IgG concentration from RID. The Se, Sp, and accuracy of digital Brix and optical refractometers for assessing FTPI using previously recommended cut-offs were calculated. A receiver operating characteristic curve was created and used to identify the optimal cut off for this dataset. RESULTS: The RID IgG concentration was positively correlated with digital Brix (r = 0.79) and optical (r = 0.74) refractometers. The best combination of Se (85.5%), Sp (82.8%), and accuracy (83.5%) of digital Brix refractometer was at 8.3%Brix. For optical refractometer, the best combination of Se (80%), Sp (80.7%), and accuracy (80.5%) was at 5.5 g/dL. CONCLUSIONS AND CLINICAL IMPORTANCE: Both refractometers exhibited utility in assessing FTPI in dairy calves. PMID- 25818226 TI - Plasma exchange as a treatment for hyperbilirubinemia in 2 foals with neonatal isoerythrolysis. PMID- 25818228 TI - Four new tetramic acid and one new furanone derivatives from the plant endophytic fungus Neopestalotiopsis sp. AB - Four new tetramic acid analogues neopestalotins A-D (1-4), one new furanone derivative neopestalotin E (6), and the known compound hymenosetin have been isolated from the solid cultures of the plant endophytic fungus Neopestalotiopsis sp. The structures of the new compounds were determined mainly by nuclear magnetic resonance (NMR) experiments. The absolute configurations of 1 and 2 were assigned by circular dichroism (CD) data, whereas those of 3 and 4 were deduced by a combination of CD and heteronuclear long range coupling (HETLOC) data. Compound 2 showed modest antimicrobial activity against the Gram-positive bacteria, Bacillus subtilis, Staphylococcus aureus col, and Streptococcus pneumoniae. PMID- 25818229 TI - Lignans from the root of Paeonia lactiflora and their anti-beta-amyloid aggregation activities. AB - Four new neolignans (1-4), together with two known lignans (5 and 6), were isolated from the root of Paeonia lactiflora. Compounds 1 and 2 were two racemates and were separated by chiral high performance liquid chromatography (HPLC) to give all of the four stereoisomeric forms sharing a common planar structure. Compounds 3 and 4 were two neolignan glycoside diastereomers but interestingly appeared to be enantiomers: they had the extremely similar (1)H and (13)C NMR spectra and had to be solved only by chiral HPLC. Their structures were determined by spectroscopic analysis, including 1D and 2D NMR, HRESIMS and electronic circular dichroism experiments. All compounds were evaluated for their inhibitory effects on beta-amyloid aggregation, and the optical pure compound 2b was found to show the optimal Abeta(1-42) aggregation inhibition potency (81.1% at 20 MUM). In addition, despite large amount of chemical studies performed on genus Paeonia, the lignans were reported for the first time. PMID- 25818230 TI - Sesquiterpene coumarins from seeds of Ferula sinkiangensis. AB - A new sesquiterpene coumarin with a novel sesquiterpene carbon framework, Sinkiangenorin D, and ten known sesquiterpene coumarins were isolated from the seeds of Ferula sinkiangensis. The structures of these compounds, including the relative stereochemistry, were elucidated on the basis of spectroscopic data. All of the isolated compounds were tested against the AGS, HeLa, and K562 human cancer cell lines and showed cytotoxic activities with 50% inhibitory concentration values between 12.7 and 226.6 MUM. PMID- 25818231 TI - Red macroalgae as a sustainable resource for bio-based products. AB - Red macroalgae are being actively investigated as a renewable biomass source because of their advantageous characteristics such as abundant carbohydrate contents, low lignin contents, and the absence of conflicts with food production. With recent technological advances, the efficient utilization of red macroalgae for biofuel and chemical production is now possible. PMID- 25818233 TI - The scope and impact of obesity in Vermont - Strategies for change. AB - Obesity is a complex, multi-faceted condition amplified by a confluence of socio economic and environmental forces. Even in Vermont, a state long ranked as one of the healthiest, 25% of adults are obese, a rate better than 44 other states, but more than double that in 1990. Obesity puts people at greater risk for a number of serious health conditions, and may soon overtake tobacco as the #1 real killer if the current trend is not reversed. Beyond the cost to an individual's health, the projected financial impacts of an increasingly obese population are great. Nationally, the estimated direct and indirect costs of obesity add up to more than $190 billion each year. In public health terms, the challenge we are facing with obesity can well be compared to our experience with tobacco. We can easily track advances in policy, counter-marketing and other changes that together have created an environment in which smoking is no longer the norm. The Vermont Department of Health is beginning to apply strategies similar to those used to successfully cut smoking rates. This commentary describes Vermont's efforts to increase physical activity, decrease caloric intake, and enlist partners to help make healthy choices easier and more accessible for everyone. PMID- 25818232 TI - Changes in cervical cancer incidence following the introduction of organized screening in Italy. AB - OBJECTIVE: To quantify the impact of organized cervical screening programs (OCSPs) on the incidence of invasive cervical cancer (ICC), comparing rates before and after activation of OCSPs. METHODS: This population-based investigation, using individual data from cancer registries and OCSPs, included 3557 women diagnosed with ICC at age 25-74years in 1995-2008. The year of full activation of each OCSP was defined as the year when at least 40% of target women had been invited. Incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) were calculated as the ratios between age-standardized incidence rates observed in periods after full-activation of OCSPs vs those observed in the preceding quinquennium. RESULTS: ICC incidence rates diminished with time since OCSPs full-activation: after 6-8years, the IRR was 0.75 (95% CI: 0.67-0.85). The reduction was higher for stages IB-IV (IRR=0.68, 95% CI: 0.58-0.80), squamous cell ICCs (IRR=0.74, 95% CI: 0.64-0.84), and particularly evident among women aged 45-74years. Conversely, incidence rates of micro-invasive (stage IA) ICCs increased, though not significantly, among women aged 25-44years (IRR=1.34, 95% CI: 0.91-1.96). Following full-activation of OCSPs, micro-invasive ICCs were mainly and increasingly diagnosed within OCSPs (up to 72%). CONCLUSION(S): Within few years from activation, organized screening positively impacted the already low ICC incidence in Italy and favored down-staging. PMID- 25818234 TI - Sequential healing events of osseointegration at UnicCa((r)) and SLActive((r)) implant surfaces: an experimental study in the dog. AB - AIM: To study the sequential events in osseointegration at implants with highly hydrophilic surfaces. MATERIAL AND METHODS: All premolars and the first molars were bilaterally extracted in 12 Beagle dogs. After 3 months, full-thickness flaps were elevated and two different implants systems with various surfaces were randomly installed in the edentulous premolar region in one side of the mandible. One surface was acid etched and further modified with calcium ions (UnicCa((r))), while the other was sandblasted with large grits and acid etched (SLActive((r))). The flaps were sutured to allow a fully submerged healing. The surgery on the other side of the mandible and the sacrifices were planned in such a way to obtain biopsies representing the healing after 1, 2, 4, and 8 weeks (n = 6 per period). RESULTS: After one week of healing, new bone apposition was found at both surfaces with percentages of 6.9 +/- 3.3% and 6.1 +/- 4.6% at UnicCa((r)) and SLActive((r)), respectively. After 2 weeks, the percentages had increased to 29.1 +/- 11.9% and 21.6 +/- 14.3%, respectively. After 4 and 8 weeks of healing, mean values of 46.3 +/- 7.3% and 58.7 +/- 15.1% at UnicCa((r)) and 51.2 +/- 16.1% and 68.9 +/- 15.4% at SLActive((r)) surfaces were found, respectively. None of the differences in percentages were statistically significant. Concomitantly, the old bone was resorbed at both surfaces from about 21-22% after 1 week to about 4 6% after 8 weeks of healing. CONCLUSIONS: The osseointegration process onto moderately rough titanium implant surfaces of high hydrophilicity was very similar for two implant systems that were both nanotechnologically modified. PMID- 25818236 TI - Emotional functioning: Long-term outcomes after pediatric epilepsy surgery. AB - OBJECTIVE: Children with epilepsy are at a high risk for developing symptoms of anxiety and depression. By improving seizure control, epilepsy surgery has the potential to improve patients' anxiety and depression symptoms. Few studies have assessed the long-term outcomes of anxiety and depressive symptoms after pediatric epilepsy surgery while using an appropriate control group. This study examined anxiety and depressive symptoms 4-11 years after surgery in surgical patients and in a control group of nonsurgical patients with pediatric-onset epilepsy. METHODS: Seventy-three surgical patients with a mean age of 19.87 (standard deviation [SD] 4.46, range 10.08-28.50) and 40 nonsurgical controls with a mean age of 20.31 (SD 4.01, range 12.08-27.25) completed the study measures. Patients completed the Child Depression Inventory II/Beck Depression Inventory II and State Trait Anxiety Inventory for Children/State Trait Anxiety Inventory and parents completed the Child Behavior Checklist/Adult Behavior Checklist to assess the patients' anxiety and depressive symptoms. Baseline measurements of affective symptoms (Child Behavior Checklist) were retrieved from the patients' medical records. RESULTS: Patient-reported affective functioning was obtained at the follow-up visit only. Patient-reported depressive symptoms and state and trait anxiety were similar for both groups. Based on parent reports at follow-up, patients with seizures were found to have significantly more depressive problems and anxious/depressed symptoms, and marginally more withdrawn symptoms relative to patients without seizures. SIGNIFICANCE: Seizure status was related to the presence of affective symptoms, irrespective of whether the patient had undergone surgery. In addition, parents and not patients reported the presence of anxiety and depressive symptoms, which indicates the importance of obtaining multiple informants to assess affective symptomatology. PMID- 25818235 TI - MARK-AGE biomarkers of ageing. AB - Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation. PMID- 25818237 TI - Archaeal enrichment in the hypoxic zone in the northern Gulf of Mexico. AB - Areas of low oxygen have spread exponentially over the past 40 years, and are cited as a key stressor on coastal ecosystems. The world's second largest coastal hypoxic (<= 2 mg of O2 l(-1)) zone occurs annually in the northern Gulf of Mexico. The net effect of hypoxia is the diversion of energy flow away from higher trophic levels to microorganisms. This energy shunt is consequential to the overall productivity of hypoxic water masses and the ecosystem as a whole. In this study, water column samples were collected at 39 sites in the nGOM, 21 of which were hypoxic. Analysis of the microbial community along a hypoxic to oxic dissolved oxygen gradient revealed that the relative abundance (iTag) of Thaumarchaeota species 16S rRNA genes (> 40% of the microbial community in some hypoxic samples), the absolute abundance (quantitative polymerase chain reaction; qPCR) of Thaumarchaeota 16S rRNA genes and archaeal ammonia-monooxygenase gene copy number (qPCR) were significantly higher in hypoxic samples. Spatial interpolation of the microbial and chemical data revealed a continuous, shelfwide band of low dissolved oxygen waters that were dominated by Thaumarchaeota (and Euryarchaeota), amoA genes and high concentrations of phosphate in the nGOM, thus implicating physicochemical forcing on microbial abundance. PMID- 25818238 TI - MicroRNA-124 inhibits cancer cell growth through PTB1/PKM1/PKM2 feedback cascade in colorectal cancer. AB - Altered levels and functions of microRNAs (miRs) have been associated with carcinogenesis. In this study, we investigated the role of miR-124 in colorectal adenoma (CRA) and cancer (CRC). The expression levels of miR-124 were decreased in CRA (81.8%) and CRC (57.6%) in 55 clinical samples. The ectopic expression of miR-124 induced apoptosis and autophagy in colon cancer cells. Also, miR-124 targeted polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of pyruvate kinase muscles 1 and 2 (PKM1 and PKM2) and induced the switching of PKM isoform expression from PKM2 to PKM1. Also, siR-PTB1 induced drastic apoptosis in colon cancer cells. Furthermore, we found that the ectopic expression of miR-124 enhanced oxidative stress and the miR-124/PTB1/PKM1/PKM2 axis constituted a feedback cascade. Finally, we showed that intratumor injection of miR-124 and siR PTB1 induced a tumor-suppressive effect in xenografted mice. The axis was established by both in vitro and in vivo experiments to function in human colorectal cancer cells. These findings suggest that miR-124 acts as a tumor suppressor and a modulator of energy metabolism through a PTB1/PKM1/PKM2 feedback cascade in human colorectal tumor cells. PMID- 25818239 TI - Total cholesterol performance of Abell-Levy-Brodie-Kendall reference measurement procedure: Certification of Japanese in-vitro diagnostic assay manufacturers through CDC's Cholesterol Reference Method Laboratory Network. AB - BACKGROUND: Accurate measurement of total cholesterol (TC) is important for cardiovascular disease risk management. The US Centers for Disease Control and Prevention (CDC) and Cholesterol Reference Method Laboratory Network (CRMLN) perform Abell-Levy-Brodie-Kendall (AK) reference measurement procedure (RMP) for TC as a secondary reference method, and implement Certification Protocol for Manufacturers. Japanese CRMLN laboratory at Osaka performed the AK RMP for 22 years, and conducted TC certification for reagent/calibrator/instrument systems of six Japanese manufacturers every 2 years for 16 years. Osaka TC performance was examined and compared to CDC's reference values. METHODS: AK RMP involved sample hydrolysis, cholesterol extraction, and determination of cholesterol levels by spectrophotometry. The Certification Protocol for Manufacturers includes comparison with AK RMP using at least 40 fresh specimens. Demonstration of average bias <=3% and total coefficient of variation <=3% qualified an analytical system for certification. RESULTS: In the AK RMP used in the Osaka CRMLN laboratory, the regression equation for measuring TC was y (Osaka)=1.000x (CDC)+0.032 (n=619, R(2)=1.000). Six Japanese manufacturers had allowable performance for certification. CONCLUSIONS: The AK RMP for TC measurement was accurate, precise, and stable for 22 years. Six Japanese manufacturers were certified for 16 years. PMID- 25818240 TI - Error rates during blood collection in emergency departments and outpatient clinics: Results of a prospective multicenter study. PMID- 25818241 TI - Gasomediators (.NO, CO, and H2S) and their role in hemostasis and thrombosis. AB - Hemostasis is a group of mechanisms used to prevent the outflow of blood from its vessels, and to ensure its liquidity and flow within them. The system incorporates aspects of the blood vessel wall (mainly the intima), the clotting process, together with its factors (i.e. fibrinogen) and coagulation inhibitors, as well as fibrinolysis, blood platelets and the phagocyte system. The modulation of hemostasis is associated with the pathogenesis of cardiovascular diseases, such as thrombosis. The study examines the action of three selected gasomediators, nitric oxide ((*)NO), carbon monoxide (CO) and hydrogen sulfide (H2S), on hemostasis and thrombosis, although these gasses are also involved in a multitude of other physiological functions. (*)NO inhibits blood platelet activation, relaxes blood vessels and, as a free radical chain, may rapidly react with superoxide anion (O2(-*)) in blood platelets to form peroxynitrite (ONOO( )). ONOO(-) is a reactive nitrating and nitrosating agent which induces oxidative/nitrative stress in blood platelets and plasma. Moreover, ONOO(-) changes the structure and function of fibrinogen and proteins associated with fibrinolysis. Recently, proteomic studies have provided unequivocal evidence that human platelets lack any expression of nitric oxide synthase isoforms. Other studies have demonstrated that CO and H2S, reduce blood platelet reactivity. Moreover, H2S has been reported to demonstrate anticoagulatory activity, and CO may act not only as an anticoagulant, but also aprocoagulant. This review article summarizes current knowledge of the biological roles of gasomediators (NO, CO, H2S) in hemostasis and in cardiovascular diseases. PMID- 25818242 TI - Collection and laboratory methods for dried blood spots for hemoglobin A1c and total and high-density lipoprotein cholesterol in population-based surveys. AB - BACKGROUND: The Health Measures at Home Study was a study designed to evaluate the feasibility of incorporating dried blood spots (DBS) collection into the National Health Interview Survey and to compare the proficiencies between field interviewers and health technicians in obtaining DBS. METHODS: DBS collection and venipuncture were attempted on 125 participants. The DBS were collected in the participant's home and venous blood was collected in the National Health and Nutrition Examination Survey (NHANES) mobile examination center. The DBS results were compared to venous results in the NHANES for the measurements of hemoglobin A1c (HbA1c) and total and high-density lipoprotein (HDL) cholesterol. RESULTS: Field interviewers and health technicians were able to collect the DBS for greater than 95% of participants. For DBS, health technicians and field interviewers were highly correlated for HbA1c (r=0.92) and total cholesterol (r=0.89), but not for HDL cholesterol (r=0.72). The DBS results of interviewers and health technicians compared to the venous method for HbA1c (r=0.90), but did not compare well for HDL cholesterol (r=0.64-0.66) and total cholesterol (r=0.65 0.67). CONCLUSION: DBS was comparable to venous HbA1c, but not for total and HDL cholesterol. Health technicians and field interviewers had similar performance for DBS methods, except HDL cholesterol. PMID- 25818243 TI - Coronary severity score and C-reactive protein predict major adverse cardiovascular events in patients with stable coronary artery disease (from the Taichung CAD study). AB - BACKGROUND: Whether angiographic coronary severity really predicts future major adverse cardiovascular events (MACEs) in patients with coronary artery disease (CAD) is uncertain. Few studies have compared the efficacy of SYNTAX, Gensini and Jeopardy scores in predicting MACE in stable CAD. METHODS: We collected data of MACE, including all-cause mortality, all strokes, new myocardial infarction and unplanned repeat revascularization, in subjects with stable CAD from our catheterization databank. Coronary severity was graded with SYNTAX, Gensini and Jeopardy scoring systems. RESULTS: During a median follow-up period of 42months, 39 out of the 181 subjects developed at least 1 MACE. Those with MACE had a significantly higher baseline high sensitivity C-reactive protein (hs-CRP) (p=0.025). Multivariate analysis showed that coronary severity score, hs-CRP and diabetes mellitus were significant predictors for MACE. Kaplan-Meier estimates showed a significant difference in MACE-free rates between SYNTAX binary scores (>=15 vs. <15, p=0.043), Gensini binary scores (>=36 vs. <36, p=0.048) and Jeopardy binary scores (>=4 vs. <4, p=0.001). CONCLUSION: Coronary severity score, hs-CRP and diabetes mellitus independently predicted MACE in patients with stable CAD. The Jeopardy score is simple to calculate and as effective for predicting MACE in stable CAD as the complex SYNTAX score. PMID- 25818244 TI - Factors affecting A1C in non-diabetic individuals: Review and meta-analysis. AB - We carried out a systematic review and meta-analyses of studies that evaluated the possible effects of anemia, variant hemoglobin, and uremia on A1C levels in individuals without diabetes (DM). Medline and Embase were searched for studies that measured A1C values in groups with and without iron deficiency anemia (IDA) and/or iron deficiency (ID), variant hemoglobin and/or uremia by standardized methods. The difference between A1C levels in the groups with and without interferences was obtained by using random-effects meta-analysis and the effect size was presented as absolute difference of means (95% CI). Ten studies fulfilled the inclusion criteria, providing data from 11,176 participants without DM. There were no statistically significant differences in A1C in the presence of IDA/ID, HbS, and uremia by HPLC and uremia by immunoassay [0.79% (95% IC -0.39; 1.97), -0.13% (95% IC -0.51; 0.26), 0.15% (95% CI -0.58; 0.88) and -0.19% (95% CI -0.78; 0.40), respectively]. The effects of HbAS and uremia on A1C levels are within the expected individual variation and should not affect A1C results to diagnose DM. However, the effects of IDA/ID remain inconclusive and further studies are needed to clarify the glycation mechanisms in individuals with IDA/ID without diabetes. PMID- 25818245 TI - Collision cross section measurements for biomolecules within a high-resolution Fourier transform ion cyclotron resonance cell. AB - To understand the role and function of a biomolecule in a biosystem, it is important to know both its composition and structure. Here, a mass spectrometric based approach has been proposed and applied to demonstrate that collision cross sections and high-resolution mass spectra of biomolecule ions may be obtained simultaneously by Fourier transform ion cyclotron resonance mass spectrometry. With this method, the unfolding phenomena for ubiquitin ions that possess different number of charges have been investigated, and results agree well with ion mobility measurements. In the present approach, we extend ion collision cross section measurements to lower pressures than in prior ion cyclotron resonance (ICR)-based experiments, thereby maintaining the potentially high resolution of Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS), and enabling collision cross section (CCS) measurements for high-mass biomolecules. PMID- 25818246 TI - MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults. AB - The first study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of social anxiety in autistic adults commenced in the spring of 2014. The search for psychotherapeutic options for autistic individuals is imperative considering the lack of effective conventional treatments for mental health diagnoses that are common in this population. Serious Adverse Events (SAEs) involving the administration of MDMA in clinical trials have been rare and non-life threatening. To date, MDMA has been administered to over 1133 individuals for research purposes without the occurrence of unexpected drug related SAEs that require expedited reporting per FDA regulations. Now that safety parameters for limited use of MDMA in clinical settings have been established, a case can be made to further develop MDMA-assisted therapeutic interventions that could support autistic adults in increasing social adaptability among the typically developing population. As in the case with classic hallucinogens and other psychedelic drugs, MDMA catalyzes shifts toward openness and introspection that do not require ongoing administration to achieve lasting benefits. This infrequent dosing mitigates adverse event frequency and improves the risk/benefit ratio of MDMA, which may provide a significant advantage over medications that require daily dosing. Consequently, clinicians could employ new treatment models for social anxiety or similar types of distress administering MDMA on one to several occasions within the context of a supportive and integrative psychotherapy protocol. PMID- 25818247 TI - The potential use of histone deacetylase inhibitors in the treatment of depression. AB - Numerous preclinical studies demonstrate that changes in gene expression in the brain occur in animal models of depression using exposure to stress, such as social defeat and leaned helplessness, and that repeated administration of antidepressants ameliorates these stress-induced changes in gene expression. These findings suggest that alteration in gene transcription in the central nervous system in response to stress plays an important role in the pathophysiology of depression. Recent advances in epigenetics have led to the realization that chromatin remodeling mediated by histone deacetylase (HDAC) is closely involved in the regulation of gene transcription. In this context, we first review several preclinical studies demonstrating the antidepressant-like efficacy of HDAC inhibitors. We then suggest the efficacy of HDAC inhibitors in treatment-resistant depression based on the mechanism of action of HDAC. Finally, we discuss the possibility of using HDAC inhibitors in patients with treatment resistant depression. PMID- 25818248 TI - Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease. AB - Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA) matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD. PMID- 25818249 TI - The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE /- mice. AB - OBJECTIVE: The nitroxide compound TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine N-oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with TEMPOL inhibits inflammation and atherosclerosis in apoE-/- mice fed a high fat diet (HFD). METHODS: ApoE-/- mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10 mg/g TEMPOL in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high density lipoprotein cholesterol, inflammatory cytokines and markers (interleukin 6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. RESULTS: High fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary TEMPOL decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin and a decrease in adiponectin. TEMPOL supplementation reversed these effects. When compared to HFD fed mice, TEMPOL supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. CONCLUSIONS: These data indicate that in a well-established model of obesity-associated hyperlipidaemia and atherosclerosis, TEMPOL had a significant impact on body mass, atherosclerosis, hyperlipidaemia and inflammation. TEMPOL may therefore be of value in suppressing obesity, metabolic disorders and increasing atherosclerotic plaque stability. PMID- 25818250 TI - Statin eligibility and cardiovascular risk burden assessed by coronary artery calcium score: comparing the two guidelines in a large Korean cohort. AB - OBJECTIVE: To investigate the statin eligibility and the predictabilities for cardiovascular disease between AHA/ACC and ATPIII guidelines, comparing those results to concomitant coronary artery calcium scores (CACS) in a large cohort of Korean individuals who met statin-eligibility criteria. METHODS: Among 19,920 participants in a health screening program, eligibility for statin treatment was assessed by the two guidelines. The presence and extent of coronary artery calcification (CAC) was measured by multi-detector computed tomography and compared among the various groups defined by the two guidelines. RESULTS: Applying the new ACC/AHA guideline to the health screening cohort increased the statin-eligible population from 18.7% (as defined by ATP III) to 21.7%. Statin eligible subjects as defined only by ACC/AHA guideline manifested a higher proportion of subjects with CAC compared with those meeting only ATP-III criteria even after adjustment for age and sex (47.1 vs. 33.8%, p<0.01). Statin-eligible subjects as defined by ACC/AHA guideline showed higher odds ratio for the presence of CACS>0 compared with those meeting ATP-III criteria {3.493 (3.245~3.759) vs. 2.865 (2.653~3.094)}, which was attenuated after adjusted for age and sex. CONCLUSIONS: In this large Korean cohort, more subjects would have qualified for statin initiation under the new ACC/AHA guideline as compared with the proportion recommended for statin treatment by ATP III guideline. Among statin-eligible Korean health screening subjects, the new ACC/AHA guideline identified a greater extent of atherosclerosis as assessed by CACS as compared to ATP III guideline assessment. PMID- 25818251 TI - GLP-1 analog liraglutide protects against cardiac steatosis, oxidative stress and apoptosis in streptozotocin-induced diabetic rats. AB - OBJECTIVE: Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits cardiac steatosis, oxidative stress and apoptosis in streptozotocin (STZ)-induced type 1 diabetic rats, via activation of AMPK-Sirt1 pathway. METHODS: Diabetic rats were treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Myocardial steatosis (detected by oil red O staining and myocardial triglyceride and diacylglycerol (DAG) contents assay), expression of protein kinase C (PKC), heart NAD(P)H oxidase activity, oxidative stress markers (8-hydroxy-2'-deoxyguanosine staining), apoptosis (TUNEL analysis) and genes that affect apoptosis and lipid metabolism were evaluated. RESULTS: Administration of liraglutide did not affect plasma glucose and insulin levels or body weights in STZ-induced diabetic rats, but normalized myocardial steatosis, expression of PKC, NAD(P)H oxidase activity, oxidative stress markers and apoptosis, all of which were significantly increased in diabetic hearts. Additionally, expression of genes mediating lipid uptake, synthesis and oxidation were increased in the diabetic hearts, and these increases were all reduced by liraglutide. In addition, liraglutide increased expression of Sirt1 and phosphorylated AMPK in the diabetic hearts. CONCLUSIONS: Liraglutide may have a beneficial effect on cardiac steatosis, DAG-PKC-NAD(P)H pathway, oxidative stress and apoptosis via activation of AMPK-Sirt1 pathway, independently of a glucose-lowering effect. PMID- 25818252 TI - An unusual cause of massive gastrointestinal bleeding. PMID- 25818253 TI - Helicobacter pylori and small intestinal bacterial overgrowth affect gastrointestinal symptoms in Fabry's disease. PMID- 25818254 TI - Importance of sentinel node mapping in Merkel cell carcinoma: important new evidence by Tseng et al. PMID- 25818255 TI - Social anxiety disorder in recent onset schizophrenia spectrum disorders: The relation with symptomatology, anxiety, and social rank. AB - Social anxiety disorder (SAD) represents a common comorbidity in schizophrenia, but questions remain regarding how this comorbidity is related to symptomatology and self-perceptions. Forty-two patients with recent-onset schizophrenia were evaluated for SAD, and assessed with the Positive and Negative Syndrome Scale (PANSS), as well as the Social Comparison Scale (SCS), which assessed how participants perceived themselves in relation with others (i.e., social rank). Eighteen patients met criteria for SAD (SZ+) while 24 patients did not (SZ-). Analysis of symptoms using a five-factor model of the PANSS revealed that the SZ- group had more severe symptoms than SZ+ on the Cognitive/Disorganization factor. Further analyses of individual symptoms demonstrated that the SZ- group was more affected in attention, abstract thinking, and cognitive disorganization (Cognitive/Disorganization symptoms), while the SZ+ group was more severely affected in anxiety, suspiciousness/persecution, and active social avoidance. Interestingly, severity of social anxiety symptom ratings correlated with certain PANSS symptoms only in the SZ- group. Perception of social rank, which was reduced in SZ+, displayed a trend level correlation with the positive symptoms in SZ-. Overall, the results suggest that SZ+ and SZ- may have different clinical profiles that could be important to consider when tailoring treatments for these patients. PMID- 25818256 TI - Atrial electrogram discordance during baseline vs reinduced atrial fibrillation: Potential ramifications for ablation procedures. AB - BACKGROUND: There are scant data comparing the electrogram (EGM) signal characteristics of atrial fibrillation (AF) at baseline vs electrically induced states during ablation procedures. OBJECTIVE: The purpose of this study was to use novel intracardiac signal analysis techniques to gain insights into the effects of catheter ablation and AF reinduction on AF EGMs in patients with persistent AF. METHODS: We collected left atrial EGMs in patients undergoing first ablation for persistent AF at 3 time intervals: (1) AF at baseline; (2) AF after pulmonary vein isolation (PVI); and (3) AF after post-PVI cardioversion and subsequent reinduction. We analyzed 2 EGM spectral characteristics: (1) dominant frequency and (2) spectral complexity; and 2 EGM morphologic characteristics: (1) morphology variation and (2) pattern repetitiveness. RESULTS: There were no differences in AF dominant frequency, dominant amplitude, spectral complexity, or metrics of EGM morphology or repetitiveness at baseline vs after PVI. However, dominant frequency, dominant amplitude, and spectral complexity differed significantly after direct current cardioversion and reinduction of AF. CONCLUSION: The frequency, spectral complexity, and local EGM morphologies of AF do not significantly change over the course of a PVI procedure in patients with persistent AF. However, reinduction of AF after direct current cardioversion results in different dominant frequency and spectral complexity, consistent with a change in the characteristics of the perpetuating source(s) of the newly induced AF. These data suggest that AF properties can vary significantly between baseline and reinduced AF, with potential clinical ramifications for outcomes of catheter ablation procedures. PMID- 25818257 TI - Secondary thermophilic microaerobic treatment in the anaerobic digestion of corn straw. AB - Thermophilic microaerobic pretreatment (TMP) has been proved to be an alternative pretreatment method during anaerobic digestion (AD) of corn straw. In this study, in order to improve the fermentation efficiency during late AD stage, improve the methane yield and volatile solid (VS) removal efficiency, a secondary thermophilic microaerobic treatment (STMT) was applied in the late AD stage of corn straw. Results showed STMT obviously improved the fermentation efficiency, methane yield and VS removal efficiency. The maximum methane yield and maximum VS removal efficiency were simultaneously obtained when the oxygen loads during STMT was 10 ml/g VS (VS of residual substrate). The maximum methane yield was 380.6 ml/g VS(substrate), which was 28.45% and 10.61% higher than those of untreated and once thermophilic microaerobic pretreated samples, respectively. The maximum VS removal efficiency was 81.85%, which was 29.43% and 17.23% higher than those of untreated and once thermophilic microaerobic pretreated samples, respectively. PMID- 25818258 TI - Butanol production from alkali-pretreated rice straw by co-culture of Clostridium thermocellum and Clostridium saccharoperbutylacetonicum. AB - The co-culture of cellulolytic Clostridium thermocellum NBRC 103400 and butanol producing Clostridium saccharoperbutylacetonicum strain N1-4 produced 5.5 g/L of butanol from 40 g/L of delignified rice straw pretreated with 1% (wt/vol) NaOH. The addition of cellulase (100 U/g biomass) in a co-culture system significantly increased butanol production to 6.9 g/L using 40 g/L of delignified rice straw. Compared to the control, this increase in butanol production was attributed to the enhancement of exoglucanase activity on lignocellulose degradation in experimental samples. The results showed that the co-culture system in conjunction with enhanced exoglucanase activity resulted in cost-effective butanol production from delignified rice straw. PMID- 25818259 TI - Identification and metabolomic analysis of chemical modulators for lipid accumulation in Crypthecodinium cohnii. AB - In the study, fourteen chemical modulators from five groups (i.e., auxin, gibberellin, cytokinin, signal transducer and amine) were evaluated for their effects on lipid accumulation in Crypthecodinium cohnii. The results showed that naphthoxyacetic acid (BNOA), 2-chlorodracylicacid, salicylic acid (SA), abscisic acid (ABA) and ethanolamine (ETA), increased lipid accumulation in C. cohnii by 10.00-18.78%. In addition, the combined uses of the above chemicals showed that two combinations, 1.0mg/L SA & 152.7 mg/L ETA and 4.0mg/L BNOA & 152.7 mg/L ETA, increased lipid accumulation by 22.45% and 20.54%, respectively. Moreover, a targeted metabolomic approach was employed to decipher the possible mechanisms responsible for the increased lipid accumulation, and the results showed that the enhanced metabolism in glycolysis and TCA cycle as well as the decreased metabolism in PPP pathway could be important for the stimulatory roles of BNOA & ETA and SA & ETA on lipid accumulation in C. cohnii. PMID- 25818260 TI - Effect of additives on adsorption and desorption behavior of xylanase on acid insoluble lignin from corn stover and wheat straw. AB - The competitive adsorption between cellulases and additives on lignin in the hydrolysis of lignocelluloses has been confirmed, whereas the effect of additives on the interaction between xylanase and lignin is not clear. In this work, the effects of additives, poly(ethylene glycol) 2000, poly(ethylene glycol) 6000, Tween 20, and Tween 80, on the xylanase adsorption/desorption onto/from acid insoluble lignin from corn stover (CS-lignin) and wheat straw (WS-lignin) were investigated. The results indicated that the additives could adsorb onto isolated lignin and reduce the xylanase adsorption onto lignin. Compared to CS-lignin, more additives could adsorb onto WS-lignin, making less xylanase adsorbed onto WS lignin. In addition, the additives could enhance desorption of xylanase from lignin, which might be due to the competitive adsorption between xylanase and additives on lignin. The released xylanase from lignin still exhibited hydrolytic capacity in the hydrolysis of isolated xylan and xylan in corn stover. PMID- 25818261 TI - Response to the letter to the editor from Dr. Kawada, "Characteristics of patients with hypersomnia by actigraphy". PMID- 25818262 TI - Characteristics of patients with hypersomnia by actigraphy. PMID- 25818263 TI - A rheumatology perspective on cutaneous vasculitis: assessment and investigation for the non-rheumatologist. AB - Vasculitis, by definition, is inflammation of the vasculature. This inflammation can result in either vessel wall destruction causing aneurysm or rupture, or stenosis causing ischaemia or necrosis. This autoimmune response does not always have a clear cause. Vasculitis is a heterogeneous group of disorders that has been categorised not only by primary and secondary causes, but also by the size of the affected vessel. The secondary causes that can trigger vasculitis include infection (particularly hepatitis B and C and haemorrhagic fever);cancer, autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's; drugs or allergic reactions. As vasculitis can affect any part of the vasculature, it can result in a wide range of signs and symptoms. However, one of the most common presentations of vasculitis is a rash, due to small vessel vasculitis, which is most common. A vasculitic rash has certain characteristics that are easily identifiable and differentiate it from other rashes. This is a review from a rheumatologist's perspective of how to identify vasculitis skin changes. If cutaneous vasculitis is suspected, this article identifies other areas of skin that can be affected that need identification, in addition to what to screen for in the history and other differential diagnoses to consider. Subsequently, the article addresses the key investigations to request and a brief overview of the treatment principles for primary vasculitis. PMID- 25818264 TI - Analysis of the clinical safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for adults with Peyronie's disease (PD). AB - OBJECTIVE: To examine the safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for the treatment of Peyronie's disease (PD), using a pooled safety analysis of patients who received at least one dose of CCH in any of six clinical studies. PATIENTS AND METHODS: Patients from six clinical studies, including three randomised, double-blind, placebo-controlled studies and three open-label safety and efficacy studies, were included if they had received at least one dose of 0.58 mg CCH. Adverse events (AEs), including treatment emergent AEs, treatment-related AEs, and serious AEs (SAEs), were characterised. Potential immunogenicity-related AEs were evaluated through examination of increased anti-AUX-I and anti-AUX-II antibody levels, AEs, and reported terms possibly associated with immunological or hypersensitivity events. RESULTS: Overall, 85.8% of 1 044 pooled patients reported at least one treatment-related AE. The most frequently reported (>=25.0% of patients) treatment-related AEs included penile haematoma (82.7% had the verbatim 'penile bruising'), penile pain, and penile swelling. Most patients (75.2%) had mild- or moderate-severity treatment-related AEs, and 14.2% had no treatment-related AEs. Nine patients (0.9%) had treatment-related SAEs: five with penile haematoma and four with corporal rupture. There was no association between AEs and anti-AUX-I or anti-AUX II antibody levels across treatment cycles, and no systemic hypersensitivity reactions occurred. CONCLUSIONS: This pooled safety analysis shows that although non-serious and serious treatment-related AEs can occur after CCH treatment for PD, most were non-serious and the SAEs were manageable. Providers should be prepared to manage possible SAEs. PMID- 25818265 TI - New cellular mechanisms of gap junction degradation and recycling. AB - BACKGROUND INFORMATION: Connexins (Cxs), the constitutive proteins of gap junctions, are key actors of many physiological processes. Therefore, alterations of Cx expression and degradation lead to the development of physiopathological disorders. Because of the formation of a double membrane vesicle termed annular gap junction (AGJ), gap junction degradation is a unique physiological process for which many cellular aspects remain unclear. RESULTS: By using a combination of time-lapse fluorescence microscopy and high-resolution transmission electron microscopy, we evidenced new specific cellular events concerning gap junction degradation and recycling. Indeed, by time lapse video microscopy we demonstrated, for the first time to our knowledge, that an entire AGJ can be fully recycled back to the plasma membrane. Moreover, we dissected the degradative processes of gap junction by electron microscopy approaches. Interestingly, in addition to canonical autophagy and heterophagy pathways, previously described, we discovered that both pathways could sometimes intermingle. Strikingly, our results also highlighted a new lysosome-based autophagy pathway that could play a pivotal role in common autophagy degradation. CONCLUSIONS: The present investigation reveals that AGJ degradation is a more complex process that it was previously thought. First, a complete recycling of the gap junction plaque after its internalisation could occur. Second, the degradation of this peculiar double membrane structure is possible through autophagy, heterophagy, hetero-autophagy or by lysosomal-based autophagy. Altogether, this work underlines novel aspects of gap junction degradation that could be extended to other cell biology processes. PMID- 25818266 TI - Management of resistant hypertension: aldosterone antagonists or intensification of diuretic therapy? AB - OBJECTIVE: No consensus has been established as to which is the best fourth-line agent in patients with resistant hypertension (RHT). The aim of the present study was to assess the effect of intensifying diuretic treatment with loop diuretic (furosemide) or aldosterone antagonist (spironolactone) on blood pressure (BP) control in RHT. METHODS: The study population comprised 30 patients with RHT who were divided into two treatment arms. Fifteen patients received furosemide 40 mg/day and 15 patients received spironolactone 25 mg/day. Ambulatory BP monitoring was performed baseline, 3 and 6 months. RESULTS: Baseline BP was 162 +/- 8/90 +/- 6 mmHg, 70% men, mean age 63.3 +/- 9.1 years 56.1% diabetic and estimated glomerular filtration rate (eGFR) 55.8 +/- 16.5 mL/min per 1.73 m(2) . There were no significant differences between groups at baseline in age, gender, percentage diabetics, eGFR, BP, number of antihypertensive drugs, or aldosterone levels. At 6 months, systolic BP decreased by 24 +/- 9.2 mmHg (from 163.6 +/- 8.6 to 139.6 +/- 8.1 mmHg) in the spironolactone group, compared with 13.8 +/- 2.8 mmHg (from 162 +/- 7.9 to 148 +/- 6.4 mmHg) in the furosemide group (P < 0.01). Diastolic BP fell 11 +/- 8.1 mmHg in the spironolactone group compared with 5.2 +/- 2.2 mmHg in the furosemide group (P < 0.01). Significant reduction in urinary albumin creatinine ratio (from 173 +/- 268 to 14 +/- 24 mg/g, P < 0.01) was observed in the spironolactone group at 6 months. Multiple regression analysis showed that only treatment with spironolactone was associated with control of BP < 140/90 mmHg at 6 months. No severe adverse events were recorded. CONCLUSION: Spironolactone is more effective than furosemide for control of BP in RHT patients, with a positive added effect on albuminuria. Spironolactone is safe in patients with mild kidney impairment, although serum potassium should be closely monitored, especially in diabetics. PMID- 25818267 TI - The effect of occupational noise exposure on tinnitus and sound-induced auditory fatigue among obstetrics personnel: a cross-sectional study. AB - OBJECTIVE: There is a lack of research on effects of occupational noise exposure in traditionally female-dominated workplaces. Therefore, the aim of this study was to assess risk of noise-induced hearing-related symptoms among obstetrics personnel. DESIGN: A cross-sectional study was performed at an obstetric ward in Sweden including a questionnaire among all employees and sound level measurements in 61 work shifts at the same ward. PARTICIPANTS: 115 female employees responded to a questionnaire (72% of all 160 employees invited). MAIN OUTCOME MEASURES: Self-reported hearing-related symptoms in relation to calculated occupational noise exposure dose and measured sound levels. RESULTS: Sound levels exceeded the 80 dB LAeq limit for protection of hearing in 46% of the measured work shifts. One or more hearing-related symptoms were reported by 55% of the personnel. In logistic regression models, a significant association was found between occupational noise exposure dose and tinnitus (OR=1.04, 95% CI 1.00 to 1.09) and sound-induced auditory fatigue (OR=1.04, 95% CI 1.00 to 1.07). Work-related stress and noise annoyance at work were reported by almost half of the personnel. Sound-induced auditory fatigue was associated with work-related stress and noise annoyance at work, although stress slightly missed significance in a multivariable model. No significant interactions were found. CONCLUSIONS: This study presents new results showing that obstetrics personnel are at risk of noise induced hearing-related symptoms. Current exposure levels at the workplace are high and occupational noise exposure dose has significant effects on tinnitus and sound-induced auditory fatigue among the personnel. These results indicate that preventative action regarding noise exposure is required in obstetrics care and that risk assessments may be needed in previously unstudied non-industrial communication-intense sound environments. PMID- 25818268 TI - The difficulty of professional continuation among female doctors in Japan: a qualitative study of alumnae of 13 medical schools in Japan. AB - OBJECTIVES: To investigate the difficulties Japanese female doctors face in continuing professional practice. DESIGN: A qualitative study using the Kawakita Jiro method. SETTING: A survey conducted in 2011 of 13 private Japanese medical school alumni associations. PARTICIPANTS: 359 female doctors. PRIMARY OUTCOME MEASURES: Barriers of balancing work and gender role. RESULTS: The female doctors reported that professional practice was a struggle with long working hours due to a current shortage of doctors in Japan. There was also a severe shortage of childcare facilities in the workplace. Some women appeared to have low confidence in balancing the physician's job and personal life, resulting in low levels of professional pursuit. There appeared to be two types of stereotypical gender roles, including one expected from society, stating that "child rearing is a woman's job", and the other perceived by the women themselves, that some women had a very strong desire to raise their own children. Male doctors and some female doctors who were single or older were perceived to be less enthusiastic about supporting women who worked while raising children because these coworkers feared that they would have to perform additional work as a result of the women taking long periods of leave. CONCLUSIONS: Important factors identified for promoting the continuation of professional practice among female doctors in Japan were the need to improve working conditions, including cutting back on long working hours, a solution to the shortage of nurseries, a need for the introduction of educational interventions to clarify professional responsibilities, and redefinition of the gender division of labour for male and female doctors. In addition, we identified a need to modernise current employment practices by introducing temporary posts to cover maternity leave and introducing flexible working hours during specialist training, thus supporting and encouraging more women to continue their medical careers. PMID- 25818269 TI - Neuropsychiatric and cardiometabolic comorbidities in patients with previously diagnosed Cushing's disease: a longitudinal observational study. AB - INTRODUCTION: Only few studies have systematically investigated neuropsychiatric aspects in patients with Cushing's disease (CD). Pain syndromes have been described in patients with pituitary adenomas, but so far no systematical investigation has been conducted in patients with CD. Additionally, CD has an association with cardiometabolic comorbidities which ultimately leads to increased morbidity and mortality. Long-term treatment of the hypercortisolic state cannot prevent the persistence of an unfavourable cardiometabolic risk profile. Finally, chronic hypercortisolism is known to impact the health-related quality of life (HRQoL). We aim to systematically investigate the neuropsychiatric and cardiometabolic comorbidities, as well as assess the HRQoL, in patients with previously diagnosed CD in a longitudinal fashion. METHODS AND ANALYSIS: In this longitudinal study, we will assess 20 patients with CD displaying biochemical control 24 months after recruitment in the initial cross sectional study (n=80). This will be a mixed cohort including patients after surgical, after radiation therapy and/or under current medical treatment for CD. Primary outcomes include changes in mean urinary free cortisol and changes in specific pain patterns. Secondary/exploratory neuropsychiatric domains include depression, anxiety, personality, sleep, body image and quality of life. Secondary/exploratory cardiometabolic domains include anthropometric parameters, cardiometabolic risk biomarkers and insulin resistance. Additional domains will be investigated if warranted by clinical indication. Safety assessment under medical therapy will include liver enzymes, ECG abnormalities and hyperglycaemia. ETHICS AND DISSEMINATION: Risk of damage from study-conditioned measures is very small and considered ethically justified. Dual-energy X-ray absorptiometry may call for detailed fracture risk assessment. However, the radiation dose is very small and only administered on clinical indication; therefore, it is considered ethically justified. This protocol has been approved by the local medical ethics committee. PMID- 25818270 TI - The AIDS epidemic and economic input impact factors in Chongqing, China, from 2006 to 2012: a spatial-temporal analysis. AB - OBJECTIVE: To analyse the spatial-temporal clustering of the HIV/AIDS epidemic in Chongqing and to explore its association with the economic indices of AIDS prevention and treatment. METHODS: Data on the HIV/AIDS epidemic and economic indices of AIDS prevention and treatment were obtained from the annual reports of the Chongqing Municipal Center for Disease Control for 2006-2012. Spatial clustering analysis, temporal-spatial clustering analysis, and spatial regression were used to conduct statistical analysis. RESULTS: The annual average new HIV infection rate, incidence rate for new AIDS cases, and rate of people living with HIV in Chongqing were 5.97, 2.42 and 28.12 per 100,000, respectively, for 2006 2012. The HIV/AIDS epidemic showed a non-random spatial distribution (Moran's I>=0.310; p<0.05). The epidemic hotspots were distributed in the 15 mid-western counties. The most likely clusters were primarily located in the central region and southwest of Chongqing and occurred in 2010-2012. The regression coefficients of the total amount of special funds allocated to AIDS and to the public awareness unit for the numbers of new HIV cases, new AIDS cases, and people living with HIV were 0.775, 0.976 and 0.816, and -0.188, -0.259 and -0.215 (p<0.002), respectively. CONCLUSIONS: The Chongqing HIV/AIDS epidemic showed temporal-spatial clustering and was mainly clustered in the mid-western and south western counties, showing an upward trend over time. The amount of special funds dedicated to AIDS and to the public awareness unit showed positive and negative relationships with HIV/AIDS spatial clustering, respectively. PMID- 25818271 TI - Risk factors for postneonatal, infant, child and under-5 mortality in Nigeria: a pooled cross-sectional analysis. AB - OBJECTIVES: To identify common factors associated with post-neonatal, infant, child and under-5 mortality in Nigeria. DESIGN, SETTING AND PARTICIPANTS: A cross sectional data of three Nigeria Demographic and Health Surveys (NDHS) for the years 2003, 2008 and 2013 were used. A multistage, stratified, cluster random sampling method was used to gather information on 63,844 singleton live-born infants of the most recent birth of a mother within a 5-year period before each survey was examined using cox regression models. MAIN OUTCOME MEASURES: Postneonatal mortality (death between 1 and 11 months), infant mortality (death between birth and 11 months), child mortality (death between 12 and 59 months) and under-5 mortality (death between birth and 59 months). RESULTS: Multivariable analyses indicated that children born to mothers with no formal education was significantly associated with mortality across all four age ranges (adjusted HR=1.30, 95% CI 1.01 to 1.66 for postneonatal; HR=1.38, 95% CI 1.11 to 1.84 for infant; HR=2.13, 95% CI 1.56 to 2.89 for child; HR=1.19, 95% CI 1.02 to 1.41 for under-5). Other significant factors included living in rural areas (HR=1.48, 95% CI 1.16 to 1.89 for postneonatal; HR=1.23, 95% CI 1.03 to 1.47 for infant; HR=1.52, 95% CI 1.16 to 1.99 for child; HR=1.29, 95% CI 1.11 to 1.50 for under 5), and poor households (HR=2.47, 95% CI 1.76 to 3.47 for postneonatal; HR=1.40, 95% CI 1.10 to 1.78 for infant; HR=1.72, 95% CI 1.19 to 2.49 for child; HR=1.43, 95% CI 1.17 to 1.76 for under-5). CONCLUSIONS: This study found that no formal education, poor households and living in rural areas increased the risk of postneonatal, infant, child and under-5 mortality among Nigerian children. Community-based interventions for reducing under-5 deaths are needed and should target children born to mothers of low socioeconomic status. PMID- 25818273 TI - Health technology assessment in Switzerland: a descriptive analysis of "Coverage with Evidence Development" decisions from 1996 to 2013. AB - OBJECTIVES: To identify factors associated with the decisions of the Federal Department of Home Affairs concerning coverage with evidence development (CED) for contested novel medical technologies in Switzerland. DESIGN: Quantitative, retrospective, descriptive analysis of publicly available material and prospective, structured, qualitative interviews with key stakeholders. SETTING: All 152 controversial medical services decided on by the Federal Commission on Health Insurance Benefits within the framework of the new federal law on health insurance in Switzerland from 1997 to 2013, with focus on 33 technologies assigned initially to CED and 33 to evidence development without coverage. MAIN OUTCOME MEASURES: Factors associated with numbers and type of contested services assigned to CED per year, the duration and final outcome of the evaluations and perceptions of key stakeholders. RESULTS: The rate of CED decisions (82 total; median 1.5/year; range 0-9/year), the time to final decision (4.5 years median; 0.75 to +11 years) and the probability of a final 'yes' varied over time. In logistic regression models, the change of office of the commission provided the best explanation for the observed outcomes. Good intentions but absence of scientific criteria for decisions were reported as major comments by the stakeholders. CONCLUSIONS: The introduction of CED enabled access to some promising technologies early in their life cycle, and might have triggered establishment of registries and research. Impact on patients' outcome and costs remain unknown. The primary association of institutional changes with measured end points illustrates the need for evaluation of the current health technology assessment (HTA) system. PMID- 25818272 TI - Assessment of PaO2/FiO2 for stratification of patients with moderate and severe acute respiratory distress syndrome. AB - OBJECTIVES: A recent update of the definition of acute respiratory distress syndrome (ARDS) proposed an empirical classification based on ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) at ARDS onset. Since the proposal did not mandate PaO2/FiO2 calculation under standardised ventilator settings (SVS), we hypothesised that a stratification based on baseline PaO2/FiOv would not provide accurate assessment of lung injury severity. DESIGN: A prospective, multicentre, observational study. SETTING: A network of teaching hospitals. PARTICIPANTS: 478 patients with eligible criteria for moderate (100300). PRIMARY AND SECONDARY OUTCOMES: Group severity and hospital mortality. RESULTS: At ARDS onset, 173 patients had a PaO2/FiO2<=100 but only 38.7% met criteria for severe ARDS at 24 h under SVS. When assessed under SVS, 61.3% of patients with severe ARDS were reclassified as moderate, mild and non-ARDS, while lung severity and hospital mortality changed markedly with every PaO2/FiO2 category (p<0.000001). Our model of risk stratification outperformed the stratification using baseline PaO2/FiO2 and non-standardised PaO2/FiO2 at 24 h, when analysed by the predictive receiver operating characteristic (ROC) curve: area under the ROC curve for stratification at baseline was 0.583 (95% CI 0.525 to 0.636), 0.605 (95% CI 0.552 to 0.658) at 24 h without SVS and 0.693 (95% CI 0.645 to 0.742) at 24 h under SVS (p<0.000001). CONCLUSIONS: Our findings support the need for patient assessment under SVS at 24 h after ARDS onset to assess disease severity, and have implications for the diagnosis and management of ARDS patients. TRIAL REGISTRATION NUMBERS: NCT00435110 and NCT00736892. PMID- 25818274 TI - Body mass, cardiovascular risk and metabolic characteristics of young persons presenting for mental healthcare in Sydney, Australia. AB - OBJECTIVES: To determine the body mass, cardiovascular and metabolic characteristics of young people presenting for mental healthcare. DESIGN: Cross sectional assessments of body mass, cardiovascular and metabolic risk factors. SETTING: Two primary-care based sites in Sydney, Australia for young people in the early stages of mental disorders. PARTICIPANTS: A clinical sample of young people (12-30 years) with mental health problems. OUTCOME MEASURES: Daily smoking rates, body mass index (BMI), blood glucose and lipids, blood pressure (BP) and pulse rate. RESULTS: Of 1005 young people who had their BMI determined (62% female; 19.0+/-3.5 years), three quarters (739/1005) also had BP recordings and one-third (298/1005) had blood sampling. Clinically, 775 were assigned to one of three diagnostic categories (anxious-depression: n=541; mania-fatigue, n=104; developmental-psychotic n=130). The profile of BMI categories approximated that of the comparable segments of the Australian population. Older age, lower levels of social functioning and higher systolic BP were all associated with high BMI. In a subset (n=129), current use of any psychotropic medication was associated (p<0.05) with increased BMI. Almost one-third of cases were current daily smokers (compared to population rate of 11%). Males had a higher proportion of raised glucose and high-density lipoprotein (HDL) compared to females (9.3% and 34.1% vs 2.1% and 5.9%, respectively). Overall, there was no relationship between BMI and fasting glucose but significant relationships with triglycerides and HDL were noted. Furthermore, there were no significant relationships between diagnostic subgroup and metabolic profiles. CONCLUSIONS: Daily smoking rates are increased among young people presenting for mental healthcare. However, these young people do not demonstrate adverse cardiometabolic profiles. The high levels of smoking, and association of BMI with adverse social circumstances, suggest that risk factors for chronic disease are already present and likely to be compounded by medication and social disadvantage. PMID- 25818275 TI - Changes in HIV and syphilis prevalence among female sex workers from three serial cross-sectional surveys in Karnataka state, South India. AB - OBJECTIVES: This paper examined trends over time in condom use, and the prevalences of HIV and syphilis, among female sex workers (FSWs) in South India. DESIGN: Data from three rounds of cross-sectional surveys were analysed, with HIV and high-titre syphilis prevalence as outcome variables. Multivariable analysis was applied to examine changes in prevalence over time. SETTING: Five districts in Karnataka state, India. PARTICIPANTS: 7015 FSWs were interviewed over three rounds of surveys (round 1=2277; round 2=2387 and round 3=2351). Women who reported selling sex in exchange for money or gifts in the past month, and aged between 18 and 49 years, were included. INTERVENTIONS: The surveys were conducted to monitor a targeted HIV prevention programme during 2004-2012. The main interventions included peer-led community outreach, services for the treatment and prevention of sexually transmitted infections, and empowering FSWs through community mobilisation. RESULTS: HIV prevalence declined significantly from rounds 1 to 3, from 19.6% to 10.8% (adjusted OR (AOR)=0.48, p<0.001); high-titre syphilis prevalence declined from 5.9% to 2.4% (AOR=0.50, p<0.001). Reductions were observed in most substrata of FSWs, although reductions among new sex workers, and those soliciting clients using mobile phones or from home, were not statistically significant. Condom use 'always' with occasional clients increased from 73% to 91% (AOR=1.9, p<0.001), with repeat clients from 52% to 86% (AOR=5.0, p<0.001) and with regular partners from 12% to 30% (AOR=4.2, p<0.001). Increased condom use was associated with exposure to the programme. However, condom use with regular partners remained low. CONCLUSIONS: The prevalences of HIV infection and high-titre syphilis among FSWs have steadily declined with increased condom use. Further reductions in prevalence will require intensification of prevention efforts for new FSWs and those soliciting clients using mobile phones or from home, as well as increasing condom use in the context of regular partnerships. PMID- 25818276 TI - The Australian primary healthcare experiment: a national survey of Medicare Locals. AB - OBJECTIVE: The objectives of this study are to evaluate the development and implementation of Medicare Locals as new primary care organisations and consider the implications of these findings for the wider challenge of strengthening primary healthcare in Australia and internationally. DESIGN: National survey of Medicare Locals which involved the use of content analysis and a descriptive survey tool. SETTING: 61 Medicare Locals in Australia. PARTICIPANTS: The survey was distributed electronically to all 61 Medicare Local Chief Executive Officers (CEOs) between October and December 2013. MAIN OUTCOME MEASURES: The research was interested in exploring the following areas; the form and function of Medicare Locals; the confidence and capacity of Medicare Locals to perform against their objectives around population planning and system integration; their ability to engage relevant stakeholder groups; and the barriers and facilitators to reform. RESULTS: A total of 43 (70%) of Medicare Locals completed the survey with representation from six of the eight Australian states and Territories. Results suggest differences in the form and function of the Medicare Local organisations and considerable diversity in the implementation of Medicare Local organisations across Australia. This diversity and lack of guidance from government impacted on the overall success of the reform. Other barriers to reform included difficulties in stakeholder relationships and limited incentives (financial and other) to drive and influence change. CONCLUSIONS: Findings from this study produce important insights for primary care reform in Australia; and internationally it adds to the growing body of knowledge around primary care reform. PMID- 25818277 TI - An investigation into the therapeutic effects of statins with metformin on polycystic ovary syndrome: a meta-analysis of randomised controlled trials. AB - OBJECTIVES: To investigate the therapeutic effects of statins with metformin on polycystic ovary syndrome (PCOS). SETTINGS: Endocrinology department. PARTICIPANTS: MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials were searched until October 2014. Studies comparing statins and placebo, as well as the combination of statins and metformin and metformin alone, were included in the analysis. INTERVENTIONS: Data were independently extracted by two researchers; any convergence was resolved by a third reviewer. PRIMARY AND SECONDARY OUTCOME MEASURES: The following properties were extracted from the qualified trials to identify the effects of statins: clinical variables, metabolic characteristics, hormone outcomes, sign of inflammation, glucose parameters and insulin outcomes. RESULTS: Data from four trials comparing statin and metformin with metformin alone were analysed. The combination of statins and metformin decreases the levels of C reactive protein (standardised mean difference (SMD) -0.91; 95% CI -1.81 to -0.02; p=0.046), triglyceride (SMD -1.37; 95% CI -2.46 to -0.28; p=0.014), total cholesterol (SMD -1.28; 95% CI -1.59 to 0.97; p=0.000) and low-density lipoprotein (LDL) cholesterol (SMD -0.74; 95% CI 1.03 to -0.44; p=0.000). However, the combined therapy fails to reduce fasting insulin (SMD -0.92; 95% CI -2.07 to 0.24; p=0.120), homeostasis model assessment of insulin resistance (SMD -1.15; 95% CI -3.36 to 1.06; p=0.309) and total testosterone (SMD -1.12; 95% CI -2.29 to 0.05; p=0.061). Analysis of the five trials comparing statin with placebo shows that statin monotherapy reduces LDL cholesterol, triglyceride and total cholesterol. CONCLUSIONS: Combined statin and metformin therapy can improve lipid and inflammation parameters, but cannot effectively improve insulin sensitivity and reduce hyperandrogenism in women with PCOS. A large-scale randomised controlled study must be conducted to ascertain the long-term effects of the therapy. PMID- 25818278 TI - Exploring the effect of space and place on response to exercise therapy for knee and hip pain--a protocol for a double-blind randomised controlled clinical trial: the CONEX trial. AB - INTRODUCTION: Context effects are described as effects of a given treatment, not directly caused by the treatment itself, but rather caused by the context in which treatment is delivered. Exercise is a recommended core treatment in clinical guidelines for musculoskeletal disorders. Although moderately effective overall, variation is seen in size of response to exercise across randomised controlled trial (RCT) studies. Part of this variation may be related to the fact that exercise interventions are performed in different physical environments, which may affect participants differently. The study aims to investigate the effect of exercising in a contextually enhanced physical environment for 8 weeks in people with knee or hip pain. METHODS AND ANALYSIS: The study is a double blind RCT. Eligible participants are 35 years or older with persisting knee and/or hip pain for 3 months. Participants are randomised to one of three groups: (1) exercise in a contextually enhanced environment, (2) exercise in a standard environment and (3) waiting list. The contextually enhanced environment is located in a newly built facility, has large windows providing abundant daylight and overlooks a recreational park. The standard environment is in a basement, has artificial lighting and is marked by years of use; that is, resembling many clinical environments. The primary outcome is the participant's global perceived effect rated on a seven-point Likert scale after 8 weeks exercise. Patient reported and objective secondary outcomes are included. ETHICS AND DISSEMINATION: The Regional Scientific Ethical Committee for Southern Denmark has approved the study. Study findings will be disseminated in peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02043613. PMID- 25818279 TI - Cryogenic-temperature electron microscopy direct imaging of carbon nanotubes and graphene solutions in superacids. AB - Cryogenic electron microscopy (cryo-EM) is a powerful tool for imaging liquid and semiliquid systems. While cryogenic transmission electron microscopy (cryo-TEM) is a standard technique in many fields, cryogenic scanning electron microscopy (cryo-SEM) is still not that widely used and is far less developed. The vast majority of systems under investigation by cryo-EM involve either water or organic components. In this paper, we introduce the use of novel cryo-TEM and cryo-SEM specimen preparation and imaging methodologies, suitable for highly acidic and very reactive systems. Both preserve the native nanostructure in the system, while not harming the expensive equipment or the user. We present examples of direct imaging of single-walled, multiwalled carbon nanotubes and graphene, dissolved in chlorosulfonic acid and oleum. Moreover, we demonstrate the ability of these new cryo-TEM and cryo-SEM methodologies to follow phase transitions in carbon nanotube (CNT)/superacid systems, starting from dilute solutions up to the concentrated nematic liquid-crystalline CNT phases, used as the 'dope' for all-carbon-fibre spinning. Originally developed for direct imaging of CNTs and graphene dissolution and self-assembly in superacids, these methodologies can be implemented for a variety of highly acidic systems, paving a way for a new field of nonaqueous cryogenic electron microscopy. PMID- 25818280 TI - Fighting fire with fire: a patent for the combined application of oncolytic herpes viruses and antiangiogenic agents in the battle against human cancers. AB - Specific elimination of tumor cells by replication-competent viral vectors is mediated through active viral replication, spread in tumor tissue and direct cytopathic effects. In addition, immune responses are induced against virally infected tumor cells. Recently, oncolytic vectors were constructed with mutations in neurovirulence genes or DNA synthesis genes. Viral replication should only be restricted to malignant cells to prevent severe viral disease. These constructed vectors terminate cells by mechanisms different from standard anti-cancer therapies; they offer another treatment modality which can be used in combination with chemotherapy, radiotherapy and gene therapies with additive or synergistic effects. Combination therapies are usually necessary to control tumorigenic diseases. Inhibiting angiogenesis represents another new field in current anticancer treatment development. Combining an oncolytic virus with antiangiogenesis is able to potentiate both treatment effects compared to each treatment modality alone in both primary and advanced disease. This combination might be beneficial for cancer patients in the future. We have also outlined some relevant patents. PMID- 25818281 TI - Cervical lymphadenopathy secondary to rhabdomyosarcoma presenting as Horner syndrome in an infant. AB - A 4-week-old boy with left ptosis, anisocoria, and a mass on his left hand was diagnosed with Horner syndrome. The diagnosis precipitated a work-up for a possible malignant etiology. Magnetic resonance imaging demonstrated enlarged left cervical and axillary lymph nodes. A biopsy of the hand lesion confirmed embryonal rhabdomyosarcoma, but a biopsy of the axillary lymph node was negative. Mechanical pressure by noncancerous enlarged lymph nodes is hypothesized to cause the Horner syndrome. PMID- 25818282 TI - Intraocular pressure control with echothiophate iodide in children's eyes with glaucoma after cataract extraction. AB - PURPOSE: To report the intraocular pressure (IOP)-lowering ability and side effect profile of echothiophate iodide (EI) in the control of glaucoma in aphakic and pseudophakic eyes of children. METHODS: The medical records of all aphakic and pseudophakic children treated with EI for IOP lowering after developing glaucoma were retrospectively reviewed. RESULTS: A total of 32 eyes of 21 children were included. Mean age at cataract removal was 3.9 months (range, 5 days-2.7 years). Mean age of glaucoma diagnosis was 3.2 years (range, 40 days-12 years). Mean duration from cataract removal and diagnosis of glaucoma was 2.9 years (range, 16 days-12 years). EI reduced IOP in 31 of 32 eyes. Mean baseline IOP (29.1 +/- 5.3 mm Hg) dropped to 19.6 +/- 6.7 mm Hg. Six eyes had IOP spikes that could not be controlled with other medications when commercial unavailability led to discontinuation of EI. Average duration of use was 3.5 years. Mean final IOP on an average of 2.2 medications was 16.9 +/- 5.1 mm Hg 7.9 years following initial glaucoma diagnosis. Four eyes required surgery for uncontrolled IOP. Side-effects included transient redness (3/32 eyes), not necessitating discontinuation of EI. CONCLUSIONS: EI lowered IOP to within an acceptable range with no significant adverse events. In several patients it was the only pharmacologic agent that was successful. PMID- 25818283 TI - Pediatric eye injuries due to nonpowder guns in the United States, 2002-2012. AB - PURPOSE: To identify epidemiologic trends in nonpowder gun-related pediatric eye injuries and to determine factors associated with severe injury requiring hospital admission. METHODS: US emergency department data on pediatric eye injuries between 2002 and 2012 were reviewed using the National Electronic Injury Surveillance System. Literature review was conducted to determine trends in visual outcomes after treatment and use of eye protection. RESULTS: In 2012 roughly 3,161 children were treated in US emergency departments for nonpowder gun related eye injuries. Since 2010 rates of severe nonpowder gun pediatric eye injury have increased by over 500% (P = 0.039). Specifically, while rates of hospital admission due to paintball gun eye injury have dropped precipitously (P = 0.0077), rates of admissions for air gun eye injuries have increased by over 600% since 2010 (P = 0.033). Children sustaining eye injury due to air guns are more likely to be diagnosed and admitted with foreign body or ocular puncture injury. Roughly 28% of documented cases of airsoft or BB gun-related injury had visual acuity worse than 20/50 after initial treatment. Over 98% of injuries occurred without eye protection. CONCLUSIONS: Air guns are rising in popularity and now account for the majority of pediatric eye injuries requiring hospital admissions. These eye injuries occur without ocular protection and may lead to permanent eye injury. Increasing regulations for eye protection, sales, and usage of air guns are needed to prevent serious pediatric eye injuries. PMID- 25818284 TI - Permanent tonic pupil following inferior oblique myectomy. AB - The postoperative dilation of the pupil following an inferior oblique weakening procedure is a disconcerting event. Previous studies have reported nearly full recovery of the pupil within a few months. We report the case of a patient with who experienced permanent tonic pupil following inferior oblique myectomy. PMID- 25818285 TI - Ocular abnormalities in patients treated with a novel anti-GD2 monoclonal antibody, hu14.18K322A. AB - PURPOSE: To determine the incidence of and factors associated with the development of mydriasis and impaired accommodation in patients with refractory or recurrent neuroblastoma receiving the anti-GD2 antibody hu14.18K322A. METHODS: The medical records of eligible patients with refractory or recurrent neuroblastoma who received escalating doses of hu14.18K322A, ranging from 2 to 70 mg/m(2)/dose for 4 consecutive days every 28 days, were retrospectively reviewed to identify ocular abnormalities arising during the treatment period. RESULTS: A total of 38 patients (median age, 7 years; 23 males) were included. All patients underwent comprehensive eye examinations prior to each course of therapy. Mydriasis was seen in 13 patients (34%), and impaired accommodation was seen in 9 (24%), indicating a dose-related effect between hu14.18K322A and both mydriasis (P = 0.021) and impaired accommodation (P = 0.029). Age and sex were not associated with ocular abnormalities. Ocular symptoms resolved in the majority of patients after the drug was discontinued. CONCLUSIONS: Side effects of mydriasis and impaired accommodation have a dose-dependent relationship with hu14.18K322A. These side effects do not warrant discontinuation of treatment, as they usually resolve after completion of therapy. Management of ocular side effects should focus on treating symptoms with manifest refraction, bifocals, or tinted spectacles. PMID- 25818286 TI - Inverted mucoepidermoid papilloma of conjunctiva in a child. AB - Inverted papillomas are benign epithelial tumors usually arising from the mucous membrane of the sinonasal cavity and the urinary tract. Similar tumors of the conjunctiva are much rarer. We describe a case of juxtalimbal inverted papilloma in an 11-year-old boy who presented with a pigmented lesion that simulated a conjunctival nevus. Excisional biopsy established the diagnosis of inverted papilloma. The patient was carefully followed for 2 years, because the tumor's behavior in the conjunctiva is unknown. There was no recurrence of the lesion. PMID- 25818287 TI - Examination about the effects of future career choice on time perspective in Japanese high school students. AB - This study investigated types of career choice in high school students and examined the effects of career paths on time perspective development. The participants were 4,756 third grade students from nine public high schools in Tokyo. The high school questionnaire survey was conducted throughout autumn of 2008, 2009, and 2010. One year later, 962 graduates participated in the follow-up questionnaire survey by post. Distinguishing gender difference among career paths was found. Girls tend to choose significantly shorter learning careers (p < .01), for example junior college or vocational school in comparison to boys. Career indecision, i.e., students who could not set a concrete future career in high school, had significantly more negative time perspective than other groups (p < .05), which was caused by a deficiency of their basic cognitive ability. Longitudinal data showed different patterns of fluctuation in time perspective between "school to school transition" and "school to work transition". It is suggested that the "school to work transition" tends to be more critical for adolescents and has negative effects on time perspective. These results suggest that the goal content in careers may promote or inhibit the formation of time perspectives during the graduation transition. PMID- 25818288 TI - UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold. AB - We identified ubiquitin-like with PHD and RING finger domain 1 (UHRF1) as a binding factor for DNA interstrand crosslink (ICL) lesions through affinity purification of ICL-recognition activities. UHRF1 is recruited to DNA lesions in vivo and binds directly to ICL-containing DNA. UHRF1-deficient cells display increased sensitivity to a variety of DNA damages. We found that loss of UHRF1 led to retarded lesion processing and reduced recruitment of ICL repair nucleases to the site of DNA damage. UHRF1 interacts physically with both ERCC1 and MUS81, two nucleases involved in the repair of ICL lesions. Depletion of both UHRF1 and components of the Fanconi anemia (FA) pathway resulted in increased DNA damage sensitivity compared to defect of each mechanism alone. These results suggest that UHRF1 promotes recruitment of lesion-processing activities via its affinity to recognize DNA damage and functions as a nuclease recruitment scaffold in parallel to the FA pathway. PMID- 25818289 TI - Kinesin's front head is gated by the backward orientation of its neck linker. AB - Kinesin-1 is a two-headed motor that takes processive 8-nm hand-over-hand steps and transports intracellular cargos toward the plus-end of microtubules. Processive motility requires a gating mechanism to coordinate the mechanochemical cycles of the two heads. Kinesin gating involves neck linker (NL), a short peptide that interconnects the heads, but it remains unclear whether gating is facilitated by the NL orientation or tension. Using optical trapping, we measured the force-dependent microtubule release rate of kinesin monomers under different nucleotide conditions and pulling geometries. We find that pulling NL in the backward direction inhibits nucleotide binding and subsequent release from the microtubule. This inhibition is independent of the magnitude of tension (2-8 pN) exerted on NL. Our results provide evidence that the front head of a kinesin dimer is gated by the backward orientation of its NL until the rear head releases from the microtubule. PMID- 25818290 TI - Absence of SARM1 rescues development and survival of NMNAT2-deficient axons. AB - SARM1 function and nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) loss both promote axon degeneration, but their relative relationship in the process is unknown. Here, we show that NMNAT2 loss and resultant changes to NMNAT metabolites occur in injured SARM1-deficient axons despite their delayed degeneration and that axon degeneration specifically induced by NMNAT2 depletion requires SARM1. Strikingly, SARM1 deficiency also corrects axon outgrowth in mice lacking NMNAT2, independently of NMNAT metabolites, preventing perinatal lethality. Furthermore, NAMPT inhibition partially restores outgrowth of NMNAT2 deficient axons, suggesting that the NMNAT substrate, NMN, contributes to this phenotype. NMNAT2-depletion-dependent degeneration of established axons and restricted extension of developing axons are thus both SARM1 dependent, and SARM1 acts either downstream of NMNAT2 loss and NMN accumulation in a linear pathway or in a parallel branch of a convergent pathway. Understanding the pathway will help establish relationships with other modulators of axon survival and facilitate the development of effective therapies for axonopathies. PMID- 25818291 TI - Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor beta repression. AB - The role of ERbeta in prostate cancer is unclear, although loss of ERbeta is associated with aggressive disease. Given that mice deficient in ERbeta do not develop prostate cancer, we hypothesized that ERbeta loss occurs as a consequence of tumorigenesis caused by other oncogenic mechanisms and that its loss is necessary for tumorigenesis. In support of this hypothesis, we found that ERbeta is targeted for repression in prostate cancer caused by PTEN deletion and that loss of ERbeta is important for tumor formation. ERbeta transcription is repressed by BMI-1, which is induced by PTEN deletion and important for prostate tumorigenesis. This finding provides a mechanism for how ERbeta expression is regulated in prostate cancer. Repression of ERbeta contributes to tumorigenesis because it enables HIF-1/VEGF signaling that sustains BMI-1 expression. These data reveal a positive feedback loop that is activated in response to PTEN loss and sustains BMI-1. PMID- 25818292 TI - Direct involvement of retinoblastoma family proteins in DNA repair by non homologous end-joining. AB - Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ involves a mechanism independent of RB1's cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution. PMID- 25818293 TI - Differential association of chromatin proteins identifies BAF60a/SMARCD1 as a regulator of embryonic stem cell differentiation. AB - Embryonic stem cells (ESCs) possess a distinct chromatin conformation maintained by specialized chromatin proteins. To identify chromatin regulators in ESCs, we developed a simple biochemical assay named D-CAP (differential chromatin associated proteins), using brief micrococcal nuclease digestion of chromatin, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Using D CAP, we identified several differentially chromatin-associated proteins between undifferentiated and differentiated ESCs, including the chromatin remodeling protein SMARCD1. SMARCD1 depletion in ESCs led to altered chromatin and enhanced endodermal differentiation. Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) analyses suggested that SMARCD1 is both an activator and a repressor and is enriched at developmental regulators and that its chromatin binding coincides with H3K27me3. SMARCD1 knockdown caused H3K27me3 redistribution and increased H3K4me3 around the transcription start site (TSS). One of the identified SMARCD1 targets was Klf4. In SMARCD1-knockdown clones, KLF4, as well as H3K4me3 at the Klf4 locus, remained high and H3K27me3 was abolished. These results propose a role for SMARCD1 in restricting pluripotency and activating lineage pathways by regulating H3K27 methylation. PMID- 25818294 TI - Piwi proteins and piRNAs in mammalian oocytes and early embryos. AB - Germ cells of most animals critically depend on piRNAs and Piwi proteins. Surprisingly, piRNAs in mouse oocytes are relatively rare and dispensable. We present compelling evidence for strong Piwi and piRNA expression in oocytes of other mammals. Human fetal oocytes express PIWIL2 and transposon-enriched piRNAs. Oocytes in adult human ovary express PIWIL1 and PIWIL2, whereas those in bovine ovary only express PIWIL1. In human, macaque, and bovine ovaries, we find piRNAs that resemble testis-borne pachytene piRNAs. Isolated bovine follicular oocytes were shown to contain abundant, relatively short piRNAs that preferentially target transposable elements. Using label-free quantitative proteome analysis, we show that these maturing oocytes strongly and specifically express the PIWIL3 protein, alongside other, known piRNA-pathway components. A piRNA pool is still present in early bovine embryos, revealing a potential impact of piRNAs on mammalian embryogenesis. Our results reveal that there are highly dynamic piRNA pathways in mammalian oocytes and early embryos. PMID- 25818295 TI - Optical dissection of experience-dependent pre- and postsynaptic plasticity in the Drosophila brain. AB - Drosophila represents a key model organism for dissecting neuronal circuits that underlie innate and adaptive behavior. However, this task is limited by a lack of tools to monitor physiological parameters of spatially distributed, central synapses in identified neurons. We generated transgenic fly strains that express functional fluorescent reporters targeted to either pre- or postsynaptic compartments. Presynaptic Ca(2+) dynamics are monitored using synaptophysin coupled GCaMP3, synaptic transmission is monitored using red fluorescent synaptophysin-pHTomato, and postsynaptic Ca(2+) dynamics are visualized using GCaMP3 fused with the postsynaptic matrix protein, dHomer. Using two-photon in vivo imaging of olfactory projection neurons, odor-evoked activity across populations of synapses is visualized in the antennal lobe and the mushroom body calyx. Prolonged odor exposure causes odor-specific and differential experience dependent changes in pre- and postsynaptic activity at both levels of olfactory processing. The approach advances the physiological analysis of synaptic connections across defined groups of neurons in intact Drosophila. PMID- 25818296 TI - The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin. AB - Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co repressor KAP1, and its overexpression results in the sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR. PMID- 25818297 TI - The Rab2A GTPase promotes breast cancer stem cells and tumorigenesis via Erk signaling activation. AB - Proline-directed phosphorylation is regulated by the prolyl isomerase Pin1, which plays a fundamental role in driving breast cancer stem-like cells (BCSCs). Rab2A is a small GTPase critical for vesicle trafficking. Here, we show that Pin1 increases Rab2A transcription to promote BCSC expansion and tumorigenesis in vitro and in vivo. Mechanistically, Rab2A directly interacts with and prevents dephosphorylation/inactivation of Erk1/2 by the MKP3 phosphatase, resulting in Zeb1 upregulation and beta-catenin nuclear translocation. In cancer cells, Rab2A is activated via gene amplification, mutation or Pin1 overexpression. Rab2A overexpression or mutation endows BCSC traits to primary normal human breast epithelial cells, whereas silencing Rab2A potently inhibits the expansion and tumorigenesis of freshly isolated BCSCs. Finally, Rab2A overexpression correlates with poor clinical outcome in breast cancer patients. Thus, Pin1/Rab2A/Erk drives BCSC expansion and tumorigenicity, suggesting potential drug targets. PMID- 25818298 TI - Structural basis for molecular discrimination by a 3',3'-cGAMP sensing riboswitch. AB - Cyclic dinucleotides are second messengers that target the adaptor STING and stimulate the innate immune response in mammals. Besides protein receptors, there are bacterial riboswitches that selectively recognize cyclic dinucleotides. We recently discovered a natural riboswitch that targets 3',3'-cGAMP, which is distinguished from the endogenous mammalian signal 2',3'-cGAMP by its backbone connectivity. Here, we report on structures of the aptamer domain of the 3',3' cGAMP riboswitch from Geobacter in the 3',3'-cGAMP and c-di-GMP bound states. The riboswitch adopts a tuning fork-like architecture with a junctional ligand binding pocket and different orientations of the arms are correlated with the identity of the bound cyclic dinucleotide. Subsequent biochemical experiments revealed that specificity of ligand recognition can be affected by point mutations outside of the binding pocket, which has implications for both the assignment and reengineering of riboswitches in this structural class. PMID- 25818299 TI - Structure and function of Neisseria gonorrhoeae MtrF illuminates a class of antimetabolite efflux pumps. AB - Neisseria gonorrhoeae is an obligate human pathogen and the causative agent of the sexually transmitted disease gonorrhea. The control of this disease has been compromised by the increasing proportion of infections due to antibiotic resistant strains, which are growing at an alarming rate. N. gonorrhoeae MtrF is an integral membrane protein that belongs to the AbgT family of transporters for which no structural information is available. Here, we describe the crystal structure of MtrF, revealing a dimeric molecule with architecture distinct from all other families of transporters. MtrF is a bowl-shaped dimer with a solvent filled basin extending from the cytoplasm to halfway across the membrane bilayer. Each subunit of the transporter contains nine transmembrane helices and two hairpins, posing a plausible pathway for substrate transport. A combination of the crystal structure and biochemical functional assays suggests that MtrF is an antibiotic efflux pump mediating bacterial resistance to sulfonamide antimetabolite drugs. PMID- 25818300 TI - An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition. AB - Hedgehog (Hh) signaling plays an integral role in vertebrate development, and its dysregulation has been accepted widely as a driver of numerous malignancies. While a variety of small molecules target Smoothened (Smo) as a strategy for Hh inhibition, Smo gain-of-function mutations have limited their clinical implementation. Modulation of targets downstream of Smo could define a paradigm for treatment of Hh-dependent cancers. Here, we describe eggmanone, a small molecule identified from a chemical genetic zebrafish screen, which induced an Hh null phenotype. Eggmanone exerts its Hh-inhibitory effects through selective antagonism of phosphodiesterase 4 (PDE4), leading to protein kinase A activation and subsequent Hh blockade. Our study implicates PDE4 as a target for Hh inhibition, suggests an improved strategy for Hh-dependent cancer therapy, and identifies a unique probe of downstream-of-Smo Hh modulation. PMID- 25818301 TI - DNAM-1 expression marks an alternative program of NK cell maturation. AB - Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM 1(+) and DNAM-1(-) NK cells. DNAM-1(+) NK cells produce high levels of inflammatory cytokines, have enhanced interleukin 15 signaling, and proliferate vigorously. By contrast, DNAM-1(-) NK cells that differentiate from DNAM-1(+) NK cells have greater expression of NK-cell-receptor-related genes and are higher producers of MIP1 chemokines. Collectively, our data reveal the existence of a functional program of NK cell maturation marked by DNAM-1 expression. PMID- 25818303 TI - Genome engineering with CRISPR-Cas9 in the mosquito Aedes aegypti. AB - The mosquito Aedes aegypti is a potent vector of the chikungunya, yellow fever, and dengue viruses, responsible for hundreds of millions of infections and over 50,000 human deaths per year. Mutagenesis in Ae. aegypti has been established with TALENs, ZFNs, and homing endonucleases, which require the engineering of DNA binding protein domains to provide genomic target sequence specificity. Here, we describe the use of the CRISPR-Cas9 system to generate site-specific mutations in Ae. aegypti. This system relies on RNA-DNA base-pairing to generate targeting specificity, resulting in efficient and flexible genome-editing reagents. We investigate the efficiency of injection mix compositions, demonstrate the ability of CRISPR-Cas9 to generate different types of mutations via disparate repair mechanisms, and report stable germline mutations in several genomic loci. This work offers a detailed exploration into the use of CRISPR-Cas9 in Ae. aegypti that should be applicable to non-model organisms previously out of reach of genetic modification. PMID- 25818302 TI - Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. AB - Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology. PMID- 25818304 TI - Factors associated with nutritional status in children aged 5-24 months in the Republic of Cameroon. AB - This study was conducted to clarify nutritional status and associated factors in 5-24 month old children in the district of Batouri, Republic of Cameroon. Mothers were interviewed using a semistructured questionnaire, and the child's weight, length, head circumference, and mid-upper arm circumference was collected. The data were compared with child growth standards proposed by the World Health Organization using Z-scores; chi(2) -test, Fisher's exact test, and Wilcoxon rank sum test were used to determine variables associated with malnutrition. A total of 100 mother-child pairs participated in this study; valid data from 100 pairs were subjected to analysis. The percentages of children with malnutrition indicators were wasting (6%), stunting (31%), underweight (14%), and low mid upper arm circumference (16%). Five factors were found to be statistically significant in their association with the children's malnutrition: mother's age, child's age, mother's educational level, mothers who had family planning information, and the source of tap water. A high percentage of stunting was positively associated with a high percentage of chronic malnutrition. We speculate that insufficient nutrition was more likely to begin after weaning. PMID- 25818305 TI - The Development of Assessment Tools for Plastic Surgery Competencies. AB - BACKGROUND: Objective tools to assess procedural skills in plastic surgery residency training are currently lacking. There is an increasing need to address this deficit in order to meet today's training standards in North America. OBJECTIVES: The purpose of this pilot study was to establish a methodology for determining the essential procedural steps for two plastic surgery procedures to assist resident training and assessment. METHODS: Following a literature review and needs assessment of resident training, the authors purposefully selected two procedures lacking robust assessment metrics (breast augmentation and facelift) and used a consensus process to complete a list of procedural steps for each. Using an online survey, plastic surgery Program Directors, Division Chiefs, and the Royal College Specialty Training Committee members in Canada were asked to indicate whether each step was considered essential or non-essential when assessing competence among graduating plastic surgery trainees. The Delphi methodology was used to obtain consensus among the panel. Panelist reliability was measured using Cronbach's alpha. RESULTS: A total of 17 steps for breast augmentation and 24 steps for facelift were deemed essential by consensus (Cronbach's alpha 0.87 and 0.85, respectively). CONCLUSION: Using the aforementioned technique, the essential procedural steps for two plastic surgery procedures were determined. Further work is required to develop assessment instruments based on these steps and to gather validity evidence in support of their use in surgical education. PMID- 25818306 TI - Fluorescence quenching study of 2,6-bis(5-(4-methylphenyl)-1-H-pyrazol-3 yl)pyridine with metal ions. AB - A novel bispyrazole derivative 2,6-bis(5-(4-methylphenyl)-1-H-pyrazol-3 yl)pyridine was synthesized and its structure was confirmed by (1)H NMR, FTIR, MS techniques and elemental analysis. The binding interactions of BMPP with Cd(2+), Co(2+), Pb(2+) and Cu(2+) ions were investigated in MeOH-H2O solution by fluorescence quenching technique at two temperatures (25 and 35 degrees C). Their quenching constants KSV, binding constants K, binding sites n and thermodynamic parameters (DeltaH, DeltaG and DeltaS) were determined. The results indicated that the metal ions quenched the intrinsic fluorescence of the bispyrazole by forming the bispyrazole-metal complexes and their quenching process was a static quenching mechanism. In addition, the process of interaction was spontaneous and mainly DeltaS-driven. PMID- 25818307 TI - FT-IR and micro-Raman spectroscopic studies of archaeological potteries recently excavated in Poompuhar, Tamilnadu, India. AB - Ancient ceramics are the abundant artifacts that give the knowledge of the past societies. Therefore it is of great importance to acquire knowledge about the chemical composition of the clay in archaeological artifacts. The spectroscopic techniques represent one of the most powerful tools to investigate the structure of all the materials and chemical composition of the cultural object like potteries. An attempt has been made in the present work to estimate the firing temperature of the archaeological pottery shreds excavated from the archaeological site Poompuhar in the state of Tamilnadu in India. The firing temperature of the archaeological pottery shreds were estimated by recording the corresponding FT-IR spectra in the range 4000-450 cm(-1) and Micro Raman spectra in the range 1800-400 cm(-1). The clay mineral present in the pottery samples are identified through FT-IR method and was confirmed with Micro Raman spectroscopy as both are complement to each other. The major primary mineral present in the samples is Kaolinite and the secondary mineral present is quartz and the accessory minerals present in the samples are hematite, magnetite and feldspar. The results of Raman spectra showed that the potters of this site used a mixture of clays as raw materials. The firing temperature for some of the samples did not exceed 800 degrees C which suggests the use of open fire. PMID- 25818308 TI - Biosimilar monoclonal antibodies in lymphoma: a critical appraisal. AB - Rituximab, an anti-CD20 monoclonal antibody, revolutionized the treatment of lymphoma. Although newer generation anti-CD20 monoclonal antibodies are being examined, patent expiries and patient demand have fueled the development of rituximab biosimilars. The development of such agents is both an important and difficult undertaking. By definition, although they aim to have safety and efficacy comparable with their reference agents, biosimilars are not exact replicas of those agents, and small changes in nonclinical and preclinical properties may ultimately affect in vivo activity. Consideration must be given to the complex mechanisms of action, sensitive patient populations that may be treated, and appropriate clinical trial endpoints. Furthermore, extrapolation of indications is multifaceted, deserving close examination. This review represents a critical look at biosimilars in lymphoma and their safety, efficacy and long term effects on patient outcomes. PMID- 25818309 TI - Anillin localization suggests distinct mechanisms of division plane specification in mouse oogenic meiosis I and II. AB - Anillin is a conserved cytokinetic ring protein implicated in actomyosin cytoskeletal organization and cytoskeletal-membrane linkage. Here we explored anillin localization in the highly asymmetric divisions of the mouse oocyte that lead to the extrusion of two polar bodies. The purposes of polar body extrusion are to reduce the chromosome complement within the egg to haploid, and to retain the majority of the egg cytoplasm for embryonic development. Anillin's proposed roles in cytokinetic ring organization suggest that it plays important roles in achieving this asymmetric division. We report that during meiotic maturation, anillin mRNA is expressed and protein levels steadily rise. In meiosis I, anillin localizes to a cortical cap overlying metaphase I spindles, and a broad ring over anaphase spindles that are perpendicular to the cortex. Anillin is excluded from the cortex of the prospective first polar body, and highly enriched in the cytokinetic ring that severs the polar body from the oocyte. In meiosis II, anillin is enriched in a cortical stripe precisely coincident with and overlying the meiotic spindle midzone. These results suggest a model in which this cortical structure contributes to spindle re-alignment in meiosis II. Thus, localization of anillin as a conserved cytokinetic ring marker illustrates that the geometry of the cytokinetic ring is distinct between the two oogenic meiotic cytokineses in mammals. PMID- 25818310 TI - Effects of inter-implant distance and implant length on the response to frontal traumatic force of two anterior implants in an atrophic mandible: three dimensional finite element analysis. AB - The aim of this three-dimensional finite element analysis study was to examine the biomechanical behaviour of dental implants and the surrounding bone under traumatic frontal force. Models were created of an edentulous atrophic mandible using cone beam computed tomography data from a patient; two titanium alloy implants (Ti-6Al-4V) were virtually inserted into the anterior of the mandible. Six different variations were modelled to represent differences in implant location (lateral incisor vs. canine placement) and implant length (monocortical, bicortical, and long-bicortical). A static force of 10 MPa was applied frontally to the symphysis region of each model, and the maximum equivalent von Mises strain of bone, maximum von Mises stress of implants, and chromatic force distributions in bone and implants were recorded. In general, when compared to lateral incisor placement, canine placement of implants resulted in greater von Mises stress on implants and greater equivalent von Mises strain on bone. The findings of the present study showed the distribution of traumatic force to be affected more by inter-implant distance than by implant length. The insertion of implants in the lateral incisor area was found to be a better solution than canine area placement in terms of frontal plane trauma and fracture risk. PMID- 25818311 TI - Cellular and molecular mechanisms in the pathophysiology of systemic sclerosis. AB - Fibrosis is characterized by disproportionate accumulation of collagens and other extracellular matrix substances, resulting in organ dysfunction and failure. In systemic sclerosis, cellular and molecular mechanisms involved in the pathophysiology of fibrosis are highly complex and yet barely understood. Anatomopathological findings showed the coexistence of patchy inflammatory cell infiltration, microvascular injuries, and fibrotic foci. One of the most commonly accepted hypotheses considers endothelial activation as the triggering phenomenon inducing inflammatory and autoimmunity activation. The resulting cytokines and autoantibodies production accelerates the proliferating rate of normal fibroblasts and their transformation into myofibroblasts, leading to diffuse fibrosis. This review aims to focus on cellular and molecular mechanisms implicated in the fibrogenesis of systemic sclerosis. PMID- 25818312 TI - Advanced imaging tools to investigate multiple sclerosis pathology. AB - Conventional MR imaging techniques still lack specificity for the underlying central nervous system tissue damage in multiple sclerosis (MS), impeding a comprehensive investigation of the key mechanisms responsible for neurological disability such as myelin damage and repair, neurodegeneration and neuroinflammation. A range of novel and advanced imaging tools, using quantitative magnetic resonance (MR) or positron emission tomography (PET) technologies are now emerging and open the perspective to obtain unique insights into the disease mechanisms. Both can be employed either in experimental models or in patients with MS, and they have already allowed to obtain imaging metrics that significantly correlate with clinical scores. In this review, we summarize the main evidence supporting the use of quantitative MR and PET as essential investigation tools to explore myelin changes, neuronal damage and compartmentalized inflammation in MS. The clinical translation of these imaging techniques has the potential to improve the design of future clinical trials and to allow the measurement of the effects of new drugs aimed at enhancing myelin repair and reducing neurodegeneration and neuroinflammation. PMID- 25818313 TI - Plasticity of empty major histocompatibility complex class I molecules determines peptide-selector function. AB - Major histocompatibility complex class I (MHC I) proteins provide protection from intracellular pathogens and cancer via each of a cell's MHC I molecules binding and presenting a peptide to cytotoxic T lymphocytes. MHC I genes are highly polymorphic and can have significant diversity, with polymorphisms predominantly localised in the peptide-binding groove where they can change peptide-binding specificity. However, polymorphic residues may also determine other functional properties, such as how dependent MHC I alleles are on the peptide-loading complex for optimal acquisition of peptide cargo. We describe how differences in the peptide-binding properties of two MHC I alleles correlates with altered conformational flexibility in the peptide-empty state. We hypothesise that plasticity is an intrinsic property encoded by the protein sequence, and that co ordinated movements of the membrane-proximal and membrane-distal domains collectively determines how dependent MHC I are on the peptide-loading complex for efficient assembly with high affinity peptides. PMID- 25818314 TI - Paroxysmal nocturnal hemoglobinuria (PNH) and primary p.Cys89Tyr mutation in CD59: Differences and similarities. AB - CD59 encodes a 77 amino acid glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that inhibits the final step of membrane attack complex (MAC) formation. CD59 deficiency is a common finding in adult patients with paroxysmal nocturnal hemoglobinuria (PNH). In this condition, there is a clonal expansion of hematopoietic stem cells that have acquired a mutation in the PIGA gene (phosphatidylinositol glycan anchor biosynthesis, class A). PIGA encodes a GPI biosynthesis protein, phosphatidylinositol N-acetylglucosaminyltransferase subunit A, and erythrocytes deficient in GPI-anchored membrane proteins, including CD59, undergo complement-mediated hemolysis. We have recently described a primary homozygous Cys89Tyr CD59 deficiency in humans that resulted in the amino acid substitution p.Cys89Tyr with resulting failure of proper localization of the CD59 protein to the cell surface. The Cys89Tyr mutation in CD59 was clinically manifested in infancy, and associated with chronic hemolysis and relapsing peripheral demyelinating disease resembling recurrent Guillain-Barre syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP). In this review we describe differences and similarities in the pathogenesis and clinical manifestations of PNH and primary CD59 Cys89Tyr mutation with the aim of tracking the contribution of CD59 deficiency to the pathophysiology and perhaps deepening our understanding of both diseases. PMID- 25818315 TI - ADAMTS proteases in fertility. AB - The reproductive organs are unique among adult organs in that they must undergo continual tissue remodelling as a key aspect of their normal function. The processes for persistent maturation and release of new gametes, as well as fertilisation, implantation, placentation, gestation and parturition involve cyclic development and regression of tissues that must continually regenerate to support fertility. The ADAMTS family of proteases has been shown to contribute to many aspects of the tissue morphogenesis required for development and function of each of the reproductive organs. Dysregulation or functional changes in ADAMTS family proteases have been associated with reproductive disorders such as polycystic ovarian syndrome (PCOS) and premature ovarian failure (POF). Likewise, proteolytic substrates of ADAMTS enzymes have also been linked to reproductive function. New insight into the roles of ADAMTS proteases has yielded a deeper understanding of the molecular mechanisms behind fertility with clinical potential to generate therapeutic targets to resolve infertility, develop biomarkers that predict dysfunction of the reproductive organs and potentially offer targets for development of non-hormonal male and female contraceptives. PMID- 25818316 TI - Anesthetic and pathological changes following high doses of ketamine and xylazine in Sprague Dawley rats. AB - The main objective of this study was to compare the effects of ketamine and xylazine in aging rats when coadministered intraperitoneally at high anesthetic doses. Three groups (n=6 rats/group) consisting of rats at 3, 6 and 12 months of age were used. During anesthesia, animals were monitored for heart rate, respiratory frequency, blood oxygen saturation, and rectal temperature. The corneal and paw withdrawal reflex were also examined during anesthesia. During anesthesia, withdrawal and corneal reflexes were absent for progressively longer durations with increasing age. Significant decreases in cardiac and respiratory frequency and, blood oxygen saturation occurred for the 6- and 12-month-old animals. Respiratory frequency and blood oxygen saturation returned to normal at the end of the anesthesia; however, the significant decrease in cardiac frequency persisted in the 6- and 12-month-old animals. Rectal temperature was decreased significantly only in the 3-month-old animals. Pulmonary edema and effusion occurred in 50% of the 12-month-old animals. In conclusion, if ketamine-xylazine are used for anesthesia, the doses should be optimized for the age of the subjects prior to initiation of the research project. PMID- 25818317 TI - The effect of impaired angiogenesis on intestinal function following massive small bowel resection. AB - PURPOSE: Intestinal adaptation involves villus lengthening, crypt deepening, and increased capillary density following small bowel resection (SBR). Mice lacking the proangiogenic chemokine CXCL5 have normal structural adaptation but impaired angiogenesis. This work evaluates the impact of incomplete adaptive angiogenesis on the functional capacity of the intestine after SBR. METHODS: CXCL5 knockout (KO) and C57BL/6 wild-type (WT) mice underwent 50% SBR. Magnetic resonance imaging measured weekly body composition. Intestinal absorptive capacity was evaluated through fecal fat analysis. Gene expression profiles for select macronutrient transporters were measured via RT-PCR. Postoperative crypt and villus measurements were assessed for structural adaptation. Submucosal capillary density was measured through CD31 immunohistochemistry. RESULTS: Comparable postoperative weight gain occurred initially. Diminished weight gain, impaired fat absorption, and elevated steatorrhea occurred in KO mice after instituting high-fat diet. Greater postoperative upregulation of ABCA1 fat transporter occurred in WT mice, while PEPT1 protein transporter was significantly downregulated in KO mice. KO mice had impaired angiogenesis but intact structural adaptation. CONCLUSION: After SBR, KO mice display an inefficient intestinal absorption profile with perturbed macronutrient transporter expression, impaired fat absorption, and slower postoperative weight gain. In addition to longer villi and deeper crypts, an intact angiogenic response may be required to achieve functional adaptation to SBR. PMID- 25818318 TI - Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation. AB - PURPOSE: Intestinal adaptation structurally represents increases in crypt depth and villus height in response to small bowel resection (SBR). Previously, we found that neither epidermal growth factor receptor (EGFR) nor insulin-like growth factor 1 receptor (IGF1R) function was individually required for normal adaptation. In this study, we sought to determine the effect of disrupting both EGFR and IGF1R expression on resection-induced adaptation. METHODS: Intestinal specific EGFR and IGF1R double knockout mice (EGFR/IGF1R-IKO) (n=6) and wild-type (WT) control mice (n=7) underwent 50% proximal SBR. On postoperative day (POD) 7, structural adaptation was scored by measuring crypt depth and villus height. Rates of crypt cell proliferation, apoptosis, and submucosal capillary density were also compared. RESULTS: After 50% SBR, normal adaptation occurred in both WT and EGFR/IGF1R-IKO. Rates of proliferation and apoptosis were no different between the two groups. The angiogenic response was less in the EGFR/IGF1R-IKO compared to WT mice. CONCLUSION: Disrupted expression of EGFR and IGF1R in the intestinal epithelial cells does not affect resection-induced structural adaptation but attenuates angiogenesis after SBR. These findings suggest that villus growth is driven by receptors and pathways that occur outside the epithelial cell component, while angiogenic responses may be influenced by epithelial-endothelial crosstalk. PMID- 25818319 TI - Utility of onsite interviews in the pediatric surgery match. AB - PURPOSE: The value of onsite interviews for the pediatric surgery match remains undefined despite substantial cost to applicants. This study assesses the impact of onsite interviews on the rank order lists submitted to the match by pediatric surgery residency training program directors (PDs). METHODS: PDs were asked prospectively to evaluate pediatric surgery residency candidates based solely on their ERAS application and generate a "pre-interview rank list." Interviews were then held based on the usual practice of each program. PDs then submitted de identified pre-interview and final rank lists. The impact of the interview process upon rank list movement of candidates was assessed. RESULTS: Of 44 programs, 16 (36%) provided data for analysis. Onsite interviews resulted in candidates moving a mean of 5.2 +/- 1.2 rank positions, whereas candidates ranked in the first 5 positions moved an average of 4 +/- 2 places, 81% of the initial top-ranked candidates moved out of this position, and 36% of top 10 candidates moved out of the top 10. CONCLUSIONS: Onsite interviews are high-stakes events which substantially affect the final rank order list in the pediatric surgery match. Programs should take these data into account when determining the number of interview invitations. PMID- 25818320 TI - Repeated mechanical lengthening of intestinal segments in a novel model. AB - PURPOSE: Currently, animal models used for mechanical intestinal lengthening utilize a single lengthening procedure prior to analysis or restoration back into continuity. Here we developed a novel surgical model to examine the feasibility of repeated lengthening of intestinal segments. METHODS: A Roux-en-Y jejunojejunostomy with a blind Roux limb was created in rats. An encapsulated polycaprolactone spring was placed into a 1cm segment of the Roux limb. After 4 weeks, a second encapsulated PCL spring was inserted into a 1cm portion of the lengthened segment. After another 4 weeks, the repeatedly lengthened segments were retrieved for histological analyses. RESULTS: Jejunal segments of the Roux limb were successfully lengthened from 1.0 cm to 2.6 +/- 0.7 cm. Four weeks after the second PCL spring placement, 1.0 cm of the previously lengthened segment increased to 2.7 +/- 0.8 cm. Stronger mechanical force was required to achieve subsequent re-lengthening. Lengthened and re-lengthened segments had increased smooth muscle thickness and crypt depth when compared to normal jejunal mucosa. CONCLUSION: Using the Roux-en-Y model, previously lengthened segments of intestine can be successfully re-lengthened. Intestinal segments may be subjected to multiple lengthening procedures to achieve clinically significant length for the treatment of short bowel syndrome. PMID- 25818321 TI - Variation in bowel preparation among pediatric surgeons for elective colorectal surgery: A problem of equipoise or a knowledge gap of the available clinical evidence? AB - PURPOSE: Despite rigorous data from adult literature demonstrating that oral antibiotics (OA) reduce infectious complications and mechanical bowel preparation (MBP) alone does not, MBP alone remains the preferred approach among pediatric surgeons. We aimed to explore the nature of this discrepancy through a survey of the American Pediatric Surgical Association membership. METHODS: Surgeons were queried for their choice of bowel preparation, factors influencing their practice, and their impression of the strength and relevance of the adult literature to pediatric practice. RESULTS: Surgeons who used MBP alone (31%) cited a reduction in stool burden and infectious complications as important factors, whereas surgeons choosing not to use OA (70%) reported a lack of benefit in reducing infectious complications as the primary reason. Although 53% of surgeons reported that evidence from adult literature was the most important influence, 73% of surgeons reported there was poor evidence supporting the use of OA (+/-MBP), and only 25% used a preparation supported by adult randomized data. CONCLUSIONS: Wide variation exists among pediatric surgeons in the perceived utility of MBP and OA. Although the majority of pediatric surgeons cited the adult literature as the strongest influence on their practice, this is not consistent with stated perceptions or practice. PMID- 25818322 TI - Commentary regarding: A randomized trial of icatibant in ACE-inhibitor-induced angioedema. PMID- 25818323 TI - Biochemical and molecular characterization of the calcineurin in Echinococcus granulosus larval stages. AB - Calcineurin (CaN) is a Ca(2+)-calmodulin activated serine-threonine protein phosphatase that couples the local or global calcium signals, thus controlling important cellular functions in physiological and developmental processes. The aim of this study was to characterize CaN in Echinococcus granulosus (Eg-CaN), a human cestode parasite of clinical importance, both functionally and molecularly. We found that the catalytic subunit isoforms have predicted sequences of 613 and 557 amino acids and are substantially similar to those of the human counterpart, except for the C-terminal end. We also found that the regulatory subunit consists of 169 amino acids which are 87% identical to the human ortholog. We cloned a cDNA encoding for one of the two catalytic subunit isoforms of CaN (Eg-can-A1) as well as the only copy of the Eg-can-B gene, both constitutively transcribed in all Echinococcus larval stages and responsible for generating a functionally active heterodimer. Eg-CaN native enzyme has phosphatase activity, which is enhanced by Ca(2+)/Ni(2+) and reduced by cyclosporine A and Ca(2+) chelators. Participation of Eg-CaN in exocytosis was demonstrated using the FM4-64 probe and Eg-CaN-A was immunolocalized in the cytoplasm of tegumental cells, suckers and excretory bladder of protoscoleces. We also showed that the Eg-can-B transcripts were down-regulated in response to low Ca(2+) intracellular level, in agreement with decreased enzyme activity. Confocal microscopy revealed a striking pattern of Eg-CaN-A in discrete fluorescent spots in the protoscolex posterior bladder and vesicularized protoscoleces beginning the vesicular differentiation. In contrast, Eg-CaN-A was undetectable during the pre-microcyst closing stage while a high DDX-like RNA helicase expression was evidenced. Finally, we identified and analyzed the expression of CaN-related endogenous regulators. PMID- 25818324 TI - Conventional parasitology and DNA-based diagnostic methods for onchocerciasis elimination programmes. AB - Commonly used methods for diagnosing Onchocerca volvulus infections (microscopic detection of microfilariae in skin snips and nodule palpation) are insensitive. Improved methods are needed for monitoring and evaluation of onchocerciasis elimination programmes and for clinical diagnosis of individual patients. A sensitive probe-based qPCR assay was developed for detecting O. volvulus DNA, and this was tested with samples collected from an endemic area in eastern Cote d'Ivoire. The new test was evaluated with dried skin snip pairs from 369 subjects and compared to routine skin snip microscopy and nodule palpation results from the same individuals. Onchocerciasis prevalence for these samples by qPCR, skin snip microscopy, and nodule palpation were 56.9%, 26.0%, and 37.9%, respectively. Furthermore, the combination of all three tests produced an infection prevalence of 72.9%, which was significantly higher than 53.1% detected by microscopy plus nodule palpation without qPCR. However, the qPCR assay was negative for 54 of 229 individuals with palpable nodules. qPCR could be a useful tool for detecting residual O. volvulus infections in human populations as prevalence decreases in areas following community-directed treatment with ivermectin. PMID- 25818325 TI - Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity. AB - Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect. PMID- 25818326 TI - RNA-RNA interactions in gene regulation: the coding and noncoding players. AB - The past few years have witnessed an exciting increase in the richness and complexity of RNA-mediated regulatory circuitries, including new types of RNA-RNA interaction that underlie key steps in gene expression control in an organized and probably hierarchic system to dictate final protein output. Both small (especially miRNAs) and long coding (lc) and noncoding (nc) RNAs contain structural domains that can sense and bind other RNAs via complementary base pairing. The versatility of the interaction confers multiple roles to RNA-RNA hybrids, from control of RNA biogenesis to competition for common targets. Here, we focus on the emerging evidence around RNA networks and their impact on gene expression regulation in light of recent breakthroughs around the crosstalk between coding RNAs and ncRNAs. PMID- 25818327 TI - Superoxide Dismutase and Catalase Genotypes in Pediatric Migraine Patients. AB - This study compared superoxide dismutase (SOD) and catalase (CAT) alleles in 97 consecutive children and adolescents with migraine to 96 healthy children and adolescents. Isolated genomic DNA was used as a template for SOD1 (35 A/C), SOD2 16 C/T, and CAT2 [(-262 C/T) and (-21 A/T)] allele genotyping. The SOD2 16 C/T genotype and C allele frequency differed significantly between controls and migraine (P = .047; P = .038). CAT -21 AA genotype and A allele frequency were significantly higher in both migraine with aura patients (P = .013; P = .004) and migraine without aura patients (P = .003; P = .001) compared to controls. To our knowledge, this is the first demonstration of differences in SOD and CAT genotypes between pediatric migraine patients and age-matched controls. Further studies on the functional implications of these genetic variants on neural antioxidant capacity and the use of antioxidant modulators for migraine treatment are warranted. PMID- 25818328 TI - Maternal Postsecondary Education Associated With Improved Cerebellar Growth After Preterm Birth. AB - The preterm cerebellum is vulnerable to impaired development impacting long-term outcome. Preterm newborns (<32 weeks) underwent serial magnetic resonance imaging (MRI) scans. The association between parental education and cerebellar volume at each time point was assessed, adjusting for age at scan. In 26 infants, cerebellar volumes at term (P = .001), but not birth (P = .4), were associated with 2-year volumes. For 1 cm(3) smaller cerebellar volume (4% total volume) at term, the cerebellum was 3.18 cm(3) smaller (3% total volume) by 2 years. Maternal postsecondary education was not associated with cerebellar volume at term (P = .16). Maternal postsecondary education was a significant confounder in the relationship between term and 2-year cerebellar volumes (P = .016), with higher education associated with improved volumes by 2 years. Although preterm birth has been found to be associated with smaller cerebellar volumes at term, maternal postsecondary education is associated with improved growth detectable by 2 years. PMID- 25818329 TI - Suppressed expression of mitogen-activated protein kinases in hyperthermia induced defective neural tube. AB - Neural tube defects (NTDs) are common congenital malformations. Mitogen-activated protein kinases (MAPKs) pathway is involved in many physiological processes. HMGB1 has been showed closely associated with neurulation and NTDs induced by hyperthermia and could activate MAPKs pathway. Since hyperthermia caused increased activation of MAPKs in many systems, the present study aims to investigate whether HMGB1 contributes to hyperthermia induced NTDs through MAPKs pathway. The mRNA levels of MAPKs and HMGB1 between embryonic day 8.5 and 10 (E8.5-10) in hyperthermia induced defective neural tube were detected by real time quantitative polymerase chain reaction (qPCR). By immunofluorescence and western blotting, the expressions of HMGB1 and phosphorylated MAPKs (ERK1/2, JNK and p38) in neural tubes after hyperthermia were studied. The mRNA levels of MAPKs and HMGB1, as well as the expressions of HMGB1 along with phosphorylated JNK, p38 and ERK, were downregulated in NTDs groups induced by hyperthermia compared with control. The findings suggested that HMGB1 may contribute to hyperthermia induced NTDs formation through decreased cell proliferation due to inhibited phosphorylated ERK1/2 MAPK. PMID- 25818330 TI - Brain activities of visual thinkers and verbal thinkers: A MEG study. AB - In this study we measured activation patterns in the primary visual cortex and the frontal language areas and compared them in individuals with strong and weak capacities to mentally visualize information during spontaneous thinking. Subjects were first administered a 5-item questionnaire to assess their ability to create mental pictures, and were divided into two groups (strong and weak visualizers) on this basis. They then performed tasks requiring visual imagery and verbal recollection, and their local neural activities were measured, using magnetoencephalography (MEG). Notably in the high beta-band (25Hz), the visual area (BA 17) was more strongly activated in strong visualizers, whereas, the frontal language areas were more strongly activated in weak visualizers. Strong visualizers are considered to be visual thinkers, and weak visualizers are verbal thinkers. PMID- 25818331 TI - The role of the frontopolar cortex in manipulation of integrated information in working memory. AB - Cognitive operations often require integration of information. Previous studies have shown that, integration of information in working memory recruits frontopolar cortex (FPC). In this fMRI study, we sought to reveal neural mechanisms of FPC underlying the integration of information during arithmetic tasks. We compared a condition requiring manipulation of two features of an item held in working memory with manipulation of one feature. The results showed that, FPC was equally recruited in both conditions, while dorsolateral prefrontal cortex (DLPFC) tended to be more activated when manipulating two features. We suggest that, FPC plays an integrative role and is recruited by the production of representations in accordance with task constraints, whereas DLPFC appears to be sensitive to processing demands induced by the manipulation of information. PMID- 25818332 TI - Curcumin inhibits Abeta-induced microglial inflammatory responses in vitro: Involvement of ERK1/2 and p38 signaling pathways. AB - Amyloid beta (Abeta) plays an important role in Alzheimer's disease (AD) by inducing microglia activation. Once activated, microglial cells promote the release of reactive species and cytokines that are known to enhance immune responses in AD brain. Thus, negative regulators of microglia activation are considered as potential therapeutic candidates for AD. Curcumin, the major yellow pigment in turmeric (Curcuma longa), is proposed for its anti-inflammatory properties. Several studies have indicated the suppressive effects of curcumin on LPS-induced microglia activation and MAPK activities. However, the effects of curcumin on Abeta-treated microglia and the possible mechanisms are still not fully understood. In the present study, we found that curcumin improved microglial viability against Abeta42 in a time- and dose-dependent manner and remarkably suppressed Abeta42-induced CD68 expression. Moreover, curcumin concentration-dependently abolished Abeta42-induced interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production in mRNA and protein levels in microglia. Besides, curcumin exerted an inhibitory effect on phosphorylation of ERK1/2 and p38 in Abeta42-activated microglia. Further experiments indicated that blockage of ERK1/2 and p38 pathways reduced inflammatory cytokines production from microglia. These results show that curcumin suppresses ERK1/2 and p38 signaling, thus, attenuating inflammatory responses of brain microglia. PMID- 25818333 TI - The future healthcare? AB - BACKGROUND: Healthcare systems in Australia and around the world are failing to address the challenges ofthe modern world. Healthcare leaders are calling for radical, transformational change and entirely new systems of care. However it is unclear what a future, sustainable healthcare system would look like. METHODS: A narrative review to examine emerging trends in health and social care was conducted. RESULTS AND CONCLUSIONS: Six key trends were identified. Collectively, they suggest that future systems are likely to be characterised by increasingly sophisticated technology, but at the same time greater personal and community responsibility for health and well being, innovative use of social capital, and a new approach to ageing and end-of-life care. PMID- 25818335 TI - An unusual presentation of dose dependent SIADH secondary to mirtazapine therapy. PMID- 25818334 TI - Males' mental health disadvantage: An estimation of gender-specific changes in service utilisation for mental and substance use disorders in Australia. AB - BACKGROUND: Concerns about low levels of service utilisation for mental and substance use disorders in Australia - especially among males - have prompted targeted help-seeking and stigma-reduction initiatives. Resulting changes in service utilisation according to gender are unknown. We modelled the percentage of Australian males with a mental or substance use disorder who used services each year between 2006-2007 and 2011-2012, and the types of services they used, relative to females. METHODS: Twelve-month prevalence of mental and substance use disorders, stratified by gender, was synthesised from existing estimates. The percentage of males and females with these disorders who used mental health services in each year from 2006-2007 to 2011-2012 was modelled from published programme activity data, supplemented by analyses of epidemiological survey data. Uncertainty analysis quantified the effects of sampling error and assumptions on the estimates. RESULTS: Modelling showed a significant increase in the percentage of people with mental or substance use disorders who used services for their mental health - from 32.0% in 2006-2007 to 40.0% in 2011-2012 in males and from 45.1% in 2006-2007 to 54.6% in 2011-2012 in females. Growth was driven largely by uptake of private specialised services - males' use of these services grew by 92.7% and females' by 115.4%. There appeared to be a non-significant decrease in use of general practitioner-only mental health care for males (-17.9%), and a significant decrease in the same for females (-35.1%); however, some assumptions made in the modelling of general practitioner-only care require validation. In 2006-2007, the percentage of females treated was 40.9% higher than for males; in 2011-2012, it was 36.6% greater. CONCLUSIONS: Recently implemented initiatives have improved males' likelihood of service utilisation, particularly their use of specialised mental health services. Although the gender gap may have narrowed, improving males' access to services should remain a policy priority. PMID- 25818336 TI - Outcomes of Infection-Related Hospitalization according to Dialysis Modality. AB - BACKGROUND AND OBJECTIVES: Peritoneal dialysis (PD) is associated with an increased risk of infection-related hospitalization (IRH) compared with hemodialysis. The objective of this study was to compare mortality and overall readmission after an IRH between PD and hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This propensity score-matched retrospective cohort study assessed patients undergoing long-term dialysis patients, derived from the Canadian Organ Replacement Register and Regie de l'assurance maladie du Quebec, who had at least one IRH between January 2001 and December 2007. Patients were followed until death, kidney transplantation, or end of the study period. To estimate the probability of receiving PD versus hemodialysis, propensity scores were obtained using multivariable logistic regression. Mortality and overall readmission risks after the initial IRH were compared using a Cox survival model. RESULTS: A total of 354 pairs of patients who had at least one IRH were matched for propensity score. During follow-up (median, 1.25 years), 138 hemodialysis patients (24.7/100 patient-years; 95% confidence interval [95% CI], 20.7 to 29.1) and 130 PD patients (21.2/100 patient-years; 95% CI, 17.7 to 25.1) died; 265 hemodialysis patients (144.6/100 patient-years; 95% CI, 127.7 to 163.1) and 299 PD patients (173.2/100 patient-years; 95% CI, 154.1 to 194.0) were readmitted for any cause; and 121 hemodialysis patients (29.7/100 patient-years; 95% CI, 24.7 to 35.5) and 168 PD patients (44.7/100 patient-years; 95% CI, 38.2 to 52.0) were readmitted for an infection. Compared with hemodialysis, PD was not associated with a different mortality risk after an IRH (hazard ratio [HR], 0.87; 95% CI, 0.69 to 1.11). PD was associated with a higher risk of infection-related overall readmission compared with hemodialysis (HR, 1.44; 95% CI, 1.14 to 1.81), but not with the risk of all-cause overall readmission (HR, 1.15; 95% CI, 0.98 to 1.36). CONCLUSIONS: PD was not associated with higher mortality or all-cause overall readmission following an IRH compared with hemodialysis, but PD patients were at higher risk of infection-related overall readmission after IRH. IRHs are associated with significant mortality and overall readmissions. Evaluation of strategies to reduce infections in both hemodialysis and PD recipients are needed to improve patient care and outcomes. PMID- 25818338 TI - Dirac surface states and nature of superconductivity in Noncentrosymmetric BiPd. AB - In non-magnetic bulk materials, inversion symmetry protects the spin degeneracy. If the bulk crystal structure lacks a centre of inversion, however, spin-orbit interactions lift the spin degeneracy, leading to a Rashba metal whose Fermi surfaces exhibit an intricate spin texture. In superconducting Rashba metals a pairing wavefunction constructed from these complex spin structures will generally contain both singlet and triplet character. Here we examine the possible triplet components of the order parameter in noncentrosymmetric BiPd, combining for the first time in a noncentrosymmetric superconductor macroscopic characterization, atomic-scale ultra-low-temperature scanning tunnelling spectroscopy, and relativistic first-principles calculations. While the superconducting state of BiPd appears topologically trivial, consistent with Bardeen-Cooper-Schrieffer theory with an order parameter governed by a single isotropic s-wave gap, we show that the material exhibits Dirac-cone surface states with a helical spin polarization. PMID- 25818337 TI - Clinical and molecular characterization of patients with heterozygous mutations in wilms tumor suppressor gene 1. AB - BACKGROUND AND OBJECTIVES: The Wilms tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1, including patients without proteinuria or WT. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. RESULTS: Median age was 12.4 (interquartile range [IQR], 6-19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1-1.5] years) than in those with truncating (9.7 [IQR, 5.7-11.9]; P<0.001) and splice site (4.0 [IQR, 2.6-6.6]; P=0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01-9.3] years) than those with truncating mutations (16.5 [IQR, 16.5-16.8]; P<0.001) and splice site mutations (12.3 [IQR, 7.9-18.2]; P=0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations (n=19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. CONCLUSIONS: Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases. PMID- 25818340 TI - Tuberculosis in South Asian communities in the UK: a systematic review of the literature. AB - BACKGROUND: Rates of tuberculosis (TB) in UK South Asian communities are up to 17 times higher than in white British groups. Latent infection in new migrants provides only a partial explanation. We undertook a systematic review of the literature to establish existing knowledge about TB in South Asian communities. METHODS: We undertook a search for literature relating to TB and its management in South Asian communities in the UK. Articles initially identified were screened for relevance. A narrative review of relevant articles was then conducted. RESULTS: We found 18 relevant articles. Associated risk factors for TB included poverty, deprivation, return visits to the Indian subcontinent, history of close contact with a case, gender, religion, possible dietary factors such as Vitamin D deficiency, duration of stay in the UK and country of birth. However, the evidence for these factors was often conflicting or weak, and suggests that commonly proposed hypotheses may not provide robust explanations for the higher rates of diagnosis. CONCLUSIONS: Migration patterns and the demographic profile of the South Asian communities are constantly changing. Further research into the determinants of TB infection in these communities in the UK is urgently needed to inform the commissioning of TB health services. PMID- 25818339 TI - Immune evasion in cancer: Mechanistic basis and therapeutic strategies. AB - Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, gammadelta T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. PMID- 25818341 TI - [Colonoscopy sedation: clinical trial comparing propofol and fentanyl with or without midazolam]. AB - Colonoscopy is one of the most common procedures. Sedation and analgesia decrease anxiety and discomfort and minimize risks. Therefore, patients prefer to be sedated when undergoing examination, although the best combination of drugs has not been determined. The combination of opioids and benzodiazepines is used to relieve the patient's pain and discomfort. More recently, propofol has assumed a prominent position. This randomized prospective study is unique in medical literature that specifically compared the use of propofol and fentanyl with or without midazolam for colonoscopy sedation performed by anesthesiologists. The aim of this study was to evaluate the side effects of sedation, discharge conditions, quality of sedation, and propofol consumption during colonoscopy, with or without midazolam as preanesthetic. The study involved 140 patients who underwent colonoscopy at the University Hospital of the Federal University of Juiz de Fora. Patients were divided into two groups: Group I received intravenous midazolam as preanesthetic five minutes before sedation, followed by fentanyl and propofol; Group II received intravenous anesthesia with fentanyl and propofol. Patients in Group II had a higher incidence of reaction (motor or verbal) to the colonoscope introduction, bradycardia, hypotension, and increased propofol consumption. Patient satisfaction was higher in Group I. According to the methodology used, the combination of midazolam, fentanyl, and propofol for colonoscopy sedation reduces propofol consumption and provides greater patient satisfaction. PMID- 25818342 TI - A general strategy for nanohybrids synthesis via coupled competitive reactions controlled in a hybrid process. AB - A new methodology based on core alloying and shell gradient-doping are developed for the synthesis of nanohybrids, realized by coupled competitive reactions, or sequenced reducing-nucleation and co-precipitation reaction of mixed metal salts in a microfluidic and batch-cooling process. The latent time of nucleation and the growth of nanohybrids can be well controlled due to the formation of controllable intermediates in the coupled competitive reactions. Thus, spatiotemporal-resolved synthesis can be realized by the hybrid process, which enables us to investigate nanohybrid formation at each stage through their solution color changes and TEM images. By adjusting the bi-channel solvents and kinetic parameters of each stage, the primary components of alloyed cores and the second components of transition metal doping ZnO or Al2O3 as surface coatings can be successively formed. The core alloying and shell gradient-doping strategy can efficiently eliminate the crystal lattice mismatch in different components. Consequently, varieties of gradient core-shell nanohybrids can be synthesized using CoM, FeM, AuM, AgM (M = Zn or Al) alloys as cores and transition metal gradient-doping ZnO or Al2O3 as shells, endowing these nanohybrids with unique magnetic and optical properties (e.g., high temperature ferromagnetic property and enhanced blue emission). PMID- 25818343 TI - A meta-synthesis of factors influencing nursing home staff decisions to transfer residents to hospital. AB - AIM: To report a meta-synthesis of qualitative research studies exploring the role of nursing home staff in decisions to transfer residents to hospital. BACKGROUND: Nurses and nurse assistants provide the majority of care to residents living in nursing homes and may be the only health workers present when a resident deteriorates. To inform future strategies, it is vital to understand the role of nursing home staff in decisions to transfer to hospital. DESIGN AND REVIEW METHODS: A systematic review identified 17 studies to be included. The process of meta-synthesis was undertaken using the Joanna Briggs Institute's guidelines. DATA SOURCES: Qualitative research papers published between January 1989-October 2012 were identified in key databases including Cinahl, Embase, Medline and PsycInfo. RESULTS: Nursing home staff members play a key role in decision-making at the time of a resident's deterioration. Multiple factors influence decisions to transfer to hospital including an unclear expectation of the nursing home role; limited staffing capacity; fear of working outside their scope of practice; poor access to multidisciplinary support and difficulties communicating with other decision-makers. CONCLUSIONS: There is a lack of consensus regarding the role of the nursing home when a resident's health deteriorates. Nursing home staff would benefit from a clear prescription of their expected minimum clinical skill set; a staffing capacity that allows for the increased requirements to manage residents on-site, greater consistency in access to outside resources and further confidence and skills to optimize their role in resident advocacy. PMID- 25818344 TI - ADRA2A is involved in neuro-endocrine regulation of bone resorption. AB - Adrenergic stimulation is important for osteoclast differentiation and bone resorption. Previous research shows that this happens through beta2-adrenergic receptor (AR), but there are conflicting evidence on presence and role of alpha2A AR in bone. The aim of this study was to investigate the presence of alpha2A-AR and its involvement in neuro-endocrine signalling of bone remodelling in humans. Real-time polymerase chain reaction (PCR) and immunohistochemistry were used to investigate alpha2A-AR receptor presence and localization in bone cells. Functionality of rs553668 and rs1800544 single nucleotide polymorphism SNPs located in alpha2A-AR gene was analysed by qPCR expression on bone samples and luciferase reporter assay in human osteosarcoma HOS cells. Using real-time PCR, genetic association study between rs553668 A>G and rs1800544 C>G SNPs and major bone markers was performed on 661 Slovenian patients with osteoporosis. alpha2A AR is expressed in osteoblasts and lining cells but not in osteocytes. SNP rs553668 has a significant influence on alpha2A-AR mRNA level in human bone samples through the stability of mRNA. alpha2A-AR gene locus associates with important bone remodelling markers (BMD, CTX, Cathepsin K and pOC). The results of this study are providing comprehensive new evidence that alpha2A-AR is involved in neuro-endocrine signalling of bone turnover and development of osteoporosis. As shown by our results the neurological signalling is mediated through osteoblasts and result in bone resorption. Genetic study showed association of SNPs in alpha2A-AR gene locus with bone remodelling markers, identifying the individuals with higher risk of development of osteoporosis. PMID- 25818345 TI - The Japanese version of the Postpartum Bonding Questionnaire: Examination of the reliability, validity, and scale structure. AB - OBJECTIVE: The purpose of this study was to develop the Japanese version of the Postpartum Bonding Questionnaire (PBQ) to gather data on Japanese mothers for comparison with other cultures and to examine the scale structure of the PBQ among Japanese mothers. METHODS: We administered the PBQ to a cross-section of 244 mothers 4 weeks after delivery and again 2 weeks later to 199 mothers as a retest to examine reliability. We used exploratory factor analysis to evaluate the factor structure of the PBQ. Correlations with the Mother-to-Infant Bonding Scale (MIBS), the Maternal Attachment Inventory (MAI), Edinburgh Postnatal Depression Scale (EPDS), and sociodemographic variables were calculated for validation. RESULTS: The 14-item version of the PBQ extracted by exploratory analysis consisted of four factors: 'impaired bonding', 'rejection and anger', 'anxiety about care', and 'lack of affection'. We found significant correlations of the total scores of the PBQ and the 14-item version of the PBQ positively with the MIBS and negatively with the MAI. Moderate significant correlations with total scores were also found with the EPDS. Total scores for primiparous and depressed mothers were higher than those for multiparous mothers and mothers without depression. CONCLUSION: The results of this study demonstrated the reliability and validity of the PBQ and the 14-item version of the PBQ in Japanese mothers 4 weeks after delivery. PMID- 25818346 TI - A new questionnaire to identify bodily distress in primary care: The 'BDS checklist'. AB - BACKGROUND: Functional symptoms and disorders are common in primary care. Bodily distress syndrome (BDS) is a newly proposed clinical diagnosis for functional disorders. The BDS diagnosis is based on empirical research, and the symptoms stated in the BDS criteria have been translated into a self-report questionnaire called the BDS checklist. The aim of the present study was to investigate the psychometric properties of the checklist and to test the construct of BDS. METHOD: The 30-item BDS checklist was completed by 2480 adult primary care patients in a cross-sectional study on contact and disease patterns in Danish general practice. We performed (internal) validation analyses of the collected checklist data. We also performed factor and latent class analyses to identify both BDS symptom groups and BDS patient groups. RESULTS: Internal validation analyses revealed acceptable and usable psychometric properties of the BDS checklist. The factor analyses identified the four distinct determining factors for BDS: cardiopulmonary, gastrointestinal, musculoskeletal and general symptoms. Results from factor and multi-trait analyses suggested a shortening of the BDS checklist (from 30 to 25 items). The latent class analyses resulted in three severity levels (no, moderate and severe BDS); the best fit index was found for a threshold of >=4 symptoms in a symptom group. CONCLUSION: The results provide empirical support for the previously described construct of BDS with four symptom groups and three patient groups. The BDS checklist is a self-report instrument that may be used for case finding in both clinical practice and in research. PMID- 25818347 TI - Airway management considerations in children with I-cell disease. AB - Inclusion-cell disease (mucolipidosis II/I-cell disease) is a lysosomal storage disease characterized by a constellation of physical findings which complicate airway management. There is currently a deficit of published literature describing appropriate strategies for acute management of these children's airways. This paper details emergency and anesthetic airway management concerns and potential solutions in a small series of children with I-cell disease. PMID- 25818348 TI - Pediatric patients with chronic cough and recurrent croup: the case for a multidisciplinary approach. AB - OBJECTIVE: To evaluate the results of our multidisciplinary approach to recurrent croup and chronic cough. METHODS: Retrospective chart review of all patients with recurrent croup and chronic cough managed at a tertiary care children's hospital by our Comprehensive Airway, Respiratory, and Esophageal (CARE) Team. Charts were reviewed for all patients who carried a diagnosis of recurrent croup or chronic cough. Patients were excluded if they did not receive a full workup, including micro-direct laryngoscopy, flexible and/or rigid bronchoscopy, bronchioalveolar lavage (BAL), and upper endoscopy with biopsies. We reviewed the records for the presence of gastrointestinal complaints, abdominal pain and failure to thrive (FTT) and compared the children with documented esophagitis to the remaining children. RESULTS: Forty patients met inclusion criteria. 53% had airway abnormalities; the most common was tracheomalacia, followed by enlarged adenoids. 38% had esophagitis (group 1) while 62% had normal esophageal biopsies (group 2). Among the children in group 1, 27% met criteria for eosinophilic esophagitis (>15 eosinophils per high powered field). There was no significant difference between groups 1 and 2 based on the presence of gastrointestinal complaints, abdominal pain and/or FTT (p>0.05). There was no significant difference between the groups based on the location or presence of an airway abnormality (p>0.05). CONCLUSIONS: Children with recurrent croup and chronic cough may benefit from a multidisciplinary approach to management. Our CARE Team approach led to a specific diagnosis in almost 95% of patients. PMID- 25818349 TI - A case of HPV and acquired genital lymphangioma: over-lapping clinical features. AB - Lymphatic malformation or lymphangioma is a benign proliferation of the lymphatics accounting for 4% of all vascular malformations and 26% of all benign vascular tumors. There are several reports about genital lymphangiomas mimicking venereal lesions, such as genital warts. Hereby we described a case of a 24 year old man affected by multiple vesicles and warts in genital area. All hematological and biochemical parameters, Human Immunodeficiency Virus (HIV) and Treponema Pallidum tests, C1-Inhibitor and C1-Q values were within limits. An accurate fulguration and wide excision of bigger lesions were performed. Histological examination showed numerous dilated lymphatic vessels in the superficial dermis with infiltration of inflammatory cells, that is a histopathological picture compatible with genital lymphangioma. Considering our clinical suspicion of condylomatosis, HPV (Human Papilloma Virus) Polimerase Chain Reaction (PCR) Genotyping, named INNOLiPA test, was performed, that revealed a genital infection by HPV - genotype 6. We think that our case can be considered an example of HPV infection and acquired genital lymphangioma overlap clinical syndrome. The patient presented any lesions one year after the procedure at follow-up examination. PMID- 25818351 TI - A retrospective evaluation of aesthetic outcomes for single-tooth implants in the anterior maxilla. AB - OBJECTIVES: To investigate objective and patient-centred aesthetic outcomes for single-tooth implants in the anterior maxilla. MATERIALS AND METHODS: Ninety eight patients (21 men and 77 women) with a mean age of 51.2 +/- 3.8 years were included in this retrospective study. A total of 98 maxillary anterior single tooth implant crowns with a mean functional time of 68.1 months (range 12-245) were evaluated. Aesthetic outcomes were measured by PES and WES. Statistical analysis was performed using the Mood's median and stepwise logistic regression with backward elimination to assess the effect of patient demographics, clinical parameters and surgical methods on aesthetic outcome (P < 0.05). RESULTS: The median PES was 11 and 94% of implants were deemed aesthetically acceptable. The median WES was 9 and 98% of implants were deemed aesthetically acceptable. The PES was positively influenced by the use of a connective tissue graft (CTG), adding 1 to the score (P = 0.002) and negatively influenced by membrane use (P = 0.026). Flapless techniques employed as part of an immediate implant placement protocol yielded better outcomes compared to flapped sites (P = 0.017). Immediate implant placement demonstrated greater variability in outcomes compared to early implant placement. CONCLUSIONS: Satisfactory objective and patient-reported aesthetic outcomes were achieved with dental implants replacing missing single teeth in the anterior maxilla. The use of CTG improved the aesthetic outcome mainly by increasing the alveolar process contour. Less variation in outcomes was observed with early (type 2) placement compared to immediate (type 1 placement). PMID- 25818350 TI - The Adh adhesin domain is required for trimeric autotransporter Apa1-mediated Actinobacillus pleuropneumoniae adhesion, autoaggregation, biofilm formation and pathogenicity. AB - Actinobacillus pleuropneumoniae is a causative agent of porcine pleuropneumonia, which is a highly contagious endemic disease of pigs. Adhesion is a critical first step in the infection process. Trimeric autotransporter adhesions (TAAs) have been identified as novel virulence factors; however, little is known on their roles in A. pleuropneumoniae pathogenicity. Here, our data show that YadA like head region (Adh) of Apa1 was the optimal adhesion functional domain via segment expression and adhesion assays in vitro. Additionally, Adh induced partial protection against A. pleuropneumoniae 5b L20 and serotypes 1, 3, and 5a in mice. The deletion of Adh gene significantly decreased autoaggregation, biofilm formation and adherence to host cells in vitro. Furthermore, with delaying of clinical symptoms, reducing production of pro-inflammatory cytokines and lessening the lung injury after infection, Adh deletion strain (5bphiAdh) significantly reduced the pathogenicity to piglets. To elucidate the mechanism of lung injury, the differentially expressed genes in the lung tissues of piglets infected with the 5b L20 or 5bphiAdh strains were investigated using microarray analysis and validated by qRT-PCR. Compared with the 5b L20 infected piglets, 495 genes were differentially expressed in 5bphiAdh infected lung tissue (221 upregulated and 274 downregulated). Especially, the antigen processing and presentation gene IFI30 was increased following infection with the 5bphiAdh strain. Thus, Adh may enhance pathogenicity by depressing host immune recognition. We conclude that the head domain of the A. pleuropneumoniae trimeric autotransporter Apa1 regulates autoagglutination, biofilm formation, adhesion to host cells and pathogenicity. PMID- 25818352 TI - What Should Be Done With Survivors of a Cardiac Arrest? Induce Hypothermia or Just Avoid Hyperthermia? PMID- 25818353 TI - Quo vadis, troponin? PMID- 25818354 TI - Effects of hydrothermal temperature and time on hydrothermal synthesis of colloidal hydroxyapatite nanorods in the presence of sodium citrate. AB - In this paper, colloidal hydrophilic hydroxyapatite nanorods were synthesized in the presence of sodium citrate via thermal-decomplexing method. The influences of hydrothermal temperature and time on the synthesis of HA nanorods were characterized in terms of structure, size, morphology, and colloidal stability through TEM, XRD, zeta potential, DLS and long-term standing test. Results show that increasing hydrothermal temperature and prolonging hydrothermal time would evidently improve crystallinity and enlarge size of HA nanorods but decrease the colloidal stability of nanorods. It is worth noting that the effect of raising the hydrothermal temperature and time on diameter increase is far greater than that on length increase; meanwhile, the colloidal stability would be seriously deteriorated when the hydrothermal temperature is over 180 degrees C for 24 h or when the hydrothermal temperature is 150 degrees C for over 48 h, in these cases, dispersion of HA nanorods would apparently settle within 2 months. The origin responding to the results is that although the charge density of HA nanorods is not obviously affected, the dynamic diameters of HA particles increase greatly, which reduces colloidal stability of the dispersion. This work provides new insights into the role of hydrothermal temperature and time on tailoring morphology, crystallinity and colloidal stability of HA nanorods. Moreover, it would be helpful to optimize the experimental procedure both on scientific and industrial applications related to HA. For example, on the premise of satisfying the necessary requirements including crystallinity, size, morphology and colloid stability, it is feasible to compress the consumption of experimental time through raising the hydrothermal temperature, or vice versa. PMID- 25818355 TI - A hybrid PCL/collagen scaffold consisting of solid freeform-fabricated struts and EHD-direct-jet-processed fibrous threads for tissue regeneration. AB - Hybrid biomedical structures have been used widely in various tissue-regenerating materials because they effectively induce exceptional physical and cellular responses. In this study, a new hybrid process was used to design a three dimensional (3D) biomedical hybrid scaffold with a controlled pore-structure and high mechanical strength. A melt-dispensing method was used to obtain mechanical properties and electrohydrodynamic direct-jet (EHD-DJ) printing was used to provide microsized fibrous structures for the scaffold. Furthermore, the poly(epsilon-caprolactone) (PCL) hybrid scaffolds were coated biomimetically with type-I collagen to increase bioactive interactions between cells and scaffolds. The fabricated scaffolds showed similar mechanical properties to the two control scaffolds; however, the results of culturing osteoblast-like (MG63) cells showed significant increases in in vitro cellular activities (cell viability>twofold and calcium deposition>sevenfold). Based on these results, we propose a newly designed hybrid scaffold that can support significant in vitro cellular activities at the interface between cells and the 3D micro-pore structure for soft and hard tissue regeneration. PMID- 25818356 TI - PdCo alloy nanoparticle-embedded carbon nanofiber for ultrasensitive nonenzymatic detection of hydrogen peroxide and nitrite. AB - PdCo alloy nanoparticle-embedded carbon nanofiber (PdCo/CNF) prepared by electrospinning and thermal treatment was employed as a high-performance platform for the determination of hydrogen peroxide and nitrite. The as-obtained PdCo/CNF were characterized by transmission electron microscopy, energy-dispersive X-ray spectroscopy and X-ray diffraction. Electrochemical impedance spectroscopy, cyclic voltammetry and differential pulse voltammetry were employed to investigate the electrochemical behaviors of the resultant biosensor. The proposed PdCo/CNF-based biosensor showed excellent analytical performances toward hydrogen peroxide (detection limit: 0.1 MUM; linear range: 0.2 MUM-23.5 mM) and nitrite (detection limit: 0.2 MUM; linear range: 0.4-30 MUM and 30-400 MUM). The superior analytical properties could be attributed to the synergic effect and firmly embedment of well-dispersed PdCo alloy nanoparticles. These attractive electrochemical properties make this robust electrode material promising for the development of effective electrochemical sensors. PMID- 25818357 TI - Synthesis of fluorinated ceramic Janus particles via a Pickering emulsion method. AB - HYPOTHESIS: Dispersion or aggregation of ceramic nanoparticles in suspension is mainly influenced by their surface properties. The preparation of hydrophobic/hydrophilic nanoparticles was studied by synthesizing for the first time fluorinated Janus particles via a Pickering emulsion method. EXPERIMENTS: Fluorinated silica Janus particles were synthesized with a "grafting to" method using silica/wax emulsions. The parameters investigated to control the emulsion were (i) the SiO2 particles/wax ratio, (ii) the cetyltrimethylammonium bromide (CTAB)/SiO2 ratio and (iii) the ionic strength, i.e. NaCl concentration. Prior to grafting with fluorinated molecules, the partially wax-embedded silica particles were functionalized with an aminosilane. Fourier Transformed Infrared and Nuclear Magnetic Resonance spectroscopies, thermogravimetric and zeta potential analyzes were conducted to characterize the fluorinated Janus particles. FINDINGS: Silica quantity has an influence on the silica nanoparticles distribution at the surface of the wax solid droplets. CTAB amount controls the size and shape of silica/wax solid droplets, whereas the ionic strength in the range 0-6.22 g L(-1) does not influence the silica/wax emulsion. Aminosilane functionalization was successfully employed on partially wax-embedded silica particles, followed by a grafting step with a carboxylic acid fluorinated compound. PMID- 25818358 TI - Anti-ictogenic and antiepileptogenic properties of brivaracetam in mature and immature rats. AB - OBJECTIVE: Brivaracetam (BRV) is a new antiepileptic drug candidate rationally designed for high affinity and selectivity for the synaptic vesicle protein 2A. This study explored anti-ictogenic and antiepileptogenic effects of BRV in rats at different stages of development. METHODS: Using a rapid kindling model in P14, P21, P28, and P60 rats, we studied two doses of BRV: 10 and 100 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of BRV 30 min after the injection. RESULTS: BRV 100 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas BRV at 10 mg/kg increased ADT in P60, P28, and P21 rats. BRV also shortens the afterdischarge duration (ADD), achieving statistical significance with 10 and 100 mg/kg at P60 and with 100 mg/kg at P21. At P60, BRV increases the number of stimulations required to achieve a stage 4-5 seizure in a dose dependent manner. At P28 and P21, BRV increased the number of stimulations required to develop a stage 4-5 seizure in a dose-dependent manner with almost complete elimination of stage 4-5 seizures. In contrast, at P14, BRV had no effect on the number of stage 4-5 seizures. An age-related decrease in blood and brain concentrations of BRV was observed 30 min after injection of BRV 10 mg/kg, whereas with 100 mg/kg there were no significant age-correlated differences in brain and serum BRV concentrations. SIGNIFICANCE: BRV exerted dose-dependent anti ictogenic effects from P60 to P14 independent of brain maturation. BRV also exhibited antiepileptogenic effects at P60, whereas this effect need to be further evaluated at P28 and P21. We did not observe any effect on epileptogenesis at P14 at either dose. PMID- 25818359 TI - [50th annual meeting of the Societe de Pneumologie de l'Ouest. The journey of chest medicine: From past to its future]. PMID- 25818360 TI - Expanding roles for AMPK in skeletal muscle plasticity. AB - Skeletal muscle possesses a remarkable plasticity and responds to environmental and physiological challenges by changing its phenotype in terms of size, composition, and metabolic properties. Muscle fibers rapidly adapt to drastic changes in energy demands during exercise through fine-tuning of the balance between catabolic and anabolic processes. One major sensor of energy demand in exercising muscle is AMP-activated protein kinase (AMPK). Recent advances have shed new light on the relevance of AMPK both as a multitask gatekeeper and as an energy regulator in skeletal muscle. Here we summarize recent findings on the function of AMPK in skeletal muscle adaptation to contraction and highlight its role in the regulation of energy metabolism and the control of skeletal muscle regeneration post-injury. PMID- 25818361 TI - Evaluation of inertial cavitation activity in tissue through measurement of oxidative stress. AB - Ultrasound cavitation is an essential mechanism involved in the therapeutic local enhancement of drug delivery by ultrasound for cancer treatment. Inertial cavitation also triggers chemical reactions that generate free radicals and subsequent oxidative stress in the tissue. The aim of this study was to measure the oxidative stress induced by inertial cavitation in ex vivo tissue and to test the association between the exposure conditions and the oxidative stress. A confocal ultrasound setup was used to sonicate and create inertial cavitation in freshly excised adipose pig tissue. The ex vivo tissue samples were then processed to measure the quantity of malondialdehyde (MDA), an end-product of polyunsaturated free fatty acid oxidation. The creation of hydroxyterephthalic acid (HTA) from the reaction of terephthalic acid (TA) with free radicals in water was also quantified in vitro. Samples were sonicated for different durations using various amplitudes for the applied pressure. The results showed a minimum 2-fold increase in the amount of detected MDA in the sonicated tissue samples compared to baseline clearly suggesting the generation of free radicals by inertial cavitation. The method exhibited a moderate dependence of MDA generated upon the duration of exposure (R(2)=057,p<0.0001). The average increase in MDA concentration was approximately 2-fold, 5-fold, 6-fold, and 9-fold for exposure durations per unit of volume of 0.13, 0.17, 0.25, and 0.50s/mm(3), respectively. The results showed no statistically significant dependence on the amplitude of the pressure within the used range. Both pressure amplitude and exposure duration, however, influenced the HTA concentration (R(2)>0.95,p<0.0001). This biochemical method can be used on ex vivo tissue to detect the generation of free radicals induced by inertial cavitation. In large enough sample populations, the cavitation activity is linked to the exposure conditions of the sonication. PMID- 25818362 TI - Ultrasonic cavitation erosion of Ti in 0.35% NaCl solution with bubbling oxygen and nitrogen. AB - The influences of oxygen and nitrogen on the ultrasonic cavitation erosion of Ti in 0.35%NaCl solution at room temperature, were investigated using a magnetostrictive-induced ultrasonic cavitation erosion (CE) facility and scanning electron microscopy (SEM). The roles of oxygen and nitrogen in the composition and the electronic property of the passive film on Ti, were studied by Mott Schottky plot and X-ray photoelectron spectroscopy (XPS). The results showed that the mass loss of Ti in 0.35%NaCl solution increased with increasing cavitation time. Bubbling oxygen can evidently increase the resistance of ultrasonic cavitation erosion comparing with bubbling nitrogen. XPS results showed that the thickness of the passive film on Ti in 0.35%NaCl solution in the case of bubbling oxygen for 3 weeks, was about 7 nm, and the passive film was mainly composed of TiO2 with an anatase structure. While TiO2 with a rutile structure was found to be the major component of the passive film on Ti in 0.35%NaCl solution in the case of bubbling nitrogen for 3 weeks, and the film thickness was 5 nm. The results extracted from Mott-Schottky plot showed that the passive film on Ti in the case of bubbling oxygen had more donor density than the passive film on Ti in the case of bubbling nitrogen. PMID- 25818363 TI - Sulfur removal from bauxite water slurry (BWS) electrolysis intensified by ultrasonic. AB - Effects of ultrasonic on desulfurization ratio from bauxite water slurry (BWS) electrolysis in NaOH solution were examined under constant current. The results indicated that ultrasonic improved the desulfurization ratio at high temperatures because of the diffusion and transfer of oxygen gas in electrolyte. However, due to the increase in oxygen gas emission, ultrasonic could not improve the desulfurization ratio obviously at low temperatures. Additionally, the particle size of bauxite became fine in the presence of ultrasonic, indicating that the mass transfer of FeS2 phase was improved. According to the polarization curves, the current density increased in the presence of ultrasonic, indicating that the mass transfer of liquid phase was improved. The apparent activation energy (AAE) of electrode reaction revealed that ultrasonic did not change the pathway of water electrolysis. However, ultrasonic changed the pathway of BWS electrolysis, converting indirect oxidation into direct oxidation. The AAE of BWS electrolysis in the presence of ultrasonic was higher than that in the absence of ultrasonic. And the low AAEs (less than 20 kJ/mol) clearly indicated the diffusion control during BWS electrolysis reaction. PMID- 25818364 TI - Immunomodulatory effect of cathelicidins in response to a beta-glucan in intestinal epithelial cells from rainbow trout. AB - The aim of the present study was to characterize intestinal immune mechanisms involved in the response to beta-glucans in rainbow trout. Among the immune effectors regulated in response to immunostimulants, host defense peptides (HDPs) are abundantly expressed in epithelial linings, suggesting their important role in the mucosal immune response. Therefore, the immunomodulatory properties of expressed HDPs in the epithelial intestinal cells of rainbow trout in response to the beta-glucan, zymosan, were assessed. The results showed that zymosan increased the production of the HDP, cathelicidin, and the cytokine, IL-1beta, in the intestinal epithelial RTgutGC cell line at the transcript and protein levels. Thus, cathelicidin-2 variants were produced and were shown to (i) induce the production of IL-1beta in RTgutGC cells and (ii) display a synergic effect with zymosan in IL-1beta upregulation. Importantly, the colocalization of both rtCATH 2 and IL-1beta was detected in the intestinal epithelial cells of rainbow trout fed with a 0.3% zymosan-supplemented diet. We propose that trout cathelicidins are expressed by intestinal epithelial cells and exert immunomodulatory effects to improve the local intestinal immune response triggered by immunostimulants. PMID- 25818365 TI - Fighting the force: Potential of homeobox genes for tumor microenvironment regulation. AB - Tumor cells exist in a constantly evolving stromal microenvironment composed of vasculature, immune cells and cancer-associated fibroblasts, all residing within a dynamic extracellular matrix. In this review, we examine the biochemical and biophysical interactions between these various stromal cells and their matrix microenvironment. While the stroma can alter tumor progression via multiple mechanisms, we emphasize the role of homeobox genes in detecting and modulating the mechanical changes in the microenvironment during tumor progression. PMID- 25818366 TI - An analytical model accounting for tip shape evolution during atom probe analysis of heterogeneous materials. AB - An analytical model describing the field evaporation dynamics of a tip made of a thin layer deposited on a substrate is presented in this paper. The difference in evaporation field between the materials is taken into account in this approach in which the tip shape is modeled at a mesoscopic scale. It was found that the non existence of sharp edge on the surface is a sufficient condition to derive the morphological evolution during successive evaporation of the layers. This modeling gives an instantaneous and smooth analytical representation of the surface that shows good agreement with finite difference simulations results, and a specific regime of evaporation was highlighted when the substrate is a low evaporation field phase. In addition, the model makes it possible to calculate theoretically the tip analyzed volume, potentially opening up new horizons for atom probe tomographic reconstruction. PMID- 25818367 TI - Study of frozen low density lipoprotein particles by using nanotechnology. AB - OBJECTIVES: To investigate the impact of freezing in -80 degrees C on the structure of isolated low density lipoproteins (LDLs), using nanotechnology, such as Atomic Force Microscopy (AFM). DESIGN AND METHODS: Blood EDTA plasma was obtained from healthy subject and used immediately to isolate LDL by sequential ultracentrifugation at 10 degrees C in 55,000 rpm for 3h, using a Beckmann XL-90 ultracentrifuge (75Ti rotor), in the presence of KBr in PBS. LDLs were then diluted with PBS until final concentrations of 5 and 15 mg LDL/dl. After initial observation, samples were frozen in -80 degrees C for two weeks and observed again after thawing. Experiments were performed in triplicate on two smooth and clean substrates of different hydrophobicity, glass (HOPG) and Si (c-Si). Statistical significance was set at 0.05. RESULTS: Macroscopically, LDL particles formed aggregations in a dendroid layout. There were no differences between images taken from both substrates (HOPG and c-Si). Frozen samples presented significantly smaller LDL particles, than fresh ones. In specific, mean diameter of LDL particle in the fresh LDL sample was 19.77 nm, ranging from 13.34 to 28.76 nm. The frozen LDL sample had a mean diameter of 5.2 nm, ranging from 2.0 to 8.0 nm, which was significantly different from the unfrozen. CONCLUSIONS: Atomic Force Microscopy showed that freezing of LDL causes alterations in their size. PMID- 25818368 TI - Screening for melanoma resistance genes in vivo. PMID- 25818369 TI - Splenic infarction - A rare cause of acute abdominal pain following gastric surgery: A case series. AB - INTRODUCTION: The dissection of splenic hilar lymph nodes in gastric cancer surgery is indispensable for treating gastric cancers located in the proximal third of the stomach. Splenic vascular injury is a matter of debate resulting on time or delayed splenectomy. We aimed to share our experience and plausible mechanisms causing this complication in two case reports. CASE PRESENTATIONS: Two male patients with gastric cancer were diagnosed with acute splenic infarction following gastric surgery in the early postoperative period. Both underwent emergent exploratory laparotomy. Splenectomy was performed due to splenic infarction. DISCUSSION: Because we observed this rare complication in recent patients whose surgery was performed using vessel-sealing device for splenic hilar dissection, we suggested that extensive mobilization of the surrounding tissues of splenic vascular structures hilum using the vessel sealer could be the reason. CONCLUSION: In case of acute abdominal pain radiating to left shoulder, splenic complications should be taken into consideration in gastric cancer patients performed radical gastrectomy. Meticulous dissection of splenic hilar lymph nodes should be carried out to avoid any splenic vascular injury. PMID- 25818370 TI - Colon cancer metastasis mimicking intraductal papillary neoplasm of the extra hepatic bile duct. AB - INTRODUCTION: An accurate diagnosis of the primary cancer in cases with metastatic lesions is quite important because misdiagnosis may lead to the selection of incorrect adjuvant therapy and worse long-term outcomes after surgery. The metastatic sites associated with the dissemination of colon cancer are well known and normally predictable, which includes the lymphatic, haematogenous, or peritoneal regions, while other locations are quite rare. PRESENTATION OF CASE: In this report, we present a case of colon cancer with an unusual metastatic pattern mimicking an intraductal papillary neoplasm of the bile duct (IPNB) present in the extra-hepatic bile duct with a cytokeratin (CK)-7 negative and CK-20-positive profile (intestinal type). DISCUSSION: In the case of this patient who had a history of colon cancer, immunohistochemical staining for the CKs was useful for distinguishing between primary IPNB and colon cancer metastases. We suspect that the metastatic pattern of this case of colon cancer that mimicked IPNB at the extra-hepatic bile duct developed incidentally via the bile stream. CONCLUSION: This is a rare case of colon cancer metastasis mimicking IPNB at the extra-hepatic bile duct. Our findings also suggest that there may be an incidental 4th metastatic route via the bile stream. PMID- 25818371 TI - Robotic-assisted surgery for excision of an enlarged prostatic utricle. AB - INTRODUCTION: Prostatic utricle is a rare malformation arising from incomplete regression of the Mullerian ducts. Diagnosis is easily made but management may be challenging. The minimally invasive approach has so far been considered the gold standard for surgical treatment. Many endoscopic and surgical procedures have been described for removal, but to date only few cases of robot-assisted procedures have been mentioned in the literature and there are no reports of redos. PRESENTATION OF THE CASE: We report the case of a giant prostatic utricle cyst successfully treated with robotic-assisted surgery two years after an unsuccessful first attempt at laparoscopic excision. No relapse was found at one year follow up. DISCUSSION: We were able to excise a retro-vescical structure in spite of adhesions caused by the previous surgery and the very large size of the diverticulum thanks to the high magnification and 3-D visualization available in robotic assisted laparoscopy. CONCLUSION: Robot assisted laparoscopy should be considered an advantageous technique for the treatment of prostatic utricle. PMID- 25818372 TI - Cecal volvulus caused by a large uterine leiomyoma. AB - INTRODUCTION: Cecal volvulus is a relatively uncommon encountered clinical condition. PRESENTATION OF CASE: A 48-year-old patient known with a large uterine leiomyoma, presented with progressive abdominal pain since one week. An abdominal computed tomography scan revealed a very large leiomyoma of the uterus, severely distended loops of the small bowel with a caliber change and a suggested 'whirl sign' of the mesenteric vessels. A laparotomy was performed, showing a very large uterus as well as torsion of the mesentery of the cecum with a sharp demarcated area of necrosis of the right hemicolon. DISCUSSION: Cecal volvulus due to a large uterine mass is a rare encountered clinical entity. The suggested mechanism might be the same mechanism causing cecal volvulus during pregnancy; the enlarged uterus raisingout the mobile cecum out of the pelvis. Obstruction may occur from kinking of the colon at a fixed point. CONCLUSION: This case demonstrates that uterine leiomyoma can be a cause of a cecal volvulus, leading to severe intestinal strangulation. PMID- 25818373 TI - Secondary prevention: the Heart Foundation's experience in driving change through advocacy. AB - INTRODUCTION: Heart disease is the leading single cause of death for men and women in Australia. There are 685,000 people living with heart disease, approximately 50% will be experiencing signs and symptoms of heart failure. This article aims to articulate the key advocacy activities required to improve the provision of evidence-based secondary prevention including cardiac rehabilitation and multidisciplinary chronic heart failure management services. METHOD: The Heart Foundation undertook an extensive consultation process with many experts, policy makers, health and public health professionals through forums, evidence reviews and working groups. A range of actions are required to improve access to secondary prevention, but only those that the Heart Foundation could drive and support have been included. RESULTS: The results identified three synergistic advocacy areas between heart failure and cardiac rehabilitation to drive secondary prevention advocacy. These were data, policy and people. DISCUSSION: The priority actions are discrete and tangible to progress rather than revisit established evidence-based recommendations, and to support uptake and implementation at a national and state/territory level. We must consider the current landscape within which secondary prevention sits and identify the intersecting barriers and enablers that can be influenced. There is no single solution or lever for change. CONCLUSION: Best-practice management of heart disease can be achieved through a co-ordinated effort to implement system change. Focus should be paid to a multi-faceted approach in the key advocacy areas identified here - data, policy and people - as these will provide benefit across the disease continuum, from secondary prevention and cardiac rehabilitation through to heart failure management. PMID- 25818374 TI - Transcatheter Aortic Valve Implantation (TAVI) in Patients With Bicuspid Aortic Valve Stenosis--Systematic Review and Meta-Analysis. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a feasible interventional technique for severe aortic stenosis in patients who are deemed inoperable or at high surgical risk. There is limited evidence for the safety and efficacy of TAVI in patients with bicuspid aortic valves (BAV), the most common congenital valve abnormality. In many TAVI trials, patients with BAV have been contraindicated due to concerns surrounding abnormal valve geometry, leading to malfunction or malpositioning. A systematic review and meta-analysis was conducted in order to assess the current evidence and relative merits of TAVI in aortic stenosis patients with BAV. METHOD: From six electronic databases, seven articles including 149 BAV and 2096 non-BAV patients undergoing TAVI were analysed. RESULTS: Between the BAV and no-BAV cohorts, there was no difference in 30-day mortality (8.3% vs 9.0%; P=0.68), post-TAVI mean peak gradients (weighted mean difference, 0.36 mmHg; P=0.55), moderate or severe paravalvular leak (25.7% vs 19.9%; P=0.29), pacemaker implantations (18.5% vs 27.9%; P=0.52), life threatening bleeding (8.2% vs 13.9%; P=0.33), major bleeding (20% vs 16.8%; P=0.88), conversion to conventional surgery (1.9% vs 1.2%; P=0.18) and vascular complications (8.6% vs 10.1%; P=0.32). CONCLUSIONS: Preliminary short and mid term pooled data from observation studies suggest that TAVI is feasible and safe in older patients with BAV. While future randomised trials are not likely, larger adequately-powered multi-institutional studies are warranted to assess the long term durability and complications associated with TAVI in older BAV patients with severe aortic stenosis. PMID- 25818375 TI - Protein-losing enteropathy associated with refractory systemic lupus erythematosus with a good response to rituximab. AB - A case is presented of a protein-losing enteropathy (PLE) as the initial manifestation of systemic lupus erythematosus (SLE) in a 17 year-old female patient, who presented with ascites, edema and hypoalbuminemia. The diagnosis of SLE was based on the presence of: malar rash, oral ulcers, thrombocytopenia, antinuclear antibodies, IgM anticardiolipin antibody, and lupus anticoagulant. Renal and liver diseases were ruled out. The PLE diagnosis was confirmed with fecal alpha 1-antitrypsin clearance. The PLE was refractory to different lines of immunosuppressive agents like glucocorticoids, cyclophosphamide, azathioprine, and cyclosporine, showing a satisfactory and sustained response with rituximab, allowing steroid sparing and long term remission. PMID- 25818376 TI - Sacroiliitis and gluteal abscess secondary to Staphylococcus aureus infection. PMID- 25818377 TI - Is it Time to Take a Second Look at Second-look Laparoscopy? PMID- 25818378 TI - Trends and structural shifts in health tourism: evidence from seasonal time series data on health-related travel spending by Canada during 1970-2010. AB - There has been a growing interest in better understanding the trends and determinants of health tourism activities. While much of the expanding literature on health tourism offers theoretical or qualitative discussion, empirical evidences has been lacking. This study employs Canada's outbound health tourism activities as an example to examine the trends in health tourism and its association with changing domestic health care market characteristics. A time series model that accounts for potential structural changes in the trend is employed to analyze the quarterly health-related travel spending series reported in the Balance of Payments Statistics (BOPS) during 1970-2010 (n = 156). We identified a structural shift point which marks the start of an accelerated growth of health tourism and a flattened seasonality in such activities. We found that the health tourism activities of Canadian consumers increase when the private investment in medical facilities declines or when the private MPI increases during the years following the structural-change. We discussed the possible linkage of the structural shift to the General Agreement on Trade in Services (GATS), which went into effect in January, 1995. PMID- 25818379 TI - The role of perceived impact on relationship quality in pharmacists' willingness to influence indication-based off-label prescribing decisions. AB - Little is known about factors that affect pharmacists' roles in off-label prescribing. This study examined the effect of perceived impact on relationship quality (IRQ) on hospital pharmacists' willingness to influence a physician's decision regarding an indication-based off-label medication order (WTIP) (i.e., beyond FDA-approved indications) and the moderating roles of the appropriateness of the medication order and the relative expert power of the pharmacist. Pharmacists practicing in U.S. hospitals, recruited from membership rolls of state affiliates of the American Society of Health-System Pharmacists, were sent an electronic link to a questionnaire via their respective affiliates. A cross sectional, randomized, 2 * 2 experimental design was used; participants were assigned to one of the indication-based off-label medication order scenarios. Relative expert power (i.e., power differential between the pharmacist and the physician) and appropriateness of the prescription were manipulated. Perceived IRQ was measured with multiple items. Pharmacists' WTIP in the scenario was the outcome variable. A total of 243 responses were included in multiple linear regression analyses. After controlling for dependence power, information power, communication effectiveness, perceived responsibility, and attitude, pharmacists' WTIP was negatively affected by perceived IRQ (estimate = -0.309, P < 0.05). This effect was more pronounced in groups exposed to the scenario where the pharmacist had lower relative expert power (estimate = -0.438, P < 0.05) and where the medication was less appropriate (estimate = -0.503, P < 0.05). Although willing to ensure rationality of off-label prescribing, pharmacists' WTIP was affected by a complex array of factors - the perceived impact of influence attempts on relationship quality between the pharmacist and the prescriber, the pharmacist's relative expert power, and the appropriateness of the off-label prescription. Increasing pharmacists' expert power and collaboration with physicians and promoting pharmacists' multifaceted contribution, collaborative or independent, to patient care may facilitate pharmacist services in off-label pharmaceutical care. PMID- 25818380 TI - Social networks and health policy: the case of misoprostol and the WHO model essential medicine list. AB - The WHO Essential Medicines List (EML) was established to help countries prioritise medicines according to their health care needs. Selection for the List is based on rigorous scrutiny of public health relevance, evidence on efficacy and safety, and comparative cost effectiveness. The WHO ideal is that a medicine and its efficacy are based on science, but in reality a medicine has a social life and the acceptance of a pharmaceutical intervention involves the interaction of a wide array of governmental and civil society organisations, and industry. Misoprostol is a medicine widely used for both abortion and prevention of postpartum haemorrhage in low income countries. Although the evidence for the latter is highly contested it was nevertheless added to the WHO EML in 2011. We use social network analysis to examine the social, political and economic field surrounding the WHO EML applications and health policy. We describe a chronology of the drug's use and of the applications to the WHO EML and carry out a social network analysis of the organisations and individuals involved in the applications, research and dissemination. The research identified a network of 238 organisations and individuals involved in the promotion of misoprostol for postpartum haemorrhage and present at the time of the WHO EML applications. There is a strong interdependency between the funding bodies, civil society organisations, researchers and clinician organisations. The research was part of an EU FP7 funded project on Accessing Medicines in Africa and South Asia (2010 2013). PMID- 25818381 TI - Privatization of solid waste collection services: Lessons from Gaborone. AB - Formal privatization of solid waste collection activities has often been flagged as a suitable intervention for some of the challenges of solid waste management experienced by developing countries. Proponents of outsourcing collection to the private sector argue that in contrast to the public sector, it is more effective and efficient in delivering services. This essay is a comparative case study of efficiency and effectiveness attributes between the public and the formal private sector, in relation to the collection of commercial waste in Gaborone. The paper is based on analysis of secondary data and key informant interviews. It was found that while, the private sector performed comparatively well in most of the chosen indicators of efficiency and effectiveness, the public sector also had areas where it had a competitive advantage. For instance, the private sector used the collection crew more efficiently, while the public sector was found to have a more reliable workforce. The study recommends that, while formal private sector participation in waste collection has some positive effects in terms of quality of service rendered, in most developing countries, it has to be enhanced by building sufficient capacity within the public sector on information about services contracted out and evaluation of performance criteria within the contracting process. PMID- 25818382 TI - Recovery of lead from lead paste in spent lead acid battery by hydrometallurgical desulfurization and vacuum thermal reduction. AB - Lead sulfate, lead oxides and lead metal are the main component of lead paste in spent lead acid battery. When lead sulfate was desulfurized and transformed into lead carbonate by sodium carbonate, lead metal and lead oxides remained unchanged. Lead carbonate is easily decomposed to lead oxide and carbon dioxide under high temperature. Namely, vacuum thermal process is the reduction reaction of lead oxides. A compatible environmental process consisted of hydrometallurgical desulfurization and vacuum thermal reduction to recycle lead was investigated in this research. Lead paste was firstly desulfurized with sodium carbonate, by which, the content of sulfur declined from 7.87% to 0.26%. Then, the desulfurized lead paste was reduced by charcoal under vacuum. Under the optimized reaction conditions, i.e., vacuum thermal reduction at temperature 850 degrees C under 20 Pa for 45 min, a 22.11*10(-2) g cm(-2) min(-1) reduction rate, and a 98.13% direct recovery ratio of fine lead (99.77%) had been achieved, respectively. PMID- 25818383 TI - Costs of food waste in South Africa: Incorporating inedible food waste. AB - The economic, social and environmental costs of food waste are being increasingly recognised. Food waste consists of both edible and inedible components. Whilst wastage of edible food is problematic for obvious reasons, there are also costs associated with the disposal of the inedible fraction to landfill. This is the third in a series of papers examining the costs of food waste throughout the value chain in South Africa. The previous papers focused on the edible portion of food waste. In this paper, costs associated with inedible food waste in South Africa are estimated, in terms of the value foregone by not recovering this waste for use in downstream applications, such as energy generation or composting; as well as costs associated with disposal to landfill. Opportunity costs are estimated at R6.4 (US$0.64) billion per annum, or R2668 (US$266) per tonne. Adding this to the previous estimate for edible food waste of R61.5 billion per annum (in 2012 prices; equivalent to R65 billion in 2013 prices) results in a total opportunity cost of food waste in South Africa (in terms of loss of a potentially valuable food source or resource) of R71.4 (US$7.14) billion per annum, or R5667 (US$567) per tonne. Thereafter, estimates of the costs associated with disposal of this food waste to landfill, including both financial costs and externalities (social and environmental costs), are taken into account. These costs amount to R255 (US$25) per tonne, giving rise to a total cost of food waste in South Africa of R75 billion (US$7.5 billion) per annum, or R5922 (US$592) per tonne. This is equivalent to 2.2% of South Africa's 2013 GDP. PMID- 25818384 TI - Model development and evaluation of methane potential from anaerobic co-digestion of municipal wastewater sludge and un-dewatered grease trap waste. AB - The performance of anaerobic co-digestion of municipal wastewater sludge with un dewatered grease trap waste was assessed using modified biochemical methane potential tests under mesophilic conditions (35 degrees C). Methane potentials, process inhibition and chemical behavior of the process were analyzed at different grease trap waste feed ratios on volatile solids basis. Nonlinear regression analyses of first order reaction and modified Gompertz equations were performed to assist in interpretation of the experimental results. Methane potential of un-dewatered grease trap waste was measured as 606 mL CH4/g VS(added), while methane potential of municipal wastewater sludge was only 223 mL CH4/g VS(added). The results indicated that anaerobic digestion of grease trap waste without dewatering yields less methane potential than concentrated/dewatered grease trap waste because of high wastewater content of un dewatered grease trap waste. However, anaerobic co-digestion of municipal wastewater sludge and grease trap waste still yields over two times more methane potential and approximately 10% more volatile solids reduction than digestion of municipal wastewater sludge alone. The anaerobic co-digestion process inhibitions were reported at 70% and greater concentrated/dewatered grease trap waste additions on volatile solids basis in previous studies; however, no inhibition was observed at 100% un-dewatered grease trap waste digestion in the present study. These results indicate that anaerobic co-digestion of un-dewatered grease trap waste may reduce the inhibition risk compared to anaerobic co-digestion of concentrated/dewatered grease trap waste. In addition, a mathematical model was developed in this study for the first time to describe the relationship between grease trap waste feed ratio on volatile solids basis and resulting methane potential. Experimental data from the current study as well as previous biochemical methane potential studies were successfully fit to this relationship and allowed estimation of key performance parameters that provide additional insight into the factors affecting biochemical methane potential. PMID- 25818386 TI - Prospective memory impairment in chronic heart failure. AB - Although cognitive deficits are common in patients with chronic heart failure (CHF), no study to date has investigated whether these deficits extend to the capacity to execute delayed intentions (prospective memory, PM). This is a surprising omission given the critical role PM plays in correctly implementing many important CHF self-care behaviors. The present study aimed to provide the first empirical assessment of PM function in people with CHF. The key dependent measure was a laboratory measure of PM that closely simulates PM tasks in daily life - Virtual Week. A group comparison design was used, with 30 CHF patients compared to 30 demographically matched controls. Background measures assessing executive functions, working memory, and verbal memory were also administered. The CHF group exhibited significant PM impairment, with difficulties generalizing across different types of PM tasks (event, time, regular, irregular). The CHF group also had moderate deficits on several of the background cognitive measures. Given the level of impairment remained consistent even on tasks that imposed minimal demands on memory for task content, CHF-related difficulties most likely reflects problems with the prospective component. However, exploratory analyses suggest that difficulties with retrospective memory and global cognition (but not executive control), also contribute to the PM difficulties seen in this group. The implications of these data are discussed, and in particular, it is argued that problems with PM may help explain why patient engagement in CHF self-care behaviors is often poor. PMID- 25818385 TI - Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. AB - PURPOSE: To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0-18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). METHODS: The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. RESULTS: We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. CONCLUSIONS: All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted. PMID- 25818387 TI - Impact of sex on uric acid levels and its relationship with the extent of coronary artery disease: A single-centre study. AB - BACKGROUND: Serum uric acid (SUA) elevation has been largely addressed in the past as a possible risk factor for cardiovascular disease. However, uric acid has not clearly emerged as independent risk factor for coronary artery disease. Several studies in literature have assessed sex-related differences in the association between elevated SUA levels and cardiovascular events with conflicting results. Therefore, aim of the current study was to evaluate the relationship between uric acid levels and the extent of coronary artery disease in male and female patients undergoing coronary angiography. METHODS: Our population is represented by 3520 consecutive patients undergoing coronary angiography from March 2007 to October 2012. Patients were divided according to Tertiles of SUA (Males, Group 1, <=5.5 mg/dL-0.33 mmol/mol, n = 762, Group 2, 5.5 6.8 mg/dL-0.33-0.40 mmol/mol, n = 829 and Group 3 >=6.8 mg/dL-0.40 mmol/mol, n = 851), (Females, Group 1, <=4.8 mg/dL-0.28 mmol/mol, n = 349, Group 2, 4.8-6.3 mg/dL-0.28-0.37 mmol/mol, n = 359 and Group 3 >= 6.3 mg/dL-0.37 mmol/mol, n = 370). Fasting samples were collected for uric acid levels assessment. Coronary disease was defined for at least 1 vessel stenosis >50% as evaluated by QCA. Severe coronary disease was defined as three-vessel disease and/or left main disease. RESULTS: Among 3520 patients, we identified 2442 men (69.4%) and 1078 women (30.6%). Males had higher levels of uric acid than women (6.33 +/- 1.7 vs 5.8 +/- 1.9 - p < 0.001). The association between elevated uric acid (>=7 mg/dl or 0.42 mmol/l) and male gender was confirmed after correction for baseline confounding factors (Adjusted OR = 1.28 [1.01-1.62], p = 0.004). Males displayed a significantly higher prevalence and extent of CAD (p < 0.001) and more complex coronary lesions (p < 0.001). However, no significant relationship was observed between uric acid and CAD (Adjusted OR [95%CI] = 0.90 [0.76-1.06], p = 0.22) or severe CAD (Adjusted OR [95%CI] = 0.89 [0.79-1.01], p = 0.08). Among females, higher SUA levels were significantly associated with higher prevalence of severe CAD (p < 0.001) (Adjusted OR [95% CI] = 1.29 [1.03-1.62], p = 0.03). CONCLUSION: Our study showed that uric acid levels are significantly higher in men. However, high uric acid levels are associated with severe CAD only in women. Future large studies are certainly needed to confirm our findings and to evaluate the effects of SUA lowering therapies on cardiovascular prevention and outcome, especially in women. PMID- 25818388 TI - Effects of the oriental herbal medicine Bofu-tsusho-san in obesity hypertension: a multicenter, randomized, parallel-group controlled trial (ATH-D-14-01021.R2). AB - OBJECTIVE: There is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity. METHODS: The study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization. RESULTS: Daytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0+/-3.3 vs -1.0+/-3.3%; p=0.006). CONCLUSION: The BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment. CLINICAL TRIAL REGISTRATION: UMIN000003878. PMID- 25818389 TI - Interplay of robustness and plasticity of life-history traits drives ecotypic differentiation in thermally distinct habitats. AB - Phenotypic plasticity describes the ability of an individual to alter its phenotype in response to the environment and is potentially adaptive when dealing with environmental variation. However, robustness in the face of a changing environment may often be beneficial for traits that are tightly linked to fitness. We hypothesized that robustness of some traits may depend on specific patterns of plasticity within and among other traits. We used a reaction norm approach to study robustness and phenotypic plasticity of three life-history traits of the collembolan Orchesella cincta in environments with different thermal regimes. We measured adult mass, age at maturity and growth rate of males and females from heath and forest habitats at two temperatures (12 and 22 degrees C). We found evidence for ecotype-specific robustness of female adult mass to temperature, with a higher level of robustness in the heath ecotype. This robustness is facilitated by plastic adjustments of growth rate and age at maturity. Furthermore, female fecundity is strongly influenced by female adult mass, explaining the importance of realizing a high mass across temperatures for females. These findings indicate that different predicted outcomes of life history theory can be combined within one species' ontogeny and that models describing life-history strategies should not assume that traits like growth rate are maximized under all conditions. On a methodological note, we report a systematic inflation of variation when standard deviations and correlation coefficients are calculated from family means as opposed to individual data within a family structure. PMID- 25818390 TI - Uncertainty and perspectives in studies of atmospheric nitrogen deposition in China: A response to Liu et al. (2015). AB - In this paper, we have formally responded to the speculation in "Liu et al. suspect that Zhu et al. (2015) may have underestimated dissolved organic N but overestimated total particulate N in wet deposition in China" by Liu et al. (2015). Here, we first discussed the uncertainty and plausible reasons of atmospheric deposition in China, which have been reported in different studies. We disagree with their interpretation on some points. Firstly, the difficulties in quality control from sampling to analyzing are common to all studies regarding atmospheric deposition, including the studies cited by Liu et al. (2015). More importantly, their discussion did not fully consider the apparent influence of different scaling-up methods (from an observation site scale to a national scale) on estimations of atmospheric N deposition in China. Furthermore, we provided the optimal approaches to resolve these challenges discussed in order to promote the related studies of atmospheric N deposition in China in the future. PMID- 25818392 TI - Discovery of C5-C17 poly- and perfluoroalkyl substances in water by in-line SPE HPLC-Orbitrap with in-source fragmentation flagging. AB - The presence of unknown organofluorine compounds in environmental samples has prompted the development of nontargeted analytical methods capable of detecting new perfluoroalkyl and polyfluoroalkyl substances (PFASs). By combining high volume injection with high performance liquid chromatography (HPLC) and ultrahigh resolution Orbitrap mass spectrometry, a sensitive (0.003-0.2 ng F/mL for model mass-labeled PFASs) untargeted workflow was developed for discovery and characterization of novel PFASs in water. In the first step, up to 5 mL of water is injected to in-line solid phase extraction, chromatographed by HPLC, and detected by electrospray ionization with mass spectral acquisition in parallel modes cycling back and forth: (i) full scan with ultrahigh resolving power (RP = 120,000, mass accuracy <=3 ppm), and (ii) in-source fragmentation flagging scans designed to yield marker fragment ions including [C2F5](-) (m/z 118.992), [C3F7]( ) (m/z 168.988), [SO4H](-) (m/z 96.959), and [Cl](-) (m/z 34.9). For flagged PFASs, plausible empirical formulas were generated from accurate masses, isotopic patterns, and fragment ions. In the second step, another injection is made to collect high resolution MS/MS spectra of suspect PFAS ions, allowing further confirmation of empirical formulas while also enabling preliminary structural characterization. The method was validated by applying it to an industrial wastewater, and 36 new PFASs were discovered. Of these, 26 were confidently assigned to 3 new PFAS classes that have not previously been reported in the environment: polyfluorinated sulfates (CnFn+3Hn-2SO4(-); n = 5, 7, 9, 11, 13, and 15), chlorine substituted perfluorocarboxylates (ClCnF2nCO2(-); n = 4-11), and hydro substituted perfluorocarboxylates (HCnF2nCO2(-); n = 5-16). Application of the technique to environmental water samples is now warranted. PMID- 25818391 TI - Can salinity trigger cascade effects on streams? A mesocosm approach. AB - Human activities have greatly increased the salt concentration of the world's rivers, and this might be amplified by water scarcity in the future. While the lethal effects of salinity have been documented for a wide variety of stream invertebrates, the sub-lethal effects (i.e. changes in biological condition without mortality) are not deeply understood yet. One important sub-lethal effect that has yet to be investigated is changes in predation efficiency, which could trigger cascade effects associated to the abundance of herbivorous invertebrates that control algae biomass. In this study we combined the use of biomarkers with community-level data in a stream mesocosm to evaluate the potential cascade effect of increased salinity on the trophic food web. Both predation and salt treatments had an effect on the aquatic invertebrate abundance, richness and community composition. The presence of predators had a clear cascade effect, it reduced herbivorous invertebrate abundance and richness leading to higher chlorophyll a concentrations. The salt treatment significantly reduced taxa richness, but only in the gravel bed. The predators were significantly stressed by salt addition, as shown by the different analyzed biomarkers. Concordantly, in the presence of predators, Tanytarsini registered higher abundances and chlorophyll a showed a lower concentration when salt was added. However, none of these changes was significant. Therefore, although salt addition significantly stressed Dina lineata, our results suggest that a longer exposure time is needed to fully capture cascading effects (e.g. a decrease in chlorophyll a due to a relaxation of predation on herbivorous invertebrates). We suggest that the potential cascade effects of salinization need to be evaluated when addressing the impacts of water scarcity (as caused by climate change and increasing water demand) on river ecosystems, since flow reductions will lead to higher salt concentrations. PMID- 25818393 TI - Preterm patent ductus arteriosus: A continuing conundrum for the neonatologist? AB - How to manage the preterm patent ductus arteriosus (PDA) remains a conundrum. On the one hand, physiology and statistical association with adverse outcomes suggest that it is pathological. On the other hand, clinical trials of treatment strategies have failed to show any long-term benefit. Ultrasound studies of PDA have suggested that the haemodynamic impact may be much earlier after birth than previously thought (in the first hours); however, we still do not know when to treat PDA. Studies that have tested symptomatic or pre-symptomatic treatment are mainly historical and have not tested the effect of no treatment. Prophylactic treatment is the best-studied regimen but improvements in some short-term outcomes do not translate to any difference in longer-term outcomes. Neonatologists have been reluctant to engage in trials that test treatment against almost never treating. Observations of very early postnatal haemodynamic significance suggest that targeting treatment on the basis of the early postnatal constrictive response of the duct may optimize benefits. A pilot trial of this strategy showed reduction in the incidence of pulmonary haemorrhage but more trials of this strategy are needed. PMID- 25818394 TI - Tumor recurrence and in-field control after multimodality treatment of locally advanced esophageal cancer. AB - PURPOSE: Neoadjuvant chemoradiotherapy is used prior to surgery in curative treatment of esophageal cancer (EC). We evaluated the in-field control of this multimodal treatment by extraction of radiation dose parameters and determination of the spatial relation between tumor recurrence location(s) and radiation target volume (RTV). METHODS AND MATERIALS: Treatment consisted of neoadjuvant chemotherapy (5-FU and cisplatin) and radiotherapy (36 Gy) followed by Ivor-Lewis esophagectomy. For patients with locoregional recurrence(s), image fusion was performed between radiotherapy planning CT and follow-up CT(s). A region-of interest was contoured on the planning CT around each locoregional recurrence. Mean and maximum radiation doses were then extracted to classify recurrences as out-of-field, marginal or in-field. RESULTS: Eighty patients were included. The median follow-up duration was 19 months. Fifteen of 95 locoregional recurrences were detected in the RTV. These in-field relapses occurred in only 6 patients (7.8%) on 12 different anatomical locations. None of the patients with in-field failure had a pCR and all had concurrent distant failure on multiple anatomical sites. CONCLUSION: Neoadjuvant chemoradiotherapy followed by Ivor-Lewis esophagectomy yields excellent in-field control, as only a clear minority (7.8%) of patients developed a relapse in the RTV. In-field recurrence is associated with widespread tumor dissemination and poor pathological response to neoadjuvant treatment. PMID- 25818395 TI - Contrasting analytical and data-driven frameworks for radiogenomic modeling of normal tissue toxicities in prostate cancer. AB - BACKGROUND AND PURPOSE: We explore analytical and data-driven approaches to investigate the integration of genetic variations (single nucleotide polymorphisms [SNPs] and copy number variations [CNVs]) with dosimetric and clinical variables in modeling radiation-induced rectal bleeding (RB) and erectile dysfunction (ED) in prostate cancer patients. MATERIALS AND METHODS: Sixty-two patients who underwent curative hypofractionated radiotherapy (66 Gy in 22 fractions) between 2002 and 2010 were retrospectively genotyped for CNV and SNP rs5489 in the xrcc1 DNA repair gene. Fifty-four patients had full dosimetric profiles. Two parallel modeling approaches were compared to assess the risk of severe RB (Grade?3) and ED (Grade?1); Maximum likelihood estimated generalized Lyman-Kutcher-Burman (LKB) and logistic regression. Statistical resampling based on cross-validation was used to evaluate model predictive power and generalizability to unseen data. RESULTS: Integration of biological variables xrcc1 CNV and SNP improved the fit of the RB and ED analytical and data-driven models. Cross-validation of the generalized LKB models yielded increases in classification performance of 27.4% for RB and 14.6% for ED when xrcc1 CNV and SNP were included, respectively. Biological variables added to logistic regression modeling improved classification performance over standard dosimetric models by 33.5% for RB and 21.2% for ED models. CONCLUSION: As a proof-of concept, we demonstrated that the combination of genetic and dosimetric variables can provide significant improvement in NTCP prediction using analytical and data driven approaches. The improvement in prediction performance was more pronounced in the data driven approaches. Moreover, we have shown that CNVs, in addition to SNPs, may be useful structural genetic variants in predicting radiation toxicities. PMID- 25818396 TI - Preliminary clinical evaluation of a 4D-CBCT estimation technique using prior information and limited-angle projections. AB - BACKGROUND AND PURPOSE: A technique has been previously reported to estimate high quality 4D-CBCT using prior information and limited-angle projections. This study is to investigate its clinical feasibility through both phantom and patient studies. MATERIALS AND METHODS: The new technique used to estimate 4D-CBCT is called MMFD-NCC. It is based on the previously reported motion modeling and free form deformation (MMFD) method, with the introduction of normalized-cross correlation (NCC) as a new similarity metric. The clinical feasibility of this technique was evaluated by assessing the accuracy of estimated anatomical structures in comparison to those in the 'ground-truth' reference 4D-CBCTs, using data obtained from a physical phantom and three lung cancer patients. Both volume percentage error (VPE) and center-of-mass error (COME) of the estimated tumor volume were used as the evaluation metrics. RESULTS: The average VPE/COME of the tumor in the prior image was 257.1%/10.1 mm for the phantom study and 55.6%/3.8 mm for the patient study. Using only orthogonal-view 30 degrees projections, the MMFD-NCC has reduced the corresponding values to 7.7%/1.2 mm and 9.6%/1.1 mm, respectively. CONCLUSION: The MMFD-NCC technique is able to estimate 4D-CBCT images with geometrical accuracy of the tumor within 10% VPE and 2 mm COME, which can be used to improve the localization accuracy of radiotherapy. PMID- 25818397 TI - [Comment on: "Survival and neurological outcome in out-of-hospital cardiac arrests due to shockable rhythms treated with mild therapeutic hypothermia"]. PMID- 25818398 TI - Chronic Lymphocytic Leukemia and Invasive Ductal Carcinoma Presenting as a Collision Breast Tumor. PMID- 25818399 TI - [Medicinal plants in France, between pharmacy and herb trade: historical and legislative aspects]. AB - Medicinal plants are registered on the French Pharmacopoeia in its successive editions, the first dated 1818. The edition which is currently in force, the XIth (2012), comprises two plant lists drawn up by a working group of experts belonging to the ANSM: List A (medicinal plants traditionally used [365 plants]) and list B (medicinal plants with the ratio benefit/risk's evaluation negative [123 plants]). Moreover, a list of medicinal plants with non exclusive therapeutic use has been established. This last list is composed of 147 plants which are thus liberated from the pharmaceutical monopoly, in application of decrees n(o) 2008-839 and 2008-841 dated August 22nd 2008. Medicinal plants are a matter, in France, from pharmaceutical monopoly, which means that they can only be dispensed to public in pharmacy, according to article L. 4211-1/5 degrees of the Public Health Code, except however for a certain number of plants "liberated" from this monopoly. Nevertheless, besides officinal pharmacists, herbalists who obtained their diploma as far as 1941, were habilitated to deliver medicinal plants, even non "liberated", on condition that they are not registered on a list of venomous substances nor classified among the stupefacients, according to the article L. 4211-7 of Public Health Code. Concerning plants for herbal teas, which should be differentiated from herbal teas classified among the herbal medicines, they can be delivered in mixtures form, which are considered as officinal preparations, according to the new French Pharmacopoeia monography of August 1st 2013. PMID- 25818400 TI - Further circulation of West Nile and Usutu viruses in wild birds in Italy. AB - Usutu virus (USUV) and West Nile virus (WNV) are emerging pathogens that can cause neurological disease in humans. From March 2012 to June 2013, a sero-survey on wild birds was carried out to investigate the circulation of both viruses in Northwest (NW) Italy. Samples belonging to 47 different bird species have been collected using a volunteer based network and a wildlife rehabilitation center. Four of 297 serum samples had neutralizing antibodies against USUV (P=1.34%, IC 95% 0.36-3.4), while 10 of 233 samples tested positive for WNV (P=4.29%, IC 95% 2.07-7.75). Neutralizing antibodies for WNV were significantly more prevalent (p<0.001) in trans-Saharan migrants (P=21%, IC 95% 9.55-37.3) than in resident and short-distance birds, but no migratory habit-related differences were found for USUV. Antibodies in resident bird species suggest that both viruses are circulating in NW Italy. PMID- 25818401 TI - Prevalence of Enterocytozoon bieneusi and genetic diversity of ITS genotypes in sheep and goats in China. AB - Enterocytozoon bieneusi is the most common microsporidia species, recognized in more than 90% cases of human microsporidiosis and has been found in a variety of animal hosts. To explore the prevalence of E. bieneusi in sheep and goats in China, genetic diversity and zoonotic potential of E. bieneusi, 193 fecal specimens from 138 sheep and 55 goats from eight farms in Heilongjiang Province, China were analyzed for the occurrence of E. bieneusi by PCR and sequencing of the single internal transcribed spacer (ITS) of the rRNA gene. The average prevalence of E. bieneusi was 22.3% (43/193), with 22.5% (31/138) for sheep versus 21.8% (12/55) for goats. Altogether 14 genotypes of E. bieneusi were identified, including six known genotypes-BEB6 (n=15), Peru6 (8), D (n=6), O (n=3), EbpC (n=2), and EbpA (n=1)-and eight novel genotypes named COS-I to COS VII and COG-I (one each). Six of the genotypes were previously detected in humans. In phylogenetic analysis, the five novel genotypes COG-I and CCOS-IV to COS-VII were clustered into group 1 with zoonotic potential. These results indicate that these animals may play a potential role in the transmission of E. bieneusi to humans. PMID- 25818402 TI - Identification of putative vaccine candidates against Helicobacter pylori exploiting exoproteome and secretome: a reverse vaccinology based approach. AB - Helicobacter pylori (H. pylori) is an important pathogen associated with diverse gastric disorders ranging from peptic ulcer to malignancy. It has also been recognized by the World Health Organization (WHO) as class I carcinogen. Conventional treatment regimens for H. pylori seem to be ineffective, possibly due to antibiotic resistance mechanisms acquired by the pathogen. In this study we have successfully employed a reverse vaccinology approach to predict the potential vaccine candidates against H. pylori. The predicted potential vaccine candidates include vacA, babA, sabA, fecA and omp16. Host-pathogen interactions analysis elaborated their direct or indirect role in the specific signaling pathways including epithelial cell polarity, metabolism, secretion system and transport. Furthermore, surface-exposed antigenic epitopes were predicted and analyzed for conservation among 39 complete genomes of H. pylori (Genbank) for all the candidate proteins. These epitopes may serve as a base for the development of broad spectrum peptide or multi-component vaccines against H. pylori. We also believe that the proposed pipeline can be extended to other pathogens and for the identification of novel candidates for the development of effective vaccines. PMID- 25818404 TI - Competitive spatially distributed population dynamics models: Does diversity in diffusion strategies promote coexistence? AB - We study the interaction between different types of dispersal, intrinsic growth rates and carrying capacities of two competing species in a heterogeneous environment: one of them is subject to a regular diffusion while the other moves in the direction of most per capita available resources. If spatially heterogeneous carrying capacities coincide, and intrinsic growth rates are proportional then competitive exclusion of a regularly diffusing population is inevitable. However, the situation may change if intrinsic growth rates for the two populations have different spatial forms. We also consider the case when carrying capacities are different. If the carrying capacity of a regularly diffusing population is higher than for the other species, the two populations may coexist; as the difference between the two carrying capacities grows, competitive exclusion of the species with a lower carrying capacity occurs. PMID- 25818403 TI - A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. AB - BACKGROUND: Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA). METHODS: Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400mg orally BID with one cycle being 28days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha=10% (at a 10% assumed null response probability). RESULTS: The median age of the 50 eligible patients was 57years (range 37-94) and 14, 18, and 18 patients had 1, 2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n=3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events >10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18months. CONCLUSIONS: The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation. PMID- 25818405 TI - Estimating the costs associated with the management of patients with chronic wounds using linked routine data. AB - Chronic wounds are known to represent a significant burden to patients and National Health Service (NHS) alike. However, previous attempts to estimate the costs associated with the management of chronic wounds have been based on literature studies or broad estimates derived from incidence rates and extrapolations from relatively small-scale studies. The aim of this study is therefore to determine the extent of resource utilisation by patients classed as having chronic wounds within Wales using linked routine data - available through the Secure Anonymised Information Linkage (SAIL) database - to estimate the costs associated with the management of these patients by the NHS in Wales. The SAIL database brings together, and anonymously links, a wide range of person-based data from general practitioner (GP) practices within Wales, which includes primary and secondary care consultations to create an encrypted anonymised linking field for each individual. This linkage allows the patient pathway to be tracked through the NHS system both retrospectively and prospectively from a specific reference date. The estimated costs were derived by extrapolating to an all-Wales level from the results gleaned from the SAIL database using the respective READ codes to capture relevant patients with chronic wounds. The number of patients identified as having chronic wounds within the SAIL database was 78 090, which equates to 190 463 across Wales as a whole and a prevalence of 6% of the Welsh population. The total cost of managing patients with chronic wounds in Wales amounted to L328.8 million - an average cost of L1727 per patient and 5.5% of total expenditure on the health service in Wales. A relatively few READ codes represented a significant proportion of expenditure, with diabetic foot ulcers, leg ulcers, foot ulcers, varicose eczema, bed sores and postoperative wound care constituting 93% of total expenditure. When a more conservative perspective was used in relation to classification of chronic wounds, the total cost amounted to L303 million. However, these are likely to be underestimates because of the lack of information for patients with treatments lasting over 6 months and not including patients who might have entered the health care system of wound management elsewhere - such as patients contracting pressure ulcers in hospitals and having surgical wound infections. PMID- 25818406 TI - Symptoms, unmet needs, psychological well-being and health status in survivors of prostate cancer: implications for redesigning follow-up. AB - OBJECTIVE: To explore ongoing symptoms, unmet needs, psychological wellbeing, self-efficacy and overall health status in survivors of prostate cancer. PATIENTS AND METHODS: An invitation to participate in a postal questionnaire survey was sent to 546 men, diagnosed with prostate cancer 9-24 months previously at two UK cancer centres. The study group comprised men who had been subject to a range of treatments: surgery, radiotherapy, hormone therapy and active surveillance. The questionnaire included measures of prostate-related quality of life (Expanded Prostate cancer Index Composite 26-item version, EPIC-26); unmet needs (Supportive Care Needs Survey 34-item version, SCNS-SF34); anxiety and depression (Hospital Anxiety and Depression Scale, HADS), self-efficacy (modified Self efficacy Scale), health status (EuroQol 5D, EQ-5D) and satisfaction with care (questions developed for this study). A single reminder was sent to non responders after 3 weeks. Data were analysed by age, co-morbidities, and treatment group. RESULTS: In all, 316 men completed questionnaires (64.1% response rate). Overall satisfaction with follow-up care was high, but was lower for psychosocial than physical aspects of care. Urinary, bowel, and sexual functioning was reported as a moderate/big problem in the last month for 15.2% (n = 48), 5.1% (n = 16), and 36.5% (n = 105) men, respectively. The most commonly reported moderate/high unmet needs related to changes in sexual feelings/relationships, managing fear of recurrence/uncertainty, and concerns about the worries of significant others. It was found that 17% of men (51/307) reported potentially moderate-to-severe levels of anxiety and 10.2% (32/308) reported moderate-to-severe levels of depression. The presence of problematic side-effects was associated with higher psychological morbidity, poorer self efficacy, greater unmet needs, and poorer overall health status. CONCLUSION: While some men report relatively few problems after prostate cancer treatment, this study highlights important physical and psycho-social issues for a significant minority of survivors of prostate cancer. Strategies for identifying those men with on-going problems, alongside new interventions and models of care, tailored to individual needs, are needed to improve quality of life. PMID- 25818407 TI - A phase I/II study of sunitinib and intensive chemotherapy in patients over 60 years of age with acute myeloid leukaemia and activating FLT3 mutations. AB - Acute myeloid leukaemia (AML) with FLT3 mutation has a dismal prognosis in elderly patients. Treatment with a combination of FLT3 inhibitors and standard chemotherapy has not been extensively studied. Therefore, we instigated a phase I/II clinical trial of chemotherapy with cytosine arabinoside (Ara C)/daunorubicin induction (7+3) followed by three cycles of intermediate-dose Ara C consolidation in 22 AML patients with activating FLT3 mutations. Sunitinib was added at predefined dose levels and as maintenance therapy for 2 years. At dose level 1, sunitinib 25 mg daily continuously from day 1 onwards resulted in two cases with dose-limiting toxicity (DLT), prolonged haemotoxicity and hand-foot syndrome. At dose level -1, sunitinib 25 mg was restricted to days 1-7 of each chemotherapy cycle. One DLT was observed in six evaluable patients. Six additional patients were treated in an extension phase. Thirteen of 22 patients (59%; 8/14 with FLT3-internal tandem duplication and 5/8 with FLT3-tyrosine kinase domain) achieved a complete remission/complete remission with incomplete blood count recovery. For the 17 patients included at the lower dose level, median overall, relapse-free and event-free survival were 1.6, 1.0 and 0.4 years, respectively. Four out of five analysed patients with relapse during maintenance therapy lost their initial FLT3 mutation, suggesting outgrowth of FLT3 wild-type subclones. PMID- 25818408 TI - A case of sporadic medullary cystic kidney disease type 1 (MCKD1) with kidney enlargement complicated by IgA nephropathy. AB - Medullary cystic kidney disease (MCKD) is a progressive tubulointerstitial nephropathy, and it leads to end-stage kidney disease (ESKD). It is an autosomal dominant inherited disease, and is categorized into two types according to the localizing chromosome and timing of ESKD onset. Its pathogenesis has not been revealed clearly, thus accumulation of the cases is very valuable. We report here the first reported case of MCKD with kidney enlargement complicated by IgA nephropathy. A 70-year-old male was admitted to our hospital because of renal dysfunction and bilateral kidney enlargement. He was diagnosed as having MCKD complicated by IgA nephropathy (IgA-N) by renal biopsy. We speculated that he had MCKD type 1 on the basis of the late onset of renal failure and no significant evidence of mutation in the UMOD gene that is associated with MCKD type 2. Thereafter, his kidney function decreased progressively and he started to receive hemodialysis. This is an interesting case of MCKD1 in terms of its sporadic nature, kidney enlargement, and complication of IgA-N. PMID- 25818409 TI - Gene therapy for nucleus pulposus regeneration by heme oxygenase-1 plasmid DNA carried by mixed polyplex micelles with thermo-responsive heterogeneous coronas. AB - Safe and high-efficiency gene therapy for nucleus pulposus (NP) regeneration was urgently desired to treat disc degeneration-associated diseases. In this work, an efficient nonviral cationic block copolymer gene delivery system was used to deliver therapeutic plasmid DNA (pDNA), which was prepared via complexation between the mixed cationic block copolymers, poly(ethylene glycol)-block-poly{N [N-(2-aminoethyl)-2-aminoehtyl]aspartamide} [PEG-b-PAsp(DET)] and poly(N isopropylacrylamide)-block-PAsp(DET) [PNIPAM-b-PAsp(DET)], and pDNA at 25 degrees C. The mixed polyplex micelles (MPMs) containing heterogeneous coronas with hydrophobic and hydrophilic microdomains coexisting could be obtained upon heating from 25 to 37 degrees C, which showed high tolerability against nuclease and strong resistance towards protein adsorption. The gene transfection efficiency of MPMs in NP cells was significantly higher than that of regular polyplex micelles prepared from sole block copolymer of PEG-b-PAsp(DET) (SPMs) in in vitro and in vivo evaluation due to the synergistic effect of improved colloidal stability and low cytotoxicity. High expression of heme oxygenase-1 (HO 1) in NP cells transfected by MPMs loading HO-1 pDNA significantly decreased the expression activity of matrix metalloproteinases 3 (MMP-3) and cyclo-oxygenase-2 (COX-2) induced by interleukin-1beta (IL-1beta), and simultaneously increased the NP phenotype-associated genes such as aggrecan, type II collagen, and SOX-9. Moreover, the therapeutic effects of MPMs loading pDNA were tested to treat disc degeneration induced by stab injury. The results demonstrated that administration of HO-1 pDNA carried by MPMs in rat tail discs apparently reduced inflammatory responses induced by need stab and increased glycosaminoglycan (GAG) content, finally achieving better therapeutic efficacy as compared with SPMs. Consequently, MPMs loading HO-1 pDNA were demonstrated to be potential as a safe and high-efficiency nonviral gene delivery system for retarding or regenerating the degenerative discs. PMID- 25818410 TI - In vivo selective imaging and inhibition of leukemia stem-like cells using the fluorescent carbocyanine derivative, DiOC5(3). AB - Elimination of leukemia stem cells (LSCs) is necessary for the destruction of malignant cell populations. Owing to the very small number of LSCs in leukemia cells, xenotransplantation studies are difficult in terms of functionally and pathophysiologically replicating clinical conditions of cell culture experiments. There is currently a limited number of lead compounds that target LSCs. Using the LSC-xenograft zebrafish screening method we previously developed, we found that the fluorescent compound 3,3'-dipentyloxacarbocyanine iodide (DiOC5(3)) selectively marked LSCs and suppressed their proliferation in vivo and in vitro. DiOC5(3) had no obvious toxicity to human umbilical cord blood CD34+ progenitor cells and normal zebrafish. It accumulated in mitochondria through organic anion transporter polypeptides that are overexpressed in the plasma membrane of LSCs, and induced apoptosis via ROS overproduction. DiOC5(3) also inhibited the nuclear translocation of NF-kappaB through the downregulation of LSC-selective pathways, as indicated from DNA microarray analysis. In summary, DiOC5(3) is a new type of anti-LSC compound available for diagnostic imaging and therapeutics that has the advantage of being a single fluorescent chemical. PMID- 25818412 TI - Systematic in vitro and in vivo study on porous silicon to improve the oral bioavailability of celecoxib. AB - Mesoporous materials are promising candidates for improving dissolution rate of poorly water-soluble drugs in vitro and their bioavailability in vivo. In the present study, sixteen batches of celecoxib-loaded PSi particles with pore sizes ranging from 17 to 58 nm and celecoxib content from 5 to 36 w-% were prepared and a detailed physicochemical characterization of the drug was performed by several methods. Interaction between co-culture of Caco-2/HT29-MTX cells and unloaded PSi particles was tested in toxicity assays, and increased toxicity for particles with large pore size was observed. Dissolution rate of celecoxib was improved in vitro by lowering the drug loading degree which hindered the recrystallization of celecoxib on the external surface of the particles. The fastest permeation of loaded celecoxib through the co-culture monolayer as well as the highest bioavailability in rats was observed with the particles with small pore size and low loading degree. New insights were obtained on how various parameters of the mesoporous delivery system affect the state of the drug inside the pores and its release in vitro and in vivo. PMID- 25818413 TI - Combination of aligned PLGA/Gelatin electrospun sheets, native dental pulp extracellular matrix and treated dentin matrix as substrates for tooth root regeneration. AB - In tissue engineering, scaffold materials provide effective structural support to promote the repair of damaged tissues or organs through simulating the extracellular matrix (ECM) microenvironments for stem cells. This study hypothesized that simulating the ECM microenvironments of periodontium and dental pulp/dentin complexes would contribute to the regeneration of tooth root. Here, aligned PLGA/Gelatin electrospun sheet (APES), treated dentin matrix (TDM) and native dental pulp extracellular matrix (DPEM) were fabricated and combined into APES/TDM and DPEM/TDM for periodontium and dental pulp regeneration, respectively. This study firstly examined the physicochemical properties and biocompatibilities of both APES and DPEM in vitro, and further investigated the degradation of APES and revascularization of DPEM in vivo. Then, the potency of APES/TDM and DPEM/TDM in odontogenic induction was evaluated via co-culture with dental stem cells. Finally, we verified the periodontium and dental pulp/dentin complex regeneration in the jaw of miniature swine. Results showed that APES possessed aligned fiber orientation which guided cell proliferation while DPEM preserved the intrinsic fiber structure and ECM proteins. Importantly, both APES/TDM and DPEM/TDM facilitated the odontogenic differentiation of dental stem cells in vitro. Seeded with stem cells, the sandwich composites (APES/TDM/DPEM) generated tooth root-like tissues after being transplanted in porcine jaws for 12 w. In dental pulp/dentin complex-like tissues, columnar odontoblasts-like layer arranged along the interface between newly-formed predentin matrix and dental pulp-like tissues in which blood vessels could be found; in periodontium complex like tissues, cellular cementum and periodontal ligament (PDL)-like tissues were generated on the TDM surface. Thus, above results suggest that APES and DPEM exhibiting appropriate physicochemical properties and well biocompatibilities, in accompany with TDM, could make up an ECM microenvironment for tooth root regeneration, which also offers a strategy for complex tissue or organ regeneration. PMID- 25818411 TI - On human pluripotent stem cell control: The rise of 3D bioengineering and mechanobiology. AB - Human pluripotent stem cells (hPSCs) provide promising resources for regenerating tissues and organs and modeling development and diseases in vitro. To fulfill their promise, the fate, function, and organization of hPSCs need to be precisely regulated in a three-dimensional (3D) environment to mimic cellular structures and functions of native tissues and organs. In the past decade, innovations in 3D culture systems with functional biomaterials have enabled efficient and versatile control of hPSC fate at the cellular level. However, we are just at the beginning of bringing hPSC-based regeneration and development and disease modeling to the tissue and organ levels. In this review, we summarize existing bioengineered culture platforms for controlling hPSC fate and function by regulating inductive mechanical and biochemical cues coexisting in the synthetic cell microenvironment. We highlight recent excitements in developing 3D hPSC-based in vitro tissue and organ models with in vivo-like cellular structures, interactions, and functions. We further discuss an emerging multifaceted mechanotransductive signaling network--with transcriptional coactivators YAP and TAZ at the center stage--that regulate fates and behaviors of mammalian cells, including hPSCs. Future development of 3D biomaterial systems should incorporate dynamically modulated mechanical and chemical properties targeting specific intracellular signaling events leading to desirable hPSC fate patterning and functional tissue formation in 3D. PMID- 25818414 TI - Self-assembling multidomain peptides tailor biological responses through biphasic release. AB - Delivery of small molecules and drugs to tissues is a mainstay of several tissue engineering strategies. Next generation treatments focused on localized drug delivery offer a more effective means in dealing with refractory healing when compared to systemic approaches. Here we describe a novel multidomain peptide hydrogel that capitalizes on synthetic peptide chemistry, supramolecular self assembly and cytokine delivery to tailor biological responses. This material is biomimetic, shows shear stress recovery and offers a nanofibrous matrix that sequesters cytokines. The biphasic pattern of cytokine release results in the spatio-temporal activation of THP-1 monocytes and macrophages. Furthermore, macrophage-material interactions are promoted without generation of a proinflammatory environment. Subcutaneous implantation of injectable scaffolds showed a marked increase in macrophage infiltration and polarization dictated by cytokine loading as early as 3 days, with complete scaffold resorption by day 14. Macrophage interaction and response to the peptide composite facilitated the (i) recruitment of monocytes/macrophages, (ii) sustained residence of immune cells until degradation, and (iii) promotion of a pro-resolution M2 environment. Our results suggest the potential use of this injectable cytokine loaded hydrogel scaffold in a variety of tissue engineering applications. PMID- 25818415 TI - Design and validation of a clinical-scale bioreactor for long-term isolated lung culture. AB - The primary treatment for end-stage lung disease is lung transplantation. However, donor organ shortage remains a major barrier for many patients. In recent years, techniques for maintaining lungs ex vivo for evaluation and short term (<12 h) resuscitation have come into more widespread use in an attempt to expand the donor pool. In parallel, progress in whole organ engineering has provided the potential perspective of patient derived grafts grown on demand. As both of these strategies advance to more complex interventions for lung repair and regeneration, the need for a long-term organ culture system becomes apparent. Herein we describe a novel clinical scale bioreactor capable of maintaining functional porcine and human lungs for at least 72 h in isolated lung culture (ILC). The fully automated, computer controlled, sterile, closed circuit system enables physiologic pulsatile perfusion and negative pressure ventilation, while gas exchange function, and metabolism can be evaluated. Creation of this stable, biomimetic long-term culture environment will enable advanced interventions in both donor lungs and engineered grafts of human scale. PMID- 25818416 TI - Development and functional evaluation of biomimetic silicone surfaces with hierarchical micro/nano-topographical features demonstrates favourable in vitro foreign body response of breast-derived fibroblasts. AB - Reproducing extracellular matrix topographical cues, such as those present within acellular dermal matrix (ADM), in synthetic implant surfaces, may augment cellular responses, independent of surface chemistry. This could lead to enhanced implant integration and performance while reducing complications. In this work, the hierarchical micro and nanoscale features of ADM were accurately and reproducibly replicated in polydimethylsiloxane (PDMS), using an innovative maskless 3D grayscale fabrication process not previously reported. Human breast derived fibroblasts (n=5) were cultured on PDMS surfaces and compared to commercially available smooth and textured silicone implant surfaces, for up to one week. Cell attachment, proliferation and cytotoxicity, in addition to immunofluorescence staining, SEM imaging, qRT-PCR and cytokine array were performed. ADM PDMS surfaces promoted cell adhesion, proliferation and survival (p=<0.05), in addition to increased focal contact formation and spread fibroblast morphology when compared to commercially available implant surfaces. PCNA, vinculin and collagen 1 were up-regulated in fibroblasts on biomimetic surfaces while IL8, TNFalpha, TGFbeta1 and HSP60 were down-regulated (p=<0.05). A reduced inflammatory cytokine response was also observed (p=<0.05). This study represents a novel approach to the development of functionalised biomimetic prosthetic implant surfaces which were demonstrated to significantly attenuate the acute in vitro foreign body reaction to silicone. PMID- 25818418 TI - Antimicrobial delivery systems for local infection prophylaxis in orthopedic- and trauma surgery. AB - Infectious complications occur in a minor but significant portion of the patients undergoing joint replacement surgery or fracture fixation, particularly those with severe open fractures, those undergoing revision arthroplasty or those at elevated risk because of poor health status. Once established, infections are difficult to eradicate, especially in the case of bacterial biofilm formation on implanted hardware. Local antibiotic carriers offer the prospect of controlled delivery of antibiotics directly in target tissues and implant, without inducing toxicity in non-target organs. Polymeric carriers have been developed to optimize the release and targeting of antibiotics. Passive polymeric carriers release antibiotics by diffusion and/or upon degradation, while active polymeric carriers release their antibiotics upon stimuli provided by bacterial pathogens. Additionally, some polymeric carriers gelate in-situ in response to physiological stimuli to form a depot for antibiotic release. As antibiotic resistance has become a major issue, also other anti-infectives such as silver and antimicrobial peptides have been incorporated in research. Currently, several antibiotic loaded biomaterials for local infection prophylaxis are available for use in the clinic. Here we review their advantages and limitations and provide an overview of new materials emerging that may overcome these limitations. PMID- 25818417 TI - Ex vivo non-invasive assessment of cell viability and proliferation in bio engineered whole organ constructs. AB - Decellularized organ scaffolds allow whole organ regeneration and study of cell behavior in three-dimensional culture conditions. Cell viability within the bio engineered organ constructs is an essential parameter reflecting the performance of participating cells during long-term ex vivo culture, and is a prerequisite for further functional performance. Resazurin-based redox metabolic assays have been used to monitor cell viability in both two- and three-dimensional cell cultures. Here we developed a method for monitoring cell viability and proliferation in bio-engineered organ constructs using a resazurin perfusion assay. This method allows non-invasive, repetitive and rapid estimation of viable cell numbers during long-term ex vivo culture. As a proof-of-principle, we assessed the performance of two different endothelial sources and the impact of different perfusion programs on endothelial viability after re-endothelialization of decellularized lung scaffolds. The resazurin-based perfusion assay revealed changes in endothelial viability and proliferation during long-term ex vivo culture, which was consistent with histological assessment at different time points. Finally, we showed that this method could be used for assessment of proliferation and cytotoxicity after pharmacological treatment on a three dimensional non-small cell lung cancer culture model. PMID- 25818419 TI - Overcoming drug-resistant lung cancer by paclitaxel loaded dual-functional liposomes with mitochondria targeting and pH-response. AB - Mitochondrion-orientated transportation of smart liposomes has been developed as a promising strategy to deliver anticancer drugs directly to tumor sites, and these have a tremendous potential for killing cancer cells, especially those with multidrug resistance (MDR). Herein we report a novel dual-functional liposome system possessing both extracellular pH response and mitochondrial targeting properties to enhance drug accumulation in mitochondria and trigger apoptosis of drug-resistant cancer cells. Briefly, peptide D[KLAKLAK]2 (KLA) was modified with 2, 3-dimethylmaleic anhydride (DMA) and combined with 1, 2-distearoyl-sn-glycero 3-phosphoethanolamine (DSPE) to yield a DSPE-KLA-DMA (DKD) lipid. This dual functional DKD was then mixed with other commercially available lipids to fabricate liposomes. In vitro anticancer efficacy of this liposome system was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/Taxol cells. At tumor extracellular pH (~6.8), liposomes could reverse their surface charge (negative to positive), facilitating liposome internalization. After cellular uptake, KLA peptide directed delivery-enabled selective accumulation of these liposomes into mitochondria and favored release of their cargo paclitaxel (PTX) into desired sites. Specifically, enhanced apoptosis of MDR cancer cells through mitochondrial signaling pathways was evidenced by release of cytochrome c and increased activity of caspase-9 and -3. These dual functional liposomes had the greatest efficacy for treating A549 cells and A549/Taxol cells in vitro, and in treating drug-resistant lung cancer A549/Taxol cells xenografted onto nude mice (tumor growth inhibition 86.7%). In conclusion, dual-functional liposomes provide a novel and versatile approach for overcoming MDR in cancer treatment. PMID- 25818420 TI - 3D surface topology guides stem cell adhesion and differentiation. AB - Polymerized high internal phase emulsion (polyHIPE) foams are extremely versatile materials for investigating cell-substrate interactions in vitro. Foam morphologies can be controlled by polymerization conditions to result in either open or closed pore structures with different levels of connectivity, consequently enabling the comparison between 2D and 3D matrices using the same substrate with identical surface chemistry conditions. Additionally, here we achieve the control of pore surface topology (i.e. how different ligands are clustered together) using amphiphilic block copolymers as emulsion stabilizers. We demonstrate that adhesion of human mesenchymal progenitor (hES-MP) cells cultured on polyHIPE foams is dependent on foam surface topology and chemistry but is independent of porosity and interconnectivity. We also demonstrate that the interconnectivity, architecture and surface topology of the foams has an effect on the osteogenic differentiation potential of hES-MP cells. Together these data demonstrate that the adhesive heterogeneity of a 3D scaffold could regulate not only mesenchymal stem cell attachment but also cell behavior in the absence of soluble growth factors. PMID- 25818421 TI - A delivery system specifically approaching bone resorption surfaces to facilitate therapeutic modulation of microRNAs in osteoclasts. AB - Dysregulated microRNAs in osteoclasts could cause many skeletal diseases. The therapeutic manipulation of these pathogenic microRNAs necessitates novel, efficient delivery systems to facilitate microRNAs modulators targeting osteoclasts with minimal off-target effects. Bone resorption surfaces characterized by highly crystallized hydroxyapatite are dominantly occupied by osteoclasts. Considering that the eight repeating sequences of aspartate (D-Asp8) could preferably bind to highly crystallized hydroxyapatite, we developed a targeting system by conjugating D-Asp8 peptide with liposome for delivering microRNA modulators specifically to bone resorption surfaces and subsequently encapsulated antagomir-148a (a microRNA modulator suppressing the osteoclastogenic miR-148a), i.e. (D-Asp8)-liposome-antagomir-148a. Our results demonstrated that D-Asp8 could facilitate the enrichment of antagomir-148a and the subsequent down-regulation of miR-148a in osteoclasts in vivo, resulting in reduced bone resorption and attenuated deterioration of trabecular architecture in osteoporotic mice. Mechanistically, the osteoclast-targeted delivery depended on the interaction between bone resorption surfaces and D-Asp8. No detectable liver and kidney toxicity was found in mice after single/multiple dose(s) treatment of (D-Asp8)-liposome-antagomir-148a. These results indicated that (D Asp8)-liposome as a promising osteoclast-targeting delivery system could facilitate clinical translation of microRNA modulators in treating those osteoclast-dysfunction-induced skeletal diseases. PMID- 25818422 TI - Chitosan-catechol: a polymer with long-lasting mucoadhesive properties. AB - Numerous mucoadhesive polymers have been exploited for prolonging the residence time of formulated drugs or pharmaceuticals at specific delivery sites. However, it has been difficult to achieve satisfactory mucoadhesive properties. The two major modification strategies such as thiolation or lectin functionalization have been extensively studied, but disulfide bond reversibility in the case of thiolation and the toxicity of lectins have been problems. Thus, approaches for further improvement of mucoadhesive properties need to be developed. With an overwhelming library of mucoadhesive polymers, one practical way to improve mucoadhesion is chemical modification of existing mucoadhesive polymers. In other words, the method is based on utilizing the cooperative effect that might be achieved by chemical tethering of a small adhesive moiety to an available mucoadhesive polymer. Here, we conjugated catechols derived from mussel adhesive proteins to chitosan, which is a widely known mucoadhesive polymer. We demonstrated that the gastrointestinal (GI) tract retention of chitosan-catechol was improved compared to unmodified chitosan, which is due to the formation of irreversible catechol mediated-crosslinking with mucin. The results indicate that catechol modification of mucoadhesive polymers may possibly lead to a new generation of mucoadhesive polymers for mucosal drug delivery. PMID- 25818423 TI - Design strategy of cell-penetrating copolymers for high efficient drug delivery. AB - Finding a highly effective drug delivery carrier with low cytotoxicity is essential for disease therapy. In this work, we design a cell-penetrating copolymer (CPC) carrier, in which the inspiration comes from cell-penetrating peptides that have both hydrophilic and hydrophobic residues and are capable of penetrating membranes without inducing membrane disruption. Further dissipative particle dynamics simulations indicate that the CPCs also have an effective penetration capacity. Importantly, we found that the penetration mechanism of the CPC is in a zipper way, i.e. the adjacent hydrophobic segments of the CPC could cross the membrane in a cooperative way. Moreover, we determine the optimal parameters for the CPC crossing lipid membrane, i.e. the hydrophobic segment length of the CPC is close to the membrane thickness, and the CPC has more segment number. Finally, by grafting the CPC with the optimal structure on the hydrophilic drug, we found that the CPCs can definitely help the hydrophilic drug penetrate the lipid membrane effectively, which is an excellent prototype of drug delivery carriers. It is expected that this work can provide the fundamental for further design of drug delivery carriers. PMID- 25818424 TI - Impact of an autologous oxygenating matrix culture system on rat islet transplantation outcome. AB - Disruption of the pancreatic islet environment combined with the decrease in oxygen supply that occurs during isolation leads to poor islet survival. The aim of this study was to validate the benefit of using a plasma-based scaffold supplemented with perfluorodecalin to improve islet transplantation outcome. Rat islets were cultured in three conditions: i) control group, ii) plasma based matrix (P-matrix), and iii) P-matrix supplemented with emulsified perfluorodecalin. After 24 h culture, matrix/cell contacts (Integrinbeta1, p FAK/FAK, p-Akt/Akt), survival (caspase 3, TUNEL, FDA/PI), function, and HIF 1alpha translocation were assessed. Afterwards, P-matrices were dissolved and the islets were intraportally transplanted. Graft function was monitored for 31 days with glycaemia and C-peptide follow up. Inflammation was assessed by histology (macrophage and granulocyte staining) and thrombin/anti-thrombin complex measurement. Islet survival correlated with an increase in integrin, FAK, and Akt activation in P-matrices and function was maintained. Perfluorodecalin supplementation decreased translocation of HIF-1alpha in the nucleus and post transplantation islet structure was better preserved in P-matrices, but a quicker activation of IBMIR resulted in early loss of graft function. "Oxygenating" P matrices provided a real benefit to islet survival and resistance in vivo. However, intraportal transplantation is not suitable for this kind of culture due to IBMIR; thus, alternative sites must be explored. PMID- 25818425 TI - Hyaluronic acid controls the uptake pathway and intracellular trafficking of an octaarginine-modified gene vector in CD44 positive- and CD44 negative-cells. AB - The cellular uptake pathway for a gene vector is an important factor in transgene expression. We previously constructed an original gene vector, multifunctional envelope-type nano device (MEND). The use of octaarginine (R8), a cell penetrating peptide dramatically enhanced the transfection activity of the MEND since efficient cellular uptake via macropinocytosis, while the R8 should overcome its poor cell selectivity. Here we prepared an R8-MEND equipped with GALA (a peptide for endosomal escape) (R8/GALA-MEND) coated with hyaluronic acid (HA) (HA-R8/GALA-MEND), a natural ligand for cancer cells overexpressing CD44. We investigated the cellular uptake pathway of the HA-R8/GALA-MEND and the R8/GALA MEND using HCT116 cells overexpressing CD44. Both carriers were taken up by cells mainly via macropinocytosis, whereas only the HA-R8/GALA-MEND was partially internalized into cells via a CD44-mediated pathway. Investigation of transgene expression showed that the HA-R8/GALA-MEND had a high transfection activity in HCT116 cells via both macropinocytotic and CD44-mediated pathways. On the other hand, the value for the HA-R8/GALA-MEND was significantly decreased compared with the value for the R8/GALA-MEND in NIH3T3 cells (CD44-negative cells). These findings indicate that the HA-coating controls the intracellular pathway for R8 modified nanocarriers, and that a CD44-mediated pathway is an important route for transgene expression. PMID- 25818426 TI - Influence of stepwise chondrogenesis-mimicking 3D extracellular matrix on chondrogenic differentiation of mesenchymal stem cells. AB - Extracellular matrix (ECM) has drawn a broad attention for preparation of tissue engineering scaffolds and stem cell study. ECM scaffolds stepwise mimicking development of tissues can provide useful models to investigate the interactions between stem cells and ECM during the process of tissue development. In this study, 3D stepwise chondrogenesis-mimicking ECM scaffolds were prepared from mesenchymal stem cells (MSCs) by controlling the stages of chondrogenic differentiation. ECM scaffolds mimicking the early stage and late stage of chondrogenesis were obtained when MSCs were cultured in the chondrogenic medium for 1 and 3 w, respectively. The ECM scaffolds had different compositions as shown by immunohistochemical analysis. Stem cell (SC)-ECM scaffold was rich in collagen I and biglycan. Early stage chondrogenesis-mimicking (CE)-ECM scaffold had moderate amount of collagen II and aggrecan while late stage chondrogenesis mimicking (CL)-ECM scaffold were rich in collagen II and aggrecan. These three ECM scaffolds had different effects on chondrogenesis of MSCs. The CE-ECM scaffold facilitated chondrogenesis, however the CL-ECM scaffolds remarkably inhibited chondrogenesis of MSCs. These ECM scaffolds not only can provide new 3D ECM models to investigate the effects of ECM on MSCs functions, but also can be used as favorable ECM scaffolds for tissue engineering. PMID- 25818427 TI - Scaffold composition affects cytoskeleton organization, cell-matrix interaction and the cellular fate of human mesenchymal stem cells upon chondrogenic differentiation. AB - The stem cell niche, or microenvironment, consists of soluble, matrix, cell and mechanical factors that together determine the cellular fates and/or differentiation patterns of stem cells. Collagen and glycosaminoglycans (GAGs) are important scaffolding materials that can mimic the natural matrix niche. Here, we hypothesize that imposing changes in the scaffold composition or, more specifically, incorporating GAGs into the collagen meshwork, will affect the morphology, cytoskeletal organization and integrin expression profiles, and hence the fate of human mesenchymal stem cells (MSCs) upon the induction of differentiation. Using chondrogenesis as an example, we microencapsulated MSCs in three scaffold systems that had varying matrix compositions: collagen alone (C), aminated collagen (AC) and aminated collagen with GAGs (ACG). We then induced the MSCs to differentiate toward a chondrogenic lineage, after which, we characterized the cell viability and morphology, as well as the level of cytoskeletal organization and the integrin expression profile. We also studied the fate of the MSCs by evaluating the major chondrogenic markers at both the gene and protein level. In C, MSC chondrogenesis was successfully induced and MSCs that spread in the scaffolds had a clear actin cytoskeleton; they expressed integrin alpha2beta1, alpha5 and alphav; promoted sox9 nuclear localization transcription activation; and upregulated the expression of chondrogenic matrix markers. In AC, MSC chondrogenesis was completely inhibited but the scaffold still supported cell survival. The MSCs did not spread and they had no actin cytoskeleton; did not express integrin alpha2 or alphav; they failed to differentiate into chondrogenic lineage cells even on chemical induction; and there was little colocalization or functional interaction between integrin alpha5 and fibronectin. In ACG, although the MSCs did not express integrin alpha2, they did express integrin alphav and there was strong co-localization and hence functional binding between alphav and fibronectin. In addition, vimentin was the dominant cytoskeletal protein in these cells, and the chondrogenic marker genes were expressed but at a much lower level than in the MSCs encapsulated in C alone. This work suggests the importance of controlling the matrix composition as a strategy to manipulate cell-matrix interactions (through changes in the integrin expression profile and cytoskeleton organization), and hence stem cell fates. PMID- 25818428 TI - Successful matrix guided tissue regeneration of decellularized pulmonary heart valve allografts in elderly sheep. AB - In vivo repopulation of decellularized allografts with recipient cells leads to a positive remodeling of the graft matrix in juvenile sheep. In light of the increasing number of heart valve replacements among older patients (>65 years), this study focused on the potential for matrix-guided tissue regeneration in elderly sheep. Pulmonary valve replacement was performed in seven-year old sheep using decellularized (DV), decellularized and CCN1-coated (RV), or decellularized and in vitro reendothelialized pulmonary allografts (REV) (n=6, each group). CCN1 coating was applied to support re-endothelialization. In vitro re endothelialization was conducted with endothelial-like cells derived from peripheral blood. Echocardiograms of all grafts showed adequate graft function after implantation and at explantation 3 or 6 months later. All explants were macroscopically free of thrombi at explantation, and revealed repopulation of the allografts on the adventitial side of valvular walls and proximal in the cusps. Engrafted cells expressed vimentin, sm alpha-actin, and myosin heavy chain 2, while luminal cell lining was positive for vWF and eNOS. Cellular repopulation of valvular matrix demonstrates the capacity for matrix-guided regeneration even in elderly sheep but is not improved by in vitro endothelialization, confirming the suitability of decellularized matrix for heart valve replacement in older individuals. PMID- 25818429 TI - Effects of mannose density on in vitro and in vivo cellular uptake and RNAi efficiency of polymeric nanoparticles. AB - To evaluate the effects of mannose density on in vitro and in vivo cellular uptake and RNA interference (RNAi) efficiency of polymeric nanoparticles (NPs) in macrophages, mannose-modified trimethyl chitosan-cysteine (MTC) conjugates with mannose densities of 4%, 13%, and 21% (MTC-4, MTC-13, and MTC-21) were synthesized. Tumor necrosis factor-alpha (TNF-alpha) siRNA loaded MTC NPs with particle sizes of ~150 nm exhibited desired structural stability and effectively protected siRNA from enzymatic degradation. Generally, cellular uptake and RNAi efficiency were affected by mannose density. As expected, MTC-21 NPs presented the maximum in vitro uptake and RNAi efficacy in Raw 264.7 cells among all NPs tested. However, MTC-4 NPs exhibited the optimal in vivo uptake by peritoneal exudate cell macrophages (PECs). In the inflammation model of acute hepatic injury, orally delivered MTC-4 and MTC-13 NPs worked better in silencing TNF alpha expression and alleviating liver damage than MTC-21 NPs. As for the ulcerative colitis model, MTC-4 NPs outperformed MTC-13 and MTC-21 NPs with respect to TNF-alpha knockdown and therapeutic efficacy following oral administration. These results highlighted the importance of ligand density in cellular uptake and RNAi efficiency, which could serve as a guideline in the rational design of targeted nanocarriers for anti-inflammation therapy. PMID- 25818430 TI - Hierarchical targeted hepatocyte mitochondrial multifunctional chitosan nanoparticles for anticancer drug delivery. AB - The overwhelming majority of drugs exert their pharmacological effects after reaching their target sites of action, however, these target sites are mainly located in the cytosol or intracellular organelles. Consequently, delivering drugs to the specific organelle is the key to achieve maximum therapeutic effects and minimum side-effects. In the work reported here, we designed, synthesized, and evaluated a novel mitochondrial-targeted multifunctional nanoparticles (MNPs) based on chitosan derivatives according to the physiological environment of the tumor and the requirement of mitochondrial targeting drug delivery. The intelligent chitosan nanoparticles possess various functions such as stealth, hepatocyte targeting, multistage pH-response, lysosomal escape and mitochondrial targeting, which lead to targeted drug release after the progressively shedding of functional groups, thus realize the efficient intracellular delivery and mitochondrial localization, inhibit the growth of tumor, elevate the antitumor efficacy, and reduce the toxicity of anticancer drugs. It provides a safe and efficient nanocarrier platform for mitochondria targeting anticancer drug delivery. PMID- 25818431 TI - In vivo multimodal magnetic particle imaging (MPI) with tailored magneto/optical contrast agents. AB - Magnetic Particle Imaging (MPI) is a novel non-invasive biomedical imaging modality that uses safe magnetite nanoparticles as tracers. Controlled synthesis of iron oxide nanoparticles (NPs) with tuned size-dependent magnetic relaxation properties is critical for the development of MPI. Additional functionalization of these NPs for other imaging modalities (e.g. MRI and fluorescent imaging) would accelerate screening of the MPI tracers based on their in vitro and in vivo performance in pre-clinical trials. Here, we conjugated two different types of poly-ethylene-glycols (NH2-PEG-NH2 and NH2-PEG-FMOC) to monodisperse carboxylated 19.7 nm NPs by amide bonding. Further, we labeled these NPs with Cy5.5 near infra red fluorescent (NIRF) molecules. Bi-functional PEG (NH2-PEG-NH2) resulted in larger hydrodynamic size (~98 nm vs. ~43 nm) of the tracers, due to inter particle crosslinking. Formation of such clusters impacted the multimodal imaging performance and pharmacokinetics of these tracers. We found that MPI signal intensity of the tracers in blood depends on their plasmatic clearance pharmacokinetics. Whole body mice MPI/MRI/NIRF, used to study the biodistribution of the injected NPs, showed primary distribution in liver and spleen. Biodistribution of tracers and their clearance pathway was further confirmed by MPI and NIRF signals from the excised organs where the Cy5.5 labeling enabled detailed anatomical mapping of the tracers.in tissue sections. These multimodal MPI tracers, combining the strengths of each imaging modality (e.g. resolution, tracer sensitivity and clinical use feasibility) pave the way for various in vitro and in vivo MPI applications. PMID- 25818432 TI - A paper-based invasion assay: assessing chemotaxis of cancer cells in gradients of oxygen. AB - This work describes a 3D, paper-based assay that can isolate sub-populations of cells based on their invasiveness (i.e., distance migrated in a hydrogel) in a gradient of concentration of oxygen (O2). Layers of paper impregnated with a cell compatible hydrogel are stacked and placed in a plastic holder to form the invasion assay. In most assays, the stack comprises a single layer of paper containing mammalian cells suspended in a hydrogel, sandwiched between multiple layers of paper containing only hydrogel. Cells in the stack consume and produce small molecules; these molecules diffuse throughout the stack to generate gradients in the stack, and between the stack and the bulk culture medium. Placing the cell-containing layer in different positions of the stack, or modifying the permeability of the holder to oxygen or proteins, alters the profile of the gradients within the stack. Physically separating the layers after culture isolates sub-populations of cells that migrated different distances, and enables their subsequent analysis or culture. Using this system, three independent cell lines derived from A549 cancer cells are shown to produce distinguishable migration behavior in a gradient of oxygen. This result is the first experimental demonstration that oxygen acts as a chemoattractant for cancer cells. PMID- 25818433 TI - Feasibility of islet magnetic resonance imaging using ferumoxytol in intraportal islet transplantation. AB - There is a clinical need for an alternative labeling agent for magnetic resonance imaging (MRI) in islet transplantation. We aimed to evaluate the feasibility of islet MRI using ferumoxytol, which is the only clinically-available ultrasmall superparamagnetic iron oxide. We compared islet function and viability of control islets and islets labeled with ferumoxytol and/or a heparin-protamine complex (HPF). Efficacy of ferumoxytol labeling was assessed in both ex vivo and in vivo models. Labeling for 48 h with HPF, but not up to 800 MUg/mL ferumoxytol, deranged ex vivo islet viability and function. The T2* relaxation time was optimal when islets were labeled with 800 MUg/mL of ferumoxytol for 48 h. Prussian blue stain, iron content assay, transmission electron microscopy (TEM) supported internalization of ferumoxytol particles. However, the labeling intensity in the ex vivo MRI of islets labeled with ferumoxytol was much weaker than that of islets labeled with ferucarbotran. In syngeneic intraportal islet transplantation, there was a correlation between the total area of visualized islets and the transplanted islet mass. In conclusion, islet MRI using ferumoxytol was feasible in terms of in vitro and in vivo efficacy and safety. However, the weak labeling efficacy is still a hurdle for the clinical application. PMID- 25818434 TI - Efficient nuclear drug translocation and improved drug efficacy mediated by acidity-responsive boronate-linked dextran/cholesterol nanoassembly. AB - The present study reported a lysosome-acidity-targeting bio-responsive nanovehicle self-assembled from dextran (Dex) and phenylboronic acid modified cholesterol (Chol-PBA), aiming at the nucleus-tropic drug delivery. The prominent advantage of this assembled nanoconstruction arose from its susceptibility to acidity-labile dissociation concurrently accompanied with the fast liberation of encapsulated drugs, leading to efficient nuclear drug translocation and consequently favorable drug efficacy. By elaborately exploiting NH4Cl pretreatment to interfere with the cellular endosomal acidification progression, this study clearly evidenced at a cellular level the strong lysosomal-acidity dependency of nuclear drug uptake efficiency, which was shown to be the main factor influencing the drug efficacy. The boronate-linked nanoassembly displayed nearly no cytotoxicity and can remain structural stability under the simulated physiological conditions including 10% serum and the normal blood sugar concentration. The cellular exposure to cholesterol was found to bate the cellular uptake of nanoassembly in a dose-dependent manner, suggesting a cholesterol-associated mechanism of the intracellular internalization. The in vivo antitumor assessment in xenograft mouse models revealed the significant superiority of DOX-loaded Dex/Chol-PBA nanoassembly over the controls including free DOX and the DOX-loaded non-sensitive Dex-Chol, as reflected by the more effective tumor-growth inhibition and the better systematic safety. In terms of the convenient preparation, sensitive response to lysosomal acidity and efficient nuclear drug translocation, Dex/Chol-PBA nanoassembly derived from natural materials shows promising potentials as the nanovehicle for nucleus-tropic drug delivery especially for antitumor agents. More attractively, this study offers a deeper insight into the mechanism concerning the contribution of acidity responsive delivery to the enhanced chemotherapy performance. PMID- 25818435 TI - Nanostructured medical sutures with antibacterial properties. AB - Bacterial repellence in suture materials is a desirable property that can potentially improve the healing process by preventing infection. We describe a method for generating nanostructures at the surface of commercial sutures of different composition, and their potential for preventing biofilm formation. We show how bacteria attachment is altered in the presence of nanosized topographies and identify optimum designs for preventing it without compromising biocompatibility and applicability in terms of nanostructure robustness or tissue friction. These studies open new possibilities for flexible and cost-effective realization of topography-based antibacterial coatings for absorbable biomedical textiles. PMID- 25818436 TI - L-cysteine: a biocompatible, breathable and beneficial coating for graphene oxide. AB - Graphene oxide (GO) has been employed in various fields, and its ecological and health risks have attracted much attention. A small and inexpensive biomolecule, L-cysteine, was covalently immobilized onto GO to form L-cysteine-GO (CysGO) as a thio-functionalized nanosheet of 1.4 nm in thickness. Both the d-spacing and crystallinity of CysGO were observed to be lower than those of GO, whereas the D and G peaks remained similar to those of GO. CysGO exhibited remarkable uptake in vivo: no tissue defects, malformation, death or significant hatching delay were observed in zebrafish embryos. Significant DNA damage, decreased Na+/K+-ATPase activity and decreased mitochondrial membrane potential were not observed for CysGO. As a nonspecific activity linked to nanotoxicology, the unpaired electron spinning intensity of CysGO was approximately two orders of magnitude lower than that of GO. Oxygen microsensor analysis showed that the hypoxic and normoxic environments resulting from the presence of GO and CysGO envelopment, respectively, contributed to the difference in biocompatibility. CysGO also protected embryos from arsenic poisoning. Thus, CysGO has the advantageous properties of GO, exhibits excellent biocompatibility, acts as a breathable coating and antidote, and is suitable for various applications. PMID- 25818437 TI - Experimental modulation and computational model of nano-hydrophobicity. AB - We demonstrate that nano-hydrophobicity, which governs the biological aggressiveness of nanoparticles, is determined by the outermost regions of surface ligands. We have also successfully modulated nano-hydrophobicity using systematic surface ligand modifications and built the first computational model of nano-hydrophobicity. PMID- 25818438 TI - Stem cell impregnated nanofiber stent sleeve for on-stent production and intravascular delivery of paracrine factors. AB - Stem cell therapies for atherosclerotic diseases are promising, but benefits remain modest with present cell delivery devices in part due to cell washout and immune attack. Many stem cell effects are believed mediated by paracrine factors (PFs) secreted by the stem cells which potentiate tissue repair via activation and enhancement of intrinsic host repair mechanisms We therefore sought to create an "intravascular paracrine factor factory" by harnessing stem cells on a stent using a nanofiber (NF) stent sleeve, and thus providing a sheltered milieu for cells to continuously produce PFs on-stent. The NF sleeve acts as a substrate on which stem cells grow, and as a semi-permeable barrier that protects cells from washout and host immune response while allowing free outward passage of PFs. NF stent sleeves were created by covering stents with electrospun poly-lactic-co glycolic acid nanofibers and were then uniformly coated with mesenchymal stem cells (MSCs). NF sleeves blocked cell passage but did not hamper MSC attachment or proliferation, and did not alter MSC morphology or surface markers. NF sleeve MSCs continued to secrete PFs that were biologically active and successfully induced tubulogenesis in human endothelial cells. NF stent sleeves seeded with allogeneic MSCs implanted in pigs remained patent at 7 days without thrombotic occlusion or immune rejection. Our results demonstrate the feasibility of creating an intravascular PF factory using a stem cell impregnated NF stent sleeve, and pave the way for animal studies to assess the efficacy of local PF production to treat ischemic artery disease. PMID- 25818439 TI - Cold atmospheric plasma in combination with mechanical treatment improves osteoblast growth on biofilm covered titanium discs. AB - Treatment of implants with peri-implantitis is often unsuccessful, because an instrumented implant surface and residual microbial biofilm impedes re osseointegration. The application of cold atmospheric plasma (CAP) could be a simple and effective strategy to overcome the inherent problems of peri implantitis treatment. CAP is able to destroy and eliminate bacterial biofilms. Additionally, it increases the wettability of titanium, which supports cellular attachment. In this study, the behaviour of osteoblasts on titanium discs was analysed after treatment of bacterial biofilms with CAP, brushing, or a combination of both. A human plaque biofilm was cultured on titanium discs. Treatment with a brush (BR), 1% oxygen/argon CAP (PL), or brushing combined with CAP (BR+PL) was used to eliminate the biofilm. Discs without biofilm (C), autoclaved biofilm (AUTO) and untreated biofilm (BIO) served as controls. Subsequently, human osteoblastic cell growth (MG-63) was observed after 1 and 24 h. Biofilm remnants on BR and PL impaired osteoblastic cell development, whereas the BR+PL provided an increased area of osteoblastic cells. A five-day cell growth was only detectable on BR+PL treated discs. The combination of established brushing and CAP application may be a promising strategy to treat peri implantitis. PMID- 25818441 TI - Controlled 3D culture in Matrigel microbeads to analyze clonal acinar development. AB - 3D culture systems are a valuable tool for modeling morphogenesis and carcinogenesis of epithelial tissue in a structurally appropriate context. We present a novel approach for 3D cell culture based on a flow-focusing microfluidic system that encapsulates epithelial cells in Matrigel beads. As a model we use prostatic and breast cells and assay for development of acini, polarized cellular spheres enclosing lumen. Each individual bead on average acts as a single 3D cell culture compartment generating one acinus per bead. Compared to standard protocols microfluidics provides increased control over the environment leading to more a uniform acini population. The increased facility of bead manipulation allowed us to isolate single cells which are self-sufficient to fully develop into acini in presence of Matrigel. Furthermore, combination of our microfluidic approach with large particle FACS opens new avenues in high throughput screening on single acini or spheroids. PMID- 25818440 TI - A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors. AB - Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20 120 nm) depending on the PPT-to-PEG molar ratio (2-20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ~5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (~2.5%/day and ~1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity. PMID- 25818442 TI - Hypoxia-mimicking bioactive glass/collagen glycosaminoglycan composite scaffolds to enhance angiogenesis and bone repair. AB - One of the biggest challenges in regenerative medicine is promoting sufficient vascularisation of tissue-engineered constructs. One approach to overcome this challenge is to target the cellular hypoxia inducible factor (HIF-1alpha) pathway, which responds to low oxygen concentration (hypoxia) and results in the activation of numerous pro-angiogenic genes including vascular endothelial growth factor (VEGF). Cobalt ions are known to mimic hypoxia by artificially stabilising the HIF-1alpha transcription factor. Here, resorbable bioactive glass particles (38 MUm and 100 MUm) with cobalt ions incorporated into the glass network were used to create bioactive glass/collagen-glycosaminoglycan scaffolds optimised for bone tissue engineering. Inclusion of the bioactive glass improved the compressive modulus of the resulting composite scaffolds while maintaining high degrees of porosity (>97%). Moreover, in vitro analysis demonstrated that the incorporation of cobalt bioactive glass with a mean particle size of 100 MUm significantly enhanced the production and expression of VEGF in endothelial cells, and cobalt bioactive glass/collagen-glycosaminoglycan scaffold conditioned media also promoted enhanced tubule formation. Furthermore, our results prove the ability of these scaffolds to support osteoblast cell proliferation and osteogenesis in all bioactive glass/collagen-glycosaminoglycan scaffolds irrespective of the particle size. In summary, we have developed a hypoxia mimicking tissue-engineered scaffold with pro-angiogenic and pro-osteogenic capabilities that may encourage bone tissue regeneration and overcome the problem of inadequate vascularisation of grafts commonly seen in the field of tissue engineering. PMID- 25818443 TI - The phenotype of cancer cell invasion controlled by fibril diameter and pore size of 3D collagen networks. AB - The behavior of cancer cells is strongly influenced by the properties of extracellular microenvironments, including topology, mechanics and composition. As topological and mechanical properties of the extracellular matrix are hard to access and control for in-depth studies of underlying mechanisms in vivo, defined biomimetic in vitro models are needed. Herein we show, how pore size and fibril diameter of collagen I networks distinctively regulate cancer cell morphology and invasion. Three-dimensional collagen I matrices with a tight control of pore size, fibril diameter and stiffness were reconstituted by adjustment of concentration and pH value during matrix reconstitution. At first, a detailed analysis of topology and mechanics of matrices using confocal laser scanning microscopy, image analysis tools and force spectroscopy indicate pore size and not fibril diameter as the major determinant of matrix elasticity. Secondly, by using two different breast cancer cell lines (MDA-MB-231 and MCF-7), we demonstrate collagen fibril diameter--and not pore size--to primarily regulate cell morphology, cluster formation and invasion. Invasiveness increased and clustering decreased with increasing fibril diameter for both, the highly invasive MDA-MB-231 cells with mesenchymal migratory phenotype and the MCF-7 cells with amoeboid migratory phenotype. As this behavior was independent of overall pore size, matrix elasticity is shown to be not the major determinant of the cell characteristics. Our work emphasizes the complex relationship between structural-mechanical properties of the extracellular matrix and invasive behavior of cancer cells. It suggests a correlation of migratory and invasive phenotype of cancer cells in dependence on topological and mechanical features of the length scale of single fibrils and not on coarse-grained network properties. PMID- 25818444 TI - Oxygen delivery from hyperbarically loaded microtanks extends cell viability in anoxic environments. AB - Oxygen diffusion limitations within nascent tissue engineered (TE) grafts lead to the development of hypoxic regions, cell death, and graft failure. Previous efforts have been made to deliver oxygen within TE scaffolds, including peroxide doping, perfluorocarbons, and hyperbaric oxygen therapy, to mitigate these effects and help maintain post transplantation cell viability, but these have suffered from significant drawbacks. Here we present a novel approach utilizing polymeric hollow-core microspheres that can be hyperbarically loaded with oxygen and subsequently provide prolonged oxygen delivery. These oxygen carriers are termed, microtanks. With an interest in orthopedic applications, we combined microtanks within polycaprolactone to form solid phase constructs with oxygen delivery capabilities. The mathematical laws governing oxygen delivery from microtank-loaded constructs are developed along with empirical validation. Constructs achieved periods of oxygen delivery out to 6 days, which was shown to prolong the survival of human adipose derived stem cells (hASCs) and human umbilical vein endothelial cells (HUVECs) as well as to enhance their cellular morphology under anoxic conditions. The results of this study suggest the microtank approach may be a feasible means of maintaining cell viability in TE scaffolds during the critical period of vascularization in vivo. PMID- 25818445 TI - A gene expression-based comparison of cell adhesion to extracellular matrix and RGD-terminated monolayers. AB - This work uses global gene expression analysis to compare the extent to which model substrates presenting peptide adhesion motifs mimic the use of conventional extracellular matrix protein coated substrates for cell culture. We compared the transcriptional activities of genes in cells that were cultured on matrix-coated substrates with those cultured on self-assembled monolayers presenting either a linear or cyclic RGD peptide. Cells adherent to cyclic RGD were most similar to those cultured on native ECM, while cells cultured on monolayers presenting the linear RGD peptide had transcriptional activities that were more similar to cells cultured on the uncoated substrates. This study suggests that biomaterials presenting the cyclic RGD peptide are substantially better mimics of extracellular matrix than are uncoated materials or materials presenting the common linear RGD peptide. PMID- 25818447 TI - Highly efficient ablation of metastatic breast cancer using ammonium-tungsten bronze nanocube as a novel 1064 nm-laser-driven photothermal agent. AB - Photothermal ablation (PTA) therapy has been viewed as an invasive option for cancer therapy with minimal deconstruction of healthy tissues. In this study, a potent candidate of (NH4)xWO3 nanocube was developed for PTA treatment of metastatic breast cancer in the second near-infrared (NIR) window. It was found that the as-synthesized (NH4)xWO3 nanocube had significant photoabsorption across the whole NIR window of 780-2500 nm and exhibited considerable photo-heat conversion efficiency. Moreover, the as-prepared (NH4)xWO3 nanocube displayed good biocompatibility and high cellular uptake efficiency through endocytosis pathway without nuclei entry. The PTA study employing 1064 nm laser in the second NIR window revealed that (NH4)xWO3 nanocubes induced significant cell necrosis and apoptosis by producing obviously hyperthermia effect inside cancer cells. Using an orthotopicly implanted breast tumor model, it demonstrated that the (NH4)xWO3 nanocube was a promising photothermal agent for effective ablation of solid tumors and suppressing their distant metastasis. PMID- 25818446 TI - Actin grips: circular actin-rich cytoskeletal structures that mediate the wrapping of polymeric microfibers by endothelial cells. AB - Interaction of endothelial-lineage cells with three-dimensional substrates was much less studied than that with flat culture surfaces. We investigated the in vitro attachment of both mature endothelial cells (ECs) and of less differentiated EC colony-forming cells to poly-epsilon-capro-lactone (PCL) fibers with diameters in 5-20 MUm range ('scaffold microfibers', SMFs). We found that notwithstanding the poor intrinsic adhesiveness to PCL, both cell types completely wrapped the SMFs after long-term cultivation, thus attaining a cylindrical morphology. In this system, both EC types grew vigorously for more than a week and became increasingly more differentiated, as shown by multiplexed gene expression. Three-dimensional reconstructions from multiphoton confocal microscopy images using custom software showed that the filamentous (F) actin bundles took a conspicuous ring-like organization around the SMFs. Unlike the classical F-actin-containing stress fibers, these rings were not associated with either focal adhesions or intermediate filaments. We also demonstrated that plasma membrane boundaries adjacent to these circular cytoskeletal structures were tightly yet dynamically apposed to the SMFs, for which reason we suggest to call them 'actin grips'. In conclusion, we describe a particular form of F-actin assembly with relevance for cytoskeletal organization in response to biomaterials, for endothelial-specific cell behavior in vitro and in vivo, and for tissue engineering. PMID- 25818448 TI - Isoniazid conjugated poly(lactide-co-glycolide): long-term controlled drug release and tissue regeneration for bone tuberculosis therapy. AB - Bone tuberculosis (TB) is one of the most common extrapulmonary TB. Effective integration of chemotherapy and bone regeneration is an optimal solution for bone TB therapy. Herein, we produce a composite scaffold drug delivery system fabricated with an isoniazid conjugated star poly(lactide-co-glycolide) (PLGA INH4) and beta-TCP. The cytological assay indicated the composite system possesses good biocompatibility. The in vitro and in vivo drug release evaluations showed that the composite system can intactly release the pristine INH and maintain effective INH concentration in a controlled manner for more than 100 days, and achieve high localized drug concentration and low systemic drug concentration. The rabbit radius repair experiment testified the scaffold has good bone regeneration capacity. Our work demonstrate the composite system can simultaneously achieve localized long-term drug controlled release and bone regeneration, which provides a promising route for improved bone TB treatment. PMID- 25818450 TI - Dextran-coated fluorapatite crystals doped with Yb3+/Ho3+ for labeling and tracking chondrogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo. AB - Upconversion fluorescent nanoparticles are becoming more widely used as imaging contrast agents, owing to their high resolution and penetration depth, and avoidance of tissue auto-fluorescence and photodamage to cells. Here, we synthesized upconversion fluorescent crystals from rare-earth Yb3+ and Ho3+ co doped fluorapatite (FA:Yb3+/Ho3+) suitable for long-term tracking and monitoring cartilage development (chondrogenesis) in bone marrow mesenchymal stem cells (BMSCs) in vitro and in vivo. We initially determined the structure, morphology and luminescence of the products using X-ray powder diffraction, transmission electron microscopy and two-photon confocal microscopy. When excited at 980 nm, FA:Yb3+/Ho3+ crystals exhibited distinct upconversion fluorescence peaks at 543 nm and 654 nm. We then conjugated FA:Yb3+/Ho3+ crystals with dextran to enhance hydrophilicity, biocompatibility and cell penetration. Next, we employed the dextran-coated FA:Yb3+/Ho3+ crystals in labeling and tracking chondrogenic differentiation processes in BMSCs stably expressing green fluorescent protein (BMSCsGFP) in vitro and in vivo. Labeled BMSCsGFP were shown to reproducibly exhibit chondrogenic differentiation potential in RT-PCR analysis, histological assessment and immunohistochemistry. We observed continuous luminescence from the FA:Yb3+/Ho3+ upconversion crystals at 4 weeks and 12 weeks post transplantation in BMSCsGFP, while GFP fluorescence in both control and crystal-treated groups significantly decreased at 12 weeks after BMSCsGFP transplantation. We therefore demonstrate the high biocompatibility and stability of FA:Yb3+/Ho3+ crystals in tracking and monitoring BMSCs chondrogenesis in vitro and in vivo, highlighting their excellent cell labeling potential in cartilage tissue engineering. PMID- 25818449 TI - Emulating native periosteum cell population and subsequent paracrine factor production to promote tissue engineered periosteum-mediated allograft healing. AB - Emulating autograft healing within the context of decellularized bone allografts has immediate clinical applications in the treatment of critical-sized bone defects. The periosteum, a thin, osteogenic tissue that surrounds bone, houses a heterogenous population of stem cells and osteoprogenitors. There is evidence that periosteum-cell derived paracrine factors, specifically vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2), orchestrate autograft healing through host cell recruitment and subsequent tissue elaboration. In previous work, we demonstrated that the use of poly(ethylene glycol) (PEG) hydrogels as a tissue engineered (T.E.) periosteum to localize mesenchymal stem cells (MSCs) to the surface of decellularized bone enhances allograft healing and integration. Herein, we utilize a mixed population of 50:50 MSCs and osteoprogenitor cells to better mimic native periosteum cell population and paracrine factor production to further promote allograft healing. This mixed cell population was localized to the surface of decellularized allografts within degradable hydrogels and shown to expedite allograft healing. Specifically, bone callus formation and biomechanical graft-host integration are increased as compared to unmodified allografts. These results demonstrate the dual importance of periosteum-mediated paracrine factors orchestrating host cell recruitment as well as new bone formation while developing clinically translatable strategies for allograft healing and integration. PMID- 25818451 TI - Engineered cartilaginous tubes for tracheal tissue replacement via self-assembly and fusion of human mesenchymal stem cell constructs. AB - There is a critical need to engineer a neotrachea because currently there are no long-term treatments for tracheal stenoses affecting large portions of the airway. In this work, a modular tracheal tissue replacement strategy was developed. High-cell density, scaffold-free human mesenchymal stem cell-derived cartilaginous rings and tubes were successfully generated through employment of custom designed culture wells and a ring-to-tube assembly system. Furthermore, incorporation of transforming growth factor-beta1-delivering gelatin microspheres into the engineered tissues enhanced chondrogenesis with regard to tissue size and matrix production and distribution in the ring- and tube-shaped constructs, as well as luminal rigidity of the tubes. Importantly, all engineered tissues had similar or improved biomechanical properties compared to rat tracheas, which suggests they could be transplanted into a small animal model for airway defects. The modular, bottom up approach used to grow stem cell-based cartilaginous tubes in this report is a promising platform to engineer complex organs (e.g., trachea), with control over tissue size and geometry, and has the potential to be used to generate autologous tissue implants for human clinical applications. PMID- 25818452 TI - Mechano growth factor (MGF) and transforming growth factor (TGF)-beta3 functionalized silk scaffolds enhance articular hyaline cartilage regeneration in rabbit model. AB - Damaged cartilage has poor self-healing ability and usually progresses to scar or fibrocartilaginous tissue, and finally degenerates to osteoarthritis (OA). Here we demonstrated that one of alternative isoforms of IGF-1, mechano growth factor (MGF) acted synergistically with transforming growth factor beta3 (TGF-beta3) embedded in silk fibroin scaffolds to induce chemotactic homing and chondrogenic differentiation of mesenchymal stem cells (MSCs). Combination of MGF and TGF beta3 significantly increased cell recruitment up to 1.8 times and 2 times higher than TGF-beta3 did in vitro and in vivo. Moreover, MGF increased Collagen II and aggrecan secretion of TGF-beta3 induced hMSCs chondrogenesis, but decreased Collagen I in vitro. Silk fibroin (SF) scaffolds have been widely used for tissue engineering, and we showed that methanol treated pured SF scaffolds were porous, similar to compressive module of native cartilage, slow degradation rate and excellent drug released curves. At 7 days after subcutaneous implantation, TGF beta3 and MGF functionalized silk fibroin scaffolds (STM) recruited more CD29+/CD44+cells (P<0.05). Similarly, more cartilage-like extracellular matrix and less fibrillar collagen were detected in STM scaffolds than that in TGF-beta3 modified scaffolds (ST) at 2 months after subcutaneous implantation. When implanted into articular joints in a rabbit osteochondral defect model, STM scaffolds showed the best integration into host tissues, similar architecture and collagen organization to native hyaline cartilage, as evidenced by immunostaining of aggrecan, collagen II and collagen I, as well as Safranin O and Masson's trichrome staining, and histological evalution based on the modified O'Driscoll histological scoring system (P<0.05), indicating that MGF and TGF-beta3 might be a better candidate for cartilage regeneration. This study demonstrated that TGF beta3 and MGF functionalized silk fibroin scaffolds enhanced endogenous stem cell recruitment and facilitated in situ articular cartilage regeneration, thus providing a novel strategy for cartilage repair. PMID- 25818453 TI - Au nanoparticles decorated C60 nanoparticle-based label-free electrochemiluminesence aptasensor via a novel "on-off-on" switch system. AB - Herein, a label-free electrochemiluminescence (ECL) aptasensor for highly sensitive determination of kanamycin was developed based on a novel "on-off-on" switch system. The first "switch on" state with remarkably high ECL intensity was obtained by the tri-layer composite films modified glassy carbon electrode towards the S2O8(2-)-O2 system. To be specific, the first layer was the Au nanoparticles decorated C60 nanoparticles (abbreviation as Au@nano-C60) as inner layer which was prepared by the in situ generating of Au nanoparticles onto the surface of bovine serum albumin decorated nano-C60 nanoparticles. Then poly-L histidine was first selected as a novel coreactant of S2O8(2-)-O2 system and it was adsorbed on the Au@nano-C60 modified electrode as inter-layer. Finally, a self-assembling layer of colloidal Au nanoparticles (AuNPs) was the outer-layer. The three layers were interaction by the Au-N covalent bond which could achieve a desirable initial amplified ECL signal. Successively, the capture probes (CPs) of the aptamer for the target of kanamycin was anchored on the resultant tri-layer composite films modified electrode. Later, the "switch off" state was made by the quenching effect of hemin/G-quadruplex DNAzymes towards S2O8(2-)-O2 system according to the DNA hybridization reaction of an assistant probes (APs, guanine rich nucleic acid) with CPs which could generate a large amount of hemin/G quadruplex DNAzymes in the presence of hemin with a simple and label-free process. As expected, the second "switch on" state was the ECL signal recovery when the target of kanamycin was present, it is attributed to that the formation of the aptamer-kanamycin complex makes the quencher of hemin/G-quadruplex DNAzymes release from the sensing interface. With the association of "on-off-on" switch system, a linear response about 9 orders of magnitude for kanamycin detection was obtained from 0.15 nM to 170 mm as well as a detection limit down to 45 pM. PMID- 25818454 TI - Photochemical tissue penetration via photosensitizer for effective drug penetration in a non-vascular tumor. AB - To improve the tissue penetration efficiency (PE%) of hydrophilic-drugs in non vascular drug eluting stents (DES), we designed photochemical tissue penetration (PTP) invested DES (PTP-DES). The PTP technology was applied to the stent as a covering membrane to generate singlet oxygen. Singlet oxygen damages the epithelial layer, so the PE% of released drugs could be improved. To prepare the PTP-DES membrane, chlorin e6 (Ce6, photosensitizer) was incorporated in a gemcitabine (GEM) eluting polyurethane (PU) membrane (Ce6-GEM-PU). Ce6-GEM-PU has smooth surface that is ~40 MUm thick. The photoactivity of Ce6 was maintained for 2 weeks (in vitro GEM releasing period). In a separate cell culture system, both 1.5 folds higher PE% and an improved tumor cell growth inhibition effect were shown after light exposure. Additionally, in tissue penetration experimental system, 2 folds increased in the PE% of GEM was induced by laser exposure at 80 J/cm2. Additionally, improved PE% of hydrophilic molecules (Fluorescein and GEM) was confirmed in colon tumor bearing mice. Consequentially, tumor growth, when implanted with Ce6-GEM-PU, was effectively inhibited without significant side effects. Based on these results, we believe that the PTP-DES system has great potential for improving the therapeutic effect of conventional DES. PMID- 25818455 TI - Polyethylenimine-coated SPIONs trigger macrophage activation through TLR-4 signaling and ROS production and modulate podosome dynamics. AB - Polyethylenimine (PEI) is widely used as transfection agent in preclinical studies, both in vitro and in vivo. Due to their unique chemical and physical properties, SPIONs (superparamagnetic iron oxide nanoparticles) have been thoroughly studied as nanocarriers. PEI appears to activate different immune cells to an inflammatory response (M1/TH1), whereas the SPION-induced response seems to be context-dependent; the immunogenicity of the combination of these components has not been studied. Here we show that PEI-coated SPIONs (PMag) activate macrophages, as determined by measuring IL-12 secretion into culture medium and upregulation of several genes linked to the M1 phenotype. PMag-induced phosphorylation of p38 MAPK, p44/p42 MAPK and JNK, and upregulation of CD40, CD80, CD86 and I-A/I-E activation markers. PMag-induced macrophage activation depended partially on TLR4 (Toll-like receptor 4) and ROS (reactive oxygen species) signaling. Comparison of these responses with the LPS (lipopolysaccharide)-induced phenotype showed differences in gene expression profiling. PMag positively modulated podosome formation in murine macrophages, but hampered gelatin degradation by these cells. In conclusion, PMag induced an M1-like phenotype that was partially dependent on both TLR4 and ROS. These results show the adjuvant potential of PMag and suggest their use in vaccination schedules. PMID- 25818457 TI - Characterization of cell selectivity, physiological stability and endotoxin neutralization capabilities of alpha-helix-based peptide amphiphiles. AB - While naturally occurring antimicrobial peptides (AMPs) have been of increasing interest as alternative antibiotics due to their broad-spectrum antimicrobial activity and reduced possibility for the development of bacterial drug resistance, some concerns such as potential cytotoxicity, poor antimicrobial activity and weak physiological stability may ultimately weaken their development as antimicrobial agents. To generate AMPs with enhanced therapeutic potential, we designed alpha-helical hybrid peptides based on PRW4, Fowlicidin-2, Protegrin-3 and Tritrpticin sequences to gain insights into their selectivities, physiological stabilities and endotoxin neutralization capabilities. The designed hybrid peptides PR-FO, PR-PG and PR-TR exhibited high cell selectivity towards bacterial cells over human red blood cells (hRBCs). Their activities were maintained in the presence of physiological concentrations of salts or serum, indicating a high stability in vitro. The results from fluorescence spectroscopy, flow cytometry, scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that these designed peptides killed microbial cells by increasing membrane permeability and damaging membrane envelope integrity. Moreover, the hybrid peptides effectively neutralized endotoxins while causing minimal cytotoxicities. Collectively, our results suggest that these hybrid peptides, in particular PR-FO, have tremendous potential for use as novel antimicrobial and antisepsis agents. PMID- 25818456 TI - Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers. AB - Effective blood-brain tumor barrier penetration and uniform solid tumor distribution can significantly enhance therapeutic delivery to brain tumors. Hydroxyl-functionalized, generation-4 poly(amidoamine) (PAMAM) dendrimers, with their small size, near-neutral surface charge, and the ability to selectively localize in cells associated with neuroinflammation may offer new opportunities to address these challenges. In this study we characterized the intracranial tumor biodistribution of systemically delivered PAMAM dendrimers in an intracranial rodent gliosarcoma model using fluorescence-based quantification methods and high resolution confocal microscopy. We observed selective and homogeneous distribution of dendrimer throughout the solid tumor (~6 mm) and peritumoral area within fifteen minutes after systemic administration, with subsequent accumulation and retention in tumor associated microglia/macrophages (TAMs). Neuroinflammation and TAMs have important growth promoting and pro invasive effects in brain tumors. The rapid clearance of systemically administered dendrimers from major organs promises minimal off-target adverse effects of conjugated drugs. Therefore, selective delivery of immunomodulatory molecules to TAM, using hydroxyl PAMAM dendrimers, may hold promise for therapy of glioblastoma. PMID- 25818458 TI - Dhvar5 antimicrobial peptide (AMP) chemoselective covalent immobilization results on higher antiadherence effect than simple physical adsorption. AB - Bacterial colonization and subsequent biofilm formation is still one of the major problems associated with medical devices. Antimicrobial peptides (AMP) immobilization onto biomaterials surface is a promising strategy to avoid bacterial colonization. However, a correct peptide orientation and exposure from the surface is essential to maintain AMP antimicrobial activity. This work aims to evaluate the effect of the immobilization on antibacterial activity of Dhvar5 (LLLFLLKKRKKRKY), an AMP with a head-to-tail amphipathicity. Dhvar5 was linked to thin chitosan coatings in i) a controlled orientation and exposure, testing covalent immobilization of its N- or C-terminus and using spacers with different lengths and flexibilities or in ii) a random orientation by physical adsorption. Chitosan coating was chosen due to its antimicrobial properties and readiness to be functionalized. Surface characterization demonstrated the chemoselective immobilization of the peptide with different spacers in a similar concentration (~2 ng/cm2). Efficacy assays demonstrated that covalent immobilization of Dhvar5 exposing its cationic end, improves the chitosan coating antimicrobial effect by decreasing Methicillin-resistant Staphylococcus aureus (MRSA) colonization. This effect was enhanced when longer spacers were used independently of their flexibility. In opposite, immobilized Dhvar5 exposing its hydrophobic end has no effect on bacterial adhesion to chitosan, and when adsorbed in a random orientation even induces bacterial adhesion to chitosan coating. PMID- 25818460 TI - Sustained regeneration of high-volume adipose tissue for breast reconstruction using computer aided design and biomanufacturing. AB - Adipose tissue engineering offers a promising alternative to the current breast reconstruction options. Here we investigated patient-specific breast scaffolds fabricated from poly(d,l)-lactide polymer with pore sizes>1 mm for their potential in long-term sustained regeneration of high volume adipose tissue. An optimised scaffold geometry was modelled in silico via a laser scanning data set from a patient who underwent breast reconstruction surgery. After the design process scaffolds were fabricated using an additive manufacturing technology termed fused deposition modelling. Breast-shaped scaffolds were seeded with human umbilical cord perivascular cells and cultured under static conditions for 4 weeks and subsequently 2 weeks in a biaxial rotating bioreactor. These in vitro engineered constructs were then seeded with human umbilical vein endothelial cells and implanted subcutaneously into athymic nude rats for 24 weeks. Angiogenesis and adipose tissue formation were observed throughout all constructs at all timepoints. The percentage of adipose tissue compared to overall tissue area increased from 37.17% to 62.30% between week 5 and week 15 (p<0.01), and increased to 81.2% at week 24 (p<0.01), while the seeded endothelial cells self organised to form a functional capillary network. The presented approach of fabricating customised scaffolds using 3D scans represents a facile approach towards engineering clinically relevant volumes of adipose tissue for breast reconstruction. PMID- 25818459 TI - The utilization of decellularized tendon slices to provide an inductive microenvironment for the proliferation and tenogenic differentiation of stem cells. AB - The extracellular matrix (ECM) microenvironment for the stem cell niches, including but not limited to the biochemical composition, matrix topography, and stiffness, is crucial to stem cell proliferation and differentiation. The purpose of this study was to explore the capacity of the decellularized tendon slices (DTSs) to induce stem cell proliferation and tenogenic differentiation. Rat adult stem cells, including tendon-derived stem cells (TDSCs) and bone marrow-derived stem cells (BMSCs), were identified to have universal stem cell characteristics. The DTSs were found to retain the native tendon ECM microenvironment cues, including the inherent surface topography, well-preserved tendon ECM biochemical composition and similar stiffness to native tendon. When the TDSCs and BMSCs were cultured on the DTSs respectively, the LIVE/DEAD assay, alamarBlue(r) assay, scanning electron microscopy examination and qRT-PCR analysis demonstrated that the DTSs have the capacity to support these stem cells homogeneous distribution, alignment, significant proliferation and tenogenic differentiation. Taken together, the findings of this study indicate that the DTSs can provide a naturally inductive microenvironment for the proliferation and tenogenic differentiation of TDSCs and BMSCs, supporting the use of decellularized tendon ECM as a promising and valuable approach for tendon repair/reconstruction. PMID- 25818461 TI - A FRET-based assay for screening SIRT5 specific modulators. AB - A fluorogenic assay for SIRT5 has been developed to screen their small molecule modulators based on the recent discovery that SIRT5 is a demalonylase and desuccinylase. However, this assay uses a fluorogenic peptide containing 7-amino 4-methylcoumarin (AMC), which becomes the cause of false positive hits from the screening. To overcome this, we have developed an alternative method called a FRET-based assay, which will be reliable and useful for screening SIRT5 modulators in a high-throughput format since no AMC group present in this assay. PMID- 25818462 TI - Effects of maternal vitamin B6 deficiency and over-supplementation on DNA damage and oxidative stress in rat dams and their offspring. AB - Vitamin B6 is a cofactor for more than 140 essential enzymes and plays an important role in maternal health and fetal development. The goal of this study was to investigate the effects of maternal vitamin B6 on DNA damage and oxidative stress status in rat dams and their offspring. Female Wistar rats were randomly assigned to three dietary groups fed a standard diet (control diet), a diet supplemented with 30 mg/kg of vitamin B6, or a deficient diet (0 mg/kg of vitamin B6) for 10 weeks before and during mating, pregnancy and lactation. The dams were euthanized at weaning, and their male pups were euthanized either 10 days or 100 days after birth. We found that maternal vitamin B6 deficiency increased the micronucleus frequency in peripheral blood and bone marrow cells and also increased the concentration of hepatic TBARS (thiobarbituric acid reactive substances) in newborn pups (10 days old). In conclusion, maternal 5- to 6-fold over-supplementation of vitamin B6 had no adverse effects, however its deficiency may induce chromosomal damage and hepatic lipid peroxidation in the offspring. PMID- 25818463 TI - Tetrabromobisphenol A (TBBPA): Possible modes of action of toxicity and carcinogenicity in rodents. AB - Due to potential consumer exposures, the toxicity of tetrabromobisphenol A (TBBPA) has been extensively studied. Reviews of TBBPA concluded no concerns regarding human health risks. The low toxicity of TBBPA is consistent with low bioavailability. However, some oral toxicity studies in rodents with TBBPA reported changes in thyroid hormone levels and a carcinogenicity study with TBBPA showed increased incidences of uterine tumors in rats. This review analyzes several modes of action (MoA) that may account for the observed thyroxine hormone changes and the uterine tumors. It concludes that the potential modes of action for thyroid changes induced by TBBPA are expected to exhibit a threshold for adverse effects due to the ability of the mammalian organism to compensate small changes in thyroid hormone levels. Regarding MoAs for the uterine tumors, TBBPA does not exert genotoxic or estrogenic effects. Available evidence suggests that TBBPA may increase levels of circulating estrogens by a competitive inhibition of estrogen conjugation and produce uterine tumors by promoting pre-existing Tp53 mutations due to increased estrogen levels resulting in increased cell proliferation. PMID- 25818464 TI - Sulforaphane protects against acetaminophen-induced hepatotoxicity. AB - Oxidative stress is closely associated with acetaminophen (APAP)-induced toxicity. Heme oxygenase-1 (HO-1), an antioxidant defense enzyme, has been shown to protect against oxidant-induced tissue injury. This study investigated whether sulforaphane (SFN), as a HO-1 inducer, plays a protective role against APAP hepatotoxicity in vitro and in vivo. Pretreatment of primary hepatocyte with SFN induced nuclear factor E2-factor related factor (Nrf2) target gene expression, especially HO-1 mRNA and protein expression, and suppressed APAP-induced glutathione (GSH) depletion and lipid peroxidation, which eventually leads to hepatocyte cell death. A comparable effect was observed in mice treated with APAP. Mice were treated with 300 mg/kg APAP 30 min after SFN (5 mg/kg) administration and were then sacrificed after 6 h. APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic reactive oxygen species (ROS) levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation. These results suggest that SFN plays a protective role against APAP-mediated hepatotoxicity through antioxidant effects mediated by HO-1 induction. SFN has preventive action in oxidative stress-mediated liver injury. PMID- 25818465 TI - Assessing dietary exposure to caffeine from beverages in the U.S. population using brand-specific versus category-specific caffeine values. AB - Recent reports on caffeine intakes in the United States have highlighted the importance of obtaining accurate and valid measures of caffeine exposure. The objective of this study is to compare two methods of assigning caffeine values to beverages: brand-specific values versus an aggregate single value representing a broader range of products within a beverage category (i.e., category-specific). The two methods yielded some small, but statistically significant differences in the estimation of caffeine intake from coffee, tea, and carbonated soft drinks (CSDs) for all ages combined and within several of the adult age groups (i.e., 35 49, 50-64, and >=65 years). These differences, while small, suggest that detailed brand-specific data, particularly for CSDs, commercially pre-packaged or bottled teas, coffee, and specialty coffee drinks, provide more accurate estimates of caffeine exposure for some age groups. Despite these differences, these data provide some assurance that studies using a single aggregate caffeine value provide reasonable measures of caffeine exposure, particularly for studies conducted over a decade ago when there were fewer caffeinated products and brand specific data available. As the caffeinated beverage marketplace continues to evolve, the use of more detailed, brand-specific data will likely strengthen the assessment of caffeine exposure in the United States. PMID- 25818466 TI - Investigation of melamine and cyanuric acid deposition in pig tissues using LC MS/MS methods. AB - Four LC-MS/MS methods were developed to quantify melamine (MEL) and cyanuric acid (CYA) in various pig tissues at or above the level of concern (2.5 mg/kg). Pigs treated with 200 mg/kg bw/day CYA daily for 7 days did not accumulate significant residue concentrations in muscle, liver or kidney. Pigs treated with 200 mg/kg bw MEL daily for 7 or 28 days had MEL residues in muscles (3-13 ppm), liver (2.8 14.1 ppm) and kidney (9.4-27.2 ppm). Treatment with MEL and CYA at 100 mg/kg bw of each triazine daily for 7 days resulted in MEL (26-59 ppm in muscle, 30-49 ppm in liver and 367-6300 ppm in kidney) and CYA (1.8-5.8 ppm in muscle, 2.6-6.5 ppm in liver and 303-7100 ppm in kidney). Treatment with MEL and CYA at 1, 3 or 10 mg/kg bw/day for 7 days did not result in residues greater than the level of concern in all tissues tested. Pigs dosed with 33 mg/kg bw/day of MEL + CYA for 7 days contained residues above the level of concern only in kidney. Deposition of MEL and CYA depends on the tissue type (muscles, liver and kidney), dosage and whether the triazines are given alone or in combination. PMID- 25818467 TI - RIFM fragrance ingredient safety assessment, ethyl anthranilate, CAS registry number 87-25-2. PMID- 25818468 TI - The ACROPOLIS project: Its aims, achievements, and way forward. PMID- 25818469 TI - RIFM fragrance ingredient safety assessment, allyl phenylacetate, CAS registry number 1797-74-6. PMID- 25818470 TI - Microbial players involved in the decline of filamentous and colonial cyanobacterial blooms with a focus on fungal parasitism. AB - In the forthcoming decades, it is widely believed that the dominance of colonial and filamentous bloom-forming cyanobacteria (e.g. Microcystis, Planktothrix, Anabaena and Cylindrospermopsis) will increase in freshwater systems as a combined result of anthropogenic nutrient input into freshwater bodies and climate change. While the physicochemical parameters controlling bloom dynamics are well known, the role of biotic factors remains comparatively poorly studied. Morphology and toxicity often - but not always - limit the availability of cyanobacteria to filter feeding zooplankton (e.g. cladocerans). Filamentous and colonial cyanobacteria are widely regarded as trophic dead-ends mostly inedible for zooplankton, but substantial evidence shows that some grazers (e.g. copepods) can bypass this size constraint by breaking down filaments, making the bloom biomass available to other zooplankton species. A wide range of algicidal bacteria (mostly from the Alcaligenes, Flavobacterium/Cytophaga group and Pseudomonas) and viruses (Podoviridae, Siphoviridae and Myoviridae) may also contribute to bloom control, via their lytic activity underpinned by a diverse array of mechanisms. Fungal parasitism by the Chytridiomycota remains the least studied. While each of these biotic factors has traditionally been studied in isolation, emerging research consistently point to complex interwoven interactions between biotic and environmental factors. PMID- 25818471 TI - Onartuzumab in lung cancer: the fall of Icarus? AB - The development of targeted therapies has led to a revolution in non-small-cell lung cancer, and opened up possibilities for improved personalized medicine. With the constant findings of new targets, a lot of inhibitors are being developed. However, reliable biomarkers are urgently needed. The design of clinical trials needs to become more flexible in order to obtain the best results and gain the US FDA/EMEA approval for the new drugs. A recent example of a failed trial is the Phase III MetLung trial that compared the effects of the c-MET monovalent antibody onartuzumab with erlotinib versus erlotinib alone in late-stage non small-cell lung cancer. Here, we discuss several points as to why this trial could have failed. PMID- 25818472 TI - Effectiveness of a self-management support program for Thais with type 2 diabetes: Evaluation according to the RE-AIM framework. AB - Delivering diabetes self-management support is an enormous challenge for healthcare providers with limited human resources. We conducted a cluster randomized controlled trial to assess the effectiveness of a DSMS program incorporating the computer-assisted instruction. The RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework was applied to evaluate the DSMS program. Ten Public Health Centers in Bangkok, Thailand were randomized into either DSMS program or usual care. Forty eligible patients with type 2 diabetes in each Public Health Center were randomly selected. Totally, 403 patients (200 controls and 203 interventions) participated. About 93.8% participants completed the six-month follow-up. Over six months, adjusted mean changes of hemoglobin A1c (-0.14%, 95% confidence interval = -0.02 to -0.26, fasting plasma glucose (-6.37 mg/dL, -1.95 to -10.78), health behaviors (3.31 score, 2.27 to 4.34), and quality of life (1.41 score, 0.69 to 2.12) were significantly improved in intervention compared to control group. In conclusion, the DSMS program facilitates Public Health Centers to accomplish their support for people with diabetes. PMID- 25818473 TI - Performance evaluation of SD A1cCare as a HbA1c analyzer for point-of-care testing. AB - OBJECTIVES: Some studies have shown that a rapid feedback of HbA1c results is helpful for controlling plasma glucose levels. Point-of-care (POC) instruments that are fast, portable, and easy to use are suitable for rapid determination of HbA1c levels. Here, we evaluated the analytical performance of a newly developed POC HbA1c analyzer, SD A1cCare (SD Biosensor, Inc.). DESIGN AND METHODS: The precision, linearity, and correlation with the Variant II Turbo instrument (Bio Rad Laboratories, Inc.) were evaluated according to CLSI guidelines for SD A1cCare. All tests were performed according to the manufacturer instructions, and statistical analyses, including linear regression and Passing-Bablok regression, were performed. Bias from the IFCC reference targets was also evaluated with 12 duplicate specimens (n=24 in total). RESULTS: The coefficients of variation based on EP9-A2 protocol were 2.6% in SI unit and 1.8% in NGSP unit. The calibration curve was linear, with R(2)=0.9911 in the range of 23.5 to 125.1 mmol/mol in SI units (4.3% to 13.6% in NGSP units). The results of the SD A1cCare correlated with those of the Variant II Turbo (r=0.986). Deviations from IFCC targets at 30, 60, and 90 mmol/mol IFCC levels were -1.95, -1.85, and -1.74 mmol/mol, respectively. CONCLUSIONS: The SD A1cCare analyzer showed excellent precision, linearity, correlation with the Variant II Turbo analyzer, and accuracy with IFCC targets. Therefore, it may be suitable for HbA1c assays in the POC setting and in small laboratories. PMID- 25818475 TI - How appropriate is therapeutic drug monitoring for lithium? Data from the Belgian external quality assessment scheme. AB - BACKGROUND: Lithium remains a mainstay in the management of mood disorders. As with many psychotropic drugs, lithium treatment requires continuous observation for adverse effects and strict monitoring of serum concentrations. The present study aimed to assess the appropriateness of lithium assays used by Belgian laboratories, and to evaluate acceptability of their clinical interpretations. METHODS: Nine in-house serum samples spiked with predetermined concentrations of lithium were distributed to 114 participants in the Belgian external quality assessment scheme. Laboratories were requested to report the assay technique, lithium measurements and interpretations with regard to measured concentrations. Inter/intramethod imprecision and bias were reported and acceptability of clinical interpretations was assessed. The intramethod variability was evaluated by selecting methods used by 6 laboratories or more. Flame photometry (IL 943) was considered as the reference method. RESULTS: Laboratories returned assay results using colorimetry (69.3%), ion selective electrode (15.8%), flame photometry (8.8%), atomic absorption spectroscopy (5.2%) or mass spectrometry (0.9%). Lithium concentrations were systematically higher when measured with the Vitros assay (median bias: 4.0%), and were associated with consecutive biased interpretations. In contrast, the Thermo Scientific Infinity assay showed a significant negative bias (median bias: 9.4%). 36.0% of laboratories reported numerical values below their manufacturer cut-off for the blank sample; 16.6% of these laboratories detected residual lithium concentrations. CONCLUSIONS: The present study revealed assay-related differences in lithium measurements and their interpretations. Overall, there appeared to be a need to continue EQA of therapeutic drug monitoring for lithium in Belgium. PMID- 25818474 TI - Blood lipid profiles and factors associated with dyslipidemia assessed by a point of-care testing device in an outpatient setting: A large-scale cross-sectional study in Southern China. AB - OBJECTIVE: To promote the concept of POCT and to investigate dyslipidemia in Guangzhou, China, we performed a study examining blood lipids assessed by POCT and reported factors associated with dyslipidemia. DESIGN AND METHODS: This multicenter, cross-sectional study enrolled outpatients from 9 Guangzhou hospitals from May through September 2013. After informed consent was obtained, the following information was collected: age; gender; the presence of diabetes mellitus, obesity, and hypertension as well as current use of cigarettes or alcohol. Patients were asked to fast for 8h before the blood examination performed on a POCT device, the CardioChek PA. RESULTS: Of 4012 patients enrolled (1544 males, 2468 females; mean age 60.35+/-9.41 years), 1993 (49.7%) patients had dyslipidemia, but only 101 (5.1%) took statins. The multivariate tests of associations between demographic variables, comorbidities, and the risk of having dyslipidemia found that the significant predictors of dyslipidemia were male gender, age >=60 years, being a current smoker or alcohol drinker, and hypertension. CONCLUSION: Most dyslipidemia patients in Guangzhou remain untreated. POCT in China is feasible, and its widespread use might improve dyslipidemia awareness, treatment and control. PMID- 25818476 TI - Interferon-gamma stimulates human follicular dendritic cell-like cells to produce prostaglandins via the JAK-STAT pathway. AB - IFN-gamma plays a critical role in the regulation of innate and adaptive immunity. Paying attention to the emerging role of prostaglandins (PGs) as immune regulators, we attempted to establish the effect of IFN-gamma on PG production in human follicular dendritic cell-like HK cells and the underlying signaling pathway by using RNA interference technology. IFN-gamma induced COX-2 protein expression in HK cells in a time- and dose-dependent manner, which was not observed in peripheral blood monocytes. Although IFN-gamma induced phosphorylation of STAT1, STAT3, and STAT5, only STAT1 was essential for the COX 2 augmentation. The JAK kinases responsible for IFN-gamma-triggered STAT1 phosphorylation were JAK1 and JAK2, which were also required for the COX-2 induction. The essential requirement of JAK1 and JAK2 was verified by confocal microscopic analysis, since STAT1 phosphorylation and nuclear translocation were impaired in HK cells with these two kinases knocked down. Finally, we demonstrated that JAK1, JAK2, and STAT1 were indispensable for the actual enhancement of PG production in response to IFN-gamma stimulation. These results provide a novel insight into our understanding of IFN-gamma under inflammatory conditions and support the emerging concept of PGs as important immune regulators. PMID- 25818478 TI - Oral Candida carriage among individuals chewing betel-quid with and without tobacco: an observation. PMID- 25818477 TI - DEEP Study: does EQ-5D-5L measure the impacts of persistent oro-facial pain? AB - The EQ-5D-5L is a generic quality of life (QOL) measure widely used throughout the world, which has the advantage that it allows health-state preferences to be elicited. The aim of this study was to examine whether: a) variation in the standardised reference period for EQ-5D-5L from 'today' to 'the last month' had a minimal clinically meaningful difference; (b) EQ-5D-5L had convergent validity with a multidimensional pain measure in quantifying the impacts of pain. As part of a larger study into the effectiveness and efficiency of care pathways for persistent orofacial pain (POFP) (http://research.ncl.ac.uk/deepstudy), participants with POFP (n = 100) completed two versions of the EQ-5D-5L at the same time with different reference periods ('today' vs. 'last month'). Participants also completed the first section of the West Haven-Yale Multidimensional Pain Inventory (v3) to assess convergent validity. Two-tailed nonparametric inferential statistics, intra-class correlation coefficients (ICC), and within-subject change scores were used to compare the two EQ-5D-5L versions. Convergent validity was assessed using Spearman's rho correlation coefficients. Health-state valuations were significantly different (P < 0.01), and there was good similarity between the two versions' ICC 0.86 (95% CI 0.79-0.91). The within subject mean change was 0.03 (95% CI 0.01-0.06). For convergent validity, all relationships were significant (P < 0.05) and in the expected directions. EQ-5D 5L demonstrates sufficient convergent validity to be used with POFP, and a change in the standard reference period may be unnecessary if a multidimensional pain measure is also used. PMID- 25818479 TI - Gene therapy for heart failure. AB - Heart failure is a major public health problem throughout the world and it is likely that its prevalence will continue to grow over the next several decades. Despite advances in the treatment of heart failure, morbidity and mortality remain unacceptably high. Gene transfer therapy provides a novel strategy for targeting abnormalities in cardiac cells that adversely affect cardiac function. New vectors for gene delivery, mainly adeno-associated viruses (AAVs) that are preferentially taken up by cardiomyocytes, can result in sustained transgene expression. The cardiac isoform of sarco(endo)plasmic reticulum Ca(2+)ATPase (SERCA2a) plays a major role in regulating calcium levels in cardiomyocytes. Abnormal calcium handling by the failing heart caused by a reduction in SERCA2a activity adversely affects both systolic and diastolic function. The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study was a Phase 2a double-blind, randomized, placebo-controlled, dose finding study that was performed in patients with advanced heart failure due to systolic dysfunction. Eligible patients received AAV/SERCA2a or placebo by direct antegrade infusion into the coronary circulation. At the end of 12 months, patients receiving high-dose therapy (i.e. 1*10(13) DNase Resistant Particles) had evidence of favorable changes in several clinically relevant domains compared to patients treated with placebo. There were no safety concerns at any dose of AAV/SERCA2a. Patients treated with AAV/SERCA2a exhibited a striking reduction in cardiovascular events that persisted through 36 months of follow-up compared to patients who received placebo. Transgene expression was detected in the myocardium of patients receiving AAV/SERCA2a gene therapy as long as 31 months after delivery. A second Phase 2b study, CUPID 2, designed to confirm this favorable effect on heart failure events, is currently underway with the results expected to be presented later in 2015. Additional studies using other vectors and targets are in planning or underway making gene transfer therapy one of the most exciting new approaches under development for treating heart failure. PMID- 25818480 TI - Current and state of the art on the electrophysiologic characteristics and catheter ablation of arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited genetic disease caused by defective desmosomal proteins, and it has typical histopathological features characterized by predominantly progressive fibro-fatty infiltration of the right ventricle. Clinical presentations of ARVD/C vary from syncope, progressive heart failure (HF), ventricular tachyarrhythmias, and sudden cardiac death (SCD). The 2010 modified Task Force criteria were established to facilitate the recognition and diagnosis of ARVD/C. An implantable cardiac defibrillator (ICD) remains to be the cornerstone in prevention of SCD in patients fulfilling the diagnosis of definite ARVD/C, especially among ARVD/C patients with syncope, hemodynamically unstable ventricular tachycardia (VT), ventricular fibrillation, and aborted SCD. Further risk stratification is clinically valuable in the management of patients with borderline or possible ARVD/C and mutation carriers of family members. However, given the entity of heterogeneous penetrance and non-uniform phenotypes, the standardization of clinical practice guidelines for at-risk individuals will be the next frontier to breakthrough. Antiarrhythmic drugs are prescribed frequently to patients experiencing frequent ventricular tachyarrhythmias and/or appropriate ICD shocks. Amiodarone is the recommended drug of choice. Radiofrequency catheter ablation (RFCA) has been demonstrated to effectively eliminate the drug-refractory VT in patients with ARVD/C. However, the efficacy and clinical prognosis of RFCA via endocardial approach alone was disappointing prior to the era of epicardial approach. In recent years, it has been proven that the integration of endocardial and epicardial ablation by targeting the critical isthmus or eliminating abnormal electrograms within the diseased substrates could yield higher acute success and lower recurrence of ventricular tachyarrhythmias during long-term follow-up. Heart transplantation is the final option for patients with extensive disease, biventricular HF with uncontrollable hemodynamic compromise, and refractory ventricular tachyarrhythmias despite aggressive medical and ablation therapies. PMID- 25818481 TI - Effects of four-week feed restriction on toxicological parameters in beagle dogs. AB - This study was conducted to examine any changes caused by feed restriction in dogs to contribute to safety evaluation in toxicity studies. Two male 7-month-old beagle dogs/group were fed 300 (control), 150 (50% of control), or 70 g/animal of diet daily (23% of control) for 4 weeks. Effects of feed restriction, except for clinical signs, were noted depending on the feed dosage in almost all examinations. The principal outcomes were: decreased body weight and water consumption, ECG changes (decreased heart rate and prolonged QTc), and hematopoietic and lymphopoietic suppression (decreased reticulocyte ratio or white blood cell count in hematology, decreased nucleated cell count in bone marrow, decreased erythroid parameters in myelography, and hypocellularity of bone marrow and thymic atrophy in histopathology). In addition, some changes were noted in urinalysis (decreased urine volume and sodium and potassium excretion), blood chemistry (decreased ALP and inorganic phosphorus and increased creatinine), organ weights, and gastric histopathology. These results provide important reference data for distinguishing the primary effects of test compounds from secondary effects of decreased food consumption in toxicity studies in beagle dogs. PMID- 25818482 TI - Cysteine cathepsins as digestive enzymes in the spider Nephilengys cruentata. AB - Cysteine cathepsins are widely spread on living organisms associated to protein degradation in lysosomes, but some groups of Arthropoda (Heteroptera, Coleoptera, Crustacea and Acari) present these enzymes related to digestion of the meal proteins. Although spiders combine a mechanism of extra-oral with intracellular digestion, the sporadic studies on this subject were mainly concerned with the digestive fluid (DF) analysis. Thus, a more complete scenario of the digestive process in spiders is still lacking in the literature. In this paper we describe the identification and characterization of cysteine cathepsins in the midgut diverticula (MD) and DF of the spider Nephilengys cruentata by using enzymological assays. Furthermore, qualitative and quantitative data from transcriptomic followed by proteomic experiments were used together with biochemical assays for results interpretation. Five cathepsins L, one cathepsin F and one cathepsin B were identified by mass spectrometry, with cathepsins L1 (NcCTSL1) and 2 (NcCTSL2) as the most abundant enzymes. The native cysteine cathepsins presented acidic characteristics such as pH optima of 5.5, pH stability in acidic range and zymogen conversion to the mature form after in vitro acidification. NcCTSL1 seems to be a lysosomal enzyme with its recombinant form displaying acidic characteristics as the native ones and being inhibited by pepstatin. Evolutionarily, arachnid cathepsin L may have acquired different roles but its use for digestion is a common feature to studied taxa. Now a more elucidative picture of the digestive process in spiders can be depicted, with trypsins and astacins acting extra-orally under alkaline conditions whereas cysteine cathepsins will act in an acidic environment, likely in the digestive vacuoles or lysosome-like vesicles. PMID- 25818483 TI - Ostrinia furnacalis serpin-3 regulates melanization cascade by inhibiting a prophenoloxidase-activating protease. AB - Serine protease cascade-mediated prophenolxidase activation is a prominent innate immune response in insect defense against the invading pathogens. Serpins regulate this reaction to avoid excessive activation. However, the function of serpins in most insect species, especially in some non-model agriculture insect pests, is largely unknown. We here cloned a full-length cDNA for a serpin, named as serpin-3, from Asian corn borer, Ostrinia furnacalis (Guenee). The open reading frame of serpin-3 encodes 462-amino acid residue protein with a 19 residue signal peptide. It contains a reactive center loop strikingly similar to the proteolytic activation site in prophenoloxidase. Sequence comparison indicates that O. furnacalis serpin-3 is an apparent ortholog of Manduca sexta serpin-3, a defined negative regulator of melanization reaction. Serpin-3 mRNA and protein levels significantly increase after a bacterial or fungal injection. Recombinant serpin-3 efficiently blocks prophenoloxidase activation in larval plasma in a concentration-dependent manner. It forms SDS-stable complexes with serine protease 13 (SP13), and prevents SP13 from cleaving prophenoloxidase. Injection of recombinant serpin-3 into larvae results in decreased fungi-induced melanin synthesis and reduced the expression of attacin, cecropin, gloverin, and peptidoglycan recognition protein-1 genes in the fat body. Altogether, serpin-3 plays important roles in the regulation of prophenoloxidase activation and antimicrobial peptide production in O. furnacalis larvae. PMID- 25818484 TI - Targeting gut microbiota as a possible therapy for diabetes. AB - The incidence of diabetes has increased rapidly across the entire world in the last 2 decades. Accumulating evidence suggests that gut microbiota contribute to the pathogenesis of diabetes. Several studies have demonstrated that patients with diabetes are characterized by a moderate degree of gut microbial dysbiosis. However, there are still substantial controversies regarding altered composition of the gut microbiota and the underlying mechanisms by which gut microbiota interact with the body's metabolism. The purpose of this review is to define the association between gut microbiota and diabetes. In doing so an electronic search of studies published in English from January 2004 to the November 2014 in the National Library of Medicine, including the original studies that addressed the effects of gut microbiota on diabetes, energy metabolism, inflammation, the immune system, gut permeability and insulin resistance, was performed. Herein, we discuss the possible mechanisms by which the gut microbiota are involved in the development of diabetes, including energy metabolism, inflammation, the innate immune system, and the bowel function of the intestinal barrier. The compositional changes in the gut microbiota in type 2 and type 1 diabetes are also discussed. Moreover, we introduce the new findings of fecal transplantation, and use of probiotics and prebiotics as new treatment strategies for diabetes. Future research should be focused on defining the primary species of the gut microbiota and their exact roles in diabetes, potentially increasing the possibility of fecal transplants as a therapeutic strategy for diabetes. PMID- 25818485 TI - The role of methylglyoxal and the glyoxalase system in diabetes and other age related diseases. AB - The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role. PMID- 25818486 TI - NADPH oxidases and cancer. AB - The mechanism by which reactive oxygen species (ROS) are produced by tumour cells remained incompletely understood until the discovery over the last 15 years of the family of NADPH oxidases (NOXs 1-5 and dual oxidases DUOX1/2) which are structural homologues of gp91phox, the major membrane-bound component of the respiratory burst oxidase of leucocytes. Knowledge of the roles of the NOX isoforms in cancer is rapidly expanding. Recent evidence suggests that both NOX1 and DUOX2 species produce ROS in the gastrointestinal tract as a result of chronic inflammatory stress; cytokine induction (by interferon-gamma, tumour necrosis factor alpha, and interleukins IL-4 and IL-13) of NOX1 and DUOX2 may contribute to the development of colorectal and pancreatic carcinomas in patients with inflammatory bowel disease and chronic pancreatitis, respectively. NOX4 expression is increased in pre-malignant fibrotic states which may lead to carcinomas of the lung and liver. NOX5 is highly expressed in malignant melanomas, prostate cancer and Barrett's oesophagus-associated adenocarcinomas, and in the last it is related to chronic gastro-oesophageal reflux and inflammation. Over-expression of functional NOX proteins in many tissues helps to explain tissue injury and DNA damage from ROS that accompany pre-malignant conditions, as well as elucidating the potential mechanisms of NOX-related damage that contribute to both the initiation and the progression of a wide range of solid and haematopoietic malignancies. PMID- 25818489 TI - Should we aim to reduce relative or absolute inequalities in mortality? PMID- 25818490 TI - The politics of tobacco regulation. PMID- 25818491 TI - President's column. PMID- 25818492 TI - Ropivacaine: a new local anaesthetic agent in maxillofacial surgery. AB - We have compared the anaesthetic efficacy, duration of action, pain, pulpal anaesthesia, and cardiovascular effects of 0.5% ropivacaine or 2% lignocaine hydrochloride in bilateral symmetrical impacted third molars. In a randomised single-blind trial we studied 78 healthy patients who required bilateral extraction of identical impacted lower third molars. A test dose was given to all patients with subdermal infiltration of 0.5% ropivacaine 0.5 ml. A classic inferior alveolar and long buccal nerve block was created using 0.5% ropivacaine 2 ml on one side and 2% lignocaine hydrochloride 2 ml with adrenaline on the other. The time to onset and duration of action were noted. Pain, numbness of the lip and tip of the tongue, and haemodynamic changes were monitored throughout the procedure. The teeth were extracted two weeks apart. The onset of anaesthesia ranged between 2 and 3 min after the injection and lasted for more than 5h. Ropivacaine alone did not cause appreciable changes in the cardiovascular variables, but lignocaine with adrenaline caused a transient increase in arterial pressure and heart rate 2 min after injection. We conclude the 0.5% ropivacaine alone does not affect the cardiovascular system and has more beneficial effects than 2% lignocaine hydrochloride with adrenaline. These findings may be useful for oral and maxillofacial surgeons who are looking for a local anaesthetic with minimal cardiovascular risk and without a vasoconstrictor to provide regional anaesthesia for long procedures. PMID- 25818494 TI - Early experience with the medial sural artery perforator flap as an alternative to the radial forearm flap for reconstruction in the head and neck. AB - The medial sural artery perforator (MSAP) flap has been well-described but has yet to find popularity in the United Kingdom. We describe our early experience of its use in 6 patients and our simplified method of marking up. Flaps ranged in size from 7*4cm to 12*5.5cm, and were thin (between 4 and 10mm). Pedicles were between 11 and 14cm long, arterial diameters were 1-2mm, and venous calibres were 2-6mm. We raised 4 flaps without the use of a tourniquet and found it helpful. Straightening the leg as the popliteal fossa was approached also eased dissection. There can be 2 separate pedicles. The donor site was closed primarily in 5 cases and all flaps survived. The MSAP is easier to do than the radial artery forearm free flap (RAFFF) and is a reliable alternative with low morbidity. PMID- 25818493 TI - Medium-term outcomes and complications after total replacement of the temporomandibular joint. Prospective outcome analysis after 3 and 5 years. AB - In this prospective analysis, we assess the medium-term benefits, efficacy, and safety of the TMJ Concepts joint replacement system in the United Kingdom. Outcome measures of pain, maximum mouth opening, and diet were recorded preoperatively and at intervals up to 3 and 5 years. All patients who had replacement temporomandibular joints (TMJ) within a 6-year period were included. A total of 58 patients (84 joints) were followed up for 3 years (mean age 47, range 19-72) and 26 (42 joints) for 5 years (mean age 46, range 27-70). The female to male ratio was 52:6 at 3 years and 23:3 at 5 years. The most common diagnosis was degenerative disease, and the mean number of previous TMJ procedures was 2.4 (range 0-14). There were significant improvements in pain scores (7.4 reduced to 0.6 at 3 years and 0.8 at 5 years), maximum mouth opening (21.0-35.5mm at 3 years and 23.8-33.7mm at 5 years), and dietary scores (4.1-9.7 at 3 years and 3.7-9.6 at 5 years). Revision operations were required in 2 patients (not included in the outcome data) for biofilm infection of the prosthesis secondary to local infection in the head and neck. One patient had weakness of the temporal branch of the facial nerve that needed correction. TMJ replacement is an effective form of management for an irreparably damaged joint, particularly in cases of ankylosis. It lessens pain and improves function with minimal long-term morbidity. PMID- 25818495 TI - Baseline Q waves and time from symptom onset to ST-segment elevation myocardial infarction: insights from PLATO on the influence of sex. AB - BACKGROUND: The prognostic value of time from symptom onset to reperfusion may be enhanced by the identification of Q waves on the presenting electrocardiogram (ECG) in patients with ST-segment elevation myocardial infarction (STEMI). We evaluated whether the relative prognostic utility of these 2 metrics was altered by sex. METHODS: Q waves in the distribution of the ST-segment elevation on the baseline ECG were evaluated by a blinded core laboratory in 2838 STEMI patients (2163 men and 675 women) from the PLATelet inhibition and patient Outcomes (PLATO) trial who underwent percutaneous coronary intervention (PCI) within 12 hours of symptom onset. RESULTS: Women were older (median 63 vs 57 years), more likely to be diabetic (24.1% vs 15.5%), hypertensive (69.2% vs 50.9%), and a higher Killip class > I (8.6% vs 5.9%), as compared with men. Whereas the Q waves frequency rose progressively over time to ECG in men, this relationship was attenuated in women (P = .057). Q waves on the baseline ECG were associated with a higher excess hazard of 1-year vascular death in men (hazard ratio [HR] 2.03; 95% confidence interval [CI], 1.13-3.72), and a similar trend existed in women (HR 1.97; 95% CI, 0.86-4.51). Women with baseline Q waves tended to have higher risk of 1-year vascular death than men as continuous time from symptom onset to PCI increased (P[interaction] = .182). CONCLUSIONS: These differences in the evolution of baseline Q waves and relationship between time from symptom onset and vascular death in women and men deserve recognition in future studies of STEMI. PMID- 25818496 TI - Prevention of knee osteoarthritis in overweight females: the first preventive randomized controlled trial in osteoarthritis. AB - BACKGROUND: With accumulating knowledge on osteoarthritis development, the next step is to focus on possibilities for primary prevention. METHODS: In a 2 * 2 factorial design, the effects of a diet-and-exercise program and of oral glucosamine sulfate (double blind and placebo-controlled) on the incidence of knee osteoarthritis were evaluated in a high-risk group of 407 middle-aged women with a body mass index >= 27 kg/m(2) without clinical signs of knee osteoarthritis at baseline (ISRCTN 42823086). Primary outcome was the incidence of knee osteoarthritis, defined as Kellgren & Lawrence grade >= 2, joint space narrowing of >= 1.0 mm, or clinical knee osteoarthritis (clinical and radiographic American College of Rheumatology criteria) after 2.5 years. RESULTS: After 2.5 years, only 10% of all subjects were lost to follow-up, and 17% of all knees showed incident knee osteoarthritis. Accounting for the significant interaction between the interventions, no significant main effect of either intervention was found. Independently, both interventions alone showed indications of reduced knee osteoarthritis incidence (odds ratio [OR] 0.69; 95% CI, 0.39-1.21 for the diet-and-exercise program and OR 0.60; 95% CI, 0.31-1.12 for the glucosamine intervention). These effects were neutralized in subjects receiving both interventions (OR 0.97; 95% CI, 0.55-1.71). CONCLUSIONS: No significant main effects of the diet-and-exercise program and of glucosamine sulfate were found on incident knee osteoarthritis. Nevertheless, this trial provides valuable insights for future trial design for preventive osteoarthritis studies. PMID- 25818497 TI - Meaningful utilization of after-visit summaries in the ambulatory setting. PMID- 25818498 TI - Pyogenic granulomas in childhood: New treatment modalities. PMID- 25818500 TI - Antiviral activity of theaflavin digallate against herpes simplex virus type 1. AB - Tea is the second most consumed drink in the world. The beneficial effects of tea have been mostly attributed to its catechin content. Black tea is derived from the leaves of Camellia sinensis plant, and it is rich in theaflavin polyphenols, in particular theaflavin (TF1), theaflavin-3-monogallate (TF2A), theaflavin-3' monogallate (TF2B), and theaflavin-3,3'-digallate (TF3). Vero and A549 cells were used to evaluate the effect of purified individual black tea theaflavins as anti herpes simplex virus 1 agents. With the rise of HSV resistant strains, there is a critical need to develop novel antiherpesviral treatments. Results of the cytotoxicity assay tested by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium] showed that TF1, TF2, and TF3 are not toxic to Vero and A549 cells at a concentration up to 75 MUM. The antiviral activity of the individual theaflavins was tested by plaque reduction assay, MTS assay, flow cytometric analysis and confocal microscopy observations. The results showed that TF1, TF2, and TF3 exhibit potent, dose-dependent anti-HSV 1 effect, with TF3 being the most efficient in both Vero and A549 cells. A concentration of 50 MUM TF3 and above was sufficient to inhibit >99% of the production of HSV-1 viral particles. The anti-HSV-1 effect of TF3 is due to a direct effect on the virions, and treating Vero or A549 cells with TF3 for 1h prior to infection, or treating the cells at different times post infection does not inhibit HSV-1 production. TF3 is stable at vaginal pH, indicating its potential to be a promising natural and affordable remedy against herpes simplex viral infections. PMID- 25818501 TI - White spotting phenotype induced by targeted REST disruption during neural crest specification to a melanocyte cell lineage. AB - Neural crest cells (NCCs) emerge from the dorsal region of the neural tube of vertebrate embryos and have the pluripotency to differentiate into both neuronal and non-neuronal lineages including melanocytes. Rest, also known as NRSF (neuro restrictive silencer factor), is a regulator of neuronal development and function and suggested to be involved in the lineage specification of NCCs. However, further investigations of Rest gene functions in vivo have been hampered by the fact that Rest null mice show early embryonic lethality. To investigate the function of Rest in NCC development, we recently established NCC-specific Rest conditional knockout (CKO) mice and observed their neonatal death. Here, we have established viable heterozygous NCC-specific Rest CKO mice to analyze the function of Rest in an NCC-derived melanocyte cell lineage and found that the white spotting phenotype was associated with the reduction in the number of melanoblasts in the embryonic skin. The Rest deletion induced after the specification to melanocytes did not reduce the number of melanoblasts; therefore, the expression of REST during the early neural crest specification stage was necessary for the normal development of melanoblasts to cover all of the skin. PMID- 25818499 TI - Associations between Gut Microbial Colonization in Early Life and Respiratory Outcomes in Cystic Fibrosis. AB - OBJECTIVE: To examine patterns of microbial colonization of the respiratory and intestinal tracts in early life in infants with cystic fibrosis (CF) and their associations with breastfeeding and clinical outcomes. STUDY DESIGN: A comprehensive, prospective longitudinal analysis of the upper respiratory and intestinal microbiota in a cohort of infants and young children with CF followed from birth was performed. Genus-level microbial community composition was characterized using 16S-targeted pyrosequencing, and relationships with exposures and outcomes were assessed using linear mixed-effects models, time-to-event analysis, and principal components analysis. RESULTS: Sequencing of 120 samples from 13 subjects collected from birth to 34 months revealed relationships between breastfeeding, microbial diversity in the respiratory and intestinal tracts, and the timing of onset of respiratory complications, including exacerbations and colonization with Pseudomonas aeruginosa. Fluctuations in the abundance of specific bacterial taxa preceded clinical outcomes, including a significant decrease in bacteria of the genus Parabacteroides within the intestinal tract prior to the onset of chronic P aeruginosa colonization. Specific assemblages of bacteria in intestinal samples, but not respiratory samples, were associated with CF exacerbation in early life, indicating that the intestinal microbiome may play a role in lung health. CONCLUSIONS: Our findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions. Further studies in larger cohorts validating these findings are needed. PMID- 25818502 TI - Long term survivorship following Scorpio Total Knee Replacement. AB - BACKGROUND: The Scorpio Total Knee Replacement (TKR) is one of the most commonly used prosthesis in the United Kingdom. Concerns arose at our institution that there was a high revision rate for this prosthesis. No study has assessed survivorship of this prosthesis over 10 years. METHODS: Four hundred and fifty six consecutive patients, who underwent a primary Scorpio TKR, were clinically and radiologically evaluated. WOMAC, Oxford Knee Score and all complications including the reason for revision surgery were recorded. The Knee Society Roentgenographic Evaluation and Scoring System was used to evaluate all radiographs for prosthesis alignment and degree of subsequent lucency. Survival analysis for the prosthesis was calculated using Kaplan-Meier curves, with revision as an end-point. Patient reported outcome measures were compared against radiographic evaluation. RESULTS: At a mean of 12.5 years (range 10-14 years), 196 (43.0%) patients were available for review; 124 (27.2%) were lost to follow up and 136 (29.8%) patients had died of unrelated causes. Seven (3.6%) patients required revision surgery at a mean of 5.4 years; five because of aseptic loosening and two because of septic loosening. Cumulative survival for the prosthesis was 99.5% for any cause at five years and 97.4% at 14 years. The mean OKS and WOMAC score at final follow-up was 30.64 (range 12-48) and 74 (18.9-100) respectively. CONCLUSION: The Scorpio TKR has good long term survivorship and functional outcomes. There is no apparent increased revision rate for this prosthesis in our study. LEVEL OF EVIDENCE: Level IV case series. PMID- 25818503 TI - Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer's Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline. AB - BACKGROUND: Growing evidence suggests that the endocannabinoid system is involved in the pathogenesis of Alzheimer's disease (AD) and atherosclerosis. OBJECTIVE: The purpose of this study was to investigate the activation of the endocannabinoid system in AD in vivo and the possible intermediate role of atherosclerosis. METHODS: We enrolled 41 patients with probable AD, and 30 age- and gender-matched controls. All subjects underwent: ultrasound examination of cerebral and neck vessels (including intima-media thickness and plaque stenosis evaluation); blood sampling to measure levels of endocannabinoid [anandamide (AEA), 2-arachidonoylglycerol (2-AG)] and endogenous AEA analogues [N-palmitoyl ethanolamide (PEA); N-oleoyl-ethanolamide]; neuropsychological evaluation and brain MRI (atrophy, white matter hyperintensity volume). RESULTS: 2-AG levels were higher in AD patients compared to controls (Mann-Whitney test p = 0.021). In the AD group, 2-AG correlated to white matter hyperintensity volume (r = 0.415, p = 0.015) and was higher in patients with chronic heart ischemic disease (p = 0.023). In AD patients, 2-AG was also positively related to memory (r = 0.334, p = 0.05) and attention (r = 0.423, p = 0.018) performances. Constructional praxia test scores were lower in patients with higher levels of PEA (r =-0.389, p = 0.019). CONCLUSION: AD patients present high plasma 2-AG levels, also in relation to heart ischemic disease and cerebral leukoaraiosis. This may be a protective mechanism hindering neurodegeneration, but it may also play an ambivalent role on cerebrovascular circulation. The increase in 2-AG and PEA levels observed with ongoing pathological processes may differently modulate cognitive performances. PMID- 25818504 TI - Prevalence of FOB testing in eastern-Australian general practice patients: what has a national bowel cancer screening program delivered? AB - ISSUES ADDRESSED: The National Bowel Cancer Screening Program (NBCSP) was introduced in Australia in 2006, offering free immunochemical Faecal Occult Blood Test (FOBT) to persons aged 50, 55 or 65. The study aimed to examine the prevalence of self-reported screening for colorectal cancer (CRC) using the FOBT and factors associated with not having an FOBT. METHODS: A cross-sectional study of Australian general practice patients aged 50 and over with no personal history of CRC completed a health risk survey while waiting for scheduled appointments between November 2010 and November 2011. RESULTS: A total of 5671 patients from 12 practices were approached to participate. Of the 4707 eligible patients (adults attending for care who understood English and were capable of providing informed consent), 4062 (86%) consented to participate, with 2269 eligible to complete the FOBT items. Approximately half (52%) of participants reported ever having an FOBT. More than one-third (39.7%) of the sample reported having an FOBT in the prior three years. Those who recalled receiving a mailed kit as part of the NBCSP were five times more likely to report being screened. Those less likely to report screening were aged 50-59 years, were female and had been diagnosed with a form of cancer other than CRC. CONCLUSIONS: There is justification for the extension of the NBCSP to ensure a majority of the age-appropriate population is screened for CRC. SO WHAT?: Further work is needed to identify whether high rates of screening are achievable using the mailed-kit approach, and how to increase participation by females, those aged 50-69 years and those diagnosed with other cancers. PMID- 25818505 TI - Cytomegalovirus induces apoptosis in acute leukemia cells as a virus-versus leukemia function. AB - Cytomegalovirus (HCMV) reactivation occurs frequently after hematopoietic stem cell transplantation and is associated with an increased treatment-related mortality. Induction of apoptosis by HCMV is unusual because HCMV utilizes various strategies to prevent apoptosis in infected cells in order to delay cell death and maintain viral replication. Here we show that HCMV can infect the acute leukemia cell lines Kasumi-1 (AML) and SD-1 (BCR-ABL-positive ALL), which inhibited their proliferation and induced apoptosis in almost all cells after 14 days. Although HCMV induced a significant up-regulation of the anti-apoptotic gene cFLIP and the anti-stress gene Gadd45a, and simultaneously down-regulated the pro-apoptotic genes p53, Gadd45gamma in Kasumi-1 and SD-1 cells, we found that these anti-apoptotic mechanisms failed in HCMV-infected acute leukemia cells and apoptosis occurred via a caspase-dependent pathway. We conclude that HCMV can provide anti-leukemic effects in vitro. To determine if this phenomenon may be clinically relevant further investigations will be required. PMID- 25818506 TI - Strain-induced metal-semiconductor transition observed in atomic carbon chains. AB - Carbyne, the sp(1)-hybridized phase of carbon, is still a missing link in the family of carbon allotropes. While the bulk phases of carbyne remain elusive, the elementary constituents, that is, linear chains of carbon atoms, have already been observed using the electron microscope. Isolated atomic chains are highly interesting one-dimensional conductors that have stimulated considerable theoretical work. Experimental information, however, is still very limited. Here we show electrical measurements and first-principles transport calculations on monoatomic carbon chains. When the 1D system is under strain, the chains are semiconducting corresponding to the polyyne structure with alternating bond lengths. Conversely, when the chain is unstrained, the ohmic behaviour of metallic cumulene with uniform bond lengths is observed. This confirms the recent prediction of a metal-insulator transition that is induced by strain. The key role of the contacting leads explains the rectifying behaviour measured in monoatomic carbon chains in a nonsymmetric contact configuration. PMID- 25818509 TI - Dimeric WH2 repeats of VopF sequester actin monomers into non-nucleating linear string conformations: An X-ray scattering study. AB - VopF and VopL are highly similar virulence-factors of Vibrio cholerae and Vibrio parahaemolyticus respectively that disrupt the host's actin cytoskeleton, using a unique organization in dimerized WH2 repeats. Association of dimerized WH2 domains with the barbed face of actin confers multifunctional activities to VopF in vitro, including G-actin sequestration and filament nucleation, barbed end tracking and uncapping. Here, small angle X-ray scattering (SAXS) measurements of complexes of VopF with actin and structural modeling reveal that VopF stabilizes linear actin-strings that differ from canonical actin filament architectures but represent non-polymerizable sequestered forms of actin. The results exclude that VopL binds the pointed end of actin filaments in the template filament nucleation mechanism derived from crystallographic studies. PMID- 25818510 TI - Functionalization of biomineral reinforcement in crustacean cuticle: Calcite orientation in the partes incisivae of the mandibles of Porcellio scaber and the supralittoral species Tylos europaeus (Oniscidea, Isopoda). AB - In arthropods the cuticle forms an exoskeleton with its physical and chemical properties adapted to functions of distinct skeletal elements. The cuticle of the partes incisivae (PI) in mandibles of terrestrial isopods is a composite of chitin-protein fibrils/fibres and minerals. It consists of an unmineralized tip, a middle region with organic fibrils reinforced mainly with amorphous calcium phosphate and a base region mineralized with amorphous calcium carbonate and calcite. In this study we extend our work on the structure and material properties of the incisive cuticle employing electron backscatter diffraction (EBSD), and investigate calcite orientation patterns in the PI of two terrestrial isopod species from different habitats. We trace small-scale differences in texture sharpness and calcite microstructure, and compare calcite organization and orientation patterns in the PI with those in the tergites of the same isopod species. We observe that in the PI calcite orientation, the degree of crystal alignment, and mode of crystalline domain assemblage is highly varied within short length scales. This contrasts to calcite organization in the tergite cuticle, where calcite has only one specific texture pattern. Such a large range in the variation of calcite organization has not been observed in other carbonate biological hard tissues, such as shells and teeth, where one specific texture and microstructure prevails. Thus, the investigated isopod species are able to control crystallization of the amorphous carbonate precursor in a differential way, most probably related to the function of the individual skeletal element and the animals' behavior. PMID- 25818511 TI - Imaging of cellular aging in human retinal blood vessels. AB - To date two main aging vascular lesions have been reported in elderly human retinas: acellular capillaries and microaneurysms. However, their exact mechanism of formation remains unclear. Using high resolution microscopy techniques we revise cellular alterations observed in aged human retinal vessels, such as lipofuscin accumulation, caveolae malfunction, blood basement membrane disruption and enhanced apoptosis that could trigger the development of these aging vascular lesions. Moreover, we have generated a set of original images comparing retinal vasculature between middle and old aged healthy humans to show in a comprehensive manner the main structural and ultrastructural alterations occurred during age in retinal blood vessels. PMID- 25818512 TI - Influence of nursing interventions on adherence to treatment with antituberculosis drugs in children and young people: research protocol. AB - AIM: To evaluate the efficacy of nursing interventions on adherence to antituberculosis medication in a paediatric cohort (aged 0-18 years) and to identify the risk factors for non-compliance. BACKGROUND: After primary infection, children have a higher risk of developing tuberculosis and the severity of the disease is worse in children. Adherence to treatment is essential to control both latent infection and tuberculosis disease. DESIGN: Phase 1: retrospective descriptive analysis (n = 270) in children and young people receiving antituberculosis treatment. Phase 2: quasi-experimental, longitudinal, prospective study (n = 100). The results of the two phases will be compared. METHODS: Phase 1: in children followed up during the period 2011-2013 (non intervention group), the level of adherence and its associated epidemiological, sociocultural and clinical risk factors will be analysed. Phase 2: educational (written information in the child's mother tongue and follow-up telephone calls) and monitoring (Eidus-Hamilton test and follow-up questionnaire) nursing interventions will be implemented. The results of the two phases will be compared. The definitive Nurse-led Follow-up Programme will then be designed. This project was funded in October 2013. DISCUSSION: The risk factors for poor adherence to antituberculosis therapy need to be identified to optimize treatment success in latent tuberculosis infection and disease in children and young people. Simultaneous application of several educational and monitoring methods in nurse-led follow-up shall improve adherence in children and adolescents in our setting. These results may also be applicable in other settings, where tuberculosis is more prevalent and directly observed treatment strategies are not available. PMID- 25818513 TI - A large mimotonid from the middle Eocene of China sheds light on the evolution of lagomorphs and their kin. AB - Mimotonids share their closest affinity with lagomorphs and were a rare and endemic faunal element of Paleogene mammal assemblages of central Asia. Here we describe a new species, Mimolagus aurorae from the Middle Eocene of Nei Mongol (China). This species belongs to one of the most enigmatic genera of fossil Glires, previously known only from the type and only specimen from the early Oligocene of Gansu (China). Our finding extends the earliest occurrence of the genus by at least 10 million years in the Paleogene of Asia, which closes the gap between Mimolagus and other mimotonids that are known thus far from middle Eocene or older deposits. The new species is one of the largest known pre-Oligocene Glires. As regards duplicidentates, Mimolagus is comparable with the largest Neogene continental leporids, namely hares of the genus Lepus. Our results suggest that ecomorphology of this species was convergent on that of small perissodactyls that dominated faunas of the Mongolian Plateau in the Eocene, and probably a result of competitive pressure from other Glires, including a co occurring mimotonid, Gomphos. PMID- 25818514 TI - Identification of C-terminal Hsp70-interacting protein as a mediator of tumour necrosis factor action in osteoblast differentiation by targeting osterix for degradation. AB - In patients with inflammatory arthritis, tumour necrosis factor (TNF)-alpha are overproduced in inflamed joints. This leads to local erosion of cartilage and bone, periarticular osteopenia, as well as osteoporosis. But less is known regarding the molecular mechanisms that mediate the effect of TNF-alpha on osteoblast function. The purpose of this study was to test that C terminus of Hsc70-interacting protein (CHIP) has a specific role in suppressing the osteogenic activity of osteoblasts under inflammatory conditions. C2C12, MC3T3-E1 and HEK293T cell lines were cultured and cotransfected with related plasmids. After transfection, the cells were cultured further in the presence or absence of murine TNF-alpha and subjected to real time RT-PCR, Western blot, Ubiquitination assay, Co-immunoprecipitation, Luciferase reporter assay, Small interfering RNAs and Mineralization assay. The expression levels of TNF-alpha-induced CHIP and Osx were examined by RT-PCR and Western blot analysis. Co-immunoprecipitation and ubiquitination assays revealed ubiquitinated Osx, confirmed that CHIP indeed interacted with Osx and identified K55 and K386 residues as the ubiquitination sites in Osx, Luciferase reporter assay and Small interfering RNAs examined whether TNF-alpha target the bone morphogenetic protein signalling through CHIP. We established stable cell lines with the overexpression of HA-CHIP, Mineralization assay and CHIP siRNA demonstrated the important roles of CHIP on osteoblast function in conditions in which TNF-alpha is overexpressed. We found that the K55 and K386 residues are ubiquitination site(s) in Osx, and that TNF alpha inhibits osteoblast differentiation by promoting Osx degradation through up regulation of E3 ubiquitin ligase CHIP in osteoblast. Thus, CHIP targets Osx for ubiquitination and degradation in osteoblasts after chronic exposure to TNF alpha, and inhibition of CHIP expression in osteoblasts may be a new mechanism to limit inflammation-mediated osteoporosis by promoting their differentiation into osteoblasts. PMID- 25818515 TI - High quality RNA extraction of the mammalian cochlea for qRT-PCR and transcriptome analyses. AB - Molecular investigations of the hearing organ, the cochlea, have been hampered due to the difficulty of isolating pure RNA and in quantities sufficient enough for quantitative real-time RT-PCR or microarray analysis. The complex architecture of the cochlea, the presence of liquids, bone and cartilage tissue, are a major hurdle in obtaining contamination-free RNA to a level that does not affect downstream applications. Here, we present a protocol to extract RNA from the mouse cochlea, with yields and quality suitable for real-time RT-PCR or Affymetrix labeling. In contrast to current methods, such as TRIZOL or column based extraction, this protocol combines the two and, within 4 h, yields a 2 MUg of total RNA from a single pair of adult mouse cochleae. This protocol allows the isolation of RNA molecules from the mammalian cochlea providing access to whole transcript expression analyses. PMID- 25818516 TI - Real-time imaging of in-vitro human middle ear using high frequency ultrasound. AB - Imaging techniques currently used in the clinic to inspect ears in patients are generally limited to views terminating at the tympanic membrane (TM) surface. For imaging past the TM, methods such as computed tomography are typically used, but in addition to disadvantages such as being costly, time consuming, and causing radiation exposure, these often do not provide sufficient resolution of the middle ear structures of interest. This study presents an investigation into the capability of high frequency ultrasound to image the middle ear with high resolution in real-time, as well as measure vibrations of TM and middle ear structures in response to sound stimuli. In unfixed cadaver ears, the TM, ossicles, and ossicular support tissues were all readily identifiable, with capabilities demonstrated for real-time imaging and video capture, and vibrometry of middle ear structures. Based on these results, we conclude that high frequency ultrasonography is a relatively simple and minimally invasive technology with great potential to provide clinicians with new tools for diagnosing and monitoring middle ear pathologies. PMID- 25818517 TI - Population pharmacokinetics of cyclosporine in hematopoietic stem cell transplant patients: consideration of genetic polymorphisms. AB - BACKGROUND: Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce. OBJECTIVE: The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data. METHODS: A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program. RESULTS: A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA. CONCLUSIONS: In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study. PMID- 25818518 TI - Optimizing intramedullary entry location on the proximal humerus based on variations of neck-shaft angle. AB - BACKGROUND: The purpose of this study was to define the relationship between the humeral neck-shaft angle (NSA) and variations in the ideal entry portal aligned with the long axis of the intramedullary canal of the proximal humerus. METHODS: Three-dimensional images of 36 cadaveric humeri with various NSAs were reconstructed by a computerized surgical simulation program. The anteroposterior, mediolateral, and linear distances between a line from the center of the proximal medullary canal to the bicipital groove were measured. Differences among humeri with various NSAs were analyzed. RESULTS: The intramedullary axis line was located a mean of 9 +/- 2 mm posteriorly and 11 +/- 3 mm medially from the bicipital groove. The axis line was 9 +/- 2 mm posterior and 11 +/- 2 mm medial with a standard NSA. The axis line in humeri with a varus NSA was 8 +/- 2 mm posteriorly and 9 +/- 2 mm medially, whereas the axis line was 10 +/- 3 mm posteriorly and 14 +/- 3 mm medially with a valgus NSA. The differences in the mediolateral distances between the groups were significant (P < .00009). CONCLUSION: Care should be taken in choosing the entry portal position in humeri with various NSAs as the entry portal position differs according to the NSA. It is recommended that the location of the entry portal be moved toward the center of the humeral head to align with the centerline of the intramedullary canal in humeri with a valgus NSA in particular. PMID- 25818519 TI - Arthrolysis and delayed internal fixation combined with hinged external fixation for elbow stiffness associated with malunion or nonunion of capitellum fracture. AB - BACKGROUND: This study assessed outcomes after treatment of patients with capitellum fracture diagnosed >4 weeks after the trauma (delayed) who presented with stiff elbow. METHODS: We reviewed 7 patients with stiff elbows after delayed diagnosis of capitellum fractures between February 2007 and February 2012. They were treated with arthrolysis by twin incisions, late open reduction and internal fixation, and a hinged external fixator. According to the Bryan-Morrey-McKee classification, 3 patients had type I capitellum fractures and 4 patients had type IV. RESULTS: Mean follow-up was 28 months (range, 24-38 months). The mean delay from the initial trauma was 3.7 months. The flexion arc improved from a preoperative mean of 24 degrees to a postoperative mean of 122 degrees . The Mayo Elbow Performance Score increased from a mean of 56 points to 93 points. Anatomic fracture union occurred in all cases, and there was no secondary displacement. CONCLUSIONS: Arthrolysis, late internal fixation, and use of a hinged external fixator can solve problems associated with stiff elbow after delayed diagnosis of capitellum fracture. Combined use of these techniques may be a safe and effective treatment option. PMID- 25818520 TI - Herd-level risk factors for infection with bovine leukemia virus in Canadian dairy herds. AB - Enzootic bovine leukosis (EBL) is an economically important infection of dairy cattle worldwide, which is caused by bovine leukemia virus (BLV). The prevalence of infection in Canadian dairy herds is high and continues to increase; however, there has not been a national program to control BLV. This cross-sectional study was conducted to identify potentially important risk factors for BLV infection on Canadian dairy herds, which is a prerequisite to developing an effective control program. During 1998-2003, based on a stratified two-stage random sampling process, 315 dairy farms from seven provinces of Canada were selected. Within each farm, 9-45 cows were bled and tested with a commercial serum ELISA kit for BLV antibodies. A comprehensive questionnaire, targeting potentially important herd-level management indicators, was successfully administered in 272 herds. A zero-inflated negative binomial (ZINB) regression model was fit to the resulting data to assess the potential associations between BLV seropositivity and a variety of herd-level factors. Seventy-eight percent of the herds were identified as BLV-positive (had one or more test positive animals). In the negative-binomial part of the final ZINB model, herds with clinical cases of leukosis during the 12 months prior to sampling, as well as herds which purchased animals with unknown BLV infection status in the last five years, had a significantly larger proportion of BLV positive animals. Based on a significant interaction between two of the risk factors, changing gloves between cows during pregnancy examination was not statistically associated with lower proportion of infected cows compared with not changing gloves, in the western Canadian provinces. In the logistic part of the model, herds from eastern Canadian provinces and those not purchasing cows in the last five years had increased odds of being free from BLV. The high prevalence of infection across Canada should be addressed through the development and implementation of a nationwide control program which will address the regional and herd-level risk factors for BLV infection identified in this study. PMID- 25818521 TI - Ultimobranchial gland respond in a different way in male and female fresh water teleost Mastacembelus armatus (Lacepede) during reproductive cycle. AB - The present study was carried out to analyze the differences in the activity of ultimobranchial gland (UBG) between male and female fresh water teleost Mastacembelus armatus during reproductive cycle. Considerable variations in the nuclear diameter of UBG cells and plasma calcitonin (CT) levels during different reproductive phases of testicular and ovarian cycle suggested that the activity of the UBG depends upon the sexual maturity of fishes. A positive correlation was observed between plasma CT and sex steroid levels and the gonadosomatic index in both sexes which further confirmed the involvement of UBG in the processes related to gonadal development in fishes irrespective of the sex. Sudden increase in the level of plasma CT and nuclear diameter of UBG cells after administration of 17 alpha-methyltestosterone in males and 17 beta-estradiol in females during resting phase of the reproductive cycle clearly showed that UBG becomes hyperactive with increases in the level of sex steroids. Plasma calcium level was also found to be positively correlated with gonadal maturation in females. However no such change in plasma calcium level in relation to testicular cycle was observed. Thus it can be concluded that UBG becomes hyperactive during gonadal maturation but its role differs between male and female fishes. In females it may involved in both gonadal maturation and plasma calcium regulation while in males its involvement in calcium regulation was not justified. Variations in the level of CT during various phases of testicular cycle evidenced its involvement in gonadal maturation only. PMID- 25818522 TI - Reproductive hormonal patterns in pregnant, pseudopregnant and acyclic captive African wild dogs (Lycaon pictus). AB - African wild dogs are one of the most endangered canid species, with free-living populations declining as a consequence of habitat loss, disease and human conflict. Captive breeding is considered an important conservation strategy, but is hampered by a poor overall understanding of the reproductive biology of the species. To improve our basic knowledge, we studied hormone patterns in 15 female wild dogs using non-invasive faecal collections. By comparing longitudinal hormone profiles with behavioural and anatomical changes, females could be allocated among three reproductive classes: pregnant (n=1), pseudopregnant (n=9) and acyclic (n=4). We also monitored a single female in which contraception was induced with a deslorelin implant. Comparison of pseudopregnant and acyclic females showed that, in both classes, faecal oestradiol concentrations increased from anoestrus to pro-oestrus then declined into the oestrous and dioestrous phases. Progestagen concentrations rose steadily from anoestrus to the dioestrous phase in both pseudopregnant and acyclic females and, pseudopregnant females had significantly higher concentrations of progestagens than acyclic females in all phases of the oestrous cycle. Most females classed as pseudopregnant were found in female-only groups, suggesting that wild dogs are spontaneous ovulators. Furthermore, only one adult female did not ovulate, so suppression of reproduction in subordinates is likely to be behavioural rather than physiological. PMID- 25818523 TI - Egg laying characteristics, egg weight, embryo development, hatching weight and post-hatch growth in relation to oviposition time of broiler breeders. AB - Two experiments were conducted to determine egg laying characteristics and the effects of oviposition time on egg weight, embryo development and post-hatch growth in broiler breeders. In experiment 1, eggs collected for 3 consecutive days on hourly basis between 06:30 and 17:30h were categorized to early, middle and late oviposition times in the clutch. In experiment 2, eggs were incubated to study embryo development, remaining albumen, liver weight, heart weight and the tibia length of embryos at 12, 14, 16 and 18 days of incubation as well as the body weight of hatchlings and chickens at 7, 21 and 42 days of age in relation to oviposition time. About 76% of nest eggs were laid from 06:30 to 11:30h. A similar pattern was observed in floor eggs. Egg weight decreased (P<0.01) with advanced position in the clutch. Generally, oviposition time had no effect on embryo growth parameters. At hatch, body weight of chicks derived from eggs of late oviposition times was less (P<0.01) than that of chicks from eggs produced earlier in the clutch. From 3-week-old onwards, chickens of early oviposition time sustained heavier (P<0.05) weight than chickens of middle oviposition time whereas chickens of late oviposition time obtained a middle weight. Differences in egg weights, body weight at hatch and post-hatch growth due to time of oviposition suggest that oviposition time together with incubation conditions should be considered for obtaining greater uniformity and growth of chickens. PMID- 25818524 TI - Formulation and testing of a non-steroidal aromatase inhibitor intravaginal device for the control of ovarian function in cattle. AB - The study was designed to formulate intravaginal devices that provide biologically active circulating concentrations of an aromatase inhibitor for a minimum of 4 days, and to determine their physiologic effects in cattle. Three compounds with estradiol inhibitory capability (letrozole, anastrozole and fenbendazole) were tested in vitro using bovine granulosa cell culture. Letrozole was found to be the most efficient and potent inhibitor. A wax-based vehicle was selected for further development of a letrozole intravaginal device based on its steady release rate. Cycling heifers were assigned randomly to be given an intravaginal device containing wax plus gel coat (n=4), wax formulation (n=4), no formulation (blank device, control, n=4). Intravaginal devices were inserted on Day 3 (Day 0=ovulation) and kept in place for 8 days. The addition of a letrozole containing gel coating hastened the initial increase on plasma concentrations, while the letrozole-containing wax-based vehicle maintained prolonged delivery from the intravaginal device. The dominant follicle diameter profile was larger in heifers treated with the wax plus gel coat device (P<0.04), and the interwave interval was prolonged in heifers in the letrozole-treated groups compared to controls (P<0.001). Plasma estradiol concentrations were reduced significantly in the letrozole-treated groups. Plasma progesterone concentrations were lower in the wax letrozole-treated group (P<0.02). We concluded that wax base plus gel coat intravaginal devices are suitable for the development of a letrozole-based protocol for the synchronization of ovulation in cattle. It effectively reduced estradiol production resulting in prolonged dominant follicle growth and lifespan, without adversely affecting progesterone production. PMID- 25818525 TI - Fucosterol attenuates lipopolysaccharide-induced acute lung injury in mice. AB - BACKGROUND: Fucosterol has been reported to have antioxidant, antidiabetic, and anti-inflammatory effects. In this study, we investigated the protective effect and the possible mechanism of fucosterol on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: Lung injury was assessed by a histologic study, pulmonary edema, and inflammatory cytokines production in bronchoalveolar lavage fluid. Alveolar macrophages were stimulated with LPS in the presence or absence of fucosterol. The expressions of inflammatory cytokines were determined by enzyme-linked immunosorbant assay. Nuclear factor-kappa B (NF kappaB) expression was detected by Western blotting. RESULTS: The results showed that fucosterol attenuated lung histopathologic changes, wet-to-dry ratio, and tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1beta production in LPS induced ALI in mice. Meanwhile, fucosterol inhibited NF-kappaB activation and tumor necrosis factor-alpha, IL-6, and IL-1beta production in LPS-stimulated alveolar macrophages. CONCLUSIONS: In conclusion, the present study demonstrated that fucosterol exhibited a protective effect on LPS-induced acute lung injury, and the possible mechanism is involved in inhibiting NF-kappaB activation, thereby inhibiting LPS-induced inflammatory response. PMID- 25818526 TI - Spinal muscle activity in simulated rugby union scrummaging is affected by different engagement conditions. AB - Biomechanical studies of rugby union scrummaging have focused on kinetic and kinematic analyses, while muscle activation strategies employed by front-row players during scrummaging are still unknown. The aim of the current study was to investigate the activity of spinal muscles during machine and live scrums. Nine male front-row forwards scrummaged as individuals against a scrum machine under "crouch-touch-set" and "crouch-bind-set" conditions, and against a two-player opposition in a simulated live condition. Muscle activities of the sternocleidomastoid, upper trapezius, and erector spinae were measured over the pre-engagement, engagement, and sustained-push phases. The "crouch-bind-set" condition increased muscle activity of the upper trapezius and sternocleidomastoid before and during the engagement phase in machine scrummaging. During the sustained-push phase, live scrummaging generated higher activities of the erector spinae than either machine conditions. These results suggest that the pre-bind, prior to engagement, may effectively prepare the cervical spine by stiffening joints before the impact phase. Additionally, machine scrummaging does not replicate the muscular demands of live scrummaging for the erector spinae, and for this reason, we advise rugby union forwards to ensure scrummaging is practiced in live situations to improve the specificity of their neuromuscular activation strategies in relation to resisting external loads. PMID- 25818528 TI - Modulation of actin dynamics by Rac1 to target cognitive function. AB - The small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in cells. Formation of extensions at the surface of the cell is required for migration and even for cell invasion and metastases. Because an elevated level and hyperactivation of this protein has been associated with metastasis in cancer, direct regulators of Rac1 are currently envisioned as a potential strategy to treat certain cancers. Less research, however, has been done regarding the role of this small GTP-binding protein in brain development, where it has an important role in dendritic spine morphogenesis through the regulation of actin. Alteration of dendritic development and spinogenesis has been often associated with mental disorders. Rac1 is associated with and required for learning and the formation of memories in the brain. Rac1 appears to be dysregulated in certain neurodevelopmental disorders that present all these three alterations: mental retardation, atypical synaptic plasticity and aberrant spine morphology. Thus, to develop novel therapies for rescuing cognitive impairment, a reasonable approach might be to target this protein, Rac1, which plays a pivotal role in directing signals that regulate actin dynamics, which in turn might have an effect in spine cytoarchitecture and synaptic function. It is possible that novel drugs that regulate Rac1 activation and function could modulate actin cytoskeleton and spine dynamics, representing potential candidates to repair intellectual disability in disorders associated with spine abnormalities. Herein, we present a list of the current Rac1 inhibitors that might fulfill this role together with a summary of the latest findings concerning their function as they relate to neuronal studies. While the small GTPase Rac1 is well known for regulating actin cytoskeleton reorganization in different type of cells, it appears to be also required for learning and the formation of memories in the brain. Abnormal regulation of this protein has been associated with cognitive disabilities, atypical synaptic plasticity and abnormal morphology of dendritic spines in certain neurodevelopmental disorders. Thus, modulation of Rac1 activity using novel inhibitors might be a strategy to reestablish cognitive function. PMID- 25818527 TI - Scapula insufficiency fractures after reverse total shoulder arthroplasty in rotator cuff arthropathy: What is their functional impact? AB - INTRODUCTION-OBJECTIVES: To describe the incidence, etiological factors, functional impairment and therapeutic management of scapular fractures after reverse shoulder arthroplasty (RSA) in rotator cuff arthropathy. MATERIAL AND METHOD: A retrospective study was conducted on 126 RSA between 2009 and 2011, in which 4 fractures were identified that were compared with a control group of 40 patients. An analysis was performed on the variables related to the surgical technique, functional results, and quality of life (Constant scale, EQ-5D). RESULTS: The fracture incidence was 3.28% with a mean age of 74.7 years. The mean time until diagnosis was 11.9 months. The preoperative Constant score in the control group was 37.3%, and 34.7% in the fracture group (P>.05); postoperative Constant score: 81.2 and 66.5%, respectively (P>.001). Forward elevation and abduction in fracture patients decreased by 39 degrees (P=.02), and 34 degrees (P=.057) respectively. The perceived quality of life (EQ-VAS) was lower in the fracture group (60 vs. 76) (P=.002). There were no instability cases, and no revision surgery was required. The union rate was 50% after a mean follow-up 39.6 months. CONCLUSIONS: Scapular fracture after RSA is a rare complication. Despite its presence, the functional outcomes and quality of life of these patients are higher than preoperatively; however, they are lower than that obtained in patients with RSA without this complication. More prospective studies are needed to define guidelines for therapeutic action against this complication. PMID- 25818529 TI - A rare case of a carcinoid myocardial mass. AB - Right-sided valvular disease is characteristic of the carcinoid syndrome. In contrast, myocardial involvement is unusual. We present a case of an asymptomatic patient who had a myocardial carcinoid tumor discovered during surgery for coronary artery disease. The clinical presentation, diagnostic tests and modalities, and outcomes after surgery are discussed in this case report. PMID- 25818530 TI - Energy drink overconsumption in adolescents: implications for arrhythmias and other cardiovascular events. PMID- 25818532 TI - Bacterial co-infection is rare in patients with Ebola virus disease in a military Ebola virus disease treatment unit in Sierra Leone. PMID- 25818531 TI - Neutrophils and inflammatory resolution in the mucosa. AB - Inflammatory diseases in mucosal organs as diverse as the lung, liver and intestine inevitably require the intimate interactions between neutrophils and epithelia. The physiologic consequences of such interactions often determine endpoint organ function, and for this reason, much recent interest has developed in identifying mechanisms and novel targets to promote the resolution of mucosal inflammation. Physiologically-relevant in vitro and in vivo model systems have aided in discovery of novel pathways to define basic inflammatory mechanisms and approaches to defining the concepts of inflammatory resolution. Here, we will review the recent literature regarding the contribution of neutrophils to inflammatory resolution, with an emphasis on the role of the tissue microenvironment, endogenous pathways for promoting resolution and the molecular determinants of neutrophil-epithelial cell interactions during ongoing inflammation. These recent studies highlight the dynamic nature of pro-resolving pathways and lend insight into the complexity of treating mucosal inflammation. PMID- 25818533 TI - Factors influencing combination antiretroviral therapy choice: Do doctors really know best? PMID- 25818534 TI - Functional polymorphisms of the CCL2 and MBL genes cumulatively increase susceptibility to severe acute respiratory syndrome coronavirus infection. AB - OBJECTIVES: To assess associations between the functional polymorphisms G-2518A at the chemokine (C-C motif) ligand 2 gene (CCL2) and mannose binding lectin (MBL) codon 54 variant (A/B) and susceptibility to SARS. METHODS: We genotyped the CCL2 G-2518A and MBL codon 54 variant (A/B) in 4 case-control populations of Chinese descent, totally consisting of 932 patients with SARS and 982 control subjects. RESULTS: Both the high-CCL2-producing GG genotype and the low-MBL producing B allele were consistently associated with increased risks of SARS-CoV infection in all 4 case-control populations (joint P = 1.6 * 10(-4) and 4.9 * 10( 8), for CCL2 and MBL respectively), with no interaction between polymorphisms could be detected. Furthermore, all the 4 case-control studies demonstrated a cumulative effect on risk of SARS-CoV infection for the combination of polymorphisms (joint P = 1.3 * 10(-10)). However, tests using the area under the curve (AUC) indicated that at this stage, the polymorphisms were unlikely to be appropriate for risk prediction testing because of low AUC values (all <66%). Additionally, no association was observed between the polymorphisms and severity of SARS. CONCLUSIONS: The CCL2 G-2518A and MBL codon 54 variant have a significantly cumulative effect on increased risk of SARS-CoV infection. PMID- 25818535 TI - Why are voluntary head movements in cervical dystonia slow? AB - INTRODUCTION: Rapid head movements associated with a change in fixation (head saccades) have been reported to be slow in cervical dystonia (CD). Such slowing is typically measured as an increase in time to complete a movement. The mechanisms responsible for this slowing are poorly understood. METHODS: We measured head saccades in 11 CD patients and 11 healthy subjects using a magnetic search coil technique. RESULTS: Head saccades in CD took longer to reach a desired target location. This longer duration was due to multiple pauses in the trajectory of the head movement. The head velocity of each segment of the (interrupted) head movement was appropriate for the desired total movement amplitude. The head velocity was, however, higher for the amplitude of the individual interrupted movements. These results suggest that brain programs the proper head movement amplitude, but the movement is interrupted by pathological pauses. CONCLUSION: Voluntary head saccades have a longer duration in CD due to frequent pauses. The frequent pauses reflect pathological interruptions of normally programmed intended head movement. PMID- 25818536 TI - Health-related quality of life in patients with Parkinson's disease: Implications for falling. AB - INTRODUCTION: It has been demonstrated that various domains of health-related quality of life (HRQoL) have predictive value in progression of disability and depression in a neurological setting. The aim of this study was to assess potential predictive value of domains of HRQoL in occurrence of falls among persons with Parkinson's disease (PD) over one year of follow-up. METHODS: The study comprised cross-sectional design at baseline and 1-year prospective cohort study. Those who denied having fallen in the past 6 months were followed for one year, while participants were asked to record falls prospectively in a falls diary for a year. A total of 300 consecutive PD outpatients without cognitive impairment were recruited from August 15, 2011 to December 15, 2012 in the outpatient Department of Movement Disorders, Institute of Neurology, Clinical Center of Serbia in Belgrade. The HRQoL was evaluated using the SF-36 questionnaire. RESULTS: All domains of the SF-36, except Role Emotional, were significantly lower among fallers. After controlling for potential confounding factors, the domain of Role Physical (p = 0.027), Physical Composite Score (p = 0.023) and the total SF-36 score (p = 0.029) were significant predictors of occurrence of falls within one year of follow-up. CONCLUSION: Assessment of quality of life represents an additional tool to the established measures of clinical course of the disease and could provide further insight in complex distinction of risk factors for falling in PD. PMID- 25818537 TI - Early numerical abilities and cognitive skills in kindergarten children. AB - In this study, a unitary path analysis model was developed to investigate the relationship between cognitive variables (derived from published studies) and early numerical abilities in children attending the last year of kindergarten. We tested 100 children starting their last year of kindergarten on the following cognitive abilities: intelligence, phonological abilities, counting, verbal and visuospatial short-term memory and working memory, processing speed, and early numerical abilities. The same children were tested again on early numerical abilities at the end of the same year. The children's early numerical abilities at the beginning of the final year of kindergarten were found to be directly related to their verbal intelligence, phonological abilities, processing speed, and working memory and to be indirectly related to their nonverbal intelligence. Early numerical abilities at the end of the same year are directly related not only to early numerical abilities assessed at the beginning of the year but also to working memory and phonological abilities as well as have an indirect relationship with verbal and nonverbal intelligence. Overall, our results showed that both general and specific abilities are related to early mathematic learning in kindergarten-age children. PMID- 25818538 TI - Repeated syncope caused by intractable vasospastic angina: A case report. PMID- 25818539 TI - The relationship between coronary artery calcium score and the long-term mortality among patients with minimal or absent coronary artery risk factors. AB - BACKGROUND: Coronary artery calcium (CAC) is strongly predictive of all-cause mortality in intermediate-risk groups, but this relationship is not well defined in very low-risk individuals. We investigated the relationship between CAC scoring and the long-term all-cause mortality among patients with <= 1 cardiovascular disease (CVD) risk factor. METHODS: We analyzed a retrospective cohort of 5584 asymptomatic patients with no known CVD (mean 56.6 +/- 11.6 years, 69%men) and <= 1 risk factor who were physician referred for a CAC scan. Mortality was ascertained through linkage with the Social Security Death Index. We calculated the prevalence of CAC stratified by age and risk factors. We also examined the association between CAC and mortality using multivariable Cox Proportional hazards models. RESULTS: During a mean follow-up of 10.4 +/- 3.1 years, 168 individuals (3.0%) died. Overall, 54.5% of patients had a CAC >0 and 9.8% had CAC >= 400. There was a greater risk of mortality with increasing CAC 1 99 (HR 1.9, 95% CI 1.2-3.1), 100-399 (HR 2.1, 95% CI 1.2-3.6) and >= 400 (HR 2.8, 95% CI 1.6-4.8) compared to CAC=0 (p<0.0001 for trend). Similar results were observed when the population was stratified by zero or one risk factor. Among patients < 45 years old, there was a 0.7% incidence of mortality compared to 8.1% for individuals >= 65 years old. CONCLUSIONS: During long-term follow-up, an increasing CAC was significantly associated with a higher risk of all-cause mortality among patients with a very low CVD risk factor profile. CAC scanning may be a potentially useful tool for risk stratification among low CVD risk individuals who are >= 45 years old. PMID- 25818540 TI - Mortality in takotsubo syndrome is similar to mortality in myocardial infarction A report from the SWEDEHEART registry. AB - BACKGROUND: Takotsubo syndrome is an acute cardiovascular condition that predominantly affects women. In this study, we compared patients with takotsubo syndrome and those with acute myocardial infarction with respect to patient characteristics, angiographic findings, and short- and long-term mortality. METHODS: From the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA), we obtained and merged data on patients undergoing coronary angiography in Vastra Gotaland County in western Sweden between January 2005 and May 2013. Short- and long-term mortality in patients with takotsubo (n=302) and patients with ST-elevation myocardial infarction (STEMI, n=6595) and non-ST-elevation myocardial infarction (NSTEMI, n=8207) were compared by modeling unadjusted and propensity score-adjusted logistic and Cox proportional-hazards regression. RESULTS: The proportion of the patients diagnosed with takotsubo increased from 0.16% in 2005 to 2.2% in 2012 (P<0.05); 14% of these patients also had significant coronary artery disease. Cardiogenic shock developed more frequently in patients with takotsubo than NSTEMI (adjusted OR 3.08, 95% CI 1.80 5.28, P<0.001). Thirty-day mortality was 4.1% and was comparable to STEMI and NSTEMI. The long-term risk of dying from takotsubo (median follow-up 25 months) was also comparable to NSTEMI (adjusted HR 1.01, 95% CI 0.70-1.46, P=0.955) STEMI (adjusted HR 0.83, 95% CI 0.57-1.20, P=0.328). CONCLUSIONS: The proportion of acute coronary syndromes attributed to takotsubo syndrome in Western Sweden has increased over the last decade. The prognosis of takotsubo syndrome is poor, with similar early and late mortality as STEMI and NSTEMI. PMID- 25818541 TI - Variability in bioavailability of small molecular tyrosine kinase inhibitors. AB - Small molecular tyrosine kinase inhibitors (smTKIs) are in the centre of the very quickly expanding area of personalized chemotherapy and oral applicability thereof. The number of drugs in this class is rapidly growing, with twenty current approvals by both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA). The drugs are, however, generally characterized by a poor oral, and thus variable, bioavailability. This results in significant variation in plasma levels and exposure. The cause is a complex interplay of factors, including poor aqueous solubility, issued permeability, membrane transport and enzymatic metabolism. Additionally, food and drug-drug interactions can play a significant role. The issues related with an impaired bioavailability generally receive little attention. To the best of our knowledge, this article is the first to provide an overview of the factors that determine the bioavailability of the smTKIs. PMID- 25818542 TI - Charcot foot syndrome. AB - Charcot foot syndrome is an uncommon complication of diabetes but is potentially devastating in its consequences. Outcome is made worse by widespread professional ignorance leading to delayed diagnosis, but it is also hampered by lack of understanding of its causes and lack of treatments with proven effectiveness, other than offloading. There remains a desperate need for studies into its causes as well as comparative audit and trials designed to determine the best treatment for this difficult condition. Such work can probably only be effectively carried out through the establishment of multicentre networks. Nevertheless, improved understanding in recent years of the likely role of inflammatory pathways has raised awareness of the multiple ways in which the effects of neuropathy may be manifest in the development of the Charcot foot. This awareness is also leading to the realization that similar processes may conceivably contribute to the refractoriness of other foot diseases in diabetes, including both chronic unhealing ulcers and osteomyelitis. PMID- 25818543 TI - Ampullectomy versus pancreaticoduodenectomy for ampullary tumors. AB - BACKGROUND: Considerable controversy surrounds the treatment of ampullary neoplasms. This report describes the authors' experiences regarding the choice of either ampullectomy or pancreaticoduodenectomy for treatment of ampullary tumors. METHODS: Demographics, statistical findings concerning diagnosis, surgical risks including morbidity and mortality, and outcomes were evaluated and compared between the ampullectomy and pancreaticoduodenectomy groups for ampullary tumors retrieved from a prospectively collected computer database of 992 periampullary tumors resected during the period from 1965 to 2013. RESULTS: A total of 377 patients with ampullary tumors were included; 15 underwent ampullectomy and 362 underwent pancreaticoduodenectomy. The overall false-negative rate for diagnosis of ampullary malignancy was 11.2%, specificity was 50.0%, positive predictive value was 98.3%, negative predictive value was 12.2%, and the overall accuracy was 87.6% (77.5% by preoperative endoscopic biopsy and 83.9% by intraoperative frozen-section biopsy). Ampullectomy was associated with shorter postoperative stays and lower surgical morbidity. There was no statistical difference observed between the two groups regarding surgical mortality, pancreatic leakage, or gastric atonia. The tumor recurrence rate was lower after pancreaticoduodenectomy, but the difference between the groups was not significant. Overall, there was no difference in survival observed between the two groups. CONCLUSION: Because biopsy is not routinely reliable, pancreaticoduodenectomy is preferable to ampullectomy for an ampullary tumor of uncertain diagnosis. Ampullectomy is associated with lower surgical morbidity and should therefore remain in the armamentarium of the pancreatic surgeon when comorbidity precludes major surgery. PMID- 25818544 TI - MicroRNA-93 regulates collagen loss by targeting MMP3 in human nucleus pulposus cells. AB - OBJECTIVES: Degenerated disc disease is one of the most common medical conditions in patients suffering from low back pain. Recent studies have shown that microRNAs can regulate cell function in many pathological conditions. The aim of this study was to investigate expression and role of miR-93 in disc degeneration. MATERIALS AND METHODS: Quantitative RT-PCR was employed to investigate level of miR-93 in degenerative nucleus pulposus (NP) tissues. Then, functional analysis of miR-93 in regulating collagen II expression was performed. Subsequently, western blotting and luciferase reporter assay were used to detect the target gene. RESULTS: We showed that miR-93 was significantly down-regulated in degenerative NP tissues and its levels were associated with grade of disc degeneration. Overexpression of miR-93 stimulated type II collagen expression in NP cells. Moreover, MMP3 was identified as a putative target of miR-93. MiR-93 inhibited MMP3 expression by directly targeting its 3'UTR, and this was abolished by miR-93 binding site mutations. Additionally, restoration of MMP3 in miR-93 overexpressed NP cells reversed effects of type II collagen expression. Expression of MMP3 inversely correlated with miR-93 expression in degenerative NP tissues. CONCLUSIONS: Taken together, we demonstrated that miR-93 contributed to abnormal NP cell type II collagen expression by targeting MMP3, involved in intervertebral disc degeneration. PMID- 25818545 TI - Gold mining for PDT: Great expectations from tiny nanoparticles. AB - Among many and various products, born by the modern nanotechnology, gold nanoparticles roused a special interest of biomedical researchers. Unique features of the nanoparticles allow to use them not only as effective transporters for therapeutic agents but also as basic components of nanocomposite preparations intended for targeted photodynamic and photothermal therapy of tumours. In the review, physical, chemical and biological properties of gold nanoparticles which can promote PDT efficiency of a designed nanocomposite, are briefly characterized, and promising trends in creation of gold-containing composite photosensitizers are analysed. PMID- 25818546 TI - Low dose 5-aminolevulinic acid: Implications in spectroscopic measurements during brain tumor surgery. AB - BACKGROUND: Using 5-aminolevulinic acid (ALA) as an intraoperative fluorescence contrast has been proven to improve the resection of glioblastoma and contribute to prolonged patient survival. ALA accumulates as protoporphyrin IX (PpIX) in the tumor cells and is administered in an advised dose of 20 mg/kg body weight (b.w.) for brain tumor resection using fluorescence surgical microscopes. PpIX fluorescence availability and intensities of a four folds lower ALA dose (5 mg/kgb.w.) has been investigated in glioblastomas and skin using a spectroscopy system adapted for surgical guidance. METHODS: A total of 30 adult patients diagnosed with high grade gliomas were included in the analysis. ALA was orally administered in doses of 5 mg/kg b.w. (n = 15) dissolved in orange juice or 20 mg/kgb.w. (n = 15) dissolved in water. A fluorescence spectroscopy system with a handheld fiber-optical probe was used for performing the quantitative fluorescence measurements. RESULTS: The binominal comparison of the diagnostic performance parameters showed no significant statistical difference (p > 0.05). The median fluorescence values in tumor were 2-3 times higher for the high ALA dose group. No PpIX was detected in the skin of the patients in the low dose group (0/4) while PpIX was detected in the skin of the majority of the patients in the high ALA dose group (13/14). CONCLUSIONS: Application of 5mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients. PMID- 25818548 TI - Outcome of localised blastemal-type Wilms tumour patients treated according to intensified treatment in the SIOP WT 2001 protocol, a report of the SIOP Renal Tumour Study Group (SIOP-RTSG). PMID- 25818547 TI - Racial disparities in reaching the renal transplant waitlist: is geography as important as race? AB - BACKGROUND: In the United States, African Americans and whites differ in access to the deceased donor renal transplant waitlist. The extent to which racial disparities in waitlisting differ between United Network for Organ Sharing (UNOS) regions is understudied. METHODS: The US Renal Data System (USRDS) was linked with US census data to examine time from dialysis initiation to waitlisting for whites (n = 188,410) and African Americans (n = 144,335) using Cox proportional hazards across 11 UNOS regions, adjusting for potentially confounding individual, neighborhood, and state characteristics. RESULTS: Likelihood of waitlisting varies significantly by UNOS region, overall and by race. Additionally, African Americans face significantly lower likelihood of waitlisting compared to whites in all but two regions (1 and 6). Overall, 39% of African Americans with ESRD reside in Regions 3 and 4--regions with a large racial disparity and where African Americans comprise a large proportion of the ESRD population. In these regions, the African American-white disparity is an important contributor to their overall regional disparity. CONCLUSIONS: Race remains an important factor in time to transplant waitlist in the United States. Race contributes to overall regional disparities; however, the importance of race varies by UNOS region. PMID- 25818549 TI - Should whole blood replace the shock pack? AB - When haemorrhage occurs on the battlefield, the soldier rapidly loses whole blood; it therefore stands to reason that the optimum fluid for resuscitation is whole blood. Indeed, this was the case for the first 250 years of transfusion practice, but since the 1970s component therapy has been used, with little evidence for that change. It is hardly surprising that 'balanced' component therapy, which seeks to replicate whole blood, has been found to offer the best results in resuscitation. This article explores the role of whole blood in resuscitation and how it may be useful in the contemporary military environment. PMID- 25818550 TI - Incidence and risk factors for backpack palsy in young Korean soldiers. AB - OBJECTIVES: Backpack palsy (BPP) is a common aetiology of brachial plexopathy in military hospitals. We aimed to determine the incidence and risk factors of BPP in young Korean soldiers. METHODS: We identified enlisted patients who were diagnosed with BPP from a review of the medical records of all the Korean military hospitals in 2011 and 2012 and investigated their clinical findings and medical study results. To identify risk factors of BPP, we also surveyed, by questionnaire, healthy recruits of a company in a training centre who had just finished night marches. We divided them according to whether they had paresthaesia and/or weakness in their arm(s) during marching and compared their characteristics. RESULTS: The incidence of BPP in Korean soldiers was 29.7 per 100,000 person-years (95% CI 17.2 to 24.3). Body mass index (BMI) was significantly lower in patients with BPP than it was in healthy recruits. Among healthy recruits, those who had experienced paresthaesia and/or weakness during marching had a significantly lower BMI than did those who had not. CONCLUSIONS: We report the incidence of BPP in young Korean soldiers. A low BMI was a risk factor for BPP. These results may be helpful in establishing a strategy for the prevention of BPP in the setting of military training. PMID- 25818551 TI - Pathogenic potential of SLC25A15 mutations assessed by transport assays and complementation of Saccharomyces cerevisiae ORT1 null mutant. AB - HHH syndrome is an autosomal recessive urea cycle disorder caused by alterations in the SLC25A15 gene encoding the mitochondrial ornithine carrier 1, which catalyzes the transport of cytosolic ornithine into the mitochondria in exchange for intramitochondrial citrulline. In this study the functional effects of several SLC25A15 missense mutations p.G27R, p.M37R, p.N74A, p.F188L, p.F188Y, p.S200K, p.R275Q and p.R275K have been tested by transport assays in reconstituted liposomes and complementation of Saccharomyces cerevisiae ORT1 null mutant in arginine-less synthetic complete medium. The HHH syndrome-causing mutations p.G27R, p.M37R, p.F188L and p.R275Q had impaired transport and did not complement ORT1? cells (except p.M37R slightly after 5 days in solid medium). The experimentally produced mutations p.N74A, p.S200K and p.R275K exhibited normal or considerable transport activity and complemented ORT1? cells after 3 days (p.N74A, p.S200K) or 5 days (p.R275K) incubation. Furthermore, the experimentally produced p.F188Y mutation displayed a substantial transport activity but did not complement the ORT1? cells in both liquid and solid media. In view of the disagreement in the results obtained between the two methods, it is recommended that the method of complementing the S. cerevisiae ORT1 knockout strain is used complimentary with the measurement of the catalytic activity, in order to distinguish HHH syndrome-causing mutations from isomorphisms. PMID- 25818552 TI - Adaptive changes of extracellular amino acid concentrations in mouse dorsal striatum by 4-AP-induced cortical seizures. AB - The striatum is a major target of cerebral cortical output. The cortico-striatal projection has been well described, however, the neurochemical changes that occur in the striatum after prolonged cortical hyperactivation remain to be investigated. In this study, extracellular levels of glutamate, GABA, and alanine levels were measured in the dorsal striatum using microdialysis in anesthetized mice at resting condition and during 4-aminopyridine (4-AP)-induced cortical seizures. After topical application of 4-AP on the primary motor cortex that induced cortical seizures, the extracellular level of striatal GABA increased by 40% in 60 min. By contrast, the extracellular level of striatal glutamate decreased by 20%. Moreover, the surface amounts of striatal glutamate/aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1), the major astrocytic high-affinity glutamate transporters, tended to increase by cortical seizures in 60 min, suggesting a recruitment of the glutamate transporters from internal stores. 4-AP also resulted in a steady increase of alanine levels which are thought to reflect glutamate and pyruvate metabolism in neurons and astrocytes. These observations possibly delineate adaptive changes of striatal metabolism by severe cortical seizures. PMID- 25818553 TI - Behavioral and fMRI evidence of the differing cognitive load of domain-specific assessments. AB - Standards-referenced educational reform has increased the prevalence of standardized testing; however, whether these tests accurately measure students' competencies has been questioned. This may be due to domain-specific assessments placing a differing domain-general cognitive load on test-takers. To investigate this possibility, functional magnetic resonance imaging (fMRI) was used to identify and quantify the neural correlates of performance on current, international standardized methods of spelling assessment. Out-of-scanner testing was used to further examine differences in assessment results. Results provide converging evidence that: (a) the spelling assessments differed in the cognitive load placed on test-takers; (b) performance decreased with increasing cognitive load of the assessment; and (c) brain regions associated with working memory were more highly activated during performance of assessments that were higher in cognitive load. These findings suggest that assessment design should optimize the cognitive load placed on test-takers, to ensure students' results are an accurate reflection of their true levels of competency. PMID- 25818554 TI - Simulation of the capacity and precision of working memory in the hypodopaminergic state: Relevance to schizophrenia. AB - Working memory (WM) impairment has received attention as a behavioral characteristic of schizophrenia. Neurobiological studies have led to the hypothesis that a deficit in dopamine transmission through D1 receptors in the prefrontal cortex (PFC) is associated with WM impairment in schizophrenia. However, empirical approaches that aim to clarify the nature of the impairment and its underlying mechanism are difficult to enact, especially in unmedicated patients. By contrast, computational approaches using biologically plausible models have formed a powerful theoretical framework for the study of WM impairment in schizophrenia. This article attempts to directly connect neurobiological findings to the neuropsychological behaviors present in patients with schizophrenia. Using a biologically plausible prefrontal cortical circuit model, we simulated sustained activity during a simultaneous, multi-target WM task. We subsequently analyzed how dopaminergic modulation via D1 receptor activation alters the capacity and precision of WM and investigated the underlying mechanism. Hypodopaminergic modulation resulted in imprecision and a reduced capacity in WM primarily due to decreased N-methyl-d-aspartate (NMDA) conductance. Increasing NMDA conductance ameliorated both impairments. These results account for the mechanism that underlies WM impairments in schizophrenia and provide a theoretical basis for combination therapy with antipsychotic drugs and drugs that enhance NMDA receptor function, which is expected to be effective for the treatment of WM impairments in these patients. PMID- 25818555 TI - Is the future of meat palatable? Perceptions of in vitro meat as evidenced by online news comments. AB - OBJECTIVE: To understand current public perceptions of in vitro meat (IVM) in light of its potential to be a more environmentally sustainable alternative to conventional meat. DESIGN: A qualitative content analysis of the comments made on online news articles highlighting the development of IVM and the world's first IVM hamburger in August 2013. SETTING: News article comment sections across seven US-based online news sources (The New York Times, The Los Angeles Times, The Washington Post, The Wall Street Journal, USA Today, Cable News Network and National Public Radio). SUBJECTS: Four hundred and sixty-two commenters who made eight hundred and fourteen publicly available online comments addressing IVM. RESULTS: Key themes in commenter perceptions of IVM included environmental and public health benefits, but also negative themes such as IVM's status as an unnatural and unappealing food. Overall, the tone of comments was more negative than positive. CONCLUSIONS: Findings suggest that while the environmental and public health motivations for developing and in turn consuming IVM resonate with some segments of the population, others find that reasoning both uncompelling and problematic. Concerns about IVM as an unnatural and risky product also appear to be a significant barrier to public acceptance of IVM. Supporters of IVM may wish to begin to develop a regulatory strategy for IVM to build public trust and explore messaging strategies that cast IVM as a new technology with benefits to individuals rather than primarily a solution to global challenges. Those in the public health nutrition field can make an important contribution to the emerging public discussion about IVM. PMID- 25818556 TI - Scale-up protein separation on stainless steel wide bore toroidal columns in the type-J counter-current chromatography. AB - Manufacturing high-value added biotech biopharmaceutical products (e.g. therapeutic proteins) requires quick-to-develop, GMP-compliant, easy-to-scale and cost effective preparatory chromatography technologies. In this work, we describe the construction and testing of a set of 5-mm inner diameter stainless steel toroidal columns for use on commercially available preparatory scale synchronous J-type counter-current chromatography (CCC) machinery. We used a 20.2m long column with an aqueous two-phase system containing 14% (w/w) PEG1000 and 14% (w/w) potassium phosphate at pH 7, and tested a sample loading of 5% column volume and a mobile phase flow rate of 20ml/min. We then satisfactorily demonstrated the potential for a weekly protein separation and preparation throughput of ca. 11g based on a normal weekly routine for separating a pair of model proteins by making five stacked injections on a single portion of stationary phase with no stripping. Compared to our previous 1.6mm bore PTFE toroidal column, the present columns enlarged the nominal column processing throughput by nearly 10. For an ideal model protein injection modality, we observed a scaling up factor of at least 21. The 2 scales of protein separation and purification steps were realized on the same commercial CCC device. PMID- 25818557 TI - Systematic and practical solvent system selection strategy based on the nonrandom two-liquid segment activity coefficient model for real-life counter-current chromatography separation. AB - Solvent system selection is the first step toward a successful counter-current chromatography (CCC) separation. This paper introduces a systematic and practical solvent system selection strategy based on the nonrandom two-liquid segment activity coefficient (NRTL-SAC) model, which is efficient in predicting the solute partition coefficient. Firstly, the application of the NRTL-SAC method was extended to the ethyl acetate/n-butanol/water and chloroform/methanol/water solvent system families. Moreover, the versatility and predictive capability of the NRTL-SAC method were investigated. The results indicate that the solute molecular parameters identified from hexane/ethyl acetate/methanol/water solvent system family are capable of predicting a large number of partition coefficients in several other different solvent system families. The NRTL-SAC strategy was further validated by successfully separating five components from Salvia plebeian R.Br. We therefore propose that NRTL-SAC is a promising high throughput method for rapid solvent system selection and highly adaptable to screen suitable solvent system for real-life CCC separation. PMID- 25818558 TI - A size exclusion-reversed phase two dimensional-liquid chromatography methodology for stability and small molecule related species in antibody drug conjugates. AB - Antibody drug conjugates (ADCs) are complex therapeutic agents combining the specific targeting properties of antibodies and highly potent cytotoxic small molecule drugs to selectively eliminate tumor cells while limiting the toxicity to normal healthy tissues. One unique critical quality attribute of ADCs is the content of unconjugated small molecule drug present from either incomplete conjugation or degradation of the ADC. In this work, size exclusion chromatography (SEC) was coupled with reversed-phase (RP) HPLC in an online 2 dimensional chromatography format for identification and quantitation of unconjugated small molecule drugs and related small molecule impurities in ADC samples directly without sample preparation. The SEC method in the 1st dimension not only separated the small molecule impurities from the intact ADC, but also provided information about the size variants (monomer, dimer, aggregates, etc.) of the ADC. The small molecule peak from the SEC was trapped and sent to a RP HPLC in the 2nd dimension to further separate and quantify the different small molecule impurities present in the ADC sample. This SEC-RP 2D-LC method demonstrated excellent precision (%RSD<2.0), linearity (r(2)=0.9999), sensitivity (LOQ of 0.05MUg/mL of free drug in ADC sample) and accuracy (95-105% recovery of spiked samples). The 2D-LC method was further utilized to study the stability of an ADC drug product at different temperatures and pHs. Both small molecule degradation products and aggregation of the conjugate were observed in the stability samples and the degradation pathways of the ADC were investigated. This 2D-LC method offers a powerful tool for ADC characterization and provides valuable information for conjugation and formulation development. PMID- 25818560 TI - Long-term analyses in automated electrophoretic analyzer in hydrodynamically closed separation system. AB - Some potential problems that can occur during the analyses of complex samples by on-line combination of capillary isotachophoresis-capillary zone electrophoresis (cITP-CZE) in automated electrophoretic analyzer with the column-coupling configuration of the separation unit were studied in this work. The main focus was devoted on the reproducibility of important analytes' parameters (migration time, peak height and peak area) and also on the stability studies of selected low and high molecular mass analytes of inorganic/organic origins (bromate, vitamins, proteins) present at low concentration levels in different kinds of matrices (mineral water, human urine). Such study was carried out for the first time for the electrophoretic analyzer operating in the hydrodynamically closed separation system provided with contact-less conductivity detectors and UV detector in CZE step. Hydrodynamic and electroosmotic flows of the buffer solutions were suppressed and therefore, only the electrophoretic transport of ions was significant. Obtained results showed the different stabilities of the analytes and samples depending on their origin. The focus in the long-term analyses should be paid on the storage of the samples and on the regular changing the contents of electrolyte vessels to keep the electrolyte composition and separation conditions as constant as possible. PMID- 25818559 TI - Octadecyl functionalized core-shell magnetic silica nanoparticle as a powerful nanocomposite sorbent to extract urinary volatile organic metabolites. AB - In this present study, magnetic Fe3O4@SiO2 nanoparticles (MNPs) functionalized with octadecyl groups (Fe3O4@SiO2-C18 NPs) were synthesized, characterized and employed, for the first time, as powerful nanosorbent to extract endogenous volatile organic metabolites (EVOMs) namely, hexanal, heptanal, decanal, benzaldehyde, 4-heptanone, 5-methyl-2-furfural and phenol, described as potential biomarkers of cancer, from human urine. By using co-precipitation, surface modification methods, the carbon-ferromagnetic nanocomposite was synthesized and characterized by infrared spectrum (IR) and transmission electron microscopy (TEM). By coupling with gas chromatography-mass spectrometry (GC-qMS), a reliable, sensitive and cost-effective method was validated. To test the extraction efficiency of the carbon-ferromagnetic nanocomposite toward urinary EVOMs experimental variables affecting the extraction performance, including nanosorbent amount, adsorption time, elution time, and nature of elution solvent, were investigated in detail. The extraction process was performed by dispersing Fe3O4@SiO2-C18 NPs into working solution containing targeted VOMs, and into urine samples, and then eluted with an adequate organic solvent. The eluate was collected, concentrated and analyzed by GC-qMS. Under the optimized conditions, the LODs and LOQs achieved were in the range of 9.7-57.3 and 32.4-190.9ng/mL, respectively. Calibration curves were linear (r(2)>=0. 988) over the concentration ranges from 0.25 to 250ng/mL. In addition, a satisfying reproducibility was achieved by evaluating the intra- and inter-day precisions with relative standard deviations (RSDs) less than 3 and 11%, respectively. The method also afforded satisfactory results in terms of the matrix effect (72.8 96.1%) and recoveries (accuracy) higher than 75.1% for most of the studied EVOMs. The Fe3O4@SiO2-C18 NPs-based sorbent extraction combined with GC-qMS revealed that the new nanosorbent had a strong ability to retain the target metabolites providing a new, reliable and high throughput strategy for isolation of targeted EVOMs in human urine, suggesting their potential to be applied in other EVOMs. PMID- 25818561 TI - Sex differences in the effects of juvenile and adult diet on age-dependent reproductive effort. AB - Sexual selection should cause sex differences in patterns of resource allocation. When current and future reproductive effort trade off, variation in resource acquisition might further cause sex differences in age-dependent investment, or in sensitivity to changes in resource availability over time. However, the nature and prevalence of sex differences in age-dependent investment remain unclear. We manipulated resource acquisition at juvenile and adult stages in decorated crickets, Gryllodes sigillatus, and assessed effects on sex-specific allocation to age-dependent reproductive effort (calling in males, fecundity in females) and longevity. We predicted that the resource and time demands of egg production would result in relatively consistent female strategies across treatments, whereas male investment should depend sharply on diet. Contrary to expectations, female age-dependent reproductive effort diverged substantially across treatments, with resource-limited females showing much lower and later investment in reproduction; the highest fecundity was associated with intermediate lifespans. In contrast, long-lived males always signalled more than short-lived males, and male age-dependent reproductive effort did not depend on diet. We found consistently positive covariance between male reproductive effort and lifespan, whereas diet altered this covariance in females, revealing sex differences in the benefits of allocation to longevity. Our results support sex specific selection on allocation patterns, but also suggest a simpler alternative: males may use social feedback to make allocation decisions and preferentially store resources as energetic reserves in its absence. Increased calling effort with age therefore could be caused by gradual resource accumulation, heightened mortality risk over time, and a lack of feedback from available mates. PMID- 25818562 TI - Overexpressed Arabidopsis Annexin4 accumulates in inclusion body-like structures. AB - Large protein complexes form in the cytosol of prokaryotes and eukaryotes as assemblies of functional enzymes or aggregates of misfolded proteins. Their roles in the cell range from critical components of metabolism to disease-causing agents. We have observed a novel structure in the cells of transgenic Arabidopsis thaliana that appears to be a form of inclusion body. These long, spindle-shaped structures form when Arabidopsis are transformed to express high levels of the protein Annexin4 fused to a fluorescent protein. These structures, previously named darts, are visible in all cells of the plant throughout development. Darts take on a variety of morphologies including rings and figure-eights. These structures are not associated with the endomembrane system and are not membrane bounded. Darts appear to be insoluble aggregates of protein analogous to bacterial inclusion bodies and eukaryotic aggresomes. Similar structures have not been observed in untransformed plants, suggesting darts are artifacts of transgenic overexpression. PMID- 25818563 TI - High-resolution twin-ion metabolite extraction (HiTIME) mass spectrometry: nontargeted detection of unknown drug metabolites by isotope labeling, liquid chromatography mass spectrometry, and automated high-performance computing. AB - The metabolic fate of a compound can often determine the success of a new drug lead. Thus, significant effort is directed toward identifying the metabolites formed from a given molecule. Here, an automated and nontargeted procedure is introduced for detecting drug metabolites without authentic metabolite standards via the use of stable isotope labeling, liquid chromatography mass spectrometry (LC/MS), and high-performance computing. LC/MS of blood plasma extracts from rats that were administered a 1:1 mixture of acetaminophen (APAP) and (13)C6-APAP resulted in mass spectra that contained "twin" ions for drug metabolites that were not detected in control spectra (i.e., no APAP administered). Because of the development of a program (high-resolution twin-ion metabolite extraction; HiTIME) that can identify twin-ions in high-resolution mass spectra without centroiding (i.e., reduction of mass spectral peaks to single data points), 9 doublets corresponding to APAP metabolites were identified. This is nearly twice that obtained by use of existing programs that make use of centroiding to reduce computational cost under these conditions with a quadrupole time-of-flight mass spectrometer. By a manual search for all reported APAP metabolite ions, no additional twin-ion signals were assigned. These data indicate that all the major metabolites of APAP and multiple low-abundance metabolites (e.g., acetaminophen hydroxy- and methoxysulfate) that are rarely reported were detected. This methodology can be used to detect drug metabolites without prior knowledge of their identity. HiTIME is freely available from https://github.com/bjpop/HiTIME . PMID- 25818564 TI - Short sprints (30s) attenuate post-prandial blood glucose in young healthy males. AB - AIMS: Low-volume, high-intensity exercise is a time-efficient method of inducing physiological responses and may also improve glucose homeostasis. Therefore, effects of two different volumes of sprint-interval cycling on post-prandial blood glucose were assessed. METHODS: Twenty healthy young males undertook two Wingate anaerobic tests (2WAT), four Wingate anaerobic (4WAT) and without exercise (CON) 90 min after eating a standard meal. Blood glucose was examined at 60, 90, 105, 120, 135 and 150 min post-prandially. RESULTS: 2WAT and 4WAT both accelerated the decrease of blood glucose compared with CON (P<0.05). There were significant reductions at 120 (4.45 +/- 0.64 vs. 4.93 +/- 0.9 vs. 5.68 +/- 0.69), 135 (4.28 +/- 0.50 vs. 4.48 +/- 0.75 vs. 5.54 +/- 0.6) and 150 min (4.64 +/- 0.71 vs. 4.71 +/- 0.73 vs. 5.36 +/- 0.48, all P<0.05). Blood glucose at 120 min was lower after 2WAT than 4WAT (4.45 +/- 0.64 vs. 4.93 +/- 0.9, P<0.05), this producing a significant statistical interaction between groups and post-exercise time (P<0.005). CONCLUSIONS: 2WAT and 4WAT tests both accelerate the post prandial decrease in blood glucose in young healthy males, 2WAT being superior to 4WAT in producing this response, even though 2WAT is easier to perform and less time consuming. PMID- 25818178 TI - Pyrosequencing and de novo assembly of Antarctic krill (Euphausia superba) transcriptome to study the adaptability of krill to climate-induced environmental changes. AB - The Antarctic krill, Euphausia superba, has a key position in the Southern Ocean food web by serving as direct link between primary producers and apex predators. The south-west Atlantic sector of the Southern Ocean, where the majority of the krill population is located, is experiencing one of the most profound environmental changes worldwide. Up to now, we have only cursory information about krill's genomic plasticity to cope with the ongoing environmental changes induced by anthropogenic CO2 emission. The genome of krill is not yet available due to its large size (about 48 Gbp). Here, we present two cDNA normalized libraries from whole krill and krill heads sampled in different seasons that were combined with two data sets of krill transcriptome projects, already published, to produce the first knowledgebase krill 'master' transcriptome. The new library produced 25% more E. superba transcripts and now includes nearly all the enzymes involved in the primary oxidative metabolism (Glycolysis, Krebs cycle and oxidative phosphorylation) as well as all genes involved in glycogenesis, glycogen breakdown, gluconeogenesis, fatty acid synthesis and fatty acids beta oxidation. With these features, the 'master' transcriptome provides the most complete picture of metabolic pathways in Antarctic krill and will provide a major resource for future physiological and molecular studies. This will be particularly valuable for characterizing the molecular networks that respond to stressors caused by the anthropogenic CO2 emissions and krill's capacity to cope with the ongoing environmental changes in the Atlantic sector of the Southern Ocean. PMID- 25818565 TI - Astrocyte regulation of blood flow in the brain. AB - Neuronal activity results in increased blood flow in the brain, a response named functional hyperemia. Astrocytes play an important role in mediating this response. Neurotransmitters released from active neurons evoke Ca(2+) increases in astrocytes, leading to the release of vasoactive metabolites of arachidonic acid from astrocyte endfeet onto blood vessels. Synthesis of prostaglandin E2 (PGE2) and epoxyeicosatrienoic acids (EETs) dilate blood vessels, whereas 20 hydroxyeicosatetraenoic acid (20-HETE) constricts vessels. The release of K(+) from astrocyte endfeet may also contribute to vasodilation. Oxygen modulates astrocyte regulation of blood flow. Under normoxic conditions, astrocytic Ca(2+) signaling results in vasodilation, whereas under hyperoxic conditions, vasoconstriction is favored. Astrocytes also contribute to the generation of vascular tone. Tonic release of both 20-HETE and ATP from astrocytes constricts vascular smooth muscle cells, generating vessel tone. Under pathological conditions, including Alzheimer's disease and diabetic retinopathy, disruption of normal astrocyte physiology can compromise the regulation of blood flow. PMID- 25818567 TI - Malaria in Europe: a rare disease? PMID- 25818568 TI - Early outcomes of pulmonary valve replacement with the mitroflow bovine pericardial bioprosthesis. AB - BACKGROUND: Bovine pericardial valves are often used for pulmonary valve replacement (PVR) in patients with previously repaired congenital heart disease. Attention has recently focused on the safety of the Mitroflow (Sorin Group USA, Arvada, CO) bovine pericardial valve after a national alert describing several cases of sudden valve failure in young patients. In response, we reviewed our experience using the Mitroflow bioprosthesis for PVR. METHODS: Medical records were reviewed for all patients who underwent PVR using a Mitroflow valve at our center (2008-2013). RESULTS: The cohort included 84 patients with a median age of 18.3 years (range, 0.8-62.1 years) and weight of 48.4 kg (range, 5.7-167.8 kg). Indications for surgical intervention included native outflow tract insufficiency (59 patients), valved conduit failure (20 patients), and isolated prosthetic valve failure (5 patients). Median length of stay was 3 days (range, 2-13 days). There were no hospital deaths. Median follow-up was 2.4 years (range, 0.2-5.6 years). Pulmonary valve insufficiency and peak gradient increased with time. At latest follow-up, freedom from insufficiency greater than or equal to a moderate degree was 83%, and freedom from a peak gradient greater than or equal to 50 mm Hg was 92%. Reintervention was required in 4 patients. One patient experienced endocarditis and underwent surgical PVR (0.6 years after initial intervention). Three patients underwent transcatheter treatment for valve stenosis including PVR (at 4.2 and 4.4 years in 2 patients) and balloon valvuloplasty (at 5.2 years in the third patient). Kaplan-Meier freedom from reintervention at 5 years was 81%. CONCLUSIONS: Early outcomes using the Mitroflow bovine pericardial valve for PVR in children and adults with repaired congenital heart disease appear acceptable and similar to reported outcomes for other tissue valve options. Valve failure from premature structural deterioration was not observed. PMID- 25818566 TI - Perineurial glia. AB - Although the ultrastructure of peripheral nerves has been known for nearly 200 years, the developmental origins and functional roles of all five main components of these specialized nervous system conduits are still poorly understood. One of these understudied nerve elements, the perineurium, is a component of the blood nerve barrier and is essential for protecting axons and their associated Schwann cells from ionic flux, toxins, and infection. However, until recently, it was thought that this vital nerve tissue was derived from the mesoderm and simply served a structural/barrier function with no other influence on the development, maintenance, or regeneration of peripheral nerves. Recent work in zebrafish using in vivo time-lapse imaging, genetic manipulation, and laser axotomy is shedding light on the origin and roles of this previously ignored glial nerve component and is changing how we view development of the nervous system. PMID- 25818569 TI - Lung function predicts pulmonary complications regardless of the surgical approach. AB - BACKGROUND: Although postoperative predicted forced expiratory volume in the first second and diffusing capacity of lung (ppoFEV1% and ppoDLCO%, respectively) have been identified as independent predictors of postoperative pulmonary complications after open lobectomy, it has been suggested that their predictive abilities may not extend to patients undergoing minimally invasive lobectomy. METHODS: We evaluated outcomes in 805 patients undergoing isolated lobectomy through open (n = 585) or minimally invasive approaches (n = 220) using a prospective database. Demographic and physiologic data were extracted and compared with complications classified as pulmonary, cardiac, other, mortality, and any. RESULTS: Patients included 428 women and 377 men; mean age was 65.0 years. Minimally invasive patients were older (66.6 versus 64.3 years, p = 0.006), had better ppoFEV1% (71.5% versus 65.6%, p < 0.001) and performance status (0,1 94.1% versus 88.4%, p = 0.017), and less often underwent induction therapy (0.5% versus 4.8%, p = 0.003). Pulmonary and other complications were less common after minimally invasive lobectomy (3.6% versus 10.4%, p = 0.0034; 8.6% versus 15.8%, p = 0.008). Operative mortality occurred in 1.4% of minimally invasive patients and 3.9% of open patients (p = 0.075). Pulmonary complication incidence was related to predicted postoperative lung function for both minimally invasive and open approaches. On multivariate analysis with stratification for stage, ppoFEV1% and ppoDLCO% were predictive of pulmonary complications for both minimally invasive and open approaches. CONCLUSIONS: Our results suggest that the predictive abilities of ppoFEV1% and ppoDLCO% are retained for minimally invasive lobectomy and can be used to estimate the risk of pulmonary complications. PMID- 25818570 TI - Results of palliation with an initial modified Blalock-Taussig shunt in neonates with single ventricle anomalies associated with restrictive pulmonary blood flow. AB - BACKGROUND: We report our current-era results after placement of a modified Blalock-Taussig shunt (mBTS) as the first surgery in the multistage palliation strategy of neonates born with single ventricle (SV) anomalies associated with restrictive pulmonary blood flow. METHODS: Between 2002 and 2012, 174 neonates with SV underwent mBTS. Competing risks analysis modeled events after mBTS (death or transplantation, transition to Glenn) and subsequently after Glenn (death or transplantation, transition to Fontan) and examined risk factors affecting outcomes. RESULTS: Competing risks analysis showed that 2 years after mBTS 27% of patients had died or received transplantation and 73% had undergone Glenn. Five years after Glenn, 6% had died, 73% had undergone Fontan, and 21% were alive awaiting Fontan. Overall survival 8 years after mBTS was 68%. On multivariable analysis, risk factors for mortality were increased shunt size to weight ratio (hazard ratio [HR]:1.2 per 0.1 ratio increase [1.0 to 1.4], p = 0.015), postoperative extracorporeal membrane oxygenation (HR: 4.0 [2.2 to 7.4], p < 0.001), chromosomal and extracardiac malformations (HR: 2.5 [1.3 to 5.0], p = 0.008), cardiopulmonary bypass use (HR: 2.5 [1.3 to 4.5], p = 0.004), and underlying pulmonary atresia with intact ventricular septum (PAIVS) or atrial isomerism (HR: 2.1 [1.1 to 4.2], p = 0.035). CONCLUSIONS: Palliation outcomes with mBTS in SV patients trail behind the generally improved results of congenital heart surgery. Several anatomic and patient-related factors continue to affect survival. Mortality is high in low weight neonates in whom a balance between overcirculation due to large shunt and low pulmonary blood flow and risk of occlusion due to small shunt is difficult to attain. Patients with chromosomal and extracardiac malformations, atrial isomerism, and PAIVS continue to be the most challenging and are associated with higher hospital and interstage mortality. PMID- 25818571 TI - Bronchoscopic management of patients with symptomatic airway stenosis and prognostic factors for survival. AB - BACKGROUND: Interventional bronchoscopy is effective in the management of patients with symptomatic airway obstruction for both malignant and benign conditions. The main aim of this study is to report our experience with emergency interventional bronchoscopy in patients with symptomatic airway obstruction and identify prognostic factors for survival. METHODS: This is a retrospective observational study of patients undergoing emergency interventional bronchoscopy over a 4-year period. Survival times were analyzed separately for patients with benign and malignant airway obstruction by the Kaplan-Meier method. RESULTS: Between June 2009 and July 2013, 168 emergency interventional bronchoscopies were performed in 112 patients for airway obstruction. The median age was 63 years (range, 20 to 86), and 91 patients (54%) patients were female. Seventy-two cases (43%) had airway obstruction due to malignant disease. There were 3 in-hospital deaths (2.7%). Median survival of the study population was 5.6 months (range, 0 to 51) with a median follow-up of 7.3 months (range, 0 to 51). Median survival for patients with malignant airway obstruction was 3.5 months (range, 0 to 21), and 9.8 months (range, 0.1 to 51) for those with benign disease. Airway intervention facilitated palliative chemotherapy in 32 patients (44%) of those with malignant airway obstruction. At multivariate analysis in patients with malignant airway obstruction, presence of stridor (hazard ratio 1.919, 95% confidence interval: 1.082 to 3.404, p = 0.026) and not receiving postprocedure chemotherapy (hazard ratio 2.05, 95% confidence interval: 1.156 to 3.636, p = 0.014) were independent prognostic factors for death. CONCLUSIONS: Emergency interventional bronchoscopy for airway obstruction is safe, relieved symptoms, and facilitated palliative chemotherapy, which improved survival. PMID- 25818572 TI - Marfan syndrome is associated with recurrent dissection of the dissected aorta. AB - BACKGROUND: Recurrent dissection of a previously dissected aortic segment has been reported as a rare, late complication in single case reports. The infrequency of this event makes informed risk assessment in an individual patient challenging. METHODS: To investigate this issue we examined the database of the Massachusetts General Hospital Thoracic Aortic Center between January 1, 2003 and December 31, 2012. A retrospective review was performed to identify patients with both (1) an acute aortic dissection after a prior aortic dissection and (2) evidence of a new dissection within a previously dissected aortic segment creating a triple lumen aorta. Data were reviewed to identify factors predisposing to dissection of a previously dissected aortic segment. RESULTS: Over a 10-year period we identified 5 cases of aortic dissection within a previously dissected aortic segment presenting as a new acute aortic syndrome. On average, the recurrent dissection occurred 1 decade after the first aortic dissection (mean = 9.8 +/- 1.9 years). Patients identified in this series were significantly younger at first dissection and more likely to carry the diagnosis of Marfan syndrome. Aortic aneurysm diameter was quantified before and after the new dissection event and demonstrated a marked increase in aneurysmal size (mean increase = 1.6 +/- 0.3 cm). CONCLUSIONS: We conclude that medial degeneration, as seen in the Marfan aorta, represents a predisposing factor for recurrent dissection of the dissected aorta. Our data indicate that double aortic dissections cause significant arterial destabilization and a low threshold for surgical intervention is appropriate. PMID- 25818573 TI - Heparin reduces overcirculation-induced pulmonary artery remodeling through p38 MAPK in piglet. AB - BACKGROUND: Artery remodeling is the principal change of pulmonary artery hypertension. Heparin has been shown to inhibit vascular smooth muscle cell proliferation. We hypothesized that heparin may modulate vascular remodeling in pulmonary artery hypertension, and explored the mechanism. METHODS: A localized overcirculation-induced artery remodeling was created in piglets by anastomosing the left lower lobe pulmonary artery (LLLPA) to the thoracic aortic artery. Piglets were treated with heparin or saline for 4 weeks. Hemodynamic data were collected, and histology of the lung was assessed. We investigated the expressions of several candidate genes in lung and further observed the involvement of P38 mitogen-activated protein kinases (MAPK). The effects of heparin on the growth of cultured pulmonary arterial vascular smooth muscle cell and P38 MAPK expression were further determined under various conditions. RESULTS: Four weeks after the shunt setup, overcirculation caused significant LLLPA remodeling, pressure increase, and pulmonary vascular resistance increase, and LLLPA flow reduction compared with that immediately after the shunt setup. Heparin reduced the LLLPA remodeling, pressure, and pulmonary vascular resistance, and increased the LLLPA flow compared with that not heparin treated. Shunt and heparin treatment did not change the piglet's systemic hemodynamics. Shunt increased the expression of P38 MAPK and heparin decreased its expression in the shunted LLLPA. Both heparin and P38 MAPK inhibitor suppressed VSMC growth and P38 MAPK expression in the cultured VSMC, but they did not present additive effects when the two treatments were combined. CONCLUSIONS: Heparin reduces overcirculation-induced pulmonary artery remodeling through a P38 MAPK-dependent pathway. PMID- 25818574 TI - Reduced transfusion requirement with use of fresh whole blood in pediatric cardiac surgical procedures. AB - BACKGROUND: Pediatric patients undergoing cardiac operations are at high risk for blood loss and transfusion. A practice intended to reduce transfusion using a standard order of 2 units fresh whole blood (< 48 hours from donation) for elective cardiac operations in patients younger than 2 years of age was in place from 1995 to 2010. The objective of this study was to describe blood use in this population and to compare the results with those in published reports describing the use of blood components exclusively for transfusion. METHODS: Retrospective data from a surgical registry and blood bank records for 15 consecutive years were analyzed. Transfusion requirements were identified as donor exposures for the day of operation and the next postoperative day. Transfusions were fresh whole blood, packed red blood cells, platelets, and cryoprecipitate. Donor exposures for subgroups according to procedure and age were compared with those in published reports. RESULTS: The cohort consisted of 4,111 patients with a median age of 94 days and a median weight of 4.4 kg. The median donor exposure was 2 (range, 0 to 28). Younger patients having complex procedures had the most donor exposures. Fewer donor exposures were incurred in all subgroups compared with reports of component use in the literature. CONCLUSIONS: The use of fresh whole blood for cardiac operations in children younger than 2 years old reduces donor exposures compared with published reports of component use. PMID- 25818575 TI - The discrepancy between central foveal thickness and best corrected visual acuity in cystoid macular edema secondary to central retinal vein occlusion after intravitreal lucentis(r) injection. AB - Cystoid macular edema is a common retinal disorder with the potential for significant vision-related morbidity, and intravitreal lucentis((r)) injection is confirmed to be an effective therapy approach. In the present study, we investigated the discrepancy between central foveal thickness and best corrected visual acuity in such lesions and infered that intravitreal lucentis((r)) injection may help the visual function, related to the renewal of cells. PMID- 25818576 TI - Prophylactic treatment with melatonin before recurrent neonatal seizures: Effects on long-term neurobehavioral changes and the underlying expression of metabolism related genes in rat hippocampus and cerebral cortex. AB - Although it has been suggested that the protective effect of melatonin against seizure-induced neurotoxicity involves inhibition of neuronal lipid peroxidation, current data concerning the exact molecular mechanism are still limited. This study was undertaken to investigate the changes in neurobehavioral, cognitive and lipid metabolism-related gene expressions in both hippocampus and cerebral cortex of rats subjected to recurrent neonatal seizures, and the effects of melatonin treatment before seizure (55mg/kg, 1mg/ml). 6-day-old (P6) SD rats were randomly divided into four groups of control (CONT, the same below), melatonin treated control (Mel), recurrent neonatal seizure (RS) and melatonin and RS combination treatment (Mel+RS). Neurological behavioral parameters of brain damage (plane righting reflex, negative geotaxis reaction reflex, Cliff avoidance reflex, forelimb suspension reflex) were observed on P31. Morris water maze test was performed during P29-P35. Then the protein levels of ACAT1, Cathepsin-E and Ca(2+)/calmodulin-dependent protein kinase II (CAMK II) in hippocampus and cerebral cortex were detected by western blot method. As expected, RS group showed a significant delay or reduce of the four reflexes, as well as bad performance in the Morris water maze test. Flurothyl-induced neurobehavioral toxicology was blocked by pre-treatment with melatonin. In parallel with these behavioral changes, gene expression by western blot method demonstrated that rats pretreated with melatonin (Mel+RS) showed a significant down-regulated expression of ACAT-1, Cathepsin-E and up-regulated CAMK II in hippocampus and cerebral cortex when compared with RS group. Our findings provide support for ACAT 1/Cathepsin-E as well as CaMK II being potential targets for the treatment of neonatal seizure-induced brain damage by melatonin. PMID- 25818577 TI - Nasal immunization with M cell-targeting ligand-conjugated ApxIIA toxin fragment induces protective immunity against Actinobacillus pleuropneumoniae infection in a murine model. AB - Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia and severe economic loss in the swine industry has been caused by the infection. Therefore, the development of an effective vaccine against the bacteria is necessary. ApxII toxin, among several virulence factors expressed by the bacteria, is considered to be a promising vaccine candidate because ApxII toxin not only accompanies cytotoxic and hemolytic activities, but is also expressed in all 15 serotypes of bacteria except serotypes 10 and 14. In this study, we identified the peptide ligand capable of targeting the ligand-conjugated ApxIIA #5 fragment antigen to nasopharynx-associated lymphoid tissue. It was found that nasal immunization with ligand-conjugated ApxIIA #5 induced efficient mucosal and systemic immune responses measured at the levels of antigen-specific antibodies, cytokine-secreting cells after antigen exposure, and antigen-specific lymphocyte proliferation. More importantly, the nasal immunization induced protective immunity against nasal challenge infection of the bacteria, which was confirmed by histopathological studies and bacterial clearance after challenge infection. Collectively, we confirmed that the ligand capable of targeting the ligand conjugated antigen to nasopharynx-associated lymphoid tissue can be used as an effective nasal vaccine adjuvant to induce protective immunity against A. pleuropneumoniae infection. PMID- 25818578 TI - Complete genome sequence of canine astrovirus with molecular and epidemiological characterisation of UK strains. AB - Astroviruses are a common cause of gastroenteritis in children worldwide. These viruses can also cause infection in a range of domestic and wild animal species. Canine astrovirus (CaAstV) was first identified in the USA, and has since been reported in dogs from Europe, the Far East and South America. We sought to determine whether CaAstV is circulating in the UK dog population, and to characterise any identified strains. Stool samples were collected from pet dogs in the UK with and without gastroenteritis, and samples were screened for CaAstV by qPCR. Four CaAstV positive samples were identified from dogs with gastroenteritis (4/67, 6.0%), whereas no samples from healthy dogs were positive (p<0.001). Sequencing of the capsid sequences from the four CaAstV strains found significant genetic heterogeneity, with only 80% amino acid identity between strains. The full genome sequence of two UK CaAstV strains was then determined, confirming that CaAstV conforms to the classic genome organisation of other astroviruses with ORF1a and ORF1b separated by a frameshift and ORF2 encoding the capsid protein. This is the first report describing the circulation of CaAstV in UK dogs with clinical signs of gastroenteritis, and the first description of the full-length genomes of two CaAstV strains. PMID- 25818579 TI - Determination of common genetic variants within the non-structural proteins of foot-and-mouth disease viruses isolated in sub-Saharan Africa. AB - The non-structural proteins of foot-and-mouth disease virus (FMDV) are responsible for RNA replication, proteolytic processing of the viral polyprotein precursor, folding and assembly of the structural proteins and modification of the cellular translation apparatus. Investigation of the amino acid heterogeneity of the non-structural proteins of seventy-nine FMDV isolates of SAT1, SAT2, SAT3, A and O serotypes revealed between 29 and 62% amino acid variability. The Leader protease (L(pro)) and 3A proteins were the most variable whilst the RNA-dependent RNA polymerase (3D(pol)) the most conserved. Phylogeny based on the non structural protein-coding regions showed separate clusters for southern African viruses for both the L(pro) and 3C protease (3C(pro)) and sequences unique to this group of viruses, e.g. in the 2C and 3C(pro) proteins. These groupings were unlike serotype groupings based on structural protein-coding regions. The amino acid substitutions and the nature of the naturally occurring substitutions provide insight into the functional domains and regions of the non-structural proteins that are critical for structure-function. The L(pro) of southern African SAT type isolates differed from A, O and SAT isolates in northern Africa, particularly in the auto-processing region. Three-dimensional structures of the 3C protease (3C(pro)) and 3D(pol) showed that the observed variation does not affect the enzymatic active sites or substrate binding sites. Variation in the 3C(pro) cleavage sites demonstrates broad substrate specificity. PMID- 25818580 TI - Multivariate optimization of the denitration reaction of nitrocelluloses for safer determination of their nitrogen content. AB - The nitrogen content is of paramount importance to predict the explosive or non explosive character of nitrocellulose (NC), and hence its applications. There are still quite a few really effective analytical methodologies allowing its determination, due to great NC molecular complexity. One of the approaches giving access to nitrogen content consists in releasing the nitrogenic moieties through alkaline hydrolysis. For the first time, this work reports on the optimization of the denitration yield by means of an experimental design within reasonable ranges of sodium hydroxide concentration, temperature, and time. The experiments were conducted with non-explosive and explosive NC standards. An original capillary electrophoresis (CE) method was used to monitor nitrite and nitrate ions released during hydrolysis. Because of their very different chemical properties, denitration conditions were optimized separately for both sub-classes of NCs to maximize their denitration yields, applying desirability analysis on modeled denitration yields. Mild, safe, and robust optimized conditions were drawn. The denitration yields (95% for non-explosive NCs, 92% for explosive NCs) experimentally obtained under these conditions were in good agreement with model predictions. For practical purposes, correction factors based on these maximal denitration yields are proposed for the first time to correct the determination of nitrogen content, based on preliminary alkaline denitration. This new strategy was successfully applied to determine nitrogen contents of NCs in real explosive samples (smokeless gunpowders). PMID- 25818581 TI - Testing photogrammetry-based techniques for three-dimensional surface documentation in forensic pathology. AB - Three-dimensional surface technologies particularly close range photogrammetry and optical surface scanning have recently advanced into affordable, flexible and accurate techniques. Forensic postmortem investigation as performed on a daily basis, however, has not yet fully benefited from their potentials. In the present paper, we tested two approaches to 3D external body documentation - digital camera-based photogrammetry combined with commercial Agisoft PhotoScan((r)) software and stereophotogrammetry-based Vectra H1((r)), a portable handheld surface scanner. In order to conduct the study three human subjects were selected, a living person, a 25-year-old female, and two forensic cases admitted for postmortem examination at the Department of Forensic Medicine, Hradec Kralove, Czech Republic (both 63-year-old males), one dead to traumatic, self inflicted, injuries (suicide by hanging), the other diagnosed with the heart failure. All three cases were photographed in 360 degrees manner with a Nikon 7000 digital camera and simultaneously documented with the handheld scanner. In addition to having recorded the pre-autopsy phase of the forensic cases, both techniques were employed in various stages of autopsy. The sets of collected digital images (approximately 100 per case) were further processed to generate point clouds and 3D meshes. Final 3D models (a pair per individual) were counted for numbers of points and polygons, then assessed visually and compared quantitatively using ICP alignment algorithm and a cloud point comparison technique based on closest point to point distances. Both techniques were proven to be easy to handle and equally laborious. While collecting the images at autopsy took around 20min, the post-processing was much more time-demanding and required up to 10h of computation time. Moreover, for the full-body scanning the post-processing of the handheld scanner required rather time-consuming manual image alignment. In all instances the applied approaches produced high-resolution photorealistic, real sized or easy to calibrate 3D surface models. Both methods equally failed when the scanned body surface was covered with body hair or reflective moist areas. Still, it can be concluded that single camera close range photogrammetry and optical surface scanning using Vectra H1 scanner represent relatively low-cost solutions which were shown to be beneficial for postmortem body documentation in forensic pathology. PMID- 25818582 TI - Advanced magnetic resonance spectroscopy and imaging techniques applied to brain development and animal models of perinatal injury. AB - Magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) are widely used in the field of brain development and perinatal brain injury. Due to technical progress the magnetic field strength (B0) of MR systems has continuously increased, favoring (1)H-MRS with quantification of up to 18 metabolites in the brain and short echo time (TE) MRI sequences including phase and susceptibility imaging. For longer TE techniques including diffusion imaging modalities, the benefits of higher B0 have not been clearly established. Nevertheless, progress has also been made in new advanced diffusion models that have been developed to enhance the accuracy and specificity of the derived diffusion parameters. In this review, we will describe the latest developments in MRS and MRI techniques, including high-field (1)H-MRS, phase and susceptibility imaging, and diffusion imaging, and discuss their application in the study of cerebral development and perinatal brain injury. PMID- 25818583 TI - Disruption of Tgfbr2 in odontoblasts leads to aberrant pulp calcification. AB - Transforming growth factor beta (TGF-beta) signaling has been implicated in dentin formation and repair; however, the molecular mechanisms underlying dentin formation remain unclear. To address the role of TGF-beta signaling in dentin formation, we analyzed odontoblast-specific Tgfbr2 conditional knockout mice. The mutant mice had aberrant teeth with thin dysplastic dentin and pulpal obliteration, similar to teeth from human patients with dentinogenesis imperfecta type II and dentin dysplasia. In mutant, the odontoblasts lost their cellular polarity, and matrix secretion was disrupted after mantle dentin formation. As a consequence, the amount of predentin decreased significantly, and an ectopic fibrous matrix was formed below the odontoblast layer. This matrix gradually calcified and obliterated the pulp chamber with increasing age. Immunohistochemistry revealed decreased expression of alkaline phosphatase in mutant odontoblasts. In mutant dentin, Dsp expression was reduced, but Dmp1 expression increased significantly. Collagen type I, biglycan, and Dsp were expressed in the ectopic matrix. These results suggest that loss of responsiveness to TGF-beta in odontoblasts results in impaired matrix formation and pulpal obliteration. Our study indicates that TGF-beta signaling plays an important role in dentin formation and pulp protection. Furthermore, our findings may provide new insight into possible mechanisms underlying human hereditary dentin disorders and reparative dentin formation. PMID- 25818584 TI - Norepinephrine Regulates Condylar Bone Loss via Comorbid Factors. AB - Degenerative changes of condylar subchondral bone occur frequently in temporomandibular disorders. Although psychologic stresses and occlusal abnormalities have been implicated in temporomandibular disorder, it is not known if these risks represent synergistic comorbid factors that are involved in condylar subchondral bone degradation that is regulated by the sympathetic nervous system. In the present study, chronic immobilization stress (CIS), chemical sympathectomy, and unilateral anterior crossbite (UAC) were sequentially applied in a murine model. Norepinephrine contents in the subjects' serum and condylar subchondral bone were detected by ELISA; bone and cartilage remodeling parameters and related gene expression in the subchondral bone were examined. Subchondral bone loss and increased subchondral bone norepinephrine level were observed in the CIS and UAC groups. These groups exhibited decreased bone mineral density, volume fraction, and bone formation rate; decreased expressions of osterix, collagen I, and osteocalcin; but increased trabecular separation, osteoclast number and surface, and RANKL expression. Combined CIS + UAC produced more severe subchondral bone loss, higher bone norepinephrine level, and decreased chondrocyte density and cartilage thickness when compared to CIS or UAC alone. Sympathectomy simultaneously prevented subchondral bone loss and decreased bone norepinephrine level in all experimental subgroups when compared to the vehicle-treated counterparts. Norepinephrine also decreased mRNA expression of osterix, collagen I, and osteocalcin by mesenchymal stem cells at 7 and 14 d of stimulation and increased the expression of RANKL and RANKL/OPG ratio by mesenchymal stem cells at 2 h. In conclusion, CIS and UAC synergistically promote condylar subchondral bone loss and cartilage degradation; such processes are partially regulated by norepinephrine within subchondral bone. PMID- 25818585 TI - Dental Follicle Cells Participate in Tooth Eruption via the RUNX2-MiR-31-SATB2 Loop. AB - Cleidocranial dysplasia (CCD) is characterized by the runt-related transcription factor 2 (RUNX2) mutation, which results in delayed tooth eruption due to disturbed functions of dental follicle. Accumulating evidence has revealed a key regulatory circuit, including RUNX2, miR-31, and special AT-rich binding protein 2 (SATB2) acting in concert in mesenchymal stem cell homeostasis and functions. However, whether such a regulatory loop works in dental follicle cells (DFCs) remains unknown. Herein, we investigated the roles of RUNX2-miR-31-SATB2 in DFCs from patients with CCD (DFCs-CCD) to advance our understanding regarding physical tooth eruption. We identified a novel mutation on exon 5 (c.634T>G, p.T212P) in RUNX2 via exome sequencing in the CCD patient with typical clinical presentations. Compared with DFCs from healthy donors, DFCs-CCD displayed significantly lower osteogenic, osteoclast-inductive, and matrix-degrading capacities and had lower RUNX2 (a transcriptional inhibitor of miR-31), higher miR-31, and downregulated SATB2. Lower ratios of RANKL/OPG and RANKL/RANK, as well as decreased expression of matrix metalloproteinase 9 (MMP9) and matrix metalloproteinase 2 (MMP2), would lead to inactivation of osteoclasts and suppression of bone matrix remodeling in DFCs-CCD. Furthermore, the roles of the RUNX2-miR-31-SATB2 loop in DFCs-CCD were revealed by endogenous miR-31 knockdown, which resulted in increased SATB2 and RUNX2, as well as osteoclast-inductive and matrix degradation capacities. Conversely, SATB2, RUNX2, MMP9, MMP2, and osteoclast-inductive factors expression declined upon ectopic miR-31 overexpression in normal DFCs. Importantly, neonatal mice with in vivo siRUNX2 delivery exhibited less activated osteoclasts around dental follicles and delayed tooth eruption. Together, these results suggest that RUNX2 mutation/haploinsufficiency disturbs osteoclast-inductive signaling in DFCs, which may be responsible for delayed tooth eruption in CCD patients. Manipulation of the RUNX2-miR-31-SATB2 loop may be a potential way to facilitate tooth eruption in CCD patients. PMID- 25818586 TI - Impact of Patient Compliance on Tooth Loss during Supportive Periodontal Therapy: A Systematic Review and Meta-analysis. AB - Periodontal treatment consists of active periodontal therapy (APT) and supportive periodontal therapy (SPT). Regular SPT is recommended to prevent and control the occurrence of periodontal disease following APT. A patient's compliance with SPT is considered one of the most important factors affecting long-term periodontal status. Tooth loss is generally considered the final outcome of periodontitis. This review aimed to analyze the relationship between patient compliance with regular SPT and tooth loss. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline for systematic reviews was used. A search of articles was conducted using MEDLINE (PubMed) and other databases. Quality assessments of selected studies were performed. To assess the effect of compliance on tooth loss during SPT, pooled risk ratio of tooth loss (RRTL) was used as the primary outcome. Pooled risk difference of tooth loss (RDTL) and weighted mean difference of tooth loss rate (WDTLR) were used as secondary outcomes. Subgroup analysis and meta-regression were conducted to evaluate the effects of different variables. In total, 710 articles were screened. Eight studies, which had a regular-compliance (RC) group and an erratic-compliance (EC) group with at least a 5-y follow-up period, qualified for the meta-analysis. The risk of tooth loss in the RC group was significantly lower than that in the EC group (pooled RRTL: 0.56 [confidence interval (CI): 0.38, 0.82]; pooled RDTL: 0.05 [CI: -0.08, -0.01]). The definition of compliance was a variable significantly related to risk ratio of tooth loss. Patients in the RC group had significantly lower tooth loss rate during SPT than did patients in the EC group (WDTLR: -0.12 [CI: -0.19, -0.05]). Teeth have less risk of being lost if patients are more compliant with supportive periodontal therapy. However, unidentified variables causing data heterogeneity and affecting the risk of tooth loss may have been present. More well-controlled prospective studies are needed in the future. PMID- 25818587 TI - NICE guidance on pomalidomide for relapsed and refractory multiple myeloma previously treated with lenalidomide and bortezomib. PMID- 25818588 TI - Targeting the annexin 1-formyl peptide receptor 2/ALX pathway affords protection against bacterial LPS-induced pathologic changes in the murine adrenal cortex. AB - Hypothalamo-pituitary-adrenocortical dysfunction contributes to morbidity and mortality in a high proportion of patients with sepsis. Here, we provide new insights into the underlying adrenal pathology. Using a murine model of endotoxemia (LPS injection), we demonstrate that adrenal insufficiency is triggered early in the disease. LPS induced a local inflammatory response in the adrenal gland within 4 hours of administration, coupled with increased expression of mRNAs for annexin A1 (AnxA1) and the formyl peptide receptors [(Fprs) 1, 2, and 3], a loss of lipid droplets in cortical cells (index of availability of cholesterol, the substrate for steroidogenesis), and a failure to mount a steroidogenic response to ACTH. Deletion of AnxA1 or Fpr2/3 in mice prevented lipid droplet loss, but not leukocyte infiltration. LPS increased adrenal myeloid differentiation primary response gene 88 and TLR2 mRNA expression, but not lymphocyte antigen 96 or TLR4. By contrast, neutrophil depletion prevented leukocyte infiltration and increased AnxA1, Fpr1, and Fpr3 mRNAs but had no impact on lipid droplet loss. Our novel data demonstrate that AnxA1 and Fpr2 have a critical role in the manifestation of adrenal insufficiency in this model, through regulation of cholesterol ester storage, suggesting that pharmacologic interventions targeting the AnxA1/FPR/ALX pathway may provide a new approach for the maintenance of adrenal steroidogenesis in sepsis. PMID- 25818590 TI - The review articles, letters, potpourri and a list of the articles together with an extended abstract will be published in hard copy whilst the rest of the Journal appears on line. PMID- 25818591 TI - Introduction to Computer Enhanced Visual Learning (CEVL). PMID- 25818592 TI - CEVL training for coronal/distal shaft hypospadias repair: a guide for attendings, residents, and OR staff. PMID- 25818589 TI - Microphthalmia-associated transcription factor in melanoma development and MAP kinase pathway targeted therapy. AB - Malignant melanoma is a neoplasm of melanocytes, and the microphthalmia associated transcription factor (MITF) is essential for the existence of melanocytes. MITF's relevance for this cell lineage is maintained in melanoma, where it is an important regulator of survival and balances melanoma cell proliferation with terminal differentiation (pigmentation). The MITF gene is amplified in ~20% of melanomas and MITF mutation can predispose to melanoma development. Furthermore, the regulation of MITF expression and function is strongly linked to the BRAF/MEK/ERK/MAP-kinase (MAPK) pathway, which is deregulated in >90% of melanomas and central target of current therapies. MITF expression in melanoma is heterogeneous, and recent findings highlight the relevance of this heterogeneity for the response of melanoma to MAPK pathway targeting drugs, as well as for MITF's role in melanoma progression. This review aims to provide an updated overview on the regulation of MITF function and plasticity in melanoma with a focus on its link to MAPK signaling. PMID- 25818593 TI - The acceptability of contraception task-sharing among pharmacists in Canada--the ACT-Pharm study. AB - BACKGROUND: Access to prescription contraception is often limited by the availability of physicians, particularly in rural areas. Pharmacists are available but are not authorized in Canada to prescribe contraceptives, an innovation proved successful in the United States. It is unknown whether Canadian pharmacists, particularly those in rural areas, are willing to adopt this innovation and what barriers and facilitators they predict. We explored the acceptability and feasibility for independent provision of contraception at pharmacies throughout British Columbia (BC). METHODS: This mixed-methods study used validated questionnaires followed by optional structured interviews among all rural, and a sample of urban, community pharmacies in BC. Analyses use descriptive, logistic regression and qualitative thematic evaluation. RESULTS: Responding community pharmacies represent all geographic health regions of BC and the range of pharmacy business models. Respondents reported a mean of 17 years in practice. Seventy percent of pharmacies reported a private counseling area. Over 80%, including pharmacies in all regions, indicated willingness to prescribe hormonal contraceptives. Factors associated with willingness to prescribe were comfort using a protocol to assess sexual history, confidence about staff availability and public acceptability, and fewer years in practice. Pharmacists requested training in assessment protocols and liability issues prior to implementation. INTERPRETATION: Pharmacies from all areas throughout BC, responded and report a high degree of acceptability and feasibility for independent prescription of hormonal contraceptives. As pharmacists are often the most accessible health professional in rural areas, pharmacist provision of hormonal contraceptives has potential to improve access to contraception. PMID- 25818594 TI - Immediate postabortion initiation of levonorgestrel implants reduces the incidence of births and abortions at 2 years and beyond. AB - OBJECTIVES: The aims of this study were to compare immediate postabortion uptake of recently subsidized (no-cost) levonorgestrel-releasing implants with already available intrauterine and shorter-acting methods and to compare the incidence of subsequent pregnancies (ending in birth or abortion) within 2 years. STUDY DESIGN: Retrospective chart review of 4698 women attending a New Zealand public hospital abortion clinic over 2 years (2010-2012) to describe postabortion contraceptive choice, with follow-up via clinic and national births records to assess subsequent pregnancies at 12, 24, 36, and 48 months. RESULTS: Twenty percent of the cohort (934/4698) received an implant, 26% an intrauterine method (927 copper intrauterine device, 301 levonorgestrel-releasing intrauterine system [LNG-IUS]), and 54% chose other shorter-acting methods (2536/4698). Method choice was significantly associated with age, ethnicity, and pregnancy history (p < .001). At 24 months, the unadjusted incidence of subsequent abortion for implant users was 3.8% (95% confidence interval [CI] = 2.5-5.0) and 11.6% (95% CI = 10.3 12.8) for those choosing other short-acting methods. By 48 months, 6.6% of implant users had a subsequent abortion (compared with 18.3% for short-acting methods). The incidence of continued pregnancy at 24 months was 6.3% (95% CI = 4.4-8.1) for implant users and 15.7% (95% CI = 14-17.2) for those choosing other short-acting methods. Adjusted hazard ratios (HRs) for subsequent abortion were lowest for women initiating an implant (HR = 0.26, 95% CI = 0.20-0.35) or LNG-IUS (HR = 0.26, 0.16-0.44, reference group: short-acting methods). CONCLUSIONS: Immediate postabortion insertion of an implant significantly reduced rates of subsequent pregnancy for at least 2 years. Abortion service providers should ensure women have barrier-free access to all long-acting reversible contraceptions to delay or prevent pregnancy. IMPLICATIONS: Initiation of an levonorgestrel implant immediately postabortion was associated with a 74% reduction in subsequent abortion over the next 4 years compared with use of short acting methods. Implants were popular among adolescents-a group at high-risk of subsequent pregnancy, and who have not historically been considered appropriate candidates for intrauterine contraceptive methods. PMID- 25818595 TI - Comparison of the finger counting method, the Broselow tape and common weight estimation formulae in Filipino children after Typhoon Haiyan. AB - OBJECTIVES: We sought to evaluate commonly used paediatric weight estimation techniques in a sample of children in the Philippines. METHODS: We prospectively collected age, height and weight data for a sample of 207 children aged 1-9 years seen during a medical aid trip. Weights were estimated using the finger counting method, the Broselow method and four formulae. Bland-Altman analysis was performed to evaluate agreement with measured weight. RESULTS: Mean difference and range of agreement in kilograms were as follows: 0.6 (95% CI 0.1-1.1) and 14.9 (95% CI 13.1-16.7) for the Broselow method; 1.1 (95% CI 0.5-1.7) and 17.3 (95% CI 15.2-19.3) for the traditional APLS formula; 3.1 (95% CI 2.4-3.7) and 18.6 (95% CI 16.4-20.8) for the finger counting method; 4.0 (95% CI 3.2-4.8) and 23.1 (95% CI 20.3-25.8) for the updated APLS method; 5.1 (95% CI 4.4-5.8) and 21.1 (95% CI 18.6-23.6) for the Luscombe formula; and 5.3 (95% CI 4.5-6.1) and 22.5 (95% CI 20-25.2) for the Best Guess formulae. CONCLUSIONS: The Broselow tape and the traditional APLS formula performed best in our sample. The finger counting method also outperformed newer weight estimation formulae. 'Updated' age based formulae created recently in developed countries should not be used in disaster relief efforts in the Philippines. Caution should be used when applying these formulae to other developing countries and in disaster response. PMID- 25818596 TI - Enzalutamide: targeting the androgen signalling pathway in metastatic castration resistant prostate cancer. AB - Significant progress has been made in the understanding of the underlying cancer biology of castration-resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC. PMID- 25818597 TI - An unusual case of diffuse Merkel cell carcinoma successfully treated with low dose radiotherapy. AB - Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine carcinoma of the skin. MCC should be included in the diagnosis of a rapidly growing infiltrating mass and histology as well as laboratory investigations such as Merkel cell polyoma virus (MCPyV) detection are valuable in its diagnosis. We present an unusual case of giant MCC-positive MCPyV in a Greek woman located on the lower leg. Our patient is very unusual in terms of her extensive MCC and her rapid and complete response to radiotherapy. PMID- 25818598 TI - Tat-CBR1 inhibits inflammatory responses through the suppressions of NF-kappaB and MAPK activation in macrophages and TPA-induced ear edema in mice. AB - Human carbonyl reductase 1 (CBR1) plays a crucial role in cell survival and protects against oxidative stress response. However, its anti-inflammatory effects are not yet clearly understood. In this study, we examined whether CBR1 protects against inflammatory responses in macrophages and mice using a Tat-CBR1 protein which is able to penetrate into cells. The results revealed that purified Tat-CBR1 protein efficiently transduced into Raw 264.7 cells and inhibited lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2), nitric oxide (NO) and prostaglandin E2 (PGE2) expression levels. In addition, Tat-CBR1 protein leads to decreased pro-inflammatory cytokine expression through suppression of nuclear transcription factor-kappaB (NF-kappaB) and mitogen activated protein kinase (MAPK) activation. Furthermore, Tat-CBR1 protein inhibited inflammatory responses in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation when applied topically. These findings indicate that Tat-CBR1 protein has anti inflammatory properties in vitro and in vivo through inhibition of NF-kappaB and MAPK activation, suggesting that Tat-CBR1 protein may have potential as a therapeutic agent against inflammatory diseases. PMID- 25818599 TI - Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen induced liver injury. AB - Metabolic activation and oxidant stress are key events in the pathophysiology of acetaminophen (APAP) hepatotoxicity. The initial mitochondrial oxidative stress triggered by protein adduct formation is amplified by c-jun-N-terminal kinase (JNK), resulting in mitochondrial dysfunction and ultimately cell necrosis. Apoptosis signal-regulating kinase 1 (ASK1) is considered the link between oxidant stress and JNK activation. The objective of the current study was to assess the efficacy and mechanism of action of the small-molecule ASK1 inhibitor GS-459679 in a murine model of APAP hepatotoxicity. APAP (300 mg/kg) caused extensive glutathione depletion, JNK activation and translocation to the mitochondria, oxidant stress and liver injury as indicated by plasma ALT activities and area of necrosis over a 24h observation period. Pretreatment with 30 mg/kg of GS-459679 almost completely prevented JNK activation, oxidant stress and injury without affecting the metabolic activation of APAP. To evaluate the therapeutic potential of GS-459679, mice were treated with APAP and then with the inhibitor. Given 1.5h after APAP, GS-459679 was still protective, which was paralleled by reduced JNK activation and p-JNK translocation to mitochondria. However, GS-459679 treatment was not more effective than N-acetylcysteine, and the combination of GS-459679 and N-acetylcysteine exhibited similar efficacy as N acetylcysteine monotherapy, suggesting that GS-459769 and N-acetylcysteine affect the same pathway. Importantly, inhibition of ASK1 did not impair liver regeneration as indicated by PCNA staining. In conclusion, the ASK1 inhibitor GS 459679 protected against APAP toxicity by attenuating JNK activation and oxidant stress in mice and may have therapeutic potential for APAP overdose patients. PMID- 25818600 TI - Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma. AB - Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia inducible factor-1alpha expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2 polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. PMID- 25818601 TI - Polychlorinated biphenyl quinone induces oxidative DNA damage and repair responses: The activations of NHEJ, BER and NER via ATM-p53 signaling axis. AB - Our previous studies demonstrated that polychlorinated biphenyl (PCB) quinone induced oxidative DNA damage in HepG2 cells. To promote genomic integrity, DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair and apoptosis. PCB quinone-induced cell cycle arrest and apoptosis have been documented, however, whether PCB quinone insult induce DNA repair signaling is still unknown. In this study, we identified the activation of DDR and corresponding signaling events in HepG2 cells upon the exposure to a synthetic PCB quinone, PCB29-pQ. Our data illustrated that PCB29-pQ induces the phosphorylation of p53, which was mediated by ataxia telangiectasia mutated (ATM) protein kinase. The observed phosphorylated histone H2AX (gamma-H2AX) foci and the elevation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) indicated that DDR was stimulated by PCB29-pQ treatment. Additionally, we found PCB29-pQ activates non homologous end joining (NHEJ), base excision repair (BER) and nucleotide excision repair (NER) signalings. However, these repair pathways are not error-free processes and aberrant repair of DNA damage may cause the potential risk of carcinogenesis and mutagenesis. PMID- 25818602 TI - A quantitative multiplex nuclease protection assay reveals immunotoxicity gene expression profiles in the rabbit model for vaginal drug safety evaluation. AB - Any vaginal product that alters the mucosal environment and impairs the immune barrier increases the risk of sexually transmitted infections, especially HIV infection, which thrives on mucosal damage and inflammation. The FDA-recommended rabbit vaginal irritation (RVI) model serves as a first line selection tool for vaginal products; however, for decades it has been limited to histopathology scoring, insufficient to select safe anti-HIV microbicides. In this study we incorporate to the RVI model a novel quantitative nuclease protection assay (qNPA) to quantify mRNA levels of 25 genes representing leukocyte differentiation markers, toll-like receptors (TLR), cytokines, chemokines, epithelial repair, microbicidal and vascular markers, by designing two multiplex arrays. Tissue sections were obtained from 36 rabbits (6 per treatment arm) after 14 daily applications of a placebo gel, saline, 4% nonoxynol-9 (N-9), and three combinations of the anti-HIV microbicides tenofovir (TFV) and UC781 in escalating concentrations (highest: 10% TFV+2.5%UC781). Results showed that increased expression levels of toll-like receptor (TLR)-4, interleukin (IL)-1beta, CXCL8, epithelial membrane protein (EMP)-1 (P<0.05), and decreased levels of TLR2 (P<0.05), TLR3 and bactericidal permeability increasing protein (BPI) (P<0.001) were associated with cervicovaginal mucosal alteration (histopathology). Seven markers showed a significant linear trend predicting epithelial damage (up with CD4, IL-1beta, CXCL8, CCL2, CCL21, EMP1 and down with BPI). Despite the low tissue damage RVI scores, the high-dose microbicide combination gel caused activation of HIV host cells (SLC and CD4) while N-9 caused proinflammatory gene upregulation (IL-8 and TLR4) suggesting a potential for increasing risk of HIV via different mechanisms depending on the chemical nature of the test product. PMID- 25818603 TI - Attitude Toward Ambiguity: Empirically Robust Factors in Self-Report Personality Scales. AB - Two studies were conducted to examine the factor structure of attitude toward ambiguity, a broad personality construct that refers to personal reactions to perceived ambiguous stimuli in a variety of context and situations. Using samples from two countries, Study 1 mapped the hierarchical structure of 133 items from seven tolerance-intolerance of ambiguity scales (N = 360, Italy; N = 306, United States). Three major factors-Discomfort with Ambiguity, Moral Absolutism/Splitting, and Need for Complexity and Novelty-were recovered in each country with high replicability coefficients across samples. In Study 2 (N = 405, Italian community sample; N =366, English native speakers sample), we carried out a confirmatory analysis on selected factor markers. A bifactor model had an acceptable fit for each sample and reached the construct-level invariance for general and group factors. Convergent validity with related traits was assessed in both studies. We conclude that attitude toward ambiguity can be best represented a multidimensional construct involving affective (Discomfort with Ambiguity), cognitive (Moral Absolutism/Splitting), and epistemic (Need for Complexity and Novelty) components. PMID- 25818605 TI - Comment on "Determination of the quaternary phase diagram of the water-ethylene glycol-sucrose-NaCl system and a comparison between two theoretical methods for synthetic phase diagrams" Cryobiology 61 (2010) 52-57. AB - Recently, measurements of a considerable portion of the phase diagram for the quaternary system water-ethylene glycol-sucrose-NaCl were published (Han et al., 2010). In that article, the data were used to evaluate the accuracy of two non ideal multi-solute solution theories: the Elliott et al. form of the multi-solute osmotic virial equation and the Kleinhans and Mazur freezing point summation model. Based on this evaluation, it was concluded that the freezing point summation model provides more accurate predictions for the water-ethylene glycol sucrose-NaCl system than the multi-solute osmotic virial equation. However, this analysis suffered from a number of issues, notably including the use of inconsistent solute-specific coefficients for the multi-solute osmotic virial equation. Herein, we reanalyse the data using a recently-updated and consistent set of solute-specific coefficients (Zielinski et al., 2014). Our results indicate that the two models have very similar performance, and, in fact, the multi-solute osmotic virial equation can provide more accurate predictions than the freezing point summation model depending on the concentration units used. PMID- 25818604 TI - Effects of trehalose supplementation on cell viability and oxidative stress variables in frozen-thawed bovine calf testicular tissue. AB - Trehalose is widely used for cryopreservation of various cells and tissues. Until now, the effect of trehalose supplementation on cell viability and antioxidant enzyme activity in frozen-thawed bovine calf testicular tissue remains unexplored. The objective of the present study was to compare the effect of varying doses of trehalose in cryomedia on cell viability and key antioxidant enzymes activities in frozen-thawed bovine calf testicular tissue. Bovine calf testicular tissue samples were collected and cryopreserved in the cryomedias containing varying doses (0, 5, 10, 15, 20 and 25%; v/v) of trehalose, respectively. Cell viability, total antioxidant capacity (T-AOC) activity, catalase (CAT) activity, superoxide dismutase (SOD) activity, glutathione (GSH) content and malondialdehyde (MDA) content were measured and analyzed. The results showed that cell viability, T-AOC activity, SOD activity, CAT activity and GSH content of frozen-thawed bovine calf testicular tissue was decreased compared with that of fresh group (P<0.05). MDA content in frozen-thawed bovine calf testicular tissue was significantly increased compared with that of fresh group (P<0.05). The cryomedia added 15% trehalose exhibited the greatest percentage of cell viability and antioxidant enzyme activity (SOD and CAT) among frozen-thawed groups (P<0.05). Meanwhile, GSH content was the lowest among frozen-thawed groups (P<0.05). However, there were no significance differences in MDA content among the groups added 10, 15 and 20% trehalose (P>0.05). In conclusion, the cryomedia added 15% trehalose reduced the oxidative stress and improved the cryoprotective effect of bovine calf testicular tissue. Further studies are required to obtain more concrete results on the determination of antioxidant capacity of trehalose in frozen-thawed bovine calf testicular tissue. PMID- 25818606 TI - [Myositis ossificans of the temporal muscle]. PMID- 25818613 TI - Stem-cell transplantation increases fracture risk. PMID- 25818614 TI - Increasing prevalence of euthanasia in Belgium. PMID- 25818615 TI - Mogamulizumab benefits seen in cutaneous T-cell lymphoma. PMID- 25818616 TI - BRAF and CDKN2A mutations in secondary high-grade glioma. PMID- 25818617 TI - Effects of geniposide on hepatocytes undergoing epithelial-mesenchymal transition in hepatic fibrosis by targeting TGFbeta/Smad and ERK-MAPK signaling pathways. AB - Liver fibrosis results from increased deposition of type-I collagen within the hepatic extracellular space and constitutes a common cardinal signature in all forms of liver injury, regardless of etiology. Transforming growth factor beta1 (TGF-beta1) plays a crucial role in the pathogenesis of liver fibrosis. Geniposide is recognized as being useful against hyperlipidemia and fatty liver. However, its cellular mechanism and anti-fibrotic effect in TGF-beta1-induced hepatocytes have not been explored. In the present study, we investigated its anti-epithelial-mesenchymal transition (EMT) mechanism by examining the effect of geniposide on TGF-beta1-induced hepatocytes. The effect of geniposide on TGF beta1-induced AML12 cells was assessed using Western blotting, quantitative real time PCR, immunofluorescence staining and DNA binding activity. We found that geniposide significantly inhibited TGF-beta1-induced mRNA and protein expression of type-I collagen. Cells treated concurrently with TGF-beta1 and geniposide retained high levels of localized E-cadherin expression with no increase in vimentin. Treatment with geniposide almost completely blocked the phosphorylation of Smad2/3, extracellular signal-regulated kinase (ERK) and Akt in AML12 cells. Taken together, these results suggest that geniposide may suppress TGF-beta1 induced EMT in hepatic fibrosis by inhibiting the TGFbeta/Smad and ERK-mitogen activated protein kinase (MAPK) signaling pathways. Our results may help researchers better understand the pathogenesis of liver fibrosis so they can develop novel therapeutic strategies for treatment of liver diseases. PMID- 25818618 TI - Unifying ecology and macroevolution with individual-based theory. AB - A contemporary goal in both ecology and evolutionary biology is to develop theory that transcends the boundary between the two disciplines, to understand phenomena that cannot be explained by either field in isolation. This is challenging because macroevolution typically uses lineage-based models, whereas ecology often focuses on individual organisms. Here, we develop a new parsimonious individual based theory by adding mild selection to the neutral theory of biodiversity. We show that this model generates realistic phylogenies showing a slowdown in diversification and also improves on the ecological predictions of neutral theory by explaining the occurrence of very common species. Moreover, we find the distribution of individual fitness changes over time, with average fitness increasing at a pace that depends positively on community size. Consequently, large communities tend to produce fitter species than smaller communities. These findings have broad implications beyond biodiversity theory, potentially impacting, for example, invasion biology and paleontology. PMID- 25818619 TI - Meningitis in adolescents: the role of commensal microbiota. AB - The pathogen Neisseria meningitidis causes disease amongst infants and adolescents/young adults. Here we argue that disease amongst adolescents is due largely to interaction between N. meningitidis and other members of the upper respiratory tract microbiota, through a metabolic interaction involving exchange of propionic acid. PMID- 25818620 TI - The Safety and Feasibility of Admitting Patients With Intracerebral Hemorrhage to the Step-Down Unit. AB - BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating and costly condition. Although the American Heart Association/American Stroke Association recommends admitting patients with ICH to a neurocritical care unit (NCCU), this strategy may accrue unnecessary cost for patients with relatively milder presentation. We conducted a prospective observational study to determine the safety and feasibility of admitting patients with mild ICH directly to a step-down unit (SDU) instead of an NCCU. METHODS: Consecutive patients with "mild presentation," defined as a combination of ICH score <=2, National Institutes of Health Stroke Scale (NIHSS) <= 15, and Graeb score <=2 (if intraventricular hemorrhage was present), were admitted to the SDU. Data were collected on age, gender as well as the initial NIHSS, Glasgow Coma Scale (GCS), ICH, and Graeb scores. Primary end point was any complication or death during hospital stay. RESULTS: Twenty patients were admitted to the SDU. No patient was transferred to the NCCU from the SDU. One patient, who eventually died, had respiratory insufficiency due to hospital-acquired pneumonia. CONCLUSION: Admission of ICH patients with mild symptoms to the SDU is safe and feasible. Larger prospective studies are needed to define the specific criteria for admission. PMID- 25818621 TI - Computerized tomographic pulmonary angiography discriminates invasive mould disease of the lung from lymphoma. PMID- 25818622 TI - A comparison of 454 sequencing and clonal sequencing for the characterization of hepatitis C virus NS3 variants. AB - We compared 454 amplicon sequencing with clonal sequencing for the characterization of intra-host hepatitis C virus (HCV) NS3 variants. Clonal and 454 sequences were obtained from 12 patients enrolled in a clinical phase I study for telaprevir, an NS3-4a protease inhibitor. Thirty-nine datasets were used to compare the consensus sequence, average pairwise distance, normalized Shannon entropy, phylogenetic tree topology and the number and frequency of variants derived from both sequencing techniques. In general, a good concordance was observed between both techniques for the majority of datasets. Discordant results were observed for 5 out of 39 clonal and 454 datasets, which could be attributed to primer-related selective amplification used for clonal sequencing. Both 454 and clonal datasets consisted of a few major variants and a large number of low frequency variants. Telaprevir resistance-associated variants were observed in low frequencies and were detected more often by 454. We conclude that performance of 454 and clonal sequencing is comparable for the characterization of intra-host virus populations. Not surprisingly, 454 is superior for the detection of low frequency resistance-associated variants. However, despite the greater coverage, 454 failed to detect some low frequency variants detected by clonal sequencing. PMID- 25818624 TI - YCF1: A Green TIC? AB - A pivotal step in the transformation of an endosymbiotic cyanobacterium to a plastid some 1.5 billion years ago was the evolution of a protein import apparatus, the TOC/TIC machinery, in the common ancestor of Archaeplastida. Recently, a putative new TIC member was identified in Arabidopsis thaliana: TIC214. This finding is remarkable for a number of reasons: (1) TIC214 is encoded by ycf1, so it would be the first plastid-encoded protein of this apparatus; (2) ycf1 is unique to the green lineage (Chloroplastida) but entirely lacking in glaucophytes (Glaucophyta) and the red lineage (Rhodophyta) of the Archaeplastida; (3) ycf1 has been shown to be one of the few indispensable plastid genes (aside from the ribosomal machinery), yet it is missing in the grasses; and (4) 30 years of previous TOC/TIC research missed it. These observations prompted us to survey the evolution of ycf1. We found that ycf1 is not only lacking in grasses and some parasitic plants, but also for instance in cranberry (Ericaceae). The encoded YCF proteins are highly variable, both in sequence length and in the predicted number of N-terminal transmembrane domains. The evolution of the TOC/TIC machinery in the green lineage experienced specific modifications, but our analysis does not support YCF1 to be a general green TIC. It remains to be explained how the apparent complete loss of YCF1 can be tolerated by some embryophytes and whether what is observed for YCF1 function in a member of the Brassicaceae is also true for, e.g., algal and noncanonical YCF1 homologs. PMID- 25818625 TI - Sterols Modulate Cell-to-Cell Connectivity at Plasmodesmata. PMID- 25818623 TI - Specific membrane lipid composition is important for plasmodesmata function in Arabidopsis. AB - Plasmodesmata (PD) are nano-sized membrane-lined channels controlling intercellular communication in plants. Although progress has been made in identifying PD proteins, the role played by major membrane constituents, such as the lipids, in defining specialized membrane domains in PD remains unknown. Through a rigorous isolation of "native" PD membrane fractions and comparative mass spectrometry-based analysis, we demonstrate that lipids are laterally segregated along the plasma membrane (PM) at the PD cell-to-cell junction in Arabidopsis thaliana. Remarkably, our results show that PD membranes display enrichment in sterols and sphingolipids with very long chain saturated fatty acids when compared with the bulk of the PM. Intriguingly, this lipid profile is reminiscent of detergent-insoluble membrane microdomains, although our approach is valuably detergent-free. Modulation of the overall sterol composition of young dividing cells reversibly impaired the PD localization of the glycosylphosphatidylinositol-anchored proteins Plasmodesmata Callose Binding 1 and the beta-1,3-glucanase PdBG2 and altered callose-mediated PD permeability. Altogether, this study not only provides a comprehensive analysis of the lipid constituents of PD but also identifies a role for sterols in modulating cell-to cell connectivity, possibly by establishing and maintaining the positional specificity of callose-modifying glycosylphosphatidylinositol proteins at PD. Our work emphasizes the importance of lipids in defining PD membranes. PMID- 25818626 TI - Brain structure abnormalities in first-episode psychosis patients with persistent apathy. AB - BACKGROUND: Apathy is an enduring and debilitating feature related to poor outcome in patients with first-episode psychosis (FEP). The biological underpinnings of apathy are unknown. We tested if FEP patients with persistent apathy (PA) differed from FEP patients without persistent apathy (NPA) in specific brain structure measures in the early phase of illness. METHODS: A total of 70 Norwegian FEP patients were recruited within 1 year of first adequate treatment. They were defined as having PA (N=18) or NPA (N=52) based on Apathy Evaluation Scale score at baseline and 1 year later. MRI measures of cortical thickness and subcortical structure volumes were compared between the PA and NPA groups. RESULTS: The PA group had significantly thinner left orbitofrontal cortex and left anterior cingulate cortex. The results remained significant after controlling for depressive symptoms and antipsychotic medication. DISCUSSION: FEP patients with persistent apathy in the early phase of their illness show brain structural changes compared to FEP patients without persistent apathy. The changes are confined to regions associated with motivation, occur early in the disease course and appear selectively in PA patients when both groups are compared to healthy controls. PMID- 25818627 TI - Actigraphic-measured sleep disturbance predicts increased positive symptoms in adolescents at ultra high-risk for psychosis: A longitudinal study. AB - BACKGROUND: Sleep disturbance is prevalent among patients with psychosis, yet little is known about sleep health during the ultra high-risk (UHR) period. This study used actigraphy to evaluate sleep in healthy control (HC) and UHR adolescents to examine the relationship between sleep disturbance and psychosis symptoms at baseline and 12-month follow-up, as well as comparisons between objective and subjective measurements of sleep functioning in UHR youth. METHOD: Thirty-six UHR and 31 HC youth participated in a baseline evaluation including 5 nights of actigraphy, subjective measurement of sleep health (Pittsburgh Sleep Quality Index; PSQI), and clinical interviews. Clinical measures were repeated with UHR youth (N=23) at a 12-month follow-up. RESULTS: The actigraphy data indicated that UHR youth displayed increased wake time after onset (WASO), increased movements during sleep, and decreased efficiency compared to HC, and several markers of sleep disturbance including decreased efficiency, increased WASO, number of awakenings, and increased movements were associated with symptomatology in the UHR group. Interestingly, there were associations between actigraph and self-report indices of sleep duration and efficiency (at the trend level) but not awakenings. Several objective measures of sleep disturbance and one self-reported measure (disrupted continuity) predicted the longitudinal course of symptoms over 12 months in the UHR group. CONCLUSIONS: Taken together, the results suggest a potential role for sleep problems in the etiology of schizophrenia, and highlight sleep health as a possible target for prevention/intervention efforts. Additionally, actigraphy represents an inexpensive, sensitive measurement providing unique information not captured by self-report, and may be an informative adjunct to UHR assessments. PMID- 25818628 TI - Age at onset mixture analysis and systematic comparison in schizophrenia spectrum disorders: Is the onset heterogeneity dependent on heterogeneous diagnosis? AB - A major obstacle to the identification of the neurobiological correlates of schizophrenia is the substantial diagnostic heterogeneity of this disorder. Dividing schizophrenia into "early" and "late" subtypes may reduce heterogeneity and facilitate identification of biomarkers related to this disease. Our objective was to assess the presence of different sub-groups in schizophrenia by age at onset analysis. The participants in this study were 612 unrelated patients with schizophrenia. Admixture analysis was applied in order to identify a model of separate normal distributions of age at onset characterized by different means, variances and population proportions to evaluate the effect of winter birth and ethnicity on early onset schizophrenia. The best-fitting model suggested three subgroups with means and standard deviations of 17.11 +/- 2.09, 21.96 +/- 3.43 and 30.02 +/- 7.1 years, comprising 34.6%, 42.6% and 22.8% of the sample respectively. We considered as predictors of early onset schizophrenia: male gender, winter birth, white ethnicity and positive family history for psychiatric disorders. Earlier onset was significantly associated with male gender. We also compared our age at onset distribution with those published in other studies and we found significant differences with several studies suggesting heterogeneity in age at onset that is likely influenced by diagnostic heterogeneity in applying the DSM-IV criteria. Overall, our study showed that a typical early onset schizophrenia patient is more likely to be a white male with cannabis abuse and positive family history of psychiatric disorders. The heterogeneity in reporting age at onset across different studies suggests the application of more stringent criteria in diagnosing schizophrenia. PMID- 25818629 TI - The threshold of hypothyroidism after radiation therapy for head and neck cancer: a retrospective analysis of 116 cases. AB - The purpose of the present study was to determine the risk factors for developing thyroid disorders based on a dose-volume histograms (DVHs) analysis. Data from a total of 116 consecutive patients undergoing 3D conformal radiation therapy for head and neck cancers was retrospectively evaluated. Radiation therapy was performed between April 2007 and December 2010. There were 108 males and 8 females included in the study. The median follow-up term was 24 months (range, 1 62 months). The thyroid function was evaluated by measuring thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels. The mean thyroid dose, and the volume of thyroid gland spared from doses >=10, 20, 30 and 40 Gy (VS10, VS20, VS30 and VS40) were calculated for all patients. The thyroid dose and volume were calculated by the radiotherapy planning system (RTPS). The cumulative incidences of hypothyroidism were 21.1% and 36.4% at one year and two years, respectively, after the end of radiation therapy. In the DVH analyses, the patients who received a mean thyroid dose <30 Gy had a significantly lower incidence of hypothyroidism. The univariate analyses showed that the VS10, VS20, VS30 and VS40 were associated with the risk of hypothyroidism. Hypothyroidism was a relatively common type of late radiation-induced toxicity. A mean thyroid dose of 30 Gy may be a useful threshold for predicting the development of hypothyroidism after radiation therapy for head and neck cancers. PMID- 25818631 TI - Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans. AB - BACKGROUND: Understanding the neural causes and consequences of posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) is a high research priority, given the high rates of associated disability and suicide. Despite remarkable progress in elucidating the brain mechanisms of PTSD and mTBI, a comprehensive understanding of these conditions at the level of brain networks has yet to be achieved. The present study sought to identify functional brain networks and topological properties (measures of network organization and function) related to current PTSD severity and mTBI. METHODS: Graph theoretic tools were used to analyze resting-state functional magnetic resonance imaging data from 208 veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn, all of whom had experienced a traumatic event qualifying for PTSD criterion A. Analyses identified brain networks and topological network properties linked to current PTSD symptom severity, mTBI, and the interaction between PTSD and mTBI. RESULTS: Two brain networks were identified in which weaker connectivity was linked to higher PTSD re-experiencing symptoms, one of which was present only in veterans with comorbid mTBI. Re-experiencing was also linked to worse functional segregation (necessary for specialized processing) and diminished influence of key regions on the network, including the hippocampus. CONCLUSIONS: Findings of this study demonstrate that PTSD re-experiencing symptoms are linked to weakened connectivity in a network involved in providing contextual information. A similar relationship was found in a separate network typically engaged in the gating of working memory, but only in veterans with mTBI. PMID- 25818632 TI - New light on old methods. PMID- 25818630 TI - Loss of Microtubule-Associated Protein 2 Immunoreactivity Linked to Dendritic Spine Loss in Schizophrenia. AB - BACKGROUND: Microtubule-associated protein 2 (MAP2) is a neuronal protein that plays a role in maintaining dendritic structure through its interaction with microtubules. In schizophrenia (Sz), numerous studies have revealed that the typically robust immunoreactivity (IR) of MAP2 is significantly reduced across several cortical regions. The relationship between MAP2-IR reduction and lower dendritic spine density, which is frequently reported in Sz, has not been explored in previous studies, and MAP2-IR loss has not been investigated in the primary auditory cortex (Brodmann area 41), a site of conserved pathology in Sz. METHODS: Using quantitative spinning disk confocal microscopy in two cohorts of subjects with Sz and matched control subjects (Sz subjects, n = 20; control subjects, n = 20), we measured MAP2-IR and dendritic spine density and spine number in deep layer 3 of BA41. RESULTS: Subjects with Sz exhibited a significant reduction in MAP2-IR. The reductions in MAP2-IR were not associated with neuron loss, loss of MAP2 protein, clinical confounders, or technical factors. Dendritic spine density and number also were reduced in Sz and correlated with MAP2-IR. In 12 (60%) subjects with Sz, MAP2-IR values were lower than the lowest values in control subjects; only in this group were spine density and number significantly reduced. CONCLUSIONS: These findings demonstrate that MAP2-IR loss is closely linked to dendritic spine pathology in Sz. Because MAP2 shares substantial sequence, regulatory, and functional homology with MAP tau, the wealth of knowledge regarding tau biology and the rapidly expanding field of tau therapeutics provide resources for identifying how MAP2 is altered in Sz and possible leads to novel therapeutics. PMID- 25818633 TI - Symphysiotomy. AB - The place of symphysiotomy, as an alternative to Caesarean section (CS), in the management of established obstructed labour in low- and middle-income, resource poor countries (LMICs), is reviewed. It is suggested that it does have a very definite place, especially in mothers of low age and parity, in circumstances where medical facilities are limited, where antenatal care and hospital delivery are not assured in a future pregnancy, and in cultures where it is important to the woman that a vaginal delivery is achieved. PMID- 25818635 TI - Thromboelastography as a Surrogate Marker of Perisurgical Hemostasis in Gaucher Disease. AB - Thromboelastography (TEG) has long been available for routine monitoring of perisurgical and postpartum hemostasis, especially at point of care. The purpose of this study is to retrospectively compare TEG parameters to concomitant standard clotting test results in an unselected cohort of patients with Gaucher disease to ascertain whether TEG values are specific and sensitive enough to substitute for classic coagulation tests for decision making. This remains a cogent concern because of high incidence of thrombocytopenia in patients with Gaucher disease. Thromboelastography values were compared to concomitant platelet counts, partial thromboplastin time, international normalization ratio, and plasma fibrinogen. Demographic characteristics were collected from patients' files. There were 22 patients with Gaucher disease (2 children; 12.5%) for whom there were 24 TEG results at the same time as classic coagulation test results and 30% performed platelet function tests. The current study shows linear and/or monotonic relationships between platelet counts and several TEG values that were significant over a range of platelet counts including severe thrombocytopenia. The fibrinogen component, correlating only with the rate of clot lysis, played a lesser role. Based on these preliminary results albeit in a small cohort with only 1 case of hemorrhage, there is putative support for the intention to treat patients with Gaucher disease based on TEG results using the same TEG protocol as for other patients undergoing comparable procedures in our institution. PMID- 25818636 TI - High Atrial Defibrillation Threshold With Internal Cardioversion Indicates Arrhythmogenicity of Superior Vena Cava in Non-Long-Standing Persistent Atrial Fibrillation. AB - BACKGROUND: The purpose of this study was to clarify the relation between atrial defibrillation threshold (ADFT) for internal cardioversion (IC) and arrhythmogenicity of the superior vena cava (SVC). METHODS AND RESULTS: A total of 159 consecutive patients (139 male, age 59.9+/-10.3 years) who underwent radiofrequency catheter ablation of atrial fibrillation (AF) were assessed. IC was performed in 50 patients with non-long-standing persistent AF (non-LSAF) with a purpose-built cardioversion catheter in which direct current is delivered between the right atrium and the coronary sinus. SVC arrhythmogenicity was defined as SVC firing initiating AF, SVC associated with maintenance of AF, or frequent ectopy in the SVC. In all 50 non-LSAF patients, AF termination was obtained on IC during the procedure except in 1 patient with SVC AF. In the patients with ADFT >10 J (n=10), SVC arrhythmogenicity was observed more often than in those with ADFT <=10 J (n=40; 60% vs. 13%; P=0.004). There were no significant differences between the 2 groups in left atrial diameter (40.8+/-7.6 vs. 40.6+/-6.3 mm; P=0.92), persistent AF (33% vs. 50%; P=0.46), or other clinical parameters. The patients who underwent SVC isolation, however, had higher ADFT before SVC isolation than those who did not (15.5+/-8.8 vs. 9.2+/-4.4 J; P=0.01). CONCLUSIONS: High IC ADFT is associated with SVC arrhythmogenicity in non-LSAF patients. PMID- 25818637 TI - Assessment of In-Stent Restenosis Using High-Definition Computed Tomography With a New Gemstone Detector. AB - BACKGROUND: Until now, there have been few reports on the accuracy of in-stent restenosis (ISR) detection using high-definition computed tomography (HDCT). The purpose of this study was to assess ISR using HDCT with a new gemstone detector and to examine the diagnostic accuracy compared with invasive coronary angiography. METHODS AND RESULTS: We evaluated 162 consecutive patients with 316 stents and the image quality (IQ) scores used to assess ISR, and analyzed whether stent strut thickness and diameter affected IQ score and assessability. In the 316 stents, 278 were diagnosed as assessable with HDCT (88.0%). IQ score for stent diameter >=3 mm was significantly higher than that for stent diameter <3 mm, for stents with both thick struts >=140 MUm in thickness (mean IQ: 2.04+/ 0.97 vs. 2.83+/-1.06, P<0.001) and thin struts <140 MUm (mean IQ: 1.92+/-0.87 vs. 2.64+/-0.96, P=0.01). Assessability for stent diameter >=3 mm was significantly higher than that for stent diameter <3 mm only for stents with thick struts (92.8% vs. 76.1%, P<0.001). Stent strut thickness, however, was not statistically significantly associated with either IQ score or assessability. CONCLUSIONS: In stent lumens have high HDCT assessability, and HDCT is useful to evaluate thick strut stents with diameter <3 mm. PMID- 25818638 TI - Quality of bystander cardiopulmonary resuscitation - can a smartphone bring about a revolution? PMID- 25818639 TI - Congenital mesoblastic nephroma with focal anaplastic lesion. PMID- 25818640 TI - Mobilization of sca1/flk-1 positive endothelial progenitor cells declines in apolipoprotein E-deficient mice with a high-fat diet. AB - BACKGROUND: Atherosclerosis features a deterioration of the endothelial layer in all stages. Restoration of the endothelium is associated with circulating stem cell antigen 1 (sca1) and vascular endothelial growth factor receptor type 2 (flk 1) positive endothelial progenitor cells (EPCs). We investigated whether EPC production and/or a mobilization from bone marrow are reduced in severe atherosclerosis. METHODS AND RESULTS: EPCs in peripheral blood were diminished in ApoE-/- mice with high-fat diet (HFD) whereas bone marrow levels of these cells were not significantly altered compared to controls. In situ perfusion of the hind limbs demonstrated that EPC mobilization was reduced compared to ApoE-/- mice with normal chow, although increased plasma stromal cell-derived factor (SDF) 1alpha and responsivity suggested a mobilizing stimulus. The proliferation of sca1/flk-1 positive cells showed no functional impairment. EPCs could not only be significantly mobilized from the bone marrow through the application of granulocyte colony stimulating factor (GCSF), but also led by trend to a depletion of the bone marrow pool. GCSF levels in plasma were equal in ApoE-/- mice with normal chow or HFD, which excluded a decline in GCSF production. CONCLUSION: The capability of the bone marrow pool to adapt the proliferation and mobilization of sca1/flk-1 positive EPCs seems overstrained in ApoE-/- mice with a HFD. PMID- 25818641 TI - The expression profile analysis of NKX2-5 knock-out embryonic mice to explore the pathogenesis of congenital heart disease. AB - BACKGROUND: Mutation of NKX2-5 could lead to the development of congenital heart disease (CHD) which is a common inherited disease. This study aimed to investigate the pathogenesis of CHD in NKX2-5 knock-out embryonic mice. METHODS: The expression profile in the NKX2-5 knock-out embryonic mice (GSE528) was downloaded from Gene Expression Omnibus. The heart tissues from the null/heterozygous embryonic day 12.5 mice were compared with wild-type mice to identify differentially expressed genes (DEGs), and then DEGs corresponding to the transcriptional factors were filtered out based on the information in the TRANSFAC database. In addition, a transcriptional regulatory network was constructed according to transcription factor binding site information from the University of California Santa Cruz database. A pathway interaction network was constructed by latent pathways identification analysis. RESULTS: The 42 DEGs corresponding to transcriptional factors from the null and heterozygous embryos were identified. The transcriptional regulatory networks included five down regulated DEGs (SP1, SRY, JUND, STAT6, and GATA6), and six up-regulated DEGs [POU2F1, NFY (NFYA/NFYB/NFYC), USF2 and MAX]. Latent pathways analysis demonstrated that ribosome, glycolysis/gluconeogenesis, and dilated cardiomyopathy pathways significantly interacted. CONCLUSION: The identified DEGs and latent pathways could provide new comprehensive view for understanding the pathogenesis of CHD. PMID- 25818642 TI - Relationship between CHA2DS2-VASc score and atrial electromechanical function in patients with paroxysmal atrial fibrillation: A pilot study. AB - BACKGROUND: CHA2DS2-VASc score is the most widely preferred method for prediction of stroke risk in patients with atrial fibrillation. We hypothesized that CHA2DS2 VASc score may represent atrial remodeling status, and therefore echocardiographic evaluation of left atrial electromechanical remodeling can be used to identify patients with high risk. METHODS: A total of 65 patients who had documented diagnosis of paroxysmal atrial fibrillation (PAF) were divided into three risk groups according to the CHA2DS2-VASc score: patients with low risk (score=0, group 1), with moderate risk (score=1, group 2), and with high risk score (score >=2, group 3). We compared groups according to atrial electromechanical intervals and left atrium mechanical functions. RESULTS: Atrial electromechanical intervals including inter-atrial and intra-atrial electromechanical delay were not different between groups. However, parameters reflecting atrial mechanical functions including LA phasic volumes (Vmax, Vmin and Vp) were significantly higher in groups 2 and 3 compared with group 1. Likewise, LA passive emptying volume (LATEV) in the groups 2 and 3 was significantly higher than low-risk group (14.12+/-8.13ml/m(2), 22.36+/ 8.78ml/m(2), 22.89+/-7.23ml/m(2), p: 0.031). Univariate analysis demonstrated that Vmax, Vmin and Vp were significantly correlated with CHA2DS2-VASc score (r=0.428, r=0.456, r=0.451 and p<0.001). Also, LATEV (r=0.397, p=0.016) and LA active emptying volume (LAAEV) (r=0.281, p=0.023) were positively correlated with CHA2DS2-VASc score. In the ROC analysis, Vmin>=11ml/m(2) has the highest predictive value for CHA2DS2-VASc score >=2 (88% sensitivity and 89% specificity; ROC area 0.88, p<0.001, CI [0.76-0.99]). CONCLUSION: Echocardiographic evaluation of left atrial electromechanical function might represent a useful method to identify patients with high risk. PMID- 25818643 TI - Skp2-macroH2A1-CDK8 axis orchestrates G2/M transition and tumorigenesis. AB - Understanding the mechanism by which cell growth, migration, polyploidy, and tumorigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-cyclin-dependent kinase 8 (CDK8) axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression on Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy. PMID- 25818644 TI - Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing. AB - Chromosomes of metazoan organisms are partitioned in the interphase nucleus into discrete topologically associating domains (TADs). Borders between TADs are formed in regions containing active genes and clusters of architectural protein binding sites. The transcription of most genes is repressed after temperature stress in Drosophila. Here we show that temperature stress induces relocalization of architectural proteins from TAD borders to inside TADs, and this is accompanied by a dramatic rearrangement in the 3D organization of the nucleus. TAD border strength declines, allowing for an increase in long-distance inter-TAD interactions. Similar but quantitatively weaker effects are observed upon inhibition of transcription or depletion of individual architectural proteins. Heat shock-induced inter-TAD interactions result in increased contacts among enhancers and promoters of silenced genes, which recruit Pc and form Pc bodies in the nucleolus. These results suggest that the TAD organization of metazoan genomes is plastic and can be reconfigured quickly. PMID- 25818645 TI - Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms. AB - Protein isoforms are widely expressed in biological systems. How isoforms that co exist within the same sub-cellular domain are differentially activated remains unclear. Here, we compare the regulatory mechanism of two closely related transcription factor isoforms, NFAT1 and NFAT4, that migrate from the cytoplasm to the nucleus following the increase in intracellular Ca(2+) that accompanies the opening of store-operated Orai1/CRAC channels. We demonstrate that NFAT1 has a private line of communication with Orai1, activating in response to Ca(2+) microdomains near the open channels. By contrast, NFAT4 stimulation requires both local Ca(2+) entry and a nuclear Ca(2+) rise. We mapped differences in nuclear location to amino acids within the SP-3 motif of the NFAT regulatory domain. The different Ca(2+) dependencies enable agonists to recruit different isoform combinations as stimulus strength increases. Our study uncovers a mechanism whereby co-existing cytoplasmic transcription factor isoforms are differentially activated by distinct sub-cellular Ca(2+) signals. PMID- 25818646 TI - Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC. AB - MYC is an oncoprotein transcription factor that is overexpressed in the majority of malignancies. The oncogenic potential of MYC stems from its ability to bind regulatory sequences in thousands of target genes, which depends on interaction of MYC with its obligate partner, MAX. Here, we show that broad association of MYC with chromatin also depends on interaction with the WD40-repeat protein WDR5. MYC binds WDR5 via an evolutionarily conserved "MYC box IIIb" motif that engages a shallow, hydrophobic cleft on the surface of WDR5. Structure-guided mutations in MYC that disrupt interaction with WDR5 attenuate binding of MYC at ~80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis. Our data reveal WDR5 as a key determinant for MYC recruitment to chromatin and uncover a tractable target for the discovery of anticancer therapies against MYC-driven tumors. PMID- 25818647 TI - Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. AB - Acetylation of histones at DNA regulatory elements plays a critical role in transcriptional activation. Histones are also modified by other acyl moieties, including crotonyl, yet the mechanisms that govern acetylation versus crotonylation and the functional consequences of this "choice" remain unclear. We show that the coactivator p300 has both crotonyltransferase and acetyltransferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree than histone acetylation. Levels of histone crotonylation are regulated by the cellular concentration of crotonyl-CoA, which can be altered through genetic and environmental perturbations. In a cell-based model of transcriptional activation, increasing or decreasing the cellular concentration of crotonyl-CoA leads to enhanced or diminished gene expression, respectively, which correlates with the levels of histone crotonylation flanking the regulatory elements of activated genes. Our findings support a general principle wherein differential histone acylation (i.e., acetylation versus crotonylation) couples cellular metabolism to the regulation of gene expression. PMID- 25818649 TI - Understanding and treating painful diabetic neuropathy: time for a paradigm shift. AB - The pathogenesis of diabetic neuropathy (DN) continues to be unclear and as a result, progress in developing effective therapies has been disappointing. In particular, there is only limited understanding of why some patients suffer severe chronic pain, whilst others have painless symptoms. Assessment of the peripheral nerves frequently shows no differences between painful and painless DN. There is growing evidence that the nerve damage in DN is more generalized, including the central nervous system, and these central changes are key to the development and persistence of pain in DN. The advent of new radiological techniques provides us with non-invasive modalities to study central pathophysiological processes in greater detail. These insights are increasingly leading to the recognition that painful DN is a complex and heterogeneous disorder, which requires a multimodal approach to treatment. PMID- 25818648 TI - Differential phosphorylation of DNA-PKcs regulates the interplay between end processing and end-ligation during nonhomologous end-joining. AB - Nonhomologous end-joining (NHEJ) is a major DNA double-strand break repair pathway that is conserved in eukaryotes. In vertebrates, NHEJ further acquires end-processing capacities (e.g., hairpin opening) in addition to direct end ligation. The catalytic subunit of DNA-PK (DNA-PKcs) is a vertebrate-specific NHEJ factor that can be autophosphorylated or transphosphorylated by ATM kinase. Using a mouse model expressing a kinase-dead (KD) DNA-PKcs protein, we show that ATM-mediated transphosphorylation of DNA-PKcs regulates end-processing at the level of Artemis recruitment, while strict autophosphorylation of DNA-PKcs is necessary to relieve the physical blockage on end-ligation imposed by the DNA PKcs protein itself. Accordingly, DNA-PKcs(KD/KD) mice and cells show severe end ligation defects and p53- and Ku-dependent embryonic lethality, but open hairpin sealed ends normally in the presence of ATM kinase activity. Together, our findings identify DNA-PKcs as the molecular switch that coordinates end processing and end-ligation at the DNA ends through differential phosphorylations. PMID- 25818650 TI - Response to Time to resize the role of liver transplant for Budd-Chiari syndrome. PMID- 25818651 TI - Discrepancies between ESMO and NCCN breast cancer guidelines: An appraisal. AB - An ever growing number of medical organizations, societies, working groups and governmental agencies issue algorithms i.e. guidelines, of decision making flowcharts in diagnosis and treatment in a variety of diseases. In the field of evidence-based diagnosis and treatment of breast cancer, a large number of guidelines are available both from medical associations and national health departments. Among the most appreciated and utilized comprehensive guides is the European Society for Medical Oncology (ESMO) Breast Cancer Guidelines and from the other side of the Atlantic the National Comprehensive Cancer Network (NCCN) Guidelines in Breast Cancer. Although there is much concordance between the guidelines from these two organizations, it is intriguing to locate their discrepancies also. The aim of this report is to present a number of different points between ESMO and NCCN in the whole spectrum of breast cancer management, from prevention and diagnosis to treatment and follow up. This systematic review was performed in accordance with the PRISMA guidelines using a predefined search strategy and summarizes in detail, the differences between ESMO and NCCN guidelines regarding genetic risk evaluation and screening, surgery, chemotherapy, endocrine treatment, targeted biological agents, radiotherapy, pregnancy and fertility and follow-up. PMID- 25818653 TI - Postoperative Delirium in Patients Undergoing Total Joint Arthroplasty: A Systematic Review. AB - We systematically reviewed the English-language literature to assess the incidence, risk factors and prevention strategies for postoperative delirium following total joint arthroplasty (TJA). A total of 10 studies were included in the final review, of which 3 (30%) were Level I studies, 6 were Level II (60%) studies and 1 (10%) was a Level III study. Incidence of postoperative delirium ranged from 5% to 14.3%. Pre-screening of patients was shown to reduce its incidence. Independent predictors include age, history of psychiatric illness, decreased functional status and decreased verbal memory. PMID- 25818652 TI - The Streptococcus pyogenes NAD(+) glycohydrolase modulates epithelial cell PARylation and HMGB1 release. AB - Streptococcus pyogenes uses the cytolysin streptolysin O (SLO) to translocate an enzyme, the S. pyogenes NAD(+) glycohydrolase (SPN), into the host cell cytosol. However, the function of SPN in this compartment is not known. As a complication, many S. pyogenes strains express a SPN variant lacking NAD(+) glycohydrolase (NADase) activity. Here, we show that SPN modifies several SLO- and NAD(+) dependent host cell responses in patterns that correlate with NADase activity. SLO pore formation results in hyperactivation of the cellular enzyme poly-ADP ribose polymerase-1 (PARP-1) and production of polymers of poly-ADP-ribose (PAR). However, while SPN NADase activity moderates PARP-1 activation and blocks accumulation of PAR, these processes continued unabated in the presence of NADase inactive SPN. Temporal analyses revealed that while PAR production is initially independent of NADase activity, PAR rapidly disappears in the presence of NADase active SPN, host cell ATP is depleted and the pro-inflammatory mediator high mobility group box-1 (HMGB1) protein is released from the nucleus by a PARP-1 dependent mechanism. In contrast, HMGB1 is not released in response to NADase inactive SPN and instead the cells release elevated levels of interleukin-8 and tumour necrosis factor-alpha. Thus, SPN and SLO combine to induce cellular responses subsequently influenced by the presence or absence of NADase activity. PMID- 25818654 TI - Delayed recurrence of renal cell carcinoma presenting as a haemorrhoid. AB - Metastatic non-colorectal cancer of the anal canal is a rare entity. To date, only four cases have been described in the literature. We present a 76-year-old man who was referred with an unusual perianal lesion. He had a history of renal cell carcinoma 7 years previously. Histologically, the lesion revealed clear cell carcinoma in keeping with metastasis. To our knowledge, this is only the second time a renal carcinoma metastasis to the anal canal has been identified. PMID- 25818655 TI - Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons. AB - Ras homolog enriched in striatum (Rhes) is highly expressed in striatal medium spiny neurons (MSNs) of rodents. In the present study, we characterized the expression of Rhes mRNA across species, as well as its functional role in other striatal neuron subtypes. Double in situ hybridization analysis showed that Rhes transcript is selectively localized in striatal cholinergic interneurons (ChIs), but not in GABAergic parvalbumin- or in neuropeptide Y-positive cell populations. Rhes is closely linked to dopamine-dependent signaling. Therefore, we recorded ChIs activity in basal condition and following dopamine receptor activation. Surprisingly, instead of an expected dopamine D2 receptor (D2R)-mediated inhibition, we observed an aberrant excitatory response in ChIs from Rhes knockout mice. Conversely, the effect of D1R agonist on ChIs was less robust in Rhes mutants than in controls. Although Rhes deletion in mutants occurs throughout the striatum, we demonstrate that the D2R response is altered specifically in ChIs, since it was recorded in pharmacological isolation, and prevented either by intrapipette BAPTA or by GDP-beta-S. Moreover, we show that blockade of Cav2.2 calcium channels prevented the abnormal D2R response. Finally, we found that the abnormal D2R activation in ChIs was rescued by selective PI3K inhibition thus suggesting that Rhes functionally modulates PI3K/Akt signaling pathway in these neurons. Our findings reveal that, besides its expression in MSNs, Rhes is localized also in striatal ChIs and, most importantly, lack of this G-protein, significantly alters D2R modulation of striatal cholinergic excitability. PMID- 25818656 TI - Effect of prosthetic restoration on oral health-related quality of life in patients with shortened dental arches: a multicentre study. AB - The aim of this multicentre prospective study was to investigate the effect of prosthetic restoration for missing posterior teeth in patients with shortened dental arches (SDAs). SDA patients with 2-12 missing occlusal units (a pair of occluding premolars corresponds to one unit, and a pair of occluding molars corresponds to two units) were consecutively recruited from seven university based dental hospitals in Japan. Patients chose no replacement of missing teeth or prosthetic treatment with removable partial dentures (RPDs) or implant supported fixed partial dentures (IFPDs). Oral health-related quality of life (OHRQoL) was measured using the oral health impact profile (Japanese version - OHIP-J) at baseline and follow-up/post-treatment evaluation. Of the 169 subjects who completed baseline evaluation, 125 subjects (mean age; 63.0 years) received follow-up/post-treatment evaluation. No-treatment was chosen by 42% (53/125) of the subjects, and 58% (72/125) chose treatment with a RPD (n = 53) or an IFPD (n = 19). In the no-treatment (NT) group, the mean OHIP summary score at baseline was similar to that at follow-up evaluation (P = 0.69). In the treatment (TRT) group, the mean OHIP summary score decreased significantly after the RPD treatment (P = 0.002), and it tended to decrease, though not statistically significant (P = 0.18), after the IFPD treatment. The restoration of one occlusal unit was associated with a 1.2-point decrease in OHIP summary score (P = 0.034). These results suggest that the replacement of missing posterior teeth with RPDs or IFPDs improved OHRQoL. Prosthetic restoration for SDAs may benefit OHRQoL in patients needing replacement of missing posterior teeth. PMID- 25818657 TI - Genetic polymorphism of KIR2DL4 in the Polish population. AB - The KIR2DL4 gene is characterized by alleles with either 9 or 10 consecutive adenines in exon 7, which encodes the transmembrane domain. The 9A variant produces either a protein with a truncated cytoplasmic tail or one lacking the transmembrane region. This causes a lack of KIR2DL4 expression. In contrast, 10A alleles encode receptors that may be expressed at the cell surface. We tested 438 healthy individuals for polymorphism of the KIR2DL4 gene. KIR2DL4 9A/10A alleles were distinguished by the high resolution melting (HRM) method, and restriction fragment length polymorphism (RFLP) was used for genotyping of three other single nucleotide polymorphisms (SNPs) spanning the near vicinity of the poly-adenine fragment. We found a weak difference between males and females in 9769 C/A genotypes and alleles. In addition, we observed complete linkage disequilibrium (LD) between 9A insertion/deletion in the 9620 position and the 9571T/C position of the gene (r(2) = 1) both in females and males and almost complete LD with the 9797G/A position (r(2) = 0.963 for females and r(2) = 0.892 for males). Most importantly, we detected, in a group of fertile women, a high frequency (30.2%) of homozygosity for the defective 9A variant, which suggests that KIR2DL4 as a functional cell surface receptor is not absolutely necessary for reproduction. On the other hand, lower representation of 10A/10A homozygotes and high frequency of 10A/9A heterozygotes indicates a need for both cell membrane-anchored and soluble KIR2DL4 molecules. Finally, cost-reducing RFLP instead of HRM is proposed for typing 9A and 10A variants. PMID- 25818658 TI - Peritoneal metastases from small bowel cancer: Results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in The Netherlands. AB - INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is currently considered the standard of care for pseudomyxoma peritonei, mesothelioma and peritoneal metastases (PM) from colorectal cancer. CRS + HIPEC has also been suggested as a potential treatment option in PM of the much rarer small bowel cancer. Therefore, the current study was undertaken to investigate the results of CRS + HIPEC in all HIPEC centers in The Netherlands. METHODS: From the 4 tertiary referral centers for peritoneal surface malignancies in The Netherlands, data from all patients with peritoneally metastasized small bowel carcinoma intended to undergo CRS and HIPEC were collected between January 2005 and July 2014. Primary tumor characteristics, operative details, and survival outcomes were collected. RESULTS: Sixteen of 19 patients (84.2%) who underwent explorative laparotomy underwent CRS + HIPEC. Of these patients, 81.3% were female, and primary tumors were mainly located in the ileum (50%). A complete macroscopic resection was achieved in 93.8%. Serious adverse events requiring re-intervention occurred in 25%, and no in-hospital mortality was observed. Recurrent disease was observed in 50% of patients and median survival after CRS and HIPEC was 31 months. CONCLUSION: In a select group of patients in whom a complete macroscopic resection can be achieved, survival rates comparable with those in colorectal PM are attainable with acceptable morbidity. The role of adjuvant chemotherapy needs further research. PMID- 25818660 TI - Treatment of invasive candidiasis: between guidelines and daily clinical practice. AB - Invasive candidiasis, including candidemia (IC/C), is a major cause of morbidity and mortality among hospitalized patients. While incidence is higher in intensive care units, the majority of cases of candidemia are documented in medical wards. Although Candida albicans is still the most frequently isolated species, IC/C due to non-albicans species, usually less susceptible to fluconazole, is increasing. Early identification of patients at risk, knowledge of local epidemiology and prompt efforts to define etiologic diagnosis play a pivotal role for appropriateness. Starting therapy with an echinocandin, switching then to fluconazole when possible, seems to represent a potentially useful strategy for the management of IC/C. The choice between the three echinocandins should be based on the specific indications, pharmacokinetic/pharmacodynamic profile, clinical experience and relative cost. PMID- 25818659 TI - Neutrophil to lymphocyte ratio is a strong predictor of tumor recurrence in early colon cancers: A propensity score-matched analysis. AB - BACKGROUND: Systemic inflammation and immune response play a crucial role in tumor growth, and the neutrophil to lymphocyte ratio (NLR) may be a simple way to assess the host inflammatory response. The NLR has been shown to be a prognostic indicator in many human tumors; in early colon cancers, it has been evaluated only in a few studies and its role remains controversial. METHODS: We analyzed data from 503 colon cancer patients. The best cutoff value for NLR was defined by receiver operating characteristic curve analysis. We grouped 276 Dukes A/B colon cancers, not receiving adjuvant chemotherapy, into low (<2.36) and high (>2.36) NLR and subjected to further analyses related to disease-free survival (DFS). A propensity score-matched analysis and the inverse probability of treatment weighting (IPTW) were performed to avoid confounding bias. RESULTS: The NLR correlated with tumor stage and oncologic outcome. The best NLR cutoff value was identical in the whole cohort and in Dukes A/B patients. Low NLR patients had a significantly better DFS rate than high NLR patients (hazard ratio [HR], 0.27; P = .0001); along with elevated carcinoembryonic antigen levels and Dukes B stage, high NLR was an independent prognostic factor of worse prognosis (HR, 2.86; P = .0033). Even in Dukes A patients, NLR discriminated between relapsing and nonrelapsing patients. Propensity score and IPTW analyses confirmed such results, thus excluding possible misinterpretation. CONCLUSION: Preoperative NLR, an inexpensive and readily available biomarker, can predict tumor relapse and should be assessed for implementation of tailored therapy in early stage colon cancer. PMID- 25818661 TI - A Review Study on the Effect of Iranian Herbal Medicines on Opioid Withdrawal Syndrome. AB - Addiction is a chronic and recurring disease that recurrence phenomenon is the most important challenge in treatment of this disease. Recent experiences have shown that synthetic drugs have undesirable side effects. Recent studies on medicinal plants have shown that they might be effective in treatment of different stages of addiction with lower side effects and costs. The aim of this study was to review the effects of medicinal plants in the treatment of morphine addiction in experimental animals. In this review article, by using keywords of morphine, withdrawal, and plants or herbal medicine in databases of indexing cites, desired articles were obtained since 1994. Inclusion criteria for selecting articles were the articles related to application of medicinal plants in decreasing symptoms resulting from morphine withdrawal were selected. Results of this study on experimental studies have shown that medicinal plants such as Trachyspermum copticum L and Melissa officinalis decrease the symptoms of withdrawal syndrome in a dose-dependent. Also, medicinal plants like Avena sativa, Hypericum perforatu, Passiflora incarnate, Valeriana officinalis, Satureja hortensis L, and Mentha piperita can have effects on behavior, emotions, and other problems of addicts, decreasing withdrawal symptoms. Results of this study showed that medicinal plants can be effective in controlling deprivation, decreasing dependency creation, and possibly DETOXIFICATION: of opioid addicts. PMID- 25818662 TI - Individual and population-level sex-dependent lateralization in yellow-legged gull (Larus michahellis) chicks. AB - Behavioral lateralization at the population level is widespread across vertebrates, with considerable variation among species. However, evidence for individual-level and sex-dependent lateralization is sparse and inconsistent in fish, reptiles and birds. In addition, covariation of lateralization with position in the laying sequence, which is expected because the concentration of maternal egg hormones varies with laying order, has never been investigated. We analyzed lateralization of yellow-legged gull (Larus michahellis) chicks in reverting from supine to prone posture ('RTP' response) and in pecking at a dummy parental bill to solicit food provisioning ('begging' response). Chicks were lateralized both at the population and at the individual level in the RTP response and at the individual level in begging. Lateralization in the RTP was sex-dependent, as females showed a leftward preference. Lateralization in either motor task was not correlated within individuals. Lateralization did not differ among families, suggesting little additive genetic variation. Lateral preference in begging response varied according to laying order and matched variation in egg androgens concentration. Our study confirms previous findings on population-level lateralization and adds to the scant information on individual-level and heritable variation in lateralization in birds. Moreover, it hints at epigenetic components in lateralization depending on maternal effects. PMID- 25818663 TI - Human Endometrial Transcriptomics: Implications for Embryonic Implantation. AB - Human endometrium has been extensively investigated in the search for markers capable of predicting its receptive status. The completion of the Human Genome Project has triggered a rapid development of new fields in molecular biology, the "transcriptomics" being a major turning point in the knowledge acquisition of endometrial receptivity. Based on this, a customized Endometrial Receptivity Array (ERA) has been developed, which is capable of identifying the genomic signature of receptivity. This diagnostic tool showed that the window of implantation (WOI) is displaced in one out of four patients with implantation failure, allowing the identification of their personalized WOI. This strategy allows performing a personalized embryo transfer (pET) on the day in which the endometrium is receptive. The combination of a systems biology approach and next generation sequencing will overcome the limitations of microarrays, and will, in the future, allow elucidation of the mechanisms involved in embryo implantation. PMID- 25818665 TI - Introduction to Intellectual Property: A U.S. Perspective. AB - This review introduces patents and trade secrets, the two mechanisms that U.S. law provides inventors to protect their inventions. These mechanisms are mutually exclusive: One demands disclosure and the other calls for concealment. Many biotechnology innovators opt for patents, which grant legal, time-limited monopolies to eligible inventions.To obtain a patent in the United States, an invention must be useful to the public and made or altered by the hand of man. It must then clear the hurdles of novelty and nonobviousness. If an invention can do that, obtaining a patent becomes a matter of form: Who qualifies as an inventor? Does the application demonstrate possession, stake a clear claim to the protection sought, and enable "ordinary" colleagues to replicate it? Has the inventor purposely withheld anything? This review addresses each of these hurdles as they apply to biotech inventions. PMID- 25818664 TI - The Mycobacterial Cell Wall--Peptidoglycan and Arabinogalactan. AB - The mycobacterial bacillus is encompassed by a remarkably elaborate cell wall structure. The mycolyl-arabinogalactan-peptidoglycan (mAGP) complex is essential for the viability of Mycobacterium tuberculosis and maintains a robust basal structure supporting the upper "myco-membrane." M. tuberculosis peptidoglycan, although appearing to be unexceptional at first glance, contains a number of unique molecular subtleties that become particularly important as the TB-bacilli enters into nonreplicative growth during dormancy. Arabinogalactan, a highly branched polysaccharide, serves to connect peptidoglycan with the outer mycolic acid layer, and a variety of unique glycolsyltransferases are used for its assembly. In this review, we shall explore the microbial chemistry of this unique heteropolysacchride, examine the molecular genetics that underpins its fabrication, and discuss how the essential biosynthetic process might be exploited for the development of future anti-TB chemotherapies. PMID- 25818666 TI - miR-709 up-regulated in hepatocellular carcinoma, promotes proliferation and invasion by targeting GPC5. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the most common cancers and is a significant leading cause of cancer-related deaths worldwide. Emerging evidence has shown that microRNAs (miRNAs) are associated with cancer development and progression. However, up to now little has been known concerning the role of miR-709 in HCC. MATERIALS AND METHODS: Real-time RT-PCR was performed to detect expression of miR-709 in HCC cell lines and tissues. To further understand its role in HCC, we restored its expression in HepG2 cell line through transfection with miR-709 mimics or inhibitors. CCK-8 proliferation assay, migration assay and invasion assay were used to detect functional roles of miR-709. Luciferase assay and western blotting were performed to detect the target gene of miR-709. RESULTS: We found that miR-709 was highly expressed in HCC tissues and in HCC cell lines by qRT-PCR. Re-expression of miR-709 in HCC cells remarkably promoted cell migration and invasiveness in vitro. Subsequent investigation revealed that glypican-5 (GPC5) was a direct and functional target of miR-709 in HCC cells where overexpression of miR-709 impaired GPC5-induced inhibition of proliferation and invasion. Finally, analysis of miR-709 and GPC5 levels in human HCC tissues revealed that miR-709 inversely correlated with GPC5 expression. CONCLUSIONS: These results suggest that miR-709 may positively regulate invasion and metastasis of HCC through targeting GPC5. PMID- 25818667 TI - A manifesto on the preservation of sexual function in women and girls with cancer. AB - Malignancies that affect females who survive cancer commonly originate in, invade, and/or metastasize to the sexual organs, including the ovaries, uterine corpus, uterine cervix, vagina, vulva, fallopian tubes, anus, rectum, breast(s), and brain. Females comprise most of the population (in number and proportion) with cancers that directly affect the sexual organs. Most females in the age groups most commonly affected by cancer are sexually active in the year before diagnosis, which includes most menopausal women who have a partner. Among female cancer survivors, the vast majority have cancers that are treated with local or systemic therapies that result in removal, compromise, or destruction of the sexual organs. Additionally, female cancer survivors often experience abrupt or premature onset of menopause, either directly with surgery, radiation, or other treatments or indirectly through disruption of female sex hormone or other neuroendocrine physiology. For many female patients, cancer treatment has short term and long-lasting effects on other aspects of physical, psychological, and social functioning that can interfere with normal sexual function; these effects include pain, depression, and anxiety; fatigue and sleep disruption; changes in weight and body image; scars, loss of normal skin sensation, and other skin changes; changes in bodily odors; ostomies and loss of normal bowel and bladder function; lymphedema, and strained intimate partnerships and other changes in social roles. In spite of these facts, female patients who are treated for cancer receive insufficient counseling, support, or treatment to preserve or regain sexual function after cancer treatment. PMID- 25818669 TI - Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bile acid levels. PMID- 25818668 TI - The effect of menopause on the innate antiviral activity of cervicovaginal lavage. AB - OBJECTIVE: Reproductive hormones are known to impact innate mucosal immune function of the lower genital tract. Our objectives were to determine the effect of hormonal status on intrinsic antiviral (herpes simplex virus [HSV]-1, HSV-2, and human immunodeficiency virus [HIV]-1) activity of cervicovaginal lavage (CVL). STUDY DESIGN: CVL was collected from 165 asymptomatic women including postmenopausal women (n = 29); women not on contraception in days 1-14 (n = 26) or days 15-28 (n = 27) of the menstrual cycle; and women using the levonorgestrel intrauterine device (n = 28), depot medroxyprogesterone acetate (n = 28), or combined oral contraceptives (n = 27). The anti-HSV-1/-2 and the anti-HIV-1 activity of the CVL were measured using plaque assays and the Jurkat-Tat-CCR5 assay, respectively. RESULTS: CVL from all of the groups had modest antiviral activity. Anti-HIV-1 activity was decreased in CVL from postmenopausal women when compared to premenopausal women (11% vs 34%, P = .002). However, there was no difference in anti-HIV-1 activity among premenopausal women regardless of phase of menstrual cycle or contraceptive use. Anti-HIV-1 activity was associated with the protein content of the CVL (r = 0.44, P < .001). There was no difference in anti-HSV-1 or -2 activity by hormonal group. CONCLUSION: Menopause is associated with decreased innate HIV-1 activity in the lower genital tract, suggesting that factors in the vaginal fluid could play a role in increased susceptibility of HIV 1 infection in postmenopausal women. Hormonal contraceptive use, menopause, and phase of menstrual cycle did not have a measurable impact on the intrinsic anti HSV-1 or -2 activity. PMID- 25818670 TI - Reply: To PMID 25046809. PMID- 25818671 TI - New insights in the pathophysiology of ovarian cancer and implications for screening and prevention. AB - Despite advances in medicine, ovarian cancer remains the deadliest of the gynecological malignancies. Herein we present the latest information on the pathophysiology of ovarian cancer and its significance for ovarian cancer screening and prevention. A new paradigm for ovarian cancer pathogenesis presupposes 2 distinct types of ovarian epithelial carcinoma with distinct molecular profiles: type I and type II carcinomas. Type I tumors include endometrioid, clear-cell carcinoma, and low-grade serous carcinoma and mostly arise via defined sequence either from endometriosis or from borderline serous tumors, mostly presenting in an early stage. More frequent type II carcinomas are usually high-grade serous tumors, and recent evidence suggests that the majority arise from the fimbriated end of the fallopian tube. Subsequently, high-grade serous carcinomas usually present at advanced stages, likely as a consequence of the rapid peritoneal seeding from the open ends of the fallopian tubes. On the other hand, careful clinical evaluation should be performed along with risk stratification and targeted treatment of women with premalignant conditions leading to type I cancers, most notably endometriosis and endometriomas. Although the chance of malignant transformation is low, an understanding of this link offers a possibility of prevention and early intervention. This new evidence explains difficulties in ovarian cancer screening and helps in forming new recommendations for ovarian cancer risk evaluation and prophylactic treatments. PMID- 25818672 TI - Diagnostic accuracy of fundal height and handheld ultrasound-measured abdominal circumference to screen for fetal growth abnormalities. AB - OBJECTIVE: We sought to compare fundal height and handheld ultrasound-measured fetal abdominal circumference (HHAC) for the prediction of fetal growth restriction (FGR) or large for gestational age. STUDY DESIGN: This was a diagnostic accuracy study in nonanomalous singleton pregnancies between 24 and 40 weeks' gestation. Patients underwent HHAC and fundal height measurement prior to formal growth ultrasound. FGR was defined as estimated fetal weight less than 10%, whereas large for gestational age was defined as estimated fetal weight greater than 90%. Sensitivity and specificity were calculated and compared using methods described elsewhere. RESULTS: There were 251 patients included in this study. HHAC had superior sensitivity and specificity for the detection of FGR (sensitivity, 100% vs 42.86%) and (specificity, 92.62% vs 85.24%). HHAC had higher specificity but lower sensitivity when screening for LGA (specificity, 85.66% vs 66.39%) and (sensitivity, 57.14% vs 71.43%). CONCLUSION: HHAC could prove to be a valuable screening tool in the detection of FGR. Further studies are needed in a larger population. PMID- 25818673 TI - Placement of a distal implant to convert a mandibular removable Kennedy class I to an implant-supported partial removable Class III dental prosthesis: A systematic review. AB - STATEMENT OF PROBLEM: A number of authors have reported the placement of a distal implant associated with a partial removable dental prosthesis (PRDP) to make this rehabilitation more stable. This strategy may represent an option for resolving the problem of the intrusive movements of the PRDP and for reducing treatment costs. PURPOSE: The purpose of this systematic review was to evaluate the current evidence about the placement of a distal implant associated with a mandibular PRDP to improve patient satisfaction and the clinical performance of the abutment tooth and distal implant. MATERIAL AND METHODS: Two independent prosthetic specialist reviewers conducted this systematic review. The search was performed using selected clinical studies with PRDP associated with distal implants published in English up to May 2014 from the PubMed and Cochrane Library databases. A data extraction form was developed to collect general information: authors, title, year of publication, aim of study, level of evidence, number of participants, number of implants used, implant system, implant length and diameter, abutment type, masticatory performance, patient satisfaction, implant mean bone loss, abutment tooth mean bone loss, prosthetic complications, follow up period, and implant survival rate. The quality of the selected studies and the risk of bias were also reported. RESULTS: The initial electronic search identified 231 studies, and the manual process identified 15 studies (total of 246 studies). After the title and abstract reading and the removal of duplicates, the full texts of 43 studies were obtained. The articles that did not meet the inclusion criteria were excluded (28 studies), and the data from 15 studies were extracted. Seven were retrospective studies, 1 a crossover pilot study, 2 case series, 2 paired clinical studies, and 3 case reports, demonstrating that a high number of the selected studies were of low methodological quality. Nevertheless, the high survival rates for PRDP associated with dental implants have been described. CONCLUSIONS: The use of a PRDP associated with dental implants to convert a Kennedy class I to class III dental prosthesis benefits patients by improving their satisfaction and masticatory abilities without decreasing implant survival rates. Considering the abutment tooth survival rate, clinical studies with comparable methodology are still lacking to define protocols regarding the use of distal implants associated with PRDP. Long-term, prospective clinical trials are still needed to understand which implant abutments increase abutment tooth survival rate. PMID- 25818674 TI - The potential use of mesenchymal stem cells in stroke therapy--From bench to bedside. AB - Stroke is the second main cause of morbidity and mortality worldwide. The rationale for the use of mesenchymal stem cells (MSCs) in stroke is based on the capacity of MSCs to secrete a large variety of bioactive molecules such as growth factors, cytokines and chemokines leading to reduction of inflammation, increased neurogenesis from the germinative niches of central nervous system, increased angiogenesis, effects on astrocytes, oligodendrocytes and axons. This review presents the data derived from experimental studies and the evidence available from clinical trials about the use of MSCs in stroke therapy. PMID- 25818675 TI - Creutzfeldt-Jakob disease with homozygous M232R mutation: A case report. PMID- 25818676 TI - Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats. AB - Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours. All animals were sacrificed after different reperfusion times. Rats were administered either DMSO or thalidomide (20mg/kg (i.p.)) at different times before or during reperfusion: 1) 1h before reperfusion; the infarct area was measured 2h after reperfusion. 2) 10min before reperfusion and 80min after reperfusion; the infarct area was measured 24h after reperfusion; and 3) 10min before reperfusion and 1h, 24h, 48h, and 68h after reperfusion; the infarct area was measured 72h after reperfusion. Thalidomide reduced the infarct area 24h and 72h after MCAO, and decreased the neurological deficit in all groups with respect to controls. Thalidomide also lowered significantly the number of TUNEL-positive cells, levels of Bax, caspase 3, lipoperoxidation, and pro-inflammatory cytokines, and increased the levels of SOD1, Bcl-2 and pAkt. These results show that thalidomide has neuroprotective effects, apparently due to its anti-apoptotic, anti-oxidant, and anti inflammatory effects. PMID- 25818678 TI - Soluble c5b-9 as a biomarker for complement activation in atypical hemolytic uremic syndrome. PMID- 25818677 TI - Gout after living kidney donation: a matched cohort study. AB - BACKGROUND: In the general population, high serum uric acid concentration is a risk factor for gout. It is unknown whether donating a kidney increases a living donor's risk of gout as serum uric acid concentration increases in donors after nephrectomy. STUDY DESIGN: Retrospective matched cohort study using large health care databases. SETTING & PARTICIPANTS: We studied living kidney donors who donated in 1992 to 2010 in Ontario, Canada. Matched nondonors were selected from the healthiest segment of the general population. 1,988 donors and 19,880 matched nondonors were followed up for a median of 8.4 (maximum, 20.8) years. PREDICTOR: Living kidney donor nephrectomy. OUTCOMES: The primary outcome was time to a diagnosis of gout. The secondary outcome in a subpopulation was receipt of medications typically used to treat gout (allopurinol or colchicine). MEASUREMENTS: We assessed the primary outcome with health care diagnostic codes. RESULTS: Donors compared with nondonors were more likely to be given a diagnosis of gout (3.4% vs 2.0%; 3.5 vs 2.1 events/1,000 person-years; HR, 1.6; 95% CI, 1.2 2.1; P<0.001). Similarly, donors compared with nondonors were more likely to receive a prescription for allopurinol or colchicine (3.8% vs 1.3%; OR, 3.2; 95% CI, 1.5-6.7; P=0.002). Results were consistent in multiple additional analyses. LIMITATIONS: The primary outcome was assessed using diagnostic codes in health care databases. Laboratory values for serum uric acid and creatinine in follow-up were not available in our data sources. CONCLUSIONS: The findings suggest that donating a kidney modestly increases an individual's absolute long-term incidence of gout. This unique observation should be corroborated in future studies. PMID- 25818679 TI - Aortic Stiffness, Ambulatory Blood Pressure, and Predictors of Response to Antihypertensive Therapy in Hemodialysis. AB - BACKGROUND: Arterial stiffness is associated with elevated blood pressure (BP), but it is unclear whether it also makes hypertension more resistant to treatment. Among hypertensive dialysis patients, this study investigated whether aortic stiffness determines ambulatory BP and predicts its improvement with therapy. STUDY DESIGN: Post hoc analysis of the Hypertension in Hemodialysis Patients Treated With Atenolol or Lisinopril (HDPAL) trial. SETTINGS & PARTICIPANTS: 179 hypertensive hemodialysis patients with echocardiographic left ventricular hypertrophy. PREDICTOR: Baseline aortic pulse wave velocity (PWV). OUTCOME: Baseline and treatment-induced change in 44-hour ambulatory BP at 3, 6, and 12 months. MEASUREMENTS: Aortic PWV was assessed with an echocardiographic-Doppler technique (ACUSON Cypress, Siemens Medical), and 44-hour interdialytic ambulatory BP monitoring was performed with a Spacelabs 90207 monitor. RESULTS: Mean baseline aortic PWV was 7.6+/-2.7 (SD) m/s. Overall treatment-induced changes in ambulatory systolic BP (SBP) were -15.6+/-20.4, -18.9+/-22.5, and -20.0+/-19.7 mmHg at 3, 6, and 12 months. Changes in SBP were no different among tertiles of baseline PWV. Aortic PWV was associated directly with baseline ambulatory SBP and pulse pressure (PP) and inversely with diastolic BP (DBP). After adjustment for several cardiovascular risk factors, each 1-m/s higher PWV was associated with 1.34-mm Hg higher baseline SBP (beta=1.34+/-0.46; P=0.004) and 1.02-mm Hg higher PP (beta=1.02+/-0.33; P=0.002), whereas the association with DBP was no longer significant. Baseline PWV did not predict treatment-induced changes in SBP (Wald test, P=0.3) and DBP (Wald test, P=0.7), but was a predictor of an overall improvement in PP during follow-up (Wald test, P=0.03). LIMITATIONS: Observational design; predominantly black patients were studied. CONCLUSIONS: Because aortic PWV is not a predictor of treatment-induced change in ambulatory BP among hypertensive dialysis patients, it indicates that among these patients, hypertension can be controlled successfully regardless of aortic stiffness. PMID- 25818680 TI - Pap smear rates among Australian community-attached lesbian and bisexual women: some good news but disparities persist. AB - Background Research in the US and UK shows that lesbian women are less likely than their heterosexual peers to attend for routine Pap smear tests. This study examined Pap smear test rates among community-attached lesbian, bisexual and queer (LBQ) women in New South Wales (NSW), to investigate if rates had changed between 2002 and 2012, compare rates to the general NSW population and identify predictive factors for Pap smear test attendance. METHODS: Data was taken from the Sydney Women and Sexual Health (SWASH) survey, a self-completed biennial questionnaire of LBQ women's health and wellbeing. RESULTS: Of the 4083 respondents, 83% had ever had a Pap smear test. Recent attendance rates were similar to the general NSW population. Significant predictors for ever having attended for a Pap smear test were older age, post Year 12 education, ever having had a sexually transmissible infection test, being out about sexuality to a regular doctor and ever having had sex with men. CONCLUSIONS: Pap smear rates for LBQ women are encouraging when compared with rates from countries such as the US or UK. A significant proportion of LBQ women are never receiving Pap smear tests. Predictive factors suggest a continued perception that women who have not had sex with men are not at risk of human papillomavirus, and highlight the importance of health providers providing a safe and welcoming environment for LBQ women to openly discuss their health. PMID- 25818681 TI - Regulation of peroxisome proliferator-activated receptors (PPAR) alpha and -gamma of rat brain astrocytes in the course of activation by toll-like receptor agonists. AB - Peroxisome proliferator-activated receptors (PPAR)-alpha and -gamma in astrocytes play important roles in inflammatory brain pathologies. Understanding the regulation of both activity and expression levels of PPARs is an important neuroscience issue. Toll-like receptor (TLR) agonists are inflammatory stimuli that could modulate PPAR, but the mechanisms of their control in astrocytes are poorly understood. In the present study, we report that lipopolysaccharide, peptidoglycan, and flagellin, which are agonists of TLR4, TLR1/2, and TLR5, respectively, exert time- and nuclear factor kappa-light-chain-enhancer of activated B cells-dependent suppression of mRNA, protein and activity of PPARalpha and PPARgamma. In naive astrocytes, PPARalpha and PPARgamma mRNA have short turnover time (half-life about 30 min for PPARalpha, 75 min for PPARgamma) with a nearly two-fold stabilization after TLR-activation. p38 inhibition abolished TLR-induced stabilization. The levels of PPARalpha and PPARgamma mRNA, and protein and DNA-binding activity could be modified using c-Jun N-terminal Kinase and p38 inhibitors. In addition, the expression levels of both PPARalpha and PPARgamma isotypes were induced after inhibition of protein synthesis. This induction signifies participation of additional regulatory proteins with short life-time. They are p38-sensitive for PPARalpha and c-Jun N-terminal Kinase sensitive for PPARgamma. Thus, PPARalpha and PPARgamma are regulated in astrocytes on mRNA and protein levels, mRNA stability, and DNA-binding activity during TLR-mediated responses. Astrocytes have the triad of PPARalpha, PPARbeta/delta, and PPARgamma in regulation of proinflammatory responses. Activation of Toll-like receptors (TLR) leads to PPARbeta/delta overexpression, PPARalpha and PPARgamma suppression via TLR/NF-kappaB pathway on mRNA, protein and activity levels. Mitogen-activated protein kinases (MAPK) p38 and JNK are involved in regulation of PPAR expression. p38 MAPK plays a special role in stabilization of PPAR mRNA. PMID- 25818682 TI - Attentional bias to affective faces and complex IAPS images in early visual cortex follows emotional cue extraction. AB - Emotionally arousing stimuli are known to rapidly draw the brain's processing resources, even when they are task-irrelevant. The steady-state visual evoked potential (SSVEP) response, a neural response to a flickering stimulus which effectively allows measurement of the processing resources devoted to that stimulus, has been used to examine this process of attentional shifting. Previous studies have used a task in which participants detected periods of coherent motion in flickering random dot kinematograms (RDKs) which generate an SSVEP, and found that task-irrelevant emotional stimuli withdraw more attentional resources from the task-relevant RDKs than task-irrelevant neutral stimuli. However, it is not clear whether the emotion-related differences in the SSVEP response are conditional on higher-level extraction of emotional cues as indexed by well-known event-related potential (ERPs) components (N170, early posterior negativity, EPN), or if affective bias in competition for visual attention resources is a consequence of a time-invariant shifting process. In the present study, we used two different types of emotional distractors - IAPS pictures and facial expressions - for which emotional cue extraction occurs at different speeds, being typically earlier for faces (at ~170ms, as indexed by the N170) than for IAPS images (~220-280ms, EPN). We found that emotional modulation of attentional resources as measured by the SSVEP occurred earlier for faces (around 180ms) than for IAPS pictures (around 550ms), after the extraction of emotional cues as indexed by visual ERP components. This is consistent with emotion related re allocation of attentional resources occurring after emotional cue extraction rather than being linked to a time-fixed shifting process. PMID- 25818683 TI - Robust MR assessment of cerebral blood volume and mean vessel size using SPION enhanced ultrashort echo acquisition. AB - Intravascular superparamagnetic iron oxide nanoparticles (SPION)-enhanced MR transverse relaxation rates (?R2(*) and ?R2) are widely used to investigate in vivo vascular parameters, such as the cerebral blood volume (CBV), microvascular volume (MVV), and mean vessel size index (mVSI, ?R2(*)/?R2). Although highly efficient, regional comparison of vascular parameters acquired using gradient echo based ?R2(*) is hampered by its high sensitivity to magnetic field perturbations arising from air-tissue interfaces and large vessels. To minimize such demerits, we took advantage of the dual contrast property of SPION and both theoretically and experimentally verified the direct benefit of replacing gradient-echo based ?R2(*) measurement with ultra-short echo time (UTE)-based ?R1 contrast to generate the robust CBV and mVSI maps. The UTE acquisition minimized the local measurement errors from susceptibility perturbations and enabled dose independent CBV measurement using the vessel/tissue ?R1 ratio, while independent spin-echo acquisition enabled simultaneous ?R2 measurement and mVSI calculation of the cortex, cerebellum, and olfactory bulb, which are animal brain regions typified by significant susceptibility-associated measurement errors. PMID- 25818684 TI - Putting the brakes on inhibitory models of frontal lobe function. AB - There has been much recent debate regarding the neural basis of motor response inhibition. An influential hypothesis from the last decade proposes that a module within the right inferior frontal cortex (RIFC) of the human brain is dedicated to supporting response inhibition. However, there is growing evidence to support the alternative view that response inhibition is just one prominent example of the many cognitive control processes that are supported by the same set of 'domain general' functional networks. Here, I test directly between the modular and network accounts of motor response inhibition by applying a combination of data-driven, event-related and functional connectivity analyses to fMRI data from a variety of attention and inhibition tasks. The results demonstrate that there is no inhibitory module within the RIFC. Instead, response inhibition recruits a functionally heterogeneous ensemble of RIFC networks, which can be dissociated from each other in the context of other task demands. PMID- 25818685 TI - Multi-vendor reliability of arterial spin labeling perfusion MRI using a near identical sequence: implications for multi-center studies. AB - INTRODUCTION: A main obstacle that impedes standardized clinical and research applications of arterial spin labeling (ASL), is the substantial differences between the commercial implementations of ASL from major MRI vendors. In this study, we compare a single identical 2D gradient-echo EPI pseudo-continuous ASL (PCASL) sequence implemented on 3T scanners from three vendors (General Electric Healthcare, Philips Healthcare and Siemens Healthcare) within the same center and with the same subjects. MATERIAL AND METHODS: Fourteen healthy volunteers (50% male, age 26.4+/-4.7years) were scanned twice on each scanner in an interleaved manner within 3h. Because of differences in gradient and coil specifications, two separate studies were performed with slightly different sequence parameters, with one scanner used across both studies for comparison. Reproducibility was evaluated by means of quantitative cerebral blood flow (CBF) agreement and inter session variation, both on a region-of-interest (ROI) and voxel level. In addition, a qualitative similarity comparison of the CBF maps was performed by three experienced neuro-radiologists. RESULTS: There were no CBF differences between vendors in study 1 (p>0.1), but there were CBF differences of 2-19% between vendors in study 2 (p<0.001 in most gray matter ROIs) and 10-22% difference in CBF values obtained with the same vendor between studies (p<0.001 in most gray matter ROIs). The inter-vendor inter-session variation was not significantly larger than the intra-vendor variation in all (p>0.1) but one of the ROIs (p<0.001). CONCLUSION: This study demonstrates the possibility to acquire comparable cerebral CBF maps on scanners of different vendors. Small differences in sequence parameters can have a larger effect on the reproducibility of ASL than hardware or software differences between vendors. These results suggest that researchers should strive to employ identical labeling and readout strategies in multi-center ASL studies. PMID- 25818686 TI - Rivalry of homeostatic and sensory-evoked emotions: Dehydration attenuates olfactory disgust and its neural correlates. AB - Neural correlates have been described for emotions evoked by states of homeostatic imbalance (e.g. thirst, hunger, and breathlessness) and for emotions induced by external sensory stimulation (such as fear and disgust). However, the neurobiological mechanisms of their interaction, when they are experienced simultaneously, are still unknown. We investigated the interaction on the neurobiological and the perceptional level using subjective ratings, serum parameters, and functional magnetic resonance imaging (fMRI) in a situation of emotional rivalry, when both a homeostatic and a sensory-evoked emotion were experienced at the same time. Twenty highly dehydrated male subjects rated a disgusting odor as significantly less repulsive when they were thirsty. On the neurobiological level, we found that this reduction in subjective disgust during thirst was accompanied by a significantly reduced neural activity in the insular cortex, a brain area known to be considerably involved in processing of disgust. Furthermore, during the experience of disgust in the satiated condition, we observed a significant functional connectivity between brain areas responding to the disgusting odor, which was absent during the stimulation in the thirsty condition. These results suggest interference of conflicting emotions: an acute homeostatic imbalance can attenuate the experience of another emotion evoked by the sensory perception of a potentially harmful external agent. This finding offers novel insights with regard to the behavioral relevance of biologically different types of emotions, indicating that some types of emotions are more imperative for behavior than others. As a general principle, this modulatory effect during the conflict of homeostatic and sensory-evoked emotions may function to safeguard survival. PMID- 25818687 TI - High and low gamma EEG oscillations in central sensorimotor areas are conversely modulated during the human gait cycle. AB - Investigating human brain function is essential to develop models of cortical involvement during walking. Such models could advance the analysis of motor impairments following brain injuries (e.g., stroke) and may lead to novel rehabilitation approaches. In this work, we applied high-density EEG source imaging based on individual anatomy to enable neuroimaging during walking. To minimize the impact of muscular influence on EEG recordings we introduce a novel artifact correction method based on spectral decomposition. High gamma oscillations (>60Hz) were previously reported to play an important role in motor control. Here, we investigate high gamma amplitudes while focusing on two different aspects of a walking experiment, namely the fact that a person walks and the rhythmicity of walking. We found that high gamma amplitudes (60-80Hz), located focally in central sensorimotor areas, were significantly increased during walking compared to standing. Moreover, high gamma (70-90Hz) amplitudes in the same areas are modulated in relation to the gait cycle. Since the spectral peaks of high gamma amplitude increase and modulation do not match, it is plausible that these two high gamma elements represent different frequency specific network interactions. Interestingly, we found high gamma (70-90Hz) amplitudes to be coupled to low gamma (24-40Hz) amplitudes, which both are modulated in relation to the gait cycle but conversely to each other. In summary, our work is a further step towards modeling cortical involvement during human upright walking. PMID- 25818688 TI - Towards a statistical test for functional connectivity dynamics. AB - Sliding-window correlation is an emerging method for mapping time-resolved, resting-state functional connectivity. To avoid mapping spurious connectivity fluctuations (false positives), Leonardi and Van De Ville recently recommended choosing a window length exceeding the longest wavelength composing the BOLD signal, usually assumed to be ~100s. Here, we provide further statistical support for this rule of thumb. However, we demonstrate that non-stationary fluctuations in functional connectivity can in theory be detected with much shorter window lengths (e.g. 40s), while maintaining nominal control of false positives. We find that statistical power is near-maximal for window lengths chosen according to Leonardi and Van De Ville's rule of thumb. Furthermore, we lay some foundations for a parametric test to identify non-stationary fluctuations in functional connectivity, also noting limitations of the sinusoidal model upon which our work, and the work of Leonardi and Van De Ville, is based. Most notably, our analytical results pertain to covariances, as does our statistical test, whereas functional connectivity is more commonly measured using correlations. PMID- 25818689 TI - Repetition enhancement and memory effects for duration. AB - A remarkable aspect of conscious perception is that moments carryover from one to the next, also known as temporal continuity. This ability is thus crucial for detecting regularities, such as in speech and music, and may rely on an accurate perception of time. Investigations of human time perception have detailed two electroencephalographic (EEG) components associated with timing, the contingent negative variation (CNV) and late positive component of timing (LPCt); however, the precise roles of these components in timing remain elusive. Recently, we demonstrated that the perception of duration is influenced by durations presented on prior trials, which we explained by the creation of an implicit memory standard that adapts to local changes in sequence presentation. Here, we turn to the neural basis of this effect. Human participants performed a temporal bisection task in which they were required to classify the duration of auditory stimuli into short and long duration categories; crucially, the presentation order was first-order counterbalanced, allowing us to measure the effect of each presented duration on the next. EEG recordings revealed that the CNV and LPCt signals both covaried with the duration presented on the current trial, with CNV predicting reaction time and LPCt predicting choice. Additionally, both signals covaried with the duration presented in the prior trial but in different ways, with the CNV amplitude reflecting the change in the memory standard and the LPCt reflecting decision uncertainty. Furthermore, we observed a repetition enhancement effect of duration only for the CNV, suggesting that this signal additionally indexes the similarity of successive durations. These findings demonstrate dissociable roles for the CNV and LPCt, and demonstrate that both signals are continuously updated on a trial-by-trial basis that reflects shifts in temporal decisions. PMID- 25818690 TI - Oxytocin reduces neural activity in the pain circuitry when seeing pain in others. AB - Our empathetic abilities allow us to feel the pain of others. This phenomenon of vicarious feeling arises because the neural circuitry of feeling pain and seeing pain in others is shared. The neuropeptide oxytocin (OXT) is considered a robust facilitator of empathy, as intranasal OXT studies have repeatedly been shown to improve cognitive empathy (e.g. mind reading and emotion recognition). However, OXT has not yet been shown to increase neural empathic responses to pain in others, a core aspect of affective empathy. Effects of OXT on empathy for pain are difficult to predict, because OXT evidently has pain-reducing properties. Accordingly, OXT might paradoxically decrease empathy for pain. Here, using functional neuroimaging we show robust activation in the neural circuitry of pain (insula and sensorimotor regions) when subjects observe pain in others. Crucially, this empathy-related activation in the neural circuitry of pain is strongly reduced after intranasal OXT, specifically in the left insula. OXT on the basis of our neuroimaging data thus remarkably decreases empathy for pain, but further research including behavioral measures is necessary to draw definite conclusions. PMID- 25818691 TI - Predicting N2pc from anticipatory HbO activity during sustained visuospatial attention: a concurrent fNIRS-ERP study. AB - Understanding the properties of attentional control, along with the neural mechanisms subserving them, has long invited intense scrutiny in research groups. However, it has not been demonstrated how the top-down anticipatory hemodynamic activation influences the subsequent attentional processing of targets and distractors. Here, with concurrent fNIRS-ERP recording, we explored the potential contribution of anticipatory oxygenated hemoglobin (HbO) based brain activity to attentional control by examining how HbO influences the subsequent ERP N2pc components assumed to reflect attentional selection. We found that expecting a target led to a larger increase of preparatory HbO response over the visual cortex contralateral to the upcoming target, which was positively correlated with the subsequent target-evoked N2pc amplitude. Further, anticipation concerning the presence of a competing distractor resulted in large and prolonged preparatory HbO signals in the visual cortex contralateral to the distractor, indicating that the salient distractor might be actively suppressed by preparatory top-down attentional control. However, the pre-suppressed distractor still captured part of the attention in the subsequent visual search as revealed by a decrease in the N2pc amplitude, and such a distraction effect on N2pc was negatively correlated with preparatory HbO enhancement contralateral to the anticipated distractor. Overall, each individuals attentional shift to the target and resistance to the distractor measured by ERP is predictable in advance via anticipatory hemodynamic activity in the visual cortex measured by fNIRS. PMID- 25818692 TI - 90 Days toxicological assessment of hydroethanolic leaf extract of Ipomoea asarifolia (Desr.) Roem. and Schult. (Convolvulaceae) in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ipomoea asarifolia (Convolvulacae), commonly known as "morning glory" is found across West Africa. Preparations of the plant are used traditionally for the treatment of diverse ailments including diabetes, neuralgia, arthritic pain and stomach ache. This study was designed to assess the safety profile of the hydroethanolic leaf extract of I. asarifolia through a 90 day subchronic toxicity study in rats. MATERIALS AND METHODS: I. asarifolia was administered p.o. at doses of 40, 200 and 1000mg/kg to separate groups of rats for 90 days. Distilled water was given p.o. to rats in the control group. Some set of rats in each group were left for additional 30 days without administration of the extract for reversibility study. Animals were weighed weekly and relevant parameters were assayed at the end of the main and reversibility study periods. RESULTS: There was no significant change (p>0.05) in the body weight of rats, and food and water intake in I. asarifolia treated groups compared with control. I. asarifolia (40-1000 mg/kg) significantly but reversibly reduced (p<0.05, 0.001) sperm motility and count. The extract did not generally cause significant change (p>0.05) in the weight of vital organs and haematological parameters except in the case of reversible reduction in the level of haemoglobin and red blood cell count (p<0.01; 40 mg/kg). The level of biochemical parameters and electrolytes were not significantly changed (p>0.05) except for the reversible reduction in the level of aspartate aminotransferase (AST; p<0.0001; 200 and 1000 mg/kg) and increase in the level of Na(+) (p<0.01; 200 mg/kg). The level of kidney reduced glutathione (GSH) was reversibly increased (p<0.01; 1000 mg/kg) while the level of enzymatic and non-enzymatic in vivo antioxidants was generally comparable and not significantly different (p>0.05) from control in respect of all other vital organs. Histological presentations were generally normal in respect of the liver, kidneys, brain, heart, lungs, pancreas, spleen and testes. CONCLUSIONS: The findings in this study suggest that the hydroethanolic leaf extract of I. asarifolia is relatively safe administered orally for an extended period with potential renal in vivo antioxidant activities. However, the extract may cause reversible male sterility, anaemia and hypernatraemia. PMID- 25818693 TI - Ethnomedicinal uses of plants for the treatment of snake and scorpion bite in Northern Pakistan. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Medicinal plants represent one of the most accessible resources available for snake and scorpion bite among the rural communities of Northern Pakistan. This first ethno-botanical study aimed to document the indigenous knowledge and practices of using plants for snake and scorpion bite disorders in Northern Pakistan. METHODS: Ethno-medicinal data is documented from 187 informants using semi-structured interviews. The data is analyzed using quantitative ethno-botanical indices of frequency citation (FC) and relative Frequency of Citation (RFC). In addition to this, the ethno medicinal findings of this survey were compared with 10 previous published studies in order to report novel uses of medicinal plants against snake and scorpion bite disorders. RESULTS: In total 62 medicinal plants belonging to 40 families are reported against snake and scorpion bite in this study. Our results showed that Asteraceae is the most used family (10 species), dominant life form is herb (48.38%), leaves were the most used plants part (18 Use-reports) and the paste is most used method of administration (22 reports). The range of RFC was 0.08-0.27 about the use of documented species. Compared to previous published studies, 33.87% similarity index while 66.12% novelty index is reported. About 40 plant species are first time reported with medicinal uses against snake and scorpion bite from Northern Pakistan. CONCLUSIONS: This study presents useful traditional knowledge of rural communities for the control of snake and scorpion bite using medicinal plants. The study mainly focused on ethno-medicinal documentation to preserve the valuable traditional knowledge that can be used in future phytochemical and pharmacological studies on medicinal plants of the area. PMID- 25818694 TI - Thuja occidentalis L. and its active compound, alpha-thujone: Promising effects in the treatment of polycystic ovary syndrome without inducing osteoporosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Thuja occidentalis L. (Cupressaceae) has been used in folk medicine for the treatment of rheumatism, amenorrhea, cystitis, and uterine carcinomas, and as an abortifacient and contraceptive. AIM OF THE STUDY: The present study aimed to determine whether T. occidentalis oil and alpha thujone could be beneficial in the treatment of polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: T. occidentalis oil and alpha-thujone were administered to rats with letrozole-induced PCOS for 21 days. At the end of 21 days, the rats were sacrificed and blood samples were taken by cardiac puncture. The levels of serum gonadotropins, steroids, blood lipid, leptin, and glucose and the values of antioxidant parameters were measured. RESULTS: The results demonstrated that estradiol and progesterone levels significantly increased, while luteinizing hormone (LH) and testosterone levels decreased in the T. occidentalis- and alpha thujone-administered groups. The plasma low-density lipoprotein-cholesterol (LDL C), leptin, and glucose concentrations were also significantly decreased in the T. occidentalis and alpha-thujone groups when compared to the control group. Histopathological findings demonstrated that the T. occidentalis and alpha thujone groups displayed good healing. According to the phytochemical analyses, 25 compounds were identified in the T. occidentalis oil. The main constituents of the oil were the monoterpene ketones alpha- and beta-thujone, fenchone, and sabinene, as well as the diterpenes beyerene and rimuene. CONCLUSION: T. occidentalis essential oil and its active component, alpha-thujone, can be used for the treatment of PCOS without inducing osteoporosis. PMID- 25818695 TI - Embelia ribes ameliorates lipopolysaccharide-induced acute respiratory distress syndrome. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Embelia ribes Burm. f. (Fam. Myrsinaceae) locally known as Vidanga have been used for treating tumors, ascites, bronchitis, jaundice, diseases of the heart and brain in traditional Indian medicine. However, no scientific studies providing new insights in its pharmacological properties with respect to acute respiratory distress syndrome have been investigated. AIM: The present investigation aimed to elucidate the effectiveness of Embelin isolated from Embelia ribes seeds on attenuation of LPS-induced acute respiratory distress syndrome in murine models. METHODS: Embelin (5, 10 and 20 mg/kg/day, i.p.) and Roflumilast (1 mg/kg/day, p.o.) were administered for four days and prior to LPS in rats (i.t.). Four hour after LPS challenge animals were anesthesized and bronchoalveolar lavage was done with ice-cold phosphate buffer. Assessment of BAL fluid was done for albumin, total protein, total cell and neutrophil count, TNF-alpha levels, nitrosoative stress. Superior lobe of right lung was used for histopathologic evaluation. Inferior lobe of right lung was used to obtain lung edema. Left lung was used for myeloperoxidase estimation. Arterial blood was collected immediately and analyzed for pH, pO2 and pCO2 were estimated. RESULTS: Pretreatment with embelin (5, 10 and 20 mg/kg, i.p.) decreased lung edema, mononucleated cellular infiltration, nitrate/nitrite, total protein, albumin concentrations, TNF-alpha in the bronchoalveolar lavage fluid and myeloperoxidase activity in lung homogenate. Embelin markedly prevented pO2 down-regulation and pCO2 augmentation. Additionally, it attenuated lung histopathological changes in acute respiratory distress syndrome model. CONCLUSION: The study demonstrates the effectiveness of Embelia ribes Burm. f. (Fam. Myrsinaceae) seeds in acute respiratory distress syndrome possibly related to its anti-inflammatory and protective effect against LPS induced airway inflammation by reducing nitrosative stress, reducing physiological parameters of blood gas change, TNF-alpha and mononucleated cellular infiltration indicating it as a potential therapeutic agent for acute respiratory distress syndrome. PMID- 25818696 TI - Role of adipose-derived stem cells in chronic cutaneous wound healing. AB - AIM: Adipose tissue represent an alternative source of multipotent stem cells with characteristics similar to bone marrowderived mesenchymal stem cells (BMSCs), easier to isolate and effective in wound healing enhancement. MATERIAL OF STUDY: Each patient being considered for stem cells graft was subjected to a conventional liposuction procedure (local anaesthesia, aspirated volume about 80cc), in order to isolate a pellet of adipose-derived stem cells (ASCs), which was then mixed with the platelet-rich plasma (PRP) previously collected, in order to obtain an enhanced-ASCs- PRP (e-PRP), now ready for grafting in the context of skin edges as well as at the bottom of the lesion itself. RESULTS: Flow cytometric analysis performed on the pellet obtained with our isolation process, showed that a mean of 5 x 105 ASCs (range: 4,0-6,0 x 105, SD: +/- 1 x 105) were collected from 80 ml of adipose tissue, harvested with standard wet liposuction procedure. It represented the 5% of all sample cells (1 x 107), while the others 95% were mostly being blood-derived and endothelial cells. DISCUSSION: By now, the most used isolation protocols take about two hours due to the complex isolation procedure, requiring both animal-derived reagents and collagenase. The amount of ASCs obtained with our isolation process is sufficient to be directly engrafted in the wound without the need of in vitro expansion but, neither serum nor animalderived reagents are used, and it takes only 15' minutes. CONCLUSION: ASCs application is an innovative, effective approach in the treatment of chronic wounds. PMID- 25818697 TI - A Mathematical View of Water Table Fluctuations in a Shallow Aquifer in Brazil. AB - Detailed monitoring of the groundwater table can provide important data about both short- and long-term aquifer processes, including information useful for estimating recharge and facilitating groundwater modeling and remediation efforts. In this paper, we presents results of 4 years (2002 to 2005) of monitoring groundwater water levels in the Rio Claro Aquifer using observation wells drilled at the Rio Claro campus of Sao Paulo State University in Brazil. The data were used to follow natural periodic fluctuations in the water table, specifically those resulting from earth tides and seasonal recharge cycles. Statistical analyses included methods of time-series analysis using Fourier analysis, cross-correlation, and R/S analysis. Relationships could be established between rainfall and well recovery, as well as the persistence and degree of autocorrelation of the water table variations. We further used numerical solutions of the Richards equation to obtain estimates of the recharge rate and seasonable groundwater fluctuations. Seasonable soil moisture transit times through the vadose zone obtained with the numerical solution were very close to those obtained with the cross-correlation analysis. We also employed a little used deep drainage boundary condition to obtain estimates of seasonable water table fluctuations, which were found to be consistent with observed transient groundwater levels during the period of study. PMID- 25818698 TI - Mechanisms of azole resistance among clinical isolates of Candida glabrata in Poland. AB - Candida glabrata is currently ranked as the second most frequently isolated aetiological agent of human fungal infections, next only to Candida albicans. In comparison with C. albicans, C. glabrata shows lower susceptibility to azoles, the most common agents used in treatment of fungal infections. Interestingly, the mechanisms of resistance to azole agents in C. albicans have been much better investigated than those in C. glabrata. The aim of the presented study was to determine the mechanisms of resistance to azoles in 81 C. glabrata clinical isolates from three different hospitals in Poland. The investigation was carried out with a Sensititre Yeast One test and revealed that 18 strains were resistant to fluconazole, and 15 were cross-resistant to all other azoles tested (voriconazole, posaconazole and itraconazole). One isolate resistant to fluconazole was cross-resistant to voriconazole, and resistance to voriconazole only was observed in six other isolates. All strains were found to be susceptible to echinocandins and amphotericin B, and five were classified as resistant to 5 fluorocytosine. The sequence of the ERG11 gene encoding lanosterol 14-alpha demethylase (the molecular target of azoles) of 41 isolates, including all strains resistant to fluconazole and three resistant only to voriconazole, was determined, and no amino acid substitutions were found. Real-time PCR studies revealed that 13 of 15 azole-resistant strains showed upregulation of the CDR1 gene encoding the efflux pump. No upregulation of expression of the CDR2 or ERG11 gene was observed. PMID- 25818699 TI - Calorespirometry, oxygen isotope analysis and functional-marker-assisted selection ('CalOxy-FMAS') for genotype screening: A novel concept and tool kit for predicting stable plant growth performance and functional marker identification. AB - We propose a novel concept and tool kit for predictive phenotyping. The proposed technology measures respiration properties as functions of growth conditions to identify genotypes with higher plasticity via homeostasis and adaptive morphophysiology. Combining calorespirometry, oxygen isotope analysis and functional-marker-assisted selection ('CalOxy-FMAS') for genotype screening will enable predicting the genetic potential for stable plant growth performance. Application of this novel tool kit can help identify genotypes with controlled homeostasis in changing environments and optimized growth performance. Simultaneously, it will allow a better balance in breeding for high yields and quality characteristics. Applying 'CalOxy-FMAS' can efficiently narrow the pool of genotypes to be screened for final phenotyping in the field. PMID- 25818700 TI - Salt stress reduces root meristem size by nitric oxide-mediated modulation of auxin accumulation and signaling in Arabidopsis. AB - The development of the plant root system is highly plastic, which allows the plant to adapt to various environmental stresses. Salt stress inhibits root elongation by reducing the size of the root meristem. However, the mechanism underlying this process remains unclear. In this study, we explored whether and how auxin and nitric oxide (NO) are involved in salt-mediated inhibition of root meristem growth in Arabidopsis (Arabidopsis thaliana) using physiological, pharmacological, and genetic approaches. We found that salt stress significantly reduced root meristem size by down-regulating the expression of PINFORMED (PIN) genes, thereby reducing auxin levels. In addition, salt stress promoted AUXIN RESISTANT3 (AXR3)/INDOLE-3-ACETIC ACID17 (IAA17) stabilization, which repressed auxin signaling during this process. Furthermore, salt stress stimulated NO accumulation, whereas blocking NO production with the inhibitor N(omega)-nitro-l arginine-methylester compromised the salt-mediated reduction of root meristem size, PIN down-regulation, and stabilization of AXR3/IAA17, indicating that NO is involved in salt-mediated inhibition of root meristem growth. Taken together, these findings suggest that salt stress inhibits root meristem growth by repressing PIN expression (thereby reducing auxin levels) and stabilizing IAA17 (thereby repressing auxin signaling) via increasing NO levels. PMID- 25818701 TI - Medicago truncatula natural resistance-associated macrophage Protein1 is required for iron uptake by rhizobia-infected nodule cells. AB - Iron is critical for symbiotic nitrogen fixation (SNF) as a key component of multiple ferroproteins involved in this biological process. In the model legume Medicago truncatula, iron is delivered by the vasculature to the infection/maturation zone (zone II) of the nodule, where it is released to the apoplast. From there, plasma membrane iron transporters move it into rhizobia containing cells, where iron is used as the cofactor of multiple plant and rhizobial proteins (e.g. plant leghemoglobin and bacterial nitrogenase). MtNramp1 (Medtr3g088460) is the M. truncatula Natural Resistance-Associated Macrophage Protein family member, with the highest expression levels in roots and nodules. Immunolocalization studies indicate that MtNramp1 is mainly targeted to the plasma membrane. A loss-of-function nramp1 mutant exhibited reduced growth compared with the wild type under symbiotic conditions, but not when fertilized with mineral nitrogen. Nitrogenase activity was low in the mutant, whereas exogenous iron and expression of wild-type MtNramp1 in mutant nodules increased nitrogen fixation to normal levels. These data are consistent with a model in which MtNramp1 is the main transporter responsible for apoplastic iron uptake by rhizobia-infected cells in zone II. PMID- 25818702 TI - The barley Uniculme4 gene encodes a BLADE-ON-PETIOLE-like protein that controls tillering and leaf patterning. AB - Tillers are vegetative branches that develop from axillary buds located in the leaf axils at the base of many grasses. Genetic manipulation of tillering is a major objective in breeding for improved cereal yields and competition with weeds. Despite this, very little is known about the molecular genetic bases of tiller development in important Triticeae crops such as barley (Hordeum vulgare) and wheat (Triticum aestivum). Recessive mutations at the barley Uniculme4 (Cul4) locus cause reduced tillering, deregulation of the number of axillary buds in an axil, and alterations in leaf proximal-distal patterning. We isolated the Cul4 gene by positional cloning and showed that it encodes a BROAD-COMPLEX, TRAMTRACK, BRIC-A-BRAC-ankyrin protein closely related to Arabidopsis (Arabidopsis thaliana) BLADE-ON-PETIOLE1 (BOP1) and BOP2. Morphological, histological, and in situ RNA expression analyses indicate that Cul4 acts at axil and leaf boundary regions to control axillary bud differentiation as well as the development of the ligule, which separates the distal blade and proximal sheath of the leaf. As, to our knowledge, the first functionally characterized BOP gene in monocots, Cul4 suggests the partial conservation of BOP gene function between dicots and monocots, while phylogenetic analyses highlight distinct evolutionary patterns in the two lineages. PMID- 25818703 TI - Metabolomics of adherent mammalian cells by capillary electrophoresis-mass spectrometry: HT-29 cells as case study. AB - In this work, the optimization of an effective protocol for cell metabolomics is described with special emphasis in the sample preparation and subsequent analysis of intracellular metabolites from adherent mammalian cells by capillary electrophoresis-mass spectrometry. As case study, colon cancer HT-29 cells, a human cell model to investigate colon cancer, are employed. The feasibility of the whole method for cell metabolomics is demonstrated via a fast and sensitive profiling of the intracellular metabolites HT-29 cells by capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF MS). The suitability of this methodology is further corroborated through the examination of the metabolic changes in the polyamines pathway produced in colon cancer HT-29 cells by difluoromethylornithine (DFMO), a known potent ornithine decarboxylase inhibitor. The selection of the optimum extraction conditions allowed a higher sample volume injection that led to an increase in CE-TOF MS sensitivity. Following a non targeted metabolomics approach, 10 metabolites (namely, putrescine, ornithine, gamma-aminobutyric acid (GABA), oxidized and reduced glutathione, 5'-deoxy-5' (methylthio)adenosine, N-acetylputrescine, cysteinyl-glycine, spermidine and an unknown compound) were found to be significantly altered by DFMO (p<0.05) in HT 29 cells. In addition to the effect of DFMO on polyamine metabolism, minor modifications of other metabolic pathways (e.g., related to intracellular thiol redox state) were observed. PMID- 25818704 TI - Molecular salts and co-crystals of mirtazapine with promising physicochemical properties. AB - Pharmaceutically suitable non-sublimating salts and molecular salts of anti depressant drug R/S-mirtazapine with one of several dicarboxilic acids were studied. The salts/salt molecules were characterized by powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis and crystal structure of tartarate and oxalate molecular salt were determined by single crystal X-ray diffraction. The salts/salt molecules of mirtazapine do not show any sublimation at elevated temperature whereas sublimation of mirtazapine has been observed at ambient temperature. The aqueous solubility of the mirtazapine molecular salts was significantly improved with a maximum of citrate salt which was about 180 times more than the solubility of the parent mirtazapine at 35 degrees C. PMID- 25818705 TI - The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged <=65 years. AB - OBJECTIVES: To prospectively test the diagnostic accuracy of the percentage of prostate specific antigen (PSA) isoform [-2]proPSA (%p2PSA) and the Prostate Health Index (PHI), and to determine their role for discrimination between significant and insignificant prostate cancer at initial and repeat prostate biopsy in men aged <=65 years. PATIENTS AND METHODS: The diagnostic performance of %p2PSA and PHI were evaluated in a multicentre study. In all, 769 men aged <=65 years scheduled for initial or repeat prostate biopsy were recruited in four sites based on a total PSA (t-PSA) level of 1.6-8.0 ng/mL World Health Organization (WHO) calibrated (2-10 ng/mL Hybritech-calibrated). Serum samples were measured for the concentration of t-PSA, free PSA (f-PSA) and p2PSA with Beckman Coulter immunoassays on Access-2 or DxI800 instruments. PHI was calculated as (p2PSA/f-PSA * ?t-PSA). Uni- and multivariable logistic regression models and an artificial neural network (ANN) were complemented by decision curve analysis (DCA). RESULTS: In univariate analysis %p2PSA and PHI were the best predictors of prostate cancer detection in all patients (area under the curve [AUC] 0.72 and 0.73, respectively), at initial (AUC 0.67 and 0.69) and repeat biopsy (AUC 0.74 and 0.74). t-PSA and %f-PSA performed less accurately for all patients (AUC 0.54 and 0.62). For detection of significant prostate cancer (based on Prostate Cancer Research International Active Surveillance [PRIAS] criteria) the %p2PSA and PHI equally demonstrated best performance (AUC 0.70 and 0.73) compared with t-PSA and %f-PSA (AUC 0.54 and 0.59). In multivariate analysis PHI we added to a base model of age, prostate volume, digital rectal examination, t PSA and %f-PSA. PHI was strongest in predicting prostate cancer in all patients, at initial and repeat biopsy and for significant prostate cancer (AUC 0.73, 0.68, 0.78 and 0.72, respectively). In DCA for all patients the ANN showed the broadest threshold probability and best net benefit. PHI as single parameter and the base model + PHI were equivalent with threshold probability and net benefit nearing those of the ANN. For significant cancers the ANN was the strongest parameter in DCA. CONCLUSION: The present multicentre study showed that %p2PSA and PHI have a superior diagnostic performance for detecting prostate cancer in the PSA range of 1.6-8.0 ng/mL compared with t-PSA and %f-PSA at initial and repeat biopsy and for predicting significant prostate cancer in men aged <=65 years. They are equally superior for counselling patients before biopsy. PMID- 25818706 TI - Limitation of care orders in patients with a diagnosis of dementia. AB - The prevalence of dementia is growing with an ageing population. Most persons with dementia die of acute illness and many are hospitalised at the end of life. In the acute hospital setting, limitation of care orders (LCOs) such as Do Not Attempt CPR and Physician Orders For Life Sustaining Treatment (POLST), appear to be underused in patients with dementia. These patients receive the same aggressive life-prolonging therapies as any other patient, despite drastically higher mortality. However, limitation of care orders in patients with dementia is not addressed by current guidelines or policies. Systems and processes for obtaining and documenting LCO need improvement at the individual, organisational and societal level. The issue is controversial amongst the public and poorly understood by clinicians. Balanced and empathetic decision-making requires an individualised approach and recognition of the complexities (legal, ethical and clinical) of this issue. We examine the domains of: (a) treatment effectiveness, (b) burden of care and quality of life and (c) patient autonomy and capacity. PMID- 25818707 TI - Urban and rural differences in out-of-hospital cardiac arrest in Ireland. AB - BACKGROUND: More than a third of Ireland's population lives in a rural area, defined as the population residing in all areas outside clusters of 1500 or more inhabitants. This presents a challenge for the provision of effective pre hospital resuscitation services. In 2012, Ireland became one of three European countries with nationwide Out-of-Hospital Cardiac Arrest (OHCA) register coverage. An OHCA register provides an ability to monitor quality and equity of access to life-saving services in Irish communities. AIM: To use the first year of national OHCAR data to assess differences in the occurrence, incidence and outcomes of OHCA where resuscitation is attempted and the incident is attended by statutory Emergency Medical Services between rural and urban settings. METHODS: The geographical coordinates of incident locations were identified and co ordinates were then classified as 'urban' or 'rural' according to the Irish Central Statistics Office (CSO) definition. RESULTS: 1798 OHCA incidents were recorded which were attended by statutory Emergency Medical Services (EMS) and where resuscitation was attempted. There was a higher percentage of male patients in rural settings (71% vs. 65%; p = 0.009) but the incidence of male patients did not differ significantly between urban and rural settings (26 vs. 25 males/100,000 population/year p = 0.353). A higher proportion of rural patients received bystander cardiopulmonary resuscitation (B-CPR) 70% vs. 55% (p <= 0.001), and had defibrillation attempted before statutory EMS arrival (7% vs. 4% (p = 0.019), respectively). Urban patients were more likely to receive a statutory EMS response in 8 min or less (33% vs. 9%; p <= 0.001). Urban patients were also more likely to be discharged alive from hospital (6% vs. 3%; p = 0.006) (incidence 2.5 vs. 1.1/100,000 population/year; p <= 0.001). Multivariable analysis of survival showed that the main variable of interest i.e. urban vs. rural setting was also independently associated with discharge from hospital alive (OR 3.23 (95% CI 1.43-7.31)). CONCLUSION: There are significant disparities in the incidence of resuscitation attempts in urban and rural areas. There are challenges in the provision of services and subsequent outcomes from OHCA that occur outside of urban areas requiring novel and innovative solutions. An integrated community response system is necessary to improve metrics around OHCA response and outcomes in rural areas. PMID- 25818708 TI - Dendritic cell SIRPalpha regulates homeostasis of dendritic cells in lymphoid organs. AB - Signal regulatory protein alpha (SIRPalpha), an immunoglobulin superfamily protein that is expressed predominantly in myeloid lineage cells such as dendritic cells (DCs) or macrophages, mediates cell-cell signaling. In the immune system, SIRPalpha is thought to be important for homeostasis of DCs, but it remains unclear whether SIRPalpha intrinsic to DCs is indeed indispensable for such functional role. Thus, we here generated the mice, in which SIRPalpha was specifically ablated in CD11c(+) DCs (Sirpa(Delta) (DC) ). Sirpa(Delta) (DC) mice manifested a marked reduction of CD4(+) CD8alpha(-) conventional DCs (cDCs) in the secondary lymphoid organs, as well as of Langerhans cells in the epidermis. Such reduction of cDCs in Sirpa(Delta) (DC) mice was comparable to that apparent with the mice, in which SIRPalpha was systemically ablated. Expression of SIRPalpha in DCs was well correlated with that of either endothelial cell selective adhesion molecule (ESAM) or Epstein-Barr virus-induced molecule 2 (EBI2), both of which were also implicated in the regulation of DC homeostasis. Indeed, ESAM(+) or EBI2(+) cDCs were markedly reduced in the spleen of Sirpa(Delta) (DC) mice. Thus, our results suggest that SIRPalpha intrinsic to CD11c(+) DCs is essential for homeostasis of cDCs in the secondary lymphoid organs and skin. PMID- 25818709 TI - Psychosocial aspects of rehabilitation in sports. AB - When an athlete is injured, the primary focus of the sports medicine team is to treat the physical effects of the injury. However, many injured athletes experience negative psychological responses that should also be addressed throughout the rehabilitation process. Sports medicine professions should use psychosocial skills to help decrease the negative consequences of the injury, such as fear of reinjury, anxiety, depression, and adherence to rehabilitation. These psychosocial skills include goal setting, imagery, relaxation techniques, motivation, and self-talk. This article addresses the negative consequences of injury, psychosocial skills used to aid in the rehabilitation process, and clinical implications of the psychological aspects of rehabilitation in sport. PMID- 25818711 TI - Knowing the speed limit: weighing the benefits and risks of rehabilitation progression after arthroscopic rotator cuff repair. AB - Rotator cuff repairs have increased. Although clinical trials have examined the effect of immobilization and timing of passive range of motion (ROM) on patient outcomes and structural integrity, there is controversy as to the timing and progression for therapy. Primary goals are restoring function while maintaining the structural integrity of the repair. We advocate for a protocol of 4 to 6 weeks of immobilization, followed by protected passive ROM, which is followed by a gradual progression to active ROM and then appropriate resistance exercise program for most all rotator cuff repairs. The rate of progression should be adjusted individually. PMID- 25818710 TI - Current and emerging rehabilitation for concussion: a review of the evidence. AB - Concussion is one of the most hotly debated topics in sports medicine today. Research surrounding concussion has experienced significant growth recently, especially in the areas of incidence, assessment, and recovery. However, there is limited research on the most effective rehabilitation approaches for this injury. This review evaluates the current literature for evidence for and against physical and cognitive rest and the emerging areas targeting vestibular, oculomotor, and pharmacologic interventions for the rehabilitation of sport related concussion. PMID- 25818712 TI - Rehabilitation of the throwing athlete: where we are in 2014. AB - The overhead athlete has unique physical traits and adaptive changes as a result of the repetitive nature of throwing. An effective rehabilitation program depends on an accurate evaluation to determine the causative factors for an athlete's pathology. A treatment program is individualized with specific strengthening and flexibility exercises to achieve dynamic stability that is required for overhead function. In this article the characteristics of the throwing shoulder and specific injuries are described. The rehabilitation program is described in a multiphased approach that allows for the restoration of strength, mobility, endurance, and power to return to sporting activity. PMID- 25818713 TI - Rehabilitation of acute hamstring strain injuries. AB - Acute hamstring injuries are responsible for significant time loss for athletes. As there are a multitude of injury mechanisms, thorough evaluation is imperative for determining the appropriate plan of care and adequate rehabilitation is required to reduce the risk of recurrent injuries. PMID- 25818714 TI - Clinical strategies for addressing muscle weakness following knee injury. AB - Muscle strength is a determinate of physical function and increasing muscle strength is an important clinical goal for patients with knee injury. This article discusses the emerging evidence regarding a novel rehabilitation strategy that uses disinhibitory modalities to increase neuromuscular activation in conjunction with traditional muscle strengthening for the purpose of maximizing strength gains following acute knee injury or surgery and in patients with knee osteoarthritis. The use of disinhibitory modalities and specific types of neuromuscular training for clinically maximizing strength are discussed. PMID- 25818716 TI - Patellofemoral pain: epidemiology, pathophysiology, and treatment options. AB - Patients with anterior knee pain present a complex and common problem to health care providers. The diagnosis and treatment of these patients often involve a comprehensive evaluation that includes assessing the chronicity of the pain, the specific location of the complaint, and the previous treatment modalities attempted by the patient. This common diagnosis includes a wide variety of different pathologic abnormalities that can be present independently or concomitantly and cause a spectrum of disabilities for the patient. PMID- 25818715 TI - Controversies in knee rehabilitation: anterior cruciate ligament injury. AB - Controversy in management of athletes exists after anterior cruciate ligament (ACL) injury and reconstruction. Consensus criteria for evaluating successful outcomes following ACL injury include no reinjury or recurrent giving way, no joint effusion, quadriceps strength symmetry, restored activity level and function, and returning to preinjury sports. Using these criteria, the success rates of current management strategies after ACL injury are reviewed and recommendations are provided for the counseling of athletes after ACL injury. PMID- 25818718 TI - Freeing the foot: integrating the foot core system into rehabilitation for lower extremity injuries. AB - The intrinsic muscles of the foot play a critical role in the regulation of absorption and propulsion during dynamic activities. Dysfunction of these may lead to an increased demand on the remaining components within the foot core system to maintain dynamic foot control, leading to a more rapid breakdown of these contributors and those proximal to the foot. Training the intrinsic foot muscles through a systematic progression of isolation via the short foot exercise offers the opportunity to reincorporate their contribution into the foot core system. This article discusses the function of the intrinsic foot muscles, their contributions to dynamic foot control, and a progressive training paradigm. PMID- 25818717 TI - Supervised rehabilitation versus home exercise in the treatment of acute ankle sprains: a systematic review. AB - In competitive sports medicine, supervised rehabilitation is the standard of care; in the general population, unsupervised home exercise is more common. We systematically reviewed randomized, controlled trials comparing outcomes for supervised rehabilitation versus home exercise programs. Supervised rehabilitation programs resulted in (1) less pain and subjective instability, (2) greater gains in ankle strength and joint position sense, and (3) inconclusive results regarding prevention of recurrent ankle sprains. We recommend supervised rehabilitation over home exercise programs owing to the improved short-term patient-recorded evidence with a strength-of-recommendation taxonomy level of evidence of 2B. PMID- 25818719 TI - Treating tendinopathy: perspective on anti-inflammatory intervention and therapeutic exercise. AB - Tendinopathy is a common and complex disorder. Once viewed as an inflammatory condition labeled tendinitis, it is now viewed along a continuum that can lead to tissue necrosis and risk of tendon rupture. Anti-inflammatory medications can alter symptoms but may also promote tissue degeneration. Loading of the tendon through exercise, especially exercise involving eccentric muscle contraction, has been shown to promote symptom resolution and functional recovery in many patients. This article reviews the pathoetiology of tendinopathy and the role anti-inflammatory interventions and therapeutic exercise in treatment of active patients. PMID- 25818720 TI - Foreword. PMID- 25818721 TI - Sports rehabilitation. PMID- 25818722 TI - Visual Similarity of Words Alone Can Modulate Hemispheric Lateralization in Visual Word Recognition: Evidence From Modeling Chinese Character Recognition. AB - In Chinese orthography, the most common character structure consists of a semantic radical on the left and a phonetic radical on the right (SP characters); the minority, opposite arrangement also exists (PS characters). Recent studies showed that SP character processing is more left hemisphere (LH) lateralized than PS character processing. Nevertheless, it remains unclear whether this is due to phonetic radical position or character type frequency. Through computational modeling with artificial lexicons, in which we implement a theory of hemispheric asymmetry in perception but do not assume phonological processing being LH lateralized, we show that the difference in character type frequency alone is sufficient to exhibit the effect that the dominant type has a stronger LH lateralization than the minority type. This effect is due to higher visual similarity among characters in the dominant type than the minority type, demonstrating the modulation of visual similarity of words on hemispheric lateralization. PMID- 25818723 TI - Indian proteomics efforts and human proteome project. AB - The Draft Maps of Human Proteome published in two independent articles provide a catalogue of proteins encoded in the human genome including missing proteins, based on large scale mass spectrometric analysis. Six months later, a Tissue based Human Proteome Map was published which includes a study of expression and distribution of human proteins across tissues and cells using specific antibodies. Independently, in an ongoing global effort - the Chromosome centric, and Biology and Disease centric Human Proteome Project (C-HPP and B/D-HPP) initiated by the Human Proteome Organization aims to study in-depth human proteins and their variants in terms of biology and disease in a chromosome centric manner. Under this initiative, a consortium formed among five Asian research teams including India aims to study Chromosome 12 encoded proteins and their disease context. Together, the group has recently published the first series of 3 papers giving the overall vision and the initial contributions. While one of the draft maps of the human proteome is largely contributed by an Indian team, Indian researchers have significant role in the other two initiatives as well. These efforts will be pursued further as more teams join and more disease and biology components get incorporated. BIOLOGICAL SIGNIFICANCE: This article focuses on the complexity and challenges of deciphering human proteome and contribution of Indian researchers in the human proteome projects, including the on-going C-HPP. This article is part of a Special Issue entitled: Proteomics in India. PMID- 25818724 TI - Proteomic analysis of soybean hypocotyl during recovery after flooding stress. AB - Soybean is a nutritionally important crop, but exhibits reduced growth and yields under flooding stress. To investigate soybean responses during post-flooding recovery, a gel-free proteomic technique was used to examine the protein profile in the hypocotyl. Two-day-old soybeans were flooded for 2 days and hypocotyl was collected under flooding and during the post-flooding recovery period. A total of 498 and 70 proteins were significantly changed in control and post-flooding recovering soybeans, respectively. Based on proteomic and clustering analyses, three proteins were selected for mRNA expression and enzyme activity assays. Pyruvate kinase was increased under flooding, but gradually decreased during post flooding recovery period at protein abundance, mRNA, and enzyme activity levels. Nucleotidylyl transferase was decreased under flooding and increased during post flooding recovery at both mRNA expression and enzyme activity levels. Beta ketoacyl reductase 1 was increased under flooding and decreased during recovery at protein abundance and mRNA expression levels, but its enzyme activity gradually increased during the post-flooding recovery period. These results suggest that pyruvate kinase, nucleotidylyl transferase, and beta-ketoacyl reductase play key roles in post-flooding recovery in soybean hypocotyl by promoting glycolysis for the generation of ATP and regulation of secondary metabolic pathways. BIOLOGICAL SIGNIFICANCE: This study analyzed post-flooding recovery response mechanisms in soybean hypocotyl, which is a model organ for studying secondary growth, using a gel-free proteomic technique. Mass spectrometry analysis of proteins extracted from soybean hypocotyls identified 20 common proteins between control and flooding-stressed soybeans that changed significantly in abundance over time. The hypocotyl proteins that changed during post-flooding recovery were assigned to protein, development, secondary metabolism, and glycolysis categories. The analysis revealed that three proteins, pyruvate kinase, nucleotidylyl transferase, and beta-ketoacyl reductase, were increased in hypocotyl under flooding conditions and during post-flooding recovery. The proteins are involved in glycolysis, nucleotide synthesis and amino acid activation, and complex fatty acid biosynthesis. PMID- 25818725 TI - Comparative proteomic analysis of lung tissue from guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) reveals a decrease in abundance of host proteins involved in cytoskeletal and cellular organization. AB - Leptospiral pulmonary haemorrhage syndrome (LPHS) is a particularly severe form of leptospirosis. LPHS is increasingly recognized in both humans and animals and is characterized by rapidly progressive intra-alveolar haemorrhage leading to high mortality. The pathogenic mechanisms of LPHS are poorly understood which hampers the application of effective treatment regimes. In this study a 2-D guinea pig proteome lung map was created and used to investigate the pathogenic mechanisms of LPHS. Comparison of lung proteomes from infected and non-infected guinea pigs via differential in-gel electrophoresis revealed highly significant differences in abundance of proteins contained in 130 spots. Acute phase proteins were the largest functional group amongst proteins with increased abundance in LPHS lung tissue, and likely reflect a local and/or systemic host response to infection. The observed decrease in abundance of proteins involved in cytoskeletal and cellular organization in LPHS lung tissue further suggests that infection with pathogenic Leptospira induces changes in the abundance of host proteins involved in cellular architecture and adhesion contributing to the dramatically increased alveolar septal wall permeability seen in LPHS. BIOLOGICAL SIGNIFICANCE: The recent completion of the complete genome sequence of the guinea pig (Cavia porcellus) provides innovative opportunities to apply proteomic technologies to an important animal model of disease. In this study, the comparative proteomic analysis of lung tissue from experimentally infected guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) revealed a decrease in abundance of proteins involved in cellular architecture and adhesion, suggesting that loss or down-regulation of cytoskeletal and adhesion molecules plays an important role in the pathogenesis of LPHS. A publically available guinea pig lung proteome map was constructed to facilitate future pulmonary proteomics in this species. PMID- 25818726 TI - Quantitative changes in proteins responsible for flavonoid and anthocyanin biosynthesis in strawberry fruit at different ripening stages: A targeted quantitative proteomic investigation employing multiple reaction monitoring. AB - To better understand the regulation of flavonoid and anthocyanin biosynthesis, a targeted quantitative proteomic investigation employing LC-MS with multiple reaction monitoring was conducted on two strawberry cultivars at three ripening stages. This quantitative proteomic workflow was improved through an OFFGEL electrophoresis to fractionate peptides from total protein digests. A total of 154 peptide transitions from 47 peptides covering 21 proteins and isoforms related to anthocyanin biosynthesis were investigated. The normalized protein abundance, which was measured using isotopically-labeled standards, was significantly changed concurrently with increased anthocyanin content and advanced fruit maturity. The protein abundance of phenylalanine ammonia-lyase; anthocyanidin synthase, chalcone isomerase; flavanone 3-hydroxylase; dihydroflavonol 4-reductase, UDP-glucose:flavonoid-3-O-glucosyltransferase, cytochrome c and cytochrome C oxidase subunit 2, was all significantly increased in fruit of more advanced ripeness. An interaction between cultivar and maturity was also shown with respect to chalcone isomerase. The good correlation between protein abundance and anthocyanin content suggested that a metabolic control point may exist for anthocyanin biosynthesis. This research provides insights into the process of anthocyanin formation in strawberry fruit at the level of protein concentration and reveals possible candidates in the regulation of anthocyanin formation during fruit ripening. BIOLOGICAL SIGNIFICANCE: To gain insight into the molecular mechanisms contributing to flavonoids and anthocyanin biosynthesis and regulation of strawberry fruit during ripening is challenging due to limited molecular biology tools and established hypothesis. Our targeted proteomic approach employing LC-MS/MS analysis and MRM technique to quantify proteins in relation to flavonoids and anthocyanin biosynthesis and regulation in strawberry fruit during fruit ripening is novel. The identification of peptides and proteins provided reliable design and validation of quantitative approaches using SRM on targeted proteins proposed involved in strawberry fruit. Our data revealed the identifying candidate proteins and their quantitative changes in relation to fruit ripening and flavonoids and anthocyanin biosynthesis and regulation. More importantly, this quantitative proteomic data is also compared with chemical analysis to reveal possible control levels of this important quality trait. Although, MRM approach is not new in plant biology research, the application has been very rare. This is the first systematic multi-targeted interrogation of the possible regulation of entire pathway of flavonoids and anthocyanin biosynthesis in strawberry fruit at different ripening stages using quantitative MRM technique on mass spectrometry. Our results demonstrate the power of targeted quantitative mass spectrometry data for analysis of proteins in biological regulation. These results indicate that distinct and diverse control of flavonoids and anthocyanin biosynthesis mechanisms at metabolism and proteins levels. This important and complementary knowledge will be useful for systematically characterizing the flavonoids and anthocyanin biosynthesis pathway of any fruit/plant species. PMID- 25818727 TI - Stereoselective Synthesis of Arylglycine Derivatives via Palladium-Catalyzed alpha-Arylation of a Chiral Nickel(II) Glycinate. AB - A practical and efficient stereoselective synthesis of arylglycine derivatives was realized via palladium-catalyzed alpha-arylation of a chiral nickel(II) glycinate complex with aryl bromides. The structurally diverse arylglycine products were obtained in excellent isolated yields and with good diastereoselectivity. A simple acidic hydrolysis furnished optically pure arylglycines in high yield, and the chiral ligand (S)-BPB could be efficiently recovered and reused. PMID- 25818728 TI - Impact of psychiatric comorbidity in individuals at Ultra High Risk of psychosis Findings from the Longitudinal Youth at Risk Study (LYRIKS). AB - Recent studies have reported a high prevalence of psychiatric comorbidities in Ultra High Risk (UHR) for psychosis populations. This study examined the prevalence of comorbidity and its impact on symptoms, functioning, cognition and transition to psychosis in the Longitudinal Youth at Risk Study (LYRIKS) sample. The Comprehensive Assessment of At-Risk Mental State (CAARMS) was used to identify UHR individuals and 163 participants were included in the study. Comorbid disorders were identified using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Participants were evaluated on the CAARMS, Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, Beck Anxiety Inventory, Global Assessment of Functioning and Brief Assessment of Cognition in Schizophrenia. Clinical, functioning and cognitive characteristics by lifetime and current comorbidity groups were compared using multivariate tests. Independent predictors of comorbidity were identified through logistic regression. Chi-squared tests were used to compare comorbidity rates between those who had developed psychosis at one year and those who had not. We found that 131 UHR participants (80.4%) had a lifetime comorbidity while 82 (50.3%) had a current comorbidity with depressive disorders being the most common. UHR individuals with comorbidity had more severe symptoms, higher distress and lower functioning with no differences in general cognition. Lower functioning was associated with current comorbidity. Eleven participants (6.7%) had developed psychosis after one year and there were no differences in the comorbidity rates between those who developed psychosis and those who did not. Psychiatric comorbidities in the UHR group are associated with adverse clinical outcomes and warrant closer attention. PMID- 25818729 TI - Prediction of microvascular invasion of hepatocellular carcinomas with gadoxetic acid-enhanced MR imaging: Impact of intra-tumoral fat detected on chemical-shift images. AB - PURPOSE: To investigate the impact of intra-tumoral fat detected by chemical shift MR imaging in predicting the MVI of HCC. MATERIALS AND METHODS: Gadoxetic acid-enhanced MR imaging of 365 surgically proven HCCs from 365 patients (306 men, 59 women; mean age, 55.6 years) were evaluated. HCCs were classified into two groups, fat-containing and non-fat-containing, based on the presence of fat on chemical-shift images. Fat-containing HCCs were subdivided into diffuse or focal fatty change groups. Logistic regression analyses were used to identify clinical and MR findings associated with MVI. RESULTS: Based on MR imaging, 66 tumors were classified as fat-containing HCCs and 299 as non-fat-containing HCCs. Among the 66 fat-containing HCCs, 38 (57.6%) showed diffuse fatty changes and 28 (42.4%) showed focal fatty changes. MVI was present in 18 (27.3%) fat-containing HCCs and in 117 (39.1%) non-fat-containing HCCs (P=0.07). Univariate analysis revealed that serum alpha-fetoprotein (AFP) and tumor size were significantly associated with MVI (P<0.001). A multiple logistic regression analysis showed that log AFP (odds ratio 1.178, P=0.0016), tumor size (odds ratio 1.809, P<0.001), and intra-tumoral fat (odds ratio 0.515, P=0.0387) were independent variables associated with MVI. CONCLUSION: Intra-tumoral fat detected with MR imaging may suggest lower risk for MVI of HCC and, therefore, a possibly more favorable prognosis, but the clinical value of this finding is uncertain. PMID- 25818730 TI - Four-dimensional computed tomography angiographic evaluation of cranial dural arteriovenous fistula before and after embolization. AB - PURPOSE: This study aimed to evaluate the usefulness of four-dimensional CTA before and after embolization treatment with ONYX-18 in eleven patients with cranial dural arteriovenous fistulas, and to compare the results with those of the reference standard DSA. PATIENTS AND METHODS: Eleven patients with cranial dural arteriovenous fistulas detected on DSA underwent transarterial embolization with ONYX-18. Four-dimensional CTA was performed an average of 2 days before and 4 days after DSA. Four-dimensional CTA and DSA images were reviewed by two neuroradiologists for identification of feeding arteries and drainage veins and for determining treatment effects. Interobserver and intermodality agreement between four-dimensional CTA and DSA were assessed. RESULTS: Forty-two feeding arteries were identified for 14 fistulas in the 11 patients. Of these, 36 (85.71%) were detected on four-dimensional CTA. After transarterial embolization, one patient got partly embolized, and the fistulas in the remaining 10 patients were completely occluded. The interobserver agreement for four-dimensional CTA and intermodality agreement between four-dimensional CTA and DSA were excellent (kappa=1) for shunt location, identification of drainage veins, and fistula occlusion after treatment. CONCLUSION: Four-dimensional CTA images are highly accurate when compared with DSA images both before and after transarterial embolization treatment. Four-dimensional CTA can be used for diagnosis as well as follow-up of cranial dural arteriovenous fistulas in clinical settings. PMID- 25818731 TI - Contrast-enhanced spectral mammography: Impact of the qualitative morphology descriptors on the diagnosis of breast lesions. AB - OBJECTIVE: To analyze the morphology and enhancement characteristics of breast lesions on contrast-enhanced spectral mammography (CESM) and to assess their impact on the differentiation between benign and malignant lesions. MATERIALS AND METHOD: This ethics committee approved study included 168 consecutive patients with 211 breast lesions over 18 months. Lesions classified as non-enhancing and enhancing and then the latter group was subdivided into mass and non-mass. Mass lesions descriptors included: shape, margins, pattern and degree of internal enhancement. Non-mass lesions descriptors included: distribution, pattern and degree of internal enhancement. The impact of each descriptor on diagnosis individually assessed using Chi test and the validity compared in both benign and malignant lesions. The overall performance of CESM were also calculated. RESULTS: The study included 102 benign (48.3%) and 109 malignant (51.7%) lesions. Enhancement was encountered in 145/211 (68.7%) lesions. They further classified into enhancing mass (99/145, 68.3%) and non-mass lesions (46/145, 31.7%). Contrast uptake was significantly more frequent in malignant breast lesions (p value <= 0.001). Irregular mass lesions with intense and heterogeneous enhancement patterns correlated with a malignant pathology (p value <= 0.001). CESM showed an overall sensitivity of 88.99% and specificity of 83.33%. The positive and negative likelihood ratios were 5.34 and 0.13 respectively. CONCLUSION: The assessment of the morphology and enhancement characteristics of breast lesions on CESM enhances the performance of digital mammography in the differentiation between benign and malignant breast lesions. PMID- 25818732 TI - Microwave ablation of focal hepatic malignancies regardless of size: A 9-year retrospective study of 64 patients. AB - PURPOSE: To retrospectively evaluate the safety and efficacy of microwave ablation (MWA) as treatment for single, focal hepatic malignancies. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA compliant study. From December 2003 to May 2012, 64 patients were treated with MWA for a single hepatic lesion, in 64 sessions. Hepatocellular carcinoma (HCC) was treated in 25 patients (geometric mean tumor size, 3.33-cm; 95% CI, 2.65-4.18 cm; range, 1.0-12.0-cm), metastatic colorectal cancer (CRC) was treated in 27 patients (geometric mean tumor size, 2.7-cm; 95% CI, 2.20-3.40-cm; range, 0.8-6.0 cm), and other histological-types were treated in 12 patients (geometric mean tumor size, 3.79-cm; 95% CI, 2.72-5.26-cm; range, 1.7-8.0-cm). Kaplan-Meier (K-M) method was used to analyze time event data. Chi-square and correlation evaluated the relationship between tumor size and treatment parameters. RESULTS: Technical success rate was 95.3% (61/64). Treatment parameters were tailored to tumor size; as size increased more antennae were used (p<0.001), treatment with multiple activations increased (p<0.028), and treatment time increased (p<0.001). There was no statistically significant relationship between time to recurrence and tumor size, number of activations, number of antennae, and treatment time. At one year, K-M analysis predicted a likelihood of local recurrence of 39.8% in HCC patients, 45.7% in CRC metastases patients, and 70.8% in patients with other metastases. Median cancer specific survivals for patients were 38.3 months for HCC patients, 36.3 months for CRC metastases, and 13.9 months for other histological-types. Complications occurred in 23.4% (15/64) of sessions. CONCLUSION: In our sample, tumor size did not appear to impact complete ablation rates or local recurrence rates for focal hepatic malignancies treated with MWA. PMID- 25818733 TI - A retrospective clinical study of bevacizumab combined with gemcibabine or paclitaxel in the treatment of recurrent ovarian cancer. AB - BACKGROUND: Bevacizumab, a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A, was described to be effective in the treatment of recurrent or platinum-resistance ovarian cancer. The present retrospective study was performed to further evaluate the clinical efficacy and toxicity of bevacizumab in the treatment of Chinese recurrent ovarian cancer patients who had been previously treated by platinum-based chemotherapy. MATERIALS AND METHODS: We reviewed the hospital database and finally included 26 recurrent ovarian cancer patients who were treated with bevacizumab combined with gemcibabine or paclitaxel or single agent. All included patients received >3 cycle of bevacizumab treatment. The tumor response, overall survival, and toxicities were documented. RESULTS: Under the treatment of bevacizumab combined with gemcibabine or paclitaxel, 2 complete response (7.7%), 8 partial response (30.8%), 7 stable disease (26.9%) and 9 progression disease (34.6%) was documented with the objective response rate of 38.5% and disease control rate of 65.4%. The median overall survival from the first application of bevacizumab was 15.3 months [Figure 1] for all of the 26 patients. The median overall survival time was 16.2 and 14.0 months for bevacizumab + gemcitabine and bevacizumab + paclitaxel treatment schedule respectively. The overall survival was not different between bevacizumab + gemcitabine and bevacizumab + paclitaxel treatment regimen hazard ratio = 0.80 (95% confidence interval: 0.32-2, P = 0.64). The hypertension and proteinuria were the major bevacizumab related toxicities. CONCLUSIONS: Bevacizumab combined with gemcibabine or paclitaxel was a promising treatment schedule for platinum-resistance recurrent ovarian cancer. PMID- 25818734 TI - Endostar combined with chemotherapy compared with chemotherapy alone in the treatment of nonsmall lung carcinoma: A meta-analysis based on Chinese patients. AB - INTRODUCTION: Lung cancer is the leading cause of cancer-associated death world wide. And the lung cancer is generally divided into small cell lung carcinoma and non-small cell lung cancer. For advanced NSCLC, the chemotherapy and target therapy were the important treatment modality. This meta-analysis was to evaluate the clinical efficacy and toxicity between endostar combined chemotherapy and chemotherapy alone in Chinese patients. MATERIALS AND METHODS: We searched the PubMed, EMBASE, and CNKI databases to find the potential relevant articles reporting the endostar combined with chemotherapy regimen in the treatment of nonsmall cell lung cancer in Chinese patients. The tumor response and toxicity difference between the two groups were demonstrated by odds ratio (OR) and its 95% confidence interval (95% CI). All the data was pooled by Stata 11.0 (http://www.stata.com; Stata Corporation, College Station, TX) software. RESULTS: We included 14 studies published in Chinese or English studies. The pooled results showed adding endostar in the chemotherapy regimen can significant increase the objective response rate (OR = 2.42, 95% CI = 1.87-3.12, P = 0.00) and disease control rate (OR = 2.22, 95% CI = 1.68-2.94, P = 0.00). For toxicities, the pooled data showed no statistical difference for grade III-IV granulocytopenia risk (OR = 1.04, 95% CI = 0.74-1.44, P = 0.83). Nausea and vomiting (OR = 0.93 95% CI: 0.51-1.52, P = 0.78) and grade III-IV alopecia (OR = 0.99, 95% CI: 0.76-1.29, P = 0.95). The funnel plot showed no statistical publications. CONCLUSION: Combined treatment with endostar can improve the response rate for NSCLC patients without increasing the risk of developing severe adverse event. PMID- 25818735 TI - Chemotherapy combined with target drugs in the treatment of advanced colorectal cancer: a meta-analysis based on Chinese patients. AB - BACKGROUND: Colorectal carcinoma is one of most diagnosed solid malignant carcinoma. The chemotherapy combined with target drugs in the treatment of advanced colorectal cancer in not conclusive. METHODS: The clinical studies reporting the activity and adverse events between chemotherapy alone versus chemotherapy combined with anti-epidermal growth factor receptor drugs were screened in the databases of Medline, the Cochrane Library, Wanfang and CNKI and included in this meta-analysis. The risk ratio (RR) and its 95% confidence interval (CI) for treatment response and adverse events were pooled by random or fixed effect model. RESULTS: A total of 10 clinical studies reporting chemotherapy combined with the target in the treatment of advanced colorectal cancer were included in this study. The pooled RR was 3.26 (95% CI: 1.74-6.11, P < 0.05), 1.49 (95% CI: 1.23-1.80) and 1.65 (95% CI: 1.37-1.98) for complete response (CR), partial response and objective response rate, respectively. For nausea and vomiting events, the RR was 1.62 (95% CI: 1.33-1.97, P < 0.05) indicating higher incidence of nausea and vomiting was observed in the combined group compared with chemotherapy alone. However, the diarrhea (RR = 1.10, 95% CI: 0.86-1.42, P > 0.05), liver function damage (RR = 1.03, 95% CI: 0.74-1.42), myelosuppression (RR = 1.04, 95% CI: 0.83-1.31) and neurotoxicity (RR = 1.12, 95% CI: 0.93-1.35) were not different between the two groups. CONCLUSION: For Chinese patients with advanced colorectal cancer, chemotherapy combined with target drug can improve the response rate, but also increase the risk of nausea and vomiting. PMID- 25818736 TI - A meta analysis of cetuximab plus oxaliplatin based chemotherapy regimen for metastatic colorectal cancer. AB - BACKGROUND: Oxaliplatin based chemotherapy regimen was one of the most used chemotherapy modality for metastatic colorectal cancer. The purpose of this meta analysis was to assess the clinical activity and toxicities of cetuximab plus oxaliplatin-based chemotherapy regimen for metastatic colorectal Cancer. METHODS: We searched the clinical studies about the cetuximab plus oxaliplatin-based chemotherapy regimen versus oxaliplatin-based chemotherapy alone for metastatic colorectal cancer in the databases of PubMed, EMBASE, Cochran, and CNKI. The data of response and toxicities were extracted and pooled by random or fixed effects model. And publication bias was evaluated by begg's funnel plot and egger's regression test. RESULTS: Seven papers were included in this study. Adding cetuximab to oxaliplatin-based chemotherapy regime can significant increase response rate in K-RAS mutation metastatic colorectal patients (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.17-1.80, Z = 3.38, P = 0.001) and metastatic colorectal patients without knowing the K-RAS status (OR: 1.36, 95% CI: 1.11-1.65, Z = 1.89, P = 0.003). But for patients with mutated K-RAS, the improvement for objective response rate was not statistical significant (OR: 0.70, 95% CI: 0.49-1.01, Z = 3.00, P = 0.058) when adding cetuximab to oxaliplatin-based chemotherapy regime. The pooled results indicating the rash and diarrhea risk was significantly increased in the combined treatment group (P < 0.05). The toxicity of peripheral neuritis was decreased by adding the cetuximab (P < 0.05). And other toxicities were not statistical different between the two groups (P > 0.05). Significant publication bias was found in toxicities evaluation. CONCLUSION: Cetuximab plus oxaliplatin-based chemotherapy regimen significant increase the response rate for metastatic colorectal cancer. But the some toxicities such rash and diarrhea risk was also increased. PMID- 25818737 TI - S100 protein in breast tumor. AB - S100 protein is the largest subtribe in calcium binding protein family. According to recent researches, abnormal expression of S100 protein is often related to tumor, including breast tumor. Breast tumor is the most common malignant disease in female with high mortality mainly due to metastasis. Estimating early diagnostic and prognostic markers are helpful to conduct treatment for patients with breast cancer. Accumulating investigations focused on the role of S100 proteins in breast tumor development and metastasis. This paper summarizes the expression situation of S100 proteins in breast tumor as well as its effects on metastasis and prognosis of breast tumor. PMID- 25818738 TI - Advances in tumor markers of ovarian cancer for early diagnosis. AB - Ovarian cancer often occurs in perimenopausal women. The mortality of ovarian cancer is in the first place among gynecological cancers because of no obvious early symptoms and the lack of effective diagnostic approach. Gene chips, proteomics, immunohistochemistry and other methods have become hot topics for early diagnosis of ovarian cancer. However, due to the variety of pathology and not clear enough of mechanism and etiology, there is still no ideal tumor markers with both high specific and sensitivity, which can be applied into clinical early diagnosis for ovarian cancer. Therefore, a new systematic method with high sensitivity and specificity for early diagnosis of ovarian cancer and new tumor markers need to be identified. We should make an examination of ovarian cancer in the early period in the crowd for early diagnosis and early treatment to further improve life quality of patients. This paper reviewed the recent advancements of tumor markers for early diagnosis of ovarian cancer. PMID- 25818739 TI - MicroRNA-449a inhibits cell growth in lung cancer and regulates long noncoding RNA nuclear enriched abundant transcript 1. AB - OBJECTIVE: Lung cancer has become the primary cause of cancer-related death now. New therapies targeting the molecular regulatory machinery were required imperatively. MicroRNAs and long noncoding RNAs can respectively or cooperatively function as oncogenes or tumor suppressor genes in human cancers. The present study identified that miR-449a was down-regulated in tissue of human lung cancer. In this study, we aimed to investigate the function of miR-449a in NL9980 and L9981 lung carcinoma cells lines and the relationship with lncRNA nuclear enriched abundant transcript 1 (NEAT1). MATERIALS AND METHODS: miR-449a was profiled in several lung carcinoma cell lines by quantitative reverse transcription-polymerase chain reaction RT-PCR. We analyzed the effects of miR 449a overexpression on proliferation, apoptosis and cell cycle in L9981 cells. The regulatory relationship between miR-449a and NEAT1 was predicted in silico and further studied by miR-449a inhibitor and mimics assay. RESULTS: miR-449a was expressed in four cell lines, which we selected, however miR-449a was in high level in NL9980 and in low level in L9981 (P < 0.05). When the miR-449a was the overexpression in L9981 cells, the cell growth was suppressed, and the apoptosis cells were promoted compared with the control group (P < 0.05). The G1/G0 became longer and S, G2/M became shorter (P < 0.05) by miR-449a overexpression. Further study of the interaction between miR-449a and NEAT1 show that NEAT1 was up regulated when cells were transfected with miR-449a inhibitor, and NEAT1 was down regulated when cells transfected with miR-449a mimics. CONCLUSIONS: Our data indicate that miR-449a may function as a suppressor of lung cancer, and affects the expression of NEAT1 in lung cancer cells. PMID- 25818740 TI - The efficacy of pemetrexed and bevacizumab intrapleural injection for malignant pleural mesothelioma-mediated malignant pleural effusion. AB - OBJECTIVE: The aim of the present study was to evaluate the efficacy and safety of pemetrexed chemotherapy combined with intrapleural injection of pemetrexed and bevacizumab in the treatment of malignant pleural mesothelioma (MPM)-mediated malignant pleural effusion, and analyze the objective response rate (ORR), the median progression-free survival (PFS) and the median overall survival (OS). METHODS: We analyzed the clinical data of 23 MPM patients with pleural effusion who were treated with a combination chemotherapy of pemetrexed at 500 mg/m 2 , on day 1 plus cisplatin (DDP) at 20 mg/m 2 on day 1-5 of each 21 days cycle, and concurrently, intrapleural injection of pemetrexed 0.5 g and bevacizumab 300 mg was administered on day 3 or day 4 after complete effusion drainage. ELISA test was applied to detect the vascular endothelial growth factor (VEGF) level in the pleural effusion and serum, and assess the ORR and survival. RESULTS: In the 23 evaluable patients, the VEGF level in the pleural effusion and serum was significantly decreased, P < 0.01, pleural effusion of 20 patients (86.96%) was controlled effectively. There were 8 complete responses, 7 partial responses, 5 stable disease and 3 progressive disease, the ORR was 65.21%, the disease control rate was 86.96%, the median PFS was 6 months, the median OS was 14.5 months, and the 1-year survival rate was 41.22%. Toxicities were generally mild and manageable; the major toxicities included myelosuppression, fatigue, and anemia, mainly were grade 1-2 which could be managed by symptomatic treatments. CONCLUSION: The combination of pemetrexed chemotherapy with intrapleural injection of pemetrexed and bevacizumab is efficacious and safe for MPM pleural effusion, and results of the present study demonstrate some improvement in the PFS and OS. The expression of VEGF in the pleural effusion and serum plays a guiding role in monitoring the efficacy of bevacizumab in the treatment of malignant pleural effusion. PMID- 25818741 TI - The comparisons of the efficacy and toxicity between gefitinib and docetaxel for patients with advanced nonsmall-cell lung cancer: a meta-analysis from randomized controlled clinical trials. AB - BACKGROUND: The extent of the benefit of gefitinib in the treatment of advanced nonsmall-cell lung cancer (NSCLC) is till controversial, when compared with docetaxel. We performed this meta-analysis to compare the efficacy and toxicity of gefitinib with docetaxel for different patients with advanced NSCLC. MATERIALS AND METHODS: We searched PubMed, Cochrane Library, and identified 5 randomized controlled clinical trials published within 2000-2013. After further full-text screening, 4 clinical trials were included in the final meta-analysis. RESULTS: The outcomes of treatment efficacy included progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Comparing gefitinib to docetaxel for advanced NSCLC patients, the pooled hazard ratio (HR) of PFS was 0.91, (95% confidential index [CI] = 0.83-0.99), the pooled HR of OS was 1.02, (95% CI = 0.93-1.13), the pooled risk ratio of ORR was 1.57, (95% CI = 1.01 2.47). CONCLUSIONS: Gefitinib was found to significantly improve patients' PFS and response rate compared with docetaxel. There is no difference of OS between gefitinib and docetaxel. PMID- 25818742 TI - Bevacizumab combined with chemotherapy in the treatment of recurrence or platinum refractory ovarian cancer: a retrospective study of 37 cases. AB - BACKGROUND: Ovarian cancer was one of the most diagnostic cancers for women and leading cause of death from gynecologic cancer. Most of the cases were at advanced stage when diagnosed. Platinum-based regimen was considered as the firs line chemotherapy treatment modality. But most of the cases developed recurrence or resistance to platinum. The aim of this retrospective study was to evaluate the activity and toxicity of bevacizumab combined with chemotherapy in the treatment of recurrence or platinum-refractory ovarian cancer. MATERIALS AND METHODS: Totally, 37 ovarian cancer patients with complete data who treated with bevacizumab combined with chemotherapy were reviewed from the databases of Beijing Cancer hospital and included in this retrospective study. All included patients received >1 cycle of bevacizumab based combination therapy with eligible for the efficacy and toxicity assessments. The objective response rate (ORR) and toxicity were recorded and evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) National Cancer Institute's Common Toxicity Criteria. RESULTS: The ORR and disease control rate were 32.4% and 54.1% respectively by the RECIST criteria and 43.2%, 67.6% by CA125 criteria. The median progression-free survival for the 37 cases was 5.4 months with its range of 2.3-11.2 months. The two complete response patens had longest disease-free survival interval with one for 10.0 months and another for 11.2 months. The total grade III-IV hematologic toxicity and nonhematologic toxicity were 8.1% and 21.6% respectively. CONCLUSIONS: With acceptable toxicity and relative well clinical activity, the bevacizumab combined chemotherapy can be a potential treatment modality for the recurrent or platinum-refractory ovarian cancer. PMID- 25818743 TI - A meta-analysis of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. AB - INTRODUCTION: Angiogenesis plays an important role in the biology of ovarian cancer. The clinical efficacy and side effects of bevacizumab, the vascular endothelial growth factor inhibitor, on survival and toxicity in women with this ovarian cancer, was not conclusive. We performed this systematic review and meta analysis in order to clarify the efficacy of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. MATERIALS AND METHODS: We searched the electronic database of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and CNKI for clinical controlled trials of comparing bevacizumab combined with chemotherapy and chemotherapy alone in the treatment of ovarian cancer. The primary outcomes of eligible studies included median progression-free survival (PFS), overall survival (OS), and toxicities such as enterobrosis, hypertension, albuminuria, congestive heart failure (CHF), neutrophils, thrombosis, and bleeding. The Hazard ratio (HR) and relative risk were used for the meta-analysis and were expressed with 95% confidence intervals (CIs). All the statistical analyses were carried out by Stata 11.0 software (http://www.stata.com; Stata Corporation, College Station, TX, USA). RESULTS: We included 5 studies with 1798 cases in the bevacizumab combined with the chemotherapy group and 1810 subjects in the chemotherapy alone group. The pooled results showed that bevacizumab + chemotherapy compared with chemotherapy alone can significant prolong the median PFS (HR, 0.64; 95% CI, 0.46-0.82; P < 0.05) but not the OS (HR, 0.84; 95% CI, 0.59-10.9; P > 0.05); the toxicity analysis showed that the enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding were significantly increased in the bevacizumab + chemotherapy group compared with chemotherapy alone (Pall < 0.05). But the CHF risk between the two groups was not statistical different (P > 0.05). CONCLUSION: Bevacizumab combined with chemotherapy prolonged the median PFS in patients with ovarian cancer but also increase the risk of developing enterobrosis, hypertension, albuminuria, neutrophils, thrombosis, and bleeding. PMID- 25818744 TI - Noncoding RNA small nucleolar RNA host gene 1 promote cell proliferation in nonsmall cell lung cancer. AB - BACKGROUND: Nonsmall cell lung cancer (NSCLC) is the major cause of cancer death worldwide. Increasing evidence shows that noncoding RNAs (ncRNAs) are widely involved in the development and progression of NSCLC. ncRNA small nucleolar RNA host gene 1 (SNHG1) has not been studied in cancer, especially its role in lung cancer remains unknown. Our studies were designed to investigate the expression and biological significance of SNHG1 in lung cancer. SNHG1 may be a novel ncRNA in early diagnosis in lung cancer. METHODS: Noncoding RNA SNHG1 expression in 7 lung cancer cell lines was measured by quantitative real-time polymerase chain reaction. RNA interference approaches were used to find the biological functions of SNHG1. The effect of SNHG1 on proliferation was evaluated by cell count and crystal violet stains. RESULTS: Noncoding RNA SNHG1 expression was significantly upregulated in lung cancer cells when compared with normal bronchial epithelial cells. In addition, in vitro assays our results indicated that knockdown of SNHG1 inhibited cell proliferation. CONCLUSIONS: Our data indicated that ncRNA SNHG1 is significantly upregulated in NSCLC cell lines and may represent a new biomarker and a potential therapeutic target for NSCLC intervention. PMID- 25818745 TI - Action potential duration gradients in the heart ventricles and the cardiac electric field during ventricular repolarization (a model study). AB - BACKGROUND: We simulated contributions of transmural, apicobasal, anteroposterior and interventricular action potential duration (APD) gradients to the body surface potential distribution (BSPD) with constant or varied magnitudes of the transmural and apicobasal gradients. METHODS: Simulations were done in the framework of the discrete computer model of the rabbit heart ventricles on the basis of realistic activation sequence and APDs. The APD gradients were set constant at 20 ms or varied in the range of +/-80 ms. RESULTS: The apicobasal, transmural and interventricular APD gradients of 20 ms produced similar BSPDs, whereas the BSPD inversion was caused by the inverted apicobasal or transmural 80 ms gradients. The transmural APD gradient produced transversal and mainly apicobasal T-wave vectors due to wall curvature and cancellation effects. The "normal" transversal and apicobasal repolarization gradients were decreased and increased by activation sequence, respectively. CONCLUSION: The different APD gradients contributed consistently to the development of BSPD. PMID- 25818746 TI - Is it possible to differentiate between Takotsubo cardiomyopathy and acute anterior ST-elevation myocardial infarction? AB - INTRODUCTION: Several studies have investigated the ability of the twelve-lead electrocardiogram (ECG) to reliably distinguish Takotsubo cardiomyopathy (TC) from an acute anterior ST-segment elevation myocardial infarction (STEMI). In these studies, only ECG changes were required - ST-segment deviation and/or T wave inversion - in TC whereas in acute anterior STEMI, ECGs had to meet STEMI criteria. In the majority of these studies, patients of both genders were used even though TC predominantly occurs in women. The aim of this study is to see whether TC can be distinguished from acute anterior STEMI in a predominantly female study population where all patients meet STEMI-criteria. METHODS: Retrospective analysis of the ST-segment changes was done on the triage ECGs of 37 patients with TC (34 female) and was compared to the triage ECGs of 103 female patients with acute anterior STEMI. The latter group was divided into the following subgroups: 46 patients with proximal, 47 with mid and 10 with distal LAD occlusion. Three ST-segment based ECG features were investigated: (1) Existing criterion for differentiating anterior STEMI from TC: ST-segment depression >0.5mm in lead aVR+ST-segment elevation <=1mm in lead V1, (2) frontal plane ST-vector and (3) mean amplitude of ST-segment deviation in each lead. RESULTS: The existing ECG criterion was less accurate (76%) than in the original study (95%), with a large difference in sensitivity (26% vs. 91%). Only a frontal plane ST-vector of 60 degrees could significantly distinguish TC from all acute anterior STEMI subgroups (p<0.01) with an overall diagnostic accuracy of 81%. The mean amplitude in inferior leads II and aVF was significantly higher for patients with TC compared to all patients with acute anterior STEMI (p<0.01 and p<0.05 respectively) and the mean amplitude in the precordial leads V1 and V2 was significantly lower compared to proximal and mid LAD occlusion (p<0.01). CONCLUSIONS: Given the consequences of missing the diagnosis of an acute anterior STEMI the diagnostic accuracy of the ECG criteria investigated in this retrospective study were insufficient to reliably distinguish patients with TC from patients with an acute anterior STEMI. To definitely exclude the diagnosis of an acute anterior STEMI coronary angiography, which remains the gold standard, will need to be performed. PMID- 25818748 TI - From neural to genetic substrates of panic disorder: Insights from human and mouse studies. AB - Fear is an ancestral emotion, an intrinsic defensive response present in every organism. Although fear is an evolutionarily advantageous emotion, under certain pathologies such as panic disorder it might become exaggerated and non-adaptive. Clinical and preclinical work pinpoints that changes in cognitive processes, such as perception and interpretation of environmental stimuli that rely on brain regions responsible for high-level function, are essential for the development of fear-related disorders. This review focuses on the involvement of cognitive function to fear circuitry disorders. Moreover, we address how animal models are contributing to understand the involvement of human candidate genes to pathological fear and helping achieve progress in this field. Multidisciplinary approaches that integrate human genetic findings with state of the art genetic mouse models will allow to elucidate the mechanisms underlying pathology and to develop new strategies for therapeutic targeting. PMID- 25818749 TI - Estimating vaccine efficacy using animal efficacy data. AB - Animal models are used to predict the effect of an intervention in humans. An example is the prediction of the efficacy of a vaccine when it is considered unethical or infeasible to challenge humans with the target disease to assess the effect of the vaccine on the disease in humans directly. In such cases, data from animal studies are used to develop models relating antibody level to protection probability in the animal, and then data from a study or studies in human subjects vaccinated with the proposed vaccine regimen are used in combination with the relevant animal models to predict protection in humans, and hence estimate vaccine efficacy. We explain the statistical techniques required to provide an estimate of vaccine efficacy and its precision. We present simulated examples showing that precise estimation of the relationship between antibody levels and protection in animals, at levels likely to be induced in humans by the vaccine regimen, is key to precise estimation of the vaccine efficacy. Because the confidence interval for the estimate of vaccine efficacy cannot be expressed in analytical form, but must be estimated from resampling, or bootstrapping, it is not possible to design studies with required power analytically. Therefore we propose that a simulation-based design of experiments approach using preliminary data is used to maximise the power of further studies and thus minimise the human and animal experimentation required. PMID- 25818751 TI - Neurobiological studies of chronic pain and analgesia: Rationale and refinements. AB - Chronic pain is a complex condition for which the need for specialized research and therapies has been recognized internationally. This review summarizes the context for the international call for expansion of pain research to improve our understanding of the mechanisms underlying pain in order to achieve improvements in pain management. The methods for conducting sensory assessment in animal models are discussed and the development of animal models of chronic pain is specifically reviewed, with an emphasis on ongoing refinements to more closely mimic a variety of human pain conditions. Pharmacological correspondences between pre-clinical pain models and the human clinical experience are noted. A discussion of the 3Rs Framework (Replacement, Reduction, Refinement) and how each may be considered in pain research is featured. Finally, suggestions are provided for engaging principal investigators, IACUC reviewers, and institutions in the development of strong partnerships to simultaneously expand our knowledge of the mechanisms underlying pain and analgesia while ensuring the humane use of animals in research. PMID- 25818747 TI - Paving the path to HIV neurotherapy: Predicting SIV CNS disease. AB - HIV-induced damage to the CNS remains a major challenge for over 30 million people in the world despite the successes of combined antiretroviral therapy in limiting viral replication. Predicting development and progression of HIV associated CNS disease is crucial because prevention and early intervention could be more effective than attempts to promote repair. The SIV/macaque model is the premier platform to study HIV neuropathogenesis, including discovery of predictive factors such as neuroprotective host genes and both blood and CSF biomarkers that precede and predict development of SIV CNS disease. This report details the role of macaque MHC class I genes, longitudinal alterations in biomarkers in the circulation, and expression of inflammatory and neuronal damage markers in CSF using samples from SIV-inoculated pigtailed macaques collected during acute, asymptomatic, and terminal stages of infection. PMID- 25818750 TI - Preclinical murine models of Chronic Obstructive Pulmonary Disease. AB - Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th leading cause of death worldwide. It is believed that an exaggerated inflammatory response to cigarette smoke causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T lymphocytes are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, defined as other chronic medical conditions, in particular skeletal muscle wasting and cardiovascular disease markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Thus, there is an obvious need for new therapies that can prevent the induction and progression of COPD and effectively treat AECOPD and comorbidities of COPD. Given that access to COPD patients can be difficult and that clinical samples often represent a "snapshot" at a particular time in the disease process, many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. This review highlights the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the recent advances in modelling infectious exacerbations and comorbidities of COPD. PMID- 25818752 TI - Modified PAS stain: A new diagnostic method for onychomycosis. AB - BACKGROUND: Onychomycosis is the most common nail disease and represents around 50% of nail disorders. Accurate diagnosis with adequate evidence is ideal before starting any treatment. Current diagnostic methods offer low specificity and sensitivity. AIMS: To create a new method for the diagnosis of onychomycosis, and to compare its sensitivity and specificity with the existing methods. METHODS: One hundred and ninety-two samples with clinical suspicion of onychomycosis were included and underwent modified PAS stain (M-PAS), KOH/chlorazol black (KOH/CB) and culture testing. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: In 152 out of 192 samples (79.2%) fungi structures were found in at least one of the three tests performed, and the patients were diagnosed with onychomycosis; 40 samples out of 192 (20.8%) were negative. Using M-PAS, filaments and/or spores were seen in 143 samples from the 152 positive (94%); 39 of them were negative to KOH/CB and positive to M-PAS (25.6%). With KOH/CB, filaments and/or spores were seen in 113 cases from the 152 positive samples (73.8% of the onychomycosis cases). Thirty-five cultures were positive, of which 77% were identified as Trichophyton rubrum; 117 onychomycosis cases were diagnosed despite the negative culture (76.9%). M-PAS showed 92.5% sensitivity and 55.55% specificity, a 67.5% positive predictive value and a 81.6% negative productive value. CONCLUSIONS: This procedure, a combination of the existing methods to diagnose onychomycosis, KOH/CB together with a nail clipping biopsy, proved to have high sensitivity, as well as being rapid, easy, inexpensive and readily available in most hospital settings. M-PAS allowed us to diagnose 39 cases (25.6% of the cases of onychomycosis) that were false negative using only KOH/CB and culture. PMID- 25818753 TI - Preoperative concurrent chemoradiotherapy followed by extrapleural pneumonectomy for patients with non-small cell lung cancer with malignant pleural effusion and/or pleural nodules: Ten-year results of a prematurely terminated single institute phase II trial. AB - BACKGROUND: Malignant pleural effusion and/or pleural nodules are a final stage of disease extension of non-small cell lung cancer (NSCLC), which is currently classified as M1a-Stage IV disease. The role of surgery, especially extrapleural pneumonectomy (EPP) for local disease control and its impact on the survival of patients remains uncertain. PATIENTS AND METHODS: This single institute phase II trial was performed from March 1997 to March July 2004 to assess the effects of induction concurrent chemoradiotherapy (CRT) using a pro-drug of 5-FU, uracil tegafur (UFT((r)), Taiho Pharmaceutical Co., Ltd, Tokyo, Japan), plus cisplatin concurrently with 40 Gy hemithorax radiation followed by EPP. Intraoperative hypotonic cisplatin treatment in the pleural cavity before resection of the pericardium and diaphragm was performed. The primary endpoint of this study was the overall survival (OS), and the secondary endpoint was the disease-free survival (DFS), safety, response to the induction CRT, local disease control period in the affected thorax and the type of disease recurrence. RESULTS: This trial was prematurely terminated because of the slow registration pace. During the study period, 11 patients were enrolled. There were five males and six females, with a median age of 55 (36-64) years. All patients had adenocarcinoma. All patients received the planned induction CRT. Five patients achieved a partial response and five achieved stable disease, and one patient could not be evaluated. One patient underwent exploratory thoracotomy due to unresectable chest wall invasion, and nine patients (81.8%) underwent EPP. No perioperative deaths were encountered. The median follow-up time was matured at 32.1 (range 15.0-100) months. The one-, three- and five-year DFS rates were 77.8% (95%CI: 50.6-100%), 11.1% and 11.1% (95%CI: 95%CI: 0-31.7%), respectively. The one-, three- and five-year OS rates were 100.0%, 33.3% (95%CI: 2.5-64.1%) and 22.2% (95%CI: 0.0-49.4%), respectively. Recurrence developed in eight of nine patients who underwent EPP (88.9%). All first recurrent sites were distant regions, and no ipsilateral local recurrence was identified. CONCLUSION: The trimodality treatment used in this trial appears to be a choice of treatment for highly selected patients. However, the impact on the survival of NSCLC patients with malignant pleural effusion and/or pleural nodules still remains uncertain given the small number of patients enrolled in the study. PMID- 25818754 TI - Comparison of contrast enhancement, image quality and tolerability in Coronary CT angiography using 4 contrast agents: A prospective randomized trial. PMID- 25818755 TI - Percutaneous pulmonary valve implantation for free pulmonary regurgitation following conduit-free surgery of the right ventricular outflow tract. AB - INTRODUCTION: Pulmonary regurgitation (PR) following surgery of the right ventricular outflow tract (RVOT) is not innocent and leads to significant right heart dysfunction over time. Recent studies have demonstrated that percutaneous valves can be implanted in conduit free outflow tracts with good outcomes. OBJECTIVES: To evaluate in patients with severe PR--anticipated to require future pulmonary valve replacement--the feasibility and safety of pre-stenting dilated non-stenotic patched conduit-free right ventricular outflow tracts before excessive dilation occurs, followed by percutaneous pulmonary valve implantation (PPVI). PATIENTS AND METHODS: Twenty seven patients were evaluated, but only 23 were deemed suitable based on the presence of an adequate retention zone <= 24 mm defined by semi-compliant balloon interrogation of the RVOT. A 2 step procedure was performed: first the landing zone was prepared by deploying a bare stent, followed 2 months later by valve implantation. RESULTS: RVOT pre-stenting with an open cell bare metal stent (Andrastent XXL range) was performed at a median age of 13.0 years (range: 6.0-44.9) with a median weight of 44.3 kg (range: 20.0 88.0). Ninety six percent (22/23) of patients proceeded to PPVI a median of 2.4 months (range: 1.4-3.4) after initial pre-stent placement. Twenty one Melody valves and one 26 mm Edwards SAPIENTM valve were implanted. Complications consisted of embolization of prestent (n = 1), scrunching (n = 4) and mild stent dislocation (n = 2). During follow-up, no stent fractures were observed and right ventricular dimensions decreased significantly. CONCLUSIONS: Post-surgical conduit-free non-stenotic RVOT with free pulmonary regurgitation can be treated percutaneously with a valved stent if anatomical (predominantly size) criteria are met. In experienced hands, the technique is feasible with low morbidity. PMID- 25818756 TI - Late-acquired scaffold malapposition and discontinuity that may be attributable to pathological coronary ectasia: Insights from optical coherence tomography. PMID- 25818757 TI - Impact of pericardial injury on inflammatory biomarkers early post myocardial infarction: A cardiovascular magnetic resonance (CMR) study. PMID- 25818758 TI - Prothrombotic risk of vitamin K antagonists during the first days of treatment: One more reason to use new oral anticoagulants. PMID- 25818759 TI - Life in the unthinking depths: energetic constraints on encephalization in marine fishes. AB - Several hypotheses have been proposed to explain the limitation of brain size in vertebrates. Here, we test three hypotheses of brain size evolution using marine teleost fishes: the direct metabolic constraints hypothesis (DMCH), the expensive tissue hypothesis and the temperature-dependent hypothesis. Our analyses indicate that there is a robust positive correlation between encephalization and basal metabolic rate (BMR) that spans the full range of depths occupied by teleosts from the epipelagic (< 200 m), mesopelagic (200-1000 m) and bathypelagic (> 4000 m). Our results disentangle the effects of temperature and metabolic rate on teleost brain size evolution, supporting the DMCH. Our results agree with previous findings that teleost brain size decreases with depth; however, we also recover a negative correlation between trophic level and encephalization within the mesopelagic zone, a result that runs counter to the expectations of the expensive tissue hypothesis. We hypothesize that mesopelagic fishes at lower trophic levels may be investing more in neural tissue related to the detection of small prey items in a low-light environment. We recommend that comparative encephalization studies control for BMR in addition to controlling for body size and phylogeny. PMID- 25818760 TI - Comparative evaluation of two matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) systems, Vitek MS and Microflex LT, for the identification of Gram-positive cocci routinely isolated in clinical microbiology laboratories. AB - We evaluated the performance of two MALDI-TOF MS systems for the identification of clinically important Gram-positive cocci. Vitek MS and Microflex LT correctly identified 97.2% and 94.7%, respectively. Both systems offer reliable and rapid identification of clinically important Gram-positive cocci isolated in clinical laboratories, including staphylococci, streptococci, and enterococci. Expanding the databases, especially of coagulase-negative staphylococci and viridans streptococci, would enhance performance. PMID- 25818761 TI - [Recommendations guide for diagnosis and treatment of abdominal aortic aneurysm]. PMID- 25818762 TI - Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma. AB - The tumor microenvironment is shaped by interactions between malignant cells and host cells representing an integral component of solid tumors. Host cells, including elements of the innate and adaptive immune system, can exert both positive and negative effects on the outcome of the disease. In melanoma, studies on the prognostic impact of the lymphoid infiltrate in general, and that of T cells, yielded controversial results. According to our studies and data in the literature, a high peritumoral density of activated T cells, increased amount of B lymphocytes and mature dendritic cells (DCs) predicted longer survival, while intense infiltration by plasmacytoid DCs or neutrophil granulocytes could be associated with poor prognosis. Besides its prognostic value, evaluation of the components of immune infiltrate could provide biomarkers for predicting the efficacy of the treatment and disease outcome in patients treated with immunotherapy or other, non-immune-based modalities as chemo-, radio-, or targeted therapy. PMID- 25818764 TI - Increased risk of accidental childhood poisoning and childhood vicarious learning: Barbie and supersparkle movie invites copy behaviours. PMID- 25818763 TI - Central systolic blood pressure is associated with ethnicity and cardiovascular disease risk factors in Chinese middle-aged population. AB - BACKGROUND: Central systolic blood pressure (CSBP) is a useful prognostic aid in the reduction and prevention of cardiovascular diseases. However, data regarding the distribution of CSBP in China are not available. The study aimed at assessing the distribution of CSBP and examining its relationship with potential cardiovascular risk factors in the Chinese middle-aged population. DESIGN: A cross-sectional study. METHODS: A cross-sectional survey on cardiovascular risk factors across China was conducted in 2009-2010. CSBP levels were estimated using the non-invasive BPro device with A-Pulse central aortic systolic pressure software. The study population included 9113 individuals (mean age 49.84 years; 53.37% women). RESULTS: The CSBP levels (mean (standard deviation)) were 119.46 (17.51) mmHg in men and 119.81 (19.29) mmHg in women. CSBP levels were higher in rural than urban and lower in the southern than the northern populations (both P < 0.05). The Han ethnic group had higher CSBP levels than the Tibetans (P < 0.05) but similar to those in the Mongolian, Uyghur, Kazak and Akha groups. Irrespective of gender, the mean CSBP level was higher in individuals with diabetes and hypertension than in those without these disorders (P < 0.05). CSBP was positively associated with cardiovascular risk factors such as age, female gender, body mass index, systolic and diastolic blood pressure, and negatively associated with heart rate. CONCLUSIONS: CSBP estimated using the BPro device correlates with various cardiovascular risk factors. Our results may help establish future reference values in the Chinese middle-aged population. PMID- 25818765 TI - The CERT antagonist HPA-12: first practical synthesis and individual binding evaluation of the four stereoisomers. AB - The first unified synthetic route to the four enantiopure HPA-12 stereoisomers in multi-gram scale is reported based on Crystallization-Induced Asymmetric Transformation (CIAT) technology. This preparative stereoselective synthesis allowed the unprecedented comparative evaluation of HPA-12 stereoisomers regarding their interaction with the CERT START domain. In vitro binding assay coupled to in silico docking approach indicate a possible interaction for the four derivatives. The first TR-FRET homogeneous-phase assay was developed to quantify their binding to the START domain, allowing complete determination of HPA-12 EC50. Results indicate that not only the (1R,3S) lead to the strongest binding, but that both 1R and 3S stereocenters similarly contribute to extent of recognition This automated homogenous assay further opens up promising prospect for the identification of novel potential CERT antagonist by means of high throughput screening. PMID- 25818766 TI - Design, synthesis and preliminary bioactivity studies of 2-thioxo-4 thiazolidinone derivatives as Bcl-2 inhibitors. AB - The B-cell lymphoma-2 (Bcl-2) protein is a promising target for cancer therapy. In the present study, a series of 2-thioxo-4-thiazolidinone derivatives were designed and synthesized as Bcl-2 inhibitors. Most of them possessed decent inhibitory activity for anti-apoptotic Bcl-2 proteins. Among them, compound 31 has similar growth inhibition towards K562 compared to (R)-Gossypol. In addition, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a Ki value of 74 nM. PMID- 25818768 TI - Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore. AB - The identification of compounds with anti-mycobacterial activity within classes of molecules that have been developed for other purposes is a fruitful approach for the development of anti-tuberculosis (TB) agents. In this study we used the scaffold of celecoxib which exhibits several activities against different pathogens, for the design and focused synthesis of a library of 64 compounds. For the primary screen, we used a bioluminescence-based method by constructing a luciferase-expressing reporter M.tb strain which contains the entire bacterial Lux operon cloned in a mycobacterial integrative expression vector. Through the screening of this library, we identified 6 hit compounds with high in vitro anti mycobacterial activity (IC50 ~0.18-0.48 MUM). In particular, compounds 41, 51 and 53 were capable of inhibiting M.tb as effectively as the anti-TB drug isoniazid (INH) at 5 MUM over a 72-h period, as analyzed by both bioluminescence- and colony forming unit (CFU)-based assays. All hit compounds also showed anti-M.tb activities against several multi-drug-resistant (MDR) strains. Most of the hit compounds showed no cytotoxicity for human macrophages at concentrations as high as 40 MUM, setting the stage for further optimization and development of these anti-TB hit compounds both ex vivo and in vivo. PMID- 25818769 TI - Selective GPCR ligands. PMID- 25818767 TI - Structure-activity relationships of a novel pyranopyridine series of Gram negative bacterial efflux pump inhibitors. AB - Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8 morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-beta naphthylamide (PAbetaN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d-f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli. PMID- 25818770 TI - Investigating how menopausal factors and self-compassion shape well-being: An exploratory path analysis. AB - OBJECTIVES: A large body of work has investigated the relationship between menopausal factors and negative well-being (e.g. anxiety and depressive symptoms), but less is known about positive well-being and its correlates among midlife women. This study tests two models with both positive and negative well being indices as outcomes: the first included menopausal factors as predictors; the second model expanded the first by adding self-compassion, a protective trait, as a predictor and moderator. STUDY DESIGN: Cross-sectional study based on self-report questionnaires from 206 women aged 40-60, currently experiencing hot flushes. MAIN OUTCOME MEASURES: Hot flush interference ratings, emotional balance, satisfaction with life, eudaimonic well-being and depressive symptoms. RESULTS: In model one, menopausal stage and hot flush frequency were independent of well-being outcomes. Beliefs about perceived control over menopause was the strongest predictor of well-being (beta range: .22-.32), followed by hot flush interference ratings (beta range: .15-.33). In model two, self-compassion was the strongest predictor of well-being indices (beta range: .20-.39), followed by beliefs about control (beta range: .16-.20) and interference ratings (beta range: .17-.26). CONCLUSIONS: Psychological aspects of the menopause appear more strongly linked to well-being than physiological aspects such as menopausal stage and hot flush frequency. Specifically, self-compassion, feeling in control of menopause and low interference ratings are three factors that are associated with well-being among midlife women. These aspects could be considered in tandem, as a means to support well-being in the context of menopause. PMID- 25818771 TI - Decreasing menopausal symptoms in women undertaking a web-based multi-modal lifestyle intervention: The Women's Wellness Program. AB - Menopausal transition can be challenging for many women. This study tested the effectiveness of an intervention delivered in different modes in decreasing menopausal symptoms in midlife women. The Women's Wellness Program (WWP) intervention was delivered to 225 Australian women aged between 40 and 65 years through three modes (i.e., on-line independent, face-to-face with nurse consultations, and on-line with virtual nurse consultations). All women in the study were provided with a 12-week Program Book outlining healthy lifestyle behaviors while women in the consultation groups were supported by a registered nurse who provide tailored health education and assisted with individual goal setting for exercise, healthy eating, smoking and alcohol consumption. Pre- and post-intervention data were collected on menopausal symptoms (Greene Climacteric Scale), health related quality of life (SF12), and modifiable lifestyle factors. Linear mixed-effect models showed an average 0.87 and 1.23 point reduction in anxiety (p<0.01) and depression scores (p<0.01) over time in all groups. Results also demonstrated reduced vasomotor symptoms (beta=-0.19, SE=0.10, p=0.04) and sexual dysfunction (beta=-0.17, SE=0.06, p<0.01) in all participants though women in the face-to-face group generally reported greater reductions than women in the other groups. This lifestyle intervention embedded within a wellness framework has the potential to reduce menopausal symptoms and improve quality of life in midlife women thus potentially enhancing health and well-being in women as they age. Of course, study replication is needed to confirm the intervention effects. PMID- 25818772 TI - [Incidences of C5 nerve palsy after multi-segmental cervical decompression through different approaches]. AB - OBJECTIVE: To investigate the incidence of C5 nerve root palsy after multi segmental cervical decompression through different approaches. METHODS: This study was conducted among 375 patients undergoing multi-segmental cervical decompression in anterior corpectomy and fusion fixation, anterior cervical corpectomy and fusion fixation + posterior decompression and fusion fixation, posterior cervical laminectomy decompression, fusion and internal fixation, and posterior laminoplasty and fusion groups. The exclusion criteria included lack of follow-up data, spinal cord injury preventing preoperative or postoperative motor testing, or surgery not involving the C5 level. The incidence of C5 palsy was determined and the potential risk factors C5 palsy were analyzed including age, sex, revision surgery, preoperative weakness, diabetes, smoking, number of levels decompressed, and a history of previous upper extremity surgery. RESULTS: Of the 375 patients, 60 patients were excluded and the data of 315 patients were analyzed, including 146 women and 169 men with a mean age of 57.7 years (range 39 72 years). The overall incidence of C5 nerve palsy was 6.03% (19/315) in these patients; in the subgroups receiving different surgeries, the incidence was 8.62% in the cervical road laminectomy and fusion fixation group, 7.79% in the anterior cervical corpectomy and fusion fixation + posterior decompression and fusion and internal fixation, 4.68% in the anterior corpectomy and fusion fixation group, and 3.85% in the posterior laminoplasty and fusion group. No significant difference was found in the incidences among the subgroups, but men were more likely than women to develop cervical nerve root palsy (8.28% vs 3.42%, P<0.05). CONCLUSION: The overall incidence of C5 nerve palsy following postoperative cervical spinal decompression was 6.03% in our cohort. The incidence of C5 nerve palsy did not differ significantly following different cervical decompression surgeries, but the incidence was the highest in the posterior cervical laminectomy and fusion and internal fixation group. PMID- 25818773 TI - [MicroRNA 144 negatively regulates Toll-like receptor 2 expression in rat macrophages]. AB - OBJECTIVE: To investigate the relationship between miR-144 and Toll-like receptor 2 (TLR2). METHODS: RT-qPCR was used to determine the expression of TLR2 and its downstream inflammatory cytokine TNF-alpha in rat macrophage cell line NR8383 transfected by a mimic miR-144 or miR-144 inhibitor. The fragments of 3'UTR region of rat TLR2 mRNA including wild or mutant miR-144 binding site obtained by PCR using rat liver cDNA were ligated to pmirGLO report gene vector digested with SacI and XbaI to construct the recombinant vectors of pmir-TLR2-3'UTR and pmir mutant-TLR2-3'UTR. The miR-144 targeting TLR2 was further determined by dual luciferase reporter assay and miR-144 mimics. RESULTS: TLR2 and TNF-alpha in NR8383 cells were decreased after transfection with 100 nmol/L mimic miR-144 for 24 h and increased after transfection with 100 nmol/L miR-144 inhibitor. PCR and double-enzyme digestion with SacI and XbaI confirmed successful insertion of the target fragments. Dual luciferase reporter assay suggested the binding of miR-144 to the 3'UTR of rat TLR2 mRNA. CONCLUSION: miR-144 negatively regulates the expression of TLR2 and its down-stream cytokine TNF-alpha by targeting TLR2 in NR8383 cells. PMID- 25818774 TI - [Intragastric administration of interferon-alpha-transformed Bifidobacterium promotes lymphocyte proliferation and maturation in mice]. AB - OBJECTIVE: To investigate the effects of intragastric administration of human interferon-alpha (hIFN-alpha)-transformed Bifidobacterium on immune functions of mice. METHODS: The E.coli-Bifidobacterium shuttle expression vector containing hIFN-alpha gene was constructed and transformed into Bifidobacterium. The hIFN alpha-transformed Bifidobacterium suspension (1010 /ml) was prepared after induction with 0.2% L-arabinose for hIFN-alpha expression and administered intragastrically in male Balb/C mice at the dose of 0.1 ml every other day for 2 weeks, with the mice receiving empty vector-transformed Bifidobacteria as the negative control and those having an equal volume of saline as the blank control. The percentages of mononuclear cell subsets in the thymus, spleen and blood were detected in the mice by flow cytometry, and the serum levels of IL-4, IL-12, IFN gamma and TNF-alpha were assayed using mouse cytokine FlowCytomix Kit. RESULTS: The percentages of CD3+CD8+ and CD4+CD8+ cells in the thymus, CD3+CD4+, CD3+CD8+ and CD4+CD8+ cells in the spleen, and CD3+CD8+ cells in the blood all increased significantly in IFN group as compared with those in the negative and blank control groups (P<0.01 or 0.05). The serum level of IFN-gamma also increased significantly (P<0.05) while IL-4 level remained unchanged in IFN group compared with those in the two groups. CONCLUSION: Intragastric administration of hIFN alpha-transformed Bifidobacterium promotes lymphocyte proliferation and maturation and increases the serum levels of Th1 cytokines in mice. PMID- 25818775 TI - [Clinical evaluation of ultrasound-guided percutaneous microwave ablation of splenic tumors]. AB - OBJECTIVE: To investigate the feasibility, safety and efficacy of ultrasound guided percutaneous microwave ablation (MWA) of splenic tumors. METHODS: Seven patients with 8 pathologically confirmed splenic tumors (including 2 metastases from the ovary and 4 from the lung, gastric adenocarcinoma, hepatocellular carcinoma, or rectal carcinoma; 1 hemangioma and 1 inflammatory pseudotumor) with sizes ranging from 1.3 to 6.2 cm (mean 3.1 +/- 1.9 cm) were treated with MWA. A cooled shaft needle antenna was percutaneously inserted into the tumor under ultrasound guidance. A thermocouple was placed about 0.5 cm away from the tumor to monitor the temperature in real time during the ablation. The microwave emitting power was set at 50-60 W. The treatment efficacy was assessed by contrast-enhanced imaging at 1, 3 and 6 months following the procedure, and every 6 months thereafter. RESULTS: All the tumors were completely ablated in a single session and no complications occurred. No local tumor progression was observed during a median follow up time of 13 months (4 to 92 months). The ablation zone, well defined on contrast-enhanced imaging, was gradually reduced with time. A new metastatic lesion was detected in the spleen at 11 months after the ablation in a ovarian carcinoma patient and was successfully treated by a second MWA. The post ablation survival of the patients with splenic metastasis was 13 months (range 4 to 92 months). No complications other than fever and abdominal pain were observed in these patients. CONCLUSION: Ultrasound-guided percutaneous MWA is a safe and effective minimally-invasive technique for treatment of splenic tumors in selected patients. PMID- 25818776 TI - [Expression of miR-223 in clear cell renal cell carcinoma and its significance]. AB - OBJECTIVE: To investigate the expression of miR-223 in clear cell renal cell carcinoma (ccRcc) and its clinical implications. METHODS: Quantitative real-time PCR was employed to detect the levels of miR- 223 expression in ccRcc, pair matched adjacent normal tissues and different renal cancer cell lines. Transwell migration essay and wound healing essay were used to evaluate the invasion and migration of renal cancer 786-O cells transfected with miR-223 mimics. MTT essay was used to measure the cell proliferation, and the cell cycle changes following the transfection were analyzed with flow cytometry. RESULTS: Compared with the normal tissues, the cancer samples showed up-regulated miR-223 expression, which was associated with tumor size. In 786-O cell cultures, transfection with miR-223 mimics significantly enhanced cell migration (P<0.0001) and growth (P=0.006) and induced G1 cell cycle arrest. CONCLUSION: miR-223 promotes renal cancer cell migration and proliferation and may serve as a potential therapeutic target for ccRcc. PMID- 25818777 TI - [Effect of Rhizoma Atractylodis extract in protecting gastric mucosa and modulating gastrointestinal immune function in a rat model of spleen deficiency]. AB - OBJECTIVE: To investigate the effect of Rhizoma Atractylodis extract (ERA) in protecting gastric mucosa and modulating gastrointestinal immune function of a rat model of spleen deficiency syndrome and elucidate the mechanism by which ERA improves spleen deficiency syndrome. METHODS: Male rats were fed with Xiaochengqi decoction and subjected to irregular feeding to induce spleen deficiency syndrome. The established models were randomized into model group, high-, moderate- and low-dose ERA groups, and domperidone group. After corresponding treatment for 30 days, the content of IgA in the intestinal lavage fluid, serum IgG, and the indices of the spleen and thymus were determined. The pathological changes in the gastric mucosa was observed with HE staining, gastric mucosal blood flow was evaluated with laser Doppler rheometry, and the expression of TFF1 in the gastric mucosa and TLR4 expression in the colon tissue were detected with immunohistochemistry. RESULTS: The rat models of spleen deficiency syndrome showed obvious abnormalities in gastric mucosal morphology, blood flow and immunological indexes. Compared with the model rats, the rats receiving ERA treatment as different doses all showed significant improvements in gastric mucosal morphology, blood flow volume, gastric mucosa trefoil factor 1 (TFF1) expression, intestinal lavage fluid IgA content, serum IgG content, indices of the spleen and thymus, and TLR4 expression in the colon TLR4 (P<0.05 or P<0.01). CONCLUSION: ERA can inhibit gastric mucosal damage, protect and repair the damaged mucosal tissues, and improve the immune function of in rats with spleen deficiency. PMID- 25818778 TI - [Construction of a recombinant lentiviral vector for VHL and VHL shRNA and its effect on proliferation and apoptosis of renal cell carcinoma cells]. AB - OBJECTIVE: To construct a lentiviral expression vector for human VHL and its shRNA vector, and study the effect of VHL on proliferation and apoptosis of renal cell carcinoma cell lines. METHODS: Lentiviral vectors pZsGreen1-VHL and pLL3.7 shVHL were constructed and transfected into 293T cells with 3 packaging plasmids by Lipofectamine(TM) 2000 reagent. The supernatant was collected to infect A498 and Caki-1 cells, respectively. VHL mRNA and protein levels were detected by RT PCR and Western blotting, respectively. The effect of VHL on the proliferation, cell cycle and cell apoptosis were analyzed by MTS and flow cytometry. RESULTS: The recombinant lentiviral vectors were successfully constructed. The proliferation of A498 cells with reconstituted wild-type VHL was significantly inhibited, while the proliferation of Caki-1 cells with VHL knockdown was significantly enhanced as compared with the control cells (P<0.05). VHL induced G0/G1-S cell cycle arrest. The apoptosis rate of A498 cells with reconstituted wild-type VHL was significantly increased while that of Caki-1 cells with VHL knockdown was significantly lowered compared with the control cells (P<0.05). CONCLUSION: VHL can inhibit the proliferation and induce apoptosis of renal cell carcinoma cells. PMID- 25818779 TI - [Effect of anacardic acid, a Hsp90 inhibitor, on proliferation, invasion and migration of breast cancer MDA-MB-231 cells]. AB - OBJECTIVE: To explore the effect of the Hsp90 inhibitor anacardic acid on cell proliferation, invasion and migration of breast cancer MDA-MB-231 cells. METHODS: The inhibitory effect of anacardic acid on Hsp90 was assessed with in vitro ATPase inhibition assay and ATP-sepharose binding assay. MTT assay was used to detect the growth inhibition induced by anacardic acid in MDA-MB-231 cells. Transwell assays were used to evaluate MDA-MB-231 cell invasion and migration. Western blotting was performed to assess the effect of anacardic acid in triggering the degradation of MMP-9, TIMP-1, Hsp90, and Hsp70. RESULTS: Anacardic acid exhibited a modest activity of ATPase inhibition with an IC50 value of 82.5 umol/L. Anacardic acid significantly suppressed the proliferation of MDA-MB-231 cells in a dose-dependent manner (IC50 value of 29.3 umol/L). Treatment with 12.5, 25, and 50 umol/L anacardic acid for 36 h caused inhibition of cell invasion by 23.6%, 56.6%, and 67.0% in MDA-MB-231 cells, respectively (P<0.05), and anacardic acid treatment for 24 h inhibited the cell migration by 30.0%, 45.5%, and 77.5%, respectively (P<0.05). Anacardic acid dose-dependently induced MMP-9 degradation, but did not obviously affect Hsp90 or Hsp70 expressions. CONCLUSION: Anacardic acid can significantly inhibit the proliferation, invasion, and migration of MDA-MB-231 cells, the mechanism of which may involve the inhibition of Hsp90 ATPse activity and down-regulation of MMP-9 expression. PMID- 25818780 TI - [Screening and identification of proteins related to gastric cancer metastasis with comparative proteomics]. AB - OBJECTIVE: To screen and identify the proteins related with tumor metastasis of gastric cancer in a nude mouse model bearing orthotopic transplanted tumor. METHODS: Zinc finger protein 139 (ZNF139)-specific siRNA was synthesized and transfected into gastric cancer cell line SGC7901, which was then screened by G418. ZNF139-siRNA-transfected cells, negative plasmid-transfected cells and untreated SGC7901 cells were orthotopically transplanted separately on the stomach wall of BALB/c nude mice. The primary tumors and metastatic lymph nodes were harvested to separate the proteins by 2-D fluorescence difference gel electrophoresis (2-D DIGE); after gel digestion, the differential proteins were subjected to liquid chromatography-mass spectrometry (LC-MS) for identification and their functions were analyzed. Western blotting was performed to verify the identified proteins. RESULTS: ZNF139 expression was effectively inhibited in siRNA-transfected SGC7901 cells. ZNF139-siRNA-transfected cells showed obviously suppressed tumor growth with a lowered lymph node metastasis rate in nude mice compared with untreated cells and the negative control cells (P<0.05). Proteomic study with 2-D DIGE showed that fascin and hnRNPA2/B1 were down-regulated while ANXA1 was up-regulated in the primary tumors, and ANXA5 was down-regulated in the metastatic lymph nodes in ZNF139-siRNA-transfected group. Western blotting confirmed the results of proteomic analysis. CONCLUSION: ZNF139 gene may promote lymph node metastasis of gastric cancer by regulating fascin, hnRNPA2/B1, ANXA1, and ANXA5. PMID- 25818781 TI - [Role of macrophages in mouse uterine during the peri-implantation period]. AB - OBJECTIVE: To investigate the effect of macrophages on embryo implantation by observing the distribution of macrophages in mouse uterine tissues during the peri-implantation period. METHODS: Uterine tissues were collected from pregnant (n=30) and pseudopregnant mice (n=30) during the peri-implantation period. The distributions of macrophages, iNOS and leukemia inhibitory factor (LIF) were determined by immunohistochemistry and the correlations of macrophages with iNOS and LIF were analyzed. RESULTS: Macrophages were located mainly in the endometrium before D4.5 in the pregnant rats with D0.5 defined as the morning when a vaginal plug was observed. After D4.5, the macrophages was significantly reduced in number (P<0.05) in the endometrium and gradually migrated to the perimetrium. In the psudopregnant mice, macrophages were located mainly in the endometrium. Before D4.5, iNOS-positive cells were detected mainly in the endometrium and the myometrium in the pregnant rats and became significantly reduced on D4.5 (P<0.05); in the pseudopregnant mice, the positive cells were mostly detected in the endometrium. Significant differences were found in the distribution of the macrophages and LIF between the implantation and non implantation sites (P=0.013). LIF was mostly located in the endometrium in the pregnant mice but scarcely detected in the pseudopregnant mice. CONCLUSION: Macrophages are located mainly in the endometrium and the implantation site where iNOS and LIF are expressed, suggesting the important role of macrophages in the determination of implantation. PMID- 25818782 TI - [Establishment of a chondrocyte degeneration model by over-expression of human Wnt7b gene in 293ft cell line]. AB - OBJECTIVE: To investigate the role of human Wnt7b gene in rat chondrocyte degeneration. METHODS: Wnt7b gene obtained by PCR was cloned to PCDH-GFP. 293ft cell line was transfected with PCDH-GFP and PCDH-Wnt7b, and the supernatant and transfected cells were collected. The expression level of Wnt7b in 293ft cells was detected by Western blotting. The first passage of chondrocytes were isolated from articular cartilages of newborn born (within 24 h) SD rats were cultured in the supernatants from the transfected cells (at 10- and 50-fold dilutions). The cell morphology of the rat chondrocytes was observed under inverted microscope, and the protein expressions of MMP13, MMP3 and type II collagen and mRNA expressions of A-can, ADAMTS5, Col X and Sox9 were examined by Western blotting or real-time PCR. RESULTS: Human Wnt7b gene cloned to PCDH-GFP was expressed efficiently in 293ft cell line. Rat chndrocytes cultured for 24 h in the supernatants from PCDH-Wnt7b-transfected 293ft cells underwent changes from a polygonal to a spindle-shaped morphology. The protein expression levels of MMP13 and MMP3 increased while type II collagen decreased significantly, and the mRNA levels of A-can and Sox9 were down-regulated while Col X and ADMATS5 up-regulated in ratchondrocytes after incubation in supernatants from PCDH-Wnt7b-transfected 293ft cells. CONCLUSION: Human Wnt7b gene can be expressed efficiently in 293ft cell line and can induce rat chondrocyte degeneration in vitro. PMID- 25818783 TI - [Edge-detecting operator-based selection of Huber regularization threshold for low-dose computed tomography imaging]. AB - OBJECTIVE: To compare two methods for threshold selection in Huber regularization for low-dose computed tomography imaging. METHODS: Huber regularization-based iterative reconstruction (IR) approach was adopted for low-dose CT image reconstruction and the threshold of Huber regularization was selected based on global versus local edge-detecting operators. RESULTS: The experimental results on the simulation data demonstrated that both of the two threshold selection methods in Huber regularization could yield remarkable gains in terms of noise suppression and artifact removal. CONCLUSION: Both of the two methods for threshold selection in Huber regularization can yield high-quality images in low dose CT image iterative reconstruction. PMID- 25818784 TI - [Investigation of B-cell activating factor in serum and cerebrospinal fluid of patients with neuromyelitis optical]. AB - OBJECTIVE: To study the expression of B-cell activating factor (BAFF) in the serum and cerebrospinal fluid of patients with neuromyelitis optical (NMO). METHODS: Clinical data were collected from 44 patients with NMO and 38 patients with multiple sclerosis (MS). Thirty healthy controls and 15 controls with noninflammatory neurological diseases were also recruited. The concentration of BAFF in the serum and cerebrospinal fluid were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean serum BAFF level was 250.2 +/- 126.9 pg/ml in NMO patients, 249.6 +/- 130.7 pg/ml in MS patients, and 222.9 +/- 126.1 pg/ml in the control subjects, showing no significant difference among the 3 groups (P>0.05). The mean BAFF level in the CSF was significantly higher in NMO patients than in MS patients (525.8 +/- 230.0 pg/ml vs 298.4 +/- 141.9 pg/ml, P<0.05), and higher in MS patients than in the control subjects (141.4 +/- 76.2 pg/ml, P<0.05). Both NMO and MS group showed a positive correlation between EDSS scores and CSF BAFF level. But in NMO patients, CSF BAFF level was not associated with AQP4-antibody titer. CONCLUSION: BAFF in the CSF may be a useful biomarker for a differential diagnosis of NMO from MS and has an important value in evaluating the disease severity. PMID- 25818785 TI - [Value of dual-energy computed tomography in the diagnosis of gouty arthritis]. AB - OBJECTIVE: To investigate the value of dual-energy computed tomography (DECT) in the diagnosis of gouty arthritis. METHODS: Sixty-one patients with gout, 30 with ankylosing spondylitis and 30 with rheumatoid arthritis were included in the study. DECT scans of the hands, wrists, elbows, feet, ankles, knees, lumbar, pelvis and sacroiliac joint were performed. For post-processing, a color-coding gout software protocol was used. The demographic data and blood uric acid levels were recorded. For 3 gout patients, the findings of puncture biopsy and DECT were compared. Ten gout patients with urate crystal deposition upon recruitment underwent DECT scans again after a 6-month urate-lowering therapy. RESULTS: The positivity rates of DECT scan differed significantly among the patients with gout, ankylosing spondylitis and rheumatoid arthritis [98.4% (60/61), 13.3% (4/30), and 6.7% (2/30), respectively; chi2 =95.522, P<0.05). Of the 21 patients with acute gouty arthritis, 20 (95.2%) showed positive DECT finding, and all the 40 patients with chronic gouty arthritis showed positive findings. In the patients with patients with gout, ankylosing spondylitis and rheumatoid arthritis, the positivity rates of hyperuricemia were 97.3% (36/37), 44.4% (4/9), and 28.6% (2/7), respectively (chi2 =24.197, P<0.05). A total of 344 urate deposition sites were detected in the gout patients, involving most commonly the first metatarsophalangeal joint (22.1%), the middle and distal end of the first phalanges of the toes (19.8%), the calcaneus (17.4%), and the inferior extremity of the tibia (13.4%). Seventeen and 5 urate deposition sites were found in ankylosing spondylitis patients and rheumatoid arthritis patients, respecitvely. The 10 gout patients receiving a 6-month urate-lowering therapy showed decreased urate deposition on DECT scan. CONCLUSIONS: DECT scan can detect urate deposition to allow differentiation diagnosis and follow-up in gout patients. PMID- 25818786 TI - [Expression of connexin 43 in spinal cord dorsal horn of rats with acute incisional pain]. AB - OBJECTIVE: To examine the effect of acute incisional pain on the expression of connexin 43 in rat spinal cord dorsal horn. METHODS: Eighty rats were assigned into control group without any treatment and incisional pain group with incision surgery. For paw incisions, a 1-cm longitudinal incision was made through the skin and fascia of the plantar aspect of the right hind paw. After surgery, the 50% paw withdrawal threshold (PWT) was assessed in response to a tactile stimulus with calibrated von Frey monofilaments at 1, 2, 4 and 24 h, respectively. The spinal cord dorsal horn of rats was isolated at 1, 2, and 4 h after the surgery to assess the expression of connexin 43 using Western blotting and immunofluorescence assay. RESULTS: The 50% PWT of the rats was significantly decreased after the incision surgery, and this decrement was the most obvious at 2 and 4 h. Western blotting and immunofluorescence assay showed that the expression of connexin 43 in the spinal cord dorsal horn was significantly increased in rats receiving the surgery especially at 2 and 4 h after the surgery. CONCLUSION: Incision surgery induces an significant increase in connexin 43 expression in rat spinal cord dorsal horn, suggestting an potential role of connexin43 in postoperative incisional pain. PMID- 25818787 TI - [Adenovirus vector-mediated short hairpin RNA targeting nuclear factor-kappaB suppresses proliferation of endometrial cells of Macaca fascicularis in vitro]. AB - OBJECTIVE: To assess the effect of a high specific adenovirus vector-mediated shRNA targeting nuclear factor-kappaB (NF-kappaB) on cell proliferation of the endometrium of Macaca fascicularis. METHODS: The adenoviral vector NF-kappaB-p65 shRNA and the empty vector were separately trasnfected in cultured endometrial cells of Macaca fascicularis. The changes in the expression of the target gene protein and apoptotic proteins, cell proliferation, and cell cycle distribution were observed after the transfection. RESULTS: Compared with the control cells, infection of the endometrial cells with the NF-kappaB-p65-shRNA adenovirus significantly increased the expression levels of apoptotic proteins, promoted apoptosis of the endometrial cells, and reduced the cells in division?stage. CONCLUSIONS: NF-kappaB-p65 shRNA adenovirus can effectively promote apoptosis of endometrial cells and inhibit the proliferation of endometrial cells of Macaca fascicularis. PMID- 25818788 TI - [Effect of IgG gene silencing by RNA interference on radiosensitivity of prostate cancer PC3 cells]. AB - OBJECTIVE: To investigate the effect of RNA interference of IgG gene on the radiosensitivity of the human prostate cancer PC3 cell line. METHODS: PC3 cells were trasnfected via lipofectamine by the shRNA vector FCGR1AshRNA targeting the Fc segment of IgG, using NCshRNA as the negative control. Q-PCR and Western blotting were used to analyze the expression of IgG in the trasnfected cells. The cells were then exposed to 60Co gamma ray at 0, 2, 4, 6, 8, 10 Gy, and the cell proliferation was evaluated by MTS and the cells apoptosis estimated by flow cytometry at 12, 24 and 48 h. RESULTS: MTS assay showed that 60Co gamma ray significantly inhibited the proliferation of PC3 cells transfected with FCGR1AshRNA as compared with NCshRNA-transfected and blank control cells (P<0.05). Flow cytometry showed that the cell apoptosis rate was significantly higher in FCGR1AshRNA group than in NCshRNA and blank control groups at 48 h after gamma ray exposure (P<0.05). At 12, 24 and 48 h after 6 Gy radiation, the cells in FCGR1AshRNA group showed a significantly lowered proliferation rate and an increased apoptosis rate (P<0.05). CONCLUSION: The shRNA targeting IgG gene can significantly enhance the sensitivity of PC3 cells to radiation. The combination of RNA interference targeting IgG gene with radiotherapy may be more effective in the treatment of prostate cancer. PMID- 25818789 TI - [Screening of highly efficient small interfering RNAs against bone morphogenetic protein-7]. AB - OBJECTIVE: To obtain highly efficient small interfering RNAs (siRNAs) against bone morphogenetic protein-7 (BMP-7) for future functional analysis of BMP-7 in bone homeostasis. METHODS: We designed 4 independent siRNA sequences against rat BMP-7 and transfected them in rat umbilical vein endothelial cells. After 72 h, we examined BMP-7 mRNA and protein level in the transfected cells using real-time PCR and Western blotting, respectively. RESULTS: All the 4 siRNAs effectively reduced BMP-7 expression in rat umbilical vein endothelial cells, and among them BMP-7-3 siRNA showed the highest efficiency. CONCLUSION: We have obtained an efficient siRNA to knockdown BMP-7 expression in vitro for further investigation of the role of BMP-7 in bone and cartilage formation. PMID- 25818790 TI - [Peripheral blood apelin level in patients with acute ST-elevation myocardial infarction and its prognostic value]. AB - OBJECTIVE: To investigate peripheral blood apelin levels in patients with acute ST-elevation myocardial infarction (STEMI) and their correlation with the one year outcome of the patients. METHODS: A total of 153 consecutive patients, including 93 with acute STEMI undergoing primary percutaneous coronary intervention (PCI), 30 with acute STEMI and 30 with stable angina all undergoing elective PCI, and 10 healthy control subjects were examined for peripheral blood apelin levels and clinical parameters. The composite endpoints (CEPs) were determined at the one year follow-up. RESULTS: Apelin levels were significantly decreased in all the patients at admission, but increased following primary PCI. Apelin levels showed a negative correlation with glycosylated hemoglobin levels. At one year following PCI, the patients with a lower apelin level showed an increased risk for lowered left ventricular ejection fraction ratio, but further analysis failed to provide evidence that apelin levels were predictive of the one year outcome. CONCLUSION: Peripheral blood apelin levels might be useful for predicting the clinical outcomes of patients with acute STEMI. PMID- 25818791 TI - [The correlation between platelet parameters and acute rejection after renal transplantation]. AB - OBJECTIVE: To investigate the relationship between acute graft rejection early after renal transplantation and the variations of platelet parameters. METHODS: We retrospectively analyzed the clinical data of 167 renal transplant recipients before and within 2 months after the surgery. Before and at 1-10 days, 15 days, 30 days, 45 days and 60 days after the transplantation, 5 platelet parameters, including platelet count (PLT), platelet hematocrit (PCT), mean platelet volume (MPV), platelet volume distribution width (PDW), and large platelet ratio (P LCR), were detected in the 35 patients with acute graft rejection within two months (AR group) and in the other 132 recipients with good graft recovery (control group). RESULTS: The AR group and control group showed no significant difference in PLT, PCT, MPV, or P-LCR before the surgery, but the PDW was significantly higher in the AR group (t=2.18, P=0.035). These parameters were similar within 5 postoperative days between the two groups (P>0.05), but in postoperative days 6-15, the AR group showed significantly increased MPV, PDW and P-LCR compared with the control group (P<0.05). In postoperative days 6-9, MPV, PDW and P-LCR became stable in AR group but tended to decrease in the control group, showing obviously different patterns of variation between the two groups (P<0.05). CONCLUSIONS: Preoperative PDW may have a positive correlation with acute graft rejection after renal transplantation. Monitoring the variations of MPV, PDW and P-LCR may help in the diagnosis of acute graft rejection early after renal transplantation. PMID- 25818792 TI - [Application of 4-wavelength optical intrinsic signal imaging in monitoring peri infarct depolarizations in GFAP(+/+)Vim(+/+) mice]. AB - OBJECTIVE: To study optical intrinsic signal (OIS) imaging of peri-infarct depolarizations (PIDs) in mice and investigate the influence of knockout of glial fibrillary acidic protein and vimentin on PIDs. METHODS: GFAP(+/+)Vim(+/+) mice and GFAP(+/+)Vim(+/+) mice were subjected to MCAO by standard intraluminal filament method. The main characteristics of PIDs in 4 h were studied by 4 wavelength OIS imaging technique. RESULTS: PIDs were identified as consistent, red and blue interaction waves in the cortical reflectance that slowly propagated peripherally from the origin site. There were 5 patterns of PID propagation, namely rostro-caudal, latero-medial, caudo-rostral, contralateral and medial lateral. No significant differences were found in PID frequency, propagation patterns, velocity or duration time between the two groups (P>0.05). CONCLUSION: The 4-wavelength OIS system allows acquisition of high temporal-spatial resolution color images for analyzing temporal-spatial characteristics of PIDs in detail. Knockout of GFAP and vimentin do not affect PIDs in 4 h following middle cerebral artery occlusion. PMID- 25818793 TI - [Comparative analysis of integrated (99m)Tc-MIBI-SPECT/localizable CT and integrated 18F-FDG-PET/CT for differential diagnosis of solitary pulmonary nodules]. AB - OBJECTIVE: To compare the diagnostic value of 99Tc(m)-MIBI SPECT/localizable CT and 18FDG-PET/CT in patients with indeterminate solitary pulmonary nodules (SPNs) and assess the feasibility of using 99Tc(m)-MIBI SPECT/localizable CT as an alternative when 18FDG-PET/CT is not available. METHODS: Thirty-nine patients with indeterminate SPNs were examined by 99Tc(m)-MIBI SPECT/localizable CT, and another 46 patients by 18FDG-PET/CT. The findings of the two modalities were analyzed qualitatively and semiquantitatively to assess their efficacy for a definitive diagnosis of SNPs. RESULTS: Of the 39 patients examined by 99Tc(m) MIBI SPECT/localizable CT, 13 were identified to have malignant SPNs and 26 had benign SPNs; the diagnostic sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of the examination were 92.31% (12/13), 88.46% (23/26), 89.74% (35/39), 80% (12/15) and 95.83% (23/24), respectively. Of the 46 patients receiving 18FDG-PET/CT examination, 29 malignant cases and 17 benign cases were identified with a diagnostic sensitivity, specificity, accuracy, PPV and NPV of 96.55% (28/29), 76.47% (13/17), 89.13% (41/46), 87.50% (28/32) and 92.86% (13/14), respectively. The two modalities showed no significant differences in the diagnostic sensitivity (chi2 =0.356, P=0.55), specificity (chi2 =1.084, P=0.298), accuracy (chi2 = 0.008, P=0.927), PPV (chi2 = 0.453, P=0.501) or NPV (chi2 =0.157, P=0.692). The ROC curve showed that with the early uptake ratio (EUR) of 99Tc(m)-MIBI >= 1.474 and >= 1.38 as the cutoff values, the sensitivity of 99Tc(m)-MIBI SPECT/localizable CT was both 100% and the specificity both 76.90%; with the maximum standard uptake value (SUVmax) of 18FDG >= 2.40 as the cutoff value, the sensitivity of 18FDG-PET/CT was 96.60% and the specificity was 76.50%, showing no significant differences between the two modalities in the diagnostic efficacy. CONCLUSION: 99Tc(m)-MIBI-SPECT/localizable CT may be a useful and practical modality for early diagnosis of SNPs for patients with a medium or low income in small and medium-sized cities. PMID- 25818794 TI - [Evaluation of three methods for forensic diatom test]. AB - OBJECTIVE: To compare the efficacy of three methods for forensic diatom test, namely strong acid digestion-centrifuge enrichment-light microscopy (SD-CE-LM), microwave digestion-membrane filtration-automated scanning electron microscopy (MD-ME-SEM), and microwave digestion-membrane filtration-light microscopy (MD-MF LM). METHODS: Sixty samples were randomly divided into 3 groups for diatom test using three methods, and the sample preparation time, degree of digestion and recovery rate of diatoms were compared. RESULTS: The sample preparation time was the shortest with MD-MF-LM and the longest with SD-CE-LM (P<0.05). MD-ME-SEM and MD-MF-LM allowed more thorough tissue digestion than SD-CE-LM. MD-ME-SEM resulted in the highest total recovery rate of diatom, followed by MD-MF-LM and then by SD CE-LM (P<0.05); the recover rate of different diatom species was the highest with MD-ME-SEM, followed by MD-MF-LM and SD-CE-LM (P<0.05). CONCLUSION: SD-CE-LM has a low recovery rate of diatoms especially for those with lengths shorter than 40 um or densities less than 1/5. With a high recovery rate and accuracy in diatom test, MD-ME-SEM is suitable for diagnosis of suspected drowning cases. MD-MF-LM is highly efficient, sensitive and convenient for forensic diatom test. PMID- 25818795 TI - [Effects of alpha1-PDX, a furin inhibitor, on growth, invasion, and tumorigenicity of cervical cancer HeLa cells]. AB - OBJECTIVE: To investigate the effects of the furin inhibitor alpha1-PDX on the growth, invasion, and tumorigenicity of cervical cancer cells and explore the mechanisms. METHODS: The changes in the growth, migration and invasion of alpha1 PDX-transfected HeLa cells were observed using MTT assay, Boyden migration and invasion assay. The protein levels of furin and MT1-MMP were measured using Western blotting and furin activity was detected by enzyme activity assay in the transfected cells. HeLa cells were seeded subcutaneously in nude mice and the tumor volume changes were recorded. RESULTS: Compared with the control cells, alpha1-PDX-treated cells showed a significant growth inhibition by 18.4% at 24 h (P<0.01) with obviously lowered migration ability and cell invasiveness (P<0.01). Treatment with alpha1-PDX significantly reduced furin enzyme activity and MTI-MMP protein levels in HeLa cells. In nude mice, alpha1-PDX-treated HeLa cells exhibited a delayed and lowered tumorigenicity with reduced size of the tumors. CONCLUSION: alpha1-PDX can inhibit the growth, metastasis and tumorigenicity of HeLa cells, the mechanism of which may involve a decreased furin activity and MTI MMP expression. PMID- 25818796 TI - [Tripartite-motif protein 25 and pyruvate kinase M2 protein expression in non small cell lung cancer]. AB - OBJECTIVE: To investigate the expression of tripartite-motif protein 25 (TRIM25) and pyruvate kinase M2 (PKM2) protein in non-small cell lung cancer (NSCLC) and explore their role in the occurrence and progression of NSCLC. METHODS: The expressions of TRIM25 and PKM2 protein were detected in 60 NSCLC specimens and 20 adjacent normal lung tissue (>5 cm from the lesions) with immunofluorescence histochemical method and in 10 fresh specimens of NSCLC with Western blotting. The results were analyzed in relation with the clinicopathological features of the patients. RESULTS: The positivity rates of TRIM25 expression was 45% in the 60 lung carcinoma specimens, significantly higher than that in the 20 normal lung tissues (10%, P=0.005). TRIM25 protein was expressed in 28.6% of lung adenocarcinoma tissues and in 59.4% of squamous carcinoma tissues (P=0.017). TRIM25 protein expression was positively correlated with the TNM stages and lymph node metastasis of NSCLC (P<0.05). The expressions of PKM2 protein in 60 cases of lung carcinoma was 73.3%,while in 20 cases of normal lung tissues the expressions was 30%(P=0.001). The positivity rates of PKM2 expression differed significantly between lung adenocarcinoma and squamous carcinoma (57.1% vs 87.5%, P=0.008). An inverse correlation was noted between TRIM25 and PKM2 expressions (P=0.026). CONCLUSION: TRIM25 and PKM2 protein may participate in the occurrence and progression of NSCLC, and their expressions are inversely correlated. PMID- 25818797 TI - [Changes in portal vein and hepatic vein blood flow volume and their ratio in SD rats during induced carcinogenesis of hepatocellular carcinoma]. AB - OBJEVTIVE: To explore the feasibility and reliability of ultrasonic monitoring of portal vein (PV) and hepatic vein (HV) blood flow volume changes in the process of induced carcinogenesis of hepatocellular carcinoma and the correlation of PV/HV blood flow volume ratio (Qpv/Qhv) with the severity of liver cirrhosis. METHODS: SD rats with diethylnitrosamine-induced liver carcinogenesis underwent regular liver ultrasound examinations including color flow imaging and pulsed Doppler examination. The main PV and HV blood flow parameters were measured to calculate Qpv/Qhv until successful induction of liver cancer. RESULTS: The PV diameter increased significantly with the severity of liver cirrhosis in the rats (P<0.05), and the PV blood flow velocity reduced but the blood flow volume increased significantly in liver cancer and cirrhosis stages (P<0.05). Normal hepatic vein blood flow was significantly greater than that measured in liver cirrhosis and hepatocellular carcinoma stages. The Qpv/Qhv measured in normal rats was significantly lower than that in liver cirrhosis and liver cancer stages, but the ratios were comparable between the latter two stages. CONCLUSION: Ultrasonography is reliable to monitor the change of liver hemodynamics in rats with induced liver carcinogenesis, in which the changes of Qpv/Qhv are correlated with the severity of liver cirrhosis. PMID- 25818798 TI - [Gefitinib versus Erlotinib as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer]. AB - OBJECTIVE: To compare the efficacy of the erlotinib versus gefitinib in the first line treatment of patients with advanced EGFR mutation-positive NSCLC. METHODS: Fifty patients with untreated advanced EGFR mutation- positive NSCLC were randomly divided into gefitinib group (n=27) and erlotinib group (n=23). The progression-free survival, objective response rate and disease control rate were evaluated to compare the efficacy of gefitinib and erlotinib. RESULTS: There were no significant differences in the objective response rate (P=0.711) and disease control rate (P=0.861) between the two groups. The progression-free survival of gefitinib group and erlotinib group was 8.0 months and 10.0 months, respectively. The efficacy of the two drugs was similar (P=0.293). CONCLUSION: There is no significant differences between gefitinib and erlotinib in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. PMID- 25818799 TI - [Expression of miR-200a in colorectal carcinoma cell lines and its effect on LoVo cells]. AB - OBJECTIVE: To detect miR-200a expression in human colorectal carcinnoma (CRC) cell lines and explore the role of miR-200a in regulating the biological behavior of CRC cells. METHODS: Real-time quantitative RT-PCR (qRT-PCR) was used to detect miR-200a expression levels in 6 CRC cell lines (HCT116, HT29, LS174T, SW480, SW620 and LoVo). miR-200a mimics were transiently transfected into LoVo, and the changes in cell proliferation, apoptosis, migration, and cell-cell adhesion were assessed using CCK-8 assay, TUNEL assay, transwell migration assay, and homogenous adhesion experiment, respectively. RESULTS: The expression of miR-200a was down-regulated in the 6 CRC cell lines, among which the highly metastatic LoVo cell line showed the lowest expression and the tumorigenic but non metastatic CRC cell line HCT116 had the highest expression. Overexpression of miR 200a depressed cell proliferation and migration but promoted cell apoptosis and cell-cell adhesion in LoVo cells. CONCLUSION: miR-200a plays a role in regulating the invasiveness and metastasis of CRC, and overexpression of miR-200a causes a significant reduction of cell proliferation and migration and promotes apoptosis and cell-cell adhesion in LoVo cells. PMID- 25818800 TI - [Preliminary experience with endoscopic gastric submucosal tumor resection through the submucosal tunnel using double tunnel and double flex endoscope]. AB - OBJECTIVE: To examine the feasibility and safety of gastric submucosal tunnel dissection of gastric submucosal tumors (SMTs) by double tunnel and double flex endoscope. METHODS: Fifty patients with gastric SMTs detected by gastric endoscopy and endoscopic ultrasonography between January, 2012 and August, 2013 were enrolled in this study. Using carbon dioxide throughout the procedure, the mucous in the arc was incised along the margins of the lesion to separate the submucosa and create a tunnel. The exposed SMTs were resected completely and the mucosa was covered by endoscopic forceps followed by clipping of the incision. The complication, clinical outcomes, hospital stays and operation time were evaluated. RESULTS: Of the 50 lesions, 50 were located in the gastric fundus, 17 in the gastric antrum and 5 in the gastric body. The lesions were completely resected in all the patients. The diameter of the resected lesions ranged from 0.5 to 2.5 cm (mean 1.1 +/- 0.6 cm), and the operation lasted for 35.3 +/- 16.2 min (range 23-76 min). In 5 cases (10%), perforation occurred during the operation and was closed by clipping the incision with endoclips after the lesion resection; these patients were discharged after conservative management. Intraoperative bleeding occurred in 16 cases and was successfully managed through endoscopic methods. No delayed postoperative bleeding or perforation occurred in these patients. None of the 48 patients followed up showed tumor recurrence at one year after the operation, and 2 patients were lost for follow up. CONCLUSION: Endoscopic submucosal dissection of gastric SMTs is effective and safe using double tunnel and double flex endoscope. PMID- 25818801 TI - [Copeptin and ischemia modified albumin in early diagnosis and prognosis of myocardial damage in acute organic phosphorus pesticide poisoning]. AB - OBJECTIVE: To assess the value of combined detection of copeptin and ischemia modified albumin (IMA) in early diagnosis and prognostic evaluation of myocardial damage in patients with acute organic phosphorus pesticide poisoning (AOPP). METHODS: A total of 126 AOPP patients were examined for blood copepin and IMA levels and myocardial injury markers within 1 h after admission. RESULTS: Copeptin and IMA levels significantly increased in patients with AOPP compared with those in the control subjects. Copeptin and IMA levels were significantly higher in severe AOPP cases than in mild to moderate cases (P<0.05). Logistic regression analysis showed that increased copeptin and IMA levels and severe complications of AOPP were associated with an increased risk of cardiovascular events. CONCLUSION: Early detection of copeptin and IMA levels has important clinical value in early diagnosis and prognostic evaluation of myocardial damage in patients with AOPP, and their levels are positively correlated with the severity of the condition. PMID- 25818802 TI - Collateral sensitivity of antibiotic-resistant microbes. AB - Understanding how evolution of microbial resistance towards a given antibiotic influences susceptibility to other drugs is a challenge of profound importance. By combining laboratory evolution, genome sequencing, and functional analyses, recent works have charted the map of evolutionary trade-offs between antibiotics and have explored the underlying molecular mechanisms. Strikingly, mutations that caused multidrug resistance in bacteria simultaneously enhanced sensitivity to many other unrelated drugs (collateral sensitivity). Here, we explore how this emerging research sheds new light on resistance mechanisms and the way it could be exploited for the development of alternative antimicrobial strategies. PMID- 25818803 TI - Inducible VEGF expression by human embryonic stem cell-derived mesenchymal stromal cells reduces the minimal islet mass required to reverse diabetes. AB - Islet transplantation has been hampered by loss of function due to poor revascularization. We hypothesize that co-transplantation of islets with human embryonic stem cell-derived mesenchymal stromal cells that conditionally overexpress VEGF (hESC-MSC:VEGF) may augment islet revascularization and reduce the minimal islet mass required to reverse diabetes in mice. HESC-MSCs were transduced by recombinant lentiviruses that allowed conditional (Dox-regulated) overexpression of VEGF. HESC-MSC: VEGF were characterized by tube formation assay. After co-transplantation of hESC-MSC:VEGF with murine islets in collagen fibrin hydrogel in the omental pouch of diabetic nude mice, we measured blood glucose, body weight, glucose tolerance and serum C-peptide. As control, islets were transplanted alone or with non-transduced hESC-MSCs. Next, we compared functional parameters of 400 islets alone versus 200 islets co-transplanted with hESC-MSC:VEGF. As control, 200 islets were transplanted alone. Metabolic function of islets transplanted with hESC-MSC:VEGF significantly improved, accompanied by superior graft revascularization, compared with control groups. Transplantation of 200 islets with hESC-MSC:VEGF showed superior function over 400 islets alone. We conclude that co-transplantation of islets with VEGF-expressing hESC-MSCs allowed for at least a 50% reduction in minimal islet mass required to reverse diabetes in mice. This approach may contribute to alleviate the need for multiple donor organs per patient. PMID- 25818805 TI - Polo-like kinase 3 is associated with improved overall survival in cholangiocarcinoma. AB - BACKGROUND & AIMS: Cholangiocarcinomas (CCA) paradoxically express the death ligand TRAIL and thus, are dependent on effective survival signals to circumvent apoptosis. Hedgehog signalling exerts major survival signals in CCA by regulating serine/threonine kinase polo-like kinase (PLK)2. We here aimed to examine the role of PLK1/2/3 expression for CCA tumour biology. METHODS: We employed CCA samples from 73 patients and human HUCCT-1/Mz-CHA1/KMCH-1 CCA cells. Immunohistochemistry for PLK1/2/3 was performed using tissue microarrays from representative tumour areas. RESULTS: PLK1/2/3-immunoreactive cancer cells were present in most of the CCA samples. However, only PLK1 and especially PLK3 were expressed in higher amounts within CCA cells as compared to normal liver. Given that fibroblast growth factor (FGF) can induce PLK3 expression and also is present in CCA, we examined the effect of FGF on PLK3 in vitro. Indeed, rhFGF rapidly increased PLK3 mRNA expression all three CCA cell lines giving an explanation for the abundant PLK3 presence in the tissue samples. Clinicopathologically, PLK3 expression was associated with decreased tumour cell migration and lymph/blood vessel infiltration whereas higher levels of PLK1 were correlated with larger tumour sizes. Moreover, strong PLK3 expression was associated with prolonged overall survival. CONCLUSIONS: The results suggest that PLK3 predominantly is expressed in CCA cells and that high PLK3 expression correlates with prolonged overall survival. These observations might have implications for prognosis prediction of human CCA as well as the potential therapeutic use of polo-like kinase inhibitors (i.e., PLK1/2 specifity). PMID- 25818807 TI - Cross-sectional imaging of the Fontan circuit in adult congenital heart disease. AB - The Fontan circuit is the result of a palliative surgical procedure that is performed in patients with a functionally single ventricle cardiac anomaly. The success of this operation has resulted in an increasing population of adults with this anatomy and physiology. The purpose of this article is to familiarize the general radiologist with the expected anatomy and cross-sectional imaging findings, highlight special imaging considerations, and examine the common complications that are encountered in this group of patients. PMID- 25818808 TI - Social media: the next frontier in radiology. PMID- 25818806 TI - HIV-1 capsids bind and exploit the kinesin-1 adaptor FEZ1 for inward movement to the nucleus. AB - Intracellular transport of cargos, including many viruses, involves directed movement on microtubules mediated by motor proteins. Although a number of viruses bind motors of opposing directionality, how they associate with and control these motors to accomplish directed movement remains poorly understood. Here we show that human immunodeficiency virus type 1 (HIV-1) associates with the kinesin-1 adaptor protein, Fasiculation and Elongation Factor zeta 1 (FEZ1). RNAi-mediated FEZ1 depletion blocks early infection, with virus particles exhibiting bi directional motility but no net movement to the nucleus. Furthermore, both dynein and kinesin-1 motors are required for HIV-1 trafficking to the nucleus. Finally, the ability of exogenously expressed FEZ1 to promote early HIV-1 infection requires binding to kinesin-1. Our findings demonstrate that opposing motors both contribute to early HIV-1 movement and identify the kinesin-1 adaptor, FEZ1 as a capsid-associated host regulator of this process usurped by HIV-1 to accomplish net inward movement towards the nucleus. PMID- 25818809 TI - A new theory on children's drawings: Analyzing the role of emotion and movement in graphical development. AB - The aim of this paper is to develop a new understanding of children's drawings and to provide ideas for future research in early childhood. Starting from classic theories on child graphical development, we proceed to analyze them and provide our own views on the subject. We will also recount a number of relevant empirical studies that appear to validate our theory. Our belief is that emotion and self-expression through movement play a key role in the development of child art, and that this may be already visible during the scribbling stage of drawing. PMID- 25818810 TI - A lifestyle program of exercise and weight loss is effective in preventing and treating type 2 diabetes mellitus: Why are programs not more available? AB - There is substantial evidence that type 2 diabetes mellitus (T2DM) can be prevented in high-risk individuals by a lifestyle program of regular exercise and weight reduction. Additionally, there is emerging evidence that new onset T2DM (<1year) can go into remission after weight loss and exercise in a majority of motivated individuals, obviating a need for glucose lowering medications. Yet, lifestyle programs to support such behavior change are not widely available. Moreover, health care insurance companies generally do not provide coverage for behavioral weight loss programs to prevent or treat T2DM. Consequently, physicians caring for individuals with T2DM may find it much easier to start a chronic glucose lowering medication rather than attempting to motivate and support patients through long-term behavior change. The cardiac rehabilitation model of disease management, with a network of over 2000 programs in the U.S., is well suited to deliver medically-supervised lifestyle programs. National organizations such as the American Diabetes Association and the American Association of Cardiovascular and Pulmonary Rehabilitation should support greater availability and use of lifestyle programs for T2DM treatment and prevention. PMID- 25818811 TI - A simple and robust method for establishing homogeneous mouse epiblast stem cell lines by wnt inhibition. AB - Epiblast stem cells (EpiSCs) are pluripotent stem cells derived from epiblasts of postimplantation mouse embryos, and thus provide a useful model for studying "primed" pluripotent states. Here, we devised a simple and robust technique to derive high-quality EpiSCs using an inhibitor of WNT secretion. Using this method, we readily established EpiSC lines with high efficiency and were able to use whole embryonic portions without having to separate the epiblast from the visceral endoderm (VE). Expression analyses revealed that these EpiSCs maintained a homogeneous, undifferentiated status, yet showed high potential for differentiation both in vitro and in teratomas. Unlike EpiSCs derived by the original protocol, new EpiSC lines required continuous treatment with the Wnt inhibitor, suggesting some intrinsic differences from the existing EpiSCs. The homogeneous properties of this new version of EpiSCs should facilitate studies on the establishment and maintenance of a "primed" pluripotent state, and directed differentiation from the primed state. PMID- 25818814 TI - Metaphase cytogenetics and single nucleotide polymorphism arrays in myeloid malignancies. PMID- 25818812 TI - Long-term expandable SOX9+ chondrogenic ectomesenchymal cells from human pluripotent stem cells. AB - Here we report the successful generation and long-term expansion of SOX9 expressing CD271(+)PDGFRalpha(+)CD73(+) chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1(-)CD271(hi)PDGFRalpha(lo)CD73(-) neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorbeta (TGFbeta) inhibitor and fibroblast growth factor (FGF). When "primed" with TGFbeta, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice. The ectomesenchymal cells were expandable without loss of chondrogenic potential for at least 16 passages. They maintained normal karyotype for at least 10 passages and expressed genes representing embryonic progenitors (SOX4/12, LIN28A/B), cranial mesenchyme (ALX1/3/4), and chondroprogenitors (SOX9, COL2A1) of neural crest origin (SOX8/9, NGFR, NES). Ectomesenchyme is a source of many craniofacial bone and cartilage structures. The method we describe for obtaining a large quantity of human ectomesenchymal cells will help to model craniofacial disorders in vitro and potentially provide cells for the repair of craniofacial damage. PMID- 25818813 TI - Models of breast morphogenesis based on localization of stem cells in the developing mammary lobule. AB - Characterization of normal breast stem cells is important for understanding their role in breast development and in breast cancer. However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known. In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals. Comparing predictions of these models with immunohistochemical analysis of tissue sections for candidate stem cell markers, we defined distinct areas where stem cells reside in the mammary lobule. An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of nulliparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers. PMID- 25818815 TI - Comment on: Evaluation of erythrocyte and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease. PMID- 25818816 TI - Evaluation of erythrocyte and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of mature red cell and reticulocyte parameters to identify three conditions: iron deficiency anemia, anemia of chronic disease, and anemia of chronic disease associated with absolute iron deficiency. METHODS: Peripheral blood cells from 117 adult patients with anemia were classified according to iron status, inflammation, and hemoglobinopathies as: iron deficiency anemia (n=42), anemia of chronic disease (n=28), anemia of chronic disease associated with iron deficiency anemia (n=22), and heterozygous beta-thalassemia (n=25). The percentage of microcytic erythrocytes, hypochromic erythrocytes, and the levels of hemoglobin in both reticulocytes and mature red cells were determined. Receiver operating characteristic analysis was used to evaluate the accuracy of the parameters in differentiating anemia. RESULTS: There was no difference between the groups of iron deficiency and anemia of chronic disease associated with absolute iron deficiency for any of the parameters. The percentage of hypochromic erythrocytes was the best parameter to identify absolute iron deficiency in patients with anemia of chronic disease (area under curve=0.785; 95% confidence interval: 0.661 0.909 with sensitivity of 72.7%, and specificity of 70.4%; cut-off value 1.8%). The formula microcytic erythrocyte count minus hypochromic erythrocyte count was very accurate to differentiate iron deficiency anemia from heterozygous beta thalassemia (area under curve=0.977; 95% confidence interval: 0.950-1.005 with a sensitivity of 96.2%, and specificity of 92.7%; cut-off value 13.8). CONCLUSION: The erythrocyte and reticulocyte indices are moderately good to identify absolute iron deficiency in patients with anemia of chronic disease. PMID- 25818817 TI - Pilot randomized controlled trial to evaluate the effect of aquatic and land physical therapy on musculoskeletal dysfunction of sickle cell disease patients. AB - OBJECTIVE: To compare the effect of aquatic and land-based physiotherapy in reducing musculoskeletal hip and lower back pain and increasing overall physical capabilities of sickle cell disease patients. METHODS: Informed written consent was obtained from all volunteers who were submitted to evaluations using different functional scales: Lequesne's Algofunctional Questionnaire and Oswestry Disability Index, trunk and hip range of motion, goniometry, trunk and hip muscle strength assessment using load cell, and surface electromyography of the iliocostalis, long dorsal (longissimus), gluteus maximus, gluteus medius and tensor fasciae latae muscles. Ten patients were randomized into two groups: aquatic physiotherapy with a mean age of 42 years (range: 25-67) and conventional physiotherapy with a mean age of 49 years (range: 43-59). Both groups were submitted to a twelve-week program of two sessions weekly. RESULTS: After the intervention, significant improvements were observed regarding the Lequesne index (p-value=0.0217), Oswestry Disability Index (p-value=0.0112), range of motion of trunk extension (p-value=0.0320), trunk flexion muscle strength (p-value=0.0459), hip extension and abduction muscle strength (p-value=0.0062 and p-value=0.0257, respectively). Range of motion of trunk and hip flexion, extension, adduction and abduction, trunk extensor muscle strength and all surface electromyography variables showed no significant statistical difference. CONCLUSION: Physical therapy is efficient to treat musculoskeletal dysfunctions in sickle cell disease patients, irrespective of the technique; however, aquatic therapy showed a trend toward improvement in muscle strength. Further studies with a larger patient sample and longer periods of therapy are necessary to confirm these results. PMID- 25818818 TI - Paroxysmal nocturnal hemoglobinuria clone in 103 Brazilian patients: diagnosis and classification. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria is an acquired chronic hemolytic anemia, which often manifests as peripheral blood cytopenias and thrombosis. OBJECTIVE: The aim of this study is to describe a Brazilian population of paroxysmal nocturnal hemoglobinuria patients. METHODS: One hundred and three paroxysmal nocturnal hemoglobinuria cases were retrospectively reviewed and the clinical presentation, thrombosis, survival, and clone size were assessed. Diagnosis was established by flow cytometry. RESULTS: Fifty-two male and 51 female patients with a median age of 24.1 years (5.5-62 years) were studied. Clinical symptoms included hemoglobinuria (18.4%), infection (46.6%) and thrombosis (16.5%), and 80.6% had pancytopenia. Patients were classified as classic paroxysmal nocturnal hemoglobinuria (10), paroxysmal nocturnal hemoglobinuria with aplastic anemia (39), and paroxysmal nocturnal hemoglobinuria with subclinical features and aplastic anemia (54). There were significant differences in terms of median age, size of clone, clinical symptoms, and peripheral blood cell counts between the three subcategories. The clone size in erythrocytes and granulocytes were respectively 0.04% (range: 0-18%) and 7.3% (range: 0.3-68.7%) in patients with subclinical features and aplastic anemia, 15.8% (range: 0-99.7%) and 63.0% (range: 1.7-99.8%) in patients with aplastic anemia alone, and 82.2% (range: 0-99.85%) and 98.0% (81.3-100.0%) in Classic disease. Statistical differences were identified for platelets (p-value=0.001), lactate dehydrogenase (p-value=0.002) and the clone size (p-value<0.001) in patients who suffered thrombotic events compared to those who did not. Overall survival was 81.7%, with patients with subclinical features and aplastic anemia having lower overall survival (76.5%). CONCLUSION: This retrospective review of 103 patients over an 11-year period represents the largest collection of paroxysmal nocturnal hemoglobinuria cases from a single center in Brazil. Flow cytometry showed that a larger clone was associated with classical symptoms and increased risk of thrombosis, even in patients with bone marrow failure, whereas a smaller clone was associated with bone marrow aplasia. PMID- 25818820 TI - Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. AB - BACKGROUND: Brazil has a multiethnic population with a high diversity of hemoglobinopathies. While screenings for beta-globin mutations are far more common, alterations affecting alpha-globin genes are usually more silent and less well known. The aim of this study was to describe the results of a screening program for alpha-globin gene mutations in a representative sample of the Southeastern Brazilian population. METHODS: A total of 135,000 individuals, including patients with clinical suspicion of hemoglobinopathies and their family members, randomly chosen individuals submitted to blood tests and blood donors who were abnormal hemoglobin carriers were analyzed. The variants were screened by alkaline and acid electrophoreses, isoelectric focusing and cation-exchange high performance liquid chromatography (HPLC) and the abnormal chains were investigated by reverse-phase high performance liquid chromatography (RP-HPLC). Mutations were identified by molecular analyses, and the oxygen affinity, heme heme cooperativity and Bohr effect of the variants were evaluated by functional tests. RESULTS: Four new and 22 rare variants were detected in 98 families. Some of these variants were found in co-inheritance with other hemoglobinopathies. Of the rare hemoglobins, Hasharon, Stanleyville II and J-Rovigo were the most common, the first two being S-like and associated with alpha-thalassemia. CONCLUSION: The variability of alpha-globin alterations reflects the high degree of racial miscegenation and an intense internal migratory flow between different Brazilian regions. This diversity highlights the importance of programs for diagnosing hemoglobinopathies and preventing combinations that may lead to important clinical manifestations in multiethnic populations. PMID- 25818819 TI - CD144, CD146 and VEGFR-2 properly identify circulating endothelial cell. AB - Studies evaluating circulating endothelial cells by flow cytometry are faced by a lack of consensus about the best combination of monoclonal antibodies to be used. The rarity of these cells in peripheral blood, which represent 0.01% of mononuclear cells, drastically increases this challenge. OBJECTIVE: The aim of this study is to suggest some combinations of markers that would safely and properly identify these cells. METHODS: Flow cytometry analysis of circulating endothelial cells was performed applying three different panels composed of different combinations of the CD144, CD146, CD31, CD133, CD45 and anti-Vascular endothelial growth factor receptor-2 antibodies. RESULTS: In spite of the rarity of the events, they were detectable and presented similar inter-person numbers of circulating endothelial cells. CONCLUSION: The combination of markers successfully identified the circulating endothelial cells in healthy individuals, with the use of three different panels confirming the obtained data as reliable. PMID- 25818821 TI - A model for the functional assessment of elderly with myeloid neoplasms. AB - OBJECTIVE: Myeloid neoplasms are heterogeneous diseases that are more incident in the elderly. The goals of this study were to aggregate a geriatric approach to the patient assessment, to show the impact of gender, age, hemoglobin concentration and comorbidities on the functionality of elderly with myeloid neoplasms and to better understand how the instruments of functional assessment work according to the aggressiveness of the disease. METHODS: Elderly patients (>=60 years old) with myeloid neoplasms were assessed using the Karnofsky scale, Eastern Cooperative Oncologic Group scale, and basic and instrumental activities of daily living scales. The hematopoietic cell transplantation-comorbidity index assessed the comorbidities. A mixed logistical regression model was fitted to estimate the impact of gender, age, hemoglobin concentration and the hematopoietic cell transplantation-comorbidity index on patients' functionality. RESULTS: Eighty-two patients with a mean age of 72.8 years (range: 60-92 years) were evaluated. Eighty percent had good Karnofsky and Eastern Cooperative Oncologic Group scales and 39% were independent according to the daily living activity scales. All of the patients with poor Karnofsky and Eastern Cooperative Oncologic Group scales were classified as dependent by the daily living activity scales. The mixed logistic regression models showed that age, gender, hemoglobin concentration and the comorbidity index impacted on the daily living activity scales. Karnofsky and Eastern Cooperative Oncologic Group scales were affected by hemoglobin and the comorbidity index. The model hypothesized the hemoglobin concentration at which there was a higher risk of poor Karnofsky and Eastern Cooperative Oncologic Group scales. This hemoglobin concentration depended on comorbidities and on the aggressiveness of the myeloid neoplasm. CONCLUSION: The geriatric approach improved the sensitivity and specificity of the patients' assessment. Hemoglobin concentration associated to the risk of poor Karnofsky and Eastern Cooperative Oncologic Group scales depended on the comorbidity score and on the disease aggressiveness. The Karnofsky and Eastern Cooperative Oncologic Group scales had higher sensitivity in patients with more aggressive diseases. PMID- 25818822 TI - Prevalence of the American College of Rheumatology hematological classification criteria and associations with serological and clinical variables in 460 systemic lupus erythematosus patients. AB - OBJECTIVE: To study systemic lupus erythematosus in a Brazilian population using the American College of Rheumatology hematological classification criteria and report associations of the disease with serological and clinical profiles. METHODS: This is a retrospective study of 460 systemic lupus erythematosus patients followed in a single rheumatologic center during the last 10 years. Hematological manifestations considered for this study were hemolysis, leukopenia, lymphocytopenia and thrombocytopenia. RESULTS: The cumulative prevalences of leukopenia, thrombocytopenia, lymphocytopenia and hemolytic anemia were 29.8%, 21.08%, 17.7% and 8.4%, respectively. A higher percentage of patients with hemolysis had anticardiolipin IgM (p-value=0.002). Those with leukopenia had more lymphopenia (p-value=0.02), psychosis (p-value=0.01), thrombocytopenia (p value <0.0001) and anti-double stranded DNA antibodies (p-value=0.03). Patients with lymphopenia had more leukopenia (OR=1.8; 95% CI=1.01-3.29) and lupus anticoagulant antibodies (OR=2.2; 95% CI=1.16-4.39) and those with thrombocytopenia had more leukopenia (OR=3.1; 95% CI=1.82-5.44) and antiphospholipid syndrome (OR=3.1; 95% CI=1.28-7.87). CONCLUSION: The most common hematological finding was leukopenia and the least common was hemolysis. Associations of low platelet count and hemolysis were found with antiphospholipid syndrome and anticardiolipin IgM positivity, respectively. Leukopenia and lymphocytopenia are correlated and leukopenia is more common in systemic lupus erythematosus patients with psychosis, thrombocytopenia and anti-double stranded DNA. PMID- 25818823 TI - Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis. AB - This review discusses hemoglobin D-Punjab, also known as hemoglobin D-Los Angeles, one of the most common hemoglobin variants worldwide. It is derived from a point mutation in the beta-globin gene (HBB: c.364G>C; rs33946267) prevalent in the Punjab region, Northwestern Indian. Hemoglobin D-Punjab can be inherited in heterozygosis with hemoglobin A causing no clinical or hematological alterations, or in homozygosis, the rarest form of inheritance, a condition that is commonly not related to clinical symptomatology. Moreover, this variant can exist in association with other hemoglobinopathies, such as thalassemias; the most noticeable clinical alterations occur when hemoglobin D-Punjab is associated to hemoglobin S. The clinical manifestations of this association can be similar to homozygosis for hemoglobin S. Although hemoglobin D-Punjab is a common variant globally with clinical importance especially in cases of double heterozygosis, hemoglobin S/D-Punjab is still understudied. In Brazil, for example, hemoglobin D Punjab is the third most common hemoglobin variant. Thus, this paper summarizes information about the origin, geographic distribution, characterization and occurrence of hemoglobin D-Punjab haplotypes to try to improve our knowledge of this variant. Moreover, a list of the main techniques used in its identification is provided emphasizing the importance of complementary molecular analysis for accurate diagnosis. PMID- 25818824 TI - Burkitt's lymphoma successfully treated in pregnancy. PMID- 25818825 TI - Endemic transmission of HTLV-2 in blood donors from Sao Luis do Maranhao, northeastern Brazil: report of two asymptomatic individuals. PMID- 25818826 TI - Hairy cell leukemia variant: the importance of differential diagnosis. PMID- 25818827 TI - Remission of refractory Crohn's disease after autologous hematopoietic stem cell transplantation. PMID- 25818828 TI - Haplotype of the beta(S)-globin cluster in patients with sickle cell anemia at a University Hospital in the Triangulo Mineiro, Minas Gerais. PMID- 25818829 TI - Is the BCR-ABL/GUSB transcript level at diagnosis an early predictive marker for chronic myeloid leukemia patients treated with imatinib? PMID- 25818830 TI - Improving paediatric outreach services for urban Aboriginal children through partnerships: views of community-based service providers. AB - BACKGROUND: In Australia, Aboriginal children experience significantly poorer health outcomes compared with non-Aboriginal children. Health policies aimed at improving Aboriginal health outcomes include interventions in the early childhood period. There is a need for government health services to work in partnership with Aboriginal people and other services to achieve the highest level of health possible for Aboriginal children, who often require a range of services to meet complex needs. AIM: This paper describes the views of service providers on how paediatric outreach services work in partnership with other services, Aboriginal families and the community and how those partnerships could be improved to maximize health outcomes for children. METHODS: In-depth, semi-structured interviews and focus groups were conducted with managers and service providers over a 6-week period in 2010. The views and suggestions of participants were documented and a thematic analysis was undertaken. RESULTS AND DISCUSSION: Analysis of two focus groups with seven service providers and five individual interviews with service managers resulted in the identification of four themes: (i) using informal and formal ways of working; (ii) cultivating effective relationships; (iii) demonstrating cultural sensitivity; and (iv) forging strong leadership. Use of formal and informal approaches facilitated effective relationships between service providers and Aboriginal families and communities. Partnerships with the community were founded on a culturally appropriate model of care that recognized a holistic approach to health and wellness. Leadership emerged as an essential component of effective partnerships, cultivating the ethos of the workplace and creating an environment where collaboration is supported. CONCLUSION: Culturally appropriate child health services, which utilize effective relationships and employ a range of informal and formal collaboration with other services and community members, are well positioned to implement health policy and improve access to services for Aboriginal children with better health outcomes as a result. PMID- 25818831 TI - Response of human lymphocytes to proton radiation of 60 MeV compared to 250 kV X rays by the cytokinesis-block micronucleus assay. AB - Particle radiotherapy such as protons provides a new promising treatment modality to cancer. However, studies on its efficacy and risks are relatively sparse. Using the cytokinesis-blocked micronucleus assay, we characterized response of human peripheral blood lymphocytes, obtained from health donors irradiated in vitro in the dose range: 0-4. 0 Gy, to therapeutic proton radiation of 60 MeV from AIC-144 isochronous cyclotron, by studying nuclear division index and DNA damage and compared them with X-rays. Peripheral blood lymphocytes show decreased ability to proliferate with increasing radiation doses for both radiation types, however, in contrast to X-rays, irradiation with protons resulted in a higher proliferation index at lower doses of 0.75 and 1.0 Gy. Protons are more effective in producing MN at doses above 1.75 Gy compared to X-rays. Dose-response curves for micronucleus incidence can be best described by a cubic model for protons, while for X-rays the response was linear. The differences in the energy spectrum and intracellular distribution of energy between radiation types are also apparent at the intracellular distribution of cytogenetic damage as seen by the distribution of various numbers of micronuclei in binucleated cells. Our studies, although preliminary, further contribute to the understanding of the mechanistic differences in the response of HPBL in terms of cellular proliferation and cytogenetic damage induced by protons and X-rays as well as intra-cellular distribution of energy and thus radiobiological effectiveness. PMID- 25818832 TI - Attitudes and characteristics of health professionals working in Aboriginal health. AB - INTRODUCTION: There is an unacceptable gap in health status between Aboriginal and non-Aboriginal people in Australia. Linked to social inequalities in health and political and historical marginalisation, this health gap must be urgently addressed. It is important that health professionals, the majority of whom in Australia are non-Aboriginal, are confident and equipped to work in Aboriginal health in order to contribute towards closing the health gap. The purpose of this study was to explore the attitudes and characteristics of non-Aboriginal health professionals working in Aboriginal health. METHODS: The research was guided and informed by a social constructionist epistemology and a critical theoretical approach. It was set within a larger healthy eating and physical activity program delivered in one rural and one metropolitan community in South Australia from 2005 to 2010. Non-Aboriginal staff working in the health services where the program was delivered and who had some experience or an interest working in Aboriginal health were invited to participate in a semi-structured interview. Dietitians working across South Australia (rural and metropolitan locations) were also invited to participate in an interview. Data were coded into themes that recurred throughout the interview and this process was guided by critical social research. RESULTS: Thirty-five non-Aboriginal health professionals participated in a semi-structured interview about their experiences working in Aboriginal health. The general attitudes and characteristics of non-Aboriginal health professionals were classified using four main groupings, ranging from a lack of practical knowledge ('don't know how'), a fear of practice ('too scared'), the area of Aboriginal health perceived as too difficult ('too hard') and learning to practice regardless ('barrier breaker'). Workers in each group had different characteristics including various levels of willingness to work in the area; various understandings of Australia's historical relationship with Aboriginal peoples; varying awareness of their own cultural identity and influence on working with Aboriginal people; and different levels of (dis)comfort expressed in discussions about social, political and intercultural issues that impact on the healthcare encounter. CONCLUSIONS: These groupings can be used to assist non Aboriginal health professionals to reflect on their own levels of confidence, attitudes, characteristics, experiences, approaches and assumptions to Aboriginal health, as an important precursor to further practice and development in Aboriginal health. By encouraging self-reflection of non-Aboriginal health professionals about where their experiences, characteristics and confidence lie, the groupings presented in this paper can be used to encourage non-Aboriginal health professionals, rather than Aboriginal clients or workers, to be the focus for change and deliver health care that is more acceptable to patients and clients, hence influencing health service delivery. The groupings presented can also begin to enable discussions between all health professionals about working together in Aboriginal health. PMID- 25818833 TI - Journal paper peer-review: a broken system? PMID- 25818834 TI - Tear ferning test in horses and its correlation with ocular surface evaluation. AB - OBJECTIVE: To describe the tear ferning test (TFT) in healthy horses and its correlation with other parameters for evaluating the ocular surface. ANIMALS STUDIED: Thirty male and female adult healthy horses (60 eyes), of no defined breed. PROCEDURES: Tear sample was collected with a microcapillary tube, placed on the surface of a glass slide, and allowed to dry at room temperature. The crystallization pattern was classified according to Rolando (Chibret International Journal Ophthamology, 1984; 2, 32). The program STEPanizer((c)) stereology tool, version 1.0, was utilized for counting points on the digitally captured crystallization image. A conjunctival biopsy was performed. RESULTS: Tear ferning test was classified as Type I in 18 eyes (30%), Type II in 31 eyes (51.7%), and Type III in 11 eyes (18.3%), at a mean temperature of 27.3 +/- 1.5 degrees C and relative humidity of 61.5 +/- 5.7%. In the Type I crystallization, the count varied between 27 and 36 points (mean: 33.27 +/- 2.40), in Type II between 22 and 31 points (25.42 +/- 1.95), and in Type III between 13 and 25 points (16.82 +/- 3.76). There was no statistical difference or correlation between the right and left eyes, nor was there a statistically significant influence (P < 0.05) on TFT by the factors evaluated. The mean goblet cells values were 50 +/- 11.4 cells/field. All samples showed the presence of lymphocytes, plasmocytes, and eosinophils. CONCLUSION: Tear ferning test is easy to perform, without risks to the patient. Once standardized for horses, associated or not with the program STEPanizer((c)) stereology tool, it is an additional method for evaluating the ocular surface. PMID- 25818836 TI - Usefulness of biomarkers as prognostic factors of mortality in elderly patients with community-acquired pneumonia. PMID- 25818837 TI - Mindfulness-based stress reduction for healthy individuals: A meta-analysis. AB - BACKGROUND: An increasing number of mindfulness-based stress reduction (MBSR) studies are being conducted with nonclinical populations, but very little is known about their effectiveness. OBJECTIVE: To evaluate the efficacy, mechanisms of actions, and moderators of MBSR for nonclinical populations. DATA SOURCES: A systematic review of studies published in English journals in Medline, CINAHL or Alt HealthWatch from the first available date until September 19, 2014. STUDY SELECTION: Any quantitative study that used MBSR as an intervention, that was conducted with healthy adults, and that investigated stress or anxiety. RESULTS: A total of 29 studies (n=2668) were included. Effect-size estimates suggested that MBSR is moderately effective in pre-post analyses (n=26; Hedge's g=.55; 95% CI [.44, .66], p<.00001) and in between group analyses (n=18; Hedge's g=.53; 95% CI [.41, .64], p<.00001). The obtained results were maintained at an average of 19 weeks of follow-up. Results suggested large effects on stress, moderate effects on anxiety, depression, distress, and quality of life, and small effects on burnout. When combined, changes in mindfulness and compassion measures correlated with changes in clinical measures at post-treatment and at follow-up. However, heterogeneity was high, probably due to differences in the study design, the implemented protocol, and the assessed outcomes. CONCLUSIONS: MBSR is moderately effective in reducing stress, depression, anxiety and distress and in ameliorating the quality of life of healthy individuals; however, more research is warranted to identify the most effective elements of MBSR. PMID- 25818838 TI - Physical activity is unrelated to cognitive performance in pre-bariatric surgery patients. AB - OBJECTIVE: To investigate the relationship between physical activity (PA) and cognitive performance in extreme obesity. METHODS: Seventy-one bariatric surgery candidates (77.5% women) with a mean body mass index (BMI) of 46.9 kg/m2 (SD=6.0) and a mean age of 41.4 (SD=11.9) years completed SenseWear Pro2 activity monitoring for seven days. Cognitive functioning was assessed by a computerized test battery including tasks of executive function (Iowa Gambling Task), visuospatial short-term memory (Corsi Block Tapping Test) and verbal short-term memory (Auditory-Verbal Learning Test). Questionnaires assessing eating disturbances and depressive symptoms were administered. Somatic comorbidities were assessed by medical chart review. RESULTS: The level of PA was low with mean steps per day within wear time being 7140 (SD=3422). Most patients were categorized as sedentary (31.0%) or low active (26.8%). No significant association between PA estimates and cognitive performance was found. Lower PA was modestly correlated with higher BMI but not with age, somatic comorbidity or depressive symptoms. Moderated regression analyses suggested a significant interaction effect between depression and PA in predicting performance on the Corsi Block Tapping Test. Patients with (29.6%) and without (70.4%) regular binge eating did not differ with respect to PA or cognitive function. CONCLUSION: The findings indicate no association between daily PA and cognitive performance in morbidly obese patients. Future studies should explore the relationship between the variables with regard to dose-response-questions, a broader BMI range and with respect to potential changes after substantial weight loss due to bariatric surgery. PMID- 25818835 TI - An in vivo screen to identify candidate neurogenic genes in the developing Xenopus visual system. AB - Neurogenesis in the brain of Xenopus laevis continues throughout larval stages of development. We developed a 2-tier screen to identify candidate genes controlling neurogenesis in Xenopus optic tectum in vivo. First, microarray and NanoString analyses were used to identify candidate genes that were differentially expressed in Sox2-expressing neural progenitor cells or their neuronal progeny. Then an in vivo, time-lapse imaging-based screen was used to test whether morpholinos against 34 candidate genes altered neural progenitor cell proliferation or neuronal differentiation over 3 days in the optic tectum of intact Xenopus tadpoles. We co-electroporated antisense morpholino oligonucleotides against each of the candidate genes with a plasmid that drives GFP expression in Sox2 expressing neural progenitor cells and quantified the effects of morpholinos on neurogenesis. Of the 34 morpholinos tested, 24 altered neural progenitor cell proliferation or neuronal differentiation. The candidates which were tagged as differentially expressed and validated by the in vivo imaging screen include: actn1, arl9, eif3a, elk4, ephb1, fmr1-a, fxr1-1, fbxw7, fgf2, gstp1, hat1, hspa5, lsm6, mecp2, mmp9, and prkaca. Several of these candidates, including fgf2 and elk4, have known or proposed neurogenic functions, thereby validating our strategy to identify candidates. Genes with no previously demonstrated neurogenic functions, gstp1, hspa5 and lsm6, were identified from the morpholino experiments, suggesting that our screen successfully revealed unknown candidates. Genes that are associated with human disease, such as such as mecp2 and fmr1-a, were identified by our screen, providing the groundwork for using Xenopus as an experimental system to probe conserved disease mechanisms. Together the data identify candidate neurogenic regulatory genes and demonstrate that Xenopus is an effective experimental animal to identify and characterize genes that regulate neural progenitor cell proliferation and differentiation in vivo. PMID- 25818839 TI - Supression of sweating in palmar hyperhydrosis with 5% strontium chloride hexahydrate. PMID- 25818841 TI - DNA methylation in bacteria: from the methyl group to the methylome. AB - Formation of C(5)-methyl-cytosine, N(4)-methyl-cytosine, and N(6)-methyl-adenine in bacterial genomes is postreplicative, and occurs at specific targets. Base methylation can modulate the interaction of DNA-binding proteins with their cognate sites, and controls chromosome replication, correction of DNA mismatches, cell cycle-coupled transcription, and formation of epigenetic lineages by phase variation. During four decades, the roles of DNA methylation in bacterial physiology have been investigated by analyzing the contribution of individual methyl groups or small methyl group clusters to the control of DNA-protein interactions. Nowadays, single-molecule real-time sequencing can analyze the DNA methylation of the entire genome (the 'methylome'). Bacterial methylomes provide a wealth of information on the methylation marks present in bacterial genomes, and may open a new era in bacterial epigenomics. PMID- 25818840 TI - Risk factors for pericardial effusion in adult patients receiving allogeneic haematopoietic stem cell transplantation. AB - Pericardial effusion (PE) is a rare but potentially life-threatening complication for allogeneic haematopoietic stem cell transplantation (HSCT) recipients. The risk factors, aetiology, incidence and therapy are largely unclear. To investigate this issue, we reviewed 391 adult patients undergoing allogeneic HSCT between January 2003 and December 2013. Twelve out of 391 patients (3.1%) developed PE of moderate to large amounts, including 9 out of 12 patients (75%) identified as late-onset PE. Two out of the nine patients with late-onset PE experienced recurrent effusion. The median age at HSCT was 44.5 years (range: 22 63 years) among the 12 patients with PE and 47 years in the late-onset patients. Multivariate analysis revealed that multiple transplant procedures was a significant risk factor for PE (P = 0.036) and a trend as risk factor in patients aged>50 years (P = 0.066). For late-onset PE, pre-transplant age>50 years (P = 0.032) and extensive chronic graft-versus-host disease (cGVHD) (P = 0.006) remained statistically significant on multivariate analysis. Currently, there are no published data exploring the risk factors for post-transplant PE in adult patients of allogeneic HSCT. Our study determined the risk factors and incidence for the post-transplant PE, especially in the late-onset group. PMID- 25818842 TI - Long-term mortality and quality of life in intensive care patients treated for pneumonia and/or sepsis: Predictors of mortality and quality of life in patients with sepsis/pneumonia. AB - PURPOSE: The purpose of this study is to evaluate long-term mortality and quality of life (QoL) of intensive care patients with pneumonia and/or sepsis 1 year after discharge and to identify potential predictors for these outcome measures. METHODS: This retrospective cohort study analyzed all patients admitted to the intensive care unit (ICU) of a German university hospital with diagnosis of pneumonia and/or sepsis between 2008 and 2009. Quality of life was assessed by telephone interview or mail using the standardized EuroQol 5-dimension questionaire. RESULTS: Of 1406 patients treated in the ICU within the observational period, 217 met the inclusion criteria. Whereas in-hospital mortality differed significantly between pneumonia (17%) and sepsis (46%) (P < .001), 1-year mortality was not statistically significant (51% and 65%, P = .057). A high Simplified Acute Physiology Score (SAPS) II value was associated with high in-hospital mortality but failed to predict 1-year mortality. Quality of life, measured 1 year after discharge by visual analog scale (VAS), was 50% +/ 25%, which was significantly lower than in a matched control group (70% +/- 20%; P < .001). A high SAPS II score on admission did not correlate with VAS but was an independent predictor of a low EuroQol 5-dimension index. CONCLUSIONS: The high post-ICU mortality of patients with pneumonia and sepsis emphasizes the need to focus on long-term follow-up in ICU studies and demonstrates that even when sepsis signs are missing, critically ill patients due to pneumonia have high 1 year mortality. Simplified Acute Physiology Score II does not predict long-term mortality, but a low SAPS II on admission might be useful to identify patients with good physical status after 1 year. TAKE HOME MESSAGE: Hospital mortality of patients treated for pneumonia and/or sepsis is high and increases significantly within the first year after discharge. The SAPS II predicts in-hospital mortality and the physical components of QoL but not long-term mortality. TWEET: One-year mortality of ICU pneumonia patients is equally high as in sepsis patients. Simplified Acute Physiology Score II cannot predict long-term mortality but can predict QoL. PMID- 25818843 TI - Two variants in the KIT gene as candidate causative mutations for a dominant white and a white spotting phenotype in the donkey. AB - White spotting phenotypes have been intensively studied in horses, and although similar phenotypes occur in the donkey, little is known about the molecular genetics underlying these patterns in donkeys. White spotting in donkeys can range from only a few white areas to almost complete depigmentation and is characterised by a loss of pigmentation usually progressing from a white spot in the hip area. Completely white-born donkeys are rare, and the phenotype is characterised by the complete absence of pigment resulting in pink skin and a white coat. A dominant mode of inheritance has been demonstrated for spotting in donkeys. Although the mode of inheritance for the completely white phenotype in donkeys is not clear, the phenotype shows similarities to dominant white in horses. As variants in the KIT gene are known to cause a range of white phenotypes in the horse, we investigated the KIT gene as a potential candidate gene for two phenotypes in the donkey, white spotting and white. A mutation analysis of all 21 KIT exons identified a missense variant in exon 4 (c.662A>C; p.Tyr221Ser) present only in a white-born donkey. A second variant affecting a splice donor site (c.1978+2T>A) was found exclusively in donkeys with white spotting. Both variants were absent in 24 solid-coloured controls. To the authors' knowledge, this is the first study investigating genetic mechanisms underlying white phenotypes in donkeys. Our results suggest that two independent KIT alleles are probably responsible for white spotting and white in donkeys. PMID- 25818844 TI - Do all components of the metabolic syndrome cluster together in U.S. Hispanics/Latinos? Results from the Hispanic Community Health study/Study of Latinos. AB - PURPOSE: Metabolic syndrome (MetS), the clustering of several risk factors for cardiovascular disease, is highly prevalent in Hispanics/Latinos. We tested whether all components significantly loaded on the syndrome in Hispanics/Latinos and whether their contribution differed by sex and Hispanic ancestry. We also examined associations of MetS with prevalent diabetes and coronary heart disease in Hispanics/Latinos. METHODS: Data were obtained from a population-based cohort of n = 15,823 participants in the HCHS/SOL study who self-identified as being of Central American, Cuban, Dominican, Mexican American, Puerto Rican, or South American ancestry and were aged 18 to 74 years at screening. RESULTS: A latent variable model of waist circumference, systolic and diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol (HDL-C), and fasting glucose fit the data in men and women, but the contribution of HDL-C was weak. No difference in the latent model of MetS was detected across Hispanic/Latino ancestry groups. MetS was significantly associated with diabetes and coronary heart disease. CONCLUSIONS: Our results indicate that similar criteria for MetS may be applied across Hispanic/Latino ancestry groups but call into question the role of HDL-C in classifying the MetS in Hispanics/Latinos. PMID- 25818845 TI - Kisspeptin1 modulates odorant-evoked fear response via two serotonin receptor subtypes (5-HT1A and 5-HT2) in zebrafish. AB - Kiss1, a neuropeptide predominantly expressed in the habenula, modulates the serotonin (5-HT) system to decrease odorant cue [alarm substance (AS)]-evoked fear behaviour in the zebrafish. The purpose of this study was to assess the interaction of Kiss1 with the 5-HT system as well as to determine the involvement of the 5-HT receptor subtypes in AS-evoked fear. We utilized 0. 28 mg/kg WAY 100635 (WAY), a selective 5-HT1A receptor antagonist, to observe the effects of Kiss1 administration on AS-evoked fear. We found WAY significantly inhibited the anxiolytic effects of Kiss1 (p < 0.001) with an exception of freezing behaviour. Based on this, we utilized 92.79 mg/kg methysergide, a 5-HT1 and 5-HT2 receptor antagonist, and found that methysergide significantly blocked the anxiolytic effects of Kiss1 in the presence of the AS (p < 0.001). From this, we conclude that Kiss1 modulates AS-evoked fear responses mediated by the 5-HT1A and 5-HT2 receptors. Kiss1 peptide intracranially (IC) administrated has been shown to decrease olfactory, alarm substance (AS)-evoked fear response. Blockade of the 5 HT1A receptor utilizing WAY 100635 (0.28 mg/kg) and the 5-HT1 and 5-HT2 receptor utilizing methysergide (92.79 mg/kg) produced increased AS-evoked fear responses that were unable to be overcome even during the recovery period. Blockade of this 5-HT system followed by Kiss1 administration showed that the peptide was unable to recover the anxiolytic effects upon 5-HT1A blocking using WAY 100635 with the exception of freezing behaviour while methysergide significantly blocked all the anxiolytic effects of Kiss1. These findings implicate that Kiss1 could modulate AS-evoked fear responses mediated by 5-HT1A and 5-HT2 receptors. PMID- 25818846 TI - Regulation of extracellular Zn(2+) homeostasis in the hippocampus as a therapeutic target for Alzheimer's disease. AB - INTRODUCTION: The hippocampus plays an important role in spatial and declarative memory. Zn(2+) is released from glutamatergic (zincergic) neuron terminals in the hippocampus and serves as a signal factor. Synaptic Zn(2+) homeostasis is critical for cognitive activity in the hippocampus. Amyloid-beta (Abeta) is a candidate for the pathogenesis of Alzheimer's disease (AD) and interacts with Zn(2+). AREAS COVERED: This paper gives an overview of the interaction between Abeta and Zn(2+) in the extracellular compartment in the pathophysiology of AD. Abeta is aggregated with Zn(2+) and the aggregation of Abeta-peptides is widely considered to be the critical step in the pathogenesis of AD. The reader will gain an understanding of recent studies on the importance of the interaction of Abeta with Zn(2+) in the pathophysiology and therapeutic strategy of AD. Extracellular Zn(2+) in the hippocampus is a therapeutic target for AD. EXPERT OPINION: Recent studies show that the inhibition of the interaction of Abeta with extracellular Zn(2+) ameliorates the pathophysiology of AD and that extracellular Zn(2+) in the hippocampus is involved in transiently Abeta-induced cognition deficits. Zn(2+) may play as a key-mediating factor in pathophysiology in which Abeta is involved and is a targeting molecule to prevent the pathogenesis of AD. PMID- 25818848 TI - Born to be wild. PMID- 25818847 TI - New-onset paresthesias in inflammatory bowel disease. PMID- 25818849 TI - Parasites and wildlife in a changing world. AB - Wildlife and their parasites are everywhere. Other than those important in human or domestic animal health, understanding of these host-parasite systems is limited, especially their roles in wildlife population health. Learning more provides opportunities to explore infection ecology, and the use of parasites as sentinels and probes for environmental change. PMID- 25818850 TI - The buffalo co-infection conundrum. AB - Parasitic worms modulate host immunity, affecting co-infection with Mycobacterium bovis (BTB). Ezenwa and Jolles suggested that anthelmintic treatment reduced BTB induced mortality, but increased BTB spread. Reduced mortality should be weighed against the risk of increasing pathogen spread when adopting this strategy for human treatment of Mycobacterium tuberculosis, BTB, and HIV. PMID- 25818851 TI - A new classification of the Pied Woodpeckers assemblage (Dendropicini, Picidae) based on a comprehensive multi-locus phylogeny. AB - The pied woodpecker assemblage historically included the widespread genera Picoides and Dendrocopos. The assignment of species to either of these two genera has for long puzzled systematists due to their overall plumage similarity. Recent molecular studies not only suggested that both of these genera are not monophyletic, but also that four other genera, the African Dendropicos the South American Veniliornis and two Asian monospecific genera (Hypopicus and Sapheopipo) are nested within the Dendrocopos-Picoides clade. Yet, our current understanding of the phylogeny and taxonomy of this group is still very partial because several distinctive Old World species that have been assigned to different genera throughout their taxonomic history have not been sampled yet. Here, using DNA sequence data gathered from four loci, we reconstructed a species level phylogeny of the Indo-Malayan and Palearctic Pied Woodpeckers to understand the phylogenetic relationships and biogeographic history of the Eurasian species with respect to African and New World lineages. Our phylogenetic analyses revealed nine strongly supported clades within the Dendropicini. Noticeably, two species that had disputed affinities at the genus level clustered in clades with species from the same biogeographical region: the Brown-backed Woodpecker (D. obsoletus) is nested in Dendropicos and the Arabian Woodpecker (D. dorae) is related to two Eurasian species, the Brown-fronted (D. auriceps) and Middle-spotted woodpeckers (D. medius). The nine clades have a strong biogeographic component and very few dispersal event among bioregions occurred. For example, the African species formed a clade, suggesting that only one dispersal event is needed to explain the presence of Dendropicini in Africa. Based on our phylogenetic results, we propose a new classification of the Dendropicini that recognizes nine genera. PMID- 25818852 TI - Genetic and immunologic susceptibility to statin-related myopathy. AB - Statin-related myopathy (SRM) undermines drug adherence that is critical for achieving the benefits of lipid-lowering therapy. While the exact mechanism of SRM remains largely unknown, recent evidence supports specific genetic and immunologic influence on the development of intolerance. Genes of interest include those involved in the pharmacokinetics of statin response (i.e. drug metabolism, uptake transporters, and efflux transporters), pharmacodynamics (i.e. drug toxicity and immune-mediated myopathy), and gene expression. We examine the influence of genetic and immunologic variation on the pharmacokinetics, pharmacodynamics, and gene expression of SRM. PMID- 25818853 TI - Associations of multiple lipoprotein and apolipoprotein measures with worsening of glycemia and incident type 2 diabetes in 6607 non-diabetic Finnish men. AB - OBJECTIVE: We investigated the association of various lipoprotein traits, apolipoproteins and their ratios with the deterioration of glycemia, incident type 2 diabetes, insulin resistance and insulin secretion in a large population based Metabolic Syndrome Men (METSIM) Study. RESEARCH DESIGN AND METHODS: The METSIM Study includes 10,197 Finnish men, aged 45-73 years, and examined in 2005 2010. From 6607 non-diabetic participants without statin treatment at baseline, 386 developed incident type 2 diabetes during a 5.9-year follow-up. A total of 3330 non-diabetic participants without statin treatment had both baseline and follow-up visit data, and were included in statistical analyses of the worsening of glycemia. RESULTS: Compared to single lipid and lipoprotein measurements, lipoprotein and apolipoprotein ratios were better predictors of the glucose area under the curve and incident type 2 diabetes after adjustment for confounding factors. The apolipoprotein B/LDL cholesterol ratio was the strongest predictor of the worsening of glycemia, whereas the apolipoprotein A1/HDL cholesterol ratio was the strongest predictor of incident type 2 diabetes. The associations of lipoprotein traits, apolipoproteins and their ratios with insulin sensitivity were stronger than those with insulin secretion. CONCLUSIONS: The apolipoprotein B/LDL cholesterol and apolipoprotein A1/HDL cholesterol ratios were the strongest predictors of the worsening of glycemia and incident type 2 diabetes, respectively. PMID- 25818854 TI - Basilar plaque on high-resolution MRI predicts progressive motor deficits after pontine infarction. AB - BACKGROUND: The association between progressive motor deficits (PMD) in acute pontine infarction and basilar stenosis is unclear. High resolution MRI (HRMRI) is an emerging tool for basilar artery evaluation and might provide more accurate information. We aimed to analyze the association between basilar plaque assessed by HRMRI and PMD after acute pontine infarction. METHODS: We identified consecutive patients with unilateral pontine infarction within 24 h of stroke onset. All the patients underwent diffusion weighted MRI, MR angiography and HRMRI within 24 h of admission. PMD was defined as an increase in National Institutes of Health Stroke Scale score by >=1 during hospitalization. Factors potentially associated with PMD were validated by multivariate analyses. RESULTS: Of a total of 87 patients, 63 (72%) had paramedian pontine infarction (PPI) and PMD was observed in 28 (32%) patients. Apparent basilar plaque assessed by HRMRI was more frequent in those with PMD than in those without PMD (52% versus 33%, p<0.001). In contrast, the frequency of basilar stenosis (>30%) assessed by MR angiography was similar regardless of PMD. In the patients with PPI, PMD was associated with hypertension and apparent plaque on HRMRI. After adjusting covariates, PMD was independently associated with apparent plaque on HRMRI (OR, 9.1; 95% CI 1.4-58.9). CONCLUSIONS: Our results suggest that basilar plaque assessed by HRMRI is associated with PMD in patients with acute unilateral pontine infarction. Since basilar stenosis may be underestimated by MR angiography, HRMRI may provide additional information for predicting PMD and evaluating basilar artery stenosis. PMID- 25818855 TI - Parametric study to determine the effect of temperature on oil solidifier performance and the development of a new empirical correlation for predicting effectiveness. AB - Temperature can play a significant role in the efficacy of solidifiers in removing oil slicks on water. We studied and quantified the effect of temperature on the performance of several solidifiers using 5 different types of oils under a newly developed testing protocol by conducting experiments in constant temperature rooms set at 22 degrees C and 5 degrees C. The results indicated that solidifier efficiency decreased substantially at the lower temperature, especially at lower application rates. The removal efficiency of the solidifier was in general directly proportional to temperature, except for the heavier oils, where removal by attachment was observed. Solidifier products with lower powder bulk density exhibited the best removal effectiveness. Analysis of experimental data yielded empirical correlations involving certain operational variables such as application rate, temperature, solidifier property (bulk density), and oil property (viscosity). Regression analysis was used to fit a mathematical model to the experimental solidifier effectiveness data. PMID- 25818856 TI - Changes in bioaccumulation and translocation patterns between root and leafs of Avicennia schaueriana as adaptive response to different levels of metals in mangrove system. AB - Espirito Santo estuaries (Brazil) are impacted by industrial activities, resulting in contamination of water and sediments. This raise questions on biological uptake, storage and consequences of metal contamination to mangrove plants. The goal of this work was evaluating accumulation and translocation of metals from sediment to roots and leaves of Avicennia schaueriana, growing in areas with different degrees of contamination, correlating bioaccumulation with changes in its root anatomy. Highest bioconcentration factors (BCFs) were observed in plants growing in less polluted areas. Conversely, highest translocation factors were found in plants from highest polluted area, evidencing an adaptive response of A. schaueriana to less favourable conditions. Namely, the absorption of metals by roots is diminished when facing highest levels of metals in the environment; alternatively, plants seem to enhance the translocation to diminish the concentration of toxic metals in roots. Root also responded to highly polluted scenarios with modifications of its anatomy. PMID- 25818857 TI - Estimation of hydrogen sulfide removal efficiency with granulated coal ash applied to eutrophic marine sediment using a simplified simulation model. AB - Hydrogen sulfide generated in eutrophic marine sediment is harmful for living organisms. It is therefore necessary to remove hydrogen sulfide from the sediment to restore benthic ecosystems. Previous studies revealed that granulated coal ash, which is a by-product of coal thermal electric power stations, could remove and oxidize hydrogen sulfide. In this study, we propose a simplified simulation model to estimate the hydrogen sulfide removal efficiency of granulated coal ash. Hydrogen sulfide concentrations in eutrophic marine sediment pore water with and without the application of granulated coal ash were calculated by the proposed model, and the outputs were compared with semi-field or field observation data. The model outputs reproduced the observed data well. Using the proposed model outputs, we suggest an optimum application dosage of granulated coal ash for remediating eutrophic marine sediment. PMID- 25818860 TI - Victimization Profiles, Non-Suicidal Self-Injury, Suicide Attempt, and Post Traumatic Stress Disorder Symptomology: Application of Latent Class Analysis. AB - Few studies have incorporated multiple dimensions of victimization or examined whether victimization profiles differ by gender. Consequently, the present study sought to extend prior research by using latent class analysis (LCA) to identify naturally occurring subgroups of individuals who have experienced victimization, and to test for sex differences. Data from 4,016 females and 3,032 males in the Adult Psychiatric Morbidity Survey (APMS) were analyzed. Evidence of the existence of similar victimization subtypes for both males and females emerged, with a three-class solution providing the best fit to the data for both sexes. Furthermore, the classes were labeled "low victimization" (the baseline class; Class 3), the "high victimization class" (Class 1), and "the bullying and domestic violence class" (Class 2) for both males and females. Multinomial logistic regression was used to interpret the nature of the latent classes, or groups, by estimating the associations with post-traumatic stress disorder (PTSD) dimensions, suicide attempt, and non-suicidal self-injury. Although different constellations of victimization experiences did not emerge through the gender specific analyses, the nature of the associations between class membership and external variables differed between males and females. Findings highlight the heterogeneity of victimization experiences and their relations to functioning, and have implications for policy and practice implications. PMID- 25818859 TI - Physical activity as a determinant of fasting and 2-h post-challenge glucose: a prospective cohort analysis of the NAVIGATOR trial. AB - AIM: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. METHODS: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. RESULTS: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2) = 0.3473 vs. 0.3468). There was no association with fasting glucose. CONCLUSIONS: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control. PMID- 25818861 TI - Revisiting the Association Between Television Viewing in Adolescence and Contact With the Criminal Justice System in Adulthood. AB - A substantial number of previous studies have reported significant associations between television viewing habits and a host of detrimental outcomes including increased contact with the criminal justice system. However, it remains unclear whether the results flowing from this literature are generalizable to other samples and whether previously observed associations are confounded due to uncontrolled genetic influences. The current study addresses these limitations using the National Longitudinal Study of Adolescent to Adult Health (Add Health). The results of the preliminary models, which do not include controls for genetic influences, produced a pattern of results similar to those previously reported in the extant literature. The results of the genetically informed models revealed that the associations between television viewing and antisocial outcomes are not causal, but rather are driven by uncontrolled genetic influences. Further replication is required, but these findings suggest that results drawn from the extant literature may not be trustworthy. PMID- 25818858 TI - Purifying Selection Maintains Dosage-Sensitive Genes during Degeneration of the Threespine Stickleback Y Chromosome. AB - Sex chromosomes are subject to unique evolutionary forces that cause suppression of recombination, leading to sequence degeneration and the formation of heteromorphic chromosome pairs (i.e., XY or ZW). Although progress has been made in characterizing the outcomes of these evolutionary processes on vertebrate sex chromosomes, it is still unclear how recombination suppression and sequence divergence typically occur and how gene dosage imbalances are resolved in the heterogametic sex. The threespine stickleback fish (Gasterosteus aculeatus) is a powerful model system to explore vertebrate sex chromosome evolution, as it possesses an XY sex chromosome pair at relatively early stages of differentiation. Using a combination of whole-genome and transcriptome sequencing, we characterized sequence evolution and gene expression across the sex chromosomes. We uncovered two distinct evolutionary strata that correspond with known structural rearrangements on the Y chromosome. In the oldest stratum, only a handful of genes remain, and these genes are under strong purifying selection. By comparing sex-linked gene expression with expression of autosomal orthologs in an outgroup, we show that dosage compensation has not evolved in threespine sticklebacks through upregulation of the X chromosome in males. Instead, in the oldest stratum, the genes that still possess a Y chromosome allele are enriched for genes predicted to be dosage sensitive in mammals and yeast. Our results suggest that dosage imbalances may have been avoided at haploinsufficient genes by retaining function of the Y chromosome allele through strong purifying selection. PMID- 25818862 TI - Non-Homicidal and Homicidal Sexual Offenders: Prevalence of Maladaptive Personality Traits and Paraphilic Behaviors. AB - This study aims to examine the psychopathological profile of non-homicidal sexual offenders (NHSOs) and homicidal sexual offenders (HSOs). Using an incarcerated sample of 96 NHSOs and 74 HSOs in a federal penitentiary in Canada, these offenders are compared in terms of their offending process, maladaptive personality traits, and paraphilic behaviors. A number of cross-tabular and sequential logistic regression analyses are performed. Relative to their counterpart, findings indicate that a higher percentage of HSOs select a victim of choice, report deviant sexual fantasies, mutilate their victim, and admit to their offense upon apprehension, whereas a higher percentage of NHSOs select victims with distinctive characteristics. In addition, a higher percentage of HSOs manifest paranoid, schizotypal, borderline, histrionic, narcissistic, obsessive-compulsive, and impulsive personality traits, and overall odd and eccentric personality traits compared with NHSOs. Similarly, a higher percentage of HSOs engage in exhibitionism, fetishism, frotteurism, homosexual pedophilia, sexual masochism, and partialism compared with NHSO. These findings are discussed with their implications for offender profiling. PMID- 25818863 TI - Parameter estimation methods for gene circuit modeling from time-series mRNA data: a comparative study. AB - Parameter estimation is a challenging computational problem in the reverse engineering of biological systems. Because advances in biotechnology have facilitated wide availability of time-series gene expression data, systematic parameter estimation of gene circuit models from such time-series mRNA data has become an important method for quantitatively dissecting the regulation of gene expression. By focusing on the modeling of gene circuits, we examine here the performance of three types of state-of-the-art parameter estimation methods: population-based methods, online methods and model-decomposition-based methods. Our results show that certain population-based methods are able to generate high quality parameter solutions. The performance of these methods, however, is heavily dependent on the size of the parameter search space, and their computational requirements substantially increase as the size of the search space increases. In comparison, online methods and model decomposition-based methods are computationally faster alternatives and are less dependent on the size of the search space. Among other things, our results show that a hybrid approach that augments computationally fast methods with local search as a subsequent refinement procedure can substantially increase the quality of their parameter estimates to the level on par with the best solution obtained from the population based methods while maintaining high computational speed. These suggest that such hybrid methods can be a promising alternative to the more commonly used population-based methods for parameter estimation of gene circuit models when limited prior knowledge about the underlying regulatory mechanisms makes the size of the parameter search space vastly large. PMID- 25818865 TI - Site-specific migration of human fetal melanocytes in volar skin. AB - BACKGROUND: Melanocytes originate from the neural crest and migrate ventrally from the dorsal neural tube during embryogenesis. How human melanocytes locate at their suitable positions during embryogenesis, however, is unclear. Although a growing body of evidence indicates that melanocytes, melanoblasts, and melanocyte stem cells are closely related to hair follicles, little is known about volar skin. OBJECTIVE: The aim of this study was to observe skin development during human fetal period and clarify the site-specific migration process of human fetal sole melanocytes. METHODS: We obtained 4-mm punch biopsies from the scalp, back, abdomen, and right sole of 36 aborted fetuses (gestational age 12-21 weeks). We compared the migration process between hairly areas and volar areas by immunohistochemical staining. RESULTS: Immunohistochemical examination revealed that gp100 (HMB-45) sensitively detects human melanocytes in embryogenesis. Melanocytes were present at the epidermal base, where hair placodes/buds form at 12-15 weeks gestation. Fetal melanocytes in hair follicles are supplied from the epidermis. In volar skin, melanocytes originally localize only in the acrosyringium, where they migrate deeper into with gland development at 16-18 weeks gestation. Palmoplantar melanocyte migration and maturation processes differ considerably from those of the other hairy skin sites. CONCLUSION: Eccrine sweat glands seem to have a central role in the palmoplantar melanocyte migration process, similar to the role of hair follicles in hairy sites. PMID- 25818864 TI - Codification of bidentate pMHC interaction with TCR and its co-receptor. AB - A 1983 Immunology Today rostrum hypothesized that each T cell has two recognition units: a T cell receptor (TCR) complex, which binds antigen associated with a polymorphic region of a MHC molecule (pMHC), and a CD4 or CD8 molecule that binds to a conserved region of that same MHC gene product (class II or I, respectively). Structural biology has since precisely revealed those bidentate pMHC interactions. TCRalphabeta ligates the membrane-distal antigen-binding MHC platform, whereas CD8 clamps a membrane-proximal MHCI alpha3 domain loop and CD4 docks to a hydrophobic crevice between MHCII alpha2 and beta2 domains. Here, we review how MHC class-restricted binding impacts signaling and lineage commitment, discussing TCR force-driven conformational transitions that may optimally expose the co-receptor docking site on MHC. PMID- 25818866 TI - Evaluation of tissue hemoglobin saturation (StO2) using near-infrared spectroscopy during hypoxemia and hyperoxemia in Beagle dogs. AB - OBJECTIVE: To determine the relationship between tissue oxygen saturation (StO2) and oxygen delivery (DO2) during hypoxemia and hyperoxemia. STUDY DESIGN: Prospective, randomized study. ANIMALS: Eight purpose-bred Beagle dogs. METHODS: Dogs were anesthetized with isoflurane, ventilated to eucapnia, and instrumented for thermodilution cardiac output, invasive mean arterial pressure (MAP), sartorius muscle StO2 and airway gas monitoring. Dogs were administered rocuronium to facilitate mechanical ventilation and esmolol to minimize anesthetic effects on cardiac output. Instrumentation and baseline data collection were at 0.21 fractional inspired oxygen (FIO2). Dogs were evaluated at high (0.40 then 0.95) and low (0.15 then 0.10) FIO2 sequences in random order with a 60 minute rest period at FIO2 0.21 between sequences. Target FIO2 was achieved by manipulating nitrogen and oxygen flow rates. Data collected at each FIO2, after a 10 minute period of stabilization, included heart rate (HR), MAP, cardiac index (CI) and StO2. Arterial oxygen content (CaO2) and oxygen delivery index (DO2I) were calculated at each FIO2. Data analysis included Pearson's correlation analysis and mixed-model anova (p < 0.05). RESULTS: There were no significant differences in HR, MAP or CI across all FIO2 values. Significant decreases occurred in mean +/- standard deviation StO2 (90 +/- 4% to 69 +/- 18%; p = 0.0001), DO2I (458 +/- 70 to 281 +/- 100 mL minute(-1) m(-2); p = 0.0008) and CaO2 (13.2 +/- 1.53 to 8.4 +/- 2.05 mL dL(-1); p = 0.0001) from FIO2 0.21 to 0.10, but not at remaining FIO2 values. The correlation between StO2 and DO2I across all FIO2 values was strong (r = 0.97; p = 0.0013) and linear. CONCLUSIONS AND CLINICAL RELEVANCE: In this model of hypoxemia and hyperoxemia, the strong correlation between StO2 and DO2I suggests that StO2 can be used to estimate DO2. PMID- 25818867 TI - Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation. AB - Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the alpha-N acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes. PMID- 25818868 TI - An ImmunoChip study of multiple sclerosis risk in African Americans. AB - The aims of this study were: (i) to determine to what degree multiple sclerosis associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 * 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk. PMID- 25818869 TI - Shared dimensions of performance and activation dysfunction in cognitive control in females with mood disorders. AB - Major depressive disorder and bipolar disorder share symptoms that may reflect core mood disorder features. This has led to the pursuit of intermediate phenotypes and a dimensional approach to understand neurobiological disruptions in mood disorders. Executive dysfunction, including cognitive control, may represent a promising intermediate phenotype across major depressive disorder and bipolar disorder. This study examined dimensions of cognitive control in women with major depressive disorder or bipolar disorder in comparison to healthy control subjects using two separate, consecutive experiments. For Experiment 1, participants completed a behavioural cognitive control task (healthy controls = 150, major depressive disorder = 260, bipolar disorder = 202; age range 17-84 years). A sample of those participants (healthy controls = 17, major depressive disorder = 19, and bipolar disorder = 16) completed a similar cognitive control task in an event-related design functional magnetic resonance imaging protocol for Experiment 2. Results for Experiment 1 showed greater impairments on the cognitive control task in patients with mood disorders relative to healthy controls (P < 0.001), with more of those in the mood disorder group falling into the 'impaired' range when using clinical cut-offs (<5th percentile). Experiment 2 revealed only a few areas of shared activation differences in mood disorder greater than healthy controls. Activation analyses using performance as a regressor, irrespective of diagnosis, revealed within and extra-network areas that were more active in poor performers. In summary, performance and activation during cognitive control tasks may represent an intermediate phenotype for mood disorders. However, cognitive control dysfunction is not uniform across women with mood disorders, and activation is linked to performance more so than disease. These findings support subtype and dimensional approaches to understanding risk and expression of mood disorders and are a promising area of inquiry, in line with the Research Domain Criteria initiative of NIMH. PMID- 25818871 TI - Asymmetrical dimethylarginine promotes the senescence of human skin fibroblasts via the activation of a reactive oxygen species-p38 MAPK-microRNA-138 pathway. PMID- 25818870 TI - Structural and functional MRI abnormalities of cerebellar cortex and nuclei in SCA3, SCA6 and Friedreich's ataxia. AB - Spinocerebellar ataxia type 3, spinocerebellar ataxia type 6 and Friedreich's ataxia are common hereditary ataxias. Different patterns of atrophy of the cerebellar cortex are well known. Data on cerebellar nuclei are sparse. Whereas cerebellar nuclei have long been thought to be preserved in spinocerebellar ataxia type 6, histology shows marked atrophy of the nuclei in Friedreich's ataxia and spinocerebellar ataxia type 3. In the present study susceptibility weighted imaging was used to assess atrophy of the cerebellar nuclei in patients with spinocerebellar ataxia type 6 (n = 12, age range 41-76 years, five female), Friedreich's ataxia (n = 12, age range 21-55 years, seven female), spinocerebellar ataxia type 3 (n = 10, age range 34-67 years, three female), and age- and gender-matched controls (total n = 23, age range 22-75 years, 10 female). T1-weighted magnetic resonance images were used to calculate the volume of the cerebellum. In addition, ultra-high field functional magnetic resonance imaging was performed with optimized normalization methods to assess function of the cerebellar cortex and nuclei during simple hand movements. As expected, the volume of the cerebellum was markedly reduced in spinocerebellar ataxia type 6, preserved in Friedreich's ataxia, and mildy reduced in spinocerebellar ataxia type 3. The volume of the cerebellar nuclei was reduced in the three patient groups compared to matched controls (P-values < 0.05; two-sample t-tests). Atrophy of the cerebellar nuclei was most pronounced in spinocerebellar ataxia type 6. On a functional level, hand-movement-related cerebellar activation was altered in all three disorders. Within the cerebellar cortex, functional magnetic resonance imaging signal was significantly reduced in spinocerebellar ataxia type 6 and Friedreich's ataxia compared to matched controls (P-values < 0.001, bootstrap-corrected cluster-size threshold; two-sample t-tests). The difference missed significance in spinocerebellar ataxia type 3. Within the cerebellar nuclei, reductions were significant when comparing spinocerebellar ataxia type 6 and Friedreich's ataxia to matched controls (P < 0.01, bootstrap-corrected cluster-size threshold; two-sample t-tests). Susceptibility weighted imaging allowed depiction of atrophy of the cerebellar nuclei in patients with Friedreich's ataxia and spinocerebellar ataxia type 3. In spinocerebellar ataxia type 6, pathology was not restricted to the cerebellar cortex but also involved the cerebellar nuclei. Functional magnetic resonance imaging data, on the other hand, revealed that pathology in Friedreich's ataxia and spinocerebellar ataxia type 3 is not restricted to the cerebellar nuclei. There was functional involvement of the cerebellar cortex despite no or little structural changes. PMID- 25818872 TI - ADAM protease inhibitors reduce melanogenesis by regulating PMEL17 processing in human melanocytes. AB - BACKGROUND: ADAMs (a disintegrin and metalloprotease) are a family of proteases involved in ectodomain shedding that play a role in various biological processes such as cell adhesion and migration. ADAM10 and ADAM17 are suggested to be involved in pigmentary disorders. OBJECTIVE: We examined the effect of ADAM protease inhibitors on the modulation of melanogenesis in normal human epidermal melanocytes (NHEM). METHODS: NHEMs and B16F10 treated with ADAM protease inhibitors were analyzed. AlamarBlue cell proliferation assay, melanin content assay, tyrosinase activity assay, Western blotting analysis, electron microscopic analysis, and RNA interference were employed. RESULTS: In NHEMs, melanin content was reduced by treatment with ADAM protease inhibitors. The inhibitors did not change the protein expression of tyrosinase, TRP-1, and MITF. In B16F10 cells, treatment of the cells with ADAM protease inhibitor diminished the alpha-MSH induced increase in melanin content. Electron microscopy showed that the number of fibrillar and mature melanosomes was significantly reduced and that the vacuolar compartments were filled with dense unstructured aggregates after treatment with ADAM protease inhibitors. We therefore focused on the processing of PMEL17, a melanosomal glycoprotein that forms a fibrillar matrix on which melanin gets deposited. Proteolytic processing of PMEL17 is required to form functional fibrils during melanogenesis. Recently, gamma-secretase and beta-site amyloid precursor protein-cleaving enzyme 2 (BACE2) were found to cleave PMEL17. We found that ADAM protease inhibitors exerted effects on the processing of C terminal and N-terminal fragments of PMEL17. Using BACE2 siRNA and gamma secretase inhibitor, we showed that ADAM protease inhibitor affected PMEL17 processing in a gamma-secretase and BACE2-independent mechanism. CONCLUSION: Several proteases, including ADAM proteases, can contribute to the formation of fibrils and their assembly into sheets in melanosomes. PMID- 25818873 TI - Comparison of the 2007 and 2013 ASCO/CAP evaluation systems for HER2 amplification in breast cancer. AB - It has been proven that chromosome 17 centromere (CEP17) amplification causes misleading human epidermal growth factor receptor 2 (HER2) gene fluorescence in situ hybridization (FISH) results, precluding anti-HER2-based therapy in some patients with breast carcinoma. We used the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) scoring criteria to evaluate HER2 amplification status in 175 cases of breast carcinoma with chromosome 17 polysomy. We used immunohistochemistry (IHC) to determine the HER2 amplification status, and 2-color FISH to detect CEP17, and reviewed the results of initial evaluation using the 2007 ASCO/CAP criteria. Of the 175 cases, 17, 95, and 63 were IHC 0/1+, 2+, and 3+, respectively. Evaluation of IHC HER2 status according to the 2013 ASCO/CAP criteria identified significantly more HER2-positive cases compared to cases evaluated using the 2007 criteria (p<0.05). When the FISH results were evaluated in parallel with the 2013 criteria, we found that 22 cases were not HER2-negative despite the presence of polysomy 17, which, according to the 2013 criteria, indicates HER2-positive status. Our findings indicate that in breast carcinoma, HER2 status in the presence of polysomy 17 may vary with the scoring criteria used. In turn, performing FISH and evaluating samples using the 2013 ASCO/CAP criteria means that more patients with breast cancer may be appropriate for targeted treatment with trastuzumab, potentially improving their outcome. PMID- 25818876 TI - Sex differences in cognitive training effects of patients with amnestic mild cognitive impairment. AB - Cognitive training has been shown to be effective in improving cognitive functions in patients with Mild Cognitive Impairment (MCI). However, data on factors that may influence training gains including sociodemographic variables such as sex or age is rare. In this study, the impact of sex on cognitive training effects was examined in N = 32 age- and education-matched female (n = 16) and male (n = 16) amnestic MCI patients (total sample: age M = 74.97, SD = 5.21; education M = 13.50, SD = 3.11). Patients participated in a six-week multidomain cognitive training program including 12 sessions each 90 min twice weekly in mixed groups with both women and men. Various cognitive domains were assessed before and after the intervention. Despite comparable baseline performance in women and men, we found significant interaction effects Time * Sex in immediate (p = .04) and delayed verbal episodic memory (p= .045) as well as in working memory (p = .042) favoring the female MCI patients. In contrast, the overall analyses with the total sample did not reveal any significant within subject effects Time. In conclusion, our results give preliminary evidence for stronger cognitive training improvements of female compared to male MCI patients. More generally, they emphasize the importance of sex-sensitive evaluations of cognitive training effects. Possible underlying mechanisms of the found sex differences are discussed and directions for future research are given. PMID- 25818877 TI - Both sides of the couch: a qualitative exploration of the experiences of female healthcare professionals returning to work after treatment for cancer. AB - The aim was to explore the experiences of healthcare professionals (HCPs) who had treatment for cancer and then returned to work. The intention was to identify how HCPs' experiences differed to those of the general public with cancer, and also to explore how HCPs were reintegrated into the workplace following treatment. An interpretive phenomenological approach was employed and conversational interviews were undertaken with 13 women volunteers from a variety of healthcare disciplines including nursing, midwifery, social work, physiotherapy, radiography and general practice. During analysis 59 categories were constructed which were accommodated within 14 themes; six of which are reported here. Participants used knowledge to make sense of their diagnosis, severity and extent of cancer. Several participants covertly accessed their medical records to find out more about their clinical condition. Familiarity with both the environment and oncology personnel resulted in benefits and disadvantage in equal measure. Managers responded to participants' return to work in a variety of ways, and involvement of Occupational Health Departments was inconsistent. Healthcare professionals had distinctly unique experiences because of being patient and provider, and each made personal decisions about sharing their cancer experiences with patients. PMID- 25818878 TI - Using physiology to guide time to cord clamping. AB - Immediate clamping and cutting of the umbilical cord at birth has been the accepted standard of care for decades. The physiologic rationale relating umbilical cord clamping (UCC) to the events of the circulatory transition is not considered in arbitrarily recommended cord clamping times. Systematic review of early versus deferred UCC shows significant hemodynamic benefits to the deferred group. Mechanisms for this protective effect are considered in this review. The original concept of a placental transfusion with a volume load and prevention of low cardiac output relies on the physiological end point of the amount of blood transfused. The newer concept of an ordered physiological transition is increasingly supported. This model places aeration of the lungs and an increase in pulmonary blood flow back at the centre of the circulatory transition with timing of UCC being related to establishment of respiration. The need for "physiologically based" UCC is discussed. PMID- 25818879 TI - Hemodynamic antecedents of peri/intraventricular hemorrhage in very preterm neonates. AB - Novel hemodynamic monitoring technologies have contributed to the understanding of developmental cardiovascular physiology and pathophysiology in general, and of developmental hemodynamics in particular. Hemodynamic disturbances play a significant role in the pathogenesis of peri/intraventricular hemorrhage (P/IVH) in preterm infants. Immaturity of the myocardium, delayed and incomplete cardiopulmonary transition, sustained patency of the ductus arteriosus, and unintended consequences of respiratory and cardiovascular supportive care are all likely to be involved in the presentation of low cardiac output syndrome and decreased organ blood flow in a large number of very preterm neonates (gestational age <=28 weeks). Forebrain vessels in very preterm infants may not have achieved a "high-priority vasculature" status at the time of delivery; in these patients, forebrain perfusion is not protected during the compensated phase of shock. Reperfusion may be attenuated by the careful use of medications decreasing cerebrovascular reactivity, thus providing a potential target for the development of careful pharmacological support of transitional hemodynamics in selected patients at high risk for the development of P/IVH. PMID- 25818880 TI - Synthesis of disubstituted dithioethers: tert-butoxide promoted elimination/ring opening of 1,3-dithianes followed by palladium-catalyzed C-S bond formation. AB - We report the tandem base-promoted elimination/ring-opening of 2-benzyl-1,3 dithianes with subsequent cross coupling of the pendent thiol with a range of aryl bromides. A simple Pd(OAc)2/Xantphos catalyst system affects this new reaction and is compatible with a wide range of functional groups, including heteroaromatic coupling partners. The transformation proceeds in good to excellent yields (69-99%) and exhibits strong stereoselectivity, forming the E alkene as the major diastereomer. This new methodology provides access to nonsymmetric propylene styryl/aryl dithioethers, a previously undisclosed motif. PMID- 25818882 TI - Conflicting reports on vitamin D supplementation: Evidence from randomized controlled trials. AB - A significant number of children and adolescents worldwide have low serum 25(OH)D values relative to the 2010 Institute of Medicine criteria. Since approximately 90% of adult bone mineral content (BMC) is accrued by the end of adolescence, and approximately 40% of adult BMC accumulated during the 4 years surrounding peak BMC velocity, low circulating 25(OH)D during this time may attenuate gains in adolescent bone strength. Reduced bone mineralization and strength during pubertal growth tracks into adulthood and could lead to an increased risk of skeletal fractures. Observational studies examining the relationships between vitamin D and bone are conflicting and few randomized controlled trials (RCTs) have been conducted in children and adolescents. Four of these RCTs, however, provide moderate support for the role of vitamin D supplementation on BMC accrual in adolescent females with baseline serum concentrations <50 nmol/L. Though the daily vitamin D doses employed in these trials ranged from 200 to 3000 IU per day, it is not clear if a dose-response effect exists. Specific maturational stages were associated with optimal bone responses in each of these trials, but they were not consistent across studies. Furthermore, data on male children and among ethnicities other than white and Asian youth were limited in these studies and therefore reduce the generalizability of the findings. Finally, the evidence linking vitamin D supplementation to improved muscle gains and function, important variables to consider in bone health investigations during growth, might imply indirect effects of supplementation on bone. In conclusion, future RCTs are warranted that address the mechanisms by which vitamin D improves bone mineralization in adolescents, including trials that address the impact of vitamin D on muscle function. PMID- 25818883 TI - Autophagy in adipose tissue of patients with obesity and type 2 diabetes. AB - BACKGROUND: Pathophysiology of obesity is closely associated with enhanced autophagy in adipose tissue (AT). Autophagic process can promote survival or activate cell death. Therefore, we examine the occurrence of autophagy in AT of type 2 diabetes (T2D) patients in comparison to obese and lean individuals without diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Numerous autophagosomes accumulated within adipocytes were visualized by electron transmission microscopy and by immunofluorescence staining for autophagy marker LC3 in obese and T2D patients. Increased autophagy was demonstrated by higher LC3-II/LC3-I ratio, up regulated expression of LC3 and Atg5 mRNA, along with decreased p62 and mTOR protein levels. Increased autophagy occurred together with AT inflammation. CONCLUSIONS: Our data suggest fat depot-related differences in autophagy regulation. In subcutaneous AT, increased autophagy is accompanied by increased markers of apoptosis in patients with obesity independently of T2D. In contrast, in visceral AT only in T2D patients increased autophagy was related to higher markers of apoptosis. PMID- 25818881 TI - Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis. AB - Steroidogenesis begins with cholesterol transfer into mitochondria through the transduceosome, a complex composed of cytosolic proteins that include steroidogenesis acute regulatory protein (STAR), 14-3-3 adaptor proteins, and the outer mitochondrial membrane proteins Translocator Protein (TSPO) and Voltage Dependent Anion Channel (VDAC). TSPO is a drug- and cholesterol-binding protein found at particularly high levels in steroid synthesizing cells. Its aberrant expression has been linked to cancer, neurodegeneration, neuropsychiatric disorders and primary hypogonadism. Brain steroids serve as local regulators of neural development and excitability. Reduced levels of these steroids have been linked to depression, anxiety and neurodegeneration. Reduced serum testosterone is common among subfertile young men and aging men, and is associated with depression, metabolic syndrome and reduced sexual function. Although testosterone replacement therapy is available, there are undesired side-effects. TSPO drug ligands have been proposed as therapeutic agents to regulate steroid levels in the brain and testis. PMID- 25818885 TI - Predictors of HbA1c over 4 years in people with type 2 diabetes starting insulin therapies: The CREDIT study. AB - AIMS: To identify factors associated with glucose control, as measured by HbA1c over 4 years, in people with type 2 diabetes starting insulin therapy. METHODS: CREDIT, an observational cohort study, collected data semi-annually over 4 years, on people with type 2 diabetes starting any insulin, in 311 centres in 12 countries; 2803 people had data on HbA1c during follow-up. Multivariable backward regression analysis selected characteristics associated with glycaemic control from a limited number of candidate variables. RESULTS: Before starting insulin therapy, HbA1c was 9.3% (78 mmol/mol) and decreased to 7.6% (60 mmol/mol) after 1 year, and changed little after that. Insulin dose increased from 0.21 U/kg to 0.36 U/kg at 1 year, and then by 0.10 U/kg over the next 3 years. Body weight increased by 2.0 kg in the first year and increased little thereafter. Poorer glycaemic control over the 4 years was mainly determined by the HbA1c before starting therapy, after accounting for the other statistically significant associated variables in multivariable analysis: higher BMI, younger age, longer diabetes duration, more glucose-lowering drugs, using basal insulin alone, higher insulin dose and female sex. At 4 years, a higher current insulin dose was the characteristic most strongly associated with a higher concurrent HbA1c. CONCLUSIONS: HbA1c at the start of insulin therapy was the characteristic most predictive of later HbA1c, after accounting for other variables associated with HbA1c. This may provide some justification for earlier insulin introduction to improve glucose control to target. PMID- 25818884 TI - Knockout of the transcription factor Nrf2: Effects on testosterone production by aging mouse Leydig cells. AB - Aging in rodents and men is associated with reduced serum levels of testosterone and Leydig cell testosterone productions. To further investigate the mechanism by which Leydig cell testosterone production declines, the effect of knocking out Nrf2, a master regulator of phase 2 antioxidant genes, was examined. In wild-type mice, testosterone production and serum testosterone levels remained unchanged through middle age (8 months), but then were reduced significantly by old age (21 24 months). In contrast, serum testosterone levels and Leydig cell testosterone production were reduced significantly in the Nrf2-/- mice as early as middle age, and were reduced further in the aged mice. Reduced steroidogenesis in the knockout mice was associated with reduced antioxidant capacity, and increased expression of protein nitrotyrosine residues, a marker of ROS. These results support the hypothesis that, over time, increases in oxidative stress contribute to or cause the reduced testosterone production that characterizes Leydig cell aging. PMID- 25818887 TI - Supercritical fluid chromatography in pharmaceutical analysis. AB - In the last few years, there has been a resurgence of supercritical fluid chromatography (SFC), which has been stimulated by the introduction of a new generation of instruments and columns from the main providers of chromatographic instrumentation, that are strongly committed to advancing the technology. The known limitations of SFC, such as weak UV sensitivity, limited reliability and poor quantitative performance have been mostly tackled with these advanced instruments. In addition, due to the obvious benefits of SFC in terms of kinetic performance and its complementarity to LC, advanced packed-column SFC represents today an additional strategy in the toolbox of the analytical scientist, which may be particularly interesting in pharmaceutical analysis. In the present review, the instrumentation and experimental conditions (i.e. stationary phase chemistry and dimensions, mobile phase nature, pressure and temperature) to perform "advanced SFC" are discussed. The applicability of SFC in pharmaceutical analysis, including the determination of drugs in formulations and biofluids is critically discussed. PMID- 25818886 TI - Association between metabolic syndrome and lung function in middle-aged and elderly Chinese individuals. AB - Subjects with metabolic syndrome (MetS) had lower FVC and FEV1 than non-MetS subjects and decreased gradually with the increasing number of MetS components. After adjusting for potential risk factors, the lowest quartile of FVC and FEV1 was associated with increased risk of MetS. PMID- 25818888 TI - Supplementation with complex milk lipids during brain development promotes neuroplasticity without altering myelination or vascular density. AB - BACKGROUND: Supplementation with complex milk lipids (CML) during postnatal brain development has been shown to improve spatial reference learning in rats. OBJECTIVE: The current study examined histo-biological changes in the brain following CML supplementation and their relationship to the observed improvements in memory. DESIGN: The study used the brain tissues from the rats (male Wistar, 80 days of age) after supplementing with either CML or vehicle during postnatal day 10-80. Immunohistochemical staining of synaptophysin, glutamate receptor-1, myelin basic protein, isolectin B-4, and glial fibrillary acidic protein was performed. The average area and the density of the staining and the numbers of astrocytes and capillaries were assessed and analysed. RESULTS: Compared with control rats, CML supplementation increased the average area of synaptophysin staining and the number of GFAP astrocytes in the CA3 sub-region of the hippocampus (p<0.01), but not in the CA4 sub-region. The supplementation also led to an increase in dopamine output in the striatum that was related to nigral dopamine expression (p<0.05), but did not alter glutamate receptors, myelination or vascular density. CONCLUSION: CML supplementation may enhance neuroplasticity in the CA3 sub-regions of the hippocampus. The brain regions-specific increase of astrocyte may indicate a supporting role for GFAP in synaptic plasticity. CML supplementation did not associate with postnatal white matter development or vascular remodelling. PMID- 25818889 TI - Nutrition labelling, marketing techniques, nutrition claims and health claims on chip and biscuit packages from sixteen countries. AB - OBJECTIVE: Food packages were objectively assessed to explore differences in nutrition labelling, selected promotional marketing techniques and health and nutrition claims between countries, in comparison to national regulations. DESIGN: Cross-sectional. SETTING: Chip and sweet biscuit packages were collected from sixteen countries at different levels of economic development in the EPOCH (Environmental Profile of a Community's Health) study between 2008 and 2010. SUBJECTS: Seven hundred and thirty-seven food packages were systematically evaluated for nutrition labelling, selected promotional marketing techniques relevant to nutrition and health, and health and nutrition claims. We compared pack labelling in countries with labelling regulations, with voluntary regulations and no regulations. RESULTS: Overall 86 % of the packages had nutrition labels, 30 % had health or nutrition claims and 87 % displayed selected marketing techniques. On average, each package displayed two marketing techniques and one health or nutrition claim. In countries with mandatory nutrition labelling a greater proportion of packages displayed nutrition labels, had more of the seven required nutrients present, more total nutrients listed and higher readability compared with those with voluntary or no regulations. Countries with no health or nutrition claim regulations had fewer claims per package compared with countries with regulations. CONCLUSIONS: Nutrition label regulations were associated with increased prevalence and quality of nutrition labels. Health and nutrition claim regulations were unexpectedly associated with increased use of claims, suggesting that current regulations may not have the desired effect of protecting consumers. Of concern, lack of regulation was associated with increased promotional marketing techniques directed at children and misleadingly promoting broad concepts of health. PMID- 25818890 TI - Radiographic Detectability of Retained Neuropatties in a Cadaver Model. AB - BACKGROUND: Counts are the commonest method used to ensure that all sponges and neuropatties are removed from a surgical site before closure. When the count is not reconciled, plain radiographs of the operative site are taken to determine whether the missing patty has been left in the wound. The purpose of this study was to describe the detectability of commonly used neuropatties in the clinical setting using digital technologies. METHODS: Neuropatties were implanted into the anterior and posterior cranial fossae and the thoracolumbar extradural space of a mature male cadaver. Four neuropatty sizes were used: 3 * 1 in, 2 * 1/2 in, 1/2 * 1/2 in, and 1/4 * 1/4 in. Neuropatties, with size and location chosen at random, were placed in the surgical sites and anteroposterior/posterior-anterior and lateral radiographs were taken using standard portable digital radiographic equipment. Six clinicians reviewed the digital images for the presence or absence of neuropatties. The readers were not aware of the number and size of the patties that were included in each image. RESULTS: The detectability of neuropatties is dependent on the size of the neuropatty's radiopaque marker and the operative site. Neuropatties measuring 2 * 1/2 in and 3 * 1 in were detected reliably regardless of the operative site. 1/4 * 1/4 in neuropatties were poorly detected by neurosurgeons and radiologists in all three operative sites. Readers of various experience and background were similar in their ability to detect neuropatties under these conditions. CONCLUSIONS: Under simulated operating room conditions and using currently available neuropatties and plain radiograph imaging technology, small 1/4-in and 1/2-in neuropatties are poorly visible/detectable on digital images. PMID- 25818891 TI - Occurrence of Herpes Simplex Virus Reactivation Suggests a Mechanism of Trigeminal Neuralgia Surgical Efficacy. AB - Common to the types of surgery that are effective for the treatment of trigeminal neuralgia (TN) is reactivation of herpes simplex virus (HSV). It is likely that such HSV reactivation following surgery indicates altered trigeminal ganglion neuron function, which was caused by the surgery. It is not thought that HSV infection is related to the cause of TN or that HSV reactivation is important for surgical treatment efficacy. Rather, it is thought that HSV reactivation is a marker of altered trigeminal ganglion neuron function resulting from the TN surgery. It is suggested that HSV reactivation is a surrogate marker of ganglion neuron injury. The correlation between effective types of surgery and evidence that they alter ganglion neuron function suggests that altered trigeminal ganglion neuron function may be the basis of the surgical efficacy. PMID- 25818892 TI - Clearing your mind: a glymphatic system? PMID- 25818894 TI - Standard development at the Human Variome Project. AB - The Human Variome Project (HVP) is a world organization working towards facilitating the collection, curation, interpretation and free and open sharing of genetic variation information. A key component of HVP activities is the development of standards and guidelines. HVP Standards are systems, procedures and technologies that the HVP Consortium has determined must be used by HVP affiliated data sharing infrastructure and should be used by the broader community. HVP guidelines are considered to be beneficial for HVP affiliated data sharing infrastructure and the broader community to adopt. The HVP also maintains a process for assessing systems, processes and tools that implement HVP Standards and Guidelines. Recommended System Status is an accreditation process designed to encourage the adoption of HVP Standards and Guidelines. Here, we describe the HVP standards development process and discuss the accepted standards, guidelines and recommended systems as well as those under acceptance. Certain HVP Standards and Guidelines are already widely adopted by the community and there are committed users for the others. PMID- 25818893 TI - Colorectal cancer drug target prediction using ontology-based inference and network analysis. AB - Identification of novel drug targets is a critical step in drug development. Many recent studies have produced multiple types of data, which provides an opportunity to mine the relationships among them to predict drug targets. In this study, we present a novel integrative approach that combines ontology reasoning with network-assisted gene ranking to predict new drug targets. We utilized colorectal cancer (CRC) as a proof-of-concept use case to illustrate the approach. Starting from FDA-approved CRC drugs and the relationships among disease, drug, gene, pathway, and SNP in an ontology representing PharmGKB data, we inferred 113 potential CRC drug targets. We further prioritized these genes based on their relationships with CRC disease genes in the context of human protein-protein interaction networks. Thus, among the 113 potential drug targets, 15 were selected as the promising drug targets, including some genes that are supported by previous studies. Among them, EGFR, TOP1 and VEGFA are known targets of FDA-approved drugs. Additionally, CCND1 (cyclin D1), and PTGS2 (prostaglandin endoperoxide synthase 2) have reported to be relevant to CRC or as potential drug targets based on the literature search. These results indicate that our approach is promising for drug target prediction for CRC treatment, which might be useful for other cancer therapeutics. PMID- 25818895 TI - SCAN database: facilitating integrative analyses of cytosine modification and expression QTL. AB - Functional annotation of genetic variants including single nucleotide polymorphisms (SNPs) and copy number variations (CNV) promises to greatly improve our understanding of human complex traits. Previous transcriptomic studies involving individuals from different global populations have investigated the genetic architecture of gene expression variation by mapping expression quantitative trait loci (eQTL). Functional interpretation of genome-wide association studies (GWAS) has identified enrichment of eQTL in top signals from GWAS of human complex traits. The SCAN (SNP and CNV Annotation) database was developed as a web-based resource of genetical genomic studies including eQTL detected in the HapMap lymphoblastoid cell line samples derived from apparently healthy individuals of European and African ancestry. Considering the critical roles of epigenetic gene regulation, cytosine modification quantitative trait loci (mQTL) are expected to add a crucial layer of annotation to existing functional genomic information. Here, we describe the new features of the SCAN database that integrate comprehensive mQTL mapping results generated in the HapMap CEU (Caucasian residents from Utah, USA) and YRI (Yoruba people from Ibadan, Nigeria) LCL samples and demonstrate the utility of the enhanced functional annotation system. PMID- 25818897 TI - Age-associated skin changes in innate immunity markers reflect a complex interaction between aging mechanisms in the sebaceous gland. AB - Skin aging is the most apparent form of senescence and could reflect the aging of inner organs. Molecular changes involved in innate immunity signaling, tumorigenesis, and inflammation were studied. Protein levels were evaluated based on the immunohistochemistry of the skin of 42 young and old individuals. The investigated molecules (peroxisome proliferator-activated receptors-alpha and gamma, Toll-like receptor 4, and interleukin-6 and 8) were expressed in almost all skin compartments and exhibited significant aging-associated downregulation in epithelial tissues, mostly in the sebaceous glands, the sweat glands, and the epidermis. With the exception of interleukin-6 in the dermal tissue, no upregulation was detected in the aged group. The results obtained indicate an interesting interaction between different pathways of aging, namely defective stress responses, downregulated innate immunity responses, and activation of the tumorigenesis pathway, which was especially apparent in the sebaceous glands. PMID- 25818896 TI - Post-transplant survival is improved for hepatitis C recipients who are RNA negative at time of liver transplantation. AB - Hepatitis C virus (HCV) infection recurs universally in patients who are viremic at liver transplantation and likely accounts for the diminished post-transplant graft and patient survival. We evaluated whether undetectable HCV RNA pretransplant improves graft and patient survival after transplantation. Cases, defined by HCV listing diagnosis and positive HCV antibody, were selected from the Scientific Registry of Transplant Recipients database and further grouped as HCV RNA-positive (n = 4978) or negative (n = 445) based upon pretransplant testing. Controls were non-HCV recipients (n = 2995). RNA-negative cases had significantly better 5-year graft (72% vs. 64%) and patient (79% vs. 69%) survival than RNA-positive cases (P < 0.01 for both), and similar survival as controls (Graft: 72% vs. 74%, PATIENT: 79% vs. 80%; P > 0.05 for both). Nonproportional hazards modeling of RNA-positive cases identified a subgroup with rapid progression leading to early graft loss and death. Multivariable analyses confirmed that a positive HCV RNA prior to transplantation was a significant independent predictor of graft loss and death. In conclusion, HCV patients who have undetectable RNA at the time of liver transplantation experience improved long-term graft and patient outcomes. We speculate that the post-transplant survival of HCV recipients could be improved by safe and tolerable pretransplant antiviral strategies. PMID- 25818898 TI - [Correlation of authorized prescriptions with increased spending in primary care]. PMID- 25818899 TI - [Acalculous cholecystitis in an intravenous heroin consumer]. PMID- 25818900 TI - Effect of an intense period of competition on race performance and self-reported illness in elite cross-country skiers. AB - The aim of this study was to determine whether participating in a cross-country skiing stage race (Tour de Ski; TDS) affects subsequent illness incidence, training, and race performance. Self-reported training and illness data from 44 male and female elite cross-country skiers were included. In total, 127 years of data were collected (2-3 seasons per athlete). Illness incidence, training load, and performance in international competitions were calculated for athletes who did and did not participate in TDS. Forty-eight percent of athletes reported becoming ill during or in the days immediately after taking part in TDS vs 16% of athletes who did not participate. In both groups, illness incidence was somewhat lower for female athletes. For male athletes, race performance was significantly worse for 6 weeks following TDS vs 6 weeks before TDS. Furthermore, while female athletes who participated in TDS performed relatively better than controls in Olympics/World Championships, male athletes who participated in TDS typically performed worse in subsequent major championships. Participating in TDS appears to result in ~ 3-fold increase in risk of illness in this period. Male athletes appear more prone to illness and also see a drop in race performance following TDS, possibly linked to differences in training load before and after the event. PMID- 25818901 TI - Aortic Valve Reconstruction Using Autologous Pericardium for Aortic Stenosis. AB - BACKGROUND: To determine the feasibility of original aortic valve reconstruction (AVRec) for patients with aortic stenosis (AS), 416 consecutive cases were reviewed. METHODS AND RESULTS: AVRecs for AS were performed for 416 patients from April 2007 through April 2013. All 416 patients were retrospectively reviewed. One hundred and fourteen patients had bicuspid valves and 16 had unicuspid valves. There were 182 men and 234 women. Mean age was 71.2+/-12.0 years old. On preoperative echocardiography, peak pressure gradient averaged 79.0+/-33.6 mmHg. Surgical annular diameter was 20.1+/-2.8 mm. The procedure is based on independent tricuspid replacement by autologous pericardium using original sizing apparatus and template. There was no conversion to prosthetic valve replacement. There were 8 in-hospital mortalities due to non-cardiac cause. On postoperative echocardiography, peak pressure gradient averaged 21.2+/-10.7 mmHg 1 week after surgery and 14.3+/-5.0 mmHg 5.5 years after surgery. Four reoperations were done for infective endocarditis. The other 412 patients had less than mild regurgitation. No thrombo-embolic events were recorded. The mean follow-up period was 25.2+/-17.5 months. Freedom from reoperation was 96.7% with 73-month follow up. CONCLUSIONS: Medium-term results were excellent. Original AVRec was feasible for the patients with AS. Long-term data will be presented in the future. PMID- 25818902 TI - Comparison of Percutaneous Coronary Intervention With Coronary Artery Bypass Grafting in Unprotected Left Main Coronary Artery Disease - 5-Year Outcome From CREDO-Kyoto PCI/CABG Registry Cohort-2 - . AB - BACKGROUND: Studies evaluating long-term (>=5 years) outcome of percutaneous coronary intervention (PCI) compared with coronary artery bypass grafting (CABG) in patients with unprotected left main coronary artery disease (ULMCAD) are still limited, despite concerns for late adverse events after drug-eluting stents implantation. METHODS AND RESULTS: We identified 1,004 patients with ULMCAD (PCI: n=364, CABG: n=640) among 15,939 patients with first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG registry cohort-2. The primary outcome measure in the current analysis was a composite of death, myocardial infarction, and stroke (death/MI/stroke). The cumulative 5-year incidence of and the adjusted risk for death/MI/stroke were significantly higher in the PCI group than in the CABG group (34.5% vs. 24.1%, log-rank P<0.001, adjusted hazard ratio (HR): 1.48 [95% confidence interval (CI): 1.07-2.05, P=0.02]). The adjusted risks for all cause death was not significantly different between the 2 groups. Regarding the stratified analysis by the SYNTAX score, the adjusted risk for death/MI/stroke was not significantly different between the 2 groups in patients with low (<23) or intermediate (23-33) SYNTAX score, whereas it was significantly higher in the PCI group than in the CABG group in patients with high (<=33) SYNTAX score. CONCLUSIONS: CABG as compared with PCI was associated with better long-term outcome in patients with ULMCAD, especially those with high anatomical complexity. PMID- 25818903 TI - Is low body weight a novel risk factor for thromboembolic events in patients with non-valvular atrial fibrillation? PMID- 25818904 TI - Can a single short-term mechanism account for priming of pop-out? AB - Trial-to-trial feature repetition speeds response times in pop-out visual search tasks. These priming effects are often ascribed to a short-term memory system. Recently, however, it has been reported that a 'build-up' sequence of repetitions could facilitate responses over 16 trials later - well beyond twice the typically reported time course (Vision Research, 2011, 51, 1972-1978). Here, we first report two replication attempts that yielded little to no support for such long term priming of pop-out. The results instead fell in line with the predictions of a previously proposed computational model that describes priming as short-lived facilitation that decays over approximately eight trials (Vision Research, 2010, 50, 2110-2115). In the second part of this study, we show that these data are consistent with a simple formulation of decay with a single timescale, and that there is no significant priming beyond eight trials. PMID- 25818905 TI - Discovering hierarchical motion structure. AB - Scenes filled with moving objects are often hierarchically organized: the motion of a migrating goose is nested within the flight pattern of its flock, the motion of a car is nested within the traffic pattern of other cars on the road, the motion of body parts are nested in the motion of the body. Humans perceive hierarchical structure even in stimuli with two or three moving dots. An influential theory of hierarchical motion perception holds that the visual system performs a "vector analysis" of moving objects, decomposing them into common and relative motions. However, this theory does not specify how to resolve ambiguity when a scene admits more than one vector analysis. We describe a Bayesian theory of vector analysis and show that it can account for classic results from dot motion experiments, as well as new experimental data. Our theory takes a step towards understanding how moving scenes are parsed into objects. PMID- 25818906 TI - Depression and anxiety in men with sexual dysfunction: a retrospective study. AB - BACKGROUND: Comorbid anxiety disorders and depression are commonly seen in men with sexual disorders such as erectile dysfunction (ED) and premature ejaculation (PE). However, they are often undiagnosed and untreated, and their relationship to sexual dysfunction is complex. This study examines the frequency and correlates of comorbid anxiety and depression in men with ED or PE. METHODS: The case records of 64 men with ED or PE attending a clinic for psychosexual disorders in a general hospital psychiatry unit during the period 2010-14 were reviewed. Information on comorbid anxiety disorders and depression was extracted from these records, and their clinical and demographic associations were analyzed. RESULTS: Eight (12.5%) men had comorbid depressive disorders, and fifteen (23.4%) had anxiety disorders. These disorders predated the onset of sexual dysfunction in the majority of patients. Generalized anxiety disorder was the commonest anxiety disorder. Men with comorbid depression had significantly elevated rates of suicidal ideation or behavior related to their sexual dysfunction, and were more likely to report a lack of libido. Men with pre existing anxiety disorders were more likely to experience performance anxiety related to sex, and to have PE without comorbid ED. CONCLUSIONS: Depression and anxiety affect a substantial minority of men with sexual dysfunction. Men presenting for the evaluation of ED and PE should be carefully screened for these disorders. The links between anxiety disorders and sexual performance anxiety merit further investigation in this patient group. PMID- 25818907 TI - Multimodal management of a pediatric cervical yolk sac tumor. AB - Even though vaginal bleeding is an unusual clinical presentation in infants and young children, thorough evaluation by the pediatric urologist requires the recognition and knowledge of less-common conditions, including malignancy. Extragonadal germ cell tumors are rare in children aged <15 years, representing approximately 1% of all cancers. Because of the close collaboration between pediatric oncologists and pediatric urologists, a multidisciplinary approach to the management and treatment of these tumors includes chemotherapy and surgical resection, aiming for fertility preservation when possible. We present a 10-month old infant with a cervical or uterine germ cell tumor and the challenges found during her treatment. PMID- 25818908 TI - A Case of Colon Cancer Metastasis to the Penis. PMID- 25818909 TI - Laparoscopic omentoplasty to support anastomotic urethroplasty in complex and redo pelvic fracture urethral defects. AB - OBJECTIVE: To test the hypothesis that a new surgical technique using elaborated perineal anastomotic urethroplasty combined with laparoscopic omentoplasty for patients with complex and prior failed pelvic fracture urethral defect repair was feasible, safe, and effective. METHODS: We performed a prospective, observational, stage 2a study to observe treatment outcomes of combined perineal and laparoscopic approach for urethroplasty in patients with pelvic fracture urethral defect at a single center in Pune, India, between January 2012 and February 2013. Complex and redo patients with pelvic fracture urethral defect occurring after pelvic fracture urethral injury were included in the study. Anterior urethral strictures were excluded. The primary study outcome was the success rate of the surgical technique, and the secondary outcome was to evaluate feasibility and safety of the procedure. The clinical outcome was considered a failure when any postoperative instrumentation was needed. RESULTS: Fifteen male patients with a median age of 19 years were included in the study. Seven patients were adolescents (12-18 years) and 8 patients (53.3%) were adults (19-49 years). The mean number of prior urethroplasties was 1.8 (range, 1-3). All patients underwent elaborated bulbomembranous anastomosis using a perineal approach with inferior pubectomy combined with laparoscopic mobilization of the omentum into the perineum to envelope the anastomosis and to fill the perineal dead space. Of 15 patients, 14 (93.3%) were successful and 1 (6.6%) failed. One adolescent boy 14 years old developed a recurrent stricture 2 months after the procedure and was managed using internal urethrotomy. Median follow-up was 18 months (range, 13-24 months). CONCLUSION: Combining a laparoscopic omentoplasty to a membranobulbar anastomosis for complex and redo pelvic fracture urethral injury is successful, feasible, safe, and with minimal additional morbidity to the patient. The technique has the advantage of a perineal incision and the ability to use the omentum to support the anastomosis. PMID- 25818910 TI - Editorial comment. PMID- 25818912 TI - Reply: To PMID 25818910. PMID- 25818911 TI - Is periurethral calcification associated with urinary flow rate and symptom severity in men with lower urinary tract symptoms-benign prostatic hyperplasia? A retrospective review. AB - OBJECTIVE: To evaluate the association of periurethral calcification (PUC) with urine flow rate and symptom severity in men with lower urinary tract symptoms benign prostatic hyperplasia (LUTS-BPH). METHODS: The records of 1199 LUTS-BPH patients were obtained from a prospectively maintained database of men on their first visit from April 2010 to April 2013. Patients with incomplete data or comorbidities affecting voiding function were excluded. The degree of PUC was scored by evaluating the ratio of the calcified urethra to the entire prostatic urethra on the midsagittal plane of a transrectal ultrasonogram. The relationships between prostate-related parameters, International Prostate Symptom Score (IPSS), and uroflowmetric parameters were evaluated. RESULTS: A total of 1030 patients were eligible for final analysis. There were 654 patients (63.5%) with no PUC, 233 (22.6%) with mild PUC, and 143 (13.9%) with moderate to severe PUC. The total IPSS was 16.21 +/- 7.29, 17.74 +/- 7.77, and 17.75 +/- 7.60 in no, mild, and moderate to severe PUC groups, respectively (P = .007), whereas peak urinary flow rate (Qmax) was 15.05 +/- 7.59, 13.62 +/- 6.68, and 12.20 +/- 6.39 mL/s, respectively (P <.001). In an age-adjusted partial correlation test, PUC significantly associated with total IPSS, the storage symptom score, and Qmax (P <.05). Multivariate analysis revealed that PUC independently associated with Qmax (P = .012), total IPSS (P = .042), and the storage symptom score (P = .018) but not with postvoid residue, the voiding symptom score, or the postmicturition symptom score. CONCLUSION: PUC is independently associated with Qmax and urinary symptoms indirectly advocating for the recent idea that periurethral fibrosis and stiffness could cause LUTS-BPH in men. PMID- 25818913 TI - Body and Self-image in Individuals With Bladder Exstrophy: What Happens After... The Age of 60? AB - An unusual case report to stress the complexity of development of identity and intimacy in people with bladder exstrophy. The psychosocial support seems to play a fundamental role to promote self-esteem of abdominal scarring and altered genital appearance. PMID- 25818914 TI - Catheter-associated Urinary Tract Infections in Children: Room for Improvement. Commentary on: Reducing Catheter-associated Urinary Tract Infections: A Quality improvement Initiative. PMID- 25818915 TI - Small rural emergency services can electronically collect accurate episode-level data: A cross-sectional study. AB - OBJECTIVE: There is little evidence that useful electronic data could be collected at Australian small rural emergency services. If in future their funding model changed to the Activity-Based Funding model, then they would need to collect and submit more data. We determine whether it is possible to collect episode-level data at six small rural emergency services and quantify the accuracy of eight fields. DESIGN: A prospective cross-sectional study. SETTING: South-West Victoria, Australia. PARTICIPANTS: Six small rural emergency services. INTERVENTION: We collected and audited episode-level emergency data from participating services between 1 February 2011 and 31 January 2012. A random sample of these data were audited monthly. Research assistants located at each service supported data entry and audited data accuracy for four hours per week. MAIN OUTCOME MEASURES: Rates for data completeness, accuracy and total accuracy were calculated using audit data. RESULTS: Episode-level data were collected for 20 224 presentations across six facilities. The audit dataset consisted of 8.5% (1504/17 627) of presentations from five facilities. For all fields audited, the accuracy of entered data was high (>93%).Triage category was deemed appropriate for 95.9% (95% confidence interval (CI): 94.9-96.9%) of the patient records reviewed. Some procedures were missing (28.7%, 95%CI: 27.2-30.3%). No significant improvement in data accuracy over 12 months was observed. CONCLUSION: All six services collected useful episode-level data for 12-months with four hours per week of assistance. Data entry accuracy was high for all fields audited, and data entry completeness was low for procedures. PMID- 25818917 TI - Metastases to oro-maxillo-facial region from distant sites: are they so rare? A single centre 8-years experience. AB - AIM: The goal of our study is investigate the frequency of metastasis to oro maxillo-facial region to understand if they are really so rare. MATERIAL OF STUDY: In this eight year's retrospective study (2004-2012) we collected 15 cases of metastasis localized in the maxilla-facial region from distant primary tumor. RESULTS: Our results show breast and kidney as the most frequent primary site (40% and 20% respectively), adenocarcinoma as most common histological type (60%). Bone involvement has found to be much frequent than the soft tissue one (53.3%). The mandible (5/15 cases) is more affected than the maxilla, and most common interested subsites are molar and retromolar region. In our study we found only one case of unknown primary tumor, it was a mandibular bone metastasis from a renal clear cell carcinoma. CONCLUSION: Finally, according to our results and considering the increase of survival in cancer disease, even if metastases to oro maxilla- facial region from distant sites are not frequent, it is important to suspect secondary lesions both in patients that was referred a tumor in their medical history and in those that present a head and neck lesion. PMID- 25818918 TI - Impact of clinical pharmacists in the emergency department of an Australian public hospital: A before and after study. AB - OBJECTIVE: To evaluate the impact of an ED pharmacy service on ED clinical staff and hospital pharmacist activity. METHODS: A prospective study measuring pharmacist activities and surveying ED staff attitudes and experience before and after commencement of an ED pharmacy service. RESULTS: There were 2275 and 2072 hospital-wide pharmacist occasions of service recorded over a 1 month period before and after implementation of the ED pharmacy service, respectively; 339 (16.4%) of these occurred in the ED post-implementation. ED pharmacists most commonly were involved in obtaining medication histories (74% of ED occasions of service); 43% of all pharmacist-performed medication histories occurred in the ED. Post-implementation of the service, 26% of medication interventions occurred in the ED with the number of medication errors identified by ward pharmacists decreasing by 11%; 59% of ED pharmacist medication interventions were clinically significant. ED clinicians perceived the greatest impact of the service to be on patient education and medication safety. Qualitative feedback was overwhelmingly positive. CONCLUSIONS: Pharmacy staff can rapidly become a vital component of clinical service provision in the ED, contributing to medication safety from the point of patient entry into the hospital and impacting ED clinicians and whole of hospital activity for pharmacists. PMID- 25818916 TI - Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains. AB - Voltage-gated channels open paths for ion permeation upon changes in membrane potential, but how voltage changes are coupled to gating is not entirely understood. Two modules can be recognized in voltage-gated potassium channels, one responsible for voltage sensing (transmembrane segments S1 to S4), the other for permeation (S5 and S6). It is generally assumed that the conversion of a conformational change in the voltage sensor into channel gating occurs through the intracellular S4-S5 linker that provides physical continuity between the two regions. Using the pathophysiologically relevant KCNH family, we show that truncated proteins interrupted at, or lacking the S4-S5 linker produce voltage gated channels in a heterologous model that recapitulate both the voltage-sensing and permeation properties of the complete protein. These observations indicate that voltage sensing by the S4 segment is transduced to the channel gate in the absence of physical continuity between the modules. PMID- 25818920 TI - Use of a triiodide resin for isolation of axenic cultures of microalgal Nannochloropsis gaditana. AB - Triiodide resin (TR) was used to generate axenic cultures of microalgae by employing the antibacterial capability of triiodide. A Nannochloropsis gaditana culture contaminated with bacteria was passed through a column filled with TR using the gravity flow. Based on analyses of flow cytometry and vital staining using a fluorescent dye SYTOX Green, three cycles of TR treatments remarkably reduced the number of viable bacteria but had little effects on the microalgae. This novel approach is a simple, rapid, and cost-effective method that can be used to isolate axenic cultures of microalgae. PMID- 25818919 TI - [Clinical research outside of teaching hospitals: Current situation in north eastern France]. AB - BACKGROUND: Most clinical research in France takes place in teaching hospitals. There are, however, many advantages to developing it in other hospitals: access to innovative treatments, improvement in healthcare quality, attractiveness of hospitals, increased trial inclusion rates and reduced selection bias. The objectives of our study were to report on the current situation of clinical research outside teaching hospitals. METHODS: A three-stage survey was conducted between January 2012 and May 2013 in non-teaching hospitals of north-eastern France. First, questionnaires were sent to administrative and medical boards of all hospitals with more than 100 beds, then to head doctors of every department in hospitals with more than 300 beds and finally meetings were organized with members of 20 selected hospitals. RESULTS: The administrative and medical boards of 85 hospitals participated in the first stage of the survey; half of these hospitals were engaged in clinical research activities and for 10 the internal structuring was cross-disciplinary. Answers from 178 departments were obtained during the second stage; 47% reported a clinical research activity. Meetings with research teams in 20 hospitals allowed us to identify difficulties concerning research funding, transversal organization and sponsoring. CONCLUSION: Clinical research existed in more than half of the respondent non-teaching hospitals. Obstacles to its development can be grouped in three categories: 1) internal structuring of clinical research, 2) access to information and knowledge of how clinical research functions and to interlocutors outside the hospital and 3) access to skills necessary to sponsor clinical research. PMID- 25818921 TI - Microwave-assisted pyrolysis of methyl ricinoleate for continuous production of undecylenic acid methyl ester (UAME). AB - Undecylenic acid methyl ester (UAME) was continuously produced from methyl ricinoleate using a microwave-assisted pyrolysis system with atomization feeding. The UAME yield of 77 wt.% was obtained at 500 degrees C using SiC as the microwave absorbent and heating medium. The methyl ricinoleate conversion and UAME yield from microwave-assisted pyrolysis process were higher than those from conventional pyrolysis. The effect of temperature on the pyrolysis process was also investigated. The methyl ricinoleate conversion increased but the cracking liquid yield decreased when the temperature increased from 460 degrees C to 560 degrees C. The maximum UAME yield was obtained at the temperature of 500 degrees C. PMID- 25818922 TI - Effect of mixing ratio of food waste and rice husk co-digestion and substrate to inoculum ratio on biogas production. AB - Aim of this study was to find out suitable mixing ratio of food waste and rice husk for their co-digestion in order to overcome VFA accumulation in digestion of food waste alone. Four mixing ratios of food waste and rice husk with C/N ratios of 20, 25, 30 and 35 were subjected to a lab scale anaerobic batch experiment under mesophilic conditions. Highest specific biogas yield of 584L/kgVS was obtained from feedstock with C/N ratio of 20. Biogas yield decreased with decrease in food waste proportion. Further, fresh cow dung was used as inoculum to investigate optimum S/I ratio with the selected feedstock. In experiment 2, feedstock with C/N ratio 20 was subjected to anaerobic digestion at five S/I ratios of 0.25, 0.5, 1.0, 1.5 and 2.0. Specific biogas yield of 557L/kgVS was obtained at S/I ratio of 0.25. However, VFA accumulation occurred at higher S/I ratios due to higher organic loadings. PMID- 25818923 TI - Work-related psychosocial stress and glycemic control among working adults with diabetes mellitus. AB - OBJECTIVE: To examine the association between glycosylated hemoglobin (HbA1c) and four subscales of work-related psychosocial stress at study baseline and over time. MATERIALS AND METHODS: We used survey data from a major HMO located in the Southeastern part of the US on health and healthy behaviors linked with patients' clinical, pharmacy and laboratory records for the period between 2005 and 2009. Study participants (n=537) consisted of working adults aged 25-59 years, diagnosed with diabetes mellitus (DM) but without advanced micro or macrovascular complications at the time of the survey. We estimated the baseline (2005) association between HbA1c and work-related psychosocial stress and their interactions using linear regression analysis. Using individual growth model approach, we estimated the association between HbA1c over time and work-related psychosocial stress. Each of the models controlled for socio-demographic variables, diet and physical activity factor, laboratory factor, physical examinations variables and medication use in a hierarchical fashion. RESULTS: After adjusting for all study covariates, we did not find a significant association between work-related psychosocial stress and glycemic control either at baseline or over time. CONCLUSION: Among fairly healthy middle aged working adults with DM, work-related psychosocial stress was not directly associated with glycemic control. PMID- 25818924 TI - Identification of a novel HLA-A*24 variant allele, A*24:02:60. AB - HLA-A*24:02:60 allele differs from A*24:02:01:01 by one nucleotide substitution at nt 564 from C to T. PMID- 25818925 TI - Characterization of Anatomic and Visual Function Outcomes in Patients With Full Thickness Macular Hole in Ocriplasmin Phase 3 Trials. AB - PURPOSE: To characterize anatomic and visual outcomes in patients with full thickness macular hole (FTMH) at baseline in ocriplasmin phase 3 clinical trials, focusing on the relationship between resolution of vitreomacular adhesion and FTMH closure. DESIGN: Two multicenter, randomized, double-masked clinical trials. METHODS: Pharmacologic FTMH closure was one of multiple secondary endpoints. OCT scans were obtained at baseline and at all postinjection visits, and for patients with baseline FTMH, evaluated for FTMH width, vitreomacular adhesion, and epiretinal membrane. RESULTS: FTMH closure was observed in a greater proportion of ocriplasmin- vs vehicle-injected patients with baseline FTMH width <=250 MUm (58.3% vs 16.0%, P < .001) and >250 to <=400 MUm (36.8% vs 5.3%, P = .009). Among FTMH patients in the ocriplasmin group, >=2-line visual acuity gains at month 6 were achieved by a greater percentage of those who achieved hole closure at day 28 vs those who did not achieve this outcome (72.1% vs 25.4%). CONCLUSIONS: Ocriplasmin demonstrated efficacy in closure of small and medium FTMH, and in FTMH without epiretinal membrane at baseline. Visual acuity gains occurred more frequently when hole closure was achieved after ocriplasmin treatment compared to when this outcome did not occur. Ocriplasmin treatment is an additional option for the management of patients with FTMH and vitreomacular adhesion. PMID- 25818926 TI - [An unusual retropharyngeal lipoma]. PMID- 25818927 TI - Osteoporosis: new treatments. PMID- 25818928 TI - [Preservation of fertility in children with cancer]. AB - Preserving fertility is a requisite for any child undergoing gonadotoxic treatment for cancer. Techniques vary depending on the age, sex of the patient and nature of the treatment. Boys undergoing irradiation have testicular protection or transposition. Post-pubertal boys undergoing chemotherapy can have semen cryopreservation like adults. However, fertility preservation for pre pubertal boys undergoing chemotherapy implies testicular tissue cryopreservation. Research concentrates on germ cell transplantation, autotransplantation of testicular tissue or in vitro spermatogonial maturation in order to later restore spermatogenesis. Ovarian transposition can be undergone in case of brachytherapy or external beam radiotherapy in girls and has published success rates of 80%. Ovarian cryopreservation has been developed since 1995 for pre-pubertal and post pubertal girls undergoing chemotherapy. The ovary is retrieved surgically and ovarian cortical segments are frozen. Thawing and transplantation of gonadal tissue are the next steps to restoring fertility. However, immature oocytes will have to be matured either in vivo or in vitro in order to restore fertility. Fertility preservation must be offered to children with cancer even if maturation of immature germ cells is uncertain for research 20 to 30 years from now will probably enable fertility restoration. PMID- 25818929 TI - [Satisfaction of Breast Cancer patients treated by chemotherapy outpatient clinics: Results of the TemporELLES survey]. AB - Three thousand eight hundred and twelve patients participated in the TemporELLES survey; these patients were treated for breast cancer with intravenous chemotherapy in 105 different outpatient clinics in France. The survey shows that patients spend on average 3hours in the outpatient clinic per chemotherapy session, which includes on average 50minutes of waiting time. Forty percent of patients would like to reduce this waiting time. Availability of new dosage forms and ready to use medications will address the need for reduced waiting time while freeing up time for providing support to the patients. PMID- 25818930 TI - Valsartan Promoting Atherosclerotic Plaque Stabilization by Upregulating Renalase: A Potential-Related Gene of Atherosclerosis. AB - BACKGROUND: Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase. OBJECTIVE: This study examined the tissue distribution of renalase in ApoE(-/-) mice fed with a high-fat diet and the effect of valsartan on expression of renalase. METHODS: ApoE(-/-) mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE(-/-) mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high fat diet. RESULTS: Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver. CONCLUSIONS: Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque. PMID- 25818931 TI - Lack of Benefit of Ischemic Postconditioning After Routine Thrombus Aspiration During Reperfusion: Immediate and Midterm Results. AB - OBJECTIVES: The underutilization of manual thrombus aspiration (MTA) may have reduced the benefits of ischemic postconditioning (PostCon), as it reduces thrombus embolization. We aimed to assess the benefits of PostCon in patients with ST-segment elevation myocardial infarction (STEMI) after the systematic utilization of MTA. METHODS: A total of 87 patients were enrolled in a prospective, randomized trial (43 PostCon and 44 controls). After MTA, PostCon was performed on the treatment group by applying 4 cycles of alternate reperfusion and reocclusion (60 seconds each) using the angioplasty balloon. The primary end point was infarct size assessed by the area under the curve (AUC) of troponin T (TnT) activity. The secondary end points were left ventricle ejection fraction (LVEF) and major cardiac events (new myocardial infarction or cardiac death) both at discharge and at follow-up. RESULTS: The AUC for TnT was no different with respect to study arms (median [interquartile range]): PostCon = 8.9 (10.6) versus control = 8.2 (10.6), P = .68. Left ventricle ejection fraction improved from in-hospital to follow-up (9 +/- 3 months) for the entire cohort (46.3% +/- 7.3% vs 52.2% +/- 10.7%, P < .001), with no differences between PostCon and controls (51.6% +/- 9.5% vs 52.7% +/- 11.9%, P = .89); major cardiac events at 14 +/- 4 months of follow-up were also no different (PostCon = 1.0 (2.3%) vs control = 0, P = .49). CONCLUSION: In patients with STEMI treated with MTA, PostCon offered no benefits to infarct size, LVEF, or major cardiac events. PMID- 25818932 TI - Using FTIR spectra and pattern recognition for discrimination of tea varieties. AB - In order to classify typical Chinese tea varieties, Fourier transform infrared spectroscopy (FTIR) of tea polysaccharides (TPS) was used as an accurate and economical method. Partial least squares (PLS) modeling method along with a self organizing map (SOM) neural network method was utilized due to the diversity and heterozygosis between teas. FTIR spectra results of tea extracts after spectra preprocessing were used as input data for PLS and SOM multivariate statistical analyses respectively. The predicted correlation coefficient of optimization PLS model was 0.9994, and root mean square error of calibration and cross-validation (RMSECV) was 0.03285. The features of PLS can be visualized in principal component (PC) space, contributing to discover correlation between different classes of spectra samples. After that, a data matrix consisted of the scores on the selected 3PCs computed by principle component analysis (PCA) and the characteristic spectrum data was used as inputs for training of SOM neural network. Compared with the PLS linear technique's recognition rate of 67% only, the correct recognition rate of the PLS-SOM as a non-linear classification algorithm to differentiate types of tea reaches up to 100%. And the models become reliable and provide a reasonable clustering of tea varieties. PMID- 25818933 TI - Purification, cDNA cloning, and characterization of LysM-containing plant chitinase from horsetail (Equisetum arvense). AB - Chitinase-A (EaChiA), molecular mass 36 kDa, was purified from the vegetative stems of a horsetail (Equisetum arvense) using a series of column chromatography. The N-terminal amino acid sequence of EaChiA was similar to the lysin motif (LysM). A cDNA encoding EaChiA was cloned by rapid amplification of cDNA ends and polymerase chain reaction. It consisted of 1320 nucleotides and encoded an open reading frame of 361 amino acid residues. The deduced amino acid sequence indicated that EaChiA is composed of a N-terminal LysM domain and a C-terminal plant class IIIb chitinase catalytic domain, belonging to the glycoside hydrolase family 18, linked by proline-rich regions. EaChiA has strong chitin-binding activity, however, no antifungal activity. This is the first report of a chitinase from Equisetopsida, a class of fern plants, and the second report of a LysM-containing chitinase from a plant. PMID- 25818939 TI - Closed-loop cognition: the next frontier arrives. AB - A new study trains attention by implementing a closed-loop neurofeedback approach that monitors attention status in the whole brain using real-time fMRI. Offline analyses underscore information carried by the frontoparietal attention network as most relevant for the training-driven behavioral improvements. PMID- 25818940 TI - Dressings and drains in posterior spine surgery and their effect on wound complications. AB - The purpose of this study was to systematically search, critically appraise and summarize published randomized control trials (RCT) and non-RCT examining the effect of drains and dressings on wound healing rates and complications in posterior spine surgery. The use of post-operative drains and the type of post operative dressing is at the discretion of the treating surgeon with no available clinical guidelines. Drains will theoretically decrease incidence of post operative hematoma and therefore, potentially decrease the risk of neurologic compromise when the neural elements have been exposed. Occlusive dressings have more recently been advocated, potentially maintaining a sterile barrier for longer time periods post-operatively. A systematic review of databases from 1969 2013 was undertaken. All papers examining drains in spine surgery and dressings in primary healing of surgical wounds were included. Revman (version 5.2; The Nordic Cochrane Centre, The Cochrane Collaboration, Oxford, UK) was used to test for overall treatment effect, clinical heterogeneity and risk of bias. Of the papers identified, 1348 examined post-operative drains in spine surgery and 979 wound dressings for primary wound healing of all surgical wounds. Seven studies were included for analysis for post-operative drains and 10 studies were analyzed for primary wound healing. The use of a post-operative drain did not influence healing rates and had no effect secondarily on infection (odds ratio [OR] 1.33; 95% confidence interval [CI] 0.76-2.30). We were not able to establish whether surgical drains prevent hematomas causing neurologic compromise. There was a slight advantage to using occlusive dressings versus non-occlusive dressings in wound healing (OR 2.09; 95% CI 1.44-3.02). Incisional vacuum dressings as both an occlusive barrier and superficial drainage system have shown promise for wounds at risk of dehiscence. There is a relatively high risk of bias in the methodology of many of the studies reviewed. We recommend favoring of occlusive dressings based on heterogeneous and potentially biased evidence. Drain use does not affect wound healing based on similar evidence. Incisional vacuum dressings have shown promise in managing potentially vulnerable wounds. PMID- 25818941 TI - Intraventricular granulomatous mass associated with Mycobacterium haemophilum: A rare central nervous system manifestation in a patient with human immunodeficiency virus infection. AB - We report a rare case of Mycobacterium haemophilum presenting as an intraventricular granulomatous mass with loculated hydrocephalus and seizures in a patient with human immunodeficiency virus. M. haemophilum, a slow-growing mycobacteria, causes localized and disseminated disease among immunocompromised hosts. Central nervous system infection with M. haemophilum is extremely rare. Preoperative laboratory testing of our patient for tuberculosis, toxoplasmosis, sarcoidosis and histoplasmosis were negative. Surgical resection of the mass revealed a caseating granuloma that stained positive for acid-fast bacillus suggesting possible tuberculoma. Despite negative testing for tuberculosis, a polymerase chain reaction analysis was ultimately performed from the resected mass which revealed M. haemophilum. To our knowledge, this is the first case of M. haemophilum presenting as an intraventricular mass. We review the clinical manifestations of this pathogen and discuss the medical and surgical management. PMID- 25818942 TI - High mortality in cirrhotic patients following hemorrhagic stroke. AB - The impact of hemorrhagic stroke (HS) on the mortality of cirrhotic patients is unknown. To evaluate the morality risk of HS in cirrhotic patients, we used the Taiwan National Health Insurance Database to evaluate cirrhotic patients with HS who were discharged between 1 January and 31 December 2007. In total, there were 321 cirrhotic patients with HS. We randomly selected 3210 cirrhotic patients without HS as a comparison group. The 30 and 90 day mortality rates were 29.6% and 43.0% in the HS group, and 9.1% and 17.7% in the comparison group, respectively (p<0.001). After Cox proportional hazard regression model adjustment of patients' sex, age, and other comorbid disorders, the hazard ratio (HR) for 90 day mortality in the HS group was 3.89 (95% confidence interval [CI] 3.20-4.71, p<0.001), compared to the comparison group. In the subgroup analysis, the HR for 90 day mortality in the subarachnoid hemorrhage and other HS groups were 7.93 (95% CI 5.23-12.0, p<0.001) and 3.51 (95% CI 2.85-4.32, p<0.001), respectively, compared to the comparison group. In conclusion, HS is associated with a very high 90 day mortality risk in cirrhotic patients, in whom subarachnoid hemorrhage can also increase the risk of mortality eight-fold. PMID- 25818943 TI - The safety, efficacy and regulatory triangle in drug development: Impact for animal models and the use of animals. AB - Nonclinical studies in animals are conducted to demonstrate proof-of-concept, mechanism of action and safety of new drugs. For a large part, in particular safety assessment, studies are done in compliance with international regulatory guidance. However, animal models supporting the initiation of clinical trials have their limitations, related to uncertainty regarding the predictive value for a clinical condition. The 3Rs principles (refinement, reduction and replacement) are better applied nowadays, with a more comprehensive application with respect to the original definition. This regards also regulatory guidance, so that opportunities exist to revise or reduce regulatory guidance with the perspective that the optimal balance between scientifically relevant data and animal wellbeing or a reduction in animal use can be achieved. In this manuscript we review the connections in the triangle between nonclinical efficacy/safety studies and regulatory aspects, with focus on in vivo testing of drugs. These connections differ for different drugs (chemistry-based low molecular weight compounds, recombinant proteins, cell therapy or gene therapy products). Regarding animal models and their translational value we focus on regulatory aspects and indications where scientific outcomes warrant changes, reduction or replacement, like for, e.g., biosimilar evaluation and safety testing of monoclonal antibodies. On the other hand, we present applications where translational value has been clearly demonstrated, e.g., immunosuppressives in transplantation. Especially for drugs of more recent date like recombinant proteins, cell therapy products and gene therapy products, a regulatory approach that allows the possibility to conduct combined efficacy/safety testing in validated animal models should strengthen scientific outcomes and improve translational value, while reducing the numbers of animals necessary. PMID- 25818944 TI - European Journal of Pharmacology, Special issue on translational value of animal models: Introduction. PMID- 25818945 TI - Non-invasive deep tissue imaging of iodine modified poly(caprolactone-co-1-4 oxepan-1,5-dione) using X-ray. AB - When biodegradable polyester devices, like sutures and screws, are implanted into the body, it is very challenging to image them in deep tissue, monitor their degradation, and detect defects. We report our recent findings on non-invasive deep tissue imaging of polyester degradation, stability and integrity using an iodinated-polycaprolactone (i-P(CLcoOPD)) X-ray imaging contrast agent. The results of experiments performed with i-P(CLcoOPD) demonstrate the feasibility to quantify in-situ polyester degradation in vitro and in vivo using rats. We also demonstrate that X-ray imaging could be used to identify and quantify physical defects, such as cracks, in polymeric implants using rabbit animal models. This approach enables non-invasive monitoring of polyester materials and is expected to become an important technology for improving the imaging of polymers at clinically relevant depths. PMID- 25818946 TI - Relevance of glycosylation of S-layer proteins for cell surface properties. AB - Elucidating the building principles and intrinsic features modulating certain water-associated processes (e.g., surface roughness in the nanometer scale, surface hydration and accompanied antifouling property, etc.) of surface structures from (micro)organisms is nowadays a highly challenging task in fields like microbiology, biomimetic engineering and (bio)material sciences. Here, we show for the first time the recrystallization of the wild-type S-layer glycoprotein wtSgsE from Geobacillus stearothermophilus NRS 2004/3a and its recombinantly produced non-glycosylated form, rSgsE, on gold sensor surfaces. Whereas the proteinaceous lattice of the S-layer proteins is forming a rigid layer on the sensor surface, the glycan chains are developing an overall soft, highly dissipative film. Interestingly, to the wtSgsE lattice almost twice the amount of water is bound and/or coupled in comparison with the non-glycosylated rSgsE with the preferred region being the extending glycan residues. The present results are discussed in terms of the effect of the glycan residues on the recrystallization, the adjoining hydration layer, and the nanoscale roughness and fluidic behavior. The latter features may turn out to be one of the most general ones among bacterial and archaeal S-layer lattices. PMID- 25818947 TI - Covalently-crosslinked mucin biopolymer hydrogels for sustained drug delivery. AB - The sustained delivery of both hydrophobic and hydrophilic drugs from hydrogels has remained a challenge requiring the design and scalable production of complex multifunctional synthetic polymers. Here, we demonstrate that mucin glycoproteins, the gel-forming constituents of native mucus, are suitable for assembly into robust hydrogels capable of facilitating the sustained release of hydrophobic and hydrophilic drugs. Covalently-crosslinked mucin hydrogels were generated via exposure of methacrylated mucin to ultraviolet light in the presence of a free radical photoinitiator. The hydrogels exhibited an elastic modulus similar to that of soft mammalian tissue and were sensitive to proteolytic degradation by pronase. Paclitaxel, a hydrophobic anti-cancer drug, and polymyxin B, a positively-charged hydrophilic antibacterial drug, were retained in the hydrogels and released linearly with time over seven days. After four weeks of drug release, the hydrogels continued to release sufficient amounts of active paclitaxel to reduce HeLa cell viability and sufficient amounts of active polymyxin B to prevent bacterial proliferation. Along with previously established anti-inflammatory, anti-viral, and hydrocarbon-solubilizing properties of mucin, the results of this study establish mucin as a readily available, chemically-versatile, naturally-biocompatible alternative to complex multifunctional synthetic polymers as building blocks in the design of biomaterials for sustained drug delivery. PMID- 25818948 TI - Enhanced differentiation of human osteoblasts on Ti surfaces pre-treated with human whole blood. AB - Early and effective integration of a metal implant into bone tissue is of crucial importance for its long-term stability. While different material properties including surface roughness and wettability but also initial blood-implant surface interaction are known to influence this osseointegration, implications of the latter process are still poorly understood. In this study, early interaction between blood and the implant surface and how this affects the mechanism of osseointegration were investigated. For this, blood coagulation on a micro roughened hydrophobic titanium (Ti) surface (SLA-H(phob)) and on a hydrophilic micro-roughened Ti surface with nanostructures (SLActive-H(phil)NS), as well as the effects of whole human blood pre-incubation of these two surfaces on the differentiation potential of primary human bone cells (HBC) was assessed. Interestingly, pre-incubation with blood resulted in a dense fibrin network over the entire surface on SLActive-H(phil)NS but only in single patches of fibrin and small isolated fibre complexes on SLA-H(phob). On SLActive-H(phil)NS, the number of HBCs attaching to the fibrin network was greatly increased and the cells displayed enhanced cell contact to the fibrin network. Notably, HBCs displayed increased expression of the osteogenic marker proteins alkaline phosphatase and collagen-I when cultivated on both surfaces upon blood pre-incubation. Additionally, blood pre-treatment promoted an earlier and enhanced mineralization of HBCs cultivated on SLActive-H(phil)NS compared to SLA-H(phob). The results presented in this study therefore suggest that blood pre-incubation of implant surfaces mimics a more physiological situation, eventually providing a more predictive in vitro model for the evaluation of novel bone implant surfaces. PMID- 25818949 TI - Hyaluronic acid decreases IL-6 and IL-8 secretion and permeability in an inflammatory model of interstitial cystitis. AB - Hyaluronic acid (HA) has received a lot of attention recently as a biomaterial with applications in wound healing, drug delivery, vascular repair and cell and/or gene delivery. Interstitial cystitis (IC) is characterised by an increase in the permeability of the bladder wall urothelium due to loss of the glycosaminoglycan (GAG) layer. The degradation of the urothelium leads to chronic pain and urinary dysfunction. The aetiology of the degradation of the GAG layer in this instance is currently unknown. At a clinical level, GAG replacement therapy using a HA solution is currently utilised as a treatment for IC. However, there is a significant lack of data on the mechanism of action of HA in IC. The current study investigates the mechanistic effect of clinically relevant HA treatment on an in vitro model of IC using urothelial cells, examining cytokine secretion, GAG secretion and trans-epithelial permeability. This study demonstrates that HA can significantly decrease induced cytokine secretion (4-5 fold increase), increase sulphated GAG production (2-fold increase) and without altering tight junction expression, decrease trans-epithelial permeability, suggesting that the HA pathway is a clinical target and potential treatment vector. PMID- 25818950 TI - Development of Ti-Nb-Zr alloys with high elastic admissible strain for temporary orthopedic devices. AB - A new series of beta Ti-Nb-Zr (TNZ) alloys with considerable plastic deformation ability during compression test, high elastic admissible strain, and excellent cytocompatibility have been developed for removable bone tissue implant applications. TNZ alloys with nominal compositions of Ti-34Nb-25Zr, Ti-30Nb-32Zr, Ti-28Nb-35.4Zr and Ti-24.8Nb-40.7Zr (wt.% hereafter) were fabricated using the cold-crucible levitation technique, and the effects of alloying element content on their microstructures, mechanical properties (tensile strength, yield strength, compressive yield strength, Young's modulus, elastic energy, toughness, and micro-hardness), and cytocompatibilities were investigated and compared. Microstructural examinations revealed that the TNZ alloys consisted of beta phase. The alloy samples displayed excellent ductility with no cracking, or fracturing during compression tests. Their tensile strength, Young's modulus, elongation at rupture, and elastic admissible strain were measured in the ranges of 704-839 MPa, 62-65 GPa, 9.9-14.8% and 1.08-1.31%, respectively. The tensile strength, Young's modulus and elongation at rupture of the Ti-34Nb-25Zr alloy were measured as 839 +/- 31.8 MPa, 62 +/- 3.6 GPa, and 14.8 +/- 1.6%, respectively; this alloy exhibited the elastic admissible strain of approximately 1.31%. Cytocompatibility tests indicated that the cell viability ratios (CVR) of the alloys are greater than those of the control group; thus the TNZ alloys possess excellent cytocompatibility. PMID- 25818951 TI - A systematic review of nutrition-based practices in prevention of hypertension among healthy youth. AB - The aim of this systematic review was to analyze the results of observational and interventional research/studies on nutrition-based practices in the prevention of hypertension among healthy youth. The MEDLINE/PubMed database was searched using the key words, "hypertension," "nutrition/diet," "prevention" and "youth." Inclusion criteria were: 1) sample with a majority of adolescents, defined as 10 24 years of age, or findings for adolescents reported separately from other age groups; 2) primary research reports; 3) studies with normotensive participants; and 4) studies that focused on preventing hypertension/lowering blood pressure through at least one nutritional practice. Results of the analysis indicated that increased consumption of unsaturated fats, fruits, vegetables and low-fat dietary products, decreased consumption of dietary sodium and beverages containing caffeine, and breastfeeding were found to have preventive effects against high blood pressure in later years of life. The effects of training given during youth to encourage a healthy lifestyle and behavior changes based on diet and physical activity were also noted. PMID- 25818952 TI - Accuracy of HLA-DQ genotyping in combination with IgA anti-tissue transglutaminase serology and a "scoring system" for the diagnosis of celiac disease in Turkish children. AB - The aim of the study was to analyze the accuracy of (i) HLA-DQ typing and anti tissue transglutaminase antibodies immunoglobulin A (tTG-IgA) serology and (ii) a "simple scoring system" (SSS) for the diagnosis of celiac disease (CD). The study included 91 patients with positive tTG-IgA, who had been tested for HLA-DQ. Patients were divided into 3 groups: typical CD, atypical CD, and non-CD. The sensitivity, specificity, positive (PPV) and negative predictive value (NPV), positive (PLR) and negative likelihood ratio (NLR) and accuracy of the test combining genotyping and tTG-IgA positivity and the simple scoring system for the diagnosis of CD were evaluated. The combination of genotyping and strong tTG-IgA positivity had a sensitivity of 93.5%, specificity of 61.5%, PPV of 93.5%, NPV of 61.5%, PLR of 2.4, NLR of 0.1 and accuracy of 89% for "CD." SSS had a higher specificity (84.6%), higher PPV (97.3%), higher NPV (68.7%), higher PLR and higher accuracy (92.3%). The combination of genotyping and strong tTG-IgA positivity missed two patients with typical CD (4%) and three patients with atypical CD (10.7%). Two cases with malabsorptive symptoms (33.3%) and three patients without malabsorptive symptoms (42.8%) would have been misdiagnosed as CD if these tests were used. Intestinal biopsy is still mandatory for diagnosis of CD in Turkish children. PMID- 25818953 TI - Viral etiology of acute lower respiratory tract infections in hospitalized young children in a children's referral hospital in Iran. AB - Viruses are considered major causes of acute respiratory tract infections among children under 5 years old. In this study we investigated the prevalence of three respiratory viruses--respiratory syncytial virus (RSV), influenza virus (INF) and adenovirus (ADV)--among hospitalized children with acute viral lower respiratory tract infections (LRTIs). Nasopharyngeal aspirates were collected from children under five who had been hospitalized for LRTIs. The clinical data, including demographic data (age and sex), vital symptoms and signs at admission, duration of fever, duration of hospitalization, chest X-ray findings and outcome were considered. All inpatient specimens were tested by reverse transcriptase polymerase chain reaction (RT-PCR) for RSV and the INF-A, INF-B and parainfluenza viruses and by polymerase chain reaction (PCR) for ADV. Out of those from 232 patients, 58 (25%) specimens were positive for either RSV, INF or ADV. The most predominant pathogens were RSV (40 cases, 17.2%), followed by INF (10 cases, 4%; including 8 type A and 2 type B) and ADV (8 cases, 3.4%). A total of 32 (55.1%) viral cases were identified in the spring, followed by 19 (32.7%) in the autumn and 7 (12%) in the winter. There was no significant correlation between clinical symptoms and the individual virus detected. In our study, RSV and INF were the two most common causes of LRTIs. These data are helpful for guiding the development of further vaccines as well as the use of antiviral drugs. Further studies will be needed to investigate other respiratory viruses such as parainfluenza, human metapneumovirus and rhinovirus. PMID- 25818954 TI - Molecular epidemiology and antibiotic susceptibility pattern of Acinetobacter baumannii isolated from children in a Turkish university hospital. AB - The aim of the present study is to investigate the types of healthcare-associated infections (HC-AIs) caused by Acinetobacter baumannii and the related antibiotic susceptibility patterns as well as the genotypic characteristics of the Acinetobacter baumannii isolates from our center. Sixty-nine Acinetobacter baumannii isolates originating from various samples collected from 69 pediatric patients during their hospital stays were included in the study. The types of healthcare-associated infections caused by these isolates were evaluated, and the antibiotic susceptibility pattern and the genotypic characteristics of the isolates were determined using the pulsed-field gel electrophoresis (PFGE) method. Fifty of the 69 children were observed to have HC-AIs, and 19 children had Acinetobacter baumannii colonization. Healthcare-associated pneumonia (58%) was the most common type of these infections. The rate of carbapenem resistance was found as 91.3%, while tigecycline resistance was found as 18.84%. No colistin resistance was observed in any of the isolates. A total of 10 groups, comprising eight major and two minor groups, were determined using the pulsed-field gel electrophoresis method. Acinetobacter baumannii isolates are the leading cause of healthcare-associated infections, and they show high rates of multidrug antibiotic resistance. Molecular epidemiological evaluation using PFGE plays an important role in preventing healthcare-associated infections. PMID- 25818955 TI - Placental findings of IUGR and non-IUGR. AB - This study aims to define the placental findings in intrauterine growth restriction (IUGR). The study group consisted of 40 neonates without IUGR and 24 neonates with IUGR, including their placentas. The cases were separated into three groups according to gestational age. Group A (n=21): 37 <= weeks, Group B (n=27): 32<= - <37 weeks, Group C (n=16): < 32 weeks. Each group had two subgroups, IUGR and non-IUGR. The placentas from the non-IUGR subgroup were heavier than the IUGR subgroup placentas in the term group (p<0.05). Infarct (over 5%), increased syncytial knots and histiocytic intervillositis were more common in the IUGR cases (p<0.05). This study shows that chronic patterns of injury are significantly increased in placentas from pregnancies complicated by IUGR. If the injury in the placenta is acute or mild, fetal adaptation can compensate and prevent fetal growth restriction. PMID- 25818956 TI - Development of a screening tool for children prior to school entrance. AB - The present study describes the development, application and validation of the Alpha' TEST, a screening tool administered individually to kindergarten children to determine their school preparedness. The A' TEST evaluates six cognitive domains (abstract thinking, critical reasoning, language skills, visual perception, visual motor skills and organizational skills). It was administered to 2002 preschool children, and validated through comparison with well established classification systems. Also, in order to examine the predictive value of the A' TEST, 201 of the examined children were reevaluated by their teachers two years after initial assessment. Analysis provided evidence of structure, convergent, concurrent and discriminant validity and reliability, as well as predictive validity. Overall, the Alpha' TEST predicted that 9.1% of the children were not school-ready, giving a 98.5% correct prediction when compared with the teachers' evaluations two years later. In conclusion, the Alpha' TEST is a valid and appropriate screening tool for school readiness. PMID- 25818957 TI - Safety assessment of essential and toxic metals in infant formulas. AB - The aim of this study was to assess toxic metal (Cd, Pb and Al) contamination and levels of three essential trace elements (Mn, Cr and Co) in 63 infant formulas. In addition, the levels of these metals in the study samples were compared with the acceptable limits of toxic heavy metals and the recommended daily allowances (RDAs) of essential trace elements. According to our results, the toxic metal levels measured in the formulas were within the acceptable limits, with the exception of Al levels in 8 of the 63 samples. In 16 samples, Mn levels exceeded 600 MUg/day, and the Cr content in 7 samples was higher than 5.5 MUg/day, these amounts being the adequate intake levels for infants. Cobalt levels in 10 formulas were higher than the RDA. In view of these findings, which indicate that metal levels in infant formulas are generally much higher than those found in breast milk, breast milk should be preferred for infant feeding. Moreover, since infants are potentially more susceptible to metals, infant foods should be monitored regularly and checked for contamination by toxic metals as well as for levels of essential trace elements. PMID- 25818958 TI - Another face of Kawasaki disease. AB - We aimed both to define the characteristics of patients with Kawasaki Disease (KD), and to highlight infrequent and unusual findings of the disease by presenting selected cases. We retrospectively evaluated 35 patients diagnosed with KD in our clinic between January 1994 and January 2013. The male to female ratio was 1.33 and the median age at admission was 22 months (1.5-132 months). Fourteen patients (40%) had coronary artery lesions (CAL). Twenty-five cases (72%) had complete and 10 cases (28%) had incomplete KD; the incidence of CAL in these groups was 36% and 50%, respectively. Two patients had giant coronary aneurysms. Six cases received a second dose of intravenous immunoglobulin, and one patient received pulse methylprednisolone. Seven cases had unusual and/or infrequent presentation patterns and/or follow-up. Physicians should be aware of all symptoms and laboratory findings of KD in order to avoid any delays in diagnosis and decrease the risk of life-threatening complications. PMID- 25818959 TI - Development of fatty liver in children with non-Hodgkin lymphoma. AB - The aim of this study is to investigate the development of hepatosteatosis in children with non-Hodgkin lymphoma. Twenty-eight patients were evaluated retrospectively for hepatosteatosis by computed tomography. Mild, moderate and severe hepatosteatosis were defined as the difference between the average liver attenuation and the average spleen attenuation, equaling (-10)-(-19); (-20)-( 29); and >=30 HU, respectively. "Vaguely" and "obvious" hepatosteatosis were defined as none or mild hepatosteatosis, and moderate and severe hepatosteatosis, respectively. In T-cell lymphoma, obvious hepatosteatosis was determined in 1 of 12 patients (8.3%) at the first evaluation, 8 of 12 patients (66.7%) at the second evaluation and 4 of 12 patients (33.3%) at the third evaluation. In B-cell lymphoma, obvious hepatosteatosis was determined in none of 16 patients at the first evaluation, 2 of 16 patients (12%) at the second evaluation and none of the patients at the third evaluation. In the second evaluation, severe high serum total cholesterol and triglyceride levels were determined in 4 of 5 patients. We observed higher fatty liver ratios, and high triglyceride and cholesterol levels, although the data were obtained from a small number of patients. PMID- 25818960 TI - Hearing stimulation of the pediatric patient with congenital aural atresia: surgical and audiological evaluation of 38 patients. AB - The aim of this work is to stress the importance of and discuss the timing and options for the treatment of congenital aural atresia (CAA), including non surgical alternative treatment modalities and amplification, and to report the audiological and surgical results of a series of patients. Thirty-eight children with CAA were evaluated with regard to hearing and anatomical anomalies accompanying CAA: the state of the ossicles and the facial nerve, postoperative complications and audiological results. The ages of the patients ranged between 4 and 18 years, with a mean of 10 years. All underwent surgical treatment; 32 had unilateral atresia, while 6 had bilateral atresia. The mean follow-up duration was 7 months. The facial canal was dehiscent in 36.8% of cases. In 70.2% cases, the malleus and incus were present as an ossicular mass, fixed and attached to the atretic bone. The stapes was normal in 97.3% of the patients; in 2.7% the suprastructure was deformed. The success rate, defined as an air-bone gap of 20 dB or less, was 63.1% in this series of patients. If atresia is bilateral, very early hearing stimulation to prevent the maldevelopment of children's speech and cognitive skills is of the utmost importance. In unilateral cases, surgery may be postponed until early adulthood, when the patient is able to make his/her own decision and cooperate in the treatment and postoperative aspects. PMID- 25818961 TI - Efficacy of topical 0.05% cyclosporine treatment in children with severe vernal keratoconjunctivitis. AB - We aimed to determine the efficacy of topical cyclosporine in children with vernal keratoconjunctivitis refractory to topical mast cell stabilizer and antihistamine therapy. Thirty-one patients, 24 boys and 7 girls younger than 16 years of age, were included in the study. All patients were scored on a four point scale from 0 to 3 for symptoms and signs. Each patient received topical cyclosporine 0.05% emulsion (Restasis, Allergan Inc., Irvine, CA, USA) four times daily in addition to preservative-free artificial tears and was followed for 6 months. The data was recorded before the initiation of treatment (day 0) and at the 1st, 3rd, and 6th months following treatment. After six months of treatment, severity of all symptoms and signs showed a statistically significant decrease (p<0.05). Patients did not report any serious adverse effects. Topical cyclosporine 0.05% emulsion treatment is a safe and effective treatment option for controlling the symptoms and signs of vernal keratoconjunctivitis in children. PMID- 25818962 TI - Neonatal multiple sulfatase deficiency with a novel mutation and review of the literature. AB - Multiple sulfatase deficiency is a rare autosomal recessive disorder in which affected individuals present a complex phenotype due to the impaired activity of all sulfatases. There are different types of multiple sulfatase deficiency; among them, the neonatal form is the most severe, with a broad range of mucopolysaccharidosis-like symptoms and death within the first year of life. The disorder is caused by homozygous or compound heterozygous mutations in the sulfatase-modifying factor-1 (SUMF1) gene. In this article, we describe a non ichthyotic neonatal multiple sulfatase deficiency patient with a novel mutation in the SUMF1 gene. The missense mutation c.777C>G, for which the patient was homozygous, had been caused by a p.N259K amino acid substitution. We evaluated the patient using clinical findings, neuroimaging studies and molecular analysis via the literature; we also wanted to note the difficulties in the diagnosis of this rare disease. PMID- 25818963 TI - Diverse phenotypic expression of NPHP4 mutations in four siblings. AB - Nephronophthisis (NPHP) is an autosomal recessive disease characterized by renal tubular basement membrane disruption, interstitial fibrosis and tubular cysts that progresses to end-stage kidney disease (ESKD). There are also characteristic extrarenal manifestations. Mutations of more than thirteen genes that can cause NPHP have been identified. We herein report four siblings from a consanguineous family, who carried the same NPHP4 mutations but presented with different disease phenotypes ranging from enuresis nocturna to ESKD. Diluted urine and echogenic kidneys in ultrasound examination were consistent, which is typical for 100% of the NPHP cases that have been described. Chronic kidney disease developed in the older two brothers. The observed phenotypic differences are likely to be related to environmental and epigenetic factors, oligogenic inheritance and modifier genes affecting the age of presentation of signs and symptoms. NPHP should be considered as an important cause of CKD in children, which insidiously progresses to ESKD, with no specific therapy available. PMID- 25818964 TI - Hypotonic hyporesponsive episode and the 13-valent pneumococcal vaccine. AB - Hypotensive-hyporesponsive episodes are rare events after immunizations performed for diphtheria, tetanus, Haemophilus influenzae type b and hepatitis B virus vaccines, but most of the reported episodes have been associated with pertussis containing vaccines. We report the case of a 3-month-old girl, previously healthy otherwise, presenting with the unusual event of a hypotonic-hyporesponsive episode after vaccination with the 13-valent pneumococcal vaccine. Diagnosis was established after a thorough evaluation of the patient and by exclusion of other clinical conditions. PMID- 25818965 TI - A case of fucosidosis type II: diagnosed with dysmorphological and radiological findings. AB - Fucosidosis is a rare autosomal recessive lysosomal storage disorder in which fucose-containing glycolipids, glycoproteins and oligosaccharides accumulate in tissues, as a result of a deficiency of alpha-L-fucosidase. In this report we describe clinical, dysmorphological and radiological findings of a boy with this disorder. Developmental delay, skeletal deformities and mild coarsening of the face began at two years of age. Clinical signs typical for fucosidosis evolved over time. Psychomotor deterioration progressed slowly. At age 12, he could not walk without help; he was admitted to the hospital with intellectual disability, short stature and coarse facial features. A skeletal survey showed dysostosis multiplex. Cranial MRI demonstrated high intensities on the periventricular white matter and low intensities on the basal ganglia on T2-weighted images. Despite the absence of angiokeratoma on the skin, type II fucosidosis with clinical, dysmorphological and radiological signs was suspected. The diagnosis was established on the basis of severely decreased activity of alpha-L-fucosidase in the leukocytes. The natural history and specific dysmorphic and radiological findings should, even in the absence of angiokeratoma, assist in the differential diagnosis of this rare condition when lysosomal storage disorders are suspected, particularly in populations in which consanguineous marriages are common. PMID- 25818966 TI - An uncommon disorder with multiple skeletal anomalies: Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome is an uncommon disorder transmitted through autosomal dominant inheritance. This syndrome is characterized by multiple odontogenic keratocysts, along with congenital skeletal anomalies and basal cell carcinomas. A 16-year-old girl was admitted with a complaint of swelling on the lower jaw. She had multiple basal cell nevi on both hands. Multiple lytic bone lesions on radiographs were defined as odontogenic keratocysts following the biopsy. The patient was referred to the Department of Physical Medicine and Rehabilitation for detailed musculoskeletal evaluation. Adam's forward bend test revealed a hump on the right side representing right thoracic scoliosis. Cervical kyphosis, thoracic lordosis and scoliosis, bifid rib and sacral and lumbar spina bifida on plain radiographs led to the diagnosis of Gorlin-Goltz syndrome. Since early diagnosis may provide optimum surveillance for related neoplasms, it is of paramount importance for pediatricians as well as physicians dealing with the musculoskeletal system to be aware of this rare condition. PMID- 25818967 TI - A rare cause of aeroallergen-induced anaphylaxis: horse allergy. AB - Animal epithelia and saliva contain a substantial amount of aeroallergen material, causing both acute onset of symptoms related to hypersensitivity, and chronic inflammation of the airways leading to allergic rhinitis or asthma. Although allergy to horses is generally considered to be more prevalent in rural areas, sensitization to horse allergens is more frequent than might be expected in urban residents without any direct or occupational exposure to horses. However, horse allergy is seldom mentioned among animal-induced allergic reactions. Anaphylaxis due to horse exposure is reported even more rarely. Here, a pediatric patient with a hypersensitivity reaction after horse allergen exposure is reported, and the definition of the type of reaction is discussed, as it may be the whole set of locally induced multisystemic reactions that resembles anaphylaxis. PMID- 25818968 TI - A rare cause of congenital diarrhea in a Turkish newborn: tufting enteropathy. AB - Tufting enteropathy is an autosomal recessive congenital enteropathy presenting with early-onset severe intractable diarrhea. It presents with watery diarrhea that develops in the first days after birth and persists despite bowel rest. Growth is impaired, and most patients require total parenteral nutrition. The histological characteristic of tufting enteropathy is the presence of epithelial tufts. We hereby present a patient who was referred to our neonatal intensive care unit because of chronic diarrhea and diagnosed with tufting enteropathy according to histological examination. To the best of our knowledge, the newborn case presented here is the first one reported from Turkey. As TE is a very rare disease, it should be considered in patients with continuing diarrhea beginning in the first days of life. PMID- 25818969 TI - Chronic eosinophilic leukemia with monosomy 8 in a five-year-old girl: a rare case. AB - A 5-year-old girl was admitted to our hospital due to fatigue and fever lasting for six months. She had systolic murmur in the mesocardiac and apex regions and hepatosplenomegaly. Laboratory evaluation revealed leukocyte and eosinophil counts of 176 and 144.32 x 10(9)/L, 3.4% blasts in bone marrow and monosomy 8. She developed pulmonary, cardiac, nervous system, ocular and bone involvement. Upon diagnosis of "chronic eosinophilic leukemia, not otherwise specified" (WHO 2008 classification), she received methylprednisolone, vincristine, cytarabine and 6-thioguanine. After hematopoietic stem cell transplantation from a full matched sibling was performed, the patient expired due to graft failure and septicemia. PMID- 25818970 TI - Hemophagocytic lymphohistiocytosis arising in a child with Langerhans cell histiocytosis. AB - Langerhans cell histiocytosis (LCH) is characterized by the proliferation of clonal dendritic cells, while hemophagocytic lymphohistiocytosis (HLH) is an extreme inflammatory process sustained by the uncontrolled activation of macrophages. HLH can be primary or secondary, the latter arising in infectious, autoimmune or neoplastic disorders. We hereby present a young girl who developed secondary HLH while being treated for relapsed multisystem LCH under the LCH III Protocol. She fulfilled 5 of 8 HLH-2004 criteria (fever, splenomegaly, pancytopenia, ferritin level >500 MU/l and sIL-2R >2400 IU/ml) and was successfully treated by the HLH-2004 Protocol for secondary HLH. She remains in good health, apart from insipid diabetes she developed as a complication of LCH. Considering that the occurrence of HLH in LCH patients has been reported before, the case history presented here yields additional support for the hypothesis that the pathogenesis of the two histiocytoses--LCH and HLH--may indeed overlap to a considerable extent. PMID- 25818971 TI - Development of end-stage renal disease at a young age in two cases with Joubert syndrome. AB - Joubert syndrome (JS) is an autosomal recessive genetic disorder. To date, mutations in 20 genes of the genetically heterogeneous JS and JS-related disorders (JSRD) have been reported. Renal involvement occurs in 2-20% of JS cases. Identified renal abnormalities are cystic dysplasia and nephronophthisis. Here we report the clinical course and management of renal failure in early childhood. We present two cases diagnosed with JS that developed end-stage renal disease at young ages. In the genetic studies, a c.5668G>T (p.G1890*) homozygous stop mutation was identified in the CEP290 gene of one of the patients and a c.1303C>G (p.R435G) homozygous mutation in the INPP5E gene of the other. It has been emphasized that it is important to evaluate patients in terms of renal disease when monitoring the progress of Joubert syndrome, a condition that predominantly causes mental and motor development retardation. PMID- 25818972 TI - Neonate born to hepatitis B carrier mother presenting with congenital onychodysplasia of the index finger (Iso-Kikuchi syndrome). PMID- 25818973 TI - Controversy regarding paracetamol- and codeine phosphate-induced acute tubulointerstitial nephritis-uveitis (TINU) syndrome. PMID- 25818974 TI - Reply: To PMID 24827955. PMID- 25818975 TI - Ultrasonographic measurement of the subclavian vein diameter for assessment of intravascular volume status in patients undergoing gastrointestinal surgery: comparison with central venous pressure. AB - BACKGROUND: Previous studies have demonstrated that ultrasonographic measurement of the inferior vena cava diameter is a useful tool for the evaluation of intravascular volume status in preoperative patients. However, ultrasonographic measurement of inferior vena cava diameter could be limited by factors including obesity, bowel gas, or complex abdominal wounds. Our study sought to determine whether subclavian vein (SCV) diameter measured by ultrasound correlate with central venous pressure (CVP), as another indicator of intravascular volume status in patients undergoing gastrointestinal surgery. METHODS: Forty patients (American Society of Anesthesiologists I-II) who underwent elective gastrointestinal surgery and 40 healthy volunteers were enrolled in the study. In the patient group, SCV diameters, during both expiration (dSCVe) and inspiration (dSCVi), were measured with ultrasonography before and after fluid resuscitation. Volunteer baseline measurements were conducted without liquid therapy and the subsequent measurement. RESULTS: Forty patients (mean age 46 y; 40% female) and 40 volunteers (mean age 43 y; 45% female) underwent SCV sonographic measurements. The average diameters of the SCVe and SCVi in hypovolemic patients (0.68, 0.48 cm) were significantly lower as compared with the SCVe and SCVi diameters of healthy volunteers (0.92, 0.73 cm), whereas the SCV-collapsibility index (0.35) was higher in the hypovolemic patients as compared with the healthy volunteers (0.20). After fluid resuscitation, the SCVe and SCVi diameters in hypovolemic patients (0.88, 0.67 cm) significantly increased, whereas the SCV-collapsibility index decreased (0.23). The pre-SCVe and the post-SCVe were closely correlated to the CVP (R = 0.612 and R = 0.547, respectively). Similarly, the pre-SCVi and the post-SCVi were correlated to the CVP (R = 0.452 and R = 0.507, respectively). CONCLUSIONS: SCV diameter is consistently low in patients undergoing gastrointestinal surgery as compared with healthy subjects. Measuring the SCV diameter maybe an important addition to the ultrasonographic evaluation of hypovolemia and other potentially volume-depleted patients. PMID- 25818976 TI - Isoperistaltic versus antiperistaltic stapled side-to-side anastomosis for colon cancer surgery: a randomized controlled trial. AB - BACKGROUND: Isoperistaltic stapled side-to-side anastomosis (SSSA), which is a modified technique from conventional antiperistaltic SSSA, has the benefits of antiperistaltic SSSA but requires less intestinal mobility. The aim of this randomized controlled trial was to evaluate short-term outcomes of isoperistaltic SSSA comparing them with antiperistaltic SSSA during colon cancer surgery. MATERIALS AND METHODS: We conducted a randomized controlled trial of patients with colon cancer who underwent elective curative resection and had enough intestinal mobility at anastomosis. The primary outcome was the presence of anastomotic failure, including leakage, hemorrhage, and stenosis. RESULTS: Between July 2012 and January 2014, forty patients were enrolled (20 patients in each group). The study was suspended on detecting excess morbidity in the isoperistaltic SSSA group. No significant differences were observed in all preoperative backgrounds between the two groups. Anastomotic leakage was seen in two patients in the isoperistaltic SSSA group, compared with none in the antiperistaltic SSSA group, although the difference was not statistically significant (P = 0.487). One patient in the antiperistaltic SSSA group had anastomotic stenosis, which improved conservatively, compared with none in the isoperistaltic SSSA group (P = 1.000). No anastomotic hemorrhage was seen in either group. There was no significant difference in the median postoperative hospital stay (P = 0.313). CONCLUSIONS: This study did not show any short-term advantage or disadvantage of isoperistaltic SSSA compared with that of antiperistaltic SSSA. However, considering that anastomotic leakage occurred only in the isoperistaltic SSSA group, additional modifications are recommended to perform safe isoperistaltic SSSA for colon surgery. PMID- 25818977 TI - Recombinant human augmenter of liver regeneration protects hepatocyte mitochondrial DNA in rats with obstructive jaundice. AB - BACKGROUND: Hepatocyte mitochondrial DNA (mtDNA) damage is an important cause of mitochondrial and hepatic function impairment in obstructive jaundice (OJ). This study investigated the protective effect of recombinant human augmenter of liver regeneration (rhALR) on hepatocyte mtDNA in rats with OJ. MATERIALS AND METHODS: Wistar rats were randomly divided into three groups as follows: sham-operation, biliary obstruction and recanalization with rhALR treatment (BDO-RBF-rhALR), and BDO-RBF-Vehicle (n = 48 per group). After biliary obstruction, rats were intraperitoneally injected with 40 MUg/kg rhALR in BDO-RBF-rhALR group and same volume of normal saline in other two groups once every 12 h, until sacrifice. Mitochondrial transcription factor A (mtTFA) and nuclear respiratory factor-1 (NRF-1) expression in hepatocytes were detected by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte mtDNA damage was evaluated by real-time-polymerase chain reaction. Mitochondrial and hepatic functions were also assessed. RESULTS: After biliary obstruction, hepatic function was clearly impaired, as shown by the increases in serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels, and the decrease in albumin level. Mitochondrial respiratory control ratio, phosphorus oxygen ratio, and ATP levels (all indicators of mitochondrial function) were decreased. The relative amount of total mtDNA, mtTFA, and NRF-1 expression in rat liver tissues were decreased, whereas the relative amount of deleted mtDNA was increased. However, the damage was significantly improved in the BDO-RBF-rhALR group. After recanalization, these changes were gradually restored, but the recovery was faster in the BDO-RBF-rhALR group than in BDO-RBF-Vehicle group. CONCLUSIONS: rhALR may protect and improve mitochondrial and hepatic functions in rats with OJ by promoting the expression of mtTFA and NRF-1 and by protecting and repairing damaged mtDNA. PMID- 25818978 TI - Hydrogen gas inhibits high-mobility group box 1 release in septic mice by upregulation of heme oxygenase 1. AB - BACKGROUND: Sepsis is a potentially fatal whole-body inflammation caused by severe infection. Hydrogen gas (H2) is effective for treating sepsis. In this study, we hypothesized that the protective function of H2 in mice with septic lung injury occurred through the activation of heme oxygenase 1 (HO-1) and its upstream regulator nuclear factor-erythroid 2 p45-related factor 2 (Nrf2). MATERIALS AND METHODS: Male institute of cancer research mice were subjected to sepsis by cecal ligation and puncture (CLP) with the presence or absence of H2. Beginning at 1 and 6 h after CLP or sham operation, respectively, 2% H2 was inhaled for 1 h. We intraperitoneally injected the HO-1 inhibitor zinc protoporphyrin IX (40 mg/kg) 1 h before CLP. To assess the severity of septic lung injury, we observed the 7-d survival rate, wet/dry weight ratio of lung, lung histopathologic score, oxygenation index, and so forth. Serum and homogenates from the lung, liver, and kidney were acquired for measuring the levels of high-mobility group box 1 (HMGB1) at 6, 12, and 24 h after CLP or sham operation. Furthermore, the protein and messenger RNA expression of Nrf2, HO-1, and HMGB1 was measured at 6, 12, and 24 h. RESULTS: Septic mice had a lower survival rate and more severe lung injury compared with the sham group. However, therapy with H2 increased the survival rate and alleviated the severity of lung injury, reduced the HMGB1 level, and increased the HO-1 and Nrf2 levels in septic mice. Moreover, the HO-1 inhibitor zinc protoporphyrin IX significantly eliminated the protective effect of H2 on septic lung injury. CONCLUSIONS: H2 plays a significant role in regulating the release of the inflammatory cytokine HMGB1 in septic mice, which is partially mediated through the activation of HO-1 as a downstream molecule of Nrf2. PMID- 25818979 TI - Epidermal growth factor mediated healing in stem cell-derived vocal fold mucosa. AB - BACKGROUND: The goal of vocal fold wound healing is the reconstitution of functional tissue, including a structurally and functionally intact epithelium. Mechanisms underlying reepithelialization in vocal folds are not known, although it is suspected that healing involves the interplay between several growth factors. We used a three-dimensional human embryonic stem cell-derived model of vocal fold mucosa to examine the effects of one growth factor, exogenous epidermal growth factor (EGF), on wound healing. MATERIALS AND METHODS: A scratch wound was created in the in vitro model. Rate of wound healing, epidermal growth factor receptor (EGFR) activation, and cell proliferation after injury were analyzed with and without application of both exogenous EGF and an EGFR inhibitor, gefitinib. RESULTS: Wound repair after injury was significantly hastened by application of exogenous EGF (13.3 MUm/h, +/- 2.63) compared with absence of exogenous EGF (7.1 MUm/h +/- 2.84), but inhibited with concurrent addition of Gefitinib (5.2 MUm/h, +/- 2.23), indicating that EGF mediates wound healing in an EGFR-dependent manner. Immunohistochemistry revealed that EGFR activation occurred only in the presence of exogenous EGF. Although not statistically significant, increased density of Ki67 staining in the epithelium adjacent to the scratch wound was observed after treatment with EGF, suggesting a tendency for exogenous EGF to increase epithelial cell proliferation. CONCLUSIONS: Exogenous EGF increases the rate of wound healing in an EGFR dependent manner in a three-dimensional stem cell-derived model of vocal fold mucosa. This model of wound healing can be used to gain insight into the mechanisms that regulate vocal fold epithelial repair after injury. PMID- 25818980 TI - Surgeon and nonsurgeon personalities at different career points. AB - BACKGROUND: Previous studies have demonstrated correlations between personality traits and job performance and satisfaction. Evidence suggests that personality differences exist between surgeons and nonsurgeons, some of which may develop during medical training. Understanding these personality differences may help optimize job performance and satisfaction among surgical trainees and be used to identify individuals at risk of burnout. This study aims to identify personality traits of surgeons and nonsurgeons at different career points. MATERIALS AND METHODS: We used The Big Five Inventory, a 44-item measure of the five factor model. Personality data and demographics were collected from responses to an electronic survey sent to all faculty and house staff in the Departments of Surgery, Medicine, and Family Medicine at The Ohio State University College of Medicine. Data were analyzed to identify differences in personality traits between surgical and nonsurgical specialties according to level of training and to compare surgeons to the general population. RESULTS: One hundred ninety-two house staff and faculty in surgery and medicine completed the survey. Surgeons scored significantly higher on conscientiousness and extraversion but lower on agreeableness compared to nonsurgeons (all P < 0.05). Surgery faculty scored lower in agreeableness compared with that of surgery house staff (P = 0.001), whereas nonsurgeon faculty scored higher on extraversion compared with that of nonsurgeon house staff (P = 0.04). CONCLUSIONS: There appears to be inherent personality differences between surgical and nonsurgical specialties. The use of personality testing may be a useful adjunct in the residency selection process for applicants deciding between surgical and nonsurgical specialties. It may also facilitate early intervention for individuals at high risk for burnout and job dissatisfaction. PMID- 25818981 TI - Protective effect of oroxylin A against lipopolysaccharide and/or D-galactosamine induced acute liver injury in mice. AB - BACKGROUND: Oroxylin A, a natural flavonoid isolated from Scutellariae baicalensis, has been reported to possess a wide spectrum of pharmacologic activities. However, the effects of oroxylin A on liver injury are poor understood. The purpose of this study was to investigate the effects of oroxylin A on acute liver injury in mice induced by lipopolysaccharide and/or D galactosamine (LPS and/or D-GalN). METHODS: Mice acute liver injury model was induced by LPS (50 MUg/kg) and/or GalN (800 mg/kg). Serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha levels, hepatic tissue histology, malondialdehyde content, and myeloperoxidase activity were analyzed. Meanwhile, nuclear factor kappa B (NF-kappaB), heme oxygenase-1 (HO-1), and nuclear factor erythroid2-related factor 2 (Nrf2) expression were detected by Western blotting. RESULTS: The results showed that oroxylin A dose-dependently inhibited LPS and/or GalN-induced serum alanine aminotransferase, aspartate aminotransferase, and tumor necrosis factor-alpha levels. Hepatic malondialdehyde content and myeloperoxidase activity were also suppressed by oroxylin A. We also found that oroxylin A inhibited LPS and/or GalN induced toll like receptor 4 (TLR4) expression and NF-kappaB activation. In addition, oroxylin A upregulated the expression of Nrf2 and HO-1 in a dose dependent manner. CONCLUSIONS: In conclusion, oroxylin A protected against LPS and/or GalN-induced liver injury through activating Nrf2 and inhibiting TLR4 signaling pathway. PMID- 25818982 TI - Editor's Choice - Minimizing Radiation Exposure During Endovascular Procedures: Basic Knowledge, Literature Review, and Reporting Standards. AB - CONTEXT: Endovascular procedures, requiring X-ray guidance, are commonly performed in vascular surgery. X-ray exposure is associated with biological risks for both patients and physicians. Medical X-ray use must follow "as low as reasonably achievable" (ALARA) principles, which aim at using the lowest radiation exposure to achieve a procedure safely. This is underlined by European and international recommendations that also suggest that adequate theoretical and practical training is mandatory during the initial education of physicians. However, the content of this education and professional practices vary widely from one country to another. OBJECTIVE: This review aims to summarize the basic knowledge required for vascular surgeons on X-ray physics and image production. METHODS: A panel of endovascular therapists (vascular surgeons and radiologists) and physicists dedicated to X-rays was gathered. International recommendations were summarized. A literature review was performed via MEDLINE to identify studies reporting dosages of common endovascular procedures. RESULTS: The different mechanisms inducing biological risks, and the associated potential effects on health, are described. Details on dose metrics are provided and a common nomenclature to measure, estimate, and report dose is proposed in order to perform accurate comparisons between publications and practices. Key points of the European and international legislation regarding medical X-ray use are summarized, and radiation protection basics for patients and staff, are detailed. Finally, a literature review is proposed for physicians to evaluate their practice. CONCLUSIONS: Today's trainees will be highly exposed to radiation throughout their practice. It is thus compulsory that they undergo dedicated radiation education during their initial training, and regular refresher sessions later. In daily practice, focus on dose reduction and monitoring of patient and staff exposure are mandatory. PMID- 25818983 TI - Conducting Slug Tests in Mini-Piezometers. AB - Slug tests performed using mini-piezometers with internal diameters as small as 0.43 cm can provide a cost effective tool for hydraulic characterization. We evaluated the hydraulic properties of the apparatus in a laboratory environment and compared those results with field tests of mini-piezometers installed into locations with varying hydraulic properties. Based on our evaluation, slug tests conducted in mini-piezometers using the fabrication and installation approach described here are effective within formations where the hydraulic conductivity is less than 1 * 10(-3) cm/s. While these constraints limit the potential application of this method, the benefits to this approach are that the installation, measurement, and analysis is cost effective, and the installation can be completed in areas where other (larger diameter) methods might not be possible. Additionally, this methodology could be applied to existing mini piezometers previously installed for other purposes. Such analysis of existing installations could be beneficial in interpreting previously collected data (e.g., water-quality data or hydraulic head data). PMID- 25818984 TI - The arsenic accumulation and its effect on oxidative stress responses in juvenile rockfish, Sebastes schlegelii, exposed to waterborne arsenic (As3+). AB - Juvenile rockfish (mean length 16.4 +/- 1.9 cm, and mean weight 71.6 +/- 6.4 g) were exposed for 20 days with the different levels of waterborne arsenic concentration (0, 50, 100, 200 and 400 MUg/L). The profile of As accumulation among tissue of rockfish is dependent on the exposure periods and As concentration. After 4 weeks, the highest accumulation of As was observed in the kidney, and the order of As accumulation in tissues was liver > kidney > spleen > gill > intestine > muscle. Generally, significant As accumulation increase in most tissues was observed at the higher concentration of 200 MUg/L waterborne As exposure, whereas there was no considerable increase in muscle except the concentration of 400 MUg/L at 20 days. In oxidative stress indicators, liver and gill superoxide dismutase (SOD) activity and glutathione-S-transferase (GST) activity were considerably increased after the 20 days exposure. Glutathione (GSH) level in liver and gill was also notably increased in response to the waterborne As exposure after 20 days. The results demonstrated that waterborne As exposure can induce considerable As accumulation in major tissues and alterations in antioxidant enzyme parameters of experimental fish, rockfish. PMID- 25818985 TI - Naringin attenuates the cytotoxicity of hepatotoxin microcystin-LR by the curious mechanisms to OATP1B1- and OATP1B3-expressing cells. AB - Microcystin-LR, which is an inhibitor of serine/threonine protein phosphatase (PP)1 and PP2A, induces liver injury by its selective uptake system into the hepatocyte. It is also thought that microcystin-LR induces reactive oxygen species (ROS). We tried to establish the chemical prevention of microcystin-LR poisoning. We investigated the effect of grapefruit flavanone glycoside naringin on cytotoxicity of microcystin-LR using human hepatocyte uptake transporter OATP1B3-expressing HEK293-OATP1B3 cells. We found cytotoxicity of microcystin-LR was attenuated by naringin in a dose dependent manner. The inhibition magnitude of total cellular serine/threonine protein phosphatase activity induced by microcystin-LR was suppressed by naringin. In addition, uptake of microcystin-LR into HEK293-OATP1B3 cells was inhibited by naringin. Furthermore, microcystin-LR induced phosphorylation of p53 was inhibited by naringin. Regardless of the difference in the exposure pattern of pre-processing and post-processing of naringin, the toxicity of microcystin-LR was comparable. These results suggested that naringin is promising remedy as well as preventive medicine for liver damage with microcystin-LR. In addition, involvement of ROS production after exposure to the sublethal concentrations of microcystin-LR in the onset of cytotoxicity was negligible. Therefore, inhibition of microcystin-LR uptake and the pathway other than ROS production would be involved in the effect of naringin on the attenuation of microcystin-LR toxicity. PMID- 25818986 TI - Esculetin induces death of human colon cancer cells via the reactive oxygen species-mediated mitochondrial apoptosis pathway. AB - The present study investigated the apoptotic effects of esculetin, a coumarin derivative, on the human colon cancer cell line HT-29. Esculetin had cytotoxic effects on HT-29 cells in a dose- and time-dependent manner; treatment with 55 MUg/mL esculetin reduced cell viability by 50%. Esculetin induced apoptosis, as evidenced by apoptotic body formation, an increased percentage of cells in sub-G1 phase, and DNA fragmentation. Moreover, esculetin increased mitochondrial membrane depolarization, released cytochrome c into cytosol, and modulated the expression of apoptosis-associated proteins, resulting in reduced expression of B cell lymphoma-2, increased expression of Bcl-2-associated X protein, and activation of caspase-9 and caspase-3. Esculetin induced the formation of reactive oxygen species; however, treatment with an antioxidant reduced the apoptotic cell death induced by esculetin treatment. In addition, esculetin activated mitogen-activated protein kinases and specific inhibitors of these kinases abrogated the reduction in cell viability induced by esculetin treatment. PMID- 25818987 TI - A persistently high body mass index increases the risk of atopic asthma at school age. AB - AIM: Being overweight has been associated with the risk of developing childhood asthma, but studies have produced conflicting results, for example with regard to possible links to allergic diseases. This study aimed to explore the relationship between body mass index (BMI) and school-age asthma. METHODS: Data were obtained from a prospective, longitudinal study of 5044 children born in western Sweden. The parents answered questionnaires at six months and one, four-and-a-half and eight years of age. The response rate to the final questionnaire at the age of eight was just over 80%. BMI was adjusted for age and gender, and a high BMI was defined as the 85th percentile and above. RESULTS: A multivariate analysis showed an independently increased risk of doctor-diagnosed asthma among children with a persistently high BMI, both in infancy and at school age, with an adjusted odds ratio (aOR) of 2.9 and a 95% confidence interval (CI) of 1.3-6.4. In addition, persistently high BMI was associated with an increased risk of atopic asthma (aOR 4.7, 95% CI 2.0-11.0). CONCLUSION: A persistently high BMI during childhood increased the risk of doctor-diagnosed asthma at school age. The increased risk of atopic asthma suggests an effect mediated via the immune system. PMID- 25818988 TI - Clinical features, therapy, and outcome of calciphylaxis in patients with end stage renal disease on renal replacement therapy: Case series. PMID- 25818989 TI - In-line phase-contrast and grating-based phase-contrast synchrotron imaging study of brain micrometastasis of breast cancer. AB - Current bio-medical imaging researches aim to detect brain micrometastasis in early stage for its increasing incidence and high mortality rates. Synchrotron phase-contrast imaging techniques, such as in-line phase-contrast (IPC) and grating-based phase-contrast (GPC) imaging, could provide a high spatial and density imaging study of biological specimens' 3D structures. In this study, we demonstrated the detection efficiencies of these two imaging tools on breast cancer micrometastasis in an ex vivo mouse brain. We found that both IPC and GPC can differentiate abnormal brain structures induced by micrometastasis from the surrounding normal tissues. We also found that GPC was more sensitive in detecting the small metastasis as compared to IPC. PMID- 25818990 TI - Conjunctival habronemiasis in a square-lipped rhinoceros (Ceratotherium simum). AB - A captive female square-lipped rhinoceros born in 1993 had been showing intermittent signs of bilateral conjunctivitis and conjunctival proliferation since 1998. Periodic improvement was noted, especially in winter, but overall the condition had deteriorated over the years. Treatment with various topical, intralesional, and systemic antibiotics and glucocorticosteroids was largely ineffective, as were repeated dewormings. No primary cause for these lesions was found in biopsies taken in 2000 and 2006, although a severe infiltrate of numerous eosinophils was observed in the latter. As the condition worsened, secondary corneal changes were noted, and eventually vision was lost due to proliferative conjunctival tissue. Aggressive resection of the proliferating tissue in 2013 restored vision and submitted biopsies yielded a diagnosis of severe allergic conjunctivitis, eosinophilic granuloma, and habronematid (Habronema or Draschia) larval infection. As no other rhinoceros in the herd was affected, including two calves born to the patient who were in close contact with their mother, it was concluded the presentation was most likely due to a hypersensitivity reaction to the dead or dying larvae. Fly repellent is now regularly applied around the eye of this rhinoceros, and a protective face mask has been fitted. Ongoing periodic relapses are treated with oral ivermectin, topical antibiotics, and steroids. PMID- 25818991 TI - Maternal serum progesterone-induced blocking factor (PIBF) in the prediction of preterm birth. AB - The objective of this study was to analyze the maternal serum concentration of progesterone-induced blocking factor (PIBF) with regard to the prediction and the interval between sampling and the onset of preterm birth. A prospective study was conducted on a sample of 37 women with threatened pre-term birth and 41 healthy pregnant women between the 24th and 28th gestational weeks. Out of 37 patients with threatened preterm birth 11 delivered pre-term and three groups of patients were formed: the preterm delivery group, patients with threatened preterm delivery, and healthy pregnant women. In samples that were taken within 5 days before labor started (6/11, 54.5%), PIBF concentrations were significantly lower than in those obtained more than 5 days before labor (5/11, 45.5%; the mean interval between sampling and the onset of labor was 4.1 +/- 1.8 days). Multiple regression analysis of the individual contributions of each observed parameter for preterm delivery demonstrated the significant contribution of a lack of PIBF to preterm birth (p = 0.002). Receiver operating characteristics (ROC) analysis was performed to evaluate the diagnostic accuracy of PIBF for the prediction of preterm birth of women with symptoms of pre-term delivery. The PIBF demonstrated an excellent diagnostic value in the prediction of preterm birth with an area under the ROC curve (AUC) of 0.956 (95% CI = 0.884-0.989; p < 0.0001). Our data suggest that pregnancy termination can be predicted by lower than normal pregnancy PIBF values within 5 days before labor and can contribute to the diagnosis of preterm birth. PMID- 25818992 TI - Immunology in reproduction. PMID- 25818993 TI - Blood alcohol concentration in drivers of Liege area (Belgium): a 5-year analysis. AB - OBJECTIVES: The objective of the study was to describe 'the results of the blood alcohol determinations made on drivers from the Liege area between 2007 and 2012. METHODS: The results were interpreted according to the sex, to the age, to the circumstances and temporal variation of the test. Statistical analysis was performed using R(r) software. RESULTS: 2725 determinations were done, mainly after crashes. The mean blood alcohol concentration (BAC) was 1.69 g/L, and 2132 drivers were above the legal threshold. A majority of offenders were men, but the mean BAC did not differ significantly between men and women. A correlation between age and mean BAC can be observed on the positive cases. Lowest and highest mean BACs are observed during the daytime and during the night, respectively, but no significant difference can be observed between the week and the weekend. Finally, no significant difference in BAC was observed over years. PMID- 25818994 TI - The use of renal replacement therapy in critically ill pediatric small bowel transplantation candidates and recipients: Experience from one center. AB - Outcomes for pediatric SBT patients requiring perioperative RRT in the PICU remain unknown. The objectives were to document our center's experience with PICU SBT patients receiving perioperative RRT and to identify variables predictive of survival to discharge. A retrospective chart review of patients (ages, 0-18 yr) between January 1, 2000 and December 31, 2011 that received RRT within a SBT perioperative period and were transplanted at our university-affiliated, tertiary care children's hospital was performed. Six SBT patients received perioperative RRT (ages, 5-12 yr). Three patients (50%) survived to hospital discharge. Among survivors, RRT was required for a total of 1-112 days (mean, 49.7 days). All three survivors survived to hospital discharge without renal transplantation and free of RRT. There was a trend toward increased survival among older patients receiving RRT (p = 0.05). Survivors had a higher I-125 GFR prior to PICU admission (p = 0.045). A higher I-125 GFR prior to PICU admission among survivors may support this test's utility during SBT evaluation. In our experience, a high survival rate and freedom from RRT at the time of discharge support RRT use in the SBT population. PMID- 25818995 TI - The utility of thromboelastometry in prophylactic platelet transfusion for hematological malignancies. AB - There is still debate on how platelet transfusions should be used to prevent severe bleeding. The aim of our study is to assess the clinical efficacy of thromboelastometry in reducing number of prophylactic platelet transfusions in patients with hematological malignancies. One hundred hematological malignancy patients were included in the study. Six units random donor platelets (RDPs) was given to the first group, three units RDPs was given to the second group, one unit single donor platelets (SDPs) was given to the third group, and 1/2 unit SDPs was given to the fourth group. Before and 15 minutes after transfusion, rotation thromboelastometry (ROTEM) was performed (Pentapharm GmbH, Munich, Germany). ROTEM((r)) parameters did not show any statistical difference between 'low dose' and 'high dose' random or single donor platelet transfusions. Therefore, low dose platelet transfusion can be considered because of its reduced adverse transfusion reactions and economic burden. PMID- 25818996 TI - Red cell alloimmunisation in oncology patients: A study from eastern India. AB - BACKGROUND: Red cell alloimmunisation is an important complication in multi transfused patients with haematologic and surgical malignancies. Antibody screening with identification is necessary to ensure transfusion safety. Data on the prevalence of alloimmunisation in oncology patients is limited. In this study we assessed multitransfused haematology-oncology patients for red cell alloimmunisation. This was a retrospective analysis undertaken to assess the alloantibody prevalence and determine the antibody specificity. MATERIALS AND METHOD: Retrospective analysis of antibody screening data was done for haematopoietic stem cell transplant (HSCT) patients as well as surgical oncology patients, from April 2013 to May 2014. This included the antibody screening done prior to surgery, antibody screening prior to HSCT and any antibody screening performed for these patients at cross match. Antibody screening was done using the three cell panel (surgiscreen) and if positive, further identification performed using the 11 cell panel (Resolve Panel A). If the antibody screen (three cell panel) was positive, an autocontrol was performed using reverse diluent (Ortho Biovue System) card. Patients with autoantibodies were excluded from this study. RESULT AND DISCUSSION: Our overall red cell alloimmunisation rate was 2.5%. Alloimmunisation rate among HSCT transplant patients was 1.6% as compared to the 2.4% in patients with solid organ malignancies. Keeping in view the low alloimmunisation rate, the justification of repeating antibody screening 72 hours post transfusion in this category of patients needs to be re-assessed. PMID- 25818997 TI - Frequency of DEL phenotype in RhD negative donor population of north India. AB - BACKGROUND: There is a paucity of data for DEL phenotype in the Indian population. Ours is a tertiary care Regional Blood Transfusion Centre in north India collecting more than 50,000 blood units out of which 8-9% are RhD negative donors. AIM: To determine the frequency of DEL phenotype in RhD negative blood donor population at our centre. MATERIAL AND METHODS: A total of 200 RhD-negative blood donor samples were included in this study which was conducted over a period of 4 months (October 2013 to January 2014). All these blood samples were tested for extended Rh typing including C, E, c and e antigens and also for adsorption elution testing. The heat elution method at 56 degrees C in water bath for 10 minutes was utilized. The eluate and the last wash supernatant were used for indirect antiglobulin test against O RhD positive and O RhD negative cells by gel technique using the LISS Coombs' AHG gel cards (Biorad, Morat, Switzerland). Those donor samples which were found positive on adsorption elution testing were also further investigated by gel technique for Direct Antiglobulin test (DAT), Weak D testing and Auto Control test. RESULTS: Out of the total 200 Rh D negative donor samples tested, 3 (1.5%) samples were found to give positive result and, thus, were the DEL phenotypes. It was found that 20 (10%) donor samples were positive for C antigen, 5 (2.5%) for E antigen, 200 (100%) for c antigen and 200 (100%) for e antigen. Among the DEL negative (= 197), 193 (98%) were E antigen negative and only 4 (2%) were E antigen positive, whereas among the DEL positive samples (= 3), 2 (66.6%) were E antigen negative and 1 (33.3%) was E antigen positive. The C antigen positivity was only in 2 (66.6%) individuals in the DEL positive group and 178 (90.3%) in the DEL negative samples. All the three samples which were found to be positive as DEL phenotype also gave negative result for DAT, Weak D testing and Auto Control. CONCLUSION: The frequency of DEL phenotype in north Indian RhD negative donor population is 1.5%. PMID- 25818998 TI - Association of single nucleotide polymorphisms in the microRNA miR-1596 locus with residual feed intake in chickens. AB - MicroRNAs are an abundant class of small non-coding RNAs that regulate gene expression. Genetic variations in microRNA sequences may be associated with phenotype differences by influencing the expression of microRNAs and/or their targets. This study identified two single nucleotide polymorphisms (SNPs) in the genomic region of the microRNA miR-1596 locus of chicken. Of the two SNPs, one was 95 bp upstream of miR-1596 (g.5678784A>T) and the other was in the middle of the sequence producing the mature microRNA gga-miR-1596-3p (g.5678944A>G). Genotypic distribution of the two SNPs had large differences among 12 chicken breeds (lines), especially between the fast-growing commercial lines and the slow growing Chinese indigenous breeds for the g.5678784A>T SNP. Only the g.5678784A>T SNP was significantly associated with residual feed intake (RFI) in the F2 population derived from a fast-growing and a slow-growing broiler as well as in the pure Huiyang bearded chicken. The birds with the AA genotype of the g.5678784A>T SNP had lower RFI and higher expression of the mature gga-miR-1596 3p microRNA of miR-1596 than did those with the other genotypes of the same SNP. We also found that the expression of the mature gga-miR-1596-3p microRNA of miR 1596 was significantly associated with RFI. These findings suggest that miR-1596 can become a candidate gene related to RFI, and its genetic variation may contribute to changes in RFI by altering expression levels of the mature gga-miR 1596-3p microRNA in chicken. PMID- 25818999 TI - Expression, purification and characterization of inactive and active forms of ERK2 from insect expression system. AB - Extracellular signal-regulated kinase 2 (ERK2) is a serine/threonine protein kinase involved in many cellular programs, such as cell proliferation, differentiation, motility and programed cell-death. It is therefore considered an important target in the treatment of cancer. In an effort to support biochemical screening and small molecule drug discovery, we established a robust system to generate both inactive and active forms of ERK2 using insect expression system. We report here, for the first time, that inactive ERK2 can be expressed and purified with 100% homogeneity in the unphosphorylated form using insect system. This resulted in a significant 20-fold yield improvement compared to that previously reported using bacterial expression system. We also report a newly developed system to generate active ERK2 in insect cells through in vivo co expression with a constitutively active MEK1 (S218D S222D). Isolated active ERK2 was confirmed to be doubly phosphorylated at the correct sites, T185 and Y187, in the activation loop of ERK2. Both ERK2 forms, inactive and active, were well characterized by biochemical activity assay for their kinase function. Inactive and active ERK2 were the two key reagents that enabled successful high through put biochemical assay screen and structural drug discovery studies. PMID- 25819000 TI - Distribution and content of ellagitannins in Finnish plant species. AB - The results of a screening study, in which a total of 82 Finnish plant species were studied for their ellagitannin composition and content, are presented. The total ellagitannin content was determined by HPLC-DAD, the detected ellagitannins were further characterized by HPLC-ESI-QTOF-MS and divided into four structurally different sub-groups. Thirty plant species were found to contain ellagitannins and the ellagitannin content in the crude extracts varied from few mgg(-1) to over a hundred mgg(-1). Plant families that were rich in ellagitannins (>90mgg( 1) of the crude extract) were Onagraceae, Lyhtraceae, Geraniaceae, Elaeagnaceae, Fagaceae and some species from Rosaceae. Plant species that contained moderate amounts of ellagitannins (31-89mgg(-1) of the crude extract) were representatives of the family Rosaceae. Plant species that contained low amounts of ellagitannins (1-30mgg(-1) of the crude extract) were representatives of the families Betulaceae and Myricaceae. The specific ellagitannin composition of the species allowed their chemotaxonomic classification and the comparison between the older Cronquist's classification and the nowadays preferred Angiosperm Phylogeny Group classification. PMID- 25819001 TI - Allium sativum produces terpenes with fungistatic properties in response to infection with Sclerotium cepivorum. AB - This study investigated terpene biosynthesis in different tissues (root, protobulb, leaf sheath and blade) of in vitro-grown garlic plants either infected or not (control) with Sclerotium cepivorum, the causative agent of Allium White Rot disease. The terpenes identified by gas chromatography-electron impact mass spectrometry (GC-EIMS) in infected plants were nerolidol, phytol, squalene, alpha pinene, terpinolene, limonene, 1,8-cineole and gamma-terpinene, whose levels significantly increased when exposed to the fungus. Consistent with this, an increase in terpene synthase (TPS) activity was measured in infected plants. Among the terpenes identified, nerolidol, alpha-pinene and terpinolene were the most abundant with antifungal activity against S. cepivorum being assessed in vitro by mycelium growth inhibition. Nerolidol and terpinolene significantly reduced sclerotia production, while alpha-pinene stimulated it in a concentration dependent manner. Parallel to fungal growth inhibition, electron microscopy observations established morphological alterations in the hyphae exposed to terpinolene and nerolidol. Differences in hyphal EtBr uptake suggested that one of the antifungal mechanisms of nerolidol and terpinolene might be disruption of fungal membrane integrity. PMID- 25819002 TI - Barrier properties of heat treated starch Pickering emulsions. AB - HYPOTHESIS: There is a recognized technological need for delivery systems encapsulating lipophilic substances in food and pharmaceutical products. Pickering emulsions can provide well-defined and highly stable systems, but may not provide good enough barrier properties. Starch granules, recently being used for Pickering stabilization, have the advantage of the ability to swell during gelatinization. Hence, this property could be used to tune and control barrier properties. EXPERIMENTS: Oil-in-water Pickering emulsions stabilized by starch were subject to heat treatment at different conditions. The influence of temperature, time, and storage on emulsion drop characteristics was evaluated. In order to further evaluate the barrier properties, lipolysis using the pH-stat method was applied and the effect of starch concentration, treatment temperature, and preliminary oral conditions were also investigated. FINDINGS: A better encapsulating barrier was obtained by starch swelling at the oil drop interface. This was seen as reduced lipase activity. The internal oil drop size remained intact and the starch was kept at the interface during heat treatment. The extent of swelling could be controlled by the heating conditions and had impact on the ability to prevent lipase transport through the starch barrier layer. Addition of alpha-amylase simulating oral digestion only had minor impact on the barrier effect. PMID- 25819003 TI - Hierarchical MWCNTs/Fe3O4/PANI magnetic composite as adsorbent for methyl orange removal. AB - Multi-wall carbon nanotubes (MWCNTs) decorated with Fe3O4 nanoparticles (MWCNTs/Fe3O4) were modified by polyaniline (PANI). The adsorption kinetics of methyl orange (MO) on MWCNTs/Fe3O4/PANI could be fitted well by the pseudo-second order model. The adsorption of MO on MWCNTs/Fe3O4/PANI was strongly dependent on pH values. The Langmuir isotherm model fitted MO adsorption isotherm better than the Freundlich model. The hierarchical MWCNTs/Fe3O4/PANI showed high adsorption capacity toward ionic dyes (446.25 mg g(-1) for MO and 417.38 mg g(-1) for Congo red (CR)). The nitrogen-containing functional groups of PANI decorated on MWCNTs/Fe3O4/PANI contributed to many effective adsorption sites and thus increased the adsorption capacity toward MO and CR. Moreover, PANI prevented Fe3O4 nanoparticles from dissolution, and hence improved the stability of MWCNTs/Fe3O4/PANI in solution. The experimental results showed that the MWCNTs/Fe3O4/PANI composite was a promising magnetic material for the preconcentration and separation of ionic dye pollutants from aqueous solutions in environmental pollution cleanup. PMID- 25819004 TI - Structure-function relationships affecting the sensing mechanism of monolayer protected cluster doped xerogel amperometric glucose biosensors. AB - A systematic study of the structure-function relationships critical to understanding the sensing mechanism of 1st generation amperometric glucose biosensors with an embedded nanoparticle (NP) network is presented. Xerogel-based films featuring embedded glucose oxidase enzyme and doped with alkanethiolate protected gold NPs, known as monolayer protected clusters (MPCs), exhibit significantly enhanced performance compared to analogous systems without NPs including higher sensitivity, faster response time, and extended linear/dynamic ranges. The proposed mechanism involves diffusion of the glucose to glucose oxidase within the xerogel, enzymatic reaction production of H2O2 with subsequent diffusion to the embedded network of MPCs where it is oxidized, an event immediately reported via fast electron transfer (ET) through the MPC system to the working electrode. Various aspects of the film construct and strategy are systematically probed using amperometry, voltammetry, and solid-state electronic conductivity measurements, including the effects of MPC peripheral chain length, MPC functionalization via place-exchange reaction, MPC core size, and the MPC density or concentration within the xerogel composite films. The collective results of these experiments support the proposed mechanism and identify interparticle spacing and the electronic communication through the MPC network is the most significant factor in the sensing scheme with the diffusional aspects of the mechanism that may be affected by film/MPC hydrophobicity and functionality (i.e., glucose and H2O2 diffusion) shown to be less substantial contributors to the overall enhanced performance. Understanding the structure-function relationships of effective sensing schemes allows for the employment of the strategy for future biosensor design toward clinically relevant targets. PMID- 25819005 TI - Suppression of inflammatory response by chrysin, a flavone isolated from Potentilla evestita Th. Wolf. In silico predictive study on its mechanistic effect. AB - Flavonoids are the most abundant natural polyphenols widely distributed in plants. Among them, chrysin has recently attracted the attention for its anti tumor and anti-oxidant activities and also for its protective effects on allergic inflammation. Therefore, in this study, we set out to investigate and characterize the effects of chrysin in classical models of inflammation reasoning that this would expand our knowledge on the pharmacological properties of this flavone. To this aim we have firstly isolated chrysin from Potentilla evestita Th. Wolf. and successively evaluated its anti-inflammatory and analgesic potential on writhing and formalin test and also on carrageenan-induced paw oedema. Finally, the present study was planned to investigate, by the aim of docking analysis, the molecular interaction of this compound on the binding site of COX-1 and COX-2 enzymes. On writhing test, we observed a significant inhibition of writhings after the administration of chrysin at 5.0 and 10.0 mg/kg i.p. (25.00+/-9.22% and 55.67+/-7.62% respectively). On formalin test, the flavone at dose of 10.0 mg/kg i.p. displayed its maximum analgesic and anti inflammatory effect on both early (35.67+/-7.88%) and late phase (50.57+/-5.36%) and similarly displayed at 4h a significant anti-inflammatory effect in carrageenan-induced paw oedema. Moreover, in silico analysis of receptor ligand complex shows that chrysin interacts weakly with COX-1 binding site whereas displayed a remarkable interaction with COX-2. These findings suggest that the flavone chrysin isolated from P. evestita Th. Wolf. possesses in vivo anti inflammatory and anti-nociceptive potential, which are supported in silico by an interaction with COX-2 binding site. PMID- 25819006 TI - Cadinane sesquiterpenes from Curcuma phaeocaulis with their inhibitory activities on nitric oxide production in RAW 264.7 cells. AB - Four new cadinane-type sesquiterpenes named phacadinanes A-D (1-4) were isolated from the rhizomes of Curcuma phaeocaulis. Their structures were elucidated by 1D and 2D NMR, as well as accurate mass measurements. Compound 4 was the first example of a rare 4,5-seco-cadinane sesquiterpene isolated from the Zingiberaceae family. Furthermore, inhibitory effects of the isolated compounds on nitric oxide production in LPS-activated macrophages were evaluated. Compounds 1 and 2 showed strong inhibitory activities on NO production with IC50 values of 3.88+/-0.58 and 2.25+/-0.71 MUM, respectively. A possible biogenetic pathway for 4,5-seco cadinane sesquiterpene (4) was postulated. PMID- 25819007 TI - Four doses of unpegylated versus one dose of pegylated filgrastim as supportive therapy in R-CHOP-14 for elderly patients with diffuse large B-cell lymphoma. AB - The primary objective of this prospective, randomized study was to compare the efficacy of a reduced regimen of only four doses of unpegylated filgrastim from day +8 to +11 per cycle with a standard once per cycle administration of pegylated filgrastim to maintain dose-intensity of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone given every 14 d) in previously untreated elderly patients with diffuse large B-cell lymphoma (DLBCL). We included 51 patients (median age 66 years, range 60-76). Median dose intensity did not differ between the group of 24 patients receiving four doses of unpegylated filgrastim of each cycle (87.5%) and the group of 27 patients receiving pegylated filgrastim once per cycle on day 2 (89.4%) (P = 0.9). There was also no difference in the frequency of adverse events, such as episodes of neutropenic fever and unplanned hospitalizations. Patient characteristics that negatively influenced dose intensity were reduced performance status, advanced stage disease and poor-risk International Prognostic Index, with Eastern Cooperative Oncology Group performance status >=2 being the most significant factor. In conclusion, a limited support with 4 d of filgrastim appears to be equivalent to pegylated filgrastim administered once per cycle, and appears to be sufficient to maintain dose-intensity of the R-CHOP-14 regimen in elderly patients with DLBCL without risk factors. PMID- 25819008 TI - Effect of preservation method on spider monkey (Ateles geoffroyi) fecal microbiota over 8 weeks. AB - Studies of the gut microbiome have become increasingly common with recent technological advances. Gut microbes play an important role in human and animal health, and gut microbiome analysis holds great potential for evaluating health in wildlife, as microbiota can be assessed from non-invasively collected fecal samples. However, many common fecal preservation protocols (e.g. freezing at -80 degrees C) are not suitable for field conditions, or have not been tested for long-term (greater than 2 weeks) storage. In this study, we collected fresh fecal samples from captive spider monkeys (Ateles geoffroyi) at the Columbian Park Zoo (Lafayette, IN, USA). The samples were pooled, homogenized, and preserved for up to 8 weeks prior to DNA extraction and sequencing. Preservation methods included: freezing at -20 degrees C, freezing at -80 degrees C, immersion in 100% ethanol, application to FTA cards, and immersion in RNAlater. At 0 (fresh), 1, 2, 4, and 8 weeks from fecal collection, DNA was extracted and microbial DNA was amplified and sequenced. DNA concentration, purity, microbial diversity, and microbial composition were compared across all methods and time points. DNA concentration and purity did not correlate with microbial diversity or composition. Microbial composition of frozen and ethanol samples were most similar to fresh samples. FTA card and RNAlater-preserved samples had the least similar microbial composition and abundance compared to fresh samples. Microbial composition and diversity were relatively stable over time within each preservation method. Based on these results, if freezers are not available, we recommend preserving fecal samples in ethanol (for up to 8weeks) prior to microbial extraction and analysis. PMID- 25819009 TI - Characterization of the Carbohydrate Binding Module 18 gene family in the amphibian pathogen Batrachochytrium dendrobatidis. AB - Batrachochytrium dendrobatidis (Bd) is the causative agent of chytridiomycosis responsible for worldwide decline in amphibian populations. Previous analysis of the Bd genome revealed a unique expansion of the carbohydrate-binding module family 18 (CBM18) predicted to be a sub-class of chitin recognition domains. CBM expansions have been linked to the evolution of pathogenicity in a variety of fungal species by protecting the fungus from the host. Based on phylogenetic analysis and presence of additional protein domains, the gene family can be classified into 3 classes: Tyrosinase-, Deacetylase-, and Lectin-like. Examination of the mRNA expression levels from sporangia and zoospores of nine of the cbm18 genes found that the Lectin-like genes had the highest expression while the Tyrosinase-like genes showed little expression, especially in zoospores. Heterologous expression of GFP-tagged copies of four CBM18 genes in Saccharomyces cerevisiae demonstrated that two copies containing secretion signal peptides are trafficked to the cell boundary. The Lectin-like genes cbm18-ll1 and cbm18-ll2 co localized with the chitinous cell boundaries visualized by staining with calcofluor white. In vitro assays of the full length and single domain copies from CBM18-LL1 demonstrated chitin binding and no binding to cellulose or xylan. Expressed CBM18 domain proteins were demonstrated to protect the fungus, Trichoderma reeseii, in vitro against hydrolysis from exogenously added chitinase, likely by binding and limiting exposure of fungal chitin. These results demonstrate that cbm18 genes can play a role in fungal defense and expansion of their copy number may be an important pathogenicity factor of this emerging infectious disease of amphibians. PMID- 25819010 TI - Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes. AB - AIM: To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction. METHODS: The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates. RESULTS: A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease. CONCLUSIONS: Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population. PMID- 25819011 TI - Mutations conferring resistance to first- and second-line drugs in multidrug resistant Mycobacterium tuberculosis clinical isolates in southeast Mexico. PMID- 25819012 TI - Prior ultrasound-indicated cerclage: how should we manage the next pregnancy? AB - OBJECTIVE: To determine the subsequent need for cerclage and pregnancy outcome, in women with a prior ultrasound-indicated cerclage. STUDY DESIGN: Analysis of a prospectively collected database from November 2010 to July 2014 from 15 Preterm Surveillance clinics across the UK was performed. Women with an index and previous singleton pregnancy with an ultrasound-indicated cerclage were eligible for inclusion (n=55). Previous ultrasound-indicated cerclage was defined as cerclage inserted prior to 24 weeks' for cervical length <25 mm as detected by transvaginal ultrasound. Women were managed in their subsequent pregnancy with either history-indicated cerclage, transvaginal ultrasound surveillance of cervical length with cerclage if <25 mm or transabdominal cerclage at the discretion of the physician. Exact logistic regression was used to estimate the odds ratio on the chance of delivery before 34 weeks'. Adjustments were made for major risk factors for prematurity: previous spontaneous preterm birth, previous late miscarriage (16+0 to 23+6 weeks') and previous cervical surgery; both individually and in combination. RESULTS: Of the 55 eligible women, 23 underwent history-indicated cerclage, 23 underwent transvaginal ultrasound cervical length surveillance and 8 underwent abdominal cerclage in the index pregnancy. Of those that had ultrasound surveillance, 13 (57%) did not require cerclage and all delivered after 34 weeks'. Of those that had a history-indicated cerclage, six delivered before 34 weeks'. Therefore, women that received a history-indicated cerclage had greater risk of preterm birth compared to women that underwent ultrasound surveillance with cerclage insertion only if cervical shortening was detected (OR 0.09 95% CI 0.00-0.74, p=0.02). Adjustments for risk factors for preterm birth did not significantly affect this risk. CONCLUSION: In women with prior ultrasound-indicated cerclage, who undergo cervical surveillance in the next pregnancy, the majority will not require intervention for a short cervix. Those women receiving a history-indicated vaginal cerclage were more likely to deliver preterm; this cannot be explained by their risk status. All women receiving an abdominal elective cerclage had good outcomes. Ultrasound surveillance is appropriate in women with a prior ultrasound-indicated cerclage who do not require an abdominal cerclage. PMID- 25819013 TI - Two myostatin genes exhibit divergent and conserved functions in grass carp (Ctenopharyngodon idellus). AB - Myostatin (MSTN) is an important negative regulator of myogenesis, which inhibits myoblast proliferation and differentiation. Here, we report the isolation and characterization of two mstn genes in grass carp (Ctenopharyngodon idellus). Grass carp mstn-1 and mstn-2 cDNAs are highly divergent, sharing a relatively low amino acid sequence identity of 66%. In adult fish, both orthologs are expressed in numerous tissues and they are differentially regulated during a fasting/refeeding treatments. During embryogenesis, the mRNA levels of both mstn 1 and -2 were upregulated significantly at the beginning of somitogenesis, and maintained at high levels until hatching. Using in situ hybridization, grass carp mstn-1 mRNA was found to ubiquitously express at 12hpf, with strong signals in the notochord, and in the eyes, brain and tailbud at 24hpf, and in brain and notochord at 36hpf. In comparison, the mstn-2 mRNA can be detected in the eyes, brain and notochord at 24hpf, and in the notochord and hindbrain at 36hpf. Further overexpression of mstn-1 mRNA caused a strongly ventralized phenotype by inhibiting dorsal tissue development, while injection of mstn-2 mRNA resulted in obvious embryonic abnormalities in grass carp. These results provide some new insights into the functional conservation and divergence of mstn genes in teleost species. PMID- 25819014 TI - Spiritual care competence for contemporary nursing practice: A quantitative exploration of the guidance provided by fundamental nursing textbooks. AB - Spirituality is receiving unprecedented attention in the nursing literature. Both the volume and scope of literature on the topic is expanding, and it is clear that this topic is of interest to nurses. There is consensus that the spiritual required by clients receiving health ought to be an integrated effort across the health care team. Although undergraduate nurses receive some education on the topic, this is ad hoc and inconsistent across universities. Textbooks are clearly a key resource in this area however the extent to which they form a comprehensive guide for nursing students and nurses is unclear. This study provides a hitherto unperformed analysis of core nursing textbooks to ascertain spirituality related content. 543 books were examined and this provides a range of useful information about inclusions and omissions in this field. Findings revealed that spirituality is not strongly portrayed as a component of holistic care and specific direction for the provision of spiritual care is lacking. Fundamental textbooks used by nurses and nursing students ought to inform and guide integrated spiritual care and reflect a more holistic approach to nursing care. The religious and/or spiritual needs of an increasingly diverse community need to be taken seriously within scholarly texts so that this commitment to individual clients' needs can be mirrored in practice. PMID- 25819015 TI - Blood transfusion and the World Wars. AB - This article summarizes the remarkable development in the science and practice of blood transfusion during the 20 years either side of 1900, progressing through the challenges of surgical vascular access, the propensity of shed blood to clot and the more mysterious apparently arbitrary acute reactions (later revealed as due to blood group incompatibility), to describe in more detail, the developments at the Western Front, then giving a precis of the advances in the interwar years through to the mid-twentieth-century 'blood-banking'. PMID- 25819016 TI - Solamargine inhibits migration and invasion of human hepatocellular carcinoma cells through down-regulation of matrix metalloproteinases 2 and 9 expression and activity. AB - Solamargine is a steroidal alkaloid glycoside isolated from Solanum nigrum. The aim of this study was to investigate the effects of solamargine on tumor migration and invasion in aggressive human hepatocellular carcinoma cells. The MTT assay was used to assess the effects of solamargine on the viability of HepG2 cells. Migration and invasion ability of HepG2 cells under solamargine treatment were examined by a wound healing migration assay and Boyden chamber assay, respectively. Western blotting assays were used to detect the expression of MMP-2 and MMP-9 proteins and MMP-2 and MMP-9 activity were analyzed by gelatin zymography assay. Solamargine reduced HepG2 cell viability in a concentration dependent manner. At 7.5MUM solamargine decreased cell viability by less than 20% in HepG2 cells. A wound healing migration assay and Boyden chamber invasion assay showed that solamargine significantly inhibited in vitro migration and invasion of HepG2 cells. At the highest dose, solamargine decreased cell migration and invasion by more than 70% and 72% in HepG2 cells, respectively. Western blotting and gelatin zymography results showed that solamargine reduced expression and function of MMP-2 and MMP-9 proteins. In conclusion, the results showed that solamargine significantly inhibits migration and invasion of HepG2 cells by down regulating MMP-2 and MMP-9 expression and activity. PMID- 25819017 TI - Effects of intramuscular dexmedetomidine in combination with ketamine or alfaxalone in swine. AB - OBJECTIVE: To evaluate and compare the use of intramuscular (IM) premedication with dexmedetomidine in combination with ketamine or alfaxalone in pigs. STUDY DESIGN: Prospective, randomized, 'blinded' trial. ANIMALS: Fourteen healthy 2 month-old Landrace * Large White pigs weighing 21.5 +/- 0.6 kg. METHODS: Animals were distributed randomly into two groups: group KD (n = 7) was given 10 mg kg( 1) IM ketamine + 10 MUg kg(-1) IM dexmedetomidine; and group AD (n = 7) was given 5 mg kg(-1) IM alfaxalone + 10 MUg kg(-1) IM dexmedetomidine mixed in the same syringe. Pain on injection, degree of sedation and quality of induction were scored. The time from induction of anaesthesia to recumbency was recorded. Once pigs were recumbent, reflexes were evaluated. Pulse and respiratory rates, end tidal carbon dioxide and arterial oxygen saturation were recorded at 5 and 10 minutes after drug administration. Data were compared using a two-way anova or a t-test for unpaired data as relevant. Data are presented as the mean +/- standard deviation (range). RESULTS: Two animals in both groups showed slight pain on drug injection. The time to lateral recumbency in group KD [187 +/- 34 seconds (153 230)] was similar to group AD [206 +/- 36 seconds (150-248)]. In group AD, sedation was deeper, and the quality of anaesthetic induction was smoother. When moved for anaesthesia, five pigs in group KD vocalized. There were no differences between groups in pulse rates, arterial oxygen saturation and end-tidal carbon dioxide; however, the respiratory rate at 10 minutes was significantly higher in group KD than in group AD. CONCLUSIONS AND CLINICAL RELEVANCE: IM dexmedetomidine in combination with ketamine in pigs induced moderate to deep sedation and fair to smooth induction of anaesthesia. When dexmedetomidine was combined with alfaxalone, sedation was deeper, and induction was of a better quality. PMID- 25819018 TI - EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders. AB - Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1beta, IL-12, IL 17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions. PMID- 25819019 TI - Early-stage non-Spitzoid cutaneous melanoma in patients younger than 22 years of age at diagnosis: long-term follow-up and survival analysis. AB - PURPOSE: We evaluated prognostic factors among young patients with early stage melanoma, with particular attention to survival, recurrence, and development of a second primary melanoma. METHODS: We retrospectively reviewed patients (age <22 years) with pathologically confirmed in-situ and stage 1 non-Spitzoid melanoma treated at our institution from 1980-2010, assessing demographics, clinical presentation, treatment, disease-specific survival, recurrence-free survival, and probability of developing a second primary melanoma. RESULTS: One hundred patients with in-situ melanoma (n=16) or stage 1A (n=48) or 1B (n=36) melanoma were identified. Median age was 19.4 years (range, 11.2-21.9), and median follow up was 7.6 years (range, 0.1-31.7). Median tumor thickness was 0.76 mm (range, 0.23-2.0). No lesions were ulcerated. All patients underwent wide local excision with negative margins, and 21 had a concomitant negative sentinel lymph node biopsy (SLNB). Sixteen patients developed recurrences, and 8 subsequently died of progressive melanoma. There were 2 non-melanoma-related deaths. Endpoints were 20 year overall survival (77.4%), melanoma-specific mortality (20.1%), recurrence rate (34.0%), and probability of developing a second primary melanoma (24.7%). Greater tumor depth and Clark level were associated with worse prognosis, but age, sex, and tumor mitotic rate were not correlated with recurrence or survival. CONCLUSION: Among younger early-stage melanoma patients, greater lesion depth conferred higher recurrence risk and mortality. Our data did not define the role of sentinel lymph node biopsy in this group. PMID- 25819020 TI - Pediatric papillary thyroid cancer >1 cm: is total thyroidectomy necessary? AB - PURPOSE: Treatment of pediatric papillary thyroid cancer (p-PTC) often follows adult guidelines, including total thyroidectomy for tumors >1cm. This study examined the association between operation type and overall survival (OS) for tumors >1cm in size in the pediatric population. METHODS: Patients <= 21 years of age with primary papillary thyroid cancer >1cm were reviewed from the National Cancer Data Base (NCDB) from 1998 to 2011. Kaplan-Meier analysis followed by Cox proportional hazard models estimated the impact of total thyroidectomy (TT) vs. partial thyroidectomy (PT) on overall survival. Models were adjusted for patient, tumor, and treatment factors. RESULTS: 3,861 cases (3474 TT, 387 PT) were included. Estimated 15-year overall survival was 96.10% after TT and 96.18% after PT (p=0.0855). In multivariate analysis of 3173 patients, only lowest socioeconomic level (HR 4.93, p=0.001) and unfavorable histology (HR 6.11, p=0.016) were associated with worse OS. Survival for patients undergoing TT was not statistically improved over those undergoing PT (HR 0.81, p=0.694). CONCLUSION: p-PTC >1cm has an excellent 15-year overall survival. Treatment with TT did not have an improved OS compared to PT. Lower socioeconomic status and unfavorable histology were associated with decreased OS. PMID- 25819024 TI - Medial Forebrain Bundle Deep Brain Stimulation has Symptom-specific Anti depressant Effects in Rats and as Opposed to Ventromedial Prefrontal Cortex Stimulation Interacts With the Reward System. AB - BACKGROUND: In recent years, deep brain stimulation (DBS) has emerged as a promising treatment option for patients suffering from treatment-resistant depression (TRD). Several stimulation targets have successfully been tested in clinical settings, including the subgenual cingulum (Cg25) and the medial forebrain bundle (MFB). MFB-DBS has led to remarkable results, surpassing the effect of previous targets in terms of response latency and number of responders. However, the question remains as to which mechanisms underlie this difference. OBJECTIVE/HYPOTHESIS: The aim of the present study was to thoroughly study the anti-depressant effect of MFB-DBS in the Flinders sensitive line (FSL) rat model of depression as well as to investigate whether MFB-DBS and Cg25-DBS operate through the same neurobiological circuits. METHODS: FSL and control rats received bilateral high-frequency stimulation to the MFB at the level of the lateral hypothalamus, while being subjected to a variety of depression- and anxiety related behavioral paradigms. To further compare the effects of MFB-DBS and Cg25 DBS on reward-related behavior, animals were stimulated in either the MFB or ventromedial prefrontal cortex (vmPFC, rodent analog to Cg25), while being tested in the intra-cranial self-stimulation paradigm. RESULTS: A marked symptom specific anti-depressant effect of MFB-DBS was demonstrated. The ICSS-paradigm revealed that MFB-DBS, as opposed to vmPFC-DBS interacts with the reward system. CONCLUSION: Our data suggest that MFB-DBS and Cg25-DBS do not operate via the same neurobiological circuits. This differentiation might be of interest when selecting patients for either Cg25- or MFB-DBS. PMID- 25819025 TI - Enhancer-associated RNAs as therapeutic targets. AB - INTRODUCTION: Regulation of gene expression involves a variety of mechanisms driven by a complex regulatory network of factors. Control of transcription is an important step in gene expression regulation, which integrates the function of cis-acting and trans-acting elements. Among cis-regulatory elements, enhancer RNA (eRNA)-producing domains recently emerged as widespread and potent regulators of transcription and cell fate decision. Thus, manipulation of eRNA levels becomes a novel and appealing avenue for the design of new therapeutic treatments. AREAS COVERED: In this review, we focus on eRNA-producing domains. We describe mechanisms involved in their cell-type specific selection and activation as well as their epigenetic features. In addition, we present their function and the growing evidences of their deregulation in human diseases. Finally, we discuss eRNAs as potential therapeutic targets. EXPERT OPINION: As key factors in the control of transcription, eRNAs appear to possess a great potential for the establishment of new therapy options. However, thorough testing as well as providing the genetic toolbox to target eRNAs will be needed to fully assess the practical and clinical possibilities. PMID- 25819021 TI - A review of pharmacogenetic studies of substance-related disorders. AB - BACKGROUND: Substance-related disorders (SRDs) are a major cause of morbidity and mortality worldwide. Family, twin, and adoption studies have demonstrated the substantial heritability of SRDs. To determine the impact of genetic variation on risk for SRD and the response to treatment, researchers have conducted a number of secondary data analyses and quasi-experimental studies that target one or more candidate gene variants. METHODS: This review examines studies in which candidate polymorphisms were examined as mediator variables to identify pharmacogenetic effects on subjective responses to drug administration or cues or outcomes of medication trials for SRDs. Efforts to use a meta-analytic approach to quantify these effects are premature because the number of available studies using similar methods and outcomes is limited, so the present review is qualitative. RESULTS: Findings from these studies provide preliminary evidence of clinically relevant pharmacogenetic effects. However, independent replication of these findings has been sparse. CONCLUSIONS: Although this growing body of literature has produced conflicting results, improved statistical controls may help to clarify the findings. Additionally, the use of empirically derived sub-phenotypes (i.e., which serve to differentiate distinct groups of affected individuals) may also help to identify genetic mediators of pharmacologic response in relation to SRDs. The identification of genetic mediators can inform clinical care both by identifying risk factors for SRDs and predicting adverse events and therapeutic outcomes associated with specific pharmacotherapies. PMID- 25819026 TI - Nursing psychotherapeutic interventions: a review of clinical studies. AB - AIMS AND OBJECTIVES: To summarise current knowledge about nursing psychotherapeutic interventions in adults. BACKGROUND: In Portugal, the provision of psychotherapeutic interventions is considered a competence of mental health nurses. However, literature is not totally clear about the differences between 'psychotherapy' and 'psychotherapeutic interventions' and about the specific characteristics that define a nursing psychotherapeutic intervention. DESIGN: Narrative review. METHODS: A literature review utilising MEDLINE, PsycINFO, CINAHL, the Web of Science, Psychology and Behavioral Sciences Collection, and MedicLatina computerised databases for the period from 2003-2013. A total of 151 eligible articles were identified. Relevant data were extracted, and findings were synthetised in a narrative synthesis. RESULTS: Nursing psychotherapeutic interventions are frequently based on 'Cognitive-Behavioural' rationale. The usual length of these interventions varies between 5-16 weeks, in a total of 5-12 sessions of 45-60 minutes. The mechanisms of change are heterogeneous, but the therapeutic relationship between the nurse and the client seems to be the most important positive predictive factor of nursing psychotherapeutic interventions. Some of the most used outcome assessment measures include the Beck Depression Inventory, the Hospital Anxiety and Depression Scale, and the CORE-OM. The effectiveness of nursing psychotherapeutic interventions has been widely demonstrated in many studies. However, the need of further studies to prove its cost effectiveness is evident. CONCLUSIONS: It is necessary to have a better understanding of nursing psychotherapeutic interventions, one that explains its conceptual limits, to improve mental health nursing knowledge and create suitable models of psychotherapeutic intervention in nursing. RELEVANCE TO CLINICAL PRACTICE: The findings of this review can create awareness for some weaknesses of nursing knowledge about the psychotherapeutic intervention and for the need to produce knowledge, to nurture the nursing discipline in the area of psychotherapeutic intervention with even more theoretical and practical support. PMID- 25819027 TI - 'Paradox' of troponin elevations after non-cardiac surgery. PMID- 25819028 TI - Molecular structures of free-base corroles: nonplanarity, chirality, and enantiomerization. AB - The molecular structures of free-base corroles are illustrative of a variety of bonded and nonbonded interactions including aromaticity, intra- as well as intermolecular hydrogen bonding, steric interactions among multiple NH hydrogens within a congested central cavity, and the effects of peripheral substituents. Against this backdrop, an X-ray structure of 2,3,7,8,12,13,17,18-octabromo 5,10,15-tris(pentafluorophenyl)corrole, H3[Br8TPFPCor], corresponding to a specific tautomer, has been found to exhibit the strongest nonplanar distortions observed to date for any free-base corrole structure. Two adjacent N-protonated pyrrole rings are tilted with respect to each other by approximately 97.7 degrees , while the remainder of the molecule is comparatively planar. Dispersion corrected DFT calculations were undertaken to investigate to what extent the strong nonplanar distortions can be attributed to steric effects of the peripheral substituents. For meso-triphenylcorrole, DFT calculations revealed nonplanar distortions that are only marginally less pronounced than those found for H3(Br8TPFPCor). A survey of X-ray structures of sterically unhindered corroles also uncovered additional examples of rather strong nonplanar distortions. Detailed potential energy calculations as a function of different saddling dihedrals also emphasized the softness of the distortions. Because of nonplanar distortions, free-base corrole structures are chiral. For H3[Br8TPFPCor], DFT calculations led to an estimate of 15 kcal/mol (0.67 eV) as the activation barrier for enantiomerization of the free-base structures, which is significantly higher than the barrier for NH tautomerism calculated for this molecule, about 5 kcal/mol (0.2 eV). In summary, steric crowding of the internal NH hydrogens appears to provide the main driving force for nonplanar distortions of meso-triarylcorroles; the presence of additional beta-substituents adds marginally to this impetus. PMID- 25819029 TI - One-stage dual latissimus dorsi muscle flap transfer with a pair of vascular anastomoses and double nerve suturing for long-standing facial paralysis. AB - OBJECTIVE: Various types of neurovascular free-muscle transfers have been reported as surgical treatments for long-standing facial paralysis. Among one stage methods, two approaches, that is, latissimus dorsi transfer with nerve suturing to the contralateral facial nerve and gracilis transfer with nerve suturing to the ipsilateral masseteric nerve, have recently become popular. The former method has the advantage of making spontaneous smiling possible, but the contraction strength of the transferred muscle varies, whereas the latter approach has the advantage of guaranteeing voluntary contraction of the transferred muscle, but makes spontaneous smiling difficult. Recently, dual innervation methods have also been reported, but uncertainty remains about the utility of such approaches. To overcome these drawbacks, we devised a hybrid method combining the two previously established techniques. METHODS: Two latissimus dorsi muscle flaps containing the thoracodorsal vessels from one side are transferred with a pair of vascular anastomoses. The true trunk of the thoracodorsal nerve, which innervates one of the muscle flaps, is sutured to the contralateral facial nerve, while the short branch of the thoracodorsal nerve, which innervates the other muscle flap, is sutured to the ipsilateral masseteric nerve. From November 2011 to October 2013, we used this method in four patients with long-standing facial paralysis. RESULTS: Smiling was assessed in the three patients who were followed up for more than 1 year, and satisfactory results were obtained (Harii score: 4-5). In one patient, the movement mediated via the contralateral facial nerve was a little weak, but this was compensated for by the muscles controlled by the ipsilateral masseteric nerve. CONCLUSION: Our novel one stage method, which involves a combination of two previously established methods, guarantees early voluntary smiling, and spontaneous smiling becomes possible later. In addition, it is free from the uncertainty associated with double innervation and does not require nerve grafts. So, stable results can be expected in most patients with long-standing facial paralysis. PMID- 25819031 TI - MicroRNA-490-3P targets CDK1 and inhibits ovarian epithelial carcinoma tumorigenesis and progression. AB - The expression of microRNA-490-3P has been reported to regulate hepatocellular carcinoma cell proliferation, migration and invasion, and its overexpression significantly inhibits A549 lung cancer cell proliferation. Here, we demonstrated for the first time that miR-490 mRNA expression was significantly lower in ovarian carcinoma and borderline tumors compared to benign tumors, and lower in metastatic ovarian carcinoma (omentum) than primary ovarian carcinoma, and was negatively associated with differentiation and International Federation of Gynecology and Obstetrics (FIGO) staging. MiR-490-3P overexpression promoted G1/S or G2/M arrest and apoptosis; reduced cell proliferation, migration and invasion; reduced CDK1, Bcl-xL, MMP2/9, CCND1, SMARCD1 mRNA or protein expression; and induced P53 expression. Dual-luciferase reporter assay indicated miR-490-3P directly targeted CDK1. In vivo studies showed that miR-490-3P transfection suppressed tumor development and CDK1, Bcl-xL, MMP2/9 expression while inducing P53 expression. These findings indicate that miR-490-3P may target CDK1 and inhibit ovarian epithelial carcinoma tumorigenesis and progression. PMID- 25819030 TI - Radiation takes its Toll. AB - The ability to recognize and respond to universal molecular patterns on invading microorganisms allows our immune system to stay on high alert, sensing danger to our self-integrity. Our own damaged cells and tissues in pathological situations activate similar warning systems as microbes. In this way, the body is able to mount a response that is appropriate to the danger. Toll-like receptors are at the heart of this pattern recognition system that initiates innate pro-oxidant, pro-inflammatory signaling cascades and ultimately bridges recognition of danger to adaptive immunity. The acute inflammatory lesions that are formed segue into resolution of inflammation, repair and healing or, more dysfunctionally, into chronic inflammation, autoimmunity, excessive tissue damage and carcinogenesis. Redox is at the nexus of this decision making process and is the point at which ionizing radiation initially intercepts to trigger similar responses to self damage. In this review we discuss our current understanding of how radiation damaged cells interact with Toll-like receptors and how the immune systems interprets these radiation-induced danger signals in the context of whole-body exposures and during local tumor irradiation. PMID- 25819032 TI - Progesterone generates cancer stem cells through membrane progesterone receptor triggered signaling in basal-like human mammary cells. AB - Ionizing radiation and cumulative exposure to steroid hormones are known risk factors for breast cancer. There is increasing evidence that breast tumors are driven by a subpopulation of tumor-initiating cancer stem cells (CSCs). In MCF10A non-cancerous basal-like PR(-) cells, progesterone treatment and X-rays generated ALDH(+) and CD44(+)/CD24(-) CSCs. Here, we report that in irradiated MCF10A cells, progesterone activated the PI3K/Akt pathway via membrane progesterone receptor (mPR). Inhibition of the PI3K/Akt pathway counteracted the generation of CSCs by progesterone and irradiation. The stimulation of PI3K/Akt via mPR resulted in the inactivation of FOXO transcriptional activity, the upregulation of snail and slug expression and a downregulation of miR-29 expression, which led to increased levels of KLF4, a transcription factor required for breast CSC maintenance. Stabilization of miR-29 expression impeded the generation of CSCs, while its inhibition alone was sufficient to generate CSCs. This study provides a new mechanistic basis for progesterone and radiation-induced breast cancer risk in basal cells. In addition, the elucidation of new pathways and miRNA regulations involved in CSC generation and maintenance may open the door to potential novel anti-CSC strategies. PMID- 25819033 TI - Modeling and motion compensation of a bidirectional tendon-sheath actuated system for robotic endoscopic surgery. AB - Recent study shows that tendon-sheath system (TSS) has great potential in the development of surgical robots for endoscopic surgery. It is able to deliver adequate power in a light-weight and compact package. And the flexibility and compliance of the tendon-sheath system make it capable of adapting to the long and winding path in the flexible endoscope. However, the main difficulties in precise control of such system fall on the nonlinearities of the system behavior and absence of necessary sensory feedback at the surgical end-effectors. Since accurate position control of the tool is a prerequisite for efficacy, safety and intuitive user-experience in robotic surgery, in this paper we propose a system modeling approach for motion compensation. Based on a bidirectional actuated system using two separate tendon-sheaths, motion transmission is firstly characterized. Two types of positional errors due to system backlash and environment loading are defined and modeled. Then a model-based feedforward compensation method is proposed for open-loop control, giving the system abilities to adjust according to changes in the transmission route configuration without any information feedback from the distal end. A dedicated experimental platform emulating a bidirectional TSS robotic system for endoscopic surgery is built for testing. Proposed positional errors are identified and verified. The performance of the proposed motion compensation is evaluated by trajectory tracking under different environment loading conditions. And the results demonstrate that accurate position control can be achieved even if the transmission route configuration is updated. PMID- 25819034 TI - Tablet PC-enabled application intervention for patients with gastric cancer undergoing gastrectomy. AB - BACKGROUND: Gastric cancer is among the most common gastrointestinal cancers worldwide. Patients who have undergone surgery for gastric cancer may suffer from malnutrition and potential consequences such as gastrointestinal complications, surgical stress, and cancer cachexia. A tablet PC-based intervention via a mobile application might enhance the early recovery of postgastrectomy patients. OBJECTIVE: The aim of this study was to develop and test a tablet personal computer (PC)-assisted intervention to hasten the recovery of postgastrectomy cancer patients with respect to nutritional status. METHODS: This single-arm pilot study investigated a tablet PC application developed to serve the functions of nutritional monitoring, medical information management, drainage follow-up, and wound care. All services were delivered by medical professionals. RESULTS: Twenty consecutive gastrectomy patients at the National Taiwan University Hospital received perioperative care via this application (App group). During the study period, we retrospectively collected an additional 20 demographically matched gastrectomy cases as a control group. The App group had a lower body weight loss percentage relative to the control group during a 6-month follow-up period (4.8+/-1.2% vs. 8.7+/-2.4%; p<0.01). However, the patients in the App group had more outpatient clinic (OPC) visits than did those in the control group (9.8+/-0.9 vs. 5.6+/-0.8; p<0.01). CONCLUSIONS: This study supported the feasibility of a tablet PC-based application for the perioperative care of gastric cancer subjects to promote a lower body weight loss and the collection of comprehensive surgical records. PMID- 25819035 TI - Role of PMK-1/p38 MAPK defense in Caenorhabditis elegans against Klebsiella pneumoniae infection during host-pathogen interaction. AB - The present study reports that Klebsiella pneumoniae (KP) killed the Caenorhabditis elegans as a consequence of an accumulation and proliferation of the pathogen inside the worms' intestine. The real-time PCR analysis of the genes responsible for vulval development (let-23) and egg laying (lin-29) in KP infected C. elegans confirmed the reproductive defects provoked by KP at the molecular level. In addition, the genetic analysis in N2 wild type, tol-1, sek-1 and pmk-1 mutants unveiled that KP attenuates the toll-dependent p38 mitogen activated protein kinase (p38 MAPK) by chiefly inhibiting the production of antimicrobial factors such as nlp-29, lys-1 and C-type lectins. Conclusively, the surrendering of the host immune system appears to be attenuated by the toll dependent p38 MAPK pathway regulation in C. elegans. PMID- 25819036 TI - THE HAPPINESS AND SUBJECTIVE WELL-BEING OF PEOPLE ON HAEMODIALYSIS. AB - BACKGROUND: Happiness is a construct that has been gaining more prominence in both social and health research. The measure of happiness, subjective well-being, has not been rigorously explored in the end-stage kidney disease (ESKD) population. OBJECTIVES: To measure the subjective well-being of people with ESKD on haemodialysis and to compare their subjective well-being with a general population cohort. DESIGN: A cross-sectional design measuring the subjective well being of an Australian haemodialysis cohort compared with a non-dialysis age matched cohort. PARTICIPANTS: The haemodialysis cohort (N = 172), recruited from eight dialysis centres, had a mean age of 64.04 years (SD = 14.82) and included 104 males (60.5%) and 66 (38.4%) females. The non-dialysis cohort (N = 200), randomly extracted from the 2012 Australian Unity Wellbeing Index, had a mean age of 63.97 (SD = 14.68) and included 101 males (50.5%) and 99 females (49.5%). MEASUREMENT: Subjective well-being was measured using the Personal Wellbeing Index. This seven-item measure rates satisfaction with life in seven domains: standard of living, health, achievements in life, relationships, safety, community and future security. RESULTS: The haemodialysis cohort reported lower general life satisfaction, life achievements, relationship and personal safety compared to the general population. There were no differences between the two groups for health, community and future security. Standard of living and satisfaction with life achievements carried higher importance in subjective well being compared with health satisfaction CONCLUSION: Subjective well-being can be an important indicator of people's life quality to be considered by clinicians and nephrology researchers in future studies. PMID- 25819038 TI - Predictive value of the usual clinical signs and laboratory tests in the diagnosis of septic arthritis. AB - OBJECTIVE: To determine the sensitivity and specificity of clinical and laboratory signs for the diagnosis of septic arthritis (SA). Patients and methods This prospective study included all adult patients with suspected SA seen in the emergency department or rheumatology department at the University Hospital, Clermont-Ferrand, France, over a period of 18 months. RESULTS: In total, 105 patients with suspected SA were included, 38 (36%) presenting with SA (29 [28%] with bacteriologically documented SA). In the univariate analysis, chills (p=0.015), gradual onset (p=0.04), local redness (p=0.01), as well as an entry site for infection (p=0.01) were most often identified in SA. A history of crystal-induced arthritis (p=0.004) was more frequent in non-SA cases. An erythrocyte sedimentation rate (ESR)>50 mm (p=0.005), a C-reactive protein (CRP) level >100 mg/L (p=0.019), and radiological signs suggestive of SA (p=0.001) were more frequent in the SA cases. Synovial fluid appearance: purulent (p50,000/MUL (p < 0.001), differentiated between SA and non-SA. In multivariate analysis, only chills (odds ration [OR]=4.7, 95% confidence interval [CI] 1.3-17.1), a history of crystal-induced arthritis (OR=0.09, 95% CI 0.01-0.9), purulent appearance of the joint fluid (OR=8.4, 95% CI 2.4-28.5), synovial WBC count >50,000/mm3 (OR=6.8, 95% CI 1.3-36), and radiological findings (OR=7.1, 95% CI 13-37.9) remained significant. CONCLUSION: No clinical sign or laboratory test (excluding bacteriological test), taken alone, is conclusive for the differentiation between SA and non-SA, but the association of several signs, notably chills, history of crystal-induced arthritis, radiological findings, and the appearance and cellularity of joint fluid may be suggestive. PMID- 25819037 TI - Outcome of tuberculosis treatment in HIV-positive adults diagnosed through active versus passive case-finding. AB - BACKGROUND: The World Health Organization strongly recommends regular screening for tuberculosis (TB) in HIV-positive individuals. OBJECTIVE: To compare the outcome of anti-tuberculosis treatment (ATT) in HIV-positive adults diagnosed with TB through active case-finding (ACF) or passive case-finding (PCF). DESIGN: Antiretroviral therapy (ART)-naive adults diagnosed with TB were included from two prospective cohort studies conducted in Ethiopia between September 2010 and March 2013. The PCF cohort was based at out-patient TB clinics, whereas participants in the ACF cohort were actively screened for TB by bacteriological sputum testing (smear microscopy, Xpert MTB/RIF assay, and liquid culture) without pre-selection on the basis of symptoms and signs. Outcomes of ATT were compared between participants in the two cohorts; characteristics at diagnosis and predictors of adverse outcomes were analysed. RESULTS: Among 439 TB/HIV co infected participants, 307 and 132 belonged to PCF and ACF cohorts, respectively. Compared with the ACF participants, hemoptysis, conjunctival pallor, bedridden status, and low mid upper-arm circumference (MUAC) were significantly more common in participants identified through PCF. Sputum smear-positivity rates among pulmonary TB cases were 44.2% and 21.1% in the PCF and ACF cohorts, respectively (p<0.001). Treatment success was ascertained in 247 (80.5%) of the participants in the PCF cohort and 102 (77.2%) of the participants in the ACF cohorts (p=0.223). Low MUAC (p=0.001) independently predicted mortality in the participants in both cohorts. CONCLUSION: Although patients identified through ACF had less advanced TB disease, ATT outcome was similar to the patients identified through PCF. To achieve a better outcome, case management in ACF strategy should be strengthened through enhanced patient-centred counselling and adherence support. PMID- 25819040 TI - Mechanistic and therapeutic insights gained from studying rare skeletal diseases. AB - Rare bone diseases account for 5% of all birth defects and can cause significant morbidity throughout patients' lives. Significant progress is being made to elucidate the pathophysiological mechanisms underlying these diseases. This paper summarizes presentation highlights of a workshop on Rare Skeletal Diseases convened to explore how the study of rare diseases has influenced the field's understanding of bone anabolism and catabolism and directed the search for new therapies benefiting patients with rare conditions as well as patients with common skeletal disorders. PMID- 25819041 TI - Virtual PRA replaces traditional PRA: small change but significantly more justice for sensitized patients. PMID- 25819039 TI - Epigenetic histone modifications and master regulators as determinants of context dependent nuclear receptor activity in bone cells. AB - Genomic annotation of unique and combinatorial epigenetic modifications along with transcription factor occupancy is having a profound impact on our understanding of the genome. These studies have led to a better appreciation of the dynamic nature of the epigenetic and transcription factor binding components that reveal overarching principles of the genome as well as tissue specificity. In this minireview, we discuss the presence and potential functions of several of these features across the genome in osteoblast lineage cells. We examine how these features are modulated during cellular maturation, affect transcriptional output and phenotype, and how they alter the ability of cells to respond to systemic signals directed by calcemic hormones such as 1,25-dihydroxyvitamin D3 and PTH. In particular, we describe recent experiments which indicate that progressive stages of bone cell differentiation affect RUNX2 binding to the genome, modify and restrict patterns of gene expression, and dramatically alter cellular response to the vitamin D hormone. These studies expand our understanding of mechanisms that govern steroid hormone regulation of gene expression, while highlighting the increasing complexity that is evident relative to these basic cellular processes. The results also have profound implications with respect to the impact of skeletal diseases on transcriptional outcomes as well. This article is part of a Special Issue entitled Epigenetics and Bone. PMID- 25819042 TI - Multicenter randomized study of inosine pranobex versus acyclovir in the treatment of recurrent herpes labialis and recurrent herpes genitalis in Chinese patients. AB - The objective of the study is to evaluate the efficacy and safety of oral inosine pranobex as compared with acyclovir in the treatment of recurrent herpes labialis (RHL) and recurrent herpes genitalis (RHG). A multicenter double-blind, double dummy, randomized, controlled, parallel group trial was conducted in 144 patients with RHL and 144 RHG. Patients were assigned to treatment in one of two groups: (i) inosine pranobex group (active inosine pranobex, 1 g four times daily, and acyclovir placebo); or (ii) acyclovir group (active acyclovir, 200 mg five times daily, and inosine pranobex placebo). The total symptom score (TSS) of patients with RHL did not differ in the inosine pranobex and acyclovir group on the 3rd or 7th day of treatment. There was also no difference in the efficacy rates between the two groups. No difference of TSS was observed between patients with RHG taking inosine pranobex and acyclovir on days 3 or 5 of the treatment, respectively. The short-term clinical recurrence rate of RHG at 3-month follow-up was much lower in the inosine pranobex group than acyclovir group. The incidence of hyperuricemia was higher in the inosine pranobex group than acyclovir group. In conclusion, inosine pranobex was as effective as acyclovir in treating RHL and RHG with significantly greater reduction of the short-term recurrence rate of herpes genitalis at 3-month follow up. Long-term recurrence rates at 6 months or longer remain to be determined. Hyperuricemia should be monitored during the treatment. PMID- 25819044 TI - Health status of users of the Bologna local health authority drug addiction treatment services: a study of hospital admissions in the period 2004-2013. AB - The aim of this study was to monitor the health status of the users of the services for drug addiction (SERT) in the metropolitan area of Bologna by analysing the hospital discharge records (SDO). For the period 2004-2013, among the residents of the metropolitan areas aged 15-64, we compared the trend in hospital admissions of SERT users with that of the general population. We calculated the standardised rates of hospitalisation and the likelihood of admission. Over the period in question the standardised hospitalisation rates decreased, with a larger drop among SERT users (330.17 males per 10,000 inhabitants in 2004, 215.91 in 2013; 547.60 females per 10,000 inhabitants in 2004, 283.20 in 2013) as compared with the general population (109.49 males in 2004, 82.16 in 2013; 161.40 females in 2004, 124.38 in 2013). Admission likelihood was always higher for SERT users, but was lower in 2013 than in 2004, especially for infectious diseases and psychic disorders. The results highlight the effectiveness of Bologna's local system of services in taking care of aspects connected to addiction, as well as health-related disorders. PMID- 25819045 TI - A survey on antibiotic therapy knowledge among physicians of a tertiary care and university hospital. AB - Antibiotic therapy has resulted in major progress in the fight against infectious diseases and is associated with an improved quality of life and increased survival. However, the emergence of resistant bacterial strains represents an inevitable consequence of antibiotic treatment and yields a loss of beneficial effects. Due to the scarce availability of new molecules in the near future, physicians have to learn how to best use currently available molecules. The aim of the present study was to evaluate the criteria that physicians use in choosing targeted antibiotic therapy. To achieve this goal, we used a questionnaire comprising seven questions. The questionnaire was administered, with the guarantee of anonymity, to a pool of physicians at the Federico II University Hospital of Naples who could prescribe antibiotics. Of the physicians interviewed, 68% chose antibiotic therapy autonomously or in cooperation with other doctors of the same structure, whereas 30% of interviewees referred to the infectious diseases consultant (8% after the first bacterial isolation and 22% after antibiotic therapy failure). The definition and meaning of minimum inhibitory concentration (MIC) were known to the vast majority of physicians (82% and 83%, respectively). In contrast, few of the interviewees knew the definition or meaning of breakpoint (16% and 17%, respectively). The key question of the questionnaire focused on the main criterion for antibiotic choice: 68% of interviewees gave an incorrect answer, most interviewees considering only the lowest MIC value for the isolated bacterium as the fundamental parameter in antibiotic choice. Our study shows that antibiotic therapy in a teaching hospital is often chosen using inappropriate criteria. Due to the well-known effects of the wrong antibiotic choice on therapeutic failure rate and on healthcare cost, information and training programmes for physicians who prescribe antibiotics are urgently needed. PMID- 25819046 TI - Evaluation of various staphylococcal cassette chromosome mec (SCCmec) types in Staphylococcus epidermidis invasive strains from hospitalised patients in Iran. AB - Staphylococcus epidermidis is known to be a major cause of nosocomial infections particularly in catheter-associated bacteraemia, prosthetic valve endocarditis (PVE) and immunocompromised patients in different health care units. The emergence of multidrug-resistant strains, especially to beta-lactam antibiotics such as methicillin, has increased the mortality due to S. epidermidis. A kind of low affinity penicillin-binding protein (PBP2alpha), which is encoded by the mecA gene that is located in the staphylococcal cassette chromosome mec (SCCmec), mediates the resistance to methicillin. The aim of this study was to investigate the prevalence of SCCmec types and evaluate the antibiotic profile assay in invasive strains isolated from clinical samples. The study focused on invasive strains, determining the antimicrobial resistance profile, designing new primers for detection of the mecA gene and SCCmec typing with the multiplex PCR method. By using the PCR molecular test, 87.1% of all isolates were found to be positive for the mecA gene. In SCCmec typing, different types (I-V) were identified, in which SCCmec type I was detected in 3 isolates, SCCmec type II in 5 isolates, SCCmec type III in 22 isolates, SCCmec type IV in 27 isolates and SCCmec type V was distinguished in 4 isolates. Since coagulase-negative staphylococci are reported as a major cause of hospital infections, molecular typing methods like SCCmec typing would be a helpful method to control and prevent bacterial infections. PMID- 25819047 TI - Determination of CTX-M beta-lactamase in Escherichia coli strains isolated from clinical samples. AB - The aim of this study was to determine the ESBL with phenotypic tests and investigate the bla(CTX-M) genes with the PCR method in Escherichia coli strains. The presence of ESBL in E. coli strains was determined with the Vitek 2 automated system. ESBL-positive 100 and ESBL-negative 50 E. coli strains were included in the study. The ESBL disk diffusion screening test (DDST) and the combined disk confirmation tests (CDCT) were performed on these strains and the results of these tests were compared with each other. bla(CTX-M) genes were investigated with the PCR method. The results of CDCT-CAZ-CZC and CDCT-CTX-CTC were found to be consistent in 90% of strains. Those of the automated system, DDST and CDCT-CAZ CZC were compatible with each other in 83.3% of strains. Also the results of the automated system and CDCT-CTX-CTC were found to be compatible in 83.3% of strains. Based on PCR, bla(CTX-M) genes were found in 67.3% of 150 strains. According to the order of frequency, 46%, 38.7%, 20%, 7.3% of strains were determined to carry groups I, IV, II and III, respectively. PMID- 25819048 TI - Tenofovir disoproxil fumarate treatment in HbeAg-positive patients. AB - Tenofovir disoproxil fumarate (Tenofovir DF) is a nucleotide analogue. This multicentre study reports retrospectively the long-term efficacy and safety data with tenofovir DF treatment in nucleosid(t)e-naive, hepatitis B e antigen (HBeAg) positive chronic hepatitis B patients. Thirty-one patients (11 females, 20 males) received 245 mg tenofovir DF per diem. All patients' initial serum hepatitis B virus (HBV) DNA levels were over 2,000 IU/ml. Serum alanine aminotransferase (ALT) levels, HBeAg, hepatitis B e antibodies (anti-HBe), hepatitis B surface antigen (HBsAg), hepatitis B surface antibodies (Anti-HBs), HBV DNA, creatinine and urea levels were evaluated at baseline, and at weeks 12, 24, 48 and 96 during therapy. Thirty-one patients completed 96 weeks of treatment. Mean age was 37.6 +/- 9.4 years. The initial mean value of ALT was 79 +/- 39.9 IU/L. At baseline, mean of fibrosis (Ishak) of liver biopsies was 2.3 +/- 0.7. Two of the patients (5.9%) achieved HBV DNA less than 300 copies at week 12 of treatment and 97.1 % at week 96. HBeAg loss was observed in 6.7% of patients. At week 96, HBsAg loss was not observed in any of the patients. Mean ALT at week 48 was 32.7 U/L, at week 96 32.6 U/L. Renal safety was good. Creatinine remained stable. Tenofovir DF was well tolerated and produced potent, continuous viral suppression with increasing HBeAg loss. PMID- 25819049 TI - A prospective evaluation of maraviroc administration in patients with advanced HIV disease and multiple comorbidities: focus on efficacy and tolerability issues. AB - In our HIV outpatient centre where over 1,200 patients are followed, maraviroc as an entry inhibitor was introduced in 2010. We aimed to assess the background, the therapeutic challenges and the prospective monitoring of all patients treated with a combination antiretroviral therapy (cART) including maraviroc. Sixty-six patients started a maraviroc-containing cART with a history of HIV infection lasting 13.9+/-10.7 years. This interim analysis presents patients who had at least 12 (mean 16.9+/-12.8) months of follow-up. One to 17 previous cART changes prompted the introduction of maraviroc in rescue regimens in the great majority of patients considered (53 of 66); in 13 cases, maraviroc was given to patients with advanced HIV disease and no immune recovery after 2-3 years of a virologically-effective cART. The most frequent companion antiretroviral agents were: darunavir/ritonavir (51 cases), raltegravir (49 subjects), and etravirine (36 cases). The most common underlying conditions were: AIDS (41 cases), liver cirrhosis (21), AIDS-related or other malignancies (20 cases), major cardiovascular events (18 cases), osteonecrosis and haemodialysis-treated kidney failure (3 cases each). A chronic HCV and HBV hepatitis were of concern in 25 and 13 patients. The addition of maraviroc added favourably to clinical-laboratory markers of HIV disease progression, and those of comorbid conditions. HIV viraemia became (or remained) undetectable in 55 patients of 66 (83.3%). An improvement in CD4+ count was observed in all 66 patients, based on a mean 24.9+/ 19.2% increase versus baseline, paralleled by an improvement in mean absolute CD4+ count of 134.7+/-121.1 cells/MUL. A tendency towards an increased mean and peak CD4+ count was observed in the subgroup receiving a maraviroc-raltegravir based cART. As no clinical-laboratory adverse events attributable to maraviroc occurred, nobody discontinued the study drug. Only mild-transient gastrointestinal disturbances, fatigue and anorexia, were reported during maraviroc administration, but their relationship with the study drug was difficult to assess because of the multiple comorbidities and polypharmacy. Our preliminary experience with maraviroc, even considering the limits of the proportionally reduced sample, the patients' salvage stage of advanced disease and the related-unrelated morbidities, underlines its excellent efficacy and safety profile. PMID- 25819050 TI - Aerosolized amphotericin B lipid complex and invasive pulmonary aspergillosis: a case report. AB - Invasive pulmonary aspergillosis (IPA) is an emerging life-threatening infection in immuno-compromised patients. The incidence of IPA following kidney transplantation is low (between 0.7 and 4%), yet mortality remains unacceptably high (75-80%). A first line therapy with voriconazole or lipid formulations of amphotericin B is often limited by co-morbidities, adverse effects and drug interactions. The case within this publication is the first described report of IPA in a renal transplant recipient responding to aerosolized amphotericin B lipid complex. PMID- 25819051 TI - Performance of Alere Determine HIV-1/2 Ag/Ab Combo rapid test for acute HIV infection: a case report. AB - We describe a case of symptomatic acute HIV infection in a young man where a fourth-generation rapid screening test combining HIV-specific antibody and p24 antigen was negative. In highly suspicious cases of acute HIV infection, plasma HIV RNA assays together with conventional, non-rapid screening tests should be used. PMID- 25819052 TI - [Thalamo-mesencephalic aspergillus abscess in a heart transplant subject: a case report and literature review]. AB - Cerebral aspergillosis is a rare and highly fatal infection that mainly affects immunocompromised patients. We report on a case of a heart transplanted Caucasian man, who arrived at our hospital because of the onset of diplopy. We performed a broad diagnostic work-up: the brain MRI showed a single ring-enhancing thalamo mesencephalic area suggestive of abscess lesion; cerebrospinal fluid (CSF) analysis disclosed galactomannan and beta-D-glucan antigens. Thus the antifungal therapy was immediately started. We decided to discontinue the therapy 16 months later because of severe hepatic toxicity, given that the patient was persistently asymptomatic, brain imaging showed a progressive resolution of the abscess area and CSF antigen analysis was persistently negative. The follow-up at three months was unchanged. PMID- 25819053 TI - An 81-year-old male with iliopsoas abscess by Streptococcus sanguis. AB - Iliopsoas muscle abscess is an uncommon condition, which has been growing in incidence. We describe a primary iliopsoas abscess by Streptococcus sanguis affecting an 81-year-old man cured by antibiotic therapy and aspiration procedure. The objective is to enhance the suspicion index about the iliopsoas abscess that may be mistaken for other causes of acute abdomen. The important diagnostic role of abdominal imaging studies is also emphasised. PMID- 25819054 TI - [Histoplasmosis: the multiple sides of an uncommon disease]. AB - Disseminated histoplasmosis is an invasive fungal infection documented in patients with impaired cellular immunity coming from endemic areas (America, Asia, Africa). We report two cases of disseminated histoplasmosis in AIDS patients paradigmatic of the multifaceted nature of the disease, which may be an expression either of an advanced state of immunosuppression or the immune reconstitution inflammatory syndrome (IRIS). PMID- 25819055 TI - Leg ulcer and osteomyelitis due to methicillin-susceptible Staphylococcus aureus infection after fracture repair treatment: a case highlighting the potential role of prostaglandin E1 vasodilator. AB - Prostaglandins appear to reduce biofilm formation and chronicization of infections, and stimulate a rapid and effective clearance of infecting micro organisms. We report a case of recovery from methicillin-susceptible Staphylococcus aureus (MSSA) osteomyelitis after multidisciplinary management with antibiotics, anti-thrombotics and prostaglandin E1 (PGE1) vasodilator, in a patient with tibial plateau fracture repaired with internal fixation devices. A 47-year-old HIV-negative male with chronic ulcer on the proximal third of the left leg was admitted to the Orthopaedic Unit of the Orestano Clinic in Palermo, Italy, for suspected osteomyelitis. A biopsy of the skin ulcer and blood cultures were performed and resulted positive for MSSA. Labelled leukocyte scintigraphy confirmed osteomyelitis. No clinical improvement was observed after combined antibiotic treatment with rifampicin plus trimethoprim-sulfamethoxazole. The patient underwent a 4-day therapeutic cycle: PGE1 (alprostadil 60 mg/day IV) combined with nadroparin calcium plus gentamicin, followed by treatment with aminaftone plus sulodexide plus levofloxacin. At discharge, the patient's painful symptoms had completely resolved and the ulcer had cicatrized; recovery from osteomyelitis was confirmed by scintigraphy. This treatment protocol including PGE1 may result in a significant improvement in quality of life and functional status of patients with a reduction in direct and indirect costs and economic benefit for the National Health Service. PMID- 25819056 TI - Macroscopic haemoglobinuria associated with Mycoplasma pneumoniae infection successfully treated by clarithromycin. AB - A 25-year-old man developed macroscopic haemoglobinuria after a persistent dry cough. Although chest radiograph findings were normal, since the serum antibody for Mycoplasma pneumoniae was significantly elevated, a diagnosis infection with this organism was made. Despite the absence of apparent anaemia, a marked increase in serum haemolytic markers and positive result for urine haemoglobin indicated the haemolysis of red blood cells, which was likely to have occurred secondarily to M. pneumoniae infection. Shortly after the initiation of a macrolide antibiotic, clarithromycin, the patient's haemoglobinuria completely disappeared together with a complete resolution of his respiratory symptoms. In this case, due to the lymphocyte-stimulatory nature of M. pneumoniae, an enhanced immune response, such as the production of cold agglutinins, was likely to be involved in the pathogenesis of erythrocyte haemolysis. The immunomodulatory property of clarithromycin was thought to repress the increased immunological reaction and thus enable the resolution of the urine abnormality. PMID- 25819057 TI - The first announcement about the 1918 "Spanish flu" pandemic in Greece through the writings of the pioneer newspaper "Thessalia" almost a century ago. AB - A local pioneer newspaper, "Thessalia", was the first to announce the arrival of "Spanish Flu" in Greece. It was July 19th 1918 when an epidemic outbreak occurred in the city of Patras. Until then, "Thessalia" had dealt in depth with the flu pandemic in the Greek district of Thessaly, informing the readers of the measures taken, as well as the social and economic aspects of the flu. PMID- 25819058 TI - [Mycobacterium infection in prehistoric humans: co-evolution in remote ages]. AB - The introduction of agriculture and animal husbandry at the end of the Mesolithic era, despite enabling a significant demographic growth through an increase in food storage and availability, caused new infectious noxae to enter the pathocoenosis. However in the Palaeolithic era, hunter-gatherers were already in contact with infectious diseases of animal origin, albeit episodically. Modern biomedical technologies allow us to estimate, with better approximation, how long mankind has been in contact with Mycobacterium tuberculosis. Archaeological finds, including human and animal remains (especially the aurochs), are particularly studied by palaeopathologists, as mycobacteria frequently cause bone involvement and this characteristic is of particular interest for palaeopathological (even macroscopic) studies; the interest is to detect the ancient DNA of MT, which is the cause of bone tuberculosis in skeletal remains as well as in mummies. According to our present knowledge, palaeopathological findings, confirmed by molecular techniques, suggest that tuberculosis in human skeletons goes back at most to 9000 years ago, while, in a veterinary environment, the most ancient DNA of MTBC to be detected in an American bison dates back about 17,000 years. The possibility of discovering archaeological finds making even more ancient human remains available leaves opens up the possibility of dating back to previous eras the transmission of MTBC infection to mankind. Phylogenetic works examining the available materials (DNAa) suggest that Mycobacterium tuberculosis, the cause of tuberculosis infection in humans and cattle (Aurochs), would have had a co-evolutionary process. On the basis of recent phylogenetic studies, the MTBC genome would have had a wide span of time to reach a suitable adjustment, co-evolving in geographical environments both at high and low host density. It is likely that the strains that did not show this strong "flexibility" underwent extinction, in favour of more versatile, adaptable strains, that are able to infect susceptible hosts "always" and in any environmental condition. PMID- 25819059 TI - Individual and area-level factors correlated with death by suicide in older adults. AB - OBJECTIVE: To determine the influence of individual and area-level characteristics associated with suicide in older adults. METHOD: This study used two complementary data sources. The first used administrative data from the Quebec Coroner's office and included information on suicide deaths in older adults aged 65years and over who died by suicide between 2000 and 2005 (n=903 persons). The second data source, which was used to identify the control group, came from a longitudinal study on seniors' health that was conducted in Quebec between 2004 and 2005 (n=2493 persons). Logistic regression analyses were used to test for associations between suicide and individual and area-level level characteristics. RESULTS: Suicide was associated with male gender, age, the presence of a physical and mental disorder and the use of health services. At the area-level level, suicide was associated with a higher population density, concentration of men, lower rates of education and higher rate of unemployment. Gender specific analyses also showed different patterns of associations on suicide risk. CONCLUSIONS: Suicide in older adults is associated with area-level and individual characteristics. This suggests that policies targeting only one level of risk factors are less likely to significantly influence suicide among this population. PMID- 25819060 TI - Automated colon cancer detection using hybrid of novel geometric features and some traditional features. AB - Automatic classification of colon into normal and malignant classes is complex due to numerous factors including similar colors in different biological constituents of histopathological imagery. Therefore, such techniques, which exploit the textural and geometric properties of constituents of colon tissues, are desired. In this paper, a novel feature extraction strategy that mathematically models the geometric characteristics of constituents of colon tissues is proposed. In this study, we also show that the hybrid feature space encompassing diverse knowledge about the tissues' characteristics is quite promising for classification of colon biopsy images. This paper thus presents a hybrid feature space based colon classification (HFS-CC) technique, which utilizes hybrid features for differentiating normal and malignant colon samples. The hybrid feature space is formed to provide the classifier different types of discriminative features such as features having rich information about geometric structure and image texture. Along with the proposed geometric features, a few conventional features such as morphological, texture, scale invariant feature transform (SIFT), and elliptic Fourier descriptors (EFDs) are also used to develop a hybrid feature set. The SIFT features are reduced using minimum redundancy and maximum relevancy (mRMR). Various kernels of support vector machines (SVM) are employed as classifiers, and their performance is analyzed on 174 colon biopsy images. The proposed geometric features have achieved an accuracy of 92.62%, thereby showing their effectiveness. Moreover, the proposed HFS-CC technique achieves 98.07% testing and 99.18% training accuracy. The better performance of HFS-CC is largely due to the discerning ability of the proposed geometric features and the developed hybrid feature space. PMID- 25819061 TI - A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naive patients with type 2 diabetes. AB - The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naive patients with type 2 diabetes in a double-blind randomized placebo controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 +/- 9.77 years and 25.01 +/- 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 +/- 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 +/- 0.45 % and -0.51 +/- 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 +/- 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 +/- 1.25 mmol/L and -0.72 +/- 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 +/- 0.15 and -0.07 +/- 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes. PMID- 25819062 TI - Whole-exome sequencing of Ethiopian patients with ichthyosis vulgaris and atopic dermatitis. PMID- 25819063 TI - Sinus microbiota varies among chronic rhinosinusitis phenotypes and predicts surgical outcome. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a prevalent multifactorial disease process in which bacteria are believed to play a role in the propagation of inflammation. Multiple subtypes of CRS have been described based on clinical and pathologic features, but a detailed examination of the sinus microbiota in patients with CRS and its clinical subtypes has yet to be performed. OBJECTIVE: We sought to examine the resident microbiota of CRS subtypes and determine whether bacterial diversity is a predictor of disease outcomes. METHODS: Sinus swabs from patients with CRS and healthy subjects collected during endoscopic sinus surgery were analyzed by means of molecular phylogenetic analysis of 16S rDNA pyrosequences. RESULTS: Fifty-six patients with CRS and 26 control subjects were studied. Biodiversity was similar between the CRS and control groups. Among the CRS subtypes examined, only 2 conditions (presence of purulence and comorbid condition of asthma) were associated with significant alterations in microbial community composition. In 27 patients with CRS who were followed postoperatively, those with better outcomes had more diverse bacterial communities present at the time of surgery, along with higher relative abundances of Actinobacteria. CONCLUSION: Analysis of microbiota in a large cohort reveals that particular CRS phenotypes (asthma and purulence) are characterized by distinct compositions of resident bacterial communities. We found that bacterial diversity and composition are predictors of surgical outcome, promoting the concept of community ecology in patients with CRS. PMID- 25819064 TI - Developing challenges in the urbanisation of village doctors in economically developed regions: A survey of 844 village doctors in Changzhou, China. AB - OBJECTIVE: To reveal the challenges of village doctors' survival and training in economically developed areas in eastern China. DESIGN: A field survey was used to assess the challenges of village doctors. SETTING: The study was conducted in Changzhou, Jiangsu province, which is an economically developed region in eastern China. PARTICIPANTS: The participants included 844 village doctors, 15 township hospital staff members and 6 health bureau leaders. RESULTS: The main challenges in Changzhou include an insufficient amount of village doctors, difficulties in obtaining professional qualification for village doctors, low salaries and benefits, and difficulties in recruitment. CONCLUSION: With increasing urbanisation in China, the gap between actual and expected income and social security has been increasing. Changes to training have influenced the stability of village doctor teams. Declining attachment of young people to their hometown village has contributed to recruitment difficulties. PMID- 25819065 TI - The nuclear translocation of ERK1/2 as an anticancer target. AB - A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter. In culture, the peptide induces apoptosis of melanoma cells inhibits the viability of other cancer cells, but has no effect on non transformed, immortalized cells. It even inhibits the viability of PLX4032- and U0126-resistant melanoma cells. In xenograft models, the peptide inhibits several cancers, and acts much better than PLX4032 in preventing melanoma recurrence. This study provides a proof of concept for using the nuclear translocation of ERK1/2 as a drug target for the combat of various ERK1/2-related cancers. PMID- 25819066 TI - Is surgery always the best treatment for severe carotid stenosis in the frail elderly? AB - OBJECTIVES: Presentation of a case of carotid stenosis in an elderly patient with multiple co-morbidities, and its management. METHODS: Pre-operative management of an elderly patient affected by carotid artery stenosis with cardiac, metabolic and renal comorbidities and a recent history of buccal squamous carcinoma. RESULTS: Pre-operative anestesiologic assessment showed an increased risk for the presence of heart failure, cardiogenic pulmonary hypertension, mild/moderate stage renal disease. CONCLUSION: The frail elderly represents a real challenge for the surgeon, because in choosing treatment other options must be taken into account both in view of local disease and of various systemic comorbidities. PMID- 25819067 TI - Editorial: scientific journal relies. PMID- 25819068 TI - Tools to support teaching and conducting research. PMID- 25819069 TI - Inter-rater reliability and validity of the Ministry of Health of Turkey's mandatory emergency triage instrument. AB - OBJECTIVES: In 2009, the Ministry of Health in Turkey mandated a three-level emergency triage scale coded with the colours red, yellow and green in descending order of acuity. This study was conducted to assess the reliability and validity of this mandatory emergency triage instrument in Turkey. METHODS: This prospective study was conducted in the ED of an academic hospital with 40,000 presentations per year. The reliability assessment was between triage of a real life patient by an emergency medical technician vs the consensus of the investigators based on retrospective medical record review. The inter-rater agreement method with quadratic weighted kappa analysis was used. The instrument's validity was measured by ED length of stay, admission rates, in hospital mortality, ED resource utilisation and lifesaving intervention. RESULTS: A total of 618 patients were assigned to either red (n = 126), yellow (n = 352), or green (n = 140) by acuity level at triage. In this study, the triage scale demonstrated 'substantial' reliability with a quadratic weighted kappa value of 0.725 (95% CI 0.68-0.77). It also suggested validity regarding all the measured surrogate markers, as they were strongly associated with acuity level (P < 0.001 for each). Spearman's rank correlation coefficient between triage acuity and total number of used resources was 0.482 (95% CI 0.42-0.54). CONCLUSIONS: This study demonstrates substantial reliability of Turkey's Ministry of Health's mandatory three-level triage instrument. Significant association was also observed between the triage levels and the validity parameters measured in the study. PMID- 25819070 TI - The value of energy spectral CT in the differential diagnosis between benign and malignant soft tissue masses of the musculoskeletal system. AB - OBJECTIVE: To explore the value of energy spectral CT in the differential diagnosis between benign and malignant tumor of the musculoskeletal system. METHODS: Energy spectral CT scan was performed on 100 patients with soft tissue mass caused by musculoskeletal tumors found by MRI. Solid areas with homogenous density were chosen as region of interests (ROI), avoiding necrosis, hemorrhage and calcification region. Select the optimal keV on single energy images, and then the keV-CT curve was automatically generated. All 100 cases of tumors proved by histological examination were divided into four groups, 38 cases were in benign group, 10 cases in borderline group, 49 cases in malignant group, and 3 cases of lipoma (that were analyzed separately since its curve was arc shaped, significantly different from other curves). The formula used to calculate the slope of spectral curve was as follows: slope=(Hu40 keV-Hu80 keV)/40. As the slope was steep within the range of 40-80 keV based on preliminary observations, 40 keV and 80 keV were used as the reference points to calculate the slope value of the energy spectral curve. Kruskal-Wallis rank sum test was applied for statistical analysis, and P<0.05 was considered to indicate a statistically significant difference. RESULTS: The spectral curve of benign group was gradually falling type with a mean slope of 0.75 +/- 0.30, that of malignant group was sharply falling type with a mean slope of 1.64 +/- 1.00, and that of borderline group was a falling type between the above two groups with a mean slope of 1.34 +/- 0.45. The differences of slopes between benign and malignant group, benign and borderline group were of statistical significance (P<0.05) respectively. The spectral curves of 3 cases of lipoma showed arc shaped rising type with a mean slope of -2.00. CONCLUSION: Spectral curve is useful in the differential diagnosis of benign and malignant tumor of the musculoskeletal system. Arc shaped curve is a specific sign for tumors containing abundant fat. PMID- 25819071 TI - [Sudden epigastric pain]. PMID- 25819072 TI - Stent deformation at the edge of a high pressure balloon. AB - Focal ultrashort balloons are essential tools for lesion preparation and final stent expansion. However, they may cause a major distortion of the adjacent segments. Here we report a case with a stent deformation emphasizing the importance of utilizing intravascular imaging techniques for optimal interventions. PMID- 25819074 TI - The Listeria monocytogenes strain 10403S BioCyc database. AB - Listeria monocytogenes is a food-borne pathogen of humans and other animals. The striking ability to survive several stresses usually used for food preservation makes L. monocytogenes one of the biggest concerns to the food industry, while the high mortality of listeriosis in specific groups of humans makes it a great concern for public health. Previous studies have shown that a regulatory network involving alternative sigma (sigma) factors and transcription factors is pivotal to stress survival. However, few studies have evaluated at the metabolic networks controlled by these regulatory mechanisms. The L. monocytogenes BioCyc database uses the strain 10403S as a model. Computer-generated initial annotation for all genes also allowed for identification, annotation and display of predicted reactions and pathways carried out by a single cell. Further ongoing manual curation based on published data as well as database mining for selected genes allowed the more refined annotation of functions, which, in turn, allowed for annotation of new pathways and fine-tuning of previously defined pathways to more L. monocytogenes-specific pathways. Using RNA-Seq data, several transcription start sites and promoter regions were mapped to the 10403S genome and annotated within the database. Additionally, the identification of promoter regions and a comprehensive review of available literature allowed the annotation of several regulatory interactions involving sigma factors and transcription factors. The L. monocytogenes 10403S BioCyc database is a new resource for researchers studying Listeria and related organisms. It allows users to (i) have a comprehensive view of all reactions and pathways predicted to take place within the cell in the cellular overview, as well as to (ii) upload their own data, such as differential expression data, to visualize the data in the scope of predicted pathways and regulatory networks and to carry on enrichment analyses using several different annotations available within the database. PMID- 25819073 TI - BioXpress: an integrated RNA-seq-derived gene expression database for pan-cancer analysis. AB - BioXpress is a gene expression and cancer association database in which the expression levels are mapped to genes using RNA-seq data obtained from The Cancer Genome Atlas, International Cancer Genome Consortium, Expression Atlas and publications. The BioXpress database includes expression data from 64 cancer types, 6361 patients and 17 469 genes with 9513 of the genes displaying differential expression between tumor and normal samples. In addition to data directly retrieved from RNA-seq data repositories, manual biocuration of publications supplements the available cancer association annotations in the database. All cancer types are mapped to Disease Ontology terms to facilitate a uniform pan-cancer analysis. The BioXpress database is easily searched using HUGO Gene Nomenclature Committee gene symbol, UniProtKB/RefSeq accession or, alternatively, can be queried by cancer type with specified significance filters. This interface along with availability of pre-computed downloadable files containing differentially expressed genes in multiple cancers enables straightforward retrieval and display of a broad set of cancer-related genes. PMID- 25819075 TI - LOTUS-DB: an integrative and interactive database for Nelumbo nucifera study. AB - Besides its important significance in plant taxonomy and phylogeny, sacred lotus (Nelumbo nucifera Gaertn.) might also hold the key to the secrets of aging, which attracts crescent attentions from researchers all over the world. The genetic or molecular studies on this species depend on its genome information. In 2013, two publications reported the sequencing of its full genome, based on which we constructed a database named as LOTUS-DB. It will provide comprehensive information on the annotation, gene function and expression for the sacred lotus. The information will facilitate users to efficiently query and browse genes, graphically visualize genome and download a variety of complex data information on genome DNA, coding sequence (CDS), transcripts or peptide sequences, promoters and markers. It will accelerate researches on gene cloning, functional identification of sacred lotus, and hence promote the studies on this species and plant genomics as well. Database URL: http://lotus-db.wbgcas.cn PMID- 25819077 TI - Identification of a small set of plasma signalling proteins using neural network for prediction of Alzheimer's disease. AB - MOTIVATION: Alzheimer's disease (AD) is a dementia that gets worse with time resulting in loss of memory and cognitive functions. The life expectancy of AD patients following diagnosis is ~7 years. In 2006, researchers estimated that 0.40% of the world population (range 0.17-0.89%) was afflicted by AD, and that the prevalence rate would be tripled by 2050. Usually, examination of brain tissues is required for definite diagnosis of AD. So, it is crucial to diagnose AD at an early stage via some alternative methods. As the brain controls many functions via releasing signalling proteins through blood, we analyse blood plasma proteins for diagnosis of AD. RESULTS: Here, we use a radial basis function (RBF) network for feature selection called feature selection RBF network for selection of plasma proteins that can help diagnosis of AD. We have identified a set of plasma proteins, smaller in size than previous study, with comparable prediction accuracy. We have also analysed mild cognitive impairment (MCI) samples with our selected proteins. We have used neural networks and support vector machines as classifiers. The principle component analysis, Sammmon projection and heat-map of the selected proteins have been used to demonstrate the proteins' discriminating power for diagnosis of AD. We have also found a set of plasma signalling proteins that can distinguish incipient AD from MCI at an early stage. Literature survey strongly supports the AD diagnosis capability of the selected plasma proteins. PMID- 25819076 TI - Does the addition of specific acupuncture to standard swallowing training improve outcomes in patients with dysphagia after stroke? a randomized controlled trial. AB - OBJECTIVE: To assess the effect of adding acupuncture to standard swallowing training for patients with dysphagia after stroke. DESIGN: Single-blind randomized controlled trial. SETTING: Inpatient and outpatient clinics. SUBJECTS: A total of 124 patients with dysphagia after stroke were randomly divided into two groups: acupuncture and control. INTERVENTIONS: The acupuncture group received standard swallowing training and acupuncture treatment. In comparison, the control group only received standard swallowing training. Participants in both groups received six days of therapy per week for a four-week period. MAIN MEASURES: The primary outcome measures included the Standardized Swallowing Assessment and the Dysphagia Outcome Severity Scale. The secondary outcome measures included the Modified Barthel Index and Swallowing-Related Quality of Life, which were assessed before and after the four-week therapy period. RESULTS: A total of 120 dysphagic subjects completed the study (60 in acupuncture group and 60 in control group). Significant differences existed in the Standardized Swallowing Assessment, Dysphagia Outcome Severity Scale, Modified Barthel Index, and Swallowing-Related Quality of Life scores of each group after the treatment (P < 0.01). After the four-week treatment, the Standardized Swallowing Assessment (mean difference - 2.9; 95% confidence interval (CI) - 5.0 to - 0.81; P < 0.01), Dysphagia Outcome Severity Scale (mean difference 2.3; 95% CI 0.7 to 1.2; P < 0.01), Modified Barthel Index (mean difference 17.2; 95% CI 2.6 to 9.3; P < 0.05) and Swallowing-Related Quality of Life scores (mean difference 31.4; 95% CI 3.2 to 11.4; P < 0.01) showed more significant improvement in the acupuncture group than the control group. CONCLUSIONS: Acupuncture combined with the standard swallowing training may be beneficial for dysphagic patients after stroke. PMID- 25819078 TI - Halvade: scalable sequence analysis with MapReduce. AB - MOTIVATION: Post-sequencing DNA analysis typically consists of read mapping followed by variant calling. Especially for whole genome sequencing, this computational step is very time-consuming, even when using multithreading on a multi-core machine. RESULTS: We present Halvade, a framework that enables sequencing pipelines to be executed in parallel on a multi-node and/or multi-core compute infrastructure in a highly efficient manner. As an example, a DNA sequencing analysis pipeline for variant calling has been implemented according to the GATK Best Practices recommendations, supporting both whole genome and whole exome sequencing. Using a 15-node computer cluster with 360 CPU cores in total, Halvade processes the NA12878 dataset (human, 100 bp paired-end reads, 50* coverage) in <3 h with very high parallel efficiency. Even on a single, multi core machine, Halvade attains a significant speedup compared with running the individual tools with multithreading. PMID- 25819079 TI - DEOD: uncovering dominant effects of cancer-driver genes based on a partial covariance selection method. AB - MOTIVATION: The generation of a large volume of cancer genomes has allowed us to identify disease-related alterations more accurately, which is expected to enhance our understanding regarding the mechanism of cancer development. With genomic alterations detected, one challenge is to pinpoint cancer-driver genes that cause functional abnormalities. RESULTS: Here, we propose a method for uncovering the dominant effects of cancer-driver genes (DEOD) based on a partial covariance selection approach. Inspired by a convex optimization technique, it estimates the dominant effects of candidate cancer-driver genes on the expression level changes of their target genes. It constructs a gene network as a directed weighted graph by integrating DNA copy numbers, single nucleotide mutations and gene expressions from matched tumor samples, and estimates partial covariances between driver genes and their target genes. Then, a scoring function to measure the cancer-driver score for each gene is applied. To test the performance of DEOD, a novel scheme is designed for simulating conditional multivariate normal variables (targets and free genes) given a group of variables (driver genes). When we applied the DEOD method to both the simulated data and breast cancer data, DEOD successfully uncovered driver variables in the simulation data, and identified well-known oncogenes in breast cancer. In addition, two highly ranked genes by DEOD were related to survival time. The copy number amplifications of MYC (8q24.21) and TRPS1 (8q23.3) were closely related to the survival time with P values = 0.00246 and 0.00092, respectively. The results demonstrate that DEOD can efficiently uncover cancer-driver genes. PMID- 25819080 TI - MSA-PAD: DNA multiple sequence alignment framework based on PFAM accessed domain information. AB - Here we present the MSA-PAD application, a DNA multiple sequence alignment framework that uses PFAM protein domain information to align DNA sequences encoding either single or multiple protein domains. MSA-PAD has two alignment options: gene and genome mode. PMID- 25819081 TI - Assessing allele-specific expression across multiple tissues from RNA-seq read data. AB - MOTIVATION: RNA sequencing enables allele-specific expression (ASE) studies that complement standard genotype expression studies for common variants and, importantly, also allow measuring the regulatory impact of rare variants. The Genotype-Tissue Expression (GTEx) project is collecting RNA-seq data on multiple tissues of a same set of individuals and novel methods are required for the analysis of these data. RESULTS: We present a statistical method to compare different patterns of ASE across tissues and to classify genetic variants according to their impact on the tissue-wide expression profile. We focus on strong ASE effects that we are expecting to see for protein-truncating variants, but our method can also be adjusted for other types of ASE effects. We illustrate the method with a real data example on a tissue-wide expression profile of a variant causal for lipoid proteinosis, and with a simulation study to assess our method more generally. PMID- 25819083 TI - Cloning and primary immunological study of TGF-beta1 and its receptors TbetaR I /TbetaR II in tilapia(Oreochromis niloticus). AB - The transforming growth factor beta (TGF-beta) superfamily plays critical roles in tumor suppression, cell proliferation and differentiation, tissue morphogenesis, lineage determination, cell migration and apoptosis. Recently, TGF beta1, one important member of TGF-beta superfamily, is suggested as an immune regulator in the teleost. In this study, we cloned the cDNAs of TGF-beta1 and its receptors, TbetaR I and TbetaR II (including three isoforms) from tilapia (Genbank accession numbers: KP754231- KP754235). A tissue distribution profile analysis indicated that TGF-beta1 was highly expressed in the head kidney, gill, spleen, kidney and PBLs (peripheral blood leukocytes); TbetaR I only showed considerable expression in the liver; and TbetaR II-2 was highly expressed in the kidney, gill, liver, head kidney and heart. We determined that the mRNA expressions of TGF-beta and TbetaR I /TbetaR II-2 were significantly increased in tilapia head kidney and spleen leukocytes by the stimulation of Lipopolysaccharide (LPS) or Poly I: C. We also examined their expressions in the spleen and head kidney of tilapia after IP injection of streptococcus agalactiae. The results showed that the mRNA expressions of these three genes all increased in the head kidney as early as 6 h post infection, and in the spleen 3 d post infection. In addition, the protein level of TGF-beta1 was also up-regulated in the head kidney and the spleen after infection. Taken together, our data indicate that the TGF-beta1-TbetaR I /TbetaR II-2 system functions potentially in tilapia immune system. PMID- 25819084 TI - Diagnostic criteria of chronic inflammatory demyelinating polyneuropathy in diabetes mellitus. AB - OBJECTIVE: The possibility of co-association between diabetes mellitus (DM) and chronic inflammatory demyelinating polyneuropathy (CIDP) has long been a focus of interest as well as of clinical significance. As CIDP is a potentially treatable condition, it is diagnosis in the context of DM is of great importance. However, diagnostic criteria to identify CIDP in patients with diabetes are not available. We propose a diagnostic tool that should help clinicians to decide what is the probability that a patient with diabetes might have CIDP. METHODS: We list several clinical, electrophysiological, and laboratory parameters that, when combined, have the power of discriminating an immune-mediated neuropathy in patients with DM. By summing the points assigned to each of these parameters, we define four levels of probability for a patient with diabetes to have CIDP. To analyze the validity of the diagnostic toll, we applied it in three different patient populations: (i) Patients with diabetes with peripheral neuropathy, (ii) Patients with CIDP without DM, and (iii) Patients with diabetes with CIDP. RESULTS: The scores of patients with diabetes without CIDP ranged from -7 to 2, while those of patients with DM-CIDP ranged from 2 to 20. The scores of non diabetic patients with CIDP were similar to those of patients with DM-CIDP and ranged from 6 to 16. The mean score of patients with DM-CIDP was 9.083, while the score of patients with CIDP was 11.16 and that of patients with diabetic polyneuropathy was -3.59. CONCLUSIONS: These results show that this diagnostic tool is able to identify patients with diabetes with overlapping CIDP. PMID- 25819085 TI - Genetic study of complex diseases in the post-GWAS era. AB - Genome-wide association studies (GWASs) have identified thousands of genes and genetic variants (mainly SNPs) that contribute to complex diseases in humans. Functional characterization and mechanistic elucidation of these SNPs and genes action are the next major challenge. It has been well established that SNPs altering the amino acids of protein-coding genes can drastically impact protein function, and play an important role in molecular pathogenesis. Functions of regulatory SNPs can be complex and elusive, and involve gene expression regulation through the effect on RNA splicing, transcription factor binding, DNA methylation and miRNA recruitment. In the present review, we summarize the recent progress in our understanding of functional consequences of GWAS-associated non coding regulatory SNPs, and discuss the application of systems genetics and network biology in the interpretation of GWAS findings. PMID- 25819086 TI - Large noncoding RNAs are promising regulators in embryonic stem cells. AB - Embryonic stem cells (ESCs) hold great promises for treating and studying numerous devastating diseases. The molecular basis of their potential is not completely understood. Large noncoding RNAs (lncRNAs) are an important class of gene regulators that play essential roles in a variety of physiologic and pathologic processes. Dozens of lncRNAs are now identified to control ESC self renewal and differentiation. Research on lncRNAs may provide novel insights into manipulating the cell fate or reprogramming somatic cells into induced pluripotent stem cells (iPSCs). In this review, we summarize the recent research efforts in identifying functional lncRNAs and understanding how they act in ESCs, and discuss various future directions of this field. PMID- 25819088 TI - Downregulation of rice DWARF 14 LIKE suppress mesocotyl elongation via a strigolactone independent pathway in the dark. AB - Strigolactones (SLs) are a class of plant hormones that control plant development in response to environmental conditions. In rice, mesocotyl elongation is regulated by SLs in the dark, while mesocotyls are longer in SL deficient or insensitive mutants. SLs are perceived by DWARF14 (D14), which is a member of a small gene family. In this study, we examined the function of another D14 family gene in rice, D14 LIKE (D14L), focusing on mesocotyl growth. The mesocotyls of D14L RNAi lines are longer than those of WT in the dark. This phenotype is enhanced when the D14L RNAi lines are combined with the d14 mutation, suggesting that D14 and D14L work independently to inhibit mesocotyl elongation. This phenotype is alleviated by the exogenous supply of GR24, a synthetic SL, suggesting that D14L is not necessary for SL signaling. D14L mRNA is predominantly expressed in vascular bundles and crown root primordia. Our results suggest that D14L and D14 confer their effects via an SL independent pathway and an SL signaling pathway respectively. PMID- 25819087 TI - Genome-wide linkage and positional association analyses identify associations of novel AFF3 and NTM genes with triglycerides: the GenSalt study. AB - We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2-2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3 11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM) with triglycerides (P = 4 * 10(-4), 1.00 * 10(-5), 2.00 * 10(-5), and 1.00 * 10(-7), respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 * 10(-7) and 8.00 * 10(-5), respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11. PMID- 25819089 TI - Generation of an lncRNA Gtl2-GFP reporter for rapid assessment of pluripotency in mouse induced pluripotent stem cells. PMID- 25819090 TI - Development of Triticum aestivum-Leymus mollis translocation lines and identification of resistance to stripe rust. PMID- 25819091 TI - A novel method for furfural recovery via gas stripping assisted vapor permeation by a polydimethylsiloxane membrane. AB - Furfural is an important platform chemical with a wide range of applications. However, due to the low concentration of furfural in the hydrolysate, the conventional methods for furfural recovery are energy-intensive and environmentally unfriendly. Considering the disadvantages of pervaporation (PV) and distillation in furfural separation, a novel energy-efficient 'green technique', gas stripping assisted vapor permeation (GSVP), was introduced in this work. In this process, the polydimethylsiloxane (PDMS) membrane was prepared by employing water as solvent. Coking in pipe and membrane fouling was virtually non-existent in this new process. In addition, GSVP was found to achieve the highest pervaporation separation index of 216200 (permeate concentration of 71.1 wt% and furfural flux of 4.09 kg m(-2) h(-1)) so far, which was approximately 2.5 times higher than that found in pervaporation at 95 degrees C for recovering 6.0 wt% furfural from water. Moreover, the evaporation energy required for GSVP decreased by 35% to 44% relative to that of PV process. Finally, GSVP also displayed more promising potential in industrial application than PV, especially when coupled with the hydrolysis process or fermentation in biorefinery industry. PMID- 25819092 TI - Calcium-phosphate and parathyroid intradialytic profiles: A potential aid for tailoring the dialysate calcium content of patients on different hemodialysis schedules. AB - Severe hyperparathyroidism is a challenge on hemodialysis. The definition of dialysate calcium (Ca) is a pending issue with renewed importance in cases of individualized dialysis schedules and of portable home dialysis machines with low flow dialysate. Direct measurement of calcium mass transfer is complex and is imprecisely reflected by differences in start-to-end of dialysis Ca levels. The study was performed in a dialysis unit dedicated to home hemodialysis and to critical patients with wide use of daily and tailored schedules. The Ca-phosphate (P)-parathyroid hormone (PTH) profile includes creatinine, urea, total and ionized Ca, albumin, sodium, potassium, P, PTH levels at start, mid, and end of dialysis. "Severe" secondary hyperparathyroidism was defined as PTH > 300 pg/mL for >=3 months. Four schedules were tested: conventional dialysis (polysulfone dialyzer 1.8-2.1 m(2) ), with dialysate Ca 1.5 or 1.75 mmol/L, NxStage (Ca 1.5 mmol/L), and NxStage plus intradialytic Ca infusion. Dosages of vitamin D, calcium, phosphate binders, and Ca mimetic agents were adjusted monthly. Eighty Ca-P-PTH profiles were collected in 12 patients. Serum phosphate was efficiently reduced by all techniques. No differences in start-to-end PTH and Ca levels on dialysis were observed in patients with PTH levels < 300 pg/mL. Conversely, Ca levels in "severe" secondary hyperparathyroid patients significantly increased and PTH decreased during dialysis on all schedules except on Nxstage (P < 0.05). Our data support the need for tailored dialysate Ca content, even on "low-flow" daily home dialysis, in "severe" secondary hyperparathyroid patients in order to increase the therapeutic potentials of the new dialysis techniques. PMID- 25819093 TI - Synthesis of [(11)C]GSK1482160 as a new PET agent for targeting P2X(7) receptor. AB - The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3 (trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [(11)C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [(11)C]CH3OTf through N-[(11)C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/MUmol with a total synthesis time of ~40-min from EOB. PMID- 25819094 TI - Synthesis and biological evaluation of nonionic substrate mimics of UDP-Galp as candidate inhibitors of UDP galactopyranose mutase (UGM). AB - The synthesis of 1-[5-O-(alpha-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H) dione and 1-[(5-O-(beta-D-galactopyranosyl)-D-glucityl]pyrimidine-2,4(3H)-dione as non-ionic substrate mimics of UDP-Galp are described. UDP-Galp is a precursor of Galf, which is a primary component of the cell-wall glycans of several microorganisms. The interconversion of UDP-Galp and UDP-Galf is catalyzed by UDP galactopyranose mutase (UGM); its inhibition comprises a mode of compromising the microorganisms. The nonionic polyhydroxylated chain was intended to mimic the ionic pyrophosphate group and the ribose moiety in UDP-Galp and increase the bioavailabilities of the candidate inhibitors. Inhibition assays with UGM of Mycobacterium tuberculosis showed only weak inhibition of the enzyme by these compounds. PMID- 25819095 TI - Pharmacokinetic, pharmacodynamic and metabolic characterization of a brain retentive microtubule (MT)-stabilizing triazolopyrimidine. AB - Previous studies revealed that examples of the non-naturally occurring microtubule (MT)-stabilizing triazolopyrimidines are both brain penetrant and orally bioavailable, indicating that this class of compounds may be potentially attractive in the development of MT-stabilizing therapies for the central nervous system (CNS). We now report on the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of a selected triazolopyrimidine congener, (S)-3-(4-(5-chloro-7 ((1,1,1-trifluoropropan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5 difluorophenoxy)-propan-1-ol (4). These studies revealed that 4 exhibits longer brain than plasma half-life that may be exploited to achieve a selective accumulation of the compound within the CNS. Furthermore, compound metabolism studies suggest that in plasma 4 is rapidly oxidized at the terminal hydroxyl group to form a comparatively inactive carboxylic acid metabolite. Peripheral administration of relatively low doses of 4 to normal mice was found to produce a significant elevation in acetylated alpha-tubulin, a marker of stable MTs, in the brain. Collectively, these results indicate that 4 may effectively target brain MTs at doses that produce minimal peripheral exposure. PMID- 25819096 TI - Five new phorbol esters with cytotoxic and selective anti-inflammatory activities from Croton tiglium. AB - Five new phorbol esters, (four phorbol diesters, 1-4, and one 4-deoxy-4alpha phorbol diester, 5), as well as four known phorbol esters analogues (6-9) were isolated and identified from the branches and leaves of Croton tiglium. Their structures were elucidated mainly by extensive NMR spectroscopic, and mass spectrometric analysis. Among them, compound (1) was the first example of a naturally occurring phorbol ester with the 20-aldehyde group. Compounds 2-5, and 7-9 showed potent cytotoxicity against the K562, A549, DU145, H1975, MCF-7, U937, SGC-7901, HL60, Hela, and MOLT-4 cell lines, with IC50 values ranging from 1.0 to 43 MUM, while none of the compounds exhibited cytotoxic effects on normal human cell lines 293T and LX-2, respectively. In addition, compound 3 exhibited moderate COX-1 and COX-2 inhibition, with IC50 values of 0.14 and 8.5 MUM, respectively. PMID- 25819097 TI - Asymmetric hydrogenation of aromatic ketones by new recyclable ionic tagged ferrocene-ruthenium catalyst system. AB - Newly developed ferrocene-oxazoline-phosphine ligands containing quaternary ammonium ionic groups exhibited excellent catalytic performance for the ruthenium catalyzed hydrogenation of aromatic ketonic substrates to give chiral secondary alcohols with high levels of conversions and enantioselectivities. Simple manipulation process, water tolerance, high activity and good recyclable property make this catalysis practical and appealing. PMID- 25819098 TI - Canthinone alkaloids are novel protein tyrosine phosphatase 1B inhibitors. AB - Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes. Screening of a natural compound library resulted in six canthinone alkaloids, namely, picrasidine L (1), 3,4 dimethyl-canthin-5,6-dione (2), 4-ethyl-3-methyl-canthin-5,6-dione (3), eurycomine E (4), 5-methoxy-canthin-6-one (5), and 5-acethoxy-canthin-6-one (6), as novel PTP1B inhibitors. Among these, 1 is the competitive PTP1B inhibitor with the best inhibitory selectivity between PTP1B and other PTPs and was shown to promote activity in the insulin signaling pathway in cell-based assays. Molecular docking simulations and structure-activity relationship analysis of 1 will add to its potential as a lead compound in future anti-insulin-resistant drug developments. PMID- 25819099 TI - Prognostic factors in pterygopalatine and infratemporal fossa malignant tumours: A single institution experience. AB - PURPOSE: To elucidate the clinical characteristics of malignancies involving the pterygopalatine and infratemporal fossa and identify the outcome-related predictors. METHODS: A retrospective review of the patients diagnosed with malignancies involving these spaces between 2006 and 2013 was conducted. We investigated the 5-year recurrence free survival, metastasis free survival and overall survival, and univariate and multivariate analysis were used to identify the outcome-related factors. RESULTS: A total of 80 patients (46 male and 34 female) aged from 1 to 82 years were retrospectively analysed. The most frequent location for involved malignancies included the pterygopalatine fossa (n = 35, 43.8%), followed by the infratemporal fossa (n = 25, 31.2%) and the pterygopalatine and infratemporal fossa together (n = 20, 25%). In multivariate analysis, gender (HR: 2.59, 95% CI: 1.034-6.488, p = 0.042), margin status (HR: 6.158, 95% CI: 2.115-17.932, p = 0.001) and adjuvant radiotherapy (HR: 3.116, 95% CI: 1.057-9.191, p = 0.039) were predictors for the 5-year recurrence-free survival rate, and brain invasion (HR: 6.218, 95% CI: 1.375-28.115, p = 0.018) and surgical margin (HR: 21.961, 95% CI: 2.383-202.418, p = 0.006) were predictors for the 5-year overall survival rate. CONCLUSION: These results indicate that malignancies involving the pterygopalatine and infratemporal fossa have a poor prognosis. Brain invasion is a dangerous sign for decreased survival. An ideal surgical margin is associated with a lower recurrence and higher survival rate. Adjuvant radiotherapy should be performed to achieve better local control. PMID- 25819100 TI - Linguistic labels, dynamic visual features, and attention in infant category learning. AB - How do words affect categorization? According to some accounts, even early in development words are category markers and are different from other features. According to other accounts, early in development words are part of the input and are akin to other features. The current study addressed this issue by examining the role of words and dynamic visual features in category learning in 8- to 12 month-old infants. Infants were familiarized with exemplars from one category in a label-defined or motion-defined condition and then tested with prototypes from the studied category and from a novel contrast category. Eye-tracking results indicated that infants exhibited better category learning in the motion-defined condition than in the label-defined condition, and their attention was more distributed among different features when there was a dynamic visual feature compared with the label-defined condition. These results provide little evidence for the idea that linguistic labels are category markers that facilitate category learning. PMID- 25819101 TI - [Christoph Willibald Gluck (Erasbach [berching], Germany, 1714/Vienna, Austria, 1787)]. PMID- 25819102 TI - Post-trauma administration of the pifithrin-alpha oxygen analog improves histological and functional outcomes after experimental traumatic brain injury. AB - Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Programmed death of neuronal cells plays a crucial role in acute and chronic neurodegeneration following TBI. The tumor suppressor protein p53, a transcription factor, has been recognized as an important regulator of apoptotic neuronal death. The p53 inactivator pifithrin-alpha (PFT-alpha) has been shown to be neuroprotective against stroke. A previous cellular study indicated that PFT alpha oxygen analog (PFT-alpha (O)) is more stable and active than PFT-alpha. We aimed to investigate whether inhibition of p53 using PFT-alpha or PFT-alpha (O) would be a potential neuroprotective strategy for TBI. To evaluate whether these drugs protect against excitotoxicity in vitro, primary rat cortical cultures were challenged with glutamate (50mM) in the presence or absence of various concentrations of the p53 inhibitors PFT-alpha or PFT-alpha (O). Cell viability was estimated by LDH assay. In vivo, adult Sprague Dawley rats were subjected to controlled cortical impact (CCI, with 4m/s velocity, 2mm deformation). Five hours after injury, PFT-alpha or PFT-alpha (O) (2mg/kg, i.v.) was administered to animals. Sensory and motor functions were evaluated by behavioral tests at 24h after TBI. The p53-positive neurons were identified by double staining with cell specific markers. Levels of mRNA encoding for p53-regulated genes (BAX, PUMA, Bcl 2 and p21) were measured by reverse transcription followed by real time-PCR from TBI animals without or with PFT-alpha/PFT-alpha (O) treatment. We found that PFT alpha(O) (10 MUM) enhanced neuronal survival against glutamate-induced cytotoxicity in vitro more effectively than PFT-alpha (10 MUM). In vivo PFT-alpha (O) treatment enhanced functional recovery and decreased contusion volume at 24h post-injury. Neuroprotection by PFT-alpha (O) treatment also reduced p53-positive neurons in the cortical contusion region. In addition, p53-regulated PUMA mRNA levels at 8h were significantly reduced by PFT-alpha (O) administration after TBI. PFT-alpha (O) treatment also decreased phospho-p53 positive neurons in the cortical contusion region. Our data suggest that PFT-alpha (O) provided a significant reduction of cortical cell death and protected neurons from glutamate induced excitotoxicity in vitro, as well as improved neurological functional outcome and reduced brain injury in vivo via anti-apoptotic mechanisms. The inhibition of p53-induced apoptosis by PFT-alpha (O) provides a useful tool to evaluate reversible apoptotic mechanisms and may develop into a novel therapeutic strategy for TBI. PMID- 25819103 TI - Lesion-induced accumulation of platelets promotes survival of adult neural stem / progenitor cells. AB - The presence of neural stem/progenitor cells (NSPCs) in specific areas of the central nervous system (CNS) supports tissue maintenance as well as regeneration. The subependymal zone (SEZ), located at the lateral ventricle's wall, represents a niche for NSPCs and in response to stroke or demyelination becomes activated with progenitors migrating towards the lesion and differentiating into neurons and glia. The mechanisms that underlie this phenomenon remain largely unknown. The vascular niche and in particular blood-derived elements such as platelets, has been shown to contribute to CNS regeneration in different pathological conditions. Indeed, intracerebroventricularly administrated platelet lysate (PL) stimulates angiogenesis, neurogenesis and neuroprotection in the damaged CNS. Here, we explored the presence of platelets in the activated SEZ after a focal demyelinating lesion in the corpus callosum of mice and we studied the effects of PL on proliferating SEZ-derived NSPCs in vitro. We showed that the lesion-induced increase in the size of the SEZ and in the number of proliferating SEZ-resident NSPCs correlates with the accumulation of platelets specifically along the activated SEZ vasculature. Expanding on this finding, we demonstrated that exposure of NSPCs to PL in vitro led to increased numbers of cells by enhanced cell survival and reduced apoptosis without differences in proliferation and in the differentiation potential of NSPCs. Finally, we demonstrate that the accumulation of platelets within the SEZ is spatially correlated with reduced numbers of apoptotic cells when compared to other periventricular areas. In conclusion, our results show that platelet-derived compounds specifically promote SEZ-derived NSPC survival and suggest that platelets might contribute to the enlargement of the pool of SEZ NSPCs that are available for CNS repair in response to injury. PMID- 25819105 TI - Spreading depolarizations mediate excitotoxicity in the development of acute cortical lesions. AB - Spreading depolarizations (SD) are mass depolarizations of neurons and astrocytes that occur spontaneously in acute brain injury and mediate time-dependent lesion growth. Glutamate excitotoxicity has also been extensively studied as a mechanism of neuronal injury, although its relevance to in vivo pathology remains unclear. Here we hypothesized that excitotoxicity in acute lesion development occurs only as a consequence of SD. Using glutamate-sensitive microelectrodes, we found that SD induced by KCl in normal rat cortex elicits increases in extracellular glutamate (11.6+/-1.3MUM) that are synchronous with the onset, sustainment, and resolution of the extracellular direct-current shift of SD. Inhibition of glutamate uptake with d,l-threo-beta-benzyloxyaspartate (TBOA, 0.5 and 1mM) significantly prolonged the duration of the direct-current shift (148% and 426%, respectively) and the glutamate increase (167% and 374%, respectively) in a dose dependent manner (P<0.05). These prolonged events produced significant cortical lesions as indicated by Fluoro-Jade staining (P<0.05), while no lesions were observed after SD in control conditions or after cortical injection of 1mM glutamate (extracellular increase: 243+/-50.8MUM) or 0.5mM TBOA (glutamate increase: 8.5+/-1.6MUM) without SD. We then used an embolic focal ischemia model to determine whether glutamate elevations occur independent of SD in the natural evolution of a cortical lesion. In both the ischemic core and penumbra, glutamate increased only in synchrony with anoxic terminal SD (6.1+/-1.1MUM) and transient SDs (11.8+/-2.4MUM), and not otherwise. Delayed terminal SDs were also observed in two animals at 98 and 150min after ischemic onset and induced similar glutamate elevations. Durations of SDs and glutamate increases were significantly correlated in both normal and ischemic animals (P<0.05). These data suggest that pathologically prolonged SDs are a required mechanism of acute cortical lesion development and that glutamate elevations and the mass electrochemical changes of SD and are merely different facets of the same pathophysiologic process. PMID- 25819106 TI - Cumulative mental health consequences of acne: 23-year follow-up in a general population birth cohort study. PMID- 25819107 TI - MY APPROACH to the patient with pulmonary embolism. PMID- 25819104 TI - Demyelination as a rational therapeutic target for ischemic or traumatic brain injury. AB - Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients. PMID- 25819108 TI - Bisphenol A exposure accelerated the aging process in the nematode Caenorhabditis elegans. AB - Bisphenol A (BPA) is a well-known environmental estrogenic disruptor that causes adverse effects. Recent studies have found that chronic exposure to BPA is associated with a high incidence of several age-related diseases. Aging is characterized by progressive function decline, which affects quality of life. However, the effects of BPA on the aging process are largely unknown. In the present study, by using the nematode Caenorhabditis elegans as a model, we investigated the influence of BPA exposure on the aging process. The decrease in body length, fecundity, and population size and the increased egg laying defection suggested that BPA exposure resulted in fitness loss and reproduction aging in this animal. Lifetime exposure of worms to BPA shortened the lifespan in a dose-dependant manner. Moreover, prolonged BPA exposure resulted in age-related behavior degeneration and the accumulation of lipofuscin and lipid peroxide products. The expression of mitochondria-specific HSP-6 and endoplasmic reticulum (ER)-related HSP-70 exhibited hormetic decrease. The expression of ER-related HSP 4 decreased significantly while HSP-16.2 showed a dose-dependent increase. The decreased expression of GCS-1 and GST-4 implicated the reduced antioxidant ability under BPA exposure, and the increase in SOD-3 expression might be caused by elevated levels of reactive oxygen species (ROS) production. Finally, BPA exposure increased the generation of hydrogen peroxide-related ROS and superoxide anions. Our results suggest that BPA exposure resulted in an accelerated aging process in C. elegans mediated by the induction of oxidative stress. PMID- 25819109 TI - Tributyltin chloride leads to adiposity and impairs metabolic functions in the rat liver and pancreas. AB - Tributyltin chloride (TBT) is an environmental contaminant used in antifouling paints of boats. Endocrine disruptor effects of TBT are well established in animal models. However, the adverse effects on metabolism are less well understood. The toxicity of TBT in the white adipose tissue (WAT), liver and pancreas of female rats were assessed. Animals were divided into control and TBT (0.1 MUg/kg/day) groups. TBT induced an increase in the body weight of the rats by the 15th day of oral exposure. The weight gain was associated with high parametrial (PR) and retroperitoneal (RP) WAT weights. TBT-treatment increased the adiposity, inflammation and expression of ERalpha and PPARgamma proteins in both RP and PR WAT. In 3T3-L1 cells, estrogen treatment reduced lipid droplets accumulation, however increased the ERalpha protein expression. In contrast, TBT treatment increased the lipid accumulation and reduced the ERalpha expression. WAT metabolic changes led to hepatic inflammation, lipid accumulation, increase of PPARgamma and reduction of ERalpha protein expression. Accordingly, there were increases in the glucose tolerance and insulin sensitivity tests with increases in the number of pancreatic islets and insulin levels. These findings suggest that TBT leads to adiposity in WAT specifically, impairing the metabolic functions of the liver and pancreas. PMID- 25819110 TI - Femoral Traction Splints in Mountain Rescue Prehospital Care: To Use or Not to Use? That Is the Question. AB - OBJECTIVES: To determine the incidence of femur fractures in mountain rescue in England and Wales. To investigate the attitudes of rescuers toward the use of femoral traction splints. To review the literature for evidence on the use of traction splints in prehospital medicine and test the hypothesis that femoral traction splints reduce morbidity and mortality in patients with a fractured femur. METHODS: The Mountain Rescue England and Wales database was searched for cases of suspected fractured femur occurring between 2002 and 2012, a questionnaire was sent to all mountain rescue teams in England and Wales, and a literature review was performed. Relevant articles were critically reviewed to identify the evidence base for the use of femoral traction splints. RESULTS: Femur fractures are uncommon in mountain rescue, with an incidence of suspected femur fractures on scene at 9.3 a year. Traction splints are used infrequently; 13% of the suspected femur fractures were treated with traction. However, rescuers have a positive attitude toward traction splints and perceive few disadvantages to their use. No trials demonstrate that traction splints reduce morbidity or mortality, but a number describe complications resulting from their use. CONCLUSIONS: Femur fractures are rare within mountain rescue. Traction splints may be no more effective than other methods of splinting in prehospital care. We failed to identify evidence that supports the hypothesis that traction splints reduce morbidity or mortality. We advocate the use of a femoral traction splints but recognize that other splints may also be appropriate in this environment. PMID- 25819111 TI - Cardiovascular and Perceptual Responses to an Ultraendurance Channel Swim: A Case Study. AB - Ultraendurance open water swimming presents unique physiological challenges. This case study aimed to describe cardiovascular and perceptual responses during a successful solo channel swim. Investigators followed a female swimmer's Catalina Channel (32.2 km) crossing, monitoring water temperature (T(water)) and air temperature (T(air)), distance remaining (DR), average velocity, and heart rate (HR(swim)) at regular intervals. Every 24 minutes, the swimmer reported perceived pain (on a scale of 0-10), rating of perceived exertion (RPE [scale of 6-20]), perceived thermal sensation (scale 0-8), and thirst (scale 1-9). Data are presented as mean +/- SD where applicable. The participant finished in 9 hours, 2 minutes, and 48 seconds; T(water) averaged 19.1 +/- 0.4oC, and T(air) averaged 18.6 +/- 0.9oC. Her HR(swim) ranged from 148 to 155 beats/min, and thermal sensation ranged from 3 to 4. Pain inconsistently varied from 0 to 5 during the swim. The RPE remained between 12 and 14 for the first 8 hours, but increased dramatically near the end (reaching 18). Thirst sensation steadily increased throughout the swim, again reaching maximal values on completion. Physiologically and statistically significant correlations existed between thirst and DR (r = 0.905), RPE and HR(swim) (r = 0.741), RPE and DR (r = -0.694), and pain and DR (r = -0.671). The primary findings were that, despite fluctuations in perceptual stressors, the swimmer maintained a consistent exercise intensity as indicated by HR(swim); and during ultraendurance swimming, pain, RPE, and thirst positively correlated with distance swum. We hope these findings aid in the preparation and performance of future athletes by providing information on what swimmers may expect during an ultraendurance attempt and by increasing the understanding of physiological and perceptual responses during open water swimming. PMID- 25819112 TI - Enhancing vaccine design strategies: applications for protein science, proteomics and adjuvants. PMID- 25819113 TI - Decreased thalamic glutamate level in unmedicated adult obsessive-compulsive disorder patients detected by proton magnetic resonance spectroscopy. AB - BACKGROUND: Previous neuroimaging studies implied that the dysfunction of cortico striato-thalamo-cortical (CSTC) circuit served as the neural basis for the pathophysiology of obsessive-compulsive disorder (OCD). The imbalances in neuronal metabolite and neurotransmitter within CSTC circuit have been shown as the leading reasons of the OCD onset. The aim of this study is to investigate the metabolic alterations, especially the glutamatergic signal dysfunction within CSTC circuit, and the relationships between neural metabolites and the symptom severity of OCD patients. METHODS: Single voxel magnetic resonance spectroscopy (MRS) was conducted in medial prefrontal cortex (mPFC) and bilateral thalamus areas for thirteen unmedicated adult OCD patients with age-, gender-, and education-matched healthy controls. Quantification and multivariate analysis were performed to identify vital metabolic biomarkers for patients and healthy controls group differentiation. Moreover, we performed Spearman's rank correlation analysis for OCD patients to examine the relationship between the metabolite concentration level and OCD symptomatology. RESULTS: Patients with OCD showed significantly decreased glutamate level in mPFC (p=0.021) and right thalamus (p=0.039), and significantly increased choline compounds in left thalamus (p=0.044).The glutamate in right thalamus was shown as the most important metabolite for group separation from multivariate analysis (Q(2)=0.134) and was significantly correlated with the patients' compulsion scores (Spearman r=-0.674, p=0.016). LIMITATIONS: Limited sample size, the use of creatine and phosphocreatine (Cr) ratios rather than absolute concentrations and unresolved glutamine (Gln) are limitations of the present study. CONCLUSION: Our study results consolidated the hypothesis about glutamatergic signaling dysfunction in OCD. To our knowledge, it is the first finding about a reduced thalamic glutamate level in adult unmedicated OCD patients. The dysregulation of glutamate serves as a potential target for the OCD pharmacotherapy and the detailed mechanisms underlying the glutamate alterations within CSTC circuits merit further investigations. PMID- 25819114 TI - Systematic review with meta-analysis: early infant feeding and coeliac disease- update 2015. AB - BACKGROUND: New evidence emerged on early feeding practices and the risk of coeliac disease. AIM: To systematically update evidence on these practices to find out whether there is a need to revise current recommendations. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from July 2012 (end of last search) to February 2015 for studies of any design that assessed the effect of gluten consumption and breastfeeding on the development of coeliac disease and/or coeliac disease-related autoimmunity. RESULTS: We identified 21 publications, including two, new, large, randomised controlled trials performed in high-risk infants. Exclusive or any breastfeeding, as well as breastfeeding at the time of gluten introduction, did not reduce the risk of developing coeliac disease during childhood. For infants at high risk of developing coeliac disease, gluten introduction at 4 months of age in very small amounts, or at 6 or 12 months of age, resulted in similar rates of coeliac disease diagnosis in early childhood. Later gluten introduction was associated with later development of coeliac specific autoimmunity and coeliac disease during childhood, but not total risk reduction. Observational studies indicate that consumption of a higher amount of gluten at weaning may increase the risk for coeliac disease development. CONCLUSIONS: Infant feeding practices (breastfeeding, time of gluten introduction) have no effect on the risk of developing coeliac disease during childhood (at least at specific timeframes evaluated in the included studies), necessitating an update of current European recommendations. PMID- 25819115 TI - Serum biomarkers of oxidative stress in cats with feline infectious peritonitis. AB - The purpose of this study was to elucidate the possible presence of oxidative stress in cats naturally affected by feline infectious peritonitis (FIP) by investigating two antioxidant biomarkers in serum: paraoxonase-1 (PON1) and total antioxidant capacity (TAC). PON1 was measured by spectrophotometric assays using three different substrates: p-nitrophenyl acetate (pNA), phenyl acetate (PA) and 5-thiobutil butyrolactone (TBBL), in order to evaluate possible differences between them. The PA and TBBL assays for PON1 and the assay for TAC were validated, providing acceptable precision and linearity although PA and TAC assays showed limit of detection higher than the values found in some cats with FIP. Cats with FIP and other inflammatory conditions showed lower PON1 values compared with a group of healthy cats with the three assays used, and cats with FIP showed significant decreased TAC concentrations. This study demonstrated the existence of oxidative stress in cats with FIP. PMID- 25819116 TI - Clinical features and outcome of typhoid fever and invasive non-typhoidal salmonellosis in a tertiary hospital in Belgium: analysis and review of the literature. AB - OBJECTIVES: Typhoid fever (TF) occurs rarely in industrialized countries because of advances in health care and improvement of drinking water. Conversely, non typhoid salmonellosis (NTS) remains widespread, because of food contamination or asymptomatic carriage. Non-typhoid salmonellosis can be severe when becoming invasive non-typhoid salmonellosis (iNTS). Although established prognostic indicators of the two pathologies are different, direct comparisons between iNTS and TF in the literature remain scarce. The purpose of this study was to analyse and compare demographic, clinical features and outcome of hospitalized patients with TF and iNTS. METHODS: Demographic, clinical features and outcome were retrospectively analysed in a series of patients hospitalized between 2007 and 2012. RESULTS: A total of 33 patients were enrolled, including 13 with established TF and 20 with iNTS. No differences between TF and iNTS patients were observed in incidence of fever, abdominal cramps, diarrhoea, headache, nausea and vomiting and duration of antibiotic therapy (<= 7 days in both groups). Although the clinical outcome of TF patients was identical to that of iNTS patients, including incidence of complications, length of hospitalization and mortality (1/13 (7.7%) vs 2/20 (10%), P = 0.43), comorbidities were less frequent in the TF group than in the iNTS group (2/13 vs 15/20, P = 0.003). CONCLUSION: The clinical profile and outcome of TF patients are similar to those with iNTS. Although comorbidities are more often associated with iNTS, the results of our study suggest that clinical management of these two diseases should remain similar. PMID- 25819117 TI - A galectin from shrimp Litopenaeus vannamei is involved in immune recognition and bacteria phagocytosis. AB - Galectins are conserved family members with beta-galactosides affinity that play multiple functions in embryogenesis, development and regulation of innate and adaptive immunity. However, little functional studies were reported in crustaceans. Here, a shrimp Litopenaeus vannamei galectin (LvGal) cDNA was identified with an open reading frame of 1017 bp, which encodes a putative protein of 338 amino acids. A carbohydrate recognition domain (CRD) and several amino acids residues involved in dimerization were found in LvGal. LvGal mRNA was mainly expressed in gills and hemocytes and upregulated post Vibrio anguillarum challenge. Recombinant LvGal (rLvGal) was expressed in Escherichia coli BL21 (DE3) and the purified rLvGal could strongly bind G(-) bacteria V. anguillarum and G(+) bacteria Micrococcus lysodeikticus. Besides, rLvGal exhibited strong activity to agglutinate V. anguillarum and weak activity to agglutinate M. lysodeikticus but no obvious antibacterial activity was found with selected bacteria. In addition, in vivo experiments showed rLvGal could promote phagocytosis of bacteria by hemocytes. Thus, through these collective data we predicted LvGal is involved in immune recognition and functions as a potential pattern recognition receptor. PMID- 25819118 TI - Neuron-restrictive silencer factor in periaqueductal gray contributes to remifentanil-induced postoperative hyperalgesia via repression of the mu-opioid receptor. AB - BACKGROUND: The ultra-short-acting mu-opioid receptor (MOR) agonist remifentanil induces postoperative hyperalgesia both in preclinical and clinical research studies. However, the precise mechanisms remain unclear, although changes in opioid receptor expression might be a correlative feature. Neuron-restrictive silencer factor (NRSF) functions as a crucial regulator of MOR expression in specific neuronal cells. Using a mouse model of incisional postoperative pain, we assessed the expression of MOR and NRSF and investigated whether disruption of NRSF expression could prevent the postoperative nociceptive sensitization induced by surgical incision and subcutaneous infusion of remifentanil. METHODS: Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were independently used to assess mechanical allodynia and thermal hyperalgesia after surgery and cerebral ventricle injection of NRSF antisense oligonucleotide. Western blotting analyses were preformed to assess the expression levels of MOR and NRSF. RESULTS: NRSF expression levels were enhanced after intraoperative infusion of remifentanil, resulting in repression of MOR expression in the periaqueductal gray (PAG). NRSF blockade with an NRSF antisense oligonucleotide significantly enhanced the expression levels of MOR and alleviated mechanical allodynia and thermal hyperalgesia induced by intraoperative infusion of remifentanil. CONCLUSION: NRSF functions as a negative regulator of MOR in PAG and contributes to remifentanil-induced postoperative hyperalgesia. NRSF in PAG may be a potential target for this pain therapy. PMID- 25819119 TI - Eye of the tiger sign in a 23 year patient with mitochondrial membrane protein associated neurodegeneration. PMID- 25819120 TI - Delayed diagnosis of vestibular epilepsy due to temporal cavernous malformation. PMID- 25819121 TI - [Management of side effects of targeted therapies in renal cancer: stomatological side effects (mucositis, epistaxis)]. AB - The advent of targeted therapies in the treatment of renal cancer has shown different types of lesions of the oral cavity, which appear to be specific to the drug classes used (mTOR inhibitors, anti-angiogenic agents and conventional cytotoxic drugs). Before starting treatment with targeted therapy, it is essential to have an oral and a dental examination. The treatment of mucositis induced by targeted therapies is based on bicarbonate-based mouthwash, with the optional addition of an antifungal or a local antiseptic. It is possible to use topical or systemic analgesics for the pain. Dietary advice for patients is also useful. Most cases of epistaxis caused by anti-angiogenics stop spontaneously and require no medical intervention. Regular application of an emollient can be used to prevent the formation of scabs. PMID- 25819122 TI - [Management of side effects of targeted therapies in renal cancer: sexual disorders]. AB - Since sexual disorders were not specifically studied in the principal series, epidemiological data is scarce. Nevertheless, in practice, when sexuality is dealt with during the monitoring of patients undergoing targeted therapies, more than half of the patients questioned say that they attach importance to their quality of sex life, despite the severity of their metastatic renal cancer. At the start of treatment, it is therefore important to inform patients of the possible occurrence of problems and to encourage them to report them. During treatment, screening for sexual disorders by questioning is desirable: desire, lubrication, dyspareunia, erectile dysfunction. In the event of the onset of a sexual disorder during treatment, it is not usually necessary to stop or modify the treatment. Therapeutic measures depend on the discomfort felt and are under the control of the specialist: erectile dysfunction, male libido disorders, vaginal dryness and vulvovaginitis. A consultation with an oncology psychologist and/or sex therapist is useful, if possible with the partner, based on the impact of the sexual problems. PMID- 25819123 TI - [Management of side-effects of targeted therapies in renal cancer: cardiovascular side-effects]. AB - Several types of cardiovascular complications can occur during treatment with targeted therapies: heart failure, QTc lengthening, arterial and venous thrombosis. A clinical examination, ECG and cardiac ultrasound are essential before starting treatment with targeted therapy. Patients with no medical history, who are asymptomatic with a normal ECG and a left ventricular ejection fraction (LVEF) greater than 50% can begin molecular targeted therapy (MTT). Patients must be assessed by a cardiologist before the introduction of MTT if they have a history of ischemic or valvular heart disease, heart failure, atrial fibrillation, stroke, transient ischemic attack, or ECG anomalies (Q wave, supraventricular arrhythmia, QT greater than 500ms), or LVEF less than 50%. In patients who are symptomatic (dyspnoea, angina, syncope, embolism etc.) and/or present with a modification to the ECG or alteration to the LVEF, MTT must be stopped and reassessment by a cardiologist is indicated. The restarting of MTT following a cardiovascular complication must be subject to a multidisciplinary discussion taking into account the severity of the cardiac event, its reversibility with cardiac treatment, life expectancy of the patient as well as the expected efficacy of the drug. PMID- 25819124 TI - [Toxicities of targeted therapies and their management in renal cancer: methodology of guidelines]. AB - Advanced renal cell carcinoma (RCC) is associated with a poor prognosis and is refractory to standard chemotherapy. Recent progress in the understanding of molecular biology and pathogenesis of renal cell cancer has been translated into the development of new therapeutic strategies. The management of metastatic RCC has been revolutionized with the development of targeted molecular therapies against VEGF-VEGFR and mTOR. Randomized phase III clinical trials demonstrated clinical benefit for patients with advanced RCC in overall survival and progression free survival. Guidelines for the management of side effects induced by these targeted therapies seem to be warranted. PMID- 25819125 TI - [Management of side effects of targeted therapies in renal cancer: cutaneous side effects]. AB - Targeted therapies used (angiogenesis inhibitors and mTOR inhibitors) in advanced renal cell carcinoma have a constellation of reaction affecting the skin, hair and nails. This guideline describes the incidence, clinical presentation and treatment of dermatologic side effects that develop with the use of targeted therapies (sunitinib, sorafenib, pazopanib, bevacizumab, everolimus, temsirolimus). PMID- 25819126 TI - [Management of side-effects of targeted therapies in renal cancer: endocrine side effects and metabolic disorders]. AB - Several types of endocrine complications and metabolic disorders can occur during treatment with targeted therapies: thyroid dysfunction, hyperglycaemia, hyperlipidaemia, etc. Thyroid dysfunctions are mainly observed with tyrosine kinase inhibitors (TKI), with a high frequency with sunitinib (18 to 85%) and sorafenib (21%). Hypothyroidism can be symptomatic with clinical signs including asthenia, constipation, cold intolerance, with elevated TSH and low free T 4 levels; or subclinical with non-specific clinical signs (asthenia) with TSH less than 8-10mIU/L and free T 4 normal, and often requiring supplementation with thyroid hormones. The occurrence of thyroid dysfunction does not mean that treatment with TKI must be stopped. Thyrotoxicosis, usually transient, can precede the onset of hypothyroidism during treatment with TKI. Specialist opinion from an endocrinologist should be considered with the occurrence of thyroid dysfunction. Abnormalities in the glycaemic and lipid profile are often seen with mTOR inhibitors and require monitoring before and during the treatment, as well as a specialist opinion from an endocrinologist in the event of hyperglycaemia or dyslipidaemia. PMID- 25819127 TI - [Managing side-effects of targeted therapies in renal cancer:surgical complications]. AB - The principal surgical complication feared in a patient under anti-angiogenic targeted therapy is gastrointestinal perforation. It is therefore important to be alert to situations "potentially at risk" of perforation: diverticulitis, carcinomatosis, intra-abdominal abscess, history of external radiotherapy, colonoscopy in the 4 weeks preceding the treatment, inflammatory disease and gastrointestinal mucosal ulceration, colonic stent, NSAID. It is essential to make an early diagnosis, and for treatment to be conservative if possible, with nasogastric aspiration without surgery. Surgical treatment is only offered in the event of worsening or failure of medical treatment. The time periods between surgery and the initiation of anti-angiogenic treatment vary according to the medication. With bevacizumab: major surgery: 4 weeks; 6 weeks if the patient has comorbidities. Minor surgery (e.g. dental extraction): wait for the wound to heal. With insertion of a PAC, bevacizumab can be administered the day after the insertion if necessary. With TKI: it is recommended to wait for the scar to heal in cases of major surgery. There is no specific recommendation for mTOR inhibitors. The time periods between termination of an anti-angiogenic treatment and scheduling of surgery also vary depending on the medication. With bevacizumab: 6 to 8 weeks for scheduled surgery. In the event of emergency surgery, the surgeon must be aware of an increased risk of post-operative complications. With TKI, 2 days for sorafenib, and 4 days for sunitinib. There is no specific recommendation for mTOR inhibitors. PMID- 25819128 TI - [Management of side-effects of targeted therapies in renal cancer: gastrointestinal side-effects]. AB - Several types of gastrointestinal complications can occur during treatment with targeted therapies: diarrhoea, nausea and vomiting, abnormalities in hepatic and pancreatic profiles, etc. Gastrointestinal problems in targeted therapy can have a significant impact on the general status of patients, their weight and their adherence to the treatment. The prevention, screening and rapid treatment of these side-effects are essential elements of patient care and can limit the associated dose reductions and loss of therapeutic benefit. In the case of diarrhoea, treatment must be started at the onset of grade 1 or 2 diarrhoea (four to six stools per day), with loperamide or racecadotril. Treatment with targeted therapy must be stopped if there is diarrhoea of grade 3 or 4 (more than six stools per day). In the case of nausea/vomiting or burning pain in the oesophagus, symptomatic treatment without stopping the targeted therapy is recommended. Biological assessment including transaminases, total and conjugated bilirubin should be prescribed before treatment initiation with targeted therapy. An elevation in alkaline phosphatases without elevation of transaminases suggests primarily the existence of hepatic metastases. In the event of worsening of the hepatic profile, if ALT greater than 5N, treatment must be stopped and specialist advice sought. PMID- 25819129 TI - [Management of side effects of targeted therapies in renal cancer: nephrological side effects]. AB - Several types of nephrological side-effects can occur during treatment with targeted therapy: high blood pressure, proteinuria, thrombotic microangiopathy, kidney failure, etc. Screening and treatment for high blood pressure, proteinuria and kidney failure are recommended during treatment with molecular targeted therapy (mainly for anti-VEGF). If BP is greater than 140/90mmHg on two measurements, it must be treated before the start of treatment. Self-measurement or ambulatory measurement of blood pressure is recommended. All antihypertensive drugs may be used apart from those, which interfere with cytochrome P450 (verapamil and diltiazem). Specialist advice (cardiology or nephrology) is recommended in the event of uncontroled hypertension. It is essential to monitor proteinuria with a urine strip test: if proteinuria is less than 2+ (grade 1), maintain treatment with molecular targeted therapy; if proteinuria is greater or equal to 2+ (grade2 or 3, confirmed by weight assay), specialist advice is required. Persisting proteinuria of grade2 or 3 requires nephrological monitoring. Thrombotic microangiopathy must be investigated in the event of hypertension greater than grade2 and/or proteinuria greater than 2+. PMID- 25819130 TI - [Management of side effects of targeted therapies in renal cancer: iatrogenic side effects]. AB - Since premedication of patients with an H1 antihistamine is recommended before the start of the intravenous infusion of temsirolimus, temsirolimus is to be used with caution in cases where there is a history of hypersensitivity to this class of antihistamines, or medical contra-indication for treatment with antihistamines. Comorbidities and co-medications must be taken into account in the prescription of targeted therapies. For sunitinib, sorafenib, and pazopanib: potential drug interactions are possible with inducers/inhibitors of CYP3A4, anti hypertensive drugs, antidiabetic drugs, thyroid hormones, and anticoagulant treatments. The combination of bevacizumab and sunitinib is very toxic (microangiopathic haemolytic anaemia), and is contra-indicated unless part of a clinical trial. Screening, equilibration or treatment of hypothyroidism, anaemia, undernutrition, hypophosphatemia, hypomagnesaemia, sleep disorders, depression or other comorbidities, which may contribute to asthenia is recommended. In patients treated with sunitinib or pazopanib, a thyroid function test is recommended at the treatment centre as well as regular TSH assays. PMID- 25819131 TI - [Management of side effects of targeted therapies in renal cancer: pulmonary side effects]. AB - Several types of pulmonary complications can occur during treatment with targeted therapies: haemoptysis; cough; dyspnoea; pleural effusions, etc. Only bevacizumab seems to be associated with an increased risk of haemoptysis, but this risk is low (less than 2% for haemoptysis greater or equal to grade 3). There are no validated predictive criteria for haemoptysis with bevacizumab in pulmonary metastases of renal cancer. In cases of haemoptysis, its severity must be evaluated and appropriate examinations used to determine its cause. Administration of an mTOR inhibitor, in particular everolimus, is associated with the occurrence of both asymptomatic and potentially life-threatening pneumopathies. In cases of respiratory symptoms with normal chest radiography, a chest CT scan must be carried out, due to its superior sensitivity and specificity in the diagnosis of pneumopathies with everolimus. In cases of pneumopathies with mTOR inhibitors, specialist advice (pulmonologist) is recommended. A bronchoscopy with lavage must be discussed if an opportunistic infection is suspected. A temporary stop to mTOR inhibitor, dose reduction and treatment with corticosteroids are discussed depending on the symptoms. PMID- 25819132 TI - Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients. AB - AIM: Dolutegravir is the newest integrase inhibitor approved for HIV treatment and has demonstrated potent antiviral activity in patient populations with a broad range of treatment experience. This analysis aimed to characterize the population pharmacokinetics of dolutegravir in treatment-naive patients and to evaluate the influence of patient covariates. METHODS: A population pharmacokinetic model was developed using a non-linear mixed effect modelling approach based on data from 563 HIV-infected, treatment-naive adult patients in three phase 2/3 trials who received dolutegravir (ranging from 10-50 mg once daily) alone or in combination with abacavir/lamivudine or tenofovir/emtricitabine. RESULTS: The pharmacokinetics of dolutegravir were adequately described by a linear one compartment model with first order absorption, absorption lag time and first order elimination. Population estimates for apparent clearance, apparent volume of distribution, absorption rate constant and absorption lag time were 0.901 l h(-1) , 17.4 l, 2.24 h(-1) , and 0.263 h, respectively. Weight, smoking status, age and total bilirubin were predictors of clearance, weight was a predictor of volume of distribution and gender was a predictor of bioavailability. However, the magnitude of the effects of these covariates on steady-state dolutegravir plasma exposure was relatively small (<32%) and was not considered clinically significant. Race/ethnicity, HBV/HCV co infection, CDC classification, albumin, creatinine clearance, alanine aminotransferase or aspartate aminotransferase did not influence the pharmacokinetics of dolutegravir in this analysis. CONCLUSIONS: A population model that adequately characterizes dolutegravir pharmacokinetics has been developed. No dolutegravir dose adjustment by patient covariates is necessary in HIV-infected treatment-naive patients. PMID- 25819133 TI - Ras, Rac1, and phosphatidylinositol-3-kinase (PI3K) signaling in nitric oxide induced endothelial cell migration. AB - The small GTP-binding proteins Ras and Rac1 are molecular switches exchanging GDP for GTP and converting external signals in response to a variety of stimuli. Ras and Rac1 play an important role in cell proliferation, cell differentiation, and cell migration. Rac1 is directly involved in the reorganization and changes in the cytoskeleton during cell motility. Nitric oxide (NO) stimulates the Ras - ERK1/2 MAP kinases signaling pathway and is involved in the interaction between Ras and the phosphatidyl-inositol-3 Kinase (PI3K) signaling pathway and cell migration. This study utilizes bradykinin (BK), which promotes endogenous production of NO, in an investigation of the role of NO in the activation of Rac1 in rabbit aortic endothelial cells (RAEC). NO-derived from BK stimulation of RAEC and incubation of the cells with the s-nitrosothiol S-nitrosoglutathione (GSNO) activated Rac1. NO-derived from BK stimulation promoted RAEC migration over a period of 12 h. The use of RAEC permanently transfected with the dominant negative mutant of Ras (Ras(N17)) or with the non-nitrosatable mutant of Ras (Ras(C118S)); and the use of specific inhibitors of: Ras, PI3K, and Rac1 resulted in inhibition of NO-mediated Rac1 activation. BK-stimulated s-nitrosylation of Ras in RAEC mediates Rac1 activation and cell migration. Inhibition of NO mediated Rac1 activation resulted in inhibition of endothelial cell migration. In conclusion, the NO indirect activation of Rac1 involves the direct participation of Ras and PI3K in the migration of endothelial cells stimulated with BK. PMID- 25819134 TI - Increased brain nitric oxide levels following ethanol administration. AB - Nitric oxide is a ubiquitous messenger molecule, which at elevated concentrations has been implicated in the pathogenesis of several neurological disorders. Its role in oxidative stress, attributed in particular to the formation of peroxynitrite, proceeds through its high affinity for the superoxide radical. Alcoholism has recently been associated with the induction of oxidative stress, which is generally defined as a shift in equilibrium between pro-oxidant and anti oxidant species in the direction of the former. Furthermore, its primary metabolite acetaldehyde, has been extensively associated with oxidative damage related toxic effects following alcohol ingestion. The principal objective of this study was the application of long term in vivo electrochemistry (LIVE) to investigate the effect of ethanol (0.125, 0.5 and 2.0 g kg(-1)) and acetaldehyde (12.5, 50 and 200 mg kg(-1)) on NO levels in the nucleus accumbens of freely moving rats. Systemic administrations of ethanol and acetaldehyde resulted in a dose-dependent increases in NO levels, albeit with very differing time courses. Subsequent to this the effect on accumbal NO levels, of subjecting the animal to different drug combinations, was also elucidated. The nitric oxide synthase inhibitor L-NAME (20 mg kg(-1)) and acetaldehyde sequestering agent D penicillamine (50 mg kg(-1)) both attenuated the increase in NO levels following ethanol (1 g kg(-1)) administration. Conversely, the alcohol dehydrogenase inhibitor 4-methylpyrazole (25 mg kg(-1)) and catalase inhibitor sodium azide (10 mg kg(-1)) potentiated the increase in NO levels following ethanol administration. Finally, dual inhibition of aldehyde dehydrogenase and catalase by cyanamide (25 mg kg(-1)) caused an attenuation of ethanol effects on NO levels. Taken together these data highlight a robust increase in brain NO levels following systemic alcohol administration which is dependent on NO synthase activity and may involve both alcohol- and acetaldehyde-dependent mechanisms. PMID- 25819135 TI - The photovoltaic efficiency of the fabrication of copolymer P3HT:PCBM on different thickness nano-anatase titania as solar cell. AB - Organic solar cells based on (3-hexylthiophene):[6,6]-phenyl C61-butyric acid methylester (P3HT:PCBM) bulk heterojunction (BHJ) with an inverted structure have been fabricated using nano-anatase crystalline titanium dioxide (TiO2) as their electron transport layer, which was prepared on the indium tin oxide coated glass (ITO-glass), silicon wafer and glass substrates by sol-gel method at different spin speed by using spin-coating (1000, 2000 and 3,000 rpm) for nano-thin film 58, 75 and 90 nm respectively. The effect of thickness on the surface morphology and optical properties of TiO2 layer were investigated by atomic force microscopy (AFM), X-ray diffraction and UV-visible spectrophotometer. The optical band gap of the films has been found to be in the range 3.63-3.96 eV for allowed direct transition and to be in the range 3.23-3.69 eV for forbidden direct transition to the different TiO2 thickness. The samples were examined to feature current and voltages darkness and light extraction efficiency of the solar cell where they were getting the highest open-circuit voltage, Voc, and power conversion efficiency were 0.66% and 0.39% fabricated with 90 nm respectively. PMID- 25819137 TI - Scaffold assembly based on genome rearrangement analysis. AB - Advances in DNA sequencing technology over the past decade have increased the volume of raw sequenced genomic data available for further assembly and analysis. While there exist many algorithms for assembly of sequenced genomic material, they often experience difficulties in constructing complete genomic sequences. Instead, they produce long genomic subsequences (scaffolds), which then become a subject to scaffold assembly aimed at reconstruction of their order along genome chromosomes. The balance between reliability and cost for scaffold assembly is not there just yet, which inspires one to seek for new approaches to address this problem. We present a new method for scaffold assembly based on the analysis of gene orders and genome rearrangements in multiple related genomes (some or even all of which may be fragmented). Evaluation of the proposed method on artificially fragmented mammalian genomes demonstrates its high reliability. We also apply our method for incomplete anophelinae genomes, which expose high fragmentation, and further validate the assembly results with referenced-based scaffolding. While the two methods demonstrate consistent results, the proposed method is able to identify more assembly points than the reference-based scaffolding. PMID- 25819136 TI - An audit of best evidence topic reviews in the International Journal of Surgery. AB - INTRODUCTION: IJS launched best evidence topic reviews (BETs) in 2011, when the guidelines for conducting and reporting these reviews were published in the journal. AIMS: (1) Audit the adherence of all published BETs in IJS to these guidelines. (2) Assess the reach and impact of BETs published in IJS. METHODS: BETs published between 2011 and February 2014 were identified from http://www.journal-surgery.net/. Standards audited included: completeness of description of study attrition, and independent verification of searches. Other extracted data included: relevant subspecialty, duration between searches and publication, and between acceptance and publication. Each BET's number of citations (http://scholar.google.co.uk/), number of tweets (http://www.altmetric.com/) and number of Researchgate views (https://www.researchgate.net/) were recorded. RESULTS: Thirty-four BETs were identified: the majority, 19 (56%), relating to upper gastrointestinal surgery and none to cardiothoracic, orthopaedic or paediatric surgery. Twenty-nine BETs (82%) fully described study attrition. Twenty-one (62%) had independently verified search results. The mean times from literature searching to publication and acceptance to publication were 38.5 weeks and 13 days respectively. There were a mean 40 (range 0-89) Researchgate views/article, mean 2 (range 0-7) citations/article and mean 0.36 (range 0-2) tweets/article. CONCLUSIONS: Adherence to BET guidelines has been variable. Authors are encouraged to adhere to journal guidelines and reviewers and editors to enforce them. BETs have received similar citation levels to other IJS articles. Means of increasing the visibility of published BETs such as social media sharing, conference presentation and deposition of abstracts in public repositories should be explored. More work is required to encourage more submissions from other surgical subspecialties other than gastrointestinal specialties. PMID- 25819138 TI - Ancestral population genomics using coalescence hidden Markov models and heuristic optimisation algorithms. AB - With full genome data from several closely related species now readily available, we have the ultimate data for demographic inference. Exploiting these full genomes, however, requires models that can explicitly model recombination along alignments of full chromosomal length. Over the last decade a class of models, based on the sequential Markov coalescence model combined with hidden Markov models, has been developed and used to make inference in simple demographic scenarios. To move forward to more complex demographic modelling we need better and more automated ways of specifying these models and efficient optimisation algorithms for inferring the parameters in complex and often high-dimensional models. In this paper we present a framework for building such coalescence hidden Markov models for pairwise alignments and present results for using heuristic optimisation algorithms for parameter estimation. We show that we can build more complex demographic models than our previous frameworks and that we obtain more accurate parameter estimates using heuristic optimisation algorithms than when using our previous gradient based approaches. Our new framework provides a flexible way of constructing coalescence hidden Markov models almost automatically. While estimating parameters in more complex models is still challenging we show that using heuristic optimisation algorithms we still get a fairly good accuracy. PMID- 25819139 TI - Intensive multifactorial treatment modifies the effect of family history of diabetes on glycaemic control in people with Type 2 diabetes: a post hoc analysis of the ADDITION-Denmark randomized controlled trial. AB - AIM: To investigate whether intensive multifactorial treatment can reverse the predisposed adverse phenotype of people with Type 2 diabetes who have a family history of diabetes. METHODS: Data from the randomized controlled trial ADDITION Denmark were used. A total of 1441 newly diagnosed patients with diabetes (598 with family history of diabetes) were randomized to intensive treatment or routine care. Family history of diabetes was defined as having one parent and/or sibling with diabetes. Linear mixed-effects models were used to assess the changes in risk factors (BMI, waist circumference, blood pressure, lipids and HbA1c ) after 5 years of follow-up in participants with and without a family history of diabetes. An interaction term between family history of diabetes and treatment group was included in the models to test for a modifying effect of the intervention. All analyses were adjusted for age, sex, baseline value of the risk factor and general practice (random effect). RESULTS: At baseline, participants with a family history of diabetes were younger and had a 1.1 mmol/mol (0.1%) higher HbA1c concentration at the time of diagnosis than those without a family history of diabetes. Family history of diabetes modified the effect of the intervention on changes in HbA1c levels. In the group receiving routine care, participants with a family history of diabetes experienced an improvement in HbA1c concentration that was 3.3 mmol/mol (0.3%) lower than the improvement found in those without a family history of diabetes after 5 years of follow-up. In the intensive treatment group, however, there was no difference in HbA1c concentrations between participants with and without a family history of diabetes after 5 years of treatment. CONCLUSIONS: Intensive treatment of diabetes may partly remove the adverse effects of family history of diabetes on glycaemic control. The effect of this improvement on long-term diabetic complications warrants further investigation. PMID- 25819140 TI - Asia Pacific Consensus Statements on Crohn's disease. Part 1: Definition, diagnosis, and epidemiology: (Asia Pacific Crohn's Disease Consensus--Part 1). AB - Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever-changing field. PMID- 25819141 TI - Effect of small donor weight and donor-recipient weight ratio on the outcome of liver transplantation in children. AB - A small donor weight is a risk factor for HAT with potential for graft loss. To test this hypothesis, we evaluated outcomes of pediatric liver transplants utilizing donors <20 kg using the UNOS database from 01/2003 to 01/2012 (n = 1311). All isolated liver transplants with whole organ grafts were included. Recipients were divided into four groups based on donor weight: group 1, donor weight <5 kg (n = 34 [2%]); group 2, 5-10 kg (431 [33%]); group 3, 10-15 kg (560 [43%]); and group 4, 15-20 kg (286 [22%]). Actuarial patient survival for the first year post-transplant was significantly lower in groups 1 and 2 compared to groups 3 and 4 (p = 0.002), similarly the one-yr graft function (p < 0.0001). The difference was due to graft loss within the first month for groups 1 and 2. HAT was significantly higher in groups 1 and 2 compared to others (p = 0.0006). Logistic regression analysis demonstrated donor weight as the most predictive factor with analysis of the ROC curve showing a cutoff point at 7.8 kg. The donor recipient weight ratio did, in none of the models, gain statistical significance. PMID- 25819142 TI - Research on food and nutrition characteristics of conjugated fatty acids. AB - In this study, the physiological effects of fatty acids with conjugated double bonds were widely examined in vitro and in vivo. Initially, a method for determination of conjugated fatty acids in food and biological samples was established. I then clarified that the oxidative stability of conjugated fatty acids was improved by the form of triacylglycerol and addition of an antioxidant, and the influence of this effect on the metabolism and pharmacokinetics of conjugated fatty acids was clarified in vivo. In addition, antitumor, anti angiogenesis, and antiobesity effects of conjugated fatty acids were found for the first time, thus demonstrating the usefulness of conjugated fatty acids. This communication mainly outlines the data obtained for conjugated linolenic acid. In addition, this review summarizes my research on conjugated fatty acid. PMID- 25819143 TI - Genetic determinants of cognitive responses to caffeine drinking identified from a double-blind, randomized, controlled trial. AB - The widely observed between-subject variability in cognitive responses to coffee may have a genetic basis. We evaluated cognitive responses to caffeine throughout three complex cognitive tasks assessing different subdomains of attention, namely Alerting and Orienting (Categorical Search Task) and Executive Control (Stroop Task and Eriksen Flanker Task). We explored whether they are influenced by gene variants affecting adenosine metabolism or catecholamine receptors. We recruited 106 healthy male subjects who were administered, in a double-blind design, 40mL of either a decaffeinated coffee preparation plus 3mg/kg caffeine (caf) or the corresponding vehicle (decaf). The protocol was repeated 24h later with the alternative preparation. Cognitive tasks were performed between 30min and 2h after caf or decaf administration. Each subject underwent ambulatory blood pressure monitoring for 2h. Blood samples were collected for genetic evaluations and for plasma caffeine and catecholamines measures. We found a significant reduction of reaction times in two of the cognitive tasks (Categorical Search Task and Stroop Task) after caf compared with decaf, indicating that caffeine, on average, improved the attention level in the domains under investigation. We also found, however, a great inter-individual variability in the cognitive performance responses to caffeine. In exploring genetic sources for such variability, we found a relation between polymorphisms of adenosine A2A and the caffeine effects on the attentional domains of Orienting and Executive control. In conclusion, variability in the attentional response to coffee may be partly explained by genetic polymorphisms of adenosine and adrenergic receptors. PMID- 25819144 TI - Altered serotonin and dopamine transporter availabilities in brain of depressed patients upon treatment with escitalopram: A [123 I]beta-CIT SPECT study. AB - Altered SERT and DAT availabilities during treatment with escitalopram were investigated with [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta CIT) SPECT in a series of patients fulfilling the criteria for unipolar major depressive disorder (MDD). 27 patients (10m, 42+/-16y) with diagnosis of MDD were recruited for the study. All patients underwent neuropsychiatric testing for assessment of Hamilton Depression (HAM-D) and Beck Depression Inventory (BDI) scores. At baseline, [(123)I]beta-CIT SPECT recordings were acquired 4h (SERT weighted) and 20-24h p.i (DAT-weighted). Follow-up scans and neuropsychiatric testing were performed after six weeks of stable escitalopram medication. Voxel wise parametric maps of specific/ non-specific ratios-1 (~BPND) were calculated. At baseline, DAT-weighted BPND was 5.06+/-0.81 in striatum and SERT-weighted BPND was 0.94+/-0.18 in thalamus. There were significant negative correlations with age for DAT in striatum (R=-0.60; p<0.01) and SERT in thalamus (R=-0.45; p<0.05). Under SSRI treatment there was an apparent 42% occupancy of SERT in thalamus (p<0.0001), whereas DAT availability increased significantly by 20% in striatum (p<0.001); higher apparent SERT occupancy in thalamus was associated with lesser DAT increase in striatum (R=-0.62; p<0.005). The low apparent SERT occupancy may be confounded by alterations in SERT expression during treatment. Thus, [(123)I]beta-CIT SPECT revealed age-dependent declines in DAT and SERT availabilities in un-medicated MDD patients, comparable to that seen previously in healthy controls. At follow-up, the SSRI-evoked increase in DAT was less pronounced in the older patients, even though apparent SERT occupancy and clinical improvement were not age-dependent. Present findings may have implications for escitalopram dosage and side effect profile in younger MDD patients. PMID- 25819145 TI - A prospective study of the prevalence of corneal surface disease in dogs receiving prophylactic topical lubrication under general anesthesia. AB - OBJECTIVE: To identify the prevalence of corneal ulceration in dogs receiving prophylactic gel lubrication under general anesthesia (GA). MATERIALS AND METHODS: An ophthalmic examination was performed before premedication and 24 h after GA in 100 dogs (199 eyes) undergoing nonophthalmic procedures. Individuals with known pre-existing ocular surface conditions were excluded. An ocular lubricating gel containing carmellose sodium was applied by the anesthetist at induction and every 2-4 h until extubation. Logistic regression analysis was used to calculate risk factors for ulcerative disease, including signalment, length of GA, patient position, procedure performed, pre-, and post-GA ophthalmic examination findings and admitting service. A Wilcoxon rank sum test compared pre and post-GA Schirmer tear test-1 (STT-1) values. RESULTS: One dog (0.5% of total eyes) developed fluorescein stain uptake consistent with superficial corneal ulceration that resolved within 48 h with supportive treatment. Twenty-five (18.6% of total eyes) developed a faint, patchy corneal uptake of stain in the axial cornea that was consistent with epithelial erosion. All erosions resolved with lubrication 24 h later. The decrease in STT-1 readings at 24 h post-GA was statistically significant from those pre-GA (P < 0.001). No significant risk factors for corneal erosion/ulceration were identified. CONCLUSIONS: The results of this study show that a basic protocol of prophylactic lubrication during GA was associated with a low prevalence of corneal ulceration but a higher prevalence of epithelial erosion. In addition, the study supports the need for post-GA corneal examination. PMID- 25819146 TI - Assessing the Nonlinearity of Karst Response Function under Variable Boundary Conditions. AB - The hydraulic and transfer response of karst aquifers is complex and often highly nonlinear: due to their high transmissivity and connection with the surface, such systems are very sensitive to modifications of their boundary conditions. The aim of this study was to assess the variation of the response depending on both upstream and downstream parameters, and propose a methodology to simulate the response of the karst system depending on those parameters. The impact of the variations of multiple environmental parameters on the response of a karstic system submitted to tidal variations (Normandy, France) was investigated after a campaign of artificial tracer tests acquired in very different hydrologic conditions (rainfall events, low tide, high tide, low/high piezometric level, and low/high waters). Principal components analysis and hierarchical clustering were applied on both environmental variables and karstic system response variables (parameters of the residence time distribution [RTD] curves). Equations between the RTD parameters and the most relevant variables were established using a symbolic regression algorithm. It appeared that the variations of the RTD parameters depend mainly on the cumulated rainfall preceding the injection, the piezometric level of the aquifer, and on the tide parameters. The hydraulic conditions downstream of the aquifer have a strong influence on the hydraulic and transfer response of the aquifer. The response of the aquifer in various and extreme conditions has been simulated using the equations resulting from the symbolic regression algorithm. Such relationships can be useful for management of water resources in karst media, and support decision making. PMID- 25819147 TI - [Non-invasive assessment of fatty liver]. AB - As the result of various harmful effects (infectious agents, metabolic diseases, unhealthy diet, obesity, toxic agents, autoimmune processes) hepatic damage may develop, which can progress towards liver steatosis, and fibrosis as well. The most common etiological factors of liver damages are hepatitis B and C infection, alcohol consumption and non-alcoholic fatty liver disease. Liver biopsy is considered as the gold standard for the diagnosis of chronic liver diseases. Due to the dangers and complications of liver biopsy, studies are focused on non invasive markers and radiological imaging for liver steatosis, progression of fatty liver, activity of the necroinflammation and the severity of the fibrosis. Authors review the possibilities of non-invasive assessment of liver steatosis. The statistical features of the probes (positive, negative predictive values, sensitivity, specificity) are reviewed. The role of radiological imaging is also discussed. Although the non-invasive methods discussed in this article are useful to assess liver steatosis, further studies are needed to validate to follow progression of the diseases and to control therapeutic response. PMID- 25819148 TI - [Reducing invasiveness of laparoscopic surgery using natural orifices and abdominal wall defects for extraction of the specimen]. AB - INTRODUCTION: Due to significant technical evolution complex surgeries can be performed laparoscopically nowadays. However, laparotomy is needed frequently for the extraction of the specimen, which decreases the advantages of laparoscopy. AIM: The aim of the authors was to analyse and present their experience on the use of natural orifices and abdominal wall defects for extraction of the surgical specimen. METHOD: From 2009 the authors used natural orifices (stomach, vagina, rectum) when viscerotomy was an obligate part of laparoscopic surgery and, in a special gastrointestinal laparoscopic operation, the gate of the inguinal hernia for specimen extraction. RESULTS: In 3 patients benign lesions of the stomach were extracted using gastroscope. In 6 patients with bowel endometriosis, in whom the wall of the vagina was completely infiltrated, the resected bowel was extracted transvaginally, and in 5 patients transrectal extraction of the specimen was performed. In 2 patients the inguinal hernia was used for the surgical specimen extraction after laparoscopic sigmoid resection, and in one patient a single-port was inserted into the gate of the hernia during laparoscopic cholecystectomy. Complications occurred only after transvaginal specimen extraction (rectovaginal fistula in 2 patients). CONCLUSIONS: Use of natural orifices and abdominal wall defects for surgical specimen extraction further decreases the invasiveness of laparoscopic surgery, if indications made appropriately. PMID- 25819149 TI - [Thrombotic events and significance of the IPSET thrombosis risk evaluation score in essential thrombocythaemia]. AB - INTRODUCTION: Thrombo-haemorrhagic complications contribute to both morbidity and mortality in patients with essential thrombocythaemia. AIM: The aim of the authors was to estimate the incidence of thrombotic events and to examine the clinical utility of IPSET thrombosis risk evaluation score against conventional two-categorical (low and high) risk assessment. METHOD: A retrospective analysis was carried out on 155 patients with essential thrombocythaemia (106 females; median age, 61 years) in a period between 1999 and 2014. RESULTS: The analysis revealed 55 (35.5%) major thrombotic events before and 25 (16.1%) major thrombotic complications after establishment of the haematologic diagnosis. Significant differences were observed in thrombosis-free survival between the different IPSET groups (p = 0.002). CONCLUSIONS: The IPSET model was first examined in this cohort of patients with essential thrombocythaemia diagnosed in a single Hungarian haematologic centre. The results suggest that this score may provide more information than the conventional thrombosis risk assessment. PMID- 25819150 TI - [Burnout among Hungarian physicians. Who are the most at risk?]. AB - INTRODUCTION: Burnout is one of the most challenging questions of the healthcare systems in the 21st century. AIM: The aim of this study was to analyze the Hungarian physicians' burnout and its associations with workload factors (work hours, shift work, multiple workplaces). METHOD: Data of this representative, cross-sectional, online epidemiological study was obtained from online questionnaires completed by 4784 physicians. RESULTS: Medium or high level personal accomplishment was present in 75.9% and emotional exhaustion in 58% among physicians, while medium or high level of depersonalization subscale was 53%. All of the 3 dimensions showed association with young ages (<35 years), work in in-patient care, shift hours and multiple workplaces. The physician partner increased the risk of depersonalization, however, children were protective factors. The work-home interface was associated with higher burnout scores. CONCLUSIONS: Physicians' burnout is an important indicator of the functioning and effectiveness of the healthcare system. The results suggest the importance of prevention and intervention. PMID- 25819151 TI - [The role of Sir William Osler (1849-1919) in the universal history of medicine]. PMID- 25819153 TI - Inhibition of melanogenesis by beta-caryophyllene from lime mint essential oil in mouse B16 melanoma cells. AB - OBJECTIVE: Volatile essential oils of mint species are used for cosmetics and in skin care products. In this study, we evaluated the main chemical components of the lime mint and the anti-melanogenic properties of its main components. METHODS: The essential oil was analysed by gas chromatography-mass spectrometry (GC/MS). The anti-melanogenic effects of mint essential oil and beta caryophyllene were investigated in B16F10 murine melanoma cells. RESULTS: The main components of lime mint essential oil were found to be D-limonene (41.10%), D-carvone (8.58%), delta-selinene (6.73%) and beta-caryophyllene (6.24%). The lime mint essential oil reduced melanin production in a dose-dependent manner in murine B16F10 cells. beta-Caryophyllene, one of the main compounds in lime mint essential oil, could reduce melanogenesis by down-regulating the expression of MITF, TRP-1, TRP-2 and tyrosinase, resulting in a decrease in melanin content decrease. CONCLUSION: These results reveal that lime mint essential oil and beta caryophyllene are considered to be valuable as potential skin-whitening agents. PMID- 25819154 TI - Combination of eccentric exercise and neuromuscular electrical stimulation to improve quadriceps function post-ACL reconstruction. AB - BACKGROUND: Neuromuscular electrical stimulation (NMES) has been shown to reduce quadriceps activation failure (QAF), and eccentric exercise has been shown to lessen muscle atrophy post-ACL reconstruction. Given that these are two critical components of quadriceps strength, intervention combining these therapies may be effective at reinstituting quadriceps function post-reconstruction. Thus, the aim of this study was to evaluate the effectiveness of a combined NMES and eccentric exercise intervention to improve the recovery of quadriceps activation and strength post-reconstruction. METHODS: Thirty-six individuals post-injury were placed into four treatment groups (N&E, NMES and eccentrics; E-only, eccentrics only; N-only, NMES-only; and STND, standard of care) and ten healthy controls participated. N&E and N-only received the NMES protocol 2* per week for the first 6 weeks post-reconstruction. N&E and E-only received the eccentric exercise protocol 2* per week beginning 6 weeks post-reconstruction. Quadriceps activation was assessed via the superimposed burst technique and quantified via the central activation ratio. Quadriceps strength was assessed via maximal voluntary isomeric contractions (Nm/kg). Data was gathered on three occasions: pre-operative, 12 weeks-post-surgery and at return-to-play. RESULTS: No differences in pre operative measures existed (P>0.05). E-only recovered quadriceps activation better than N-only or STND (P<0.05). N&E and E-only recovered strength better than N-only or the STND (P<0.05) and had strength values that were similar to healthy at return-to-play (P>0.05). CONCLUSION: Eccentric exercise was capable of restoring levels of quadriceps activation and strength that were similar to those of healthy adults and better than NMES alone. LEVEL OF EVIDENCE: Level 3, Parallel longitudinal study. PMID- 25819155 TI - Reconstruction techniques and clinical results of patellar tendon ruptures: Evidence today. AB - BACKGROUND: The analysis of the different operative reconstructions of patellar tendon ruptures has not been reported. A critical review of the existing literature was performed to identify the different operative techniques and the post-operative outcomes in acute, chronic and post-total knee arthroplasty (TKA) patellar tendon rupture repairs. METHODS: Using PRISMA guidelines, a review of the English-written literature published after 1947 was performed using the MEDLINE, PubMed and Cochrane libraries in November 2013 to retrieve case series with the keywords "Patellar tendon" AND "Rupture" AND "Repair" in their title or abstract. RESULTS: Forty-one manuscripts, reporting on 503 patients were analysed. Three-hundred-and-fifty-four acute repairs described eight different operative techniques. One-hundred-and-forty-nine chronic repairs described eight different operative techniques. Sixty-eight post-TKA repairs described nine different operative techniques. Six acute, four chronic and seven post-TKA repair operative techniques reported failures. In acute repair, using a primary repair method augmented with cerclage wire, Dall-Miles cable or non-absorbable sutures reported the best clinical results, with a 2% failure rate. Alternatively, for chronic and post-TKA repair, autogeneous grafts were significantly better than primary repair (p=0.0252, 0.0038 respectively). CONCLUSION: Acute surgical repair of a patellar tendon rupture using augmented primary repair is associated with the best post-operative outcomes. In chronic and post-TKA repair, autogeneous grafts produce best post-operative outcomes. Immediate post-operative mobilisation should be considered in all repairs. Future papers reporting on patellar operative repairs should have a standardised scoring method of functional outcome to allow more comprehensive comparison and evaluation. PMID- 25819156 TI - Low incidence of complications in computer assisted total knee arthroplasty--A retrospective review of 1596 cases. AB - BACKGROUND: Computer assisted total knee arthroplasty (CATKA) has its own unique complications. The aim of this study was to present our experience of early complications in a large consecutive series of CATKA. METHOD: We investigated retrospective data on the complications specific to computer navigation that were encountered with a consecutive series of 1596 CATKA. RESULTS: Intraoperatively, eight episodes of software failure occurred, two requiring conversion to conventional jig based TKA. There were four broken drill bits when positioning the pins for data entry. Repeat cuts of bone due to malalignment were required on two occasions. There were 17 episodes of superficial pin site infections at the tibial pin-site managed conservatively with antibiotics. One tibial fracture occurred through an old tibial tracker pin site hole. CONCLUSION: This large study shows a low complication rate related to CATKA which is reassuring to the orthopaedic community. CLINICAL RELEVANCE: Level of evidence: III. PMID- 25819157 TI - Human tuberculosis predates domestication in ancient Syria. AB - The question of pre-neolithic tuberculosis is still open in paleopathological perspective. One of the major interests is to explore what type of infection could have existed around the early stage of animal domestication. Paleopathological lesions evoking skeletal TB were observed on five human skeletons coming from two PPNB sites in Syria, which belongs to the geographical cradle of agriculture. These sites represent respectively pre-domestication phase (Dja'de el Mughara, Northern Syria, 8800-8300 BCE cal.) and early domestication phase (Tell Aswad, Southern Syria, 8200-7600 BCE cal.). MicroCT scan analyses were performed on two specimens (one per site) and revealed microscopic changes in favor of TB infection. Detection of lipid biomarkers is positive for two specimens (one per site). Initial molecular analysis further indicates the presence of TB in one individual from Dja'de. Interestingly, no morphological evidence of TB was observed on animal remains of wild and newly domesticated species, discovered in these sites. These observations strongly suggest the presence of human tuberculosis before domestication and at its early stages. PMID- 25819158 TI - The cell envelope of tubercle bacilli. AB - The envelope of tubercle bacilli and of other mycobacteria is important for the bacterial physiology since inhibition of the production of some of its constituents kills the cells. It consists of a plasma membrane, which is apparently homologous to plasma membranes of other bacteria, surrounded by a complex wall of carbohydrate and lipid, which is in turn surrounded by an outermost layer, called 'capsule' in the case of pathogenic species. The wall possesses a fundamental, covalently linked 'cell-wall skeleton' composed of peptidoglycan covalently linked to arabinogalactan esterified by very long-chain (up to C90) fatty acids (mycolic acids). These fatty acids form the inner leaflet of a typical outer membrane (mycomembrane) whose outer leaflet consists of a great variety of non-covalently linked lipids and glycolipids. The thickness of the mycomembrane is similar to that of the plasma membrane, implying dedicated conformations of mycolic acids. Finally, a periplasmic space also exists in mycobacteria, between the membrane and the peptidoglycan. PMID- 25819159 TI - Feasibility of a subcutaneously administered block/homo-mixed polyplex micelle as a carrier for DNA vaccination in a mouse tumor model. AB - In this study, the potential of DNA vaccine by subcutaneously (s.c.) administered block/homo-mixed (B/H) polyplex micelles carrying genes encoding tumor-associated antigen SART3 as well as CD40L and GM-CSF was compared with the intraperitoneal (i.p.) and intravenous (i.v.) administrations or electroporation method. Confocal laser microscopy revealed high localization of polyplexes in groin lymph nodes and local skin tissues after s.c. administration, and in the mesenteric lymph nodes, liver, and spleen after i.p. administration, but not after i.v. administration. Real-time RT-PCR and immunohistochemistry showed transgene expression in the above organs by s.c. and i.p. administered B/H polyplex micelles, but not by the i.v. administration or electroporation. Polyplex-carried DNA vaccines significantly decreased the weight of subcutaneous CT26 tumors in mice compared to the mock (2.9+/-0.8 vs 6.4+/-2.6 g, P<0.05 for s.c.; 3.2+/-1.1 vs 4.7+/-2.1 g, P<0.05 for i.p. administration). The survival rate was improved by s.c. administration of the DNA vaccine (P<0.05) and by the i.p. administered DNA vaccine (P<0.01) compared with that of the mock controls in mice with peritoneally disseminated CT26 cancer. Such therapeutic effects were not observed by the naked DNA, i.v. administered DNA vaccine or electroporation. CTL and NK cell activities of splenocytes and infiltration of CD11c(+) DCs, and CD4(+) and CD8a(+) T cells into tumor tissues were upregulated in the s.c. administered DNA vaccine group (P<0.05), which was consistent with i.p. administration. No abnormal findings in local injection sites, body weight, or blood examinations were observed by s.c. or i.p. administration of polyplex micelles, whereas proinflammatory cytokine production was minimized in visceral organs with the s.c. administered polyplex-carried DNA vaccine. In conclusion, s.c. administration of B/H polyplex micelles may be a safe and useful modality for DNA vaccination. PMID- 25819160 TI - The effect of butorphanol on the incidence of dexmedetomidine-induced emesis in cats. AB - OBJECTIVE: Tauo evaluate the antiemetic effect of butorphanol (BUT) when co administered with dexmedetomidine (DEX) in cats. STUDY DESIGN: Double-blind, randomized controlled cross-over experimental study. ANIMALS: Fourteen purpose bred healthy Domestic Short Hair cats, seven females and seven males, aged median (range) 14-84 (78) months and weighing 1.7-5.5 (4.0) kg. METHODS: Each cat received five different treatment protocols intramuscularly (IM): (A) 25 MUg kg( 1) DEX; (B) 20 MUg kg(-1) DEX and 0.2 mg kg(-1) BUT; (C) 20 MUg kg(-1) DEX and 0.1 mg kg(-1) BUT; (D) 25 MUg kg(-1) DEX and 0.2 mg kg(-1) BUT; and (E) 20 MUg kg(-1) DEX. Episodes of emesis, incidence and severity of nausea, and time to lateral recumbency were recorded for a period of 8 minutes after treatment administration, and the sedation was scored at the end of this period. The Friedman test and the Cochran's Q-test were used to analyse the data. Significance was evaluated at the 5% level. RESULTS: The proportion of cats that vomited was significantly lower with the treatment protocols that included BUT (B, C and D) compared with the protocols that included only DEX (A and E). The proportion of cats that had nausea was significantly higher with the protocols that included only DEX (A and E) compared with protocols B and D. Time to lateral recumbency (p=0.09) and sedation score (p=0.07) was not statistically different between the treatment protocols. CONCLUSIONS AND CLINICAL RELEVANCE: Butorphanol can be used to prevent emesis and reduce the incidence and the severity of nausea caused by DEX in cats. It seems that the combination of BUT and DEX is very useful not only when emesis could result in serious complications, but also to provide comfort and well-being in cats sedated for minor procedures. PMID- 25819162 TI - Respiratory and Acoustical Differences Between Belt and Neutral Style of Singing. AB - OBJECTIVES: Belt is a style of singing commonly used in nonclassical genres. Its respiratory, phonatory, and resonatory characteristics are unclear. DESIGN: Basic research. METHODS: Six female singers, professionally performing in the belt styles since many years, sang an excerpt of a song in belt and nonbelt/neutral style, two times with the lyrics and two times replacing the lyrics with /pae/ syllables. On separate channels, recordings were made of audio, oral pressure, and rib cage and abdominal wall movements, as picked up by respiratory inductive plethysmography. Lung volume and breathing patterns during inhalation and phonation were normalized with respect to duration and averaged. Voice source was analyzed in terms of flow glottograms derived from the audio signal by inverse filtering. RESULTS: Belt was produced with higher pressures and yielded higher sound levels, but no consistent breathing pattern was observed, neither for the belt, nor for the neutral style. Voice source differences suggested that belt was produced with firmer glottal adduction than neutral. Also, in four of the singers, the first formant was closer to a spectrum harmonic in belt than in neutral. CONCLUSIONS: Belt style of singing is not associated with a characteristic breathing behavior but is produced with higher subglottal pressures, higher sound levels, and firmer glottal adduction than a neutral style of singing. PMID- 25819161 TI - Mycobacterium tuberculosis has diminished capacity to counteract redox stress induced by elevated levels of endogenous superoxide. AB - Mycobacterium tuberculosis (Mtb) has evolved protective and detoxification mechanisms to maintain cytoplasmic redox balance in response to exogenous oxidative stress encountered inside host phagocytes. In contrast, little is known about the dynamic response of this pathogen to endogenous oxidative stress generated within Mtb. Using a noninvasive and specific biosensor of cytoplasmic redox state of Mtb, we for first time discovered a surprisingly high sensitivity of this pathogen to perturbation in redox homeostasis induced by elevated endogenous reactive oxygen species (ROS). We synthesized a series of hydroquinone based small molecule ROS generators and found that ATD-3169 permeated mycobacteria to reliably enhance endogenous ROS including superoxide radicals. When Mtb strains including multidrug-resistant (MDR) and extensively drug resistant (XDR) patient isolates were exposed to this compound, a dose-dependent, long-lasting, and irreversible oxidative shift in intramycobacterial redox potential was detected. Dynamic redox potential measurements revealed that Mtb had diminished capacity to restore cytoplasmic redox balance in comparison with Mycobacterium smegmatis (Msm), a fast growing nonpathogenic mycobacterial species. Accordingly, Mtb strains were extremely susceptible to inhibition by ATD 3169 but not Msm, suggesting a functional linkage between dynamic redox changes and survival. Microarray analysis showed major realignment of pathways involved in redox homeostasis, central metabolism, DNA repair, and cell wall lipid biosynthesis in response to ATD-3169, all consistent with enhanced endogenous ROS contributing to lethality induced by this compound. This work provides empirical evidence that the cytoplasmic redox poise of Mtb is uniquely sensitive to manipulation in steady-state endogenous ROS levels, thus revealing the importance of targeting intramycobacterial redox metabolism for controlling TB infection. PMID- 25819164 TI - Special issue on "Recent progress in lipid peroxidation based on novel approaches". PMID- 25819163 TI - Novel approaches to identify protein adducts produced by lipid peroxidation. AB - Lipid peroxidation is responsible for the generation of chemically reactive, diffusible lipid-derived electrophiles (LDEs) that covalently modify cellular protein targets. These protein modifications modulate protein activity and macromolecular interactions and induce adaptive and toxic cell signaling. Protein modifications induced by LDEs can be identified and quantified by affinity enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based techniques. Tagged LDE analog probes with different electrophilic groups can be covalently captured by click chemistry for LC-MS/MS analyses, thereby enabling in depth studies of proteome damage at the protein and peptide sequence levels. Conversely, click-reactive, thiol-directed probes can be used to evaluate thiol damage caused by LDE by difference. These analytical approaches permit systematic study of the dynamics of protein damage caused by LDE and mechanisms by which oxidative stress contribute to toxicity and diseases. PMID- 25819166 TI - Specialized Referral Centers for Rectal Cancer. PMID- 25819165 TI - Necroptosis: The Trojan horse in cell autonomous antiviral host defense. AB - Herpesviruses suppress cell death to assure sustained infection in their natural hosts. Murine cytomegalovirus (MCMV) encodes suppressors of apoptosis as well as M45-encoded viral inhibitor of RIP activation (vIRA) to block RIP homotypic interaction motif (RHIM)-signaling and recruitment of RIP3 (also called RIPK3), to prevent necroptosis. MCMV and human cytomegalovirus encode a viral inhibitor of caspase (Casp)8 activation to block apoptosis, an activity that unleashes necroptosis. Herpes simplex virus (HSV)1 and HSV2 incorporate both RHIM and Casp8 suppression strategies within UL39-encoded ICP6 and ICP10, respectively, which are herpesvirus-conserved homologs of MCMV M45. Both HSV proteins sensitize human cells to necroptosis by blocking Casp8 activity while preventing RHIM-dependent RIP3 activation and death. In mouse cells, HSV1 ICP6 interacts with RIP3 and, surprisingly, drives necroptosis. Thus, herpesviruses have illuminated the contribution of necoptosis to host defense in the natural host as well as its potential to restrict cross-species infections in nonnatural hosts. PMID- 25819167 TI - Albumin concentration significantly impacts on free teicoplanin plasma concentrations in non-critically ill patients with chronic bone sepsis. AB - The impact of decreased serum albumin concentrations on free antibiotic concentrations in non-critically ill patients is poorly described. This study aimed to describe the pharmacokinetics of a high-dose regimen of teicoplanin, a highly protein-bound antibiotic, in non-critically ill patients with hypoalbuminaemia. Ten patients with chronic bone sepsis and decreased serum albumin concentrations (<35 g/L) receiving teicoplanin 12 mg/kg 12-hourly intravenously for 48 h followed by 12 mg/kg once daily were enrolled. Surgical debridement was performed on Day 3. Samples of venous blood were collected pre infusion and post-infusion during the first 4 days of therapy. Total and free teicoplanin concentrations were assayed using validated chromatographic methods. The median serum albumin concentration for the cohort was 18 (IQR 15-24) g/L. After 48 h, the median (IQR) free trough (fC(min)) and total trough (tC(min)) concentrations were 2.90 (2.67-3.47) mg/L and 15.54 (10.28-19.12) mg/L, respectively, although trough concentrations declined thereafter. Clearance of the free concentrations was significantly high relative to the total fraction at 38.6 (IQR 29.9-47.8) L/h and 7.0 (IQR 6.8-9.8) L/h, respectively (P<0.001). Multiple linear regression analysis demonstrated that whereas total teicoplanin concentration did not impact on free concentrations (P=0.174), albumin concentration did (P<0.001). This study confirms the significant impact of hypoalbuminaemia on free concentrations of teicoplanin in non-critically ill patients, similar to that in critically ill patients. Furthermore, the poor correlation with total teicoplanin concentration suggests that therapeutic drug monitoring of free concentrations should be used in these patients. PMID- 25819168 TI - In vitro bactericidal property of levornidazole against Bacteroides fragilis studied by time-kill assay and sigmoid Emax model analysis. PMID- 25819169 TI - Meta-analysis of association between the TP53 Arg72Pro polymorphism and risk of endometriosis based on case-control studies. AB - OBJECTIVE: In the light of the relationship between the TP53 Arg72Pro (rs1042522) polymorphism and the risk of endometriosis remains inclusive or controversial. For better understanding of the effect of TP53 Arg72Pro polymorphism on endometriosis risk, we performed a meta-analysis. METHODS: The relevant studies were identified through a search of PubMed, Web of Science, EMBASE, Ovid, Springer, China National Knowledge Infrastructure (CNKI), cqvip, Wanfang database, and Chinese Biomedical Literature (CBM) databases up to December, 2014. The association between the TP53 Arg72Pro polymorphism and endometriosis risk was pooled by conducted by odds ratios and 95% confidence intervals. RESULTS: A total of fifteen case-control studies with 2683 cases and 3335 controls were eventually identified. There was significant association between Arg72Pro polymorphism and endometriosis risk in all of the five models in overall populations (C vs. G: OR=1.32, 95%CI=1.14-1.53, p=0.00; CC vs. GG: OR=1.80, 95%CI=1.28-2.53, p=0.001; GC vs. GG: OR=1.52, 95%CI=1.22-1.88, p=0.00; CC vs. GC/GG: OR=1.32, 95%CI=1.05 1.66, p=0.016; CC/GC vs. GG: OR=1.59, 95%CI=1.26-2.00, p=0.00). In the sub-group analysis according to ethnicity, the results suggested that TP53 Arg72Pro polymorphism was not associated with endometriosis risk in Caucasians. However, the significant association was found in Asians and Mixed race (MIX) under the five models. CONCLUSIONS: The results of this meta-analysis suggest that the TP53 Arg72Pro polymorphism can increase the risk of endometriosis, especially among Asians and MIX populations. Considering the limited sample size and ethnicities included in the meta-analysis, further larger scaled and well-designed studies are needed to confirm our results. PMID- 25819171 TI - A naturalistic study of recovering gamblers: What gets better and when they get better. AB - Gambling recovery has typically been assessed through the lens of gambling behavior and its consequences. Little attention has been given to less obvious features of gambling disorder, such as negative affectivity, gambling cognitive distortions, impulsivity, cognitive flexibility, planning, inhibitory control, and decision-making. The current study investigates how gambling treatment affected these variables and if any are related to gambling recovery. One hundred and thirteen patients were assigned to psycho-education and psychiatric treatment. A subset of 48 patients was additionally assigned to cognitive behavioral therapy (CBT). Seventy-two patients were reassessed 6 months after treatment onset. Recovered and non-recovered gamblers did not differ in pre treatment demographic, gambling, and psychiatric profiles. Three outcome variables were strongly related with gambling recovery: negative affectivity, cognitive distortions and decision-making. Logistic regression identified reduction of gambling cognitive distortions and better performance on decision making as the best predictors of gambling recovery, regardless of the type of treatment received. Beyond the standard outcome measures for gambling treatment, increased sensitivity to loss and decreased positive expectancies towards gambling are key targets to promote recovery in gambling treatment. PMID- 25819170 TI - Heart rate and respiratory response to doxapram in patients with panic disorder. AB - Panic disorder (PD) is characterized by anticipatory anxiety and panic, both causing physiological arousal. We investigated the differential responses between anticipatory anxiety and panic in PD and healthy controls (HC). Subjects (15 PD and 30 HC) received an injection of a respiratory stimulant, doxapram, with a high rate of producing panic attacks in PD patients, or an injection of saline. PD subjects had significantly higher scores in anxiety and panic symptoms during both conditions. Analysis of heart rate variability (HRV) indices showed higher sympathetic activity (LF) during anticipatory anxiety and panic states, an increase in the ratio of LF/HF during the anticipatory and panic states and a decrease in parasympathetic (HF) component in PD patients. During doxapram PD subjects increased their LF/HF ratio while HC had a reduction in LF/HF. Parasympathetic component of HRV was lower during anticipatory anxiety in PD. In general, PD showed greater sympathetic and psychological responses related to anxiety and sensations of dyspnea, reduced parasympathetic responses during anticipatory and panic states, but no differences in respiratory response. This confirms previous studies showing that PD patients do not have an intrinsic respiratory abnormality (either heightened or dysregulated) at the level of the brain stem but rather an exaggerated fear response. PMID- 25819172 TI - Parenting clinically anxious versus healthy control children aged 4-12 years. AB - This study investigated whether parenting behaviors differed between parents of 68 clinically anxious children and 106 healthy control children aged 4-12 years. The effects of parent gender, child gender and child age on parenting were explored. Mothers and fathers completed a questionnaire to assess parenting behaviors in for children hypothetically anxious situations. Results showed that parents of clinically anxious children reported more anxiety-enhancing parenting (reinforcement of dependency and punishment) as well as more positive parenting (positive reinforcement). For the clinical sample, fathers reported using more modeling/reassurance than mothers, and parents reported using more force with their 4-7-year-olds than with their 8-12-year-olds. No interaction effects were found for child gender with child anxiety status on parenting. Results indicate that for intervention, it is important to measure parenting behaviors, and to take into account father and mother differences and the age of the child. PMID- 25819174 TI - Increased impulsivity in pathological gambling: Considering nicotine dependence. AB - INTRODUCTION: It has been highlighted that increased impulsivity is an important etiological factor in pathological gambling (PG). However, the role of the highly prevalent comorbid mental disorders in PG remains unclear. This is of special concern as the highest comorbidity was found between PG and nicotine dependence (ND), which, in turn, has also been associated with heightened impulsivity. This study aimed to find out whether increased impulsivity in PG is a specific characteristic related to comorbid mental disorders in general or especially to ND. METHOD: A cross-sectional study was designed that included a healthy control group and three disorder groups with comorbid PG excluding ND, comorbid PG including ND, and ND alone according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. Impulsivity was assessed according to the dimensions response and choice impulsivity applying behavioral and self-report measures. RESULTS: We found (a) increased response impulsivity in the comorbid PG group when compared to the control group. Furthermore, increased choice impulsivity was found (b) in comorbid PG excluding ND and (c) in comorbid PG including ND when compared to ND alone. Other group differences did not reach significance. CONCLUSIONS: Our findings highlight that comorbid PG shares deficits in inhibitory control with ND. In contrast, maladaptive choices are a specific disorder characteristic of comorbid PG when compared to ND. If replicated in further studies, intervention strategies strengthening cognitive control skills might be effective for comorbid PG as well as ND whereas strategies enhancing maladaptive valuation of rewards might be specifically effective in comorbid PG. PMID- 25819173 TI - Re-evaluating "transitional neonatal hypoglycemia": mechanism and implications for management. PMID- 25819175 TI - Malignant potential in pancreatic neoplasm; new insights provided by circulating miR-223 in plasma. AB - BACKGROUND: Recent studies have identified that microRNAs are stably detectable in plasma/serum because of their binding to specific proteins or being packaged in secretory vesicles. METHODS: We tested miR-223 as a candidate of novel plasma biomarker in pancreatic cancer (PCa) and intraductal papillary mucinous neoplasm (IPMN). RESULTS: i) miR-223 expression was significantly higher in PCa tissues (p = 0.0069) than in normal tissues. ii) Plasma miR-223 levels were significantly higher in 71 PCa patients than 67 healthy volunteers (p < 0.0001). iii) Plasma miR-223 levels were significantly reduced in postoperative samples (p = 0.0297). iv) Plasma miR-223 levels tended to discriminate the malignant potential between benign IPMN and malignant IPMN (p = 0.0963), and the progressive extent of invasiveness between malignant IPMN and pancreatic invasive ductal carcinoma (PIDC) (p = 0.0004). Multivariate logistic regression analysis revealed that a low level of plasma miR-223 was an independent risk factor for PIDC (p = 0.0012, odds ratio 7.90 [95% CI: 2.06 - 41.2]). v) There was no significant correlation between plasma miR-223 levels and the number of any blood cell types in the peripheral blood. CONCLUSION: Plasma miR-223 might be a clinically useful biomarker for screening PCa, and predicting malignant potential of IPMN and the invasiveness of PCa. PMID- 25819176 TI - Fractional flow reserve for coronary bifurcation lesions: can fractional flow reserve-guided side branch intervention strategy improve clinical outcomes compared with angiography-guided strategy? PMID- 25819177 TI - The effect of transradial coronary catheterization on upper limb function. AB - OBJECTIVES: The aim of this study was to analyze the change of upper limb function when percutaneous coronary procedures were performed through the radial artery. BACKGROUND: It is currently unknown if upper limb function is affected by transradial (TR) catheterization. METHODS: Between January 2013 and February 2014, upper limb function was assessed in a total of 338 patients undergoing coronary catheterization in an ambulatory setting (85% radial approach, 15% femoral approach). Upper limb function was assessed with the self-reported shortened version of the Disabilities of Arm, Shoulder, and Hand questionnaire. The presence and severity of upper extremity cold intolerance was assessed with the self-reported Cold Intolerance Symptom Severity questionnaire. Both questionnaires were completed before the catheterization and at 30-day follow-up. Higher scores represent worse upper limb functionality or symptoms. The nonparametric Wilcoxon signed-rank test was used to assess the change of upper limb function and symptoms over time. RESULTS: Upper limb function did not change significantly over time when catheterization was performed through the radial artery (p=0.06). The number of procedure-related extremity complaints that persisted during 30-day follow-up were not different between both access groups (TR access 10.5%, transfemoral access 11.5%; p=0.82). The upper extremity was not affected by cold intolerance after TR access at 30-day follow-up (p=0.91). CONCLUSIONS: Upper limb function was not affected when coronary catheterizations and interventions were performed through the radial artery. PMID- 25819178 TI - Tandem middle cerebral artery-internal carotid artery occlusions: primary stenting of M1 and M2 tract crossing the anterior communicating artery. PMID- 25819179 TI - Neoatherosclerosis as the cause of late failure of a bioresorbable vascular scaffold. PMID- 25819180 TI - Fractional flow reserve and coronary bifurcation anatomy: a novel quantitative model to assess and report the stenosis severity of bifurcation lesions. AB - OBJECTIVES: The aim of this study was to develop a new model for assessment of stenosis severity in a bifurcation lesion including its core. The diagnostic performance of this model, powered by 3-dimensional quantitative coronary angiography to predict the functional significance of obstructive bifurcation stenoses, was evaluated using fractional flow reserve (FFR) as the reference standard. BACKGROUND: Development of advanced quantitative models might help to establish a relationship between bifurcation anatomy and FFR. METHODS: Patients who had undergone coronary angiography and interventions in 5 European cardiology centers were randomly selected and analyzed. Different bifurcation fractal laws, including Murray, Finet, and HK laws, were implemented in the bifurcation model, resulting in different degrees of stenosis severity. RESULTS: A total of 78 bifurcation lesions in 73 patients were analyzed. In 51 (65%) bifurcations, FFR was measured in the main vessel. A total of 34 (43.6%) interrogated vessels had an FFR<=0.80. Correlation between FFR and diameter stenosis was poor by conventional straight analysis (rho=-0.23, p<0.001) but significantly improved by bifurcation analyses: the highest by the HK law (rho=-0.50, p<0.001), followed by the Finet law (rho=-0.49, p<0.001), and the Murray law (rho=-0.41, p<0.001). The area under the receiver-operating characteristics curve for predicting FFR<=0.80 was significantly higher by bifurcation analysis compared with straight analysis: 0.72 (95% confidence interval: 0.61 to 0.82) versus 0.60 (95% confidence interval: 0.49 to 0.71; p=0.001). Applying a threshold of >=50% diameter stenosis, as assessed by the bifurcation model, to predict FFR<=0.80 resulted in 23 true positives, 27 true negatives, 17 false positives, and 11 false negatives. CONCLUSIONS: The new bifurcation model provides a comprehensive assessment of bifurcation anatomy. Compared with straight analysis, identification of lesions with preserved FFR values in obstructive bifurcation stenoses was improved. Nevertheless, accuracy was limited by using solely anatomical parameters. PMID- 25819181 TI - Recurrent Myocardial Infarctions Due to Thrombosis of a Coronary Aneurysm in Neurofibromatosis Type 1: Is Antiplatelet Treatment Enough? PMID- 25819182 TI - Approaching the post-femoral era for coronary angiography and intervention. PMID- 25819183 TI - Percutaneous treatment of a giant right coronary artery aneurysm. PMID- 25819184 TI - Vessel Caging Versus Vascular Restoration in the Same Artery: Long-Term Vascular Remodeling and Healing in Response to Overlapping Metal Stent and Bioresorbable Polymer Scaffold. PMID- 25819185 TI - Tricuspid Regurgitation Is Associated With Increased Risk of Mortality in Patients With Low-Flow Low-Gradient Aortic Stenosis and Reduced Ejection Fraction: Results of the Multicenter TOPAS Study (True or Pseudo-Severe Aortic Stenosis). AB - OBJECTIVES: This study sought to examine the impact of tricuspid regurgitation (TR) on mortality in patients with low-flow, low-gradient (LF-LG) aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF). BACKGROUND: TR is often observed in patients with LF-LG AS and low LVEF, but its impact on prognosis remains unknown. METHODS: A total of 211 patients (73+/-10 years of age; 77% men) with LF-LG AS (mean gradient<40 mm Hg and indexed aortic valve area [AVA]<=0.6 cm2/m2) and reduced LVEF (<=40%) were prospectively enrolled in the TOPAS (True or Pseudo-Severe Aortic Stenosis) study and 125 (59%) of them underwent aortic valve replacement (AVR) within 3 months following inclusion. The severity of AS was assessed by the projected AVA (AVAproj) at normal flow rate (250 ml/s), as previously described and validated. The severity of TR was graded according to current guidelines. RESULTS: Among the 211 patients included in the study, 22 (10%) had no TR, 113 (54%) had mild (grade 1), 50 (24%) mild-to moderate (grade 2), and 26 (12%) moderate-to-severe (grade 3) or severe (grade 4) TR. During a mean follow-up of 2.4+/-2.2 years, 104 patients (49%) died. Univariable analysis showed that TR>=2 was associated with increased risk of all cause mortality (hazard ratio [HR]: 1.82, 95% confidence interval [CI]: 1.22 to 2.71; p=0.004) and cardiovascular mortality (HR: 1.85, 95% CI: 1.20 to 2.83; p=0.005). After adjustment for age, sex, coronary artery disease, AVAproj, LVEF, stroke volume index, right ventricular dysfunction, mitral regurgitation, and type of treatment (AVR vs. conservative), the presence of TR>=2 was an independent predictor of all-cause mortality (HR: 1.88, 95% CI: 1.08 to 3.23; p=0.02) and cardiovascular mortality (HR: 1.92, 95% CI: 1.05 to 3.51; p=0.03). Furthermore, in patients undergoing AVR, TR>=3 was an independent predictor of 30 day mortality compared with TR=0/1 (odds ratio [OR]: 7.24, 95% CI: 1.56 to 38.2; p=0.01) and TR=2 (OR: 4.70, 95% CI: 1.00 to 25.90; p=0.05). CONCLUSIONS: In patients with LF-LG AS and reduced LVEF, TR is independently associated with increased risk of cumulative all-cause mortality and cardiovascular mortality regardless of the type of treatment. In patients undergoing AVR, moderate/severe TR is associated with increased 30-day mortality. Further studies are needed to determine whether TR is a risk marker or a risk factor of mortality and whether concomitant surgical correction of TR at the time of AVR might improve outcomes for this high-risk population. PMID- 25819186 TI - Provisional T-stenting with bioresorbable vascular scaffolds in vivo: insights from optical frequency domain imaging. PMID- 25819187 TI - Randomized Comparison of FFR-Guided and Angiography-Guided Provisional Stenting of True Coronary Bifurcation Lesions: The DKCRUSH-VI Trial (Double Kissing Crush Versus Provisional Stenting Technique for Treatment of Coronary Bifurcation Lesions VI). AB - OBJECTIVES: This study sought to compare the outcomes of fractional flow reserve (FFR)-guided and angiography (Angio)-guided provisional side-branch (SB) stenting for true coronary bifurcation lesions. BACKGROUND: Angio-guided provisional SB stenting after stenting of the main vessel provides favorable outcomes for the majority of coronary bifurcation lesions. Whether an FFR-guided provisional stenting approach is superior has not been studied. METHODS: A total of 320 patients with single Medina 1,1,1 and 0,1,1 coronary bifurcation lesions undergoing stenting with a provisional SB approach were randomly assigned 1:1 to Angio-guided and FFR-guided groups. SB stenting was performed for Thrombolysis In Myocardial Infarction flow grade<3, ostial SB stenosis>70%, or greater than type A dissection after main vessel stenting in the Angio-guided group and for SB FFR<0.80 in the FFR-guided group. The primary endpoint was the 1-year composite rate of major adverse cardiac events (cardiac death, myocardial infarction, and clinically driven target vessel revascularization). RESULTS: Comparing the Angio guided and FFR-guided groups, treatment of the SB (balloon or stenting) was performed in 63.1% and 56.3% of lesions respectively (p=0.07); stenting of the SB was attempted in 38.1% and 25.9%, respectively (p=0.01); and, when attempted, stenting was successful in 83.6% and 73.3% of SBs, respectively (p=0.01). The 1 year composite major adverse cardiac event rate was 18.1% in both groups (hazard ratio: 0.91, 95% confidence interval: 0.48 to 1.88; p=1.00). The 1-year target vessel revascularization and stent thrombosis rates were 6.9% and 5.6% (p=0.82) and 1.3% and 0.6% (p=0.56) in the Angio-guided and FFR-guided groups, respectively. CONCLUSIONS: In this multicenter, randomized trial, angiographic and FFR guidance of provisional SB stenting of true coronary bifurcation lesions provided similar 1-year clinical outcomes. (Randomized Study on DK Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions; ChiCTR-TRC-07000015). PMID- 25819188 TI - Fractional Flow Reserve in the Transradial Era: Will Hand Vein Adenosine Infusion Suffice?: A Comparative Study of the Extent, Rapidity, and Stability of Hyperemia From Hand and Femoral Venous Routes of Adenosine Administration. AB - OBJECTIVES: The aim of this study was to assess adenosine infusion via a cannula in the back of the hand compared with central venous access to achieve peak hyperemia during fractional flow reserve (FFR). BACKGROUND: Adenosine is often used to induce maximal hyperemia when measuring FFR. The gold standard is continuous infusion via a large central vein; however, the increasing use of the transradial route for angiography makes it desirable to have an alternative route for adenosine. Peripheral venous access is frequently obtained in the hand, but concern exists as to whether adenosine delivery from this site can achieve adequate vasodilation for accurate FFR measurement. Our aim was to address this. METHODS: Subjects were selected from patients presenting for coronary angiography/intervention who required a pressure-wire study. Subjects received intravenous adenosine infusion sequentially via 2 routes: first, via a 20-gauge hand cannula, and then, after a washout period, via a 5- or 6-F femoral venous sheath. Adenosine was administered at 140 MUg/kg/min from each site. Data interpretation was blinded. Minimal FFR achieved with intravenous adenosine from each infusion site was recorded as was the time to peak hyperemia. RESULTS: Paired (hand and femoral adenosine) recordings taken from 84 vessels in 61 patients were suitable for blinded analysis. The mean FFR measured using adenosine administered via hand and femoral routes was 0.85 with an SD of 0.08 (intraclass correlation=0.986). Time to peak hyperemia was longer on average with hand-administered adenosine compared with femoral adenosine administration (63 s vs. 43 s; mean difference, 22 s with a 95% confidence interval: 18 s to 27 s; p<0.0001). Formal comparison of FFR stability using Mann-Whitney analysis (2 tailed) gives p=0.43, indicating no significant evidence of a difference in stability between the 2 routes. CONCLUSIONS: Hand vein adenosine infusion produced FFR values very similar to those obtained using central femoral vein adenosine administration, with no systematic bias toward higher or lower reading from 1 site. This has important practical implications for radial access cases involving pressure-wire studies. PMID- 25819189 TI - Slow-flow phenomenon after Paclitaxel-coated balloon angioplasty: findings from optical coherence tomography and coronary angioscopy. PMID- 25819190 TI - Additional perspectives on the prognostic significance of tricuspid regurgitation: more lessons from the study of patients with low-flow aortic stenosis. PMID- 25819191 TI - Attitudes towards rotating shift work in clinical nurses: a Q-methodology study. AB - AIMS AND OBJECTIVES: To identify clinical nurses' attitudes towards rotating shift work. BACKGROUND: Many hospitals worldwide employ rotating shift work patterns to staff their facilities. Attitudes of clinical nurses towards rotating shift work vary. DESIGN: To understand clinical nurses' attitudes towards rotating shift work, Q-methodology, a method for the analysis of subjective viewpoints with the strengths of both qualitative and quantitative methods, was used. METHODS: Forty-six selected Q-statements from each of the 39 participants were classified into a normal distribution using an 11-point bipolar scale. The collected data were analysed using pc-QUANL program. RESULTS: Three discrete factors emerged as follows: factor I (rotating shift work is frustrating: objectionable perspective), factor II (rotating shift work is satisfactory: constructive perspective) and factor III (rotating shift work is problematic, but necessary: ambivalent perspective). CONCLUSIONS: The subjective viewpoints of the three identified factors can be applied in developing various roster designs for nurses engaging in rotating shift work. RELEVANCE TO CLINICAL PRACTICE: The findings provide the baseline for nurse leaders in helping nurses adjust and deal with rotating shift work. PMID- 25819192 TI - CT imaging for left atrial appendage closure: a review and pictorial essay. AB - Cardioembolic stroke is an important complication of atrial fibrillation. The thrombus responsible for this arises from the left atrial appendage (LAA) in >90% of cases, providing the rationale for device-based LAA closure as a means of thromboprophylaxis. Although oral anticoagulant therapy remains the mainstay for reducing the risk of stroke in patients with atrial fibrillation, an increasing number of patients, particularly those ineligible for conventional pharmacotherapy, are being offered percutaneous left atrial appendage closure. Cardiovascular CT can provide important information to assess the suitability of patients for LAA interventions and guide device selection and approach. The high spatial resolution and multiplanar capability of contemporary contrast-enhanced gated multidetector cardiovascular CT render it an ideal modality for noninvasively evaluating patients before intervention and assessing patients after intervention both for complications and procedural outcome. PMID- 25819193 TI - Determination and distribution of left ventricular size as measured by noncontrast CT in the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Left ventricular (LV) volume and mass have prognostic relevance. Overall size of the left ventricle as it appears in noncontrast CT is a composite of the ventricular volume and myocardial mass. We describe a method to estimate the LV size using a single cross-section in noncontrast CT and determined normal ranges on the basis of a large population cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis with 6814 participants from 4 ethnicities who were free of known cardiovascular disease and enrolled between 2000 and 2002 form the basis of our analysis. LV size was calculated from a single cross-sectional slice obtained by either nonenhanced electron beam or multidetector CT. LV size was adjusted to body surface area to obtain the LV size index, which was adjusted for age, sex, race or ethnicity, hypertension, hyperlipidemia, and diabetes. RESULTS: There were significant differences in LV size index by race which were further influenced by age and sex. Higher values were noted in men in all ethnic groups across all age groups. Similarly, LV size index uniformly decreased with age across all ethnic and sex categories. Caucasians had the lowest and African Americans had the highest LV size index across all age and sex categories. In multivariate regression analyses adjusted for age, sex, race or ethnicity, hypertension, hyperlipidemia, smoking, and diabetes mellitus, the significant differences were noted between male vs female (median difference, 17.5 cc/m(2); P < .001), ethnic groups (Caucasian, reference group; Asian, 3.7 cc/m(2); African American, 8.3 cc/m(2); and Hispanic, 5.6 cc/m(2); P < .001), and age groups (45 54 years, reference group; 55-64 years, -5.2 cc/m(2); 65-74 years, -11.4 cc/m(2); and 74-84 years, -12.5 cc/m(2)). CONCLUSIONS: This study provides normative values for LV size as determined from a single, nonenhanced CT cross-section and indexed to body surface area, and it demonstrates that the LV size index varies by age, sex, and ethnic background. PMID- 25819194 TI - Diagnostic accuracy and discrimination of ischemia by fractional flow reserve CT using a clinical use rule: results from the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography study. AB - BACKGROUND: Fractional flow reserve (FFR) is the gold standard for determining lesion-specific ischemia. Computed FFRCT derived from coronary CT angiography (coronary CTA) correlates well with invasive FFR and accurately differentiates between ischemia-producing and nonischemic lesions. The diagnostic performance of FFRCT when applied in a clinically relevant way to all vessels >= 2 mm in diameter stratified by sex and age has not been previously examined. METHODS: Two hundred fifty-two patients and 407 vessels underwent coronary CTA, FFRCT, invasive coronary angiography, and invasive FFR. FFRCT and FFR <= 0.80 were considered ischemic, whereas CT stenosis >= 50% was considered obstructive. The diagnostic performance of FFRCT was assessed following a prespecified clinical use rule which included all vessels >= 2 mm in diameter, not just those assessed by invasive FFR measurements. Stenoses <30% were assigned an FFR of 0.90, and stenoses >90% were assigned an FFR of 0.50. Diagnostic performance of FFRCT was stratified by vessel diameter, sex, and age. RESULTS: By FFR, ischemia was identified in 129 of 252 patients (51%) and in 151 of 407 vessels (31%). Mean age (+/- standard deviation) was 62.9 +/- 9 years, and women were older (65.5 vs 61.9 years; P = .003). Per-patient diagnostic accuracy (83% vs 72%; P < .005) and specificity (54% vs 82%, P < .001) improved significantly after application of the clinical use tool. These were significantly improved over standard coronary CTA values before application of the clinical use rule. Discriminatory power of FFRCT also increased compared with baseline (area under the receiver operating characteristics curve [AUC]: 0.93 vs 0.81, P < .001). Diagnostic performance improved in both sexes with no significant differences between the sexes (AUC: 0.93 vs 0.90, P = .43). There were no differences in the discrimination of FFRCT after application of the clinical use rule when stratified by age >= 65 or <65 years (AUC: 0.95 vs 0.90, P = .10). CONCLUSIONS: The diagnostic accuracy and discriminatory power of FFRCT improve significantly after the application of a clinical use rule which includes all clinically relevant vessels >2 mm in diameter. FFRCT has similar diagnostic accuracy and discriminatory power for ischemia detection in men and women irrespective of age using a cut point of 65 years. PMID- 25819195 TI - Atherosclerosis burden of the aortic valve and aorta and risk of acute kidney injury after transcatheter aortic valve implantation. AB - BACKGROUND: Atheroembolic renal disease, due to dislodgement of cholesterol crystals during maneuvering of a large catheter across the aorta and deployment of the transcatheter prosthesis within a calcified aortic valve, may be one of the pathophysiological mechanisms of acute kidney injury (AKI) complicating transcatheter aortic valve implantation (TAVI). OBJECTIVE: To investigate the association between the atherosclerotic burden and plaque characteristics of the aortic valve and thoracic aorta, evaluated with multidetector CT (MDCT), and the occurrence of AKI after TAVI. METHODS: Aortic valve calcification, atherosclerosis burden, and plaque characteristics of the thoracic aorta (including aortic root, ascending aorta, aortic arch, and descending aorta) were analyzed in preprocedural MDCT data of 210 TAVI patients (age, 81 +/- 7.1 years; 51.4% men). The thoracic aorta was divided into ascending aorta, aortic arch, and descending thoracic aorta which was further divided into 5 to 8 segments according to the posterior intercostal arteries. Each segment where the maximum wall thickness exceeded >= 2 mm was defined as diseased segment with atherosclerotic plaque. Aortic atherosclerosis burden was defined as the proportion of thoracic aortic segments with atherosclerosis. AKI was defined by a creatinine level >= 1.5 * baseline or >= 26.4 MUmol/L above baseline. MDCT data were correlated with the occurrence of postprocedural AKI in a multivariate logistic regression model. RESULTS: Postprocedural AKI occurred in 51 patients (24.3%). In patients with AKI, the burden of overall (87.5% [75%-90%] vs 71.4% [50%-87.5%]; P < .001) and noncalcified atherosclerosis (42.9% [22.2%-62.5%] vs 12.5% [0%-28.6%]; P < .001) and the maximum plaque thickness (5.7 +/- 1.8 mm vs 4.5 +/- 1.4 mm; P < .001) were larger compared with patients without AKI. The burden of noncalcified atherosclerosis remained independently associated with AKI (odds ratio, 1.03 [per each 1% of increase in aortic segments with noncalcified atherosclerosis]; 95% confidence interval 1.01-1.05; P = .006) after adjusting for baseline renal function, logistic EuroSCORE, and procedural access. In contrast, aortic valve calcification was not independently associated with AKI. CONCLUSION: In patients undergoing TAVI, occurrence of postprocedural AKI was associated with the extent of noncalcified atherosclerotic plaque burden of the thoracic aorta. PMID- 25819196 TI - Esmolol is noninferior to metoprolol in achieving a target heart rate of 65 beats/min in patients referred to coronary CT angiography: a randomized controlled clinical trial. AB - BACKGROUND: Coronary CT angiography (CTA) is an established tool to rule out coronary artery disease. Performance of coronary CTA is highly dependent on patients' heart rates (HRs). Despite widespread use of beta-blockers for coronary CTA, few studies have compared various agents used to achieve adequate HR control. OBJECTIVE: We sought to assess if the ultrashort-acting beta-blocker intravenous esmolol is at least as efficacious as the standard of care intravenous metoprolol for HR control during coronary CTA. METHODS: Patients referred to coronary CTA with a HR >65 beats/min despite oral metoprolol premedication were enrolled in the study. We studied 412 patients (211 male; mean age, 57 +/- 12 years). Two hundred four patients received intravenous esmolol, and 208 received intravenous metoprolol with a stepwise bolus administration protocol. HR and blood pressure were recorded at arrival, before, during, immediately after, and 30 minutes after the coronary CTA scan. RESULTS: Mean HRs of the esmolol and metoprolol groups were similar at arrival (78 +/- 13 beats/min vs 77 +/- 12 beats/min; P = .65) and before scan (68 +/- 7 beats/min vs 69 +/- 7 beats/min; P = .60). However, HR during scan was lower in the esmolol group vs the metoprolol group (58 +/- 6 beats/min vs 61 +/- 7 beats/min; P < .0001), whereas HRs immediately and 30 minutes after the scan were higher in the esmolol group vs the metoprolol group (68 +/- 7 beats/min vs 66 +/- 7 beats/min; P = .01 and 65 +/- 8 beats/min vs 63 +/- 8 beats/min; P < .0001; respectively). HR <= 65 beats/min was reached in 182 of 204 patients (89%) who received intravenous esmolol vs 162 of 208 of the patients (78%) who received intravenous metoprolol (P < .05). Of note, hypotension (systolic BP <100 mm Hg) was observed right after the scan in 19 patients (9.3%) in the esmolol group and in 8 patients (3.8%) in the metoprolol group (P < .05), whereas only 5 patients (2.5%) had hypotension 30 minutes after the scan in the esmolol group compared to 8 patients (3.8%) in the metoprolol group (P = .418). CONCLUSION: Intravenous esmolol with a stepwise bolus administration protocol is at least as efficacious as the standard of care intravenous metoprolol for HR control in patients who undergo coronary CTA. PMID- 25819197 TI - Rosebush injury: an unusual cause of fibular artery pseudoaneurysm. AB - Fibular and tibial artery pseudoaneurysms are common and mainly associated with trauma. We reported here a case with an uncommon presentation of fibular artery pseudoaneurysm. PMID- 25819198 TI - President's page: Implementation of coronary CT angiography to assess chest pain patients in the Emergency Department--a call for action! PMID- 25819200 TI - Anaphylaxis with intravenous immunoglobulin: a time for introspection. PMID- 25819199 TI - Mechanical properties of gray and white matter brain tissue by indentation. AB - The mammalian brain is composed of an outer layer of gray matter, consisting of cell bodies, dendrites, and unmyelinated axons, and an inner core of white matter, consisting primarily of myelinated axons. Recent evidence suggests that microstructural differences between gray and white matter play an important role during neurodevelopment. While brain tissue as a whole is rheologically well characterized, the individual features of gray and white matter remain poorly understood. Here we quantify the mechanical properties of gray and white matter using a robust, reliable, and repeatable method, flat-punch indentation. To systematically characterize gray and white matter moduli for varying indenter diameters, loading rates, holding times, post-mortem times, and locations we performed a series of n=192 indentation tests. We found that indenting thick, intact coronal slices eliminates the common challenges associated with small specimens: it naturally minimizes boundary effects, dehydration, swelling, and structural degradation. When kept intact and hydrated, brain slices maintained their mechanical characteristics with standard deviations as low as 5% throughout the entire testing period of five days post mortem. White matter, with an average modulus of 1.89 5kPa +/- 0.592 kPa, was on average 39% stiffer than gray matter, p<0.01, with an average modulus of 1.389 kPa +/- 0.289 kPa, and displayed larger regional variations. It was also more viscous than gray matter and responded less rapidly to mechanical loading. Understanding the rheological differences between gray and white matter may have direct implications on diagnosing and understanding the mechanical environment in neurodevelopment and neurological disorders. PMID- 25819201 TI - Closed reduction of metatarsophalangeal joint dislocations in acute and subacute presentations: a novel technique. PMID- 25819202 TI - Predelivery extracorporeal membrane oxygenation in a life-threatening peripartum cardiomyopathy: save both mother and child. PMID- 25819203 TI - Sedation with the Combination of Ketamine and Propofol in a Pediatric ED: A Retrospective Case Series Analysis. AB - BACKGROUND: Literature to date has suggested advantages of sedation with the combination of ketamine and propofol over ketamine alone or propofol alone. However, there is a paucity of data regarding sedation with the combination of ketamine and propofol in pediatric emergency medicine. METHODS: A retrospective case series analysis of children who underwent sedation with the combination of ketamine and propofol in a pediatric emergency department was conducted. Study covariates were extracted from the emergency department medical records. RESULTS: Four hundred twenty-nine patients, 297 males and 132 females, with a median age of 6.8 years (interquartile range, 3.9-10.9 years), underwent sedation by pediatric emergency physicians. Serious adverse events during sedation (SAEDS) were recorded in 52 procedures (12.1%), which included 39 hypoxic events (9.1%), 12 apneic events (2.8%), and 1 laryngospasm (0.2%). All SAEDS were managed successfully, and no child underwent intubation because of an adverse reaction or required hospitalization. Multivariate logistic regression analysis did not reveal any association between age, weight, fasting time, analgesic medication provided before sedation, length of procedure, capnography use, dosages of medications, and the presence of SAEDS. CONCLUSIONS: This is the largest reported series of sedation with the combination of ketamine and propofol in pediatric emergency medicine. Findings suggest that sedation with the combination of ketamine and propofol can be safely performed by a skilled emergency physician. PMID- 25819204 TI - Fulminant dengue myocarditis complicated with profound shock and fatal outcome under intra-aortic balloon pumping support. PMID- 25819205 TI - Scope of shared decision making in patients with psychologic complaints. PMID- 25819206 TI - Charlie Hebdo attacks: lessons from the military milieu. PMID- 25819207 TI - Successful use of ECMO as a bridge to surgical embolectomy in Life-Threatening Pulmonary Embolism. PMID- 25819208 TI - Transnasal sphenopalatine ganglion block for the treatment of postdural puncture headache in the ED. PMID- 25819209 TI - SHARP VERSUS BLUNT DIALYSIS NEEDLE USE WITH BUTTONHOLE METHOD: OPEN RANDOMISED TRIAL. AB - BACKGROUND: Current protocols recommend the use of a blunt needle to access the arteriovenous fistula via a buttonhole. This study aims to demonstrate whether a sharp needle can be used at the same buttonhole site without causing complications. GOAL: To measure and compare fistula cannulation failures between the use of blunt and sharp needles. PLAN: Open-crossover randomised controlled trial. PARTICIPANTS: Adult out-patients who had provided consent and were on dialysis with a mature arteriovenous fistula and buttonhole cannulation. OUTCOME MEASURES: Failed cannulation-difficulty in inserting the needle and the trampoline effect; incidence of complications, such as infection and haematomas; times to haemostasis; patients' pain; and patients' preferences. RESULTS: Based on analysis of the data from the 35 patients enrolled, no significant differences were detected in failed cannulation of the fistulae between the use of a blunt needle and a sharp needle for the 335 venous accesses (p = 0.071). However, a significant difference was detected for the 335 arterial accesses (p = 0.001), in which the sharp needle was more effective. Significant differences were also detected in the difficulty of insertion and in the trampoline effect for both venous and arterial access (p < 0.05); the use of a sharp needle was more favourable. CONCLUSION: This study demonstrates an increased incidence of failed cannulation using a blunt needle compared with using a sharp needle, although this was not significant. In addition, the use of a sharp needle did not result in any increase in complications. PMID- 25819210 TI - The Swedish Hayling task, and its relation to working memory, verbal ability, and speech-recognition-in-noise. AB - Cognitive functions and speech-recognition-in-noise were evaluated with a cognitive test battery, assessing response inhibition using the Hayling task, working memory capacity (WMC) and verbal information processing, and an auditory test of speech recognition. The cognitive tests were performed in silence whereas the speech recognition task was presented in noise. Thirty young normally-hearing individuals participated in the study. The aim of the study was to investigate one executive function, response inhibition, and whether it is related to individual working memory capacity (WMC), and how speech-recognition-in-noise relates to WMC and inhibitory control. The results showed a significant difference between initiation and response inhibition, suggesting that the Hayling task taps cognitive activity responsible for executive control. Our findings also suggest that high verbal ability was associated with better performance in the Hayling task. We also present findings suggesting that individuals who perform well on tasks involving response inhibition, and WMC, also perform well on a speech-in-noise task. Our findings indicate that capacity to resist semantic interference can be used to predict performance on speech-in noise tasks. PMID- 25819211 TI - Modelling runway incursion severity. AB - Analysis of the causes underlying runway incursions is fundamental for the development of effective mitigation measures. However, there are significant weaknesses in the current methods to model these factors. This paper proposes a structured framework for modelling causal factors and their relationship to severity, which includes a description of the airport surface system architecture, establishment of terminological definitions, the determination and collection of appropriate data, the analysis of occurrences for severity and causes, and the execution of a statistical analysis framework. It is implemented in the context of U.S. airports, enabling the identification of a number of priority interventions, including the need for better investigation and causal factor capture, recommendations for airfield design, operating scenarios and technologies, and better training for human operators in the system. The framework is recommended for the analysis of runway incursions to support safety improvements and the methodology is transferable to other areas of aviation safety risk analysis. PMID- 25819212 TI - A risk analysis of winter navigation in Finnish sea areas. AB - Winter navigation is a complex but common operation in north-European sea areas. In Finnish waters, the smooth flow of maritime traffic and safety of vessel navigation during the winter period are managed through the Finnish-Swedish winter navigation system (FSWNS). This article focuses on accident risks in winter navigation operations, beginning with a brief outline of the FSWNS. The study analyses a hazard identification model of winter navigation and reviews accident data extracted from four winter periods. These are adopted as a basis for visualizing the risks in winter navigation operations. The results reveal that experts consider ship independent navigation in ice conditions the most complex navigational operation, which is confirmed by accident data analysis showing that the operation constitutes the type of navigation with the highest number of accidents reported. The severity of the accidents during winter navigation is mainly categorized as less serious. Collision is the most typical accident in ice navigation and general cargo the type of vessel most frequently involved in these accidents. Consolidated ice, ice ridges and ice thickness between 15 and 40cm represent the most common ice conditions in which accidents occur. Thus, the analysis presented in this article establishes the key elements for identifying the operation types which would benefit most from further safety engineering and safety or risk management development. PMID- 25819213 TI - Extracellular vesicle-depleted fetal bovine and human sera have reduced capacity to support cell growth. AB - BACKGROUND: Fetal bovine serum (FBS) is the most widely used serum supplement for mammalian cell culture. It supports cell growth by providing nutrients, growth signals, and protection from stress. Attempts to develop serum-free media that support cell expansion to the same extent as serum-supplemented media have not yet succeeded, suggesting that FBS contains one or more as-yet-undefined growth factors. One potential vehicle for the delivery of growth factors from serum to cultured cells is extracellular vesicles (EVs). METHODS: EV-depleted FBS and human serum were generated by 120,000g centrifugation, and its cell growth supporting activity was measured. Isolated EVs from FBS were quantified and characterized by nanoparticle tracking analysis, electron microscopy, and protein assay. EV internalization into cells was quantified using fluorescent plate reader analysis and microscopy. RESULTS: Most cell types cultured with EV depleted FBS showed a reduced growth rate but not an increased sensitivity to the DNA-damaging agent etoposide and the endoplasmic reticulum stress-inducing chemical tunicamycin. Supplying cells with isolated FBS-derived EVs enhanced their growth. FBS-derived EVs were internalized by mouse and human cells wherein 65+/-26% of them interacted with the lysosomes. EV-depleted human serum also exhibited reduced cell growth-promoting activity. CONCLUSIONS: EVs play a role in the cell growth and survival-promoting effects of FBS and human serum. Thus, it is important to take the effect of EV depletion under consideration when planning EV extraction experiments and while attempting to develop serum-free media that support rapid cell expansion. In addition, these findings suggest roles for circulating EVs in supporting cell growth and survival in vivo. PMID- 25819214 TI - Ready-made chromatography columns for extracellular vesicle isolation from plasma. AB - Proteomic studies of circulating vesicles are hampered by difficulties in purifying vesicles from plasma and serum. Isolations are contaminated with high abundance blood proteins that may mask genuine vesicular-associated proteins and/or simply provide misleading data. In this brief report, we explored the potential utility of a commercially available size exclusion chromatography column for rapid vesicle purification. We evaluated the performance of the column, with cancer cell line conditioned medium or healthy donor plasma, in terms of removing non-vesicular protein and enriching for vesicles exhibiting exosome characteristics. Serial fractions revealed a peak for typical exosomal proteins (CD9, CD81 etc.) that preceded the peak for highly abundant proteins, including albumin, for either sample type, and harvesting only this peak would represent elimination of >95% of protein from the sample. The columns showed good reproducibility, and streamlining the workflow would allow the exosome-relevant material to be collected in less than 10 minutes. Surprisingly, however, subsequent post-column vesicle concentration steps whilst resulting in some protein loss also lead to low vesicle recoveries, with a net effect of reducing sample purity (assessed by the particle-to-protein ratio). The columns provide a convenient, reproducible and highly effective means of eliminating >95% of non vesicular protein from biological fluid samples such as plasma. PMID- 25819215 TI - Clinical features and course of generalized pustular psoriasis in Korea. AB - The clinical course of generalized pustular psoriasis (GPP) is variable and unpredictable. Sufficient data on the clinical course of the disease has not been reported due to its rarity. To investigate the clinical features and course of GPP according to its subtypes, medical records of patients diagnosed with GPP from 2002 to 2012 at two tertiary hospitals were reviewed. The data included patient demographics, associated symptoms, aggravating factors, patterns of relapse and prognosis. Thirty-three patients with GPP were included in our study, with a mean age of 45.6 years and a male : female ratio of 1:1.2. Patients were categorized based on the following subtypes: acute GPP, 21 (63.6%); GPP of pregnancy, two (6.1%); juvenile GPP, three (9.1%); and annular GPP, seven (21.2%). In the acute GPP population, skin lesions cleared within 2 months in 11 (73.3%) patients, and six (40.0%) of these had no relapse. Severe complications, abortion or death, were observed in two patients (100.0%) with GPP of pregnancy. Nineteen (76.0%) of the GPP patients experienced persistence or relapse of skin lesions. The patterns of skin lesions upon relapse included plaques in six patients (31.6%), pustules in eight patients (42.1%), and plaques and pustules in five patients (26.3%). Among acute GPP patients, 16.7% of patients with no relapse had a history of plaque psoriasis. However, 77.8% of patients with persistence and relapse in their clinical course had a history of plaque psoriasis. In conclusion, our study presents the detailed clinical course of GPP by subtype in Korean patients. PMID- 25819216 TI - Management of neutropenia in patients with rheumatoid arthritis. AB - Neutropenia is defined as a neutrophil count lower than 1.5g/L, with categorization as mild, moderate, or severe when the count is 1.5-1g/L, 1-0.5g/L, or<0.5g/L, respectively. The main complication is infection, whose risk increases with the depth and duration of the neutropenia. Comprehensive etiological investigations are mandatory to determine the best treatment strategy. Constitutional neutropenia is rarely seen in everyday rheumatology practice. It predominantly affects patients of African descent and is usually moderate and well tolerated. Congenital neutropenia due to genetic abnormalities is severe and chiefly seen in the pediatric population. Most cases of neutropenia in patients with rheumatoid arthritis (RA) are acquired. Medications are the most common causes, making detailed history-taking crucial. Many medications used to treat RA can induce neutropenia. Folic acid deficiency should be sought routinely in patients taking methotrexate. A less common cause of neutropenia is an RA-related autoimmune reaction. Splenomegaly suggests Felty's syndrome, which is accompanied with large granular lymphocytic (LGL) leukemia in 40% of cases. The treatment depends on the depth of the neutropenia and findings from the etiological workup. A neutrophil count below 0.5g/L, a fever, and the presence of clinical signs indicate a life-threatening condition requiring emergent treatment. In other patients, the first step is immediate discontinuation of any possibly involved drugs, simultaneously with the etiological workup. PMID- 25819217 TI - [Second generation ALK inhibitors in non-small cell lung cancer: systemic review]. AB - The identification of the EML4-ALK rearrangement in 5% of NSCLC enhanced the development of 1st generation ALK inhibitors such as crizotinib. Two phase III trials demonstrated crizotinib efficacy in second line metastatic (PROFILE 1007) and more recently first line metastatic (PROFILE 1014) NSCLC in terms of progression-free survival and also objective response. However, within 12 to 16 months, patients will progress due to the emergence of acquired resistance mechanisms such as mutation (L1196M) or amplification of the ALK gene, as well as activation of alternative signaling pathways (EGFR, KRAS). Second generation ALK inhibitors have been developed such as ceritinib, alectinib, and AP26113. This review will present those new drugs, summarize the results of their ongoing trials, and discuss the best way to treat ALK+ NSCLC patients. PMID- 25819218 TI - The effect of graft type on mortality in liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Liver transplantation (LT) with living-donor (LD-P) and deceased donor (DD-P) partial grafts for hepatocellular carcinoma (HCC) may be associated with worse outcomes. Using the United Network for Organ Sharing (UNOS), we aimed to: (1) examine the risk of mortality in LT for HCC, (2) to establish if this risk is affected by partial graft use, and (3) to determine if this effect is mitigated by improved tumor-associated risk stratification. MATERIAL AND METHODS: All first-time adult LT recipients were analyzed (3/2002-12/2012), including 2,353 LD-P, 727 DD-P, and 47,833 DD whole (DD-W) grafts. Cox proportional hazards models were used to examine the risk of mortality given HCC. Interaction/subset analyses were used to examine the effect of tumor-risk and graft-type on outcome. Presence of an HCC exception and low alpha-fetoprotein (AFP) level (<66 ng/mL) were considered favorable. RESULTS: Overall, HCC was associated with an increased mortality risk compared to the absence of HCC (HR 1.21 [1.15-1.27]), and the use of partial grafts was noted to further intensify this risk. However, HCC with a favorable risk profile had more comparable outcomes to patients without HCC and this finding was similar across all graft-types (Given LD-P: HR 1.14 [0.76-1.73]; Given DD-P: HR1.05 [0.71-1.56]; Given DD-W: HR1.08 [1.02-1.14]). On subset analysis, all graft types had similar outcomes given either favorable-risk HCC or the absence of HCC. CONCLUSIONS: There is no significant difference in outcomes between whole and partial grafts given (1) patients with HCC with a favorable risk-profile or (2) patients without HCC. PMID- 25819219 TI - Comparison of predicted extinction coefficients of monoclonal antibodies with experimental values as measured by the Edelhoch method. AB - Pace et al. (1995) [1] recommended an equation used to predict extinction coefficient of a protein. However, no antibody data was included in the development of this equation. The main objective of this study was to therefore investigate how the predicted value of the extinction coefficient is comparable to the experimentally determined extinction coefficient of antibodies measured by the Edelhoch method. We have measured the extinction coefficients (E) of 13 IgG1 monoclonal antibodies (mAbs) in phosphate buffer at pH 7.2. The maximum variability in the experimentally measured extinction coefficient of a given mAb molecule was found to be about 2%. Experimentally determined extinction coefficients of all mAbs were found to be lower than the predicted value, with the maximum difference found to being 4.7%. The highest and lowest values of experimental extinction coefficient among the thirteen IgG1 monoclonal antibodies obtained were 230525.9M(-1)cm(-1) (i.e. 1.55(mg/ml)(-1)cm(-1)) and 191,411.6M( 1)cm(-1) (i.e. 1.29(mg/ml)(-1)cm(-1)). A difference of <3% (with respect to mean value) was observed between the experimental and predicted values of the extinction coefficient. A comprehensive analysis and interpretation of the comparison of the predicted and experimentally determined extinction coefficient by the Edelhoch method is discussed in terms of structural characterization and accessible surface area (ASA). PMID- 25819220 TI - Biochemical analysis and hypoglycemic activity of a polysaccharide isolated from the fruit of Lycium barbarum L. AB - Purification, characterization and hypoglycemic activities of polysaccharide from Lycium barbarum L. were investigated in this study. A water soluble polysaccharide (LBP) was obtained with ultrafiltration membranes separation, which was further purified by chromatography of DEAE cellulose column and Sephadex G-150 to get LBP3a and LBP3b. The high performance permeation chromatography (HPGPC) analysis showed that the average molecular weight (Mw) of LBP3b was 4.92kDa. Monosaccharide composition analysis revealed that the LBP3b was comprised of mannose, rhamnose, glucose, galactose and xylose with a molar ratio of 5.52:5.11:28.06:1.00:1.70. The preliminary structure features of LBP3b were investigated by UV, FT-IR, NMR and SEM. In vitro cell experiments showed that LBP3b had significantly inhibited the absorption of glucose in a dose dependent manner. The study showed that LBP3b had potential use as an anti diabetic agent. PMID- 25819221 TI - Regulatory divergence between parental alleles determines gene expression patterns in hybrids. AB - Both hybridization and allopolyploidization generate novel phenotypes by conciliating divergent genomes and regulatory networks in the same cellular context. To understand the rewiring of gene expression in hybrids, the total expression of 21,025 genes and the allele-specific expression of over 11,000 genes were quantified in interspecific hybrids and their parental species, Coffea canephora and Coffea eugenioides using RNA-seq technology. Between parental species, cis- and trans-regulatory divergences affected around 32% and 35% of analyzed genes, respectively, with nearly 17% of them showing both. The relative importance of trans-regulatory divergences between both species could be related to their low genetic divergence and perennial habit. In hybrids, among divergently expressed genes between parental species and hybrids, 77% was expressed like one parent (expression level dominance), including 65% like C. eugenioides. Gene expression was shown to result from the expression of both alleles affected by intertwined parental trans-regulatory factors. A strong impact of C. eugenioides trans-regulatory factors on the upregulation of C. canephora alleles was revealed. The gene expression patterns appeared determined by complex combinations of cis- and trans-regulatory divergences. In particular, the observed biased expression level dominance seemed to be derived from the asymmetric effects of trans-regulatory parental factors on regulation of alleles. More generally, this study illustrates the effects of divergent trans-regulatory parental factors on the gene expression pattern in hybrids. The characteristics of the transcriptional response to hybridization appear to be determined by the compatibility of gene regulatory networks and therefore depend on genetic divergences between the parental species and their evolutionary history. PMID- 25819222 TI - Ectopic ACTH syndrome caused by desmopressin-responsive thymic neuroendocrine tumor. AB - A 32-year-old Chinese woman with rapid weight gain and progressive edema was found to have typical Cushingoid features. Her endocrine data were consistent with a diagnosis of ACTH-dependent Cushing's syndrome. To differentiate ectopic ACTH syndrome (EAS) from Cushing's disease (CD), various dynamic endocrine and imaging tests were performed. Her ACTH response was negative to corticotropin releasing hormone (CRH) and positive to desmopressin. Magnetic resonance imaging of the pituitary showed no mass lesion. Computed tomography scan of the chest revealed a large mass (21 * 15 mm) in the anterior mediastinum, where positron emission tomography showed accumulation of [(18)F] fluorodeoxyglucose. Selective venous sampling showed marked step-up in ACTH level in the internal thoracic vein but not in the cavernous sinus after CRH stimulation. These data are compatible with the diagnosis of EAS. The resected tumor was pathologically consistent with thymic neuroendocrine tumor (NET) positive for ACTH by immunohistochemistry and abundant V1b receptor gene expression by RT-PCR. Postoperatively, her circulating ACTH/cortisol levels became normalized, and responded to stimulation with CRH but not with desmopressin. Her Cushingoid appearance gradually disappeared, and she was free from recurrence 5 years after surgery. This is a rare case of desmopressin-responsive EAS caused by thymic NET with predominant V1b gene expression, which was successfully localized by imaging modalities combined with selective venous sampling. PMID- 25819223 TI - Serum human chorionic gonadotropin levels and thyroid hormone levels in gestational transient thyrotoxicosis: Is the serum hCG level useful for differentiating between active Graves' disease and GTT? AB - Gestational transient thyrotoxicosis (GTT) is defined as transient thyrotoxicosis caused by the stimulating effect of human chorionic gonadotropin (hCG) during pregnancy. We attempted to identify the serum hCG level that causes GTT, and we compared the serum hCG levels and thyroid hormone levels of GTT patients according to whether they had a background of thyroid disease. We also evaluated serum hCG as a parameter for differentiating between active Graves' disease (GD) and GTT. We reviewed the 135 cases of pregnant women who came to our hospital to be evaluated for thyrotoxicosis during their 7th to 14th week of pregnancy, and their serum hCG level was measured at that time. Among the 135 pregnant women with thyrotoxicosis; 103 of the women had GTT, and the other 32 women had active GD. There were no correlations between their serum hCG levels and free thyroid hormone levels. There were no significant differences in thyroid hormone levels or hCG levels among the GTT groups with different thyroid disease backgrounds; i.e., the GTT group without thyroid disease, GTT group with chronic thyroiditis, GTT group with non-functioning thyroid nodules, and GTT group with GD in remission. The serum hCG level of the GTT group was significantly higher than in the active GD group, but it was not a good parameter for differentiating between the two groups. The FT3/FT4 ratio of the active GD was significantly higher than in GTT group, and was a better parameter for differentiation. PMID- 25819224 TI - Sequential treatment with resveratrol-trolox improves development of porcine embryos derived from parthenogenetic activation and somatic cell nuclear transfer. AB - We investigated the effect of resveratrol supplementation during IVM and/or trolox during IVC on the development of porcine embryos derived from parthenogenetic activation (PA) and SCNT. In this study, we evaluated intracellular glutathione (GSH) and reactive oxygen species (ROS) levels, gene expression in blastocysts, and embryonic development after PA and SCNT. To determine the combined effects of resveratrol during IVM and trolox during IVC on PA embryos, we selected optimal concentrations (2 MUM of resveratrol and 200 MUM of trolox) and designed four groups: (1) control, (2) resveratrol, (3) trolox, and (4) combined. All treatment groups showed significantly increased intracellular GSH levels and decreased ROS levels. Resveratrol supported significantly higher cleavage and blastocyst formation rates than the control (80.3% and 38.0% vs. 71.1% and 22.4%, respectively) by downregulating Bax/Bcl-2, Caspase-3, and Bak. Trolox showed significantly increased blastocyst formation rates (36.7%) compared with the control (22.4%) by downregulating only Caspase-3. The combined group had significantly higher cleavage and blastocyst formation rates and greater total cell numbers than the control (81.7%, 36.3%, and 67.1 vs. 71.1%, 22.4%, and 47.8, respectively) by downregulating Bax/Bcl-2, Caspase-3, and Bak. On the basis of these results, we applied sequential treatments with resveratrol and trolox to SCNT, and blastocyst formation rates and total cell numbers were significantly increased compared with the control (17.2% and 52.1 vs. 11.8% and 36.6, respectively), with increased GSH, decreased ROS levels, upregulated proliferating cell nuclear antigen, and downregulated Bax/Bcl-2 and Caspase-3. These results indicate that sequential treatment with resveratrol during IVM and trolox during IVC improved the development of PA and SCNT porcine embryos by regulating intracellular GSH, ROS levels, and gene expression. PMID- 25819225 TI - Asbestos in Asia. AB - Asbestos is a global killer. Despite lessons learned in the developed world on the use of asbestos and its hazardous pulmonary consequences, its use continues to increase in Asia. Although some countries such as Japan, Korea and Singapore have curtailed the use of this mineral, there are numerous countries in Asia that continue to mine, import and use this fibre, particularly China, which is one of the largest consumers in the world. Numerous factors ranging from political and economic to the lack of understanding of asbestos and the management of asbestos related lung disease are keys to this observed trend. Awareness of these factors combined with early intervention may prevent the predicted Asian 'tsunami' of asbestos diseases. PMID- 25819226 TI - Perceived profitability and well-being in Australian dryland farmers and irrigators. AB - OBJECTIVE: To describe the relationship between self-reported farm profitability and farmer well-being, and to explore potential implications for farmer assistance policy. DESIGN: Cross-sectional analysis of farmers from Regional Wellbeing Survey data (wave 1, 2013) and comparison between groups. PARTICIPANTS: Participants were 1172 dryland farmers (35% women) and 707 irrigators (24% women). MAIN OUTCOME MEASURE: The Personal Wellbeing Index and the Kessler 10 item measure of general psychological distress. RESULTS: There is a consistent and significant relationship between higher profitability, greater well-being and less distress among dryland farmers and irrigators. CONCLUSIONS: The relationship between farm profitability and the well-being of Australian dryland farmers and irrigators has the potential to inform farmer assistance policy. Assistance programs can be more effective if they explicitly incorporate a profitability assessment into their targeting and eligibility requirements and a well-being component into program design and delivery. SETTING: Rural Australia. INTERVENTION: Not applicable. PMID- 25819228 TI - MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity. AB - Recurrent mutations in MYD88 have been identified in >90% of lymphoplasmacytic lymphoma (LPL). Recently, WHIM (warts, hypogammaglobulinaemia, infections, myelokathexis) syndrome-like mutations in CXCR4 have been described in 28% of LPL cases, and seem to impact clinical presentation and response to therapy. We investigated the presence of the MYD88 L265P mutation in 90 decalcified, formalin fixed, paraffin-embedded (FFPE) bone marrow (BM) biopsies, including 51 cases of LPL, 14 cases of B-cell chronic lymphocytic leukaemia (CLL), 13 cases of marginal zone lymphoma (MZL) and 12 normal controls. In addition, the C-terminal domain of CXCR4 was sequenced in LPL cases. MYD88 L265P was found in 49/51 (96%) LPL cases and in 1/13 (7.6%) MZL (splenic type), whereas all CLL samples remained negative. The two MYD88 wild type LPL cases were associated with cold agglutinin disease. Mutations in CXCR4 were detected in 17/47 (36.2%) LPL cases, which showed a higher extent of BM infiltration and lower leucocyte counts (P = 0.02), haemoglobin (P = 0.05) and platelet counts (P = 0.01). In conclusion the detection of MYD88 L265P mutation in FFPE samples is reliable and useful for subtyping small B-cell lymphomas in BM biopsies. In addition, the presence of CXCR4 mutations identifies a subgroup of LPL patients with higher disease activity. PMID- 25819227 TI - The ancestral role of nodal signalling in breaking L/R symmetry in the vertebrate forebrain. AB - Left-right asymmetries in the epithalamic region of the brain are widespread across vertebrates, but their magnitude and laterality varies among species. Whether these differences reflect independent origins of forebrain asymmetries or taxa-specific diversifications of an ancient vertebrate feature remains unknown. Here we show that the catshark Scyliorhinus canicula and the lampreys Petromyzon marinus and Lampetra planeri exhibit conserved molecular asymmetries between the left and right developing habenulae. Long-term pharmacological treatments in these species show that nodal signalling is essential to their generation, rather than their directionality as in teleosts. Moreover, in contrast to zebrafish, habenular left-right differences are observed in the absence of overt asymmetry of the adjacent pineal field. These data support an ancient origin of epithalamic asymmetry, and suggest that a nodal-dependent asymmetry programme operated in the forebrain of ancestral vertebrates before evolving into a variable trait in bony fish. PMID- 25819229 TI - Digoxin ameliorates autoimmune arthritis via suppression of Th17 differentiation. AB - Digoxin is a cardiac glycoside that is commonly used to treat heart failure. Based on its known anti-inflammatory effect, this study was undertaken to investigate the effect of digoxin on collagen-induced arthritis (CIA) and to delineate the underlying mechanism. Digoxin or vehicle was injected intraperitoneally thrice weekly in mice with CIA, from day 7 or day 35 after immunization to investigate preventive or therapeutic effect, respectively. The incidence and severity of arthritis was evaluated. Digoxin treatment suppressed the incidence of arthritis and joint inflammation in mice with CIA. The expression of IL-17 and other proinflammatory cytokines, including IL-1beta, IL 6, TNF-alpha and IL-21, were markedly reduced in the arthritic joints of digoxin treated CIA mice. Th17 cells and CD4(+) pSTAT3(+) cells were less frequently observed in the spleen of digoxin-treated CIA mice than controls. The mRNA expression of IL-17 and ROR gammat was consistently lower in total splenocytes or draining lymph node cells obtained from digoxin-treated CIA mice. Digoxin also reduced in vitro Th17 differentiation and LPS-stimulated IgG production. The number of osteoclasts in the arthritic joint was lower in digoxin-treated mice, whereas digoxin treatment did not directly suppress in vitro osteoclastogenesis. Our findings suggest that digoxin can regulate Th17 and reciprocally promote Treg cells and suppress joint inflammation and bone erosion in CIA. Digoxin may be a therapeutic option by targeting pathogenic Th17 and immunoglobulin production, for treatment of autoimmune arthritis and other Th17-related diseases. PMID- 25819230 TI - Coronary artery bypass grafting in the octogenarian. Is complete revascularization always necessary? AB - AIM: The aim of this study was to investigate whether the completeness of revascularization affects the outcomes in the octogenarian. MATERIAL OF STUDY: We retrospectively reviewed 130 consecutive octogenarians who underwent isolated coronary artery bypass grafting (CABG) between January 2003 and September 2010. According to operative technique, patients were categorized in Complete Revascularization (CRV) Group (96 patients) and in Incomplete Revascularization (IRV) Group (34 patients). Follow-up was 98% complete (mean: 30 +/- 25 months). RESULTS: The overall in-hospital mortality was 13% and was similar in both groups (p=0.0553). Multivariate regression analysis identified preoperative left ventricular ejection fraction <= 40% (p= 0.0060; OR= 0.19) and NHYA class > II (p= 0.0042; OR= 0.17) as risk factor for in-hospital death. Cox regression analysis not identified incomplete revascularization as risk factor for early or late death (p= 0.1381 and p= 0.8865). No differences in 5-year survival and freedom from major adverse cardiac and cerebrovascular events (MACCE) was found between two groups (p=0.8865 and p=0.6283). DISCUSSION: CRV is important in young patients undergoing CABG, but this principle remains less absolute in elderly patients. In our study, the survival benefit of CRV was less in octogenarians. Probably, the major benefit of CRV was seen in patients less than 80 years of age. This makes sense because these patients have a longer expected survival, and there were more patients available to statistically confirm any difference in outcome. CONCLUSIONS: In octogenarians undergoing CABG, IRV does not affect survival and freedom from MACCE. Patients' preoperative conditions are important in determining short and long term outcomes. PMID- 25819231 TI - [Electric chemotherapy in extensive tumor infiltration of skin and subcutaneous tissue --a valuable extension of dermato-oncologic armamentariums]. PMID- 25819232 TI - New systemic agents in dermatology with respect to fertility, pregnancy, and lactation. AB - With the increasing use of new, predominantly biologic drugs in dermatology, questions frequently arise in clinical practice as to their safety in women wishing to conceive as well as during pregnancy and lactation. Apart from the Summary of Product Characteristics and the Physician's Desk Reference, reliable information may be obtained from databases such as the one compiled by the Center for Pharmacovigilance and Consultation on Embryonal Toxicology at Charite University Medical Center Berlin (https://www.embryotox.de). Another source of information is researching recent publications, for example via PubMed (http://www.ncbi.nlm.nih.gov/pubmed). This article presents current knowledge from the sources mentioned above, and gives detailed information about the use of new biologic agents in women wishing to conceive as well as during pregnancy and lactation. Drugs reviewed include: infliximab, adalimumab, etanercept, metastatic for psoriasis, vemurafenib, dabrafenib, imatinib, ipilimumab for melanoma, vismodegib for basal cell carcinoma, rituximab for cutaneous lymphoma as well as omalizumab and anakinra used in the treatment of allergies. PMID- 25819235 TI - Biosimilars: a systematic review of published and ongoing clinical trials of antipsoriatics in chronic inflammatory diseases. AB - Biosimilars for psoriasis treatment are currently being developed. Comparison of their efficacy and safety is a challenge. For approval, the European Medicines Agency (EMA) considers indirect evidence from other indications (for example, rheumatoid arthritis) as sufficient. Systematic review of biosimilars for psoriasis and other indications, review of ongoing trials in trial registers. Systematic search for randomized controlled trials (RCT) on biosimilars to adalimumab, etanercept, infliximab, and ustekinumab compared to their reference medication: (1) Publications in Medline, Medline In-Process, Embase, Cochrane Library (efficacy, safety, immunogenicity) and (2) ongoing studies in clinical trial registers. No trials on biosimilars in psoriasis patients were identified. As to the infliximab biosimilar, there is data on patients with ankylosing spondylitis and rheumatoid arthritis, indicating no clinically relevant differences regarding efficacy and safety. Currently, there are two registered studies of an adalimumab biosimilar and one study of an etanercept biosimilar in psoriasis patients. Further ongoing studies on biosimilars to adalimumab, etanercept, and infliximab - all in rheumatoid arthritis patients - were identified. There is currently only limited data regarding RCTs with biosimilars. Provision of further clinical data and inclusion of patients in patient registers will be crucial. PMID- 25819237 TI - Wnt signaling in skin homeostasis and pathology. AB - The mammalian skin mediates the primary interphase between the body and the external environment and provides the first line of defense against pathogens, mechanical trauma, sunlight injuries, and chemical stress. Proper physical, biochemical, and immunological composition of the skin is necessary to maintain its barrier function. Therefore, the skin reflects a complex dynamic organ with high cellular turnover during normal tissue replacement and wound repair. Stem cell reservoirs ensure constant skin renewal. Wnt signaling controls stem cell maintenance and fate decisions in various tissues and also reflects a key pathway in controlling skin development and homeostasis. Disruption of Wnt signaling in the skin causes disorders such as alopecia, chronic inflammatory skin diseases or cancer. This review summarizes the role of Wnt signaling during skin development, homeostasis, and disease. PMID- 25819239 TI - Electrochemotherapy in advanced skin tumors and cutaneous metastases - a retrospective multicenter analysis. AB - BACKGROUND AND OBJECTIVES: Once classic treatments such as chemotherapy or radiation therapy have been exhausted, only few therapeutic options remain for extensive skin tumors or cutaneous metastases. In such cases, electrochemotherapy may be considered as alternative therapy. PATIENTS AND METHODS: In this retrospective study, clinical features, treatment response, and adverse effects were evaluated in 56 patients treated with electrochemotherapy at six German dermatology departments. RESULTS: The mean age of the patient cohort (14 men, 42 women) was 69.3 years. Included were 20 patients with skin metastasis of advanced malignant melanoma, 13 patients with breast cancer metastases, 15 patients with primary squamous cell carcinoma of the skin or cutaneous metastases of other carcinoma types, and 8 patients with cutaneous lymphoma or sarcoma. The overall response rate was 44.6% (10.7% complete response; 33.9% partial response). By contrast, 31 (55.4%) patients did not respond (12.5% had stable disease; 42.9%, tumor progression). Patients with melanoma and cutaneous lymphoma or sarcoma responded significantly better than those with carcinoma. Roughly one quarter of patients showed an improvement in tumor-related exudation, fetor, and chronic bleeding. CONCLUSION: Showing only few adverse effects, electrochemotherapy was effective in about one half of the patients with advanced tumors. Treatment response appears to depend on the tumor entity. PMID- 25819243 TI - An ulcerated giant pilomatricoma mimicking malignancy. PMID- 25819246 TI - A case of histiocytic lymphophagocytic panniculitis (Rosai-Dorfman disease) with positive autoantibodies. PMID- 25819248 TI - Erythema ab igne and dermal scarring caused by cupping and moxibustion treatment. PMID- 25819250 TI - White papules on forehead and decollete. PMID- 25819252 TI - Exophytic and ulcerated nodule on the hand. PMID- 25819254 TI - S3 guidelines for the management of anticoagulation in cutaneous surgery. AB - BACKGROUND: An increasing number of patients are being treated with anticoagulants and platelet inhibitors. Whenever surgical procedures of the skin are required, questions arise regarding the perioperative management of anticoagulation. METHODS: Development of S3 guidelines following the requirements of the Association of Scientific Medical Societies, systematic literature search and analysis, use of GRADE methodology, structured consensus conference using a nominal group process. RESULTS: During cutaneous surgery, treatment with acetylsalicylic acid (ASA) should be continued if medically necessary. In procedures with a higher risk of bleeding and a positive bleeding history, INR should be determined preoperatively. Surgical procedures of the skin with a higher risk of bleeding should not be performed if the INR is above therapeutic range. Bridging from vitamin K antagonists (VKA) to heparin should not be performed just because of the surgery of the skin. As to direct-acting oral anticoagulants, the last dose should be taken 24 h preoperatively. CONCLUSIONS: The recommendations issued by the German guidelines group are mostly in line with recommendations provided by other guidelines. The American iChest-Guidelinei recommends continuing VKAs and acetylsalicylic acid during minor dermatologic procedures. In their guidelines, the German College of General Practitioners and Family Physicians considers an INR of 2 to be adequate in surgical procedures on the skin. PMID- 25819262 TI - Re: Diagnostic error: Missed fractures in emergency medicine. PMID- 25819263 TI - SCAI/AATS/ACC/STS Operator and Institutional Requirements for Transcatheter Valve Repair and Replacement, Part III: Pulmonic Valve. PMID- 25819264 TI - Restricted participation in stroke caregivers: who is at risk? AB - OBJECTIVE: To identify caregiver-, stroke survivor-, and caregiving situation related factors that are associated with caregivers' restriction from participation in their normative activities (ie, participation restriction) over the first 2 years poststroke. DESIGN: Longitudinal cohort study. SETTING: Acute care facilities and community. PARTICIPANTS: A secondary data analysis of caregiver/survivor dyads (N=399). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data were collected at 1, 3, 6, 12, 18, and 24 months poststroke. The primary outcome was caregivers' participation restriction and was assessed using the Caregiver Impact Scale. Caregivers also provided demographic information and completed standardized measures to capture assistance provided, mastery, and depression. From stroke survivors we collected demographic characteristics, stroke severity, and cognitive and physical functioning. Data were analyzed using individual growth curve modeling. RESULTS: Participation restriction level improved over time. Caregiver factors associated with restricted participation included younger age, being employed, higher depression, and lower mastery level. Stroke survivor factors associated with caregivers' restricted participation included hemorrhagic stroke, more severe stroke, more physical and memory impairments, and lower participation. Significant factors related to the caregiving situation included providing high levels of assistance and caring for a spouse. CONCLUSIONS: Depressed younger caregivers, with low levels of mastery, who provide high-intensity support to spouses with cognitive difficulties may be at risk. Screening for these factors may help identify stroke families at risk for poor outcomes and may be used to more efficiently allocate health resources. PMID- 25819265 TI - A case of dry eye secondary to ocular ischemic syndrome due to carotid artery occlusion. AB - A case of unilateral dry eye associated with ipsilateral carotid artery occlusion. PMID- 25819266 TI - History and symptom taking in contact lens fitting and aftercare. AB - AIM: To appraise history and symptom taking for contact lens consultations, to determine current practice and to make recommendations for best practice. METHOD: The peer reviewed academic literature was reviewed and the results informed a survey completed by 256 eye care practitioners (ECPs) on their current practice and influences. RESULTS: The last eye-test date, last contact lens aftercare (for existing wearers) and reason for visit are key questions for most ECPs. Detailed use of contact lens questions are more commonly applied in aftercares than when refitting patients who have previously discontinued wear (87% vs 56% use), whereas questions on ocular and general history, medication and lifestyle were generally more commonly utilised for new patients than in aftercares (72% vs 50%). 75% of ECPs requested patients bring a list of their medication to appointments. Differential diagnosis questioning was thorough in most ECPs (87% of relevant questions asked). Attempts to optimise compliance included oral instruction (95% always) and written patient instructions (95% at least sometimes). Abbreviations were used by 39% of respondents (26% used ones provided by a professional body). CONCLUSION: There is scope for more consistency in history and symptom taking for contact lens consultations and recommendations are made. PMID- 25819267 TI - The use and application of drama in nursing education--an integrative review of the literature. AB - BACKGROUND: Caring is grounded on universal humanistic values such as kindness, empathy, concern and love for self and others. Nurses need to learn how to implement these values in the care for patients. Nursing students find it hard to assimilate theoretical knowledge in practice. Experiential learning in the form of drama has been used in several studies to enhance nursing students' learning. AIM: The aim of this study was to review empirical and theoretical articles on the use and application of drama in nursing education. DESIGN: An integrative review of the literature. METHOD: The databases CINAHL, PubMed, ProQuest and Academic search elite were searched for articles. RESULT: The search generated 64 articles, with 20 articles meeting the inclusive criteria. Three themes with their attendant subthemes emerged through the analysis. The themes are: The Framing, The Objectives and The Embodiment. CONCLUSION: Drama is effective in entry level courses in nursing education to enhance student learning and can be flexible and adjusted to various contexts. Further research using drama to enroll nursing students as fictive patients and relatives and thereby explore different perspectives is suggested, and more research on the application of drama in nursing education at an advanced level is required. PMID- 25819268 TI - Exploring the use of standardized patients for simulation-based learning in preparing advanced practice nurses. AB - The use of standardized patients for simulation-based learning was integrated into the Master of Nursing curriculum in the 2012-2013 academic year. The study aimed to explore the Master of Nursing students' experiences with and perceptions of using standardized patients in simulations, and to identify the students' learning needs in preparing to become advanced practice nurses. The study adopted an exploratory descriptive qualitative design, using a focus group interview. The study was conducted at a university in Singapore. Seven Master of Nursing students who were enrolled in the Acute Care Track of Master of Nursing program in the 2012-2013 academic year participated in the study. The data were gathered at the end of the first semester. Content analysis was used to analyze the data. Three main categories - usefulness, clinical limitations, and realism - were identified in the study. The results revealed that the students felt using standardized patients was useful and realistic for developing skills in history taking, communication, and responding to an emergency situation. On the other hand, they found that the standardized patients were limited in providing critical signs and symptoms of case scenarios. To meet the learning objectives, future development and integration of standardized patients in the Master of Nursing curriculum might need to be considered along with the use of a high fidelity simulator. This can be an alternative strategy to fill the gaps in each method. Obviously, using standardized patients for simulation-based learning has added value to the students' learning experiences. It is highly recommended that future studies explore the impact of using standardized patients on students' performance in clinical settings. PMID- 25819269 TI - Tiotropium Respimat in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials. AB - BACKGROUND: Tiotropium Respimat improved lung function in a phase 2 trial in patients with cystic fibrosis (CF). We investigated its efficacy and safety in a phase 3 trial, including a pre-specified pooled analysis of the phase 2 and 3 trials. METHODS: 12-week, randomized, double-blind, placebo-controlled trial of tiotropium Respimat 5 MUg once daily in patients with CF (N=463). RESULTS: Co primary efficacy endpoints showed no statistical difference between tiotropium and placebo: percent-predicted forced expiratory volume in 1s (FEV1) area under the curve from 0-4h (AUC0-4h) (95% CI): 1.64% (0.27,3.55; p=0.092); percent predicted trough FEV1 (95% CI) 1.40% (0.50,3.30; p=0.15). Adverse events were similar between groups. Pooled phase 2/3 trial results showed a treatment difference in favor of tiotropium: percent-predicted FEV1 AUC0-4h (95% CI): 2.62% (1.34,3.90). CONCLUSION: Tiotropium was well tolerated in patients with CF; lung function improvements compared with placebo were not statistically significant in the phase 3 trial. CLINICAL TRIALS: These studies are registered with clinical trial identifier numbers NCT00737100 and NCT01179347 NCT00737100 NCT01179347. These studies are also registered with the EudraCT number: 2008-001156-43 and 2010-019802-17. PMID- 25819270 TI - Could Ex Vivo Lung Perfusion Be a Platform to Decrease the Incidence of Chronic Lung Allograft Dysfunction? AB - The number of patients requiring lung transplantation is increasing, with a significant unmet demand for grafts. Ex vivo lung perfusion has been developed to increase graft recruitment. The major complications of lung transplantation include chronic allograft dysfunction (CLAD) whose cumulative incidence ranges from 43-80% within the first 5 years of transplantation. Many risk factors are listed for development of CLAD and almost all of those risk factors would involve activation of Toll-like receptors. This paper represents the author's overview regarding the development of CLAD as a complication of lung transplantation and the possible protective potential of ex vivo lung perfusion in this regard. PMID- 25819271 TI - Overexpression of squamous cell carcinoma antigen 1 is associated with the onset and progression of human hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Previous studies indicated Squamous Cell Carcinoma Antigen 1 (SCCA1) may be involved in tumorigenesis and progress of various human malignancies by inhibiting cell apoptosis and promoting cell proliferative activity. The aim of the study was to further investigate SCCA1 expression in different extent of liver diseases and evaluate the clinical significance and prognostic value in HCC. METHODS: Eighty nine patient-matched tumors and peritumoral surgical specimens and 56 liver biopsies specimens from 23 patients with chronic hepatitis B (CHB), 19 with dysplastic nodule (DN), and 14 with HCC were enrolled. An additional four normal liver (NL) samples were used as controls. SCCA1 expression in liver tissue was measured by immunochemistry. Another 28 HCC specimens and paired non-tumor tissues were used for SCCA1 detection by Western blot. The prognostic value of SCCA1 expression in HCC was evaluated by the Cox proportional hazards regression model analysis. RESULTS: Western blot analysis showed SCCA1 positive rate in HCC was higher than the matched adjacent noncancerous tissues (p <0.001). Immunohistochemistry revealed that SCCA1-positive rate increased gradually from NL, CHB, PNT to DN and HCC (p <0.05). Clinicopathological analysis showed that SCCA1 expression was positively associated with tumor differentiation (p = 0.043) and patients' Child-Pugh score (p = 0.021). The SCCA1-poistive group showed better overall survival than the negative group (p = 0.029). Importantly, SCCA1 expression was an independent prognostic factor for the overall survival of HCC patients (hazard ratio = 3.757, p <0.001). CONCLUSION: SCCA1 expression pattern may relate to the progression of chronic liver diseases. Furthermore, our study supports a potential association of negative SCCA1 expression with poor outcome in HCC. PMID- 25819272 TI - APOE and AGT in the Finnish p.Arg133Cys CADASIL population. AB - BACKGROUND: CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype. AIMS AND METHODS: Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine. RESULTS: We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine. CONCLUSIONS: The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype. PMID- 25819273 TI - Cell source-dependent in vivo immunosuppressive properties of mesenchymal stem cells derived from the bone marrow and synovial fluid of minipigs. AB - The in vitro differentiation and immunosuppressive capacity of mesenchymal stem cells (MSCs) derived from synovial fluid (SF-MSCs) and bone marrow extract (BM MSCs) in an isogenic background of minipigs were comparatively analyzed in a collagen-induced arthritis (CIA) mouse model of rheumatoid arthritis (RA). The proliferation capacity and expression of pluripotent transcription factors (Oct3/4 and Sox2) were significantly (P<0.05) higher in SF-MSCs than in BM-MSCs. The differentiation capacity of SF-MSCs into adipocytes, osteocytes and neurocytes was significantly (P<0.05) lower than that of BM-MSCs, and the differentiation capacity of SF-MSCs into chondrocytes was significantly (P<0.05) higher than that of BM-MSCs. Systemic injection of BM- and SF-MSCs significantly (P<0.05) ameliorated the clinical symptoms of CIA mice, with SF-MSCs having significantly (P<0.05) higher clinical and histopathological recovery scores than BM-MSCs. Furthermore, the immunosuppressive properties of SF-MSCs in CIA mice were associated with increased levels of the anti-inflammatory cytokine interleukin (IL)-10, and decreased levels of the pro-inflammatory cytokine IL 1beta and osteoclast-related sRANKL. In conclusion, SF-MSCs exhibited eminent pluripotency and differentiation capacity into chondrocytes, addition to substantial in vivo immunosuppressive capacity by elevating IL-10 and reducing IL 1beta levels in CIA mice. PMID- 25819274 TI - Myosin-X and disease. AB - Myosin-X (Myo10) is a motor protein best known for its role in filopodia formation. New research implicates Myo10 in a number of disease states including cancer metastasis and pathogen infection. This review focuses on these developments with emphasis on the emerging roles of Myo10 in formation of cancer cell protrusions and metastasis. A number of aggressive cancers show high levels of Myo10 expression and knockdown of Myo10 has been shown to dramatically limit cancer cell motility in 2D and 3D systems. Myo10 knockdown also limits spread of intracellular pathogens marburgvirus and Shigella flexneri. Consideration is given to how these properties might arise and potential paths of future research. PMID- 25819275 TI - Protein- and Peptide-drug conjugates: an emerging drug delivery technology. AB - Protein- and peptide-drug conjugates hold a promising stance in the delivery of therapeutic agents by providing distinct advantage of improving therapeutic potential of drugs. Recent advancements in the proteomics and recombinant DNA technology, by enabling identification of distinct structural features of proteins and making it feasible to introduce specific functionalities in protein/peptide structure, has made it possible to synthesize high quality protein- and peptide-drug conjugates though a wide variety of coupling techniques. Additionally, use of specialized linkers makes them unique in their in vivo therapeutic application by providing target tissue-specific release of drug. Several protein- and peptide-drug conjugates are currently under clinical trials warranting their huge market potential in near future. Increased understanding in this field will surely enable us to produce high quality protein and peptide-drug conjugates which will serve therapeutic needs demanded from drug delivery systems in clinical settings. PMID- 25819277 TI - Hybrid protein-synthetic polymer nanoparticles for drug delivery. AB - Among the most common nanoparticulate systems, the polymeric nanocarriers have a number of key benefits, which give a great choice of delivery platforms. Nevertheless, polymeric nanoparticles possess some limitations that include use of toxic solvents in the production process, polymer degradation, drug leakage outside the diseased tissue, and polymer cytotoxicity. The combination of polymers of biological and synthetic origin is an appealing modern strategy for the production of novel nanocarriers with unprecedented properties. Proteins' interface can play an important role in determining bioactivity and toxicity and gives perspective for future development of the polymer-based nanoparticles. The design of hybrid constructs composed of synthetic polymer and biological molecules such as proteins can be considered as a straightforward tool to integrate a broad spectrum of properties and biofunctions into a single device. This review discusses hybrid protein-synthetic polymer nanoparticles with different structures and levels in complexity and functionality, in view of their applications as drug delivery systems. PMID- 25819278 TI - Efficient delivery of therapeutic agents by using targeted albumin nanoparticles. AB - Albumin nanoparticles are one of the most important drug carriers for the delivery of therapeutic drugs, especially for the treatment of malignancies. This potential is due to their high binding capacity for both hydrophobic and hydrophilic drugs and the possibility of surface modification. Accumulation of albumin-bound drugs in the tumor interstitium occurs by the enhanced permeability and retention effect, which is also facilitated by the 60-kDa glycoprotein transcytosis pathway and binding to secreted protein, acidic and rich in cysteine located in the tumor extracellular matrix. In addition, specific ligands such as monoclonal antibodies, folic acid, transferrin, and peptides can be conjugated to the surface of albumin nanoparticles to actively target the drug to its site of action. The albumin-bound paclitaxel, Abraxane, is one of the several therapeutic nanocarriers that have been approved for clinical use. By the development of Abraxane that demonstrates a higher response rate and improved tolerability and therapeutic efficiency in comparison with solvent-based formulation, and with consideration of its commercial success, albumin is attracting the interest of many biotechnological and pharmaceutical companies. This chapter explores the current targeted and nontargeted albumin-based nanoparticles that are in various stages of development for the delivery of therapeutic agents in order to enhance the efficacy of cancer treatment. PMID- 25819276 TI - Modifications of natural peptides for nanoparticle and drug design. AB - Natural products serve as an important source of novel compounds for drug development. Recently, peptides have emerged as a new class of therapeutic agents due to their versatility and specificity for biological targets. Yet, their effective application often requires use of a nanoparticle delivery system. In this chapter, we review the role of natural peptides in the design and creation of nanomedicines, with a particular focus on cell-penetrating peptides, antimicrobial peptides, and peptide toxins. The use of natural peptides in conjunction with nanoparticle delivery systems holds great promise for the development of new therapeutic formulations as well as novel platforms for the delivery of various cargoes. PMID- 25819279 TI - Vasoactive Intestinal Peptide (VIP) Nanoparticles for Diagnostics and for Controlled and Targeted Drug Delivery. AB - Neuropeptides are potentially valuable tools for clinical applications as they offer many distinct advantages over other bioactive molecules like proteins and monoclonal antibodies due to their reduced side effects and simple chemical modifications. Despite such advantages, the difficulty with neuropeptides often relies on their poor metabolic stability and reduced biological activity intervals. Among the neuropeptides, VIP has been identified as a potentially bioactive agent for inflammatory, neurodegenerative, and cancer-related diseases. However, the effective translation of preclinical studies related to VIP to clinical realities faces several major challenges, most of which are commonplace for other neuropeptides. Here, we present recent studies aimed at developing nanostructured organic and inorganic systems either for the appropriate delivery of VIP or for VIP targeting. These technologies stand as an alternative starting point for chemical manipulations of the neuropeptides in order to improve potency, selectivity, or pharmacokinetic parameters. PMID- 25819280 TI - Implications of protein- and Peptide-based nanoparticles as potential vehicles for anticancer drugs. AB - Protein-based nanocarriers have gained considerable attention as colloidal carrier systems for the delivery of anticancer drugs. Protein nanocarriers possess various advantages including their low cytotoxicity, abundant renewable sources, high drug-binding capacity, and significant uptake into the targeted tumor cells. Moreover, the unique protein structure offers the possibility of site-specific drug conjugation and tumor targeting using various ligands modifying the surface of protein nanocarriers. In this chapter, we highlight the most important applications of protein nanoparticles (NPs) for the delivery of anticancer drugs. We examine the various techniques that have been utilized for the preparation of anticancer drug-loaded protein NPs. Finally, the current chapter also reviews the major outcomes of the in vitro and in vivo investigations of surface-modified tumor-targeted protein NPs. PMID- 25819281 TI - Polysaccharide nanoparticles for protein and Peptide delivery: exploring less known materials. AB - Finding adequate carriers for protein and peptide delivery has become an urgent need, owing to the growing number of macromolecules identified as having therapeutic potential. Nanoparticles have emerged in the field as very promising vehicles and much work has been directed to testing the capacity of different materials to compose the matrix of these carriers. Natural materials and, specifically, polysaccharides have been taking the forefront of the challenge, because of several favoring properties that include the higher propensity to exhibit biodegradability and biocompatibility, and also the high structural flexibility. The majority of works found in the literature regarding polysaccharide nanoparticles uses very popular materials like chitosan or hyaluronic acid. This review is aimed at describing and exploring the potential of polysaccharides that are not so well known or that are less explored. For those, the main properties will be described, together with an overview of the reported applications as nanoparticle matrix materials. PMID- 25819282 TI - Bioconjugation of silk fibroin nanoparticles with enzyme and Peptide and their characterization. AB - Bombyx mori silk fibroin is a type of protein-based polymer with unique characteristics that is widely used in the research and development of medical biomaterials. The degummed filament of silk fibroin can be dissolved in a highly concentrated salt solution. After desalination, the regenerated liquid silk fibroin (LSF) solution could be made into various forms of silk biomaterials, such as powder, fiber, film, porous matrix, 3D scaffold, and hydrogel, depending on its application. In this study, we mixed the liquid silk solution with enzymes, including oxidase and hydrolase, and rapidly injected the mixture into an excess of acetone. The enzyme retained most of its enzymatic activity and was also captured in silk fibroin nanoparticles (SFNs), which instantly formed via a configuration transition of the regenerated silk protein from a random coil and alpha-helix to a beta-sheet. The resulting enzyme-captured SFNs displayed a fine crystal structure with a high activity recovery and good thermal stability. Moreover, the affinities of these modified enzymes to their substrate did not evidently suffer from the capture. When only the liquid silk solution was rapidly injected into acetone, the resulting globular SFNs with the same crystallinity were also a good carrier that was covalently conjugated to enzymes and insulin. Thus, silk protein nanoparticles are of potential value as an enzyme or peptide delivery system for the research and development of medical biomaterials. In this report, the bioconjugation of SFNs with glucose oxidase, superoxidase, beta glucosidase, L-asparaginase, neutral protease, and insulin and their characterization are described in detail. PMID- 25819284 TI - Preface. PMID- 25819283 TI - Food-grade protein-based nanoparticles and microparticles for bioactive delivery: fabrication, characterization, and utilization. AB - Proteins can be used to fabricate nanoparticles and microparticles suitable for use as delivery systems for bioactive compounds in pharmaceutical, food, cosmetic, and other products. Food proteins originate from various animal or vegetal sources and exhibit a wide diversity of molecular and physicochemical characteristics, e.g., molecular weight, conformation, flexibility, polarity, charge, isoelectric point, solubility, and interactions. As a result, protein particles can be assembled using numerous different preparation methods, from one or more types of protein or from a combination of a protein and another type of biopolymer (usually a polysaccharide). The final characteristics of the particles produced are determined by the proteins and/or polysaccharides used, as well as the fabrication techniques employed. This chapter provides an overview of the functional properties of food proteins that can be used to assemble nanoparticles and microparticles, the fabrication techniques available to create those particles, the factors that influence their stability, and their potential applications within the food industry. PMID- 25819285 TI - Aerosol-assisted extraction of silicon nanoparticles from wafer slicing waste for lithium ion batteries. AB - A large amount of silicon debris particles are generated during the slicing of silicon ingots into thin wafers for the fabrication of integrated-circuit chips and solar cells. This results in a significant loss of valuable materials at about 40% of the mass of ingots. In addition, a hazardous silicon sludge waste is produced containing largely debris of silicon, and silicon carbide, which is a common cutting material on the slicing saw. Efforts in material recovery from the sludge and recycling have been largely directed towards converting silicon or silicon carbide into other chemicals. Here, we report an aerosol-assisted method to extract silicon nanoparticles from such sludge wastes and their use in lithium ion battery applications. Using an ultrasonic spray-drying method, silicon nanoparticles can be directly recovered from the mixture with high efficiency and high purity for making lithium ion battery anode. The work here demonstrated a relatively low cost approach to turn wafer slicing wastes into much higher value added materials for energy applications, which also helps to increase the sustainability of semiconductor material and device manufacturing. PMID- 25819286 TI - Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy. AB - Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment. PMID- 25819287 TI - Is high dose rate brachytherapy reliable and effective treatment for prostate cancer patients? A review of the literature. AB - The intrinsic physical and radiobiological characteristics of High Dose Rate Brachytherapy (HDR-BT) are well suited to the treatment of prostate cancer. HDR BT was initially used as a boost to external beam brachytherapy, but has subsequently been employed as the sole treatment, which is termed HDR monotherapy. This review summarizes the clinical outcomes and toxicity results of the principal studies and discusses the radiobiological basis supporting its use. PMID- 25819288 TI - Longitudinal relationships between language and verbal short-term memory skills in children with Down syndrome. AB - Children with Down syndrome are at risk for language difficulties, the nature of which is not well understood. This study compared the longitudinal predictors of language skills in children with Down syndrome with those in typically developing control children matched for initial level of nonverbal mental ability. An age cohort of children with Down syndrome (n=43) and 57 typically developing control children was assessed on measures of vocabulary, grammar, and verbal short-term memory three times at yearly intervals. Children with Down syndrome showed slower development on all measures than the typically developing controls. Longitudinal analyses showed moderate to high stability of language and verbal short-term memory skills. Our results confirm earlier evidence of pervasive language learning difficulties in this group and suggest that early language intervention should be given high priority. PMID- 25819289 TI - One-stage cosmetic finger reconstruction using a second toe island flap containing terminal branches of the toe artery. AB - INTRODUCTION: A finger reconstructed by toe transfer may have morphological defects. We report the results of second toe transfer for 1-stage finger reconstruction with an island flap based on terminal branches of the toe artery. HYPOTHESIS: The technique can improve the morphological outcomes of reconstructed fingers. MATERIALS AND METHOD: Between January 2008 and June 2011, toe-to-finger transfer was performed for 36 fingers in 31 patients. An island flap containing terminal branches of the toe artery was embedded in the neck of the second toe to eliminate the morphological defect caused by stenosis in that area. RESULTS: All reconstructed fingers and all flaps survived. No donor site complications occurred. The mean follow-up was 8 months (range, 5 to 25 months). The morphology of the reconstructed finger was close to that of a normal finger, and a natural transition could be observed in the finger pulp, the finger neck, and the junction between the toe and the finger. Sensory recovery of the finger pulp ranged from S1 to S3+. The mean pinch strength of the reconstructed fingers was 48% to 60% of that of the contralateral side. The mean DASH scores were 52.9, 48.9, and 46.0 for patients that had the index, third, and fourth fingers reconstructed, respectively, and the lowest mean aesthetic score was 70. DISCUSSION: The method provides good aesthetic and functional outcomes, and overcomes aesthetic difficulties associated with other methods of toe transfer for finger reconstruction. PMID- 25819290 TI - Treatment of dystonia in extensor hallucis longus and digitorum muscles with neurotomy of the branches of the deep fibular nerve: Preliminary results. AB - INTRODUCTION: Dystonia in extensor hallucis and/or digitorum muscles can be observed in pyramidal and extrapyramidal lesions and results in pain in these toes, spontaneous or when walking, problems and discomfort when putting on shoes and socks, and cutaneous lesions on the toes. The objective of this study was to assess the efficacy and safety of deep fibular nerve neurotomy for the extensor hallucis longus (EHL) and/or the extensor digitorum longus (EDL) branches in the treatment of extension dystonia of the hallux and/or other toes. PATIENTS AND METHODS: A deep fibular nerve neurotomy was performed in 20 patients (n=19 for the EHL, n=6 for the EDL). We retrospectively analyzed the treatment's efficacy and safety and assessed the patients' self-reported improvement and overall treatment satisfaction. RESULTS: Dystonia totally disappeared in 15 cases (75%); it persisted at a minimal level in the other patients. The patients reported a decrease in pain (P<0.01) and fewer difficulties putting on shoes and socks (P<0.001) and had a high median level of satisfaction (8.5/10). Adverse effects were rare and transient. The identification of the nerve branches was sometimes difficult. DISCUSSION: Deep fibular nerve neurotomy for the EHL and/or EDL branches seems to be an effective treatment for extension dystonia of the hallux and/or other toes and its consequences for the adult neurological patient. However, these encouraging preliminary results should be confirmed by prospective, longer-term studies. PMID- 25819291 TI - Abridged republication of FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum. PMID- 25819292 TI - Recognizing the journey and celebrating the achievement of cochlear implants. PMID- 25819294 TI - Extract of Bowdichia virgilioides and maackiain as larvicidal agent against Aedes aegypti mosquito. AB - The larvicidal activities of extracts of three hardwood species (Hymenaea stigonorcapa, Anadenanthera colubrina and Bowdichia virgilioides) against 4th instar larvae of Aedes aegypti were evaluated using WHO guidelines. Extracts of H. stignocarpa and A. colubrina showed weak activity. The highest larvicidal effect was obtained with the cyclohexane extract of the heartwood of B. virgilioides, which caused 100% mortality at concentrations at 50 and 100 ug/mL. Fraction toluene/EtOAc (8:2) from this extract showed larvicidal activity (LC50 = 34.90 +/- 1.27 ug/mL). A mixture of two compounds identified as medicarpin and maackiain exhibited a very good larvicidal activity (sub-fraction 2, LC50 = 17.5 +/- 1.87 ug/mL) and maackiain showed to be a strong larvicidal compound (LC50 = 21.95 +/- 1.34 ug/mL). This result can be of value in the search for new natural larvicidal compounds from other hardwood plant extracts and presents the first report of B. virgilioides being used to control a mosquito vector. PMID- 25819293 TI - Enhancing Parent-Child Communication and Parental Self-Esteem With a Video Feedback Intervention: Outcomes With Prelingual Deaf and Hard-of-Hearing Children. AB - Evidence on best practice for optimizing communication with prelingual deaf and hard-of-hearing (DHH) children is lacking. This study examined the effect of a family-focused psychosocial video intervention program on parent-child communication in the context of childhood hearing loss. Fourteen hearing parents with a prelingual DHH child (Mage = 2 years 8 months) completed three sessions of video interaction guidance intervention. Families were assessed in spontaneous free play interactions at pre and postintervention using the Emotional Availability (EA) Scales. The Rosenberg Self-esteem Scale was also used to assess parental report of self-esteem. Compared with nontreatment baselines, increases were shown in the EA subscales: parental sensitivity, parental structuring, parental nonhostility, child responsiveness, and child involvement, and in reported self-esteem at postintervention. Video-feedback enhances communication in families with prelingual DHH children and encourages more connected parent child interaction. The results raise implications regarding the focus of early intervention strategies for prelingual DHH children. PMID- 25819295 TI - Cymbopogon citratus-synthesized gold nanoparticles boost the predation efficiency of copepod Mesocyclops aspericornis against malaria and dengue mosquitoes. AB - Plant-borne compounds can be employed to synthesize mosquitocidal nanoparticles that are effective at low doses. However, how they affect the activity of mosquito predators in the aquatic environment is unknown. In this study, we synthesized gold nanoparticles (AuN) using the leaf extract of Cymbopogon citratus, which acted as a reducing and capping agent. AuN were characterized by a variety of biophysical methods and sorted for size in order to confirm structural integrity. C. citratus extract and biosynthesized AuN were tested against larvae and pupae of the malaria vector Anopheles stephensi and the dengue vector Aedes aegypti. LC50 of C. citratus extract ranged from 219.32 ppm to 471.36 ppm. LC50 of AuN ranged from 18.80 ppm to 41.52 ppm. In laboratory, the predatory efficiency of the cyclopoid crustacean Mesocyclops aspericornis against A. stephensi larvae was 26.8% (larva I) and 17% (larva II), while against A. aegypti was 56% (I) and 35.1% (II). Predation against late-instar larvae was minimal. In AuN-contaminated environment,predation efficiency against A. stephensi was 45.6% (I) and 26.7% (II), while against A. aegypti was 77.3% (I) and 51.6% (II). Overall, low doses of AuN may help to boost the control of Anopheles and Aedes larval populations in copepod-based control programs. PMID- 25819296 TI - Characterization of a gut-associated asparaginyl endopeptidase of Clonorchis sinensis. AB - Asparaginyl endopeptidases (AEP: EC 3.4.22.34) are a family of cysteine proteases classified into the MEROPS clan CD, family C13. In this study, we characterized the biochemical and antigenic properties of an AEP of Clonorchis sinensis (CsAEP). The recombinant CsAEP showed hydrolytic activity at pH values ranging from acidic to neutral with optimum activity at pH 6.0. While the recombinant CsAEP was stable at neutral pHs, it was unstable at acidic pHs and resulted in loss of enzymatic activity. The recombinant enzyme was effectively inhibited by iodoacetic acid and N-ethylmaleimide, but not by E-64. The partially purified native CsAEP showed biochemical properties similar to the recombinant enzyme. Native CsAEP is likely to be cleaved into an N-terminal mature enzyme and a C terminal fragment via autocatalytic activation at acidic pHs. Polyclonal antibody raised against the recombinant CsAEP recognized three forms of CsAEP, proenzyme, the N-terminal mature enzyme and the C-terminal fragment, in the worm extract (WE) of C. sinensis. However, only the C-terminal fragment was mainly found in the excretory and secretory (ES) products of the parasite. Strong CsAEP activity was found in the WE, but only a trace level of CsAEP activity was detected in the ES products of the parasite. CsAEP was expressed in various developmental stages of C. sinensis, from metacercariae to adults, and was found to be localized in the intestine of the parasite as well as in intestinal contents. Sera from rats experimentally infected with C. sinensis reacted with CsAEP beginning 4 weeks after infection. These results suggest that CsAEP is a gut-associated enzyme synthesized in the intestine of C. sinensis and subsequently secreted into the intestinal lumen of the parasite. PMID- 25819298 TI - Induction of Sd(a)-sialomucin and sulfated H-sulfomucin in mouse small intestinal mucosa by infection with parasitic helminth. AB - Mucin is a major component of mucus on gastrointestinal mucosa. Mucin alteration in the host is considered to be the principal event for expulsion of intestinal helminths. However, it is unclear what mucin alterations are induced by various helminth infections. In this study, the alterations of mouse small intestinal mucin after infection with two nematodes, Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which parasitize the jejunal epithelium, and a cestode, Vampirolepis nana, which parasitizes the ileal epithelium, were examined biochemically and histologically using two anti-mucin monoclonal antibodies (mAbs), HCM31 and PGM34, which recognize Sd(a) antigen, NeuAcalpha2-3(GalNAcbeta1 4)Galbeta1-4GlcNAcbeta-, and sulphated H type 2 antigen, Fucalpha1-2Galbeta1 4GlcNAc(6SO3H)beta-, respectively. The goblet cell mucins that reacted with HCM31 increased conspicuously on the jejunal mucosa concurrently with expulsion of N. brasiliensis. Increased levels of HCM31-reactive mucins were observed in the jejunal mucosa after H. polygyrus infection, despite the ongoing parasitism. Goblet cell mucins that reacted with PGM34 increased on the ileal mucosa during V. nana parasitism. Small intestinal goblet cells reacting with the two mAbs were not observed in non-infected mice, although sialomucins and sulfomucins were abundantly present. Additionally, the number of ileal goblet cells that reacted with the two mAbs was increased at the time of expulsion of heterophyid trematode. These results indicate that the type of specific acidic mucins expressed after infection varies among species of intestinal helminth, and, furthermore, that the relationship with worm expulsion is also different. PMID- 25819299 TI - Kinetic and biochemical characterization of Trypanosoma evansi nucleoside triphosphate diphosphohydrolase. AB - Nucleoside triphosphate diphospho-hydrolases (NTPDases) catalyze the hydrolysis of several nucleosides tri and diphosphate playing major roles in eukaryotes including purinergic signaling, inflammation, hemostasis, purine salvage and host pathogen interactions. These enzymes have been recently described in parasites where several evidences indicated their involvement in virulence and infection. Here, we have investigated the presence of NTPDase in the genome of Trypanosoma evansi. Based on the genomic sequence from Trypanosoma brucei, we have amplified an 1812 gene fragment corresponding to the T. evansi NTPDase gene. The protein was expressed in the soluble form and purified to homogeneity and enzymatic assays were performed confirming the enzyme identity. Kinetic parameters and substrate specificity were determined. The dependence of cations on enzymatic activity was investigated indicating the enzyme is stimulated by divalent cations and carbohydrates but inhibited by sodium. Bioinformatic analysis indicates the enzyme is a membrane bound protein facing the extracellular side of the cell with 98% identity to the T. brucei homologous NTPDase gene. PMID- 25819297 TI - Immuno-evasive tactics by schistosomes identify an effective allergy preventative. AB - Many chronic inflammatory diseases can be improved by helminth infection, but the mechanisms are poorly understood. Allergy and helminthiasis are both associated with Th2-like immune responses; thus, defining how infection with parasites leads to reduced allergy has been particularly challenging. We sought to better understand this conundrum by evaluating host-parasite interactions involved in Th2 immunity in human schistosomiasis. Immune cells were cultured with schistosomes and the effect on CD23, an IgE receptor associated with resistance in schistosomiasis, was evaluated. Cells treated with schistosomes demonstrated reduced surface CD23 levels with a parallel accumulation of soluble (s) CD23 suggesting this IgE receptor is proteolytically cleaved by the parasite. Consistent with this hypothesis, a schistosome-generated (SG)-sCD23 fragment of 15 kDa was identified. SG-sCD23 inhibited IgE from binding to CD23 and FcepsilonRI, but lacked the ability to bind CD21. These results suggested that schistosomes target IgE-mediated immunity in immuno-evasive tactics. Based on its characteristics, we predicted that SG-sCD23 would function as an efficacious allergy preventative. Treatment of human FcepsilonRI-transgenic mice with recombinant (r) SG-sCD23 reduced the ability of human IgE to induce an acute allergic response in vivo. In addition, an optimized form of rSG-sCD23 with an introduced point mutation at Asp258 (D258E)to stabilize IgE binding had increased efficacy compared to native rSG-sCD23. Schistosome infection may thus inhibit allergic-like protective immune responses by increasing soluble IgE decoy receptors. Allergy treatments based on this naturally occurring phenomenon may be highly effective and have fewer side effects with long-term use. PMID- 25819300 TI - Clearing up misunderstandings around core outcomes for atopic dermatitis. PMID- 25819301 TI - Cardiac magnetic resonance: Is it time to replace the endomyocardial biopsy to detect heart transplant rejection? PMID- 25819302 TI - Organ donation after death of chronic lung allograft dysfunction patients. PMID- 25819303 TI - Making governance work in the health care sector: evidence from a 'natural experiment' in Italy. AB - The Italian Health care System provides universal coverage for comprehensive health services and is mainly financed through general taxation. Since the early 1990s, a strong decentralization policy has been adopted in Italy and the state has gradually ceded its jurisdiction to regional governments, of which there are twenty. These regions now have political, administrative, fiscal and organizational responsibility for the provision of health care. This paper examines the different governance models that the regions have adopted and investigates the performance evaluation systems (PESs) associated with them, focusing on the experience of a network of ten regional governments that share the same PES. The article draws on the wide range of governance models and PESs in order to design a natural experiment. Through an analysis of 14 indicators measured in 2007 and in 2012 for all the regions, the study examines how different performance evaluation models are associated with different health care performances and whether the network-shared PES has made any difference to the results achieved by the regions involved. The initial results support the idea that systematic benchmarking and public disclosure of data are powerful tools to guarantee the balanced and sustained improvement of the health care systems, but only if they are integrated with the regional governance mechanisms. PMID- 25819304 TI - Review article: spontaneous bacterial peritonitis--bacteriology, diagnosis, treatment, risk factors and prevention. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites. AIM: To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP. METHODS: Information was obtained from reviewing medical literature accessible on PubMed Central. The search term 'spontaneous bacterial peritonitis' was cross-referenced with 'bacteria', 'risk factors', 'ascites', 'paracentesis', 'ascitic fluid analysis', 'diagnosis', 'treatment', 'antibiotics', 'prophylaxis', 'liver transplantation' and 'nutrition'. RESULTS: Gram-positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at risk individuals. CONCLUSIONS: Third-generation, broad-spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long-term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin-tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta-adrenergic antagonist therapy in patients with end-stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications. PMID- 25819305 TI - Beware of multiplicity problems in clinical trials. PMID- 25819306 TI - Memory detection using fMRI - does the encoding context matter? AB - Recent research revealed that the presentation of crime related details during the Concealed Information Test (CIT) reliably activates a network of bilateral inferior frontal, right medial frontal and right temporal-parietal brain regions. However, the ecological validity of these findings as well as the influence of the encoding context are still unclear. To tackle these questions, three different groups of subjects participated in the current study. Two groups of guilty subjects encoded critical details either only by planning (guilty intention group) or by really enacting (guilty action group) a complex, realistic mock crime. In addition, a group of informed innocent subjects encoded half of the relevant details in a neutral context. Univariate analyses showed robust activation differences between known relevant compared to neutral details in the previously identified ventral frontal-parietal network with no differences between experimental groups. Moreover, validity estimates for average changes in neural activity were similar between groups when focusing on the known details and did not differ substantially from the validity of electrodermal recordings. Additional multivariate analyses provided evidence for differential patterns of activity in the ventral fronto-parietal network between the guilty action and the informed innocent group and yielded higher validity coefficients for the detection of crime related knowledge when relying on whole brain data. Together, these findings demonstrate that an fMRI-based CIT enables the accurate detection of concealed crime related memories, largely independent of encoding context. On the one hand, this indicates that even persons who planned a (mock) crime could be validly identified as having specific crime related knowledge. On the other hand, innocents with such knowledge have a high risk of failing the test, at least when considering univariate changes of neural activation. PMID- 25819307 TI - Pulmonary embolism severity index, age-based markers and evaluation in the emergency department. AB - OBJECTIVES: The purpose of this study was to assess the severity of pulmonary embolism in the emergency department using vital signs and age-based vital parameters and compare these parameters with pulmonary embolism severity index (PESI) score. METHODS: Between January 2011 and October 2014, there were 284 patients diagnosed with pulmonary embolism in the Emergency Unit of Selcuk University Hospital. Patient records were reviewed retrospectively. The PESI scores were calculated, and patients were divided into high- and low-risk groups. Shock index (SI), age-based shock index (SIA), maximum heart rate (MHR), minpulse (MP) and pulse maximum index (PMI) were calculated. The association of these parameters with PESI was evaluated. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the association of risk and mortality with age based markers. RESULTS: There were 75 men (43%) in the 173 patients included in the study. The PESI classification showed 54 patients in the low-risk group and 119 patients in the high-risk group. Mortality was higher in the PESI high-risk group, and no deaths occurred in the low-risk group. Comparison of the age-based markers and PESI for patients who died or survived showed that AUC for PESI was 0.807, AUC for SI was 0.824 and AUC for SIA was 0.825. CONCLUSIONS: The SIA risk classification was more efficient than SI in pulmonary embolism patients who presented to the emergency unit. The SIA was more accurate than SI or PESI in predicting mortality. PMID- 25819308 TI - Evaluation of peptide nucleic acid-mediated multiplex real-time PCR kits for rapid detection of carbapenemase genes in gram-negative clinical isolates. AB - The emergence of clinical isolates of carbapenemase-producing microbes confers multidrug-resistance to these bacteria and renders them difficult to treat. This study was performed to evaluate peptide nucleic acid (PNA) probe-based multiplex real-time PCR kits used to detect carbapenemase genes. In total, 324 carbapenemase genes, collected from 318 gram-negative clinical isolates in 36 different hospital laboratories, were assayed to evaluate multiplex real-time PCR kits (PANAGENE; Daejeon, Korea). The nine most prevalent carbapenemase genes (KPC, OXA-48, GES, IMP, VIM, NDM, ISAba1-OXA-51, OXA-23, and OXA-58) were included in this study. The sensitivity and specificity of the multiplex real time PCR assay to all of the carbapenemase genes were above 99.0%, except for ISAba1-OXA-51. The detection limit of the assay was 100 target copies per 25 MUL of reaction volume for all of the nine genetic types of carbapenemases, and the genes were all detected in a single three-hour PCR. The assay also showed considerable efficiency (above 80.0%), stable reproducibility (coefficient of variation, below 5.0%) and a long shelf-life (more than eight months) with no cross reactivity. The developed PNA-mediated multiplex real-time PCR assay was useful for the rapid, accurate and simultaneous identification of nine carbapenemase genes in gram-negative clinical isolates, suggesting its potential to help choose the appropriate antibiotics and aid the control of carbapenemase genes. PMID- 25819309 TI - Metabolic engineering of Escherichia coli for the biosynthesis of various phenylpropanoid derivatives. AB - Plants produce a variety of natural products with promising biological activities, such as the phenylpropanoids resveratrol and curcumin. While these molecules are naturally assembled through dedicated plant metabolic pathways, combinatorial biosynthesis has become an attractive tool to generate desired molecules. In this work, we demonstrated that biosynthetic enzymes from different sources can be recombined like legos to make various molecules. Seven biosynthetic genes from plants and bacteria were used to establish a variety of complete biosynthetic pathways in Escherichia coli to make valuable compounds. Different combinations of these biosynthetic bricks were made to design rationally various natural product pathways, yielding four phenylpropanoid acids (cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid), three bioactive natural stilbenoids (resveratrol, piceatannol and pinosylvin), and three natural curcuminoids (curcumin, bisdemethoxycurcumin and dicinnamoylmethane). A curcumin analog dicaffeoylmethane was synthesized by removing a methyltransferase from the curcumin biosynthetic pathway. Furthermore, introduction of a fungal flavin dependent halogenase into the resveratrol biosynthetic pathway yielded a novel chlorinated molecule 2-chloro-resveratrol. This work thus provides a novel and efficient biosynthetic approach to creating various bioactive molecules. Further expansion of the library of the biosynthetic bricks will provide a resource for rational design of various phenylpropanoids via the combinatorial biosynthesis approach. PMID- 25819310 TI - Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review. AB - AIMS: A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children. METHODS: MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed. RESULTS: From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants. CONCLUSIONS: Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base. PMID- 25819311 TI - Asia-Pacific consensus statements on Crohn's disease. Part 2: Management. AB - The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field. PMID- 25819312 TI - Physicochemical properties of potential porphyrin photosensitizers for photodynamic therapy. AB - This research evaluated the suitability of synthetic photosensitizers for their use as potential photosensitizers in photodynamic therapy using steady state and time-resolved spectroscopic techniques. Four tetraphenylporphyrin derivatives were studied in ethanol and dimethyl sulfoxide. The spectroscopic properties namely electronic absorption and emission spectra, ability to generate singlet oxygen, lifetimes of the triplet state, as well as their fluorescence quantum yield were determined. Also time-correlated single photon counting method was used to precisely determine fluorescence lifetimes for all four compounds. Tested compounds exhibit high generation of singlet oxygen, low generation of fluorescence and they are chemical stable during irradiation. The studies show that the tested porphyrins satisfy the conditions of a potential drug in terms of physicochemical properties. PMID- 25819313 TI - Resonance light scattering spectroscopy of procyanidin-CPB-DNA ternary system and its potential application. AB - A new method for the determination of calf thymus DNA at nanogram level was proposed based on the enhanced resonance light scattering (RLS) signals of DNA in the presence of procyanidin and cetylpyridinium bromide dihydrate (CPB). Under the experimental conditions, the RLS intensity of DNA at 291.0 nm was greatly enhanced by procyanidin-CPB at pH 7.0. There was a good linear relationship (r=0.9993) between the enhanced RLS intensity (DeltaI(RLS)) and DNA concentration of 0.0084-3.36 MUg mL(-1). The limit of detection (LOD) was 2.27 ng mL(-1) (3S0/S). Three synthetic DNA samples were measured with satisfactory, and the recovery was 102.3-107.2%. PMID- 25819314 TI - Synthesis and spectroscopical study of rhodanine derivative using DFT approaches. AB - The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of (E)-5-benzylidene-2-thioxothiazolidine-4-one (E5BTTO) have been investigated experimentally and theoretically based on Density Functional Theory (DFT) approach. The FT-Raman and FT-IR spectra of E5BTTO were recorded in solid phase. Theoretical calculations were performed at the DFT level using the Gaussian 03 program. The experimental bands were assigned and characterized on the basis of the scaled theoretical wavenumber by their Total Energy Distribution (TED). The results of the calculation were applied to simulate infrared and raman spectra of the title compound which showed good agreement with the observed spectra. The calculated HOMO and LUMO energies show that charge transfer occur within the molecule. Stability arising from hyperconjugative interactions leading to its NLO activity and charge delocalization were analyzed using Natural Bond Orbital (NBO) analysis. PMID- 25819315 TI - Electrolytic coloration below 0 degrees C and spectral properties of ammonium alum crystals using a pointed anode. AB - Ammonium alum crystals are colored electrolytically below 0 degrees C and under various voltages using a pointed anode and a flat cathode. SO2(-), O3(-), O2(-), O(-) hole-trapped centers and O(0), O(2-), H(+) radicals are produced in colored ammonium alum crystals. The absorption bands of the SO2(-) and O3(-) hole-trapped centers are observed in the absorption spectra of the colored ammonium alum crystals. The hole-trapped centers and radicals come mainly from the electric field-induced decomposition of the SO4(2-) radicals and crystalline water molecules. Current is measured during electrolytic coloration. Electron exchanges from electrons and small charged radicals to electrodes induce complete current. PMID- 25819316 TI - Quantum dots and ionic liquid-sensitized effect as an efficient and green catalyst for the sensitive determination of glucose. AB - A novel fluorescence (FL) method using water-soluble CdSe quantum dots (QDs) is proposed for the fluorometric determination of hydrogen peroxide and glucose. Water-soluble CdSe QDs were synthesized by using thioglycolic acid as stabilizer in aqueous solutions. The nanoparticles were structurally and optically characterized by X-ray powder diffraction (XRD), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), UV-Vis absorption spectroscopy, photoluminescence (PL) emission spectroscopy and transmission electron microscope (TEM). Ionic liquid-sensitized effect in aqueous solution was then investigated. In the presence of ionic liquid as catalyst, H2O2 was decomposed into radical that could quench the fluorescence of CdSe QDs more efficiently and rapidly. Then the oxidization of glucose by glucose oxidase was coupled with the fluorescence quenching of CdSe QDs by H2O2 producer with ionic liquid catalyst, which can be used to detect glucose. Therefore, a new FL analysis system was developed for the determination of glucose. Under the optimum conditions, there is a good linear relationship between the relative PL emission intensity and the concentration of glucose in the range of 5.0*10(-7)-1.0*10(-4) M of glucose with a correlation coefficient (R(2)) of 0.9973. The limit of detection of this system was found to be 1.0*10(-7) M. This method is not only simple, sensitive and low cost, but also reliable for practical applications. PMID- 25819317 TI - Photocatalytic activity of biogenic silver nanoparticles synthesized using potato (Solanum tuberosum) infusion. AB - In this study, we have reported a fast and eco-benign procedure to synthesis silver nanoparticle at room temperature using potato (Solanum tuberosum) infusion along with the study of its photocatalytic activity on methyl orange dye. After addition of potato infusion to silver nitrate solution, the color of the mixture changed indicating formation of silver nanoparticles. Time dependent UV-Vis spectra were obtained to study the rate of nanoparticle formation with time. Purity and crystallinity of the biogenic silver nanoparticles were examined by X ray diffraction (XRD). Average size and morphology of the nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Fourier transform infra-red spectroscopy (FTIR) was employed to detect functional bio-molecules responsible that contribute to the reduction and capping of biosynthesized Ag nanoparticles. Further, these synthesized nanoparticles were used to investigate their ability to degrade methyl orange dye under sunlight irradiation and the results showed effective photocatalytic property of these biogenic silver nanoparticles. PMID- 25819319 TI - Rapid, synergistic extractive spectrophotometric determination of copper(II) by using sensitive chromogenic reagent N",N"'-bis[(E)-(4-fluorophenyl) methylidene]thiocarbonohydrazide. AB - A rapid and simple spectrophotometric method was developed for the determination of copper(II) by using newly synthesized chromogenic reagent, N",N"'-bis[(E)-(4 fluorophenyl)methylidene]thiocarbonohydrazide [bis(4-fluoroPM)TCH]. The reagent is highly sensitive and it forms yellow colored ternary complex with copper(II) in presence pyridine having composition 1:1:2 (M:L:Py) in the acidic pH range. Absorption of colored complex in amyl acetate is measured with reagent as a blank at lambdamax 375 nm. The synergistic effect is observed due to pyridine forming adduct with reagent in the organic phase. Beer's law was obeyed in the concentration range from 2.0 to 14 MUg mL(-1) for copper(II)-[bis(4-fluoroPM)TCH] Py complex. Molar absorptivity and Sandell's sensitivity values for Cu(II)-bis(4 fluoroPM)TCH]-Py complex are 0.42545*10(5) and 0.0014 MUg/cm(2), respectively. The selectivity of the developed method was checked in the presence of various foreign ions. The developed method showed relative standard deviation (R.S.D.) of 0.13% for n=10. The composition of Cu(II)-[bis(4-fluoroPM)TCH]-Py complex was determined by known methods such as Job's method of continuous variation, mole ratio method and slope ratio method. It is found that the ternary complex is stable for more than 24h. Various factors influencing on the degree of complexation, such as, effect of pH, reagent concentration, synergent concentration, solvent etc. were studied. The accuracy and reliability of method was verified by AAS. This method is found to be simple, rapid and reproducible. PMID- 25819318 TI - DNA interaction, SOD, peroxidase and nuclease activity studies of iron complex having ligand with carboxamido nitrogen donors. AB - Complex (Et3HN)[Fe(III)(bpb)Cl2], 1 {where H2bpb: N,N'-(1,2 phenylene)bis(pyridine-2-carboxamide)} was synthesized and characterized by reported procedure (Yang et al., 1991). Complex 1 was found to be effective in superoxide scavenging activity and an IC50 value of 4.1 MUM was obtained in xanthine-xanthine oxidase nitro blue tetrazolium assay. Peroxidase-like activity of this complex was determined by the oxidation of 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS). DNA interaction studies of complex 1 showed binding of DNA through external or groove binding. Complex 1 exhibited chemical nuclease activity in the presence of hydrogen peroxide and cleaved supercoiled pBR322 DNA to its linear and nicked circular form at physiological pH. Mechanistic studies indicated possible role of hydroxyl radical (.OH) species in DNA cleavage activity via hydroperoxo intermediate: [Fe(III)OOH(-)](2+) >[Fe(IV)O](2+)+(.)OH. PMID- 25819320 TI - Spectroscopic investigation (FT-IR and FT-Raman), vibrational assignments, HOMO LUMO, NBO, MEP analysis and molecular docking study of 2-(4-hydroxyphenyl)-4,5 dimethyl-1H-imidazole 3-oxide. AB - In this work, the vibrational spectral analysis was carried out using FT-IR and FT-Raman spectroscopy of 2-(4-hydroxyphenyl)-4,5-dimethyl-1H-imidazole 3-oxide. The computations were performed at DFT levels of theory to get the optimized geometry and vibrational frequencies of the normal modes of the title compound using Gaussian09 software. The complete vibrational assignments of frequencies were made on the basis of potential energy distribution. The calculated HOMO and LUMO energies show the chemical activity of the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The hyperpolarizability values are reported and the first hyperpolarizability of the title compound is 19.61 times that of standard NLO material urea. From the MEP plot, the negative charge covers the nitro group and the positive region is over the hydroxyl group and N-H part of the imidazole ring. The calculated (1)H NMR results are in good agreement with experimental data. Molecular docking study is also reported. PMID- 25819321 TI - Electro-bioremediation of contaminated sediment by electrode enhanced capping. AB - In-situ capping often eliminates or slows natural degradation of hydrocarbon due to the reducing conditions in the sediments. The purpose of this research was to demonstrate a reactive capping technique, an electrode enhanced cap, to produce favorable conditions for hydrocarbon degradation and evaluate this reactive capping technique for contaminated sediment remediation. Two graphite electrodes were placed horizontally at different layers in a cap and connected to external power of 2 V. Redox potentials increased and pH decreased around the anode. Phenanthrene concentration decreased and PAH degradation genes increased in the vicinity of the anode. Phenanthrene concentrations at 0-1 cm sediment beneath the anode decreased to ~50% of initial concentration over ~70 days, while phenanthrene levels in control reactor kept unchanged. A degradation model of electrode enhanced capping was developed to simulate reaction-diffusion processes, and model results show that a reaction-dominated region was created in the vicinity of the anode. Although the degradation dominated region was thin, transport processes in a sediment cap environment are typically sufficiently slow to allow this layer to serve as a permeable reactive barrier for hydrocarbon decontamination. PMID- 25819322 TI - Idiopathic hyperammonemia after hematopoietic stem cell transplantation: A case report. AB - IHA is characterized by a sudden increase in plasma ammonia levels in the absence of any identifiable causes, which mostly results in intractable coma and high mortality. It has been reported in some patients after receiving intensive chemotherapy for hematological malignancy or HSCT. We describe a case of a patient with FA that developed acute idiopathic hyperammonemia after the preparative regimen for HSCT. PMID- 25819323 TI - Impact of the Diabetes Inpatient Care and Education (DICE) project and the DICE Care Pathway on patient outcomes and trainee doctor's knowledge and confidence. AB - AIM: To evaluate the impact of the Diabetes Inpatient Care and Education project and a comprehensive diabetes care pathway, the Diabetes Inpatient Care and Education Care Pathway, on patient outcomes and on the knowledge and confidence of trainee doctors. METHODS: The effect on patient outcomes was evaluated by comparing the National Diabetes Inpatient Audit data before (2012) and after (2013) implementing the Diabetes Inpatient Care and Education project. The impact on trainee doctors was evaluated using the Modified Kirkpatrick model. Just before the project began and again 3 months later, trainee doctors were surveyed to assess their knowledge and confidence in inpatient diabetes care. RESULTS: Patient harm was found to have been reduced significantly when National Diabetes Inpatient Audit data for 2012 and 2013 were compared. Severe hypoglycaemia decreased from 15.4 to 9.7%, medication errors from 56.9 to 21.1% and insulin errors from 31 to 7%. Across the 96 trainee doctors surveyed, the mean (sd) knowledge and confidence scores increased significantly (P < 0.001 for both) from 57.1 (16.8) and 61.8 (14.9) to 68.4 (13.3) and 74.3 (11.7), respectively. CONCLUSION: The Diabetes Inpatient Care and Education project and the Diabetes Inpatient Care and Education Care Pathway improved patient outcomes and the knowledge and confidence of trainee doctors in this hospital. The impact of a similar project in other hospitals needs to be evaluated. PMID- 25819325 TI - Enzyme-Artificial Enzyme Interactions as a Means for Discriminating among Structurally Similar Isozymes. AB - We describe the design and function of an artificial enzyme-linked receptor (ELR) that can bind different members of the glutathione-S-transferase (GST) enzyme family. The artificial enzyme-enzyme interactions distinctly affect the catalytic activity of the natural enzymes, the biomimetic, or both, enabling the system to discriminate among structurally similar GST isozymes. PMID- 25819324 TI - Stimulation of Rotator Cuff Repair by Sustained Release of Bone Morphogenetic Protein-7 Using a Gelatin Hydrogel Sheet. AB - Bone morphogenetic protein-7 (BMP-7) promotes not only osteogenesis but also matrix production in chondrocytes and tenocytes. However, because of its short half-life, maintaining local concentrations of BMP-7 is difficult. We examined the use of a gelatin hydrogel sheet (GHS) for the sustained release of BMP-7 in stimulating rotator cuff repair at the tendon-to-bone insertion. Twelve-week-old male Sprague-Dawley rats were used. Radiolabeled BMP-7 ((125)I-BMP-7) was injected into the subacromial bursa in the (125)I-BMP-7 group, whereas a GHS impregnated with (125)I-BMP-7 was implanted on the tendon attached to the tendon to-bone insertion in the (125)I-BMP-7+GHS group. Levels of (125)I-BMP-7 in the tendon-to-bone insertion were assessed at 1, 3, 7, 14, and 21 postoperative days. The BMP-7 concentrations were significantly higher in the (125)I-BMP-7+GHS group than in the (125)I-BMP-7 group. Next, the bilateral supraspinatus tendons were resected and sutured to the greater tuberosity of the humerus using the Mason Allen technique. Treatment groups were created as follows: either phosphate buffered saline (PBS) or BMP-7 was injected into the subacromial bursa in the PBS and BMP-7 groups, whereas a GHS impregnated with either PBS or BMP-7 was implanted on the repaired tendon attached to the tendon-to-bone insertion in the PBS+GHS and BMP-7+GHS groups. The resected specimens were stained at 2, 4, and 8 postoperative weeks with hematoxylin and eosin as well as Safranin O, and tissue repair was evaluated histologically by using the tendon-to-bone maturing score. Tissue repair was assessed biomechanically at 4 and 8 postoperative weeks. The BMP-7+GHS group at 8 postoperative weeks demonstrated a favorable cartilage matrix production and tendon orientation; moreover, the tendon-to-bone maturing score and the ultimate force-to-failure were the highest in this group. The ability of GHS to provide controlled release of various growth factors has been previously reported. We confirmed that the GHS releases BMP-7 in a sustained manner in the rat shoulder joint. At 8 postoperative weeks, the repaired tissue was mostly restored, both histologically and biomechanically, in the BMP-7+GHS group. We therefore conclude that the sustained release of BMP-7 from a GHS can stimulate rotator cuff repair. PMID- 25819326 TI - Remove or not, that is the question: A case report on carotid artery cannulation during indwelling venous hemodialysis catheter. AB - A 58-year-old woman visited the emergency department for acute occlusion of arteriovenous fistula. One session of hemodialysis was scheduled via temporary venous hemodialysis catheter before thrombectomy. Unfortunately, neck arterial cannulation was discovered after complete placement of catheter. The catheter was removed immediately but bleeding could not be stopped. Pseudoaneurysm over the right carotid artery was proved by angiography and repaired by graft stent. Arterial cannulation during venous hemodialysis catheter insertion is a rare but serious complication and there is no standard response recommended. Immediate removal of the misplaced hemodialysis catheter might not be the best choice. We suggest to leave the misplaced catheter in artery until further intervention in consideration of complications and repair access. Every hemodialysis center should standardize responses to arterial cannulation during venous hemodialysis catheter indwelling, especially carotid puncture happens, according to the medical facility. PMID- 25819327 TI - Neutralizing epitopes on the respiratory syncytial virus fusion glycoprotein. AB - Respiratory syncytial virus (RSV) is a leading cause of pneumonia and bronchiolitis, but despite decades of research a safe and effective vaccine has remained elusive. The viral fusion glycoprotein (RSV F) plays an obligatory role in the entry process and is the major target of neutralizing antibodies, making it an attractive target for vaccine development. This review will summarize the recently determined structures of RSV F in the prefusion and postfusion conformations and describe the location and properties of neutralizing epitopes on RSV F, including the newly identified prefusion-specific epitopes. The influence of these findings on vaccine development will also be discussed, with a focus on the rational design and optimization of vaccine antigens. PMID- 25819328 TI - Advection, dispersion, and confusion. PMID- 25819329 TI - Integrated approach in the assessment of skin compatibility of cosmetic formulations with green coffee oil. AB - OBJECTIVE: Green coffee oil (GCO) has been used in cosmetic formulations due to its emollient and anti-ageing properties. However, there are insufficient studies about its safety when applied in cosmetic formulations. METHODS: Cytotoxicity of GCO and of formulations containing 2.5-15% of GCO was evaluated by the MTT reduction assay, in human keratinocytes. Formulations containing 15% of GCO and the vehicle were applied under in use conditions in the volar forearm of human volunteers during 3 days. Transepidermal water loss, stratum corneum water content and erythema index were evaluated each 24 h using biophysical techniques. The same formulations were probed for skin tolerance through a patch test. RESULTS: Neither pure GCO nor its formulations showed cytotoxic effects in concentrations up to 100 MUg mL(-1) . Transepidermal water loss values showed a slight reduction when the formulation containing GCO was applied. Stratum corneum water content and erythema index did not show significant differences, as the results observed in the first day of the study were maintained throughout 3 days. None of the volunteers display any reaction after using an occlusive patch. CONCLUSION: The results obtained in the study indicate that GCO seems to be safe for topical applications and showed good skin compatibility under the experimental conditions of the study. PMID- 25819330 TI - Synthesis and antimycobacterial properties of ring-substituted 6 hydroxynaphthalene-2-carboxanilides. AB - In this study, a series of twenty-two ring-substituted 6-hydroxynaphthalene-2 carboxanilides was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, Mycobacterium avium complex and M. avium subsp. paratuberculosis. Derivatives substituted by trifluoromethyl, bromo, methyl and methoxy moieties in C'(3) and C'(4) positions of the anilide ring showed 2-fold higher activity against M. tuberculosis than isoniazid and 4.5-fold higher activity against M. avium subsp. paratuberculosis than rifampicin. 6-Hydroxy-N-(2-methylphenyl)naphthalene-2 carboxamide had MIC=29 MUM against M. avium complex. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT assay. Screening of the cytotoxicity of the most effective antimycobacterial compounds was performed using the THP-1 cells, and no significant lethal effect was observed. The structure-activity relationships are discussed. PMID- 25819331 TI - Development of a clickable activity-based protein profiling (ABPP) probe for agmatine deiminases. AB - Agmatine deiminases (AgDs) catalyze the hydrolytic conversion of agmatine (decarboxylated arginine) to N-carbamoylputrescine with concomitant release of ammonia. These enzymes, which are encoded by some pathogenic bacterial species, confer a competitive survival advantage by virtue of energy production and acid tolerance through agmatine catabolism. Herein we report the development of a clickable activity-based protein profiling (ABPP) probe that targets the AgD encoded by Streptococcus mutans with high selectivity and sensitivity. PMID- 25819332 TI - Nucleobase modified neamines with a lysine as a linker, their inhibition specificity for TAR-Tat derived from HIV-1. AB - Nucleobase modified neamines with a lysine as the linker (NbK-neamines) were synthesized and their binding toward hairpin RNAs derived from HIV-1 activator region were studied. NbK-neamines were bind those RNAs with micro molar level of binding affinities and compete with corresponding activator peptide for TAR RNA, but not for RRE RNA. GbK-neamine denotes the highest binding affinity with TAR RNA, three to five times higher than other three NbK-neamines. GbK-neamine could be a candidate of potential inhibitor for TAR-Tat. PMID- 25819333 TI - Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety. AB - Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC50 values in the range of 0.2-6.0 MUM. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated. PMID- 25819334 TI - Design, synthesis and biological evaluation of a highly-potent and cancer cell selective folate-taxoid conjugate. AB - The folate receptor (FR) has been widely recognized as an excellent target for the tumor-selective delivery of cytotoxic agents, and four folate-drug conjugates have entered clinical evaluations for the treatment of solid tumors to date. However, most of these conjugates required structural modification of the cytotoxic warheads in order to achieve efficient drug release from the linkers. We designed and constructed a novel folate conjugate of a highly-potent next generation taxoid, SB-T-1214, by exploiting bioorthogonal Cu-free 'click' chemistry. The synthesis was highly convergent and required no HPLC purification to obtain the final folate-taxoid conjugate 1. Conjugate 1 demonstrated highly FR specific potency (IC50 2.1-3.5 nM) against a panel of cancer cell lines, with a >1000-fold decrease in cytotoxicity against normal human cells (IC50>5000 nM). The remarkable potency and selectivity of conjugate 1 can be attributed to highly FR-specific receptor-mediated endocytosis as well as efficient release of the unmodified cytotoxic warhead using a mechanism-based self-immolative linker. PMID- 25819335 TI - Synthesis and structure-activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors. AB - A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure-activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC50: 2.36 and 2.13 MUM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50 MUM, respectively. PMID- 25819336 TI - Molecular blood group typing in Banjar, Jawa, Mandailing and Kelantan Malays in Peninsular Malaysia. AB - In this study we genotyped ABO, Rhesus, Kell, Kidd and Duffy blood group loci in DNA samples from 120 unrelated individuals representing four Malay subethnic groups living in Peninsular Malaysia (Banjar: n = 30, Jawa: n = 30, Mandailing: n = 30 and Kelantan: n = 30). Analyses were performed using commercial polymerase chain reaction-sequence specific primer (PCR-SSP) typing kits (BAG Health Care GmbH, Lich, Germany). Overall, the present study has successfully compiled blood group datasets for the four Malay subethnic groups and used the datasets for studying ancestry and health. PMID- 25819337 TI - Chronic replicative stress induced by CCl4 in TRF1 knockout mice recapitulates the origin of large liver cell changes. AB - BACKGROUND & AIMS: Large liver cell changes (LLCC) are characterized by pleomorphic large nuclei frequently found in liver diseases as chronic viral hepatitis and liver cirrhosis. The origin of this lesion remains cryptic, but the presence of LLCC is correlated with an increased risk of hepatocellular carcinoma. Telomeric repeat binding factor 1 (TRF1) is part of the shelterin complex and is essential for telomere protection. Ablation of TRF1 induces telomere fragility and fusions and chromosomal instability. METHODS: In this study, we addressed the role of TRF1 in liver regeneration generating a mouse model with conditional deletion of TRF1 in the liver. RESULTS: TRF1 deletion has no deleterious effects in liver and leads to increased ploidy of hepatocytes after 2/3 hepatectomy. Mice lacking TRF1 in the liver can survive for over one year without any evidence for altered liver function. Importantly, applying chronic replicative stress by frequent carbon tetrachloride (CCl4) injections, TRF1 deleted mice undergo ploidy changes consistent with endoreduplication and develop LLCC like lesions in the liver positive for p21, Cyclin D1 and PCNA as observed in humans. CONCLUSION: In summary, we provide mechanistic insight into the role of TRF1 in liver regeneration and provide a mouse model recapitulating the clinical features of LLCC. PMID- 25819338 TI - Clinical evaluation of the v-gel supraglottic airway device in comparison with a classical laryngeal mask and endotracheal intubation in cats during spontaneous and controlled mechanical ventilation. AB - OBJECTIVE: To compare airway management during induction of anaesthesia, in spontaneous ventilation and controlled mechanical ventilation (CMV), using a cat specific supraglottic airway device (the v-gel), a classical laryngeal mask (LM) or an endotracheal tube (ETT). STUDY DESIGN: Prospective, randomized clinical trial. ANIMALS: Forty-five healthy cats. METHODS: After premedication, cats were randomly allocated to one of three groups to secure the airway: 1) v-gel; 2) LM; or 3) ETT (cuff pressure: 20 cm H2O). Cats were anaesthetized for elective procedures. The dose of propofol necessary to insert the v-gel, LM or ETT, the number of attempts required to achieve insertion and leakage during spontaneous ventilation and CMV at different peak inspiratory pressures (8, 10, 12, 14 and 16 cm H2O) were recorded. Leakage of >20% of tidal volume was considered as a criterion for exclusion. Significance was set at a p-value of <0.05. RESULTS: Cats in the v-gel group required a median (range) of 3 mg kg(-1) (2-5 mg kg(-1)) of propofol for successful placement, which was significantly less than the 5 mg kg(-1) (3-7 mg kg(-1)) required for endotracheal intubation (p = 0.005). No significant difference in the total dose of propofol was observed between the v gel and LM [3 mg kg(-1) (2-7 mg kg(-1))] groups or the ETT and LM groups. Significantly more cats in the ETT group were excluded for leakage of >20% during CMV at all pressure settings. CONCLUSIONS AND CLINICAL RELEVANCE: The v-gel is a practical alternative to the LM and ETT for securing the airway after induction of anaesthesia and for CMV up to 16 cm H2O in healthy cats. The v-gel can be inserted at a more superficial level of anaesthesia than the ETT and showed significantly less leakage during CMV than the ETT. PMID- 25819339 TI - PDGF-D signaling in portal myofibroblasts and hepatic stellate cells proves identical to PDGF-B via both PDGF receptor type alpha and beta. AB - Platelet-derived growth factor-D (PDGF-D) is one member of PDGF growth factors and known to signal by binding to and activating its cognate receptor type beta (PDGFR-beta). Beside PDGF-B, PDGF-D is a potent growth factor for stellate cell growth and proliferation and therefore potentiates the extracellular matrix deposition in liver fibrogenesis. We aimed to explore the signaling and molecular mechanisms of PDGF-D in liver fibrogenesis using the primary liver portal myofibroblasts and hepatic stellate cells. Unexpectedly we found PDGF-D to bind to PDGFR-alpha, thus inducing receptor endocytosis and decreasing the amount of PDGFR-alpha significantly. PDGF-D activates PDGFR-alpha specific tyrosine 754 and -1018 phosphorylation and CrkII, the adaptor protein that is specifically recruited by activated PDGFR-alpha. As a novel finding we could also demonstrate that recombinant PDGFR-alpha-Fc chimera homodimer is able to bind PDGF-D and thus prevent PDGF-D signaling. PDGF-D does induce individual PDGFR-beta specific tyrosine phosphorylation similar to the PDGF-B. Additionally, PDGF-D enhances extracellular matrix accumulation comparable to the PDGF-B isoform. CONCLUSION: PDGF-D signaling in pMF and HSC is identical to that of PDGF-B by binding to both PDGFR-alpha and -beta. PMID- 25819340 TI - Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine. AB - Macrophages are projected as one of the key players responsible for the progression of cancer. Classically activated (M1) macrophages are pro inflammatory and have a central role in host defense, while alternatively activated (M2) macrophages are associated with immunosuppression. Macrophages residing at the site of neoplastic growth are alternately activated and are referred to as tumor-associated macrophages (TAMs). These "cooperate" with tumor tissue, promoting increased proliferation and immune escape. Selective serotonin reuptake inhibitors like fluoxetine have recently been reported to possess anti inflammatory activity. We used fluoxetine to target tumor-associated inflammation and consequent alternate polarization of macrophages. We established that murine peritoneal macrophages progressed towards an altered activation state when exposed to cell-free tumor fluid, as evidenced by increased IL-6, IL-4 and IL-10 levels. These polarized macrophages showed significant pro-oxidant bias and increased p65 nuclear localization. It was further observed that these altered macrophages could induce oxidative insult and apoptosis in cultured mouse CD3(+) T cells. To validate these findings, we replicated key experiments in vivo, and observed that there was increased serum IL-6, IL-4 and IL-10 in tumor-bearing animals, with increased % CD206(+) cells within the tumor niche. TAMs showed increased nuclear localization of p65 with decreased Nrf2 expression in the nucleus. These results were associated with increase in apoptosis of CD3(+) T cells co-cultured with TAM-spent media. We could establish that fluoxetine treatment could specifically re-educate the macrophages both in vitro and in vivo by skewing their phenotype such that immune suppression mediated by tumor dictated macrophages was successfully mitigated. PMID- 25819341 TI - Impact of Cardiac Resynchronization Therapy on Left Ventricular Mechanics: Understanding the Response through a New Quantitative Approach Based on Longitudinal Strain Integrals. AB - BACKGROUND: The mechanisms of improvement of left ventricular (LV) function with cardiac resynchronization therapy (CRT) are not yet elucidated. The aim of this study was to describe a new tool based on automatic quantification of the integrals of regional longitudinal strain signals and evaluate changes in LV strain distribution after CRT. METHODS: This was a retrospective observational study of 130 patients with heart failure before CRT device implantation and after 3 to 6 months of follow-up. Integrals of regional longitudinal strain signals (from the beginning of the cardiac cycle to strain peak [IL,peak] and to the instant of aortic valve closure [IL,avc]) were analyzed retrospectively with custom-made algorithms. Response to CRT was defined as a decrease in LV end systolic volume of >=15%. RESULTS: Responders (61%) and nonresponders (39%) showed similar baseline values of regional IL,peak and IL,avc. At follow-up, significant improvements of midlateral IL,peak and of midlateral IL,avc were noted only in responders. Midlateral IL,avc showed a relative increase of 151 +/- 276% in responders, whereas a decrease of 33 +/- 69% was observed in nonresponders. The difference between IL,avc and IL,peak (representing wasted energy of the LV myocardium) of the lateral wall showed a relative change of -59 +/- 103% in responders between baseline and CRT, whereas in nonresponders, the relative change was 21 +/- 113% (P = .009). CONCLUSIONS: Strain integrals revealed changes between baseline and CRT in the lateral wall, demonstrating the beneficial effects of CRT on LV mechanics with favorable myocardial reverse remodeling. PMID- 25819342 TI - Left Ventricular Rotational Mechanics in Preterm Infants Less Than 29 Weeks' Gestation over the First Week after Birth. AB - BACKGROUND: There is a paucity of data on left ventricular (LV) rotational physiology, twist, and torsional mechanics in preterm infants. The principal aims of the present study were to assess the feasibility and reproducibility of measuring LV rotation, twist, and torsion in preterm infants (<29 weeks' gestation) using two-dimensional speckle-tracking echocardiography and to examine the changes in those parameters over the first week after birth. METHODS: This was a prospective observational study involving preterm infants <29 weeks' gestation. Echocardiographic evaluations were performed on days 1, 2, and 5 to 7 after delivery. LV basal and apical rotation, LV twist, LV twist rate (LVTR), and LV untwist rate (LVUTR) were measured from the basal and apical short-axis parasternal views and calculated using two-dimensional speckle-tracking echocardiography. Torsion was also calculated by normalizing LV twist to LV end diastolic length. One-way repeated-measures analysis of variance was used to compare values across the three time points. Intra- and interobserver reproducibility were assessed using Bland-Altman analysis and the intraclass correlation coefficient. RESULTS: Fifty-one infants with a mean +/- SD gestational age of 26.8 +/- 1.5 weeks and a mean birth weight of 945 +/- 233 g were included. There was high intra- and interobserver reproducibility for basal and apical rotation, LV twist, and LV torsion, with intraclass correlation coefficients ranging from 0.78 to 0.96 (P < .001 for all). Intra- and interobserver intraclass correlation coefficients for LVTR and LVUTR ranged from 0.70 to 0.88 (P < .001 for all). Apical rotation remained constant over the first week of age in a positive counterclockwise fashion (11.8 +/- 5.0 degrees vs 12.1 +/- 6.1 degrees vs 11.7 +/- 8.3 degrees , P = .92). Basal rotation changed from counterclockwise on day 1 to clockwise on day 7 (median, 5.5 degrees [interquartile range, -0.3 degrees to 8.3 degrees ] vs 4.0 [interquartile range, -4.7 degrees to 7.2 degrees ] vs -4.5 degrees [interquartile range, -5.8 degrees to -2.3 degrees ], P < .001), with resultant net increases in twist and torsion (P < .05). There was no change in LVTR (P = .60), but LVUTR increased across the same time period (P = .01). CONCLUSIONS: Assessment of twist, LVTR, and LVUTR is feasible in preterm infants, with acceptable reproducibility. There are increases in LV twist and torsion in addition to LVUTR, suggesting changes in LV mechanics during the first week of age. PMID- 25819343 TI - Bufadienolides and polyhydroxycholestane derivatives from Bufo bufo gargarizans. AB - A new polyhydroxycholestane sulfate ester, 3alpha,12beta,25,26-tetrahydroxy-7-oxo 5beta-cholestane 26-O-sulfate (1), was isolated from dried skin of Bufo bufo gargarizans Cantor and its structure was elucidated on the basis of extensive 1D and 2D NMR as well as HR-ESI-MS analysis. A comparison of steroidal metabolite profiles, based on HPLC and LC-MS analyses, indicates that the chemical compositions of the various parts of toads, such as venom, skin and stratum corneum, are significantly different. PMID- 25819344 TI - Feasibility study for intraepidermal delivery of proteins using a solid microneedle array. AB - Solid microneedles (MN) are a promising tool for dermal drug delivery. Particular focus lies on the field of vaccination due to pain-free, safe, hygienic and patient compliant antigen deposition. Diverse coating techniques and formulations have been developed to preserve vaccine activity and to enable targeted drug deposition in the skin. Process and long-term storage stability of coated MN, however, have not yet been studied in detail. Hence, a feasibility study was conducted determining the appropriate needle length (300 MUm) for local intraepidermal protein delivery. Moreover, a protein-stabilizing coating formulation was developed. Coating of the MN resulted in protein concentrations between 10 and 23 MUg, 90% of the bioactivity of the model protein asparaginase was maintained for 3 months. Skin experiments verified the intraepidermal deposition of 68.0 +/- 11.7% of the coated model protein after single application. Slightly increased interleukin 8 levels right after MN insertion indicated minor skin irritation due to the mechanical piercing stress. Thus, specifically highlighting protein stabilization during storage, we demonstrated that selective intraepidermal deposition of proteins or peptides' using solid MN is a feasible approach. PMID- 25819345 TI - Bilateral Ovarian Burkitt's Lymphoma: Successful Treatment with Preservation of Ovarian Function. AB - BACKGROUND: Bilateral ovarian Burkitt's lymphoma was diagnosed in a 10-year-old girl who presented with abdominal pain, constipation, and signs of ovarian torsion. CASE: Left salpingo-oopherectomy and biopsy of the right ovary were carried out as initial surgical intervention. She remained well in first complete remission at 25 months after multiagent chemotherapy, with pubertal development on clinical examination, hormonal measurements, and pelvic sonography. SUMMARY AND CONCLUSION: Although rare, Burkitt's lymphoma should be included in the differential diagnosis of bilateral ovarian tumors in childhood, and more conservative surgical management is indicated to preserve ovarian function and fertility. PMID- 25819346 TI - A geometric morphometrics comparative analysis of Neandertal humeri (epiphyses fused) from the El Sidron cave site (Asturias, Spain). AB - A new collection of 49,000 year old Neandertal fossil humeri from the El Sidron cave site (Asturias, Spain) is presented. A total of 49 humeral remains were recovered, representing 10 left and 8 right humeri from adults, adolescents, and a juvenile (not included in the analyses). 3D geometric morphometric (GM) methods as well as classic anthropological variables were employed to conduct a broad comparative analysis by means of mean centroid size and shape comparisons, principal components analysis, and cluster studies. Due to the fragmentary nature of the fossils, comparisons were organized in independent analyses according to different humeral portions: distal epiphysis, diaphysis, proximal epiphysis, and the complete humerus. From a multivariate viewpoint, 3D-GM analyses revealed major differences among taxonomic groups, supporting the value of the humerus in systematic classification. Notably, the Australopithecus anamensis (KP-271) and Homo ergaster Nariokotome (KNM-WT 15000) distal humerus consistently clusters close to those of modern humans, which may imply a primitive condition for Homo sapiens morphology. Australopithecus specimens show a high degree of dispersion in the morphospace. The El Sidron sample perfectly fits into the classic Neandertal pattern, previously described as having a relatively wide olecranon fossa, as well as thin lateral and medial distodorsal pillars. These characteristics were also typical of the Sima de los Huesos (Atapuerca) sample, African mid-Pleistocene Bodo specimen, and Lower Pleistocene TD6-Atapuerca remains and may be considered as a derived state. Finally, we hypothesize that most of the features thought to be different between Neandertals and modern humans might be associated with structural differences in the pectoral girdle and shoulder joint. PMID- 25819347 TI - A splitting brain: Imbalanced neural networks in schizophrenia. AB - Dysconnectivity between key brain systems has been hypothesized to underlie the pathophysiology of schizophrenia. The present study examined the pattern of functional dysconnectivity across whole-brain neural networks in 121 first episode, treatment-naive patients with schizophrenia by using resting-state functional magnetic resonance imaging (rsfMRI). Group independent component analysis (ICA) was first applied to rsfMRI data to extract 90 functional components of the brain. The functional connectivity between these ICA components was then evaluated and compared between the patient and control groups. To examine the functional roles of significantly altered between-component connections in patients, each ICA component was ascribed to one of 10 previously well-defined brain networks/areas. Relative to findings in healthy controls (n=103), 29 altered functional connections including 19 connections with increased connectivity and 10 connections with decreased connectivity in schizophrenia patients were found. Increased connectivity was mainly within the default mode network (DMN) and between the DMN and cognitive networks, whereas decreased connectivity was predominantly associated with sensory networks. Given the key roles of the DMN in internal mental processes and sensory networks in inputs from the external environment, these patterns of altered brain network connectivity could suggest imbalanced neural processing of internal and external information in schizophrenia. PMID- 25819348 TI - Efforts to reduce the disparity between permanent residents and temporary migrants: Stop TB experiences in Shanghai, China. AB - OBJECTIVE: Eight of 17 districts of Shanghai have offered transportation and living allowances subsidies to patients with tuberculosis (TB) among the migrant population. The study aimed to assess the impact of the subsidising initiative on the treatment success rate (TSR) and identify the social determinants of treatment outcomes. METHODS: The participants included 7072 residents and 5703 migrants who were registered in the TB Information Management System with smear positive pulmonary TB from January 2006 to December 2010. The Cochran-Armitage test was employed to test the trends of TSR and logistic regressions to identify the factors associated with treatment outcome. RESULTS: Without subsidies, migrant TB cases had lower odds of successful treatment [OR = 0.20 (95% CI 0.18 0.23)] than resident cases. Subsidisation was associated with a 65% increased odds ratio of success [1.65 (1.40-1.95)] among migrant cases. The TSR has stabilised at 87% for both permanent residents and temporary migrants since 2009. Living in districts with a population density >=20,000/km(2) was associated with a low odds ratio [0.42 (0.26-0.68)] among resident cases, whereas among migrant cases those living in districts out of central downtown had a higher odds ratio of treatment success [peripheral downtown: 1.73 (1.36-2.20), suburban: 1.69 (1.16 2.46)]. The TB cases in districts with 2.0-2.9 TB specialists/100 cases had a higher odds ratio [2.99 (1.91-4.69)] of successful treatment than cases from districts with fewer specialists. CONCLUSIONS: Besides free medical services, transport and living allowance subsidies to migrant patients with TB improved the treatment outcome significantly. PMID- 25819349 TI - Interleukin-21 induces proliferation and modulates receptor expression and effector function in canine natural killer cells. AB - Interleukin (IL)-21 is an important modulator of natural killer (NK) cell function. However, little is known about IL-21 function in canine NK cells because the phenotype of these cells remains undefined. In this study, we selectively expanded non-B and non-T large granular NK lymphocytes (CD3(-)CD21( )CD5(-)CD4(-)TCRalphabeta(-)TCRgammadelta(-)) ex vivo from the peripheral blood mononuclear cells (PBMCs) of healthy dogs using a combination of IL-2, IL-15, and IL-21 in the presence of 100 Gy-irradiated K562 cells. We investigated the effects of varying the duration and timing of IL-21 treatment on stimulation of proliferation, expression of NK-related receptors, anti-tumor activity and production of interferon (IFN)-gamma. The expanded NK cells in each treatment group became enlarged and highly granular after 21 days in culture. NK cells proliferated rapidly in response to activation by IL-21 for 3 weeks, and IL-21 was able to induce changes in the mRNA expression of NK cell-related receptors and enhance the effector function of NK cells in perforin- and granzyme-B dependent manners. The duration, frequency and timing of IL-21 stimulation during culture affected the rate of proliferation, patterns of receptor expression, cytokine production, and anti-tumor activity. The optimal conditions for maximizing the IL-21-induced proliferation and effector function of NK cells in the presence of IL-2 and IL-15 were seen in cells treated with IL-21 for the first 7 days of culture but without any further IL-21 stimulation other than an additional 2-day treatment prior to harvesting on day 21. The results of this study suggest that synergistic interactions of IL-21 with IL-2 and IL-15 play an important role in the proliferation, receptor expression, and effector function of canine NK cells. PMID- 25819350 TI - Environmental risk assessment of water quality in harbor areas: a new methodology applied to European ports. AB - This work presents a standard and unified procedure for assessment of environmental risks at the contaminant source level in port aquatic systems. Using this method, port managers and local authorities will be able to hierarchically classify environmental hazards and proceed with the most suitable management actions. This procedure combines rigorously selected parameters and indicators to estimate the environmental risk of each contaminant source based on its probability, consequences and vulnerability. The spatio-temporal variability of multiple stressors (agents) and receptors (endpoints) is taken into account to provide accurate estimations for application of precisely defined measures. The developed methodology is tested on a wide range of different scenarios via application in six European ports. The validation process confirms its usefulness, versatility and adaptability as a management tool for port water quality in Europe and worldwide. PMID- 25819351 TI - Adsorptive/photo-catalytic process for naphthalene removal from aqueous media using in-situ nickel doped titanium nanocomposite. AB - The present study investigates the synthesis and characterization of in-situ nickel doped titanium nanocomposite (TiO2/NiO) use as an adsorbent and a photo catalyst for naphthalene removal from aqueous phase. Nickel-titanium nanocomposites were synthesized by using an in-situ process for the nickel doping and further calcined at 600 degrees C for 6 h to produce the desired TiO2/NiO nanocomposite, which was then characterized by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and UV-Vis analysis before and after naphthalene removal. The removal of naphthalene was explored with effect of pH, time and initial concentration of naphthalene (2-25 mg/L) in the presence of dark and light phases. Naphthalene removal tests were conducted under both batch and continuous flow conditions. A special column without any channeling problem was successfully designed for the removal of naphthalene by continuous flow process in the presence of visible light source. The removal was maximized at pH 6.5. The maximum amount of naphthalene removed by TiO2/NiO(0.1) nanocomposite in the presence of visible light phase was 322.1 mg/g, which was 2.5 times greater than that of the parent TiO2. The removal of naphthalene obtained during the breakthrough analysis was consistent with the batch equilibrium data. PMID- 25819352 TI - First Person Perspectives: An Introductory Note. PMID- 25819354 TI - Comparison of the effects of calcium carbonate and ossein-hydroxyapatite complex on back and knee pain and quality of life in osteopenic perimenopausal women. AB - BACKGROUND: Back and knee pain (BP; KP), which often accompanies osteoporosis, is a prevalent health problem affecting quality of life (QoL) in middle-aged women. AIM: To compare the effects of calcium carbonate (CC) and ossein-hydroxyapatite complex (OHC) on BP and KP and QoL in perimenopausal osteopenic women. SUBJECTS: 74 perimenopausal women were randomized to receive 1,200 mg/day of CC (n=38) or 1,660 mg/day of OHC (n=36) for 6 months. METHODS: This was a randomized, open label, parallel-group, controlled, prospective study. Back and knee basal pain was recorded using a visual analogue scale (VAS) at each control and exercise induced pain was recorded using a visual rating system (VRS). Changes in QoL were evaluated using the SF-36 questionnaire. RESULTS: In patients treated with OHC, mean VAS and VRS pain scores decreased significantly after 5 and 6 months of treatment, indicating a significant analgesic effect. In the CC group, however, changes were minor and non-significant. Two-way analysis of variance using treatment group and time as independent variables revealed a significantly greater effect of OHC over CC on VAS and VRS scores. SF-36 showed significant improvement for OHC on the physical component summary score and no changes for CC. Responses to items assessing emotional and social aspects of QoL showed only a significant improvement in vitality for OHC and no significant changes for CC in any of the four dominions constituting the SF-36 mental component. CONCLUSION: OHC has a significant analgesic effect and improves the physical component of QoL to a greater extent than CC. PMID- 25819355 TI - Shear bond strength between resin cement and colored zirconia made with metal chlorides. AB - STATEMENT OF PROBLEM: Although the application of zirconia in esthetic prostheses has increased, the shear bond strength (SBS) between colored zirconia and resin cement has not been investigated. PURPOSE: The purpose of this study was to compare the SBS between resin cement and colored zirconia made with metal chlorides. MATERIAL AND METHODS: Sixty-four zirconia specimens were divided into 2 groups: one in which the specimens were bonded with resin cement, including 4 META (4-methacryloxyethyl trimellitic anhydride), and one in which the specimens were bonded with resin cement (SEcure, Sun Medical) after being processed with zirconia primer (Zirconia Liner), including 4-META. Each group was then divided into 4 subgroups depending on the coloring liquid. The subgroups were noncolored (control), commercial coloring liquid VITA In-Ceram 2000 YZ LL1, aqueous chromium chloride solution 0.1 wt%, and aqueous molybdenum chloride solution 0.1 wt%. Composite resin cylinders (Filtek Z250, 3M ESPE) were fabricated and bonded to the surface of the zirconia specimen with resin cement (SEcure). All specimens were stored in 37 degrees C distilled water for 24 hours, and the SBS was measured with a universal testing machine. All data were analyzed statistically with 2-way ANOVA and tested post hoc with the Tukey test (alpha=.05). RESULTS: Significant differences were observed among the SBS values of the colored zirconia depending on the coloring liquid (P<.001) and whether they were processed with zirconia primer (P<.001). The SBS between colored zirconia and resin cement was significantly higher than that of noncolored zirconia and resin cement in groups processed with zirconia primer (P<.05). Colored zirconia immersed in aqueous molybdenum chloride solution showed a significantly higher SBS. CONCLUSIONS: Coloring liquid enhanced the SBS between resin cement and zirconia processed with zirconia primer. In particular, colored zirconia immersed in aqueous molybdenum chloride solution showed the highest SBS. PMID- 25819356 TI - Technique for systematic bone reduction for fixed implant-supported prosthesis in the edentulous maxilla. AB - Bone reduction for maxillary fixed implant-supported prosthodontic treatment is often necessary to either gain prosthetic space or to conceal the prosthesis tissue junction in patients with excessive gingival display (gummy smile). Inadequate bone reduction is often a cause of prosthetic failure due to material fractures, poor esthetics, or inability to perform oral hygiene procedures due to unfavorable ridge lap prosthetic contours. Various instruments and techniques are available for bone reduction. It would be helpful to have an accurate and efficient method for bone reduction at the time of surgery and subsequently create a smooth bony platform. This article presents a straightforward technique for systematic bone reduction by transferring the patient's maximum smile line, recorded clinically, to a clear radiographic smile guide for treatment planning using cone beam computed tomography (CBCT). The patient's smile line and the amount of required bone reduction are transferred clinically by marking bone with a sterile stationery graphite wood pencil at the time of surgery. This technique can help clinicians to accurately achieve the desired bone reduction during surgery, and provide confidence that the diagnostic and treatment planning goals have been achieved. PMID- 25819357 TI - Mechanical performance of implant-supported posterior crowns. AB - STATEMENT OF PROBLEM: The fracture of implant-supported restorations, especially of the veneering layer, is a common problem in dentistry. Monolithic ceramic or resin restorations might help solve this problem. PURPOSE: The purpose of this in vitro study was to obtain additional insight into the risk of fracture of implant supported restorations. MATERIAL AND METHODS: Identical crowns (n=10) of 10 different ceramic and composite resin materials were cemented on conventional abutments on implant replicas embedded in polymethyl methacrylate blocks. The specimens were subjected to compressive load in a universal testing machine to record initial load to failure (ILF). Additionally, the flexural strength (FS), compressive strength (CS), and elastic modulus (E) of the investigated materials were determined. These results were used in a finite element analysis model of a composite resin and a lithium disilicate crown. RESULTS: Anatomic contour zirconia (Lava Plus) crowns had the highest ILF (6065 N), followed by lithium disilicate (IPS e.max) (2788 N) and the composite resin materials (Protemp 4, Majesty Flow, Telio CAD, Estenia C&B, Lava Ultimate, VITA Enamic) (2386 to 1935 N). Veneered zirconia (Lava) crowns showed the lowest ILF (1477 N). The highest FS, CS, and E were found for Lava Plus and IPS e.max. No direct relationship was found between ILF and the FS, CS, or E. The finite element analysis showed stresses that did not exceed the FS or CS of IPS e.max. The surface roughness of these crowns might have caused initial failure at relatively low stresses. CONCLUSIONS: In this laboratory study, monolithic implant-supported crowns showed a higher ILF than conventional veneered ceramic crowns. Monolithic ceramic restorations might perform better than composite resin crowns. PMID- 25819358 TI - Prospective, 1-year observational study of double-threaded tapered body dental implants with immediate loading. AB - STATEMENT OF PROBLEM: Unlike conventional loading protocols, the immediate loading of single implants has not been fully investigated. PURPOSE: The purpose of this study was to assess the prosthetic and esthetic periimplant mucosal outcomes of immediately restored dental implants during a 1-year follow-up. MATERIAL AND METHODS: Twenty participants meeting the established inclusion criteria received double-threaded, tapered body dental implants (SuperLine; Dentium). Implants were placed and stabilized at a minimum of 35 Ncm of torque and restored immediately after the surgery with interim restorations. These were replaced with definitive restorations 6 months after implant placement. Clinical measurements at each visit included resonance frequency analysis, the evaluation of the participants' oral health (gingival and plaque indices), and the esthetic outcome of the interim or definitive restoration. RESULTS: Implants placed in this clinical study had a 100% success rate. The oral health and esthetic outcomes were favorable for all participants. CONCLUSIONS: Double-threaded, tapered body dental implants that were placed and immediately restored with fixed interim prostheses and with definitive prostheses after 6 months remained stable and functional after 1 year. PMID- 25819359 TI - Anti-inflammatory, anti-bacterial, and cytotoxic activity of fibrous clays. AB - Produced worldwide at 1.2m tons per year, fibrous clays are used in the production of pet litter, animal feed stuff to roof parcels, construction and rheological additives, and other applications needing to replace long-fiber length asbestos. To the authors' knowledge, however, information on the beneficial effects of fibrous clays on health remains scarce. This paper reports on the anti-inflammatory, anti-bacterial, and cytotoxic activity by sepiolite (Vallecas, Spain) and palygorskite (Torrejon El Rubio, Spain). The anti inflammatory activity was determined using the 12-O-tetradecanoylphorbol-13 acetate (TPA) and myeloperoxidase (MPO) methods. Histological cuts were obtained for quantifying leukocytes found in the epidermis. Palygorkite and sepiolite caused edema inhibition and migration of neutrophils ca. 68.64 and 45.54%, and 80 and 65%, respectively. Fibrous clays yielded high rates of infiltration, explained by cleavage of polysomes and exposure of silanol groups. Also, fibrous clays showed high inhibition of myeloperoxidase contents shortly after exposure, but decreased sharply afterwards. In contrast, tubular clays caused an increasing inhibition of myeloperoxidase with time. Thus, clay structure restricted the kinetics and mechanism of myeloperoxidase inhibition. Fibrous clays were screened in vitro against human cancer cell lines. Cytotoxicity was determined using the protein-binding dye sulforhodamine B (SRB). Exposing cancer human cells to sepiolite or palygorskite showed growth inhibition varying with cell line. This study shows that fibrous clays served as an effective anti-inflammatory, limited by chemical transfer and cellular-level signals responding exclusively to an early exposure to clay, and cell viability decreasing significantly only after exposure to high concentrations of sepiolite. PMID- 25819360 TI - Improved stability and skin permeability of sodium hyaluronate-chitosan multilayered liposomes by Layer-by-Layer electrostatic deposition for quercetin delivery. AB - Layer-by-Layer (LbL) technology, based on the electrostatic interaction of polyelectrolytes, is used to improve the stability of drug delivery systems. In the present study, we developed multilayered liposomes with up to 10 alternating layers based on LbL deposition of hyaluronate-chitosan for transdermal delivery. Dihexadecyl phosphate was used to provide liposomes with a negative charge; the liposomes were subsequently coated with cationic chitosan (CH) followed by anionic sodium hyaluronate (HA). The resulting particles had a cumulative size of 528.28+/-29.22nm and an alternative change in zeta potential. Differential scanning calorimetry (DSC) and transmission electron microscopy (TEM) revealed that the multilayered liposomes formed a spherical polyelectrolyte complex (PEC) after deposition. Observations in size distribution after 1 week found that the particles coated with even layers of polyelectrolytes, hyaluronate and chitosan (HA-CH), were more stable than the odd layers. Membrane stability in the presence of the surfactant Triton X-100 increased with an increase in bilayers as compared to uncoated liposomes. An increase in the number of bilayers deposited on the liposomal surface resulted in a sustained release of quercetin, with release kinetics that fit the Korsmeyer-Peppas model. In an in vitro skin permeation study, negatively charged (HA-CH)-L and positively charged CH-L were observed to have similar skin permeability, which were superior to uncoated liposomes. These results indicate that multilayered liposomes properly coated with polyelectrolytes of HA and CH by electrostatic interaction improve stability and can also function as potential drug delivery system for the transdermal delivery of the hydrophobic antioxidant quercetin. PMID- 25819361 TI - Dextrin-coated zinc substituted cobalt-ferrite nanoparticles as an MRI contrast agent: In vitro and in vivo imaging studies. AB - Application of superparamagnetic iron oxide nanoparticles (NPs) as a negative contrast agent in magnetic resonance imaging (MRI) has been of widespread interest. These particles can enhance contrast of images by altering the relaxation times of the water protons. In this study, dextrin-coated zinc substituted cobalt-ferrite (Zn0.5Co0.5Fe2O4) NPs were synthesized by a co precipitation method, and the morphology, size, structure and magnetic properties of the NPs were investigated. These NPs had superparamagnetic behavior with an average size of 3.9 (+/-0.9, n=200)nm measured by transmission electron microscopy. Measurements on the relaxivities (r2 and r2(*)) of the NPs were performed in vitro by agarose phantom. In addition, after subcutaneous injection of the NPs into C540 cell line in C-57 inbred mice, the relaxivities were measured in vivo by a 1.5T MRI system. These NPs could effectively increase the image contrast in both T2-and T2(*)-weighted samples. PMID- 25819362 TI - Functionalized graphene oxide as a drug carrier for loading pirfenidone in treatment of subarachnoid hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a life-threatening disease that causes high morbidity and mortality. Pirfenidone is a SAH drug that prevents secondary bleeding and cerebral infarction. To improve its therapeutic efficacy, this study aimed to employ a functionalized graphene oxide nanosheet (FGO) as a drug carrier loading pirfenidone to treat SAH. The graphene oxide nanosheet was introduced with transcription activator peptide (Tat), followed by functionalization with methoxy polyethylene glycol (mPEG) and loading with pirfenidone. The pirfenidone loaded FGO (pirfenidone-FGO) exhibits better treatment efficacy than the single pirfenidone due to more effective loading and controlled release of the drug in tissue. The introduction of Tat and mPEG onto GO nanosheet contributes to the ability to cross the blood-brain barrier and the stability in blood circulation of the drug. At lower pH values, the highly efficient release of the drug from the pirfenidone-FGO exerts effective treatment to acidic inflammatory lesion after severe SAH. Besides its treatment function, FGO is also shown as a strong near infrared absorbing material which can be applied in photoacoustic imaging, allowing rapid real-time monitoring with deep resolution of brain tissues after SAH. The treatment efficacy of pirfenidone-FGO for central nervous system injuries is further demonstrated by hematoxylin and eosin staining of coronal brain slices, as well as measurements of brain water content and blood-brain barrier permeability. Our study supports the potential of FGO in clinical application in treatment of SAH. PMID- 25819363 TI - Cyclodextrin-based star polymers as a versatile platform for nanochemotherapeutics: Enhanced entrapment and uptake of idarubicin. AB - A series of cyclodextrin-based star polymers were synthesized using beta cyclodextrin (CD) as hydrophilic core, methyl methacrylate (MMA) and tert-butyl acrylate (tBA) as hydrophobic arms. Star polymers, either homopolymers or random/block copolymers, showed narrow molecular weight distributions. Grafting hydrophobic arms created CD-based nanoparticles (CD-NPs) in the size range (130 200nm) with narrow PdI <0.15 and slightly negative zeta-potential. Particle surface could be modified with chitosan to impart a positive surface charge. Colloidal stability of CD-NPs was a function of pH as revealed by the pH titration curves. CD-NPs were used as carrier for the chemotherapeutic drug idarubicin (encapsulation efficiency, EE ~40%) ensuring prolonged release profile (~80% after 48h). For cell-based studies, coumarin-6 was encapsulated as a fluorescent marker (EE ~75%). Uptake studies carried out on A549 and Caco-2 cell lines proved the uptake of coumarin-loaded NPs as a function of time and preferential localization in the cytoplasm. Uptake kinetics revealed no saturation or plateau over 6h. Chitosan-modified NPs showed significantly improved, concentration-dependent cellular uptake. Meanwhile, CD-NPs were non cytotoxic on both cell lines over the concentration range (0.25-3mg/ml) as studied by MTT and LDH assays. In conclusion, CD star polymers can be considered a versatile platform for a new class of biocompatible nanochemotherapy. PMID- 25819364 TI - Preparation and in vitro characterization of chitosan nanobubbles as theranostic agents. AB - Theranostic delivery systems are nanostructures that combine the modality of therapy and diagnostic imaging. Polymeric micro- and nanobubbles, spherical vesicles containing a gas core, have been proposed as new theranostic carriers for MRI-guided therapy. In this study, chitosan nanobubbles were purposely tuned for the co-delivery of prednisolone phosphate and a Gd(III) complex, as therapeutic and MRI diagnostic agent, respectively. Perfluoropentane was used for filling up the internal core of the formulation. These theranostic nanobubbles showed diameters of about 500nm and a positive surface charge that allows the interaction with the negatively charged Gd-DOTP complex. Pluronic F68 was added to the nanobubble aqueous suspension as stabilizer agent. The encapsulation efficiency was good for both the active compounds, and a prolonged drug release profile was observed in vitro. The effect of ultrasound stimulation on prednisolone phosphate release was evaluated at 37 degrees C. A marked increase on drug release kinetics with no burst effect was obtained after the exposure of the system to ultrasound. Furthermore, the relaxivity of the MRI probe changed upon incorporation in the nanobubble shell, thereby offering interesting opportunity in dual MRI-US experiments. The ultrasound characterization showed a good in vitro echogenicity of the theranostic nanobubbles. In summary, chitosan drug-loaded nanobubbles with Gd(III) complex bound to their shell might be considered a new platform for imaging and drug delivery with the potential of improving anti-cancer treatments. PMID- 25819365 TI - Wettability studies of topologically distinct titanium surfaces. AB - Biomedical implants made of titanium-based materials are expected to have certain essential features including high bone-to-implant contact and optimum osteointegration, which are often influenced by the surface topography and physicochemical properties of titanium surfaces. The surface structure in the nanoscale regime is presumed to alter/facilitate the protein binding, cell adhesion and proliferation, thereby reducing post-operative complications with increased lifespan of biomedical implants. The novelty of our TiO2 nanostructures lies mainly in the high level control over their morphology and roughness by mere compositional change and optimisation of the experimental parameters. The present work focuses on the wetting behaviour of various nanostructured titanium surfaces towards water. Kinetics of contact area of water droplet on macroscopically flat, nanoporous and nanotubular titanium surface topologies was monitored under similar evaporation conditions. The contact area of the water droplet on hydrophobic titanium planar surface (foil) was found to decrease during evaporation, whereas the contact area of the droplet on hydrophobic nanorough titanium surfaces practically remained unaffected until the complete evaporation. This demonstrates that the surface morphology and roughness at the nanoscale level substantially affect the titanium dioxide surface-water droplet interaction, opposing to previous observations for microscale structured surfaces. The difference in surface topographic nanofeatures of nanostructured titanium surfaces could be correlated not only with the time-dependency of the contact area, but also with time-dependency of the contact angle and electrochemical properties of these surfaces. PMID- 25819367 TI - Animal models for acute radiation syndrome drug discovery. AB - INTRODUCTION: Although significant scientific advances have been made over the past six decades in developing safe, nontoxic and effective radiation/medical countermeasures (MCMs) for acute radiation syndrome (ARS), no drug has been approved by the US FDA. The availability of adequate animal models is a prime requisite under the criteria established by the FDA 'animal rule' for the development of novel MCMs for ARS and the discovery of biomarkers for radiation exposure. AREAS COVERED: This article reviews the developments of MCMs to combat ARS, with particular reference to the various animal models (rodents: mouse and rat; canine: beagle; minipigs and nonhuman primates [NHPs]) utilized for the in depth evaluation. The objective, pathways and challenges of the FDA Animal Efficacy Rule are also discussed. EXPERT OPINION: There are a number of well defined animal models, the mouse, canine and NHP, that are being used for the development of MCMs. Additional animal models, such as the minipig, are under development to further assist in the identification, efficacy testing and approval of MCMs under the FDA Animal Efficacy Rule. PMID- 25819368 TI - A meta-analysis reveals a positive correlation between genetic diversity metrics and environmental status in the long-lived seagrass Posidonia oceanica. AB - The seagrass Posidonia oceanica is a key engineering species structuring coastal marine systems throughout much of the Mediterranean basin. Its decline is of concern, leading to the search for short- and long-term indicators of seagrass health. Using ArcGIS maps from a recent, high-resolution (1-4 km) modelling study of 18 disturbance factors affecting coastal marine systems across the Mediterranean (Micheli et al. 2013, http://globalmarine.nceas.ucsb.edu/mediterranean/), we tested for correlations with genetic diversity metrics (allelic diversity, genotypic/clonal diversity and heterozygosity) in a meta-analysis of 56 meadows. Contrary to initial predictions, weak but significantly positive correlations were found for commercial shipping, organic pollution (pesticides) and cumulative impact. This counterintuitive finding suggests greater resistance and resilience of individuals with higher genetic and genotypic diversity under disturbance (at least for a time) and/or increased sexual reproduction under an intermediate disturbance model. We interpret the absence of low and medium levels of genetic variation at impacted locations as probable local extinctions of individuals that already exceeded their resistance capacity. Alternatively, high diversity at high impact sites is likely a temporal artefact, reflecting the mismatch with pre environmental impact conditions, especially because flowering and sexual recruitment are seldom observed. While genetic diversity metrics are a valuable tool for restoration and mitigation, caution must be exercised in the interpretation of correlative patterns as found in this study, because the exceptional longevity of individuals creates a temporal mismatch that may falsely suggest good meadow health status, while gradual deterioration of allelic diversity might go unnoticed. PMID- 25819366 TI - Higher infection rate after 7- compared with 5-day cycle of azacitidine in patients with higher-risk myelodysplastic syndrome. AB - INTRODUCTION: Azacitidine (AZA) dose reduction is a common practice in cytopenic patients. However, a correlation between AZA dose and infection complications has never been studied. PATIENTS AND METHODS: Higher-risk patients with myelodysplastic syndrome or acute myeloid leukemia treated with AZA in 18 Israeli hospitals between the years 2008 and 2011 were included in a former national survey. To reveal the effect of AZA dosage on infection risk we limited our analysis to the infection rate after the first AZA dose alone. We excluded subsequent cycles of AZA from the analysis, because infectious events during these cycles might be related to other cofactors such as disease response to AZA therapy. RESULTS: After the first AZA cycle, infectious events were more frequent after doses of 75 mg/m(2) for 7 days than 75 mg/m(2) for 5 days (36/106 [34%] and 10/67 [14.9%], respectively; P = .008), regardless of the patient's age. Of the 46 recorded infectious events, the causative pathogen was identified as bacterial in 25 (54.3%) and as viral or fungal in 2 (4.3%) and 2 (4.3%) cases, respectively. No pathogen was identified in 17 (37%) cases. Infections were significantly more prevalent among patients who presented with platelet counts < 20,000 (43.6% vs. 23.6%; P = .012) and poor risk cytogenetics (40.7% vs. 19.8%; P = .008). CONCLUSION: Reduction of AZA dose might decrease infection rate and therefore should be considered in patients with high infection risk. PMID- 25819369 TI - The discriminative ability of waist circumference, body mass index and waist-to hip ratio in identifying metabolic syndrome: Variations by age, sex and race. AB - OBJECTIVES: Many studies have suggested that there is variation in the capabilities of BMI, WC and WHR in predicting cardiometabolic risk and that it might be confounded by gender, ethnicity and age group. The objective of this study is to examine the discriminative abilities of body mass index (BMI), waist circumference (WC) and waist-hip ratio (WHR) to predict two or more non-adipose components of the metabolic syndrome (high blood pressure, hypertriglyceridemia, low high density lipoprotein-cholesterol and high fasting plasma glucose) among the adult Malaysian population by gender, age group and ethnicity. METHODS: Data from 2572 respondents (1044 men and 1528 women) aged 25-64 years who participated in the Non Communicable Disease Surveillance 2005/2006, a population-based cross sectional study, were analysed. Participants' socio-demographic details, anthropometric indices (BMI, WC and WHR), blood pressure, fasting lipid profile and fasting glucose level were assessed. Receiver operating characteristics curves analysis was used to evaluate the ability of each anthropometric index to discriminate MetS cases from non-MetS cases based on the area under the curve. RESULTS: Overall, WC had better discriminative ability than WHR for women but did not perform significantly better than BMI in both sexes, whereas BMI was better than WHR in women only. Waist circumference was a better discriminator of MetS compared to WHR in Malay men and women. Waist circumference and BMI performed better than WHR in Chinese women, men aged 25-34 years and women aged 35-44 years. CONCLUSIONS: The discriminative ability of BMI and WC is better than WHR for predicting two or more non-adipose components of MetS. Therefore, either BMI or WC measurements are recommended in screening for metabolic syndrome in routine clinical practice in the effort to combat cardiovascular disease and type II diabetes mellitus. PMID- 25819370 TI - Mechanistic Insight into Peroxydisulfate Reactivity: Oxidation of the cis,cis [Ru(bpy)2(OH2)]2O(4+) "Blue Dimer". AB - One-electron oxidation of the MU-oxo dimer (cis,cis-[Ru(III)(bpy)2(OH2)]2O(4+), {3,3}) to {3,4} by S2O8(2-) can be described by three concurrent reaction pathways corresponding to the three protic forms of {3,3}. Free energy correlations of the rate constants, transient species dynamics determined by pulse radiolysis, and medium and temperature dependencies of the alkaline pathway all suggest that the rate-determining step in these reactions is a strongly nonadiabatic dissociative electron transfer within a precursor ion pair leading to the {3,4}|SO4(2-)|SO4(*-) ion triple. As deduced from the SO4(*-) scavenging experiments with 2-propanol, the SO4(*-) radical then either oxidizes {3,4} to {4,4} within the ion triple, effecting a net two-electron oxidation of {3,3}, or escapes in solution with ~25% probability to react with additional {3,3} and {3,4}, that is, effecting sequential one-electron oxidations. The reaction model presented also invokes rapid {3,3} + {4,4} -> 2{3,4} comproportionation, for which kcom ~5 * 10(7) M(-1) s(-1) was independently measured. The model provides an explanation for the observation that, despite favorable energetics, no oxidation beyond the {3,4} state was detected. The indiscriminate nature of oxidation by SO4(*-) indicates that its fate must be quantitatively determined when using S2O8(2-) as an oxidant. PMID- 25819371 TI - Streamlined method for parallel identification of single domain antibodies to membrane receptors on whole cells. AB - BACKGROUND: Owing to their minimal size, high production yield, versatility and robustness, the recombinant variable domains (nanobodies) of camelid single chain antibodies are valued affinity reagents for research, diagnostic, and therapeutic applications. While their preparation against purified antigens is straightforward, the generation of nanobodies to difficult targets such as multi pass or complex membrane cell receptors remains challenging. Here we devised a platform for high throughput identification of nanobodies to cell receptor based on the use of a biotin handle. METHODS: Using a biotin-acceptor peptide tag, the in vivo biotinylation of nanobodies in 96 well culture blocks was optimized allowing their parallel analysis by flow cytometry and ELISA, and their direct use for pull-down/MS target identification. RESULTS: The potential of this strategy was demonstrated by the selection and characterization of panels of nanobodies to Mac-1 (CD11b/CD18), MHC II and the mouse Ly-5 leukocyte common antigen (CD45) receptors, from a VHH library obtained from a llama immunized with mouse bone marrow derived dendritic cells. By on and off switching of the addition of biotin, the method also allowed the epitope binning of the selected Nbs directly on cells. CONCLUSIONS: This strategy streamlines the selection of potent nanobodies to complex antigens, and the selected nanobodies constitute ready-to-use biotinylated reagents. GENERAL SIGNIFICANCE: This method will accelerate the discovery of nanobodies to cell membrane receptors which comprise the largest group of drug and analytical targets. PMID- 25819372 TI - Comparative venomics of the Prairie Rattlesnake (Crotalus viridis viridis) from Colorado: Identification of a novel pattern of ontogenetic changes in venom composition and assessment of the immunoreactivity of the commercial antivenom CroFab(r). AB - Here we describe and compare the venomic and antivenomic characteristics of both neonate and adult Prairie Rattlesnake (Crotalus viridis viridis) venoms. Although both neonate and adult venoms contain unique components, similarities among protein family content were seen. Both neonate and adult venoms consisted of myotoxin, bradykinin-potentiating peptide (BPP), phospholipase A2 (PLA2), Zn(2+) dependent metalloproteinase (SVMP), serine proteinase, L-amino acid oxidase (LAAO), cysteine-rich secretory protein (CRISP) and disintegrin families. Quantitative differences, however, were observed, with venoms of adults containing significantly higher concentrations of the non-enzymatic toxic compounds and venoms of neonates containing higher concentrations of pre digestive enzymatic proteins such as SVMPs. To assess the relevance of this venom variation in the context of snakebite and snakebite treatment, we tested the efficacy of the common antivenom CroFab(r) for recognition of both adult and neonate venoms in vitro. This comparison revealed that many of the major protein families (SVMPs, CRISP, PLA2, serine proteases, and LAAO) in both neonate and adult venoms were immunodepleted by the antivenom, whereas myotoxins, one of the major toxic components of C. v. viridis venom, in addition to many of the small peptides, were not efficiently depleted by CroFab(r). These results therefore provide a comprehensive catalog of the venom compounds present in C. v. viridis venom and new molecular insight into the potential efficacy of CroFab(r) against human envenomations by one of the most widely distributed rattlesnake species in North America. BIOLOGICAL SIGNIFICANCE: Comparative proteomic analysis of venoms of neonate and adult Prairie Rattlesnake (Crotalus viridis viridis) from a discrete population in Colorado revealed a novel pattern of ontogenetic shifts in toxin composition for viperid snakes. The observed stage-dependent decrease of the relative content of disintegrins, catalytically active D49-PLA2s, L-amino acid oxidase, and SVMPs, and the concomitant increase of the relative abundance of paralytic small basic myotoxins and ohanin-like toxin, and hemostasis disrupting serine proteinases, may represent an age-dependent strategy for securing prey and avoiding injury as the snake switches from small ectothermic prey and newborn rodents to larger endothermic prey. Such age-dependent shifts in venom composition may be relevant for antivenom efficacy and treatment of snakebite. However, applying a second-generation antivenomics approach, we show that CroFab(r), developed against venom of three Crotalus and one Agkistrodon species, efficiently immunodepleted many, but not all, of the major compounds present in neonate and adult C. v. viridis venoms. PMID- 25819373 TI - Self-management interventions for young people with chronic conditions: A systematic overview. AB - OBJECTIVE: To provide a systematic overview of self-management interventions (SMI) for young people with chronic conditions with respect to content, formats, theories, and evaluated outcomes. METHODS: Embase, Medline, PsycINFO, Web-of Science, CINAHL, and Cochrane were searched. Reviews' reference lists were scrutinized. Selected studies were: Original research articles in English published between 2003 and March 2014; about the evaluation of SMI for 7 to 25 year-olds with somatic chronic conditions/physical disabilities; with clear outcomes and intervention descriptions. The classification of medical, role and emotion management served to review content. Formats, theories, and evaluated outcomes were summarized. RESULTS: 86 studies were reviewed. Most aimed at medical management and were unclear about theoretical bases. Although a variety of outcomes was evaluated and the distribution over self-management domains was quite unpredictable, outcomes conceptually related to specific content. A content based framework for the evaluation of self-management interventions is presented. CONCLUSIONS AND PRACTICE IMPLICATIONS: SMI relate to self-management tasks and skill-building. Yet, conceptualizations of self-management support often remained unclear and content focuses predominantly on the medical domain, neglecting psycho-social challenges for chronically ill young people. Future evaluations should match outcomes/themes to content and characteristics. Our framework and overview of SMI characteristics and outcomes may assist clinicians in providing self-management support. PMID- 25819374 TI - Continuous local anesthetic infusion for children with spina bifida undergoing major reconstruction of the lower urinary tract. AB - OBJECTIVE: While many options for postoperative analgesia are available to the general patient population, choices are limited for individuals with spinal dysraphism. We hypothesized that the use of continuous local anesthetic infusion following major reconstruction of the lower urinary tract in children with spina bifida would significantly decrease need for opiate use, while maintaining adequate pain control. MATERIALS AND METHODS: Children with spina bifida who underwent major reconstruction of the lower urinary tract at Children's Hospital Colorado were identified from January, 2003 through January, 2013 were identified. In addition to enterocycstoplasty, procedures included Mitrofanoff or Monti creation, bladder neck reconstruction, and Malone antegrade continence enema. Patients who had local anesthetic infusion catheters placed in the incision were compared to patients without catheters. Opioid consumption was calculated by conversion of any opiates into IV morphine (mg/kg) on postoperative days (POD) 0-3. Pain was assessed by mean and maximum FLACC scores on POD 0-2. Use of antiemetic medications and wound related complications were recorded as secondary metrics. Patients with other etiologies for neurogenic bladder and bowel were excluded. Patients whose pain was assessed by other assessment scales were excluded. Chi-squared analysis was used for nominal variables, students t test was used for analysis of continuous variables. P values <0.05 were considered significant. RESULTS: 36 myelomeningocele patients who underwent primary enterocystoplasty met the inclusion criteria. All surgeries were open procedures. 24 patients in the infusion catheter group were compared to 12 patients who received primary analgesia by PCA or IV narcotics. There were no significant differences in age, sex, weight or spinal defect level between the two groups. Opioid use, as defined by IV morphine equivalents, was significantly less in the wound soaker group on all PODs. The total opioid use after POD #0-3 was 0.55 mg/kg in the wound soaker group vs 1.66 mg/kg in the IV/PCA group (p = 0.03). FLACC scores were uniformly lower in the wound soaker group, but were not significantly different. There was a significant decrease in need for postoperative antiemetic use in the wound soaker group (36.5% vs 83.3%, p = 0.014). Complications and hospital stay were similar between both groups. DISCUSSION: The advantage of local anesthesia is the reduction of systemic opioids and their subsequent adverse side effects. Our results suggest that in children with spina bifida undergoing major reconstruction of the lower urinary tract narcotic consumption is approximately 1/3 when continuous local anesthetic catheters are placed into the incision. The need for antiemetic medication is also significantly less. While this technique has been validated in a variety of other settings, it may be most beneficial in patients with myelomeningocele or other spinal dysraphism where epidural placement is generally contraindicated and narcotic use may have a particularly deleterious effect on preexisting neurogenic bowel function. The primary limitation of our study is that it is a retrospective review of a limited number of patients. Patients were not randomized and subject to other management differences that could have influenced our results in unknown ways. CONCLUSIONS: Continuous local anesthetic catheters are a simple, effective alternative strategy to provide postoperative analgesia while reducing systemic opiate use and associated adverse effects. PMID- 25819375 TI - Intravesical tunnel length to ureteral diameter ratio insufficiently explains ureterovesical junction competence: A parametric simulation study. AB - OBJECTIVE: In 1959, Paquin recommended a tunnel length five times the diameter of the ureter to prevent vesicoureteral reflux (VUR) during ureteral reimplants. In 1969, Lyon et al. challenged Paquin's conclusions and proposed that the ureteral orifice was more important than the intravesical tunnel for UVJ competence. It is not known if the two mechanisms of UVJ competence (tunnel length and UO spatial orientation) are interdependent or if one is more critical. Although in clinical practice Paquin's rule has stood the test of time, classical mechanics of materials would predict more coaptation (less reflux) with larger diameter ureters and this contradicts Paquin's rule. The aim of this study was to test Paquin's tunnel length theory by parametrically modeling the ureterovesical junction (UVJ) to determine variables critical for ureteral closure. STUDY DESIGN: LS-DYNA finite-element simulation software was use to model ureteral collapse (Figure). Intravesical tunnel length, ureteral diameter, ureteral thickness and ureteral stiffness were all modeled. Changes in the pressure required to collapse the ureter were studied as each variable was changed on the model. The modeled ureteral orifice was not affected by changes in bladder volume (in a real bladder, bladder distention would pull the ureteral office open) and had no constraints (which could occur by suturing the ureteral orifice to a stiff bladder). RESULTS: As predicted by classical mechanics of materials, the pressure required to collapse the ureter was inversely related to its diameter. Above 1 cm tunnel length, pressures required to collapse a ureter did not decrease by any significant amount. Increasing ureteral thickness or ureteral stiffness did increase the pressure required to collapse the ureter, but only significantly for ureteral thicknesses not commonly seen in practice (i.e. wall thickness of 2.5 mm in a 6.4 mm ureter). DISCUSSION: Our model showed that for most ureters seen in clinical practice (3-30 mm in diameter), and when the ureteral orifice is not constrained by the bladder mucosa, a 1 cm tunnel would allow the ureter to collapse under low pressures. Contrary to Paquin's belief, larger diameter ureters collapsed more easily. It is important to understand that our model's main limitation was that it did not study the effects of the ureteral orifice, which in light of our findings must play an important role in preventing reflux as suggested by Lyon et al., in 1969. For example, a 3 cm ureteral orifice sutured to the bladder mucosa would be difficult to collapse as the bladder distends and pulls open the orifice. One way of compensating for a difficult to collapse ureteral orifice would be creating a larger diameter tunnel, but another would be to create a better ureteral orifice, perhaps by narrowing the diameter of the UO (distal ureteral tapering) and making it protrude into the bladder like a volcano (i.e. advancement sutures, or creating an intravesical nipple). CONCLUSION: We hope that this new understanding of the variables involved in ureterovesical junction competence can lead to further refinement in our surgical techniques to correct vesicoureteral reflux. PMID- 25819376 TI - The influence of hormonal treatment with beta-human chorionic gonadotropin for cryptorchidism on future fertility in rats. AB - INTRODUCTION: There have been two treatment modalities for cryptorchidism such that surgical and hormonal; the latter being highly controversial. While some authors suggest that hormonal treatment increases the number and maturation of germ cells in cryptorchid testes, others believe just the opposite. OBJECTIVE: We aimed to find out the sperm counts and testicular index; briefly fertility potential of the normally descended contralateral testes in adulthood period in rats treated with Beta-HCG in early period of their lives. MATERIALS AND METHODS: Three groups, each including 10 rats aged 22 days old, in which delactation and normal feeding can be started, were formed to be Group 1: Sham operated, Group 2: Experimental cryptorchidism (EC) and Group 3: Hormone-treated after experimental cryptorchidism was performed (HT-EC). Left testis was placed in the abdomen in group 2 and 3. In group 1, a sham operation was performed. The rats in EC-HT group received subcutaneous injections of 50 IU/kg Beta-HCG daily for 7 days. Right orchidectomy was performed when they reached reproductive period to evaluate fertility potential with sperm counts and testicular index. Testicular index was calculated according to the formula "testicular length * width/weight of rat". Epididymal sperm count was made with hemocytometer. RESULTS: DISCUSSION: We evaluated the physical characteristics and fertility potential (sperm counts) of contralateral normal testes during adulthood in rats that underwent experimental unilateral cryptorchidism during infancy. A relationship between testis weight and sperm counts were also investigated. We could not find any direct correlation of sperm count with either testicular weight or testicular index in our study. Although the rats had normal testes at birth, we found decreased sperm counts in contralateral normal testes in EC group. This suggests that unilateral cryptorchidism may cause some systemic effects that reach the other testis. Hormone treatment was not beneficial. This is comparable to Nambirajan et al. who reported histological changes and decreased spermatogenic cell count in contralateral scrotal testes in experimentally induced unilateral cryptorchidism in early period of life in rats. Heiskanen et al. reported that treatment with Beta-HCG leads to decreased total sperm counts in the future due to increased germ cell apoptosis caused by hormonal withdrawal after treatment. Cortes et al. also reported decreased number of germ cells in 1-3 year-old boys who underwent surgery after unsuccessful Beta-HCG treatment. The reasons could be delayed testicular descent or adverse effect of hormone treatment though. Our results concurred with them. Apparently, our model has failed to mimic the pathophysiologic mechanisms of congenital cryptorchidism in humans. Furthermore, we applied hormone treatment in normal rats with normally descended testes. Therefore, the "by-product" information of our study is that, unnecessary use of Beta-HCG during infancy may impair future fertility. CONCLUSION: Our study suggests that Beta-HCG treatment may decrease sperm counts and decrease the future fertility potential. We could not find any direct correlation of sperm count with either testicular weight or testicular index. PMID- 25819377 TI - Laser Doppler spectroscopy of testes after unilateral orchiopexy. AB - OBJECTIVE: Undescended testes are the most common urogenital malformation in boys. Impaired microcirculation is among other factors addressed as a potential complication of surgery and scar formation, leading to long-term suboptimal results. OBJECTIVE: Our aim was to compare the postoperative microcirculation in operated versus non-operated contralateral testis groups after unilateral orchiopexies versus a healthy control cohort. METHODS: Ninety-nine consecutive patients were included after unilateral orchiopexy procedures at the age of 3.5 years (+/-2.9 years) at a single center for pediatric surgery. Eight-five patients were examined with a combination of laser Doppler (blood flow determination) and white-light spectroscopy (oxygen saturation and hemoglobin amount determinations) to determine the microcirculation at two different depth levels non-invasively. All relevant surgery data were obtained retrospectively. RESULTS: The right side was operated in 53.5% of cases. Previous hormone treatment had been prescribed in 46.5%. There were no significant differences in perfusion measurements between patients with previous hormone therapy and patients without. There was no significant difference in age and clinical pubertal stage between groups; however, 65% of patients underwent surgery after their second birthday. When comparing oxygen saturation (So2), relative hemoglobin (rHb), flow, and velocity in the operated testis with the contralateral testis of the same patients, we found significantly higher flows and velocities for the contralateral testes (p = 0.041, p = 0.022). Similar higher flows and velocities were found in the healthy controls (p < 0.001). The differences between healthy controls and contralateral testis that were not operated on did not reach statistical significance. There was no difference in measurements at 2 mm depth (skin and subcutaneous tissue) between groups to rule out systemic or capillary differences. DISCUSSION: Important limitations include the limited and relatively heterogeneous samples that were obtained for follow-up and retrospective surgery data collection. An additional limitation is missing presurgical data, which we hope to obtain in future studies. Hormonal data or bone age could not be obtained for study reasons. The age in our study was on average above the recommended age for orchiopexy in Germany (6-12 months), which could also restrict generalizability. In terms of complications, we observed reascending testes within the range but a rather high incidence of wound infections. The combination of Doppler and white-light spectroscopy was easily applicable and produced reliable data at 2 and 8 mm depth simultaneously in a standardized setting. CONCLUSIONS: After orchiopexy, differences were found in the microcirculation between the operated and contralateral testes or healthy controls. It remains unclear if this is an effect of primary disease or surgery. The microcirculation of contralateral testes was also seemingly different from controls. This is most likely not a consequence of surgery alone, but a common problem for both testes in the affected patients. PMID- 25819378 TI - What is the risk of urinary tract infection in children with antenatally presenting dilating vesico-ureteric reflux? AB - INTRODUCTION: The incidence of recurrent urinary tract infection (UTI) in children with primary vesico-ureteric reflux (VUR) presenting symptomatically is well documented. The risk of UTI in asymptomatic primary VUR diagnosed on investigation of antenatal hydronephrosis (ANH) is less clear. Paradoxically, several previous studies have suggested a lower risk (1-25%). We ascertain the incidence of UTI amongst antenatally-presenting primary VUR and explore risk factors. STUDY DESIGN: All patients <16 years managed for primary VUR between 1997 and 2013 were retrospectively reviewed. Patients were identified by searching 'VUR, vesicoureteric reflux' and 'vesico' in the clinical database. Sex, follow up, antibiotic prophylaxis, age at UTI, grade of VUR, radioisotope imaging findings (CRN-congenital reflux nephropathy, NRD-new renal defects), evidence of bladder dysfunction, surgical intervention and resolution were recorded. UTI diagnosis was based on positive urine culture with symptoms including fever. SPSS statistical package and Pearson's Chi-squared test were used to explore significance. RESULTS: Of 308 patients with primary VUR aged <16 years treated, 242 were diagnosed following presentation with UTI. The remaining 66 (21%) were initially asymptomatic, and VUR was diagnosed on investigation of ANH. All were given prophylaxis from birth. Six months to 16years (median 6years) follow-up was available for 54 (42 males, 12 females). All but two patients had grade III-V VUR (96%), bilaterally in 41 (76%). CRN was evident in 30 (56%; all male) and bladder dysfunction in 12 (22%; 10 males). Twenty-eight patients (52%) developed a UTI. The risk of UTI was 58% in girls, 33% in boys without CRN and 57% in boys with CRN (p = 0.17). Bladder dysfunction was a significant risk factor for UTI (p = 0.03). All 8 (15%; 7 males) with NRD had had a UTI. A single UTI appeared responsible for the majority of NRD (6/8; 75%). UTI occurred in 6/27 (22%) boys after circumcision compared to 17/25 (68%) prior/without circumcision (p < 0.05). CONCLUSIONS: The incidence of UTI in VUR detected after presentation with ANH was 52%. CRN and bladder dysfunction were risk factors for developing a UTI. Circumcision appears to significantly reduce the risk of infection. Antenatal presentation of primary VUR does not carry a reduced risk of UTI. A single UTI, in half before the age of six months, seemed responsible for the majority of NRD. In boys, the highest risk of UTI is in the first few months of infancy, despite antibiotic prophylaxis, and other interventions, particularly circumcision, should therefore be considered as early as possible. PMID- 25819379 TI - A comparative bibliometric analysis of the top 150 cited papers in hypospadiology (1945-2013). AB - INTRODUCTION: Hypospadias, the most common congenital malformation of the penis, is characterized by an abnormal ventral opening of the urethral meatus, abnormal ventral curvature of the penis, and an abnormal distribution of the foreskin around the glans, with a ventrally-deficient hooded foreskin, and has been described in modern peer-reviewed literature since Noble's description in 1853. A dramatic increase in the literature on hypospadiology has focused on two main topics: The aetiology of the condition including molecular mechanisms and environmental influences, as well as surgical techniques to repair the defect, however there have been a number of facets of research stemming from this poorly understood condition in a developing subspecialty (Figure). The majority of these publications focus on the evolution of surgical technique and management. Urethral reconstruction should offer the ability to stand to urinate and combine a satisfactory cosmetic result. The tubularized incised plate repair, popularized by Snodgrass et al., and the Mathieu repair, have been the mainstay for distal hypospadias, however, there have still been a large number of well-described techniques, with no consensus as to the ideal method of repair, some of which is attributed to non-uniform standards of reporting outcomes. There is also no standard objective means to qualitatively assess the importance of each of these contributions. OBJECTIVE: The objective of this study was to determine the top 150 peer-reviewed articles in the field of hypospadiology by way of citation analysis as a means to determine the importance/relevance of each contribution throughout 8 decades of research. STUDY DESIGN: A cited reference search was carried out for indexed citations within Web of ScienceTM Core Collection. The top 150 indexed cited articles containing the topic "hypospadias" in specific subject categories were compiled using a component of Science Citation Index command. References were then evaluated, and analysed across a number of indices, and over time. RESULTS: The mean number of citations was 76 for each article. The top 150 articles were published across 21 countries, with the majority originating from the USA. The lead research institution was the University of Texas (Southwestern) Medical Center. In total, the top 3 centers represented 33 publications within the top 150 citations. The most commonly utilized journal was the Journal of Urology. The most cited author was W.T. Snodgrass. 39% papers in the top 150 cited articles were published prior to 1990. Three out of the five papers cited in the 1940s dealt with operative technique to repair hypospadias. The period 2000-2010 in contrast, demonstrated a significant inverse correlation between molecular biology citations, and those for operative techniques, with the incidence of the latter dropping to 6% of all cited papers. DISCUSSION: This is the first study of its kind to analyse the most influential articles in hypospadiology, and their characteristics assessed for authorship, content and impact factor. Furthermore it allows data analysis by topic and between time points. This not only de-clutters the wealth of accumulated data on this subject, but also provides an important adjunct to education and training. As with this study, other citation analytical studies in urology found a significant preponderance in cited studies originating from the USA. The prevalence of the US in cited papers doesn't reflect any inherent bias, just a greater number of publications. CONCLUSION: Although there are inherent potential elements of bias in citation analysis, this study demonstrates that citation analysis in a complicated topic can provide a high-throughput, uncomplicated method of quickly deciphering important contributions of authors and institutions to the field of hypospadias research. PMID- 25819380 TI - Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis. AB - OBJECTIVE: Renal disorders can cause hypertension, but less is known about the influence of hydronephrosis on blood pressure. Hydronephrosis due to pelvo ureteric junction obstruction (PUJO) is a fairly common condition (incidence in newborns of 0.5-1%). Although hypertensive effects of hydronephrosis have been suggested, this has not been substantiated by prospective studies in humans [1 3]. Experimental studies with PUJO have shown that animals with induced hydronephrosis develop salt-sensitive hypertension, which strongly correlate to the degree of obstruction [4-7]. Moreover, relief of the obstruction normalized blood pressure [8]. In this first prospective study our aim was to study the blood pressure pattern in pediatric patients with hydronephrosis before and after surgical correction of the ureteral obstruction. Specifically, we investigated if preoperative blood pressure is reduced after surgery and if split renal function and renographic excretion curves provide any prognostic information. PATIENTS AND METHODS: Twelve patients with unilateral congenital hydronephrosis were included in this prospective study. Ambulatory blood pressure (24 h) was measured preoperatively and six months after surgery. Preoperative evaluations of bilateral renal function by Tc99m-MAG3 scintigraphy, and renography curves, classified according to O'Reilly, were also performed. RESULTS: As shown in the summary figure, postoperative systolic (103 +/- 2 mmHg) and diastolic (62 +/- 2 mmHg) blood pressure were significantly lower than those obtained preoperatively (110 +/- 4 and 69 +/- 2 mmHg, respectively), whereas no changes in circadian variation or pulse pressure were observed. Renal functional share of the hydronephrotic kidney ranged from 11 to 55%. There was no correlation between the degree of renal function impairment and the preoperative excretory pattern, or between the preoperative excretory pattern and the blood pressure reduction postoperatively. However, preoperative MAG3 function of the affected kidney correlated with the magnitude of blood pressure change after surgery. DISCUSSION: Correction of the obstruction lowered blood pressure, and the reduction in blood pressure appeared to correlate with the degree of renal functional impairment, but not with the excretory pattern. Thus, in the setting of hypertension, it appears that the functional share of the hydronephrotic kidney should be considered an indicator of the need for surgery, whereas the renography curve is less reliable. The strength of the present study is the prospective nature and that ambulatory blood pressure monitoring was used. Future longitudinal prolonged follow-up studies are warranted to confirm the present findings, and to understand if a real nephrogenic hypertension with potential necessity of treatment will develop. CONCLUSION: This novel prospective study in patients with congenital hydronephrosis demonstrates a reduction in blood pressure following relief of the obstruction. Based on the present results, we propose that the blood pressure level should also be taken into account when deciding whether to correct hydronephrosis surgically or not. PMID- 25819381 TI - Declining prevalence of hepatitis E antibodies among Danish blood donors. AB - BACKGROUND: The increasing incidence of reported hepatitis E cases in Europe has focused attention on hepatitis E virus (HEV) and the risk of transfusion transmitted hepatitis E. The aim of this study was to investigate the prevalence of antibodies to HEV (anti-HEV) among Danish blood donors in 2013 and to compare it to previous studies in Denmark. In addition we wanted to compare the relative reactivity of two different assays. STUDY DESIGN AND METHODS: Samples from 504 blood donors were collected and analyzed for anti-HEV with an in-house assay developed at the National Institutes of Health (NIH). In addition the samples were analyzed with the Wantai anti-HEV assay. Demographic information and possible HEV exposure was collected by self-administered questionnaire. RESULTS: Using the NIH assay the prevalence of anti-HEV among Danish blood donors was 10.7% and with the Wantai assay the prevalence of anti-HEV was 19.8% (p < 0.001). In both cases the presence of anti-HEV was significantly correlated with increasing age. In addition, anti-HEV as measured by the Wantai test was significantly associated with contact with children (p = 0.01), but in multivariate analysis only age was associated with anti-HEV in both assays. By the NIH assay, the prevalence had declined from 20.6% in 2003 to 10.7% in 2013. CONCLUSIONS: Anti-HEV prevalence had decreased by half among Danish blood donors over 10 years, but was still highly prevalent. The difference in reactivity of the two assays demonstrates the importance of using the same assay when comparing the anti-HEV prevalence in populations over time. PMID- 25819382 TI - IgA NEPHROPATHY IN PATIENTS RECEIVING A RENAL TRANSPLANT. AB - BACKGROUND: IgA nephropathy (IgAN) is the third most frequent cause of renal graft loss among patients with primary glomerulonephritis. OBJECTIVES: To assess clinical and laboratorial profile of patients with pre and/or post transplant IgAN, in addition to patient and graft survival in both groups. DESIGN: Data from 146 patients who had received a renal transplant were retrospectively collected and were divided in two groups: group 1-patients with biopsy-documented IgAN as the underlying native kidney disease (n = 128); group 2-patients who developed post-transplant IgAN independent of the underlying disease (n = 18). PARTICIPANTS: Patients submitted to renal transplantation (1998-2010) with pre and/or post transplant IgAN. MEASUREMENTS: Clinical and laboratorial evaluation of renal function of 146 post transplant IgAN patients. RESULTS: Recipients and deceased donors exhibited a higher degree of HLA compatibility (1.0 vs. 2.5 mismatches for groups 1 and 2, respectively). The main post-transplant IgAN presentation was haematuria associated with non-nephrotic proteinuria (44.4%). A histological pattern of focal segmental glomerulosclerosis was observed in 59.2% of biopsy samples. The 10-year patient survival was 93.5% in group 1 and 100% in group 2, and the graft survival rates were 58.5 and 87.2%, respectively. CONCLUSION: The rate of post-transplant IgA diagnosis in our case series was 11%, and IgAN was diagnosed late in the course of transplantation. In most cases, IgAN manifested as haematuria and non-nephrotic proteinuria, without renal graft dysfunction, and this picture might explain late indication of graft biopsies. The 10-year patient survival rates were excellent. PMID- 25819383 TI - Does myasthenia gravis influence overall survival and cumulative incidence of recurrence in thymoma patients? A Retrospective clinicopathological multicentre analysis on 797 patients. AB - OBJECTIVE: Aim of this study is to evaluate whether Myasthenia Gravis (MG) might influence Overall Survival (OS) and Cumulative Incidence of Recurrence (CIR) in thymoma patients. METHODS: this is a multicenter retrospective study of patients operated in 6 high-volume Italian Institutions between 1990 and 2012. OS was estimated by the Kaplan-Meier method and CIR by considering death from any cause as a competing event. Crude and adjusted comparisons by MG for OS and CIR were performed using Cox and Fine&Gray models. Adjusted models included MG, age, gender, stage, histology, induction therapy, completeness of resection, adjuvant therapy. RESULTS: Seven hundred ninety-seven patients were included: 375 (47%) had MG. MG patients were younger and more frequently female, with a B2-B3 thymoma. At the end of the study, 129 patients (54 with MG) developed a recurrence and 165 (66 with MG) died. At univariate analysis, MG showed a slight protective effect on OS, not confirmed by the multivariate model. Age, incomplete resection, advanced stages and thymic carcinoma were negative prognostic variables. Univariate analyses showed no evidence of MG protective effect on CIR. Advanced stages and induction therapy were significant negative predictors. CONCLUSION: our study showed that MG was significantly associated with female, lower age and B2-B3 thymoma; it demonstrated a slight protective effect on OS at the univariate analysis which was not confirmed in multivariate as well as no impact on CIR. Advanced tumor stages and thymic carcinoma histology for OS and induction therapy and advanced stages for CIR were negative prognostic variables. PMID- 25819384 TI - The frequency and impact of FGFR1 amplification on clinical outcomes in Korean patients with small cell lung cancer. AB - OBJECTIVES: Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in many human cancers. We tried to identify the frequency of FGFR1 amplifications among Korean patients with small cell lung cancer (SCLC). Additionally, we examined the clinical significance of FGFR1 amplifications for overall survival (OS) and progression-free survival (PFS) among SCLC patients who received standard chemotherapies. MATERIALS AND METHODS: Tumor tissues from 158 Korean patients diagnosed with SCLC from September 2009 to February 2013 were collected and analyzed using an FGFR1 FISH assay with a probe that hybridized to chromosome region 8p12-8p11.23 (Abbott Molecular, Abbott Park, IL). RESULTS AND CONCLUSION: FGFR1 amplification was detected in three patients (1.9%) harboring extensive disease (ED). A multivariate analysis showed that among the patients with ED, FGFR1 amplification was associated with shorter disease-free survival to first line chemotherapy with etoposide plus cisplatin or carboplatin (hazard ratio [HR]=7.1; 95% confidence interval [CI]=2.0-25.4; P=0.003). The median overall survival time of the patients with ED was 8.2 and 10.2 months among patients with and without FGFR1 amplification, respectively (P=0.37). Although FGFR1 amplification is rare in SCLC compared to non-small cell lung cancer or other malignancies with squamous histology, it is associated with poor survival following standard chemotherapy in SCLC. Further studies in large cohorts of patients with SCLC are needed to verify these results. Our results imply that FGFR1 may be a potential therapeutic target in SCLC and it could be confirmed in a clinical trial. PMID- 25819385 TI - You may look unhappy unless you smile: the distinctiveness of a smiling face against faces without an explicit smile. AB - An expressionless face is often perceived as rude whereas a smiling face is considered as hospitable. Repetitive exposure to such perceptions may have developed stereotype of categorizing an expressionless face as expressing negative emotion. To test this idea, we displayed a search array where the target was an expressionless face and the distractors were either smiling or frowning faces. We manipulated set size. Search reaction times were delayed with frowning distractors. Delays became more evident as the set size increased. We also devised a short-term comparison task where participants compared two sequential sets of expressionless, smiling, and frowning faces. Detection of an expression change across the sets was highly inaccurate when the change was made between frowning and expressionless face. These results indicate that subjects were confused with expressed emotions on frowning and expressionless faces, suggesting that it is difficult to distinguish expressionless face from frowning faces. PMID- 25819386 TI - Red blood cell distribution width is increased in patients with psoriasis vulgaris: A retrospective study on 261 patients. AB - Circulating inflammatory cytokines and markers are increased in patients with psoriasis. Recent studies have shown that a higher red blood cell distribution width (RDW) is associated with disease activity in various disorders. Our objective was to investigate whether RDW is increased in psoriasis patients, and to evaluate its possible association with disease severity. We conducted a retrospective study of psoriasis patients seen in a university hospital in South Korea. Information about demographics, hematological parameters and disease severity were collected. Statistical analysis was performed using Student's t test, multivariable logistic regression, Fisher's exact test and Spearman's rank correlation coefficient analysis as appropriate. A total of 261 psoriasis patients and 102 healthy controls were included in our study. The mean RDW value was significantly increased in psoriasis patients compared with healthy control (P = 0.037). Compared with mild psoriasis patients (Psoriasis Area and Severity Index [PASI], <7), moderate to severe patients (PASI, >=7) showed significantly higher RDW values (P = 0.044). However, RDW did not show significant correlation with PASI (P = 0.358). When patients were divided into two groups according to their RDW value (<14.6% and >=14.6%), the mean value of PASI was not significantly different (P = 0.219). Patients with psoriasis showed increased RDW values compared with healthy controls. It was also higher in the moderate and severe disease group than the mild group. Though this is only a pilot study, it is possible that RDW value can reflect the inflammatory status of psoriasis patients. PMID- 25819387 TI - Severe micrognathia with 21 trisomy assessed prenatally by performing three dimensional computed tomography. AB - Severe micrognathia can lead to death shortly after birth without a proper resuscitation. However, it is difficult to develop an effective resuscitation strategy without a prenatal diagnosis of the severity of micrognathia. In the present case, we used fetal three-dimensional computed tomography (3D-CT) to assess the severity of micrognathia. Its images clearly demonstrated bony framework of mandible and suggested that mandibular hypoplasia was too severe to allow for oral intubation. We therefore decided that the ex utero intrapartum treatment (EXIT) procedure would be more appropriate to establish the airway at birth. The prenatal 3D-CT is useful to evaluate the mandibular anatomy in utero if the severity of the micrognathia is not confirmed by the ultrasound or magnetic resonance imaging (MRI). PMID- 25819388 TI - [Locoregional surgery for stage IV breast cancer patients]. AB - Three to 6% of women newly diagnosed with breast cancers have stage IV disease. Overall survival was improved during the last few years (16-45 months). The treatment of stage IV breast cancer has traditionally been palliative with surgical resection reserved for symptomatic wound complications. Since 2000, several retrospective studies have compared surgery versus no local therapy in women presenting with stage IV breast cancer with an intact primary tumor. All showed a survival advantage for the surgical cohort. However, these studies are limited by the fact that it is not possible to control for biases that led to surgical resection of the primary tumor. Several prospective randomized trials have been undertaken. We have partial results for two of them and they show no survival differences between patients who benefit from local surgery and patients who did not have surgery. However, breast surgery is at low risk of complication, if not considering psychological aspect of mastectomy, and can be proposed to patients with no progression after first chemotherapy. Conservative management can be an option, but surgery must be optimal with negative margins. No benefit of axillary surgery has been shown but this treatment can lead to complications and impact quality of life of patients. Therefore, axillary node resection is not recommended for stage IV breast cancer. Finally, radiotherapy can be an alternative option of local therapy associated or no to surgery in stage IV breast cancer. PMID- 25819389 TI - [The prenatal diagnosis is not the eugenics]. PMID- 25819390 TI - [G. Bleu et D. Subtil in reply to the correspondence by L. Marpeau on their article entitled: Assessment of vacuum-assisted delivery in a Frank breech presentation. Gynecol Obstet Fertil 2015;43:123-7]. PMID- 25819391 TI - [HRT and ovarian cancer risk]. PMID- 25819392 TI - [L. Marpeau in reply to the article by G. Bleu et al.: Assessment of vacuum assisted delivery in a Frank breech presentation. Gynecol Obstet Fertil 2015;43:123-7]. PMID- 25819394 TI - Study identifies first-ever human population adaptation to toxic chemical, arsenic. PMID- 25819393 TI - [The access of independent midwives to maternity ward technical facilities: the experimentation of a level-1 department]. AB - OBJECTIVES: The first aim of this study was to evaluate the access of independent midwives to the technical facilities of a level-1 maternity hospital, with a follow-up of 2 years. The second aim was to evaluate the transfer of clinical responsibility, when a patient stops being managed by the independent midwife to be taken care of by the hospital team. PATIENTS AND METHODS: A retrospective study including 51 patients. Analysis of maternal and perinatal data. RESULTS: Of the 51 births, there were 42 vaginal deliveries without intervention (82.35%), 3 instrumental deliveries (5.88%), 6 caesarean sections (11.76%). The midwife-led care was completed in 70.59% of cases. The rate of transfer of clinical responsibility during labor was 25.49%. We conducted a neonatal transfer due to a respiratory distress syndrome. DISCUSSION AND CONCLUSION: The access to technical support appears as an opportunity for independent midwives to establish a special relationship with their patients. However, this device preserves the possibility of a traditional hospital care when needed. This way, access to the technical support is a safe alternative that has the consent of the users (patients and midwives) as well as of the entire hospital team. Moreover, such device allowed an increase of 5% per year of our obstetrical activity with an estimated increase of 10% per year. PMID- 25819395 TI - Turning a vole into a mighty rodent. PMID- 25819396 TI - An Evolutionary Approach Reveals New Clues toward Understanding the Roots of Schizophrenia. PMID- 25819397 TI - Getting to the origins of photosynthesis. PMID- 25819398 TI - Endovascular therapy for fibromuscular dysplasia of the bilateral external iliac arteries visualized with optical coherence tomography. AB - BACKGROUND: Fibromuscular dysplasia (FMD) is a non-inflammatory, non atherosclerotic, degenerative vascular disease that most frequently affects renal and carotid arteries in women aged 30-50 years, and rarely complicating arteries of the lower limbs. CASE REPORT: A 60-year-old woman was admitted with intermittent claudication of both legs. We performed pelvic and bilateral lower extremities angiography, which revealed that the bilateral external iliac arteries (EIAs) had the 'string of beads' appearance with a diagnosis of FMD. Endovascular therapy (EVT) was performed for the bilateral EIAs. Optical coherence tomography (OCT) images showed thickening and thinning of the middle layer, while three-dimensional OCT images showed a 'haustra coli'-like appearance. After successful balloon angioplasty, claudication completely disappeared. CONCLUSIONS: We report a rare case of EVT successfully performed for FMD of the bilateral EIAs. Our findings suggest that OCT may provide unique diagnostic clues in FMD patients. PMID- 25819399 TI - Acidogenicity and acidurance of dental plaque and saliva sediment from adults in relation to caries activity and chlorhexidine exposure. AB - BACKGROUND: The ecological plaque hypothesis for the etiopathogenesis of caries implies a microbial shift towards a more aciduric dental plaque microbiota, due to a frequent carbohydrate intake. Acid tolerance has been suggested as an important property of the caries-associated bacteria and several in vitro studies with mixed cultures indicated that a low pH rather than the carbohydrate availability is responsible for microbiota shifts associated with the development of dental caries. OBJECTIVE: To examine 1) the acidogenic potential (amount lactate produced per mg plaque and minute, at pH 7.0 or pH 5.5) and the aciduric potential (acidogenic potential at pH 5.5/acidogenic potential at pH 7.0) of dental plaque and salivary sediment taken from caries-active or caries-free adults, and 2) the effect of a short-term chlorhexidine treatment on these potentials. DESIGN: Dental plaque and saliva sediment samples were taken from caries-free and caries-active subjects and suspended in Ringer's solution containing 1% sucrose and buffered with 0.5 M 3-[N-morpholino]propanesulfonic acid (MOPS), pH 7.0, or 3-[N-morpholino]ethanesulfonic acid (MES), pH 5.5. After incubation at 37 degrees C for 10-20 min, the concentration of lactic acid in the suspension was determined by an enzymatic assay. The acid production of dental plaque was also determined after a period of mouth rinsing with 0.2% chlorhexidine. RESULTS: Both dental plaque and salivary sediment from caries-free subjects exhibited significantly lower acidogenic potentials at both pHs compared to caries-active volunteers. The opposite was observed with the aciduric potential. Chlorhexidine treatment significantly reduced all three potentials but had no effect on the relative proportion of bacteria grown on acidic agar. CONCLUSIONS: Caries-active adults have an oral microbiota characterised by an increased catabolic velocity for sugar. The increase is more pronounced at neutral than acidic pH. Exposure to chlorhexidine, through mouthwash, temporarily decreases the acidogenicity of the microbiota. PMID- 25819400 TI - Plasmids in antibiotic susceptible and antibiotic resistant commensal Escherichia coli from healthy Australian adults. AB - A collection of 111 commensal Escherichia coli isolated from 84 faecal samples from healthy Australian adults were screened using PCR-based replicon typing. Each isolate represented a distinct strain found in a particular faecal sample. Fifty-one isolates were resistant to one or more of 12 antibiotics tested. FII and FIB replicons were most common and usually found together. The FII replicon was detected in 63 isolates (35 susceptible, 28 resistant), the FIB replicon was present in 65 (32 susceptible, 33 resistant) and 54 (30 susceptible, 24 resistant) included both. Other replicon types were found infrequently (A/C, I1, K, L/M, P, R, Y, FIA and FIC) or not at all (HI1, HI2, N, T, U, W, X). Only the B/O amplicon, found in 21 resistant but only 4 susceptible isolates, was associated with antibiotic resistance. Detailed analysis of this group revealed that the B/O PCR also detected Z plasmids of several distinguishable types. PCR assays were developed to detect the two repA genes (repABKI and repAZ) found in members of the I-complex (I, B/O, K and Z plasmids). These assays distinguished the B/O and Z plasmids detected by the original "B/O" PCR. One isolate carried repABKI and the remainder carried repAZ. These genes were also detected in further isolates in the collection. Conjugative transfer of resistance genes was detected for the B/O plasmid and two Z groups. Evidence for transfer of repAZ plasmids in the human colon in the absence of antibiotic selection was also obtained. PMID- 25819401 TI - Status of autophagy, lysosome activity and apoptosis during corpus luteum regression in cattle. AB - Corpus luteum (CL) regression is required during the estrous cycle. During CL regression, luteal cells stop producing progesterone and are degraded by apoptosis. However, the detailed mechanism of CL regression in cattle has not been fully elucidated. The aim of this study was to evaluate autophagy, lysosome activity, and apoptosis during CL regression in cattle. The expression of autophagy-related genes (LC3alpha, LC3beta, Atg3, and Atg7) and the protein LC3 II was significantly higher in the late CL than in the mid CL. In addition, autophagy activity was significantly increased in the late CL. Moreover, gene expression of the autophagy inhibitor mammalian target of rapamycin (mTOR) was significantly lower in the late CL than in the mid CL. Lysosome activation and expression of cathepsin-related genes (CTSB, CTSD, and CTSZ) showed significant increases in the late CL and were associated with an increase in cathepsin B protein. In addition, mRNA expression and activity of caspase 3 (CASP3), an apoptotic enzyme, were significantly higher in the late CL than in the mid CL. These results suggest simultaneous upregulation of autophagy-related factors, lysosomal enzymes and apoptotic mediators, which are involved in regression of the bovine CL. PMID- 25819402 TI - Sound identification in human auditory cortex: Differential contribution of local field potentials and high gamma power as revealed by direct intracranial recordings. AB - High gamma power has become the principal means of assessing auditory cortical activation in human intracranial studies, albeit at the expense of low frequency local field potentials (LFPs). It is unclear whether limiting analyses to high gamma impedes ability of clarifying auditory cortical organization. We compared the two measures obtained from posterolateral superior temporal gyrus (PLST) and evaluated their relative utility in sound categorization. Subjects were neurosurgical patients undergoing invasive monitoring for medically refractory epilepsy. Stimuli (consonant-vowel syllables varying in voicing and place of articulation and control tones) elicited robust evoked potentials and high gamma activity on PLST. LFPs had greater across-subject variability, yet yielded higher classification accuracy, relative to high gamma power. Classification was enhanced by including temporal detail of LFPs and combining LFP and high gamma. We conclude that future studies should consider utilizing both LFP and high gamma when investigating the functional organization of human auditory cortex. PMID- 25819403 TI - Aetiology of bronchiectasis in Guangzhou, southern China. AB - BACKGROUND AND OBJECTIVE: Aetiologies of bronchiectasis in mainland China and their comparisons with those in western countries are unknown. We aimed to investigate bronchiectasis aetiologies in Guangzhou, southern China, and to determine ethnic or geographic differences with reports from western countries. METHODS: Consecutive patients with steady-state bronchiectasis were randomly recruited. Past history was meticulously extracted. Patients underwent physical examination, saccharine test, humoral immunity assays, gastroesophageal reflux scoring and sputum culture. Fiberoptic bronchoscopy, total immunoglobin E (IgE) and Aspergillus fumigatus-specific IgE measurement, 24-h gastroesophageal pH monitoring and miscellaneous screening tests were performed, if indicated. This entailed comparisons on aetiologies with literature reports. RESULTS: We enrolled 148 patients (44.6 +/- 13.8 years, 92 females), most of whom had mild to moderate bronchiectasis. Idiopathic (46.0%), post-infectious (27.0%) and immunodeficiency (8.8%) were the most common aetiologies. Miscellaneous aetiologies consisted of asthma (5.4%), gastroesophageal reflux (4.1%), aspergillosis (2.7%), congenital lung malformation (2.0%), Kartagener syndrome (1.4%), rheumatoid arthritis (1.4%), chronic obstructive pulmonary disease (0.7%), Young's syndrome (0.7%), yellow nail's syndrome (0.7%), eosinophilic bronchiolitis (0.7%) and foreign bodies (0.7%). No notable differences in clinical characteristics between idiopathic and known aetiologies were found. Ethnic or geographic variations of aetiologies were overall unremarkable. CONCLUSIONS: Idiopathic, post-infectious and immunodeficiency constitute major bronchiectasis aetiologies in Guangzhou. Clinical characteristics of patients between known aetiologies and idiopathic bronchiectasis were similar. Ethnicity and geography only account for limited differences in aetiologic spectra. These findings will offer rationales for early diagnosis and management of bronchiectasis in future studies and clinical practice in China. PMID- 25819404 TI - Mechanical surface waves accompany action potential propagation. AB - Many diverse studies have shown that a mechanical displacement of the axonal membrane accompanies the electrical pulse defining the action potential (AP). We present a model for these mechanical displacements as arising from the driving of surface wave modes in which potential energy is stored in elastic properties of the neuronal membrane and cytoskeleton while kinetic energy is carried by the axoplasmic fluid. In our model, these surface waves are driven by the travelling wave of electrical depolarization characterizing the AP, altering compressive electrostatic forces across the membrane. This driving leads to co-propagating mechanical displacements, which we term Action Waves (AWs). Our model allows us to estimate the shape of the AW that accompanies any travelling wave of voltage, making predictions that are in agreement with results from several experimental systems. Our model can serve as a framework for understanding the physical origins and possible functional roles of these AWs. PMID- 25819405 TI - CD133 allows elaborated discrimination and quantification of haematopoietic progenitor subsets in human haematopoietic stem cell transplants. AB - The success of haematopoietic stem cell (HSC) transplantation largely depends on numbers of transplanted HSCs, which reside in the CD34(+) populations of bone marrow (BM), peripheral blood stem cells (PBSC) and umbilical cord blood (UCB). More specifically HSCs reside in the CD38(low/-) subpopulation, which cannot be objectively discriminated from mature CD34(+) CD38(+) progenitors. Thus, better marker combinations for the quantification of more primitive haematopoietic stem and progenitor cells in transplants are required. Recently, by combining CD34 and CD133 we could clearly distinguish CD133(+) CD34(+) multipotent and lympho myeloid from CD133(low) CD34(+) erythro-myeloid progenitors in UCB samples. To qualify the assessment of CD133 for routine quality control of adult HSC sources, we analysed the developmental potentials of CD133(+) and CD133(low) subpopulations in BM and PBSC. Similar to UCB, CD133 expression objectively discriminated functionally distinct subpopulations in adult HSC sources. By implementing anti-CD45RA staining, which separates multipotent (CD133(+) CD34(+) CD45RA(-) ) from lympho-myeloid (CD133(+) CD34(+) CD45RA(+) ) progenitor fractions, UCB was found to contain 2-3 times higher multipotent progenitor frequencies than BM and PBSC. To test for the consistency of CD133 expression, we compared CD133(+) CD34(+) contents of 128 UCB samples with maternal and obstetrical factors and obtained similar correlations to related studies focusing on CD34(+) cell contents. In conclusion, implementation of anti-CD133 staining into existing routine panels will improve the quality control analyses for HSC transplants. PMID- 25819406 TI - Elevated serum CA 19-9 level associated with a splenic cyst: which is the actual clinical management? Review of the literature. AB - Splenic cysts are relatively rare entities. The differential diagnosis for these lesions includes parasite infections, results of previous trauma or infarction, congenital forms, primitive splenic neoplasm or cystic metastasis. They can be either symptomatic, causing mainly abdominal pain, or asymptomatic, thus being diagnosed as in incidental finding during radiological examination for other clinical reasons: among these a raised serum level of CA 19-9 can be a case. It has been demonstrated that epidermoid and mesothelial congenital cyst can be associated with a pathological level of this tumor marker which is usually correlated to biliopancreatic and colonic carcinomas. The aim of the present study is to present the case of an asymptomatic epidermoid splenic cyst associated with a continuous increase of CA 19-9 and to describe the applied clinical workup and surgical management by laparoscopic total splenectomy. Moreover, to analyze the demographics, clinical and pathological features of these infrequent lesions and to confront our therapeutic management with that of the other reported cases, we conducted a systematic review of the literature. PMID- 25819407 TI - Cardiac tamponade caused by paradoxical immune reconstitution inflammatory syndrome. PMID- 25819408 TI - The utilization of clinical and radiologic tools for the diagnosis of acute appendicitis. PMID- 25819409 TI - In response to "Scope of shared decision making in patients with psychologic complaints". PMID- 25819410 TI - Pectus excavatum: a cause of serious cardiac dysfunction and dysrhythmia. PMID- 25819411 TI - Recurrent idiopathic ventricular fibrillation induced by high fever. PMID- 25819412 TI - How rare is hypertensive brain stem encephalopathy? PMID- 25819413 TI - Factitious snake envenomation and narcotic-seeking behavior. PMID- 25819414 TI - Glucose metabolism provide distinct prosurvival benefits to non-small cell lung carcinomas. AB - Heterogeneity within the same tumor type has been described to be complex and occur at multiple levels. Less is known about the heterogeneity at the level of metabolism, within a tumor set, yet metabolic pathways are highly relevant to survival signaling in tumors. In this study, we profiled the glucose metabolism of several non-small cell lung carcinoma (NSCLC) cell lines and could show that, NSCLC display distinct glycolytic metabolism. Genetic and pharmacological perturbation of glycolysis was selectively toxic to NSCLCs with high rates of glycolysis. Furthermore, high expression of hexokinase-2, localized at the mitochondria, was a feature of the NSCLCs dependent on glucose catabolism. Our study provides evidence for quantitative metabolic diversity in NSCLCs and indicates that glucose metabolism provide differential prosurvival benefits to NSCLCs. PMID- 25819415 TI - Insulin-like growth factor-binding protein 7 is up-regulated during EAE and inhibits the differentiation of oligodendrocyte precursor cells. AB - Oligodendrocyte precursor cells (OPCs) differentiation failure is one of the leading causes for remyelination defects in the demyelinating lesions of multiple sclerosis (MS). In this study, we explored the roles of insulin-like growth factor-binding proteins 7 (IGFBP-7) on OPCs differentiation during experimental autoimmune encephalomyelitis (EAE). We first investigated the expression pattern of IGFBP-7 by real-time PCR and immunofluorescence staining. It showed that IGFBP 7 was expressed in astrocytes (ACs), oligodendrocytes (OLs) and neurons both in vitro and in vivo. The mRNA and protein level of IGFBP-7 was also increased in the spinal cord from mice at the peak of EAE disease. Next we found that IGFBP-7 acted as a negatively regulator of the OPCs differentiation. Together, these data suggest that IGFBP-7 was up regulated during EAE and inhibit the transition from OPCs to mature OLs, implying its use as a potential therapeutic target for the treatment of inflammatory demyelinating diseases. PMID- 25819416 TI - The impact of obesity and weight gain on development of sleep problems in a population-based sample. AB - OBJECTIVES: The objective of this study was to investigate the role of obesity and weight gain in the development of sleep problems in a population-based cohort. MATERIAL AND METHODS: A population-based sample of men (n = 1896, aged 40 79 years) and women (n = 5116, age >=20 years) responded to questionnaires at baseline and follow-up after 10-13 years. Sleep problems were assessed through questions about difficulties initiating sleep (DIS), difficulties maintaining sleep (DMS), excessive daytime sleepiness (EDS), and insomnia. Body mass index (BMI) was calculated from self-reported weight and height at both baseline and follow-up, while confounding factors (physical activity, tobacco and alcohol use, somatic disease, and snoring) were based on responses at baseline. RESULTS: Although overweight and obese subjects reported more sleep problems at baseline, there was no independent association between BMI level at baseline and development of new sleep problems. Subjects in the quartile with the highest rise in BMI with a weight gain exceeding 2.06 kg/m2 had a higher risk of developing DMS [adjusted odds ratio (OR) 1.58; 95% confidence interval (CI) 1.25-2.01), EDS (2.25; 1.65-3.06], and insomnia (2.78; 1.60-4.82). Weight gain was not associated with the development of DIS. CONCLUSIONS: Weight gain is an independent risk factor for developing several sleep problems and daytime sleepiness. The presence of overweight and weight gain should be considered when treating patients with sleep problems. PMID- 25819417 TI - Commentary on "Impact of sleep-disordered breathing on metabolic dysfunctions in patients with polycystic ovary syndrome". PMID- 25819418 TI - High-frequency heart rate variability during worry predicts stress-related increases in sleep disturbances. AB - OBJECTIVE: The aim of this study was to evaluate whether high-frequency heart rate variability (HF-HRV) during waking restfulness and during worry predicts increases in sleep disturbances in response to a stressful life event. METHODS: A longitudinal study following up 22 individuals from well-defined periods of lower and higher stress was conducted. HF-HRV during waking restfulness and in response to a worry induction was measured during a low-stress period. Sleep disturbances were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) during low-stress and high-stress periods. RESULTS: During both the low- and high-stress periods, lower HF-HRV during worry was associated with greater PSQI scores. Importantly, lower HF-HRV during the worry induction prospectively predicted greater increases in the PSQI score from the low-stress to the high-stress periods. CONCLUSION: HF-HRV during worry might represent an index of vulnerability to stress-induced sleep disturbances. PMID- 25819419 TI - Diagnostic accuracy of the Spanish version of the Pediatric Sleep Questionnaire for screening of obstructive sleep apnea in habitually snoring children. AB - OBJECTIVES: We aimed to determine the diagnostic test accuracy of the Spanish version of the respiratory symptoms scale of the Pediatric Sleep Questionnaire (PSQ) in habitually snoring children for identifying obstructive sleep apnea (OSA). METHODS: Habitually snoring children referred for polysomnography (PSG) were recruited. Parents answered the PSQ prior to PSG. Based on an apnea-hypopnea index (AHI) >1.0 in PSG, children were divided into OSA and primary snorers. Correlations to PSG indices and diagnostic test accuracy measures were calculated. RESULTS: Of the 83 (n = 53 males, mean age 9.5 +/- 3.6 years) habitually snoring children included, 35 had OSA. The previously validated PSQ cutoff value of 0.33 showed a specificity of 0.72 and sensitivity of 0.78. The PSQ score correlated significantly with the AHI rs = 0.313 (p-value = 0.004). Six items of the PSQ were significantly different between cases and controls. A subscale constructed on these six PSQ items concerning respiratory symptoms showed a good sensitivity (0.886) and an excellent negative likelihood ratio (0.261). PSQ was able to identify 89% of the children with OSA correctly. CONCLUSIONS: This version of the PSQ was able to identify children with OSA, separating them from those with primary snoring. The use of this simple, standardized questionnaire tool seems to be helpful and may improve clinical decision making in habitually snoring children. PMID- 25819420 TI - Postoperative ileus: Recent developments in pathophysiology and management. AB - BACKGROUND & AIMS: Postoperative ileus (POI) is a frequent occurrence after abdominal and other types of surgery, and is associated with significant morbidity and costs to health care providers. The aims of this narrative review were to provide an update of classification systems, preventive techniques, pathophysiological mechanisms, and treatment options for established POI. METHODS: The Web of Science, MEDLINE, PubMed and Google Scholar databases were searched using the key phrases 'ileus', 'postoperative ileus' and 'definition', for relevant studies published in English from January 1997 to August 2014. RESULTS: POI is still a problematic and frequent complication of surgery. Fluid overload, exogenous opioids, neurohormonal dysfunction, and gastrointestinal stretch and inflammation are key mechanisms in the pathophysiology of POI. Evidence is supportive of thoracic epidural analgesia, avoidance of salt and water overload, alvimopan and gum chewing as measures for the prevention of POI, and should be incorporated into perioperative care protocols. Minimal access surgery and avoidance of nasogastric tubes may also help. Novel strategies are emerging, but further studies are required for the treatment of prolonged POI, where evidence is still lacking. CONCLUSIONS: Although POI is often inevitable, methods to reduce its duration and facilitate recovery of postoperative gastrointestinal function are evolving rapidly. Utilisation of standardised diagnostic classification systems will help improve applicability of future studies. PMID- 25819421 TI - Stroke treated at a neurosurgical ward: a cohort study. AB - OBJECTIVES: Little is known about the long-term recovery of patients treated with neurosurgery after stroke. This study aimed to explore the recovery of patients with first-time stroke treated in a neurosurgical ward, including their function, the presence of disability and life situation at admission, discharge and 4 years later. METHODS: In this cohort study, 28 subjects (average age 55 years) were included. All had first-time stroke and were treated at the neurosurgical ward consecutively for 18 months. Baseline characteristics were identified, and follow up home visits (n = 13) were performed 4 years post-stroke to explore the life situation, health status and recovery. RESULTS: At admission, the median Glasgow Coma Scale score was 8 (range 3-15). Craniectomy or craniotomy was performed on 12 of the subjects. Average hospitalization time was 58 days. Two subjects died during the hospital stay, and an additional five died before the follow-up. Significant improvement in function from discharge to follow-up was noted: four of 13 were back at work, two were in need of personal assistance and one lived in a nursing home. Follow-up questionnaires showed a relatively high level of participation and independence. CONCLUSIONS: Patients with stroke who were admitted to a neurosurgical ward had a low mortality rate during the acute treatment, and at 4 years post-stroke, the survival rate was 75%. The level of disability and dependence at discharge was high, but at 4 years post-stroke, there was both measurable and self-perceived improvement in function. PMID- 25819422 TI - Neural correlates of individual differences in fear learning. AB - Variability in fear conditionability is common, and clarity regarding the neural regions responsible for individual differences in fear conditionability could uncover brain-based biomarkers of resilience or vulnerability to trauma-based psychopathologies (e.g., post-traumatic stress disorder). In recent years, neuroimaging work has yielded a detailed understanding of the neural mechanisms underlying fear conditioning common across participants, however only a minority of studies have investigated the brain basis of inter-individual variation in fear learning. Moreover, the majority of these studies have employed small sample sizes (mean n=17; range n=5-27) and all have failed to meet the minimum recommended sample size for functional magnetic resonance imaging (fMRI) studies of individual differences. Here, using fMRI, we analyzed blood-oxygenation level dependent (BOLD) response recorded simultaneously with skin conductance response (SCR) and ratings of unconditioned stimulus (US) expectancy in 49 participants undergoing Pavlovian fear conditioning. On average, participants became conditioned to the conditioned stimulus (CS+; higher US expectancy ratings and SCR for the CS+ compared to the unpaired conditioned stimulus, CS-); the CS+ also robustly increased activation in the bilateral insula. Amygdala activation was revealed from a regression analysis that incorporated individual differences in fear conditionability (i.e., a between-subjects regressor of mean CS+>CS- SCR). By replicating results observed using much smaller sample sizes, the results confirm that variation in amygdala reactivity covaries with individual differences in fear conditionability. The link between behavior (SCR) and brain (amygdala reactivity) may be a putative endophenotype for the acquisition of fear memories. PMID- 25819423 TI - Responses of rat medial prefrontal cortical neurons to Pavlovian conditioned stimuli and to delivery of appetitive reward. AB - In the present experiments, medial prefrontal cortical (mPFC) neurons were extracellularly recorded by means of tetrode electrodes to examine their possible role in the prediction of appetitive reward. Two different cue tones (CS) and sucrose solution or water reward (US) were associated in a Pavlovian conditioning paradigm. In order to test behavioral correlate of the CS-US association, the head acceleration before the first lick of licking cluster was measured. Neuronal activity changes in the mPFC were analyzed (i) during the CS presentations; (ii) before the first lick of licking clusters; (iii) during consummation; and (iv) we also examined whether consummation was represented in neurons responding to the CSs. There was a difference between the head accelerations to the different USs during early or late occurring first approaches, but there was no such a difference during intercluster approaches. A significant proportion of neurons changed their firing rate during the CS presentation, before the first lick of licking cluster or during licking of the reward. Both, excitatory and inhibitory responses were observed. A subpopulation of neurons responding to the CSs also responded during reward consumption. Differential population activities of excitatory neurons were recorded in response to the different CSs, CS evoked approach behaviors and consumption of different rewards. Neuronal responses also discriminated among the CSs and trials with or without consummation. These results provided evidence for the involvement of mPFC neurons in the prediction, representation and organization of conditioned behavioral actions, such as approaches to rewards and consummation. PMID- 25819424 TI - Interaction of neuropeptidase activities in cortico-limbic regions after acute restraint stress. AB - Brain enkephalin, vasopressin and oxytocin are anxiolytic agents involved in the stress response. Acute restraint stress influences certain neuropeptidase activities, such as some enkephalin-degrading peptidases and vasopressinase/oxytocinase, in the medial prefrontal cortex (mPFC), amygdala (AM) or hippocampus (HC), which are involved in this response. Because these regions form a unified circuit and cooperate in their response to stress, it is important to analyze the profile of the regional distribution of these activities as well as their inter-regional model of interaction in this circuit. Regarding the regional study, although most activities showed a marked predominance of the AM over the HC and mPFC, both in control and stressed animals, enkephalin-degrading activity, assayed as membrane-bound alanyl aminopeptidase activity, showed a change after stress, increasing in the HC and decreasing in the AM. The correlational study in controls indicated essentially a positive interaction between the mPFC and AM. In marked contrast, there was a highly significant change in the functional status of this circuit after stress, showing mainly a positive correlation between the mPFC and HC and between the AM and HC. The existence of correlations does not demonstrate a direct relationship between regions. However, reasons for such strong associations after restraint stress should be examined. The present study may indicate a connection between neuropeptidase activities and their corresponding neuropeptidergic substrates due to significant changes in the functional status of the cortico-limbic circuit after restraint stress. PMID- 25819425 TI - The neglected foundation of global health. PMID- 25819426 TI - Multivalent conjugation of antibody to dendrimers for the enhanced capture and regulation on colon cancer cells. AB - Circulation tumor cells (CTCs) in the bloodstream of early-stage cancer patients carry the important information about valuable biomarkers and biological properties of primary tumor. However, detection and capture of CTCs are challenging owing to their low concentrations. Traditional technologies have the limited detection sensitivity and the low capture efficiency. We, herein, report an effective approach to specifically bind and capture colon cancer HT29 cells by using multiple Sialyl Lewis X antibodies (aSlex)-conjugated PAMAM dendrimers. The conjugation was characterized by using atom force microscope, UV and fluorescence measurements. The capturing and regulating HT29 cells by the aSlex-coated dendrimer conjugate were analyzed by microscopy and flow cytometry. The results indicated that the conjugate showed the enhanced capture of HT29 cells in a concentration-dependent manner and the maximum capture efficiency of 77.88% was obtained within 1 h-exposure. G6-5aSlex-FITC conjugate showed capture efficiency better than FITC-G6-COOH-5aSlex conjugate. G6-5aSlex-FITC conjugate could specifically capture HT29 cells even when the target HT29 cells were diluted with the interfering cells (e.g., RBCs) to a low concentration. The capture resulted in a concentration-dependent restraint of the cell activity. In conclusion, the aSlex-coated dendrimer conjugate displayed the great potential in capturing and restraining colorectal CTCs in blood. PMID- 25819427 TI - A comparison of three different radiotherapy boost techniques after breast conserving therapy for breast cancer. AB - PURPOSE: Compare different boost techniques after breast conserving therapy (BCT) in terms of local and loco-regional recurrences. MATERIALS AND METHODS: From 2000 to 2005, patients treated with BCT for invasive breast cancer (BC) were included. An electron boost (EB) was performed for a superficial boost-volume (less than 29 mm under the epidermis), in all other cases a brachytherapy boost (BTB) was proposed. When patients refused a BTB or it was not possible for technical reasons, a photon boost (PB) was given. The primary endpoints were local and loco regional recurrences. Secondary endpoints were metastasis-free and overall survival. RESULTS: 1379 patients were eligible for analysis. Most patients (1052) received an EB, 225 a BTB and 76 a PB. At a median follow-up of 8.8 years, 35 (2.5%) patients developed a local or loco-regional recurrence. Ten years local relapse-free rate was 97.9%. No differences between boost techniques were observed in relapse risk, metastasis-free and overall survival after multivariate analyses. CONCLUSION: In women treated with BCT followed by a boost irradiation to the tumor bed, no difference in local and loco-regional recurrence, metastasis free and overall survival was observed comparing three different boost techniques. Outcome was excellent regardless of the boost technique. PMID- 25819429 TI - Spatial regulation of IL-4 signalling in vivo. AB - Type 2 immune responses are defined by the cytokines interleukin 4 (IL-4), IL-5 and IL-13 and the cellular and physiological changes that these cytokines induce, including IgE production, eosinophilia, mast cell degranulation, mucus secretion and smooth muscle contraction. Together these responses provide a "weep and sweep" reflex that is optimised to expel parasitic worms. The same response can also be pathological when mis-timed or activated inappropriately. Current understanding of the orchestration and regulation of type 2 immunity is rapidly advancing, with recent identification of participating innate cells and elucidation of the cytokine signals responsible for their activation. In vivo, the outcome of cytokine signalling is critically dependent on timing, location and context. In this commentary, we describe the spatiotemporal control of type 2 cytokine signalling, consider its implications for bystander cells, and discuss its significance during co-infection. PMID- 25819428 TI - Insights into antiviral innate immunity revealed by studying hepatitis C virus. AB - Experimental studies on the interactions of the positive strand RNA virus hepatitis C virus (HCV) with the host have contributed to several discoveries in the field of antiviral innate immunity. These include revealing the antiviral sensing pathways that lead to the induction of type I interferon (IFN) during HCV infection and also the importance of type III IFNs in the antiviral immune response to HCV. These studies on HCV/host interactions have contributed to our overall understanding of viral sensing and viral evasion of the antiviral intracellular innate immune response. In this review, I will highlight how these studies of HCV/host interactions have led to new insights into antiviral innate immunity. Overall, I hope to emphasize that studying antiviral immunity in the context of virus infection is necessary to fully understand antiviral immunity and how it controls the outcome of viral infection. PMID- 25819430 TI - Space and time: New considerations about the relationship between Toll-like receptors (TLRs) and type I interferons (IFNs). AB - The Toll like receptors (TLRs) and the type I interferons have critical roles to play in innate immunity. In this review we will discuss new developments relating to the important area of TLR/IFN cross regulation. PMID- 25819431 TI - Multi-state relative survival modelling of colorectal cancer progression and mortality. AB - Accurate identification of factors associated with progression of colorectal cancer remains a challenge. In particular, it is unclear which statistical methods are most suitable to separate the effects of putative prognostic factors on cancer progression vs cancer-specific and other cause mortality. To address these challenges, we analyzed 10 year follow-up data for patients who underwent curative surgery for colorectal cancer in 1985-2000. Separate analyses were performed in two French cancer registries. Results of three multivariable models were compared: Cox model with recurrence as a time-dependent variable, and two multi-state models, which separated prognostic factor effects on recurrence vs death, with or without recurrence. Conventional multi-state model analyzed all cause mortality while new relative survival multi-state model focused on cancer specific mortality. Among the 2517 and 2677 patients in the two registries, about 50% died without a recurrence, and 28% had a recurrence, of whom almost 90% died. In both multi-state models men had significantly increased risk of cancer recurrence in both registries (HR=0.79; 95% CI: 0.68-0.92 and HR=0.83; 95% CI: 0.71-0.96). However, the two multi-state models identified different prognostic factors for mortality without recurrence. In contrast to the conventional model, in the relative survival analyses gender had no independent association with cancer-specific mortality whereas patients diagnosed with stage III cancer had significantly higher risks in both registries (HR=1.67; 95% CI: 1.27-2.22 and HR=2.38; 95% CI: 1.29-3.27). In conclusion, relative survival multi-state model revealed that different factors may be associated with cancer recurrence vs cancer-specific mortality either after or without a recurrence. PMID- 25819432 TI - Ultrafast excited-state charge-transfer dynamics in laccase type I copper site. AB - Femtosecond pump-probe spectroscopy was used to investigate the excited state dynamics of the T1 copper site of laccase from Pleurotus ostreatus, by exciting its 600 nm charge transfer band with a 15-fs pulse and probing over a broad range in the visible region. The decay of the pump-induced ground-state bleaching occurs in a single step and is modulated by clearly visible oscillations. Global analysis of the two-dimensional differential transmission map shows that the excited state exponentially decays with a time constant of 375 fs, thus featuring a decay rate slower than those occurring in quite all the investigated T1 copper site proteins. The ultrashort pump pulse induces a vibrational coherence in the protein, which is mainly assigned to ground state activity, as expected in a system with fast excited state decay. Vibrational features are discussed also in comparison with the traditional resonance Raman spectrum of the enzyme. The results indicate that both excited state dynamics and vibrational modes associated with the T1 Cu laccase charge transfer have main characteristics similar to those of all the T1 copper site-containing proteins. On the other hand, the differences observed for laccase from P. ostreatus further confirm the peculiar hypothesized trigonal T1 Cu site geometry. PMID- 25819433 TI - The lived experience of US parents of children with autism spectrum disorders: a systematic review and meta-synthesis. AB - Current US statistics indicate that 1 in 68 children is diagnosed with an autistic spectrum disorder (Centers for Disease Control (2014) Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 Sites, United States, 2010. Morbidity and Mortality Weekly Report (MMWR)). The lived experience of parents with children diagnosed with autism spectrum disorder is important to know since quantitative studies have indicated that higher rates of mental disorders exist in this population as compared to parents of typically developing children (Yirmiya and Shaked (2005) Psychiatric disorders in parents of children with autism: a meta analysis. Journal of Child Psychology and Psychiatry 46: 69-83). This study was a meta-synthesis of the qualitative literature in this area embedded within a systematic review. A comprehensive search and review yielded 14 studies. A total of six major themes were identified: (a) emotional stress and strain; (b) adaptation; (c) impact on the family; (d) services; (e) stigmatization; and (f) appreciating the little things. Implications of these results are discussed. PMID- 25819434 TI - Acetylcholine contributes to control the physiological inflammatory response during the peri-implantation period. AB - BACKGROUND: Maternal antigen-presenting cells attracted to the pregnant uterus interact with trophoblast cells and modulate their functional profile to favour immunosuppressant responses. Non-neuronal cholinergic system is expressed in human cytotrophoblast cells and in immune cells with homeostatic regulatory functions. AIM: The aim of this work was to evaluate whether non-neuronal acetylcholine conditions maternal monocyte and DC migration and activation profiles. METHODS: We used an in vitro model resembling maternal-placental interface represented by the co-culture of human trophoblast cells (Swan-71 cell line) and monocytes or DC. RESULTS: When cytotrophoblast cells were treated with neostigmine (Neo) to concentrate endogenous acetylcholine levels, monocyte migration was increased. In parallel, high levels of IL-10 and decreased levels of TNF-alpha were observed upon interaction of maternal monocytes with trophoblast cells. This effect was synergized by Neo and was prevented by atropine, a muscarinic acetylcholine receptor antagonist. Similarly, trophoblast cells increased the migration of DC independently of Neo treatment; however, enhanced IL-10 and MCP-1 synthesis in trophoblast-DC co-cultures with no changes in TNF-alpha and IL-6 was observed. In fact, there were no changes in HLA-DR, CD86 or CD83 expression. Finally, trophoblast cells treated with Neo increased the expression of two antigen-presenting cells attracting chemokines, MCP-1, MIP 1alpha and RANTES through muscarinic receptors, and it was prevented by atropine. CONCLUSIONS: Our present results support a novel role of acetylcholine synthesized by trophoblast cells to modulate antigen-presenting cell migration and activation favouring an immunosuppressant profile that contributes to immune homeostasis maintenance at the maternal-foetal interface. PMID- 25819435 TI - Pannexin 1 facilitates arterial relaxation via an endothelium-derived hyperpolarization mechanism. AB - Pannexin 1 (Panx1) is involved in endothelium-dependent vasodilation in large arteries, but the exact mechanistic role remains poorly understood. We hypothesized that Panx1 facilitates large vessel relaxations regulating endothelium-derived hyperpolarization (EDH)-like mechanisms. The EDH-like component of acetylcholine-induced relaxation of saphenous arteries studied in isometric myograph after inhibition of NO-synthase and cyclooxygenase was significantly impaired in mice with genetically ablated Panx1 (KO) relative to that in the wild type (WT) mice. Application of P1-receptor antagonist and apyrase significantly reduced this component in WT, but not in KO mice, indicating participation of ATP released via Panx1 in the EDH-like relaxation. PMID- 25819436 TI - A single PXXP motif in the C-terminal region of srGAP3 mediates binding to multiple SH3 domains. AB - The Slit-Robo GTPase-activating protein 3 (srGAP3) has been implicated in different critical aspects of neuronal development. These findings have mainly been based on the characterisation of the three conserved globular N-terminal domains, while the function of the C-terminal region (CTR) is still unknown. We show that this predicted unstructured region acts as an adaptor by binding to the endocytic proteins Amphiphysin, Endophilin-A2, Endophilin-A1, as well as the Ras signalling protein Grb2. All these interactions depend on a single proline-rich motif in the CTR and the Src-homology 3 domains of the binding partners. Via these interactions srGAP3 could link receptor signalling events to the endocytic machinery. PMID- 25819437 TI - LeNRT2.3 functions in nitrate acquisition and long-distance transport in tomato. AB - Nitrogen plays an important role in plant growth and development. Nitrate transporters have been extensively studied in Arabidopsis, but in tomato they have not been functionally characterized. In this study, we report the functions of LeNRT2.3 in nitrate transport in tomato. Our results show that LeNRT2.3 is induced by nitrate, and mainly localizes to the plasma membranes of rhizodermal and pericycle cells in roots. Further analysis in Xenopus oocytes showed that LeNRT2.3 mediates low-affinity nitrate transport. 35S:LeNRT2.3 increased nitrate uptake in root and transport from root to shoot. More interestingly, 35S:LeNRT2.3 showed high biomass and fruit weight. Taken together, these results suggest that LeNRT2.3 plays a double role in nitrate uptake and long-distance transport in tomato. PMID- 25819438 TI - Inositol transport proteins. AB - The cyclic polyol myo-inositol is a key molecule in many different metabolic pathways among all organisms; in addition, it is fundamental for osmotic balance in the mammalian brain. This review sums up inositol transporters from eukaryotic organisms, elucidating their vital role in regulating the intracellular distribution and uptake of inositol. They can be divided into two groups according to their transport mechanisms: (1) sodium ion coupled inositol transporters that belong to the Solute Carrier Families 5 and 6-like Superfamily and, (2) proton coupled inositol symporters that are members of the Major Facilitator Superfamily. Intriguingly members of both families offer promising targets for medical treatment of a variety of diseases. PMID- 25819439 TI - GGPPS deficiency aggravates CCl4-induced liver injury by inducing hepatocyte apoptosis. AB - GGPPS catalyses the expression of GGPP, a key protein in the mevalonate metabolic pathway. HMG-CoA reductase inhibitor statins can induce liver injury by inhibiting GGPP. However, the function of GGPPS in liver injury has not yet been revealed. In this study, we found that GGPPS increased in liver injury and that GGPPS deletion augmented liver injury and fibrosis. GGPPS inhibition induced hepatocyte apoptosis, inflammation and TGF-beta1 secretion, which activated hepatic stellate cells. Our findings imply that GGPPS deletion induces hepatocyte apoptosis, which makes the liver vulnerable to hepatotoxicity. PMID- 25819440 TI - Vibrio vulnificus glycogen branching enzyme preferentially transfers very short chains: N1 domain determines the chain length transferred. AB - The glycogen branching enzyme from Vibrio vulnificus (VvGBE) transfers short side chains (DP 3-5) significantly greater than any other bacterial glycogen branching enzyme (GBE). To elucidate the role of the N-domain of VvGBE in the unique branching pattern, domain-truncated (N1 and N) and N1-domain-swapped (with VvGBE N1 replacing the counter part of Escherichia coli GBE) mutants were constructed. The truncation mutants synthesized branched products with a greatly reduced proportion of short chains. The swapping mutant exhibited a branching pattern of the short chain region similar to that of VvGBE. We conclude that the N1-domain of VvGBE has a crucial role in the determination of the branching pattern of glycogen. PMID- 25819441 TI - Brain inflammation and psoriasis: a [11 C]-(R)-PK11195 positron emission tomography study. PMID- 25819442 TI - The scientific abstract: a beginner's guide. PMID- 25819443 TI - Molecular identification of black-pigmented bacteria from subgingival samples of cats suffering from periodontal disease. AB - OBJECTIVES: To characterise the black-pigmented bacterial species found in the subgingival samples of cats with periodontal disease using molecular-based microbiological techniques. METHODS: Sixty-five subgingival samples obtained from 50 cats with periodontal disease were analysed by polymerase chain reaction amplified ribosomal DNA restriction analysis and cloning and sequencing of the 16S rRNA genes. RESULTS: Among the 65 subgingival samples, eight phylogenetic profiles were obtained, of which the most prevalent species were: Porphyromonas gulae (40%), P. gingivalis/P. gulae (36 . 9%), P. gulae/Porphyromonas sp. UQD 406 (9 . 2%), Odoribacter denticanis (6 . 2%), P. gulae/Porphyromonas sp. UQD 348 (1 . 5%) and P. circumdentaria (1 . 5%). When compared with the species resulting from biochemical diagnosis, the identification of P. gulae was congruent in 70% of the cases, while colonies identified as P. intermedia-like corresponded in 80% of cases to P. gulae. CLINICAL SIGNIFICANCE: The use of molecular-based microbiological diagnostic techniques resulted in a predominance of Porphyromonas spp. in the subgingival plaque of cats suffering from periodontal disease. Further characterisation of these bacteria identified P. gulae, O. denticanis and P. circumdentaria. The more frequently detected phylogenetic profiles corresponded to P. gingivalis and P. gulae. PMID- 25819445 TI - RASP (Reconstruct Ancestral State in Phylogenies): a tool for historical biogeography. AB - We announce the release of Reconstruct Ancestral State in Phylogenies (RASP), a user-friendly software package for inferring historical biogeography through reconstructing ancestral geographic distributions on phylogenetic trees. RASP utilizes the widely used Statistical-Dispersal Vicariance Analysis (S-DIVA), the Dispersal-Extinction-Cladogenesis (DEC) model (Lagrange), a Statistical DEC model (S-DEC) and BayArea. It provides a graphical user interface (GUI) to specify a phylogenetic tree or set of trees and geographic distribution constraints, draws pie charts on the nodes of a phylogenetic tree to indicate levels of uncertainty, and generates high-quality exportable graphical results. RASP can run on both Windows and Mac OS X platforms. All documentation and source code for RASP is freely available at http://mnh.scu.edu.cn/soft/blog/RASP. PMID- 25819444 TI - The effects of endoxifen and other major metabolites of tamoxifen on the sulfation of estradiol catalyzed by human cytosolic sulfotransferases hSULT1E1 and hSULT1A1*1. AB - Tamoxifen is successfully used for both treatment and prevention of estrogen dependent breast cancer, yet side effects and development of resistance remain problematic. Endoxifen is a major active metabolite of tamoxifen that is being investigated for clinical use. We hypothesized that endoxifen and perhaps other major metabolites of tamoxifen may affect the ability of human estrogen sulfotransferase 1E1 (hSULT1E1) and human phenol sulfotransferase 1A1 isoform 1 (hSULT1A1*1) to catalyze the sulfation of estradiol, an important mechanism in termination of estrogen signaling through loss of activity at estrogen receptors. Our results indicated that endoxifen, N-desmethyltamoxifen (N-desTAM), 4 hydroxytamoxifen (4-OHTAM), and tamoxifen-N-oxide were weak inhibitors of hSULT1E1 with Ki values ranging from 10 MUM to 38 MUM (i.e., over 1000 times higher than the 8.1 nM Km value for estradiol as substrate for the enzyme). In contrast to the results with hSULT1E1, endoxifen and 4-OHTAM were significant inhibitors of the sulfation of 2.0 uM estradiol catalyzed by hSULT1A1*1, with IC50 values (9.9 MUM and 1.6 MUM, respectively) that were similar to the Km value (1.5 MUM) for estradiol as substrate for this enzyme. Additional investigation of the interaction of these metabolites with the two sulfotransferases revealed that endoxifen, 4-OHTAM, and N-desTAM were substrates for hSULT1E1 and hSULT1A1*1, although the relative catalytic efficiencies varied with both the substrate and the enzyme. These results may assist in future elucidation of cell- and tissue specific effects of tamoxifen and its metabolites. PMID- 25819446 TI - Long-term hydrodynamic modeling of the Arabian Gulf. AB - A 3-D prognostic baroclinic hydrodynamic model of the Arabian Gulf (AG) was developed using Delft3D-FLOW. The model was forced with long-term time averaged climatological data over the computational domain and long-term salinity and temperature boundary conditions applied at its tidal open boundary. The model simulation results were thoroughly validated against measured tides from 5 stations and measured currents at 4 locations in the central and southern parts. Water salinity and temperature were validated in space and time using observations spanning over 73 years from 1923 to 1996 for the AG, the Strait of Hormuz and the Gulf of Oman. The bottom flow of the AG basin at the vicinity of the Strait of Hormuz was also validated against the available measurements. Seasonal evaporation and surface density spatial distribution maps were produced and compared with available records. The developed model setup successfully generated the AG seasonal stratification and hydrographic conditions. PMID- 25819447 TI - Marine governance in the English Channel (La Manche): Linking science and management. AB - The English Channel is one of the world's busiest sea areas with intense shipping and port activity juxtaposed with recreation, communications and important conservation areas. Opportunities for marine renewable energy vie with existing activities for space. The current governance of the English Channel is reviewed and found to lack integration between countries, sectors, legislation and scientific research. Recent developments within the EU's marine management frameworks are significantly altering our approach to marine governance and this paper explores the implications of these new approaches to management of the English Channel. Existing mechanisms for cross-Channel science and potential benefits of an English Channel scale perspective are considered. In conclusion, current management practices are considered against the 12 Malawi Principles of the ecosystem approach resulting in proposals for enhancing governance of the region through science at the scale of the English Channel. PMID- 25819448 TI - Agreement on urgency assessment between secretaries and general practitioners: an observational study in out-of-hours general practice service in Belgium. AB - BACKGROUND: In some European countries telephone triage (TT) during out-of-hours primary care showed to be safe and effective. Other countries, such as Belgium, may not have trained auxiliary personnel while their national health services want to establish TT. OBJECTIVES: To compare urgency levels assessed by secretaries and general practitioners in one general practice cooperative in Belgium. METHODS: Percentage of correct-, under-, and over-triage were calculated in total and per reason for encounter. Inter-rater agreement was investigated. RESULTS: The secretaries correctly triaged (same urgency level) 77% of the telephone calls, under-triaged 10% and over-triaged 13%.'Shortness of breath', 'skin cuts', 'chest pain', 'feeling unwell' and 'syncope' were often under triaged. CONCLUSION: Before introducing TT, auxiliary staff should be trained and protocols should be used. PMID- 25819449 TI - Introduction to Special Issue on ocular ECM. PMID- 25819450 TI - Structure and function of the interphotoreceptor matrix surrounding retinal photoreceptor cells. AB - The interphotoreceptor matrix (IPM) is a highly organized structure with interconnected domains surrounding cone and rod photoreceptor cells and extends throughout the subretinal space. Based on known roles of the extracellular matrix in other tissues, the IPM is thought to have several prominent functions including serving as a receptor for growth factors, regulating retinoid transport, participating in cytoskeletal organization in surrounding cells, and regulation of oxygen and nutrient transport. In addition, a number of studies suggest that the IPM also may play a significant role in the etiology of retinal degenerative disorders. In this review, we describe the present knowledge concerning the structure and function of the IPM under physiological and pathological conditions. PMID- 25819452 TI - The role of extracellular matrix in retinal vascular development and preretinal neovascularization. AB - Extracellular matrix (ECM) plays a central role in angiogenesis. ECM degrading enzymes breakdown the pre-existing vascular basement membrane at an early stage of angiogenesis and subsequently degrade stromal ECM as the new vessels invade into tissues. Conversely certain ECM components including collagen, fibronectin or fibrin are required for endothelial cell migration and tube morphogenesis. As the new vessels form they lay down a basement membrane that surrounds the endothelial tubes and is essential for their stability. In the rodent eye the transient expression of fibronectin and matricellular proteins plays a key role in retinal vascular development. In pathological retinal angiogenesis, such as in proliferative diabetic retinopathy, preretinal neovascularization occurs where new blood vessels invade the cortical vitreous gel and these blood vessels require vitreous collagen for their growth. The vitreous is normally anti angiogenic and contains endogenous ECM inhibitors of angiogenesis including opticin and thombospondins, and ECM fragments such as endostatin. In preretinal neovascularization, the combined anti-angiogenic effects of these molecules are overcome by an excess of growth factors such as vascular endothelial growth factor-A, and new vessels grow into the vitreous with potentially blinding sequelae. PMID- 25819451 TI - Optic nerve head biomechanics in aging and disease. AB - This nontechnical review is focused upon educating the reader on optic nerve head biomechanics in both aging and disease along two main themes: what is known about how mechanical forces and the resulting deformations are distributed in the posterior pole and ONH (biomechanics) and what is known about how the living system responds to those deformations (mechanobiology). We focus on how ONH responds to IOP elevations as a structural system, insofar as the acute mechanical response of the lamina cribrosa is confounded with the responses of the peripapillary sclera, prelaminar neural tissues, and retrolaminar optic nerve. We discuss the biomechanical basis for IOP-driven changes in connective tissues, blood flow, and cellular responses. We use glaucoma as the primary framework to present the important aspects of ONH biomechanics in aging and disease, as ONH biomechanics, aging, and the posterior pole extracellular matrix (ECM) are thought to be centrally involved in glaucoma susceptibility, onset and progression. PMID- 25819453 TI - The role of CTGF in diabetic retinopathy. AB - Connective tissue growth factor (CTGF, CCN2) contributes to fibrotic responses in diabetic retinopathy, both before clinical manifestations occur in the pre clinical stage of diabetic retinopathy (PCDR) and in proliferative diabetic retinopathy (PDR), the late clinical stage of the disease. CTGF is a secreted protein that modulates the actions of many growth factors and extracellular matrix (ECM) proteins, leading to tissue reorganization, such as ECM formation and remodeling, basal lamina (BL) thickening, pericyte apoptosis, angiogenesis, wound healing and fibrosis. In PCDR, CTGF contributes to thickening of the retinal capillary BL and is involved in loss of pericytes. In this stage, CTGF expression is induced by advanced glycation end products, and by growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta. In PDR, the switch from neovascularization to a fibrotic phase - the angio-fibrotic switch - in PDR is driven by CTGF, in a critical balance with vascular endothelial growth factor (VEGF). We discuss here the roles of CTGF in the pathogenesis of DR in relation to ECM remodeling and wound healing mechanisms, and explore whether CTGF may be a potential novel therapeutic target in the clinical management of early as well as late stages of DR. PMID- 25819455 TI - Extracellular matrix, gap junctions, and retinal vascular homeostasis in diabetic retinopathy. AB - The vascular basement membrane (BM) contains extracellular matrix (ECM) proteins that assemble in a highly organized manner to form a supportive substratum for cell attachment facilitating myriad functions that are vital to cell survival and overall retinal homeostasis. The BM provides a microenvironment in which bidirectional signaling through integrins regulates cell attachment, turnover, and functionality. In diabetic retinopathy, the BM undergoes profound structural and functional changes, and recent studies have brought to light the implications of such changes. Thickened vascular BM in the retinal capillaries actively participate in the development and progression of characteristic changes associated with diabetic retinopathy. High glucose (HG)-induced compromised cell cell communication via gap junctions (GJ) in retinal vascular cells may disrupt homeostasis in the retinal microenvironment. In this review, the role of altered ECM synthesis, compromised GJ activity, and disturbed retinal homeostasis in the development of retinal vascular lesions in diabetic retinopathy are discussed. PMID- 25819454 TI - Mechanical interactions and crosstalk between corneal keratocytes and the extracellular matrix. AB - The generation of cellular forces and the application of these physical forces to the ECM play a central role in mediating matrix patterning and remodeling during fundamental processes such as developmental morphogenesis and wound healing. In addition to growth factors and other biochemical factors that can modulate the keratocyte mechanical phenotype, another key player in the regulation of cell induced ECM patterning is the mechanical state of the ECM itself. In this review we provide an overview of the biochemical and biophysical factors regulating the mechanical interactions between corneal keratocytes and the stromal ECM at the cellular level. We first provide an overview of how Rho GTPases regulate the sub cellular pattern of force generation by corneal keratocytes, and the impact these forces have on the surrounding ECM. We next review how feedback from local matrix structural and mechanical properties can modulate keratocyte phenotype and mechanical activity. Throughout this review, we provide examples of how these biophysical interactions may contribute to clinical outcomes, with a focus on corneal wound healing. PMID- 25819456 TI - Regulation of corneal stroma extracellular matrix assembly. AB - The transparent cornea is the major refractive element of the eye. A finely controlled assembly of the stromal extracellular matrix is critical to corneal function, as well as in establishing the appropriate mechanical stability required to maintain corneal shape and curvature. In the stroma, homogeneous, small diameter collagen fibrils, regularly packed with a highly ordered hierarchical organization, are essential for function. This review focuses on corneal stroma assembly and the regulation of collagen fibrillogenesis. Corneal collagen fibrillogenesis involves multiple molecules interacting in sequential steps, as well as interactions between keratocytes and stroma matrix components. The stroma has the highest collagen V:I ratio in the body. Collagen V regulates the nucleation of protofibril assembly, thus controlling the number of fibrils and assembly of smaller diameter fibrils in the stroma. The corneal stroma is also enriched in small leucine-rich proteoglycans (SLRPs) that cooperate in a temporal and spatial manner to regulate linear and lateral collagen fibril growth. In addition, the fibril-associated collagens (FACITs) such as collagen XII and collagen XIV have roles in the regulation of fibril packing and inter lamellar interactions. A communicating keratocyte network contributes to the overall and long-range regulation of stromal extracellular matrix assembly, by creating micro-domains where the sequential steps in stromal matrix assembly are controlled. Keratocytes control the synthesis of extracellular matrix components, which interact with the keratocytes dynamically to coordinate the regulatory steps into a cohesive process. Mutations or deficiencies in stromal regulatory molecules result in altered interactions and deficiencies in both transparency and refraction, leading to corneal stroma pathobiology such as stromal dystrophies, cornea plana and keratoconus. PMID- 25819457 TI - From nano to macro: studying the hierarchical structure of the corneal extracellular matrix. AB - In this review, we discuss current methods for studying ocular extracellular matrix (ECM) assembly from the 'nano' to the 'macro' levels of hierarchical organization. Since collagen is the major structural protein in the eye, providing mechanical strength and controlling ocular shape, the methods presented focus on understanding the molecular assembly of collagen at the nanometre level using X-ray scattering through to the millimetre to centimetre level using non linear optical (NLO) imaging of second harmonic generated (SHG) signals. Three dimensional analysis of ECM structure is also discussed, including electron tomography, serial block face scanning electron microscopy (SBF-SEM) and digital image reconstruction. Techniques to detect non-collagenous structural components of the ECM are also presented, and these include immunoelectron microscopy and staining with cationic dyes. Together, these various approaches are providing new insights into the structural blueprint of the ocular ECM, and in particular that of the cornea, which impacts upon our current understanding of the control of corneal shape, pathogenic mechanisms underlying ectatic disorders of the cornea and the potential for corneal tissue engineering. PMID- 25819458 TI - The dynamic sclera: extracellular matrix remodeling in normal ocular growth and myopia development. AB - Myopia is a common ocular condition, characterized by excessive elongation of the ocular globe. The prevalence of myopia continues to increase, particularly among highly educated groups, now exceeding 80% in some groups. In parallel with the increased prevalence of myopia, are increases in associated blinding ocular conditions including glaucoma, retinal detachment and macular degeneration, making myopia a significant global health concern. The elongation of the eye is closely related to the biomechanical properties of the sclera, which in turn are largely dependent on the composition of the scleral extracellular matrix. Therefore an understanding of the cellular and extracellular events involved in the regulation of scleral growth and remodeling during childhood and young adulthood will provide future avenues for the treatment of myopia and its associated ocular complications. PMID- 25819461 TI - Primary defects in lipolysis and insulin action in skeletal muscle cells from type 2 diabetic individuals. AB - A decrease in skeletal muscle lipolysis and hormone sensitive-lipase (HSL) expression has been linked to insulin resistance in obesity. The purpose of this study was to identify potential intrinsic defects in lipid turnover and lipolysis in myotubes established from obese and type 2 diabetic subjects. Lipid trafficking and lipolysis were measured by pulse-chase assay with radiolabeled substrates in myotubes from non-obese/non-diabetic (lean), obese/non-diabetic (obese) and obese/diabetic (T2D) subjects. Lipolytic protein content and level of Akt phosphorylation were measured by Western blot. HSL was overexpressed by adenovirus-mediated gene delivery. Myotubes established from obese and T2D subjects had lower lipolysis (-30-40%) when compared to lean, using oleic acid as precursor. Similar observations were also seen for labelled glycerol. Incorporation of oleic acid into diacylglycerol (DAG) and free fatty acid (FFA) level was lower in T2D myotubes, and acetate incorporation into FFA and complex lipids was also lower in obese and/or T2D subjects. Both protein expression of HSL (but not ATGL) and changes in DAG during lipolysis were markedly lower in cells from obese and T2D when compared to lean subjects. Insulin-stimulated glycogen synthesis (-60%) and Akt phosphorylation (-90%) were lower in myotubes from T2D, however, overexpression of HSL in T2D myotubes did not rescue the diabetic phenotype. In conclusion, intrinsic defects in lipolysis and HSL expression co-exist with reduced insulin action in myotubes from obese T2D subjects. Despite reductions in intramyocellular lipolysis and HSL expression, overexpression of HSL did not rescue defects in insulin action in skeletal myotubes from obese T2D subjects. PMID- 25819460 TI - Role of tyrosine-sulfated proteins in retinal structure and function. AB - The extracellular matrix (ECM) plays a significant role in cellular and retinal health. The study of retinal tyrosine-sulfated proteins is an important first step toward understanding the role of ECM in retinal health and diseases. These secreted proteins are members of the retinal ECM. Tyrosine sulfation was shown to be necessary for the development of proper retinal structure and function. The importance of tyrosine sulfation is further demonstrated by the evolutionary presence of tyrosylprotein sulfotransferases, enzymes that catalyze proteins' tyrosine sulfation, and the compensatory abilities of these enzymes. Research has identified four tyrosine-sulfated retinal proteins: fibulin 2, vitronectin, complement factor H (CFH), and opticin. Vitronectin and CFH regulate the activation of the complement system and are involved in the etiology of some cases of age-related macular degeneration. Analysis of the role of tyrosine sulfation in fibulin function showed that sulfation influences the protein's ability to regulate growth and migration. Although opticin was recently shown to exhibit anti-angiogenic properties, it is not yet determined what role sulfation plays in that function. Future studies focusing on identifying all of the tyrosine-sulfated retinal proteins would be instrumental in determining the impact of sulfation on retinal protein function in retinal homeostasis and diseases. PMID- 25819459 TI - Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma. AB - The trabecular meshwork (TM) is located in the anterior segment of the eye and is responsible for regulating the outflow of aqueous humor. Increased resistance to aqueous outflow causes intraocular pressure to increase, which is the primary risk factor for glaucoma. TM cells reside on a series of fenestrated beams and sheets through which the aqueous humor flows to exit the anterior chamber via Schlemm's canal. The outer trabecular cells are phagocytic and are thought to function as a pre-filter. However, most of the outflow resistance is thought to be from the extracellular matrix (ECM) of the juxtacanalicular region, the deepest portion of the TM, and from the inner wall basement membrane of Schlemm's canal. It is becoming increasingly evident that the extracellular milieu is important in maintaining the integrity of the TM. In glaucoma, not only have ultrastructural changes been observed in the ECM of the TM, and a significant number of mutations in ECM genes been noted, but the stiffness of glaucomatous TM appears to be greater than that of normal tissue. Additionally, TGFbeta2 has been found to be elevated in the aqueous humor of glaucoma patients and is assumed to be involved in ECM changes deep with the juxtacanalicular region of the TM. This review summarizes the current literature on trabecular ECM as well as the development and function of the TM. Animal models and organ culture models targeting specific ECM molecules to investigate the mechanisms of glaucoma are described. Finally, the growing number of mutations that have been identified in ECM genes and genes that modulate ECM in humans with glaucoma are documented. PMID- 25819462 TI - Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of concept study. AB - AIM: The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. METHODS: This was a randomized, double blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 30(0/7) and 35(6/7) weeks' gestation with an uncomplicated singleton pregnancy in an in patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety. RESULTS: Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups. CONCLUSIONS: Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile. PMID- 25819463 TI - A systematic review of the relationship between postpartum sleep disturbance and postpartum depression. AB - OBJECTIVE: To examine the relationship between postpartum sleep disturbance and postpartum depression and describe the characteristics and demographics of the samples. DATA SOURCES: Electronic databases Medline, PubMed, Cochrane, EPOC, CINAHL, ProQuest, and Psych INFO. In addition, hand searches of bibliographies supplemented the electronic search. STUDY SELECTION: English language primary studies on the relationship between postpartum sleep disturbance and postpartum depression were included. Thirteen observational studies met the inclusion criteria. DATA EXTRACTION: Data that specified the relationship between sleep disturbance and postpartum depression were extracted from the studies. The data were organized per author, year, participants, setting, country, demographics, design, sample size, outcomes, evidence, and effect size. DATA SYNTHESIS: The effect size indicating the relationship between sleep disturbance and postpartum depression across the studies ranged between 0.4 and 1.7. There was evidence of a strong relationship between sleep disturbance and postpartum depression; however, the participants in the 13 studies were predominantly educated, middle class, older than age 30 years, and White. Likewise, the definition and measurement of postpartum sleep varied across the studies, which increased the possibility of bias. CONCLUSIONS: Further research within the postpartum period involving underserved, younger women and samples with more diversity in race and ethnicity are needed. PMID- 25819464 TI - Hybrid encapsulation structures based on beta-carotene-loaded nanoliposomes within electrospun fibers. AB - Hybrid encapsulation structures based on beta-carotene-loaded nanoliposomes incorporated within the polymeric ultrathin fibers produced through electrospinning were developed to improve the photostability of the antioxidant. These novel materials were intended to incorporate beta-carotene into water-based food formulations, overcoming the existing limitations associated with its hydrophobic character. Initially, both empty and antioxidant-loaded nanoliposomes were developed and incorporated into polyvinyl alcohol (PVOH) and polyethylene oxide (PEO) solutions. The changes in the solution properties were evaluated to determine their effects on the electrospinning processing. The mixed polymer solutions were subsequently electrospun to produce hybrid nanoliposome-loaded ultrathin fibers. FTIR analysis confirmed the presence of phospholipid molecules inside the electrospun fibers. These ultrathin fibers were evaluated regarding their morphology, diameter, internal beta-carotene distribution and stability against UV irradiation. Liposomal release studies from the electrospun fibers were also undertaken, confirming the presence of the liposomal structures after dissolving the electrospun fibers in water. PMID- 25819465 TI - Restructuring fundamental predator-prey models by recognising prey-dependent conversion efficiency and mortality rates. AB - Incorporating protozoa into population models (from simple predator-prey explorations to complex food web simulations) is of conceptual, ecological, and economic importance. From theoretical and empirical perspectives, we expose unappreciated complexity in the traditional predator-prey model structure and provide a parsimonious solution, especially for protistologists. We focus on how prey abundance alters two key components of models: predator conversion efficiency (e, the proportion of prey converted to predator, before mortality loss) and predator mortality (delta, the portion of the population lost though death). Using a well-established model system (Paramecium and Didinium), we collect data to parameterize a range of existing and novel population models that differ in the functional forms of e and delta. We then compare model simulations to an empirically obtained time-series of predator-prey population dynamics. The analysis indicates that prey-dependent e and delta should be considered when structuring population models and that both prey and predator biomass also vary with prey abundance. Both of these impact the ability of the model to predict population dynamics and, therefore, should be included in theoretical model evaluations and assessment of ecosystem dynamics associated with biomass flux. PMID- 25819466 TI - Ultrasound Imaging for Analyzing Lateral Tongue Movements during Mastication in Adults with Cerebral Palsy Compared with Adults without Oral Motor Disabilities. AB - Described here is an ultrasound technique used to study tongue movements, particularly lateral tongue movements, during mastication. A method to analyze spatial and temporal tongue movements was developed, and the feasibility of using this method was evaluated. Biplane ultrasound images of tongue movements of four adults without oral motor disability and two adults with oral motor disability as a result of cerebral palsy, were acquired. Tongue movements were analyzed in the coronal and sagittal planes using B-mode and M-mode ultrasonography. Inter-rater and intra-rater agreement for manual tracing of tongue contours was good (ICC = 0.81 and 0.84, respectively). There were significant differences between the two adult groups in movement frequency in the horizontal direction in both coronal and sagittal planes. In the coronal plane, differences in movement frequency and range of vertical movement were detected. Data obtained from sagittal images, with the exception of vertical frequency, indicated no differences between the groups. The protocol developed in this study (using B-mode and M-mode) proved to be valid and reliable. By using this protocol with individuals with and without oral motor disability, we were able to illustrate the clinical application of our protocol to evaluation of differences in tongue movements during mastication. PMID- 25819467 TI - Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual Frequency "Acoustic Angiography" Imaging. AB - Early-stage tumors in many cancers are characterized by vascular remodeling, indicative of transformations in cell function. We have previously presented a high-resolution ultrasound imaging approach to detecting these changes that is based on microbubble contrast agents. In this technique, images are formed from only the higher harmonics of microbubble contrast agents, producing images of vasculature alone with 100- to 200-MUm resolution. In this study, shaped transmit pulses were used to image the higher broadband harmonic echoes of microbubble contrast agents, and the effects of varying pulse window and phasing on microbubble and tissue harmonic echoes were evaluated using a dual-frequency transducer in vitro and in vivo. An increase in the contrast-to-tissue ratio of 6.8 +/- 2.3 dB was observed in vitro using an inverted pulse with a cosine window relative to a non-inverted pulse with a rectangular window. The increase in mean image intensity resulting from contrast enhancement in vivo in five rodents was 13.9 +/- 3.0 dB greater for an inverted cosine-windowed pulse and 17.8 +/- 3.6 dB greater for a non-inverted Gaussian-windowed pulse relative to a non-inverted pulse with a rectangular window. Implications for pre-clinical and diagnostic imaging are discussed. PMID- 25819468 TI - Guiding and controlling percutaneous pancreas biopsies with contrast-enhanced ultrasound: target lesions are not localized on B-mode ultrasound. AB - The aim of the study described here was to prospectively investigate the clinical and practical value of percutaneous contrast-enhanced ultrasound (CEUS)-guided biopsy of pancreatic lesions that are not definitively localized by B-mode ultrasound (US). Fifty-three patients underwent CEUS-guided biopsy. The rate of satisfactory percutaneous biopsy was 96.23% (51/53) with a median number of puncture attempts per patient of 3.0, and the diagnostic accuracy in satisfactory sampling was 96.08% (49/51). The sensitivity of CEUS-guided biopsy in diagnosing malignancy was 90.48% (38/42). There was only one major complication in our study, a patient (1/51, 1.96%) with biliary peritonitis. For pancreatic lesions that are not definitively localized by B-mode US, puncture guided by CEUS could improve accuracy, lower the incidence of complications and avoid unnecessary biopsy. PMID- 25819469 TI - Nitric Oxide-Enhanced Molecular Imaging of Atheroma using Vascular Cellular Adhesion Molecule 1-Targeted Echogenic Immunoliposomes. AB - The aim of this study was to determine whether pre-treatment with nitric oxide loaded echogenic liposomes (NO-ELIP) plus ultrasound can improve highlighting by molecularly targeted (anti-vascular cell adhesion molecule 1 [VCAM-1]) ELIP of atheroma components. Atherosclerotic animals were treated with anti-VCAM-1-ELIP or immunoglobulin (IgG)-ELIP. Each group was selected at random to receive pre treatment with standard ELIP plus ultrasound, NO-ELIP without ultrasound and NO ELIP plus ultrasound. Intravascular ultrasound highlighting data for the same arterial segments were collected before and after treatment. Pre-treatment with NO-ELIP plus ultrasound resulted in a significant increase in acoustic enhancement by anti-VCAM-1-ELIP (21.3 +/- 1.5% for gray-scale value, 53.9 +/- 3.1% for radiofrequency data; p < 0.001 vs. IgG-ELIP, p < 0.05 vs. pre-treatment with standard ELIP plus ultrasound or NO-ELIP without ultrasound). NO-ELIP plus ultrasound can improve highlighting of atheroma by anti-VCAM-1 ELIP. This NO pre treatment strategy may be useful in optimizing contrast agent delivery to the vascular wall for both diagnostic and therapeutic applications. PMID- 25819470 TI - The evaluation of bone metabolism in children with renal transplantation. AB - This study aims to evaluate BMD and bone biomarkers and to investigate the effects of immunosuppressives on bone disease after RTx. Thirty-three RTR aged 16.7 +/- 3.7 yr and healthy controls (n = 32) were enrolled. There was no difference between pre-RTx BMD and BMD at the time of study (45.9 +/- 30.9 months after RTx), while both values were lower than controls (p < 0.01 and p < 0.05, respectively). Worst BMD scores were obtained at sixth month after RTx (-0.2 +/- 0.9) and best at fourth year (1.4 +/- 1.3). 25-hydroxy-(OH) vitamin D and OPG were higher in RTR (p < 0.001). BMD z scores negatively correlated with OPG and cumulative CS doses at the time of study (r = -0.344, p < 0.05 and r = -0.371, p < 0.05, respectively). Regression analysis revealed OPG as the only predictor of BMD (beta -0.78, 95% CI -0.004 to -0.013, p < 0.001). The increase in OPG, a significant predictor of BMD, could either be secondary to graft dysfunction or for protection against bone loss. CS doses should be minimized to avoid their untoward effects on bone metabolism. PMID- 25819471 TI - A New Preparation Method for Anisotropic Silk Fibroin Nerve Guidance Conduits and Its Evaluation In Vitro and in a Rat Sciatic Nerve Defect Model. AB - Over the past decade, silk fibroin (SF) has been emergently used in peripheral nerve tissue engineering. Current approaches aiming at producing SF-based nerve guidance conduits (SF-NGCs) used dissolved silk based on either aqueous solutions or organic solvents. In this study, we describe a novel procedure to produce SF NGCs: A braided tubular structure of raw Bombyx mori silk is subsequently processed with the ternary solvent CaCl2/H2O/ethanol, formic acid, and methanol to improve its mechanical and topographical characteristics. Topographically, the combination of the treatments results in a fusion of the outer single silk fibers to a closed layer with a thickness ranging from about 40 to 75 MUm. In contrast to the outer wall, the inner lumen (not treated with processing solvents) still represents the braided structure of single fibers. Mechanical stability, elasticity, and kink characteristics were evaluated with a custom-made test system. The modification procedure described here drastically improved the elastic properties of our tubular raw scaffold, favoring its use as a NGC. A cell migration assay with NIH/3T3-fibroblasts revealed the impermeability of the SF NGC wall for possible invading and scar-forming cells. Moreover, the potential of the SF-NGC to serve as a substratum for Schwann cells has been demonstrated by cytotoxicity tests and live-dead stainings of Schwann cells grown on the inner surface of the SF-NGC. In vivo, the SF-NGC was tested in a rat sciatic nerve injury model. In short-term in vivo studies, it was proved that SF-NGCs are not triggering host inflammatory reactions. After 12 weeks, we could demonstrate morphological and functional reinnervation of the distal targets. Filled with collagen, a higher number of axons could be found in the distal to the graft (1678+/-303), compared with the empty SF-NGC (1274+/-146). The novel SF-NGC presented here shows promising results for the treatment of peripheral nerve injuries. The modification of braided structures to adapt their mechanical and topographical characteristics may support the translation of SF-based scaffolds into the clinical setting. However, further improvements and the use of extracellular matrix molecules and Schwann cells are suggested to enable silk tube based conduits to bridge long-distance nerve gaps. PMID- 25819472 TI - Quantitative analysis by GC-MS/MS of 18 aroma compounds related to oxidative off flavor in wines. AB - A quantitation method for 18 aroma compounds reported to contribute to "oxidative" flavor in wines was developed. The method allows quantitation of the (E)-2-alkenals ((E)-2-hexenal, (E)-2-heptenal, (E)-2-octenal, and (E)-2-nonenal), various Strecker aldehydes (methional, 2-phenylacetaldehyde, 3-methylbutanal, and 2-methylpropanal), aldehydes (furfural, 5-methylfurfural, hexanal, and benzaldehyde), furans (sotolon, furaneol, and homofuraneol), as well as alcohols (methionol, eugenol, and maltol) in the same analysis. The aldehydes were determined after derivatization directly in the wine with O-(2,3,4,5,6 pentafluorobenzyl)hydroxylamine hydrochloride; the formed oximes along with the underivatized aroma compounds were isolated by solid-phase extraction and analyzed by means of GC-MS/MS. The method was used to investigate the effect of different closures (synthetic closures, natural corks, and screw cap) on the formation of oxidation-related compounds in 14 year old white wine. Results showed a significant increase in the concentration of some of the monitored compounds in the wine, particularly methional, 2-phenylacetaldehyde, and 3 methylbutanal. PMID- 25819473 TI - Artificial Pancreas Project at Cambridge 2013. AB - The development and clinical testing of closed-loop systems (the artificial pancreas) is underpinned by advances in continuous glucose monitoring and benefits from concerted academic and industry collaborative efforts. This review describes the progress of the Artificial Pancreas Project at the University of Cambridge from 2006 to 2014. Initial studies under controlled laboratory conditions, designed to collect representative safety and performance data, were followed by short to medium free-living unsupervised outpatient studies demonstrating the safety and efficacy of closed-loop insulin delivery using a model predictive control algorithm. Accompanying investigations included assessment of the psychosocial impact and key factors affecting glucose control such as insulin kinetics and glucose absorption. Translation to other disease conditions such as critical illness and Type 2 diabetes took place. It is concluded that innovation of iteratively enhanced closed-loop systems will provide tangible means to improve outcomes and quality of life in people with Type 1 diabetes and their families in the next decade. PMID- 25819474 TI - Investigation of a Novel PLGA/CaP Scaffold in the Healing of Tooth Extraction Sockets to Alveolar Bone Preservation in Humans. AB - BACKGROUND: It is expected that 40% to 60% of initial alveolar bone volume will be lost up to 6 months after tooth extraction. OsteoScaf(TM) (TRT, Toronto, ON, Canada) (poly (DL-lactide-co-glycololide/calcium phosphate [PLGA/CaP] scaffold) is a novel bone substitute material and represents a promising alternative for maintaining alveolar bone integrity in this clinical scenario. PURPOSE: Here it was hypothesized that OsteoScaf would reduce alveolar bone lost after tooth extraction in patient, acting as a clot-retention device. MATERIAL AND METHODS: A total of 10 patients (32 sockets) were included in the study, of which 16 sockets were grafted with OsteoScaf and 16 were used as control (coagulum alone). Cone beam computed tomography (CBCT) was performed both immediately following extraction and also at 120 days postoperatively, at which time biopsy samples were also harvested for histological analyses. RESULTS: Quantitative analysis of CBCT showed less bone resorption in the OsteoScaf groups, being 10.5% to 14.4% less bone lost in the center of the socket, 15.4% in the buccal region, and 12.6% in the palatal. Qualitative histological analysis showed new bone tissue in direct apposition to the scaffold - demonstrating its osteoconductive nature. CONCLUSION: OsteoScaf diminished the expected bone lost during the postextraction remodeling of the alveolar bone ridge at 120 days postextraction. PMID- 25819475 TI - The bold and the fearless among us: elevated psychopathic traits and levels of anxiety and fear are associated with specific aberrant driving behaviors. AB - In spite of the well-documented connection between personality traits like impulsivity, sensation seeking and fearlessness with aberrant driving behaviors, scarce research exists to examine the association between risky and aggressive driving and psychopathic characteristics, which encompass the above traits. The present investigation examines in two studies the association between specific sub-types of driving misconduct, i.e., unintentional mistakes and deliberate rule violations with psychopathic characteristics, with a focus on the role of levels of fear and anxiety in aberrant driving. Findings support the hypotheses that fearlessness, i.e., the bold, unemotional aspect of psychopathic traits, characterizes drivers who engage in frequent deliberate driving code violations, whereas the more impulsive/antisocial aspect of psychopathy, associated with higher levels of fear and anxiety, is more characteristic of drivers who engage in unintentional mistakes. Fearless features are also associated with higher self reported driving misconduct and accidents. Study 2 conceptually replicated this finding by showing that mistakes are positively related to high sensitivity to punishment, while violations are negatively related to it. Findings are discussed in light of psychopathy theory and in relation to prevention and intervention. PMID- 25819476 TI - The effects of changes in the traffic scene during overtaking. AB - Overtaking maneuvers were studied in real traffic, by comparing cases where a change in the opposite traffic occurred during the overtaking maneuver i.e., appearance of an oncoming car, with cases where no change occurred during the maneuver i.e., either an already apparent oncoming car or no oncoming car. In total 45 naturally occurring cases of overtaking were analysed. By examining the time headways (TH) between the overtaking car and the other cars involved, at the end of the maneuver, a significant correlation was found between the TH to opposite traffic and the TH rear to the overtaken car. In cases where a change in the opposite traffic occurred and the proximity to opposite traffic was below a critical TH (<4s) the appearance of a new-oncoming car caused the overtakers to actively press, both longitudinally and laterally, close to the overtaken car. In cases of overtaking where no change in the opposite traffic occurred, the TH rear to the overtaking vehicle was unaffected by the TH to the opposite traffic. Interestingly, in comparing cases where an oncoming car appeared during overtaking with cases where an oncoming car was apparent from the start of the maneuver both the TH to the opposite traffic and the duration of the maneuver were not found to be significantly different. It is suggested that drivers were probably expecting to be confronted with an oncoming car during the overtaking. However, the decreased available time to disambiguate this situation leads the overtaking driver to limit the rear safety margin of the vehicle being overtaken. The appropriateness of this practice, in terms of safety, remains questionable. PMID- 25819477 TI - Prediction at long-term condyle screw fixation of temporomandibular joint implant: A numerical study. AB - The fixation of commercial temporomandibular joint (TMJ) implant is accomplished by using screws, which, in some cases, can lead to loosening of the implant. The aim of this study was to predict the evolution of fixation success of a TMJ. Numerical models using a Christensen TMJ implant were developed to analyze strain distributions in the adjacent mandibular bone. The geometry of a human mandible was developed based on computed tomography (CT) scans from a cadaveric mandible on which a TMJ implant was subsequently placed. In this study, the five most important muscle forces acting were applied and the anatomical conditions replicated. The evolution of fixation was defined according to bone response methodology focused in strain distribution around the screws. Strain and micromotions were analyzed to evaluate implant stability, and the evolution process conduct at three different stages: start with all nine screws in place (initial stage); middle stage, with three screws removed (middle stage), and end stage, with only three screws in place (final stage). With regard to loosening, the implant success fixation changed the strains in the bone between 21% and 30%, when considering the last stage. The most important screw positions were #1, #7, and #9. It was observed that, despite the commercial Christensen TMJ implant providing nine screw positions for fixation, only three screws were necessary to ensure implant stability and fixation success. PMID- 25819478 TI - Why physicians do not initiate dual therapy as recommended by AACE guidelines: A survey of clinicians in the United States. AB - AIMS: The American Association of Clinical Endocrinologists (AACE) recommends initiating dual therapy with antihyperglycemic agents in untreated patients with type 2 diabetes mellitus and HbA1c between 7.6% (60 mmol/mol) and 9.0% (75 mmol/mol). In practice physicians do not always follow guidelines. This study assessed why physicians do not prescribe dual therapy when treating eligible patients. METHODS: 1235 primary care physicians (PCPs) and 290 specialists in the United States reviewed medical charts for 5995 patients whose HbA1c was between 7.6% (60 mmol/mol) and 9.0% (75 mmol/mol) at diagnosis and were being treated with metformin monotherapy. In an online survey physicians rated the relevance of 22 reasons for not initiating dual therapy using a 5-point Likert scale. Relevant reasons were compared between PCPs vs. specialists, and younger vs. older patients, using multivariate general linear regression and mixed-effect models. RESULTS: Four relevant reasons for not following AACE guidelines were physician related: (1) "Metformin monotherapy is sufficient to improve glycemic control"; (2) "Monotherapy is easier to handle than dual therapy"; (3) "I believe that monotherapy and changes in lifestyle are enough for hyperglycemia control"; and (4) "I recommend monotherapy before considering dual therapy." One relevant reason was patient-related: (5) "Patient has mild hyperglycemia." Regression analysis demonstrated that PCPs rated each physician-related reason as significantly more relevant than specialists. Three physician-related reasons were significantly more relevant for younger patients than older patients. CONCLUSIONS: Physicians do not follow AACE guidelines due to physicians' beliefs toward therapy and the perception of mild hyperglycemia in patients. PMID- 25819479 TI - Two patients with HNF4A-related congenital hyperinsulinism and renal tubular dysfunction: A clinical variation which includes transient hepatic dysfunction. AB - The HNF4A p.R76W mutation causes congenital hyperinsulinism with Fanconi syndrome. Here, we report two cases who also presented with increased urinary calcium excretion and one had a transient hepatic dysfunction with hepatomegaly. Clinical variations including transient liver dysfunction is a likely mutation specific clinical characteristic. PMID- 25819480 TI - Causal and bidirectional linkages over time between depression and diabetes regimen distress in adults with type 2 diabetes. AB - AIMS: Diabetes regimen distress (RD) and depression are related constructs, however the nature of their relationship has not been explored over time, leading to difficulties differentiating between RD and depression and for selection of programs of care. We examined longitudinal associations between RD and depression to explicate the direction and mechanism of operation between these two constructs. METHODS: 392 adults with type 2 diabetes participated in a randomized control trial (RCT) to reduce diabetes distress. Participants were assessed for RD and depression symptoms, using the PHQ-8, at baseline, and at 4 and 12 months. Latent growth curve models tested both predictive unidirectional and bidirectional longitudinal associations between changes in RD and depression. RESULTS: Changes in RD did not significantly predict changes in PHQ-8, nor did changes in PHQ-8 predict changes in RD. A significant bidirectional association was found (Coefficient Estimate=.081, p=.001), where decreases in RD were associated with decreases in PHQ-8. The association was strongest among those with high baseline RD or PHQ-8 scores. CONCLUSIONS: In the context of an RCT to reduce distress, support was found for a covarying association, in which changes in RD and depression symptoms occurred in tandem over time. No support was found for a causative association. Findings point to RD and depression containing properties that may be related to a shared underlying dimension of emotional distress. Results suggest consideration of both RD and depression in clinical decision making, with interventions selected based on source of distress. PMID- 25819481 TI - Assessment of a screening protocol for type 2 diabetes in community pharmacy. The DiabNow Study. AB - The aim of this study was to assess the performance and feasibility of a protocol for screening type 2 diabetes in community pharmacy. Performance was primarily assessed by measuring stakeholders' adherence (pharmacists, patients and physicians) to the protocol's components. PMID- 25819482 TI - Stuart Lipton: UFOs and flying tigers. PMID- 25819483 TI - Brain CT signs and the effect of alteplase after stroke. PMID- 25819485 TI - Introductory paragraph. PMID- 25819486 TI - Imaging regional lung function: a critical tool for developing inhaled antimicrobial therapies. AB - Alterations in regional lung function due to respiratory infection have a significant effect on the deposition of inhaled treatments. This has consequences for treatment effectiveness and hence recovery of lung function. In order to advance our understanding of respiratory infection and inhaled treatment delivery, we must develop imaging techniques that can provide regional functional measurements of the lung. In this review, we explore the role of functional imaging for the assessment of respiratory infection and development of inhaled treatments. We describe established and emerging functional lung imaging methods. The effect of infection on lung function is described, and the link between regional disease, function, and inhaled treatments is discussed. The potential for lung function imaging to provide unique insights into the functional consequences of infection, and its treatment, is also discussed. PMID- 25819484 TI - Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial. AB - BACKGROUND: Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase. METHODS: IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0.9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0-2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518. FINDINGS: 3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0.66, 95% CI 0.55-0.81), large lesion (0.51, 0.38 0.68), swelling (0.59, 0.46-0.75), hyperattenuated artery (0.59, 0.47-0.75), atrophy (0.74, 0.59-0.94), and leukoaraiosis (0.72, 0.59-0.87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1.72, 95% CI 1.18-2.51), tissue hypoattenuation (1.54, 1.04-2.27), and hyperattenuated artery (1.54, 1.03-2.29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13.8%, 95% CI 6.9-20.7; both signs absent, excess 3.2%, 1.4-5.1). However, no imaging findings-individually or combined-modified the effect of alteplase on independence or symptomatic intracranial haemorrhage. INTERPRETATION: Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke. FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders. PMID- 25819487 TI - In vitro, in silico and integrated strategies for the estimation of plasma protein binding. A review. AB - Plasma protein binding (PPB) strongly affects drug distribution and pharmacokinetic behavior with consequences in overall pharmacological action. Extended plasma protein binding may be associated with drug safety issues and several adverse effects, like low clearance, low brain penetration, drug-drug interactions, loss of efficacy, while influencing the fate of enantiomers and diastereoisomers by stereoselective binding within the body. Therefore in holistic drug design approaches, where ADME(T) properties are considered in parallel with target affinity, considerable efforts are focused in early estimation of PPB mainly in regard to human serum albumin (HSA), which is the most abundant and most important plasma protein. The second critical serum protein alpha1-acid glycoprotein (AGP), although often underscored, plays also an important and complicated role in clinical therapy and thus the last years it has been studied thoroughly too. In the present review, after an overview of the principles of HSA and AGP binding as well as the structure topology of the proteins, the current trends and perspectives in the field of PPB predictions are presented and discussed considering both HSA and AGP binding. Since however for the latter protein systematic studies have started only the last years, the review focuses mainly to HSA. One part of the review highlights the challenge to develop rapid techniques for HSA and AGP binding simulation and their performance in assessment of PPB. The second part focuses on in silico approaches to predict HSA and AGP binding, analyzing and evaluating structure-based and ligand-based methods, as well as combination of both methods in the aim to exploit the different information and overcome the limitations of each individual approach. Ligand-based methods use the Quantitative Structure-Activity Relationships (QSAR) methodology to establish quantitate models for the prediction of binding constants from molecular descriptors, while they provide only indirect information on binding mechanism. Efforts for the establishment of global models, automated workflows and web-based platforms for PPB predictions are presented and discussed. Structure-based methods relying on the crystal structures of drug protein complexes provide detailed information on the underlying mechanism but are usually restricted to specific compounds. They are useful to identify the specific binding site while they may be important in investigating drug-drug interactions, related to PPB. Moreover, chemometrics or structure-based modeling may be supported by experimental data a promising integrated alternative strategy for ADME(T) properties optimization. In the case of PPB the use of molecular modeling combined with bioanalytical techniques is frequently used for the investigation of AGP binding. PMID- 25819488 TI - An adverse reaction to intravenously administered marbofloxacin in a dog during general anaesthesia. PMID- 25819489 TI - Development and application of a fluorescent glucose uptake assay for the high throughput screening of non-glycoside SGLT2 inhibitors. AB - Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are of current interest as a treatment for type 2 diabetes. Efforts have been made to discover phlorizin-related glycosides with good SGLT2 inhibitory activity. To increase structural diversity and better understand the role of non-glycoside SGLT2 inhibitors on glycemic control, we initiated a research program to identify non glycoside hits from high-throughput screening. Here, we report the development of a novel, fluorogenic probe-based glucose uptake system based on a Cu(I)-catalyzed [3+2] cycloaddition. The safer processes and cheaper substances made the developed assay our first priority for large-scale primary screening as compared to the well-known [(14)C]-labeled alpha-methyl-D-glucopyranoside ([(14)C]-AMG) radioactive assay. This effort culminated in the identification of a benzimidazole, non-glycoside SGLT2 hit with an EC50 value of 0.62 MUM by high throughput screening of 41,000 compounds. PMID- 25819491 TI - Open access? Yes! But how? PMID- 25819490 TI - WHO/ISH total risk approach for primary prevention of cardiovascular disease shows greater decrease in costs for women but not the elderly in Jamaica. AB - OBJECTIVES: To investigate cost savings from and implications of replacing the single risk with a total cardiovascular risk approach in primary prevention of cardiovascular disease (CVD). STUDY DESIGN AND SETTING: A cost analysis using data from the 2007-08 Jamaica Health and Lifestyle Survey of 1,432 persons aged 40 years and older with 10-year risk estimated from region-specific World Health Organization/International Society for Hypertension (WHO/ISH) CVD risk charts. The WHO/ISH and local treatment guidelines were used to cost lifestyle changes, medications, and provider visits. RESULTS: Use of the total cardiovascular risk approach was less costly regardless of age. Women showed greater cost disparity. However, if 10-year CVD risk was estimated without measured cholesterol, both approaches resulted in similar costs in men >=60 years. The annual per capita cost of lifestyle recommendations, critical in the absence of pharmacotherapy, was estimated at US $869.05 for diet and US $80 for physical activity. This represents about a third of the annual income of a minimum wage earner. At the national level, implementation of the WHO/ISH total risk approach could reduce health care costs by US $5 million annually. CONCLUSION: Cost savings that mainly resulted from reduced care for women may lead to gender disparity in CVD outcomes. PMID- 25819497 TI - Congenital intra-oral adhesions: a surgical approach to cleft palate lateral synechia syndrome. AB - An array of genetic syndromes has been associated with intra-oral adhesions in neonates. The primary medical issues arise from airway obstruction, feeding difficulties and poor oral development, specifically with cleft palate lateral synechia syndrome (CPLSS). Despite this, a paucity of data exists for the clinical management of intra-oral adhesions in this population. We report the cases of a father and daughter diagnosed with CPLSS who presented with respiratory and feeding difficulties at birth undergoing surgical correction. Early surgical ligation of intra-oral bands allows for a stabilization of the airway, improved feeding and oral development with a good long-term outcome. PMID- 25819496 TI - Cortical cross-modal plasticity following deafness measured using functional near infrared spectroscopy. AB - Evidence from functional neuroimaging studies suggests that the auditory cortex can become more responsive to visual and somatosensory stimulation following deafness, and that this occurs predominately in the right hemisphere. Extensive cross-modal plasticity in prospective cochlear implant recipients is correlated with poor speech outcomes following implantation, highlighting the potential impact of central auditory plasticity on subsequent aural rehabilitation. Conversely, the effects of hearing restoration with a cochlear implant on cortical plasticity are less well understood, since the use of most neuroimaging techniques in CI recipients is either unsafe or problematic due to the electromagnetic artefacts generated by CI stimulation. Additionally, techniques such as functional magnetic resonance imaging (fMRI) are confounded by acoustic noise produced by the scanner that will be perceived more by hearing than by deaf individuals. Subsequently it is conceivable that auditory responses to acoustic noise produced by the MR scanner may mask auditory cortical responses to non auditory stimulation, and render inter-group comparisons less significant. Uniquely, functional near-infrared spectroscopy (fNIRS) is a silent neuroimaging technique that is non-invasive and completely unaffected by the presence of a CI. Here, we used fNIRS to study temporal-lobe responses to auditory, visual and somatosensory stimuli in thirty profoundly-deaf participants and thirty normally hearing controls. Compared with silence, acoustic noise stimuli elicited a significant group fNIRS response in the temporal region of normally-hearing individuals, which was not seen in profoundly-deaf participants. Visual motion elicited a larger group response within the right temporal lobe of profoundly deaf participants, compared with normally-hearing controls. However, bilateral temporal lobe fNIRS activation to somatosensory stimulation was comparable in both groups. Using fNIRS these results confirm that auditory deprivation is associated with cross-modal plasticity of visual inputs to auditory cortex. Although we found no evidence for plasticity of somatosensory inputs, it is possible that our recordings may have included activation of somatosensory cortex that masked any group differences in auditory cortical responses due to the limited spatial resolution associated with fNIRS. PMID- 25819498 TI - Onabotulinum toxin injection for parotid fistula treatment in a case of recurrent parotitis complicated with abscess formation. PMID- 25819499 TI - Influence of the physicochemical properties of inorganic supports on the activity of immobilized bacteria for water denitrification. AB - The denitrification of polluted water was studied by using supported E-coli bacteria. The physicochemical characteristics of supports and the influence of these properties on the bacteria performance were analyzed. Inorganic supports oxides and zeolites were selected in order to cover a wide range of porosity and surface chemical properties and the denitrification process systematically studied. Consecutive denitrification cycles in batch experiments and the toxicity of supports were also analyzed. The acidity of supports provokes a slower reduction processes, favoring also a high concentration of intermediate nitrites in solution for longer periods. The NO3(-) reduction is faster than the NO2(-) one, being also less influenced by the support characteristics. Anyway, the total denitrification is reached in all cases. The best performance was obtained with bacteria supported on mesoporous and non-acid silica support. PMID- 25819501 TI - High salt intake negatively impacts ovarian follicle development. AB - Many human disorders induce high salinity in tissues and organs, interfering with their normal physiological functions. Using a mouse model, we demonstrated that high salt intake caused infertility. Specifically, we established that high salinity dramatically affects ovarian follicle development and the extent of follicular atresia. However, it did not significantly influence the primordial follicles. TUNEL assays revealed that high salt intake inhibited follicle development by inducing the granulosa and theca cells that surround the oocytes to undergo apoptosis. Furthermore, immunohistological staining for the proliferation markers Ki67 and PH3 showed that high salt intake also repressed granulosa cell proliferation. In vitro testing of granulosa cells also confirmed that high salt significantly repressed cell proliferation and promoted cell apoptosis. In summary, high salt consumption negatively impacts reproductive functions in female mice by interfering with ovarian folliculogenesis. PMID- 25819500 TI - Elevated Hippocampal Cholinergic Neurostimulating Peptide precursor protein (HCNP pp) mRNA in the amygdala in major depression. AB - The amygdala is innervated by the cholinergic system and is involved in major depressive disorder (MDD). Evidence suggests a hyper-activate cholinergic system in MDD. Hippocampal Cholinergic Neurostimulating Peptide (HCNP) regulates acetylcholine synthesis. The aim of the present work was to investigate expression levels of HCNP-precursor protein (HCNP-pp) mRNA and other cholinergic related genes in the postmortem amygdala of MDD patients and matched controls (females: N = 16 pairs; males: N = 12 pairs), and in the mouse unpredictable chronic mild stress (UCMS) model that induced elevated anxiety-/depressive-like behaviors (females: N = 6 pairs; males: N = 6 pairs). Results indicate an up regulation of HCNP-pp mRNA in the amygdala of women with MDD (p < 0.0001), but not males, and of UCMS-exposed mice (males and females; p = 0.037). HCNP-pp protein levels were investigated in the human female cohort, but no difference was found. There were no differences in gene expression of acetylcholinesterase (AChE), muscarinic (mAChRs) or nicotinic receptors (nAChRs) between MDD subjects and controls or UCMS and control mice, except for an up-regulation of AChE in UCMS-exposed mice (males and females; p = 0.044). Exploratory analyses revealed a baseline expression difference of cholinergic signaling-related genes between women and men (p < 0.0001). In conclusion, elevated amygdala HCNP-pp expression may contribute to mechanisms of MDD in women, potentially independently from regulating the cholinergic system. The differential expression of genes between women and men could also contribute to the increased vulnerability of females to develop MDD. PMID- 25819502 TI - Influence of gender and time diet exposure on endocrine pancreas remodeling in response to high fat diet-induced metabolic disturbances in mice. AB - In this study, we investigated a possible sexual dimorphism regarding metabolic response and structural and functional adaptations of the endocrine pancreas after exposure to a high-fat diet (HFd). On chow diet, male and female C57BL/6/JUnib mice showed similar metabolic and morphometric parameters, except that female islets displayed a relatively lower beta-cell:non-beta-cell ratio. After 30 days on HFd, both male and female mice showed increased weight gain, however only the males displayed glucose intolerance associated with high postprandial glycemia when compared to their controls. After 60 days on HFd, both genders became obese, hyperglycemic, hyperinsulinemic, insulin resistant and glucose intolerant, although the metabolic changes were more pronounced in males, while females displayed greater weight gain. In both genders, insulin resistance induced by HFd feeding was compensated by expansion of beta-cell mass without changes in islet cytoarchitecture. Interestingly, we found a strong correlation between the degree of beta-cell expansion and the levels of hyperglycemia in the fed state: male mice fed a 60d-HFd, showing higher glycemic levels also displayed a greater beta-cell mass increase in comparison with female mice. Additionally, sexual dimorphism was also observed regarding the source of beta-cell mass expansion following 60d-HFd: while in males, both hypertrophy and hyperplasia (revealed by morphometry and Ki67 immunoreaction) of beta-cells were observed, female islets displayed only a significant increase in beta-cell size. In conclusion, this study describes gender differences in metabolic response to high fat diet, paralleled by distinct compensatory morphometric changes in pancreatic islets. PMID- 25819503 TI - Weight loss: indication of brain damage and effect of combined normobaric oxygen and ethanol therapy after stroke. AB - BACKGROUND AND PURPOSE: Weight loss is commonly seen after stroke. However, there is paucity of data that objectively examines the relationship between weight loss and infarction. We have used two unique models of middle cerebral artery (MCA) occlusion in rats to determine if weight loss can be used as indicator for severity of brain damage and for beneficial effects of stroke therapy. METHODS: Sprague-Dawley rats underwent MCA occlusion using the rat intraluminal filament or auto-thrombus stroke models. Reperfusion was established at different intervals by removing the intraluminal filament or injecting r-tPA, followed by treatment with either ethanol (EtOH), normobaric oxygen (NBO), NBO plus EtOH or no treatment. The extent of brain injury was determined using infarct volume and motor performance. RESULTS: The intraluminal filament ischaemic model demonstrated a significant positive correlation between weight loss and infarct volume size after acute stroke, as well as compared to infarct volumes post treatment with NBO, EtOH and NBO plus EtOH. There was also a positive significant correlation between weight loss and infarct volume size in the thromboembolism ischaemic model with or without treatment. Furthermore a positive correlation was observed between weight loss and deficit score in both ischaemic models. DISCUSSION: Degree of weight loss after stroke is largely associated with severity of infarction as well as damage reduction after treatment administration. PMID- 25819508 TI - Large local reactions to insect stings. AB - Large local reactions (LLRs) are IgE-mediated late-phase inflammatory reactions that can cause great morbidity but are associated with a relatively low risk of future anaphylaxis. Patients with LLR may benefit from consultation with an allergist to help clarify the relative risk, to plan the best treatment for future stings, and to determine whether or not to pursue testing or venom immunotherapy (VIT). The chance of anaphylaxis to future stings is <5%, so VIT is not generally recommended to people who have had LLR. Whether to prescribe an epinephrine injector is often determined by the frequency of exposure, the proximity to medical care, and the impact on quality of life. For people who have unavoidable exposure and need treatment almost every year for LLR, VIT can be recommended with confidence that it will significantly and safely reduce the severity of LLR to stings. PMID- 25819509 TI - Safety of infliximab for the treatment of inflammatory bowel disease: current understanding of the potential for serious adverse events. AB - INTRODUCTION: Infliximab , a chimeric monoclonal antibody directed towards TNF alpha, has revolutionized the treatment of inflammatory bowel disease (IBD). Since this therapy suppresses the immune system by neutralizing the immunological activity of TNF, concerns exist regarding the potential for infection, malignancy and immune disorders. AREAS COVERED: Comprehensive data from randomized controlled trials, meta-analyses and cohort studies have defined the risk of infection and malignancy with infliximab. Additional data regarding associations with immune disorders, such as drug-induced lupus, demyelinating syndromes and psoriaform skin disease have emerged, primarily from case reports. We report evidence from the most robust data sources that have examined these adverse events. EXPERT OPINION: A modest increase in the incidence of serious infection with infliximab and TNF-antagonists has been observed in methodologically rigorous studies. Combination therapy with an immunosuppressant does not confer a higher risk of serious infection than infliximab monotherapy. TNF-antagonist therapy alone with an immunosuppressant is not associated with higher rates of malignancy. Additional data are required to define causality, the magnitude and determinants of risk for other immune-related complications. Available data suggest the therapeutic index of infliximab is favorable for treatment of moderate-to-severe IBD. PMID- 25819510 TI - Habitat fragmentation in coastal southern California disrupts genetic connectivity in the cactus wren (Campylorhynchus brunneicapillus). AB - Achieving long-term persistence of species in urbanized landscapes requires characterizing population genetic structure to understand and manage the effects of anthropogenic disturbance on connectivity. Urbanization over the past century in coastal southern California has caused both precipitous loss of coastal sage scrub habitat and declines in populations of the cactus wren (Campylorhynchus brunneicapillus). Using 22 microsatellite loci, we found that remnant cactus wren aggregations in coastal southern California comprised 20 populations based on strict exact tests for population differentiation, and 12 genetic clusters with hierarchical Bayesian clustering analyses. Genetic structure patterns largely mirrored underlying habitat availability, with cluster and population boundaries coinciding with fragmentation caused primarily by urbanization. Using a habitat model we developed, we detected stronger associations between habitat-based distances and genetic distances than Euclidean geographic distance. Within populations, we detected a positive association between available local habitat and allelic richness and a negative association with relatedness. Isolation-by distance patterns varied over the study area, which we attribute to temporal differences in anthropogenic landscape development. We also found that genetic bottleneck signals were associated with wildfire frequency. These results indicate that habitat fragmentation and alterations have reduced genetic connectivity and diversity of cactus wren populations in coastal southern California. Management efforts focused on improving connectivity among remaining populations may help to ensure population persistence. PMID- 25819511 TI - Midwives' comprehension of care for women with intellectual disability during pregnancy and childbirth: An open-ended questionnaire study in Sweden. AB - BACKGROUND: Few studies have investigated midwifery care for women with intellectual disability (ID). AIM: To gain a deeper understanding of midwives' comprehension of care for women with ID during pregnancy and childbirth. METHODS: A cross-sectional study among 375 midwives at antenatal clinics and delivery wards in Sweden. Findings 2476 quotations were sorted into six categories: information; communication and approach; the role of the midwife; preparing for and performing interventions and examinations; methods and assessments; and organisation of care. The midwives affirmed that individual, clear and repeated information together with practical and emotional support was important for women with ID. The midwives planned the care as to strengthen the capacity of the women, open doors for the unborn child and reinforce the process of becoming a mother. Extra time could be needed. They tried to minimise interventions. The midwives felt a dual responsibility, to support the mother-child contact but also to assess and identify any deficits in the caring capacity of the mother and to involve other professionals if needed. CONCLUSIONS: The midwives described specially adapted organisation of care, models of information, practical education and emotional support to facilitate the transition to motherhood for women with ID. They have a dual role and responsibility in supporting the woman, while making sure the child is properly cared for. Healthcare services should offer a safe and trusted environment to enable such midwifery care. When foster care is planned, the society should inform and co-operate with midwives in the care of these women. PMID- 25819512 TI - Functional discomfort and a shift in midwifery paradigm. AB - OBJECTIVE: To determine and critically examine maternity attitudes surrounding labour pain and how midwives can best facilitate women navigating intrapartum discomfort without relying on 'pain-relief' strategies or immediate recourse for analgesic assistance. APPROACH: This article examines current literature using seminal research and wider international perspectives, exploring the complex and fluctuating needs of women negotiating the composite factors of labour discomfort are investigated. FINDINGS: Factors such as birth environment, fear, midwifery presence, and self-efficacy, have a significant impact on the uptake of intrapartum analgesia. A holistic view of intrapartum discomfort is needed to shift the current paradigm of pathologising labour pain into one which situates it as a source of positive physiology and functional discomfort. CONCLUSION: Continuing to practice with a pharmacological outlook, aiming to rid the labouring body of discomfort, is reductionist for both midwives and women. Midwives must seek to employ a new lexicon with which to communicate and facilitate women within the dynamic and continually changing territory of labour. If this conceptual shift is realised, the subsequent positive sequalae of women rediscovering their innate birthing capabilities could create a situation where birth can be considered as an aesthetic peak experience, improving satisfaction on both sides of the midwife-mother diad. PMID- 25819514 TI - Our challenge to industry and to each other. PMID- 25819513 TI - Outcomes of covered expandable stents for the treatment of TASC D aorto-iliac occlusive lesions. AB - INTRODUCTION: Aortoiliac arterial occlusive disease is frequently encountered in the management of lower limb vascular insufficiency. We report our experience with covered balloon-expandable stents for treatment of TASC D lesions of the abdominal aorta and common iliac arteries. METHODS: A retrospective study of 30 patients who underwent aortoiliac stenting with the Atrium Advanta V12 from March 2010 to September 2012 was conducted. Patient demographic data, clinical signs and symptoms and procedural details were recorded. Outcomes assessed were primary patency, secondary patency, technical success, complications, limb salvage and survival. RESULTS: Median age was 67 years (range 48-84) and 40% of patients underwent treatment for critical limb ischaemia. Median follow-up was 13 months (range 3-38 months). Stent configuration comprised of long iliac stents in 20 patients, a large diameter aortic stent with iliac stenting in six patients, and aortic stent alone in four patients. Radiological success was achieved in 100% and the complication rate was 6%. Primary patency at 6, 12 and 24 months was 97%, 90% and 79%, respectively. Four cases of in-stent stenosis were reported, with three of these undergoing re-interventions resulting in a secondary patency rate of 97% at the end of follow-up. One patient death occurred within the follow-up period. DISCUSSION: This case series demonstrates that treatment of complex aortoiliac occlusive disease with covered balloon-expandable stents can have acceptable results with good patency and good clinical outcome. Secondary patency rates are comparable to open surgical revascularisation, with lower morbidity. PMID- 25819515 TI - Celebrate national workplace wellness week using the worksite wellness toolkit. PMID- 25819516 TI - Global food practices, cultural competency, and dietetics: part 2. PMID- 25819517 TI - 2015 academy member benefits update. PMID- 25819518 TI - Position of the Academy of Nutrition and Dietetics: nutrition services for individuals with intellectual and developmental disabilities and special health care needs. AB - It is the position of the Academy of Nutrition and Dietetics that nutrition services provided by registered dietitian nutritionists (RDNs) and nutrition and dietetics technicians, registered (NDTRs), who work under RDN supervision, are essential components of comprehensive care for adults with intellectual and developmental disabilities (IDD) and children and youth with special health care needs (CYSHCN). Nutrition services should be provided throughout life in a manner that is interdisciplinary, family-centered, community based, and culturally competent. Individuals with IDD and CYSHCN have many risk factors requiring nutrition interventions, including growth alterations (eg, failure to thrive, obesity, or growth retardation), metabolic disorders, poor feeding skills, drug nutrient interactions, and sometimes partial or total dependence on enteral or parenteral nutrition. Furthermore, these individuals are also more likely to develop comorbid conditions, such as obesity or endocrine disorders that require nutrition interventions. Poor nutrition-related health habits, limited access to services, and long-term use of multiple medications are considered health risk factors. Timely and cost-effective nutrition interventions can promote health maintenance and reduce risk and cost of comorbidities and complications. Public policy for individuals with IDD and CYSHCN has evolved, resulting in a transition from institutional facilities and programs to community and independent living. The expansion of public access to technology and health information on the Internet challenges RDNs and NDTRs to provide accurate scientific information to this rapidly growing and evolving population. RDNs and NDTRs with expertise in this area are best prepared to provide appropriate nutrition information to promote wellness and improve quality of life. PMID- 25819519 TI - Academy of Nutrition and Dietetics: standards of practice and standards of professional performance for registered dietitian nutritionists (competent, proficient, and expert) in adult weight management. AB - Weight management encompasses the inter-relationship of nutrition, physical activity, and health behavior change. Nutrition is key for the prevention and treatment of obesity and chronic disease and maintenance of overall health. Thus, the Weight Management Dietetic Practice Group, with guidance from the Academy of Nutrition and Dietetics Quality Management Committee, has developed Standards of Practice and Standards of Professional Performance for Registered Dietitian Nutritionists (RDNs) in Adult Weight Management as a resource for RDNs working in weight management. This document allows RDNs to assess their current skill levels and to identify areas for further professional development in this expanding practice area. This document describes the current standards for weight management practice for RDNs. The Standards of Practice represent the four steps in the Nutrition Care Process as applied to the care of patients/clients. The Standards of Professional Performance consist of six domains of professionalism: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Within each standard, specific indicators provide measurable action statements that illustrate how the standard can be applied to practice. The indicators describe three skill levels (competent, proficient, and expert) for RDNs working in weight management. The Standards of Practice and Standards of Professional Performance are complementary resources for the Registered Dietitian Nutritionist in weight management. PMID- 25819520 TI - Developing an advanced practice credential for registered dietitian nutritionists in clinical nutrition practice. PMID- 25819521 TI - Report from the advanced-level clinical practice audit task force of the commission on dietetic registration: results of the 2013 advanced-level clinical practice audit. PMID- 25819523 TI - Adjusted or ideal body weight for nutrition assessment? PMID- 25819524 TI - Galectin expression in cancer diagnosis and prognosis: A systematic review. AB - Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients. PMID- 25819525 TI - Comparison of Direct Side-to-End and End-to-End Hypoglossal-Facial Anastomosis for Facial Nerve Repair. AB - BACKGROUND: The hypoglossal facial anastomosis (HFA) is the gold standard for facial reanimation in patients with severe facial nerve palsy. The major drawbacks of the classic HFA technique are lingual morbidities due to hypoglossal nerve transection. The side-to-end HFA is a modification of the classic technique with fewer tongue-related morbidities. OBJECTIVES: In this study we compared the outcome of the classic end-to-end and the direct side-to-end HFA surgeries performed at our center in regards to the facial reanimation success rate and tongue-related morbidities. METHODS: Twenty-six successive cases of HFA were enrolled. In 9 of them end-to-end anastomoses were performed, and 17 had direct side-to-end anastomoses. The House-Brackmann (HB) and Pitty and Tator (PT) scales were used to document surgical outcome. The hemiglossal atrophy, swallowing, and hypoglossal nerve function were assessed at follow-up. RESULTS: The original pathology was vestibular schwannoma in 15, meningioma in 4, brain stem glioma in 4, and other pathologies in 3. The mean interval between facial palsy and HFA was 18 months (range: 0-60). The median follow-up period was 20 months. The PT grade at follow-up was worse in patients with a longer interval from facial palsy and HFA (P value: 0.041). The lesion type was the only other factor that affected PT grade (the best results in vestibular schwannoma and the worst in the other pathologies group, P value: 0.038). The recovery period for facial tonicity was longer in patients with radiation therapy before HFA (13.5 vs. 8.5 months) and those with a longer than 2-year interval from facial palsy to HFA (13.5 vs. 8.5 months). Although no significant difference between the side-to-end and the end to-end groups was seen in terms of facial nerve functional recovery, patients from the side-to-end group had a significantly lower rate of lingual morbidities (tongue hemiatrophy: 100% vs. 5.8%, swallowing difficulty: 55% vs. 11.7%, speech disorder 33% vs. 0%). CONCLUSION: With the side-to-end HFA technique the functional restoration outcome is at least as good as that following the classic end-to-end HFA, but the complications related to the complete hypoglossal nerve transection can be avoided. Best results are achieved if this procedure is performed within the first 2 years after facial nerve injury. Patients with facial palsy of longer duration also have the chance for good functional restoration after HFA. PMID- 25819526 TI - Persistent Outpatient Hypertension Is Independently Associated with Spinal Cord Dysfunction and Imaging Characteristics of Spinal Cord Damage among Patients with Cervical Spondylosis. AB - OBJECTIVE: Hypertension and cervical spondylosis are diseases of the adult population that are approaching near pandemic proportions. However, the interactions between these two disease processes are poorly understood. We set out to determine the associations among systemic hypertension, clinical status, and imaging findings of spinal cord damage for patients with cervical stenosis. METHODS: A retrospective chart review was performed on patients with symptomatic cervical stenosis related to degenerative disease and divided on the basis of outpatient blood pressure control (normal <140/<90 mm Hg). Sagittal T2-weighted magnetic resonance imaging (MRI) of the cervical spine was analyzed to determine the degree of maximal canal stenosis (MCS; %), surface area of increased signal intensity (ISI; cm(2)), and signal intensity ratio (SIR). Functional status was evaluated using the modified Japanese Orthopaedic Association (mJOA) scale and the Nurick scale. RESULTS: One hundred twenty-two patients were identified (64 hypertensive, 58 nonhypertensive). Likelihood of ISI was higher in hypertensive patients (P < 0.05). Average ISI was significantly higher in patients with uncontrolled blood pressure (P = 0.02) despite MCS being identical between the two groups. The mJOA and Nurick scores were worse for patients with systemic hypertension (P < 0.02). Diabetes mellitus and smoking history did not affect these findings. CONCLUSIONS: Persistent hypertension in outpatients is associated with worsened clinical status and increased markers of spinal cord damage on MRI. Perioperative management of blood pressure may serve to improve clinical outcomes. Larger prospective trials are necessary to further validate these findings. PMID- 25819527 TI - Cerebral Angiography for Multimodal Surgical Planning in Epilepsy Surgery: Description of a New Three-Dimensional Technique and Literature Review. AB - OBJECTIVE: Cerebrovascular imaging is critical for safe and accurate planning of Stereo-ElectroEncephaloGraphy (SEEG) electrode trajectory. We developed a new technique for Cone Beam Computed Tomography (CBCT) Three-Dimensional Digital Subtraction Angiography (3D DSA). METHODS: The workflow core is the acquisition of computed tomography datasets without (bone mask) and with selective injection of contrast medium in the main brain-feeding arteries, followed by dataset registration and subtraction. The images were acquired with the O-armTM 1000 System (Medtronic). Images were postprocessed with FSL software package. We retrospectively analyzed 191 3D DSA procedures and qualitatively analyzed the quality of each 3D DSA dataset. RESULTS: The quality of 3D DSA was good in 150 procedures, sufficient in 37, and poor in 4. 3D rendering of the vascular tree was helpful for both SEEG implantation and resective surgery planning. Angiography complications occurred in only one procedure that was aborted due to a major allergic reaction to contrast medium. No other complications directly related to 3D DSA occurred. Minor intracerebral hemorrhage occurred in 2/191 patients after SEEG implantation, with no permanent sequelae. CONCLUSIONS: CBCT 3D DSA is a safe diagnostic procedure for SEEG electrode trajectory planning and for 3D reconstructions of the vascular tree in multimodal scenes for resections. The high fidelity and geometric accuracy contribute to the safety of electrode implantation. PMID- 25819528 TI - Simple Accuracy Enhancing Techniques in Neuronavigation. AB - BACKGROUND: Neuronavigation is an essential tool in cranial neurosurgery. Despite continuing improvements in the technologies used for neuronavigation, certain events can lead to unacceptable mismatches. To provide the best possible outcome for the patients, surgeons need to do everything possible to reduce mismatches. METHODS AND RESULTS: Some simple techniques can greatly improve neuronavigation accuracy and patient safety. We describe two simple methods that were developed or refined in the Department of Neurosurgery at Inselspital, Bern, Switzerland: the transdermal navigation landmark and use of bone screws for co-registration. CONCLUSIONS: Both techniques are easy to use, do not require expensive additional instruments, and are helpful in procedures involving neuronavigation. PMID- 25819529 TI - Osteointegration in Custom-made Porous Hydroxyapatite Cranial Implants: From Reconstructive Surgery to Regenerative Medicine. AB - BACKGROUND: Custom-made porous hydroxyapatite (HA) implant (Fin-Ceramica Faenza S.p.A., Italy) is a biomimetic, osteoconductive material. Margin fusion at the bone-implant edge, cell proliferation within implant pores, and osteointegration in an animal model have already been described. CASE DESCRIPTION: Radiological, microtomographical, and histological analyses were performed on two patients who underwent surgical explantation of cranial implants after postoperative complication. Primary devices explanted after 2 years showed areas of newly formed bone strictly osteointegrated with pores of the prosthesis. These prostheses showed a focal zone of resorption in correspondence of the newly formed bone, and no signs of inflammation or cytotoxicity were observed. A back up prosthesis, explanted from the same patient after 6 months because of an infection, did not show presence of newly formed bone both on the surface and in the internal part of the prosthesis. CONCLUSIONS: Custom-made porous HA implant is an osteoconductive material able to promote osteogenesis, osteointegrate with bone tissue, provide an effective cranial reconstruction, and restore functional features of the skull. However, complete bone healing is still a complex and long process. PMID- 25819530 TI - Acetaldehyde production capacity of salivary microflora in alcoholics during early recovery. AB - This study investigated whether a relationship exists between the acetaldehyde production capacity of salivary microflora (sAPC) in recovering alcoholics, and craving, and/or resumption of drinking within 12 weeks after embarking on an abstinence-based treatment program. Serial sAPC measurements were determined by gas chromatography on spontaneous saliva samples of 30 male alcoholics on days 2, 4, 11, and 18 during a 21-day in-patient treatment program. Craving was measured simultaneously with the Penn Alcohol Craving Scale. Outcome over 12 weeks was assessed by telephone interviews. There was no significant change in sAPC values from day 2 to day 18, while craving scores decreased markedly between day 2 to day 4. Sixteen participants remained abstinent for the full 12 weeks. Statistically significant differences were found between the sAPC values of the group that remained abstinent and the group that resumed drinking within 12 weeks. The highest sAPC value measured on day 2 had a strong predictive value for maintained abstinence at 12 weeks for beer-only drinkers or drinkers consuming less than 320 g of alcohol per week. The study is the first investigation into a potential relationship between the acetaldehyde production capacity of salivary microflora and early resumption of drinking in recovering alcoholics. The findings suggest that such a relationship indeed exists for beer-only drinkers, possibly linked to lower alcohol intake, and that it is unrelated to withdrawal craving. sAPC is proposed as a candidate biomarker with diagnostic and/or prognostic potential. PMID- 25819531 TI - Replacing Insulin Glargine with Neutral Protamine Hagedorn (NPH) Insulin in a Subpopulation of Study Subjects in the Action to Control Cardiovascular Risk in Diabetes (ACCORD): Effects on Blood Glucose Levels, Hypoglycemia and Patient Satisfaction. AB - OBJECTIVE: To ensure patient safety when replacing insulin glargine (IG) with neutral protamine Hagedorn (NPH) insulin and to determine differences in blood glucose control, frequency of hypoglycemia, insulin dosing, health resource utilization and quality of life between users of IG and NPH insulin. METHODS: A single-site, open-label, randomized, 6-month comparative study of 66 patients from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Randomization was 1:1 to receive IG or NPH insulin. Data regarding blood glucose control, insulin dosage adjustment and recording of hypoglycemia episodes were obtained through telephone calls; office visits were conducted to measure weight, glycated hemoglobin, fasting plasma glucose and blood glucose profile. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) was used to measure patients' satisfaction with their diabetes treatment. RESULTS: Rates of symptomatic hypoglycemia did not differ significantly between groups: 37.5+/-2.2 for the IG group and 31.1+/-2.1 for the NPH group. However, patients treated with NPH insulin had higher frequencies of severe hypoglycemia (6.1+/-0.9) compared with 2.7+/-0.6 for the IG group. A significant difference in changes in glycated hemoglobin (A1C) was observed between the groups: the mean +/- standard error A1C decreases from baseline were -0.34%+/-0.11 for the IG group, vs -0.01%+/-0.10 for the NPH insulin group. The data obtained from the DTSQ showed greater treatment satisfaction in the IG group compared with the NPH insulin group. CONCLUSIONS: Switching from IG to NPH insulin resulted in more than double the rate of severe hypoglycemias and led to decreased metabolic control. Greater treatment satisfaction was observed with IG, compared with NPH insulin, as measured by change from baseline in the DTSQ scores. PMID- 25819532 TI - Supernatants from stored red blood cell (RBC) units, but not RBC-derived microvesicles, suppress monocyte function in vitro. AB - BACKGROUND: We have previously shown that critically ill children transfused with red blood cells (RBCs) of longer storage durations have more suppressed monocyte function after transfusion compared to children transfused with fresher RBCs and that older stored RBCs directly suppress monocyte function in vitro, through unknown mechanisms. We hypothesized that RBC-derived microvesicles (MVs) were responsible for monocyte suppression. STUDY DESIGN AND METHODS: To determine the role of stored RBC unit-derived MVs, we cocultured monocytes with supernatants, isolated MVs, or supernatants that had been depleted of MVs from prestorage leukoreduced RBCs that had been stored for either 7 or 30 days. Isolated MVs were characterized by electron microscopy and flow cytometry. Monocyte function after coculture experiments was measured by cytokine production after stimulation with lipopolysaccharide (LPS). RESULTS: Monocyte function was suppressed after exposure to supernatants from 30-day RBC units compared to monocytes cultured in medium alone (LPS-induced tumor necrosis factor-alpha production, 17,611 +/- 3,426 vs. 37,486 +/- 5,598 pg/mL; p = 0.02). Monocyte function was not suppressed after exposure to MV fractions. RBC supernatants that had been depleted of MVs remained immunosuppressive. Treating RBC supernatants with heat followed by RNase (to degrade protein-bound RNA) prevented RBC supernatant-induced monocyte suppression. CONCLUSION: Our findings implicate soluble mediators of stored RBC induced monocyte suppression outside of MV fractions and suggest that extracellular protein-bound RNAs (such as microRNA) may play a role in transfusion-related immunomodulation. PMID- 25819533 TI - Tattoo of vascular cannulation site as a self-cannulation aid. AB - BACKGROUND: Haemodialysis can be provided either in a healthcare setting or home environment. Patients receiving dialysis at home report a better quality of life. Patients or their carers must be able to cannulate their fistula confidently and independently when dialysing at home. METHOD: We describe a patient with a functional fistula which was difficult to palpate, leading to difficulties in cannulation and multiple referrals to the home therapies team. PROCEDURE: A series of discrete dots were tattooed to delineate the borders of the fistula and served to guide cannulation. RESULTS: Following this simple intervention, our patient was able to self-cannulate confidently, dialysing at home four times per week. There were no further referrals to the home therapies team. CONCLUSION: Permanent tattoo of the skin to guide cannulation can used when a fistula is difficult to palpate or if a further superficialisation procedure is not desired. Patients have to be made aware that the markings are permanent and might outlast the fistula. PMID- 25819534 TI - [Assessment of anesthesiologist intervention during cataract surgery under topical anesthesia]. AB - OBJECTIVES: The current demographic situation in France regarding anesthesiologists calls for a reconsideration of anesthesia management for patients undergoing cataract surgery under topical anesthesia. This prospective observational study aimed to assess the requirement for anesthesiologist intervention during cataract surgery performed under topical anesthesia. PATIENTS AND METHODS: Patients operated between November 2, 2011 and July 31, 2012 were included after indication of topical anesthesia for phacoemulsification proposed by the surgeon and confirmed by the anesthesiologist. Each patient was premedicated. All patients were monitored and supervised during the surgery by a nurse anesthesiologist. An anesthesiologist could be called at any time at the request of the surgeon or nurse anesthesiologist. For each patient, medical histories were recorded as well as the event "anesthesiologist called", along with the reason and the treatment performed. RESULTS: Five hundred and seventy five phacoemulsifications were performed in 486 patients. The event "anesthesiologist called" was recorded 20 times: 18 times for hypertension, once for anxiety and once for non-emergent conversion to general anesthesia after a surgical complication. Each episode of hypertension was successfully treated by following the nicardipine protocol. Preoperatively uncontrolled hypertension was the only significant predictive risk factor for anesthesiologist requirement. CONCLUSIONS: These results question the usefulness of preoperative anesthesia consultation for all patients who underwent phacoemulsification under topical anesthesia, since this consultation does not lead to an anesthesiologist service. Intraoperative medical complications may be treated according to medical protocols developed jointly by surgeons and anesthesiologists. This practice may free up anesthesiologists' time, without compromising patient safety. PMID- 25819535 TI - [Classification of vitreomacular adhesion and macular holes]. AB - BACKGROUND: Optical coherence tomography has significantly changed the approach to vitreomacular diseases, including macular holes (MH). OCT provides information on differential diagnoses (lamellar hole, pseudo-hole), the MH size, the status of the vitreous, and the status of the various retinal layers. The evolution of diagnostic tools and treatment justifies the need for an update of the current classification of vitreomacular diseases. METHOD: A group of retina specialists met several times to discuss the international classification, recently published by The International Vitreomacular Traction Study Group, focusing on vitreomacular adhesion (VMA), vitreomacular traction (VMT) and MH. It was compared to the classification currently used in France, based on the ophthalmoscopic system of Gass, then further delineated by Gaudric's OCT studies, in order to suggest a French adaptation to the international classification. RESULTS: An adapted classification for clinical use in France and in connection with the international classification is proposed. VMA are classified as an "associated" or "isolated" VMA respectively with or without macular disease. MH are distinguished as "primary" or "secondary" MH depending on whether the etiology is known or not, and classified as "small", "medium" and "large" depending on the size of the hole, and according to the presence or absence of VMT. Finally, VMT are described according to presence or absence of an epimacular membrane and according to the width of the adhesion. PMID- 25819536 TI - Patient delay in skin cancer: Influence of clinical characteristics and questionnaire results. PMID- 25819537 TI - Prevention of gastrointestinal events in patients on antithrombotic therapy in the peri-endoscopy period: review of new evidence and recommendations from recent guidelines. AB - Management of patients on antithrombotic therapy undergoing endoscopic procedures can be challenging. Although guidelines from major gastrointestinal endoscopy societies provide useful recommendations in this regard, data are limited concerning the bleeding risk of new complex endoscopic procedures and the management of novel anticoagulants in patients needing invasive procedures. The approach to the management of antithrombotic therapy often needs to be formulated on an individual basis, especially in patients with high thrombotic risk undergoing a high-risk endoscopic procedure. In addition to the procedure-related bleeding risk, endoscopists also need to consider the urgency of the endoscopic procedure, the thromboembolic risk of the patient if antithrombotic therapy is temporarily withheld, and the timing of discontinuation/resumption of antithrombotic therapy in the decision-making process. Diagnostic endoscopic procedures with or without biopsy can often be done without interruption of antithrombotic therapy. If possible, elective procedures with high bleeding risk should be delayed in patients on antithrombotic therapy for conditions with high thrombotic risk. If high-risk procedures cannot be delayed in these patients, thienopyridines, traditional and novel anticoagulants are usually withheld, whereas aspirin withdrawal is decided on a case by case basis. In patients with high thrombotic risk, communication with the prescribing clinician before proceeding to procedures with high bleeding risk is particularly important in optimizing the peri-procedural management plan of antithrombotic therapy. PMID- 25819538 TI - A case of sudden death after Japanese encephalitis vaccination. AB - Japanese encephalitis (JE) virus is estimated to result in 3500-50,000 clinical cases every year, with mortality rates of up to 20-50% and a high percentage of neurological sequelae in survivors. Vaccination is the single most important measure in preventing this disease. Inactivated Vero cell culture-derived JE vaccines have not been linked to any fatalities, and few serious adverse events after vaccination have been reported. Here, we report a case of sudden death in which a 10-year-old boy experienced cardiopulmonary arrest 5 min after receiving a Japanese encephalitis vaccination. He had been receiving psychotropic drugs for the treatment of pervasive developmental disorders. Postmortem examinations were nonspecific, and no signs of dermatologic or mucosal lesions or an elevation of the serum tryptase level, which are characteristic of anaphylaxis, were observed. A toxicological examination revealed that the blood concentrations of the orally administered psychotropic drugs were within the therapeutic ranges. The patient was considered to have died of an arrhythmia that was not directly associated with the vaccination. PMID- 25819539 TI - Coconut atrium in long-standing rheumatic valvular heart disease. AB - BACKGROUND: Complete calcification of the left atrium (LA) is called "coconut atrium", which decreases the compliance of LA, leading to the elevation of LA pressure that is transmitted to the right-side of the heart. The pathogenesis of LA calcification in patients with rheumatic heart disease is unknown; however, possible mechanisms include chronic strain force in the atrial wall and inflammation. We report here a patient with long-standing rheumatic valvular heart disease with coconut atrium. CASE REPORT: A 76-year-old man presented with breathlessness and leg edema due to right-sided heart failure. He was diagnosed with rheumatic fever at 8 years of age. Mitral commissurotomy and the mitral and aortic valve replacement were previously performed to treat mitral and aortic valvular stenosis. The profile view of the chest X-ray indicated a diffuse calcified outline of the LA wall. A transthoracic echocardiogram revealed pulmonary hypertension and dilatation of both atria. Moreover, computed tomography showed nearly circumferential calcification of the LA wall. Despite intense medical treatment, he succumbed to heart failure. An autopsy demonstrated that the LA was markedly dilated, its wall was calcified, and its appearance was similar to the surface of an atherosclerotic aorta. Microscopic examination revealed intensive calcification in the endocardium. Minimal accumulation of inflammatory cells was noted. Although slight fibrosis was observed, the cardiac musculature was preserved. CONCLUSIONS: To the best of our knowledge, this is the first report that identifies the histological changes of LA calcification associated with long-standing rheumatic valvular heart disease. PMID- 25819540 TI - An optimized method to process mouse CNS to simultaneously analyze neural cells and leukocytes by flow cytometry. AB - BACKGROUND: Flow cytometry is an efficient and powerful technique to characterize and quantify numerous cells. However, the strengths of this technique have not been widely harnessed in neurosciences due to the critical step of CNS tissue preparation into a single cell suspension. Previous reports assessed either neural cells or infiltrating leukocytes but simultaneous detection has not been extensively implemented. We optimized CNS tissue preparation for flow cytometry analysis. NEW METHOD: We subjected CNS tissue from individual adult mice to different digestion protocols and PercollTM methods. We quantified and characterized by flow cytometry neural cells (neurons, oligodendrocytes, microglia) and leukocytes (macrophages, T lymphocytes). RESULTS: The one step PercollTM method significantly increased cell yield compared to the gradient PercollTM method. The collagenase D+DNase I digestion led to the maximal cell number recovery while preserving cell marker (O4, NeuN, CD45, CD11b, CD3, CD4, CD8) integrity compared to papain, trypsin digestion, and no digestion. The combination of collagenase D+DNase I digestion and one step PercollTM method was optimal for the recovery and analysis of cells from the CNS of naive and experimental autoimmune encephalomyelitis (multiple sclerosis model) mice. COMPARISON WITH EXISTING METHOD(S): Although flow cytometry does not reveal CNS localization, this technique allows concurrent quantification of multiple parameters. In contrast to other protocols, our novel method simultaneously analyzes neural and immune cells in individual mice in healthy and pathological conditions. CONCLUSIONS: We strongly believe that the field of neurosciences will benefit from an optimal use of flow cytometry to elucidate physiological and pathological processes. PMID- 25819541 TI - Longitudinal measures of perfluoroalkyl substances (PFAS) in serum of Gullah African Americans in South Carolina: 2003-2013. AB - BACKGROUND: Charleston Harbor has elevated concentrations of PFAS in dolphins, but local human exposure data are limited. OBJECTIVES: We sought to describe PFAS serum concentrations' temporal trends among Gullah African American residents of coastal South Carolina. METHODS: Longitudinal measures of PFAS in blood serum from a Gullah clinical sample, without lupus, were examined using spaghetti plots and visit-to-visit change scores (e.g., differences in concentrations between visits) among the 68 participants with repeated measures available. We also modeled population-level trends among the 71 participants with any data using proportionate percentile models, accounting for clustering through robust standard errors. In a post-hoc analysis we examined heterogeneity of temporal trends by age through mixed-effects models for the log-transformed PFAS compounds. RESULTS: Population concentrations of PFOS dropped approximately 9 (95% CI: 8, 10) percent each year over 2003-2013. This was concordant with individual PFOS trajectories (median PFOS change score -21.7 ng/g wet weight, interquartile range of PFOS change scores: -32.8, -14.9) and reports for other populations over this time period. Several other compounds including PFOA, PFHxS, and PFuNDA also showed a population-level decrease. However, examination of individual trajectories suggested substantial heterogeneity. Post-hoc analyses indicated that PFAS trajectories were heterogeneous by age. CONCLUSIONS: Many PFAS compounds are decreasing in a sample of Gullah African Americans from coastal South Carolina. There may be age differences in the elimination kinetics of PFASs. The possible role of age as a modifier of PFAS serum trends merits further research. PMID- 25819542 TI - Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population. AB - BACKGROUND: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile. METHODS: We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G>C, *3A (c.460 G>A and c.719 A>G), *3B (c.460 G>A), and *3C (c.719 A>G). RESULTS: Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL. CONCLUSIONS: We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression. PMID- 25819543 TI - Expression of regulatory dendritic cell-related cytokines in cattle experimentally infected with Trypanosoma evansi. AB - Trypanosoma evansi causes wasting disease in many livestock. T. evansi infection gives rise to inflammatory immune responses, which contribute to the development of inflammation-associated tissue injury. We previously reported that regulatory dendritic cells (DCs), which act as potential regulators of inflammation, were activated in infected mice and transfer of regulatory DCs to infected mice prolonged their survival. However, the kinetics of regulatory DCs in cattle, which are natural hosts of T. evansi, remained unclear. In this study, we report that the expressions of CCL8 and IL-10, which promote the development of regulatory DCs, were up-regulated in cattle experimentally infected with T. evansi. This finding is potentially useful for studying the control strategy of T. evansi infection in cattle. PMID- 25819544 TI - Molecular characterization of Cryptosporidium parvum detected in Japanese black and Holstein calves in Iwate Prefecture and Tanegashima Island, Kagoshima Prefecture, Japan. AB - Cryptosporidium oocysts were found in 43 out of 77 calves from two farms in Iwate Prefecture and nine farms on Tanegashima Island, Kagoshima Prefecture, Japan. The DNA fragments of 18S ribosomal RNA (18S rRNA) gene were amplified by a nested PCR from 43 oocyst-positive as well as one oocyst-negative samples. All of them were precisely identified as C. parvum by analyzing the nucleotide sequences of the 18S rRNA gene. C. parvum oocyst-positive calves ranged in age from 6 to 13 days old and significantly have watery diarrhea (P<0.05). Sequences of the gene encoding the 60-kDa glycoprotein (GP60) in 43 Cryptosporidium oocyst-positive samples were identical to that of the zoonotic IIaA15G2R1 subtype. We therefore suggest that calves could be potential sources of C. parvum infections in humans. PMID- 25819545 TI - Is the Glasgow Coma Scale Score in Children in the Emergency Department Lower During the Night? AB - The body clock may, through stimulation of melatonin secretion, influence the Glasgow Coma Scale (GCS) score. The aim of this study was to investigate whether the time of presentation of children in the emergency department is associated with GCS scores. METHODS: We performed a retrospective review of 6,649 records of children presenting to an emergency department, with comparison of patients with GCS scores lower than 15 seen during the daytime and night time regarding diagnosis, disease severity, GCS score, age, sex, and ethnic group. RESULTS: Of 4,034 children seen during the daytime, 25 had GCS scores lower than 15, whereas 34 of 2,592 children seen during the night had GCS scores lower than 15 (P = .005). There were no differences in age, sex, ethnicity, or disease severity between the group of patients seen during the daytime and those seen during the night. Conditions presenting with reduced GCS scores were seizures (32%), respiratory tract infection (17%), other infections (20%), trauma (13%), and other conditions (18%). Significantly more children with respiratory tract infections and low GCS scores presented during the night (P = .029). DISCUSSION: The presentation of children with low GCS scores was more common during the night. Children with reduced GCS scores and viral respiratory tract infections presented more frequently during the night. Assessment of patients' level of consciousness during the night needs to discriminate difficulties in eliciting a response due to fatigue from features of cerebral dysfunction. PMID- 25819546 TI - Neonatal sepsis in a rapidly growing, tertiary neonatal intensive care unit: Trends over 18 years. AB - BACKGROUND: We investigated changes in the admission patterns of neonatal intensive care units and the epidemiology of neonatal sepsis following the rapid expansion and improvements in neonatal intensive care. METHODS: Data on the admission of neonates with culture-proven sepsis between 1996 and 2013 (period I, 1996-2005; period II, 2006-2013) were collected retrospectively. RESULTS: The admission of extremely low-birthweight (ELBW) infants increased between periods I and II (11.1 vs 28.7 infants per 1000 live births, P < 0.001). The survival rate of the ELBW infants improved (57.5 vs 80.1%, P < 0.001), and duration of hospital stay increased (median, 64 vs 80 days, P = 0.001). The incidence of sepsis among all infants and ELBW infants increased (all infants, 5.9 vs 12.7 cases per 1000 live births; ELBW infants, 189.5 vs 290.1 cases per 1000 live births). In ELBW infants, the incidence of sepsis caused by coagulase-negative Staphylococcus (CONS), significantly increased during period II (8.8 vs 25.4%, P = 0.039). On multivariate analysis, central vascular catheters and prolonged hospitalization were independently associated with increased sepsis rate, particularly CONS in ELBW infants. CONCLUSIONS: The inborn admission rate for ELBW infants has increased significantly and is accompanied by improved survival and longer hospital stay. The incidence of neonatal sepsis, particularly in ELBW infants, has also increased, and CONS has emerged as a major pathogen. Central vascular catheters and prolonged hospitalization could be independent risk factors for the increased sepsis rate, particularly sepsis due to CONS. PMID- 25819547 TI - Ultrafast and reversible control of the exchange interaction in Mott insulators. AB - The strongest interaction between microscopic spins in magnetic materials is the exchange interaction Jex. Therefore, ultrafast control of Jex holds the promise to control spins on ultimately fast timescales. We demonstrate that time-periodic modulation of the electronic structure by electric fields can be used to reversibly control Jex on ultrafast timescales in extended antiferromagnetic Mott insulators. In the regime of weak driving strength, we find that Jex can be enhanced and reduced for frequencies below and above the Mott gap, respectively. Moreover, for strong driving strength, even the sign of Jex can be reversed and we show that this causes time reversal of the associated quantum spin dynamics. These results suggest wide applications, not only to control magnetism in condensed matter systems, for example, via the excitation of spin resonances, but also to assess fundamental questions concerning the reversibility of the quantum many-body dynamics in cold atom systems. PMID- 25819548 TI - Characterization of bone marrow mesenchymal stromal cells in aplastic anaemia. AB - In aplastic anaemia (AA), haemopoietic activity is significantly reduced and generally attributed to failure of haemopoietic stem cells (HSC) within the bone marrow (BM). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the BM microenvironment, including mesenchymal stromal cells (MSC). MSC involvement in the functional restriction of HSC in AA is largely unknown and therefore, the physical and functional properties of AA MSC were studied in vitro. MSC were characterized by their phenotype and ability to form adherent stromal layers. The functional properties of AA MSC were assessed through proliferative, clonogenic and cross-over culture assays. Results indicate that although AA MSC presented typical morphology and distinctive mesenchymal markers, stromal formation was reduced, with 50% of BM samples failing to produce adherent layers. Furthermore, their proliferative and clonogenic capacity was markedly decreased (P = 0.03 and P = 0.04 respectively) and the ability to sustain haemopoiesis was significantly reduced, as assessed by total cell proliferation (P = 0.032 and P = 0.019 at Week 5 and 6, respectively) and clonogenic potential of HSC (P = 0.02 at Week 6). It was concluded that the biological characteristics of AA MSC are different from those of control MSC and their in vitro haemopoiesis-supporting ability is significantly reduced. PMID- 25819549 TI - Management and treatment of splenic trauma in children. AB - AIM: To assess types of splenic traumas, accompanying injuries, their management and results. METHODS: We studied the reports of 90 patients (64 boys, 26 girls) who were treated for splenic injuries as a result of blunt abdominal trauma between 2005-2012. Age, sex, hospitalization time, mechanisms of traumas, accompanying injuries and management methods were recorded. RESULTS: Causes of trauma were falls from height (46 patients, 51%), pedestrian traffic accidents (17 patients, 19%), passenger traffic accidents (11 patients, 12%), bicycle accidents (10 patients, 11%) and falling objects from height (6 patients, 6.6%). Splenic injury alone was observed in 57 patients (63.3%) and other organ injuries together with splenic injury in 33 patients (36.7%). Splenectomy was performed in six patients (6.6%) due to hemodynamic instability and small intestine repair due to small intestine injury in one patient (1.1%). None of these patients died from their injuries. CONCLUSION: A large proportion of splenic injuries recover with conservative therapy. Some of the advantages of conservative therapy include short hospitalization time, less need for blood transfusion, and less morbidity and mortality. Falls from height and traffic accidents are important factors in etiology. The possibility of other organ injuries together with splenic injuries should be considered. PMID- 25819550 TI - An ACCUMULATION AND REPLICATION OF CHLOROPLASTS 5 gene mutation confers light green peel in cucumber. AB - The peel color of fruit is an important commercial trait in cucumber, but the underlying molecular basis is largely unknown. A mutant showing light green exocarp was discovered from ethyl methane sulfonate (EMS) mutagenized cucumber line 406 with dark green exocarp. Genetic analysis showed the mutant phenotype is conferred by a single recessive gene, here designated as lgp (light green peel). By re-sequencing of bulked segregants, we identified the candidate gene Csa7G051430 encoding ACCUMULATION AND REPLICATION OF CHLOROPLASTS 5 (ARC5) that plays a vital role in chloroplast division in Arabidopsis. A single nucleotide polymorphism (SNP) causing amino acid alteration in the conserved GTPase domain of Csa7G051430 showed co-segregation with the altered phenotype. Furthermore, the transient RNA interference of this gene resulted in reduced number and enlarged size of chloroplasts, which were also observed in the lgp mutant. This evidence supports that the non-synonymous SNP in Csa7G051430 is the causative mutation for the light green peel. This study provides a new allele for cucumber breeding for light green fruits and additional resource for the study of chloroplast development. PMID- 25819551 TI - Social factors and barriers to self-care adherence in Hispanic men and women with diabetes. AB - OBJECTIVE: To explore quantitatively the extent to which social support, social norms and barriers are associated with self-efficacy and self-care adherence in Hispanic patients with diabetes and the extent to which these differ for men and women. METHODS: Baseline survey data were collected from 248 low-SES, Hispanic men and women who were participants in a randomized controlled trial of a culturally targeted intervention for diabetes management. Student's t, Pearson correlations and multiple regression were used to analyze the data. RESULTS: Compared to men, women were less likely to receive support, faced more barriers, reported less self-efficacy and had lower levels of self-care adherence. Perceived support was consistently correlated with better self-efficacy in women but not men, even though men reported higher levels of support. CONCLUSION: The lack of adequate support seems to be a fundamental barrier for Hispanic women with diabetes. PRACTICE IMPLICATIONS: Health care providers should be sensitive to sociocultural influences in Hispanic groups that may facilitate men's self care adherence, but could potentially hamper women's efforts. Interventions designed for Hispanics should augment women's support needs and address culture and social factors that may differentially impact the ability of men and women to manage their diabetes. PMID- 25819552 TI - The Effect of a Polyvalent Antivenom on the Serum Venom Antigen Levels of Naja sputatrix (Javan Spitting Cobra) Venom in Experimentally Envenomed Rabbits. AB - The treatment protocol of antivenom in snake envenomation remains largely empirical, partly due to the insufficient knowledge of the pharmacokinetics of snake venoms and the effects of antivenoms on the blood venom levels in victims. In this study, we investigated the effect of a polyvalent antivenom on the serum venom antigen levels of Naja sputatrix (Javan spitting cobra) venom in experimentally envenomed rabbits. Intravenous infusion of 4 ml of Neuro Polyvalent Snake Antivenom [NPAV, F(ab')2 ] at 1 hr after envenomation caused a sharp decline of the serum venom antigen levels, followed by transient resurgence an hour later. The venom antigen resurgence was unlikely to be due to the mismatch of pharmacokinetics between the F(ab')2 and venom antigens, as the terminal half-life and volume of distribution of the F(ab')2 in serum were comparable to that of venom antigens (p > 0.05). Infusion of an additional 2 ml of NPAV was able to prevent resurgence of the serum venom antigen level, resulting in a substantial decrease (67.1%) of the total amount of circulating venom antigens over time course of envenomation. Our results showed that the neutralization potency of NPAV determined by neutralization assay in mice may not be an adequate indicator of its capability to modulate venom kinetics in relation to its in vivo efficacy to neutralize venom toxicity. The findings also support the recommendation of giving high initial dose of NPAV in cobra envenomation, with repeated doses as clinically indicated in the presence of rebound antigenemia and symptom recurrence. PMID- 25819553 TI - Cdk5 contributes to inflammation-induced thermal hyperalgesia mediated by the p38 MAPK pathway in microglia. AB - BACKGROUND: The mechanisms underlying cyclin-dependent kinase 5 (Cdk5)-mediated thermal hyperalgesia induced by inflammation remain poorly understood. In the present study, we examined thermal hyperalgesia provoked by peripheral injection of complete Freund's adjuvant (CFA) to test for Cdk5 signaling in the spinal dorsal horns of rats through the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway, which is known to function in mediating inflammatory pain. METHODS: We induced the inflammatory pain model by plantar injection of CFA and compared the inhibitory effects of roscovitine and SB203580 on thermal hyperalgesia. We measured localization of Cdk5, p35, OX-42, and glial fibrillary acidic protein (GFAP) in the dorsal horn at 1 and 3 days after CFA injection using immunohistochemistry, and we measured protein levels of OX-42 and phosphorylated-p38 (p-p38) using Western blot analysis. Tumor necrosis factor-a (TNF-a) was measured by ELISA. RESULTS: The maximum thermal hyperalgesia induced by CFA occurred at 1d following injection and decreased until 5 d. We found colocalization of the Cdk5 activator p35, the microglial marker OX-42 and p-p38 in the same microglial cells and neurons of the spinal cord at day 1 after CFA injection; however, we saw no colocalization of p35 and GFAP, a marker of activated astrocytes. The thermal hyperalgesia induced by CFA was inhibited by intrathecal administration of the Cdk5 inhibitor roscovitine and by the p38 inhibitor SB203580. Furthermore, the expression of OX-42, p-p38, and TNF-a was remarkably increased from days 1 to 5 post-CFA injection and were significantly reversed by roscovitine between 1 and 3 days. CONCLUSIONS: Cdk5, an upstream regulator of p38 and TNF-a, mediates CFA-induced thermal hyperalgesia. As such, pharmacological blocking of the generation of p-p38 mediated by Cdk5 may present a novel approach for diminishing inflammatory pain. This article is part of a Special Issue entitled SI: Spinal cord injury. PMID- 25819554 TI - Repetition priming results in sensitivity attenuation. AB - Repetition priming refers to the change in the ability to perform a task on a stimulus as a consequence of a former encounter with that very same item. Usually, repetition results in faster and more accurate performance. In the present study, we used a contrast discrimination protocol to assess perceptual sensitivity and response bias of Gabor gratings that are either repeated (same orientation) or alternated (different orientation). We observed that contrast discrimination performance is worse, not better, for repeated than for alternated stimuli. In a second experiment, we varied the probability of stimulus repetition, thus testing whether the repetition effect is due to bottom-up or top down factors. We found that it is top-down expectation that determines the effect. We discuss the implication of these findings for repetition priming and related phenomena as sensory attenuation. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25819555 TI - Cytokines, but not corticotropin-releasing factor and endothelin-1, participate centrally in the febrile response in zymosan-induced arthritis in rats. AB - Recent literature has revealed that centrally generated prostaglandins participate in the febrile response in zymosan-induced arthritis in rats. However, it is not clear whether other centrally acting pyrogenic mediators such as cytokines, endothelins (ETs), and the corticotropin-releasing factor (CRF) contribute to the febrile response in this model. In the present study, rats were pretreated with intracerebroventricular (i.c.v.) injections of soluble TNF receptor I (sTNFRI), recombinant IL-1 receptor antagonist (IL-1ra), anti-rat IL-6 monoclonal antibody (AbIL-6), alpha-helical CRF9-41 (a nonselective CRF1/CRF2 receptor antagonist), BQ-123 (an ETA receptor antagonist), BQ-788 (an ETB receptor antagonist), and artificial cerebrospinal fluid (aCSF, control) prior to an intra-articular zymosan (4 mg) injection. Rectal temperatures were measured with a telethermometer. The administration of IL-1ra (200 ug), sTNFRI (500 ng), and AbIL-6 (5 ug) attenuated body temperature elevations after a zymosan injection. The administration of BQ-788 (3 pmol), BQ-123 (3 pmol), and alpha helical CRF9-41 (25 ug) did not affect the zymosan-induced febrile response. All the compounds used to pretreat the animals did not significantly alter their basal body temperatures. Together, the results here demonstrate that the febrile response in zymosan-induced arthritis in rats depends on the centrally acting pyrogenic cytokines TNF-alpha, IL-1beta, and IL-6, but does not depend on either CRF or ET-1. PMID- 25819556 TI - An outbreak of swimming-pool related respiratory symptoms: An elusive source of trichloramine in a municipal indoor swimming pool. AB - BACKGROUND: Several members of a swimming club complained of respiratory symptoms associated with attending a municipal indoor swimming pool. Trichloramine, a volatile chlorination by-product and a potent respiratory irritant, was the most probable culprit, but the exact cause for its presence in excessive concentrations remained elusive. METHODS: Twenty-two competitive swimmers and six coaches were evaluated during the outbreak and nine swimmers and four coaches were re-evaluated one year later. Symptoms were recorded by non-standardized history taking; pulmonary function testing included spirometry, measurement of fraction of exhaled nitric oxide (FENO) and histamine provocation. Concentrations of trichloramine in air were measured repeatedly by the method of Hery. RESULTS: The most commonly reported symptoms consisted of cough (n=16), dyspnoea (n=13), tearing eyes (n=10) and blocked or runny nose (n=6). Mean FEV1% predicted was 109.1%. Mean FENO level was 19.7 ppb (higher than 25 ppb in 3 subjects). Airway hyperreactivity to histamine (PC20 <= 8 mg/ml) was detected in 22/26 subjects. Measured trichloramine concentrations in air exceeded the maximal concentration (WHO) of 0.5mg/m(3) four times between May and October 2011 and four times between January and March 2012. Polyamine compounds, present in glue used for repairing pipework, were identified as a probable external source of nitrogen resulting in increasing trichloramine concentrations. After the removal of the presumed cause of the excessive trichloramine concentrations, most subjects improved clinically, but several subjects remained symptomatic and had bronchial hyperreactivity. DISCUSSION: A high prevalence of airway hyperreactivity, accompanied by symptoms of upper and lower airways, was detected in swimmers who had been repeatedly exposed to high trichloramine concentrations. A glue containing polyamines, used to repair a pipework, was suspected to be the source of this excessive production of trichloramine. PMID- 25819557 TI - Standard bowel cleansing is highly ineffective in cirrhotic patients undergoing screening colonoscopy. AB - BACKGROUND: Few data are available on tolerability and quality of standard bowel cleansing for colonoscopy in patients with chronic disease. AIM: We seek to evaluate the tolerability and results of lavage solution for colonoscopy in cirrhotic patients in comparison with controls. METHODS: Fifty-three cirrhotic and fifty-two normal subjects undergoing colonoscopy were prospectively enrolled in the study. Data regarding tolerability of lavage solution were harvested at the pre-procedure visit. Data on level of bowel cleansing and other endoscopic variables were recorded after the procedure. RESULTS: Rate of failure to complete the prescribed bowel preparation and incidence of side effects during its administration were similar between cirrhotic and normal subjects. Despite this, cirrhotic patients exhibited an insufficient level of bowel preparation with approximately half exhibiting bad colon cleansing level (49% versus 5% control, p<0.001). CONCLUSION: Alternative bowel cleansing protocols are needed for cirrhotic subjects to better match their colonoscopic screening needs. PMID- 25819558 TI - Current methods for capsular typing of Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a major respiratory tract pathogen causing pneumococcal disease mainly in children aged less than five years and in the elderly. Ninety-eight different capsular types (serotypes) of pneumococci have been reported, but pneumococcal conjugate vaccines (PCV) include polysaccharide antigens against only 7, 10 or 13 serotypes. It is therefore important to track the emergence of serotypes due to the clonal expansion of non-vaccine serotypes. Increased numbers of carried and disease-causing pneumococci are now being analysed as part of the post-PCV implementation surveillance studies and hence rapid, accurate and cost-effective typing methods are important. Here we describe serotyping methods published prior to 10th November 2014 for pneumococcal capsule typing. Sixteen methods were identified; six were based on serological tests using immunological properties of the capsular epitopes, eight were semi automated molecular tests, and one describes the identification of capsular type directly from whole genome data, which also allows for further intra and inter genome analyses. There was no single method that could be recommended for all pneumococcal capsular typing applications. Although the Quellung reaction is still considered to be the gold-standard, laboratories should take into account the number of pneumococcal isolates and the type of samples to be used for testing, the time frame for the results and the resources available in order to select the most appropriate method. Most likely, a combination of phenotypic and genotypic methods would be optimal to monitor and evaluate the impact of pneumococcal conjugate vaccines and to provide information for future vaccine formulations. PMID- 25819559 TI - p-Aminophenyl-alpha-D-mannopyranoside engineered lipidic nanoparticles for effective delivery of docetaxel to brain. AB - Lipidic systems are considered to be the most promising carrier for drug delivery to brain. Metabolic substrates like carbohydrates and amino acids are able to traverse the blood-brain barrier (BBB) by specific carrier-mediated transport systems like glucose transporters present on the both luminal and abluminal side of the BBB. With this objective, the docetaxel (DTX) loaded solid lipidic nanoparticles were formulated and surface modified with a mannose derived ligand p-aminophenyl-alpha-D-mannopyranoside (MAN) to develop MAN conjugated lipidic nanoparticles for targeting DTX to brain. Lipidic nanoparticles were prepared using emulsification and solvent evaporation method using stearic acid as charge modifying lipid and conjugated with MAN using carbodimide coupling. These lipidic nanoparticles were successfully characterized using various techniques like DLS, TEM, DSC and FTIR spectroscopy. Cytotoxicity and cell uptake unveiled enhanced efficacy of conjugated lipidic nanoparticles. Pharmacokinetic and brain distribution studies demonstrated increased DTX concentrations using lipidic nanoparticles in brain and conjugating MAN on surface of lipidic nanoparticles further augmented the inflow of the drug to brain. Present study revealed the prospective of mannose analog, MAN-conjugated lipidic nanoparticles as efficient vehicle for anticancer drug delivery to brain. PMID- 25819560 TI - The extent of inflammatory infiltration in primary cancer tissues is associated with lymphomagenesis in immunodeficient mice. AB - Xenotransplantation of human cancers into immunodeficient mice is a very useful approach for studying human tumor biology. However, the occasional occurrence of lymphomagenesis in some mice can spoil the model and must be investigated in detail. We found that a high percentage (32.5%, 26/80) of cancer patient-derived xenografts (PDXs) resembled lymphoma in NOD/SCID mice. Of the 26 xenografts, 23 were human-derived expressing human CD45 (hCD45+) and proved to be of the B-cell subtype (CD3-/CD20+), and they were all positive for Epstein-Barr virus (EBV). The remaining 3 xenografts proved to be mouse-derived for both hCD45- and negative amplification of a human gene. The most interesting finding is that gastric cancer had much higher rates (24/126, 19.0%) of lymphoma formation in the PDX model than did colorectal cancer (1/43, 2.3%). Statistical analysis revealed that cancer type and inflammation in the parent tumor are significantly associated with lymphomagenesis. Further validation discovered lymphomagenesis by inoculating only gastritis mucosa. Therefore, our findings suggest that it is necessary to take precautions when directly xenografting cancer tissues with remarkable baseline inflammation, such as gastric cancer into immunodeficient NOD/SCID strains. Further, the established xenograft models should be validated by both leukocyte markers and human gene signatures. PMID- 25819561 TI - Centrosome-Associated Degradation Limits beta-Catenin Inheritance by Daughter Cells after Asymmetric Division. AB - Caenorhabditis elegans embryos rapidly diversify cell fate using a modified Wnt/beta-catenin signaling strategy to carry out serial asymmetric cell divisions (ACDs). Wnt-dependent ACDs rely on nuclear asymmetry of the transcriptional coactivator SYS-1/beta-catenin between daughter cells to differentially activate Wnt-responsive target genes. Here, we investigate how dynamic localization of SYS 1 to mitotic centrosomes influences SYS-1 inheritance in daughter cells and cell fate outcomes after ACD. Through yeast two-hybrid screening, we identify the centrosomal protein RSA-2 as a SYS-1 binding partner and show that localization of SYS-1 to mitotic centrosomes is dependent on RSA-2. Uncoupling SYS-1 from the centrosome by RSA-2 depletion increases SYS-1 inheritance after ACD and promotes Wnt-dependent cell fate. Photobleaching experiments reveal that centrosome-bound SYS-1 turns over rapidly. Interestingly, disruption of the proteasome leads to an increased accumulation of SYS-1 at the centrosome but disrupts its dynamic turnover. We conclude that centrosomal targeting of SYS-1 promotes its degradation during asymmetric cell division. We propose a model whereby centrosome-associated SYS-1 degradation couples negative regulation with cell division timing to facilitate SYS-1 clearance from the mother cell at the time of asymmetric division. Based on our observations of centrosomal SYS-1 dynamics, we discuss the possibility that the centrosome may coordinate various cell-cycle dependent processes by synchronizing mitosis and protein regulation. PMID- 25819562 TI - Fitness Trade-offs Result in the Illusion of Social Success. AB - Cooperation is ubiquitous across the tree of life, from simple microbes to the complex social systems of animals. Individuals cooperate by engaging in costly behaviors that can be exploited by other individuals who benefit by avoiding these associated costs. Thus, if successful exploitation of social partners during cooperative interactions increases relative fitness, then we expect selection to lead to the emergence of a single optimal winning strategy in which individuals maximize their gain from cooperation while minimizing their associated costs. Such social "cheating" appears to be widespread in nature, including in several microbial systems, but despite the fitness advantages favoring social cheating, populations tend to harbor significant variation in social success rather than a single optimal winning strategy. Using the social amoeba Dictyostelium discoideum, we provide a possible explanation for the coexistence of such variation. We find that genotypes typically designated as "cheaters" because they produce a disproportionate number of spores in chimeric fruiting bodies do not actually gain higher fitness as a result of this apparent advantage because they produce smaller, less viable spores than putative "losers." As a consequence of this trade-off between spore number and viability, genotypes with different spore production strategies, which give the appearance of differential social success, ultimately have similar realized fitness. These findings highlight the limitations of using single fitness proxies in evolutionary studies and suggest that interpreting social trait variation in terms of strategies like cheating or cooperating may be misleading unless these behaviors are considered in the context of the true multidimensional nature of fitness. PMID- 25819563 TI - Investigating the regulation of stem and progenitor cell mitotic progression by in situ imaging. AB - Genome stability relies upon efficacious chromosome congression and regulation by the spindle assembly checkpoint (SAC). The study of these fundamental mitotic processes in adult stem and progenitor cells has been limited by the technical challenge of imaging mitosis in these cells in situ. Notably, how broader physiological changes, such as dietary intake or age, affect mitotic progression in stem and/or progenitor cells is largely unknown. Using in situ imaging of C. elegans adult germlines, we describe the mitotic parameters of an adult stem and progenitor cell population in an intact animal. We find that SAC regulation in germline stem and progenitor cells is distinct from that found in early embryonic divisions and is more similar to that of classical tissue culture models. We further show that changes in organismal physiology affect mitotic progression in germline stem and progenitor cells. Reducing dietary intake produces a checkpoint dependent delay in anaphase onset, and inducing dietary restriction when the checkpoint is impaired increases the incidence of segregation errors in mitotic and meiotic cells. Similarly, developmental aging of the germline stem and progenitor cell population correlates with a decline in the rate of several mitotic processes. These results provide the first in vivo validation of models for SAC regulation developed in tissue culture systems and demonstrate that several fundamental features of mitotic progression in adult stem and progenitor cells are highly sensitive to organismal physiological changes. PMID- 25819564 TI - Expectations and Outcomes of Reserve Network Performance following Re-zoning of the Great Barrier Reef Marine Park. AB - Networks of no-take marine reserves (NTMRs) are widely advocated for preserving exploited fish stocks and for conserving biodiversity. We used underwater visual surveys of coral reef fish and benthic communities to quantify the short- to medium-term (5 to 30 years) ecological effects of the establishment of NTMRs within the Great Barrier Reef Marine Park (GBRMP). The density, mean length, and biomass of principal fishery species, coral trout (Plectropomus spp., Variola spp.), were consistently greater in NTMRs than on fished reefs over both the short and medium term. However, there were no clear or consistent differences in the structure of fish or benthic assemblages, non-target fish density, fish species richness, or coral cover between NTMR and fished reefs. There was no indication that the displacement and concentration of fishing effort reduced coral trout populations on fished reefs. A severe tropical cyclone impacted many survey reefs during the study, causing similar declines in coral cover and fish density on both NTMR and fished reefs. However, coral trout biomass declined only on fished reefs after the cyclone. The GBRMP is performing as expected in terms of the protection of fished stocks and biodiversity for a developed country in which fishing is not excessive and targets a narrow range of species. NTMRs cannot protect coral reefs directly from acute regional-scale disturbance but, after a strong tropical cyclone, impacted NTMR reefs supported higher biomass of key fishery-targeted species and so should provide valuable sources of larvae to enhance population recovery and long-term persistence. PMID- 25819565 TI - PLETHORA Genes Control Regeneration by a Two-Step Mechanism. AB - Regeneration, a remarkable example of developmental plasticity displayed by both plants and animals, involves successive developmental events driven in response to environmental cues. Despite decades of study on the ability of the plant tissues to regenerate a complete fertile shoot system after inductive cues, the mechanisms by which cells acquire pluripotency and subsequently regenerate complete organs remain unknown. Here, we show that three PLETHORA (PLT) genes, PLT3, PLT5, and PLT7, regulate de novo shoot regeneration in Arabidopsis by controlling two distinct developmental events. Cumulative loss of function of these three genes causes the intermediate cell mass, callus, to be incompetent to form shoot progenitors, whereas induction of PLT5 or PLT7 can render shoot regeneration hormone-independent. We further show that PLT3, PLT5, and PLT7 establish pluripotency by activating root stem cell regulators PLT1 and PLT2, as reconstitution of either PLT1 or PLT2 in the plt3; plt5-2; plt7 mutant re established the competence to regenerate shoot progenitor cells but did not lead to the completion of shoot regeneration. PLT3, PLT5, and PLT7 additionally regulate and require the shoot-promoting factor CUP-SHAPED COTYLEDON2 (CUC2) to complete the shoot-formation program. Our findings uncouple the acquisition of competence to regenerate shoot progenitor cells from completion of shoot formation, indicating a two-step mechanism of de novo shoot regeneration that operates in all tested plant tissues irrespective of their origin. Our studies reveal intermediate developmental phases of regeneration and provide a deeper understanding into the mechanistic basis of regeneration. PMID- 25819566 TI - Transforming the thermal grill effect by crossing the fingers. AB - The relation between pain perception and spatial representation of the body is poorly understood. In the thermal grill illusion (TGI), alternating non-noxious warm and cold temperatures cause a paradoxical, sometimes painful, sensation of burning heat. We combined thermal grill stimulation with crossing the fingers to investigate whether nociceptively mediated sensation depends on the somatotopic or spatiotopic configuration of thermal inputs. We stimulated the index, middle, and ring fingers when the middle finger either was or was not crossed over the index to generate "warm-cold-warm" patterns in either somatotopic or spatiotopic coordinates. Participants adjusted a temperature delivered to the other hand until it matched their perception of the cold target finger (index or middle). We found significant temperature overestimation when the target was central within the spatial configuration (warm-cold-warm) compared to when it was peripheral (cold-warm-warm). Crucially, this effect depended on the spatiotopic configuration of thermal inputs, but it was independent of the finger posture and present for both index and middle target fingers-the thermal grill effect for the middle finger was abolished when it was crossed over the index to adopt a spatiotopically peripheral position, while the same effect was newly generated for the index finger by the same postural change. Our results suggest that the locations of multiple stimuli are remapped into external space as a group; nociceptively mediated sensations depended not on the body posture, but rather on the external spatial configuration formed by the pattern of thermal stimuli in each posture. PMID- 25819567 TI - ImmVar project: Insights and design considerations for future studies of "healthy" immune variation. AB - The Immune Variation (ImmVar) project is one of a series of recent efforts to map the extent of variation in immune function in healthy human subjects. The focus of our initial studies involved a careful mapping of the genetic architecture of the adaptive and innate immunologic transcriptomes. Our studies highlight the shared nature of this immunogenetic architecture across human populations, the important role of context in uncovering effects of genetic variation, and the fact that, over all tested genes, common genetic variation account for a minority of the variance in the immune transcriptome in healthy subjects. Yet, it is an element of the variance that can be measured very precisely and will play an important role in the design of future studies. We therefore discuss how insights from ImmVar and similar studies inform experimental strategies and frame the design of future studies of immune function in health and disease. PMID- 25819568 TI - Utilization of a real-time PCR assay for diagnosis of Babesia microti infection in clinical practice. AB - Babesiosis is an emerging tick-borne disease mainly caused Babesia microti, a protozoan that infects erythrocytes. Microscopic examination of blood smears is the current gold standard for detection of Babesia infection, but this diagnostic test has several limitations. We developed and assessed the clinical utilization of a multiplex real-time PCR assay targeting the 18S rRNA gene of B. microti and the human gapdh gene. The limit of detection of this PCR assay was approximately 1-3parasites/MUl of blood. The assay showed a diagnostic sensitivity and probable specificity of 100% based on testing 145 retrospective and 185 prospective blood specimens from controls and patients with confirmed babesiosis. Notably, the PCR assay was more sensitive than blood smear examination in patients during and following anti-babesia drug therapy. Our study suggests that PCR testing is as good or better than a blood smear for detection of B. microti in routine clinical practice. PCR testing may confirm the presence of babesiosis in patients whose level of infection is too low for reliable microscopic detection. PMID- 25819569 TI - Modeling and optimization of photo-Fenton degradation of 2,4-D using ferrioxalate complex and response surface methodology (RSM). AB - This study reports the application of the photo-Fenton process for the degradation of the herbicide 2,4-dichlorophenoxyacetic (2,4-D). The objective of this research was the evaluation of the procedure at natural pH (pH = 5) using the ferrioxalate complex as iron source at two incident irradiation levels. For this purpose, different combinations of attenuation filters from a solar simulator were tested. Since the process depends on several parameters, the influence of the temperature (T) and peroxide to 2,4-D initial concentration ratio (R) were investigated and optimized by the application of a three-level factorial experimental design combined with the Response Surface Methodology (RSM). The significance of models and their coefficients were assessed with the analysis of variance (ANOVA). The found optimal conditions were: T = 50 degrees C and R = 46.3 and T = 41.53 degrees C and R = 41.46, achieving experimental conversions of 91.4 and 95.9% for the low and high radiation levels, respectively. The obtained results are very close to the values predicted by the quadratic models (93.8 and 100.0%). It was concluded that temperature and hydrogen peroxyde concentration have different influences on the response factor depending on the incident irradiation level. It was demonstrated that RSM is a good tool for studying the effects of different variables and their interactions on 2,4-D conversion percentage in the photo-Fenton process. In addition, solution acute toxicity was also evaluated during the treatments under optimum conditions, since some degradation by-products of 2,4-D can be more toxic than the parent compound. For this purpose, the commonly used Microtox((r)) test based on the bacteria Vibrio fischeri was employed. PMID- 25819570 TI - Rhizoremediation of phenanthrene and pyrene contaminated soil using wheat. AB - Rhizoremediation, the use of the plant rhizosphere and associated microorganisms represents a promising method for the clean up of soils contaminated with polycyclic aromatic hydrocarbons (PAHs) including phenanthrene and pyrene, two model PAHs. Although numerous studies have been published reporting the degradation of phenanthrene and pyrene, very few evaluate the microbial basis of the rhizoremediation process through the application of molecular tools. The aim of this study was to investigate the effect of wheat on the degradation of two model PAHs (alone or in combination) and also on soil bacterial, fungal and nidA gene (i.e. a key gene in the degradation of pyrene) communities. The addition of wheat plants led to a significant enhancement in the degradation of both phenanthrene and pyrene. In pyrene-contaminated soils, the degradation rate increased from 15% (65 mg/kg) and 18% (90 mg/kg) in unplanted soils to 65% (280 mg/kg) and 70% (350 mg/kg) in planted treatments while phenanthrene reduction was enhanced from 97% (394 mg/kg) and 87% (392 mg/kg) for unplanted soils to 100% (406 mg/kg) and 98% (441 mg/kg) in the presence of wheat. PCR-DGGE results showed that the plant root let to some changes in the bacterial and fungal communities; these variations did not reflect any change in hydrocarbon-degrading communities. However, plate counting, traditional MPN and MPN-qPCR of nidA gene revealed that the wheat rhizosphere led to an increase in the total microbial abundance including PAH degrading organisms and these increased activities resulted in enhanced degradation of phenanthrene and pyrene. This clearer insight into the mechanisms underpinning PAH degradation will enable better application of this environmentally friendly technique. PMID- 25819571 TI - Can incentives make a difference? Assessing the effects of policy tools for encouraging tree-planting on private lands. AB - This study uses a mail survey of private landowners in the Midwest United States to understand the characteristics of owners who have planted trees or intend to plant trees in the future. The analysis examines what policy tools encourage owners to plant trees, and how policy tools operate across different ownership attributes to promote tree-planting on private lands. Logistic regression results suggest that cost-subsidizing policy tools, such as low-cost and free seedlings, significantly increase the odds of actual and planned reforestation when landowners consider them important for increasing forest cover. Individuals most likely to plant trees, when low-cost seedlings are available and important, are fairly recent (<5 years), college-educated owners who own small parcels (<4 ha) and use the land for recreation. Motivations to reforest were also shaped by owners' planning horizons, connection to the land, previous tree-planting experience, and peer influence. The study has relevance for the design of policy approaches that can encourage private forestation through provision of economic incentives and capacity to private landowners. PMID- 25819572 TI - Novel roles of Xin-repeat protein in skeletal muscle: a new insight into monogenetic myopathies. PMID- 25819573 TI - Our New President--Michael Camilleri, MD, MPhil, MRCP, FACP, AGAF. PMID- 25819574 TI - Disturbed postprandial glucose metabolism and gut hormone responses in non diabetic patients with psoriasis. PMID- 25819575 TI - Histomorphologic and molecular phenotypes predict gemcitabine response and overall survival in adenocarcinoma of the ampulla of Vater. AB - BACKGROUND: The need for adjuvant chemotherapy after resection of ampullary cancer (PapCa) remains undefined. Recent data suggest that a different epithelial origin of PapCa might be associated with different tumor biology. The aim of the present study was to assess the clinical value of morphologic and immunohistochemic subclassification of PapCa into intestinal-type (IT) and pancreaticobiliary-type (PT) to predict chemotherapy response and overall survival (OS). METHODS: Via a prospective database, 112 PapCa were identified, of which 95 could be included in the present study. Those were compared with 206 matching patients with periampullary pancreatic cancer (ie, pancreatic ductal adenocarcinoma, PDAC). IT and PT PapCa were classified morphologically, and tissue microarray was prepared with immunohistochemistry for CK7, CK20, MUC2, CDX2, beta-Catenin, and Villin. Multivariate survival analysis was performed. RESULTS: OS of PT patients was less compared with IT patients (25 vs 98 months; P < .001), whereas it was comparable with patients with PDAC (25 vs 14 months; P = .123). PT patients receiving adjuvant gemcitabine chemotherapy featured improved OS (32 vs 13 months; P = .013), whereas gemcitabine tended to be associated with decreased OS in IT patients (35 vs 112 months; P = .193). Besides histopathologic classification, expression of CK7 and MUC2 were important prognostic variables. PT patients with CK7-positivity or MUC2-negativity were segregated into an even poorer prognostic group. CONCLUSION: PapCa is not a separate tumor entity. We demonstrate important differences between IT-PapCa and PT-PapCa not only in long term survival but also in response to adjuvant gemcitabine. Tumor biology and clinical course of PT tumors resemble those of PDAC. PT tumors should therefore be treated like PDAC. PMID- 25819576 TI - Adolescents' and Young Adults' Online Risk Taking: The Role of Gist and Verbatim Representations. AB - Young people are exposed to and engage in online risky activities, such as disclosing personal information and making unknown friends online. Little research has examined the psychological mechanisms underlying young people's online risk taking. Drawing on fuzzy trace theory, we examined developmental differences in adolescents' and young adults' online risk taking and assessed whether differential reliance on gist representations (based on vague, intuitive knowledge) or verbatim representations (based on specific, factual knowledge) could explain online risk taking. One hundred and twenty two adolescents (ages 13 17) and 172 young adults (ages 18-24) were asked about their past online risk taking behavior, intentions to engage in future risky online behavior, and gist and verbatim representations. Adolescents had significantly higher intentions to take online risks than young adults. Past risky online behaviors were positively associated with future intentions to take online risks for adolescents and negatively for young adults. Gist representations about risk negatively correlated with intentions to take risks online in both age groups, while verbatim representations positively correlated with online risk intentions, particularly among adolescents. Our results provide novel insights about the underlying mechanisms involved in adolescent and young adults' online risk taking, suggesting the need to tailor the representation of online risk information to different age groups. PMID- 25819577 TI - Comprehensive protein profiling of synovial fluid in osteoarthritis following protein equalization. AB - OBJECTIVE: The aim of the study was to characterise the protein complement of synovial fluid (SF) in health and osteoarthritis (OA) using liquid chromatography mass spectrometry (LC-MS/MS) following peptide-based depletion of high abundance proteins. DESIGN: SF was used from nine normal and nine OA Thoroughbred horses. Samples were analysed with LC-MS/MS using a NanoAcquityTM LC coupled to an LTQ Orbitrap Velos. In order to enrich the lower-abundance protein fractions protein equalisation was first undertaken using ProteoMinerTM. Progenesis-QITM LC-MS software was used for label-free quantification. In addition immunohistochemistry, western blotting and mRNA expression analysis was undertaken on selected joint tissues. RESULTS: The number of protein identifications was increased by 33% in the ProteoMinerTM treated SF compared to undepleted SF. A total of 764 proteins (462 with>=2 significant peptides) were identified in SF. A subset of 10 proteins were identified which were differentially expressed in OA SF. S100-A10, a calcium binding protein was upregulated in OA and validated with western blotting and immunohistochemistry. Several new OA specific peptide fragments (neopeptides) were identified. CONCLUSION: The protein equalisation method compressed the dynamic range of the synovial proteins identifying the most comprehensive SF proteome to date. A number of proteins were identified for the first time in SF which may be involved in the pathogenesis of OA. We identified a distinct set of proteins and neopeptides that may act as potential biomarkers to distinguish between normal and OA joints. PMID- 25819578 TI - Is the contralateral hip at risk in patients with unilateral symptomatic cam femoroacetabular impingement? A quantitative T1rho MRI study. AB - OBJECTIVES: To assess the profile of weight-bearing cartilage of hips with a cam deformity using T1rho magnetic resonance imaging (MRI) and evaluate for a side-to side difference in the T1rho profile of patients with bilateral cam morphology but only unilateral hip pain. METHODS: 19 patients with bilateral cam morphology undergoing osteochondroplasty for unilateral hip pain were prospectively recruited. Anterior and anterosuperior alpha angles were measured using computer tomography. All patients underwent bilateral 1.5T T1rho MRI. The cartilage bilayer of the hip joint was evaluated and the mean T1rho relaxation time calculated for each quadrant of the weight-bearing surface. RESULTS: Mean T1rho relaxation times were not significantly different when each quadrant was compared to the rest of the weight-bearing surface of the symptomatic (P = 0.068) and asymptomatic hips (P = 0.102). There was also no significant side-to-side difference between the same quadrants of symptomatic and asymptomatic hips. No correlation was detected between alpha angle and the mean T1rho relaxation time in each quadrant. There was no significant difference in mean alpha angles between the symptomatic and asymptomatic sides at the anterior (54.2 vs 56.0 degrees ; P = 0.382) and anterosuperior positions (65.1 vs 65.2 degrees ; P = 0.971). CONCLUSION: We conclude that previously observed regional variation in T1rho values of normal hips is altered in hips with cam morphology. No difference in T1rho values between symptomatic and asymptomatic cam hips was demonstrated. Therefore, regardless of the presence of hip pain, a cam deformity may predispose to hip joint cartilage degradation and increase the risk of hip osteoarthritis. PMID- 25819579 TI - The ability of systemic biochemical markers to reflect presence, incidence, and progression of early-stage radiographic knee and hip osteoarthritis: data from CHECK. AB - OBJECTIVE: To relate systemic biochemical markers of joint metabolism to presence, incidence, and progression of early-stage radiographic knee and/or hip osteoarthritis (OA). METHOD: The cartilage markers uCTX-II, sCOMP, sPIIANP, and sCS846, bone markers uCTX-I, uNTX-I, sPINP, and sOC, and synovial markers sHA and sPIIINP were assessed by enzyme-linked immunosorbent assay or radioactive immunoassay in baseline samples of CHECK (Cohort Hip and Cohort Knee), a cohort study of early-stage symptomatic knee and/or hip OA. Knee and hip radiographs were obtained at baseline and 5-year follow-up. Presence of OA at baseline was defined as Kellgren and Lawrence (K&L) = 1 (maximum observed). Incidence of OA was defined as K&L = 0 at baseline and K&L >= 1 at 5-year follow-up. Progression of OA was defined as K&L = 1 at baseline and K&L >= 2 at 5-year follow-up. RESULTS: Data were available for 801 subjects at baseline and for 723 subjects at both baseline and 5-year follow-up. Multiple cartilage and synovial markers showed positive associations with presence and progression of knee and hip OA and with incidence of hip OA, except for negative associations of uCTX-II and sCOMP with incidence of knee OA. uCTX-II and sCOMP showed multiple interactions with other biomarkers in their associations with knee and hip OA. Bone markers were positively associated with presence of radiographic knee OA, but negatively associated with progression of radiographic hip OA. CONCLUSION: Especially metabolism in cartilage and synovial matrix appear to be of relevance in knee and hip OA. The role of bone metabolism appears to differ between knee and hip OA. PMID- 25819580 TI - Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes. AB - OBJECTIVE: SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro. DESIGN: First, the localization of SIRT6 and proliferation cell nuclear antigen (PCNA) in human cartilages was examined by immunohistochemistry. Next, SIRT6 was depleted by RNA interference (RNAi), and the effect of SIRT6 depletion on changes in gene expression, protein levels, proliferation, and senescence in human chondrocytes was assessed. Furthermore, to detect DNA damage and telomere dysfunction, gammaH2AX foci and telomere dysfunction-induced foci (TIFs) were examined using immunofluorescence microscopy. The protein levels of two mediators for DNA damage induced-senescence, p16 and p21, were examined by western blotting. RESULTS: Immunohistochemical analysis showed SIRT6 was preferentially expressed in the superficial zone chondrocytes and PCNA-positive cluster-forming chondrocytes in the osteoarthritic cartilage tissue samples. Real-time PCR analysis showed that matrix metalloproteinase 1 (MMP-1) and MMP-13 mRNA were significantly increased by SIRT6 inhibition. Moreover, SIRT6 inhibition significantly reduced proliferation and increased senescence associated beta-galactosidase (SA-beta Gal)-positive chondrocytes; it also led to increased p16 levels. Immunofluorescence microscopy showed that gammaH2AX foci and TIFs were increased by SIRT6 inhibition. CONCLUSION: Depletion of SIRT6 in human chondrocytes caused increased DNA damage and telomere dysfunction, and subsequent premature senescence. These findings suggest that SIRT6 plays an important role in the regulation of senescence of human chondrocytes. PMID- 25819581 TI - Knee osteoarthritis and all-cause mortality: the Wuchuan Osteoarthritis Study. AB - BACKGROUND: Previous studies showed that knee osteoarthritis (OA) is associated with increased mortality in Caucasians. While prevalence of knee OA is higher in Chinese than in Caucasians, no study has examined whether knee OA increases mortality in Chinese population. METHODS: Between 8/2005-10/2005 1025 residents aged >=50 years were recruited in randomly selected rural communities in Wuchuan, China. Subjects completed a home interview and had weight-bearing posteroanterior semiflexed view of radiographs at tibiofemoral joints and skyline view of radiographs at patellofemoral joints, and were followed until end of 2013. A knee was defined as having radiographic osteoarthritis (ROA) if either Kellgren/Lawrence (KL) score at tibiofemoral joint >=2 or presence of OA at patellofemoral joint based on OARSI criteria. Symptomatic knee osteoarthritis (SxOA) was defined if both pain (i.e., knee pain occurred on most days in past month) and ROA were present at the same knee. We examined the relation of knee SxOA and knee ROA to the all-cause mortality, respectively, using Cox proportional hazard models adjusting for potential confounders. RESULTS: Over the follow-up period 99 subjects died. The mortality rates were 32.6 (95% confidence interval (CI): 19.6-54.0) and 10.9 (95% CI: 8.8-13.5) per 1000 person-years among subjects with and without SxOA, respectively. Multivariable adjusted hazard ratio of all-cause mortality for knee SxOA was 1.9 (95% CI: 1.0-3.5). However, no such association was observed for knee ROA (hazard ratio = 1.2, 95% CI: 0.7-1.9). CONCLUSIONS: Knee SxOA was associated with an increased risk of all-cause mortality among the residents in the rural areas of China. PMID- 25819582 TI - Socio-economic status and the risk of developing hand, hip or knee osteoarthritis: a region-wide ecological study. AB - OBJECTIVE: To determine the association between socio-economic status (SES) and risk of hand, hip or knee osteoarthritis (OA) at a population level. DESIGN: Retrospective ecological study using the System for the Development of Research in Primary Care (SIDIAP) database (primary care anonymized records for >5 million people in Catalonia (Spain)). Urban residents >15 years old (2009-2012) were eligible. OUTCOMES: Validated area-based SES deprivation index MEDEA (proportion of unemployed, temporary workers, manual workers, low educational attainment and low educational attainment among youngsters) was estimated for each area based on census data as well as incident diagnoses (ICD-10 codes) of hand, hip or knee OA (2009-2012). Zero-inflated Poisson models were fitted to study the association between MEDEA quintiles and the outcomes. RESULTS: Compared to the least deprived, the most deprived areas were younger (43.29 (17.59) vs 46.83 (18.49), years (Mean SD), had fewer women (49.1% vs 54.8%), a higher percentage of obese (16.2% vs 8.4%), smokers (16.9% vs 11.9%) and high-risk alcohol consumption subjects (1.5% vs 1.3%). Compared to the least deprived, the most deprived areas had an excess risk of OA: age-sex-adjusted Incidence Rate Ratio (IRR) 1.26 (1.11 1.42) for hand, 1.23 (1.17-1.29) hip, and 1.51 (1.45-1.57) knee. Adjustment for obesity attenuated this association: 1.06 (0.93-1.20), 1.04 (0.99-1.09), and 1.23 (1.19-1.28) respectively. CONCLUSIONS: Deprived areas have higher rates OA (hand, hip, knee). Their increased prevalence of obesity accounts for a 50% of the excess risk of knee OA observed. Public health interventions to reduce the prevalence of obesity in this population could reduce health inequalities. PMID- 25819583 TI - Relationship of unilateral total hip arthroplasty (THA) to contralateral and ipsilateral knee joint degeneration - a longitudinal 3T MRI study from the Osteoarthritis Initiative (OAI). AB - OBJECTIVE: To evaluate the association of prevalent unilateral total hip arthroplasty (THA) with worsening of degenerative knee abnormalities and clinical outcomes in the ipsilateral and contralateral knee. METHODS: Both knees of 30 individuals in the Osteoarthritis Initiative (OAI) with unilateral THA (n = 14 left, n = 16 right) at baseline were assessed at baseline and at 4-year follow-up for Whole-organ MR Imaging Scores (WORMS), cartilage T2 relaxation times (only available for right knees), Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores and upper leg isometric strength. Right knees of 30 individuals without THA were analyzed as controls. Contralateral knees were compared to ipsilateral knees with paired t-tests and to control knees with multivariate regression analysis adjusting for covariates. RESULTS: In paired analyses, compared to ipsilateral knees, contralateral knees had higher WORMS total (P = 0.008) and cartilage scores (P = 0.007) at baseline. Over 4 years contralateral knees worsened more on WORMS total score (P = 0.008). Cartilage T2 values were higher in knees contralateral to the THA (baseline, P = 0.02; follow up, P < 0.001). Contralateral knees had greater declines in knee extension strength (P = 0.04) and had a trend for greater worsening in WOMAC pain, stiffness, function and total scores (P = 0.04-0.09). Similar results were found comparing contralateral knees with control knees in multivariate regression models. CONCLUSIONS: Prevalent unilateral THA is associated with an greater progression of degenerative findings for the knee contralateral to THA. PMID- 25819584 TI - Nevirapine Resistance in Previously Nevirapine-Unexposed HIV-1-Infected Kenyan Infants Initiating Early Antiretroviral Therapy. AB - Nevirapine (NVP) resistance occurs frequently in infants following NVP use in prevention of mother-to-child transmission (PMTCT) regimens. However, among previously NVP-unexposed infants treated with NVP-antiretroviral therapy (ART), the development and impact of NVP resistance have not been well characterized. In a prospective clinical trial providing early ART to HIV-infected infants <5 months of age in Kenya (OPH03 study), we followed NVP-unexposed infants who initiated NVP-ART for 12 months. Viral loads were assessed and resistance determined using a population-based genotypic resistance assay. Of 99 infants screened, 33 had no prior NVP exposure, 22 of whom were initiated on NVP-ART. Among 19 infants with follow-up, seven (37%) infants developed resistance: one at 3 months and six at 6 months after ART initiation. The cumulative probability of NVP resistance was 5.9% at 3 months and 43.5% at 6 months. Baseline HIV RNA levels (p=0.7) and other characteristics were not associated with developing resistance. Post-ART, higher virus levels at visits preceding the detection of resistance were significantly associated with increased detection of resistance (p=0.004). Virus levels after 6 and 12 months of ART were significantly higher in infants with resistance than those without (p=0.007, p=0.030, respectively). Among infants without previous NVP exposure, development of NVP resistance was frequent and was associated with virologic failure during the first year of ART. Earlier development of NVP resistance in infants than in adults initiating NVP ART may be due to longer viremia following ART or inadequate NVP levels resulting from NVP lead-in dosing. The development of NVP resistance may, in part, explain the superiority of protease inhibitor-based ART in infants. PMID- 25819585 TI - Helical coil electrode radiofrequency ablation designed for application in osteolytic vertebral tumors--initial evaluation in a porcine model. AB - BACKGROUND CONTEXT: Radiofrequency ablation (RFA) is emerging as a complementary treatment for vertebral metastases. Traditional RFA induces frictional heating leading to local tissue necrosis but often yields small, incomplete, and inhomogeneous zones of ablation in bone. We have developed a new bone-specific RFA electrode that uses a nontraditional frequency (27.12 MHz) and geometry (helical), exploiting a magnetic field and an electric field to generate larger and more comprehensive treatment zones. PURPOSE: The purpose of the study was to evaluate the feasibility and safety of the Bone Coil RFA electrode in the spine. STUDY DESIGN: This is a preclinical in vivo study based on basic science. METHODS: Under institutional approval, six healthy Yorkshire pigs received a sham and an RF treatment in two adjacent cervical vertebrae. To deploy the Bone Coil RFA device in dense porcine vertebrae, a surgical approach was required; an irrigated coring drill bit created a cylindrical path in the vertebral bodies through which the RFA electrodes were placed. The electronic circuit was completed by four grounding pads. Treatment was delivered for 10 minutes at 20 W (n=1), 25 W (n=1), and 30 W (n=4). To monitor the thermal rise and for safety, fiber-optic probes recorded temperatures in the center of each coil and near the spinal foramen. After the procedure, animals were monitored for 2 weeks. Magnetic resonance imaging (MRI) was completed immediately after treatment and at 14 days. Magnetic resonance image segmentation and histology were used to evaluate the ablation volume. RESULTS: Comprehensive treatment of the porcine vertebrae was demonstrated by temperature monitoring, MRI, and histology. Large zones of RF ablation were obtained (RF: 3.72+/-0.73 cm3 vs. sham: 1.98+/-0.16 cm3, p<.05), confined within the vertebral body. Internal temperatures were elevated with RF (66.1 degrees C-102.9 degrees C), without temperature rise outside of the vertebrae (38.2 degrees C +/- 1.5 degrees C). Mobility, neurological responses, and behavior were normal, consistent with preprocedural examination. Magnetic resonance imaging best visualized ablation at Day 14. Histology revealed comprehensive homogeneous coagulative necrosis with little peripheral sign of repair. CONCLUSIONS: The Bone Coil RFA device created large intravertebral ablation volumes with no neurologic sequelae. Radiofrequency thermal ablation (clearly distinguished from the much smaller effects arising from core drilling) corresponded to the homogeneous necrosis visible on histology. PMID- 25819586 TI - Thoracolumbar pneumorrhachis after nonspinal gunshot wound. PMID- 25819587 TI - Cholangiocarcinoma presenting as cervical spine metastasis. PMID- 25819588 TI - Open reduction and posterior instrumented spinopelvic fixation for traumatic grade IV lateral spondylolisthesis of the thoracolumbar spine. PMID- 25819589 TI - Thoracic neuroblastoma presenting with Guillain-Barre-like symptoms. PMID- 25819590 TI - Mirabegron. AB - Mirabegron is used for the treatment of symptoms associated with overactive bladder syndrome. It selectively stimulates the beta3 -adrenoreceptor, which relaxes the detrusor muscle. This improves urine storage by distension of the bladder body. PMID- 25819591 TI - Development of a Neonatal End-of-Life Care Education Program for NICU Nurses in Japan. AB - We developed the first end-of-life care education program for neonatal intensive care unit (NICU) nurses in Japan. It focused on ethical decision making, care of dying neonates, bereavement, and cultural communication. The program improved nurses' knowledge, F(2.16, 62.5) = 260.6, p < .001, and understanding, F(2.05, 59.4) = 29.1, p < .001, and significantly reduced weaknesses in neonatal end-of life care. It was considered well designed and may provide further mentoring support for NICU nurses. PMID- 25819592 TI - [Imaging strategy for children after a first episode of pyelonephritis]. AB - Pyelonephritis is a common bacterial disease in young children and is a serious infection because of its potential to produce renal scarring. One of the concerns of physicians is therefore the diagnosis of uropathy at risk for recurrence of pyelonephritis, especially high-grade reflux. There are no French recommendations on imaging evaluation after a first episode of pyelonephritis. Voiding cystography was systematically proposed years ago and recommended by the American Academy of Pediatrics until 1999. This systematic strategy exposed all children to a painful, irradiating exam, and exposed them to urinary tract infection. The American recommendations changed in 2011 and cystography is now only proposed to children with recurrence of pyelonephritis or with ultrasound abnormalities. A collaborative review of the literature involving the Pediatric Emergency, Nephrology and Surgery Departments at Necker-Enfants-Malades Hospital led us to propose an algorithm for imaging after the first episode of pyelonephritis in children. This algorithm was based on data from the past medical history (results of prenatal ultrasonography or recurrence of pyelonephritis), the results of the ultrasound exam at the time of diagnosis, and the procalcitonin concentration, to limit the indications for voiding cystography, limiting risk for delaying high grade reflux diagnosis. Children with low risk for high-grade reflux can be followed up with an ultrasound exam 6 months after acute infection. PMID- 25819593 TI - Single-port laparoscopic ovarian transposition in an 11-year-old girl. AB - Ovarian transposition was the first procedure proposed for children with cancer to preserve ovarian function from damage caused by abdominal and pelvic radiotherapy. In this paper, we describe the first pediatric case of single-port laparoscopic ovarian transposition. PMID- 25819594 TI - How best to measure cough clinically. AB - It is possible to measure cough by assessing its severity, frequency, intensity, associated urge and its impact on quality of life. Cough severity can simply be assessed with a Visual Analogue Scale. Cough frequency can be assessed objectively with cough frequency monitors. Validated cough monitors include the Leicester Cough Monitor and the VitaloJAK. Cough reflex sensitivity measurement is better used to investigate the mechanisms of action of antitussive medications, rather than assessing efficacy. Health-Related Quality of Life measures are available to assess the impact of cough; they include the validated Leicester Cough Questionnaire and Cough-specific Quality of Life Questionnaire for adult patients. It is best to assess cough with a combination of subjective and objective tools, to capture its wide-ranging impact. PMID- 25819595 TI - Editorial: emerging issues in sociotechnical systems thinking and workplace safety. AB - The burden of on-the-job accidents and fatalities and the harm of associated human suffering continue to present an important challenge for safety researchers and practitioners. While significant improvements have been achieved in recent decades, the workplace accident rate remains unacceptably high. This has spurred interest in the development of novel research approaches, with particular interest in the systemic influences of social/organisational and technological factors. In response, the Hopkinton Conference on Sociotechnical Systems and Safety was organised to assess the current state of knowledge in the area and to identify research priorities. Over the course of several months prior to the conference, leading international experts drafted collaborative, state-of-the-art reviews covering various aspects of sociotechnical systems and safety. These papers, presented in this special issue, cover topics ranging from the identification of key concepts and definitions to sociotechnical characteristics of safe and unsafe organisations. This paper provides an overview of the conference and introduces key themes and topics. PRACTITIONER SUMMARY: Sociotechnical approaches to workplace safety are intended to draw practitioners' attention to the critical influence that systemic social/organisational and technological factors exert on safety-relevant outcomes. This paper introduces major themes addressed in the Hopkinton Conference within the context of current workplace safety research and practice challenges. PMID- 25819596 TI - Fructosamine; is the current interest in alternative glycaemic markers justified? PMID- 25819597 TI - Highlight: After the bottleneck--how a tiny group of macaques founded a thriving population on Mauritius. PMID- 25819598 TI - Is an attention-based associative account of adjacent and nonadjacent dependency learning valid? AB - Pacton and Perruchet (2008) reported that participants who were asked to process adjacent elements located within a sequence of digits learned adjacent dependencies but did not learn nonadjacent dependencies and conversely, participants who were asked to process nonadjacent digits learned nonadjacent dependencies but did not learn adjacent dependencies. In the present study, we showed that when participants were simply asked to read aloud the same sequences of digits, a task demand that did not require the intentional processing of specific elements as in standard statistical learning tasks, only adjacent dependencies were learned. The very same pattern was observed when digits were replaced by syllables. These results show that the perfect symmetry found in Pacton and Perruchet was not due to the fact that the processing of digits is less sensitive to their distance than the processing of syllables, tones, or visual shapes used in most statistical learning tasks. Moreover, the present results, completed with a reanalysis of the data collected in Pacton and Perruchet (2008), demonstrate that participants are highly sensitive to violations involving the spacing between paired elements. Overall, these results are consistent with the Pacton and Perruchet's single-process account of adjacent and nonadjacent dependencies, in which the joint attentional processing of the two events is a necessary and sufficient condition for learning the relation between them, irrespective of their distance. However, this account should be completed to encompass the notion that the presence or absence of an intermediate event is an intrinsic component of the representation of an association. PMID- 25819599 TI - A novel multimodular methodology to investigate external cervical tooth resorption. AB - AIM: To introduce a multimodular combination of techniques as a novel minimal invasive approach to investigate efficiently and accurately external cervical resorption (ECR). METHODOLOGY: One case of a central incisor with extensive external cervical resorption was selected to demonstrate the potential of a comparative novel study methodology. ECR diagnosis was based on clinical inspection, digital radiography and cone-beam computed tomography (CBCT). After extraction, the tooth was investigated using microfocus computed tomography (micro-CT), nano-CT and hard tissue histology. These techniques were compared for their accuracy and applicability to highlight their advantages and disadvantages. RESULTS: Nano-CT was more effective than micro-CT and CBCT for detailed ex vivo exploration of ECR. The reparative tissue, pericanalar resorption resistant sheet (PRRS), pulp tissue reactions, resorption channels and their interconnection with the periodontal ligament space were accurately visualized by detailed processing and analysis of the nano-CT data set with Dataviewer and CTAn software. Nano-CT analysis provided better insight in the true extent of the resorption, based on quantitative measurements and 3D visualization of the tooth structure. Nano-CT imaging results were similar to hard tissue histology at the mineralized tissue level. To clarify the dynamic phenomenon of reparative tissue formation and substitution of the resorbed tissues, nano-CT needed to be associated with hard tissue histology. CONCLUSION: Nano-CT is a fast and minimal invasive technique for the ex vivo analysis and understanding of ECR and is complementary with hard tissue histology. A combined approach of clinical and CBCT examination, with nano CT and histological mapping measurements, can provide an ideal platform for future ECR imaging and exploration studies. PMID- 25819600 TI - Bladder calculi in the augmented bladder: a follow-up study of 160 children and adolescents. AB - INTRODUCTION: Bladder augmentation (BA) has been used for various congenital and acquired conditions to create a low pressure, continent catheterizable reservoir. The prevalence of calculi within the BA have been reported to be from 3 to 52.5%. The present study reports the prevalence and risk factors of bladder calculi in patients with BA. MATERIAL AND METHODS: A retrospective review of 160 patients was performed from January 1997 through December 2012. The various risk factors for the formation of bladder calculi such as the nature of the anatomical defect, presence of preoperative urinary calculi, type of bowel augmentation, addition of a mitrofanoff and/or bladder neck procedure, prevalence of post-operative urinary tract infections (UTIs), need for mitrofanoff revision due to stenosis/difficulty catheterization, postoperative significant hydronephrosis and bladder calculi were recorded for analysis. The children underwent open removal or endoscopic cystolithotripsy. One hundred and eight males and 52 females (average age 6.3 years) were followed up for a median of 70.5 months. All patients performed daily bladder irrigation with tap or drinking water. RESULTS: Post-operative bladder calculi were noted in 14 (8.8%) of 160 patients following BA. Median time to stone formation was 37.5 months (11-120 months). Recurrent febrile UTIs were noted in 16 of the 160 patients following BA. The various risk factors and their outcomes are summarized in table. Eight patients underwent open cystolithotomy and four patients were treated by cystolithotripsy. Post-operative recurrent bladder calculi were noted in 2 patients. Multivariate analysis revealed that exstrophy/epispadias (OR 17.2) and recurrent UTI (OR 55.4) were independent risk factors for developing postoperative calculi in bladder augmentations. All other risk factors did not achieve statistical significance. DISCUSSION: There seemed to be no difference in the prevalence of calculi in the ileal or colonic augmentations. Mucus secreted by the bowel segment blocks catheters leading to incomplete drainage, stagnation and UTIs. Our protocol consists of daily bladder irrigation till the effluents are clear of mucus. This is probably the key to the low prevalence of postoperative calculi (8.8%) in our patients. CONCLUSION: Bladder exstrophy/epispadias and UTIs are independent statistically significant risk factors for the formation of bladder calculi in BA patients. Other risk factors such as preoperative calculi, bladder neck procedures and the use of mitrofanoff though not statistically significant, may contribute to the overall risk. The performance of daily bladder irrigation is an important part of our management of mucus. PMID- 25819601 TI - Meta-analysis of complication rates of the tubularized incised plate (TIP) repair. AB - OBJECTIVE: To determine overall complication rates of the tubularized incised plate (TIP) repair and assess the effects of technical modifications, length of follow-up and geographical location of reported results. MATERIALS AND METHODS: A systematic literature search was undertaken, using Medline and Pubmed, in order to identify relevant articles. Random effects models were used to estimate pooled complication rates. Meta-regression was performed for each outcome by using mixed effects models with type of hypospadias (primary distal, primary proximal and secondary) as predictors. RESULTS: Of the 189 articles that were identified, 49 studies (4675 patients) were included in the analysis. Fistula and re-operation rates were significantly higher in secondary repairs (15.5% and 23.3%) compared to primary proximal (10.3% and 12.2%) and primary distal (5.7% and 4.5%) (P = 0.045 and P < 0.001, respectively). Technical modifications reduced fistula rates from 10.3% to 3.3% (P = 0.003) and re-operation rates from 13.6% to 2.8% (P = 0.001). The rate of meatal stenosis was highest in the secondary repairs, with follow-up >1 year (12.7%). Comparison of geographical location showed that complication rates for all but one variable were significantly lower in North America when compared to Europe and the rest of the world. Mean meatal stenosis rates were 1.8% in North America, 3.4% in Europe and 8.2% in the rest of the world (P = 0.002). This remained significant in a multivariable model incorporating repair technique and length of follow-up (P = 0.046). Mean rates of urethral stricture, fistula and re-operation followed a similar pattern (P = 0.045, P = 0.009 and P < 0.001, respectively). Mean follow-up was shortest in the North American group, at 11.9 months, compared to Europe, at 17.8 months, and the rest of the world, at 18.9 months. DISCUSSION: The present meta-analysis has shown that the lowest complication rates for the TIP repair are when it is applied to primary distal hypospadias. Complication rates are higher for all variables when the TIP repair is used for primary proximal hypospadias. Lower complication rates than those reported in this TIP review have been documented in some studies using a staged repair for correction of primary proximal or secondary hypospadias [11,12,68], implying that a staged approach may be superior to the TIP repair in these settings. Documentation of follow-up duration was limited, making assessment of the impact of length of follow-up difficult. Geographical location had a noticeable effect on outcome, with all but one complication being lower in the North American than the other groups. Mean follow up was shortest in North America and it is suggested that the short follow-up in the North American studies may have led to under-reporting of late complications. CONCLUSION: The TIP repair has evolved to incorporate modifications that have significantly lowered complications. Higher complication rates are seen with secondary and proximal repairs; however, limited, published long-term data impair a true assessment of outcome. PMID- 25819602 TI - Supine pediatric percutaneous nephrolithotomy (PCNL). AB - INTRODUCTION/BACKGROUND: Many authors reported their experience with supine PCNL in adult population comparing the outcome with prone PCNL and they found that the stone free rate and the operative time were in favor of prone PCNL with a lower patient morbidity among patients with supine PCNL. This encouraged us to perform supine PCNL in pediatric population. AN OBJECTIVE: In this study we evaluated the safety and efficacy of supine PCNL in pediatric population. STUDY DESIGN (SUBJECTS/PATIENTS/MATERIALS/METHODS): Between April 2011 and February 2014 a total of 27 children (6 girls and 21 boys) presented with renal calculi. The stones were single pelvic stone in 14 cases, pelvic stone with lower calyceal stones in 7 cases and pelvic stone with upper calyceal stones in 6 cases. The mean stone size was 32 mm (range 20-47 mm). All patients were managed with supine PCNL performed by a single surgeon. Marking the posterior axillary line in standing position before the operation is a mandatory initial step. The patients were placed in supine position with elevation of the ipsilateral shoulder and hip by means of two bags one underneath the shoulder and the other underneath the hip to widen the operative field. The technique was performed using a sheathless 19 fr. Richard wolf rigid nephroscope after acute tract dilation by amplatz dilators. Complications (intraoperative and postoperative) and stone free rate rates were reported. RESULTS: A single lower calyceal access was used in all cases through which we could successfully remove even the upper calyceal stones. Kinking of the guide wire during tract dilatation were encountered in 4 cases and the guide wire was successfully exchanged using a small Teflon dilator in 2 cases while ultrasonographic guided lower calyceal repuncture was done in 2 cases. The average operative time (from the beginning of the puncture trial to nephrostomy tube insertion) was (41 +/- 15) min. The operation was successfully completed as planned in all cases with two cases of intraoperative complications (one case of pelvicalyceal system perforation and another case of intraoperative bleeding and blood transfusion). The initial stone free rate was (92.5%). Postoperative complications was reported in the form of 2 cases of fever that respond to medical treatment for 72 h. DISCUSSION: The main advantages of supine pediatric PCNL is that it is comfortable for the surgeon, the anesthetist and the child. The main disadvantages of supine pediatric PCNL is that it is not familiar for most urologists and small field of operation. The short outcome of our study is the small number of cases and the lack of comparative study with prone pediatric PCNL. CONCLUSIONS: Pediatric supine PCNL is a safe and effective method for management of pediatric renal stones. It carries the advantages of easily upper calyx access through the lower calyceal tract, low incidence of fluid absorption or hypothermia and easy anesthesia monitoring. However a larger number of cases are needed to be evaluated. PMID- 25819603 TI - Attitudes and beliefs of Australian adults on reality television cooking programmes and celebrity chefs. Is there cause for concern? Descriptive analysis presented from a consumer survey. AB - BACKGROUND: There is evidence suggesting that the nutritional content of recipes promoted by celebrity chefs or television cooking programmes contradict healthy eating guidelines. This study aims to investigate people's attitudes and beliefs about popular television cooking programmes and celebrity chefs. METHODS: Males and females who watch television cooking programmes were recruited to participate in a self-administered online questionnaire (22-items) which included multiple choice and rank order questions. RESULTS: A total of n = 207 participants undertook the questionnaire with fully completed questionnaires available for n = 150 participants (Males, n = 22; Females, n = 128; aged 38.4 +/- 14 years). The majority of respondents watch <=30 minutes of television cooking programming per day (total responses, n = 153/207; 74%) with almost three-quarters (total responses, n = 130/175; 74%) having attempted a recipe. New cooking ideas (total responses, n = 81/175; 46%) and entertainment (total responses, n = 64/175; 36.5%) were the two main reasons participants gave for watching these programmes. Significantly more respondents believed recipes use excessive amounts of unhealthy fat, sugar or salt (unhealthy: 24%; healthy: 7%; P < 0.0001). Almost half of all respondents (total responses, n = 67/151; 44%) believed these programmes have no impact on their habitual diet. DISCUSSION AND CONCLUSION: Our results suggest television cooking programmes and celebrity chefs are unlikely to impact habitual dietary intake; rather, vicarious viewing and entertainment appear important factors relating to why people watch these programmes. However results generated from the present study are descriptive and subjective and further investigation into the impact of television cooking programmes and celebrity chefs on behavioural change requires attention. Further investigation including a systematic investigation into the dietary quality of recipes promoted by celebrity chefs against national healthy eating benchmarks is also warranted. PMID- 25819604 TI - Influence of choice on vegetable intake in children: an in-home study. AB - Children's vegetable consumption is still far below that recommended, and stimulating their intake is a challenge for caregivers. The objective of this study was to investigate whether choice-offering is an effective strategy to increase children's vegetable intake in an in-home situation. Seventy children (mean age 3.7; SD 1) randomly assigned to a choice or a no-choice condition, were exposed 12 times to six familiar target vegetables at home during dinner. In the choice group, two selected vegetables were offered each time, whereas the no choice group only received one vegetable. Vegetable intake was measured by weighing children's plates before and after dinner. A mixed linear model with age, gender, and baseline vegetable liking as covariates was used to compare intake between the choice and the no-choice group. Mixed linear model analysis yielded estimated means for vegetable intake of 48.5 g +/- 30 in the no-choice group and 57.7 g +/- 31 for the choice group (P = 0.09). In addition, baseline vegetable liking (P <0.001) and age (P = 0.06) predicted vegetable intake to be higher when the child liked vegetables better and with older age. These findings suggest that choice-offering has some, but hardly robust, effect on increasing vegetable intake in children. Other factors such as age and liking of vegetables also mediate the effect of offering a choice. PMID- 25819605 TI - Association of distorted eating behaviors with cardiometabolic risk indices in preadolescents. The Healthy Growth Study. AB - The association between distorted eating behavior (DEB) with cardiometabolic risk (CMR) in children has been poorly investigated. The aim of the study was to examine the association between DEB with certain CMR indices in 9- to 13-year-old children in Greece. A cross-sectional epidemiological study was conducted among 1803 schoolchildren from 77 primary schools in 4 counties of Greece with full data on DEBQ and ChEAT questionnaires and CMR indices. Children underwent anthropometric measurements and Tanner stage, serum lipid, glucose, insulin and HOMA-IR levels assessments. Univariate and multivariate linear regression analyses were performed to test for the association between components of DEBQ and ChEAT with CMR indices. Several significant associations between components of DEBQ and ChEAT with CMR indices were observed when tested at univariate regression models in both boys and girls. However, after adjusting for several possible confounders, including Tanner stage, all significant associations were lost in girls while only a few remained in boys. Thus, DEB might have an unfavorable effect also in certain CMR indices, besides nourishment status. This is more pronounced in preadolescent boys for whom hormonal changes due to the transition to adolescence have not yet been established compared to girls. Still further research is needed to shed more light on these associations. PMID- 25819606 TI - Insula tuning towards external eating versus interoceptive input in adolescents with overweight and obesity. AB - This study was aimed to examine if adolescent obesity is associated with alterations of insula function as indexed by differential correlations between insula activation and perception of interoceptive feedback versus external food cues. We hypothesized that, in healthy weight adolescents, insula activation will positively correlate with interoceptive sensitivity, whereas in excess weight adolescents, insula activation will positively correlate with sensitivity towards external cues. Fifty-four adolescents (age range 12-18), classified in two groups as a function of BMI, excess weight (n = 22) and healthy weight (n = 32), performed the Risky-Gains task (sensitive to insula function) inside an fMRI scanner, and completed the heartbeat perception task (measuring interoceptive sensitivity) and the Dutch Eating Behaviour Questionnaire (measuring external eating as well as emotional eating and restraint) outside the scanner. We found that insula activation during the Risky-Gains task positively correlated with interoceptive sensitivity and negatively correlated with external eating in healthy weight adolescents. Conversely, in excess weight adolescents, insula activation positively correlated with external eating and negatively correlated with interoceptive sensitivity, arguably reflecting obesity related neurocognitive adaptations. In excess weight adolescents, external eating was also positively associated with caudate nucleus activation, and restrained eating was negatively associated with insula activation. Our findings suggest that adolescent obesity is associated with disrupted tuning of the insula system towards interoceptive input. PMID- 25819607 TI - The role of action control and action planning on fruit and vegetable consumption. AB - Globally, fruit and vegetable intake is lower than recommended despite being an important component to a healthy diet. Adopting or maintaining a sufficient amount of fruit and vegetables in one's diet may require not only motivation but also self-regulatory processes. Action control and action planning are two key volitional determinants that have been identified in the literature; however, it is not fully understood how these two factors operate between intention and behavior. Thus, the aim of the current study was to explore the roles of action control and action planning as mediators between intentions and dietary behavior. A longitudinal study with three points in time was conducted. Participants (N = 286) were undergraduate students and invited to participate in a health behavior survey. At baseline (Time 1), measures of intention and fruit and vegetable intake were assessed. Two weeks later (Time 2), action control and action planning were assessed as putative sequential mediators. At Time 3 (two weeks after Time 2), fruit and vegetable consumption was measured as the outcome. The results revealed action control and action planning to sequentially mediate between intention and subsequent fruit and vegetable intake, controlling for baseline behavior. Both self-regulatory constructs, action control and action planning, make a difference when moving from motivation to action. Our preliminary evidence, therefore, suggests that planning may be more proximal to fruit and vegetable intake than action control. Further research, however, needs to be undertaken to substantiate this conclusion. PMID- 25819608 TI - Functional dissection of a strong and specific microbe-associated molecular pattern-responsive synthetic promoter. AB - Synthetic promoters are important for temporal and spatial gene expression in transgenic plants. To identify novel microbe-associated molecular pattern (MAMP) responsive cis-regulatory sequences for synthetic promoter design, a combination of bioinformatics and experimental approaches was employed. One cis-sequence was identified which confers strong MAMP-responsive reporter gene activity with low background activity. The 35-bp-long cis-sequence was identified in the promoter of the Arabidopsis thaliana DJ1E gene, a homologue of the human oncogene DJ1. In this study, this cis-sequence is shown to be a tripartite cis-regulatory module (CRM). A synthetic promoter with four copies of the CRM linked to a minimal promoter increases MAMP-responsive reporter gene expression compared to the wild type DJ1E promoter. The CRM consists of two WT-boxes (GGACTTTT and GGACTTTG) and a variant of the GCC-box (GCCACC), all required for MAMP and salicylic acid (SA) responsivity. Yeast one-hybrid screenings using a transcription factor (TF)-only prey library identified two AP2/ERFs, ORA59 and ERF10, interacting antagonistically with the CRM. ORA59 activates reporter gene activity and requires the consensus core sequence GCCNCC for gene expression activation. ERF10 down-regulates MAMP-responsive gene expression. No TFs interacting with the WT boxes GGACTTTT and GGACTTTG were selected in yeast one-hybrid screenings with the TF-only prey library. In transgenic Arabidopsis, the synthetic promoter confers strong and specific reporter gene activity in response to biotrophs and necrotrophs as well as SA. PMID- 25819609 TI - Exploring the drug migration process through ethyl cellulose-based films from infrared-spectral insights. AB - Using novel time-dependent ATR-FTIR technique and two-dimensional correlation analysis (2 Dcos), the migration behavior of drugs with varying water solubilities was investigated with ethyl cellulose (EC) films prepared with different kinds of pore formers and/or plasticizers. Three major stages were determined for drug migration: (1) water migrated from the drug-saturated solution to the other side of the EC film, (2) upon saturation of the film, water migration ceased and enough pore former was dissolved, and (3) upon dissolution of enough pore former, channels were formed between both sides of the EC film causing drug migration to begin and water migration to return. Further investigations demonstrated a reduction or elimination in second stage with increasing water solubility of the pore former and/or decreasing water solubility of the drug. These results offer a mechanistic understanding of water and drug migration across EC films not previously studied and might provide an effective guide for the preparation of EC pharmaceutical coating with desired drug release behavior. PMID- 25819610 TI - Dysfunction of cortical dendritic integration in neuropathic pain reversed by serotoninergic neuromodulation. AB - Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target. PMID- 25819611 TI - Visually cued action timing in the primary visual cortex. AB - Most behaviors are generated in three steps: sensing the external world, processing that information to instruct decision-making, and producing a motor action. Sensory areas, especially primary sensory cortices, have long been held to be involved only in the first step of this sequence. Here, we develop a visually cued interval timing task that requires rats to decide when to perform an action following a brief visual stimulus. Using single-unit recordings and optogenetics in this task, we show that activity generated by the primary visual cortex (V1) embodies the target interval and may instruct the decision to time the action on a trial-by-trial basis. A spiking neuronal model of local recurrent connections in V1 produces neural responses that predict and drive the timing of future actions, rationalizing our observations. Our data demonstrate that the primary visual cortex may contribute to the instruction of visually cued timed actions. PMID- 25819612 TI - Modular deconstruction reveals the dynamical and physical building blocks of a locomotion motor program. AB - The neural substrates of motor programs are only well understood for small, dedicated circuits. Here we investigate how a motor program is constructed within a large network. We imaged populations of neurons in the Aplysia pedal ganglion during execution of a locomotion motor program. We found that the program was built from a very small number of dynamical building blocks, including both neural ensembles and low-dimensional rotational dynamics. These map onto physically discrete regions of the ganglion, so that the motor program has a corresponding modular organization in both dynamical and physical space. Using this dynamic map, we identify the population potentially implementing the rhythmic pattern generator and find that its activity physically traces a looped trajectory, recapitulating its low-dimensional rotational dynamics. Our results suggest that, even in simple invertebrates, neural motor programs are implemented by large, distributed networks containing multiple dynamical systems. PMID- 25819613 TI - Medial prefrontal cortex predicts internally driven strategy shifts. AB - Many daily behaviors require us to actively focus on the current task and ignore all other distractions. Yet, ignoring everything else might hinder the ability to discover new ways to achieve the same goal. Here, we studied the neural mechanisms that support the spontaneous change to better strategies while an established strategy is executed. Multivariate neuroimaging analyses showed that before the spontaneous change to an alternative strategy, medial prefrontal cortex (MPFC) encoded information that was irrelevant for the current strategy but necessary for the later strategy. Importantly, this neural effect was related to future behavioral changes: information encoding in MPFC was changed only in participants who eventually switched their strategy and started before the actual strategy change. This allowed us to predict spontaneous strategy shifts ahead of time. These findings suggest that MPFC might internally simulate alternative strategies and shed new light on the organization of PFC. PMID- 25819614 TI - A coding transformation for temporally structured sounds within auditory cortical neurons. AB - Although the coding transformation between visual thalamus and cortex has been known for over 50 years, whether a similar transformation occurs between auditory thalamus and cortex has remained elusive. Such a transformation may occur for time-varying sounds, such as music or speech. Most subcortical neurons explicitly encode the temporal structure of sounds with the temporal structure of their activity, but many auditory cortical neurons instead use a rate code. The mechanisms for this transformation from temporal code to rate code have remained unknown. Here we report that the membrane potential of rat auditory cortical neurons can show stimulus synchronization to rates up to 500 Hz, even when the spiking output does not. Synaptic inputs to rate-coding neurons arose in part from temporal-coding neurons but were transformed by voltage-dependent properties and push-pull excitatory-inhibitory interactions. This suggests that the transformation from temporal to rate code can be observed within individual cortical neurons. PMID- 25819615 TI - Protective and immunomodulatory effect of flos Lonicerae japonicae by augmenting IL-10 expression in a murine model of acute lung inflammation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae japonicae has shown antibacterial, anti inflammatory, antipyretic, antioxidant, antiviral, and protective effects in animal models of chronic obstructive pulmonary disease. AIM OF THE STUDY: To investigate the effects of Flos L. japonicae (FLJ), a traditional Chinese medicinal herb, on acute lung inflammation induced by lipopolysaccharide (LPS), in vivo, using a murine model. MATERIALS AND METHODS: Thirty 6-week-old female BALB/c mice were challenged with intratracheal LPS before treatment with FLJ or vehicle. FLJ was examined for its capacity to influence an LPS-induced increase in IL-10 and decrease in TNF-alpha, IL-1beta and IL-6 as measured in murine bronchoalveolar lavage (BALF). RESULTS: FLJ increased nuclear Sp1 binding activity thereby enhancing the expression of IL-10 and decreased nuclear NF kappaB binding activities thereby inhibiting the expression of TNF-alpha, IL 1beta and IL-6 in the lung. The up-regulation of Sp1 activity by FLJ was through incremental phosphorylation of ERK. By contrast, the down-regulation of NF-kappaB activity by FLJ was through suppression of the phosphorylation of IkappaB, p38, and JNK. CONCLUSIONS: We demonstrated FLJ has protective activity against LPS induced lung inflammatory cytokine release. Anti-inflammatory cytokine, IL-10, may prove beneficial in the treatment of endotoxin-associated lung inflammation. PMID- 25819616 TI - Ethnobotanical study on medicinal plants in villages of Catak (Van-Turkey). AB - ETHNOPHARMACOLOGICAL RELEVANCE: This paper provides significant ethnobotanical information on medicinal plants in the villages of Catak in the Eastern Anatolia Region. Recording such data calls for urgency. This is the first ethnobotanical study in which statistical calculations about plants are carried out by means of FIC method in Eastern (Van) part of Turkey. AIM OF THE STUDY: This study aims to identify the wild plants collected for medicinal purposes by locals of Catak which is located in the Eastern Anatolia Region of Turkey, and to identify the uses and local names of these wild plants. MATERIALS AND METHODS: A field study had been carried out for a period of approximately 2 years (2010-2012). During this period, 78 plants taxa were collected. Demographic characteristics of participants, names of the local plants, their utilized parts and preparation methods were investigated and recorded. The plant taxa were collected within the scope of the study; and herbarium materials were prepared. In addition, the relative significance value of the taxa was determined, and informant consensus factor (FIC) was calculated for the medicinal plants included in the study. RESULTS: We have found out in the literature review of the plants included in our study that 78 plant taxa are already used for medicinal purposes while 19 plants are not available among the records in the literature. The most common families are Asteraceae, Apiaceae, Lamiaceae, Rosaceae, Euphorbiaceae, Fabaceae, and Malvaceae. We include in our study and report for the first time the medicinal uses of Alchemilla buseriana Rothm., Astragalus longifolius Lam., Cephalaria microcephala Boiss., Euphorbia grisophylla M.S. Khan, Fritillaria crassifolia Boiss. & Huet. subsp. kurdica (Boiss. & Noe) Rix, Fritillaria pinardii Boiss., Malabaila lasiocarpa Boiss., Nepeta betonicifolia C.A. Mey., Onobrychis altissima Grossh., Onobrychis carduchorum C.C. Townsend, Papaver bracteatum Lindl., Phlomis tuberosa L., Psephellus karduchorum (Boiss.) Wagenitz, Scutellaria orientalis L. subsp. pichleri (Stapf.) Edmondson, Stachys kurdica Boiss. & Hohen var. kurdica, Tanacetum kotschyi (Boiss.) Grierson, Tanacetum zahlbruckneri (Nab.) Grierson, Turanecio eriospermus (DC.) Hamzaoglu, Verbascum pyramidatum M.Bieb. Names of local plants in Turkey vary especially due to vernaculars. The plants that the locals of Catak use are called with the same or different local names in various parts of Anatolia. CONCLUSION: We found out that locals living in the research area use for therapeutic purpose 78 plants taxa which belong to 22 families. Turkish citizens with different ethnic backgrounds took the questionnaire. These people use these wild plants in treatment of several diseases. Comparison of the data obtained in this study with the experimental data obtained in the previous laboratory studies on the wild plants which grow in Catak proved ethnobotanical usages to a great extent. Literature review indicated that the therapeutic plants that grow in Catak are used in different parts of the world for the treatment of similar diseases. PMID- 25819617 TI - Retrocaval ureter in a ferret. PMID- 25819618 TI - Ammonia and temperature determine potential clustering in the anaerobic digestion microbiome. AB - Anaerobic digestion is regarded as a key environmental technology in the present and future bio-based economy. The microbial community completing the anaerobic digestion process is considered complex, and several attempts already have been carried out to determine the key microbial populations. However, the key differences in the anaerobic digestion microbiomes, and the environmental/process parameters that drive these differences, remain poorly understood. In this research, we hypothesized that differences in operational parameters lead to a particular composition and organization of microbial communities in full-scale installations. A total of 38 samples were collected from 29 different full-scale anaerobic digestion installations, showing constant biogas production in function of time. Microbial community analysis was carried out by means of amplicon sequencing and real-time PCR. The bacterial community in all samples was dominated by representatives of the Firmicutes, Bacteroidetes and Proteobacteria, covering 86.1 +/- 10.7% of the total bacterial community. Acetoclastic methanogenesis was dominated by Methanosaetaceae, yet, only the hydrogenotrophic Methanobacteriales correlated with biogas production, confirming their importance in high-rate anaerobic digestion systems. In-depth analysis of operational and environmental parameters and bacterial community structure indicated the presence of three potential clusters in anaerobic digestion. These clusters were determined by total ammonia concentration, free ammonia concentration and temperature, and characterized by an increased relative abundance of Bacteroidales, Clostridiales and Lactobacillales, respectively. None of the methanogenic populations, however, could be significantly attributed to any of the three clusters. Nonetheless, further experimental research will be required to validate the existence of these different clusters, and to which extent the presence of these clusters relates to stable or sub-optimal anaerobic digestion. PMID- 25819619 TI - Treatment for Metastatic Penile Cancer After First-line Chemotherapy Failure: Analysis of Response and Survival Outcomes. AB - OBJECTIVE: To retrospectively estimate the efficacy of various treatments used in men with metastatic penile cancer that progresses after first-line chemotherapy. METHODS: Patients were from a 30-patient cohort with stage TxN2-3M0 penile squamous cell carcinoma treated with neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy before planned lymphadenectomy. Nineteen patients (63.3%) had tumor progression or recurrence, and we evaluated the response to subsequent treatment and survival. RESULTS: Seventeen had received >= 1 salvage therapies; their median survival from first treatment failure was 5.7 months (range, 1.4 30.3 months). Four patients underwent salvage surgery, all of whom experienced further disease progression within 2 months. Four patients received chemoradiotherapy, 1 with stable disease for 13.5 months and 3 with no apparent benefit. Two of 5 evaluable patients (40%) who had received bleomycin, methotrexate, and cisplatin had objective responses (1 complete, 1 partial) but 1 developed fatal pneumonitis. There were no other documented responses to systemic therapy. Median overall survival was 5.6 months for patients who had received a second cisplatin-based treatment at any time and 4.3 months for those who had not (P = .4). CONCLUSION: Patients whose metastatic penile carcinoma progresses through or recurs after front-line cisplatin-based chemotherapy experience poor responses to the described salvage treatments, with a median overall survival time of <6 months. Emphasis should be placed on clinical trials for development of effective therapy in this setting. PMID- 25819620 TI - Medical testosterone: an iatrogenic cause of male infertility and a growing problem. AB - OBJECTIVE: To determine (1) the frequency of testosterone (T) use in 2 academic male infertility practices, (2) the effect on semen parameters, and (3) the potential for reversibility. METHODS: We performed a retrospective review. Inclusion criteria were supplemental T usage at the time of initial visit, T cessation, and semen analyses before and after T cessation. RESULTS: From January 2005 to March 2011, 110 of 1540 patients evaluated for infertility (7.1%) were on supplemental T. Thirty-nine patients met the inclusion criteria. Twenty-two of 39 patients (56%) were started on medical recovery by medical treatment. Median sperm concentration increased from 0 to 6.3 million/mL (P <.0001) after T cessation, with median follow-up of 4.5 months. Eight men (21%) remained azoospermic, and 3 men had sperm concentrations of <= 0.1 million/mL. Fifteen of 22 men given medical treatment and 16 of 17 men given no treatment had sperm return to the semen, respectively (P = .1061). Final sperm concentration did not differ between those who received medical treatment and those who did not. CONCLUSION: Exogenous T treatment causes infertility and is common among reproductive-aged men. These effects are transient for some, but not all men had return of sperm to the semen during the study interval, suggesting a possible underlying primary testicular dysfunction or ongoing hypothalamic-pituitary testicular axis suppression. Education about exogenous T's negative reproductive effects is necessary to avoid this preventable form of infertility. Men with low T levels should have sufficient evaluation to evaluate for underlying pathology before starting T. PMID- 25819622 TI - Editorial comment. PMID- 25819621 TI - Editorial comment. PMID- 25819623 TI - Reply: To PMID 25819619. PMID- 25819625 TI - Editorial comment. PMID- 25819624 TI - The cost of surveillance after urethroplasty. AB - OBJECTIVE: To determine variability in urethral stricture surveillance. Urethral strictures impact quality of life and exact a large economic burden. Although urethroplasty is the gold standard for durable treatment, strictures recur in 8% 18%. There are no universally accepted guidelines for posturethroplasty surveillance. We performed a literature search to evaluate variability in surveillance protocols, analyzed costs, and reviewed performance of each commonly used modality. METHODS: MEDLINE search was performed using the keywords "urethroplasty," "urethral stricture," and "stricture recurrence" to ascertain commonly used surveillance strategies for stricture recurrence. We included English language articles from the past 10 years with at least 10 patients, and age >18 years. Cost data were calculated based on standard 2013 Centers for Medicare and Medicaid Services physician's fees. RESULTS: Surveillance methods included retrograde urethrogram or voiding cystourethrogram, cystourethroscopy, urethral ultrasound, American Urological Association Symptom Score, and postvoid residual and urine flowmetry (UF) measurement. Most protocols call for a retrograde urethrogram or voiding cystourethrogram at the time of catheter removal. After this, UF or PVR, cystoscopy, urine culture, or a combination of UF and American Urological Association Symptom Score was performed at variable intervals. The first-year follow-up cost of anterior urethral surgery ranged from $205 to $1784. For posterior urethral surgery, follow-up cost for the first year ranged from $404 to $961. CONCLUSION: Practice variability for surveillance of urethral stricture recurrence after urethroplasty leads to significant differences in cost. PMID- 25819626 TI - Reply: To PMID 25819620. PMID- 25819627 TI - Extravascular incidental findings in run-off CT angiography in patients with acute limb ischaemia: incidence and clinical relevance. AB - AIM: To evaluate the incidence and clinical relevance of extravascular incidental findings (EVIFs) in CT angiography of the abdominal aorta and lower extremities (run-off CTA) in patients presenting with acute limb ischaemia (ALI). MATERIALS AND METHODS: In this institutional review board-approved, retrospective study, 141 run-off CTA examinations conducted between 2005 and 2013 of patients (67 women, mean age 80 years; 74 men, mean age 69 years) presenting with clinical symptoms of ALI were re-evaluated by two radiologists (2 and 7 years of experience in interpreting run-off CTA). Imaging was conducted using 16- and 64 section CT systems. Image acquisition ranged from the costodiaphragmatic recess to the forefoot. The medical history form of each patient served as the standard of reference for assessment of incidence of EVIFs. CT morphology was assessed to assign EVIFs to one of three categories of clinical relevance: (I) immediate, (II) potential, and (III) no clinical relevance. RESULTS: Thirty-eight patients had category I findings, including four patients (2.8%) with previously unknown malignancy and 67 patients with category II EVIFs. In total 473 extravascular EVIFs were found in 141 patients: 52 category I, 163 category II and 258 category III. CONCLUSION: EVIFs with immediate clinical relevance are very common in run off CTA in patients presenting with acute peripheral artery disease. Therefore, it is important to evaluate all body regions included in a CT examination carefully, even if the clinical focus is on vascular evaluation. The adequate classification of these EVIFs is required to avoid possible unnecessary diagnostic work-up with associated risks and costs. PMID- 25819628 TI - Field evaluation of the efficacy, compatibility and serologic profiling of a combined vaccine against porcine reproductive and respiratory syndrome and Haemophilus parasuis in nursery pigs. AB - The aim of the study was to compare the efficacy and compatibility of a separate or combined vaccination against the porcine reproductive and respiratory syndrome (PRRS) and Haemophilus (H.) parasuis. The study was conducted in a 1200 head nursery farm. A total of 360 piglets at an age of 26 days were randomized into three groups. Group A was vaccinated separately against H. parasuis (Porcilis((r))Glasser) and PRRS (Porcilis((r))PRRS), group B was vaccinated with a combined vaccine of both vaccines and group C remained unvaccinated as control group. The compatibility was evaluated by measurement of the body temperature and a palpation score of the injection site 0, 4, 24 and 72 h after vaccination. During the nursery and the fattening period the average daily weight gain (ADWG), the number of runts and the mortality was evaluated. Additionally blood samples were taken every 2 weeks during the nursery period to perform an OppA-ELISA and a PCR for PRRS virus. No significant difference could be seen regarding the body temperature between group A and group C. Piglets which were vaccinated with the combined vaccine showed a significantly higher body temperature 4 and 72 h post vaccination than piglets from group A. The palpation score was significantly higher in group A 4 and 24h post vaccination compared to the control group, whereas no significant difference was observed between group A and B. No significant differences between groups were seen in the ADWG during the nursery period. The mortality rate during the nursery period was significantly higher in group C than in group A. The ADWG during fattening was significantly higher in the vaccinated groups than in group C. A PRRS genotype1 field virus was detected at the end of the nursery period. No significant differences were observed in the number of OppA-ELISA positive animals, but vaccinated pigs seemed to react earlier. All pigs of the vaccinated groups that were positive in the OppA-ELISA did not develop Glasser's disease and remained in the study until slaughter. The combined administration had no negative influence on efficacy but showed a slightly worse compatibility than the separate administration of both vaccines. The results of the present study indicate that vaccination against Glasser's disease using Porcilis((r))Glasser might influence the results of the OppA-ELISA. PMID- 25819629 TI - [Nationwide survey on pediatric infectious disease organisation and antibiotic management in French hospitals]. AB - Skills in pediatric infectious disease (PID) and antibiotic management are of critical importance in hospitals. This nationwide survey aimed to assess the characteristics, training, and tasks of PID consultants in French hospitals. The management of PID and antibiotic therapy was also analyzed in hospitals lacking PID consultants. METHODS: An electronic survey linked to a dedicated website was sent to French hospitals with a pediatric department in June 2012. In hospitals where PID consultants were available, they were asked to answer the questionnaire. In hospitals lacking PID consultants, pediatricians were asked to send the questionnaire to their infectious disease consultant, if available. RESULTS: A total of 86 individual responses were received from 76 hospitals (including 26 academic hospitals). The existence of a PID consultant was declared in 53 hospitals. Responses were received from the person claiming to be "the" or "one of the" PID consultants in 46 cases, representing 39 centers. PID consultants had a degree in PID (46%) or antibiotic therapy (37%), or a complementary qualification as a specialist in infectious diseases (13%). The PID consultants worked in departments of general pediatrics (61%) and emergency medicine (15%), or neonatology (15%). They were involved in the Nosocomial Infection Prevention Committee (43%) or the Antimicrobial Therapy Committee (63%) and had teaching activities (65%). There was a specific unit with a PID label in 10% of the 39 centers reporting at least one consultant and consultations of infectious diseases took place in 28%. CONCLUSION: PID consultants are rare. Their important role in patient care should be recognized. Efforts should focus on recruiting and training such specialists. PMID- 25819630 TI - [Unscheduled pediatrician office visits: A national survey]. AB - INTRODUCTION: Unscheduled visits (UV) are defined as visits to the family pediatrician (FP) without an appointment or when the appointment was made less than 24h before. Because the number of FPs has decreased since the 2000s, the FP might be less available for UVs and that might be one of the reasons for the increase in emergency department visits. OBJECTIVES: The main objective of the study was to evaluate the proportion of UVs among visits with a FP. The secondary objective was to describe the daily activity of FPs. METHODS: In February 2012, e mail requests were sent to 1022 FPs, asking them to complete an anonymous questionnaire online at the website of the French Association of Pediatricians in Outpatient Practice (AFPA). The questionnaire was about 1 day of activity. RESULTS: A total of 434 FPs participated in the study (42.5%). Among the 10,263 visits a day conducted by these FPs, 4574 were UVs (44.6% [95% CI: 43.6-45.5]). Two hundred and fifty FPs (59.5%) could not conduct one or more UVs because of a lack of availability. The number of children who were not treated on the same day because of a lack of availability was 959, i.e., 2.2 children per day and pediatrician. An absence of off-hour pediatricians in outpatient practice during weekends and during the night was reported by 61% (266) and 90% (391) of the FPs, respectively. CONCLUSION: FPs' activity includes a considerable number of UVs. However, a large number of UVs could not be made because of a lack of pediatricians' availability. PMID- 25819631 TI - [Carbamazepine and psychotropic treatment interaction: Two case studies of carbamazepine overdosage]. AB - Drug interaction is a frequent situation in pediatrics and child psychiatry. Carbamazepine (CBZ) is an antiepileptic drug used as a mood stabilizer in child psychiatry. CBZ is known to be a potent inducer of various CYP isoenzymes of cytochrome P450, which might result in a decrease in the plasma concentration of associated treatments. We describe two cases of CBZ overdosage in adolescent inpatients (14 and 16 years). The patients were treated with risperidone associated with fluoxetine in one and with loxapine in the other case, and CBZ was introduced as a mood stabilizer. Patients presented typical clinical symptoms (fatigue, dizziness, gastrointestinal signs, blurred vision). Overdosage was confirmed by an elevated CBZ plasma concentration (17 and 15.5 mg/L, therapeutic range 4-12 mg/L). We recommend introducing CBZ very progressively in patients treated with psychotropics, particularly when it is associated to several treatments. An intensification of clinical and biological follow-up with early plasma concentration testing should allow for better treatment adjustment. PMID- 25819632 TI - [Pediatric reversible acute velar palsy: A case report]. AB - INTRODUCTION: Approximately 40 cases of acute idiopathic velopharyngeal reversible paralysis in the pediatric population have been reported in the literature. OBSERVATION: We present the case of a 12-year-old boy who had consulted in pediatric emergency departments for symptomatology including rhinolalia, nasal regurgitation, and deviation of the labial commissure. Paraclinical explorations helped diagnose rhombencephalitis with enterovirus. The introduction of oral corticosteroids was followed by rapid clinical improvement in 3 days. Monitoring 1 month later showed complete regression of symptoms. DISCUSSION: Similar cases in the literature describe the occurrence of nasal regurgitation and rhinolalia, sometimes associated with other cranial nerve impairment. The pathogenesis is rarely highlighted and the imaging results are always normal. Ad integrum recovery with or without corticosteroids is the rule. In light of this literature review, it is possible to conclude that the occurrence of such a suggestive clinical picture should limit the often costly and unnecessary additional tests. PMID- 25819633 TI - [Prognostic value of VZV PCR in cerebrospinal fluid in neurological manifestations of varicella]. AB - Varicella-zoster virus (VZV) is, like other alphaherpes viruses, neurotropic. Of the admissions to hospital for varicella, 7.6-25% are due to neurologic manifestations. Most of the time, the concomitant skin lesions facilitate the diagnosis. The justification of qualitative PCR (polymerase chain reaction) for VZV DNA in cerebrospinal fluid in the management of these patients is not clear. The aim of this study was to evaluate the prognostic value of qualitative PCR for VZV DNA in cerebrospinal fluid and to assess its impact on patient management. We conducted a retrospective monocentric study in Versailles Hospital (France). It included every child admitted for neurologic manifestations associated with varicella and compared the patients with positive PCR for VZV DNA to those with a negative PCR in the cerebrospinal fluid. Seven patients with positive PCR and 16 patients with negative PCR were included. The median age of the children included was 3 years (range, 1.6-12 years) and 2 years (range, 0.6-5 years), respectively. In the positive PCR group, 86% of the children had fever on first examination and the average time between the onset of skin lesions and neurological signs was +1.28 days (range, -2 to +5 days). In comparison, in the negative PCR group, 81% of the children had fever and the average time delay was +1.75 days (-2 to +7 days). There was no significant difference in terms of length of hospitalization; 3 days (range, 0-6 days) and 3 days (range, 2-7 days), respectively. All patients discharged from our department went home. In addition, there was no significant difference between the two groups in terms of treatment with acyclovir; two children (28.5%) were treated in the positive PCR group versus four (25%) in the negative PCR group. Our study showed no prognostic value for qualitative PCR for VZV DNA in the cerebrospinal fluid of patients with neurologic manifestations of varicella. Therefore, its relevance can be questioned in clinical practice. However, in case of encephalitis and meningitis during primary infection with VZV, quantitative PCR for VZV DNA might have a prognostic value and therefore requires further study. PMID- 25819634 TI - Evoked potentials and disability in multiple sclerosis: A different perspective to a neglected method. AB - Evoked potentials and disability in multiple sclerosis: a different perspective to a neglected method. OBJECTIVE: Because evoked potentials (EP) are reflections of the functional integrity of sensory-motor systems, they are expected to reflect the abnormality in patients with disabilities and handicaps and also be in correlation with scales. This assumption was tested. METHODS: Patients with multiple sclerosis (MS) and myelopathy (M) and normal controls were investigated by EP, Multiple Sclerosis Walking Scale-12, timed 25-foot walk test and extended disability status scale (EDSS). EP results were converted to ordinal values, and correlations of these values with scales were calculated. Sensitivity and specificity analysis of EP parameters was also performed. RESULTS: Total EP scores revealed high rates of abnormality in both groups, but MS revealed a different correlation pattern from M. The SEP+MEP summed score showed high sensitivity and specificity for MS and this was also correlated with the MS related disability-ambulation scales including EDSS. The most specific parameter was the minimum M latency in the MEP study. CONCLUSIONS: Four extremity recordings of EP with the use of more parameters than usual and ordinal expression of results seem to be benefical in MS. Although this study was cross sectional in nature, results indicated that EP might be useful in clinical follow up. PMID- 25819635 TI - Perceptions of paramedics and emergency staff about the care they provide to people who self-harm: Constructivist metasynthesis of the qualitative literature. AB - OBJECTIVE: Presentations of self-harm to paramedic and emergency staff are increasing, and despite being the first professionals encountered, patients who self-harm report the quality of care and attitudes from these staff are unsatisfactory. Understanding this care may provide opportunities to improve services. The aim of this study is to enhance knowledge building and theory generation in order to develop practice and policy through a metasynthesis of qualitative research relating to perceptions of paramedic and emergency care for people who self-harm. METHODS: The metasynthesis draws on Evolved Grounded Theory Methodology (EGTM). A search was undertaken of CINAHL, MEDLINE, OVID and Psych INFO, and grey literature. Subject headings of 'self-harm' were used alongside key words 'suicide', 'paramedic' 'emergency', 'overdose', 'pre-hospital' mental health, ambulance, perceptions of care, emergency. RESULTS: A total of 1103 papers were retrieved; 12 were finally included. No papers investigated paramedic care for self-harm. The following metaphors emerged: (a) frustration, futility and legitimacy of care; (b) first contact in the pre-hospital environment: talking, immediate and lasting implications of the moral agent; (c) decision making in self-harm: balancing legislation, risk and autonomy; (d) paramedics' perceptions: harnessing professionalism and opportunities to contribute to the care of self-harm. CONCLUSION: Paramedics are often the first health professional contact following self-harm, yet limited qualitative literature has explored this encounter. Metaphors revealed in this paper highlight challenges in decision making and legislation, also opportunities to improve care through professionalization and tailored education. PMID- 25819636 TI - Neuroprotection by peripheral nerve electrical stimulation and remote postconditioning against acute experimental ischaemic stroke. AB - OBJECTIVE: Local electrical stimulation (ES) was reported to protect the brain during ischaemic injury, while the protective effect of limb remote ischaemic postconditioning (RIPostC) was confirmed. The aim of this study was to explore whether remote peripheral nerve ES exerted neuroprotection and whether this procedure shared the same neuroprotective mechanism underlying RIPostC. METHODS: Stroke in Sprague-Dawley rats was induced by distal middle cerebral artery occlusion (dMCAO). Rats were divided into five groups: dMCAO, RIPostC, ES, nerve resection (NR) + ES and RIPostC+ES. Twenty-four hours after reperfusion, rats were examined for neurobehavioural function, including forelimb fault placing test, Ludmila Belayev 12 score test, and infarct volume. The expression of Bcl-2 and cleaved-caspase-3 in ischaemic cortex was assessed by Western blot. RESULTS: In forelimb fault placing test, as compared to the highest score in the stroke only group, RIPostC, ES and RIPostC+ES groups showed a significantly (P < 0.01) lower score. The results were similar for the Ludmila Belayev 12 score test. The infarct volume of the treatment groups also exhibited significant (P < 0.01) reduction as compared to the stroke-only group. The volume of infarct tissue in the combination of RIPostC+ES was significantly less than RIPostC and ES alone (P < 0.05). Furthermore, NR blocked the ES's protection (P < 0.05) as compared to the ES group by using above-mentioned methods. Bcl-2 was upregulated, while cleaved-caspase-3 was downregulated in the experimental groups as compared to the control group. No difference was found among the experimental groups. DISCUSSION: Peripheral nerve ES appears to have a neuroprotective effect in a rat dMCAO model. This effect may indicate a neural protective mechanism underlying beneficial effect of RIPostC. PMID- 25819642 TI - CTLA4 blockade in patients with malignant mesothelioma. PMID- 25819643 TI - Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy resistant malignant mesothelioma: an open-label, single-arm, phase 2 study. AB - BACKGROUND: CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma. METHODS: In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888. FINDINGS: Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21.3 months (IQR 18.7-25.9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10.9 months (95% CI 8.2-13.6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever. INTERPRETATION: Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo controlled, phase 2b study. FUNDING: Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune. PMID- 25819644 TI - How do you solve a problem like tobacco? PMID- 25819645 TI - A Prospective Randomized Study of Pfannenstiel Versus Expanded Port Site Incision for Intact Specimen Extraction in Laparoscopic Radical Nephrectomy. AB - PURPOSE: To compare intra- and postoperative outcome of patients undergoing laparoscopic radical nephrectomy with intact specimen extraction through a Pfannenstiel (PFN) transverse suprapubic or expanded port site (EPS) incision in a prospective randomized fashion. PATIENTS AND METHODS: Patients undergoing laparoscopic transperitoneal radical nephrectomies for suspected renal tumors were randomized for intact renal specimen extraction via a PFN or EPS incision. Operative, perioperative, 1 week, 6 weeks, and 6 months postoperative parameters were prospectively recorded and analyzed including specimen weight, size in maximum diameter, incision length, total operative time, extraction time, estimated blood loss, length of hospital stay, pain score in the postoperative holding area and on the first post operative day, narcotic consumption, time to fluid intake/full diet intake, unassisted ambulation, cosmesis, and wound-related complications. A postoperative quality-of-life questionnaire was also filled out by all the patients. RESULTS: Our series included 51 patients: 26 in the PFN group and 25 in the EPS group. The two groups were similar in demographic characteristics and intraoperative and postoperative parameters apart from a longer PFN incision (P<0.00). First postoperative day pain score was significantly less in the PFN group than in the EPS group (P=0.023). Complication rate was less in the PFN group, although not statistically significant. Hospital stay was significantly shorter in the PFN than in the EPS group (P=0.01). Mean cosmesis and operative satisfaction scores at week 1, week 6, and 6 month visits were not significantly different between both groups. Compared with the EPS group, PFN group patients significantly will choose the same operation if they would do it again (P=0.004). CONCLUSIONS: PFN incision has less morbidity, pain score, and hospital stay compared with EPS incision for intact specimen extraction after transperitoneal laparoscopic radical nephrectomy. Both incisions are associated with high operative satisfaction, good cosmesis, and a low rate of wound complications. PMID- 25819646 TI - Community assembly of a euryhaline fish microbiome during salinity acclimation. AB - Microbiomes play a critical role in promoting a range of host functions. Microbiome function, in turn, is dependent on its community composition. Yet, how microbiome taxa are assembled from their regional species pool remains unclear. Many possible drivers have been hypothesized, including deterministic processes of competition, stochastic processes of colonization and migration, and physiological 'host-effect' habitat filters. The contribution of each to assembly in nascent or perturbed microbiomes is important for understanding host-microbe interactions and host health. In this study, we characterized the bacterial communities in a euryhaline fish and the surrounding tank water during salinity acclimation. To assess the relative influence of stochastic versus deterministic processes in fish microbiome assembly, we manipulated the bacterial species pool around each fish by changing the salinity of aquarium water. Our results show a complete and repeatable turnover of dominant bacterial taxa in the microbiomes from individuals of the same species after acclimation to the same salinity. We show that changes in fish microbiomes are not correlated with corresponding changes to abundant taxa in tank water communities and that the dominant taxa in fish microbiomes are rare in the aquatic surroundings, and vice versa. Our results suggest that bacterial taxa best able to compete within the unique host environment at a given salinity appropriate the most niche space, independent of their relative abundance in tank water communities. In this experiment, deterministic processes appear to drive fish microbiome assembly, with little evidence for stochastic colonization. PMID- 25819647 TI - Prevention, screening, and a chance of rain. PMID- 25819648 TI - Tale of woe questioned. PMID- 25819649 TI - Author's response. PMID- 25819650 TI - Hemostatic agents. PMID- 25819651 TI - Sage advice. PMID- 25819652 TI - Authors' response. PMID- 25819653 TI - Reducing early childhood caries in a Medicaid population: a systems model analysis. AB - BACKGROUND: Despite early childhood caries (ECC) being largely preventable, its repair accounts for a disproportionate share of Medicaid expenditures. In this study, the authors model disease reductions and cost savings from ECC management alternatives. METHODS: The authors apply system dynamics modeling to the New York State Medicaid population of young children to compare potential outcomes of 9 preventive interventions (water fluoridation, fluoride varnish, fluoride toothpaste, medical screening and fluoride varnish application, bacterial transmission reduction, motivational interviewing, dental prevention visits, secondary prevention, and combinations) and the effect of defluoridating New York City. RESULTS: Model simulations help project 10-year disease reductions and net savings from water fluoridation, motivational interviewing, and fluoride toothpaste. Interventions requiring health professionals cost more than they save. Interventions that target children at high risk, begin early, and combine multiple strategies hold greatest potential. Defluoridating New York City would increase disease and costs dramatically. CONCLUSIONS: The variety of population level and individual-level interventions available to control ECC differ substantially in their capacity to improve children's oral health and reduce state Medicaid expenditures. PRACTICAL IMPLICATIONS: Using Medicaid and health department dollars to deliver ECC preventive and management interventions holds strong promise to improve children's oral health while reducing state dental expenditures in Medicaid. PMID- 25819654 TI - Effectiveness of and tooth sensitivity with at-home bleaching in smokers: a multicenter clinical trial. AB - BACKGROUND: The authors conducted a 2-center controlled clinical study to show the equivalence of at-home bleaching in smokers and nonsmokers at 1 week and 1 month and evaluate tooth sensitivity (TS). METHODS: The authors selected 60 smokers and 60 nonsmokers with central incisors of shade A2 or darker. The participants performed bleaching with 10% carbamide peroxide for 3 hours daily for 3 weeks. The authors evaluated the color by using a shade guide and a spectrophotometer before, during, and after bleaching (1 week and 1 month). Patients recorded TS by using a 0-4 scale and a visual analog scale. The authors used multivariable regression analysis to test factors associated with color change and TS (alpha = .05). RESULTS: Smokers and nonsmokers showed significant color change statistically equivalent to within +/- 2.0 units at 1 week after bleaching. Overall, color shade improved by 4.1 shade guide units (95% confidence interval [CI], 3.7-4.5) and 7.8 units of color change measured with the spectrophotometer (95% CI, 7.1-8.5) at 1 month. None of the factors affected the TS risk. TS absolute risk and intensity were similar between groups (P > .05), with an overall estimate of 47% (95% CI, 38-56%). CONCLUSIONS: The immediate effectiveness of whitening- and bleaching-related TS were not affected by smoking. PRACTICAL IMPLICATIONS: Smoking did not affect the immediate color change (1 week). Effective whitening was achieved regardless of whether the patient was a smoker. However, this equivalence was not apparent 1 month after bleaching, with smokers having slightly darker teeth. PMID- 25819655 TI - Isolation of Raoultella planticola from refillable antimicrobial liquid soap dispensers in a dental setting. AB - BACKGROUND: Liquid antimicrobial soaps are commonly used in the dental health care setting for hand washing to minimize the potential spread of infectious agents to health care workers and patients. The purpose of the current study was to evaluate possible bacterial contamination of antimicrobial liquid soap dispensers located in 2 institutional comprehensive dental care clinics. METHODS: Fourteen soap dispensers and 16 original stock containers were sampled. A 1 milliliter aliquot was diluted in 10 mL of phosphate buffer (Tween-80; Acros). Serial dilutions were plated in duplicate on neutralizing agar and incubated for 7 days. Molecular identification was performed using 500 base pair comparisons of 16S ribosomal ribonucleic acid sequencing. Taq polymerase chain reaction was performed with sequence-specific primers for Raoultella species. RESULTS: Bacterial growth was observed at 18 hours for 57% (8 of 14) of soap dispenser samples. Bacterial densities ranged from 4 * 10(2) to 6 * 10(9) colony-forming units per milliliter. Original commercial containers exhibited no growth. Isolates were identified as Raoultella (Klebsiella) planticola. CONCLUSIONS: This is the first study to the authors' knowledge indicating recovery of R. planticola from antimicrobial liquid soap dispensers. R. planticola is a recognized environmental opportunistic pathogen that potentially poses a health concern. PRACTICAL IMPLICATIONS: These findings indicate compliance problems with infection prevention recommendations and support the US Centers for Disease Control and Prevention's recommendation that dispensers should not be topped off. High bacterial loads of R. planticola are inconsistent with infection control practices and are a concern because transmission and possible infection to the health care worker or the patient may occur. PMID- 25819656 TI - Reporting of adverse events and statistical details of efficacy estimates in randomized clinical trials of pain in temporomandibular disorders: Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks systematic review. AB - BACKGROUND: Statistical methods and adverse events (that is, harms) data affect the accuracy of conclusions about the risk-to-benefit ratio of treatments for temporomandibular disorders (TMDs). The authors reviewed the quality of reporting in TMD clinical trials to highlight practices that are in need of improvement. TYPES OF STUDIES REVIEWED: The authors included articles published between 1969 and May 31, 2013, in which the investigators reported randomized clinical trials of TMD treatments with pain as a principal outcome variable. Investigators in trials of nonpharmacologic and noninvasive treatments were required to at least mask the participants and assessors; all others were required to be double masked. RESULTS: Ninety articles qualified for this review: 39 published between 1971 and 2005 (older articles) and 51 published between 2006 and 2013 (newer articles). Specification of primary outcome analyses, methods to accommodate missing data, and adverse event collection methods and rates were generally poor. In some cases, there was apparent improvement from the older to the newer cohort; however, reporting of these methodological details remained inadequate even in the newer articles. PRACTICAL IMPLICATIONS: This review is designed to alert authors, reviewers, editors, and readers of TMD clinical trials to these issues and improve reporting quality in the future. PMID- 25819657 TI - A practical approach to evidence-based dentistry: VI: How to use a systematic review. AB - BACKGROUND AND OVERVIEW: Dental practitioners face new clinical challenges on a daily basis. New treatment options and diagnostic tools are disseminated quickly, and the volume of articles and new evidence is overwhelming. Systematic reviews summarize and synthesize the available evidence related to diagnosis, therapy, prognosis, and harm for clinicians, patients, and decision makers. Such reviews represent one of the most powerful tools to translate knowledge into action. PRACTICAL IMPLICATIONS: The critical appraisal of this type of study involves assessing the risk of bias, results, and applicability of such study. The authors provide guidance for clinicians to critically appraise systematic reviews and apply the findings in clinical practice. PMID- 25819658 TI - Diagnosis and endodontic treatment of type II dens invaginatus by using cone-beam computed tomography and splint guides for cavity access: a case report. AB - BACKGROUND AND OVERVIEW: Dens invaginatus (DI) is defined as a rare dental malformation. The inherent structural variants of this anatomic disorder make it difficult to perform conventional endodontic treatment procedures by means of a conservative access cavity. In this clinical case report, the authors describe the treatment of a type II DI by means of guided splints for cavity access. CASE DESCRIPTION: This is a clinical report of a case of type II DI in a maxillary lateral incisor. The authors established the diagnosis by means of cone-beam computed tomography (CBCT). The authors manufactured 3 splint guides from a Digital Imaging and Communications in Medicine file and a stereolithography file obtained from a plaster model of the patient by using software for guided implant placement, for access opening, and for locating the root canals. CONCLUSIONS: CBCT is an effective method for obtaining information about the root canal system in teeth with DI. In addition, guided implant surgery software is effective for manufacturing splint guides for endodontic treatment with conservative pulp chamber access. PRACTICAL IMPLICATIONS: Information obtained from CBCT allows the clinician to fabricate splint guides for minimally invasive access opening in this type of case, thus reducing the loss of dental tissue. PMID- 25819659 TI - Use of recombinant factor VII for tooth extractions in a patient with severe congenital factor VII deficiency: a case report. AB - BACKGROUND AND OVERVIEW: Patients with factor VII deficiency have an increased risk of prolonged perioperative hemorrhage. In this article, the authors present a case of severe factor VII deficiency in a patient who required tooth extraction. CASE DESCRIPTION: A 44-year-old woman with severe congenital factor VII deficiency sought care for a symptomatic, carious, and nonrestorable maxillary right second molar that required extraction. The authors obtained hematologic consultation, and the patient underwent the extraction under general anesthesia in the inpatient setting. Perioperative management included performing relevant laboratory studies, preoperative recombinant factor VII infusion, and postoperative intravenous aminocaproic acid administration. No hemorrhagic complications occurred throughout the perioperative course. CONCLUSIONS AND PRACTICAL IMPLICATIONS: The degree of factor VII deficiency correlates poorly with bleeding risk. Perioperative management is variable, requiring preoperative consultation with a hematologist. PMID- 25819660 TI - Recombinant human growth factor for periodontal regeneration may be efficacious. PMID- 25819661 TI - Considering a 2-office practice strategy. PMID- 25819662 TI - Your mobile dental home. PMID- 25819663 TI - For the patient. Keeping your gums healthy. PMID- 25819664 TI - Brain glucose metabolism in an animal model of depression. AB - An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on alpha-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to all experimental conditions, i.e., prenatal stress, acute stress, and glucose administration. Our data indicate that glycolysis is increased and the Krebs cycle is decreased in the brain of a prenatal stress animal model of depression. PMID- 25819665 TI - Protective effect of Jolkinolide B on LPS-induced mouse acute lung injury. AB - Jolkinolide B (JB), an ent-abietane diterpenoid, isolated from the dried root of Euphorbia fischeriana, has been reported to have potent anti-tumor and anti inflammatory activities. However, the effects of JB on acute lung injury (ALI) and underlying molecular mechanisms have not been investigated. The present study aimed to investigate the effect of JB on lipopolysaccharide (LPS)-induced ALI. Male C57BL/6 mice were pretreated with dexamethasone or JB 1h before intranasal instillation of LPS. The results showed that JB markedly attenuated LPS-induced histological alterations, lung edema, inflammatory cell infiltration, myeloperoxidase (MPO) activity as well as the production of TNF-alpha, IL-6 and IL-1beta. Furthermore, JB also significantly inhibited LPS-induced the degradation of IkappaBalpha and phosphorylation of NF-kappaB p65 and MAPK. Therefore, our study provides the first line of evidence that pretreatment of JB has a protective effect on LPS-induced ALI in mice. The anti-inflammatory mechanism of JB may be attributed to its suppression of NF-kappaB and MAPK activation. PMID- 25819666 TI - New polycomb group protein enhancer of zeste homolog (EZH) 2-derived peptide with the potential to induce cancer-reactive cytotoxic T lymphocytes in prostate cancer patients with HLA-A3 supertype alleles. AB - Analyses on reactivity of anti-cancer cytotoxic T lymphocytes (CTLs) and clinical application of peptide-based anti-cancer vaccine have been mainly focused on patients with HLA-A2 or -A24 alleles. In this study, we identified an enhancer of zeste homolog (EZH) 2-derived peptide applicable for anti-cancer vaccine for prostate cancer patients with HLA-A3 supertype alleles. Five EZH2-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11, -A31, and -A33) were functionally screened for their potential to induce peptide-specific CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A3 supertype allele(+) prostate cancer patients. As a result, EZH2733-741 peptide was found to efficiently induce peptide-specific CTLs. The EZH2733-741 peptide-stimulated and purified CD8(+) T cells from PBMCs of HLA-A3 supertype allele(+) prostate cancer patients showed higher cytotoxicity against HLA-A3 supertype allele-expressing LNCaP prostate cancer cells than against parental LNCaP cells. This cytotoxicity against HLA-A3 supertype allele-expressing LNCaP cells was partially but significantly inhibited by the addition of EZH2733-741 peptide-pulsed competitive cells. These results indicate that the EZH2733-741 peptide could be a promising candidate for peptide-based immunotherapy for HLA-A3 supertype allele(+) prostate cancer patients. PMID- 25819667 TI - Optimal Elbow Angle for Sonographic Visualization of the Ulnar Collateral Ligament. AB - OBJECTIVE: To formally examine the sonographic appearance of the elbow ulnar collateral ligament (UCL) at 30 degrees versus 70 degrees of elbow flexion in asymptomatic baseball pitchers. DESIGN: A prospective, cross-sectional design. SETTING: Sports medicine clinic in a tertiary academic medical center. PARTICIPANTS: Thirty asymptomatic adolescent baseball pitchers 13-18 years of age (mean 15.8 years), with at least 3 years of continuous pitching experience and no significant history of elbow pain or injury. METHODS: Static sonographic images of the bilateral UCLs were obtained at 30 degrees and 70 degrees of elbow flexion by a single experienced examiner. Images were anonymized and randomized into a slide set. Three clinicians with different levels of ultrasound experience reviewed the static 30 degrees and 70 degrees images for each elbow and chose their preferred image based on UCL conspicuity. The clinicians reviewed a re randomized slide set 1 week later. A different study co-investigator measured UCL cross-sectional area (CSA) on all images using ultrasound machine electronic calipers. MAIN OUTCOME MEASURES: Preference for the sonographic conspicuity of the UCL at 30 degrees versus 70 degrees of elbow flexion, and UCL CSA at 30 degrees versus 70 degrees of flexion. RESULTS: Each clinician demonstrated a significant preference for UCL images obtained at 70 degrees of flexion when compared to those obtained at 30 degrees (80.3% overall preference for 70 degrees , P < .001). There was no statistically significant effect of clinician experience or arm dominance on image preference. The sonographically determined CSA of the UCLs were on average 1.4 mm(2) greater at 70 degrees than at 30 degrees of flexion (P < .001) when combining dominant and nondominant arms. CONCLUSIONS: Static sonographic evaluation of the UCL at 70 degrees of elbow flexion should be integrated into UCL imaging protocols. Furthermore, when performing sonographically guided procedures targeting the UCL, clinicians should consider positioning the elbow at >30 degrees of flexion to optimize UCL conspicuity and CSA. PMID- 25819668 TI - Intra-rater Reliability of Arm and Hand Muscle Strength Measurements in Persons With Late Effects of Polio. AB - BACKGROUND: Muscle weakness in the upper limb is common in persons with late effects of polio. To be able to measure muscle strength and follow changes over time, reliable measurements are needed. OBJECTIVE: To evaluate the intra-rater reliability of isometric and isokinetic arm and hand muscle strength measurements in persons with late effects of polio. DESIGN: A test-retest design. SETTINGS: A university hospital outpatient clinic. PARTICIPANTS: Twenty-eight persons (mean age 68 years, SD 11 years) with late effects of polio in their upper limbs. METHODS: Isometric shoulder abduction, isokinetic concentric elbow flexion and extension, isometric elbow flexion, and isometric grip strength were measured twice, 14 days apart. Reliability was evaluated with the intra-class correlation coefficient, the mean difference between the test sessions (d-), together with the 95% confidence intervals for d- , the standard error of measurement (SEM and SEM%), the smallest real difference (SRD and SRD%), and Bland-Altman graphs. MAIN OUTCOME MEASUREMENTS: A fixed dynamometer (Biodex) was used to measure arm strength and an electronic dynamometer (GRIP-it) was used to measure grip strength. RESULTS: Intra-rater reliability was high, with intra-class correlation coefficients between 0.87 and 0.98. The SEM%, representing the smallest change for a group of persons, ranged from 7%-24% for all strength measurements, and the SRD%, representing the smallest change for an individual person, ranged from 20% 67%. CONCLUSION: Muscle strength in the upper limbs can be reliably measured in persons with late effects of polio. However, the measurement errors indicate that the method is more suitable to detect changes in muscle strength for a group of persons than for an individual person. PMID- 25819669 TI - High school completion programs recommended to improve health equity. PMID- 25819670 TI - bio-samtools 2: a package for analysis and visualization of sequence and alignment data with SAMtools in Ruby. AB - MOTIVATION: bio-samtools is a Ruby language interface to SAMtools, the highly popular library that provides utilities for manipulating high-throughput sequence alignments in the Sequence Alignment/Map format. Advances in Ruby, now allow us to improve the analysis capabilities and increase bio-samtools utility, allowing users to accomplish a large amount of analysis using a very small amount of code. bio-samtools can also be easily developed to include additional SAMtools methods and hence stay current with the latest SAMtools releases. RESULTS: We have added new Ruby classes for the MPileup and Variant Call Format (VCF) data formats emitted by SAMtools and introduced more analysis methods for variant analysis, including alternative allele calculation and allele frequency calling for SNPs. Our new implementation of bio-samtools also ensures that all the functionality of the SAMtools library is now supported and that bio-samtools can be easily extended to include future changes in SAMtools. bio-samtools 2 also provides methods that allow the user to directly produce visualization of alignment data. PMID- 25819671 TI - Outlier detection at the transcriptome-proteome interface. AB - BACKGROUND: In high-throughput experimental biology, it is widely acknowledged that while expression levels measured at the levels of transcriptome and the corresponding proteome do not, in general, correlate well, messenger RNA levels are used as convenient proxies for protein levels. Our interest is in developing data-driven computational models that can bridge the gap between these two levels of measurement at which different mechanisms of regulation may act on different molecular species causing any observed lack of correlations. To this end, we build data-driven predictors of protein levels using mRNA levels and known proxies of translation efficiencies as covariates. Previous work showed that in such a setting, outliers with respect to the model are reliable candidates for post-translational regulation. RESULTS: Here, we present and compare two novel formulations of deriving a protein concentration predictor from which outliers may be extracted in a systematic manner. The first approach, outlier rejecting regression, allows explicit specification of a certain fraction of the data as outliers. In a regression setting, this is a non-convex optimization problem which we solve by deriving a difference of convex functions algorithm (DCA). With post-translationally regulated proteins, one expects their concentrations to be affected primarily by disruption of protein stability. Our second algorithm exploits this observation by minimizing an asymmetric loss using quantile regression and extracts outlier proteins whose measured concentrations are lower than what a genome-wide regression would predict. We validate the two approaches on a dataset of yeast transcriptome and proteome. Functional annotation check on detected outliers demonstrate that the methods are able to identify post translationally regulated genes with high statistical confidence. PMID- 25819672 TI - Global optimization-based inference of chemogenomic features from drug-target interactions. AB - MOTIVATION: Gaining insight into chemogenomic drug-target interactions, such as those involving the substructures of synthetic drugs and protein domains, is important in fragment-based drug discovery and drug repositioning. Previous studies evaluated the interactions locally, thereby ignoring the competitive effects of different substructures or domains, but this could lead to high false positive estimation, calling for a computational method that presents more predictive power. RESULTS: A statistical model, termed Global optimization-based InFerence of chemogenomic features from drug-Target interactions, or GIFT, is proposed herein to evaluate substructure-domain interactions globally such that all substructure-domain contributions to drug-target interaction are analyzed simultaneously. Combinations of different chemical substructures were included since they may function as one unit. When compared to previous methods, GIFT showed better interpretive performance, and performance for the recovery of drug target interactions was good. Among 53 known drug-domain interactions, 81% were accurately predicted by GIFT. Eighteen of the top 100 predicted combined substructure-domain interactions had corresponding drug-target structures in the Protein Data Bank database, and 15 out of the 18 had been proved. GIFT was then implemented to predict substructure-domain interactions based on drug repositioning. For example, the anticancer activities of tazarotene, adapalene, acitretin and raloxifene were identified. In summary, GIFT is a global chemogenomic inference approach and offers fresh insight into drug-target interactions. PMID- 25819673 TI - Overlap and diversity in antimicrobial peptide databases: compiling a non redundant set of sequences. AB - MOTIVATION: The large variety of antimicrobial peptide (AMP) databases developed to date are characterized by a substantial overlap of data and similarity of sequences. Our goals are to analyze the levels of redundancy for all available AMP databases and use this information to build a new non-redundant sequence database. For this purpose, a new software tool is introduced. RESULTS: A comparative study of 25 AMP databases reveals the overlap and diversity among them and the internal diversity within each database. The overlap analysis shows that only one database (Peptaibol) contains exclusive data, not present in any other, whereas all sequences in the LAMP_Patent database are included in CAMP_Patent. However, the majority of databases have their own set of unique sequences, as well as some overlap with other databases. The complete set of non duplicate sequences comprises 16 990 cases, which is almost half of the total number of reported peptides. On the other hand, the diversity analysis identifies the most and least diverse databases and proves that all databases exhibit some level of redundancy. Finally, we present a new parallel-free software, named Dover Analyzer, developed to compute the overlap and diversity between any number of databases and compile a set of non-redundant sequences. These results are useful for selecting or building a suitable representative set of AMPs, according to specific needs. PMID- 25819674 TI - Power and sample-size estimation for microbiome studies using pairwise distances and PERMANOVA. AB - MOTIVATION: The variation in community composition between microbiome samples, termed beta diversity, can be measured by pairwise distance based on either presence-absence or quantitative species abundance data. PERMANOVA, a permutation based extension of multivariate analysis of variance to a matrix of pairwise distances, partitions within-group and between-group distances to permit assessment of the effect of an exposure or intervention (grouping factor) upon the sampled microbiome. Within-group distance and exposure/intervention effect size must be accurately modeled to estimate statistical power for a microbiome study that will be analyzed with pairwise distances and PERMANOVA. RESULTS: We present a framework for PERMANOVA power estimation tailored to marker-gene microbiome studies that will be analyzed by pairwise distances, which includes: (i) a novel method for distance matrix simulation that permits modeling of within group pairwise distances according to pre-specified population parameters; (ii) a method to incorporate effects of different sizes within the simulated distance matrix; (iii) a simulation-based method for estimating PERMANOVA power from simulated distance matrices; and (iv) an R statistical software package that implements the above. Matrices of pairwise distances can be efficiently simulated to satisfy the triangle inequality and incorporate group-level effects, which are quantified by the adjusted coefficient of determination, omega-squared (omega2). From simulated distance matrices, available PERMANOVA power or necessary sample size can be estimated for a planned microbiome study. PMID- 25819675 TI - ExaML version 3: a tool for phylogenomic analyses on supercomputers. AB - MOTIVATION: Phylogenies are increasingly used in all fields of medical and biological research. Because of the next generation sequencing revolution, datasets used for conducting phylogenetic analyses grow at an unprecedented pace. We present ExaML version 3, a dedicated production-level code for inferring phylogenies on whole-transcriptome and whole-genome alignments using supercomputers. RESULTS: We introduce several improvements and extensions to ExaML: Extensions of substitution models and supported data types, the integration of a novel load balance algorithm as well as a parallel I/O optimization that significantly improve parallel efficiency, and a production level implementation for Intel MIC-based hardware platforms. PMID- 25819676 TI - The role of laparoscopy in staging of different gynaecological cancers. AB - Apart from cervical and vaginal cancers that are staged by clinical examination, most gynaecological cancers are staged surgically. Not only can pelvic and para aortic lymphadenectomy offer accurate staging information that helps determine patients' prognosis and hence their treatment plan, but it may also provide a therapeutic effect under certain circumstances. In the past, such a procedure required a big laparotomy incision. With the advent of laparoscopic lighting and instrument, laparoscopic lymphadenectomy became popular since the late 1980s. Dargent et al. published the first report on laparoscopic staging in cervical cancers, and many studies then followed. To date, there are numerous case series and trials evaluating the efficacy and safety of laparoscopic surgery in managing gynaecological cancers. In general, compared with laparotomy, laparoscopic lymphadenectomy has less intraoperative blood loss and post-operative pain, fewer wound complications, shorter length of hospital stay and more speedy recovery. However, this is at the expense of longer operative time. The incidence of port site metastasis is extremely low, although it may be higher in advanced ovarian cancer. Preliminary data showed that there was no significant effect on recurrence and survival, but long-term data are lacking. In this article, the roles of laparoscopy in staging of uterine, cervical and ovarian cancers, the three most common gynaecological cancers, will be reviewed. Novel technologies such as robot-assisted surgery, single-port surgery and sentinel node biopsy will also be discussed. PMID- 25819677 TI - Autogenous bone and a bovine bone substitute for ridge preservation: preliminary clinical and histologic findings. AB - BACKGROUND: Tooth extractions lead to morphological changes of the alveolar ridge. For oral rehabilitation sufficient bone volume of the alveolar ridge is required. This clinical study compared the ability of Bio-Oss(r) Collagen to autogenous bone to preserve bone volume after tooth extraction. METHODS: A total of 17 patients with 20 extraction sites were examined. After extraction, 10 sockets were each filled with either autogenous bone or Bio-Oss(r) Collagen and covered with a resorbable membrane. The width of the alveolar ridge was measured postoperatively, and after 4 and 6 months respectively. Prior to implant insertion, a bone biopsy was taken from the grafted sites and evaluated histologically. RESULTS: The width of the alveolar ridge in the Bio-Oss(r) Collagen group decreased about 5.33 +/- 6.62% after 4 months and 9.45 +/- 10.51% after 6 months. The reduction in the group augmented with autogenous bone was 14.31 +/- 21.41% after 4 months and 19.17 +/- 8.38% after 6 months. No statistically significant differences were observed. The histological examination showed comparable area fractions of total bone in both groups (Bio-Oss(r) Collagen: 59.99 +/- 24.23%; autogenous bone: 61.55 +/- 25.13%; p = 1.0). CONCLUSIONS: The present study demonstrated that autogenous bone and Bio-Oss(r) Collagen are suitable for ridge preservation. However, both techniques could not entirely prevent tissue volume loss. PMID- 25819678 TI - Case of atrial fibrillation induced by interferon beta treatment for melanoma. PMID- 25819679 TI - Neurodegenerative changes in patients with clinical history of bipolar disorders. AB - Neurodegeneration in bipolar disorder (BPD) is poorly understood. Therefore, the current study was designed to assess the immunohistochemical changes in neurodegenerative markers in patients with BPD. Eleven consecutive autopsy cases diagnosed with BPD were analyzed. Sections were obtained from archival paraffin blocks of representative areas and stained using conventional methods, as well as immunostained with several antibodies to screen for neurodegenerative diseases. Age- and non-argyrophilic grains (AGs) degeneration matched controls were selected for each case. Clinical information was retrospectively collected from medical charts. All patients were men, and the average age of death was 70 years. Neuropathological diagnoses included dementia with grains (2), argyrophilic grain disease (2), corticobasal degeneration (CBD, 1), Lewy body disease (1), hypoxic encephalopathy (1) and cerebral infarction (1). All cases showed AGs to various degrees. Three patients died in their 50s; one demonstrated dementia with Lewy bodies, while the other two showed abundant AGs in the thalamus and amygdala. Of the three patients who died in their 60s, one showed AGs preferentially in the thalamus and amygdala, while the others demonstrated limbic predominance. The patients who died in/after their 70s demonstrated AGs similar to controls, except for the patient with CBD. Our data provides potentiality that neurodegenerative diseases may be an underlying pathology in certain cases of BPD. PMID- 25819680 TI - Measuring cavitation and its cleaning effect. AB - The advantages and limitations of techniques for measuring the presence and amount of cavitation, and for quantifying the removal of contaminants, are provided. After reviewing chemical, physical, and biological studies, a universal cause for the cleaning effects of bubbles cannot yet be concluded. An "ideal sensor" with high spatial and temporal resolution is proposed. Such sensor could be used to investigate bubble jetting, shockwaves, streaming, and even chemical effects, by correlating cleaning processes with cavitation effects, generated by hydrodynamics, lasers or ultrasound. PMID- 25819681 TI - Facile synthesis of gallium oxide hydroxide by ultrasonic irradiation of molten gallium in water. AB - This work describes the single-step synthesis of GaO(OH) by ultrasonic irradiation of molten gallium in warm water. The ultrasonic energy causes dispersion of the liquid gallium into micrometric spheres, as-well-as decomposition of some of the water into H and OH radicals. The OH radicals and the dissolved oxygen react on the surface of the gallium spheres to form crystallites of GaO(OH). These crystallites prevent the re-coalescence of the gallium spheres, and as the reaction proceeds all the gallium is converted into crystalline GaO(OH). PMID- 25819682 TI - Allogeneic adipose-derived stem cells regenerate bone in a critical-sized ulna segmental defect. AB - Adipose-derived stem cells (ASCs) with multilineage potential can be induced into osteoblasts, adipocytes and chondrocytes. ASCs as seed cell are widely used in the field of tissue engineering, but most studies either use autologous cells as the source or an immunodeficient animal as the host. In our present study, we explored the feasibility of applying allogeneic ASCs and demineralized bone matrix (DBM) scaffolds for repairing tubular bone defects without using immunosuppressive therapy. Allogeneic ASCs were expanded and seeded on DBM scaffolds and induced to differentiate along the osteogenic lineage. Eight Sprague-Dawley (SD) rats were used in this study and bilateral critical-sized defects (8 mm) of the ulna were created and divided into two groups: with ASC-DBM constructs or DBM alone. The systemic immune response and the extent of bone healing were evaluated post-operatively. Twenty-four weeks after implantation, digital radiography (DR) testing showed that new bones had formed in the experimental group. By contrast, no bone tissue formation was observed in the control group. This study demonstrated that allogeneic ASCs could promote bone regeneration and repair tubular bone defects combined with DBM by histologically typical bone without systemic immune response. PMID- 25819683 TI - Anti-inflammatory and wound healing potential of cashew apple juice (Anacardium occidentale L.) in mice. AB - Cashew apple is a tropical pseudofruit consumed as juice due to its excellent nutritional and sensory properties. In spite of being well known for its important antioxidant properties, the cashew apple has not been thoroughly investigated for its therapeutic potential. Thereby, this study evaluated the antioxidant capacity, anti-inflammatory, and wound-healing activities of cashew apple juice. Juices from ripe and immature cashew apples were analyzed for antioxidant, anti-inflammatory, and wound-healing properties. Those were evaluated in murine models of xylene-induced ear edema and wound excision. Swiss mice were treated with cashew juice by gavage. Edema thickness was measured and skin lesions were analyzed by planimetry and histology. Both antioxidant content and total antioxidant activity were higher in ripe cashew apple juice (RCAJ) than in unripe cashew apple juice (UNCAJ). The UNCAJ presented the main anti inflammatory activity by a significant inhibition of ear edema (66.5%) when compared to RCAJ (10%). Moreover, UNCAJ also showed the best result for wound contraction (86.31%) compared to RCAJ (67.54%). Despite of higher antioxidant capacity, RCAJ did not promote better anti-inflammatory, and healing responses, which may be explained by the fact that treatment increased antioxidants level leading to a redox "imbalance" turning down the inflammatory response modulation exerted by reactive oxygen species (ROS). The results suggest that UNCAJ presents a greater therapeutic activity due to a synergistic effect of its phytochemical components, which improve the immunological mechanisms as well as an optimal balance between ROS and antioxidants leading to a better wound healing process. PMID- 25819684 TI - A budding yeast's perspective on aging: the shape I'm in. AB - Aging is exemplified by progressive, deleterious changes that increase the probability of death. However, while the effects of age are easy to recognize, identification of the processes involved has proved to be much more difficult. Somewhat surprisingly, research using the budding yeast has had a profound impact on our current understanding of the mechanisms involved in aging. Herein, we examine the biological significance and implications surrounding the observation that genetic pathways involved in the modulation of aging and the determination of lifespan in yeast are highly complicated and conserved. PMID- 25819685 TI - Efficacy of linezolid, teicoplanin, and vancomycin in prevention of an experimental polytetrafluoroethylene graft infection model caused by methicillin resistant Staphylococcus aureus. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of linezolid, teicoplanin, and vancomycin in prevention of prosthetic vascular graft infections in a vascular graft infection model. MATERIAL AND METHODS: Fifty rats were divided into 5 groups. A polytetrafluoroethylene graft was implanted on the back of each rat. Methicillin-resistant Staphylococcus aureus (MRSA) strain was inoculated into all rats except Group 1. Group 2 was not given any treatment, Group 3 received linezolid, Group 4 received vancomycin, and Group 5 received teicoplanin. The grafts were removed for microbiological and histological examinations on the 7th day. In addition, C-reactive protein and prealbumin levels and leukocyte counts in obtained blood specimens were determined. RESULTS: Group 1 did not have infection. Group 2 had bacteria 5.7 * 10(4) CFU/cm(2). Group 3 and Group 4 had less bacterial growth. Group 5 had no bacterial growth. The number of bacteria was significantly higher in Group 2 than in the other experimental groups and the control group (p<0.001). Although there was no bacterial growth in Group 5, it did not significantly differ from Group 3 and Group 4. Group 2 had a significantly higher CRP level and leukocyte count and a significantly lower prealbumin level than the other groups. CONCLUSIONS: Linezolid, teicoplanin, and vancomycin are effective in prevention of prosthetic vascular graft infections. PMID- 25819686 TI - Development and evaluation of a polydiacetylene based biosensor for the detection of H5 influenza virus. AB - H5N1 avian influenza has caused serious economic losses as well as posed significant threats to public health, agriculture and wildlife. It is important to develop a rapid, sensitive and specific detection platform suitable for disease surveillance and control. In this study, a highly sensitive, specific and rapid biosensor based on polydiacetylene was developed for detecting H5 influenza virus. The polydiacetylene based biosensor was produced from an optimized ratio of 10,12-pentacosadiynoic acid and 1,2-dimyristoyl-sn-glycero-3-phosphocholine, with the anti-H5 influenza antibody embedded onto the vesicle surface. The optimized polydiacetylene vesicle could detect H5 influenza virus sensitively with a detection limit of 0.53 copies/MUL, showing a dramatic blue-to-red color change that can be observed directly by the naked eye and recorded by a UV-vis spectrometer. The sensitivity, specificity and accuracy of the biosensor were also evaluated. The sensor could specifically differentiate H5 influenza virus from H3 influenza virus, Newcastle disease virus and porcine reproductive and respiratory syndrome virus. Detection using tracheal swabs was in accord with virus isolation results, and comparable to the RT-PCR method. These results offer the possibility and potential of simple polydiacetylene based bio-analytical method for influenza surveillance. PMID- 25819687 TI - Determination of anti-adeno-associated virus vector neutralizing antibody titer with an in vitro reporter system. AB - Adeno-associated virus (AAV) vectors are a platform of choice for in vivo gene transfer applications. However, neutralizing antibodies (NAb) to AAV can be found in humans and some animal species as a result of exposure to the wild-type virus, and high-titer NAb develop following AAV vector administration. In some conditions, anti-AAV NAb can block transduction with AAV vectors even when present at low titers, thus requiring prescreening before vector administration. Here we describe an improved in vitro, cell-based assay for the determination of NAb titer in serum or plasma samples. The assay is easy to setup and sensitive and, depending on the purpose, can be validated to support clinical development of gene therapy products based on AAV vectors. PMID- 25819688 TI - Urinary albumin and transferrin as early diagnostic markers of chronic kidney disease. AB - Feline renal diseases are increasingly noted in veterinary practice. It is important to diagnose and identify the pathological basis of renal dysfunction accurately at an early stage, but there are only a few reports on this area in clinical veterinary medicine. We investigated the efficacy of measurement of urinary albumin (u-Alb) and urinary transferrin (u-Tf) for early diagnosis using 5-ul urine samples collected noninvasively by catheterization from normal (IRIS stage I) cats and cats with stage I chronic kidney disease (CKD). The u-Alb levels in normal and stage I CKD cats were 6.0 +/- 4.5 and 11.2 +/- 8.4 mg/dl, respectively, and the u-Tf levels were 0.09 +/- 0.42 and 0.52 +/- 0.79 mg/dl, respectively. Based on ROC curve analysis, the sensitivity and specificity of u Alb and u-Tf were higher than those of the currently used biomarker, the plasma creatinine level. The sensitivity of u-Alb was higher than that of u-Tf, whereas the specificity of u-Tf was higher than that of u-Alb. The validity of the threshold albumin level (20 mg/dl) was confirmed by measurements using SDS-PAGE. Since leakage of u-Tf in urine precedes leakage of u-Alb, inclusion of u-Tf in biochemistry tests may be appropriate for IRIS staging as a diagnostic marker of early diagnosis of renal disorder in cats. PMID- 25819689 TI - Five scientists win the 2015 Gairdner International Awards. PMID- 25819690 TI - Peter Piot wins 2015 Canada Gairdner Global Health Award. PMID- 25819692 TI - Eliglustat for Gaucher's disease: trippingly on the tongue. PMID- 25819691 TI - Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non inferiority trial. AB - BACKGROUND: The mainstay of treatment for Gaucher's disease type 1 is alternate week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. METHODS: In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged >=18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008 005223-28. FINDINGS: Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8.8%; 95% CI -17.6 to 4.2). The lower bound of the 95% CI of -17.6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). INTERPRETATION: Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. FUNDING: Genzyme, a Sanofi company. PMID- 25819693 TI - The relationship between academic performance and recreation use among first-year medical students. AB - INTRODUCTION: Self-care activities, including exercise, may be neglected by medical students in response to increasing academic demands. Low levels of exercise among medical students may have ripple effects on patient care and counseling. This study investigates the reciprocal role of recreation use and academic performance among first-year medical students. METHODS: We combined retrospective administrative data from four cohorts of first-year medical students at the University of Illinois at Urbana-Champaign from 2006 to 2010 (n=408). We estimated regression models to clarify the role of changes in recreation use before examinations on changes in academic performance, and vice versa. RESULTS: The use of recreation facilities by first-year medical students was highly skewed. We found that changes in recreation use before an exam were positively associated with changes in exam performance, and vice versa. Students who make large decreases in their recreation use are likely to decrease their exam scores, rather than increase them. DISCUSSION: Students who make decreases in their recreation, on average, are likely to decrease their exam scores. These findings suggest that medical students may be able to boost their achievement through wellness interventions, even if they are struggling with exams. We find no evidence that decreasing wellness activities will help improve exam performance. PMID- 25819695 TI - The current status of prophylactic replacement therapy in children and adults with haemophilia. AB - Initiating prophylactic treatment at an early age is considered to be the optimal form of therapy for a child with haemophilia A or B. The pioneering long term experiences of prophylactic treatment from Sweden and The Netherlands demonstrated the benefit of prophylaxis in retrospective and observational studies. Decades later, these benefits were confirmed in a randomized controlled study in USA. We review the current status of prophylactic replacement therapy of haemophilia in children, adolescents, adults and the elderly. Prophylaxis should begin at an early age and there are arguments for continuing it into adulthood. The dose of prophylaxis is dependent on the goal of treatment, economic resources and venous access and should be tailored individually. Starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels. PMID- 25819694 TI - Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus. AB - The recently identified avian-originated influenza H7N9 virus causes severe pulmonary disease and may lead to death in humans. Currently, treatment options for the prevention and control of fatal H7N9 infections in humans remain limited. Here we characterize two human monoclonal antibodies (HuMAbs), HNIgGA6 and HNIgGB5, by screening a Fab antibody phage library derived from patients who recovered from H7N9 infection. Both antibodies exhibit high neutralizing activity against H7N9 virus in cells. Two amino acids in the receptor-binding site, 186V and 226L, are crucial for the binding of these two HuMAbs to viral haemagglutinin antigens. Prophylaxis with HNIgGA6 and HNIgGB5 confers significant immunity against H7N9 virus in a mouse model and significantly reduces the pulmonary virus titre. When administered post infection, therapeutic doses of the HuMAbs also provide robust protection against lethality. These antibodies might represent a potential alternative or adjunct to H7N9 pandemic interventions. PMID- 25819696 TI - A comparative analysis between laparoscopy and open colectomy: assessment of perioperative and oncological outcomes. AB - AIM: Aim of the study was to compare two groups of patients affected by colorectal adenocarcinoma that underwent to open colectomy and laparoscopic colectomy respectively, highlighting the advantage and problems. MATERIAL OF STUDY: This is a retrospective analysis. Between January 2003 and December 2006, 54 patients who underwent colectomy were recruited. Of these, 26 patients underwent open colectomy, and 28 laparoscopy. RESULTS: For open colectomy the average duration of surgery was 177.9 minutes (surgical time) and 280.4 minutes (time of operating room) with a minimum of 110 and a maximum of 360 minutes, with significant differences according to type of surgery performed and the patient's clinical history. For laparoscopy the average duration was 293 minutes, (range 135 - 520), with significant differences depending on the portion of the intestinal tract removed. DISCUSSION: The comparison of two different surgical techniques, laparoscopic and open colectomy revealed some differences. The duration of the resection was greater for laparoscopy when compared to the traditional technique. CONCLUSIONS: Both approaches are technically feasible, safe and oncologically correct. Laparoscopic technique shows a much more favorable outcome in terms of pain, absence of extensive scarring, the incidence of incisional hernias and hospital stay -surgery compared with surgery laparotomy. PMID- 25819697 TI - Provision of lipid-based nutrient supplements to Honduran children increases their dietary macro- and micronutrient intake without displacing other foods. AB - Inadequate energy intake and poor diet quality are important causes of chronic child undernutrition. Strategies for improving diet quality using lipid-based nutrient supplements (LNS) are currently being tested in several countries. To date, information on children's dietary intakes during LNS use is available only from Africa. In this study, we collected 24-h dietary recalls at baseline, 3, 6, 9 and 12 months on Honduran children (n = 298) participating in a cluster randomised trial of LNS. Generalised estimating equations were used to examine differences in number of servings of 12 food groups in the LNS and control arms, and multi-level mixed effects models were used to compare macro- and micronutrient intakes. Models accounted for clustering and adjusted for child's age, season and breastfeeding status. Mean daily servings of 12 food groups did not differ by study arm at baseline and remained similar throughout the study with the exception of groups that were partially or entirely supplied by LNS (nuts and nut butters, fats, and sweets). Baseline intakes of energy, fat, carbohydrates, protein, folate and vitamin A, but not vitamin B12, iron and zinc were lower in the LNS than control arm. The change in all macro- and micronutrients from baseline to each study visit was larger for the LNS arm than the control, except for carbohydrates from baseline to 9 months. These findings indicate that LNS improved the macro- and micronutrient intakes of young non malnourished Honduran children without replacing other foods in their diet. PMID- 25819698 TI - Using the Electronic Health Record in Nursing Research: Challenges and Opportunities. AB - Changes in the patient record from the paper to the electronic health record format present challenges and opportunities for the nurse researcher. Current use of data from the electronic health record is in a state of flux. Novel data analytic techniques and massive data sets provide new opportunities for nursing science. Realization of a strong electronic data output future relies on meeting challenges of system use and operability, data presentation, and privacy. Nurse researchers need to rethink aspects of proposal development. Joining ongoing national efforts aimed at creating usable data output is encouraged as a means to affect system design. Working to address challenges and embrace opportunities will help grow the science in a way that answers important patient care questions. PMID- 25819699 TI - Nurses' Use of Computerized Clinical Guidelines to Improve Patient Safety in Hospitals. AB - Computerized clinical guidelines are frequently used to translate research into evidence-based behavioral practices and to improve patient outcomes. The purpose of this integrative review is to summarize the factors influencing nurses' use of computerized clinical guidelines and the effects of nurses' use of computerized clinical guidelines on patient safety improvements in hospitals. The Embase, Medline Complete, and Cochrane databases were searched for relevant literature published from 2000 to January 2013. The matrix method was used, and a total of 16 papers were included in the final review. The studies were assessed for quality with the Critical Appraisal Skills Program. The studies focused on nurses' adherence to guidelines and on improved patient care and patient outcomes as benefits of using computerized clinical guidelines. The nurses' use of computerized clinical guidelines demonstrated improvements in care processes; however, the evidence for an effect of computerized clinical guidelines on patient safety remains limited. PMID- 25819700 TI - Naltrexone-facilitated buprenorphine discontinuation: a feasibility trial. AB - RATIONALE: Buprenorphine is an effective and popular treatment for opioid dependence. It remains unclear, however, when or how to transition stable buprenorphine-maintained individuals to complete abstinence. This trial investigates the feasibility of using naltrexone to facilitate buprenorphine discontinuation in stable individuals who had tolerated a taper to 2mg or less but were unable to terminate entirely due to withdrawal-related distress. METHODS: The sample consisted of 6 buprenorphine-maintained individuals in sustained full remission, and who had tolerated a taper but were unable to discontinue altogether. A rapid induction procedure was performed, which included supervised buprenorphine discontinuation, oral naltrexone titration with a starting dose of 6.25mg, and administration of long-acting injectable naltrexone. Participants were followed weekly for 5weeks after the injection, with telephone follow-up occurring at 6months. RESULTS: The rapid induction procedure was well tolerated. There was no observed or reported clinical worsening over the course of study participation. Notably, no participants experienced an increase in Subjective Opioid Withdrawal Scale (SOWS) scores after the first oral dose of NTX as compared to day 1 (24hours after last dose of buprenorphine); instead, SOWS scores decreased between days 1 and 7 (p=0.043). All participants were able to discontinue buprenorphine and to remain opioid free during the trial and at follow-up. CONCLUSIONS: This preliminary trial represented for all participants the first successful attempt at buprenorphine discontinuation. Further research is needed to better understand if naltrexone is effective at facilitating buprenorphine discontinuation, as well as the feasibility of a sequential approach (buprenorphine stabilization to naltrexone) for opioid use disorders. PMID- 25819702 TI - 4,4'-DMAR: chemistry, pharmacology and toxicology of a new synthetic stimulant of abuse. AB - In recent years, the spread of new psychoactive substances has dramatically increased in term of availability of both number of compounds and chemical families. In November 2012, 4,4'-Dimethylaminorex (4,4'-DMAR), a novel synthetic stimulant, was first detected in the Netherlands. Between June 2013 and June 2014, thirty-one deaths associated with the consumption of this new drug have been registered across Europe. In this MiniReview, we have summarized the chemical, pharmacological and toxicological information about this new legal high. PMID- 25819701 TI - Feasibility randomized controlled trial of cognitive and behavioral interventions for depression symptoms in patients accessing drug and alcohol treatment. AB - Depressed mood often co-exists with frequent drug and alcohol use. This trial examined the feasibility of screening, recruitment, randomization and engagement of drug and alcohol users in psychological interventions for depression symptoms. A total of 50 patients involved in community drugs and alcohol treatment (CDAT) were randomly allocated to behavioral activation delivered by psychological therapists (n = 23) or to cognitive behavioral therapy based self-help introduced by CDAT workers (n = 27). We examined recruitment and engagement rates, as well as changes in depression (PHQ-9) symptoms and changes in percent days abstinent (PDA within last month) at 24 weeks follow-up. The ratio of screened to recruited participants was 4 to 1, and the randomization schedule successfully generated 2 groups with comparable characteristics. Follow-up was possible with 78% of participants post-treatment. Overall engagement in psychological interventions was low; only 42% of randomized participants attended at least 1 therapy session. Patients offered therapy appointments co-located in CDAT clinics were more likely to engage with treatment (odds ratio = 7.14, p = .04) compared to those offered appointments in community psychological care clinics. Intention-to-treat analyses indicated no significant between-group differences at follow-up in mean PHQ-9 change scores (p = .59) or in PDA (p = .08). Overall, it was feasible to conduct a pragmatic trial within busy CDAT services, maximizing external validity of study results. Moderate and comparable improvements in depression symptoms over time were observed for participants in both treatment groups. PMID- 25819703 TI - Normative MRI, ultrasound and muscle functional MRI findings in the forearms of asymptomatic elite rowers. AB - OBJECTIVES: Forearm injuries are common and debilitating to elite rowers. Chronic exertional compartment syndrome, intersection syndrome and proximal radial bone stress injuries have been documented in this population. This paper explores the imaging findings related to these conditions in asymptomatic elite rowers. DESIGN: Observational study. METHODS: 19 asymptomatic senior elite and under-23 rowers currently competing at National level or above underwent ultrasound (US), Magnetic Resonance Imaging (MRI) and muscle functional MRI evaluation of their forearms. A comprehensive evaluation sheet identifying characteristics of bone stress, intersection syndrome and chronic exertional compartment syndrome was utilised based on a literature search and review by senior clinicians working with this population. RESULTS: Peritendinous fluid of Extensor Carpi Radialis Longus (n=10, 53%) or Extensor Carpi Radialis Brevis (n=6, 32%) was a common finding on US. MRI had a higher rate of identification than US. Extensor Digitorum (Coeff=-1.76, 95%CI -3.04 to -0.49), Flexor Carpi Radialis (Coeff= 2.86, 95%CI -5.35 to -0.38) and Flexor Carpi Ulnaris (Coeff=-3.31, 95%CI -5.30 to -1.32), Pronator Teres (Coeff=-3.94, 95%CI -6.89 to -0.99), and Supinator (Coeff= 168, 95%CI -3.28 to -0.02) showed statistically significant changes immediately post-exercise. Mild proximal radial marrow hyperintensity was present (n=15, 78.9%) with three participants (15.8%) also having mild periosteal oedema of the radius. CONCLUSIONS: Imaging findings commonly seen in symptomatic populations are observed in elite, asymptomatic rowers. Care should be taken when diagnosing bone stress injuries, intersection syndrome and compartment syndrome on imaging findings alone. Data presented can be utilised as a normative dataset for future case studies. PMID- 25819704 TI - Effects of footwear on running economy in distance runners: A meta-analytical review. AB - OBJECTIVES: Previous studies reported inconsistent findings about the effects of footwear on running economy, which is a surrogate measure of running performance. This meta-analytical review compared the running economy between running in barefoot, minimalists, and standard running shoes. DESIGN: Meta-analysis. METHODS: Electronic searches on MEDLINE, CINAHL, SPORTDiscus, and Cochrane Library databases were performed and the reference lists of the screened articles were also scrutinized. Two reviewers screened clinical trials that measured the oxygen cost of runners in different footwear conditions. RESULTS: Thirteen studies were selected in this meta-analysis with a total of 168 runners included. Barefoot running was shown to be more economic than shod running (p<0.01; standardized mean difference=-0.43; 95% Confidence Interval=-0.21 to -0.64; Z=3.96). Similar pattern was found when comparing minimalist and shoe (p<0.01; standardized mean difference=-0.49; 95% Confidence Interval=-0.29 to -0.70; Z=4.64). The observed changes were of small effect. Conversely, no significant difference in the metabolic cost was found between running in minimalists and barefoot running (p=0.45). CONCLUSIONS: Barefoot running or running in minimalist may require lower utilization of oxygen than shod running. Theoretically, the lower oxygen cost may improve long distance running performance. However, more than half of the runners in the included studies had previous barefoot experience and the findings may not apply to those habitual shod runners who are undergoing the transition. In addition, high risk of bias was reported in the included studies and quality study in the future is still warranted. PMID- 25819705 TI - Supporting New Zealand graduate midwives to stay in the profession: An evaluation of the Midwifery First Year of Practice programme. AB - BACKGROUND: the transition from undergraduate midwifery student to working as a confident midwife can be challenging for many newly qualified midwives. Supporting a smooth transition may have a positive impact on the confidence and retention of the new graduates within the workforce. In New Zealand the Midwifery First Year of Practice programme (MFYP) was introduced in 2007 as a structured programme of support for new graduate midwives for the whole of their first year of practice. The main components of the programme include support during clinical practice, provision of a funded mentor midwife chosen by the new graduate midwife, financial assistance for education and a requirement to undertake a quality assessment and reflection process at the end of the first year. AIM: the aim of this study was to explore the retention of new graduates in midwifery practice following participation in the Midwifery First Year of Practice programme. METHOD: data was obtained from the register of MFYP participants between the years 2007 and 2010. This data was cross referenced with the Midwifery Council of New Zealand register and workforce data for 2012. FINDINGS: between the years 2007 and 2010 there were 441 midwives who graduated from a midwifery pre-registration education programme in New Zealand. Of these 415 participated in the MFYP programme. The majority were of New Zealand European ethnicity with 10% identifying as Maori. The mean age of participants reduced from 36.4 (SD 7.3) in 2007 to 33.4 (SD 8.1) in 2010. The overall retention rate for new graduate midwives who had participated in the MFYP programme was 86.3%, with 358 midwives still practising in 2012. CONCLUSION: there is good retention of new graduate midwives within New Zealand and the MFYP programme would appear to support retention. PMID- 25819706 TI - Exploration of preterm birth rates associated with different models of antenatal midwifery care in Scotland: Unmatched retrospective cohort analysis. AB - OBJECTIVES: preterm birth represents a significant personal, clinical, organisational and financial burden. Strategies to reduce the preterm birth rate have had limited success. Limited evidence indicates that certain antenatal care models may offer some protection, although the causal mechanism is not understood. We sought to compare preterm birth rates for mixed-risk pregnant women accessing antenatal care organised at a freestanding midwifery unit (FMU) and mixed-risk pregnant women attending an obstetric unit (OU) with related community-based antenatal care. METHODS: unmatched retrospective 4-year Scottish cohort analysis (2008-2011) of mixed-risk pregnant women accessing (i) FMU antenatal care (n=1107); (ii) combined community-based and OU antenatal care (n=7567). Data were accessed via the Information and Statistics Division of the NHS in Scotland. Aggregates analysis and binary logistic regression were used to compare the cohorts' rates of preterm birth; and of spontaneous labour onset, use of pharmacological analgesia, unassisted vertex birth, and low birth weight. Odds ratios were adjusted for age, parity, deprivation score and smoking status in pregnancy. FINDINGS: after adjustment the 'mixed risk' FMU cohort had a statistically significantly reduced risk of preterm birth (5.1% [n=57] versus 7.7% [n=583]; AOR 0.73 [95% CI 0.55-0.98]; p=0.034). Differences in these secondary outcome measures were also statistically significant: spontaneous labour onset (FMU 83.9% versus OU 74.6%; AOR 1.74 [95% CI 1.46-2.08]; p<0.001); minimal intrapartum analgesia (FMU 53.7% versus OU 34.4%; AOR 2.17 [95% CI 1.90 2.49]; p<0.001); spontaneous vertex delivery (FMU 71.9% versus OU 63.5%; AOR 1.46 [95% CI 1.32-1.78]; p<0.001). Incidence of low birth weight was not statistically significant after adjustment for other variables. There was no significant difference in the rate of perinatal or neonatal death. CONCLUSIONS: given this study's methodological limitations, we can only claim associations between the care model and or chosen outcomes. Although both cohorts were mixed risk, differences in risk levels could have contributed to these findings. Nevertheless, the significant difference in preterm birth rates in this study resonates with other research, including the recent Cochrane review of midwife led continuity models. Because of the multiplicity of risk factors for preterm birth we need to explore the salient features of the FMU model which may be contributing to this apparent protective effect. Because a randomised controlled trial would necessarily restrict choice to pregnant women, we feel that this option is problematic in exploring this further. We therefore plan to conduct a prospective matched cohort analysis together with a survey of unit practices and experiences. PMID- 25819707 TI - Retrospective study of the association between epidural analgesia during labour and complications for the newborn. AB - OBJECTIVE: our objective was to determine the association between epidural analgesia and different variables. BACKGROUND: the effect on newborns of epidural analgesia administered to the mother during labour remains under debate. METHOD: this association was retrospectively investigated in a cohort of 2399 children born in a Spanish public hospital. Only full-term (>37 weeks of gestation) deliveries were included. Other exclusion criteria were: induced delivery (medical or obstetric indication), elective caesarean section, or the presence of an important pregnancy risk factors (hypertension, diabetes, severe disease, toxaemia, retarded intrauterine growth, chronologically prolonged pregnancy, prolonged membrane rupture (>24 hours), oligoamnios, or polyhydramnios). The Mann Whitney U test and Fisher's exact test were applied to determine the relationship between variables. KEY CONCLUSIONS: Apgar index values at one minute and five minutes were slightly but significantly lower in neonates whose mothers had received epidural analgesia. Neonatal intensive care unit admission was significantly more frequent in the epidural versus non-epidural group. Resuscitation was significantly more frequent in the epidural versus non-epidural group. Early breast feeding onset was more frequent in the non-epidural group. The adverse effect of epidural analgesia on early lactation remained significant after adjusting for NICU admission and the need for resuscitation in a logistic regression analysis. Epidural analgesia may have adverse effects on newborns, although the risks are low, and further research is required to elucidate the causal nature of this relationship. PMID- 25819708 TI - Risk factors for predicting visual field progression in Chinese patients with primary open-angle glaucoma: A retrospective study. AB - BACKGROUND: Glaucoma is a leading cause of irreversible blindness worldwide. It is characterized by progressive deterioration of the visual field (VF) that results in a complete loss of vision. This study aimed to determine the risk factors associated with VF progression in Chinese patients with primary open angle glaucoma (POAG). METHODS: We reviewed the charts of POAG patients who visited our clinic between July 2009 and June 2010. We included patients with five or more reliable VF tests using the Humphrey Field Analyzer (Humphrey Instruments, San Leandro, CA, USA) during a period of at least 2 years. The scoring system of the Collaborative Initial Glaucoma Treatment Study (CIGTS) was used to code the VF. Progression was defined as an increasing score >=3, compared to the averaged baseline data. Univariate and multivariate logistic regression analyses were performed to identify the risk factors of VF progression. RESULTS: There were 92 patients (representing 92 eyes) with an average of 8.9 reliable VFs over a mean follow up of 5.4 years. Multivariate logistic regression showed that eyes with more VF tests [odds ratio (OR) = 1.500, p < 0.010] and either increased peak intraocular pressure (IOP) (OR = 1.235, p = 0.044) or a wide IOP range (OR = 1.165, p = 0.041) favored VF progression. High myopia (less than -6.0 D) was not a risk factor (OR = 1.289, p = 0.698) for VF progression in this study. CONCLUSION: In addition to a greater number of VF tests, Chinese patients with treated POAG who experienced a high peak IOP or a wide range of IOP during follow up were more likely to have VF deterioration. PMID- 25819709 TI - Outsourcing vaccine logistics to the private sector: The evidence and lessons learned from the Western Cape Province in South-Africa. AB - With few exceptions, immunization supply chains in developing countries continue to face chronic difficulties in providing uninterrupted availability of potent vaccines up to service delivery levels, and in the most efficient manner possible. As these countries struggle to keep pace with an ever growing number of vaccines, more and more Ministries of Health are considering options of engaging the private sector to manage vaccine storage, handling and distribution on their behalf. Despite this emerging trend, there is limited evidence on the benefits or challenges of this option to improve public supply chain performance for national immunization programmes. To bridge this knowledge gap, this study aims to shed light on the value proposition of outsourcing by documenting the specific experience of the Western Cape Province of South Africa. The methodology for this review rested on conducting two key supply chain assessments which allowed juxtaposing the performance of the government managed segments of the vaccine supply chain against those managed by the private sector. In particular, measures of effective vaccine management best practice and temperature control in the cold chain were analysed. In addition, the costs of engaging the private sector were analysed to get a better understanding of the economics underpinning outsourcing vaccine logistics. The results from this analysis confirmed some of the theoretical benefits of outsourcing to the private sector. Yet, if the experience in the Western Cape can be deemed a successful one, there are several policy and practice implications that developing countries should be mindful of when considering engaging the private sector. While outsourcing can help improve the performance of the vaccine supply chain, it has the potential to do the reverse if done incorrectly. The findings and lessons learnt from the Western Cape experience can serve as a step towards understanding the role of the private sector in immunization supply chain and logistics systems for developing countries. PMID- 25819710 TI - Bacillus subtilis spores as adjuvants for DNA vaccines. AB - Recently, Bacillus subtilis spores were shown to be endowed with strong adjuvant capacity when co-administered with purified antigenic proteins. In the present study we assessed whether spores possess adjuvant properties when combined with DNA vaccines. We showed that B. subtilis spores promoted the activation of dendritic cells in vitro and induced migration of pro-inflammatory cells after parenteral administration to mice. Likewise, co-administration of spores with a DNA vaccine encoding the human papillomavirus type 16 (HPV-16) E7 protein enhanced the activation of antigen-specific CD8(+) T cell responses in vivo. Mice immunized with the DNA vaccine admixed with spores presented a protective immunity increase to previously implanted tumor cells, capable of expressing HPV 16 oncoproteins. Finally, we observed that the adjuvant effect can vary accordingly to the number of co-administered spores which may be ascribed with the ability to induce. Collectively, the present results demonstrate for the first time that B. subtilis spores can also confer adjuvant effects to DNA vaccines. PMID- 25819711 TI - Meningococcal C conjugate age-dependant long-term loss of effectiveness. AB - INTRODUCTION: Although different epidemiological studies have assessed meningococcal C conjugate vaccine effectiveness within 1 and >1 year since vaccination, none of them evaluated long-term effectiveness. In order to assess if epidemiological data correlates with the findings described in seroprevalence studies we evaluated long-term vaccine effectiveness over time, up to 10 years since vaccination. METHODS: Cases targeted by vaccination programs and notified to the Spanish Surveillance System between 2001 and 2013 were included in the study. Vaccine effectiveness was estimated using the screening method. Relationship between vaccine effectiveness and time since vaccination was explored using point estimates, simple logistic regression or restricted cubic splines logistic regression model for all and for those vaccinated at <1, 1-11 and at 12-19 years of age. RESULTS: From 345 confirmed cases reported in the period and targeted by vaccination programs, 125 (36.23%) were vaccine failures. Proportion of vaccine failures decreased with age of vaccination: 63.97% at <1 year; 36.84% at 1-11 years; and 3.88% at 12-19 years. Using the best model for each group, vaccine effectiveness decreased from 99.12% to 90.85% (%change=-8.3%) for all; from 99.04% to 48.60% (%change=-50.9%) for those vaccinated at <1 years and from 99.45% to 90.18% (%change=-9.3%) for those vaccinated at 1-11 years after 10 years since vaccination. For those vaccinated at 12-19 years no changes were observed in vaccine effectiveness after 10 years (p=0.968). CONCLUSIONS: After 10 years, vaccine effectiveness decreased by 50% in those vaccinated at <1 year, while those vaccinated with one dose at 12-19 years showed no changes. Vaccine failures occurred early after vaccination and more frequently in those vaccinated at younger ages. Vaccination at >=12 years seems to be related to a low number of vaccine failures and a higher and endurable protection over time. PMID- 25819712 TI - Feature-specific transition from positive mismatch response to mismatch negativity in early infancy: mismatch responses to vowels and initial consonants. AB - This study investigated how phonological saliency, deviance size, and maturation affect mismatch responses (MMRs) in early infancy. MMRs to Mandarin vowels and initial consonants were measured using a multi-deviant oddball paradigm in adults, newborns, and 6-month-olds. The vowel condition consisted of Mandarin syllable da as the standard, du as the large deviant and di as small deviant. As for initial consonant condition, we took syllable ba as standard, ga as large deviant, and ba as small deviant. While adults showed typical mismatch negativities (MMNs), newborns demonstrated broad positive MMRs (P-MMRs) to both initial consonants and vowels. For 6-month-olds, deviance size affected the polarity of MMRs to vowels. The large deviant du/da contrast elicited an adult like MMN, while the small deviant di/da contrast elicited a P-MMR. Initial consonant changes elicited only P-MMRs, regardless of deviance size. In summary, MMRs to vowels switched from P-MMR at birth to MMN at 6 months. However, the polarity transition was not found for MMRs to initial consonants. The developmental trajectories of MMRs to vowels and initial consonants further support the phonological saliency hypothesis. PMID- 25819713 TI - Differential tolerances to ocean acidification by parasites that share the same host. AB - Ocean acidification is predicted to cause major changes in marine ecosystem structure and function over the next century, as species-specific tolerances to acidified seawater may alter previously stable relationships between coexisting organisms. Such differential tolerances could affect marine host-parasite associations, as either host or parasite may prove more susceptible to the stressors associated with ocean acidification. Despite their important role in many ecological processes, parasites have not been studied in the context of ocean acidification. We tested the effects of low pH seawater on the cercariae and, where possible, the metacercariae of four species of marine trematode parasite. Acidified seawater (pH 7.6 and 7.4, 12.5 degrees C) caused a 40-60% reduction in cercarial longevity and a 0-78% reduction in metacercarial survival. However, the reduction in longevity and survival varied distinctly between parasite taxa, indicating that the effects of reduced pH may be species-specific. These results suggest that ocean acidification has the potential to reduce the transmission success of many trematode species, decrease parasite abundance and alter the fundamental regulatory role of multi-host parasites in marine ecosystems. PMID- 25819714 TI - Development of a Schistosoma mansoni shotgun O-glycan microarray and application to the discovery of new antigenic schistosome glycan motifs. AB - Upon infection with Schistosoma, antibody responses are mounted that are largely directed against glycans. Over the last few years significant progress has been made in characterising the antigenic properties of N-glycans of Schistosoma mansoni. Despite also being abundantly expressed by schistosomes, much less is understood about O-glycans and antibody responses to these have not yet been systematically analysed. Antibody binding to schistosome glycans can be analysed efficiently and quantitatively using glycan microarrays, but O-glycan array construction and exploration is lagging behind because no universal O-glycanase is available, and release of O-glycans has been dependent on chemical methods. Recently, a modified hydrazinolysis method has been developed that allows the release of O-glycans with free reducing termini and limited degradation, and we applied this method to obtain O-glycans from different S. mansoni life stages. Two-dimensional HPLC separation of 2-aminobenzoic acid-labelled O-glycans generated 362 O-glycan-containing fractions that were printed on an epoxide modified glass slide, thereby generating the first shotgun O-glycan microarray containing naturally occurring schistosome O-glycans. Monoclonal antibodies and mass spectrometry showed that the O-glycan microarray contains well-known antigenic glycan motifs as well as numerous other, potentially novel, antibody targets. Incubations of the microarrays with sera from Schistosoma-infected humans showed substantial antibody responses to O-glycans in addition to those observed to the previously investigated N- and glycosphingolipid glycans. This underlines the importance of the inclusion of these often schistosome-specific O glycans in glycan antigen studies and indicates that O-glycans contain novel antigenic motifs that have potential for use in diagnostic methods and studies aiming at the discovery of vaccine targets. PMID- 25819715 TI - Phylogenomic analysis uncovers the evolutionary history of nutrition and infection mode in rice blast fungus and other Magnaporthales. AB - The order Magnaporthales (Ascomycota, Fungi) includes devastating pathogens of cereals, such as the rice blast fungus Pyricularia (Magnaporthe) oryzae, which is a model in host-pathogen interaction studies. Magnaporthales also includes saprotrophic species associated with grass roots and submerged wood. Despite its scientific and economic importance, the phylogenetic position of Magnaporthales within Sordariomycetes and the interrelationships of its constituent taxa, remain controversial. In this study, we generated novel transcriptome data from 21 taxa that represent key Magnaporthales lineages of different infection and nutrition modes and phenotypes. Phylogenomic analysis of >200 conserved genes allowed the reconstruction of a robust Sordariomycetes tree of life that placed the monophyletic group of Magnaporthales sister to Ophiostomatales. Among Magnaporthales, three major clades were recognized: 1) an early diverging clade A comprised of saprotrophs associated with submerged woods; 2) clade B that includes the rice blast fungus and other pathogens that cause blast diseases of monocot plants. These species infect the above-ground tissues of host plants using the penetration structure, appressorium; and 3) clade C comprised primarily of root-associated species that penetrate the root tissue with hyphopodia. The well-supported phylogenies provide a robust framework for elucidating evolution of pathogenesis, nutrition modes, and phenotypic characters in Magnaporthales. PMID- 25819716 TI - Foot posture is associated with kinematics of the foot during gait: A comparison of normal, planus and cavus feet. AB - Variations in foot posture are associated with the development of some lower limb injuries. However, the mechanisms underlying this relationship are unclear. The objective of this study was to compare foot kinematics between normal, pes cavus and pes planus foot posture groups using a multi-segment foot model. Ninety-seven healthy adults, aged 18-47 were classified as either normal (n=37), pes cavus (n=30) or pes planus (n=30) based on normative data for the Foot Posture Index, Arch Index and normalised navicular height. A five segment foot model was used to measure tri-planar motion of the rearfoot, midfoot, medial forefoot, lateral forefoot and hallux during barefoot walking at a self-selected speed. Angle at heel contact, peak angle, time to peak angle and range of motion was measured for each segment. One way ANOVAs with post-hoc analyses of mean differences were used to compare foot posture groups. The pes cavus group demonstrated a distinctive pattern of motion compared to the normal and pes planus foot posture groups. Effect sizes of significant mean differences were large and comparable to similar studies. Three key differences in overall foot function were observed between the groups: (i) altered frontal and transverse plane angles of the rearfoot in the pes cavus foot; (ii) Less midfoot motion in the pes cavus foot during initial contact and midstance; and (iii) reduced midfoot frontal plane ROM in the pes planus foot during pre-swing. These findings indicate that foot posture does influence motion of the foot. PMID- 25819717 TI - Assessment of walking, running, and jumping movement features by using the inertial measurement unit. AB - PURPOSE: To observe various modes of lower limb locomotion, an inertial measurement unit (IMU) was used. Digital signals were used to identify signal characteristics that help to distinguish among locomotion modes and intensity levels. METHODS: A wireless IMU was installed on the outside of shoes and three forms of locomotion (walking, running, and jumping) were assessed at two intensity levels (low and high) to observe the acceleration, foot angular velocity variations, and characteristics of the curve variations in the anteroposterior, mediolateral, and superior-inferior directions. RESULTS: Most interactions between intensity and locomotion were statistically significant, except for the acceleration in the anteroposterior direction and on the horizontal plane. In addition, as the intensity increased, the values of all the parameters increased. Thus, both the acceleration values and range of angular velocity variation can be used to distinguish the intensity levels. Moreover, the results indicated that the angular velocity in the frontal axis, which is the sequence of the plantar/dorsiflexion movements, can also be used to identify different locomotion. CONCLUSIONS: Uniaxial acceleration or the range of angular velocity variation could be used to identify locomotion intensities, whereas the characteristics of the uniaxial angular velocity curve could be used to identify the locomotion modes. PMID- 25819718 TI - Radical antegrade pancreatosplenectomy (with video). PMID- 25819719 TI - HAL-RAR(r) procedure: A safe operation for hemorrhoids. PMID- 25819721 TI - Prostate cancer risk calculators using ERSPC-derived data underestimate the risk if the WHO IRP 96/670 standard is used in prostate-specific antigen analysis. PMID- 25819720 TI - Polymorphisms of Genes Involved in Glucose and Energy Metabolic Pathways and Prostate Cancer: Interplay with Metformin. AB - BACKGROUND: Energy metabolism is important in cancer proliferation and progression, but its role in prostate cancer (PCa) remains unclear. OBJECTIVE: We explored whether single-nucleotide polymorphisms (SNPs) of genes involved in energy metabolic pathways are associated with PCa risk and prognosis, and whether antidiabetic treatment modifies any such association. DESIGN, SETTING, AND PARTICIPANTS: The PRACTICAL Consortium genotyped 397 SNPs among 3241 screened participants (including 801 PCa cases) in the Finnish Prostate Cancer Screening Trial and 1983 hospital-based PCa cases. Information on medication use was obtained from a national prescription database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Genetic risk scores were calculated in terms of SNPs associated with PCa incidence or survival at a significance level of p < 5*10( 3). Hazard ratios for PCa and disease-specific death were calculated via Cox regression modelling. The predictive value of the genetic risk score was evaluated using receiver operating characteristic and Harrell's c-index analyses. RESULTS AND LIMITATIONS: A total of 30 SNPs were associated with PCa risk and ten SNPs with survival. The genetic risk score was consistently associated with PCa survival. The risk association was non-significantly weaker in metformin users. The genetic risk score did not improve prediction of PCa risk, but slightly improved the ability to predict PCa survival when added to conventional predictors (c-index improved from 87.4 to 87.9; p<0.001). A limitation is that information on diabetes apart from medication use was unavailable for the study population. CONCLUSIONS: SNPs of genes involved in energy metabolic pathways are associated with PCa survival. This suggests an important role of glucose metabolism in PCa progression, which could point to new avenues for prevention of PCa death. PATIENT SUMMARY: Genetic changes in glucose and energy metabolic pathways are associated with a higher risk of high-risk prostate cancer and adverse outcomes. PMID- 25819722 TI - Precision Medicine in Active Surveillance for Prostate Cancer: Development of the Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator. AB - BACKGROUND: Men on active surveillance (AS) face repeated biopsies. Most biopsy specimens will not show disease progression or change management. Such biopsies do not contribute to patient management and are potentially morbid and costly. OBJECTIVE: To use a contemporary AS prospective trial to develop a tool to predict AS biopsy outcomes. DESIGN, SETTING, AND PARTICIPANTS: Biopsy samples (median: 2; range: 2-9 per patient) from 859 men participating in the Canary Prostate Active Surveillance Study and with Gleason 6 prostate cancer (median follow-up: 35.8 mo; range: 3.0-148.7 mo) were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic regression was used to predict progression, defined as an increase in Gleason score from <=6 to >=7 or increase in percentage of cores positive for cancer from <34% to >=34%. Fivefold internal cross validation was performed to evaluate the area under the receiver operating characteristic curve (AUC). RESULTS AND LIMITATIONS: Statistically significant risk factors for progression on biopsy were prostate-specific antigen (odds ratio [OR]: 1.045; 95% confidence interval [CI], 1.028-1.063), percentage of cores positive for cancer on most recent biopsy (OR: 1.401; 95% CI, 1.301-1.508), and history of at least one prior negative biopsy (OR: 0.524; 95% CI, 0.417-0.659). A multivariable predictive model incorporating these factors plus age and number of months since last biopsy achieved an AUC of 72.4%. CONCLUSIONS: A combination of readily available clinical measures can stratify patients considering AS prostate biopsy. Risk of progression or upgrade can be estimated and incorporated into clinical practice. PATIENT SUMMARY: The Canary-Early Detection Research Network Active Surveillance Biopsy Risk Calculator, an online tool, can be used to guide patient decision making regarding follow-up prostate biopsy. PMID- 25819723 TI - Cryoablation for Small Renal Masses: Selection Criteria, Complications, and Functional and Oncologic Results. AB - CONTEXT: Cryoablation (CA) is a minimally invasive modality with low complication rates, but its use in urology is relatively recent. OBJECTIVE: To summarize available evidence for CA for small renal masses (SRMs) and to assess the selection criteria, complications, and functional and oncologic results based on the latest CA literature. EVIDENCE ACQUISITION: A systematic literature search of the Medline, Embase, and Scopus databases was performed in August 2014 using Medical Subject Headings and free-text protocol. The following search terms were included: kidney cryosurgery, renal cryosurgery, kidney cryoablation, renal cryoablation, kidney cryotherapy, and renal cryotherapy. EVIDENCE SYNTHESIS: Due to the relatively recent mainstream utilization of CA and lack of long-term efficacy data from large prospective or randomized studies, most of the data available on CA are limited to treatment of SRMs in patients who are often older or are poor surgical candidates. The rates of major complications across the CA literature remain relatively low. Studies assessing renal function after CA suggest a degree of functional decline following CA because proper application includes freezing of a tumor margin; however, often this is not clinically significant. Specific oncologic outcomes should be evaluated in patients with biopsy-proven renal cell carcinoma; when SRM series include benign or unbiopsied tumors, the results of these outcomes are skewed. Although earlier series were suggestive of a higher recurrence rate after CA, some studies have challenged this view reporting recurrence rates comparable with extirpative nephron-sparing surgery. CONCLUSIONS: CA represents an alternative approach to treatment for patients diagnosed with renal neoplasm. There is no consensus within the literature on the best patient selection criteria. Due to higher rates of treatment failure, it is often not offered to patients with minimal comorbidities and good life expectancy. In terms of functional outcomes, CA signifies a modality with minimum impact on renal function; however, well-designed studies precisely assessing this factor are lacking. CA is a minimally invasive modality with suitably low rates of complications, particularly if delivered via the percutaneous route. PATIENT SUMMARY: Cryoablation (CA) represents an alternative approach for treating renal neoplasm. Excellent functional outcomes and low rates of complications make CA an ideal minimally invasive modality. Patient selection criteria and oncologic outcomes require further study. PMID- 25819725 TI - Thyroglossal duct cyst: patient demographics and surgical outcome of 159 primary operations. PMID- 25819724 TI - Predicting Life Expectancy in Men Diagnosed with Prostate Cancer. AB - CONTEXT: The widespread use of prostate-specific antigen (PSA) screening has led to the detection of more indolent prostate cancer (PCa) in healthy men. PCa treatment and screening must therefore balance the potential for life gained against the potential for harm. Fundamental to this balance is physician awareness of a patient's estimated life expectancy (LE). OBJECTIVE: To review the evidence on LE differences between men diagnosed with PCa and the general population. To examine clinician- and model-predicted LE and publicly available LE calculators. EVIDENCE ACQUISITION: A comprehensive search of the PubMed database between 1990 and September 2014 was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Free text protocols of the following search terms were used "life expectancy prostate cancer", "life expectancy non-cancer", "non-cancer mortality prostate", and "comorbidity-adjusted life expectancy". Two internet search engines were queried daily for 1 mo for the search term "life expectancy calculator", and the top 20 results were examined. EVIDENCE SYNTHESIS: Of 992 articles and 32 websites screened, 17 articles and nine websites were selected for inclusion. Men with non screening-detected PCa and distant disease at diagnosis were found to have shorter LE than age-matched peers, whereas men with localized PCa had prolonged LE. In general, clinician-predicted 10-yr LE was pessimistic and of limited accuracy; however, model-predicted LE provided only modest improvements in accuracy (c-index of models 0.65-0.84). Online LE calculators provide consistent LE estimates, but government life tables provide LE estimates near the mean for all calculators examined. CONCLUSIONS: The accuracy of clinician-predicted survival is limited, and while available statistical models offer improvement in discrimination, it is unclear whether they provide advantages over freely available government life tables. PATIENT SUMMARY: We examined differences in life expectancy between men diagnosed with prostate cancer and the general population, and ways of predicting life expectancy to help guide treatment decisions. We found that current models for predicting life expectancy specific to prostate cancer might not be any better than government life tables or simple rules of thumb. PMID- 25819726 TI - Topical minoxidil improves congenital hypotrichosis caused by LIPH mutations. PMID- 25819728 TI - Screening of direct thrombin inhibitors from Radix Salviae Miltiorrhizae by a peak fractionation approach. AB - Thrombin plays a significant role in thromboembolic disease. In this work, a peak fractionation approach combined with an activity assay method was used to screen direct thrombin inhibitors from Radix Salviae Miltiorrhizae (RSM), a famous herbal remedy for the treatment of cardiovascular diseases in China. A total of 91 fractions were collected from the RSM extract, and 19 fractions out of them showed thrombin inhibitory effects with dose-effect relationship. Among them, three compounds were unambiguously identified as 15, 16-dihydrotanshinone I, cryptotanshinone and tanshinone IIA with IC50 values of 29.39, 81.11 and 66.60MUM, respectively. The three compounds were reported with direct thrombin inhibition activities for the first time and their ligand-thrombin interactions were explored by a molecular docking research. These results may contribute to explain the medical benefit of RSM for the prevention and treatment of cardiovascular diseases. PMID- 25819727 TI - The influence of stress and gonadal hormones on neuronal structure and function. AB - This article is part of a Special Issue "SBN 2014". The brain is highly plastic, allowing us to adapt and respond to environmental and physiological challenges and experiences. In this review, we discuss the relationships among alterations in dendritic arborization, spine morphology, and behavior due to stress exposure, endogenous hormone fluctuation, or exogenous hormonal manipulation. Very few studies investigate structure-function associations directly in the same cohort of animals, and there are notable inconsistencies in evidence of structure function relationships in the prefrontal cortex and hippocampus. Moreover, little work has been done to probe the causal relationship between dendritic morphology and neuronal excitability, leaving only speculation about the adaptive versus maladaptive nature of experience-dependent dendritic remodeling. We propose that future studies combine electrophysiology with a circuit-level approach to better understand how dendritic structure contributes to neuronal functional properties and behavioral outcomes. PMID- 25819729 TI - Outcomes for ulnar collateral ligament reconstruction: a retrospective review using the KJOC assessment score with two-year follow-up in an overhead throwing population. AB - BACKGROUND: Injury to the ulnar collateral ligament (UCL) often results in valgus elbow instability requiring reconstruction. No standardized and validated outcome measure has compared outcomes between surgical techniques and institutions in the overhead throwing athlete. The aim of this study was to use the Kerlan-Jobe Orthopaedic Clinic shoulder and elbow score (KJOC score) to report functional outcomes in overhead throwing athletes undergoing UCL reconstruction. We predict that the KJOC score in our general throwing population will provide an accurate assessment of postoperative outcomes consistent with previously published reports. METHODS: A retrospective review of 33 patients undergoing UCL reconstruction was carried out during a 5-year period between 2004 and 2009. Minimum follow-up was 2.2 years with an average of 3.7 years. All surgeries were performed by fellowship-trained surgeons using either the docking (n = 12) or modified Jobe technique (n = 21). Age, sport, position, and return to play status were obtained. The KJOC score was administered to assess final functional outcome. RESULTS: A total of 33 athletes underwent UCL reconstruction-30 baseball players and 3 javelin throwers. Of these, 27 (82%) returned to their sport at their previous level in an average of 12.25 months. The overall average KJOC score was 76. Athletes who returned to their previous level of play had a mean KJOC score of 77. Those who were unable to return to play had a mean score of 69. CONCLUSION: Our study demonstrates consistent outcomes for UCL reconstruction using the KJOC shoulder and elbow score compared with previously reported data. PMID- 25819730 TI - Optimal baseplate rotational alignment for locking-screw fixation in reverse total shoulder arthroplasty: a three-dimensional computer-aided design study. AB - BACKGROUND: Baseplate loosening in reverse total shoulder arthroplasty (RTSA) remains a concern. Placing peripheral screws into the 3 pillars of the densest scapular bone is believed to optimize baseplate fixation. Using a 3-dimensional computer-aided design (3D CAD) program, we investigated the optimal rotational baseplate alignment to maximize peripheral locking-screw purchase. METHODS: Seventy-three arthritic scapulae were reconstructed from computed tomography images and imported into a 3D CAD software program along with representations of an RTSA baseplate that uses 4 fixed-angle peripheral locking screws. The baseplate position was standardized, and the baseplate was rotated to maximize individual and combined peripheral locking-screw purchase in each of the 3 scapular pillars. RESULTS: The mean +/- standard error of the mean positions for optimal individual peripheral locking-screw placement (referenced in internal rotation) were 6 degrees +/- 2 degrees for the coracoid pillar, 198 degrees +/ 2 degrees for the inferior pillar, and 295 degrees +/- 3 degrees for the scapular spine pillar. Of note, 78% (57 of 73) of the screws attempting to obtain purchase in the scapular spine pillar could not be placed without an in-out-in configuration. In contrast, 100% of coracoid and 99% of inferior pillar screws achieved full purchase. The position of combined maximal fixation was 11 degrees +/- 1 degrees . CONCLUSIONS: These results suggest that approximately 11 degrees of internal rotation is the ideal baseplate position for maximal peripheral locking-screw fixation in RTSA. In addition, these results highlight the difficulty in obtaining optimal purchase in the scapular spine. PMID- 25819731 TI - Magnetic resonance rotator cuff fat fraction and its relationship with tendon tear severity and subject characteristics. AB - BACKGROUND: Compared with the Goutallier classification, chemical shift-based magnetic resonance (MR) fat quantification has superior reliability and accuracy in evaluation of muscle fatty infiltration. We used this method to assess the relationship between rotator cuff (RC) muscle fat fractions, tendon disease severity, and subject characteristics. METHODS: In total, 182 subjects with shoulder symptoms underwent shoulder MR imaging including additional sequences for fat quantitation. Then, fat fraction maps were manually segmented, and custom software was used to compute the fat fraction. Goutallier scores were also obtained. The relationship between fat fraction and tendon tear severity and subject characteristics was assessed with descriptive statistics, analysis of variance, Student t test of different subgroups, and simple and multiple linear regression analysis. RESULTS: Statistically higher supraspinatus fat fractions were observed in subgroups with tendon tears >3 cm, retraction >1 cm, age >50 years, body mass index (BMI) >30, higher Goutallier score, female gender, and longer symptom duration. A significant linear relationship was seen between RC fat fraction and tendon disease severity, age, and BMI but not symptom duration. Multiple regression models with fat fraction and tendon disease, age, BMI, and gender were significant for all 4 muscles (P < .001). The slope of fatty infiltration increase with age was reduced after adjustment for tendon disease, BMI, and gender. CONCLUSION: RC fat fraction assessed by chemical shift MR demonstrated a significant linear relationship with tendon tear severity, age, BMI, and gender but not with symptom duration. PMID- 25819733 TI - "Turn on" and label-free core-shell Ag@SiO2 nanoparticles-based metal-enhanced fluorescent (MEF) aptasensor for Hg(2+). AB - A turn on and label-free fluorescent apasensor for Hg(2+) with high sensitivity and selectivity has been demonstrated in this report. Firstly, core-shell Ag@SiO2 nanoparticles (NPs) were synthetized as a Metal-Enhanced Fluorescent (MEF) substrate, T-rich DNA aptamers were immobilized on the surface of Ag@SiO2 NPs and thiazole orange (TO) was selected as fluorescent reporter. After Hg(2+) was added to the aptamer-Ag@SiO2 NPs and TO mixture buffer solution, the aptamer strand can bind Hg(2+) to form T-Hg(2+)-T complex with a hairpin structure which TO can insert into. When clamped by the nucleic acid bases, the fluorescence quanta yield of TO will be increased under laser excitation and emitted a fluorescence emission. Furthermore, the fluorescence emission can be amplified largely by the MEF effect of the Ag@SiO2 NPs. The whole experiment can be finished within 30 min and the limit of detection is 0.33 nM even with interference by high concentrations of other metal ions. Finally, the sensor was applied for detecting Hg(2+) in different real water samples with satisfying recoveries over 94%. PMID- 25819732 TI - Prognostic impact of des-gamma-carboxyl prothrombin in living-donor liver transplantation for recurrent hepatocellular carcinoma. AB - BACKGROUND: Although the Milan criteria are widely accepted for liver transplantation (LT) in patients for hepatocellular carcinoma (HCC), they have not been fully evaluated for salvage LT in patients with recurrent HCC. We have previously reported outcomes of living-donor LT (LDLT) for HCC and identified 2 risk factors affecting recurrence-free survival (RFS): tumor size >5 cm and des gamma-carboxyl prothrombin (DCP) concentration >300 mAU/mL (Kyushu University criteria). This study was designed to clarify risk factors for tumor recurrence after LDLT in patients with recurrent HCC. METHODS: Outcomes in 114 patients who underwent LDLT for recurrent HCC were analyzed retrospectively. RFS rates after LDLT were calculated, and risk factors for tumor recurrence were identified. RESULTS: The 1-, 3-, and 5-year RFS rates after LDLT were 90.6%, 80.4%, and 78.8%, respectively. Univariate analysis showed that tumor recurrence was associated with alpha-fetoprotein concentration >= 300 ng/mL, DCP concentration >= 300 mAU/mL, tumor number >= 4, tumor size >= 5 cm, transarterial chemotherapy before LDLT, duration of last treatment of HCC to LDLT <3 months, bilobar distribution, exceeding Milan criteria, exceeding Kyushu University criteria, poor differentiation, and histologic vascular invasion. Multivariate analysis showed that DCP >= 300 mAU/mL (P = .03) and duration from last treatment to LDLT <3 months (P = .01) were independent predictors of RFS. CONCLUSIONS: DCP concentration and time between last treatment and LDLT are prognostic of RFS in patients undergoing LDLT for HCC. PMID- 25819734 TI - Long term results of bivalvular mechanical replacement: A historical thirty year follow-up. PMID- 25819735 TI - CHA2DS2-VASc scores predict mortality after hospitalization for atrial fibrillation. AB - OBJECTIVE: The outcome of patients hospitalized for atrial fibrillation (AF) is relatively poor. We sought to determine the mortality rate and predictors of mortality following hospitalization for AF and to evaluate whether the CHA2DS2 VASc score was a predictor of mortality. METHODS: We examined the national database of Thailand residents who registered for government provided health insurance in 2005 and reviewed patient records from 2005 to 2010 to determine all cause mortality. A total of 8981 patients (mean age, 65 years; 42% male) were admitted to the hospital with a diagnosis of AF. Data on demographics and comorbidities were retrieved from the database. The CHA2DS2-VASc score was calculated for each patient. RESULTS: The hospitalization rate for AF was 15.5 per 100,000 person-years. The two most common comorbidities were hypertension (N=1638, 18.2%) and diabetes (N=1349, 15.0%). The average CHA2DS2-VASc score for all patients was 1.8. By the 72-month follow-up (average 46 months), 3948 patients (44.0%) had died. The CHA2DS2-VASc score was directly related to the mortality rate (P log-rank <0.0001). Multivariate analysis showed that a CHA2DS2 VASc score >= 6 (hazard ratio [HR] 2.2, 95% confidence interval [CI], 1.4-3.7, P=0.002) and the presence of chronic kidney disease (HR 2.0, 95% CI 1.7-2.4, P<0.0001) were the strongest predictors of death. CONCLUSION: The outcome after hospitalization for AF is relatively poor. The CHA2DS2-VASc score is an independent prognostic marker of poor outcomes following hospitalization for AF. PMID- 25819736 TI - Changes in visceral and subcutaneous fat mass in patients with pheochromocytoma. AB - CONTEXT: Overproduction of catecholamine induces not only hypertension but also glucose intolerance and hyperlipidemia. However, little is known about its effect on visceral and subcutaneous fat. OBJECTIVE: Our objective was to investigate changes of metabolic factors including visceral and subcutaneous fat areas in patients with pheochromocytoma (Pheo). DESIGN AND PATIENTS: This was a cross sectional and longitudinal follow-up study of cases collected from Gunma University Hospital between 2002 and 2013. Forty-two patients with Pheo and 23 with non-functioning adrenal adenoma (NFA) were analyzed before and after adrenalectomy. RESULTS: Multivariate logistic-regression analysis adjusted by age and gender revealed that glucose intolerance was more common in patients with Pheo than in patients with NFA (21/42, 51% vs. 4/23, 17%, p<0.05). Abdominal visceral fat area (VFA) and subcutaneous fat area (SFA) were significantly lower in patients with Pheo than in those with NFA (80.2+/-38.7 vs. 124.3+/-61.8cm(2), p<0.05; 114.6+/-58.9 vs. 164.3+/-40.3cm(2), p<0.05, respectively). Significant correlations were observed between fractionated urine noradrenaline level and serum HDL-cholesterol level (r = 0.36, p<0.05), urine normetanephrine level and tumor size (r=0.57, p<0.01), and urine adrenaline level and systolic blood pressure (r=0.35, p<0.05) in Pheo. However, there were no significant correlations between adrenaline and noradrenaline levels and other parameters, including serum LDL-cholesterol and triglyceride levels, and HbA1c. Furthermore, both VFA and SFA, body weight, and BMI were significantly increased, and serum HbA1c as well as HDL-cholesterol levels were decreased after adrenalectomy in Pheo. CONCLUSION: These findings suggest for the first time that catecholamines might regulate the serum HDL-cholesterol level and both abdominal visceral and subcutaneous fat mass in men. PMID- 25819737 TI - Exercising insulin sensitivity: AMPK turns on autophagy! PMID- 25819738 TI - PNIPAAm-MAA nanoparticles as delivery vehicles for curcumin against MCF-7 breast cancer cells. AB - Breast cancer is the most frequently occurring cancer among women throughout the world. Natural compounds such as curcumin hold promise to treat a variety of cancers including breast cancer. However, curcumin's therapeutic application is limited, due to its rapid degradation and poor aqueous solubility. On the other hand, previous studies have stated that drug delivery using nanoparticles might improve the therapeutic response to anticancer drugs. Poly(N-isopropylacrylamide co-methacrylic acid) (PNIPAAm-MAA) is one of the hydrogel copolymers utilized in the drug delivery system for cancer therapy. The aim of this study was to examine the cytotoxic potential of curcumin encapsulated within the NIPAAm-MAA nanoparticle, on the MCF-7 breast cancer cell line. In this work, polymeric nanoparticles were synthesized through the free radical mechanism, and curcumin was encapsulated into NIPAAm-MAA nanoparticles. Then, the cytotoxic effect of curcumin-loaded NIPAAm-MAA on the MCF-7 breast cancer cell line was measured by MTT assays. The evaluation of the results showed that curcumin-loaded NIPAAm-MAA has more cytotoxic effect on the MCF-7 cell line and efficiently inhibited the growth of the breast cancer cell population, compared with free curcumin. In conclusion, this study indicates that curcumin-loaded NIPAAm-MAA suppresses the growth of the MCF-7 cell line. Overall, it is concluded that encapsulating curcumin into the NIPAAm-MAA copolymer could open up new avenues for breast cancer treatment. PMID- 25819739 TI - Unavailability of thymidine kinase does not preclude the use of German comprehensive prognostic index: results of an external validation analysis in early chronic lymphocytic leukemia and comparison with MD Anderson Cancer Center model. AB - A comprehensive prognostic index that includes clinical (i.e., age, sex, ECOG performance status), serum (i.e., beta2-microglobulin, thymidine kinase [TK]), and molecular (i.e., IGVH mutational status, del 17p, del 11q) markers developed by the German CLL Study Group (GCLLSG) was externally validated in a prospective, community-based cohort consisting of 338 patients with early chronic lymphocytic leukemia (CLL) using as endpoint the time to first treatment (TTFT). Because serum TK was not available, a slightly modified version of the model based on seven instead of eight prognostic variables was used. By German index, 62.9% of patients were scored as having low-risk CLL (score 0-2), whereas 37.1% had intermediate-risk CLL (score 3-5). This stratification translated into a significant difference in the TTFT [HR = 4.21; 95% C.I. (2.71-6.53); P < 0.0001]. Also the 2007 MD Anderson Cancer Center (MDACC) score, barely based on traditional clinical parameters, showed comparable reliability [HR = 2.73; 95% C.I. (1.79-4.17); P < 0.0001]. A comparative performance assessment between the two models revealed that prediction of the TTFT was more accurate with German score. The c-statistic of the MDACC model was 0.65 (range, 0.53-0.78) a level below that of the German index [0.71 (range, 0.60-0.82)] and below the accepted 0.7 threshold necessary to have value at the individual patient level. Results of this external comparative validation analysis strongly support the German score as the benchmark for comparison of any novel prognostic scheme aimed at evaluating the TTFT in patients with early CLL even when a modified version which does not include TK is utilized. PMID- 25819740 TI - 17alpha-Ethinylestradiol can disrupt hemoglobin catabolism in amphibians. AB - Different chemical substances, which enter the environment due to anthropogenic influences, can affect the endocrine system and influence development and physiology of aquatic animals. One of these endocrine disrupting chemicals is the synthetic estrogen, 17alpha-ethinylestradiol (EE2), which is a main component of various oral contraceptives and demonstrably affects many different aquatic vertebrates at extremely low concentrations by feminization phenomena. The aim of the present study was to investigate whether a four week exposure to three different concentrations of EE2 (0.3 ng/L, 29.6 ng/L and 2960 ng/L) affects the catabolism of hemoglobin of the amphibian Xenopus laevis. The results of this study demonstrate for the first time that beside an increase of the hepatic vitellogenin gene expression, exposure to EE2 also decreases the gene expression of the hepatic heme oxygenase 1 and 2 (HO1, HO2), degrading heme of different heme proteins to biliverdin, as well as of the biliverdin reductase A (BLVRA), which converts biliverdin to bilirubin. The results further suggest that EE2 already at the environmentally relevant concentration of (29.6 ng/L) can disrupt hemoglobin catabolism, indicated by decreased gene expression of HO2, which becomes evident at the highest EE2 concentration that led to a severe increase of biliverdin in plasma. PMID- 25819741 TI - Toxicity of noradrenaline, a novel anti-biofouling component, to two non-target zooplankton species, Daphnia magna and Ceriodaphnia dubia. AB - Noradrenaline (NA) is the active component of novel antifouling agents and acts by preventing attachment of fouling organisms. The goal of this study was to examine the toxicity of NA to the non-target zooplankton D. magna and C. dubia. Neonates were exposed to one of five concentrations of NA and effects on survival, reproduction and molting were determined. Calculated LC50 values were determined to be 46 and 38 MUM in C. dubia and D. magna, respectively. A 10-day C. dubia study found that reproduction metrics were significantly impacted at non lethal concentrations. In D. magna, concentrations greater than 40 MUM significantly impacted molting. A toxicity test was conducted with D. magna using oxidized NA, which yielded similar results. These data indicate that both NA and oxidized NA are toxic to non-target zooplankton. Results obtained from this study can be used to guide future ecological risk assessments of catecholamine-based antifouling agents. PMID- 25819742 TI - Busulfan dosing algorithm and sampling strategy in stem cell transplantation patients. AB - AIM: The aim of this investigation was to develop a model-based dosing algorithm for busulfan and identify an optimal sampling scheme for use in routine clinical practice. METHODS: Clinical data from an ongoing study (n = 29) in stem cell transplantation patients were used for the purposes our analysis. A one compartment model was selected as basis for sampling optimization and subsequent evaluation of a suitable dosing algorithm. Internal and external model validation procedures were performed prior to the optimization steps using ED-optimality criteria. Using systemic exposure as parameter of interest, dosing algorithms were considered for individual patients with the scope of minimizing the deviation from target range as determined by AUC(0,6 h). RESULTS: Busulfan exposure after oral administration was best predicted after the inclusion of adjusted ideal body weight and alanine transferase as covariates on clearance. Population parameter estimates were 3.98 h(-1), 48.8 l and 12.3 l h(-1) for the absorption rate constant, volume of distribution and oral clearance, respectively. Inter-occasion variability was used to describe the differences between test dose and treatment. Based on simulation scenarios, a dosing algorithm was identified, which ensures target exposure values are attained after a test dose. Moreover, our findings show that a sparse sampling scheme with five samples per patient is sufficient to characterize the pharmacokinetics of busulfan in individual patients. CONCLUSION: The use of the proposed dosing algorithm in conjunction with a sparse sampling scheme may contribute to considerable improvement in the safety and efficacy profile of patients undergoing treatment for stem cell transplantation. PMID- 25819743 TI - Self-report of eating disorder symptoms among women with and without infertility. AB - OBJECTIVE: To compare eating disorder (ED) symptoms in women seeking treatment for infertility to women receiving routine primary care. DESIGN: A cross sectional comparative design. SETTING: Women were recruited from two infertility centers and a general hospital primary care setting. PARTICIPANTS: Participants included 51 women seeking treatment for ovulatory and unexplained infertility and 34 women attending routine primary care. MEASURES: Participants completed a battery of standardized rating scales measuring self-reported ED symptoms, drive for thinness, bulimic symptoms, body dissatisfaction, and related clinical characteristics. RESULTS: Multivariate analysis of covariance confirmed that women seeking treatment for infertility had significantly greater scores on measures of drive for thinness (p = .001) and bulimic symptoms (p = .002) than those receiving routine primary care. However, the comparison group had significantly greater scores on measures of body dissatisfaction (p < .001) and dietary restraint (p = .001) than the infertility group. Both groups had elevated rates of lifetime ED diagnoses compared to national prevalence rates. CONCLUSIONS: Results demonstrated that women seeking treatment for ovulatory and unexplained infertility have greater drive for thinness and bulimic symptoms but not body dissatisfaction or dietary restraint compared to women seeking primary care. The results suggest that infertility and routine health care visits may provide opportunities for early identification and treatment of women with ED symptomatology. Future studies may benefit from further elucidation of the potential role of ED symptoms in the etiology and maintenance of infertility in, particularly, normal-weight women. PMID- 25819744 TI - Distinct domains of impulsivity are impaired in juvenile myoclonic epilepsy but not in temporal lobe epilepsy. AB - OBJECTIVE: The Barratt Impulsiveness Scale (BIS-11) is the most widely used questionnaire to study impulsivity in persons with psychiatric disorders, but it has rarely been applied to persons with epilepsy. The present study aimed to evaluate the usefulness of BIS-11 as a tool to explore impulsivity in two distinct epilepsy syndromes. METHOD: The BIS-11 was applied to 20 patients with juvenile myoclonic epilepsy (JME) (32.5+/-8.95years old), 20 patients with temporal lobe epilepsy (TLE) (37.7+/-13.25years old), and 26 healthy controls (31.86+/-11.25years old). The scores in motor, attentional, and lack of planning impulsivity were compared between groups. RESULTS: Patients with JME showed higher scores than patients with TLE and controls in all domains: motor (JME vs TLE: 28.60 vs 13.25 (mean score), p<0.001 and JME vs controls: 28.60 vs 14.12, p<0.001), attentional (JME vs TLE: 21.55 vs 13.45, p<0.001 and JME vs controls: 21.55 vs 14.88, p<0.001) and nonplanning (JME vs TLE: 28.05 vs 13.10, p<0.001 and JME vs controls: 28.05 vs 16.15, p<0.001). CONCLUSION: Higher BIS-11 scores in all domains of impulsivity [i.e., motor, attentional, and lack of planning] corroborated previous findings described in patients with JME. On the other hand, BIS-11 could not demonstrate problem solving and inhibitory control deficits related to impulsive behavior, which were described in patients with TLE. Other behavioral measures may be more sensitive to some aspects of impulsivity in TLE. Our results reinforce the concept that distinct epileptic syndromes require different neuropsychological approaches, especially considering a complex construct such as impulsivity. PMID- 25819745 TI - A cluster of rotavirus enteritis in pediatric liver recipients. AB - We observed a cluster of 4 pediatric liver recipients who developed diarrhea in a liver transplant unit within 5 days. Feces from these 4 patients were rotavirus positive when tested with Colloidal Gold Diagnostic Kit. Nucleic acid from 3 fecal specimens was extracted and reverse transcribed. Two were amplified positively. The complementary DNAs were sequenced. Alignment and phylogenetic analysis were performed with MEGA 6.06. Although involving only 4 pediatric liver recipients, this cluster was caused by at least 2 distinct G9P[8] rotavirus strains and included community infection and nosocomial infection. PMID- 25819747 TI - Prioritization of psychological well-being in the care of diabetes: moving beyond excuses, bringing solutions. PMID- 25819746 TI - DNA vaccines encoding DEC205-targeted antigens: immunity or tolerance? AB - Targeting of antigens to the endocytic uptake receptor DEC205 resulted in enhanced antigen presentation by dendritic cells (DCs). In combination with adjuvants for DC maturation, proteins coupled to an antibody against DEC205 induced strong pathogen-specific immune responses, whereas without additional adjuvant tolerance could be induced. As less is known about DNA vaccines encoding DEC205-targeted antigens, we explored the immunogenicity and efficacy of a dendritic cell-targeted DNA vaccine against influenza A virus (IAV) delivered by electroporation. Although coupling of haemagglutinin to a single-chain antibody against DEC205 enhanced antigen presentation on MHC class II and activation of T cell receptor-transgenic CD4 T cells, the T-cell responses induced by the targeted DNA vaccine in wild-type BALB/c mice were significantly reduced compared with DNA encoding non-targeted antigens. Consistently, these mice were less protected against an IAV infection. Adoptive transfer experiments were performed to assess the fate of the antigen-specific T cells in animals vaccinated with DNA encoding DEC205-targeted antigens. By this, we could exclude the general deletion of antigen-specific T cells as cause for the reduced efficacy, but observed a local expansion of antigen-specific regulatory T cells, which could suppress the activation of effector cells. In conclusion, DNA vaccines encoding DEC205 targeted antigens induce peripheral tolerance rather than immunity in our study. Finally, we evaluated our DNA vaccines as prophylactic or therapeutic treatment in an allergen-induced asthma mouse model. PMID- 25819748 TI - The outcome of apical microsurgery using MTA as the root-end filling material: 2- to 6-year follow-up study. AB - AIM: To evaluate the influence of various predictors on the healing outcome 2-6 years after apical microsurgery (AMS) using MTA as the root-end filling material. METHODOLOGY: A total of 90 anterior teeth with asymptomatic persistent periradicular periodontitis of strictly endodontic origin that failed after either nonsurgical or surgical treatment were included. Surgery was completed under local anaesthesia using a standardized clinical protocol. Clinical and radiographic measures as well as the follow-up period were used to determine the healing outcome. For statistical analysis of the predictors, the outcome was dichotomized into healed cases and nonhealed cases. Odds ratios were calculated, and Pearson chi-square or Fisher's exact tests were used to analyse the data. RESULTS: Clinical and radiographic assessment of AMS revealed that 80% were healed, 14.4% were nonhealed, whilst 5.6% were judged to be uncertain. None of the various predictors investigated had a significant influence on the outcome of AMS. CONCLUSIONS: The results of this clinical study demonstrated that 80% of cases that received apical microsurgery healed when using MTA as the root-end filling material. PMID- 25819749 TI - The relevance of ADCC for EGFR targeting: A review of the literature and a clinically-applicable method of assessment in patients. AB - BACKGROUND: Advances in the understanding of tumor biology have led to the development of targeted therapies as monoclonal antibodies (MoAbs) in clinical oncology. Among their suggested mechanisms of action monoclonal antibodies (IgG1) selectively directed against tumor membrane receptors mediate of antibody dependent cellular cytotoxicity (ADCC) by triggering Fc-gammaRIII on natural killer (NK) cells. METHODS: This study reviews the clinical context of ADCC measurement with a particular focus on EGFR targeting and describes an ex vivo ADCC method applied to MoAbs (cetuximab and panitumumab), against epidermal growth factor receptor (EGFR). The test performance was evaluated on different target cells lines (CAL166, A431, HNO91, CAL27), with different effector cells (peripheral blood mononuclear cells or natural killers -NK-) and in various experimental conditions, in order to establish a truly clinically applicable method. RESULTS: Using the experience available in the published literature, we optimized all variables involved in the experimental design: target cells type, numbers and ratio target cells and NK cells (effector cells) per well, time of exposure and repeatability. CONCLUSION: ADCC measurement may be of clinical relevance in the context of treatment with MoAbs. This study describes a non radioactive method which has proven satisfactory in terms of sensitivity, reproducibility, feasibility and cost effectiveness for the measurement of ADCC activity mediated by NK with an orientation towards the EGFR target. PMID- 25819750 TI - Haematological problems in obstetrics. AB - Physiologic changes occur during pregnancy, which influence normal haematologic values and impact the diagnosis and management of haematologic disease in pregnancy. Physiologic changes of pregnancy also commonly lead to mimicking symptoms of haematologic disease that may prompt investigations for haematologic disease. The toxicity and radiation associated with the diagnostic imaging and pharmacologic management of both benign and malignant haematological conditions during pregnancy present unique challenges. Strategies for diagnosis and treatment must weigh the benefits and risks to the mother while also taking foetal outcome into consideration. In this review, we highlight the common haematologic diseases encountered by obstetricians and try to provide guidance for the most prevalent diagnostic and therapeutic questions. At the other end of the spectrum, we also comment on less common but very challenging haematologic diseases in pregnancy that require multidisciplinary effort to arrive at difficult individual diagnostic and treatment decisions. PMID- 25819751 TI - Abba Kastin: The melanocyte stimulating hormone story and the future of the proteophathies. AB - From a personal viewpoint, Abba was always a congenial colleague and a good friend. I recall the hours of unraveling complex, confusing, and many times contradictory data sets with him and the excitement we both felt as what had been puzzling began to make sense. Most of all, I feel privileged to have Abba as a long and valued friend. PMID- 25819752 TI - Effect of suppression of arabinoxylan synthetic genes in wheat endosperm on chain length of arabinoxylan and extract viscosity. AB - Arabinoxylan (AX) is the dominant component within wheat (Triticum aestivum L.) endosperm cell walls, accounting for 70% of the polysaccharide. The viscosity of aqueous extracts from wheat grain is a key trait influencing the processing for various end uses, and this is largely determined by the properties of endosperm AX. We have previously shown dramatic effects on endosperm AX in transgenic wheat by down-regulating either TaGT43_2 or TaGT47_2 genes (orthologues to IRX9 and IRX10 in Arabidopsis, respectively) implicated in AX chain extension and the TaXAT1 gene responsible for monosubstitution by 3-linked arabinose. Here, we use these transgenic lines to investigate the relationship between amounts of AX in soluble and insoluble fractions, the chain-length distribution of these measured by intrinsic viscosity and the overall effect on extract viscosity. In transgenic lines expressing either the TaGT43_2 or TaGT47_2 RNAi transgenes, the intrinsic viscosities of water-extractable (WE-AX) and of a water-insoluble alkaline extracted fraction (AE-AX) were decreased by between 10% and 50% compared to control lines. In TaXAT1 RNAi lines, there was a 15% decrease in intrinsic viscosity of WE-AX but no consistent effect on that of AE-AX. All transgenic lines showed decreases in extract viscosity with larger effects in TaGT43_2 and TaGT47_2 RNAi lines (by up to sixfold) than in TaXAT1 RNAi lines (by twofold). These effects were explained by the decreases in amount and chain length of WE AX, with decreases in amount having the greater influence. Extract viscosity from wheat grain can therefore be greatly decreased by suppression of single gene targets. PMID- 25819753 TI - ING3 protein expression profiling in normal human tissues suggest its role in cellular growth and self-renewal. AB - Members of the INhibitor of Growth (ING) family of proteins act as readers of the epigenetic code through specific recognition of the trimethylated form of lysine 4 of histone H3 (H3K4Me3) by their plant homeodomains. The founding member of the family, ING1, was initially identified as a tumor suppressor with altered regulation in a variety of cancer types. While alterations in ING1 and ING4 levels have been reported in a variety of cancer types, little is known regarding ING3 protein levels in normal or transformed cells due to a lack of reliable immunological tools. In this study we present the characterization of a new monoclonal antibody we have developed against ING3 that specifically recognizes human and mouse ING3. The antibody works in western blots, immunofluorescence, immunoprecipitation and immunohistochemistry. Using this antibody we show that ING3 is most highly expressed in small intestine, bone marrow and epidermis, tissues in which cells undergo rapid proliferation and renewal. Consistent with this observation, we show that ING3 is expressed at significantly higher levels in proliferating versus quiescent epithelial cells. These data suggest that ING3 levels may serve as a surrogate for growth rate, and suggest possible roles for ING3 in growth and self renewal and related diseases such as cancer. PMID- 25819754 TI - Lipids, blood pressure and kidney update 2014. AB - This paper is an effort to review all the most important studies and guidelines in the topics of lipid, blood pressure and kidney published in 2014. Irrespective of advances, the options for improving simultaneous hypercholesterolemia and hypertension management (as well as its complication - chronic kidney disease) remain a problem. Recommending hypolidemic, hypotensive and kidney disease drugs to obtain therapy targets in cardiovascular, diabetic, elderly and kidney disease (=high risk) patients might strengthen risk factor control, improve compliance and the therapy efficacy, and in the consequence reduce the risk of cardiovascular events and mortality rate. That is why the authors have decided to summary and discuss the recent scientific achievements in the field of lipid, blood pressure and kidney. PMID- 25819756 TI - The association of subclinical hypocalcemia, negative energy balance and disease with bodyweight change during the first 30 days post-partum in dairy cows milked with automatic milking systems. AB - In a prospective cohort study, the daily bodyweight (BW) and milk production of 92 cows were recorded using automatic milking systems. The objectives were to characterize calcium serum concentration variability on days 1-3 post-partum and to evaluate the association between subclinical hypocalcemia (SHPC) and change in BW over the first 30 days in milk (DIM) in Holstein dairy cows, while controlling for concurrent disease and negative energy balance (NEB). SHPC was defined as total serum calcium concentration between 6 and 8 mg/dL, NEB was defined as non esterified fatty acids (NEFA) > 0.7 mEq/L or beta-hydroxybutyrate (BHB) >= 1.2 mmol/L. The peak incidence of SHPC was at 1 DIM for all groups (11%, 42% and 60% for parities 1, 2, and >=3, respectively). All parity groups lost weight (21, 33, and 34 kg) during the first 30 DIM. Parity 1 animals with disease compared with those without disease lost the most weight (2.6 kg/day BW loss vs. <1.9 kg/day, respectively). Normocalcemic parity 2 animals with either NEB or disease lost the most weight (>5 kg/day) compared with those in the SHPC group (<=4.5 kg/day). In parity >= 3 animals, SHPC was an important factor for BW loss; SHPC animals lost the most weight (>3.7 kg/day) vs. normocalcemic cows (<=3.3 kg/day) regardless of NEB or disease status. Even though all animals lost weight during early lactation the effect of disease, NEB, and SHPC on BW loss was different in each parity group. PMID- 25819755 TI - Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population - The Nagahama study. AB - Anti-citrullinated peptide antibody (ACPA) is a highly specific autoantibody to rheumatoid arthritis (RA). Recent studies have revealed that periodontal disease (PD) is closely associated with RA and production of ACPA in RA. Analyses of associations between PD and ACPA production in a healthy population may deepen our understandings. Here, we analyzed a total of 9554 adult healthy subjects. ACPA and IgM-rheumatoid factor (RF) was quantified and PD status was evaluated using the number of missing teeth (MT), the Community Periodontal Index (CPI) and Loss of Attachment (LA) for these subjects. PD status was analyzed for its association with the positivity and categorical levels of ACPA and RF conditioned for covariates which were shown to be associated with PD, ACPA or RF. As a result, all of MT, CPI and LA showed suggestive or significant associations with positivity (p = 0.024, 0.0042 and 0.037, respectively) and levels of ACPA (p <= 0.00031), but none of the PD parameters were associated with those of RF. These association patterns were also observed when we analyzed 6206 non-smokers of the participants. The significant associations between PD parameters and positivity and levels of ACPA in healthy population support the fundamental involvement of PD with ACPA production. PMID- 25819757 TI - Transient plant transformation mediated by Agrobacterium tumefaciens: Principles, methods and applications. AB - Agrobacterium tumefaciens is widely used as a versatile tool for development of stably transformed model plants and crops. However, the development of Agrobacterium based transient plant transformation methods attracted substantial attention in recent years. Transient transformation methods offer several applications advancing stable transformations such as rapid and scalable recombinant protein production and in planta functional genomics studies. Herein, we highlight Agrobacterium and plant genetics factors affecting transfer of T-DNA from Agrobacterium into the plant cell nucleus and subsequent transient transgene expression. We also review recent methods concerning Agrobacterium mediated transient transformation of model plants and crops and outline key physical, physiological and genetic factors leading to their successful establishment. Of interest are especially Agrobacterium based reverse genetics studies in economically important crops relying on use of RNA interference (RNAi) or virus induced gene silencing (VIGS) technology. The applications of Agrobacterium based transient plant transformation technology in biotech industry are presented in thorough detail. These involve production of recombinant proteins (plantibodies, vaccines and therapeutics) and effectoromics-assisted breeding of late blight resistance in potato. In addition, we also discuss biotechnological potential of recombinant GFP technology and present own examples of successful Agrobacterium mediated transient plant transformations. PMID- 25819758 TI - I'm positive, but i'm negative: Competing Voices in Informed Consent and Implications for HIV vaccine trials. AB - HIV vaccine trials (HVTs) are ethically complex, and sound informed consent processes should facilitate optimal decision-making for participants. This study aimed to explore representations of critical HVT-related concepts to enhance the consent process. Four focus group discussions were conducted with participants from key constituencies at a South African HVT site. Thematic analysis was employed to identify representations of key HVT-related concepts. The findings suggest that (potential) participants may negotiate multiple, competing versions of HVT-related concepts in a somewhat unrecognized process, which may have significant implications for the consent process. Stakeholders involved in consent and engagement activities at sites should be assisted to elicit, engage, and resolve competing representations of HVT-related concepts. More empirical research is needed to explore how such stakeholders address competing representations in their interactions with potential participants. PMID- 25819759 TI - Biomedical Research Ethics Committees in sub-Saharan Africa: a collective review of their structure, functioning, and outcomes. AB - Research Ethics Committees (RECs) are mandated to protect human participants by conducting ethical reviews of biomedical research. To date, there is a dearth of information on the structure, functioning, and outcomes of RECs in Africa. This article reviews empirical studies investigating African RECs, with the aim of providing an overview of what is known and identifying gaps in our knowledge. We conducted a literature search of the EBSCO, PubMed, and Google Scholar electronic databases. Twenty-three empirical studies reporting on the structure, functions, and outcomes of African RECs were included in our analysis. The review yielded limited systematic data on RECs in Africa. Available empirical evidence suggests that challenges hampering the effective functioning of RECs included lack of membership diversity, scarcity of resources, insufficient training of members, inadequate capacity to review and monitor studies, and lack of national ethics guidelines and accreditation. Relatively little data on the review outcomes of African RECs were described. There is an ongoing need for concerted efforts from various stakeholders to support capacity development and enhancement of African RECs. PMID- 25819760 TI - How to distinguish research from quality improvement. PMID- 25819762 TI - Lead and copper removal from aqueous solutions using carbon foam derived from phenol resin. AB - Phenolic resin-based carbon foam was prepared as an adsorbent for removing heavy metals from aqueous solutions. The surface of the produced carbon foam had a well developed open cell structure and the specific surface area according to the BET model was 458.59m(2)g(-1). Batch experiments showed that removal ratio increased in the order of copper (19.83%), zinc (34.35%), cadmium (59.82%), and lead (73.99%) in mixed solutions with the same initial concentration (50mgL(-1)). The results indicated that the Sips isotherm model was the most suitable for describing the experimental data of lead and copper. The maximum adsorption capacity of lead and copper determined to Sips model were 491mgg(-1) and 247mgg( 1). The obtained pore diffusion coefficients for lead and copper were found to be 1.02*10(-6) and 2.42*10(-7)m(2)s(-1), respectively. Post-sorption characteristics indicated that surface precipitation was the primary mechanism of lead and copper removal by the carbon foam, while the functional groups on the surface of the foam did not affect metal adsorption. PMID- 25819761 TI - Sestrin2 inhibits mTORC1 through modulation of GATOR complexes. AB - Sestrins are stress-inducible metabolic regulators that suppress a wide range of age- and obesity-associated pathologies, many of which are due to mTORC1 overactivation. Upon various stresses, the Sestrins inhibit mTORC1 activity through an indirect mechanism that is still unclear. GATORs are recently identified protein complexes that regulate the activity of RagB, a small GTPase essential for mTORC1 activation. GATOR1 is a GTPase activating protein (GAP) for RagB whereas GATOR2 functions as an inhibitor of GATOR1. However, how the GATORs are physiologically regulated is unknown. Here we show that Sestrin2 binds to GATOR2, and liberates GATOR1 from GATOR2-mediated inhibition. Released GATOR1 subsequently binds to and inactivates RagB, ultimately resulting in mTORC1 suppression. Consistent with this biochemical mechanism, genetic ablation of GATOR1 nullifies the mTORC1-inhibiting effect of Sestrin2 in both cell culture and Drosophila models. Collectively, we elucidate a new signaling cascade composed of Sestrin2-GATOR2-GATOR1-RagB that mediates stress-dependent suppression of mTORC1 activity. PMID- 25819763 TI - Refinement of the SWN-20 based on the Rasch rating model. AB - OBJECTIVES: The aim of the present study was to refine the 20-item Subjective Well-Being under Neuroleptic Treatment Scale (SWN-20) using the Rasch rating model to validate measurements of subjective well-being in patients with schizophrenia undergoing antipsychotic treatment. METHODS: In total, 854 (403 males, 451 females) inpatients (n=213) and outpatients (n=641) with schizophrenia participated in this study, which was designed as an open-label investigation of paliperidone extended release. The participants completed the Korean version of the SWN-20 themselves. Refinement of the Korean version of the SWN-20 was accomplished using the Rasch rating model. RESULTS: Infit and outfit statistics for all 20 items satisfied the criterion for construct validity. Second, all items except items 2 and 20 had suitable point-measure correlations, reflecting content validity. Third, item characteristic curves indicated that roughly 18 items were evenly distributed along the person ability continuum. Finally, option analysis of the category characteristics showed that categories 3 and 4 in the SWN-20 response format were unnecessary. CONCLUSIONS: We offer several recommendations for improving the SWN-20: (a) items 2 and 20 should be omitted to ensure construct validity; (b) easier items would be added related to the person ability estimates in the process of validating a short form of the SWN scale based on item response theory; and (c) the number of response categories should be reduced for schizophrenic patients. PMID- 25819765 TI - Genome editing at the crossroads of delivery, specificity, and fidelity. AB - Genome editing (GE) entails the modification of specific genomic sequences in living cells for the purpose of determining, changing, or expanding their function(s). Typically, GE occurs after delivering sequence-specific designer nucleases (e.g., ZFNs, TALENs, and CRISPR/Cas9) and donor DNA constructs into target cells. These designer nucleases can generate gene knockouts or gene knock ins when applied alone or in combination with donor DNA templates, respectively. We review progress in this field, with an emphasis on designer nuclease and donor template delivery into mammalian target cell populations. We also discuss the impact that incremental improvements to these tools are having on the specificity and fidelity attainable with state-of-the-art DNA-editing procedures. Finally, we identify areas that warrant further investigation. PMID- 25819764 TI - Selection strategies for anticancer antibody discovery: searching off the beaten path. AB - Antibody-based drugs represent one of the most successful and promising therapeutic approaches in oncology. Large combinatorial phage antibody libraries are available for the identification of therapeutic antibodies and various technologies exist for their further conversion into multivalent and multispecific formats optimized for the desired pharmacokinetics and the pathological context. However, there is no technology for antigen profiling of intact tumors to identify tumor markers targetable with antibodies. Such constraints have led to a relative paucity of tumor-associated antigens for antibody targeting in oncology. Here we review novel approaches aimed at the identification of antibody-targetable, accessible antigens in intact tumors. We hope that such advanced selection approaches will be useful in the development of next-generation antibody therapies for cancer. PMID- 25819766 TI - Metastasectomy for Sarcoma. PMID- 25819767 TI - Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing. AB - INTRODUCTION: CDKL5-related encephalopathy is an X-linked dominantly inherited disorder that is characterized by early infantile epileptic encephalopathy or atypical Rett syndrome. We describe a 5-year-old Japanese boy with intractable epilepsy, severe developmental delay, and Rett syndrome-like features. Onset was at 2 months, when his electroencephalogram showed sporadic single poly spikes and diffuse irregular poly spikes. METHODS: We conducted a genetic analysis using an Illumina(r) TruSightTM One sequencing panel on a next-generation sequencer. RESULTS: We identified two epilepsy-associated single nucleotide variants in our case: CDKL5 p.Ala40Val and KCNQ2 p.Glu515Asp. CDKL5 p.Ala40Val has been previously reported to be responsible for early infantile epileptic encephalopathy. In our case, the CDKL5 heterozygous mutation showed somatic mosaicism because the boy's karyotype was 46,XY. The KCNQ2 variant p.Glu515Asp is known to cause benign familial neonatal seizures-1, and this variant showed paternal inheritance. CONCLUSIONS: Although we believe that the somatic mosaic CDKL5 mutation is mainly responsible for the neurological phenotype in the patient, the KCNQ2 variant might have some neurological effect. Genetic analysis by next-generation sequencing is capable of identifying multiple variants in a patient. PMID- 25819768 TI - Lead extraction from cathode ray tube funnel glass melted under different oxidizing conditions. AB - Lead was extracted into hydrochloric acid from cathode ray tube funnel glass melted under reducing atmosphere, oxidizing atmosphere, or a sequential combination of both to mechanistically investigate effects of the melting atmosphere on lead extraction. Melting funnel glass in a reductive atmosphere led to the generation of metallic lead particles that were readily soluble in the acid, increasing the quantity of lead extracted into the acid. Meanwhile, the glass product obtained after melting funnel glass in an oxidative atmosphere exhibited higher corrosion resistance in the acid, and the quantity of lead extracted from the treated glass decreased. However, Na2CO3 addition to the glass during melting hindered the enhancement of corrosion resistance and the immobilization of lead in the acid. X-ray photoelectron spectroscopic analysis of the treated glass samples showed that the positions of the peak or the profiles of the spectra attributed to Pb 4f, Si 2p, and O 1s signals were modified by oxidative melting, an indication that oxidative melting results in structural changes in the SiO2 framework of the glass. PMID- 25819769 TI - Intestinal lengthening and reversed segment in a piglet short bowel syndrome model. AB - BACKGROUND: Treatment of short bowel syndrome (SBS) remains difficult, entailing severe morbidity and mortality. Accepted surgical treatment modalities for SBS are the Bianchi intestinal lengthening procedure and reversed-segment procedure. We seek to investigate the short-term effects regarding growth, nutrition, and microscopic and functional adaptation after the intestinal lengthening and RS procedures in a piglet SBS-model. MATERIAL AND METHODS: Twenty-four piglets (Sus scrofa, +/-30 kg) were divided into four groups (n = 6 each) as follows: sham, SBS, Bianchi lengthening procedure (BIA), and reversed-segment (RS). At day one either sham laparotomy (sham) or 75% small bowel resection (SBS, BIA, and RS) was performed. After 2 wk sham laparotomy (sham and SBS), BIA, or RS procedure was performed. After 8 wk all animals were terminated. During the experimental time course, the following parameters were assessed: body weight, intestinal length, diameter, and weight, fat absorption, and biochemical parameters from serum and urine. Citrulline was used as a marker of absorptive enteral mass to demonstrate massive functional bowel loss. Intestinal biopsies were obtained for histologic analysis and electrophysiological measurements to analyze glucose absorptive capacity. RESULTS: Eight weeks after bowel resection, piglet growth was reduced in SBS, BIA, and RS piglets as demonstrated by reduced weight (51 +/- 4 kg, 47 +/ 2 kg, and 53 +/- 1 kg, respectively) compared with sham (69 +/- 3 kg; P < 0.01), with no demonstrable difference between SBS and treatment groups. Malabsorption and malnutrition occurred in SBS, BIA, and RS piglets reflected by increased fecal fat loss per 24 h (35 +/- 4%, 30 +/- 2%, and 32 +/- 4%, respectively versus 18 +/- 1% in sham; P < 0.01) and reduced serum albumin levels (24 +/- 1 g/L, 22 +/- 1 g/L, and 24 +/- 1 g/L, respectively versus sham 33 +/- 1 g/L; P < 0.01), but there was no significant difference between SBS and treatment groups. Serum citrulline levels reflected massive functional bowel loss (SBS 36 +/- 7 MUmol/L, BIA 23 +/- 1 MUmol/L, and RS 24 +/- 2 MUmol/L) compared with sham (64 +/- 5 MUmol/L; P < 0.01). Electrophysiological measurements demonstrated reduced glucose absorption after intestinal resection, which did not return to base levels within the experimental time course. However, the intestine of BIA and RS piglets adapted more profoundly than SBS piglets, as reflected by a greater crypt depth (490 +/- 25 MUm and 492 +/- 21 MUm versus 388 +/- 20 MUm; P < 0.01); and BIA piglets showed greater villus length (884 +/- 58 MUm) than RS or SBS piglets (715 +/- 30 MUm and 737 +/- 64 MUm, respectively; P < 0.01) after 8 wk. CONCLUSIONS: Despite increased histologic intestinal adaptation, neither intestinal lengthening nor RS procedure demonstrated significantly improved absorption, nutrition, or weight gain for the treatment of SBS during the study period. Reduced glucose uptake on electrophysiology measurements and persistent low levels of citrulline may indicate reduced small bowel enterocyte functioning during the initial phase of intestinal adaptation. PMID- 25819770 TI - Papillary thyroid cancer-derived exosomes contain miRNA-146b and miRNA-222. AB - BACKGROUND: With the increasing diagnosis of indolent papillary thyroid cancer (PTC), the task of identifying those likely to suffer from recurrence is becoming ever more challenging. MicroRNA (miRNA/miR) in the circulation has been demonstrated as potential biomarkers of recurrence in PTC. This study aimed to investigate in vitro if extracellular miRNAs are contained in exosomes, and their potential effect on other cells. METHODS: TPC-1 (PTC) and NTHY (normal thyroid follicular) cell lines were treated with exosome isolates and conditioned medium (CM), both containing miR-146b and miR-222. The changes in proliferation over a 72-h period of TPC-1 and NTHY were compared. Student t-test and analysis of variance were used for significance testing, and P < 0.05 was considered significant. RESULTS: Exosomes derived from TPC-1 cells were demonstrated to contain miR-146b and miR-222 in relative abundance. These exosomes caused a negative proliferative effect on both TPC-1 and NTHY cells. Exosomes derived from NTHY cells did not exert a significant proliferative effect on either cell line. CM from both cell types caused an initial increase in TPC-1 proliferation at 24 h. No significant change in proliferation was seen with NTHY cells when treated with either of the CM. CONCLUSIONS: The results showed that PTC cells overexpress miR-146b and miR-222 in exosomes; and that factors released by both normal thyroid and PTC cells alter proliferation of other cells in a complex manner. The intercellular interactions were likely conferred in part by exosomal miRNA, which can potentially be developed as biomarkers of PTC recurrence. PMID- 25819771 TI - Team interaction during surgery: a systematic review of communication coding schemes. AB - BACKGROUND: Communication problems have been systematically linked to human errors in surgery and a deep understanding of the underlying processes is essential. Although a number of tools exist to assess nontechnical skills, methods to study communication and other team-related processes are far from being standardized, making comparisons challenging. We conducted a systematic review to analyze methods used to study events in the operating room (OR) and to develop a synthesized coding scheme for OR team communication. MATERIALS AND METHODS: Six electronic databases were accessed to search for articles that collected individual events during surgery and included detailed coding schemes. Additional articles were added based on cross-referencing. That collection was then classified based on type of events collected, environment type (real or simulated), number of procedures, type of surgical task, team characteristics, method of data collection, and coding scheme characteristics. All dimensions within each coding scheme were grouped based on emergent content similarity. Categories drawn from articles, which focused on communication events, were further analyzed and synthesized into one common coding scheme. RESULTS: A total of 34 of 949 articles met the inclusion criteria. The methodological characteristics and coding dimensions of the articles were summarized. A priori coding was used in nine studies. The synthesized coding scheme for OR communication included six dimensions as follows: information flow, period, statement type, topic, communication breakdown, and effects of communication breakdown. CONCLUSIONS: The coding scheme provides a standardized coding method for OR communication, which can be used to develop a priori codes for future studies especially in comparative effectiveness research. PMID- 25819772 TI - Emerging enhanced imaging technologies of the esophagus: spectroscopy, confocal laser endomicroscopy, and optical coherence tomography. AB - BACKGROUND: Despite advances in diagnoses and therapy, esophageal adenocarcinoma remains a highly lethal neoplasm. Hence, a great interest has been placed in detecting early lesions and in the detection of Barrett esophagus (BE). Advanced imaging technologies of the esophagus have then been developed with the aim of improving biopsy sensitivity and detection of preplastic and neoplastic cells. The purpose of this article was to review emerging imaging technologies for esophageal pathology, spectroscopy, confocal laser endomicroscopy (CLE), and optical coherence tomography (OCT). METHODS: We conducted a PubMed search using the search string "esophagus or esophageal or oesophageal or oesophagus" and "Barrett or esophageal neoplasm" and "spectroscopy or optical spectroscopy" and "confocal laser endomicroscopy" and "confocal microscopy" and "optical coherence tomography." The first and senior author separately reviewed all articles. Our search identified: 19 in vivo studies with spectroscopy that accounted for 1021 patients and 4 ex vivo studies; 14 clinical CLE in vivo studies that accounted for 941 patients and 1 ex vivo study with 13 patients; and 17 clinical OCT in vivo studies that accounted for 773 patients and 2 ex vivo studies. RESULTS: Human studies using spectroscopy had a very high sensitivity and specificity for the detection of BE. CLE showed a high interobserver agreement in diagnosing esophageal pathology and an accuracy of predicting neoplasia. We also found several clinical studies that reported excellent diagnostic sensitivity and specificity for the detection of BE using OCT. CONCLUSIONS: Advanced imaging technology for the detection of esophageal lesions is a promising field that aims to improve the detection of early esophageal lesions. Although advancing imaging techniques improve diagnostic sensitivities and specificities, their integration into diagnostic protocols has yet to be perfected. PMID- 25819773 TI - Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy. AB - OBJECTIVES: Hypothermia is a well-recognised and effective neuroprotectant because of its depressive effect on metabolism. However, its application in focal ischaemic stroke is limited by delayed onset, prolonged duration, the need for extensive medical and nursing efforts and significant complications. This study combined mild hypothermia with phenothiazine drugs to enhance its neuroprotective effects, thus potentially avoiding side effects. METHODS: Fifty-four male Sprague Dawley rats were induced with a 2-hour right middle cerebral artery (MCA) occlusion using an intraluminal filament. Five groups were tested: the stroke group without treatment (anal temperature 37.8-38.3 degrees C), the mild hypothermia group (anal temperature 35.0 degrees C), the drugs group (1 mg/kg chlorpromazine and 1 mg/kg promethazine, anal temperature at 37.8-38.3 degrees C), combination therapy with the mild hypothermia and drugs group and the normal control group (anal temperature 37.8-38.3 degrees C). The treatments immediately followed reperfusion. The extent of brain injury was evaluated by infarct volume and behaviour performance. RESULTS: The combination treatment of mild hypothermia with phenothiazine drugs demonstrated salient and significant (P < 0.001) reductions in infarct volume (30.0 +/- 15.14%) when compared to the stroke group (52.77 +/- 8.99%). A better recovery of long-term motor performance was also observed for those receiving the combination therapy. However, when administered independently, neither the mild hypothermia therapy (53.8 +/- 10.3%) nor phenothiazine regimen (55.7 +/- 9.00%) had significant therapeutic effects on infarct volume (P = 0.85 and 0.61, respectively). DISCUSSION: This study provides a novel and promising therapeutic strategy in the management of acute stroke. PMID- 25819779 TI - Prediction of cardiovascular disease worldwide. PMID- 25819780 TI - A photoluminescent layer for improving the performance of dye-sensitized solar cells. AB - A pyrene photoluminescent layer is coated on the front side of a dye-sensitized solar cell to enhance the power conversion efficiency. The power conversion efficiency of the dye-sensitized solar cell coated with a pyrene photoluminescent layer improves from 9.12 +/- 0.06% to 10.30 +/- 0.11% (an improvement of 12.94%). PMID- 25819778 TI - A novel risk score to predict cardiovascular disease risk in national populations (Globorisk): a pooled analysis of prospective cohorts and health examination surveys. AB - BACKGROUND: Treatment of cardiovascular risk factors based on disease risk depends on valid risk prediction equations. We aimed to develop, and apply in example countries, a risk prediction equation for cardiovascular disease (consisting here of coronary heart disease and stroke) that can be recalibrated and updated for application in different countries with routinely available information. METHODS: We used data from eight prospective cohort studies to estimate coefficients of the risk equation with proportional hazard regressions. The risk prediction equation included smoking, blood pressure, diabetes, and total cholesterol, and allowed the effects of sex and age on cardiovascular disease to vary between cohorts or countries. We developed risk equations for fatal cardiovascular disease and for fatal plus non-fatal cardiovascular disease. We validated the risk equations internally and also using data from three cohorts that were not used to create the equations. We then used the risk prediction equation and data from recent (2006 or later) national health surveys to estimate the proportion of the population at different levels of cardiovascular disease risk in 11 countries from different world regions (China, Czech Republic, Denmark, England, Iran, Japan, Malawi, Mexico, South Korea, Spain, and USA). FINDINGS: The risk score discriminated well in internal and external validations, with C statistics generally 70% or more. At any age and risk factor level, the estimated 10 year fatal cardiovascular disease risk varied substantially between countries. The prevalence of people at high risk of fatal cardiovascular disease was lowest in South Korea, Spain, and Denmark, where only 5-10% of men and women had more than a 10% risk, and 62-77% of men and 79-82% of women had less than a 3% risk. Conversely, the proportion of people at high risk of fatal cardiovascular disease was largest in China and Mexico. In China, 33% of men and 28% of women had a 10-year risk of fatal cardiovascular disease of 10% or more, whereas in Mexico, the prevalence of this high risk was 16% for men and 11% for women. The prevalence of less than a 3% risk was 37% for men and 42% for women in China, and 55% for men and 69% for women in Mexico. INTERPRETATION: We developed a cardiovascular disease risk equation that can be recalibrated for application in different countries with routinely available information. The estimated percentage of people at high risk of fatal cardiovascular disease was higher in low-income and middle-income countries than in high-income countries. FUNDING: US National Institutes of Health, UK Medical Research Council, Wellcome Trust. PMID- 25819781 TI - Understanding Miltefosine-Membrane Interactions Using Molecular Dynamics Simulations. AB - Coarse-grained molecular dynamics simulations are used to calculate the free energies of transfer of miltefosine, an alkylphosphocholine anticancer agent, from water to lipid bilayers to study its mechanism of interaction with biological membranes. We consider bilayers containing lipids with different degrees of unsaturation: dipalmitoylphosphatidylcholine (DPPC, saturated, containing 0%, 10%, and 30% cholesterol), dioleoylphosphatidylcholine (DOPC, diunsaturated), palmitoyloleoylphosphatidylcholine (POPC, monounsaturated), diarachidonoylphosphatidylcholine (DAPC, polyunsaturated), and dilinoleylphosphatidylcholine (DUPC, polyunsaturated). These free energies, calculated using umbrella sampling, were used to compute the partition coefficients (K) of miltefosine between water and the lipid bilayers. The K values for the bilayers relative to that of pure DPPC were found to be 5.3 (DOPC), 7.0 (POPC), 1.0 (DAPC), 2.2 (DUPC), 14.9 (10% cholesterol), and 76.2 (30% cholesterol). Additionally, we calculated the free energy of formation of miltefosine-cholesterol complexes by pulling the surfactant laterally in the DPPC + 30% cholesterol system. The free energy profile that we obtained provides further evidence that miltefosine tends to associate with cholesterol and has a propensity to partition into lipid rafts. We also quantified the kinetics of the transport of miltefosine through the various bilayers by computing permeance values. The highest permeance was observed in DUPC bilayers (2.28 * 10(-2) m/s) and the lowest permeance in the DPPC bilayer with 30% cholesterol (1.10 * 10(-7) m/s). Our simulation results show that miltefosine does indeed interact with lipid rafts, has a higher permeability in polyunsaturated, loosely organized bilayers, and has higher flip-flop rates in specific regions of cellular membranes. PMID- 25819782 TI - Sesquiterpenes from the essential oil of Curcuma wenyujin and their inhibitory effects on nitric oxide production. AB - Three new sesquiterpenes including a new elemane-type sesquiterpene, 5betaH-elem 1,3,7,8-tetraen-8,12-olide (1), and two new carabrane-type sesquiterpenes, 7alpha,11-epoxy-6alpha-methoxy-carabrane-4,8-dione (2) and 8,11-epidioxy-8 hydroxy-4-oxo-6-carabren (3), together with eight known sesquiterpenes (4-11) were isolated from Curcuma wenyujin Y. H. Chen et C. Ling. Their structures were elucidated based on extensive spectroscopic analyses. A possible biogenetic scheme for the related compounds was postulated. All of the isolated compounds were tested for inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages. Meanwhile, preliminary structure-activity relationships for these compounds are discussed. PMID- 25819783 TI - Cytidine-stabilized gold nanocluster as a fluorescence turn-on and turn-off probe for dual functional detection of Ag(+) and Hg(2+). AB - In this study, we have developed a label-free, dual functional detection strategy for highly selective and sensitive determination of aqueous Ag(+) and Hg(2+) by using cytidine stabilized Au NCs and AuAg NCs as fluorescent turn-on and turn off probes, respectively. The Au NCs and AuAg NCs showed a remarkably rapid response and high selectivity for Ag(+) and Hg(2+) over other metal ions, and relevant detection limit of Ag(+) and Hg(2+) is ca. 10 nM and 30 nM, respectively. Importantly, the fluorescence enhanced Au NCs by doping Ag(+) can be conveniently reusable for the detection of Hg(2+) based on the corresponding fluorescence quenching. The sensing mechanism was based on the high-affinity metallophilic Hg(2+)-Ag(+) interaction, which effectively quenched the fluorescence of AuAg NCs. Furthermore, these fluorescent nanoprobes could be readily applied to Ag(+) and Hg(2+) detection in environmental water samples, indicating their possibility to be utilized as a convenient, dual functional, rapid response, and label-free fluorescence sensor for related environmental and health monitoring. PMID- 25819784 TI - Tutorial review on validation of liquid chromatography-mass spectrometry methods: part II. AB - This is the part II of a tutorial review intending to give an overview of the state of the art of method validation in liquid chromatography mass spectrometry (LC-MS) and discuss specific issues that arise with MS (and MS-MS) detection in LC (as opposed to the "conventional" detectors). The Part II starts with briefly introducing the main quantitation methods and then addresses the performance related to quantification: linearity of signal, sensitivity, precision, trueness, accuracy, stability and measurement uncertainty. The last section is devoted to practical considerations in validation. With every performance characteristic its essence and terminology are addressed, the current status of treating it is reviewed and recommendations are given, how to handle it, specifically in the case of LC-MS methods. PMID- 25819785 TI - Tutorial review on validation of liquid chromatography-mass spectrometry methods: part I. AB - This is the part I of a tutorial review intending to give an overview of the state of the art of method validation in liquid chromatography mass spectrometry (LC-MS) and discuss specific issues that arise with MS (and MS/MS) detection in LC (as opposed to the "conventional" detectors). The Part I briefly introduces the principles of operation of LC-MS (emphasizing the aspects important from the validation point of view, in particular the ionization process and ionization suppression/enhancement); reviews the main validation guideline documents and discusses in detail the following performance parameters: selectivity/specificity/identity, ruggedness/robustness, limit of detection, limit of quantification, decision limit and detection capability. With every method performance characteristic its essence and terminology are addressed, the current status of treating it is reviewed and recommendations are given, how to determine it, specifically in the case of LC-MS methods. PMID- 25819786 TI - Identifying bioactive components in natural products through chromatographic fingerprint. AB - Bioactive component identification is a crucial issue in search for new drug leads. We provide a new strategy to search for bioactive components based on Sure Independence Screening (SIS) and interval PLS (iPLS). The method, which is termed as SIS-iPLS, is not only able to find out the chief bioactive components, but also able to judge how many components should be there responsible for the total bioactivity. The method is totally "data-driven" with no need for prior knowledge about the unknown mixture analyzed, therefore especially suitable for effect directed work like bioassay-guided fractionation. Two data sets, a synthetic mixture system of twelve components and a suite of Radix Puerariae Lobatae extracts samples, are used to test the identification ability of the SIS-iPLS method. PMID- 25819787 TI - Simultaneous electrochemical sensing of thallium, lead and mercury using a novel ionic liquid/graphene modified electrode. AB - In the present manuscript, an electrochemical sensor for the sensitive detection of Tl(+), Pb(2+) and Hg(2+) is described. A new composite electrode has been fabricated using graphene, 1-n-octylpyridinum hexafluorophosphate (OPFP), and [2,4-Cl2C6H3C(O)CHPPh3] (L), as a new synthetic phosphorus ylide. The physicochemical and electrochemical characterizations of fabricated sensor were investigated in details. The advantages of the proposed composite electrode are its ability in simultaneous electrochemical detection of Tl(+), Pb(2+) and Hg(2+) with good selectivity, stability and no need for separating of the three species from complex mixtures prior to electrochemical measurements. The analytical performance of the proposed electrode was examined using square wave voltammetry. Tl(+), Pb(2+) and Hg(2+) can be determined in linear ranges from 1.25*10(-9) to 2.00*10(-7) mol L(-1). Low detection limits of 3.57*10(-10) mol L(-1) for Tl(+), 4.50*10(-10) mol L(-1) for Pb(2+) and 3.86*10(-10) mol L(-1) for Hg(2+) were achieved. Finally, the proposed electrochemical sensor was applied to detect trace analyte ions in various water and soil samples with satisfactory results. PMID- 25819788 TI - Metal-organic framework-templated synthesis of magnetic nanoporous carbon as an efficient absorbent for enrichment of phenylurea herbicides. AB - Nanoporous carbon with a high specific surface area and unique porous structure represents an attractive material as an adsorbent in analytical chemistry. In this study, a magnetic nanoporous carbon (MNC) was fabricated by direct carbonization of Co-based metal-organic framework in nitrogen atmosphere without using any additional carbon precursors. The MNC was used as an effective magnetic adsorbent for the extraction and enrichment of some phenylurea herbicides (monuron, isoproturon, diuron and buturon) in grape and bitter gourd samples prior to their determination by high performance liquid chromatography with ultraviolet detection. Several important experimental parameters that could influence the extraction efficiency were investigated and optimized. Under the optimum conditions, a good linearity was achieved in the concentration range of 1.0-100.0 ng g(-1) for monuron, diuron and buturon and 1.5-100.0 ng g(-1) for isoproturon with the correlation coefficients (r) larger than 0.9964. The limits of detection (S/N=3) of the method were in the range from 0.17 to 0.46 ng g(-1). The results indicated that the MNC material was stable and efficient adsorbent for the magnetic solid-phase extraction of phenylurea herbicides and would have a great application potential for the extraction and preconcentration of more organic pollutants from real samples. PMID- 25819789 TI - Improving detection sensitivity of amino acids in thyroid tissues by using phthalic acid as a mobile phase additive in hydrophilic interaction chromatography-electrospray ionization-tandem mass spectrometry. AB - In this work, 0.08 mmol L(-1) of phthalic acid was introduced as a mobile phase additive to quantify free amino acids (AAs) by hydrophilic interaction liquid chromatography (HILIC) coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS). The addition of phthalic acid significantly increased the signal intensity of protonated AA ions, resulting from the decrease of the relative abundance of AA sodium adducts. Meanwhile, the chromatographic peak shapes of AAs were optimized. As a consequence, there was a noticeable increase in the sensitivity of detection for AAs. The limits of detection (LOD) and quantification (LOQ) of the AAs ranged from 0.0500 to 20.0 ng mL(-1) and from 0.100 to 50.0 ng mL(-1), respectively, which were 4-50 times lower compared to the values measured without the addition of phthalic acid. The enhanced detection and separation of AAs were obtained by merely adding phthalic acid to the mobile phase without changing other conditions. Eventually, this simple method was validated and successfully applied to the analysis of twenty-four kinds of free AAs in human thyroid carcinoma and para-carcinoma tissues, demonstrating a significant increase of most AAs in thyroid carcinoma tissues (p<0.05). PMID- 25819790 TI - Highly-controllable imprinted polymer nanoshell at the surface of silica nanoparticles based room-temperature phosphorescence probe for detection of 2,4 dichlorophenol. AB - This paper reports a facile and general method for preparing an imprinted polymer thin shell with Mn-doped ZnS quantum dots (QDs) at the surface of silica nanoparticles by stepwise precipitation polymerization to form the highly controllable core-shell nanoparticles (MIPs@SiO2-ZnS:Mn QDs) and sensitively recognize the target 2,4-dichlorophenol (2,4-DCP). Acrylamide (AM) and ethyl glycol dimethacrylate (EGDMA) were used as the functional monomer and the cross linker, respectively. The MIPs@SiO2-ZnS:Mn QDs had a controllable shell thickness and a high density of effective recognition sites, and the thickness of uniform core-shell 2,4-DCP-imprinted nanoparticles was controlled by the total amounts of monomers. The MIPs@SiO2-ZnS:Mn QDs with a shell thickness of 45 nm exhibited the largest quenching efficiency to 2,4-DCP by using the spectrofluorometer. After the experimental conditions were optimized, a linear relationship was obtained covering the linear range of 1.0-84 MUmol L(-1) with a correlation coefficient of 0.9981 and the detection limit (3sigma/k) was 0.15 MUmol L(-1). The feasibility of the developed method was successfully evaluated through the determination of 2,4-DCP in real samples. This study provides a general strategy to fabricate highly-controllable core-shell imprinted polymer-contained QDs with highly selective recognition ability. PMID- 25819791 TI - Enzyme-regulated the changes of pH values for assembling a colorimetric and multistage interconnection logic network with multiple readouts. AB - Based on enzymatic reactions-triggered changes of pH values and biocomputing, a novel and multistage interconnection biological network with multiple easy detectable signal outputs has been developed. Compared with traditional chemical computing, the enzyme-based biological system could overcome the interference between reactions or the incompatibility of individual computing gates and offer a unique opportunity to assemble multicomponent/multifunctional logic circuitries. Our system included four enzyme inputs: beta-galactosidase (beta gal), glucose oxidase (GOx), esterase (Est) and urease (Ur). With the assistance of two signal transducers (gold nanoparticles and acid-base indicators) or pH meter, the outputs of the biological network could be conveniently read by the naked eyes. In contrast to current methods, the approach present here could realize cost-effective, label-free and colorimetric logic operations without complicated instrument. By designing a series of Boolean logic operations, we could logically make judgment of the compositions of the samples on the basis of visual output signals. Our work offered a promising paradigm for future biological computing technology and might be highly useful in future intelligent diagnostics, prodrug activation, smart drug delivery, process control, and electronic applications. PMID- 25819792 TI - Microdamage induced calcium efflux from bone matrix activates intracellular calcium signaling in osteoblasts via L-type and T-type voltage-gated calcium channels. AB - Mechanisms by which bone microdamage triggers repair response are not completely understood. It has been shown that calcium efflux ([Ca(2+)]E) occurs from regions of bone undergoing microdamage. Such efflux has also been shown to trigger intracellular calcium signaling ([Ca(2+)]I) in MC3T3-E1 cells local to damaged regions. Voltage-gated calcium channels (VGCCs) are implicated in the entry of [Ca(2+)]E to the cytoplasm. We investigated the involvement of VGCC in the extracellular calcium induced intracellular calcium response (ECIICR). MC3T3-E1 cells were subjected to one dimensional calcium efflux from their basal aspect which results in an increase in [Ca(2+)]I. This increase was concomitant with membrane depolarization and it was significantly reduced in the presence of Bepridil, a non-selective VGCC inhibitor. To identify specific type(s) of VGCC in ECIICR, the cells were treated with selective inhibitors for different types of VGCC. Significant changes in the peak intensity and the number of [Ca(2+)]I oscillations were observed when L-type and T-type specific VGCC inhibitors (Verapamil and NNC55-0396, respectively) were used. So as to confirm the involvement of L- and T-type VGCC in the context of microdamage, cells were seeded on devitalized notched bone specimen, which were loaded to induce microdamage in the presence and absence of Verapamil and NNC55-0396. The results showed significant decrease in [Ca(2+)]I activity of cells in the microdamaged regions of bone when L- and T-type blockers were applied. This study demonstrated that extracellular calcium increase in association with damage depolarizes the cell membrane and the calcium ions enter the cell cytoplasm by L- and T-type VGCCs. PMID- 25819793 TI - New Insights into the Post-Translational Regulation of DNA Damage Response and Double-Strand Break Repair in Caenorhabditis elegans. AB - Although a growing number of studies have reported the importance of SUMOylation in genome maintenance and DNA double-strand break repair (DSBR), relevant target proteins and how this modification regulates their functions are yet to be clarified. Here, we analyzed SUMOylation of ZTF-8, the homolog of mammalian RHINO, to test the functional significance of this protein modification in the DSBR and DNA damage response (DDR) pathways in the Caenorhabditis elegans germline. We found that ZTF-8 is a direct target for SUMOylation in vivo and that its modification is required for DNA damage checkpoint induced apoptosis and DSBR. Non-SUMOylatable mutants of ZTF-8 mimic the phenotypes observed in ztf-8 null mutants, including reduced fertility, impaired DNA damage repair, and defective DNA damage checkpoint activation. However, while mutants for components acting in the SUMOylation pathway fail to properly localize ZTF-8, its localization is not altered in the ZTF-8 non-SUMOylatable mutants. Taken together, these data show that direct SUMOylation of ZTF-8 is required for its function in DSBR as well as DDR but not its localization. ZTF-8's human ortholog is enriched in the germline, but its meiotic role as well as its post translational modification has never been explored. Therefore, our discovery may assist in understanding the regulatory mechanism of this protein in DSBR and DDR in the germline. PMID- 25819794 TI - Efficient CRISPR/Cas9-Mediated Genome Editing in Mice by Zygote Electroporation of Nuclease. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein (Cas) system is an adaptive immune system in bacteria and archaea that has recently been exploited for genome engineering. Mutant mice can be generated in one step through direct delivery of the CRISPR/Cas9 components into a mouse zygote. Although the technology is robust, delivery remains a bottleneck, as it involves manual injection of the components into the pronuclei or the cytoplasm of mouse zygotes, which is technically demanding and inherently low throughput. To overcome this limitation, we employed electroporation as a means to deliver the CRISPR/Cas9 components, including Cas9 messenger RNA, single guide RNA, and donor oligonucleotide, into mouse zygotes and recovered live mice with targeted nonhomologous end joining and homology-directed repair mutations with high efficiency. Our results demonstrate that mice carrying CRISPR/Cas9 mediated targeted mutations can be obtained with high efficiency by zygote electroporation. PMID- 25819796 TI - Literacy after cerebral hemispherectomy: Can the isolated right hemisphere read? AB - OBJECTIVES: Cerebral hemispherectomy, a surgical procedure undergone to control intractable seizures, is becoming a standard procedure with more cases identified and treated early in life [33]. While the effect of the dominant hemisphere resection on spoken language has been extensively researched, little is known about reading abilities in individuals after left-sided resection. Left lateralized phonological abilities are the key components of reading, i.e., grapheme-phoneme conversion skills [1]. These skills are critical for the acquisition of word-specific orthographic knowledge and have been shown to predict reading levels in average readers as well as in readers with mild cognitive disability [26]. Furthermore, impaired phonological processing has been implicated as the cognitive basis in struggling readers. Here, we explored the reading skills in participants who have undergone left cerebral hemispherectomy. METHODS: Seven individuals who have undergone left cerebral hemispherectomy to control intractable seizures associated with perinatal infarct have been recruited for this study. We examined if components of phonological processing that are shown to reliably separate average readers from struggling readers, i.e., phonological awareness, verbal memory, speed of retrieval, and size of vocabulary, show the same relationship to reading levels when they are mediated by the right hemisphere [2]. RESULTS: We found that about 60% of our group developed both word reading and paragraph reading in the average range. Phonological processing measured by both phonological awareness and nonword reading was unexpectedly spared in the majority of participants. Phonological awareness levels strongly correlated with word reading. Verbal memory, a component of phonological processing skills, together with receptive vocabulary size, positively correlated with reading levels similar to those reported in average readers. Receptive vocabulary, a bilateral function, was preserved to a certain degree similar to that of strongly left-lateralized phonological skills [3]. Later seizure onset was associated with better reading levels. CONCLUSIONS: When cerebral hemispherectomy is performed to control seizures associated with very early (in utero) insult, it has been found that the remaining right hemisphere is still able to support reading and phonological processing skills that are normally mediated by the left hemisphere. Our results also suggest the existence of variability in individuals after hemispherectomy, even within groups having the same etiology and similar timing of insult. PMID- 25819795 TI - An Rtf2 Domain-Containing Protein Influences Pre-mRNA Splicing and Is Essential for Embryonic Development in Arabidopsis thaliana. AB - Alternative splicing is prevalent in plants, but little is known about its regulation in the context of developmental and signaling pathways. We describe here a new factor that influences pre-messengerRNA (mRNA) splicing and is essential for embryonic development in Arabidopsis thaliana. This factor was retrieved in a genetic screen that identified mutants impaired in expression of an alternatively spliced GFP reporter gene. In addition to the known spliceosomal component PRP8, the screen recovered Arabidopsis RTF2 (AtRTF2), a previously uncharacterized, evolutionarily conserved protein containing a replication termination factor 2 (Rtf2) domain. A homozygous null mutation in AtRTF2 is embryo lethal, indicating that AtRTF2 is an essential protein. Quantitative RT PCR demonstrated that impaired expression of GFP in atrtf2 and prp8 mutants is due to inefficient splicing of the GFP pre-mRNA. A genome-wide analysis using RNA sequencing indicated that 13-16% of total introns are retained to a significant degree in atrtf2 mutants. Considering these results and previous suggestions that Rtf2 represents an ubiquitin-related domain, we discuss the possible role of AtRTF2 in ubiquitin-based regulation of pre-mRNA splicing. PMID- 25819797 TI - Can anesthetic treatment worsen outcome in status epilepticus? AB - Status epilepticus refractory to first-line and second-line antiepileptic treatments challenges neurologists and intensivists as mortality increases with treatment refractoriness and seizure duration. International guidelines advocate anesthetic drugs, such as continuously administered high-dose midazolam, propofol, and barbiturates, for the induction of therapeutic coma in patients with treatment-refractory status epilepticus. The seizure-suppressing effect of anesthetic drugs is believed to be so strong that some experts recommend using them after benzodiazepines have failed. Although the rationale for the use of anesthetic drugs in patients with treatment-refractory status epilepticus seems clear, the recommendation of their use in treating status epilepticus is based on expert opinions rather than on strong evidence. Randomized trials in this context are lacking, and recent studies provide disturbing results, as the administration of anesthetics was associated with poor outcome independent of possible confounders. This calls for caution in the straightforward use of anesthetics in treating status epilepticus. However, there are still more questions than answers, and current evidence for the adverse effects of anesthetic drugs in patients with status epilepticus remains too limited to advocate a change of treatment algorithms. In this overview, the rationale and the conflicting clinical implications of anesthetic drugs in patients with treatment-refractory status epilepticus are discussed, and remaining questions are elaborated. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25819798 TI - The role of obesity in cognitive dysfunction in people with epilepsy. AB - OBJECTIVE: In the general population, obesity is associated with accelerated age related cognitive decline. The impact of obesity on cognitive function in neurological populations who already have a heightened risk of cognitive decline is unknown. This study explored the relationship between obesity and cognitive underfunction in people with medically intractable epilepsy. METHODS: Eighty-one consecutive patients admitted for evaluation for medically intractable epilepsy (36 females and 45 males) underwent tests of memory and intellectual function. Optimal level of function was assessed using the National Adult Reading Test - Revised. Measures of underfunction were calculated by subtracting current measures of intellectual ability from the NART IQ. Body mass index (BMI) was used as an index of obesity. RESULTS: Twenty-nine people had a BMI in the healthy range (36%), 31 were overweight (38%), and 21 were obese (26%). The healthy weight, overweight, and obese groups did not differ in age at the time of assessment, age at seizure onset, or optimal level of function (NART IQ). The obese group had a greater degree of suboptimal processing speed and demonstrated a greater degree of underfunction on the Full Scale IQ (FSIQ) measure compared to the healthy weight group. Body mass index accounted for 14% of the variance in underfunction in processing speed and 10% of the variance in underfunction in FSIQ. Controlling for the effects of age, all measures of memory function were significantly correlated with BMI, with poorer scores associated with higher BMIs. SIGNIFICANCE: A small but significant proportion of the variance in memory function and intellectual underfunction in people with epilepsy is explained by BMI. Further work is needed to establish whether a reduction in BMI to within healthy limits is associated with improvements in cognitive function in this group. PMID- 25819799 TI - Hypothesis: CeM-RVLM circuits may be implicated in sudden unexpected death in epilepsy by melanocortinergic-sympathetic signaling. PMID- 25819800 TI - Cross-cultural adaptation of the Malay version of the parent-proxy Health-Related Quality of Life Measure for Children with Epilepsy (CHEQOL-25) in Malaysia. AB - PURPOSE: We aimed to cross-culturally adapt the parent-proxy Health-Related Quality of Life Measure for Children with Epilepsy (CHEQOL-25) into Malay and to determine its validity and reliability among parents of children with epilepsy in Malaysia. METHODS: The English version of the parent-proxy CHEQOL-25 was translated according to international guidelines to Malay. Content validity was verified by an expert panel and piloted in five parents of children with epilepsy (CWE). The Malay parent-proxy CHEQOL-25 was then administered to 40 parents of CWE, aged 8-18years from two tertiary hospitals, at baseline and 2weeks later. Parents were also required to complete the Malay PedsQLTM 4.0 so that convergent validity could be assessed. Hypothesis testing was assessed by correlating the individual subscales in the parent-proxy CHEQOL-25 with epilepsy severity, the number of anticonvulsants, and the number of close friends. RESULTS: Participants from the pilot study did not encounter any problems in answering the final translated Malay parent-proxy CHEQOL-25. Hence, no further modifications were made. Cronbach's alpha for each subscale of the Malay parent-proxy CHEQOL-25 ranged from 0.67 to 0.83. The intraclass correlation coefficient for all items at test-retest ranged from 0.70 to 0.94. Both the CHEQOL-25 and the PedsQLTM 4.0 showed good correlation in the social and emotional subscales (r=0.598, p=0.002 and r=0.342, p=0.031, respectively). The severity of epilepsy, higher number of antiepileptic drug(s), poorer cognitive ability of the child, lower number of close friends, and lesser amount of time spent with friends were significantly associated with poorer health-related quality of life. CONCLUSIONS: The Malay parent-proxy CHEQOL-25 was found to be a valid and reliable instrument to assess parents' perceived HRQOL of their CWE in Malaysia. PMID- 25819801 TI - Distribution of Candida albicans and non-albicans Candida species in oral candidiasis patients: Correlation between cell surface hydrophobicity and biofilm forming activities. AB - OBJECTIVES: The purposes of this investigation were to study the prevalence of Candida albicans and non-albicans Candida (NAC) species from oral candidiasis patients and evaluate the cell surface hydrophobicity (CSH) and biofilm forming capacity of the clinical isolates Candida species from oral cavity. DESIGN: This study identified a total of 250 Candida strains isolated from 207 oral candidiasis patients with PCR-RFLP technique. CSH value, total biomass of biofilm and biofilm forming ability of 117 oral Candida isolates were evaluated. RESULTS: C. albicans (61.6%) was still the predominant species in oral candidiasis patients with and without denture wearer, respectively, followed by C. glabrata (15.2%), C. tropicalis (10.4%), C. parapsilosis (3.2%), C. kefyr (3.6%), C. dubliniensis (2%), C. lusitaniae (2%), C. krusei (1.6%), and C. guilliermondii (0.4%). The proportion of mixed colonization with more than one Candida species was 18% from total cases. The relative CSH value and biofilm biomass of NAC species were greater than C. albicans (p<0.001). Ninety-two percent of oral isolates NAC species had biofilm forming ability, whereas 78% of C. albicans were biofilm formers. Furthermore, the significant difference of relative CSH values between biofilm formers and non-biofilm formers was observed in the NAC species (p<0.005), whereas the difference was not statistically significant in C. albicans. CONCLUSION: The frequency of the NAC species colonization in oral cavity was gradually increasing. The possible contributing factors might be high cell surface hydrophobicity and biofilm forming ability. The relative CSH value could be a putative factor for determining biofilm formation ability of the non albicans Candida species. PMID- 25819803 TI - Intermittent application of hypergravity by centrifugation attenuates disruption of rat gait induced by 2 weeks of simulated microgravity. AB - The effects of intermittent hypergravity on gait alterations and hindlimb muscle atrophy in rats induced by 2 weeks of simulated microgravity were investigated. Rats were submitted to hindlimb unloading for 2 weeks (unloading period), followed by 2 weeks of reloading (recovery period). During the unloading period, animals were subjected to the following treatments: (1) free in cages (Control); (2) continuous unloading (UL); (3) released from unloading for 1 hour per day (UL+1G); (4) hypergravity for 1h per day using a centrifuge for small animals (UL+2G). The relative weights of muscles to the whole body weight and kinematics properties of hindlimbs during gait were evaluated. UL rats walked with their hindlimbs overextended, and the oscillation of their limb motion had become narrowed and forward-shifted after the unloading period, and this persisted for at least 2 weeks after the termination of unloading. However, these locomotor alterations were attenuated in rats subjected to UL+2G centrifugation despite minor systematic changes in muscle recovery. These findings indicate hypergravity application could counteract the adverse effects of simulated or actual microgravity environments. PMID- 25819804 TI - Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1. AB - BACKGROUND: Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations. OBJECTIVE: Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations. MATERIALS & METHODS: The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours. CONCLUSIONS: This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype. PMID- 25819805 TI - Multiple calcifying pseudoneoplasms of the neuraxis. AB - Calcified pseudoneoplasms of the neuraxis (CAPNON) are a rare diagnostic entity. They have been reported intra-cranially as well as in the spine, and are most commonly found at the skull base. This is a case report of a 38-year-old woman who presented with bilateral CAPNON, diagnosed 8 years apart. While there are approximately 46 reported in the current literature of cerebral and spinal fibro osseous lesions, this is the first report of separate lesions. PMID- 25819806 TI - Changes of cerebral white matter in patients suffering from Pantothenate Kinase Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study. AB - BACKGROUND: To look for microstructural white matter alterations in patients with dystonia due to Pantothenate Kinase-Associated Neurodegeneration. MATERIAL AND METHODS: We examined 21 genetically confirmed patients and an age-matched group of 21 healthy controls by diffusion tensor imaging. Evaluation of data was performed by tract-based spatial statistics analysis and a voxel-wise comparison of calculated maps of fractional anisotropy. Findings were compared between groups and correlated to the dystonia score of the Burke-Fahn-Marsden Scale (p <= 0.05). RESULTS: Patients showed reductions of fractional anisotropy mainly in the periventricular substance surrounding the third ventricle, in the medial part of both putamina and in the frontal white matter including the anterior limbs of the internal capsules and the corpus callosum. Infratentorially, the cerebellar white matter and dorsal parts of the pons and medulla were affected. CONCLUSION: In addition to cortical grey matter changes, we now have a second structural finding pointing to a more widespread affection of cerebral tissue in PKAN dystonia than just the lesion and iron accumulation in the globus pallidus. PMID- 25819807 TI - Secondary treatment failure in cervical dystonia after treatment with inco- and abobotulinumtoxinA. PMID- 25819808 TI - Detecting and monitoring the symptoms of Parkinson's disease using smartphones: A pilot study. AB - BACKGROUND: Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking. METHODS: Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS. RESULTS: Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11-34) was 1.26 UPDRS points (SD 0.16). CONCLUSION: Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool. PMID- 25819809 TI - Involvement of hypoxia and inflammation in early pregnancy loss mediated by Shiga toxin type 2. AB - INTRODUCTION: Symptomatic or asymptomatic Shiga toxin producing Escherichia coli (STEC) infections during early pregnancy may cause maternal or fetal damage mediated by Shiga toxin type 2 (Stx2). The aim of this study is to elucidate the mechanisms responsible for early pregnancy loss in rats treated with Stx2. METHODS: Sprague Dawley pregnant rats were intraperitoneally injected at day 8 of gestation with a sublethal dose (0.5 ng of Stx2/g of total body weight, 250 MUl) of purified Stx2. Control rats were injected with the same volume of PBS. The expression of globotriaosylceramide (Gb3) glycosphingolipid receptor for Stx2 was evaluated by thin-layer chromatography (TLC). Regions of hypoxia in decidual tissue were determined by pimonidazole immunohistochemistry and vascular endothelial growth factor (VEGF) expression by Western blot and immunohistochemistry. Tumor necrosis factor-alpha (TNF-alpha) levels in serum and decidual tissue were evaluated by ELISA. Serum progesterone levels were determined by RIA. RESULTS: Decidual tissue from both, control and Stx2-treated rats showed similar expression of Gb3 receptor. Intrauterine growth restriction was observed in Stx2-treated rats, associated with hypoxia and an increase of decidual TNF-alpha levels. Decrease of serum progesterone levels and decidual VEGF expression were also demonstrated. DISCUSSION: Our findings indicate that Stx2 reaches the uteroplacental unit, binds Gb3 and triggers damage in decidual tissue. Poor oxygen supply accompanied with damage in the uteroplacental unit and inflammation could be responsible for the early pregnancy loss. Decrease in the pregnancy protective factors, serum progesterone and local VEGF, may contribute to the pregnancy loss. PMID- 25819810 TI - Animal models of fetal growth restriction: Considerations for translational medicine. AB - Fetal growth restriction (FGR) is the failure of a fetus to reach its full genetic growth potential. It occurs in up to 8% of pregnancies, and after premature birth is the second leading cause of infant mortality and morbidity. There is no treatment currently available for FGR. Its primary cause, when not attributable to structural or genetic defects of the fetus, is 'placental insufficiency'. This broad definition covers the inability of the fetus to acquire sufficient nutrients and oxygen, and is influenced by a number of factors including altered maternal or fetal blood flow, reduced nutrient transport or changes in the placenta such as increased barrier thickness inhibiting nutrient transfer. For those researchers studying FGR and developing new therapies, choosing an animal model is a crucial consideration. It is vital to clearly frame the question being asked, as this will impact the factor influencing fetal nutrient delivery in the model, and will also affect the applicability of the results to the human condition. This review examines the range of in vivo models of FGR available for those engaged in translational research. PMID- 25819811 TI - Flatfoot in school-age children: prevalence and associated factors. AB - BACKGROUND: Flatfoot has been shown to cause abnormal stresses on the foot and lower extremity. The altered mechanical stresses on these structures can aggravate the foot deformity. Screening of the flatfoot and its associated factors helps detect underlying risks influencing the stresses on the foot. The purpose of this study was to analyze the structure of the medial foot arch and investigate its associated factors in students, aged 7 to 14 years. METHODS: Multistage cluster sampling was used and each cluster included 2 other random sampling levels. A total of 667 Iranian school children were recruited and their feet were bilaterally evaluated using a static footprint while standing in a fully weightbearing position. The footprint, an observational measurement, and a questionnaire were used for the foot assessment. RESULTS: The prevalence of flatfoot was 17.1% in the population studied. There was no gender difference but the prevalence of flatfoot did decrease with age. The significant differences were observed in the prevalence of flatfoot between normal-weight, overweight, and obese groups (P < .01); more overweight participants had flatter feet. CONCLUSION: This study demonstrated that development of the longitudinal plantar arch in school-age children is influenced by age and weight. Age and weight were the primary predictive factors of flatfoot. LEVELS OF EVIDENCE: Prognostic, Level IV: Case series. PMID- 25819812 TI - MiR-191 modulates malignant transformation of endometriosis through regulating TIMP3. AB - BACKGROUND: Although aberrant expression of several miRNAs was found during the pathological development of endometriosis to endometriosis-associated ovarian cancer (EAOC), their roles are not fully understood. miR-191 is a miRNA significantly upregulated in endometriosis and EAOC patients. However, its downstream network is still not clear. This study explored its role in malignant transformation of endometriosis to EAOC. MATERIAL AND METHODS: Tissues from 12 healthy controls, 12 patients with endometriomas, and 12 patients with EAOC were used to verify miR-191 expression by using qRT-PCR. Endometriosis cell line CRL 7566 and ovarian endometrioid carcinoma cell line CRL-11731 were used to explore the downstream regulative function of miR-191. RESULTS: By using tissue and serum samples from healthy, endometriosis, and EAOC participants, we confirmed that miR 191 expression was significantly higher in endometriosis and EAOC participants. Interestingly, we also observed that TIMP3 expression was negatively correlated with miR-191 expression. Overexpressing miR-191 in CRL-7566 significantly increased cell proliferation and invasion, while miR-191 knockdown in CRL-11731 cells significantly decreased cell proliferation and invasion. These modulating effects of miR-191 are achieved through its regulation of TIMP3. CONCLUSIONS: miR 191 can directly regulate TIMP3 expression, thereby affecting cell proliferation rate and invasion ability. The miR-191-TIMP3 axis might be critical in the malignant transformation of endometriosis to EAOC. PMID- 25819813 TI - DTB Select: 4 | April 2015. AB - Navigating the new drug-driving law ? EMA recommends suspension of medicines over trial concerns ? NICE updates approach to biosimilars ? Chondroitin for OA? ? The impact of molluscum contagiosum ? Reassessing treatments for neuropathic pain ? First-line drugs for hypertension ? Stopping smoking and mental health ? Warnings and advice on ? valproate treatment. PMID- 25819814 TI - Aortic pseudocoarctation: a late presentation of an uncommon anomaly. PMID- 25819815 TI - Prostate cancer: beware of disseminated intravascular coagulation. AB - Disseminated intravascular coagulation (DIC) is a pathological systemic condition resulting from aberrant activation of the coagulation system. It is characterised by the release and activation of procoagulants into the blood, with an associated consumption coagulopathy. Its association with solid and haematological malignancies is well described in literature. This case describes an elderly man, known to have prostate cancer, who following transurethral resection of the prostate developed DIC with haematuria, spontaneous ecchymoses and mucosal bleeding. Subsequent investigations revealed a prostate-specific antigen (PSA) >1000 ug/L, and staging CT showed multiple sclerotic metastatic lesions affecting the thoracic and lumbar vertebra, as well as infiltration into his left femur. Coagulation normalised with blood products and vitamin K within 1 week, and the patient responded to antiandrogen therapy with a reduction in pain and PSA on discharge. PMID- 25819816 TI - Cavernous sinus syndrome: need for early diagnosis. AB - Cavernous sinus syndrome (CSS) is a rare condition characterised by ophthalmoplegia, proptosis, ocular and conjunctival congestion, trigeminal sensory loss and Horner's syndrome. These signs and symptoms result from the involvement of the cranial nerves passing through the cavernous sinus. We report the case of a 53-year-old man with a history of daily stabbing headache associated with dizziness, progressive blurred vision, right ocular pain, ptosis and ophthalmoplegia. After working up the patient, a meningioma was identified as the cause of the CSS. Despite advances in neuroimaging techniques, in some cases, the aetiology of CSS remains difficult to determine. We highlight the clinical and radiological features of a meningioma, one of the causes of CSS. Early diagnosis and treatment of CSS play a key role in a better prognosis. PMID- 25819817 TI - Juvenile polymyositis with unremitting pain and progressive loss of motor and bulbar function on a background of sickle cell disease. AB - The diagnosis of acute autoimmune rheumatic disorders in sickle cell disease (SCD) can be challenging. Polymyositis is an inflammatory myopathy which, like SCD, may present with myalgia but is usually associated with proximal muscle weakness. We describe an adolescent boy presenting with limb pain, difficulty in mobilisation, with progressive loss of motor function and later bulbar weakness. Investigations showed massive elevation of creatine kinase, and MRI and muscle biopsy findings consistent with severe polymyositis. The patient was treated with corticosteroids, intravenous immunoglobulin and intensive rehabilitation therapy. He made a good recovery and was discharged on azathioprine and prednisolone. In the context of SCD, multisystem symptoms, unexplained muscle pain and weakness, unresponsive to conventional treatment in the presence of steady state haemoglobin, should alert the clinician to autoimmune phenomena. Key factors in making a diagnosis are an autoimmune screen and early discussion with a rheumatology expert. PMID- 25819818 TI - An unusual cause of abdominal pain in an HIV-positive man. AB - We report a case of an HIV-positive man on antiretroviral therapy (ART) who developed abdominal pain due to acute-on-chronic intestinal ischaemia secondary to superior mesenteric vein thrombosis (SMVT) requiring emergency surgery. He was found to have persistently low levels of protein C on thrombophilia screening. To the best of our knowledge, the association linking SMVT to protein C deficiency in an HIV-infected patient has never been reported in the literature. PMID- 25819819 TI - Cystic duct carcinoma mimicking a middle bile duct tumour. AB - Cystic duct carcinoma was defined by Farrar as a tumour restricted to the cystic duct, making it a rare disease. The authors describe a case of a cystic duct carcinoma that fulfils Farrar's strict diagnostic criteria and that became clinically relevant by compressing the common hepatic duct, thus causing cholestasis. A cholecystectomy was performed with en bloc resection of the cystic and extrahepatic bile duct with a regional lymphadenectomy. PMID- 25819820 TI - Primary hyperparathyroidism in pregnancy leading to hypercalcaemic crisis and uraemic encephalopathy. AB - Primary hyperparathyroidism is rare during pregnancy. Recognition may be challenging as symptoms overlap with those of other common disorders of pregnancy. Furthermore, physiological changes of pregnancy affecting calcium homoeostasis mean awareness of the condition and careful interpretation of results in the light of pregnancy are essential for diagnosis. Maternal complications of primary hyperparathyroidism include nephrolithiasis, pancreatitis, cardiac arrhythmias, hypertension and peptic ulcers. At its most severe, hypercalcaemic crisis may occur, presenting with acute neurological disturbance. Most commonly, the underlying aetiology is a solitary parathyroid adenoma whereby parathyroidectomy is the only cure. A 30-year-old Caucasian woman booked under Consultant care presented at 32 weeks gestation with vomiting and right-sided loin pain. Following presentation, she was diagnosed with renal calculi. She was delivered by caesarean section (CS) due to deterioration in renal function. Post-CS, she had a grand mal seizure. She was found to have hypercalcaemia with underlying hyperparathyroidism. PMID- 25819821 TI - Orbital metastasis as initial manifestation of a widespread papillary thyroid microcarcinoma. AB - Papillary thyroid carcinomas (PTCs), particularly microcarcinomas, rarely metastasise to the orbit. We report a case of a 49-year-old woman with a right supraorbital mass and unremarkable physical examination of the thyroid gland region. Orbital CT scan showed an expansile lytic lesion in the orbital plate of the frontal bone with a soft tissue component. An incision biopsy revealed metastatic well-differentiated thyroid carcinoma. Thyroid ultrasound was normal except for a subcentimetre nodule in the right lobe. The patient underwent total thyroidectomy where histopathology showed a subcentimetre follicular variant PTC. She subsequently received radioactive iodine therapy. Post-therapy whole body scan revealed metastatic thyroid tissues in the right orbital and posterior parietal, and left shoulder and hip areas. Although infrequent, metastatic thyroid carcinoma should be considered in patients with orbital metastasis even when neck examination is normal. In rare cases, this may be the initial manifestation of a widely metastatic papillary thyroid microcarcinoma. PMID- 25819822 TI - A significant 'coronary steal' by thebesian veins, a rare congenital coronary defect masquerading as acute coronary syndrome. PMID- 25819824 TI - Fistula formation between the external iliac artery and ileal conduit following a radical cystoprostatectomy: a rare complication with prewarning signs of haemorrhage. AB - A 76-year-old man was admitted with bleeding per-urostomy following a collapse at home. Three weeks prior to the admission, he had undergone a radical cystoprostatectomy and formation of ileal-conduit for an extensive bladder carcinoma. A CT angiogram revealed a possible small source of bleeding within the ileal-conduit itself, which settled with conservative management. However, prior to discharge he developed profuse fresh bleeding from the urostomy, which could not be controlled. The patient underwent an emergency endoscopy of the conduit and laparotomy, which revealed a fistula between the right external iliac artery and the proximal end of the ileal-conduit. The right iliac artery was ligated and an emergency left-to-right femoral-femoral crossover bypass was performed. The right ureter was stented and rediverted through the ileal-conduit and the left ureter was stented at a later date. He unfortunately had a stormy postoperative recovery with further episodes of per-urostomy bleeding and no identified source. PMID- 25819823 TI - Headache during haemodialysis in a patient with shunt: a cause for concern? AB - A 20-year-old woman with a functioning ventriculoperitoneal (VP) shunt consistently reported unbearable vertex headaches and nausea during the last hour of her haemodialysis (HD) sessions. After one particularly severe episode, which was associated with vomiting, restlessness and blurred vision, her team suspected that she was developing dialysis disequilibrium syndrome. She improved fully on cessation of HD, requiring simple analgaesia only, and continued dialysis three times per week. Several more distressing episodes of nausea and headaches compelled us to give intravenous mannitol during HD, resulting in temporary improvement. Subsequently, shorter and more frequent dialysis sessions along with intravenous mannitol resulted in satisfactory clinical response. PMID- 25819825 TI - Locally aggressive cavernous haemangioma of the mandible: an unusual presentation. PMID- 25819826 TI - Coronary artery aneurysm presenting as a large mass encroaching on the right atrium in an adult patient with untreated Kawasaki disease. AB - A 26-year-old man presented with atypical chest pain and dyspnoea for several days before admission that was not related to exertion. The patient had no medical history other than a long duration of fever and rash as a child, which resolved after a few weeks. The initial blood investigations showed thrombocytopenia and raised inflammatory markers with a negative troponin level. The patient had positive antiplatelet antibodies and was diagnosed with immune thrombocytopenic purpura (ITP). Echocardiography showed a large cystic mass at the right atrium. Coronary multislice CT showed a huge aneurysm at the origin of the right coronary artery (RCA), which was confirmed by coronary angiography. The patient received intravenous immunoglobulin and platelet transfusion before coronary artery bypass surgery and he had a successful resection of the aneurysm with a saphenous vein graft to distal RCA. The patient had a good recovery and was discharged home. PMID- 25819827 TI - Strongyloidiasis: an unusual cause of septic shock with pneumonia and enteropathy in western countries. AB - We report a case of invasive strongyloidiasis in a patient from the French Antilles who had been living in France for many years, with no history of immunosuppression, and who was hospitalised in the intensive care unit for septic shock with multimicrobial hypoxaemia pneumonia and exudative enteropathy. Initiation of systemic corticosteroid therapy for septic shock seems to have precipitated onset of the parasitic infection, with recurrence of hypoxaemic pneumonia complicated by hypoxic cardiac arrest. The diagnosis was confirmed after roundworm larvae were found on bronchoalveolar lavage. Treatment with ivermectin was initiated, but the patient died in a context of postanoxic encephalopathy. PMID- 25819828 TI - Exceptional penetrating orbital injury that spared the eye globe. PMID- 25819829 TI - Trifascicular block progressing to complete AV block on exercise: a rare presentation demonstrating the usefulness of exercise testing. AB - A 41-year-old man presented with dyspnoea and giddiness on exertion for the last 1 month. A resting ECG during showed trifascicular block with complete right bundle branch block, left anterior fascicular block and a prolonged PR interval of >0.24 s. His echocardiography showed no evidence of wall motion abnormality. He was subjected to a treadmill test for exercise-induced ischaemia, which showed complete atrioventricular (AV) block during first stage of Bruce protocol. His symptoms of dyspnoea and giddiness were also reproduced. The test was terminated and ECG returned to trifascicular block, similar to that at his baseline ECG during recovery. Coronary angiogram (CAG) was performed to rule out any ischaemic cause for this exercise-induced AV block, which was normal. In view of his reproducible symptoms and demonstration of complete AV block on exercise, a dual chamber pacemaker (DDD) was implanted. His symptoms disappeared and he remained asymptomatic on follow-up. PMID- 25819830 TI - Oral verruciform xanthoma. AB - Verruciform xanthoma (VX) of the oral cavity is a benign mucosal growth that often presents as a pink, yellow or grey raised plaque or papule with granular, papillary or verrucous surface morphology. Intraorally this often presents on the masticatory mucosa and extraorally often involves the skin and anogenital mucosa. There are several proposed aetiological factors and the clinical features of VX can be misleading; clinically it can resemble malignancy. Histopathological diagnosis is a key for the correct management of this lesion. Excision of this lesion is curative. PMID- 25819831 TI - A new technique of closing a gastroatmospheric fistula with a rectus abdominis muscle flap. AB - Proximal enteroatmospheric fistulae are difficult to manage and carry high mortality from sepsis and electrolyte imbalances. Conservative management with total parenteral nutrition, exclusion of fistula, resection and anastomosis are conventional methods of treatment with low success rate. Providing muscle cover to manage an enteroatmospheric fistula is a noble concept. A postoperative high output gastroatmospheric fistula (GAF) was repaired by superior epigastric artery based rectus abdominis muscle flap (RAMF). Postoperative recovery was uneventful. This technique may be useful for closure of proximal enteroatmospheric fistulae that fail to heal through medical and conventional surgical management. PMID- 25819832 TI - Subcutaneous sarcoidosis in a rhinoplasty scar. AB - The presence of a subcutaneous hard bony-like lump at the lateral nasal wall after a septorhinoplasty procedure is an unfavourable result. The reported patient developed this complication 2 years after a revision surgery, in which percutaneous osteotomies were performed. An excision biopsy of the lump took place and the histopathological analysis revealed a granulomatous gigantocellular inflammation with absence of birefringent particles on polarised lamp and negative mycobacteria culture. After additional investigations, the final diagnosis was consistent with grade 2 pulmonary sarcoidosis associated with subcutaneous sarcoidosis. No treatment was initiated. The facial symptoms resolved without any additional treatment and the pulmonary function tests have not deteriorated after 1 year of follow-up. The polymorphism of cutaneous lesions in sarcoidosis, the absence of systemic symptoms and the unrecognised entity of subcutaneous sarcoidosis in a scar illustrate the diagnostic challenge with this patient. PMID- 25819834 TI - Light-controlled reversible formation and dissociation of nanorods via interconversion of pseudorotaxanes. AB - Nanorod-like supramolecular aggregates are fabricated by the self-assembly of the amphiphilic [2]pseudorotaxane, which can be dissociated and rebuilt by the alternating UV/vis irradiation. PMID- 25819833 TI - Stability and compatibility of recombinant adeno-associated virus under conditions commonly encountered in human gene therapy trials. AB - Recombinant adeno-associated virus (rAAV) vectors are rapidly becoming the first choice for human gene therapy studies, as clinical efficacy has been demonstrated in several human trials and proof-of-concept data have been demonstrated for correction of many others. When moving into human use under the auspices of an FDA Investigational New Drug (IND) application, it is necessary to demonstrate the stability of vector material under various conditions of storage, dilution, and administration when used in humans. Limited data are currently available in the literature regarding vector compatibility and stability, leading most IND sponsors to repeat all necessary studies. The current study addresses this issue with an rAAV vector (rAAV1-CB-chAATmyc) containing AAV2-inverted terminal repeat sequences packaged into an AAV1 capsid. Aliquots of vector were exposed to a variety of temperatures, diluents, container constituents, and other environmental conditions, and its functional biological activity (after these various treatments) was assessed by measuring transgene expression after intramuscular injection in mice. rAAV was found to be remarkably stable at temperatures ranging from 4 degrees C to 55 degrees C (with only partial loss of potency after 20 min at 70 degrees C), at pH ranging from 5.5 to 8.5, after contact with mouse or human serum (with or without complement depletion) or with gadolinium and after contact with glass, polystyrene, polyethylene, polypropylene, and stainless steel. The only exposure resulting in near-total loss of vector activity (10,000-fold loss) was UV exposure for 10 min. The stability of rAAV1 preparations bodes well for future dissemination of this therapeutic modality. PMID- 25819835 TI - The applicability of the WHO classification in paediatric AML. A NOPHO-AML study. AB - The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18 years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n = 14) had significantly poorer outcome than del(7q) (n = 11); 5-year event free survival 26% vs. 67%, (P = 0.02), and 5-year overall survival 51% vs. 90%, (P = 0.04). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n = 280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML. PMID- 25819836 TI - ESCRT-0 protein hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is targeted to endosomes independently of signal-transducing adaptor molecule (STAM) and the complex formation with STAM promotes its endosomal dissociation. PMID- 25819837 TI - The role of laparoscopy in recurrent right lower quadrant pain in children. AB - According to scientific literature, laparoscopy as aid in diagnosis and therapy for chronic pain in the right iliac quadrant shows a undeniable advantage thanks to its mini-invasiveness, the possibility of a methodical and thorough exploration of the entire abdominal cavity in those cases of recurrent pain, emotionally and socially debilitating, that do not find an answer in the usual etiological diagnostic clinical-instrumental. In those cases in which any significant organic pathology that justifies the recurring pain in the right iliac fossa is found during laparoscopic exploration, it has been seen that it is useful to perform appendectomy anyway, that leads to the disappearance of symptoms, which are probably due to inflammatory recurrent catarrhal phenomena of appendix in such patients, as it is demonstrated by the adhesions found at cecum appendicular level. From January 2011 to December 2013, 24 children with chronic recurrent right lower quadrant pain were subjected to diagnostic laparoscopy. Ages varied from 11 to 18 years (mean, 14 years). There were 6 males and 18 females. Laparoscopic findings included macroscopical signs of acute appendicitis in 15 patients; cecal adhesions in 20 patients, kink of the appendix in 3. The abdominal pain completely resolved in all the patients following laparoscopy. PMID- 25819838 TI - Novel clinical uses for cord blood derived mesenchymal stromal cells. AB - Regenerative medicine offers new hope for many debilitating diseases that result in damage to tissues and organs. The concept is straightforward with replacement of damaged cells with new functional cells. However, most tissues and organs are complex structures involving multiple cell types, supportive structures, a microenvironment producing cytokines and growth factors and a vascular system to supply oxygen and other nutrients. Therefore repair, particularly in the setting of ischemic damage, may require delivery of multiple cell types providing new vessel formation, a new microenvironment and functional cells. The field of stem cell biology has identified a number of stem cell sources including embryonic stem cells and adult stem cells that offer the potential to replace virtually all functional cells of the body. The focus of this article is a discussion of the potential of mesenchymal stromal cells (MSCs) from cord blood (CB) for regenerative medicine approaches. PMID- 25819839 TI - Ruptured aneurysmal subarachnoid hemorrhage in the emergency department: Clinical outcome of patients having a lumbar puncture for red blood cell count, visual and spectrophotometric xanthochromia after a negative computed tomography. AB - OBJECTIVES: Over the last decade, computed tomography scanners have gained resolution and have become the standard of care in the investigation of neurologically intact patients suffering from acute headache. The added value of the combined assessment of red blood cells count, visual and spectrophotometric xanthochromia, to detect ruptured aneurysmal subarachnoid hemorrhage (ASAH) following a negative head computed tomography (NHCT) was studied. METHODS: The population consisted of all patients who had cerebrospinal fluid tested for spectrophotometric xanthochromia between 2003 and 2009 identified through the clinical-laboratory database and who met all the inclusion criteria: >14 years old, had an initial Glasgow Coma Score of 15, a non-traumatic acute headache with a suspected subarachnoid hemorrhage recorded in the initial ED differential diagnosis and an initial negative head CT scan. RESULTS: A total of 706 patients were included. LP identified 5 ASAH (prevalence: 0.7%). In these patients, LP parameters were as follows: high red blood cell count (from 1310 to 63,000*10(6)/L), positive visual xanthochromia in 4 out of 5 ASAH, and positive spectrophotometric xanthochromia in 5 out of 5 ASAH. All ASAH patients were neurologically intact after intervention. No deaths or missed ASAH were reported. Angiographies were performed on 127 patients (19.5%) of which 47 (34.1%) had positive xanthochromia (visual or spectrophotometric). CONCLUSIONS: Considering the low prevalence of ASAH following an NHCT, intense resources were utilized to identify all 5 ASAH. Lumbar puncture analyses combining red blood cell count, visual and spectrophotometric xanthochromia identified all ASAH, allowing intervention and a positive clinical outcome. Our data support 1) that LP identifies the presence of a ruptured ASAH after an NHCT and 2)' that a guide to define a subpopulation of patients who would benefit from a lumbar puncture after an NHCT would be desirable. PMID- 25819840 TI - LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases. AB - BACKGROUND: Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. METHODS: We established a LC-MS/MS assay to measure Cholestane-3beta, 5alpha, 6beta-triol (C triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. RESULTS: The reported method is linear (r>0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5 102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46%+/-23% for C-triol and 52%+/-29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients. CONCLUSIONS: The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases. PMID- 25819841 TI - Can crayfish take the heat? Procambarus clarkii show nociceptive behaviour to high temperature stimuli, but not low temperature or chemical stimuli. AB - Nociceptors are sensory neurons that are tuned to tissue damage. In many species, nociceptors are often stimulated by noxious extreme temperatures and by chemical agonists that do not damage tissue (e.g., capsaicin and isothiocyanate). We test whether crustaceans have nociceptors by examining nociceptive behaviours and neurophysiological responses to extreme temperatures and potentially nocigenic chemicals. Crayfish (Procambarus clarkii) respond quickly and strongly to high temperatures, and neurons in the antenna show increased responses to transient high temperature stimuli. Crayfish showed no difference in behavioural response to low temperature stimuli. Crayfish also showed no significant changes in behaviour when stimulated with capsaicin or isothiocyanate compared to controls, and neurons in the antenna did not change their firing rate following application of capsaicin or isothiocyanate. Noxious high temperatures appear to be a potentially ecologically relevant noxious stimulus for crayfish that can be detected by sensory neurons, which may be specialized nociceptors. PMID- 25819842 TI - ILDR1 deficiency causes degeneration of cochlear outer hair cells and disrupts the structure of the organ of Corti: a mouse model for human DFNB42. AB - Immunoglobulin-like domain containing receptor 1 (ILDR1) is a poorly characterized gene that was first identified in lymphoma cells. Mutations in ILDR1 are responsible for DFNB42, but the pathogenesis of hearing loss caused by ILDR1 mutations remains to be elucidated. To explore the role of ILDR1 in hearing, we created Ildr1 knockout mice. In heterozygous mice, ILDR1 expression was found in outer hair cells (OHCs) and inner hair cells (IHCs) of the organ of Corti. ILDR1-deficient mice are profoundly deaf by postnatal day 21 (P21). No significant difference was observed in the supporting cells and IHCs of ILDR1 deficient mice, but progressive degeneration of OHCs occurred at P15 and disruption of the tunnel running through the organ of Corti was noticeable at P21. By P28, there were no OHCs visible in any of the turns of the organ of Corti, and the tunnel of the organ of Corti was entirely destroyed. ILDR1 deficiency affects expression of tricellulin in vivo, and this provides a possible explanation to hearing loss. To further elucidate the mechanism of deafness related to ILDR1 deficiency, we pursued a differential proteomic approach to comprehensively assess differential protein expression in the cochleae of Ildr1(+/-) and Ildr1(-/-) mice at P21. Altogether, 708 proteins were up-regulated (fold change >1.5) and 114 proteins were down-regulated (fold change <0.5) in the Ildr1(-/-) mice compared with Ildr1(+/-) mice. Gene ontology classification indicated that a number of differentially expressed proteins are involved in cell adhesion, protein and vesicle-mediated transport, cell death, membrane organization, and cellular homeostasis. A few of these proteins are closely related to hearing development. Taken together, our data suggest that ILDR1 is important for the survival of OHCs and provide novel insights into the pathogenesis of human deafness DFNB42 deafness. PMID- 25819844 TI - Young people with intellectual disability--the role of self-advocacy in a transformed Swedish welfare system. AB - A growing number of young people in Sweden with intellectual disability have organized themselves during the last 15 years in self-advocacy groups for socializing, empowerment, and expressing opposition to the norms and attitudes in a society that labels them as disabled. At the same time, the Swedish welfare system has transformed dramatically with processes of far-reaching individualization, closure of the major institutions, decentralization of responsibility from the state to local governments, and an emerging welfare market where service users are turned into customers. The aim of this article is to analyse and discuss the significance of self-advocacy in the new welfare context. Data were collected over a period of more than 10 years using repeated interviews with members of two self-advocacy groups and participation observations. Findings suggest that participation in self-advocacy groups opens up members for increasing health and well-being through new roles and identities, and it strengthens their control over everyday life. Support is still needed, however, but in new ways; otherwise, the restrictions of the institutions will simply be reconstructed in the new welfare system. PMID- 25819843 TI - Bridging the gap between postembryonic cell lineages and identified embryonic neuroblasts in the ventral nerve cord of Drosophila melanogaster. AB - The clarification of complete cell lineages, which are produced by specific stem cells, is fundamental for understanding mechanisms, controlling the generation of cell diversity and patterning in an emerging tissue. In the developing Central Nervous System (CNS) of Drosophila, neural stem cells (neuroblasts) exhibit two periods of proliferation: During embryogenesis they produce primary lineages, which form the larval CNS. After a phase of mitotic quiescence, a subpopulation of them resumes proliferation in the larva to give rise to secondary lineages that build up the CNS of the adult fly. Within the ventral nerve cord (VNC) detailed descriptions exist for both primary and secondary lineages. However, while primary lineages have been linked to identified neuroblasts, the assignment of secondary lineages has so far been hampered by technical limitations. Therefore, primary and secondary neural lineages co-existed as isolated model systems. Here we provide the missing link between the two systems for all lineages in the thoracic and abdominal neuromeres. Using the Flybow technique, embryonic neuroblasts were identified by their characteristic and unique lineages in the living embryo and their further development was traced into the late larval stage. This comprehensive analysis provides the first complete view of which embryonic neuroblasts are postembryonically reactivated along the anterior/posterior-axis of the VNC, and reveals the relationship between projection patterns of primary and secondary sublineages. PMID- 25819845 TI - Involvements of galanin and its receptors in antinociception in nucleus accumbens of rats with inflammatory pain. AB - This study tested the hypothesis that antinociceptive effects of galanin and its receptors in nucleus accumbens (NAc) of rats with inflammatory pain provoked by subcutaneous injection of 0.1 ml of 2% carrageenin into the sole of the rat's left hindpaw. The hindpaw withdrawal latencies (HWLs) in response to thermal and mechanical stimulation significantly decreased in bilateral hindpaws at 3 and 4 hour after a subcutaneous injection of carrageenin. However intra-NAc injection of 2 and 3 nmol, but not 1 nmol of galanin markedly induced an increase in the HWLs in a dose-dependent way. Western blot also showed, that the expression of galanin receptor 1 (GalR1) and galanin receptor 2 (GalR2) were significantly upregulated in NAc at 3 hour after a subcutaneous injection of carrageenin. In addition, the rats were intra-NAc injected galanin, 5 min later following by intra-NAc injection of galanin receptor antagonist galantide, the galanin-induce antinociceptive effects were suppressed by galantide. The results demonstrated that galanin and its receptors might be involved in antinociception in the NAc of rats with inflammatory pain. PMID- 25819846 TI - Susceptibility of the Giant African snail (Achatina fulica) exposed to the gastropod parasitic nematode Phasmarhabditis hermaphrodita. AB - The Giant African snail (Achatina fulica) is a major pest in tropical countries. Current control methods involve the use of slug pellets (metaldehyde) but they are ineffective, therefore new methods of control are needed. We investigated whether A. fulica is susceptible to the gastropod parasitic nematode Phasmarhabditis hermaphrodita, which has been developed as a biological control agent for slugs and snails in northern Europe. We exposed A. fulica to P. hermaphrodita applied at 30 and 150nematodes per cm(2) for 70days and also assessed feeding inhibition and changes in snail weight. We show that unlike the susceptible slug species Deroceras panormitanum, which is killed less than 30days of exposure to P. hermaphrodita, A. fulica is remarkably resistant to the nematode at both doses. Also P. hermaphrodita does not reduce feeding in A. fulica nor did it have any effect on weight gain over 70days. Upon dissection of infected A. fulica we found that hundreds of P. hermaphrodita had been encapsulated, trapped and killed in the snail's shell. We found that A. fulica is able to begin encapsulating P. hermaphrodita after just 3days of exposure and the numbers of nematodes encapsulated increased over time. Taken together, we have shown that A. fulica is highly resistant to P. hermaphrodita, which could be due to an immune response dependent on the snail shell to encapsulate and kill invading parasitic nematodes. PMID- 25819847 TI - Tuning the electronic and magnetic properties of graphene-like AlN nanosheets by surface functionalization and thickness. AB - In this paper, the structural, electronic, and magnetic properties as well as the relative stabilities of fully and partially hydrogenated AlN nanosheets have been systematically investigated by first-principles calculations based on density functional theory. The results indicate that full hydrogenation is more energetically favorable for thinner AlN nanosheets, whereas semi-hydrogenation at N sites is preferred for thicker ones. Moreover, semiconductor -> half-metal -> metal transition with nonmagnetic -> magnetic transfer can be achieved for AlN nanosheets by surface hydrogenation and increasing nanosheet thickness. The diverse electronic and magnetic properties highlight the potential applications of AlN nanosheets in electronics and spintronics. PMID- 25819850 TI - Atrial fibrillation: A major risk factor for cognitive decline. AB - Atrial fibrillation is a common disease of the elderly, conferring considerable morbidity and mortality related to cardiovascular effects and thromboembolic risks. Anticoagulation, antiarrhythmic medications, and rate control are the cornerstone of contemporary management, whereas ablation and evolving surgical techniques continue to play important secondary roles. Growing evidence shows that atrial fibrillation is also a risk factor for significant cognitive decline through a multitude of pathways, further contributing to morbidity and mortality. At the same time, cognitive decline associated with cryptogenic strokes may be the first clue to previously undiagnosed atrial fibrillation. These overlapping associations support the concept of cognitive screening and rhythm monitoring in these populations. New research suggests modulating effects of currently accepted treatments for atrial fibrillation on cognition; however, there remains the need for large multicenter studies to examine the effects of novel oral anticoagulants, rhythm and rate control, and left atrial appendage occlusion on long-term cognitive function. PMID- 25819851 TI - Authorship in a multicenter clinical trial: The Heart Failure-A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) Authorship and Publication (HAP) scoring system results. AB - BACKGROUND: Few guidelines exist regarding authorship on manuscripts resulting from large multicenter trials. The HF-ACTION investigators devised a system to address assignment of authorship on trial publications and tested the outcomes in the course of conducting the large, multicenter, National Heart, Lung, and Blood Institute-funded trial (n = 2,331; 82 clinical sites; 3 countries). The HF-ACTION Authorship and Publication (HAP) scoring system was designed to enhance rate of dissemination, recognize investigator contributions to the successful conduct of the trial, and harness individual expertise in manuscript generation. METHODS: The HAP score was generated by assigning points based on investigators' participation in trial enrollment, follow-up, and adherence, as well as participation in committees and other trial activity. Overall publication rates, publication rates by author, publication rates by site, and correlation between site publication and HAP score using a Poisson regression model were examined. RESULTS: Fifty peer-reviewed, original manuscripts were published within 6.5 years after conclusion of study enrollment. In total, 137 different authors were named in at least 1 publication. Forty-five (55%) of the 82 sites had an author named to at least 1 article. A Poisson regression model examining incident rate ratios revealed that a higher HAP score resulted in a higher incidence of a manuscript, with a 100-point increase in site score corresponding to an approximately 32% increase in the incidence of a published article. CONCLUSIONS: Given the success in publishing a large number of manuscripts and widely distributing authorship, regular use of a transparent, objective authorship assignment system for publishing results from multicenter trials may be recommended to optimize fairness and dissemination of trial results. PMID- 25819852 TI - Rationale and design of a study exploring the efficacy of once-daily oral rivaroxaban (X-TRA) on the outcome of left atrial/left atrial appendage thrombus in nonvalvular atrial fibrillation or atrial flutter and a retrospective observational registry providing baseline data (CLOT-AF). AB - There are still many unresolved issues concerning patient outcomes and prognostic factors in patients with atrial fibrillation (AF) and left atrial/left atrial appendage (LA/LAA) thrombi. Rivaroxaban (Xarelto(r)), a potent and highly selective oral, direct factor Xa inhibitor, is a new therapeutic option in this setting. The planned study program will consist of a prospective interventional study (X-TRA) and a retrospective observational registry (CLOT-AF). The primary objective of the X-TRA study is to explore the efficacy of rivaroxaban in the treatment of LA/LAA thrombi in patients with nonvalvular AF or atrial flutter, scheduled to undergo cardioversion or AF ablation, in whom an LA/LAA thrombus has been found on transesophageal echocardiography (TEE) before the procedure. The primary end point is the complete LA/LAA thrombus resolution rate at 6 weeks of end of treatment confirmed by TEE. The secondary objectives are to describe categories of thrombus outcome in patients (resolved, reduced, unchanged, larger, or new) confirmed on TEE at the end of treatment (after 6 weeks of treatment), incidence of the composite of stroke and noncentral nervous system systemic embolism at the end of treatment and during follow-up, and incidence of all bleeding at the end of treatment and during follow-up. The objective of the CLOT AF registry is to provide retrospective thrombus-related patient outcome data after standard-of-care anticoagulant treatment in patients with nonvalvular AF or atrial flutter, who have TEE-documented LA/LAA thrombi. The data will be used as a reference for the prospective X-TRA study. In conclusion, X-TRA and CLOT-AF will provide some answers to the many unresolved issues concerning patient outcomes and prognostic factors in patients with AF and LAA thrombi. Results from this study program would provide the first prospective interventional study (X TRA) and a large international retrospective observational registry (CLOT-AF) on the prevalence and natural history of LA/LAA thrombi. Unique data on clot resolution with rivaroxaban in a prospective cohort would be obtained in X-TRA. PMID- 25819853 TI - An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). AB - BACKGROUND: Guidelines recommendations regarding anticoagulant therapy after percutaneous coronary intervention (PCI) among patients with atrial fibrillation (AF) rely on retrospective, nonrandomized observational data. Currently, patients are treated with triple-therapy (dual antiplatelet therapy [DAPT] + oral anticoagulation therapy), but neither the duration of DAPT nor the level of anticoagulation has been studied in a randomized fashion. Recent studies also suggest dual pathway therapy with clopidogrel plus oral anticoagulation therapy may be superior, and other studies suggest that novel oral anticoagulants such as rivaroxaban may further improve patient outcomes. DESIGN: PIONEER AF-PCI (ClinicalTrials.gov NCT01830543) is an exploratory, open-label, randomized, multicenter clinical study assessing the safety of 2 rivaroxaban treatment strategies and 1 vitamin K antagonist (VKA) treatment strategy in subjects who have paroxysmal, persistent, or permanent nonvalvular AF and have undergone PCI with stent placement. Approximately 2,100 subjects will be randomized in a 1:1:1 ratio to receive either rivaroxaban 15 mg once daily plus clopidogrel 75 mg daily for 12 months (a WOEST trial-like strategy), or rivaroxaban 2.5 mg twice daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, an ATLAS trial-like strategy), or dose-adjusted VKA once daily (with stratification to a prespecified duration of DAPT 1, 6, or 12 months, traditional triple therapy). All patients will be followed up for 12 months for the primary composite end point of Thrombolysis in Myocardial Infarction major bleeding, bleeding requiring medical attention, and minor bleeding (collectively, clinically significant bleeding). CONCLUSION: The PIONEER AF-PCI study is the first randomized comparison of VKA vs novel oral anticoagulant therapy in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risks of bleeding complications. PMID- 25819854 TI - Drug-coated balloons to improve femoropopliteal artery patency: Rationale and design of the LEVANT 2 trial. AB - BACKGROUND: Atherosclerotic peripheral artery disease (PAD) is common and results in limitations in quality of life and potential progression to limb loss. Options for therapy include medical therapy, supervised exercise, surgical revascularization, and, more recently, endovascular therapies to restore arterial perfusion to the limb. Endovascular revascularization has evolved over the past 2 decades, from percutaneous transluminal angioplasty (PTA) to self-expanding stents, atherectomy, laser angioplasty, and drug-eluting stents. Despite impressive technologic advances, PTA remains the standard of care at many institutions and is the recommended primary treatment modality for femoral popliteal PAD according to current American College of Cardiology Foundation/American Heart Association guidelines. However, restenosis after PTA is common. Therefore, a significant clinical need remains for a device that is able to achieve more durable patency than PTA but does not require a permanent implant. Drug-coated balloons (DCBs) have the potential to address this need. Several randomized controlled clinical trials of PTA balloons coated with different formulations of paclitaxel have been conducted in Europe (N Engl J Med 2008;358:689-699) (Circulation 2008;118:1358-1365) (Circ Cardiovasc Interv 2012;5:831-840) (JACC Cardiovas Interv 2014;7:10-19) and demonstrated more durable efficacy than PTA with comparable safety. These studies were limited by small sample sizes and powered solely for an angiographic primary end point. The pivotal LEVANT 2 trial was designed in collaboration with the US Food and Drug Administration to demonstrate safety and efficacy in a large population and to obtain US Food and Drug Administration approval. METHODS: A prospective, multicenter, single-blind trial comparing the Lutonix DCB (Bard Lutonix; New Hope, MN) versus PTA for treatment of femoropopliteal PAD (LEVANT 2) is the first US-based 2:1 randomized controlled trial of 476 patients with femoral-popliteal PAD designed to demonstrate superior efficacy and noninferior safety of a novel paclitaxel DCB compared with PTA. The primary efficacy end point is primary patency at 12 months. The primary safety end point is composite freedom at 12 months from perioperative death, index limb amputation, reintervention, and limb related mortality. A series of important secondary end points include physical functioning, quality of life, revascularizations, and alternative measures of patency. To minimize bias potential for confounding variables, LEVANT 2 (1) excluded patients stented after predilation before randomization, (2) incorporated very stringent criteria for bailout stenting, (3) did not count bailout stenting as a target lesion revascularization or failure of any end point, (4) required a blinded clinician to perform clinical evaluations at follow up, and (5) required clinical assessment before review of duplex ultrasound results. CONCLUSIONS: LEVANT 2 represents the first US-inclusive multicenter, randomized controlled trial to assess the safety and efficacy of a novel DCB compared with PTA as primary therapy for symptomatic PAD on the background of standard medical therapy. PMID- 25819855 TI - Cardiovascular Safety Outcome Trials: A meeting report from the Cardiac Safety Research Consortium. AB - This White Paper provides a summary of presentations and discussions at a Cardiovascular Safety Outcome Trials Think Tank cosponsored by the Cardiac Safety Research Consortium, the US Food and Drug Administration, and the American College of Cardiology, held at American College of Cardiology's Heart House, Washington, DC, on February 19, 2014. Studies to assess cardiovascular (CV) risk of a new drug are sometimes requested by regulators to resolve ambiguous safety signals seen during its development or among other members of its class. Think Tank participants thought that important considerations in undertaking such studies were as follows: (1) plausibility-how likely it is that a possible signal indicating risk is real, based on strength of evidence, and/or whether a plausible mechanism of action for potential CV harm has been identified; (2) relevance-what relative and absolute CV risk would need to be excluded to determine that the drug had an acceptable benefit-to-risk balance for its use in the intended patient population; and (3) how plausibility and relevance influence the timing and approach to further safety assessment. PMID- 25819857 TI - Parkinson disease and risk of acute myocardial infarction: A population-based, propensity score-matched, longitudinal follow-up study. AB - OBJECTIVES: Previous studies on the risk of acute myocardial infarction (AMI) in patients with Parkinson disease (PD) have generated inconsistent results. The purpose of this population-based longitudinal follow-up study was to investigate whether incident PD is associated with an increased risk of AMI. METHODS: A total of 3,211 subjects with at least 2 ambulatory visits with the principal diagnosis of PD in 2001 were enrolled in the PD group. The non-PD group consisted of 3,211 propensity score-matched subjects without PD. The propensity scores were computed using a logistic regression model that included age, sex, preexisting comorbidities, and socioeconomic status. The 3-year AMI-free survival rates of the 2 groups were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression with patients matched by propensity score was used to estimate the effect of PD on subsequent occurrence of AMI. RESULTS: During the 3-year follow-up period, 83 subjects in the PD group and 53 in the non-PD group developed AMI (either fatal or nonfatal) events. The hazard ratio of AMI for the PD group compared with the non-PD group was 1.67 (95% CI 1.15-2.41, P = .0067). The AMI-free survival rate of the PD group was significantly lower than that of the non-PD group (P = .0032). The hazard ratios associated with PD for the combined end point 1 (AMI or cardiovascular death) and combined end point 2 (AMI or all-cause death) were 1.46 (95% CI 1.14-1.88, P = .0029) and 1.42 (95% CI 1.24 1.64, P < .0001), respectively. CONCLUSIONS: This study shows that PD is related to an increased risk of AMI. Further studies are required to investigate the mechanism underlying this association. PMID- 25819856 TI - Platelet aggregation and mental stress induced myocardial ischemia: Results from the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) study. AB - BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and associated with a poorer cardiovascular prognosis. Platelet hyperactivity is an important factor in acute coronary syndrome. This study examined associations between MSIMI and resting and mental stress-induced platelet activity. METHODS: Eligible patients with clinically stable IHD underwent a battery of 3 mental stress tests during the recruitment phase of REMIT study. MSIMI was assessed by echocardiography and electrocardiography. Ex vivo platelet aggregation in response to ADP, epinephrine, collagen, serotonin, and combinations of serotonin plus ADP, epinephrine, and collagen were evaluated as was platelet serotonin transporter expression. RESULTS: Of the 270 participants who completed mental stress testing, and had both resting and post-stress platelet aggregation evaluation , 43.33% (n=117) met criteria for MSIMI and 18.15% (n=49) had normal left ventricular response to stress (NLVR). The MSIMI group, relative to the NLVR groups, demonstrated heightened mental stress-induced aggregation responses, as measured by area under the curve, to collagen 10MUM (6.95[5.54] vs. -14.23[8.75].; P=0.045), epinephrine 10MUM (12.84[4.84] vs. -6.40[7.61].; P=0.037) and to serotonin 10 MUM plus ADP 1 MUM (6.64[5.29] vs. -27.34[8.34]; P<.001). The resting platelet aggregation and serotonin transporter expression, however, were not different between the two groups. CONCLUSIONS: These findings suggest that the dynamic change of platelet aggregation caused by mental stress may underlie MSIMI. While the importance of these findings requires additional investigation, they raise concern given the recognized relationship between mental stress induced platelet hyperactivity and cardiovascular events in patients with IHD. PMID- 25819858 TI - Cardiac arrest and clinical characteristics, treatments and outcomes among patients hospitalized with ST-elevation myocardial infarction in contemporary practice: A report from the National Cardiovascular Data Registry. AB - BACKGROUND: Cardiac arrest (CA) is a major complication of patients with ST elevation myocardial infarction (STEMI). Its prevalence and prognostic impact in contemporary US practice has not been well assessed. METHODS: We evaluated STEMI patients included in the National Cardiovascular Data Registry (NCDR) Acute Coronary Treatment Intervention Outcomes Network Registry-Get With the Guidelines (ACTION Registry-GWTG) from 4/1/11 to 6/30/12. Patient clinical characteristics, treatments, and inhospital outcomes were compared by the presence or absence of CA on first medical contact-either before hospital arrival or upon presentation to the ACTION hospital. RESULTS: Of the 49,279 STEMI patients included, 3,716 (7.5%) had CA. Cardiac arrest patients were more likely to have heart failure (15.5% vs 6.9%) and shock (42.9% vs 4.9%) on presentation and higher median (25th and 75th percentiles) ACTION Registry-GWTG mortality risk scores (42 [32, 54] vs 32 [26, 38]) than non-CA patients (all P < .001). Primary percutaneous coronary intervention was performed in most patients with and without CA (76.7% vs 79.1%). Inhospital mortality was significantly higher in patients with than without CA (28.8% vs 4.0%; P < .001), both in patients who presented with cardiogenic shock (46.9% vs 27.1%; P < .001) and those without shock (15.4% vs 2.9%; P < .001). The ACTION Registry-GWTG inhospital mortality model underestimated mortality risk in CA patients; however, prediction significantly improved after adding CA to the model. CONCLUSIONS: Almost 8% of STEMI patients present with CA. More than 25% die during the hospitalization, despite high use of primary percutaneous coronary intervention. Cardiogenic shock and CA frequently coexist. Our results suggest that development of systems of care and treatments for both STEMI and CA is needed to reduce the high mortality in these patients. PMID- 25819859 TI - Comparison of different interdialytic intervals among hemodialysis patients on their echocardiogram-based cardiovascular parameters. AB - BACKGROUND: Although cardiovascular events in hemodialysis (HD) patients are the most frequent on the day after a long (2 days) interdialytic interval (IDT), it has been uncertain whether accumulation or elimination of large extracellular fluid volume, electrolyte, and/or uremic substances is the culprit for this. We sought to test our hypothesis that the long IDT alters echocardiographic parameters at rest and during exercise in stable maintenance HD patients compared with other IDTs. METHODS: We performed a cross-sectional comparison using 1-way repeated analysis of variance or Friedman test of echocardiograms at 3 different IDTs, just after HD, after short IDT (1 day), and after long IDT, among 80 stable Japanese outpatients (age 61 +/- 9 years, 60 males) on thrice weekly maintenance. End-systolic elastance (Ees), arterial elastance (Ea), and pressure-volume area (PVA) were estimated using a noninvasive single-beat technique. Ventricular arterial coupling was assessed by Ea/Ees ratio. Measurements were repeated after 2-minute handgrip stress to evaluate cardiac reserve. RESULTS: Resting left ventricular end-diastolic volume index and stroke volume index were significantly larger after a 1-day IDT compared with just after HD and even more after a 2-day IDT. Although Ees, Ea, and Ea/Ees ratio at rest remained similar between short and long intervals, stroke work (SW) and PVA were higher after the long interval. During handgrip stress, a significant increase in Ea without corresponding rise in Ees was observed only after long IDT, resulting in decreased stroke volume index, SW, and SW/PVA efficiency. CONCLUSIONS: In a selective Japanese outpatient population on maintenance HD, there were no differences in resting cardiovascular function measured by echocardiography at 3 different IDTs. However, exercise induced afterload mismatch assessed by the changes in Ea, SV, SW, and SW/PVA efficiency was most pronounced in individuals after the long IDT compared with other IDTs. Our findings report potential pathophysiologic echocardiographic parameters that attempt to explain why cardiovascular events are highest on the day after the long IDT compared to other IDTs in dialysis patients. PMID- 25819860 TI - Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: Insights from the APixaban for PRevention of Acute ISchemic Events 2 trial. AB - BACKGROUND: Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations. METHODS: High-risk patients were randomly assigned post-ACS to apixaban 5.0 mg or placebo twice daily. Median follow-up was 8 (4-12) months. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The main safety outcome was thrombolysis in myocardial infarction major bleeding. RESULTS: Heart failure was reported in 2,995 patients (41%), either as prior HF (2,076 [28%]) or acute HF (2,028 [27%]). Patients with HF had a very high baseline risk and were more often managed medically. Heart failure was associated with a higher rate of the primary outcome (prior HF: adjusted hazard ratio [HR] 1.73, 95% CI 1.42-2.10, P < .0001, acute HF: adjusted HR 1.65, 95% CI 1.35-2.01, P < .0001) and cardiovascular death (prior HF: HR 2.54, 95% CI 1.82-3.54, acute HF: adjusted HR 2.52, 95% CI 1.82-3.50). Patients with acute HF also had significantly higher rates of thrombolysis in myocardial infarction major bleeding (prior HF: adjusted HR 1.22, 95% CI 0.65-2.27, P = .54, acute HF: adjusted HR 1.78, 95% CI 1.03-3.08, P = .04). There was no statistical evidence of a differential effect of apixaban on clinical events or bleeding in patients with or without prior HF; however, among patients with acute HF, there were numerically fewer events with apixaban than placebo (14.8 vs 19.3, HR 0.76, 95% CI 0.57-1.01, interaction P = .13), a trend that was not seen in patients with prior HF or no HF. CONCLUSIONS: In high-risk patients post-ACS, both prior and acute HFs are associated with an increased risk of subsequent clinical events. Apixaban did not significantly reduce clinical events and increased bleeding in patients with and without HF; however, there was a tendency toward fewer clinical events with apixaban in patients with acute HF. PMID- 25819861 TI - Results of the Chronic Heart Failure Intervention to Improve MEdication Adherence study: A randomized intervention in high-risk patients. AB - BACKGROUND: Poor adherence to evidence-based medications in heart failure (HF) is a major cause of avoidable hospitalizations, disability, and death. To test the feasibility of improving medication adherence, we performed a randomized proof-of concept study of a self-management intervention in high-risk patients with HF. METHODS: Patients with HF who screened positively for poor adherence (<6 Morisky Medication Adherence Scale 8-item) were randomized to either the intervention or attention control group. In the intervention group (n = 44), a nurse conducted self-management training before discharge that focused on identification of medication goals, facilitation of medication-symptom associations, and use of a symptom response plan. The attention control group (n = 42) received usual care; both groups received follow-up calls at 1 week. However, the content of follow-up calls for the attention control group was unrelated to HF medications or symptoms. General linear mixed models were used to evaluate the magnitude of change in adherence and symptom-related events at 3-, 6-, and 12-month follow-up clinic visits. Efficacy was measured as improved medication adherence using nurse assessed pill counts at each time point. RESULTS: Pooled over all time points, patients in the intervention group were more likely to be adherent to medications compared with patients in the attention control group (odds ratio 3.92, t = 3.51, P = .0007). CONCLUSIONS: A nurse-delivered, self-care intervention improved medication adherence in patients with advanced HF. Further work is needed to examine whether this intervention can be sustained to improve clinical outcomes. PMID- 25819862 TI - Copeptin is an independent predictor of diabetic heart disease and death. AB - BACKGROUND: We previously discovered that high copeptin is associated with incidence of diabetes mellitus (diabetes), abdominal obesity, and albuminuria. Furthermore, copeptin predicts cardiovascular events after myocardial infarction in diabetic patients, but whether it is associated with heart disease and death in individuals without diabetes and prevalent cardiovascular disease is unknown. In this study, we aim to test whether plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin prohormone, predicts heart disease and death differentially in diabetic and nondiabetic individuals. METHODS: We related plasma copeptin to a combined end point composed of coronary artery disease (CAD), heart failure (HF), and death in diabetes (n = 895) and nondiabetes (n = 4187) individuals of the Malmo Diet and Cancer Study-Cardiovascular cohort. RESULTS: Copeptin significantly interacted with diabetes regarding the combined end point (P = .006). In diabetic individuals, copeptin predicted the combined end point (hazard ratio [HR] 1.32 per SD, 95% CI 1.10-1.58, P = .003) after adjustment for conventional risk factors, prevalent HF and CAD, and remained significant after additional adjustment for either fasting glucose (P = .02) or hemoglobin A1c (P = .02). Furthermore, in diabetic individuals, copeptin predicted CAD (HR 1.33 per SD, 95% CI 1.04-1.69, P = .02), HF (HR 1.62 per SD, 95% CI 1.09-2.41, P = .02), and death (HR 1.32 per SD, 95% CI 1.04-1.68, P = .02). Interestingly, among nondiabetic individuals, copeptin was not associated with any of the end points. CONCLUSIONS: Copeptin predicted heart disease and death, specifically in diabetes patients, suggesting copeptin and the vasopressin system as a prognostic marker and therapeutic target for diabetic heart disease and death. PMID- 25819863 TI - A nationwide survey on perception, experience, and expectations of hybrid coronary revascularization among top-ranked US hospitals. AB - BACKGROUND: Hybrid coronary revascularization (HCR) combines a surgical and percutaneous approach for treatment of multivessel coronary artery disease. METHODS: A survey was conducted among 200 cardiologists and cardiac surgeons from 100 top-ranked US hospitals. Questions were asked involving the perception, experience, and future expectations of HCR. RESULTS: Of physicians invited to the survey, 90 completed the survey (45.5%). Relative to nonresponders, responders were more often affiliated with an academic institution (80.0% vs 61.8%, P=.005), with higher patient volumes, and with the availability of a hybrid operating room (90.0% vs 67.3%, P<.001). Survey responders felt that HCR should be considered in an older and relatively healthy patient population without complex lesions. Cardiac surgeons were more favorable to use HCR in patients with chronic lung disease (42.0% vs 10.0%, P<.001) or renal failure (28.0% vs 15.0%, P=.06). Among responders with HCR experience (n=54), 94% reported good to excellent results, and the learning curve differed depending on the surgical technique used. Inappropriate patient selection (41.2%) was the most common cause for complications. Three-quarter of responders believe that the future role for HCR will expand in the next decade. Important determinants of greater HCR use in the future were collaborative associations between cardiac surgeons and cardiologists (86.7%), appropriate patient selection (67.8%), and the outcomes of ongoing clinical trials (57.8%). CONCLUSION: In this nationwide survey, cardiologists and cardiac surgeons felt that HCR is a reasonable alternative technique for coronary revascularization among suitable patients. Most felt that use of HCR would increase in the next decade. PMID- 25819864 TI - A novel coronary angiography index (DILEMMA score) for prediction of functionally significant coronary artery stenoses assessed by fractional flow reserve: A novel coronary angiography index. AB - BACKGROUND: Angiographic evaluation of diameter stenosis has modest predictive value for functionally significant coronary artery stenoses as assessed by fractional flow reserve (FFR). Lesion length and assessment of area of myocardium at risk (Bypass Angioplasty Revascularization Investigation [BARI] Myocardial Jeopardy Index [MJI]) subtended by the stenotic coronary arteries are also predictors of functionally significant coronary artery stenoses. We sort to assess the diagnostic accuracy of DILEMMA score, which combines minimal lumen diameter (MLD), lesion length, and BARI MJI in prediction of significantly reduced FFR (<=0.8). METHODS: We assessed patients who underwent coronary angiography and FFR. Lesion length and MLD were assessed by quantitative coronary angiography. Estimation of area of myocardium at risk subtended by coronary stenoses was performed using the BARI MJI. RESULTS: A total of 296 patients (age 64 +/- 10.6 years, 68% male, 497 vessels) were included. DILEMMA score was significantly higher in vessels with significant FFR, 6.09 +/- 3.23 versus 3.84 +/- 2.99 (P < .001). In the derivation cohort, the optimism-adjusted Harrell c statistic for DILEMMA score was 0.82 compared with 0.76 for BARI MJI, 0.75 for lesion length, and 0.7 for MLD. In the validation cohort, the c-statistic for DILEMMA score, BARI MJI, lesion length, and MLD was 0.88, 0.77, 0.81, and 0.72, respectively. The DILEMMA score was a better predictor of FFR <=0.8 compared with MLD, lesion length, and BARI MJI individually (P < .001, P < .02, and P < .045, respectively) on Bonferroni-adjusted pairwise comparison. CONCLUSIONS: DILEMMA score, taking into account MLD, lesion length, and BARI MJI, may have incremental predictive value beyond the individual indices alone for detecting functionally significant coronary artery stenoses. PMID- 25819865 TI - Sensitive troponin assays in patients with suspected acute coronary syndrome: Results from the multicenter rule out myocardial infarction using computer assisted tomography II trial. AB - BACKGROUND: Sensitive troponin (Tn) assays have been developed for the evaluation of patients with suspected acute coronary syndrome (ACS). We sought to compare the performance of a commercially available sensitive Tn I (sTnI) and precommercial highly sTnI (hsTnI) method to conventional Tn (cTn) assays. METHODS: Among patients with acute chest pain but normal cTn in the emergency department of 6 centers, sTnI and hsTnI were measured at baseline, 2 and 4 hours after presentation. Diagnostic accuracy of sTnI and hsTnI relative to cTn for diagnosis during index hospitalization as well as their associations with coronary artery disease in patients randomized to coronary computed tomographic angiography (CTA) was assessed. RESULTS: Overall, 322 patients were enrolled, of whom 161 had a CTA; 28 had ACS (8.7%), including 21 with unstable angina pectoris (UAP). Both sTnI and hsTnI values at baseline and second draw had significantly higher sensitivity for ACS and UAP than cTn and had significantly greater area under the receiver operator characteristic curve than cTn at first and second draws. Compared with cTn, 29% of ACS cases previously categorized as UAP were reclassified to acute myocardial infarction with sTnI or hsTnI. An hsTnI below limit of detection had 100% negative predictive value for ACS or significant coronary artery stenosis in those randomized to CTA. CONCLUSIONS: In patients with acute chest discomfort, use of sTnI and hsTnI methods led to significant improvement in the early diagnostic accuracy for ACS, reclassifying one-third of UAP to myocardial infarction. Very low values for hsTnI excluded underlying coronary artery disease. PMID- 25819866 TI - Genetic markers of repolarization and arrhythmic events after acute coronary syndromes. AB - BACKGROUND: There is a genetic contribution to the risk of ventricular arrhythmias in survivors of acute coronary syndromes (ACS). We wished to explore the role of 33 candidate single nucleotide polymorphisms (SNPs) in prolonged repolarization and sudden death in patients surviving ACS. METHODS: A total of 2,139 patients (1680 white ethnicity) surviving an admission for ACS were enrolled in the prospective Coronary Disease Cohort Study. Extensive clinical, echocardiographic, and neurohormonal data were collected for 12 months, and clinical events were recorded for a median of 5 years. Each SNP was assessed for association with sudden cardiac death (SCD)/cardiac arrest (CA) and prolonged repolarization at 3 time-points: index admission, 1 month, and 12 months postdischarge. RESULTS: One hundred six SCD/CA events occurred during follow-up (6.3%). Three SNPs from 3 genes (rs17779747 [KCNJ2], rs876188 [C14orf64], rs3864180 [GPC5]) were significantly associated with SCD/CA in multivariable models (after correction for multiple testing); the minor allele of rs17779747 with a decreased risk (hazard ratio [HR] 0.68 per copy of the minor allele, 95% CI 0.50-0.92, P = .012), and rs876188 and rs386418 with an increased risk (HR 1.52 [95% CI 1.10-2.09, P = .011] and HR 1.34 [95% CI 1.04-1.82, P = .023], respectively). At 12 months postdischarge, rs10494366 and rs12143842 (NOS1AP) were significant predictors of prolonged repolarization (HR 1.32 [95% CI 1.04 1.67, P = .022] and HR 1.30 [95% CI 1.01-1.66, P = .038], respectively), but not at earlier time-points. CONCLUSION: Three SNPs were associated with SCD/CA. Repolarization time was associated with variation in the NOS1AP gene. This study demonstrates a possible role for SNPs in risk stratification for arrhythmic events after ACS. PMID- 25819867 TI - Metabolic and cardiac phenotype characterization in 37 atypical Dunnigan patients with nonfarnesylated mutated prelamin A. AB - BACKGROUND: Laminopathies are associated with a broad spectrum of clinical manifestations, from lipodystrophy to cardiac diseases. The purpose of this study was to assess genotype-phenotype correlations in a lipodystrophic laminopathy caused by the Lamin A (LMNA) mutation T655fsX49. This mutation leads to synthesis of nonfarnesylated-mutated prelamin A that does not undergo the physiologic lamin A maturation process. METHODS AND RESULTS: We studied 35 patients originating from Reunion Island who carried the LMNA T655fsX49 mutation. Comparisons of cardiac and endocrinologic features were made between homozygous and heterozygous patients. Homozygous patients presented more overlapping syndromes with severe cardiac phenotypes, defined by cardiolaminopathy, early atheroma with coronary heart disease (CHD) and high-degree conduction disorder compared with heterozygous (40% vs 4%; P = .016). Moreover, homozygous patients had earlier onset (49.6 vs 66 years old; P = .0002). Left ventricle lowered ejection fraction associated with heart failure was more frequent in homozygous than in heterozygous patients (40% vs 0%, respectively). Lipodystrophic traits were more marked in the homozygous group but only reached statistical significance for L4 subcutaneous fat measurement (2.8 +/- 2.16 vs 18.7 +/- 8.9 mm; P = .008) and leptin levels (2.45 +/- 1.6 vs 11.26 +/- 7.2 ng/mL; P = .0001). CONCLUSIONS: Our results suggest that there is a relationship between mutated prelamin-A accumulation and the severity of the phenotypes in homozygous familial partial lipodystrophy type 2 patients who harbor the LMNA T655fsX49 mutation. A dose dependent effect seems likely. PMID- 25819868 TI - Letter to the editor regarding the manuscript "Rationale and design of PRIMA II: A multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT ProBNP target on the reduction of readmission and Mortality rAtes". PMID- 25819869 TI - Response to: Letter to the editor regarding the manuscript "Rationale and design of PRIMA II: A multicenter, randomized clinical trial to study the impact of in hospital guidance for acute decompensated heart failure treatment by a predefined NT-ProBNP target on the reduction of readmission and Mortality rAtes". PMID- 25819870 TI - Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: Design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. PMID- 25819871 TI - Efficacy of ginger-based treatments against infection with Gyrodactylus turnbulli in the guppy (Poecilia reticulata (Peters)). AB - Monogenean infections of commercially farmed fishes are responsible for significant economic losses and existing chemical therapeutants, often stressful to the fish, pose associated risks. As part of a recent trend to move towards the use of alternative, plant-based remedies for commonly occurring aquaculture related diseases, the efficiency of ginger (Zingiber officinale) was investigated against the monogenean parasite Gyrodactylus turnbulli in the guppy. In vitro trials revealed the clear anti-parasitic effects of ginger. Ethanolic and aqueous extracts, prepared from freeze dried ginger, were tested. An increase in extract concentration was associated with reduced time to parasite immobilisation, with ethanolic extract being more efficient; at 75 and 200ppt aqueous ginger extract parasites died at 65.6+/-2.8 and 1.8+/-0.2min, respectively, whereas at 5 and 40ppt ethanolic extract parasites died at 26.1+/-0.7 and 4.9+/-0.3min, respectively. Bathing G. turnbulli-infected fish in ethanolic ginger extract (i.e. 5 and 7.5ppt for 90 and 30min, respectively) significantly reduced infection prevalence and intensity when compared to the water and ethanol controls. The higher concentration (i.e. 7.5ppt) proved as equally effective as Praziquantel, the conventionally used chemical treatment for gyrodactylosis, with the fish appearing to be completely cleared of the infection in both cases. Oral treatments of G. turnbulli-infected guppies with diets supplemented with 10 and 20% ginger powder proved to be ineffective in decreasing parasite load. These findings demonstrate that immersion in ginger extract offers an effective, alternative treatment against monogenean infection in fish. PMID- 25819874 TI - Does in utero exposure of antiepileptic drugs lead to failure to reach full cognitive potential? AB - A clinical scenario of a young female on 800 mg of sodium valproate (VPA) who has recently failed lamotrigine (LTG) and levetiracetam (LEV) and who is currently planning a pregnancy is presented. Currently available data pertaining to the longer-term development of children exposed to antiepileptic drugs (AEDs) are reviewed along with considerations around the methodology and interpretation of such research. There is an accumulation of data highlighting significant risks associated with prenatal exposed to VPA, with the level of risk being mediated by dose. The majority of published evidence does not find a significant risk associated with carbamazepine (CBZ) exposure in utero for global cognitive abilities however the evidence for more specific cognitive skills are unclear. Limited data indicate that LTG may be a preferred treatment to VPA in terms of foetal outcome but further evidence is required. Too little data pertaining to LEV exposure is available and a lack of evidence regarding risk of this and other new AEDs should not be interpreted as evidence of safety. PMID- 25819872 TI - PHY906(KD018), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Sorafenib by changing the tumor microenvironment. AB - PHY906 (KD018) is a four-herb Chinese Medicine Formula. It has been shown to potentially enhance the therapeutic indices of different class anticancer agents in vivo. Here, PHY906 is reported to enhance the anti-tumor activity of Sorafenib in nude mice bearing HepG2 xenografts. Among the four herbal ingredients of PHY906, Scutellaria baicalensis Georgi (S) and Paeonia lactiflora Pall (P) are required; however, S plays a more important role than P in increasing tumor apoptosis induced by Sorafenib with an increase of mouse(m)FasL and human(h)FasR expression. PHY906 may potentiate Sorafenib action by increasing hMCP1 expression and enhancing infiltration of macrophages into tumors with a higher M1/M2 (tumor rejection) signature expression pattern, as well as affect autophagy by increasing AMPKalpha-P and ULK1-S555-P of tumors. Depletion of macrophage could counteract PHY906 to potentiate the anti-tumor activity of Sorafenib. It was reported that tumor cells with higher levels of ERK1/2-P are more susceptible to Sorafenib, and the S component of PHY906 may increase ERK1/2-P via inhibition of ERK1/2 phosphatase in HepG2 tumors. PHY906 may potentiate the anti-hepatoma activity of Sorafenib by multiple mechanisms targeting on the inflammatory state of microenvironment of tumor tissue through two major ingredients (P and S) of PHY906. PMID- 25819875 TI - Re-annotation of presumed noncoding disease/trait-associated genetic variants by integrative analyses. AB - Using RefSeq annotations, most disease/trait-associated genetic variants identified by genome-wide association studies (GWAS) appear to be located within intronic or intergenic regions, which makes it difficult to interpret their functions. We reassessed GWAS-Associated single-nucleotide polymorphisms (herein termed as GASs) for their potential functionalities using integrative approaches. 8834 of 9184 RefSeq "noncoding" GASs were reassessed to have potential regulatory functionalities. As examples, 3 variants (rs3130320, rs3806932 and rs6890853) were shown to have regulatory properties in HepG2, A549 and 293T cells. Except rs3130320 as a known expression quantitative trait loci (eQTL), rs3806932 and rs6890853 were not reported as eQTLs in previous reports. 1999 of 9184 "noncoding" GASs were re-annotated to the promoters or intragenic regions using Ensembl, UCSC and AceView gene annotations but they were not annotated into corresponding regions in RefSeq database. Moreover, these GAS-harboring genes were broadly expressed across different tissues and a portion of them was expressed in a tissue-specific manner, suggesting that they could be functional. Collectively, our study demonstrates the benefits of using integrative analyses to interpret genetic variants and may help to predict or explain disease susceptibility more accurately and comprehensively. PMID- 25819876 TI - Tobacco plants over-expressing the sweet orange tau glutathione transferases (CsGSTUs) acquire tolerance to the diphenyl ether herbicide fluorodifen and to salt and drought stresses. AB - The glutathione transferases (GSTs) are members of a superfamily of enzymes with pivotal role in the detoxification of both xenobiotic and endogenous compounds. In this work, the generation and characterization of transgenic tobacco plants over-expressing tau glutathione transferases from Citrus sinensis (CsGSTU1 and CsGSTU2) and several cross-mutate forms of these genes are reported. Putative transformed plants were verified for the presence of the transgenes and the relative quantification of transgene copy number was evaluated by Taqman real time PCR. The analysis of gene expression revealed that transformed plants exhibit high levels of CsGSTU transcription suggesting that the insertion of the transgenes occurred in transcriptional active regions of the tobacco genome. In planta studies demonstrate that transformed tobacco plants gain tolerance against fluorodifen. Simultaneously, the wild type CsGSTU genes were in vitro expressed and their kinetic properties were determined using fluorodifen as substrate. The results show that CsGSTU2 follows a Michaelis-Menten hyperbolic kinetic, whereas CsGSTU1 generates a sigmoid plot typical of the regulatory enzymes, thus suggesting that when working at sub-lethal fluorodifen concentrations CsGSTU2 can counteract the herbicide injury more efficiently than the CsGSTU1. Moreover, the transgenic tobacco plant over-expressing CsGSTs exhibited both drought and salinity stress tolerance. However, as we show that CsGSTUs do not function as glutathione peroxidase in vitro, the protective effect against salt and drought stress is not due to a direct scavenging activity of the oxidative stress byproducts. The transgenic tobacco plants, which are described in the present study, can be helpful for phytoremediation of residual xenobiotics in the environment and overall the over-expression of CsGSTUs can be helpful to develop genetically modified crops with high resistance to abiotic stresses. PMID- 25819877 TI - Influence of temperature on ultrasound absorption in waveguides made out of refractory materials. AB - We studied the influence of temperature increase to 1500 degrees C on ultrasound absorption at frequencies from 0.1 to 1.0 MHz in tungsten, molybdenum, vanadium, graphite, and fused silica. The ultrasound absorption coefficient in these materials was calculated. It was shown that the fused silica has the smallest ultrasound absorption coefficient for temperatures up to 1000 degrees C. Vanadium and graphite also have small values of this coefficient for the considered temperature. The ultrasound absorption was investigated experimentally in graphite and fused silica waveguides. We demonstrated that the ultrasound absorption did not change in graphite with the temperature increase, but it increased in fused silica by a factor 2 for the temperature above 1000 degrees C. We show that different acoustical and mechanical properties of vanadium, graphite, and fused silica allow using them for waveguide applications and buffer rods in crystal growth at temperatures below 1500 degrees C and ultrasound frequency below 1.0 MHz. PMID- 25819878 TI - Bulk and surface acoustic waves in solid-fluid Fibonacci layered materials. AB - We study theoretically the propagation and localization of acoustic waves in quasi-periodic structures made of solid and fluid layers arranged according to a Fibonacci sequence. We consider two types of structures: either a given Fibonacci sequence or a periodic repetition of a given sequence called Fibonacci superlattice. Various properties of these systems such as: the scaling law and the self-similarity of the transmission spectra or the power law behavior of the measure of the energy spectrum have been highlighted for waves of sagittal polarization in normal and oblique incidence. In addition to the allowed modes which propagate along the system, we study surface modes induced by the surface of the Fibonacci superlattice. In comparison with solid-solid layered structures, the solid-fluid systems exhibit transmission zeros which can break the self similarity behavior in the transmission spectra for a given sequence or induce additional gaps other than Bragg gaps in a periodic structure. PMID- 25819879 TI - Extended temperature dependence of elastic constants in cubic crystals. AB - To extend the theory of the temperature dependence of the elastic constants in cubic crystals beyond the second- and third-order elastic constants, the fourth order elastic constants, as well as the non-linearity in the thermal expansion temperature dependence, have been taken into account. Theoretical results were represented as temperature functions of the effective elastic constants and compared with experimental data for a number of cubic crystals, such as alkali metal halides, and elements gold and silver. The relations obtained give a more accurate description of the experimental temperature dependences of second-order elastic constants for a number of cubic crystals, including deviations from linear behavior. A good agreement between theoretical estimates and experimental data has been observed. PMID- 25819880 TI - Dysregulation of gene expression in human fetal endothelial cells from gestational diabetes in response to TGF-beta1. AB - Enhanced biosynthesis of several cytokines, such as, transforming growth factor beta1 (TGF-beta1), is detected in gestational diabetes mellitus (GDM). In this study, we addressed the question of whether the exposure to the abnormal milieu of GDM in vivo affects gene expression pattern of human umbilical vein endothelial cells (HUVEC) in response to TGF-beta1. We found that HUVEC isolated from GDM (dHUVEC) had reduced migratory capacity versus those of healthy women (nHUVEC) and this quiescent phenotype was associated with higher expression levels of the TGF-betatype I receptor ALK5 and a slight increase in the endogenous production of TGF-beta1 (mainly in its latent form). Moreover, we performed transcriptome analysis, using microarray technology, of dHUVEC versus nHUVEC, after 3h treatment with exogenous TGF-beta1 (10 ng/ml). The treatment of dHUVEC with TGF-beta1 caused downregulation of the transcription of multiple genes involved in development, cell movement and migration of cells versus TGF beta1-treated nHUVEC. These changes in transcriptome profile might contribute to GDM-dependent alterations in cardiac morphogenesis and placental development. PMID- 25819882 TI - Influence of non-covalent preorganization on supramolecular effective molarities. AB - A family of closely related zinc porphyrin-pyridine complexes were used to examine the influence of linker preorganization on supramolecular effective molarities for formation of intramolecular H-bonds. Each pyridine ligand was equipped with a side-chain containing two H-bond acceptors, one on the end of the chain (terminal) and one in the middle of the chain (linker). These H-bond acceptors make intramolecular interactions with phenol H-bond donors on the porphyrin periphery. Two different H-bonding acceptors were used as linker groups in order to construct frameworks with significantly different degrees of preorganization: ester linkers populate the H-bonded state 60-70% of the time, whereas amide linkers populate the H-bonded state 90-100% of the time. Thus the amide linkers provide a significantly more preorganised ligand framework than the ester linkers. Effective molarities (EM) for intramolecular H-bonds between the terminal H-bond acceptor groups on the ligands (esters and amides) and the porphyrin phenol groups were quantified using 32 chemical double mutant cycles. The values of EM for interactions with the terminal H-bond acceptors are independent of the nature of the linker H-bond acceptor (weakly bonded ester or strongly bonded amide), which indicates that preorganization of the linker has no effect on chelate cooperativity in these systems. PMID- 25819881 TI - Physiology, pathogenicity and immunogenicity of live, attenuated Salmonella enterica serovar Enteritidis mutants in chicks. AB - To construct a novel live, attenuated Salmonella vaccine, the lon, cpxR and cpdB genes were deleted from a wild-type Salmonella enterica serovar Enteritidis-6 (SM 6) strain using the phage lambda Red homologous recombination system, resulting in SM-?CpxR, SM-?C/Lon and SM-?C/L/CpdB. The growth curves of strain SM-?C/Lon grew more rapidly than the other strains and had OD 600 values higher than the other strains starting at the 4 h time point. The growth curves of strain SM ?C/L/CpdB were relatively flat. The colonization time of SM-?C/L/CpdB is about 8 10 days. Deleting the lon/cpxR/cpdB (SM-6) genes resulted in an approximate 10(3) fold attenuation in virulence assessed by the analysis of the LD50 of specific pathogen-free (SPF) chicks. This result indicated that the deletion of the lon, cpxR and cpdB genes induced significant virulence attenuation. The protective effects of SM-?C/L/CpdB vaccination in SPF chicks against 5 * 10(9) colony forming units (CFU) of S. Enteritidis were resulted from the induction of an effective immune response. These findings demonstrate the potential of mutant SM ?C/L/CpdB to be used as an effective vaccine. PMID- 25819883 TI - The association between intradialytic exercise and hospital usage among hemodialysis patients. AB - Hemodialysis (HD) patients have high hospitalization rates. Benefits of intradialytic exercise have been proven in numerous studies yet exercise programs are still rarely used in the treatment of end-stage kidney disease (ESKD). Our objective was to determine if there was an association between a 6-month intradialytic bicycling program and hospitalization rates and length of stay (LOS) in ESKD patients. This was a retrospective cohort study that took place 6 months prior to and 6 months during an intradialtyic exercise program at an outpatient HD unit in Calgary, Alberta, Canada. Participants comprised 102 patients who had commenced HD <6 months (incident) or >6 months (prevalent) prior to starting exercise. The intervention comprised a 6-month intradialytic bicycling program. Main outcome measures were hospitalization rate, cause of hospitalization, and LOS. Patients were predominantly male (67.6%) aged 65.6 +/- 13.5 years and median HD vintage 1 year (range: 0-12). Comorbidities included diabetes mellitus (50%) and cardiac disease (38.2%). The hospitalization incidence rate ratio (IRR) was 0.48 (0.23-0.98; P = 0.04) in incident and 0.89 (0.56-1.42; P = 0.64) in prevalent patients. The LOS decreased from 7.8 (95% confidence interval (CI): 7.3-8.4) to 3.1 (95% CI: 2.8-3.4) days and LOS IRR was 0.39 (0.35-0.45; P < 0.001). The main predictors of hospitalization were lower albumin levels (P = 0.007) and lack of intradialytic exercise program participation (P < 0.001). In conclusion, 6 months of intradialytic exercise was associated with decreased LOS in both incident and prevalent HD patients. PMID- 25819884 TI - Toxicity of silica nanoparticles depends on size, dose, and cell type. AB - Monodisperse spherical silica nanoparticles (SNPs) with diameters of 20-200 nm were employed to study size, dose, and cell-type dependent cytotoxicity in A549 and HepG2 epithelial cells and NIH/3T3 fibroblasts. These uniform SNPs of precisely controlled sizes eliminated uncertainties arising from mixed sizes, and uniquely allowed the probing of effects entirely size-dependent. Cell viability, membrane disruption, oxidative stress, and cellular uptake were studied. The extent and mechanism of SNP cytotoxicity were found to be not only size and dose dependent, but also highly cell type dependent. Furthermore, the 60 nm SNPs exhibited highly unusual behavior in comparison to particles of other sizes tested, implying interesting possibilities for controlling cellular activities using nanoparticles. Specifically, the 60 nm SNPs were preferentially endocytosed by cells and, at high doses, caused a disproportionate decrease in cell viability. The present work may help elucidate certain contradictions among existing results on nanoparticle-induced cytotoxicity. FROM THE CLINICAL EDITOR: Silica nanoparticles are being investigated in many research areas for their use in clinical applications. Nonetheless, the relationship between particle size and potential toxicity remains to be elucidated. In this article, the authors studied the biological effects of spherical SNPs with precise diameters between 20 and 200 nm on three different cell types and their results should provide more data on safety for better drug design. PMID- 25819885 TI - Stimuli-responsive liposomes for the delivery of nucleic acid therapeutics. AB - Nucleic acid therapeutics (NATs) are valuable tools in the modulation of gene expression in a highly specific manner. So far, NATs have been actively pursued in both pre-clinical and clinical studies to treat diseases such as cancer, infectious and inflammatory diseases. However, the clinical application of NATs remains a considerable challenge owing to their limited cellular uptake, low biological stability, off-target effect, and unfavorable pharmacokinetics. One concept to address these issues is to deliver NATs within stimuli-responsive liposomes, which release their contents of NATs upon encountering environmental changes such as temperature, pH, and ion strength. In this case, before reaching the targeted tissue/organ, NATs are protected from degradation by enzymes and immune system. Once at the area of interest, localized and targeted delivery can be achieved with minimal influence to other parts of the body. Here, we discuss the latest developments and existing challenges in this field. FROM THE CLINICAL EDITOR: Nucleic acid therapeutics have been shown to enhance or eliminate specific gene expression in experimental research. Unfortunately, clinical applications have so far not been realized due to problems of easy degradation and possible toxicity. The use of nanosized carriers such as liposomes to deliver nucleic acids is one solution to overcome these problems. In this review article the authors describe and discuss the potentials of various trigger-responsive "smart" liposomes, with a view to help other researchers to design better liposomal nucleic acid delivery systems. PMID- 25819887 TI - Nanometric agents in the service of neuroscience: Manipulation of neuronal growth and activity using nanoparticles. AB - Nerve regeneration and recovery could provide great therapeutic benefits for individuals suffering from nerve damage post trauma or degenerative diseases. However, manipulation of nerves presents a huge challenge for neuroscientists and is not yet clinically feasible. In recent years, nanoparticles have emerged as novel effective agents for control of neuronal growth and behavior. Nanoparticles may facilitate the needed nerve manipulation abilities for therapeutic and diagnostic purposes including within the brain. This review aims at presenting the currently available literature regarding the interactions between inorganic nanoparticles and neurons. A wide range of nanoparticles are presented, including gold, iron oxide, cerium oxide, nanotubes and quantum-dots. The nanoparticles enhance neuronal differentiation and survival, direct growth and regulate electrical activity. The studies are summarized in a concise table, arranged by the function and type of nanoparticle. The latest studies present a novel interdisciplinary approach, which could be harnessed for clinical applications in nanomedicine. FROM THE CLINICAL EDITOR: Nerve regeneration remains the Holy Grail for patients with neuron loss. Nonetheless, this goal has not been realized in clinical setting thus far. In this article, the authors present a comprehensive review on various nanoparticle-based approaches, in both diagnosis and therapy, which should stimulate and generate more research ideas to the advancement in this field. PMID- 25819886 TI - Aerosol droplet delivery of mesoporous silica nanoparticles: A strategy for respiratory-based therapeutics. AB - A highly versatile nanoplatform that couples mesoporous silica nanoparticles (MSNs) with an aerosol technology to achieve direct nanoscale delivery to the respiratory tract is described. This novel method can deposit MSN nanoparticles throughout the entire respiratory tract, including nasal, tracheobronchial and pulmonary regions using a water-based aerosol. This delivery method was successfully tested in mice by inhalation. The MSN nanoparticles used have the potential for carrying and delivering therapeutic agents to highly specific target sites of the respiratory tract. The approach provides a critical foundation for developing therapeutic treatment protocols for a wide range of diseases where aerosol delivery to the respiratory system would be desirable. FROM THE CLINICAL EDITOR: Delivery of drugs via the respiratory tract is an attractive route of administration. In this article, the authors described the design of mesoporous silica nanoparticles which could act as carriers for drugs. The underlying efficacy was successfully tested in a mouse model. This drug carrier inhalation nanotechnology should potentially be useful in human clinical setting in the future. PMID- 25819889 TI - Myopericarditis and Takotsubo cardiomyopathy association. PMID- 25819890 TI - Acute myocardial infarction in a young woman with rheumatoid arthritis. PMID- 25819888 TI - Regulation and evolution of cardiopharyngeal cell identity and behavior: insights from simple chordates. AB - The vertebrate heart arises from distinct first and second heart fields. The latter also share a common origin with branchiomeric muscles in the pharyngeal mesoderm and transcription regulators, such as Nkx2-5, Tbx1 and Islet1. Despite significant progress, the complexity of vertebrate embryos has hindered the identification of multipotent cardiopharyngeal progenitors. Here, we summarize recent insights in cardiopharyngeal development gained from ascidian models, among the closest relatives to vertebrates. In a simplified cellular context, progressive fate specification of the ascidian cardiopharyngeal precursors presents striking similarities with their vertebrate counterparts. Multipotent cardiopharyngeal progenitors are primed to activate both the early cardiac and pharyngeal muscles programs, which segregate following asymmetric cells divisions as a result of regulatory cross-antagonisms involving Tbx1 and Nkx2-5 homologs. Activation of Ebf in pharyngeal muscle founder cells triggers both Myogenic Regulatory Factor-associated differentiation and Notch-mediated maintenance of an undifferentiated state in distinct precursors. Cross-species comparisons revealed the deep conservation of the cardiopharyngeal developmental sequence in spite of extreme genome sequence divergence, gene network rewiring and specific morphogenetic differences. Finally, analyses are beginning to uncover the influence of surrounding tissues in determining cardiopharyngeal cell identity and behavior. Thus, ascidian embryos offer a unique opportunity to study gene regulation and cell behaviors at the cellular level throughout cardiopharyngeal morphogenesis and evolution. PMID- 25819891 TI - Soluble ST2 may possess special superiority as a risk predictor in heart failure patients. PMID- 25819892 TI - Endovascular treatment of peripheral artery disease reduces blood pressure and improves long-term prognosis. PMID- 25819893 TI - Decision making in a presumptive case of STEMI-like myocarditis. PMID- 25819894 TI - Epicardial adipose tissue has an increased thickness and is a source of inflammatory mediators in patients with calcific aortic stenosis. PMID- 25819895 TI - Mortality, sudden death and indication for cardioverter defibrillator implantation in a dialysis population. AB - BACKGROUND: The incidence of sudden death among dialysis patients is high, but end stage renal disease was an exclusion criterion in the trials that demonstrated the benefit of implantable cardioverter defibrillator (ICD) for sudden death prevention. METHODS: Dialysis patients alive on January 2010 or starting dialysis between January 2010 and January 2013 were enrolled and retrospectively evaluated. Patients were divided into three groups: No Indication, Indication-With ICD and Indication-Without ICD. Cox and Fine and Gray regression models were used to estimate the total and cause-specific (sudden or non-sudden) mortality hazard ratio (HR, HR(cpRisk)), respectively. Survival was defined as the time from start of dialysis to the time of death. RESULTS: 154/2072 patients (7.4%) had indication for ICD implantation and 52 (33.8%) of them received the device; 688 (33.2%) deaths were recorded. Mortality was different among groups [Indication-With ICD vs No-Indication: HR 1.59 (95% CI 1.06-2.38) and Indication-Without ICD vs No-Indication: HR 2.67 (95% CI 2.09 3.39, p < 0.001)]. 84/688 (12.2%) were sudden deaths. The cumulative incidence of sudden death was higher in patients with ICD indication [Indication-With ICD vs No-Indication HR(cpRisk) 3.21 (95% CI 1.38-7.40) and Indication-Without ICD vs No Indication: HR(cpRisk) 4.19 (95% CI 2.38-7.39), p < 0.001], but also No Indication patients showed a high rate of sudden death [8.5% (95% CI.6.5-10.9) at 8 years of follow-up]. CONCLUSIONS: Dialysis patients with ICD indication had a worse survival than No-Indication subjects and the prognosis was particularly poor for the Indication-Without ICD group. Sudden death incidence was much higher than in the general population, even among No-Indication subjects. PMID- 25819896 TI - Common variants in or near ZNRF1, COLEC12, SCYL1BP1 and API5 are associated with diabetic retinopathy in Chinese patients with type 2 diabetes. AB - AIMS/HYPOTHESIS: Three recent genome-wide association studies (GWAS) identified several single-nucleotide polymorphisms (SNPs) with modest effects on diabetic retinopathy in Mexican-American and white patients with diabetes. This study aimed to evaluate the effects of these variants on diabetic retinopathy in Chinese patients with type 2 diabetes. METHODS: A total of 1,972 patients with type 2 diabetes were recruited to this study, including 819 patients with diabetic retinopathy and 1,153 patients with diabetes of >=5 years duration but without retinopathy. Forty SNPs associated with diabetic retinopathy in three GWAS were genotyped. Fundus photography was performed to diagnose and classify diabetic retinopathy. RESULTS: rs17684886 in ZNRF1 and rs599019 near COLEC12 were associated with diabetic retinopathy (OR 0.812, p = 0.0039 and OR 0.835, p = 0.0116, respectively) and with the severity of diabetic retinopathy (p = 0.0365 and p = 0.0252, respectively, for trend analysis). Sub-analysis in patients with diabetic retinopathy revealed that rs6427247 near SCYL1BP1 (also known as GORAB) and rs899036 near API5 were associated with severe diabetic retinopathy (OR 1.368, p = 0.0333 and OR 0.340, p = 0.0005, respectively). The associations between rs6427247 and rs899036 and severe diabetic retinopathy became more evident after a meta-analysis of published GWAS data (OR 1.577, p = 2.01 * 10(-4) for rs6427247; OR 0.330, p = 5.84 * 10(-7) for rs899036). CONCLUSIONS/INTERPRETATION: We determined that rs17684886 and rs599019 are associated with diabetic retinopathy and that rs6427247 and rs899036 are associated with severe diabetic retinopathy in Chinese patients with type 2 diabetes. PMID- 25819907 TI - Pediatrics after-hours: a twenty-year academic-community partnership for acute care delivery. PMID- 25819909 TI - 50 years ago in The Journal of Pediatrics: Calorie intake of children with Down's syndrome (Mongolism) (sic). PMID- 25819908 TI - Dead wrong: the growing list of racial/ethnic disparities in childhood mortality. PMID- 25819910 TI - 50 years ago in The Journal of Pediatrics: Spontaneous closure of ventricular septal defect following cardiac failure in infancy. PMID- 25819911 TI - 50 years ago in The Journal of Pediatrics: Infection with Haemophilus aphrophilus: brain abscess (comment on current literature). PMID- 25819912 TI - 50 years ago in The Journal of Pediatrics: Necrotizing enterocolitis in premature infants. PMID- 25819913 TI - 50 years ago in The Journal of Pediatrics: Tyrosinemia--an inborn error of tyrosine metabolism with cirrhosis of the liver and multiple renal defects. PMID- 25819914 TI - Establishing a child rights, health equity, and social justice-based practice of pediatrics. PMID- 25819915 TI - DNA intercalative 4-butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline induces cell cycle arrest and apoptosis in leukemia cells. AB - PURPOSE: DNA intercalators are one of the interesting groups in cancer chemotherapy. The development of novel anticancer small molecule has gained remarkable interest over the last decade. In this study, we synthesized and investigated the ability of a tetracyclic-condensed quinoline compound, 4 butylaminopyrimido[4',5':4,5]thieno(2,3-b)quinoline (BPTQ), to interact with double-stranded DNA and inhibit cancer cell proliferation. METHODS: Circular dichroism, topological studies, molecular docking, absorbance, and fluorescence spectral titrations were employed to study the interaction of BPTQ with DNA. Cytotoxicity was studied by performing 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. Further, cell cycle analysis by flow cytometry, annexin V staining, mitochondrial membrane potential assay, DNA fragmentation, and western blot analysis were used to elucidate the mechanism of action of BPTQ at the cellular level. RESULTS: Spectral, topological, and docking studies confirmed that BPTQ is a typical intercalator of DNA. BPTQ induces dose-dependent inhibitory effect on the proliferation of cancer cells by arresting cells at S and G2/M phase. Further, BPTQ activates the mitochondria-mediated apoptosis pathway, as explicated by a decrease in mitochondrial membrane potential, increase in the Bax:Bcl-2 ratio, and activation of caspases. CONCLUSION: These results confirmed that BPTQ is a DNA intercalative anticancer molecule, which could aid in the development of future cancer therapeutic agents. PMID- 25819916 TI - A Comparative Study on the Effects of Millisecond- and Microsecond-Pulsed Electric Field Treatments on the Permeabilization and Extraction of Pigments from Chlorella vulgaris. AB - The interdependencies of the two main processing parameters affecting "electroporation" (electric field strength and pulse duration) while using pulse duration in the range of milliseconds and microseconds on the permeabilization, inactivation, and extraction of pigments from Chlorella vulgaris was compared. While irreversible "electroporation" was observed above 4 kV/cm in the millisecond range, electric field strengths of >=10 kV/cm were required in the microseconds range. However, to cause the electroporation of most of the 90 % of the population of C. vulgaris in the millisecond (5 kV/cm, 20 pulses) or microsecond (15 kV/cm, 25 pulses) range, the specific energy that was delivered was lower for microsecond treatments (16.87 kJ/L) than in millisecond treatments (150 kJ/L). In terms of the specific energy required to cause microalgae inactivation, treatments in the microsecond range also resulted in greater energy efficiency. The comparison of extraction yields in the range of milliseconds (5 kV, 20 ms) and microseconds (20, 25 pulses) under the conditions in which the maximum extraction was observed revealed that the improvement in the carotenoid extraction was similar and chlorophyll a and b extraction was slightly higher for treatments in the microsecond range. The specific energy that was required for the treatment in the millisecond range (150 kJ/L) was much higher than those required in the microsecond range (30 kJ/L). The comparison of the efficacy of both types of pulses on the extraction enhancement just after the treatment and after a post-pulse incubation period seemed to indicate that PEF in the millisecond range created irreversible alterations while, in the microsecond range, the defects were a dynamic structure along the post-pulse time that caused a subsequent increment in the extraction yield. PMID- 25819917 TI - Efficacy of Broadline(r) spot-on against Aelurostrongylus abstrusus and Troglostrongylus brevior lungworms in naturally infected cats from Italy. AB - The increasing reports of Aelurostrongylus abstrusus infection and the new information on Troglostrongylus brevior have spurred the interest of the scientific community towards the research of pharmaceutical compounds effective against both pathogens. A novel topical combination of fipronil, (S)-methoprene, eprinomectin and praziquantel (Broadline(r), Merial) has been released for the treatment of a variety of feline parasitic infections. The present study reports the efficacy of this spot-on in treating cats naturally infected by feline lungworms. Client owned cats (n=191) were enrolled from three geographical areas of Italy and faecal samples were examined by floatation and Baermann techniques. Twenty-three individuals were positive for L1 of A. abstrusus (n=18) or T. brevior (n=3) or for both species (n=2) and they were topically treated with Broadline(r). Seventeen of them were also concomitantly infected by other parasites. Four weeks after treatment, faecal samples were collected and examined to assess the efficacy of a single administration of the product. Based on lungworm larvae counts, the efficacy of the treatment was 90.5% or 100% for A. abstrusus or T. brevior, respectively. Cats released significantly lower amounts of lungworm larvae after treatment compared to pre-treatment (p<0.0001). All but three cats were negative for other nematodes after treatment and all cats recovered from respiratory signs. Results of this study indicate that a single administration of the topical combination fipronil, (S)-methoprene, eprinomectin and praziquantel is effective and safe for the treatment of A. abstrusus and/or T. brevior infections in cats living under field conditions. PMID- 25819918 TI - A model for the dynamics of the free-living stages of equine cyathostomins. AB - Anthelmintic resistance in strongyle nematode parasites of horses is an expanding global problem and steps need to be taken to slow its development before control becomes more problematic. A move away from traditional deworming programmes, involving frequent whole-herd treatments with broad spectrum anthelmintics, to a more strategic or targeted use of chemicals is required. However, anthelmintic resistance management strategies which also maintain effective control are invariably more complicated and often require a greater understanding of both nematode epidemiology and grazing management, than does the simple routine use of chemicals. Here, as a first step in applying a modelling approach to resistance management in horses, a model is proposed to describe the dynamics on pasture of the free-living stages of equine cyathostomins. Firstly, the development and survival of the pre-infective stages is considered as a single process driven by temperature, and secondly, two populations of infective stage larvae (L3) are considered; those within the faecal pat and those on the herbage. Both are modelled using the box-car train approach which allows for variable development rates within a cohort of individuals and full overlap of generations. Uniquely, L3 survival is modelled as an ageing process where larvae progress through physiological age classes at a rate determined by temperature and rainfall. Model output reflects the dynamics of free-living stages under a range of environments. Under extreme cold, there is no development to L3 but eggs can survive for long periods to develop if conditions become favourable, while L3 survival is reduced under repeated freeze-thaw cycles. Under tropical conditions, development is rapid and a large number of L3 can be produced but survival of L3 is short. In temperate climates development tends to be slower, with large numbers of L3 produced over the warmer months but fewer over winter, and L3 survival tends to be higher all year round. Although attempts to validate model output against field studies were compromised by the lack of published detail or an inability to access specific weather records, outputs averaged over multiple sets of weather data was often appropriate for that location. Variation in model output when using weather data sets which started on different days within the same week suggests that day-to-day differences in weather may affect the number of L3 developing on pasture and that optimisation of anthelmintic use to minimise pasture infectivity may require a more detailed understanding of weather effects than previously thought. PMID- 25819919 TI - Strabismus in infants following congenital cataract surgery. AB - PURPOSE: This study aimed to determine the incidence and characteristics of strabismus following congenital cataract surgery in infants. MATERIALS AND METHODS: Patients aged <12 months who underwent surgery for congenital cataract and were followed-up for >=1 years were included. Patients that had strabismus prior to surgery were excluded. Data regarding gender, cataract laterality, morphology, and density, age at the time of cataract surgery, ocular motility post surgery, and the presence of nystagmus were retrospectively obtained from the patients' records. RESULTS: The study included 79 patients (48 male and 31 female). Unilateral surgery was performed in 14 of the patients, versus bilateral surgery in 65. Strabismus did not occur post surgery in 32 (40.5 %) of the patients (group 1), whereas 47 (59.5 %) (group 2) developed strabismus following surgery. The patients in group 1 were followed-up for a mean 50.7 +/- 38.5 months, versus 50.3 +/- 39 months in group 2. Mean age at the time of cataract surgery in groups 1 and 2 was 3.6 +/- 1.9 years and 4.6 +/- 3.2 months respectively. Mean duration of time between cataract surgery and the development of strabismus was 13.3 +/- 13 months (range: 1-60 months). Unilateral cases were more prone to develop strabismus, which was statistically significant (p = 0.028). Age at the time of cataract surgery, gender, cataract density, the occurrence of aphakic glaucoma, the presence of nystagmus, and additional ocular surgery were not significantly associated with the development of strabismus. CONCLUSION: Strabismus develops more frequently in children undergoing cataract surgery. In the present study strabismus occurred in more of the patients that underwent unilateral surgery. Based on the present findings, we think that long term careful follow-up to monitor the development of strabismus is required in all infants undergoing cataract surgery, especially unilateral cases. PMID- 25819920 TI - Index clinical manifestation of venous thromboembolism predicts early recurrence type and frequency: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Observational studies suggest index clinical manifestation of venous thromboembolism (VTE) predicts recurrence type. Data regarding the association between index manifestation and recurrence rates are conflicting. OBJECTIVES: To perform a meta-analysis of randomized controlled trials (RCTs) to determine the type and frequency of recurrent VTE (rVTE) in persons after an index deep vein thrombosis (DVT) or pulmonary embolism (PE). PATIENTS/METHODS: We searched bibliographic databases for RCTs of acute (early) treatment of rVTE in persons with an index DVT or PE (+/-DVT), enrolling >= 50 subjects anticoagulated >= 3 months and reporting types of rVTE. We pooled (random-effects) the proportion of rVTEs that were DVTs, PEs, and fatal PEs, the proportion of recurrent PEs that were fatal, and absolute rVTE rates. RESULTS: In nine RCTs (N = 13 640; 413 rVTEs) evaluating persons with an index PE; 66% (95% CI, 60-72%) of rVTEs were PE and 27% (95% CI, 22-33%) were fatal PE. Among 25 RCTs (N = 17 340; 692 rVTEs) evaluating persons with an index DVT, 36% (95% CI, 29-44%) experienced a recurrent PE and 10% (95% CI, 7-13%) a fatal PE. Recurrent PEs following an index PE had a higher fatality rate than after an index DVT (41%; 95% CI, 33-48% vs. 25%; 95% CI, 18-33%; P = 0.007). The rVTE rate was higher following an index DVT compared with a PE (2.6%; 95% CI, 1.6-3.8% vs. 4.9%; 95% CI, 4.0-6.0%; P = 0.002). CONCLUSIONS: Our meta-analysis suggests most rVTEs will be the same type as the index event. While index DVTs are associated with a higher rVTE rate than index PEs; recurrent PEs are associated with high fatality. PMID- 25819921 TI - Long intervening non-coding RNA 00320 is human brain-specific and highly expressed in the cortical white matter. AB - Pervasive transcription of the genome produces a diverse array of functional non coding RNAs (ncRNAs). One particular class of ncRNAs, long intervening non-coding RNAs (lincRNAs) are thought to play a role in regulating gene expression and may be a major contributor to organism and tissue complexity. The human brain with its heterogeneous cellular make-up is a rich source of lincRNAs; however, the functions of the majority of lincRNAs are unknown. Recently, by completing RNA sequencing (RNA-Seq) of the human frontal cortex, we identified linc00320 as being highly expressed in the white matter compared to grey matter in multiple system atrophy (MSA) brain. Here, we further investigate the expression patterns of linc00320 and conclude that it is involved in specific brain regions rather than having involvement in the MSA disease process. We also show that the full length linc00320 is only expressed in human brain tissue and not in other primates, suggesting that it may be involved in improved functional connectivity for higher human brain cognition. PMID- 25819922 TI - Oral allergy syndrome in children. AB - Oral allergy syndrome (OAS) is an allergic reaction that occurs after consumption of fresh fruits and vegetables in patients with allergy to pollen. It is mediated by immunoglobulin E (IgE) antibodies and symptoms arise as a result of cross reactivity between pollen and plant-derived food. OAS is rarely seen in young children, but the prevalence increases with age. The objectives of the study were to identify the prevalence of OAS and probable risk factors in children and adolescents with seasonal allergic rhinitis (AR). One-hundred and twenty patients with seasonal AR were included. Patients were diagnosed based on their clinical history, skin prick test outcome and specific IgE. In patients describing OAS, prick-by-prick tests with fresh fruit or vegetables were carried out. Thirty-two patients had OAS and it was more frequent in female patients than in male patients. OAS was more frequent in adolescents than in small children and in patients with higher total IgE. OAS was significantly more prevalent in patients with AR and asthma (P=0.0016), as was the case in patients with AR and atopic dermatitis (P=0.0004). OAS is rarely diagnosed in small children, partly because of an inadequate clinical history. Patients with OAS may have some risk factors in addition to pollen allergy, and those with more severe atopy are more likely to develop OAS. PMID- 25819923 TI - Evaluation of river water quality variations using multivariate statistical techniques: Sava River (Croatia): a case study. AB - For the evaluation of seasonal and spatial variations and the interpretation of a large and complex water quality dataset obtained during a 7-year monitoring program of the Sava River in Croatia, different multivariate statistical techniques were applied in this study. Basic statistical properties and correlations of 18 water quality parameters (variables) measured at 18 sampling sites (a total of 56,952 values) were examined. Correlations between air temperature and some water quality parameters were found in agreement with the previous studies of relationship between climatic and hydrological parameters. Principal component analysis (PCA) was used to explore the most important factors determining the spatiotemporal dynamics of the Sava River. PCA has determined a reduced number of seven principal components that explain over 75 % of the data set variance. The results revealed that parameters related to temperature and organic pollutants (CODMn and TSS) were the most important parameters contributing to water quality variation. PCA analysis of seasonal subsets confirmed this result and showed that the importance of parameters is changing from season to season. PCA of the four seasonal data subsets yielded six PCs with eigenvalues greater than one explaining 73.6 % (spring), 71.4 % (summer), 70.3 % (autumn), and 71.3 % (winter) of the total variance. To check the influence of the outliers in the data set whose distribution strongly deviates from the normal one, in addition to standard principal component analysis algorithm, two robust estimates of covariance matrix were calculated and subjected to PCA. PCA in both cases yielded seven principal components explaining 75 % of the total variance, and the results do not differ significantly from the results obtained by the standard PCA algorithm. With the implementation of robust PCA algorithm, it is demonstrated that the usage of standard algorithm is justified for data sets with small numbers of missing data, nondetects, and outliers (less than 4 %). The clustering procedure highlighted four different groups in which the sampling sites have similar characteristics and pollution levels. The first and the second group correspond to relatively low and moderately polluted sites while stations which are located in the middle of the river belong to the third and fourth group and correspond to highly and moderately polluted sites. PMID- 25819924 TI - Phosphorus and nitrogen fluxes carried by 21 Finnish agricultural rivers in 1985 2006. AB - The Finnish Agri-Environmental Programme aims to reduce nutrient load to waters. Using national monitoring data, we estimated the agricultural load (incl. natural background) of total phosphorus (TP) and total nitrogen (TN) transported by 21 Finnish rivers to the northern Baltic Sea and analysed the flow-adjusted trends in the loads and concentrations from 1985 to 2006. We also related the loads to spatial and temporal patterns in catchment and agricultural characteristics. Agricultural load of TN increased, especially in the rivers discharging into the Bothnian Bay, while the load of TP decreased in most of the rivers, except those discharging into the Archipelago Sea. The trends may partly be related to a decrease in grassed area (TP, TN) and increased mineralisation (TN), but the available data on catchment and agricultural characteristics did not fully explain the observed pattern. Our study showed that data arising from relatively infrequent monitoring may prove useful for analysing long-term trend. The mutual correlation among the explaining variables hampered the analysis of the load generating factors. PMID- 25819925 TI - Total petroleum hydrocarbons in edible marine biota from Northern Persian Gulf. AB - To provide a baseline information for consumer's health, distribution of total petroleum hydrocarbons in 18 edible marine biota species from northern Persian Gulf was evaluated. The samples were purchased from fish market of Hormozgan Province, South of Iran. Marine biota samples included different species with various feeding habits and were analyzed based on ultraviolet florescence spectroscopy. Petroleum hydrocarbons showed narrow variation, ranging from 0.67 to 3.36 MUg/g dry weight. The maximum value was observed in silver pomfret. Anchovy and silver pomfret with the highest content of petroleum hydrocarbons were known as good indicator for oil pollution in the studied area. From public health point of view, the detected concentrations for total petroleum hydrocarbons were lower than hazardous guidelines. The results were recorded as background data and information in the studied area; the continuous monitoring of pollutants is recommended, according to the rapid extension of industrial and oily activities in Hormozgan Province. PMID- 25819926 TI - Posthumous Reproduction (PHR) in Israel: Policy Rationales Versus Lay People's Concerns, a Preliminary Study. AB - Israeli policy concerning PHR has been decided upon in an expertocratic manner, leaving the voice of the public unheard. Based on 26 semi-structured in-depth interviews with 13 Jewish-Israeli young couples, this preliminary study provides the first empirical data regarding lay attitudes toward PHR in Israel. Findings suggest major dissimilarities between the policy and lay people's wishes and rationales. While policy is built on the "presumed wish" assumption, supposing all men living in a loving relationship wish to have their partner carry their child post-mortem, this was empirically unsupported. However, the findings suggest that many interviewees were willing to defer to their surviving spouse's wishes to have their post-mortem child, sometimes even against their own wish, indicating a support for presumed consent. Respecting the wishes of the dead, a dominant argument in the bioethical discussion in Israel and beyond, was mainly irrelevant to informants, whereas interviewees considered the future child's welfare, a concern overlooked by Israeli policy. Likewise, while posthumous grandparenthood is on the rise in Israel, it clearly contradicts the wishes of the majority of this study's informants. Nonetheless, existing policy is not expected to raise any opposition, due to the extreme liberalism of the participants and their support of reproductive autonomy. PMID- 25819927 TI - Comparison between landfill gas and waste incineration for power generation in Astana, Kazakhstan. AB - The city of Astana, the capital of Kazakhstan, which has a population of 804,474, and has been experiencing rapid growth over the last 15 years, generates approximately 1.39 kg capita(-1) day(-1) of municipal solid waste (MSW). Nearly 700 tonnes of MSW are collected daily, of which 97% is disposed of at landfills. The newest landfill was built using modern technologies, including a landfill gas (LFG) collection system.The rapid growth of Astana demands more energy on its path to development, and the viability analysis of MSW to generate electricity is imperative. This paper presents a technical-economic pre-feasibility study comparing landfill including LFG utilization and waste incineration (WI) to produce electricity. The performance of LFG with a reciprocating engine and WI with steam turbine power technologies were compared through corresponding greenhouse gases (GHG) reduction, cost of energy production (CEP), benefit-cost ratio (BCR), net present value (NPV) and internal rate of return (IRR) from the analyses. Results demonstrate that in the city of Astana, WI has the potential to reduce more than 200,000 tonnes of GHG per year, while LFG could reduce slightly less than 40,000 tonnes. LFG offers a CEP 5.7% larger than WI, while the latter presents a BCR two times higher than LFG. WI technology analysis depicts a NPV exceeding 280% of the equity, while for LFG, the NPV is less than the equity, which indicates an expected remarkable financial return for the WI technology and a marginal and risky scenario for the LFG technology. Only existing landfill facilities with a LFG collection system in place may turn LFG into a viable project. PMID- 25819928 TI - Compost maturity and nitrogen availability by co-composting of paddy husk and chicken manure amended with clinoptilolite zeolite. AB - The availability of paddy husk from rice processing plants remains high owing to increase in the worldwide rice consumption. Increasing demand for chicken products leads to poultry wastes production. Co-composting of the aforementioned wastes could solve the indiscriminate disposal of these wastes. Thus, co composting of paddy husk and chicken slurry with clinoptilolite zeolite and urea as additive was carried out. Clinoptilolite zeolite was used to enhance ammonium and nitrate retention in the compost. Temperature of the compost was monitored three times daily for 55 days. Cation exchange capacity, organic matter, ash, humic acids, pH, total C, N, C/N ratio; total P, exchangeable Ca, Mg, K, NH4+, NO3-, and heavy metals contents were determined using standard procedures. pH, total N, humic acids, ash, NH4+, NO3-, P, Ca, Mg, and K contents increased but the salinity, heavy metals contents, and microbial population were low after the co-composting process. Zea mays L. (test crop) seed germination rate in distilled water and the compost were not significantly different. Growth of Spinach oleracea (test crop) on a peat-based growing medium and the compost was also not significantly different. These findings were possible because the clinoptilolite zeolite used in co-composting reduced accumulation of heavy metals that may have damage effects on the test crops. Mature compost with good agronomic properties can be produced by co-composting chicken slurry and paddy husk using clinoptilolite zeolite and urea as additives. PMID- 25819929 TI - Design of an innovative, ecological portable waste compressor for in-house recycling of paper, plastic and metal packaging waste. AB - Waste management in Greece relies heavily on unsustainable waste practices (mainly landfills and in certain cases uncontrolled dumping of untreated waste). Even though major improvements have been achieved in the recycling of municipal solid waste during recent years, there are some barriers that hinder the achievement of high recycling rates. Source separation of municipal solid waste has been recognised as a promising solution to produce high-quality recycled materials that can be easily directed to secondary materials markets. This article presents an innovative miniature waste separator/compressor that has been designed and developed for the source separation of municipal solid waste at a household level. The design of the system is in line with the Waste Framework Directive (2008/98/EC), since it allows for the separate collection (and compression) of municipal solid waste, namely: plastic (polyethylene terephthalate and high-density polyethylene), paper (cardboard and Tetrapak) and metal (aluminium and tin cans). It has been designed through the use of suitable software tools (LS-DYNA, INVENTROR and COMSOL). The results from the simulations, as well as the whole design process and philosophy, are discussed in this article. PMID- 25819930 TI - An incentive-based source separation model for sustainable municipal solid waste management in China. AB - Municipal solid waste (MSW) management (MSWM) is most important and challenging in large urban communities. Sound community-based waste management systems normally include waste reduction and material recycling elements, often entailing the separation of recyclable materials by the residents. To increase the efficiency of source separation and recycling, an incentive-based source separation model was designed and this model was tested in 76 households in Guiyang, a city of almost three million people in southwest China. This model embraced the concepts of rewarding households for sorting organic waste, government funds for waste reduction, and introducing small recycling enterprises for promoting source separation. Results show that after one year of operation, the waste reduction rate was 87.3%, and the comprehensive net benefit under the incentive-based source separation model increased by 18.3 CNY tonne(-1) (2.4 Euros tonne(-1)), compared to that under the normal model. The stakeholder analysis (SA) shows that the centralized MSW disposal enterprises had minimum interest and may oppose the start-up of a new recycling system, while small recycling enterprises had a primary interest in promoting the incentive-based source separation model, but they had the least ability to make any change to the current recycling system. The strategies for promoting this incentive-based source separation model are also discussed in this study. PMID- 25819931 TI - Opinion of the Scientific Committee on Consumer Safety (SCCS)--The safety of the use of formaldehyde in nail hardeners. PMID- 25819932 TI - A novel approach to assess the population health impact of introducing a Modified Risk Tobacco Product. AB - Based on the Food and Drug Administration's Modified Risk Tobacco Product (MRTP) Application draft guideline, Philip Morris International (PMI) has developed a Population Health Impact Model to estimate the reduction in the number of deaths over a period following the introduction of an MRTP. Such a model is necessary to assess the effect that its introduction would have on population health, given the lack of epidemiological data available prior to marketing authorization on any risks from MRTPs. The model is based on publicly available data on smoking prevalence and on the relationships between smoking-related disease-specific mortality and various aspects of the smoking of conventional cigarettes (CCs), together with an estimate of exposure from the MRTP relative to that from CCs, and allows the exploration of possible scenarios regarding the effect of MRTP introduction on the prevalence of CC and MRTP use, individually and in combination. By comparing mortality attributable in a scenario where the MRTP is introduced with one where it is not, the model can estimate the mortality attributable to CCs and the MRTP, as well as the reduction in the deaths attributable to the introduction of the MRTP. PMID- 25819933 TI - Glucocorticoid with or without additional immunosuppressant therapy for patients with lupus podocytopathy: a retrospective single-center study. AB - Lupus podocytopathy is a newly recognized class of lupus nephritis characterized by extensive glomerular foot process effacement without capillary wall immune deposits. The treatment response and relapse of glucocorticoid with or without additional immunosuppressive agents has not been well investigated. In this study, 50 patients with lupus podocytopathy were included and received glucocorticoid alone (glucocorticoid monotherapy) or glucocorticoid plus additional immunosuppressive agents (combination therapy) for their induction or maintenance treatment regimens. The treatment response and relapse rate in the two groups were respectively analyzed. We found that the induction treatment with glucocorticoid monotherapy and combination therapy led to remission in 47 patients (94.0%) at 12 weeks treatment, with complete remission (CR) occurring in 38 patients (76.0%). The CR rate compared between glucocorticoid monotherapy and combination therapy showed no difference (76.7% vs 75.0%, p = 0.9), the median time to CR was four weeks (range: 2.0-6.0 weeks) in glucocorticoid monotherapy and 8.0 weeks (range: 3.7-12.0 weeks) in combination therapy (p = 0.076). Twenty seven of 47 patients (57.4%) relapsed during maintenance, the relapse rate was much higher in the glucocorticoid monotherapy group than in the combination therapy group (89.5% vs 35.7%, p < 0.001), regardless of the induction regimens being glucocorticoid monotherapy or combination therapy. No patient developed end stage renal disease or died during follow-up for 6-125 months (median 62 months). In conclusion, the remission of lupus podocytopathy could be induced by glucocorticoid monotherapy or glucocorticoid plus other immunosuppressive agents, while the remission should be maintained by the combination regimen. PMID- 25819934 TI - Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders. AB - Because of their neuroprotective properties, cannabinoids are being investigated in neurodegenerative disorders, mainly in preclinical studies. These disorders also include amyotrophic lateral sclerosis (ALS), a degenerative disease produced by the damage of the upper and lower motor neurons leading to muscle denervation, atrophy and paralysis. The studies with cannabinoids in ALS have been conducted exclusively in a transgenic mouse model bearing mutated forms of human superoxide dismutase-1, the first gene that was identified in relation with ALS. The present study represents the first attempt to investigate the endocannabinoid system in an alternative model, the transgenic mouse model of TAR-DNA binding protein-43 (TDP-43), a protein related to ALS and also to frontotemporal dementia. We used these mice for behavioral and histological characterization at an early symptomatic phase (70-80 days of age) and at a post-symptomatic stage (100-110 days of age). TDP-43 transgenic mice exhibited a worsened rotarod performance at both disease stages. This was accompanied by a loss of motor neurons in the spinal cord (measured by Nissl staining) and by reactive microgliosis (measured by Iba-1 immunostaining) at the post-symptomatic stage. We also detected elevated levels of the CB2 receptor (measured by qRT-PCR and western blotting) in the spinal cord of these animals. Double-staining studies confirmed that this up regulation occurs in microglial cells in the post-symptomatic stage. Some trends towards an increase were noted also for the levels of endocannabinoids, which in part correlate with a small reduction of FAAH. Some of these parameters were also analyzed in the cerebral cortex of TDP-43 transgenic mice, but we did not observe any significant change, in agreement with the absence of anomalies in cognitive tests. In conclusion, our data support the idea that the endocannabinoid signaling system, in particular the CB2 receptor, may serve for the development of a neuroprotective therapy in TDP-43-related disorders. We are presently engaged in pharmacological experiments to investigate this possibility. PMID- 25819935 TI - Premorbid adjustment and clinical correlates of cognitive impairment in first episode psychosis. The PEPsCog Study. AB - BACKGROUND: The extent to which socio-demographic, clinical, and premorbid adjustment variables contribute to cognitive deficits in first-episode schizophrenia spectrum disorders remains to be ascertained. AIMS: To examine the pattern and magnitude of cognitive impairment in first-episode psychosis patients, the profile of impairment across psychosis subtypes and the associations with premorbid adjustment. METHODS: 226 first-episode psychosis patients and 225 healthy controls were assessed in the PEPsCog study, as part of the PEPs study. RESULTS: Patients showed slight to moderate cognitive impairment, verbal memory being the domain most impaired compared to controls. Broad affective spectrum patients had better premorbid IQ and outperformed the schizophrenia and other psychosis groups in executive function, and had better global cognitive function than the schizophrenia group. Adolescent premorbid adjustment together with age, gender, parental socio-economic status, and mean daily antipsychotic doses were the factors that best explained patients' cognitive performance. General and adolescent premorbid adjustment, age and parental socio-economic status were the best predictors of cognitive performance in controls. CONCLUSIONS: Poorer premorbid adjustment together with socio demographic factors and higher daily antipsychotic doses were related to a generalized cognitive impairment and to a lower premorbid intellectual reserve, suggesting that neurodevelopmental impairment was present before illness onset. PMID- 25819936 TI - Prediction of outcome in the psychosis prodrome using neuroanatomical pattern classification. AB - To date, research into the biomarker-aided early recognition of psychosis has focused on predicting the transition likelihood of clinically defined individuals with different at-risk mental states (ARMS) based on structural (and functional) brain changes. However, it is currently unknown whether neuroimaging patterns could be identified to facilitate the individualized prediction of symptomatic and functional recovery. Therefore, we investigated whether cortical surface alterations analyzed by means of multivariate pattern recognition methods could enable the single-subject identification of functional outcomes in twenty-seven ARMS individuals. Subjects were dichotomized into 'good' vs. 'poor' outcome groups on average 4years after the baseline MRI scan using a Global Assessment of Functioning (GAF) threshold of 70. Cortical surface-based pattern classification predicted good (N=14) vs. poor outcome status (N=13) at follow-up with an accuracy of 82% as determined by nested leave-one-cross-validation. Neuroanatomical prediction involved cortical area reductions in superior temporal, inferior frontal and inferior parietal areas and was not confounded by functional impairment at baseline, or antipsychotic medication and transition status over the follow-up period. The prediction model's decision scores were correlated with positive and general symptom scores in the ARMS group at follow up, whereas negative symptoms were not linked to predicted poorer functional outcome. These findings suggest that poorer functional outcomes are associated with non-resolving attenuated psychosis and could be predicted at the single subject level using multivariate neuroanatomical risk stratification methods. However, the generalizability and specificity of the suggested prediction model should be thoroughly investigated in future large-scale and cross-diagnostic MRI studies. PMID- 25819938 TI - New prevalence estimate of Torque Teno virus (TTV) infection in healthy population and patients with chronic viral hepatitis in Jiujiang, China. PMID- 25819939 TI - Atypical presentation of crusted (Norwegian) scabies. PMID- 25819937 TI - Neuroimaging findings from childhood onset schizophrenia patients and their non psychotic siblings. AB - Childhood onset schizophrenia (COS), with onset of psychosis before age 13, is a rare form of schizophrenia that represents a more severe and chronic form of the adult onset illness. In this review we examine structural and functional magnetic resonance imaging (MRI) studies of COS and non-psychotic siblings of COS patients in the context of studies of schizophrenia as a whole. Studies of COS to date reveal progressive loss of gray matter volume and cortical thinning, ventricular enlargement, progressive decline in cerebellar volume and a significant but fixed deficit in hippocampal volume. COS is also associated with a slower rate of white matter growth and disrupted local connectivity strength. Sibling studies indicate that non-psychotic siblings of COS patients share many of these brain abnormalities, including decreased cortical thickness and disrupted white matter growth, yet these abnormalities normalize with age. Cross-sectional and longitudinal neuroimaging studies remain some of the few methods for assessing human brain function and play a pivotal role in the quest for understanding the neurobiology of schizophrenia as well as other psychiatric disorders. Parallel studies in non-psychotic siblings provide a unique opportunity to understand both risk and resilience in schizophrenia. PMID- 25819940 TI - Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma. AB - BACKGROUND: BRAF mutations occur in some melanomas. We hypothesized that BRAF mutation rates may differ in melanomas found in Asian compared to white populations. OBJECTIVE: We performed a metaanalysis of BRAF mutations and their associations with the clinicopathologic characteristics of primary melanoma (PM), with a subgroup analysis to compare Asian and white patients with PM. METHODS: The PubMed, EMBASE, and Cochrane databases were searched up to November 2013. The incidence rates and odds ratios (ORs) of BRAF mutations were calculated using a fixed or random effects model. RESULTS: BRAF mutation was associated with younger age (OR = 1.734; P < .001), trunk location (OR = 2.272; P < .001), non chronically sun damaged skin (OR = 2.833; P < .001), superficial spreading melanoma (OR = 2.081; P < .001), and advanced melanoma stage (OR = 1.551; P = .003). The incidence of BRAF mutations in Asian patients with PM was half that of white patients with PM, but it was linked to the same clinicopathologic characteristics. LIMITATIONS: Only a small number of studies have been conducted on Asian patients with PMs. CONCLUSIONS: The BRAF mutation in PM was associated with age, anatomic site based on ultraviolet radiation exposure, histologic subtype, and advanced stage of melanoma. The clinicopathologic associations with BRAF mutations were similar in Asian and white patients with PM. PMID- 25819941 TI - A clinical characteristic analysis of pregnancy-associated intracranial haemorrhage in China. AB - Intracerebral haemorrhage (ICH) occurring during pregnancy and the puerperium is an infrequent but severe complication with a high mortality and poor prognosis. Until recently, previous studies have mainly focused on the effect of different treatments on prognosis. However, few studies have provided solid evidence to clarify the key predisposing factors affecting the prognosis of ICH. In the present study, based on a unique sample with a high ICH incidence and mortality rate, we described the main clinical characteristics of ICH patients and found that the prognosis of patients who underwent surgical intervention was not better than that of patients who received other treatment modalities. However, pre eclampsia patients had higher maternal and neonatal mortality rates than other aetiology groups. Furthermore, univariate regression analysis identified onset to diagnosis time (O-D time) and pre-eclampsia as the only factors showing independent correlation with poor maternal outcomes (modified Rankin Scale, mRS >= 3), and only O-D time was identified as a predictor of maternal mortality. These results revealed that the aetiology of ICH and O-D time might be crucial predisposing factors to prognosis, especially for patients with pre-eclampsia. The study highlighted a novel direction to effectively improve the prognosis of pregnancy-associated ICH. PMID- 25819942 TI - Expression and purification of short hydrophobic elastin-like polypeptides with maltose-binding protein as a solubility tag. AB - Elastin-like polypeptides (ELPs) are biodegradable polymers with interesting physico-chemical properties for biomedical and biotechnological applications. The recombinant expression of hydrophobic elastin-like polypeptides is often difficult because they possess low transition temperatures, and therefore form aggregates at sub-ambient temperatures. To circumvent this difficulty, we expressed in Escherichia coli three hydrophobic ELPs (VPGIG)n with variable lengths (n=20, 40, and 60) in fusion with the maltose-binding protein (MBP). Fusion proteins were soluble and yields of purified MBP-ELP ranged between 66 and 127mg/L culture. After digestion of the fusion proteins by enterokinase, the ELP moiety was purified by using inverse transition cycling. The purified fraction containing ELP40 was slightly contaminated by traces of undigested fusion protein. Purification of ELP60 was impaired because of co-purification of the MBP tag during inverse transition cycling. ELP20 was successfully purified to homogeneity, as assessed by gel electrophoresis and mass spectrometry analyses. The transition temperature of ELP20 was measured at 15.4 degrees C in low salt buffer. In conclusion, this method can be used to produce hydrophobic ELP of low molecular mass. PMID- 25819943 TI - Newer antiepileptic drug use and other factors decreasing hospital encounters. AB - A retrospective analysis was conducted in one claims database and was confirmed in a second independent database (covering both commercial and government insurance plans between 11/2009 and 9/2011) for the understanding of factors influencing antiepileptic drug (AED) use and the role of AEDs and other health care factors in hospital encounters. In both datasets, epilepsy cases were identified by AED use and epilepsy diagnosis coding. Variables analyzed for effect on hospitalization rates were as follows: (1) use of first-generation AEDs or second-generation AEDs, (2) treatment changes, and (3) factors that may affect AED choice. Lower rates of epilepsy-related hospital encounters (encounters with an epilepsy diagnosis code) were associated with use of second-generation AEDs, deliberate treatment changes, and treatment by a neurologist. Epilepsy-related hospital encounters were more frequent for patients not receiving an AED and for those with greater comorbidities. On average, patients taking >=1 first generation AED experienced epilepsy-related hospitalizations every 684days, while those taking >=1second-generation AED were hospitalized every 1001days (relative risk reduction of 31%, p<0.01). Prescriptions for second-generation AEDs were more common among neurologists and among physicians near an epilepsy center. Use of second-generation AEDs, access to specialty care, and deliberate efforts to change medications following epilepsy-related hospital encounters improved outcomes of epilepsy treatment based on average time between epilepsy-related hospital encounters. These factors may be enhanced by public health policies, private insurance reimbursement policies, and education of patients and physicians. PMID- 25819944 TI - Single versus combinatorial therapies in status epilepticus: Novel data from preclinical models. AB - Drug-refractory status epilepticus (RSE) is a major medical emergency with a mortality of up to 40% and the risk of severe long-term consequences. The mechanisms involved in RSE are incompletely understood. Animal models are important in developing treatment strategies for more effective termination of SE and prevention of its long-term outcomes. The pilocarpine and lithium-pilocarpine rat models are widely used in this respect. In these models, resistance to diazepam and other antiseizure drugs (ASDs) develops during SE so that an SE that is longer than 30 min is difficult to suppress. Furthermore, because all ASDs used in SE treatment are much more rapidly eliminated by rodents than by humans, SE recurs several hours after ASD treatment. Long-term consequences include hippocampal damage, behavioral alterations, and epilepsy with spontaneous recurrent seizures. In this review, different rational polytherapies for SE, which are more effective than monotherapies, are discussed, including a novel polytherapy recently developed by our group. Based on data from diverse seizure models, we hypothesized that cholinergic mechanisms are involved in the mechanisms underlying ASD resistance of SE. We, therefore, developed an intravenous drug cocktail, consisting of diazepam, phenobarbital, and the anticholinergic scopolamine. This drug combination irreversibly terminated SE when administered 60, 90, or 120 min after SE onset. The efficacy of this cocktail in terminating SE was comparable with the previously reported efficacy of polytherapies with the glutamate receptor antagonist ketamine. Furthermore, when injected 60 min after SE onset, the scopolamine-containing cocktail prevented development of epilepsy and hippocampal neurodegeneration, which was not observed with high doses of diazepam or a combination of phenobarbital and diazepam. Our data add to the existing preclinical evidence that rational polytherapy can be more effective than monotherapy in the treatment of SE and that combinatorial therapy may offer a clinically useful option for the treatment of RSE. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25819945 TI - Beyond medical diagnosis: Factors contributing to life satisfaction of women with epilepsy in Israel. AB - This study was an exploratory study aimed to examine the contribution of both objective variables (such as education, occupational status, and leisure activity) and subjective variables (such as perceived disability, body image, and feminine self-image) to the life satisfaction of women with epilepsy in Israel. The study also sought to compare the findings with earlier studies of women with epilepsy or other disabilities in order to identify similar patterns in their life satisfaction. The study included 70 women, who had applied in the past to the Israel Epilepsy Association to obtain information and leisure activities. They were asked about their degree of life satisfaction in the context of their personal data including occupational status, leisure activity, perceived disability, body image, and feminine self-image. Findings indicated that higher education and perception of body image and femininity were positively correlated with higher life satisfaction. The regression model showed that perceived severity of disability and body image had the highest contribution to satisfaction with life, a fact that attests to the paramount importance of women's perception of their health disability in dealing with the disorder. These findings are discussed in relation to earlier comparative studies of those with/without epilepsy. The implications for practice suggest aspects that ought to be included in therapeutic interventions such as including contents related to feminine self-image and body image in the rehabilitation process as well as recommendations for future studies. PMID- 25819946 TI - Eyelid myoclonia seizures in adults: An alternate look at the syndrome paradox. AB - OBJECTIVES: Eyelid myoclonia (EM), without or with absences (EMA), is induced by eye closure (ECL)-associated generalized paroxysms of polyspikes and waves. Although considered as an epileptic syndrome, it has been listed as a type of seizure in the recent epilepsy classifications, perhaps because of its clinical heterogeneity. In this study, we aimed to specifically study the clinical and electroencephalogram (EEG) features and the prognosis of long-term followed-up adult patients with EMs and to determine common points between EMAs, idiopathic generalized epilepsies (IGEs), and symptomatic epilepsies. METHODS: Between 1996 and November 2011, 61 adult patients with EMs with or without absences and bilateral EEG paroxysms were retrospectively enrolled in the study and followed up for 1-34 years (mean: 5.8 years). RESULTS: According to patient history, seizure semiology, and EEG findings, we classified the patients having EM seizures into three main groups. In group 1 (n=31), all patients had prominent EMs with or without absences associated with upward rolling of eyeballs. The second group included 20 patients with EM seizures associated with generalized tonic-clonic seizures (GTCSs) and/or massive myoclonias. The third group of 7 patients had varying diagnosis of symptomatic epilepsies. In the first group with pure EMA, the diagnosis was more delayed than in the other groups (p=0.01). In the group with pure EMA, EMs continued in adulthood (p=0.00), and only 24% of patients were seizure-free, which was considered poor prognosis. On EEG, occipital (n=3) and frontal (n=4) focal discharges were found in the group with pure EMA. Interestingly, 2 patients with symptomatic epilepsy with frontal lesions also had EM seizures. CONCLUSION: The patients with pure EMA have many similarities to patients with IGEs. We also demonstrated that EMs could be seen as a seizure type in symptomatic epilepsies. Eyelid myoclonia with absences meets the criteria for an epileptic syndrome with the early onset and long duration of seizures, special seizure type, specific EEG findings, possibility of cognitive impairment, precipitating modalities, photosensitivity, and presence of family history, suggesting a strong genetic background. PMID- 25819947 TI - Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus. AB - We provide some evidence concerning the efficacy of perampanel (PER) in refractory status epilepticus (SE). We retroactively identified patients with SE treated in our department by searching for the term "status epilepticus" in the electronic archive of medical records. We present and analyze in this paper the subset of data of the patients treated with PER. We analyzed ten episodes of SE in nine patients. At the first administration, PER was given in a dosage of 6mg to most of our patients (7 of 10). On average, PER was administered as the 6th antiepileptic drug (AED) (range: 2-10). Depending on the criterion for efficacy, PER appears effective for the termination of SE in 2 to 6 (of 10) episodes. Unfortunately, safety data for the administration of PER with loading doses needed for the treatment of SE are lacking. Because of this, PER should be used very carefully in refractory SE and only after first-line treatment options have failed. PMID- 25819948 TI - Economic evaluation of a behavior-modifying intervention to enhance antiepileptic drug adherence. AB - Between 35% and 50% of patients with epilepsy are reported to be not fully adherent to their medication schedule. We aimed to conduct an economic evaluation of strategies for improving adherence to antiepileptic drugs. Based on the findings of a systematic review, we identified an implementation intention intervention (specifying when, where, and how to act) which was tested in a trial that closely resembled current clinical management of patients with epilepsy and which measured adherence with an objective and least biased method. Using patient level data, trial patients were matched with those recruited for the Standard and New Antiepileptic Drugs trial according to their clinical characteristics and adherence. Generalized linear models were used to adjust cost and utility in order to estimate the incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the National Health Service in the UK. The mean cost of the intervention group, L1340 (95% CI: L1132, L1688), was marginally lower than that of the control group representing standard care, L1352 (95% CI: L1132, L1727). Quality-adjusted life-year values in the intervention group were higher than those in the control group, i.e., 0.75 (95% CI: 0.70, 0.79) compared with 0.74 (95% CI: 0.68, 0.79), resulting in a cost saving of L12 (?15, US$19) and with the intervention being dominant. The probability that the intervention is cost-effective at a threshold of L20,000 per QALY is 94%. Our analysis lends support to the cost-effectiveness of a self-directed, implementation intention intervention for improving adherence to antiepileptic drugs. However, as with any modeling dependent on limited data on efficacy, there is considerable uncertainty surrounding the clinical effectiveness of the intervention which would require a substantive trial for a more definitive conclusion. PMID- 25819949 TI - Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation. AB - PURPOSE: The primary efficacy and safety measures from a trial of responsive neurostimulation for focal epilepsy were previously published. In this report, the findings from the same study are presented for quality of life, which was a supportive analysis, and for mood, which was assessed as a secondary safety endpoint. METHODS: The study was a multicenter randomized controlled double blinded trial of responsive neurostimulation in 191 patients with medically resistant focal epilepsy. During a 4-month postimplant blinded period, patients were randomized to receive responsive stimulation or sham stimulation, after which all patients received responsive neurostimulation in open label to complete 2years. Quality of life (QOL) and mood surveys were administered during the baseline period, at the end of the blinded period, and at year 1 and year 2 of the open label period. RESULTS: The treatment and sham groups did not differ at baseline. Compared with baseline, QOL improved in both groups at the end of the blinded period and also at 1year and 2years, when all patients were treated. At 2years, 44% of patients reported meaningful improvements in QOL, and 16% reported declines. There were no overall adverse changes in mood or in suicidality across the study. Findings were not related to changes in seizures and antiepileptic drugs, and patients with mesial temporal seizure onsets and those with neocortical seizure onsets both experienced improvements in QOL. CONCLUSIONS: Treatment with targeted responsive neurostimulation does not adversely affect QOL or mood and may be associated with improvements in QOL in patients, including those with seizures of either mesial temporal origin or neocortical origin. PMID- 25819950 TI - Classical neurotransmitters and neuropeptides involved in generalized epilepsy in a multi-neurotransmitter system: How to improve the antiepileptic effect? AB - Here, we describe in generalized epilepsies the alterations of classical neurotransmitters and neuropeptides acting at specific subreceptors. In order to consider a network context rather than one based on focal substrates and in order to make the interaction between neurotransmitters and neuropeptides and their specific subreceptors comprehensible, neural networks in the hippocampus, thalamus, and cerebral cortex are described. In this disease, a neurotransmitter imbalance between dopaminergic and serotonergic neurons and between presynaptic GABAergic neurons (hypoactivity) and glutaminergic neurons (hyperactivity) occurs. Consequently, combined GABAA agonists and NMDA antagonists could furthermore stabilize the neural networks in a multimodal pharmacotherapy. The antiepileptic effect and the mechanisms of action of conventional and recently developed antiepileptic drugs are reviewed. The GASH:Sal animal model can contribute to examine the efficacy of antiepileptic drugs. The issues of whether the interaction of classical neurotransmitters with other subreceptors (5-HT7, metabotropic 5 glutaminergic, A2A adenosine, and alpha nicotinic 7 cholinergic receptors) or whether the administration of agonists/antagonists of neuropeptides might improve the therapeutic effect of antiepileptic drugs should be addressed. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 25819951 TI - Risk of cardiovascular abnormalities in relatives of SUDEP victims: How should we proceed? PMID- 25819952 TI - Molecular and functional studies of retinal degeneration as a clinical presentation of SACS-related disorder. AB - BACKGROUND: ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. METHODS: We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. RESULTS: A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. CONCLUSIONS: Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype. PMID- 25819953 TI - A MarR Family Transcriptional Regulator, DptR3, Activates Daptomycin Biosynthesis and Morphological Differentiation in Streptomyces roseosporus. AB - Daptomycin produced by Streptomyces roseosporus is an important lipopeptide antibiotic used to treat human infections caused by Gram-positive pathogenic bacteria, including drug-resistant strains. The genetic basis for regulatory mechanisms of daptomycin production is poorly known. Here, we characterized the dptR3 gene, which encodes a MarR family transcriptional regulator located adjacent to the known daptomycin biosynthetic (dpt) genes. Deletion of dptR3 reduced daptomycin production significantly and delayed aerial mycelium formation and sporulation on solid media. Dissection of the mechanism underlying the function of DptR3 in daptomycin production revealed that it stimulates daptomycin production indirectly by altering the transcription of dpt structural genes. DptR3 directly activated the transcription of its own gene, dptR3, but repressed the transcription of the adjacent, divergent gene orf16 (which encodes a putative ABC transporter ATP-binding protein). A 66-nucleotide DptR3-binding site in the intergenic region of dptR3-orf16 was determined by DNase I footprinting, and the palindromic sequence TCATTGTTACCTATGCTCACAATGA (underlining indicates inverted repeats) in the protected region was found to be essential for DptR3 binding. orf16, the major target gene of DptR3, exerted a positive effect on daptomycin biosynthesis. Our findings indicate that DptR3 functions as a global regulator that positively controls daptomycin production and morphological development in S. roseosporus. PMID- 25819954 TI - Immunogenicity in Swine of Orally Administered Recombinant Lactobacillus plantarum Expressing Classical Swine Fever Virus E2 Protein in Conjunction with Thymosin alpha-1 as an Adjuvant. AB - Classical swine fever, caused by classical swine fever virus (CSFV), is a highly contagious disease that results in enormous economic losses in pig industries. The E2 protein is one of the main structural proteins of CSFV and is capable of inducing CSFV-neutralizing antibodies and cytotoxic T lymphocyte (CTL) activities in vivo. Thymosin alpha-1 (Talpha1), an immune-modifier peptide, plays a very important role in the cellular immune response. In this study, genetically engineered Lactobacillus plantarum bacteria expressing CSFV E2 protein alone (L. plantarum/pYG-E2) and in combination with Talpha1 (L. plantarum/pYG-E2-Talpha1) were developed, and the immunogenicity of each as an oral vaccine to induce protective immunity against CSFV in pigs was evaluated. The results showed that recombinant L. plantarum/pYG-E2 and L. plantarum/pYG-E2-Talpha1 were both able to effectively induce protective immune responses in pigs against CSFV infection by eliciting immunoglobulin A (IgA)-based mucosal, immunoglobulin G (IgG)-based humoral, and CTL-based cellular immune responses via oral vaccination. Significant differences (P < 0.05) in the levels of immune responses were observed between L. plantarum/pYG-E2-Talpha1 and L. plantarum/pYG-E2, suggesting a better immunogenicity of L. plantarum/pYG-E2-Talpha1 as a result of the Talpha1 molecular adjuvant that can enhance immune responsiveness and augment specific lymphocyte functions. Our data suggest that the recombinant Lactobacillus microecological agent expressing CSFV E2 protein combined with Talpha1 as an adjuvant provides a promising strategy for vaccine development against CSFV. PMID- 25819955 TI - Diversity of Shiga Toxin-Producing Escherichia coli (STEC) O26:H11 Strains Examined via stx Subtypes and Insertion Sites of Stx and EspK Bacteriophages. AB - Shiga toxin-producing Escherichia coli (STEC) is a food-borne pathogen that may be responsible for severe human infections. Only a limited number of serotypes, including O26:H11, are involved in the majority of serious cases and outbreaks. The main virulence factors, Shiga toxins (Stx), are encoded by bacteriophages. Seventy-four STEC O26:H11 strains of various origins (including human, dairy, and cattle) were characterized for their stx subtypes and Stx phage chromosomal insertion sites. The majority of food and cattle strains possessed the stx(1a) subtype, while human strains carried mainly stx(1a) or stx(2a). The wrbA and yehV genes were the main Stx phage insertion sites in STEC O26:H11, followed distantly by yecE and sbcB. Interestingly, the occurrence of Stx phages inserted in the yecE gene was low in dairy strains. In most of the 29 stx-negative E. coli O26:H11 strains also studied here, these bacterial insertion sites were vacant. Multilocus sequence typing of 20 stx-positive or stx-negative E. coli O26:H11 strains showed that they were distributed into two phylogenetic groups defined by sequence type 21 (ST21) and ST29. Finally, an EspK-carrying phage was found inserted in the ssrA gene in the majority of the STEC O26:H11 strains but in only a minority of the stx-negative E. coli O26:H11 strains. The differences in the stx subtypes and Stx phage insertion sites observed in STEC O26:H11 according to their origin might reflect that strains circulating in cattle and foods are clonally distinct from those isolated from human patients. PMID- 25819956 TI - The RpoE Stress Response Pathway Mediates Reduction of the Virulence of Enteropathogenic Escherichia coli by Zinc. AB - Zinc supplements are an effective clinical treatment for infantile diarrheal disease caused by enteric pathogens. Previous studies demonstrated that zinc acts on enteropathogenic Escherichia coli (EPEC) bacteria directly to suppress several virulence-related genes at a concentration that can be achieved by oral delivery of dietary zinc supplements. Our in vitro studies showed that a micromolar concentration of zinc induced the envelope stress response and suppressed virulence in EPEC, providing a possible mechanistic explanation for zinc's therapeutic action. In this report, we investigated the molecular and physiological changes in EPEC induced by zinc. We found that micromolar concentrations of zinc reduced the bacterial growth rate without affecting viability. We observed increased membrane permeability caused by zinc. Zinc upregulated the RpoE-dependent envelope stress response pathway and suppressed EPEC virulence gene expression. RpoE alone was sufficient to inhibit virulence factor expression and to attenuate attaching and effacing lesion formation on human host cells. By mutational analysis we demonstrate that the DNA-binding motif of RpoE is necessary for suppression of the LEE1, but not the LEE4, operon. Predictably, inhibition of the RpoE-mediated envelope stress response in combination with micromolar concentrations of zinc reduced EPEC viability. In conclusion, zinc induces the RpoE and stress response pathways in EPEC, and the alternate sigma factor RpoE downregulates EPEC LEE and non-LEE virulence genes by multiple mechanisms. PMID- 25819957 TI - Identification of anthraquinone-degrading bacteria in soil contaminated with polycyclic aromatic hydrocarbons. AB - Quinones and other oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are toxic and/or genotoxic compounds observed to be cocontaminants at PAH contaminated sites, but their formation and fate in contaminated environmental systems have not been well studied. Anthracene-9,10-dione (anthraquinone) has been found in most PAH-contaminated soils and sediments that have been analyzed for oxy-PAHs. However, little is known about the biodegradation of oxy-PAHs, and no bacterial isolates have been described that are capable of growing on or degrading anthraquinone. PAH-degrading Mycobacterium spp. are the only organisms that have been investigated to date for metabolism of a PAH quinone, 4,5 pyrenequinone. We utilized DNA-based stable-isotope probing (SIP) with [U (13)C]anthraquinone to identify bacteria associated with anthraquinone degradation in PAH-contaminated soil from a former manufactured-gas plant site both before and after treatment in a laboratory-scale bioreactor. SIP with [U (13)C]anthracene was also performed to assess whether bacteria capable of growing on anthracene are the same as those identified to grow on anthraquinone. Organisms closely related to Sphingomonas were the most predominant among the organisms associated with anthraquinone degradation in bioreactor-treated soil, while organisms in the genus Phenylobacterium comprised the majority of anthraquinone degraders in the untreated soil. Bacteria associated with anthracene degradation differed from those responsible for anthraquinone degradation. These results suggest that Sphingomonas and Phenylobacterium species are associated with anthraquinone degradation and that anthracene-degrading organisms may not possess mechanisms to grow on anthraquinone. PMID- 25819958 TI - Genome Sequence and Transcriptome Analysis of Meat-Spoilage-Associated Lactic Acid Bacterium Lactococcus piscium MKFS47. AB - Lactococcus piscium is a psychrotrophic lactic acid bacterium and is known to be one of the predominant species within spoilage microbial communities in cold stored packaged foods, particularly in meat products. Its presence in such products has been associated with the formation of buttery and sour off-odors. Nevertheless, the spoilage potential of L. piscium varies dramatically depending on the strain and growth conditions. Additional knowledge about the genome is required to explain such variation, understand its phylogeny, and study gene functions. Here, we present the complete and annotated genomic sequence of L. piscium MKFS47, combined with a time course analysis of the glucose catabolism based transcriptome. In addition, a comparative analysis of gene contents was done for L. piscium MKFS47 and 29 other lactococci, revealing three distinct clades within the genus. The genome of L. piscium MKFS47 consists of one chromosome, carrying 2,289 genes, and two plasmids. A wide range of carbohydrates was predicted to be fermented, and growth on glycerol was observed. Both carbohydrate and glycerol catabolic pathways were significantly upregulated in the course of time as a result of glucose exhaustion. At the same time, differential expression of the pyruvate utilization pathways, implicated in the formation of spoilage substances, switched the metabolism toward a heterofermentative mode. In agreement with data from previous inoculation studies, L. piscium MKFS47 was identified as an efficient producer of buttery odor compounds under aerobic conditions. Finally, genes and pathways that may contribute to increased survival in meat environments were considered. PMID- 25819959 TI - Latex Clearing Protein (Lcp) of Streptomyces sp. Strain K30 Is a b-Type Cytochrome and Differs from Rubber Oxygenase A (RoxA) in Its Biophysical Properties. AB - Specific polyisoprene-cleaving activities of 1.5 U/mg and 4.6 U/mg were determined for purified Strep-tagged latex clearing protein (Lcp) of Streptomyces sp. strain K30 at 23 degrees C and 37 degrees C, respectively. Metal analysis revealed the presence of approximately one atom of iron per Lcp molecule. Copper, which had been identified in Lcp1VH2 of Gordonia polyisoprenivorans previously, was below the detection limit in LcpK30. Heme was identified as a cofactor in purified LcpK30 by (i) detection of characteristic alpha-, beta-, and gamma (Soret)-bands at 562 nm, 532 nm, and 430 nm in the visible spectrum after chemical reduction, (ii) detection of an acetone-extractable porphyrin molecule, (iii) determination of a heme b-type-specific absorption maximum (556 nm) after chemical conversion of the heme group to a bipyridyl-heme complex, and (iv) detection of a b-heme-specific m/z value of 616.2 via mass spectrometry. Spectroscopic analysis showed that purified Lcp as isolated contains an oxidized heme-Fe(3+) that is free of bound dioxygen. This is in contrast to the rubber oxygenase RoxA, a c-type heme-containing polyisoprene-cleaving enzyme present in Gram-negative rubber degraders, in which the covalently bound heme firmly binds a dioxygen molecule. LcpK30 also differed from RoxA in the lengths of the rubber degradation cleavage products and in having a higher melting point of 61.5 degrees C (RoxA, 54.3 degrees C). In summary, RoxA and Lcp both are equipped with a heme cofactor and catalyze an oxidative C-C cleavage reaction but differ in the heme subgroup type and in several biochemical and biophysical properties. These findings suggest differences in the catalytic reaction mechanisms. PMID- 25819960 TI - Polyphenolic extract from maple syrup potentiates antibiotic susceptibility and reduces biofilm formation of pathogenic bacteria. AB - Phenolic compounds are believed to be promising candidates as complementary therapeutics. Maple syrup, prepared by concentrating the sap from the North American maple tree, is a rich source of natural and process-derived phenolic compounds. In this work, we report the antimicrobial activity of a phenolic-rich maple syrup extract (PRMSE). PRMSE exhibited antimicrobial activity as well as strong synergistic interaction with selected antibiotics against Gram-negative clinical strains of Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa. Among the phenolic constituents of PRMSE, catechol exhibited strong synergy with antibiotics as well as with other phenolic components of PRMSE against bacterial growth. At sublethal concentrations, PRMSE and catechol efficiently reduced biofilm formation and increased the susceptibility of bacterial biofilms to antibiotics. In an effort to elucidate the mechanism for the observed synergy with antibiotics, PRMSE was found to increase outer membrane permeability of all bacterial strains and effectively inhibit efflux pump activity. Furthermore, transcriptome analysis revealed that PRMSE significantly repressed multiple-drug resistance genes as well as genes associated with motility, adhesion, biofilm formation, and virulence. Overall, this study provides a proof of concept and starting point for investigating the molecular mechanism of the reported increase in bacterial antibiotic susceptibility in the presence of PRMSE. PMID- 25819961 TI - Infection Density Dynamics of the Citrus Greening Bacterium "Candidatus Liberibacter asiaticus" in Field Populations of the Psyllid Diaphorina citri and Its Relevance to the Efficiency of Pathogen Transmission to Citrus Plants. AB - Huanglongbing, or citrus greening, is a devastating disease of citrus plants recently spreading worldwide, which is caused by an uncultivable bacterial pathogen, "Candidatus Liberibacter asiaticus," and vectored by a phloem-sucking insect, Diaphorina citri. We investigated the infection density dynamics of "Ca. Liberibacter asiaticus" in field populations of D. citri with experiments using field-collected insects to address how "Ca. Liberibacter asiaticus" infection density in the vector insect is relevant to pathogen transmission to citrus plants. Of 500 insects continuously collected from "Ca. Liberibacter asiaticus" infected citrus trees with pathological symptoms in the spring and autumn of 2009, 497 (99.4%) were "Ca. Liberibacter asiaticus" positive. The infections were systemic across head-thorax and abdomen, ranging from 10(3) to 10(7) bacteria per insect. In spring, the infection densities were low in March, at ~ 10(3) bacteria per insect, increasing up to 10(6) to 10(7) bacteria per insect in April and May, and decreasing to 10(5) to 10(6) bacteria per insect in late May, whereas the infection densities were constantly ~ 10(6) to 10(7) bacteria per insect in autumn. Statistical analysis suggested that several factors, such as insect sex, host trees, and collection dates, may be correlated with "Ca. Liberibacter asiaticus" infection densities in field D. citri populations. Inoculation experiments with citrus seedlings using field-collected "Ca. Liberibacter asiaticus"-infected insects suggested that (i) "Ca. Liberibacter asiaticus" transmitting insects tend to exhibit higher infection densities than do nontransmitting insects, (ii) a threshold level (~ 10(6) bacteria per insect) of "Ca. Liberibacter asiaticus" density in D. citri is required for successful transmission to citrus plants, and (iii) D. citri attaining the threshold infection level transmits "Ca. Liberibacter asiaticus" to citrus plants in a stochastic manner. These findings provide valuable insights into understanding, predicting, and controlling this notorious citrus pathogen. PMID- 25819962 TI - Lincomycin at Subinhibitory Concentrations Potentiates Secondary Metabolite Production by Streptomyces spp. AB - Antibiotics have either bactericidal or bacteriostatic activity. However, they also induce considerable gene expression in bacteria when used at subinhibitory concentrations (below the MIC). We found that lincomycin, which inhibits protein synthesis by binding to the ribosomes of Gram-positive bacteria, was effective for inducing the expression of genes involved in secondary metabolism in Streptomyces strains when added to medium at subinhibitory concentrations. In Streptomyces coelicolor A3(2), lincomycin at 1/10 of its MIC markedly increased the expression of the pathway-specific regulatory gene actII-ORF4 in the blue pigmented antibiotic actinorhodin (ACT) biosynthetic gene cluster, which resulted in ACT overproduction. Intriguingly, S. lividans 1326 grown in the presence of lincomycin at a subinhibitory concentration (1/12 or 1/3 of its MIC) produced abundant antibacterial compounds that were not detected in cells grown in lincomycin-free medium. Bioassay and mass spectrometry analysis revealed that some antibacterial compounds were novel congeners of calcium-dependent antibiotics. Our results indicate that lincomycin at subinhibitory concentrations potentiates the production of secondary metabolites in Streptomyces strains and suggest that activating these strains by utilizing the dose-response effects of lincomycin could be used to effectively induce the production of cryptic secondary metabolites. In addition to these findings, we also report that lincomycin used at concentrations for markedly increased ACT production resulted in alteration of the cytoplasmic protein (FoF1 ATP synthase alpha and beta subunits, etc.) profile and increased intracellular ATP levels. A fundamental mechanism for these unique phenomena is also discussed. PMID- 25819963 TI - Mutational Analysis of the Antitoxin in the Lactococcal Type III Toxin-Antitoxin System AbiQ. AB - The lactococcal abortive phage infection mechanism AbiQ recently was classified as a type III toxin-antitoxin system in which the toxic protein (ABIQ) is regulated following cleavage of its repeated noncoding RNA antitoxin (antiQ). In this study, we investigated the role of the antitoxin in antiphage activity. The cleavage of antiQ by ABIQ was characterized using 5' rapid amplification of cDNA ends PCR and was located in an adenine-rich region of antiQ. We next generated a series of derivatives with point mutations within antiQ or with various numbers of antiQ repetitions. These modifications were analyzed for their effect on the antiphage activity (efficiency of plaquing) and on the endoribonuclease activity (Northern hybridization). We observed that increasing or reducing the number of antiQ repeats significantly decreased the antiphage activity of the system. Several point mutations had a similar effect on the antiphage activity and were associated with changes in the digestion profile of antiQ. Interestingly, a point mutation in the putative pseudoknot structure of antiQ mutants led to an increased AbiQ antiphage activity, thereby offering a novel way to increase the activity of an abortive infection mechanism. PMID- 25819964 TI - Amphibian Symbiotic Bacteria Do Not Show a Universal Ability To Inhibit Growth of the Global Panzootic Lineage of Batrachochytrium dendrobatidis. AB - Microbiomes associated with multicellular organisms influence the disease susceptibility of hosts. The potential exists for such bacteria to protect wildlife from infectious diseases, particularly in the case of the globally distributed and highly virulent fungal pathogen Batrachochytrium dendrobatidis of the global panzootic lineage (B. dendrobatidis GPL), responsible for mass extinctions and population declines of amphibians. B. dendrobatidis GPL exhibits wide genotypic and virulence variation, and the ability of candidate probiotics to restrict growth across B. dendrobatidis isolates has not previously been considered. Here we show that only a small proportion of candidate probiotics exhibited broad-spectrum inhibition across B. dendrobatidis GPL isolates. Moreover, some bacterial genera showed significantly greater inhibition than others, but overall, genus and species were not particularly reliable predictors of inhibitory capabilities. These findings indicate that bacterial consortia are likely to offer a more stable and effective approach to probiotics, particularly if related bacteria are selected from genera with greater antimicrobial capabilities. Together these results highlight a complex interaction between pathogens and host-associated symbiotic bacteria that will require consideration in the development of bacterial probiotics for wildlife conservation. Future efforts to construct protective microbiomes should incorporate bacteria that exhibit broad-spectrum inhibition of B. dendrobatidis GPL isolates. PMID- 25819966 TI - Electrical stimulation improves microbial salinity resistance and organofluorine removal in bioelectrochemical systems. AB - Fed batch bioelectrochemical systems (BESs) based on electrical stimulation were used to treat p-fluoronitrobenzene (p-FNB) wastewater at high salinities. At a NaCl concentration of 40 g/liter, p-FNB was removed 100% in 96 h in the BES, whereas in the biotic control (BC) (absence of current), p-FNB removal was only 10%. By increasing NaCl concentrations from 0 g/liter to 40 g/liter, defluorination efficiency decreased around 40% in the BES, and in the BC it was completely ceased. p-FNB was mineralized by 30% in the BES and hardly in the BC. Microorganisms were able to store 3.8 and 0.7 times more K(+) and Na(+) intracellularly in the BES than in the BC. Following the same trend, the ratio of protein to soluble polysaccharide increased from 3.1 to 7.8 as the NaCl increased from 0 to 40 g/liter. Both trends raise speculation that an electrical stimulation drives microbial preference toward K(+) and protein accumulation to tolerate salinity. These findings are in accordance with an enrichment of halophilic organisms in the BES. Halobacterium dominated in the BES by 56.8% at a NaCl concentration of 40 g/liter, while its abundance was found as low as 17.5% in the BC. These findings propose a new method of electrical stimulation to improve microbial salinity resistance. PMID- 25819965 TI - Comparison of the Prevalences and Diversities of Listeria Species and Listeria monocytogenes in an Urban and a Rural Agricultural Watershed. AB - Foods and related processing environments are commonly contaminated with the pathogenic Listeria monocytogenes. To investigate potential environmental reservoirs of Listeria spp. and L. monocytogenes, surface water and point source pollution samples from an urban and a rural municipal water supply watershed in Nova Scotia, Canada, were examined over 18 months. Presumptive Listeria spp. were cultured from 72 and 35% of rural and urban water samples, respectively, with 24% of the positive samples containing two or three different Listeria spp. The L. innocua (56%) and L. welshimeri (43%) groups were predominant in the rural and urban watersheds, respectively. Analysis by the TaqMan assay showed a significantly (P < 0.05) higher prevalence of L. monocytogenes of 62% versus 17% by the culture-based method. Both methods revealed higher prevalences in the rural watershed and during the fall and winter seasons. Elevated Escherichia coli (>= 100 CFU/100 ml) levels were not associated with the pathogen regardless of the detection method. Isolation of Listeria spp. were associated with 70 times higher odds of isolating L. monocytogenes (odds ratio = 70; P < 0.001). Serogroup IIa was predominant (67.7%) among the 285 L. monocytogenes isolates, followed by IVb (16.1%), IIb (15.8%), and IIc (0.4%). L. monocytogenes was detected in cow feces and raw sewage but not in septic tank samples. Pulsotyping of representative water (n = 54) and local human (n = 19) isolates suggested genetic similarities among some environmental and human L. monocytogenes isolates. In conclusion, temperate surface waters contain a diverse Listeria species population and could be a potential reservoir for L. monocytogenes, especially in rural agricultural watersheds. PMID- 25819967 TI - An L-Fucose Operon in the Probiotic Lactobacillus rhamnosus GG Is Involved in Adaptation to Gastrointestinal Conditions. AB - L-Fucose is a sugar present in human secretions as part of human milk oligosaccharides, mucins, and other glycoconjugates in the intestinal epithelium. The genome of the probiotic Lactobacillus rhamnosus GG (LGG) carries a gene cluster encoding a putative L-fucose permease (fucP), L-fucose catabolic pathway (fucI, fucK, fucU, and fucA), and a transcriptional regulator (fucR). The metabolism of L-fucose in LGG results in 1,2-propanediol production, and their fucI and fucP mutants displayed a severe and mild growth defect on L-fucose, respectively. Transcriptional analysis revealed that the fuc genes are induced by L-fucose and subject to a strong carbon catabolite repression effect. This induction was triggered by FucR, which acted as a transcriptional activator necessary for growth on L-fucose. LGG utilized fucosyl-alpha1,3-N acetylglucosamine and contrarily to other lactobacilli, the presence of fuc genes allowed this strain to use the L-fucose moiety. In fucI and fucR mutants, but not in fucP mutant, L-fucose was not metabolized and it was excreted to the medium during growth on fucosyl-alpha1,3-N-acetylglucosamine. The fuc genes were induced by this fucosyl-disaccharide in the wild type and the fucP mutant but not in a fucI mutant, showing that FucP does not participate in the regulation of fuc genes and that L-fucose metabolism is needed for FucR activation. The l-fucose operon characterized here constitutes a new example of the many factors found in LGG that allow this strain to adapt to the gastrointestinal conditions. PMID- 25819968 TI - "Quorum Non-Sensing": Social Cheating and Deception in Vibrio cholerae. AB - Quorum sensing (QS) is widely used by bacteria to coordinate behavior in response to external stimuli. In Vibrio cholerae, this process is important for environmental survival and pathogenesis, though, intriguingly, a large percentage of natural isolates are QS deficient. Here, we show that QS-deficient mutants can spread as social cheaters by ceasing production of extracellular proteases under conditions requiring their growth. We further show that mutants stimulate biofilm formation and are over-represented in biofilms compared to planktonic communities; on this basis, we suggest that QS-deficient mutants may have the side effect of enhancing environmental tolerance of natural populations due to the inherent resistance properties of biofilms. Interestingly, high frequencies of QS-deficient individuals did not impact production of QS signaling molecules despite mutants being unable to respond to these inducers, indicating that these variants actively cheat by false signaling under conditions requiring QS. Taken together, our results suggest that social cheating may drive QS deficiency emergence within V. cholerae natural populations. PMID- 25819969 TI - Evaluation of Molecular Methods To Improve the Detection of Burkholderia pseudomallei in Soil and Water Samples from Laos. AB - Burkholderia pseudomallei is the cause of melioidosis, a severe and potentially fatal disease of humans and animals. It is endemic in northern Australia and Southeast Asia and is found in soil and surface water. The environmental distribution of B. pseudomallei worldwide and within countries where it is endemic, such as the Lao People's Democratic Republic (Laos), remains unclear. However, this knowledge is important to our understanding of the ecology and epidemiology of B. pseudomallei and to facilitate public health interventions. Sensitive and specific methods to detect B. pseudomallei in environmental samples are therefore needed. The aim of this study was to compare molecular and culture based methods for the detection of B. pseudomallei in soil and surface water in order to identify the optimal approach for future environmental studies in Laos. Molecular detection by quantitative real-time PCR (qPCR) was attempted after DNA extraction directly from soil or water samples or after an overnight enrichment step. The positivity rates obtained by qPCR were compared to those obtained by different culture techniques. The rate of detection from soil samples by qPCR following culture enrichment was significantly higher (84/100) than that by individual culture methods and all culture methods combined (44/100; P < 0.001). Similarly, qPCR following enrichment was the most sensitive method for filtered river water compared with the sensitivity of the individual methods and all individual methods combined. In conclusion, molecular detection following an enrichment step has proven to be a sensitive and reliable approach for B. pseudomallei detection in Lao environmental samples and is recommended as the preferred method for future surveys. PMID- 25819970 TI - Carbon source preference in chemosynthetic hot spring communities. AB - Rates of dissolved inorganic carbon (DIC), formate, and acetate mineralization and/or assimilation were determined in 13 high-temperature (>73 degrees C) hot springs in Yellowstone National Park (YNP), Wyoming, in order to evaluate the relative importance of these substrates in supporting microbial metabolism. While 9 of the hot spring communities exhibited rates of DIC assimilation that were greater than those of formate and acetate assimilation, 2 exhibited rates of formate and/or acetate assimilation that exceeded those of DIC assimilation. Overall rates of DIC, formate, and acetate mineralization and assimilation were positively correlated with spring pH but showed little correlation with temperature. Communities sampled from hot springs with similar geochemistries generally exhibited similar rates of substrate transformation, as well as similar community compositions, as revealed by 16S rRNA gene-tagged sequencing. Amendment of microcosms with small (micromolar) amounts of formate suppressed DIC assimilation in short-term (<45-min) incubations, despite the presence of native DIC concentrations that exceeded those of added formate by 2 to 3 orders of magnitude. The concentration of added formate required to suppress DIC assimilation was similar to the affinity constant (K(m)) for formate transformation, as determined by community kinetic assays. These results suggest that dominant chemoautotrophs in high-temperature communities are facultatively autotrophic or mixotrophic, are adapted to fluctuating nutrient availabilities, and are capable of taking advantage of energy-rich organic substrates when they become available. PMID- 25819971 TI - The N-Terminal GH10 Domain of a Multimodular Protein from Caldicellulosiruptor bescii Is a Versatile Xylanase/beta-Glucanase That Can Degrade Crystalline Cellulose. AB - The genome of the thermophilic bacterium Caldicellulosiruptor bescii encodes three multimodular enzymes with identical C-terminal domain organizations containing two consecutive CBM3b modules and one glycoside hydrolase (GH) family 48 (GH48) catalytic module. However, the three proteins differ much in their N termini. Among these proteins, CelA (or C. bescii Cel9A [CbCel9A]/Cel48A) with a GH9/CBM3c binary partner in the N terminus has been shown to use a novel strategy to degrade crystalline cellulose, which leads to its outstanding cellulose cleaving activity. Here we show that C. bescii Xyn10C (CbXyn10C), the N-terminal GH10 domain from CbXyn10C/Cel48B, can also degrade crystalline cellulose, in addition to heterogeneous xylans and barley beta-glucan. The data from substrate competition assays, mutational studies, molecular modeling, and docking point analyses point to the existence of only one catalytic center in the bifunctional xylanase/beta-glucanase. The specific activities of the recombinant CbXyn10C on Avicel and filter paper were comparable to those of GH9/CBM3c of the robust CelA expressed in Escherichia coli. Appending one or two cellulose-binding CBM3bs enhanced the activities of CbXyn10C in degrading crystalline celluloses, which were again comparable to those of the GH9/CBM3c-CBM3b-CBM3b truncation mutant of CelA. Since CbXyn10C/Cel48B and CelA have similar domain organizations and high sequence homology, the endocellulase activity observed in CbXyn10C leads us to speculate that CbXyn10C/Cel48B may use the same strategy that CelA uses to hydrolyze crystalline cellulose, thus helping the excellent crystalline cellulose degrader C. bescii acquire energy from the environment. In addition, we also demonstrate that CbXyn10C may be an interesting candidate enzyme for biotechnology due to its versatility in hydrolyzing multiple substrates with different glycosidic linkages. PMID- 25819972 TI - Alamethicin suppresses methanogenesis and promotes acetogenesis in bioelectrochemical systems. AB - Microbial electrosynthesis (MES) systems with mixed cultures often generate a variety of gaseous and soluble chemicals. Methane is the primary end product in mixed-culture MES because it is the thermodynamically most favorable reduction product of CO2. Here, we show that the peptaibol alamethicin selectively suppressed the growth of methanogens in mixed-culture MES systems, resulting in a shift of the solution and cathode communities to an acetate-producing system dominated by Sporomusa, a known acetogenic genus in MES systems. Archaea in the methane-producing control were dominated by Methanobrevibacter species, but no Archaea were detected in the alamethicin-treated reactors. No methane was detected in the mixed-culture reactors treated with alamethicin over 10 cycles (~ 3 days each). Instead, acetate was produced at an average rate of 115 nmol ml(-1) day(-1), similar to the rate reported previously for pure cultures of Sporomusa ovata on biocathodes. Mixed-culture control reactors without alamethicin generated methane at nearly 100% coulombic recovery, and no acetate was detected. These results show that alamethicin is effective for the suppression of methanogen growth in MES systems and that its use enables the production of industrially relevant organic compounds by the inhibition of methanogenesis. PMID- 25819973 TI - Vernalophrys algivore gen. nov., sp. nov. (Rhizaria: Cercozoa: Vampyrellida), a New Algal Predator Isolated from Outdoor Mass Culture of Scenedesmus dimorphus. AB - Microbial contamination is the main cause of loss of biomass yield in microalgal cultures, especially under outdoor environmental conditions. Little is known about the identities of microbial contaminants in outdoor mass algal cultures. In this study, a new genus and species of vampyrellid amoeba, Vernalophrys algivore, is described from cultures of Scenedesmus dimorphus in open raceway ponds and outdoor flat-panel photobioreactors. This vampyrellid amoeba was a significant grazer of Scenedesmus and was frequently associated with a very rapid decline in algal numbers. We report on the morphology, subcellular structure, feeding behavior, molecular phylogeny, and life cycle. The new amoeba resembles Leptophrys in the shape of trophozoites and pseudopodia and in the mechanism of feeding (mainly by engulfment). It possesses two distinctive regions in helix E10_1 (nucleotides 117 to 119, CAA) and E23_1 (nucleotides 522 and 523, AG) of the 18S rRNA gene. It did not form a monophyletic group with Leptophrys in molecular phylogenetic trees. We establish a new genus, Vernalophrys, with the type species Vernalophrys algivore. The occurrence, impact of the amoeba on mass culture of S. dimorphus, and means to reduce vampyrellid amoeba contamination in Scenedesmus cultures are addressed. The information obtained from this study will be useful for developing an early warning system and control measures for preventing or treating this contaminant in microalgal mass cultures. PMID- 25819974 TI - Cardiac cephalgia. AB - "Cardiac cephalgia" is a type of secondary headache disorder, usually initiated by exertion that is related to myocardial ischemia. Primary exertional headaches such as sex-, cough-, or exercise-induced headaches are typically benign. Cardiac cephalgia, on the other hand, can have life-threatening complications. Due to overlapping features and similarities in presentation, cardiac cephalgia can be misdiagnosed as a primary headache disorder such as migraine. However, the management of these conditions is unique, and treatment of cardiac cephalgia with vasoconstrictors intended for migraine can potentially worsen myocardial ischemia. Thus, it is important to make the correct diagnosis by evaluating cardiac function with an electrocardiogram and/or stress testing. In this review, we examine reported cases of cardiac cephalgia from the past 5 years to highlight the importance of this condition in the differential diagnosis of a headache in a patient with a history of cardiovascular risk factors, as well as to discuss the appropriate approach to diagnosis and the proposed pathogenic mechanisms of this condition. PMID- 25819975 TI - Emerging behavioral treatments for migraine. AB - Although the efficacy of behavioral interventions for migraine (e.g., relaxation training, stress management, cognitive-behavioral therapy, biofeedback) is well established, other behavioral interventions that have shown efficacy for other conditions are being adapted to treat migraine. This paper reviews the literature to date on acceptance and commitment therapy (ACT), mindfulness-based interventions, and behavioral interventions for common migraine comorbidities. ACT and mindfulness interventions prioritize the outcome of improved functioning above headache reduction and have demonstrated efficacy for chronic pain broadly. These emerging behavioral therapies show considerable promise for improving outcomes of migraine patients, particularly in reducing headache-related disability and affective distress, but efficacy to date is limited by small trials, short follow-up periods, and a need for comparison or integration with established pharmacologic and behavioral migraine treatments. PMID- 25819976 TI - The Mental and Physical Health Consequences of Changes in Private Insurance Before and After Early Retirement. AB - OBJECTIVES: This study evaluated the impact of private insurance coverage on the symptoms of depression, activities of daily living (ADLs), and instrumental activities of daily living (IADLs) in the years leading up to Medicare eligibility focusing on the transition from full-time work to early full retirement. METHOD: The Health and Retirement Study was used to (a) estimate 2 stage selection equations of (i) the transition to retirement and (ii) current insurance status, and (b) the impact of insurance coverage on health, net of endogeneity associated retirement and insurance coverage. RESULTS: Employment based insurance coverage was generally associated with better health. Moreover, being without employment-based insurance was particularly problematic during the transition to retirement. Non-group insurance only moderated the association between losing employment-based insurance and IADLs. DISCUSSION: Results indicated that private insurance coverage is an important contextual factor for the health of early retirees. Those who maintain steady coverage tend to fare the best in retirement. This highlights the dynamic nature of changes in health in later life. PMID- 25819977 TI - Self-organization in the limb: a Turing mechanism for digit development. AB - The statistician George E. P. Box stated, 'Essentially all models are wrong, but some are useful.' (Box GEP, Draper NR: Empirical Model-Building and Response Surfaces. Wiley; 1987). Modeling biological processes is challenging for many of the reasons classically trained developmental biologists often resist the idea that black and white equations can explain the grayscale subtleties of living things. Although a simplified mathematical model of development will undoubtedly fall short of precision, a good model is exceedingly useful if it raises at least as many testable questions as it answers. Self-organizing Turing models that simulate the pattern of digits in the hand replicate events that have not yet been explained by classical approaches. The union of theory and experimentation has recently identified and validated the minimal components of a Turing network for digit pattern and triggered a cascade of questions that will undoubtedly be well-served by the continued merging of disciplines. PMID- 25819978 TI - Shaping of biological tubes by mechanical interaction of cell and extracellular matrix. AB - The shape of biological tubes is optimized for supporting efficient circulation of liquid and gas and to maintain organismal homeostasis. Maintaining a constant tube diameter and fitting tube length to body size are two requirements for proper tube function. The tracheal system of the Drosophila embryo is established through branching of ectodermal epithelia in the absence of environmental air, and the branching pattern and geometry of this system are genetically specified. Recent studies identified apical extracellular matrix (aECM) as a crucial regulator of tube expansion and elongation. Evidence suggests that aECM coordinates apical membrane growth and cell contractility to control tube growth at the tissue level. In the present review, we will discuss the physical mechanisms underlying this interaction. PMID- 25819979 TI - Improving our resolution of kidney morphogenesis across time and space. AB - As with many mammalian organs, size and cellular complexity represent considerable challenges to the comprehensive analysis of kidney organogenesis. Traditional analyses in the mouse have revealed early patterning events and spatial cellular relationships. However, an understanding of later events is lacking. The generation of a comprehensive temporospatial atlas of gene expression during kidney development has facilitated advances in lineage definition, as well as selective compartment ablation. Advances in quantitative and dynamic imaging have allowed comprehensive analyses at the level of organ, component tissue and cell across kidney organogenesis. Such approaches will enhance our understanding of the links between kidney development and final postnatal organ function. The final frontier will be translating this understanding to outcomes for renal disease in humans. PMID- 25819980 TI - Effectiveness of a walking group intervention to promote physical activity and cardiovascular health in predominantly non-Hispanic black and Hispanic urban neighborhoods: findings from the walk your heart to health intervention. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of the Walk Your Heart to Health (WYHH) intervention, one component of the multilevel Community Approaches to Cardiovascular Health: Pathways to Heart Health (CATCH:PATH) intervention designed to promote physical activity and reduce cardiovascular risk among non-Hispanic Black and Hispanic residents of Detroit, Michigan. The study was designed and implemented using a community-based participatory research approach that actively engaged community residents, health service providers and academic researchers. It was implemented between 2009 and 2012. METHOD: WYHH was a 32-week community health promoter-facilitated walking group intervention. Groups met three times per week at community-based or faith based organizations, and walked for 45 to 90 minutes (increasing over time). The study used a cluster randomized control design to evaluate effectiveness of WYHH, with participants randomized into intervention or lagged intervention (control) groups. Psychosocial, clinical, and anthropometric data were collected at baseline, 8, and 32 weeks, and pedometer step data tracked using uploadable peisoelectric pedometers. RESULTS: Participants in the intervention group increased steps significantly more during the initial 8-week intervention period, compared with the control group (beta = 2004.5, p = .000). Increases in physical activity were associated with reductions in systolic blood pressure, fasting blood glucose, total cholesterol, waist circumference and body mass index at 8 weeks, and maintained at 32 weeks. CONCLUSION: The WYHH community health promoter facilitated walking group intervention was associated with significant reductions in multiple indicators of cardiovascular risk among predominantly Hispanic and non-Hispanic Black participants in a low-to-moderate income urban community. Such interventions can contribute to reductions in racial, ethnic, and socioeconomic inequities in cardiovascular mortality. PMID- 25819981 TI - Characterization of humins from different natural sources and the effect on microbial reductive dechlorination of pentachlorophenol. AB - Humins have been reported to function as an electron mediator for microbial reducing reactions. However, the physicochemical properties and the functional moieties of humins from different natural sources have been poorly characterized. In this study, humins extracted from seven types of soil and from a river sediment were examined on the effect on microbial reductive dechlorination of pentachlorophenol (PCP) and characterized polyphasically. All humins facilitated microbial reductive dechlorination of PCP as electron mediators using formate as carbon source, with different dechlorination rates ranging from 0.99 to 7.63 (MUmol Cl-) L(-1) d(-1). The highest rates were observed in humins with high carbon contents, extracted from Andisols containing allophone as major clay. Yields of the humins and the elemental compositions varied among sources. Fourier transform infrared analysis showed that all the humins exhibited similar spectra with different absorbance intensity; these data are indicative of their similar structures and identical classes of functional groups. The electron spin resonance spectra of humins prepared at different pH showed typical changes for the semiquinone-type radicals, suggestive of quinone moieties for the redox activity of the humins. Cyclic voltammetry analysis confirmed the presence of redox-active moieties in all the humins, with the estimated redox potentials in the range of -0.30 to -0.13 V (versus a standard hydrogen electrode), falling into the range of standard redox potential between the oxidation of formate as electron donor and the initial dechlorination of PCP as electron acceptor. PMID- 25819982 TI - Prevalence and characteristics of asthma in the aquatic disciplines. AB - BACKGROUND: Despite the health benefits of swimming as a form of exercise, evidence exists that both the swimming pool environment and endurance exercise are etiologic factors in the development of asthma. The prevalence of asthma in swimmers is high compared with that in participants in other Olympic sport disciplines. There are no publications comparing the prevalence of asthma in the 5 aquatic disciplines. OBJECTIVE: The purpose of this study is to examine and compare the prevalence of asthma in the aquatic disciplines and in contrast with other Olympic sports. METHODS: Therapeutic Use Exemptions containing objective evidence of athlete asthma/airway hyperresponsiveness (AHR) were collected for all aquatic athletes participating in swimming, diving, synchronized swimming, water polo, and open water swimming for major events during the time period from 2004-2009. The prevalence of asthma/AHR in the aquatic disciplines was analyzed for statistical significance (with 95% CIs) and also compared with that in other Olympic sports. RESULTS: Swimming had the highest prevalence of asthma/AHR in comparison with the other aquatic disciplines. The endurance aquatic disciplines have a higher prevalence of asthma/AHR than the aquatic nonendurance disciplines. Asthma/AHR is more common in Oceania, Europe, and North America than in Asia, Africa, and South America. In comparison with other Olympic sports, swimming, synchronized swimming, and open water swimming were among the top 5 sports for asthma/AHR prevalence. CONCLUSION: Asthma/AHR in the endurance aquatic disciplines is common at the elite level and has a varied geographic distribution. Findings from this study demonstrate the need for development of aquatic discipline-specific prevention, screening, and treatment regimens. PMID- 25819983 TI - Respiratory syncytial virus infection of primary human mast cells induces the selective production of type I interferons, CXCL10, and CCL4. AB - BACKGROUND: Respiratory syncytial virus (RSV) causes severe respiratory tract infections, which might have a role in the development of airway hyperreactivity. Mast cells are important effector cells in allergy, with sentinel cell roles in host defense. However, the role of mast cells in response to RSV infection is unknown. OBJECTIVE: Human mast cell responses to RSV were investigated with a view to better understanding the role of mast cells in RSV-induced disease. METHODS: Human cord blood-derived mast cells and the HMC-1 mast cell line were exposed to RSV or UV-inactivated RSV. Viral gene and protein expression were evaluated by using PCR and flow cytometry. The expression of interferon stimulated genes and selected mediators were evaluated by using quantitative PCR and ELISA. RESULTS: Human mast cells expressed multiple RSV genes after exposure to RSV, and a small percentage of mast cells supported RSV antigen protein expression. RSV induced mast cells to upregulate production of chemokines, including CCL4, CCL5, and CXCL10, as well as type I interferons, and interferon stimulated gene expression. However, production of the granulocyte chemoattractants CXCL8 and CCL11 was not induced. Antibody blockade of the type I interferon receptor on human cord blood-derived mast cells reduced the RSV mediated induction of CXCL10 and CCL4 but not CCL5. Leukotriene C4 production by mast cells was not enhanced by exposure to RSV. CONCLUSION: Despite low levels of infection, human mast cells produce multiple chemokines in response to RSV through mechanisms that include responses to type I interferons. Such mast cell responses might enhance effector cell recruitment during RSV-induced disease. PMID- 25819984 TI - IL-13 desensitizes beta2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism. AB - BACKGROUND: beta2-Adrenergic receptor (beta2AR) agonists are critical treatments for asthma. However, receptor desensitization can lead to loss of therapeutic effects. Although desensitization to repeated use of beta2-agonists is well studied, type 2 inflammation could also affect beta2AR function. OBJECTIVE: We sought to evaluate the effect of the type 2 cytokine IL-13 on beta2AR desensitization in human airway epithelial cells (HAECs) and determine whether 15 lipoxygenase-1 (15LO1) binding with phosphatidylethanolamine-binding protein 1 (PEBP1) contributes to desensitization through release of G protein receptor kinase 2 (GRK2). METHODS: HAECs in air-liquid interface culture with or without IL-13 (48 hours) or isoproterenol hydrochloride (ISO; 30 minutes) pretreatment were stimulated with ISO (10 minutes). Cyclic adenosine 3, 5-monophosphate (cAMP) levels were measured using ELISA, and beta2AR and GRK2 phosphorylation was measured using Western blotting. Short interfering RNA was used for 15LO1 knockdown. Interactions of GRK2, PEBP1, and 15LO1 were detected by means of immunoprecipitation/Western blotting and immunofluorescence. HAECs and airway tissue from control subjects and asthmatic patients were evaluated for I5LO1, PEBP1, and GRK2. RESULTS: Pretreatment with ISO or IL-13 decreased ISO-induced cAMP generation compared with ISO for 10 minutes alone paralleled by increases in beta2AR and GRK2 phosphorylation. GRK2 associated with PEBP1 after 10 minutes of ISO in association with low phosphorylated GRK2 (pGRK2) levels. In contrast, in the presence of IL-13 plus ISO (10 minutes), binding of GRK2 to PEBP1 decreased, whereas 15LO1 binding and pGRK2 levels increased. 15LO1 knockdown restored ISO induced cAMP generation. These findings were recapitulated in freshly brushed HAECs from cells and tissue of asthmatic patients. CONCLUSION: IL-13 treatment of HAECs leads to beta2AR desensitization, which involves 15LO1/PEBP1 interactions to free GRK2, and allows it to phosphorylate (and desensitize) beta2ARs, suggesting that the beneficial effects of beta2-agonists could be blunted in patients with type 2 associated asthma. PMID- 25819985 TI - Weaning age in an expanding population: stable carbon and nitrogen isotope analysis of infant feeding practices in the Okhotsk culture (5th-13th centuries AD) in Northern Japan. AB - OBJECTIVE: The Okhotsk people were sedentary hunter-gatherer-fishers who lived and prospered in Sakhalin, Hokkaido, and the Kurile Islands during the 5th to 13th centuries AD. They expanded rapidly along the northeastern coast of Hokkaido. We reconstructed infant feeding practices of the Moyoro population of the Okhotsk culture in eastern Hokkaido, Japan. METHODS: Stable isotope ratios in 58 subadult human skeletons were measured. RESULTS: The results suggest that complementary foods with a relatively low carbon isotope ratio were consumed during and after weaning, as observed in ethnographic descriptions of northern human populations such as the Ainu and isotopically suggested in ancient northern hunter-gatherer-fisher populations. Nitrogen isotope ratios of subadults showed that the age at the end of weaning in the Moyoro population was 1.8 (1.4-2.2 in 95% credible interval) years, which is earlier than that in other northern hunter gatherer-fisher populations. CONCLUSIONS: Because weaning age is one of the most important determinants of fertility, a shorter breastfeeding period suggests increased fertility. Furthermore, better nutrition would further promote the population increase, and thus populations of the Okhotsk culture could expand into new regions. These findings are consistent with recent emerging evidence of great contributions of the Okhotsk to the formation of later Ainu populations and culture. PMID- 25819986 TI - Interplay of reactive oxygen species and nitric oxide: nitric oxide coordinates reactive oxygen species homeostasis. PMID- 25819987 TI - A stochastic transcriptional switch model for single cell imaging data. AB - Gene expression is made up of inherently stochastic processes within single cells and can be modeled through stochastic reaction networks (SRNs). In particular, SRNs capture the features of intrinsic variability arising from intracellular biochemical processes. We extend current models for gene expression to allow the transcriptional process within an SRN to follow a random step or switch function which may be estimated using reversible jump Markov chain Monte Carlo (MCMC). This stochastic switch model provides a generic framework to capture many different dynamic features observed in single cell gene expression. Inference for such SRNs is challenging due to the intractability of the transition densities. We derive a model-specific birth-death approximation and study its use for inference in comparison with the linear noise approximation where both approximations are considered within the unifying framework of state-space models. The methodology is applied to synthetic as well as experimental single cell imaging data measuring expression of the human prolactin gene in pituitary cells. PMID- 25819988 TI - Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing. AB - INTRODUCTION AND OBJECTIVES: Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. METHODS: We identified the KCNH2-H562R mutation in a 65-year old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. RESULTS: The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. CONCLUSIONS: Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment. PMID- 25819989 TI - Small-size Microparticles as Indicators of Acute Decompensated State in Ischemic Heart Failure. AB - INTRODUCTION AND OBJECTIVES: Microparticles are markers for cell activation and apoptosis and could provide valuable information that is not available from clinical data. This study assesses the clinical and biological relationship of small-sized microparticles in different forms of ischemic systolic heart failure and their relation to markers of inflammation and repair. METHODS: We compared 49 patients with acute heart failure, 39 with stable heart failure and 25 patients with stable coronary artery disease. Small-size microparticles counts were determined by high-resolution flow cytometry. Moreover, 3 different monocyte subpopulations and their expression of inflammatory and adhesive scavenger receptors were analyzed using a conventional flow cytometer. RESULTS: Endothelial CD144+ microparticle counts were decreased in heart failure groups (P=.008). Annexin V-binding microparticle counts were found increased in heart failure (P=.024) and in patients with lower functional class (P=.013). Platelet CD42b+ microparticle counts positively correlated with left ventricular ejection fraction (P=.006), and annexin V-binding microparticle counts with interleukin-6 levels in stable heart failure (P=.034). Annexin V-binding microparticle counts in the acute status strongly correlated with toll-like receptor-4 expression on all monocyte subsets (all P<.01). Three months after admission with acute heart failure, annexin V-binding microparticle counts were positively correlated with receptors for interleukin-6, CD163 and CD204 (all P<.05). CONCLUSIONS: Annexin V binding microparticle counts constitute valuable hallmarks of acute decompensated state in systolic heart failure. The observed relationship between small-size annexin V-binding microparticles and scavenger receptors supports their involvement in the progression of the acute response to injury, and thus their contribution to the pathogenesis of acute decompensated heart failure. PMID- 25819990 TI - Fenton degradation of sulfanilamide in the presence of Al,Fe-pillared clay: Catalytic behavior and identification of the intermediates. AB - Liquid phase catalytic degradation of sulfanilamide with H2O2 was carried out in the presence of Fe,Al/M-pillared clay (Fe,Al/M-MM, M=Na(+), Ca(2+) and Ba(2+)) as heterogeneous Fenton type catalyst. Fe,Al/M-MMs were prepared by swelling of layered aluminosilicate (90-95 wt.% montmorillonite) from a bed located in Mukhortala (Buryatia, Russia) in Na(+), Ca(2+) and Ba(2+) forms by means of the exchange of these cations with bulky Fe,Al-polyoxocations prepared at Al/Fe=10/1 and OH/(Al+Fe)=2.0, and then calcinated at 500 degrees C. XRD method and chemical analysis demonstrated that the rate of crystalline swelling was dependent on the interlayer cations and decreased in the order: Fe,Al-/Na-MM>Fe,Al/Ca-MM>Fe,Al/Ba MM. It was found that the catalytic properties of Fe,Al/M-MMs depended on the type of exchangeable cations. The effect of the H2O2/sulfanilamide molar ratio, the catalyst content, the reaction temperature and the reaction pH on the removal rate of sulfanilamide has been studied in the presence of Fe,Al/Na-MM. The catalyst can be applied for degradation of sulfanilamide with H2O2 for at least three successive cycles without loss of activity. HPLC analyses pointed out that the main degradation intermediate products were sulfanilic acid, benzenesulfonic acid, p-benzoquinone and aliphatic carboxylic acids. PMID- 25819992 TI - [Surveillance and detection of unusual events in toxicovigilance: Review of relevant methods]. AB - BACKGROUND: Declared cases of exposures related to potential toxic agents are reported through a national database, the French Network of Poison Centers, and account on average for 200,000 cases per year, including 75,000 to 80,000 symptomatic cases. These data are currently used to investigate signals from local, national or international institutional partners (such as hospitals, local health authorities, and the Rapid Alert System for Food and Feed). Our objective is to complete this classical toxicovigilance activity through the automated detection of unexpected or unusual events in order to identify precociously signals representing potential threats for public health. To reach this objective, the inventory of surveillance and detection methods of unexpected events is necessary. METHODS: A literature review was conducted via Scopus((r)) and Pubmed((r)) databases, completed with grey literature and data available on worldwide vigilance systems' websites. RESULTS: The most commonly used methods are disproportional measures in the field of pharmacovigilance, some of which are subject to a routine detection at regular time intervals. Criteria of signal generation differ from one system to another, which have implemented data filtering strategies before or after analysis, in order to decrease the number of generated signals and improve their priority level. These signals are then transmitted to an experts committee for a clinical and epidemiological evaluation, and at times, for informing the patient's medical records. We also notice an interest in other approaches such as surveillance methods of temporal series or symbolic methods for associative rules extraction between one or more drugs and one or more adverse effects, with the possibility to include other types of variables, such a demographic data. The developments of probabilistic based algorithms have also been recently developed, opening new opportunities. CONCLUSION: These surveillance and detection methods are of high interest for the automated detection of signals from the French toxicovigilance network. The initial step to developing these methods consists in studying the statistical quality of data and targeting the needs and expectations of the toxicovigilance network for what we want and what we can detect. PMID- 25819991 TI - Targeted removal of trichlorophenol in water by oleic acid-coated nanoscale palladium/zero-valent iron alginate beads. AB - A new material was developed and evaluated for the targeted removal of trichlorophenol (TCP) from among potential interferents which are known to degrade removal activity. To achieve TCP-targeted activity, an alginate bead containing nanoscale palladium/zero-valent iron (Pd/nZVI) was coated with a highly hydrophobic oleic acid layer. The new material (Pd/nZVI-A-O) preferentially sorbed TCP from a mixture of chlorinated phenols into the oleic acid cover layer and subsequently dechlorinated it to phenol. The removal efficacy of TCP by Pd/nZVI-A-O was not affected by co-existing organic substances such as Suwannee River humic acid (SRHA), whereas the material without the oleic acid layer (Pd/nZVI-A) became less effective with increasing SRHA concentration. The inorganic substances nitrate and phosphate significantly reduced the reactivity of Pd/nZVI-A, however, Pd/nZVI-A-O showed similar TCP removal efficacies regardless of the initial inorganic ion concentrations. The influence of bicarbonate on the TCP removal efficacies of both Pd/nZVI-A and Pd/nZVI-A-O was not significant. The findings from this study suggest that Pd/nZVI-A-O, with its targeted, constant reactivity for TCP, would be effective for treating this contaminant in surface water or groundwater containing various competitive substrates. PMID- 25819993 TI - [Contract for improving professional practices: What is the impact perceived by GPs?]. AB - BACKGROUND: The CAPI (contract for improving professional practices) is a voluntary pay for performance scheme for primary care physicians introduced in France in 2009. Our objective was to analyze general practitioners' (GPs) perceptions of the impact of the CAPI on their healthcare practices. METHOD: The methodology was both qualitative, using thematic analysis of responses to three items of a questionnaire mailed to GPs in 2011, and quantitative using thematic multiple correspondence analysis of responses together with cluster analysis based on the ward aggregation criterion. RESULTS: A total of 1050 general practitioners answered, 31% had signed a CAPI. For CAPI-participating GPs, the contract was mostly related to changing practices for drug prescription. GPs who did not participate in the CAPI focused on ethical issues. They denounced a conflict of interest between the doctor and the patient and also the risk of patient selection. They connected these concepts to selected indicators. Due to their relationship with the health insurance fund, they feared their freedom of practice would be restricted. CONCLUSION: GP involvement in designing indicators would favor better balance between economic goals and values of care. The patients' viewpoint should be studied. Pay for performance has been renewed in the 2011. Further studies will analyze the impact of this new scheme in a medical and economic perspective. PMID- 25819994 TI - [The impact of screening sickle-cell carriers in the general population. A retrospective study in the Paris screening center]. AB - BACKGROUND: Since 2006 the CIDD, the Paris information and screening center for sickle-cell disease, provides free assistance for adults who may be at risk of having children with sickle-cell disease. Recently, an increasing number of parents of a silent-carrier newborn detected by systematic neonatal screening are attending the center. We present a retrospective study of the impact of such information and screening on people. METHODS: The study involved 81 silent carrier men and women aged 18 to 45 years, interviewed using a telephone questionnaire (n=70) or during consultation (n=11) one to three years after screening. RESULTS: The study group represented 12% of individuals attending the center with the same characteristics. In general, the information delivered concerning sickle-cell disease and silent-carriers was well understood although concerns about personal and family history and the correctness of prior knowledge revealed a lack of information input from the environment (media, schools, health professionals). Poorly assimilated information involved three subjects: the difference between trait and disease; the difference between type of hemoglobin and blood group; and Mendelian transmission. The screening result was not a cause of separation among couples and was often passed on to family or friends. Disparities in adherence to prenatal diagnosis and termination of pregnancy were mainly related to different representations of disease severity. CONCLUSION: Joint screening of newborns and their parents is a good measure for adults, who are satisfied with being informed despite the psychological difficulties involved. However the implication for children detected remains a relevant issue because of the persistent perception of the trait as a pseudo-disease and the risk of reification of a biological difference between relatives. PMID- 25819995 TI - Comment on 'Multi-modality functional image guided dose escalation in the presence of uncertainties'. PMID- 25819997 TI - Personal characteristics and job satisfaction: India-Nigeria comparison. AB - This study examines the relationship between job satisfaction and personal characteristics on samples of 778 Indians and 620 Nigerians. The results indicate no relationship between sex, marital status, and annual income and job satisfaction for both the samples. Age showed quadratic and linear relationship with satisfaction for Indian and Nigerian samples respectively. Satisfaction increased with increasing number of dependents and work experience and decreased with increasing years of education for both the samples. The regression analysis showed that all seven personal characteristics accounted for 34.9 per cent and 71.7 per cent variation in job satisfaction for Indian and Nigerian employees, respectively. Culture and level of industrialization have been examined to explain the differences in the results. PMID- 25819996 TI - Pathological stage after neoadjuvant chemoradiation and esophagectomy superiorly predicts survival in patients with esophageal squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: To assess the usefulness of pathological stage according to the 7th edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) as a prognostic tool in patients undergoing neoadjuvant chemoradiation followed by esophagectomy (trimodality therapy, TMT) for locally advanced esophageal squamous cell carcinoma. MATERIAL AND METHODS: One hundred twenty-five eligible patients completing TMT were enrolled for analysis. The clinical (cTNM7) and pathological (ypTNM7) stage groups of their tumors were prospectively classified, and re-grouped by the 6th edition (ypTNM6). Survival was analyzed using the Kaplan-Meier method. The Cox proportional hazard model and the Akaike information criterion (AIC) were used to compare the performance of staging systems. RESULTS: With a median follow-up of 24.6 months, 54 patients (43.2%) died. Forty patients (32%) achieved pathological complete remission (pCR). The median survival was 31.8 months. On multivariate analysis, ypTNM7 (but not pCR or pN) was the only independent factor affecting overall survival (p<0.001). The ypTNM7 was superior to cTNM7 or ypTNM6 in predicting both overall and recurrence-free survival after TMT based on AIC values and Cox proportional hazard model analysis. CONCLUSIONS: In patients with locally advanced esophageal squamous cell carcinoma undergoing TMT, ypTNM7 is the best predictor of survival. PMID- 25819998 TI - Predicting job satisfaction from life satisfaction: is there a general satisfaction factor? AB - Job satisfaction has been shown to be related to a number of individual and organizational effectiveness variables. Consequently, it is suggested that attempts to select individuals with inclinations towards satisfaction would be of theoretical and practical importance. For five samples of individuals representing a wide variety of occupations, regression analyses were used to assess the usefulness of life satisfaction in the prediction of subsequent job satisfaction, while statistically controlling various demographic variables, pay, tenure, and perceptions of task characteristics. In a sixth sample of workers eligible for retirement, the hypothesis that life satisfaction can be predicted from job satisfaction was also examined. The results showed that in three of the first five samples, life satisfaction was a significant predictor of job satisfaction. In the sample of retirees, significant results were also obtained using job satisfaction to predict subsequent life satisfaction. It is suggested that satisfaction may be a relatively stable and general aspect of certain individuals which is a function of particular personality characteristics and/or an inclination towards interpreting various situations in a favorable manner. PMID- 25819999 TI - Source of performance variance as a moderator of the job satisfaction-job performance relationship. AB - Herman's (1973) proposition that satisfaction and performance can only be related when performance is at least partially under the worker's control was tested. Subjects were hired to work under conditions of high or low situational control of performance. Two performance measures were used, only one of which was designed to be susceptible to the situational control manipulation. Satisfaction was then predicted by performance, situational control condition, and their cross product. As expected, the interaction term was significant when the performance measure susceptible to situational control was used and nonsignificant when the nonsusceptible measure was used. It was concluded that the amount of performance variance which is individually rather than situationally controlled is an important moderator of the satisfaction-performance relationship. PMID- 25820000 TI - A dialectical approach to investigating role conflict, job satisfaction and situational anxiety in an african industrial context. AB - A dialectical approach incorporating both nomothetic and idiographic perspectives is proposed as a possible solution to the problem of concept validation encountered in industrial psychological and industrial sociological investigations by providing them with a more complete criterion of validity. The use of the proposed method is illustrated in an empirical research investigation. PMID- 25820001 TI - Work and the quality of life. AB - Wilensky's (1960, 1961) proposition that the integration of work into one's total life is contingent upon the technological and social organization of the work was tested in a national probability sample of approximately 1,025 men and women. In line with Wilensky's arguments, it was found that a composit measure of job complexity and occupational status moderated the job satisfaction-life satisfaction relationship. Specifically, the relationship between job- and life satisfaction was greatest for individuals with occupations characterized as complex and high in status. The magnitude of the detected moderating effects, as well as that of job satisfaction per se, on life satisfaction, were small, however. It is argued that the scope of variables considered in attempts to understand the relationship between life- and job satisfaction should be expanded and suggestions for future research are offered. PMID- 25820002 TI - The effects of need for achievement and need for independence on the relationship between perceived job attributes and managerial satisfaction and performance. AB - Work-manifest needs for achievement and independence were examined as moderators of relations between perceptions of five job attributes (skill variety, task identity, task significance, autonomy and feed-back) and job satisfaction and job performance among a sample of 346 middle-managers. Need for achievement and need for independence were unrelated to the perceived job attributor and to both job satisfaction and job performance. However, most of the relations between the perceived job attributes and both job satisfaction and job performance were significantly higher among the managers high in need for achievement and need for independence than among those low in these needs. These results point to the importance of differentiating between managers high and low in these needs when redesigning jobs. PMID- 25820003 TI - Job dissatisfaction: what are the consequences? AB - Although job dissatisfaction has been of central importance to industrial psychology for many years, there exists no general theory of the behavioral and psychological consequences of job dissatisfaction. This paper reviews the concept of job dissatisfaction, and argues that no particular consequence of job dissatisfaction is inevitable or necessary. The various psychological and behavioral consequences of job dissatisfaction are considered, and a heuristic guide for further research is suggested. PMID- 25820004 TI - Cognition vs affect in measures of job satisfaction. AB - The authors find reasons to question whether conventional measures of job satisfaction capture the original conception of 'morale'. In particular, evidence suggests that these measures reflect primarily cognitive evaluation rather than affective state or hedonic tone. Recent developments indicate that cognitive and affective systems may be somewhat independent of each other. Questions are raised concerning the appropriate means of measuring affect, as well as whether the antecedents and consequences of affect are expected to differ from those associated with cognitive appraisal. PMID- 25820005 TI - Position characteristics organizational setting characteristics and employee reactions: test of conceptual framework. AB - This research examines the effectiveness of a conceptual framework designed to explain the relationships between several position and setting characteristics (e.g., position level, payment type, union representation, and geographical location of the organization) and employee reactions to the work and the work context. In general, the framework posits that position and setting characteristics influence employee reactions through their impact on the personal attributes of employees and on the characteristics of jobs these employees perform. Results provide substantial support for the conceptual framework. Implications of the findings for future research on the interactions among people, jobs, and organizational conditions are discussed. PMID- 25820007 TI - Underlying presuppositions in solving two-term series problems. AB - Researchers are traditionally interested in the sort of psychological processes in which the subjects are engaged when solving two- and three-term series problems under time restrictions. Three models, the Linguistic (Clark), the Spatial Imagery Theory (mainly Huttenlocher) and the Mixed (Sternberg) propose alternative views for explaining the cognitive processes involved during problem solving. The present study was designed to examine the kind of presuppositions the native speakers use when solving two-term series problems under no time restrictions with four classes of adjectives: Ratio (or spatial) with and without context. Ordinal1 and Ordinal2 without context. The results show: (1) contrary to the theories absolute presuppositions is the predominant answer pattern on all adjective groups; (2) context exerts a strong effect on the form of presuppositions elicited by the subjects; (3) the unmarkedness-markedness concept appears pshychologically inconsistent; and (4) presuppositions in two-term series problems under no time restrictions seem to reflect a different sort of cognitive processes from that espoused by the models mentioned. PMID- 25820006 TI - School attitudes and adolescents' aspirations: ethnic group differences. AB - In this study data were collected from 16-year-old Australians from Anglo Australian, Greek and Southern Italian families to examine relations between adolescents' school-related attitudes and their educational and occupational aspirations, after taking into account the influence on aspirations of social status and intellectual ability. Regression surfaces were constructed from hierarchical models that examined possible linear, interaction and curvilinear associations between the variables. The findings suggest the propositions that: (a) social status acts as an allocation factor such that low social status inhibits associations between early school attitudes and later aspirations; (b) in relation to intellectual ability, attitudes of early schooling have negligible or modest unique associations with adolescents' aspirations; and (c) relationships between social status, intelligence, attitudes and aspirations vary for adolescents from different ethnic groups indicating that ethnicity is an important contextual variable to include in investigations of aspirations. PMID- 25820008 TI - Free and matrix classification: an experimental investigation of the responses of nine- and twelve-year-old children. AB - This study investigated the relationship between free and matrix classification performance as a function of stimulus dimensionality (2-D vs 3-D) and repealed trials. The subjects were 30 boys and 30 girls, mean age 12 years, and 30 boys and 30 girls, mean age 9 years. The results indicated that subjects succeeded on the matrix tasks more frequently than they were able to give multidimensional free classification responses. Subjects succeeded more frequently with 3-D than with 2-D stimuli. Retrials on both free and matrix classification tasks did not significantly improve performance. Possible reasons for the findings and their future implications were discussed. PMID- 25820012 TI - International union of psychological science. PMID- 25820009 TI - A cross-cultural perspective of self-related conceptions in adolescence. AB - Adolescence has been described as a transitional phase of life often involving turbulence, stress and strain in five major problem areas. Osgood et al.'s (1975) Atlas of Affective Meaning provided three basic measures of Evaluation, Potency and Activity for some 620 concepts that are representative of human life experiences in 30 language/culture communities around the world. The ratings of 30 concepts from the Atlas that represent the five major problem areas of adolescence were analyzed with the Three-Mode Multidimensional Scaling with Points-of-View Solution Technique (Tzeng and Landis 1978). The major results included the identification of cross-cultural common concept factors, 12 'idealized' cultural groups, and the factor structures of 12 'private' configurations. The concept structures that emerged from this study accurately recovered the problem areas of adolescence cited in the literature and also revealed unexpected homogeneities and differences in the cultures involved. Implications for government, social planning and education were discussed. PMID- 25820013 TI - International council of scientific unions (icsu). PMID- 25820014 TI - Psychologists for peace. PMID- 25820015 TI - Report on the first network-seminar of the international union of psychological sciences on man-computer-interaction research (macinter). PMID- 25820016 TI - All-round development as a fundamental right of youth. PMID- 25820017 TI - Direct retrospective comparison of adalimumab and infliximab in preventing early postoperative endoscopic recurrence after ileocaecal resection for crohn's disease: results from the MULTIPER database. AB - BACKGROUND AND AIMS: Both adalimumab [ADA] and infliximab [IFX] seem to be effective in the prevention of early postoperative endoscopic recurrence [EPER] after ileocaecal resection in Crohn's disease [CD] patients. There is lack of data with direct comparison between the two agents in the postoperative scenario. The aim of this study was to compare the rates of EPER in patients treated with ADA and IFX after ileocaecal resection for CD. METHODS: This was a multicentre retrospective analysis of EPER rates in CD patients after ileocaecal resections, from seven referral centres in three countries. Endoscopic recurrence was defined as Rutgeerts' score >= i2. The patients were allocated according to treatment to two groups: ADA or IFX. The EPER rates were compared between the two treatment groups. RESULTS: Among the 168 patients included in the database, 96 received anti-tumour necrosis factor [TNF] agents after resection [37 in the ADA and 59 in the IFX groups] and were included in this comparative study. The groups were comparable in all baseline characteristics, mainly age, gender, previous resections, perianal CD, and mono or combination therapy. EPER was identified in 9/37 [24.32%] in the ADA group vs 16/59 [27.12%] in the IFX group [p = 0.815]. CONCLUSIONS: In this retrospective direct comparison between ADA and IFX therapy after ileocaecal resection, there was no significant difference between the two anti-TNF agents in terms of EPER rates. However, prospective randomised studies are needed to confirm these data and better define the role of each agent in the prevention of EPER. PMID- 25820019 TI - Ingenol mebutate gel is effective against anogenital warts - a case series in 17 patients. PMID- 25820018 TI - Changes in Epithelial Barrier Function in Response to Parasitic Infection: Implications for IBD Pathogenesis. AB - BACKGROUND AND AIMS: Mast cells [MCs] are implicated in epithelial barrier alterations that characterize inflammatory and functional bowel disorders. In this study, we describe mast cell proteinases [chymases and tryptases] and tight junction [TJ] proteins kinetics in a rat model of postinfectious gut dysfunction. METHODS: Jejunal tissues of control and -infected rats were used. Inflammation related changes in MCs and the expression of TJ-related proteins were evaluated by immunostaining and reverse transcription-quantitative polymerase chain reaction. Epithelial barrier function was assessed in vitro (Ussing chambers) and in vivo. RESULTS: After infection, intestinal inflammation was associated with a generalized overexpression of MC chymases, peaking between Days 6 and 14. Thereafter, a mucosal MC hyperplasia and a late increase in connective tissue MC counts were observed. From Day 2 post-infection, TJ proteins occludin and claudin 3 expression was down-regulated whereas the pore-forming protein claudin-2 was overexpressed. The expression of proglucagon, precursor of the barrier-enhancing factor glucagon-like peptide-2, was reduced. These changes were associated with an increase in epithelial permeability, both in vitro and in vivo. CONCLUSIONS: Proteinases expression and location of mucosal and connective tissue MCs indicate a time-related pattern in the maturation of intestinal MCs following infection. Altered expression of TJ-related proteins is consistent with a loss of epithelial tightness, and provides a molecular mechanism for the enhanced epithelial permeability observed in inflammatory conditions of the gut. PMID- 25820020 TI - No increase in synovial fluid level of matrix metalloproteinase-3 by systemic administration of glucocorticoids in rheumatoid arthritis. PMID- 25820021 TI - Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier. AB - Mechanisms regulating fetal transfer of olmesartan, an angiotensin-II receptor type 1 antagonist, are important as potential determinants of life-threatening adverse fetal effects. The purpose of this study was to examine the olmesartan transport mechanism through the basal plasma membrane (BM) of human syncytiotrophoblasts forming the placental barrier. Uptake of olmesartan by human placental BM vesicles was potently inhibited by dehydroepiandrosterone sulfate (DHEAS), estrone 3-sulfate, and bromosulfophthalein, which are all typical substrates of organic anion transporter (OAT) 4 localized at the BM of syncytiotrophoblasts, and was increased in the absence of chloride. In tetracycline-inducible OAT4-expressing cells, [(3) H]olmesartan uptake was increased by tetracycline treatment. Olmesartan uptake via OAT4 was concentration dependent with a Km of 20 MUM, and was increased in the absence of chloride. [(3) H]Olmesartan efflux via OAT4 was also observed and was trans-stimulated by extracellular chloride and DHEAS. Thus, OAT4 mediates bidirectional transport of olmesartan and appears to regulate fetal transfer of olmesartan at the BM of syncytiotrophoblasts. Efflux transport of olmesartan via OAT4 from syncytiotrophoblasts to the fetal circulation might be facilitated in the presence of an inwardly directed physiological chloride gradient and extracellular DHEAS. PMID- 25820022 TI - [Anterior pure tibiotalar dislocation: A rare lesion]. PMID- 25820023 TI - Men's contraceptive practices in France: evidence of male involvement in family planning. AB - OBJECTIVE: To describe contraceptive practices of men in a relationship in France, where use of female-controlled methods is predominant, and to explore their involvement in managing contraception within the couple. STUDY DESIGN: Data are drawn from a national probability cross-sectional survey on sexual and reproductive health conducted in France in 2010. The study sample comprised 3373 men aged 15-49, 1776 of whom were asked about their current contraceptive practices after they reported that they were fecund and sexually active and did not currently want a child. Analyses were performed with logistic regression models. RESULTS: Few men aged 15-49 with a partner did not use contraception (3.4%). Most reported using only a female method (71.7%), 20.4% only cooperative methods, such as condoms, withdrawal and the rhythm method and 4.5% both. Among contraceptive users, withdrawal (7.7%) was more likely to be used by men with low incomes or low educational levels. Condom use was reported as a contraceptive method by 18.9% of men. Its prevalence was higher for those in new and noncohabiting relationships (36.1%) and lower for those in cohabiting relationships (12.4%), in which STIs/HIV prevention is less of a concern. CONCLUSION: Men's high awareness of contraceptive practices and their use of some cooperative methods reveal their involvement in contraceptive practices within the context of relationships. Condom use is associated with the prevention of STIs/HIV for noncohabiting men, but men who live with their female partner seem to use condoms mainly as a contraceptive method. Withdrawal appears to be associated with low level of education and financial difficulties. Finally, having engendered a pregnancy that was terminated appears to influence men's contraceptive practices. IMPLICATIONS: Studying men's contraceptive practices helps to understand their involvement in contraceptive management within relationships. PMID- 25820024 TI - Primary stroke prevention in China - a new approach. AB - The growing burden of stroke in China, along with the increasing cost of health care calls for new, more effective strategies for stroke prevention. These strategies should include increasing awareness of stroke symptoms, awareness of risk factors, and provision of easily available information on means of modifying risk factors. The Stroke Riskometer App is exactly such a tool, available in Mandarin, for adult individuals to calculate their risk of stroke over the next 5 and 10 years, and to identify their individual stroke risk factors and linking them to possible means of modifying these risk factors. The use of this App could reduce the risk of stroke for individuals in the Chinese population and contribute to significant reduction in stroke burden in China. PMID- 25820025 TI - Influence of H- and OH-adsorbates on the ethanol oxidation reaction--a DEMS study. AB - The ethanol oxidation reaction (EOR) was investigated by potentiodynamic techniques on Pt/C, Rh/C, Pt-Rh/C, Pt-SnO2/C and Pt-Rh-SnO2/C by differential electrochemical mass spectrometry (DEMS) in a flow cell system. Prior to the cyclic voltammetries, adsorption of H- and OH-species was carried out by chronoamperometry at Ead = 0.05 and 1 V vs. RHE, respectively, in order to examine their influence on the EOR on the different electrocatalysts. For the sake of comparison, another adsorption potential was chosen at Ead = 0.3 V vs. RHE, in the double layer region (i.e. in the absence of such adsorbates). For this study, 20 wt% electrocatalysts were synthesized using a modified polyol method and were physically characterized by inductively coupled plasma atomic emission spectrometry (ICP-AES), X-ray diffraction (XRD) and transmission electron microscopy (TEM). When comparing the first and second cycles of the cyclic voltammograms (CVs) on Pt/C and Pt-SnO2/C, the presence of Had on the electrocatalyst surface seems to hinder the initiation of the ethanol electrooxidation, whereas the reaction onset potential is shifted negatively with the presence of OH-adsorbates. In contrast to them, the EOR on Rh/C is enhanced when the electrocatalyst surface is covered with Had and is inhibited after adsorption at Ead = 0.3 and 1 V vs. RHE. Finally, on Pt-Rh/C and Pt-Rh-SnO2/C, neither the H- nor OH-adsorbates do impact the EOR initiation. The lowest EOR onset was recorded on Pt-SnO2/C and Pt-Rh-SnO2/C electrocatalysts. The CO2 currency efficiency (CCE) was also determined for each electrocatalyst and demonstrated higher values on Pt-Rh-SnO2/C. PMID- 25820026 TI - Selective nitrogen functionalization of graphene by Bucherer-type reaction. AB - Nitrogen functionalization of graphene offers new hybrid materials with improved performance for important technological applications. Despite studies highlighting the dependence of the performance of nitrogen-functionalized graphene on the types of nitrogen functional groups that are present, precise synthetic control over their ratio is challenging. Herein, the synthesis of nitrogen-functionalized graphene rich in amino groups by a Bucherer-type reaction under hydrothermal conditions is reported. The efficiency of the synthetic method under two hydrothermal conditions was examined for graphite oxide produced by Hummers and Hofmann oxidation routes. The morphological and structural properties of the amino-functionalized graphene were fully characterized. The use of a synthetic method with a well-known mechanism for derivatization of graphene will open new avenues for highly reproducible functionalization of graphene materials. PMID- 25820027 TI - A General Strategy for the Synthesis of Enantiomerically Pure Azetidines and Aziridines through Nickel-Catalyzed Cross-Coupling. AB - In this communication, we report a straightforward synthesis of enantiomerically pure 2-alkyl azetidines. The protocol is based on a highly regioselective nickel catalyzed cross-coupling of aliphatic organozinc reagents with an aziridine that features a tethered thiophenyl group. Activation by methylation transforms the sulfide into an excellent leaving group and triggers the formation of the 2 substituted azetidine core structure by cyclization. In addition, we have expanded this concept to the synthesis of enantiomerically pure, terminal alkyl aziridines. Coupling of a TMS-protected aziridine alcohol, followed by acidic work-up to remove the silyl group, provides 1,2-amino alcohol products that are readily cyclized to aziridines. Both of these sequences display excellent functional group tolerance and deliver the desired azetidine and aziridine products in good to excellent yields. PMID- 25820028 TI - Programmed cell death 4 protein (Pdcd4) and homeodomain-interacting protein kinase 2 (Hipk2) antagonistically control translation of Hipk2 mRNA. AB - The tumor suppressor protein programmed cell death 4 (Pdcd4) is a highly conserved RNA-binding protein that inhibits the translation of specific mRNAs. Here, we have identified the homeobox-interacting protein kinase-2 (Hipk2) mRNA as a novel translational target of Pdcd4. Unlike most other protein kinases Hipk2 is constitutively active after being synthesized by the ribosome and its expression and activity are thought to be mainly controlled by modulation of the half-life of the kinase. Our work provides the first evidence that Hipk2 expression is also controlled on the level of translation. We show that Hipk2 stimulates the translation of its own mRNA and that Pdcd4 suppresses the translation of Hipk2 mRNA by interfering with this auto-regulatory feedback mechanism. We also show that the translation of the related kinase Hipk1 is controlled by a similar feedback loop and that Hipk2 also stimulates the translation of Hipk1 mRNA. Taken together, our work describes a novel mechanism of translational suppression by Pdcd4 and shows for the first time that Hipk2 controls its own synthesis by an auto-regulatory feedback mechanism. Furthermore, the effect of Hipk2 on the translation of Hipk1 RNA suggests that Hipk2 and Pdcd4 can act in similar manner to control the translation of other mRNAs. PMID- 25820029 TI - Analysis of differentially expressed lncRNAs in differentiation of bone marrow stem cells into neural cells. AB - Many studies have reported micro RNAs involved in the differentiation of bone marrow mesenchymal stem cells (BMSCs) into neural cells; however, the roles of long non-coding RNAs (lncRNAs) in the differentiation of BMSCs into neural cells remain poorly understood. We used microarray assays to compare the lncRNA and messenger RNA (mRNA) expression profiles in BMSCs and neural-induced BMSCs. We found a total of 24 lncRNAs and 738 mRNAs that were upregulated and 32 lncRNAs and 682 mRNAs that were downregulated in samples induced for 3h; 27 lncRNAs and 864 mRNAs that were upregulated and 37 lncRNAs and 968 mRNAs that were downregulated in 6h samples; and 23 lncRNAs and 1159 mRNAs that were upregulated or downregulated in both the 3h and 6h samples. For 23 differentially lncRNAs and 83 differentially mRNAs, 256 matched lncRNA-mRNA pairs were found. GO (Gene ontology) analysis showed that these lncRNAs were associated with biological processes, cellular components, and molecular functions. Twenty-five pathways were identified by pathway analysis. Then, RT-qPCR validation of the differentially expressed H19, Esco2, Pcdhb18, and RGD1560277 genes confirmed the microarray data. Our study revealed the expression patterns of lncRNAs in the differentiation of BMSCs into neural cells, and many lncRNAs were differentially expressed in induced BMSCs, suggesting that they may play key roles in processes of differentiation. Our findings may promote the use of BMSCs to treat neurodegenerative diseases and trauma. PMID- 25820030 TI - Ethnic differences in susceptibility to malaria: what have we learned from immuno epidemiological studies in West Africa? AB - There are many fundamental aspects of the immunobiology of Plasmodium falciparum infections that are not fully understood, therefore limiting our comprehension of how people become immune to malaria and why some ethnic groups living in malaria endemic areas are less susceptible than others. The complexity of parasite-host interactions and the genetic diversity of the parasites as well as the human host complicate our strategy to address this issue. In this mini-review we discuss and summarize what we have learned about African ethnic differences in susceptibility to malaria from immuno-epidemiological studies. Additionally, we suggest research topics that might be of great value for dissecting the mechanisms of protection by providing new insights into molecular interactions between the parasite and the host. PMID- 25820031 TI - Ectoparasite fauna of rodents collected from two wildlife research centres in Saudi Arabia with discussion on the implications for disease transmission. AB - The majority of human pathogens are zoonotic and rodents play an important role as reservoirs of many of these infectious agents. In the case of vector-borne pathogens, rodent reservoirs not only act as a source of infection for vectors but also serve as hosts for the vectors themselves, supporting their populations. Current data on rodent-ectoparasite relationships is limited in Saudi Arabia, however, this is needed to assess disease risk and the relative importance of different hosts for the maintenance of vector-borne pathogen cycles. In order to provide baseline data for the region that could be used to assess zoonotic disease risk, we collected and identified 771 ectoparasite specimens (ticks, fleas and mites) from 161 rodents at two wildlife research centres in Saudi Arabia and discuss our results in the context of possible zoonotic disease risk based on the hosts and vectors present. PMID- 25820032 TI - Emergency physicians and firearm violence. PMID- 25820033 TI - Emergency Department Corticosteroid Use for Allergy or Anaphylaxis Is Not Associated With Decreased Relapses. AB - STUDY OBJECTIVE: Corticosteroids (steroids) are often used to mitigate symptoms and prevent subsequent reactions in emergency department (ED) patients with allergic reactions, despite a lack of evidence to support their use. We sought to determine the association of steroid administration with improved clinical outcomes. METHODS: Adult allergy-related encounters to 2 urban EDs during a 5 year period were identified and classified as "anaphylaxis" or "allergic reaction." Regional and provincial databases identified subsequent ED visits or deaths within a 7-day period. The primary outcome was allergy-related ED revisits in the steroid- and nonsteroid-exposed groups, adjusting for potential confounders with a propensity score analysis; secondary outcomes included the number of clinically important biphasic reactions and deaths. RESULTS: Two thousand seven hundred one encounters (473 anaphylactic) were included; 48% were treated with steroids. Allergy-related ED revisits occurred in 5.8% and 6.7% of patients treated with and without steroids, respectively (adjusted odds ratio [OR] 0.91; 95% confidence interval [CI] 0.64 to 1.28), with a number needed to treat (NNT) to benefit of 176 (95% CI NNT to benefit 39 to infinity to NNT to harm 65). The adjusted OR in the anaphylaxis subgroup was 1.12 (95% CI 0.41 to 3.27). In the allergic reaction group, the adjusted OR was 0.91 (95% CI 0.63 to 1.31), with an NNT to benefit of 173 (95% CI NNT to benefit 38 to infinity to NNT to harm 58). In the steroid and nonsteroid groups, there were 4 and 1 clinically important biphasic reactions, respectively. There were no deaths. CONCLUSION: Among ED patients with allergic reactions or anaphylaxis, corticosteroid use was not associated with decreased relapses to additional care within 7 days. PMID- 25820034 TI - Interactions of CO2 with various functional molecules. AB - The CO2 capturing and sequestration are of importance in environmental science. Understanding of the CO2-interactions with various functional molecules including multi-N-containing superbases and heteroaromatic ring systems is essential for designing novel materials to effectively capture the CO2 gas. These interactions are investigated using density functional theory (DFT) with dispersion correction and high level wave function theory (resolution-of-identity (RI) spin-component scaling (scs) Moller-Plesset second-order perturbation theory (MP2) and coupled cluster with single, double and perturbative triple excitations (CCSD(T))). We found intriguing molecular systems of melamine, 1,5,7-triazabicyclo[4.4.0]dec-5 ene (TBD), 7-azaindole and guanidine, which show much stronger CO2 interactions than the well-known functional systems such as amines. In particular, melamine could be exploited to design novel materials to capture the CO2 gas, since one CO2 molecule can be coordinated by four melamine molecules, which gives a binding energy (BE) of ~85 kJ mol(-1), much larger than in other cases. PMID- 25820035 TI - Management of Parapneumonic Pleural Effusion in Adults. AB - Pleural infections have high morbidity and mortality, and their incidence in all age groups is growing worldwide. Not all infectious effusions are parapneumonic and, in such cases, the organisms found in the pleural space are not the same as those observed in lung parenchyma infections. The diagnostic difficulty lies in knowing whether an infectious effusion will evolve into a complicated effusion/empyema, as the diagnostic methods used for this purpose provide poor results. The mainstays of treatment are to establish an early diagnosis and to commence an antibiotic regimen and chest drain as soon as possible. This should preferably be carried out with fine tubes, due to certain morphological, bacteriological and biochemical characteristics of the pleural fluid. Fluid analysis, particularly pH, is the most reliable method for assessing evolution. In a subgroup of patients, fibrinolytics may help to improve recovery, and their combination with DNase has been found to obtain better results. If medical treatment fails and surgery is required, video-assisted thoracoscopic surgery (VATS) is, at least, comparable to decortication by thoracotomy, so should only undertaken if previous techniques have failed. Further clinical trials are needed to analyze factors that could affect the results obtained, in order to define new evidence-based diagnostic and therapeutic strategies that provide more effective, standardized management of this disease. PMID- 25820036 TI - Quality of spirometric data in Spain: The 3E study. PMID- 25820037 TI - A phylogenetically informed delineation of floristic regions within a biodiversity hotspot in Yunnan, China. AB - Traditional attempts to delineate floristic regions typically focus on species distributions, often ignoring the rich context that phylogenetic relationships can provide. In this study, we explore how phylogenetic relatedness, taxonomic composition, and regional phylogenetic structure change across a global biodiversity hotspot region, Yunnan, located in southwestern China. We propose a system of floristic regions within Yunnan by combining data on the distributions and phylogenetic relationships of 1,983 genera of native seed plants. We identified eight distinct floristic regions in Yunnan, which were grouped into two larger northern and southern geographical units. Phylogenetic relatedness was well correlated with taxonomic composition between floras in Yunnan. Across the Yunnan region we examined, the central Yunnan region shows the lowest level of spatial turnover in phylogenetic relationships and taxonomic composition of the floristic assemblages. Using null model analyses, we found evidence of nonrandom phylogenetic structure across the region, in which four areas show higher phylogenetic turnover than expected given the underlying taxonomic composition between sites. Our results show that the integration of phylogenetic information can provide valuable insight in floristic assessments, and help us to better understand the structure of a global biodiversity hotspot. PMID- 25820038 TI - Chromosomal DNA damage in APOE E4 carriers and noncarriers does not appear to be different. AB - DNA damage may play a key role in promoting disease-onset and accelerated disease progression in Alzheimer's disease (AD) by increasing the rates of neuronal cell death. The E4 allele of the APOE gene is the best characterised genetic risk factor for AD, however, it is unknown if APOE E4 carriers exhibit increased levels of DNA damage which may contribute to increased AD risk. 175 healthy participants (aged 34-67 years old) from South Australia were recruited into the study and provided a single blood sample for the isolation of peripheral blood lymphocytes, APOE genotyping and lymphocyte chromosomal DNA damage analysis using the Cytokinesis-Block micronucleus cytome (CBMN-Cyt) assay with the micronucleus index being the primary outcome measure. When compared to non-APOE E4 carriers, APOE E4 carriers did not exhibit altered rates of i) cell division, represented by the nuclear division index (NDI, P = 0.372), ii) cell death as represented by apoptotic (P = 0.457) and necrotic (P = 0.393) frequencies and iii) chromosomal DNA damage as indicated by the number of micronuclei (MNi, P = 0.795), nucleoplasmic bridges (NPBs, P = 0.221) or nuclear buds (NBUDs, P = 0.293) scored in binucleated cells. In conclusion, although we and others have previously shown that rates of chromosomal DNA damage measured using the CBMN-Cyt assay are elevated in individuals with cognitive impairment, in this South Australian cohort the frequency of genome instability is not substantially influenced by the presence of the APOE E4 allele. PMID- 25820039 TI - Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases. AB - Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their efficacy and safety in cancer and other diseases. PMID- 25820040 TI - What ails the practice of medicine: the Atlas has shrugged. AB - Health-care providers are currently facing a huge challenge. At one end they are expending a huge amount of time and energies on health-care delivery including time spent on upgradation of their knowledge and skills (to remain abreast with the field and be able to provide state-of-art patient care), sometimes even at the expense of themselves and their families. On the other hand they are not receiving adequate re-imbursement for their efforts. To compound the problem several "traders" have entered the profession who are well adept in the materialistic approach abandoning the ethics (which currently happens to be the flavor of society in general), giving a bad name to the whole profession and causing severe grief, embarrassment and even dis-illusion to an average physician. The solution to the problem may lie in weeding out these "black sheep" as also realization by the society that the whole profession should not be wrongly labeled, rather a hard toiling and a morally driven practitioner should be given his/her due worth. PMID- 25820041 TI - From 'Make in India' to 'Made in India': the saroglitazar story. PMID- 25820042 TI - Vitamin D and cardiovascular disease - have we found the answers? PMID- 25820043 TI - The CRRIS study: beginning of a new era of enquiry and educational intervention in India. PMID- 25820044 TI - Challenges of STEMI care in India & the real world. PMID- 25820045 TI - "Hypertension guidelines: good-bye to confusion and welcome to clarity". PMID- 25820046 TI - Observational study to evaluate the safety and efficacy of saroglitazar in Indian diabetic dyslipidemia patients. AB - Saroglitazar is a dual PPAR alpha/gamma agonist approved in India for the management of diabetic dyslipidemia. AIMS: The objective of this study was to evaluate the safety and efficacy of saroglitazar 4 mg once daily in clinical practice. METHODS: This was an observational, multicenter, single-arm study. Patients with type 2 diabetes (with on-going antidiabetic medication), age above 18 years, and triglycerides >=200 mg/dL were included. RESULTS: A total 2804 patients with a mean duration of diabetes 6.29 yrs were included in this analysis. The baseline demographic profile was: mean age of 53 yrs, mean body weight 72.3 kg and mean BMI of 27 kg/m(2). 62.5% patients were male and 57.8% were reported to be on statin therapy at baseline. All 2804 patients were on antidiabetic medications with 15.4% patients on monotherapy and rest were on two or more than two antidiabetic medications at baseline. The baseline triglycerides and HbA1C values were 312.3 mg/dL and 8.3% respectively. At 3 months follow-up, use of saroglitazar 4 mg led to significant reduction in TG (35.8%), LDL-C (16.4%), total cholesterol (19%) and non-HDL-C (23.4%). Addition of saroglitazar to baseline antidiabetic medications showed a significant 0.9% absolute reduction in HbA1c with significant improvement in fasting and post prandial plasma glucose. No serious adverse events, alteration in liver or renal enzymes and edema or weight gain were reported. CONCLUSION: Saroglitazar is a potential therapeutic option in type 2 diabetic patients with high TG levels, not controlled by statins, for comprehensive control of lipid and glycemic parameters with acceptable safety profile. PMID- 25820047 TI - Independent association of severe vitamin D deficiency as a risk of acute myocardial infarction in Indians. AB - BACKGROUND: Association of vitamin D deficiency with coronary heart disease (CHD) has been widely reported. Emerging data has shown high prevalence of vitamin D deficiency among Indians. However, this association has not been studied in Indians. METHODS: A case-control study with 120 consecutive cases of first incident acute myocardial infarction (MI) and 120 age and gender matched healthy controls was conducted at All India Institute of Medical Sciences, New Delhi. The standard clinical and biochemical risk factors for MI were assessed for both cases and controls. Serum 25 (OH) vitamin D assay was performed from stored samples for cases and controls using radioimmunoassay. RESULTS: Vitamin D deficiency [25(OH) D < 30 ng/ml] was highly prevalent in cases and controls (98.3% and 95.8% respectively) with median levels lower in cases (6 ng/ml and 11.1 ng/ml respectively; p < 0.001). The cases were more likely to have diabetes, hypertension and consume tobacco and alcohol. They had higher waist hip ratio, total and LDL cholesterol. Multivariate logistic regression analysis revealed severe vitamin D deficiency [25(OH) vitamin D < 10 ng/ml] was associated with a risk of MI with an odds ratio of 4.5 (95% CI 2.2-9.2). CONCLUSIONS: This study reveals high prevalence of vitamin D deficiency among cases of acute MI and controls from India, with levels of 25 (OH)D being significantly lower among cases. Despite rampant hypovitaminosis, severe vitamin D deficiency was associated with acute MI after adjusting for conventional risk factors. This association needs to be tested in larger studies in different regions of the country. PMID- 25820048 TI - Cardiovascular risk reduction intervention among school-students in Kolkata, West Bengal - the CRRIS study protocol. AB - BACKGROUND: Increasing burden of cardiovascular risk-factors among adolescent school-children is a major concern in India. Dearth of information regarding the burden of these factors and the efficacy of educational intervention in minimizing them among urban school-students of India called for a school-based, educational intervention involving a representative sample of these students and their caregivers. METHODOLOGY: Using a randomized-controlled design with stratified-random sampling, 1000 students (approximately 50/school) of 9th grade from 20 randomly selected schools (representing all socio-economic classes and school-types) and their caregivers (preferably mothers) will be recruited. Objectives of the study will include: estimation of the baseline burden and post interventional change in cardiovascular risk-factors, related knowledge, perception and practice among participants in Kolkata. DATA COLLECTION: After obtaining appropriate consent (assent for adolescents), collection of the questionnaire-based data (regarding cardiovascular disease/risk-factor related knowledge, perception, practice), anthropometric measurements, stress assessment and cardiological check-up (pulse and blood pressure measurement along with auscultation for any abnormal heart sounds) will be conducted for each participating students twice at an interval of six months. In between 6 educational sessions will be administered in 10 of the 20 schools randomized to the intervention arm. After the follow-up data collection, same sessions will be conducted in the non-interventional schools. DATA ANALYSES AND DELIVERABLE: Descriptive and inferential analyses (using SAS 9.3) will be conducted to determine the distribution of the risk-factors and efficacy of the intervention in minimizing them so that policy-making can be guided appropriately to keep the adolescents healthy in their future life. PMID- 25820049 TI - NT pro B type natriuretic peptide levels in constrictive pericarditis and restrictive cardiomyopathy. AB - BACKGROUND: The differentiation of constrictive pericarditis (CP) from restrictive cardiomyopathy (RCM) may be clinically difficult and may require multiple investigations. Even though brain natriuretic peptide (BNP) is shown to be higher in patients with RCM as compared to CP, the clinical utility is not fully established especially in Indian patients known to have advanced CP and myocardial involvement. METHODS AND RESULTS: We measured NT-pro-BNP levels in 49 patients suspected of having either CP or RCM, diagnosed on the basis of echocardiography, computed tomography, magnetic resonance imaging, endomyocardial biopsy and cardiac catheterization data as needed. Twenty nine patients (Mean age - 26 yrs, 24 males) had CP and 20 patients (Mean age - 39 yrs, 14 males) had RCM. The median plasma NT-pro-BNP levels were significantly higher in RCM as compared to CP [1775 (208-7500) pg/ml vs 124 (68-718) pg/ml, respectively; p = 0.001]. A cut off value of 459 pg/ml had sensitivity, specificity and overall accuracy of 90%, 86% and 88% respectively, for differentiating CP from RCM. CONCLUSIONS: The NT-pro-BNP levels are significantly elevated in RCM as compared to CP. PMID- 25820050 TI - Prevalence of rheumatic fever and rheumatic heart disease in Bangladeshi children. AB - BACKGROUND: Recent prevalence data on rheumatic fever (RF) and rheumatic heart disease (RHD) are lacking in Bangladeshi population. AIM: We have done this national level cross-sectional survey to determine the prevalence of RF and RHD in Bangladeshi children. METHODS: Samples were drawn from three out of seven divisions of Bangladesh from both urban and rural areas. Trained and experienced enumerators visited households to suspect cases of RF or RHD in 5-19 years children by asking structured questions on symptoms and signs of RF and RHD (n = 56,827). Then trained doctors again took history and examined them for RF/RHD. RF was defined according to the Modified Jones Criteria 1992. Doppler echocardiography was done to confirm the diagnosis in all suspected cases of RF/RHD. RESULTS: A total of 36 RF cases (new and old) and 16 Doppler echocardiography confirmed RHD cases were identified. Prevalence of RF and RHD was 0.9 per 1000 (95% confidence interval: 0.7-1.2) while prevalence of RF was 0.6 per 1000 (95% CI: 0.4-0.9) and RHD 0.3 per 1000 (95% CI: 0.2-0.5). CONCLUSION: Observed prevalence of RF and RHD indicates that RF/RHD is disappearing from Bangladesh. However, studies using new technology of portable echocardiographic screening are needed. PMID- 25820051 TI - Comparing stress testing and fractional flow reserve to evaluate presence, location and extent of ischemia in coronary artery disease. AB - BACKGROUND: FFR provides an accurate and reproducible assessment of the functional severity of coronary stenosis. Whereas stress testing remains the preferred initial modality for assessment of ischemia, there is limited data comparing it with FFR. We sought to determine the correlation between cardiac stress testing and coronary fractional flow reserve (FFR) measurement for assessing the presence, location, and burden of myocardial ischemia in patients referred for evaluation of coronary artery disease (CAD). METHODS: Over 5-year study period, of the 5420 consecutive coronary angiograms that were screened, 326 patients had FFR measurements. Of these, 96 patients with FFR measurements who had a preceding stress test (stress echocardiography [SE] or myocardial perfusion imaging [MPI]) within a year were included. RESULTS: Of the 96 patients, there were 46 (48%) men and 50 (52%) women with a mean age of 61 +/- 10 years. SE was performed in 57 (59.3%) and MPI in 32 (40.7%) of patients. FFR was <=0.79 in 54 (56%) patients. Stress testing had low sensitivity (55%) and specificity (47%) compared to FFR. The concordance between FFR and stress testing was low for both presence (k=0.03) and location (k=0.05) of the ischemic territory. The number of ischemic vascular territories was correctly estimated in only 39% of the stress tests. SE was more likely to overestimate and MPI more likely to underestimate extent of ischemia. CONCLUSIONS: In patients referred for evaluation of CAD, there was poor correlation between stress testing and FFR. A prospective study comparing these two modalities with FFR is needed. PMID- 25820052 TI - Inappropriate shock for myopotential over-sensing in a patient with subcutaneous ICD. AB - Inappropriate ICD shocks are common adverse events; they are mainly due to supraventricular arrhythmias and secondly are related to noise, undersensing, oversensing, device malfunctions. We present a case of inappropriate device therapy due to myopotential oversensing in a patient with a subcutaneous ICD (s ICD). A 58 years old male with an s-ICD during the device interrogation showed a previous episode of suspected sustained ventricular tachycardia at 210 bpm, which was effectively treated with ICD shock. The patient experienced the electrical shock while holding a big gas-cylinder in his arms. The EGM analysis revealed many irregular ventricular signals of low amplitude lasting for 24 s and interrupted by the shock. The device showed no malfunctions. This is the first case report of inappropriate S-ICD shock related to myopotential over-sensing. By recording intracardiac EGM, we demonstrated that the noise was created by the activity of the pectorals muscles. PMID- 25820053 TI - Iatrogenic mitral stenosis following transcatheter aortic valve replacement (TAVR). AB - A 57 year old female underwent transcatheter aortic valve replacement (TAVR) for severe aortic stenosis. Mild iatrogenic mitral stenosis was noted intraoperatively. Attempts to reposition the device were hampered by aortic angulation. One year later, severe mitral stenosis was confirmed on transoesophageal echocardiography. It is important to recognise that iatorgenic mitral stenosis due to TAVR may progress over time. Care should be taken to minimise the risk of this rare complication. PMID- 25820054 TI - 3-D optical coherence tomographic image of bifurcation lesion treated with two Absorb scaffolds. PMID- 25820055 TI - Methemoglobinemia and arterial blood gas. PMID- 25820056 TI - Hypertrophy to failure: what goes wrong with the fibers of the heart? PMID- 25820057 TI - How to perform transeptal puncture. PMID- 25820058 TI - Value of FFR in clinical practice. AB - Fractional flow reserve is an important tool in the cardiac catheterization lab to assess the physiological significance of coronary lesions. This article discusses the basic concepts about FFR and its utility in clinical decision making. PMID- 25820059 TI - Yoga: from cardiovascular benefit to the gates of God. PMID- 25820060 TI - A/H1N1 pandemic influenza vaccination: A retrospective evaluation of adverse maternal, fetal and neonatal outcomes in a cohort of pregnant women in Italy. AB - Although concerns about safety of influenza vaccination during pregnancy have been raised in the past, vaccination of pregnant women was recommended in many countries during the 2009 A/H1N1 pandemic influenza. A retrospective cohort study was conducted to evaluate the risk of adverse maternal, fetal and neonatal outcomes among pregnant women vaccinated with a MF59-adjuvanted A/H1N1 pandemic influenza vaccine. The study was carried out in four Italian regions (Piemonte, Friuli-Venezia-Giulia, Lazio, and Puglia) among 102,077 pregnant women potentially exposed during the second or third trimester of gestation to the vaccination campaign implemented in 2009/2010. Based on data retrieved from the regional administrative databases, the statistical analysis was performed using the Cox proportional-hazards model, adjusting for the propensity score to account for the potential confounding effect due to the socio-demographic characteristics and the clinical and reproductive history of women. A total of 100,332 pregnant women were eligible for the analysis. Of these, 2003 (2.0%) received the A/H1N1 pandemic influenza vaccination during the second or third trimester of gestation. We did not observe any statistically significant association between the A/H1N1 pandemic influenza vaccination and different maternal outcomes (hospital admissions for influenza, pneumonia, hypertension, eclampsia, diabetes, thyroid disease, and anaemia), fetal outcomes (fetal death after the 22nd gestational week) and neonatal outcomes (pre-term birth, low birth weight, low 5-min Apgar score, and congenital malformations). Pre-existing health-risk conditions (hospital admissions and drug prescriptions for specific diseases before the onset of pregnancy) were observed more frequently among vaccinated women, thus suggesting that concomitant chronic conditions increased vaccination uptake. The results of this study add some evidence on the safety of A/H1N1 pandemic influenza vaccination during pregnancy but, because of the reduced statistical power, meta-analyses and large multi-centres studies are needed in order to obtain more conclusive results, especially for rare outcomes. PMID- 25820061 TI - Porcine reproductive and respiratory syndrome virus (PRRSv) modified-live vaccine reduces virus transmission in experimental conditions. AB - Some vaccination strategies have shown good results in reducing the clinical outcomes of PRRS. Nevertheless the effect of vaccines on viral transmission is poorly described, so we aimed to fill this gap with the present study. Twelve Specific Pathogen Free (SPF) piglets, vaccinated against PRRSv at 3 weeks of age (Porcilis PRRS ID((r)), MSD), were inoculated at 31 days post-vaccination with a heterologous genogroup 1.1 strain, and put in contact with 12 vaccinated piglets during 49 days. The same protocol was carried out simultaneously with SPF non vaccinated piglets. Piglets were monitored individually for clinical symptoms on a daily basis and individual blood samples were taken twice a week. In inoculated piglets, the genome viral load specific to the inoculated strain was reduced and viraemia shortened in vaccinated piglets (28 days versus 38 days in non vaccinated piglets). In contact pigs, the challenge strain was detected in the serum of only one vaccinated piglet whereas it was detected in all contact non vaccinated piglets. Transmission parameters were estimated by a Bayesian analysis of transmission data in the two groups. The estimated transmission rate was 10 times lower in vaccinated than in non-vaccinated piglets and the duration of infectiousness was reduced, leading to a reproduction ratio R significantly lower (0.30 [0.05-0.96] versus 5.42 [2.94-9.04] in non vaccinated piglets). Hence, in our experimental conditions, vaccination was able to decrease considerably PRRSv spread. A complementary evaluation in field conditions would be required to identify circumstances associated with infection control failures that can be observed in pig farms. PMID- 25820062 TI - Accounting for personal and professional choices for pandemic influenza vaccination amongst English healthcare workers. AB - BACKGROUND: Healthcare workers (HCWs) are encouraged to get vaccinated during influenza pandemics to reduce their own, and patients', risk of infection, and to encourage their patients to get immunised. Despite extensive research on HCWs' receipt of vaccination, little is known about how HCWs articulate pandemic influenza vaccination advice to patients. AIMS: To explore HCWs' uptake of the A/H1N1 vaccine during the pandemic of 2009-2010, their recommendations to patients at the time, and their anticipated choices around influenza vaccination under different pandemic scenarios. METHOD: We conducted semi-structured interviews and focus groups with eight vaccinated and seventeen non-vaccinated HCWs from primary care practices in England. The data was analysed using thematic analysis. RESULTS: The HCWs constructed their receipt of vaccination as a personal choice informed by personal health history and perceptions of vaccine safety, while they viewed patients' vaccination as choices made following informed consent and medical guidelines. Some HCWs received the A/H1N1 vaccine under the influence of their local practice organizational norms and values. While non-vaccinated HCWs regarded patients' vaccination as patients' choice, some vaccinated HCWs saw it also as a public health issue. The non-vaccinated HCWs emphasised that they would not allow their personal choices to influence the advice they gave to patients, whereas some vaccinated HCWs believed that by getting vaccinated themselves they could provide a reassuring example to patients, particularly those who have concerns about influenza vaccination. All HCWs indicated they would accept vaccination under the severe pandemic scenario. However, most non-vaccinated HCWs expressed reticence to vaccinate under the mild pandemic scenario. CONCLUSIONS: Providing evidence-based arguments about the safety of new vaccines and the priority of public health over personal choice, and creating strong social norms for influenza vaccination as part of the organizational culture, should increase uptake of influenza vaccination among primary care HCWs and their patients. PMID- 25820063 TI - A cytomegalovirus-based vaccine provides long-lasting protection against lethal Ebola virus challenge after a single dose. AB - Ebola virus (Zaire ebolavirus; EBOV) is a highly lethal hemorrhagic disease virus that most recently was responsible for two independent 2014 outbreaks in multiple countries in Western Africa, and the Democratic Republic of the Congo, respectively. Herein, we show that a cytomegalovirus (CMV)-based vaccine provides durable protective immunity from Ebola virus following a single vaccine dose. This study has implications for human vaccination against ebolaviruses, as well as for development of a 'disseminating' vaccine to target these viruses in wild African great apes. PMID- 25820065 TI - Socioeconomic status and HIV vaccine preparedness studies in North America. AB - Educational level, employment, and income are key components of socioeconomic status (SES). This article is a systematic review of SES variables in North American countries, and their relationship to willingness to participate (WTP) and retention in a hypothetical preventive phase 3 HIV vaccine trial and in actual HIV vaccine trials. Men who have sex with men (MSM) tended to have higher educational levels, be more employed, and had higher income levels than injection drug users (IDU) and women at heterosexual risk (WAHR). In large part, there was no relationship between educational level and WTP, as well as between educational level and retention. Similarly, there was no relationship between employment and WTP. In WAHR who were African-American, those employed were less likely than others to complete the study at 18 months. The exact occupations of participants analyzed have not been specified, and specification of these occupations may help determine whether enhanced retention (ER) strategies are required. PMID- 25820064 TI - Evaluation of the protective efficacy of four novel identified membrane associated proteins of Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 (S. suis 2) is an important zoonotic pathogen that can also cause epidemics of life-threatening infections in humans. Surface proteins of pathogens play a critical role in the interaction with host system or environment, as they take part in processes like virulence, cytotoxicity, adhesion, signaling or transport, etc. Thus, surface proteins identified by the screening of immunoproteomic techniques are promising vaccine candidates or diagnostic markers. In this study, four membrane associated proteins (MAP) identified by immunoproteomic method were cloned and expressed as recombinant proteins with his-tag. Screening for vaccine candidates were firstly performed by protection assay in vivo and immunization with Sbp markedly protected mice against systemic S. suis 2 infection. The immune responses and protective of Sbp were further evaluated. The results showed that Sbp could elicit a strong humoral antibody response and protect mice from lethal challenge with S. suis 2. The antiserum against Sbp could efficiently impede survival of bacterial in whole blood killing assay and conferred significant protection against S. suis 2 infection in passive immunization assays. The findings indicate that Sbp may serve as an important factor in the pathogenesis of S. suis 2 and would be a promising subunit vaccine candidate. PMID- 25820066 TI - Anthrax vaccine recipients lack antibody against the loop neutralizing determinant: A protective neutralizing epitope from Bacillus anthracis protective antigen. AB - BACKGROUND: Epitope-focused immunogens can elicit antibody against the loop neutralizing determinant (LND), a neutralizing epitope found within the 2beta2 2beta3 loop of protective antigen (PA), which can protect rabbits from high-dose inhalation challenge with Bacillus anthracis Ames strain. Interestingly, data suggests that this epitope is relatively immunosilent in rabbits and non-human primates immunized with full length PA. METHODS: To determine whether the LND is immunosilent among humans vaccinated with PA, we screened antisera from AVA- or placebo-vaccinees from a clinical trial for antibody reactive with the LND. RESULTS: AVA-vaccinee sera had significant PA-specific antibody compared to placebo-vaccinee sera; however, sera from the two cohorts were indistinguishable with regard to the frequency of individuals with antibody specific for the LND. CONCLUSIONS: AVA-vaccinees have a low frequency of antibody reactive with the LND. As with rabbits and non-human primates, the elicitation of LND-specific antibody in humans appears to require immunization with an epitope-focused vaccine. PMID- 25820067 TI - Multiple factors affect immunogenicity of DNA plasmid HIV vaccines in human clinical trials. AB - Plasmid DNA vaccines have been licensed for use in domesticated animals because of their excellent immunogenicity, but none have yet been licensed for use in humans. Here we report a retrospective analysis of 1218 healthy human volunteers enrolled in 10 phase I clinical trials in which DNA plasmids encoding HIV antigens were administered. Elicited T-cell immune responses were quantified by validated intracellular cytokine staining (ICS) stimulated with HIV peptide pools. HIV-specific binding and neutralizing antibody activities were also analyzed using validated assays. Results showed that, in the absence of adjuvants and boosting with alternative vaccines, DNA vaccines elicited CD8+ and CD4+ T cell responses in an average of 13.3% (95% CI: 9.8-17.8%) and 37.7% (95% CI: 31.9 43.8%) of vaccine recipients, respectively. Three vaccinations (vs. 2) improved the proportion of subjects with antigen-specific CD8+ responses (p=0.02), as did increased DNA dosage (p=0.007). Furthermore, female gender and participants having a lower body mass index were independently associated with higher CD4+ T cell response rate (p=0.001 and p=0.008, respectively). These vaccines elicited minimal neutralizing and binding antibody responses. These findings of the immunogenicity of HIV DNA vaccines in humans can provide guidance for future clinical trials. PMID- 25820068 TI - High-yield production of recombinant virus-like particles of enterovirus 71 in Pichia pastoris and their protective efficacy against oral viral challenge in mice. AB - Enterovirus 71 (EV71) is one of the major causative pathogens of hand, foot and mouth disease (HFMD), which is highly prevalent in the Asia-Pacific regions. Severe HFMD cases with neurological complications and even death are often associated with EV71 infections. However, no licensed EV71 vaccine is currently available. Recombinant virus-like particles (VLPs) of EV71 have been produced and shown to be a promising vaccine candidate in preclinical studies. However, the performance of current recombinant expression systems for EV71 VLP production remains unsatisfactory with regard to VLP yield and manufacturing procedure, and thus hinders further product development. In this study, we evaluated the expression of EV71 VLPs in Pichia pastoris and determined their protective efficacy in mouse models of EV71 infections. We showed that EV71 VLPs could be produced at high levels up to 4.9% of total soluble protein in transgenic P. pastoris yeast co-expressing P1 and 3CD proteins of EV71. The resulting yeast produced VLPs potently induced neutralizing antibodies against homologous and heterologous EV71 strains in mice. More importantly, maternal immunization with VLPs protected neonatal mice in both intraperitoneal and oral challenge experiments. Collectively, these results demonstrated the success of simple, high yield production of EV71 VLPs in transgenic P. pastoris, thus lifting the major roadblock in commercial development of VLP-based EV71 vaccines. PMID- 25820069 TI - Development of a dual vaccine for prevention of Brucella abortus infection and Escherichia coli O157:H7 intestinal colonization. AB - Zoonoses that affect human and animal health have an important economic impact. In the study now presented, a bivalent vaccine has been developed that has the potential for preventing the transmission from cattle to humans of two bacterial pathogens: Brucella abortus and Shiga toxin-producing Escherichia coli (STEC). A 66kDa chimeric antigen, composed by EspA, Intimin, Tir, and H7 flagellin (EITH7) from STEC, was constructed and expressed in B. abortus Deltapgm vaccine strain (BabDeltapgm). Mice orally immunized with BabDeltapgm(EITH7) elicited an immune response with the induction of anti-EITH7 antibodies (IgA) that clears an intestinal infection of E. coli O157:H7 three times faster (t=4 days) than mice immunized with BabDeltapgm carrier strain (t=12 days). As expected, mice immunized with BabDeltapgm(EITH7) strain also elicited a protective immune response against B. abortus infection. A Brucella-based vaccine platform is described capable of eliciting a combined protective immune response against two bacterial pathogens with diverse lifestyles-the intracellular pathogen B. abortus and the intestinal extracellular pathogen STEC. PMID- 25820071 TI - mAb C19 targets a novel surface marker for the isolation of human cardiac progenitor cells from human heart tissue and differentiated hESCs. AB - AIMS: Cardiac progenitor cells (CPCs) have been isolated from adult and developing hearts using an anti-mouse Sca-1 antibody. However, the absence of a human Sca-1 homologue has hampered the clinical application of the CPCs. Therefore, we generated novel monoclonal antibodies (mAbs) specifically raised against surface markers expressed by resident human CPCs. Here, we explored the suitability of one of these mAbs, mAb C19, for the identification, isolation and characterization of CPCs from fetal heart tissue and differentiating cultures of human embryonic stem cells (hESCs). METHODS & RESULTS: Using whole-cell immunization, mAbs were raised against Sca-1+ CPCs and screened for reactivity to various CPC lines by flow cytometry. mAb C19 was found to be specific for Sca-1+ CPCs, with high cell surface binding capabilities. mAb C19 stained small stem like cells in cardiac tissue sections. Moreover, during differentiation of hESCs towards cardiomyocytes, a transient population of cells with mAb C19 reactivity was identified and isolated using magnetic-activated cell sorting. Their cell fate was tracked and found to improve cardiomyocyte purity from hESC-derived cultures. mAb C19+ CPCs, from both hESC differentiation and fetal heart tissues, were maintained and expanded in culture, while retaining their CPC-like characteristics and their ability to further differentiate into cardiomyocytes by stimulation with TGFbeta1. Finally, gene expression profiling of these mAb C19+ CPCs suggested a highly angiogenic nature, which was further validated by cell based angiogenesis assays. CONCLUSION: mAb C19 is a new surface marker for the isolation of multipotent CPCs from both human heart tissues and differentiating hESCs. PMID- 25820070 TI - Evaluation of a Salmonella Enteritidis vaccine and related ELISA for respective induction and assessment of acquired immunity to the vaccine and/or Echinacea purpurea in Awassi Ewes. AB - The aim of this study was to evaluate an experimental Salmonella Enteritidis (SE) bacterin and an indirect ELISA system to assess quantitatively the acquired immunity in Awassi ewes to the vaccine and/or Echinacea purpurea (EP) dried roots. Four treatments of the ewes were included in the experimental design, with 6 ewes/treatment. The first treatment (T1) had the controls that were non vaccinated and non-treated with EP. The T2 ewes were only treated with EP. The T3 and T4 ewes were vaccinated at D1 (initiation of trial) and D10, while the T4 ewes were additionally administered the EP dried roots. Blood was collected from the jugular vein of all ewes at D1, D10, D21 and D45. The construction of the vaccine and the ELISA are detailed within the manuscript. The ELISA was able to detect quantitatively the significant acquired primary and secondary immunity to the vaccine in T3 and T4 ewes, compared to their low level of background immunities at initiation of the experiment (p<0.05). In addition, the ELISA detected the absence of seroconversion at all blood sampling times (p>0.05) in T1 control ewes, and in the T2 ewes that were given only the (EP) (p>0.05). Moreover, the ELISA was able to uncover the significant seroconversion of secondary immune response in T4 ewes at D21 compared to that at D10 (p<0.05), and the absence of significant seroconversion of secondary response in T3 ewes. This is the first work in literature that reports the need to supplement the vaccination by the experimental SE bacterin with daily oral intake of 250mg of EP dried roots, effective the first vaccination day and up to 21 days, for obtaining a statistically significant seroconversion. PMID- 25820073 TI - Nickel-catalyzed direct thiolation of unactivated C(sp(3))-H bonds with disulfides. AB - The first nickel-catalyzed thiolation of unactivated C(sp(3))-H bonds with disulfides was described. This transformation uses (dppp)NiCl2 as a catalyst and BINOL as a ligand, which are efficient for the thiolation of beta-methyl C(sp(3)) H bonds of a broad range of aliphatic carboxamides. The reaction provides an efficient synthetic pathway to access diverse thioethers. PMID- 25820072 TI - Maternal occupational exposure to ionizing radiation and major structural birth defects. AB - BACKGROUND: Ionizing radiation (IR) is known to be carcinogenic and mutagenic, but little is known about the association between maternal occupational exposure to IR and birth defects. METHODS: We studied 38,009 mothers who participated in the National Birth Defects Prevention Study and delivered between 1997 and 2009. We assessed odds ratios [ORs] for the association between maternal occupations with potential exposure to IR and 39 birth defects. RESULTS: We observed significant odds ratios (ORs) for isolated hydrocephaly (adjusted OR [AOR], 2.1; 95% confidence interval [CI], 1.1-4.2), isolated anotia/microtia (AOR, 2.0; 95% CI, 1.0-4.0), isolated colonic atresia (crude OR, 7.5; 95% CI, 2.5-22.3), isolated omphalocele (AOR, 2.3; 95% CI, 1.1-4.6) and isolated anencephaly (crude OR, 0.23; 95% CI, 0.06-0.94). We also observed a nonsignificant OR for birth defects in aggregate (AOR, 2.0; 95% CI, 0.9-4.6) among mothers with potential occupational exposure to fluoroscopy. CONCLUSION: We assessed 39 birth defects, observing that maternal occupations with potential exposure to IR were associated with a significantly increased risk for 4 birth defects and a significantly protected risk for 1 birth defect. These results should be interpreted cautiously because our measurement of exposure is qualitative, some of these associations may be due to occupational exposures that are correlated with IR and some may be due to chance. However, these findings serve as the first evaluation of these relationships in a large study and may be useful for generating hypotheses for future studies. PMID- 25820074 TI - Duodenal diverted sleeve gastrectomy with ileal interposition does not cause biliary salt malabsorption. AB - BACKGROUND: Duodenal diverted sleeve gastrectomy with ileal interposition (DDSG II) is a bariatric-metabolic operation designed to treat type 2 diabetes mellitus (T2DM). It is restrictive (SG) but also acts on the small bowel with functional effects. The objective of the present study was to investigate whether or not it is also a malabsorptive operation. METHODS: Twelve obese patients (9 female and 3 male) affected by T2DM had DDSG-II. Follow-up was every 3 months, and the results after 1 year are reported here. Clinical conditions, related to diabetes and malnutrition, changes in weight, body mass index, fasting glucose plasma levels, HbA1c (glycated hemoglobin %), basal insulin, vitamin B12, folic acid, vitamin D, total proteins, albumin, and hemoglobin were recorded. Basal plasma levels of FGF19 (pg/mL) and of 7alpha-hydroxy-4-cholesten-3-one (C4) (MUg/dL) were also determined for the diagnosis of biliary salt malabsorption. The results were expressed as mean+/-SEM, and the differences between times compared by the Mann Whitney U test; P<.05 was considered significant. RESULTS: After 1 year, all patients had a significant weight loss (-33.2+/-3 kg) with T2DM remission according to the American Diabetes Association criteria (11), criteria. No significant changes in total proteins, albumin, hemoglobin, and vitamins (B6, B12, and D) were detected. C4 did not change after the operation (2+/-.5 ug/dL versus 1.6+/-.5 ug/dL), whereas FGF19 significantly increased (from 85+/-11.2 pg/mL to 166.4+/-28.2 pg/mL, P<.04). Only 2 patients had mild symptoms of malabsorption. CONCLUSIONS: DDSG-II is effective for treatment of T2DM obese patients, increases the enterokine FGF19, and does not cause biliary salt malabsorption. PMID- 25820075 TI - Roux-en-Y gastric bypass is associated with an increased exposure to ionizing radiation. AB - BACKGROUND: Bariatric surgery provides for a reliable and sustainable solution to the obesity epidemic. The gold standard bariatric surgical procedure is the Roux en-Y gastric bypass (RYGB). Assessment of this population preoperatively and work up of postoperative complications often includes radiographic evaluation. Repeated exposure to radiation is not without complication. OBJECTIVE: Assess the association between the RYGB and exposure to ionizing radiation. SETTING: Academic medical center. METHODS: Patients were identified by their ICD-9 code as having had a RYGB at the Massachusetts General Hospital (MGH) from 2002 to 2012. The number of abdominal and pelvis (A/P) computed tomography (CT) scans performed was determined and converted into an effective dose (ED) and expressed as milliSeiverts (mSv) to illustrate the biologic effects of radiation. RESULTS: From 2002 to 2012, 1789 primary laparoscopic RYGBs were completed. Fifty-five revisional operations were completed on 51 patients. Of these, 38 had both their index and second operation at the MGH. A total of 1065 A/P CTs were completed in the laparoscopic RYGB population (mean = .6), and 106 A/P CTs were done in the revisional surgery cohort (mean = 2.8). The mean ED of radiation was 56.1 mSv and 19.5 mSv for the index and revisional populations, respectively. CONCLUSIONS: This study demonstrated the significant cumulative radiation exposure attributable to A/P CTs. This exposes the patient to a potential increased risk of malignancy as well as imposing a financial burden on the healthcare system. The findings of this study raise the awareness of an increased risk of radiation exposure for this population and the necessity of creation of a dedicated algorithm for the mindful utilization of CT imaging. PMID- 25820076 TI - Modification of Belsey (Mark IV) fundoplication in the management of hiatal hernia and gastroesophageal reflux disease after sleeve gastrectomy: a case report. PMID- 25820077 TI - A tribute to Dr. Edward E. Mason, M.D. PMID- 25820078 TI - Effect of bismuth subgallate on the quality of life in patients undergoing Scopinaro's biliopancreatic diversion. AB - BACKGROUND: Malabsorptive techniques, such as biliopancreatic diversion, described by Scopinaro, can cause disabling steatorrhea that affects patients' quality of life. Although it usually improves over time, a reduced group of patients can require treatment. The objective of the present study was to assess the effects of bismuth subgallate on the quality of life (QoL) of patients undergoing Scopinaro's biliopancreatic diversion (SBPD) for morbid obesity. The study was conducted at the Hospital Universitario Insular de Gran Canaria, Spain, a public hospital. METHODS: A prospective, observational study in clinical practice was performed to ascertain the effects of bismuth subgallate on QoL in a group of patients undergoing SBPD who reported disabling diarrhea and related odor. Patients received treatment with 2 courses of oral bismuth subgallate, 200 mg every 8 hours for 12 weeks, with a 4-week rest period. Pretreatment and posttreatment surveys were performed. The Gastrointestinal Quality of Life Index (GIQLI) questionnaire was used, which evaluates symptoms, physical status, emotional status, social performance, and treatment effects. RESULTS: Sixty patients--90% women--with a mean age of 45.6 years were included in the study, 65% of which had superobesity. GIQLI scores obtained at treatment completion were significantly higher--both overall and in the various domains--than those obtained before treatment onset (P<.01). When the morbid obesity and superobesity groups were analyzed separately, a significant increase in the scores for both patient groups was also observed (P< .01). CONCLUSIONS: In clinical practice, treatment with bismuth subgallate resulted in a short-term improvement of QoL for patients undergoing SBPD. PMID- 25820079 TI - Endometrial histology in severely obese bariatric surgery candidates: an exploratory analysis. AB - BACKGROUND: Endometrial pathology risk has been linked to obesity; however, little is known of its prevalence in severely obese women not seeking care for endometrial pathology associated symptoms. This pilot study was designed to explore the frequency and risk factors associated with endometrial pathology in cancer-free, severely obese, bariatric surgery candidates using the Pipelle endometrial sampling technique (SureFlex Preferred Curette, Bioteque America, Inc, New Taipei City, Taiwan). METHODS: Twenty-nine severely obese bariatric surgery candidates with intact uteruses and no history of endometrial cancer or endometrial ablation were included in this subanalysis from a larger cohort of 47. Endometrial samples were obtained using a Pipelle endometrial suction curette at a single time point before surgery. Logistic regression was used to assess the relationship between body mass index and endometrial pathology when adjusting for age and race. RESULTS: Of the 29 successful biopsies, 8 (27.6%) were classified as abnormal endometrium: 1 was classified as complex atypical hyperplasia, 1 was classified as hyperplasia without atypia, 4 samples were identified with endometrial polyps, and 2 samples were identified with metaplasia. None presented with cancer. Increasing body mass index was significantly associated with higher risk of abnormal endometrium (OR = 1.19, 95% CI [1.03-1.36], P = .01). CONCLUSIONS: The findings in this sample suggest that obesity may be associated with increased risk of having undiagnosed endometrial pathology. More thorough examination of relationships between levels of obesity and endometrial pathology are needed to better characterize high cancer risk groups who may benefit from introducing new screening measures. PMID- 25820081 TI - One-stage robotically assisted laparoscopic biliopancreatic diversion with duodenal switch: analysis of 179 patients. AB - BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) has been reported to be the most effective procedure for weight loss and minimizing postoperative weight regain. However, because of its technical complexity and concerns for higher operative and metabolic complications, it has not obtained widespread acceptance among patients or bariatric surgeons. Nevertheless, the use of robotic systems has been increasing because of its ability to overcome technical challenges, such as torque, freedom of movement, and precision. The objective of this study was to review the efficacy and safety of robotic assistance in laparoscopic BPD-DS. METHODS: A prospectively maintained database of patients who underwent robotic-assisted laparoscopic BPD-DS between 2008 and 2013 was reviewed retrospectively. RESULTS: A total of 179 consecutive patients (137 female and 42 male) were included in the study. The mean age was 44 years (20-72 yr). Mean body mass index (BMI) was 50.3 kg/m(2) (35-78.8 kg/m(2)), and the number of preoperative co-morbidities was 6.6 (2-14). Mean operative time for a typical BPD-DS with appendectomy was 249 minutes (162-413 min), which increased to 278 minutes (193-463 min) in adhesiolysis associated cases and increased to 272 minutes (186-431 min) if additional procedures, such as hiatal hernia repair, cholecystectomy, or Meckel's diverticulum resection, were included. All procedures were completed as a single-stage operation. There were no major intraoperative complications. Two patients had unexpected returns to the operating room during the same admission: one for an endoscopic release of an inadvertently sutured nasogastric tube and the other for port site infection. Median hospital stay was 2.7 days (1-13). Two patients had significantly longer stays for carpal tunnel syndrome exacerbation (9 d) and port site infection (13 d). Postoperatively, the median excess weight loss at 1, 3, 6, 9, 12, 18, 24, and 36 months with follow-up of 71% of patients at 1 year, 45% of patients at 2 years, and 15% of patients at 5 years, was 19%, 35.9%, 53.1%, 65.6%, 74.6%, 79.9%, and 75.8%, respectively. Diabetes, hypertension, and hyperlipidemia went into remission 95.5%, 92.1%, and 92% of the time, respectively. No mortality occurred. CONCLUSIONS: Robotically assisted duodenoileal anastomosis during laparoscopic BPD-DS is a feasible, well-tolerated, and effective alternative to assist in the technically challenging part of the operation. PMID- 25820080 TI - Hospital volume and outcomes for laparoscopic gastric bypass and adjustable gastric banding in the modern era. AB - BACKGROUND: Over the past decade, there has been a rapid decline in adverse events after bariatric surgery. As a result, it is possible that the influence of hospital volume on outcomes has attenuated over time. The objective of the present study was to examine whether the relationship between hospital volume and adverse events has persisted in the era of laparoscopic surgery. This study is based on analysis of State Inpatient Databases (SID) for 12 states from 2006 through 2011, which included 446,127 patients. METHODS: Using hospital discharge data, changes in serious complications, reoperations and mortality over time, and the impact of hospital volume on outcomes among patients undergoing laparoscopic adjustable gastric band (LAGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB) were studied. Hospitals were stratified by operative volume, and using multivariable logistic regression to adjust for patient characteristics and procedure-type, the relationships between hospital volume and outcomes during 3 2 year periods were examined: 2006-2007, 2008-2009, and 2010-2011. RESULTS: The rate of reoperations and mortality were low, and there were no significant differences between the highest (>125 cases/yr) and lowest (<50 cases/yr) volume hospitals for both LAGB and LRYGB. The volume-outcome relationship was most prominent when examining rates of adjusted odds ratios for serious complications at the lowest volume hospitals compared with the highest volume hospitals (LAGB: 1.65 [CI: 1.18, 2.30] for 2006-2007, 1.81 [CI: 1.36, 2.41] for 2008-2009, and 2.08 [CI:1.40, 3.09] for 2010-2011; LRYGB: 1.55 [CI:1.23, 1.95] for 2006-2007, 1.39 [CI:1.09, 1.76], and 1.39 [CI:1.07, 1.80] for 2010-2011). CONCLUSIONS: Outcomes improved over the study period at both high- and low-volume volume hospitals. There remain significant differences in serious complications between the highest and lowest volume hospitals for both stapled and nonstapled procedures. PMID- 25820082 TI - Health-related quality of life after bariatric surgery: a systematic review of prospective long-term studies. AB - Impaired health-related quality of life (HRQoL) is common in bariatric surgery candidates and is often one of the motivating factors for seeking bariatric surgery. Although many studies have reported changes in HRQoL after bariatric surgery, few are long-term prospective studies and no systematic review has been conducted. A systematic database search identified studies reporting HRQoL preoperatively and>=5 years after bariatric surgery. Change in HRQoL over time was the outcome variable, divided into primary and secondary outcomes. Seven prospective cohort studies met the inclusion criteria. Eight HRQoL measures and 6 surgical methods were identified. Long-term follow-up time ranged from 5-10 years, sample sizes from 44 to 655 patients, and follow-up rates from 61% to 92%. None of the 7 studies were randomized controlled trials, and only 2 studies used control groups. Six of 7 studies showed statistically significant improvements in all of the primary outcomes, and 1 study showed statistically significant improvements in 1 of 2 primary outcomes. Of the statistically significant HRQoL improvements, 92% were clinically meaningful. Peak improvements in primary HRQoL outcomes were typically observed during the first years of follow-up, followed by a gradual decline that seemed to stabilize 5 years postoperatively. Long-term HRQoL scores typically remained improved relative to preoperative scores but were somewhat below population norm scores. In conclusion, while bariatric surgery candidates reported impaired HRQoL presurgically, their HRQoL improved considerably after bariatric surgery and much of the initial HRQoL improvements were maintained over the long term. PMID- 25820083 TI - Improvement in nonalcoholic fatty liver disease and metabolic syndrome in adolescents undergoing bariatric surgery. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children. It is linked to obesity and the metabolic syndrome (MS), predisposing to future cirrhosis. The objective of this study was to demonstrate the effects that weight loss achieved with laparoscopic adjustable gastric band (LAGB) has on the metabolic parameters and NAFLD scores of obese adolescents with evidence of fatty liver disease. METHODS: Adolescents undergoing LAGB were evaluated for NAFLD with evidence of fatty liver on preoperative sonogram, serum biochemistry, or both between 2005 and 2011. Primary endpoint was change in NAFLD scores after LAGB and secondary endpoint change in MS criteria. RESULTS: Fifty-six out of 155 adolescents had evidence of fatty liver disease at presentation. The group consisted of 17 (30%) male and 39 (70%) females, mean age 16.1 years (range 14-17.8 yr). Preoperative body mass index (BMI) was 48.8 kg/m(2) (+/-7) dropping to 37.9 kg/m(2) (+/-8.3) at 12 months and 36.8 kg/m(2) (+/-8.2) at 24 months. Fifteen (27%) patients met the criteria for MS. When comparing 1-year postsurgery to presurgery, the NAFLD score decreased by an average of .68 (SD = 1.03, P<.01). The 2-year NAFLD score decreased by a mean of .38 (SD = .99, P = .01). The reoperation rate for band/port related complications was 10.7% at 2 years with no mortality. MS rates improved from 27% to 2% at 2 years (P< .01). CONCLUSIONS: LAGB is a safe and effective operation for obese adolescents with NAFLD. There was significant improvement in NAFLD scores and resolution of MS. PMID- 25820084 TI - Synthesis of diastereomerically pure Lys(Nepsilon-lipoyl) building blocks and their use in Fmoc/tBu solid phase synthesis of lipoyl-containing peptides for diagnosis of primary biliary cirrhosis. AB - Primary Biliary Cirrhosis is an immune-mediated disease in which one of the epitopes recognized by antimitochondrial autoantibodies is a lipoylated fragment of the PDC-E2 protein. Accordingly, the synthesis of lipoylated peptides as diagnostic tools is a relevant target. Up to now, the proper tools for the introduction of lipoylation on building blocks to be used in Fmoc/tBu solid phase peptide synthesis (SPPS) are lacking, and the role of chirality in lipoylation remains poorly studied. In this paper, we present the synthesis of lipoylated lysine derivatives as pure diastereomeric building blocks suitable for Fmoc/tBu SPPS and their introduction in relevant peptide sequences to possibly serve as synthetic probes for the development of novel diagnostic tools for this disease. The optimization of the synthesis of lipoylated building blocks derived from racemic, (R)-, and (S)-alpha-lipoic acid is described. Synthesis of peptide probes incorporating lipoylation is described. An insight regarding the cleavage of lipoylated peptides is given, as well as a method to oxidize or reduce the 1,2 dithiolane ring of the lipoyl moiety directly on the peptide without any subsequent purification. PMID- 25820085 TI - Cooling of burns: Mechanisms and models. AB - The role of cooling in the acute management of burns is widely accepted in clinical practice, and is a cornerstone of basic first aid in burns. This has been underlined in a number of animal models. The mechanism by which it delivers its benefit is poorly understood, but there is a reduction in burns progression over the first 48 h, reduced healing time, and some subjective improvements in scarring when cooling is administered after burning. Intradermal temperature normalises within a matter of seconds to a few minutes, yet the benefits of even delayed cooling persist, implying it is not simply the removal of thermal energy from the damaged tissues. Animal models have used oedema formation, preservation of dermal perfusion, healing time and hair retention as indicators of burns severity, and have shown cooling to improve these indices, but pharmacological or immunological blockade of humoural and cellular mediators of inflammation did not reproduce the benefit of cooling. More recently, some studies of tissue from human and animal burns have shown consistent, reproducible, temporal changes in gene expression in burned tissues. Here, we review the experimental evidence of the role and mechanism of cooling in burns management, and suggest future research directions that may eventually lead to improved treatment outcomes. PMID- 25820086 TI - Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration. AB - Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. PMID- 25820087 TI - Use of the New Antiplatelet Agents in Acute Coronary Syndromes: Limitations Related to Patient Characteristics. PMID- 25820088 TI - Two-stage observer based offset-free MPC. AB - This paper addresses design of model predictive control (MPC) for dynamic systems in the presence of disturbances. For the systems with disturbances, it is common to use observers to estimate states and disturbances, allowing control algorithm to reject disturbances. In this paper, we demonstrate how one can extend model predictive control for systems with disturbances by applying full state and disturbance observer. To this aim, a two-stage approach is proposed where the observer design procedure is completely decoupled from the MPC problem, known as the separation principle. We focus on the decoupling principal and it is shown that the observer can be designed independently via a norm minimization problem to reduce effects of disturbances and model mismatch. On the other hand, the MPC law is obtained using the multi-parametric quadratic programming approach where the parameters are the components of the state vector. PMID- 25820089 TI - Design of RTDA controller for industrial process using SOPDT model with minimum or non-minimum zero. AB - This research paper focuses on the design and development of simplified RTDA control law computation formulae for SOPDT process with minimum or non-minimum zero. The design of RTDA control scheme consists of three main components namely process output prediction, model prediction update and control action computation. The systematic approach for computation of the above three components for SOPDT process with minimum or non-minimum zero is developed in this paper. The design, implementation and performance evaluation of the developed controller is demonstrated via simulation examples. The closed loop equation, block diagram representation and theoretical stability derivation for RTDA controller are developed. The performance of proposed controller is compared with IMC, SPC, MPC and PID controller and it is demonstrated on Industrial non linear CSTR process. PMID- 25820090 TI - Adaptive control schemes for improving dynamic performance of efficiency optimized induction motor drives. AB - Model Based Control (MBC) is one of the energy optimal controllers used in vector controlled Induction Motor (IM) for controlling the excitation of motor in accordance with torque and speed. MBC offers energy conservation especially at part-load operation, but it creates ripples in torque and speed during load transition, leading to poor dynamic performance of the drive. This study investigates the opportunity for improving dynamic performance of a three-phase IM operating with MBC and proposes three control schemes: (i) MBC with a low pass filter (ii) torque producing current (iqs) injection in the output of speed controller (iii) Variable Structure Speed Controller (VSSC). The pre and post operation of MBC during load transition is also analyzed. The dynamic performance of a 1-hp, three-phase squirrel-cage IM with mine-hoist load diagram is tested. Test results are provided for the conventional field-oriented (constant flux) control and MBC (adjustable excitation) with proposed schemes. The effectiveness of proposed schemes is also illustrated for parametric variations. The test results and subsequent analysis confer that the motor dynamics improves significantly with all three proposed schemes in terms of overshoot/undershoot peak amplitude of torque and DC link power in addition to energy saving during load transitions. PMID- 25820091 TI - MY APPROACH to the long QT syndrome (LQTS). PMID- 25820092 TI - MY APPROACH to low-level troponin elevations. PMID- 25820093 TI - Elevated cerebrospinal fluid endothelin 1 associated with neurogenic pulmonary edema in children with enterovirus 71 encephalitis. AB - OBJECTIVES: Neurogenic pulmonary edema (NPE) is a fatal complication in children with enterovirus 71 (EV71) encephalitis. Endothelin 1 (ET-1), a potent vasoconstrictor, can induce pulmonary edema in rats via intrathecal injections. Thus, it was hypothesized that ET-1 in the central nervous system may correlate with NPE in children with EV71 encephalitis. METHODS: Clinical data and ET-1 in the cerebrospinal fluid (CSF) were compared between three groups: (1) EV71 encephalitis with NPE; (2) EV71 encephalitis without NPE; and (3) non-EV71 aseptic meningitis. ET-1 immunostaining was performed on the brainstem of autopsy patients. RESULTS: The EV71 with NPE group showed significantly increased CSF levels of ET-1 compared to the EV71 without NPE and the non-EV71 aseptic meningitis groups (both p<0.01). The optimum cut-off point of ET-1 to predict NPE in EV71 patients, based on the receiver operating characteristic curve, was 0.5 pg/ml (sensitivity 83%, specificity 100%). Immunostaining in the brainstem showed increased ET-1 expression, mainly in the oligodendrocytes, in EV71 with NPE patients compared with control patients. CONCLUSION: ET-1 in the central nervous system may play a role in the development of NPE in children with EV71 infection and could be used as a biomarker or therapeutic target for NPE in EV71 encephalitis. PMID- 25820094 TI - Eosinophilic pleural effusion due to Spirometra mansoni spargana: a case report and review of the literature. AB - A 36-year-old female presented with an eosinophilic pleural effusion. The eosinophilic pleural effusion was considered to have been caused by a parasitic infection. Spirometra mansoni spargana was confirmed by semi-rigid thoracoscopy. About 2 months after treatment with praziquantel for 3 days, the pleural effusion had disappeared on the chest roentgenogram. PMID- 25820095 TI - Tuberculosis risk-associated single nucleotide polymorphisms do not show association with leprosy in Chinese population. AB - OBJECTIVE: Leprosy and tuberculosis (TB) are chronic granulomatous infectious diseases. As well as pathogen and environmental factors, host genetic factors make a substantial contribution to susceptibility to both diseases. More importantly, leprosy and TB also have pathogenic mechanisms and clinical features in common. In this study, the genetic association between leprosy and TB was investigated in a Chinese Han population. METHODS: A genetic association study that included 46 TB susceptibility single nucleotide polymorphisms (SNPs) was performed, involving 1150 leprosy cases and 1150 controls from the Chinese Han population. The Sequenom MassARRAY system was used. RESULTS: No significant association was found between the 46 SNPs and leprosy. Therefore, according to the present study, there is no shared susceptibility locus between leprosy and TB in the Chinese Han population. CONCLUSIONS: Although leprosy and TB have a number of similar characteristics, no shared susceptibility loci were found in the Chinese Han population. Thus, this study demonstrated that the genetic basis of the pathogenesis of the two diseases may vary greatly. PMID- 25820096 TI - Rabies in Saudi Arabia: a need for epidemiological data. AB - Rabies is endemic in animals in the Arabian Peninsula. Although Saudi Arabia is the largest country in the Peninsula, little has been published about the rabies situation in the country. A total of 11,069 animal bites to humans were reported during 2007-2009, and 40 animals suspected of rabies were examined for rabies infection from 2005 through 2010. Results suggest that animal-related injuries in Saudi Arabia remain a public health problem, with feral dogs accounting for the majority of bites to humans and for the majority of animals found to be rabid. Over the last 10 years, no confirmed human rabies case has been reported. More detailed information about the epidemiology of animal bites and that of animal rabies in Saudi Arabia would be of great interest, notably to provide a basis on which vaccination recommendations could be made for the numerous international travellers visiting the country. PMID- 25820097 TI - Non-coding RNA in control of gene regulatory programs in cardiac development and disease. AB - Organogenesis of the vertebrate heart is a highly specialized process involving progressive specification and differentiation of distinct embryonic cardiac progenitor cell populations driven by specialized gene programming events. Likewise, the onset of pathologies in the adult heart, including cardiac hypertrophy, involves the reactivation of embryonic gene programs. In both cases, these intricate genomic events are temporally and spatially regulated by complex signaling networks and gene regulatory networks. Apart from well-established transcriptional mechanisms, increasing evidence indicates that gene programming in both the developing and the diseased myocardium are under epigenetic control by non-coding RNAs (ncRNAs). MicroRNAs regulate gene expression at the post transcriptional level, and numerous studies have now established critical roles for this species of tiny RNAs in a broad range of aspects from cardiogenesis towards adult heart failure. Recent reports now also implicate the larger family of long non-coding RNAs (lncRNAs) in these processes as well. Here we discuss the involvement of these two ncRNA classes in proper cardiac development and hypertrophic disease processes of the adult myocardium. This article is part of a Special Issue entitled: Non-coding RNAs. PMID- 25820098 TI - Segmental marking: A new technique to prevent pedicle twisting. PMID- 25820099 TI - Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib. AB - We report the photophysical properties, binding-induced turn-on emission, and fluorescence imaging of the cellular uptake and distribution of lapatinib, an EGFR/ERBB inhibitor. Lapatinib, a type II, i.e. inactive state, inhibitor that targets the ATP binding pocket of the EGFR family of receptor tyrosine kinases. DFT calculations predict that the 6-furanylquinazoline core of lapatinib should exhibit an excited state with charge transfer character and an S0 to S1 transition energy of 3.4 eV. Absorption confirms an optical transition in the near UV to violet, while fluorescence spectroscopy shows that photoemission is highly sensitive to solvent polarity. The hydrophobicity of lapatinib leads to fluorescent aggregates in solution, however, binding to the lipid-carrier protein, BSA or to the kinase domain of ERBB2, produces spectroscopically distinct photoemission. Confocal fluorescence microscopy imaging of lapatinib uptake in ERBB2-overexpressing MCF7 and BT474 cells reveals pools of intracellular inhibitor with emission profiles consistent with aggregated lapatinib. PMID- 25820100 TI - Calculus formation: nurses' decision-making in abortion-related care. AB - Nurses routinely provide care to patients in ethically challenging situations. To explore the continuum between conscientious objectors and designated staff in the provision of care to women seeking abortions, the aim of this study was to thickly describe decision-making, using abortion as the clinical context to elucidate how nurses approach ethically challenging work. A purposive sample of 25 nurses who worked in abortion clinics, emergency departments, intensive care units, labor, and delivery, operating rooms, and post anesthesia care units were interviewed. Qualitative description and thematic analysis were used to identify the cognitive, emotional, and behavioral processes in nurses' decisions to care for women needing abortions. Nurses developed and used multifaceted, real-time calculi when making decisions about their participation in emergent or routine abortion care. Nurses tacked back and forth between the personal and professional and/or held multiple contradictory positions simultaneously. Nurses weighed the role and opinion of others to determine if they know how to or know why they would provide abortion care to women, particularly in the elective abortion context. The parameters of the nurse-patient relationship were complex and specific to the experiences of both the nurse and patient. Findings from this study further develop the science of ethically challenging decision-making and expand our understanding of factors that influence how nurses develop relationships to ethically challenging work. PMID- 25820105 TI - Information disclosure and peer effects in the use of antibiotics. AB - Mandatory information disclosure may allow sellers to observe and respond to other sellers' attributes (seller peer effects) as well as informing consumers of the sellers' attributes (consumer learning effect). Using the data from mandatory information disclosure of antibiotic prescription rates for the common cold in Korea, this paper shows that while average prescription rates decreased after the disclosure, more than 30% of the clinics increased their antibiotic prescriptions. Moreover, clinics that were prescribing relatively fewer antibiotics than other local clinics before the disclosure requirement were more likely to increase their prescription rate. The average prescription rates also declined less in markets with stronger clinic competition. These results are consistent with seller peer effects. PMID- 25820106 TI - Ovarian microcystic stromal tumor: A novel extracolonic tumor in familial adenomatous polyposis. AB - Ovarian microcystic stromal tumor (MCST) is a very rare neoplasm; hence, its nomenclature was recently designated as "Distinctive morphologic and immunohistochemical features" in 2009. Its exact origin, etiological genetic alterations, and background are not yet clearly known. Familial adenomatous polyposis (FAP) is an autosomal dominant disease that leads to development of colorectal polyps via germ-line mutations of the APC gene on chromosome 5q21~22. In this study, we report a 40-year-old female patient who had ovarian MCST and FAP. On sequencing the APC gene in ovarian MSCT, we detected a novel somatic mutation of the APC gene in exon 11, with a heterozygous deletion at nucleotide position c.1540delG (p.Ala514 Profs*9). Mutations of beta-catenin (CTNNB1) and FOXL2 were not detected. Although one case demonstrating involvement of Wnt/beta catenin in ovarian MCST associated with FAP has been presented previously, no detailed information was provided. Thus, this is the ovarian MCST with a somatic mutation of APC in a patient with FAP. PMID- 25820108 TI - A restless abdomen and propriospinal myoclonus like at sleep onset: an unusual overlap syndrome. AB - We report for the first time the association between restless abdomen, a phenotypic variant of restless legs syndrome in which symptoms are limited to the abdomen, and propriospinal myoclonus at sleep onset causing severe insomnia. The treatment with a low-dosage of dopaminergic drug (pramipexole) induced the immediate disappearance of both symptoms, which was documented by video polysomnography. PMID- 25820109 TI - Healthcare-associated infective endocarditis of the pulmonary valve. AB - We report a case of a 66-year-old man with known ischaemic heart disease, diabetes mellitus and stage 4 kidney disease who was admitted to our tertiary centre with shortness of breath and atrial flutter. Transoesophageal echocardiography (TOE) was without suspicion of endocarditis. During hospitalisation, the patient suffered a nosocomial infection in a peripheral vascular catheter caused by Staphylococcus aureus. TOE after positive blood cultures revealed a new vegetation on the pulmonary valve that resolved after antibiotic treatment. PMID- 25820110 TI - Unusual cause of infective endocarditis in an elderly patient with a rare condition. AB - A 77-year-old woman presented to the emergency department with a 1-week history of anorexia, fatigue, general malaise and a 3-day history of fever. Clinical examination revealed livedo reticularis across the anterior aspect of her knees and a pansystolic murmur. Laboratory evaluation found neutrophil leucocytosis; elevated C reactive protein and blood cultures grew Streptococcus acidominimus. Transthoracic echocardiography displayed vegetation on the mitral valve and a left atrial myxoma. She was treated with intravenous benzylpenicillin and erythromycin for the infective endocarditis (IE) and remains well 3 months post treatment. S. acidominimus is considered a common veterinary pathogen rarely found in humans. To the best of our knowledge, only two prior reports of IE due to this organism exist in the literature. This case highlights how rare pathogens can cause unusual presentation and the importance of IE as a differential even in the absence of classical signs, if fever and new murmur are present. PMID- 25820111 TI - The crying sign: the winking umbilical cord. AB - A preterm baby girl, born at 34 weeks gestation, with features of Beckwith Wiedemann syndrome was noted to have a relatively large umbilical stump. No fetal abnormalities had been detected on anatomy scan at 28 weeks and only mild polyhydramnios and macrosomia were noted on a 32-week ultrasound scan. Although there was no obvious omphalocoele, clinical assessment of the umbilical cord revealed an abdominal wall defect through which bowel would protrude into the umbilicus when the infant was crying. In keeping with an abdominal wall defect alpha-fetoprotein was found to be elevated. Surgical consultation advised conservative management. Subsequently, detachment of the umbilical cord occurred 1 week postdischarge and a large umbilical hernia persists. Genetic analysis confirmed a diagnosis of Beckwith-Wiedemann syndrome. PMID- 25820112 TI - Laparoendoscopic Single-site Compared With Conventional Laparoscopic Ovarian Cystectomy for Ovarian Endometrioma. AB - STUDY OBJECTIVE: To estimate the efficacy of laparoendoscopic single-site (LESS) ovarian cystectomy in ovarian endometrioma. DESIGN: Retrospective study. Canadian Task Force Classification II-2. SETTING: University hospital. PATIENTS: Three hundred forty-three premenopausal women with previously untreated ovarian endometrioma. INTERVENTION: The surgical and follow-up outcomes were compared between LESS (n = 154) and conventional laparoscopic ovarian cystectomy (n = 189). MEASUREMENTS AND MAIN RESULTS: Four patients (2.6%) in the LESS group but no patients in conventional group required additional ports (p = .040). No patient in either group required conversion to laparotomy. Operating times, estimated blood loss, perioperative hemoglobin level changes, and transfusions did not differ between groups. However, the length of postoperative hospital stay was significantly shorter in the LESS group (2 +/- .4 days vs 2.3 +/- .8 days, p = .001) and significantly more patients in this group were discharged within 2 days of surgery (93.5% vs 79.4%, p < .001). Perioperative complications occurred in 1 patient (0.6%) in the LESS group and in 2 patients (1.1%) in the conventional group (p > .999). The LESS group showed significantly lower pain scores at 16 (3.2 vs 3.6, p < .001), 24 (2.8 vs 3, p = .004), and 30 hours (2.7 vs 3, p = .040) after surgery. The requirement for additional analgesics was significantly lower in the LESS group (27.9% vs 45%, p = .001). After a median follow-up time of 48 months, 11 patients (7.1%) in the LESS group and 21 patients (11.1%) in the conventional group showed recurrent endometrioma (p = .209). CONCLUSION: LESS ovarian cystectomy has similar feasibility and efficacy with conventional laparoscopic surgery in the management of endometrioma. However, LESS is associated with less postoperative pain, lower analgesic requirement, and earlier discharge. PMID- 25820113 TI - Postoperative Analgesia after Laparoscopic Ovarian Cyst Resection: Double-blind Multicenter Randomized Control Trial Comparing Intraperitoneal Nebulization and Peritoneal Instillation of Ropivacaine. AB - STUDY OBJECTIVE: To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain. DESIGN: Multicenter, randomized, case-control trial. DESIGN CLASSIFICATION: Canadian Task Force Classification I. SETTING: University hospitals in Italy. PATIENTS: One hundred forty patients scheduled for laparoscopic ovarian cystectomy. INTERVENTIONS: Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland). MEASUREMENTS AND MAIN RESULTS: One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 +/- 7.5 mg in the nebulization group vs 9.2 +/- 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035). CONCLUSION: Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation. PMID- 25820114 TI - Is There Excess Oxidative Stress and Damage in Eyes of Patients with Retinitis Pigmentosa? AB - Retinitis pigmentosa (RP) is a group of diseases in which a mutation in one of the large variety of genes causes death of rod photoreceptors. After rods die, cone photoreceptors gradually die resulting in constriction of visual fields and eventual blindness in many patients. Studies in animal models of RP have demonstrated that oxidative damage is a major contributor to cone cell death. In this study, we extended those findings to patients with RP, because compared to control patients, those with RP showed significant reduction in the reduced to oxidized glutathione (GSH/GSSG) ratio in aqueous humor and a significant increase in aqueous protein carbonyl content. In contrast, there was no significant decrease in the serum GSH/GSSG ratio or increase in carbonyl content of serum proteins. These data indicate that patients with RP have ocular oxidative stress and damage in the absence of manifestations of systemic oxidative stress and/or damage indicating that demonstrations of oxidative damage-induced cone cell death in animal models of RP may translate to human RP. These observations lead to the hypothesis that potent antioxidants will promote cone survival and function in patients with RP and that the aqueous GSH/GSSG ratio and carbonyl content on proteins may provide useful biomarkers. Antioxid. Redox Signal. 23, 643-648. PMID- 25820115 TI - Fluorescence-Raman dual modal endoscopic system for multiplexed molecular diagnostics. AB - Optical endoscopic imaging, which was recently equipped with bioluminescence, fluorescence, and Raman scattering, allows minimally invasive real-time detection of pathologies on the surface of hollow organs. To characterize pathologic lesions in a multiplexed way, we developed a dual modal fluorescence-Raman endomicroscopic system (FRES), which used fluorescence and surface-enhanced Raman scattering nanoprobes (F-SERS dots). Real-time, in vivo, and multiple target detection of a specific cancer was successful, based on the fast imaging capability of fluorescence signals and the multiplex capability of simultaneously detected SERS signals using an optical fiber bundle for intraoperative endoscopic system. Human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) on the breast cancer xenografts in a mouse orthotopic model were successfully detected in a multiplexed way, illustrating the potential of FRES as a molecular diagnostic instrument that enables real-time tumor characterization of receptors during routine endoscopic procedures. PMID- 25820116 TI - Increased Complications in Obese Patients Undergoing Direct Anterior Total Hip Arthroplasty. AB - The direct anterior (DA) approach for total hip arthroplasty (THA) has demonstrated successful short term outcomes in several studies. However, there is no consensus about which patients are appropriate candidates for DA total hip arthroplasty. It is also unclear if short term outcomes in obese patients undergoing THA through a DA approach are elevated in comparison to non-obese patients. The purpose of this study was to evaluate complication rates and short term outcomes of obese, pre-obese, and normal body mass index (BMI) patients undergoing THA with a DA approach in a consecutive group of patients. This study was a retrospective review of 210 consecutive patients who underwent unilateral THA through a DA approach for osteoarthritis or avascular necrosis during the early peri-operative period. The study included 61 patients with normal BMI, 70 pre-obese patients, and 79 obese patients according to World Health Organization (WHO) classification (49 class I obese, 22 class II obese, and 8 class III obese patients). Patient charts were reviewed to determine differences in surgical time, length of stay, disposition, major complications, wound complications, and short term outcome measures. When comparing normal and pre-obese patients (BMI <30) to a combined group of WHO class I, II, and III obese patients (BMI >30), the obese group demonstrated increased surgical times by 12.7 minutes (P<0.0001), as well as increased length of stay (P=0.0303), narcotic use (P=0.0037), and assistive device use at two weeks (P<0.0030). In addition, major complications and wound complications were both significantly increased in the obese group (odds ratio [OR], 8.8; P=0.0493 and OR, 3.6; P=0.0431, respectively). There was also a trend toward increased use of rehabilitation facilities in the obese group at disposition, 15.4% vs 7.6% (P=0.0774). This study demonstrates that obese patients undergoing a DA approach have a 8.8 and 3.6 times increase in major and wound complications, respectively, compared to patients with a BMI <30. Obese patients also demonstrated significant increases in operative time, use of narcotics, use of assistive devices, and length of stay. There was a trend toward higher use of rehabilitation placement. While significant, these findings are similar to complication rates in the literature for other THA operative approaches. This study further defines the risks associated with performing THA on obese patients regardless of approach. PMID- 25820117 TI - Short-Term Metal Ion Trends Following Removal of Recalled Modular Neck Femoral Stems. AB - Elevated serum metal ions have been well documented with the Rejuvenate modular neck femoral stem (Stryker, Mahwah, NJ); however, the rate at which ion levels decline following revision is less clear. This study included fifty-nine consecutive revisions of Rejuvenate stems for symptomatic ALTR. Blood tests prior to revision and postoperatively at 6weeks, 3months, 6months, and 1year measured serum cobalt and chromium concentrations, ESR, and CRP. At six weeks following revision of a unilateral Rejuvenate, cobalt and chromium levels dropped from preoperative levels by 67% and 42%, respectively. At three months, cobalt levels declined to 19% of preoperative values, but chromium levels remained stable. With this information, surgeons can set realistic expectations for serum metal ion levels following Rejuvenate stem revision. PMID- 25820118 TI - Are Nonagenarians Too Old For Total Hip Arthroplasty? An Evaluation of Morbidity and Mortality Within a Total Joint Replacement Registry. AB - A greater number of patients aged 90 and over will become candidates for total hip arthroplasty (THA) as the nonagenarian population continues to grow. This study evaluated the patient characteristics and incidence of postoperative morbidity and mortality of 183 nonagenarian THA patients among 43,543 primary THA patients followed by a total joint replacement registry. Nonagenarians had a greater number of comorbidities preoperatively, experienced a higher one year mortality and had a longer hospital length of stay. However, nonagenarians did not have an increased risk of infection, deep vein thrombosis or pulmonary embolism and postoperative mortality was within expected rates for individuals 90 years and older. Higher readmission rates, however, highlight the benefits of close follow up during a prolonged postoperative period. PMID- 25820119 TI - Radiological and Functional Outcomes in Computer Assisted Total Knee Arthroplasty Between Consultants and Trainees - A Prospective Randomized Controlled Trial. AB - Computer Aided Surgery has consistently shown superior alignment of components when compared to non-navigated jig based techniques. The aim of this study is to assess the mid-term clinical outcome of TKA performed by a consultant orthopedic surgeon, compared to trainee surgeons. Ninety-two patients were matched and randomly allocated to have CAS surgery performed by either a consultant or trainee and followed up prospectively for 5-years. Knee society scores, mechanical axis, tourniquet time and blood loss data were collected. Our study demonstrated that trainees were able to achieve equal coronal alignment (P=0.15), blood loss (P=0.45) and functional scores (P=0.15). The Consultant group had a significantly (P<0.001) shorter tourniquet time. We confirm that CAS can assist less experienced surgeons to reliably achieve good mid-term outcomes in TKA. PMID- 25820120 TI - Hierarchical zeolites and their catalytic performance in selective oxidative processes. AB - Hierarchical ZSM-5 zeolites prepared using a simple alkali treatment and subsequent HCl washing are found to exhibit unprecedented catalytic activities in selective oxidation of benzyl alcohol under microwave irradiation. The metal-free zeolites promote the microwave-assisted oxidation of benzyl alcohol with hydrogen peroxide in yields ranging from 45-35 % after 5 min of reaction under mild reaction conditions as well as the epoxidation of cyclohexene to valuable products (40-60 % conversion). The hierarchically porous systems also exhibited an interesting catalytic activity in the dehydration of N,N-dimethylformamide (25 30 % conversion), representing the first example of transition-metal free catalysts in this reaction. PMID- 25820121 TI - Evaluation of adaptive combination of 30-channel head receive coil array data in 23Na MR imaging. AB - PURPOSE: The aim was to optimally combine multichannel coil array data in sodium ((23) Na) MRI. METHODS: (23) Na MRI was conducted on a 3 Tesla MR system using a 30-channel head receive coil array. The parameters used for the adaptive combination (ADC) reconstruction of the low signal-to-noise ratio (SNR) dataset have been optimized by finding the maximum mean SNR. A pseudo multiple-replica approach has been used to obtain SNR maps of the combined images. To prove reproducibility of the combination algorithm, the procedure was repeated for several measurements. RESULTS: For low SNR data, sum-of-squares (SOS) reconstruction leads to high background noise and a signal bias in the imaged object. The ADC reconstruction clearly reduces noise in the image and leads to an increase of the mean SNR in the range of 8% to 50%, compared to weighted SOS depending on the absolute SNR of the image. The evaluation of the effects of different noise scans showed that a small number of projections can be used to estimate noise statistics of the coil array without substantially decreasing the resulting SNR. CONCLUSION: (23) Na MRI can be markedly improved by using a 30 channel receive array and ADC reconstruction. The ADC reconstruction showed robust results for all measurements without the need for sensitivity maps. PMID- 25820122 TI - Comparison between bioluminescence imaging technique and CFU count for the study of oropharyngeal candidiasis in mice. AB - We recently described a bioluminescence in vivo imaging technique, representing a powerful tool to test the real-time progression of oropharyngeal candidiasis, hence potentially useful to evaluate the efficacy of antifungal therapies. In this study, the in vivo imaging technique was compared with CFU measurement of target organs (tongue, esophagus and stomach) for monitoring and quantifying oropharyngeal candidiasis. We have correlated these two analytical methods at different times post-infection using engineered, luminescent Candida albicans in mice rendered susceptible to oral candidiasis by cortisone-acetate. Scatter plots, Pearson correlation and Student's t test were used to compare the methods. We observed that the bioluminescence in vivo imaging technique was more reliable than CFU counts in detecting early infection of, and its extent in, the oral cavity of the mouse. This was also evident following the introduction of a variable such as treatment with fluconazole. The results described in this study could validate the bioluminescence in vivo imaging technique as a method to monitor and quantify oropharyngeal candidiasis and to assess early discovery of active compounds in vivo. PMID- 25820124 TI - Search and the Aging Mind: The Promise and Limits of the Cognitive Control Hypothesis of Age Differences in Search. AB - Search is a prerequisite for successful performance in a broad range of tasks ranging from making decisions between consumer goods to memory retrieval. How does aging impact search processes in such disparate situations? Aging is associated with structural and neuromodulatory brain changes that underlie cognitive control processes, which in turn have been proposed as a domain-general mechanism controlling search in external environments as well as memory. We review the aging literature to evaluate the cognitive control hypothesis that suggests that age-related change in cognitive control underlies age differences in both external and internal search. We also consider the limits of the cognitive control hypothesis and propose additional mechanisms such as changes in strategy use and affect that may be necessary to understand how aging affects search. PMID- 25820123 TI - 'Carriers of variant luteinizing hormone (V-LH) among 1593 Baltic men have significantly higher serum LH'. AB - Luteinizing hormone (LH) is a pituitary heterodimeric glycoprotein essential in male and female reproduction. Its functional polymorphic variant (V-LH) is determined by two missense mutations (rs1800447, A/G, Trp8Arg; rs34349826, A/G, Ile15Thr) in the LH beta-subunit encoding gene (LHB; 19q13.3; 1111 bp; 3 exons). Among women, V-LH has been associated with higher circulating LH and reduced fertility, but the knowledge of its effect on male reproductive parameters has been inconclusive. The objective of this study was to assess the effect of V-LH on hormonal, seminal and testicular parameters in the Baltic young men cohort (n = 986; age: 20.1 +/- 2.1 years) and Estonian idiopathic infertility patients (n = 607; 35.1 +/- 5.9 years). V-LH was detected by genotyping of the underlying DNA polymorphisms using PCR-RFLP combined with resequencing of a random subset of subjects. Genetic associations were tested using linear regression under additive model and results were combined in meta-analysis. No significant difference was detected between young men and infertility patients for the V-LH allele frequency (11.0 vs. 9.3%, respectively). V-LH was associated with higher serum LH in both, the young men cohort (p = 0.022, allelic effect = 0.26 IU/L) and the idiopathic infertility group (p = 0.008, effect = 0.59 IU/L). In meta-analysis, the statistical significance was enhanced (p = 0.0007, resistant to Bonferroni correction for multiple testing; effect = 0.33 IU/L). The detected significant association of V-LH with increased serum LH remained unchanged after additional adjustment for the SNPs previously demonstrated to affect LH levels (FSHB 211G/T, FSHR Asn680Ser, FSHR -29A/G). Additionally, a suggestive trend for association with reduced testicular volume was observed among young men, and with lower serum FSH among infertility patients. The V-LH carrier status did not affect sperm parameters and other circulating reproductive hormones. For the first time, we show a conclusive contribution of V-LH to the natural variance in male serum LH levels. Its downstream clinical consequences are still to be learned. PMID- 25820126 TI - The chain length of biologically produced (R)-3-hydroxyalkanoic acid affects biological activity and structure of anti-cancer peptides. AB - Conjugation of DP18L peptide with (R)-3-hydroxydecanoic acid, derived from the biopolymer polyhydroxyalkanoate, enhances its anti-cancer activity (O'Connor et al., 2013. Biomaterials 34, 2710-2718). However, it is unknown if other (R)-3 hydroxyalkanoic acids (R3HAs) can enhance peptide activity, if chain length affects enhancement, and what effect R3HAs have on peptide structure. Here we show that the degree of enhancement of peptide (DP18L) anti-cancer activity by R3HAs is carbon chain length dependent. In all but one example the R3HA conjugated peptides were more active against cancer cells than the unconjugated peptides. However, R3HAs with 9 and 10 carbons were most effective at improving DP18L activity. DP18L peptide variant DP17L, missing a hydrophobic amino acid (leucine residue 4) exhibited lower efficacy against MiaPaCa cells. Circular dichroism analysis showed DP17L had a lower alpha helix content and the conjugation of any R3HA ((R)-3-hydroxyhexanoic acid to (R)-3-hydroxydodecanoic acid) to DP17L returned the helix content back to levels of DP18L. However (R)-3 hydroxyhexanoic did not enhance the anti-cancer activity of DP17L and at least 7 carbons were needed in the R3HA to enhance activity of D17L. DP17L needs a longer chain R3HA to achieve the same activity as DP18L conjugated to an R3HA. As a first step to assess the synthetic potential of polyhydroxyalkanoate derived R3HAs, (R)-3-hydroxydecanoic acid was synthetically converted to (+/-)3 chlorodecanoic acid, which when conjugated to DP18L improved its antiproliferative activity against MiaPaCa cells. PMID- 25820125 TI - Magnetic nanoparticle hyperthermia induced cytosine deaminase expression in microencapsulated E. coli for enzyme-prodrug therapy. AB - Engineered bacterial cells that are designed to express therapeutic enzymes under the transcriptional control of remotely inducible promoters can mediate the de novo conversion of non-toxic prodrugs to their cytotoxic forms. In situ cellular expression of enzymes provides increased stability and control of enzyme activity as compared to isolated enzymes. We have engineered Escherichia coli (E. coli), designed to express cytosine deaminase at elevated temperatures, under the transcriptional control of thermo-regulatory lambdapL-cI857 promoter cassette which provides a thermal switch to trigger enzyme synthesis. Enhanced cytosine deaminase expression was observed in cultures incubated at 42 degrees C as compared to 30 degrees C, and enzyme expression was further substantiated by spectrophotometric assays indicating enhanced conversion of 5-fluorocytosine to 5 fluorouracil. The engineered cells were subsequently co-encapsulated with magnetic iron oxide nanoparticles in immunoprotective alginate microcapsules, and cytosine deaminase expression was triggered remotely by alternating magnetic field-induced hyperthermia. The combination of 5-fluorocytosine with AMF activated microcapsules demonstrated tumor cell cytotoxicity comparable to direct treatment with 5-fluorouracil chemotherapy. Such enzyme-prodrug therapy, based on engineered and immunoisolated E. coli, may ultimately yield an improved therapeutic index relative to monotherapy, as AMF mediated hyperthermia might be expected to pre-sensitize tumors to chemotherapy under appropriate conditions. PMID- 25820127 TI - Regulation of stimulus-inducible gene expression in myeloid cells. AB - One of the best-characterized and biologically important gene expression programmes in myeloid cells is their response to pro-inflammatory stimuli. Macrophages and DCs in particular are key mediators of immune responses, and are widely-used as prototypes to understand and define the determinants of specific and inducible gene expression. In this review we summarize advances and concepts which have been made towards the understanding of inducible gene expression, with a particular focus on insights gained using the myeloid system as a model. We discuss the emerging concept of layered control of gene regulation and cell identity by different functional classes of transcription factors; and examine recent progress to understanding the molecular processes involved, including the involvement of nucleosome positioning, chromatin modifications, and nuclear architecture. We also address the exciting but less-well understood role of non coding RNAs in controlling specific gene expression programmes in myeloid and other cell-types. PMID- 25820128 TI - Towards changing healthcare workers' behaviour: a qualitative study exploring non compliance through appraisals of infection prevention and control practices. AB - BACKGROUND: Improving behaviour in infection prevention and control (IPC) practice remains a challenge, and understanding the determinants of healthcare workers' (HCWs) behaviour is fundamental to develop effective and sustained behaviour change interventions. AIM: To identify behaviours of HCWs that facilitated non-compliance with IPC practices, focusing on how appraisals of IPC duties and social and environmental circumstances shaped and influenced non compliant behaviour. This study aimed to: (1) identify how HCWs rationalized their own behaviour and the behaviour of others; (2) highlight challenging areas of IPC compliance; and (3) describe the context of the working environment that may explain inconsistencies in IPC practices. METHODS: Clinical staff at a National Health Service hospital group in London, UK were interviewed between December 2010 and July 2011 using qualitative methods. Responses were analysed using a thematic framework. FINDINGS: Three ways in which HCWs appraised their behaviour were identified through accounts of IPC policies and practices: (1) attribution of responsibilities, with ambiguity about responsibility for certain IPC practices; (2) prioritization and risk appraisal, which demonstrated a divergence in values attached to some IPC policies and practices; and (3) hierarchy of influence highlighted that traditional clinical roles challenged work relationships. CONCLUSIONS: Overall, behaviours are not entirely independent of policy rules, but often an amalgamation of local normative practices, individual preferences and a degree of professional isolation. PMID- 25820129 TI - How the brain predicts people's behavior in relation to rules and desires. Evidence of a medio-prefrontal dissociation. AB - Forming and updating impressions about others is critical in everyday life and engages portions of the dorsomedial prefrontal cortex (dMPFC), the posterior cingulate cortex (PCC) and the amygdala. Some of these activations are attributed to "mentalizing" functions necessary to represent people's mental states, such as beliefs or desires. Evolutionary psychology and developmental studies, however, suggest that interpersonal inferences can also be obtained through the aid of deontic heuristics, which dictate what must (or must not) be done in given circumstances. We used fMRI and asked 18 participants to predict whether unknown characters would follow their desires or obey external rules. Participants had no means, at the beginning, to make accurate predictions, but slowly learned (throughout the experiment) each character's behavioral profile. We isolated brain regions whose activity changed during the experiment, as a neural signature of impression updating: whereas dMPFC was progressively more involved in predicting characters' behavior in relation to their desires, the medial orbitofrontal cortex and the amygdala were progressively more recruited in predicting rule-based behavior. Our data provide evidence of a neural dissociation between deontic inference and theory-of-mind (ToM), and support a differentiation of orbital and dorsal prefrontal cortex in terms of low- and high level social cognition. PMID- 25820130 TI - Toxicity Evaluation of a New Zn-Doped CuO Nanocomposite With Highly Effective Antibacterial Properties. AB - The increased resistances to conventional antibiotics determine a strong need for new antibacterials, and specific syntheses at the nanoscale promise to be helpful in this field. A novel Zinc-doped Copper oxide nanocomposite (nZn-CuO) has been recently sonochemically synthesized and successfully tested also against multi drug resistant bacteria. After synthesis and characterization of the physicochemical properties, the new nZn-CuO is here evaluated by the Frog Embyo Teratogenesis Assay-Xenopus test for its toxicological potential and this compared with that of nCuO and nZnO synthesized under the same conditions. No lethal effects are observed, while malformations and growth retardation slightly increase after nZn-CuO exposure. Nevertheless, these effects are smaller than those of nZnO. NP uptake by embryo tissues increase significantly with increasing NP concentrations, while no significant accumulation and adverse effects are seen after exposure to soluble Cu(2+) and Zn(2+) at the concentrations dissolved from the NPs. Key oxidative response genes are upregulated by nZn-CuO, as well as by nCuO and nZnO, suggesting the common mechanism of action. Considering the enhanced biocidal activity shown by the nanocomposite, together with the results presented in this study, we can affirm that the doping of the metal oxide nanoparticles should be considered a useful tool to engineer a safer nano antibacterial. PMID- 25820131 TI - Sarcopenia Is Associated With Incident Disability, Institutionalization, and Mortality in Community-Dwelling Older Men: The Concord Health and Ageing in Men Project. AB - INTRODUCTION: Sarcopenia is associated with an increased risk of adverse outcomes. The aim of this study was to explore the relationship between severity of sarcopenia and incident activities of daily living (ADL) disability, institutionalization, and all-cause mortality among community-dwelling older men participating in the Concord Health and Ageing in Men Project (CHAMP). METHODS: Longitudinal analysis of 1705 participants aged 70 years or older at baseline (2005-2007) living in the community in Sydney, Australia. MEASUREMENTS: The main outcome measures were incident ADL disability, institutionalization, and mortality. Of the 1705 participants who completed the baseline assessments, a total of 1678 men (mean age 77 years) had complete measures by dual-energy x-ray absorptiometry, to assess sarcopenia in terms of low appendicular lean mass (ALM), using the Foundation for the National Institutes of Health (FNIH) criteria. To differentiate between severity of sarcopenia we used low ALM alone (sarcopenia I), low ALM with weakness (sarcopenia II), and sarcopenia with weakness and poor gait speed (sarcopenia III). Cox proportional hazard models and logistic regression models were used to assess the risk of mortality and institutionalization, and incidence of ADL disability. RESULTS: From baseline to follow-up, 103 (11.3%) men had incident ADL disability, 191 (11.2%) men were institutionalized, and 535 (31.9%) had died. At baseline, 14.2% had sarcopenia I, 5.3% had sarcopenia II, and 3.7% had sarcopenia III. Fully adjusted analysis (adjusted for demographics, lifestyle factors, comorbidities and health conditions, and blood measures) showed that sarcopenia I, II, and III were associated with increased risk of disability, institutionalization, and mortality. Associations between sarcopenia I, II, and III and risk of incident disability were as follows: odds ratio (OR) 2.77 95% confidence interval (CI) 1.30-5.87, OR 3.78 95% CI 1.23-11.64, and OR 4.53 95% CI 0.90-22.72; associations with institutionalization were hazard ratio (HR) 1.96 95% CI 1.14-3.35, HR 2.53 95% CI 1.31-4.90, and HR 2.27 95% CI 1.08-4.80; and with mortality were HR 1.65 95% CI 1.30-2.09, HR 1.50 95% CI 1.08-2.08, and HR 1.69 95% CI 1.17-2.44. CONCLUSIONS: This study shows that, in community-dwelling older men, sarcopenia defined by the FNIH criteria is associated with increased risk of incident disability, institutionalization, and mortality. PMID- 25820132 TI - Response To Dr Raider's JAMDA Letter to the Editor. PMID- 25820133 TI - Carbamates: A study on genotoxic, cytotoxic, and apoptotic effects induced in Chinese hamster ovary (CHO-K1) cells. AB - In vitro effects of the carbamates pirimicarb and zineb and their formulations Aficida(r) (50% pirimicarb) and Azzurro(r) (70% zineb), respectively, were evaluated in Chinese hamster ovary (CHO-K1) cells. Whereas the cytokinesis blocked micronucleus cytome assay was employed to test for genotoxicity, MTT, neutral red (NR), and apoptosis evaluation were used as tests for estimating cell viability and succinic dehydrogenase activity, respectively. Concentrations tested were 10-300 MUg/ml for pirimicarb and Aficida(r), and 1-50 MUg/ml for zineb and Azzurro(r). All compounds were able to increase the frequency of micronuclei. A marked reduction in the nuclear division index was observed after treatment with 5 MUg/ml of zineb and Azzurro(r) and 10 MUg/ml of Azzurro(r). Alterations in the cellular morphology not allowing the recognition of binucleated cells exposed to 300 MUg/ml pirimicarb and Aficida(r) as well as 10 50 MUg/ml zineb and Azzurro(r). All four compounds induced inhibition of both cell viability and succinic dehydrogenase activity and trigger apoptosis in CHO K1 cells, at least when exposed for 24 h. The data herein demonstrate the genotoxic and cytotoxic effects exerted by these carbamates and reveal the potential risk factor of these pesticides, still extensively used worldwide, for both human health and the environment. PMID- 25820134 TI - Cytotoxicity and mutagenicity assessment of organomodified clays potentially used in food packaging. AB - Modern food packaging has made great advances as result of global trends and consumer preferences, which are oriented to obtain improved food quality and safety. In this regard, clay minerals, and mainly Montmorillonite (Mt) are attracting considerable interest in food packaging because of the improvements developed in mechanical and barrier properties. Hence, the present work aim to assess the toxicity of four Montmorillonite-based clay minerals, an unmodified clay, Cloisite(r)Na+ (CNa+), and three modified Mt clays: Cloisite(r)30B (C30B), a commercial clay, and Clay1 and Clay2, two novel modified organoclays developed by the Packaging, Transport, & Logistics Research Institute (ITENE). First, the cytotoxic effects were studied in the Human Umbilical Vein Endothelial Cells (HUVEC). In addition, the potential mutagenicity of the clays was evaluated by the Ames test. Clay1 did not induce any cytotoxic effects in HUVEC, although it exhibited potential mutagenicity in TA98 Salmonella typhimurium strain. In contrast, Clay2 produced cytotoxicity in endothelial cells but no mutagenicity was recorded. However, CNa+ was not cytotoxic neither mutagenic. And finally, C30B showed positive results in both assays. Therefore, results showed that clay minerals have a different toxicity profile and a case by case toxicity evaluation is required. PMID- 25820135 TI - The Myeloid U937 Skin Sensitization Test (U-SENS) addresses the activation of dendritic cell event in the adverse outcome pathway for skin sensitization. AB - The U-SENSTM assay, formerly known as MUSST (Myeloid U937 Skin Sensitization Test), is an in vitro method to assess skin sensitization. Dendritic cell activation following exposure to sensitizers was modelled in the U937 human myeloid cell line by measuring the induction of the expression of CD86 by flow cytometry. The predictive performance of U-SENSTM was assessed via a comprehensive comparison analysis with the available human and LLNA data of 175 substances. U-SENSTM showed 79% specificity, 90% sensitivity and 88% accuracy. A four laboratory ring study demonstrated the transferability, reliability and reproducibility of U-SENSTM, with a reproducibility of 95% within laboratories and 79% between-laboratories, showing that the U-SENSTM assay is a promising tool in a skin sensitization risk assessment testing strategy. PMID- 25820136 TI - Peeling back the layers of locomotor control in the spinal cord. AB - Vertebrate locomotion is executed by networks of neurons within the spinal cord. Here, we describe recent advances in our understanding of spinal locomotor control provided by work using optical and genetic approaches in mice and zebrafish. In particular, we highlight common observations that demonstrate simplification of limb and axial motor pool coordination by spinal network modularity, differences in the deployment of spinal modules at increasing speeds of locomotion, and functional hierarchies in the regulation of locomotor rhythm and pattern. We also discuss the promise of intersectional genetic strategies for better resolution of network components and connectivity, which should help us continue to close the gap between theory and function. PMID- 25820137 TI - Matrix metalloproteinase-2 negatively regulates cardiac secreted phospholipase A2 to modulate inflammation and fever. AB - BACKGROUND: Matrix metalloproteinase (MMP)-2 deficiency makes humans and mice susceptible to inflammation. Here, we reveal an MMP-2-mediated mechanism that modulates the inflammatory response via secretory phospholipase A2 (sPLA2), a phospholipid hydrolase that releases fatty acids, including precursors of eicosanoids. METHODS AND RESULTS: Mmp2(-/-) (and, to a lesser extent, Mmp7(-/-) and Mmp9(-/-)) mice had between 10- and 1000-fold elevated sPLA2 activity in plasma and heart, increased eicosanoids and inflammatory markers (both in the liver and heart), and exacerbated lipopolysaccharide-induced fever, all of which were blunted by adenovirus-mediated MMP-2 overexpression and varespladib (pharmacological sPLA2 inhibitor). Moreover, Mmp2 deficiency caused sPLA2 mediated dysregulation of cardiac lipid metabolic gene expression. Compared with liver, kidney, and skeletal muscle, the heart was the single major source of the Ca(2+)-dependent, ~20-kDa, varespladib-inhibitable sPLA2 that circulates when MMP 2 is deficient. PLA2G5, which is a major cardiac sPLA2 isoform, was proinflammatory when Mmp2 was deficient. Treatment of wild-type (Mmp2(+/+)) mice with doxycycline (to inhibit MMP-2) recapitulated the Mmp2(-/-) phenotype of increased cardiac sPLA2 activity, prostaglandin E2 levels, and inflammatory gene expression. Treatment with either indomethacin (to inhibit cyclooxygenase dependent eicosanoid production) or varespladib (which inhibited eicosanoid production) triggered acute hypertension in Mmp2(-/-) mice, revealing their reliance on eicosanoids for blood pressure homeostasis. CONCLUSIONS: A heart centric MMP-2/sPLA2 axis may modulate blood pressure homeostasis, inflammatory and metabolic gene expression, and the severity of fever. This discovery helps researchers to understand the cardiovascular and systemic effects of MMP-2 inhibitors and suggests a disease mechanism for human MMP-2 gene deficiency. PMID- 25820138 TI - RpoS-dependent expression of OsmY in Salmonella enterica serovar typhi: activation under stationary phase and SPI-2-inducing conditions. AB - OsmY is a periplasmic protein with two BON domains which may attach to phospholipid membranes. Previous reports showed that the expression of OsmY in Escherichia coli was hyperosmotically inducible and RpoS dependent. But little work was done to investigate the expression and function of OsmY in Salmonella. Here, we detected the endogenous OsmY in Salmonella enterica serovar Typhi (S. Typhi) with polyclonal antibody. The results showed that the expression of OsmY was also RpoS dependent and was activated under stationary phase. Further, using in vitro culture, we established the Salmonella pathogenesis island (SPI)-1 and SPI-2-inducing conditions with hyperosmolarity and low-phosphate, low-magnesium medium (pH 5.8), respectively, and found that only SPI-2-inducing conditions can activate the expression of OsmY. osmY deletion mutant showed delayed growth compared with wild-type S. Typhi in SPI-2-inducing conditions. The results indicated that OsmY may function to resist the stress and be favorable for Salmonella's replication in the Salmonella-containing vesicles of macrophage. PMID- 25820139 TI - Modified coil protection for proper coil frame configuration in wide-necked aneurysms. AB - INTRODUCTION: Although various protective techniques for treating wide-necked intracranial aneurysms currently exist and continue to evolve, their utility may be limited in some lesions with complex configurations, small-caliber channels, or inherently tortuous vascular patterns. Described herein is a modified coil protection technique as a novel adjunct for proper coil frame configuration. METHODS: Initially, a microcatheter is passed into aneurysmal sac, and the first coil is inserted to build a frame. Inevitably, some coils may abut opposite poles of aneurysms and protrude into parent arteries. Should this happen, a second microcatheter may be placed at the site of coil protrusion, so that a separate and smaller coil may be partially deployed for protection. A framing coil may then be configured within aneurysmal sac, under protection of the secondary coil. Once the first coil is entirely in place, the remainder of second coil is carefully inserted, and additional coil may be inserted as needed via dual microcatheters. RESULTS: This technique was successfully applied to 23 saccular intracranial aneurysms of internal carotid (n = 8), middle cerebral (n = 6), anterior cerebral (n = 6), and superior cerebellar artery (n = 3), combining stent protection in two patients and balloon remodeling in one. Selective endovascular treatment was effective as a result. Excellent outcomes were achieved in all patients, with no morbidity or mortality directly related to the modified procedure. CONCLUSION: As suggested by outcomes of this small study, our modified coil protection method may be a safe option if traditional coiling strategies are not feasible, enabling stable coil frame configuration in wide necked aneurysms. PMID- 25820140 TI - Phenazine-1-carboxamide (PCN) from Pseudomonas sp. strain PUP6 selectively induced apoptosis in lung (A549) and breast (MDA MB-231) cancer cells by inhibition of antiapoptotic Bcl-2 family proteins. AB - Phenazine-1-carboxamide (PCN), a naturally occurring simple phenazine derivative isolated from Pseudomonas sp. strain PUP6, exhibited selective cytotoxic activity against lung (A549) and breast (MDA-MB-231) cancer cell lines in differential and dose-dependent manner compared to normal peripheral blood mononuclear cells. PCN treated cancer cells showed the induction of apoptosis as evidenced by the release of low level of LDH, morphological characteristics, production of reactive oxygen species, loss of mitochondrial membrane potential (DeltaPsim) and induction of caspase-3. At molecular level, PCN instigates apoptosis by mitochondrial intrinsic apoptotic pathway via the overexpression of p53, Bax, cytochrome C release and activation of caspase-3 with the inhibition of oncogenic anti-apoptotic proteins such as PARP and Bcl-2 family proteins (Bcl-2, Bcl-w and Bcl-xL). The in silico docking studies of PCN targeted against the anti-apoptotic members of Bcl-2 family proteins revealed the interaction of PCN with the BH3 domain, which might lead to the induction of apoptosis due to the inhibition of antiapoptotic proteins. Due to its innate inhibition potential of antiapoptotic Bcl-2 family proteins, PCN may be used as potent anticancer agent against both lung and breast cancer. PMID- 25820142 TI - Erratum to: Mutations of HNRNPA0 and WIF1 predispose members of a large family to multiple cancers. PMID- 25820141 TI - Mitochondrial DNA damage by bleomycin induces AML cell death. AB - Mitochondria contain multiple copies of their own 16.6 kb circular genome. To explore the impact of mitochondrial DNA (mtDNA) damage on mitochondrial (mt) function and viability of AML cells, we screened a panel of DNA damaging chemotherapeutic agents to identify drugs that could damage mtDNA. We identified bleomycin as an agent that damaged mtDNA in AML cells at concentrations that induced cell death. Bleomycin also induced mtDNA damage in primary AML samples. Consistent with the observed mtDNA damage, bleomycin reduced mt mass and basal oxygen consumption in AML cells. We also demonstrated that the observed mtDNA damage was functionally important for bleomycin-induced cell death. Finally, bleomycin delayed tumor growth in xenograft mouse models of AML and anti-leukemic concentrations of the drug induced mtDNA damage in AML cells preferentially over normal lung tissue. Taken together, mtDNA-targeted therapy may be an effective strategy to target AML cells and bleomycin could be useful in the treatment of this disease. PMID- 25820144 TI - A critical perspective on second-order empathy in understanding psychopathology: phenomenology and ethics. AB - The centenary of Karl Jaspers' General Psychopathology was recognised in 2013 with the publication of a volume of essays dedicated to his work (edited by Stanghellini and Fuchs). Leading phenomenological-psychopathologists and philosophers of psychiatry examined Jaspers notion of empathic understanding and his declaration that certain schizophrenic phenomena are 'un-understandable'. The consensus reached by the authors was that Jaspers operated with a narrow conception of phenomenology and empathy and that schizophrenic phenomena can be understood through what they variously called second-order and radical empathy. This article offers a critical examination of the second-order empathic stance along phenomenological and ethical lines. It asks: (1) Is second-order empathy (phenomenologically) possible? (2) Is the second-order empathic stance an ethically acceptable attitude towards persons diagnosed with schizophrenia? I argue that second-order empathy is an incoherent method that cannot be realised. Further, the attitude promoted by this method is ethically problematic insofar as the emphasis placed on radical otherness disinvests persons diagnosed with schizophrenia from a fair chance to participate in the public construction of their identity and, hence, to redress traditional symbolic injustices. PMID- 25820143 TI - Exercise vasodilation is greater in women: contributions of nitric oxide synthase and cyclooxygenase. AB - PURPOSE: We hypothesized exercise vasodilation would be greater in women due to nitric oxide synthase (NOS) and cyclooxygenase (COX) signaling. METHODS: 45 healthy adults (23 women, W, 22 men, M, 26 +/- 1 years) completed two 10-min trials of dynamic forearm exercise at 15 % intensity. Forearm blood flow (FBF; Doppler ultrasound), arterial pressure (brachial catheter), and forearm lean mass were measured to calculate relative forearm vascular conductance (FVCrel) = FBF 100 mmHg(-1) 100 g(-1) lean mass. Local intra-arterial infusion of L-NMMA or ketorolac acutely inhibited NOS and COX, respectively. In Trial 1, the first 5 min served as control exercise (CON), followed by 5 min of L-NMMA or ketorolac over the last 5 min of exercise. In Trial 2, the remaining drug was infused during 5-10 min, to achieve combined NOS-COX inhibition (double blockade, DB). RESULTS: Are mean +/- SE. Women exhibited 29 % greater vasodilation in CON (DeltaFVCrel, 19 +/- 1 vs. 15 +/- 1, p = 0.01). L-NMMA reduced DeltaFVCrel (p < 0.001) (W: Delta -2.3 +/- 1.3 vs. M: Delta -3.7 +/- 0.8, p = 0.25); whereas, ketorolac modestly increased DeltaFVCrel (p = 0.04) similarly between sexes (W: Delta 1.6 +/- 1.1 vs. M: Delta 2.0 +/- 1.6, p = 0.78). DB was also found to be similar between the sexes (p = 0.85). CONCLUSION: These data clearly indicate women produce a greater exercise vasodilator response. Furthermore, contrary to experiments in animal models, these data are the first to demonstrate vascular control by NOS and COX is similar between sexes. PMID- 25820145 TI - Comments on Mohammed Abouelleil Rashed's "A critical perspective on second-order empathy in understanding psychopathology: phenomenology and ethics". AB - Understanding the mental life of persons with psychosis/schizophrenia has been the crucial challenge of psychiatry since its origins, both for scientific models as well as for every therapeutic encounter between persons with and without psychosis/schizophrenia. Nonetheless, a preliminary understanding is always the first step of phenomenological as well as other qualitative research methods addressing persons with psychotic experiences in their life-world. In contrast to Rashed's assertions, in order to achieve such understanding, phenomenological psychopathologists need not necessarily adopt the transcendental-phenomenological attitude, which, however, is often required if performing phenomenological philosophy. Additionally, in the course of these (non-philosophical) scientific endeavors, differences between persons with psychosis/schizophrenia and so-called normal people seem to have a methodological function and value driving the scientist in her enterprise. Yet, these differences do not extend to ethical dimensions, and therefore, do not by any means touch ethical equality. PMID- 25820146 TI - Tolerability and efficacy of erythropoietin (EPO) treatment in traumatic spinal cord injury: a preliminary randomized comparative trial vs. methylprednisolone (MP). AB - The only available treatment of traumatic spinal cord injury (TSCI) is high-dose methylprednisolone (MP) administered acutely after injury. However, as the efficacy of MP is controversial, we assessed the superiority of erythropoietin (EPO) versus MP in improving clinical outcome of acute TSCI. Patients aged 18 to 65 years after C5-T12 injury, and grade A or B of the ASIA Impairment Scale (AIS), admitted within 8 h, hemodynamically stable, were randomized to MP according to the NASCIS III protocol or EPO iv (500 UI/kg, repeated at 24 and 48 h). Patients were assessed by an investigator blind to treatment assignment at baseline and at day 3, 7, 14, 30, 60 and 90. Primary end point: number of responders (reduction of at least one AIS grade). Secondary end points: treatment safety and the effects of drugs on a number of disability measures. Frequentistic and post hoc Bayesian analyses were performed. Eight patients were randomized to MP and 11 to EPO. Three patients (27.3 %) on EPO and no patients on MP reached the primary end point (p = 0.17). No significant differences were found for the other disability measures. No adverse events or serious adverse events were reported in both groups. The Bayesian analysis detected a 91.8 % chance of achieving higher success rates on the primary end point with EPO in the intention to-treat population with a 95 % chance the difference between EPO and MP falling in the range (-0.10, 0.51) and a median value of 0.2. The results of Bayesian analysis favored the experimental treatment. PMID- 25820147 TI - The diagnostic value of minor salivary gland biopsy in clinically diagnosed patients with Parkinson's disease: comparison with DAT PET scans. AB - To investigate the predictive value of minor salivary gland biopsy in clinically diagnosed early stage Parkinson's disease (PD) patients, and to provide more evidence of minor salivary gland biopsy as a pathological diagnostic biomarker of PD. Thirteen patients with early stage PD and 13 age-matched controls were recruited. Hoehn and Yahr stage and Unified Parkinson's disease Rating Scale Part III were employed to evaluate their severity of the disease. All the subjects underwent minor salivary gland biopsy and (11)C-methyl-N-2beta-carbomethoxy-3beta (4-fluorophenyl) tropane ((11)C-CFT) DAT-PET scan. Immunohistochemical staining for Lewy-type alpha-synucleinopathy using antibody against alpha-synuclein (alpha Syn) was performed in the tissues obtained from minor salivary gland. Abnormal accumulation of alpha-Syn was found around the gland cells in 9 of the 13 patients with PD, but in none of the control subjects. The alpha-Syn immunoreactive structures were located in the periacinar space. Twelve clinically diagnosed PD patients showed asymmetrical and relatively severe reduction of (11)C-CFT uptake in the posterior putamen compared with the control. The sensitivity, specificity, positive predictive value and negative predictive value of minor salivary gland biopsy were 75, 100, 100 and 25%, respectively, when compared with the DAT-PET imaging. Our results suggest that minor salivary gland biopsy does not hold high diagnostic accuracy as DAT-PET, but still has the potential to be a useful pathologic biomarker for PD, which is worth more investigations. PMID- 25820148 TI - A meta-analysis of the benefits of mindfulness-based stress reduction (MBSR) on psychological function among breast cancer (BC) survivors. AB - BACKGROUND: Psychological issue is the most common co-morbidity of women with breast cancer (BC) after receiving treatment. Effective coping with this problem is significant importance. The aim of this meta-analysis is to evaluate the benefits of mindfulness-based stress reduction (MBSR) on psychological distress among breast cancer survivors. METHODS: PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched from their inception to June 30, 2014. Two reviewers independently reviewed and extracted the data. The primary outcomes of interest were psychological domains. Review Manager 5.3 was used to pool collected data. RESULTS: Nine articles involving 964 participants were identified. Compared with those in control group, patients in MBSR group have a significant improvement on psychological domains: depression [mean difference (MD), 5.09; 95 % confidence interval (CI), 3.63-6.55; P < 0.00001], anxiety (MD, 2.79; 95 % CI, 1.62-3.96; P < 0.00001), stress (MD, 4.10; 95 % CI, 2.46-5.74; P < 0.00001). MBSR can also improve the overall quality of life (QOL) (MD, -1.16; 95 % CI, -2.21 to -0.12; P = 0.03). CONCLUSIONS: On the basis of our findings, MBSR shows a positive effect on psychological function and QOL of breast cancer survivors. This approach can be recommended to breast cancer patients as a part of their rehabilitation. PMID- 25820149 TI - Validity and reliability of an instrument for assessing case analyses in bioengineering ethics education. AB - Assessment in ethics education faces a challenge. From the perspectives of teachers, students, and third-party evaluators like the Accreditation Board for Engineering and Technology and the National Institutes of Health, assessment of student performance is essential. Because of the complexity of ethical case analysis, however, it is difficult to formulate assessment criteria, and to recognize when students fulfill them. Improvement in students' moral reasoning skills can serve as the focus of assessment. In previous work, Rosa Lynn Pinkus and Claire Gloeckner developed a novel instrument for assessing moral reasoning skills in bioengineering ethics. In this paper, we compare that approach to existing assessment techniques, and evaluate its validity and reliability. We find that it is sensitive to knowledge gain and that independent coders agree on how to apply it. PMID- 25820150 TI - gamma-Glutamyltransferase, but not markers of hepatic fibrosis, is associated with cardiovascular disease in older people with type 2 diabetes mellitus: the Edinburgh Type 2 Diabetes Study. AB - AIMS/HYPOTHESIS: We examined the association of prevalent and incident cardiovascular disease (CVD) with chronic liver disease in a cohort of community based people with type 2 diabetes, in order to clarify the relationship between these two important conditions. METHODS: 1,066 participants with type 2 diabetes aged 60-75 years underwent assessment of a range of liver injury markers (non specific injury, steatosis, steatohepatitis, fibrosis, portal hypertension). Individuals were followed up for incident cardiovascular events. RESULTS: At baseline there were 370/1,033 patients with prevalent CVD, including 317/1,033 with coronary artery disease (CAD). After a mean follow-up of 4.4 years there were 44/663 incident CVD events, including 27/663 CAD events. There were 30/82 CVD-related deaths. Risk of dying from or developing CVD was no higher in participants with steatosis than in those without (HR 0.90; 95% CI 0.40, 2.00; p > 0.05). The only notable relationship was with gamma-glutamyltransferase (GGT) (incident CVD: adjusted HR for doubling GGT 1.24 [95% CI 0.97, 1.59] p = 0.086; incident CAD: adjusted HR 1.33 [95% CI 1.00, 1.78] p = 0.053), suggesting that in our study population, chronic liver disease may have little effect on the development of, or mortality from, CVD. CONCLUSIONS/INTERPRETATION: An independent association between GGT and CVD warrants further exploration as a potentially useful addition to current cardiovascular risk prediction models in diabetes. However, overall findings failed to suggest that there is a clinical or pathophysiological association between chronic liver disease and CVD in elderly people with type 2 diabetes. PMID- 25820152 TI - Novel Genes Affecting Blood Pressure Detected Via Gene-Based Association Analysis. AB - Hypertension is a common disorder and one of the most important risk factors for cardiovascular diseases. The aim of this study was to identify more novel genes for blood pressure. Based on the publically available SNP-based P values of a meta-analysis of genome-wide association studies, we performed an initial gene based association study in a total of 69,395 individuals. To find supplementary evidence to support the importance of the identified genes, we performed GRAIL (gene relationships among implicated loci) analysis, protein-protein interaction analysis, functional annotation clustering analysis, coronary artery disease association analysis, and other bioinformatics analyses. Approximately 22,129 genes on the human genome were analyzed for blood pressure in gene-based association analysis. A total of 43 genes were statistically significant after Bonferroni correction (P < 2.3*10(-6)). The evidence obtained from the analyses of this study suggested the importance of ID1 (P = 2.0*10(-6)), CYP17A1 (P = 4.58*10(-9)), ATXN2 (P = 1.07*10(-13)), CLCN6 (P = 4.79*10(-9)), FURIN (P = 1.38*10(-6)), HECTD4 (P = 3.95*10(-11)), NPPA (P = 1.60*10(-6)), and PTPN11 (P = 8.89*10(-10)) in the genetic basis of blood pressure. The present study found some important genes associated with blood pressure, which might provide insights into the genetic architecture of hypertension. PMID- 25820151 TI - Par-3 modulates intestinal epithelial barrier function through regulating intracellular trafficking of occludin and myosin light chain phosphorylation. AB - BACKGROUND: Tight junctions play a critical role in the maintenance of intestinal barrier function. Partitioning-defective protein 3 (Par-3) can regulate intestinal barrier function through the modulation of tight junction assembly and cell polarity. However, the mechanisms are still not fully understood. METHODS: Adult C57BL/6 mice were treated with dextran sulfate sodium for 7 days, and segments of colon were harvested for immunofluorescent staining of Par-3. Caco-2 intestinal epithelial cells were treated with tumor necrosis factor alpha (TNF alpha) for 24 h, and Par-3 expression was detected by Western blot analysis and immunofluorescence. Additionally, Caco-2 cells were treated with Par-3 small interfering RNA, and altered expression and subcellular localization of tight junction proteins were studied by Western blot analysis and immunofluorescence. Furthermore, the interaction between Par-3 and myosin light chain (MLC) was detected by immunoprecipitation. RESULTS: Par-3 was downregulated in murine dextran sulfate sodium induced acute inflammation and TNF-alpha-treated Caco-2 cells. Depletion of Par-3 expression by small interfering RNA delayed intestinal epithelial barrier development in Caco-2 cells. This regulation was due to the redistribution of the tight junction protein occludin rather than the altered total levels of tight junction proteins. Par-3 silencing blocked the trafficking of occludin from or through the Golgi complex to the cell surface, and dramatically induced occludin accumulated at the Golgi complex. Importantly, Par 3 can interact with MLC, and loss of Par-3 upregulated MLC kinase expression and MLC phosphorylation, which contributed to intestinal epithelial barrier dysfunction. CONCLUSIONS: These results indicate that Par-3 plays an important role in the modulation of intestinal barrier function by regulating delivery of occludin as well as suppression of MLC phosphorylation. PMID- 25820153 TI - Time-varying signal analysis to detect high-altitude periodic breathing in climbers ascending to extreme altitude. AB - This work investigates the performance of cardiorespiratory analysis detecting periodic breathing (PB) in chest wall recordings in mountaineers climbing to extreme altitude. The breathing patterns of 34 mountaineers were monitored unobtrusively by inductance plethysmography, ECG and pulse oximetry using a portable recorder during climbs at altitudes between 4497 and 7546 m on Mt. Muztagh Ata. The minute ventilation (VE) and heart rate (HR) signals were studied, to identify visually scored PB, applying time-varying spectral, coherence and entropy analysis. In 411 climbing periods, 30-120 min in duration, high values of mean power (MP(VE)) and slope (MSlope(VE)) of the modulation frequency band of VE, accurately identified PB, with an area under the ROC curve of 88 and 89%, respectively. Prolonged stay at altitude was associated with an increase in PB. During PB episodes, higher peak power of ventilatory (MP(VE)) and cardiac (MP(LF)(HR) ) oscillations and cardiorespiratory coherence (MP(LF)(Coher)), but reduced ventilation entropy (SampEn(VE)), was observed. Therefore, the characterization of cardiorespiratory dynamics by the analysis of VE and HR signals accurately identifies PB and effects of altitude acclimatization, providing promising tools for investigating physiologic effects of environmental exposures and diseases. PMID- 25820154 TI - Hepatoprotective effects of selenium during diabetes in rats. AB - The present study investigated the hepatoprotective role of selenium during alloxan-induced diabetes in rats. Male Wistar rats were divided into four groups, namely, normal control, selenium treated, diabetic, and selenium-treated diabetic. Diabetes was induced in the animals by injecting alloxan intraperitoneally at a dose rate of 150 mg/kg body weight. Selenium in the form of sodium selenite was supplemented to rats at a dose level of 1 ppm in drinking water, ad libitum for two time durations of 2 and 4 weeks. The effects of different treatments were studied on various parameters in rat liver, which included serum glucose levels, serum insulin levels, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lipid peroxidation (LPO), glutathione reduced (GSH), oxidized glutathione (GSSG), total glutathione (TG), superoxide dismutase (SOD), catalase (CAT), glutathione reductase, glutathione peroxidase, metallothionein (MT), and histoarchitecture. A significant increase in the serum glucose levels, LPO levels, and in enzyme activities of ALP, ALT, and AST was observed in diabetic rats which, however, got decreased significantly upon supplementation with selenium. On the contrary, decreased enzyme activities of GSSG, SOD, and CAT and depressed levels of GSH as well as serum insulin levels were observed in diabetic rats which got improved following selenium supplementation. Interestingly, MT levels were increased both in diabetic and selenium-treated diabetic rats. Further, marked alterations in histoarchitecture were seen in diabetic rats with the prominent features being congestion in sinusoids, lipid accumulation, and centrilobular hepatocyte degeneration. However, selenium treatment to diabetic rats showed overall improvement in the hepatic histoarchitecture. PMID- 25820155 TI - Satisfaction with NHS is rising, but funding fears are high. PMID- 25820156 TI - Surgical management of extranasal nasal glioma. PMID- 25820157 TI - 6-Min walk-test data in severe obstructive-sleep-apnea-hypopnea-syndrome (OSAHS) under continuous-positive-airway-pressure (CPAP) treatment. AB - INTRODUCTION: Few studies have evaluated the functional capacity of severe OSAHS. AIMS: To assess their functional capacity, identify their 6-min walking-distance (6MWD) influencing factors and compare their data with those of two control groups. METHODS: Sixty (42 males) clinically consecutive stable patients with severe OSAHS under CPAP were included. Clinical, Epworth questionnaire, anthropometric, polysomnographic, plethysmographic and 6-min walk-test (6MWT) data were collected. Univariate and multivariate analyses were used to identify the 6MWD influencing factors. Data of a subgroup of severe OSAHS aged >=40 Yrs (n = 49) were compared with those of non-obese (n = 174) and obese (n = 55) groups. RESULTS: The means +/- SD of age and apnea-hypopnea-index were, respectively, 49 +/- 10 Yr and 62 +/- 18/h. The profile of OSAHS patients carrying the 6MWT, was as follows: at the end of the 6MWT, 31% and 25% had, respectively, a high dyspnea (>5/10, visual analogue scale) and a low heart-rate (<60% of-maximal-predicted), 13% had an abnormal 6MWD ( 5 points and 3% stopped the walk. The factors that significantly influenced the 6MWD, explaining 80% of its variability, are included in the following equation: 6MWD (m) = 29.66 * first-second-forced expiratory-volume (L) - 4.19 * Body-mass-index (kg/m(2)) - 51.89 * arterial hypertension (0. No; 1. Yes) + 263.53 * Height (m) + 2.63 * average oxy-sat during sleep (%) - 51.06 * Diuretic-use (0. No; 1. Yes) - 20.68 * Dyspnea (NYHA) (0. No; 1. Yes) - 38.09 * Anemia (0. No; 1. Yes) + 5.79 * Resting oxy-sat (%) - 586.25. Compared with non-obese and obese groups, the subgroup of OSAHS has a significantly lower 6MWD [100 +/- 9%, 100 +/- 8% and 83 +/- 12%, respectively). CONCLUSION: Severe OSAHS may play a role in reducing the functional capacity. PMID- 25820158 TI - Factors associated with asthma control in patients with aspirin-exacerbated respiratory disease. AB - BACKGROUND: Effective control of asthma is the primary goal of its treatment. Despite an improved understanding of asthma pathogenesis and accessibility of novel therapies, the rate of uncontrolled asthma remains high. OBJECTIVE: To find potential factors associated with asthma control in patients with aspirin exacerbated respiratory disease (AERD). METHODS: Clinical data were collected from a specifically structured questionnaire. Demographics, a history of upper airway symptoms, asthma course, exacerbations expressed as emergency department (ED) visits/hospitalizations, and asthma treatment were considered. Spirometry, skin prick tests, total IgE concentration, and blood eosinophil count were evaluated. Asthma control was assessed through the Asthma Control Test (ACT). RESULTS: Out of 201 AERD patients, 41 (20.4%), 69 (34.3%), and 91 (45.3%) had controlled, partially controlled, and uncontrolled asthma, respectively. A multivariate ordered logistic regression analysis revealed that hospitalizations for asthma in the previous 12 months (OR 2.88; 95%CI, 1.11-7.46), ED visits for asthma throughout its duration (OR 1.05; 95%CI, 1.004-1.10), and total IgE concentration (OR 1.28; 95%CI, 1.02-1.60) were positively associated with poor asthma control, whereas FEV1 values (OR 0.98; 95%CI, 0.96-0.99) and medical care at a referential specialty clinic (OR 0.50; 95%CI, 0.27-0.95) were positively associated with good asthma control. CONCLUSIONS: The prevalence of uncontrolled asthma in AERD patients is high and similar to that observed in different asthmatic populations. Owing both to the specificity and complexity of the disease, AERD patients should stay under regular care of well experienced referential medical centers to ensure that this asthma phenotype is dealt with effectively. PMID- 25820159 TI - Evidence that the MEK/ERK but not the PI3K/Akt pathway is required for protection from myocardial ischemia-reperfusion injury by 3',4'-dihydroxyflavonol. AB - The novel pro-drug of 3'4'-dihydroxyflavonol, NP202, potently reduces myocardial infarct size resulting from ischemia-reperfusion (I/R) through mechanisms that remain to be fully defined. In this study, we investigated whether cardioprotection induced by NP202 depended on activation of the reperfusion injury survival kinase (RISK) pathways. We therefore examined the effects of PD98059 and LY294002, specific inhibitors of the MEK/ERK1/2 and PI3K/Akt pathways, respectively. In isolated cardiomyocytes, H2O2induced oxidative stress activated ERK1/2 and this was further enhanced by DiOHF, the active parent compound of NP202. Although oxidative stress did not stimulate Akt in cardiomyocytes, co-treatment with DiOHF substantially increased Akt phosphorylation. This suggests that DiOHF is a potent modulator of RISK pathways specifically in the context of stress stimulation. In anesthetised sheep, following 1h ischemia and 3h reperfusion, the contribution of the RISK pathways to NP202-mediated cardioprotection was determined by treating the animals with PD98059, LY294002 or vehicle prior to NP202 administration and reperfusion. Infarct size, as a percentage of the area-at-risk, was substantially reduced by NP202 (from 78+/-6 to 46+/-4%, P<0.05). Inhibition of MEK/ERK1/2 abolished the cardioprotective effects of NP202 (infarct size 81+/-4%), whereas inhibition of PI3K/Akt had no effect (infarct size 53+/-4%). Our combined cellular and animal studies indicate that NP202 potently protects against myocardial I/R injury through complex mechanisms that involved augmentation of MEK/ERK1/2 signaling, but not PI3K/Akt signaling. PMID- 25820160 TI - Chelation of dietary iron prevents iron accumulation and macrophage infiltration in the type I diabetic kidney. AB - We previously reported that the functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice attenuated renal cell senescence in streptozotocin (STZ)-induced type 1 diabetic mice. In the present study, we investigated the effect of iron chelation on renal cell senescence and inflammation in the type 1 diabetic kidney. STZ-treated mice showed increase in iron accumulation, tubular cell senescence and macrophage infiltration at week 28 in the kidney. Administering deferasirox, which removes only dietary iron, significantly attenuated iron accumulation in proximal tubules and the number of infiltrating F4/80-positive cells without effecting blood glucose, hematocrit or hemoglobin levels. In contrast however, deferasirox did not influence renal cell senescence. The lack of p21 decreased the renal tubular iron accumulation and did not change tubular cell senescence. Interestingly, the STZ-treated animals showed an increase in p16, another cyclin-dependent kinase inhibitor. The results suggest that type 1 diabetes increases renal tubular iron accumulation and macrophage infiltration through a p21-dependent mechanism, and that the chelation of dietary iron attenuates these responses. PMID- 25820162 TI - Enhanced thermoelectric efficiency of porous silicene nanoribbons. AB - There is a critical need to attain new sustainable materials for direct upgrade of waste heat to electrical energy via the thermoelectric effect. Here we demonstrate that the thermoelectric performance of silicene nanoribbons can be improved dramatically by introducing nanopores and tuning the Fermi energy. We predict that values of electronic thermoelectric figure of merit ZTe up to 160 are achievable, provided the Fermi energy is located approximately 100 meV above the charge neutrality point. Including the effect of phonons yields a value for the full figure of merit of ZT = 3.5. Furthermore the sign of the thermopower S can be varied with achievable values as high as S = +/- 500 MUV/K. As a method of tuning the Fermi energy, we analyse the effect of doping the silicene with either a strong electron donor (TTF) or a strong electron acceptor (TCNQ) and demonstrate that adsorbed layers of the former increases ZTe to a value of 3.1, which is insensitive to temperature over the range 100 K - 400 K. This combination of a high, temperature-insensitive ZTe, and the ability to choose the sign of the thermopower identifies nanoporous silicene as an ideal thermoelectric material with the potential for unprecedented performance. PMID- 25820163 TI - Plasma-cell mastitis with two other concomitant diseases. PMID- 25820161 TI - The European Registry for Patients with Mechanical Circulatory Support (EUROMACS): first annual report. AB - The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) was founded on 10 December 2009 with the initiative of Roland Hetzer (Deutsches Herzzentrum Berlin, Berlin, Germany) and Jan Gummert (Herz- und Diabeteszentrum Nordrhein-Westfalen, Bad Oeynhausen, Germany) with 15 other founding international members. It aims to promote scientific research to improve care of end-stage heart failure patients with ventricular assist device or a total artificial heart as long-term mechanical circulatory support. Likewise, the organization aims to provide and maintain a registry of device implantation data and long-term follow-up of patients with mechanical circulatory support. Hence, EUROMACS affiliated itself with Dendrite Clinical Systems Ltd to offer its members a software tool that allows input and analysis of patient clinical data on a daily basis. EUROMACS facilitates further scientific studies by offering research groups access to any available data wherein patients and centres are anonymized. Furthermore, EUROMACS aims to stimulate cooperation with clinical and research institutions and with peer associations involved to further its aims. EUROMACS is the only European-based Registry for Patients with Mechanical Circulatory Support with rapid increase in institutional and individual membership. Because of the expeditious data input, the European Association for Cardiothoracic Surgeons saw the need to optimize the data availability and the significance of the registry to improve care of patients with mechanical circulatory support and its potential contribution to scientific intents; hence, the beginning of their alliance in 2012. This first annual report is designed to provide an overview of EUROMACS' structure, its activities, a first data collection and an insight to its scientific contributions. PMID- 25820164 TI - Impact of a clinical pharmacist stress ulcer prophylaxis management program on inappropriate use in hospitalized patients. AB - PURPOSE: Appropriate utilization of stress ulcer prophylaxis should be limited to high-risk, intensive care unit (ICU) patients. However, inappropriate stress ulcer prophylaxis use among all hospitalized patients remains a concern. The purpose of this study was to evaluate the clinical and economic impact of a novel pharmacist-managed stress ulcer prophylaxis program in ICU and general ward patients. METHODS: This retrospective, pre- and poststudy design was conducted in adult ICU and general ward patients at a large academic medical center between January 1, 2011 and January 31, 2012 to compare the rates of inappropriate stress ulcer prophylaxis before and after the implementation of a pharmacist-led stress ulcer prophylaxis management program. RESULTS: A total of 1134 unique patients consisting of 16,415 patient days were evaluated. The relative reduction in the rate of inappropriate stress ulcer prophylaxis days after program implementation in ICU and general ward patients was 58.3% and 83.5%, respectively (P < .001). The rates of ICU patients inappropriately continued on stress ulcer prophylaxis upon hospital discharge in the pre- and postimplementation groups were 29.9% and 3.6%, respectively (P < .001), whereas general ward patients significantly decreased from 36.2% to 5.4% in the pre- and postimplementation groups, respectively (P < .001). Total inpatient costs associated with all stress ulcer prophylaxis administered was $20,052.70 in the pre- and $3280.49 in the postimplementation group (P < .001), resulting in an estimated cost savings of > $200,000 annually. No differences in clinical outcomes were observed. CONCLUSIONS: The implementation of a pharmacist-managed stress ulcer prophylaxis program was associated with a decrease in inappropriate acid suppression rates during hospitalization and upon discharge, as well as significant cost savings. PMID- 25820165 TI - Diagnosis of unstable angina pectoris has declined markedly with the advent of more sensitive troponin assays. AB - BACKGROUND: Since the arrival of the universal definition of myocardial infarction more sensitive troponin assays have been developed. How these occurrences have influenced the proportions and clinical features of the components of acute coronary syndrome have not been studied prospectively in unselected hospital patients. METHODS: During 2010 we evaluated all patients in whom cardiac troponin I had been measured at a single university hospital. The diagnosis of acute myocardial infarction (ST-elevation myocardial infarction [STEMI] or non-ST-elevation myocardial infarction [NSTEMI]) was established in cases of a rise and/or fall of cardiac troponin I together with cardiac ischemic features. Patients with unstable chest discomfort and cardiac troponin I values below the decision limit of myocardial infarction were diagnosed as having unstable angina pectoris. The definition of acute coronary syndrome included unstable angina pectoris, NSTEMI, and STEMI. Mortality data were obtained from the Danish Civil Personal Registration System. RESULTS: Of 3762 consecutive patients, 516 had acute coronary syndrome. Unstable angina pectoris was present in 7%, NSTEMI in 67%, and STEMI in 26%. The NSTEMI patients were older, more frequently women, and had more comorbidities than patients with unstable angina pectoris and STEMI. At median follow-up of 3.2 years 195 patients had died: 14% of unstable angina pectoris, 45% of NSTEMI, and 25% of STEMI patients. Age adjusted log-rank statistics revealed differences in mortality: NSTEMI vs unstable angina pectoris (P = .0091) and NSTEMI vs STEMI (P = .0045). CONCLUSIONS: The application of the universal definition together with the use of a contemporary troponin assay seems to have reduced the proportion of patients with unstable angina pectoris to the benefit of patients with NSTEMI. Despite this, NSTEMI patients have a sustained higher mortality than patients with STEMI. PMID- 25820166 TI - Spontaneous bacterial peritonitis in a patient with anorexia nervosa with profound zinc and iron deficiency. PMID- 25820167 TI - Primary risk prevention in the elderly: use clinician-patient discussions, not automatic statin prescribing. PMID- 25820168 TI - Gastrointestinal bleeding, aortic stenosis, and the hiding culprit. PMID- 25820169 TI - Intravenous Imaging Contrast Media Complications: The Basics That Every Clinician Needs to Know. AB - Intravenous contrast is commonly used in noninvasive imaging procedures such as magnetic resonance imaging and computed tomography and can evaluate blood vessels and better characterize soft-tissue lesions. Although the incidence of adverse events after administration of contrast is low, it is important that clinicians and radiologists minimize risks and respond quickly and effectively when reactions occur. We will discuss a range of adverse events to iodinated and gadolinium-based contrast agents, including allergic-like reactions, nephrotoxicity, extravasation, and nephrogenic systemic fibrosis. We will review risk stratification for patients, as well as premedication and treatment of adverse events. PMID- 25820170 TI - Scope of problem of pulmonary arterial hypertension. AB - BACKGROUND: As with many uncommon diseases, data in patients with pulmonary arterial hypertension are sparse in regard to emergency service visits, hospitalizations, and mortality. The purpose of this investigation is to assess the scope of the problem of Group 1 pulmonary arterial hypertension in adults in the US and trends from 2001 to 2007. METHODS: The Nationwide Emergency Department Sample, 2007-2011, was used to determine the number of emergency department visits, hospitalizations, and all-cause mortality of patients aged >=18 years with Group 1 pulmonary arterial hypertension. We assessed patients with a discharge code for "primary pulmonary hypertension," and excluded patients with known causes of pulmonary hypertension that are not classified as Group 1. RESULTS: There were 64,451 emergency department visits and 52,779 hospitalizations for pulmonary arterial hypertension from 2007-2011 in patients aged >=18 years. The proportion of all emergency department visits that were for pulmonary arterial hypertension decreased from 16.4/100,000 visits in 2007 to 8.9/100,000 visits in 2011 (P < .0001). The proportion of all hospitalizations that were for pulmonary arterial hypertension decreased from 79/100,000 hospitalizations in 2007 to 38/100,000 hospitalizations in 2011 (P < .0001). Population-based death rates in patients with pulmonary arterial hypertension decreased from 4.6/million population in 2007 to 1.7/million population in 2011 (P < .0001). CONCLUSIONS: Decreasing rates of emergency department visits, hospitalizations, and deaths in patients with Group 1 pulmonary arterial hypertension were shown from 2007-2011. We speculate that this resulted from improved treatment during the period of observation. PMID- 25820171 TI - Compensatory erythropoiesis has no impact on the outcome of the in vivo Pig-a mutation assay in rats following treatment with the haemolytic agent 2 butoxyethanol. AB - The Pig-a assay has rapidly gained international interest as a useful tool for assessing the mutagenic potential of compounds in vivo. Although a large number of compounds, including both mutagens and non-mutagens, have been tested in the rat Pig-a assay in haematopoietic cells, there is limited understanding of how perturbations in haematopoiesis affect assay performance. Of particular concern is the possibility that regenerative haematopoiesis alone, without exposure to a genotoxic agent, could result in elevated Pig-a mutant cell frequencies. To address this concern, Wistar-Han rats were dosed by oral gavage with a non genotoxic haemolytic agent, 2-butoxyethanol (2-BE). Dose levels ranging from 0 to 450 mg/kg were tested using both single administration and 28-day treatment regimens. Haematology parameters were assessed at minimum within the first 24h of treatment and 8 days after the final administration. Pig-a mutant frequencies were assessed on Days 15 and ~30 for both treatment protocols and also on Days 43 and 57 for the 28-day protocol. Even at doses of 2-BE that induced marked intravascular lysis and strong compensatory erythropoiesis, the average Pig-a mutant phenotype red blood cell and reticulocyte frequencies were within the historical vehicle control distribution. 2-BE therefore showed no evidence of in vivo mutagenicity in these studies. The data suggest that perturbations in haematopoiesis alone do not lead to an observation of increased mutant frequency in the Pig-a assay. PMID- 25820172 TI - Confirmation of Pig-a mutation in flow cytometry-identified CD48-deficient T lymphocytes from F344 rats. AB - The Pig-a assay is used for monitoring somatic cell mutation in laboratory animals and humans. The assay detects haematopoietic cells deficient in glycosylphosphatidylinositol (GPI)-anchored protein surface markers using flow cytometry. However, given that synthesis of the protein markers (and the expression of their genes) is independent of the expression of the X-linked Pig-a gene and the function of its enzyme product, the deficiency of markers at the surface of the cells may be caused by a number of events (e.g. by mutation or epigenetic silencing in the marker gene itself or in any of about two dozen autosomal genes involved in the synthesis of GPI). Here we provide direct evidence that the deficiency of the GPI-anchored surface marker CD48 in rat T cells is accompanied by mutation in the endogenous X-linked Pig-a gene. We treated male F344 rats with N-ethyl-N-nitrosourea (ENU), and established colonies from flow cytometry-identified and sorted CD48-deficient spleen T-lymphocytes. Molecular analysis confirmed that the expanded sorted cells have mutations in the Pig-a gene. The spectrum of Pig-a mutation in our model was consistent with the spectrum of ENU-induced mutation determined in other in vivo models, mostly base pair substitutions at A:T with the mutated T on the non-transcribed strand of Pig a genomic DNA. We also used next generation sequencing to derive a similar mutational spectrum from a pool of 64 clones developed from flow-sorted CD48 deficient lymphocytes. Our findings confirm that Pig-a assays detect what they are designed to detect-gene mutation in the Pig-a gene. PMID- 25820173 TI - The renaissance of black phosphorus. AB - One hundred years after its first successful synthesis in the bulk form in 1914, black phosphorus (black P) was recently rediscovered from the perspective of a 2D layered material, attracting tremendous interest from condensed matter physicists, chemists, semiconductor device engineers, and material scientists. Similar to graphite and transition metal dichalcogenides (TMDs), black P has a layered structure but with a unique puckered single-layer geometry. Because the direct electronic band gap of thin film black P can be varied from 0.3 eV to around 2 eV, depending on its film thickness, and because of its high carrier mobility and anisotropic in-plane properties, black P is promising for novel applications in nanoelectronics and nanophotonics different from graphene and TMDs. Black P as a nanomaterial has already attracted much attention from researchers within the past year. Here, we offer our opinions on this emerging material with the goal of motivating and inspiring fellow researchers in the 2D materials community and the broad readership of PNAS to discuss and contribute to this exciting new field. We also give our perspectives on future 2D and thin film black P research directions, aiming to assist researchers coming from a variety of disciplines who are desirous of working in this exciting research field. PMID- 25820175 TI - APOBEC3 genes: retroviral restriction factors to cancer drivers. AB - The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Recent advances in cancer genomics, together with biochemical characterization of the APOBEC3 enzymes, have now implicated at least two family members in somatic mutagenesis during tumor development. We review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk. PMID- 25820177 TI - Pyrene magic: chiroptical enciphering and deciphering 1,3-dioxolane bearing two wirepullings to drive two remote pyrenes. AB - 2,2-Dimethyl-1,3-dioxolane connected to two pyrene moieties through flexible wires in chloroform exhibited cryptochirality in the ground state, as proven by the lack of detectable circular dichroism signals. This cryptochirality was deciphered in the photoexcited state by circularly polarised luminescence signals. PMID- 25820174 TI - Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis. AB - Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32gamma gene is expressed using the surfactant protein C promoter (SPC-IL-32gammaTg). Wild-type and SPC-IL 32gammaTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC IL-32gammaTg mice, including tumor necrosis factor-alpha (TNFalpha) positive lung macrophages and dendritic cells, and IFN-gamma (IFNgamma) and TNFalpha positive CD4(+) and CD8(+) T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32gamma but not the splice variant IL-32beta were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32gamma enhances host immunity to MTB. PMID- 25820176 TI - Using brachial-ankle pulse wave velocity to screen for metabolic syndrome in community populations. AB - The aim of this study is to investigate the viability of using brachial-ankle pulse wave velocity (baPWV) as a primary tool to screen metabolic syndrome (MetS), and to explore the risk factors of MetS in community populations. A total of 1914 subjects completed medical examination in Shanghai. BaPWV was significantly associated with the components of MetS. The area under curve (AUC) and its 95% confidence interval (CI) in total group were 62.50% and 60.00%-65.30% with the appropriate cut-off point being 1435 cm/sec. The AUC (95%CI) of three subgroups (40-50 yrs, 50-60 yrs and over 60 yrs group) were 75.30% (67.48% 83.35%), 63.35% (58.96%-67.60%), 55.37% (51.19%-60.01%), respectively. A clear pattern surfaced in the process of investigation: the younger were the subjects group, the better receiver operating characteristic (ROC) efficacy would emerge; and the higher sensitivity was, the better negative predictive value (NPV) would be. Male gender, high baPWV values, elevated uric acid (UA) and excess hypersensitive C reaction protein (hs-CRP) levels were stayed in the two regression models as the independent risk factors for MetS. We conclude that baPWV may serve as a potential screening tool for MetS at the cut-off point of 1435 cm/sec. PMID- 25820179 TI - Synthesis and antifungal activities of novel polyheterocyclic spirooxindole derivatives. AB - A series of spirooxindole tetrahydrofuran derivatives 3 were obtained in moderate to good yields via oxindole derivatives 1 and beta-arylacrylonitrile derivatives 2via base-mediated cascade [3 + 2] double Michael reactions under mild conditions and the application of this method in the synthesis of bioactive analogues, such as functionalized spirooxindole octahydrofuro[3,4-c]pyridine derivatives 4 which contain two new heterocyclic rings and two quaternary carbon centers, has also been developed. Subsequently, antifungal activities of all of the synthesized compounds were evaluated against five phytopathogenic fungi (Rhizoctonia solani, Fusarium semitectum, Alternaria solani, Valsa mali and Fusarium graminearum) using the mycelium growth rate method. The preliminary results showed that the spirooxindole octahydrofuro[3,4-c]pyridine derivative 4 showed higher growth inhibition of Valsa mali and Fusarium graminearum, than spirooxindole tetrahydrofuran derivatives 3. For example, spirooxindole octahydrofuro[3,4 c]pyridine derivative 4ab, having a bromine atom at the meta position of the benzene ring, was the best compound in inhibiting F. g. with an IC50 value of 3.31, in particular with inhibition of 4ab on F. g. being similar to that of the control cycloheximide (IC50 = 3.3 MUg mL(-1)). PMID- 25820178 TI - A Comparison of 8 Nutrition-Related Tests to Predict Mortality in Hemodialysis Patients. AB - OBJECTIVE: Protein-energy wasting (PEW) describes a state of decreased protein and energy fuels and is highly prevalent in hemodialysis patients. As PEW is associated with mortality, it should be detected accurately and easily. This study investigated which nutrition-related test predicts mortality and morbidity best in hemodialysis patients. DESIGN AND SUBJECTS: Data were used from CONTRAST, a cohort of end-stage kidney disease patients. Subjective Global Assessment (SGA), Malnutrition Inflammation Score (MIS), Geriatric Nutritional Risk Index (GNRI), composite score of Protein-Energy Nutritional Status (cPENS), serum albumin, serum creatinine, body mass index, and normalized protein nitrogen appearance rate were assessed at baseline. End points were all-cause mortality, cardiovascular events, and infection. Discriminative value of every test was assessed with Harrell's C statistic and calibration tested using the Hosmer Lemeshow goodness-of-fit test. Ultimately, in every test, 4 groups were created to compare (1) hazard ratios (HR; worst vs best group), (2) HR increase per group, and (3) HR of worst group versus other groups. RESULTS: In total, 489 patients were analyzed. Median follow-up was 2.97 years (interquartile range, 1.67-4.47 years). MIS, GNRI, albumin, and creatinine discriminated all-cause mortality equally. SGA, cPENS, body mass index, and normalized protein nitrogen appearance were inferior. cPENS and creatinine were inadequately calibrated. Of the remaining tests, GNRI predicted mortality less when comparing HRs. MIS and albumin predicted mortality equally well. In a subanalysis, these also predicted infection equally well, but MIS predicted cardiovascular events better. CONCLUSION: Of the 8 investigated nutrition-related tests, MIS and albumin predict mortality best in hemodialysis patients. As one has no added value over the other, we conclude that mortality is most easily predicted in hemodialysis patients by serum albumin. PMID- 25820180 TI - pi-Conjugated [2]Catenanes Based on Oligothiophenes and Phenanthrolines: Efficient Synthesis and Electronic Properties. AB - Novel pi-conjugated topologies based on oligothiophenes and phenanthroline have been assembled by combining their outstanding electronic and structural benefits with the specific properties of the topological structure. Macrocycles and catenanes are prepared by using an optimized protocol of transition metal templated macrocyclization followed by efficient Pd-catalyzed cross-coupling reaction steps. By using this method, [2]catenanes comprising two interlocked pi conjugated macrocycles with different ring sizes have been synthesized. The structures of the [2]catenanes and corresponding macrocycles are confirmed by detailed (1) H NMR spectroscopy and high resolution mass spectrometry. Single crystal X-ray structural analysis of the quaterthiophene-diyne macrocycle affords important insight into the packing features and intermolecular interaction of the new systems. The fully conjugated interlocked [2]catenanes are fully characterized by spectroscopic and electrochemical measurements. PMID- 25820182 TI - Developmental defects in the teeth of three wild chimpanzees from the Tai forest. AB - OBJECTIVES: Developmental defects in teeth (accentuated lines and hypoplasias) have played a critical role in studies of childhood disease, nutrition, weaning, environmental variation, and early mortality. While these enigmatic structures have been lauded for their potential insights into human evolution, few studies have examined defects in individuals of known histories. MATERIALS AND METHODS: Here we document defects in the molars of three wild juvenile chimpanzees from the Tai forest (Pan troglodytes verus) and compare them with behavioral, epidemiological, and environmental records. RESULTS: Accentuated lines of differing intensities were found throughout molar crown and root growth, and were most common in a juvenile who demonstrated slow skeletal growth and prolonged maternal dependence. These defects were observed in association with some but not all injuries and disease outbreaks in this community. A 10-year record of accentuated line frequency across individuals shows a significant negative correlation with rainfall, but does not correlate with fruit availability or reveal significant annual trends. Several hypoplasias formed between ~0.6 and 5.8 years of age on molar crowns and roots of the three individuals, however, available behavioral and epidemiological records do not explain their causation. DISCUSSION: While teeth may provide precise and accurate records of illness and trauma in some cases, inferring seasonal cycles, social stress, or weaning in living or fossil primate dentitions requires additional evidence beyond the presence, absence, or degree of expression of these defects. Studies that microsample bulk and trace elements may provide a more secure context for the interpretation of environmental, physiological, and dietary changes that impact dental tissue formation. PMID- 25820181 TI - Oligoclonal bands predict multiple sclerosis in children with optic neuritis. AB - We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Multiple Cox proportional-hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 3.39-10.39, p < 0.001), presence of cerebrospinal fluid immunoglobulin G oligoclonal bands (OCB; HR = 3.69, 95% CI = 2.32-5.86, p < 0.001), and age (HR = 1.08 per year of age, 95% CI = 1.02-1.13, p = 0.003) as independent predictors of conversion, whereas sex and laterality (unilateral vs bilateral) had no influence. Combined cMRI and OCB positivity indicated a 26.84-fold higher HR for developing MS compared to double negativity (95% CI = 12.26-58.74, p < 0.001). Accordingly, cerebrospinal fluid analysis may supplement cMRI to determine the risk of MS in children with isolated ON. PMID- 25820184 TI - Dinuclear Face-Sharing Bi-octahedral Tungsten(VI) Core and Unusual Thermal Behavior in Complex Th Tungstates. AB - Invited for the cover of this issue are the groups of Evgeny V. Alekseev at the Forchungszentrum Julich and Thorstem M. Gesing at the University of Bremen. The image depicts the complex thorium tungstate polyanions, having a six-leafed lily cross-section, containing a rare confacial [W2 O9 ](6-) bioctahedral core. Read the full text of the article at 10.1002/chem.201500500. PMID- 25820183 TI - Test battery with the human cell line activation test, direct peptide reactivity assay and DEREK based on a 139 chemical data set for predicting skin sensitizing potential and potency of chemicals. AB - To develop a testing strategy incorporating the human cell line activation test (h-CLAT), direct peptide reactivity assay (DPRA) and DEREK, we created an expanded data set of 139 chemicals (102 sensitizers and 37 non-sensitizers) by combining the existing data set of 101 chemicals through the collaborative projects of Japan Cosmetic Industry Association. Of the additional 38 chemicals, 15 chemicals with relatively low water solubility (log Kow > 3.5) were selected to clarify the limitation of testing strategies regarding the lipophilic chemicals. Predictivities of the h-CLAT, DPRA and DEREK, and the combinations thereof were evaluated by comparison to results of the local lymph node assay. When evaluating 139 chemicals using combinations of three methods based on integrated testing strategy (ITS) concept (ITS-based test battery) and a sequential testing strategy (STS) weighing the predictive performance of the h CLAT and DPRA, overall similar predictivities were found as before on the 101 chemical data set. An analysis of false negative chemicals suggested a major limitation of our strategies was the testing of low water-soluble chemicals. When excluded the negative results for chemicals with log Kow > 3.5, the sensitivity and accuracy of ITS improved to 97% (91 of 94 chemicals) and 89% (114 of 128). Likewise, the sensitivity and accuracy of STS to 98% (92 of 94) and 85% (111 of 129). Moreover, the ITS and STS also showed good correlation with local lymph node assay on three potency classifications, yielding accuracies of 74% (ITS) and 73% (STS). Thus, the inclusion of log Kow in analysis could give both strategies a higher predictive performance. PMID- 25820185 TI - Impedance analysis of inherently redox-active ionic-liquid-based photoelectrochemical cells: charge-transfer mechanism in the presence of an additional redox couple. AB - An intensive electrochemical impedance study was carried out to understand the charge-transfer processes in photoelectrochemical (PEC) cells based on ionic liquid (IL) electrolytes. Three different electrolytes were utilized to understand the role of redox species as well as the medium on the charge-transfer mechanism. The negligible diffusion resistance, despite the presence of two different redox species in the case of Fe(CN)(6) (-4/-3) in IL, was explained on the basis of charge transfer between species of two different redox couples. Accordingly, the redox species are not required to travel through the bulk of the electrolyte for the removal of accumulated charges, as short-range charge transfer between the IL and the Fe(CN)(6) (-4/-3) species facilitates the removal of accumulated charges. It is also shown that PEC cells utilizing dual redox couples are highly stable with larger photoelectrochmeical windows, >3 V. PMID- 25820186 TI - Heme oxygenase-1 modulates microRNA expression in cultured astroglia: implications for chronic brain disorders. AB - BACKGROUND: Over-expression of the heme-degrading enzyme, heme oxygenase-1 (HO-1) promotes iron deposition, mitochondrial damage, and autophagy in astrocytes and enhances the vulnerability of nearby neuronal constituents to oxidative injury. These neuropathological features and aberrant brain microRNA (miRNA) expression patterns have been implicated in the etiopathogeneses of various neurodevelopmental and aging-related neurodegenerative disorders. OBJECTIVE: To correlate glial HO-1 overexpression with altered miRNA patterns, which have been linked to the aforementioned "core" neuropathological features. METHODS: miRNA microchip assays were performed on HMOX1- and sham-transfected primary rat astroglia and affected miRNAs were further validated by qPCR. The roles of the heme degradation products, carbon monoxide (CO), iron (Fe) and bilirubin on miRNA expression were assessed and salient mRNA targets of the impacted miRNAs were ascertained. RESULTS: In HMOX1-transfected astrocytes, rno-miR-140*, rno-miR-17, and rno-miR-16 were significantly up-regulated, and rno-miR-297, rno-miR-206, rno miR-187, rno-miR-181a, rno-miR-138 and rno-miR-29c were down-regulated, compared to sham-transfected controls. CO and Fe were implicated in the HMOX1 effects, whereas bilirubin was inert or counteracted the HMOX1-related changes. mRNA levels of Ngfr, Vglut1, Mapk3, Tnf-alpha, and Sirt1, known targets of the down regulated miRNAs and abnormal in various human brain disorders, were significantly increased in the HMOX-1-transfected astrocytes. CONCLUSIONS: In chronic CNS disorders, altered expression of salient miRNAs and their mRNA targets may contribute to the neural damage accruing from the over-expression of glial HO-1. PMID- 25820187 TI - Cerebellar granule cells are predominantly generated by terminal symmetric divisions of granule cell precursors. AB - BACKGROUND: Neurons in the central nervous system (CNS) are generated by symmetric and asymmetric cell division of neural stem cells and their derivative progenitor cells. Cerebellar granule cells are the most abundant neurons in the CNS, and are generated by intensive cell division of granule cell precursors (GCPs) during postnatal development. Dysregulation of GCP cell cycle is causal for some subtypes of medulloblastoma. However, the details and mechanisms underlying neurogenesis from GCPs are not well understood. RESULTS: Using long term live-cell imaging of proliferating GCPs transfected with a fluorescent newborn-granule cell marker, we found that GCPs underwent predominantly symmetric divisions, generating two GCPs or two neurons, while asymmetric divisions generating a GCP and a neuron were only occasionally observed, in both dissociated culture and within tissues of isolated cerebellar lobules. We found no significant difference in cell cycle length between proliferative and neurogenic divisions, or any consistent changes in cell cycle length during repeated proliferative division. CONCLUSIONS: Unlike neural stem cells in the cerebral cortex and spinal cord, which generate many neurons by repeated asymmetric division, cerebellar GCPs produce neurons predominantly by terminal symmetric division. These results indicate diverse mechanisms of neurogenesis in the mammalian brain. PMID- 25820188 TI - An in vitro analysis of separation of multi-use ProTaper Universal and ProTaper Next instruments in extracted mandibular molar teeth. AB - This study investigated the separation incidence of reused ProTaper Universal and ProTaper Next rotary instruments and identified the location of separated fragments. The root canals of extracted human mandibular molars were prepared with 10 assorted sets of ProTaper Universal and ProTaper Next instruments. After each preparation, instrument sets were autoclaved. This arrangement was repeated until an instrument fractured. The number of prepared teeth until fracture occurred was recorded for each instrument set. Teeth in which the instruments fractured were analyzed to determine the separation grade, apical relation, and coronal position. Fracture surfaces of the instruments were examined with scanning electron microscope. ProTaper Universal instruments fractured after application to a mean of 7.3 teeth, and ProTaper Next instruments after application to a mean of 5.7 teeth (p > 0.05). In the ProTaper Universal and ProTaper Next groups, F2 and X1 were the most commonly fractured instruments, respectively. Torsional and cyclic failures were evenly distributed in both the groups. The mean lengths of the fractured fragments of the instruments showed no statistically significant difference. The distance between the tip of the fractured instruments and apical constriction was similar (p > 0.05). However, the mean distance between the root canal orifice and coronal part of the fractured instrument was shorter in the ProTaper Next group (p < 0.05). The life span of ProTaper Universal and ProTaper Next instruments was the same for preparation of mandibular molar teeth. None of the instruments were fractured in the first usage. PMID- 25820189 TI - Improving Trastuzumab's Stability Profile by Removing the Two Degradation Hotspots. AB - Stability of recombinant monoclonal antibodies (mAbs) is essential for their clinical application. The presence of the two degradation hotspots, namely, LC Asn30 and HC-Asp102, in its complementary determinant regions prevents trastuzumab (Herceptin(r)) from being supplied in a drug product format of liquid formulation. To improve the stability, a new antibody was created by replacing the two residues with chemically similar amino acids of LC-Gln30 and HC-Glu102. This new mAb, named as T-mAb2, exhibited a simple and more uniform charge heterogeneity profile than T-mAb1, which is trastuzumab made in our laboratory, as displayed by the difference between their main peak area percentages (82.9% for T-mAb2 vs. 60.5% for T-mAb1). Computer modeling results, physicochemical and biological characterization, and stability profiling studies on T-mAb2 and T-mAb1 demonstrated that stability of T-mAb2 was significantly improved. In comparison with T-mAb1, although its in vitro human epidermal growth factor receptor 2 (HER2)-target binding activities were reduced slightly, in vivo tumor growth inhibiting activity was not affected, as demonstrated by the study results using the SKOV3 xenograft mouse model. Hence, a new anti-HER2 antibody was generated with improved stability that could be used to produce the drug product in liquid formulation for cost saving and more convenient usage. PMID- 25820191 TI - Delayed Anticipatory Spoken Language Processing in Adults with Dyslexia-Evidence from Eye-tracking. AB - It is now well established that anticipation of upcoming input is a key characteristic of spoken language comprehension. It has also frequently been observed that literacy influences spoken language processing. Here, we investigated whether anticipatory spoken language processing is related to individuals' word reading abilities. Dutch adults with dyslexia and a control group participated in two eye-tracking experiments. Experiment 1 was conducted to assess whether adults with dyslexia show the typical language-mediated eye gaze patterns. Eye movements of both adults with and without dyslexia closely replicated earlier research: spoken language is used to direct attention to relevant objects in the environment in a closely time-locked manner. In Experiment 2, participants received instructions (e.g., 'Kijk naar de(COM) afgebeelde piano(COM)', look at the displayed piano) while viewing four objects. Articles (Dutch 'het' or 'de') were gender marked such that the article agreed in gender only with the target, and thus, participants could use gender information from the article to predict the target object. The adults with dyslexia anticipated the target objects but much later than the controls. Moreover, participants' word reading scores correlated positively with their anticipatory eye movements. We conclude by discussing the mechanisms by which reading abilities may influence predictive language processing. PMID- 25820190 TI - Advances in ultrasound imaging for congenital malformations during early gestation. AB - BACKGROUND: With refinement in ultrasound technology, detection of fetal structural abnormalities has improved and there have been detailed reports of the natural history and expected outcomes for many anomalies. The ability to either reassure a high-risk woman with normal intrauterine images or offer comprehensive counseling and offer options in cases of strongly suspected lethal or major malformations has shifted prenatal diagnoses to the earliest possible gestational age. METHODS: When indicated, scans in early gestation are valuable in accurate gestational dating. Stricter sonographic criteria for early nonviability guard against unnecessary intervention. Most birth defects are without known risk factors, and detection of certain malformations is possible in the late first trimester. RESULTS: The best time for a standard complete fetal and placental scan is 18 to 20 weeks. In addition, certain soft anatomic markers provide clues to chromosomal aneuploidy risk. Maternal obesity and multifetal pregnancies are now more common and further limit early gestation visibility. CONCLUSION: Other advanced imaging techniques during early gestation in select cases of suspected malformations include fetal echocardiography and magnetic resonance imaging. PMID- 25820192 TI - Dismantling papillary renal cell carcinoma classification: The heterogeneity of genetic profiles suggests several independent diseases. AB - Papillary renal cell carcinoma (pRCC) is the second most frequent renal cell carcinoma (RCC) after clear cell RCC. In contrast to clear cell RCC, there is no consensual protocol using targeted therapy for metastatic pRCC. Moreover, diagnosis of some pRCC, especially pRCC of type 2 (pRCC2) may be challenging. Our aim was to identify molecular biomarkers that could be helpful for the diagnosis and treatment of pRCC. We studied the clinical, histological, immunohistological, and comprehensive genetic features of a series of 31 pRCC including 15 pRCC1 and 16 pRCC2. We aimed to determine whether pRCC represents a unique entity or several diseases. In addition, we compared the genetic features of pRCC2 to those of eight RCC showing various degrees of tubulo-papillary architecture, including three TFE-translocation RCC and five unclassified RCC. We demonstrate that pRCC is a heterogeneous group of tumors with distinct evolution. While most pRCC2 had genetic profiles similar to pRCC1, some shared genomic features, such as loss of 3p and loss of chromosome 14, with clear cell RCC, TFE-translocation RCC, and unclassified RCC. We identified variants of the MET gene in three pRCC1. A mutation in the BRAF gene was also identified in one pRCC1. In addition, using next-generation sequencing (NGS), we identified several variant genes. Genomic profiling completed by NGS allowed us to classify pRCC2 in several groups and to identify novel mutations. Our findings provide novel information on the pathogenesis of pRCC that allow insights for personalized treatment. PMID- 25820198 TI - Association of body mass index with chromosome damage levels and lung cancer risk among males. AB - Epidemiological studies have shown an etiological link between body mass index (BMI) and cancer risk, but evidence supporting these observations is limited. This study aimed to investigate potential associations of BMI with chromosome damage levels and lung cancer risk. First, we recruited 1333 male workers from a coke-oven plant to examine their chromosome damage levels; and then, a cohort study of 12,052 males was used to investigate the association of BMI with lung cancer incidence. We further carried out a meta-analysis for BMI and male lung cancer risk based on cohort studies. We found that men workers with excess body weight (BMI >= 25 kg/m(2)) had lower levels of MN frequencies than men with normal-weight (BMI: 18.5-24.9). Our cohort study indicated that, the relative risk (RR) for men with BMI >= 25 to develop lung cancer was 35% lower than RR for normal-weight men. Further meta-analysis showed that, compared to normal-weight men, men with BMI >= 25 had decreased risk of lung cancer among both the East Asians and others populations. These results indicate that men with excess body weight had significant decreased chromosome damage levels and lower risk of lung cancer than those with normal-weight. However, further biological researches were needed to validate these associations. PMID- 25820199 TI - A semi-interpenetrating network approach for dimensionally stabilizing highly charged anion exchange membranes for alkaline fuel cells. AB - There is a delicate balance between ion exchange capacity (IEC), conductivity, and dimensional stability in anion exchange membranes as higher charge content can lead to increased water uptake, causing excessive swelling and charge dilution. Using highly-charged benzyltrimethylammonium polysulfone (IEC=2.99 mEq g(-1) ) as a benchmark (which ruptured in water even at room temperature), we report the ability to dramatically decrease water uptake using a semi interpenetrating network wherein we reinforced the linear polyelectrolyte with a crosslinked poly(styrene-co-divinylbenzene) network. These membranes show enhanced dimensional stability as a result of lower water uptake (75 % vs. 301 % at 25 degrees C) while maintaining excellent hydroxide conductivity (up to 50 mS cm(-1) at 25 degrees C). These improvements produced an enhanced alkaline fuel cell capable of generating 236 mW cm(-2) peak power density at 80 degrees C. This method is easily adaptable and can be a viable strategy for stabilizing existing systems. PMID- 25820200 TI - Metabolite and macromolecule T1 and T2 relaxation times in the rat brain in vivo at 17.2T. AB - PURPOSE: To measure the T1 and T2 relaxation times of water, metabolites, and macromolecules in the rat brain in vivo at 17.2T and achieve absolute quantification of the neurochemical profile. Relaxation times were compared with values from the literature found at lower magnetic fields. METHODS: (1) H NMR spectra were measured using a LASER localization sequence. T1 - and T2 -weighted spectra were analyzed using LCModel with an original parameterization of the macromolecule baseline. RESULTS: The T1 relaxation times of 20 metabolites and the T2 relaxation times of 16 singlets and J-coupled metabolites were measured. The mean T1 and T2 relaxation times for metabolites were 1721 +/- 237 ms and 148 +/- 53 ms, respectively. In addition, we measured the T1 and T2 relaxation times of 4 macromolecule resonance groups, their mean T1 and T2 relaxation times being 690 +/- 100 ms and 37 +/- 15 ms, respectively. Absolute quantification of 21 metabolites and 4 groups of macromolecule resonances was achieved with Cramer-Rao Lower Bounds below 5% for Cr, Gln, Glu, GPC, Ins, NAA, PCr, and Tau and below 25% for the remaining resonances. CONCLUSION: Comparison of our relaxation times to previously published values suggests a small increase of T1 values and a clear decrease of T2 values between 11.7 and 17.2T. PMID- 25820201 TI - Hospital management of acute exacerbations of chronic obstructive pulmonary disease. AB - The course of chronic obstructive pulmonary disease (COPD) is often complicated by episodes of acute worsening of respiratory symptoms, which may lead to escalation of therapy and occasionally emergency department visits and hospitalization. Acute exacerbations of COPD (AECOPD) have a negative impact on quality of life and hasten the decline of lung function. They also significantly contribute to the direct and indirect healthcare costs of this disease. Severe exacerbations (those leading to hospital admission) have been associated with significant poor outcomes including an increased risk of readmissions and mortality. COPD is currently the fourth leading cause of hospital readmission in the United States. In this review, we will provide a broad overview on the etiology, assessment, management, discharge planning, and follow-up care of patients hospitalized with AECOPD. PMID- 25820202 TI - Does near-roadway air pollution contribute to childhood obesity? PMID- 25820203 TI - New European Food Safety Authority recommendation for infant formulae contradicts the physiology of human milk and infant development. AB - The European Food Safety Authority (EFSA) has concluded from a limited review of the literature that although docosahexaenoic acid (DHA) was required for infant formula, arachidonic acid was not 'even in the presence of DHA'. The EFSA report mistakes a nutrient ubiquitous in the diets of infants, and with wide-ranging effects, for an optional drug targeted to a particular outcome that is properly excluded when no benefit is found for that particular outcome. The EFSA's conclusion is not evidence-based. Its conclusions are grounded in trials which tested functionality of DHA, not arachidonic acid. Arachidonic acid has very different biological functions, for instance, in the vasculature and in specific aspects of immunity. None of the trials cited tested any property specific to arachidonic acid. The test of time through natural selection and human evolution has resulted in milk composition in which arachidonic acid and its long-chain polyenoic family members are conserved and occupy a prominent position. As DHA suppresses arachidonic acid, an infant formula with DHA and no arachidonic acid runs the risk of cardio- and cerebrovascular morbidity through suppression of the favourable eicosanoid derivatives of arachidonic acid and cell structural integrity. The EFSA recommendation should be rejected forthwith as unsafe and risking lifelong disability. PMID- 25820204 TI - Anthropometric indices and dietary intake: prospective determinants of geriatric cognitive impairment? AB - OBJECTIVE: To assess the magnitude of elderly (aged 60-85 years) persons with cognitive impairment and its relation with their dietary and anthropometric status. METHODS: DESIGN: Cross-sectional study. The cognitive status of the subjects was screened using the Mini Mental Score Examination (MMSE). The binary logistic regression coefficients were ascertained for determining the association of predictors like MMSE score, body mass index (BMI) and waist-to-hip ratio (WHR) with the age of the subjects. SETTING: Government hospitals, Vadodara, India. SUBJECTS: Geriatric subjects (n = 50) aged 60-85 years. RESULTS: The mean age of the elderly subjects was around 68 years old. The majority of subjects fell into the mild cognitive impairment (MCI) category, with Grade I obesity. We noted significant correlations (p < 0.05; p < 0.01) with energy, protein, vitamin B12, WHR and BMI. CONCLUSIONS: Cognitive abnormalities doubly elevate with advancing age, with decreased intake of dietary nutrients. The cognitive assessment undertaken focused on this rampant under-diagnosed cognition. The burgeoning prodromal insidious stage of cognitive impairment demands rapid diagnosis for preserving mental health, or else severe deterioration takes over, leading to compromised mental abilities in the elderly. PMID- 25820206 TI - Self-regulation of eating behaviour among adolescents. PMID- 25820205 TI - Mice perceive synergistic umami mixtures as tasting sweet. AB - Previous electrophysiological investigation shows that combinations of compounds classified by humans as umami-tasting, such as glutamate salts and 5' ribonucleotides, elicit synergistic responses in neurons throughout the rodent taste system and produce a pattern that resembles responses to sweet compounds. The current study tested the hypothesis that a synergistic mixture of monopotassium glutamate (MPG) and inositol monophosphate (IMP) possesses perceptual similarity to sucrose in mice. We estimated behavioral similarity among these tastants and the individual umami compounds using a series of conditioned taste aversion (CTA) tests, a procedure that measures whether a CTA formed to one stimulus generalizes to another. Our primary finding was that a CTA to a synergistic mixture of MPG + IMP generalizes to sucrose, and vice-versa. This indicates umami synergistic mixtures are perceived as having a sweet, or at least sucrose-like, taste to mice. Considering other recent studies, our data argue strongly in favor of multiple receptor mechanisms for umami detection, and complexity in taste perception models for rodents. PMID- 25820207 TI - Comparison of Brucella canis genomes isolated from different countries shows multiple variable regions. AB - Brucella canis is a pathogenic bacterium for dogs and its zoonotic potential has been increasing in recent years. In this study, we report the sequencing, annotation and analysis of the genome of Brucella canis strain Oliveri isolated from a dog in a breeding kennel in Medellin, Colombia, South America. Whole genome shotgun sequencing was carried out using the ROCHE 454 GS FLX Titanium technology at the National Center for Genomic Sequencing-CNSG in Medellin, Colombia. The assembly procedure was performed using Newbler v2.6. In the genome annotation process, each contig was analyzed independently using as reference Brucella suis ATCC 1330 chromosomes. This new genome could be useful for the development of diagnostic tools and for vaccines search as well, in order to reduce the health impact of this infection in both, dogs and humans. The sequence was deposited in EMBL-EBI with accession numbers HG803175 and HG803176 for chromosomes 1 and 2, respectively. PMID- 25820208 TI - Glochidioboside Kills Pathogenic Bacteria by Membrane Perturbation. AB - The aim of this study was to evaluate the antibacterial effects of glochidioboside and determine its mechanism of action. Glochidioboside has been reported to be isolated from some plants but the underlying biological properties have remained largely obscure until now. To identify the antibacterial activity of all biological properties, pathogenic bacteria susceptibility test was performed, and the result shows that the compound displays remarkable antibacterial activity against antibiotic-resistant bacteria not to mention general pathogen. To demonstrate membrane disruption and depolarization, SYTOX green and bis-(1,3-dibutylbarbituric acid) trimethine oxonol were used with Escherichia coli O157, and indicated that glochidioboside affected cytoplasmic membranes by permeabilization and depolarization, respectively. Calcein efflux was evident in a membrane model that encapsulated fluorescent dye, and supported the hypothesis of a membrane-active mechanism. To confirm the release of intracellular matrix owing to membrane damage, the movements of potassium ion were observed; the results indicated that the cells treated with glochidioboside leaked potassium ion, thus the damage induced by the compounds lead to leaking intracellular components. We propose that glochidioboside kills pathogenic bacteria via perturbation of integrity of the membrane. PMID- 25820209 TI - Retrograde intrarenal surgery versus percutaneous nephrolithotomy in patients with significant comorbidities and solitary kidney. PMID- 25820210 TI - Mitochondrial DNA-Based Analyses of Relatedness Among Turkeys, Meleagris gallopavo. AB - The domesticated turkey, Meleagris gallopavo, is believed to be a single breed with several varieties whose relatedness and origins remain poorly understood. Using the mitochondrial genome sequence (GenBank accession no. EF153719) that our group first reported, we investigated the relationships among 15 of the most widely occurring turkey varieties using D-loop and 16S RNA sequences. We included, as a non-traditional outgroup, mtDNA sequence information from wild turkey varieties. A total of 24 SNPs, including 18 in the D-loop and 6 in the 16S rRNA, was identified, validated and used. Of the 15 haplotypes detected based on these SNPs, 7 were unique to wild turkeys. Nucleotide diversity estimates were relatively low when compared to those reported for chickens and other livestock. Network and phylogenetic analyses showed a closer relationship among heritage varieties than between heritage and wild turkeys. The mtDNA data provide additional evidence that suggest a recent divergence of turkey varieties. PMID- 25820211 TI - A simple and convenient sticky/blunt-end ligation method for fusion gene construction. AB - Here we present a simple and convenient sticky/blunt-end ligation method for fusion gene construction. The fusion gene is constructed by seamless ligation of 5'-end phosphorylated blunt ends instead of by overlap extension PCR (OE-PCR). Therefore, the challenge of amplifying large DNA fragments (e.g., the large bifunctional enzyme gene constructed by fusion of two monofunctional enzyme genes) by PCR can be avoided. In addition, synthesis of the inner primers for OE PCR is not necessary, indicating that this method should be especially convenient for construction of fusion genes with various combinations of multiple fragments (e.g., chimeric gene libraries, fusion gene libraries). As a modification of the commonly used fusion gene construction technique, this method may find a wide range of applications in bioscience and biotechnology. PMID- 25820212 TI - Implementing a telephone based peer support intervention for women with a BRCA1/2 mutation. AB - Women with a BRCA1/2 gene mutation face complex risk management decisions and communication issues that can lead to increased levels of distress and unmet needs. We describe the implementation of a peer-support program that aims to reduce distress among women with a BRCA1/2 mutation, including peer and support recipient satisfaction with the program, challenges and lessons learnt. Participants with a BRCA1/2 mutation were matched with a trained peer volunteer (also a mutation carrier) to have regular one-on-one phone calls, over 4 months. Details of the calls, including topics discussed, time spent and number, were collected. Peers and recipients completed surveys assessing how they felt the contact went, satisfaction with the program, and preferences for matching. Satisfaction with the program was high for both peers and recipients. 80% of pairs ended contact through mutual agreement. Peers and recipients differed in the importance placed on age and surgery experience to determine matches. The most challenging aspect of the program for peers was difficulty in contacting recipients. Peer support for women with a BRCA1/2 mutation is feasible. However, to encourage continued involvement by peers and recipients greater flexibility in the method and delivery of contact is needed. We advocate the use of text messaging and/or email as mechanisms for pairs to arrange and maintain contact. These strategies should be in addition to, rather than replacing, calls. A mixed medium intervention, where recipients can tailor the method of communication to suit their needs, may be preferable and effective, though this would need to be tested. PMID- 25820213 TI - Influence of isolated or simultaneous application of electromyostimulation and vibration on leg blood flow. AB - PURPOSE: The aim of this study was to analyze the acute effects of isolated or simultaneously applied whole-body vibration (WBV) and electromyostimulation (ES) on the popliteal arterial blood velocity and skin temperature (ST) of the calf. METHODS: Thirteen healthy males were assessed in five different sessions. After a familiarization session, four interventions were applied in random order; WBV, ES, simultaneous WBV and ES (WBV+ES), and 30 s of WBV followed by 30 s of ES (WBV30/ES30). Each intervention consisted of 10 sets * 1 min ON + 1 min OFF. The subject was standing on the vibration platform (squat position, 30 degrees knee flexion, 26 Hz, 5 mm peak-to-peak), and ES was applied on the gastrocnemius of both the legs (8 Hz, 400 us). RESULTS: The WBV+ES intervention was the only one that maintained the mean blood velocity (MBV) elevated above baseline during the 10 sets, from set-1 (134.6 % p < 0.01) to set-10 (112.6 % p < 0.05). The combined interventions were the only ones that maintained the peak blood velocity (PBV) elevated above baseline during all the sets, from set-1 (113.5 % p < 0.001) to set-10 (88.8 % p < 0.01) and from set-1 (58.4 % p < 0.01) to set-10 (49.1 % p < 0.05) for WBV+ES and WBV30/ES30, respectively. CONCLUSION: The simultaneous application of WBV and ES produced a general greater increase in MBV and PBV than the application of each method alone or consecutive. This novel methodological proposal could be interesting in different fields such as sports or the rehabilitation process of different pathologies, to achieve an enhanced peripheral blood flow. PMID- 25820214 TI - BRAF V600E mutation is a useful marker for differentiating Rathke's cleft cyst with squamous metaplasia from papillary craniopharyngioma. PMID- 25820215 TI - Association between rs6812193 polymorphism and sporadic Parkinson's disease susceptibility. AB - Recently, the association of a single nucleotide polymorphism rs6812193 C/T with sporadic Parkinson's disease (PD) susceptibility has been widely evaluated, but the results remained inconsistent. This association should be clarified because of the importance of it on human health and quality of life. We performed a comprehensive meta-analysis to evaluate the association between the rs6812193 polymorphism and sporadic PD. PubMed was used to retrieve articles published up to June 2014 for all studies evaluating the rs6812193 polymorphism and PD in humans. Ethnicity-specific subgroup analysis was also performed based on ethnicity susceptibility. A total of 17 independent study samples (15 Caucasians and 2 Asians) including 17,956 cases and 52,751 controls were used in the presented study. The MAFT (minor allele T frequency) in PD patients of European descent is obviously higher than Asian cases (p < 0.01). The results suggested the rs6812193 polymorphism (allele T vs. C) is significantly associated with PD susceptibility among overall samples (OR 0.882, 95 % CI 0.856-0.908) and Caucasian population (OR 0.881, 95 % CI 0.856-0.907), but not in Asian samples (OR 0.918, 95 % CI 0.721-1.168). No evidence of publication bias was observed. Throughout our analysis, the rs6812193 polymorphism is significantly associated with sporadic PD susceptibility in Caucasian samples, and ethnicity might be the key point of inconsistency in rs6812193 studies. Further studies are warranted to re-examine the observed associations, especially in different ethnicities. PMID- 25820216 TI - Has the diagnosis of a stroke been overlooked in the symptoms of Julius Caesar? PMID- 25820217 TI - Analysis of prior mammography with negative result in women with interval breast cancer. AB - PURPOSE: The purpose of our study was to review mammographic findings which were previously negative in women with interval breast cancer and to analyze the histopathological features of the interval breast cancer. MATERIALS AND METHODS: A total of 5521 women underwent surgery for breast cancer between January 2009 and December 2011. Among them, 240 women who had undergone available, previous mammography studies reported as normal or benign (mean interval between examinations, 9.7 months) were included in our study. We reviewed the previous mammographic features and categorized as true interval breast cancer, minimal sign, and missed interval breast cancer. Histopathological findings were also reviewed. RESULTS: Of the 240 diagnosed cancers, 78 (32.5 %) were classified as true interval breast cancer, 78 (32.5 %) as minimal sign, and 84 (35 %) as missed interval breast cancer. True interval breast cancer occurred in a younger age and showed dense breast compared with missed breast cancer. The breast density of 169 patients (70.4 %) was dense. In the minimal sign group, the most common finding was normal appearing tissue (61/78), followed by benign-appearing calcification (17/78). There were no significant differences in the histopathological findings in each of the three groups and tended to have smaller tumor size, negative nodal status, a lower AJCC stage, and frequent luminal A subtype. CONCLUSION: The majority of interval breast cancers was not detectable in patients with dense breast or showed subtle mammographic findings on previous mammography. Although the majority of breast cancers showed a low grade in the histopathological findings, a better understanding of the mammographic findings will influence the sensitivity of mammography. PMID- 25820218 TI - The role of professional knowledge in case-based reasoning in practical ethics. AB - The use of case-based reasoning in teaching professional ethics has come of age. The fields of medicine, engineering, and business all have incorporated ethics case studies into leading textbooks and journal articles, as well as undergraduate and graduate professional ethics courses. The most recent guidelines from the National Institutes of Health recognize case studies and face to-face discussion as best practices to be included in training programs for the Responsible Conduct of Research. While there is a general consensus that case studies play a central role in the teaching of professional ethics, there is still much to be learned regarding how professionals learn ethics using case based reasoning. Cases take many forms, and there are a variety of ways to write them and use them in teaching. This paper reports the results of a study designed to investigate one of the issues in teaching case-based ethics: the role of one's professional knowledge in learning methods of moral reasoning. Using a novel assessment instrument, we compared case studies written and analyzed by three groups of students whom we classified as: (1) Experts in a research domain in bioengineering. (2) Novices in a research domain in bioengineering. (3) The non research group--students using an engineering domain in which they were interested but had no in-depth knowledge. This study demonstrates that a student's level of understanding of a professional knowledge domain plays a significant role in learning moral reasoning skills. PMID- 25820219 TI - Muscle atrophy as pre-sarcopenia in Japanese patients with chronic liver disease: computed tomography is useful for evaluation. AB - BACKGROUND/AIM: The definition of muscle atrophy (pre-sarcopenia) and its diagnostic criteria have not been well reported. To elucidate the frequency of pre-sarcopenia in chronic liver disease (CLD), we examined clinical features of Japanese CLD patients using abdominal computed tomography (CT) findings. METHODS: We enrolled 988 CLD (736 with naive hepatocellular carcinoma) and 372 normal control subjects (NCs). The psoas muscle area index [PI, psoas muscle area at the mid-L3 level in CT (cm(2))/height (m)(2)] was calculated using personal computer software. The cut-off level for pre-sarcopenia was defined as less than two standard deviations (SDs) below the mean PI value in the NCs under 55 years old [males, 45.6 +/- 5.7 years (n = 61), 4.24 cm(2)/m(2); females, 47.0 +/- 6.1 years (n = 49), 2.50 cm(2)/m(2)]. Elderly was defined as 65 years or older. Clinical features were retrospectively evaluated. RESULTS: In the CLD group (HCV:HBV:HBV and HCV:alcohol:non-HBV and HCV = 652:88:7:82:159), pre-sarcopenia was observed in 15.3% of patients with chronic hepatitis (CH), 24.4% of those with liver cirrhosis (LC) Child-Pugh A, 37.7% of those with LC Child-Pugh B, and 37.1% of those with LC Child-Pugh C. A comparison between NC and CH by age (<55, 55-64, 65 74, >=75 years) showed that the frequency of pre-sarcopenia was higher in CH regardless of age (1.8 vs. 3.6%, 3.2 vs. 15.9%, 4.9 vs. 13.4%, 14.3 vs. 20.2%, respectively). PI values showed correlations with BMI (r = 0.361), age (r = 0.167), albumin (r = 0.115), and branched-chain amino acids (r = 0.199) (P < 0.01). CONCLUSION: Retrospective evaluate for pre-sarcopenia was easy to perform with CT findings. Nutrition and exercise instruction should be considered for early stage and even non-elderly CLD as well as LC. PMID- 25820220 TI - Love on lockdown: how social network characteristics predict separational concurrency among low income African-American women. AB - One out of nine African-American men between the ages of 20 and 34 is behind bars, resulting in many African-American women losing their primary romantic partners to incarceration. Research suggests that partner incarceration may contribute to increased risk of sexually transmitted infections (STIs)/human immunodeficiency virus (HIV); however, factors associated with women's decisions to begin new sexual partnerships following partner incarceration (i.e., separational concurrency) have not been well studied. This study examined the social context relevant to initiating separational concurrency, following incarceration of a primary male partner. Cross-sectional secondary data analysis of 6-month follow-up data from the CHAT Project, a social-network based HIV/sexually transmitted disease (STD) prevention study in Baltimore, MD, USA. Participants were N = 196 African-American women, who reported ever having had a partner who was incarcerated for at least 6 months during the relationship. The majority (81.5%) of women were unemployed with a mean age of 41.7 years. Over half of the sample (59.5%) reported having used crack or heroin at least once in the previous 12 months; 48.5% of the women had experienced physical abuse, with over half of the sample reporting a lifetime history of emotional abuse (54.6%). Separational concurrency, defined as answering yes to the item, "While [your] partner was incarcerated, did you have any other sexual partners?," was the primary outcome measure. After adjusting for age, drug use and unemployment the multiple logistic regression model found that women who reported a history of physical or emotional abuse were over two times as likely to report separational concurrency than women without an abuse history [adjusted odds ratio (AOR), 2.24; 95% CI, 1.24, 4.05; p = .007 and AOR, 2.44; 95% CI, 1.33, 4.46; p = .004, respectively]. Individuals who reported a higher number of drug-using sex partners (AOR, 2.49; 95% CI, 1.4, 4.5; p = .002), sex exchange partners (AOR, 4.0; 95% CI, 1.8 8.9; p = .001), and sexual partners who engaged in concurrency (AOR: 2.67; 95% CI: 1.5, 4.8; p = .001) were significantly more likely to report separational concurrency. Conversely, participants who reported more female kin in their social networks (AOR, .808; 95% CI, .67, .97; p = .025), having known network members a longer time (AOR, .997; 95% CI, .993, .999; p = .043), and higher levels of trust for network members (AOR, .761; 95% CI, .63, .92; p = .005) were significantly less likely to report separational concurrency. Results of this study demonstrate that social network characteristics may be crucial to understanding separational concurrency among African-American urban women who have lost a partner to incarceration. Social network and other resource-based interventions, which provide instrumental, social, and economic resources to women who have experienced the loss of a partner to incarceration, may be important tools in empowering women and helping to reduce the disproportionate burden of STIs/HIV among low income, African-American women. PMID- 25820221 TI - A large temperature fluctuation may trigger an epidemic erythromelalgia outbreak in China. AB - Although erythromelalgia (EM) has been documented in the literature for almost 150 years, it is still poorly understood. To overcome this limitation, we examined the spatial distribution of epidemic EM, and explored the association between temperature fluctuation and epidemic EM outbreaks in China. We searched all peer-reviewed literature on primary epidemic EM outbreaks in China. A two stage model was used to characterize the relationship between temperature fluctuation and epidemic EM outbreaks. We observed that epidemic EM outbreaks were reported from 13 provinces during 1960-2014 and they mainly occurred between February and March in southern China. The majority of EM cases were middle school students, with a higher incidence rate in female and resident students. The major clinical characteristics of EM cases included burning, sharp, tingling and/or stinging pain in toes, soles and/or dorsum of feet, fever, erythema and swelling. A large "V"-shaped fluctuation of daily average temperature (TM) observed during the epidemic EM outbreaks was significantly associated with the number of daily EM cases (beta = 1.22, 95%CI: 0.66 ~ 1.79), which indicated that this "V"-shaped fluctuation of TM probably triggered the epidemic EM outbreaks. PMID- 25820222 TI - Dietary and exercise change following acute cardiac syndrome onset: A latent class growth modelling analysis. AB - The present study aim determine sub-group trajectories of change on measures of diet and exercise following acute coronary syndrome. 150 participants were assessed in hospital, 1 month and 6 months subsequently on measures including physical activity, diet, illness beliefs, coping and mood. Change trajectories were measured using latent class growth modelling. Multinomial logistic regression was used to predict class membership. These analyses revealed changes in exercise were confined to a sub-group of participants already reporting relatively high exercise levels; those eating less healthily evidenced modest dietary improvements. Coping, gender, depression and perceived control predicted group membership to a modest degree. PMID- 25820223 TI - Comparison of the plasmonic performances between lithographically fabricated and chemically grown gold nanorods. AB - Noble metal nanostructures, especially gold nanocrystals, have attracted intensive interest due to their rich plasmonic properties and enormous potential technological applications. The preparation process of gold nanocrystals can strongly affect their plasmonic properties and therefore their performances in various applications. Chemically synthesized colloidal gold nanocrystals are usually employed in biomedical fields, while lithographically fabricated ones are highly preferred for constructing optical meta-structures. A detailed careful comparison of the plasmonic performances between lithographical and chemical metal nanostructures is strongly desired for using them for different applications. Herein, we experimentally measured and quantitatively compared the plasmonic properties, including longitudinal localized surface plasmon wavelengths (LLSPWs) and plasmon peak widths, scattering intensities, and local electric field enhancements, of lithographically fabricated and chemically grown gold nanorods. The lithographical nanorods exhibit much weaker scattering, largely broadened spectral widths, and considerably reduced electric field enhancements. Electrodynamic simulations suggest that the reduction in the plasmonic performance of the lithographical nanorods is caused mainly by the use of an adhesive metal layer and slightly by their polycrystalline nature. Our quantitative comparison results will be very helpful in guiding the selection of proper types of metal nanostructures for targeted technological applications. PMID- 25820224 TI - MPs criticise government for inaction since Winterbourne View scandal. PMID- 25820225 TI - Emergence of electrophilic alumination as the counterpart of established nucleophilic lithiation: an academic sojourn in organometallics with William Kaska as fellow traveler. AB - William Kaska pursued doctoral studies with John Eisch in mechanistic organometallic chemistry, first with organolithium reactions at St. Louis University and then at the University of Michigan with organoaluminum reactions. Thereby he revealed the change in mechanism from nucleophilic lithiation and carbolithiation to that of electrophilic alumination, carboalumination and hydroalumination of organic substrates, which reactions were previously observed by Karl Ziegler in his empirical studies of organoaluminum reactions. Our findings were the first mechanistic studies attempting to set such Ziegler chemistry on a modern theoretical basis. PMID- 25820226 TI - A polyamine-modified near-infrared fluorescent probe for selective staining of live cancer cells. AB - We report the synthesis of novel polyamine-modified near-infrared (NIR) probes, which show excellent water-solubility and good optical properties. One probe was taken up efficiently by living cancer cell lines whereas no staining of the non cancer cells was observed. PMID- 25820227 TI - A new subset of deutan colour vision defect associated with an L/M visual pigment gene array of normal order and -71C substitution in the Japanese population. AB - In 524 Japanese individuals with deutan colour vision defect, 76 had a normal order pigment gene array, where the L gene is at the first position and the M gene(s) is located downstream. Of these 76 individuals, 69 had a -71A>C substitution in the M gene without any other mutation. Because the expression of L/M genes is up-regulated by thyroid hormone (T3) in human retinoblastoma WERI cells, we examined the effects of T3 on promoter activity; T3 increased the activity of the -71A promoter 2-fold, but it had no effect on the -71C promoter. Similarly, the -71C promoter was much less activated by T3 than the -71A promoter in HEK293 cells expressing thyroid hormone receptor isoform beta2. Such a weak response of the -71C promoter to T3 may cause a decrease in the number of M cones and/or the density of M pigment during the differentiation of M cones. The average Rayleigh match midpoint was 18.9 +/- 4.1 in 162 ordinary deuteranomaly individuals, but was 37.3 +/- 9.1 in 63 deuteranomaly individuals with -71C. The 71A>C substitution was found to be specific to eastern Asia. These results suggest that there may be a new subset of deuteranomaly associated with -71C in the Japanese (and probably eastern Asian) population(s). PMID- 25820228 TI - Identification of large channels in cationic PEGylated cubosome nanoparticles by synchrotron radiation SAXS and Cryo-TEM imaging. AB - Extra-large nanochannel formation in the internal structure of cationic cubosome nanoparticles results from the interplay between charge repulsion and steric stabilization of the lipid membrane interfaces and is evidenced by cryogenic transmission electron microscopy (Cryo-TEM) and synchrotron radiation small-angle X-ray scattering (SAXS). The swollen cubic symmetry of the lipid nanoparticles emerges through a shaping transition of onion bilayer vesicle intermediates containing a fusogenic nonlamellar lipid. Cationic amphiphile cubosome particles, thanks to the advantages of their liquid crystalline soft porous nanoarchitecture and capability for multi-drug nanoencapsulation, appear to be of interest for the design of mitochondrial targeting devices in anti-cancer therapies and as siRNA nanocarriers for gene silencing. PMID- 25820229 TI - Ruthenium(II) Complexes Containing Lutidine-Derived Pincer CNC Ligands: Synthesis, Structure, and Catalytic Hydrogenation of C-N bonds. AB - A series of Ru complexes containing lutidine-derived pincer CNC ligands have been prepared by transmetalation with the corresponding silver-carbene derivatives. Characterization of these derivatives shows both mer and fac coordination of the CNC ligands depending on the wingtips of the N-heterocyclic carbene fragments. In the presence of tBuOK, the Ru-CNC complexes are active in the hydrogenation of a series of imines. In addition, these complexes catalyze the reversible hydrogenation of phenantridine. Detailed NMR spectroscopic studies have shown the capability of the CNC ligand to be deprotonated and get involved in ligand assisted activation of dihydrogen. More interestingly, upon deprotonation, the Ru CNC complex 5 e(BF4 ) is able to add aldimines to the metal-ligand framework to yield an amido complex. Finally, investigation of the mechanism of the hydrogenation of imines has been carried out by means of DFT calculations. The calculated mechanism involves outer-sphere stepwise hydrogen transfer to the C-N bond assisted either by the pincer ligand or a second coordinated H2 molecule. PMID- 25820231 TI - SQUIRE and the evolving science of healthcare improvement. PMID- 25820230 TI - Syndromic parkinsonism and dementia associated with OPA1 missense mutations. AB - OBJECTIVE: Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia. METHODS: Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements. RESULTS: Affected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase-negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy. INTERPRETATION: The association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. PMID- 25820232 TI - Technical note: A linear model for predicting delta13 Cprotein. AB - OBJECTIVE: Development of a model for the prediction of delta(13) Cprotein from delta(13) Ccollagen and Delta(13) Cap-co . Model-generated values could, in turn, serve as "consumer" inputs for multisource mixture modeling of paleodiet. METHODS: Linear regression analysis of previously published controlled diet data facilitated the development of a mathematical model for predicting delta(13) Cprotein (and an experimentally generated error term) from isotopic data routinely generated during the analysis of osseous remains (delta(13) Cco and Delta(13) Cap-co ). RESULTS: Regression analysis resulted in a two-term linear model (delta(13) Cprotein (%) = (0.78 * delta(13) Cco ) - (0.58* Delta(13) Cap-co ) - 4.7), possessing a high R-value of 0.93 (r(2) = 0.86, P < 0.01), and experimentally generated error terms of +/-1.9% for any predicted individual value of delta(13) Cprotein . This model was tested using isotopic data from Formative Period individuals from northern Chile's Atacama Desert. CONCLUSIONS: The model presented here appears to hold significant potential for the prediction of the carbon isotope signature of dietary protein using only such data as is routinely generated in the course of stable isotope analysis of human osseous remains. These predicted values are ideal for use in multisource mixture modeling of dietary protein source contribution. PMID- 25820234 TI - Stereoselective Preparation of Polyfunctional Alkenylindium(III) Halides and Their Cross-Coupling with Unsaturated Halides. AB - The direct insertion of indium powder to cycloalkenyl iodides in the presence of LiCl in THF allows the preparation of new highly functionalized cycloalkenylindium(III) derivatives. In addition, we discovered that, in contrast to many metal insertions to alkenyl iodides which proceed with a loss of stereochemistry, the insertion of In/LiCl to stereodefined (Z)- and (E)-styryl iodides in THF proceeded with high retention of stereochemistry. After a palladium-catalyzed cross-coupling, various polyfunctionalized (Z)- and (E) stilbenes were obtained with high stereoselectivity. PMID- 25820235 TI - Parameterization of the Hamiltonian Dielectric Solvent (HADES) Reaction-Field Method for the Solvation Free Energies of Amino Acid Side-Chain Analogs. AB - Optimization of the Hamiltonian dielectric solvent (HADES) method for biomolecular simulations in a dielectric continuum is presented with the goal of calculating accurate absolute solvation free energies while retaining the model's accuracy in predicting conformational free-energy differences. The solvation free energies of neutral and polar amino acid side-chain analogs calculated by using HADES, which may optionally include nonpolar contributions, were optimized against experimental data to reach a chemical accuracy of about 0.5 kcal mol(-1). The new parameters were evaluated for charged side-chain analogs. The HADES results were compared with explicit-solvent, generalized Born, Poisson-Boltzmann, and QM-based methods. The potentials of mean force (PMFs) between pairs of side chain analogs obtained by using HADES and explicit-solvent simulations were used to evaluate the effects of the improved parameters optimized for solvation free energies on intermolecular potentials. PMID- 25820233 TI - Nonsense-mediated RNA decay--a switch and dial for regulating gene expression. AB - Nonsense-mediated RNA decay (NMD) represents an established quality control checkpoint for gene expression that protects cells from consequences of gene mutations and errors during RNA biogenesis that lead to premature termination during translation. Characterization of NMD-sensitive transcriptomes has revealed, however, that NMD targets not only aberrant transcripts but also a broad array of mRNA isoforms expressed from many endogenous genes. NMD is thus emerging as a master regulator that drives both fine and coarse adjustments in steady-state RNA levels in the cell. Importantly, while NMD activity is subject to autoregulation as a means to maintain homeostasis, modulation of the pathway by external cues provides a means to reprogram gene expression and drive important biological processes. Finally, the unanticipated observation that transcripts predicted to lack protein-coding capacity are also sensitive to this translation-dependent surveillance mechanism implicates NMD in regulating RNA function in new and diverse ways. PMID- 25820236 TI - Enhanced characterization of contractility in cardiomyocytes during early drug safety assessment. AB - We sought to investigate whether drug-induced changes in contractility were affected by pacing rates that represent the range of heart rates encountered in vivo. Using the cell geometry measurement system (IonOptix), we paced dog cardiomyocytes at different cycle lengths (CLs) of 2000, 1000, 500, and 333.3 ms, before and after exposure to 13 inotropic drugs. Time course data using vehicle control (0.1% dimethyl sulfoxide (DMSO)) demonstrated stability of the system at all CLs tested. Seven positive inotropes (eg isoproterenol) exerted rate dependent increases in sarcomere shortening (Sarc. short.; maximal effect at a CL of 333.3 ms [0.1 uM isoproterenol increased Sarc. short. by 41.1% and 145.9% at 2000 and 333.3 ms, respectively]). Omecamtiv mecarbil showed an atypical profile (increased Sarc. short. at 2000 ms [106.9%] and decreased at 333.3 ms [IC(50) = 0.64 uM]). Four negative inotropes (eg flecainide) showed rate-independent inhibition of Sarc. short. (IC(50)s: 3.3 uM [2000 ms] versus 2.3 uM [333.3 ms]). The remaining negative inotropes, verapamil, and BTS (N-benzyl-p-toluene sulphonamide) produced an increase (IC(50)s: 3.9 uM [2000 ms] versus 0.043 uM [333.3ms]) and decrease (IC(50)s: 18.3 uM [2000 ms] versus 34.0 uM [333.3 ms]) in potency, respectively. Negative inotropes (eg flecainide, BTS, and verapamil) decreased the area of the Ca(2+) transient versus Sarc. short. hysteresis loop, although rate dependency was seen with verapamil only. Positive inotropes (eg isoproterenol and levosimendan) induced a rate-dependent increase in the area, however Omecamtiv mecarbil increased and decreased the area at CLs of 2000 and 333.3 ms, respectively. Thus, the use of different pacing rates may improve the detection of inotropes in early drug discovery and illustrate the potential for finger-printing different mechanisms of action. PMID- 25820238 TI - High effective cytosolic H+ buffering in mouse cortical astrocytes attributable to fast bicarbonate transport. AB - Cytosolic H(+) buffering plays a major role for shaping intracellular H(+) shifts and hence for the availability of H(+) for biochemical reactions and acid/base coupled transport processes. H(+) buffering is one of the prime means to protect the cell from large acid/base shifts. We have used the H(+) indicator dye BCECF and confocal microscopy to monitor the cytosolic H(+) concentration, [H(+)]i, in cultured cortical astrocytes of wild-type mice and of mice deficient in sodium/bicarbonate cotransporter NBCe1 (NBCe1-KO) or in carbonic anhydrase isoform II (CAII-KO). The steady-state buffer strength was calculated from the amplitude of [H(+)]i transients as evoked by CO2/HCO3(-) and by butyric acid in the presence and absence of CO2/HCO3(-). We tested the hypotheses if, in addition to instantaneous physicochemical H(+) buffering, rapid acid/base transport across the cell membrane contributes to the total, "effective" cytosolic H(+) buffering. In the presence of 5% CO2/26 mM HCO3(-), H(+) buffer strength in astrocytes was increased 4-6 fold, as compared with that in non-bicarbonate, HEPES-buffered solution, which was largely attributable to fast HCO3 (-) transport into the cells via NBCe1, supported by CAII activity. Our results show that within the time frame of determining physiological H(+) buffering in cells, fast transport and equilibration of CO2/H(+)/HCO3(-) can make a major contribution to the total "effective" H(+) buffer strength. Thus, "effective" cellular H(+) buffering is, to a large extent, attributable to membrane transport of base equivalents rather than a purely passive physicochemical process, and can be much larger than reported so far. Not only physicochemical H(+) buffering, but also rapid import of HCO3(-) via the electrogenic sodium-bicarbonate cotransporter NBCe1, supported by carbonic anhydrase II (CA II), was identified to enhance cytosolic H(+) buffer strength substantially. PMID- 25820237 TI - Long-term Coexposure to Hexavalent Chromium and B[a]P Causes Tissue-Specific Differential Biological Effects in Liver and Gastrointestinal Tract of Mice. AB - Complex mixtures of environmental agents often cause mixture-specific health effects that cannot be accounted for by a single mechanism. To study the biological effects of exposure to a mixture of chromium-VI and benzo[a]pyrene (B[a]P), often found together in the environment, we exposed mice for 60 days to 0, 55, 550, or 5500 ppb Cr(VI) in drinking water followed by 90 days of coexposure to B[a]P at 0, 1.25, 12.5, or 125 mg/kg/day and examined liver and gastrointestinal (GI) tract for exposure effects. In the liver, the mixture caused more significant histopathology than expected from the sum of effects of the individual components, while in the GI tract, Cr(VI) alone caused significant enterocyte hypertrophy and increases in cell proliferation and DNA damage that were also observed in mice coexposed to B[a]P. Expression of genes involved in drug metabolism, tumor suppression, oxidative stress, and inflammation was altered in mixed exposures relative to control and to singly exposed mice. Drug metabolism and oxidative stress genes were upregulated and tumor suppressor and inflammation genes downregulated in the proximal GI tract, whereas most markers were upregulated in the distal GI tract and downregulated in the liver. Oral exposure to Cr(VI) and B[a]P mixtures appears to have tissue-specific differential consequences in liver and GI tract that cannot be predicted from the effects of each individual toxicant. Tissue specificity may be particularly critical in cases of extended exposure to mixtures of these agents, as may happen in the occupational setting or in areas where drinking water contains elevated levels of Cr(VI). PMID- 25820239 TI - Tissue-specific roles of FGF signaling in external genitalia development. AB - BACKGROUND: The developmental processes of the genital tubercle (GT), the anlage of the external genitalia, possess several developmental aspects, including GT outgrowth, urethral tube formation, and epithelial differentiation of the urethra. The GT comprises the mesenchyme derived from the lateral mesoderm, ectodermal epithelium, and endodermal epithelium (embryonic urethral epithelium). The three tissue layers develop the GT coordinately. RESULTS: Around the initial stage of GT outgrowth (E11.5), FGF signaling was detected in the mesenchyme of the GT. FGF signaling was detected in the three tissue layers of the GT around the early stage of urethral formation (E13.5). Subsequently, FGF signaling was predominantly detected in the urethral epithelium (E14.5). Tissue-specific roles of FGF signaling in GT development were revealed by conditional Fgfr gene knockout approaches. Mesenchymal FGF signaling in the early-stage GT is required for its outgrowth. Ectodermal FGF signaling in the GT is required for the differentiation of the ectoderm and urethral epithelium at their junction to form the proper urethral tube. Endodermal FGF signaling in the GT is required for the stratification and cell adhesive characteristics of the urethral epithelium. CONCLUSIONS: The current study suggests that spatiotemporally regulated FGF signaling plays tissue-specific roles in multiple processes of external genitalia development. PMID- 25820240 TI - Analysis of transthyretin in human serum by capillary zone electrophoresis electrospray ionization time-of-flight mass spectrometry. Application to familial amyloidotic polyneuropathy type I. AB - Transthyretin (TTR) is known to misfold and aggregate, causing different types of amyloidosis. Familial amyloidotic polyneuropathy type I (FAP-I), which is the most common hereditary systemic amyloidosis, is associated with a TTR variant that presents a single amino acid substitution of valine for methionine at position 30 (Met 30). To screen for TTR-related amyloidosis rapidly and reliably, we have developed a novel procedure based on the analysis of monomers from the homotetrameric protein (~56 kDa). First, we established a CZE-ESI-TOF-MS method to detect wild-type (normal) TTR with or without several PTMs, as well as an extra minor isoform in TTR standard solutions. Later, a sample pretreatment based on immunoprecipitation (IP) and centrifugal filtration was optimized to analyze serum samples from healthy controls and FAP-I patients (including an asymptomatic patient, a symptomatic patient, a liver-transplanted patient with the specific mutation, and a patient originally without the mutation who received a liver transplant from an FAP-I patient (iatrogenic FAP-I)). The mutant TTR (Met 30) variant with a relative molecular mass 32.07 higher than the wild-type TTR was found in the asymptomatic, the symptomatic and the iatrogenic FAP-I patients, who interestingly also presented the same concentration ratio between both variants of TTR (abnormal and normal). In contrast, as in the healthy controls, the abnormal TTR variant was not detected in the liver-transplanted patient with the specific mutation, which confirms the effectiveness of the treatment. The proposed procedure could be regarded as a suitable screening system for individuals with suspected TTR amyloidosis, and to gain insight into TTR structure, to understand the mechanism underlying the disease. PMID- 25820241 TI - Somatostatin receptor-mediated specific delivery of paclitaxel prodrugs for efficient cancer therapy. AB - In this study, a novel PTX prodrug, octreotide(Phe)-polyethene glycol-paclitaxel [OCT(Phe)-PEG-PTX], was successfully synthesized and used for targeted cancer therapy. A nontargeting conjugate, mPEG-PTX, was also synthesized and used as a control. Chemical structures of OCT(Phe)-PEG-PTX and mPEG-PTX were confirmed using (1) H nuclear magnetic resonance and circular dichroism. The drug contents in both the conjugates were 12.0% and 14.0%, respectively. Compared with the parent drug (PTX), OCT(Phe)-PEG-PTX, and mPEG-PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from mPEG-PTX and OCT(Phe)-PEG-PTX exhibited a pH-dependent profile. Moreover, compared with mPEG-PTX, OCT(Phe)-PEG-PTX exhibited significantly stronger cytotoxicity against NCI-H446 cells (SSTR overexpression) but comparable cytotoxicity against WI-38 cells (no SSTR expression). Results of confocal laser scanning microscopy revealed that the targeting prodrug labeled with fluorescence probe was selectively taken into tumor cells via SSTR-mediated endocytosis. In vivo investigation of prodrugs in nude mice bearing NCI-H446 cancer xenografts confirmed that OCT(Phe)-PEG-PTX prodrug exhibited stronger antitumor efficacy and lower systemic toxicity than mPEG-PTX and commercial Taxol. These results suggested that OCT(Phe)-PEG-PTX is a promising anticancer drug delivery system for targeted cancer therapy. PMID- 25820242 TI - Expression of Calcium Channel Subunit Variants in Small Mesenteric Arteries of WKY and SHR. AB - BACKGROUND: Enhanced function of dihydropyridine-sensitive Ca2+ channels (CaV) in hypertensive arterial myocytes (HAM) is well accepted. Increased protein expression of pore forming alpha1-subunits contributes to this effect, but cannot explain all of the differences in CaV properties in HAM. We hypothesized that differences in expression of CaV subunits and/or their splice variants also contribute. METHODS: RNA, protein, and myocytes were isolated from small mesenteric arteries (SMA) of 20-week-old male WKY and SHR and analyzed by polymerase chain reaction (PCR), sequencing, immunoblotting, and patch clamp methods. RESULTS: Cav1.2 alpha1, beta2c, and alpha2delta1d were the dominant subunits expressed in both WKY and SHR with a smaller amount of beta3a. Real-time PCR indicated that the mRNA abundance of beta3a and alpha2delta1 but not total Cav1.2 alpha1 or beta2c were significantly larger in SHR. Analysis of alternative splicing of Cav1.2 alpha1 showed no differences in abundance of mutually exclusive exons1b, 8, 21 and 32 or alternative exons33 and 45. However, inclusion of exon9* was higher and a 73 nucleotide (nt) deletion in exon15 (exon15Delta73) was lower in SHR. Immunoblot analysis showed higher protein levels of Cav1.2 alpha1 (1.61+/-0.05), beta3 (1.80+/-0.32), and alpha2delta1 (1.80+/-0.24) but not beta2 in SHR. CONCLUSIONS: The lower abundance of exon15Delta73 transcripts in SHR results in a larger fraction of total Cav1.2 mRNA coding for full-length CaV protein, and the higher abundance of exon9* transcripts and CaVbeta3a protein likely contribute to differences in gating and kinetics of CaV currents in SHR. Functional studies of Ca2+ currents in native SMA myocytes and HEK cells transiently transfected with CaV subunits support these conclusions. PMID- 25820243 TI - Treatment of Sleep Apnea With CPAP Lowers Central and Peripheral Blood Pressure Independent of the Time-of-Day: A Randomized Controlled Study. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a risk factor for hypertension and randomized controlled trials have shown that OSA treatment with continuous positive airway pressure (CPAP) reduces peripheral blood pressure and arterial stiffness. Arterial stiffness is known to augment central aortic blood pressure independent of peripheral brachial blood pressure. Currently, it is unclear whether the reduction in blood pressure with CPAP is similar between central and peripheral sites. It is also unknown whether there are any time-of-day influences on central blood pressure changes after CPAP. METHODS: Thirty-eight patients received therapeutic and sham CPAP in random order for 8 weeks each with an intervening 1-month washout. Peripheral and central blood pressure and arterial stiffness (augmentation index and time to reflection) were measured by pulse wave analysis at end-of-treatment visits. Measurements were taken in the afternoon (~2 pm) and the next morning (~9 am). RESULTS: Compared to sham, CPAP significantly reduced central systolic (mean difference: -4.1 mm Hg; P = 0.003), central diastolic (-3.9 mm Hg; P = 0.0009), peripheral systolic (-4.1mm Hg; P = 0.004), and peripheral diastolic (-3.8 mm Hg; P = 0.001) blood pressure. These effects were not influenced by time-of-day. Time to reflection was improved with CPAP compared to sham (3.7 ms; P = 0.01). There was no overall difference in augmentation index however when examined by time-of-day, a modest reduction with CPAP was observed in the morning (-2.5%; P = 0.03) but not in the evening (0.12%; P = 0.91). CONCLUSION: CPAP reduces both central and peripheral blood pressure independent of the time-of-day. In contrast, modest improvements in conduit arterial stiffness after CPAP may only occur in the morning. PMID- 25820245 TI - Serial block face-scanning electron microscopy: a tool for studying embryonic development at the cell-matrix interface. AB - Studies of gene regulation, signaling pathways, and stem cell biology are contributing greatly to our understanding of early embryonic vertebrate development. However, much less is known about the events during the latter half of embryonic development, when tissues comprising mostly extracellular matrix (ECM) are formed. The matrix extends far beyond the boundaries of individual cells and is refractory to study by conventional biochemical and molecular techniques; thus major gaps exist in our knowledge of the formation and three dimensional (3D) organization of the dense tissues that form the bulk of adult vertebrates. Serial block face-scanning electron microscopy (SBF-SEM) has the ability to image volumes of tissue containing numerous cells at a resolution sufficient to study the organization of the ECM. Furthermore, whereas light microscopy was once relatively straightforward and electron microscopy was performed in specialist laboratories, the tables are turned; SBF-SEM is relatively straightforward and is becoming routine in high-end resolution studies of embryonic structures in vivo. In this review, we discuss the emergence of SBF SEM as a tool for studying embryonic vertebrate development. PMID- 25820244 TI - Associations of Renin-Angiotensin-Aldosterone System Genes With Blood Pressure Changes and Hypertension Incidence. AB - BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure (BP) regulation. The current study uses single-marker and gene-based analyses to examine the association between RAAS genes and longitudinal BP phenotypes in a Han Chinese population. METHODS: A total of 1,768 participants from the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study were included in the current study. Twenty-seven BP measurements were taken using random-zero sphygmomanometers at baseline and 2 follow-up visits. Mixed-effect models were used to assess the additive associations of 106 single-nucleotide polymorphisms (SNPs) in 10 RAAS genes with longitudinal BP changes and hypertension incidence. Gene-based analyses were conducted using the truncated product method. Attempts were made to replicate significant findings among Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). False discovery rate procedures were used to adjust for multiple testing. RESULTS: During an average of 7.2 years of follow-up, average systolic and diastolic BP increased, and 32.1% (512) of participants free from hypertension at baseline developed hypertension. NR3C2 SNPs rs7694064 and rs6856803 were significantly associated with longitudinal changes in systolic BP (P interaction = 6.9*10(-5) and 8.2*10(-4), respectively). Through gene-based analysis, NR3C2 was found to be significantly associated with longitudinal systolic BP change (P value of 1.00*10(-7)), even after removal of significant markers rs7694064 and rs6856803 from the analysis. The association between NR3C2 and longitudinal systolic BP change was replicated in Asian MESA participants (P value of 1.00*10( 4)). CONCLUSIONS: These findings indicate that NR3C2 may play an important role in BP progression and development of hypertension. PMID- 25820246 TI - Cystic fibrosis: a look into the future of prenatal screening and therapy. AB - Despite recent guidelines suggesting prenatal screening for carriers of cystic fibrosis (CF) mutations, many physicians do not offer patients this service or even counseling. Some argue that the risks of miscarriage associated with prenatal diagnostic techniques outweigh the benefit of added insight, but with the advent of newer, noninvasive techniques, risks of miscarriage may be significantly lowered. Prenatal diagnosis provides parents the time to prepare for raising a child with CF, and soon, could provide treatment options in utero that could improve quality of life. Here, we describe two of the most promising gene therapy approaches: lentivirus and adenoassociated virus (AAV)-mediated gene transduction. Thus, prenatal detection and treatment is in a most crucial stage for care of patients with CF. PMID- 25820248 TI - Response to the letter to the editor: 1q gain is a frequent finding in preoperatively treated Wilms tumors, but of limited prognostic value for risk satisfaction in the SIOP2009/Gesellschaft fur Padiatrische Onkologie und Hamatologie (GPOH) trial. PMID- 25820249 TI - VEGF Enhances the Migration of MSCs in Neural Differentiation by Regulating Focal Adhesion Turnover. AB - Mesenchymal stem cells (MSCs) hold great promise in neural regeneration, due to their intrinsic neuronal potential and migratory tropism to damaged nervous tissues. However, the chemotactic signals mediating the migration of MSCs remain poorly understood. Here, we investigated the regulatory roles for focal adhesion kinase (FAK) and Rac1 in vascular endothelial growth factor (VEGF)-stimulated migration of MSCs in neural differentiation. We found that MSCs in various differentiation states show significant different chemotactic responses to VEGF and cells in 24-h preinduction state possess the highest migration speed and efficiency. FAK, as the downstream signaling molecule, is involved in the VEGF induced migration by regulating the assembly and distribution of focal adhesions (FAs) and reorganization of F-actin. The features of FAs and cytoskeletons and the ability of lamellipodia formation are closely related to the neural differentiation states of MSCs. VEGF promotes FA formation with an asymmetric distribution of FAs and induces the activation of Y397-FAK and Y31/118-paxillin of undifferentiated and 24-h preinduced MSCs in a time-dependent manner. Inhibition of FAK by PF-228 or expressing FAK-Y397F mutant impairs the dynamics of FAs in MSCs during VEGF-induced migration. Furthermore, Rac1 regulates FA formation in a FAK-dependent manner. Overexpression of constitutive activated mutants of Rac1 increases the number of FAs in undifferentiated and 24-h preinduced MSCs, while VEGF-induced increase of FA formation is decreased by inhibiting FAK by PF-228. Collectively, these results demonstrate that FAK and Rac1 signalings coordinately regulate the dynamics of FAs during VEGF-induced migration of MSCs in varying neural differentiation states. PMID- 25820250 TI - A novel method for assessing bladder-related pain reveals the involvement of nerve growth factor in pain associated with cyclophosphamide-induced chronic cystitis in mice. AB - BACKGROUND: Pain is a prominent feature of interstitial cystitis/painful bladder syndrome (IC/PBS), but the underlying mechanisms are not fully understood. There is a lack of well-characterized research tools, such as pain evaluation methods and experimental animal models, for investigating non-ulcerative cystitis. We developed a novel method for evaluating bladder pain in mice with cyclophosphamide (CYP)-induced cystitis. METHODS: Cystitis was produced by a single intraperitoneal injection of CYP (300 mg/kg) or repeated injections of CYP (150 mg/kg once daily for 4 days). Blunt stimulation with a cotton probe was applied to the abdominal region, and the thresholds for withdrawal responses were measured quantitatively using an anaesthesiometer. RESULTS: The single injection of CYP provoked acute cystitis with severe bladder inflammation in mice. In these mice, we could detect an increased sensitivity to blunt stimulation, which was abolished by intravesical lidocaine. The stimulation induced phosphorylation of extracellular signal-regulated kinases in bladder-projecting sensory neurons. Chronic treatment with CYP produced persistent pain responses to the blunt stimulus. Although there were few signs of bladder inflammation in these mice, the concentration of nerve growth factor (NGF) was elevated in bladder tissue, and NGF antiserum inhibited the hypersensitivity. CONCLUSIONS: The blunt probe method is useful for evaluating bladder pain signalling in mice, and revealed the involvement of an NGF-sensitive pain pathway in chronic cystitis pain. This assessment method may be useful for studying the pathophysiology of bladder pain and for developing therapeutic strategies for non-ulcerative IC/PBS in patients. PMID- 25820251 TI - Development of an aquacatalytic system based on the formation of vesicles of an amphiphilic palladium NNC-pincer complex. AB - Two amphiphilic palladium NNC-pincer complexes bearing hydrophilic tri(ethylene glycol) chains and hydrophobic dodecyl chains were designed and prepared for the development of a new aquacatalytic system. In water, these amphiphilic complexes self-assembled to form vesicles, the structures which were established by means of a range of physical techniques. When the catalytic activities of the vesicles were investigated in the arylation of terminal alkynes in water, they were found to catalyze the reaction of aryl iodides with terminal alkynes to give good yields of the corresponding internal alkynes. The formation of a vesicular structure was shown to be essential for efficient promotion of this reaction in water. PMID- 25820252 TI - Interactome of the negative regulator of nuclear import BRCA1-binding protein 2. AB - Although the negative regulator of nuclear import (NRNI) BRCA1 binding protein 2 (BRAP2) is highly expressed in testis, its role is largely unknown. Here we address this question by documenting the BRAP2 interactome from human testis, using the yeast 2-hybrid system to identify BRAP2-interacting proteins with roles in diverse cellular processes, including regulation of the actin cytoskeleton, ubiquitinylation, cell cycle/apoptosis and transcription. Interaction with BRAP2 in adult mouse testis with three of these, PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1), A-Kinase anchor protein (AKAP3) and DNA methyl transferase 1 (DNMT1), was confirmed by coimmunoprecipitation assays. BRAP2's ability to inhibit PHLPP1 and DNMT1 nuclear localisation was also confirmed by quantitative confocal microscopy. Importantly, the physiological relevance thereof was implied by the cytoplasmic localisation of PHLPP1, AKAP3 and DNMT1 in pachytene spermatocytes/round spermatids where BRAP2 is present at high levels, and nuclear localisation of PHLPP1 and DNMT1 in spermatogonia concomitant with lower levels of BRAP2. Interestingly, BRAP2 was also present in murine spermatozoa, in part colocalised with AKAP3. Together the results indicate for the first time that BRAP2 may play an important NRNI role in germ cells of the testis, with an additional, scaffold/structural role in mature spermatozoa. PMID- 25820253 TI - Characterization of ferromagnetic or conductive properties of metallic foreign objects embedded within the human body with magnetic iron detector (MID): Screening patients for MRI. AB - PURPOSE: A preliminary assessment of the MRI-compatibility of metallic object possibly embedded within the patient is required before conducting the MRI examination. The Magnetic Iron Detector (MID) is a highly sensitive susceptometer that uses a weak magnetic field to measure iron overload in the liver. MID might be used to perform a screening procedure for MRI by determining the ferromagnetic/conductive properties of embedded metallic objects. METHODS: The study was composed by: (i) definition of MID sensitivity threshold; (ii) application of MID in a procedure to characterize the ferromagnetic/conductive properties of metallic foreign objects in 958 patients scheduled for MID examination. RESULTS: The detection threshold for ferromagnetic objects was found to be the equivalent of a piece of wire of length 2 mm and gauge 0.8 mm(2) and, representing purely conductive objects, an aluminum sheet of area 2 * 2 cm(2) . Of 958 patients, 165 had foreign bodies of unknown nature. MID was able to detect those with ferromagnetic and/or conducting properties based on fluctuations in the magnetic and eddy current signals versus control. CONCLUSION: The high sensitivity of MID makes it suitable for assessing the ferromagnetic/conductive properties of metallic foreign objects embedded within the body of patients scheduled for MRI. PMID- 25820254 TI - Early skeletal muscle adaptations to short-term high-fat diet in humans before changes in insulin sensitivity. AB - OBJECTIVE: The purpose of this investigation was to understand the metabolic adaptations to a short-term (5 days), isocaloric, high-fat diet (HFD) in healthy, young males. METHODS: Two studies were undertaken with 12 subjects. Study 1 investigated the effect of the HFD on skeletal muscle substrate metabolism and insulin sensitivity. Study 2 assessed the metabolic and transcriptional responses in skeletal muscle to the transition from a fasted to fed state using a high-fat meal challenge before and after 5 days of the HFD. RESULTS: Study 1 showed no effect of a HFD on skeletal muscle metabolism or insulin sensitivity in fasting samples. Study 2 showed that a HFD elicits significant increases in fasting serum endotoxin and disrupts the normal postprandial excursions of serum endotoxin, as well as metabolic and transcriptional responses in skeletal muscle. These effects after 5 days of the HFD were accompanied by an altered fasting and postprandial response in the ratio of phosphorylated- to total-p38 protein. These changes all occurred in the absence of alterations in insulin sensitivity. CONCLUSIONS: Our findings provide evidence for early biological adaptations to high-fat feeding that proceed and possibly lead to insulin resistance. PMID- 25820255 TI - Irisin levels before and after physical activity among school-age children with different BMI: a direct relation with leptin. AB - OBJECTIVE: Irisin is a novel myokine that seems to mediate the beneficial effects of exercise. Levels of circulating irisin before and after an 8-month physical activity program (PAP) in school-age children were evaluated. METHODS: Irisin and leptin were measured at baseline and at follow-up among 85 children with different BMI. RESULTS: Of the 85 children (mean age 8.9; 47% female), 25 children had normal weight, 23 were overweight, and 37 had obesity. We observed no significant difference in irisin serum levels between boys and girls. Irisin was positively associated with BMI before and after the PAP (r(before) = 0.42; r(after) = 0.37, P < 0.001), with the highest levels in children with obesity. There was a slight decrease of circulating irisin after PAP, but this decrease was not of statistical significance. We observed a high and positive association between irisin and leptin levels before and after the PAP (r(before) = 0.78; r(after) = 0.82, P < 0.001). Moreover, changes in leptin correlated with changes in irisin (r = 0.72, P < 0.001). CONCLUSIONS: Circulating irisin is positively linked to BMI and leptin in school-age children, supporting the notion that that irisin is produced by adipose tissue. As in previous reports, this study failed to observe changes in irisin levels after exercise, likely because higher irisin levels are produced only during exercise. PMID- 25820256 TI - Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota in diet-induced obese rats. AB - OBJECTIVE: Oligofructose (OFS) is a prebiotic that reduces energy intake and fat mass via changes in gut satiety hormones and microbiota. The effects of OFS may vary depending on predisposition to obesity. The aim of this study was to examine the effect of OFS in diet-induced obese (DIO) and diet-resistant (DR) rats. METHODS: Adult, male DIO, and DR rats were randomized to: high-fat/high-sucrose (HFS) diet or HFS diet + 10% OFS for 6 weeks. Body composition, food intake, gut microbiota, plasma gut hormones, and cannabinoid CB(1) receptor expression in the nodose ganglia were measured. RESULTS: OFS reduced body weight, energy intake, and fat mass in both phenotypes (P < 0.05). Select gut microbiota differed in DIO versus DR rats (P < 0.05), the differences being eliminated by OFS. OFS did not modify plasma ghrelin or CB(1) expression in nodose ganglia, but plasma levels of GIP were reduced and PYY were elevated (P < 0.05) by OFS. CONCLUSIONS: OFS was able to reduce body weight and adiposity in both prone and resistant obese phenotypes. OFS-induced changes in gut microbiota profiles in DIO and DR rats, along with changes in gut hormone levels, likely contribute to the sustained lower body weights. PMID- 25820257 TI - All in the family: correlations between parents' and adolescent siblings' weight and weight-related behaviors. AB - OBJECTIVE: To examine whether and how parents' and adolescent siblings' weight and weight-related behaviors are correlated. Results will inform which family members may be important to include in adolescent obesity prevention interventions. METHODS: Data from two linked population-based studies, EAT 2010 and F-EAT, were used for cross-sectional analyses. Parents (n = 58; 91% females; mean age = 41.7 years) and adolescent siblings (sibling #1 n = 58, 50% girls, mean age = 14.3 years; sibling #2 n = 58, 64% girls, mean age = 14.8 years) were socioeconomically and racially/ethnically diverse. RESULTS: Some weight-related behaviors between adolescent siblings were significantly positively correlated (i.e., fast food consumption, breakfast frequency, sedentary patterns, p < 0.05). There were no significant correlations between parents' weight and weight-related behaviors and adolescent siblings' same behaviors. Some of the significant correlations found between adolescent siblings' weight-related behaviors were statistically different from correlations between parents' and adolescent siblings' weight-related behaviors. CONCLUSIONS: Although not consistently, adolescent siblings' weight-related behaviors were significantly correlated as compared with parents' and adolescent siblings' weight-related behaviors. It may be important to consider including siblings in adolescent obesity prevention interventions or in recommendations healthcare providers give to adolescents regarding their weight and weight-related behaviors. PMID- 25820258 TI - Maternal weight change from prepregnancy to 7 years postpartum--the influence of behavioral factors. AB - OBJECTIVE: We studied the influence of maternal behavior on weight change from prepregnancy to 7 years postpartum. METHODS: We used linear regression to study the independent and combined associations between self-reported behavior in pregnancy (dietary intake, leisure-time exercise, sedentary activity, smoking) and postpartum (breastfeeding duration and smoking) on weights at 6 months, 18 months, and 7 years postpartum. RESULTS: Women's average 7-year weight gain was 2.07 kg, with 23% gaining >5 kg. Multivariable analyses suggested that women with healthier dietary intake, more leisure-time exercise, less sedentary behavior, and longer duration of breastfeeding on average gained 1.66 kg [95% confidence interval (CI): 1.40; 1.91] with a significantly reduced odds [OR 0.56 (95% CI: 0.49; 0.64)] of gaining >5 kg from prepregnancy to 7 years postpartum compared to women with none or one of these behaviors [mean gain 3.03 kg (95% CI: 2.68; 3.39)]. Women who ceased smoking had higher long-term weight gain than nonsmokers, but not smokers. CONCLUSIONS: Adherence to healthy behaviors during pregnancy lowered long-term weight gain considerably by lowering postpartum weight retention and subsequent weight gain. Public health efforts to help mothers achieve healthy behaviors might prevent childbearing-related weight gain. PMID- 25820260 TI - Determination of Flurbiprofen in Human Plasma by High-Performance Liquid Chromatography. AB - A simple high-performance liquid chromatography method has been developed for determination of flurbiprofen in human plasma. The method was validated on an Ace C18 column using UV detection. The mobile phase was acetonitrile-0.05 M potassium dihydrogen phosphate solution (60:40, v/v) adjusted to pH 3.5 with phosphoric acid. The calibration curve was linear between the concentration range of 0.10 5.0 MUg/mL. Intra- and inter-day precision values for flurbiprofen in plasma were <4.47, and accuracy (relative error) was better than 3.67%. The extraction recoveries of flurbiprofen from human plasma were between 93.0 and 98.9%. The limits of detection and quantification of flurbiprofen were 0.03 and 0.10 MUg/mL, respectively. In addition, this assay was applied to determine the pharmacokinetic parameters of flurbiprofen in six healthy Turkish volunteers who had been given 100 mg flurbiprofen. PMID- 25820259 TI - Isoflavones in soy flour diet have different effects on whole-genome expression patterns than purified isoflavone mix in human MCF-7 breast tumors in ovariectomized athymic nude mice. AB - SCOPE: Soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied here. METHODS AND RESULTS: Ovariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either Soy flour diet (MS) or purified isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor growth suppressing genes ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS-induced gene expression alterations were predictive of prolonged survival among estrogen receptor-positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival. CONCLUSION: Our findings suggest that dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice. PMID- 25820261 TI - Reprogramming of cell fate: epigenetic memory and the erasure of memories past. AB - Cell identity is a reflection of a cell type-specific gene expression profile, and consequently, cell type-specific transcription factor networks are considered to be at the heart of a given cellular phenotype. Although generally stable, cell identity can be reprogrammed in vitro by forced changes to the transcriptional network, the most dramatic example of which was shown by the induction of pluripotency in somatic cells by the ectopic expression of defined transcription factors alone. Although changes to cell fate can be achieved in this way, the efficiency of such conversion remains very low, in large part due to specific chromatin signatures constituting an epigenetic barrier to the transcription factor-mediated reprogramming processes. Here we discuss the two-way relationship between transcription factor binding and chromatin structure during cell fate reprogramming. We additionally explore the potential roles and mechanisms by which histone variants, chromatin remodelling enzymes, and histone and DNA modifications contribute to the stability of cell identity and/or provide a permissive environment for cell fate change during cellular reprogramming. PMID- 25820262 TI - Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation. AB - Mutations of CSB account for the majority of Cockayne syndrome (CS), a devastating hereditary disorder characterized by physical impairment, neurological degeneration and segmental premature aging. Here we report the generation of a human CSB-knockout cell line. We find that CSB facilitates HR and represses NHEJ. Loss of CSB or a CS-associated CSB mutation abrogating its ATPase activity impairs the recruitment of BRCA1, RPA and Rad51 proteins to damaged chromatin but promotes the formation of 53BP1-Rif1 damage foci in S and G2 cells. Depletion of 53BP1 rescues the formation of BRCA1 damage foci in CSB-knockout cells. In addition, knockout of CSB impairs the ATM- and Chk2-mediated DNA damage responses, promoting a premature entry into mitosis. Furthermore, we show that CSB accumulates at sites of DNA double-strand breaks (DSBs) in a transcription dependent manner. The kinetics of DSB-induced chromatin association of CSB is distinct from that of its UV-induced chromatin association. These results reveal novel, important functions of CSB in regulating the DNA DSB repair pathway choice as well as G2/M checkpoint activation. PMID- 25820263 TI - Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. AB - The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction. PMID- 25820264 TI - Weight loss in a man from West Africa. S. stercoralis hyperinfection. PMID- 25820265 TI - Call to improve transparency of trials of non-regulated interventions. PMID- 25820266 TI - Mapping the zoonotic niche of Marburg virus disease in Africa. AB - BACKGROUND: Marburg virus disease (MVD) describes a viral haemorrhagic fever responsible for a number of outbreaks across eastern and southern Africa. It is a zoonotic disease, with the Egyptian rousette (Rousettus aegyptiacus) identified as a reservoir host. Infection is suspected to result from contact between this reservoir and human populations, with occasional secondary human-to-human transmission. METHODS: Index cases of previous human outbreaks were identified and reports of infection in animals recorded. These data were modelled within a species distribution modelling framework in order to generate a probabilistic surface of zoonotic transmission potential of MVD across sub-Saharan Africa. RESULTS: Areas suitable for zoonotic transmission of MVD are predicted in 27 countries inhabited by 105 million people. Regions are suggested for exploratory surveys to better characterise the geographical distribution of the disease, as well as for directing efforts to communicate the risk of practices enhancing zoonotic contact. CONCLUSIONS: These maps can inform future contingency and preparedness strategies for MVD control, especially where secondary transmission is a risk. Coupling this risk map with patient travel histories could be used to guide the differential diagnosis of highly transmissible pathogens, enabling more rapid response to outbreaks of haemorrhagic fever. PMID- 25820268 TI - Exploiting the Spur of the Moment to Enhance Healthy Consumption: Verbal Prompting to Increase Fruit Choices in a Self-Service Restaurant. AB - BACKGROUND: People often have good intentions to eat healthily, but these intentions may get overruled by temporary moments of temptation. The current study examined the effectiveness of "verbal prompting" as a nudge to increase fruit salad sales in a natural setting. METHODS: A field experiment was conducted in a self-service restaurant during breakfast time. After an initial baseline period, the intervention involved four different prompts suggesting ordering a side dish (i.e. orange juice, fruit salad, pancakes) given by cashiers to visitors. The intervention phase lasted 13 weeks. Cash register and observational data were obtained. In addition, a sample of visitors (N = 393) responded to a survey. RESULTS: A significant increase in sales of orange juice was observed during the orange juice verbal prompts intervention periods (35-42% of all breakfasts sold) compared to baseline (20% of all breakfasts sold). Similarly, sales of fruit salad (9%) and pancakes (3%) rose to a small but significant extent compared to baseline sales (3% and 1%, respectively). Survey results showed that customers did not feel pressurised into purchasing a side dish. CONCLUSION: Together, findings suggest that verbal prompts involving healthy side dishes are a potential useful nudge to implement in other food service settings. PMID- 25820267 TI - The structural organization of seed oil bodies could explain the contrasted oil extractability observed in two rapeseed genotypes. AB - MAIN CONCLUSION: The protein, phospholipid and sterol composition of the oil body surface from the seeds of two rapeseed genotypes was compared in order to explain their contrasted oil extractability. In the mature seeds of oleaginous plants, storage lipids accumulate in specialized structures called oil bodies (OBs). These organelles consist of a core of neutral lipids surrounded by a phospholipid monolayer in which structural proteins are embedded. The physical stability of OBs is a consequence of the interactions between proteins and phospholipids. A detailed study of OB characteristics in mature seeds as well as throughout seed development was carried out on two contrasting rapeseed genotypes Amber and Warzanwski. These two accessions were chosen because they differ dramatically in (1) crushing ability, (2) oil extraction yield and, (3) the stability of purified OBs. Warzanwski has higher crushing ability, better oil extraction yield and less stable purified OBs than Amber. OB morphology was investigated in situ using fluorescence microscopy, transmission electron microscopy and pulsed field gradient NMR. During seed development, OB diameter first increased and then decreased 30 days after pollination in both Amber and Warzanwski embryos. In mature seeds, Amber OBs were significantly smaller. The protein, phospholipid and sterol composition of the hemi-membrane was compared between the two accessions. Amber OBs were enriched with H-oleosins and steroleosins, suggesting increased coverage of the OB surface consistent with their higher stability. The nature and composition of phospholipids and sterols in Amber OBs suggest that the hemi membrane would have a more rigid structure than that of Warzanwski OBs. PMID- 25820269 TI - Evaluation of DXA vs. MRI for body composition measures in 1-month olds. AB - BACKGROUND: Detailed measures of infant body composition are needed for understanding the impact of genes and environment on growth early in life. OBJECTIVE: The purpose of this study was to compare the accuracy and bias of body composition in infants. METHODS: Dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) were used to determine body composition and the trunk depot. The depots measured were total fat mass (FM), total fat-free mass (FFM) and trunk FM and FFM using DXA and MRI in 14 infants. RESULTS: None of the regression lines between DXA and MRI significantly deviate from the line of identity for any of the depots studied. However, Bland-Altman analyses revealed bias for trunk FM and trunk FFM. CONCLUSION: Our data showed DXA to be accurate (regression not significantly deviating from the line of identity), with high agreement (indicated by high R(2) ) and without bias (non-significant Bland Altman) when estimating total FM and FFM. This could not be said for trunk estimates. PMID- 25820270 TI - Desflurane anesthesia and postoperative cognitive function. PMID- 25820272 TI - Ebola mortality is highest among babies, finds study. PMID- 25820271 TI - The uses of laryngeal mask airway ProSealTM and endobronchial blocker for one lung anesthesia. AB - PURPOSE: The use of an endobronchial blocker in conjunction with a supraglottic device in elective thoracic cases has never been studied. The aim of this study was to report the success rate and time to placement of the endobronchial blocker in anaesthetized patients with a laryngeal mask airway (LMA)-ProSealTM in place. METHODS: This was a single-center, prospective, descriptive pilot study that enrolled 30 patients aged 18-75 years, with ASA I-III, who underwent elective thoracotomy or video-assisted thoracoscopy. We collected data on time to placement of the endobronchial blocker into the selected bronchus, time consumed for final blocker positioning and inflation, lung deflation score at chest opening, and postoperative airway complications. RESULTS: One patient was excluded because of high peak airway pressure during LMA ventilation. The time required for blocker placement in the right main bronchus was shorter [mean 160 (78-480) s] compared with that for the left main bronchus [225 (117-420) s]. The blocker was successfully placed on the first attempt in 25 patients. Lung deflation score graded by the surgeon was 8/10 (median). Minor postoperative airway complications, such as sore throat (28.6 %) and hoarseness of voice (17.9 %), were reported. CONCLUSIONS: The use of LMA-ProSealTM in conjunction with the COOPDECH Endobronchial Blocker Tube may be considered an alternative one-lung ventilation technique in selected cases. However, success rates and time required for placement of the blocker seem dependent on the operator's skill. Although postoperative sore throat and hoarseness of voice were reported, these improved in 24 h. PMID- 25820273 TI - Tuning the reactivity of a dissociative force field: proton transfer properties of aqueous H3O(+) and their dependence on the three-body interaction. AB - The proton transfer properties of the dissociative water potential developed by Garofalini et al. were closely examined by carefully analyzing the pairwise screening functions of the three-body interaction. It was shown that a simultaneous adjustment of the exponential screening factor and the three-body cutoff distance enables a selective adjustment of the diffusive properties of an excess proton, while at the same time structural and other dynamical data remain unaffected to a large extend. To investigate proton transfer properties without the influence of nuclear quantum effects, deuterated systems have been investigated in addition to their hydrogen counterparts. It was shown that the suggested parameter set A leads to significantly improved diffusion coefficients and proton hopping rates. Comparison of proton transfer correlation functions to simulation data obtained from Car-Parrinello molecular dynamics simulations confirms the improved performance of the adjusted parametrization. PMID- 25820274 TI - Evolution on one foot. PMID- 25820275 TI - A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most common fatal motor neuron disease in adults. Numerous studies indicate that ALS is a systemic disease that affects whole body physiology and metabolic homeostasis. Using a mouse model of the disease (SOD1(G86R)), we investigated muscle physiology and motor behavior with respect to muscle metabolic capacity. We found that at 65 days of age, an age described as asymptomatic, SOD1(G86R) mice presented with improved endurance capacity associated with an early inhibition in the capacity for glycolytic muscle to use glucose as a source of energy and a switch in fuel preference toward lipids. Indeed, in glycolytic muscles we showed progressive induction of pyruvate dehydrogenase kinase 4 expression. Phosphofructokinase 1 was inhibited, and the expression of lipid handling molecules was increased. This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression. Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation. In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology. PMID- 25820276 TI - Targeting DDX3 with a small molecule inhibitor for lung cancer therapy. AB - Lung cancer is the most common malignancy worldwide and is a focus for developing targeted therapies due to its refractory nature to current treatment. We identified a RNA helicase, DDX3, which is overexpressed in many cancer types including lung cancer and is associated with lower survival in lung cancer patients. We designed a first-in-class small molecule inhibitor, RK-33, which binds to DDX3 and abrogates its activity. Inhibition of DDX3 by RK-33 caused G1 cell cycle arrest, induced apoptosis, and promoted radiation sensitization in DDX3-overexpressing cells. Importantly, RK-33 in combination with radiation induced tumor regression in multiple mouse models of lung cancer. Mechanistically, loss of DDX3 function either by shRNA or by RK-33 impaired Wnt signaling through disruption of the DDX3-beta-catenin axis and inhibited non homologous end joining-the major DNA repair pathway in mammalian somatic cells. Overall, inhibition of DDX3 by RK-33 promotes tumor regression, thus providing a compelling argument to develop DDX3 inhibitors for lung cancer therapy. PMID- 25820278 TI - Editorial Commentary: Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) and HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis. PMID- 25820277 TI - Neurological Manifestations in Human T-Cell Lymphotropic Virus Type 1 (HTLV-1) Infected Individuals Without HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis: A Longitudinal Cohort Study. AB - BACKGROUND: Human T-cell lymphotropic virus type 1 (HTLV-1) is the agent of HTLV 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), observed in up to 5% of infected individuals. Despite low prevalence, many HTLV-1-infected patients who do not fulfill criteria for HAM/TSP present with neurological complaints related to sensory, motor, urinary, or autonomic manifestations. The aim of this study was to determine the incidence of neurologic manifestations and risk factors associated with these outcomes. METHODS: The incidence of HAM/TSP and new signs and neurologic symptoms were computed in a group of patients enrolled in a cohort study. RESULTS: Of 414 subjects, 76 had definite HAM/TSP, 87 had possible or probable HAM/TSP, and 251 subjects had no neurologic manifestation and were selected for analysis. Definite HAM/TSP developed in 5 (1.47%) patients. Follow up of at least 3 years was achieved in 51% of patients. The incidence rate was computed in 1000 person-years (206 for hand numbness, 187 for feet numbness, 130 for nocturia, and 127 for urgency). Average incidence rate in neurological exam was 76 for leg hyperreflexia, 53 for leg weakness, and 37 for Babinski sign. In the applied Expanded Disability Status Scale, the incidence rate of worsening 1 point was 134 per 1000 person-years. Kaplan-Meier curves stratified by sex and proviral load showed that females and patients with proviral load >50,000 copies/10(6) peripheral blood mononuclear cells had a higher risk of progression. CONCLUSIONS: Development of neurological symptoms or signs occurred in up to 30% of asymptomatic subjects during 8 years of follow-up. PMID- 25820279 TI - Genetic Resources of Pinus cembra L. Marginal Populations from the Tatra Mountains: Implications for Conservation. AB - The levels of variation and genetic diversity of offspring of randomly selected old mother trees in four marginal populations of the Pinus cembra in the Tatra Mountains were analyzed. Twenty-four isozyme loci were analyzed (nine of them were monomorphic). The analyzed offspring of Swiss stone pine showed highly diverse polymorphism at the levels of both provenances and individual families (the offspring of one mother tree). The mean observed heterozygosity was low and very similar to that of other Carpathian populations. The genetic diversity (mean Fst = 11%) between the four provenances was higher than that observed for populations from the Carpathian Mountains and the Alps. The genetic uniqueness (high genetic richness and diversity) of the analyzed Tatra populations of P. cembra as a whole and particular tree stands requires protection because of their valuable contribution to the species total genetic diversity (gene pool). PMID- 25820286 TI - Largest set of human genomes from a single population is sequenced. PMID- 25820288 TI - Programmable Mg(2+)-dependent DNAzyme switch by the catalytic hairpin DNA assembly for dual-signal amplification toward homogeneous analysis of protein and DNA. AB - The catalytic hairpin DNA assembly-programmed active Mg(2+)-dependent DNAzyme was proposed for dual-signal amplified detection toward protein and DNA. The protein detection was implemented with the further combination of an additional terminal protection strategy. The detection limit toward avidin and target DNA could be achieved as 2 pM and 0.5 pM, respectively, with a high selectivity. PMID- 25820287 TI - Organ-on-a-chip: development and clinical prospects toward toxicity assessment with an emphasis on bone marrow. AB - Conventional approaches for toxicity evaluation of drugs and chemicals, such as animal tests, can be impractical due to the large experimental scale and the immunological differences between species. Organ-on-a-chip models have recently been recognized as a prominent alternative to conventional toxicity tests aiming to simulate the human in vivo physiology. This review focuses on the organ-on-a chip applications for high-throughput screening of candidate drugs against toxicity, with a particular emphasis on bone-marrow-on-a-chip. Studies in which organ-on-a-chip models have been developed and utilized to maximize the efficiency and predictability in toxicity assessment are introduced. The potential of these devices to replace tests of acute systemic toxicity in animals, and the challenges that are inherent in simulating the human immune system are also discussed. As a promising approach to overcome the limitations, we further focus on an in-depth analysis of the development of bone-marrow-on-a chip that is capable of simulating human immune responses against external stimuli due to the key roles of marrow in immune systems with hematopoietic activities. Owing to the complex interactions between hematopoietic stem cells and marrow microenvironments, precise control of both biochemical and physical niches that are critical in maintenance of hematopoiesis remains a key challenge. Thus, recently developed bone-marrow-on-a-chip models support immunogenicity and immunotoxicity testing in long-term cultivation with repeated antigen stimulation. In this review, we provide an overview of clinical studies that have been carried out on bone marrow transplants in patients with immune-related diseases and future aspects of clinical and pharmaceutical application of bone marrow-on-a-chip. PMID- 25820289 TI - Specificity of hemodynamic brain responses to painful stimuli: a functional near infrared spectroscopy study. AB - Assessing pain in individuals not able to communicate (e.g. infants, under surgery, or following stroke) is difficult due to the lack of non-verbal objective measures of pain. Near-infrared spectroscopy (NIRS) being a portable, non-invasive and inexpensive method of monitoring cerebral hemodynamic activity has the potential to provide such a measure. Here we used functional NIRS to evaluate brain activation to an innocuous and a noxious electrical stimulus on healthy human subjects (n = 11). For both innocuous and noxious stimuli, we observed a signal change in the primary somatosensory cortex contralateral to the stimulus. The painful and non-painful stimuli can be differentiated based on their signal size and profile. We also observed that repetitive noxious stimuli resulted in adaptation of the signal. Furthermore, the signal was distinguishable from a skin sympathetic response to pain that tended to mask it. Our results support the notion that functional NIRS has a potential utility as an objective measure of pain. PMID- 25820290 TI - Antimicrobial susceptibility of rapidly growing mycobacteria using the rapid colorimetric method. AB - Drug susceptibility testing (DST) of rapidly growing mycobacteria (RGM) are recommended for guiding the antimicrobial therapy. We have evaluated the use of resazurin in Mueller-Hinton medium (MHR) for MIC determination of RGM and compared the results with those obtained with the reference standard broth microdilution in Mueller-Hinton (MH) and with the resazurin microtiter assay (REMA) in 7H9 broth. The MIC of eight drugs: amikacin (AMI), cefoxitin (FOX), ciprofloxacin (CIP), clarithromycin (CLA), doxycycline (DOX), linezolid (LZD), moxifloxacin (MXF) and trimethoprim-sulfamethoxazole (TMP-SMX) were evaluated against 76 RGM (18 species) using three methods (MH, MHR, and REMA) in a 96-well plate format incubated at 37 degrees C over 3-5 days. Results obtained in the MH plates were interpreted by the appearance of turbidity at the bottom of the well before adding the resazurin. MHR and 7H9-REMA plates were read by visual observation for a change in color from blue to pink. The majority of results were obtained at day 5 for MH and 1 day after for MHR and 7H9-REMA. However, the preliminary experiment on time to positivity results using the reference strain showed that the resazurin can be added to the MH at day 2 to produce the results at day 3, but future studies with large sets of strains are required to confirm this suggestion. A high level of agreement (kappa 1.000-0.884) was obtained between the MH and the MHR. Comparison of results obtained with 7H9-REMA, on the other hand, revealed several discrepancies and a lower level of agreement (kappa 1.000-0.111). The majority of the strains were resistant to DOX and TMP-SMX, and the most active antimicrobials for RGM were AMI and FOX. In the present study, MHR represented an excellent alternative for MIC determination of RGM. The results could be read reliably, more easily, and more quickly than with the classical MH method. PMID- 25820291 TI - Predictive parameters for medical expulsive therapy in ureteral stones: a critical evaluation. AB - To evaluate the predictive value of some certain radiological as well as stone related parameters for medical expulsive therapy (MET) success with an alpha blocker in ureteral stones. A total 129 patients receiving MET for 5 to 10 mm ureteral stones were evaluated. Patients were divided into two subgroups where MET was successful in 64 cases (49.61%) and unsuccessful in 65 cases (50.39%). Prior to management, stone size, location, position in the ureter, degree of hydronephrosis, diameter of ureteral lumen proximal to the stone, ureteral wall thickness along with patient's demographics including body mass index (BMI) values were evaluated and recorded. The possible predictive values of these parameters for stone expulsion (and stone expulsion time) were evaluated in a comparative manner between two groups. The overall mean patient age and stone size values were 38.02 +/- 0.94 years and 40.31 +/- 1.13 mm(2), respectively. Regarding the predictive values of these parameters for MET-success, while stone size and localization, degree of hydronephrosis, proximal ureteral diameter and ureteral wall thickness were found to be highly predictive for MET-success, patients age, BMI values and stone density had no predictive value on this aspect. Our findings indicated that some stone and anatomical factors may be used to predict the success of MET in an effective manner. With this approach unnecessary use of these drugs that may cause a delay for stone removal will be avoided and the possible adverse effects of obstruction as well as stone-related clinical symptoms could be minimized. PMID- 25820292 TI - The hounsfield unit value calculated with the aid of non-contrast computed tomography and its effect on the outcome of percutaneous nephrolithotomy. AB - To evaluate the effect of the Hounsfield unit (HU) value, calculated with the aid of non-contrast computed tomography, on the outcome of percutaneous nephrolithotomy (PCNL). Data for 83 patients evaluated in our clinic between November 2011 and February 2014 that had similar stone sizes, localizations, and radio opacities were retrospectively reviewed. The patients were grouped according to their HU value, in a low HU group (HU <= 1000) or a high HU group (HU > 1000). The two groups were compared based on their PCNL success rates, complications, duration of surgery, duration of fluoroscopy, and decrease in the hematocrit. There were no significant differences in terms of mean age, female male ratio, or mean body mass index between the two groups (p > 0.05). The stone size and stone surface area did not differ significantly between the groups (p = 0.820 and p = 0.394, respectively). The unsuccessful PCNL rate and the prevalence of complications did not differ significantly between the two groups (p > 0.05). The duration of surgery, duration of fluoroscopy, and decrease in the hematocrit were significantly greater in the high HU group compared to the low HU group (p < 0.001). Calculating the HU value using this imaging method may predict cases with longer surgery durations, longer fluoroscopy durations, and greater decreases in hematocrite levels, but this value is not related to the success rate of PCNL. PMID- 25820293 TI - Milk of calcium stones: radiological signs and management outcome. AB - Milk of calcium (MOC) is a rare type of stone that was first described in 1940 by Ludin and Howald who reported MOC in renal cysts. Milk of calcium is a viscous colloidal suspension of calcium salts. Stasis, obstruction and infection are important predisposing factors. Due to a layering effect, characteristic radiological signs especially in CT can help in diagnosis to avoid unsuccessful shock wave lithotripsy. This is the largest reported case series, in which radiological signs by CT scan to predict renal MOC stones, clinical picture and management outcome are described in detail. Cases with suspected renal milk of calcium stones were studied over 7 years (2008-2015). All cases were diagnosed preoperatively by non-contrast CT. Urine cultures were performed in all patients preoperatively. Intra-operative and postoperative findings were reported. Stones retrieved were sent for chemical analysis using an infrared method. Seven cases of milk of calcium renal stones were included in this study. These stones were faint radio-opaque in two cases and radiolucent in five cases. All cases were diagnosed preoperatively with non-contrast CT. Their Hounsfield units (HU) ranged from 114 to 612. All stones were located in a dependent position (gravitational effect) in the posterior aspect of dilated calyces. Five cases exhibited the typical fluid level and two cases demonstrated semilunar (half moon) pattern in the anterior surface of the stones. All cases underwent PCNL with suction and retrieval of soft stones without the need for disintegration. When stones demonstrate a low Hounsfield unit, are arranged in dependent positions within dilated calyces and exhibit fluid level or semilunar pattern on non-contrast CT, milk of calcium stones should be considered. PCNL is an effective modality for management of renal milk of calcium stones. PMID- 25820294 TI - Metagenomic analysis of the sludge microbial community in a lab-scale denitrifying phosphorus removal reactor. AB - Denitrifying phosphorus removal is an attractive wastewater treatment process due to its reduced carbon source demand and sludge minimization potential. In the present study, the metagenome of denitrifying phosphorus removal sludge from a lab-scale anaerobic-anoxic SBR was generated by Illumina sequencing to study the microbial community. Compared with the aerobic phosphorus removal sludge, the denitrifying phosphorus removal sludge demonstrated quite similar microbial community profile and microbial diversity with sludge from Aalborg East EBPR WWTP. Proteobacteria was the most dominant phylum; within Proteobacteria, beta Proteobacteria was the most dominant class, followed by alpha-, gamma-, delta-, and epsilon-Proteobacteria. The genes involved in phosphate metabolism and biofilm formation reflected the selective pressure of the phosphorus removal process. Moreover, ppk sequence from DPAO was outside the Accumulibacter clusters, which suggested different core phosphorus removal bacteria in denitrifying and aerobic phosphorus removal systems. In a summary, putative DPAO might be a novel genus that is closely related between Accumulibacter and Dechloromonas within Rhodocyclus. The microbial community and metabolic profiles achieved in this study will eventually help to improve the understanding of key microorganisms and the entire community in order to improve the phosphorus removal efficiency of EBPR processes. PMID- 25820295 TI - Purification of substances from Achyrocline satureioides with inhibitory activity against Paenibacillus larvae, the causal agent of American foulbrood in honeybees' larvae. AB - Achyrocline satureioides extracts were tested in vitro against the growth of Paenibacillus larvae. Four different extracts were obtained by liquid-liquid extraction from an aqueous-ethyl alcohol macerate of the aerial parts of the plant. The biological activity was tested by the broth microdilution technique. Hexane extract showed the highest activity (minimum inhibitory concentration = 0.060 +/- 0.037 mg/mL). Transmission electron microscopy experiments showed that the main effect exerted by the hexane extract on the cell was at the cellular membrane level. The hexane extract was analyzed by thin-layer chromatography, and the activity of its components was tested by bioautography. Four growth inhibition zones were observed in the bioautographic experiments (using hexane acetone (7:3) as mobile phase), with that at Rf = 0.57 showing the largest zone of inhibition. High-performance liquid chromatographic experiments, using ultraviolet and electrospray ionization coupled to tandem mass spectrometric detection, showed the presence of one compound with a m/z ratio of 442, which may be related to phloroglucinols alpha-pyrone compounds recently discovered. The high antibacterial activity of the hexane extract and of the isolated compound determined in this work may be useful for the development of future new alternatives for the treatment of American foulbrood. PMID- 25820296 TI - Exhaustive study of the novel hyper alkalophil, thermostable, and chelator resistant metalloprotease. AB - Our newly discovered metalloprotease, designated as ALP NS12 was selected using gelatin agar plates with incubation at 100 degrees C. Subcloning of the fragments in to pUC118 to make E. coli HB101 (pPEMP01NS) with following two-step chromatography using diethylaminoethyl sepharose (DEAE-sepharose) and Sephadex G 100 columns to purify 97-kDa expressed enzyme was performed. Although activity of immobilized ALP NS12 on glass surface was established at temperatures between 70 and 120 degrees C and pH ranges 4.0-13.0, the optimum temperature and pH were achieved at 100 degrees C and 11.0, respectively. Enhancement of enzyme activity was obtained in the presence of 5 mM MnCl2 (91 %), CaCl2 (357 %), FeCl2 (175 %), MgCl2 (94 %), ZnCl2 (412 %), NiCl (86 %), NaCl (239 %), and Na-sulfate (81 %) while inhibition was observed with EDTA (5 mM), PMSF (3 mM), urea (8 M), and SDS (1 %) at 65, 37, 33, and 42 %, respectively. Consequently, the enzyme was well analyzed using crystallography and protein modeling. ALP NS12 can be applied in industrial processes at extreme temperatures and under highly basic conditions, chelators, and detergents. PMID- 25820297 TI - Gliotoxin-producing endophytic Acremonium sp. from Zingiber officinale found antagonistic to soft rot pathogen Pythium myriotylum. AB - Soft rot caused by Pythium sp. is a major cause of economic loss in ginger cultivation. Endophytic fungi isolated from Zingiber officinale were screened for its activity against the soft rot pathogen Pythium myriotylum. Among the isolates screened, an endophytic fungus which was identified as Acremonium sp. showed promising activity against the phytopathogen in dual culture. The selected fungus was cultured in large scale on solid rice media and was extracted with ethyl acetate. The crude extract was subjected to column chromatography and preparative HPLC to obtain the fraction with the antifungal activity. LC-QTOF-MS/MS analysis of this fraction done using water-acetonitrile gradient identified a mass of m/z 327 (M + H) corresponding to gliotoxin with specific fragments m/z 263, 245, 227, and 111. The result was reconfirmed in negative mode ionization. Gliotoxin is the major antagonistic peptide produced by the commercially used biocontrol agent, Trichoderma sp., which shows high antagonism against Pythium sp. The gliotoxin production by the isolated endophytic Acremonium sp. of Z. officinale shows the possible natural biocontrol potential of this endophytic fungus. PMID- 25820298 TI - A 2D bilayered metal-organic framework as a fluorescent sensor for highly selective sensing of nitro explosives. AB - A novel Cd-MOF (metal organic framework) [Cd3(NTB)2(DMA)3].2DMA (H3NTB = 4,4',4'' nitrilotrisbenzoic acid; DMA = N,N-dimethylacetamide) () was obtained under solvothermal conditions. The resulting MOF exhibits a novel (2D->3D) interdigitated architecture that is obtained from a bilayered motif with hexagonal grids. Luminescence properties of the activated phase of well dispersed in different solvents have also been investigated systematically, which demonstrate distinct solvent-dependent luminescence spectra with emission intensities significantly quenched toward nitrobenzene (NB) and 2,4,6 trinitrophenol (TNP). The results reveal that can be applied as a fluorescent sensor for the detection of TNP with high sensitivity, selectivity, and recyclability. PMID- 25820300 TI - Patterned paper sensors printed with long-chain DNA aptamers. AB - There is growing interest in developing printable paper sensors to enable rapid testing of analytes for environmental, food safety, and clinical applications. A major challenge is to find suitable bioinks that are amenable to high-speed printing and remain functional after printing. We report on a simple and effective approach wherein an aqueous ink composed of megadalton-sized tandem repeating structure-switching DNA aptamers (concatemeric aptamers) is used to rapidly create patterned paper sensors on filter paper by inkjet printing. These concatemeric aptamer reporters remain immobilized at the point of printing through strong adsorption but retain sufficient segmental mobility to undergo structure switching and fluorescence signaling to provide both qualitative and quantitative detection of small molecules and protein targets. The convenience of inkjet printing allows for the patterning of internally referenced sensors with multiplexed detection, and provides a generic platform for on-demand printing of sensors even in remote locations. PMID- 25820301 TI - Uncontrolled before-after studies: discouraged by Cochrane and the EMJ. PMID- 25820299 TI - The role of auxiliary subunits for the functional diversity of voltage-gated calcium channels. AB - Voltage-gated calcium channels (VGCCs) represent the sole mechanism to convert membrane depolarization into cellular functions like secretion, contraction, or gene regulation. VGCCs consist of a pore-forming alpha(1) subunit and several auxiliary channel subunits. These subunits come in multiple isoforms and splice variants giving rise to a stunning molecular diversity of possible subunit combinations. It is generally believed that specific auxiliary subunits differentially regulate the channels and thereby contribute to the great functional diversity of VGCCs. If auxiliary subunits can associate and dissociate from pre-existing channel complexes, this would allow dynamic regulation of channel properties. However, most auxiliary subunits modulate current properties very similarly, and proof that any cellular calcium channel function is indeed modulated by the physiological exchange of auxiliary subunits is still lacking. In this review we summarize available information supporting a differential modulation of calcium channel functions by exchange of auxiliary subunits, as well as experimental evidence in support of alternative functions of the auxiliary subunits. At the heart of the discussion is the concept that, in their native environment, VGCCs function in the context of macromolecular signaling complexes and that the auxiliary subunits help to orchestrate the diverse protein protein interactions found in these calcium channel signalosomes. Thus, in addition to a putative differential modulation of current properties, differential subcellular targeting properties and differential protein-protein interactions of the auxiliary subunits may explain the need for their vast molecular diversity. PMID- 25820302 TI - Randomised controlled trials: understanding effect sizes. PMID- 25820304 TI - Hydrogenated graphene and hydrogenated silicene: computational insights. AB - Density functional calculations are performed to study the energetic, structural, and electronic properties of graphene and silicene functionalized with hydrogen. Our calculations predict that H atoms bind much more strongly to silicene than to graphene. The adsorbed H atoms tend to cooperatively stabilize each other leading to a two-dimensional nucleation and growth mechanism. The different structural and electronic modifications induced by H in fully functionalized graphene and silicene (known as graphane and silicane) are also explained. Finally, the electronic properties of defective graphane with multiple hydrogen vacancies are investigated. Engineering the vacancies in graphane offers a way to modify the electronic properties of this material. PMID- 25820303 TI - Coil combination for receive array spectroscopy: Are data-driven methods superior to methods using computed field maps? AB - PURPOSE: Combining spectra from receive arrays, particularly X-nuclear spectra with low signal-to-noise ratios (SNRs), is challenging. We test whether data driven combination methods are better than using computed coil sensitivities. THEORY: Several combination algorithms are recast into the notation of Roemer's classic formula, showing that they differ primarily in their estimation of coil receive sensitivities. This viewpoint reveals two extensions of the whitened singular-value decomposition (WSVD) algorithm, using temporal or temporal + spatial apodization to improve the coil sensitivities, and thus the combined spectral SNR. METHODS: Radiofrequency fields from an array were simulated and used to make synthetic spectra. These were combined with 10 algorithms. The combined spectra were then assessed in terms of their SNR. Validation used phantoms and cardiac (31) P spectra from five subjects at 3T. RESULTS: Combined spectral SNRs from simulations, phantoms, and humans showed the same trends. In phantoms, the combined SNR using computed coil sensitivities was lower than with WSVD combination whenever the WSVD SNR was >14 (or >11 with temporal apodization, or >9 with temporal + spatial apodization). These new apodized WSVD methods gave higher SNRs than other data-driven methods. CONCLUSION: In the human torso, at frequencies >=49 MHz, data-driven combination is preferable to using computed coil sensitivities. Magn Reson, 2015. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Magn Reson Med 75:473-487, 2016. (c) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. PMID- 25820305 TI - Empowering academic research in chemical risk assessment and management. PMID- 25820306 TI - In response to Bales (2014). PMID- 25820308 TI - The rationale for moving beyond monetization in valuing ecosystem services. PMID- 25820309 TI - Introduction to 3 learned discourses on ecological valuation. PMID- 25820310 TI - Why money matters in ecological valuation. PMID- 25820311 TI - Ecosystem services: value is in the eye of the beholder. PMID- 25820312 TI - Nanomaterial environmental risk assessment. PMID- 25820313 TI - Whole-system perspectives in rivers: insights and implications. PMID- 25820315 TI - Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members. AB - BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals. METHODS AND RESULTS: Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed. Mutations were identified in 276 index-patients (63%). Index-patients presented predominantly with sustained ventricular arrhythmias (268; 61%). During a median follow-up of 7 years, 301 of the 416 index-patients presenting alive (72%) experienced sustained ventricular arrhythmias. Sudden cardiac death during follow up occurred more frequently among index-patients without an implantable cardioverter-defibrillator (10/63, 16% versus 2/335, 0.6%). Overall, cardiac mortality and the need for cardiac transplantation were low (6% and 4%, respectively). Clinical characteristics and outcomes were similar in index patients with and without mutations, as well as in those with familial and nonfamilial ARVD/C. ARVD/C was diagnosed in 207 family members (37%). Symptoms at first evaluation correlated with disease expression. Family members with mutations were more likely to meet Task Force Criteria for ARVD/C (40% versus 18%), experience sustained ventricular arrhythmias (11% versus 1%), and die from a cardiac cause (2% versus 0%) than family members without mutations. CONCLUSIONS: Long-term outcome was favorable in diagnosed and treated ARVD/C index-patients and family members. Outcome in index-patients was modulated by implantable cardioverter-defibrillator implantation, but not by mutation status and familial background of disease. One third of family members developed ARVD/C. Outcome in family members was determined by symptoms at first evaluation and mutations. PMID- 25820316 TI - Spinal cord compression injury in lysophosphatidic acid 1 receptor-null mice promotes maladaptive pronociceptive descending control. AB - BACKGROUND: Although activation of the lysophosphatidic acid receptor 1 (LPA1) is known to mediate pronociceptive effects in peripheral pain models, the role of this receptor in the modulation of spinal nociception following spinal cord injury (SCI) is unknown. AIM: In this study, LPA1 regulation of spinal excitability mediated by supraspinal descending antinociceptive control systems was assessed following SCI in both wild-type (WT) and maLPA1-null receptor mice. METHODS: The effect of a T8 spinal compression in WT and maLPA1-null mice was assessed up to 1 month after SCI using histological, immunohistochemical and behavioural techniques analysis including electrophysiological recording of noxious toes-Tibialis Anterior (TA) stimulus-response reflex activity. The effect of a T3 paraspinal transcutaneous electrical conditioning stimulus on TA noxious reflex temporal summation was also assessed. RESULTS: Histological analysis demonstrated greater dorsolateral funiculus damage after SCI in maLPA1-null mice, without a change in the stimulus-response function of the TA noxious reflex when compared to WT mice. While T3 conditioning stimulation in the WT group inhibited noxious TA reflex temporal summation after SCI, this stimulus strongly excited TA reflex temporal summation in maLPA1-null mice. The functional switch from descending inhibition to maladaptive facilitation of central excitability of spinal nociception demonstrated in maLPA1-null mice after SCI was unrelated to a general change in reflex activity. CONCLUSIONS: These data suggest that the LPA1 receptor is necessary for inhibition of temporal summation of noxious reflex activity, partly mediated via long-tract descending modulatory systems acting at the spinal level. PMID- 25820317 TI - Synthesis of 1-C-Glycoside-Linked Lipid II Analogues Toward Bacterial Transglycosylase Inhibition. AB - Preparation of Lipid II analogues containing an enzymatically uncleavable 1-C glycoside linkage between the disaccharide moiety and the pyrophosphate- or pyrophosphonate-lipid moiety is described. The synthesis of a common 1-C-vinyl disaccharide intermediate has been developed that allows easy preparation of both an elongated sugar-phosphate bond and a sugar-phosphonate moiety, which are coupled with the polyprenyl phosphate to give the desired molecules. Inhibition studies show how a subtle structural modification results in dramatically different potency toward bacterial transglycosylase (TGase), and the results identify Lipid II-C-O-PP (IC50 =25 MUM) as a potential TGase inhibitor. PMID- 25820319 TI - Morphological diversity in the orbital bones of two teleosts with experimental and natural variation in eye size. AB - BACKGROUND: Understanding differences in tissue morphology has not been well researched, yet provides crucial insight into evolution. We investigate the effect of eye reduction on the shape of surrounding bones by examining two morphs of the Mexican tetra (Tinaja cavefish and sighted fish), F1 intermediates, zebrafish, a sighted tetra after lens removal and a zebrafish mutant, bum-/- , which has a degenerating lens. RESULTS: Significantly, by comparing the skulls, we show that there are broadly similar effects on bone shape after eye reduction with bones posterior and dorsal to the eye consistently most affected in both species. We conclude that there are conserved mechanisms underlying bone shape changes in response to a reduced or lost eye. Of interest, when we compare the shapes of individual bones and the mode of eye reduction, differences suggest that the finer details of these underlying mechanisms may indeed vary. We also show that cavefish occupy a unique morphospace with respect to skull morphology and that F1 intermediates are most similar to sighted fish than their cavefish parent. CONCLUSIONS: This study highlights the dynamic nature of the vertebrate skull and its ability to respond to tissue changes within the head, a topic which has been largely overlooked in the literature. Developmental Dynamics 244:1109 1120, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 25820318 TI - Getting to the heart of hERG K(+) channel gating. AB - Potassium ion channels encoded by the human ether-a-go-go related gene (hERG) form the ion-conducting subunit of the rapid delayed rectifier potassium current (IKr ). Although hERG channels exhibit a widespread tissue distribution they play a particularly important role in the heart. There has been considerable interest in hERG K(+) channels for three main reasons. First, they have very unusual gating kinetics, most notably rapid and voltage-dependent inactivation coupled to slow deactivation, which has led to the suggestion that they may play a specific role in the suppression of arrhythmias. Second, mutations in hERG are the cause of 30-40% of cases of congenital long QT syndrome (LQTS), the commonest inherited primary arrhythmia syndrome. Third, hERG is the molecular target for the vast majority of drugs that cause drug-induced LQTS, the commonest cause of drug induced arrhythmias and cardiac death. Drug-induced LQTS has now been reported for a large range of both cardiac and non-cardiac drugs, in which this side effect is entirely undesired. In recent years there have been comprehensive reviews published on hERG K(+) channels (Vandenberg et al. 2012) and we will not re-cover this ground. Rather, we focus on more recent work on the structural basis and dynamics of hERG gating with an emphasis on how the latest developments may facilitate translational research in the area of stratifying risk of arrhythmias. PMID- 25820320 TI - "Cross-linked fibrous" spherulites formed from a low molecular weight compound, Fmoc-functionalized phenolic amino acid. AB - While biomacromolecules such as proteins are shown to form fibrous spherulites, which are generally "semicrystalline" in nature, here we show that a simple, low molecular weight compound such as fluorenylmethoxycarbonyl-functionalized phenolic amino acid (Fmoc-l-tyrosine) can form "fibrous" spherulites with highly "cross-linked" microfibrils using the supramolecular self-assembly process. PMID- 25820321 TI - Aberrant immunostaining pattern of the CD24 glycoprotein in clinical samples and experimental models of pediatric medulloblastomas. AB - The CD24 glycoprotein is a mediator of neuronal proliferation, differentiation and immune suppression in the normal CNS, and a proposed cancer biomarker in multiple peripheral tumor types. We performed a comparative analysis of CD24 gene expression in a large cohort of pediatric and adult brain tumors (n = 813), and further characterized protein expression in tissue sections (n = 39), primary brain tumor cultures (n = 12) and a novel orthotopic group 3 medulloblastoma xenograft model. Increased CD24 gene expression was demonstrated in ependymomas, medulloblastomas, anaplastic astrocytomas and glioblastomas, although medulloblastomas displayed higher expression than all other tumor entities. Preferential expression of CD24 in medulloblastomas was confirmed at protein level by immunostaining and computerized image analysis of cryosections. Morphologies and immunophenotyping of CD24(+) cells in tissue sections tentatively suggested disparate functions in different tumor subsets. Notably, protein staining of medulloblastoma cells was associated with prominent cytoplasmic and membranous granules, enabling rapid and robust identification of medulloblastoma cells in clinical tissue samples, as well as in experimental model systems. In conclusion, our results implicate CD24 as a clinically and experimentally useful medulloblastoma immunomarker. Although our results encourage further functional studies of CD24 as a potential molecular target in subsets of brain tumors, the promiscuous expression of CD24 in vivo highlights the importance of specificity in the future design of such targeted treatment. PMID- 25820322 TI - Evidence that periweaning failure-to-thrive syndrome (PFTS) has a genetic predisposition. AB - Genetic susceptibility or resistance to diseases is currently drawing increasing attention. This work describes two different breeding herds showing signs of periweaning failure-to-thrive syndrome (PFTS), an emergent swine disease. The disease was diagnosed based on clinical picture and confirmed by histopathology. The possibility of main infectious pathogens was ruled out by immunohistochemistry and PCR. In a simple approach, sires of the affected piglets have been determined using microsatellite paternity analysis, including a healthy group in each case. In each of the two farms, a single boar was found to have sired 45-50 per cent sick animals. Removal of this sire from two farms resulted in a significant decrease in the prevalence of the disease among the offspring, in accordance with other two cases diagnosed, although without including a control group. Since the analysed animals belonged to three different genetic lines, these findings point to the existence of individual genetic susceptibility to this syndrome. PMID- 25820323 TI - Decreased dose of radiation to dogs during acquisition of elbow radiographs using draped shielding. AB - Protective lead equivalent shielding of patients is not routinely used in veterinary radiology. The goal of this study was to determine whether the use of lead equivalent shielding results in a significant reduction in dose of radiation to dogs during acquisition of elbow radiographs. The authors measured radiation doses in the primary beam and over and under protective lead equivalent shielding that was placed at the level of the eyes, body and gonads during acquisition of elbow radiographs using 0.01 mSv sensitivity dosimetry badges. Shielding consisted of 0.5 mm lead equivalent aprons and thyroid shields placed over bodies and eyes, respectively. All badges in the primary beam-detected radiation. Shielding significantly decreased the dose of radiation with significantly less scatter and tube leakage radiation detected under compared with over shielding (P=0.0001). The dose of radiation detected over shielding was significantly greater than zero (P=0.0001), while that under shielding did not differ significantly from zero (P=0.09). Based on these results, the authors recommend protective shielding be used on veterinary patients during radiography. PMID- 25820324 TI - Relationship between age at gonadectomy and health problems in kittens adopted from shelters. AB - Prepubertal gonadectomy (PPG) is promoted as a way of managing overpopulation in cats, but concerns about PPG and potential health issues still exist. The objective of the present study was to evaluate short-term and long-term health problems in cats subjected to PPG in comparison to gonadectomy at traditional age (TAG). In a prospective clinical trial, 800 shelter kittens aged between approximately 8 weeks and 12 weeks were recruited before adoption and randomly assigned to either the PPG group (gonadectomy performed immediately) or the TAG group (gonadectomy delayed until six months to eight months of age). Short-term health issues included mortality between when kittens arrived at the clinic and up to seven days after they returned to the shelter, as well as the occurrence of various other health issues arising in the first month following adoption. Kittens were followed-up until 24 months of age specifically for feline lower urinary tract disease, urethral obstruction (male cats), lameness, fractures and hypersensitivity disorders with dermatological presentation. In the short term, there were no significant differences between health problems in PPG and TAG kittens. Similarly, no significant differences were observed between treatment groups in terms of the type or number of health issues in the long term. In conclusion, there are no health-related contraindications to advocating PPG strategies in shelter cats. Ideally, PPG should be performed at the shelter facility itself as long as excellent infectious disease control and postoperative clinical observation before adoption are guaranteed. PMID- 25820325 TI - Canine hip dysplasia in Tibetan terriers. PMID- 25820327 TI - Microwave-assisted hydrothermal synthesis of Cu/Cu2O hollow spheres with enhanced photocatalytic and gas sensing activities at room temperature. AB - Cu/Cu2O nano-heterostructure hollow spheres with a submicron diameter (200-500 nm) were prepared by a microwave-assisted hydrothermal method using Cu(OAc)2.H2O, PVP and ascorbic acid solution as the precursors. The morphology of the products could evolve with the hydrothermal time from solid spheres to thick-shell hollow spheres, then to thin-shell hollow spheres, and finally to nanoparticles. Moreover, the content of Cu in the products could be controlled by adjusting the hydrothermal time. The spontaneous forming of the hollow structure spheres was found to result from the Ostwald ripening effect during the low temperature (100 degrees C) hydrothermal reaction process. The photocatalytic degradation activities on MO under visible-light irradiation and the gas sensing activities toward the oxidizing NO2 gas of different Cu/Cu2O nano-heterostructure hollow spheres were investigated. As a result, the Cu/Cu2O nano-heterostructure hollow spheres obtained at the hydrothermal time of 30 min, with a rough/porous thin shell structure and a Cu content of about 10.5 wt%, exhibited the best photocatalytic and gas sensing performances compared with others. PMID- 25820326 TI - Ability of the gut microbiota to produce PUFA-derived bacterial metabolites: Proof of concept in germ-free versus conventionalized mice. AB - SCOPE: The gut microbiota is able to modulate host physiology through the production of bioactive metabolites. Our recent studies suggest that changes in gut microbiota composition upon prebiotics supplementation alter tissue levels of PUFA-derived metabolites in mice. However, in vivo evidence that gut microbes produces PUFA-derived metabolites is lacking. This study aimed to decipher the contribution of gut microbes versus that of the host in PUFA-derived metabolite production. METHODS AND RESULTS: To achieve this goal, we compared the proportion of PUFA-derived metabolites and the expression of fatty acid desaturases in germ free (GF) and conventionalized (CONV) mice fed either a low fat or Western diet. Higher concentrations of PUFA-derived metabolites were found in the colonic contents of conventionalized mice (CONV) mice compared to GF mice. The abundance of these metabolites in host tissues was modulated by dietary treatments but not by microbial status. Although microbial status did significantly influence desaturase expression, no correlations between host enzymes and tissue PUFA derived metabolite levels were observed. CONCLUSION: Together, these results highlight the ability of the gut microbiota to produce PUFA-derived metabolites from dietary PUFA. However, microbial production of these metabolites in colonic contents is not necessarily associated with modifications of their concentration in host tissues. PMID- 25820329 TI - Advancing ethical neuroscience. PMID- 25820328 TI - A novel PKD2L1 C-terminal domain critical for trimerization and channel function. AB - As a transient receptor potential (TRP) superfamily member, polycystic kidney disease 2-like-1 (PKD2L1) is also called TRPP3 and has similar membrane topology as voltage-gated cation channels. PKD2L1 is involved in hedgehog signaling, intestinal development, and sour tasting. PKD2L1 and PKD1L3 form heterotetramers with 3:1 stoichiometry. C-terminal coiled-coil-2 (CC2) domain (G699-W743) of PKD2L1 was reported to be important for its trimerization but independent studies showed that CC2 does not affect PKD2L1 channel function. It thus remains unclear how PKD2L1 proteins oligomerize into a functional channel. By SDS-PAGE, blue native PAGE and mutagenesis we here identified a novel C-terminal domain called C1 (K575-T622) involved in stronger homotrimerization than the non-overlapping CC2, and found that the PKD2L1 N-terminus is critical for dimerization. By electrophysiology and Xenopus oocyte expression, we found that C1, but not CC2, is critical for PKD2L1 channel function. Our co-immunoprecipitation and dynamic light scattering experiments further supported involvement of C1 in trimerization. Further, C1 acted as a blocking peptide that inhibits PKD2L1 trimerization as well as PKD2L1 and PKD2L1/PKD1L3 channel function. Thus, our study identified C1 as the first PKD2L1 domain essential for both PKD2L1 trimerization and channel function, and suggest that PKD2L1 and PKD2L1/PKD1L3 channels share the PKD2L1 trimerization process. PMID- 25820330 TI - The relation between measures of cognitive and motor functioning in 5- to 6-year old children. AB - Specific relations between executive functions (working memory capacity, planning and problem-solving, inhibitory control) and motor skill performance (anticipatory motor planning, manual dexterity) were examined in 5- to 6-year-old children (N = 40). Results showed that the two motor skill components were not correlated. Additionally, it was found that response planning performance was a significant predictor of anticipatory motor planning performance, whereas inhibitory control and working memory capacity measures were significant predictors of manual dexterity scores. Taken together, these results suggest that cognitive and motor skills are linked, but that manual dexterity and anticipatory motor planning involve different specialized skills. The current study provides support for specific relations between cognitive and motor performance, which has implications for early childhood cognitive-motor training and intervention programs. PMID- 25820331 TI - Calibrating Independence Goals and Partner Support: Couples Adjust to Functional Limitations after Tumor Surgery. AB - BACKGROUND: When patients recover from disease-related functional limitations, support received from partners may not always match patients' changing independence goals. The lines of defense (LoD) model proposes a hierarchy of independence goals (LoDs), ranging from minimising discomfort by disengagement (lowest LoD) to protection of self-reliance (highest LoD). Prostate cancer patients' LoDs were examined as moderators of the association between partner support and patients' and partners' affect during patients' recovery from postsurgical functional limitations. METHODS: Data from 169 couples were assessed four times within 7 months following patients' surgery. Patients reported on post surgery functional limitations (i.e. incontinence), LoDs, affect, and received partner support. Partners reported on affect and support provided to patients. RESULTS: In patients endorsing lower LoDs, more received support was associated with less negative affect. Also, not endorsing high LoDs while receiving strong partner support was related to patients' lower negative and higher positive affect. Partners' support provision to patients tended to be associated with increases in partners' negative affect when patients had endorsed higher LoDs and with increases in positive affect when patients had endorsed lower LoDs. CONCLUSIONS: Matching patients' independence goals or LoDs with partners' support may be beneficial for patients' and partners' affect. PMID- 25820332 TI - Experience with HSP90 inhibitor AUY922 in patients with relapsed or refractory non-Hodgkin lymphoma. PMID- 25820333 TI - Imatinib-treated chronic myeloid leukemia patients with discordant response between cytogenetic and molecular tests at 3 and 6 month time-points have a reduced probability of subsequent optimal response. PMID- 25820334 TI - Azacitidine as post-remission consolidation for sorafenib-induced remission of Fms-like tyrosine kinase-3 internal tandem duplication positive acute myeloid leukemia. PMID- 25820335 TI - Efficacy of single versus boost vaccination against influenza virus in patients with multiple myeloma. PMID- 25820337 TI - Hypertrophic preconditioning: short-term tricks for long-term gain. PMID- 25820338 TI - Metabolic switching: synergistic induction of carotenogenesis in the aerial microalga, Vischeria helvetica, under environmental stress conditions by inhibitors of fatty acid biosynthesis. AB - OBJECTIVES: To investigate the roles of fatty acid biosynthesis in carotenogenesis in the high-lipid accumulating aerial microalga Vischeria helvetica KGU-Y001, we cultured algal cells with fatty acid biosynthesis inhibitors. RESULTS: Under nitrogen-deficient, high-light (200 umol photons m(-2) s(-1)) conditions, the alga accumulated 6.2 mg carotenoids g(-1) dry weight cells (DWC) after 1 week of culture. The total fatty acid content increased gradually, and reached 290 mg g(-1) DWC after 9 weeks. When algal cells were cultured with a fatty acid biosynthesis inhibitor (molinate) under nitrogen-deficient, high-light conditions for 1 week, carotenoid accumulation was synergistically increased to 2.4 times that in algal cells cultured without the inhibitor in nitrogen deficient, low-light conditions (40 umol photons m(-2) s(-1)). The synergistic induction of carotenogenesis was suppressed by an inhibitor of c-jun N-terminal kinase, a mitogen-activated protein kinase-like protein. CONCLUSION: In a commercial context, carotenoid production could be increased by using fatty acid biosynthesis inhibitors to redirect metabolic flux to carotenoid biosynthesis instead of fatty acid synthesis. PMID- 25820336 TI - Myocardial Hypertrophic Preconditioning Attenuates Cardiomyocyte Hypertrophy and Slows Progression to Heart Failure Through Upregulation of S100A8/A9. AB - BACKGROUND: Transient preceding brief ischemia provides potent cardioprotection against subsequent long ischemia, termed ischemic preconditioning. Here, we hypothesized that transient short-term hypertrophic stimulation would induce the expression of hypertrophy regression genes and render the heart resistant to subsequent hypertrophic stress, and slow the progression to heart failure, as well. METHODS AND RESULTS: Cardiomyocyte hypertrophy was induced in mice by either transverse aortic constriction or an infusion of phenylephrine, and in neonatal rat ventricular cardiomyocytes by norepinephrine exposures. In the preconditioning groups, hypertrophic stimulation was provided for 1 to 7 days and then withdrawn for several days by either aortic debanding or discontinuing phenylephrine or norepinephrine treatment, followed by subsequent reexposure to the hypertrophic stimulus for the same period as in the control group. One or 6 weeks after transverse aortic constriction, the heart weight/body weight ratio was lower in the preconditioning group than in the control group, whereas the lung weight/body weight ratio was significantly decreased 6 weeks after transverse aortic constriction. Similar results were obtained in mice receiving phenylephrine infusion and neonatal rat ventricular cardiomyocytes stimulated with norepinephrine. Both mRNA and protein expression of S100A8 and S100A9 showed significant upregulation after the removal of hypertrophic stimulation and persisted for 6 weeks in response to reimposition of transverse aortic constriction. The treatment with recombinant S100A8/A9 inhibited norepinephrine induced myocyte hypertrophy and reduced the expression of calcineurin and NFATc3, but the silencing of S100A8/A9 prevented such changes. CONCLUSIONS: Preconditioning with prohypertrophic factors exerts an antihypertrophic effect and slows the progression of heart failure, indicating the existence of the phenomenon for hypertrophic preconditioning. PMID- 25820339 TI - Surveying treatment preferences in U.S. Iraq-Afghanistan Veterans with PTSD symptoms: a step toward veteran-centered care. AB - This study examined health care barriers and preferences among a self-selected sample of returning U.S. veterans drawn from a representative, randomly selected frame surveyed about posttraumatic stress disorder (PTSD) symptomatology and mental health utilization in the prior year. Comparisons between treated (n = 160) and untreated (n = 119) veterans reporting PTSD symptoms were conducted for measures of barriers and preferences, along with logistic models regressing mental health utilization on clusters derived from these measures. Reported barriers corroborated prior research findings as negative beliefs about treatment and stigma were strongly endorsed, but only privacy concerns were associated with lower service utilization (B = -0.408, SE = 0.142; p = .004). The most endorsed preference (91.0%) was for assistance with benefits, trailed by help for physical problems, and particular PTSD symptoms. Help-seeking veterans reported stronger preferences for multiple interventions, and desire for services for families (B = 0.468, SE = 0.219; p = .033) and specific PTSD symptoms (B = 0.659, SE = 0.302; p = .029) were associated with increased utilization. Outcomes of the study suggested PTSD severity drove help-seeking in this cohort. Results also support the integration of medical and mental health services, as well as coordination of health and benefits services. Finally, the study suggested that outreach about privacy protections and treatment options could well improve engagement in treatment. PMID- 25820340 TI - Analysis of underivatized cellodextrin oligosaccharides by capillary electrophoresis with direct photochemically induced UV-detection. AB - This work focuses on the development of a CE method allowing, for the first time, the simultaneous separation of the underivatized first seven cellodextrin oligomers (glucose, cellobiose, cellotriose, cellotetraose, cellopentaose, cellohexaose, and celloheptaose), with a view to analyze the hydrolysates obtained after partial acid depolymerization of nitrocellulose, and eight carbohydrates (ribose, xylose, fructose, mannose, galactose, maltose, lactose, and sucrose), which might be potential interfering compounds in explosives samples. Separation was achieved with a highly alkaline BGE containing sodium chloride and direct mid-UV-absorbance detection was performed after photo oxidation in the detection window. EOF was reversed to speed up the analysis using a dynamic capillary coating by hexadimethrine bromide. A central composite design was carried out to determine the effects of BGE conductivity and sodium hydroxide concentration on resolutions between neighboring peaks, and analysis time. A desirability analysis on modeled responses was applied to maximize resolutions and to minimize analysis time. The simultaneous analysis in 20 min total runtime of the 15 carbohydrates plus internal reference (naphthalene sulfonate) was carried out at 25 degrees C with a BGE composed of 77.4 mM NaOH and 183 mM NaCl to adjust the conductivity at the optimum value. Finally, the resolution robustness was checked. This new method should also be of interest to monitor food and nonfood crop products. PMID- 25820341 TI - The transverse diameter of the chest on routine radiographs reliably estimates gestational age and weight in premature infants. AB - BACKGROUND: Prior to digital radiography it was possible for a radiologist to easily estimate the size of a patient on an analog film. Because variable magnification may be applied at the time of processing an image, it is now more difficult to visually estimate an infant's size on the monitor. Since gestational age and weight significantly impact the differential diagnosis of neonatal diseases and determine the expected size of kidneys or appearance of the brain by MRI or US, this information is useful to a pediatric radiologist. Although this information may be present in the electronic medical record, it is frequently not readily available to the pediatric radiologist at the time of image interpretation. OBJECTIVE: To determine if there was a correlation between gestational age and weight of a premature infant with their transverse chest diameter (rib to rib) on admission chest radiographs. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, which waived informed consent. The maximum transverse chest diameter outer rib to outer rib was measured on admission portable chest radiographs of 464 patients admitted to the neonatal intensive care unit (NICU) during the 2010 calendar year. Regression analysis was used to investigate the association between chest diameter and gestational age/birth weight. Quadratic term of chest diameter was used in the regression model. RESULTS: Chest diameter was statistically significantly associated with both gestational age (P < 0.0001) and birth weight (P < 0.0001). CONCLUSION: An infant's gestational age and birth weight can be reliably estimated by comparing a simple measurement of the transverse chest diameter on digital chest radiograph with the tables and graphs in our study. PMID- 25820342 TI - Magnetic resonance imaging acquisition techniques intended to decrease movement artefact in paediatric brain imaging: a systematic review. AB - Attaining paediatric brain images of diagnostic quality can be difficult because of young age or neurological impairment. The use of anaesthesia to reduce movement in MRI increases clinical risk and cost, while CT, though faster, exposes children to potentially harmful ionising radiation. MRI acquisition techniques that aim to decrease movement artefact may allow diagnostic paediatric brain imaging without sedation or anaesthesia. We conducted a systematic review to establish the evidence base for ultra-fast sequences and sequences using oversampling of k-space in paediatric brain MR imaging. Techniques were assessed for imaging time, occurrence of movement artefact, the need for sedation, and either image quality or diagnostic accuracy. We identified 24 relevant studies. We found that ultra-fast techniques had shorter imaging acquisition times compared to standard MRI. Techniques using oversampling of k-space required equal or longer imaging times than standard MRI. Both ultra-fast sequences and those using oversampling of k-space reduced movement artefact compared with standard MRI in unsedated children. Assessment of overall diagnostic accuracy was difficult because of the heterogeneous patient populations, imaging indications, and reporting methods of the studies. In children with shunt-treated hydrocephalus there is evidence that ultra-fast MRI is sufficient for the assessment of ventricular size. PMID- 25820343 TI - Estimating the within-household infection rate in emerging SIR epidemics among a community of households. AB - This paper is concerned with estimation of the within-household infection rate gammaL for a susceptible --> infective --> recovered epidemic among a population of households, from observation of the early, exponentially growing phase of an epidemic. Specifically, it is assumed that an estimate of the exponential growth rate is available from general data on an emerging epidemic and more-detailed, household-level data are available in a sample of households. Estimates of gammaL obtained using the final size distribution of single-household epidemics are usually biased owing to the emerging nature of the epidemic. A new method, which accounts correctly for the emerging nature of the epidemic, is developed by exploiting the asymptotic theory of supercritical branching processes and proved to yield a strongly consistent estimator of gammaL as the population and sampled households both tend to infinity in an appropriate fashion. The theory is illustrated by simulations which demonstrate that the new method is feasible for finite populations and numerical studies are used to explore how changes to the parameters governing the spread of an epidemic affect the bias of estimates based on single-household final size distributions. PMID- 25820344 TI - Microfluidic Organ-on-a-Chip Technology for Advancement of Drug Development and Toxicology. AB - In recent years, the exploitation of phenomena surrounding microfluidics has seen an increase in popularity, as researchers have found a way to use their unique properties to create superior design alternatives. One such application is representing the properties and functions of different organs on a microscale chip for the purpose of drug testing or tissue engineering. With the introduction of "organ-on-a-chip" systems, researchers have proposed various methods on various organ-on-a-chip systems to mimic their in vivo counterparts. In this article, a systematic approach is taken to review current technologies pertaining to organ-on-a-chip systems. Design processes with attention to the particular instruments, cells, and materials used are presented. PMID- 25820345 TI - Patient-controlled analgesia at the end of life at a pediatric oncology institution. AB - BACKGROUND: Patient controlled anesthesia (PCA) is increasingly used to manage pain in pediatric cancer patients and is important in the treatment of escalating pain at the end of life. The description of the use of opioid PCA in this population has been limited. PROCEDURE: This retrospective chart review of the last 2 weeks of life addressed the following objectives: (1) to describe the patient population treated with opioid PCA; (2) to describe the morphine equivalent doses (MED) (mg/kg/day); and (3) to describe the pain scores (PS). RESULTS: Twenty-eight percent of inpatients used opioid PCA for pain control during the last 2 weeks of life. The mean MED (mg/kg/day) (SD) at 2 weeks prior and the day of death were 10.7 (17.9) and 19 (25.8). The mean MED increased over the last 2 weeks of life for all patients and across age groups and cancer diagnoses (all P < 0.05). The mean MED was significantly higher in the younger age group (age <13 vs. age >= 13) on the day of death (P < 0.04). There was a significant change in mean PS over the last 2 weeks of life (P < 0.001), with the highest PS on the day before death. The most frequently used concurrent medications were benzodiazepines (91%). CONCLUSIONS: Children and young adults with cancer experience high opioid requirements and significant dose increases during the last 2 weeks of life. Additionally, PS increase toward the end of life. Opioid rotation and addition of adjuvant medications merit consideration in the context of escalating opioid requirements. PMID- 25820347 TI - The gene encoding the mouse contactin-1 axonal glycoprotein is regulated by the collier/Olf1/EBF family early B-Cell factor 2 transcription factor. AB - The Contactin-1 axonal glycoprotein (formerly F3/Contactin) plays a relevant role in cerebellar ontogenesis, as shown in Contactin-1 KO-mice and in transgenic mice misexpressing the corresponding cDNA from a heterologous promoter. Likewise, null mutant mice for the Collier/Olf1/Early B-cell family transcription factor EBF2, in which Purkinje neuron development is primarily affected, exhibit abnormalities in cerebellar corticogenesis. Here, to evaluate the contribution to the Ebf2 null phenotype of changes in the profile of Contactin-1, we study its expression in Ebf2 null mice. In addition, we explore the activation profile of the Cntn1 gene promoter upon transferring the Ebf2 mutation to transgenic mice expressing an enhanced green fluorescent protein reporter under control of Cntn1 gene regulatory sequences. In Ebf2 null mice, Contactin-1 protein expression and Cntn1 gene promoter activity are both downregulated during embryonic and early postnatal cerebellar development, both in the rostral and caudal folia, while in the latter an upregulation is observed at postnatal day 8. In vitro, vectors driving EBF1,2,3 transcription factors from a cytomegalovirus (CMV) promoter transactivate a Cntn1-Choline acetyltransferse (CAT) promoter-reporter construct in cotransfection assays and, accordingly, by chromatin immunoprecipitation, we show that the Cntn1 gene 5' flanking region is bound by the EBF2 transcription factor, consistent with the evidence that this region bears the cognate deoxyribonucleic acid (DNA) consensus sequences. These data indicate that Contactin-1 expression is dependent upon EBF factors, suggesting that the Cntn1 gene belongs to the expanding regulatory cascade driven by these transcriptional regulators so that changes in its activation may contribute to the phenotype of Ebf2 null mutant mice. PMID- 25820346 TI - Acid-base and electrolyte abnormalities in heart failure: pathophysiology and implications. AB - Electrolyte and acid-base abnormalities are a frequent and potentially dangerous complication in subjects with congestive heart failure. This may be due either to the pathophysiological alterations present in the heart failure state leading to neurohumoral activation (stimulation of the renin-angiotensin-aldosterone system, sympathoadrenergic stimulation), or to the adverse events of therapy with diuretics, cardiac glycosides, and ACE inhibitors. Subjects with heart failure may show hyponatremia, magnesium, and potassium deficiencies; the latter two play a pivotal role in the development of cardiac arrhythmias. The early identification of these alterations and the knowledge of the pathophysiological mechanisms are very useful for the management of these patients. PMID- 25820348 TI - Designed synthesis of a series of zwitterion-polyoxometalate hybrid materials for selective scavenging and photolysis of dyes. AB - Zwitterions and polyoxometalates (POMs) are two kinds of functional moieties with very different properties for applications in different fields. We have developed an effective strategy to successfully immobilize these two different moieties into the frameworks of porous hybrid materials, in which the POM units act as templates and photoactive moieties. These hybrid materials demonstrate remarkable efficiency for selective scavenging and photolysis of cationic dyes from polluted water, and up to 10% dye uptake and quantitative photolysis of dyes have been realized. PMID- 25820350 TI - Causal relevance of circulating high-density lipoprotein cholesterol with cancer: a Mendelian randomization meta-analysis. AB - We summarized published data on the associations of apolipoprotein E (APOE) gene epsilon2/epsilon3/epsilon4 polymorphism with both cancer risk and circulating lipid profiles, aiming to examine the causal relevance between lipids and cancer risk. Article identification and data abstraction were conducted in duplicate and independently by two authors. Data were analyzed by STATA software. Twenty-five articles that examined the associations of APOE gene epsilon2/epsilon3/epsilon4 polymorphism with either cancer risk (n = 22) or circulating lipid changes (n = 4) were eligible. The presence of epsilon2 and epsilon4 alleles showed no overall associations with overall cancer risk when compared with epsilon3 allele. The epsilon4 allele was significantly associated with 1.40-fold (odds ratio or OR = 1.40; 95% confidence interval or CI: 1.00-1.94; P = 0.047) increased risk of developing cancer in Asian populations, and the presence of heterogeneity was low (I(2) = 37.6%). Carriers of epsilon3/epsilon4 genotype had a significant reduction in circulating HDL-C (WMD = -2.62; 95% CI: -4.19 to -1.04; P = 0.001) without heterogeneity (I(2) = 16.6%). The predicted odds of having cancer for 1 mg/dL reduction in circulating HDL-C was 1.14 (95% CI: 1.00 to 1.89). The findings of this Mendelian randomization meta-analysis demonstrate that reduced circulating HDL-C might be a potentially causal risk factor for the development of overall cancer in Asians. PMID- 25820351 TI - Selective serotonin reuptake inhibitors and beta-blocker transformation products may not pose a significant risk of toxicity to aquatic organisms in wastewater effluent-dominated receiving waters. AB - A probabilistic ecological risk assessment was conducted for the transformation products (TPs) of 3 beta-blockers (atenolol, metoprolol, and propranolol) and 5 selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) to assess potential threats to aquatic organisms in effluent-dominated surface waters. To this end, the pharmacokinetic literature, the University of Minnesota's Biocatalysis/Biodegradation Database Pathway Prediction System aerobic microbial degradation software, and photolysis literature pertaining to beta-blockers and SSRIs were used to determine their most likely TPs formed via human metabolism, aerobic biodegradation, and photolysis, respectively. Monitoring data from North American and European surface waters receiving human wastewater inputs were the basis of the exposure characterizations of the parent compounds and the TPs, where available. In most cases, where monitoring data for TPs did not exist, we assumed a conservative 1:1 parent-to-TP production ratio (i.e., 100% of parent converted). The US Environmental Protection Agency (USEPA)'s EPISuite and ECOSAR v1.11 software were used to estimate acute and chronic toxicities to aquatic organisms. Hazard quotients, which were calculated using the 95(th) percentile of the exposure distributions, ranged from 10(-11) to 10(-3) (i.e., all significantly less than 1). Based on these results, the TPs of interest would be expected to pose little to no environmental risk in surface waters receiving wastewater inputs. Overall, we recommend developing analytical methods that can isolate and quantify human metabolites and TPs at environmentally relevant concentrations to confirm these predictions. Further, we recommend identifying the major species of TPs from classes of pharmaceuticals that could elicit toxic effects via specific modes of action (e.g., norfluoxetine via the serotonin 5-hydroxytryptamine [5-HT]1A receptors) and conducting aquatic toxicity tests to confirm these findings. To our knowledge, this is the first quantitative probabilistic ecotoxicological assessment of all of the predicted and probable TPs of these pharmaceuticals, and our approach provides a framework for future such studies with other compound classes as data become available. PMID- 25820349 TI - Controlled expression of Drosophila homeobox loci using the Hostile takeover system. AB - BACKGROUND: Hostile takeover (Hto) is a Drosophila protein trapping system that allows the investigator to both induce a gene and tag its product. The Hto transposon carries a GAL4-regulated promoter expressing an exon encoding a FLAG mCherry tag. Upon expression, the Hto exon can splice to a downstream genomic exon, generating a fusion transcript and tagged protein. RESULTS: Using rough-eye phenotypic screens, Hto inserts were recovered at eight homeobox or Pax loci: cut, Drgx/CG34340, Pox neuro, araucan, shaven/D-Pax2, Zn finger homeodomain 2, Sex combs reduced (Scr), and the abdominal-A region. The collection yields diverse misexpression phenotypes. Ectopic Drgx was found to alter the cytoskeleton and cell adhesion in ovary follicle cells. Hto expression of cut, araucan, or shaven gives phenotypes similar to those of the corresponding UAS cDNA constructs. The cut and Pox neuro phenotypes are suppressed by the corresponding RNAi constructs. The Scr and abdominal-A inserts do not make fusion proteins, but may act by chromatin- or RNA-based mechanisms. CONCLUSIONS: Hto can effectively express tagged homeodomain proteins from their endogenous loci; the Minos vector allows inserts to be obtained even in transposon cold-spots. Hto screens may recover homeobox genes at high rates because they are particularly sensitive to misexpression. PMID- 25820352 TI - Radiographic outcomes of anterior column realignment for adult sagittal plane deformity: a multicenter analysis. AB - PURPOSE: Anterior column reconstruction (ACR) is a minimally invasive technique for the treatment of sagittal plane deformity. ACR uses a lateral transpsoas approach with ALL release and the application of an interbody device to achieve correction. Here, we present 1-year radiographic results from a multicenter study of adult spinal deformity (ASD) patients. METHODS: A multicenter database was queried from 2005 to 2013 for ASD patients treated with ACR. Demographics, surgical data, and radiographic measurements were collected and retrospectively analyzed. Radiographic time points included preoperative (pre-op), postoperative (post-op; first visit prior to 3 months), and last follow-up (last FU; minimum of 1 year). Sagittal radiographic measurements included regional lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), T1 spinopelvic inclination (T1SPi), and segmental lordosis (disc angle). RESULTS: Mean patient age was 67.4 years (range 46.5-80.0) and 11 patients (32.4 %) were male. Twenty patients (58.8 %) had previous lumbar surgery. All patients had a minimal of one level ACR with ALL release (mean 1.7; range 1-4). Mean number of lateral interbody fusion (LLIF) levels without ALL release per patient was 0.7 (range 0 3). Thirty-three patients (97.1 %) received supplemental posterior fixation and 1 patient (2.9 %) had lateral fixation only. In 26 patients (76.5 %), supplemental posterior fixation was performed using an open approach, and 7 patients (20.6 %) were treated with percutaneous placement. Mean of number of levels fused was 7.1 (range 2-16). There was a significant improvement in LL (p < 0.001), PI-LL mismatch (p < 0.001), and PT (p = 0.03) from pre-op to post-op, and pre-op to last FU. There was no change in T1SPi, SS, or PI. Segmental lordosis improved at ACR levels from mean of -2.2 degrees pre-op to -16.0 degrees post-op (p < 0.01) and -16.3 degrees at last FU (p < 0.001). The addition of posterior column osteotomy increased the change in segmental lordosis with ACR by 72.7 % (p < 0.001). LLIF without ALL release led to significant improvement in segmental lordosis from pre-op (-2.4 degrees ) to post-op (-7.1 degrees ; p < 0.01) but not from pre-op to last FU (-5.7 degrees ; p = 0.06). CONCLUSION: ACR successfully restores lumbar lordosis in ASD patients with sagittal imbalance. ACR results in greater segmental correction than is achieved with LLIF alone. Supplementing with posterior osteotomies allows for even greater correction. The ability to achieve the desired radiographic goals is expected to improve as technical nuances are refined and patient selection is optimized. PMID- 25820353 TI - Comparison of MIS vs. open PLIF/TLIF with regard to clinical improvement, fusion rate, and incidence of major complication: a meta-analysis. AB - PURPOSE: Meta-analysis was conducted to estimate whether MiTLIF could reduce the complication rate while maintaining the similar clinical result to that of open procedures. METHODS: A search of the literature was conducted on pubmed or EMBASE. A database including patient clinical information was created. A systematic review of eligible studies with multivariate regression analysis was performed to quantitatively review the correlation of VAS improvement rate and the performance of MiTLIF. RESULTS: Fourteen articles with a minimum of 12-month follow-up met our inclusion criteria. The hypothesis of homogeneity could be accepted. The fixed-effects model was used to calculate the summary risk ratio (odds ratio). In the pooled analysis, the summary risk ratio (odds ratio) in patients with MiTLIF against those with open procedure for fusion rate, complication rate and revision/readmission rate was 0.99 (p = 0.36), 1.15 (p = 0.5) and 2.59 (p = 0.003), respectively, suggesting that MiTLIF was a risk factor for revision/readmission. Multivariate regression analysis showed that the percentage of male patients and the length of surgery exert a significant impact on VAS improvement rate. The selection of MiTLF was not significant. CONCLUSION: Fusion rate and complication rate for both open and MiTLIF were similar. Moreover, the MiTLIF group tended to have a higher revision/readmission rate, which might be associated with the deep learning curve. Therefore, to achieve the level of surgical skill required of an MiTLIF surgeon, many years of training and experience are necessary. Otherwise, MiTLIF may yield unsatisfactory result upon patients. PMID- 25820355 TI - Genome-wide analysis and differential expression of chitinases in banana against root lesion nematode (Pratylenchus coffeae) and eumusa leaf spot (Mycosphaerella eumusae) pathogens. AB - Knowledge on structure and conserved domain of Musa chitinase isoforms and their responses to various biotic stresses will give a lead to select the suitable chitinase isoform for developing biotic stress-resistant genotypes. Hence, in this study, chitinase sequences available in the Musa genome hub were analyzed for their gene structure, conserved domain, as well as intron and exon regions. To identify the Musa chitinase isoforms involved in Pratylenchus coffeae (root lesion nematode) and Mycosphaerella eumusae (eumusa leaf spot) resistant mechanisms, differential gene expression analysis was carried out in P. coffeae- and M. eumusae-challenged resistant and susceptible banana genotypes. This study revealed that more number of chitinase isoforms (CIs) were responses upon eumusa leaf spot stress than nematode stress. The nematode challenge studies revealed that class II chitinase (GSMUA_Achr9G16770_001) was significantly overexpressed with 6.75-fold (with high fragments per kilobase of exon per million fragments mapped (FPKM)) in resistant genotype (Karthobiumtham-ABB) than susceptible (Nendran-AAB) genotype, whereas when M. eumusae was challenge inoculated, two class III CIs (GSMUA_Achr9G25580_001 and GSMUA_Achr8G27880_001) were overexpressed in resistant genotype (Manoranjitham-AAA) than the susceptible genotype (Grand Naine-AAA). However, none of the CIs were found to be commonly overexpressed under both stress conditions. This study reiterated that the chitinase genes are responding differently to different biotic stresses in their respective resistant genotypes. PMID- 25820354 TI - Clinical outcomes and toxicity after exclusive versus postoperative radiotherapy in supraglottic cancer: new solutions for old problems? The case of stage I and II disease. AB - PURPOSE: To compare acute and late toxicities, survival, and laryngeal preservation after radiotherapy alone (RR) or radiotherapy after partial laryngectomy (PLR) in early supraglottic laryngeal cancer. MATERIALS AND METHODS: From 1984 to 2012, 172 patients were treated in our department. We analyzed and compared toxicities (CTCAE v 4.0), overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), metastasis-free survival (MFS), and the number of salvage total laryngectomies. RESULTS: Patients in the RR group were older (p = 0.05) and had more often comorbidities (p = 0.025); those in the PLR group had mostly T2 disease (p = 0.014). No difference in number of local, nodal, and distant recurrences was found. A higher incidence of late mild dry mouth in patients treated with RR (38 vs. 4 %, p = 0.000) was reported. At univariate analysis, only a younger age, a better performance status, and the absence of comorbidities favorably impacted on OS and DSS. No differences were found in DFS, LRFS, NRFS, MFS, and the number of rescue laryngectomies between the two groups. Younger age and a good performance status persisted as a predictive factor of better survival (OS and DSS) at multivariate analysis. CONCLUSION: Radical radiotherapy appears to be a viable alternative to conservative surgery, even in elderly patients with poor performance status and comorbidities. Salvage laryngectomy in the RR group was compared favorably with those reported in other conservative surgery series and in the group treated postoperatively of our series. PMID- 25820356 TI - Comparison and evaluation of two diagnostic methods for detection of npt II and GUS genes in Nicotiana tabacum. AB - To diminish the time required for some diagnostic assays including polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP) and also a visual detection protocol on the basis of npt II and GUS genes in transgenic tobacco plants were used. Agrobacterium tumefaciens-mediated transformation of Nicotiana tabacum leaf discs was performed with plant transformation vector of pBI 121. From kanamycin-resistant plants selected by their antibiotic resistance, four plants were selected for DNA isolation. Presence of the transgene was confirmed in the transformants by PCR and LAMP. In this regard, all LAMP and PCR primers were designed on the basis of the gene sequences of npt II and GUS. The LAMP assay was applied for direct detection of gene marker from plant samples without DNA extraction steps (direct LAMP assay). Also, a novel colorimetric LAMP assay for rapid and easy detection of npt II and GUS genes was developed here, its potential compared with PCR assay. The LAMP method, on the whole, had the following advantages over the PCR method: easy detection, high sensitivity, high efficiency, simple manipulation, safety, low cost, and user friendly. PMID- 25820357 TI - Effects of C-terminal domain truncation on enzyme properties of Serratia marcescens chitinase C. AB - A chitinase gene (SmChiC) and its two C-terminal truncated mutants, SmChiCG426 and SmChiCG330 of Serratia marcescens, were constructed and cloned by employing specific polymerase chain reaction (PCR) techniques. SmChiCG426 is derived from SmChiC molecule without its C-terminal chitin-binding domain (ChBD) while SmChiCG330 is truncated from SmChiC by its C-terminal deletion of both ChBD and fibronectin type III domain (FnIII). To study the role of the C-terminal domains of SmChiC on the enzyme properties, SmChiC, SmChiCG426, and SmChiCG330 were expressed in Escherichia coli by using the pET-20b(+) expression system. The His tag affinity-purified SmChiC, SmChiCG426, and SmChiCG330 enzymes had a calculated molecular mass of 51, 46, and 36 kDa, respectively. Certain biochemical characterizations indicated that the enzymes had similar physicochemical properties, such as the optimum pH (5), temperature (37 degrees C), thermostability (50 degrees C), and identical hydrolyzing product (chitobiose) from both the soluble and insoluble chitin substrates. The overall catalytic efficiency k cat /K M was higher for both truncated enzymes toward the insoluble alpha-chitin, whereas the binding abilities toward the insoluble alpha-chitin substrate were reduced moderately. The fluorescence and circular dichroism (CD) spectroscopy data suggested that both mutants retained a similar folding conformation as that of the full-length SmChiC enzyme. However, a CD-monitored melting study showed that the SmChiCG330 had no obvious transition temperature, unlike the SmChiC and SmChiCG426. PMID- 25820358 TI - Increased vulnerability to physical stress by inactivation of NdgR in Streptomyces coelicolor. AB - The antibiotic production and spore formation process in Streptomyces coelicolor need complex decision making processes by several regulatory units. These regulatory units are involved in both primary and secondary metabolism. As a result, most regulators have several functions, and those are worthwhile themes to study about different functions of a known regulator. In this study, a deletion mutant of ndgR, which encodes the nitrogen-dependent growth regulator, was examined by the cell viability test, TEM, and growth in N acetylglucosamine/asparagine (GlcNAc/Asn) liquid medium. The results of the study show that NdgR is also involved in the structure of the cell membrane affecting survival under physical shocks. Deletion of ndgR leads to abnormal cell membrane resulting in the vulnerable cells to physical stress caused by shaking with beads in liquid culture condition. This empirical observation is the first meaningful explanation to why ndgR mutant could not grow well in a liquid minimal medium due to the defect of N-acetylglucosamine (GlcNAc) utilization and phospholipid synthesis. PMID- 25820359 TI - Enhanced expression of bioactive recombinant VEGF-111 with insertion of intronic sequence in mammalian cell lines. AB - Among all VEGF-A isoforms, VEGF-111 is particularly important in molecular biology research owing to its potent angiogenic properties and its remarkable resistance to proteolysis. These features make it a potential candidate for therapeutic use in ischemic diseases. VEGF-111 is not expressed in normal cells, but expression is induced by UV-B irradiation and exposure to genotoxic agents. Here, to increase expression at the transcriptional and translational levels, we synthesized and cloned recombinant VEGF-111 cDNA. Two fragments encoding exons 1 4 and intron 4/5 plus exon 8a were amplified and cloned into the pBud.CE4.1 vector using a class IIs restriction enzyme-based method. The expression of VEGF 111 in CHO-dhfr - and HEK 293 cell lines was evaluated with real-time PCR, dot blotting, and ELISA. VEGF expression was increased about 10- and 18-fold in transfected CHO-dhfr - and HEK 293 cells, respectively. Dot blotting and ELISA confirmed successful production of VEGF-111 in both cell lines. PMID- 25820360 TI - A trypsin inhibitor from rambutan seeds with antitumor, anti-HIV-1 reverse transcriptase, and nitric oxide-inducing properties. AB - Nephelium lappaceum L., commonly known as "rambutan," is a typical tropical tree and is well known for its juicy and sweet fruit which has an exotic flavor. Chemical studies on rambutan have led to the identification of various components such as monoterpene lactones and volatile compounds. Here, a 22.5-kDa trypsin inhibitor (N . lappaceum trypsin inhibitor (NLTI)) was isolated from fresh rambutan seeds using liquid chromatographical techniques. NLTI reduced the proteolytic activities of both trypsin and alpha-chymotrypsin. Dithiothreitol reduced the trypsin inhibitory activity of NLTI at a concentration of 1 mM, indicating that an intact disulfide bond is essential to the activity. NLTI inhibited HIV-1 reverse transcriptase with an IC50 of 0.73 MUM. In addition, NLTI manifested a time- and dose-dependent inhibitory effect on growth in many tumor cells. NLTI is one of the few trypsin inhibitors with nitric oxide-inducing activity and may find application in tumor therapy. PMID- 25820363 TI - Eliminating voltage decay of lithium-rich li1.14 mn0.54 ni0.14 co0.14 o2 cathodes by controlling the electrochemical process. AB - A lithium-rich cathode material Li1.14 Mn0.54 Ni0.14 Co0.14 O2 (LNMCO) is prepared by a co-precipitation method. The issue of voltage decay in long-term cycling is largely eliminated by control of the charge-discharge voltage range. The LNMCO material exhibits 9.8 % decay in discharge voltage over 200 cycles between 2.0-4.6 V, during which the working voltage decays significantly, from 3.57 V to 3.22 V. The decay was decelerated by a factor of six by using a voltage window of 2.0-4.4 V, from 3.53 V to 3.47 V. IR and Raman spectra reveal that the transformation of layered structure to spinel is significantly retarded under 2.0 4.4 V cycling conditions. Transmission electron microscopy (TEM) was also applied for examining phase change in an individual particle during cycling, showing that the spinel phase occurs both at 2.0-4.6 V and at 2.0-4.4 V, but is not dominant in the latter. Normalization of Li can remove the additional impact on the voltage decay which is brought by different amounts of Li intercalation. The mechanism of no voltage decay at 2.0-4.4 V cycling is raised and electrochemical impedance spectrum data also support the hypothesis. PMID- 25820365 TI - Flavylium based dual photochromism: addressing cis-trans isomerization and ring opening-closure by different light inputs. AB - The multistate system of 4',7-dihydroxy-3-methoxyflavylium is constituted by a multiequilibrium involving trans-chalcone, cis-chalcone, hemiketal, flavylium cation and quinoidal base. This system possesses two independently addressable inter-connected photochromic systems based on the cis-trans isomerization and ring opening-closure of the hemiketal. PMID- 25820366 TI - Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. AB - Mortality from ovarian cancer may be dramatically reduced with the implementation of attainable prevention strategies. The new understanding of the cells of origin and the molecular etiology of ovarian cancer warrants a strong recommendation to the public and health care providers. This document discusses potential prevention strategies, which include 1) oral contraceptive use, 2) tubal sterilization, 3) risk-reducing salpingo-oophorectomy in women at high hereditary risk of breast and ovarian cancer, 4) genetic counseling and testing for women with ovarian cancer and other high-risk families, and 5) salpingectomy after childbearing is complete (at the time of elective pelvic surgeries, at the time of hysterectomy, and as an alternative to tubal ligation). The Society of Gynecologic Oncology has determined that recent scientific breakthroughs warrant a new summary of the progress toward the prevention of ovarian cancer. This review is intended to emphasize the importance of the fallopian tubes as a potential source of high-grade serous cancer in women with and without known genetic mutations in addition to the use of oral contraceptive pills to reduce the risk of ovarian cancer. PMID- 25820364 TI - Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice. AB - At least 170 million people are chronically infected with hepatitis C virus (HCV). Owing to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small nonhuman primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV-RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be owing to the diminished capacity of HCV to antagonize mitochondrial antiviral-signaling protein-dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks. CONCLUSION: Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species-specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection, and vaccine development. PMID- 25820367 TI - Exploring perceptions of community health policy in Kenya and identifying implications for policy change. AB - BACKGROUND: Global interest and investment in close-to-community health services is increasing. Kenya is currently revising its community health strategy (CHS) alongside political devolution, which will result in revisioning of responsibility for local services. This article aims to explore drivers of policy change from key informant perspectives and to study perceptions of current community health services from community and sub-county levels, including perceptions of what is and what is not working well. It highlights implications for managing policy change. METHODS: We conducted 40 in-depth interviews and 10 focus group discussions with a range of participants to capture plural perspectives, including those who will influence or be influenced by CHS policy change in Kenya (policymakers, sub-county health management teams, facility managers, community health extension worker (CHEW), community health workers (CHWs), clients and community members) in two purposively selected counties: Nairobi and Kitui. Qualitative data were digitally recorded, transcribed, translated and coded before framework analysis. RESULTS: There is widespread community appreciation for the existing strategy. High attrition, lack of accountability for voluntary CHWs and lack of funds to pay CHW salaries, combined with high CHEW workload were seen as main drivers for strategy change. Areas for change identified include: lack of clear supervisory structure including provision of adequate travel resources, current uneven coverage and equity of community health services, limited community knowledge about the strategy revision and demand for home-based HIV testing and counselling. CONCLUSION: This in-depth analysis which captures multiple perspectives results in robust recommendations for strategy revision informed by the Five Wonders of Change Framework. These recommendations point towards a more people-centred health system for improved equity and effectiveness and indicate priority areas for action if success of policy change through the roll-out of the revised strategy is to be realized. PMID- 25820368 TI - Chloride transporters and receptor-mediated endocytosis in the renal proximal tubule. AB - KEY POINTS: The reabsorptive activity of renal proximal tubule cells is mediated by receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Loss-of-function mutations of the endosomal chloride proton exchanger ClC-5 (Dent's disease) cause a major trafficking defect in proximal tubule cells, associated with lysosomal dysfunction, oxidative stress and dedifferentiation/proliferation. A similar but milder defect is associated with mutations in CFTR (cystic fibrosis transmembrane conductance regulator). Vesicular chloride transport appears to be important for the integrity of the endolysosomal pathway in epithelial cells. ABSTRACT: The epithelial cells lining the proximal tubules of the kidney reabsorb a large amount of filtered ions and solutes owing to receptor-mediated endocytosis and polarized transport systems that reflect final cell differentiation. Dedifferentiation of proximal tubule cells and dysfunction of receptor-mediated endocytosis characterize Dent's disease, a rare disorder caused by inactivating mutations in the CLCN5 gene that encodes the endosomal chloride-proton exchanger, ClC-5. The disease is characterized by a massive urinary loss of solutes (renal Fanconi syndrome), with severe metabolic complications and progressive renal failure. Investigations of mutations affecting the gating of ClC-5 revealed that the proximal tubule dysfunction may occur despite normal endosomal acidification. In addition to defective endocytosis, proximal tubule cells lacking ClC-5 show a trafficking defect in apical receptors and transporters, as well as lysosomal dysfunction and typical features of dedifferentiation, proliferation and oxidative stress. A similar but milder defect is observed in mouse models with defective CFTR, a chloride channel that is also expressed in the endosomes of proximal tubule cells. These data suggest a major role for endosomal chloride transport in the maintenance of epithelial differentiation and reabsorption capacity of the renal proximal tubule. PMID- 25820369 TI - Free lymph node flap transfer and laser-assisted liposuction: a combined technique for the treatment of moderate upper limb lymphedema. AB - Upper limb lymphedema following breast cancer surgery is a challenging problem for the surgeon. Lymphatico-venous or lymphatico-lymphatic anastomoses have been used to restore the continuity of the lymphatic system, offering a degree of improvement. Long-term review indicates that lumen obliteration and occlusion at the anastomosis level commonly occurs with time as a result of elevated venous pressure. Lymph node flap transfer is another microsurgical procedure designed to restore lymphatic system physiology but does not provide a complete volume reduction, particularly in the presence of hypertrophied adipose tissue and fibrosis, common in moderate and advanced lymphedema. Laser-assisted liposuction has been shown to effectively reduce fat and fibrotic tissues. We present preliminary results of our practice using a combination of lymph node flap transfer and laser-assisted liposuction. Between October 2012 and May 2013, ten patients (mean 54.6 +/- 9.3 years) with moderate (stage II) upper extremity lymphedema underwent groin or supraclavicular lymph node flap transfer combined with laser-assisted liposuction (high-power diode pulsed laser with 1470-nm wavelength, LASEmaR 1500-EUFOTON, Trieste, Italy). A significant decrease of upper limb circumference measurements at all levels was noted postoperatively. Skin tonicity was improved in all patients. Postoperative lymphoscintigraphy revealed reduced lymph stasis. No patient suffered from donor site morbidity. Our results suggest that combining laser liposuction with lymph node flap transfer is a safe and reliable procedure, achieving a reduction of upper limb volume in treated patients suffering from moderate upper extremity lymphedema. PMID- 25820371 TI - Reappraisal of PLA2R1 in membranous nephropathy: immunostaining method influence and association with IgG4-dominant phenotype. AB - The M-type phospholipase A2 receptor (PLA2R1) was identified recently as a specific target antigen in idiopathic membranous nephropathy. However, the influence of different sample preparation techniques on the immunostaining of PLA2R1 is unclear. Previous studies have identified IgG4 as the dominant subclass of PLA2R1 antibodies. However, it remains unclear whether the IgG subclass profiles of the glomerular immune complexes of PLA2R1-positive and -negative idiopathic membranous nephropathy cases are similar. To address these questions, we conducted the present study of 58 idiopathic membranous nephropathy cases. The PLA2R1 positivity rate for the paraffin-embedded sections was 61%, whereas that for the frozen sections was 65%. Nonspecific background staining was observed in the frozen sections. Discrepancies between different sample preparations occurred in three cases (6%); two cases were PLA2R1-positive in paraffin sections and PLA2R1-negative in frozen sections and one case was PLA2R1-negative in paraffin sections and PLA2R1-positive in frozen sections. Regarding the IgG subclass profile, 89% of the PLA2R1-positive cases demonstrated the IgG4 dominant/codominant phenotype versus 31% of the PLA2R1-negative cases (p < 0.001). Clinical characteristics and pathological findings did not significantly differ between PLA2R1-positive and -negative cases. In summary, the PLA2R1 immunofluorescence results were not affected by the different sample preparation techniques, although paraffin-embedded sections were preferred for the histological detection of PLA2R1 because of the nonspecific background staining observed in frozen sections. The observed lower frequency of the non-IgG4 dominant/codominant phenotype in PLA2R1-negative idiopathic membranous nephropathy cases may suggest that there are heterogeneous subgroups of this disease. PMID- 25820372 TI - Giant cell angioblastoma of bone: four new cases provide further evidence of its distinct clinical and histopathological characteristics. AB - Giant cell angioblastoma is a rare locally aggressive vascular neoplasm that occurs predominantly in the soft tissue of infants and children. As very few cases have been reported, the diagnostic criteria of this tumor type have not been clearly defined. The majority of earlier reported cases occurred in soft tissues, only one case being reported to arise in bone. In this study, we describe four additional cases of giant cell angioblastoma with primary presentation in bone. Two cases occurred in males: one in a 23-month-old baby and the other in an 8-year-old boy. The other two cases occurred in adult females, at an age of 37 and 56 years, respectively. The involved sites were right femur, left hip and knee joint, lumbar vertebra, left metacarpus, and phalange. The main presenting symptoms were skeletal pain (n = 3) and limping (n = 1). Clinically, three cases were suspected as tuberculosis and one case as fibrous dysplasia. Histologically, all tumors were composed of infiltrative nodules composed of angiomatous vessels surrounded by spindled-to-ovoid cells and variable numbers of histiocytoid and multinucleate giant cells. By immunohistochemistry, the angiomatous vessels were positive for endothelial markers, whereas surrounding pericytes were positive for actin. The variable histiocytoid cells and multinucleate giant cells showed a histiocytic phenotype. Follow-up revealed no signs of local recurrence or metastasis after surgery, but the follow-up periods were of limited duration. This study illustrates that giant cell angioblastoma represents a locally aggressive endothelial neoplasm characterized by nodular proliferation of small vessels with scattered multinucleate giant cells. It can occur in bone and also in adults, although very rarely. PMID- 25820373 TI - Placental C4d deposition is a feature of defective placentation: observations in cases of preeclampsia and miscarriage. AB - Placental C4d deposition is frequent in preeclampsia, and shallow placentation is a characteristic of both preeclampsia and miscarriage. This study was conducted to determine the relationship among placental C4d, maternal human leukocyte antigen (HLA) antibodies, and placental pathology in preeclampsia and miscarriage cases. The patient population (N = 104) included those with (1) preterm preeclampsia with fetal growth restriction (PE-FGR; n = 21), (2) preterm preeclampsia (PE; n = 20), (3) spontaneous preterm delivery (sPTD; n = 39), and (4) miscarriage (n = 24). C4d immunohistochemistry was performed, and the presence of maternal plasma HLA antibodies was examined. C4d staining of the syncytiotrophoblast was more frequent in PE-FGR patients (76.2 %) than in PE (10.0 %; p < 0.001) and sPTD (2.6 %; p < 0.001) patients. Maternal HLA antibody positive rate was not different among the study groups. There was a significant correlation between C4d immunoreactivity and placental pathology consistent with maternal vascular underperfusion (p < 0.001) but not with maternal HLA antibody status. In miscarriages, the positive rates of C4d, HLA class I, and HLA class II antibodies were 58.3, 25.0, and 12.5 %, respectively. There was no correlation between the presence of maternal HLA class I or II antibodies and placental C4d immunoreactivity. This study confirms frequent placental C4d deposition in preeclampsia with fetal growth restriction and miscarriage. The association between placental C4d deposition and pathological findings of maternal vascular underperfusion suggests that C4d staining of the syncytiotrophoblast is a consequence of defective placentation rather than of a specific maternal immune response against fetal HLA. The study also demonstrates the usefulness of C4d as a biomarker of placentas at risk. PMID- 25820375 TI - Nuclear Translocation of Calpain-2 Mediates Apoptosis of Hypertrophied Cardiomyocytes in Transverse Aortic Constriction Rat. AB - Apoptosis of cardiomyocytes plays an important role in the transition from cardiac hypertrophy to heart failure. Hypertrophied cardiomyocytes show enhanced susceptibility to apoptosis. Therefore, the aim of this study was to determine the susceptibility to apoptosis and its mechanism in hypertrophied cardiomyocytes using a rat model of transverse abdominal aortic constriction (TAC). Sixteen weeks of TAC showed compensatory and pathological hypertrophy in the left ventricle. TUNEL-positive nuclei were significantly increased in TAC with angiotensin II (Ang II) treatment. Calpain inhibitor, PD150606, effectively inhibited Ang II-induced apoptosis of hypertrophied cardiomyocytes. Ang II increased nuclear translocation of intracellular Ca(2+) activated calpain-2 in hypertrophied cardiomyocytes. Ang II enhanced the interaction between activated calpain-2 and Ca(2+)/calmodulin-dependent protein kinase II deltaB (CaMKIIdeltaB), and promoted the degradation of CaMKIIdeltaB by calpain-2 in the nuclei of hypertrophied cardiomyocytes. Consequently, the depressed CaMKIIdeltaB downregulated the expression of antiapoptotic Bcl-2 leading to mitochondrial depolarization and release of cytochrome c led to apoptosis of hypertrophied cardiomyocytes. In conclusion, hypertrophied cardiomyocytes show increased susceptibility to apoptosis during Ang II stimulation via nuclear calpain-2 and CaMKIIdeltaB pathway. PMID- 25820374 TI - Prevalence of HPV infection in head and neck carcinomas shows geographical variability: a comparative study from Brazil and Germany. AB - Rising prevalence rates of high-risk human papillomaviruses (hrHPV) infection in oropharyngeal carcinoma (up to 80 %) have been reported in North America and Scandinavia. We have analysed 424 German and 163 Brazilian head and neck squamous cell carcinomas (HNSCC) from the oral cavity (OSCC), oropharynx (OPSCC) and hypopharynx (HPSCC) using p16 immunohistochemistry, HPV DNA PCR and sequencing, hrHPV DNA in situ hybridisation (ISH) and hrHPV E6/E7 RNA ISH. In the German series, 52/424 cases (12.3 %) were p16-positive/hrHPV-positive (OSCC 3.8 % [10/265], OPSCC 34.4 % [42/122], HPSCC 0 % [0/37]). In addition, there were 9 cases that were p16-positive/hrHPV-negative (5 OPSCC and 4 OSCC). In the Brazilian series, the overall hrHPV DNA prevalence by PCR was 11.0 % ([18/163]; OSCC 6 % [5/83], OPSCC 15.5 % [11/71], HPSCC 22.2 % [2/9]). Ten of these cases were hrHPV-positive/p16-positive. The remaining 8 hrHPV-positive/p16-negative cases were also negative in both ISH assays. Furthermore, 5 p16-positive/hrHPV negative cases (2 OPSCC and 3 OSCC) were identified. In both series, HPV16 was by far the most common HPV type detected. We confirm that regardless of geographical origin, the highest hrHPV prevalence in HNSCC is observed in oropharyngeal carcinomas. The proportion of HPV-associated OPSCC was substantially higher in the German cohort than in the Brazilian series (34.4 vs. 15.5 %), and in both groups, the prevalence of hrHPV in OPSCC was much lower than in recent reports from North America and Scandinavia. We suggest, therefore, that it may be possible to define areas with high (e.g. USA, Canada, Scandinavia), intermediate (e.g. Germany) and low (e.g. Brazil) prevalences of HPV infection in OPSCC. PMID- 25820376 TI - Effects of mefenoxam fungicide on soil biochemical properties. AB - We studied the effect of mefenoxam on soil biochemical properties. Soil was mixed with three rates of mefenoxam (0.5, 1 and 2 L ha(-1)) and incubated for 83 days. Fungicide was applied to the soil four times during the experiment, according to the manufacturer's instructions. Soil ergosterol, dehydrogenase, urease, beta glucosidase, and phosphatase activities were measured during the experiment. Compared to controls, soils with the highest doses of mefenoxam demonstrated decreased ergosterol and dehydrogenase activities by 81 and 27 %, respectively; whereas, urease, beta-glucosidase, and phosphatase activities increased. These results suggest that mefenoxam may possibly have consequences for agronomic crop production due to the negative effect on soil fungal populations and stimulation of the growth of soil bacterial activity. PMID- 25820378 TI - The effect of Li(+) ions on the luminescent properties of a single-phase white light-emitting phosphor alpha-Sr2P2O7:Dy(3.). AB - Two series of phosphors, alpha-Sr2(1-x)Dy2xP2O7 and alpha-Sr2(1-2x)Dy2xLi2xP2O7, with different x values were synthesized successfully using a conventional solid state method at high temperature for the first time, and their luminescence properties were investigated comparatively. The effect of Li(+) ions on the luminescence properties of Dy(3+) in alpha-Sr2P2O7 host, including luminescence intensity, optimal doping concentration, concentration quenching mechanism, and decay behavior, was discussed in detail by considering the defect generation in alpha-Sr2P2O7:Dy(3+), the charge compensation of Li(+) ions and the role of Li2CO3 as solid flux expected in phosphors. The obtained excitation and emission spectra indicate that these as-prepared phosphors can be excited by ultraviolet light and show white light emission due to the combination of the (4)F9/2 >(6)H15/2 and (4)F9/2->(6)H13/2 transitions of Dy(3+) ions. The CIE chromaticity coordinates and color correlated temperature of Dy(3+) emission in the phosphor alpha-Sr2(1-2x)Dy2xLi2xP2O7 (x = 0.03) with optimal fluorescence intensity was also calculated. The present work could be helpful for understanding the effect of the charge compensator (e.g. Li(+) ion) on the luminescent properties of phosphors with non-equivalent ion-displacement and the design of novel phosphors by efficiently taking advantage of charge compensator (e.g. Li(+) ion). PMID- 25820379 TI - Archaea on the move. PMID- 25820377 TI - Neurocognitive long-term impact of two-field conventional radiotherapy in adult patients with operated pituitary adenomas. AB - PURPOSE: To assess the long-term impact of postoperative two-field-conventional radiotherapy (RT) on neurocognitive functions of adult patients with operated pituitary adenomas (PA). METHODS: We selected 124 adult patients with operated PA 56 of whom had also received RT-recorded their main clinical data and performed a neuropsychological assessment in all of them that included 15 standardized tests, and a cerebral SPECT in eight patients. Comparative analyses were carried out on major clinical and neurocognitive domains between irradiated and not irradiated patients, and on cerebral SPECT source. RESULTS: Compared with non-irradiated patients, irradiated patients performed significantly worse on Barcelona's story recall test (P < 0.001) and arithmetic problems (P < 0.03) and on five categories of the Wisconsin card sorting test, especially on perseverative answers and errors (P < 0.001) without differences in other examined functional domains. RT was the only factor associated with worse results in these tests regardless other clinical and treatment-related variables. Kaplan-Meier analysis suggested that the probability of achieving poorer results with time was related to RT total dose and field-size, type of PA and age at the time of RT. Four of the five SPECTS performed in irradiated patients revealed a similar altered perfusion in the left temporal lobe cortical region. CONCLUSIONS: In adult patients with operated PA, RT was independently associated with an impairment on verbal memory and executive function, when compared to non-irradiated patients. Our data suggest that diagnosis of acromegaly or Cushing's disease, and age at the time of RT were able to modulate this long-term radio-induced neurocognitive sequelae. PMID- 25820380 TI - Domain walls and anchoring transitions mimicking nematic biaxiality in the oxadiazole bent-core liquid crystal C7. AB - We investigate the origin of "secondary disclinations" that were recently described as new evidence of a biaxial nematic phase in an oxadiazole bent-core thermotropic liquid crystal C7. Using an assortment of optical techniques such as polarizing optical microscopy, LC PolScope, and fluorescence confocal polarizing microscopy, we demonstrate that the secondary disclinations represent non singular domain walls formed in a uniaxial nematic phase during the surface anchoring transition, in which surface orientation of the director changes from tangential (parallel to the bounding plates) to tilted. Each domain wall separates two regions with the director tilted in opposite azimuthal directions. At the centre of the wall, the director remains parallel to the bounding plates. The domain walls can be easily removed by applying a moderate electric field. The anchoring transition is explained by the balance of (a) the intrinsic perpendicular surface anchoring produced by the polyimide aligning layer and (b) tangential alignment caused by ionic impurities forming electric double layers. The model is supported by the fact that the temperature of the tangentially tilted anchoring transition decreases as the cell thickness increases and as the concentration of ionic species (added salt) increases. We also demonstrate that the surface alignment is strongly affected by thermal degradation of the samples. This study shows that C7 exhibits only a uniaxial nematic phase and demonstrates yet another mechanism (formation of "secondary disclinations") by which a uniaxial nematic phase can mimic a biaxial nematic behaviour. PMID- 25820381 TI - An efficient calculation method for pharmacokinetic parameters in brain permeability study using dynamic contrast-enhanced MRI. AB - PURPOSE: To develop an efficient method for calculating pharmacokinetic (PK) parameters in brain DCE-MRI permeability studies. METHODS: A linear least-squares fitting algorithm based on a derivative expression of the two-compartment PK model was proposed to analytically solve for the PK parameters. Noise in the expression was minimized through low-pass filtering. Simulation studies were conducted in which the proposed method was compared with two existing methods in terms of accuracy and efficiency. Five in vivo brain studies were demonstrated for potential clinical application. RESULTS: In the simulation studies using chosen parameter values, the calculated percent difference of K(trans) by the proposed method was <5.0% with a temporal resolution (Deltat) < 5 s, and the accuracies of all parameter results were better or comparable to existing methods. When analyzed within certain parameter intensity ranges, the proposed method was more accurate than the existing methods and improved the efficiency by a factor of up to 458 for a Deltat = 1 s and up to 38 for a Deltat = 5 s. In the in vivo study, the calculated parameters using the proposed method were comparable to those using the existing methods with improved efficiencies. CONCLUSIONS: An efficient method was developed for the accurate and efficient calculation of parameters in brain DCE-MRI permeability studies. PMID- 25820383 TI - Varenicline-induced acute liver injury with jaundice. PMID- 25820382 TI - Uncovering pharmacological mechanisms of Wu-tou decoction acting on rheumatoid arthritis through systems approaches: drug-target prediction, network analysis and experimental validation. AB - Wu-tou decoction (WTD) has been extensively used for the treatment of rheumatoid arthritis (RA). Due to lack of appropriate methods, pharmacological mechanisms of WTD acting on RA have not been fully elucidated. In this study, a list of putative targets for compositive compounds containing in WTD were predicted by drugCIPHER-CS. Then, the interaction network of the putative targets of WTD and known RA-related targets was constructed and hub nodes were identified. After constructing the interaction network of hubs, four topological features of each hub, including degree, node betweenness, closeness and k-coreness, were calculated and 79 major hubs were identified as candidate targets of WTD, which were implicated into the imbalance of the nervous, endocrine and immune (NEI) systems, leading to the main pathological changes during the RA progression. Further experimental validation also demonstrated the preventive effects of WTD on inflammation and joint destruction in collagen-induced arthritis (CIA) rats and its regulatory effects on candidate targets both in vitro and in vivo systems. In conclusion, we performed an integrative analysis to offer the convincing evidence that WTD may attenuate RA partially by restoring the balance of NEI system and subsequently reversing the pathological events during RA progression. PMID- 25820384 TI - Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl cobalamin in prevention or treatment of cobalamin deficiency. AB - Methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are coenzymes for methionine synthase and methylmalonyl-CoA mutase, respectively. Hydroxylcobalamin (HOCbl) and cyanocobalamin (CNCbl) are frequently used for supplementation. MeCbl and AdoCbl have recently emerged as alternative forms in supplements. In the light of metabolic transformation of Cbl into its cofactor forms, this review discusses current evidence on efficacy and utility of different Cbl forms in preventing or treating Cbl deficiency. Cbl-transporting proteins bind and mediate the uptake of all aforementioned forms of Cbl. After internalization and lysosomal release, Cbl binds to the cytosolic chaperon MMACHC that is responsible for (i) flavin-dependent decyanation of [CN-Co(3+) Cbl to [Co(2+)]Cbl; (ii) glutathione-dependent dealkylation of MeCbl and AdoCbl to [Co(2+/1+)]Cbl; and (iii) glutathione-dependent decyanation of CNCbl or reduction of HOCbl under anaerobic conditions. MMACHC shows a broad specificity for Cbl forms and supplies the Cbl(2+) intermediate for synthesis of MeCbl and AdoCbl. Cobalamin chemistry, physiology, and biochemistry suggest that MeCbl and AdoCbl follow the same route of intracellular processing as CNCbl does. We conclude that supplementing MeCbl or AdoCbl is unlikely to be advantageous compared to CNCbl. On the other hand, there are obvious advantages of high parenteral doses (1-2 mg) of HOCbl in treating inborn errors of Cbl metabolism. PMID- 25820386 TI - The antibacterial activity of ceramsite coated by silver nanoparticles in micropore. AB - In the present study, ceramsite was combined with silver nanoparticles (AgNPs) to fabricate a new nanocomposite for water disinfection. The ceramsite was prepared by fly ash, straw ash, and cement. AgNPs were synthesized using polyvinylpyrrolidone (PVP) as the capping agent. The nanocomposite was prepared by self-aggregation of AgNPs on the surface of the ceramsite. AgNPs capped with PVP can form a thin film on the surface of micropore in ceramsite. The nanocomposite can inhibit bacteria growth and induce damage of the cell membrane of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Therefore, the nanocomposite is a new material which can be used for disinfection in drinking water. PMID- 25820387 TI - Protopine production by fumaria cell suspension cultures: effect of light. AB - Protopine biosynthesis in Fumaria rostellata and Fumaria officinalis cell suspensions was investigated. For the first time, we reported for calli and cell suspensions obtained from F. rostellata and F. officinalis. Callus induction was initiated on a Murashige and Skoog medium, supplemented with sucrose and various concentrations of plant growth regulators: 2,4-dichlorophenoxyacetic acid (2,4-D) and 6-benzylaminopurine (BAP). The best morphological characteristics, growth behavior, and protopine biosynthesis were observed for two callus lines (5FRL14 and 12FOL1) cultivated under submerged conditions, at low concentration of 2,4-D (0.2 and 0.5 mg/L) and higher concentration of BAP (2.0 and 3.0 mg/L). The maximal yield of protopine was accumulated from cell suspension of F. rostellata (line 5FRL14) cultivated under illumination-49.6 mg/L. Time courses of utilization of sucrose, ammonium, nitrate, and phosphate ions in cultural liquid and acetylcholinesterase inhibitory activity of alkaloid extracts of studied suspensions are also presented. PMID- 25820385 TI - An update on the transport and metabolism of iron in Listeria monocytogenes: the role of proteins involved in pathogenicity. AB - Listeria monocytogenes is a Gram-positive bacterium that causes a rare but severe human disease with high mortality rate. The microorganism is widespread in the natural environment where it shows a saprophytic lifestyle. In the human body it infects many different cell types, where it lives intracellularly, however it may also temporarily live extracellularly. The ability to survive and grow in such diverse niches suggests that this bacterium has a wide range of mechanisms for both the acquisition of various sources of iron and effective management of this microelement. In this review, data about the mechanisms of transport, metabolism and regulation of iron, including recent findings in these areas, are summarized with focus on the importance of these mechanisms for the virulence of L. monocytogenes. These data indicate the key role of haem transport and maintenance of intracellular iron homeostasis for the pathogenesis of L. monocytogenes. Furthermore, some of the proteins involved in iron homeostasis like Fri and FrvA seem to deserve special attention due to their potential use in the development of new therapeutic antilisterial strategies. PMID- 25820388 TI - 9H-Carbazole Derivatives Containing the N-Benzyl-1,2,3-triazole Moiety as New Acetylcholinesterase Inhibitors. AB - A series of triazole-containing carbazole derivatives were designed as new anti acetylcholinesterase (AChE) agents. The target compounds 6a-q were simply prepared via a one-pot three-component click reaction of N-propargyl-9H carbazole, sodium azide, and an appropriate benzyl halide. The in vitro anti cholinesterase assay showed that the unsubstituted benzyl derivative 6p along with the 2-F, 2-Me, 3-Me, 3-MeO, and 3-F analogs (6a, 6c, and 6g-i) had significant anti-AChE activity (IC50s <= 3.8 MUM). Among them, the 2-methylbenzyl derivative 6c with an IC50 value of 1.9 MUM was the most active compound. The SAR studies revealed that small halogen atoms such as the fluorine atom or electron donating groups such as methyl or methoxy at the ortho or meta positions of the benzyl pendent group could be tolerated or improved the anti-AChE activity. PMID- 25820389 TI - NLRC5 Mediates IL-6 and IL-1beta Secretion in LX-2 Cells and Modulated by the NF kappaB/Smad3 Pathway. AB - Recent data have shown that nucleotide-binding domain leucine-rich repeat proteins (NLRs), a class of innate immune receptors that respond to pathogen attack or cellular stress, have gained increasing attention. NLRC5 (NLR family, CARD domain containing 5) is the largest member of the NLR family, which has recently been identified as a critical regulator of immune responses. Until recently, the function of NLRC5 has been a matter of debate. In this study, we explore the role of NLRC5 in cytokine secretion and the role of the nuclear factor-kappaB (NF-kappaB) signaling pathway in tumor necrosis factor-alpha (TNF alpha)-induced NLRC5 expression in LX-2 cells. We demonstrated that overexpression of NLRC5 results in an upregulation of IL-6 and IL-1beta secretion. On the other hand, knockdown of NLRC5 by transfecting siRNA decreased IL-6 and IL-1beta secretion in LX-2 cells. Meanwhile, the results showed that pyrrolidine dithiocarbamate (PDTC) (a specific inhibitor of the NF-kappaB signaling pathway) inhibited NLRC5 expression and NLRC5 silencing could increase the expression levels of p65 in cell nucleus accompanied with upregulated phosphorylation of Smad3 protein levels in response to TNF-alpha. These results indicated that NLRC5 plays a significant role in TNF-alpha-enhanced cytokine (IL 6 and IL-1beta) secretion of LX-2 cells and the NF-kappaB/Smad3 signal pathway is involved in its induction of expression. PMID- 25820390 TI - Growth Differentiation Factor-15 Is a Novel Biomarker Predicting Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - Exacerbations in chronic obstructive pulmonary disease (COPD) reduce quality of life and are associated with a more rapid deterioration of the disease. Growth differentiation factor-15 (GDF-15) is a novel candidate exacerbation biomarker. In this study, we aimed to assess GDF-15 as a biomarker of acute exacerbation of COPD (AE-COPD). Lung function parameters, arterial blood gas analysis, and circulating levels of GDF-15, C-reactive protein (CRP), and fibrinogen were assessed in 29 patients on admission to the hospital for AE-COPD, in 29 age-, gender-, and body mass index (BMI)-matched patients with stable COPD, and 29 matched controls with normal lung function. Patients with AE-COPD had higher circulating concentrations of GDF-15 (p < 0.001), CRP (p < 0.001), and fibrinogen (p < 0.002) compared with patients with stable COPD and healthy controls. GDF-15 levels correlated with systemic inflammatory marker CRP in patients with AE-COPD (r = 0.677, p < 0.001) and with stable COPD (r = 0.417, p = 0.024). Multivariate logistic regression analysis revealed GDF-15 (odds ratio 18.16, 95% confidence interval (CI) 2.51-134.32; p = 0.005) as an independent predictor of AE-COPD. In receiver operating characteristic analysis, GDF-15 achieved an area under the curve of 0.78 for the identification of AE-COPD. In conclusion, GDF-15 is a novel blood biomarker of AE-COPD that is more sensitive than that of CRP. GDF-15 may offer new insights into the pathogenesis of AE-COPD. PMID- 25820392 TI - Exercise intensity and the protection from postprandial vascular dysfunction in adolescents. AB - Acute exercise transiently improves endothelial function and protects the vasculature from the deleterious effects of a high-fat meal (HFM). We sought to identify whether this response is dependent on exercise intensity in adolescents. Twenty adolescents (10 male, 14.3 +/- 0.3 yr) completed three 1-day trials: 1) rest (CON); 2) 8 * 1 min cycling at 90% peak power with 75 s recovery [high intensity interval exercise (HIIE)]; and 3) cycling at 90% of the gas exchange threshold [moderate-intensity exercise (MIE)] 1 h before consuming a HFM (1.50 g/kg fat). Macrovascular and microvascular endothelial function was assessed before and immediately after exercise and 3 h after the HFM by flow-mediated dilation (FMD) and laser Doppler imaging [peak reactive hyperemia (PRH)]. FMD and PRH increased 1 h after HIIE [P < 0.001, effect size (ES) = 1.20 and P = 0.048, ES = 0.56] but were unchanged after MIE. FMD and PRH were attenuated 3 h after the HFM in CON (P < 0.001, ES = 1.78 and P = 0.02, ES = 0.59). FMD remained greater 3 h after the HFM in HIIE compared with MIE (P < 0.001, ES = 1.47) and CON (P < 0.001, ES = 2.54), and in MIE compared with CON (P < 0.001, ES = 1.40). Compared with CON, PRH was greater 3 h after the HFM in HIIE (P = 0.02, ES = 0.71) and MIE (P = 0.02, ES = 0.84), with no differences between HIIE and MIE (P = 0.72, ES = 0.16). Plasma triacylglycerol concentration and total antioxidant status concentration were not different between trials. We conclude that exercise intensity plays an important role in protecting the vasculature from the deleterious effects of a HFM. Performing HIIE may provide superior vascular benefits than MIE in adolescent groups. PMID- 25820391 TI - Coronary vasomotor responses to isometric handgrip exercise are primarily mediated by nitric oxide: a noninvasive MRI test of coronary endothelial function. AB - Endothelial cell release of nitric oxide (NO) is a defining characteristic of nondiseased arteries, and abnormal endothelial NO release is both a marker of early atherosclerosis and a predictor of its progression and future events. Healthy coronaries respond to endothelial-dependent stressors with vasodilatation and increased coronary blood flow (CBF), but those with endothelial dysfunction respond with paradoxical vasoconstriction and reduced CBF. Recently, coronary MRI and isometric handgrip exercise (IHE) were reported to noninvasively quantify coronary endothelial function (CEF). However, it is not known whether the coronary response to IHE is actually mediated by NO and/or whether it is reproducible over weeks. To determine the contribution of NO, we studied the coronary response to IHE before and during infusion of N(G)-monomethyl-l-arginine (l-NMMA, 0.3 mg.kg(-1).min(-1)), a NO-synthase inhibitor, in healthy volunteers. For reproducibility, we performed two MRI-IHE studies ~8 wk apart in healthy subjects and patients with coronary artery disease (CAD). Changes from rest to IHE in coronary cross-sectional area (%CSA) and diastolic CBF (%CBF) were quantified. l-NMMA completely blocked normal coronary vasodilation during IHE [%CSA, 12.9 +/- 2.5 (mean +/- SE, placebo) vs. -0.3 +/- 1.6% (l-NMMA); P < 0.001] and significantly blunted the increase in flow [%CBF, 47.7 +/- 6.4 (placebo) vs. 10.6 +/- 4.6% (l-NMMA); P < 0.001]. MRI-IHE measures obtained weeks apart strongly correlated for CSA (P < 0.0001) and CBF (P < 0.01). In conclusion, the normal human coronary vasoactive response to IHE is primarily mediated by NO. This noninvasive, reproducible MRI-IHE exam of NO-mediated CEF promises to be useful for studying CAD pathogenesis in low-risk populations and for evaluating translational strategies designed to alter CAD in patients. PMID- 25820393 TI - Angiotensin II in human skin: an age-dependent role for core temperature regulation? PMID- 25820394 TI - Acute inhibition of ATP-sensitive K+ channels impairs skeletal muscle vascular control in rats during treadmill exercise. AB - The ATP-sensitive K(+) (KATP) channel is part of a class of inward rectifier K(+) channels that can link local O2 availability to vasomotor tone across exercise induced metabolic transients. The present investigation tested the hypothesis that if KATP channels are crucial to exercise hyperemia, then inhibition via glibenclamide (GLI) would lower hindlimb skeletal muscle blood flow (BF) and vascular conductance during treadmill exercise. In 27 adult male Sprague-Dawley rats, mean arterial pressure, blood lactate concentration, and hindlimb muscle BF (radiolabeled microspheres) were determined at rest (n = 6) and during exercise (n = 6-8, 20, 40, and 60 m/min, 5% incline, i.e., ~60-100% maximal O2 uptake) under control and GLI conditions (5 mg/kg intra-arterial). At rest and during exercise, mean arterial pressure was higher (rest: 17 +/- 3%, 20 m/min: 5 +/- 1%, 40 m/min: 5 +/- 2%, and 60 m/min: 5 +/- 1%, P < 0.05) with GLI. Hindlimb muscle BF (20 m/min: 16 +/- 7%, 40 m/min: 30 +/- 9%, and 60 m/min: 20 +/- 8%) and vascular conductance (20 m/min: 20 +/- 7%, 40 m/min: 33 +/- 8%, and 60 m/min: 24 +/- 8%) were lower with GLI during exercise at 20, 40, and 60 m/min, respectively (P < 0.05 for all) but not at rest. Within locomotory muscles, there was a greater fractional reduction present in muscles comprised predominantly of type I and type IIa fibers at all exercise speeds (P < 0.05). Additionally, blood lactate concentration was 106 +/- 29% and 44 +/- 15% higher during exercise with GLI at 20 and 40 m/min, respectively (P < 0.05). That KATP channel inhibition reduces hindlimb muscle BF during exercise in rats supports the obligatory contribution of KATP channels in large muscle mass exercise-induced hyperemia. PMID- 25820395 TI - 20-Hydroxyeicosatetraenoic acid involved in endothelial activation and thrombosis. AB - Endothelial cells play an important role in the process of coagulation and the function of platelets. We have previously reported that 20 hydroxyeicosatetraenoic acid (20-HETE), a metabolite of arachidonic acid, increased platelet aggregation and induced hemostasis. The purpose of the present study is to investigate whether 20-HETE-mediated endothelial activation has effect on the coagulation and platelet aggregation. C57Bl/6 mice were treated with PBS or 20-HETE (20 MUg/kg) for 2 h, and then we performed a carotid artery or femoral artery thrombosis model by FeCl3. Detection of blood flow indicated that 20-HETE pretreatment accelerated formation of thrombus in both common carotid artery and femoral artery. In vitro, the secretion and expression of von Willebrand factor (vWF) in cultured human umbilical vein endothelial cells (HUVECs) with 20-HETE stimulation were increased, subsequently. The protein level of vWF in HUVECs was decreased at 1 h but increased with prolonged treatment with 20-HETE (>4 h). In contrast, vWF in the culture medium was increased under administration of 20-HETE at 1 h. As a result, adhesion of platelets on HUVECs was significantly increased by 20-HETE. In HUVECs, the extracellular signal regulated kinase (ERK) pathway was activated by 20-HETE in a dose-dependent manner, and the inhibitors of ERK and L-type Ca(2+) channel blocked the release of vWF mediated by 20-HETE. In conclusion, 20-HETE instigates endothelial activation and induces the expression and secretion of vWF via the activation of ERK and calcium channel and therefore triggers thrombosis. PMID- 25820396 TI - Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury. AB - Interleukin-6 (IL-6) is a pleiotropic cytokine that protects against cardiac ischemia-reperfusion (I/R) injury following pharmacological and ischemic preconditioning (IPC), but the affiliated role in exercise preconditioning is unknown. Our study purpose was to characterize exercise-induced IL-6 cardiac signaling (aim 1) and evaluate myocardial preconditioning (aim 2). In aim 1, C57 and IL-6(-/-) mice underwent 3 days of treadmill exercise for 60 min/day at 18 m/min. Serum, gastrocnemius, and heart were collected preexercise, immediately postxercise, and 30 and 60 min following the final exercise session and analyzed for indexes of IL-6 signaling. For aim 2, a separate cohort of exercise preconditioned (C57 EX and IL-6(-/-) EX) and sedentary (C57 SED and IL-6(-/-) SED) mice received surgical I/R injury (30 min I, 120 min R) or a time-matched sham operation. Ischemic and perfused tissues were examined for necrosis, apoptosis, and autophagy. In aim 1, serum IL-6 and IL-6 receptor (IL-6R), gastrocnemius, and myocardial IL-6R were increased following exercise in C57 mice only. Phosphorylated (p) signal transducer and activator of transcription 3 was increased in gastrocnemius and heart in C57 and IL-6(-/-) mice postexercise, whereas myocardial iNOS and cyclooxygenase-2 were unchanged in the exercised myocardium. Exercise protected C57 EX mice against I/R-induced arrhythmias and necrosis, whereas arrhythmia score and infarct outcomes were higher in C57 SED, IL-6(-/-) SED, and IL-6(-/-) EX mice compared with SH. C57 EX mice expressed increased p-p44/42 MAPK (Thr(202)/Tyr(204)) and p-p38 MAPK (Thr(180)/Tyr(182)) compared with IL-6(-/-) EX mice, suggesting pathway involvement in exercise preconditioning. Findings indicate exercise exerts cardioprotection via IL-6 and strongly implicates protective signaling originating from the exercised skeletal muscle. PMID- 25820398 TI - Persistence of mullerian duct structures in a genetic male with distal monosomy 10q. AB - Persistent mullerian duct syndrome (PMD) with antimullerian hormone (AMH) deficiency is usually associated with mutations or deletions of the AMH gene, although many cases have no identified gene association. We report on a genetic male with PMD and AMH deficiency associated with distal monosomy 10q. A term 3,230 g infant was born to a healthy 27-year-old. Fetal ultrasound had shown possible genital ambiguity. Postnatal exam showed a 0.5 cm phallus with basal meatus, normal scrotum with no palpable gonads, no vaginal orifice, and a rectal fistula with an imperforate anus. Voiding cystourethrogram with ultrasound, cystoscopy, and laparoscopy showed normal bladder, urethral orifice, distal vagina, cervix, and bilateral abdominal testis. At 24 hours of life, testosterone was within normal range with low AMH level. Chromosome microarray analysis showed 46, XY, del10(10q25.3q26.13) involving an 8.2 MB interstitial deletion. Whole exome sequencing identified a NOTCH2 variant (1p11.2). AMH sequencing revealed no abnormalities. Following multidisciplinary team and parent discussion, male gender was assigned. Testosterone treatment resulted in penile length of 1.5 cm. Bilateral orchiopexy and posterior sagittal anorectoplasty were performed at 11 months of age; rudimentary mullerian structures were identified. This observation suggests an association of 10qter elements with male differentiation including AMH expression and is similar to a patient with 46, XY, del(10q26.1) in which AMH levels were not reported. Regional candidate genes include FGFR2 (10q26.13). The possible contribution of a NOTCH2 variant cannot be excluded. PMID- 25820401 TI - Legal, ethical issues loom over topic of recontacting patients: advances in research, next-generation sequencing lead geneticists to consider approaching former patients with results about genetic variants. PMID- 25820402 TI - Settlement reached over medicaid coverage of cystic fibrosis drug: Arkansas federal court case highlights medical necessity, high cost of targeted therapies. PMID- 25820397 TI - Induction and functional significance of the heme oxygenase system in pathological shear stress in vivo. AB - The present study examined the heme oxygenase (HO) system in an in vivo murine model of pathological shear stress induced by partial carotid artery ligation. In this model, along with upregulation of vasculopathic genes, HO-1 is induced in the endothelium and adventitia, whereas HO-2 is mainly upregulated in the endothelium. Within minutes of ligation, NF-kappaB, a transcription factor that upregulates vasculopathic genes and HO-1, is activated. Failure to express either HO-1 or HO-2 exaggerates the reduction in carotid blood flow and exacerbates vascular injury. After artery ligation, comparable induction of HO-2 occurred in HO-1(+/+) and HO-1(-/-) mice, whereas HO-1 induction was exaggerated in HO-2(-/-) mice compared with HO-2(+/+) mice. Upregulation of HO-1 by an adeno-associated viral vector increased vascular HO-1 expression and HO activity and augmented blood flow in both ligated and contralateral carotid arteries. Acute inhibition of HO activity decreased flow in the ligated carotid artery, whereas a product of HO, carbon monoxide (CO), delivered by CO-releasing molecule-3, increased carotid blood flow. In conclusion, in the partial carotid artery ligation model of pathological shear stress, this study provides the first demonstration of 1) upregulation and vasoprotective effects of HO-1 and HO-2 and the vasorelaxant effects of CO as well as 2) vascular upregulation of HO-1 in vivo by an adeno associated viral vector that is attended by a salutary vascular response. Induction of HO-1 may reside in NF-kappaB activation, and, along with induced HO 2, such upregulation of HO-1 provides a countervailing vasoprotective response in pathological shear stress in vivo. PMID- 25820404 TI - Measurement of distinctive features of cortical spreading depolarizations with different MRI contrasts. AB - Growing clinical evidence suggests critical involvement of spreading depolarizations (SDs) in the pathophysiology of neurological disorders such as migraine and stroke. MRI provides powerful tools to detect and assess co occurring cerebral hemodynamic and cellular changes during SDs. This study reports the feasibility and advantages of two MRI scans, based on balanced steady state free precession (b-SSFP) and diffusion-weighted multi-spin-echo (DT2), heretofore unexplored for monitoring SDs. These were compared with gradient-echo MRI. SDs were induced by KCl application in rat brain. Known for high SNR, the T2 and T1-based b-SSFP contrast was hypothesized to provide higher spatiotemporal specificity than T2*-based gradient-echo scanning. DT2 scanning was designed to provide simultaneous T2 and apparent diffusion coefficient (ADC) measurements, thus enabling combined quantitative assessment of hemodynamic and cellular changes during SDs. Procedures were developed to automate identification of SD induced responses in all the scans. These responses were analyzed to determine detection sensitivity and temporal characteristics of signals from each scanning method. Cluster analysis was performed to elucidate unique temporal patterns for each contrast. All scans allowed detection of SD-induced responses. b-SSFP scans showed significantly larger relative intensity changes, narrower peak widths and greater spatial specificity compared with gradient-echo MRI. SD-induced effects on ADC, calculated from DT2 scans, showed the most pronounced signal changes, displaying about 20% decrease, as against 10-15% signal increases observed with b SSFP and gradient-echo scanning. Cluster analysis revealed additional temporal sub-patterns, such as an initial dip on gradient-echo scans and temporally shifted T2 and proton density changes in DT2 data. To summarize, b-SSFP and DT2 scanning provide distinct information on SDs compared with gradient-echo MRI. DT2 scanning, with its potential to simultaneously provide cellular and hemodynamic information, can offer unique information on the inter-relationship between these processes in pathologic brain, which may improve monitoring of spreading depolarizations in (pre)clinical settings. PMID- 25820405 TI - Comparison of the dental anomalies found in maxillary canine-first premolar transposition cases with those in palatally displaced canine cases. AB - AIM: To compare the developmental dental anomalies associated with maxillary canine-first premolar (MxCP1) transposition and those of palatally displaced canine (PDC) with each other and with the background prevalence in the Maltese population in order to elucidate whether the two conditions have similar or differing genetic backgrounds. MATERIALS AND METHODS: Dental records of 477 subjects with PDC, 57 subjects with MxCP1, and a control group of 500 subjects with no history of a PDC or tooth transposition were compared for canine eruption anomalies and hypodontia. RESULTS: A high frequency of bilateral occurrence was present for both canine malpositions and when unilateral, a trend to right-sided occurrence was evident. The occurrence of transpositions in the PDC group and of PDC in the MxCP1 group was higher than expected. The prevalence of incisor hypodontia was significantly higher in subjects with PDC and MxCP1, as compared to the control group. LIMITATIONS: The size of the MxCP1 group is relatively small. The study population is a small isolated Caucasian population and the results may not be applicable to other populations. CONCLUSIONS: There is no significant difference between the MxCP1 and PDC groups in the prevalence or distribution of hypodontia and each of these groups exhibits a higher prevalence of the other canine anomaly. These findings support the theory that PDC and MxCP1 form part of a group of interrelated dental anomalies that share a common genetic basis. PMID- 25820406 TI - Cephalometric appraisal of post-treatment tooth eruption: a 20 year follow-up study. AB - AIM: To assess the amount of tooth eruption that occurs during 20 years after completion of orthodontic treatment and analyse possible correlations with age and mandibular growth pattern present. MATERIALS AND METHODS: A retrospective longitudinal cephalometric investigation of dento-alveolar changes was performed in 72 patients (50 women and 22 men). Two lateral cephalograms, taken at the end of orthodontic treatment and on average 20 years later, were available for each subject. The mean age at the beginning of the observation period was 21.5 years and the mean observation period was 19.7 years. Changes in the cephalometric measurements were evaluated statistically. RESULTS: For all parameters, there is evidence for an increase in tooth eruption parameters during the 20 year interval. Furthermore, a significant difference in change was found between different growth patterns for all parameters. For the majority of the parameters, the increase is higher for subjects being younger at the end of orthodontic treatment. There is no evidence for a difference in change between males and females. CONCLUSION: Continued tooth eruption readily occurs after termination of orthodontic treatment in all patients. There is a correlation between the mandibular growth pattern present and the amount of tooth eruption in posterior and anterior regions in both the mandible and the maxilla after completion of the orthodontic treatment. These changes are more pronounced in patients treated orthodontically during adolescence. PMID- 25820408 TI - Conservation of writhe helicity under anti-parallel reconnection. AB - Reconnection is a fundamental event in many areas of science, from the interaction of vortices in classical and quantum fluids, and magnetic flux tubes in magnetohydrodynamics and plasma physics, to the recombination in polymer physics and DNA biology. By using fundamental results in topological fluid mechanics, the helicity of a flux tube can be calculated in terms of writhe and twist contributions. Here we show that the writhe is conserved under anti parallel reconnection. Hence, for a pair of interacting flux tubes of equal flux, if the twist of the reconnected tube is the sum of the original twists of the interacting tubes, then helicity is conserved during reconnection. Thus, any deviation from helicity conservation is entirely due to the intrinsic twist inserted or deleted locally at the reconnection site. This result has important implications for helicity and energy considerations in various physical contexts. PMID- 25820407 TI - Stability of Class II fixed functional appliance therapy--a systematic review and meta-analysis. AB - OBJECTIVES: To systematically search for scientific evidence concerning the stability of treatment (Tx) results achieved by means of Class II fixed functional appliance therapy and to assess possible differences between appliances. SEARCH METHODS: An electronic search of databases and orthodontic journals was carried out (until December 2013), with supplemental hand searching. In addition to the names of all identified appliances, the term fixed functional was used in combination with each of the following search terms: long-term, post Tx, relapse, retention, stability. SELECTION CRITERIA: To be included in the review, the articles had to contain clear data on: Class II Tx with a fixed functional appliance (>5 patients), post-Tx period >= 1 year, assessment of ANB angle, Wits appraisal, molar relationship, soft-tissue profile convexity excluding the nose, overjet and/or overbite. DATA COLLECTION AND ANALYSIS: The literature search revealed 20 scientific investigations which corresponded to only two of the 76 identified appliances (Herbst and Twin Force Bite Corrector). As only one publication was found for the Twin Force Bite Corrector, a meta analysis could only be performed for Herbst Tx. The data were extracted, pooled and weighted according to the number of patients in each study. RESULTS: The mean values for post-Tx relapse (percentages relative to the Tx changes) were: ANB angle 0.2 degrees (12.4 per cent), Wits appraisal 0.5mm (19.5 per cent), sagittal molar relationship 1.2mm/0.1 cusp widths (21.8 per cent /6.5 per cent); soft tissue profile convexity excluding nose less than 0.1 degrees (1.0 per cent), overjet 1.8mm (26.2 per cent), overbite Class II:1 1.4mm (44.7 per cent), overbite Class II:2 1.0mm (22.2 per cent). CONCLUSIONS: The scientific evidence concerning the stability of Tx results is inexistent for most fixed functional appliances for Class II correction except for Herbst appliance Tx. Even if the evidence level of most included studies is rather low, good dentoskeletal stability without clinically relevant changes was found for most variables. PMID- 25820410 TI - UV Emission of Gd3+ in the Presence of Cu2+ : Towards Luminescence Quenching through Quantum Cutting? AB - The first investigation into the ultraviolet (UV) photoluminescence of gadolinium(III) in the presence of copper(II) is reported. A melt-quenched barium phosphate glass was used as a model matrix. The optical spectroscopy assessment shows that with increasing CuO concentration the Cu(2+) absorption band grows steadily, whereas the UV emission from Gd(3+) ions is progressively quenched. The data, thus, suggests the existence of a Gd(3+) ->Cu(2+) energy-transfer process ocurring through quantum cutting. A downconversion/cross-relaxation pathway proceeding through a virtual state in Gd(3+) is proposed. These findings suggest gadolinium(III) could potentially be used in the optical sensing of copper(II). PMID- 25820409 TI - Additive-manufactured patient-specific titanium templates for thoracic pedicle screw placement: novel design with reduced contact area. AB - PURPOSE: Image-based navigational patient-specific templates (PSTs) for pedicle screw (PS) placement have been described. With recent advances in three dimensional computer-aided designs and additive manufacturing technology, various PST designs have been reported, although the template designs were not optimized. We have developed a novel PST design that reduces the contact area without sacrificing stability. It avoids susceptibility to intervening soft tissue, template geometric inaccuracy, and difficulty during template fitting. METHODS: Fourteen candidate locations on the posterior aspect of the vertebra were evaluated. Among them, locations that had high reproducibility on computed tomography (CT) images and facilitated accurate PS placement were selected for the final PST design. An additive manufacturing machine (EOSINT M270) fabricated the PSTs using commercially pure titanium powder. For the clinical study, 36 scoliosis patients and 4 patients with ossification of the posterior longitudinal ligament (OPLL) were treated with thoracic PSs using our newly developed PSTs. We intraoperatively and postoperatively evaluated the accuracy of the PS hole created by the PST. RESULTS: Based on the segmentation reproducibility and stability analyses, we selected seven small, round contact points for our PST: bilateral superior and inferior points on the transverse process base, bilateral inferior points on the laminar, and a superior point on the spinous process. Clinically, the success rates of PS placement using this PST design were 98.6 % (414/420) for scoliosis patients and 100 % (46/46) for OPLL patients. CONCLUSION: This study provides a useful design concept for the development and introduction of patient-specific navigational templates for placing PSs. PMID- 25820412 TI - Elucidating factors important for monovalent cation selectivity in enzymes: E. coli beta-galactosidase as a model. AB - Many enzymes require a specific monovalent cation (M(+)), that is either Na(+) or K(+), for optimal activity. While high selectivity M(+) sites in transport proteins have been extensively studied, enzyme M(+) binding sites generally have lower selectivity and are less characterized. Here we study the M(+) binding site of the model enzyme E. coli beta-galactosidase, which is about 10 fold selective for Na(+) over K(+). Combining data from X-ray crystallography and computational models, we find the electrostatic environment predominates in defining the Na(+) selectivity. In this lower selectivity site rather subtle influences on the electrostatic environment become significant, including the induced polarization effects of the M(+) on the coordinating ligands and the effect of second coordination shell residues on the charge distribution of the primary ligands. This work expands the knowledge of ion selectivity in proteins to denote novel mechanisms important for the selectivity of M(+) sites in enzymes. PMID- 25820411 TI - Data quality in diffusion tensor imaging studies of the preterm brain: a systematic review. AB - BACKGROUND: To study early neurodevelopment in preterm infants, evaluation of brain maturation and injury is increasingly performed using diffusion tensor imaging, for which the reliability of underlying data is paramount. OBJECTIVE: To review the literature to evaluate acquisition and processing methodology in diffusion tensor imaging studies of preterm infants. MATERIALS AND METHODS: We searched the Embase, Medline, Web of Science and Cochrane databases for relevant papers published between 2003 and 2013. The following keywords were included in our search: prematurity, neuroimaging, brain, and diffusion tensor imaging. RESULTS: We found 74 diffusion tensor imaging studies in preterm infants meeting our inclusion criteria. There was wide variation in acquisition and processing methodology, and we found incomplete reporting of these settings. Nineteen studies (26%) reported the use of neonatal hardware. Data quality assessment was not reported in 13 (18%) studies. Artefacts-correction and data-exclusion was not reported in 33 (45%) and 18 (24%) studies, respectively. Tensor estimation algorithms were reported in 56 (76%) studies but were often suboptimal. CONCLUSION: Diffusion tensor imaging acquisition and processing settings are incompletely described in current literature, vary considerably, and frequently do not meet the highest standards. PMID- 25820413 TI - Distribution and Molecular Characterization of Hepatitis E virus in Domestic Animals and Wildlife in Croatia. AB - Hepatitis E is becoming a growing health concern in European countries as an increase of sporadic human cases of unknown origin has been recorded lately. Its causative agent, Hepatitis E virus (HEV), is known to have zoonotic potential and thus the role of domestic and wild animals in the chain of viral spread should be considered when investigating risk factors and the epidemiology of the disease. A comprehensive survey based on viral RNA detection was carried out in Croatia including blood, spleen and liver samples originating from 1816 different domestic and wild animals and digestive gland samples from 538 molluscs. A high HEV prevalence was detected in domestic pigs (24.5%) and wild boars (12.3%), whereas cattle, molluscs, ruminant and carnivore wildlife samples tested negative. Molecular characterization of both ORF1 and ORF2 genomic regions confirmed the phylogenetic clustering of the obtained sequences into genotype 3, previously reported in Europe. Furthermore, our results proved the presence of identical sequence variants in different samples, regardless of their origin, age or habitat of the host, suggesting transmission events between domestic swine, as well as between domestic swine and wild boars in the country. Moreover, a close genetic relationship of Croatian animal strains and known human HEV strains from GenBank opens the question of possible cross-species HEV transmission in Croatia, especially in the areas with an intensive swine production. PMID- 25820414 TI - BWH emergency radiology--surgical correlation: small-bowel GI stromal tumor perforation. AB - We present the radiological and intraoperative correlation of a large necrotic gastrointestinal stromal tumor (GIST) with features of a tumor-bowel fistula and perforation in a 49-year-old woman presenting to the emergency department with a 4-day history of worsening abdominal pain, vomiting, and diarrhea. The patient underwent urgent exploratory laparotomy for partial resection of the small bowel, with primary anastomosis. The purpose of this article is to emphasize the importance for emergency radiologists to be familiar with this entity and its possible complications to help guide the surgeons in the patient's management. PMID- 25820415 TI - Keratin 19, a Cancer Stem Cell Marker in Human Hepatocellular Carcinoma. AB - PURPOSE: Keratin 19 (K19) is a known marker of poor prognosis and invasion in human hepatocellular carcinoma (HCC). However, the relationship between K19 and cancer stem cells (CSCs) is unclear. Here, we determined whether K19 can be used as a new CSC marker and therapeutic target in HCC. EXPERIMENTAL DESIGN: HCC cell lines were transfected with a K19 promoter-driven enhanced green fluorescence protein gene. CSC characteristics, epithelial-mesenchymal transition (EMT), and TGFb/Smad signaling were examined in FACS-isolated K19(+)/K19(-) cells. K19 and TGFb receptor 1 (TGFbR1) expression in 166 consecutive human HCC surgical specimens was examined immunohistochemically. RESULTS: FACS-isolated single K19(+) cells showed self-renewal and differentiation into K19(-) cells, whereas single K19(-) cells did not produce K19(+) cells. K19(+) cells displayed high proliferation capacity and 5-fluorouracil resistance in vitro. Xenotransplantation into immunodeficient mice revealed that K19(+) cells reproduced, differentiated into K19(-) cells, and generated large tumors at a high frequency in vivo. K19(+) cells were found to be involved in EMT and the activation of TGFb/Smad signaling, and these properties were suppressed by K19 knockdown or treatment with a TGFbR1 inhibitor. The TGFbR1 inhibitor also showed high therapeutic effect against K19(+) tumor in the mouse xenograft model. Immunohistochemistry of HCC specimens showed that compared with K19(-) patients, K19(+) patients had significantly poorer recurrence-free survival and higher tumor TGFbR1 expression. CONCLUSIONS: K19 is a new CSC marker associated with EMT and TGFb/Smad signaling, and it would thus be a good therapeutic target for TGFbR1 inhibition. PMID- 25820418 TI - Band alignment and enhanced photocatalytic activation of alpha/beta-Bi2O3 heterojunctions via in situ phase transformation. AB - The assembling heterojunction, one of the key topics in photocatalysts and semiconductors (SCs), is generally accomplished in at least two steps, of which the first step is the synthesis of a matrix, and then the growth of the second phase on the matrix. Herein we present the preparation of alpha/beta-Bi2O3 heterojunctions by an in situ phase transformation technique. Under normal pressure, a facile citrate method was used to synthesize beta-Bi2O3 nanosheets and alpha/beta-Bi2O3 heterojunctions. The novel features of the process are the mild operating conditions by an appropriate selection of heat treatment temperature and time. Using transmission electron microscopy (TEM), we found that a number of nano-sized alpha-Bi2O3 form on the beta-Bi2O3 nanosheet via a controlled beta->alpha phase transition, generating a large number of heterojunctions. The CM1 (calcining beta-Bi2O3 precursor at 363 degrees C for 4 h) heterojunction achieves a strong visible light absorption and dye absorption capacity and produces a very high reaction rate for Rhodamine B (RhB) photodegradation. Electrochemical impedance spectroscopy (EIS) revealed excellent charge transfer characteristics of the heterojunction, which accounts for its high photoactivity. Using the X-ray electron valence band spectra, it is found that the valence band of alpha-Bi2O3 is more negative than that of beta-Bi2O3. Thus, in heterojunctions, the photogenerated holes in beta-Bi2O3 are transferred to alpha-Bi2O3 with good charge transport characteristics by the intrinsic driving force in the interface field. Furthermore, a separated hole can accomplish a transfer process from alpha-Bi2O3 to the aqueous solution within its lifetime due to the diameter of alpha-Bi2O3 being less than 17.6 nm. PMID- 25820416 TI - Mutation spectrum in the Wnt/beta-catenin signaling pathway in gastric fundic gland-associated neoplasms/polyps. AB - Frequent activation of the Wnt/beta-catenin signaling pathway has recently been demonstrated in gastric adenocarcinoma/neoplasia of chief cell predominant type (GA-CCP/GN-CCP) with submucosal involvement. In this study, we examined the activation status of the Wnt/beta-catenin signaling pathway in GN-CCP without submucosal involvement, which is referred to as gastric dysplasia-CCP (GD-CCP). We also examined beta-catenin expression and the mutation spectrum of PPP2R1A and Wnt pathway genes in 11 cases of GD-CCP, 25 cases of gastric polyps of fundic gland type (GPs-FG), and 21 cases of GPs-FG with dysplasia (GP-FGD). beta-catenin nuclear staining was observed in 3 cases of GD-CCP, none of GPs-FG, and 6 cases of GPs-FGD. Mutations in Wnt pathway genes, including PPP2R1A, were observed in 4 cases of GDs-CCP, 10 cases of GPs-FG, and 7 cases of GPs-FGD. Two of these seven GPs-FGD cases showed beta-catenin nuclear staining. However, none of the 4 GD-CCP cases with mutations or the 10 GPs-FG cases with mutations showed beta-catenin nuclear staining. PPP2R1A mutations were observed in 1 GD-CCP case and 1 GPs-FGD case. Although the mutation spectra of the Wnt pathway genes in GD-CCP and GP-FG differed, based on the absence of beta-catenin nuclear staining despite the genetic alterations, GD-CCP is more similar to GP-FG than to GN-CCP, which shows beta-catenin nuclear staining and submucosal involvement. Activation of the Wnt/beta-catenin signaling by the beta-catenin nuclear transition may be required during progression from GD-CCP to GN-CCP. Furthermore, this is the first report describing PPP2R1A mutations in gastric fundic gland-associated neoplasms. PMID- 25820419 TI - Visible-light sensitization and photoenergy storage in quantum dot/polyoxometalate systems. AB - Recently, the process by which energy is transferred from photoexcited semiconductor nanocrystals, called quantum dots (QDs), to other semiconductors has attracted much attention and has potential application in solar energy conversion (i.e., QD-sensitized solar cells). Sensitization of wide band gap polyoxometalates (POMs) to visible light by using CuInS2 QDs dispersed in an organic solution is demonstrated herein. Photoluminescence quenching and lifetime studies revealed efficient electron transfer from the CuInS2 QDs to POMs, such as SiW12 O40 and W10 O32 , that were hybridized with a cationic surfactant. CuInS2 QDs function as an antenna that absorbs visible light and supplies electrons to the POMs to enable certain photocatalytic reactions, including noble-metal-ion reduction. The photoenergy storage capabilities of the QD-POM system, in which electrons photogenerated in QDs by visible-light excitation are trapped and accommodated by POMs to form reduced POM, are also demonstrated. Electrons stored in the POM can be later discharged through reductive reactions, such as oxygen reduction, in the dark. PMID- 25820417 TI - In rectal cancer, the type of desmoplastic response after preoperative chemoradiotherapy is associated with prognosis. AB - Although the essential contribution of the desmoplastic reaction (DR) to aggressive tumor behavior is increasingly recognized, its prognostic value has not been investigated in rectal cancer after preoperative chemoradiotherapy. We retrospectively analyzed 101 consecutive patients with rectal cancer treated with short-course chemoradiotherapy followed by surgery (2001-2007). The DR in the resected primary tumor was pathologically classified into three patterns on the basis of products of cancer-associated fibroblasts (CAFs): mature (multilayered fibrotic), intermediate (keloid-like hyalinized), and immature (mostly myxoid). We classified 46 tumors as mature, 30 as intermediate, and 25 as immature DR. In addition, immunostaining of CD8(+) and FoxP3(+) cells was performed to characterize the immune response accompanying DR. Mature DR correlated with higher density of CD8(+) and FoxP3(+) cells in both resected surgical and pretreatment biopsy specimens. A significant association with DR category was observed for T stage, lymphatic invasion, and venous invasion (P <= 0.0001 0.0006). Mature DR was significantly associated with higher grade of pathological response (P = 0.0350). The 5-year disease-free survival (DFS) rates were 82, 72, and 47 % for mature, intermediate, and immature DR, respectively (P = 0.0055). On multivariate analysis, DR category and ypN were independently predictive of DFS. The pattern of the DR in rectal cancers after chemoradiotherapy treatment might have a prognostic value, as it likely reflects pretreatment desmoplastic environment. PMID- 25820420 TI - On benchmark problems, challenges, and competitions in electrokinetics-A review. AB - In this critical review, we comment on the absence of widely shared benchmark problems and relevant challenges or even attractive competitions in the field of electrokinetics. We argue that in some other scientific domains that are, similarly as electrokinetics, strongly multidisciplinary, the existence of these tools is very beneficial because it stimulates the discussion about what constitutes the bottleneck of further progress, allows easier exploitation of results provided by other scientific and engineering disciplines, and, last but not least, makes the research domain attractive and visible to a broader public, including students. The goal of this review is to provoke some discussion that might perhaps lead to compensating for these shortcomings. PMID- 25820421 TI - Modeling the relationship of epigenetic modifications to transcription factor binding. AB - Transcription factors (TFs) and epigenetic modifications play crucial roles in the regulation of gene expression, and correlations between the two types of factors have been discovered. However, methods for quantitatively studying the correlations remain limited. Here, we present a computational approach to systematically investigating how epigenetic changes in chromatin architectures or DNA sequences relate to TF binding. We implemented statistical analyses to illustrate that epigenetic modifications are predictive of TF binding affinities, without the need of sequence information. Intriguingly, by considering genome locations relative to transcription start sites (TSSs) or enhancer midpoints, our analyses show that different locations display various relationship patterns. For instance, H3K4me3, H3k9ac and H3k27ac contribute more in the regions near TSSs, whereas H3K4me1 and H3k79me2 dominate in the regions far from TSSs. DNA methylation plays relatively important roles when close to TSSs than in other regions. In addition, the results show that epigenetic modification models for the predictions of TF binding affinities are cell line-specific. Taken together, our study elucidates highly coordinated, but location- and cell type-specific relationships between epigenetic modifications and binding affinities of TFs. PMID- 25820422 TI - New insights into the performance of human whole-exome capture platforms. AB - Whole exome sequencing (WES) is increasingly used in research and diagnostics. WES users expect coverage of the entire coding region of known genes as well as sufficient read depth for the covered regions. It is, however, unknown which recent WES platform is most suitable to meet these expectations. We present insights into the performance of the most recent standard exome enrichment platforms from Agilent, NimbleGen and Illumina applied to six different DNA samples by two sequencing vendors per platform. Our results suggest that both Agilent and NimbleGen overall perform better than Illumina and that the high enrichment performance of Agilent is stable among samples and between vendors, whereas NimbleGen is only able to achieve vendor- and sample-specific best exome coverage. Moreover, the recent Agilent platform overall captures more coding exons with sufficient read depth than NimbleGen and Illumina. Due to considerable gaps in effective exome coverage, however, the three platforms cannot capture all known coding exons alone or in combination, requiring improvement. Our data emphasize the importance of evaluation of updated platform versions and suggest that enrichment-free whole genome sequencing can overcome the limitations of WES in sufficiently covering coding exons, especially GC-rich regions, and in characterizing structural variants. PMID- 25820423 TI - RoboOligo: software for mass spectrometry data to support manual and de novo sequencing of post-transcriptionally modified ribonucleic acids. AB - Ribosomal ribonucleic acid (RNA), transfer RNA and other biological or synthetic RNA polymers can contain nucleotides that have been modified by the addition of chemical groups. Traditional Sanger sequencing methods cannot establish the chemical nature and sequence of these modified-nucleotide containing oligomers. Mass spectrometry (MS) has become the conventional approach for determining the nucleotide composition, modification status and sequence of modified RNAs. Modified RNAs are analyzed by MS using collision-induced dissociation tandem mass spectrometry (CID MS/MS), which produces a complex dataset of oligomeric fragments that must be interpreted to identify and place modified nucleosides within the RNA sequence. Here we report the development of RoboOligo, an interactive software program for the robust analysis of data generated by CID MS/MS of RNA oligomers. There are three main functions of RoboOligo: (i) automated de novo sequencing via the local search paradigm. (ii) Manual sequencing with real-time spectrum labeling and cumulative intensity scoring. (iii) A hybrid approach, coined 'variable sequencing', which combines the user intuition of manual sequencing with the high-throughput sampling of automated de novo sequencing. PMID- 25820424 TI - RNA polymerase II pausing can be retained or acquired during activation of genes involved in the epithelial to mesenchymal transition. AB - Promoter-proximal RNA polymerase II (Pol II) pausing is implicated in the regulation of gene transcription. However, the mechanisms of pausing including its dynamics during transcriptional responses remain to be fully understood. We performed global analysis of short capped RNAs and Pol II Chromatin Immunoprecipitation sequencing in MCF-7 breast cancer cells to map Pol II pausing across the genome, and used permanganate footprinting to specifically follow pausing during transcriptional activation of several genes involved in the epithelial to mesenchymal transition (EMT). We find that the gene for EMT master regulator Snail (SNAI1), but not Slug (SNAI2), shows evidence of Pol II pausing before activation. Transcriptional activation of the paused SNAI1 gene is accompanied by a further increase in Pol II pausing signal, whereas activation of non-paused SNAI2 gene results in the acquisition of a typical pausing signature. The increase in pausing signal reflects increased transcription initiation without changes in Pol II pausing. Activation of the heat shock HSP70 gene involves pausing release that speeds up Pol II turnover, but does not change pausing location. We suggest that Pol II pausing is retained during transcriptional activation and can further undergo regulated release in a signal specific manner. PMID- 25820425 TI - The structural impact of DNA mismatches. AB - The structure and dynamics of all the transversion and transition mismatches in three different DNA environments have been characterized by molecular dynamics simulations and NMR spectroscopy. We found that the presence of mismatches produced significant local structural alterations, especially in the case of purine transversions. Mismatched pairs often show promiscuous hydrogen bonding patterns, which interchange among each other in the nanosecond time scale. This therefore defines flexible base pairs, where breathing is frequent, and where distortions in helical parameters are strong, resulting in significant alterations in groove dimension. Even if the DNA structure is plastic enough to absorb the structural impact of the mismatch, local structural changes can be propagated far from the mismatch site, following the expected through-backbone and a previously unknown through-space mechanism. The structural changes related to the presence of mismatches help to understand the different susceptibility of mismatches to the action of repairing proteins. PMID- 25820426 TI - Significance of ligand interactions involving Hop2-Mnd1 and the RAD51 and DMC1 recombinases in homologous DNA repair and XX ovarian dysgenesis. AB - The evolutionarily conserved Hop2-Mnd1 complex is a key cofactor for the meiosis specific recombinase Dmc1. However, emerging evidence has revealed that Hop2-Mnd1 is expressed in somatic tissues, primary human fibroblasts and cell lines, and that it functions in conjunction with the Rad51 recombinase to repair damaged telomeres via the alternate lengthening of telomeres mechanism. Here, we reveal how distinct DNA-binding activities of Hop2-Mnd1 mediate the stabilization of the RAD51-ssDNA presynaptic filament or stimulate the homologous DNA pairing reaction. We have also endeavored to define the interface that governs the assembly of the higher order complex of Hop2-Mnd1 with RAD51. Unexpectedly, we find that ATP enhances the interaction between Hop2-Mnd1 and RAD51, and that both Hop2 and Mnd1 are involved in RAD51 interaction via their C-terminal regions. Importantly, mutations introduced into these Hop2 and Mnd1 domains, including the HOP2 p.del201Glu mutation present in a patient of XX ovarian dysgenesis, diminish the association and functional synergy of Hop2-Mnd1 with both RAD51 and DMC1. Our findings help delineate the intricate manner in which Hop2-Mnd1 engages and functions with RAD51 and DMC1 in mammalian cells and speak to the possible cause of XX ovarian dysgenesis. PMID- 25820427 TI - A method for mutagenesis of mouse mtDNA and a resource of mouse mtDNA mutations for modeling human pathological conditions. AB - Mutations in human mitochondrial DNA (mtDNA) can cause mitochondrial disease and have been associated with neurodegenerative disorders, cancer, diabetes and aging. Yet our progress toward delineating the precise contributions of mtDNA mutations to these conditions is impeded by the limited availability of faithful transmitochondrial animal models. Here, we report a method for the isolation of mutations in mouse mtDNA and its implementation for the generation of a collection of over 150 cell lines suitable for the production of transmitochondrial mice. This method is based on the limited mutagenesis of mtDNA by proofreading-deficient DNA-polymerase gamma followed by segregation of the resulting highly heteroplasmic mtDNA population by means of intracellular cloning. Among generated cell lines, we identify nine which carry mutations affecting the same amino acid or nucleotide positions as in human disease, including a mutation in the ND4 gene responsible for 70% of Leber Hereditary Optic Neuropathies (LHON). Similar to their human counterparts, cybrids carrying the homoplasmic mouse LHON mutation demonstrated reduced respiration, reduced ATP content and elevated production of mitochondrial reactive oxygen species (ROS). The generated resource of mouse mtDNA mutants will be useful both in modeling human mitochondrial disease and in understanding the mechanisms of ROS production mediated by mutations in mtDNA. PMID- 25820428 TI - A thesaurus of genetic variation for interrogation of repetitive genomic regions. AB - Detecting genetic variation is one of the main applications of high-throughput sequencing, but is still challenging wherever aligning short reads poses ambiguities. Current state-of-the-art variant calling approaches avoid such regions, arguing that it is necessary to sacrifice detection sensitivity to limit false discovery. We developed a method that links candidate variant positions within repetitive genomic regions into clusters. The technique relies on a resource, a thesaurus of genetic variation, that enumerates genomic regions with similar sequence. The resource is computationally intensive to generate, but once compiled can be applied efficiently to annotate and prioritize variants in repetitive regions. We show that thesaurus annotation can reduce the rate of false variant calls due to mappability by up to three orders of magnitude. We apply the technique to whole genome datasets and establish that called variants in low mappability regions annotated using the thesaurus can be experimentally validated. We then extend the analysis to a large panel of exomes to show that the annotation technique opens possibilities to study variation in hereto hidden and under-studied parts of the genome. PMID- 25820429 TI - The feedback control of UPF3 is crucial for RNA surveillance in plants. AB - Nonsense-mediated-decay (NMD) is a eukaryotic RNA surveillance mechanism that controls the levels of both aberrant and normal transcripts. The regulation of this process is not well understood. The Arabidopsis NMD factor UPF3 is regulated by a negative feedback-loop that targets its own transcript for NMD. We investigated the functional significance of this control for the overall regulation of NMD in Arabidopsis. For this, we tested the ability of NMD sensitive and -insensitive forms of UPF3, expressed under the control of UPF3 promoter, to complement NMD functionality in NMD-mutant plants and investigated their impact in wild-type (WT) plants. The sensitivity of UPF3 transcript to NMD was essential for efficient complementation of NMD in upf3 mutants. Upregulated UPF3 expression in WT plants resulted in over-degradation of certain transcripts and inhibited degradation of other transcripts. Our results demonstrate that, in contrast to mammalian cells, a delicate balance of UPF3 transcript levels by its feedback loop and by restriction of its transcription, are crucial for proper NMD regulation in Arabidopsis. Interestingly, the levels of many small-nucleolar-RNAs (snoRNAs) were decreased in upf1 and upf3 mutants and increased upon enhanced UPF3 expression. This suggests that proper snoRNA homeostasis in Arabidopsis depends on the integrity of the NMD pathway. PMID- 25820431 TI - IntFOLD: an integrated server for modelling protein structures and functions from amino acid sequences. AB - IntFOLD is an independent web server that integrates our leading methods for structure and function prediction. The server provides a simple unified interface that aims to make complex protein modelling data more accessible to life scientists. The server web interface is designed to be intuitive and integrates a complex set of quantitative data, so that 3D modelling results can be viewed on a single page and interpreted by non-expert modellers at a glance. The only required input to the server is an amino acid sequence for the target protein. Here we describe major performance and user interface updates to the server, which comprises an integrated pipeline of methods for: tertiary structure prediction, global and local 3D model quality assessment, disorder prediction, structural domain prediction, function prediction and modelling of protein-ligand interactions. The server has been independently validated during numerous CASP (Critical Assessment of Techniques for Protein Structure Prediction) experiments, as well as being continuously evaluated by the CAMEO (Continuous Automated Model Evaluation) project. The IntFOLD server is available at: http://www.reading.ac.uk/bioinf/IntFOLD/. PMID- 25820430 TI - Distribution of DNA-condensing protein complexes in the adenovirus core. AB - Genome packing in adenovirus has long evaded precise description, since the viral dsDNA molecule condensed by proteins (core) lacks icosahedral order characteristic of the virus protein coating (capsid). We show that useful insights regarding the organization of the core can be inferred from the analysis of spatial distributions of the DNA and condensing protein units (adenosomes). These were obtained from the inspection of cryo-electron tomography reconstructions of individual human adenovirus particles. Our analysis shows that the core lacks symmetry and strict order, yet the adenosome distribution is not entirely random. The features of the distribution can be explained by modeling the condensing proteins and the part of the genome in each adenosome as very soft spheres, interacting repulsively with each other and with the capsid, producing a minimum outward pressure of ~0.06 atm. Although the condensing proteins are connected by DNA in disrupted virion cores, in our models a backbone of DNA linking the adenosomes is not required to explain the experimental results in the confined state. In conclusion, the interior of an adenovirus infectious particle is a strongly confined and dense phase of soft particles (adenosomes) without a strictly defined DNA backbone. PMID- 25820432 TI - Transgenerational plasticity mitigates the impact of global warming to offspring sex ratios. AB - Global warming poses a threat to organisms with temperature-dependent sex determination because it can affect operational sex ratios. Using a multigenerational experiment with a marine fish, we provide the first evidence that parents developing from early life at elevated temperatures can adjust their offspring gender through nongenetic and nonbehavioural means. However, this adjustment was not possible when parents reproduced, but did not develop, at elevated temperatures. Complete restoration of the offspring sex ratio occurred when parents developed at 1.5 degrees C above the present-day average temperature for one generation. However, only partial improvement in the sex ratio occurred at 3.0 degrees C above average conditions, even after two generations, suggesting a limitation to transgenerational plasticity when developmental temperature is substantially increased. This study highlights the potential for transgenerational plasticity to ameliorate some impacts of climate change and that development from early life may be essential for expression of transgenerational plasticity in some traits. PMID- 25820433 TI - Lysosomal membrane stability of the mussel, Mytilus galloprovincialis (L.), as a biomarker of tributyltin exposure. AB - The effect of tributyltin (TBT) on the stability of hemocytic lysosome membranes of the mussel, Mytilus galloprovincialis, and the use thereof as a biomarker of TBT-induced stress, was investigated. Mussels were exposed to 0.1 and 1.0 ug/L tributyltin respectively for 4 weeks. Lysosomal membrane stability of hemocytes was tested weekly by means of the neutral red retention time (NRRT) assay, after which the mussel samples were analyzed for TBT content. The two exposed groups exhibited significantly increased (p < 0.05) whole body TBT concentrations with concomitant significant decreases (p < 0.05) in NRRT (R(2) values of 0.85 and 0.971 for lower and higher exposure groups, respectively). The higher exposure group showed a typical dose-response curve. For the control, no TBT was detected and NRRT remained stable. It was concluded that the NRRT assay could be considered as a useful technique, and lysosomal membrane destabilization a useful early warning and cellular biomarker of stress due to TBT exposure in M. galloprovincialis. PMID- 25820434 TI - Identification of a new microcystin-degrading bacterium isolated from Lake Chaohu, China. AB - A microcystin-LR (MC-LR)-degrading bacterium was isolated from Lake Chaohu, a eutrophic freshwater lake containing toxic cyanobacterial blooms. Based on the analysis of 16S rDNA gene sequence and physiobiochemical characteristics, the isolated strain, most likely belongs to the genus Bacillus with the highest sequence similarity value with Bacillus nanhaiencis strain K-W39 (JQ799091.1), was named B. nanhaiencis strain JZ-2013. The strain JZ-2013 could grow on mineral salt medium supplied with MC-LR as sole carbon and nitrogen sources. The optimal temperature and pH for strain JZ-2013 growth and MC-LR biodegradation were 30 degrees C and 8.0, respectively. The MC-LR with the initial concentration of 15 mg/L could be consumed 80 % by strain JZ-2013 within 9 days. The existence of exogenous carbon and nitrogen sources could significantly increase the removal efficiency of MC-LR. The strain JZ-2013 can efficiently removed MC-LR of low concentration in real water sample. PMID- 25820435 TI - Cognitive predictors and risk factors of PTSD following stillbirth: a short-term longitudinal study. AB - This short-term longitudinal study investigated cognitive predictors and risk factors of posttraumatic stress disorder (PTSD) in mothers following stillbirth. After a stillbirth at >= 24 weeks gestational age, 65 women completed structured clinical interviews and questionnaires assessing PTSD symptoms, cognitive predictors (appraisals, dysfunctional strategies), and risk factors (perceived social support, trauma history, obstetric history) at 3 and 6 months. PTSD symptoms decreased between 3 and 6 months (Cohen's d ranged .34-.52). Regression analyses also revealed a specific positive relationship between Rumination and concurrent frequency of PTSD symptoms (beta = .45). Negative Self-View and Negative World-View related positively and Self-Blame related negatively to concurrent number of PTSD symptoms (beta = .48, .44, -.45, respectively). Suppression and Distraction predicted a decrease and Numbing predicted an increase in time-lagged number of PTSD symptoms (beta = -.33, -.28, .30, respectively). Risk factors for PTSD symptoms were younger age (beta = -.25), lower income (beta = -.29), fewer previous pregnancies (beta = -.31), and poorer perceived social support (beta = -.26). Interventions addressing negative appraisals, dysfunctional strategies, and social support are recommended for mothers with PTSD following stillbirth. Knowledge of cognitive predictors and risk factors of PTSD may inform the development of a screening instrument. PMID- 25820436 TI - Ovarian cancer prevention: Time for primetime? PMID- 25820438 TI - In memoriam: L. Emmerson Ward, MD, 1918-2014. PMID- 25820437 TI - Proton therapy for pediatric and adolescent esthesioneuroblastoma. AB - BACKGROUND: Esthesioneuroblastoma (EN) of the paranasal sinus comprises less than 3% of tumors of in pediatric and adolescent patients [1]. The collective adult literature indicates a critical role for radiotherapy in attaining cure [2], yet pediatric outcome data is limited. Radiation in pediatric patients with EN can cause significant morbidity due to the proximity of critical structures. Proton radiotherapy offers a potential dosimetric benefit that may improve long-term survival and toxicity outcomes in the pediatric population [3]. METHODS: We retrospectively identified eight patients treated for EN with proton radiotherapy from 2000-2013. Times to event clinical endpoints are summarized using the Kaplan Meier methods and are from the date of radiotherapy completion. Toxicities are reviewed and graded according to CTCAE v. 4.0. RESULTS: Median follow up was 4.6 years for survivors (range 0.8-9.4 years). The 4 year overall survival was 87.5%. Four of eight patients (one elective) had comprehensive neck radiotherapy. No local or regional failures were observed. Two patients failed distantly with diffuse leptomeningeal disease and intraparenchymal brain metastases, at 0.6 and 1.3 months respectively. Four patients developed radiation related late toxicities including endocrine dysfunction, two cases of grade 2 retinopathy and one case of grade 3 optic neuropathy. CONCLUSIONS: In a limited cohort, proton radiotherapy appears to provide excellent locoregional disease control even in those patients with locally advanced disease and intracranial extension. Distant failure determined overall survival in our cohort. Toxicities were acceptable given disease location and extent. PMID- 25820442 TI - Red emissive AIE luminogens with high hole-transporting properties for efficient non-doped OLEDs. AB - Two bifunctional red AIE luminogens with efficient solid-state emission and good hole-transporting characteristics are reported. Efficient non-doped OLEDs are fabricated with high external quantum efficiencies of up to 3.9%. Bilayer EL devices using them as both EMLs and HTLs are fabricated with good performances. PMID- 25820444 TI - [Molecular diagnostics in neuropathology]. AB - As in only few other areas of oncology, molecular markers in neurooncology have become an integral part of clinical decision-making. This development is driven by a bustling scientific activity exploring the molecular basis and pathogenesis of human brain tumors. In addition, a high percentage of brain tumor patients are included in clinical studies in which molecular markers are assessed and linked with clinical informativeness. First steps towards more differentiated therapeutic strategies against brain tumors have thus been taken. The implementation in the clinical and diagnostic routine requires a detailed knowledge and a close collaboration between all medical disciplines involved. PMID- 25820445 TI - [Molecular diagnostics of non-small cell lung cancer: New markers and technologies]. AB - Lung cancer is the prototypical tumor entity for the development of new diagnostic and individualized therapeutic strategies based on molecular patient stratification. Developments in this field specifically concentrate on predictive biomarkers for the response to conventional therapeutic agents, novel drugs targeting specific mutations and also new immunomodulatory drugs. The multitude of upcoming new predictive biomarkers requires the development and implementation of efficient test strategies and comprehensive technical methods, specifically when tissue restrictions inherent to lung cancer diagnostics are also taken into account. Novel procedures and technical aspects of these issues are discussed in this review. PMID- 25820446 TI - [Histological diagnosis and complications of celiac disease. Update according to the new S2k guidelines]. AB - Celiac disease is a relatively common immunological systemic disease triggered by the protein gluten in genetically predisposed individuals. Classical symptoms like chronic diarrhea, steatorrhea, weight loss and growth retardation are nowadays relatively uncommon. Diagnostic workup includes serological tests for IgA antibodies against tissue transglutaminase 2 (anti-TG2-IgA) and total IgA and histology of duodenal biopsies. Histomorphological classification should be done according to the modified Marsh-Oberhuber classification. Diagnosis of celiac disease should be based on serological, clinical, and histological findings. The only treatment is a life-long gluten-free diet. Unchanged or recurrent symptoms under gluten-free diet may indicate refractory celiac disease. Enteropathy associated T-cell lymphoma and adenocarcinomas of the small intestine are known complications of celiac disease. PMID- 25820447 TI - Lactogenic hormone stimulation and epigenetic control of L-amino acid oxidase expression in lactating mammary glands. AB - L-amino acid oxidase (LAO), a classic flavoprotein, shows antibacterial activity by producing hydrogen peroxide. LAO exists in many tissues such as salivary gland, thymus, spleen, small intestine and testis. In particular, LAO was highly expressed in mice milk and plays an important factor in innate immunity of mammary glands. However, the mechanism which LAO expression is regulated spatially and temporally in lactating mammary glands has been unclear. In this study, we showed the contribution of lactogenic hormone and epigenetic control on LAO gene expression. In monolayer of mammary epithelial cells, treatment of lactogenic hormone mixture, dexamethasone, insulin and prolactin, did not induce LAO mRNA expression and its promoter activity, even though one of milk protein beta-casein expression was stimulated. However, increase of LAO expression was observed when the cells were treated with lactogenic hormones in a 3-dimensional culture. The results of chromatin immunoprecipitation analysis revealed that histone H3K18 acetylation increased and histone H3K27 tri-methylation decreased with lactation, which is associated with a period of high LAO expression. Moreover, the treatment of histone methylation inhibitor (DZNep) as well as histone deacetylation inhibitor (Trichostatine A) induced LAO expression in monolayer of mammary cells. Taken together, this is the first demonstration showing that LAO expression is induced in cell culture, and stimulation of lactogenic hormone and change of histone modification are promising signals to show highly expression of LAO in lactating mammary glands. PMID- 25820449 TI - Detergent-Stable Salt-Activated Proteinases from Virgibacillus halodenitrificans SK1-3-7 Isolated from Fish Sauce Fermentation. AB - The NaCl-activated and detergent-stable proteinases from Virgibacillus halodenitrificans SK1-3-7 isolated from fish sauce fermentation were purified and characterized. The enzymes with molecular masses of 20 and 36 kDa showed caseinolytic activity on a zymogram. Optimum azocaseinolytic activity was at 60 degrees C and pH 9. The proteolytic activity increased in the presence of 10 mM CaCl2 and 0.5 M NaCl and showed high stability at 0-2 M NaCl. The enzymes were stable at pH 4-10 and 10-50 degrees C. The enzymes preferably hydrolyzed Suc-Ala Ala-Pro-Phe-pNA and were completely inhibited by phenylmethanesulfonyl fluoride (PMSF), showing subtilisin-like characteristics. Activity and stability remained high in the presence of H2O2 and various surfactants. The enzymes exhibited high stability (>95%) in various organic solvents (DMSO, butanol, ethanol, 2-propanol, and acetonitrile) at concentration of 50%. The V. halodenitrificans SK1-3-7 proteinases showed potential as a biocatalyst in aqueous-organic solvent systems and as an additive in laundry detergent. PMID- 25820450 TI - Expression and Characterization of a Recombinant Laccase with Alkalistable and Thermostable Properties from Streptomyces griseorubens JSD-1. AB - Streptomyces griseorubens JSD-1 is a novel actinomycete that could grow efficiently upon lignin, and the ligninolytic genes active in this biotransformation were expected to be crucial. To investigate the molecular mechanism of utilizing lignin, genome sequencing was carried out to obtain its draft genome, which was deposited at GenBank under the accession No. JJMG00000000. Multiple copper oxidase (MCO) was obtained, which proved to be an extracellular enzyme and have relative high expression with the stimulation of ligninolytic materials. Judging from its putative 3D structure, the N-terminal of MCO was bared, which was fit for the linkage of poly-HIS10 tag. As a result, heterogeneous expression conditions of recombinant laccase was achieved with TransB(DE3) grown in a modified terrific broth (TB) medium with an extra addition of 0.5% glucose at 30 degrees C until optical density at 600 nm (OD600) reached 0.8 when expression was induced by 25 MUM isopropyl beta-D-1 thiogalactopyranoside (IPTG) and also 100 MUM copper sulphate as supplement. Finally, it exhibited special characters of thermal robustness, alkaline activity profiles, high resistance to metallic ions and chemical inhibitors as well as dye decolourization. In summary, our findings illustrated the genetic basic of utilizing lignin in this isolate. Additionally, a novel laccase expected to be potential in agricultural and industrial application was expressed and characterized as well. PMID- 25820452 TI - Deciding who should be treated for hepatitis C infection in a rapidly changing therapeutic landscape. PMID- 25820453 TI - Call for studies in implementation science: improving reading comprehension in school-age children. AB - PURPOSE: In this article, the Editor of Language, Speech, and Hearing Services in Schools makes the case for more studies in implementation science in order to improve the reading comprehension of school-age children, particularly those with specific language impairment and nonspecific language impairment. PMID- 25820451 TI - Asymptomatic metastasis to cricoid from prostate carcinoma: an incidental finding detected on 18F-choline PET/CT. AB - Metastases to the larynx from prostate carcinoma are rare. We describe a case of asymptomatic prostate carcinoma metastasis to the right cricoid cartilage detected on 18F-fluorocholine PET/CT. This was histologically proven on open biopsy and the patient was offered local radiotherapy. PMID- 25820448 TI - Patterning, specification, and differentiation in the developing hypothalamus. AB - Owing to its complex structure and highly diverse cell populations, the study of hypothalamic development has historically lagged behind that of other brain regions. However, in recent years, a greatly expanded understanding of hypothalamic gene expression during development has opened up new avenues of investigation. In this review, we synthesize existing work to present a holistic picture of hypothalamic development from early induction and patterning through nuclear specification and differentiation, with a particular emphasis on determination of cell fate. We will also touch on special topics in the field including the prosomere model, adult neurogenesis, and integration of migratory cells originating outside the hypothalamic neuroepithelium, and how these topics relate to our broader theme. PMID- 25820454 TI - Do nitric oxide synthase and cyclooxygenase contribute to the heat loss responses in older males exercising in the heat? AB - This study evaluated the separate and combined roles of nitric oxide synthase (NOS) and cyclooxygenase (COX) in forearm sweating and cutaneous vasodilatation in older adults during intermittent exercise in the heat. Twelve healthy older (62 +/- 7 years) males performed two 30 min cycling bouts at a fixed rate of metabolic heat production (400 W) in the heat (35 degrees C, 20% relative humidity). The exercise bouts were followed by 20 and 40 min of recovery, respectively. Forearm sweat rate (ventilated capsule) and cutaneous vascular conductance (CVC, laser Doppler perfusion units/mean arterial pressure) were evaluated at four skin sites that were continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control), (2) 10 mm ketorolac (non-selective COX inhibitor), (3) 10 mm N(G) -nitro-l-arginine methyl ester (l NAME; non-selective NOS inhibitor) or (4) a combination of 10 mm ketorolac + 10 mm l-NAME. Sweating was not different between the four sites during either exercise bout (main effect P = 0.92) (average of last 5 min of second exercise, Control, 0.80 +/- 0.06; ketorolac, 0.77 +/- 0.09; l-NAME, 0.74 +/- 0.07; ketorolac + l-NAME, 0.77 +/- 0.09 mg min(-1) cm(-2) ). During both exercise bouts, relative to CVC evaluated at the Control site (average of last 5 min of second exercise, 69 +/- 6%max), CVC was similar at the ketorolac site (P = 0.62; 66 +/- 4%max) whereas it was attenuated to a similar extent at both the l-NAME (49 +/- 8%max) and ketorolac + l-NAME (54 +/- 8%max) sites (both P < 0.05). Thus, we demonstrate that NOS and COX are not functionally involved in forearm sweating whereas only NOS contributes to forearm cutaneous vasodilatation in older adults during intermittent exercise in the heat. PMID- 25820455 TI - A case study of brain morphometry in triplets discordant for Down syndrome. AB - Down syndrome, the most common genetic cause of intellectual disability, offers the opportunity to explore the associations between genetics and both neuroanatomic and neuropsychological phenotypes. This case report summarizes the findings of a neuroimaging and neuropsychology study of two adolescent females with Down syndrome and their same-sex discordant triplet siblings (one from each family; n = 4). Using high-resolution magnetic resonance imaging and surface based morphometric approaches, we offer the first in vivo report of cortical surface area reductions and increases in the thickness of the cortical sheet in youth with Down syndrome relative to their typically developing same-sex triplet siblings. PMID- 25820457 TI - Liposomes as a model for the study of high frequency dielectrophoresis. AB - Liposomes were used as a physical model to study the dielectrophoretic response of single-shelled particles at high frequencies. For a typical particle, the single-shelled theoretical model predicts a lower cross-over frequency that depends upon the dielectric properties of the shell and an upper crossover frequency that depends upon the dielectric properties of the interior. Dried liposomes were rehydrated in media with conductivity ranging from 100 to 2000 MUS/cm. The high frequency dielectrophoresis response of the liposomes was observed in the range of 1-80 MHz at 30 volts peak-to-peak, and the upper cross over frequency was recorded. The experimental results closely matched the theoretical expectations. In particular, the upper cross-over frequency ranged from 9 to 60 MHz and was found to depend linearly on the interior conductivity of the liposome. These results further confirm the single-shell model at high frequencies. Moreover, they suggest liposomes may be a useful model particle for use during the development of dielectrophoresis-based devices. PMID- 25820456 TI - Concussion recovery time among high school and collegiate athletes: a systematic review and meta-analysis. AB - BACKGROUND: Concussion diagnosis and management is made through the clinical exam using assessment tools that include self-report symptomatology, postural control, and cognitive evaluations. The specific timing of concussion resolution varies between individuals. However, despite a lack of research in concussion recovery, it is widely accepted that the majority of young adults will recover in 7-10 days, with youth athletes taking longer. OBJECTIVES: The purpose of this review is to directly compare the recovery duration among high school and collegiate athletes on symptom reports and cognitive assessments following concussion. DATA SOURCES: Data were collected from a literature search comprising high school or college athletes only. This included studies (n = 6) that reported symptom or cognitive performance recovery to the exact day. RESULTS: High school athletes self-reported symptom recovery at 15 days compared with 6 days in collegiate athletes. Both college and high school athletes showed cognitive recovery at similar rates of 5 and 7 days. LIMITATIONS: This review only included articles that were directly related to concussed high school or college athletes. Additionally, athletes in the high school and college setting typically receive a battery of neurocognitive tests that may not be as sensitive or as comprehensive as a full neuropsychological exam. CONCLUSION: The review finds that neurocognitive recovery rates are similar among high school and college athletes, while symptom reporting shows longer recovery time points in high school than in college. IMPLICATIONS OF KEY FINDINGS: An individualized and stepwise concussion management plan is important for proper concussion recovery regardless of age. PMID- 25820458 TI - Signal-to-noise ratio and MR tissue parameters in human brain imaging at 3, 7, and 9.4 tesla using current receive coil arrays. AB - PURPOSE: Relaxation times, transmit homogeneity, signal-to-noise ratio (SNR) and parallel imaging g-factor were determined in the human brain at 3T, 7T, and 9.4T, using standard, tight-fitting coil arrays. METHODS: The same human subjects were scanned at all three field strengths, using identical sequence parameters and similar 31- or 32-channel receive coil arrays. The SNR of three-dimensional (3D) gradient echo images was determined using a multiple replica approach and corrected with measured flip angle and T2 (*) distributions and the T1 of white matter to obtain the intrinsic SNR. The g-factor maps were derived from 3D gradient echo images with several GRAPPA accelerations. RESULTS: As expected, T1 values increased, T2 (*) decreased and the B1 -homogeneity deteriorated with increasing field. The SNR showed a distinctly supralinear increase with field strength by a factor of 3.10 +/- 0.20 from 3T to 7T, and 1.76 +/- 0.13 from 7T to 9.4T over the entire cerebrum. The g-factors did not show the expected decrease, indicating a dominating role of coil design. CONCLUSION: In standard experimental conditions, SNR increased supralinearly with field strength (SNR ~ B0 (1.65) ). To take full advantage of this gain, the deteriorating B1 -homogeneity and the decreasing T2 (*) have to be overcome. PMID- 25820459 TI - Suzuki Coupling Reactions Catalyzed by PdO Dispersed on Dealuminated Y Zeolite in Air under Ambient Conditions. AB - Suzuki coupling reactions are performed using PdO loaded on dealuminated Y (USY) zeolite. The reaction between bromobenzene and phenylboronic acid is complete in 15 min at room temperature in air, with a turnover number of 1300. The reaction can be repeated at least five times by using 1 wt % Pd. Inductively coupled plasma analysis does not reveal the dissolution of Pd from products, even if the reaction is repeated up to four times. Pd K-edge extended X-ray absorption fine structure analysis reveals the presence of molecular-like PdO and a mixture of Pd(0) -PdO before and after the reaction, respectively. This is probably because Pd stabilized by Al sites is present at the II sites of the Y-type zeolite, as estimated using first-principles calculations. Conversely, Pd species change to PdO clusters after repeated reactions in air using the thermally treated sample. PMID- 25820460 TI - Contact effects in thin 3D-topological insulators: how does the current flow? AB - The effect of different contact configurations (semi-infinite extended-channel, normal metal and ferromagnetic metal) on quantum transport through thin Bi2Se3 three-dimensional (3D) topological insulator (TI) slab (channel) has been investigated through Non-Equilibrium Green Function. The issue of contact dependent current flow and distribution across quintuple layers of 3D-TI has been addressed in this work and applied to expound the explanation for recent experimental work on electrical detection of spin-momentum locking on topological surface for long channel device. A theoretical model is propounded to develop a microscopic understanding of transport in 3D-TI in which contact type and magnetization concur with helical surface states of the TI channel to manifest seemingly counter-intuitive current distribution across layers. The quantum transport calculations for short channel devices with magnetic source and drain contacts postulate negative surface current for anti-phase magnetization whose axis is transverse to both current and quintuple layers. For in-phase magnetization at the two terminals, it is shown that observations can change fundamentally to result in anomalous current distribution. Such results are explained to stem from the confinement of 3D-TI between ferromagnetic contacts along the transport direction. A simple mechanism to validate topological insulators via quantum transport experiments has also been suggested. PMID- 25820461 TI - Recent progress on pyrazole scaffold-based antimycobacterial agents. AB - New and reemerging infectious diseases will continue to pose serious global health threats well into the 21st century and according to the World Health Organization report, these are still the leading cause of death among humans worldwide. Among infectious diseases, tuberculosis claims approximately 2 million deaths per year worldwide. Also, agents that reduce the duration and complexity of the current therapy would have a major impact on the overall cure rate. Due to the development of resistance to conventional antibiotics there is a need for new therapeutic strategies to combat Mycobacterium tuberculosis. Subsequently, there is an urgent need for the development of new drug candidates with newer targets and alternative mechanism of action. In this perspective, pyrazole, one of the most important classes of heterocycles, has been the topic of research for thousands of researchers all over the world because of its wide spectrum of biological activities. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review, we have collated published reports on the pyrazole core to provide an insight so that its full therapeutic potential can be utilized for the treatment of tuberculosis. In this article, the possible structure-activity relationship of pyrazole analogs for designing better antituberculosis (anti-TB) agents has been discussed and is also helpful for new thoughts in the quest for rational designs of more active and less toxic pyrazole-based anti-TB drugs. PMID- 25820462 TI - Mechanical interplay between invadopodia and the nucleus in cultured cancer cells. AB - Invadopodia are actin-rich membrane protrusions through which cells adhere to the extracellular matrix and degrade it. In this study, we explored the mechanical interactions of invadopodia in melanoma cells, using a combination of correlative light and electron microscopy. We show here that the core actin bundle of most invadopodia interacts with integrin-containing matrix adhesions at its basal end, extends through a microtubule-rich cytoplasm, and at its apical end, interacts with the nuclear envelope and indents it. Abolishment of invadopodia by microtubules or src inhibitors leads to the disappearance of these nuclear indentations. Based on the indentation profile and the viscoelastic properties of the nucleus, the force applied by invadopodia is estimated to be in the nanoNewton range. We further show that knockdown of the LINC complex components nesprin 2 or SUN1 leads to a substantial increase in the prominence of the adhesion domains at the opposite end of the invadopodia. We discuss this unexpected, long-range mechanical interplay between the apical and basal domains of invadopodia, and its possible involvement in the penetration of invadopodia into the matrix. PMID- 25820464 TI - Digestive absorption of silicon, supplemented as orthosilicic acid-vanillin complex. AB - SCOPE: Silicon (Si) is an abundant element on earth. It is found naturally in water in the form of orthosilicic acid (OSA), however this form is not stable under certain conditions such as in highly concentrated and non-neutral pH solutions, which lead to its polymerization and reduced bioavailability. This study aimed to assess the bioavailability of Si from OSA stabilized by vanillin (OSA-VC). METHODS AND RESULTS: This was a single-center, double-blind, cross-over randomized controlled trial. Fourteen healthy subjects were recruited and consumed either OSA-VC or a placebo on two separate occasions. Blood and urine samples were collected during 6 h following ingestion and analyzed to determine Si absorption and excretion. Plasma Si area under the curve (0-6 h) was significantly higher after OSA-VC ingestion compared to placebo ingestion (p = 0.0002). Significantly higher urinary Si excretion was also reported over the 6-h period after OSA-VC ingestion compared to placebo (p<0.0001). Approximately 21% of ingested Si was excreted in urine during this period. CONCLUSION: Although many studies have investigated the metabolism and bioavailability of Si supplemented in foods or as a food ingredient, this was the first to investigate and demonstrate the digestibility of OSA administered in a complex form with vanillin. PMID- 25820463 TI - Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome. AB - Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. PMID- 25820465 TI - Endoscopic endonasal resection of clival xanthoma: case report and literature review. AB - Bone xanthoma is an extremely rare and benign tumor in terms of its nature and growth over time. We describe the first case coexisting with ventriculomegaly secondary to aqueduct stenosis (non-tumoral hydrocephalus), the second xanthoma of the clivus described to date. The patient was a 51-year-old woman with headaches and absence seizures. Axial T1-weighted MRI showed a well-demarcated, hypointense, osteolytic, 25 * 18 * 15 mm lesion with cortical erosion located at the right margin of the clivus. Sagittal T2-weighted MRI demonstrated a hypointense mass without associated edema. Sagittal gadolinium-enhanced T1 weighted MRI showed contrast uptake with a partially hypointense rim. The increased ventricular size without periventricular edema was associated with aqueduct stenosis, and there was no contiguity with the tumor. A neuronavigation image-guided transsphenoidal approach was chosen to perform a macroscopically complete resection. Intraoperative histopathological study showed a chordoma of the clivus. Exhaustive postsurgical study revealed the benign nature of a bone xanthoma. Given the finding of a clival lesion, the differential diagnosis is essentially with other malignant entities with a rapidly fatal outcome, such as metastases, or with a possible invasive evolution, such as clivus chordomas. This report describes the clinical, radiological, and pathological keys for such differentiation in order to avoid unnecessarily aggressive treatment with ablative surgery and radiotherapy. PMID- 25820466 TI - Pu-erh tea polysaccharides decrease blood sugar by inhibition of alpha glucosidase activity in vitro and in mice. AB - Type 2 diabetes is mainly induced by environmental factors such as being overweight, decreased physical activity and inbalanced energy metabolism, such as pancreatic beta-cell dysfunction and peripheral insulin resistance. Acarbose, a microbial carbohydrate and an alpha-glucosidase inhibitor, is currently a useful agent for attenuating type 2 diabetes. However, it is usually accompanied by many side effects, such as abdominal distention, flatulence, diarrhea and meteorism. These side effects may be caused by its strong inhibition of alpha-amylase, leading to the accumulation of several undigested carbohydrates. The bacteria residing in the colon can further ferment the undigested carbohydrate to release gas. Finding a new alpha-glucosidase inhibitor with a low inhibitory effect on alpha-amylase is highly anticipated. In this report we describe a group of carbohydrates found in pu-erh tea polysaccharide (PTPS) that can inhibit alpha glucosidase but have less of an inhibitory effect on alpha-amylase. The preliminary experiments on mice indicate that PTPS might be better than acarbose at suppressing blood glucose after oral administration of a carbohydrate diet; it is recommended that further clinical trials are required in type 2 diabetes in future studies. PMID- 25820468 TI - Mechanofluorochromic materials based on aggregation-induced emission-active boron ketoiminates: regulation of the direction of the emission color changes. AB - We report a series of mechanofluorochromic (MFC) compounds based on organoboron complexes with aggregation-induced emission (AIE) characteristics. We synthesized a variety of boron ketoiminates and investigated the effect of the substituents on the optical properties by altering the end groups in the compounds. The synthesized boron ketoiminates showed AIE properties and MFC behavior. Interestingly, the hypsochromic and bathochromic shifts of the emission bands individually observed for boron ketoiminates depended on the chemical structures of the end groups. From the X-ray diffraction and differential scanning calorimetry analyses, it was confirmed that the MFC property of boron ketoiminates should be derived from a phase transition between crystalline and amorphous states. In addition, the direction of the peak shifts of the emission bands was controlled by the degree of steric hindrance of the end group. PMID- 25820467 TI - H2 Treatment Attenuated Pain Behavior and Cytokine Release Through the HO-1/CO Pathway in a Rat Model of Neuropathic Pain. AB - Neuropathic pain (NP) is characterized by persistent pain, tactile allodynia, or hyperalgesia. Peripheral nerve injury contributes to rapid progress of inflammatory response and simultaneously generates neuropathic pain. Hydrogen (H2) has anti-inflammation, anti-apoptosis, and anti-oxidative stress effects. Therefore, we hypothesized that H2 treatment could alleviate allodynic and hyperalgesic behaviors and the release of inflammatory factors in rats with neuropathic pain. Peripheral neuropathic pain was established by chronic constriction injury of sciatic nerve in rats. H2 was given twice through intraperitoneal injection at a daily dose of 10 mL/kg during days 1-7 after the operation. Hyperalgesia and allodynia were tested, pro-inflammatory factors of dorsal root ganglia (DRG) and the spinal cord were measured by enzyme-linked immunosorbent assay (ELISA) during days 1-14 after the operation, and heme oxygenase (HO)-1 messenger RNA (mRNA) and protein expression and activities were measured at day 14 after sciatic nerve injury in rats. After Sn (IV) protoporphyrin IX dihydrochloride (SnPP)-IX, hemin, and carbon monoxide-releasing molecule (CORM)-2 had been given for chronic constriction injury (CCI) in rats, the above indicators were assessed. We found that H2 clearly inhibited hyperalgesia and allodynia in neuropathic pain and also attenuated the pro inflammatory cytokines TNF-alpha, IL-1beta, and high-mobility group box (HMGB) 1. H2 improved HO-1 mRNA and protein expression and activities in the process of pain. SnPP-IX reversed the inhibitory effect of H2 on hyperalgesia and allodynia and on pro-inflammatory cytokines in DRG and the spinal cord. The antinociceptive and anti-inflammatory effects of H2 were involved in the activation of HO-1/CO signaling during neuropathic pain in rats. PMID- 25820469 TI - The smell of change: warming affects species interactions mediated by chemical information. AB - Knowledge of how temperature influences an organism's physiology and behaviour is of paramount importance for understanding and predicting the impacts of climate change on species' interactions. While the behaviour of many organisms is driven by chemical information on which they rely on to detect resources, conspecifics, natural enemies and competitors, the effects of temperature on infochemical mediated interactions remain largely unexplored. Here, we experimentally show that temperature strongly influences the emission of infochemicals by ladybeetle larvae, which, in turn, modifies the oviposition behaviour of conspecific females. Temperature also directly affects female perception of infochemicals and their oviposition behaviour. Our results suggest that temperature-mediated effects on chemical communication can influence flows across system boundaries (e.g. immigration and emigration) and thus alter the dynamics and stability of ecological networks. We therefore argue that investigating the effects of temperature on chemical communication is a crucial step towards a better understanding of the functioning of ecological communities facing rapid environmental changes. PMID- 25820470 TI - Family CHAOS is associated with glycaemic control in children and adolescents with type 1 diabetes mellitus. AB - BACKGROUND: Despite advances in the medical management of type 1 diabetes mellitus (T1DM), for many, glycaemic control remains substandard. Other factors are clearly important in determining success, or lack thereof, with diabetes management. With this in mind, we have investigated whether family CHAOS may provide a novel tool to identify when environmental confusion could impact on diabetes management and subsequent glycaemic control. METHODS: A case-control study of children and adolescents with established T1DM and age-/sex-matched controls was conducted. Demographic information, both maternal and paternal CHAOS scores, and HbA1c were collected. Statistical analysis was undertaken to explore associations between T1DM and CHAOS and between CHAOS and HbA1c. RESULTS: Data on 65 children with T1DM and 60 age-/sex-matched controls were obtained. There was no evidence of group differences for maternal CHAOS (p = 0.227), but paternal CHAOS scores were higher for the T1DM group (p = 0.041). Greater maternal and paternal CHAOS scores were both associated with higher HbA1c (p <= 0.027). The maternal association remained after controlling for diabetes duration, SMBG frequency, and insulin therapy. CONCLUSION: In children with T1DM, there appears to be a negative association between increased environmental confusion, as rated by CHAOS, and glycaemic control. In addition, when compared to controls, fathers of children and adolescents with T1DM appear to experience CHAOS differently to mothers. These findings contribute to the growing body of literature exploring psychosocial factors in T1DM. Continuing efforts are required to fully understand how the family and psychosocial environment interact with diabetes to impact on long-term health outcomes. PMID- 25820472 TI - Enantioselective Degradation of (2RS, 3RS)-Paclobutrazol in Rat Liver Microsomes. AB - Paclobutrazol, with two stereogenic centers, but gives only (2R, 3R) and (2S, 3S) enantiomers because of steric-hindrance effects, is an important plant growth regulator in agriculture and horticulture. Enantioselective degradation of paclobutrazol was investigated in rat liver microsomes in vitro. The degradation kinetics and the enantiomer fraction were determined using a Lux Cellulose-1 chiral column on a reverse-phase liquid chromatography-tandem mass spectrometry system. The t1/2 of (2R, 3R)-paclobutrazol is 18.60 min, while the t1/2 of (2S, 3S)-paclobutrazol is 10.93 min. Such consequences clearly indicated that the degradation of paclobutrazol in rat liver microsomes was stereoselective and the degradation rate of (2S, 3S)-paclobutrazol was much faster than (2R, 3R) paclobutrazol. In addition, significant differences between the two enantiomers were also observed in enzyme kinetic parameters. The Vmax of (2S, 3S) paclobutrazol was more than 2-fold of (2R, 3R)-paclobutrazol and the Clint of (2S, 3S)-paclobutrazol was higher than that of (2R, 3R)-paclobutrazol after incubation in rat liver microsomes. These results may have potential implications for better environmental and ecological risk assessment for paclobutrazol. PMID- 25820471 TI - Shifts in soil testate amoeba communities associated with forest diversification. AB - We studied changes of testate amoeba communities associated with the conversion of spruce monocultures into mixed beech-fir-spruce forests in the Southern Black Forest Mountains (Germany). In this region, forest conversion is characterized by a gradual development of beech undergrowth within thinned spruce tree stands leading to multiple age continuous cover forests with a diversified litter layer. Strong shifts in the abundance of testate amoeba observed in intermediate stages levelled off to monoculture conditions again after the final stage of the conversion process had been reached. The average number of species per conversion stage (i.e., local richness) did not respond strongly to forest conversion, but the total number of species (i.e., regional richness) was considerably higher in the initial stage than in the mixed forests, due to the large number of hygrophilous species inhabiting spruce monocultures. Functional diversity of the testate amoeba community, however, significantly increased during the conversion process. This shift was closely associated with improved C and N availability as well as higher niche diversity in the continuous cover stands. Lower soil acidity in these forests coincided with a higher relative abundance of eurytopic species. Our results suggest that testate amoeba communities are much more affected by physicochemical properties of the soil than directly by litter diversity. PMID- 25820473 TI - Extensive and interrelated subcortical white and gray matter alterations in preterm-born adults. AB - Preterm birth is a leading cause for impaired neurocognitive development with an increased risk for persistent cognitive deficits in adulthood. In newborns, preterm birth is associated with interrelated white matter (WM) alterations and deep gray matter (GM) loss; however, little is known about the persistence and relevance of these subcortical brain changes. We tested the hypothesis that the pattern of correspondent subcortical WM and GM changes is present in preterm-born adults and has a brain-injury-like nature, i.e., it predicts lowered general cognitive performance. Eighty-five preterm-born and 69 matched term-born adults were assessed by diffusion- and T1-weighted MRI and cognitive testing. Main outcome measures were fractional anisotropy of water diffusion for WM property, GM volume for GM property, and full-scale IQ for cognitive performance. In preterm-born adults, reduced fractional anisotropy was widely distributed ranging from cerebellum to brainstem to hemispheres. GM volume was reduced in the thalamus, striatum, temporal cortices, and increased in the cingulate cortices. Fractional anisotropy reductions were specifically associated with GM loss in thalamus and striatum, with correlation patterns for both regions extensively overlapping in the WM of brainstem and hemispheres. For overlap regions, fractional anisotropy was positively related with both gestational age and full scale IQ. Results provide evidence for extensive, interrelated, and adverse WM and GM subcortical changes in preterm-born adults. Data suggest persistent brain injury-like changes of subcortical-cortical connectivity after preterm delivery. PMID- 25820476 TI - Triphenylene-based tris-N-heterocyclic stannylenes. AB - Two planar tridentate N-heterocyclic stannylenes are synthesized from the corresponding 2,3,6,7,10,11-hexaamino-triphenylene and Sn[N(TMS)2]2. Multinuclear NMR and absorption spectra of these tris-stannylenes are reported. Molecular structure of the N-benzhydryl-substituted tris-stannylene is also realized. PMID- 25820475 TI - Irisin is more strongly predicted by muscle oxidative potential than adiposity in non-diabetic men. AB - Numerous controversies surround the peptide hormone irisin. Although implicated as a myokine promoting the browning of adipose tissue in rodents, its roles in humans remain unclear. Contradictory results have also been found with respect to the relationships between adiposity or metabolic health and plasma irisin levels in humans. We investigated the relationship between irisin levels and body composition (hydrostatic weighing), insulin sensitivity (hyperinsulinemic euglycemic clamp), fitness level (ergocycle VO2max) and skeletal muscle metabolic profile in 53 men (aged 34-53 years) from four groups: sedentary non-obese controls (body mass index [BMI] <25 kg/m(2)), sedentary obese (BMI >30 kg/m(2)), sedentary obese glucose-intolerant, and non-obese highly trained endurance active. Baseline plasma irisin levels were significantly different between groups, being lowest in trained men (140.6 +/- 38.2 ng/mL) and highest in metabolically deteriorated glucose-intolerant subjects (204.0 +/- 50.5 ng/mL; ANOVA p = 0.01). Including all subjects, irisin levels were positively associated with adiposity (e.g. fat mass, r = 0.430, p < 0.01) and negatively associated with fitness (r = -0.369, p < 0.01), insulin sensitivity (M/I, r = -0.355, p < 0.01) and muscle citrate synthase (CS) activity (r = -0.482, p < 0.01). Most correlations lost statistical significance when excluding active individuals, except for insulin resistance (r = -0.413, p < 0.01) and CS (r = -0.462, p < 0.01). Multiple regression analyses reveal CS as the strongest independent predictor of irisin levels (r(2) range 0.214 to 0.237). We conclude that muscle oxidative potential is an important factor linked to circulating irisin levels. PMID- 25820477 TI - Time to divest from tobacco-funded research. PMID- 25820474 TI - Circulating irisin and glucose metabolism in overweight/obese women: effects of alpha-lipoic acid and eicosapentaenoic acid. AB - Irisin is a myokine/adipokine with potential role in obesity and diabetes. The objectives of the present study were to analyse the relationship between irisin and glucose metabolism at baseline and during an oral glucose tolerance test (OGTT) and to determine the effects of eicosapentaenoic acid (EPA) and/or alpha lipoic acid treatment on irisin production in cultured human adipocytes and in vivo in healthy overweight/obese women following a weight loss program. Seventy three overweight/obese women followed a 30% energy-restricted diet supplemented without (control) or with EPA (1.3 g/day), alpha-lipoic acid (0.3 g/day) or both EPA + alpha-lipoic acid (1.3 + 0.3 g/day) during 10 weeks. An OGTT was performed at baseline. Moreover, human adipocytes were treated with EPA (100-200 MUM) or alpha-lipoic acid (100-250 MUM) during 24 h. At baseline plasma, irisin circulating levels were positively associated with glucose levels; however, serum irisin concentrations were not affected by the increment in blood glucose or insulin during the OGTT. Treatment with alpha-lipoic acid (250 MUM) upregulated Fndc5 messenger RNA (mRNA) and irisin secretion in cultured adipocytes. In overweight/obese women, irisin circulating levels decreased significantly after weight loss in all groups, while no additional differences were induced by EPA or alpha-lipoic acid supplementation. Moreover, plasma irisin levels were positively associated with higher glucose concentrations at beginning and at endpoint of the study. The data from the OGTT suggest that glucose is not a direct contributing factor of irisin release. The higher irisin levels observed in overweight/obese conditions could be a protective response of organism to early glucose impairments. PMID- 25820478 TI - Curious cases of 3,6-dinitropyrazolo[4,3-c]pyrazole-based energetic cocrystals with high nitrogen content: an alternative to salt formation. AB - Two structurally interesting 3,6-dinitropyrazolo[4,3-c]pyrazole-based energetic cocrystals were prepared and confirmed by single crystal X-ray diffraction. As novel energetic materials, these two unusual neutral acid-base complexes possess high nitrogen content, good detonation properties, and improved impact and friction sensitivities which highlight their potential energetic applications. PMID- 25820479 TI - Validation of a method to differentiate arterial and venous vessels in CT perfusion data using linear combinations of quantitative time-density curve characteristics. AB - OBJECTIVES: We aimed to develop and evaluate a new method that reliably differentiates between cerebral arteries and veins using voxel-wise CT-perfusion derived parameters. MATERIALS AND METHODS: Fourteen consecutive patients with suspected stroke but without pathological findings were examined on a multi detector CT system: 32 dynamic phases (?t = 1.5 s) during application of 35 mL iomeprol-350 were acquired at 80 kV/200mAs. Three hemodynamic parameters were calculated for 18 arterial and venous vessel segments: A (maximum of the time density-curve), T (time-to-peak), and W (full-width-at-half-maximum). Using receiver operator characteristic (ROC) curve analysis and Fisher's linear discriminant analysis (FLDA), the performance of every classifier (A, T, W) and of all linear combinations for the differentiation of arterial and venous vessels was determined. RESULTS: A maximum area under the ROC-curve (AUC) of 0.945 (accuracy = 86.8%) was obtained using the FLDA combination of A&T or the triplet FLDA of A&T&W for the classification of venous and arterial vessels. The best single parameter was T with an AUC of 0.871 (accuracy = 79.0%), which performed significantly worse than the combination A&T (p < 0.001). CONCLUSIONS: Arteries and veins can be accurately differentiated based on dynamic CT perfusion data using the maximum of the time-density curve, its time-to-peak, its width, and FLDA combinations of these parameters, which yield accuracies up to 87%. KEY POINTS: * For classification of cerebral vasculature, time-to-peak has the best single-parameter accuracy. * Fisher's linear discriminant analysis improves the performance of the individual classifiers. * Combining signal maximum and time-to peak parameters significantly increased the classifying potential. * Pre processing of time-density-curves by Gaussian filtering or fitting can improve diagnostic accuracy. PMID- 25820481 TI - Hydrogen bonding and pi-pi interactions in imidazolium-chloride ionic liquid clusters. AB - A systematic electronic structure analysis of hydrogen bonding (H-bonding), anion pi(+) and pi(+)-pi(+) interactions present in [C1C1im]Cl ion-pairs (IPs) and selected [C1C1im]2Cl2 IP-dimers has been carried out. Interactions have been characterised using a combination of QTAIM, NCIPLOT, NBO and qualitative MO theory. IP-dimers form non-directional charge quadrupolar arrangements due to Coulombic interactions. These are found to associate either as clusters or as loosely associated IP-IP structures. Large conformational changes are found to occur for very little cost in energy, indicating that charge screening is essentially independent of the cation ring orientation. H-bond formation is accompanied by charge transfer and polarisation of the entire [C1C1im](+) ring. Charge transfer does not follow the same trend for the CHelpG, QTAIM and NBO methods. Weak "stacked" pi(+)-pi(+) interactions are stabilised in the presence of anions, which locate between and at the periphery of the rings, novel strongly bent H-bonds are also present. Primary (ring; C-H...Cl(-)) H-bonds and anion pi(+) (C(2)...Cl(-)) interactions are found to decay more rapidly with distance than secondary (aliphatic; C(M)-H...Cl(-)) H-bonds. This leads to an increase in the relative importance of secondary H-bond interactions in the IP-dimers. Moreover, rotation of the methyl groups within the "stacked" pi(+)-pi(+) IP dimers facilitates the formation of (stronger) linear secondary H-bonds. Thus, compared to isolated IPs, secondary H-bonds may play an increased role within the condensed phase. Overall we find that structural fluidity is facilitated by fluctuating hydrogen bond, pi(+)-pi(+) and anion-pi(+) interactions. PMID- 25820480 TI - Recurrent peripheral vestibulopathy: Is MRI useful for the diagnosis of endolymphatic hydrops in clinical practice? AB - OBJECTIVES: Recurrent peripheral vestibulopathy (RPV) is a public health problem, yet the aetiology remains unclear. Recent developments in MRI of endolymphatic hydrops (EH) allow for a better understanding of inner ear disorders. We intended to study the prevalence of EH in patients with RPV, in comparison to those with Meniere's disease (MD). METHODS: MRI examinations were performed 4 hours after intravenous injection of gadoteric acid in 132 patients with RPV (n = 64) and MD (n = 68). Two radiologists retrospectively studied the prevalence and localization of EH in RPV and MD groups. Patients were graded based on the number and localization of hydrops, between 1 (EH in either cochlea or vestibule on one side) and 4 (EH in cochlea and vestibule on both ears). RESULTS: We identified EH in 31 out of 64 patients and in 61 out of 68 patients in the RPV and MD groups, respectively. There was a significant difference regarding the number of subjects with EH between the two groups (p <= 0.01), with a higher average number of hydrops localization in MD group (p <= 0.01). CONCLUSION: MRI may reveal EH in some cases among patients with RPV, suggesting a similar pathophysiological mechanism in comparison with MD. KEY POINTS: * MRI may reveal endolymphatic hydrops in some patients with recurrent peripheral vestibulopathy. * We suggest a similar pathophysiological mechanism in recurrent vestibulopathy and Meniere's Disease. * MRI with delayed acquisition helps clinicians to assess patients with recurrent vestibulopathy. * The outcome would be to aid the development of adapted therapeutic strategies. * MRI of endolymphatic hydrops should probably be included in future diagnostic protocols. PMID- 25820483 TI - Design of experiments reveals critical parameters for pilot-scale freeze-and-thaw processing of L-lactic dehydrogenase. AB - Freezing constitutes an important unit operation of biotechnological protein production. Effects of freeze-and-thaw (F/T) process parameters on stability and other quality attributes of the protein product are usually not well understood. Here a design of experiments (DoE) approach was used to characterize the F/T behavior of L-lactic dehydrogenase (LDH) in a 700-mL pilot-scale freeze container equipped with internal temperature and pH probes. In 24-hour experiments, target temperature between -10 and -38 degrees C most strongly affected LDH stability whereby enzyme activity was retained best at the highest temperature of -10 degrees C. Cooling profile and liquid fill volume also had significant effects on LDH stability and affected the protein aggregation significantly. Parameters of the thawing phase had a comparably small effect on LDH stability. Experiments in which the standard sodium phosphate buffer was exchanged by Tris-HCl and the non ionic surfactant Tween 80 was added to the protein solution showed that pH shift during freezing and protein surface exposure were the main factors responsible for LDH instability at the lower freeze temperatures. Collectively, evidence is presented that supports the use of DoE-based systematic analysis at pilot scale in the identification of F/T process parameters critical for protein stability and in the development of suitable process control strategies. PMID- 25820482 TI - Determinants of Muscle and Bone Aging. AB - Loss of bone and muscle with advancing age represent a huge threat to loss of independence in later life. Osteoporosis represents a major public health problem through its association with fragility fractures, primarily of the hip, spine and distal forearm. Sarcopenia, the age related loss of muscle mass and function, may add to fracture risk by increasing falls risk. In the context of muscle aging, it is important to remember that it is not just a decline in muscle mass which contributes to the deterioration of muscle function. Other factors underpinning muscle quality come into play, including muscle composition, aerobic capacity and metabolism, fatty infiltration, insulin resistance, fibrosis and neural activation. Genetic, developmental, endocrine and lifestyle factors, such as physical activity, smoking and poor diet have dual effects on both muscle and bone mass in later life and these will be reviewed here. Recent work has highlighted a possible role for the early environment. Inflammaging is an exciting emerging research field that is likely to prove relevant to future work, including interventions designed to retard to reverse bone and muscle loss with age. PMID- 25820485 TI - The Association Between Serum Levels of Selenium, Copper, and Magnesium with Thyroid Cancer: a Meta-analysis. AB - There are conflicting reports on the correlation between serum levels of selenium (Se), copper (Cu), and magnesium (Mg) with thyroid cancer. The purpose of the present study is to clarify the association between Se, Cu, and Mg levels with thyroid cancer using a meta-analysis approach. We searched articles indexed in PubMed published as of January 2015 that met our predefined criteria. Eight eligible articles involving 1291 subjects were identified. Overall, pooled analysis indicated that subjects with thyroid cancer had lower serum levels of Se and Mg, but higher levels of Cu than the healthy controls [Se: standardized mean difference (SMD) = -0.485, 95% confidence interval (95%CI) = (-0.878, -0.092), p = 0.016; Cu: SMD = 2.372, 95%CI = (0.945, 3.799), p = 0.001; Mg: SMD = -0.795, 95%CI = (-1.092, -0.498), p < 0.001]. Further subgroup analysis found lower serum levels of Se in thyroid cancer in Norway [SMD = -0.410, 95%CI = (-0.758, -0.062), p = 0.021] and Austria [SMD = -0.549, 95%CI = (-0.743, -0.355), p < 0.001], but not in Poland (SMD = -0.417, 95%CI = (-1.724, 0.891), p = 0.532]. Further subgroup analysis also found that patients with thyroid cancer had higher serum levels of Cu in China [SMD = 1.571, 95%CI = (1.121, 2.020), p < 0.001] and Turkey [SMD = 0.977, 95%CI = (0.521, 1.432), p < 0.001], but not in Poland [SMD = 3.471, 95%CI = (-0.056, 6.997], p = 0.054]. In conclusion, this meta-analysis supports a significant association between serum levels of Se, Cu, and Mg with thyroid cancer. However, the subgroup analysis found that there was significant effect modification of Se, Cu levels by ethnic, like China and Poland. Thus, this finding needs further confirmation by a trans-regional multicenter study to obtain better understanding of causal relationship between Se, Cu, and Mg with thyroid cancer of different human races or regions. PMID- 25820484 TI - Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients. AB - Steatosis and inherited host factors influence liver damage progression in chronic hepatitis C (CHC). The transmembrane 6 superfamily member 2 (TM6SF2) gene E167K variant increases liver fat and risk of progressive steatohepatitis by interfering with lipoprotein secretion. Our aim was to determine whether the E167K variant affects histological severity of steatosis, necroinflammation, and fibrosis in a cross-sectional cohort of 815 Italian therapy-naive CHC patients. The association with clinically significant fibrosis was replicated in 645 Swiss/German patients. The TM6SF2 E167K variant was genotyped by TaqMan assays, steatosis graded according to the nonalcoholic fatty liver disease activity score, and necroinflammation and fibrosis graded and staged according to Ishak in Italian, and to Metavir in Swiss/German patients. The E167K variant was detected in 69 (9%) Italian patients and was associated with more severe steatosis, independently of confounders (P = 0.038). The association between E167K and steatosis severity was present in patients not infected by genotype 3 (G3) HCV (P = 0.031), but not in those infected by G3 HCV (P = 0.58). Furthermore, the E167K variant was associated with more severe necroinflammation (Ishak grade; adjusted P = 0.037) and nearly associated with more severe fibrosis (Ishak stage; adjusted P = 0.058). At multivariate logistic regression analysis, the E167K variant was independently associated with histologically probable or definite cirrhosis (Ishak stage S6; odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.18-3.93; P = 0.010). After further conditioning for steatosis and necroinflammation, the E167K variant remained associated with cirrhosis (OR, 3.15; 95% CI: 1.60-5.99; P < 0.001). In Swiss/German patients, the E167K variant was independently associated with clinically significant fibrosis Metavir stage F2-F4 (OR, 1.81; 95% CI: 1.12-3.02; P = 0.016). CONCLUSION: TM6SF2 E167K variant impacts on steatosis severity and is associated with liver damage and fibrosis in patients with CHC. PMID- 25820486 TI - Preoperative risk factors and radiographic findings predictive of laparoscopic conversion to open procedures in Crohn's disease. AB - INTRODUCTION: Laparoscopy is accepted as a standard surgical approach for Crohn's disease. However, the rate of conversion is high, ranging from 15 to 70 % depending on the population. There are also concerns that conversion results in worsened outcomes versus an initial open procedure. METHODS: This study evaluated preoperative radiographic findings to determine who is at increased risk of conversion and may therefore benefit from an initial open approach. A case matched study included patients from 2004 to 2013 with preoperative CTE/MRE who underwent laparoscopic surgery converted to an open approach, and compared them to laparoscopically completed controls with similar age, same surgeon, and number of previous abdominal operations. Studies were reviewed by two blinded radiologists. Variables included abdominal AP diameter, amount of subcutaneous fat, peritoneal versus pelvic location of disease (greater or lesser hemipelvis or abdomen), intestinal location of disease (colon, TI, ileum, jejunum), and presence, length, and location of strictures, simple or complex fistula, phlegmon, or abscess. Conditional logistic regression evaluated relationships between radiographic variables and conversion. Twenty-seven patients meeting study criteria were compared with 81 controls. RESULTS: A negative association between conversion and disease in the left lesser pelvis was found (p = 0.019) and neared significance for left abdomen (p = 0.08). Positive correlations were found with pelvic fistulas (p = 0.003), complex fistulas (p = 0.017), and pelvic abscesses (p = 0.009) and neared significance for Society of Abdominal Radiology classification (p = 0.058). CONCLUSION: Preoperative imaging in patients with Crohn's disease can help in selecting the most suitable cases to approach laparoscopically and reduce conversion rates and should be evaluated in conjunction with other preoperative factors. PMID- 25820487 TI - Prognostic Impact of Tumor Growth Type on 7th AJCC Staging System for Intrahepatic Cholangiocarcinoma: a Single-Center Experience of 659 Cases. AB - OBJECTIVE: Because noticeable changes were made to the 7th American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging for intrahepatic cholangiocarcinoma (IHCC), we validated the prognostic impact of tumor staging after macroscopic curative resection of IHCC. METHODS: A cohort of 659 IHCC patients who underwent R0 (n = 539) or R1 (n = 120) resection were selected with exclusion of R2 resection (n = 111). Study patients were followed up for >=24 months or until death with no patient lost during survival analysis. RESULTS: Anatomical resection was performed in 599 (90.9%) and concurrent bile duct resection was conducted in 97 (14.7%). Median survival periods following R0, R1, and R2 resections were 28, 12, and 3 months, respectively (p = 0.000). In the R0 resection group, the 1-, 3-, 5-, and 10-year tumor recurrence rates were 36.4%, 57.9%, 64.7%, and 65.0%, respectively, and the 1-, 3-, 5-, and 10-year patient survival rates were 73.1%, 44.2%, 33.0%, and 23.1%, respectively. Independent risk factors for tumor recurrence and patient survival were tumor growth type, tumor size > 5 cm, perineural invasion, and lymph node metastasis. According to the 7th AJCC staging system, the prognostic contrast was marginal in stage T2-4 tumors without lymph node metastasis (p > 0.8). With our redefined staging system with tumor growth types and risk factors including tumor number and perineural/lymphovascular invasion, clear prognostic contrast was achieved among T1-3 stages (p = 0.000). CONCLUSION: Growth type of IHCC seems to be essential for determining tumor stage. Although the stratification of the 7th AJCC IHCC staging system seems reasonably established, refinements and further validation could improve prognostic predictability. PMID- 25820488 TI - Ex vivo resection of hepatic neoplasia and autotransplantation: a case report and review of the literature. AB - INTRODUCTION: Ex situ liver resection is an uncommon procedure but offers an opportunity for R0 surgical resection of liver tumors that are otherwise unresectable. Liver insufficiency following extensive resections is a risk in this patient population; consequently, all measures should be taken to prevent this highly morbid complication. METHOD: We report a case of a patient with an extensive cholangiocarcinoma involving all three hepatic veins that required ex vivo resection and liver autotransplantation to achieve an R0 resection. Postoperatively, the patient demonstrated signs of worsening liver function that, in addition to standard medical therapy, underwent a brief treatment with molecular adsorbent recirculating system (MARS) therapy. RESULTS: Although the role of MARS remains unclear, the patient tolerated it well and her liver graft dysfunction and hepatic encephalopathy slowly resolved. The patient was discharged to a rehabilitation facility. She is currently alive and well with no evidence of recurrence 3 years later. CONCLUSION: We present a review of the literature on ex situ resection and liver autotransplantation. In addition to numerous case reports, there are a few moderate series of ex situ resection and autotransplantation. We suggest that the use of artificial liver devices, if indicated, in the postoperative ex situ resection liver autotransplant patient may assist in the support of the patient while the transplanted liver remnant recovers. PMID- 25820489 TI - Role of electron transport chain of chloroplasts in oxidative burst of interaction between Erwinia amylovora and host cells. AB - Erwinia amylovora is a necrogenic bacterium, causing the fire blight disease on many rosaceous plants. Triggering oxidative burst by E. amylovora is a key response by which host plants try to restrain pathogen spread. Electron transport chain (ETC) of chloroplasts is known as an inducible source of reactive oxygen species generation in various stresses. This research was performed to assess the role of this ETC in E. amylovora-host interaction using several inhibitors of this chain in susceptible and resistant apple and pear genotypes. All ETC inhibitors delayed appearance of disease necrosis, but the effects of methyl viologen, glutaraldehyde, and DCMU were more significant. In the absence of inhibitors, resistant genotypes showed an earlier and severe H2O2 generation and early suppression of redox dependent, psbA gene. The effects of inhibitors were corresponding to the redox potential of ETC inhibitory sites. In addition, delayed necrosis appearance was associated with the decreased disease severity and delayed H2O2 generation. These results provide evidences for the involvement of this ETC in host oxidative burst and suggest that chloroplast ETC has significant role in E. amylovora-host interaction. PMID- 25820490 TI - In memoriam: S. Harvey Mudd. PMID- 25820492 TI - Electrochemical paper-based microfluidic devices. AB - Self-pumping porous microfluidic devices have attracted significant interest because of their low cost and broad applicability in point-of-care and low resource settings. One limitation of many of the devices is sensitivity and selectivity for detection. Electrochemistry can provide a sensitive, selective detection method while still using low cost, portable instrumentation as typified by handheld glucometers. Here, the development of electrochemical paper-based analytical devices (ePADs) is reviewed. Given the importance of electrode geometry and composition, fabrication methods are reviewed first. This is followed by a review of example applications demonstrated for ePADs. Finally, major accomplishments and future directions are summarized. PMID- 25820491 TI - State-dependent control of breathing by the retrotrapezoid nucleus. AB - KEY POINTS: This study explores the state dependence of the hypercapnic ventilatory reflex (HCVR). We simulated an instantaneous increase or decrease of central chemoreceptor activity by activating or inhibiting the retrotrapezoid nucleus (RTN) by optogenetics in conscious rats. During quiet wake or non-REM sleep, hypercapnia increased both breathing frequency (fR ) and tidal volume (VT ) whereas, in REM sleep, hypercapnia increased VT exclusively. Optogenetic inhibition of RTN reduced VT in all sleep-wake states, but reduced fR only during quiet wake and non-REM sleep. RTN stimulation always increased VT but raised fR only in quiet wake and non-REM sleep. Phasic RTN stimulation produced active expiration and reduced early expiratory airflow (i.e. increased upper airway resistance) only during wake. We conclude that the HCVR is highly state dependent. The HCVR is reduced during REM sleep because fR is no longer under chemoreceptor control and thus could explain why central sleep apnoea is less frequent in REM sleep. ABSTRACT: Breathing has different characteristics during quiet wake, non-REM or REM sleep, including variable dependence on PCO2. We investigated whether the retrotrapezoid nucleus (RTN), a proton-sensitive structure that mediates a large portion of the hypercapnic ventilatory reflex, regulates breathing differently during sleep vs. wake. Electroencephalogram, neck electromyogram, blood pressure, respiratory frequency (fR ) and tidal volume (VT ) were recorded in 28 conscious adult male Sprague-Dawley rats. Optogenetic stimulation of RTN with channelrhodopsin-2, or inhibition with archaerhodopsin, simulated an instantaneous increase or decrease of central chemoreceptor activity. Both opsins were delivered with PRSX8-promoter-containing lentiviral vectors. RTN and catecholaminergic neurons were transduced. During quiet wake or non-REM sleep, hypercapnia (3 or 6% FI,CO2 ) increased both fR and VT whereas, in REM sleep, hypercapnia increased VT exclusively. RTN inhibition always reduced VT but reduced fR only during quiet wake and non-REM sleep. RTN stimulation always increased VT but raised fR only in quiet wake and non-REM sleep. Blood pressure was unaffected by either stimulation or inhibition. Except in REM sleep, phasic RTN stimulation entrained and shortened the breathing cycle by selectively shortening the post-inspiratory phase. Phasic stimulation also produced active expiration and reduced early expiratory airflow but only during wake. VT is always regulated by RTN and CO2 but fR is regulated by CO2 and RTN only when the brainstem pattern generator is in autorhythmic mode (anaesthesia, non-REM sleep, quiet wake). The reduced contribution of RTN to breathing during REM sleep could explain why certain central apnoeas are less frequent during this sleep stage. PMID- 25820493 TI - The "syncope and dementia" study: a prospective, observational, multicenter study of elderly patients with dementia and episodes of "suspected" transient loss of consciousness. AB - BACKGROUND AND AIM: Syncope and related falls are one of the main causes and the predominant cause of hospitalization in elderly patients with dementia. However, the diagnostic protocol for syncope is difficult to apply to patients with dementia. Thus, we developed a "simplified" protocol to be used in a prospective, observational, and multicenter study in elderly patients with dementia and transient loss of consciousness suspected for syncope or unexplained falls. Here, we describe the protocol, its feasibility and the characteristics of the patients enrolled in the study. METHODS: Patients aged >=65 years with a diagnosis of dementia and one or more episodes of transient loss of consciousness during the previous 3 months, subsequently referred to a Geriatric Department in different regions of Italy, from February 2012 to May 2014, were enrolled. A simplified protocol was applied in all patients. Selected patients underwent a second-level evaluation. RESULTS: Three hundred and three patients were enrolled; 52.6% presented with episodes suspected to be syncope, 44.5% for unexplained fall and 2.9% both. Vascular dementia had been previously diagnosed in 53.6% of participants, Alzheimer's disease in 23.5% and mixed forms in 12.6%. Patients presented with high comorbidity (CIRS score = 3.6 +/- 2), severe functional impairment, (BADL lost = 3 +/- 2), and polypharmacy (6 +/- 3 drugs). CONCLUSION: Elderly patients with dementia enrolled for suspected syncope and unexplained falls have high comorbidity and disability. The clinical presentation is often atypical and the presence of unexplained falls is particularly frequent. PMID- 25820494 TI - Balanced SSFP-like steady-state imaging using small-tip fast recovery with a spectral prewinding pulse. AB - PURPOSE: Small-tip fast recovery (STFR) imaging has been proposed recently as a potential alternative to balanced steady-state free precession (bSSFP). STFR relies on a tailored "tip-up" radio-frequency pulse to achieve comparable signal level as bSSFP, but with reduced banding artifacts and transient oscillations, and is compatible with magnetization-preparation pulses. Previous STFR implementations used two-dimensional or three-dimensional pulses spatially tailored to the accumulated phase calculated from a B0 field map, making the steady-state STFR signal contain some T2* weighting. Here, we propose to replace the spatially tailored pulse with a recently introduced spectrally selective "pre winding" pulse that is precomputed to a target frequency range. The proposed "spectral-STFR" sequence produces T2/T1-weighted images similar to bSSFP, but with reduced banding and potentially other benefits. THEORY AND METHODS: We investigated the steady-state signal properties of spectral-STFR using simulations, and phantom and human volunteer experiments. RESULTS: Our simulation and experimental results showed that the spectral-STFR sequence has similar signal level and tissue contrast as bSSFP, but has a wider passband and more consistent banding profiles across different tissues (e.g., less hyperintense signal at band edges for low flip angles). Care is needed in designing the spectral radio-frequency pulse to ensure that the small tip angle approximation holds during radio-frequency transmission. CONCLUSION: Spectral-STFR has similar tissue contrast as bSSFP but a wider passband and more consistent cerebrospinal fluid/brain tissue contrast across the passband. The spectral-STFR sequence is a potential alternative to bSSFP in some applications. Compared to a spatially tailored STFR sequence, spectral-STFR can be precomputed, is easier to implement in practice, and potentially has more uniform image contrast and minimal T2* weighting. PMID- 25820495 TI - Teaching bioprocess engineering to undergraduates: Multidisciplinary hands-on training in a one-week practical course. AB - Bioprocess engineering is a highly interdisciplinary field of study which is strongly benefited by practical courses where students can actively experience the interconnection between biology, engineering, and physical sciences. This work describes a lab course developed for 2nd year undergraduate students of bioprocess engineering and related disciplines, where students are challenged with a real-life bioprocess-engineering application, the production of recombinant protein in a fed-batch process. The lab course was designed to introduce students to the subject of operating and supervising an experiment in a bioreactor, along with the analysis of collected data and a final critical evaluation of the experiment. To provide visual feedback of the experimental outcome, the organism used during class was Escherichia coli which carried a plasmid to recombinantly produce enhanced green fluorescent protein (eGFP) upon induction. This can easily be visualized in both the bioreactor and samples by using ultraviolet light. The lab course is performed with bioreactors of the simplest design, and is therefore highly flexible, robust and easy to reproduce. As part of this work the implementation and framework, the results, the evaluation and assessment of student learning combined with opinion surveys are presented, which provides a basis for instructors intending to implement a similar lab course at their respective institution. PMID- 25820496 TI - Chondroitin Sulfate-E Binds to Both Osteoactivin and Integrin alphaVbeta3 and Inhibits Osteoclast Differentiation. AB - Integrins and their ligands have been suggested to be associated with osteoclast mediated bone resorption. The present study was designed to investigate whether chondroitin sulfate E (CS-E), which is one of the sulfated glycosaminoglycans (GAGs), is involved in osteoactivin (OA) activity, and osteoclast differentiation. The binding affinity of sulfated GAGs to integrin and its ligand was measured using biotin-labeled CS-E, and the osteoclast differentiation was evaluated by tartrate-resistant acid phosphatase staining and a pit formation assay. CS-E as well as CS-B, synthetic chondroitin polysulfate, and heparin inhibited osteoclast differentiation of bone marrow-derived macrophages. Pre coating of OA to synthetic calcium phosphate-coated plates enhanced the osteoclastic differentiation of RAW264 cells, and addition of a neutralizing antibody to OA inhibited its differentiation. CS-E bound not only to OA, fibronectin, and vitronectin, but also to its receptor integrin alphaVbeta3, and inhibited the direct binding of OA to integrin alphaVbeta3. Furthermore, CS-E blocked the binding of OA to cells and inhibited OA-induced osteoclastic differentiation. On the other hand, heparinase treatment of RAW264 cells inhibited osteoclastic differentiation. Since binding of OA to the cells was inhibited by the presence of heparan sulfate or heparinase treatment of cells, heparan sulfate proteoglycan (HSPG) was also considered to be an OA receptor. Taken together, the present results suggest that CS-E is capable of inhibiting OA induced osteoclast differentiation by blocking the interaction of OA to integrin alphaVbeta3 and HSPG. PMID- 25820497 TI - Let the sunshine in--making industry payments to New Zealand doctors transparent. PMID- 25820498 TI - Predictors of outcome for cutaneous squamous cell cancer. PMID- 25820499 TI - Availability and quantity of antidotes in New Zealand. PMID- 25820500 TI - Availability of antidotes, antivenoms, and antitoxins in New Zealand hospital pharmacies. AB - AIM: To assess the adequacy of the types and quantities of antidotes, antivenoms and antitoxins held by New Zealand hospital pharmacies. METHODS: A list of 61 antidotes, antivenoms, antitoxins and their various forms was developed following literature review and consideration of national pharmaceutical listings. An Internet-accessible survey was then developed, validated and, during the period 28 February to 7 April 2014, sent to 24 hospital pharmacies nationally for completion. Results were assessed and compared with published guidelines for adequate stocking of antidotes in hospitals that provide emergency care. RESULTS: The response rate for the survey was 100%. Wide variation in stock levels were reported with only N- acetylcysteine and octreotide held in adequate quantities by all hospitals to manage a single patient for 24 hours. While archaic compounds were still stocked, newer and more effective pharmaceuticals were not. The national replacement cost for expiring drugs was estimated at $171,024, with smaller, more isolated facilities facing the greatest expense and difficulty in achieving timely resupply. CONCLUSION: Shortcomings in the types and quantities of antidotes, antivenoms and antitoxins held by New Zealand hospital pharmacies were recognised. This situation may be improved through national rationalisation of pharmaceutical storage and supply, and implementation of a national antidote database. PMID- 25820501 TI - Removal of Special Authority requirements for clopidogrel improved optimal care following percutaneous coronary intervention across sociodemographic groups. AB - AIM: To examine if optimal clopidogrel therapy following percutaneous coronary intervention (PCI) differed systematically by sociodemographic characteristics during and after special authority (SA) restrictions, which required hospital specialist approval for full funding. METHOD: National health databases were anonymously linked for New Zealanders discharged following publicly-funded PCI between 1/07/2009-31/12/2009 when SA criteria applied and from 1/09/2010 28/02/2011 after funding restrictions ceased. The proportion of days that patients were dispensed clopidogrel in the two 6-month periods post-discharge was calculated (medicine possession ratio;MPR). Optimal clopidogrel-dispensing (defined as a MPR>0.8) was analysed by sociodemographic characteristics. RESULTS: During the first discharge period, 74% (95% CI 72-75%) of patients (n=2416) had optimal dispensing compared with 81% (95% CI 79-82%) of discharges from 1/09/2010 28/02/2011 (n=2347). In both discharge periods, 2-3% of patients received no therapy. Minimal relative differences in optimal dispensing were noted by age, sex, or deprivation status in either discharge period. However, optimal clopidogrel-dispensing was 13-14% less likely among Maori and Pacific peoples relative to 'Other' patients during funding restrictions. Relative ethnic differences changed little once funding restrictions ended despite absolute increases in dispensing. CONCLUSIONS: Optimal clopidogrel coverage following PCI improved by 7% across sociodemographic groups after funding restrictions ceased, but ethnic disparities were unaltered. PMID- 25820502 TI - Paediatric EEG provision in New Zealand: a survey of practice. AB - AIM: Epilepsy is a common neurological disorder in children. Electroencephalography (EEG) is integral to the diagnosis of an electroclinical epilepsy syndrome. Here we aim to describe provision of paediatric EEGs in New Zealand. METHOD: All neurophysiology departments in New Zealand performing paediatric EEGs were invited to participate. Personal interviews were conducted to ascertain the number and type of EEGs performed in children and the paediatric protocols used in each department. RESULTS: 12 of the 13 eligible neurophysiology departments participated. These departments performed between 2-950 paediatric EEGs each year. Waiting times were variable: urgent (8 hours-14 days); semi urgent (1 day-8 weeks); routine (1 week-4 months); with two centres unable to perform urgent or semi urgent EEGs. Seven departments routinely sleep deprived children. The percentage of all outpatient paediatric EEGs that were sleep deprived ranged from 1-100%. Children's EEGs were reported by either paediatric (five departments) or adult neurologists (seven departments). CONCLUSIONS: There is marked variability between neurophysiology departments in the provision of EEGs for New Zealand children. As EEGs are important for epilepsy diagnosis, increased resources are required to ensure New Zealand children have equitable access to timely quality paediatric EEGs. PMID- 25820503 TI - Computer Assisted Learning for the Mind (CALM): the mental health of medical students and their use of a self-help website. AB - AIMS: The aim of this study was to develop an evidence-based self-help website, Computer Assisted Learning for the Mind (CALM) designed to improve mental health amongst medical students; and to assess the proportion, demographics and mental health of students who chose to use the site. METHODS: All 2nd and 3rd year medical students from one New Zealand university were invited to participate. Demographics and mental health scores of those accessing CALM were compared with those not accessing it. Outcome measures included depression (PHQ-9) and anxiety (GADS-7) scores recorded at baseline. Anonymous identifiers were used to track website use. RESULTS: Baseline questionnaires were completed by 279/321 (87%) of eligible students. CALM was accessed by 80/321 (25%) of the students over a 5 week period. Those who accessed CALM and could be linked by unique identifier (n=49) had significantly higher anxiety scores (p=0.01) but not higher depression scores (p=0.067) at baseline, than those who did not access CALM (n=230). Of those students with both PHQ-9 scores and GAD-7 scores =10 (at risk of significant depression and anxiety) at baseline, 41% went on to access CALM. CONCLUSIONS: The CALM website was used by 25% of medical students, particularly those with poorer anxiety scores. Self-selection to a web-based resource may provide assistance to those most in need, but further research would be needed to assess effectiveness. PMID- 25820504 TI - Predicting lymph node metastases in cutaneous squamous cell carcinoma: use of a morphological scoring system. AB - BACKGROUND: Predicting which patients will develop nodal metastasis from cutaneous squamous cell carcinoma (cSCC) remains difficult. This study evaluates a recently described histological risk model validated for mucosal head and neck SCC (HNSCC) when applied to cutaneous tumours. In this model, morphologic variables including worst pattern of invasion, lymphocytic host response and perineural invasion were shown to predict disease recurrence, loco regional recurrence and overall survival in mucosal HNSCC. METHODS: Patients with cSCC and known metastatic spread were identified from the author's database over a 5-year period between July 2007 and July 2012. Histology specimens from the original primary tumour were separately analysed by 2 histopathologists. Scores were compared against T-Stage matched control specimens without metastatic spread. RESULTS: 27 patients with metastatic cSCC were identified. Scores for worst pattern of invasion (WPOI) were significantly higher in individuals with lymph node metastases (p=0.02). CONCLUSIONS: Adverse pattern of invasion, defined as presence of small tumour islands or tumour satellites may be an independent risk factor for developing nodal metastases in cSCC. These tumours are difficult to investigate histopathologically as it is difficult to be confident the correct primary is chosen for study. PMID- 25820505 TI - Association of point prevalence diagnosis of delirium on length of stay, 6-month mortality, and level of care on discharge at Waitemata District Health Board, Auckland. AB - BACKGROUND: Delirium in hospitalised older persons is common and is correlated with adverse outcomes. Few studies of this have been done in New Zealand. The study aimed to measure the impact of delirium on 6-month mortality, length of inpatient stay and level of care. METHOD: We performed a retrospective analysis utilising data from the Delirium Point Prevalence Audit conducted at Waitemata District Health Board. The subjects were older inpatients (>65 years) surveyed between 15/05/2012 to 24/07/2012. Delirium was defined as screening positive on the Confusion Assessment Method (CAM). Patients were dichotomised into those with delirium or without. RESULTS: 250 patients were identified. 28(11.2%) were CAM positive while 222 (88.8%) were CAM-negative. Mortality at 6 months for the CAM positive group was 39%, compared to 10% in the CAM-negative group (p<0.005). The mean inpatient day stay for the CAM-positive group was 25.4 days; for the CAM negative group it was 21.6 days (p=0.721). The proportion requiring an increased level of care at discharge was 66.6% for the CAM-positive group, while for CAM negative persons the rate was 13.8% (p<0.00003). CONCLUSION: In hospitalised older adults, the presence of a positive CAM test for delirium was strongly associated with both a higher mortality rate at 6 months and a requirement for an increased level of care at discharge as compared to a negative CAM. No effect was observed on inpatient length of stay. PMID- 25820506 TI - Nicotine and toxicant yield ratings of electronic cigarette brands in New Zealand. AB - AIMS: To analyse electronic cigarette (EC) brands available in New Zealand for nicotine and toxicant yield ratings. METHOD: Fourteen EC brands were analysed before and after nicotine exhaustion for nicotine and nine for major toxicants. Concentration of nicotine and aldehydes in vapour was measured and compared with the nicotine and aldehydes in the smoke of a Marlboro cigarette. RESULTS: ECs labelled as high strength (16-18+ mg nicotine) contained 5-46 mg nicotine. Nicotine EC brands yielded 19-93 mcg nicotine per puff compared to 147 mcg per puff for Marlboro cigarettes, and emitted 200 times less toxic aldehydes (acetaldehyde, formaldehyde and acrolein) than Marlboro cigarette smoke. Compared with the first generation EC, study ECs emitted 73% less aldehydes. Diethylene and monoethylene glycol were not detected in vapour. CONCLUSION: ECs available in New Zealand in 2013 exposed users to higher levels of nicotine than in older brands but lower than cigarettes, and to far lower levels of toxicants than cigarettes and earlier ECs, indicating potential as safer substitutes for tobacco. PMID- 25820507 TI - What should be the management policy for asymptomatic inguinal hernias? AB - Elective surgical repair was the general policy for the treatment of asymptomatic and minimally symptomatic inguinal hernias, based on reducing the risks of possible future bowel obstruction or visceral strangulation. Two randomised controlled trials in 2006 suggested that an alternative policy of "watchful waiting" was safe and appropriate. As a result, some health authorities in the UK withdrew funding for elective surgical repair for asymptomatic hernias in 2010. The long-term follow-up results of these two trials, however, showed high rates of surgery in the watchful waiting arms due to the development of symptoms. Two recent studies have called the watchful waiting policy into question on the basis of cost-effectiveness, quality of life and mortality data. The current article shows the results of an Official Information Act request of the New Zealand Ministry of Health and the 20 District Health Boards on their current policies for the management of such hernias. The results show a range of policies, with two District Health Boards employing watchful waiting, seven with policies or health pathways that can restrict or deny access to treatment, and all District Health Boards required to comply with Ministry of Health performance indicators. It is concluded that, at least with some District Health Boards, patients with asymptomatic and minimally symptomatic inguinal hernias are given a lower priority for surgical treatment than they might merit on clinical grounds. Further research is needed to formulate appropriate policy for the management of this common disorder, and should perhaps be extended to cover other similarly common conditions. PMID- 25820508 TI - A rare case of anti-N-methyl-D-aspartate receptor encephalitis during pregnancy. AB - Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis was first described as a severe form of encephalitis by Dalmau et al in 2006. This is an autoimmune disorder usually associated with paraneoplastic mechanism that manifests as neuropsychiatric disorder affecting mainly women of child-bearing age. Nevertheless anti- NMDA receptor encephalitis is a rare condition during pregnancy. To -date, there have been only four reported cases during pregnancy. We report a case of a 23-year-old primigravida in first trimester pregnancy with altered mental status and multiple neurological symptoms related to anti-NMDA receptor encephalitis. To the best of our knowledge, this is the first reported anti-NMDA receptor encephalitis during pregnancy in Australasia. PMID- 25820509 TI - Medical image. Metal pigmentation of gingiva. PMID- 25820510 TI - The Auckland Surgical Theatre Educational Environment Measure: does attending surgery benefit house officers? PMID- 25820511 TI - LMNA Mutation c.917T>G (p.L306R) Leads to Deleterious Hyper-Assembly of Lamin A/C and Associates with Severe Right Ventricular Cardiomyopathy and Premature Aging. AB - Mutations in the LMNA gene coding for the nuclear lamina proteins lamin A and its smaller splice form lamin C associate with a heterogeneous group of diseases collectively called laminopathies. Here, we describe a 2-year-old patient with a previously undescribed phenotype including right ventricular cardiomyopathy, progeroid features, and premature death. Sequencing of LMNA revealed a novel heterozygous de novo mutation p.L306R located in the alpha-helical rod domain of A-type lamins. Fibroblasts from the patient showed reduced proliferation and early premature replicative senescence, as characterized by progressive hyperlobulation of the nuclei, abnormally clustered centromeres, loss of lamin B1, and reorganization of promyelocytic leukemia nuclear bodies. Furthermore, the patient cells were more sensitive to double-strand DNA breaks. Similar structural and phenotypic defects were observed in normal fibroblasts transfected with FLAG tagged p.L306R lamin A. Correspondingly, in vitro assembly studies revealed that the p.L306R generates a "hyper-assembly" mutant of lamin A that forms extensive fiber arrays under physiological conditions where wild-type lamin A is still largely soluble. In summary, we report a novel LMNA p.L306R mutation that leads to previously undescribed hyper-assembly of lamin A, heavy distortion of nuclear shape and that manifests as right ventricular cardiomyopathy and premature aging. PMID- 25820512 TI - Opposite rheological properties of neuronal microcompartments predict axonal vulnerability in brain injury. AB - Although pathological changes in axonal morphology have emerged as important features of traumatic brain injury (TBI), the mechanical vulnerability of the axonal microcompartment relative to the cell body is not well understood. We hypothesized that soma and neurite microcompartments exhibit distinct mechanical behaviors, rendering axons more sensitive to a mechanical injury. In order to test this assumption, we combined protein micropatterns with magnetic tweezer rheology to probe the viscoelastic properties of neuronal microcompartments. Creep experiments revealed two opposite rheological behaviors within cortical neurons: the cell body was soft and characterized by a solid-like response, whereas the neurite compartment was stiffer and viscous-like. By using pharmacological agents, we demonstrated that the nucleus is responsible for the solid-like behavior and the stress-stiffening response of the soma, whereas neurofilaments have a predominant contribution in the viscous behavior of the neurite. Furthermore, we found that the neurite is a mechanosensitive compartment that becomes softer and adopts a pronounced viscous state on soft matrices. Together, these findings highlight the importance of the regionalization of mechanical and rigidity-sensing properties within neuron microcompartments in the preferential damage of axons during traumatic brain injury and into potential mechanisms of axonal outgrowth after injury. PMID- 25820514 TI - Desmoid tumor fistulating to small bowel. PMID- 25820513 TI - The PNEI holistic approach in coloproctology. AB - The psycho-neuroendocrine-immune approach relies on the concept of considering diseases from a holistic point of view: the various components (psyche, nervous system, endocrine system, and immune system) control the diseased organ/apparatus and in turn are influenced by a feedback mechanism. In this article, we will consider the psycho-neuroendocrine-immune approach to coloproctological disorders, by providing clinical cases and discussing them in light of this approach. PMID- 25820515 TI - Reply to the 'Comment on "How to interpret Onsager cross terms in mixed ionic electronic conductors"' by H.-I. Yoo, M. Martin, and J. Janek, Phys. Chem. Chem. Phys., 2015, 7, DOI: 10.1039/C4CP05737F. AB - The origin of the Onsager cross terms in mixed-ionic-electronic-conductor (MIEC) oxides is re-examined. Experiments are suggested to determine which of the two suggested explanations is applicable. PMID- 25820516 TI - Esterase- and pH-responsive poly(beta-amino ester)-capped mesoporous silica nanoparticles for drug delivery. AB - Gating of mesoporous silica nanoparticles (MSNs) with the stimuli-responsive poly(beta-amino ester) has been achieved. This hybrid nanocarrier releases doxorubicin (DOX) under acidic conditions or in the presence of porcine liver esterase. The DOX loaded poly(beta-amino ester)-capped MSNs reduce cell viability when tested on MDA-MB-231 human breast cancer cells. PMID- 25820517 TI - A novel Hartman Shack-based topography system: repeatability and agreement for corneal power with Scheimpflug+Placido topographer and rotating prism auto keratorefractor. AB - The purpose of this study is to analyze the repeatability and agreement of corneal power using a new Hartman type topographer in comparison to Scheimpflug+Placido and autorefractor devices. In this cross sectional, observational study performed at the cornea services of a specialty hospital, 100 normal eyes (100 consecutive candidates) without any previous ocular surgery or morbidity except refractive error were evaluated. All candidates underwent three measurements each on a Full gradient, Hartman type topographer (FG) (iDesign, AMO), Scheimpflug+Placido topographer (SP) (Sirius, CSO) and rotating prism auto keratorefractor (AR) (KR1, Nidek). The parameters assessed were flat keratometry (K1), steep keratometry (K2), steep axis (K2 axis), mean K, J 0 and J 45. Intra device repeatability and inter-device agreement were evaluated. On repeatability analysis, the intra-device means were not significantly different (ANOVA, p > 0.05). Intraclass correlations (ICC) were >0.98 except for J 0 and J 45. In terms of intra-measurement standard deviation (Sw), the SP and FG groups fared better than AR group (p < 0.001, ANOVA). On Sw versus Average plots, no significantly predictive fit was seen (p > 0.05, R (2) < 0.1 for all the values). On inter device agreement analysis, there was no difference in means (ANOVA, p > 0.05). ICC ranged from 0.92 to 0.99 (p < 0.001). Regression fits on Bland-Altman plots suggested no clinically significant effect of average values over difference in means. The repeatability of Hartman type topographer in normal eyes is comparable to SP combination device and better than AR. The agreement between the three devices is good. However, we recommend against interchanging these devices between follow-ups or pooling their data. PMID- 25820518 TI - Agreement between diurnal variations of intraocular pressure by Tono-Pen and Goldmann applanation tonometer in patients on topical anti-glaucoma medication. AB - To estimate agreement in diurnal variations of intraocular pressure (IOP) by Tono Pen (TP) and Goldmann applanation tonometer (GAT) in glaucoma patients on topical anti-glaucoma medication(s). IOP was measured at every 3 h from 7 a.m. to 10 a.m. in 50 eyes of glaucoma patients on topical medication(s). Diurnal fluctuation of IOP by each method was calculated as maximum-minimum IOP in a day. Central corneal thickness (CCT) was measured by ultrasonic pachymeter. There was good correlation between TP and GAT at all times during a day, minimum, and maximum IOPs during a day (Correlation coefficient, 0.706 at 7 a.m., 0.624 at 10 a.m., 0.682 at 1 p.m., 0.814 at 4 p.m., 0.652 at 7 p.m., 0.572 at 10 p.m., 0.668 minimum IOP, 0.689 maximum IOP). Mean IOPs by TP were always higher than GAT at all times during a day. Bland-Altman plots suggested a close relationship between the two sets of readings, and that this relationship was consistent at different times in a day, in maximum IOPs, minimum IOPs and also in fluctuation of IOPs. Linear regression analysis between the differences of diurnal fluctuation (diurnal fluctuation by GAT-diurnal fluctuation by TP) and CCT showed strong association (R 2 = 0.857, p < 0.001). The mean change in difference of diurnal fluctuation (GAT-TP) for a 10-micron increase in CCT was 0.69 mmHg. TP can be considered a reliable alternative to GAT in glaucoma patients for knowing the diurnal control of IOP; however these two methods should not be used interchangeably. Difference of diurnal fluctuation between two methods is dependent on CCT. PMID- 25820519 TI - Targeting thyroid hormone receptor beta in triple-negative breast cancer. AB - The purpose of this study was to discover novel nuclear receptor targets in triple-negative breast cancer. Expression microarray, Western blot, qRT-PCR analyses, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, and statistical analysis were performed in this study. We performed microarray analysis using 227 triple-negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TRbeta) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TRbeta low expressing patients were associated with poor outcome. We evaluated the role of TRbeta in triple-negative breast cancer cell lines representing group 5 tumors. Knockdown of TRbeta increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TRbeta protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TRbeta knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TRbeta specific agonists enhanced TRbeta expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. TRbeta represents a novel nuclear receptor target in triple-negative breast cancer; low TRbeta levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TRbeta-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TRbeta's effects on response to chemotherapy. PMID- 25820521 TI - In Vivo Function of PTEX88 in Malaria Parasite Sequestration and Virulence. AB - Malaria pathology is linked to remodeling of red blood cells by eukaryotic Plasmodium parasites. Central to host cell refurbishment is the trafficking of parasite-encoded virulence factors through the Plasmodium translocon of exported proteins (PTEX). Much of our understanding of its function is based on experimental work with cultured Plasmodium falciparum, yet direct consequences of PTEX impairment during an infection remain poorly defined. Using the murine malaria model parasite Plasmodium berghei, it is shown here that efficient sequestration to the pulmonary, adipose, and brain tissue vasculature is dependent on the PTEX components thioredoxin 2 (TRX2) and PTEX88. While TRX2 deficient parasites remain virulent, PTEX88-deficient parasites no longer sequester in the brain, correlating with abolishment of cerebral complications in infected mice. However, an apparent trade-off for virulence attenuation was spleen enlargement, which correlates with a strongly reduced schizont-to-ring stage transition. Strikingly, general protein export is unaffected in PTEX88 deficient mutants that mature normally in vitro. Thus, PTEX88 is pivotal for tissue sequestration in vivo, parasite virulence, and preventing exacerbation of spleen pathology, but these functions do not correlate with general protein export to the host erythrocyte. The presented data suggest that the protein export machinery of Plasmodium parasites and their underlying mechanistic features are considerably more complex than previously anticipated and indicate challenges for targeted intervention strategies. PMID- 25820520 TI - The SrkA Kinase Is Part of the SakA Mitogen-Activated Protein Kinase Interactome and Regulates Stress Responses and Development in Aspergillus nidulans. AB - Fungi and many other eukaryotes use specialized mitogen-activated protein kinases (MAPK) of the Hog1/p38 family to transduce environmental stress signals. In Aspergillus nidulans, the MAPK SakA and the transcription factor AtfA are components of a central multiple stress-signaling pathway that also regulates development. Here we characterize SrkA, a putative MAPK-activated protein kinase, as a novel component of this pathway. DeltasrkA and DeltasakA mutants share a derepressed sexual development phenotype. However, DeltasrkA mutants are not sensitive to oxidative stress, and in fact, srkA inactivation partially suppresses the sensitivity of DeltasakA mutant conidia to H2O2, tert-butyl hydroperoxide (t-BOOH), and menadione. In the absence of stress, SrkA shows physical interaction with nonphosphorylated SakA in the cytosol. We show that H2O2 induces a drastic change in mitochondrial morphology consistent with a fission process and the relocalization of SrkA to nuclei and mitochondria, depending on the presence of SakA. SakA-SrkA nuclear interaction is also observed during normal asexual development in dormant spores. Using SakA and SrkA S-tag pulldown and purification studies coupled to mass spectrometry, we found that SakA interacts with SrkA, the stress MAPK MpkC, the PPT1-type phosphatase AN6892, and other proteins involved in cell cycle regulation, DNA damage response, mRNA stability and protein synthesis, mitochondrial function, and other stress-related responses. We propose that oxidative stress induces DNA damage and mitochondrial fission and that SakA and SrkA mediate cell cycle arrest and regulate mitochondrial function during stress. Our results provide new insights into the mechanisms by which SakA and SrkA regulate the remodelling of cell physiology during oxidative stress and development. PMID- 25820523 TI - Plank-shaped column-forming mesogens with substituents on one side only. AB - Prolonged glyoxylation of pyrenyl-1-glyoxylic acid ethyl ester leads to a mixture of isomers with polar pyrenylene-1,8-diglyoxylic acid as the main product, whereas the centrosymmetric 1,6-isomer is obtained in good yield from the corresponding dibromopyrene. Perkin condensations followed by Pd-catalyzed cyclizations lead to isomeric dinaphthopyrene-tetracarboxdiimides that self assemble into columnar liquid crystals of hexagonal and rectangular symmetry, of which the rectangular mesophases have unusually elongated unit cells. The cisoid diimides with both alkylimide substituents on the same side of the oblong arene system show a much greater tendency to self-assemble into fluid stacks of disks than their centrosymmetric isomers. With racemically branched alkyl substituents, uniform vertical surface alignment of the columns in the high-temperature hexagonal mesophase is resilient to cycling through the lower-temperature rectangular and crystalline phases. PMID- 25820522 TI - Role of Pex11p in Lipid Homeostasis in Yarrowia lipolytica. AB - Peroxisomes are essential organelles in the cells of most eukaryotes, from yeasts to mammals. Their role in beta-oxidation is particularly essential in yeasts; for example, in Saccharomyces cerevisiae, fatty acid oxidation takes place solely in peroxisomes. In this species, peroxisome biogenesis occurs when lipids are present in the culture medium, and it involves the Pex11p protein family: ScPex11p, ScPex25p, ScPex27p, and ScPex34p. Yarrowia lipolytica has three Pex11p homologues, which are YALI0C04092p (YlPex11p), YALI0C04565p (YlPex11C), and YALI0D25498p (Pex11/25p). We found that these genes are regulated by oleic acid, and as has been observed in other organisms, YlPEX11 deletion generated giant peroxisomes when mutant yeast were grown in oleic acid medium. Moreover, DeltaYlpex11 was unable to grow on fatty acid medium and showed extreme dose dependent sensitivity to oleic acid. Indeed, when the strain was grown in minimum medium with 0.5% glucose and 3% oleic acid, lipid body lysis and cell death were observed. Cell death and lipid body lysis may be partially explained by an imbalance in the expression of the genes involved in lipid storage, namely, DGA1, DGA2, and LRO1, as well as that of TGL4, which is involved in lipid remobilization. TGL4 deletion and DGA2 overexpression resulted in decreased oleic acid sensitivity and delayed cell death of DeltaYlpex11, which probably stemmed from the release of free fatty acids into the cytoplasm. All these results show that YlPex11p plays an important role in lipid homeostasis in Y. lipolytica. PMID- 25820525 TI - Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension. AB - Endothelial cell (EC) dysfunction plays a role in the pathobiology of occlusive vasculopathy in pulmonary arterial hypertension (PAH). Purinergic signaling pathways, which consist of extracellular nucleotide and nucleoside-mediated cell signaling through specific receptors, are known to be important regulators of vascular tone and remodeling. Therefore, we hypothesized that abnormalities in the vascular purinergic microenvironment are associated with PAH. Enzymatic clearance is crucial to terminate unnecessary cell activation; one of the most abundantly expressed enzymes on the EC surface is E-NTPDase1/CD39, which hydrolyzes ATP and ADP to AMP. we used histological samples from patients and healthy donors, radioisotope-labeled substrates to measure ectoenzyme activity, and a variety of in vitro approaches to study the role of CD39 in PAH. Immunohistochemistry on human idiopathic PAH (IPAH) patients' lungs demonstrated that CD39 was significantly downregulated in the endothelium of diseased small arteries. Similarly, CD39 expression and activity were decreased in cultured pulmonary ECs from IPAH patients. Suppression of CD39 in vitro resulted in EC phenotypic switch that gave rise to apoptosis-resistant pulmonary arterial endothelial cells and promoted a microenvironment that induced vascular smooth muscle cell migration. we also identified that the ATP receptor P2Y11 is essential for ATP-mediated EC survival. Furthermore, we report that apelin, a known regulator of pulmonary vascular homeostasis, can potentiate the activity of CD39 both in vitro and in vivo. we conclude that sustained attenuation of CD39 activity through ATP accumulation is tightly linked to vascular dysfunction and remodeling in PAH and could represent a novel target for therapy. PMID- 25820524 TI - Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair. AB - Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands on bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors, and signaling targets in wild-type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested by using a doxycycline (dox) based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0 28) or during later stages (days 6-28 and 14-28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin-induced lung injury in mice. PMID- 25820526 TI - Evaluation of cigarette smoke-induced emphysema in mice using quantitative micro computed tomography. AB - Chronic cigarette smoke (CS) exposure provokes variable changes in the lungs, and emphysema is an important feature of chronic obstructive pulmonary disease. The usefulness of micro-computed tomography (CT) to assess emphysema in different mouse models has been investigated, but few studies evaluated the dynamic structural changes in a CS-induced emphysema mouse model. A novel micro-CT technique with respiratory and cardiac gating has resulted in high-quality images that enable processing for further quantitative and qualitative analyses. Adult female C57BL/6J mice were repeatedly exposed to mainstream CS, and micro-CT scans were performed at 0, 4, 12, and 20 wk. Emphysema was also histologically quantified at each time point. Air-exposed mice and mice treated with intratracheal elastase served as controls and comparisons, respectively. End expiratory lung volume, corresponding to functional residual volume, was defined as the calculated volume at the phase of end-expiration, and it evaluated air trapping. The end-expiratory lung volumes of CS-exposed mice were significantly larger than those of air controls at 12 and 20 wk, which was in line with alveolar enlargement and destruction by histological quantification. However, CS exposure neither increased low attenuation volume nor decreased the average lung CT value at any time point, unlike the elastase-instilled emphysema model. CS exposed mice had rather higher average lung CT values at 4 and 12 wk. This is the first study characterizing a CS-induced emphysema model on micro-CT over time in mice. Moreover, these findings extend our understanding of the distinct pathophysiology of CS-induced emphysema in mice. PMID- 25820527 TI - Platelet-derived miR-103b as a novel biomarker for the early diagnosis of type 2 diabetes. AB - AIMS: MicroRNA-103 (miR-103) plays a critical role in regulating glucose homeostasis in type 2 diabetes (DM2). Recent data suggest that secreted frizzled related protein 4 (SFRP4) serves as a potential risk biomarker for prediabetic mellitus (pre-DM) and that platelets are enriched for miR-103. The objective of this study was to test the hypothesis that platelet-derived miR-103b (miR-103 as), which regulates SFRP4, might be a novel biomarker for the early diagnosis of DM2. METHODS: We evaluated platelet miR-103b expression in healthy subjects (n = 46), pre-DM subjects (n = 48), non-complicated diabetic subjects (n = 43) and diabetes mellitus type 2-coronary heart disease subjects (n = 36), respectively, and analyzed the relationship of these levels with its target gene SFRP4. RESULTS: In qRT-PCR assays, miR-103b were significantly down-regulated, and conversely, the expression of the SFRP4 gene was up-regulated in pooled leukocyte depleted platelets and individual subjects with pre-DM. Additionally, patients who had undergone antiplatelet treatment were characterized by decreased gene expression of SFRP4 and increased levels of platelet-derived miR-103b. miR-103b modulated reporter gene expression through SFRP4 mRNA 3'-UTR seed sequence and negatively regulated its expression. Furthermore, SFRP4 mRNA and protein levels were down-regulated by a miR-103b mimic but were up-regulated by a miR-103b inhibitor. CONCLUSIONS: The results suggest that platelet-derived miR-103b could negatively regulate the expression of SFRP4 mRNA/protein in pre-DM2, indicating that miR-103b could be a novel biomarker for the early diagnosis of DM2. PMID- 25820529 TI - The complex morphology of acute kidney injury with microangiopathic hemolytic anemia and hyposplenism. PMID- 25820528 TI - Animal and cellular models of hepatocellular carcinoma bone metastasis: establishment and characterisation. AB - BACKGROUND: An increasingly high occurrence of bone metastases in hepatocellular carcinoma (HCC) patients highlights the importance of fundamental research on HCC bone metastasis, which has been limited in its success due to the lack of a model system. PURPOSE: Establishment of animal and cellular models of HCC bone metastasis and discovery of HCC bone metastasis-related genes. METHODS: Luciferase-transfected HCC cell lines HCCLM3, MHCC97H, and SMMC-7721 were used to inoculate nude mice intracardially. Formation of bone metastases was examined by bioluminescence imaging, SPECT, and pathology study. Metastatic cells in bone were isolated and subcultured. Differences between bone metastatic cells and their parental cells were studied by in vitro/in vivo assays. RESULTS: Mouse model of HCC bone metastasis was successfully established. Injected tumour cells formed metastases in the skull, the spine, the hind limbs, and the sternum, causing osteolytic lesions via act of MMP-1 and recruitment of osteoclasts. Four bone metastatic cell lines were extracted from HCCLM3-inoculated mice and were demonstrated to exhibit a much stronger ability to form bone metastases as well as other phenotypes, including enhanced in vitro migration/invasion and colony formation. Moreover, the expression of PTHrP, MMP-1, and CTGF was significantly elevated in bone metastatic cells compared to parental HCC cells. CONCLUSION: The nude mouse model and bone metastatic cell lines together provide an effective simulation of HCC bone metastasis. This model system will become powerful tool with which to explore the mechanisms and therapies of HCC bone metastasis. Additionally, PTHrP, MMP-1, and CTGF are candidate genes related to HCC bone metastasis. PMID- 25820530 TI - Trace membrane additives affect lipid phases with distinct mechanisms: a modified Ising model. AB - The addition of trace molecules into membranes can significantly alter the morphology of the co-existing liquid phases and lipid phase transition temperature. Membrane additives may affect lipid phase dynamics through preferentially partitioning to the boundary between lipid phases or preferentially mixing into one lipid phase. The characteristic differences between these mechanisms are demonstrated here in a minimalistic nearest neighbor model to provide a framework for how slight changes to membrane composition may affect lipid-phase-dependent processes, such as lipid-raft formation, immunological signaling, and molecular sorting preceding endocytosis with coexisting liquid phases. Within the low mole fractions explored here (<=3 mol%), increasing the additive concentration linearly changed the phase miscibility temperature. Rotationally asymmetric Janus particles reduced the miscibility transition temperature for all fractions and degree of phase polarization. Rotationally symmetric additives, however, either increased or decreased the phase miscibility temperature depending on the phase preference of the additive. While most experimental molecules may contain aspects of both of these idealized additives, this model provides a broad framework to quantify the effects of membrane additives in regard to lipid phase preference, lipid-raft association, and contribution to lipid phase-dependent molecular sorting. PMID- 25820532 TI - Bad luck, no luck, good luck! PMID- 25820531 TI - Characterization of the flexible lip regions in bacteriophage lambda lysozyme using MD simulations. AB - The upper and lower lip regions in lysozyme from bacteriophage lambda (lambda lysozyme) are flexible in solution and exhibit two different conformations in crystal structures of the protein. MD simulations have been used to characterize the structure and dynamics of these lip regions, which surround the active site. Ten different simulations have been run including those with restraining to experimental NOE distance and (1)H-(15)N order parameter data. The simulations show that the lower lip region, although undergoing considerable backbone fluctuations, contains two persistent beta-strands. In the upper lip region, a wide range of conformations are populated and it is not clear from the available data whether some helical secondary structure is present. The work provides a clear example of the advantages of combining MD simulations with experimental data to obtain a structural interpretation of the latter. In this case, time averaged order parameter restraining has played an essential role in enabling convergence between two different starting structures and identifying the extent to which flexible regions in solution can contain persistent secondary structure. PMID- 25820533 TI - Safety of antidiabetes medications: An update. AB - Adverse iatrogenic effects of especial relevance for antidiabetes medications include hypoglycemic episodes, major adverse cardiovascular (CV) events, cancer, bone fractures, pancreatic effects, genital/urinary tract infections, and weight gain. Here, recent clinical studies addressing safety profiles of antidiabetes medications are reviewed. On balance, new prospective and population-based studies continue to indicate that the benefits of improved glucose control outweigh the risks associated with antidiabetes medications in most patients with type 2 diabetes. PMID- 25820534 TI - Synthesis of a Fluorine-Containing Cis-Cisoidal One-Handed Helical Polyphenylacetylene and Application of Highly Selective Photocyclic Aromatization Product on Oxygen Permselective Membrane. AB - A novel phenylacetylene monomer having a perfluorinated alkyl group (M-F) was synthesized and polymerized in a chiral catalytic system to yield a one-handed helical polymer. The ability and efficiency of the chiral induction of the fluorine-containing monomer in the helix-sense-selective polymerization (HSSP) was much higher than those of a monomer having the corresponding alkyl group (M H) we reported before. The resulting polymer showed cis-cisoidal one-handed helical conformation, and was suitable for highly selective photocyclic aromatization (SCAT) to give a 2D surface modifier (). Oxygen permselectivity through a base polymer membrane was highly enhanced from 1.83 to 2.36 by adding a small amount (1-5 wt%) of the 2D surface modifier . The improvement was thought to be caused by improvement of solution selectivity on the membrane surface which the 2D surface modifier effectively covered. PMID- 25820535 TI - A general, eco-friendly synthesis procedure of self-assembled ZnO-based materials with multifunctional properties. AB - A bioinspired one-pot approach for the synthesis of ZnO-carbohydrate hierarchical architectures was developed. The synergy between a saccharide (mono-, di- or polysaccharide) that contains d-glucose units and triethanolamine is the key parameter of the synthetic methodology. The morphology of the ZnO composites is dictated by the saccharide used, and rod, spindle, solid and hollow spherical like ZnO structures are obtained by varying the carbohydrate. The synthesized composites present good photocatalytic and antimicrobial activity. PMID- 25820536 TI - 4-Phosphopyrazol-2-yl alanine: a non-hydrolysable analogue of phosphohistidine. AB - We report the synthesis of a stable analogue of tau-phosphohistidine: 4 phosphopyrazol-2-yl alanine (pPza). Polyclonal antibodies generated against the mimic show high reactivity and selectivity for tau-phosphohistidine, with minor or no cross-reactivity towards non-phosphorylated histidine or O-phosphoamino acids, including phosphotyrosine. PMID- 25820538 TI - A Study of Teacher-Learner Interactions: A Continuum Between Monologic and Dialogic Interactions. AB - PURPOSE: Teachers and learners must be able to shift flexibly along the continuum of monologic and dialogic interactional repertoires to advance learning. This article describes how teachers and learners interacted during whole-class instruction along the continuum between monologic and dialogic interaction in primary school classrooms in Western Cape, South Africa. METHOD: A video observation method was used to analyze teacher-learner interactions (TLIs) across 15 lessons in intermediate-phase classrooms. TLIs were analyzed in relation to indicators such as authority, questions, feedback, explanation, metalevel connection, and collaboration. The transcriptions of TLIs were described using quantitative and qualitative techniques. RESULTS: The study found that teachers sustained dominant monologic interactions by asserting their authority, asking mainly closed-ended questions, and providing confirming/correcting feedback that constrained the interaction. Learners had limited opportunities for explanations or collaboration. Across most lessons, there were episodic shifts from monologic TLIs to transitional TLIs. These transitions were achieved by using mainly open ended questions and feedback to expand the interaction. Dialogic TLIs were not evident. CONCLUSIONS: Monologic TLIs were dominant, closing down opportunities for communication. Although transitional TLIs were evident, they were episodic and showed the potential for opening interaction opportunities. The absence of dialogic TLIs suggested that collaborative engagement opportunities were unavailable. The opportunity for intervention to increase dialogic TLIs is discussed. PMID- 25820537 TI - Prostate Cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI. AB - PURPOSE: To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. MATERIALS AND METHODS: The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K(trans)) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. RESULTS: Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K(trans) decreased significantly only in tumours (p < 0.001); relative K(trans) changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. CONCLUSIONS: Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. KEY POINTS: * Androgen-deprivation therapy caused changes of ADC, K (trans) in tumour and benign prostate. * Prostate volume and PSA values decreased significantly with therapy. * ADC values may be helpful for monitoring treatment response. PMID- 25820539 TI - Angiogenic Role of MMP-2/9 Expressed on the Cell Surface of Early Endothelial Progenitor Cells/Myeloid Angiogenic Cells. AB - Since the introduction of angiogenic cell therapy using early endothelial progenitor cells (EPCs), myeloid angiogenic cells (MACs) have been expected to be useful in treating ischemic diseases. In order to elucidate the angiogenic properties of MACs/EPCs, we clarified the characteristics of MACs as compared to M2 macrophages (Mphis). Comparison of the gene expression profiles of MACs and late EPCs revealed that MACs expressed greater amounts of metalloproteinase (MMP) 9. It should be noted that the profile of MMP-2/9 expression on the cell surface of MACs was similar to that of M2 Mphis, and that cell surface MMP-2/9 might be an active form based on molecular size. In addition, the invasion of MACs was prohibited not only by MMP-2/9 inhibitor, but also by the hyaluronidase treatment that caused the down-regulation of MMP-9 on the cell surface of MACs and inhibited their invasion activity. These results indicate that cell surface MMP 2/9 plays an important role in the high invasion ability of MACs. The conditioned medium of both MACs and M2 Mphis stimulated tube formation of endothelial cells in vitro. MACs caused an increase in vessel formation in in vivo models through the production of IL-8. We propose that the role of MACs with cell surfaces expressing MMP-2/9 is rapidly invading ischemic tissue. PMID- 25820543 TI - Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives. AB - Mesenchymal stem/stromal cells (MSCs) are progenitors which share plastic adherence capacity and cell surface markers but have different properties according to their cell and tissue sources and to culture conditions applied. Many recent publications suggest that MSCs can differentiate into hepatic-like cells, which can be a consequence of either a positive selection of rare in vivo pluripotent cells or of the original plasticity of some cells contributing to MSC cultures. A possible role of MSCs in hereditary transmission of obesity and/or diabetes as well as properties of MSCs regarding immunomodulation, cell fusion and exosome release capacities are discussed according to recent literature. Limitations in methods used to track MSCs in vivo especially in the context of liver cirrhosis are addressed as well as strategies explored to enhance their migratory, survival and proliferation properties, which are known to be relevant for their future clinical use. Current knowledge regarding mechanisms involved in liver cirrhosis amelioration mediated by naive and genetically modified MSCs as well as the effects of applying preconditioning and combined strategies to improve their therapeutic effects are evaluated. Finally, first reports of GMP guidelines and biosafety issues in MSCs applications are discussed. PMID- 25820545 TI - Erratum to: Risk factors for target non-attainment during empirical treatment with beta-lactam antibiotics in critically ill patients. PMID- 25820544 TI - Glyceronephosphate O-acyltransferase as a hemochromatosis modifier gene: Another iron in the fire? PMID- 25820546 TI - Capsule commentary on Mukhtar et al., Assessment of HBV preventive services in a medically underserved Asian and Pacific Islander population using provider and patient data. PMID- 25820547 TI - Unlicensed Health Care Personnel and Patient Outcomes. PMID- 25820549 TI - Electrochemical and physicochemical properties of small phosphonium cation ionic liquid electrolytes with high lithium salt content. AB - Electrolytes of a room temperature ionic liquid (RTIL), trimethyl(isobutyl)phosphonium (P111i4) bis(fluorosulfonyl)imide (FSI) with a wide range of lithium bis(fluorosulfonyl)imide (LiFSI) salt concentrations (up to 3.8 mol kg(-1) of salt in the RTIL) were characterised using a combination of techniques including viscosity, conductivity, differential scanning calorimetry (DSC), electrochemical impedance spectroscopy (EIS), nuclear magnetic resonance (NMR) and cyclic voltammetry (CV). We show that the FSI-based electrolyte containing a high salt concentration (e.g. 1 : 1 salt to IL molar ratio, equivalent to 3.2 mol kg(-1) of LiFSI) displays unusual transport behavior with respect to lithium ion mobility and promising electrochemical behavior, despite an increase in viscosity. These electrolytes could compete with the more traditionally studied nitrogen-based ionic liquids (ILs) in lithium battery applications. PMID- 25820548 TI - Dutch-Flemish translation of nine pediatric item banks from the Patient-Reported Outcomes Measurement Information System (PROMIS)(r). AB - PURPOSE: The Patient-Reported Outcomes Measurement Information System (PROMIS((r))) is a new, state-of-the-art assessment system for measuring patient reported health and well-being of adults and children. It has the potential to be more valid, reliable, and responsive than existing PROMs. The items banks are designed to be self-reported and completed by children aged 8-18 years. The PROMIS items can be administered in short forms or through computerized adaptive testing. This paper describes the translation and cultural adaption of nine PROMIS item banks (151 items) for children in Dutch-Flemish. METHODS: The translation was performed by FACITtrans using standardized PROMIS methodology and approved by the PROMIS Statistical Center. The translation included four forward translations, two back-translations, three independent reviews (at least two Dutch, one Flemish), and pretesting in 24 children from the Netherlands and Flanders. RESULTS: For some items, it was necessary to have separate translations for Dutch and Flemish: physical function-mobility (three items), anger (one item), pain interference (two items), and asthma impact (one item). Challenges faced in the translation process included scarcity or overabundance of possible translations, unclear item descriptions, constructs broader/smaller in the target language, difficulties in rank ordering items, differences in unit of measurement, irrelevant items, or differences in performance of activities. By addressing these challenges, acceptable translations were obtained for all items. CONCLUSION: The Dutch-Flemish PROMIS items are linguistically equivalent to the original USA version. Short forms are now available for use, and entire item banks are ready for cross-cultural validation in the Netherlands and Flanders. PMID- 25820550 TI - A familial GLI2 deletion (2q14.2) not associated with the holoprosencephaly syndrome phenotype. AB - Molecular alterations of the GLI2 gene in 2q14.2 are associated with features from the holoprosencephaly spectrum. However, the phenotype is extremely variable, ranging from unaffected mutation heterozygotes to isolated or combined pituitary hormone deficiency, and to patients with a phenotype that overlaps with holoprosencephaly, including abnormal pituitary gland formation/function, craniofacial dysmorphisms, branchial arch anomalies, and polydactyly. Although many point mutations within the GLI2 gene have been identified, large (sub) microscopic deletions affecting 2q14.2 are rare. We report on a family with a 4.3 Mb deletion in 2q14 affecting GLI2 without any dysmorphologic features belonging to the holoprosencephaly spectrum. This family confirms the incomplete penetrance of genomic disturbances affecting the GLI2 gene. However, the family presented here is unique as none of the three identified individuals with a GLI2 deletion showed any typical signs of holoprosencephaly, whereas all patients reported so far were referred for genetic testing because at least one member exhibited holoprosencephaly and related features. PMID- 25820552 TI - Isotachophoresis for fractionation and recovery of cytoplasmic RNA and nucleus from single cells. AB - There is a substantial need for simultaneous analyses of RNA and DNA from individual single cells. Such analysis provides unique evidence of cell-to-cell differences and the correlation between gene expression and genomic mutation in highly heterogeneous cell populations. We present a novel microfluidic system that leverages isotachophoresis to fractionate and isolate cytoplasmic RNA and genomic DNA (gDNA) from single cells. The system uniquely enables independent, sequence-specific analyses of these critical markers. Our system uses a microfluidic chip with a simple geometry and four end-channel electrodes, and completes the entire process in <5 min, including lysis, purification, fractionation, and delivery to DNA and RNA output reservoirs, each containing high quality and purity aliquots with no measurable cross-contamination of cytoplasmic RNA versus gDNA. We demonstrate our system with simultaneous, sequence-specific quantitation using off-chip RT-qPCR and qPCR for simultaneous cytoplasmic RNA and gDNA analyses, respectively. PMID- 25820551 TI - Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats. AB - KEY POINTS: Some studies suggest that neuregulin 1 (NRG1) could be involved in the regulation of skeletal muscle energy metabolism in rodents. Here we assessed whether unbalanced diet is associated with alterations of the NRG1 signalling pathway and whether exercise and diet might restore NRG1 signalling in skeletal muscle of obese rats. We show that diet-induced obesity does not impair NRG1 signalling in rat skeletal muscle. We also report that endurance training and a well-balanced diet activate the NRG1 signalling in skeletal muscle of obese rats, possibly via a new mechanism mediated by the protease ADAM17. These results suggest that some beneficial effects of physical activity and diet in obese rats could be partly explained by stimulation of the NRG1 signalling pathway. ABSTRACT: Some studies suggest that the signalling pathway of neuregulin 1 (NRG1), a protein involved in the regulation of skeletal muscle metabolism, could be altered by nutritional and exercise interventions. We hypothesized that diet induced obesity could lead to alterations of the NRG1 signalling pathway and that chronic exercise could improve NRG1 signalling in rat skeletal muscle. To test this hypothesis, male Wistar rats received a high fat/high sucrose (HF/HS) diet for 16 weeks. At the end of this period, NRG1 and ErbB expression/activity in skeletal muscle was assessed. The obese rats then continued the HF/HS diet or were switched to a well-balanced diet. Moreover, in both groups, half of the animals also performed low intensity treadmill exercise training. After another 8 weeks, NRG1 and ErbB expression/activity in skeletal muscle were tested again. The 16 week HF/HS diet induced obesity, but did not significantly affect the NRG1/ErbB signalling pathway in rat skeletal muscle. Conversely, after the switch to a well-balanced diet, NRG1 cleavage ratio and ErbB4 amount were increased. Chronic exercise training also promoted NRG1 cleavage, resulting in increased ErbB4 phosphorylation. This result was associated with increased protein expression and phosphorylation ratio of the metalloprotease ADAM17, which is involved in NRG1 shedding. Similarly, in vitro stretch-induced activation of ADAM17 in rat myoblasts induced NRG1 cleavage and ErbB4 activation. These results show that low intensity endurance training and well-balanced diet activate the NRG1-ErbB4 pathway, possibly via the metalloprotease ADAM17, in skeletal muscle of diet-induced obese rats. PMID- 25820553 TI - Italian Society of Endocrinology Consensus Statement: definition, evaluation and management of patients with mild primary hyperparathyroidism. PMID- 25820554 TI - ROS-Induced Nuclear Translocation of Calpain-2 Facilitates Cardiomyocyte Apoptosis in Tail-Suspended Rats. AB - Isoproterenol (ISO) induced nuclear translocation of calpain-2 which further increased susceptibility of cardiomyocyte apoptosis in tail-suspended rats. The underlying mechanisms remain elusive. In the present study, the results showed that ISO (10 nM) significantly elevated NADPH oxidases (NOXs) activity and NOXs derived ROS productions which induced nuclear translocation of calpain-2 in cardiomyocytes of tail-suspended rats. In contrast, the inhibition of NADPH oxidase or cleavage of ROS not only reduced ROS productions, but also resisted nuclear translocation of calpain-2 and decreased ISO-induced apoptosis of cardiomyocyte in tail-suspended rats. ISO also increased the constitutive binding between calpain-2 and Ca(2+)/calmodulin-dependent protein kinase II deltaB (CaMK II deltaB) in nuclei, concomitant with the promotion of CaMK II deltaB degradation and subsequent down-regulation of Bcl-2 mRNA expression and the ratio of Bcl-2 to Bax protein in tail-suspended rat cardiomyocytes. These effects of ISO on cardiomyocytes were abolished by a calpain inhibitor PD150606. Inhibition of calpain significantly reduced ISO-induced loss of the mitochondrial membrane potential, cytochrome c release into the cytoplasm, as well as the activation of caspase-3 and caspase-9 in mitochondrial apoptotic pathway. In summary, the above results suggest that ISO increased NOXs-derived ROS which activated nuclear translocation of calpain-2, subsequently nuclear calpain-2 degraded CaMK II deltaB which reduced the ratio of Bcl-2 to Bax, and finally the mitochondria apoptosis pathway was triggered in tail-suspended rat cardiomyocytes. Therefore, calpain-2 may represent a potentially therapeutic target for prevention of oxidative stress-associated cardiomyocyte apoptosis. PMID- 25820555 TI - Metformin reduces ovarian cancer risk in Taiwanese women with type 2 diabetes mellitus. AB - BACKGROUND: Whether metformin therapy affects ovarian cancer risk in Asian patients with type 2 diabetes mellitus has not been investigated. METHODS: Data analysis was performed in 2014. The reimbursement databases of Taiwanese female patients with a new diagnosis of type 2 diabetes mellitus between 1998 and 2002 (n = 479,475) were retrieved from the National Health Insurance for follow-up of ovarian cancer until the end of 2009. Metformin was treated as a time-dependent variable; and of these patients, 286,106 were never-users, and 193,369 were ever users. A time-dependent approach was used to calculate ovarian cancer incidence and estimate hazard ratios by Cox regression for never-users (as referent group), ever-users and subgroups of metformin exposure (tertiles of cumulative duration and cumulative dose). RESULTS: During follow-up, 601 metformin ever-users and 2600 never-users developed ovarian cancer, representing an incidence of 49.4 and 146.4 per 100,000 person-years, respectively. The overall fully adjusted hazard ratio (95% confidence intervals) for ever-users versus never-users was 0.658 (0.593-0.730). The fully adjusted hazard ratios for the first, second and third tertiles of cumulative duration of metformin therapy were 1.169 (1.019-1.341), 0.761 (0.644-0.898) and 0.276 (0.225-0.340), respectively (p trend < 0.01) and 1.220 (1.067-1.395), 0.610 (0.513-0.725) and 0.305 (0.248-0.374), respectively (p trend < 0.01), for a cumulative dose of metformin. In additional analyses, sulfonylureas but not the other antidiabetic drugs were associated with a reduced risk of ovarian cancer. CONCLUSIONS: Metformin use is associated with a decreased risk of ovarian cancer. PMID- 25820556 TI - Effect of interleukin-1beta and dehydroepiandrosterone on the expression of lumican and fibromodulin in fibroblast-like synovial cells of the human temporomandibular joint. AB - Several epidemiological studies have reported that temporomandibular disorders (TMDs) are more prevalent in women than in men. It has recently been proposed that sex hormones such as estrogen, testosterone and dehydroepiandrosterone (DHEA) are involved with the pathogenesis of TMDs. Although studies have investigated the relationship between estrogen and testosterone and the restoration of TMDs, the relationship between DHEA and TMDs is unknown. The synovial tissue of the temporomandibular joint (TMJ) is made up of connective tissue with an extracellular matrix (ECM) composed of collagen and proteoglycan. One proteoglycan family, comprised of small leucine-rich repeat proteoglycans (SLRPs), was found to be involved in collagen fibril formation and interaction. In recent years, the participation of SLRPs such as lumican and fibromodulin in the internal derangement of TMJ has been suggested. Although these SLRPs may contribute to the restoration of the synovium, their effect is still unclear. The purpose of this study was to investigate the effect of DHEA, a sex hormone, on the expression of lumican and fibromodulin in human temporomandibular specimens and in cultured human TMJ fibroblast-like synovial cells in the presence or absence of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). In the in vivo study, both normal and osteoarthritic (OA) human temporomandibular synovial tissues were immunohistochemically examined. In the in vitro study, five fibroblast-like synoviocyte (FLS) cell lines were established from human TMJ synovial tissue of patients with osteoarthritis. The subcultured cells were then incubated for 3, 6, 12 or 24 h with/without IL-1beta (1 ng/mL) in the presence or absence of DHEA (10 MUM). The gene expression of lumican and fibromodulin was examined using the real-time polymerase chain reaction (PCR) and their protein expression was examined using immunofluorescent staining. We demonstrated that the expression of lumican significantly differs from that of fibromodulin in synovial tissue in OA and furthermore, that IL-1beta induced a significant increase in lumican mRNA and immunofluorescent staining in FLS compared to cells without IL-1beta. DHEA plus IL-1beta induced a significant increase in fibromodulin, but not in lumican mRNA, compared to DHEA alone, IL-1beta alone and in the absence of DHEA and IL-1beta. In immunofluorescent staining, weaker fibromodulin staining of FLS cells was observed in cells cultured in the absence of both DHEA and IL-1beta compared to fibromodulin staining of cells cultured with DHEA alone, with DHEA plus IL-1beta, or with IL-1beta alone. These results indicate that DHEA may have a protective effect on synovial tissue in TMJ by enhancing fibromodulin formation after IL-1beta induced inflammation. DHEA enhancement of fibromodulin expression may also exert a protective effect against the hyperplasia of fibrous tissue that TGF-beta1 induces. In addition lumican and fibromodulin are differentially expressed under different cell stimulation conditions and lumican and fibromodulin may promote regeneration of the TMJ after degeneration and deformation induced by IL-1beta. PMID- 25820557 TI - Are podoplanin and ezrin involved in the invasion process of the ameloblastomas? AB - The association between podoplanin and ezrin in the process of odontogenic tumors invasion has been suggested, but was not studied yet. Our purpose was to investigate the relationship between podoplanin and ezrin expressions in the odontogenic epithelium of ameloblastomas. Forty-seven ameloblastomas were analyzed by immunohistochemistry using anti-podoplanin and anti-ezrin antibodies. The expressions of both proteins were evaluated using a score method and the comparison and association between these proteins were verified, respectively, by Wilcoxon Signed-Rank test and by Spearman's rank correlation coefficient, using a statistical significance level of 0.05. The majority of tumors (87.2%) exhibited strong membranous expression of podoplanin in the peripheral cells. Cytoplasmic expression of ezrin in the peripheral cells of ameloblastomas was stronger than its membranous expression. No statistically significant correlation was observed between podoplanin and ezrin. However, there was statistically significant difference between membranous podoplanin and membranous ezrin expressions, between cytoplasmic podoplanin and membranous ezrin expressions, and between cytoplasmic podoplanin and cytoplasmic ezrin expressions. There was no statistical difference between membranous podoplanin and cytoplasmic ezrin expressions. These results suggest a synergistic role of both proteins in the process of invasion of ameloblastomas. PMID- 25820558 TI - RANK/RANKL/OPG signaling pathways in necrotic jaw bone from bisphosphonate treated subjects. AB - Osteonecrosis of the jaw (ONJ) is a chronic complication affecting long-term bisphosphonate-treated subjects, recognized by non-healing exposed bone in the maxillofacial region. The pathophysiological mechanism underlying ONJ has not been fully elucidated. The aim of the present study was to investigate the role of RANK/RANKL/OPG signaling pathway and, in parallel, to evaluate angiogenic and matrix mineralization processes in jaw bone necrotic samples obtained from bisphosphonate-treated subjects with established ONJ. Necrotic bone samples and native bone samples were processed for Light and Field Emission in Lens Scanning Electron Microscope (FEISEM) analyses, for Real-Time RT-PCR to evaluate the gene expression of TNFRSF11A (RANK), TNFSF11 (RANKL), and TNFSF11B (OPG) and for immunohistochemical analyses of VEGF and BSP expression. Morphological analyses performed by Light microscope and FEISEM show empty osteocytic lacunae and alteration of lamellar organization with degradation of the mineralized bone matrix in necrotic bone samples. A significant increase in TNFRSF11A, TNFSF11, TRAF6 and NFAT2 gene expression, and a reduction of TNFSF11B gene transcription level compared is also showed in necrotic bone compared to control samples. No significant difference of VEGF expression is evidenced, while lower BSP expression in necrotic bone compared to healthy samples is found. Even if the pathogenesis of bisphosphonate-associated ONJ remains unknown, a link between oral pathogens and its development seems to exist. We suppose lipopolysaccharide produced by bacteria colonizing and infecting necrotic bone and the surrounding viable area could trigger RANK/RANKL/OPG signaling pathway and, in this context, osteoclasts activation could be considered as a protective strategy carried out by the host bone tissue to delimitate the necrotic area and to counteract infection. PMID- 25820559 TI - Seasonal expression of androgen receptor, aromatase, and estrogen receptor alpha and beta in the testis of the wild ground squirrel (Citellus dauricus Brandt). AB - The aim of this study was to investigate the seasonal expression of androgen receptor (AR), estrogen receptors alpha and beta (ERalpha and ERbeta) and aromatase cytochrome P450 (P450arom) mRNA and protein by real-time PCR and immunohistochemistry in the wild ground squirrel (WGS) testes. Histologically, all types of spermatogenic cells including mature spermatozoa were identified in the breeding season (April), while spermatogonia and primary spermatocytes were observed in the nonbreeding season (June), and spermatogonia, primary spermatocytes and secondary spermatocytes were found in pre-hibernation (September). AR was present in Leydig cells, peritubular myoid cells and Sertoli cells in the breeding season and pre-hibernation with more intense staining in the breeding season, whereas AR was only found in Leydig cells in the nonbreeding season; P450arom was expressed in Leydig cells, Sertoli cells and germ cells during the breeding season, whereas P450arom was found in Leydig cells and Sertoli cells during pre-hibernation, but P450arom was not present in the nonbreeding season; stronger immunohistochemical signal for ERalpha was present in Sertoli cells and Leydig cells during the breeding season; ERbeta was only expressed in Leydig cells of the breeding season. Consistent with the immunohistochemical results, the mean mRNA level of AR, P450arom, ERalpha and ERbeta were higher in the testes of the breeding season when compared to pre hibernation and the nonbreeding season. These results suggested that the seasonal changes in spermatogenesis and testicular recrudescence and regression process in WGSs might be correlated with expression levels of AR, P450arom and ERs, and that estrogen and androgen may play an important autocrine/paracrine role to regulate seasonal testicular function. PMID- 25820560 TI - Elastofibroma dorsi: a histochemical and immunohistochemical study. AB - Elastofibroma dorsi (ED) is considered a member of a heterogeneous group of benign fibrous (fibroblastic or myofibroblastic) soft-tissue tumors, frequently localized in the periscapular region in middle aged or older individuals. However, the pathogenesis of ED is still unclear and many authors believe that ED results from a reactive hyperproliferation of fibroblastic tissue, while others suggest that it may be a consequence of a mechanical friction. In our study, we examined 11 cases of ED using histochemical and immunohistochemical methods, in order to extend the knowledge about extracellular matrix composition and histopathogenesis of ED. From the results it appeared that stroma and interspersed spindle cells of ED were positive for both periostin and tenascin-C. Mast cells tryptase-positive were also abundant throughout the lesion. The perivascular distribution of periostin and tenascin-C, associated with the CD34 positivity, suggest that endothelial-mesenchymal transition events can account for neovascularization and production of fibroelastic tissue characteristic of elastofibroma. Our data obtained in endothelial cells cultures demonstrated that elastin production is higher when the status of confluence of the cells is low. So, we can assume that such a phenomenon is a characteristic of mesenchymal/endothelial cells CD34 positive, in which elastin production results to be inversely proportional to the vascular differentiation of cellular elements. In the light of these considerations, we think that a cancerous nature of ED is unlikely. Overall, our study report, for the first time, a detailed description of extracellular matrix composition in ED, suggesting that a mechanical strain-dependent reactivation of periostin and tenascin-C expression, as well as of elastin deposition, could be responsible for development of ED. PMID- 25820561 TI - Effects of lead pollution on Ammonia parkinsoniana (foraminifera): ultrastructural and microanalytical approaches. AB - The responses of Ammonia parkinsoniana (Foraminifera) exposed to different concentrations of lead (Pb) were evaluated at the cytological level. Foraminifera bearing sediments were placed in mesocosms that were housed in aquaria each with seawater of a different lead concentration. On the basis of transmission electron microscopy and environmental scanning electron microscopy coupled with energy dispersive spectrometer analyses, it was possible to recognize numerous morphological differences between untreated (i.e., control) and treated (i.e., lead enrichment) specimens. In particular, higher concentrations of this pollutant led to numerical increase of lipid droplets characterized by a more electron-dense core, proliferation of residual bodies, a thickening of the organic lining, mitochondrial degeneration, autophagosome proliferation and the development of inorganic aggregates. All these cytological modifications might be related to the pollutant-induced stress and some of them such as the thickening of organic lining might suggest a potential mechanism of protection adopted by foraminifera. PMID- 25820562 TI - Muc5ac mucin expression during rat skin development. AB - Some mucin genes have been detected during human embryonic and fetal organ development; however, little is known about mucin expression in epidermal development, neither in humans nor in other species. The present research was developed to explore Muc5ac skin expression during prenatal and postnatal rat development. Immunohistochemistry (IHC), Western blotting (WB) and RT-PCR were employed. By IHC, Muc5ac protein was found early in embryonic epidermis from day 13 of gestation until seven days after birth when the surface epidermis became negative and the reaction was restricted to secreting sebum cells. In coincidence with IHC findings, WB analysis showed a band at approximately 200KDa at the same periods of development. Results were also confirmed by RT-PCR. Muc5ac expression in rat embryonic epidermis suggests that Muc5ac may play a protective role in embryonic skin previous to birth which may be replaced by pile covering. To our knowledge, this is the first report which confirmed Muc5ac expression during skin development. CONCLUSION: Muc5ac expression in rat embryonic epidermis suggests that Muc5ac may play a protective role in embryonic skin previous to birth which may be replaced by pile covering. To our knowledge, this is the first report which confirmed Muc5ac expression during skin development. PMID- 25820563 TI - Preferentially regulated expression of connexin 43 in the developing spiral ganglion neurons and afferent terminals in post-natal rat cochlea. AB - The expression pattern of connexin 43 (Cx43) in the cochlea is not determined and is controversial. Since the presence of Cx43 is essential for hearing, we re examined its distribution during postnatal development of rat cochlea. Cx43 protein was expressed in spiral ganglion neurons (SGNs) and their neurite terminals innervating the inner and outer hair cells (IHCs and OHCs) as early as birth (post-natal day 0, P0), and persisted until P14. Double immunofluorescence staining, using two antibodies against Cx43 and TUJ1, a marker for all SGNs and afferent terminals, showed that immunoreactivity for Cx43 and TUJ1 was perfectly colocalized in SGNs and afferent terminals associated with the IHCs and OHCs. However, beyond P14, Cx43 immunostaining could no longer be detected in the region of the synaptic terminals at the bases of IHCs and OHCs (P17, adult). In contrast, Cx43 maintained its expression in SGNs into adulthood. We further performed quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) to identify the presence of Cx43 mRNA in the modiolus (mainly containing SGNs). Cx43 mRNA was higher at P8, compared with P1, and subsequently decreased at P14. These results indicated that Cx43 correlated with cochlear synaptogenesis and establishment of auditory neurotransmission. PMID- 25820564 TI - Lipofuscin, lipofuscin-like pigments and autofluorescence. AB - A brief overview is here provided on lipofuscin and lipofuscin-like substances, with particular reference to their biological significance as well as to their cellular origin and pathophysiological role. Special emphasis is also placed on the mutual relationships between lipofuscin and lipofuscin-like lipopigments on one side, and cell autofluorescence on the other. PMID- 25820565 TI - Internalized chitosan nanoparticles persist for long time in cultured cells. AB - Chitosan-based nanoparticles (chiNPs) are considered to be potentially good carriers for the sustained intracellular delivery of specific molecules. However, scarce attention has been paid to the long-lasting permanence of these NPs in the intracellular milieu, as well as to their intracellular fate (i.e., distribution, interaction with cell organelles, and degradation) in the long term. In the present study, the presence and subcellular location of FITC-labelled chiNPs were monitored in HeLa cells up to 14 days post-administration using multicolor fluorescence confocal microscopy and diaminobenzidine photo-oxidation at transmission electron microscopy. The main result of the present study is the demonstration that internalized chiNPs persist inside the cell up to two weeks, occurring in both the cytoplasm and nucleus; accordingly, chiNPs are able to pass from mother to daughter cells through several mitotic cycles. The cells did not show increased mortality or structural damage up to 14 days after chiNP exposure. PMID- 25820568 TI - The fuss over lipo"fuss"cin: not all autofluorescence is the same. AB - Since the first description of cellular autofluorescence over a century ago, we have now come to appreciate that autofluorescence should not be discarded as a biological artifact but embraced as a biological phenomenon with potentially important cellular relevance. Indeed, cellular and tissue autofluorescence has been attributed to a spectrum of unrelated molecules such as porphyrins, vitamins (vitamin A, riboflavin, thiamine), structural proteins, lipofuscin and ceroid pigments. We have recently shown that freshly isolated epithelial cancer stem cells (CSCs) bear autofluorescent vesicles in the cytoplasm. Our studies definitively prove that riboflavin and not lipofuscin is the source of autofluorescence in CSCs as the inhibition of ATP and not autophagy eliminates CSC autofluorescence, that the ATP-dependent transporter ABCG2, for which riboflavin is a substrate, is overexpressed in autofluorescent CSCs and co localizes with the membrane of intracellular autofluorescent vesicles, the ABCG2 specific inhibitor Fumitremorgin C reversibly eliminates CSC autofluorescence, riboflavin is a substrate for ABCG2, and only the addition of riboflavin to vitamin-deprived CSC cultures is capable of restoring autofluorescence. Thus, the sum of these data unequivocally supports the conclusion that the source of CSC autofluorescence is the vitamin riboflavin. PMID- 25820569 TI - Erratum - Analysis of extracellular superoxide dismutase and Akt in ascending aortic aneurysm with tricuspid or bicuspid aortic valve. AB - This correct the article published on European Journal of Histochemistry 2014;58:200-206 doi: 10.4081/ejh.2014.2383. PMID- 25820570 TI - Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. AB - MUTYH-associated polyposis (MAP) is an adenomatous polyposis transmitted in an autosomal-recessive pattern, involving biallelic inactivation of the MUTYH gene. Loss of a functional MUTYH protein will result in the accumulation of G:T mismatched DNA caused by oxidative damage. Although p.Y179C and p.G396D are the two most prevalent MUTYH variants, more than 200 missense variants have been detected. It is difficult to determine whether these variants are disease-causing mutations or single-nucleotide polymorphisms. To understand the functional consequences of these variants, we generated 47 MUTYH gene variants via site directed mutagenesis, expressed the encoded proteins in MutY-disrupted Escherichia coli, and assessed their abilities to complement the functional deficiency in the E. coli by monitoring spontaneous mutation rates. Although the majority of variants exhibited intermediate complementation relative to the wild type, some variants severely interfered with this complementation. However, some variants retained functioning similar to the wild type. In silico predictions of functional effects demonstrated a good correlation. Structural prediction of MUTYH based on the MutY protein structure allowed us to interpret effects on the protein stability or catalytic activity. These data will be useful for evaluating the functional consequences of missense MUTYH variants detected in patients with suspected MAP. PMID- 25820572 TI - On-line visualization of multicolor chemical images with stimulated Raman scattering spectral microscopy. AB - We demonstrate multicolor, on-line visualization in label-free biomedical microscopy based on stimulated Raman scattering (SRS). Fast data acquisition of SRS spectral images and subsequent image generation are achieved. The loading vectors for the blind separation of chemical components are predetermined by multivariate analysis at a certain field of view (FOV) and are applied to execute on-line visualization of chemical images at other FOVs. We also show that the response time can be shortened by reducing the number of spectral data points. This on-line visualization system is expected to increase the usability of the Raman imaging system and the analytical throughput for screening. PMID- 25820571 TI - Downregulation of ubiquitin inhibits the proliferation and radioresistance of non small cell lung cancer cells in vitro and in vivo. AB - Radioresistance has been an important factor in restricting efficacy of radiotherapy for non-small cell lung cancer (NSCLC) patients and new approaches to inhibit cancer growth and sensitize irradiation were warranted. Despite the important role of ubiquitin/proteasome system (UPS) during cancer progression and treatment, the expression and biological role of ubiquitin (Ub) in human NSCLC has not been characterized. In this study, we found that ubiquitin was significantly overexpressed in 75 NSCLC tissues, compared to their respective benign tissues by immunohistochemistry (P < 0.0001). Knock-down of ubiquitin by mixed shRNAs targeting its coding genes ubiquitin B (UBB) and ubiquitin C (UBC) suppressed the growth and increased the radiosensitivity in NSCLC H1299 cells. Apoptosis and gamma H2AX foci induced by X-ray irradiation were enhanced by knock down of ubiquitin. Western blot and immunostaining showed that knock-down of ubiquitin decreased the expression and translocation of NF-kappaB to the nucleus by reduced phospho-IkappaBalpha after irradiation. Suppression of ubiquitin decreased the proliferation and radioresistance of H1299 transplanted xenografts in nude mice by promoting apoptosis. Taken together, our results demonstrate the critical role of ubiquitin in NSCLC proliferation and radiosensitivity. Targeting ubiquitin may serve as a potentially important and novel approach for NSCLC prevention and therapy. PMID- 25820573 TI - Identification of the dye adsorption modes in dye-sensitised solar cells with X ray spectroscopy techniques: a computational study. AB - Adsorption geometry of dye molecules can have a substantial impact on the efficiency and functional lifespan of a dye-sensitised solar cell (DSSC) and therefore, its reliable assessment is an important step in engineering more efficient DSSCs. X-ray photoelectron spectroscopy (XPS) of oxygen is empirically proved to be the most efficient technique in distinguishing between the two most occurring adsorption geometries, i.e. monodentate and bidentate. In this computational study, we provide a comprehensive analysis of XPS and X-ray absorption spectroscopy (XAS) of carbon and oxygen for these binding modes in a perylene-sensitised TiO2. We confirm that O 1s XPS has an excellent sensitivity in mode identification. Moreover, we show that adsorption has a great impact on the XPS binding energies and reduces them by ~4 eV, and using this effect, we extend the XPS usage to study dye desorption in the cell. Finally, our results for XAS indicate that although less sensitive, the spectra from carbon can be used in mode detection. PMID- 25820574 TI - Effectiveness and safety of calcineurin inhibitor withdrawal in kidney transplantation: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The purpose was to compare the effectiveness and safety of calcineurin inhibitors (CNIs) withdrawal and continued therapies in kidney transplant recipients. METHODS: We searched the PubMed, MEDLINE, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar up to May 2014. Risk ratio (RR) or weighted mean difference (WMD) and their 95 % confidence intervals (CIs) were calculated in fixed-effects model or random-effects model when appropriate. Besides, sensitivity analysis was performed based on the addition of sirolimus in initial immunosuppression protocols. RESULTS: Total seven studies with 1071 kidney transplant recipients received CNIs withdrawal therapy (experimental group) and 792 kidney transplant recipients received CNIs continued therapy (control group) were included in the meta-analysis. The overall estimates of acute rejection rate (RR = 1.64, 95 % CI: 1.19-2.27, P = 0.003), mean measured glomerular filtration rate (WMD = 9.50, 95 % CI = 2.96-16.03, P = 0.004), thrombocytopenia (RR = 3.39, 95 % CI: 2.27-5.05, P < 0.00001) and hypertension (RR = 0.56, 95 % CI: 0.40-0.78, P = 0.0006) showed that there were significant differences between the CNIs withdrawal and continued therapies in kidney transplant recipients, while no significant differences were found between groups in survival rate, graft survival rate, diabetes, hypercholesterolemia, hypertriglyceridemia and malignancies. In addition, two studies, in which sirolimus was not used in initial immunosuppression protocol, were excluded in sensitivity analysis and the results were still consistent with the overall analysis. CONCLUSIONS: CNIs withdrawal therapy in kidney transplant recipients could significantly decrease risk of hypertension and improve glomerular filtration rate, accompanying with increased risk of acute rejection and thrombocytopenia, compared with the CNIs continued therapy. PMID- 25820575 TI - CO oxidation catalysed by Pd-based bimetallic nanoalloys. AB - Density functional theory based global geometry optimization has been used to demonstrate the crucial influence of the geometry of the catalytic cluster on the energy barriers for the CO oxidation reaction over Pd-based bimetallic nanoalloys. We show that dramatic geometry change between the reaction intermediates can lead to very high energy barriers and thus be prohibitive for the whole process. This introduces challenges for both the design of new catalysts, and theoretical methods employed. On the theory side, a careful choice of geometric configurations of all reaction intermediates is crucial for an adequate description of a possible reaction path. From the point of view of the catalyst design, the cluster geometry can be controlled by adjusting the level of interaction between the cluster and the dopant metal, as well as between the adsorbate molecules and the catalyst cluster by mixing different metals in a single nanoalloy particle. We show that substitution of a Pd atom in the Pd5 cluster with a single Ag atom to form Pd4Ag1 leads to a potential improvement of the catalytic properties of the cluster for the CO oxidation reaction. On the other hand, a single Au atom does not enhance the properties of the catalyst, which is attributed to a weaker hybridization between the cluster's constituent metals and the adsorbate molecules. Such flexibility of properties of bimetallic nanoalloy clusters illustrates the possibility of fine-tuning, which might be used for design of novel efficient catalytic materials. PMID- 25820577 TI - Precision of 5 different keratometry devices. AB - To compare the precision among currently available keratometry devices. The corneal power was measured on two separate visits with the Nidek TonoRef II Autorefractor/Keratometer, the Zeiss IOLMaster 500, the Haag-Streit Lenstar LS 900, the Oculus Pentacam, and the Oculus Keratograph 4M. The precision was evaluated as the mean absolute intersession difference (MAD) between the corneal power measurements for each patient. Only the non-operated eye was included in the study. The Keratograph was found to have the highest MAD (0.215 D), which was significantly different from the other devices except for the IOLMaster. Nidek ARK had the lowest MAD (0.097 D), but this was not significant compared to Pentacam (0.124 D), Lenstar (0.132 D), or IOLMaster (0.140 D). Only one out of 29 patients had a precision difference exceeding 0.25 D with the Nidek ARK. Among the devices studied, the Nidek ARK was found to have the highest and the Keratograph was found to have to the lowest precision for the measurement of corneal power. PMID- 25820576 TI - Clinical, anatomical, and electrophysiological assessments of the central retina following intravitreal bevacizumab for macular edema secondary to retinal vein occlusion. AB - The purpose of this study is to evaluate the long-term visual, anatomical and electrophysiological outcomes of repeated intravitreal injections of bevacizumab for macular edema due to retinal vein occlusion (RVO) and investigate any possible toxic effects on the central fovea. This is a prospective, noncomparative, interventional case series. Thirty-three eyes of 33 patients with macular edema secondary to RVO were treated with 1.25 mg/0.05 ml intravitreal bevacizumab. Nine patients had nonischemic central retinal vein occlusion (CRVO) and 24 patients had branch retinal vein occlusion (BRVO). The main outcome measures were best-corrected visual acuity, central retinal thickness (CRT), and multifocal electroretinography (mfERG) responses changes at baseline, 1 month after the third injection and at the end of the 2-year long follow-up period. Patients with CRVO had mean best-corrected Snellen visual acuity of 0.10 at baseline, which improved significantly to 0.31 after 2 years (P = 0. 028).The mean CRT at presentation was 756.28 MUm and reduced significantly to 439.14 MUm after 2 years (P = 0.05). Patients with BRVO had mean best-corrected Snellen visual acuity of 0.19 at baseline, which improved significantly to 0.40 after 2 years (P < 0.001). The mean CRT at presentation was 681.04 MUm and reduced significantly to 369.81 MUm after 2 years (P < 0.001). Mean mfERG responses within central 10 degrees (ring1, ring2) showed statistically significant differences on P1 parameters in terms of response density and implicit time after 2 years in both CRVO and BRVO patients. Repeated intravitreal bevacizumab injections for macular edema due to either CRVO or BRVO resulted in long-term improvement of visual acuity, a reduction in CRT and statistically significant changes in the mfERG responses with nondemonstrable toxic effects on the central fovea. PMID- 25820578 TI - Systematic Evaluation of the Upper Airway in a Sample Population: Factors Associated with Obstructive Sleep Apnea Syndrome. AB - OBJECTIVES: To investigate the anatomy of the upper airway (UA) of a representative sample of the adult population of Sao Paulo city, Brazil, and to identify factors associated with the presence of obstructive sleep apnea syndrome (OSAS), as confirmed using full-night polysomnography (PSG). STUDY DESIGN: Cross sectional study. SETTING: Population-based sample. METHODS: A 3-stage sampling procedure was used to proportionally recruit adult residents of Sao Paulo city according to gender, age, and socioeconomic status. A complete evaluation was performed, including a systematic evaluation of the UA prior to conducting PSG. RESULTS: Nine-hundred ninety-three (90.2%) of the participants were seen by an ear, nose, and throat (ENT) specialist. Individuals who were diagnosed with OSAS (32.9%) presented a higher frequency of nasal symptoms and structural abnormalities (both nasal and oropharyngeal) compared with those without OSAS. No anatomical differences were observed in the facial skeleton. An abnormal nasal structure visible via anterior rhinoscopy was the only UA factor predicting OSAS after adjustments for the other common OSAS risk factors (male sex, aging, obesity, and increased neck circumference). CONCLUSION: This is the first study in which a systematic evaluation of the UA was followed by a sleep study in a population-based sample. In a sample of the general population that had not previously been screened for OSAS, having an abnormal nasal structure was found to be a risk factor for OSAS, in conjunction with other well-established clinical and demographic factors, such as male gender, increased age, increased neck circumference, and body mass index. PMID- 25820579 TI - Public awareness of human papillomavirus as a causative factor for oropharyngeal cancer. AB - OBJECTIVE: To assess the public's awareness of human papillomavirus (HPV) as a causative factor for oropharyngeal cancer. STUDY DESIGN: Twenty-three-item survey. SETTING: Local shopping malls and Maxwell Air Force Base in 2012. METHODS: Respondents were randomly chosen to participate in 23-item survey at various local shopping malls and at Maxwell Air Force Base in 2012. The chi(2) test was used in statistical analysis. RESULTS: The majority of respondents (n = 319) were civilians; 158 were military officer trainees (MOTs). All MOTs had a bachelor's degree or higher, while 37% of civilian respondents had a bachelor's degree or higher. Most MOTs (82%) were aware of oropharyngeal cancer, and 53% of civilians had not heard of oropharyngeal cancer (P < .0001). Most respondents (73% civilian and 91% military) were aware of the association between HPV and cervical cancer. Conversely, 75% of civilian population and 49% of MOTs were not aware of the association between HPV and oropharyngeal cancer (P < .0001). The majority of respondents (61% military and 81% civilian) did not know that both sexes were eligible for HPV vaccine (P < .0001). CONCLUSIONS: Most respondents were aware that HPV is a causative agent of cervical cancer. However, the majority were not aware of the association between oropharyngeal cancer and HPV. Furthermore, many respondents were not aware that HPV equally affects males and females and that the vaccine is available for both sexes. This underscores the need to educate the public on the availability of HPV vaccine and the association between HPV and oropharyngeal cancer. PMID- 25820580 TI - Myringotomy and ventilation tube insertion with endoscopic or microscopic technique in adults: a pilot study. AB - The purpose of this study is to assess the feasibility of endoscopic-assisted myringotomy and ventilation tube insertion in adults affected by chronic otitis media with effusion, comparing the outcomes of this approach with those obtained with the traditional microscopic technique. Twenty-four patients were enrolled in this trial and alternately assigned to 2 groups of 12 subjects each. In group A, patients underwent myringotomy and ventilation tube insertion under endoscopic view, whereas in group B, the same procedure was performed traditionally using a microscope. All cases were evaluated 1 week after surgery and then monthly until tube extrusion. Type A tympanogram was achieved in 10 of 13 ears in both groups (76.92%). No significant difference in operative times or complication rates was observed (P > .05). Endoscopic technique could be a viable alternative to the microscopic approach for myringotomy and ventilation tube positioning in adults affected by chronic otitis media with effusion. PMID- 25820581 TI - Office-Based Photoangiolytic Laser Treatment of Reinke's Edema: Safety and Voice Outcomes. AB - OBJECTIVE: To evaluate the safety, tolerability, and voice outcomes of office based photoangiolytic laser treatment of Reinke's edema. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: We performed a retrospective analysis of patients undergoing office-based laser treatment of endoscopy-proven Reinke's edema. Safety and tolerability were evaluated by reviewing complications. Voice outcomes were analyzed by comparing pre- and postprocedural acoustic, aerodynamic, and Voice Handicap Index measurements. Complete data sets were not available for all subjects; sample size for each parameter is reported with the corresponding result. RESULTS: Nineteen patients met inclusion criteria. There were no minor or major complications. Five procedures were truncated due to patient intolerance. Phonatory frequency range increased (n = 12, P = .003), while percent jitter decreased (n = 12, P = .004). Phonation threshold pressure decreased after treatment (n = 4, P = .049). Voice Handicap Index also decreased (n = 14, P < .001). CONCLUSION: This study represents the largest series of patients undergoing office-based photoangiolytic laser treatment specifically for Reinke's edema. Our data suggest that this is a safe and effective modality to treat dysphonia associated with Reinke's edema, although patient intolerance of the procedure may represent a barrier. PMID- 25820582 TI - Objective vestibular testing of children with dizziness and balance complaints following sports-related concussions. AB - OBJECTIVE: To conduct objective assessment of children with balance and vestibular complaints following sports-related concussions and identify the underlying deficits by analyzing laboratory test outcomes. STUDY DESIGNS: Case series with chart review. SETTING: Pediatric tertiary care facility. SUBJECTS AND METHODS: Medical records were reviewed of 42 pediatric patients with balance and/or vestibular complaints following sports-related concussions who underwent comprehensive laboratory testing on their balance and vestibular function. Patients' characteristics were summarized and results analyzed. RESULTS: More than 90% of the children with protracted dizziness or imbalance following sports related concussion had at least 1 abnormal finding from the comprehensive balance and vestibular evaluation. The most frequent deficit was found in dynamic visual acuity test, followed by Sensory Organization Test and rotational test. Patient's balance problem associated with concussion seemed to be primarily instigated by vestibular dysfunction. Furthermore, semicircular canal dysfunction was involved more often than dysfunction of otolith organs. Yet, <10% of the children experienced a hearing loss following sports-related concussion. CONCLUSIONS: Vestibular impairment is common among children with protracted dizziness or imbalance following sports-related concussion. Our study demonstrated that proper and thorough evaluation is imperative to identify these underlying deficits and laboratory tests were helpful in the diagnosis and recommendation of following rehabilitations. PMID- 25820583 TI - Seeding of recipient-originated epithelial cells attenuates epithelial to mesenchymal transition in rat tracheal allotransplantation. AB - OBJECTIVE: The specific role and mechanism of epithelium in the progression of obliterative airway disease (OAD) after tracheal allotransplantation remain poorly understood. In this study, we used rat heterotopic tracheal transplantation to investigate the mechanism of epithelial cell seeding during the process of OAD. STUDY DESIGN: Prospective, basic science. SETTING: Research laboratory. SUBJECTS AND METHODS: In total, 120 Sprague Dawley (SD) rats and 90 Wistar rats were used. Tracheas from SD rats were implanted into SD rats (syngeneic, n = 30) or Wistar rats (allogeneic, n = 30), and SD rat tracheas (seeded with Wistar rat-derived epithelial cells 6 days after transplantation) were transplanted into Wistar rats (seeded allogeneic, n = 30). Grafts were harvested at 7, 14, or 30 days after transplantation for histologic, quantitative reverse transcriptional polymerase chain reaction or Western blot analyses. RESULTS: Syngrafts retained normal histologic structures, while the corresponding allografts demonstrated less ciliated epithelia and more lumenal occlusion. Seeding of epithelial cells ameliorated the histologic changes, reduced the expression of epithelial to mesenchymal transition (EMT)-related transcriptional factors and mesenchymal markers, and dampened the expression of transforming growth factor beta1 (TGF-beta1) and phosphorylation of smad3. CONCLUSION: Seeding of recipient epithelial cells inhibits the progression of OAD by attenuating EMT via TGF-beta-Smad signaling in rat heterotopic tracheal allografts. Clinically, the injection of recipient-originated epithelial cells might provide new insights into the treatment for OAD after tracheal allotransplantation. PMID- 25820584 TI - The effect of tonsillectomy alone in adult obstructive sleep apnea. AB - OBJECTIVE: The purpose of this study was to determine the effect of tonsillectomy as a single procedure in the treatment of adult obstructive sleep apnea (OSA). STUDY DESIGN: Prospective multi-institutional study evaluating adults with tonsillar hypertrophy scheduled to undergo tonsillectomy as an isolated surgery. SETTING: Tertiary care medical centers within the US Department of Defense. SUBJECTS AND METHODS: Adult subjects with tonsillar hypertrophy who were already scheduled for tonsillectomy were enrolled from October 2010 to July 2013. Subjects underwent physical examination, Epworth Sleepiness Scale, Berlin Questionnaire, and polysomnogram before surgery and after. Collected data included demographics, questionnaire scores, apnea-hypopnea index (AHI), and lowest saturation of oxygen. RESULTS: A total of 202 consecutive subjects undergoing tonsillectomy were enrolled. The final analysis included 19 subjects testing positive for OSA. The mean age was 27.9 years; mean body mass index, 29.6; median tonsil size, 3; and most frequent Friedman stage, 1. The AHI before surgery ranged from 5.4 to 56.4 events per hour. The mean AHI decreased from 18.0 to 3.2 events per hour after surgery, a reduction of 82%. The responder rate- with subjects achieving at least a 50% reduction of AHI to a value <15--was 94.7%. Following tonsillectomy, there were statistically significant reductions in median lowest saturation of oxygen level and Epworth Sleepiness Scale and Berlin scores. CONCLUSIONS: Adult tonsillectomy alone has beneficial effect in OSA management, particularly in young overweight men with large tonsils, moderate OSA, and low Friedman stage. PMID- 25820585 TI - Unexpected Detection of Parotid Gland Malignancy during Primary Extracapsular Dissection. AB - OBJECTIVE: To evaluate the oncologic and functional outcome in cases in which a false preoperative working hypothesis "benign parotid tumor" led to a primary extracapsular dissection being performed rather than a traditional, more radical surgical modality. STUDY DESIGN: Case series with chart review. SETTING: Academic tertiary referral center. SUBJECTS AND METHODS: The records of all patients treated for malignant tumors of the parotid gland between 2006 and 2012 were retrospectively studied. Patients were excluded from our study sample for insufficient data or if their histories indicated manifestation of malignant tumors without primary parotid origin (squamous cell carcinomas, lymphomas, melanomas), revision surgery, as well as concomitant or past malignant tumors. Consequently, a total of 29 patients with 30 primary malignant tumors of the parotid gland formed our study sample (14 men, 15 women; male:female ratio, 0.93:1; mean age, 55.4 years; range, 14-85 years). RESULTS: Of 30 cases, 22 had low-grade tumors. Further tumor cells were detected in only the histology specimens of the parotid in 3 of the 25 cases treated subsequently with completion parotidectomy. Five patients received adjuvant radiation. Five-year disease-specific survival was 100%; local disease control was 96.6%. Of 30 cases, 28 had House-Brackmann I after tumor treatment; the other 2 cases had a slight paralysis (House-Brackmann II). CONCLUSION: Beginning with the "false" working hypothesis and performing an extracapsular dissection in unsuspected cases seems to have no adverse impact on patients' survival and postoperative quality of life in cases in which definitive histology reveals malignancy. PMID- 25820586 TI - Corticosteroid use does not alter nasal mucus glucose in chronic rhinosinusitis. AB - OBJECTIVES: To evaluate nasal mucus glucose concentrations in patients with and without chronic rhinosinusitis and determine if corticosteroid therapy alters mucus glucose. STUDY DESIGN: Prospective observational study. SETTING: Single tertiary care center. SUBJECTS: Ninety-five patients presenting to an otolaryngology clinic. METHODS: Participants completed questionnaires that included a history of medical and surgical therapies as well as sinusitis specific quality-of-life measurements. Nasal mucus was collected in an outpatient clinic using an open cell foam technique. The nasal mucus glucose concentrations of patients with and without chronic rhinosinusitis were compared to the use of systemic and topical glucocorticoid treatment. RESULTS: A statistically significant difference was measured between mean nasal glucose secretions of control patients, 10.2 mg/dL, compared with patients diagnosed with chronic rhinosinusitis, 18.4 mg/dL (P < .0001). Use of corticosteroids, both topical and systemic, did not correlate with nasal glucose concentrations. CONCLUSION: Patients diagnosed with chronic rhinosinusitis have elevated nasal glucose concentrations compared with control patients, and this elevated nasal glucose level was independent of corticosteroid use. Nasal glucose may independently contribute to the pathophysiology of chronic rhinosinusitis. PMID- 25820587 TI - Eosinophilic Laryngitis in Children with Aerodigestive Dysfunction. AB - OBJECTIVE: To describe the presence of laryngeal eosinophils and associated symptomatology in patients with aerodigestive dysfunction. STUDY DESIGN: Case series with chart review. SETTING: Single tertiary pediatric referral center. SUBJECTS: Eighty-one consecutive pediatric patients referred to a multidisciplinary aerodigestive clinic with upper airway concerns. METHODS: Microlaryngoscopy and posterior arytenoid biopsy, flexible bronchoscopy, esophagogastroduodenoscopy and esophageal biopsy, and impedance probe testing were performed as indicated by clinical symptoms. Positive versus negative posterior arytenoid biopsy for eosinophils and the presence or absence of concomitant histopathological laryngitis and/or esophagitis were measured. RESULTS: Nine of 81 (11%) patients had positive laryngeal biopsy for eosinophils (range, 1-29 eosinophils/high-powered field [HPF]). Three of these 9 patients also had concurrent biopsy-proven eosinophilic esophagitis, while 8 of 81 total patients had biopsy-proven eosinophilic esophagitis. The frequency of biopsy proven eosinophilic esophagitis was higher in patients with posterior arytenoid eosinophils versus patients without laryngeal eosinophils (33% versus 6.9%, P = .0408). CONCLUSIONS: Eosinophilic inflammation in the larynx has not been described in children with complex aerodigestive complaints. Posterior arytenoid eosinophils may serve as a marker of chronic laryngeal inflammation in children with aerodigestive dysfunction, although their exact role in this inflammation remains unclear. In our population, >15 eosinophils/HPF within posterior arytenoid biopsies was associated with concomitant eosinophilic esophagitis. PMID- 25820588 TI - Pediatric head and neck malignancies: incidence and trends, 1973-2010. AB - OBJECTIVE: Determine the current epidemiology of head and neck (H&N) cancer in the US pediatric population. STUDY DESIGN: Analysis of national tumor registries comparing childhood H&N cancer trends to overall childhood cancer trends. SUBJECTS AND METHODS: The SEER (Surveillance, Epidemiology, and End Results) database was accessed to gather epidemiologic data regarding pediatric H&N cancer between 1973 and 2010. Specific trends related to demographic background, histologic diagnosis, tumor location, and incidence, as well as general trends of all pediatric cancers, were extracted. RESULTS: The total burden and incidence rates of pediatric cancer as well as H&N cancer continue to rise. Cancer was diagnosed in children <15 years old at a rate of 12.5 cases (95% confidence interval [CI], 11.9-13.1) per 100,000 from 1973 to 1975 and 17.3 (95% CI, 16.7 17.9) from 2007 to 2009, an increase of 38%. H&N cancers in the same age group increased from 1.1 (95% CI, 0.9-1.2) in 1973-1975 to 1.6 (95% CI, 1.4-1.8) in 2007-2009, an increase of 45%. Despite this apparent increased incidence, the proportion of H&N cancers to all cancers in the pediatric population has remained stable. CONCLUSION: As with all pediatric cancer, the public health burden of pediatric H&N cancer continues to rise. The proportion of H&N malignancy to all pediatric cancer is stable. With the incidence increasing, however, work to identify treatment strategies remains crucial. PMID- 25820589 TI - Airway Management in Severe Combat Maxillofacial Trauma. AB - OBJECTIVES: Airway stabilization is critical in combat maxillofacial injury as normal anatomical landmarks can be obscured. The study objective was to characterize the epidemiology of airway management in maxillofacial trauma. STUDY DESIGN: Retrospective database analysis. SETTING: Military treatment facilities in Iraq and Afghanistan and stateside tertiary care centers. SUBJECTS: In total, 1345 military personnel with combat-related maxillofacial injuries sustained March 2004 to August 2010 were identified from the Expeditionary Medical Encounter Database using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. METHODS: Descriptive statistics, including basic demographics, injury severity, associated injuries, and airway interventions, were collected. A logistic regression was performed to determine factors associated with the need for tracheostomy. RESULTS: A total of 239 severe maxillofacial injuries were identified. The most common mechanism of injury was improvised explosive devices (66%), followed by gunshot wounds (8%), mortars (5%), and landmines (4%). Of the subjects, 51.4% required intubation on their initial presentation. Of tracheostomies, 30.4% were performed on initial presentation. Of those who underwent bronchoscopy, 65.2% had airway inhalation injury. There was a significant relationship between the presence of head and neck burn and association with airway inhalation injury (P < .0001). There was also a significant relationship between the severity of facial injury and the need for intubation (P = .002), as well as the presence of maxillofacial fracture and the need for tracheostomy (P = .0001). CONCLUSIONS: There is a high incidence of airway injury in combat maxillofacial trauma, which may be underestimated. Airway management in this population requires a high degree of suspicion and low threshold for airway stabilization. PMID- 25820590 TI - Free flaps in head and neck reconstruction after oncologic surgery: expected outcomes in the elderly. AB - OBJECTIVE: To provide surgeons and clinicians with a critical review of microvascular reconstructive options and their expected outcomes after head and neck cancer resection in the elderly. DATA SOURCES: Medline, Isiweb, and Cochrane databases. REVIEW METHODS: A literature search was performed in May 2014 and included studies published between 2000 and 2014. Keywords were used for articles identification, and inclusion criteria were defined for consideration in the present review. CONCLUSIONS: Evaluation of the pertinent literature is hampered by a number of biases, such as a lack of general consensus of a definition of "elderly," differences among scales used to quantify comorbidities, and subjective evaluation of flap-related and systemic complications. However, our findings showed no differences in terms of free flap success, surgical complications, or mortality rate between older and younger patients. Moreover, recipient site complications do not seem to be affected by age. IMPLICATION FOR PRACTICE: Microvascular reconstruction in the elderly can be performed with high success rates, even though medical complications can occur more frequently compared to younger patients. Minor and major surgical complications in the elderly appear to be comparable to those in the younger population and do not affect final outcome or the perioperative mortality rate. Flap outcome does not seem to be significantly affected by age. Careful preoperative assessment and postoperative monitoring are mandatory to prevent adverse events, and prompt management is warranted whenever present. PMID- 25820591 TI - The Role of Obstruction Length and Height in Predicting Outcome of Velopharyngeal Surgery. AB - OBJECTIVE: To measure obstruction length and height using drug-induced sleep endoscopy (DISE) in obstructive sleep apnea (OSA) patients and to evaluate their association with outcomes of velopharyngeal surgery. STUDY DESIGN: Prospective cohort study. SETTING: University medical center. METHODS: Forty-three consecutive patients with OSA were evaluated by DISE using dexmedetomidine. The 2 new parameters, obstruction length (defined as the distance from the most superior point of the collapse to the most inferior point of the collapse) and obstruction height (the distance from the posterior border of the nasal septum to the most proximal point of the collapse), were measured by both DISE and a pressure transducer catheter method before surgery. All of the patients received velopharyngeal surgery, including revised uvulopalatopharyngoplasty with uvula preservation and transpalatal advancement pharyngoplasty. We followed up with all of the patients using polysomnography at least 3 months after surgery. RESULTS: Twenty-six (60.5%) patients were responders, and 17 (39.5%) were nonresponders. The mean obstruction length and obstruction height were 1.3 +/- 0.5 cm (range, 0.4-2.2 cm) and 3.4 +/- 0.9 cm (range, 1.1-5.0 cm), respectively. Nonresponders had a longer obstruction length and a shorter obstruction value. Multivariate logistic regression analysis revealed that obstruction length >1.4 cm (odds ratio [OR], 0.21; 95% confidence interval [CI], 0.04-0.98; P = .048) and obstruction height >=3.2 cm (OR, 9.35; 95% CI, 1.79-48.80; P = .008) were the only independent predictors of velopharyngeal surgery success. CONCLUSIONS: Accurate measurement of obstruction length and height can be performed with both DISE and a pressure transducer catheter method. The 2 parameters can predict the outcome of velopharyngeal surgery. PMID- 25820593 TI - Enantioselective Allylation of (2E,4E)-2,4-Dimethylhexadienal: Synthesis of (5R,6S)-(+)-Pteroenone. AB - Allylation, trans- and cis-crotylation of (2E,4E)-2,4-dimethylhexadienal, a representative alpha,beta,gamma,delta-unsaturated aldehyde, was carried out under different catalytic and stoichiometric conditions. The reactions catalyzed by organocatalysts TRIP-PA and N,N'-dioxides gave the best results with respect to yields, asymmetric induction, and catalyst load in comparison to other procedures. The developed methodology was applied in the enantioselective synthesis of (5R,6S)-(+)-pteroenone, a defensive metabolite (ichthyodeterrent) of the Antarctic pteropod Clione antarctica. PMID- 25820592 TI - Retrospective analysis of metastatic behaviour of breast cancer subtypes. AB - Among breast cancer patients who develop distant metastases, there is marked variability in the clinical course, including metastasis pattern. Here, we present a retrospective study of breast cancer patients who all developed distant metastases focusing on the association between breast cancer subtype and clinical course, including organ-specific metastasis. Tissue microarrays (TMAs) were assembled and stained for ER, PR, HER2, EGFR, CK5/6, CK14, E-Cadherin, TP53 and Ki67 for 263 breast cancer patients with metastatic disease. Tumours were classified into ER+/HER2-/Ki67high, ER+/HER2-/Ki67low, ER+/HER2+, ER-/HER2+ and ER-/HER2- groups. Relevant data related to metastasis pattern, metastasis timeline, systemic treatment and survival were retrieved. Associations between site-specific relapse and patient/tumour characteristics were assessed with multivariate models using logistic regression. Median time for development of distant metastasis was 30 months (range 0-15.3 years); 75.8 % of the distance metastases developed in the first 5 years after treatment of the primary tumour. Patients with ER-/HER2- tumours had a median overall survival of 27 months; those with HER2+ tumours of 52 months; those with ER+/HER2-/Ki67high of 76 months and those with ER+/HER2-/Ki67low of 79 months. Bone was the most common site for distant metastasis (70.6 %) followed by liver (54.5 %) and lung (31.4 %), respectively. Visceral metastasis was found in 76.8 % of the patients. Patients with ER-/HER2- tumours developed visceral metastases in 81 % and bone metastases in 55.2 %; those with HER2+ tumours developed visceral metastases in 77.4 % and bone metastases in 69.8 %; those with ER+/HER2-/Ki67high developed visceral metastases in 75.7 % and bone metastases in 87.8 % and those with ER+/HER2 /Ki67low developed visceral metastases in 76.9 % and bone metastases in 73.1 %. In metastatic breast cancer patients, tumour subtypes are associated with survival and pattern of distant metastases. These associations are of help in choices for surveillance and therapy in individual patients. PMID- 25820594 TI - Synthesis and conformation of 3,6-connected cyclohexadiene chains. AB - 3,6-Connected cyclohexadienes as precursors for polyphenylenes are synthesized and characterized by mass spectrometry and NMR spectroscopy. Pure fractions of trimers, hexamers, and nonamers are collected after separation of the product mixture by recycling GPC. The anticipated formation of rigid linear structures, due to the trans-configuration of the monomeric units, is supported by density functional theory and experimentally confirmed by dynamic light scattering from dilute solution at low scattering angles. The obtained translational diffusion coefficients are represented by rigid rod-like or prolate ellipsoid-like molecular shapes. The measurements of diffusion coefficients reveal a length dependent ratio of 1:2:3 between the three oligomers, which directly correlates to the expected length extension from trimer to nonamer. PMID- 25820595 TI - The Impact of the Birth of a Child with Intellectual Disabilities on Pre-Existing Parental Christian Faith from the Perspective of Parents Who Have Parented Their Child to Adulthood. AB - BACKGROUND: Faith in the lives of UK families with an adult with intellectual disabilities is an under-researched area with little existing literature. Research in the United States with Christian parents suggests that they draw on their faith for coping (Rogers-Dulan 1998) and for understanding (Skinner et al. 1999). METHODS: In this study, grounded theory methodology has been used to examine the impact on pre-existing parental faith of the birth of a child with intellectual disabilities from the perspective of parents who have parented their children to adulthood. Seventeen parents or couples took part in semistructured qualitative interviews about their faith. RESULTS: The majority of parents after their child were diagnosed with intellectual disabilities went through a period of flux when they questioned the role of God in the disability. CONCLUSIONS: The positive or negative connotations of the attempts at meaning-making did not impact on the eventual outcome for the parents. They eventually put such existential questions aside, accepted their child, and continued in their faith. The implications of the research for health professionals, church organizations and researchers are considered. PMID- 25820596 TI - Recent advances in near-infrared fluorescence-guided imaging surgery using indocyanine green. AB - Near-infrared (NIR) fluorescence imaging has better tissue penetration, allowing for the effective rejection of excitation light and detection deep inside organs. Indocyanine green (ICG) generates NIR fluorescence after illumination by an NIR ray, enabling real-time intraoperative visualization of superficial lymphatic channels and vessels transcutaneously. The HyperEye Medical System (HEMS) can simultaneously detect NIR rays under room light to provide color imaging, which enables visualization under bright light. Thus, NIR fluorescence imaging using ICG can provide for excellent diagnostic accuracy in detecting sentinel lymph nodes in cancer and microvascular circulation in various ischemic diseases, to assist us with intraoperative decision making. Including HEMS in this system could further improve the sentinel lymph node mapping and intraoperative identification of blood supply in reconstructive organs and ischemic diseases, making it more attractive than conventional imaging. Moreover, the development of new laparoscopic imaging systems equipped with NIR will allow fluorescence-guided surgery in a minimally invasive setting. Future directions, including the conjugation of NIR fluorophores to target specific cancer markers might be realistic technology with diagnostic and therapeutic benefits. PMID- 25820597 TI - Highlights of the Twelfth Japan-Korea Joint Symposium on Cancer and Ageing Research. AB - INTRODUCTION: This paper reports the highlights of the presentation at the Twelfth Japan-Korea Joint Symposium on Cancer and Ageing Research was held at the auditorium of Saitama Cancer Center in Saitama, Japan, in June 19-21, 2014. RESULTS: Thirty-two oral presentations were delivered on various themes, such as therapeutic agents, cancer stem cells, EMT signaling, molecular epidemiology, cellular senescence, and clinical research, to more than 80 participants. The significance of translational research was emphasized in clinical sessions by physicians. A special session, "Thinking about Scientific Philosophy," featured presentations by distinguished scientists from Japan and Korea. CONCLUSION: We really feel that this meeting of minds has a unique and creative purpose, and a role of a prototype for Joint Symposia in Asian countries. The next Symposium is anticipated in 2016 in Jeju, Korea. PMID- 25820598 TI - The prognostic impact of EGFR, ErbB2 and MET gene amplification in human gastric carcinomas as measured by quantitative Real-Time PCR. AB - PURPOSE: Identification of critical genes which play pivotal roles in controlling tumor growth and survival will establish the basis for developing therapeutic targets. In this study, we focused on frequencies of EGFR, ErbB2 and MET gene amplification in gastric cancer patients to develop personalized medicine to improve the treatment. METHOD: EGFR, ErbB2 and MET gene amplification, and mRNA expression were analyzed by the quantitative Real-Time PCR in paraffin-embedded samples from 115 patients with gastric cancer. RESULTS: EGFR, ErbB2 and MET genes were amplified in 11.3 % (13/115), 6.1 % (7/115) and 19.1 % (22/115) of cancerous specimens, respectively. The correlation coefficient test clearly indicated that gene amplification in these three genes was positively correlated with mRNA transcription (EGFR: R = 0.631, p = 0.009; ErbB2: R = 0.652, p = 0.023; MET: R = 0.715, p < 0.001). EGFR and MET gene amplification was significantly associated with Ki-67 MI (p = 0.022 and p = 0.015). MET amplification was also significantly associated with age of >=60 years (p = 0.021) and tumor size of >=5 cm (p = 0.032). MET amplification, but not EGFR and ErbB2, was a significant prognostic factor in poor survival among patients with gastric cancer. CONCLUSIONS: EGFR, ErbB2 and MET genes are frequently amplified in gastric carcinoma. EGFR, ErbB2 and MET gene amplification is positively correlated with mRNA transcription. MET gene amplification correlates with a poor prognosis and poor survival in gastric carcinomas. PMID- 25820599 TI - Divergent ontogenies of trophic morphology in two closely related haplochromine cichlids. AB - Fish develop morphological specializations in their trophic and locomotor systems as a result of varying functional demands in response to environmental pressures at different life stages. These specializations should maximize particular performances in specialists, adapting them to their trophic and habitat niches at each ontogenetic stage. Because differential growth rates of the structural components comprised in the head are likely to be linked to the diet of a fish throughout its development, we investigated the ontogenetic development of two haplochromine cichlid species belonging to different trophic guilds. We employed geometric morphometric techniques to evaluate whether starting from morphologically similar fry they diverge into phenotypes that characterize trophic guilds and locomotor types. Our examination of overall body shape shows that certain specialized morphological features are already present in fry, whereas other traits diverge through ontogeny due to differences in species specific allometric variation. Allometric shape variation was found to be more relevant for the biter specialist than for the sucker morphotype. Our results confirm that phenotypic changes during ontogeny can be linked to dietary and habitat shifts in these fish. Furthermore, evidence for an integrated development of trophic and locomotor specializations in morphology was observed. PMID- 25820600 TI - Cellulase recycling in biorefineries--is it possible? AB - On a near future, bio-based economy will assume a key role in our lives. Lignocellulosic materials (e.g., agroforestry residues, industrial/solid wastes) represent a cheaper and environmentally friendly option to fossil fuels. Indeed, following suitable processing, they can be metabolized by different microorganisms to produce a wide range of compounds currently obtained by chemical synthesis. However, due to the recalcitrant nature of these materials, they cannot be directly used by microorganisms, the conversion of polysaccharides into simpler sugars being thus required. This conversion, which is usually undertaken enzymatically, represents a significant part on the final cost of the process. This fact has driven intense efforts on the reduction of the enzyme cost following different strategies. Here, we describe the fundamentals of the enzyme recycling technology, more specifically, cellulase recycling. We focus on the main strategies available for the recovery of both the liquid- and solid-bound enzyme fractions and discuss the relevant operational parameters (e.g., composition, temperature, additives, and pH). Although the efforts from the industry and enzyme suppliers are primarily oriented toward the development of enzyme cocktails able to quickly and effectively process biomass, it seems clear by now that enzyme recycling is technically possible. PMID- 25820601 TI - Antimicrobial photodynamic therapy with fulleropyrrolidine: photoinactivation mechanism of Staphylococcus aureus, in vitro and in vivo studies. AB - A family of N-methylpyrrolidinium fullerene iodide salts has been intensively studied to determine their applicability in antimicrobial photodynamic therapy (APDT). This study examined in vitro the efficacy of a C60 fullerene functionalized with one methylpyrrolidinium group to kill upon irradiation with white light gram-negative and gram-positive bacteria, as well as fungal cells, and the corresponding mechanism of the fullerene bactericidal action. The in vitro studies revealed that the high antistaphylococcal efficacy of functionalized fullerene could be linked to their ability to photogenerate singlet oxygen and superoxide anion. Following Staphylococcus aureus photoinactivation, no modifications of its genomic DNA were detected. In contrast, photodamage of the cell envelope seemed to be a dominant mechanism of bactericidal action. In in vivo studies, a 2 log10 reduction in the average bioluminescent radiance between treated and non-treated mice was reached. One day post APDT treatment, moist and abundant growth of bacteria could be observed on wounds of non-fulleropyrrolidine and dark control mice. APDT-treated wounds stayed visibly clear up to the third day. Moreover, cytotoxicity test on human dermal keratinocytes revealed great safety of using the sensitizer toward eukaryotic cells. These data indicate potential application of functionalized fullerene as antistaphylococcal sensitizer for superficial infections. PMID- 25820602 TI - Functional gene-based discovery of phenazines from the actinobacteria associated with marine sponges in the South China Sea. AB - Phenazines represent a large group of nitrogen-containing heterocyclic compounds produced by the diverse group of bacteria including actinobacteria. In this study, a total of 197 actinobacterial strains were isolated from seven different marine sponge species in the South China Sea using five different culture media. Eighty-seven morphologically different actinobacterial strains were selected and grouped into 13 genera, including Actinoalloteichus, Kocuria, Micrococcus, Micromonospora, Mycobacterium, Nocardiopsis, Prauserella, Rhodococcus, Saccharopolyspora, Salinispora, Serinicoccus, and Streptomyces by the phylogenetic analysis of 16S rRNA gene. Based on the screening of phzE genes, ten strains, including five Streptomyces, two Nocardiopsis, one Salinispora, one Micrococcus, and one Serinicoccus were found to be potential for phenazine production. The level of phzE gene expression was highly expressed in Nocardiopsis sp. 13-33-15, 13-12-13, and Serinicoccus sp. 13-12-4 on the fifth day of fermentation. Finally, 1,6-dihydroxy phenazine (1) from Nocardiopsis sp. 13-33-15 and 13-12-13, and 1,6-dimethoxy phenazine (2) from Nocardiopsis sp. 13 33-15 were isolated and identified successfully based on ESI-MS and NMR analysis. The compounds 1 and 2 showed antibacterial activity against Bacillus mycoides SJ14, Staphylococcus aureus SJ51, Escherichia coli SJ42, and Micrococcus luteus SJ47. This study suggests that the integrated approach of gene screening and chemical analysis is an effective strategy to find the target compounds and lays the basis for the production of phenazine from the sponge-associated actinobacteria. PMID- 25820603 TI - Comparison of Cancer-specific and General Health Literacy Assessments in an Educated Population: Correlations and Modifying Factors. AB - An information onslaught accompanies cancer diagnoses, but patient comprehension (health literacy; HL) is frequently low, impacting both immediate care and longer term follow-up. Knowledge and adoption of preventive measures is especially important for cancer survivors due to their increased risk of secondary malignant neoplasms. We sought to evaluate the Test of Functional Health Literacy Adult (S TOFHLA) against the recently developed cancer-specific Cancer Message Literacy Test (CMLT-r) among an educated population of both cancer survivors and those cancer-free. Participants were recruited 2013 (May through December) from various units within a local hospital and from several local churches, and each completed the S-TOFHLA and CMLT-r and provided demographic information and cancer status. The 109 participants had a mean age of 58 years and were as follows: 65.1 % female; 92.7 % white, 50.4 % college graduates, and 41.3 % cancer survivors. S TOFHLA scores ranged from 12-36 (mean 34.1) and non-significantly varied by gender, education, cancer status, and age. CMLT-r scores ranged from 28.6-100 % (mean 86.4 %) and significantly varied by education (p = 0.013), but not by gender, cancer status, or age. Overall, CMLT-r and S-TOFHLA significantly correlated (p < 0.001). Assessment scores were skewed towards the maximum with non-significant differences by cancer status. As cancer survivorship improves and as the population becomes more educated, more refined approaches to assess health literacy should be considered. Increased education does not imply increased health literacy, and cancer survivorship does not imply higher health or cancer literacy. Concerted efforts to improve patient understanding and implementation of preventive measures are imperative. PMID- 25820604 TI - The Development of a Communication Tool to Facilitate the Cancer Trial Recruitment Process and Increase Research Literacy among Underrepresented Populations. AB - Despite increasing need to boost the recruitment of underrepresented populations into cancer trials and biobanking research, few tools exist for facilitating dialogue between researchers and potential research participants during the recruitment process. In this paper, we describe the initial processes of a user centered design cycle to develop a standardized research communication tool prototype for enhancing research literacy among individuals from underrepresented populations considering enrollment in cancer research and biobanking studies. We present qualitative feedback and recommendations on the prototype's design and content from potential end users: five clinical trial recruiters and ten potential research participants recruited from an academic medical center. Participants were given the prototype (a set of laminated cards) and were asked to provide feedback about the tool's content, design elements, and word choices during semi-structured, in-person interviews. Results suggest that the prototype was well received by recruiters and patients alike. They favored the simplicity, lay language, and layout of the cards. They also noted areas for improvement, leading to card refinements that included the following: addressing additional topic areas, clarifying research processes, increasing the number of diverse images, and using alternative word choices. Our process for refining user interfaces and iterating content in early phases of design may inform future efforts to develop tools for use in clinical research or biobanking studies to increase research literacy. PMID- 25820607 TI - Local and Global Dynamics: general discussion. PMID- 25820605 TI - Nutritional Online Information for Cancer Patients: a Randomized Trial of an Internet Communication Plus Social Media Intervention. AB - We hypothesized that cancer patients using an Internet website would show an improvement in the knowledge about healthy eating habits, and this might be enhanced by social media interaction. A 6-month randomized intervention was set up. Eligible subjects were allocated in intervention (IG) and control groups (CG). IG had access to the website, and CG was provided with printed versions. All enrolled participants filled in Nutrition Questionnaire (NQ), Quality of Life Questionnaire (QoL) and Psychological Distress Inventory (PDI), at baseline and after 6 months. The difference between post- vs pre-questionnaires was calculated. Seventy-four subjects (CG 39; IG 35) completed the study. There was an increase in the score after the intervention in both groups for the NQ, even if not statistically significant. Dividing the IG into three categories, no (NI), low (LI) and high interactions (HI), we found a decreased score (improvement) in the CG (-0.2) and in the HI (-1.7), and an increased score (worsening) in the NI (+3.3) (p = NS) analysing the PDI. We found an increased score in the QoL both in CG and IG (adjusted LSMeans +3.5 and +2.8 points, respectively; p = NS). This study represents an example for support cancer patients. Despite the lack of significant effects, critical points and problems encountered may be of interest to researchers and organization working in the cancer setting. Intervention strategies to support patients during the care process are needed in order to attain the full potential of patient-centred care on cancer outcomes. PMID- 25820608 TI - Image-defined risk factor assessment of neurogenic tumors after neoadjuvant chemotherapy is useful for predicting intra-operative risk factors and the completeness of resection. AB - BACKGROUND: Patients with neuroblastoma are now stratified at diagnosis according to the presence and number of image-defined risk factors (IDRFs). We examined the added value of IDRF assessment after neoadjuvant chemotherapy for predicting surgical resection. MATERIAL AND METHODS: From 2009-2012, 39 out of 91 patients operated on in our institution for neuroblastic tumors received neoadjuvant chemotherapy based on ongoing SIOPEN protocols or treatment guidelines. IDRFs were assessed both at diagnosis and preoperatively on CT and/or MRI. RESULTS: Median age at diagnosis was 30 months [range 2-191]. The tumor locations were adrenal (n = 20), paravertebral (n = 13) and perivascular (n = 6). INRGSS stages were L2 (n = 13), M (n = 25) and Ms (n = 1). Eleven tumors (28%) were MYCN amplified. Chemotherapy reduced the number of IDRFs in 54% of patients overall (21/39): 61.5% (16/26) of M and Ms patients, and 38.5% (5/13) of non metastatic patients (P < 0.001). The number of IDRFs lost after chemotherapy was proportional to the degree of tumor shrinkage (P = 0.002), independent of the primary tumor location (P = 0.73), although the number was higher in patients with left versus right adrenal locations (P = 0.004). Patients with neuroblastoma on post-surgical histology lost more IDRFs (median: 1[0-9]) than patients with ganglioneuroblastoma (median: 0[0-4]) (P < 0.001). The completeness of resection was related only to the number of preoperative IDRFs (P = 0.028). CONCLUSION: IDRF assessment after neoadjuvant chemotherapy is useful for predicting completeness of resection of neurogenic tumors. A larger international study is needed to confirm these results and to explore a possible correlation between preoperative IDRF status and survival. PMID- 25820609 TI - The long-sought seventeen-electron radical [(C6Me6)Cr(CO)3](+): isolation, crystal structure and substitution reaction. AB - A highly air-sensitive seventeen-electron half-sandwich radical, [(C6Me6)Cr(CO)3](+), which has been long sought over 40 years, was isolated and structurally characterized. EPR spectroscopy and theoretical calculations indicate that the spin density mainly resides on the chromium atom. The radical can undergo a substitution reaction with PPh3 to form a more stable cation, [(C6Me6)Cr(CO)2(PPh3)](+). This work provides a direct observation of the radical process for CO-substitution reactions found in (arene)M(CO)3 (M = Cr, Mo, or W) systems, and suggests that other stable radicals of the type [(arene)M(CO)3](+) are accessible. PMID- 25820610 TI - The use of hemostatic agents does not prevent hemorrhagic complications of robotic partial nephrectomy. AB - PURPOSE: To assess the impact of HA on robotic PN (RPN) outcomes. METHODS: We retrospectively analyzed data from patients who underwent RPN in eight centers between 2009 and 2013. Hemorrhagic complications were defined as the occurrence of a pseudoaneurysm, arteriovenous fistula or hematoma requiring transfusion. Patients were first divided into two groups: group A (use of at least one HA) and group B (no HA used), and then into five groups to assess the impact of each HA: group 1 (no HA), group 2 (Floseal((r)) only), group 3 (Surgicel((r)) only), group 4 (Tachosil((r)) only) and group 5 (Surgicel((r)) + Floseal((r))). The impact of HA was evaluated by univariate and multivariate analysis. RESULTS: Out of 515 RPN, 315 (61 %) were done using at least one HA (group A) and 200 (39 %) were done without any HA (group B). Patients in both groups had similar hemorrhagic complication rates (13 % vs. 15 %, p = 0.42) and postoperative complication rates (19 % vs. 23 %, p = 0.32). In multivariate analysis, the absence of HA was not a risk factor for hemorrhagic complications (OR 0.77, p = 0.54). When each type of HA was considered individually, none was associated with the occurrence of hemorrhagic complication either in univariate or in multivariate analysis. CONCLUSION: In this multicenter study, the use of HA was not associated with a lower risk of hemorrhagic or global complications. PMID- 25820611 TI - Alcohol Outcome Expectancies and Regrettable Drinking-Related Social Behaviors. AB - AIMS: Research has shown that alcohol outcome expectancies are predictive of heavy alcohol consumption, which can lead to risky behavior. The purpose of the present study was to assess the incidence of various low-risk social behaviors while drinking among college students. Such social behaviors may later be regretted (referred to as regrettable social behaviors) and include electronic and in-person communications. METHODS: College students (N = 236) completed measures of alcohol outcome expectancies and regrettable social behaviors. RESULTS: Regrettable social behaviors were reported by 66.1% of participants, suggesting that they may occur at a much higher rate than more serious drinking related consequences (e.g., drinking and driving, violence, etc.). Expectancies for social facilitation predicted regrettable social behavior. Further, this relationship was mediated by amount of alcohol consumed. CONCLUSION: Given the high incidence, regrettable social behaviors may be effective targets in alcohol prevention programming. PMID- 25820612 TI - Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical Trial. AB - IMPORTANCE: Treatment nonadherence and relapse are common problems in patients with schizophrenia. The long-acting 3-month formulation of paliperidone palmitate, owing to its extended elimination half-life, may offer a valuable therapeutic option for these patients. OBJECTIVE: To evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms. DESIGN, SETTING, AND PARTICIPANTS: This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase. INTERVENTIONS: Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase. MAIN OUTCOMES AND MEASURES: Time from randomization to the first relapse event (time to relapse) in the DB phase. RESULTS: In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%). CONCLUSIONS AND RELEVANCE: Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01529515. PMID- 25820614 TI - Emotion Expression and Substance Use in Newly Parenting Adolescents and Young Adults. AB - OBJECTIVE: Deficits in emotion expression skills have been associated with alcohol and substance use, but the mechanisms through which these associations occur are not well understood. The current study investigated (a) associations between emotion expression and substance use (i.e., alcohol, cigarettes, and marijuana) in newly parenting adolescents and young adults and (b) whether symptoms of depression and stress mediate these associations in young mothers and fathers. METHODS: Participants recruited from obstetrics and gynecology clinics completed the Center for Epidemiological Studies-Depression Scale, Perceived Stress Scale, Emotion Expression Scale for Children, and substance use items. RESULTS: Path analysis indicated that lower emotion expression at 6 months postpartum was significantly associated with more alcohol and marijuana use at 12 months postpartum for males but not females. Also among males, stress levels at 6 months postpartum partially mediated associations between emotion expression and alcohol and marijuana use at 12 months postpartum. CONCLUSIONS: Findings suggest that poor emotion expression skills are related to more substance use in young fathers, and levels of stress may partially account for this association. PMID- 25820615 TI - Object-location memory in adults with autism spectrum disorder. AB - This study tested implicit and explicit spatial relational memory in Autism Spectrum Disorder (ASD). Participants were asked to study pictures of rooms and pictures of daily objects for which locations were highlighted in the rooms. Participants were later tested for their memory of the object locations either by being asked to place objects back into their original locations or into new locations. Proportions of times when participants choose the previously studied locations for the objects irrespective of the instruction were used to derive indices of explicit and implicit memory [process-dissociation procedure, Jacoby, 1991, 1998]. In addition, participants performed object and location recognition and source memory tasks where they were asked about which locations belonged to the objects and which objects to the locations. The data revealed difficulty for ASD individuals in actively retrieving object locations (explicit memory) but not in subconsciously remembering them (implicit memory). These difficulties cannot be explained by difficulties in memory for objects or locations per se (i.e., the difficulty pertains to object-location relations). Together these observations lend further support to the idea that ASD is characterised by relatively circumscribed difficulties in relational rather than item-specific memory processes and show that these difficulties extend to the domain of spatial information. They also lend further support to the idea that memory difficulties in ASD can be reduced when support is provided at test. PMID- 25820613 TI - Genome-wide association study of blood lead shows multiple associations near ALAD. AB - Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993-1996 and 2002-2005 and from UK in 1991-1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 * 10(-14) for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 * 10(-6) > P > 5 * 10(-8)). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined. PMID- 25820616 TI - Selection of a hepatitis C virus with altered entry factor requirements reveals a genetic interaction between the E1 glycoprotein and claudins. AB - Hepatitis C virus (HCV) cell entry is a complex, multistep process requiring numerous host cell factors, including the tight junction protein claudin-1 (CLDN1). It is not known whether CLDN1 and the HCV glycoproteins physically interact. Therefore, the focus of this work was to study genetic interactions between CLDN1 and HCV. We used CRISPR technology to generate CLDN1 knockout (KO) Huh-7.5 cells, which could not be infected by genotype 2a Jc1 HCV unless CLDN1 expression was restored. Passage of Jc1-transfected CLDN1 KO cells resulted in the selection of a virus that could infect these cells. This virus encoded a single mutation, H316N (numbered relative to the HCV polyprotein), in the E1 glycoprotein. Whereas Jc1 H316N efficiently infected cells lacking CLDN1, such infection was blocked by an antibody targeting CLDN6, another member of the claudin family that is expressed in these cells. Furthermore, HuH6 cells, which express CLDN6, but not CLDN1, were infectable only with the mutant virus. Thus, this mutant virus adapted to the loss of CLDN1 by developing the capacity to utilize other CLDNs. Indeed, CLDN1/CLDN6 double-KO Huh-7.5 cells supported infection by the mutant virus only when CLDN1, CLDN6, or CLDN9 was expressed. Finally, this phenotype was not genotype dependent, given that the H316N mutation rendered a Japanese fulminant hepatitis 1 chimeric HCV genome encoding the genotype 5a glycoproteins able to utilize CLDN6 for host cell entry. CONCLUSION: These data demonstrate plasticity of HCV virus-host interactions, where a previously CLDN1-dependent virus was capable of evolving to use CLDN6. They also reveal a role for E1 in determining entry factor usage and imply a direct, physical interaction between E1 and CLDNs. PMID- 25820617 TI - New approaches in the design and development of cannabinoid receptor ligands: multifunctional and bivalent compounds. AB - Since the identification of the endocannabinoid system, two G protein-coupled receptors (GPCRs) of this complex system were identified and characterized: cannabinoid receptors type 1 (CB1R) and type 2 (CB2R). In addition to orthosteric and subsequently allosteric ligands, new strategies have been used to target CBRs. Bivalent ligands and multifunctional ligands acting at diverse biological targets have been designed, synthesized, and characterized for both CBRs. Due to their altered receptor binding and pharmacological profiles, they are interesting tools to explore CBR functions and their interactions with other physiological systems. Moreover, this approach may bear therapeutic advantages in the therapy of CBR-related disorders, especially multifactorial diseases. Promising prospects include anorectics with fewer side effects, analgesics with decreased tolerance, and therapeutics with multiple pharmacological activities for the treatment of cancer, inflammation, multiple sclerosis, Huntington's and Alzheimer's diseases. PMID- 25820618 TI - Unmet challenges in immune-mediated hepatobiliary diseases. AB - It is ironic that the liver, which serves a critical function in immune tolerance, itself becomes the victim of an autoimmune attack. Indeed, liver autoimmunity and the autoimmune diseases associated with both innate and adaptive responses to hepatocytes and/or cholangiocytes are models of human autoimmunity. For example, in primary biliary cirrhosis, there exists a well-defined and characteristic autoantibody and considerable homogeneity between patients. In autoimmune hepatitis, there are clinical characteristics that allow a rigorous subset definition and well-defined inflammatory infiltrates. In both cases, there are defects in a variety of immune pathways and including regulatory cells. In primary sclerosing cholangitis, with its characteristic overlap with inflammatory bowel disease, there are unique defects in innate immunity and particular important contribution of lymphoid homing to disease pathogenesis. In these diseases, as with other human autoimmune processes, there is the critical understanding that pathogenesis requires a genetic background, but is determined by environmental features, and indeed the concordance of these diseases in identical twins highlights the stochastic nature of immunopathology. Unfortunately, despite major advances in basic immunology and in immunopathology in these diseases, there remains a major void in therapy. The newer biologics that are so widely used in rheumatology, neurology, and gastroenterology have not yet seen success in autoimmune liver disease. Future efforts will depend on more rigorous molecular biology and systems analysis in order for successful application to be made to patients. PMID- 25820619 TI - Recurrence of frontometaphyseal dysplasia in two sisters with a mutation in FLNA and an atypical paternal phenotype: Insights into genotype-phenotype correlation. PMID- 25820620 TI - Blood group AB is protective factor for gestational diabetes mellitus: a prospective population-based study in Tianjin, China. AB - BACKGROUND: The ABO blood types are associated with cancers, cardiovascular diseases and type 2 diabetes mellitus but whether they are also associated with gestational diabetes mellitus (GDM) is unknown. We examined the relationship between the ABO blood types and the risk of GDM in a prospective population-based Chinese cohort. METHODS: From 2010 to 2012, we recruited 14,198 pregnant women within the first 12 weeks of gestation in Tianjin, China. All women had a glucose challenge test (GCT) at 24-28 gestational weeks, followed by a 75-g 2-h oral glucose tolerance test if the results from GCT were >=7.8 mmol/L. GDM was diagnosed based on the glucose cut-points of the International Association of Diabetes and Pregnancy Study Group criteria. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for traditional risk factors. Stratified analysis was performed by family history of diabetes (yes versus no). Sensitivity analyses were also performed by using the World Health Organization (WHO) criteria for GDM. RESULTS: Women with blood groups A, B or O (i.e. non-AB) were associated with increased risk of GDM as compared with those with blood group AB (adjusted OR: 1.44, 95% CI: 1.13-1.83). Sensitivity analyses showed that the result was consistent using WHO criteria. The adjusted OR of blood group non-AB versus AB for GDM was enhanced among women with a family history of diabetes (2.69, 1.21-5.96) and attenuated among those without (1.33, 1.03-1.71). CONCLUSIONS: Blood group AB was a protective factor against GDM in pregnant Chinese women. PMID- 25820621 TI - Overexpression of AtAP1M3 regulates flowering time and floral development in Arabidopsis and effects key flowering-related genes in poplar. AB - APETALA1 plays a crucial role in the transition from vegetative to reproductive phase and in floral development. In this study, to determine the effect of AP1 expression on flowering time and floral organ development, transgenic Arabidopsis and poplar overexpressing of AtAP1M3 (Arabidopsis AP1 mutant by dominant negative mutation) were generated. Transgenic Arabidopsis with e35Spro::AtAP1M3 displayed phenotypes with delayed-flowering compared to wild-type and flowers with abnormal sepals, petals and stamens. In addition, transgenic Arabidopsis plants exhibited reduced growth vigor compared to the wild-type plants. Ectopic expression of AtAP1M3 in poplar resulted in up- or down-regulation of some endogenous key flowering-related genes, including floral meristems identity gene LFY, B-class floral organ identity genes AP3 and PI, flowering pathway integrator FT1 and flower repressors TFL1 and SVP. These results suggest that AtAP1M3 regulates flowering time and floral development in plants. PMID- 25820623 TI - Predictors of hepatorenal syndrome in alcoholic liver cirrhosis. AB - BACKGROUND: Alcoholic liver disease is a major cause of liver cirrhosis and the hepatorenal syndrome is a serious complication. Risk factors for hepatorenal syndrome (HRS) in alcoholic liver cirrhosis are not entirely explored. AIM: To assess the risk factors for hepatorenal syndrome in alcoholic liver cirrhosis. PATIENTS AND METHODS: Consecutive patients with alcoholic liver disease were followed for two months, development of renal failure, classified either as HRS or renal failure not fulfilling criteria of HRS, was the main outcome. RESULTS: Of 171 patients, 14 (8.2%) developed HRS and 13 (7.6%), renal failure not fulfilling the HRS criteria. A significant difference was found between patients with and without HRS in serum sodium (131.1+/-3.8 vs. 135.7+/-5.2; P = 0.003), creatinine, (94.1+/-26.8 vs. 80.3+/-20.2; P < 0.001), albumin (23.5+/-4.9 vs. 29.9+/-5.8; P < 0.001), INR (1.76+/-0.45 vs. 1.44+/-0.41; P < 0.001), bilirubin (252.3+/-179.4 vs. 91.2+/-101.0; P < 0.001), MELD (23+/-6 vs 15+/-5; P < 0.001) and MELD-Na score (27+/-5 vs. 18+/-6; P < 0.001). Multivariate analysis adjusted for sex and age showed that sodium together with creatinine are the strongest HRS predictors, followed by bilirubin with respective odds' ratios (95% CI) of 1.041 (1.012-1.072) for creatinine, 0.870 (0.766-0.988) for serum sodium and 1.005 (1.001-1.010) for serum bilirubin. CONCLUSION: Serum levels of sodium, creatinine and bilirubin are important predictors of the hepatorenal syndrome. PMID- 25820622 TI - Feedback-induced glutamate spillover enhances negative feedback from horizontal cells to cones. AB - KEY POINTS: In the retina, horizontal cells feed back negatively to cone photoreceptors. Glutamate released from cones can spill over to neighbouring cones. Here we show that cone glutamate release induced by negative feedback can also spill over to neighbouring cones. This glutamate activates the glutamate transporter-associated chloride current in these neighbouring cones, which leads to a change in their membrane potential and thus modulates their output. In this way, feedback-induced glutamate spillover enhances negative feedback from horizontal cells to cones, thus forming an additional feedback pathway. This effect will be particularly prominent in cones that are strongly hyperpolarized by light. ABSTRACT: Inhibition in the outer retina functions via an unusual mechanism. When horizontal cells hyperpolarize the activation potential of the Ca(2+) current of cones shifts to more negative potentials. The underlying mechanism consists of an ephaptic component and a Panx1/ATP-mediated component. Here we identified a third feedback component, which remains active outside the operating range of the Ca(2+) current. We show that the glutamate transporters of cones can be activated by glutamate released from their neighbours. This pathway can be triggered by negative feedback from horizontal cells to cones, thus providing an additional feedback pathway. This additional pathway is mediated by a Cl(-) current, can be blocked by either removing the gradient of K(+) or by adding the glutamate transporter blocker TBOA, or low concentrations of Zn(2+) . These features point to a glutamate transporter-associated Cl(-) current. The pathway has a delay of 4.7 +/- 1.7 ms. The effectiveness of this pathway in modulating the cone output depends on the equilibrium potential of Cl(-) (ECl ) and the membrane potential of the cone. Because estimates of ECl show that it is around the dark resting membrane potential of cones, the activation of the glutamate transporter-associated Cl(-) current will be most effective in changing the membrane potential during strong hyperpolarization of cones. This means that negative feedback would particularly be enhanced by this pathway when cones are hyperpolarized. Spatially, this pathway does not reach further than the direct neighbouring cones. The consequence is that this feedback pathway transmits information between cones of different spectral type. PMID- 25820624 TI - Significantly higher incidence of skin cancer than other malignancies in patients after heart transplantation. A retrospective cohort study in the Czech Republic. AB - AIMS: To perform the first study in Czech Republic on heart transplant recipients (HTRs), compare the risks for different types of cancer and provide comprehensive analysis of skin cancer and other types of cancer morbidity from which we would be able to derive an evidence-based skin cancer surveillance program. MATERIALS AND METHODS: A retrospective cohort study was performed to determine and compare standardized morbidity ratio (SMR) of different types of cancer developed after heart transplantation. We analysed data obtained from medical documentation of 603 HTRs transplanted between 1993 and 2010. RESULTS: 191 incident cases of malignancy occurred in123 HTRs (20.4%). According to expectations, nonmelanoma skin cancer was the most frequent type of malignancy (119 cases) with SMR 7.6 (P < 0.001), followed by lung cancer with SMR 2.7 (P < 0.001). SMR for melanoma was 2.5, P = 0.129. Other types of cancer in HTRs (prostate and kidney cancer) were less frequent (SMR 2.06, P = 0.038 and SMR 2.03, P = 0.122). CONCLUSION: The risk of malignancy development is significantly higher for HTRs compared to the general population. Squamous cell carcinoma of the skin is the most frequent type of cancer followed by basal cell carcinoma. These findings emphasise the importance of regular skin cancer screening in HTRs. PMID- 25820625 TI - Stapling Versus Hand Suture for Gastroenteric Anastomosis in Roux-en-Y Gastric Bypass: a Randomized Clinical Trial. AB - BACKGROUND: Different anastomotic techniques have been evaluated during a laparoscopic Roux-en-Y gastric bypass (RYGB); however, no techniques have proven to be better than any other regarding complications and the percentage of weight loss (excess weight loss (%EWL)), and there are few controlled prospective studies to compare them. METHODS: A randomized, prospective study was conducted in 238 patients undergoing RYGB for morbid obesity between July 2008 and September 2012 to compare the early and late postoperative complications between the two surgical techniques: gastrojejunal hand-sutured anastomosis (HSA) and circular-stapled anastomosis (CSA). Minimum follow-up was 24 months. RESULTS: The two groups of patients were similar for demographic data and preoperative comorbidities. There were no significant differences between the surgical techniques regarding %EWL at 3, 12, and 24 months. The patients with CSA had a greater frequency of postoperative gastrointestinal bleeding (GIB) (4.2 vs. 0%, p = 0.024) and surgical wound infection (11.1 vs. 3.4%, p = 0.025) than the patients with HSA, with no significant differences in the other early complications. There were no significant differences in either group for late complications (gastrojejunal anastomosis (GJA) stricture, marginal ulcer, GJA perforation, bowel obstruction, and eventration). No significant differences were observed in operative time, rate of reoperation and postoperative length of hospital stay. CONCLUSIONS: HSA and CSA were techniques with similar safety and effectiveness in our study. HSA had a lower rate of bleeding complications and surgical wound infection, although it does require greater experience in laparoscopic hand suturing. PMID- 25820626 TI - Potential of prodendronic polyamines with modulated segmental charge density as novel coating for fast and efficient analysis of peptides and basic proteins by CE and CE-MS. AB - In this work, the suitability of a new polymer family has been investigated as capillary coatings for the analysis of peptides and basic proteins by CE. This polymer family has been designed to minimize or completely prevent protein capillary wall interactions and to modify the EOF. These coating materials are linear polymeric chains bearing as side cationizable moiety a dentronic triamine derived from N,N,N',N'-tetraethyldiethylenetriamine (TEDETA), which is linked to the backbone through a spacer (unit labeled as TEDETAMA). Four different polymers have been prepared and evaluated: a homopolymer which comprised only of those cationizable repetitive units of TEDETAMA, and three copolymers that randomly incorporate TEDETAMA together with neutral hydrosoluble units of N-(2 hydroxypropyl) methacrylamide (HPMA) at different molar percentages (25:75, 50:50 and 75:25). It has been demonstrated that the composition of the copolymers influences the EOF and therefore the separation of the investigated biopolymers. Among the novel polymers studied, poly-(TEDETAMA-co-HPMA) 50:50 copolymer was successfully applied as coating material of the inner capillary surface in CE-UV and CE-MS, providing EOF reversing together with fast and efficient baseline separation of peptides and basic proteins. Finally, the feasibility of the polymer-coated capillary was shown through the analysis of lysozyme in a cheese sample. PMID- 25820627 TI - Patterning of polymer brushes made easy using titanium dioxide: direct and remote photocatalytic lithography. AB - Photocatalytic lithography is proved for the realization of micropatterned polymer brushes. Initiator-functionalized titanium dioxide or silicon surfaces are respectively exposed directly to near-UV light through a photomask (direct approach) or through a transparent photoactive TiO2 film (remote approach). Initiator patterns are then amplified as polymer brushes with SI-ATRP. Features down to 10 MUm could be obtained using simple equipment. The process is intrinsically parallel, has high throughput and scalable to wafer size, making it powerful for microfabrication purposes. PMID- 25820628 TI - A novel high light-inducible carotenoid-binding protein complex in the thylakoid membranes of Synechocystis PCC 6803. AB - Synechocystis sp. PCC 6803 is a model cyanobacterium extensively used to study photosynthesis. Here we reveal a novel high light-inducible carotenoid-binding protein complex (HLCC) in the thylakoid membranes of Synechocystis PCC 6803 cells exposed to high intensity light. Zeaxanthin and myxoxanthophyll accounted for 29.8% and 54.8%, respectively, of the carotenoids bound to the complex. Using Blue-Native PAGE followed by 2D SDS-PAGE and mass spectrometry, we showed that the HLCC consisted of Slr1128, IsiA, PsaD, and HliA/B. We confirmed these findings by SEAD fluorescence cross-linking and anti-PsaD immuno-coprecipitation analyses. The expression of genes encoding the protein components of the HLCC was enhanced by high light illumination and artificial oxidative stress. Deletion of these proteins resulted in impaired state transition and increased sensitivity to oxidative and/or high light stress, as indicated by increased membrane peroxidation. Therefore, the HLCC protects thylakoid membranes from extensive photooxidative damage, likely via a mechanism involving state transition. PMID- 25820629 TI - Ecotoxicity of multiwalled carbon nanotubes: standardization of the dispersion methods and concentration measurements. AB - There are currently a variety of applications for multiwalled carbon nanotubes (MWCNTs), but considerable concerns exist regarding their release into the environment. Their potential accumulation by aquatic organisms could lead to transfer throughout food chains. Considering the divergences in experimental data published on the ecotoxicity of carbon nanotubes, further research is required. The dispersion of MWCNTs in aqueous culturing media of organisms as well as the determination of concentrations are relevant aspects to obtain accurate ecotoxicity results. Ultraviolet-visible spectroscopy is one of the most reported techniques to analyze concentration quickly and economically, but the methodologies to prepare dispersions and selecting the wavelengths for ultraviolet-visible measurements have not yet been clearly defined. The present study demonstrates that dispersion procedures influence absorbance, and an approach to determine the most appropriate measurement wavelength is proposed. Ecotoxicity tests with MWCNTs were performed on Vibrio fischeri bacteria, and divergences in the results were observed with respect to those previously reported. The present study contributes to the attempt to overcome the lack of standardization in the environmental assessment of MWCNTs. PMID- 25820630 TI - Anterior cervical discectomy and fusion: is surgical education safe? AB - BACKGROUND: Operative skills are key to neurosurgical resident training. They should be acquired in a structured manner and preferably starting early in residency. The aim of this study was to test the hypothesis that the outcome and complication rate of anterior cervical discectomy and fusion with or without instrumentation (ACDF(I)) is not inferior for supervised residents as compared to board-certified faculty neurosurgeons (BCFN). METHODS: This was a retrospective single-center study of all consecutive patients undergoing ACDF(I)-surgery between January 2011 and August 2014. All procedures were dichotomized into two groups according to the surgeon's level of experience: teaching cases (postgraduate year (PGY)-2 to PGY-6 neurosurgical residents) and non-teaching cases operated by BCFN. The primary study endpoint was patients' clinical outcome 4 weeks after surgery, categorized into a binary responder and non-responder variable. Secondary endpoints were complications, need for re-do surgery, and clinical outcome until the last follow-up. RESULTS: After exclusion of six cases because of incomplete data, a total of 287 ACDF(I) operations were enrolled into the study, of which 82 (29.2 %) were teaching cases and 199 (70.8 %) were non teaching cases. Teaching cases required a longer operation time (131 min (95 % confidence interval (CI) 122-141 min) vs. 102 min (95-108 min; p < 0.0001) and were associated with a slightly higher estimated blood loss (84 ml (95 % CI 56 111 ml) vs. 57 ml (95 % CI 47-66 ml); p = 0.0017), while there was no difference in the rate of intraoperative complications (2.4 vs. 1.5 %; p = 0.631). Four weeks after surgery, 92.7 and 93 % of the patients had a positive response to surgery (p = 1.000), respectively. There was no difference in the postoperative complication rate (4.9 vs. 3.0 %; p = 0.307). Around 30 % of the study patients were followed up in outpatient clinics for more than once up until a mean period of 6.4 months (95 % CI 5.3-7.6 months). At the last follow-up, the clinical outcome was similar with a 90 % responder rate for both groups (p = 0.834). In total, five patients from the teaching group and eight patients from the non teaching group required re-do surgery (p = 0.602). CONCLUSIONS: Short- and mid term outcomes and complication rates following microscopic ACDF(I) were comparable for patients operated on by supervised neurosurgical residents or by senior surgeons. Our data thus indicate that a structured neurosurgical education of operative skills does not lead to worse outcomes or increase the complication rates after ACDF(I). Confirmation of the results by a prospective study is desired. PMID- 25820631 TI - Authors' reply to "Pathogenesis of radiosurgery-induced cyst formation in patients with arteriovenous malformation". PMID- 25820632 TI - Simultaneous fluorescein sodium and 5-ALA in fluorescence-guided glioma surgery. PMID- 25820633 TI - The Relationship between Theoretical Orientation and Countertransference Expectations: Implications for Ethical Dilemmas and Risk Management. AB - Countertransference (CT) awareness is widely considered valuable for differential diagnosis and the proactive management of ethical dilemmas. We predicted that the more practitioners' theoretical orientation (TO) emphasizes insight into the dynamics of subjective mental life, the better they will be at using their CT expectations in differential diagnosis with high-risk patients. To test this hypothesis, we compared psychodynamic therapy (PDT) practitioners who emphasize insight into subjective mental life with practitioners who do not emphasize this epistemology. Results indicated that PDT practitioners expected significantly more CT than practitioners of cognitive-behavioural therapy (CBT) and other practitioners (e.g., family systems, humanistic/existential and eclectic) to patients with borderline personality organization overall. PDT practitioners had significantly more CT expectations to patients with borderline-level pathologies as compared with neurotic-level patients than both CBT and other practitioners. PDT practitioners were significantly more expectant of CT issues than CBT practitioners with respect to the personality disorders most associated with acting out and risk management problems (e.g., paranoid, psychopathic, narcissistic, sadistic, sadomasochistic, masochistic, hypomanic, passive aggressive, counterdependent and counterphobic). The other practitioners generally had CT expectations between PDT and CBT. These findings suggest that clinical training into CT may be useful in differential diagnoses and in helping to avoid ethical dilemmas regardless of one's theoretical preference. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Insight into countertransference can be used to help with differential diagnoses and to help prevent possible management problems with acting out patients. The Psychodynamic Diagnostic Manual is a useful taxonomy in that it includes countertransference as a diagnostic aid. PMID- 25820635 TI - Switching health insurers: the role of price, quality and consumer information search. AB - We examine the impact of price, service quality and information search on people's propensity to switch health insurers in the competitive Dutch health insurance market. Using panel data from annual household surveys and data on health insurers' premiums and quality ratings over the period 2006-2012, we estimate a random effects logit model of people's switching decisions. We find that switching propensities depend on health plan price and quality, and on people's age, health, education and having supplementary or group insurance. Young people (18-35 years) are more sensitive to price, whereas older people are more sensitive to quality. Searching for health plan information has a much stronger impact on peoples' sensitivity to price than to service quality. In addition, searching for health plan information has a stronger impact on the switching propensity of higher than lower educated people, suggesting that higher educated people make better use of available health plan information. Finally, having supplementary insurance significantly reduces older people's switching propensity. PMID- 25820636 TI - Phase-transfer and other types of catalysis with cyclopropenium ions. AB - This work establishes the cyclopropenium ion as a viable platform for efficient phase-transfer catalysis of a diverse range of organic transformations. The amenability of these catalysts to large-scale synthesis and structural modification is demonstrated. Evaluation of the molecular structure of an optimal catalyst reveals some unique structural features of these systems. Finally, a discussion of electronic charge distribution underscores an important consideration for catalyst design. PMID- 25820637 TI - Adult Siblings Consider the Future: Emergent Themes. AB - BACKGROUND: This study aimed to explore the perceptions of adult siblings regarding a future care role and compare with perceived parental wishes as family often provide a key support role in the lives of people who have an intellectual disability. MATERIALS AND METHOD: Semi-structured interviews were undertaken with 15 adult siblings and an approach aligned to IPA was used to analyse the results. RESULTS: Emergent themes demonstrated that intellectual disability has an impact upon sibling lives yet the degree and range of impact varies. Most participants were concerned about the future, service issues were raised as was futures planning, siblings' needs, the positive impact of intellectual disability and influence of life stage upon care giving. CONCLUSION: The findings highlight that whilst the impact of intellectual disability upon adult siblings is variable, siblings are concerned about the future, and that life stage and circumstance appear to influence care giving. PMID- 25820638 TI - Effects of a School-Based Social Skills Training Program for Adolescents with Autism Spectrum Disorder and Intellectual Disability. AB - Social deficits are a core characteristic of individuals with autism spectrum disorders and co-occurring intellectual disabilities (ASD-ID). Despite persistence of these deficits into adolescence, few social skills interventions have been empirically evaluated for older individuals with ASD-ID. The present investigation adapted an efficacious protocol for adolescents with ASD, video based group instruction (VGI), and extended the procedure to 4 adolescents in a public high school setting. A multiple probe across behaviors design demonstrated the effectiveness of VGI for teaching novel social behavior to three of the four participants, with mixed outcomes for the fourth participant. Long-term maintenance was observed for two participants, though generalization outcomes were mixed. The results support using VGI within high school curricula for some adolescents with ASD-ID. PMID- 25820639 TI - Response to letter to the Editor from Dr. Carbillon on our article about first pregnancy characteristics, genetics, and breast density. PMID- 25820641 TI - An experimental apparatus to simulate body-powered prosthetic usage: Development and preliminary evaluation. AB - BACKGROUND AND AIM: Harness fitting in the body-powered prosthesis remains more art than science due to a lack of consistent and quantitative evaluation. The aim of this study was to develop a mechanical, human-body-shaped apparatus to simulate body-powered upper limb prosthetic usage and evaluate its capability of quantitative examination of harness configuration. TECHNIQUE: The apparatus was built upon a torso of a wooden mannequin and integrated major mechanical joints to simulate terminal device operation. Sensors were used to register cable tension, cable excursion, and grip force simultaneously. DISCUSSION: The apparatus allowed the scapula to move up to 127 mm laterally and the load cell can measure the cable tension up to 445 N. Our preliminary evaluation highlighted the needs and importance of investigating harness configurations in a systematic and controllable manner. CLINICAL RELEVANCE: The apparatus allows objective, systematic, and quantitative evaluation of effects of realistic harness configurations and will provide insightful and working knowledge on harness fitting in upper limb amputees using body-powered prosthesis. PMID- 25820640 TI - Outcomes of knee disarticulation and the influence of surgical techniques in dysvascular patients: A systematic review. AB - BACKGROUND: Dysvascularity is the main cause of lower limb amputations in Scotland, and there is an insignificant proportion (1.7%) of knee disarticulations, despite the benefits of amputation. OBJECTIVES: The outcomes of knee disarticulation and its associated surgical techniques will be evaluated based on healing, reamputations, functional outcomes, prosthetic ambulation and gait biomechanics to determine whether a greater rate of knee disarticulations can be justified among dysvascular patients. STUDY DESIGN: Systematic review. METHODS: Key electronic databases were searched for the relevant literature based on a pre-specified eligibility criterion. RESULTS: The 17 articles included in this review were appraised for their quality, and key findings are extracted. CONCLUSION: Healing rates are favourable, but there is a need for appropriate amputation level selection to prevent reamputations. Knee disarticulation patients have better maintenance of independent living status than transfemoral patients, but overall prosthetic ambulation rates are inconsistent. In terms of gait biomechanics of knee disarticulation, there are some positive indications, but the evidence is insubstantial. A stronger body of evidence is required in this subject field, and recommendations are made for future research - Scottish Intercollegiate Guidelines Network Grade of Recommendation: C. CLINICAL RELEVANCE: This review aims to inform the multidisciplinary teams involved in the rehabilitation of dysvascular amputees about evidence-based outcomes following knee disarticulation. This knowledge will be beneficial when formulating treatment pathways for this vulnerable population group. PMID- 25820642 TI - D-pi-A conjugated molecules for optoelectronic applications. AB - Dipolar chromophores consisting of electron donor (D) and electron acceptor (A) groups connected through a conjugated pi-bridge have been actively studied and integrated in optoelectronic and electronic devices. Generally, such pi conjugated molecules provide substantial delocalization of pi-electrons over the molecules. Here, a brief overview of recent research on D-pi-A dipolar chromophores including their syntheses and several promising applications is reported, especially in nonlinear optical devices and organic photovoltaics. Structure/property relationships are discussed in order to exploit the potentials by tuning the pi-electron density, polarizability, and HOMO-LUMO band gap of the chromophores. Some of the examples may well set the stage for chip-scale integration of optoelectronics as well as the realization of an important array of new device technologies. PMID- 25820644 TI - Overexpression of the phosphofructokinase encoding gene is crucial for achieving high production of D-lactate in Corynebacterium glutamicum under oxygen deprivation. AB - We previously reported on the impacts of the overexpression of individual genes of the glycolytic pathway encoding glucokinase (GLK), glyceraldehyde phosphate dehydrogenase (GAPDH), phosphofructokinase (PFK), triosephosphate isomerase (TPI), and bisphosphate aldolase (FBA) on D-lactate productivity in Corynebacterium glutamicum under oxygen-deprived conditions. Searching for synergies, in the current study, we simultaneously overexpressed the five glycolytic genes in a stepwise fashion to evaluate the effect of the cumulative overexpression of glycolytic genes on D-lactate production. Interestingly, the final D-lactate concentration markedly differed depending on whether or not the PFK encoding gene was overexpressed when combined with overexpressing other glycolytic genes. The simultaneous overexpression of the GLK, GAPDH, TPI, and FBA encoding genes led to the highest initial D-lactate concentration at 10 h. However, this particular recombinant strain dramatically slowed producing D lactate when a concentration of 1300 mM was reached, typically after 32 h. In contrast, the strain overexpressing the PFK encoding gene together with the GLK, GAPDH, TPI, and FBA encoding genes showed 12.7 % lower initial D-lactate concentration at 10 h than that observed with the strain overexpressing the genes coding for GLK, GAPDH, TPI, and FBA. However, this recombinant strain continued to produce D-lactate after 32 h, reaching 2169 mM after a mineral salts medium bioprocess incubation period of 80 h. These results suggest that overexpression of the PFK encoding gene is essential for achieving high production of D-lactate. Our findings provide interesting options to explore for using C. glutamicum for cost-efficient production of D-lactate at the industrial scale. PMID- 25820643 TI - Microbial community analysis of switchgrass planted and unplanted soil microcosms displaying PCB dechlorination. AB - Polychlorinated biphenyls (PCBs) pose potential risks to human and environmental health because they are carcinogenic, persistent, and bioaccumulative. In this study, we investigated bacterial communities in soil microcosms spiked with PCB 52, 77, and 153. Switchgrass (Panicum virgatum) was employed to improve overall PCB removal, and redox cycling (i.e., sequential periods of flooding followed by periods of no flooding) was performed in an effort to promote PCB dechlorination. Lesser chlorinated PCB transformation products were detected in all microcosms, indicating the occurrence of PCB dechlorination. Terminal restriction fragment length polymorphism (T-RFLP) and clone library analysis showed that PCB spiking, switchgrass planting, and redox cycling affected the microbial community structure. Putative organohalide-respiring Chloroflexi populations, which were not found in unflooded microcosms, were enriched after 2 weeks of flooding in the redox-cycled microcosms. Sequences classified as Geobacter sp. were detected in all microcosms and were most abundant in the switchgrass-planted microcosm spiked with PCB congeners. The presence of possible organohalide-respiring bacteria in these soil microcosms suggests that they play a role in PCB dechlorination therein. PMID- 25820645 TI - An amino acid at position 512 in beta-glucosidase from Clavibacter michiganensis determines the regioselectivity for hydrolyzing gypenoside XVII. AB - A recombinant beta-glucosidase from Clavibacter michiganensis specifically hydrolyzed the outer and inner glucose linked to the C-3 position in protopanaxadiol (PPD)-type ginsenosides and the C-6 position in protopanaxatriol (PPT)-type ginsenosides except for the hydrolysis of gypenoside LXXV (GypLXXV). The enzyme converted gypenoside XVII (GypXVII) to GypLXXV by hydrolyzing the inner glucose linked to the C-3 position. The substrate-binding residues obtained from the GypXVII-docked homology models of beta-glucosidase from C. michiganensis were replaced with alanine, and the amino acid residue at position 512 was selected because of the changed regioselectivity of W512A. Site-directed mutagenesis for the amino acid residue at position 512 was performed. W512A and W512K hydrolyzed the inner glucose linked to the C-3 position and the outer glucose linked to the C-20 position of GypXVII to produce GypLXXV and F2. W512R hydrolyzed only the outer glucose linked to the C-20 position of GypXVII to produce F2. However, W512E and W512D exhibited no activity for GypXVII. Thus, the amino acid at position 512 is a critical residue to determine the regioselectivity for the hydrolysis of GypXVII. These wild-type and variant enzymes produced diverse ginsenosides, including GypXVII, GypLXXV, F2, and compound K, from ginsenoside Rb1. To the best of our knowledge, this is the first report of the alteration of regioselectivity on ginsenoside hydrolysis by protein engineering. PMID- 25820646 TI - Ectoparasite loads in sympatric urban populations of the northern white-breasted and the European hedgehog. AB - We investigated abundance and prevalence of ticks and fleas infesting urban populations of two species of hedgehogs: the northern white-breasted hedgehog (Erinaceus roumanicus) and the European hedgehog (Erinaceus europaeus). The hedgehogs were captured in the city of Poznan (western Poland) over the period of 4 years. Both species of hedgehogs were infested with the castor bean tick (Ixodes ricinus), the hedgehog tick (Ixodes hexagonus), and the hedgehog flea (Archeopsylla erinacei). The northern white-breasted hedgehog had higher loads of I. ricinus and A. erinacei than the European hedgehog. The abundance and prevalence of I. hexagonus were similar on both species of hosts. Co-infestation with the two species of ticks was more frequent on the northern white-breasted hedgehog than on the European hedgehog. Therefore, these two closely related species of hedgehogs differ in their importance as hosts of arthropod vectors of pathogens in urban areas and might play a different role in the dynamics of zoonotic diseases. PMID- 25820647 TI - Report of Theileria luwenshuni and Theileria sp. RSR from cervids in Gansu, China. AB - Theileria parasites are important tick-borne pathogens of animals and cause huge economic losses worldwide. Here, we undertook to assess the prevalence of Theileria spp. in cervids in Gansu, China, based on PCR analysis and sequencing of the 18S rRNA genes. Molecular survey showed that Theileria luwenshuni and Theileria sp. RSR were frequently found in Gansu cervids, and the prevalence of T. luwenshuni was 66.7% (n = 9, 6/9) in roe deer in Zhengning County, 58.3% (n = 12, 7/12) in sika deer in Ningxian County, 50% (n = 10, 5/10) in sika deer and 42.9% (n = 14, 6/14) in red deer in Weiyuan County. The prevalence of Theileria sp. RSR was 77.8% (n = 9, 7/9) in roe deer in Zhengning County, 75% (n = 12, 9/12) in sika deer in Ningxian County, 60.0% (n = 10, 6/10) in sika deer, and 50.0% (n = 14, 7/14) in red deer in Weiyuan County. The co-prevalence of the two T. luwenshuni and Theileria sp. RSR was 55.6% (n = 5, 5/9) in roe deer in Zhengning County, 50% (n = 12, 6/12) in sika deer in Ningxian county, 50% (n = 10, 5/10) in sika deer and 35.7% (n = 14, 5/14) in red deer in Weiyuan County, respectively. No other Theileria species was found in these samples. T. luwenshuni and Theileria sp. RSR were detected for the first time in cervids in Gansu, China. Animal experiments showed that four sheep were inoculated with roe deer blood from Zhengning, sika deer blood from Ningxian, sika deer blood, and red deer blood from Weiyuan, respectively, and the Theileria isolated from these inoculated sheep was identified as T. luwenshuni, but Theileria sp. RSR was not detected in these sheep. Our results extend our understanding of the epidemiology of cervine theileriosis in Gansu, China, and will facilitate the implementation of measures to control theileriosis in cervids and small ruminants. This was the first report to demonstrate the occurrence of T. luwenshuni from roe deer, sika deer, and red deer worldwide. PMID- 25820648 TI - Mechanistic studies of the apical sodium-dependent bile acid transporter. AB - In mammals, the apical sodium-dependent bile acid transporter (ASBT) is responsible for the reuptake of bile acid from the intestine, thus recycling bile acid that is secreted from the gallbladder, for the purpose of digestion. As bile acid is synthesized from cholesterol, ASBT inhibition could have important implications in regulation of cholesterol levels in the blood. We report on a simulation study of the recently resolved structures of the inward-facing ASBT from Neisseria meningitidis and from Yersinia frederiksenii, as well as of an ASBT variant from Yersinia frederiksenii suggested to be in the outward-facing conformation. Classical and steered atomistic simulations and comprehensive potential of mean force analyses of ASBT, both in the absence and presence of ions and substrate, allow us to characterize and gain structural insights into the Na(+) binding sites and propose a mechanistic model for the transport cycle. In particular, we investigate structural features of the ion translocation pathway, and suggest a third putative Na(+) binding site. Our study sheds light on the structure-function relationship of bacterial ASBT and may promote a deeper understanding of transport mechanism altogether. PMID- 25820649 TI - Hair cortisol concentrations in higher- and lower-stress mother-daughter dyads: A pilot study of associations and moderators. AB - Hair cortisol concentrations (HCC) are receiving increased attention as a novel biomarker of psychophysiological responses to chronic stress, with potential relevance for psychopathology risk research. We examined the validity of HCC as a marker of psychosocial stress in mother (M(age) = 37.87 years)-daughter (M(age) = 7.62 years) dyads characterized by higher (n = 30) or lower (n = 30) maternal chronic stress. Additionally, we examined whether early care moderated similarity of HCC levels within dyads. Higher-stress mothers had significantly lower HCC compared to lower-stress mothers, consistent with other research showing that chronic stress leads to blunted HPA axis activity over time. Further, HCC in daughters were significantly and positively associated with previously assessed salivary cortisol stress reactivity. Finally, mother-daughter HCC associations were significantly moderated by negative parenting styles, such that associations became stronger as quality of parenting decreased. Findings overall indicate that HCC may be a useful marker of cortisol responses to chronic stress. PMID- 25820650 TI - Metastability in lipid based particles exhibits temporally deterministic and controllable behavior. AB - The metastable-to-stable phase-transition is commonly observed in many fields of science, as an uncontrolled independent process, highly sensitive to microscopic fluctuations. In particular, self-assembled lipid suspensions exhibit phase transitions, where the underlying driving mechanisms and dynamics are not well understood. Here we describe a study of the phase-transition dynamics of lipid based particles, consisting of mixtures of dilauroylphosphatidylethanolamine (DLPE) and dilauroylphosphatidylglycerol (DLPG), exhibiting a metastable liquid crystalline-to-stable crystalline phase transition upon cooling from 60 degrees C to 37 degrees C. Surprisingly, unlike classically described metastable-to-stable phase transitions, the manner in which recrystallization is delayed by tens of hours is robust, predetermined and controllable. Our results show that the delay time can be manipulated by changing lipid stoichiometry, changing solvent salinity, adding an ionophore, or performing consecutive phase-transitions. Moreover, the delay time distribution indicates a deterministic nature. We suggest that the non-stochastic physical mechanism responsible for the delayed recrystallization involves several rate-affecting processes, resulting in a controllable, non-independent metastability. A qualitative model is proposed to describe the structural reorganization during the phase transition. PMID- 25820651 TI - Indanones as high-potency reversible inhibitors of monoamine oxidase. AB - Recent reports document that alpha-tetralone (3,4-dihydro-2H-naphthalen-1-one) is an appropriate scaffold for the design of high-potency monoamine oxidase (MAO) inhibitors. Based on the structural similarity between alpha-tetralone and 1 indanone, the present study involved synthesis of 34 1-indanone and related indane derivatives as potential inhibitors of recombinant human MAO-A and MAO-B. The results show that C6-substituted indanones are particularly potent and selective MAO-B inhibitors, with IC50 values ranging from 0.001 to 0.030 MUM. C5 Substituted indanone and indane derivatives are comparatively weaker MAO-B inhibitors. Although the 1-indanone and indane derivatives are selective inhibitors of the MAO-B isoform, a number of homologues are also potent MAO-A inhibitors, with three homologues possessing IC50 values <0.1 MUM. Dialysis of enzyme-inhibitor mixtures further established a selected 1-indanone as a reversible MAO inhibitor with a competitive mode of inhibition. It may be concluded that 1-indanones are promising leads for the design of therapies for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. PMID- 25820652 TI - Anesthesia in Cri du Chat syndrome: Information on 51 Italian patients. PMID- 25820653 TI - The hepatoprotective effect of aqueous extracts of Penthorum chinense Pursh against acute alcohol-induced liver injury is associated with ameliorating hepatic steatosis and reducing oxidative stress. AB - The aim of the present study was to evaluate the effects of Penthorum chinense Pursh (PCP), a health food and folk medicine, against acute alcohol-induced liver injury and further to elucidate its probable mechanisms. Male C57BL/6 mice were treated with an aqueous extract of PCP (5.2 and 10.3 g per kg BW) once daily for 7 consecutive days prior to ethanol gavage (4.7 g kg(-1)) every 12 h for a total of three doses. Pretreatment with PCP significantly decreased the elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic triglyceride after the last ethanol administration. PCP suppressed the elevation of the malondialdehyde (MDA) level, restored the glutathione (GSH) level and enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) in both the serum and liver, which were associated with the inhibition of hepatic cytochrome P450 2E1 (CYP2E1). In addition, alcohol exposure markedly induced the lipolysis of white adipose tissue (WAT) through up-regulating protein expressions of adipose triglyceride lipase (ATGL) and phosphorylation of hormone-sensitive lipase (p-HSL), and enhancing the fatty acid uptake capacity in the liver by elevated hepatic CD36 expression, which were attenuated by PCP treatment. These data demonstrated that pre-treatment with PCP protected against acute ethanol induced liver injury, possibly by reducing CYP2E1-dependent oxidative stress and ameliorating dysfunctional WAT derived-fatty acid influx to the liver. Our findings suggest that PCP might be a promising agent for the prevention of acute alcohol-induced liver injury. PMID- 25820654 TI - High correlation of the Oxford Knee Score with postoperative pain, but not with performance-based functioning. AB - PURPOSE: The Oxford Knee Score (OKS) is a widely known patient-related outcome measure (PROM) to determine pain and knee functioning before and after total knee arthroplasty (TKA). Self-reported function is mainly influenced by change in pain; therefore, it was hypothesized that the OKS correlates more with pain than with performance-based functioning. METHODS: In a prospective cohort of 88 patients, who had a cementless mobile-bearing TKA, included in a randomized clinical trial, the correlation between the overall OKS, and its subscales for pain (PCS) and function (FCS), with performance-based functioning using the DynaPort(r) Knee Score (DKS), visual analogue scale score for pain (VAS) and the Knee Society Score (KSS) was evaluated. All scores were measured preoperatively, 6 months and 1 year after surgery. Overall change in outcome over time was analysed until 5 years after surgery. RESULTS: All scores improved over time. The DKS was influenced by sex, preoperative BMI and age. The internal consistency of the OKS PCS increased over time, whereas the OKS FCS remained the same. The mean postoperative OKS FCS showed moderate correlation with the DKS (r = 0.65, p < 0.001), and the mean postoperative OKS and OKS PCS showed high correlation with the VAS (r = -0.79 and r = -0.82, respectively, p < 0.001). The mean postoperative KSS showed high correlations with the OKS (r = 0.80, p < 0.001), the OKS PCS (r = 0.72 p < 0.001) and OKS FCS (r = 0.74, p < 0.001). CONCLUSION: The postoperative OKS and the OKS PCS showed high correlation with pain, but only the postoperative OKS FCS was well correlated with performance-based functioning. This suggests that the OKS is more related to pain and tells us less on postoperative functioning. This is important when the OKS as PROM is used to evaluate the quality of orthopaedic care of patients with TKA. LEVEL OF EVIDENCE: III. PMID- 25820655 TI - The critical shoulder angle is associated with rotator cuff tears and shoulder osteoarthritis and is better assessed with radiographs over MRI. AB - PURPOSE: The purpose of this study was to determine whether there is an association between the critical shoulder angle (CSA) and rotator cuff tears (RCT) as well as osteoarthritis (OA), and to compare the reproducibility and accuracy of CSA values as measured with radiograph and MRI. METHODS: Based on a pre hoc power analysis, three independent reviewers measured CSAs for three groups of 10 age-matched patients each (RCT group, OA group, and non-RCT/non-OA group) using radiographs and MRIs. Inter- and intra-observer agreements of CSAs were determined with intraclass correlation coefficients. ANOVA analysis was performed. RESULTS: Interobserver and intra-observer agreements on radiographs were 0.87 (95 % CI 0.78-0.93) and 0.91 (95 % CI 0.82-0.96), respectively. Significant differences in mean CSAs by radiographs were found between the groups (RCT 37.3 degrees +/- 2.6 degrees ; OA 28.7 degrees +/- 2.2 degrees ; non RCT/non-OA 32.7 degrees +/- 2.5 degrees ; p < 0.001). CSAs obtained from MRI scans had interobserver agreement of 0.62 (95 % CI 0.43-0.78) and intra-observer agreement of 0.68 (95 % CI 0.50-0.80). There was a significant correlation between the patients' pathologies and CSAs measured by radiographs (r = 0.44; p = 0.02) and MRI (r = 0.50; p = 0.01). A significant difference in mean CSAs measured on radiograph versus MRI was seen in the OA group (28.7 degrees +/- 2.2 degrees vs. 31.3 degrees +/- 4.4 degrees ; p = 0.01). CONCLUSION: CSA measurements obtained from radiographs demonstrated excellent interobserver agreement with less variability than CSAs from MRI, especially in OA patients. This study confirms an association between the CSA and RCTs as well as OA pathology. Assessing the CSA may be helpful during diagnostic evaluation of patients with shoulder pain and can help predict pathology. LEVEL OF EVIDENCE: Retrospective cohort study, Level IV. PMID- 25820656 TI - Functional role and mechanism of lncRNA LOC728228 in malignant 16HBE cells transformed by anti-benzopyrene-trans-7,8-dihydrodiol-9,10-epoxide. AB - Lung cancer is a major health problem, and is considered one of the deadliest cancers in humans. It is refractory to current treatments, and the mechanisms of lung cancer are unknown. Long noncoding RNAs (lncRNAs) are involved in various biological processes and human diseases. However, the exact functional roles and mechanisms of lncRNAs are largely unclear. In this study, we attempted to identify lung-cancer-related lncRNAs. We found changes in lncRNA expression in the anti-benzo(a) pyrene-7,8-diol-9,10-epoxide (anti-BPDE)-transformed human bronchial epithelial cell line (16HBE-T cells) using microarrays and qRT-PCR. Of these lncRNAs, LOC728228 was upregulated relative to its expression in control untransformed16HBE (16HBE-N) cells. LOC728228 knockdown inhibited cell proliferation, caused G0/G1-phase cell-cycle arrest, reduced cellular migration, suppressed colony formation in vitro, and inhibited tumor growth in a nude mouse xenograft model. LOC728228 knockdown also suppressed cyclin D1 expression, and the depletion of cyclin D1 induced G0/G1-phase cell-cycle arrest and inhibited cell proliferation, thus influencing the malignant potential of cancer cells. In summary, our results suggest that lncRNA LOC728228 has an oncogene-like function and plays a vital role in human lung cancer. PMID- 25820657 TI - Existence of circulating anti-endothelial cell antibodies after heart transplantation is associated with post-transplant acute allograft rejection. AB - Anti-endothelial cell antibodies (AECA) may be involved in the development of heart allograft rejection. Its detection might be a cheap and noninvasive method to identify high-risk patients. An indirect immunofluorescence method on human umbilical vein endothelial cells was used to investigate the presence of AECAs in 260 pre- and post-transplant serum samples sequentially collected from 34 patients within the first year after heart transplantation (HTX). The presence of AECAs before (23.5 %) and early after HTX (14.7 %) was associated with a significantly increased risk of early acute rejection (75 and 60 %, respectively) compared to 33 % in AECA-negative patients (p = 0.049). Moreover, rejections from AECA-positive patients were more severe (p = 0.057) with a significantly increased incidence of multiple (p = 0.025). The mean number of the sum of rejection episodes was significantly higher in AECA-positive patients (p <= 0.05). Patients free of AECAs mainly received mycophenolate mofetil as primary immunosuppression (p = 0.067). Nevertheless, the presence of AECAs did not affect long-term outcome and mortality of HTX patients. Despite a low number of patient samples, the detection of AECAs before and early after HTX could be used as a biomarker for an increased risk of early acute rejection in high-risk patients. This easy method might be a valuable tool to support screening procedures to improve individualized immunosuppressive therapy. PMID- 25820660 TI - Effects of self-compassion workbook training on trauma-related guilt in a sample of homeless veterans: a pilot study. AB - OBJECTIVE: The present pilot study examined the effects of a 4-week-long self administered self-compassion training on trauma-related guilt and compared it to a stress inoculation control group. METHOD: A total of 47 homeless male veterans who were living in transitional housing facilities volunteered to participate in this study. Participants were randomly assigned to either a self-compassion (N = 13) or a stress inoculation (N = 14) group and were asked to complete pre-, mid-, and postintervention assessments measuring changes in self-compassion, trauma related guilt, and posttraumatic stress disorder severity. RESULTS: Participants in both interventions reported increased levels of self-compassion and equal reductions in trauma-related guilt. No other significant changes were noted. CONCLUSIONS: The results from this pilot study provide preliminary evidence for the use of self-compassion and stress inoculation trainings as effective interventions for trauma-related guilt. The findings also suggest that self administered trainings in the form of workbooks may be a viable, cost-effective form of intervention for disadvantaged populations, such as homeless veterans in transitional housing, who may lack resources or access to professionals or paraprofessionals. The effects of both self-compassion training and stress inoculation training on the study variables and directions for future research on self-compassion and trauma-related guilt are discussed. PMID- 25820658 TI - Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction. AB - Hypertrophic cardiomyopathy (HCM) with systolic dysfunction carries a poor prognosis. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance is associated with adverse cardiac events in HCM and is inversely related to left ventricular ejection fraction (LVEF), it is unknown whether LGE or LVEF more accurately predicts adverse cardiac events in HCM with systolic dysfunction. We retrospectively assessed the extent of LGE with a threshold of 6 standard deviations in 46 consecutive HCM patients with systolic dysfunction defined as LVEF <50 % (average 35 +/- 12 %) who underwent cardiac magnetic resonance (35 males, mean age 59 +/- 14 years). They were followed up over 1755 +/- 594 days. The composite adverse cardiac events end point included cardiovascular death, lethal arrhythmia, cardioembolic stroke, and unplanned heart failure hospitalization. LGE was detected in all patients, and the mean extent was 30 +/- 15 %. Twenty-nine patients developed adverse cardiac events. Multivariate Cox proportional hazard analysis revealed the extent of LGE as a good independent predictor of adverse cardiac events. Risk increased with the extent of LGE (hazard ratio = 1.62/10 % increase in LGE, 95 % confidence interval = 1.23-2.15, p < 0.001). LVEF was inversely related to the extent of LGE (r = 0.44; p = 0.002) and was also an independent predictor of adverse cardiac events. Risk decreased with LVEF (hazard ratio = 0.68/10 % increase in LVEF, 95 % confidence interval = 0.51-0.91, p = 0.010). The Akaike information criterion evaluating the fit of a model demonstrated that the extent of LGE was a better independent predictor of MACE than LVEF (Akaike information criterion = 172.20 and 178.09, respectively).The extent of LGE was a good independent predictor of adverse cardiac events and reflected mortality and morbidity more precisely than LVEF in HCM with systolic dysfunction. PMID- 25820661 TI - Routine iron supplementation and screening for iron deficiency anemia in pregnancy: a systematic review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Routine screening and supplementation for iron deficiency anemia (IDA) in asymptomatic, nonanemic pregnant women could improve maternal and infant health outcomes. PURPOSE: Update of a 2006 systematic review by the U.S. Preventive Services Task Force on screening and supplementation for IDA in pregnancy. DATA SOURCES: MEDLINE and the Cochrane Library (1996 to August 2014) and reference lists of relevant systematic reviews to identify studies published since 1996. STUDY SELECTION: English-language trials and controlled observational studies about effectiveness of screening and routine supplementation for IDA in developed countries. DATA EXTRACTION: Data extraction and quality assessment confirmed and dual-rated by a second investigator using prespecified criteria. DATA SYNTHESIS: No study directly compared clinical outcomes or harms of screening or not screening pregnant women for IDA. Twelve supplementation trials were included, and no controlled observational studies met inclusion criteria. On the basis of 11 trials, routine maternal iron supplementation had inconsistent effects on rates of cesarean delivery, small size for gestational age, and low birthweight and no effect on maternal quality of life, gestational age, Apgar scores, preterm birth, or infant mortality. Twelve trials reported improvements in maternal hematologic indices, although not all were statistically significant. Pooled analysis of 4 trials resulted in a statistically significant difference in IDA incidence at term, favoring supplementation (risk ratio, 0.29 [95% CI, 0.17 to 0.49]; I2 = 0%). Maternal iron supplementation did not affect infant iron status at 6 months. Harms, none of which were serious or had long-term consequences, were inconsistently reported in 10 of the trials, with most finding no difference between groups. LIMITATIONS: Data from trials in countries with limited generalizability to U.S. populations were included. Studies were methodologically heterogeneous, and some were small and underpowered. CONCLUSION: There is inconclusive evidence that routine prenatal supplementation for IDA improves maternal or infant clinical health outcomes, but supplementation may improve maternal hematologic indices. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 25820662 TI - Comparing Motor Skills in Autism Spectrum Individuals With and Without Speech Delay. AB - Movement atypicalities in speed, coordination, posture, and gait have been observed across the autism spectrum (AS) and atypicalities in coordination are more commonly observed in AS individuals without delayed speech (DSM-IV Asperger) than in those with atypical or delayed speech onset. However, few studies have provided quantitative data to support these mostly clinical observations. Here, we compared perceptual and motor performance between 30 typically developing and AS individuals (21 with speech delay and 18 without speech delay) to examine the associations between limb movement control and atypical speech development. Groups were matched for age, intelligence, and sex. The experimental design included: an inspection time task, which measures visual processing speed; the Purdue Pegboard, which measures finger dexterity, bimanual performance, and hand eye coordination; the Annett Peg Moving Task, which measures unimanual goal directed arm movement; and a simple reaction time task. We used analysis of covariance to investigate group differences in task performance and linear regression models to explore potential associations between intelligence, language skills, simple reaction time, and visually guided movement performance. AS participants without speech delay performed slower than typical participants in the Purdue Pegboard subtests. AS participants without speech delay showed poorer bimanual coordination than those with speech delay. Visual processing speed was slightly faster in both AS groups than in the typical group. Altogether, these results suggest that AS individuals with and without speech delay differ in visually guided and visually triggered behavior and show that early language skills are associated with slower movement in simple and complex motor tasks. PMID- 25820663 TI - Enhanced piezo-humidity sensing of a Cd-ZnO nanowire nanogenerator as a self powered/active gas sensor by coupling the piezoelectric screening effect and dopant displacement mechanism. AB - Highly sensitive humidity sensing has been realized from a Cd-doped ZnO nanowire (NW) nanogenerator (NG) as a self-powered/active gas sensor. The piezoelectric output of the device acts not only as a power source, but also as a response signal to the relative humidity (RH) in the environment. The response of Cd-ZnO (1 : 10) NWs reached up to 85.7 upon exposure to 70% relative humidity, much higher than that of undoped ZnO NWs. Cd dopant can increase the number of oxygen vacancies in the NWs, resulting in more adsorption sites on the surface of the NWs. Upon exposure to a humid environment, a large amount of water molecules can displace the adsorbed oxygen ions on the surface of Cd-ZnO NWs. This procedure can influence the carrier density in Cd-ZnO NWs and vary the screening effect on the piezoelectric output. Our study can stimulate a research trend on exploring composite materials for piezo-gas sensing. PMID- 25820664 TI - Growth and development of Colorado potato beetle larvae, Leptinotarsa decemlineata, on potato plants expressing the oryzacystatin II proteinase inhibitor. AB - Plant proteinase inhibitors (PIs) are attractive tools for crop improvement and their heterologous expression can enhance insect resistance in transgenic plants. PI oryzacystatin II (OCII), isolated from rice, showed potential in controlling pests that utilize cysteine proteinases for protein digestion. To evaluate the applicability of the OCII gene in enhancing plant defence, OCII-transformed potatoes were bioassayed for resistance to Colorado potato beetle (Leptinotarsa decemlineata Say). Feeding on transformed leaves of potato cultivars Desiree and Jelica significantly affected larval growth and development, but did not change mortality rates. During the L2 and L3 developmental stages larvae consumed the OCII-transformed foliage faster as compared to the nontransformed control. Also these larvae reached the prepupal stage (end of L4 stage) 2 days earlier than those fed on control leaves. However, the total amounts of consumed OCII transformed leaves were up to 23% lower than of control, and the maximal weights of prepupal larvae were reduced by up to 18% as compared to larvae fed on nontransformed leaves. The reduction in insect fitness reported in this study in combination with other control measures, could lead to improved CPB resistance management in potato. PMID- 25820666 TI - Organomagnesium-catalyzed isomerization of terminal alkynes to allenes and internal alkynes. AB - Organomagnesium complexes 2 were synthesized from N,N-dialkylamineimine ligands 1 and dibenzylmagnesium by benzylation of the imine moiety. 3-Aryl-1-propynes reacted with 2 to form the corresponding tetraalkynyl complexes, which acted as catalysts for the transformation of these terminal alkynes into allenes and further to internal alkynes under mild conditions. To the best of our knowledge, this example is the first of an organomagnesium-catalyzed isomerization of alkynes. Notably, the reactions proceeded through temporally separated autotandem catalysis, thus allowing the isolation of the allene or internal alkyne species in good yields. Mechanistic experiments suggested that the catalytically active tetraalkynyl complexes consist of a tautomeric mixture of alkynyl-, allenyl-, and propargylmagnesium species. PMID- 25820665 TI - In vitro comparison of three rifampicin loading methods in a reinforced porous beta-tricalcium phosphate scaffold. AB - The antibiotic compound, rifampicin (RFP), was loaded into porous reinforced beta tricalcium phosphate (beta-TCP) scaffolds using three different solution adsorption methods. This resulted in drug delivery systems (DDS) generated by vacuum adsorption (VA), dynamic adsorption (DA), and static adsorption (SA). In vitro examination of the drug loading and release profiles of the DDS indicated that the unit mass of RFP loaded into the scaffold by the VA method (0.44 mg/g) was higher than that achieved by SA (0.42 mg/g) or DA (0.38 mg/g) (P < 0.05). The mechanical strength had no significant change after RFP-loading (P > 0.05). Moreover, there were no significant differences among the mechanical strength of three beta-TCP DDS generated by loading RFP using SA, DA, and VA (P > 0.05). In vitro release testing showed an initial burst release of RFP from the three different DDS within the first 3 h and in the first 51 h, the cumulative release of RFP from VA-DDS, DA-DDS, and SA-DDS had reached 56.2, 83.6, and 88.6 %, respectively. Complete RFP release had occurred from VA-DDS, DA-DDS, and SA-DDS after 23, 17, and 15 days, respectively. As the VA-DDS method showed improved RFP loading and a more sustained drug release, this method is recommended for solution adsorption drug loading into porous beta-TCP scaffolds to form a DDS. PMID- 25820667 TI - Copper Prussian blue analogue: investigation into multifunctional activities for biomedical applications. AB - We have designed and developed stable and biocompatible copper analogues of a Prussian blue (PB) nanoparticle based drug delivery system containing doxorubicin that show selective quenching of fluorescence of doxorubicin compared to PB analogues with other metals and inhibition of cancer cell proliferation, suggesting future potential multifunctional applications in biomedical sciences. PMID- 25820668 TI - Variability of Transcutaneous Oxygen and Carbon Dioxide Pressure Measurements Associated with Sensor Location. AB - Transcutaneous measurement of oxygen and carbon dioxide pressure (PtcO2 and PtcCO2) is useful in gas exchange monitoring. However, the relationship between PtcO2, pulse oximetry (SaO2) and arterial blood gases (ABG) is unclear. The aim of the present study was to compare PtcO2 and PtcCO2 with SaO2 and ABG, to evaluate the effect of sensor location on the results and stability of PtcO2 and PtcCO2, and to assess the impact of body composition on PtcO2 and PtcCO2. PtcO2 and PtcCO2 were measured in 20 healthy volunteers at three locations: right second intercostal space, lateral surface of the abdomen, and the inner surface of the left arm. The results were recorded 10, 15, and 20 min after sensor fixation and compared with SaO2 and ABG measured 20 min after electrode placement on the chest. Body composition was evaluated by bioimpedance. The findings were that PtcO2 was stable on the chest; but on the arm and abdomen it increased and reached maximum at 20 min. Transcutaneous PCO2 stabilized at 10 min in all the three locations. No significant correlations between PtcO2 and SaO2 or PaO2 were found. Transcutaneous PCO2 correlated with PaCO2. Both PtcO2 and PtcCO2 were not influenced by body composition. We conclude that the value of PtcO2 in monitoring of blood oxygenation was not unequivocally confirmed; PtcCO2 reliably reflects PaCO2, irrespective of sensor location. Body composition does not affect PtcO2 and PtcCO2. PMID- 25820669 TI - The Prevalence of Oral Inflammation Among Denture Wearing Patients with Chronic Obstructive Pulmonary Disease. AB - Oral inflammation is an important contributor to the etiology of chronic obstructive pulmonary disease, which can impact patient's health status. Previous studies indicate that people with poor oral health are at higher risk for nosocomial pneumonia. Denture wearing is one promoting factor in the development of mucosal infections. Colonization of the denture plaque by Gram-negative bacteria, Candida spp., or other respiratory pathogens, occurring locally, may be aspirated to the lungs. The studies showed that chronic obstructive pulmonary disease (COPD) patients treated with combinations of medicines with corticosteroids more frequently suffer from Candida-associated denture stomatitis. Treatment of oral candidiasis in patients with COPD constitutes a therapeutic problem. Therefore, it is essential to pay attention to the condition of oral mucosal membrane and denture hygiene habits. The guidelines for care and maintenance of dentures for COPD patients are presented in this paper. The majority of patients required improvement of their prosthetic and oral hygiene. Standard oral hygiene procedures in relation to dentures, conducted for prophylaxis of stomatitis complicated by mucosal infection among immunocompromised patients, are essential to maintain healthy oral tissues. The elimination of traumatic denture action in dental office, compliance with oral and denture hygiene, proper use and storage of prosthetic appliances in a dry environment outside the oral cavity can reduce susceptibility to infection. Proper attention to hygiene, including brushing and rinsing the mouth, may also help prevent denture stomatitis in these patients. PMID- 25820670 TI - Central and peripheral irisin differentially regulate blood pressure. AB - INTRODUCTION: Irisin is a newly identified 112 amino acid hormone, derived as a product of fibronectin type III domain containing 5 (FNDC5), which is highly related to metabolic activity in skeletal muscle and brown fat. The effects of irisin on cardiovascular functions are unknown. PURPOSE: To explore the effects of central and peripheral irisin on cardiovascular functions. METHODS: Irisin was either administrated into 3rd ventricle of rats or intravenously, and its effects on blood pressure and cardiac contractibility measured. RESULTS: Administration of recombinant human irisin into the 3rd brain ventricle of rats activated neurons in the paraventricular nuclei of the hypothalamus. Central administration of irisin increased blood pressure and cardiac contractibility. Exogenous irisin reversed atenolol-induced inhibition of cardiac contractibility. In contrast, peripheral administration of irisin reduced blood pressure in both control and spontaneously hypertensive rats. Irisin dilated mesenteric artery rings through ATP-sensitive potassium channels. CONCLUSION: Our studies indicate that central and peripheral irisin may differentially regulate cardiovascular activities. PMID- 25820671 TI - Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study. AB - Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition, and pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine, and dopamine were studied in numerous works; however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialysis and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norpeinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders. PMID- 25820672 TI - Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria. AB - The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Delta(9) tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Delta(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation. PMID- 25820673 TI - Human pericytes isolated from adipose tissue have better differentiation abilities than their mesenchymal stem cell counterparts. AB - Multi-potent mesenchymal stem/progenitor cells are present in almost all organs and tissues, although their identity remains elusive. Several isolation strategies have been pursued to identify these cells prospectively, leading to the isolation of various cell populations endowed with multi-lineage mesodermal potential. Historically, mesenchymal stem cells (MSCs) were the first cell population to be isolated from the stromal fraction of most connective tissues. These cells are able to differentiate towards various mesodermal lineages and are currently the most studied adult mesodermal progenitors. Recently, the isolation of a subpopulation of microvascular pericytes (PCs) endowed with multi-lineage mesodermal potential has led to the identification of mesenchymal progenitors that reside in a defined anatomical location, namely the wall of small blood vessels. To gain insight into these two related cell populations, we performed a detailed analysis of the mesodermal potential of isogenic human MSCs and PCs isolated from white adipose tissue. Although both cell populations expressed known mesodermal markers at similar levels and displayed a comparable growth rate, PCs differentiated towards osteocytes, adipocytes and myocytes more efficiently than their MSC counterparts, as revealed by both histological and molecular assays. Our results show that microvascular PCs are more prone to mesenchymal differentiation than MSCs and therefore represent a preferable source of human adult mesenchymal progenitors when adipose tissue is used as a cell source. PMID- 25820674 TI - Biodistribution and radiation dosimetry of (82)Rb at rest and during peak pharmacological stress in patients referred for myocardial perfusion imaging. AB - PURPOSE: (82)Rb is an ultra-short-lived positron emitter used for myocardial blood flow quantification with PET imaging. The aim of this study was to quantify the biodistribution and radiation dosimetry in patients with coronary disease and in healthy normal volunteers. METHODS: A total of 30 subjects, 26 patients with known or suspected coronary artery disease (CAD) and four healthy volunteers were injected with (82)Rb chloride at 10 MBq/kg followed by a 10-min dynamic PET scan. Chest scans at rest were acquired in all subjects, as well as one additional biodistribution scan of the head, neck, abdomen, pelvis or thighs. Chest scans under stress were acquired in 25 of the CAD patients. (82)Rb time-integrated activity coefficients were determined in 22 source organs using volume of interest analysis, including corrections for partial-volume losses. The mean time integrated activity coefficients were used to calculate the whole-body effective dose using tissue weighting factors from the International Commission on Radiological Protection (ICRP) Publications 60 and 103. RESULTS: A total of 283 organ time-integrated activity coefficients were calculated, with a minimum of four values per source organ. The rest and stress mean effective dose was 0.8 mSv/GBq, according to the most recent ICRP definition. Using 10 MBq/kg for 3D PET imaging, the effective dose to a gender-averaged reference person (60 kg female and 73 kg male) is 1.1 mSv for a complete rest and stress perfusion study. For 2D PET using a typical injected activity of 1.1 to 2.2 GBq each for rest and stress, the effective dose for a complete study is 1.8 to 3.5 mSv. CONCLUSION: The current effective dose estimate in CAD patients is four times lower than the values reported previously by the ICRP, and about 35% lower than previous in vivo studies in young healthy subjects. PMID- 25820675 TI - Brain (18)F-DOPA PET and cognition in de novo Parkinson's disease. AB - PURPOSE: The role of mesocortical dopaminergic pathways in the cognitive function of patients with early Parkinson's disease (PD) needs to be further clarified. METHODS: The study groups comprised 15 drug-naive patients with de novo PD and 10 patients with essential tremor (controls) who underwent (18)F-DOPA PET (static acquisition, normalization on mean cerebellar counts) and an extended neuropsychological test battery. Factor analysis with varimax rotation was applied to the neuropsychological test scores, to yield five factors from 16 original scores, which explained 82 % of the total variance. Correlations between cognitive factors and (18)F-DOPA uptake were assessed with SPM8, taking age and gender as nuisance variables. RESULTS: (18)F-DOPA uptake was significantly lower in PD patients than in controls in the bilateral striatum, mainly in the more affected (right) hemisphere, and in a small right temporal region. Significant positive correlations were found only in PD patients between the executive factor and (18)F-DOPA uptake in the bilateral anterior cingulate cortex (ACC) and the middle frontal gyrus, between the verbal fluency factor and (18)F-DOPA uptake in left BA 46 and the bilateral striatum, and between the visuospatial factor and (18)F-DOPA uptake in the left ACC and bilateral striatum. No correlations were found between (18)F-DOPA uptake and either the verbal memory factor or the abstraction-working memory factor. CONCLUSION: These data clarify the role of the mesocortical dopaminergic pathways in cognitive function in early PD, highlighting the medial frontal lobe, anterior cingulate, and left BA 46 as the main sites of cortical correlation with executive and language functions. PMID- 25820676 TI - MicroRNA-494 is a master epigenetic regulator of multiple invasion-suppressor microRNAs by targeting ten eleven translocation 1 in invasive human hepatocellular carcinoma tumors. AB - Vascular invasion provides a direct route for tumor metastasis. The degree to which microRNA (miRNA) expression plays a role in tumor vascular invasion is unclear. Here, we report that miR-494 is up-regulated in human hepatocellular carcinoma (HCC) tumors with vascular invasion and can promote HCC cell invasiveness by gene inactivation of multiple invasion-suppressor miRNAs. Our results show that ten eleven translocation (TET) methylcytosine dioxygenase, predominantly TET1 in HCC cells, is a direct target of miR-494. The reduced 5' hydroxymethylcytosine levels observed in the proximal cytosine-phosphate-guanine (CpG) regions of multiple invasion-suppressor miRNA genes are strongly associated with their transcriptional repression upon miR-494 overexpression, whereas enforced DNA demethylation can abolish the repression. Furthermore, TET1 knockdown shows a similar effect as miR-494 overexpression. Conversely, miR-494 inhibition or enforced TET1 expression is able to restore invasion-suppressor miRNAs and inhibit miR-494-mediated HCC cell invasion. CONCLUSIONS: miR-494 can trigger gene silencing of multiple invasion-suppressor miRNAs by inhibiting genomic DNA demethylation by direct targeting of TET1, thereby leading to tumor vascular invasion. PMID- 25820677 TI - Organization of left-right coordination of neuronal activity in the mammalian spinal cord: Insights from computational modelling. AB - KEY POINTS: Coordination of neuronal activity between left and right sides of the mammalian spinal cord is provided by several sets of commissural interneurons (CINs) whose axons cross the midline. Genetically identified inhibitory V0D and excitatory V0V CINs and ipsilaterally projecting excitatory V2a interneurons were shown to secure left-right alternation at different locomotor speeds. We have developed computational models of neuronal circuits in the spinal cord that include left and right rhythm-generating centres interacting bilaterally via three parallel pathways mediated by V0D , V2a-V0V and V3 neuron populations. The models reproduce the experimentally observed speed-dependent left-right coordination in normal mice and the changes in coordination seen in mutants lacking specific neuron classes. The models propose an explanation for several experimental results and provide insights into the organization of the spinal locomotor network and parallel CIN pathways involved in gait control at different locomotor speeds. ABSTRACT: Different locomotor gaits in mammals, such as walking or galloping, are produced by coordinated activity in neuronal circuits in the spinal cord. Coordination of neuronal activity between left and right sides of the cord is provided by commissural interneurons (CINs), whose axons cross the midline. In this study, we construct and analyse two computational models of spinal locomotor circuits consisting of left and right rhythm generators interacting bilaterally via several neuronal pathways mediated by different CINs. The CIN populations incorporated in the models include the genetically identified inhibitory (V0D ) and excitatory (V0V ) subtypes of V0 CINs and excitatory V3 CINs. The model also includes the ipsilaterally projecting excitatory V2a interneurons mediating excitatory drive to the V0V CINs. The proposed network architectures and CIN connectivity allow the models to closely reproduce and suggest mechanistic explanations for several experimental observations. These phenomena include: different speed-dependent contributions of V0D and V0V CINs and V2a interneurons to left-right alternation of neural activity, switching gaits between the left-right alternating walking-like activity and the left-right synchronous hopping-like pattern in mutants lacking specific neuron classes, and speed-dependent asymmetric changes of flexor and extensor phase durations. The models provide insights into the architecture of spinal network and the organization of parallel inhibitory and excitatory CIN pathways and suggest explanations for how these pathways maintain alternating and synchronous gaits at different locomotor speeds. The models propose testable predictions about the neural organization and operation of mammalian locomotor circuits. PMID- 25820678 TI - DNA methylation and physio-biochemical analysis of chickpea in response to cold stress. AB - Cold stress (CS) signals are translated into physiological changes as products of direct and/or indirect of gene expression regulated by different factors like DNA methylation. In this study, some of these factors were comparatively studied in two chickpea (Cicer arietinum L.) genotypes (Sel96Th11439, cold-tolerant genotype, and ILC533, cold susceptible one) under control (23 degrees C) and days 1, 3, and 6 after exposing the seedlings to CS (4 degrees C). Under CS, tolerant genotype prevented H2O2 accumulation which led to a decrease in damage indices (malondialdehyde and electrolyte leakage index) compared to susceptible one. The significant activities of antioxidant enzymes (superoxide dismutase, catalase, ascorbate peroxidase, guaiacol peroxidase, and polyphenol oxidase) along with a significant proportion of change in DNA methylation/demethylation patterns were often effective factors in preserving cell against cold-induced oxidative stress. Chickpea cells in response to CS changed access to their genome as the number of bands without change from day 1 to day 6 of exposure to CS particularly in tolerant genotype was decreased. During CS, the methylation level was higher compared to demethylation (29.05 vs 19.79 %) in tolerant genotype and (27.92 vs 22.09 %) in susceptible one. However, for prolonged periods of CS, changes in demethylated bands in tolerant genotype were higher than that of in susceptible one (9.24 vs 4.13 %), indicating higher potential for activation of CS responsive genes. Such a status along with higher activity of antioxidants and less damage indices could be related to cold tolerance (CT) mechanisms in chickpea. Sequencing analysis confirmed the important role of some specific DNA sequences in creating CT with possible responsive components involved in CS. Thus, dynamic assessment using multi-dimensional approaches allows us to progressively fill in the gaps between physio-biochemical and molecular events in creating CT, to comprehend better the nature of the plant stress response and molecular mechanisms behind. PMID- 25820679 TI - Loss of centromeric histone H2AT120 phosphorylation accompanies somatic chromosomes inactivation in the aberrant spermatocytes of Acricotopus lucidus (Diptera, Chironomidae). AB - In the germ line of the chironomid Acricotopus lucidus, two cells with quite different chromosome constitutions result from the last unequal gonial mitosis. In the male, the future primary spermatocyte receives all the germ line-limited chromosomes (=Ks) together with somatic chromosomes (=Ss), and later on undergoes meiotic divisions, while the connected aberrant spermatocyte gets only Ss and remains undivided with chromosomes inactivated in a metaphase-like condensed state. This raises the question whether the centromeres of the permanently condensed Ss of the aberrant spermatocyte remain active during meiosis of the connected regular spermatocyte. Active centromeres exhibit an epigenetic phosphorylation mark at threonine 120 of histone H2A. To visualise the centromeric H2A phosphorylation of the Ss in the aberrant spermatocyte, meiotic stages were immunostained with different anti-phospho histone H2AT120 antibodies. Clear H2AT120ph signals appear at the centromeres of the Ss during prophase, persist on the metaphase-like condensed Ss during meiosis I of the connected primary spermatocyte and disappear during transition to meiosis II. The centromeres of the Ss and Ks of the regular spermatocytes display H2AT120ph signals from prophase I to anaphase II. The loss of the H2AT120 phosphorylation detected on the centromeres of the Ss of the aberrant spermatocyte indicating their deactivation supports the idea of a programmed inactivation of the Ss to block the entry of the germ line-derived aberrant spermatocyte, lacking Ks, into meiosis, and thus to prevent the generation of sperms possessing only Ss. This mechanism would ensure the presence of the Ks in the germ line. PMID- 25820680 TI - Clinical picture and risk prediction of short-term mortality in cardiogenic shock. AB - AIMS: The aim of this study was to investigate the clinical picture and outcome of cardiogenic shock and to develop a risk prediction score for short-term mortality. METHODS AND RESULTS: The CardShock study was a multicentre, prospective, observational study conducted between 2010 and 2012. Patients with either acute coronary syndrome (ACS) or non-ACS aetiologies were enrolled within 6 h from detection of cardiogenic shock defined as severe hypotension with clinical signs of hypoperfusion and/or serum lactate >2 mmol/L despite fluid resuscitation (n = 219, mean age 67, 74% men). Data on clinical presentation, management, and biochemical variables were compared between different aetiologies of shock. Systolic blood pressure was on average 78 mmHg (standard deviation 14 mmHg) and mean arterial pressure 57 (11) mmHg. The most common cause (81%) was ACS (68% ST-elevation myocardial infarction and 8% mechanical complications); 94% underwent coronary angiography, of which 89% PCI. Main non-ACS aetiologies were severe chronic heart failure and valvular causes. In-hospital mortality was 37% (n = 80). ACS aetiology, age, previous myocardial infarction, prior coronary artery bypass, confusion, low LVEF, and blood lactate levels were independently associated with increased mortality. The CardShock risk Score including these variables and estimated glomerular filtration rate predicted in-hospital mortality well (area under the curve 0.85). CONCLUSION: Although most commonly due to ACS, other causes account for one-fifth of cases with shock. ACS is independently associated with in-hospital mortality. The CardShock risk Score, consisting of seven common variables, easily stratifies risk of short-term mortality. It might facilitate early decision-making in intensive care or guide patient selection in clinical trials. TRIAL REGISTRATION: NCT01374867. PMID- 25820681 TI - The importance of sensory integration processes for action cascading. AB - Dual tasking or action cascading is essential in everyday life and often investigated using tasks presenting stimuli in different sensory modalities. Findings obtained with multimodal tasks are often broadly generalized, but until today, it has remained unclear whether multimodal integration affects performance in action cascading or the underlying neurophysiology. To bridge this gap, we asked healthy young adults to complete a stop-change paradigm which presented different stimuli in either one or two modalities while recording behavioral and neurophysiological data. Bimodal stimulus presentation prolonged response times and affected bottom-up and top-down guided attentional processes as reflected by the P1 and N1, respectively. However, the most important effect was the modulation of response selection processes reflected by the P3 suggesting that a potentially different way of forming task goals operates during action cascading in bimodal vs. unimodal tasks. When two modalities are involved, separate task goals need to be formed while a conjoint task goal may be generated when all stimuli are presented in the same modality. On a systems level, these processes seem to be related to the modulation of activity in fronto-polar regions (BA10) as well as Broca's area (BA44). PMID- 25820682 TI - Two-years results of native tissue versus vaginal mesh repair in the treatment of anterior prolapse according to different success criteria: A randomized controlled trial. AB - AIMS: To compare efficacy and safety of the traditional colporraphy and transvaginal polypropylene mesh for the treatment of advanced anterior vaginal prolapse according to different success criteria in two-year follow-up. METHODS: In this randomized controlled trial, women with anterior prolapse stage II or greater, with Ba point >= +1 (POP-Q quantification), were randomly assigned to have either anterior colporraphy (n = 43) or transvaginal mesh repair (n = 43). The primary outcome was to compare objective success rate under two success definitions: prolapse stage I (Ba < -1) and stage II (Ba < 0). Secondary outcomes included complications and prolapse symptoms, satisfaction and quality of life (QoL). Intention to treat was used for the primary endpoint and per protocol analysis for the secondary outcomes. RESULTS: The groups presented similar preoperative data. Thirty three patients from the colporraphy and 37 from the mesh groups completed two-year follow-up. Under Ba < -1 definition, success rate was 39.53% for both groups (P = 1.00). Considering success as Ba < 0, analysis favored the mesh group by 23% (51.16% and 74.42%; 95% CI for difference: 3-43%; P = 0.022). Patients from the mesh group were more satisfied after two years (81.8% and 97.3% for colporraphy and mesh, respectively, 15.5% difference; 95% CI for difference 1-29%; P = 0.032). Both procedures similarly improved women's symptoms and QoL. Some complications were observed, one being a 13.5% mesh exposure rate. CONCLUSIONS: Transvaginal synthetic mesh repair for advanced anterior vaginal prolapse provided higher anatomical success and satisfaction rates compared with traditional colporraphy. Both procedures equally improved quality of life. Neurourol. Urodynam. 35:509-514, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25820684 TI - Does anatomy explain the origin of a leak after sleeve gastrectomy. PMID- 25820683 TI - Systematic review and meta-analysis of objective and subjective quality of life among pediatric, adolescent, and young adult bone tumor survivors. AB - BACKGROUND: Pediatric, adolescent, and young adult survivors of bone sarcomas are at risk for poor quality of life (QOL). We conducted a systematic review and meta analysis to summarize the literature describing QOL in this population and differences in QOL based on local control procedures. PROCEDURE: Included studies described >=5 patients <25 years old who had completed local control treatment for bone sarcoma, defined QOL as a main outcome, and measured it with a validated instrument. Data extraction and quality assessments were conducted with standardized tools. Meta-analyses compared QOL based on surgical procedure (limb sparing vs. amputation) and were stratified by assessment type (objective physical function, clinician-assessed disability, patient-reported disability, and patient-reported QOL). Effect sizes were reported as the standard mean difference when multiple instruments were used within a comparison and weighted mean difference otherwise. All were weighted by inverse variance and modeled with random effects. RESULTS: Twenty-two of 452 unique manuscripts were included in qualitative syntheses, eight of which were included in meta-analyses. Manuscripts were heterogeneous with respect to included patient populations (age, tumor type, time since treatment) and QOL instruments. Prospective studies suggested that QOL improves over time, and that female sex and older age at diagnosis are associated with poor QOL. Meta-analyses showed no differences in outcomes between patients who underwent limb-sparing versus amputation for local control. CONCLUSION: QOL studies among children and AYAs with bone sarcoma are remarkably diverse, making it difficult to detect trends in patient outcomes. Future research should focus on standardized QOL instruments and interpretations. PMID- 25820685 TI - An evaluation of a high-pressure (11)CO carbonylation apparatus. AB - [(11)C]Carbon monoxide ((11)CO) is a versatile building block for the synthesis of Positron Emission Tomography (PET) radioligands. However, the difficulty of trapping (11)CO in a small solvent volume has limited its utility. We here report an evaluation of a simple, fully automated high-pressure synthesizer prototype for the use in (11)C-carbonylation reactions. [(11)C]Carbon monoxide was easily prepared by online reduction of [(11)C]carbon dioxide using either Mo(s) or Zn(s) as the reducing agent. The conversion yield of (11)CO was >99% when zinc was used as the reducing agent, and the corresponding value for Mo was approximately 71%. When the Zn or Mo column was constantly kept under inert atmosphere, no significant decrease in reducing properties was observed for more than 100 (11)CO productions. However, in our hands, Mo reductant was much easier to service. A total of nine functional groups were successfully radiolabeled using the (11)CO synthesizer prototype. All measured radiochemical yields exceeded 37%, and the (11)CO trapping efficiency was generally above 90%, except for the Suzuki coupling where the trapping efficiency was 80%. This high-pressure synthesizer using [(11)C]carbon monoxide as the labeling precursor is easy to operate allowing for (11)C-carbonylation reactions to be performed in a high yield and in a routinely fashion. PMID- 25820686 TI - Metabolic and biological profile of autochthonous Vitis vinifera L. ecotypes. AB - Vitis vinifera L. is a plant species rich in phenolic compounds that are usually associated with the health benefits of wine and grape consumption in the diet. Anthocyanins, catechins, flavonol, phenolic acids and stilbenes are key molecular constituents of the Vitis berries, affecting the quality of grape products. The purpose of this work was to identify the metabolic profiles of 37 genetically certified V. vinifera Latial accessions. In particular, qualitative and quantitative analyses of specific secondary metabolites and total phenolic and tannin contents were performed by LC-MS and spectrophotometric analysis. In addition, since plant molecules are well-known for their free radical scavenging properties, the antioxidant effects of the sample extracts were evaluated through two different antiradical assays: DPPH and FRAP tests. Finally, a preliminary screening of the antiproliferative activity of each specimen on HCT-116 human colorectal cancer cells was conducted. All the results showed a great variety and amount of phenolic compounds in all accessions; moreover, we observed a significant correlation in the extracts between the metabolite concentration and bioactivity. Besides, some samples presented extraordinary biological effects, such as reduction of tumor cell growth not associated with cytotoxicity, supporting their use as possible future adjuvants for cancer therapy. In conclusion, the present research increased the scientific knowledge about Italian autochthonous vine ecotypes in order to valorize them and support their reintroduction in the local economic system. PMID- 25820687 TI - Post-treatment-Free Solution-Processed Non-stoichiometric NiO(x) Nanoparticles for Efficient Hole-Transport Layers of Organic Optoelectronic Devices. PMID- 25820688 TI - Mutation rate analysis at 19 autosomal microsatellites. AB - Previous studies have demonstrated that a large sample size is needed to reliably estimate population- and locus-specific microsatellite mutation rates. Therefore, we conducted a long-term collaboration study and performed a comprehensive analysis on the mutation characteristics of 19 autosomal short tandem repeat (STR) loci. The STR loci located on 15 of 22 autosomal chromosomes were analyzed in a total of 21,106 samples (11,468 parent-child meioses) in a Chinese population. This provided 217,892 allele transfers at 19 STR loci. An overall mutation rate of 1.20 * 10(-3) (95% CI, 1.06-1.36 * 10(-3) ) was observed in the populations across 18 of 19 STR loci, except for the TH01 locus with no mutation found. Most STR mutations (97.7%) were single-step mutations, and only a few mutations (2.30%) comprised two and multiple steps. Interestingly, approximately 93% of mutation events occur in the male germline. The mutation ratios increased with the paternal age at child birth (r = 0.99, p<0.05), but not maternal age. Last, with the combination analysis of the data from the southern Chinese population, we drew a picture of 19 STR mutations in China. In conclusion, the data from this study will provide useful information in parentage testing, kinship analysis, and population genetics. PMID- 25820689 TI - GPR30 Mediates the Fast Effect of Estrogen on Mouse Blastocyst and its Role in Implantation. AB - Our previous work demonstrated that estrogen could rapidly increase intracellular Ca(2+) in dormant mouse blastocysts. The purpose of the present study is to investigate the physiological relevance of G protein-coupled receptor 30 (GPR30) in the fast effect of estrogen on mouse blastocyst and in embryo implantation. We used reverse transcription-polymerase chain reaction, immunofluorescence, embryo coculture with Ishikawa uterine epithelial cell line, and embryo transfer technology to detect the expression of GPR30 in mouse embryos and the nongenomic effects of estrogen via GPR30 on blastocyst. We found that GPR30 is expressed in the mouse blastocyst, and its location is mostly consistent with the binding site of estrogen. Both estrogen and GPR30-specific agonist G-1 rapidly increase the intracellular Ca(2+) and phospholipase C activation in blastocyst cells, while GPR30-specific antagonist G-15 blocked this effect of estrogen. The pretreatment of G-15 on blastocysts lead to a lower attachment rate and implantation rate. Our data collectively suggested that GPR30 can mediate the fast effect of estrogen on blastocysts and play an important role in embryo implantation. PMID- 25820690 TI - H3K27me3 is an Epigenetic Mark of Relevance in Endometriosis. AB - Epigenetic mechanisms may play an important role in the etiology of endometriosis. The modification of histones by methylation of lysine residues has been shown to regulate gene expression by changing chromatin structure. We have previously shown that endometriotic lesions had aberrant levels of histone acetylation (lower) and methylation (higher) than control tissues. We aimed to determine the levels of trimethylated histone 3 at lysine residue 27 (H3K27me3), a well-known repressive mark, by immunoassay of fresh tissues and immunohistochemistry (IHC) of an endometriosis-focused tissue microarray. Also, we aimed to determine levels of expression of enhancer of zeste homolog 2 (EZH2), the enzyme responsible for trimethylation of H3K27me3, in cell lines. Average levels of H3K27me3 measured by immunoassay were not significantly different in lesions compared to endometrium from patients and controls. However, there was a trend of higher levels of H3K27me3 in secretory versus proliferative endometrium. The results of IHC showed that lesions (ovarian, fallopian, and peritoneal) and secretory endometrium from controls have higher percentage of H3K27me3-positive nuclei than eutopic endometrium from patients. Endometriotic epithelial cells express high levels of EZH2, which is upregulated by progesterone. This study provides evidence in support of a role of H3K27me3 in the pathogenesis of endometriosis and for EZH2 as a potential therapeutic target for this disease, but more studies are necessary to understand the molecular mechanisms at play. PMID- 25820691 TI - Multispectral labeling of embryonic cells with lipophilic carbocyanine dyes. AB - Incubation of hatched Strongylocentrotus purpuratus sea urchin embryos or larvae with suspensions of the carbocyanine dyes DiI, DiO, and DiD resulted in the random labeling of membranes of some ectodermal epithelial cells and blastocoelar cells, producing a range of differentially colored cells that can be tracked during development. Simultaneous application of soluble Vybrant(r) preparations of the three dyes resulted in similar labeling of each cell. Dye labeling of the ectoderm was nearly eliminated by deciliation and some ciliated squamous epithelial cells adjacent to labelled cells were refractory to Vybrant(r) dye uptake irrespective of concentration or duration of treatment, together suggesting local variation in the properties of cell membranes or cilia. Furthermore, single cells possessing distinctive morphological features were detected. PMID- 25820693 TI - Comment on "How to interpret Onsager cross terms in mixed ionic electronic conductors" by I. Riess, Phys. Chem. Chem. Phys., 2014, 16, 22513. AB - Here we show that the Onsager cross terms for ion-electron interactions are not an artifact, but the necessity to phenomenologically and completely describe the mass/charge transport of a mixed ionic-electronic conductor in terms of mobile charged components which are the only experimentally operable species. The use of an appropriate comprehensive defect model may help to reduce the cross terms (which depend on the choice of formal charge of the mobile defects), but it cannot obviate them if long-range Coulombic interactions are in action among the defects. PMID- 25820692 TI - Autoimmune uveitis: clinical, pathogenetic, and therapeutic features. AB - Autoimmune uveitis (AU), an inflammatory non-infectious process of the vascular layer of the eye, can lead to visual impairment and, in the absence of a timely diagnosis and suitable therapy, can even result in total blindness. The majority of AU cases are idiopathic, whereas fewer than 20 % are associated with systemic diseases. The clinical severity of AU depends on whether the anterior, intermediate, or posterior part of the uvea is involved and may range from almost asymptomatic to rapidly sight-threatening forms. Race, genetic background, and environmental factors can also influence the clinical picture. The pathogenetic mechanism of AU is still poorly defined, given its remarkable heterogeneity and the many discrepancies between experimental and human uveitis. Even so, the onset of AU is thought to be related to an aberrant T cell-mediated immune response, triggered by inflammation and directed against retinal or cross-reactive antigens. B cells may also play a role in uveal antigen presentation and in the subsequent activation of T cells. The management of AU remains a challenge for clinicians, especially because of the paucity of randomized clinical trials that have systematically evaluated the effectiveness of different drugs. In addition to topical treatment, several different therapeutic options are available, although a standardized regimen is thus far lacking. Current guidelines recommend corticosteroids as the first-line therapy for patients with active AU. Immunosuppressive drugs may be subsequently required to treat steroid-resistant AU and for steroid-sparing purposes. The recent introduction of biological agents, such as those targeting tumor necrosis factor-alpha, is expected to remarkably increase the percentages of responders and to prevent irreversible sight impairment. This paper reviews the clinical features of AU and its crucial pathogenetic targets in relation to the current therapeutic perspectives. Also, the largest clinical trials conducted in the last 12 years for the treatment of AU are summarized and critically discussed. PMID- 25820694 TI - Maternal age and ovarian stimulation independently affect oocyte mtDNA copy number and cumulus cell gene expression in bovine clones. AB - STUDY QUESTION: Does maternal ageing and ovarian stimulation alter mitochondrial DNA (mtDNA) copy number and gene expression of oocytes and cumulus cells from a novel bovine model for human IVF? SUMMARY ANSWER: Oocytes collected from females with identical nuclear genetics show decreased mtDNA copy number and increased expression of an endoplasmic reticulum (ER) stress gene with repect to ovarian stimulation, whilst differences in the expression of genes involved in mitochondrial function, antioxidant protection and apoptosis were evident in relation to maternal ageing and the degree of ovarian stimulation in cumulus cells. WHAT IS KNOWN ALREADY: Oocyte quality declines with advancing maternal age; however, the underlying mechanism, as well as the effects of ovarian stimulation are poorly understood. Human studies investigating these effects are often limited by differences in age and ovarian stimulation regimens within a patient cohort, as well as genetic and environmental variability. STUDY DESIGN, SIZE, DURATION: A novel bovine cross-sectional maternal age model for human IVF was undertaken. Follicles were aspirated from young (3 years of age; n = 7 females) and old (10 years of age; n = 5 females) Holstein Freisian clones following multiple unstimulated, mild and standard ovarian stimulation cycles. These bovine cloned females were generated by the process of somatic cell nuclear transfer (SCNT) from the same founder and represent a homogeneous population with reduced genetic and environmental variability. Maternal age and ovarian stimulation effects were investigated in relation to mtDNA copy number, and the expression of 19 genes involved in mitochondrial function, antioxidant protection, oocyte-cumulus cell signalling and follicle development in both oocytes and cumulus cells. MATERIALS, SETTING, METHODS: Young (3 years of age; n = 7 females) and old (10 years of age; n = 5 females) Holstein Freisian bovine clones were maintained as one herd. Stimulation cycles were based on the long GnRH agonist down-regulation regimen used in human fertility clinics. Follicle growth rates, numbers and diameters were monitored by ultrasonography and aspirated when the lead follicles were >14 mm in diameter. Follicle characteristics were analysed using a mixed model procedure. Quantitative PCR (qPCR) was used to determine mtDNA copy number and reverse transcriptase-qPCR (RT qPCR) was used to measure gene expression in oocytes and cumulus cells. MAIN RESULTS AND THE ROLE OF CHANCE: Method of ovarian stimulation (P = 0.04), but not maternal age (P > 0.1), was associated with a lower mtDNA copy number in oocytes. Neither factor affected mtDNA copy number in cumulus cells. In oocytes, maternal age had no effect on gene expression; however, ovarian stimulation in older females increased the expression of GRP78 (P = 0.02), a gene involved in ER stress. In cumulus cells, increasing maternal age was associated with the higher expression of genes involved in mitochondrial maintenance (TXN2 P = 0.008 and TFAM P = 0.03), whereas ovarian stimulation decreased the expression of genes involved in mitochondrial oxidative stress and apoptosis (TXN2 P = 0.002, PRDX3 P = 0.03 and BAX P = 0.03). LIMITATIONS, REASON FOR CAUTION: The low number of oocyte and cumulus cell samples collected from the unstimulated cycles limited the analysis. Fertilization and developmental potential of the oocytes was not assessed because these were used for mtDNA and gene expression quantification. WIDER IMPLICATIONS OF THE FINDINGS: Delineation of the independent effects of maternal age and ovarian stimulation regimen on mtDNA copy number gene expression in oocytes and cumulus cells was enabled by the removal of genetic and environmental variability in this bovine model for human IVF. Therefore, these extend upon previous knowledge and findings provide relevant insights that are applicable for improving human ovarian stimulation regimens. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by Fertility Associates and the University of Auckland. J.C.P. is a shareholder of Fertility Associates and M.P.G. received a fellowship from Fertility Associates. The other authors of this manuscript declare no conflict of interest that could be perceived as prejudicing the impartiality of the reported research. PMID- 25820695 TI - Estrogen-dependent regulation of human uterine natural killer cells promotes vascular remodelling via secretion of CCL2. AB - STUDY QUESTION: Does intrauterine biosynthesis of estrogen play an important role in early pregnancy by altering the function of uterine natural killer (uNK) cells? SUMMARY ANSWER: Estrogens directly regulate the function of human uNK cells by increasing uNK cell migration and secretion of uNK cell-derived chemokine (C-C motif) ligand 2 (CCL2) that critically facilitates uNK-mediated angiogenesis. WHAT IS KNOWN ALREADY: uNK cells are a phenotypically distinct population of tissue-resident immune cells that regulate vascular remodelling within the endometrium and decidua. Recently we discovered that decidualisation of human endometrial stromal cells results in the generation of an estrogen-rich microenvironment in areas of decidualised endometrium. We hypothesize that intrauterine biosynthesis of estrogens plays an important role in early pregnancy by altering the function of uNK cells. STUDY DESIGN, SIZE, DURATION: This laboratory-based study used primary human uNK cells which were isolated from first trimester human decidua (n = 32). PARTICIPANTS/MATERIALS, SETTING, METHODS: Primary uNK cells were isolated from first trimester human decidua using magnetic cell sorting. The impact of estrogens on uNK cell function was assessed. Isolated uNK cells were treated with estrone (E1, 10(-8) M) or estradiol (E2, 10(-8) M) alone or in combination with the anti-estrogen ICI 182 780 (ICI, 10(-6) M). uNK cell motility was assessed by transwell migration assay and time-lapse microscopy. Expression of chemokine receptors was assessed by quantitative PCR (qPCR) and immunohistochemistry, and angiogenic factors were assessed by qPCR and cytokine array. Concentrations of CCL2 in supernatants were measured by enzyme linked immunosorbent assay. Angiogenesis was assessed in a human endometrial endothelial cell network formation assay. MAIN RESULTS AND THE ROLE OF CHANCE: Treatment with either E1 or E2 increased uNK cell migration (P = 0.0092 and P = 0.0063, respectively) compared with control. Co-administration of the anti estrogen ICI blocked the effects of E1 and E2 on cell migration. Concentrations of C-X-C chemokine receptor type 4 (CXCR4) mRNA in uNK cells were increased by E2 treatment. The network formation assay revealed that conditioned media from uNK cells treated with E2 significantly increased human endometrial endothelial cell (HEEC) angiogenesis (P = 0.0029 versus control). Analysis of media from uNK cells treated with E2 using an antibody array identified CCL2 as the most abundant cytokine. Validation assays confirmed concentrations of CCL2 mRNA and protein were increased by E2 in uNK cells (P < 0.05 versus controls). Compared with the control, recombinant human CCL2 was found to increase HEEC network formation (P < 0.05) and neutralization of CCL2 in uNK conditioned media significantly decreased E2-dependent uNK-mediated network formation (P = 0.0006). LIMITATIONS, REASONS FOR CAUTION: Our results are based on in vitro responses of primary human cells and we cannot be certain that similar mechanisms occur in vivo in humans. Primary human uNK cells were isolated from first trimester decidua at a range of gestations (8-12 weeks), which may be a source of variation. Primary human uNK cells from non-pregnant endometrium were not assessed and therefore the responses of uNK cells to E2 treatment described in this study may be distinct to uNK cells from first trimester decidua. WIDER IMPLICATIONS OF THE FINDINGS: E2 is an essential regulator of reproductive competence. This study demonstrates a critical role for E2 in regulating cellular cross-talk within the endometrium during early pregnancy. We provide the first evidence that E2 directly regulates the function of human uNK cells by altering uNK cell migration and the secretion of uNK-derived angiogenic factors. We describe a novel mechanism of estrogen dependent secretion of CCL2 which critically mediates uNK-dependent endometrial angiogenesis. Dysregulation of uNK cell function has been implicated in the aetiology of early implantation disorders and disorders of pregnancy. These novel findings provide unique insight into the regulation of uNK cell activity during the establishment of pregnancy in women and highlight key processes which may be targeted in future therapeutic strategies. STUDY FUNDING/COMPETING INTERESTS: Studies undertaken in the authors' laboratory were supported by MRC Programme Grant G1100356/1 to P.T.K.S. The authors have no conflicts of interest to disclose. PMID- 25820696 TI - Use of depot medroxyprogesterone acetate and prevalent leiomyoma in young African American women. AB - STUDY QUESTION: Is use of depot medroxyprogesterone acetate (DMPA) a risk factor for or a protective factor against prevalent uterine leiomyoma? SUMMARY ANSWER: Ever use of DMPA was associated with a decreased risk (adjusted risk ratio (RR): 0.8, 95% confidence interval (CI): 0.6, 0.9) of prevalent leiomyoma in young African American women. WHAT IS KNOWN ALREADY: Although progesterone is associated with growth of leiomyoma, previous epidemiological studies have shown a protective association for DMPA use. These previous studies may have been biased by studying clinically diagnosed leiomyoma (DMPA may mask symptoms thus delaying diagnoses). STUDY DESIGN, SIZE, DURATION: Cross sectional analysis of baseline data from a cohort study of 1696 African American women. PARTICIPANTS/MATERIALS, SETTING, METHODS: Community-based recruitment (e.g. letters, flyers, radio and TV announcements) were used to enroll African American women between 23 and 34 years old without a previous diagnosis of leiomyoma in the Metropolitan Detroit area. Extensive questionnaire data were used to determine DMPA use and screening ultrasound detected the presence of leiomyoma >=0.5 cm in diameter. Relative risks with adjustment for covariates were calculated for the presence of leiomyoma based on ever use of DMPA as well as duration and recency of use. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 1696 volunteers who enrolled, 43% had used DMPA. Leiomyoma were detected in 17% of those who had ever used DMPA compared with 26% of those who had never used DMPA. The reduction in prevalence remained after adjustment for potential confounders and was highest among women who had used DMPA for more than 4 years (adjusted RR: 0.5, 95% CI: 0.3, 0.8). The reduction in risk was seen for women whose most recent use was up to 8 years prior to study enrollment. LIMITATIONS, REASONS FOR CAUTION: The use of cross-sectional data means that the timing of initial fibroid development is not known, so the temporality of the association is uncertain. However in this sample of young women, most fibroids were small, suggesting that DMPA exposure may have occurred before leiomyoma development. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in agreement with previous epidemiological studies, but protected from the bias inherent in the use of clinically diagnosed leiomyoma. Although further studies will be needed to elucidate the mechanism, use of DMPA as a contraceptive appears to provide long lasting protection against uterine leiomyoma. STUDY FUNDING/COMPETING INTERESTS: No competing interests. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, and in part by funds allocated for health research by the American Recovery and Reinvestment Act. TRIAL REGISTRATION NUMBER: N/A. PMID- 25820697 TI - Functional expression of transient receptor potential channels in human endometrial stromal cells during the luteal phase of the menstrual cycle. AB - STUDY QUESTION: Are members of the transient receptor potential (TRP) channel superfamily functionally expressed in the human endometrial stroma? SUMMARY ANSWER: The Ca(2+)-permeable ion channels TRPV2, TRPV4, TRPC6 and TRPM7 are functionally expressed in primary endometrial stromal cells. WHAT IS KNOWN ALREADY: Intercellular communication between epithelial and stromal endometrial cells is required to initiate decidualization, a prerequisite for successful implantation. TRP channels are possible candidates as signal transducers involved in cell-cell communication, but no fingerprint is available of the functional distribution of TRP channels in the human endometrium during the luteal phase of the menstrual cycle. STUDY DESIGN, SIZE, DURATION: Endometrial biopsy samples (previously frozen) from patients of reproductive age with regular menstrual cycles, who were undergoing diagnostic laparoscopic surgery for pain and/or infertility, were analysed. Samples were obtained from the menstrual (Days 1-5, n = 3), follicular (Days 6-14, n = 6), early luteal (Days 15-20, n = 5) and late luteal (Days 21-28, n = 5) phases. In addition, a total of 13 patient samples taken during the luteal phase were used to set up primary cell cultures for further experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative real time PCR (qRT-PCR), immunocytochemistry, Fura2-based Ca(2+)-microfluorimetry and whole-cell patch clamp experiments were performed to study the functional expression pattern of TRP channels. Specific pharmacological agents, such as Delta(9)-tetrahydrocannabinol, GSK1016790A and 1-oleoyl-2-acetyl-glycerol, were used to functionally assess the expression of TRPV2, TRPV4 and TRPC6, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Expression of TRPV2, TRPV4, TRPC1, TRPC4, TRPC6, TRPM4 and TRPM7 was detected at the mRNA level in endometrial biopsies (n = 19) and in primary endometrial stromal cell cultures obtained from patients during the luteal phase (n = 5) of the menstrual cycle. Messenger RNA levels of TRPV2, TRPC4 and TRPC6 were significantly increased (P < 0.01) in the late luteal phase compared with the early luteal phase. Immunocytochemistry experiments showed a positive staining for TRPV2, TRPV4, TRPC6 and TRPM7 in the plasma membrane and in the cytoplasm of primary endometrial stromal cells. Ca(2+)-microfluorimetry revealed significant increases (P < 0.001) in intracellular Ca(2+) levels when stromal cells were incubated with specific activators of TRPV2, TRPV4 and TRPC6. Further functional characterization was performed using whole-cell patch clamp experiments. Taken together, these data provide evidence for the functional activity of TRPV2, TRPV4, TRPC6 and TRPM7 channels in primary stromal cell cultures. LIMITATIONS, REASONS FOR CAUTION: Although mRNA levels are detected for TRPV6, TRPC1, TRPC4 and TRPM4, the limited supply of specific antibodies and lack of selective pharmacological agents restricted any additional analysis of these ion channels. WIDER IMPLICATIONS OF THE FINDINGS: Embryo implantation is a dynamic developmental process that integrates many signalling molecules into a precisely orchestrated programme. Our findings identified certain members of the TRP superfamily as candidate sensors in the epithelial-stromal crosstalk. These results are very helpful to unravel the signalling cascade required for successful embryo implantation. In addition, this knowledge could lead to new strategies to correct implantation failure and facilitate the development of novel non-hormonal contraceptives. STUDY FUNDING/ COMPETING INTERESTS: This work was supported by grants from the Research Foundation-Flanders (G.0856.13N to J.V.), the Research Council of the KU Leuven (OT/13/113 to J.V. and T.D. and PF TRPLe to T.V.) and by the Planckaert-De Waele fund (to J.V.). K.D.C. and K.H. are funded by the FWO Belgium. None of the authors have a conflict of interest. PMID- 25820698 TI - Indolo[3,2-c]quinoline G-quadruplex stabilizers: a structural analysis of binding to the human telomeric G-quadruplex. AB - A library of 5-methylindolo[3,2-c]quinolones (IQc) with various substitution patterns of alkyldiamine side chains were evaluated for G-quadruplex (G4) binding mode and efficiency. Fluorescence resonance energy transfer melting assays showed that IQcs with a positive charge in the heteroaromatic nucleus and two weakly basic side chains are potent and selective human telomeric (HT) and gene promoter G4 stabilizers. Spectroscopic studies with HT G4 as a model showed that an IQc stabilizing complex involves the binding of two IQc molecules (2,9-bis{[3 (diethylamino)propyl]amino}-5-methyl-11H-indolo[3,2-c]quinolin-5-ium chloride, 3 d) per G4 unit, in two non-independent but equivalent binding sites. Molecular dynamics studies suggest that end-stacking of 3 d induces a conformational rearrangement in the G4 structure, driving the binding of a second 3 d ligand to a G4 groove. Modeling studies also suggest that 3 d, with two three-carbon side chains, has the appropriate geometry to participate in direct or water-mediated hydrogen bonding to the phosphate backbone and/or G4 loops, assisted by the terminal nitrogen atoms of the side chains. Additionally, antiproliferative studies showed that IQc compounds 2 d (2-{[3-(diethylamino)propyl]amino}-5-methyl 11H-indolo[3,2-c]quinolin-5-ium chloride) and 3 d are 7- to 12-fold more selective for human malignant cell lines than for nonmalignant fibroblasts. PMID- 25820699 TI - Method for identification of rigid domains and hinge residues in proteins based on exhaustive enumeration. AB - Many proteins undergo large-scale motions where relatively rigid domains move against each other. The identification of rigid domains, as well as the hinge residues important for their relative movements, is important for various applications including flexible docking simulations. In this work, we develop a method for protein rigid domain identification based on an exhaustive enumeration of maximal rigid domains, the rigid domains not fully contained within other domains. The computation is performed by mapping the problem to that of finding maximal cliques in a graph. A minimal set of rigid domains are then selected, which cover most of the protein with minimal overlap. In contrast to the results of existing methods that partition a protein into non-overlapping domains using approximate algorithms, the rigid domains obtained from exact enumeration naturally contain overlapping regions, which correspond to the hinges of the inter-domain bending motion. The performance of the algorithm is demonstrated on several proteins. PMID- 25820700 TI - Co-expression of beta-arrestin1 and NF-kB is associated with cancer progression and poor prognosis in lung adenocarcinoma. AB - beta-arrestin1 and NF-kappaB have been demonstrated to be associated with tumorigenesis, tumor progression, and metastasis. Thus far, there is nevertheless little study about these two molecules in lung adenocarcinoma. The aim of this study was to investigate the correlation between beta-arrestin1 and NF-kappaB expression and the clinicopathological characteristics in lung adenocarcinoma. A total of 115 surgically resected lung adenocarcinoma patients were recruited for the study. Expression of beta-arrestin1 and p65 were detected by immunohistochemistry (IHC) in lung adenocarcinoma tissue samples. Nuclear expression of beta-arrestin1 and p65 were observed in 39.1 % (45/115) and 46.1 % (53/115) cases of lung adenocarcinoma, respectively. And high expression of beta arrestin1 had negative prognostic impact for overall survival (OS) and disease free survival (DFS) (p = 0.034 and p = 0.033). In addition, overexpression of p65 indicated a significantly poor OS and DFS than those of lower-expression (p = 0.038 and p = 0.041). Furthermore, co-expression of nuclear beta-arrestin1 and p65 correlated with poorer OS and DFS in lung adenocarcinoma patients. Multivariate analysis using the Cox regression model confirmed that co-expression of nuclear beta-arrestin1 and p65 was an independent prognostic factor for tumor progression (p = 0.008). In conclusion, these data indicated that co-expression of nuclear beta-arrestin1 and p65 was a novel predictor for worse prognosis in patients with lung adenocarcinoma. PMID- 25820701 TI - Decreased expression of claudin-3 is associated with a poor prognosis and EMT in completely resected squamous cell lung carcinoma. AB - The deregulation of claudin-3 has been reported to correlate with the invasion and metastasis of various cancers, but little is known about its expression level and the prognostic value in squamous cell lung carcinoma (SqCC). The purpose of this study is to determine the expression levels and the prognostic value of claudin-3 in completely resected SqCC tissues, and the potential underlying mechanism. The protein expression of claudin-3, E-cadherin, beta-catenin, and vimentin in the tumor tissues from 103 patients with surgically resected SqCC was examined using immunohistochemistry, western blots, as well as semi-quantitative estimation. The claudin-3 protein level was significantly associated with E cadherin, beta-catenin, and vimentin protein expression. A decreased claudin-3 protein level was significantly correlated with TNM stage, lymph node metastasis, and disease recurrence. Similarly, downregulation of E-cadherin was significantly correlated with lymph node metastasis and disease recurrence. Decreased beta catenin expression also had a significant correlation with disease recurrence. Univariate analyses indicated that the T stage, lymph node metastasis, the TNM stage, and the expression of claudin-3, beta-catenin, and vimentin were significant predictors for overall survival (OS). Moreover, multivariate analyses demonstrated that the TNM stage and protein levels of claudin-3, beta-catenin, and vimentin were independent predictors for OS of SqCC patients. Claudin-3 plays an important role in the epithelial-mesenchymal transition of SqCC and might be used as a potential prognostic factor for SqCC. PMID- 25820702 TI - Human tolerogenic dendritic cells produce IL-35 in the absence of other IL-12 family members. AB - IL-35 is a cytokine of the IL-12 family, existing as a heterodimer of IL-12p35 and Ebi3. IL-35 has anti-inflammatory properties and is produced by regulatory T cells in humans and mice, where it is required for optimal suppression of immune responses. Distinct from other IL-12 cytokines, the expression of IL-35 has not been described in antigen-presenting cells. In view of the immune-regulatory properties of IL-35, we investigated the expression, regulation, and function of IL-12p35 and Ebi3 in human monocyte-derived dendritic cells and tolerogenic DCs (tolDCs). These tolDCs do not produce IL-12p70 or the homodimer IL-12p40. We demonstrate that tolDCs completely lack transcriptional expression of IL-12p40. However, tolDCs maintain mRNA expression of IL-12p35 and Ebi3. Using intracellular flow cytometry and Western blot analysis, we show that tolDCs produce Ebi3 and IL-12p35, and both can be enhanced upon stimulation with IFN gamma, LPS, or CD40L. tolDCs supernatants have the capacity to suppress T-cell activation. Using IL12A silencing, we demonstrate that IL-12p35 is required for tolDCs to reach their full suppressive potential. Taken together, our results indicate that tolDCs produce IL-35, providing an additional novel mechanism by which tolDCs elicit their tolerogenic potential. PMID- 25820703 TI - The cost-effectiveness of sofosbuvir-based regimens for treatment of hepatitis C virus genotype 2 or 3 infection. AB - BACKGROUND: Chronic infection with hepatitis C virus (HCV) genotype 2 or 3 can be treated with sofosbuvir without interferon. Because sofosbuvir is costly, its benefits should be compared with the additional resources used. OBJECTIVE: To estimate the cost-effectiveness of sofosbuvir-based treatments for HCV genotype 2 or 3 infection in the United States. DESIGN: Monte Carlo simulation, including deterministic and probabilistic sensitivity analyses. DATA SOURCES: Randomized trials, observational cohorts, and national health care spending surveys. TARGET POPULATION: 8 patient types defined by HCV genotype (2 vs. 3), treatment history (naive vs. experienced), and cirrhosis status (noncirrhotic vs. cirrhotic). TIME HORIZON: Lifetime. PERSPECTIVE: Payer. INTERVENTION: Sofosbuvir-based therapies, pegylated interferon-ribavirin, and no therapy. OUTCOME MEASURES: Discounted quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: The ICER of sofosbuvir-based treatment was less than $100,000 per QALY in cirrhotic patients (genotype 2 or 3 and treatment-naive or treatment-experienced) and in treatment-experienced noncirrhotic patients but was greater than $200,000 per QALY in treatment-naive noncirrhotic patients. RESULTS OF SENSITIVITY ANALYSIS: The ICER of sofosbuvir based therapy for treatment-naive noncirrhotic patients with genotype 2 or 3 infection was less than $100,000 per QALY when the cost of sofosbuvir was reduced by approximately 40% and 60%, respectively. In probabilistic sensitivity analyses, cost-effectiveness conclusions were robust to uncertainty in treatment efficacy. LIMITATION: The analysis did not consider possible benefits of preventing HCV transmission. CONCLUSION: Sofosbuvir provides good value for money for treatment-experienced patients with HCV genotype 2 or 3 infection and those with cirrhosis. At their current cost, sofosbuvir-based regimens for treatment naive noncirrhotic patients exceed willingness-to-pay thresholds commonly cited in the United States. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse and National Institute of Allergy and Infectious Diseases. PMID- 25820704 TI - Antibiotic-impregnated catheters reduce ventriculoperitoneal shunt infection rate in high-risk newborns and infants. AB - PURPOSE: The incidence of ventriculoperitoneal (VP) shunt infection accounts for about 5-15%, but it can rise up to 70% in specific high-risk subgroups. Antibiotic-impregnated catheters (AICs) have been designed to reduce shunt infections, but reports on their efficacy are discordant, especially in young children. The aim of this study is to assess, for the first time, the efficacy of AICs in newborns and infants at very high risk for shunt infection. METHODS: We reviewed the medical records of newborns and infants treated with a VP shunt for newly diagnosed hydrocephalus. Patients were divided in two groups: Group A was composed by children who received AICs, whereas Group B included children implanted with standard silicone catheters (non-AICs). We compared the shunt infection rate in both groups, and analyzed differences in specific high-risk subgroups (preterm newborns, children with posthemorrhagic or postinfective hydrocephalus, and children with a previous external ventricular drainage). RESULTS: Forty eight children younger than 1 year old were included in our study. Twenty two patients were implanted with an AIC, whereas 26 patients received a standard silicone catheter. The follow-up was at least 1 year (mean 8 +/- 3 years). The overall infection rate decreased from 34% in non-AIC group to 9 % in the AIC group. Moreover, AICs showed to have a protective effect against shunt infections in all the specific high-risk subgroups analyzed. CONCLUSIONS: This study demonstrates for the first time that AICs are effective in reducing VP shunt infection in high-risk pediatric patients younger than 1 year old. PMID- 25820705 TI - The Society for Craniofacial Genetics and Developmental Biology 37th annual meeting. PMID- 25820706 TI - Notice of Withdrawal. AB - Notice of Withdrawal: 'Odanacatib restores trabecular bone of skeletally mature female rabbits with osteopenia but induces brittleness of cortical bone: a comparative study of the investigational drug with PTH, Estrogen and Alendronate' by Mohd. Parvez Khan, Atul Kumar Singh, Abhishek Kumar Singh, Pragya Shrivastava, Mahesh Chandra Tiwari, Geet Kumar Nagar, Himangshu Kousik Bora, Venkitanarayanan Parameswaran, Sabyasachi Sanyal, Jayesh R. Bellare and Naibedya Chattopadhyay The above article from the Journal of Bone and Mineral Research, published online on 27 March 2015 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the journal's editor-in-chief, Juliet E. Compston, the American Society for Bone and Mineral Research, and Wiley Periodicals, Inc. This action has been agreed due to an error at the publishers which caused a duplicate of the article to be published on 22 September 2015. The correct version of the article is to be found at: 'Odanacatib restores trabecular bone of skeletally mature female rabbits with osteopenia but induces brittleness of cortical bone: a comparative study of the investigational drug with PTH, Estrogen and Alendronate' by Mohd. Parvez Khan, Atul Kumar Singh, Abhishek Kumar Singh, Pragya Shrivastava, Mahesh Chandra Tiwari, Geet Kumar Nagar, Himangshu Kousik Bora, Venkitanarayanan Parameswaran, Sabyasachi Sanyal, Jayesh R. Bellare and Naibedya Chattopadhyay (doi: 10.1002/jbmr.2719). PMID- 25820707 TI - POEMS syndrome with opticneuritis as initial symptom: a case report. AB - Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes syndrome is a rare paraneoplastic syndrome from a plasma cell dyscrasia, which most commonly presents with peripheral neuropathy. We report a 30-year-old female with blurred vision and vision loss as reasons for her initial treatment; the patient was diagnosed with bilateral opticneuritis. Five months later, the patient started to have lower extremity numbness and fatigue. Initial laboratory tests did not reveal positive monoclonal immunoglobulin. Therefore, simple peripheral neuropathy was considered for diagnosis, and the patient was treated in the Department of Neurology in our hospital; however, the symptom was not alleviated. Seven months later, the patient showed symptoms of cough, dyspnea, along with rough skin, pigmentation and drooping of both feet. Chest CT revealed bronchiectasis and infection of lungs, destruction of thoracic bones and ribs. Further examination indicated that the patient had splenomegaly, hypothyroidism and monoclonal IgA-lambda chain zone, which led to a clear diagnosis of Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes syndrome. PMID- 25820708 TI - Treating genetic disease: Expanding the options. PMID- 25820709 TI - Mechanical/physical methods of cell distribution and tissue homogenization. AB - This chapter covers the various methods of Mechanical Cell Disruption and Tissue Homogenization that are currently commercially available for processing minute samples (<1 mL) to larger production quantities. These mechanical methods of lysing do not introduce chemicals or enzymes to the system. However, the energies needed when using these "harsh" methods can be high and destroy the very proteins being sought.The destruction of cell membranes and walls by these "harsh" methods is effected by subjecting the cells (1) to shearing by liquid flow, (2) to exploding by pressure differences between inside and outside of cell, (3) to collision forces by impact of beads or paddles, or (4) a combination of these forces. Practical suggestions to optimize each method, where to acquire such equipment, and links to reference sources are included. PMID- 25820710 TI - Sample preservation through heat stabilization of proteins: principles and examples. AB - Due to post-sampling changes, caused by residual enzyme activity in the sample, levels of analytes can change from their in vivo levels so that they no longer accurately reflect conditions in the living system. The Stabilizor(TM) system accomplishes elimination of enzyme activity through heat-induced denaturation of enzymes by permanently altering the 3D protein structure of the enzymes. Heat stabilization can be introduced in the workflow either directly after sampling, with the instrument just next to where the sample is taken, or prior to sample homogenization and extraction, when samples are heat denatured directly from a frozen state. Initially, heat stabilization was developed to enable mass spectrometric analysis of neuropeptides. Heat stabilization has since been further developed and applied to a range of samples and downstream protein analysis techniques such as western blot, 2D gels and phosphorylation analysis with LC-MS. PMID- 25820711 TI - Isolating peripheral lymphocytes by density gradient centrifugation and magnetic cell sorting. AB - Combining density gradient centrifugation with magnetic cell sorting provides a powerful tool to isolate blood cells with high reproducibility, yield, and purity. It also allows for subsequent separation of multiple cell types, resulting in the possibility to analyze different purified fractions from one donor's sample. The centrifugation step divides whole blood into peripheral blood mononuclear cells (PBMC), erythrocytes, and platelet-rich plasma. In the following, lymphocyte subtypes can be consecutively isolated from the PBMC fraction. This chapter describes enrichment of erythrocytes, CD14-positive monocytes and CD3-positive T lymphocytes. Alternatively, other cell types can be targeted by using magnetic beads specific for the desired subpopulation. PMID- 25820712 TI - Investigating the adipose tissue secretome: a protocol to generate high-quality samples appropriate for comprehensive proteomic profiling. AB - In this chapter, we describe in detail how to prepare a sample containing the complete entity of secretion products from murine primary adipocytes, which are suitable for comprehensive and sensitive secretome analysis. The underlying protocol should be seen as a starting point guiding through critical steps of the complex workflow in order to approximate to the real secretome in the context of different sample types used for the diverse research questions the protocol has to be carefully adjusted. PMID- 25820713 TI - Methods for proteomics-based analysis of the human muscle secretome using an in vitro exercise model. AB - Over the last decade, the skeletal muscle as a secretory organ gained in importance. A growing number of peptides are described which are produced and released by the muscle fibers and work in an autocrine, paracrine, and endocrine fashion. The contraction-induced secretion of these myokines is considered to contribute to the health-promoting effects of exercise. To gain further insights into the molecular processes that occur during contraction an in vitro exercise model, electric pulse stimulation (EPS), was established. Recent publications show that this model is suitable to electro-stimulate human skeletal muscle cells and thus mimic muscle contraction in vitro. Here, we provide a detailed protocol for the proteomics-based analysis of the human muscle secretome, starting with the cultivation of human myotubes and their electric pulse stimulation, ending with sample preparation for targeted and untargeted proteome analysis of the cell culture supernatant. This whole workflow should allow deeper insights into the complex nature of the muscle secretome and the identification of new myokines which might help to understand the crosstalk of the working muscle with different organs and the beneficial effects of exercise. PMID- 25820714 TI - Urinary pellet sample preparation for shotgun proteomic analysis of microbial infection and host-pathogen interactions. AB - Urine is one of the most important biofluids in clinical proteomics, and in the past decades many potential disease biomarkers have been identified using mass spectrometry-based proteomics. Current studies mainly perform analyses of the urine supernatant devoid of cells and cell debris, and the pellet (or sediment) fraction is discarded. However, the pellet fraction is biologically of interest. It may contain whole human cells shed into the urine from anatomically proximal tissues and organs (e.g., kidney, prostate, bladder, urothelium, and genitals), disintegrated cells and cell aggregates derived from such tissues, viruses and microbial organisms which colonize or infect the urogenital tract. Knowledge of the function, abundance, and tissue of origin of such proteins can explain a pathological process, identify a microbe as the cause of urinary tract infection, and measure the human immune response to the infection-associated pathogen(s). Successful detection of microbial species in the urinary pellet via proteomics can serve as a clinical diagnostic alternative to traditional cell culture-based laboratory tests. Filter-aided sample preparation (FASP) has been widely used in shotgun proteomics. The methodology presented here implements an effective lysis of cells present in urinary pellets, solubilizes the majority of the proteins derived from microbial and human cells, and generates enzymatic digestion compatible protein mixtures using FASP followed by optimized desalting procedures to provide a peptide fraction for sensitive and comprehensive LC-MS/MS analysis. A highly parallel sample preparation method in 96-well plates to allow scaling up such experiments is discussed as well. Separating peptides by nano-LC in one dimension followed by online MS/MS analysis on a Q-Exactive mass spectrometer, we have shown that more than 1,000 distinct microbial proteins and 1,000 distinct human proteins can be identified from a single experiment. PMID- 25820715 TI - A protocol for the parallel isolation of intact mitochondria from rat liver, kidney, heart, and brain. AB - Mitochondria are key organelles for cellular energy production and cell death decisions. Consequently, a plethora of conditions which are toxic to cells are known to directly attack these organelles. However, mitochondria originating from different tissues differ in their sensitivity to toxic insults. Thus, in order to predict the potential organ-specific toxicity of a given drug or pathological condition at the mitochondrial level, test settings are needed that directly compare the responses and vulnerabilities of mitochondria from different organs. As a prerequisite for such test strategies, we provide here a robust, prompt, and easy-to-follow step-by-step protocol to simultaneously isolate functional and intact mitochondria from rat liver, kidney, heart, and brain. This isolation procedure ensures mitochondrial preparations of comparable purity and reproducible quantities which can be subsequently analyzed for organ-specific mitochondrial toxicity. PMID- 25820717 TI - Dynamic range compression with ProteoMinerTM: principles and examples. AB - One of the main challenges in proteomics investigation, protein biomarker research, and protein purity and contamination analysis is how to efficiently enrich and detect low-abundance proteins in biological samples. One approach that makes the detection of rare species possible is the treatment of biological samples with solid-phase combinatorial peptide ligand libraries, ProteoMiner. This method utilizes hexapeptide bead library with huge diversity to bind and enrich low-abundance proteins but remove most of the high-abundance proteins, therefore compresses the protein abundance range in the samples. This work describes optimized protocols and highlights on the successful application of ProteoMiner to protein identification and analysis. PMID- 25820716 TI - Isolation of mitochondria from cultured cells and liver tissue biopsies for molecular and biochemical analyses. AB - We recently reported a new method to isolate functionally intact mitochondria from cell culture and small tissue samples (Schmitt et al., Anal Biochem 443(1):66-74, 2013). This method comprises a semi-automated cell rupture, termed pump controlled cell rupture system (PCC), which can be precisely adjusted to the specific cellular source of isolation and which can be tightly controlled (Schmitt et al., Anal Biochem 443(1):66-74, 2013). Here we provide a detailed hands-on protocol of this PCC method which results in an efficient cell breakage but preserving the mitochondrial integrity. Upon subsequent purification steps, the obtained mitochondrial fraction meets the quality and purity required for molecular analyses, e.g. proteomic comparisons, as well as for biochemical analyses, e.g. determination of diverse enzymatic activities. PMID- 25820718 TI - Qualitative and quantitative proteomic analysis of formalin-fixed paraffin embedded (FFPE) tissue. AB - Formalin-fixed, paraffin-embedded (FFPE) tissue has recently gained interest as an alternative to fresh/frozen tissue for retrospective protein biomarker discovery. However, during the formalin fixation proteins undergo degradation and cross-linking, making conventional protein analysis technologies challenging. Cross-linking is even more challenging when quantitative proteome analysis of FFPE tissue is planned. The use of conventional protein labeling technologies on FFPE tissue has turned out to be problematic as the lysine residue labeling targets are frequently blocked by the formalin treatment. We have established a qualitative and quantitative proteomics analysis technique for FFPE tissues that combines label-free proteomic analysis with optimized protein extraction and separation conditions. PMID- 25820719 TI - Full-length protein extraction protocols and gel-based downstream applications in formalin-fixed tissue proteomics. AB - Archival formalin-fixed, paraffin-embedded (FFPE) tissue repositories and their associated clinical information can represent a valuable resource for tissue proteomics. In order to make these tissues available for protein biomarker discovery and validation studies, dedicated sample preparation procedures overcoming the intermolecular cross-links introduced by formalin need to be implemented. This chapter describes a full-length protein extraction protocol optimized for downstream gel-based proteomics applications. Using the procedures detailed here, SDS-PAGE, western immunoblotting, GeLC-MS/MS, 2D-PAGE, and 2D-DIGE can be carried out on FFPE tissues. Technical tips, critical aspects, and drawbacks of the method are presented and discussed. PMID- 25820720 TI - Enrichment of low-abundant protein targets by immunoprecipitation upstream of mass spectrometry. AB - Immunoprecipitation (IP) is commonly used upstream of mass spectrometry (MS) as an enrichment tool for low-abundant protein targets. However, several aspects of the classical IP procedure such as nonspecific protein binding to the isolation matrix, detergents or high salt concentrations in wash and elution buffers, and antibody chain contamination in elution fractions render it incompatible with downstream mass spectrometry analysis. Here, we discuss two IP workflows that are designed to minimize or eliminate these contaminants: the first employs biotinylated antibodies and streptavidin magnetic beads while the second method utilizes a traditional antibody that is oriented and cross-linked to Protein AG magnetic beads. Both modified magnetic supports have low background binding and both antibody immobilization strategies significantly reduce or eliminate antibody heavy and light chain contamination in the eluent, minimizing potential ion suppression effects and thereby maximizing detection of target antigens and interacting proteins. PMID- 25820721 TI - Principles of protein labeling techniques. AB - Protein labeling methods prior to separation and analysis have become indispensable approaches for proteomic profiling. Basically, three different types of tags are employed: stable isotopes, mass tags, and fluorophores. While proteins labeled with stable isotopes and mass tags are measured and differentiated by mass spectrometry, fluorescent labels are detected with fluorescence imagers. The major purposes for protein labeling are monitoring of biological processes, reliable quantification of compounds and specific detection of protein modifications and isoforms in multiplexed samples, enhancement of detection sensitivity, and simplification of detection workflows. Proteins can be labeled during cell growth by incorporation of amino acids containing different isotopes, or in biological fluids, cells or tissue samples by attaching specific groups to the epsilon-amino group of lysine, the N-terminus, or the cysteine residues. The principles and the modifications of the different labeling approaches on the protein level are described; benefits and shortcomings of the methods are discussed. PMID- 25820722 TI - Isolation of extracellular vesicles for proteomic profiling. AB - Extracellular vesicles are nano-sized lipid bilayer vesicles released from most cells, including archaea, bacteria, and eukaryotic cells. These membrane vesicles play multiple roles in cell-to-cell communication, including immune modulation, angiogenesis, and transformation of cells by transferring genetic material and functional proteins. They contain specific subsets of proteins, DNA, RNA, and lipids that represent their cellular status. Furthermore, extracellular vesicles are enriched in cell type- or disease-specific vesicular proteins, especially plasma membrane proteins, which have pathophysiological functions; these vesicular proteins are considered novel diagnostic biomarkers as well as therapeutic targets. To profile the proteome, various purification methods of extracellular vesicles have been developed, but density gradient ultracentrifugation is considered the most promising. In this chapter, we describe the isolation of extracellular vesicles derived from SW480 cells and the preparation of tryptic peptides for mass-spectrometry-based proteomic analysis. PMID- 25820723 TI - A protocol for exosome isolation and characterization: evaluation of ultracentrifugation, density-gradient separation, and immunoaffinity capture methods. AB - Exosomes are 40-150 nm extracellular vesicles that are released from a multitude of cell types, and perform diverse cellular functions including intercellular communication, antigen presentation, and transfer of tumorigenic proteins, mRNA and miRNA. Exosomes are important regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest their importance for diagnostic and therapeutic applications, and as drug delivery vehicles. Exosomes have been purified from biological fluids and in vitro cell cultures using a variety of strategies and techniques. In this chapter, we reveal the protocol and key insights into the isolation, purification and characterization of exosomes, distinct from shed microvesicles and apoptotic blebs. Using the colorectal cancer cell line LIM1863 as a cell model, a comprehensive evaluation of exosome isolation methods including ultracentrifugation (UC-Exos), OptiPrepTM density-based separation (DG-Exos), and immunoaffinity capture using anti-EpCAM-coated magnetic beads (IAC-Exos) were examined. All exosome isolation methodologies contained 40-150 nm vesicles based on electron microscopy, and positive for exosome markers (Alix, TSG101, HSP70) based on immunoblotting. This protocol employed a proteomic profiling approach to characterize the protein composition of exosomes, and label-free spectral counting to evaluate the effectiveness of each method in exosome isolation. Based on the number of MS/MS spectra identified for exosome markers and proteins associated with their biogenesis, trafficking, and release, IAC-Exos was shown to be the most effective method to isolate exosomes. However, the use of density based separation (DG-Exos) provides significant advantages for exosome isolation when the use of immunoaffinity capture is limited (due to antibody availability and suitability of exosome markers). PMID- 25820724 TI - Chloroplast isolation and affinity chromatography for enrichment of low-abundant proteins in complex proteomes. AB - Detailed knowledge of the proteome is crucial to advance the biological sciences. Low-abundant proteins are of particular interest to many biologists as they include, for example those proteins involved in signal transduction. Recent technological advances resulted in a tremendous increase in protein identification sensitivity by mass spectrometry (MS). However, the dynamic range in protein abundance still forms a fundamental problem that limits the detection of low-abundant proteins in complex proteomes. These proteins will typically escape detection in shotgun MS experiments due to the presence of other proteins at an abundance several-fold higher in order of magnitude. Therefore, specific enrichment strategies are required to overcome this technical limitation of MS based protein discovery. We have searched for novel signal transduction proteins, more specifically kinases and calcium-binding proteins, and here we describe different approaches for enrichment of these low-abundant proteins from isolated chloroplasts from pea and Arabidopsis for subsequent proteomic analysis by MS. These approaches could be extended to include other signal transduction proteins and target different organelles. PMID- 25820725 TI - Depletion of RuBisCO protein using the protamine sulfate precipitation method. AB - Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is a major high abundant protein (HAP) in the plant leaves which hinders analysis of low-abundant proteins (LAP). In this chapter, we describe a highly simple RuBisCO depletion method using protamine sulfate (PS). Addition of 0.1 % PS is sufficient to precipitate the RuBisCO from the leaf extracts of diverse plants including monocots and dicots. Our results of SDS-PAGE, Western blotting, and two dimensional gel electrophoresis showed that both large and small subunits of RuBisCO were precipitated in the pellet fractions, while LAPs were enriched in the supernatant fraction after PS precipitation. PMID- 25820726 TI - Step-by-step preparation of proteins for mass spectrometric analysis. AB - Nowadays, identification of proteins from biological samples by mass spectrometry is widely used. In principle there are two scenarios. Proteins are pre fractionated in some way, e.g. by gel electrophoresis or are analyzed as complex mixture (shot gun). Shot gun proteomics became recently more popular, because of technological developments on the mass spectrometer side which allows now the identification of several thousand proteins from complex biological matrix. However, in many cases it is still useful to separate proteins first in a gel. But not only mass spectrometer technology made progress. This is also true for the sample preparation. Recently, protocols and techniques were developed which make the analysis of starting material in the low microgram range possible and also simplify the whole procedure. Detailed protocols will be described allowing also inexperienced beginners to get good results. PMID- 25820727 TI - Identification of protein N-termini using TMPP or dimethyl labeling and mass spectrometry. AB - Determination of a protein's N-terminal sequence can be important for the characterization of protein processing. To increase the confidence of protein N terminal identification, chemical derivatization of the N-terminal amine group by (N-Succinimidyloxycarbonylmethyl)tris(2,4,6-trimethoxyphenyl)phosphonium bromide (TMPP) or dimethyl labeling followed by mass spectrometric analysis is commonly performed. Using this approach, proteins can be separated by SDS-PAGE, and the protein N-terminus of interest is labeled by TMPP or dimethyl in-gel before tryptic digestion and LC-MS analysis. The N-terminus of a protein can thus be easily identified because the N-terminal tryptic peptides are preferentially labeled. Peptides with N-terminal derivatization produce a better fragmentation pattern during tandem mass spectrometric analysis, which significantly facilitates sequencing of these peptides. PMID- 25820728 TI - Optimization of cell lysis and protein digestion protocols for protein analysis by LC-MS/MS. AB - Mass spectrometry-based proteomics is the method of choice for analyzing (sub-) proteomes from virtually any source; with cells grown in culture being the most frequently investigated samples. Using HeLa cells, we describe a strategy for the optimization of protocols for whole proteome analysis. We cover cell lysis, protein precipitation and digestion, comparing the results obtained using different parameters and offering various possibilities for the optimization of a proteomic workflow which can be used for virtually any type of animal cell grown in culture. PMID- 25820729 TI - Comprehensive protocol to simultaneously study protein phosphorylation, acetylation, and N-linked sialylated glycosylation. AB - Post-translational modifications (PTMs) such as phosphorylation, acetylation, and glycosylation are an essential regulatory mechanism of protein function and they are associated with a range of biological processes. Since most PTMs alter the molecular mass of a protein, mass spectrometry (MS) is the ideal analytical tool for studying various PTMs. However, PTMs are generally present in substoichiometric levels and therefore their unmodified counterpart often suppresses their signal in MS. Consequently, PTM analysis by MS is a challenging task requiring highly specialized and sensitive enrichment methods. Currently, several methods have been implemented for PTM enrichment and each of them has its drawbacks and advantages as they differ in selectivity and specificity toward specific protein modifications. Unfortunately, for most of the more than 300 known modifications we have none or poor tools for selective enrichment.Here, we describe a comprehensive workflow to simultaneously study phosphorylation, acetylation, and N-linked sialylated glycosylation from the same biological sample. The protocol involves an initial titanium dioxide (TiO2) step to enrich for phosphopeptides and sialylated N-linked glycopeptides followed by glycan release and post-fractionation using sequential elution from immobilized metal affinity chromatography (SIMAC) to separate mono-phosphorylated and deglycosylated peptides from multi-phosphorylated ones. The IMAC flow-through and acidic elution is subsequently subjected to a next round of TiO2 enrichment for further separation of mono-phosphopeptides from deglycosylated peptides. In addition, the acetylated peptides present in the first TiO2 flow-through are enriched by immunoprecipitation (IP). Finally, the samples are fractionated by hydrophilic interaction liquid chromatography (HILIC) to reduce sample complexity and increase the coverage during LC-MS/MS analysis. This allows the analysis of multiple types of modifications from the same highly complex biological sample without decreasing the quality of each individual PTM study. PMID- 25820730 TI - Protein profiling and phosphoprotein analysis by isoelectric focusing. AB - Protein profiling enables the qualitative characterization of a proteome of interest. Phosphorylation is a post-translational modification with regulatory functions in a plethora of cell processes. We present an experimental workflow for simultaneous analysis of the proteome and phosphoproteome with no additional enrichment for phosphoproteins/phosphopeptides. Our approach is based on isoelectric focusing (IEF) which allows the separation of peptide mixtures on an immobilized pH gradient (IPG) according to their isoelectric point. Due to the negative charge of the phosphogroup, most of the phosphopeptides migrate toward acidic pH values. Peptides and phosphopeptides are then identified by mass spectrometry (MS) and phosphopeptide spectra are manually checked for the assignment of phosphorylation sites. Here, we apply this methodology to investigate synaptosome extracts from whole mouse brain. IEF-based peptide separation is an efficient method for peptide and phosphopeptide identification. PMID- 25820731 TI - Principles and examples of gel-based approaches for phosphoprotein analysis. AB - Methods for analyzing the phosphorylation status of proteins are essential to investigate in detail key cellular processes, including signal transduction and cell metabolism. The transience of this post-translational modification and the generally low abundance of phosphoproteins require specific enrichment and/or detection steps prior to analysis. Here, we describe three gel-based approaches for the analysis of differentially expressed phosphoproteins. These approaches comprise (1) the sequential fluorescence staining of two-dimensional (2-D) gels using Pro-Q((r)) Diamond and SYPRO((r)) Ruby dyes to visualize and quantify phosphoproteins in total cellular lysates as well as (2) affinity enrichment of phosphoproteins in conjunction with sequential fluorescence staining of the 2-D gels and (3) affinity enrichment of proteins prior to pre-electrophoretic fluorescence labeling and 2-D gel electrophoresis. PMID- 25820732 TI - Neutral Phosphate-Affinity SDS-PAGE system for profiling of protein phosphorylation. AB - In this chapter, we describe a standard protocol for phosphate-affinity SDS-PAGE that uses a dizinc(II) complex of the phosphate-binding molecule Phos-tag in conjunction with a neutral-pH gel system (Zn(2+-)Phos-tag SDS-PAGE) to detect shifts in the mobilities of phosphoproteins. A previous protocol for affinity electrophoresis that uses polyacrylamide-bound Mn(2+)-Phos-tag and Laemmli's buffer system under conditions of alkaline pH has limitations in separating certain phosphoproteins. The current protocol provides major improvements in separation and detection of various phosphorylated protein species. We here introduce two neutral-pH gel systems buffered with Bis-Tris-HCl and Tris-AcOH, respectively, for Zn(2+)-Phos-tag SDS-PAGE, and we also discuss their characteristics on the basis of comparative studies on phosphorylation profiling of proteins with a wide range of molecular masses. Each analytical procedure, from the beginning of gel preparation to the end of electrophoresis, requires 2.5 5 h with either buffer system. PMID- 25820733 TI - Enrichment and identification of bacterial glycopeptides by mass spectrometry. AB - Large-scale analysis of protein N- and O-linked glycosylation by mass spectrometry has traditionally been performed in eukaryotes by parallel approaches aimed at elucidating glycan structures (glycomics) and their formerly glycosylated peptides (glycoproteomics) without reference to their intact state. Such analyses depend heavily on commercial glycosidases (e.g. protein N glycosidase F) that can remove glycans from the peptide backbone for separate analyses. Bacterial glycosylation has only recently been identified as a widespread phenomenon. In many cases however, unique bacterial sugars preclude enzymatic removal, therefore ultimately requiring a site-specific approach for intact glycopeptide analysis. Here, we describe protocols for the enrichment of bacterial glycopeptides using zwitterionic-hydrophilic interaction liquid chromatography (ZIC-HILIC) and their analysis using liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC-MS/MS) with collision induced dissociation (CID) and higher energy collisional dissociation (HCD) fragmentation for glycan structure elucidation and glycopeptide identification. PMID- 25820734 TI - In-gel peptide IEF sample preparation for LC/MS analysis. AB - The technique of proteolytically digesting a sample and identifying its protein components by liquid chromatography followed by mass spectrometry (LC-MS) is a widely used analytical tool. Prior fractionation by isoelectric focusing (IEF) may be performed to increase the depth of proteome coverage. Here, we describe a method for in-gel IEF separation of a proteolytic digest that utilizes commercially available immobilized pH gradient (IPG) strips and a widely used IEF instrument. PMID- 25820735 TI - Western blotting using in-gel protein labeling as a normalization control: stain free technology. AB - Western blotting is a commonly used laboratory technique for semi-quantifying protein amounts. It is important when quantifying protein expression to account for differences in the amount of total protein loaded onto the gel using a loading control. Common loading controls include housekeeping proteins, such as beta-actin or GAPDH, quantified by Western blot, or total protein, quantified using a stain such as Coomassie Brilliant Blue or Ponceau S. A more recently developed method for total protein quantification utilizes stain-free technology, which has a linear dynamic detection range and allows for protein detection on both gels and membranes. Here, we describe the theory and use of stain-free gels for total protein quantification and normalization of Western blots. PMID- 25820736 TI - 2-D Western blotting for evaluation of antibodies developed for detection of host cell protein. AB - Recombinant proteins generated for therapeutic use must be substantially free of residual host cell protein (HCP). The presence of host cell protein (HCP) is usually assayed by ELISA using a polyclonal antibody mixture raised against a population of proteins derived from the host cell background. This antibody should recognize as high a proportion as possible of the potential HCPs in a given sample. A recommended method for evaluating the assay involves two dimensional electrophoretic separation followed by Western blotting.We present here a method using commercial anti-HCP antibody and samples derived from Chinese Hamster Ovary (CHO) cells. The 2-D electrophoresis procedure gives highly reproducible spot patterns and entire procedure can be completed in less than 2 days. Software analysis enables the straightforward generation of percent coverage values for the antibody when used to probe HCP-containing samples. PMID- 25820737 TI - Free flow electrophoresis for separation of native membrane protein complexes. AB - This chapter describes the technology of free flow electrophoresis (FFE) and protocols to separate membrane protein complexes for proteome analysis. FFE is a highly versatile technology applied in the field of protein analysis. It is superior to native PAGE due to its fast continuous processing of sample at high resolution. Additionally, the dynamic separation range from ions, peptides, to proteins, protein complexes, up to organelles, and whole cells makes it the method of choice in the analysis of proteins. FFE is carried out in an aqueous medium without inducing any solid matrix, such as acrylamide, so that it simplifies the analysis of protein complexes for the downstream analysis. Here, we describe the novel zone electrophoresis interval method (IZE-FFE) for separation of protein complexes from the thylakoid membrane of Arabidopsis thaliana by charge only. Protein complexes isolated by IZE FFE were characterized according to molecular weight by Blue Native PAGE and were proteins stained with coomassie. PMID- 25820738 TI - Three-dimensional electrophoresis for quantitative profiling of complex proteomes. AB - Quantitative 2D-gel-dependent proteomics became feasible with 2D fluorescence difference gel electrophoresis (2D-DIGE), and this technique has gained wide acceptance because it has eliminated the gel to gel variations and greatly facilitated the quantitative comparisons across gels for many different experimental conditions. However, the co-migration of several proteins in the same spot is still a major limitation which detracts from the accuracy of comparative quantification and prevents unambiguous post-translational modifications (PTMs) detection.A protocol based on traditional polyacrylamide gel IEF sample fractionation, and followed by two consecutive SDS-PAGE electrophoreses alleviates co-migration limitations. The use of two different buffer systems for SDS-PAGE is central to the proposed approach. PMID- 25820739 TI - A bead-based multiplex sandwich immunoassay to assess the abundance and posttranslational modification state of beta-catenin. AB - A system-wide analysis of cell signaling involves detecting and quantifying a range of proteins and their posttranslational modification states in the same cellular sample. We propose a protocol for a miniaturized, bead-based array and describe its efficiency in characterizing the different forms and functions of beta-catenin. The protocol provides detailed instructions for cell culture and bead array assays that enable insights into complex networks at the systems level. PMID- 25820741 TI - Amyloid-binding proteins: affinity-based separation, proteomic identification, and optical biosensor validation. AB - The amyloid-beta peptide is considered as a key player in the development and progression of Alzheimer's disease (AD). Although good evidence exists that amyloid-beta accumulates inside cells, intracellular brain amyloid-beta-binding proteins remain poorly characterized. Here we describe a protocol for affinity based profiling of amyloid-beta-binding proteins of rat brain, their proteomic identification and validation by a surface plasmon resonance (SPR)-based analysis. It includes: (a) SPR-based selection of immobilization conditions for beta-amyloid coupling and choice of appropriate resin for preparation of an affinity sorbent; (b) immobilization of beta-amyloid on the selected resin; PMID- 25820742 TI - Proteomic profiling by nanomaterials-based matrix-assisted laser desorption/ionization mass spectrometry for high-resolution data and novel protein information directly from biological samples. AB - Qualitative and quantitative analyses of global proteome samples derived from biocomplex mixtures are very important to understand the cellular functions in cell biology. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based proteomics has recently become one of the most informative and attractive core technologies in proteomics. Particularly, nanomaterials-based MALDI mass spectrometric methods are quickly becoming a critical miniaturized bioanalytical tool for detecting and discerning proteins from biocomplex samples. These MALDI-developed strategies allow high-throughput identification of proteins from highly complex mixtures including accurate mass measurement of peptides derived from total proteome digests and peptides/proteins separations from various samples. The nanomaterials-integrated MALDI-MS technologies in protein arrays hold much promise for interrogating the diverse and immense proteome in cell biology. As a result, nanomaterials-assisted MALDI-MS-based proteomic workflow, including sample preparation, information on the local molecular composition, relative abundance and spatial distribution of peptides and proteins and their analysis, should make the technology more easily available to a broad community and turn it into a powerful methodology for bioanalysts. PMID- 25820740 TI - Identification of SUMO E3 ligase-specific substrates using the HuProt human proteome microarray. AB - The functional protein microarray is a powerful and versatile systems biology and proteomics tool that allows the rapid activity profiling of thousands of proteins in parallel. We have recently developed a human proteome array, the HuProt array, which includes ~80 % of all the full-length proteins of the human proteome. In one recent application of the HuProt array, we identified numerous SUMO E3 ligase dependent SUMOylation substrates. For many SUMO E3 ligases, only a small number of substrates have been identified and the target specificities of these ligases therefore remain poorly defined. In this protocol, we outline a method we developed using the HuProt array to screen the human proteome to identify novel SUMO E3 ligase substrates recognized by specific E3 ligases. PMID- 25820743 TI - Carlos F. Salinas, DMD (April 9, 1941-January 14, 2015). PMID- 25820744 TI - Free-hand transperineal targeted prostate biopsy with real-time fusion imaging of multiparametric magnetic resonance imaging and transrectal ultrasound: single center experience in China. AB - OBJECTIVES: To report our experience with free-hand transperineal targeted biopsy with real-time transrectal ultrasound (TRUS) and multiparametric magnetic resonance imaging (mpMRI) fusion images for the diagnosis of prostate cancer (PCa). PATIENTS AND METHODS: A total of 62 consecutive patients suspicious of PCa at the mpMRI scan and PSA >4.0 ng/mL were recruited prospectively. Targeted biopsies (TBs) were carried out for each cancer-suspicious lesion and followed a 12-core systematic biopsy (SB) protocol. Pathological findings of TB and SB were analyzed. RESULTS: The age of the patients was 68.38 +/- 6.57 years (range 51-79 years). The preoperative PSA value was 10.21 +/- 5.57 ng/mL (range 4.5-30.1 ng/mL). Preoperative prostate volume was 34.05 +/- 9.86 mL (range 19-64 mL). The PCa patients detected by SB and/or TB were 34 (54.8%). Cancer-detected rates of SB and TB cores were 7.53 and 26.2%, respectively (P < 0.001). The positive core length of SB and TB cores was 3.71 +/- 2.77 mm (range 1-14 mm) and 5.00 +/- 3.04 mm (range 2-17 mm), respectively (P = 0.016). The positive core percent of SB and TB cores was 28.77 +/- 20.13% (range 7-100%) and 35.76 +/- 18.73 (range 11-100%), respectively (P = 0.048). Moreover, clinically significant PCa cores detected by the SB and TB were 19 cores (2.6%) and 48 cores (18.5%), respectively (P < 0.001). CONCLUSIONS: Free-hand transperineal TB using real-time TRUS and mpMRI fusion imaging has the ability to improve sampling quality and detect more clinically significant PCa compared with SB. PMID- 25820746 TI - Altered Cortical Thickness and Tract Integrity of the Mirror Neuron System and Associated Social Communication in Autism Spectrum Disorder. AB - Previous studies using neural activity recording and neuroimaging techniques have reported functional deficits in the mirror neuron system (MNS) for individuals with autism spectrum disorder (ASD). However, a few studies focusing on gray and white matter structures of the MNS have yielded inconsistent results. The current study recruited adolescents and young adults with ASD (aged 15-26 years) and age matched typically developing (TD) controls (aged 14-25 years). The cortical thickness (CT) and microstructural integrity of the tracts connecting the regions forming the classical MNS were investigated. High-resolution T1-weighted imaging and diffusion spectrum imaging were performed to quantify the CT and tract integrity, respectively. The structural covariance of the CT of the MNS regions revealed a weaker coordination of the MNS network in ASD. A strong correlation was found between the integrity of the right frontoparietal tracts and the social communication subscores measured by the Chinese version of the Social Communication Questionnaire. The results showed that there were no significant mean differences in the CTs and tract integrity between the ASD and TD groups, but revealed a moderate or even reverse age effect on the frontal MNS structures in ASD. In conclusion, aberrant structural coordination may be an underlying factor affecting the function of the MNS in ASD patients. The association between the right frontoparietal tracts and social communication performance implies a neural correlate of communication processing in the autistic brain. This study provides evidence of abnormal MNS structures and their influence on social communication in individuals with ASD. PMID- 25820745 TI - Education, marital status, and risk of hip fractures in older men and women: the CHANCES project. AB - The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk. INTRODUCTION: The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA. METHODS: A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models. RESULTS: Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P heterogeneity > 0.05). CONCLUSIONS: The combined data from >150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting. PMID- 25820747 TI - The p53-inducible gene 3 involved in flavonoid-induced cytotoxicity through the reactive oxygen species-mediated mitochondrial apoptotic pathway in human hepatoma cells. AB - Flavonoids have been reported to exhibit prooxidant cytotoxicity against cancer cells, but the underlying mechanism is still poorly understood. Here we investigated the potential mechanism that p53-inducible gene 3 (PIG3), a NADPH:quinone oxidoreductase, mediated the prooxidant cytotoxicity of flavonoids on human hepatoma HepG2 cells. The results showed that flavonoids (apigenin, luteolin, kaempferol, and quercetin) inhibited the growth of HepG2 cells in a dosage- and time-dependent manner, and induced the morphological changes characteristic of apoptosis in HepG2 cells. We also found that expression of PIG3 was increased markedly in HepG2 cells treated with flavonoids at both mRNA and protein levels, which was accompanied by increased intracellular ROS production and a decreased mitochondrial membrane potential (DeltaPsim). All these effects were largely reversed through knockdown of the PIG3 gene in HepG2 cells. Western blotting indicated that flavonoids increased cytochrome c release, upregulated the ratio of Bax/Bcl-2, and activated the caspases-9 and -3. Moreover, knockdown of PIG3 could reverse the changes of these apoptotic-related proteins. These results suggest that PIG3 plays an important role in regulating the prooxidant activity and apoptosis-inducing action of flavonoids on HepG2 cells though the ROS-triggered mitochondrial apoptotic pathway. PMID- 25820748 TI - Resveratrol attenuates inflammation and oxidative stress in epididymal white adipose tissue: implications for its involvement in improving steroidogenesis in diet-induced obese mice. AB - Chronic, low-grade systemic inflammation has been shown to play an important role in the development of obesity-related complications. Epididymal white adipose tissue (WAT) can influence testicular function through its endocrine function. The purpose of this study was to assess the effects of resveratrol on the epididymal WAT inflammatory response and on testicular steroidogenesis in obese individuals. Seven-week-old male C57BL/6J mice were fed a high-calorie and high cholesterol diet (HCD group) or HCD supplemented with resveratrol (HCD+Res group) for 18 weeks. As we previously showed that resveratrol protects against Leydig cell steroidogenesis in HCD-induced obese mice, this study assessed macrophage infiltration in fat depots by measuring crown-like structure (CLS) density. Histological analysis showed that adipocyte size was significantly smaller and CLSs were less numerous in the HCD+Res group than the HCD group (P < 0.01). Additionally, resveratrol supplementation decreased Nfkb1 expression (P < 0.01) and increased the IkappaB-alpha protein abundance (P < 0.01) in epididymal WAT. Consistent with this alteration in NF-kappaB signaling, the expression of two classic proinflammatory cytokines, TNF-alpha (Tnfa) and IL-1beta (Il1b), were significantly decreased in the HCD+Res group compared with the HCD group (P < 0.01). Significant differences were also found in the expression of sirtuin1 (Sirt1) (P < 0.01) and manganese superoxide dismutase (Sod2) (P < 0.01) between the HCD and HCD+Res groups. Our data suggest that resveratrol can attenuate obesity-induced inflammation and oxidative stress in epididymal WAT, which partly accounts for its beneficial effects in testicular steroidogenesis. PMID- 25820749 TI - Intramolecular carbolithiation of heterosubstituted alkynes: an experimental and theoretical study. AB - A series of heterosubstitued alkynes was successfully submitted to the intramolecular carbolithiation of their triple bond. We show that the addition is stereoselective because of the control exerted by the terminal substituent X on the geometry of the transition state. A complementary DFT study suggests that the addition is anti when a strong Li-X interaction occurs. PMID- 25820750 TI - Effects of climate and plant phenology on recruitment of moose at the southern extent of their range. AB - Climate plays a fundamental role in limiting the range of a species, is a key factor in the dynamics of large herbivores, and is thought to be involved in declines of moose populations in recent decades. We examined effects of climate and growing-season phenology on recruitment (8-9 months old) of young Shiras moose (Alces alces shirasi) over three decades, from 18 herds, across a large geographic area encompassing much of the southern extent of their range. Recruitment declined in 8 of 18 herds during 1980-2009, whereas others did not exhibit a temporal trend (none showed a positive trend). During those three decades, seasonal temperatures increased, spring-summer precipitation decreased, and spring occurred earlier, became shorter in duration, and green-up occurred faster. Recruitment was influenced negatively by warm temperatures during the year before young were born, but only for herds with declining recruitment. Dry spring-summers of the previous year and rapid rates of spring green-up in the year of birth had similar negative influences across declining and stable herds. Those patterns indicate both direct (year(t)) and delayed (year(t-1)) effects of weather and plant phenology on recruitment of young, which we hypothesize was mediated through effects on maternal nutritional condition. Suppressed nutrition could have been induced by (1) increased thermoregulatory costs associated with warming temperatures and (2) shortened duration of availability of high-quality forage in spring. Progressive reductions in net energetic gain for species that are sensitive to climate may continue to hamper individual fitness and population dynamics. PMID- 25820751 TI - Nonadditive impacts of temperature and basal resource availability on predator prey interactions and phenotypes. AB - Predicting the impacts of climate change on communities requires understanding how temperature affects predator-prey interactions under different biotic conditions. In cases of size-specific predation, environmental influences on the growth rate of one or both species can determine predation rates. For example, warming increases top-down control of food webs, although this depends on resource availability for prey, as increased resources may allow prey to reach a size refuge. Moreover, because the magnitude of inducible defenses depends on predation rates and resource availability for prey, temperature and resource levels also affect phenotypic plasticity. To examine these issues, we manipulated the presence/absence of predatory Hynobius retardatus salamander larvae and herbivorous Rana pirica tadpoles at two temperatures and three basal resource levels. and measured their morphology, behavior, growth and survival. Prior work has shown that both species express antagonistic plasticity against one another in which salamanders enlarge their gape width and tadpoles increase their body width to reach a size-refuge. We found that increased temperatures increased predation rates, although this was counteracted by high basal resource availability, which further decreased salamander growth. Surprisingly, salamanders caused tadpoles to grow larger and express more extreme defensive phenotypes as resource levels decreased under warming, most likely due to their increased risk of predation. Thus, temperature and resources influenced defensive phenotype expression and its impacts on predator and prey growth by affecting their interaction strength. Our results indicate that basal resource levels can modify the impacts of increased temperatures on predator-prey interactions and its consequences for food webs. PMID- 25820752 TI - Hidden relationships between metalloproteins unveiled by structural comparison of their metal sites. AB - Metalloproteins account for a substantial fraction of all proteins. They incorporate metal atoms, which are required for their structure and/or function. Here we describe a new computational protocol to systematically compare and classify metal-binding sites on the basis of their structural similarity. These sites are extracted from the MetalPDB database of minimal functional sites (MFSs) in metal-binding biological macromolecules. Structural similarity is measured by the scoring function of the available MetalS2 program. Hierarchical clustering was used to organize MFSs into clusters, for each of which a representative MFS was identified. The comparison of all representative MFSs provided a thorough structure-based classification of the sites analyzed. As examples, the application of the proposed computational protocol to all heme-binding proteins and zinc-binding proteins of known structure highlighted the existence of structural subtypes, validated known evolutionary links and shed new light on the occurrence of similar sites in systems at different evolutionary distances. The present approach thus makes available an innovative viewpoint on metalloproteins, where the functionally crucial metal sites effectively lead the discovery of structural and functional relationships in a largely protein-independent manner. PMID- 25820753 TI - Lewis acid-assisted detection of nerve agents in water. AB - The five-coordinate compound, Salen((t)Bu)Al(Ac), prepared in situ from Salen((t)Bu)AlBr and NH4Ac, forms Lewis acid-base adducts in aqueous solution with the G-type nerve agents, Sarin and Soman, and the VX hydrolysis product, ethylmethylphosphonate (EMPA). The resulting compounds, [Salen((t)Bu)Al(NA)](+)[Ac] (-) (with NA = Sarin, Soman, and EMPA) are sufficiently stable to be identified by ESI-MS. Molecular ion peaks were detected for every compound with little or no fragmentation. The distinctive MS signatures for the [Salen((t)Bu)Al(NA)](+) compounds provide a new technique for identifying nerve agents from aqueous solution. The energetics of the displacement of Ac(-) by the nerve agents to form [Salen((t)Bu)Al(NA)](+)[Ac](-) were determined computationally. PMID- 25820754 TI - An open-label, randomized, multicenter dose-finding study of once-per-cycle pegfilgrastim versus daily filgrastim in Chinese breast cancer patients receiving TAC chemotherapy. AB - A chemotherapy regimen of docetaxel, doxorubicin and cyclophosphamide (TAC) has been accepted as a standard care because of their superior clinical benefit in early-stage breast cancer patients, but with a higher risk of neutropenia. Pegfilgrastim is a once-per-cycle therapy for prophylactic neutrophil support and neutropenia prevention. There was still a lack of direct evidences for finding an optimal fixed dose of pegfilgrastim in Chinese breast cancer patients receiving TAC regimen. An open-label, randomized, phase II study was designed to compare the effects of pegfilgrastim with filgrastim. Eighteen centers in China enrolled 171 eligible female breast cancer patients with cycles of TAC chemotherapy treatment, randomized into four arms, received a single subcutaneous injection of pegfilgrastim (60, 100 or 120 ug/kg) per chemotherapy cycle or daily subcutaneous injections of filgrastim 5 ug/kg 24 h after chemotherapy. Efficacy and safety were analyzed. In ITT population, the mean duration of grade 3+ neutropenia (neutrophil count <1.0 * 10(9)/l) was 2.09, 1.53 and 1.73 days in patients who received pegfilgrastim 60, 100 and 120 ug/kg/cycle, respectively, and 1.69 days in patients who received 5 ug/kg/day filgrastim (P = 0.043). The incidence of grade 3+ neutropenia was 76, 83 and 74 % for doses of pegfilgrastim and 90 % for filgrastim (P = 0.409). The results for febrile neutropenia, time to neutrophil recovery and neutrophil profile were also not significantly different between arms. The safety profiles of pegfilgrastim and filgrastim were similar. A single dose of 100 ug/kg once-per-cycle administration of pegfilgrastim provided neutrophil support and a safety profile comparable to daily subcutaneous injections of filgrastim in Chinese breast cancer patients receiving TAC chemotherapy. PMID- 25820755 TI - Simultaneous (68)Ga-DOTA-TOC PET/MRI with gadoxetate disodium in patients with neuroendocrine tumor. AB - OBJECTIVE: To evaluate a simultaneous PET/MRI approach to imaging patients with neuroendocrine tumor using a combination of (68)Ga-DOTA-TOC as a PET contrast agent and gadoxetate disodium as a hepatobiliary MRI contrast agent. MATERIALS AND METHODS: Ten patients with neuroendocrine tumor with known or suspected hepatic disease were imaged using a (68)Ga-DOTA-TOC PET/CT immediately followed by a 3.0T time-of-flight PET/MRI, using a combined whole body and liver specific imaging. The presence of lesions and DOTA-TOC avidity were assessed on CT, PET from PET/CT, diffusion weighted imaging, hepatobiliary phase imaging (HBP), and PET from PET/MRI. Maximum standardized uptake values (SUVmax) in hepatic lesions and nodal metastases were compared between PET/CT and PET/MRI, as were detection rates using each imaging approach. RESULTS: A total of 101 hepatic lesions were identified, 47 of which were DOTA-TOC avid and able to be individually measured on both PET/CT and PET/MRI. HBP imaging had a higher sensitivity for detection of hepatic lesions compared to CT or PET (99% vs. 46% and 64%, respectively; p values <0.001). There was a strong correlation between SUVmax of liver lesions obtained with PET/CT compared to PET/MR imaging (Pearson's correlation = 0.91). For nodal disease, CT had a higher sensitivity compared to whole body MRI (p = 0.015), although PET acquired from PET/MRI detected slightly more lesions compared to PET from PET/CT. CONCLUSIONS: A simultaneous PET/MRI using both (68)Ga-DOTA-TOC and gadoxetate disodium was successful in whole body staging of patients with neuroendocrine tumor. HBP imaging had an increased detection rate for hepatic metastases. PMID- 25820756 TI - Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse. AB - Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT 3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test. PMID- 25820757 TI - Salivary microbiota reflects changes in gut microbiota in cirrhosis with hepatic encephalopathy. AB - Altered gut microbiome is associated with systemic inflammation and cirrhosis decompensation. However, the correlation of the oral microbiome with inflammation in cirrhosis is unclear. Our aim was to evaluate the oral microbiome in cirrhosis and compare with stool microbiome. Outpatients with cirrhosis (with/without hepatic encephalopathy [HE]) and controls underwent stool/saliva microbiome analysis (for composition and function) and also systemic inflammatory evaluation. Ninety-day liver-related hospitalizations were recorded. Salivary inflammation was studied using T helper 1 cytokines/secretory immunoglobulin A (IgA), histatins and lysozyme in a subsequent group. A total of 102 patients with cirrhosis (43 previous HE) and 32 age-matched controls were included. On principal component analysis (PCA), stool and saliva microbiome clustered far apart, showing differences between sites as a whole. In salivary microbiome, with previous HE, relative abundance of autochthonous families decreased whereas potentially pathogenic ones (Enterobacteriaceae, Enterococcaceae) increased in saliva. Endotoxin-related predicted functions were significantly higher in cirrhotic saliva. In stool microbiome, relative autochthonous taxa abundance reduced in previous HE, along with increased Enterobacteriaceae and Enterococcaceae. Cirrhotic stool microbiota demonstrated a significantly higher correlation with systemic inflammation, compared to saliva microbiota, on correlation networks. Thirty-eight patients were hospitalized within 90 days. Their salivary dysbiosis was significantly worse and predicted this outcome independent of cirrhosis severity. Salivary inflammation was studied in an additional 86 age-matched subjects (43 controls/43 patients with cirrhosis); significantly higher interleukin (IL)-6/IL-1beta, secretory IgA, and lower lysozyme, and histatins 1 and 5 were found in patients with cirrhosis, compared to controls. CONCLUSIONS: Dysbiosis, represented by reduction in autochthonous bacteria, is present in both saliva and stool in patients with cirrhosis, compared to controls. Patients with cirrhosis have impaired salivary defenses and worse inflammation. Salivary dysbiosis was greater in patients with cirrhosis who developed 90-day hospitalizations. These findings could represent a global mucosal-immune interface change in cirrhosis. PMID- 25820758 TI - Synthesis and characterization of (18)F-labeled active site inhibited factor VII (ASIS). AB - Activated factor VII blocked in the active site with Phe-Phe-Arg-chloromethyl ketone (active site inhibited factor VII (ASIS)) is a 50-kDa protein that binds with high affinity to its receptor, tissue factor (TF). TF is a transmembrane glycoprotein that plays an important role in, for example, thrombosis, metastasis, tumor growth, and tumor angiogenesis. The aim of this study was to develop an (18)F-labeled ASIS derivative to assess TF expression in tumors. Active site inhibited factor VII was labeled using N-succinimidyl-4 [(18)F]fluorobenzoate, and the [(18)F]ASIS was purified on a PD-10 desalting column. The radiochemical yield was 25 +/- 6%, the radiochemical purity was >97%, and the pseudospecific radioactivity was 35 +/- 9 GBq/umol. The binding efficacy was evaluated in pull-down experiments, which monitored the binding of unlabeled ASIS and [(18)F]ASIS to TF and to a specific anti-factor VII antibody (F1A2-mAb). No significant difference in binding efficacy between [(18)F]ASIS and ASIS could be detected. Furthermore, [(18)F]ASIS was relatively stable in vitro and in vivo in mice. In conclusion, [(18)F]ASIS has for the first time been successfully synthesized as a possible positron emission tomography tracer to image TF expression levels. In vivo positron emission tomography studies to evaluate the full potential of [(18)F]ASIS are in progress. PMID- 25820759 TI - Early growth response gene-1 decoy oligonucleotides inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia of autogenous vein graft in rabbits. AB - OBJECTIVES: The excess proliferation of vascular smooth muscle cells (VSMCs) and the development of intimal hyperplasia is a hallmark of vein graft failure. This study aimed to verify that a single intraoperative transfection of early growth response gene-1 (Egr-1) decoy oligonucleotide (ODN) can suppress vein graft proliferation of VSMCs and intimal hyperplasia. METHODS: In a rabbit model, jugular veins were treated with Egr-1 decoy ODN, scrambled decoy ODN, Fugene6, or were left untreated, then grafted to the carotid artery. The vein graft samples were obtained 48 h, 1, 2 or 3 weeks after surgery. The thickness of the intima and intima/media ratio in the grafts was analysed by haematoxylin-eosin (HE) staining. The expression of the Egr-1 decoy ODN transfected in the vein was analysed using fluorescent microscopy. Egr-1 mRNA was measured using reverse transcription-polymerase chain reaction. The expression of Egr-1 protein was analysed by Western blot and immunohistochemistry. RESULTS: Transfection efficiency of the ODN was confirmed by 4', 6-diamidino-2-phenylindole staining. In the grafts treated with Egr-1 decoy ODN, our study achieved statistically significant inhibition of intimal hyperplasia by ~58% at 3 weeks. Transfection of Egr-1 decoy ODNs decreased the protein expression of Egr-1 and Egr-1 mRNA. CONCLUSIONS: We confirmed that gene therapy using in vivo transfection of an Egr 1 decoy ODN significantly inhibits proliferation of VSMC and intimal hyperplasia of vein grafts in a rabbit model. PMID- 25820760 TI - Aortic valve/root procedures in patients with an anomalous left circumflex coronary artery and a bicuspid aortic valve: anatomical and technical implications. AB - An anomalous origin of the left circumflex coronary artery that arises as a side branch of the right coronary artery from the right coronary sinus of Valsalva encircling the aortic annulus is usually an incidental finding. However, in patients undergoing aortic valve procedures, its existence can significantly complicate the surgical treatment. We report our operative strategy in patients with an anomalous left circumflex coronary artery, a bicuspid aortic valve morphology and different aortic valve pathologies. PMID- 25820761 TI - Protein kinase C bidirectionally modulates Ih and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression in hippocampal pyramidal neurons. AB - KEY POINTS: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, particularly that of the HCN1 isoform, are enriched in the distal dendrites of hippocampal CA1 pyramidal neurons; these channels have physiological functions with respect to decreasing neuronal excitability. In the present study, we aimed to investigate phosphorylation as a mechanism controlling Ih amplitude and HCN1 surface expression in hippocampal principal neurons under normal physiological conditions. Tyrosine phosphorylation decreased Ih amplitude at maximal activation (maximal Ih ), without altering HCN1 surface expression, in two classes of hippocampal principal neurons. Inhibition of serine/threonine protein phosphatases 1 and 2A decreased maximal Ih and HCN1 surface expression in hippocampal principal neurons. Protein kinase C (PKC) activation irreversibly diminished Ih and HCN1 surface expression, whereas PKC inhibition augmented Ih and HCN1 surface expression. PKC activation increased HCN1 channel phosphorylation. These results demonstrate the novel finding of a phosphorylation mechanism, dependent on PKC activity, which bidirectionally modulates Ih amplitude and HCN1channel surface expression in hippocampal principal neurons under normal physiological conditions. ABSTRACT: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels attenuate excitability in hippocampal pyramidal neurons. Loss of HCN channel-mediated current (Ih ), particularly that mediated by the HCN1 isoform, occurs with the development of epilepsy. Previously, we showed that, following pilocarpine-induced status epilepticus, there are two independent changes in HCN function in dendrites: decreased Ih amplitude associated with a loss of HCN1 surface expression and a hyperpolarizing shift in voltage-dependence of activation (gating). The hyperpolarizing shift in gating was attributed to decreased phosphorylation as a result of a loss of p38 mitogen-activated protein kinase activity and increased calcineurin activity; however, the mechanisms controlling Ih amplitude and HCN1 surface expression under epileptic or normal physiological conditions are poorly understood. We aimed to investigate phosphorylation as a mechanism regulating Ih amplitude and HCN1 surface expression (i.e. as is the case for HCN gating) in hippocampal principal neurons under normal physiological conditions. We discovered that inhibition of either tyrosine phosphatases or the serine/threonine protein phosphatases 1 and 2A decreased Ih at maximal activation in hippocampal CA1 pyramidal dendrites and pyramidal-like principal neuron somata from naive rats. Furthermore, we found that inhibition of PP1/PP2A decreased HCN1 surface expression, whereas tyrosine phosphatase inhibition did not. Protein kinase C (PKC) activation reduced Ih amplitude and HCN1 surface expression, whereas PKC inhibition produced the opposite effect. Inhibition of protein phosphatases 1 and 2A and activation of PKC increased the serine phosphorylation state of the HCN1 protein. The effect of PKC activation on Ih was irreversible. These results indicate that PKC bidirectionally modulates Ih amplitude and HCN1 surface expression in hippocampal principal neurons. PMID- 25820762 TI - New oral anticoagulants versus vitamin K antagonists for treatment of acute venous thromboembolism: do they really increase the incidence of myocardial infarction? PMID- 25820763 TI - Optimized co-solute paramagnetic relaxation enhancement for the rapid NMR analysis of a highly fibrillogenic peptide. AB - Co-solute paramagnetic relaxation enhancement (PRE) is an attractive way to speed up data acquisition in NMR spectroscopy by shortening the T 1 relaxation time of the nucleus of interest and thus the necessary recycle delay. Here, we present the rationale to utilize high-spin iron(III) as the optimal transition metal for this purpose and characterize the properties of its neutral chelate form Fe(DO3A) as a suitable PRE agent. Fe(DO3A) effectively reduces the T 1 values across the entire sequence of the intrinsically disordered protein alpha-synuclein with negligible impact on line width. The agent is better suited than currently used alternatives, shows no specific interaction with the polypeptide chain and, due to its high relaxivity, is effective at low concentrations and in 'proton-less' NMR experiments. By using Fe(DO3A) we were able to complete the backbone resonance assignment of a highly fibrillogenic peptide from alpha1-antitrypsin by acquiring the necessary suite of multidimensional NMR datasets in 3 h. PMID- 25820765 TI - A cure for the high cost of hepatitis C virus treatment. PMID- 25820764 TI - Autologous intestinal reconstruction surgery as part of comprehensive management of intestinal failure. AB - Pediatric intestinal failure (IF) remains to be associated with significant morbidity and mortality, the most frequent underlying etiologies being short bowel syndrome (SBS), and primary motility disorders. Management aims to assure growth and development, while preventing complications and facilitating weaning off parenteral support (PS) by fully utilizing adaptation potential of the remaining gut. Probability of survival and weaning off PS is improved by coordinated multidisciplinary intestinal rehabilitation combining individualized physiological enteral and parenteral nutrition (PN), meticulous central line care and medical management with carefully planned surgical care. Increasing evidence suggests that autologous intestinal reconstruction (AIR) surgery is effective treatment for selected short bowel patients. Bowel lengthening procedures normalize pathological adaptation-associated short bowel dilatation with potential to support intestinal absorption and liver function by various mechanisms. Although reversed small intestinal segment, designed to prolong accelerated intestinal transit, improves absorption in adult SBS, its feasibility in children remains unclear. Controlled bowel obstruction to induce dilatation followed by bowel lengthening aims to gain extra length in patients with the shortest duodenojejunal remnant. Reduced PS requirement limits the extent of complications, improving prognosis and quality of life. The great majority of children with SBS can be weaned from PS while prognosis of intractable primary motility disorders remains poor without intestinal transplantation, which serves as a salvage therapy for life-threatening complications such as liver failure, central vein thrombosis or recurrent bloodstream infections. PMID- 25820766 TI - Reflections on the challenges of understanding racial, cultural and sexual differences in couple relationship research. AB - : In the field of systemic psychotherapy there has been much recent interest in the areas of culture and reflexivity, and in working with couples. In this article we reflect on the process of conducting research in these areas. Drawing on findings from a large, national, empirical mixed-methods study on long-term relationships, we use two examples from the data to illustrate the complexity of researching across racial, cultural and sexual differences, in terms of research design and sampling, fieldwork and research practice, and making sense of multidimensional data. We point to findings that suggest that notions of coupledom are culturally constructed and thus challenge straightforward ideas of the procreative, sexually active couple dyad, separate from intergenerational extended families. The clinical significance of the findings for both lesbian, gay, bisexual or queer and culturally diverse couples and families are discussed. PRACTITIONER POINTS: Cultural or racial matching is not a sufficient condition for engagement and empathy with couples and families.Critical reflexivity about similarity and difference is essential in cross-cultural systemic practice.'The couple' and its distance from the extended family may be defined differently in different cultures.One research tool used in this project, the emotion map, appears to have utility in clinical practice with couples and families. PMID- 25820767 TI - Analysis of L-homoarginine in biological samples by HPLC involving precolumn derivatization with o-phthalaldehyde and N-acetyl-L-cysteine. AB - L-Homoarginine (hArg) may play a role in regulating the metabolism of its structural homologue L-arginine via multiple pathways (including nitric oxide synthase) in animals. Accurate measurement of hArg is essential for studying its synthesis and utilization by cells and the whole body. Here, we describe a simple, sensitive and automated method for analysis of hArg in biological samples by high-performance liquid chromatography involving precolumn derivatization with o-phthalaldehyde (OPA) and N-acetyl-L-cysteine (NAC) as the thiol. The hArg-OPA NAC derivative was separated at 25 degrees C on a reversed-phase C18 material and detected by fluorescence at excitation and emission wavelengths of 340 and 450 nm, respectively. The total running time for one sample (including the time for column regeneration) was 20 min, with the retention time for hArg being 10.03 min. The limit of detection was 188 fmol hArg, which was equivalent to 12 nM hArg in the 160-ul assay mixture. The assay was linear between 1.0 and 80 pmol hArg injected into the HPLC column (equivalent to 0.0625 and 5 uM hArg in the 160-ul assay mixture, respectively). The precision (relative deviation, %) and bias (relative error, %) of the HPLC method were 0.52-1.16 and 0.42-1.12, respectively, for aqueous solutions of hArg and for various biological samples (e.g., plasma, liver, brain and kidney). This is a highly sensitive, accurate, efficient and easily automated method for analysis of hArg in biological samples and provides a useful tool for studying the biochemistry, nutrition, physiology and pharmacology of hArg and arginine in animals and humans. PMID- 25820769 TI - The unique N-terminal insert in the ribosomal protein, phosphoprotein P0, of Tetrahymena thermophila: Bioinformatic evidence for an interaction with 26S rRNA. AB - Phosphoprotein P0 (P0) is part of the stalk complex of the eukaryotic large ribosomal subunit necessary for recruiting elongation factors. While the P0 sequence is highly conserved, our group noted a 15-16 residue insert exclusive to the P0s of ciliated protists, including Tetrahymena thermophila. We hypothesized that this insert may have a function unique in ciliated protists, such as stalk regulation via phosphorylation of the insert. Almost no mention of this insert exists in the literature, and although the T. thermophila ribosome has been crystallized, there is limited structural data for Tetrahymena's P0 (TtP0) and its insert. To investigate the structure and function of the TtP0 insert, we performed in silico analyses. The TtP0 sequence was scanned with phosphorylation site prediction tools to detect the likelihood of phosphorylation in the insert. TtP0's sequence was also used to produce a homology model of the N-terminal domain of TtP0, including the insert. When the insert was modeled in the context of the 26S rRNA, it associated with a region identified as expansion segment 7B (ES7B), suggesting a potential functional interaction between ES7B and the insert in T. thermophila. We were not able to obtain sufficient data to determine whether a similar relationship exists in other ciliated protists. This study lays the groundwork for future experimental studies to verify the presence of TtP0 insert/ES7 interactions in Tetrahymena, and to explore their functional significance during protein synthesis. PMID- 25820768 TI - Anhedonic behavior in cryptochrome 2-deficient mice is paralleled by altered diurnal patterns of amygdala gene expression. AB - Mood disorders are frequently paralleled by disturbances in circadian rhythm related physiological and behavioral states and genetic variants of clock genes have been associated with depression. Cryptochrome 2 (Cry2) is one of the core components of the molecular circadian machinery which has been linked to depression, both, in patients suffering from the disease and animal models of the disorder. Despite this circumstantial evidence, a direct causal relationship between Cry2 expression and depression has not been established. Here, a genetic mouse model of Cry2 deficiency (Cry2 (-/-) mice) was employed to test the direct relevance of Cry2 for depression-like behavior. Augmented anhedonic behavior in the sucrose preference test, without alterations in behavioral despair, was observed in Cry2 (-/-) mice. The novelty suppressed feeding paradigm revealed reduced hyponeophagia in Cry2 (-/-) mice compared to wild-type littermates. Given the importance of the amygdala in the regulation of emotion and their relevance for the pathophysiology of depression, potential alterations in diurnal patterns of basolateral amygdala gene expression in Cry2 (-/-) mice were investigated focusing on core clock genes and neurotrophic factor systems implicated in the pathophysiology of depression. Differential expression of the clock gene Bhlhe40 and the neurotrophic factor Vegfb were found in the beginning of the active (dark) phase in Cry2 (-/-) compared to wild-type animals. Furthermore, amygdala tissue of Cry2 (-/-) mice contained lower levels of Bdnf-III. Collectively, these results indicate that Cry2 exerts a critical role in the control of depression related emotional states and modulates the chronobiological gene expression profile in the mouse amygdala. PMID- 25820770 TI - A pyrene-fused N-heteroacene with eleven rectilinearly annulated aromatic rings. AB - A highly soluble pyrene-fused undecacene is realized by end-capping the rectilinear aromatic pi-plane with triptycenylene units. Besides the good solubility, the compound shows a high tendency to crystallize. Two polymorphs from dichlorobenzene and chloroform are described. In the polymorph from chloroform, half of the molecules are strongly bent out of the pi-plane by 26.4 degrees . PMID- 25820771 TI - Plant cell reprogramming as an adaptive strategy. PMID- 25820772 TI - Autologous fascia pubovaginal slings after prior synthetic anti-incontinence procedures for recurrent incontinence: A multi-institutional prospective comparative analysis to de novo autologous slings assessing objective and subjective cure. AB - AIMS: Given the paucity of prospective data on the treatment of incontinent women with prior synthetic mid-urethral sling (MUS), we sought to report our prospective experience with autologous fascia pubovaginal sling placement (AF PVS) after prior synthetic mid-urethral sling (MUS). METHODS: An IRB-approved, multi-institutional, prospective cohort of patients from 2010 to 2013 undergoing AF-PVS for urinary incontinence was evaluated and stratified for the presence of a prior MUS. Pre-operative characteristics and validated quality of life questionnaires (IIQ-7 and UDI-6) were compared to post-operative pad usage, scores on the IIQ-7 and UDI-6, complications, and visual analog scale assessment of improvement. RESULTS: 288 patients met inclusion criteria, 59 (20.4%) of whom had undergone a prior MUS before AF-PVS placement. Of these 59 patients, 20 (33.9%) had a prior vaginal extrusion and 5 (8.5%) had suffered from obstruction requiring sling lysis or excision. With a median of 14 months follow-up, prior MUS placement was not associated with a significant difference in objective (55.9% vs. 62.4%, P = 0.37) or subjective cure (66.1% vs. 69.0%, P = 0.75) when compared to patients undergoing placement of an initial AF-PVS. Patients undergoing AF-PVS after prior MUS did have a significantly higher rate of urinary retention requiring intermittent catheterization (8.5% vs. 3.1%, P < 0.001) and re-operation (13.6% vs. 3.5%, P = 0.01) for persistent incontinence. CONCLUSIONS: Despite higher rates of retention and need for repeat operation, AF-PVS after failed MUS is an acceptable treatment option with no difference in success as compared to patients undergoing initial AF-PVS placement. Neurourol. Urodynam. 35:604-608, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 25820774 TI - How many molecules does it take to tell a story? Case studies, language, and an epistemic view of medicinal chemistry. AB - Medicinal chemistry has always been closer to the arts than other disciplines in the natural sciences. Instead of searching for natural laws, medicinal chemistry creates new molecular entities entailing desired pharmaceutical characteristics. While the productive output of medicinal chemistry is comprehensively documented, the epistemic paths of the creative process are less well described. Here we show how such paths could be visualized and how these visualizations relate to images developed in the history and philosophy of science. Based on the discussion of these visualizations, we argue that there is a need for a new language of creativity that can be employed during the very course of research, as opposed to its retrospective analysis. This language should be able to reflect both the status and directions in highly complex research processes that may have a clear goal, yet must remain open to unexpected moments of serendipity. PMID- 25820773 TI - T1rho imaging in premanifest Huntington disease reveals changes associated with disease progression. AB - BACKGROUND: Imaging biomarkers sensitive to Huntington's disease (HD) during the premanifest phase preceding motor diagnosis may accelerate identification and evaluation of potential therapies. For this purpose, quantitative MRI sensitive to tissue microstructure and metabolism may hold great potential. We investigated the potential value of T1rho relaxation to detect pathological changes in premanifest HD (preHD) relative to other quantitative relaxation parameters. METHODS: Quantitative MR parametric mapping was used to assess differences between 50 preHD subjects and 26 age- and sex-matched controls. Subjects with preHD were classified into two progression groups based on their CAG-age product (CAP) score; a high and a low/moderate CAP group. Voxel-wise and region-of interest analyses were used to assess changes in the quantitative relaxation times. RESULTS: T1rho showed a significant increase in the relaxation times in the high-CAP group, as compared to controls, largely in the striatum. The T1rho changes in the preHD subjects showed a significant relationship with CAP score. No significant changes in T2 or T2* relaxation times were found in the striatum. T2* relaxation changes were found in the globus pallidus, but no significant changes with disease progression were found. CONCLUSION: These data suggest that quantitative T1rho mapping may provide a useful marker for assessing disease progression in HD. The absence of T2 changes suggests that the T1rho abnormalities are unlikely owing to altered water content or tissue structure. The established sensitivity of T1rho to pH and glucose suggests that these factors are altered in HD perhaps owing to abnormal mitochondrial function. PMID- 25820775 TI - A national survey of Rett syndrome: age, clinical characteristics, current abilities, and health. AB - As part of a wider study to investigate the behavioral phenotype of a national sample of girls and women with Rett syndrome (RTT) in comparison to a well-chosen contrast group and its relationship to parental well-being, the development, clinical severity, current abilities and health of 91 participants were analyzed in relation to diagnostic, clinical and genetic mutation categories. Early truncating mutations or large deletions were associated with greater severity. Early regression was also associated with greater severity. All three were associated with lower current abilities. Epilepsy and weight, gastrointestinal and bowel problems were common co-morbidities. Participants with classic RTT had greater health problems than those with atypical RTT. A substantial minority of respondents reported fairly frequent signs of possible pain experienced by their relative with RTT. Overall, the study provides new data on the current abilities and general health of people with RTT and adds to the evidence that the severity of the condition and variation of subsequent disability, albeit generally within the profound range, may be related to gene mutation. The presence of certain co morbidities represents a substantial ongoing need for better health. The experience of pain requires further investigation. PMID- 25820777 TI - Metabolomics analysis of muscle from piglets fed low protein diets supplemented with branched chain amino acids using HPLC-high-resolution MS. AB - Low protein (LP) diet can reduce feed costs and decrease nitrogen emission. Branched chain amino acids (BCAA), especially leucine, have been shown to influence muscle protein metabolism. Here, we used HPLC-high-resolution MS-based metabolomics approach to investigate the effects of LP diet supplemented with BCAA on metabolome in the muscle of piglets. The 10-21 kg piglets were fed with LP diet supplemented with BCAA. Amino acids (AAs) and metabolomics profiles of plasma, muscle, and liver were analyzed. Free AA profiles of plasma showed increased levels of BCAA. Multivariate analysis showed significant difference in skeletal muscle metabolites among different diet treatment groups, and most of the identified differential compounds were involved in AA metabolism and protein anabolism. These compounds, including alanine, glutamine, sarcosine, ornithine, proline, methionine, and threonine, all increased in the BCAA supplemented group compared with normal protein diet group. Metabolic pathway analysis suggested that BCAA could be converted to nonessential AAs and their metabolites by direct or indirect synthesis under LP diets, which could participate in the muscle protein synthesis or energy metabolism, and ultimately reduced nitrogen emission. PMID- 25820776 TI - L-Asparaginase lowers plasma antithrombin and mannan-binding-lectin levels: Impact on thrombotic and infectious events in children with acute lymphoblastic leukemia. AB - BACKGROUND: L-asparaginase, a key therapeutic agent in the management of patients with acute lymphoblastic leukemia (ALL), dramatically impairs hepatic protein synthesis. We investigated the effects of prolonged exposure to L-asparaginase on antithrombin (AT), fibrinogen and mannan-binding-lectin (MBL) levels, and on the occurrence of thrombotic events (TE) and febrile neutropenia episodes (FN) in pediatric patients. PROCEDURE: Protein levels were measured in 97 children during 30 weeks of chemotherapy with L-asparaginase and up to 1 year following remission. TE and FN episodes were recorded during this period. RESULTS: Median AT level decreased from 0.96 IU/mL prior to treatment (range: 0.69-1.38) to 0.55 IU/mL (0.37-0.76) during therapy. Fibrinogen and MBL decreased from 3.18 g/L (1.29-7.28) and 1,177 ng/mL (57-5,343) to 1.56 g/L (0.84-2.13) and 193 ng/mL (57 544), respectively. All three proteins had recovered 1-4 weeks after L asparaginase cessation. TE were reported in 22 (23%) patients. Of these, 11 occurred after a median of 10 administrations of L-asparaginase. Fifty-one FN were associated with infections, of which 36 occurred during treatment with L asparaginase. Patients with low levels of MBL at diagnosis were at higher risk of FN associated with infections (RR = 1.59, 95%CI: 1.026-2.474). Both AT and MBL decreases were moderately correlated with fibrinogen (r = 0.51 and 0.58, respectively). CONCLUSIONS: Children with ALL are exposed to significant decrease in AT, fibrinogen and MBL levels, and concomitant increased risk of thrombosis and FN with infection during L-asparaginase treatment. Measuring plasma levels of these liver-derived proteins could help predict the occurrence of adverse events. PMID- 25820778 TI - A rigid naphthalenediimide triangle for organic rechargeable lithium-ion batteries. PMID- 25820779 TI - RORgammat(+) hematopoietic cells are necessary for tumor cell proliferation during colitis-associated tumorigenesis in mice. AB - Colorectal cancer (CRC) is one of the most common tumor entities. In patients with inflammatory bowel diseases, the development of colitis-associated colon cancer is considered a dangerous long-term complication. IL-17A and the transcription factor retinoic acid receptor-related orphan receptor gammat (RORgammat) play fundamental roles in the pathogenesis of inflammatory bowel diseases; in human studies, we detected a dense infiltration of RORgammat dependent CD4(+) IL17A(+) T helper (Th)17 cells in specimens of CRC, ulcerative colitis, and ulcerative colitis-associated colorectal cancer. However, the mechanistic role of RORgammat(+) hematopoietic cells in colitis-associated tumorigenesis remains unclear. To investigate colitis-associated colon tumorigenesis, we conducted studies in the AOM+DSS mouse model that revealed the importance of RORgammat for colon tumor progression. In the absence of RORgammat dependent Th17 lymphocytes, mice showed signs of intense chronic colitis, but developed significantly fewer macroscopic tumor nodules. The reduction of tumor development in RORgammat(-/-) mice was not due to reduced colon tumor initiation. However, the proliferation rate of tumor cells was reduced in the absence of RORgammat-dependent Th17 cells and tumor cells showed pronounced signs of senescence-associated epigenetic and lysosomal changes. These results indicate an important role for the immunological milieu in colitis-associated cancer, which is shaped in-part by RORgammat-dependent Th17 lymphocytes that support CRC growth. PMID- 25820780 TI - Ability and Disability in Autism Spectrum Disorder: A Systematic Literature Review Employing the International Classification of Functioning, Disability and Health-Children and Youth Version. AB - OBJECTIVE: This study is the first in a series of four empirical investigations to develop International Classification of Functioning, Disability and Health (ICF) Core Sets for Autism Spectrum Disorder (ASD). The objective was to use a systematic review approach to identify, number, and link functional ability and disability concepts used in the scientific ASD literature to the nomenclature of the ICF-CY (Children and Youth version of the ICF, covering the life span). METHODS: Systematic searches on outcome studies of ASD were carried out in Medline/PubMed, PsycINFO, ERIC and Cinahl, and relevant functional ability and disability concepts extracted from the included studies. These concepts were then linked to the ICF-CY by two independent researchers using a standardized linking procedure. New concepts were extracted from the studies until saturation of identified ICF-CY categories was reached. RESULTS: Seventy-one studies were included in the final analysis and 2475 meaningful concepts contained in these studies were linked to 146 ICF-CY categories. Of these, 99 categories were considered most relevant to ASD (i.e., identified in at least 5% of the studies), of which 63 were related to Activities and Participation, 28 were related to Body functions, and 8 were related to Environmental factors. The five most frequently identified categories were basic interpersonal interactions (51%), emotional functions (49%), complex interpersonal interactions (48%), attention functions (44%), and mental functions of language (44%). CONCLUSION: The broad variety of ICF-CY categories identified in this study reflects the heterogeneity of functional differences found in ASD--both with respect to disability and exceptionality--and underlines the potential value of the ICF-CY as a framework to capture an individual's functioning in all dimensions of life. The current results in combination with three additional preparatory studies (expert survey, focus groups, and clinical study) will provide the scientific basis for defining the ICF Core Sets for ASD for multipurpose use in basic and applied research and every day clinical practice of ASD. PMID- 25820781 TI - Quantum interference measurement of spin interactions in a bio organic/semiconductor device structure. AB - Quantum interference is used to measure the spin interactions between an InAs surface electron system and the iron center in the biomolecule hemin in nanometer proximity in a bio-organic/semiconductor device structure. The interference quantifies the influence of hemin on the spin decoherence properties of the surface electrons. The decoherence times of the electrons serve to characterize the biomolecule, in an electronic complement to the use of spin decoherence times in magnetic resonance. Hemin, prototypical for the heme group in hemoglobin, is used to demonstrate the method, as a representative biomolecule where the spin state of a metal ion affects biological functions. The electronic determination of spin decoherence properties relies on the quantum correction of antilocalization, a result of quantum interference in the electron system. Spin flip scattering is found to increase with temperature due to hemin, signifying a spin exchange between the iron center and the electrons, thus implying interactions between a biomolecule and a solid-state system in the hemin/InAs hybrid structure. The results also indicate the feasibility of artificial bioinspired materials using tunable carrier systems to mediate interactions between biological entities. PMID- 25820782 TI - The first wave of the 1918 influenza pandemic among soldiers of the Canadian expeditionary force. AB - OBJECTIVES: This article evaluates the evidence for the presence of the first, mild wave of the 1918 influenza pandemic among soldiers in the Canadian Expeditionary Force (CEF). METHODS: Death records for soldiers in the CEF who died in Canada in 1917 and 1918 were extracted from the Commonwealth War Graves Commission and record-linked to the Canada War Graves Registers, Circumstances of Casualty database. Monthly mortality rates from pneumonia and influenza (P&I) were compared with mortality rates from all other causes for 1917 and 1918, and by region for 1918. RESULTS: The herald wave of influenza was present among CEF soldiers in 1918. P&I mortality was significantly higher in March and April 1918 than during the same period in 1917. P&I mortality rates varied across the country and were significantly higher among soldiers who died in the Maritime region of Canada. In March, Maritime P&I mortality was significantly higher than its counterpart in the West; in April it was significantly higher than P&I mortality in both the Central and Western regions. CONCLUSIONS: The CEF findings suggest that local, geographic heterogeneity characterized the first wave of the 1918 influenza pandemic in Canada and illustrate the ways in which well established, historical patterns of cross-border social contact with the United States, coupled with the special conditions created by warfare, disproportionately funnelled influenza into particular regions. Identification of the mild first wave among soldiers in the CEF calls for more research on the civilian experience of both waves of influenza in Canada. PMID- 25820783 TI - Gaucher-Associated Parkinsonism. AB - Gaucher disease is associated with Parkinson's disease (PD) by mutations in glucocerebrosidase (GCase). The gene encoding GCase, glucosidase beta acid (GBA), is an important risk factor for PD. Findings from large studies have shown that patients with PD have an increased frequency of mutations in GBA and that GBA mutation carriers exhibit diverse parkinsonian phenotypes and Lewy body pathology. Although the mechanism for this association remains elusive, some hypotheses have been proposed to explain it, including gain of function caused by GBA mutations, which increases alpha-synuclein (alpha-syn) aggregation, loss of function due to lysosomal enzyme deficiency, which affects alpha-syn clearance, and even a bidirectional feedback loop, but each of these hypotheses has its limitations. It is also worth noting that many findings have implicated the interaction between alpha-syn and GCase, indicating the essential role of the interaction in the pathogenesis of GBA-associated parkinsonism. Therefore, the current review focuses on alpha-syn and GCase, and it provides some new thoughts that may be helpful for understanding the alpha-syn-GCase interaction and unraveling the exact mechanism underlying GBA-associated parkinsonism. PMID- 25820784 TI - Protective Effect of Pyrroloquinoline Quinone (PQQ) in Rat Model of Intracerebral Hemorrhage. AB - Pyrroloquinoline quinone (PQQ) has invoked considerable interest because of its presence in foods, antioxidant properties, cofactor of dehydrogenase, and amine oxidase. Protective roles of PQQ in central nervous system diseases, such as experimental stroke and spinal cord injury models have been emerged. However, it is unclear whether intracerebral hemorrhage (ICH), as an acute devastating disease, can also benefit from PQQ in experimental conditions. Herein, we examined the possible effect of PQQ on neuronal functions following ICH in the adult rats. The results showed that rats pretreated with PQQ at 10 mg/kg effectively improved the locomotor functions, alleviated the hematoma volumes, and reduced the expansion of brain edema after ICH. Also, pretreated rats with PQQ obviously reduced the production of reactive oxygen species after ICH, probably due to its antioxidant properties. Further, we found that, Bcl-2/Bax, the important indicator of oxidative stress insult in mitochondria after ICH, exhibited increasing ratio in PQQ-pretreated groups. Moreover, activated caspase 3, the apoptotic executor, showed coincident alleviation in PQQ groups after ICH. Collectively, we speculated that PQQ might be an effective and potential neuroprotectant in clinical therapy for ICH. PMID- 25820785 TI - Mitochondrial Cyclophilin D as a Potential Therapeutic Target for Ischemia Induced Facial Palsy in Rats. AB - Many studies have demonstrated that ischemia could induce facial nerve (FN) injury. However, there is a lack of a suitable animal model for FN injury study and thus little knowledge is available about the precise mechanism for FN injury. The aims of this study were to establish a reliable FN injury model induced by blocking the petrosal artery and to investigate whether dysfunctional interaction between cyclophilin D (CypD) and mitochondrial permeability transition pore (MPTP) can mediate cell dysfunction in ischemic FN injury. The outcomes of ischemia-induced FN injury rat model were evaluated by behavioral assessment, histological observation, electrophysiology, and electron microscopy. Then the levels of CypD and protein that forms the MPTP were evaluated under the conditions with or without the treatment of Cyclosporin A (CsA), which has been found to disrupt MPTP through the binding of CypD. The blocking of petrosal artery caused significant facial palsy signs in the ischemia group but not in the sham group. Furthermore, ischemia can induce the dysfunction of facial nucleus neurons and destruction of the myelin sheath and increase the protein levels of CypD and MPTP protein compared with sham group. Interestingly, treatment with CsA significantly improved neurological function and reversed the ischemia-induced increase of CypD and MPTP proteins in ischemia group. These results demonstrated that blocking of petrosal artery in rats can induce FN injury and the mechanism may be related to the disruption of MPTP by CypD. PMID- 25820787 TI - Synthesis of metalloporphyrin-based conjugated microporous polymer spheres directed by bipyridine-type ligands. AB - Zinc porphyrin (TP-Zn)-based conjugated microporous polymer (Zn-CMP) spheres were obtained via Sonagashira-Hagihara cross coupling reactions between 5,10,15,20 tetrakis(4-ethynylphenyl)porphyrin-Zn(II) and brominated monomers directed by bidentate bipyridine (BP)-type ligands for the first time, and the sphere diameters could be adjusted from 320 to 740 nm. The coordination between BP and TP-Zn was proved to be the key to forming spheres. PMID- 25820786 TI - Comparison of dynamic transperineal ultrasound and defecography for the evaluation of pelvic floor disorders. AB - INTRODUCTION: X-ray defecography is considered the gold standard for imaging pelvic floor pathology. However, it is limited by the capability to demonstrate only the posterior pelvic compartment, significant radiation exposure, and inconvenience. Dynamic transperineal ultrasound (DTP-US) can visualize all of three pelvic floor compartments, is free of radiation, and does not cause significant discomfort. The aim of this study was to evaluate the level of consistency between defecography (DEF) and DTP-US in the diagnosis of pelvic floor deformations. METHODS: One hundred and five women (age 56 +/- 11 years) suffering from constipation and fecal incontinence were clinically evaluated and further examined by DEF and DTP-US. The rate of diagnosis of pelvic floor hernias using the DTP-US was compared to that found on DEF. RESULTS: The specificity for the diagnosis of rectoceles was of 82% for mid-size rectocele and 98% for large rectoceles, and the sensitivity was of 59% for mid-size rectoceles and 50% for larger rectoceles. The sensitivity for the detection of intussusceptions, enteroceles, and rectal prolapse were 82, 74, and 75%, respectively. The specificity was 84% for the detection of intussusception, 92% for enteroceles, and 97% for the diagnosis of rectal prolapse. Higher rates of DTP-US diagnosis were obtained when the intussuscepted rectum moved closer toward the ultrasound probe. CONCLUSIONS: The sensitivity of DTP-US was good to excellent and the specificity was high. The added value of this technique in exploring all the compartments of the pelvic floor as well as the perineal muscles makes DTP-US a preferred procedure. PMID- 25820788 TI - Conspecific density modulates the effect of predation on dispersal rates. AB - Dispersal decisions underlie the spatial dynamics of metacommunities. Prey individuals may disperse to reduce the risk of either predation or starvation, and both of these risks may depend on conspecific density. Surprisingly, there is little theory examining how dispersal rates should change in response to the combined effects of predation and changes in conspecific density. We develop such a model and show that, under certain conditions, predators may induce dispersal at low prey densities but not high prey densities. We then experimentally manipulate the density of the ciliate Paramecium aurelia and the perceived presence of its predator, the flatworm Stenostomum virginiamum, in a two-patch metacommunity to parameterise the model. Paramecium dispersed in response to Stenostomum at low densities, but they reduced their dispersal in response to predation risk at high predator densities. By applying our model to the empirical data, we show that this switch in dispersal strategy, linked to increases in prey density, occurred because predators increased the difficulty or risk of dispersal. Together, the model and experiment reveal that the effects of predators on dispersal are contingent on prey density. Previous studies have sometimes reported an increase in dispersal rate when predation risk is elevated, and other times a decrease in dispersal rate. Our demonstration of a switch point, with predation risk increasing dispersal at low prey densities but reducing dispersal above a threshold of prey density, may reconcile the diversity of prey dispersal behaviours reported in these previous investigations and observed in nature. PMID- 25820789 TI - Biometallization-Based Electrochemical Magnetoimmunosensing Strategy for Avian Influenza A (H7N9) Virus Particle Detection. AB - A highly sensitive electrochemical immunosensor for avian influenza A (H7N9) virus (H7N9 AIV) detection was proposed by using electrochemical magnetoimmunoassay coupled with biometallization and anodic stripping voltammetry. This strategy could accumulate the enzyme-generated product on the surface of the magneto electrode by means of silver deposition, which amplified the detection signal about 80 times. The use of magnetic beads (MBs) and the magneto electrode could also amplify the detection signal. Furthermore, a bi electrode signal transduction system was introduced into this immunosensor, which is also beneficial to the immunoassay. A concentration as low as 0.011 ng mL(-1) of H7N9 AIV could be detected in about 1.5 h with good specificity. This study not only provides a simple and sensitive approach for virus detection but also offers an effective signal enhancement strategy for the development of highly sensitive MB-based electrochemical immunoassays. PMID- 25820791 TI - Simultaneous capture, detection, and inactivation of bacteria as enabled by a surface-enhanced Raman scattering multifunctional chip. AB - Herein, we present a multifunctional chip based on surface-enhanced Raman scattering (SERS) that effectively captures, discriminates, and inactivates pathogenic bacteria. The developed SERS chip is made of a silicon wafer decorated with silver nanoparticles and modified with 4-mercaptophenylboronic acid (4 MPBA). It was prepared in a straightforward manner by chemical reduction assisted by hydrogen fluoride etching, followed by the conjugation of 4-MPBA through Ag?S bonds. The dominant merits of the fabricated SERS chip include excellent reproducibility with a relative standard deviation (RSD) value smaller than 11.0 %, adaptable bacterial-capture efficiency (ca. 60 %) at low concentrations (500 2000 CFU mL(-1) ), a low detection limit (down to a concentration of 1.0*10(2) cells mL(-1) ), and high antibacterial activity (an antibacterial rate of ca. 97 %). The SERS chip enabled sensitive and specific discrimination of Escherichia coli and Staphylococcus aureus from human blood. PMID- 25820790 TI - Heart rate variability, adiposity, and physical activity in prepubescent children. AB - PURPOSE: This study aimed at examining the associations between weight status, body fat mass, and heart rate variability in prepubescent children, adjusting for physical activity levels. METHODS: A cross-sectional investigation in which a total of 50 Caucasian pre-pubertal children (21 normal weight; 8 overweight; 21 obese), aged 6-10 years (8.33 +/- 1.14), including both boys (n = 24) and girls (n = 26), were recruited from local schools. Total body fat and trunk fat were evaluated through dual-energy X-ray absorptiometry. Free-living physical activity levels were evaluated by accelerometer. Short-term heart rate variability acquisition was performed; time- and frequency-domain parameters were analysed. Logarithmic transformations of the low-frequency (LnLFnu), high-frequency (LnHFnu) normalized units and low-frequency/high-frequency (LnLFnu/HFnu) ratio were computed. RESULTS: Adjusting for age, Tanner stage, and moderate to vigorous physical activity levels, obese children compared to normal weight children showed a significant decreased LnHfnu (3.8 +/- 0.2 vs 4.1 +/- 0.2 %) and both higher LnLFnu (4.0 +/- 0.4 vs 3.7 +/- 0.3 %) and LnLFnu/LnHFnu ratio (1.1 +/- 0.1 vs 0.9 +/- 0.1). LnHFnu showed significant negative correlation with waist circumference (r = -0.598; P = 0.000), total body fat (r = -0.409; P = 0.011) and trunk fat (r = -0.472; P = 0.003). Both LnLFnu and LnLFnu/LnHFnu ratio showed positive correlations with waist circumference (r = 0.455; r = 0.513) and trunk fat (r = 0.370; r = 0.415). CONCLUSIONS: A higher amount of body fat mass, particularly central fat, was shown to be related to decreased parasympathetic modulation in time-domain heart rate variability. This finding highlights the potential cardiovascular risk that excessive fat mass may represent even at very young age. PMID- 25820792 TI - Dimensional assessment of continuous loop cortical suspension devices and clinical implications for intraoperative button flipping and intratunnel graft length. AB - Continuous loop cortical suspension devices have been demonstrated to be more consistent and biomechanically superior compared to adjustable loop devices; however, continuous loop devices present unique challenges compared to adjustable loop devices, especially in short tunnel reconstruction applications. Specifically, adjustable loop devices have the advantage of a "one size fits all" approach, and the ability to tension these devices following button flipping allows for the intratunnel graft length to be maximized. Nevertheless, the reliability of continuous loop devices has sustained their widespread use. We hypothesized that continuous loop cortical suspension devices from different manufacturers would exhibit equivalent 15 mm loop lengths, as advertised. Loop length was measured using a tensile testing machine. Contrary to our hypothesis, continuous loop cortical suspension devices with equivalent advertised lengths exhibited different loop lengths (up to 27% discrepancy). Inconsistencies with regards to manufacturers' reported loop lengths for continuous loop devices could have serious clinical implications and additionally complicate technique transferal among devices. Consequently, the manufacturers' accurate and complete disclosure of the dimensions and specifications associated with each continuous loop device is critical. Furthermore, surgeon awareness of true loop length dimensions and inconsistencies among devices is needed to ensure optimal implantation and resultant clinical outcomes. PMID- 25820793 TI - Morphotropic Phase Boundary in the Pb-Free (1 - x)BiTi(3/8)Fe(2/8)Mg(3/8)O3 xCaTiO3 System: Tetragonal Polarization and Enhanced Electromechanical Properties. PMID- 25820794 TI - Impact of Taylor-Aris diffusivity on analyte and system zone dispersion in CZE assessed by computer simulation and experimental validation. AB - Application of pressure-driven laminar flow has an impact on zone and boundary dispersion in open tubular CE. The GENTRANS dynamic simulator for electrophoresis was extended with Taylor-Aris diffusivity which accounts for dispersion due to the parabolic flow profile associated with pressure-driven flow. Effective diffusivity of analyte and system zones as functions of the capillary diameter and the amount of flow in comparison to molecular diffusion alone were studied for configurations with concomitant action of imposed hydrodynamic flow and electroosmosis. For selected examples under realistic experimental conditions, simulation data are compared with those monitored experimentally using modular CE setups featuring both capacitively coupled contactless conductivity and UV absorbance detection along a 50 MUm id fused-silica capillary of 90 cm total length. The data presented indicate that inclusion of flow profile based Taylor Aris diffusivity provides realistic simulation data for analyte and system peaks, particularly those monitored in CE with conductivity detection. PMID- 25820795 TI - Adsorption of polyelectrolytes to like-charged substrates induced by multivalent counterions as exemplified by poly(styrene sulfonate) and silica. AB - The present study demonstrates that multivalent counterions trigger adsorption of polyelectrolytes on a like-charged substrate. In particular, adsorption of polystyrene sulfonate on silica is studied experimentally in NaCl, MgCl2, and LaCl3 solutions by optical reflectivity. While adsorption is negligible in the presence of Na(+), the polyelectrolyte adsorbs in the presence of Mg(2+) and La(3+). The adsorbed amount of the polyelectrolyte goes through a maximum as a function of the salt concentration. This maximum increases with increasing valence and shifts to lower salt concentrations. At low salt concentration, the adsorption is negligible. At intermediate salt level, ripening and multilayer formation leads to continuous growth of the adsorbed layer. At higher salt level, blocking and formation of a monolayer lead to saturation. These results are tentatively interpreted in terms of a charge reversal of the polyelectrolyte metal complex. The molecular mass of the polyelectrolyte has an important effect on the adsorption behavior, whereby the tendency towards ripening becomes more pronounced at large molecular mass. PMID- 25820796 TI - Transplantation for hepatocellular carcinoma: more haste, less speed? PMID- 25820798 TI - Twenty-year survival post-liver transplant: challenges and lessons. AB - There have been numerous reports on survival outcomes after liver transplantation with short-term and mid-term follow-up. However, only a few reports are available for 20-year long-term survivors after liver transplantation. In Korea, the first successful deceased donor liver transplantation (DDLT) in a 13-year-old Wilson's disease patient was performed in 1988, and the first successful living donor liver transplantation (LDLT) in 9-month biliary atresia patient was performed in 1994. Because of the severe shortage of deceased donors and delayed launching of LDLT from December 1994, only 38 cases of liver transplantation (two pediatric LDLTs and 36 DDLTs) from 1988 to 1994 were included in this study (Strong and Fawcett, Hepatol Int 2015 [1]. doi: 10.1007/s12072-015-9617-1) to investigate more than 20-year survivors. Six adult recipients after DDLT and three pediatric recipients (one DDLT, two LDLTs) are alive now with normal liver function in Korea. Twenty-year survivors after DDLT and LDLT do not show that significant co morbidities related to long-term immunosuppression and high-dose indefinite HBIG monotherapy has shown the reliable modality to prevent HBV-reinfection for HBV related liver transplant candidates. PMID- 25820797 TI - Management of post transplant hepatitis C in the direct antiviral agents era. AB - Hepatitis C virus (HCV) infection is one of the main indications for liver transplantation. Viral recurrence occurs in all patients with detectable serum HCV RNA at the time of transplantation leading to cirrhosis in 20-30% of patients within 5 years. Viral eradication using antiviral therapy has been shown to improve patient and graft survival. Pegylated interferon (PEG-IFN) and ribavirin (RBV) antiviral therapy achieved SVR in around 30% of transplant recipients. In the non-transplant setting, first generation NS3/4 protease inhibitors, boceprevir or telaprevir associated with PEG-IFN and RBV, has improved the SVR rates to 75% in genotype 1 infected patients. However, tolerability and drug-drug interactions with calcineurin inhibitors are both limiting factors of their use in transplant recipients. In the non-transplant patients, using new direct-acting antiviral therapy has dramatically improved the efficacy of antiviral C therapy over recent years leading to SVR rates over 90% in phase II and III clinical trials, without PEG-IFN and/or RBV. Preliminary results in transplant patients showed better efficacy, better tolerability and less drug-drug interactions. PMID- 25820799 TI - Medication risk mitigation matrix: A pharmaceutical care opportunity for precision medication. PMID- 25820800 TI - Employment of 4-(1,2,4-triazol-1-yl)phenol as a signal enhancer of the chemiluminescent luminol-H2O2-horseradish peroxidase reaction for detection of hepatitis C virus in real samples. AB - Highly sensitive detection of hepatitis C virus (HCV) in serum is a key method for diagnosing and classifying the extent of HCV infection. In this study, a p phenol derivative, 4-(1,2,4-triazol-1-yl)phenol (4-TRP), was employed as an efficient enhancer of the luminol-hydrogen peroxide (H2O2)-horseradish peroxidase (HRP) chemiluminescence (CL) system for detection of HCV. Compared with a traditional enhancer, 4-TRP strongly enhanced CL intensity with the effect of prolonging and stabilizing light emission. The developed CL system was applied to detecting HCV core antigen (HCV-cAg) using a sandwich structure inside microwells. Our experimental results showed that there was good linear relationship between CL intensity and HCV-cAg concentration in the 0.6-3.6 pg/mL range (R = 0.99). The intra- and inter-assay coefficients of variation were 4.5 5.8% and 5.0-7.3%, respectively. In addition, sensitive determination of HCV-cAg in serum samples using the luminol-H2O2-HRP-4-TRP CL system was also feasible in clinical settings. PMID- 25820801 TI - Electroconvulsive therapy during pregnancy revisited. PMID- 25820802 TI - Brachytherapy in pelvic malignancies: a review for radiologists. AB - Brachytherapy, also known as sealed source or internal radiation therapy, involves placement of a radioactive source immediately adjacent to or within tumor, thus enabling delivery of a localized high dose of radiation. Compared with external beam radiation which must first pass through non-target tissues, brachytherapy results in less radiation dose to normal tissues. In the past decade, brachytherapy use has markedly increased, thus radiologists are encountering brachytherapy devices and their associated post-treatment changes to increasing degree. This review will present a variety of brachytherapy devices that radiologists may encounter during diagnostic pelvic imaging with a focus on prostate and gynecologic malignancies. The reader will become familiar with the function, correct position, and potential complications of brachytherapy devices in an effort to improve diagnostic reporting and communication with clinicians. PMID- 25820803 TI - Computed tomography after nephron-sparing surgery. AB - The increased use of abdominal cross-sectional imaging has contributed to a greater detection of incidental small renal masses. Treatment options for localized disease renal cell carcinoma include radical nephrectomy or partial nephrectomy (PN), the former being preferred for treatment of early-stage tumors. The most adopted technique for follow-up imaging is contrast-enhanced computed tomography (CT), whose findings can cause uncertainty and unnecessary repetition of examinations. Our purpose is to describe CT findings after PN and to describe evolution in time of such images. PMID- 25820804 TI - [Fistulas of the lower urinary tract in children]. AB - A lower urinary tract fistula consist in an abnormal connection between bladder, urethra and adjacent abdominal organs or skin. There are several types of urinary fistulas in paediatric age and they may be congenital or acquired. Etiology may be due to embriological defects, infectious processes, malignant tumours, pelvic irradiation as well as complications following surgical procedures, especially postsurgical repair of hypospadia or epispadia. Clinical presentation depends on the type of fistula and diagnosis is based on signs, symptoms and radiological or endoscopic examinations. We performed PubMed research using terms such as lower urinary fistulae, urology and paediatrics and we consulted medical texts. We reviewed selected articles and used the relevant ones to perform our study concentrating on classification, diagnosis and treatment of different types of fistulas. Paediatric lower urinary fistulas are an uncommon pathology, but the knowledge of their etiology and classification is important to recognise them and lead the physician to an appropriate treatment, which is surgical in most cases. PMID- 25820806 TI - Radiologic resolution of malignant infantile osteopetrosis skeletal changes following hematopoietic stem cell transplantation. AB - INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is the only known curative treatment of malignant infantile osteopetrosis (MIOP). In this study, short-term serial bone surveys were used to assess radiologic evolution of skeletal changes after HSCT in MIOP. MATERIALS AND METHODS: Baseline whole-body bone survey was performed in all patients. HSCT was successful in 14 patients (11 with full chimerism, three with mixed chimerism) in whom follow-up bone surveys were carried out at 6 and 12 months after HSCT. RESULTS: Normal corticomedullary differentiation was evident in five (P = 0.06) and 12 (P < 0.005) patients at 6 and 12 months, respectively. Abnormal endobone appearance in long bones, present in 11 participants at baseline exam, disappeared in eight (P = 0.008) and all (P = 0.001) patients at 6 and 12 months, respectively. In 6-month follow-up, rachitic changes significantly disappeared (P < 0.01) in long bones; however, they were evident in ribs of 12 patients (P = 0.50). No patient had rickets in ribs or long bones after 12 months. CONCLUSION: We observed considerable resolution of MIOP skeletal changes after HSCT in all patients with either full or mixed chimerism. Rachitic changes in long bones, attenuated corticomedullary differentiation, and endobone appearance were the first to resolve. We propose using single long bone plain x-ray to demonstrate short-term skeletal response to HSCT. PMID- 25820805 TI - BCL::MP-fold: Membrane protein structure prediction guided by EPR restraints. AB - For many membrane proteins, the determination of their topology remains a challenge for methods like X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. Electron paramagnetic resonance (EPR) spectroscopy has evolved as an alternative technique to study structure and dynamics of membrane proteins. The present study demonstrates the feasibility of membrane protein topology determination using limited EPR distance and accessibility measurements. The BCL::MP-Fold (BioChemical Library membrane protein fold) algorithm assembles secondary structure elements (SSEs) in the membrane using a Monte Carlo Metropolis (MCM) approach. Sampled models are evaluated using knowledge-based potential functions and agreement with the EPR data and a knowledge-based energy function. Twenty-nine membrane proteins of up to 696 residues are used to test the algorithm. The RMSD100 value of the most accurate model is better than 8 A for 27, better than 6 A for 22, and better than 4 A for 15 of the 29 proteins, demonstrating the algorithms' ability to sample the native topology. The average enrichment could be improved from 1.3 to 2.5, showing the improved discrimination power by using EPR data. PMID- 25820807 TI - Plant Sterol Diversity in Pollen from Angiosperms. AB - Here we have examined the composition of free sterols and steryl esters of pollen from selected angiosperm species, as a first step towards a comprehensive analysis of sterol biogenesis in the male gametophyte. We detected four major sterol structural groups: cycloartenol derivatives bearing a 9beta,19-cyclopropyl group, sterols with a double bond at C-7(8), sterols with a double bond at C 5(6), and stanols. All these groups were unequally distributed among species. However, the distribution of sterols as free sterols or as steryl esters in pollen grains indicated that free sterols were mostly Delta(5)-sterols and that steryl esters were predominantly 9beta,19-cyclopropyl sterols. In order to link the sterol composition of a pollen grain at anthesis with the requirement for membrane lipid constituents of the pollen tube, we germinated pollen grains from Nicotiana tabacum, a model plant in reproductive biology. In the presence of radiolabelled mevalonic acid and in a time course series of measurements, we showed that cycloeucalenol was identified as the major neosynthesized sterol. Furthermore, the inhibition of cycloeucalenol neosynthesis by squalestatin was in full agreement with a de novo biogenesis and an apparent truncated pathway in the pollen tube. PMID- 25820808 TI - Proteomic Analysis Reveals PGAM1 Altering cis-9, trans-11 Conjugated Linoleic Acid Synthesis in Bovine Mammary Gland. AB - cis-9, trans-11 Conjugated linoleic acid (CLA) is one of the most extensively studied CLA isomers due to its multiple isomer-specific effects. However, the molecular mechanisms of cis-9,trans-11 CLA synthesis in ruminant mammary gland are still not clearly understood. This process may be mediated, to a certain extent, by trans-11 C18:1 regulated by stearoyl-CoA desaturase-1 (SCD1) and/or its syntrophic proteins. This study aimed to investigate the effects of TVA on SCD1-mediated cis-9,trans-11 CLA synthesis in MAC-T cells and its potential molecular mechanism. Results showed that trans-11 C18:1 was continually taken up and converted into cis-9,trans-11 CLA in MAC-T cells during the 4-h incubation of 50 MUM trans-11 C18:1. SCD1 protein expression increased more than twofold at 2 h (P < 0.01) and 2.5 h (P < 0.05) before decreasing to less than half of the normal level at 4 h (P < 0.05). One up-regulated (RAS guanyl releasing protein 4 isoform 1 [RASGRP4]) and six down-regulated proteins (glucosamine-6-phosphate deaminase 1 [GNPDA1], triosephosphate isomerase [TPI1], phosphoglycerate mutase 1 [PGAM1], heat shock protein beta-1 [HSPB1], annexin A3 [ANXA3], thiopurine S methyltransferase [TPMT]) were found in MAC-T cells treated with trans-11 C18:1. Of these seven identified proteins, the presence of GNPDA1 and PGAM1 was verified in several models. More trans-11 C18:1 was taken up after PGAM1 knockdown by small interfering RNA (siRNA). In conclusion, our data suggested that PGAM1 may have a negative relationship with SCD1 and seemed to be involved in cis-9, trans 11 CLA synthesis by facilitating the absorption of trans-11 C18:1 in the bovine mammary gland. PMID- 25820809 TI - Intuition versus cognition: a qualitative exploration of how women understand and manage their increased breast cancer risk. AB - Risk comprehension in individuals at increased familial risk of cancer is suboptimal and little is known about how risk is understood and managed by at risk individuals who do not undergo genetic testing. We qualitatively studied these issues in 36 unaffected women from high-risk breast cancer families, including both women who had and had not undergone genetic testing. Data were collected through semi-structured interviews and data analysis was guided by Grounded Theory. Risk comprehension and risk management were largely influenced by the individual's experience of coming from a high-risk family, with both tested and untested women relying heavily on their intuition. Although women's cognitive understanding of their risk appeared generally accurate, this objective risk information was considered of secondary value. The findings could be used to guide the development and delivery of information about risk and risk management to genetically tested and untested individuals at increased risk of hereditary cancer. PMID- 25820810 TI - Two novel homozygous missense mutations in the GDF5 gene cause brachydactyly type C. AB - Mutations of the GDF5 gene cause a variable phenotype including brachydactyly type C. A review of the literature showed that it is caused either by heterozygous frameshift mutations within the prodomain or heterozygous missense/nonsense mutations within the active domain. Only a single patient with a homozygous mutation (c.517A > G, which predicts p. Met173Val) has been reported in this disorder. In this paper, we report two children with novel homozygous missense mutations in the GDF5 gene associated with brachydactyly type C: one mutation was within the region coding for the prodomain (c.608C > A, which predicts p.Thr203Asn) and the other was within the region coding for the active domain (c.1456 G > A, which predicts p.Val486Met). The genotype-phenotype correlations in the mutational spectrum of the GDF5 gene are discussed. PMID- 25820811 TI - Altered structure of cortical sulci in gilles de la Tourette syndrome: Further support for abnormal brain development. AB - Gilles de la Tourette syndrome is a neurodevelopmental disorder characterized by the presence of motor and vocal tics. We hypothesized that patients with this syndrome would present an aberrant pattern of cortical formation, which could potentially reflect global alterations of brain development. Using 3 Tesla structural neuroimaging, we compared sulcal depth, opening, and length and thickness of sulcal gray matter in 52 adult patients and 52 matched controls. Cortical sulci were automatically reconstructed and identified over the whole brain, using BrainVisa software. We focused on frontal, parietal, and temporal cortical regions, in which abnormal structure and functional activity were identified in previous neuroimaging studies. Partial correlation analysis with age, sex, and treatment as covariables of noninterest was performed amongst relevant clinical and neuroimaging variables in patients. Patients with Gilles de la Tourette syndrome showed lower depth and reduced thickness of gray matter in the pre- and post-central as well as superior, inferior, and internal frontal sulci. In patients with associated obsessive-compulsive disorder, additional structural changes were found in temporal, insular, and olfactory sulci. Crucially, severity of tics and of obsessive-compulsive disorder measured by Yale Global Tic severity scale and Yale-Brown Obsessive-Compulsive scale, respectively, correlated with structural sulcal changes in sensorimotor, temporal, dorsolateral prefrontal, and middle cingulate cortical areas. Patients with Gilles de la Tourette syndrome displayed an abnormal structural pattern of cortical sulci, which correlated with severity of clinical symptoms. Our results provide further evidence of abnormal brain development in GTS. PMID- 25820812 TI - Feedback regulation of IFN-alpha/beta signaling by Axl receptor tyrosine kinase modulates HBV immunity. AB - Hepatitis B virus (HBV) is known to cause age-dependent infection outcomes wherein most infections during young age result in chronicity. The mechanism underlying the differential outcome remains elusive. By using hydrodynamic injection of the replication-competent pAAV-HBV, we established a mouse model in which HBV persistence was generated in 4-5 w/o C57BL/6 young mice, but not in adult mice over 10 w/o. HBV-tolerant young mice expressed higher interferon (IFN) alpha/beta levels in hepatocytes and intrahepatic plasmacytoid DCs (pDCs) than adult mice after pAAV-HBV injection. Excessive IFN-alpha/beta expression in young mice was associated with induction of the Axl regulatory pathway and expansion of intrahepatic Treg cells. In line with these findings, augmented IFN-beta expression increased Axl expression in the liver and HBV persistence in adult mice, whereas IFN-alpha/beta signaling blockage decreased Axl expression and HBV persistence in young mice. Accordingly, Axl overexpression decreased HBV clearance of adult mice whereas Axl silencing enhanced HBV clearance of young mice. In vitro, IFN-beta priming of pDCs and Axl-overexpressing macrophages enhanced Treg-cell differentiation. These findings suggest that age-dependent HBV chronicity is attributed to IFN-beta-Axl immune regulation, which is selectively induced in young mice by excessive IFN-alpha/beta production at early stage of HBV infection. PMID- 25820813 TI - Bacillus subtilis subsp. subtilis CBMDC3f with antimicrobial activity against Gram-positive foodborne pathogenic bacteria: UV-MALDI-TOF MS analysis of its bioactive compounds. AB - In this work a new Bacillus sp. strain, isolated from honey, was characterized phylogenetically. Its antibacterial activity against three relevant foodborne pathogenic bacteria was studied; the main bioactive metabolites were analyzed using ultraviolet matrix assisted laser desorption-ionization mass spectrometry (UV-MALDI MS). Bacillus CBMDC3f was phylogenetically characterized as Bacillus subtilis subsp. subtilis after rRNA analysis of the 16S subunit and the gyrA gene (access codes Genbank JX120508 and JX120516, respectively). Its antibacterial potential was evaluated against Listeria monocytogenes (9 strains), B. cereus (3 strains) and Staphylococcus aureus ATCC29213. Its cell suspension and cell-free supernatant (CFS) exerted significant anti-Listeria and anti-S. aureus activities, while the lipopeptides fraction (LF) also showed anti-B. cereus effect. The UV-MALDI-MS analysis revealed surfactin, iturin and fengycin in the CFS, whereas surfactin predominated in the LF. The CFS from CBMDC3f contained surfactin, iturin and fengycin with four, two and four homologues per family, respectively, whereas four surfactin, one iturin and one fengycin homologues were identified in the LF. For some surfactin homologues, their UV-MALDI-TOF/TOF (MS/MS; Laser Induced Decomposition method, LID) spectra were also obtained. Mass spectrometry analysis contributed with relevant information about the type of lipopeptides that Bacillus strains can synthesize. From our results, surfactin would be the main metabolite responsible for the antibacterial effect. PMID- 25820814 TI - Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries. AB - OBJECTIVES: This study aims at performing a systematic review and meta-analysis with the studies of genetic admixture inference of Brazilian population and to compare these results with the genetic admixture levels in other Latin American countries. METHODS: We searched for articles regarding the estimation of Brazilian genetic admixture published between 1980 and 2014 that used autosomal markers. Then, conducted meta-analyses at the whole-country and regional level. Finally, we compared the results of Brazil with other estimates from other South, Central and North American countries. RESULTS: We analyzed data from 25 studies in 38 different Brazilian populations. European (EUR) ancestry is the major contributor to the genetic background of Brazilians, followed by African (AFR), and Amerindian (AMR) ancestries. The pooled ancestry contributions were 0.62 EUR, 0.21 AFR, and 0.17AMR. The Southern region had a greater EUR contribution (0.77) than other regions. Individuals from the Northeast (NE) region had the highest AFR contribution (0.27) whereas individuals from the North regions had more AMR contribution (0.32). In the Latin America context, Brazil has the 5th high EUR contribution, the 12th for the AFR component and the 10th for the AMR ancestry. CONCLUSIONS: Admixture proportions vary greatly among Brazilian populations and also through Latin America. More studies in the Center-West, North and NE regions are needed to capture a more complete picture of the genomic ancestry of Brazil. PMID- 25820815 TI - Spatial training preserves associative memory capacity with augmentation of dendrite ramification and spine generation in Tg2576 mice. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder and there is currently no efficient cure for this devastating disease. Cognitive stimulation can delay memory loss during aging and in patients with mild cognitive impairment. In 3 * Tg-AD mice, training decreased the neuropathologies with transient amelioration of memory decline. However, the neurobiological mechanisms underlying the learning-improved memory capacity are poorly understood. Here, we found in Tg2576 mice spatial training in Morris water maze (MWM) remarkably improved the subsequent associative memory acquisition detected by contextual fear conditioning. We also found that spatial training enhanced long term potentiation, dendrite ramification and spine generation in hippocampal dentate gyrus (DG) and CA1 neurons at 24 h after the training. In the molecular level, the MWM training remarkably activated calcium/calmodulin-dependent protein kinase II (CaMKII) with elevation of glutamate AMPA receptor GluA1 subunit (GluA1), postsynaptic density protein 93 (PSD93) and postsynaptic density protein 95 (PSD95) in the hippocampus. Finally, the training also significantly ameliorated AD-like tau and amyloid pathologies. We conclude that spatial training in MWM preserves associative memory capacity in Tg2576 mice, and the mechanisms involve augmentation of dendrite ramification and spine generation in hippocampus. PMID- 25820816 TI - Rapid Linguistic Ambiguity Resolution in Young Children with Autism Spectrum Disorder: Eye Tracking Evidence for the Limits of Weak Central Coherence. AB - Individuals with autism spectrum disorders (ASD) have often been reported to have difficulty integrating information into its broader context, which has motivated the Weak Central Coherence theory of ASD. In the linguistic domain, evidence for this difficulty comes from reports of impaired use of linguistic context to resolve ambiguous words. However, recent work has suggested that impaired use of linguistic context may not be characteristic of ASD, and is instead better explained by co-occurring language impairments. Here, we provide a strong test of these claims, using the visual world eye tracking paradigm to examine the online mechanisms by which children with autism resolve linguistic ambiguity. To address concerns about both language impairments and compensatory strategies, we used a sample whose verbal skills were strong and whose average age (7; 6) was lower than previous work on lexical ambiguity resolution in ASD. Participants (40 with autism and 40 controls) heard sentences with ambiguous words in contexts that either strongly supported one reading or were consistent with both (John fed/saw the bat). We measured activation of the unintended meaning through implicit semantic priming of an associate (looks to a depicted baseball glove). Contrary to the predictions of weak central coherence, children with ASD, like controls, quickly used context to resolve ambiguity, selecting appropriate meanings within a second. We discuss how these results constrain the generality of weak central coherence. PMID- 25820818 TI - Thermally-activated recombination in one component of (CH3NH3)PbI3/TiO2 observed by photocurrent spectroscopy. AB - Photocurrent measurements on devices containing perovskite (CH3NH3)PbI3 show two distinct spectral responses when deposited in a mesoporous oxide matrix, compared with one response for planar perovskite alone. With a TiO2 matrix, the shorter wavelength response has an inverted temperature response with increasing performance on cooling. PMID- 25820817 TI - A prospective study of erythrocyte polyunsaturated fatty acid, weight gain, and risk of becoming overweight or obese in middle-aged and older women. AB - PURPOSE: omega3 and omega6 fatty acids (FA) may have divergent effects on the development of obesity. We examined the association of baseline erythrocyte omega3 and omega6 FA composition with body weight change and the risk of becoming overweight or obese in the Women's Health Study (WHS) participants. METHODS: We identified 534 women who had baseline erythrocyte FA measured and a baseline body mass index (BMI) of 18.5-<25 kg/m(2). Body weight was updated at a total of six time points during follow-up. RESULTS: Weight gain during a mean of 10.4-year follow-up increased with increasing quartiles of baseline erythrocyte cis omega6 FA, omega6/omega3 ratio, and trans FA while decreased with increasing cis omega3 FA. After multivariable adjustment including total energy intake and physical activity, the weight gain (kg) in the highest versus the lowest quartile was 3.08 versus 2.32 for erythrocyte cis omega6 FA (p trend 0.04), 2.07 versus 2.92 for cis omega3 FA (p trend 0.08), 2.93 versus 2.05 for omega6/omega3 ratio (p trend 0.046), and 3.03 versus 2.27 for trans FA (p trend 0.06). Among individual FA, the associations were significant for 18:2omega6, 18:3omega6, and trans 18:1 and marginally significant for 20:3omega6 and trans 18:2. The risk of becoming overweight or obese (defined as BMI >=25 kg/m(2) at any follow-up time point) increased across increasing omega6/omega3 ratio (multivariable model p trend 0.04). CONCLUSIONS: In this prospective study, we found suggestive evidence that erythrocyte cis omega6 FA may be positively associated, and cis omega3 FA inversely associated with weight gain in initially normal-weight women. PMID- 25820819 TI - Starch based polyhydroxybutyrate production in engineered Escherichia coli. AB - Every year, the amount of chemosynthetic plastic accumulating in the environment is increasing, and significant time is required for decomposition. Bio-based, biodegradable plastic is a promising alternative, but its production is not yet a cost effective process. Decreasing the production cost of polyhydroxyalkanoate by utilizing renewable carbon sources for biosynthesis is an important aspect of commercializing this biodegradable polymer. An Escherichia coli strain that expresses a functional amylase and accumulate polyhydroxybutyrate (PHB), was constructed using different plasmids containing the amylase gene of Panibacillus sp. and PHB synthesis genes from Ralstonia eutropha. This engineered strain can utilize starch as the sole carbon source. The maximum PHB production (1.24 g/L) was obtained with 2% (w/v) starch in M9 media containing 0.15% (w/v) yeast extract and 10 mM glycine betaine. The engineered E. coli SKB99 strain can accumulate intracellular PHB up to 57.4% of cell dry mass. PMID- 25820820 TI - Platelet VEGF and serum TGF-beta1 levels predict chemotherapy response in non small cell lung cancer patients. AB - We examined the levels of platelet vascular endothelial growth factor (VEGF(PLT)) and serum level of transforming growth factor beta 1 (TGF-beta1) in non-small cell lung cancer (NSCLC) patients before and after chemotherapy to assess their clinical value as biomarkers. A total of 115 subjects were recruited at the First Hospital of Qinhuangdao between July 2012 and October 2013, including 65 NSCLC patients receiving chemotherapy (NSCLC group) and 50 healthy controls (control group). All NSCLC patients received gemcitabine plus cisplatin (GP regimen) for a total of two courses. VEGF(PLT) and serum TGF-beta1 levels were measured before and after chemotherapy using enzyme-linked immunosorbent assay (ELISA). Platelet count was obtained using the Abbott CD-1600 auto blood analyzer. NSCLC group was categorized into complete response (CR) plus partial response (PR) group and stable disease (SD) plus progressive disease (PD) group based on the results of CT scans obtained 1 week after chemotherapy. Our results revealed that VEGF(PLT) and serum TGF-beta1 levels were significantly higher in NSCLC group before chemotherapy, compared to the control group (VEGF(PLT), 0.813 +/- 0.072 vs. 0.547 +/- 0.024; t = 26.48; P < 0.001 and TGF-beta1, 46.00 +/- 4.47 vs. 16.43 +/- 2.12; t = 44.87; P < 0.001). Importantly, VEGF(PLT) and serum TGF-beta1 levels decreased significantly after chemotherapy in CR + PR group in comparison with before chemotherapy (VEGF(PLT), 0.453 +/- 0.078 vs. 0.814 +/- 0.127; t = 15.51; P < 0.001 and TGF-beta1, 20.17 +/- 2.43 vs. 42.13 +/- 4.54; t = 27.31; P < 0.001). By contrast, VEGF(PLT) and serum TGF-beta1 levels were markedly higher after chemotherapy in the SD + PD group in comparison with before chemotherapy (VEGF(PLT), 0.816 +/- 0.043 vs. 1.065 +/- 0.016; t = 22.38; P < 0.001 and TGF beta1, 41.80 +/- 5.46 vs. 45.83 +/- 4.62; t = 2.32; P = 0. 03). Our results show that NSCLC patients exhibit high VEGF(PLT) and serum TGF-beta1 levels, and VEGF(PLT) and TGF-beta1 levels correlate with chemotherapy response to GP regimen. Therefore, VEGF(PLT) and serum TGF-beta1 levels are valuable biomarkers in clinical monitoring of NSCLC patients. PMID- 25820821 TI - Protein expression and methylation of MGMT, a DNA repair gene and their correlation with clinicopathological parameters in invasive ductal carcinoma of the breast. AB - Epigenetic mechanisms such as DNA methylation are being increasingly recognized to play an important role in cancer and may serve as a cancer biomarker. The aim of this study was to evaluate the promoter methylation status of MGMT (O6 methylguanine-DNA methyltransferase) and a possible correlation with the expression of MGMT and standard clinicopathological parameters in invasive ductal breast carcinoma patients (IDC) of Kashmir. Methylation-specific PCR was carried out to investigate the promoter methylation status of MGMT in breast tumors paired with the corresponding normal tissue samples from 128 breast cancer patients. The effect of promoter methylation on protein expression in the primary breast cancer and adjacent normal tissues was evaluated by immunohistochemistry (n = 128) and western blotting (n = 30). The frequency of tumor hypermethylation was 39.8 % and a significant difference in methylation frequency among breast tumors were found (p < 0.001) when compared with the corresponding normal tissue. Immunohistochemical analysis showed no detectable expression of MGMT in 68/128 (53.1 %) tumors. MGMT promoter methylation mediated gene silencing was associated with loss of its protein expression (rs = -0.285, p = 0.001, OR = 3.38, 95 % CI = 1.59-7.17). A significant correlation was seen between loss of MGMT and lymph node involvement (p = 0.030), tumor grade (p < 0.0001), loss of estrogen receptors (ER; p = 0.021) and progesterone receptors (PR) (p = 0.016). Also, MGMT methylation was found to be associated with tumor grade (p = 0.011), tumor stage (p = 0.009), and loss of ER (p = 0.003) and PR receptors (p = 0.009). To our knowledge, our findings, for the first time, in Kashmiri population, indicate that MGMT is aberrantly methylated in breast cancer and promoter hypermethylation could be attributed to silencing of MGMT gene expression in breast cancer. Our data suggests that MGMT promoter hypermethylation could have a potential function as molecular biomarker of breast oncogenesis. Also, based on their predictive value of response to therapy, the immunohistochemical evaluation and interpretation of MGMT may also help in future to establish therapeutic strategies for patients with breast cancer. PMID- 25820822 TI - Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration. AB - AflatoxinB1 (AFB1) is well known as a potent carcinogen. Epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. AFB1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB1-8,9-exo-epoxide, which acts as a mutagen to react with DNA. In addition, recent study demonstrates AFB1 positively regulates type I insulin-like growth factor receptor (IGF-IR) signaling in hepatoma cells. The current study aims to determine the effects of AFB1 on Src kinase and insulin receptor substrate (IRS) in lung cancer cells and the effects of AFB1 on lung cancer cell migration. To this end, the effects of AFB1 on IRS expression, Src, Akt, and ERK phosphorylation were measured by Western blot analysis. The migration of lung cancer cells was detected by wound-healing assay. AFB1 downregulates IRS1 but paradoxically upregulates IRS2 through positive regulation of the stability of IRS2 and the proteasomal degradation of IRS1 in lung cancer cell lines A549 and SPCA-1. In addition, AFB1 induces Src, Akt, and ERK1/2 phosphorylation. Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB1-induced IRS2 accumulation. Moreover, AFB1 stimulates lung cancer cell migration, which can be inhibited by saracatinib. We conclude that AFB1 may upregulate IRS2 and stimulate lung cancer cell migration through Src. PMID- 25820823 TI - Adenovirus type 12 E1B 55-kilodalton oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin. AB - The tumor suppressor p53-mediated apoptotic response plays an important role in cisplatin resistant in ovarian cancer. The adenovirus (Ad) type 12 E1B 55-kDa protein binds to p53 and inactivates its transcriptional transactivation function. In this study, we test the hypothesis that Ad12 E1B 55-kDa oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin. First, we observed the upregulation protein level of p53 target genes in cisplatin resistant or cisplatin-sensitive ovarian cancer by Western blotting. Second, after transfection of Ad12 E1b 55-kDa expression plasmid, the expressions of p53 target genes in A2780 cells were further enhanced. Co-IP experiment demonstrated Ad12 E1b 55 kDa associated with p53. MTT assay confirmed that the cell proliferation was enhanced after transfection, as well as the enhanced cell inhibitory rate in the presence of cisplatin. Using flow cytometry, transfection of Ad12 E1B 55-kDa protein induced apoptosis and promoted S-phase transition in proliferation. Finally, results showed that all these changes promoted by Ad12 E1b 55 kDa were attenuated by the exposure of specific inhibitor of p53 signaling, pifithrin-alpha. Taken together, we concluded that Ad E1B 55-kDa oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin. PMID- 25820825 TI - Peripherally Hexasulfanylated Subporphyrins. AB - Peripherally hexachlorinated meso-triphenyl subporphyrin 4 was prepared by chlorination of meso-triphenyl subporphyrin 1 with N-chlorosuccinimide and was effectively transformed to hexasulfanylated subporphyrins 5-8 via nucleophilic aromatic substitution (S(N)Ar) reactions with the corresponding thiols under basic conditions. The structures of 5-8 have been all well characterized by single-crystal X-ray analysis. (1)H NMR studies indicated that the meso-phenyl substituents undergo restricted rotation for 5-8, while the beta-sulfanyl substituents are conformationally flexible in 5, 6, and 8, and are strictly regulated to an anti-conformation in 7. Judging from the absorption spectra, the oxidation and reduction potentials, and the DFT calculations, the substituent effects decrease in the order of 5>6>7>8. Subporphyrin 8 effectively captures C60 in a 1:1 manner in [D8 ]toluene solution. PMID- 25820824 TI - Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression. AB - CtBP2, as a transcriptional corepressor of epithelial-specific genes, has been reported to promote tumor due to upregulating epithelial-mesenchymal transition (EMT) in cancer cells. CtBP2 was also demonstrated to contribute to the proliferation of esophageal squamous cell carcinoma (ESCC) cells through a negative transcriptional regulation of p16(INK4A). In this study, for the first time, we reported that CtBP2 expression, along with CCNH/CDK7, was higher in ESCC tissues with lymph node metastases than in those without lymph node metastases. Moreover, both CtBP2 and CCNH/CDK7 were positively correlated with E-cadherin, tumor grade, and tumor metastasis. However, the concrete mechanism of CtBP2's role in enhancing ESCC migration remains incompletely understood. We confirmed that CCNH/CDK7 could directly interact with CtBP2 in ESCC cells in vivo and in vitro. Furthermore, our data demonstrate for the first time that CtBP2 enhanced the migration of ESCC cells in a CCNH/CDK7-dependent manner. Our results indicated that CCNH/CDK7-CtBP2 axis may augment ESCC cell migration, and targeting the interaction of both may provide a novel therapeutic target of ESCC. PMID- 25820826 TI - A low phosphorylation potential in the acetogen Acetobacterium woodii reflects its lifestyle at the thermodynamic edge of life. AB - The anaerobic, acetogenic bacterium Acetobacterium woodii grows on hydrogen and carbon dioxide and uses the Wood-Ljungdahl pathway to fix carbon but also to synthesize ATP. The free energy change of acetogenesis from H2 + CO2 allows for synthesis of only a fraction of an ATP under environmental conditions, and A. woodii is clearly a paradigm for microbial life under extreme energy limitation. However, it was unknown how much energy is required to make ATP under these conditions. In the present study, we determined the phosphorylation potential in cells metabolizing three different acetogenic substrates. It accounts to 37.9 +/- 1.3 kJ/mol ATP during acetogenesis from fructose, 32.1 +/- 0.3 kJ/mol ATP during acetogenesis from H2 + CO2 and 30.2 +/- 0.9 kJ/mol ATP during acetogenesis from CO, the lowest phosphorylation potential ever described. The physiological consequences in terms of energy conservation under extreme energy limitation are discussed. PMID- 25820828 TI - The matricellular protein CCN1 regulates TNF-alpha induced vascular endothelial cell apoptosis. AB - Due to the epidemic obesity and associated diabetes, the incidence of atherosclerosis is increasing worldwide. Atherosclerosis is a chronic inflammatory disease characterized by the hardening and narrowing of arteries with plaques that consist of inflammatory cells, dead endothelial cells, lipids, and often hyper proliferated vascular smooth muscle cells. During the development of atherosclerosis, vascular endothelial cell (EC) apoptosis induced by the adipokine tumor necrosis factor alpha (TNF-alpha), is an early event in the plaque formation. However, TNF-alpha alone is not sufficient to induce apoptosis of endothelial cells. Recent studies suggested that the matricellular protein CCN family member 1 (CCN1) involves in endothelial cell dysfunction besides its well known angiogenic function during tissue repair by promoting vascular smooth muscle cells proliferation and migration. Herein, we explored the possibility and mechanism of CCN1 in TNF-alpha induced endothelial cells apoptosis. Both mRNA and protein levels of CCN1 are found up-regulated in endothelial cells after TNF alpha treatment. In addition, overexpression of CCN1 promoted endothelial cell apoptosis in the presence of TNF-alpha. Furthermore, CCN1 directly up-regulated the expression of TNF-alpha-target genes, and this up-regulation required the activation of P53 and NF-kappaB both in vivo and in vitro. Taken together, CNN1 regulates TNF-alpha induced endothelial cells apoptosis that may underlie poor response to TNF-alpha therapy and hence may be a better therapeutic target for preventing vascular dysfunction in obesity. PMID- 25820827 TI - The function of the autonomic nervous system during spaceflight. AB - INTRODUCTION: Despite decades of study, a clear understanding of autonomic nervous system activity in space remains elusive. Differential interpretation of fundamental data has driven divergent theories of sympathetic activation and vasorelaxation. METHODS: This paper will review the available in-flight autonomic and hemodynamic data in an effort to resolve these discrepancies. The NASA NEUROLAB mission, the most comprehensive assessment of autonomic function in microgravity to date, will be highlighted. The mechanisms responsible for altered autonomic activity during spaceflight, which include the effects of hypovolemia, cardiovascular deconditioning, and altered central processing, will be presented. RESULTS: The NEUROLAB experiments demonstrated increased sympathetic activity and impairment of vagal baroreflex function during short-duration spaceflight. Subsequent non-invasive studies of autonomic function during spaceflight have largely reinforced these findings, and provide strong evidence that sympathetic activity is increased in space relative to the supine position on Earth. Others have suggested that microgravity induces a state of relative vasorelaxation and increased vagal activity when compared to upright posture on Earth. These ostensibly disparate theories are not mutually exclusive, but rather directly reflect different pre-flight postural controls. CONCLUSION: When these results are taken together, they demonstrate that the effectual autonomic challenge of spaceflight is small, and represents an orthostatic stress less than that of upright posture on Earth. In-flight countermeasures, including aerobic and resistance exercise, as well short-arm centrifugation, have been successfully deployed to counteract these mechanisms. Despite subtle changes in autonomic activity during spaceflight, underlying neurohumoral mechanisms of the autonomic nervous system remain intact and cardiovascular function remains stable during long-duration flight. PMID- 25820829 TI - Peak loading during walking is not associated with fracture migration following tibial plateau fracture: A preliminary case series. AB - Tibial plateau fractures are common, but little evidence exists for their postoperative management, especially when recommending if patients should weight bear at all, partially, or as tolerated. In this study, we describe the loads passing through the fracture construct and the associated fracture migration over the first year following surgery. Nine patients were treated with open reduction and internal fixation and instructed to weight bear as tolerated. Fracture loading and migration were assessed at 2, 12, 26, and 52 weeks postoperative. Fracture loading was calculated as the knee joint reaction force (peak, average, the angle of the force vector, and the point of force application) using gait analysis and an inverse dynamics musculoskeletal model. Fracture migration was assessed using radiostereometric analysis. The fractures were progressively loaded during the rehabilitation phase. The point of application of the load shifted from neutral to medial by week 26 for all patients. Migration during the first postoperative year was within current clinical acceptable limits. The peak load during walking at each time point was not associated with fracture fragment migration and does not appear to exceed the elastic limit of the fracture construct. PMID- 25820830 TI - Magnetic solid-phase extraction of brominated flame retardants from environmental waters with graphene-doped Fe3O4 nanocomposites. AB - Graphene-doped Fe3O4 nanocomposites were prepared by a solvothermal reaction of an iron source with graphene. The nanocomposites were characterized by transmission electron microscopy, atomic force microscopy, X-ray diffraction, superconducting quantum interference, Raman spectroscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. This nanomaterial has been used as a magnetic solid-phase extraction sorbent to extract trace brominated flame retardants from environmental waters. Various extraction parameters were optimized including dosage and reusability of the nanocomposites, and pH of sample matrix. The reliability of the magnetic solid-phase extraction protocol based on graphene-doped Fe3O4 nanocomposites was evaluated by investigating the recoveries of 2,4,6-tribromophenol, tetrabromobisphenol A, 4 bromodiphenyl ether, and 4,4'-dibromodiphenyl ether in water samples. Good recoveries (85.0-105.0%) were achieved with the relative standard deviation ranging from 1.1-7.1%. Moreover, it is speculated from characterization and magnetic solid-phase extraction experiment that there is not only pi-pi stacking but also possible hydrophobic interaction between the graphene-doped Fe3O4 nanocomposites and analytes. PMID- 25820832 TI - Quantitative proteomic analyses of Schistosoma japonicum in response to artesunate. AB - Artesunate (ART) has high prophylactic efficacy against Schistosoma japonicum infections and has been used to treat and prevent schistosomiasis in China since 1995. However, the molecular mechanism of ART's effects on S. japonicum remains unclear. Herein, we applied isobaric tagging reagents for relative and absolute quantification analyses coupled with two-dimensional liquid chromatography and tandem mass spectrometry to investigate the effect of ART on the proteome of S. japonicum in susceptible mice. 4529 proteins were quantified on the basis of 21,825 unique peptides. Comparative proteomic analyses revealed that 145, 228 and 185 proteins were significantly differentially expressed after ART treatment in schistosomula, juvenile and adult worms, respectively. Ninety proteins were differentially expressed between each two treatment groups in response to ART treatment: 67 proteins were associated with S. japonicum development/aging and 23 were specifically associated with ART treatment. Quantitative real-time PCR of selected genes verified the proteomic data. Gene ontology annotation and Kyoto encyclopedia of genes and genomes pathway mapping analysis showed that the majority of differentially expressed proteins were involved in stress/defense/detoxification, signal transduction, carbohydrate metabolism, amino acid metabolism, transcription/translation, and protein synthesis/assembly/degradation. Thirty-four of the proteins differentially expressed under ART treatment encoded hypothetical, uncharacterized proteins with unknown functions. This study obtained the first comprehensive protein expression profile of S. japonicum in response to ART, and provides a basis for a better understanding of the molecular mechanisms of ART effects on S. japonicum. PMID- 25820833 TI - A combined experimental and computational study on the cycloisomerization of 2 ethynylbiaryls catalyzed by dicationic arene ruthenium complexes. AB - Ruthenium-catalyzed cycloisomerization of 2-ethynylbiaryls was investigated to identify an optimal ruthenium catalyst system. A combination of [eta(6) -(p cymene)RuCl2 (PR3 )] and two equivalents of AgPF6 effectively converted 2 ethynylbiphenyls into phenanthrenes in chlorobenzene at 120 degrees C over 20 h. Moreover, 2-ethynylheterobiaryls were found to be favorable substrates for this ruthenium catalysis, thus achieving the cycloisomerization of previously unused heterocyclic substrates. Moreover, several control experiments and DFT calculations of model complexes were performed to propose a plausible reaction mechanism. PMID- 25820831 TI - Dual kappa-agonist/MU-antagonist opioid receptor modulation reduces levodopa induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease. AB - OBJECTIVE: Effective medical management of levodopa-induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model. METHODS: 1 Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. RESULTS: Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of DeltaFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34. INTERPRETATION: Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID. PMID- 25820834 TI - Deposition of wafer-scale single-component and binary nanocrystal superlattice thin films via dip-coating. PMID- 25820835 TI - Combination of CE-MS and advanced chemometric methods for high-throughput metabolic profiling. AB - In this work, an untargeted approach based on capillary electrophoresis-mass spectrometry (CE-MS) in combination with multivariate data analyses is proposed as a high-throughput general methodology for metabolomic studies. First, total ion electropherograms (TIEs) were considered for exploratory and classification purposes by means of principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). Then, multivariate curve resolution alternating least squares (MCR-ALS) was applied to the multiple full scan MS data sets. This strategy permitted the resolution of a large number of metabolites being characterized by their electrophoretic peaks and their corresponding mass spectra. The proposed approach allowed solving additional electrophoretic issues, such as background noise contributions, low signal-to-noise ratios, asymmetric peaks and migration time shifts. The usefulness of the proposed methodology is demonstrated in a comparative study of the metabolic profiles from baker's yeast (Saccharomyces cerevisiae) samples cultured at two temperatures, 30 degrees C and 37 degrees C. A total number of 80 metabolites were relevant to yeast samples differentiation at the two temperatures and almost 50 of them were tentatively identified based on their accurate experimental molecular mass. The results show that changes in amino acid, nucleotide and lipid metabolic pathways participated in the acclimatization of yeast cells to grow at 37 degrees C. PMID- 25820836 TI - Formation of fluorescent polydopamine dots from hydroxyl radical-induced degradation of polydopamine nanoparticles. AB - This study describes the synthesis of fluorescent polydopamine dots (PDs) through hydroxyl radical-induced degradation of polydopamine nanoparticles. The decomposition of polydopamine nanoparticles to fluorescent PDs was confirmed using transmission electron microscopy and dark-field microscopy. The analysis of PDs by using laser desorption/ionization time-of-flight mass spectrometry revealed that the PDs consisted of dopamine, 5,6-dihydroxyindole, and trihydroxyindole units. Oligomerization and self-assembly of these units produced a broad adsorption band, resulting in an excitation-wavelength-dependent emission behavior. The maximal fluorescence of PDs appeared at 440 nm with a quantum yield of 1.2%. The coordination between the catechol groups of PDs and ferric ions (Fe(3+)) quenched the fluorescence of PDs; the limit of detection at a signal-to noise ratio of 3 for Fe(3+) was determined to be 0.3 MUM. The presence of pyrophosphate switched on the fluorescence of the PD-Fe(3+) complexes. Compared to the other reported methods for sensing Fe(3+), PDs provided simple, low-cost, and reusable detection of Fe(3+). PMID- 25820837 TI - Influence of Sn content on the hydrogenation of crotonaldehyde catalysed by colloidally prepared PtSn nanoparticles. AB - Bimetallic PtSn nanoparticles (NPs) of well-defined size and metal composition were prepared by means of colloidal methods. The mean particle diameter was about 2 nm for all samples irrespective of the Pt/Sn-ratio, which enables a systematic study of the influence of the composition on the catalytic properties while excluding particle size effects. The hydrogenation of crotonaldehyde was investigated as a reaction for which chemoselectivity is known to be a challenging task. Already very low atomic Sn contents (~10%) were found to lead to a significantly improved activity which may be attributed to an electronic effect of Sn on Pt. For further increasing tin contents the activity decreased gradually. This trend was accompanied by a steady increase in selectivity towards the desired product (crotylalcohol). The results show that the highest crotylalcohol time yields can be obtained by using catalysts with an atomic Sn content of approximately 23%. In contrast, maximum crotylalcohol selectivities are achieved by using catalysts with a high tin content (>50%). PMID- 25820838 TI - Survivorship and clinical outcome of Birmingham hip resurfacing: a minimum ten years' follow-up. AB - INTRODUCTION: Resurfacing as a percentage of total hip arthroplasty rose from 5.6 % in 2001 to 8.9 % in 2005 in Australia. During the same period the resurfacing to conventional prosthesis rose from 19.6 % to 29 % in the younger age group (less than 55 years). Long term (more than ten years) functional results of BHR are sparingly documented. Among the literatures available, the patient selection criteria vary from osteoarthritis, avascular necrosis, and dysplastic hip to slipped capital femoral epiphysis. The objective of the current study is to evaluate long term survivorship and functional outcome of Birmingham hip resurfacing surgery in osteoarthritic hip patients performed by a single surgeon. PATIENTS AND METHODS: In this retrospective clinical study, all patients who underwent hip resurfacing for osteoarthritis of hip between 1999 and 2004 are included. All surgeries were performed by single surgeon (SJM) and in all patients Smith & Nephew system (Midland Medical Technologies, Birmingham, United Kingdom)) was used. Revision surgery is considered the end point of survivorship. Means, standard deviations, and confidence interval were calculated for all continuous measures. Survival analysis was performed with the Kaplan-Meier method and 95 % confidence intervals were calculated. RESULT: The result is based on 222 patients (244 hips). This included 153 males and 69 females. Our mean follow up was 12.05 years and overall survival was 93.7 %. In terms of gender, survival in males was 95.43 % while in females it was 89.86 %. Failure was seen in 14 patients (16 hips), which included seven female (10.14 %) and seven male (4.57 %) patients. Failure of femoral components due to aseptic loosening and varus collapse was seen in eight patients after a mean 9.6 years. Metal allergy was seen in three patients (five hips), all of them were female of which two had bilateral resurfacing. Other complications included femoral neck stress fractures in two patients and acetabular component loosening in one patient. We observed that the failure rate is higher if the BHR femoral component size is 46 or less (ten out of 16 hips revised). CONCLUSION: If patient selection is judiciously done and surgical technique is meticulously followed, hip resurfacing offers acceptable survivorship, satisfactory range of motion and enables patients to resume high demand activities including sports. Future improvements in the bearing surfaces, and possibly in the design, might alleviate concerns posed by high serum metal level and provide options that continue to benefit younger patients in future. PMID- 25820839 TI - Irrigation and debridement for periprosthetic infections of the hip and factors determining outcome. AB - PURPOSE: Our purpose was to identify the success rate and factors predicting outcome of irrigation and debridement (I&D) in patients with deep periprosthetic joint infection (PJI) of the hip. METHODS: We retrospectively reviewed clinical characteristics of patients with deep PJI after primary/revision total hip arthroplasty (THA) between January 2000 and May 2013 treated with I&D. Implant retention was the outcome of interest. Sixty patients (29 men and 31 women; mean age 64.9 years) were identified. Mean follow-up was 59 months (range, 12-168). RESULTS: The implants were retained in 42 patients (70%). Failure of I&D treatment correlated with duration of symptoms >five days (p <0.001) and obesity [body mass index (BMI) >= 30)] (p = 0.0289). Treatment outcome was affected by the type of pathogen (p = 0.0482), with patients with methicillin-resistant staphylococci having significantly lower odds of success. CONCLUSIONS: I&D can be a feasible option in THA patients presenting with acute deep PJI. Duration of symptoms >five days, isolation of methicillin-resistant staphylococci and obesity should be taken into consideration in pre-operative decision making. PMID- 25820840 TI - Pretreatment Differences in BOLD Response to Emotional Faces Correlate with Antidepressant Response to Scopolamine. AB - BACKGROUND: Faster acting antidepressants and biomarkers that predict treatment response are needed to facilitate the development of more effective treatments for patients with major depressive disorders. Here, we evaluate implicitly and explicitly processed emotional faces using neuroimaging to identify potential biomarkers of treatment response to the antimuscarinic, scopolamine. METHODS: Healthy participants (n=15) and unmedicated-depressed major depressive disorder patients (n=16) participated in a double-blind, placebo-controlled crossover infusion study using scopolamine (4 MUg/kg). Before and following scopolamine, blood oxygen-level dependent signal was measured using functional MRI during a selective attention task. Two stimuli comprised of superimposed pictures of faces and houses were presented. Participants attended to one stimulus component and performed a matching task. Face emotion was modulated (happy/sad) creating implicit (attend-houses) and explicit (attend-faces) emotion processing conditions. The pretreatment difference in blood oxygen-level dependent response to happy and sad faces under implicit and explicit conditions (emotion processing biases) within a-priori regions of interest was correlated with subsequent treatment response in major depressive disorder. RESULTS: Correlations were observed exclusively during implicit emotion processing in the regions of interest, which included the subgenual anterior cingulate (P<.02) and middle occipital cortices (P<.02). CONCLUSIONS: The magnitude and direction of differential blood oxygen-level- dependent response to implicitly processed emotional faces prior to treatment reflect the potential to respond to scopolamine. These findings replicate earlier results, highlighting the potential for pretreatment neural activity in the middle occipital cortices and subgenual anterior cingulate to inform us about the potential to respond clinically to scopolamine. PMID- 25820841 TI - R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome. AB - BACKGROUND: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and gamma-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates. METHODS: To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-(14)C]leucine method in vehicle- and R-baclofen-treated wildtype and Fmr1 KO mice. We further probed signaling pathways involved in the regulation of protein synthesis. RESULTS: Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mammalian target of rapamycin pathway, particularly in synaptosome-enriched fractions, but it had no effect on extracellular-regulated kinase 1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in metabotropic glutamate receptor 5 expression in the frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug. CONCLUSIONS: Our results suggest that treatment via activation of the GABA (GABA receptor subtype B) system warrants further study in patients with FXS. PMID- 25820842 TI - Serotonergic psychedelics temporarily modify information transfer in humans. AB - BACKGROUND: Psychedelics induce intense modifications in the sensorium, the sense of "self," and the experience of reality. Despite advances in our understanding of the molecular and cellular level mechanisms of these drugs, knowledge of their actions on global brain dynamics is still incomplete. Recent imaging studies have found changes in functional coupling between frontal and parietal brain structures, suggesting a modification in information flow between brain regions during acute effects. METHODS: Here we assessed the psychedelic-induced changes in directionality of information flow during the acute effects of a psychedelic in humans. We measured modifications in connectivity of brain oscillations using transfer entropy, a nonlinear measure of directed functional connectivity based on information theory. Ten healthy male volunteers with prior experience with psychedelics participated in 2 experimental sessions. They received a placebo or a dose of ayahuasca, a psychedelic preparation containing the serotonergic 5-HT2A agonist N,N-dimethyltryptamine. RESULTS: The analysis showed significant changes in the coupling of brain oscillations between anterior and posterior recording sites. Transfer entropy analysis showed that frontal sources decreased their influence over central, parietal, and occipital sites. Conversely, sources in posterior locations increased their influence over signals measured at anterior locations. Exploratory correlations found that anterior-to-posterior transfer entropy decreases were correlated with the intensity of subjective effects, while the imbalance between anterior-to-posterior and posterior-to-anterior transfer entropy correlated with the degree of incapacitation experienced. CONCLUSIONS: These results suggest that psychedelics induce a temporary disruption of neural hierarchies by reducing top-down control and increasing bottom-up information transfer in the human brain. PMID- 25820843 TI - Recurrent abdominal pain in children: a clinical approach. AB - The term 'recurrent abdominal pain', or RAP, refers mainly to the duration of painful period and frequency of pain. The commonly accepted duration is at least three months in the preceding period, and over this three-month period, there are at least three episodes of pain that are severe enough to affect the daily activities of the affected patients. Over the years, with advances in medical technology and better understanding of the pathophysiology of abdominal pain, more and more organic causes have been identified. However, the most common cause of RAP in children is still functional in origin. PMID- 25820844 TI - Recognising sleep apnoea. AB - Most people spend a third of their lives sleeping, and thus, sleep has a major impact on all of us. As sleep is a function and not a structure, it is challenging to treat and prevent its complications. Sleep apnoea is one such complication, with serious and potentially life-threatening consequences. Local studies estimate that about 15% of Singapore's population is afflicted with sleep apnoea. The resulting sleep fragmentation may result in poor quality of sleep, leading to daytime sleepiness. Sleep apnoea may also be the underlying cause of high blood pressure, memory loss, poor concentration and work performance, motor vehicle accidents, and marital problems. Evaluation involves a sleep study, followed by patient education, and an individualised step-wise management approach should be explored. Many patients will require follow-up for a long period of time, as management options may not offer a permanent cure; other contributory causes may arise at different phases of their lives, compounded by genetic and hormonal issues, ethnicity and the modern hazards of a fast-paced society. PMID- 25820845 TI - Imaging of the spleen: what the clinician needs to know. AB - The spleen is considered 'the forgotten organ' among radiologists and clinicians, although it is well visualised on abdominal computed tomography and magnetic resonance imaging. Moreover, the spleen is commonly involved in a wide range of pathologic disorders. These include congenital anomalies, infectious and inflammatory diseases, vascular disorders, benign and malignant tumours, and systemic disorders. In this review, we focus on the key imaging findings of the normal spleen, its variants, as well as relevant congenital and acquired abnormalities. It is of utmost importance to recognise and correctly interpret the variable spectrum of abnormalities that may involve the spleen, in order to avoid unnecessary invasive procedures and to guide adequate treatment. PMID- 25820846 TI - Cerebellar strokes: a clinical outcome review of 79 cases. AB - INTRODUCTION: Cerebellar infarcts and haemorrhages are relatively uncommon, accounting for less than 10% of all strokes. The objective of the present study was to quantify and compare the outcomes of patients with cerebellar infarct and those of patients with cerebellar haemorrhage, as well as to identify the risk factors that predict poor outcome in patients with cerebellar stroke. METHODS: We retrospectively reviewed the medical records of consecutive patients admitted to National University Hospital, Singapore, between 2004 and 2006, within one week of cerebellar stroke onset. Baseline data included demographics, concomitant comorbidities, and the presence or absence of brainstem compression and hydrocephalus (on computed tomography or magnetic resonance imaging). The Glasgow Outcome Scale and modified Rankin Score were used to assess outcome at discharge and at six months after discharge. RESULTS: A total of 79 patients with cerebellar stroke were admitted during the study period. Of these 79 patients, 17.7% died and 31.6% had poor outcomes at six months after discharge. Patients with cerebellar haemorrhage were found to be more likely to have poor outcomes as compared to patients with cerebellar infarct, both at discharge (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.3-14.1) and at six months after discharge (OR 5.2, 95% CI 1.6-17.2). When compared to small lesions (< 5 cm(3)), lesions > 20 cm(3) were significantly associated with poorer outcomes and the development of hydrocephalus and brainstem compression. CONCLUSION: Cerebellar strokes are a significant cause of morbidity and mortality. The outcomes of patients with cerebellar haemorrhage are more likely to be worse than those of patients with cerebellar infarct. PMID- 25820847 TI - Integrated approach to e-learning enhanced both subjective and objective knowledge of aEEG in a neonatal intensive care unit. AB - INTRODUCTION: Various meta-analyses have shown that e-learning is as effective as traditional methods of continuing professional education. However, there are some disadvantages to e-learning, such as possible technical problems, the need for greater self-discipline, cost involved in developing programmes and limited direct interaction. Currently, most strategies for teaching amplitude-integrated electroencephalography (aEEG) in neonatal intensive care units (NICUs) worldwide depend on traditional teaching methods. METHODS: We implemented a programme that utilised an integrated approach to e-learning. The programme consisted of three sessions of supervised protected time e-learning in an NICU. The objective and subjective effectiveness of the approach was assessed through surveys administered to participants before and after the programme. RESULTS: A total of 37 NICU staff (32 nurses and 5 doctors) participated in the study. 93.1% of the participants appreciated the need to acquire knowledge of aEEG. We also saw a statistically significant improvement in the subjective knowledge score (p = 0.041) of the participants. The passing rates for identifying abnormal aEEG tracings (defined as >= 3 correct answers out of 5) also showed a statistically significant improvement (from 13.6% to 81.8%, p < 0.001). Among the participants who completed the survey, 96.0% felt the teaching was well structured, 77.8% felt the duration was optimal, 80.0% felt that they had learnt how to systematically interpret aEEGs, and 70.4% felt that they could interpret normal aEEG with confidence. CONCLUSION: An integrated approach to e-learning can help improve subjective and objective knowledge of aEEG. PMID- 25820848 TI - Effect of Pilates exercises on postpartum maternal fatigue. AB - INTRODUCTION: Postpartum fatigue is a pervasive phenomenon and often affects mothers immediately after delivery. The present study aimed to assess the effect Pilates home exercises had on postpartum maternal fatigue. METHODS: A total of 80 women participated in our clinical trial study. The women were randomly divided into two groups - the intervention group (n = 40) and the control group (n = 40). In the intervention group, the women performed Pilates exercises five times a week (30 min per session) for eight consecutive weeks. The first session was conducted 72 hours after delivery. The control group did not receive any intervention. Each woman's level of fatigue was evaluated at hospital discharge (as a baseline), and at four and eight weeks after delivery, using the standard Multidimensional Fatigue Inventory (MFI-20) questionnaire and repeated measures analysis. RESULTS: During the eight weeks of follow-up, we found that the intervention group had lower mean MFI-20 scores than the control group with regard to general fatigue (7.80 +/- 2.07 vs. 12.72 +/- 1.79; p < 0.001), physical fatigue (7.12 +/- 1.41 vs. 10.42 +/- 2.02; p < 0.001), reduced activity (6.95 +/- 1.35 vs. 11.27 +/- 1.70; p < 0.001), reduced motivation (6.20 +/- 1.01 vs. 9.80 +/- 2.04; p < 0.001) and mental fatigue (6.85 +/- 1.45 vs. 10.72 +/- 1.98; p < 0.001). CONCLUSION: The present study's findings show that physical exercise can significantly reduce postpartum maternal fatigue in all subscales. PMID- 25820849 TI - Urinary incontinence after intravenous dexamethasone sodium phosphate injection. PMID- 25820850 TI - Comment on: current status of functional gastrointestinal evaluation in clinical practice. PMID- 25820851 TI - Author's reply: current status of functional gastrointestinal evaluation in clinical practice. PMID- 25820852 TI - Interpersonal problems among psychiatric outpatients and non-clinical samples. PMID- 25820853 TI - Cerebrovascular ischaemia after carbon monoxide intoxication. PMID- 25820854 TI - Current status of functional gastrointestinal evaluation in clinical practice. PMID- 25820855 TI - Comment on: cerebrovascular ischaemia after carbon monoxide intoxication. PMID- 25820856 TI - Author's reply: cerebrovascular ischaemia after carbon monoxide intoxication. PMID- 25820857 TI - Unusual optic disc infarction in a case of arteritic anterior ischaemic optic neuropathy (AAION). AB - Herein, we report another case of arteritic anterior ischaemic optic neuropathy from Singapore, in which the initial optic disc swelling was extreme and the sequential disease resolved because the patient was already on maximum treatment. As the management of this biopsy-proven giant cell arteritis case was complicated by the presence of a number of other medical conditions, including end-stage renal failure, monitoring of the response to treatment proved problematic. PMID- 25820858 TI - Triquetral fracture with associated pisiform subluxation. AB - We herein present a case of right triquetral fracture with associated pisiform and flexor carpi ulnaris subluxation in a 29-year-old man. Initial radiography showed a right triquetral fracture. Computed tomography and magnetic resonance imaging demonstrated a triquetral fracture with a subluxated pisiform. Open reduction and lag screw fixation of the right triquetrum was performed, with good subsequent recovery of function. Although triquetral fracture with subluxation of the pisotriquetral joint is uncommon, attending clinicians should bear in mind the possibility of such an injury when managing traumatic ulnar-sided wrist pain. PMID- 25820859 TI - A rare case of multiple bronchial artery aneurysms associated with a double aortic arch. AB - Bronchial artery aneurysm is uncommon, and the occurrence of multiple aneurysms arising from a bronchial artery is even rarer. To date, there has been only one published case report describing double bronchial artery aneurysms. We herein describe a case of three aneurysms arising from a left bronchial artery, accompanied by multiple bilateral hypertrophied bronchial and intercostobronchial arteries, as well as a double aortic arch. Bronchial artery aneurysm is potentially life-threatening, and immediate treatment is recommended to minimise the potential risk of rupture. The aneurysms in our case were successfully treated via transcatheter arterial embolisation using coils. PMID- 25820860 TI - Successful endovascular embolisation of a jejunal artery aneurysm. AB - Jejunal artery aneurysms are rare, with only six cases reported in the literature to date. Endovascular embolisation of the jejunal artery is rarely performed. Herein, we report the case of a 57-year-old man who successfully underwent endovascular embolisation for bleeding caecal diverticulosis, during which a 9-mm fusiform jejunal artery aneurysm was incidentally diagnosed. Subsequently, the jejunal aneurysm was successfully embolised using Vortex coils. PMID- 25820861 TI - Bladder repair following iatrogenic cystotomy in irradiated small capacity bladders. AB - During laparotomy in a previously irradiated and operated pelvis, incidental cystotomies can occur and a tension-free, watertight, two- or three-layer closure of the bladder may be impossible. We herein report two cases of iatrogenic defects of the bladders in post-irradiated pelvises and compare the two different methods of bladder repair employed - an ileal augmentation segment used in the first case and bovine pericardial graft used in the second. Successful closures of the bladder defects were achieved in both cases. Native irradiated bowel and bovine pericardium can be useful substitutes in situations involving bladder defects in a previously irradiated pelvis. The advantages and disadvantages of the two approaches are also herein discussed. PMID- 25820862 TI - Malignant mesothelioma of tunica vaginalis: an extremely rare case presenting without risk factors. AB - Testicular tumours have many different manifestations, including hydrocele formation. Herein, we present an extremely rare case of testicular mesothelioma presenting with left hydrocele, but without risk factors. Left radical inguinal orchidectomy was performed, and pathological examination revealed a malignant mesothelioma of the tunica vaginalis of the testis. No infiltration of the spermatic cord was evident, and upon advanced radiological evaluation, no sign of metastasis was detected. Follow-up was still ongoing in our urology outpatient clinic at the time of this report. Although hydrocele is a simple and common condition that is easy to diagnose, a detailed investigation should be performed. Thus, when encountering a patient with hydrocele, the clinician should evaluate the possibility of the presence of an underlying testicular/paratesticular tumour, including a rare one such as mesothelioma of the tunica vaginalis. PMID- 25820863 TI - 20-year survival post-liver transplant: much more is needed! PMID- 25820864 TI - Topographical investigation of changes in depth-wise proteoglycan distribution in rabbit femoral articular cartilage at 4 weeks after transection of the anterior cruciate ligament. AB - In this study, we explore topographical changes in proteoglycan distribution from femoral condylar cartilage in early osteoarthritis, acquired from both the lateral and medial condyles of anterior cruciate ligament transected (ACLT) and contralateral (CNTRL) rabbit knee joints, at 4 weeks post operation. Four sites across the cartilage surface in a parasagittal plane were defined across tissue sections taken from femoral condyles, and proteoglycan (PG) content was quantified using digital densitometry. The greatest depth-wise change in PG content due to an ACLT (compared to the CNTRL group) was observed anteriorly (site C) from the most weight-bearing location within the lateral compartment. In the medial compartment, the greatest change was observed in the most weight bearing location (site B). The depth-wise changes in PG content were observed up to 48% and 28% depth from the tissue surface at these aforementioned sites, respectively (p < 0.05). The smallest depth-wise change in PG content was observed posteriorly (site A) from the most weight-bearing location within both femoral condyles (up to 20% and up to 5% depth from the tissue surface at lateral and medial compartments, respectively). This study gives further insight into how early cartilage deterioration progresses across the parasagittal plane of the femoral condyle. PMID- 25820865 TI - Assessing individual risk for high-risk colorectal adenoma at first-time screening colonoscopy. AB - Assessing risk of colorectal adenoma at first-time colonoscopy that are of higher likelihood of developing advanced neoplasia during surveillance could help tailor first-line colorectal cancer screening. We developed prediction models for high risk colorectal adenoma (at least one adenoma >=1 cm, or with advanced histology, or >=3 adenomas) among 4,881 asymptomatic white men and 17,970 women who underwent colonoscopy as their first-time screening for colorectal cancer in two prospective US studies using logistic regressions. C-statistics and Hosmer Lemeshow tests were used to evaluate discrimination and calibration. Ten-fold cross-validation was used for internal validation. A total of 330 (6.7%) men and 678 (3.8%) women were diagnosed with high-risk adenoma at first-time screening colonoscopy. The model for men included age, family history of colorectal cancer, BMI, smoking, sitting watching TV/VCR, regular aspirin/NSAID use, physical activity, and a joint term of multivitamin and alcohol. For women, the model included age, family history of colorectal cancer, BMI, smoking, alcohol, beef/pork/lamb as main dish, regular aspirin/NSAID, calcium, and oral contraceptive use. The C-statistic of the model for men was 0.67 and 0.60 for women (0.64 and 0.57 in cross-validation). Both models calibrated well. The predicted risk of high-risk adenoma for men in the top decile was 15.4% vs. 1.8% for men in the bottom decile (Odds Ratio [OR] = 9.41), and 6.6% vs. 2.1% for women (OR = 3.48). In summary, we developed and internally validated an absolute risk assessment tool for high-risk colorectal adenoma among the US population that may provide guidance for first-time colorectal cancer screening. PMID- 25820867 TI - Computational characterization of the chemical step in the GTP hydrolysis by Ras GAP for the wild-type and G13V mutated Ras. AB - The free energy profiles for the chemical reaction of the guanosine triphosphate hydrolysis GTP + H2O -> GDP + Pi by Ras-GAP for the wild-type and G13V mutated Ras were computed by using molecular dynamics protocols with the QM(ab initio)/MM potentials. The results are consistent with the recent measurements of reaction kinetics in Ras-GAP showing about two-order reduction of the rate constant upon G13V mutation in Ras: the computed activation barrier on the free energy profile is increased by 3 kcal/mol upon the G13V replacement. The major reason for a higher energy barrier is a shift of the "arginine finger" (R789 from GAP) from the favorable position in the active site. The results of simulations provide support for the mechanism of the reference reaction according to which the Q61 side chain directly participates in chemical transformations at the proton transfer stage. PMID- 25820868 TI - The role of soft-tissue traction forces in bone segment transport for callus distraction : A force measurement cadaver study on eight human femora using a novel intramedullary callus distraction system. AB - Callus distraction using bone segment transport systems is an applied process in the treatment of bone defects. However, complications such as muscle contractures, axial deviation and pin track infections occur in the treatment process using the currently available devices. Since successful treatment is influenced by the applied distraction force, knowledge of the biomechanical properties of the involved soft tissues is essential to improve clinical outcome and treatment strategies. To date, little data on distraction forces and the role of soft-tissue traction forces are available. The aim of this study was to assess traction forces generated by soft tissues during bone segment transport using a novel intramedullary callus distraction system on eight human femora. For traction force measurements, bone segment transport over 60-mm femoral defects was conducted under constant load measurement using 40- and 60-mm bone segments. The required traction forces for 60-mm bone segments were higher than forces for 40-mm bone segments. This study demonstrates that soft tissues are of relevance biomechanically in bone segment transport. The size of the bone segment and the selection of the region for osteotomy are of utmost importance in defining the treatment procedure. PMID- 25820866 TI - Association of PEDF polymorphisms with age-related macular degeneration and polypoidal choroidal vasculopathy: a systematic review and meta-analysis. AB - This study assesses the association of the pigment epithelium-derived factor (PEDF) gene with age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). Publications in MEDLINE and EMBASE up to 21/08/2014 were searched for case-control association studies of PEDF with AMD and/or PCV. Reported studies giving adequate genotype and/or allele information were included. Pooled odds ratios (OR) and 95% confidence intervals (CI) of each polymorphism were estimated. Our literature search yielded 297 records. After excluding duplicates and reports with incomplete information, 8 studies were eligible for meta-analysis, involving 2284 AMD patients versus 3416 controls, and 317 PCV patients versus 371 controls. Four PEDF polymorphisms were meta-analyzed: rs1136287, rs12150053, rs12948385 and rs9913583, but none was significantly associated with AMD or PCV. The most-investigated polymorphism, rs1136287, had a pooled-OR of 1.02 (95% CI: 0.94-1.11, P = 0.64) for AMD. In subgroup analysis by ethnicity, no significant association was identified. Polymorphisms present in single report showed no association. Therefore, existing data in literature does not support the role of PEDF in the genetic susceptibility of AMD and PCV, although replication in specific populations is warranted. Since the pooled sample size for PCV was small, there is a need of PEDF genotyping in larger samples of PCV. PMID- 25820869 TI - CXCR4 positive cell-derived Pdx1-high/Shh-low cells originated from embryonic stem cells improve the repair of pancreatic injury in mice. AB - Treatments for pancreatic injuries have been significantly improved recently, but full recovery of pancreatic function remains difficult. Embryonic stem cells have great potentialities for self-renewal and multiple differentiations. In this study, we explored an approach to induce the differentiation of pancreatic progenitor cells from embryonic stem cells in vitro. Male mouse embryonic stem cells were cultured by the hanging-drop method to form embryoid bodies. The definitive endoderm marked by CXCR4 in embryoid bodies was sorted by magnetic activated cell sorting and subsequently administrated with b-FGF, exendin-4, and cyclopamine to induce the differentiation of putative pancreatic progenitor cells, which was monitored by Pdx1, and Shh expressions. The putative pancreatic progenitor cells were transplanted into female BALB/c mice with pancreatitis induced by L-Arginine. Male donor cells were located by detecting sex-determining region of Y-chromosome DNA. Definitive endoderm cells (CXCR4(+) cells) were sorted from 5-day embryoid bodies. After 3-day administration with b-FGF, exendin 4, and cyclopamine, Pdx1-high/Shh-low cells were differentiated from CXCR4(+) cells. These cells developed into more amylase-secreted cells in vitro and could specifically reside in the damaged pancreas acinar area in mice with acute pancreatitis to enhance the regeneration. The putative pancreatic progenitor cells (Pdx1-high/Shh-low cells) derived from mouse embryonic stem cells through the administration of b-FGF, exendin-4, and cyclopamine on the CXCR4(+) cells in vitro could improve the regeneration of injured pancreatic acini in vivo. PMID- 25820870 TI - Synthesis, Spectroscopic Properties and Antioxidant Activity of Bis-Hydrazones and Schiff's bases Derived from Terephthalic Dihydrazide. AB - A series of novel Schiff base containing bis-1,2,4-triazole and bis-hydrazone derived from terephthalic dihydrazide was synthesized. All the newly synthesized compounds were characterized by (1)H, (13)C NMR, mass spectra, FTIR and elemental analysis. UV-vis spectra and fluorescent spectra of the compounds were recorded. The effect of substituent such as electron withdrawing and electron donating groups on the fluorescent spectra was studied. Also, the comparative discussion on fluorescent spectra of Schiff's base and hydrazones has been described. The antioxidant activity of the compounds revealed that compound 5c and 5f are the most potent compounds in this series. PMID- 25820871 TI - Apparent shear sensitivity of molecular rotors in various solvents. AB - Fluorescent environment-sensitive dyes often change their spectral properties concomitantly with multiple solvent properties, such as polarity, protonation, hydrogen bond formation, or viscosity. Careful consideration of the response is needed when a fluorescent dye is used to report a single property. Recently, we observed an increase of emission intensity of viscosity-sensitive molecular rotors in fluids subject to flow and speculated that either polar-polar interaction or hydrogen bond formation play a role in the apparent flow sensitivity. In this study, we show experimental evidence that photoisomerization to an isomer with a lower quantum yield, first proposed by Rumble et al. (J Phys Chem A 116(44):10786-10792, 2012), plays a key role in the observed phenomenon. We subjected four molecular rotors with different electron acceptor motifs to fluid flow in solvents of different polarity and ability to form hydrogen bonds. We also measured the isomerization dynamics in a custom fluorophotometer with extremely low light exposure. Our results indicate that the photoisomerization rate depends both on the solvent and on the electron acceptor group, as does the recovery of the original isomer in the dark. In most solvents, recovery of the dark isomer is much more rapid than originally reported, and a state of quasi equilibrium between both isomers is possible. Moreover, the sensitivity (i.e., relative intensity increase at the same flow rate) is also solvent-dependent. The intensity increase can be detected at very low velocities (as low as 0.06 mm/s). Characteristic for fluorescent dyes is the high spatial resolution, and no flow measurement device with comparable sensitivity and spatial resolution exists, although the nature of the solvent needs to be taken into account for quantitative flow measurement. PMID- 25820872 TI - Solvent Dependency in the Quantum Efficiency of 4-[(4-Aminophenyl)-(4-imino-1 cyclohexa-2, 5- dienylidene) methyl] Aniline Hydrochloride. AB - In the present work dual beam thermal lens technique is used for studying the solvent dependency on the quantum efficiency of a novel dye used for biomedical applications. The role of solvent in the absolute fluorescence quantum yield of 4 [(4-Aminophenyl)-(4-imino-1-cyclohexa-2, 5- dienylidene) methyl] aniline hydrochloride is studied using thermal lens technique. It is observed that the variation in solvents and its concentration results considerable variations in the fluorescence quantum yield. These variations are due to the non-radiative relaxation of the absorbed energy and because of the different solvent properties. The highest quantum yield of the dye is observed in the polar protic solvent-water. PMID- 25820873 TI - Estimation of Dipole Moments and Quantum Yield of 5-chloro-2-methoxyphenyl Boronic Acid in Different Solvents Environment. AB - The Photophysical properties like ground state and excited state dipole moments, change in the dipole moment and fluorescence quantum yield of a boronic acid derivative 5-chloro-2-methoxy phenyl boronic acid (5CMPBA) are characterized. The study is carried out in various solvents at room temperature using absorption and steady-state fluorescence technique. The emission wavelength of 5CMPBA is quite sensitive to the polarity of solvents. With the increase in solvent polarity red shift or bathochromic shift of about 9 nm has been observed. The excited state and ground state dipole moments are estimated using solvatochromic shift method and effect of solvents on spectral properties of the molecule are investigated using Kamlet-Taft multiple linear regression approach. The changes in dipole moment (DeltaMU) are calculated both from solvatochromic shift method and microscopic solvent polarity parameter (E T (N) ), and the values are compared. The ground state dipole moment is also evaluated using quantum chemical calculations. The bathochromic shift of the emission spectra and the increase in the excited state dipole moment indicates pi -> pi* transitions as well as the possibility of intramolecular charge transfer (ICT) character in the emitting singlet state of 5CMPBA. The relative quantum yield (Phi), radiative and non radiative decay constants are calculated using single point method. It is found that the quantum yield of the molecule varies from 11 to 64% with the change in the solvent polarity indicating the dependency of fluorescence nature on the solvent environment. PMID- 25820874 TI - Independent application of montreal cognitive assessment/mini-mental state examination conversion. PMID- 25820876 TI - Structural, spectroscopic and computational examination of the dative interaction in constrained phosphine-stibines and phosphine-stiboranes. AB - A series of phosphine-stibine and phosphine-stiborane peri-substituted acenaphthenes containing all permutations of pentavalent groups -SbCln Ph4-n (5 9), as well as trivalent groups -SbCl2 , -Sb(R)Cl, and -SbPh2 (2-4, R=Ph, Mes), were synthesised and fully characterised by single crystal diffraction and multinuclear NMR spectroscopy. In addition, the bonding in these species was studied by DFT computational methods. The P-Sb dative interactions in both series range from strongly bonding to non-bonding as the Lewis acidity of the Sb acceptor is decreased. In the pentavalent antimony series, a significant change in the P-Sb distance is observed between -SbClPh3 and -SbCl2 Ph2 derivatives 6 and 7, respectively, consistent with a change from a bonding to a non-bonding interaction in response to relatively small modification in Lewis acidity of the acceptor. In the Sb(III) series, two geometric forms are observed. The P-Sb bond length in the SbCl2 derivative 2 is as expected for a normal (rather than a dative) bond. Rather unexpectedly, the phosphine-stiborane complexes 5-9 represent the first examples of the sigma(4) P->sigma(6) Sb structural motif. PMID- 25820875 TI - Structural characteristics of pineapple pulp polysaccharides and their antitumor cell proliferation activities. AB - BACKGROUND: Pineapple has a delicious taste and good health benefits. Bioactive polysaccharides are important components of pineapple that might contribute to its health benefits. Since little structural information on these polysaccharides is currently available, the aim of this study was to investigate their structural characteristics and bioactivities. RESULTS: The polysaccharides of pineapple pulp were fractionated into three fractions (PAPs 1-3) by anion exchange chromatography. Their structural characteristics were first identified, including molecular weights and glycosidic linkages. The monosaccharide compositions were revealed as PAP 1 (Ara, Xyl, Man, Glc and Gal), PAP 2 (Rha, Ara, Xyl, Man, Glc and Gal) and PAP 3 (Rha, Ara, Xyl, Man and Gal). Nuclear magnetic resonance (NMR) spectra suggested that PAP 2 had a backbone of -> 4)-alpha-d-Manp-(1 -> 2,4) alpha-d-Manp-(1 -> with branches attached to O-4 of Manp. The NMR data of alpha-l Araf-(1->, ->3)-alpha-l-Araf-(1->, ->4)-beta-d-Galp-(1 -> and -> 4)-alpha-d GalpAMe-(1 -> were assigned. PAPs 1 and 2 showed significant antitumor cell proliferation activities against breast carcinoma cell line and strong antioxidant activities. CONCLUSION: The above findings indicated that PAPs 1-3 contributed much to the health benefits of pineapple. They could be used as health-beneficial food additives in functional foods. PMID- 25820877 TI - Elucidating the interaction of gamma-hydroxymethyl-gamma-butyrolactone substituents with model membranes and protein kinase C-C1 domains. AB - The protein kinase C (PKC) family of proteins is an attractive drug target. Dysregulation of PKC-dependent signalling pathways is related to several human diseases like cancer, immunological and other diseases. We approached the problem of altering PKC activities by developing C1 domain-based PKC ligands. In this report gamma-hydroxymethyl-gamma-butyrolactone (HGL) substituents were investigated in an effort to develop small molecule-based PKC regulators with higher specificity for C1 domain than the endogenous diacylglycerols (DAGs). Extensive analysis of membrane-ligands interaction measurements revealed that the membrane-active compounds strongly interact with the lipid bilayers and the hydrophilic parts of compounds localize at the bilayer/water interface. The pharmacophores like hydroxymethyl, carbonyl groups and acyl-chain length of the compounds are crucial for their interaction with the C1 domain proteins. The potent compounds showed more than 17-fold stronger binding affinity for the C1 domains than DAG under similar experimental conditions. Nonradioactive kinase assay confirmed that these potent compounds have similar or better PKC dependent phosphorylation capabilities than DAG under similar experimental conditions. Hence, our findings reveal that these HGL analogues represent an attractive group of structurally simple C1 domain ligands that can be further structurally altered to improve their potencies. PMID- 25820878 TI - Decision making and the cost effectiveness of our interventions. PMID- 25820879 TI - Common contra-indications and interactions of drugs in orthopaedic practice. AB - Drug therapy forms an integral part of the management of many orthopaedic conditions. However, many medicines can produce serious adverse reactions if prescribed inappropriately, either alone or in combination with other drugs. Often these hazards are not appreciated. In response to this, the European Union recently issued legislation regarding safety measures which member states must adopt to minimise the risk of errors of medication. In March 2014 the Medicines and Healthcare products Regulatory Agency and NHS England released a Patient Safety Alert initiative focussed on errors of medication. There have been similar initiatives in the United States under the auspices of The National Coordinating Council for Medication Error and The Joint Commission on the Accreditation of Healthcare Organizations. These initiatives have highlighted the importance of informing and educating clinicians. Here, we discuss common drug interactions and contra-indications in orthopaedic practice. This is germane to safe and effective clinical care. PMID- 25820880 TI - Changing trends in the management of children's fractures. AB - The management of children's fractures has evolved as a result of better health education, changes in lifestyle, improved implant technology and the changing expectations of society. This review focuses on the changes seen in paediatric fractures, including epidemiology, the increasing problems of obesity, the mechanisms of injury, non-accidental injuries and litigation. We also examine the changes in the management of fractures at three specific sites: the supracondylar humerus, femoral shaft and forearm. There has been an increasing trend towards surgical stabilisation of these fractures. The reasons for this are multifactorial, including societal expectations of a perfect result and reduced hospital stay. Reduced hospital stay is beneficial to the social, educational and psychological needs of the child and beneficial to society as a whole, due to reduced costs. PMID- 25820881 TI - Cost effectiveness of total hip arthroplasty in osteoarthritis: comparison of devices with differing bearing surfaces and modes of fixation. AB - Many different designs of total hip arthroplasty (THA) with varying performance and cost are available. The identification of those which are the most cost effective could allow significant cost-savings. We used an established Markov model to examine the cost effectiveness of five frequently used categories of THA which differed according to bearing surface and mode of fixation, using data from the National Joint Registry for England and Wales. Kaplan-Meier analyses of rates of revision for men and women were modelled with parametric distributions. Costs of devices were provided by the NHS Supply Chain and associated costs were taken from existing studies. Lifetime costs, lifetime quality-adjusted-life-years (QALYs) and the probability of a device being cost effective at a willingness to pay L20 000/QALY were included in the models. The differences in QALYs between different categories of implant were extremely small (< 0.0039 QALYs for men or women over the patient's lifetime) and differences in cost were also marginal (L2500 to L3000 in the same time period). As a result, the probability of any particular device being the most cost effective was very sensitive to small, plausible changes in quality of life estimates and cost. Our results suggest that available evidence does not support recommending a particular device on cost effectiveness grounds alone. We would recommend that the choice of prosthesis should be determined by the rate of revision, local costs and the preferences of the surgeon and patient. PMID- 25820882 TI - Does tranexamic acid alter the risk of thromboembolism after total hip arthroplasty in the absence of routine chemical thromboprophylaxis? AB - Tranexamic acid (TXA) has been used to reduce blood loss during total hip arthroplasty (THA), but its use could increase the risk of venous thromboembolic disease (VTE). Several studies have reported that TXA does not increase the prevalence of deep vein thrombosis (DVT), but most of those used routine chemical thromboprophylaxis, thereby masking the potential increased risk of TXA on VTE. We wished to ascertain whether TXA increases the prevalence of VTE in patients undergoing THA without routine chemical thromboprophylaxis. We carried out a retrospective case-control study in 254 patients who underwent a primary THA, 127 of whom received TXA (1 g given pre-operatively) and a control group of 127 who did not. All patients had mechanical but no chemical thomboprophylaxis. Each patient was examined for DVT by bilateral ultrasonography pre-operatively and on post-operative days 1 and 7. TXA was found to statistically significantly increase the incidence of total DVT on post-operative day 7 compared with the control group (24 (18.9%) and 12 (9.4%), respectively; p < 0.05) but most cases of DVT were isolated distal DVT, with the exception of one patient with proximal DVT in each group. One patient in the control group developed a non-fatal symptomatic pulmonary embolism (PE). The use of TXA did not appear to affect the prevalence of either proximal DVT or PE. PMID- 25820883 TI - The effect of frictional torque and bending moment on corrosion at the taper interface : an in vitro study. AB - The aim of this study was to assess the effect of frictional torque and bending moment on fretting corrosion at the taper interface of a modular femoral component and to investigate whether different combinations of material also had an effect. The combinations we examined were 1) cobalt-chromium (CoCr) heads on CoCr stems 2) CoCr heads on titanium alloy (Ti) stems and 3) ceramic heads on CoCr stems. In test 1 increasing torque was imposed by offsetting the stem in the anteroposterior plane in increments of 0 mm, 4 mm, 6 mm and 8 mm when the torque generated was equivalent to 0 Nm, 9 Nm, 14 Nm and 18 Nm. In test 2 we investigated the effect of increasing the bending moment by offsetting the application of axial load from the midline in the mediolateral plane. Increments of offset equivalent to head + 0 mm, head + 7 mm and head + 14 mm were used. Significantly higher currents and amplitudes were seen with increasing torque for all combinations of material. However, Ti stems showed the highest corrosion currents. Increased bending moments associated with using larger offset heads produced more corrosion: Ti stems generally performed worse than CoCr stems. Using ceramic heads did not prevent corrosion, but reduced it significantly in all loading configurations. PMID- 25820884 TI - The influence of the strength of bone on the deformation of acetabular shells: a laboratory experiment in cadavers. AB - Concerns have been raised that deformation of acetabular shells may disrupt the assembly process of modular prostheses. In this study we aimed to examine the effect that the strength of bone has on the amount of deformation of the acetabular shell. The hypothesis was that stronger bone would result in greater deformation. A total of 17 acetabular shells were inserted into the acetabula of eight cadavers, and deformation was measured using an optical measuring system. Cores of bone from the femoral head were taken from each cadaver and compressed using a materials testing machine. The highest peak modulus and yield stress for each cadaver were used to represent the strength of the bone and compared with the values for the deformation and the surgeon's subjective assessment of the hardness of the bone. The mean deformation of the shell was 129 um (3 to 340). No correlation was found between deformation and either the maximum peak modulus (r2 = 0.011, t = 0.426, p = 0.676) or the yield stress (r2 = 0.024, t = 0.614, p = 0.549) of the bone. Although no correlation was found between the strength of the bone and deformation, the values for the deformation observed could be sufficient to disrupt the assembly process of modular acetabular components. PMID- 25820885 TI - Coxa profunda in the diagnosis of pincer-type femoroacetabular impingement and its prevalence in asymptomatic subjects. AB - In many papers, the diagnosis of pincer-type femoroacetabular impingement (FAI) is attributed to the presence of coxa profunda. However, little is known about the prevalence of coxa profunda in the general population and its clinical relevance. In order to ascertain its prevalence in asymptomatic subjects and whether it is a reliable indicator of pincer-type FAI, we undertook a cross sectional study between July and December 2013. A total of 226 subjects (452 hips) were initially screened. According to strict inclusion criteria, 129 asymptomatic patients (257 hips) were included in the study. The coxa profunda sign, the crossover sign, the acetabular index (AI) and lateral centre-edge (LCE) angle were measured on the radiographs. The median age of the patients was 36.5 years (28 to 50) and 138 (53.7%) were women. Coxa profunda was present in 199 hips (77.4%). There was a significantly increased prevalence of coxa profunda in women (p < 0.05) and a significant association between coxa profunda and female gender (p < 0.001) (92% vs 60.5%). The crossover sign was seen in 36 hips (14%), an LCE > 40 degrees in 28 hips (10.9%) and an AI < 0o in 79 hips (30.7%). A total of 221 normal hips (79.2%) (normal considering the crossover) had coxa profunda, a total of 229 normal hips (75.5%) (normal considering the LCE) had coxa profunda and a total of 178 normal hips (75.3%) (normal considering AI) had coxa profunda. When the presence of all radiological signs in the same subject was considered, pincer-type FAI was found in only two hips (one subject). We therefore consider that the coxa profunda sign should not be used as a radiological indicator of pincer-type FAI. We consider profunda to be a benign alteration in the morphology of the hip with low prevalence and a lack of association with other radiological markers of FAI. We suggest that the diagnosis of pincer-type FAI should be based on objective measures, in association with clinical findings. PMID- 25820886 TI - The capsular ligaments provide more hip rotational restraint than the acetabular labrum and the ligamentum teres : an experimental study. AB - In this in vitro study of the hip joint we examined which soft tissues act as primary and secondary passive rotational restraints when the hip joint is functionally loaded. A total of nine cadaveric left hips were mounted in a testing rig that allowed the application of forces, torques and rotations in all six degrees of freedom. The hip was rotated throughout a complete range of movement (ROM) and the contributions of the iliofemoral (medial and lateral arms), pubofemoral and ischiofemoral ligaments and the ligamentum teres to rotational restraint was determined by resecting a ligament and measuring the reduced torque required to achieve the same angular position as before resection. The contribution from the acetabular labrum was also measured. Each of the capsular ligaments acted as the primary hip rotation restraint somewhere within the complete ROM, and the ligamentum teres acted as a secondary restraint in high flexion, adduction and external rotation. The iliofemoral lateral arm and the ischiofemoral ligaments were primary restraints in two-thirds of the positions tested. Appreciation of the importance of these structures in preventing excessive hip rotation and subsequent impingement/instability may be relevant for surgeons undertaking both hip joint preserving surgery and hip arthroplasty. PMID- 25820887 TI - Effects of rotational acetabular osteotomy on the mechanical stress within the hip joint in patients with developmental dysplasia of the hip: a subject-specific finite element analysis. AB - In this study we used subject-specific finite element analysis to investigate the mechanical effects of rotational acetabular osteotomy (RAO) on the hip joint and analysed the correlation between various radiological measurements and mechanical stress in the hip joint. We evaluated 13 hips in 12 patients (two men and ten women, mean age at surgery 32.0 years; 19 to 46) with developmental dysplasia of the hip (DDH) who were treated by RAO. Subject-specific finite element models were constructed from CT data. The centre-edge (CE) angle, acetabular head index (AHI), acetabular angle and acetabular roof angle (ARA) were measured on anteroposterior pelvic radiographs taken before and after RAO. The relationship between equivalent stress in the hip joint and radiological measurements was analysed. The equivalent stress in the acetabulum decreased from 4.1 MPa (2.7 to 6.5) pre-operatively to 2.8 MPa (1.8 to 3.6) post-operatively (p < 0.01). There was a moderate correlation between equivalent stress in the acetabulum and the radiological measurements: CE angle (R = -0.645, p < 0.01); AHI (R = -0.603, p < 0.01); acetabular angle (R = 0.484, p = 0.02); and ARA (R = 0.572, p < 0.01). The equivalent stress in the acetabulum of patients with DDH decreased after RAO. Correction of the CE angle, AHI and ARA was considered to be important in reducing the mechanical stress in the hip joint. PMID- 25820888 TI - The dynamic nature of alignment and variations in normal knees. AB - The restoration of knee alignment is an important goal during total knee arthroplasty (TKA). In the past surgeons aimed to restore neutral limb alignment during surgery. However, previous studies have demonstrated alignment to be dynamic, varying depending on the position of the limb and the degree of weight bearing, and between patients. We used a validated computer navigation system to measure the femorotibial mechanical angle (FTMA) in 264 knees in 77 male and 55 female healthy volunteers aged 18 to 35 years (mean 26.2). We found the mean supine alignment to be a varus angle of 1.2 degrees (standard deviation (sd) 4), with few patients having neutral alignment. FTMA differs significantly between males and females (with a mean varus of 1.7 degrees (sd 4) and 0.4 degrees (sd 3.9), respectively; p = 0.008). It changes significantly with posture, the knee hyperextending by a mean of 5.6 degrees , and coronal plane alignment becoming more varus by 2.2 degrees (sd 3.6) on standing compared with supine. Knee alignment is different in different individuals and is dynamic in nature, changing with different postures. This may have implications for the assessment of alignment in TKA, which is achieved in non-weight-bearing conditions and which may not represent the situation observed during weight-bearing. PMID- 25820889 TI - Validation of a prediction model that allows direct comparison of the Oxford Knee Score and American Knee Society clinical rating system. AB - This study demonstrates a significant correlation between the American Knee Society (AKS) Clinical Rating System and the Oxford Knee Score (OKS) and provides a validated prediction tool to estimate score conversion. A total of 1022 patients were prospectively clinically assessed five years after TKR and completed AKS assessments and an OKS questionnaire. Multivariate regression analysis demonstrated significant correlations between OKS and the AKS knee and function scores but a stronger correlation (r = 0.68, p < 0.001) when using the sum of the AKS knee and function scores. Addition of body mass index and age (other statistically significant predictors of OKS) to the algorithm did not significantly increase the predictive value. The simple regression model was used to predict the OKS in a group of 236 patients who were clinically assessed nine to ten years after TKR using the AKS system. The predicted OKS was compared with actual OKS in the second group. Intra-class correlation demonstrated excellent reliability (r = 0.81, 95% confidence intervals 0.75 to 0.85) for the combined knee and function score when used to predict OKS. Our findings will facilitate comparison of outcome data from studies and registries using either the OKS or the AKS scores and may also be of value for those undertaking meta-analyses and systematic reviews. PMID- 25820890 TI - The treatment of a rupture of the Achilles tendon using a dedicated management programme. AB - The Swansea Morriston Achilles Rupture Treatment (SMART) programme was introduced in 2008. This paper summarises the outcome of this programme. Patients with a rupture of the Achilles tendon treated in our unit follow a comprehensive management protocol that includes a dedicated Achilles clinic, ultrasound examination, the use of functional orthoses, early weight-bearing, an accelerated exercise regime and guidelines for return to work and sport. The choice of conservative or surgical treatment was based on ultrasound findings. The rate of re-rupture, the outcome using the Achilles Tendon Total Rupture Score (ATRS) and the Achilles Tendon Repair Score, (AS), and the complications were recorded. An elementary cost analysis was also performed. Between 2008 and 2014 a total of 273 patients presented with an acute rupture 211 of whom were managed conservatively and 62 had surgical repair. There were three re-ruptures (1.1%). There were 215 men and 58 women with a mean age of 46.5 years (20 to 86). Functional outcome was satisfactory. Mean ATRS and AS at four months was 53.0 (sd 14), 64.9 (sd 15) (n = 135), six months 67.8 (sd 16), 73.8 (sd 15) (n = 103) and nine months (72.4; sd 14) 72.3 (sd 13) (n = 43). The programme realised estimated cost savings exceeding L91,000 per annum. The SMART programme resulted in a low rate of re rupture, a satisfactory outcome, a reduced rate of surgical intervention and a reduction in healthcare costs. PMID- 25820891 TI - The effect of strict infection control policies on the rate of infection after elective foot and ankle surgery: a review of 1737 cases. AB - The rate of surgical site infection after elective foot and ankle surgery is higher than that after other elective orthopaedic procedures. Since December 2005, we have prospectively collected data on the rate of post-operative infection for 1737 patients who have undergone elective foot and ankle surgery. In March 2008, additional infection control policies, focused on surgical and environmental risk factors, were introduced in our department. We saw a 50% reduction in the rate of surgical site infection after the introduction of these measures. We are, however, aware that the observed decrease may not be entirely attributable to these measures alone given the number of factors that predispose to post-operative wound infection. PMID- 25820892 TI - The natural history of primary anterior dislocation of the glenohumeral joint in adolescence. AB - The natural history of primary anterior dislocation of the glenohumeral joint in adolescent patients remains unclear and there is no consensus for management of these patients. The objectives of this study were to report the natural history of primary anterior dislocation of the glenohumeral joint in adolescent patients and to identify the risk factors for recurrent dislocation. We reviewed prospectively-collected clinical and radiological data on 133 adolescent patients diagnosed with a primary anterior dislocation of the glenohumeral joint who had been managed non-operatively at our hospital between 1996 and 2008. There were 115 male (86.5%) and 18 female patients (13.5%) with a mean age of 16.3 years (13 to 18) and a mean follow-up of 95.2 months (1 to 215). During follow-up, 102 (absolute incidence of 76.7%) patients had a recurrent dislocation. The median interval between primary and recurrent dislocation was ten months (95% CI 7.4 to 12.6). Applying survival analysis the likelihood of having a stable shoulder one year after the initial injury was 59% (95% CI 51.2 to 66.8), 38% (95% CI 30.2 to 45.8%) after two years, 21% (95% CI 13.2 to 28.8) after five years, and 7% (95% CI 1.1 to 12.9) after ten years. Neither age nor gender significantly predicted recurrent dislocation during follow-up. We conclude that adolescent patients with a primary anterior dislocation of the glenohumeral joint have a high rate of recurrent dislocation, which usually occurs within two years of their initial injury: these patients should be considered for early operative stabilisation. PMID- 25820893 TI - Secondary neurological deterioration in traumatic spinal injury: data from medicolegal cases. AB - We assessed the frequency and causes of neurological deterioration in 59 patients with spinal cord injury on whom reports were prepared for clinical negligence litigation. In those who deteriorated neurologically we assessed the causes of the change in neurology and whether that neurological deterioration was potentially preventable. In all 27 patients (46%) changed neurologically, 20 patients (74% of those who deteriorated) had no primary neurological deficit. Of those who deteriorated, 13 (48%) became Frankel A. Neurological deterioration occurred in 23 of 38 patients (61%) with unstable fractures and/or dislocations; all 23 patients probably deteriorated either because of failures to immobilise the spine or because of inappropriate removal of spinal immobilisation. Of the 27 patients who altered neurologically, neurological deterioration was, probably, avoidable in 25 (excess movement in 23 patients with unstable injuries, failure to evacuate an epidural haematoma in one patient and over-distraction following manipulation of the cervical spine in one patient). If existing guidelines and standards for the management of actual or potential spinal cord injury had been followed, neurological deterioration would have been prevented in 25 of the 27 patients (93%) who experienced a deterioration in their neurological status. PMID- 25820894 TI - Total knee arthroplasty following tibial plateau fracture: a matched cohort study. AB - Radiological evidence of post-traumatic osteoarthritis (PTOA) after fracture of the tibial plateau is common but end-stage arthritis which requires total knee arthroplasty is much rarer. The aim of this study was to examine the indications for, and outcomes of, total knee arthroplasty after fracture of the tibial plateau and to compare this with an age and gender-matched cohort of TKAs carried out for primary osteoarthritis. Between 1997 and 2011, 31 consecutive patients (23 women, eight men) with a mean age of 65 years (40 to 89) underwent TKA at a mean of 24 months (2 to 124) after a fracture of the tibial plateau. Of these, 24 had undergone ORIF and seven had been treated non-operatively. Patients were assessed pre-operatively and at 6, 12 and > 60 months using the Short Form-12, Oxford Knee Score and a patient satisfaction score. Patients with instability or nonunion needed total knee arthroplasty earlier (14 and 13.3 months post-injury) than those with intra-articular malunion (50 months, p < 0.001). Primary cruciate retaining implants were used in 27 (87%) patients. Complication rates were higher in the PTOA cohort and included wound complications (13% vs 1% p = 0.014) and persistent stiffness (10% vs 0%, p = 0.014). Two (6%) PTOA patients required revision total knee arthroplasty at 57 and 114 months. The mean Oxford knee score was worse pre-operatively in the cohort with primary osteoarthritis (18 vs 30, p < 0.001) but there were no significant differences in post-operative Oxford knee score or patient satisfaction (primary osteoarthritis 86%, PTOA 78%, p = 0.437). Total knee arthroplasty undertaken after fracture of the tibial plateau has a higher rate of complications than that undertaken for primary osteoarthritis, but patient-reported outcomes and satisfaction are comparable. Cite this article: Bone Joint J 2015;97-B:532-8. PMID- 25820895 TI - Contribution of inflammation to cellular injury in compartment syndrome in an experimental rodent model. AB - Compartment syndrome, a devastating consequence of limb trauma, is characterised by severe tissue injury and microvascular perfusion deficits. We hypothesised that leucopenia might provide significant protection against microvascular dysfunction and preserve tissue viability. Using our clinically relevant rat model of compartment syndrome, microvascular perfusion and tissue injury were directly visualised by intravital video microscopy in leucopenic animals. We found that while the tissue perfusion was similar in both groups (38.8% (standard error of the mean (sem) 7.1), 36.4% (sem 5.7), 32.0% (sem 1.7), and 30.5% (sem 5.35) continuously-perfused capillaries at 45, 90, 120 and 180 minutes compartment syndrome, respectively versus 39.2% (sem 8.6), 43.5% (sem 8.5), 36.6% (sem 1.4) and 50.8% (sem 4.8) at 45, 90, 120 and 180 minutes compartment syndrome, respectively in leucopenia), compartment syndrome-associated muscle injury was significantly decreased in leucopenic animals (7.0% (sem 2.0), 7.0%, (sem 1.0), 9.0% (sem 1.0) and 5.0% (sem 2.0) at 45, 90, 120 and 180 minutes of compartment syndrome, respectively in leucopenia group versus 18.0% (sem 4.0), 23.0% (sem 4.0), 32.0% (sem 7.0), and 20.0% (sem 5.0) at 45, 90, 120 and 180 minutes of compartment syndrome in control, p = 0.0005). This study demonstrates that the inflammatory process should be considered central to the understanding of the pathogenesis of cellular injury in compartment syndrome. PMID- 25820896 TI - Cortical strut bone grafting and long-stem endoprosthetic reconstruction following massive bone tumour resection in the lower limb. AB - We determined the efficacy of a devitalised autograft (n = 13) and allograft (n = 16) cortical strut bone graft combined with long-stem endoprosthetic reconstruction in the treatment of massive tumours of the lower limb. A total of 29 patients (18 men:11 women, mean age 20.1 years (12 to 45) with a ratio of length of resection to that of the whole prosthesis of > 50% were treated between May 2003 and May 2012. The mean follow-up was 47 months (15 to 132). The stem of the prosthesis was introduced through bone graft struts filled with cement, then cemented into the residual bone. Bone healing was achieved in 23 patients (86%). The mean Musculoskeletal Tumour Society functional score was 85% (57 to 97). The five-year survival rate of the endoprostheses was 81% (95% confidence intervals 67.3 to 92.3). The mean length of devitalised autografts and allografts was 8.6 cm (5 to 15), which increased the ratio of the the length of the stem of the prosthesis to that of the whole length of the prosthesis from a theoretical 35% to an actual 55%. Cortical strut bone grafting and long-stem endoprosthetic reconstruction is an option for treating massive segmental defects following resection of a tumour in the lower limb. Patients can regain good function with a low incidence of aseptic loosening. The strut graft and the residual bone together serve as a satisfactory bony environment for a revision prosthesis, if required, once union is achieved. PMID- 25820897 TI - The effect of surgical synovectomy and radiotherapy on the rate of recurrence of pigmented villonodular synovitis of the knee: an individual patient meta analysis. AB - Pigmented villonodular synovitis (PVNS) is a rare proliferative process of the synovium which most commonly affects the knee and occurs in either a localised (LPVNS) or a diffuse form (DPVNS). The effect of different methods of surgical synovectomy and adjuvant radiotherapy on the rate of recurrence is unclear. We conducted a systematic review and identified 35 observational studies in English which reported the use of surgical synovectomy to treat PVNS of the knee. A meta analysis included 630 patients, 137 (21.8%) of whom had a recurrence after synovectomy. For patients with DPVNS, low-quality evidence found that the rate of recurrence was reduced by both open synovectomy (odds ration (OR) = 0.47; 95% CI 0.25 to 0.90; p = 0.024) and combined open and arthroscopic synovectomy (OR = 0.19, 95% CI = 0.06 to 0.58; p = 0.003) compared with arthroscopic surgery. Very low-quality evidence found that the rate of recurrence of DPVNS was reduced by peri-operative radiotherapy (OR = 0.31, 95% CI 0.14 to 0.70; p = 0.01). Very low quality evidence suggested that the rate of recurrence of LPVNS was not related to the surgical approach. This meta-analysis suggests that open synovectomy or synovectomy combined with peri-operative radiotherapy for DPVNS is associated with a reduced rate of recurrence. Large long-term prospective multicentre observational studies, with a focus on both rate of recurrence and function, are required to confirm these findings. PMID- 25820898 TI - End caps prevent nail migration in elastic stable intramedullary nailing in paediatric femoral fractures: a biomechanical study using synthetic and cadaveric bones. AB - End caps are intended to prevent nail migration (push-out) in elastic stable intramedullary nailing. The aim of this study was to investigate the force at failure with and without end caps, and whether different insertion angles of nails and end caps would alter that force at failure. Simulated oblique fractures of the diaphysis were created in 15 artificial paediatric femurs. Titanium Elastic Nails with end caps were inserted at angles of 45 degrees , 55 degrees and 65 degrees in five specimens for each angle to create three study groups. Biomechanical testing was performed with axial compression until failure. An identical fracture was created in four small adult cadaveric femurs harvested from two donors (both female, aged 81 and 85 years, height 149 cm and 156 cm, respectively). All femurs were tested without and subsequently with end caps inserted at 45 degrees . In the artificial femurs, maximum force was not significantly different between the three groups (p = 0.613). Push-out force was significantly higher in the cadaveric specimens with the use of end caps by an up to sixfold load increase (830 N, standard deviation (SD) 280 vs 150 N, SD 120, respectively; p = 0.007). These results indicate that the nail and end cap insertion angle can be varied within 20 degrees without altering construct stability and that the risk of elastic stable intramedullary nailing push-out can be effectively reduced by the use of end caps. PMID- 25820899 TI - The transverse Vulpius gastrocsoleus recession for equinus gait in children with cerebral palsy. AB - We report the results of Vulpius transverse gastrocsoleus recession for equinus gait in 26 children with cerebral palsy (CP), using the Gait Profile Score (GPS), Gait Variable Scores (GVS) and movement analysis profile. All children had an equinus deformity on physical examination and equinus gait on three-dimensional gait analysis prior to surgery. The pre-operative and post-operative GPS and GVS were statistically analysed. There were 20 boys and 6 girls in the study cohort with a mean age at surgery of 9.2 years (5.1 to 17.7) and 11.5 years (7.3 to 20.8) at follow-up. Of the 26 children, 14 had spastic diplegia and 12 spastic hemiplegia. Gait function improved for the cohort, confirmed by a decrease in mean GPS from 13.4 degrees pre-operatively to 9.0 degrees final review (p < 0.001). The change was 2.8 times the minimal clinically important difference (MCID). Thus the improvements in gait were both clinically and statistically significant. The transverse gastrocsoleus recession described by Vulpius is an effective procedure for equinus gait in selected children with CP, when there is a fixed contracture of the gastrocnemius and soleus muscles. PMID- 25820900 TI - The development of a rat model to investigate the formation of blast-related post traumatic heterotopic ossification. AB - Currently, there is no animal model in which to evaluate the underlying physiological processes leading to the heterotopic ossification (HO) which forms in most combat-related and blast wounds. We sought to reproduce the ossification that forms under these circumstances in a rat by emulating patterns of injury seen in patients with severe injuries resulting from blasts. We investigated whether exposure to blast overpressure increased the prevalence of HO after transfemoral amputation performed within the zone of injury. We exposed rats to a blast overpressure alone (BOP-CTL), crush injury and femoral fracture followed by amputation through the zone of injury (AMP-CTL) or a combination of these (BOP AMP). The presence of HO was evaluated using radiographs, micro-CT and histology. HO developed in none of nine BOP-CTL, six of nine AMP-CTL, and in all 20 BOP-AMP rats. Exposure to blast overpressure increased the prevalence of HO. This model may thus be used to elucidate cellular and molecular pathways of HO, the effect of varying intensities of blast overpressure, and to evaluate new means of prophylaxis and treatment of heterotopic ossification. PMID- 25820901 TI - Ras/ERK1/2 pathway regulates the self-renewal of dairy goat spermatogonia stem cells. AB - Spermatogonia stem cells (SSCs), also named the male germline stem cells (mGSCs), which is located at the base of the seminiferous tubules of testis, is the basis for generating sperm steadily in male animals. Currently, there are some preliminary study on the self-renewal and differentiation of SSCs, but further mechanism, especially in large animals, has not been clearly understood. Ras/ERK1/2 pathway is widely distributed in multiple cells in vivo. It plays an important role in cell proliferation, differentiation and so on. However, the study on the function for the self-renewal of dairy goats SSCs has not been investigated. In this study, the dairy goat SSCs characterization were evaluated by semi-RT-PCR, alkaline phosphatase (AP) staining, and immunofluorescence staining. Then, Ras/ERK1/2 pathway was blocked by specific MEK1/2 inhibitor PD0325901. We analyzed the proliferation by cell number, cell growth curve, Brdu incorporation assay, and cell cycle analysis. The results showed that the proliferation was significantly inhibited by PD0325901. Cell apoptosis induced by blocking the Ras/ERK1/2 pathway was analyzed by TUNEL. The expression of ETV5 and BCL6B, the downstream gene of Ras/ERK1/2 pathway, was downregulated. This study suggest that the Ras/ERK1/2 pathway plays a critical role in maintaining the self renewal of dairy goat SSCs via regulation of ETV5 and BCL6B. This study laid a foundation for insights into the mechanism of SSCs self-renewal comprehensively. PMID- 25820902 TI - ATPases, ion exchangers and human sperm motility. AB - Human sperm has several mechanisms to control its ionic milieu, such as the Na,K ATPase (NKA), the Ca-ATPase of the plasma membrane (PMCA), the Na(+)/Ca(2) (+) exchanger (NCX) and the Na(+)/H(+)-exchanger (NHE). On the other hand, the dynein ATPase is the intracellular motor for sperm motility. In this work, we evaluated NKA, PMCA, NHE, NCX and dynein-ATPase activities in human sperm and investigated their correlation with sperm motility. Sperm motility was measured by Computer Assisted Semen Analysis. It was found that the NKA activity is inhibited by ouabain with two Ki (7.9 * 10(-9) and 9.8 * 10(-5) M), which is consistent with the presence of two isoforms of alpha subunit of the NKA in the sperm plasma membranes (alpha1 and alpha4), being alpha4 more sensitive to ouabain. The decrease in NKA activity is associated with a reduction in sperm motility. In addition, sperm motility was evaluated in the presence of known inhibitors of NHE, PMCA and NCX, such as amiloride, eosin, and KB-R7943, respectively, as well as in the presence of nigericin after incubation with ouabain. Amiloride, eosin and KB-R7943 significantly reduced sperm motility. Nigericin reversed the effect of ouabain and amiloride on sperm motility. Dynein-ATPase activity was inhibited by acidic pH and micromolar concentrations of Ca(2) (+). We explain our results in terms of inhibition of the dynein-ATPase in the presence of higher cytosolic H(+) and Ca(2) (+), and therefore inhibition of sperm motility. PMID- 25820903 TI - Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models. AB - Uniparental inheritance of chromosome 14q32 causes developmental failure during gestation and early postnatal development due to mis-expression of a cluster of imprinted genes under common epigenetic control. Two syndromes associated with chromosome 14q32 abnormalities have been described, Kagami-Ogata and Temple syndromes. Both of these syndromes are characterised by specific impairments of intrauterine development, placentation and early postnatal survival. Such abnormalities arise because the processes of intrauterine growth and postnatal adaptation are critically modulated by the dosage of imprinted genes in the chromosome 14q32 cluster. Much of our understanding of how the imprinted genes in this cluster are regulated, as well as their individual functions in the molecular pathways controlling growth and postnatal adaptation, has come from murine models. Mouse chromosome 12qF1 contains an imprinted region syntenic to human chromosome 14q32, collectively referred to as the Dlk1-Dio3 cluster. In this review, we will summarise the wealth of information derived from animal models of chromosome 12 imprinted gene mis-regulation, and explore the relationship between the functions of individual genes and the phenotypic result of their mis-expression. As there is often a considerable overlap between the functions of genes in the Dlk1-Dio3 cluster, we propose that the expression dosage of these genes is controlled by common regulatory mechanisms to co ordinate the timing of growth and postnatal adaptation. While the diseases associated with mis-regulated chromosome 14 imprinting are rare, studies carried out in mice on the functions of the affected genes as well as their normal regulatory mechanisms have revealed new mechanistic pathways for the control of growth and survival in early life. PMID- 25820904 TI - Sharp molecular-sieving of alcohol-water mixtures over phenyldiboronic acid pillared graphene oxide framework (GOF) hybrid membrane. AB - A submicron thick diboronic acid linked GOF/polyvinyl alcohol hybrid membrane was prepared for the first time. The uniform inter-spacing of the GOF membrane excludes the diffusion of large molecules based on a molecular sieving mechanism. It exhibits high stability and excellent sieving performance in solvent (>=C3) dehydration (SFs > 10,000). PMID- 25820905 TI - The cyano group as a traceless activation group for the intermolecular [3+2] cycloaddition of azomethine ylides: a five-step synthesis of (+/-) isoretronecanol. AB - The cyano group was used as a traceless activation group for the [3+2] cycloaddition of azomethine ylides in a two-step process, thereby providing a highly effective approach to 5-unsubstituted pyrrolidines. The transformation includes the silver acetate catalyzed intermolecular 1,3-dipolar cycloaddition of alpha-iminonitriles and an unprecedented sodium borohydride induced reductive decyanation reaction. A diverse array of substrates is amenable to this transformation. The methodology was further extended to a five-step total synthesis of the pyrrolizidine natural product isoretronecanol. PMID- 25820906 TI - A Lightweight TiO2/Graphene Interlayer, Applied as a Highly Effective Polysulfide Absorbent for Fast, Long-Life Lithium-Sulfur Batteries. PMID- 25820907 TI - Interleukin-27, a novel cytokine induced by ischemia-reperfusion injury in rat hearts, mediates cardioprotective effects via the gp130/STAT3 pathway. AB - Patients with coronary artery disease show high serum levels of interleukin (IL) 27, a novel member of the IL-6 family. However, the function of IL-27 in hearts suffering ischemia/reperfusion (IR) injury is unclear. Here, we showed increased expression of mRNA for the IL-27 subunits, EBI3 and p28, in rat hearts after 40 min of coronary ligation and release for 7 days. This increase was associated with a peak in the release of the cardiac enzyme, creatine kinase-MB, on day 2 post-release. Moreover, levels of IL-27 receptor subunit gp130 mRNA, but not those of subunit WSX-1 mRNA, decreased in post-ischemic hearts. These results suggest that increased IL-27 production may compensate for receptor downregulation during myocardial recovery. Lactate dehydrogenase release and crystal violet staining revealed that IL-27 or IL-6 significantly attenuated severe hypoxia (SH, 2 % O2)-induced cell damage in H9c2 cardiomyoblasts and primary rat neonatal cardiomyocytes. Incubating cardiomyocytes with IL-27 or IL-6 resulted in time-dependent activation of signal transducers and activators of transcription 3 (STAT3). Interestingly, IL-27-induced STAT3 activation was attenuated by pre-treatment with a gp130-neutralizing antibody. Blocking gp130 also reduced the cytoprotective effects of IL-27 or IL-6. Moreover, IL-27 mediated protection against SH was blocked by stattic, a small-molecule inhibitor of STAT3. IL-27 markedly improved post-ischemic recovery and reduced tissue damage in isolated perfused hearts when administered 5 min before reperfusion. These results indicate that IL-27 protects the myocardium against IR injury and facilitates the recovery of damaged cardiomyocytes via the gp130/STAT3 pathway. PMID- 25820908 TI - Determination of chemotherapeutic drugs in human urine by capillary electrophoresis with UV and fluorimetric detection using solid-supported liquid liquid extraction for sample clean-up. AB - Capillary electrophoresis was used for the rapid determination of three chemotherapeutic drugs employed to treat colorectal cancer: irinotecan, tegafur, and leucovorin, and their main metabolites (7-ethyl-10-hydroxycamptothecin and 5 fluorouracil), in human urine samples. A phosphate buffer (pH 11.34; 20 mM) was selected as the background electrolyte. A hydrodynamic injection (9 s, 30 mbar) was applied and the separation was carried out using a separation temperature and voltage of 25 degrees C and 25 kV, respectively. A capillary with two detection windows for serial online UV and fluorescence detection was satisfactorily employed. A solid-supported liquid-liquid extraction procedure was optimized for the clean-up of the urine samples and the extraction of the analytes. Matrix effects were assessed and signal suppression was observed for three of the analytes, thus, matrix-matched calibration was used for compensating residual matrix effects on these analytes. The proposed method allows the separation and quantification of the chemotherapeutics in less than 6 min. Detection limits range between 0.01 and 0.30 mg/L. The method was satisfactorily applied to the determination of the target compounds in human urine samples, with recoveries of 92.4-107.7%. PMID- 25820910 TI - Laparoscopic Colorectal Cancer Resection in High-Volume Surgical Centers: Long Term Outcomes from the LAPCOLON Group Trial. AB - BACKGROUND: Strong evidence has confirmed the benefit of laparoscopy in colorectal cancer resection but remains a challenging procedure. It is not clear that such promising results in selected patients translate into a favorable risk benefit balance in real practice. We conducted a multicenter national observational registry to assess operative and oncologic long-term outcomes following laparoscopic colorectal cancer resection. METHODS: All patients with laparoscopic colorectal cancer resection between 2001 and 2004 were included. Data were extracted from the prospective Italian national database of 10 high volume centers (>=40 colorectal cancer laparoscopic resections per year). Surgical technique and follow-up were standardized. Survivals were analyzed by Kaplan-Meier method. RESULTS: We reported 1832 patients with colon (58.5%) and rectal cancer (41.5%). TNM stage was 0-I-II in 1044 patients (57%) and III-IV in 788 patients (43%). Surgery included a totally laparoscopic procedure in 1820 patients (99.3%). Conversion was 10.5%. Postoperative morbidity and 30-day mortality rates were 17 and 1.2%, respectively. Clinical anastomotic leakage rate was 8.3% (n=152). R0 resection was 95%. With a median follow-up of 54.2 months, cancer recurrence rate was 13.3%. At 5 years, cancer-free survival was 86.7%. Upon multivariate analysis, age (P=0.001) and TNM stage (P<0.001) were associated with cancer-free survival. Predictive factors of cancer recurrence were gender (P=0.029) and TNM stage (P<0.001). CONCLUSIONS: In high-volume centers and non selective patients, laparoscopic colorectal resection for cancer achieves good operative results with satisfactory long-term oncologic results. Even in the laparoscopy era, age, gender, and TNM stage remain the most powerful predictor of oncologic outcomes. PMID- 25820911 TI - Risk Factors for Re-recurrence After First Reoperative Surgery for Locoregional Recurrent/Persistent Papillary Thyroid Carcinoma. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is generally an indolent tumor indicative of favorable prognosis. However, post-treatment recurrences may be problematic, and management strategies for recurrent disease have not been established. This study investigated risk factors associated with re-recurrence of PTC after reoperative surgery. MATERIALS AND METHODS: This study included 151 patients with pathologically confirmed recurrent/persistent PTC who underwent reoperation. Clinical factors, operative and pathologic findings, serum thyroglobulin levels, postoperative complications, and recurrences were examined. Univariate and multivariate analyses were performed to identify factors associated with re-recurrence-free survival (RFS) after reoperative surgery. RESULTS: Recurrent tumors were found in thyroid remnants or previous resection bed (n=28), central nodes (n=48), and lateral neck nodes (n=102). Biochemical complete remission (stimulated thyroglobulin<1 ng/mL) was achieved in 69 (51.5%) patients after reoperative surgery. Permanent vocal fold paralysis and hypoparathyroidism developed in 6 (4.1%) and 4 (2.8%) patients, respectively. Vocal fold paralysis occurred primarily due to intentional nerve resection following tumor invasion. During a median follow-up of 57.5 months, 41 (27.2%) patients had re-recurrences. Univariate analyses showed that extranodal extension (p=0.028), recurrent laryngeal nerve invasion (p=0.037), as well as stimulated (p=0.001) and unstimulated (p=0.015) serum thyroglobulin were significant predictors of RFS. Multivariate analyses showed that postoperative biochemical remission independently predicted RFS (p=0.014). CONCLUSIONS: Postoperative thyroglobulin after reoperative surgery predicted re-recurrence. Careful follow up of these patients after reoperation is recommended. PMID- 25820912 TI - Gross motor coordination and weight status of Portuguese children aged 6-14 years. AB - OBJECTIVES: To construct age- and gender-specific percentiles for gross motor coordination (MC) tests and to explore differences in gross MC in normal-weight, overweight and obese children. METHODS: Data are from the "Healthy Growth of Madeira Study," a cross-sectional study carried out in children, aged 6-14 years. All 1,276 participants, 619 boys and 657 girls, were assessed for gross MC (Korperkoordinations Test fur Kinder, KTK), anthropometry (height and body mass), physical activity (Baecke questionnaire) and socioeconomic status (SES). Centile curves for gross MC were obtained for boys and girls separately using generalized additive models for location, scale and shape. RESULTS: A significant main effect for age was found in walking backwards and moving sideways. Boys performed significantly better than girls on moving sideways. At the upper limit of the distributions, interindividual variability was higher in hopping on one leg (girls) and jumping and moving sideways (boys and girls). One-way ANCOVA, controlling for age, physical activity and SES, indicated that normal-weight children scored significantly better than their obese peers in all gross MC tests. Overweight boys and girls also scored significantly better than their obese colleagues in some MC tests. CONCLUSIONS: These centile curves can be used as reference data in Portuguese children and youth, aged 6-14 years. Being overweight or obese was a major limitation in MC tests and, therefore, of the children's health- and performance-related physical fitness. PMID- 25820913 TI - Identifying the unmet needs of breast cancer patients post-primary treatment: the Cancer Survivor Profile (CSPro). AB - PURPOSE: The purpose of this study is to develop a brief measure of problem areas experienced by patients following primary treatment for breast cancer. METHOD: Systematic reviews of the quantitative and qualitative literature were used to inform selection of scale items using (1) valid and reliable items from a national item bank (patient reported outcomes measurement information system [PROMIS]), (2) existing scales from prior breast cancer survivorship research, or (3) items developed by the investigators. RESULTS: Participants (n = 400) were on average 51 years old, highly educated, Caucasian, diagnosed with stage I-III breast cancer, and a median of 1.96 years post-primary treatment. Principal component analysis on a random sample (n = 200) and confirmation on a second random sample (n = 200) indicated that each of the scales under consideration provided a significant measurement model for the symptom burden (CFI = 0.95), health behavior (CFI = 1.00), functional limitation (CFI = 0.99), health care seeking skill (CFI = 0.98), and cancer-related financial strain (CFI = 1.00) broad domains. The median Cronbach's alpha was 0.91. The measure demonstrated convergent, divergent, construct, and clinical validity. Lower levels of fatigue (beta = 0.251. p < 0.000) and pain (beta = 0.221, p < 0.000) and greater health competence (beta = 0.278, p < 0.000) and physical activity (beta = 0.165, p < 0.000) were associated with self-rated global health (F = 60.43, p < 0.000). The final measure consists of 73 items and requires approximately 15 min to complete. DISCUSSION: The Cancer Survivor Profile (CSPro) provides a profile of problem areas supported by epidemiological and qualitative research on unmet needs of breast cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Breast cancer survivors can use the CSPro to prioritize problem areas following cancer treatment. PMID- 25820914 TI - Obstructive sleep apnea: underdiagnosed in older adults with severe mental illness? PMID- 25820915 TI - Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRNTM) and wild-type mice. AB - Hepatic NADPH-cytochrome P450 oxidoreductase null (HRNTM) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [(14)C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [(14)C]-diclofenac was incubated with HRNTM mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRNTM mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRNTM mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRNTM mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRNTM mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRNTM mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment. PMID- 25820916 TI - 3-Aminotriazole protects from CoCl2-induced ototoxicity by inhibiting the generation of reactive oxygen species and proinflammatory cytokines in mice. AB - Cobalt is an essential heavy metal that is necessary for the formation of vitamin B12 (hydroxocobalamin). However, exposure to excess cobalt for a prolonged period can harm the human body, causing pulmonary fibrosis, blindness, deafness, and peripheral neuropathy. 3-Aminotriazole (3-AT) is a catalase inhibitor that is often used to investigate the physiological effects of catalase. The present study found that injection of 3-AT in mice significantly reduced CoCl2-induced hearing impairment. In cultured organ of Corti explants from rats, 3-AT treatment protected hair cells from CoCl2-induced cytotoxicity. To determine the mechanism by which 3-AT protected from CoCl2-induced ototoxicity, we used the HEI-OC1 auditory cell line. Pretreatment with 10 mM 3-AT attenuated CoCl2-induced accumulation of ROS and induction of proinflammatory cytokine expression. Interestingly, these protective effects of 3-AT did not require catalase activity, as demonstrated by a series of experiments using RNA interference mediated catalase knockdown in HEI-OC1 cells and using catalase-deficient mouse embryonic fibroblasts. Our results demonstrated the mechanisms of CoCl2-induced ototoxicity that may provide better ways to prevent the ototoxic effect of cobalt exposure. PMID- 25820917 TI - Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions. AB - The advent of new testing systems and "omics"-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European "regulatory status quo", while elucidating new perspectives for regulatory toxicity testing. PMID- 25820918 TI - Moving from rats to cellular omics in regulatory toxicology: great challenge toward sustainability or "up-shit-creek without a paddle"? PMID- 25820919 TI - Borderline cognitive level in a family with Bazex-Dupre-Christol syndrome. AB - Bazex-Dupre-Christol syndrome (BDCS) [OMIM 301845] is an X-linked dominant disorder of the hair follicle characterized by multiple basal cell carcinomas, follicular atrophoderma, congenital hypotrichosis, and hypohidrosis. Additional features include multiple milia, trichoepitheliomas, and axillary hidradenitis suppurativa as well as a variety of other symptoms. Some patients with a diagnosis of BDCS have had poor school performance. But no other associated psychopathological disorders have been described in the literature. We describe the neuropsychological characteristics and the co-occurring psychopathological disorders in an Italian family (brother and sister, and their mother) affected by BDCS. The BDCS phenotype in this family was characterized by hypotrichosis, atrophoderma follicularis, milia, and trichoepitheliomas. No basal cell carcinomas were documented. At neuropsychological assessment the three affected family members all had a borderline cognitive level. Other identified psychopathological disorders included attention deficit hyperactivity disorder, executive deficits, academic difficulties, deficits in lexical skills, and internalizing problems. The presence of cognitive impairment in the three family members affected by BDCS suggests that cognitive impairment may be associated with the syndrome. It may be useful to assess neuropsychological performance in patients with BDCS to identify possible associated neuropsychological disorders. PMID- 25820920 TI - The deferiprone and deferasirox combination is efficacious in iron overloaded patients with beta-thalassemia major: A prospective, single center, open-label study. AB - BACKGROUND: The high cost, coupled with the need for continuous infusion, renders Desferrioxamine (DFO), a non-feasible option for iron-chelation in a large majority of patients with beta-thalassemia major in developing countries. Monotherapy with deferiprone (DFP) or deferasirox (DFX) may not always attain optimal control, particularly in heavily iron-loaded patients. Combination of DFP and DFX is a potential alternative. PROCEDURE: A prospective, single-center, open label, uncontrolled study was conducted to evaluate the safety and efficacy of the combination in patients with beta-thalassemia major. Patients who had received either DFP or DFX for >1 year and a serum ferritin >2,000 MUg/L were enrolled. Blood counts, liver/renal functions, and serum ferritin were monitored during the 1-year study period. Facilities for cardiac T2*-MRI were unavailable. RESULTS: Thirty-six patients with a mean age of 13 +/- 6.9 years (range: 4-29) and a ferritin of 6,768 +/- 4,145 MUg/L formed the study cohort. Eight (22%) patients had transient gastrointestinal adverse effects. DFX was discontinued in one patient for persistent abdominal pain/diarrhea. Eight (22%) had joint symptoms; DFP was discontinued in two. Four (11%) patients had elevation in AST/ALT levels, managed with temporary interruption of DFX. Nine (25%) had an inconsistent elevation of creatinine to >33% of baseline; no intervention was done. One had transient proteinuria. None had neutropenia. At the end of 1 year, the serum ferritin reduced by a mean value of 3,275.3 +/- 618.2 MUg/L (P < 0.001). CONCLUSIONS: The oral combination was found to be safe, efficacious, and a feasible option in patients with suboptimal response to monotherapy. PMID- 25820922 TI - Effects of processing and storage conditions on charged metabolomic profiles in blood. AB - The development of high-throughput metabolite measurement technologies has enabled the use of metabolomics for epidemiologic studies by profiling metabolite concentrations in large cohorts of human blood samples. Standard protocols are necessary to obtain unbiased profiles through multiple runs over long periods of time and to allow reliable statistical analyses. This study assessed the effects of sampling procedures and storage conditions on the stability of metabolomic profiles in plasma and serum. Charged metabolomic profiles were determined by capillary electrophoresis-mass spectrometry (CE-MS) and compared by multivariate analyses. The effects of pre-analytical procedures, including times for clotting and incubation of serum and plasma, respectively; incubation temperatures; and number of freeze-thaw cycles, were assessed. Overall, inter-individual differences in profiles were larger than intra-individual differences, and profiles in plasma showed better stability than those in serum. These quantified datasets of metabolites, along with their stability and variation, may help in interpreting data from long-term cohort studies. PMID- 25820921 TI - Characteristics of Young Children with Obsessive-Compulsive Disorder: Baseline Features from the POTS Jr. Sample. AB - Pediatric obsessive-compulsive disorder (OCD) is a chronic and impairing condition that can emerge early in childhood and persist into adulthood. The primary aim of this paper is to examine the characteristics of a large sample of young children with OCD (age range from 5 to 8). The sample will be described with regard to: demographics, OCD symptoms/severity, family history and parental psychopathology, comorbidity, and global and family functioning. The sample includes 127 youth with a primary diagnosis of OCD who participated in a multi site, randomized control clinical trial of family-based exposure with response prevention. Key findings include moderate to severe OCD symptoms, high rates of impairment, and significant comorbidity, despite the participants' young age. Discussion focuses on how the characteristics of young children compare with older youth and with the few other samples of young children with OCD. Considerations regarding generalizability of the sample and limitations of the study are discussed. PMID- 25820923 TI - Site-specific dental plaque pH in 13-year-old Thai schoolchildren. AB - OBJECTIVE: The aim of this paper was to study pH conditions between dental sites, taking account the presence of caries, calculus, and microbial composition and alkali production. MATERIALS AND METHODS: One hundred 13-year-old Thai schoolchildren were recorded for caries experience (DMFT, DT), calculus, plaque, and gingivitis. Ex vivo urease activity was measured on 11, 26, 31, and 46 (distal aspect) with the rapid urease test and pH at baseline and after rinse with 0.25 % urea solution on mesial site in vivo. Interproximal plaque from contralateral teeth was microbiological analysed with the checkerboard technique. RESULTS: Thirty-four children were caries free. Plaque and calculus were abundant; all children showed a high resting plaque pH and the mandibular incisor showed significantly (p < 0.01) higher pH at baseline, max pH and AOC7.0 after urea challenge, ex vivo urease activity and calculus but lower caries experience than other teeth. A significant inverse correlation (p < 0.02) was found between caries frequency and ex vivo urease activity for tooth 11. Anaerobes predominated over streptococci, but no significant differences between dental sites were found. CONCLUSIONS: The study group had a high baseline plaque pH, in vivo and ex vivo urease activity, and calculus but low caries experience, which was best reflected in the lower incisor region. CLINICAL RELEVANCE: Urease activity and pH on site level may be important determinants for individuals at caries risk. PMID- 25820924 TI - Comparison of retreatment ability of full-sequence reciprocating instrumentation and 360 degrees rotary instrumentation. AB - OBJECTIVES: The purpose of the present study was to investigate the amount of root canal filling material after root canal filling removal with 360 degrees rotary instrumentation or reciprocating motion with the same file sequence. MATERIALS AND METHODS: Root canals of the 36 mandibular premolars were shaped with ProTaper Universal instruments up to size F2 and filled with corresponding single gutta-percha cone and sealer. The teeth were assigned to two retreatment groups (n = 18): group 1 360 degrees rotational motion and group 2 reciprocating motion of ATR Tecnika motors (1310 degrees clockwise and 578 degrees counterclockwise). Retreatment procedure was performed with ProTaper Universal retreatment files with a sequence of D1-3 and ProTaper Universal F3 instruments. Total time required to remove filling material were recorded. Remaining filling material was examined under stereomicroscope at *8 magnification. The data were analysed statistically using the Mann-Whitney U test, and testing was performed at 95 % confidence level (p < 0.05). RESULTS: There were no significant differences between the groups (p > 0.05) in terms of remaining filling material. The total time required for retreatment was shorter in 360 degrees rotational motion group compared to reciprocating motion group (p < 0.05). CONCLUSION: Both continuous rotation and reciprocating motion showed similar effectiveness in terms of root canal filling material removal. CLINICAL RELEVANCE: Using ProTaper Universal retreatment instruments with reciprocating motion of ATR motor and conventional rotary motion have similar efficacy in root canal filling removal. PMID- 25820925 TI - Quantifying the natural history of biofilm formation in vivo during the establishment of chronic implant-associated Staphylococcus aureus osteomyelitis in mice to identify critical pathogen and host factors. AB - While it is well known that Staphylococcus aureus establishes chronic implant associated osteomyelitis by generating and persisting in biofilm, research to elucidate pathogen, and host specific factors controlling this process has been limited due to the absence of a quantitative in vivo model. To address this, we developed a murine tibia implant model with ex vivo region of interest (ROI) imaging analysis by scanning electron microscopy (SEM). Implants were coated with Staphylococcus aureus strains (SH1000, UAMS-1, USA300LAC) with distinct in vitro biofilm phenotypes, were used to infect C57BL/6 or Balb/c mice. In contrast to their in vitro biofilm phenotype, results from all bacteria strains in vivo were similar, and demonstrated that biofilm on the implant is established within the first day, followed by a robust proliferation phase peaking on Day 3 in Balb/c mice, and persisting until Day 7 in C57BL/6 mice, as detected by SEM and bioluminescent imaging. Biofilm formation peaked at Day 14, covering ~40% of the ROI coincident with massive agr-dependent bacterial emigration, as evidenced by large numbers of empty lacunae with few residual bacteria, which were largely culture negative (80%) and PCR positive (87.5%), supporting the clinical relevance of this implant model. PMID- 25820926 TI - Cheetah interspecific SCNT followed by embryo aggregation improves in vitro development but not pluripotent gene expression. AB - The aim of this study was to evaluate the capacity of domestic cat (Dc, Felis silvestris) oocytes to reprogram the nucleus of cheetah (Ch, Acinonyx jubatus) cells by interspecies SCNT (iSCNT), by using embryo aggregation. Dc oocytes were in vitro matured and subjected to zona pellucida free (ZP-free) SCNT or iSCNT, depending on whether the nucleus donor cell was of Dc or Ch respectively. ZP-free reconstructed embryos were then cultured in microwells individually (Dc1X and Ch1X groups) or in couples (Dc2X and Ch2X groups). Embryo aggregation improved in vitro development obtaining 27.4, 47.7, 16.7 and 28.3% of blastocyst rates in the Dc1X, Dc2X, Ch1X and Ch2X groups, respectively (P<0.05). Moreover, aggregation improved the morphological quality of blastocysts from the Dc2X over the Dc1X group. Gene expression analysis revealed that Ch1X and Ch2X blastocysts had significantly lower relative expression of OCT4, CDX2 and NANOG than the Dc1X, Dc2X and IVF control groups. The OCT4, NANOG, SOX2 and CDX2 genes were overexpressed in Dc1X blastocysts, but the relative expression of these four genes decreased in the Dc2X, reaching similar relative levels to those of Dc IVF blastocysts. In conclusion, Ch blastocysts were produced using Dc oocytes, but with lower relative expression of pluripotent and trophoblastic genes, indicating that nuclear reprogramming could be still incomplete. Despite this, embryo aggregation improved the development of Ch and Dc embryos, and normalized Dc gene expression, which suggests that this strategy could improve full-term developmental efficiency of cat and feline iSCNT embryos. PMID- 25820927 TI - A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co Administration of Sitagliptin with Intensively Titrated Insulin Glargine. AB - INTRODUCTION: The objective of this study was to assess the effect of sitagliptin on insulin dose in patients with inadequately controlled type 2 diabetes who titrate basal insulin to a target fasting glucose level after initiating sitagliptin. METHODS: This was a multicenter, randomized, double-blind, placebo controlled, 24-week clinical trial in which treatment with sitagliptin 100 mg/day or placebo was administered concurrently with insulin glargine titration, targeting a fasting glucose of 4.0-5.6 mmol/L (72-100 mg/dL). The trial randomized 660 patients with type 2 diabetes and inadequate glycemic control on insulin, with or without metformin (>=1500 mg/day) or sulfonylurea, for >=10 weeks. Patients could remain on metformin but not sulfonylurea after randomization. RESULTS: The increase from baseline in the daily dose of insulin was less in the sitagliptin group (N = 329) compared to placebo (N = 329) (between group difference = -4.7 IU [95% confidence interval [CI] -8.3, -1.2]; p = 0.009). Patients in the sitagliptin group had lower glycated hemoglobin (HbA1c) levels after 24 weeks (between-group difference of -0.4% [95% CI -0.6, -0.3; -4.9 mmol/mol (95% CI -6.6, -3.2)]; p < 0.001), and more patients in the sitagliptin group reached the HbA1c goal of <7.0% (53 mmol/mol), with a between-group difference of 17.3% (95% CI 10.4%, 24.1%; p < 0.001). Fewer patients in the sitagliptin group experienced an adverse event of hypoglycemia (between-group difference = -15.5%, p < 0.001). CONCLUSION: Administration of sitagliptin prior to intensive titration of basal insulin glargine reduces the insulin dose requirement while providing superior glycemic control and less hypoglycemia, compared to an insulin-only regimen. FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA. PMID- 25820928 TI - Physical exercise and acute restraint stress differentially modulate hippocampal brain-derived neurotrophic factor transcripts and epigenetic mechanisms in mice. AB - Physical exercise and stressful experiences have been shown to exert opposite effects on behavioral functions and brain plasticity, partly by involving the action of brain-derived neurotrophic factor (BDNF). Although epigenetic modifications are known to play a pivotal role in the regulation of the different BDNF transcripts, it is poorly understood whether epigenetic mechanisms are also implied in the BDNF modulation induced by physical exercise and stress. Here, we show that total BDNF mRNA levels and BDNF transcripts 1, 2, 3, 4, 6, and 7 were reduced immediately after acute restraint stress (RS) in the hippocampus of mice, and returned to control levels 24 h after the stress session. On the contrary, exercise increased BDNF mRNA expression and counteracted the stress-induced decrease of BDNF transcripts. Physical exercise-induced up-regulation of BDNF transcripts was accounted for by increase in histone H3 acetylated levels at specific BDNF promoters, whereas the histone H3 trimethylated lysine 27 and dimethylated lysine 9 levels were unaffected. Acute RS did not change the levels of acetylated and methylated histone H3 at the BDNF promoters. Furthermore, we found that physical exercise and RS were able to differentially modulate the histone deacetylases mRNA levels. Finally, we report that a single treatment with histone deacetylase inhibitors, prior to acute stress exposure, prevented the down-regulation of total BDNF and BDNF transcripts 1, 2, 3, and 6, partially reproducing the effect of physical exercise. Overall, these results suggest that physical exercise and stress are able to differentially modulate the expression of BDNF transcripts by possible different epigenetic mechanisms. PMID- 25820929 TI - Stromal cell-derived factor-1alpha prevents endothelial progenitor cells senescence and enhances re-endothelialization of injured arteries via human telomerase reverse transcriptase. AB - Recent studies have suggested that endothelial progenitor subpopulation (EPCs) number and activity were associated with EPCs senescence. Our previous study had shown that stromal cell-derived factor-1alpha (SDF-1alpha) could prevent EPCs senescence, which may be via telomerase. In this study, we further investigated the role of human telomerase reverse transcriptase (h-TERT) on the protective effect of SDF-1alpha against senescence. Knockdown h-TERT abrogated the protective effect of SDF-1alpha and abolished the effects of SDF-1alpha on migration and proliferation. Moreover, it inhibited EPCs recruitment. In conclusion, h-TERT served a critical role in the progress that SDF-1alpha prevented EPCs senescence and enhanced re-endothelialization of the injured arteries. PMID- 25820930 TI - Cognitive dysfunction in patients with very mild Alzheimer's disease and amnestic mild cognitive impairment showing hemispheric asymmetries of hypometabolism on 18F-FDG PET. AB - OBJECTIVE: We investigated cognitive dysfunction in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) who present hemispheric asymmetries of cerebral metabolic rate of glucose (CMRglc) decrease on (18) F-fluorodeoxyglucose positron emission tomography. METHODS: Based on the hemispheric asymmetries of CMRglc decrease in the posterior cingulate cortex, precuneus, and parietotemporal cortex, the patients were divided into three groups (a left-dominant hypometabolism group, a right-dominant hypometabolism group, and a non-dominant hypometabolism group). CMRglc decrease in the whole brain was controlled among the three groups. All the patients underwent mini mental state examination (MMSE), Wechsler Memory Scale-Revised (WMS-R), and Wechsler Adult Intelligent Scale-Third (WAIS-III). RESULTS: There were no significant differences in MMSE and WAIS-III scores among the three groups. In WMS-R, the results indicated that the left-dominant group demonstrated significantly lower scores in verbal memory than the other two groups. Furthermore, the left-dominant group had a greater tendency to be diagnosed with AD rather than aMCI. CONCLUSIONS: Patients with AD and aMCI showing left-dominant hypometabolism tend to show severer impairment in verbal memory function and to be diagnosed with AD dementia. PMID- 25820931 TI - Survival benefit in women with BRCA1 mutation or familial risk in the MRI screening study (MRISC). AB - Adding MRI to annual mammography screening improves early breast cancer detection in women with familial risk or BRCA1/2 mutation, but breast cancer specific metastasis free survival (MFS) remains unknown. We compared MFS of patients from the largest prospective MRI Screening Study (MRISC) with 1:1 matched controls. Controls, unscreened if<50 years, and screened with biennial mammography if >=50 years, were matched on risk category (BRCA1, BRCA2, familial risk), year and age of diagnosis. Of 2,308 MRISC participants, breast cancer was detected in 93 (97 breast cancers), who received MRI <2 years before breast cancer diagnosis; 33 BRCA1 mutation carriers, 18 BRCA2 mutation carriers, and 42 with familial risk. MRISC patients had smaller (87% vs. 52% T (p.Tyr175Phe) in exon 3. This is the first report of RDH5 gene mutation that affects the invariant tyrosine, one of the most conserved amino acid residues in short-chain alcohol dehydrogenases/reductases (SDRs), crucial for these enzymes' activity. The location of this substitution, together with its predicted influence on the protein function, indicate that the p.Tyr175Phe mutation is the cause of FA in our patient. PMID- 25820995 TI - Orexinergic theta rhythm in the rat hippocampal formation: In vitro and in vivo findings. AB - Previous in vivo data suggested that orexin neuropeptides (ORX(A) and ORX(B) ) synthetized in hypothalamic neurons were involved in the mechanism of generation of the hippocampal formation theta rhythm. Surprisingly, this suggestion has never been directly proved by experiments using intraseptal or intrahippocampal administration of orexins. In this study, involving the use of in vitro hippocampal formation slices and in vivo model of anesthetized rat, we provide the first convergent electropharmacological evidence that in the presence of both ORX(A) and ORX(B) the hippocampal formation neuronal network is capable of producing oscillations in the theta band. This effect of orexin peptides was antagonized by selective blockers of orexin receptors (OX1 R and OX2 R), SB 334867 and TCS OX2 29, respectively. These results provide evidence for a novel, orexinergic mechanism responsible for the production of theta rhythm in the hippocampal formation neuronal network. PMID- 25820993 TI - Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation. AB - Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPbeta and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPbeta and SOCS1. In murine engraftment models of ALCL ALK( ), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPbeta target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR 155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). PMID- 25820996 TI - Termination of pregnancy for renal malformations. AB - BACKGROUND: We studied the correlation between prenatal diagnosis and postmortem investigations in pregnancies terminated for renal malformations. METHODS: Over a 5-year period, 77 cases of termination of pregnancy (TOP) for renal malformations were reviewed. Chromosomal anomalies (n = 9) and cases without conventional or virtual autopsy were excluded (n = 15). In 53 cases, prenatal ultrasound diagnosis and conventional autopsy findings were compared. In addition, we compared the accuracy of conventional and virtual autopsy findings in 17 cases. RESULTS: Full agreement was observed in 60.4% (32/53) of cases. In 26.4% (14/53) of the cases, the presence of additional malformations did not alter the final diagnosis. However, in 11.3% (6/53) the final diagnosis was adjusted because of major additional findings. One case showed a total disagreement. Conventional and virtual autopsy were in full agreement in 52.9% (9/17). Postmortem magnetic resonance imaging (MRI) description and detection of malformations was less complete and failed to correctly diagnose 5/17 cases (29.4%). In 17.6% (3/17) of the cases, postmortem MRI revealed malformations not confirmed by conventional autopsy. CONCLUSIONS: A high correlation between prenatal ultrasound and postmortem investigations was observed. Conventional autopsy remains the gold standard to reveal additional major and minor malformations, leading to a correct final diagnosis. The added value of virtual necropsy for renal pathology was limited. PMID- 25820997 TI - Prognostic Significance of CDCP1 Expression in Colorectal Cancer and Effect of Its Inhibition on Invasion and Migration. AB - BACKGROUND: To assess the correlations and functions of complement C1r/C1s, Uegf, Bmp1 domain-containing protein-1 (CDCP1) in identifying colorectal cancer (CRC) patients who are at high risk for metastasis. METHODS: Tumor specimens from 101 patients were analyzed by real-time polymerase chain reaction to detect CDCP1 expression. CDCP1 expression plasmids and shRNA were used to knock down CDCP1 expression in this study to investigate migratory and invasive abilities by Boyden chambers. The mRNA expression profiles in shCDCP1 transfectants were compared to those in control cells by conducting microarray analysis. Its downstream effectors were also invested in this study. RESULTS: CRC patients with a high CDCP1 expression had a statistically significant lower overall survival and disease-free survival compared to those exhibiting low CDCP1 expression. In vitro, knock-down CDCP1 expression significantly decreased migratory and invasive abilities in HCT116. Aberrant expression of CDCP1 increased cancer cell migration and invasion. By using integrated genomics, we identified ROCK1 (rho-associated, coiled-coil-containing protein kinase 1 pseudogene 1) as a downstream effector in CDCP1-mediated migration and as an invasion mediator. Clinically, ROCK1 and CDCP1 mRNA expression exhibited a strong positive correlation in CRC patient samples. CONCLUSIONS: Our results implicated CDCP1 as a key regulator of CRC migration and invasion, and suggest that it is a useful prognostic factor for patients with CRC. Improved identification of a high-risk subset of early metastatic patients may guide indications of individualized treatment in clinical practice. PMID- 25820998 TI - Use of Postmastectomy Radiotherapy and Survival Rates for Breast Cancer Patients with T1-T2 and One to Three Positive Lymph Nodes. AB - BACKGROUND: The effectiveness of postmastectomy radiotherapy (PMRT) in terms of survival for breast cancer patients with American Joint Committee on Cancer (AJCC) pT1-2 and one to three tumor positive lymph nodes is controversial, especially in this era of more effective systemic treatment. METHODS: Using data from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) program between 1998 and 2008, this study respectively identified 93,793 and 36,299 women with AJCC pT1-2pN1 breast cancer who underwent mastectomy. The association of PMRT use with overall and cause-specific survival was examined using multivariable Cox models in subgroups defined by tumor stage. RESULTS: In the NCDB cohort, 21.5 % of the patients (n = 20,236) received PMRT, and a very similar percentage (21.9 %, n = 7939) received PMRT in the SEER cohort. In the NCDB cohort, PMRT was associated with a 14 % relative risk reduction in all-cause mortality among the patients with two positive lymph nodes and tumors 2-5 cm in size or three positive nodes [hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.81-0.91; p < 0.0001], but PMRT had no beneficial effect for the patients with one positive node or two positive nodes and tumors 2 cm in size or smaller. Analysis of the SEER cohort confirmed this heterogeneous effect, showing PMRT to be associated with a 14 % relative risk reduction in breast cancer cause-specific mortality among the patients with two positive nodes and tumors 2-5 cm in size or three positive nodes (HR 0.86; 95 % CI 0.77-0.96; p = 0.007) but not in the other subgroup. CONCLUSION: The effectiveness of radiotherapy depends on the combination comprising the number of positive lymph nodes and tumor size, which may enable more precise patient selection for PMRT. PMID- 25821000 TI - Risk-reducing mastectomy for BRCA gene mutation carriers. PMID- 25820999 TI - Pancreatic Resection Results in a Statewide Surgical Collaborative. AB - BACKGROUND: A strong relationship between hospital caseload and adverse outcomes has been demonstrated for pancreatic resections. Participation in regional surgical collaboratives may mitigate this phenomenon. This study sought to investigate changes over time in adverse outcomes after pancreatectomy across hospitals with different caseloads in a statewide surgical collaborative. METHODS: The study investigated patients undergoing pancreatic resection from January 2008 to August 2013 at Michigan Surgical Quality Collaborative (MSQC) hospitals (1007 patients in 19 academic and community hospitals). Risk-adjusted rates of major complications, mortality, and failure to rescue were compared between hospitals based on caseloads (low, medium, and high) in early (2008-2010) and later (2011-2013) periods. Finally, the degree to which different complications explained changes in hospital outcome variation was assessed. RESULTS: Adjusted rates of major complications and mortality decreased over time, driven largely by improvements at low-caseload hospitals. In 2008-2010, risk adjusted major complication rates were higher for low-caseload than for high caseload hospitals (27.8 vs. 17.8 %; p = 0.02). However, these differences were attenuated in 2011-2013 (22.2 vs. 20.0 %; p = 0.74). Similarly, adjusted mortality rates were higher in low-caseload hospitals in 2008-2010 (6.2 vs. 0.8 %; p = 0.02), but these differences were attenuated in 2011-2013 (3.3 vs. 1.1 %; p = 0.18). Variation in major complications decreased, largely due to decreased variation in "medical" complication rates, with less change in surgical-site complications. CONCLUSION: Participation in regional quality collaboratives by lower-volume hospitals can attenuate the volume-outcome relationship for pancreatic surgery. Continued work in collaboratives with an emphasis on technical and intraoperative aspects of care may improve overall quality of care. PMID- 25821001 TI - Erratum to: Anesthetic Selection and Disease-Free Survival Following Optimal Primary Cytoreductive Surgery for Stage III Epithelial Ovarian Cancer. PMID- 25821002 TI - Different expression levels of spartin cause broad spectrum of cellular consequences in human neuroblastoma cells. AB - Hereditary spastic paraplegia describes a diverse group of neurodegenerative conditions characterised by progressive spasticity and weakness of the lower limbs. Mutations in the SPG20 gene encoding spartin cause an autosomal recessive hereditary spastic paraplegia known as Troyer syndrome. To evaluate the cellular consequences of sustained spartin depletion in neuronal cells, we established several clonal SH-SY5Y cell lines with different level of spartin knockdown. Here, we report that cells with modest spartin downregulation show signs of neuronal differentiation such as increased neuritogenesis and cytoskeleton rearrangement. Interestingly, we also indicate that permanent high level spartin depletion results in impaired cell growth and multiple mitochondrial aberrations, which we speculate, arise as a result of chronic oxidative stress. Our studies demonstrate that the scale of spartin downregulation is the major factor that determines the severity of cellular consequences observed and suggest that there is a critical level of spartin expression which must be maintained for proper cellular functions. PMID- 25821003 TI - Baseline characteristic of patients presenting with lacunar stroke and cerebral small vessel disease may predict future development of depression. AB - OBJECTIVE: Cerebral small vessel disease (SVD) is associated with late-onset depression and increases the risk for depression after stroke. We aimed to investigate baseline predictors of depression after long-term follow-up in patients with SVD, initially presenting with first-ever lacunar stroke, free of depression and cognitive impairment. METHODS: A total of 294 patients with SVD were evaluated 3-5 years after the qualifying event. We analyzed baseline demographic data, vascular risk factors, functional status expressed as a score on modified Rankin Scale (mRS), cognitive status, presence of depression, total number of lacunar infarcts and severity of white matter hyperintensities (WMH) on MRI with Age-Related White Matter Changes scale total score (tARWMC) and Fazekas scale periventricular and deep subcortical scores. RESULTS: On follow-up, depression was registered in 117 (39.8%) SVD patients. At the baseline, patients with depression compared with non-depressed were older (64.4 vs 60.9 years; p = 0.007), had higher mRS score (2.8 +/- 0.7 vs 1.5 +/- 0.7; p < 0.0001) and had more severe lesions on MRI scales (p < 0.0001 for all parameters). On follow-up, depressed patients more frequently exhibited cognitive decline (75.2% depressed vs 56.5% non-depressed; p = 0.003). No difference was detected in risk factor frequency between groups. Multivariate Cox regression analysis adjusted by age and gender revealed independent predictors of depression: baseline mRS >2 (HR 2.17, 95%CI 1.74-2.72; p < 0.0001) and tARWMC (HR 1.05, 95%CI 1.02-1.09; p = 0.005), and cognitive decline on follow-up (HR 1.80, 95%CI 1.12-2.89; p = 0.015). CONCLUSIONS: Baseline functional status and severity of WMH and development of cognitive decline predict the occurence of late-onset depression in patients with SVD. PMID- 25821005 TI - Effect of TiO2 particles on normal and resonance Raman spectra of coumarin 343: a theoretical investigation. AB - It is well known that interfacial structures and charge transfer in dye sensitized solar cells are extremely important for the enhancement of cell efficiency. Here, the normal Raman spectra (NRS) and resonance Raman spectra (RRS) of a C343-sensitized TiO2 cluster (Ti9O18) are theoretically predicted from combined electronic structure calculations and a vibrationally-resolved spectral method to reveal the relationship between interfacial geometries and excited state dynamics. The results show that although the NRS of free C343 and the C343 TiO2 cluster correspond to the vibrational motions of C343 in a high frequency domain, their mode frequencies show obvious differences due to the interaction of the TiO2 cluster on C343, and several new Raman active fingerprint modes, such as bidentate chelating bonding modes, can be used to determine interfacial geometries. However, the resonance Raman activities of low-frequency modes are significantly enhanced and several modes from the TiO2 cluster can be observed, consistent with experimental measurements. Furthermore, the RRS from a locally excited state and a charge transfer state of C343-TiO2 are dramatically different, for instance, new Raman active modes with 1212 cm(-1), 1560 cm(-1) and 1602 cm(-1), corresponding to the motions of CH2 rocking, C=C/C-N/C=O stretching and C=O/C=C stretching, appear from the charge transfer state. The obtained information on mode-specific reorganization energies from these excited states is greatly helpful to understand and control interfacial electron transfer. PMID- 25821004 TI - Targeting SLC1a5-mediated glutamine dependence in non-small cell lung cancer. AB - We previously elucidated the pleotropic role of solute carrier family A1 member 5 (SLC1A5) as the primary transporter of glutamine (Gln), a modulator of cell growth and oxidative stress in non-small cell lung cancer (NSCLC). The aim of our study was to evaluate SLC1A5 as a potential new therapeutic target and candidate biomarker predictive of survival and response to therapy. SLC1A5 targeting was examined in a panel of NSCLC and human bronchial cell lines by RNA interference and by a small molecular inhibitor, gamma-l-glutamyl-p-nitroanilide (GPNA). The effects of targeting SLC1A5 on cell growth, Gln uptake, ATP level, autophagy and cell death were examined. Inactivation of SLC1A5 genetically or pharmacologically decreased Gln consumption, inhibited cell growth, induced autophagy and apoptosis in a subgroup of NSCLC cell lines that overexpress SLC1A5. Targeting SLC1A5 function decreased tumor growth in NSCLC xenografts. A multivariate Cox proportional hazards analysis indicates that patients with increased SLC1A5 mRNA expression have significantly shorter overall survival (p = 0.01, HR = 1.24, 95% CI: 1.05-1.46), adjusted for age, gender, smoking history and disease stage. In an immunohistochemistry study on 207 NSCLC patients, SLC1A5 protein expression remained highly significant prognostic value in both univariate (p < 0.0001, HR = 1.45, 95% CI: 1.15-1.50) and multivariate analyses (p = 0.04, HR = 1.22, 95% CI: 1.01-1.31). These results position SLC1A5 as a new candidate prognostic biomarker for selective targeting of Gln-dependent NSCLC. PMID- 25821006 TI - Development of a paediatric population pharmacokinetic model for valacyclovir from literature non-compartmental values originating from sparse studies and Bayesian priors: a simulation study. AB - A preliminary population pharmacokinetic (PopPK) model of valacyclovir in children was developed from non-compartmental analysis (NCA) parameter values from literature, including several age groups, combined with Bayesian priors from a PopPK model of acyclovir, the active metabolite of valacyclovir, from literature too. Also a simulation study was carried out to evaluate the performance of various modelling choices related to the estimation of model parameters from NCA parameters originating from sparse PK studies. Assuming a one compartment model with first order absorption, a mixed effects, meta-analysis approach was utilized which allows accounting the random intergroup variability, the detection of covariates and the application of informative Bayesian priors on the parameters. The conclusions from the simulation study calculating bias and precision for various cases, were that a model which takes explicitly into account the sampling schedule, performs better than a model using the theoretical expressions of calculating the NCA parameters. Also by using the geometric rather than the arithmetic means of NCA parameters, less biased results are obtained. These findings guided the choices for the valacyclovir model, for which informative priors from a PopPK model of acyclovir were applied for some of the parameters, in order to include a richer covariate model for clearance, not supported by the NCA dataset and a value for bioavailability. This preliminary valacyclovir model can be used in simulations to provide dosage recommendations for children of various ages and to help design more efficiently prospective clinical trials. PMID- 25821007 TI - [Not Available]. PMID- 25821008 TI - Staphylococcus aureus impairs the airway epithelial barrier in vitro. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a cluster of disorders that result in sinonasal mucosal inflammation. Staphylococcus aureus (S. aureus) is associated with severe and recalcitrant CRS. The purpose of our study was to investigate the effect of S. aureus on respiratory epithelial barrier structure and function. METHODS: Conditioned media from S. aureus reference strains (American Type Culture Collection [ATCC] 13565, 14458, and 25923) was applied to air-liquid interface (ALI) cultures of primary human nasal epithelial cells (HNECs) and transepithelial electrical resistance (TEER) was measured to assess cell-to-cell integrity. Electron microscopy was used to gauge the ciliated area and tight junctions (TJs). Additionally, the expression of the TJ protein zona occludens-1 (ZO-1) was examined via immunofluorescence. Statistical analysis was performed using analysis of variance (ANOVA) with pairwise Bonferroni-adjusted t tests. RESULTS: Secreted products applied to ALI cultures from S. aureus strain 13565 caused a concentration-dependent decline in electrical impedance compared to controls and reference strains 14458 and 25923 (p < 0.001). Electron microscopy showed a distinct separation between adjacent cells apically, in the region of TJs. The ciliated area was not affected; however, ZO-1 expression became discontinuous in HNECs exposed to the 13565 strain's conditioned media. CONCLUSION: Conditioned media of the S. aureus strain 13565 damages the airway epithelium by disrupting the TJs between primary HNECs grown at an ALI. These findings suggest that strain-specific S. aureus-secreted product(s) compromise epithelial barrier function, which may constitute 1 of the roles played by S. aureus in the pathophysiology of recalcitrant CRS. Further research is required to uncover the relevant molecular mechanisms. PMID- 25821010 TI - Oral analgesia for relieving post-caesarean pain. AB - BACKGROUND: Oral analgesia is a convenient and widely used form of pain relief following caesarean section. It includes various medications used at different doses alone or in adjunction to other form of analgesia. OBJECTIVES: To determine the effectiveness, safety and cost-effectiveness of oral analgesia for post caesarean pain relief. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs). Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-randomised and cross-over trials were not eligible for inclusion.Interventions included oral medication given to women for post caesarean pain relief compared with oral medication, or placebo/no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed for inclusion all the potential studies and independently assessed trial quality, extracted the data using the agreed data extraction form, and checked them for accuracy. MAIN RESULTS: Eight small trials involving 962 women (out of 13 included trials) contributed data to the analysis, of which only four trials had low risk of bias.None of the included studies reported on 'adequate pain relief', which is one of this review's primary outcomes. 1. Opiod analgesics versus placeboBased on one trial involving 120 women, the effect of opioids versus placebo was not significant in relation to the need for additional pain relief (primary outcome) (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.06 to 1.92), and the effect in terms of adverse drug effects outcomes was also uncertain (RR 6.58, 95% CI 0.38 to 113.96).Low (75 mg) and high (150 mg) doses of tramadol had a similar effect on the need for additional pain relief (RR 0.67, 95% CI 0.12 to 3.78 and RR 0.14, 95% CI 0.01 to 2.68, respectively, one study, 80 women). 2. Non-opioid analgesia versus placeboThe confidence interval for the lower requirement for additional analgesia (primary outcome) with the non-opioid analgesia group was wide and includes little or no effect (average RR 0.70, 95% CI 0.48 to 1.01, six studies, 584 women). However, we observed substantial heterogeneity due to the variety of non-opioid drugs used (I(2) = 85%). In a subgroup analysis of different drugs, only gabapentin use resulted in less need for additional pain relief (RR 0.34, 95% CI 0.23 to 0.51, one trial, 126 women). There was no difference in need for additional pain relief with the use of celexocib, ibuprofen, ketoprofen, naproxen, paracetamol. Maternal drug effects were more common with the use of non-opioid analgesics (RR 11.12, 95% CI 2.13 to 58.22, two trials, 267 women).Gabapentin 300 mg (RR 0.25, 95% CI 0.13 to 0.49, one study, 63 women) and 600 mg (RR 0.44, 95% CI 0.27 to 0.71, one study, 63 women) as well as ketoprofen 100 mg (RR 0.55, 95% CI 0.39 to 0.79, one study 72 women) were both more effective than placebo with respect to the need for additional pain relief. However, the 50 mg ketoprofen group and the placebo group did not differ in terms of the number of women requiring additional pain relief (RR 0.82, 95% CI 0.64 to 1.07, one study, 72 women). 3. Combination analgesics versus placeboOur pooled analysis for the effect of combination analgesics on the need for additional pain relief was RR 0.70 (95% CI 0.35 to 1.40, three trials, 242 women, I(2) = 69%). When comparing different drugs within the combination oral analgesics versus placebo comparison we observed subgroup differences (P = 0.05; I2 = 65.8%). One trial comparing paracetamol plus codeine versus placebo resulted in fewer women requiring additional pain relief (RR 0.44, 95% CI 0.23 to 0.82, one trial, 65 women). However, there were no differences in the the number of women requiring additional pain relief when comparing paracetamol plus oxycodone versus placebo, or paracetamol plus propoxyphene (RR 1.00, 95% CI 0.78 to 1.28, one trial, 96 women and RR 0.65, 95% CI 0.11 to 3.69, one trial, 81 women, respectively).Maternal drug effects were more common in combination analgesics group versus placebo (RR 13.18, 95% CI 2.86 to 60.68, three trials, 252 women). 4. Opioid analgesics versus non-opioid analgesicsThe confidence interval for the effect on additional pain relief between opioid and non-opioid drugs was very wide (RR 0.51, 95% CI 0.07 to 3.51, one trial, 121 women). Side effects were more common with the use opioids versus non-opioids analgesics (RR 2.32, 95% CI 1.15 to 4.69, two trials 241 women). 5. Opioid analgesics versus combination analgesicsThere was no difference in need for additional pain relief in opioid analgesics versus combination analgesics based on one study involving 121 women comparing tramadol and paracetamol plus propoxyphene (RR 0.51, 95% CI 0.07 to 3.51). Maternal adverse effects also did not differ between the two groups (RR 6.74, 95% CI 0.39 to 116.79). 6. Non-opioid versus combination analgesicsThe need for additional pain relief was greater in the group of women who received non-opoid analgesics (RR 0.87, 95% CI 0.81 to 0.93, one trial, 192 women) compared with the group of women who received combination analgesics. Secondary outcomes not reported in the included studiesNo data were found on the following secondary outcomes: number of days in hospital post-operatively, re hospitalisation due to incisional pain, fully breastfeeding on discharge, mixed feeding at discharge, incisional pain at six weeks after caesarean section, maternal post partum depression, effect (negative) on mother and baby interaction and cost of treatment. AUTHORS' CONCLUSIONS: Eight trials with 962 women were included in the analysis, but only four trials were of high quality. All the trials were small. We carried out subgroup analysis for different drugs within the same group and for high versus low doses of the same drug. However, the relatively few studies (one to two trials) and numbers of women (40 to 136) limits the reliability of these subgroup analyses.Due to limited data available no conclusions can be made regarding the safest and the most effective form of oral analgesia for post-caesarean pain. Further studies are necessary. PMID- 25821009 TI - Quantitative elemental analysis of bovine ovarian follicles using X-ray fluorescence imaging. AB - The X-ray Fluorescence Micro-spectroscopy (XFM) beamline at the Australian Synchrotron was used to image 97 follicle histological sections from 45 different bovine ovaries focusing on healthy antral follicles ranging from small (<4 mm) up to preovulatory sizes (>16 mm) and on antral follicles undergoing atresia. This analysis identified five elements (Cu, Fe, Zn, Se and Br) consistently present within the ovarian tissue with Fe, Zn and Se localised to specific structures. GeoPIXE v6.4g was subsequently used to extract quantitative information pertaining to the elemental concentrations surrounding each of these follicles. Statistical analysis suggested that significant elemental differences were evident between follicle groups sorted according to their health status (Fe and Br), and their size (Se). Se appeared to be the element which most greatly distinguished large antral follicles from smaller counterparts. The ability to use synchrotron radiation to measure trace element distributions in bovine follicles at such high resolutions could have a significant impact on understanding the mechanisms of follicular development. This research is intended to form a baseline study of healthy cycling ovaries which could later be extended to disease states, thereby improving our current understanding of infertility and endocrine diseases involving the ovary. PMID- 25821011 TI - Low-cost facile fabrication of flexible transparent copper electrodes by nanosecond laser ablation. AB - Low-cost Cu flexible transparent conducting electrodes (FTCEs) are fabricated by facile nanosecond laser ablation. The fabricated Cu FTCEs show excellent opto electrical properties (transmittance: 83%, sheet resistance: 17.48 Omega sq(-1)) with outstanding mechanical durability. Successful demonstration of a touch screen panel confirms the potential applicability of Cu FTCEs to the flexible optoelectronic devices. PMID- 25821012 TI - Fatigue: the heavy backpack of many rheumatoid arthritis patients. PMID- 25821013 TI - Levels of potential bioactive compounds including carotenoids, vitamin C and phenolic compounds, and expression of their cognate biosynthetic genes vary significantly in different varieties of potato (Solanum tuberosum L.) grown under uniform cultural conditions. AB - BACKGROUND: In addition to their high carbohydrate content, potatoes are also an important dietary source of vitamin C and bioactive secondary metabolites, including phenolic compounds and carotenoids, which have been suggested to play a role in human health. The expression of genes encoding key enzymes involved in the synthesis of these compounds was assessed by reverse transcription quantitative polymerase chain reaction and compared to the accumulation of the corresponding product in seven potato varieties showing contrasting levels of metabolite accumulation. RESULTS: Strong positive correlations were found between phenolic content in the flesh of tubers and transcript levels of phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes. The expression of PAL and CHS was also related to that of AN1, a transcription factor involved in the synthesis of anthocyanins, suggesting that these genes are regulated in a coordinated manner. No clear relationship was found between transcript levels of phytoene synthase (PSY) or L-galactono-1,4-lactone dehydrogenase (GLDH) genes and total carotenoid or vitamin C accumulation, respectively. CONCLUSION: Data indicate that levels of total phenolic and flavonoid compounds in potato are controlled primarily by PAL and CHS gene expression. Transcript levels of PSY and GLDH did not control accumulation of carotenoids or vitamin C. PMID- 25821014 TI - Measurement of Leptin by RIA Versus MIA in a Population of Healthy Newborns. AB - BACKGROUND: Assays based on multiplex immunoassay (MIA) technology have demonstrated advantages over enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA). Its acceptance depends on how well it performs in comparison to older techniques. The aim is to compare the results of leptin using RIA versus MIA. METHODS: We analyzed 81 samples of umbilical cord blood of healthy term newborns by RIA and MIA. RESULTS: The concordance correlation coefficient was 0.158 (95% CI 0.10-0.21). Pearson's correlation coefficient was 0.6651 (95% CI 0.52-0.77; P < 0.0001). In the Bland-Altman plot, concordance is acceptable because most of the measurements are within a mean of +/-1.96 SD. CONCLUSIONS: As shown by the Bland-Altman plot, there is concordance by both methods, but with a weak correlation. PMID- 25821015 TI - A two-dimensional honeycomb coordination network based on fused triacontanuclear heterometallic {Co12Mn18} wheels. AB - An unprecedented two-dimensional honeycomb network based on fused triacontanuclear heterometallic wheels of 3.4 nm, {[Co2(Mn3O)(N3)2(pic)6(NO3)]( )}6 (Hpic = picolinic acid), has been assembled. The hexagonal {Co12Mn18} wheel motif is composed of six oxo-centered {Mn3} trinuclear and six {Co2} dinuclear moieties acting as nodes and linkers, respectively. The paramagnetic properties of this compound observed down to 1.8 K result from the competition of Mn...Mn, Mn...Co and Co...Co interactions in combination with spin-orbit coupling and single-ion behavior of the Co(II) centers. PMID- 25821017 TI - Pristine Basal- and Edge-Plane-Oriented Molybdenite MoS2 Exhibiting Highly Anisotropic Properties. AB - The layered structure of molybdenum disulfide (MoS2 ) is structurally similar to that of graphite, with individual sheets strongly covalently bonded within but held together through weak van der Waals interactions. This results in two distinct surfaces of MoS2 : basal and edge planes. The edge plane was theoretically predicted to be more electroactive than the basal plane, but evidence from direct experimental comparison is elusive. Herein, the first study comparing the two surfaces of MoS2 by using macroscopic crystals is presented. A careful investigation of the electrochemical properties of macroscopic MoS2 pristine crystals with precise control over the exposure of one plane surface, that is, basal plane or edge plane, was performed. These crystals were characterized thoroughly by AFM, Raman spectroscopy, X-ray photoelectron spectroscopy, voltammetry, digital simulation, and DFT calculations. In the Raman spectra, the basal and edge planes show anisotropy in the preferred excitation of E2g and A1g phonon modes, respectively. The edge plane exhibits a much larger heterogeneous electron transfer rate constant k(0) of 4.96*10(-5) and 1.1*10(-3) cm s(-1) for [Fe(CN)6 ](3-/4-) and [Ru(NH3 )6 ](3+/2+) redox probes, respectively, compared to the basal plane, which yielded k(0) tending towards zero for [Fe(CN)6 ](3-/4-) and about 9.3*10(-4) cm s(-1) for [Ru(NH3 )6 ](3+/2+) . The industrially important hydrogen evolution reaction follows the trend observed for [Fe(CN)6 ](3-/4-) in that the basal plane is basically inactive. The experimental comparison of the edge and basal planes of MoS2 crystals is supported by DFT calculations. PMID- 25821016 TI - Diagnostic accuracy of calretinin for malignant mesothelioma in serous effusions: a meta-analysis. AB - Numerous studies have investigated the utility of calretinin in differentiating malignant mesothelioma (MM) from metastatic carcinoma (MC) in serous effusions. However, the results remain controversial. The aim of this study is to determine the overall accuracy of calretinin in serous effusions for MM through a meta analysis of published studies. Publications addressing the accuracy of calretinin in the diagnosis of MM were selected from the Medline (Ovid), PubMed, the Cochrane Library Database and the Web of Science. Data from selected studies were pooled to yield summary sensitivity, specificity, positive and negative likelihood ratio (LR), diagnostic odds ratio (DOR), and receiver operating characteristic (SROC) curve. Statistical analysis was performed by Meta-Disc 1.4 and STATA 12.0 softwares. 18 studies met the inclusion criteria and the summary estimating for calretinin in the diagnosis of MM were: sensitivity 0.91 (95%CI: 0.87-0.94), specificity 0.96 (95%CI: 0.95-0.96), positive likelihood ratio (PLR) 14.42 (95%CI: 7.92-26.26), negative likelihood ratio (NLR) 0.1 (95%CI: 0.05-0.2) and diagnostic odds ratio 163.03 (95%CI: 54.62-486.63). The SROC curve indicated that the maximum joint sensitivity and specificity (Q-value) was 0.92; the area under the curve was 0.97. Our findings suggest that calretinin may be a useful diagnostic tool for confirming MM in serous effusions. PMID- 25821018 TI - Nuclear myocardial perfusion imaging using thallium-201 with a novel multifocal collimator SPECT/CT: IQ-SPECT versus conventional protocols in normal subjects. AB - OBJECTIVE: A novel multifocal collimator, IQ-SPECT (Siemens) consists of SMARTZOOM, cardio-centric and 3D iterative SPECT reconstruction and makes it possible to perform MPI scans in a short time. The aims are to delineate the normal uptake in thallium-201 ((201)Tl) SPECT in each acquisition method and to compare the distribution between new and conventional protocol, especially in patients with normal imaging. METHODS: Forty patients (eight women, mean age of 75 years) who underwent myocardial perfusion imaging were included in the study. All patients underwent one-day protocol perfusion scan after an adenosine-stress test and at rest after administering (201)Tl and showed normal results. Acquisition was performed on a Symbia T6 equipped with a conventional dual-headed gamma camera system (Siemens ECAM) and with a multifocal SMARTZOOM collimator. Imaging was performed with a conventional system followed by IQ-SPECT/computed tomography (CT). Reconstruction was performed with or without X-ray CT-derived attenuation correction (AC). Two nuclear physicians blinded to clinical information interpreted all myocardial perfusion images. A semi-quantitative myocardial perfusion was analyzed by a 17-segment model with a 5-point visual scoring. The uptake of each segment was measured and left ventricular functions were analyzed by QPS software. RESULTS: IQ-SPECT provided good or excellent image quality. The quality of IQ-SPECT images without AC was similar to those of conventional LEHR study. Mid-inferior defect score (0.3 +/- 0.5) in the conventional LEHR study was increased significantly in IQ-SPECT with AC (0 +/- 0). IQ-SPECT with AC improved the mid-inferior decreased perfusion shown in conventional images. The apical tracer count in IQ-SPECT with AC was decreased compared to that in LEHR (0.1 +/- 0.3 vs. 0.5 +/- 0.7, p < 0.05). The left ventricular ejection fraction from IQ-SPECT was significantly higher than that from the LEHR collimator (p = 0.0009). CONCLUSION: The images of IQ-SPECT acquired in a short time are equivalent to that of conventional LEHR. The results indicated that the IQ-SPECT system with AC is capable of correcting inferior artifacts with high image quality. PMID- 25821019 TI - Health-related factors associated with the participation in cervical cancer screening. AB - BACKGROUND: The aim of this study was to describe the coverage for cervical cancer screening among the visitors of a food exhibition in Brussels, Belgium and to describe the factors that affect their participation in the screening programs. METHODS: The participants aged between 25 and 64 years were recruited during a food exhibition at the Brussels Exhibition Centre from 6 until 21 October 2012. Their participation to the cervical cancer screening was recorded as well as their medical history and health related parameters. RESULTS: After adjustment for age and region, 66% of the 408 participants have had a cervical cancer screening during the past three years. In univariate analysis, no participation in the cervical cancer screening was related to hypertension, high body mass index (BMI), and low self-reported health. There was no adherence to breast cancer screening. Age, systolic blood pressure, abdominal circumference and BMI of the participants who did not adhere to cervical cancer screening were significantly higher as compared to the participants who did adhere. A multivariate analysis confirmed the relationship between not adhering to the screening and older age (OR=0.56; 95% CI: 0.44, 0.73) and having a high body mass index (OR=0.63; 95% CI: 0.47, 0.85). Participation to the screening was related to having a tetanus vaccination (OR=1.67; 95% CI: 1.05, 2.63) and adhering to breast cancer screening (OR=3.9; 95% CI: 2.09, 6.84). CONCLUSIONS: Our study revealed an association between not having had a cervical smear in the last three years and not having had a mammography, older age, not having had a tetanus immunisation recently and having a higher BMI. PMID- 25821020 TI - Association of obesity with the prevalence of hypertension in school children from central Thailand. AB - BACKGROUND: Obesity and underweight are both a public health concern worldwide. Being overweight, and obesity are primary risk factors for the development of chronic conditions including hypertension. Data on obesity and the underweight as well as their association with hypertension in Thai children, specifically, are scant. This study was aimed to assess the relationship between obesity or underweight status and hypertension in Thai school children. METHODS: Anthropometric data were collected from 3991 students (mean age of 9.5 yr) in Ongkharak district, central Thailand. The sex as well as the age-specific BMI criteria of the WHO were used to define what is overweight, obesity, underweight and severe underweight status of children. In order to calculate the odds ratio and the association between one's nutritional status and hypertension logistic regression was used. RESULTS: Obese and overweight children have a higher prevalence of hypertension compared with children with an average weight (49.5% and 26.5% versus 16.2%, respectively). The risks of developing hypertension is also high in obese children (OR 5.15; 95%CI: 4.27, 6.22), overweight children (1.87; 95% CI: 1.50, 2.32) and overweight/obese children (OR 3.30; 95% CI: 2.82, 3.86. Additionally, underweight children were not associated with an increased risk of hypertension (OR 1.04; 95% CI: 0.72, 1.42). CONCLUSIONS: Rates of hypertension in overweight and obese children are high in central Thailand and, as a result, this increased body weight is a risk factor for hypertension. Larger, multi-centric studies are required to evaluate the correlation between hypertension and obesity amongst children at the national level. PMID- 25821021 TI - Calculating population attributable fraction for cardiovascular risk factors using different methods in a population based cohort study. AB - BACKGROUND: Population Attributable Fraction (PAF) is one of the most practical measures for estimating the burden of risk factors with some challenges in its calculation. Cardiovascular disease (CVD) is the first cause of death worldwide and the estimation of accurate PAFs for CVD risk factors is of great importance in conducting preventive strategies. Our aim was to estimate the PAFs of CVD risk factors via direct, i.e. based on regression models, and indirect, i.e. using related equations, methods. METHODS: Participants (3200 males and 4245 females aged >=30 yr) without history of CVD were selected from the population-based cohort of Tehran Lipid and Glucose Study (TLGS). Hazard ratio (HR) and Odds ratio (OR) of conventional risk factors were calculated for CVD events after ten yr of follow-up. Levin's and Miettinen's equations were applied to indirectly estimate the PAFs and average PAF was directly derived from logistic regression model. RESULTS: The sum of PAFs resulted from indirect estimations reached to more than 100% (around 200% and 150% based on Levin's and Miettinen's formula respectively). The direct estimation attributed 80% and 86% of burden of CVD events to conventional risk factors in men and women respectively. The rank and pattern of PAFs of risk factors was somehow different among different methods. CONCLUSIONS: Estimating priorities of risk factors may differ in different methods for calculating PAF. This study provides evidence on the more expediency of direct method over indirect ways when individual data is available through a population-based cohort. PMID- 25821022 TI - Predicting hepatitis B monthly incidence rates using weighted Markov chains and time series methods. AB - BACKGROUND: Hepatitis B (HB) is a major global mortality. Accurately predicting the trend of the disease can provide an appropriate view to make health policy disease prevention. This paper aimed to apply three different to predict monthly incidence rates of HB. METHODS: This historical cohort study was conducted on the HB incidence data of Hamadan Province, the west of Iran, from 2004 to 2012. Weighted Markov Chain (WMC) method based on Markov chain theory and two time series models including Holt Exponential Smoothing (HES) and SARIMA were applied on the data. The results of different applied methods were compared to correct percentages of predicted incidence rates. RESULTS: The monthly incidence rates were clustered into two clusters as state of Markov chain. The correct predicted percentage of the first and second clusters for WMC, HES and SARIMA methods was (100, 0), (84, 67) and (79, 47) respectively. CONCLUSIONS: The overall incidence rate of HBV is estimated to decrease over time. The comparison of results of the three models indicated that in respect to existing seasonality trend and non stationarity, the HES had the most accurate prediction of the incidence rates. PMID- 25821023 TI - Association of serum 25-hydroxyvitamin d levels and vitamin D dietary intake with metabolic syndrome: a case control study. AB - BACKGROUND: Association between the vitamin D deficiency and metabolic syndrome (MetS) has previously been noted and reported to be controversial. The aim of this study was to determine the association of serum 25 (OH) D Level and Vitamin D dietary intake with MetS among Iranian population. METHODS: This analytical study was conducted on 122 patients with MetS based on the ATPIII criteria and 128 subjects without MetS as control from September 2010 to April 2011. Serum levels of calcium, phosphorus and 25(OH) D were compared between the two groups. A food frequency questionnaire (FFQ) was used to calculate dietary intake. Data were analyzed using Chi- square test, t-test, Mann-Whitney U test and logistic regression analysis. RESULTS: Serum concentrations of 25 (OH) D, calcium and phosphorus and calcium intake were significantly lower in subjects with MetS compared to the subjects without MetS. 98.4% of subjects with MetS and 88.3% without MetS had Vit. D deficiency and this difference was statistically significant (P=0.005). In regression analysis, lower concentration of serum 25 (OH) D, calcium and phosphorus and lower calcium and diary intake were predictors of MetS. CONCLUSIONS: Serum 25 (OH) D Level, calcium and phosphorus and calcium intake are associated with metabolic syndrome. However, the mechanism of this association requires further studies. PMID- 25821024 TI - Horizontal inequity in access to outpatient services among Shiraz City residents, Iran. AB - BACKGROUND: lack of access to health services has been mentioned as one of the main causes of health inequity in health system. The aim of this study was to measure horizontal inequity in access to outpatient services in Shiraz. METHODS: This household survey was conducted among 1608 participants above 18 years in Shiraz in 2012. Four-stage sampling was used. According to high amount of zero valued of outpatient services utilization, Zero inflated regression model was established. We computed concentration index (CI) for determining actual (CIM) and indirect standardized utilization (CIIS) of outpatient services in order to compute horizontal inequity index (HII). The results were analyzed using Stata software, version 8. RESULTS: The CIM was not statistically significant (-0.016, 95% CI: -0.097, 0.066). But the CIIS was statistically significant and favored the rich (0.06, 95% CI: 0.010 to 0.001). The horizontal inequity index was 0.076. CONCLUSIONS: There was no inequality in actual amount of outpatient utilization, maybe High subsidization to health care by government in public sector, high insurance coverage, low prices of health services in the public sector, quality of services and opportunity cost of high income groups were the reasons for our results. PMID- 25821025 TI - Socio-demographic characteristics associated with cigarettes smoking, drug abuse and alcohol drinking among male medical university students in Iran. AB - BACKGROUND: Substance abuse is one of the most complicated social problems. Understanding socio-demographic characteristics of those who abuse substances could help deal with this problem more efficiently. The main objective of this study was to determine socio-demographic characteristics associated with alcohol drinking, cigarettes smoking and drug abuse among a sample of male medical university students in Iran. METHODS: This cross-sectional study was conducted in 2014 among 425 male medical college students randomly selected with the proportional to size among different faculties in Isfahan and Kermanshah medical universities in Iran. A self-report written questionnaire was applied to collect data. Data were analyzed by the SPSS-20. RESULTS: Mean age of the respondents was 19.9 yr (ranging from 18 to 22 yr). About 19.4%, 3.9%, and 10.1% of the respondents had history of cigarette smoking, drug use, and alcohol drinking during the past three months, respectively. Logistic regression showed that mother's educational level, living place, economic status, and parents' divorce were the most influential predictive factors on substance abuse. CONCLUSIONS: Considering the high prevalence of substance abuse (especially smoking and alcohol drinking), it seems essential to design educational interventions to prevent substance abuse, paying attention to predictive factors mentioned above, among college students. PMID- 25821026 TI - The effect of a prevention program based on health belief model on osteoporosis. AB - BACKGROUND: Osteoporosis is one of the most common metabolic bone diseases. The purpose of this study was to investigate the effect of a prevention program based on health belief model on osteoporosis among women. METHODS: In this quasi-case study, 120 patients (60 cases and 60 control), registered under the health centers in Fasa City, Fars Province, Iran were selected in 2014. A questionnaire consisting of demographic information, Health Belief Model (HBM) constructs was used to measure nutrition and walking performance for prevention of osteoporosis before, immediately after the intervention and six months later. Bone mineral density (BMD) was recorded at the lumbar spine and femur before and six months after intervention. Data were analyzed using SPSS19 via chi-square test, independent t-test, and Repeated Measures ANOVA at significance level of 0.05. RESULTS: Immediately and six months after the intervention, the case group showed a significant increase in the knowledge, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, self-efficacy, internal cues to action, nutrition and walking performance compared to the control group. Six months after the intervention, the value of lumbar spine BMD T-Score in the case group increased to 0.127, while in the control group it reduced to -0.043. The value of the Hip BMD T-Score in the intervention group increased to 0.125 but it decreased to -0.028 in the control group. CONCLUSIONS: This study showed the effectiveness of knowledge, walking and diet on bone mass by HBM model. Hence, these models can act as a framework for designing and implementing educational interventions for the osteoporosis prevention. PMID- 25821027 TI - Timing and delay in children vaccination; evaluation of expanded program of immunization in outskirt of Iranian cities. AB - BACKGROUND: Most studies evaluated the vaccine coverage, but the time of vaccination is important as coverage. This study was conducted to evaluate the Expanded Program of Immunization (EPI) in outskirt of Iranian cities regarding to incidence of delay vaccination among children less than 4 years. METHODS: This cross sectional descriptive study was conducted among children 24-47 months old, living in the suburbs of five metropolises of Iran. Totally, 3610 eligible children selected with proportioned cluster sampling method and data of vaccination card extracted after interview with child parents. Delayed incidence rate reported and predictive factors assessed by Chi square test and Multivariate logistic regression. RESULTS: Overall, 56.6% to 93.2% vaccines were administered out of time. Delayed vaccination incidence with more than one-week delay varies from 5.5% to 74.9% for polio at birth and MMR2 at 18 month, respectively. Mother's educational level and birth order were the most important predictors of delayed vaccination. Incidence of delayed vaccination was enlarged by increasing birth order and decreased in lower educated mothers. CONCLUSIONS: Incidence rate of delayed vaccination is more than expectation. Regarding to high coverage vaccines in Iran, heath officers and health policy makers should attempt for on time vaccination beside of high immunization coverage especially in slum areas with more concentrated immigrants due to low literature and crowded families. PMID- 25821028 TI - Evaluation of interleukin-8 -251 t/a polymorphisms in visceral leishmaniasis. AB - BACKGROUND: Interleukin (IL)-8 plays important roles in the recruitment and activation of immune cells during visceral leishmaniasis (VL). Genetic variations in IL-8 modulate the expression of IL-8 protein and may be associated with VL. This study aimed to evaluate polymorphisms at the IL-8 -251 position in VL patients. METHODS: This cross-sectional study was performed on three groups: Leishmania-seropositive patients with clinical symptoms of VL (n = 91), seropositive patients without clinical symptoms (n = 104), and healthy controls (n = 110). Polymorphisms at the IL-8-251 position were analyzed using allele specific polymerase chain reaction (PCR). Anti-Leishmania antibody titers were assessed by immunofluorescence. RESULTS: IL-8-251 polymorphism was significantly associated with VL (P<0.002). The IL-8-251 T/T genotype was significantly higher in group 1 than in groups 2 and 3 (P<0.002). The validity of the data was analyzed using Hardy-Weinberg equilibrium and one-way analysis of variance (ANOVA), as well as chi2 tests. CONCLUSIONS: IL-8-251 polymorphism was significantly associated with impaired immune responses in VL and might be considered a risk factor for disease development. PMID- 25821029 TI - Levels of alarm thresholds of meningitis outbreaks in Hamadan Province, west of Iran. AB - BACKGROUND: Few studies have focused on syndromic data to determine levels of alarm thresholds to detection of meningitis outbreaks. The purpose of this study was to determine threshold levels of meningitis outbreak in Hamadan Province, west of Iran. METHODS: Data on both confirmed and suspected cases of meningitis (fever and neurological symptom) form 21 March 2010 to 20 March 2012 were used in Hamadan Province, Iran. Alarm threshold levels of meningitis outbreak were determined using four different methods including absolute values or standard method, relative increase, statistical cutoff points and upper control limit of exponentially weighted moving average (EWMA) algorithm. RESULTS: Among 723 reported cases, 41 were diagnosed to have meningitis. Standard level of alarm thresholds for meningitis outbreak was determined as incidence of 5/100000 persons. Increasing 1.5 to two times in reported cases of suspected meningitis per week was known as the threshold levels according to relative increase method. An occurrence four cases of suspected meningitis per week that equals to 90th percentile was chosen as alarm thresholds by statistical cut off point method. The corresponding value according to EWMA algorithm was 2.57 i.e. three cases. CONCLUSIONS: Policy makers and staff of syndromic surveillance systems are highly recommended to apply the above different methods to determine the levels of alarm threshold. PMID- 25821030 TI - Controllable growth of durable superhydrophobic coatings on a copper substrate via electrodeposition. AB - Superhydrophobic coatings on a copper substrate are grown via electrodeposition followed by thermal annealing. The influence of the deposition potential, zinc ion concentration, deposition time, annealing temperature and annealing time on the wetting properties was systematically investigated. The coating electrodeposited at -1.35 V for 25 min and annealed at 190 degrees C for 60 min exhibited excellent superhydrophobicity with a contact angle as high as 170 +/- 2 degrees and a sliding angle of almost 0 degrees . The water drop can fully bounce as a balloon when impinging such a solid surface, exhibiting excellent non sticking properties. By adopting various characterization methods, it was demonstrated that the as-prepared superhydrophobic surfaces also exhibited properties of anticorrosion, antiabrasion, long-term stability and durability and large buoyancy force, which offer an effective strategy and promising industrial applications for fabricating superhydrophobic surfaces on various metallic materials. PMID- 25821031 TI - Glottic and supraglottic pT3 squamous cell carcinoma: outcomes with transoral laser microsurgery. AB - Patients diagnosed with T3 squamous cell laryngeal carcinomas are nowadays offered either organ-preserving surgical or non-surgical treatment, with the optimum approach remaining undefined. No direct comparison of organ-preserving therapeutical options, stratified by anatomical subsites is available in the literature. The aim of this study is to present institutional treatment outcomes for laser-assisted microsurgery (TLM) of laryngeal T3 squamous cell carcinomas and review the relevant literature. Sixty-four consecutive, previously untreated patients were evaluated. Twenty-four supraglottic and 19 glottic patients were treated with TLM and neck dissection, tumor exposure and postoperative upstaging of the tumors through pathology evaluation of the specimens being the only exclusion criteria. Five-year disease-specific survival and organ preservation rates for supraglottic carcinomas were both 91.7 %. The respective values for glottic carcinomas were 63.2 and 73.3 %. TLM-treated T3 supraglottic tumors seem to attribute better outcomes than T3 glottic tumors in terms of recurrence-free survival, organ preservation and local control (p = 0.01, <0.0001 and 0.01, respectively). The results of this study suggest that TLM-treated T3 supraglottic tumors have a good prognosis, substantially better than that of glottic tumors. A literature review, on the other hand, attributes to chemo-radiation-treated T3 supraglottic tumors a considerably poorer prognosis. Further studies of homogenous populations in terms of anatomical subsites are needed in order to reach a consensus regarding treatment of T3 laryngeal tumors. PMID- 25821032 TI - Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia. AB - PURPOSE: Previous studies have shown that blood serum phosphoproteins are altered in schizophrenia patients in comparison to controls. However, it is not known whether phosphoproteins are also changed in response to treatment with antipsychotics. EXPERIMENTAL DESIGN: Blood samples were taken from patients (n = 23) at baseline and after 6 weeks of olanzapine treatment. Immobilized metal ion affinity chromatography (IMAC) was used for enrichment of serum phosphoproteins and these were analyzed by label-free LC-MS in expression mode (LC-MS(E) ). RESULTS: We identified 11 proteins that were changed significantly in overall abundance and 45 proteins that showed changes in phosphorylation after the antipsychotic treatment. The altered phosphoproteins were mainly involved in the acute phase response, lipid and glucose homeostasis (LXR), retinoic acid signaling (RXR), and complement pathways. Some of the proteins showed a marked increase in phosphorylation, including apolipoprotein A-I (3.4-fold), alpha-1 anti-chymotrypsin (3.1-fold), and apolipoprotein B-100 (2.2-fold). In addition, several proteins showed either decreased phosphorylation (e.g. complement C4A, collagen alpha-1 chain, complement factor H) or a mixture of increased and decreased phoshphorylation (e.g. afamin, complement C5, complement factor B). Finally, 24 of the altered phosphoproteins showed opposite directional changes in a comparison of baseline schizophrenia patients before and after treatment with olanzapine. These included alpha-1B-glycoprotein, apolipoprotein A-IV, vitamin D binding protein, and prothrombin. CONCLUSIONS AND CLINICAL RELEVANCE: These data demonstrate the potential for future studies of serum phosphoproteins as a readout of physiological function and might have utility in studies aimed at identification of biomarkers for drug response prediction or monitoring. PMID- 25821033 TI - The double-histidine Cu2+-binding motif: a highly rigid, site-specific spin probe for electron spin resonance distance measurements. AB - The development of ESR methods that measure long-range distance distributions has advanced biophysical research. However, the spin labels commonly employed are highly flexible, which leads to ambiguity in relating ESR measurements to protein backbone structure. Herein we present the double-histidine (dHis) Cu(2+)-binding motif as a rigid spin probe for double electron-electron resonance (DEER) distance measurements. The spin label is assembled in situ from natural amino acid residues and a metal salt, requires no postexpression synthetic modification, and provides distance distributions that are dramatically narrower than those found with the commonly used protein spin label. Simple molecular modeling based on an X-ray crystal structure of an unlabeled protein led to a predicted most probable distance within 0.5 A of the experimental value. Cu(2+) DEER with the dHis motif shows great promise for the resolution of precise, unambiguous distance constraints that relate directly to protein-backbone structure and flexibility. PMID- 25821034 TI - Correlation of ultrasound appearance, gross anatomy, and histology of the femoral nerve at the femoral triangle. AB - PURPOSE: Correlation between ultrasound appearance, gross anatomic characteristics, and histologic structure of the femoral nerve (FN) is lacking. Utilizing cadavers, we sought to characterize the anatomy of the FN, and provide a quantitative measure of its branching. We hypothesize that at the femoral crease, the FN exists as a group of nerve branches, rather than a single nerve structure, and secondarily, that this transition into many branches is apparent on ultrasonography. MATERIALS AND METHODS: Nineteen preserved cadavers were investigated. Ultrasonography was sufficient to evaluate the femoral nerve in nine specimens; gross dissection was utilized in all 19. Anatomic characteristics were recorded, including distances from the inguinal ligament to femoral crease, first nerve branch, and complete arborization of the nerve. The nerves from nine specimens were excised for histologic analysis. RESULTS: On ultrasound, the nerve became more flattened, widened, and less discrete as it coursed distally. Branching of the nerve was apparent in 12 of 18 images, with mean distance from inguinal ligament of 3.9 (1.0) cm. However, upon dissection, major branching of the femoral nerve occurred at 3.1 (1.0) cm distal to the inguinal ligament, well proximal to the femoral crease. Histologic analysis was consistent with findings at dissection. CONCLUSION: The femoral nerve arborizes into multiple branches between the inguinal ligament and the femoral crease. Initial branching is often high in the femoral triangle. As hypothesized, the FN exists as a closely associated group of nerve branches at the level of the femoral crease; however, the termination of the nerve into multiple branches is not consistently apparent on ultrasonography. PMID- 25821035 TI - Morphometric differences of nasopalatine canal based on 3D classifications: descriptive analysis on CBCT. AB - PURPOSE: This descriptive retrospective study analyzed differences among sagittal, coronal and axial NC groups based on the dimensions of nasopalatine canal (NC), buccal bone plate (BBP) and palatal bone plate (PBP) to canal. METHODS: Measurements were made on 224 CBCTs for NC, BBP and PBP on the three anatomic planes at three levels: level 1, when the incisive foramen is completely closed on the axial plane; level 2, at the midpoint of NC length (NCL) on the sagittal plane; and level 3, at the foramina of Stenson on the sagittal plane. ANOVA tests with post hoc tests were used. The intraclass correlation coefficient and Kappa test were used for evaluating the intraobserver agreement. RESULTS: Regarding coronal classification, these significant differences were found: BBP length (BL)level 1 was lower for the two parallel canals group; PBP length (PL)level 1 was lower for single canal group; and NCL was lower for Y-type canal group. Regarding axial classification, these significant differences were found: LPlevel 1 was lower for 3.1-3 group; PBP width (PW)level 3 was the greatest for 3.1-3; and LPlevel 3 was lower for 1.1. CONCLUSIONS: Presurgical evaluation with CBCT in premaxillae region should include analysis on coronal and axial planes and not only on sagittal plane seeing as morphometric differences were found on coronal and axial planes. Following the morphological coronal classification, two parallel canals presented a higher NCL, a higher LP and a lower LV at inferior edge of alveolar ridge. PMID- 25821036 TI - A review of iron species for visible-light photocatalytic water purification. AB - Iron species are one of the least toxic and least expensive substances that are photocatalytic in the visible region of the spectrum. Therefore, this article focuses on iron-based photocatalysts sensitive to visible light. Photo-Fenton reactions are considered with respect to those assisted by and involve the in situ production of H2O2. The possible role that photoactive iron species play by interacting with natural organic matter in water purification in the natural environment is considered. The review also considered photosensitization by phthalocyanines and the potential role that layered double hydroxides may have not only as catalyst supports but also as photosensitizers themselves. Finally, photocatalytic disinfection of water is discussed, and the desirability of standardized metrics and experimental conditions to assist in the comparative evaluation of photocatalysts is highlighted. PMID- 25821037 TI - Recovery and electrochemical performance in lithium secondary batteries of biochar derived from rice straw. AB - Renewable biomass has attracted great attention for the production of biooil, biogas, and biochar, a carbon residual applicable for carbon sequestration and environmental remediation. Rice straw is one of the most common biomasses among agricultural wastes in South Korea. As part of our advanced and environmentally friendly research, we applied biochar derived from rice straw as the anode material for lithium-ion batteries (LIBs). Porous carbons with a high surface area were prepared from rice straw. Such porous carbons have exhibited particularly large reversible capacity and hence proven to be a candidate anode material for high-rate and high-capacity LIBs. Rice straw-derived biochars were synthesized at four different temperatures: 400, 550, 700, and 900 degrees C. The surface was modified by using HCl and H2O2 on the 550 degrees C biochar in order to increase the surface area. The resulting biochar was characterized by X ray diffraction (XRD) and field-emission scanning electron microscopy (FE-SEM). The surface area was measured by Brunauer-Emmett-Teller (BET) method. The electrochemical characterizations were investigated by galvanostatic charge discharge (CD) curves, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). All samples exhibited reversible capacities of below 200 mAh g(-1). The surface-modified biochars exhibited improved cycle performance. Surface modification using HCl showed better cycle performance than H2O2. However, the capacities of the treated 550 degrees C biochar were similar to those of non-surface-modified biochar. PMID- 25821038 TI - Investigation of aromatic hydrocarbon inclusion into cyclodextrins by Raman spectroscopy and thermal analysis. AB - Among various cavitand molecules, cyclodextrins are extensively studied due to their ability to form host-guest complexes with small hydrophobic molecules. Aiming to explore cyclodextrin implementation on the scopes related to the environmental pollution monitoring or remediation, extensive studies for understanding the cyclodextrin-based host-guest complex formation with selected targeted substances are conducted. In this context, two polycyclic aromatic hydrocarbons, naphthalene and fluoranthene as well as toluene as a member of volatile organic compounds, were studied regarding their ability to encapsulate into cyclodextrin cavities. Synthesised complexes were examined by thermogravimetric analysis combined with Raman spectroscopy. The obtained results demonstrated that the size between targeted molecules and the cyclodextrin cavities strongly correlates with its ability to engage in complexation. Thus, this latter parameter plays an important role in the inclusion complex formation as well as in the strength of the interaction between the molecules. PMID- 25821039 TI - Aging effect on the leaching behavior of heavy metals (Cu, Zn, and Cd) in red paddy soil. AB - Aging effect can influence the fractions distribution and mobility of metals after they are added into soil. In this study, incubation and soil column experiments under simulated acid rain condition were conducted to evaluate aging effect on the leaching characteristic of Cu, Zn, and Cd in artificial polluted red paddy soil. Our results showed that aging effect reduced metal contents in exchangeable and HoAc soluble fractions. Power function was the most excellent to describe the variation of exchangeable fraction, while pseudo first- and second order functions were more successful to describe the leaching characteristic of metals from soil columns. The leaching amount of the metals from the polluted soil only accounted for a small part of their total content in soil, and the leachability of Cu was the weakest. Both the exchangeable and HoAc soluble fraction were available as indicators to evaluate the leachability of metals in red paddy soil. The shorter time the soil was contaminated, the more amounts of metals released from the soil. The reduction of exchangeable fraction caused by aging effect was the main reason for the decrease of metal mobility in soil. PMID- 25821040 TI - ACN9 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families. AB - A previous genome-wide linkage study of alcohol dependence (AD) in the Pittsburgh based multiplex family study found suggestive evidence for linkage on Chromosome 7q, a region in which the ACN9 gene is located. Using the same two generation Pittsburgh family data in which linkage was found, data for a third generation was added. The expanded sample included 133 pedigrees with 995 individuals. Finer mapping was undertaken using six SNPs extending from rs1917939 to rs13475 with minor allele frequency (MAF) >=0.15 and pair-wise linkage disequilibrium (LD) of r(2) <0.8 using the HapMap CEU population. Binary affection status, visual, and auditory P300 data were tested for family-based association. Family-based analyses found all six SNPs associated with affected status. Three SNPs are located upstream of the gene, two SNPs are within intron 1 and one is in Exon 4. FBAT P-values for the six SNPs ranged between 0.05 and 0.0005. Haplotype analysis revealed one four-SNP block formed by rs10499934, rs7794886, rs12056091, and rs13475 with an overall significant association at P = 0.0008. Analysis of visual P300 amplitude data, a known endophenotype of alcohol dependence risk, revealed a significant association for SNPs within intron 1 and exon 4 under a dominant model of transmission. Family-based association analysis shows the ACN9 gene significantly associated with alcohol dependence and P300 amplitude variation. The potential importance of the ACN9 gene for AD risk may be related to its role in gluconeogenesis which may be involved in the regulation of alcohol metabolism. PMID- 25821041 TI - Transplantation speed offers early hepatocyte engraftment in acute liver injured rats: A translational study with clinical implications. AB - The impact of the rate of intraportal hepatocyte transplantation on early engraftment and repopulation is unclear. The aim of this study was to address this and to improve the engraftment and repopulation efficiencies of hepatocyte transplantation for the treatment of a rat model of acute liver failure in a clinically useful way without preconditioning. Acute hepatic injury was induced into Sprague-Dawley rats with D-galactosamine. Hepatocytes were infused intraportally over a period of 30, 70, or 100 seconds to study early engraftment (2 days) and repopulation (7 days). Three groups had significant differences in hepatocyte engraftment (P = 0.018) and repopulation efficiencies (P = 0.037), and an infusion over a period of 70 seconds produced superior outcomes. After the 70 second infusion, the transplanted cells immediately transmigrated the sinusoidal endothelial layer and rarely accumulated in the portal venules, with liver function improving significantly. The mean first peak pressures, without significant differences, were 14.8 +/- 6.5, 17.7 +/- 3.7, and 13.6 +/- 3.0 mm Hg in the 30-, 70-, and 100-second groups, respectively. Differential hepatocyte transfusion rates contributed to accelerated early engraftment and repopulation in rats with acute liver injury. These proof-of-concept findings are of clinical significance because they are easy to translate into practice. PMID- 25821042 TI - Knowing What to Do and Being Able to Do It: Influences on Parent Choice and Use of Practices to Support Young People Living with Mental Illness. AB - A parent's response to a young person's mental illness can influence their recovery and wellbeing. Many parents devote considerable time and energy to supporting a young person experiencing mental illness and engage in numerous different practices to do so. Yet little is known about why parents use particular practices. This article explores this question through qualitative analysis of parent perspectives. Interviews with 32 parents of young people living with mental illness were analysed using constant comparative analysis. Findings suggest that parents' choice of and ability to carry out particular practices are shaped by: their knowledge and beliefs; their personal resources and constraints; and their social and service networks. Further, parents took active measures to optimize these influences. By understanding the complexity of their own potential influence on both knowing what to do and being able to do it, health professionals can better enable parents to support young adults experiencing mental illness. PMID- 25821043 TI - An Exploratory Factor Analysis of Coping Styles and Relationship to Depression Among a Sample of Homeless Youth. AB - The extent to which measures of coping adequately capture the ways that homeless youth cope with challenges, and the influence these coping styles have on mental health outcomes, is largely absent from the literature. This study tests the factor structure of the Coping Scale using Exploratory Factor Analysis (EFA) and then investigates the relationship between coping styles and depression using hierarchical logistic regression with data from 201 homeless youth. Results of the EFA indicate a 3-factor structure of coping, which includes active, avoidant, and social coping styles. Results of the hierarchical logistic regression show that homeless youth who engage in greater avoidant coping are at increased risk of meeting criteria for major depressive disorder. Findings provide insight into the utility of a preliminary tool for assessing homeless youths' coping styles. Such assessment may identify malleable risk factors that could be addressed by service providers to help prevent mental health problems. PMID- 25821044 TI - From small fullerenes to the graphene limit: A harmonic force-field method for fullerenes and a comparison to density functional calculations for Goldberg Coxeter fullerenes up to C980. AB - We introduce a simple but computationally very efficient harmonic force field, which works for all fullerene structures and includes bond stretching, bending, and torsional motions as implemented into our open-source code Fullerene. This gives accurate geometries and reasonably accurate vibrational frequencies with root mean square deviations of up to 0.05 A for bond distances and 45.5 cm(-1) for vibrational frequencies compared with more elaborate density functional calculations. The structures obtained were used for density functional calculations of Goldberg-Coxeter fullerenes up to C980. This gives a rather large range of fullerenes making it possible to extrapolate to the graphene limit. Periodic boundary condition calculations using density functional theory (DFT) within the projector augmented wave method gave an energy difference between -8.6 and -8.8 kcal/mol at various levels of DFT for the reaction C60 ->graphene (per carbon atom) in excellent agreement with the linear extrapolation to the graphene limit (-8.6 kcal/mol at the Perdew-Burke-Ernzerhof level of theory). PMID- 25821045 TI - Breast carcinoma with a predominant duct-replacing component and chondroid matrix production. AB - Breast carcinomas that produce chondroid matrix are extremely rare. If the carcinoma is invasive, it is classified as a matrix-producing carcinoma (MPC). Herein, we present a case of a breast carcinoma, which showed duct-replacing growth with chondroid matrix production. A 63-year-old woman underwent fine needle aspiration cytology for suspected malignancy, based on radiological findings. Cellular components showed sufficient atypia to allow a diagnosis of malignancy. A partial mastectomy was performed, and no mass-forming lesion was apparent in the surgically resected specimen. Histopathological examination showed that the carcinoma produced chondroid matrix and grew replacing ducts, which were associated with a small amount of an obvious invasive component without matrix production. Some parts of the duct-replacing component might take the form of expansile invasion due to the absence of residual duct-lining myoepithelial cells; it is difficult to decide whether the duct-replacing component is invasive or not. However, regarding a few tumor nests, they would be recognized as MPC-like intraductal components because of the focal presence of myoepithelial cells around them. Hence, this carcinoma could not be definitely diagnosed as a MPC, even though we believe they are closely related. This is the first reported case of a breast carcinoma displaying duct-replacing growth with chondroid matrix production. PMID- 25821046 TI - Are patients with low body mass index candidates for deep inferior epigastric perforator flaps for unilateral breast reconstruction? AB - Thin women have not traditionally been considered ideal candidates for autologous breast reconstruction. The purpose of this study was to examine the use of deep inferior epigastric perforator (DIEP) flap reconstruction in thin women undergoing immediate unilateral breast reconstruction. A retrospective review of 1,040 consecutive patients was performed. In total, 381 patients met the inclusion criteria. To improve clinical interpretability, patients were divided into three groups based on body mass index: "thin" (BMI <= 22.99), "traditional" (>23 and <=29.99), and "obese" (BMI >30) candidates. Flap characteristics were compared to mastectomy weights, and postoperative complications were analyzed. In all groups, flap size was generally more than sufficient to match the mastectomy specimen, as flap weight:mastectomy weight ratio ws greater than 1 in all groups with no significant difference between groups (1.1 in thin patients, 1.0 in traditional patients, and 1.0 in obese patients). Fat necrosis prevalence was lowest in the thin group (12.5%), compared to the traditional (15.9%, P = 0.443) or obese (14.4%, P = 0.698) groups. Prevalence of breast infection were lower in the thin patients (5.2%) versus the traditional (8.7%, P = 0.287) or obese (14.4%, P = 0.033). Abdominal wound healing complications and seroma were also lowest in thin patients. DIEP flap breast reconstruction may be an effective method for unilateral breast reconstruction in thin patients, with sufficient flap weights and lower incidence of complications than in heavier patients. As such, low BMI may not present a barrier in the reconstruction of a breast mound matching native breast size. PMID- 25821047 TI - Validation of Fall Risk Assessment Specific to the Inpatient Rehabilitation Facility Setting. AB - PURPOSE: To evaluate and compare the Morse Fall Scale (MFS) and the Casa Colina Fall Risk Assessment Scale (CCFRA) for identification of patients at risk for falling in an acute inpatient rehabilitation facility. The primary objective of this study was to perform a retrospective validation study of the CCFRAS, specifically for use in the inpatient rehabilitation facility (IRF) setting. DESIGN: Retrospective validation study. METHOD: The study was approved under expedited review by the local Institutional Review Board. Data were collected on all patients admitted to Cottage Rehabiliation Hospital (CRH), a 38-bed acute inpatient rehabilitation hospital, from March 2012 to August 2013. Patients were excluded from the study if they had a length of stay less than 3 days or age less than 18. The area under the receiver operating characteristic curve (AUC) and the diagnostic odds ratio were used to examine the differences between the MFS and CCFRAS. AUC between fall scales was compared using the DeLong Test. FINDINGS: There were 931 patients included in the study with 62 (6.7%) patient falls. The average age of the population was 68.8 with 503 males (51.2%). The AUC was 0.595 and 0.713 for the MFS and CCFRAS, respectively (0.006). The diagnostic odds ratio of the MFS was 2.0 and 3.6 for the CCFRAS using the recommended cutoffs of 45 for the MFS and 80 for the CCFRAS. CONCLUSION: The CCFRAS appears to be a better tool in detecting fallers vs. nonfallers specific to the IRF setting. CLINICAL RELEVANCE: The assessment and identification of patients at high risk for falling is important to implement specific precautions and care for these patients to reduce their risk of falling. The CCFRAS is more clinically relevant in identifying patients at high risk for falling in the IRF setting compared to other fall risk assessments. Implementation of this scale may lead to a reduction in fall rate and injuries from falls as it more appropriately identifies patients at high risk for falling. PMID- 25821048 TI - A new paradigm for numerical simulation of microneedle-based drug delivery aided by histology of microneedle-pierced skin. AB - Microneedle (MN) is a relatively recent invention and an efficient technology for transdermal drug delivery (TDD). Conventionally, mathematical models of MNs drug delivery define the shape of the holes created by the MNs in the skin as the same as their actual geometry. Furthermore, the size of the MN holes in the skin is considered to be either the same or a certain fraction of the length of the MNs. However, the histological images of the MN-treated skin indicate that the real insertion depth is much shorter than the length of the MNs and the shapes may vary significantly from one case to another. In addressing these points, we propose a new approach for modeling MN-based drug delivery, which incorporates the histology of MN-pierced skin using a number of concepts borrowed from image processing tools. It is expected that the developed approach will provide better accuracy of the drug diffusion profile. A new computer program is developed to automatically obtain the outline of the MNs-treated holes and import these images into computer software for simulation of drug diffusion from MN systems. This method can provide a simple and fast way to test the quality of MNs design and modeling, as well as simulate experimental studies, for example, permeation experiments on MN-pierced skin using diffusion cell. The developed methodology is demonstrated using two-dimensional (2D) numerical modeling of flat MNs (2D). However, the methodology is general and can be implemented for three dimensional (3D) MNs if there is sufficient number of images for reconstructing a 3D image for numerical simulation. Numerical modeling for 3D geometry is demonstrated by using images of an ideal 3D MN. The methodology is not demonstrated for real 3D MNs, as there are not sufficient numbers of images for the purpose of this paper. PMID- 25821049 TI - Peptide Sequence Analysis by Electron Transfer Dissociation Mass Spectrometry: A Web-Based Tutorial. AB - We created a web-based tutorial designed to teach manual interpretation and identification of spectra acquired using electron transfer dissociation (ETD). The tutorial provides an explanation of the ETD fragmentation process with the goal of identifying all of the significant peaks in a spectrum. We discuss determination of the precursor mass and charge state, neutral losses, electron transfer without dissociation (ETnoD), and the mechanisms by which fragment ions are created. Our hope is to provide a tool that presents the information already taught in D.F.H.'s short courses in a way that is easy for any student or researcher in the mass spectrometry community to access. The tutorial may be found at http://www.huntlab.org. PMID- 25821050 TI - Pyrylium Salts as Reactive Matrices for MALDI-MS Imaging of Biologically Active Primary Amines. AB - Many neuroactive substances, including endogenous biomolecules, environmental compounds, and pharmaceuticals possess primary amine functional groups. Among these are catecholamine neurotransmitters (e.g., dopamine), many substituted phenethylamines (e.g., amphetamine), as well as amino acids and neuropeptides. In most cases, mass spectrometric (ESI and MALDI) analyses of trace amounts of such compounds are challenging because of their poor ionization properties. We present a method for chemical derivatization of primary amines by reaction with pyrylium salts that facilitates their detection by MALDI-MS and enables the imaging of primary amines in brain tissue sections. A screen of pyrylium salts revealed that the 2,4-diphenyl-pyranylium ion efficiently derivatizes primary amines and can be used as a reactive MALDI-MS matrix that induces both derivatization and desorption. MALDI-MS imaging with such matrix was used to map the localization of dopamine and amphetamine in brain tissue sections and to quantitatively map the distribution of the neurotoxin beta-N-methylamino-L-alanine. PMID- 25821051 TI - An interchangeable role for kainate and metabotropic glutamate receptors in the induction of rat hippocampal mossy fiber long-term potentiation in vivo. AB - The roles of both kainate receptors (KARs) and metabotropic glutamate receptors (mGluRs) in mossy fiber long-term potentiation (MF-LTP) have been extensively studied in hippocampal brain slices, but the findings are controversial. In this study, we have addressed the roles of both mGluRs and KARs in MF-LTP in anesthetized rats. We found that MF-LTP could be induced in the presence of either GluK1-selective KAR antagonists or group I mGluR antagonists. However, LTP was inhibited when the group I mGluRs and the GluK1-KARs were simultaneously inhibited. Either mGlu1 or mGlu5 receptor activation is sufficient to induce this form of LTP as selective inhibition of either subtype alone, together with the inhibition of KARs, did not inhibit MF-LTP. These data suggest that mGlu1 receptors, mGlu5 receptors, and GluK1-KARs are all engaged during high-frequency stimulation, and that the activation of any one of these receptors alone is sufficient for the induction of MF-LTP in vivo. PMID- 25821052 TI - Attitudes of the Prekmurje Roma towards health and healthcare. AB - BACKGROUND: Knowledge of the culture, traditions and values of the Roma is important for understanding their relationship to health and the health system. The Roma in Prekmurje, the far northeastern part of Slovenia, are a unique ethnic group and in many respects different from other Roma. The aim of the study was to determine their attitudes towards health and the healthcare system. METHODS AND MATERIALS: We conducted 25 interviews in Roma settlements. The participants were between 18 and 64 years of age, with the average age being 23.46 years old; 48 % were men and 52 % women. We used qualitative content analysis as the data analysis technique. As a tool to facilitate the qualitative data analysis, we used the software Atlas.ti. In the study, we used a data-driving coding scheme. Two independent coders carried out the coding. RESULTS: We determined eight logical categories that explain the attitudes of the Roma towards health, satisfaction, problems and prospects and the functioning of the health system at the local level. These are experiences with the healthcare system, personal healthcare, the perception of health and illness, suggestions for improvement, common diseases as perceived by the Roma, poverty and socioeconomic status of the Roma, discrimination and the need for a better understanding of the Roma. CONCLUSION: Roma culture and their customs affect the Roma's relationship with health and the healthcare services in Prekmurje. The Roma are willing to participate in health status improvement, but require special attention within the national healthcare system. PMID- 25821053 TI - Clinical profile, natural history, and predictors of mortality in patients with acute-on-chronic liver failure (ACLF). AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is an increasingly recognized entity encompassing an acute deterioration of liver function in patients with cirrhosis, either secondary to superimposed liver injury or due to extrahepatic precipitating factors such as infection culminating in the end-organ dysfunction. Its main features are reversibility and high short-term mortality due to multiorgan failure (MOF). We aimed to analyze the clinical, laboratory, and etiological predictors of mortality and outcome in patients with ACLF. METHODS: We evaluated 1215 patients with chronic liver disease; 90 patients met the criteria for ACLF. RESULTS: The most common cause of underlying chronic liver disease was alcohol, and the most common acute insult (AI) in those patients was superadded alcoholic hepatitis. In all, 50% of all patients died within 30 days (71.1 % within the first 14 days after admission). MOF was the cause of death in 70 % of cases. On multivariate analysis, high serum potassium, serum creatinine higher than 90 umol/L, and C-reactive protein > 30 mg/L were found to be independent baseline predictors of mortality. APACHE II (Acute Physiology and Chronic Health Evaluation II) score was the best predictor of short-term mortality (area under the curve (AUC), 0.878). MOF was a valuable predictor of mortality (AUC, 0.923); 33 of 35 patients who had MOF at admission died. Presence of positive systemic inflammatory response syndrome criteria at admission was also correlated with in-hospital mortality (AUC, 0.742). CONCLUSION: ACLF is a serious condition with high short-term mortality. Because ACLF is reversible, it is necessary to identify at-risk patients as soon as possible to treat acute events in a timely manner. PMID- 25821054 TI - A retrospective, case-control study on traditional environmental risk factors in inflammatory bowel disease in Vukovar-Srijem County, north-eastern Croatia, 2010. AB - BACKGROUND: Traditional environmental risk factors in inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), were examined as part of the retrospective epidemiologic study conducted in Vukovar-Srijem County, north eastern Croatia in 2010. The geographical variations in the frequency of IBD in Croatia have been observed, which is also the trend in the Central Eastern European region and Europe as a whole, indicating the influence of environmental and lifestyle factors. However, the data on the spread of environmental IBD risk factors are still limited. The purpose of this study was to analyse the traditional environmental risk factors in IBD on our cohort sample, including measles virus infection and vaccination (MMR vaccine-Mumps, Measles, Rubella), tonsillectomy, appendectomy, current and former cigarette smoking and use of oral contraceptives in women. METHODS: This retrospective, case-control study was performed as a part of a wider epidemiologic study aimed at assessing the incidence, prevalence and clinical expression of IBD, in Vukovar-Srijem County (population: 204,768; 2001), which is a lesser developed part of the continental Croatia that experienced deep demographic changes in the recent past. IBD patients were identified according to the hospital's patient records. There were 119 UC patients and 31 CD patients of a total of 150 patients in the cohort. A total of 150 individuals, volunteers, not having a diagnosis of IBD, age- and sex matched, were used as the control group. Information on examined risk factors were obtained from all subjects in a previously conducted interview. Patients were contacted personally or by phone and interviewed by a gastroenterologist. RESULTS: There were no differences in the number of smokers, former smokers and non-smokers, between UC and CD patients and the controls, nor in the duration of smoking (years), in current smokers and ex-smokers. Only marginally significant longer time of non-smoking, in ex-smokers was found in IBD patients, compared to the controls, more pronounced in CD patients (p = 0.05). No difference was found in relation to tonsillectomy and risk of IBD. There was no difference in the number of female IBD patients and women from the controls using oral contraceptives. Duration (years) of oral contraceptives use was longer in women from the controls than in female IBD patients (p < 0.001). Frequency of appendectomy was the lowest in UC patients, compared to the controls and CD patients (3.4, 12.0 and 38.7%, respectively) (p < 0.001). No difference was found in relation to measles virus infection and risk of IBD. MMR vaccination rates were higher in CD patients (90.3%), compared to UC patients and the controls (74.8 and 67.3%, respectively) (p = 0.026). CONCLUSIONS: No association was found between smoking and tonsillectomy and risk of IBD. Our results do not support the idea of oral contraceptives use as a risk factor for IBD. Frequency of appendectomy was the lowest in UC patients, suggesting that appendectomy decreases the risk of UC, contributing the earlier results. MMR vaccination seemed to be associated with Crohn's disease. These results can add value to our understanding of the increasing incidence of IBD in Croatia and other Central Eastern European countries and can be introductory to future large-scale research. PMID- 25821055 TI - [Use of ECMO in adult patients with cardiogenic shock: a position paper of the Austrian Society of Cardiology]. AB - The use of ECMO to stabilize critically ill patients with severely depressed cardiac function and hemodynamics increased in the last years due to broader availability, better performance and easier implantation of the devices. The present guidelines of the Austrian Society of Cardiology focus on the use of ECMO in adult non-operated patients with cardiac diseases. Not only indications and contraindications are highlighted, but also the equally important issues of monitoring, complication management, measures during implantation and operation, and weaning of the devices are treated in detail. Thereby the present guidelines aim to optimize the use of ECMO in the individual centers, and aim to help current non-ECMO centers in developing a local ECMO-program or to contact ECMO centers for discussion of individual patients. PMID- 25821056 TI - Patient's and physician's behavior on the management of benign prostatic hyperplasia among the patients at the risk of clinical progression. A multicenter noninterventional trial in Slovakia by "Prostate and Expectations of Treatment: Epidemiology Research" (PETER) study group. AB - OBJECTIVES: The aim of the survey was to assess physician's behavior and the global knowledge about patient's preferences and their psychological burden linked to lower urinary tract symptoms (LUTS) in an outpatient setting in Slovakia. METHODS: The study included 36 outpatient urological clinics. Overall, 1132 newly diagnosed LUTS patients were screened within 1 month. A total of 454 questionnaires were obtained from 459 LUTS patients with risk of progression (RP). Inclusion criteria were: age > 50 years, IPSS > 8, prostate volume >= 30 cm3, and PSA >= 1.5 to <= 10 ng/ml. RESULTS: The digital rectal examination, PSA testing, and urinalysis were used in all the centers as first visit examinations. The least frequently performed diagnostic procedure was uroflowmetry (74 %). The physician's preferred therapy for patients with RP was standard combined treatment in (52.6 %); followed by alpha-blocker alone (45 %) and monotherapy with 5-alpha-reductase inhibitors (5-ARI) only in 3 % of all asked urologists. Patient's mean age was 63.3 years (SD +/- 7.4); baseline PSA value 2.2 ng/ml (SD + 3.2); prostate volume was 38.0 ml (SD +/- 16.7 ml); Qmax was 11.5 ml/s (SD +/- 4.6); and IPSS score 12.5 (SD +/- 6.3). The most bothersome symptoms were nocturia (prevalence of >= 75 %), weak urinary stream (61 %), and retarded voiding (43 %). Patient's expectations of treatment were rapid improvement of symptoms (36.0 %), stabilization of symptoms (35.5 %), and reduction of potential risk of surgical intervention (25.8 %). CONCLUSIONS: Our research reflects the physician's behavior, patient's self-perception of the disease and therapeutic priorities in the current outpatient practice in Slovakia. PMID- 25821057 TI - Non-specific low back pain: occupational or lifestyle consequences? AB - BACKGROUND: Nursing occupation was identified as a risk occupation for the development of low back pain (LBP). The aim of our study was to find out how much occupational factors influence the development of LBP in hospital nursing personnel. PATIENTS AND METHODS: Non-experimental approach with a cross-sectional survey and statistical analysis. Nine hundred questionnaires were distributed among nursing personnel, 663 were returned and 659 (73.2 %) were considered for the analysis. Univariate and multivariate statistics for LBP risk was calculated by the binary logistic regression. The chi(2), influence factor, 95 % confidence interval and P value were calculated. Multivariate binary logistic regression was calculated by the Wald method to omit insignificant variables. RESULTS: Not performing exercises represented the highest risk for the development of LBP (OR 2.8, 95 % CI 1.7-4.4; p < 0.001). The second and third ranked risk factors were frequent manual lifting > 10 kg (OR 2.4, 95 % CI 1.5-3.8; p < 0.001) and duration of employment >= 19 years (OR 2.4, 95 % CI 1.6-3.7; p < 0.001). The fourth ranked risk factor was better physical condition by frequent recreation and sports, which reduced the risk for the development of LBP (OR 0.4, 95 % CI 0.3-0.7; p = 0.001). Work with the computer >= 2 h per day as last significant risk factor also reduced the risk for the development of LBP (OR 0.6, 95 % CI 0.4-0.1; p = 0.049). CONCLUSION: Risk factors for LBP established in our study (exercises, duration of employment, frequent manual lifting, recreation and sports and work with the computer) are not specifically linked to the working environment of the nursing personnel. Rather than focusing on mechanical causes and direct workload in the development of non-specific LBP, the complex approach to LBP including genetics, psychosocial environment, lifestyle and quality of life is coming more to the fore. PMID- 25821058 TI - HUIEC, Human intestinal epithelial cell line with differentiated properties: process of isolation and characterisation. AB - The intestinal epithelium is composed of diverse cell types, most abundant being the enterocytes. Among other functions, they maintain the intestinal barrier and play a critical role in the absorption of nutrients, drugs and toxins. This study describes the development and characterization of human intestinal epithelial cells (HUIEC), a spontaneously arising cell line established by selective trypsinization and cloning of the intestinal epithelium, resulting in a uniform population of highly epithelial cells with a strong growth potential. PMID- 25821059 TI - Intra-arrest percutaneous coronary intervention: a case series. AB - In patients with refractory cardiac arrest presumably from acute coronary occlusion, primary percutaneous coronary intervention (PPCI) may provide an opportunity for revascularisation and, subsequently, return of spontaneous circulation. We present our experience from a 24/7 primary percutaneous coronary intervention centre serving a population of approximately 800,000 individuals. A retrospective analysis was performed in patients with cardiac arrest treated from July 2011 to January 2014. Inclusion criteria were cardiac arrest and emergency coronary angiography performed during on-going external cardiopulmonary resuscitation (CPR). Course of treatment was analysed to outline the reasons for poor survival. Eight patients met the inclusion criteria; six (75 %) were male, and the mean age was 63 +/- 16 years. Revascularisation under continuous cardiopulmonary resuscitation was achieved in all eight patients. Sustained return of spontaneous circulation was achieved in two patients (25 %). Both patients had poor neurological outcome (cerebral performance category 4), and both died within 3 months. We identified total duration of cardiopulmonary resuscitation (90.5 +/- 33.3 min), lack of prehospital mechanical cardiopulmonary resuscitation devices and lack of extra-corporeal life support devices as the most likely reasons contributing to poor survival. PMID- 25821060 TI - Enrichment and separation of antitumor triterpene acids from the epidermis of Poria cocos by pH-zone-refining counter-current chromatography and conventional high-speed counter-current chromatography. AB - Triterpene acids were extracted from the epidermis of Poria cocos (Schw.) Wolf. These acids were found to inhibit the growth of lung cancer cells in vitro and in vivo. An efficient method for the preparative separation of antitumor triterpene acids was established that involves the combination of pH-zone-refining counter current chromatography and conventional high-speed counter-current chromatography. We used pH-zone-refining counter-current chromatography to concentrate the triterpene acids using a two-phase solvent system composed of petroleum ether/ethyl acetate/methanol/water (3:7:5:5, v/v/v/v), trifluoroacetic acid (10 mM) was added to the upper phase as a retainer, and ammonia (10 mM) was added to the lower phase as an eluter. As a result, 200 mg concentrate of triterpene acids was obtained from 1.0 g of crude extract. The concentrate was further separated by conventional high-speed counter-current chromatography using a solvent system composed of petroleum ether/ethyl acetate/methanol/water (0.8:1.2:1.2:0.9, v/v), yielding 50 mg of poricoic acid A and 5 mg of poricoic acid B from 120 mg concentrate, respectively. The inhibitory activity of the major compound on lung A549 cells was examined and poricoic acid A was found to significantly inhibit the growth of A 549 cells. PMID- 25821061 TI - Human pulvinar functional organization and connectivity. AB - The human pulvinar is the largest thalamic area in terms of size and cortical connectivity. Although much is known about regional pulvinar structural anatomy, relatively little is known about pulvinar functional anatomy in humans. Cooccurrence of experimentally induced brain activity is a traditional metric used to establish interregional brain connectivity and forms the foundation of functional neuroimaging connectivity analyses. Because functional neuroimaging studies report task-related coactivations within a standardized space, meta analysis of many whole-brain studies can define the brain's interregional coactivation across many tasks. Such an analysis can also detect and define variations in functional coactivations within a particular region. Here we use coactivation profiles reported in ~ 7,700 functional neuroimaging studies to parcellate and define the pulvinar's functional anatomy. Parcellation of the pulvinar's coactivation profile identified five clusters per pulvinar of distinct functional coactivation. These clusters showed a high degree of symmetry across hemispheres and correspondence with the human pulvinar's cytoarchitecture. We investigated the functional coactivation profiles of each resultant pulvinar cluster with meta-analytic methods. By referencing existent neuroimaging and lesion-deficit literature, these profiles make a case for regional pulvinar specialization within the larger human attention-controlling network. Reference to this literature also informs specific hypotheses that can be tested in subsequent studies in healthy and clinical populations. PMID- 25821063 TI - Treatment of melanoma with a serotype 5/3 chimeric oncolytic adenovirus coding for GM-CSF: Results in vitro, in rodents and in humans. AB - Metastatic melanoma is refractory to irradiation and chemotherapy, but amenable to immunological approaches such as immune-checkpoint-inhibiting antibodies or adoptive cell therapies. Oncolytic virus replication is an immunogenic phenomenon, and viruses can be armed with immunostimulatory molecules. Therefore, oncolytic immuno-virotherapy of malignant melanoma is an appealing approach, which was recently validated by a positive phase 3 trial. We investigated the potency of oncolytic adenovirus Ad5/3-D24-GMCSF on a panel of melanoma cell lines and animal models, and summarized the melanoma-specific human data from the Advanced Therapy Access Program (ATAP). The virus effectively eradicated human melanoma cells in vitro and subcutaneous SK-MEL-28 melanoma xenografts in nude mice when combined with low-dose cyclophosphamide. Furthermore, virally-expressed granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated the differentiation of human monocytes into macrophages. In contrast to human cells, RPMI 1846 hamster melanoma cells exhibited no response to oncolytic viruses and the chimeric 5/3 fiber failed to increase the efficacy of transduction, suggesting limited utility of the hamster model in the context of viruses with this capsid. In ATAP, treatments appeared safe and well-tolerated. Four out of nine melanoma patients treated were evaluable for possible therapy benefit with modified RECIST criteria: one patient had minor response, two had stable disease, and one had progressive disease. Two patients were alive at 559 and 2,149 days after treatment. Ad5/3-D24-GMCSF showed promising efficacy in preclinical studies and possible antitumor activity in melanoma patients refractory to other forms of therapy. This data supports continuing the clinical development of oncolytic adenoviruses for treatment of malignant melanoma. PMID- 25821064 TI - Population pharmacokinetic analysis of oseltamivir and oseltamivir carboxylate following intravenous and oral administration to patients with and without renal impairment. AB - This work characterizes the pharmacokinetics (PK) of oseltamivir phosphate (OP) and its active metabolite, oseltamivir carboxylate (OC), and investigates oseltamivir i.v. dosing regimens for treatment of influenza in patients with normal renal function and with various degrees of renal impairment. Initially, data collected from 149 subjects with normal renal function and mild to severe renal impairment who were administered 40-200 mg oseltamivir i.v. were described by a four-compartment model. Two compartments described OP, one compartment described OC and one compartment described OP to OC metabolism. Then, data of 128 subjects administered 20-1,000 mg oseltamivir orally were added. The absorption model included three first-order processes with direct (via first-pass) input in the OC compartment and two (direct and delayed) inputs in the OP compartment. Simulations and PK bridging were used to recommend i.v. dosing regimens. The analysis demonstrated that renal function had a major effect on OC clearance (CL M ) and exposure. CL M for subjects with mild, moderate and severe renal impairment was 18, 50, and 84 % lower than for subjects with normal renal function. Simulations were used to select i.v. dosing regimens that provide OC Cmin coverage and exposures comparable to those achieved in subjects with normal renal function administered 75 mg b.i.d. orally. The oseltamivir dose depended on the degree of renal impairment and was independent of route of administration. Specifically, 75 mg b.i.d. is recommended for subjects with normal renal function or mild renal impairment, 30 mg b.i.d. for subjects with moderate renal impairment, and 30 mg q.d. for subjects with severe renal impairment. Recommended i.v. doses were the same as those recommended for oral administration in corresponding renal impairment groups. PMID- 25821065 TI - Development and application of an aggregate adherence metric derived from population pharmacokinetics to inform clinical trial enrichment. AB - Nonadherence to prescribed medication is a common barrier to effective treatment, and current options to determine adherence are limited. This study describes development of an aggregate adherence measure based on population pharmacokinetics (PK), and its comparison to a subjective questionnaire, the Morisky 8-item medication adherence scale (MMAS8), in a trial of psychiatric patients on stable doses of oral aripiprazole. A comprehensive model was first built using plasma drug concentration data from 24 clinical studies comprising 448 patients with over 13,500 observations. Application of this model to independent patient profiles for a given drug-dosing regimen were used to generate the primary aggregate adherence metric, a ratio of observed versus expected plasma exposures at steady-state. Although the metric is capable of comparing relative adherence across groups, simulations showed that the metric is not sufficiently sensitive as an individual diagnostic in all cases. There were no trends observed between results from calculated aggregate adherence metrics and total scores from MMAS8 in a single-visit clinical trial of 47 patients with bipolar 1 disorder or schizophrenia who were on stable doses of aripiprazole, although a strong association was observed for one MMAS8 question. The range of the metric calculated for patients was between 0.16 and 3.15. The described approach of a novel "reverse" application of population PK to quantify relative adherence with an aggregate measure may be influential for both clinical and pharmacometric communities. PMID- 25821066 TI - [Epidemiology and prevention of leishmaniasis in northern Afghanistan]. AB - BACKGROUND: Leishmaniasis is estimated to cause the ninth largest disease burden among infectious diseases worldwide and it is not preventable by vaccination or chemoprophylaxis, but only by personal protective measures preventing bites of infectious arthropod vectors. OBJECTIVES: Which leishmania species are endemic in northern Afghanistan, what are the clinical characteristics of skin lesions produced by cutanizing leishmania species, what are their epidemiological characteristics, and which preventive measures are feasible? METHODS: The medical literature was reviewed, knowledge gaps were analyzed and completed by our own data collected locally. RESULTS: Four Leishmania species are considered endemic in northern Afghanistan, of which Leishmania tropica, L. major, and L. donovani can produce skin lesions while L. donovani and L. infantum visceralize. Transmission modes and seasons vary markedly among focally epidemic urban anthroponotic L. tropica and rural enzootic L. major. Combined preventive measures may reduce the infection rate by more than 10,000-fold. CONCLUSION: Cutaneous as well as visceral leishmaniasis can occur among returnees from Afghanistan. Atypical, poorly healing skin lesions can be caused by L. donovani. Extensive use of personal protective measures against arthropod vectors is strongly recommended for all travelers. PMID- 25821067 TI - Nasal lavage levels of granulocyte-macrophage colony-stimulating factor and chronic nasal hypereosinophilia. AB - BACKGROUND: The aim of the present study was to measure levels of granulocyte macrophage colony-stimulating factor (GM-CSF) in nasal lavage of patients affected by chronic eosinophilic sinonasal inflammation to clarify the relationship with eosinophilic tissue infiltration and clinical features. METHODS: Between November 2012 and June 2013, we selected 70 patients with chronic eosinophilic inflammation (average age 41.8 years) who were classified into the following groups: persistent allergic rhinitis (group 1), noninfectious non-allergic rhinitis with eosinophilia syndrome (group 2) and chronic rhinosinusitis with polyps (group 3). Finally, we enrolled 20 healthy subjects as controls (group 4). All patients underwent symptoms score questionnaire based on a visual analogue scale, nasal endoscopy and/or computed tomography (CT) scan, and allergy testing. Nasal cytology by scraping of the mucosa and GM-CSF assays in nasal lavage were performed in all subjects. RESULTS: Detectable levels of GM CSF were found in 34 of 70 (48.57%) patients, with an average concentration of 2.67 +/- 0.8 pg/mL, whereas in controls only 1 of 20 individuals showed detectable GM-CSF levels. Eosinophil infiltration was significantly higher in patients with detectable GM-CSF compared to those with undetectable levels (49.4% vs 39.2%, respectively; p < 0.05). Furthermore, significant weakly-moderate correlation was found between GM-CSF levels and percentage of eosinophil infiltration in tissue (p < 0.05). Correlation between symptom scores and GM-CSF levels was significant only in group 2, which showed higher average concentrations of GM-CSF compared to groups 1 and 3 (2.9 pg/mL vs 1.6 pg/mL and 1.8 pg/mL, respectively; p < 0.05). CONCLUSION: Our data confirm that GM-CSF is more frequently detectable in nasal lavages of patients affected by chronic sinonasal eosinophilic inflammation than in controls. Statistical analyses revealed a significant weakly-moderate correlation between GM-CSF levels in nasal lavage of all patients and percentage of eosinophil infiltration of nasal mucosa. PMID- 25821068 TI - Graphene/polyaniline woven fabric composite films as flexible supercapacitor electrodes. AB - We report the design and preparation of graphene and polyaniline (PANI) woven fabric composite films by in situ electropolymerization. The introduction of PANI greatly improves the electrochemical properties of solid-state supercapacitors which possess capacitances as high as 23 mF cm(-2), and exhibit excellent cycling stability with ~ 100% capacitance retention after 2000 cycles. The devices have displayed superior flexibility with improved areal specific capacitances to 118% during deformation. PMID- 25821069 TI - Interventions for reducing wrong-site surgery and invasive clinical procedures. AB - BACKGROUND: Specific clinical interventions are needed to reduce wrong-site surgery, which is a rare but potentially disastrous clinical error. Risk factors contributing to wrong-site surgery are variable and complex. The introduction of organisational and professional clinical strategies have a role in minimising wrong-site surgery. OBJECTIVES: To evaluate the effectiveness of organisational and professional interventions for reducing wrong-site surgery (including wrong side, wrong-procedure and wrong-patient surgery), including non-surgical invasive clinical procedures such as regional blocks, dermatological, obstetric and dental procedures and emergency surgical procedures not undertaken within the operating theatre. SEARCH METHODS: For this update, we searched the following electronic databases: the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (January 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014), MEDLINE (June 2011 to January 2014), EMBASE (June 2011 to January 2014), CINAHL (June 2011 to January 2014), Dissertations and Theses (June 2011 to January 2014), African Index Medicus, Latin American and Caribbean Health Sciences database, Virtual Health Library, Pan American Health Organization Database and the World Health Organization Library Information System. Database searches were conducted in January 2014. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs), non-randomised controlled trials, controlled before-after studies (CBAs) with at least two intervention and control sites, and interrupted-time-series (ITS) studies where the intervention time was clearly defined and there were at least three data points before and three after the intervention. We included two ITS studies that evaluated the effectiveness of organisational and professional interventions for reducing wrong site surgery, including wrong-side and wrong-procedure surgery. Participants included all healthcare professionals providing care to surgical patients; studies where patients were involved to avoid the incorrect procedures or studies with interventions addressed to healthcare managers, administrators, stakeholders or health insurers. DATA COLLECTION AND ANALYSIS: Two review authors independently assesses the quality and abstracted data of all eligible studies using a standardised data extraction form, modified from the Cochrane EPOC checklists. We contacted study authors for additional information. MAIN RESULTS: In the initial review, we included one ITS study that evaluated a targeted educational intervention aimed at reducing the incidence of wrong-site tooth extractions. The intervention included examination of previous cases of wrong site tooth extractions, educational intervention including a presentation of cases of erroneous extractions, explanation of relevant clinical guidelines and feedback by an instructor. Data were reported from all patients on the surveillance system of a University Medical centre in Taiwan with a total of 24,406 tooth extractions before the intervention and 28,084 tooth extractions after the intervention. We re-analysed the data using the Prais-Winsten time series and the change in level for annual number of mishaps was statistically significant at -4.52 (95% confidence interval (CI) -6.83 to -2.217) (standard error (SE) 0.5380). The change in slope was statistically significant at -1.16 (95% CI -2.22 to -0.10) (SE 0.2472; P < 0.05).This update includes an additional study reporting on the incidence of neurological WSS at a university hospital both before and after the Universal Protocol's implementation. A total of 22,743 patients undergoing neurosurgical procedures at the University of Illionois College of Medicine at Peoria, Illinois, United States of America were reported. Of these, 7286 patients were reported before the intervention and 15,456 patients were reported after the intervention. The authors found a significant difference (P < 0.001) in the incidence of WSS between the before period, 1999 to 2004, and the after period, 2005 to 2011. Similarly, data were re-analysed using Prais Winsten regression to correct for autocorrelation. As the incidences were reported by year only and the intervention occurred in July 2004, the intervention year 2004 was excluded from the analysis. The change in level at the point the intervention was introduced was not statistically significant at -0.078 percentage points (pp) (95% CI -0.176 pp to 0.02 pp; SE 0.042; P = 0.103). The change in slope was statistically significant at 0.031 (95% CI 0.004 to 0.058; SE 0.012; P < 0.05). AUTHORS' CONCLUSIONS: The findings of this update added one additional ITS study to the previous review which contained one ITS study. The original review suggested that the use of a specific educational intervention in the context of a dental outpatient setting, which targets junior dental staff using a training session that included cases of wrong-site surgery, presentation of clinical guidelines and feedback by an instructor, was associated with a reduction in the incidence of wrong-site tooth extractions. The additional study in this update evaluated the annual incidence rates of wrong-site surgery in a neurosurgical population before and after the implementation of the Universal Protocol. The data suggested a strong downward trend in the incidence of wrong site surgery prior to the intervention with the incidence rate approaching zero. The effect of the intervention in these studies however remains unclear, as data reflect only two small low-quality studies in very specific population groups. PMID- 25821070 TI - Seed response to strigolactone is controlled by abscisic acid-independent DNA methylation in the obligate root parasitic plant, Phelipanche ramosa L. Pomel. AB - Seed dormancy release of the obligate root parasitic plant, Phelipanche ramosa, requires a minimum 4-day conditioning period followed by stimulation by host derived germination stimulants, such as strigolactones. Germination is then mediated by germination stimulant-dependent activation of PrCYP707A1, an abscisic acid catabolic gene. The molecular mechanisms occurring during the conditioning period that silence PrCYP707A1 expression and regulate germination stimulant response are almost unknown. Here, global DNA methylation quantification associated with pharmacological approaches and cytosine methylation analysis of the PrCYP707A1 promoter were used to investigate the modulation and possible role of DNA methylation during the conditioning period and in the PrCYP707A1 response to GR24, a synthetic strigolactone analogue. Active global DNA demethylation occurs during the conditioning period and is required for PrCYP707A1 activation by GR24 and for subsequent seed germination. Treatment with 5-azacytidine, a DNA hypomethylating molecule, reduces the length of the conditioning period. Conversely, hydroxyurea, a hypermethylating agent, inhibits PrCYP707A1 expression and seed germination. Methylated DNA immunoprecipitation followed by PCR experiments and bisulfite sequencing revealed that DNA demethylation particularly impacts a 78-nucleotide sequence in the PrCYP707A1 promoter. The results here demonstrate that the DNA methylation status during the conditioning period plays a crucial role independently of abscisic acid in the regulation of P. ramosa seed germination by controlling the strigolactone-dependent expression of PrCYP707A1. PMID- 25821071 TI - Planteose as a storage carbohydrate required for early stage of germination of Orobanche minor and its metabolism as a possible target for selective control. AB - Root parasitic weeds in Orobanchaceae cause serious damage to worldwide agriculture. Germination of the parasites requires host-derived germination stimulants, such as strigolactones, as indicators of host roots within reach of the parasite's radicles. This unique germination process was focused on to identify metabolic pathways required for germination, and to design a selective control strategy. A metabolomic analysis of germinating seeds of clover broomrape, Orobanche minor, was conducted to identify its distinctive metabolites. Consequently, a galactosyl-sucrose trisaccharide, planteose (alpha-d galactopyranosyl-(1->6)-beta-d-fructofuranosyl-(2->1)-alpha-d-glucopyranoside), was identified as a metabolite that decreased promptly after reception of the germination stimulant. To investigate the importance of planteose metabolism, the effects of several glycosidase inhibitors were examined, and nojirimycin bisulfite (NJ) was found to alter the sugar metabolism and to selectively inhibit the germination of O. minor. Planteose consumption was similar in NJ-treated seeds and non-treated germinating seeds; however, NJ-treated seeds showed lower consumption of sucrose, a possible intermediate of planteose metabolism, resulting in significantly less glucose and fructose. This inhibitory effect was recovered by adding glucose. These results suggest that planteose is a storage carbohydrate required for early stage of germination of O. minor, and NJ inhibits germination by blocking the supply of essential glucose from planteose and sucrose. Additionally, NJ selectively inhibited radicle elongation of germinated seeds of Orobanchaceae plants (Striga hermonthica and Phtheirospermum japonicum). Thus, NJ will be a promising tool to develop specific herbicides to the parasites, especially broomrapes, and to improve our understanding of the molecular mechanisms of this unique germination. PMID- 25821062 TI - Gray matter atrophy in patients with mild cognitive impairment/Alzheimer's disease over the course of developing delusions. AB - OBJECTIVE: We conducted a neuroimaging analysis to understand the neuroanatomical correlates of gray matter loss in a group of mild cognitive impairment and early Alzheimer's disease patients who developed delusions. METHODS: With data collected as part of the Alzheimer's Disease Neuroimaging Initiative, we conducted voxel-based morphometry to determine areas of gray matter change in the same Alzheimer's Disease Neuroimaging Initiative participants, before and after they developed delusions. RESULTS: We identified 14 voxel clusters with significant gray matter decrease in patient scans post-delusional onset, correcting for multiple comparisons (false discovery rate, p < 0.05). Major areas of difference included the right and left insulae, left precuneus, the right and left cerebellar culmen, the left superior temporal gyrus, the right posterior cingulate, the right thalamus, and the left parahippocampal gyrus. CONCLUSIONS: Although contrary to our initial predictions of enhanced right frontal atrophy, our preliminary work identifies several neuroanatomical areas, including the cerebellum and left posterior hemisphere, which may be involved in delusional development in these patients. PMID- 25821072 TI - Hormone activities and the cell cycle machinery in immunity-triggered growth inhibition. AB - Biotic stress and diseases caused by pathogen attack pose threats in crop production and significantly reduce crop yields. Enhancing immunity against pathogens is therefore of outstanding importance in crop breeding. However, this must be balanced, as immune activation inhibits plant growth. This immunity coupled growth trade-off does not support resistance but is postulated to reflect the reallocation of resources to drive immunity. There is, however, increasing evidence that growth-immunity trade-offs are based on the reconfiguration of hormone pathways, shared by growth and immunity signalling. Studies in roots revealed the role of hormones in orchestrating growth across different cell types, with some hormones showing a defined cell type-specific activity. This is apparently highly relevant for the regulation of the cell cycle machinery and might be part of the growth-immunity cross-talk. Since plants are constantly exposed to Immuno-activating microbes under agricultural conditions, the transition from a growth to an immunity operating mode can significantly reduce crop yield and can conflict our efforts to generate next-generation crops with improved yield under climate change conditions. By focusing on roots, we outline the current knowledge of hormone signalling on the cell cycle machinery to explain growth trade-offs induced by immunity. By referring to abiotic stress studies, we further introduce how root cell type-specific hormone activities might contribute to growth under immunity and discuss the feasibility of uncoupling the growth-immunity cross-talk. PMID- 25821073 TI - Exploiting genetic diversity from landraces in wheat breeding for adaptation to climate change. AB - Climate change has generated unpredictability in the timing and amount of rain, as well as extreme heat and cold spells that have affected grain yields worldwide and threaten food security. Sources of specific adaptation related to drought and heat, as well as associated breeding of genetic traits, will contribute to maintaining grain yields in dry and warm years. Increased crop photosynthesis and biomass have been achieved particularly through disease resistance and healthy leaves. Similarly, sources of drought and heat adaptation through extended photosynthesis and increased biomass would also greatly benefit crop improvement. Wheat landraces have been cultivated for thousands of years under the most extreme environmental conditions. They have also been cultivated in lower input farming systems for which adaptation traits, particularly those that increase the duration of photosynthesis, have been conserved. Landraces are a valuable source of genetic diversity and specific adaptation to local environmental conditions according to their place of origin. Evidence supports the hypothesis that landraces can provide sources of increased biomass and thousand kernel weight, both important traits for adaptation to tolerate drought and heat. Evaluation of wheat landraces stored in gene banks with highly beneficial untapped diversity and sources of stress adaptation, once characterized, should also be used for wheat improvement. Unified development of databases and promotion of data sharing among physiologists, pathologists, wheat quality scientists, national programmes, and breeders will greatly benefit wheat improvement for adaptation to climate change worldwide. PMID- 25821074 TI - Variance components, heritability and correlation analysis of anther and ovary size during the floral development of bread wheat. AB - Anther and ovary development play an important role in grain setting, a crucial factor determining wheat (Triticum aestivum L.) yield. One aim of this study was to determine the heritability of anther and ovary size at different positions within a spikelet at seven floral developmental stages and conduct a variance components analysis. Relationships between anther and ovary size and other traits were also assessed. The thirty central European winter wheat genotypes used in this study were based on reduced height (Rht) and photoperiod sensitivity (Ppd) genes with variable genetic backgrounds. Identical experimental designs were conducted in a greenhouse and field simultaneously. Heritability of anther and ovary size indicated strong genetic control. Variance components analysis revealed that anther and ovary sizes of floret 3 (i.e. F3, the third floret from the spikelet base) and floret 4 (F4) were more sensitive to the environment compared with those in floret 1 (F1). Good correlations were found between spike dry weight and anther and ovary size in both greenhouse and field, suggesting that anther and ovary size are good predictors of each other, as well as spike dry weight in both conditions. Relationships between spike dry weight and anther and ovary size at F3/4 positions were stronger than at F1, suggesting that F3/4 anther and ovary size are better predictors of spike dry weight. Generally, ovary size showed a closer relationship with spike dry weight than anther size, suggesting that ovary size is a more reliable predictor of spike dry weight. PMID- 25821075 TI - Heterovalent-Doping-Enabled Efficient Dopant Luminescence and Controllable Electronic Impurity Via a New Strategy of Preparing II-VI Nanocrystals. AB - Substitutional heterovalent doping represents an effective method to control the optical and electronic properties of nanocrystals (NCs). Highly monodisperse II VI NCs with deep substitutional dopants are presented. The NCs exhibit stable, dominant, and strong dopant fluorescence, and control over n- and p-type electronic impurities is achieved. Large-scale, bottom-up superlattices of the NCs will speed up their application in electronic devices. PMID- 25821076 TI - Effect of borojo (Borojoa patinoi Cuatrecasas) three-phase composition and gum arabic on the glass transition temperature. AB - BACKGROUND: The search for natural, novel, high-quality, stable food ingredients is an ongoing practice in the food industry. Pulp of borojo (Borojoa patinoi Cuatrecasas), which is a fruit of the Colombian Pacific region, can be separated into three phases: liquid (LP), medium (MP) and solid (SP) phases. The objective of this work was to evaluate the effect of the three-phase composition and gum arabic on their glass transitions temperatures (T(g)). The best mixture, LP-MP, MP-SP and LP-SP and gum arabic (GA) was identified by response surface methodology. RESULTS: When adding GA to SP borojo phase in a 1:1 proportion, the resulting T(g) of the mixture was 132.27 degrees C whereas Tg for GA and SP phase were 154.89 degrees C and 79.86 degrees C respectively, which supported this combination as attractive from a processing perspective and supports an industrial advantage of using borojo as food ingredient. Phases were characterized by high-performance liquid chromatography, Fourier transform infrared spectroscopy, confocal laser scanning microscopy and mass spectrometry. Low molecular weight compounds such as fructose for MP lowered T(g) whereas the presence of lignin increased T(g) of the mixtures as with the SP. CONCLUSIONS: The addition of GA significantly increased T(g) of borojo phases so leading to propose them as novel food processing materials. PMID- 25821077 TI - A pH-switched Pickering emulsion catalytic system: high reaction efficiency and facile catalyst recycling. AB - A smart Pickering emulsion catalytic system is constructed, which not only exhibits fivefold reaction rate enhancement effects in comparison to the conventional biphasic system but also can be facilely demulsified by tuning pH, allowing for in situ recycling nanocatalysts. PMID- 25821078 TI - Tuning oxygen vacancy photoluminescence in monoclinic Y2WO6 by selectively occupying yttrium sites using lanthanum. AB - The effect of isovalent lanthanum (La) doping on the monoclinic Y2WO6 photoluminescence was studied. Introducing the non-activated La(3+) into Y2WO6 brings new excitation bands from violet to visible regions and strong near infrared emission, while the bands position and intensity depend on the doping concentration. It is interesting to find that doping La(3+) into Y2WO6 promotes the oxygen vacancy formation according to the first-principle calculation, Raman spectrum, and synchrotron radiation analysis. Through the Rietveld refinement and X-ray photoelectron spectroscopy results, La(3+) is found to mainly occupy the Y2 (2f) site in low-concentration doped samples. With increasing doping concentration, the La(3+) occupation number at the Y3 (4g) site increases faster than those at the Y1 (2e) and Y2 (2f) sites. When La(3+) occupies different Y sites, the localized energy states caused by the oxygen vacancy pair change their position in the forbidden band, inducing the variation of the excitation and emission bands. This research proposes a feasible method to tune the oxygen vacancy emission, eliminating the challenge of precisely controlling the calcination atmosphere. PMID- 25821080 TI - Dinuclear Face-Sharing Bi-octahedral Tungsten(VI) Core and Unusual Thermal Behavior in Complex Th Tungstates. AB - Two new thorium tungstates A6 Th6 (WO4 )14 O (A=K and Rb) were synthesized by high-temperature solid-state reactions. The structures of both phases are based on a rare dinuclear confacial bi-octahedral [W2 O9 ](6-) core, encapsulated in a [Th6 W7 O46 (W2 O9 )](32-) cage showing a cross-section geometry similar to a six leafed lily. The adjacent cages are connected in two dimensional layers by WO4 tetrahedral linkers. Due to the dissimilarities in mutual orientations of adjacent layers in these two structures, K6 Th6 (WO4 )14 O crystallizes in space group of R32 while Rb6 Th6 (WO4 )14 O stabilizes in P$?bar 6$2c. The high temperature phase transition was observed in Rb6 Th6 (WO4 )14 O and investigated using high-temperature PXRD technique. The results demonstrate a very unusual thermal behavior of this compound. The Raman and IR spectra of both phases were analyzed with respect to their complex structures. PMID- 25821079 TI - Relationship between cigarette smoking and one leg with eyes closed balance in Japanese men. AB - OBJECTIVE: To investigate the link between cigarette smoking and one leg with eyes closed balance in Japanese men. SUBJECTS AND METHODS: We used data from 4224 Japanese men, aged 43.3 +/- 13.9 years, in this cross-sectional study. Balance, such as one leg with eyes closed balance was measured. In addition, cigarette smoking habits were obtained by well-trained medical staff. The effect of cigarette smoking on one leg with eye closed balance was evaluated. RESULTS: A total of 1613 men (38.2 %) had smoking habit and 1471 men (34.8 %) regularly exercised. Age-related changes in one leg with eyes closed balance were noted. One leg with eyes closed balance in subjects with cigarette smoking (30.9 +/- 31.8 s) was significantly lower than those in subjects without cigarette smoking (32.4 +/- 33.5 s) even after adjusting for confounding factors i.e. age, body weight and exercise habits. CONCLUSION: Cigarette smoking might be associated with one leg with eyes closed balance in Japanese men. PMID- 25821082 TI - Ageing of out-of-equilibrium nanoalloys by a kinetic mean-field approach. AB - This study describes the ageing of bimetallic nanoparticles using a kinetic mean field method which provides the time evolution of the concentration for each site. We consider the cuboctahedron of 309 atoms in the Cu-Ag system, which is a prototype of systems with a strong tendency to phase separate. Starting from an initial homogenous configuration, we investigate the evolution towards the equilibrium configuration at different temperatures. Surprisingly, at low temperature, the kinetics exhibits a first transition towards an onion-like configuration followed by a second transition towards the equilibrium core-shell configuration. An analysis of the kinetics of the formation and then of the dissolution of the onion-like structure allows us to identify the main paths of the kinetic process. PMID- 25821081 TI - A novel HIF-1alpha-integrin-linked kinase regulatory loop that facilitates hypoxia-induced HIF-1alpha expression and epithelial-mesenchymal transition in cancer cells. AB - Here, we described a novel regulatory feedback loop in which hypoxia induces integrin-linked kinase (ILK) expression through a HIF-1alpha-dependent mechanism and ILK, in turn, stimulates HIF-1alpha expression through cell type- and cell context-dependent pathways. HIF-1alpha increased ILK via transcriptional activation. ILK increased HIF-1alpha levels by promoting mTOR-mediated translation in PC-3 and MCF-7 cells, and by blocking GSK3beta-mediated degradation in LNCaP cells, consistent with the cell line-/cellular context specific functions of ILK as a Ser473-Akt kinase. We show that ILK can account for the effects of hypoxia on Akt, mTOR, and GSK3beta phosphorylation. Also, ILK can de-repress HIF-1alpha signaling through the YB-1-mediated inhibition of Foxo3a expression. In concert with HIF-1alpha, these downstream effectors promote epithelial-mesenchymal transition (EMT) through modulation of Snail and Zeb1. Thus, the ILK-HIF-1alpha regulatory loop could underlie the maintenance of high HIF-1alpha expression levels and the promotion of EMT under hypoxic conditions. Finally, we show that the small-molecule ILK inhibitor T315 can disrupt this regulatory loop in vivo and suppress xenograft tumor growth, thereby providing proof-of-concept that targeting ILK represents an effective strategy to block HIF 1alpha expression and aggressive phenotype in cancer cells. PMID- 25821083 TI - Comparison of higher energy collisional dissociation and collision-induced dissociation MS/MS sequencing methods for identification of naturally occurring peptides in human urine. AB - PURPOSE: The aim of this study is to determine the best fragmentation method for sequence identification of naturally occurring urinary peptides in the field of clinical proteomics. EXPERIMENTAL DESIGN: We used LC-MS/MS analysis of urine samples to determine the analytical performance of higher energy collisional dissociation (HCD), CID with high and low resolution MS/MS for the identification of naturally occurring peptides in the low molecular weight urinary proteome. RESULTS: HCD and CID high-resolution generated a 22% error rate in peptide sequence identifications. CID low-resolution showed significantly higher error rates (37%). Excluding the error rate (i.e rejection of cysteine-containing peptides), we observed a higher degree of overlap between HCD and CID high resolution for identification of peptide sequences of rank 1 and cross correlation >= 1.9 (262 peptide sequences) compared to CID low (208 peptide sequences with HCD and 192 peptide sequences with CID high). Reproducibility of detected peptides in three out of the five replicates was also higher in HCD and CID high in relation to CID low resolution. CONCLUSION AND CLINICAL RELEVANCE: Our data demonstrated that HCD and CID high-resolution performed with better accuracy and reproducibility than CID low resolution in respect to the identification of naturally occurring urinary peptide sequences. PMID- 25821084 TI - A cactus-derived toxin-like cystine knot Peptide with selective antimicrobial activity. AB - Naturally occurring cystine knot peptides show a wide range of biological activity, and as they have inherent stability they represent potential scaffolds for peptide-based drug design and biomolecular engineering. Here we report the discovery, sequencing, chemical synthesis, three-dimensional solution structure determination and bioactivity of the first cystine knot peptide from Cactaceae (cactus) family: Ep-AMP1 from Echinopsis pachanoi. The structure of Ep-AMP1 (35 amino acids) conforms to that of the inhibitor cystine knot (or knottin) family but represents a novel diverse sequence; its activity was more than 500 times higher against bacterial than against eukaryotic cells. Rapid bactericidal action and liposome leakage implicate membrane permeabilisation as the mechanism of action. Sequence homology places Ec-AMP1 in the plant C6-type of antimicrobial peptides, but the three dimensional structure is highly similar to that of a spider neurotoxin. PMID- 25821085 TI - Erratum to: Atypical chronic myeloid leukemia with concomitant CSF3R T618I and SETBP1 mutations unresponsive to the JAK inhibitor ruxolitinib. PMID- 25821086 TI - Knee morphometric risk factors for acute anterior cruciate ligament injury in skeletally immature patients. AB - STUDY DESIGN: Retrospective, case-control. PURPOSE: Knee morphometric risk factors for noncontact anterior cruciate ligament (ACL) injury have been a popular topic with skeletally mature patients. Little research has focused on the skeletally immature, with conflicting conclusions. This study performs a comprehensive analysis of identified parameters thought to predispose to ACL injury in a skeletally immature cohort. METHODS: A retrospective review of pediatric patients undergoing knee magnetic resonance imaging (MRI) was performed over a 4-year period. Inclusionary criteria included mid-substance ACL disruption, skeletal immaturity, noncontact injury, without associated ligamentous disruption, and no medical condition associated with ligamentous laxity. MRI studies were analyzed by a pediatric musculoskeletal radiologist, measuring identified bony parameters, and compared with an age-matched control group without ligamentous injury. Data were analyzed using unpaired t-tests and logistic regression. RESULTS: One hundred and twenty-eight patients sustained an ACL disruption, 39 met all inclusionary criteria (66 excluded for associated ligamentous disruption, 23 skeletally mature, three traumatic mechanisms, one with Marfan syndrome). When compared to an age-matched control cohort, the notch width index (NWI) was found to be significantly smaller in the ACL-injured group (p = 0.046). Subgroups analysis demonstrated significant differences in morphometric parameters between subjects with isolated ACL injuries and concomitant medial collateral ligament (MCL) strain. CONCLUSIONS: The NWI was significantly smaller in the ACL injury group. Significant differences were noted between isolated ACL injuries and ACL injuries with an MCL strain. This study further highlights the need for incorporating associated injury patterns when investigating the influence of morphometric factors for ACL injury in the skeletally immature. LEVEL OF EVIDENCE: Level III. PMID- 25821087 TI - Evaluation of the ability of black nightshade Solanum nigrum L. for phytoremediation of thallium-contaminated soil. AB - Thallium (Tl) pollution in agricultural areas can pose hidden danger to humans, as food consumption is the key exposure pathway of Tl. Owing to the extreme toxicity of Tl, removal of Tl from soil becomes necessary to minimize the Tl related health effects. Phytoremediation is a cost-effective method to remove heavy metals from soil, but not all plants are appropriate for this purpose. Here, the ability of Solanum nigrum L., commonly known as black nightshade, to remediate Tl-contaminated soil was evaluated. The accumulation of Tl in different organs of S. nigrum was measured under both field and greenhouse conditions. Additionally, the growth and maximal quantum efficiency of photosystem II (Fv/Fm) under different Tl concentrations (1, 5, 10, 15, and 20 mg kg(-1)) were examined after 4-month pot culture. Under both field and greenhouse conditions, Tl accumulated in S. nigrum was positively correlated with Tl concentration in the soil. Thallium mostly accumulated in the root, and bioconcentration factor was greater than 1, indicating the good capability of S. nigrum to extract Tl. Nonetheless, the growth and Fv/Fm of S. nigrum were reduced at high Tl concentration (>10 mg kg(-1)). Given the good tolerance, fast growth, high accumulation, and global distribution, we propose that S. nigrum is a competent candidate to remediate moderately Tl-contaminated soil (<10 mg kg(-1)) without causing far-reaching ecological consequences. PMID- 25821088 TI - Prevalence and characteristics of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae isolated from rural well water in Taian, China, 2014. AB - The production of extended-spectrum beta-lactamase (ESBL) is one of the major antimicrobial resistance mechanisms in Enterobacteriaceae, and the increasing number of ESBL-producing Enterobacteriaceae isolated from water environments has posed a serious threat to the public health. The study aimed to analyze prevalence and characterization of ESBL-producing Enterobacteriaceae from rural well waters in Taian, China. A total of 10 isolates expressing an ESBL phenotype, including 9 Escherichia coli (E. coli) and 1 Klebsiella pneumoniae (K. pneumoniae) was obtained from 4 (4%) out of the 100 sampled wells. ESBL genotype revealed that 9 expressed CTX-M-15 and 1 produced CTX-M-27. Five out of 8 ESBL producing E. coli expressing CTX-M-15 belonged to ST10, which are mostly detected from human feces in China. Importantly, the only strain of CTX-M-27-producing E. coli belonged to multi-locus sequence type B2:131 (ST131), which may be related with severe infection in humans and animals. PMID- 25821089 TI - Generalized joint hypermobility, joint hypermobility syndrome and Ehlers-Danlos syndrome, hypermobility type. AB - This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to generalized joint hypermobility (gJHM), joint hypermobility syndrome (JHS), and Ehlers-Danlos syndrome, hypermobility type (EDS-HT). gJHM is the best known clinical manifestation of inherited defects of the connective tissue. On the other side, JHS and EDS-HT are actually considered one and the same from a clinical perspective by most practitioners and researchers (i.e., JHS/EDS-HT), and their molecular basis remains unknown. For decades, "non-syndromic" gJHM and JHS/EDS-HT have been thought to be simple clinical curiosities or an asset for the "affected" individual. In recent years, the attention on these partially overlapping phenotypes has increased, as they are now recognized risk factors for a series of non-communicable diseases and long-term disabilities. This series consists of 10 papers focused on three main topics, namely (i) assessment and differential diagnosis of children and adults with gJHM, (ii) systematic presentation of selected key non-articular manifestations of JHS/EDS-HT and actual perception of physiotherapy as the best therapeutic resource for this condition, and (iii) exploration of the available knowledge relating "congenital laxity of tissues" to various dysfunctions of the nervous system during development and adulthood. The contributors hope that this collection raises attention to this fascinating field of knowledge, which seems to have ramifications in virtually all medical disciplines. PMID- 25821090 TI - Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type compared to other heritable connective tissue disorders. AB - Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS HT) is an evolving and protean disorder mostly recognized by generalized joint hypermobility and without a defined molecular basis. JHS/EDS-HT also presents with other connective tissue features affecting a variety of structures and organs, such as skin, eye, bone, and internal organs. However, most of these signs are present in variable combinations and severity in many other heritable connective tissue disorders. Accordingly, JHS/EDS-HT is an "exclusion" diagnosis which needs the absence of any consistent feature indicative of other partially overlapping connective tissue disorders. While both Villefranche and Brighton criteria include such an exclusion as a mandatory item, a systematic approach for reaching a stringent clinical diagnosis of JHS/EDS-HT is still lacking. The absence of a consensus on the diagnostic approach to JHS/EDS-HT concerning its clinical boundaries with similar conditions contribute to limit our actual understanding of the pathologic and molecular bases of this disorder. In this review, we revise the differential diagnosis of JHS/EDS-HT with those heritable connective tissue disorders which show a significant overlap with the former and mostly include EDS classic, vascular and kyphoscoliotic types, osteogenesis imperfecta, Marfan syndrome, Loeys-Dietz syndrome, arterial tortuosity syndrome, and lateral meningocele syndrome. A diagnostic flow chart is also offered with the attempt to support the less experienced clinician in stringently recognizing JHS/EDS-HT and stimulate the debate in the scientific community for both management and research purposes. PMID- 25821091 TI - The neuromuscular differential diagnosis of joint hypermobility. AB - Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfan syndrome and various types of Ehlers-Danlos syndrome and these will generally be the first conditions to be considered by geneticists and pediatricians in the differential diagnosis of a patient presenting with such findings. However, several congenital and adult-onset inherited myopathies also present with joint hypermobility in the context of often only mild-to-moderate muscle weakness and should, therefore, be included in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within both groups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In this review we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups of disorders have in common, and subsequently discuss the clinical features of: 1) the most common connective tissue disorders with myopathic or other neuromuscular features: Ehlers-Danlos syndrome, Marfan syndrome and Loeys Dietz syndrome; 2) myopathy and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including collagen VI related dystrophies and FKBP14 related kyphoscoliotic type of Ehlers-Danlos syndrome; and 3) various (congenital) myopathies with prominent joint hypermobility including RYR1- and SEPN1-related myopathy. The aim of this review is to assist clinical geneticists and other clinicians with recognition of these disorders. PMID- 25821092 TI - Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers Danlos syndrome, hypermobility type. AB - Gastrointestinal involvement is a well known complication of Ehlers-Danlos syndromes (EDSs), mainly in form of abdominal emergencies due to intestinal/abdominal vessels rupture in vascular EDS. In the last decade, a growing number of works investigated the relationship between a wide spectrum of chronic gastrointestinal complaints and various EDS forms, among which the hypermobility type (a.k.a. joint hypermobility syndrome; JHS/EDS-HT) was the most studied. The emerging findings depict a major role for gastrointestinal involvement in the health status and, consequently, management of JHS/EDS-HT patients. Nevertheless, fragmentation of knowledge limits its impact on practice within the boundaries of highly specialized clinics. In this paper, literature review on gastrointestinal manifestations in JHS/EDS-HT was carried out and identified papers categorized as (i) case-control/cohort studies associating (apparently non-syndromic) joint hypermobility and gastrointestinal involvement, (ii) case-control/cohort studies associating JHS/EDS-HT and gastrointestinal involvement, (iii) case reports/series on various gastrointestinal complications in (presumed) JHS/EDS-HT, and (iv) studies reporting gastrointestinal features in heterogeneous EDS patients' cohorts. Gastrointestinal manifestations of JHS/EDS HT were organized and discussed in two categories, including structural anomalies (i.e., abdominal/diaphragmatic hernias, internal organ/pelvic prolapses, intestinal intussusceptions) and functional features (i.e., dysphagia, gastro esophageal reflux, dyspepsia, recurrent abdominal pain, constipation/diarrhea), with emphasis on practice and future implications. In the second part of this paper, a summary of possible nutritional interventions in JHS/EDS-HT was presented. Supplementation strategies were borrowed from data available for general population with minor modifications in the light of recent discoveries in the pathogenesis of selected JHS/EDS-HT features. PMID- 25821093 TI - Knowledge, assessment, and management of adults with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type among Flemish physiotherapists. AB - Physiotherapy plays a fundamental role in managing adults with the joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT). However, it is a challenge for both the patient and the physiotherapist as the condition is poorly understood and treatment for JHS/EDS-HT is currently undefined. Insight into current practice is, therefore, necessary in order to establish baseline knowledge in this area and in the long term to improve the standard of patient care. Therefore, the purpose of this study was to evaluate current physiotherapists' knowledge of JHS/EDS-HT and to gain insight into current physiotherapy practice with emphasis on assessment, management, and treatment efficacy. Three hundred twenty-five Flemish physiotherapists participated in the study by filling out electronically a modified version of the "Hypermobility and Hypermobility Syndrome Questionnaire" (HHQ), which covered theoretical constructs such as general knowledge, assessment, management, and learning in relation to generalized joint hypermobility and JHS/EDS-HT. The results show that physiotherapists report a low level of confidence with regard to assessment and management of JHS/EDS-HT. Knowledge of hypermobility and JHS/EDS-HT is weak, especially regarding the features associated with JHS/EDS-HT. Many treatment approaches are used by physiotherapists with the majority showing preference for education, reassurance, muscle strengthening, proprioceptive and core stability training. Almost all approaches were perceived as being clinically effective by the physiotherapists, highlighting a lack of consensus. In conclusion, this study in Flemish physiotherapists confirms that JHS/EDS-HT is under-recognized, not well known and deemed difficult to treat. Further education is required and sought by the physiotherapists surveyed, and future research is needed. PMID- 25821094 TI - Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers-Danlos syndrome, hypermobility type: The link between connective tissue and psychological distress revised. AB - Psychological distress is a known feature of generalized joint hypermobility (gJHM), as well as of its most common syndromic presentation, namely Ehlers Danlos syndrome, hypermobility type (a.k.a. joint hypermobility syndrome - JHS/EDS-HT), and significantly contributes to the quality of life of affected individuals. Most published articles dealt with the link between gJHM (or JHS/EDS HT) and anxiety-related conditions, and a novel generation of studies is emerging aimed at investigating the psychopathologic background of such an association. In this paper, literature review was carried out with a semi-systematic approach spanning the entire spectrum of psychopathological findings in gJHM and JHS/EDS HT. Interestingly, in addition to the confirmation of a tight link between anxiety and gJHM, preliminary connections with depression, attention deficit (and hyperactivity) disorder, autism spectrum disorders, and obsessive-compulsive personality disorder were also found. Few papers investigated the relationship with schizophrenia with contrasting results. The mind-body connections hypothesized on the basis of available data were discussed with focus on somatotype, presumed psychopathology, and involvement of the extracellular matrix in the central nervous system. The hypothesis of positive Beighton score and alteration of interoceptive/proprioceptive/body awareness as possible endophenotypes in families with symptomatic gJHM or JHS/EDS-HT is also suggested. Concluding remarks addressed the implications of the psychopathological features of gJHM and JHS/EDS-HT in clinical practice. PMID- 25821095 TI - Phenotypic variability in developmental coordination disorder: Clustering of generalized joint hypermobility with attention deficit/hyperactivity disorder, atypical swallowing and narrative difficulties. AB - Developmental coordination disorder (DCD) is a recognized childhood disorder mostly characterized by motor coordination difficulties. Joint hypermobility syndrome, alternatively termed Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT), is a hereditary connective tissue disorder mainly featuring generalized joint hypermobility (gJHM), musculoskeletal pain, and minor skin features. Although these two conditions seem apparently unrelated, recent evidence highlights a high rate of motor and coordination findings in children with gJHM or JHS/EDS-HT. Here, we investigated the prevalence of gJHM in 41 Italian children with DCD in order to check for the existence of recognizable phenotypic subgroups of DCD in relation to the presence/absence of gJHM. All patients were screened for Beighton score and a set of neuropsychological tests for motor competences (Movement Assessment Battery for Children and Visual-Motor Integration tests), and language and learning difficulties (Linguistic Comprehension Test, Peabody Picture Vocabulary Test, Boston Naming Test, Bus Story Test, and Memoria-Training tests). All patients were also screening for selected JHS/EDS-HT-associated features and swallowing problems. Nineteen (46%) children showed gJHM and 22 (54%) did not. Children with DCD and gJHM showed a significant excess of frequent falls (95 vs. 18%), easy bruising (74 vs. 0%), motor impersistence (89 vs. 23%), sore hands for writing (53 vs. 9%), attention deficit/hyperactivity disorder (89 vs. 36%), constipation (53 vs. 0%), arthralgias/myalgias (58 vs. 4%), narrative difficulties (74 vs. 32%), and atypical swallowing (74 vs. 18%). This study confirms the non-causal association between DCD and gJHM, which, in turn, seems to increase the risk for non-random additional features. The excess of language, learning, and swallowing difficulties in patients with DCD and gJHM suggests a wider effect of lax tissues in the development of the nervous system. PMID- 25821096 TI - The role of narrative medicine in the management of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. AB - Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS HT) is a hereditary connective tissue disorder affecting every bodily system. It is largely underdiagnosed by many practitioners, with the result of a considerable delay in diagnosis and, consequently, in the onset of adequate management schedule and treatment. Patients may also experience to be misbelieved, erroneously considered affected by a psychiatric or psychosomatic disorders, and rejected by the medical profession, which can lead to feelings of anger and resentment. Patient journeys are often long and complicated, but if doctors allowed the patient time to tell the full story, and were more prepared to think holistically, there may be a far more positive outcome. Here, the patients' perspective is presented with a narrative medicine approach, illustrating the tri-dimensional experience of a JHS/EDS-HT patient, who is also a Bowen Practitioner and a medical writer/educator. Narrative medicine would be invaluable in working with JHS/EDS-HT so that the patient can tell the story, and offer the practitioner a whole picture of her/his suffering and, often, the key for understanding the cause(s). Once this has been achieved, it might be possible to build upon a more positive and therapeutic dialogue which would result in better treatment and more effective management. It is also important for doctors to communicate with JHS/EDS-HT experts who will ultimately improve the patient journey and treatment outcomes of such a complex connective tissue disorder. PMID- 25821097 TI - Comparison between minimally invasive and open living donor hepatectomy: A systematic review and meta-analysis. AB - Living donor liver transplantation is a valid alternative to deceased donor liver transplantation, and its safety and feasibility have been well determined. Minimally invasive living donor hepatectomy (MILDH) has taken some time to be accepted because of inherent technical difficulties and the highly demanding surgical skills needed to perform the procedure, and its role is still being debated. Because of the lack of data, a systematic review and meta-analysis comparing MILDH and open living donor hepatectomy (OLDH) was performed. A systematic literature search was performed with PubMed, Embase, Scopus, and Cochrane Library Central. Treatment outcomes, including blood loss, operative time, hospital stay, analgesia use, donor-recipient morbidity and mortality, and donor procedure costs, were analyzed. There were 573 articles, and a total of 11, dated between 2006 and 2014, fulfilled the selection criteria and were, therefore, included. These 11 studies included a total of 608 adult patients. Blood loss [mean difference (MD) = -46.35; 95% confidence interval (CI) = -94.04 1.34; P = 0.06] and operative times [MD = 19.65; 95% CI = -4.28-43.57; P = 0.11] were comparable between the groups, whereas hospital stays (MD = -1.56; 95% CI = 2.63 to -0.49; P = 0.004), analgesia use (MD = -0.54; 95% CI = -1.04 to -0.03; P = 0.04), donor morbidity rates [odds ratio (OR) = 0.62; 95% CI = 0.40-0.98; P = 0.04], and wound-related complications (OR = 0.41; 95% CI = 0.17-0.97; P = 0.04) were significantly reduced in MILDH. MILDH for right liver procurement was associated with a significantly reduced hospital stay (OR = -0.92; 95% CI = 0.17 0.97; P = 0.04). In conclusion, MILDH is associated with intraoperative results that are comparable to results for OLDH and with surgical outcomes that are no worse than those for the open procedure. PMID- 25821098 TI - High Dose Proton Pump Inhibitor Infusion Versus Bolus Injection for the Prevention of Bleeding After Endoscopic Submucosal Dissection: Prospective Randomized Controlled Study. AB - BACKGROUND: A high dose of continuous intravenous infusion of proton pump inhibitor (PPI) is the standard treatment for peptic ulcer bleeding. The optimal dose for the prevention of bleeding after endoscopic submucosal dissection (ESD) is unclear. AIM: The purpose of this study was to determine whether stronger acid suppression more effectively prevents bleeding and high risk ulcer stigma (HRS) after gastric ESD. METHODS: A total of 273 patients who underwent ESD were randomly assigned to one of two treatment groups: the continuous infusion group and the bolus injection group. Second-look endoscopy was performed on the following day after ESD. The incidences and risk factors of HRS identified by second-look endoscopy and delayed bleeding were analyzed. RESULTS: There were no differences in the incidences of HRS and delayed bleeding between two treatment groups. The incidence of HRS was 15.8 % (43/273) and the gross morphology (flat or depressed) was identified as a significant factor associated with HRS. The incidence of delayed bleeding was 8.4 % (23/273) and the gross morphology (flat) and the presence of submucosal invasive cancer were identified as the associated risk factors for delayed bleeding. CONCLUSION: The incidences of delayed bleeding and HRS identified by second-look endoscopy were not affected by PPI infusion methods. Flat or depressed morphologic lesions and submucosal invasive cancer should be closely monitored. PMID- 25821099 TI - Poor Sustained Virological Response in a Multicenter Real-Life Cohort of Chronic Hepatitis C Patients Treated with Pegylated Interferon and Ribavirin plus Telaprevir or Boceprevir. AB - BACKGROUND: There are limited data analyzing the effectiveness of boceprevir (BOC) or telaprevir (TVR) in combination with pegylated interferon (PEG-IFN) plus ribavirin (RBV) in a real-life patient cohort. AIMS: In clinical trials, patients with chronic hepatitis C (CHC) treated with BOC or TVR plus PEG-IFN and RBV achieved sustained virological response (SVR) rates of 70 %. However, it is not clear whether similar results can be realized in routine practice. Our goal is to examine SVR rates of these triple regimens for CHC in a multicenter real-life patient cohort. METHODS: We retrospectively studied 200 consecutive CHC genotype 1 patients who were initiated on PEG-IFN, RBV, and either TVR (n = 113) or BOC (n = 87) from July 2011 to February 2014 at two US academic liver clinics, a Veterans Affairs liver clinic and a community gastroenterology clinic. RESULTS: Both BOC and TVR treatment groups were similar in regard to comorbidities, BMI, and HCV RNA levels. BOC patients were more likely to have cirrhosis than TVR patients (47 vs. 24 %, P = 0.001). SVR rates were low in both cohorts (40 % for BOC, 53 % for TVR, P = 0.05). On multivariate logistic regression, treatment adherence by the "80/80/80 rule," diagnosis of cirrhosis, and use of erythropoietin were statistically significant predictors for SVR. Of these, treatment adherence was the strongest predictor (OR 4.43, 95 % CI 2.8-6.06, P < 0.001). CONCLUSION: SVR was much lower in a real-life patient cohort than in clinical trials (53 % for TVR and 40 % for BOC, compared to 66-75 % in clinical trials). PMID- 25821100 TI - Laparoscopic Extraction of a Hepatic Fish Bone Mimicking a Liver Mass After Gastric Perforation. PMID- 25821101 TI - Gastrointestinal Pathologic Abnormalities in Pediatric- and Adult-Onset Common Variable Immunodeficiency. AB - BACKGROUND: Common variable immunodeficiency is the most common form of primary symptomatic immunodeficiency. Gastrointestinal manifestations, such as gastritis, diarrhea, gastrointestinal infections, and malabsorption, may complicate the clinical history in almost 50 % of patients. AIM: To evaluate gastrointestinal histopathological findings in pediatric- and in adult-onset common variable immunodeficiency patients. METHODS: Twenty-two patients with common variable immunodeficiency (13 children, nine adults) were retrospectively studied from a clinical and histopathological point of view. RESULTS: Increased T lymphocyte infiltrate and the absence of plasma cells in duodenal lamina propria and submucosa were the most frequent findings, independently from onset age, whereas follicular lymphoid hyperplasia and polymorphonuclear infiltrate, as well as parasitic and viral infections, were only present in the adult group. Common variable immunodeficiency patients with minor gastrointestinal symptoms also presented pathological findings, mainly the absence of plasma cells, T cell infiltrate, and infections, independently of age. CONCLUSIONS: Gastrointestinal pathological abnormalities are common in both pediatric- and adult-onset common variable immunodeficiency patients. Histological alterations may vary depending upon the age of onset, possibly due to duration of disease. Minor gastrointestinal symptoms are also associated with pathological findings; therefore, these should be searched in all symptomatic patients. PMID- 25821102 TI - HIV therapy-the state of art. AB - HIV Attachment. In this cross section, HIV is shown at the top and a target cell is shown at the bottom in blues. HIV envelope protein (A) has bound to the receptor CD4 (B) and then to coreceptor CCR5 (C), causing a change in conformation that inserts fusion peptides into the cellular membrane Antiretroviral therapy changed the face of HIV/AIDS from that of soon and certain death to that of a chronic disease in the years following introduction of highly active antiretroviral therapy in 1995-1996 (initially termed HAART, but now most often abbreviated to ART since not all combinations of regimens are equally active). Since then, many new agents have been developed and introduced in response to problems of resistance, toxicity, and tolerability, and great advances have been achieved in accessibility of HIV drugs in resource-poor global regions. Potential challenges that providers of HIV therapy will face in the coming decade include continuing problems with resistance, especially where access to drugs is inconsistent, determining how best to combine new and existing agents, defining the role of preventive treatment (pre-exposure prophylaxis or PrEP), and evaluating the potential of strategies for cure in some populations. PMID- 25821103 TI - Posterior trunk reconstruction with the dorsal intercostal artery perforator based flap: Clinical experience on 20 consecutive oncological cases. AB - BACKGROUND: Few studies in the recent literature have investigated the reliability of dorsal intercostal artery perforator (DICAP) flap in posterior trunk reconstruction. The purpose of this report is to describe our clinical experience with the use of DICAP flaps in a cohort of oncological patients. PATIENTS AND METHODS: Twenty patients underwent posterior trunk reconstruction with DICAP based flaps. Patients age ranged from 45 to 76 years. All defects resulted from skin cancer ablation. Defect sizes ranged from 4 * 4 to 6 * 8 cm. The flaps were mobilized in V-Y or propeller fashion. The flaps were islanded on 1 (12 cases), 2 (6 cases), or 3 (2 cases) perforators. Donor sites were always closed primarily. RESULTS: Eleven V-Y advancement flaps were performed; one of these was converted to a perforator-plus peninsular flap design, which retained an additional source of blood supply from the opposite skin bridge. Nine flaps were mobilized in propeller fashion. Flap dimensions ranged from 4 * 6 to 6 * 14 cm. Mean operative time was 70 min. One V-Y flap complicated with marginal necrosis that healed with no need for reintervention. All the other flaps survived uneventfully. No other complications were observed at recipient and donor sites. Follow-up ranged from 3 months to 2 years. All the patients were satisfied with the surgical outcome. CONCLUSIONS: DICAP based flaps proved to be a reliable option to resurface posterior trunk defects following oncological resection, allowing to achieve like-with-like reconstruction with excellent contour and minimal donor-site morbidity. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:546-551, 2016. PMID- 25821104 TI - Functional evidence of paraventricular nucleus involvement in cardiovascular and autonomic modulation in response to acute microgravity (head-down tilt) in unanesthetized rats. AB - Exposure to microgravity induces autonomic and vestibular disorders such as alterations in cardiovascular function. The paraventricular nucleus of the hypothalamus (PVN) is known to be an important center for integrating autonomic and cardiovascular responses as blood volume reflexes. The acute effects promoted by microgravity and PVN involvement in cardiovascular and autonomic parameters have not yet been evaluated. Male Wistar rats were anesthetized to facilitate cannulae implantation in the PVN. After 3 days of surgical recovery, femoral artery and vein catheters were implanted for direct recording of blood pressure and heart rate (HR) in conscious animals to evaluate cardiovascular and autonomic changes in an acute protocol of head-down tilt (HDT) in nonanesthetized rats. During HDT, there was an increase in mean arterial pressure (11 +/- 1 mmHg, P < 0.05) and a decrease in HR (-28 +/- 5 bpm, P < 0.05). Spectral analysis of systolic arterial pressure showed an increase in the low-frequency (LF) component. In addition, HDT induced a reduction in the LF component and an increase in the high-frequency (HF) component of the pulse interval (PI). PVN inhibition with muscimol reversed bradycardia and blocked the reduction of the LF and HF increases in PI during HDT. These results suggest that the PVN participates in the cardiovascular compensation during HDT, especially modulating cardiac responses. PMID- 25821105 TI - Impact of nanosizing on solubility and dissolution rate of poorly soluble pharmaceuticals. AB - The quantitative determination of solubility and the initial dissolution rate enhancement of crystalline nanoparticles were critically investigated using a separation-based approach (ultracentrifugation and filtration). Four poorly soluble model compounds (griseofulvin, celecoxib, compound-X, and fenofibrate) were used in this investigation. The effect of the stabilizer concentration on the solubility of the unmilled compound was determined first to quantify its impact on the solubility and used for comparing solubility enhancement upon nanosizing. Methodologies were established for ultracentrifugation, ensuring satisfactory separation of crystalline nanoparticles. The data obtained using separation-based methodologies proved to be accurate, reproducible, and were in fair agreement with what would be predicted from the Ostwald-Freundlich equation. The dissolution studies under sink conditions were proved to be less efficient in quantifying the initial dissolution rate of crystalline nanoparticles. Nonsink dissolution experiments were able to reduce the high-dissolution velocity of nanoparticles and generated the best discriminative dissolution profile. The enhancement in initial dissolution rate was significantly less than that expected from the Noyes-Whitney equation based on surface area change. This discriminatory dissolution method can potentially be used further in the modeling of crystalline nanoparticles during drug development. PMID- 25821106 TI - Publisher Notice. PMID- 25821107 TI - PI3K/AKT pathway-mediated regulation of p27(Kip1) is associated with cell cycle arrest and apoptosis in cervical cancer. AB - BACKGROUND: The cyclin-dependent kinase inhibitor p27(Kip1) is known to act as a putative tumor suppressor in several human cancers, including cervical cancer. Down-regulation of p27(Kip1) may occur either through transcription inhibition or through phosphorylation-dependent proteolytic degradation. As yet, the mechanism underlying p27(Kip1) down-regulation and its putative downstream effects on cervical cancer development are poorly understood. Here we assessed the expression and sub-cellular localization of p27(Kip1) and its effects on proliferation, cell cycle progression and (inhibition of) apoptosis in cervical cancer cells. METHODS: Primary cervical cancer samples (n = 70), normal cervical tissue samples (n = 30) and cervical cancer-derived cell lines (n = 8) were used to assess the expression of p27(Kip1) and AKT1 by RT-PCR, Western blotting and immunohistochemistry, respectively. The effects of the PI3K inhibitor LY294004 and the proteasome inhibitor MG132 on cervical cancer cell proliferation were investigated using a MTT assay. Apoptosis and cell cycle analyses were carried out using flow cytometry, and sub-cellular p27(Kip1) localization analyses were carried out using immunofluorescence assays. RESULTS: We observed p27(Kip1) down regulation (p = 0.045) and AKT1 up-regulation (p = 0.046) in both the primary cervical cancer samples and the cervical cancer-derived cell lines, compared to the normal cervical tissue samples tested. Treatment of cervical cancer-derived cell lines with the PI3K inhibitor LY294002 resulted in a reduced AKT1 activity. We also observed a dose-dependent inhibition of cell viability after treatment of these cell lines with the proteasome inhibitor MG132. Treatment of the cells with LY294002 resulted in a G1 cell cycle arrest, a nuclear expression of p27(Kip1), and a cytoplasmic p27(Kip1) accumulation after subsequent treatment with MG132. Additionally, we found that the synergistic effect of MG132 and LY294002 resulted in a sub-G1 cell cycle arrest and apoptosis induction through poly (ADP-ribose) polymerase (PARP) cleavage. CONCLUSION: Our data suggest that p27(Kip1) down regulation in cervical cancer cells is primarily regulated through PI3K/AKT mediated proteasomal degradation. The observed synergistic effect of the MG132 and LY294002 inhibitors may form a basis for the design of novel cervical cancer therapies. PMID- 25821108 TI - Chemotherapy induced nausea and vomiting in bone marrow transplant: the unmet need. PMID- 25821109 TI - Determination of multi-pesticide residue in tobacco using multi-walled carbon nanotubes as a reversed-dispersive solid-phase extraction sorbent. AB - A multi-pesticide residue determination method based on a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method using multiwalled carbon nanotubes as reversed-dispersive solid-phase extraction material was validated in 37 representative pesticides in tobacco. Determination was performed using liquid chromatography with tandem mass spectrometry in multiple reaction monitoring mode. Three major types of tobacco leaf samples, namely, flue-cured, burley, and oriental tobacco were studied and compared. Three factors (extraction time, external diameter, and amount of extraction material used) that could affect the performance of multi-walled carbon nanotubes were investigated. Optimization of sample preparation and determination allowed recoveries between 70.8 and 114.8% for all 37 pesticides with < 20.0% relative standard deviations at three spiking levels of 20, 50, and 200 MUg/kg. The limits of quantification and limits of detection for the 37 pesticides ranged within 0.46-28.57 and 0.14-8.57 MUg/kg at a signal-to-noise ratio of 10 and 3, respectively. PMID- 25821111 TI - Effect of the Mitral Valve's Anterior Leaflet on Axisymmetry of Transmitral Vortex Ring. AB - The shape and formation of transmitral vortex ring are shown to be associated with diastolic function of the left ventricle (LV). Transmitral vortex ring is a flow feature that is observed to be non-axisymmetric in a healthy heart and its inherent asymmetry in the LV assists in efficient ejection of the blood during systole. This study is a first step towards understanding the effects of the mitral valve's anterior leaflet on transmitral flow. We experimentally study a single-leaflet model of the mitral valve to investigate the effect of the anterior leaflet on the axisymmetry of the generated vortex ring based on the three-dimensional data acquired using defocusing digital particle image velocimetry. Vortex rings form downstream of a D-shaped orifice in presence or absence of the anterior leaflet in various physiological stroke ratios. The results of the statistical analysis indicate that the formed vortex ring downstream of a D-shaped orifice is markedly non-axisymmetric, and presence of the anterior leaflet improves the ring's axisymmetry. This study suggests that the improvement of axisymmetry in presence of the anterior leaflet might be due to coupled dynamic interaction between rolling-up of the shear layer at the edges of the D-shaped orifice and the borders of the anterior leaflet. This interaction can reduce the non-uniformity in vorticity generation, which results in more axisymmetric behavior compared to the D-shaped orifice without the anterior leaflet. PMID- 25821110 TI - Sensation-to-cognition cortical streams in attention-deficit/hyperactivity disorder. AB - We sought to determine whether functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits are atypical in attention deficit/hyperactivity disorder (ADHD). We applied a graph-theory method to the resting-state functional magnetic resonance imaging data of 120 children with ADHD and 120 age-matched typically developing children (TDC). Starting in unimodal primary cortex-visual, auditory, and somatosensory-we used stepwise functional connectivity to calculate functional connectivity paths at discrete numbers of relay stations (or link-step distances). First, we characterized the functional connectivity streams that link sensory, attentional, and higher-order cognitive circuits in TDC and found that systems do not reach the level of integration achieved by adults. Second, we searched for stepwise functional connectivity differences between children with ADHD and TDC. We found that, at the initial steps of sensory functional connectivity streams, patients display significant enhancements of connectivity degree within neighboring areas of primary cortex, while connectivity to attention-regulatory areas is reduced. Third, at subsequent link-step distances from primary sensory cortex, children with ADHD show decreased connectivity to executive processing areas and increased degree of connections to default mode regions. Fourth, in examining medication histories in children with ADHD, we found that children medicated with psychostimulants present functional connectivity streams with higher degree of connectivity to regions subserving attentional and executive processes compared to medication-naive children. We conclude that predominance of local sensory processing and lesser influx of information to attentional and executive regions may reduce the ability to organize and control the balance between external and internal sources of information in ADHD. PMID- 25821113 TI - Design, Fabrication, and In Vitro Testing of an Anti-biofouling Glaucoma Micro shunt. AB - Glaucoma, one of the leading causes of irreversible blindness, is a progressive neurodegenerative disease. Chronic elevated intraocular pressure (IOP), a prime risk factor for glaucoma, can be treated by aqueous shunts, implantable devices, which reduce IOP in glaucoma patients by providing alternative aqueous outflow pathways. Although initially effective at delaying glaucoma progression, contemporary aqueous shunts often lead to numerous complications and only 50% of implanted devices remain functional after 5 years. In this work, we introduce a novel micro-device which provides an innovative platform for IOP reduction in glaucoma patients. The device design features an array of parallel micro-channels to provide precision aqueous outflow resistance control. Additionally, the device's microfluidic channels are composed of a unique combination of polyethylene glycol materials in order to provide enhanced biocompatibility and resistance to problematic channel clogging from biofouling of aqueous proteins. The microfabrication process employed to produce the devices results in additional advantages such as enhanced device uniformity and increased manufacturing throughput. Surface characterization experimental results show the device's surfaces exhibit significantly less non-specific protein adsorption compared to traditional implant materials. Results of in vitro flow experiments verify the device's ability to provide aqueous resistance control, continuous long-term stability through 10-day protein flow testing, and safety from risk of infection due to bacterial ingression. PMID- 25821112 TI - Patient-Specific Airway Wall Remodeling in Chronic Lung Disease. AB - Chronic lung disease affects more than a quarter of the adult population; yet, the mechanics of the airways are poorly understood. The pathophysiology of chronic lung disease is commonly characterized by mucosal growth and smooth muscle contraction of the airways, which initiate an inward folding of the mucosal layer and progressive airflow obstruction. Since the degree of obstruction is closely correlated with the number of folds, mucosal folding has been extensively studied in idealized circular cross sections. However, airflow obstruction has never been studied in real airway geometries; the behavior of imperfect, non-cylindrical, continuously branching airways remains unknown. Here we model the effects of chronic lung disease using the nonlinear field theories of mechanics supplemented by the theory of finite growth. We perform finite element analysis of patient-specific Y-branch segments created from magnetic resonance images. We demonstrate that the mucosal folding pattern is insensitive to the specific airway geometry, but that it critically depends on the mucosal and submucosal stiffness, thickness, and loading mechanism. Our results suggests that patient-specific airway models with inherent geometric imperfections are more sensitive to obstruction than idealized circular models. Our models help to explain the pathophysiology of airway obstruction in chronic lung disease and hold promise to improve the diagnostics and treatment of asthma, bronchitis, chronic obstructive pulmonary disease, and respiratory failure. PMID- 25821114 TI - Size and shape characterization of hydrated and desiccated exosomes. AB - Exosomes are stable nanovesicles secreted by cells into the circulation. Their reported sizes differ substantially, which likely reflects the difference in the isolation techniques used, the cells that secreted them, and the methods used in their characterization. We analyzed the influence of the last factor on the measured sizes and shapes of hydrated and desiccated exosomes isolated from the serum of a pancreatic cancer patient and a healthy control. We found that hydrated exosomes are close-to-spherical nanoparticles with a hydrodynamic radius that is substantially larger than the geometric size. For desiccated exosomes, we found that the desiccated shape and sizing are influenced by the manner in which drying occurred. Isotropic desiccation in aerosol preserves the near-spherical shape of the exosomes, whereas drying on a surface likely distorts their shapes and influences the sizing results obtained by techniques that require surface fixation prior to analysis. PMID- 25821115 TI - Improved detection of beta-N-methylamino-L-alanine using N-hydroxysuccinimide ester of N-butylnicotinic acid for the localization of BMAA in blue mussels (Mytilus edulis). AB - beta-N-Methylamino-L-alanine (BMAA) is an important non-protein amino acid linked to neurodegenerative diseases, specifically amyotrophic lateral sclerosis (ALS). Because it can be transferred and bioaccumulated higher up the food chain, it poses significant public health concerns; thus, improved detection methods are of prime importance for the identification and management of these toxins. Here, we report the successful use of N-hydroxysuccinimide ester of N-butylnicotinic acid (C4-NA-NHS) for the efficient separation of BMAA from its isomers and higher sensitivity in detecting BMAA compared to the current method of choice using 6 aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) derivatization. Implementation of this efficient method allowed localization of BMAA in the non visceral tissues of blue mussels, suggesting that more efficient depuration may be required to remove this toxin prior to consumption. This is a crucial method in establishing the absence or presence of the neurotoxic amino acid BMAA in food, environmental or biomedical samples. PMID- 25821116 TI - Characterization of DNA in cell culture supernatant by fluorescence-detection size-exclusion chromatography. AB - A fluorescence-detection size-exclusion chromatography (FSEC) method was developed to characterize DNA in cell culture supernatant. Samples stained with Picogreen were fractionated by size-exclusion chromatography (SEC) and monitored simultaneously by UV absorbance and fluorescence. SEC provided a size characterization capability absent from bulk fluorescent assays, and was also free from interference from other fluorescent and UV-absorbing small-molecule cell culture components. FSEC revealed that DNA in mammalian cell culture supernatant exists mostly in the form of nucleosomal arrays. FSEC combined with agarose electrophoresis revealed spontaneous degradation of DNA in mammalian cell culture supernatant over a 30 day period at 4 degrees C: from arrays containing up to ~40 nucleosomes, down to arrays containing three or fewer nucleosomes. It also detected nucleosomal DNA in wheat, soy, and yeast hydrolysates commonly used to enhance cell culture productivity. PMID- 25821117 TI - F2RL3 methylation, lung cancer incidence and mortality. AB - Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age- and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were <=0.54 compared with whose methylation intensity were >=0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants>=65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics = 0.86 for participants>=65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration. PMID- 25821118 TI - Structural aspects of a protein-surfactant assembly: native and reduced States of human serum albumin. AB - The inherently present seventeen disulfide bonds of the circulatory protein, human serum albumin (HSA) provide the necessary structural stability. Various spectroscopic approaches were used to investigate the effect of reduction of these disulfide bonds and its binding with the anionic surfactant, sodium dodecyl sulfate (SDS). Based on several spectroscopic analyses, our investigations highlight the following interesting aspects: (1) HSA on reduction loses not only its tertiary structure but also a significant amount of secondary structure as well. However, the reduced state of the protein is not like the molten-globule, (2) this structural loss of the protein due to reduction is more prominent than that caused by higher SDS concentrations alone and can certainly be attributed to the role of disulfide bonds, (3) lower surfactant concentrations provide marginal structural rigidity to the native state of the protein, whereas, higher concentrations of SDS induces secondary structure to the reduced state of HSA, (4) the binding of SDS with both the native and reduced states of HSA, occurred in three distinct stages which was followed by a saturation stage. However, the nature of such binding is different for both the states as investigated by using the Stern-Volmer equations and estimating the thermodynamic parameters. Besides, in contrast to the native state, the reduced state of HSA shows that the lone tryptophan residue gets more buried. However, there occurs a sudden decrement in the lifetime of the tryptophan and the hydrodynamic diameter increases by twofold. PMID- 25821119 TI - Use of the pedicled nasoseptal flap in the endoscopic management of cholesterol granulomas of the petrous apex. AB - BACKGROUND: Nowadays the endoscopic approach represents a useful alternative to traditional surgical approaches in the treatment of cholesterol granulomas (CGs) of the petrous apex (PA). Recently the nasoseptal flap (NSF) has been employed to permit long-term patency of drainage site. The purpose of this study is to report our experience with the NSF in the endoscopic management of CG and to analyze the advantages, limitations, and outcomes of the technique. METHODS: A retrospective analysis was carried out on 10 patients affected by CG of the PA who had been treated endoscopically, using the NSF. RESULTS: An endoscopic transpterygoid approach was used for 6 patients and the remaining 4 were treated using the transclival approach. A NSF was used in all 10 cases. In 6 cases the flap was ipsilateral to the lesion whereas in 4 it was contralateral. In 90% of our patients no evidence of disease was observed after a mean follow-up period of 35.7 months, with resolution of their symptoms. One patient presented a recurrence because of a technical error (inadequate placement of the flap in the cavity), and has been retreated endoscopically. CONCLUSION: The pedicled NSF seems to be helpful in avoiding the concentric growth of the granulomatous cyst epithelium while assuring ventilation and drainage of the cyst. However, bigger studies with longer-term follow-up are needed to confirm these findings. Correct and meticulous placement of the flap inside the cystic cavity is the most critical issue for the success of the procedure. PMID- 25821120 TI - Efficient approach to 2-hydroxy-2,3-dihydrofuran derivatives and its application for the synthesis of novel 4-(1H-pyrazol-4-yl)pyridazines. AB - A highly efficient method for the synthesis of 2-hydroxy-2,3-dihydrofuran derivatives from 1,4-enediones and phenacyl pyridinium halides via a domino reaction has been developed. This is a simple and beneficial strategy for the construction of 2-hydroxy-2,3-dihydrofuran compounds from readily available starting materials under mild conditions. Moreover, the application of this reaction provides a straightforward and practical route for the synthesis of the novel 4-(1H-pyrazol-4-yl)pyridazine skeleton. PMID- 25821121 TI - Bed rest in singleton pregnancies for preventing preterm birth. AB - BACKGROUND: Bed rest in hospital or at home is widely recommended for the prevention of preterm birth. This advice is based on the observation that hard work and hard physical activity during pregnancy could be associated with preterm birth and with the idea that bed rest could reduce uterine activity. However, bed rest may have some adverse effects on other outcomes. OBJECTIVES: To evaluate the effect of prescription of bed rest in hospital or at home for preventing preterm birth in pregnant women at high risk of preterm birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 December 2014), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 12), MEDLINE (December 2014), EMBASE (December 2014), LILACS (December 2014), and bibliographies of relevant papers. SELECTION CRITERIA: Randomized, cluster-randomized and quasi-randomized controlled trials with reported data that assess clinical outcomes in women at high risk of spontaneous preterm birth who were prescribed bed rest in hospital or at home for preventing preterm birth, and their babies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. MAIN RESULTS: Two studies met the inclusion criteria. One study was not considered for the meta-analysis, since data combined singleton and multiple pregnancies. No differences in any maternal and perinatal outcomes were reported by the authors. This study was at low risk of selection, performance, detection and attrition bias. Only data from one study were included in the meta-analysis (1266 women). This study was at unclear risk of bias for most domains due to lack of reporting. Four hundred and thirty-two women were prescribed bed rest at home and a total of 834 women received a placebo (412) or no intervention (422). Preterm birth before 37 weeks was similar in both groups (7.9% in the intervention group versus 8.5% in the control group; risk ratio (RR) 0.92, 95% confidence interval (CI) 0.62 to 1.37). No other results were reported for any of the other primary or secondary outcomes. AUTHORS' CONCLUSIONS: There is no evidence, either supporting or refuting the use of bed rest at home or in hospital, to prevent preterm birth. Although bed rest in hospital or at home is widely used as the first step of treatment, there is no evidence that this practice could be beneficial. Due to the potential adverse effects that bed rest could have on women and their families, and the increased costs for the healthcare system, clinicians should discuss the pros and cons of bed rest to prevent preterm birth. Potential benefits and harms should be discussed with women facing an increased risk of preterm birth. Appropriate research is mandatory. Future trials should evaluate both the effectiveness of bed rest, and the effectiveness of the prescription of bed rest, to prevent preterm birth. PMID- 25821122 TI - Interlocking membrane/catalyst layer interface for high mechanical robustness of hydrocarbon-membrane-based polymer electrolyte membrane fuel cells. AB - A physical interlocking interface that can tightly bind a sulfonated poly(arylene ether sulfone) (SPAES) membrane and a Nafion catalyst layer in polymer electrolyte fuel cells is demonstrated. Owing to higher expansion with hydration for SPAES than for Nafion, a strong normal force is generated at the interface of a SPAES pillar and a Nafion hole, resulting in an 8-fold increase of the interfacial bonding strength at RH 50% and a 4.7-times increase of the wet/dry cycling durability. PMID- 25821123 TI - Genotoxic effects of the antimalarial drug lumefantrine in human lymphocytes in vitro and computational prediction of the mechanism associated with its interaction with DNA. AB - Lumefantrine (LF) is an aryl-amino alcohol antimalarial drug used in artemisinin based combination therapies against malaria worldwide. In this study, we investigated the genotoxic effects of LF in human lymphocytes in vitro, and the potential noncovalent interaction of LF with DNA using a 3D DNA-docking model. The number of DNA breaks and the frequency of nuclear buds (NBUDS) was significantly increased (P < 0.01 and P < 0. 05, respectively) at LF concentrations of 60, 80, and 100 ug/mL (LF60, LF80, and LF100, respectively). Frequency (0/00) of micronuclei (MN) formation also increased after LF treatments. However, this was only significant for LF100 (P = 0.01) and LF80 (P = 0.001). LF did not affect the frequency of nucleoplasmic bridges (NPBs) (P = 0.12) or the nuclear division index (NDI) (P = 0.32). Computational analysis suggests that LF may interact noncovalently with DNA via the DNA minor groove surface with a predicted binding affinity energy of -7.2 kcal/mol and showing a favorable shape complementary to this groove. Our results suggest that LF has clastogenic effects in human lymphocytes in vitro due to noncovalent interaction with the minor groove of DNA. PMID- 25821124 TI - Magnetocaloric effect and thermal conductivity of Gd(OH)3 and Gd2O(OH)4(H2O)2. AB - Magnetocaloric effect (MCE) and thermal conductivity of two gadolinium hydroxides, Gd(OH)3 (1) and Gd2O(OH)4(H2O)2 (2), are investigated. Magnetic studies indicate that both 1 and 2 exhibit antiferromagnetic interaction, and the MCE values for 1 and 2 at 2 K and DeltaH = 7 T are 62.00 J kg(-1) K(-1) and 59.09 J kg(-1) K(-1), respectively. Investigation of their thermal conductivity reveals that the thermal conductivity for 1 is significantly better than that for 2. PMID- 25821125 TI - Identification of a novel unpaired histidine sensor kinase affecting secondary metabolism and morphological differentiation in Streptomyces acidiscabies ATCC 49003. AB - Two-component systems (TCSs) are an important signaling transduction pathway that adapt to changing environments. Commonly, a TCS comprises a sensor kinase that is usually an integral membrane histidine sensor kinase and a response regulator that mediates the cellular responses. Presently, however, we cloned a novel sensor kinase gene (tcsK) that is not adjacent to its cognate response regulator from Streptomyces acidiscabies that produces two secondary metabolites, thaxtomin A and WS5995B, and identified its functional involvement in the production of secondary metabolites and morphological differentiation. The elevated expression and disruption of the tcsK gene enhanced 7.1-fold and almost abolished WS5995B production in S. acidiscabies, respectively, but did not affect the production of thaxtomin A. In addition, spore formation of S. acidiscabies was decreased 120 fold by the disruption of tcsK, and the actinorhodin production of Streptomyces lividans TK24 was increased 5.7-fold by the high expression of tcsK. These results indicate that the novel unpaired tcsK gene may be related to the control of secondary metabolite production and spore formation in actinomycetes. PMID- 25821126 TI - Disentangling Complex Mixtures of Compounds with Near-Identical (1) H and (13) C NMR Spectra using Pure Shift NMR Spectroscopy. AB - The thorough analysis of highly complex NMR spectra using pure shift NMR experiments is described. The enhanced spectral resolution obtained from modern 2D HOBS experiments incorporating spectral aliasing in the (13) C indirect dimension enables the distinction of similar compounds exhibiting near-identical (1) H and (13) C NMR spectra. It is shown that a complete set of extremely small Deltadelta((1) H) and Deltadelta((13) C) values, even below the natural line width (1 and 5 ppb, respectively), can be simultaneously determined and assigned. PMID- 25821127 TI - Head and neck cancer subtypes with biological and clinical relevance: Meta analysis of gene-expression data. AB - Head and neck squamous cell carcinoma (HNSCC) is a disease with heterogeneous clinical behavior and response to therapies. Despite the introduction of multimodality treatment, 40-50% of patients with advanced disease recur. Therefore, there is an urgent need to improve the classification beyond the current parameters in clinical use to better stratify patients and the therapeutic approaches. Following a meta-analysis approach we built a large training set to whom we applied a Disease-Specific Genomic Analysis (DSGA) to identify the disease component embedded into the tumor data. Eleven independent microarray datasets were used as validation sets. Six different HNSCC subtypes that summarize the aberrant alterations occurring during tumor progression were identified. Based on their main biological characteristics and de-regulated signaling pathways, the subtypes were designed as immunoreactive, inflammatory, human papilloma virus (HPV)-like, classical, hypoxia associated, and mesenchymal. Our findings highlighted a more aggressive behavior for mesenchymal and hypoxia associated subtypes. The Genomics Drug Sensitivity Project was used to identify potential associations with drug sensitivity and significant differences were observed among the six subtypes. To conclude, we report a robust molecularly defined subtype classification in HNSCC that can improve patient selection and pave the way to the development of appropriate therapeutic strategies. PMID- 25821128 TI - Conversion of hemicellulose sugars catalyzed by formic acid: kinetics of the dehydration of D-xylose, L-arabinose, and D-glucose. AB - The pre-treatment of lignocellulosic biomass produces a liquid stream of hemicellulose-based sugars, which can be further converted to high-value chemicals. Formosolv pulping and the Milox process use formic acid as the fractionating agent, which can be used as the catalyst for the valorisation of hemicellulose sugars to platform chemicals. The objective of this study was to investigate the reaction kinetics of major components in the hemicelluloses fraction of biomass, that is, D-xylose, L-arabinose and D-glucose. The kinetics experiments for each sugar were performed at temperatures between 130 and 170 degrees C in various formic acid concentrations (10-64 wt %). The implications of these kinetic models on the selectivity of each sugar to the desired products are discussed. The models were used to predict the reaction kinetics of solutions that resemble the liquid stream obtained from the fractionation process of biomass using formic acid. PMID- 25821129 TI - Antimicrobial Peptides from the Aurein Family Form Ion-Selective Pores in Bacillus subtilis. AB - The mechanism of action of aurein 2.2 and aurein 2.3, antimicrobial peptides from the frog Litoria aurea, was investigated. Proteomic profiling of the Bacillus subtilis stress response indicates that the cell envelope is the main target for both aureins. Upon treatment, the cytoplasmic membrane depolarizes and cellular ATP levels decrease. Global element analysis shows that intracellular concentrations of certain metal ions (potassium, magnesium, iron, and manganese) strongly decrease. Selective translocation of some ions over others was demonstrated in vitro. The same set of ions also leaks from B. subtilis cells treated with sublethal concentrations of gramicidin S, MP196, and nisin. Aureins do not permeabilize the cell membrane for propidium iodide thus excluding formation of large, unspecific pores. Our data suggest that the aureins acts by forming small pores thereby causing membrane depolarization, and by triggering the release of certain metal ions thus disturbing cellular ion homeostasis. PMID- 25821131 TI - Pigmented villonodular synovitis of the temporomandibular joint: Case report and review of the literature. AB - BACKGROUND: We present a case of a 51-year-old male patient with pigmented villonodular synovitis (PVNS) of the left temporomandibular joint (TMJ) that initially presented as a slow-growing left facial mass. Upon further workup, a contrast-enhanced CT scan demonstrated an expansile soft tissue mass in the left TMJ. METHODS: The lesion was diagnosed through fine-needle aspiration biopsy. The patient was treated with resection of the TMJ, temporal bone, and root of the zygoma. A temporalis muscle and temporoparietal fascia flap was used for reconstruction to fill the defect and provide contour. RESULTS: Postoperatively, the patient has been tumor free with excellent cosmesis. Our case demonstrates a very successful outcome. CONCLUSION: Previous literature has also reported that complete excision is an ideal procedure for PVNS of TMJ, but temporalis rotational flap use has been rare. This case and previously reported cases in the literature are also reviewed. PMID- 25821130 TI - Cardiac autoimmunity as a novel biomarker, mediator, and therapeutic target of heart disease in type 1 diabetes. AB - Patients with type 1 diabetes (T1D) suffer excess mortality from cardiovascular disease (CVD) that has persisted despite substantial reductions in microvascular complications. Although T1D and type 2 diabetes (T2D) are etiologically distinct, it has generally been assumed that CVD in T1D is "the same disease" as that found in T2D. Here, we review the most recent epidemiological and clinical studies on heart disease in T1D, highlighting differences between CVD in T1D and T2D. In addition, we discuss experimental and clinical evidence for a post-myocardial infarction (MI) autoimmune heart syndrome in T1D, including the development of diagnostic assays which we believe can, for the first time, differentiate between heart disease in T1D and T2D. We postulate that a clinically unrecognized form of chronic myocardial inflammation ("myocarditis") triggered by MI contributes to the poor CVD outcomes in T1D. These findings provide a conceptual shift in our understanding of CVD in T1D and have important diagnostic and therapeutic implications. PMID- 25821132 TI - Jieduquyuziyin prescription suppresses IL-17 production and Th17 activity in MRL/lpr mice by inhibiting expression of Ca(2+)/calmodulin-dependent protein kinase-4. AB - Jieduquyuziyin prescription (JP) is a traditional Chinese medicinal (TCM) formula which has been demonstrated to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription for many years in China. But its mechanism of action in combating this disease is largely unknown. Our previous studies showed that JP can slow disease progression without producing significant toxic side effects. We treated MRL/lpr mice with JP to ascertain if JP could improve SLE by the suppression of Ca(2+)/calmodulin-dependent protein kinase-4 (CaMK4) expression. We investigated the role of JP in a model of SLE in MRL/lpr mice, and identified the possible mechanism of action. Mice were divided randomly into four groups: control, model, and two treatment groups. Sections of renal tissue were stained with hematoxylin and eosin (H&E). Histopathologic changes in the kidney were evaluated by light microscopy. T-helper (Th)17 cells were analyzed by flow cytometry. mRNA levels of interleukin (IL)-17, CaMK4, and RORgammat were measured by reverse transcription polymerase chain reaction (RT PCR). CaMK4 expression was assessed by Western blotting. The results showed that the percentages of Th17, IL-17, and RORgammat in mice treated with JP were decreased remarkably compared to the model group (p < 0.05). Interestingly, a high CaMK4 expression was observed in the SLE mice, which was inhibited by JP. These results suggest that CaMK4 activity was increased in T cells from MRL/lpr mice compared with the control group. Our findings support the conclusion that the effects of JP on MRL/lpr mice may involve the regulation of CaMK4 overexpression in MRL/lpr mice. PMID- 25821133 TI - How long does it take a cell to divide? PMID- 25821134 TI - Percutaneous yttrium aluminum garnet-laser lithotripsy of intrahepatic stones and casts after liver transplantation. AB - Bile duct stones and casts (BDSs) contribute importantly to morbidity after liver transplantation (LT). The purpose of this study was to estimate the clinical efficacy, safety, and long-term results of percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) in transplant recipients and to discuss underlying factors affecting the outcome. A retrospective chart review revealed 18 recipients with BDSs treated by PTCSL laser lithotripsy with a holmium-yttrium aluminum garnet laser probe at 365 to 550 um. They were analyzed in a median follow-up time of 55 months. In all but 1 patient (17/18 or 94%), it was technically feasible to clear all BDSs with a mean of 1.3 sessions. PTCSL was unsuccessful in 1 patient because of multiple stones impacting the bile ducts bilaterally; 17% had early complications (Clavien II). All biliary casts were successfully cleared; 39% had total remission; 61% needed additional interventions in the form of percutaneous transhepatic cholangiography and dilation (17%), re-PTCSL (11%), self-expandable metallic stents (22%), or hepaticojejunostomy (6%); and 22% eventually underwent retransplantation. The overall liver graft survival rate was 78%. Two patients died during follow-up for reasons not related to their BDS. Nonanastomotic strictures (NASs) were significantly associated with treatment failure. We conclude that PTCSL in LT patients is safe and feasible. NASs significantly increased the risk of relapse. Repeated minimally invasive treatments, however, prevented graft failure in 78% of the cases. PMID- 25821135 TI - Glyphosate and dicamba herbicide tank mixture effects on native plant and non genetically engineered soybean seedlings. AB - Crops engineered to contain genes for tolerance to multiple herbicides may be treated with several herbicides to manage weeds resistant to each herbicide. Thus, nearby non-target plants may be subjected to increased exposure to several herbicides used in combination. Of particular concern are native plants, as well as adjacent crops which have not been genetically engineered for tolerance to herbicides. We evaluated responses of seven species of native plants grown in a greenhouse and treated less than field application rates of glyphosate and/or dicamba: Andropogon gerardii, Asclepias syriaca, Eutrochium purpureum, Oenothera biennis, Polyganum lapathifolium, Solidago canadensis and Tridens flavus, and non herbicide resistant soybean (Glycine max, Oregon line M4). Herbicide concentrations were 0.03 or 0.1 * field application rates of 1122 g ha(-1) active ingredient (a.i) (831 g ha(-1) acid glyphosate) for glyphosate and 562 g ha(-1) a.i. for dicamba. In general, plant growth responses to combinations of glyphosate and dicamba were less than the sum of growth responses to the individual herbicides (i.e., antagonistic effect), primarily when one or both herbicides alone caused a large reduction in growth. E. purpureum, P. lapathifolium and S. canadensis were the most sensitive species to both herbicides, while A. gerardii was the most tolerant, with no response to either herbicide. The combinations of herbicides resulted in responses most similar to that from dicamba alone for G. max and from glyphosate alone for T. flavus. The results of this study indicated the need for more data such as effects on native plants in the field to assess risks to non-target plants from combinations of herbicides. PMID- 25821136 TI - Microsolvation and hydration enthalpies of CaS2O3(H2O)(n) (n = 0-19) and S2O3(2 )(H2O)(n) (n = 0-16): an ab initio study. AB - We studied microhydrated calcium thiosulfate and its ions at the restricted Hartree-Fock RHF/6-31G* level of theory. A semiempirical molecular dynamics search of progressively more hydrated species provided lowest-energy configurations that were then fully optimized and characterized as energy minima at the RHF/6-31G* level of theory. The first solvation shell of calcium thiosulfate contains 18 water molecules, while the first solvation shell of thiosulfate ion consists of 15 water molecules. QTAIM calculations show hydrogen bonding to sulfur. At 298.15 K, we estimate the total standard enthalpies of hydration for thiosulfate ion and calcium thiosulfate at infinite dilution as 301 kcal mol(-1) and -335 kcal mol(-1), respectively. The dissociation of hydrated calcium thiosulfate at infinite dilution is predicted to be an endothermic process with an enthalpy of 262 kcal mol(-1). Based on some experimental data, the predominant form of calcium thiosulfate in solution is predicted to be the contact ion pair. PMID- 25821137 TI - The DFT local reactivity descriptors of alpha-tocopherol. AB - The calculations of local reactivity descriptors, the electron donor Fukui function f(-)(r), the average local ionization energy I(r), the Fukui function dual descriptor f((2))(r), and the electron acceptor Fukui function f(+)(r) for alpha-tocopherol, the main biologically active form of vitamin E for antioxidant reactions in phospholipid membranes, is presented. The calculations are performed at B3LYP/6-311++G** level of theory in the gas-phase. The obtained results indicate that the most preferred sites for donating electron in a reaction with radical or oxidizing molecule are associated mostly with pi electrons above and below the aromatic part of the alpha-tocopherol chromanol ring. The most reactive sites for accepting electrons are associated with the leaving H(9) atom in the extension of the phenolic OH bond on the alpha-tocopherol chromanol ring plane, in the place where the formation of H-bond of the precursor complex between approaching reactive oxygen radical and phenolic OH group of alpha-tocopherol could be expected. The separated reactive sites in alpha-tocopherol suggest that the proton and electron, along with the hydrogen atom transfer (HAT) process, could also be transferred to different proton and electron acceptors as in bidirectional proton coupled electron transfer (PCET) reactions. The results presented in this paper suggest that large charge redistribution and significant pi-pi interactions may be expected in antioxidant reactions of alpha-tocopherol. PMID- 25821138 TI - The neuropeptide bursicon acts in cuticle metabolism. AB - Bursicon is a heterodimeric neuropeptide formed of bursicon alpha (burs alpha) and bursicon beta (burs beta) that controls cuticle tanning and wing expansion in insects. Burs alpha-alpha and burs beta-beta homodimers are also formed; they act via an unknown receptor to induce expression of prophylactic immune and stress genes during molting. Based on the hypothesis that burs beta-beta and/or bursicon influence expression of additional genes acting after the molt, we prepared and sequenced six Drosophila cDNA libraries from groups of flies separately injected with burs beta-beta, bursicon, or blank control. Compared to the control, the burs beta-beta treatments led to upregulation (by at least 1.5-fold) of 262 genes at 0.5 h postinjection (PI) and 298 genes at 1 h PI; 323 genes at 0.5 h PI and 269 genes at 1h PI were downregulated (by at least 0.67). Similar changes were recorded following bursicon injections. Of these genes, expression of seven transcripts encoding cuticle proteins was upregulated and three downregulated by burs beta-beta; expression of nine transcripts encoding cuticle proteins were upregulated and four downregulated following bursicon treatments. Expression of dozens of genes involved in chitin metabolism was altered by the experimental treatments. We recorded parallel changes in expression of selected genes by transcriptome and qPCR analysis. These findings support our hypothesis that burs beta-beta and bursicon influence expression of additional genes acting after the molt. We report that burs beta-beta and bursicon act in cuticle synthesis and degradation by regulating the expression of cuticular protein and chitin metabolizing related genes. PMID- 25821139 TI - Positive effects of the traditional Chinese medicine MLC901 in cognitive tasks. AB - MLC901 (NurAiDII) is used as a treatment for stroke patients. It has been shown that MLC901 improves motor and cognitive recovery in ischemic and traumatic brain injured rodents. The present study seeks to delineate cognitive effects induced by MLC901 in normal, noninjured mice. To this end, the behaviors of vehicle- and MLC901-treated C57BL/6 mice in hippocampus-dependent (passive avoidance, Morris water maze) and hippocampus-independent (novel object recognition) cognitive tasks are compared. The potential influence of the compound on the anxiety level and nycthemeral rhythm of mice is also assessed. In addition, the long-term effects of MLC901 on hippocampal neurogenesis are measured. The results clearly demonstrate that MLC901 promotes extinction in passive avoidance and reversal learning in the Morris water maze and improves the performance of mice in novel object recognition. In parallel, this study shows the long-term proneurogenesis effects of MLC901 that result in the increase in the number of mature neurons in the hippocampus. If these observations can be extended to humans, then MLC901 could represent a promising therapeutic strategy. PMID- 25821140 TI - Developability assessment during the selection of novel therapeutic antibodies. AB - Therapeutic antibodies and antibody derivatives comprise the majority of today's biotherapeutics. Routine methods to generate novel antibodies, such as immunization and phage-display, often give rise to several candidates with desired functional properties. On the contrary, resource-intense steps such as the development of a cell line, a manufacturing process, or a formulation, are typically carried out for only one candidate. Therefore, "developability," that is, the likelihood for the successful development of a lead candidate into a stable, manufacturable, safe, and efficacious drug, may be used as an additional selection criterion. Employing a set of small-scale, fast, and predictive tests addressing biochemical and biophysical features, as well as in vivo fate can help to identify a clinical candidate molecule with promising properties at an early stage of drug development. This article gives an overview of existing methods for developability testing and shows how these assays can be interlaced in the lead selection process. PMID- 25821141 TI - Network structure of functional hippocampal lateralization in birds. AB - Functional hemispheric asymmetry is a common feature of vertebrate brain organization, yet little is known about how hemispheric dominance is implemented at the neural level. One notable example of hemispheric dominance in birds is the leading role of the left hippocampal formation in controlling navigational processes that support homing in pigeons. Relying on resting state fMRI analyses (where Functional connectivity (FC) can be determined by placing a reference 'seed' for connectivity in one hemisphere), we show that following seeding in either an anterior or posterior region of the hippocampal formation of homing pigeons and starlings, the emergent FC maps are consistently larger following seeding of the left hippocampus. Left seedings are also more likely to result in FC maps that extend to the contralateral hippocampus and outside the boundaries of the hippocampus. The data support the hypothesis that broader FC is one neural organizational property that confers, with respect to navigation, functional dominance to the left hippocampus of birds. PMID- 25821142 TI - When emotions are expressed figuratively: Psycholinguistic and Affective Norms of 619 Idioms for German (PANIG). AB - Despite flourishing research on the relationship between emotion and literal language, and despite the pervasiveness of figurative expressions in communication, the role of figurative language in conveying affect has been underinvestigated. This study provides affective and psycholinguistic norms for 619 German idiomatic expressions and explores the relationships between affective and psycholinguistic idiom properties. German native speakers rated each idiom for emotional valence, arousal, familiarity, semantic transparency, figurativeness, and concreteness. They also described the figurative meaning of each idiom and rated how confident they were about the attributed meaning. The results showed that idioms rated high in valence were also rated high in arousal. Negative idioms were rated as more arousing than positive ones, in line with results from single words. Furthermore, arousal correlated positively with figurativeness (supporting the idea that figurative expressions are more emotionally engaging than literal expressions) and with concreteness and semantic transparency. This suggests that idioms may convey a more direct reference to sensory representations, mediated by the meanings of their constituting words. Arousal correlated positively with familiarity. In addition, positive idioms were rated as more familiar than negative idioms. Finally, idioms without a literal counterpart were rated as more emotionally valenced and arousing than idioms with a literal counterpart. Although the meanings of ambiguous idioms were less correctly defined than those of unambiguous idioms, ambiguous idioms were rated as more concrete than unambiguous ones. We also discuss the relationships between the various psycholinguistic variables characterizing idioms, with reference to the literature on idiom structure and processing. PMID- 25821143 TI - Geometric and electronic structure and magnetic properties of Fe-Au nanoalloys: insights from ab initio calculations. AB - We have performed density functional theory (DFT) based calculations of Fe-Au nanoalloys containing 113 atoms, Fe(x)Au(113-x) (x = 23, 56, 90), to determine their preferred geometric structure and the ensuing electronic structural and magnetic properties. We find that these nanoalloys prefer the formation of a core shell structure and the Fe core maintains almost a constant magnetic moment of ~2.8 MU(B) regardless of the Fe content, which is 27% enhancement from the bulk value and in qualitative agreement with some previous results. The local magnetic moment of Fe atoms is well correlated with the local coordination of the Fe atoms. Furthermore, the enhancement of the magnetic moment may be traced to charge depletion from the Fe atoms in the core to the Au atoms in the shell. The preference for the core-shell structure over one with segregated Fe and Au parts could be the low surface tension at the Fe-Au interface, which is larger for the core-shell structure, and can be attributed to strong Fe-Au interfacial interaction as a result of large charge transfer at the interface. PMID- 25821144 TI - The impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: The study aims to assess the relative efficacy of granulocyte colony stimulating factor (G-CSF) products administered as primary prophylaxis (PP) to patients with cancer receiving myelosuppressive chemotherapy. METHODS: A systematic literature review identified publications (January 1990 to September 2013) of randomized controlled trials evaluating PP with filgrastim, pegfilgrastim, lenograstim, or lipegfilgrastim in adults receiving myelosuppressive chemotherapy for solid tumors or non-Hodgkin lymphoma. Direct, indirect, and mixed-treatment comparison (MTC) were used to estimate the odds ratio and 95 % credible interval of febrile neutropenia (FN) during cycle 1 and all cycles of chemotherapy combined without adjusting for differences in relative dose intensity (RDI) between study treatment arms. RESULTS: Twenty-seven publications representing 30 randomized controlled trials were included. Using MTC over all chemotherapy cycles, PP with filgrastim, pegfilgrastim, lenograstim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. FN risk was also significantly reduced with pegfilgrastim PP versus filgrastim PP. Over all chemotherapy cycles, there was a numerical but statistically nonsignificant increase in the FN risk for lipegfilgrastim PP versus pegfilgrastim PP. Using MTC in cycle 1, PP with filgrastim, pegfilgrastim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. CONCLUSIONS: In this meta-analysis, using MTC without adjustment for RDI, PP with all G-CSFs evaluated reduced the FN risk in patients receiving myelosuppressive chemotherapy. Future studies are needed to assess the influence of RDI on FN outcomes and to eliminate potential bias between G-CSF arms receiving more intensive chemotherapy than control arms. PMID- 25821146 TI - Application of a fast and cost-effective in situ derivatization method prior to gas chromatography with mass spectrometry to monitor endocrine disruptors in water matrices. AB - This work deals with the optimization of a rapid, cost-effective, and eco friendly gas chromatography with mass spectrometry method for the simultaneous determination of four endocrine disruptor compounds in water matrices: estrone, 17beta-estradiol, 17alpha-ethinylestradiol, and bisphenol A, that are currently considered to be of main concern in the field of water policy and that could became candidates for future regulations. The method involves simultaneous derivatization and extraction of compounds by dispersive liquid-liquid microextraction followed by gas chromatography with mass spectrometry analysis. Derivatization and extraction parameters were optimized with the aid of experimental design approach. An excellent linear response was achieved for all analytes (r(2) >= 0.999). Limits of detection and quantification are 0.003-0.005 and 0.0094-0.0164 MUg/L, respectively. Intraday precision ranged between 1.1 and 12.6%, whereas interday precision ranged between 0.5 and 14.7%. For accuracy, bias values varied between -15.0 and 13.7%. Recoveries at three concentration levels ranged from 86.4 to 118.2%. The proposed method can be applied to the routine analysis of groundwater, river, sea, tap, and mineral water samples with excellent sensitivity, precision, and accuracy. PMID- 25821145 TI - Disparities in barriers to follow-up care between African American and White breast cancer survivors. AB - PURPOSE: Despite recommendations for breast cancer survivorship care, African American women are less likely to receive appropriate follow-up care, which is concerning due to their higher mortality rates. This study describes differences in barriers to follow-up care between African American and White breast cancer survivors. METHODS: We conducted a mailed survey of women treated for non metastatic breast cancer in 2009-2011, 6-24 months post-treatment (N = 203). Survivors were asked about 14 potential barriers to follow-up care. We used logistic regression to explore associations between barriers and race, adjusting for covariates. RESULTS: Our participants included 31 African American and 160 White survivors. At least one barrier to follow-up care was reported by 62 %. Compared to White survivors, African Americans were more likely to identify barriers related to out-of-pocket costs (28 vs. 51.6 %, p = 0.01), other health care costs (21.3 vs. 45.2 %, p = 0.01), anxiety/worry (29.4 vs. 51.6 %, p = 0.02), and transportation (4.4 vs. 16.1 %, p = 0.03). After adjustment for covariates, African Americans were three times as likely to report at least one barrier to care (odds ratio (OR) = 3.3, 95 % confidence interval (CI) = 1.1 10.1). CONCLUSIONS: Barriers to care are common among breast cancer survivors, especially African American women. Financial barriers to care may prevent minority and underserved survivors from accessing follow-up care. Enhancing insurance coverage or addressing out-of-pocket costs may help address financial barriers to follow-up care among breast cancer survivors. Psychosocial care aimed at reducing fear of recurrence may also be important to improve access among African American breast cancer survivors. PMID- 25821148 TI - Clinical outcomes in patients with acute eosinophilic pneumonia not treated with corticosteroids. AB - PURPOSE: The objective of this study was to evaluate the course of clinical stability in patients with acute eosinophilic pneumonia (AEP) who did not receive corticosteroid treatment. METHODS: Secondary analysis included 19 consecutive patients with AEP who did not receive corticosteroid treatment from a cohort of 310 patients newly diagnosed with AEP between October 2007 and December 2013. RESULTS: All patients presented with dyspnea, fever, or cough with diffuse pulmonary infiltration. All but one patient (95 %) had elevated C-reactive protein (CRP), and 11 (58 %) patients had peripheral eosinophilia at the time of diagnosis. During the follow-up period, the dyspnea improved within a median of 4 (3-6) days and defervescence occurred within a median of 5 (4-7) days. Median time to clinical stability (defined as disappearance of all initial presenting symptoms) was 9 (7-12) days. In addition, the majority of pulmonary infiltrates on chest radiographs completely disappeared within 14 days after diagnosis. However, the peripheral eosinophil count and the frequency of peripheral eosinophilia increased up to 10 days and then decreased during the follow-up period. All patients experienced peripheral eosinophilia during hospitalisation. CONCLUSION: AEP-associated symptoms and radiographic abnormalities were resolved completely within 2 weeks after diagnosis even when corticosteroid treatment was not initiated. However, these findings might be limited to relatively mild cases of AEP. PMID- 25821149 TI - "Manejar la Situacion": Partner Notification, Partner Management, and Conceptual Frameworks for HIV/STI Control Among MSM in Peru. AB - Previous analyses of partner notification (PN) have addressed individual, interpersonal, social, and structural issues influencing PN outcomes but have paid less attention to the conceptual framework of PN itself. We conducted 18 individual interviews and 8 group discussions, in a two-stage qualitative research process, to explore the meanings and contexts of PN for sexually transmitted infections (STI) among men who have sex with men (MSM) and men who have sex with men and women (MSMW) in Lima, Peru. Participants described PN as the open disclosure of private, potentially stigmatizing information that could strengthen or disrupt a partnership, structured by the tension between concealment and revelation. In addition to informing partners of an STI diagnosis, the act of PN was believed to reveal other potentially stigmatizing information related to sexual identity and practices such as homosexuality, promiscuity, and HIV co-infection. In this context, the potential development of visible, biological STI symptoms represented a risk for disruption of the boundary between secrecy and disclosure that could result in involuntary disclosure of STI status. To address the conflict between concealment and disclosure, participants cited efforts to "manejar la situacion" (manage the situation) by controlling the biological risks of STI exposure without openly disclosing STI status. We use this concept of "managing the situation" as a practical and theoretical framework for comprehensive Partner Management for HIV/STI control systems among MSM in Latin America. PMID- 25821147 TI - Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study. AB - Multisite neuroimaging studies can facilitate the investigation of brain-related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Erho2 = 0.82), inferior frontal gyrus (IFG; Erho2 = 0.83), anterior cingulate cortex (ACC; Erho2 = 0.76), insula ( Erho2 = 0.85), and fusiform gyrus ( Erho2 = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Erho2 = 0.44), IFG ( Erho2 = 0.48), ACC ( Erho2 = 0.55), insula ( Erho2 = 0.42), and fusiform gyrus ( Erho2 = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Erho2 = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta-analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single-site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level-dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms. PMID- 25821150 TI - Functionalizable low-fouling coatings for label-free biosensing in complex biological media: advances and applications. AB - This review focuses on recent advances in the development of functionalizable antifouling coatings and their applications in label-free optical biosensors. Approaches to the development of antifouling coatings, ranging from self assembled monolayers and PEG derivatives to ultra-low-fouling polymer brushes, are reviewed. Methods of preparation and characterization of antifouling coatings and the functionalization of antifouling coatings with bioreceptors are reviewed, and the effect of functionalization on the fouling properties of biofunctional coating is discussed. Special attention is given to biofunctional coatings for label-free bioanalysis of blood plasma and serum for medical diagnostics. PMID- 25821151 TI - Prevalence of incidental prostate cancer: A systematic review of autopsy studies. AB - Prostate cancer screening may detect nonprogressive cancers, leading to overdiagnosis and overtreatment. The potential for overdiagnosis can be assessed from the reservoir of prostate cancer in autopsy studies that report incidental prostate cancer rates in men who died of other causes. We aimed to estimate the age-specific incidental cancer prevalence from all published autopsy studies. We identified eligible studies by searches of Medline and Embase, forward and backward citation searches and contacting authors. We screened the titles and abstracts of all articles; checked the full-text articles for eligibility and extracted clinical and pathology data using standardized forms. We extracted mean cancer prevalence, age-specific cancer prevalence and validity measures and then pooled data from all studies using logistic regression models with random effects. The 29 studies included in the review dated from 1948 to 2013. Incidental cancer was detected in all populations, with no obvious time trends in prevalence. Prostate cancer prevalence increased with each decade of age, OR = 1.7 (1.6-1.8), and was higher in studies that used the Gleason score, OR = 2.0 (1.1-3.7). No other factors were significantly predictive. The estimated mean cancer prevalence increased in a nonlinear fashion from 5% (95% CI: 3-8%) at age <30 years to 59% (95% CI: 48-71%) by age >79 years. There was substantial variation between populations in estimated cancer prevalence. There is a substantial reservoir of incidental prostate cancer which increases with age. The high risk of overdiagnosis limits the usefulness of prostate cancer screening. PMID- 25821152 TI - The Role of Phonological versus Morphological Skills in the Development of Arabic Spelling: An Intervention Study. AB - The current study investigated the contribution of two linguistic intervention programs, phonological and morphological to the development of word spelling among skilled and poor native Arabic readers, in three grades: second, fourth and sixth. The participants were assigned to three experimental groups: morphological intervention, phonological intervention and a non-intervention control group. Phonological awareness, morphological awareness, and spelling abilities were tested before and after the intervention. Participants from both linguistic intervention programs and in all grades made significant progress in linguistic awareness and spelling after the intervention. The results showed that both intervention programs were successful in promoting children's spelling skills in both groups. Also, older poor readers showed a stronger response to the morphological intervention than the older skilled readers. A transfer effect was found with the phonological training contributing to the morphological skills and vice versa. The results of the current study were discussed in the light of developmental and psycholinguistic views of spelling acquisition as well as the characteristics of Arabic language and orthography. PMID- 25821153 TI - Predicting euarchontan body mass: A comparison of tarsal and dental variables. AB - OBJECTIVE: Multiple meaningful ecological characterizations of a species revolve around body mass. Because body mass cannot be directly measured in extinct taxa, reliable body mass predictors are needed. Many published body mass prediction equations rely on dental dimensions, but certain skeletal dimensions may have a more direct and consistent relationship with body mass. We seek to evaluate the reliability of prediction equations for inferring euarchontan body mass based on measurements of the articular facet areas of the astragalus and calcaneus. METHODS: Surface areas of five astragalar facets (n = 217 specimens) and two calcaneal facets (n = 163) were measured. Separate ordinary least squares and multiple regression equations are presented for different levels of taxonomic inclusivity, and the reliability of each equation is evaluated with the coefficient of determination, standard error of the estimate, mean prediction error, and the prediction sum of squares statistic. We compare prediction errors to published prediction equations that utilize dental and/or tarsal measures. Finally, we examine the effects of taxonomically specific regressions and apply our equations to a diverse set of non-primates. RESULTS: Our results reveal that predictions based on facet areas are more reliable than most linear dental or tarsal predictors. Multivariate approaches are often better than univariate methods, but require more information (making them less useful for fragmentary fossils). While some taxonomically specific regressions improve predictive ability, this is not true for all primate groups. CONCLUSIONS: Among individual facets, the ectal and fibular facets of the astragalus and the calcaneal cuboid facet are the best body mass predictors. Since these facets have primarily concave curvature and scale with positive allometry relative to body mass, it appears that candidate skeletal proxies for body mass can be identified based on their curvature and scaling coefficients. PMID- 25821154 TI - Application of the Ugi reaction with multiple amino acid-derived components: synthesis and conformational evaluation of piperazine-based minimalist peptidomimetics. AB - The concurrent employment of alpha-amino acid-derived chiral components such as aldehydes and alpha-isocyanoacetates, in a sequential Ugi reaction/cyclization two-step strategy, opens the door to the synthesis of three structurally distinct piperazine-based scaffolds, characterized by the presence of L-Ala and/or L-Phe derived side chains and bearing appropriate functionalities to be easily applied in peptide chemistry. By means of computational studies, these scaffolds have been demonstrated to act as minimalist peptidomimetics, able to mimic a well defined range of peptide secondary structures and therefore potentially useful for the synthesis of small-molecule PPI modulators. Preliminary biological evaluation of two different resistant hepatocellular carcinoma cellular lines, for which differentiation versus resistance ability seem to be strongly correlated with well defined types of PPIs, has revealed a promising antiproliferative activity for selected compounds. PMID- 25821155 TI - Electrically tunable selective reflection of light from ultraviolet to visible and infrared by heliconical cholesterics. AB - Electrical tuning of selective reflection of light is achieved in a very broad spectral range from ultraviolet to visible and infrared by an oblique helicoidal state of a cholesteric liquid crystal in a wide temperature range (including room temperature). The phenomenon offers potential applications in tunable smart windows, lasers, optical filters and limiters, as well as in displays. PMID- 25821156 TI - The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment. AB - Idelalisib, a phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117, an inactive metabolite, and is metabolized to a lesser extent by cytochrome P450 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In a mass balance study, the orally administered idelalisib dose was recovered mainly in feces (~78%). This study evaluated the pharmacokinetics and safety of a single 150-mg dose of idelalisib in subjects with moderate or severe hepatic impairment and in age-, sex-, and weight-matched, healthy controls. The idelalisib maximum observed plasma concentration was generally comparable in subjects with moderate or severe hepatic impairment versus healthy controls, whereas the mean area under the curve was higher (58% to 59%). GS-563117 exposures were lower in impaired versus healthy control subjects, likely because of lower formation in the setting of liver impairment. Exploratory analyses indicated no relevant relationships between idelalisib or GS-563117 plasma exposures and Child-Pugh-Turcotte scores. Single oral doses of idelalisib 150 mg were well tolerated, with most treatment emergent adverse events (AEs) and laboratory abnormalities being grades 1 or 2 in severity. As such, no dose adjustment was required when initiating idelalisib treatment in patients with mild or moderate hepatic impairment, although close monitoring for potential AEs is recommended. PMID- 25821158 TI - Palladium catalyzed selective mono-arylation of o-carboranes via B-H activation. AB - Palladium catalyzed selective mono-arylation of o-carboranes with aryl iodides has been developed, and a series of B(8)/B(9)-Ar-o-carboranes anchored with active groups have been synthesized with moderate to good yield as well as good selectivity. The mechanism involving Pd(II) catalyzed electrophilic B-H activation was also proposed. PMID- 25821159 TI - Selective functionalization of hollow nanospheres with Acid and base groups for cascade reactions. AB - The inner-surface functionalization of hollow silica spheres has rarely been reported and is still a challenging topic. Herein, we report a deacetalization Henry cascade reaction catalyzed by dual-functionalized mesoporous silica hollow nanospheres with basic amine groups (?NH2 ) on the internal shell and carboxylic acid groups (?COOH) on the external shell. The selective functionalization has been realized by a combination of "step-by-step post-grafting" and "cationic surfactant-assisted selective etching" strategy. Compared to unisolated catalyst, the selectively isolated acidic and basic dual catalyst provides excellent catalytic performance for the deacetalization-Henry cascade reaction in terms of both activity (>99 %) and selectivity (95 %). PMID- 25821157 TI - Models of germ cell development and their application for toxicity studies. AB - Germ cells are unique in their ability to transfer genetic information and traits from generation to generation. As such, the proper development of germ cells and the integrity of their genome are paramount to the health of organisms and the survival of species. Germ cells are also exquisitely sensitive to environmental influences although the testing of germ cell toxicity, especially in females, has proven particularly challenging. In this review, we first describe the remarkable odyssey of germ cells in mammals, with an emphasis on the female germline, from their initial specification early during embryogenesis to the generation of mature gametes in adults. We also describe the current methods used in germ cell toxicity testing and their limitations in examining the complex features of mammalian germ cell development. To bypass these challenges, we propose the use of alternative model systems such as Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans, and in vitro germ cell methods that have distinct advantages over traditional toxicity models. We discuss the benefits and limitations of each approach, their application to germ cell toxicity studies, and the need for computational approaches to maximize the usefulness of these models. Together, the inclusion of these alternative germ cell toxicity models will be invaluable for the examination of stages not easily accessible in mammals as well as the large scale, high-throughput investigation of germ cell toxicity. PMID- 25821160 TI - Genetic and clinical characteristics of primary and secondary glioblastoma is associated with differential molecular subtype distribution. AB - Glioblastoma multiforme (GBM) is classified into primary (pGBM) or secondary (sGBM) based on clinical progression. However, there are some limits to this classification for insight into genetically and clinically distinction between pGBM and sGBM. The aim of this study is to characterize pGBM and sGBM associating with differential molecular subtype distribution. Whole transcriptome sequencing data was used to assess the distribution of molecular subtypes and genetic alterations in 88 pGBM and 34 sGBM in a Chinese population-based cohort, and the biological progression and prognostic impact were analyzed by combining clinical information. Forty-one percentage of pGBM were designated as Mesenchymal subtype, while only 15% were the Proneural subtype. However, sGBM displayed the opposite ratio of Mesenchymal (15%) and Proneural (44%) subtypes. Mutations in isocitrate dehydrogenase-1 (IDH1) were found to be highly concentrated in the Proneural subtypes. In addition, patients with sGBM were 10 years younger on average than those with pGBM, and exhibited clinical features of shorter overall survival and frontal lobe tumor location tendency. Furthermore, in sGBM, gene sets related to malignant progression were found to be enriched. Overall, these results reveal the intrinsic distinction between pGBM and sGBM, and provide insight into the genetic and clinical attributes of GBM. PMID- 25821161 TI - Tailoring the properties of ammine metal borohydrides for solid-state hydrogen storage. AB - A series of halide-free ammine manganese borohydrides, Mn(BH4 )2 ?nNH3 , n=1, 2, 3, and 6, a new bimetallic compound Li2 Mn(BH4 )4 ?6NH3 , and the first ammine metal borohydride solid solution Mg1-x Mnx (BH4 )2 ?6NH3 are presented. Four new crystal structures have been determined by synchrotron radiation powder X-ray diffraction and the thermal decomposition is systematically investigated for all the new compounds. The solid-gas reaction between Mn(BH4 )2 and NH3 provides Mn(BH4 )2 ?6NH3 . The number of NH3 per Mn has been varied by mechanochemical treatment of Mn(BH4 )2 ?6NH3 -Mn(BH4 )2 mixtures giving rise to increased hydrogen purity for n/m<=1 for M(BH4 )m ?nNH3 . The structures of Mg(BH4 )2 ?3NH3 and Li2 Mg(BH4 )4 ?6NH3 have been revisited and new structural models are presented. Finally, we demonstrate that ammonia destabilizes metal borohydrides with low electronegativity of the metal (chip <~1.6), while metal borohydrides with high electronegativity (chip >~1.6) are generally stabilized. PMID- 25821162 TI - Engineering a bacterial tape recorder. AB - A method has been developed to produce and integrate single-stranded DNA into genomic locations in bacteria in response to exogenous signals. The system functions similarly to a cellular tape recorder by writing information into DNA and reading it at a later time. Much like other cellular memory platforms, its operation is based on DNA recombinase function. However, the scalability and recording capacity have been improved over previous designs. In addition, memory storage was reversible and could be recorded in response to analogue inputs, such as light exposure. This modular memory writing system is an important addition to the genomic editing toolbox available for synthetic biology. PMID- 25821165 TI - Pentoxifylline-tocopherol-clodronate combination: A novel treatment for osteoradionecrosis of the temporal bone. AB - BACKGROUND: Osteoradionecrosis (ORN) of the temporal bone is a complication of radiation therapy that is extremely challenging to manage. METHODS: We report the case of a patient treated at our institution and present a review of the literature. RESULTS: A 52-year-old woman presented with ORN of the temporal bone 20 years after radiation therapy for an ipsilateral parotid tumor. She failed conservative management, including serial debridements, oral and topical antibiotics/antifungals, and aural lavage. As an alternative to hyperbaric oxygen (HBO) and/or temporal bone resection, treatment with pentoxifylline-tocopherol clodronate combination (PENTOCLO) was pursued and her condition improved dramatically. CONCLUSION: This is the first document use of PENTOCLO to treat ORN of the temporal bone. PENTOCLO may represent an effective nonsurgical management option for ORN of the temporal bone. PMID- 25821163 TI - Not just chlorthalidone: evidence-based, single tablet, diuretic alternatives to hydrochlorothiazide for hypertension. AB - Accounting for 15 % of deaths worldwide, hypertension is often treated with hydrochlorothiazide (HCTZ) (50 million prescriptions annually). HCTZ has a <24-h duration of action, is less potent than chlorthalidone and all major antihypertensive drug classes, and is inferior to four antihypertensive drugs for cardiovascular event (CVE) reduction. If there were alternative diuretics, why prescribe HCTZ? Chlorthalidone is often offered as an alternative to HCTZ, but has limited pharmaceutical formulations. However, there are seven evidence-based, single-tablet, alternative diuretics. For reducing CVE, the following are superior to their comparators: chlorthalidone versus four antihypertensives in multiple hypertensive populations; indapamide versus placebo in elderly Chinese (and versus enalapril for left ventricular hypertrophy), triamterene-HCTZ versus placebo in elderly Europeans, amiloride-HCTZ versus three antihypertensives, and indapamide-perindopril versus placebo in three populations. Additionally, chlorthalidone-azilsartan and spironolactone-HCTZ are potent combinations The aldosterone antagonist component of the latter combination has been shown to reduce total mortality by 30 % in heart failure. Five of these seven have multiple dose formulations. Six cost $4-$77 monthly. In conclusion, based on both scientific and practical grounds, new prescriptions for HCTZ are rarely justified. PMID- 25821166 TI - Safety and feasibility of S-1 adjuvant chemotherapy for pancreatic cancer in elderly patients. AB - BACKGROUND: The safety and feasibility of administering S-1 adjuvant chemotherapy for pancreatic cancer has not yet been fully evaluated in elderly patients. METHODS: This retrospective study selected patients who underwent curative surgery for pancreatic cancer, were diagnosed with stage II disease or lower or stage III disease with combined resection of the celiac artery, and received adjuvant S-1 at our institution. The patients were categorized into two groups: non-elderly patients (<70 years of age: group A) and elderly patients (>70 years of age: group B). The toxicity and S-1 continuation rates were compared between the two groups. RESULTS: A total of 76 patients were evaluated in the present study. There were no grade 4 toxicities. The incidences of grade 3 hematological and non-hematological toxicities were <5 % in both groups, and the differences were not significantly different. The continuation rate at 6 months was 60.5 % in group A and 72.7 % in group B, which was also not significantly different. CONCLUSIONS: These results suggest that S-1 adjuvant chemotherapy for pancreatic cancer is safe and feasible, regardless of the age of the patient, especially for elderly patients who may be candidates for clinical trials. PMID- 25821167 TI - Human neonatal hepatocyte transplantation induces long-term rescue of unconjugated hyperbilirubinemia in the Gunn rat. AB - Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate-glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstrate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo. PMID- 25821168 TI - Low mean temperature rather than few sunshine hours are associated with an increased incidence of type 1 diabetes in children. AB - The well-known north-south gradient and the seasonal variability in incidence of childhood type 1 diabetes indicate climatological factors to have an effect on the onset. Both sunshine hours and a low temperature may be responsible. In the present study we tried to disentangle these effects that tend to be strongly connected. Exposure data were sunshine hours and mean temperature respectively obtained from eleven meteorological stations in Sweden which were linked to incidence data from geographically matched areas. Incident cases during 1983-2008 were retrieved from the population based Swedish childhood diabetes register. We used generalized additive models to analyze the incidence as a function of mean temperature and hours of sun adjusted for the time trend, age and sex. In our data set the correlation between sun hours and temperature was weak (r = 0.36) implying that it was possible to estimate the effect of these variables in a regression model. We fit a general additive model with a smoothing term for the time trend. In the model with sun hours we found no significant effect on T1 incidence (p = 0.17) whereas the model with temperature as predictor was significant (p = 0.05) when adjusting for the time trend, sex and age. Adding sun hours in the model where mean temperature was already present did not change the effect of temperature. There is an association with incidence of type 1 diabetes in children and low mean temperature independent of a possible effect of sunshine hours after adjustment for age, sex and time trend. The findings may mirror the cold effect on insulin resistance and accords with the hypothesis that overload of an already ongoing beta cell destruction may accelerate disease onset. PMID- 25821169 TI - Exposure to 50 Hz electric fields reduces stress-induced glucocorticoid levels in BALB/c mice in a kV/m- and duration-dependent manner. AB - Electric fields (EFs) can reduce elevated levels of stress-related hormones in some organisms. In this study, endocrine effects of exposure to a 50 Hz EF were investigated in male BALB/c mice. Specifically, plasma glucocorticoid (GC) levels were examined because GC is known to mediate the stress response in mice, including changes induced by immobilization. Mice were exposed to 50 Hz EFs (at 2.5-200 kV/m) for 60 min. They were immobilized for the latter half (30 min). At the end of exposure period, blood samples were collected and GC levels estimated by spectrofluorometry. GC levels were not influenced by EFs in absence of immobilization, but they were significantly higher in immobilized mice than in non-immobilized mice (P < 0.01). Elevated GC levels induced by immobilization were significantly reduced by exposure to an EF at 10 kV/m (P < 0.05), and the effect of EFs at 0-10 kV/m on GC levels increased in a kV/m-dependent manner (P < 0.05). In contrast, following treatment with EFs at 50 and 200 kV/m, GC levels were higher than those observed at 10 kV/m. To assess the effect of EF treatment duration, mice were also exposed to 50 Hz EFs (10 kV/m) for 6, 20, or 60 min. Immobilization-induced increase in GC levels was significantly suppressed by EF exposure for 20 and 60 min. Therefore, our results demonstrate that extremely low frequency EFs alter stress response of mice in a kV/m- and duration-dependent manner. PMID- 25821170 TI - [Malignant Sertoli cell tumors of the testes]. AB - Sertoli cell tumors are a rare malignancy which account for approximately 1.5 % of all testicular tumors. Although malignant Sertoli cell tumors are uncommon, they are associated with a poor prognosis. So far 36 cases of malignant courses of disease have been described. We present a patient with a lymphogenic metastasized Sertoli cell tumor, who 24 months after orchiectomy and extended retroperitoneal lymphadenectomy is relapse-free. PMID- 25821171 TI - Development and Applications of the Lectin Microarray. AB - The lectin microarray is an emerging technology for glycomics. It has already found maximum use in diverse fields of glycobiology by providing simple procedures for differential glycan profiling in a rapid and high-throughput manner. Since its first appearance in the literature in 2005, many application methods have been developed essentially on the same platform, comprising a series of glycan-binding proteins immobilized on an appropriate substrate such as a glass slide. Because the lectin microarray strategy does not require prior liberation of glycans from the core protein in glycoprotein analysis, it should encourage researchers not familiar with glycotechnology to use glycan analysis in future work. This feasibility should provide a broader range of experimental scientists with good opportunities to investigate novel aspects of glycoscience. Applications of the technology include not only basic sciences but also the growing fields of bio-industry. This chapter describes first the essence of glycan profiling and the basic fabrication of the lectin microarray for this purpose. In the latter part the focus is on diverse applications to both structural and functional glycomics, with emphasis on the wide applicability now available with this new technology. Finally, the importance of developing advanced lectin engineering is discussed. PMID- 25821172 TI - Halogen bonding in the design of organic phosphors. AB - Halogen bonding as a new strategy for introducing heavy atom perturbers in defined stoichiometry in the design of organic phosphors is reviewed. Considering ten novel cocrystals assembled by polyaromatic hydrocarbons (PAHs) and their heterocyclic analogues and haloperfluorobenzenes using the new strategy, apart from biphenyl cocrystals they all phosphoresce strongly, showing that the new methodology can induce phosphorescence by a heavy atom effect. More interesting, the phosphorescence properties, including excitation/emission wavelengths and decay dynamics, show dependence on the structure of the PAHs and interaction patterns, which is very important and valuable in modulation of the expected colors of luminescent materials. PMID- 25821173 TI - THE EFFECTS OF XANTHOTOXIN ON THE BIOLOGY AND BIOCHEMISTRY OF Galleria mellonella L. (LEPIDOPTERA: PYRALIDAE). AB - The effects of a dietary plant allelochemical, xanthotoxin (XA), on survivorship, development, male and female adult longevity, fecundity, and hatchability of the greater wax moth Galleria mellonella L. were investigated. Oxidative stress indicators, the lipid peroxidation product, malondialdehyde (MDA), and protein oxidation products, protein carbonyl (PCO) contents, and activities of a detoxification enzyme glutathione S-transferase (GST) activity were determined in wax moth adults. The insect was reared from first-instar larvae on an artificial diets containing XA at 0.001, 0.005, or 0.1% to adult stage in laboratory conditions. Relative to the controls, the diets containing XA concentrations led to decreased survivorship in seventh instar, pupal, and adult stages. Compared to control diet (77.7%), the highest dietary XA concentration decreased survivorship to adulthood to 11.0%. The highest XA concentration (0.1%) reduced female longevity from 10.4 to 5.7 days and decreased egg numbers from 95.0 to 33.5 and hatchability from 82.7 to 35.6%. The lowest XA concentration (0.001%) led to about a sixfold increase in MDA content. XA at high concentrations (0.005 and 0.1%) increased MDA (by threefold) and protein carbonyl (by twofold) contents decreased GST activity. The highest dietary XA concentration decreased GST activity from 0.28 +/- 0.025 to 0.16 +/- 0.005 MUmol/mg protein/min. We infer from these findings that XA-induced oxidative stress led to decreased biological fitness. PMID- 25821174 TI - Prediction of Pharmacokinetics and Pharmacodynamics of Doripenem in Pediatric Patients. AB - The aim of this paper was to predict the pharmacokinetics of doripenem in pediatrics from adult pharmacokinetic data and to investigate dosing regimens in pediatrics using Monte-Carlo pharmacokinetics/pharmacodynamics (PK/PD) simulations prior to the initiation of pediatric clinical trials. The pharmacokinetics in pediatrics was predicted by using a previously reported approach for beta-lactam antibiotics. Monte-Carlo simulation was employed to assess dosing regimens in pediatrics based on the predicted pharmacokinetic profiles and the minimum inhibitory concentration (MIC) distributions of Haemophilus influenzae and Streptococcus pneumoniae, which frequently cause infectious pediatric diseases. The probabilities of attaining target time above MIC (40%T>MIC) were calculated for dosing regimens of 1-30 mg/kg with two or three times daily dosing (TID) based on simulations of 5000 pediatric patients and MICs. The results suggested 15 and 5 mg/kg TID would give approximately 90% or more probability of target attainment against Haemophilus influenzae and Streptococcus pneumoniae, respectively. The pediatric phase 3 study confirmed that pharmacokinetics in pediatrics could be well predicted by this method, indicating that the dosing regimen had been appropriately selected. The framework of dose selection for pediatric clinical trials based on predictions of pharmacokinetic profiles and PK/PD indices should be applicable to the development of other beta-lactam antibiotics for pediatric use. PMID- 25821175 TI - A Viscidane Diterpene and Polyacetylenes from Cultures of Hypsizygus marmoreus. AB - Investigation on the cultures of Hypsizygus marmoreus resulted in the isolation of a new viscidane diterpene, 8-oxoviscida-3,11(18)-diene-13,14,15,19-tetraol (1) and two new polyacetylenes, (E)-10-(1,1-dimethyl-2-propenyloxy)-2-decene-4,6,8 triyn-1-ol (2) and 10-(1,1-dimethyl-2-propenyloxy)deca-4,6,8-triyn-1-ol (3), together with two known polyacetylenes, (E)-2-decen-4,6,8-triyn-1-ol (4) and 4,6,8-decatriyn-1-ol (5). Their structures were elucidated on the basis of extensive spectroscopic studies. Compound 1 is the first finding of viscidane diterpene in mushrooms. Compounds 1, 3 and 5 were tested for cytotoxicity against human tumor cell lines HL-60, SMMC-7721, A-549, MCF-7 and SW-480. None of the compounds showed cytotoxic activity (IC50 > 40 uM). PMID- 25821176 TI - MRI signatures of the frontotemporal lobar degeneration continuum. AB - OBJECTIVE: To identify overlapping and unique grey (GM) and white matter (WM) signatures within the frontotemporal lobar degeneration (FTLD) continuum, and discriminate likely FTLD-TAU and FTLD-TDP patients using structural and diffusion tensor (DT) magnetic resonance imaging (MRI). METHODS: T1-weighted and DT MRI were collected from 121 subjects: 35 motor neuron disease (MND), 14 behavioral variant of frontotemporal dementia, 12 semantic and 11 nonfluent primary progressive aphasia, 21 progressive supranuclear palsy syndrome patients, and 28 healthy controls. Patterns of GM atrophy were established using voxel-based morphometry. Tract-based spatial statistics was used to perform a WM voxelwise analysis of mean diffusivity and fractional anisotropy. RESULTS: In all clinical FTLD phenotypes, the pattern of WM damage was more distributed than that of GM atrophy. All patient groups, with the exception of MND cases with a pure motor syndrome, shared a focal GM atrophy centered around the dorsolateral and medial frontal cortex and a largely overlapping pattern of WM damage involving the genu and body of the corpus callosum and ventral frontotemporal and dorsal frontoparietal WM pathways. Surrounding this common area, phenotype (symptom) specific GM and WM regions of damage were found in each group. CONCLUSIONS: In the FTLD spectrum, WM disruption is more severe than GM damage. Frontal cortex and WM pathways represent the common target of neurodegeneration in these conditions. The topographic pattern of damage supports a "prion-like" protein propagation through WM connections as underlying mechanism of the stereotyped progression of FTLD. PMID- 25821177 TI - Impact of Left Ventricular Hypertrophy on Survival in Chronic Obstructive Pulmonary Disease. AB - PURPOSE: Left ventricular hypertrophy (LVH) is a significant cardiac risk factor, associated with increased mortality. The impact of LVH on mortality in chronic obstructive pulmonary disease (COPD) is unknown. We evaluated the impact of LVH on mortality in COPD patients by measurement of left ventricular dimensions by echocardiography. METHODS: Retrospective cohort study utilizing a NHS database of COPD patients (TARDIS), in Tayside, Scotland (2001-2010), linked with databases regarding echocardiograms, pharmacy prescription, and the General Register Office for Scotland death registry. Cox proportional hazard regression was used to determine hazard ratios for mortality and hospital admissions based upon left ventricular mass index (LVMI) and left ventricular internal diastolic diameter after correction for all available influential covariates. Increased LVIDd was defined as >5.3 cm (female) and >5.9 cm (male). LVH was defined as an LVMI of >95 g/m(2) (female) and >115 g/m(2) (male). RESULTS: 617 patients were included for analysis. Mean (SD) age at diagnosis, 70 (9); mean FEV1 % (SD), 60.6 (19.3); mean resting SaO2 % (SD), 92.7 (10). Mean follow-up 4.5 years. Increased LVIDd was not associated with increased mortality, chi (2)= 0.767, p = 0.381. Increased LVMI was associated with a significant increased risk of mortality, chi (2) = 5.447, p = 0.02 with an adjusted HR (95 % CI) of 1.542 (1.068-2.228), p = 0.021. CONCLUSIONS: The presence of LVH, demonstrated by elevated left ventricular mass index is associated with a significantly increased risk of mortality in COPD patients. Therapeutic interventions are required to address this important modifiable risk factor in COPD patients. PMID- 25821178 TI - Circulating tumor cells in small cell lung cancer: ex vivo expansion. PMID- 25821179 TI - Flavobacterium vireti sp. nov., isolated from soil. AB - A novel Gram-negative, aerobic, yellow-pigmented, non-motile and rod-shaped bacterium, designated as THG-SM1(T), was isolated from field soil collected from Suwon, South Korea. The strain was found to grow optimally at 28 degrees C, at pH 7.0 and in the absence of NaCl. Based on 16S rRNA gene sequence similarities, strain THG-SM1(T) belongs to the genus Flavobacterium and is most closely related to Flavobacterium terrae KACC 11731(T), followed by Flavobacterium columnare KACC 11683(T) and Flavobacterium enshiense KCTC 23775(T). The DNA G+C content of the novel isolate was determined to be 38.5 mol%. In DNA-DNA hybridization tests, the DNA relatedness between strain THG-SM1(T) and its closest phylogenetic neighbour F. terrae was below 50 %. Flexirubin-type pigments were found to be present. The major polar lipid and isoprenoid quinone were phosphatidylethanolamine and menaquinone 6 (MK-6), respectively. The main cellular fatty acids were identified as iso-C15:1G, iso-C15:0 3OH, iso-C16:0 and iso-C15:0. The DNA-DNA hybridization result and differentiating chemotaxonomic and phenotypic characteristics showed that strain THG-SM1(T) represents a novel species of the genus Flavobacterium, for which the name Flavobacterium vireti sp. nov. is proposed. The type strain is THG-SM1(T) (=KACC 18371(T) = CCTCC AB2014312(T)). PMID- 25821180 TI - Implicit guidance to stable performance in a rhythmic perceptual-motor skill. AB - Feedback about error or reward is regarded essential for aiding learners to acquire a perceptual-motor skill. Yet, when a task has redundancy and the mapping between execution and performance outcome is unknown, simple error feedback does not suffice in guiding the learner toward the optimal solutions. The present study developed and tested a new means of implicitly guiding learners to acquire a perceptual-motor skill, rhythmically bouncing a ball on a racket. Due to its rhythmic nature, this task affords dynamically stable solutions that are robust to small errors and noise, a strategy that is independent from actively correcting error. Based on the task model implemented in a virtual environment, a time-shift manipulation was designed to shift the range of ball-racket contacts that achieved dynamically stable solutions. In two experiments, subjects practiced with this manipulation that guided them to impact the ball with more negative racket accelerations, the indicator for the strategy with dynamic stability. Subjects who practiced under normal conditions took longer time to acquire this strategy, although error measures were identical between the control and experimental groups. Unlike in many other haptic guidance or adaptation studies, the experimental groups not only learned, but also maintained the stable solution after the manipulation was removed. These results are a first demonstration that more subtle ways to guide the learner to better performance are needed especially in tasks with redundancy, where error feedback may not be sufficient. PMID- 25821181 TI - Intermuscular coherence contributions in synergistic muscles during pedaling. AB - The execution of rhythmical motor tasks requires the control of multiple skeletal muscles by the Central Nervous System (CNS), and the neural mechanisms according to which the CNS manages their coordination are not completely clear yet. In this study, we analyze the distribution of the neural drive shared across muscles that work synergistically during the execution of a free pedaling task. Electromyographic (EMG) activity was recorded from eight lower limb muscles of eleven healthy untrained participants during an unconstrained pedaling exercise. The coordinated activity of the lower limb muscles was described within the framework of muscle synergies, extracted through the application of nonnegative matrix factorization. Intermuscular synchronization was assessed by calculating intermuscular coherence between pairs of EMG signals from co-active, both synergistic and non-synergistic muscles within their periods of co-activation. The spatiotemporal structure of muscle coordination during pedaling was well represented by four muscle synergies for all the subjects. Significant coherence values within the gamma band (30-60 Hz) were identified only for one out of the four extracted muscle synergies. This synergy is mainly composed of the activity of knee extensor muscles, and its function is related to the power production and crank propelling during the pedaling cycle. In addition, a significant coherence peak was found in the lower frequencies for the GAM/SOL muscle pair, possibly related to the ankle stabilizing function of these two muscles during the pedaling task. No synchronization was found either for the other extracted muscle synergies or for pairs of co-active but non-synergistic muscles. The obtained results seem to suggest the presence of intermuscular synchronization only when a functional force production is required, with the observed gamma band contribution possibly reflecting a cortical drive to synergistic muscles during pedaling. PMID- 25821183 TI - Schizophrenia or Possession? A Reply to Kemal Irmak and Nuray Karanci. AB - A recent paper in this journal argues that some cases of schizophrenia should be seen as cases of demon possession and treated by faith healers. A reply, also published in this journal, responds by raising concerns about the intellectual credibility and potentially harmful practical implications of demon possession beliefs. My paper contributes to the discussion, arguing that a critique of demon possession beliefs in the context of schizophrenia is needed, but suggesting an alternative basis for it. It also reflects on important differences between demonic and other forms of spirit possession and considers the implications of this for mental healthcare providers. PMID- 25821182 TI - Combined targeting of high-mobility group box-1 and interleukin-8 to control micrometastasis potential in gastric cancer. AB - Micrometastasis is the major cause of treatment failure in gastric cancer (GC). Because epithelial-to-mesenchymal transition (EMT) is considered to develop prior to macroscopic metastasis, EMT-promoting factors may affect micrometastasis. This study aimed to evaluate the role of extracellular high-mobility group box-1 (HMGB1) in EMT and the treatment effect of combined targeting of HMGB1 and interleukin-8 (IL-8) at early-stage GC progression through interrupting EMT promotion. Extracellular HMGB1 was induced by human recombinant HMGB1 and pCMV SPORT6-HMGB1 plasmid transfection. EMT activation was evaluated by immunoblotting, immunofluorescence and immunohistochemistry. Increased migration/invasion activities were evaluated by in vitro transwell migration/invasion assay using all histological types of human GC cell lines (N87, MKN28 SNU-1 and KATOIII), N87-xenograft BALB/c nude mice and human paired serum-tissue GC samples. HMGB1-induced soluble factors were measured by chemiluminescent immunoassay. Inhibition effects of tumor growth and EMT activation by combined targeting of HMGB1 and IL-8 were evaluated in N87 xenograft nude mice. Serum HMGB1 increases along the GC carcinogenesis and reaches maximum before macroscopic metastasis. Overexpressed extracellular HMGB1 promoted EMT activation and increased cell motility/invasiveness through ligation to receptor for advanced glycation end products. HMGB1-induced IL-8 overexpression contributed the HMGB1-induced EMT in GC in vitro and in vivo. Blocking HMGB1 caused significant reduction of tumor growth, and addition of human recombinant IL-8 rescues this antitumor effects. Our results imply the role of HMGB1 in EMT through IL-8 mediation, and a potential mechanism of GC micrometastasis. Our observations suggest combination strategy of HMGB1 and IL-8 as a promising diagnostic and therapeutic target to control GC micrometastasis. PMID- 25821185 TI - A Facile One-Pot Synthesis of a Two-Dimensional MoS2 /Bi2S3 Composite Theranostic Nanosystem for Multi-Modality Tumor Imaging and Therapy. AB - 2D PEG-ylated MoS2/Bi2 S3 composite nanosheets are successfully constructed by introducing bismuth ions to react with the two extra S atoms in a (NH4)2 MoS4 molecule precursor for solvothermal synthesis of MoS2. The MBP nanosheets can serve as a promising platform for computed tomography and photoacoustic-imaging guided tumor diagnosis, as well as combined tumor photothermal therapy and sensitized radiotherapy. PMID- 25821186 TI - Induction of centrosome amplification by formaldehyde, but not hydroquinone, in human lymphoblastoid TK6 cells. AB - Benzene and formaldehyde (FA) are important industrial chemicals and environmental pollutants that cause leukemia by inducing DNA damage and chromosome aberrations in hematopoietic stem cells (HSC), the target cells for leukemia. Our previous studies showed that workers exposed to benzene and FA exhibit increased levels of aneuploidy in their blood cells. As centrosome amplification is a common phenomenon in human cancers, including leukemia, and is associated with aneuploidy in carcinogenesis, we hypothesized that benzene and FA would induce centrosome amplification in vitro. We treated human lymphoblastoid TK6 cells with a range of concentrations of hydroquinone (HQ, a benzene metabolite) or FA for 24 h, allowed the cells to recover in fresh medium for 24 h, and examined centrosome amplification; chromosomal gain, loss, and breakage; and cytotoxicity. We included melphalan and etoposide, chemotherapeutic drugs that cause therapy-related acute myeloid leukemia and that have been shown to induce centrosome amplification as well as chromosomal aneuploidy and breakage, as positive controls. Melphalan and etoposide induced centrosome amplification and chromosome gain and breakage in a dose-dependent manner, at cytotoxic concentrations. HQ, though cytotoxic, did not induce centrosome amplification or any chromosomal aberration. FA-induced centrosome amplification and cytotoxicity, but did not induce chromosomal aberrations. Our data suggest, for the first time, that centrosome amplification is a potential mechanism underlying FA-induced leukemogenesis, but not benzene-induced leukemogenesis, as mediated through HQ. Future studies are needed to delineate the mechanisms of centrosome amplification and its association with DNA damage, chromosomal aneuploidy and carcinogenesis, following exposure to FA. PMID- 25821184 TI - Patrilineal populations show more male transmission of reproductive success than cognatic populations in Central Asia, which reduces their genetic diversity. AB - OBJECTIVE: The extent to which social organization of human societies impacts the patterns of genetic diversity remains an open question. Here, we investigate the transmission of reproductive success in patrilineal and cognatic populations from Central Asia using a coalescent approach. METHODS: We performed a study on the mitochondrial DNA (mtDNA) and Y chromosome polymorphism of patrilineal and cognatic populations from Central Asia. We reconstructed the gene genealogies in each population for both kind of markers and inferred the imbalance level of these genealogies, a parameter directly related to the level of transmission of reproductive success. RESULTS: This imbalance level appeared much stronger for the Y chromosome in patrilineal populations than in cognatic populations, while no difference was found for mtDNA. Furthermore, we showed that this imbalance level correlates negatively with Y-chromosomal, mtDNA, and autosomal genetic diversity. CONCLUSIONS: This shows that patrilineality might be one of the factors explaining the male transmission of reproductive success, which, in turn, lead to a reduction of genetic diversity. Thus, notwithstanding the fact that our population genetic approach clearly shows that there is a strong male-biased transmission of reproductive success in patrilineal societies, it also highlights the fact that a social process such as cultural transmission of reproductive success could play an important role in shaping human genetic diversity, although we cannot formally exclude that this transmission has also a genetic component. PMID- 25821187 TI - Palladium-catalyzed oxidative synthesis of highly functionalized ortholactones. AB - A palladium-catalyzed oxidative reaction is reported which converts dihydropyrans to their corresponding ortholactone. The products are formed in good to excellent yields with a very high level of chemoselectivity and functional group tolerance. Mechanistic studies confirm that the reaction proceeds by a Wacker-type mechanism. PMID- 25821188 TI - Cutaneous manifestations of human immunodeficiency virus: a clinical update. AB - Dermatologic diseases are common in the HIV-infected population. Many of the cutaneous diseases are not unique to this group, but the presentation can be more severe. Although the introduction of antiretroviral therapy has been followed by a decline in many of the skin diseases associated with HIV, drug reactions and other non-infectious skin conditions have increased. This article reviews the current spectrum of HIV-associated skin conditions, focusing on common complaints, infections, drug-associated toxicity and malignancies. PMID- 25821189 TI - Update on prevention and treatment of intestinal helminth infections. AB - Intestinal helminth infections are some of world's most common tropical diseases and cause significant impairments in pediatric growth and cognitive impairment as well as maternal health, particularly in areas lacking adequate access to safe water or sanitation. Routine mass drug administration (MDA) of anthelminthic medications to children living in endemic areas and interventions to improve water hygiene and sanitation form the basis of current control efforts. We review recent evidence on the effectiveness of these approaches and outline the limitations of MDA, including poor cure rates against hookworm and Trichuris trichiura, rapid post-MDA reinfection, and inadequate coverage of at-risk populations. Ultimately, alternative tools and strategies, including new drugs, drug combinations, and vaccines, will be needed to control or ultimately eliminate these infections. PMID- 25821190 TI - Skin infections in returned travelers: an update. AB - Dermatologic manifestations of travel-related illness are particularly vexing due to the broad differential diagnosis and clinicians' unfamiliarity with uncommonly seen diseases. This paper aims to educate and update the reader on selected infectious diseases in the returned traveler whose disease manifestations are primarily dermatologic. First, the evolving epidemiology of these infections is examined; understanding the geographic distribution of infectious etiologies helps refine and narrow the differential diagnosis. This is followed by a discussion of six important clinical syndromes including cutaneous larva migrans (CLM), cutaneous leishmaniasis, tungiasis, myiasis, antibiotic-resistant skin and soft tissue infection, and selected infections associated with fever and rash (e.g., measles, chikungunya virus infection, dengue fever, rickettsial spotted fevers). Familiarity with these syndromes and a situational awareness of their epidemiology will facilitate a prompt, accurate diagnosis and lead to appropriate treatment and prevention of further disease spread. PMID- 25821191 TI - Pressure ulcers in the ICU patient: an update on prevention and treatment. AB - The occurrence of hospital-acquired pressure ulcers (HAPU) is a recognized metric of quality of care by the Centers for Medicare and Medicaid Services (CMS) and the Agency for Healthcare Research and Quality. Pressure ulcer (PU) prevention and treatment have become a priority for many facilities as the reimbursement for hospital-acquired PUs has been significantly restricted by regulations implemented by CMS in 2008. Intensive care unit (ICU) patients are at higher risk for PU development due to comorbidities and life-saving treatment modalities in this environment. PU occurrence in ICUs ranges from 8.8 to 23 %. The literature was reviewed for recent advances in PU prevention and treatment in ICU patients. Advancements include risk assessment, education, turning schedules, providing staff with feedback from audits, lift teams, review of linen, consensus statement regarding unavoidable PU, treatment modalities, and an assessment of the knowledge providers have of PU prevention and treatment. PMID- 25821192 TI - Plasmodium knowlesi malaria: Overview Focussing on Travel-Associated Infections. AB - In 2004, Plasmodium knowlesi was first recognised as a relevant cause of human malaria in Southeast Asia. Since then, P. knowlesi has been described from all Southeast Asian countries except Laos and has become well-established as the fifth human malaria parasite and the first significant zoonotic Plasmodium species. As countries endemic for P. knowlesi malaria are among the most popular and most highly visited international destinations, travel medicine experts should be aware about disease and risks including prophylactic and therapeutic measures. Between 2005 and 2012, 15 cases of P. knowlesi malaria have been recognised and published in international travellers. Male gender and travel to rural/forested areas with contact to wild monkeys are risk factors for P. knowlesi infection. The present review gives an overview on current literature on the P. knowlesi parasite and summarises recent findings related to epidemiology, diagnostics, treatment and prophylaxis focussing on travellers. PMID- 25821193 TI - Good tolerance and long-term complete remission after definitive intensity modulated radiotherapy for locally advanced head and neck cancer in a patient with human immunodeficiency virus infection: A case report and literature review. AB - BACKGROUND: The main concerns with radiation therapy for head and neck cancer in human immunodeficiency virus (HIV)-infected patients include limited tumor response and profound mucosal or skin toxicities under severe immunocompromised status. METHODS: In this study, we describe the clinicopathological features, chronological changes in HIV viral loads and CD4 counts, and treatment outcomes of definitive radiotherapy for locally advanced head and neck cancer in an HIV infected patient. RESULTS: Despite low CD4 counts (80 cells/uL), a combination of highly active antiretroviral therapy (HAART) and definitive concurrent chemoradiotherapy (70 Gy of simultaneously integrated boost intensity-modulated radiotherapy (IMRT), fluorouracil, and leucovorin) was well-tolerated. Grade 3 mucositis and dermatitis were resolved 2 weeks after treatment completion. The patient was alive and remained disease-free 31 months after treatment. CONCLUSION: For patients with HIV diagnosed with locally advanced head and neck cancer, good tolerance and outcome can be achieved with definitive radiotherapy while on HAART. PMID- 25821194 TI - History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents. AB - Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD. PMID- 25821195 TI - Quantitative trait locus analysis and fine mapping of the qPL6 locus for panicle length in rice. AB - KEY MESSAGE: Two QTLs were identified to control panicle length in rice backcross lines, and one QTL qPL6 was finely mapped with potential in high yield breeding. Panicle length (PL) is the key determinant of panicle architecture in rice, and strongly affects yield components, such as grain number per panicle. However, this trait has not been well studied genetically nor its contribution to yield improvement. In this study, we performed quantitative trait locus (QTL) analysis for PL in four backcross populations derived from the cross of Nipponbare (japonica) and WS3 (indica), a new plant type (NPT) variety. Two QTLs were identified on chromosome 6 and 8, designated as qPL6 and qPL8, respectively. Near isogenic lines (NILs) were developed to evaluate their contribution to important agronomic traits. We found that qPL6 and qPL8 had additive effects on PL trait. For the qPL6 locus, the WS3 allele also increased panicle primary and secondary branches and grain number per panicle. Moreover, this allele conferred wide and strong culms, a character of lodging resistance. By analyzing key recombinants in two steps, the qPL6 locus was finely mapped to a 25-kb interval, and 3 candidate genes were identified. According to the single nucleotide polymorphisms (SNPs) within candidate genes, 5 dCaps markers were designed and used to get haplotypes of 96 modern Chinese varieties, which proved that qPL6 locus is differentiated between indica and temperate japonica varieties. Taken together, the superior qPL6 allele can be applied in rice breeding programs for large sink size, particularly for japonica varieties that originally lack the allele. PMID- 25821197 TI - Low-density lipoprotein apheresis for corticosteroid-resistant skin lesions caused by cholesterol crystal embolism: a case report and review of the literature. AB - Cholesterol crystal embolism (CCE) is an arterio-arterial embolism originating from the breakdown of atherosclerotic plaques in the aortic wall. The embolism affects the skin and kidney particularly, as well as frequently affects the gastrointestinal tract and other organs. Although there are no clearly effective direct therapies for CCE, corticosteroid therapy and combination therapy with low density lipoprotein apheresis (LDL-A) followed by corticosteroids were recently reported to be effective for renal manifestations in some cases. However, few cases offer suggestions for the treatment of skin lesions caused by CCE. We report here a case of a 58-year-old man diagnosed with CCE with skin manifestations and kidney dysfunction who achieved complete remission after LDL A. LDL-A may be a useful treatment for CCE, particularly in cases with skin manifestations. PMID- 25821196 TI - Sequencing consolidates molecular markers with plant breeding practice. AB - KEY MESSAGE: Plenty of molecular markers have been developed by contemporary sequencing technologies, whereas few of them are successfully applied in breeding, thus we present a review on how sequencing can facilitate marker assisted selection in plant breeding. The growing global population and shrinking arable land area require efficient plant breeding. Novel strategies assisted by certain markers have proven effective for genetic gains. Fortunately, cutting edge sequencing technologies bring us a deluge of genomes and genetic variations, enlightening the potential of marker development. However, a large gap still exists between the potential of molecular markers and actual plant breeding practices. In this review, we discuss marker-assisted breeding from a historical perspective, describe the road from crop sequencing to breeding, and highlight how sequencing facilitates the application of markers in breeding practice. PMID- 25821198 TI - Impact of Luminal Fluid Volume on the Drug Absorption After Oral Administration: Analysis Based on In Vivo Drug Concentration-Time Profile in the Gastrointestinal Tract. AB - The objective of this study is to clarify the influence of fluid volume in the gastrointestinal (GI) tract on the oral drug absorption. In vivo rat luminal concentrations of FITC-dextran (FD-4), a nonabsorbable marker, and drugs (metoprolol and atenolol) after oral coadministration as solutions with different osmolarity were determined by direct sampling of residual water in each segment of the GI tract. The luminal FD-4 concentration after oral administration as hyposmotic solution was significantly higher than that after administration as isosmotic or hyperosmotic solution. As the change in FD-4 concentration reflects the change in the volume of luminal fluid, it indicated that the luminal volume was greatly influenced by osmolality of solution ingested orally. Then, fraction of drug absorbed (Fa) in these segments was calculated by comparing the area under the luminal concentration-time curve of FD-4 with those of drugs. Fa values of two model drugs in each GI segment decreased with increase in luminal fluid volume, and the impact of the fluid volume was marked for Fa of atenolol (a low permeable drug) than for that of metoprolol (a high permeable drug). These findings should be beneficial to assure the effectiveness and safety of oral drug therapy. PMID- 25821199 TI - Biflavone Ginkgetin, a Novel Wnt Inhibitor, Suppresses the Growth of Medulloblastoma. AB - Medulloblastoma (MB) is a form of malignant brain tumor that predominantly arises in infants and children, of which approximately 25 % is due to upregulation of canonical Wnt pathway with mainly mutations in CTNNB1. Therefore, Wnt inhibitors could offer rational therapeutic strategies and chemoprevention for this malignant cancer. In our present study, we undertook a screening for antagonists of Wnt signaling from 600 natural compounds, and identified Ginkgetin, a biflavone isolated from Cephalotaxus fortunei var. alpina. Ginkgetin inhibited Wnt pathway with an IC50 value around 5.92 MUM and structure-activity relationship analysis suggested the methoxy group in Ginkgetin as a functional group. Biflavone Ginkgetin showed obvious cytotoxicity in Daoy and D283 MB cells. Cell cycle analysis by flow cytometry showed that Ginkgetin induced efficiently G2/M phase arrest in Daoy cells. Further mechanism studies showed that Ginkgetin reduced the expression of Wnt target genes, including Axin2, cyclinD1 and survivin in MB cells. The phosphorylation level of beta-catenin also decreased in a time- and concentration-dependent manner. Collectively, our data suggest that Ginkgetin is a novel inhibitor of Wnt signaling, and as such warrants further exploration as a promising anti-medulloblastoma candidate. PMID- 25821201 TI - Population genetic data for 17 autosomal STR markers in the Hani population from China. AB - The Hani is a local minority in the southwestern part of China. To establish a database of ethnic short tandem repeats (STRs), 17 autosomal STRs in the Hani ethnic group were investigated. A total of 706 unrelated individuals from three Hani settlements were genotyped using the PowerPlex 18D System. Allele frequency data and forensic parameters were evaluated. The genetic relationship among the Hani and 11 related populations was assessed. PMID- 25821200 TI - Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions. AB - The homeobox domain transcription factor NANOG, a key regulator of embryonic development and cellular reprogramming, has been reported to be broadly expressed in human cancers. Functional studies have provided strong evidence that NANOG possesses protumorigenic attributes. In addition to promoting self-renewal and long-term proliferative potential of stem-like cancer cells, NANOG-mediated oncogenic reprogramming may underlie clinical manifestations of malignant disease. In this review, we examine the molecular origin, expression, biological activities, and mechanisms of action of NANOG in various malignancies. We also consider clinical implications such as correlations between NANOG expression and cancer prognosis and/or response to therapy. We surmise that NANOG potentiates the molecular circuitry of tumorigenesis, and thus may represent a novel therapeutic target or biomarker for the diagnosis, prognosis, and treatment outcome of cancer. Finally, we present critical pending questions relating NANOG to cancer stem cells and tumor development. PMID- 25821202 TI - Deletion and duplication at DYS448 and DYS626 loci: unexpected patterns within the AZFc region of the Y-chromosome. AB - Increasing the knowledge of multiple and microstructural events within the Y chromosome may prove useful to better characterize abnormal short tandem repeats patterns complicating DNA profile interpretation. On the long arm of the human Y chromosome, such structural rearrangements were observed in azoospermia factor regions (AZFa, AZFb, AZFc) that play an important role in male fertility and also host Y-STRs commonly used in forensic genetics. Here, we describe two cases, involving two males formerly included in an Italian population study, where DYS448 and DYS626 loci, located within the AZFc region, simultaneously displayed a double deletion in one case and a double duplication in the other. With the aim of better defining the size of both events, low and high-resolution mapping by means of 16 sequence-tagged sites was performed, and unexpected discontinued patterns within the palindromic segments b1/b3 of the AZFc were identified. Extending the analysis to their respective male relatives revealed unaltered transmission of the patterns along the two pedigrees. Reviewing literature data describing DYS448-DYS626 deletion and duplication suggested no close correlation between the occurrence of multiple/microstructural events and geographical origin. PMID- 25821203 TI - Allele frequency distribution of 10 MiniSTRs in the Pashtun population of Pakistan. AB - Two hundred individual samples of Pashtun population from Khyber Pakhtunkhwa province of Pakistan were randomly evaluated through 10 MiniSTR loci (CSF1PO, D7S820, TPOX, D18S51, D2S1338, D13S317, FGA, D5S818, D21S11, and D16S539). The PCR product size was reduced in the range of 65 to 280 bp. A total of 112 alleles were observed containing allelic frequency ranging from 0.0025 to 0.4325. Statistical values for forensic and parentage analysis were calculated including combined power of discrimination (PD), combined power of exclusion (PE), and cumulative probability of matching (PM) and equaled to 0.99999999999768, 0.99984944, and 2.33 * 10(-12), respectively. These MiniSTRs show a high degree of polymorphism information content and discriminatory power which would be helpful to resolve forensic cases and establish DNA database for major population groups of Pakistan. In contrast to different populations, significant differences were also observed on these loci. PMID- 25821204 TI - Darunavir-based dual therapy of treatment-experienced HIV-infected patients: analysis from a national multicenter database. AB - BACKGROUND: We assessed the virological response of dual therapy with DRV/r, plus raltegravir, maraviroc or etravirine, in virological failure patients and in virologically suppressed patients collected in the Italian Antiretroviral Resistance Database (ARCA). MATERIAL AND METHODS: The primary endpoint was the percentage of patients remaining free of virological failure (confirmed >50 copies/mL or any change in the regimen). Subjects had a resistance test and at least one follow-up visit. Observation was censored at last visit under dual therapy and survival analysis and proportional hazard models were used. RESULTS: Sixty-seven percent of the 221 patients started DRV/r with RAL, 20.4 % with ETV, and 12.2 % with MAR; 31.2 % virological failures were observed. At survival analysis, the overall proportion of failure was 29.2 % at 1 year and 33.8 % at 2 years. The proportion of failure was lower in patients starting with undetectable vs. detectable viral load (13.3 and 25.2 % vs. 37.4 and 38.8 % at 1 and 2 years, respectively, p = 0.001 for both analyses) and in patients treated with DRV 600 BID vs. 800 QD (HR: 0.56, 95 % CI: 0.31-0.99, p < 0.05). By regimen, the adjusted proportional model showed no significant difference among the three regimens. A significant lower risk of failure was associated with higher GSS (HIV-DB HR: 0.53, 95 % CI: 0.32-0.88, p = 0.014; Rega 0.60, 0.40-0.88, p < 0.01; ANRS 0.55, 0.34-0.90, p = 0.017), while a higher risk of failure with detectable HIV-RNA (3.02, 1.70-5.72, p < 0.001). CONCLUSIONS: Among experienced patients, the best candidates for dual-therapy regimens including DRV/r are those with undetectable viral load and higher GSS. PMID- 25821205 TI - Energetics and structural characterization of isomers using ion mobility and gas phase H/D exchange: Learning from lasso peptides. AB - State-of-the-art characterization of proteins using MS namely relies on fragmentation methods that allow exploring featured dissociative reaction pathways. These pathways are often initiated by a series of potentially informative mass-constant conformational changes that are nonetheless frequently overlooked by lack of adequate investigation techniques. In the present study, we propose a methodology to readily address both structural and energetic aspects of stereoisomerization reactions using ion mobility coupled with MS. To this end, a commercial spectrometer was used as a reactor comprising an energy resolved collisional activation step intended at promoting controlled conformational changes and a structural assignment step dedicated to the identification of the generated isomers. This identification relies on ion mobility and other on-line coupled techniques, namely an originally designed gas-phase H/D exchange experiment. We here apply this methodology to characterize the isomerization kinetics of capistruin, a 19-residue long lasso-folded peptide. We expect this approach to bring insights into the physical origin of global dissociation thresholds monitored in MS/MS experiments and to set a promising basis for quantitative investigations of the stability of different molecular folds. PMID- 25821206 TI - Bioactive Microsphere-Based Scaffolds Containing Decellularized Cartilage. AB - The aim of this study was to fabricate mechanically functional microsphere-based scaffolds containing decellularized cartilage (DCC), with the hypothesis that this approach would induce chondrogenesis of rat bone marrow-derived mesenchymal stem cells (rBMSCs) in vitro. The DCC was derived from porcine articular cartilage and decellularized using a combination of physical and chemical methods. Four types of scaffolds were fabricated: poly(d,l-lactic-co-glycolic acid) (PLGA) only (negative control), TGF-beta-encapsulated (positive control), PLGA surface coated with DCC, and DCC-encapsulated. These scaffolds were seeded with rBMSCs and cultured up to 6 weeks. The compressive modulus of the DCC-coated scaffolds prior to cell seeding was significantly lower than all other scaffold types. Gene expression was comparable between DCC-encapsulated and TGF-beta encapsulated groups. Notably, DCC-encapsulated scaffolds contained 70% higher glycosaminoglyan (GAG) content and 85% more hydroxyproline compared to the TGF beta group at week 3 (with baseline levels subtracted out from acellular DCC scaffolds). Certainly, bioactivity was demonstrated in eliciting a biosynthetic response from the cells with DCC, although true demonstration of chondrogenesis remained elusive under the prescribed conditions. Encapsulation of DCC appeared to lead to improved cell performance relative to coating with DCC, although this finding may be a dose-dependent observation. Overall, DCC introduced via microsphere-based scaffolds appears to be promising as a bioactive approach to cartilage regeneration, although additional studies will be required to conclusively demonstrate chondroinductivity. PMID- 25821207 TI - Evaluation of new transparent tungsten containing nanocomposites for radiation protection screens. AB - Evaluation of the new lead-free optically transparent nanocomposites is provided in this paper along with the introduction to their fabrication technologies and the results of investigation of their X-ray attenuating and optical properties before and after their exposure to high doses. These materials might be considered for the construction of X-ray protective screens that are used to protect medical personnel against scattered X rays during close-to patient operations. Rough selection of possible composites was performed according to X ray attenuation modelling results. Experimental nanocomposites were prepared dissolving tungstates in different solvents or embedding tungsten structures into polymer matrix. It was found that the lead equivalent thickness of fabricated experimental samples varied from 0.15 to 0.75 mmPb and was higher for samples, containing polyanions of phosphotungstic acid. Transparency of the experimental samples to visible light varied from 20 to 60 % and was slightly increasing with irradiation dose due to radiation-induced processes in polymers. PMID- 25821208 TI - Radiation exposure during X-ray examinations in a large paediatric hospital in Serbia. AB - Objective of this work is to evaluate radiation exposure from X-ray examinations in a large paediatric hospital in Serbia, including radiographic, fluoroscopic and computed tomography (CT) examinations in four age groups: 0-1, 1-5, 5-10 and 10-15 y. Incident air kerma was assessed for the following radiographies: chest (AP, PA, LAT), spine (AP, LAT), pelvis (AP), urinary tract (AP, PA) and skull (AP, PA, LAT). Kerma-area product was measured for the fluoroscopy examinations: barium swallow, barium meal, barium enema and micturating cystography. Dose in CT was assessed in terms of volume CT dose index and dose-length product for examinations of the head, chest and abdomen. The collected data were compared with other similar studies, which indicated a need to expand such survey to other paediatric hospitals in Serbia. PMID- 25821209 TI - Basic radiation protection training for nurses and paramedical personnel: Belgian experience and future perspectives. AB - When using ionising radiation for medical diagnosis or treatment of patients, understanding of relevant radiation protection principles and issues is indispensable. In Belgium, nurses and paramedical staff are required to acquire knowledge for protecting the patient against the detrimental effects of ionising radiation by means of a vocational training course. The experience with and challenges for this training course are presented here from a lecturer's point of view, together with a proposal for a future approach that harmonises the training content, its level and quality, according to European recommended standards. PMID- 25821210 TI - Patient dosimetry in nuclear medicine. AB - In diagnostic nuclear medicine, the biokinetics of the radiopharmaceutical (actually of the radionuclide) is determined for a number of representative patients. At therapy, it is essential to determine the patient's individual biokinetics of the radiopharmaceutical in order to calculate the absorbed doses to critical normal organs/tissues and to the target volume(s) with high accuracy. For the diagnostic situations, there is still a lack of quantitative determinations of the organ/tissue contents of radiopharmaceuticals and their variation with time. Planar gamma camera imaging using the conjugate view technique combined with a limited number of SPECT/CT images is the main method for such studies. In a similar way, PET/CT is used for 3D image-based internal dosimetry for PET substances. The transition from stylised reference phantoms to voxel phantoms will lead to improved dose estimates for diagnostic procedures. Examples of dose coefficients and effective doses for diagnostic substances are given. For the therapeutic situation, a pre-therapeutic low activity administration is used for quantitative measurements of organ/tissue distribution data by a gamma camera or a SPECT- or PET-unit. Together with CT and/or MR images this will be the base for individual dose calculations using Monte Carlo technique. Treatments based on administered activity should only be used if biological variations between patients are small or if a pre-therapeutic activity administration is impossible. PMID- 25821211 TI - Experience in retake analysis for digital mammography at a university hospital. AB - Data from one digital mammograph (flat detector active area of 19.2 * 23 cm(2)) were collected over a 1-year period using locally developed software in order to evaluate retakes, their rates, their causes and the possible measures to reduce their occurrence. Among them, 7.1 % of the images were marked as repetitions, and in 16 % of the studies, at least one image was repeated. When evaluating causes of retakes, the primary cause was incorrect positioning (49 %), closely followed by additional retakes in cases of large breasts (44 %). When dealing with large breasts and using a small flat panel, additional images were necessary to fully visualise the breast, and as a consequence, some breast regions received repeated radiation exposure. Moreover, a small detector increases retakes in breasts slightly wrongly positioned. To try and reduce the retake rate, it is important to plan training sessions based on images selected from the retake analysis. PMID- 25821212 TI - Comparison of image quality among three X-ray systems for chest radiography: first step in optimisation. AB - The aim of this study was to compare the performance of three digital X-ray systems [one flat-panel (DR) and two computed radiography (CR)] for chest radiography in terms of the entrance surface air kerma (ESAK) delivered to a polymethyl methacrylate phantom of 20 cm (equivalent to an adult patient) and image quality through of numerical evaluations using a test object (TO). The tube charge applied was ranged from 0.6 to 32 mAs, to a fixed tension of 125 kVp. The DR system presented the highest mean values of ESAK (615.9 uGy) along with the highest signal-to-noise ratio values, whereas CR systems showed a better high contrast spatial resolution. Differences were statistically significant in both cases regarding the tube charge used. Thus, this parameter should be mainly considered to optimise the radiological protection through exposure settings selected. This survey represents the first effort to achieve optimisation in digital radiology for Chile. PMID- 25821213 TI - Indication-based diagnostic reference levels for adult CT-examinations in Finland. AB - A diagnostic reference level (DRL) is a predefined dose level, which should not be exceeded in an examination that is conducted appropriately on an average-sized patient. Since dose from only one examination should not be compared with a DRL, the average dose from a good sample of at least 10 average-sized patients should be compared. The previous DRLs for computed tomography (CT)-examinations for adults in Finland were issued in 2007 and only covered examinations conducted on a particular body region. Because the image quality requirements, and thus the dose needed, vary between different indications, there has been a call for indication-based DRLs for CT. The new indication-based DRLs for CT came into effect on June 2013. They are based on a dose survey performed in 2012. Doses were collected from examinations conducted on a particular body region, based on some indication and from some special examination types. The DRLs were set according to the third quartile approach. On average, the DRLs for a particular body region dropped ~ 20 % from the previous DRLs. PMID- 25821214 TI - Evaluation of automated CDMAM readings for non-standard CDMAM imaging conditions: grid-less acquisitions and scatter correction. AB - Recently, Siemens introduced a software-based scatter correction in combination with grid-less digital mammography for dose-reduced breast imaging. In this study, the potential dose reduction when compared with using a grid was calculated. Image quality was evaluated using the CDMAM phantom. Nine hundred and sixty CDMAM measurements were performed with and without grid. The images were analysed with the CDCOM software. The correlation of CDCOM readings of gold thickness thresholds with human readings for grid-less imaging was found to be linear, with slope 2.157 and off-set 0.024 (R(2) = 1), validating the further use of CDCOM. Dose reduction for 21, 32, 45, 60, 75 and 90 mm equivalent breast thickness was found to be 28, 17, 21, 18, 8 and 3 %. Scatter correction did not influence CDCOM readings, but image homogeneity was improved. Grid-less acquisitions, with or without scatter correction, can be used for reducing the dose while maintaining image quality as evaluated from the CDMAM phantom. PMID- 25821215 TI - Evaluation of an automated FDG dose infuser to PET-CT patients. AB - An experience with an automated infuser device at a university hospital is presented in this paper. Occupational doses at operators' fingertips were measured using optically stimulated luminescence dosemeters for two different scenarios: (i) using a semi-automatic system to prepare the fluorodesoxiglucose (FDG) injections that were delivered to the patient manually and (ii) using an automated infusion device that prepares and delivers the FDG dose. The accuracy of the activity prepared by the automatic system was also verified. Reductions in fingertip doses of 60 % using the fully automatic system have been measured. The difference between the programmed and the delivered activity was 2 %. The use of the automatic infuser in the authors' institution has led to a substantial reduction in hand radiation doses. But contamination risks, even though reduced, still exist; therefore, radioisotope manipulation should follow strict radiation protection rules to avoid incidents. Improved accuracy in dose delivery reduces chances of dose misadministration. PMID- 25821216 TI - Cutting edge: Antimalarial drugs inhibit IFN-beta production through blockade of cyclic GMP-AMP synthase-DNA interaction. AB - Type I IFN is strongly implicated in the pathogenesis of systemic autoimmune diseases, such as lupus, and rare monogenic IFNopathies, including Aicardi Goutieres syndrome. Recently, a new DNA-activated pathway involving the enzyme cyclic GMP-AMP synthase (cGAS) was described and potentially linked to Aicardi Goutieres syndrome. To identify drugs that could potentially inhibit cGAS activity, we performed in silico screening of drug libraries. By computational analysis, we identified several antimalarial drugs (AMDs) that were predicted to interact with the cGAS/dsDNA complex. Our studies validated that several AMDs were effective inhibitors of IFN-beta production and that they functioned by inhibiting dsDNA stimulation of cGAS. Because AMDs have been widely used in human diseases and have an excellent safety profile, our findings suggest new therapeutic strategies for the treatment of severe debilitating diseases associated with type I IFNs due to cGAS activation. PMID- 25821217 TI - A novel IL-25 signaling pathway through STAT5. AB - IL-25 is a member of the IL-17 family of cytokines that promotes Th2 cell mediated inflammatory responses. IL-25 signals through a heterodimeric receptor (IL-25R) composed of IL-17RA and IL-17RB, which recruits the adaptor molecule Act1 for downstream signaling. Although the role of IL-25 in potentiating type 2 inflammation is well characterized by its ability to activate the epithelium as well as T cells, the components of its signaling cascade remain largely unknown. In this study, we found that IL-25 can directly activate STAT5 independently of Act1. Furthermore, conditional STAT5 deletion in T cells or epithelial cells led to a defective IL-25-initiated Th2 polarization as well as defective IL-25 enhancement of Th2 responses. Finally, we found that STAT5 is recruited to the IL 25R in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Together, these findings reveal a novel Act1-independent IL-25 signaling pathway through STAT5 activation. PMID- 25821218 TI - Endoplasmic reticulum stress-induced IRE1alpha activation mediates cross-talk of GSK-3beta and XBP-1 to regulate inflammatory cytokine production. AB - IL-1beta and TNF-alpha are important proinflammatory cytokines that respond to mutated self-antigens of tissue damage and exogenous pathogens. The endoplasmic reticulum (ER) stress and unfolded protein responses are related to the induction of proinflammatory cytokines. However, the detailed molecular pathways by which ER stress mediates cytokine gene expression have not been investigated. In this study, we found that ER stress-induced inositol-requiring enzyme (IRE)1alpha activation differentially regulates proinflammatory cytokine gene expression via activation of glycogen synthase kinase (GSK)-3beta and X-box binding protein (XBP)-1. Surprisingly, IL-1beta gene expression was modulated by IRE1alpha mediated GSK-3beta activation, but not by XBP-1. However, IRE1alpha-mediated XBP 1 splicing regulated TNF-alpha gene expression. SB216763, a GSK-3 inhibitor, selectively inhibited IL-1beta gene expression, whereas the IRE1alpha RNase inhibitor STF083010 suppressed only TNF-alpha production. Additionally, inhibition of GSK-3beta greatly increased IRE1alpha-dependent XBP-1 splicing. Our results identify an unsuspected differential role of downstream mediators GSK 3beta and XBP-1 in ER stress-induced IRE1alpha activation that regulates cytokine production through signaling cross-talk. These results have important implications in the regulation of inflammatory pathways during ER stress, and they suggest novel therapeutic targets for diseases in which meta-inflammation plays a key role. PMID- 25821219 TI - Antibodies generated against Streptococci protect in a mouse model of disseminated aspergillosis. AB - Invasive aspergillosis (IA) resulting from infection by Aspergillus fumigatus is a leading cause of death in immunosuppressed populations. There are limited therapeutic options for this disease and currently no vaccine. There is evidence that some anti-A. fumigatus mAbs can provide protection against IA. However, vaccine development has been impeded by a paucity of immunological targets on this organism demonstrated to provide protective responses. Sialylated oligosaccharide epitopes found on a variety of pathogens, including fungi and group B streptococci (GBS), are thought to be major virulence factors of these organisms facilitating pathogen attachment to host cells and modulating complement activation and phagocytosis. Because some of these oligosaccharide structures are conserved across kingdoms, we screened a panel of mAbs raised against GBS serotypes for reactivity to A. fumigatus. This approach revealed that SMB19, a GBSIb type-specific mAb, reacts with A. fumigatus conidia and hyphae. The presence of this Ab in mice, as a result of passive or active immunization, or by enforced expression of the SMB19 H chain as a transgene, results in significant protection in both i.v. and airway-induced models of IA. This study demonstrates that some Abs generated against bacterial polysaccharides engage fungal pathogens and promote their clearance in vivo and thus provide rationale of alternative strategies for the development of vaccines or therapeutic mAbs against these organisms. PMID- 25821221 TI - Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORgammat. AB - RORgammat is a key transcription factor that controls the development and function of inflammatory Th17. The mechanisms that regulate RORgammat stability remain unclear. We report that Th17 cells highly express the deubiquitinase ubiquitin-specific protease (USP)4, which is essential for maintaining RORgammat and Th17 cell function. Inhibition of the catalytic activity of USP4 with vialinin A, a compound derived from Chinese traditional medicine, dampened Th17 differentiation. USP4 interacted and deubiquitinated K48-linked polyubiquitination of RORgammat, thereby promoting RORgammat function and IL-17A transcription. Interestingly, TGF-beta plus IL-6 enhanced USP4-mediated deubiquitination of RORgammat. Moreover, USP4 and IL-17 mRNA, but not RORgammat mRNA, were significantly elevated in CD4(+) T cells from patients with rheumatic heart disease. Thus, USP4 could be a novel therapeutic target for the treatment of Th17-modulated autoimmune diseases. PMID- 25821220 TI - Regulatory T cells require TCR signaling for their suppressive function. AB - Regulatory T cells (Tregs) are a subset of CD4(+) T cells that maintain immune tolerance in part by their ability to inhibit the proliferation of conventional CD4(+) T cells (Tconvs). The role of the TCR and the downstream signaling pathways required for this suppressive function of Tregs are not fully understood. To yield insight into how TCR-mediated signals influence Treg suppressive function, we assessed the ability of Tregs with altered TCR-mediated signaling capacity to inhibit Tconv proliferation. Mature Tregs deficient in Src homology 2 domain containing leukocyte protein of 76 kDa (SLP-76), an adaptor protein that nucleates the proximal signaling complex downstream of the TCR, were unable to inhibit Tconv proliferation, suggesting that TCR signaling is required for Treg suppressive function. Moreover, Tregs with defective phospholipase C gamma (PLCgamma) activation due to a Y145F mutation of SLP-76 were also defective in their suppressive function. Conversely, enhancement of diacylglycerol-mediated signaling downstream of PLCgamma by genetic ablation of a negative regulator of diacylglycerol kinase zeta increased the suppressive ability of Tregs. Because SLP-76 is also important for integrin activation and signaling, we tested the role of integrin activation in Treg-mediated suppression. Tregs lacking the adaptor proteins adhesion and degranulation promoting adapter protein or CT10 regulator of kinase/CT10 regulator of kinase-like, which are required for TCR mediated integrin activation, inhibited Tconv proliferation to a similar extent as wild-type Tregs. Together, these data suggest that TCR-mediated PLCgamma activation, but not integrin activation, is required for Tregs to inhibit Tconv proliferation. PMID- 25821222 TI - Microtubule nucleation in mouse bone marrow-derived mast cells is regulated by the concerted action of GIT1/betaPIX proteins and calcium. AB - Ag-mediated activation of mast cells initiates signaling events leading to Ca(2+) response, release of allergic mediators from cytoplasmic granules, and synthesis of cytokines and chemokines. Although microtubule rearrangement during activation has been described, the molecular mechanisms that control their remodeling are largely unknown. Microtubule nucleation is mediated by complexes that are formed by gamma-tubulin and gamma-tubulin complex proteins. In this study, we report that, in bone marrow-derived mast cells (BMMCs), gamma-tubulin interacts with p21 activated kinase interacting exchange factor beta (betaPIX) and G protein-coupled receptor kinase-interacting protein (GIT)1. Microtubule regrowth experiments showed that the depletion of betaPIX in BMMCs stimulated microtubule nucleation, whereas depletion of GIT1 led to the inhibition of nucleation compared with control cells. Phenotypic rescue experiments confirmed that betaPIX and GIT1 represent negative and positive regulators of microtubule nucleation in BMMCs, respectively. Live-cell imaging disclosed that both proteins are associated with centrosomes. Immunoprecipitation and pull-down experiments revealed that an enhanced level of free cytosolic Ca(2+) affects gamma-tubulin properties and stimulates the association of GIT1 and gamma-tubulin complex proteins with gamma tubulin. Microtubule nucleation also was affected by Ca(2+) level. Moreover, in activated BMMCs, gamma-tubulin formed complexes with tyrosine-phosphorylated GIT1. Further experiments showed that GIT1 and betaPIX are involved in the regulation of such important physiological processes as Ag-induced chemotaxis and degranulation. Our study provides for the first time, to our knowledge, a possible mechanism for the concerted action of tyrosine kinases, GIT1/betaPIX proteins, and Ca(2+) in the propagation of signals leading to the regulation of microtubule nucleation in activated mast cells. PMID- 25821223 TI - Notch signaling enhances FcepsilonRI-mediated cytokine production by mast cells through direct and indirect mechanisms. AB - Th2-type cytokines and TNF-alpha secreted by activated mast cells upon cross linking of FcepsilonRI contribute to the development and maintenance of Th2 immunity to parasites and allergens. We have previously shown that cytokine secretion by mouse mast cells is enhanced by signaling through Notch receptors. In this study, we investigated the molecular mechanisms by which Notch signaling enhances mast cell cytokine production induced by FcepsilonRI cross-linking. FcepsilonRI-mediated production of cytokines, particularly IL-4, was significantly enhanced in mouse bone marrow-derived mast cells by priming with Notch ligands. Western blot analysis showed that Notch signaling augmented and prolonged FcepsilonRI-mediated phosphorylation of MAPKs, mainly JNK and p38 MAPK, through suppression of the expression of SHIP-1, a master negative regulator of FcepsilonRI signaling, resulting in the enhanced production of multiple cytokines. The enhancing effect of Notch ligand priming on multiple cytokine production was abolished by knockdown of Notch2, but not Notch1, and FcepsilonRI mediated production of multiple cytokines was enhanced by retroviral transduction with the intracellular domain of Notch2. However, only IL-4 production was enhanced by both Notch1 and Notch2. The enhancing effect of Notch signaling on IL 4 production was lost in bone marrow-derived mast cells from mice lacking conserved noncoding sequence 2, which is located at the distal 3' element of the Il4 gene locus and contains Notch effector RBP-J binding sites. These results indicate that Notch2 signaling indirectly enhances the FcepsilonRI-mediated production of multiple cytokines, and both Notch1 and Notch2 signaling directly enhances IL-4 production through the noncoding sequence 2 enhancer of the Il4 gene. PMID- 25821224 TI - FcgammaRIIB prevents inflammatory type I IFN production from plasmacytoid dendritic cells during a viral memory response. AB - The type I IFN (IFN-alpha) response is crucial for viral clearance during primary viral infections. Plasmacytoid dendritic cells (pDCs) are important early responders during systemic viral infections and, in some cases, are the sole producers of IFN-alpha. However, their role in IFN-alpha production during memory responses is unclear. We found that IFN-alpha production is absent during a murine viral memory response, despite colocalization of virus and pDCs to the splenic marginal zone. The absence of IFN was dependent on circulating Ab and was reversed by the transgenic expression of the activating human FcgammaRIIA receptor on pDCs. Furthermore, FcgammaRIIB was required for Sendai virus immune complex uptake by splenic pDCs in vitro, and internalization via FcgammaRIIb prevented cargo from accessing TLR signaling endosomes. Thus, pDCs bind viral immune complexes via FcgammaRIIB and prevent IFN-alpha production in vivo during viral memory responses. This Ab-dependent IFN-alpha regulation may be an important mechanism by which the potentially deleterious effects of IFN-alpha are prevented during a secondary infection. PMID- 25821225 TI - Personal Protective Equipment for Filovirus Epidemics: A Call for Better Evidence. AB - Personal protective equipment (PPE) is an important part of worker protection during filovirus outbreaks. The need to protect against a highly virulent fluid borne pathogen in the tropical environment imposes a heat stress on the wearer that is itself a safety risk. No evidence supports the choice of PPE employed in recent outbreaks, and standard testing procedures employed by the protective garment industry do not well simulate filovirus exposure. Further research is needed to determine the appropriate PPE for filoviruses and the heat stress that it imposes. PMID- 25821226 TI - Ebola Virus Glycoprotein Promotes Enhanced Viral Egress by Preventing Ebola VP40 From Associating With the Host Restriction Factor BST2/Tetherin. AB - BACKGROUND: BST2/tetherin is an innate immune molecule with the unique ability to restrict the egress of human immunodeficiency virus (HIV) and other enveloped viruses, including Ebola virus (EBOV). Coincident with this discovery was the finding that the HIV Vpu protein down-regulates BST2 from the cell surface, thereby promoting viral release. Evidence suggests that the EBOV envelope glycoprotein (GP) also counteracts BST2, although the mechanism is unclear. RESULTS: We find that total levels of BST2 remain unchanged in the presence of GP, whereas surface BST2 is significantly reduced. GP is known to sterically mask surface receptors via its mucin domain. Our evaluation of mutant GP molecules indicate that masking of BST2 by GP is probably responsible for the apparent surface BST2 down-regulation; however, this masking does not explain the observed virus-like particle egress enhancement. We discovered that VP40 coimmunoprecipitates and colocalizes with BST2 in the absence but not in the presence of GP. CONCLUSIONS: These results suggest that GP may overcome the BST2 restriction by blocking an interaction between VP40 and BST2. Furthermore, we have observed that GP may enhance BST2 incorporation into virus-like particles. Understanding this novel EBOV immune evasion strategy will provide valuable insights into the pathogenicity of this deadly pathogen. PMID- 25821228 TI - Reply to Thysen et al. PMID- 25821227 TI - Does Influenza Vaccination Modify Influenza Severity? Data on Older Adults Hospitalized With Influenza During the 2012-2013 Season in the United States. AB - BACKGROUND: Some studies suggest that influenza vaccination might be protective against severe influenza outcomes in vaccinated persons who become infected. We used data from a large surveillance network to further investigate the effect of influenza vaccination on influenza severity in adults aged >=50 years who were hospitalized with laboratory-confirmed influenza. METHODS: We analyzed influenza vaccination and influenza severity using Influenza Hospitalization Surveillance Network (FluSurv-NET) data for the 2012-2013 influenza season. Intensive care unit (ICU) admission, death, diagnosis of pneumonia, and hospital and ICU lengths of stay served as measures of disease severity. Data were analyzed by multivariable logistic regression, parametric survival models, and propensity score matching (PSM). RESULTS: Overall, no differences in severity were observed in the multivariable logistic regression model. Using PSM, adults aged 50-64 years (but not other age groups) who were vaccinated against influenza had a shorter length of ICU stay than those who were unvaccinated (hazard ratio for discharge, 1.84; 95% confidence interval, 1.12-3.01). CONCLUSIONS: Our findings show a modest effect of influenza vaccination on disease severity. Analysis of data from seasons with different predominant strains and higher estimates of vaccine effectiveness are needed. PMID- 25821229 TI - Changes in BCG Vaccination Policy Should Consider the Effect on Child Health. PMID- 25821230 TI - A case of lung adenocarcinoma with multiple cavitary metastases. PMID- 25821231 TI - Severe ischemic colitis after treatment of bile-duct cancer using gemcitabine and cisplatin. PMID- 25821232 TI - Morphological distribution of lung cancer from Cancer Incidence in Five Continents Vol. X. PMID- 25821233 TI - Reactive oxygen species-mediated bacterial killing by B lymphocytes. AB - Regulated production of ROS is mainly attributed to Nox family enzymes. In neutrophil granulocytes and macrophages, Nox2 has a crucial role in bacterial killing, and the absence of phagocytic ROS production leads to the development of CGD. Expression of Nox2 was also described in B lymphocytes, where the role of the enzyme is still poorly understood. Here, we show that peritoneal B cells, which were shown recently to possess phagocytic activity, have a high capacity to produce ROS in a Nox2-dependent manner. In phagocytosing B cells, intense intraphagosomal ROS production is detected. Finally, by studying 2 animal models of CGD, we demonstrate that phagocyte oxidase-deficient B cells have a reduced capacity to kill bacteria. Our observations extend the number of immune cell types that produce ROS to kill pathogens. PMID- 25821235 TI - When Did the Swahili Become Maritime? AB - : In this article, we examine an assumption about the historic Swahili of the eastern African coast: that they were a maritime society from their beginnings in the first millennium C.E. Based on historical and archaeological data, we suggest that, despite their proximity to and use of the sea, the level of maritimity of Swahili society increased greatly over time and was only fully realized in the early second millennium C.E. Drawing on recent theorizing from other areas of the world about maritimity as well as research on the Swahili, we discuss three arenas that distinguish first- and second-millennium coastal society in terms of their maritime orientation. These are variability and discontinuity in settlement location and permanence; evidence of increased engagement with the sea through fishing and sailing technology; and specialized architectural developments involving port facilities, mosques, and houses. The implications of this study are that we must move beyond coastal location in determining maritimity; consider how the sea and its products were part of social life; and assess whether the marine environment actively influences and is influenced by broader patterns of sociocultural organization, practice, and belief within Swahili and other societies. [maritime, fishing and sailing, long-distance trade, Swahili, eastern Africa]. RESUMEN: En este articulo, evaluamos la hipotesis de que los pueblos Swahili de la costa oriental africana fueron una sociedad maritima a partir del primer milenio E.C. Basados en informacion historica y arqueologica, proponemos que la asociacion de la sociedad Swahili con el mar incremento considerablemente con el tiempo y se manifesto de una forma significativa particularmente desde principios del segundo milenio E.C. Utilizando teorias recientes sobre maritimidad en otras areas del mundo, asi como investigaciones sobre los Swahili, discutimos tres temas que marcan las diferencias del nivel de orientacion maritima de esta sociedad costera entre el primer y segundo milenio. Estas son la variabilidad y discontinuidad en la localizacion y permanencia de los asentamientos; evidencia de una conexion mayor con el mar a traves de la tecnologia de pesca y navegacion; y desarrollos arquitectonicos especializados que incluyen instalaciones portuarias, mezquitas, y casas. Las implicaciones de este estudio indican que debemos considerar otros aspectos de una sociedad aparte de su localizacion costera para determinar su maritimidad. Hay que considerar como el mar y sus productos son parte de la vida social y evaluar si existe una influencia reciproca entre el ambiente maritimo y los patrones de organizacion sociocultural, las practicas, y las creencias de los Swahili y otras sociedades. [maritimo, pesca y navegacion, comercio a larga distancia, Swahili, Africa Oriental]. PMID- 25821236 TI - The quality of social relationships in ravens. AB - The quality of a social relationship represents the history of past social interactions between two individuals, from which the nature and outcome of future interactions can be predicted. Current theory predicts that relationship quality comprises three separate components, its value, compatibility and security. This study is the first to investigate the components of relationship quality in a large-brained bird. Following methods recently used to obtain quantitative measures of each relationship quality component in chimpanzees, Pan troglodytes, we entered data on seven behavioural variables from a group of 11 ravens, Corvus corax, into a principal components analysis. The characteristics of the extracted components matched those predicted for value, compatibility and security, and were labelled as such. When the effects of kinship and sex combination on each relationship quality component were analysed, we found that kin had more valuable relationships, whereas females had less secure and compatible relationships, although the effect of sex combination on compatibility only applied to nonkin. These patterns are consistent with what little knowledge we have of raven relationships from aviary studies and show that the components of relationship quality in ravens may indeed be analogous to those in chimpanzees. PMID- 25821237 TI - Appraisal and coping styles account for the effects of temperament on preadolescent adjustment. AB - Temperament, appraisal, and coping are known to underlie emotion regulation, yet less is known about how these processes relate to each other across time. We examined temperamental fear, frustration, effortful control, and impulsivity, positive and threat appraisals, and active and avoidant coping as processes underpinning the emotion regulation of pre-adolescent children managing stressful events. Appraisal and coping styles were tested as mediators of the longitudinal effects of temperamental emotionality and self-regulation on adjustment using a community sample (N=316) of preadolescent children (8-12 years at T1) studied across one year. High threat appraisals were concurrently related to high fear and impulsivity, whereas effortful control predicted relative decreases in threat appraisal. High fear was concurrently related to high positive appraisal, and impulsivity predicted increases in positive appraisal. Fear was concurrently related to greater avoidant coping, and impulsivity predicted increases in avoidance. Frustration predicted decreases in active coping. These findings suggest temperament, or dispositional aspects of reactivity and regulation, relates to concurrent appraisal and coping processes and additionally predicts change in these processes. Significant indirect effects indicated that appraisal and coping mediated the effects of temperament on adjustment. Threat appraisal mediated the effects of fear and effortful control on internalizing and externalizing problems, and avoidant coping mediated the effect of impulsivity on internalizing problems. These mediated effects suggest that one pathway through which temperament influences adjustment is pre-adolescents' appraisal and coping. Findings highlight temperament, appraisal and coping as emotion regulation processes relevant to children's adjustment in response to stress. PMID- 25821234 TI - Phosphoinositide-specific phospholipase C in health and disease. AB - Phospholipases are widely occurring and can be found in several different organisms, including bacteria, yeast, plants, animals, and viruses. Phospholipase C (PLC) is a class of phospholipases that cleaves phospholipids on the diacylglycerol (DAG) side of the phosphodiester bond producing DAGs and phosphomonoesters. Among PLCs, phosphoinositide-specific PLC (PI-PLC) constitutes an important step in the inositide signaling pathways. The structures of PI-PLC isozymes show conserved domains as well as regulatory specific domains. This is important, as most PI-PLCs share a common mechanism, but each of them has a peculiar role and can have a specific cell distribution that is linked to a specific function. More importantly, the regulation of PLC isozymes is fundamental in health and disease, as there are several PLC-dependent molecular mechanisms that are associated with the activation or inhibition of important physiopathological processes. Moreover, PI-PLC alternative splicing variants can play important roles in complex signaling networks, not only in cancer but also in other diseases. That is why PI-PLC isozymes are now considered as important molecules that are essential for better understanding the molecular mechanisms underlying both physiology and pathogenesis, and are also potential molecular targets useful for the development of innovative therapeutic strategies. PMID- 25821238 TI - Reaction Pathway and Free Energy Barrier for Urea Elimination in Aqueous Solution. AB - To accurately predict the free energy barrier for urea elimination in aqueous solution, we examined the reaction coordinates for the direct and water-assisted elimination pathways, and evaluated the corresponding free energy barriers by using the surface and volume polarization for electrostatics (SVPE) model-based first-principles electronic-structure calculations. Based on the computational results, the water-assisted elimination pathway is dominant for urea elimination in aqueous solution, and the corresponding free energy barrier is 25.3 kcal/mol. The free energy barrier of 25.3 kcal/mol predicted for the dominant reaction pathway of urea elimination in aqueous solution is in good agreement with available experimental kinetic data. PMID- 25821239 TI - Does Hospital Competition Save Lives? Evidence from the English NHS Patient Choice Reforms. AB - Recent substantive reforms to the English National Health Service expanded patient choice and encouraged hospitals to compete within a market with fixed prices. This study investigates whether these reforms led to improvements in hospital quality. We use a difference-in-difference-style estimator to test whether hospital quality (measured using mortality from acute myocardial infarction) improved more quickly in more competitive markets after these reforms came into force in 2006. We find that after the reforms were implemented, mortality fell (i.e. quality improved) for patients living in more competitive markets. Our results suggest that hospital competition can lead to improvements in hospital quality. PMID- 25821240 TI - Responses of soil nutrient concentrations and stoichiometry to different human land uses in a subtropical tidal wetland. AB - We studied the impacts of anthropogenic changes in land use on the stoichiometric imbalance of soil carbon (C), nitrogen (N), phosphorus (P) and potassium (K) in Phragmites australis wetlands in the Minjiang River estuary. We compared five areas with different land uses: P. australis wetland (control), grassland, a mudskipper breeding flat, pond aquaculture and rice cropland. Human activity has affected the elemental and stoichiometric compositions of soils through changes in land use. In general, soil C and N concentrations were lower and total soil K concentrations were higher at the sites under human land uses relative to the control site, and total soil P concentrations were generally not significantly different. The close relationship between total soil C and N concentrations in all cases, including fertilization with N, suggested that N was the most limiting nutrient in these wetlands. Lower soil N concentrations and similar soil P concentrations and higher soil K concentrations under human land-use activities suggest that human activity has increased the role of N limitation in these wetlands. Only grassland use increases soil N contents (only in the 0-10 cm of soil). Despite N fertilization, lower soil N concentrations were also observed in the rice cropland, indicating the difficulty of avoiding N limitation in these wetlands. The observed lower soil N:P ratio, together with higher soil P and K availabilities in rice croplands, is consistent with the tendency of human activity to change the competitive relationships of plants, in this case favoring species adapted to high rates of growth (low N:P ratio) and/or favoring plants with high demands for P and K. Both, soil C storage and respiration were higher in grasslands, likely due to the introduction of grasses, which led to a high density of plants, increased grazing activity and soil compaction. Soil C storage and respiration were lower under human land uses, except in the rice cropland, with respect to natural wetland. Using overall data, soil C storage and respiration were correlated, indicating that soil respiration was correlated with plant productivity. In this wetland area the impacts of different human land-uses on soil stoichiometry and C-cycle can be very different depending on the activity. Further regeneration of natural communities can be determined by the previous type of land-use. PMID- 25821241 TI - The Criminal Corpse, Anatomists and the Criminal Law: Parliamentary Attempts to Extend the Dissection of Offenders in Late Eighteenth-Century England. AB - In the later eighteenth century two schemes were introduced in Parliament for extending the practice of handing over the bodies of executed offenders to anatomists for dissection. Both measures were motivated by the needs of anatomy - including the improvement of surgical skill, the development of medical teaching in the provinces, and for conducting public anatomical demonstrations. Yet both failed to pass into law due to concerns about the possibly damaging effects in terms of criminal justice. Through a detailed analysis of the origins and progress of these two parliamentary measures - a moment when the competing claims of anatomy and criminal justice vied for supremacy over the criminal corpse - the following article sheds light on judicial attitudes to dissection as a method of punishment and adds to our understanding of why the dread of dissection would come to fall upon the dead poor (rather than executed offenders) in the nineteenth century. PMID- 25821242 TI - ENTRY IN THE ADHD DRUGS MARKET: WELFARE IMPACT OF GENERICS AND ME-TOO'S. AB - Recent decades have seen a growth in treatments for attention deficit hyperactivity disorder (ADHD) including many branded and generic drugs. In the early 2000's, new drug entry dramatically altered market shares. We estimate a demand system for ADHD drugs and assess the welfare impact of new drugs. We find that entry induced large welfare gains by reducing prices of substitute drugs, and by providing alternative delivery mechanisms for existing molecules. Our results suggest that the success of follow-on patented drugs may come from unanticipated innovations like delivery mechanisms, a factor ignored by proposals to retard new follow-on drug approvals. PMID- 25821243 TI - The design of trapping devices in pollination traps of the genus Arum (Araceae) is related to insect type. AB - Pollinators have long been known to select for floral traits, but the nature of this relationship has been little investigated in trap pollination systems. We investigated the trapping devices of 15 Arum spp. and compared them with the types of insects trapped. Most species shared a similar general design of trap chamber walls covered in downward-pointing papillate cells, lacunose cells in the chamber wall and elongated sterile flowers partially blocking the exit of the trap. However, there was significant variation in all these morphological features between species. Furthermore, these differences related to the type of pollinator trapped. Most strikingly, species pollinated by midges had a slippery epidermal surface consisting of smaller papillae than in species pollinated by other insects. Midge-pollinated species also had more elongated sterile flowers and tended to have a larger lacunose area. We conclude that pollination traps evolve in response to the type of insect trapped and that changes to the slippery surfaces of the chamber wall are an important and previously little recognized variable in the design of pollination traps. PMID- 25821244 TI - Correlates of hyperdiversity in southern African ice plants (Aizoaceae). AB - The exceptionally high plant diversity of the Greater Cape Floristic Region (GCFR) comprises a combination of ancient lineages and young radiations. A previous phylogenetic study of Aizoaceae subfamily Ruschioideae dated the radiation of this clade of > 1500 species in the GCFR to 3.8-8.7 Mya, establishing it as a flagship example of a diversification event triggered by the onset of a summer-arid climate in the region. However, a more recent analysis found an older age for the Ruschioideae lineage (17 Mya), suggesting that the group may in fact have originated much before the aridification of the region 10 15 Mya. Here, we reassess the tempo of radiation of ice plants by using the most complete generic-level phylogenetic tree for Aizoaceae to date, a revised calibration age and a new dating method. Our estimates of the age of the clade are even younger than initially thought (stem age 1.13-6.49 Mya), supporting the hypothesis that the radiation post-dates the establishment of an arid environment in the GCFR and firmly placing the radiation among the fastest in angiosperms (diversification rate of 4.4 species per million years). We also statistically examine environmental and morphological correlates of richness in ice plants and find that diversity is strongly linked with precipitation, temperature, topographic complexity and the evolution of highly succulent leaves and wide-band tracheids. PMID- 25821245 TI - Recurrent polymorphic mating type variation in Madagascan Bulbophyllum species (Orchidaceae) exemplifies a high incidence of auto-pollination in tropical orchids. AB - The transition from outcrossing to self-fertilization is one of the most common evolutionary changes in angiosperms. The orchid family exemplifies this evolutionary trend but, because of a general lack of large-scale surveys on auto pollination in orchid taxa, the incidence and modes of auto-pollination among (sub)tropical orchids remain poorly known. In the present study, we assessed the frequency and mode of auto-pollination within and among species of a largely monophyletic group of Madagascan Bulbophyllum. The capacity for autonomous fruit set was investigated by bagging experiments in the greenhouse and the field, complemented with detailed floral micromorphological studies of the gynostemium. Our survey comprises 393 accessions, representing at least 78 species, and thus approximately 37% of the species diversity of the genus in the Madagascan region. Our studies revealed that mating type is directly related to gynostemium structure, most often involving the presence or absence of a physical barrier termed 'rostellum'. As a novel and unexpected finding, we identified eight species of a single lineage of Madagascan Bulbophyllum (termed 'clade C'), in which auto-pollinating morphs (selfers), either lacking a rostellum or (rarely) possessing a stigmatic rostellum, co-exist with their pollinator-dependent conspecifics (outcrossers). We hypothesize that auto-pollination via rostellum abortion has a simple genetic basis, and probably evolved rapidly and recurrently by subtle changes in the timing of rostellum development (heterochrony). Thus, species of clade C may have an intrinsic genetic and developmental lability toward auto-pollination, allowing rapid evolutionary response under environmental, perhaps human-disturbed conditions favouring reproductive assurance. Overall, these findings should stimulate further research on the incidence, evolution, and maintenance of mating type variation in tropical orchids, as well as how they adapt(ed) to changing environmental conditions. PMID- 25821246 TI - Can Triticum urartu (Poaceae) be identified by pollen analysis? Implications for detecting the ancestor of the extinct two-grained einkorn-like wheat. AB - The domestication of the one-grained einkorn (Triticum monococcum) in the Near East is relatively well known. However, an independent two-grained einkorn-like domestication has been archaeobotanically detected and scarce information is available. Triticum urartu, a wild wheat, was not fully described until the 1970s because the phenology does not allow it to be distinguished easily from wild einkorn (Triticum boeoticum subsp. thaoudar), although a genetic separation exists. Both species are mostly two grained and could potentially be the relatives of the extinct two-grained form. Pollen grains of several genetically well-identified wheat species, including T. urartu and T. boeoticum subsp. thaoudar, were studied by measuring the grain diameter and examining the exine sculpturing with phase-contrast microscopy and scanning electron microscopy to gain an insight into differences enabling taxonomic identification. This work showed that, although T. urartu pollen is smaller on average, grain diameter is not sufficient because of the size overlap between the species, but T. urartu presents a different exine sculpturing (scabrate) from other Triticum spp. (aerolate). This outcome is useful for taxonomists and archaeobotanists. First, it will allow a simple re-classification of herbarium materials. Second, further research could establish whether T. urartu was cultivated. PMID- 25821247 TI - Characterisation of cylindrical curves. AB - We employ moving frames along pairs of curves at constant separation to derive various conditions for a curve to belong to the surface of a circular cylinder. PMID- 25821248 TI - ON AN ALLEGED TRUTH/FALSITY ASYMMETRY IN CONTEXT SHIFTING EXPERIMENTS. AB - Keith DeRose has argued that context shifting experiments should be designed in a specific way in order to accommodate what he calls a 'truth/falsity asymmetry'. I explain and critique DeRose's reasons for proposing this modification to contextualist methodology, drawing on recent experimental studies of DeRose's bank cases as well as experimental findings about the verification of affirmative and negative statements. While DeRose's arguments for his particular modification to contextualist methodology fail, the lesson of his proposal is that there is good reason to pay close attention to several subtle aspects of the design of context shifting experiments. PMID- 25821249 TI - Calla palustris (Araceae): New palynological insights with special regard to its controversial systematic position and to closely related genera. AB - Almost all systematic treatments agree that Calla is a puzzling case, being a highly autapomorphic taxon with obscure relationships. In molecular-based classifications the variable placements of Calla within Aroideae conflict strongly with those in morphologically and anatomically based systematic classifications, which treat the genus as a subfamily (Calloideae) of its own. We studied the pollen morphology and ultrastructure of Calla by light and electron microscopy, and mapped the relevant pollen characters as well as some flower characters to the proposed placements of Calla within the Araceae as indicated in the various molecular phylogenies. Calla pollen is extraordinary within the entire Araceae. Pollen grains are small, and basically disulcate or with a ring like aperture. The ornamentation is psilate to perforate, and the pollen wall consists of a sporopolleninous tectate-columellate exine. These pollen characters are shared with those of several earlier-diverging aroid taxa, especially with those of subfamily Zamioculcadoideae, whereas pollen characters in members of subfamily Aroideae deviate significantly. These findings are in accordance with other floral characters. Therefore, we propose that Calla is best placed in a transition zone between either subfamily Zamioculcadoideae (Stylochaeton clade) and subfamily Aroideae (Aroideae clade) or between subfamily Zamioculcadoideae (Stylochaeton clade) and subfamily Lasioideae. PMID- 25821250 TI - Synthesis and Investigation of Novel Spiro-isoxazolines as Anti-Cancer Agents. AB - A series of structurally diverse 4-bromo spiro-isoxazolines possessing a variety of aromatic and aliphatic substituents at the 3 position, were synthesized through a 1,3-dipolar cycloaddition followed by intramolecular cyclization of a pendant hydroxyl or carboxylic acid group. The biochemical antiproliferative activity was evaluated in vitro by using two breast cancer cell lines (MCF-7 and MDA-MB-231) and two prostate cancer cell lines (PC-3 and DU-145) using the MTT viability assay, and the IC50 values were obtained. Spiro-isoxazoline derivatives bearing a p-chloro or an o-dichloro aromatic substituent at the 3-position of the isoxazoline showed considerable antitumor activities in all four cell lines with IC50 value ranging from 43MUM to 56MUM. PMID- 25821251 TI - Chemical Bonding and Atomic Structure in Y2O3:ZrO2-SrTiO3 Layered Heterostructures. PMID- 25821252 TI - Perovskite B-Site Compositional Control of [110]p Polar Displacement Coupling in an Ambient-Pressure-Stable Bismuth-based Ferroelectric. PMID- 25821253 TI - One-Pot Deracemization of sec-Alcohols: Enantioconvergent Enzymatic Hydrolysis of Alkyl Sulfates Using Stereocomplementary Sulfatases. PMID- 25821254 TI - Probing Local Backbone Geometries in Intrinsically Disordered Proteins by Cross Correlated NMR Relaxation. PMID- 25821255 TI - Why and How to Prefer a Causal Account of Parenthood. PMID- 25821256 TI - Cognitive Impairment in Depressed Older Adults: Implications for Prognosis and Treatment. PMID- 25821257 TI - Ectomycorrhizal Community Structure of Salix and Betula spp. at a Saline Site in Central Poland in Relation to the Seasons and Soil Parameters. AB - Saline stress is one of the most important abiotic factors limiting the growth and development of plants and associated microorganisms. While the impact of salinity on associations of arbuscular fungi is relatively well understood, knowledge of the ectomycorrhizal (EM) fungi of trees growing on saline land is limited. The main objective of this study was to determine the density and diversity of EM fungi associated with three tree species, Salix alba, Salix caprea and Betula pendula, growing in saline soil during two seasons, autumn and spring. The site was located in central Poland, and the increased salinity of the soil was of anthropogenic origin from soda production. The degree of EM colonisation of fine root tips varied between 9 and 34 % and depended on the tree species of interest (S. caprea < S. alba < B. pendula) and season (spring < autumn). Moreover, the ectomycorrhizal colonisation of B. pendula was positively correlated with pH and CaCO3, while for S. caprea and S. alba, colonisation was associated with most of the other soil parameters investigated; e.g. salinity, Corg and N. Analysis of EM fungi revealed four to five different morphotypes per each season: Tomentella sp. Sa-A, Hebeloma collariatum Sc-A, Geopora sp. Sc-A, Helotiales sp. Bp-A in the autumn and Tomentella sp. Sa-S, Tomentella sp. Sc-S and three morphotypes from the families Thelephoraceae and Pyronemataceae in the spring. In conclusion, the density of EM is related to the level of salinity (ECe), season and tree species. Tomentella spp., Hebeloma sp., Geopora sp. and Helotiales sp. are groups of species highly adapted to saline conditions. PMID- 25821258 TI - Accumulation of Major and Trace Elements in Spider Webs. AB - The spider webs of Malthonica ferruginea (Panzer, 1804) from the Agelenidae family were used for the evaluation of heavy metal contamination, and major and trace elements presence in the air of Wroclaw, Poland. The concentrations of 16 elements were determined (Mg, Al, K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, W, Pt, and Pb). Samples of webs were collected from six different locations with low, moderate, and high pollution level (urban of low and high traffic, residential, and postindustrial sites) after 60 days of exposure. Samples collected from high traffic sites and postindustrial site were found to have high contents of elements than residential sites and one of low traffic urban site. The principle component analysis (PCA) and correlation analysis provide important information about the potential sources of the elements in spider webs. Two contamination sources were identified: road traffic emissions and industrial. This was a first-time ever attempt to use webs for biomonitoring of small-scale distribution of airborne major and trace elements in the city of Wroclaw. PMID- 25821259 TI - Heavy Metal Uptake by Herbs. IV. Influence of Soil pH on the Content of Heavy Metals in Valeriana officinalis L. AB - The aim of the study was to estimate the influence of soil pH on the uptake of copper, zinc, and manganese by Valeriana officinalis. Preliminary studies involved soil analyses to determine acidity, organic matter content, and copper, zinc, and manganese total and bioavailable forms. The study involved atomic absorption spectrometry to determine the concentration of the elements, and mineral soil of pH = 5.1 was used in the study, as being typical for central Poland. The copper, zinc, and manganese contents were determined in plants grown in soils which had been modified to cover a wide range of pH values 3/13. The intensity of germination was strongly pH dependent with the highest yield obtained in original, unmodified soil. Surprisingly, high soil alkalinity stimulated copper and manganese uptake while at the same time resulting in a decrease in zinc content. PMID- 25821260 TI - Corrugated Waveguide Mode Content Analysis Using Irradiance Moments. AB - We present a novel, relatively simple method for determining the mode content of the linearly polarized modes of a corrugated waveguide using the moments of the intensity pattern of the field radiated from the end of the waveguide. This irradiance moment method is based on calculating the low-order irradiance moments, using measured intensity profiles only, of the radiated field from the waveguide aperture. Unlike the phase retrieval method, this method does not use or determine the phase distribution at the waveguide aperture. The new method was benchmarked numerically by comparison with sample mode mixtures. The results predict less than +/-0.7% error bar in the retrieval of the mode content. The method was also tested using high-resolution experimental data from beams radiated from 63.5 mm and 19 mm corrugated waveguides at 170 and 250 GHz, respectively. The results showed a very good agreement of the mode content retrieved using the irradiance moment method versus the phase retrieval technique. The irradiance moment method is most suitable for cases where the modal power is primarily in the fundamental HE11 mode, with <8% of the power in high-order modes. PMID- 25821262 TI - Volcanic sintering: Timescales of viscous densification and strength recovery. AB - [1] Sintering and densification are ubiquitous processes influencing the emplacement of both effusive and explosive products of volcanic eruptions. Here we sinter ash-size fragments of a synthetic National Institute of Standards and Technology viscosity standard glass at temperatures at which the resultant melt has a viscosity of ~108-109 Pa.s at 1bar to assess sintering dynamics under near surface volcanic conditions. We track the strength recovery via uniaxial compressive tests. We observe that volcanic ash sintering is dominantly time dependent, temperature dependent, and grain size dependent and may thus be interpreted to be controlled by melt viscosity and surface tension. Sintering evolves from particle agglutination to viscous pore collapse and is accompanied by a reduction in connected porosity and an increase in isolated pores. Sintering and densification result in a nonlinear increase in strength. Micromechanical modeling shows that the pore-emanated crack model explains the strength of porous lava as a function of pore fraction and size. PMID- 25821261 TI - Primordial argon isotope fractionation in the atmosphere of Mars measured by the SAM instrument on Curiosity and implications for atmospheric loss. AB - [1] The quadrupole mass spectrometer of the Sample Analysis at Mars (SAM) instrument on Curiosity rover has made the first high-precision measurement of the nonradiogenic argon isotope ratio in the atmosphere of Mars. The resulting value of 36Ar/38Ar = 4.2 +/- 0.1 is highly significant for it provides excellent evidence that "Mars" meteorites are indeed of Martian origin, and it points to a significant loss of argon of at least 50% and perhaps as high as 85-95% from the atmosphere of Mars in the past 4 billion years. Taken together with the isotopic fractionations in N, C, H, and O measured by SAM, these results imply a substantial loss of atmosphere from Mars in the posthydrodynamic escape phase. PMID- 25821263 TI - GPT2: Empirical slant delay model for radio space geodetic techniques. AB - Up to now, state-of-the-art empirical slant delay modeling for processing observations from radio space geodetic techniques has been provided by a combination of two empirical models. These are GPT (Global Pressure and Temperature) and GMF (Global Mapping Function), both operating on the basis of long-term averages of surface values from numerical weather models. Weaknesses in GPT/GMF, specifically their limited spatial and temporal variability, are largely eradicated by a new, combined model GPT2, which provides pressure, temperature, lapse rate, water vapor pressure, and mapping function coefficients at any site, resting upon a global 5 degrees grid of mean values, annual, and semi-annual variations in all parameters. Built on ERA-Interim data, GPT2 brings forth improved empirical slant delays for geophysical studies. Compared to GPT/GMF, GPT2 yields a 40% reduction of annual and semi-annual amplitude differences in station heights with respect to a solution based on instantaneous local pressure values and the Vienna mapping functions 1, as shown with a series of global VLBI (Very Long Baseline Interferometry) solutions. PMID- 25821264 TI - Are vegetation-related roughness changes the cause of the recent decrease in dust emission from the Sahel? AB - [1] Since the 1980s, a dramatic downward trend in North African dustiness and transport to the tropical Atlantic Ocean has been observed by different data sets and methods. The precise causes of this trend have previously been difficult to understand, partly due to the sparse observational record. Here we show that a decrease in surface wind speeds associated with increased roughness due to more vegetation in the Sahel is the most likely cause of the observed drop in dust emission. Associated changes in turbulence and evapotranspiration, and changes in large-scale circulation, are secondary contributors. Past work has tried to explain negative correlations between North African dust and precipitation through impacts on emission thresholds due to changes in soil moisture and vegetation cover. The use of novel diagnostic tools applied here to long-term surface observations suggests that this is not the dominating effect. Our results are consistent with a recently observed global decrease in surface wind speed, known as "stilling", and demonstrate the importance of representing vegetation related roughness changes in models. They also offer a new mechanism of how land use change and agriculture can impact the Sahelian climate. Citation: Cowie, S. M., P. Knippertz, and J. H. Marsham (2013), Are vegetation-related roughness changes the cause of the recent decrease in dust emission from the Sahel?, Geophys. Res. Lett., 40, 1868-1872, doi:10.1002/grl.50273. PMID- 25821265 TI - Spatially mapped reductions in the length of the Arctic sea ice season. AB - : Satellite data are used to determine the number of days having sea ice coverage in each year 1979-2013 and to map the trends in these ice-season lengths. Over the majority of the Arctic seasonal sea ice zone, the ice season shortened at an average rate of at least 5 days/decade between 1979 and 2013, and in a small area in the northeastern Barents Sea the rate of shortening reached over 65 days/decade. The only substantial non-coastal area with lengthening sea ice seasons is the Bering Sea, where the ice season lengthened by 5-15 days/decade. Over the Arctic as a whole, the area with ice seasons shortened by at least 5 days/decade is 12.4 * 106 km2, while the area with ice seasons lengthened by at least 5 days/decade is only 1.1 * 106 km2. The contrast is even greater, percentage-wise, for higher rates. KEY POINTS: Sea ice seasons have shortened by at least 5 days/decade over most of the ArcticAcross 1.9 million km2 ice seasons have shortened by at least 25 days/decadeCounter to most of the Arctic ice seasons have lengthened in the Bering Sea. PMID- 25821266 TI - Detecting fossil fuel emissions patterns from subcontinental regions using North American in situ CO2 measurements. AB - : The ability to monitor fossil fuel carbon dioxide (FFCO2) emissions from subcontinental regions using atmospheric CO2 observations remains an important but unrealized goal. Here we explore a necessary but not sufficient component of this goal, namely, the basic question of the detectability of FFCO2 emissions from subcontinental regions. Detectability is evaluated by examining the degree to which FFCO2 emissions patterns from specific regions are needed to explain the variability observed in high-frequency atmospheric CO2 observations. Analyses using a CO2 monitoring network of 35 continuous measurement towers over North America show that FFCO2 emissions are difficult to detect during nonwinter months. We find that the compounding effects of the seasonality of atmospheric transport patterns and the biospheric CO2 flux signal dramatically hamper the detectability of FFCO2 emissions. Results from several synthetic data case studies highlight the need for advancements in data coverage and transport model accuracy if the goal of atmospheric measurement-based FFCO2 emissions detection and estimation is to be achieved beyond urban scales. KEY POINTS: Poor detectability of fossil fuel CO2 emissions from subcontinental regionsDetectability assessed via attribution of emissions patterns in atmospheric dataLoss in detectability due to transport modeling errors and biospheric signal. PMID- 25821267 TI - Experimental evidence for the formation of liquid saline water on Mars. AB - : Evidence for deliquescence of perchlorate salts has been discovered in the Martian polar region while possible brine flows have been observed in the equatorial region. This appears to contradict the idea that bulk deliquescence is too slow to occur during the short periods of the Martian diurnal cycle during which conditions are favorable for it. We conduct laboratory experiments to study the formation of liquid brines at Mars environmental conditions. We find that when water vapor is the only source of water, bulk deliquescence of perchlorates is not rapid enough to occur during the short periods of the day during which the temperature is above the salts' eutectic value, and the humidity is above the salts' deliquescence value. However, when the salts are in contact with water ice, liquid brine forms in minutes, indicating that aqueous solutions could form temporarily where salts and ice coexist on the Martian surface and in the shallow subsurface. KEY POINTS: The formation of brines at Martian conditions was studied experimentallyBulk deliquescence from water vapor is too slow to occur diurnally on MarsBrines form in minutes when salts are placed in direct contact with ice. PMID- 25821268 TI - Local amplification of storm surge by Super Typhoon Haiyan in Leyte Gulf. AB - Typhoon Haiyan, which struck the Philippines in November 2013, was an extremely intense tropical cyclone that had a catastrophic impact. The minimum central pressure of Typhoon Haiyan was 895 hPa, making it the strongest typhoon to make landfall on a major island in the western North Pacific Ocean. The characteristics of Typhoon Haiyan and its related storm surge are estimated by numerical experiments using numerical weather prediction models and a storm surge model. Based on the analysis of best hindcast results, the storm surge level was 5-6 m and local amplification of water surface elevation due to seiche was found to be significant inside Leyte Gulf. The numerical experiments show the coherent structure of the storm surge profile due to the specific bathymetry of Leyte Gulf and the Philippines Trench as a major contributor to the disaster in Tacloban. The numerical results also indicated the sensitivity of storm surge forecast. PMID- 25821269 TI - Forecast cooling of the Atlantic subpolar gyre and associated impacts. AB - Decadal variability in the North Atlantic and its subpolar gyre (SPG) has been shown to be predictable in climate models initialized with the concurrent ocean state. Numerous impacts over ocean and land have also been identified. Here we use three versions of the Met Office Decadal Prediction System to provide a multimodel ensemble forecast of the SPG and related impacts. The recent cooling trend in the SPG is predicted to continue in the next 5 years due to a decrease in the SPG heat convergence related to a slowdown of the Atlantic Meridional Overturning Circulation. We present evidence that the ensemble forecast is able to skilfully predict these quantities over recent decades. We also investigate the ability of the forecast to predict impacts on surface temperature, pressure, precipitation, and Atlantic tropical storms and compare the forecast to recent boreal summer climate. PMID- 25821270 TI - Changes in global net radiative imbalance 1985-2012. AB - Combining satellite data, atmospheric reanalyses, and climate model simulations, variability in the net downward radiative flux imbalance at the top of Earth's atmosphere (N) is reconstructed and linked to recent climate change. Over the 1985-1999 period mean N (0.34 +/- 0.67 Wm-2) is lower than for the 2000-2012 period (0.62 +/- 0.43 Wm-2, uncertainties at 90% confidence level) despite the slower rate of surface temperature rise since 2000. While the precise magnitude of N remains uncertain, the reconstruction captures interannual variability which is dominated by the eruption of Mount Pinatubo in 1991 and the El Nino Southern Oscillation. Monthly deseasonalized interannual variability in N generated by an ensemble of nine climate model simulations using prescribed sea surface temperature and radiative forcings and from the satellite-based reconstruction is significantly correlated (r~0.6) over the 1985-2012 period. PMID- 25821271 TI - Do seasonal-to-decadal climate predictions underestimate the predictability of the real world? AB - Seasonal-to-decadal predictions are inevitably uncertain, depending on the size of the predictable signal relative to unpredictable chaos. Uncertainties can be accounted for using ensemble techniques, permitting quantitative probabilistic forecasts. In a perfect system, each ensemble member would represent a potential realization of the true evolution of the climate system, and the predictable components in models and reality would be equal. However, we show that the predictable component is sometimes lower in models than observations, especially for seasonal forecasts of the North Atlantic Oscillation and multiyear forecasts of North Atlantic temperature and pressure. In these cases the forecasts are underconfident, with each ensemble member containing too much noise. Consequently, most deterministic and probabilistic measures underestimate potential skill and idealized model experiments underestimate predictability. However, skilful and reliable predictions may be achieved using a large ensemble to reduce noise and adjusting the forecast variance through a postprocessing technique proposed here. PMID- 25821272 TI - Broadscale postseismic gravity change following the 2011 Tohoku-Oki earthquake and implication for deformation by viscoelastic relaxation and afterslip. AB - The analysis of GRACE gravity data revealed postseismic gravity increase by 6 MUGal over a 500 km scale within a couple of years after the 2011 Tohoku-Oki earthquake, which is nearly 40-50% of the coseismic gravity change. It originates mostly from changes in the isotropic component corresponding to the Mrr moment tensor element. The exponential decay with rapid change in a year and gradual change afterward is a characteristic temporal pattern. Both viscoelastic relaxation and afterslip models produce reasonable agreement with the GRACE free air gravity observation, while their Bouguer gravity patterns and seafloor vertical deformations are distinctly different. The postseismic gravity variation is best modeled by the biviscous relaxation with a transient and steady state viscosity of 1018 and 1019 Pa s, respectively, for the asthenosphere. Our calculated higher-resolution viscoelastic relaxation model, underlying the partially ruptured elastic lithosphere, yields the localized postseismic subsidence above the hypocenter reported from the GPS-acoustic seafloor surveying. PMID- 25821273 TI - Groundwater depletion during drought threatens future water security of the Colorado River Basin. AB - Streamflow of the Colorado River Basin is the most overallocated in the world. Recent assessment indicates that demand for this renewable resource will soon outstrip supply, suggesting that limited groundwater reserves will play an increasingly important role in meeting future water needs. Here we analyze 9 years (December 2004 to November 2013) of observations from the NASA Gravity Recovery and Climate Experiment mission and find that during this period of sustained drought, groundwater accounted for 50.1 km3 of the total 64.8 km3 of freshwater loss. The rapid rate of depletion of groundwater storage (-5.6 +/- 0.4 km3 yr-1) far exceeded the rate of depletion of Lake Powell and Lake Mead. Results indicate that groundwater may comprise a far greater fraction of Basin water use than previously recognized, in particular during drought, and that its disappearance may threaten the long-term ability to meet future allocations to the seven Basin states. PMID- 25821274 TI - Global model of low-frequency chorus (fLHR=5 days), brings warm subtropical air masses over the GIS controlling daily surface temperatures and melt. The temperature anomaly of these subtropical air mass intrusions is also important for melting. Based on the years with the greatest melt (2002 and 2012) during the MODIS era, the area-average temperature anomaly of 2 standard deviations above the 14 year June-July mean results in a melt fraction of 40% or more. Though the summer of 2007 had the most blocking days, atmospheric temperature anomalies were too small to instigate extreme melting. KEY POINTS: Short-term atmospheric blocking over Greenland contributes to melt episodesAssociated temperature anomalies are equally important for the meltDuration and strength of blocking events contribute to surface melt intensity. PMID- 25821278 TI - Decrypting geophysical signals at Stromboli Volcano (Italy): Integration of seismic and Ground-Based InSAR displacement data. AB - We present the integration of seismic and Ground-Based Interferometric Synthetic Aperture Radar system (GBInSAR) displacement data at Stromboli Volcano. Ground deformation in the area of summit vents is positively correlated with both seismic tremor amplitude and cumulative amplitudes of very long period (VLP) signals associated with Strombolian explosions. Changes in VLP amplitudes precede by a few days the variations in ground deformation and seismic tremor. We propose a model where the arrival of fresh, gas-rich magma from depth enhances gas slug formation, promoting convection and gas transfer throughout the conduit system. At the shallowest portion of the conduit, an increase in volatile content causes a density decrease, expansion of the magmatic column and augmented degassing activity, which respectively induce inflation of the conduit, and increased tremor amplitudes. The temporal delay between increase of VLP and tremor amplitudes/conduit inflation can be interpreted in terms of the different timescales characterizing bulk gas transfer versus slug formation and ascent. PMID- 25821279 TI - A numerical algorithm with preference statements to evaluate the performance of scientists. AB - Academic evaluation committees have been increasingly receptive for using the number of published indexed articles, as well as citations, to evaluate the performance of scientists. It is, however, impossible to develop a stand-alone, objective numerical algorithm for the evaluation of academic activities, because any evaluation necessarily includes subjective preference statements. In a market, the market prices represent preference statements, but scientists work largely in a non-market context. I propose a numerical algorithm that serves to determine the distribution of reward money in Mexico's evaluation system, which uses relative prices of scientific goods and services as input. The relative prices would be determined by an evaluation committee. In this way, large evaluation systems (like Mexico's Sistema Nacional de Investigadores) could work semi-automatically, but not arbitrarily or superficially, to determine quantitatively the academic performance of scientists every few years. Data of 73 scientists from the Biology Institute of Mexico's National University are analyzed, and it is shown that the reward assignation and academic priorities depend heavily on those preferences. A maximum number of products or activities to be evaluated is recommended, to encourage quality over quantity. PMID- 25821280 TI - Power laws in citation distributions: evidence from Scopus. AB - Modeling distributions of citations to scientific papers is crucial for understanding how science develops. However, there is a considerable empirical controversy on which statistical model fits the citation distributions best. This paper is concerned with rigorous empirical detection of power-law behaviour in the distribution of citations received by the most highly cited scientific papers. We have used a large, novel data set on citations to scientific papers published between 1998 and 2002 drawn from Scopus. The power-law model is compared with a number of alternative models using a likelihood ratio test. We have found that the power-law hypothesis is rejected for around half of the Scopus fields of science. For these fields of science, the Yule, power-law with exponential cut-off and log-normal distributions seem to fit the data better than the pure power-law model. On the other hand, when the power-law hypothesis is not rejected, it is usually empirically indistinguishable from most of the alternative models. The pure power-law model seems to be the best model only for the most highly cited papers in "Physics and Astronomy". Overall, our results seem to support theories implying that the most highly cited scientific papers follow the Yule, power-law with exponential cut-off or log-normal distribution. Our findings suggest also that power laws in citation distributions, when present, account only for a very small fraction of the published papers (less than 1 % for most of science fields) and that the power-law scaling parameter (exponent) is substantially higher (from around 3.2 to around 4.7) than found in the older literature. PMID- 25821281 TI - Too many journals? Towards a theory of repeated rejections and ultimate acceptance. AB - Under a set of reasonable assumptions, it is shown that all manuscripts submitted to any journal will ultimately be published, either by the first journal or by one of the following journals to which a manuscript is resubmitted. This suggests that low quality manuscripts may also be published, which further suggests that there may be too many journals. PMID- 25821282 TI - Exploring indigenous landscape classification across different dimensions: a case study from the Bolivian Amazon. AB - Decisions on landscape management are often dictated by government officials based on their own understandings of how landscape should be used and managed, but rarely considering local peoples' understandings of the landscape they inhabit. We use data collected through free listings, field transects, and interviews to describe how an Amazonian group of hunter-horticulturalists, the Tsimane', classify and perceive the importance of different elements of the landscape across the ecological, socioeconomic, and spiritual dimensions. The Tsimane' recognize nine folk ecotopes (i.e., culturally-recognized landscape units) and use a variety of criteria (including geomorphological features and landscape uses) to differentiate ecotopes from one another. The Tsimane' rank different folk ecotopes in accordance with their perceived ecological, socioeconomic, and spiritual importance. Understanding how local people perceive their landscape contributes towards a landscape management planning paradigm that acknowledges the continuing contributions to management of landscape inhabitants, as well as their cultural and land use rights. PMID- 25821283 TI - Does the Hispanic Paradox in U.S. Adult Mortality Extend to Disability? AB - Studies consistently document a Hispanic paradox in U.S. adult mortality, whereby Hispanics have similar or lower mortality rates than non-Hispanic whites despite lower socioeconomic status. This study extends this line of inquiry to disability, especially among foreign-born Hispanics, since their advantaged mortality seemingly should be paired with health advantages more generally. We also assess whether the paradox extends to U.S.-born Hispanics to evaluate the effect of nativity. We calculate multistate life tables of life expectancy with disability to assess whether racial/ethnic and nativity differences in the length of disability-free life parallel differences in overall life expectancy. Our results document a Hispanic paradox in mortality for foreign-born and U.S.-born Hispanics. However, Hispanics' low mortality rates are not matched by low disability rates. Their disability rates are substantially higher than those of non-Hispanic whites and generally similar to those of non-Hispanic blacks. The result is a protracted period of disabled life expectancy for Hispanics, both foreign- and U.S.-born. PMID- 25821284 TI - Managing Spatial Selections With Contextual Snapshots. AB - Spatial selections are a ubiquitous concept in visualization. By localizing particular features, they can be analysed and compared in different views. However, the semantics of such selections often depend on specific parameter settings and it can be difficult to reconstruct them without additional information. In this paper, we present the concept of contextual snapshots as an effective means for managing spatial selections in visualized data. The selections are automatically associated with the context in which they have been created. Contextual snapshots can also be used as the basis for interactive integrated and linked views, which enable in-place investigation and comparison of multiple visual representations of data. Our approach is implemented as a flexible toolkit with well-defined interfaces for integration into existing systems. We demonstrate the power and generality of our techniques by applying them to several distinct scenarios such as the visualization of simulation data, the analysis of historical documents and the display of anatomical data. PMID- 25821285 TI - Beyond Components of Wellbeing: The Effects of Relational and Situated Assemblage. AB - Despite multiple axes of variation in defining wellbeing, the paper argues for the dominance of a 'components approach' in current research and practice. This approach builds on a well-established tradition within the social sciences of attending to categories whether for their identification, their value or their meanings and political resonance. The paper critiques the components approach and explores how to move beyond it towards conceptually integrating the various categories and dimensions through a relational and situated account of wellbeing. Drawing on more fluid social sciences, wellbeing is framed as an effect, dependent on the mobilisation of resources from everyday encounters with complex assemblages of people, things and places. Through such a framing, wellbeing can be conceived of as stable and amenable to change, as individual and collective and as subjective and objective. Policy interventions then need to attend to the relationalities of particular social and spatial contexts. PMID- 25821286 TI - Reliability, Validity, and Associations with Sexual Behavior among Ghanaian Teenagers of Scales Measuring Four Dimensions Relationships with Parents and Other Adults. AB - Little research has been done on the social contexts of adolescent sexual behaviors in sub-Saharan Africa. As part of a longitudinal cohort study (N=1275) of teenage girls and boys in two Ghanaian towns, interviewers administered a 26 item questionnaire module intended to assess four dimensions of youth-adult relationships: monitoring conflict, emotional support, and financial support. Confirmatory factor and traditional psychometric analyses showed the four scales to be reliable. Known-groups comparisons provided evidence of their validity. All four scales had strong bivariate associations with self-reported sexual behavior (odds ratios = 1.66, 0.74, 0.47, and 0.60 for conflict, support, monitoring, and financial support). The instrument is practical for use in sub-Saharan African settings and produces measures that are reliable, valid, and predictive of sexual behavior in youth. PMID- 25821287 TI - Gastrointestinal Basidiobolomycosis, a Rare and Under-diagnosed Fungal Infection in Immunocompetent Hosts: A Review Article. AB - Gastrointestinal Basidiobolomycosis (GIB) is an unusual, rare, but emerging fungal infection in the stomach, small intestine, colon, and liver. It has been rarely reported in the English literature and most of the reported cases have been from US, Saudi Arabia, Kuwait, and Iran. In the last five years, 17 cases have been reported from one or two provinces in Iran, and it seems that it has been undiagnosed or probably unnoticed in other parts of the country. In this review, we explored the English literature from 1964 through 2013 via PubMed, Google, and Google scholar using the following search keywords: BasidiobolomycosisBasidiobolus ranarumGastrointestinal Basidiobolomycosis In this review, we attempted to collect all clinical, pathological, and radiological findings of the presenting patients; complemented with previous experiences regarding the treatment and prognosis of the GIB. Since 1964, only 71 cases have been reported, which will be fully described in terms of clinical presentations, methods of diagnosis and treatment as well as prognosis and follow up. PMID- 25821288 TI - The shape of uterine contractions and labor progress in the spontaneous active labor. AB - BACKGROUND: Dystocia is the most common indication of primary cesarean section. The most common cause of dystocia is uterine dysfunction. In prolonged labor, more attention is usually paid to the fetus and pelvis rather than to the role of uterine contractions in a delivery. Therefore, we decided to determine the relationship between the labor progress and uterine contractions shapes. METHODS: In this cross-sectional study, 200 primiparous women participated having a single pregnancy and cephalic presentation. Uterus contractions were recorded using electronic fetal monitoring at the beginning of the active phase of labor (dilatation 3-5 cm) for 30 min. Fall to rise (F:R) ratio was calculated by determining the duration of returning from a contraction peak to its baseline (fall) and the duration of the rise time from baseline to peak (rise) in two groups. The data were analyzed using t-test and Chi-square test. RESULTS: In this study, 162 women had a normal delivery and 38 women had a cesarean (CS) delivery due to the lack of labor progress. The average F:R ratio was 1.13+/-0.193 seconds in the vaginal delivery group and 1.64+/-0.301 seconds in the CS group. This difference was statistically significant (P<0.001). The frequency of contractions in the vaginal delivery group was more than the CS group (P=0.008). CONCLUSION: Our findings demonstrated that uterine contractions shapes change; and F:R ratio was higher in the group that lacked labor progress. Therefore, contraction shapes can be used to predict the labor progress. PMID- 25821289 TI - Designing a prognostic scoring system for predicting the outcomes of proximal fifth metatarsal fractures at 20 weeks. AB - BACKGROUND: Fractures of the proximal fifth metatarsal bone are among the most common fractures observed in the foot and their classification and management has been subject to much discussion and disagreement. In this study, we aim to identify and quantify the effect of possible predictors of the outcome of the treatment of proximal fifth metatarsal fractures. METHODS: Patients with established proximal fifth metatarsal fractures were enrolled in this prospective cohort and the outcome of their treatment was assessed using the AOFAS mid foot scale at 6 and 20 weeks. RESULTS: 143 patients were included in the study. Our study showed that displacement, weight and type III fractures were significant independent predictors of poor outcome at 6 weeks while at 20 weeks in addition to these factors, gender and diabetes mellitus were also shown to be significant independent predictors of poor outcome. A scoring system was designed by assigning weight to these factors and it was shown to be a strong predictor of outcome at 20 weeks. CONCLUSION: We recommend that our scoring system would help surgeons to decide whether patients' prognostic factors are significant enough for him/her to opt for a surgical approach to treatment rather than a conservative approach. PMID- 25821290 TI - Comparison of cell viability and embryoid body size of two embryonic stem cell lines after different exposure times to bone morphogenetic protein 4. AB - BACKGROUND: Activation of bone morphogenetic protein 4 (BMP4) signaling pathway in embryonic stem (ES) cells plays an important role in controlling cell proliferation, differentiation, and apoptosis. Adverse effects of BMP4 occur in a time dependent manner; however, little is known about the effect of different time exposure of this growth factor on cell number in culture media. In this study, we investigated the role of two different exposure times to BMP4 in cell viability, embryoid body (EB), size, and cavitation of ES cells. METHODS: Embryonic stem cells (R1 and B1 lines) were released from the feeder cell layers and were cultured using EBs protocol by using the hanging drop method and monolayer culture system. The cells were cultured for 5 days with 100 ng/mL BMP4 from the beginning (++BMP4) or after 48 h (+BMP4) of culture and their cell number were counted by trypan blue staining. The data were analyzed using non parametric two-tailed Mann-Whitney test. P<0.05 was considered as significant. RESULTS: In EB culture protocol, cell number significantly decreased in +BMP4 culture condition with greater cavity size compared to the ++BMP4 condition at day 5 (P=0.009). In contrast, in monolayer culture system, there was no significant difference in the cell number between all groups (P=0.91). CONCLUSION: The results suggest that short-term exposure of BMP4 is required to promote cavitation in EBs according to lower cell number in +BMP4 condition. Different cell lines showed different behavior in cavitation formation. PMID- 25821291 TI - Acute and Chronic Effects of N-acetylcysteine on Pentylenetetrazole-induced Seizure and Neuromuscular Coordination in Mice. AB - BACKGROUND: N-acetylcysteine (NAC) has been indicated against experimental seizures, but with relatively inconclusive results. This study was undertaken to evaluate whether NAC exerts a dose-dependent anticonvulsant effect and to determine NAC safe therapeutic dose range and its muscle-relaxant activity in both acute and chronic uses. METHODS: Following intraperitoneal (i.p.) administration of N-acetylcysteine acutely (50-300 mg/kg) or chronically for 8 days (25-300 mg/kg), mice were injected with PTZ (90 mg/kg, i.p.) and latency times to the onset of myoclonic and clonic seizures and protection against death were recorded. Changes in body weight and mortality rate were considered as parameters for drug safety. The muscle-relaxant activity of NAC was assessed by rotarod test. RESULTS: Acute and chronic treatment with NAC delayed latency times to myoclonic and clonic seizures in a dose-dependent manner, but with no significant prevention against PTZ-induced death. Chronic administration of 300 mg/kg NAC was fully lethal while lower doses (100 and 150 mg/kg) resulted in a significant weight loss and decreased stay time on rotarod. Acute treatment with NAC had no significant effect on stay time on rotarod at all studied doses. CONCLUSION: NAC exerts a dose-dependent anticonvulsant effect in acute and chronic uses, with no muscle relaxant activity. NAC has higher efficacy in preventing seizure in chronic than acute treatment, but its chronic use at higher doses of 75 mg/kg may be associated with side effects and/or toxicity. These findings suggest that low doses of NAC may have a potential use as a prophylactic treatment for absence seizure in human. PMID- 25821292 TI - Attenuation of morphine withdrawal syndrome by various dosages of curcumin in comparison with clonidine in mouse: possible mechanism. AB - BACKGROUND: Herbal medical compounds and their major constituent have been used in the management and treatment of opioid withdrawal syndrome and pain. This study was carried out to clarify the effect of curcumin, the major compound of turmeric, on morphine withdrawal syndrome in mouse model and its possible mechanisms of pain relieving activity by assessing in writhing test as a model of visceral pain. METHODS: Due to two separate protocols (withdrawal syndrome and pain), 144 male albino mice were divided in two major groups. In withdrawal syndrome group, test effect of various dosages of curcumin (10, 20, and 40 mg/kg) was assessed on withdrawal signs and compared with positive and negative control and standard treatment (clonidine 0.4 mg/kg) groups. In pain groups, to determine the mechanism of pain relieving activity of curcumin, various dosages of curcumin (10, 20, and 40 mg/kg) in three separated groups, were used against acetic acid induced writhing (which is a constriction) test. The most effective dose (40 mg/kg) was used in writhing test and compared with groups pretreated with antagonist of major neurotransmitters involved in pain; and compared with group pretreated with vehicle (DMSO, 0.05%) as control. RESULTS: Curcumin attenuates withdrawal syndrome in a dose dependent manner in comparison with the dependent positive control group (P<0.05). It also indicated that pretreatment with naloxone and cyproheptadine significantly attenuate antinociception effect of curcumin (P<0.05). CONCLUSION: This study advocate that antinociception of curcumin was mediated by opioidergic and adrenergic system. PMID- 25821293 TI - The role of apoptosis in the cellular response of liver and spleen of BALB/c mice in cutaneous leishmaniasis. AB - BACKGROUND: Cutaneous leishmaniasis is a common parasitic disease in Iran being mainly caused by Leishmania (L.) major. The aim of this study was to investigate the occurrence of apoptosis in the spleen and liver of female mice infected with L. major. METHODS: BALB/c mice were randomly assigned into the control and experimental groups (ten mice per group). The experimental groups were subcutaneously inoculated with promastigotes of L. major at stationary phase. The animals were sacrificed after 20, 40, 60, 90, and 120 days of injection. The liver and spleen were analyzed for various parameters of apoptosis. RESULTS: Activities of superoxide dismutase and caspase-3, levels of superoxide anion production and malondialdehyde, and the percent of DNA fragmentation were increased in the liver and spleen of the infected mice. Catalase activity in the liver was increased, while glutathione level in both tissues was decreased after 90 and 120 days of infection. The numbers of apoptotic nuclei in the spleen were higher than the liver at 90 and 120 days post-infection using the TUNEL method. CONCLUSION: L. major infection induces a time-dependent increase in apoptosis in the liver and spleen as evidenced by the production of ROS, increasing activation of caspase-3, elevated DNA fragmentation, and increasing lipid peroxidation. Induction of oxidative stress was observed in the liver and spleen after 90 and 120 days of initiation of the infection. However, the spleen tissue appears to be more sensitive to the infection to L. major on oxidative stress and apoptosis induction compared with the liver tissue. PMID- 25821294 TI - Wharton's Jelly-derived Mesenchymal Stem Cells can Differentiate into Hepatocyte like Cells by HepG2 Cell Line Extract. AB - BACKGROUND: Wharton's jelly is an unlimited source of stem cells that can be used in cell therapy and tissue engineering without any ethical concern. It has been revealed the cell-free extract could be effective to induce cell differentiation. The objective of this study was to induce Wharton's jelly-derived mesenchymal stem cells (MSCs) into hepatocyte-like cells by premeabilization of the cells in the presence of HepG2 cell line extract. METHODS: MSCs were isolated from the umbilical cord, CD marker profile and their differentiation potential into adipogenic and osteogenic lineages were determined. The cells were then, permeabilized by streptolysin O in the presence of HepG cell extract. The treated cells were cultured for 17 days. The cell phenotype was evaluated and the hepatocyte specific markers were detected by immunofluorescence and immunocytochemistry. The Periodic Acid Schiff (PAS) reaction and the cellular uptake of indocyanine green were performed to evaluate the functional behavior of the differentiated cells. RESULTS: The phenotype of extract-treated MSCs changed into a round or polygonal cells with few short processes and they could express high level of albumin, cytokeratin 18 and 19. The MSCs also could store glycogen and uptake and release indocyanine green. CONCLUSION: We demonstrated for the first time that Wharton's jelly-derived MSCs could differentiate into hepatocyte like cells by premeabilization of them in the presence of HepG2 cell extract. This study suggests a feasible method to differentiate MSCs into functional hepatocyte-like cells. PMID- 25821295 TI - The effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension: a study of antihypertensive mechanisms. AB - BACKGROUND: Resveratrol has beneficial effects on cardiovascular system. This study aimed at examining antidiabetic and antihypertensive effects of resveratrol in rats with simultaneous type 2 diabetes and renal hypertension. METHODS: Eight groups (8-10 each) of male Spargue-Dawley rats, including a control, a diabetic (induced by streptozotocin and nicotinamide), a renal hypertensive (induced by placing plexiglas clips on the left renal arteries), a sham, a simultaneously hypertensive-diabetic receiving vehicle, and 3 simultaneous hypertensive-diabetic receiving resveratrol at 5, 10 or 20 mg/kg/day were used. Four weeks after the induction of diabetes, renal hypertension was induced and animals were given vehicle or resveratrol for the next four weeks. Afterwards, blood pressure and glucose, serum markers of oxidative stress were measured and animal's aortic rings were used for isolated studies. RESULTS: Serum malondialdehyde, systolic blood pressure, heart rate, fasting blood glucose, maximal response and effective concentration 50 of phenylephrine, and inhibitory concentration 50 of acetylcholine of hypertensive-diabetic group receiving vehicle were significantly higher than those of the control group, and treatment with resveratrol caused significant reduction of these variables. Moreover, serum superoxide dismutase, glutathione reductase, and maximal response to acetylcholine of hypertensive diabetic group receiving vehicle were significantly lower than those of the control group, and treatment with resveratrol caused significant increase of these variables. CONCLUSION: The findings indicate that resveratrol has antidiabetic and antihypertensive effects, which may be partly due to antioxidant mechanism. They also show that antihypertensive effect of resveratrol may be additionally mediated by improving the release of nitric oxide and sympathoplegic activities. PMID- 25821296 TI - The prevalence of latent tuberculosis infection and smear positive pulmonary tuberculosis in people with household close contact with tuberculosis in north of iran. AB - One of the recommended strategies for preventing tuberculosis is to screen high risk populations with respect to Mycobacterium tuberculosis (TB) infection. The aim of the present study was to investigate latent infection and active tuberculosis in people with close household contact. It was a cross-sectional descriptive, analytical study with the sample size of 668 people from homes with one infected resident. In order to diagnose tuberculosis latent infection, the PPD test was done. To determine patients with smear-positive pulmonary tuberculosis, three sputum samples were taken from every patient and were examined using direct microscopy and culture. Data was analyzed by SPSS20 software. The prevalence of latent tuberculosis infection and smear-positive pulmonary tuberculosis were 42.8% and 0.9% respectively. The prevalence of latent tuberculosis infection and smear-positive pulmonary tuberculosis in people with close household contact were less than that of other studies. However, smear positive pulmonary tuberculosis in people with close household contact was 199.5 times more than that of the general population. PMID- 25821297 TI - Effect of burn sites (upper and lower body parts) and gender on extensive burns' mortality. AB - Our recent literature survey indicated a lack of clinical assessment of the influence of gender and site of burn injury on the outcome of patients with extensive burns. This report examines the effect of burn sites and gender on extensive burns' mortality. Data was gathered from 283 patients with burns larger than 65% of the total body surface area (TBSA) above the belt line or below the belt line; and without underlying diseases and inhalation burn injury. Patients were classified according to gender, site of injury (upper and lower body parts) and hospital stay period. Mortality rates of each category were then compared with each other. The hospital stay period in the female group was significantly higher compared with the male group (P<0.001) and the mortality rate among the female patients was higher compared with the male patients (P=0.004). Although the mortality rate in lower body part of the male group was significantly higher in comparison with the upper body part burn (P=0.001), there was no difference in mortality rate of upper versus lower body part in the female group. The mortality rate was generally higher among the female patients. Additionally, higher mortality rate was observed among male patients with lower body part burn compared with injuries of male patients with upper body part burn. PMID- 25821298 TI - G22A Polymorphism of Adenosine Deaminase and its Association with Biochemical Characteristics of Gestational Diabetes Mellitus in an Iranian Population. AB - Adenosine deaminase (ADA) is an important regulator of insulin action. The single nucleotide polymorphism (SNP) G22A in the ADA gene decreases enzymatic activity of ADA. The aim of this study was to investigate the relationship between the SNP G22A and blood glycemic control, insulin resistance, and obesity of gestational diabetes mellitus (GDM) patients in an Iranian population. SNP G22A was determined in women with GDM (N=70) and healthy pregnant women (control, N=70) using polymerase chain reaction-restriction fragment length polymorphism. Fasting plasma glucose (FPG), hemoglobin A1C (HbA1c), plasma insulin levels and plasma lipids were measured using commercial kits. Homeostasis model of assessment for insulin resistance (HOMA-IR) was calculated. The distribution of genotypes and alleles among GDM patients was similar to that of the control group. FPG and HbA1c were significantly higher in GDM patients with GG genotype compared with GDM patients with GA+AA genotype and non-GDM patients. The frequency of GG genotype was significantly higher in obese GDM patients compared to lean GDM patients. The SNP G22A in the ADA gene was not associated with the risk of GDM in our population. GG genotype was associated with poor glycemic control and obesity in GDM patients. PMID- 25821299 TI - An unusual case of metastatatic renal cell carcinoma presenting as melena and duodenal ulcer, 16 years after nephrectomy; a case report and review of the literature. AB - Renal cell carcinoma comprises about 2% of adult tumors. The overall 10-year survival rate of patients with RCC after nephrectomy is about 18-27%. The incidence of metastasis of initial RCC is about 24-28%, but this rate after nephrectomy is as high as 51%. The most common site of recurrence is the lung, however liver and bone metastases are common. There are many reported cases with late metastasis, however isolated late metastasis in the gastrointestinal tract especially duodenum is very rare. Herein we report our experience with a case of gastrointestinal bleeding secondary to metastatic renal cell carcinoma to duodenum, 16 years after nephrectomy. To the best of our knowledge, about 30 of such cases have been reported in the English literature. Many of the previous cases have been part of disseminated disease and isolated duodenal metastasis is very rare. The longest reported duration between nephrectomy for renal cell carcinoma and duodenal metastasis has been 13 years, thus it seems our case to be also unique because of very late duodenal metastasis. PMID- 25821300 TI - A huge lymphangioma mimicking pleural effusion with extension to both chest cavities: a case report and review of literature. AB - Mediastinal lymphangioma is primarily a benign lesion and the majority of the cases are found incidentally. These lesions account for approximately 1% of all mediastinal tumors. Here we present a giant mediastinal cystic mass in a 35-year old female who was presented with severe respiratory distress. On the plain chest radiography and CT scan, a massive left pleural effusion with large parasternal and mediastinal lymphadenopathy was seen. Thoracentesis was performed and 400 cm3 of clear fluid was drained from the left hemithorax. However, a subsequent CT scan with contrast and the same technique 40 days later showed a large cystic mass in the mediastinum protruding to the right and left hemi thoraces. The giant cystic mass was resected via right and left anterior thoracotomies. Histopathological examination revealed a diagnosis of lymphangioma. The patient has been alive and without tumor recurrence and has been followed for 2 years. PMID- 25821301 TI - An intraoral epitheloid hemangioendothelioma masquerading clinically as pyogenic granuloma. AB - Epitheloid hemangioendothelioma (EHE) is an uncommon angiocentric neoplasm of intermediate malignant potential. This tumor is frequently seen in the lungs and liver, but its presentation in the oral cavity is rare. In the oral cavity, gingival region is the common sites of occurrence. We report a rare case of epitheloid hemangioendothelioma in a 48-year-old male, presenting as a growth in the upper anterior gingiva of five months duration along with a review of its clinicopathological and immunohistochemical characteristics. PMID- 25821302 TI - Time to sensitize medical graduates to the Indian Systems of Medicine and Homeopathy. PMID- 25821304 TI - The Tamiflu fiasco and lessons learnt. AB - Oseltamivir (Tamiflu), a neuraminidase inhibitor, was approved for seasonal flu by US Food and Drug Administration in 1999. A number of randomized controlled trials, systematic reviews, and meta-analysis emphasized a favorable efficacy and safety profile. Majority of them were funded by Roche, which also first marketed and promoted this drug. In 2005 and 2009, the looming fear of pandemic flu led to recommendation by prominent regulatory bodies such as World Health Organization (WHO), Centers for Disease Control and Prevention, European Medicines Agency and others for its use in treatment and prophylaxis of influenza, and it's stockpiling as a measure to tide over the crisis. Serious Adverse Events, especially neuropsychiatric events associated with Tamiflu started getting reported leading to a cascade of questions on clinical utility of this drug. A recent Cochrane review and related articles have questioned the risk-benefit ratio of the drug, besides raising doubts about the regulatory decision of approving it. The recommendations for stockpiling the said drug as given by various international organizations viz WHO have also been put to scrutiny. Although many reviewers have labeled the Tamiflu saga as a "costly mistake," the episode leaves us with some important lessons. This article takes a comprehensive relook on the subject, and we proceed to suggest some ways and means to avoid a similar situation in the future. PMID- 25821303 TI - Diabetes-associated depression: the serotonergic system as a novel multifunctional target. AB - Diabetes associated depression is a largely understudied field which nonetheless carries a significant disease burden. The very low therapeutic efficacy of the existing conventional drugs with poor outcome may be, in part, due to uncertainty of the mechanism involved that clearly explains the existing comorbidity. The main purpose of this review was to address the sophisticated mechanisms of this comorbidity with a view of developing potential novel targets with higher efficacy and specificity. Data were collected from database searches including PubMed, references from relevant English language research/review articles and other official publications. Articles from 1990 to 2013 were included, and a broad search term criteria were followed for data mining so that relevant information was not missed out. Some of the search terms used included; diabetes induced depression, diabetes and serotonin, hypothalamic-pituitary-adrenal (HPA) axis and diabetes and glucocorticoids in diabetes. Neuropathologically, depletion of brain monoaminergic activity specifically the serotonin (5-hydroxytryptamine [5-HT]) system, due to chronically persisting diabetic state may lead to the mood and behavioral complications that further add on worsening the quality life years. The 5-HT system through multifunctional tasks regulates neurogenesis and plasticity and by complex receptor mechanism controls the emotional and behavioral activity. Persisting hyperglycemia leads to impaired neurogenesis, decreased synaptic plasticity, undesired neuro-anatomical alterations, neurochemical deficits, and reduced neurotransmitter activity. The neurotrophic factors and secondary messenger functions affected at molecular and genetic levels indicate the impact of diabetes-mediated dysregulation on neuronal circuits. HPA activity, glycogen synthase kinase 3, and insulin signaling controls were also found to be hampered, interlinked to 5-HT system following diabetic progression. PMID- 25821305 TI - Protective effect of simvastatin and rosuvastatin on trinitrobenzene sulfonic acid-induced colitis in rats. AB - OBJECTIVE: Statins have anti-inflammatory effects that are not directly related to their cholesterol lowering activity. This study was carried out to evaluate the effect of simvastatin or rosuvastatin on the extent of colonic mucosal damage and on the inflammatory response in trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis. MATERIALS AND METHODS: Ulcerative colitis was induced by single intrarectal injection of 120 mg/kg TNBS. Test groups were treated with simvastatin (10 mg/kg, p.o.) or rosuvastatin (10 mg/kg, p.o.). Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. RESULT: Disease activity index score in TNBS-treated rats, as determined by weight loss, stool consistency, fecal occult blood, were significantly lowers in simvastatin or rosuvastatin-treated rats than TNBS-treated animals. Simvastatin or rosuvastatin counteracted the reduction in colon length, decreased colon weight, neutrophil accumulation, and tumor necrosis factor-alpha level in TNBS-induced colitis. Simvastatin and rosuvastatin also inhibited the increase in oxidative stress levels after TNBS administration. CONCLUSIONS: These results suggest that simvastatin and rosuvastatin significantly ameliorate experimental colitis in rats, and these effects could be explained by their anti-inflammatory and antioxidant activity. PMID- 25821306 TI - Lead-induced adverse effects on the reproductive system of rats with particular reference to histopathological changes in uterus. AB - OBJECTIVES: This study was undertaken to elucidate the adverse effect of lead on female reproductive system following in vivo exposure in rats. MATERIALS AND METHODS: Animals of Group II, III and IV received lead acetate in drinking water (30, 100 and 300 ppm, respectively) for 28 days whereas Group I served as control. Lead levels in digested blood and bone samples were measured using atomic absorption spectrophotometer. RESULTS: Marked and a significant decrease in per cent body weight gain was observed in rats of Group IV and III, respectively, compared to that in the control group. Relative uterine weights were found to decrease by 27% in Group III and IV compared to control and low dose lead treated (30 ppm) rats. Lead levels were found to increase in a linear manner in blood along with a marked increase in bone levels in 100 ppm exposure group while there was a decrease in both the blood and bones levels at 300 ppm exposure. Compared to plasma progesterone levels in rats of the control group, a nonsignificant (12.46-21.13%) reduction in plasma progesterone were observed in different lead-treated groups. No apparent gross pathological lesions were observed in any of the vital organs, including uterus. However, histopathological examination of uteri of different groups revealed lead-induced dose-dependent inflammatory changes, which were characterized by thickening of the endometrium, narrowing of uterine lumen, damage to endometrial glands and vacuolar degeneration in endometrial epithelial cells. CONCLUSION: Findings of this study suggest lead-induced pathophysiological alterations in myometrium, which in turn may affect the reproductive efficiency of animals. PMID- 25821307 TI - Toll-like receptor 4 is involved in a protective effect of rhein on immunoglobulin A nephropathy. AB - OBJECTIVES: The objective was to investigate the protective effects of rhein on renal histology change and the effects of rhein on renal tissue toll-like receptor (TLR) 4, TLR9, transforming growth factor-beta1 (TGF-beta1) expression in immunoglobulin A nephropathy (IgAN) rats. MATERIALS AND METHODS: Bovine serum albumin-lipopolysaccharide-carbon tetrachloride 4 method was used to establish IgAN model. Thirty-two male sprague dawley rats were randomly divided into the control group, IgAN model group, rhein-prevented group, and rhein-treated group. 24-h urinary protein (UP), creatinine, urea, alanine aminotransferase (ALT), total protein (TP) contents in the serum of rats were detected with automatic biochemical analyzer and renal pathological changes were observed by the hematoxylin and eosin and periodic acid-Schiff staining. The glomerular deposition of IgA was measured by immunofluorescence staining. Real-time polymerase chain reaction and immunohistochemistry were used to detect renal tissue contents of TLR4, TLR9, TGF-beta1 messenger ribonucleic acid and protein expression. RESULTS: The biochemical parameters results of IgAN model rats showed that the 24-h UP excretion and ALT concentration were much higher, and TP concentration was much lower than those of the control group (P < 0.05). Granule like or mass-like IgA depositions in the mesangial area, glomerular hypercellularity, hyperplasia of mesangial matrix, and tubulointerstitial fibrosis were found in IgAN group. Rhein-prevented and rhein-treated both improved the biochemical parameters and relieved renal pathological injury. The expressions of renal tissue TLR4, TGF-beta1, but not TLR9 were significantly elevated in IgAN model rats (P < 0.05). Rhein-prevented and rhein-treated both inhibited TLR4 and TGF-beta1 expressions. CONCLUSION: Rhein significantly improved the serum and urine biochemical parameters, and attenuated the glomerular pathological changes and tubulointerstitial fibrosis in IgAN rats. The mechanism may involve inhibition of renal TLR4 and TGF-beta1 secretion. PMID- 25821308 TI - Evaluation of effects of T and N type calcium channel blockers on the electroencephalogram recordings in Wistar Albino Glaxo/Rij rats, an absence epilepsy model. AB - OBJECTIVES: It is suggested that excessive calcium entry into neurons is the main triggering event in the initiation of epileptic discharges. We aimed to investigate the role of T and N type calcium channels in absence epilepsy experimental model. MATERIALS AND METHODS: Wistar Albino Glaxo/Rij (WAG/Rij) rats (12-16 weeks old) were randomly allocated into four groups; sham, mibefradil (T type calcium channel blocker), w-Conotoxin MVIIA (N type calcium channel blocker), and mibefradil + w-Conotoxin MVIIA. Beta, alpha, theta, and delta wave ratios of EEG recordings and frequency and duration of spike wave discharges (SWDs) were analyzed and compared between groups. RESULTS: Beta and delta recording ratios in 1 MUM/5 MUl mibefradil group was significantly different from basal and other dose-injected groups. Beta, alpha, and theta recordings in 0.2 MUM/5 MUl w-Conotoxin MVIIA group was significantly different from basal and other dose-injected groups. In w-Conotoxin MVIIA after mibefradil group, beta, alpha, and theta recording ratios were significantly different from basal and mibefradil group. Mibefradil and w-Conotoxin MVIIA significantly decreased the frequency and duration of SWDs. The decrease of frequency and duration of SWDs in mibefradil group was significantly different from w-Conotoxin MVIIA group. The frequency and duration of SWDs significantly decreased in w-Conotoxin MVIIA after mibefradil group compared with basal, mibefradil, and w-Conotoxin MVIIA groups. CONCLUSIONS: We concluded that both T and L type calcium channels play activator roles in SWDs and have positive effects on frequency and duration of these discharges. These results are related with their central effects more than peripheral effects. PMID- 25821309 TI - Combination of Spirulina with glycyrrhizin prevents cognitive dysfunction in aged obese rats. AB - OBJECTIVES: To evaluate the cognition enhancing effect of the combination of Spirulina and glycyrrhizin in monosodium glutamate (MSG)-induced obese aged rats. MATERIALS AND METHODS: Obesity was induced in rats by administration of MSG (intraperitoneally, 4 mg/g body weight) for 14 consecutive days from day 1 after birth. Subsequently, the animals were allowed to grow for 18 months with food and water ad libitum. Hypercholesterolemia, hyperglycemia, leptin resistance, were monitored in these animals. Cognitive status was assessed by Barne's maze task and hippocampal acetylcholinesterase (AChE) levels. Further, the animals were treated with Spirulina (Sp) (oral route, 1 g/Kg body weight, for 30 days) alone or glycyrrhizin (Gly) alone (intraperitoneal route, 0.1 mg/Kg, on day 15 and day 21), or their combination (SpGly). Counting of the treatment days was done by considering first day of Sp administration as day 1. After the completion of 30 days of Spirulina treatment or 2 doses of Gly administration or the combination (SpGly) treatment, the animals were left for 3 weeks. They were then were assessed for their biochemical and cognitive changes. RESULTS: The combination of Sp with Gly showed a significant reduction (P < 0.0001) in glucose, cholesterol, leptin levels in the serum with improvement in cognitive functions with concomitant reduction in AChE activity in the hippocampal tissue homogenates (P < 0.0001) of the obese rats. CONCLUSION: SpGly combination has a potential role in reversing cognitive dysfunctions associated with aging and obesity. PMID- 25821310 TI - Effects of valproate on the carotid artery intima-media thickness in epileptics. AB - OBJECTIVE: The objective was to explore the effects of valproate (VPA) on the carotid artery intima-media thickness (CA-IMT) in epileptics. MATERIALS AND METHODS: A total of 30 epileptic patients treated with VPA was included as disease group, while 33 healthy people who matched general basic demographic details were the control group. The IMTs of the left and right carotids of the both groups were measured, and the average CA-IMT was calculated. The IMT-related risk factors were acquired for the univariate and multivariate analysis. RESULTS: The bilateral carotid and average CA-IMTs of the disease group were significantly higher than the control group (P < 0.001). The multivariant gradual regressive analysis screened out two CA-IMT-related factors, namely the disease duration and the drug administration duration were positively correlated with the average CA IMT. The epileptic patients with disease course of more than 3 years had much higher average CA-IMT than that of the epileptics with <=3 years disease (P < 0.001). The average CA-IMT of the patients with VPA-administration duration >1 year was also higher than that of the patients with VPA-administration duration <1 year, while the difference was not statistically significant (P = 0.196). CONCLUSIONS: The average CA-IMT of the epileptic patients treated with VPA was higher than that of healthy people. PMID- 25821312 TI - Effects of bleomycin A5 on caspase-3, P53, bcl-2 expression and telomerase activity in vascular endothelial cells. AB - OBJECTIVE: The aim of this study was to investigate the molecular mechanism of bleomycin A5 in inducing the apoptosis of human umbilical vein endothelial cells (ECV304). MATERIALS AND METHODS: ECV304 cells were cultured and passaged, and then were divided into control group and three treatment groups. The later three groups were treated with 15, 75, and 150 MUg/ml bleomycin A5 for 24 hours, respectively. The expressions of caspase-3, p53, and bcl-2 in ECV304 cells were detected by flow cytometry, and the activity of telomerase was determined using telomere repeat amplification protocol (TRAP)-silver staining method. RESULTS: After treatment with different concentrations of bleomycin A5, the expression of caspase-3 in ECV304 cells was increased. It was significantly decreased with the increase of bleomycin A5 concentration, but the difference between 75 MUg/ml and 150 MUg/ml groups was not significant. Bleomycin A5 could significantly increase the expression of p53, with concentration dependence. It had no obvious effect on bcl-2 expression. There was high expression of telomerase in control group. After treatment with different concentration of bleomycin A5, the telomerase activity was significantly decreased. CONCLUSION: Bleomycin A5 can increase caspase-3 and p53 levels and inhibit telomerase activity to induce ECV304 apoptosis. PMID- 25821311 TI - Resuscitation with hydroxyethyl starch 130/0.4 attenuates intestinal injury in a rabbit model of sepsis. AB - OBJECTIVE: Improvement of mucosal barrier function and reduction of bacterial translocation are important in the management of sepsis. The mechanisms that underlie the protective effects of colloids on the intestinal mucosal barrier are unclear. The study aims to investigate the effect of fluid resuscitation with hydroxyethyl starch (HES) 130/0.4 against intestinal mucosal barrier dysfunction in a rabbit model of sepsis. MATERIALS AND METHODS: Thirty healthy rabbits were randomly and equally divided into a sham-operated control, a sepsis model, or a sepsis + HES treatment group. The sepsis model and sepsis + HES treatment groups were subjected to a modified colon ascendens stent peritonitis (CASP) procedure to induce sepsis. Four hours after the CASP procedure, fluid resuscitation was performed with 6% HES 130/0.4. Arterial and superior mesenteric vein blood samples were collected 4 and 8 h after the CASP procedure for blood gas analysis and measuring tumor necrosis factor-alpha, interleukin-10, and D-lactate levels. The rabbits were euthanized 8 h after CASP, and sections of the small intestine were stained to evaluate histopathological changes. RESULTS: Respiratory rate and blood pressure were stable during the resuscitation period. Fluid resuscitation with 6% HES 130/0.4 alleviated pathological changes in the abdominal cavity, improved blood gas parameters and inflammatory mediator levels, decreased plasma D-lactate levels, and reduced intestinal mucosal injury compared with the non treated sepsis model. CONCLUSIONS: Fluid resuscitation with 6% HES 130/0.4 protects against intestinal mucosal barrier dysfunction in rabbits with sepsis, possibly via mechanisms associated with improving intestinal oxygen metabolism and reducing the release of inflammatory mediators. PMID- 25821313 TI - Evaluation of anti-osteoarthritic activity of Vigna mungo in papain induced osteoarthritis model. AB - AIM: This study was carried out to evaluate the effect of Vigna mungo hydroalcoholic extract (VMHA) by papain induced osteoarthritis (OA) in the rat model. MATERIALS AND METHODS: OA was induced by intra-articular injection of papain (4% w/v) along with cysteine (0.03 M) on day 1, 4 and 7 in rats and VMHA was administered orally in three doses (100, 200 and 400 mg/kg) after last papain injection. The anti-osteoarthritic activity was evaluated by measuring knee joint diameter, grip strength, locomotion activity and hanging time. Histopathological analysis and acute toxicity study were also performed. RESULTS: VMHA improved inflammatory condition with all the doses, but significant (P < 0.05) attenuation of inflammation was present only with 400 mg/kg dose. The grip strength, locomotion activity and hanging time were also significantly (P < 0.05) improved at dose level of 100 mg/kg however other two doses (200 mg/kg and 400 mg/kg) were not found to be effective. VMHA did not show any mortality or any toxic clinical signs after oral administration of 2 g/kg dose. CONCLUSION: VMHA improved arthritic condition by significantly reducing pain and inflammation. PMID- 25821314 TI - Under-reporting of adverse drug reactions: a challenge for pharmacovigilance in India. AB - AIM: The aim was to evaluate the extent and factors responsible for underreporting (UR) of adverse drug reactions (ADRs) in India. MATERIALS AND METHODS: A retrospective observational, cross-sectional prospective questionnaire based analysis was undertaken to evaluate the extent and factors for UR of ADRs in pharmacovigilance. RESULTS: At the time, this report was prepared, 90 ADR Monitoring Centers (AMC) were operational in India. Indian AMC functional rate was 56.45%. The average number of Individual Case Safety Reports reported by our center via VigiFlow per month was 48.038. In a period of the 3 years the total number of ADRs reported was 3024. The average number of reports per month was 80.08. Active surveillance versus spontaneous reporting contributed 66.13% versus 33.86% of the total ADRs (P < 0.0001). Outpatient Department (OPD) contribution was 76.05% and indoor contribution was 23.94% of total reports (P < 0.0001). Department of Medicine (33%), followed by oncology (19.27%) and chest disease (13.49%) contributed maximally. The contribution of Pharmacology ADR monitoring OPD was 16.20%. Eye, ear, nose and throat and surgery, private Medical Colleges, hospitals in periphery, sub-district and district contributed no ADRs. ADR detection rates by clinical presentation, biochemical investigation and diagnostic tools were 84.33%, 14.57%, and 1.09% respectively (P < 0.0001). Reporting by postgraduate, registrars, consultants and nurses were 72.65%, 6.58%, 16.56% and 4.19% respectively (P < 0.0001). PG students in Pharmacology contributed an average number of 5.61 ADR reports/month. The lack of knowledge and awareness about Pharmacovigilance Programme of India (PvPI), lethargy, indifference, insecurity, complacency, workload, lack of training were the common factors responsible for UR. Major academic activity, exams, thesis and synopsis submission time influenced reporting of ADRs by postgraduate students. CONCLUSION: UR is a matter of concern PvPI. Multiple interventions are needed to improve ADR reporting. PMID- 25821315 TI - Safety and efficacy of Qurse-e-istisqua in chronic hepatitis C infection: an exploratory study. AB - BACKGROUND: Qurse-e-istisqua (Q-e-I), an Unani medicine commonly prescribed to treat liver disorders. OBJECTIVES: To study efficacy and safety of Q-e-I in hepatitis C virus (HCV) infection. METHODS: In this randomized double-blind exploratory study, 60 naive patients of HCV infection were assigned to receive either interferonalpha2a (IFNalpha2a) (3 mIU, subcutaneous, thrice weekly), ribavirin (RBV) (1000 mg, orally, twice daily in divided doses) and placebo (n = 30) or IFNalpha2a, RBV and Q-e-I (5 g, orally, thrice daily in divided doses) (n = 30). HCV RNA levels, serum hyaluronic acid (SHA), ultrasound image scoring for fibrosis, liver and renal function test, prothrombin time, were done at the baseline and thereafter periodically. RESULTS: Early virologic response (EVR), end of treatment response (ETR) and sustained virologic response (SVR) were 90%, 96.6% and 90% in the control group and 86.6%, 90.0% and 83.3% in the treatment group. SHA level was lower in the treatment group at the end of the treatment as compared to the control group. Mean end of follow-up ultrasound image scoring for fibrosis in the control and the treatment group was 1.37 +/- 0.07 and 1.22 +/- 0.06 respectively. Aspartate aminotransferase (AST) levels were significantly lower in the treatment group than the control group at 1-month. Commonly observed adverse drug reactions included fever, hair fall, fatigue, anemia, and diarrhea. CONCLUSION: Q-e-I was well tolerated and showed anti-fibrotic activity. EVR, ETR and SVR suggested that Q-e-I do not have any anti-HCV activity. Early recovery in AST and inhibition of progress of fibrosis in Q-e-I group was probably due to the anti-inflammatory and antioxidant activity of its ingredients. PMID- 25821316 TI - Effects of combination of aliskiren and pentoxyfylline on renal function in the rat remnant kidney model of chronic renal failure. AB - OBJECTIVES: The aim was to investigate the nephroprotective effect of combination of aliskiren (ASK), a direct renin inhibitor and pentoxifylline (PTX), inhibitor of tumor necrotic factor-alpha (TNF-alpha), in rat remnant kidney model of chronic kidney disease (CKD). MATERIALS AND METHODS: Nephrectomized (NPX) rats were treated with ASK (10 mg/kg, p.o.), PTX (100 mg/kg, p.o.), and combination of PTX + ASK once daily for 28 days. We have performed analysis of various renal injury parameters after 4 weeks of treatment. RESULTS: Treatment with PTX, ASK and combination showed significant improvement in urea, creatinine and total protein in plasma when compared with vehicle treated group in NPX rats. ASK and combination of PTX + ASK elicited significant reduction in blood pressure but PTX alone did not produce blood pressure reduction. ASK treatment showed significant elevation in TNF-alpha, whereas PTX and ASK + PTX showed significant reduction in TNF-alpha in plasma. Histopathologically, the extent of the kidney injury was similar in NPX + vehicle and NPX + ASK-treated rats. PTX and ASK + PTX-treated group showed lesser extent of kidney injury. There was good correlation of mRNA expression levels of kidney injury molecule-1 and bradykinin B1 receptor data with histopathological findings in kidney samples and elevated TNF-alpha levels in plasma. CONCLUSIONS: We conclude that combination of PTX + ASK may be better therapeutic intervention for nephroprotection in CKD patients. PMID- 25821317 TI - Protective effect of rutin on impairment of cognitive functions of due to antiepileptic drugs on zebrafish model. AB - AIM: The severity of adverse reactions due to antiepileptics is observed during initiation and early treatment in which impairment of cognitive effects are common. Since long time, herbal medicine is a natural remedy to treat neural symptoms. Phytochemicals have been proven to be potent neuro-protective agents. Rutin, a bioflavonoid is established to be nootropic in many studies. In this study, we aimed to determine the protective effect of rutin in zebrafish against the side effects produced by AEDs. MATERIALS AND METHODS: Seizures were induced in zebrafish by phenylenetetrazole. Rutin pretreatment (50 mg/kg, single injection, i.p.) was done before commencement of the study. Behavioral studies were performed as: latency to move high in the tank, locomotion effects, color effect, shoal cohesion, light/dark test on Zebrafish. RESULTS: Treatment with rutin reverted the locomotor behavior to normal. Treatment with AEDs caused fishes to move in all regions while, in case of treatment with rutin, the response reverted to normal. Treatment with AEDs altered swimming behavior of zebrafish, however, rutin showed a positive effect over this behavior. Treatment with AEDs resulted in restricted movement of zebrafish to the dark zone. Treatment with rutin caused increased latency of zebrafish to move in the light compartment. Similarly, time spent in the light compartment by zebrafish treated with rutin was significantly (P < 0.01) higher as compared to zebrafish treated with AEDs. CONCLUSION: The results suggest a protective role of rutin on cognition impaired by AEDs. PMID- 25821318 TI - A comparison of enoxaparin with unfractionated heparins in patients with coronary heart disease in an emergency department in rural South Indian tertiary care teaching hospital. AB - AIM: Antithrombotic therapy with heparin plus antiplatelets reduces the rate of ischemic events in patients with coronary heart disease. Low molecular weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, does not require monitoring and is associated with less ADRs. The purpose of the present study was to evaluate and compare the clinical and cost outcomes of Enoxaparin with a standard unfractionated heparin in patients with coronary heart disease. MATERIALS AND METHODS: This was a noninvasive prospective observational descriptive study carried out at a multi specialty tertiary care teaching hospital situated in rural Tamil Nadu, India. Male and female coronary heart disease (CHD) patients aged 35-75 years newly diagnosed or those having a history of CHD were included. The intervention group received enoxaparin for 5 days. A series of resting the electrocardiogram, prothrombin time and ADRs were measured in all patients during days 1 and 21 respectively. RESULTS: Compared to unfractionated heparin group of patients, the average prothrombin time was significantly higher (P < 0.0001) whereas hypokalemia was significantly lower (P < 0.02) in enoxaparin group of patients. Even though recurrence of angina and ADRs such as bleeding, nausea, headache and sudden cough occurred less frequently in the enoxaparin group of patients compared to unfractionated heparin group of patients, the differences were not significant. CONCLUSIONS: Antithrombotic therapy with enoxaparin plus aspirin was safer and more effective than unfractionated heparin plus aspirin, in reducing the incidence of ischemic events in patients with unstable angina or myocardial infarction in the early phase. PMID- 25821320 TI - Effects of Ginkgo biloba extract on the apoptosis of oxygen and glucose-deprived SH-SY5Y cells and its mechanism. AB - OBJECTIVE: The aim was to observe the effects of the extract of Ginkgo biloba (EGb761) on the apoptosis of oxygen and glucose-deprived (OGD) human neuroblastoma cells (SH-SY5Y) cells and explore its mechanism. MATERIALS AND METHODS: SH-SY5Y cells were divided into normal control group, OGD group, OGD for 4 h and EGb761-pretreated groups including very low-concentration (20 MUg/ml), low-concentration group (25 MUg/ml), moderate-concentration group (50 MUg/ml) and high-concentration group (100 MUg/ml). Twenty four hours after reoxygenation, cell viability was determined with 3-[4, 5-dimehyl-2-thiazolyl]-2, 5-diphenyl-2H tetrazolium bromide assay, apoptosis rate was detected with annexin V-fluorescein isothiocyanate/propidium iodide double staining flow cytometry and the protein level of apoptosis-inducing factor (AIF) was observed with immunofluorescence technique in each group. RESULTS: Cell viability was significantly lower in OGD group than in EGb761-pretreated groups, especially in moderate-concentration group (50 MUg/ml) (P < 0.005). Apoptosis rate was significantly lower in EGb761 pretreated groups than in OGD group (P < 0.001). Immunofluorescent staining showed that there was AIF nuclear translocation in both EGb761-pretreated groups and OGD group, but AIF nuclear translocation was less in EGb761-pretreated groups than in OGD group. CONCLUSION: EGb761 can reduce the apoptosis of OGD SH-SY5Y cells probably through inhibiting AIF nuclear translocation. This study provides a theoretical basis for the application of EGb761 in clinical practice. PMID- 25821319 TI - Comparison of colistin monotherapy and non-colistin combinations in the treatment of multi-drug resistant Acinetobacter spp. bloodstream infections: a multicenter retrospective analysis. AB - OBJECTIVES: To compare the efficacy of colistin (COL) monotherapy versus non-COL based combinations in the treatment of bloodstream infections (BSIs) due to multidrug resistant Acinetobacter spp.(MDR-A). MATERIALS AND METHODS: Retrospective data of 107 MDR-A BSI cases from 27 tertiary centers in Turkey were included. PRIMARY END-POINT: 14-day mortality. SECONDARY END-POINTS: Microbial eradication and clinical improvement. RESULTS: Thirty-six patients in the COL monotherapy (CM) group and 71 in the non-COL based combinations (NCC) group were included in the study. Mean age was 59.98 +/- 20 years (range: 18-89) and 50.5% were male. Median duration of follow-up was 40 days (range: 9-297). The 14-day survival rates were 52.8% in CM and 47.23% in NCC group (P = 0.36). Microbiological eradication was achieved in 69% of CM and 83% of NCC group (P = 0.13). Treatment failure was detected in 22.9% of cases in both CM and NCC groups. Univariate analysis revealed that mean age (P = 0.001), Charlson comorbidity index (P = 0.03), duration of hospital stay before MDR-A BSI (P = 0.04), Pitt bacteremia score (P = 0.043) and Acute Physiology and Chronic Health Evaluation II score (P = 0.05) were significant in terms of 14-day mortality. Advanced age (P = 0.01) and duration of hospital stay before MDR-A BSI (P = 0.04) were independently associated with 14-day mortality in multivariate analysis. CONCLUSION: No significant difference was detected between CM and non-COL based combinations in the treatment of MDR-A BSIs in terms of efficacy and 14-day mortality. PMID- 25821321 TI - A questionnaire-based survey to ascertain the views of clinicians regarding rational use of antibiotics in teaching hospitals of Kolkata. AB - OBJECTIVES: The objective was to assess the views of clinicians in teaching hospitals of Kolkata regarding the use of antibiotics in their own hospitals, focusing on perceived misuse, reasons behind such misuse and feasible remedial measures. MATERIALS AND METHODS: A total of 200 clinicians from core clinical disciplines was approached in six teaching hospitals of Kolkata through purposive sampling. A structured, validated questionnaire adopted from published studies and modified to suit the responding population was completed by consenting respondents through face-to-face interaction with a single interviewer. Respondents were free to leave out questions they did not wish to answer. RESULTS: Among 130 participating clinicians (65% of approached), all felt that antibiotic misuse occurs in various hospital settings; 72 (55.4% of the respondents) felt it was a frequent occurrence and needed major rectification. Cough and cold (78.5%), fever (65.4%), and diarrhea (62.3%) were perceived to be the commonest conditions of antibiotic misuse. About half (50.76%) felt that oral preparations were more misused compared to injectable or topical ones. Among oral antibiotics, co-amoxiclav (66.9%) and cefpodoxime (63.07%) whereas among parenteral ones, ceftriaxone and other third generation cephalosporins (74.6%) followed by piperacillin-tazobactam (61.5%) were selected as the most misused ones. Deficient training in rational use of medicines (70.7%) and absence of institutional antibiotic policy (67.7%) were listed as the two most important predisposing factors. Training of medical students and interns in rational antibiotic use (78.5%), implementation of antibiotic policy (76.9%), improvement in microbiology support (70.7%), and regular surveillance on this issue (64.6%) were cited as the principal remedial measures. CONCLUSIONS: Clinicians acknowledge that the misuse of antibiotics is an important problem in their hospitals. A system of clinical audit of antibiotic usage, improved microbiology support and implementation of antibiotic policy can help to promote rational use of antimicrobial agents. PMID- 25821323 TI - Aminoglycosides induce fragility of human red cell membrane: an in vitro study. AB - OBJECTIVES: It is well-known that aminoglycosides are ototoxic and nephrotoxic. Recent advances in pharmacology research suggest that the red cell used as a carrier of aminoglycosides. This study aimed to find the effect of aminoglycosides on the human red cell membrane using osmotic fragility test. MATERIALS AND METHODS: This study was conducted in Rizgari Teaching Hospital in Erbil, Iraq. The effect of aminoglycosides, namely gentamicin, amikacin, and spectinomycin, on human red cells was investigated. The effects of aminoglycosides were evaluated by osmotic fragility test using fresh human blood in the presence of aminoglycosides in concentrations of 10-160 MUg/mL. RESULTS: The results showed that aminoglycosides drugs shifted the osmotic fragility curve to some extent, and this effect was well observed with spectinomycin. The hemolysis did not depend on the concentration of aminoglycosides. The concentration of sodium chloride to induced 50% hemolysis is higher in presence of gentamicin, amikacin and spectinomycin (at 160 MUg/mL) than corresponding control and this account to an increment in hemolysis percents of 1.88, 1.5 and 1.06%, respectively. CONCLUSION: Aminoglycosides induce human red cell membrane fragility in a concentration-independent manner. PMID- 25821322 TI - Interaction of aqueous leaf extract of Aegle marmelos (L.) Corr. with cholinergic, serotonergic and adrenergic receptors: an ex vivo study. AB - OBJECTIVES: The aim was to study interaction of aqueous leaf extract of Aegle marmelos (AM) with cholinergic, serotonergic, and adrenergic receptor systems using appropriate rat tissues-ileum, fundus and tracheal chain, respectively. MATERIALS AND METHODS: Cumulative concentration-response curves (CRC) were constructed at various doses on each tissue for AM and respective standard agonist. The CRC was again plotted in presence and absence of respective standard antagonist to confirm the interaction of receptor system and AM. RESULTS: AM induced concentration-dependent contractions in isolated rat ileum (0.2-6.4 mg/ml) and fundus (0.2-3.2 mg/ml) that were inhibited significantly (P < 0.05) in the presence of atropine (10(-7) M) and ketanserin (10(-6) M), respectively. The relaxant effect, produced by AM (0.2 mg/ml) on carbachol (10(-5) M) precontracted rat tracheal chain, was also inhibited significantly (P < 0.05) by propranolol (1 ng/ml). CONCLUSION: It may be concluded that AM possesses agonistic activity on cholinergic, serotonergic and adrenergic receptors. PMID- 25821324 TI - Effect of adiponectin on expression of vascular endothelial growth factor and pigment epithelium-derived factor: an in vitro study. AB - AIM: This study was carried out to identify the role of adiponectin (APN) in modulating the expression of vascular endothelial growth factor (VEGF) and pigment epithelial-derived factor (PEDF) in relation to ocular angiogenesis. MATERIALS AND METHODS: Human retinal pigment epithelial cell lines (ARPE-19) were cultured in Dulbeco's minimum essential medium with 10% fetal bovine serum (FBS) and exposed to varying concentrations of recombinant adiponectin (5-5 ng/ml) for 1 h. Analysis of VEGF and PEDF mRNA was done by reverse transcriptase and further quantified by quantitative polymerase chain reaction. VEGF and PEDF protein expression were studied using enzyme-linked immune sorbent assay (ELISA). STATISTICAL ANALYSIS: Unpaired Student's t-test was used to analyze the significance. P < 0.05 was accepted as statistically significant. RESULTS: ARPE cells exposed to APN showed decreased expression of VEGF mRNA, protein whereas PEDF protein is unaltered and PEDF mRNA was increased. CONCLUSION: Our in vitro study on ARPE exposed to APN showed a negative correlation with VEGF levels. Thus indicating the protective role for APN in angiogenesis-related diseases. PMID- 25821325 TI - Reversible bilateral ototoxicity in a patient with chronic hepatitis B during peginterferon alpha-2a treatment. AB - Peginterferon alpha-2a (PEG IFN alpha-2a) is frequently used in chronic hepatitis B (CHB)treatment. Numerous adverse events can be noted during this therapy such as flu-like disease, rash, weight loss and depression. However, PEG IFN alpha-2a related ototoxicity seems to be an uncommon entity. Ototoxicity can be detected objectively by audiometry. In this paper, we present a case of CHB who developed reversible bilateral ototoxicity during PEG IFN alpha-2a treatment. Due to ototoxicity detected objectively by audiogram, treatment was ceased at sixth month and ototoxicity completely recovered one month after stopping the drug. PMID- 25821326 TI - Pustular drug hypersensitivity syndrome due to allopurinol. AB - Allopurinol hypersensitivity syndrome (AHS) is a severe drug reaction. It is characterized by rash, fever, and internal organ involvement. It may present in different clinical forms. We present a case of acute generalized exanthematous pustulosis occurring as a manifestation of AHS. PMID- 25821327 TI - Cost-effectiveness of the baclofen versus chlordiazepoxide in alcohol withdrawal syndrome. PMID- 25821329 TI - A cross-sectional study of adverse drug reactions reporting among doctors of a private medical college in Bihar, India. PMID- 25821330 TI - 'Radical Interpretation' and the Assessment of Decision-Making Capacity. AB - The assessment of patients' decision-making capacity (DMC) has become an important area of clinical practice, and since it provides the gateway for a consideration of non-consensual treatment, has major ethical implications. Tests of DMC such as under the Mental Capacity Act (2005) for England and Wales aim at supporting autonomy and reducing unwarranted paternalism by being 'procedural', focusing on how the person arrived at a treatment decision. In practice, it is difficult, especially in problematic or borderline cases, to avoid a consideration of beliefs and values; that is, of the substantive content of ideas rather than simple 'cognitive' or procedural abilities. However, little attention has been paid to how beliefs and values might be assessed in the clinical context and what kind of 'objectivity' is possible. We argue that key aspects of Donald Davidson's ideas of 'Radical Interpretation' and the 'Principle of Charity' provide useful guidance as to how clinicians might approach the question of whether an apparent disturbance in a person's thinking about beliefs or values undermines their DMC. A case example is provided, and a number of implications for clinical practice are discussed. PMID- 25821331 TI - Simultaneous inference of a misclassified outcome and competing risks failure time data. AB - Ipsilateral breast tumor relapse (IBTR) often occurs in breast cancer patients after their breast conservation therapy. The IBTR status' classification (true local recurrence versus new ipsilateral primary tumor) is subject to error and there is no widely-accepted gold standard. Time to IBTR is likely informative for IBTR classification because new primary tumor tends to have a longer mean time to IBTR and is associated with improved survival as compared with the true local recurrence tumor. Moreover, some patients may die from breast cancer or other causes in a competing risk scenario during the follow-up period. Because the time to death can be correlated to the unobserved true IBTR status and time to IBTR (if relapse occurs), this terminal mechanism is non-ignorable. In this article, we propose a unified framework that addresses these issues simultaneously by modeling the misclassified binary outcome without a gold standard and the correlated time to IBTR, subject to dependent competing terminal events. We evaluate the proposed framework by a simulation study and apply it to a real dataset consisting of 4, 477 breast cancer patients. The adaptive Gaussian quadrature tools in SAS procedure NLMIXED can be conveniently used to fit the proposed model. We expect to see broad applications of our model in other studies with a similar data structure. PMID- 25821332 TI - Boron removal from aqueous solutions using alginate gel beads in fixed-bed systems. AB - BACKGROUND: A column sorption study was carried out using calcium alginate gel beads as adsorbent for the removal of boron from aqueous solutions. The breakthrough curve was obtained as a function of pH, initial concentration of boron, feed flow rate, adsorbent mass and column diameter. The breakthrough capacity values and adsorption percentage of calcium alginate gel for boron were calculated. Column data obtained at different conditions were described using the Adams-Bohart model and bed-depth service time (BDST), derived from the Adams Bohart equation to predict breakthrough curves and to determine the characteristic column parameters required for process design. RESULTS: The maximum adsorption percentage of boron on calcium alginate gel beads using an initial concentration of boron of 50 mg L-1 at pH 11 and room temperature (20+/-1 degrees C) was calculated to be 55.14%. CONCLUSION: The results indicated that calcium alginate can be used in a continuous packed-bed column for boron adsorption. The optimal conditions for boron adsorption were obtained at high pH, higher initial boron concentration, increased column depth and lower flow velocity. (c) 2014 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 25821333 TI - 'Herbals she peruseth': reading medicine in early modern England. AB - In 1631, Richard Brathwaite penned a conduct manual for 'English Gentlewomen'. In Brathwaite's mind, the ideal English gentlewoman was not only chaste, modest and honourable but also an avid reader. In fact, Brathwaite specifically recommends English gentlewomen to first peruse herbals and then to deepen their medical knowledge via conference. Centred on the manuscript notebooks of two late seventeenth-century women, Margaret Boscawen (d. 1688) and Elizabeth Freke (1642 1714), this article explores women and 'medical reading' in early modern England. It first demonstrates that whilst both women consulted herbals by contemporary authors such as John Gerard and Nicholas Culpeper, their modes of reading could not be more different. Where Freke ruminated, digested and abstracted from Gerard's large tome, Boscawen made practical lists from Culpeper's The English Physitian. Secondly, the article shows that both supplemented their herbal reading with a range of other vernacular medical texts including printed medical recipe books, contemporary pharmacopoeia and surgical handbooks. Early modern English women's medical reading, I argue, was nuanced, sophisticated and diverse. Furthermore, I contend that well-informed readers like Boscawen and Freke made smart medical consumers and formidable negotiators in their medical encounters. PMID- 25821334 TI - New challenges in the epidemiology and treatment of visceral leishmaniasis in periurban areas. AB - Visceral leishmaniasis [VL] represents a major public health problem in many areas of the world. This review focuses on the impact of periurbanization on the epidemiology and treatment of VL, using Brazil as an example. VL continues to be mostly a disease of poverty with impact on families. However, the disease has expanded in Latin America, with foci reported as far south as Argentina. There is an increasing overlap of Leishmania infantum chagasi and HIV infections and other immunosuppressive conditions, resulting in VL emerging as an opportunistic infection. This new setting poses new challenges for VL disease control and patient management. PMID- 25821336 TI - Bilingualism as a Model for Multitasking. AB - Because both languages of bilinguals are constantly active, bilinguals need to manage attention to the target language and avoid interference from the non target language. This process is likely carried out by recruiting the executive function (EF) system, a system that is also the basis for multitasking. In previous research, bilinguals have been shown to outperform monolinguals on tasks requiring EF, suggesting that the practice using EF for language management benefits performance in other tasks as well. The present study examined 203 children, 8-11 years old, who were monolingual, partially bilingual, bilingual, or trilingual performing a flanker task. Two results support the interpretation that bilingualism is related to multitasking. First, bilingual children outperformed monolinguals on the conflict trials in the flanker task, confirming previous results for a bilingual advantage in EF. Second, the inclusion of partial bilinguals and trilinguals set limits on the role of experience: partial bilingual performed similarly to monolinguals and trilinguals performed similarly to bilinguals, suggesting that degrees of experience are not well-calibrated to improvements in EF. Our conclusion is that the involvement of EF in bilingual language processing makes bilingualism a form of linguistic multitasking. PMID- 25821335 TI - The developing brain in a multitasking world. AB - To understand the problem of multitasking, it is necessary to examine the brain's attention networks that underlie the ability to switch attention between stimuli and tasks and to maintain a single focus among distractors. In this paper we discuss the development of brain networks related to the functions of achieving the alert state, orienting to sensory events, and developing self-control. These brain networks are common to everyone, but their efficiency varies among individuals and reflects both genes and experience. Training can alter brain networks. We consider two forms of training: (1) practice in tasks that involve particular networks, and (2) changes in brain state through such practices as meditation that may influence many networks. Playing action video games and multitasking are themselves methods of training the brain that can lead to improved performance but also to overdependence on media activity. We consider both of these outcomes and ideas about how to resist overdependence on media. Overall, our paper seeks to inform the reader about what has been learned about attention that can influence multitasking over the course of development. PMID- 25821337 TI - alpha-2-macroglobulin in saliva is associated with glycemic control in patients with type 2 diabetes mellitus. AB - BACKGROUND: Subjects with type 2 diabetes mellitus (DM2) require an adequate glycemic control to avoid diabetic complications. Currently, saliva biomarkers are used as a diagnostic tool and can be indicative of the degree of progression and control of various diseases. Several studies indicate that alpha-2 macroglobulin levels are elevated in diabetic patients. METHODS: 120 subjects with DM2 were enrolled and classified into two groups according to their glycemic control (percentage of glycated hemoglobin-A1c (HbA1c), <7% adequate glycemic control group; >7% inadequate glycemic control group). The relationship between alpha-2-macroglobulin levels from saliva samples and HbA1c was subsequently evaluated. RESULTS: We found a positive correlation between alpha-2-macroglobulin and HbA1c (r = 0.778 and P < 0.0001). Area under the receivers operating characteristic (ROC) curve of alpha-2-macroglobulin indicated a positive discrimination threshold of alpha-2-macroglobulin (AUC = 0.903, CI 95%: 0.847 0.959, P < 0.0001) to diagnose glycemic control. CONCLUSIONS: Our data strongly suggest that the level of saliva alpha-2-macroglobulin is an indicator for the degree of glycemic control in diabetic patients and represents a promising alternative method to evaluate this parameter. PMID- 25821338 TI - Blockade of aquaporin 1 inhibits proliferation, motility, and metastatic potential of mesothelioma in vitro but not in an in vivo model. AB - BACKGROUND: Malignant mesothelioma (MM) is an aggressive tumor of the serosal membranes, mostly the pleura. It is related to asbestos exposure and has a poor prognosis. MM has a long latency period, and incidence is predicted to remain stable or increase until 2020. Currently, no biomarkers for a specific targeted therapy are available. Previously, we observed that expression of aquaporin 1 (AQP1) was an indicator of prognosis in two independent cohorts. Here we determine whether AQP1 inhibition has therapeutic potential in the treatment of MM. METHODS: Functional studies were performed with H226 cells and primary MM cells harvested from pleural effusions. AQP1 expression and mesothelial phenotype was determined by immunohistochemistry. AQP1 function was inhibited by a pharmacological blocker (AqB050) or AQP1-specific siRNA. Cell proliferation, migration, and anchorage-independent cell growth were assessed. A nude mouse heterotopic xenograft model of MM was utilised for the in vivo studies. RESULTS: Inhibition of AQP1 significantly decreases cell proliferation, metastatic potential, and motility without inducing nonspecific cytotoxicity or increasing apoptosis. In vivo blockade of AQP1 had no biologically significant effect on growth of established tumours. CONCLUSIONS: Targeted blockade of AQP1 restricts MM growth and migration in vitro. Further work is warranted to fully evaluate treatment potential in vivo. PMID- 25821339 TI - Capillary deposition of complement C4d and C3d in Chinese renal allograft biopsies. AB - BACKGROUND: C3d is a product of both the classic and the alternative complement cascades; however, few studies have addressed the role of C3d in renal biopsies and its relationship with long-term graft survival rate is not very clear. METHODS: 94 patients with biopsy-proven acute rejection episodes were included in the study. We investigated the associations between histological findings, clinical examinations, and outcome. RESULTS: The overall prevalence for C4dPTC and C3dPTC was 42.6% and 29.8%. There was a significant association between C3dPTC and C4dPTC (P < 0.001). C3dPTC and C4dPTC were related with histological types (P = 0.024 and P < 0.001, resp.). The long-term survival rate for C4dPTC positive transplants was lower than that of C4dPTC negative transplants, but it was not statistic significant in our study (P = 0.150). The survival rate of C3dPTC positive group was much lower than the negative group (P = 0.014). Patients with double positives for C4dPTC and C3dPTC exhibited the lowest survival rate significantly different from those of the C3dPTC only and C4dPTC only groups (P = 0.01 and P = 0.0037). CONCLUSIONS: This longitudinal cohort study has demonstrated that C3d deposition in the PTC was closely related to renal dysfunction and pathological changes. PMID- 25821340 TI - Physical activity enhances metabolic fitness independently of cardiorespiratory fitness in marathon runners. AB - High levels of cardiovascular fitness (CRF) and physical activity (PA) are associated with decreased mortality and risk to develop metabolic diseases. The independent contributions of CRF and PA to metabolic disease risk factors are unknown. We tested the hypothesis that runners who run consistently >50 km/wk and/or >2 marathons/yr for the last 5 years have superior metabolic fitness compared to matched sedentary subjects (CRF, age, gender, and BMI). Case-control recruitment of 31 pairs of runner-sedentary subjects identified 10 matched pairs with similar VO2max (mL/min/kg) (similar-VO2max). The similar-VO2max group was compared with a group of age, gender, and BMI matched pairs who had the largest difference in VO2max (different-VO2max). Primary outcomes that defined metabolic fitness including insulin response to an oral glucose tolerance test, fasting lipids, and fasting insulin were superior in runners versus sedentary controls despite similar VO2max. Furthermore, performance (velocity at VO2max, running economy), improved exercise metabolism (lactate threshold), and skeletal muscle levels of mitochondrial proteins were superior in runners versus sedentary controls with similar VO2max. In conclusion subjects with a high amount of PA have more positive metabolic health parameters independent of CRF. PA is thus a good marker against metabolic diseases. PMID- 25821341 TI - Ficus insipida subsp. insipida (Moraceae) reveals the role of ecology in the phylogeography of widespread Neotropical rain forest tree species. AB - AIM: To examine the phylogeography of Ficus insipida subsp. insipida in order to investigate patterns of spatial genetic structure across the Neotropics and within Amazonia. LOCATION: Neotropics. METHODS: Plastid DNA (trnH-psbA; 410 individuals from 54 populations) and nuclear ribosomal internal transcribed spacer (ITS; 85 individuals from 27 populations) sequences were sampled from Mexico to Bolivia, representing the full extent of the taxon's distribution. Divergence of plastid lineages was dated using a Bayesian coalescent approach. Genetic diversity was assessed with indices of haplotype and nucleotide diversities, and genetic structure was examined using spatial analysis of molecular variance (SAMOVA) and haplotype networks. Population expansion within Amazonia was tested using neutrality and mismatch distribution tests. RESULTS: trnH-psbA sequences yielded 19 haplotypes restricted to either Mesoamerica or Amazonia; six haplotypes were found among ITS sequences. Diversification of the plastid DNA haplotypes began c. 14.6 Ma. Haplotype diversity for trnH-psbA was higher in Amazonia. Seven genetically differentiated SAMOVA groups were described for trnH-psbA, of which two were also supported by the presence of unique ITS sequences. Population expansion was suggested for both markers for the SAMOVA group that contains most Amazonian populations. MAIN CONCLUSIONS: Our results show marked population genetic structure in F. insipida between Mesoamerica and Amazonia, implying that the Andes and seasonally dry areas of northern South America are eco-climatic barriers to its migration. This pattern is shared with other widespread pioneer species affiliated to wet habitats, indicating that the ecological characteristics of species may impact upon large-scale phylogeography. Ficus insipida also shows genetic structure in north-western Amazonia potentially related to pre-Pleistocene historical events. In contrast, evident population expansion elsewhere in Amazonia, in particular the presence of genetically uniform populations across the south-west, indicate recent colonization. Our findings are consistent with palaeoecological data that suggest recent post glacial expansion of Amazonian forests in the south. PMID- 25821342 TI - Using groundwater age distributions to estimate the effective parameters of Fickian and non-Fickian models of solute transport. AB - Groundwater age distributions are used to estimate the parameters of Fickian, and non-Fickian, effective models of solute transport. Based on the similarities between the transport and age equations, we develop a deconvolution based approach that describes transport between two monitoring wells. We show that the proposed method gives exact estimates of the travel time distribution between two wells when the domain is stationary and that the method still provides useful information on transport when the domain is non-stationary. The method is demonstrated using idealized uniform and layered 2-D aquifers. Homogeneous transport is determined exactly and non-Fickian transport in a layered aquifer was also approximated very well, even though this example problem is shown to be scale-dependent. This work introduces a method that addresses a significant limitation of tracer tests and non-Fickian transport modeling which is the difficulty in determining the effective parameters of the transport model. PMID- 25821344 TI - ENTHUSIASM DELINEATED: WEEPING AS A RELIGIOUS ACTIVITY IN EIGHTEENTH-CENTURY BRITAIN. AB - Eighteenth-century Europe and its renowned cult of sensibility have a special place in the history of tears. This article revisits weeping in eighteenth century Britain, seeking especially to recover the religious practices, texts, and ideas involved in the production and interpretation of tears. Some of the most prolific and public weeping of the period was produced by the Methodist revival, and especially the preaching of the "Weeping Prophet", George Whitefield. A different, more melancholy form of enthusiasm was the keynote of Henry Mackenzie's famously lachrymose novel The Man of Feeling (1771), reinterpreted here as a handbook of Christian sensibility and religious weeping. On both sides of the French Revolution debate in Britain in the 1790s, tears were shed, but were also denounced. The retrospective belief that tearful sensibilities had given rise to dangerous ideologies and bloody violence cast the practice of weeping in a new light. Suspicions of religious "enthusiasm" from earlier periods were now applied to revolutionary sympathisers in Britain, and commentators, including Helen Maria Williams, began to discuss the idea that it was un-English to weep. PMID- 25821343 TI - Statistical learning as an individual ability: Theoretical perspectives and empirical evidence. AB - Although the power of statistical learning (SL) in explaining a wide range of linguistic functions is gaining increasing support, relatively little research has focused on this theoretical construct from the perspective of individual differences. However, to be able to reliably link individual differences in a given ability such as language learning to individual differences in SL, three critical theoretical questions should be posed: Is SL a componential or unified ability? Is it nested within other general cognitive abilities? Is it a stable capacity of an individual? Following an initial mapping sentence outlining the possible dimensions of SL, we employed a battery of SL tasks in the visual and auditory modalities, using verbal and non-verbal stimuli, with adjacent and non adjacent contingencies. SL tasks were administered along with general cognitive tasks in a within-subject design at two time points to explore our theoretical questions. We found that SL, as measured by some tasks, is a stable and reliable capacity of an individual. Moreover, we found SL to be independent of general cognitive abilities such as intelligence or working memory. However, SL is not a unified capacity, so that individual sensitivity to conditional probabilities is not uniform across modalities and stimuli. PMID- 25821345 TI - A unified statistical approach to non-negative matrix factorization and probabilistic latent semantic indexing. AB - Non-negative matrix factorization (NMF) is a powerful machine learning method for decomposing a high-dimensional nonnegative matrix V into the product of two nonnegative matrices, W and H, such that V ~ W H. It has been shown to have a parts-based, sparse representation of the data. NMF has been successfully applied in a variety of areas such as natural language processing, neuroscience, information retrieval, image processing, speech recognition and computational biology for the analysis and interpretation of large-scale data. There has also been simultaneous development of a related statistical latent class modeling approach, namely, probabilistic latent semantic indexing (PLSI), for analyzing and interpreting co-occurrence count data arising in natural language processing. In this paper, we present a generalized statistical approach to NMF and PLSI based on Renyi's divergence between two non-negative matrices, stemming from the Poisson likelihood. Our approach unifies various competing models and provides a unique theoretical framework for these methods. We propose a unified algorithm for NMF and provide a rigorous proof of monotonicity of multiplicative updates for W and H. In addition, we generalize the relationship between NMF and PLSI within this framework. We demonstrate the applicability and utility of our approach as well as its superior performance relative to existing methods using real-life and simulated document clustering data. PMID- 25821346 TI - Applying a Multiple Group Causal Indicator Modeling Framework to the Reading Comprehension Skills of Third, Seventh, and Tenth Grade Students. AB - This study demonstrates the utility of applying a causal indicator modeling framework to investigate important predictors of reading comprehension in third, seventh, and tenth grade students. The results indicated that a 4-factor multiple indicator multiple indicator cause (MIMIC) model of reading comprehension provided adequate fit at each grade level. This model included latent predictor constructs of decoding, verbal reasoning, nonverbal reasoning, and working memory and accounted for a large portion of the reading comprehension variance (73% to 87%) across grade levels. Verbal reasoning contributed the most unique variance to reading comprehension at all grade levels. In addition, we fit a multiple group 4-factor MIMIC model to investigate the relative stability (or variability) of the predictor contributions to reading comprehension across development (i.e., grade levels). The results revealed that the contributions of verbal reasoning, nonverbal reasoning, and working memory to reading comprehension were stable across the three grade levels. Decoding was the only predictor that could not be constrained to be equal across grade levels. The contribution of decoding skills to reading comprehension was higher in third grade and then remained relatively stable between seventh and tenth grade. These findings illustrate the feasibility of using MIMIC models to explain individual differences in reading comprehension across the development of reading skills. PMID- 25821347 TI - A Mechanically Tunable Microfluidic Cell-Trapping Device. AB - Controlled manipulation, such as isolation, positioning and trapping of cells, is important in basic biological research and clinical diagnostics. Micro/nanotechnologies have been enabling more effective and efficient cell trapping than possible with conventional platforms. Currently available micro/nanoscale methods for cell trapping, however, still lack flexibility in precisely controlling the number of trapped cells. We exploited the large compliance of elastomers to create an array of cell-trapping microstructures, whose dimensions can be mechanically modulated by inducing uniformly distributed strain via application of external force on the chip. The device consists of two elastomer polydimethylsiloxane (PDMS) sheets, one of which bears dam-like, cup shaped geometries to physically capture cells. The mechanical modulation is used to tune the characteristics of cell trapping to capture a predetermined number of cells, from single cells to multiple cells. Thus, enhanced utility and flexibility for practical applications can be attained, as demonstrated by tunable trapping of MCF-7 cells, a human breast cancer cell line. PMID- 25821348 TI - Age group estimation in free-ranging African elephants based on acoustic cues of low-frequency rumbles. AB - Animal vocal signals are increasingly used to monitor wildlife populations and to obtain estimates of species occurrence and abundance. In the future, acoustic monitoring should function not only to detect animals, but also to extract detailed information about populations by discriminating sexes, age groups, social or kin groups, and potentially individuals. Here we show that it is possible to estimate age groups of African elephants (Loxodonta africana) based on acoustic parameters extracted from rumbles recorded under field conditions in a National Park in South Africa. Statistical models reached up to 70 % correct classification to four age groups (infants, calves, juveniles, adults) and 95 % correct classification when categorising into two groups (infants/calves lumped into one group versus adults). The models revealed that parameters representing absolute frequency values have the most discriminative power. Comparable classification results were obtained by fully automated classification of rumbles by high-dimensional features that represent the entire spectral envelope, such as MFCC (75 % correct classification) and GFCC (74 % correct classification). The reported results and methods provide the scientific foundation for a future system that could potentially automatically estimate the demography of an acoustically monitored elephant group or population. PMID- 25821349 TI - Dual representation of item positions in verbal short-term memory: Evidence for two access modes. AB - Memory sets of N = 1~5 digits were exposed sequentially from left-to-right across the screen, followed by N recognition probes. Probes had to be compared to memory list items on identity only (Sternberg task) or conditional on list position. Positions were probed randomly or in left-to-right order. Search functions related probe response times to set size. Random probing led to ramped, "Sternbergian" functions whose intercepts were elevated by the location requirement. Sequential probing led to flat search functions-fast responses unaffected by set size. These results suggested that items in STM could be accessed either by a slow search-on-identity followed by recovery of an associated location tag, or in a single step by following item-to-item links in study order. It is argued that this dual coding of location information occurs spontaneously at study, and that either code can be utilised at retrieval depending on test demands. PMID- 25821350 TI - Snack food advertising in stores around public schools in Guatemala. AB - Obesity in school-age children is emerging as a public heath concern. Food marketing influences preferences and increases children's requests for food. This study sought to describe the type of snack foods advertised to children in stores in and around public schools and assess if there is an association between child oriented snack food advertising and proximity to schools. All food stores located inside and within a 200 square meter radius from two preschools and two primary schools were surveyed. We assessed store type, number and type of snack food advertisements including those child-oriented inside and outside stores. We surveyed 55 stores and found 321 snack food advertisements. Most were on sweetened beverages (37%) and soft drinks (30%). Ninety-two (29%) were child oriented. Atoles (100.0%), cereals (94.1%), and ice cream and frozen desserts (71.4%) had the greatest proportion of child-oriented advertising. We found more child-oriented advertisements in stores that were closer (<170 m) to schools compared to those farther away. In conclusion, the food industry is flooding the market, taking advantage of the lack of strict regulation in Guatemala. Child oriented advertisements are available in almost all stores within a short walking distance from schools, exposing children to an obesogenic environment. PMID- 25821351 TI - Protective effects of N-acetylcysteine in concanavalin A-induced hepatitis in mice. AB - This study was designed to study the protective effects and mechanisms of N acetylcysteine (NAC) in concanavalin A-induced hepatitis in mice. In this study, pretreatment with NAC ameliorated the histopathological changes and suppressed inflammatory cytokines in ConA-induced hepatitis. The expression of IL-2, IL-6, TNF-alpha, and IFN-gamma was significantly reduced in the NAC-treated groups. NAC activated PI3K/Akt pathway and inhibited the activation of NF-kappaB. Additionally, NAC reduced autophagosome formation, as assessed by detecting the expression of LC3 and Beclin 1. Our results demonstrate that NAC can alleviate ConA-induced hepatitis by regulating the PI3K/Akt pathway and reducing the late stages of autophagy. Our results described a new pharmaceutical to provide more effective therapies for immune hepatitis. PMID- 25821352 TI - Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients. AB - PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children's Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 +/- 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%. Nineteen variants were found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants. No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture. PMID- 25821354 TI - Short-term reproducibility of the inflammatory phenotype in different subgroups of adult asthma cohort. AB - Inflammatory phenotype classification using induced sputum appears attractive as it can be applied to inflammation-based management of the patients with asthma. The aim of the study was to determine the reproducibility of inflammatory phenotype over time in patients with asthma. In 66 adults asthma was categorized as steroid-naive (SN, n = 17), mild to moderate (MMA, n = 33), and refractory treated with oral corticosteroids (RA, n = 16). Clinical assessment, skin prick testing, spirometry, and two sputum inductions in 4-6-week interval were done. Inflammatory phenotypes were classified as eosinophilic (EA), consisting of eosinophilic and mixed granulocytic phenotypes, and noneosinophilic (NEA) consisting of paucigranulocytic and neutrophilic phenotypes. During study asthma treatment remained constant. In SN group 25% of patients changed phenotype from EA to NEA and 44% changed phenotype from NEA to EA. In MMA group 26% of patients changed phenotype from EA to NEA and 50% changed phenotype from NEA to EA. In 29% of RA patients inflammatory phenotype changed from EA to NEA and in 22% it changed from NEA to EA. Inflammatory classification, using induced sputum, is not fully reproducible in adults with asthma in short-term evaluation. EA seems to be more stable phenotype across all subgroups whereas NEA remained stable only in RA group. PMID- 25821353 TI - Helicobacter pylori outer membrane vesicle proteins induce human eosinophil degranulation via a beta2 Integrin CD11/CD18- and ICAM-1-dependent mechanism. AB - Eosinophil cationic protein (ECP), a cytotoxic protein contained in eosinophils granules, can contribute to various inflammatory responses. Although Helicobacter pylori infection increases infiltration of eosinophils, the mechanisms of eosinophil degranulation by H. pylori infection are largely unknown. The goal of this study was to investigate the role of H. pylori outer membrane vesicles (OMVs) in modulating eosinophil degranulation. We found that eosinophils treated with H. pylori OMVs released significantly more ECP compared with untreated controls. In addition, eosinophils cocultured with OMV-preexposed primary gastric epithelial cells exhibited significantly increased ECP release. Similarly, eosinophils cocultured with culture supernatant (CM) from primary gastric epithelial cells exposed to OMVs (OMV-CM) released significantly higher amounts of ECP compared with eosinophils cocultured with CM from unexposed control cells. Furthermore, OMVs and OMV-CM both induced the upregulation of ICAM-1 on gastric epithelial cells and beta2 integrin CD11b on eosinophils. In addition, both transduction of ICAM-1 shRNA into gastric epithelial cells and treatment with neutralizing mAbs to CD18 significantly decreased OMV-mediated or OMV-CM-mediated release of ECP. These results suggest that the eosinophil degranulation response to H. pylori OMVs occurs via a mechanism that is dependent on both beta2 integrin CD11/CD18 and ICAM-1. PMID- 25821355 TI - Pathogenic roles of macrophage migration inhibitory factor during dengue virus infection. AB - Dengue virus (DENV) infection is the most common cause of viral hemorrhagic fever, which can lead to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Hemorrhage and plasma leakage are two major hallmarks of DHF/DSS. Because the mechanisms causing these pathogenic changes are unclear, there is no effective therapy against DHF/DSS. In this review, we focus on the possible pathogenic effects of a pleiotropic cytokine, macrophage migration inhibitory factor (MIF), on the pathogenesis of DENV infection. MIF is a critical mediator of the host immune response and inflammation, and there is a correlation between the serum levels of MIF and disease severity in dengue patients. Furthermore, MIF knock-out mice exhibit less severe clinical disease and lethality. However, the role of MIF in the pathogenesis of DHF/DSS is not limited to immune cell recruitment. Recent evidence indicates that DENV infection induced MIF production and may contribute to vascular hyperpermeability and viral replication during DENV infection. The expression of both adhesion and coagulation molecules on MIF-stimulated monocytes and endothelial cells is also increased, which may contribute to inflammatory and anticoagulatory states during DHF/DSS. Therefore, blocking MIF production or its function may provide a solution for the treatment and prevention of DHF/DSS. PMID- 25821357 TI - The role of adenosine receptors in the central action of caffeine. AB - The behavioral effects of caffeine appear likely to be due in large measure to antagonism of the action of endogenous adenosine at A1- and A2a-receptors in the central nervous system. Other biochemical mechanisms of action of caffeine, such as release of intracellular calcium, inhibition of phosphodiesterases and blockade of regulatory sites of GABAA-reccptors, would require much higher concentrations than the micromolar concentrations of caffeine associated with behavioral stimulation. However, micromolar concentrations of caffeine also would be expected to cause only a modest blockade of adenosine receptors. Selective adenosine agonists and xanthine antagonists have provided some insights into central roles for adenosine receptor subtypes. Thus, behavioral stimulation by xanthines appears to require blockade of both A1- and A2a-receptors. Chronic blockade of adenosine receptors by caffeine would be expected to result in alterations in the central receptors and pathways that are regulated by adenosine through A1- and A2a-receptors. Indeed, chronic caffeine docs alter the density not only of adenosine receptors, but also of adrenergic, cholinergic, GABAergic and serotonergic receptors. Behavioral responses to agents acting through dopaminergic and cholinergic pathways arc altered. As yet, a coherent explanation of the acute and chronic effects of caffeine in terms of blockade of adenosine receptors has not emerged. Interactions between pathways subserved by A1 - and A2a-adcnosine receptors complicate attempts to interpret caffeine pharmacology, as does the complex control by adenosine receptors of dopamincrgic, cholinergic and other central pathways. PMID- 25821358 TI - Our duty to promote local emergency services for traumatic dental injuries. PMID- 25821356 TI - The role of innate immunity receptors in the pathogenesis of inflammatory bowel disease. AB - Innate immunity constitutes the first line of defense, fundamental for the recognition and the initiation of an inflammatory response against microorganisms. The innate immune response relies on the sensing of microbial associated molecular patterns through specialized structures such as toll-like receptors (TLRs) and the nucleotide oligomerization domain- (NOD-) like receptors (NLRs). In the gut, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms. TLRs and NLRs are distributed throughout the gastrointestinal mucosa, being more expressed in the epithelium, and in lamina propria immune and nonimmune cells. These innate immunity receptors exhibit complementary biological functions, with evidence for pathways overlapping. However, as tolerance is the predominant physiological response in the gastrointestinal mucosa, it appears that the TLRs are relatively downregulated, while NLRs play a critical role in mucosal defense in the gut. Over the past two decades, genetic polymorphisms have been associated with several diseases including inflammatory bowel disease. Special emphasis has been given to the susceptibility to Crohn's disease, in association with abnormalities in the NOD2 and in the NLRP3/inflammasome. Nevertheless, the mechanisms underlying innate immune receptors dysfunction that result in the persistent inflammation in inflammatory bowel disease remain to be clarified. PMID- 25821359 TI - Multiple jaw cysts-unveiling the Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome or basal cell nevus syndrome is a comparatively rare syndrome characterized by basal cell nevi, odontogenic keratocysts, and skeletal anomalies. Diagnosis is based on the major and minor clinical and radiographic criteria. Dentist plays a major role in the diagnosis of this disease due to the oral and maxillofacial manifestations of the syndrome. In some cases, jaw cysts are diagnosed by routine radiographs advised by the dentists. Odontogenic keratocysts in such syndromic patients will be multiple and extensive and in some cases results in cortical expansion and facial disfigurement. Thorough clinical examination and investigations prompt an early confirmation of the syndrome, which is very essential to avoid morbidity associated with the syndrome. Here, we report a case of multiple odontogenic cysts in a 16-year-old patient which later was diagnosed as a case of Gorlin Goltz syndrome. PMID- 25821361 TI - Maxillary palatal ramp prosthesis: A prosthodontic solution to manage mandibular deviation following surgery. AB - Mandibular resection following surgical treatment for neoplastic lesions of the oral cavity leads to numerous complications including altered mandibular movements, disfigurement, difficult in swallowing, impaired speech and articulation, and deviation of the mandible towards the resected site. Various prosthetic methods are employed to reduce or minimize mandibular deviation and improve and restore the lost functions and esthetic, like maxillomandibular fixation, implant supported prosthesis, removable mandibular guide flange prosthesis, and palatal based guidance restoration. This clinical report describes the rehabilitation of a patient following segmental mandibulectomy using palatal ramp prosthesis. PMID- 25821360 TI - Five years follow-up of a keratocyst odontogenic tumor treated by marsupialization and enucleation: A case report and literature review. AB - Odontogenic cysts are considered as nonneoplasic benign lesions. Among the cysts, keratocyst odontogenic tumor (KCOT) is an intra-osseous tumor characterized by parakeratinized stratified squamous epithelium and a potential for aggressive, infiltrative behavior, and for the possibility to develop carcinomas in the lesion wall. Thus, the aim of this study was to describe a clinical case of KCOT in a young patient and discuss the treatment alternatives to solve this case. A 15-year-old male was referred for treatment of a giant lesion in his left side of the mandible. After the biopsy, a diagnostic of KCOT was made, and the following procedures were planned for KCOT treatment. Marsupialization was performed for lesion decompression and consequent lesion size reduction. Afterward, enucleation for complete KCOT removal was performed followed by third mandibular molar extraction. After 5 years, no signs of recurrence were observed. The treatment proposed was efficient in removing the KCOT with minimal surgical morbidity and optimal healing process, and the first and second mandibular molars were preserved with pulp vitality. In conclusion, this treatment protocol was an effective and conservative approach for the management of the KCOT, enabling the reduction of the initial lesion, the preservation of anatomical structures and teeth, allowing quicker return to function. No signs of recurrence after 5 years were observed. PMID- 25821362 TI - Prosthetic rehabilitation of severe Siebert's Class III defect with modified Andrews bridge system. AB - Prosthetic dentistry involves the replacement of missing and contiguous tissues with artificial substitutes to restore and maintain the oral functions, appearance, and health of the patient. The treatment of edentulous areas with ridge defects poses a challenging task for the dentist. Management of such cases involves a wide range of treatment options comprising mainly of surgical interventions and non surgical techniques such as use of removable, fixed or fixed- removable partial dentures. But each treatment plan undertaken should be customized according to patient needs. A variety of factors such as quality and quantity of existing contiguous hard and soft tissues, systemic condition and economic status of the patient play an important role in treatment planning, clinical outcome and prognosis. This case report presents the restoration of a Seibert's Class III ridge defect by an economical modification of Andrews Bridge in a 32 Year old patient. PMID- 25821363 TI - Metastatic hepatocellular carcinoma in the maxilla and mandible, an extremely rare presentation. AB - Malignancy is characterized by anaplasia, invasiveness, and metastasis. Primary oral squamous cell carcinoma is the most prevalent oral malignancy, but secondary malignancy from distant sites have also been reported. Hepatocellular carcinoma (HCC) is a common primary liver malignancy that frequently metastasizes during the course of the disease, but < 1% of cases show oral involvement. Such secondary neoplasms do not have any pathognomonic clinical or radiologic findings, and therefore they pose a diagnostic challenge. Hence, in the differential diagnosis of malignant tumors of the oral cavity, it is essential to consider the occurrence of both primary as well as metastatic tumors despite the low incidence of the latter. A rare case of HCC metastasizing to both the maxilla and mandible is presented, in which the patient succumbed to the disease as a result of the delay in diagnosis. PMID- 25821364 TI - Assessment of the relationship between maxillary rotation and nasal morphology in males. AB - BACKGROUND: Nasal features are important in treatment planning for orthodontic treatment. AIMS AND OBJECTIVES: The purpose of the study was to assess the relationship between maxillary inclination and nasal morphology in males. MATERIALS AND METHODS: Forty-five samples were selected for the study between the age group of 18 and 30 years. Selected individuals were subjected to cephalometric radiography. These lateral cephalograms were traced and divided into three groups on the basis of the angle given by Schwarz for rotation of the maxilla. The nasal features of these groups were evaluated and compared using mean, standard deviation, Student's t-test and analysis of variance. RESULTS: The results suggest that there was statistically significant difference in nasal height, nasal bone length (NBL), nasal depth, nasolabial angle (NLA), nasal tip angle and upper lip inclination angle in different maxillary inclination group. CONCLUSION: The nasal height, NBL, NLA and nasal tip angle had a maximum value in retro inclination group. PMID- 25821365 TI - Accurate registration of peri-implant soft tissues to create an optimal emergence profile. AB - One of the challenges in restoring anterior space with implant restoration is maintaining the natural looking of peri-implant area. This case report presents a clinical procedure to create the soft tissue emergence profile for anterior maxillary teeth. A 49-year-old male presented with missing right maxillary lateral incisor. A provisional restoration was inserted 1 week after implant placement. Area of the provisional restoration related to the gingival tissue (transmucosal area) was adjusted to create an optimum emergence profile. Two months later, an indirect method was used to accurately transfer the soft peri implant tissues to the master cast. This clinical technique minimizes surgical procedure and avoids the possibility of soft tissue collapsing that may occur during the impression procedure. PMID- 25821366 TI - Clinical evaluation of the marginal gingiva as a donor tissue to augment the width of keratinized gingiva: Series of 2 cases with 3-year follow-up. AB - The indications to increase the width of keratinized gingiva have not been proven beyond doubt; however it becomes indispensable in certain clinical situations. Inspite of frequently encountered complications, palate is considered most preferred area to harvest the free gingival graft (FGG). This procedure aimed at investigating the potential of buccal marginal gingiva as a donor to augment keratinized gingiva. To the best of our knowledge, no such cases have been documented in the literature. FGG harvested from maxillary buccal marginal gingiva was used to augment gingiva in the mandibular anterior region for two patients. This not only improved plaque control but also resulted in acceptable esthetic results over 3 years. Furthermore, gingiva at donor sites gained its normal form and was in harmony with the neighboring teeth. It may be concluded that buccal marginal gingiva may provide a predictable substitute to other donor tissues to augment gingiva. PMID- 25821367 TI - Splinted mandibular protraction appliance. AB - Advancement of mandible rather than tooth movement is an ideal treatment for the correction of Class II malocclusion resulting from mandibular retrusion. In growing patients, forward repositioning of mandible by mandibular repositioning appliances is considered as a treatment of choice. Correction of mandibular retrusion by the conventional mandibular protraction appliances (MPAs) is mainly due to dento-alveolar changes and by altering the design of original MPAs, these limitations were minimized. The modified design enhanced the mandibular growth and contributed for the better skeletal correction of Class II malocclusion as compared to the conventional MPAs. This article highlights the design and fabrication of a splinted MPA for the correction of Class II malocclusion due to mandibular retrusion and also describes a patient managed by this appliance. PMID- 25821368 TI - Retention of resin-based filled and unfilled pit and fissure sealants: A comparative clinical study. AB - BACKGROUND AND OBJECTIVES: The most caries-susceptible period of a permanent first molar tooth is the eruption phase, during which the enamel is not fully matured and it is usually difficult for the child to clean the erupting tooth surfaces. Sealing occlusal pits and fissures with resin-based pit and fissure sealants is a proven method to prevent occlusal caries. The difference in the viscosity of the sealants differs in the penetration into pit and fissures and abrasive wear resistance property due to the addition of filler particles. The present study was conducted to evaluate and compare the retention of the resin based filled (Helioseal F, Ivoclar Vivadent) and unfilled (Clinpro, 3M ESPE) pit and fissure sealants, which is important for their effectiveness. MATERIALS AND METHODS: Fifty-six children between the age group of 6 and 9 years, with all four newly erupted permanent first molars were selected. Sealants were applied randomly using split mouth design technique on permanent first molars. Evaluation of sealant retention was performed at regular intervals over 12 months, using Simonsen's criteria at 2(nd), 4(th), 6(th), 8(th), 10(th) and 12(th) month. The results were subjected to statistical analysis. RESULTS: At the end of our study period (12(th) month), 53.57% showed complete retention, 37.50% showed partial retention, and 8.83% showed complete missing of resin-based filled (Helioseal F) pit and fissure sealant. And, 64.29% showed complete retention, 32.14% showed partial retention, and 3.57% showed complete missing of resin-based unfilled (Clinpro) pit and fissure sealant. This difference in retention rates between filled and unfilled pit and fissure sealants was not statistically significant. CONCLUSION: The difference in retention rates between Helioseal F and Clinpro was not statistically significant, but Clinpro (unfilled) sealant showed slightly higher retention rates and clinically better performance than Helioseal F (filled). PMID- 25821370 TI - Viral evolution: Influenza evolves - From rhetoric to reality? PMID- 25821369 TI - Cavity disinfection in minimally invasive dentistry - comparative evaluation of Aloe vera and propolis: A randomized clinical trial. AB - CONTEXT: The survival of atraumatic restorative treatment (ART) restorations would probably increase if near total elimination of cariogenic microorganisms could be done in the process of cavity cleaning before going ahead with the restoration. Thus, use of naturally occurring disinfecting agents for achieving this goal could herald a new beginning in the field of contemporary minimum intervention dentistry. AIMS: To evaluate the efficacy of hand instruments in excavating dental caries and comparatively evaluate the roles of Aloe vera and propolis as potential cavity disinfecting agents after minimally invasive hand excavation of dental caries. SETTINGS AND DESIGNS: Experimental, in vivo intergroup split mouth, randomized clinical trial. SUBJECTS AND METHODS: The study included Group I (Control), Group II (A. vera) and Group III (propolis). Ten patients with three teeth each have occlusal/occlusoproximal lesions suitable for ART were selected. Dentinal samples were collected three times from each tooth viz., preexcavation, postexcavation and postdisinfection of the cavities. These dentinal samples were subjected to microbiological analyses for total viable count. STATISTICAL ANALYSIS USED: Repeated measures of analysis of variance (ANOVA) with Bonferroni post-hoc test and one-way ANOVA with Tukey post hoc test. RESULTS: In all the three groups, significant amount of bacteria were left behind after hand excavation. Group II and Group III, in which cavities were treated with A. vera and propolis extracts respectively, showed a significant reduction in the bacterial counts when compared to control the group. CONCLUSIONS: Hand excavation alone does not completely eliminate bacteria, which may predispose treated teeth to secondary caries. Both propolis and A. vera extracts can be used as potential natural disinfecting agents, thereby embracing the concept of phytotherapy in minimum intervention dentistry. PMID- 25821371 TI - Neodymium:Yttrium aluminum garnet laser in the management of oral leukoplakia: A case series. AB - OBJECTIVES: Oral leukoplakia is a nonscrappable whitish patch described as a potentially malignant disorder with high prevalence in India. Besides medicinal treatment, neodymium: Yttrium aluminum garnet (Nd: YAG) laser is also used for the management of oral leukoplakia. This study evaluated the role of Nd: YAG laser in the management of oral leukoplakia and also investigated postoperative complications along with long-term prognosis of the disease. SETTINGS AND DESIGNS: The study is a prospective cohort study conducted for 24 months (June 2011 to May 2013) in Lucknow. MATERIALS AND METHODS: The study comprised of 42 patients, both male and female of Indian origin and diagnosed with oral leukoplakic lesions. Patients with biopsy proven squamous cell carcinoma and medically compromised are excluded from the study. All patients has undergone ablation of lesion by pulsed Nd: YAG laser and were followed after 24 h, 72 h, 1 week and then successively for 1, 3, 6 months and then 1(st) and 2(nd) postoperative years. RESULTS: Pain and slough were evaluated by Wicoxon rank test (P = 0.0001 statistically significant) which decreased from 24 h to 1-week and became nil in subsequent follow-ups. Similarly, McNemar's test (P = 0.001 statistically significant) was used for evaluation of burning sensation, paresthesia, infection and recurrences. Recurrence was noted in 2 patients but following the second application, there were no recurrences over the period of further follow-up. None of the patient suffered from an infection, paresthesia or anesthesia. CONCLUSION: Hence, Nd: YAG laser was found to be effective in ablating leukoplakia. It is convenient, economical with minimum complications and morbidities. PMID- 25821372 TI - Use of buccal myomucosal flap for palatal lengthening in cleft palate patient: Experience of 20 cases. AB - BACKGROUND: The purpose of this review was to assess the effectiveness of the buccal myomucosal flap in secondary repairs of cleft palate in 20 patients. PATIENTS AND METHODS: Totally, 20 patients, who underwent secondary palatoplasty between 5 years and 8 years in which a buccal myomucosal flap was used, were reviewed retrospectively. All patients had undergone at least one previous attempted repair at other institutions. Indications for the secondary repair included velopharyngeal incompetence and/or oronasal fistula. Patients were evaluated preoperatively for oronasal fistula status, velopharyngeal competence, nasal resonance, speech quality, and nasal escape. RESULTS: The buccal myomucosal flap was used in all 20 patients, and there was marked increase in the quality of speech as well as nasal regurgitation decreased. In patients with levator dysfunction due to poor primary surgery and glottal speech the results were inconclusive. CONCLUSION: Palate re-repair combined with a buccal myomucosal flap, occasionally in conjunction with other techniques, is an effective method for correcting failed cleft palate repairs. Minimum donor site morbidity and complication makes the buccal flap a useful armamentarium of a cleft surgeon. PMID- 25821373 TI - Versatile retraction mechanics: Implant assisted en-masse retraction with a boot loop. AB - The purpose of this paper is to explain the versatility offered by the use of arch wires with boot loops in retraction mechanics while taking direct anchorage from mini-screws. MATERIALS AND METHODS: The materials include the mini screws placed at the appropriate location and retraction arches made of 0.019 X 0.025 SS with boot loops placed distal to the lateral incisors. Mini screw provides a stable anchorage for enmasse retraction of the anterior teeth with the help of a boot loop using sliding and/or loop mechanics. RESULTS: The arch wires with boot loops have a definite advantage over the soldered/crimpable hooks because of the versatility it offers during the process of retraction. CONCLUSION: An innovative approach combining the advantages of absolute anchorage using mini implants and a retraction arch with boot loop is presented here. PMID- 25821374 TI - A comparative evaluation of the effect of dentin desensitizers on the retention of complete cast metal crowns. AB - CONTEXT: Desensitizers are used to reduce dentin hypersensitivity. They affect the surface texture of prepared dentin and may alter the retention of fixed restorations. AIMS: The aim was to evaluate the effect of dentin desensitizers on the retention of complete cast metal crowns luted with glass ionomer cement. SUBJECTS AND METHODS: Fifty freshly extracted human premolars were subjected to standardized tooth preparation (20 degrees total convergence, 4 mm axial height) with a computer numerically controlled machine. Individual cast metal crowns were fabricated from a base metal alloy. Dentin desensitizers included none (control), a glutaraldehyde (GLU) based primer (Gluma desensitizer), casein phosphopeptide (CPP)-amorphous calcium phosphate (ACP) (GC Mousse), erbium, chromium: YSGG laser (Waterlase MD Turbo, Biolase) and Pro-Argin (Colgate Sensitive Pro-Relief desensitizing polishing paste). After desensitization, crowns were luted with glass ionomer cement and kept for 48 h at 37 degrees C in 100% relative humidity. The samples were tested using a universal testing machine by applying a load at a crosshead speed of 0.5 mm/min. STATISTICAL ANALYSIS USED: Statistical analysis included One-way ANOVA, followed by the Scheffe post-hoc test with P < 0.05. RESULTS: All dentin desensitizers showed significantly different values: Pro Argin (4.10 Megapascals [Mpa]) < CPP-ACP (4.01 mpa) < GLU based primer (3.87 Mpa) < Virgin dentin (3.65 Mpa) < LASER (3.37 Mpa). CONCLUSIONS: On comparing the effect of prepared virgin dentin, GLU based primer, CPP-ACP, LASER and Pro-Argin on the retention of complete cast metal crowns luted with glass ionomer cement on prepared teeth, it can be concluded that Pro-Argin and CPP-ACP showed the best retention in this in vitro study. PMID- 25821375 TI - Estimation of changes in C-reactive protein level and pregnancy outcome after nonsurgical supportive periodontal therapy in women affected with periodontitis in a rural set up of India. AB - AIMS AND OBJECTIVES: Estimation of changes in C-reactive protein (CRP) level and pregnancy outcome after nonsurgical supportive periodontal therapy in pregnant women affected with Periodontitis. MATERIALS AND METHODS: A total of 100 pregnant females with periodontitis were assigned to treatment and control groups. All the details about previous and current pregnancies were obtained. Full-mouth periodontal examination was done at baseline, which included oral hygiene index simplified plaque index, gingival index, and clinical attachment loss. CRP level was also measured from collected blood sample initially at baseline and later after the delivery in both the group. Subjects in the treatment group received nonsurgical periodontal treatment during the second trimester of gestational period, and those in the control group did not receive any periodontal therapy during this period. Periodontal therapy included mechanical plaque control instructions and scaling and root planning. Outcome measures assessed were changes in CRP levels, gestational age, and birth weight of the infants. When delivery occurred at <37 weeks of gestation, it was considered as preterm birth (PTB), and low birth weight (LBW) was recorded when the infant weighed <2500 g. RESULTS: In the treatment group, 32% of PTB and 68% of Normal term birth (NTB) delivery whereas in the control group 72% PTB and 28% of NTB were recorded. Infants measured with LBW were 36% in the treatment group and 52% in the control group. Mean birth weight was 2644.44 +/- 450.53 g in the treatment group and 2447.82 +/- 368.02 g in the control group (P < 0.05). Mean gestational age in the treatment group was 35.57 +/- 2.40 weeks and 34.17 +/- 2.92 weeks in the control group (P < 0.05). The treatment group showed statistically significant reduction in mean values of CRP level after delivery in comparison to baseline values (P < 0.05), whereas control group showed no significant reduction in values (P > 0.05). CONCLUSION: Nonsurgical supportive periodontal therapy may lower the risk of preterm delivery in females affected with periodontitis by reducing CRP level. PMID- 25821376 TI - Comparison between stainless steel staples and silk sutures for primary closure of skin in patients undergoing neck dissection: A comparative clinical study. AB - INTRODUCTION: Comparison between stainless steel staples and silk sutures for primary closure of skin in patients undergoing neck dissection, in context of rapid application, approximation of the skin edges, economy and aesthetics of the resultant scar. AIM: (1) To compare surgical stainless steel staples and silk sutures for primary wound closure, with respect to presence/absence of wound infection and dehiscence (2) To compare the resultant scar following the two different methods of the closure at 3(rd) month postoperatively with the help of visual analog scale and analyze the result statistically DESIGN: This study was designed to compare skin closure using staples and silk sutures in patients undergoing neck dissection, using both methods in one-half of the same wound; thus each wound affording its own control. MATERIALS AND METHODS: The study was conducted on patients requiring collar line incision (high submandibular incision) with or without a cephalad extension of midline lower lip split incision for surgical access, who presented to the Department of Oral and Maxillo Facial Surgery. (1) SAMPLE SIZE: 10 (2) STUDY DESIGN: Prospective Comparative study (3) Study duration: One and half years (4) Surgical stainless steel staples: Proximate Plus MD 35 W, Ethicon Endo Surgery (5) Sutures: 3-0 Ethiprime NW 5003, Non-Absorbable Surgical Suture, Mersilk-90 cm, Ethicon, (16 mm 3/8 circle cutting needle). CONCLUSION: It was concluded that there is no significant difference between the scars observed in the regions of incision which underwent primary closure by two different methods, that is surgical stainless steel staples and 3-0 Mersilk Sutures. PMID- 25821377 TI - 'Sutureless' transconjunctival approach for infraorbital rim fractures. AB - AIM: To analyze the ease and surgical outcome of using sutureless transconjunctival approach for repair of infra-orbital fractures. DESIGN: Prospective clinical case series. MATERIALS AND METHODS: Totally 5 patients with infra-orbital rim or orbital floor fractures were selected and the fractures were accessed through a pre-septal transconjunctival incision. After reduction and fixation, the conjunctiva was just re-approximated and re-draped into position. Incidence of post-operative complications such as diplopia, lid retraction, eyelid dystopia, foreign body granuloma and poor conjunctival healing was assessed at intervals of 1 week, 15 days and a month post-operatively. RESULTS: No complications were observed in any of the 5 patients. Healing was satisfactory in all patients. CONCLUSION: The sutureless technique appears to be a time saving and technically simpler viable alternative to multilayered suturing in orbital trauma with minimal post-operative complications. PMID- 25821378 TI - Prevalence of glutathione S-transferase M1 null polymorphism in tobacco users, oral leukoplakia and oral squamous cell carcinoma patients in South Indian population: A polymerase chain reaction study. AB - CONTEXT: Tobacco abuse is a well-known risk factor for potentially malignant disorders as well as oral squamous cell carcinoma (SCC). Factors that influence tobacco-exposed individuals developing a malignancy may include a combination of total tobacco exposure and genetic susceptibility. AIM: This study was undertaken to determine the prevalence of the glutathione S-transferase M1 (GSTM1) null polymorphism in oral leukoplakia and oral SCC patients in South Indian population. SETTINGS AND DESIGN: This case-control study was conducted in hospital setting on South Indian population. MATERIALS AND METHODS: Totally, 280 subjects with a history of tobacco use, oral leukoplakia, oral SCC were included in this study. Three milliliter of blood was collected and transported under cold cycle and taken for evaluation of GSTM1 null polymorphism using Multiplex Polymerase Chain Reaction. RESULTS AND DISCUSSION: On comparing the prevalence of GSTM1 null polymorphism among the group with subjects with habits and no oral lesions, oral leukoplakia and oral SCC, it was observed that there was a statistically significant association between GSTM1 null polymorphism and the different groups (P < 0.01). CONCLUSION: The lack of GSTM1 activity would make the oral tissues more susceptible to action of tobacco carcinogens and to the development of a high-grade level of dysplasia in oral leukoplakia and thereby increases the susceptibility of lesion to undergo malignant changes. PMID- 25821379 TI - Estimation of salivary flow rate, pH, buffer capacity, calcium, total protein content and total antioxidant capacity in relation to dental caries severity, age and gender. AB - PURPOSE: The aim of the study was to evaluate salivary flow rate, pH, buffering capacity, calcium, total protein content and total antioxidant capacity in relation to dental caries, age and gender. MATERIALS AND METHODS: The study population consisted of 120 healthy children aged 7-15 years that was further divided into two groups: 7-10 years and 11-15 years. In this 60 children with DMFS/dfs = 0 and 60 children with DMFS/dfs >=5 were included. The subjects were divided into two groups; Group A: Children with DMFS/dfs = 0 (caries-free) Group B: Children with DMFS/dfs >=5 (caries active). Unstimulated saliva samples were collected from all groups. Flow rates were determined, and samples analyzed for pH, buffer capacity, calcium, total protein and total antioxidant status. Salivary antioxidant activity is measured with spectrophotometer by an adaptation of 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulphonate) assays. RESULTS: The mean difference of the two groups; caries-free and caries active were proved to be statistically significant (P < 0.05) for salivary calcium, total protein and total antioxidant level for both the sexes in the age group 7-10 years and for the age 11-15 years the mean difference of the two groups were proved to be statistically significant (P < 0.05) for salivary calcium level for both the sexes. Salivary total protein and total antioxidant level were proved to be statistically significant for male children only. CONCLUSIONS: In general, total protein and total antioxidants in saliva were increased with caries activity. Calcium content of saliva was found to be more in caries-free group and increased with age. PMID- 25821380 TI - Loss on drying, calcium concentration and pH of fluoride dentifrices. AB - INTRODUCTION: Fluoride dentifrices containing calcium carbonate have advantages such as control of dental plaque and progression of dental caries, also contributing to oral hygiene, represent most dentifrices marketed in Brazil. AIM: To evaluate the physicochemical properties of seven fluoride dentifrices containing calcium carbonate in relation to hydrogen potential (pH), loss on drying and calcium concentration. MATERIALS AND METHODS: Data collection was performed using the potentiometric method for pH ranges, gravimetric analysis for loss on drying and atomic absorption spectrometry for the concentration of calcium ions. All tests were performed in triplicate and the analysis was performed entirely at random according to one-way analysis of variance at 5% significance level. RESULTS: The pH values were alkaline and ranged from 8.67 (Oral-B 123((r))) to 10.03 (Colgate Maxima Protecao Anticaries((r))). The results of loss on drying ranged from 33.81% (Oral-B 123((r))) to 61.13% (Close Up((r))), with significant differences between brands tested. In relation to the calcium content, the highest and lowest concentrations were found in dentifrices Even((r)) (155.55 g/kg) and Colgate Ultra Branco((r)) (129 g/kg), respectively, with significant difference (P < 0.05). CONCLUSION: Fluoride dentifrices analyzed showed alkaline pH and high levels of loss on drying and calcium concentration. However, these physicochemical characteristics differed according to the different brands tested. PMID- 25821381 TI - Analysis of time-dependent changes in Bitemarks on Styrofoam sheets. AB - CONTEXT: The scope of Bitemarks in forensic dentistry is widening as they help the forensic expert in identifying the perpetuator in medicolegal cases. The greatest challenge in Bitemarks analysis is the time-dependent changes produced in Bitemark patterns on various substrates at the scene of the crime. AIMS: To analyze the time-dependent changes in Bitemarks on Styrofoam sheets. SETTINGS AND DESIGN: Single centered prospective study. MATERIALS AND METHODS: Twenty-five subjects were randomly chosen, and dental casts prepared. Then test bites were registered on Styrofoam sheets, overlays prepared from these test bites on subsequent days (day 1, 2, 3, 4) and checked for matching accuracy. STATISTICAL ANALYSIS USED: The data were analyzed using Kruskal-Wallis ANOVA to compare the overlays from dental stone cast with test bites on Styrofoam sheets on subsequent days. RESULTS: The P value was found to be 1 which is statistically not significant implying that there were no significant time-dependent changes in the pattern of Bitemarks. CONCLUSIONS: There were no time-dependent changes in the pattern of Bitemarks on Styrofoam sheets hence they serve as better materials than Bitemarks on human skin or food substrates obtained from the scene of the crime. PMID- 25821382 TI - Appraisal of the remineralizing potential of child formula dentifrices on primary teeth: An in vitro pH cycling model. AB - AIM: To evaluate the remineralizing potential of child formula dentifrices on primary teeth using an in vitro 7 days pH cycling model. MATERIALS AND METHODS: Twenty-one primary teeth were placed in demineralizing solution for 96 h to produce artificial carious lesions; then cut longitudinally into 100-150 MUm thick sections and randomly assigned to three groups. Sections in Group A were treated with dentifrice containing 458 ppm monofluorophosphate (MFP) and sections in Group B with 500 ppm sodium fluoride (NaF). Group C sections were treated with a nonfluoridated dentifrice. RESULTS: Group A (458 ppm MFP) and Group B (500 ppm NaF) showed significant decrease in lesion depth, whereas Group C (non F) showed a significant increase in depth (P <= 0.05, paired t-test). CONCLUSION: Though dentifrices containing 458 ppm MFP and 500 ppm NaF demonstrated remineralization of carious lesions, it was not complete. Therefore, it is also important to emphasize on other preventive methods in the prevention and/or reversal of carious lesions. PMID- 25821383 TI - Sealing ability of three hydrophilic single-cone obturation systems: An in vitro glucose leakage study. AB - AIM: The aim of this study is to compare the corono-apical sealing ability of three single-cone obturation systems using a glucose leakage model. MATERIALS AND METHODS: A total of 90 freshly extracted human maxillary single-rooted teeth was selected, and their crowns were cut. The root canal of each sample was instrumented using a rotary crown down technique and then divided into four experimental (n = 20 each) and two control groups (n = 5 each). Samples in the experimental groups were filled as follows: Group 1, cold lateral condensation using gutta-percha/AH Plus; group 2, single-cone C-points/smart-paste bio-sealer; group 3, single-cone bio-ceramic (BC) impregnated gutta-percha/endo-sequence BC sealer; group 4, single-cone Resilon/RealSeal SE after 7 days, the sealing ability of root canal fillings was tested at different time intervals using glucose leakage model. Glucose leakage values were measured using a spectrophotometer and statistically analyzed. RESULTS: The four experimental groups presented significantly different glucose leakage values at all test periods (P < 0.05). At the end of the observation period, the cumulative glucose leakage values of groups 2 and 3 were significantly lower than those of groups 1 and 4 (P < 0.05). CONCLUSION: C-points/smart-paste Bio and BC impregnated gutta percha/endo-sequence BC sealer combinations provided the superior sealing ability over the lateral condensation technique. PMID- 25821384 TI - Denture acceptance among newly rehabilitated elderly population in old age homes in South India. AB - INTRODUCTION: Elders in old age homes are mainly those who have been abandoned by their family and have one or more physical or mental disabilities. It is a major challenge for the dental professional to plan oral health strategy for this group of patients. AIM OF THE STUDY: Aim of the present study is to observe and determine the acceptance of new dental prosthesis among the elderly residing as inmates of 3 old age homes in Mangalore City. MATERIALS AND METHODS: This cross sectional study was conducted using a survey proforma. Information regarding their experience with the new denture, 1-month, 3 months and 6 months after denture insertion was gathered. Statistical analysis of the data was done using the Chi-square test with the P < 0.05 considered significant. RESULTS: One hundred and eighty-three residents out of a total of 400 residents in 3 old age homes were denture wearers. Among them, 101 (55.2%) were females, and 82 (44.8%) were males. Dental prosthesis whether worn regularly, discomfort, retention, cleansing of denture during a period of 1-month, 3 months and 6 months was found to be significant satisfaction with the prosthesis, denture adhesives used, food accumulation during a period of 1-month, 3 months and 6 months was found to be nonsignificant. CONCLUSION: The emotional makeup of the patient must be taken into consideration during the entire procedure. We must understand that the success of the prosthesis depends mainly on the patient's confidence in the dentist rather than the quality of the prosthesis. PMID- 25821385 TI - Orofacial granulomatosis affecting lip and gingiva in a 15-year-old patient: A rare case report. AB - Orofacial granulomatosis (OFG) is a rare disorder affecting the orofacial region, and clinically characterized by diffuse, nontender, soft to firm, painless swelling restricted to one or both lips and intraoral sites such as tongue, gingiva and buccal mucosa. Histologically, OFG is characterized by noncaseating granulomatous inflammation. The early diagnosis of OFG is essential for the better prognosis of the lesion. Delay in diagnosis of OFG results into formation of indurated and permanent swelling of the lip that not only compromises esthetic appearance but also causes impairment in function such as speaking and eating. Early diagnosis of OFG is challenging to the health care professionals due to clinical and histological resemblance to other chronic granulomatous disorders. Thus, dentists may act as a first person to diagnose the lesion and play an important role in the multidisciplinary treatment of granulomatous disorders. Here, we present a case of OFG affecting lips and gingiva in a 15-year-old patient without any identifiable systemic or local causes. PMID- 25821386 TI - Gingival depigmentation: A split mouth comparative study between scalpel and cryosurgery. AB - Gingival hyperpigmentation is a major esthetic concern for many people. Although it is not a medical problem, many people complain of dark gums as unesthetic. Gingival depigmentation is a periodontal plastic surgical procedure, whereby the hyperpigmentation is removed or reduced by various techniques. For depigmentation of gingival, different treatment modalities have been reported, such as scalpel, cryosurgery, electrosurgery, lasers, etc., this article compares the management of three cases with scalpel and cryosurgery and also highlights the relevance of cryosurgery. PMID- 25821387 TI - A Bayesian Approach for Graph-constrained Estimation for High-dimensional Regression. AB - Many different biological processes are represented by network graphs such as regulatory networks, metabolic pathways, and protein-protein interaction networks. Since genes that are linked on the networks usually have biologically similar functions, the linked genes form molecular modules to affect the clinical phenotypes/outcomes. Similarly, in large-scale genetic association studies, many SNPs are in high linkage disequilibrium (LD), which can also be summarized as a LD graph. In order to incorporate the graph information into regression analysis with high dimensional genomic data as predictors, we introduce a Bayesian approach for graph-constrained estimation (Bayesian GRACE) and regularization, which controls the amount of regularization for sparsity and smoothness of the regression coefficients. The Bayesian estimation with their posterior distributions can provide credible intervals for the estimates of the regression coefficients along with standard errors. The deviance information criterion (DIC) is applied for model assessment and tuning parameter selection. The performance of the proposed Bayesian approach is evaluated through simulation studies and is compared with Bayesian Lasso and Bayesian Elastic-net procedures. We demonstrate our method in an analysis of data from a case-control genome-wide association study of neuroblastoma using a weighted LD graph. PMID- 25821388 TI - A New CT Prostate Segmentation for CT-Based HDR Brachytherapy. AB - High-dose-rate (HDR) brachytherapy has become a popular treatment modality for localized prostate cancer. Prostate HDR treatment involves placing 10 to 20 catheters (needles) into the prostate gland, and then delivering radiation dose to the cancerous regions through these catheters. These catheters are often inserted with transrectal ultrasound (TRUS) guidance and the HDR treatment plan is based on the CT images. The main challenge for CT-based HDR planning is to accurately segment prostate volume in CT images due to the poor soft tissue contrast and additional artifacts introduced by the catheters. To overcome these limitations, we propose a novel approach to segment the prostate in CT images through TRUS-CT deformable registration based on the catheter locations. In this approach, the HDR catheters are reconstructed from the intra-operative TRUS and planning CT images, and then used as landmarks for the TRUS-CT image registration. The prostate contour generated from the TRUS images captured during the ultrasound-guided HDR procedure was used to segment the prostate on the CT images through deformable registration. We conducted two studies. A prostate phantom study demonstrated a submillimeter accuracy of our method. A pilot study of 5 prostate-cancer patients was conducted to further test its clinical feasibility. All patients had 3 gold markers implanted in the prostate that were used to evaluate the registration accuracy, as well as previous diagnostic MR images that were used as the gold standard to assess the prostate segmentation. For the 5 patients, the mean gold-marker displacement was 1.2 mm; the prostate volume difference between our approach and the MRI was 7.2%, and the Dice volume overlap was over 91%. Our proposed method could improve prostate delineation, enable accurate dose planning and delivery, and potentially enhance prostate HDR treatment outcome. PMID- 25821389 TI - Toward real-time endoscopically-guided robotic navigation based on a 3D virtual surgical field model. AB - The challenge is to accurately guide the surgical tool within the three dimensional (3D) surgical field for robotically-assisted operations such as tumor margin removal from a debulked brain tumor cavity. The proposed technique is 3D image-guided surgical navigation based on matching intraoperative video frames to a 3D virtual model of the surgical field. A small laser-scanning endoscopic camera was attached to a mock minimally-invasive surgical tool that was manipulated toward a region of interest (residual tumor) within a phantom of a debulked brain tumor. Video frames from the endoscope provided features that were matched to the 3D virtual model, which were reconstructed earlier by raster scanning over the surgical field. Camera pose (position and orientation) is recovered by implementing a constrained bundle adjustment algorithm. Navigational error during the approach to fluorescence target (residual tumor) is determined by comparing the calculated camera pose to the measured camera pose using a micro positioning stage. From these preliminary results, computation efficiency of the algorithm in MATLAB code is near real-time (2.5 sec for each estimation of pose), which can be improved by implementation in C++. Error analysis produced 3-mm distance error and 2.5 degree of orientation error on average. The sources of these errors come from 1) inaccuracy of the 3D virtual model, generated on a calibrated RAVEN robotic platform with stereo tracking; 2) inaccuracy of endoscope intrinsic parameters, such as focal length; and 3) any endoscopic image distortion from scanning irregularities. This work demonstrates feasibility of micro-camera 3D guidance of a robotic surgical tool. PMID- 25821390 TI - Detection of Medium-Sized Polycyclic Aromatic Hydrocarbons via Fluorescence Energy Transfer. AB - Reported herein is the use of proximity-induced non-covalent energy transfer for the detection of medium-sized polycyclic aromatic hydrocarbons (PAHs). This energy transfer occurs within the cavity of gamma-cyclodextrin in various aqueous environments, including human plasma and coconut water. Highly efficient energy transfer was observed, and the efficiency of the energy transfer is independent of the concentration of gamma-cyclodextrin used, demonstrating the importance of hydrophobic binding in facilitating such energy transfer. Low limits of detection were also observed for many of the PAHs investigated, which is promising for the development of fluorescence-based detection schemes. PMID- 25821391 TI - "Is he a licentious lewd Sort of a Person?" Constructing the child rapist in early modern England. PMID- 25821392 TI - Analysis of 1-Minute Potentially Available Fluoride from Dentifrice. AB - Previous reports found that some fluoride-containing dentifrices do not release effective concentrations of fluoride during brushing. Failure to release fluoride can be due to dentifrice matrix components that interfere with the solubilization of the fluoride salts during brushing. A new generation of dentifrices has the capability to precipitate beneficial fluoride salts during tooth brushing. Therefore, a method that assesses the potentially available fluoride during the 1 minute brushing is needed. A new filter-paper absorption method to assess the 1 min bioavailable fluoride concentration was developed to meet this need. This method utilizes coiled filter paper that rapidly absorbs the aqueous phase of the dentifrice slurry followed by centrifugation to recover that fluid for fluoride measurement via fluoride ion-selective electrode. The analytical method was used to successfully determine the total fluoride and 1-min bioavailable fluoride in eight dentifrice products containing sodium fluoride (NaF), disodium monofluorophosphate (Na2FPO3, MFP), stannous fluoride (SnF2), or NaF with amorphous calcium phosphate (NaF + ACP). The results showed that some of the dentifrices tested had significantly lower potentially available fluoride than the total fluoride. For a MFP-containing sample, aged seven years past its expiry date, there was significant reduction in the bioavailable fluoride compared to MFP products that were not aged. Other than the aged MFP and the SnF2-containing samples the bioavailable fluoride for all products tested had at least 80 % of the label fluoride concentration. The filter paper absorption method yielded reproducible results for the products tested with MFP samples showing the largest variations. PMID- 25821393 TI - Causality and Causal Inference in Social Work: Quantitative and Qualitative Perspectives. AB - Achieving the goals of social work requires matching a specific solution to a specific problem. Understanding why the problem exists and why the solution should work requires a consideration of cause and effect. However, it is unclear whether it is desirable for social workers to identify cause and effect, whether it is possible for social workers to identify cause and effect, and, if so, what is the best means for doing so. These questions are central to determining the possibility of developing a science of social work and how we go about doing it. This article has four aims: (1) provide an overview of the nature of causality; (2) examine how causality is treated in social work research and practice; (3) highlight the role of quantitative and qualitative methods in the search for causality; and (4) demonstrate how both methods can be employed to support a "science" of social work. PMID- 25821394 TI - A Riemannian framework for matching point clouds represented by the Schrodinger distance transform. AB - In this paper, we cast the problem of point cloud matching as a shape matching problem by transforming each of the given point clouds into a shape representation called the Schrodinger distance transform (SDT) representation. This is achieved by solving a static Schrodinger equation instead of the corresponding static Hamilton-Jacobi equation in this setting. The SDT representation is an analytic expression and following the theoretical physics literature, can be normalized to have unit L2 norm-making it a square-root density, which is identified with a point on a unit Hilbert sphere, whose intrinsic geometry is fully known. The Fisher-Rao metric, a natural metric for the space of densities leads to analytic expressions for the geodesic distance between points on this sphere. In this paper, we use the well known Riemannian framework never before used for point cloud matching, and present a novel matching algorithm. We pose point set matching under rigid and non-rigid transformations in this framework and solve for the transformations using standard nonlinear optimization techniques. Finally, to evaluate the performance of our algorithm-dubbed SDTM-we present several synthetic and real data examples along with extensive comparisons to state-of-the-art techniques. The experiments show that our algorithm outperforms state-of-the-art point set registration algorithms on many quantitative metrics. PMID- 25821395 TI - The ambiguous victim: Miklos Nyiszli's narrative of medical experimentation in Auschwitz-Birkenau. PMID- 25821396 TI - Not All Ideals are Equal: Intrinsic and Extrinsic Ideals in Relationships. AB - The ideal standards model suggests that greater consistency between ideal standards and actual perceptions of one's relationship predicts positive relationship evaluations; however, no research has evaluated whether this differs across types of ideals. A self-determination theory perspective was derived to test whether satisfaction of intrinsic ideals buffers the importance of extrinsic ideals. Participants (N=195) in committed relationships directly and indirectly reported the extent to which their partner met their ideal on two dimensions: intrinsic (e.g., warm, intimate) and extrinsic (e.g., attractive, successful). Relationship need fulfillment and relationship quality were also assessed. Hypotheses were largely supported, such that satisfaction of intrinsic ideals more strongly predicted relationship functioning, and satisfaction of intrinsic ideals buffered the relevance of extrinsic ideals for outcomes. PMID- 25821397 TI - Improvement in Overall Survival from Extremity Soft Tissue Sarcoma over Twenty Years. AB - Several patient demographic factors, including marital status, have been demonstrated to have prognostic significance for survival in extremity soft tissue sarcoma (ESTS). A study population of 12,546 adult patients diagnosed with ESTS from 1991 to 2010 was identified from the SEER database, a large population based registry, in order to determine whether overall survival had changed over this recent 20-year period. The study population was divided into three groups by year of diagnosis: 1991-1996, 1997-2003, and 2004-2010. We used the Kaplan-Meier method and Cox proportional hazards regression to assess survival differences between different demographic groups and prognostic clinical characteristics. Over the course of time, the 5-year overall survival rates have increased from 28% in the earliest time period to 62% in the latest (P < 0.0001). On multivariate analysis, the mortality rate progressively declined from the 1991 1996 group (HR: 3.02, CI: 2.78-3.29) to the 1997-2003 group (HR: 2.21, CI: 2.06 2.37), with the 2004-2010 group having the best overall survival, despite increases in the proportion of patients with tumors greater than 5 cm in size (P < 0.0001), and those presenting with metastasis (P < 0.0001). PMID- 25821398 TI - 'Hella Ghetto!': (Dis)locating Race and Class Consciousness in Youth Discourses of Ghetto Spaces, Subjects and Schools. AB - Based on analysis of interviews conducted during 2008-2009 in Oakland, California, this paper examines how narratives of inner-city youth reinforce and destabilize mainstream conceptions of 'ghetto.' The paper demonstrates that inner city youth discourses regarding 'ghetto' spaces, subjects and schools often exemplify a consciousness informed by both counter-hegemonic insights and internalized psychological trauma. In other words, the interviewed youth reconstitute the term 'ghetto' to signify structural and cultural processes of dislocation occurring in their neighborhood through narratives characterized by contradiction. This finding is significant because it questions how to analyze non-white narratives and offers 'dislocated consciousness' as an interpretive lens grounded in the contradictions of subaltern consciousness theorized by W.E.B. Dubois, Frantz Fanon and Antonio Gramsci. By developing the concept of 'dislocation' to illuminate how such youth negotiate, resist and internalize the material and ideological structures that condition their existence, this study contributes to the existing literature on race and class consciousness of urban youth. The paper concludes by exploring how strategies urban youth utilize to come to terms with their lives can provide new understandings of urban communities and schooling. PMID- 25821399 TI - Does logging and forest conversion to oil palm agriculture alter functional diversity in a biodiversity hotspot? AB - Forests in Southeast Asia are rapidly being logged and converted to oil palm. These changes in land-use are known to affect species diversity but consequences for the functional diversity of species assemblages are poorly understood. Environmental filtering of species with similar traits could lead to disproportionate reductions in trait diversity in degraded habitats. Here, we focus on dung beetles, which play a key role in ecosystem processes such as nutrient recycling and seed dispersal. We use morphological and behavioural traits to calculate a variety of functional diversity measures across a gradient of disturbance from primary forest through intensively logged forest to oil palm. Logging caused significant shifts in community composition but had very little effect on functional diversity, even after a repeated timber harvest. These data provide evidence for functional redundancy of dung beetles within primary forest and emphasize the high value of logged forests as refugia for biodiversity. In contrast, conversion of forest to oil palm greatly reduced taxonomic and functional diversity, with a marked decrease in the abundance of nocturnal foragers, a higher proportion of species with small body sizes and the complete loss of telecoprid species (dung-rollers), all indicating a decrease in the functional capacity of dung beetles within plantations. These changes also highlight the vulnerability of community functioning within logged forests in the event of further environmental degradation. PMID- 25821400 TI - Adapting to climate change in South East Queensland, Australia. PMID- 25821401 TI - Modelling land cover change in the Brazilian Amazon: temporal changes in drivers and calibration issues. AB - Land cover change (LCC) models are used in many studies of human impacts on the environment, but knowing how well these models predict observed changes in the landscape is a challenge. We used nearly three decades of LCC maps to run several LCC simulations to: (1) determine which parameters associated with drivers of LCC (e.g. roads) get selected for which transition (forest to deforested, regeneration to deforested or deforested to regeneration); (2) investigate how the parameter values vary through time with respect to the different activities (e.g. farming); and (3) quantify the influence of choosing a particular time period for model calibration and validation on the performance of LCC models. We found that deforestation of primary forests tends to occur along roads (included in 95 % of models) and outside protected areas (included in all models), reflecting farming establishment. Regeneration tends to occur far from roads (included in 78 % of the models) and inside protected areas (included in 38 % of the models), reflecting the processes of land abandonment. Our temporal analysis of model parameters revealed a degree of variation through time (e.g. effectiveness of protected areas rose by 73 %, p < 0.001), but for the majority of parameters there was no significant trend. The degree to which model predictions agreed with observed change was heavily dependent on the year used for calibration (p < 0.001). The next generation of LCC models may need to embed trends in parameter values to allow the processes determining LCC to change through time and exert their influence on model predictions. PMID- 25821402 TI - Synthesis in land change science: methodological patterns, challenges, and guidelines. AB - Global and regional economic and environmental changes are increasingly influencing local land-use, livelihoods, and ecosystems. At the same time, cumulative local land changes are driving global and regional changes in biodiversity and the environment. To understand the causes and consequences of these changes, land change science (LCS) draws on a wide array synthetic and meta study techniques to generate global and regional knowledge from local case studies of land change. Here, we review the characteristics and applications of synthesis methods in LCS and assess the current state of synthetic research based on a meta-analysis of synthesis studies from 1995 to 2012. Publication of synthesis research is accelerating, with a clear trend toward increasingly sophisticated and quantitative methods, including meta-analysis. Detailed trends in synthesis objectives, methods, and land change phenomena and world regions most commonly studied are presented. Significant challenges to successful synthesis research in LCS are also identified, including issues of interpretability and comparability across case-studies and the limits of and biases in the geographic coverage of case studies. Nevertheless, synthesis methods based on local case studies will remain essential for generating systematic global and regional understanding of local land change for the foreseeable future, and multiple opportunities exist to accelerate and enhance the reliability of synthetic LCS research in the future. Demand for global and regional knowledge generation will continue to grow to support adaptation and mitigation policies consistent with both the local realities and regional and global environmental and economic contexts of land change. PMID- 25821403 TI - Food and feed supply and waste disposal in the industrialising city of Vienna (1830-1913): a special focus on urban nitrogen flows. AB - Taking an urban metabolism perspective, this article investigates food and feed consumption as well as flows of nitrogen in the city of Vienna during the industrial transformation. It addresses the question of the amount of agricultural products consumed in the city and their nitrogen content, their origin and their fate after consumption. Changes in dietary nitrogen flows in nineteenth century Vienna are embedded in the context of a socio-ecological transition from an agrarian to an industrial socio-metabolic regime. Similarities and differences in the size and dynamics of urban nitrogen flows in Vienna and Paris are discussed. Critical reading of historical sources and historical material flow accounting are the methodological backbone of this study. Between 1830 and 1913, inflows of dietary nitrogen into the city increased fivefold. Throughout the time period under observation, the urban waterscape was the most important sink for human and animal excreta. The amount of nitrogen disposed of in the urban waterscape via urban excreta increased sevenfold. The average daily consumption of nitrogen per capita was very similar to that in Paris, but the composition of foodstuff differed. In Vienna, the share of meat in food consumption was considerably higher. Both cities had to face the challenge of increasing output flows. However, urban authorities in Vienna and Paris came to different solutions of how to deal with this challenge. Besides institutional settings, the specific geomorphology of the cities as well as biogeographic factors such as the absorption capacity of the Danube in Vienna and the Seine in Paris mattered. PMID- 25821404 TI - Research advancements in palm oil nutrition. AB - Palm oil is the major oil produced, with annual world production in excess of 50 million tonnes. About 85% of global palm oil produced is used in food applications. Over the past three decades, research on nutritional benefits of palm oil have demonstrated the nutritional adequacy of palm oil and its products, and have resulted in transitions in the understanding these attributes. Numerous studies have demonstrated that palm oil was similar to unsaturated oils with regards to effects on blood lipids. Palm oil provides a healthy alternative to trans-fatty acid containing hydrogenated fats that have been demonstrated to have serious deleterious effects on health. The similar effects of palm oil on blood lipids, comparable to other vegetable oils could very well be due to the structure of the major triglycerides in palm oil, which has an unsaturated fatty acid in the stereospecific numbers (sn)-2 position of the glycerol backbone. In addition, palm oil is well endowed with a bouquet of phytonutrients beneficial to health, such as tocotrienols, carotenoids, and phytosterols. This review will provide an overview of studies that have established palm oil as a balanced and nutritious oil. PMID- 25821405 TI - Neonatal effect of remifentanil in general anaesthesia for caesarean section: a randomized trial. AB - BACKGROUND: Remifentanil has been suggested for its short duration of action to replace standard opioids for induction of general anaesthesia in caesarean section. While the stabilizing effect of remifentanil on maternal circulation has been confirmed, its effect on postnatal adaptation remains unclear, as currently published studies are not powered sufficiently to detect any clinical effect of remifentanil on the newborn. METHODS: Using a double-blinded randomized design, a total of 151 parturients undergoing caesarean delivery under general anaesthesia were randomized into two groups--76 patients received a bolus of remifentanil prior to induction, while 75 patients were assigned to the control group. Remifentanil 1 MUg/kg was administered 30 seconds before the standard induction of general anaesthesia. The primary outcome measure was an assessment of neonatal adaptation using the Apgar score, while secondary outcomes included the need for respiratory support after delivery and differences in umbilical blood gas analysis (Astrup). RESULTS: The incidence of lower Apgar scores between 0 and 7 was significantly higher in the remifentanil group at one minute (25% vs. 9.3% of newborns, p = 0.017); whilst at five minutes and later no Apgar score differences were observed. There was no difference in the need for moderate (nasal CPAP) or intensive (intubation) respiratory support, but significantly more neonates in the remifentanil group required tactile stimulation for breathing support (21% vs. 7% of newborns, p = 0.017). There was no difference in the parameters from umbilical cord blood gas analysis between the groups. CONCLUSION: At a dose of 1 MUg/kg, remifentanil prior to induction of general anaesthesia increases the risk of neonatal respiratory depression during first minutes after caesarean delivery but duration of clinical symptoms is short. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01550640. PMID- 25821406 TI - Case report of Tako-Tsubo cardiomyopathy associated with repetitive anaesthesia in a female patient with Tako-Tsubo cardiomyopathy. AB - BACKGROUND: Tako-Tsubo cardiomyopathy (TTC) is a rare disorder with high relevance for anaesthesia. It is an acute cardiac syndrome characterized by an acute onset of reversible left ventricular dysfunction associated with emotional and physical stress. This is the only case published of a patient having five severe Tako-Tsubo incidents in five consecutive general anaesthesia procedures within one year. CASE PRESENTATION: A 61 years old female patient (height 1.65 m; weight 70 kg) presented with a haemorrhagic pituitary adenoma with compression of the optic chiasm and was scheduled for transnasal endoscopic tumour resection. We report a case series with five consecutive anaesthesia procedures in the same patient for neurosurgery. This case series is remarkable since the severe symptoms occurred during every anaesthesia procedure. The female patient was resuscitated two times including therapeutic hypothermia, but fortunately no neurological or cognitive deficit was detectable. CONCLUSIONS: TTC may initially present in the perioperative period with pulmonary oedema, electrocardiographic (ECG) changes, elevation of cardiac enzymes, and cardiogenic shock or cardiac arrest. Since the risk of recurrence is considered to be low in TTC, this case report is of high interest. In each procedure similar clinical signs were found which resulted in severe haemodynamic derangements in every manifestation and cardiac arrest in two of the manifestations. Despite cardiopulmonary resuscitation twice, the patient survived without any neurological deficiency. PMID- 25821407 TI - Notch signaling activation is critical to the development of neuropathic pain. AB - BACKGROUND: Nerve injury-induced neuropathic pain is a major health problem worldwide. Notch signaling is a highly conserved pathway in evolution, which has an important role in synaptic plasticity and inflammation in central nervous system. The present study was designed to investigate the potential role of notch signaling in the development of neuropathic pain. METHODS: The neuropathic pain was induced by spared nerve injury (SNI) in rats. The activation of notch signaling in the lumbar spinal dorsal horn was measured. DAPT, an inhibitor of notch signaling, was intrathecally (i.t.) administered before SNI or after appearance of pain sensitivity. Moreover, Jagged-1 (JAG-1) peptide, a ligand of notch signaling, was i.t. administered to normal rats. The mechanical allodynia was assessed by von Frey test. RESULTS: Here, we found that DAPT administered 0.5 h before SNI operation could significantly prevent the decrease of mechanical paw withdrawal threshold (PWT) for more than 4 weeks (P < 0.05 vs. SNI group). DAPT administered after appearance of pain sensitivity could also significantly reverse the decrease of mechanical PWT in a dose-dependent manner (P < 0.05). In addition, administration of Jagged-1 (JAG-1) peptide significantly decreased the mechanical PWT of normal rats in a dose-dependent manner (P < 0.05). CONCLUSIONS: Therefore, notch signaling activation might contribute to the development of neuropathic pain. This study might provide a new therapeutic target for neuropathic pain. PMID- 25821408 TI - Going back to home to die: does it make a difference to patient survival? AB - BACKGROUND: Many patients wish to stay at home during the terminal stage of cancer. However, there is concern that medical care provided at home may negatively affect survival. This study therefore explored whether the survival duration differed between cancer patients who received inpatient care and those who received home care. METHODS: We retrospectively investigated the place of care/death and survival duration of 190 cancer patients after their referral to a palliative care consultation team in a Japanese general hospital between 2007 and 2012. The patients were classified into a hospital care group consisting of those who received palliative care in the hospital until death, and a home care group including patients who received palliative care at home from doctors in collaboration with the palliative care consultation team. Details of the place of care, survival duration, and patient characteristics (primary site, gender, age, history of chemotherapy, and performance status) were obtained from electronic medical records, and analyzed after propensity score matching in the place of care. RESULTS: Median survival adjusted for propensity score was significantly longer in the home care group (67.0 days, n = 69) than in the hospital care group (33.0 days, n = 69; P = 0.0013). Cox's proportional hazard analysis revealed that the place of care was a significant factor for survival following adjustment for covariates including performance status. CONCLUSIONS: This study suggests that the general concern that home care shortens the survival duration of patients is not based on evidence. A cohort study including more known prognostic factors is necessary to confirm the results. PMID- 25821409 TI - Expression of hedgehog signal pathway in articular cartilage is associated with the severity of cartilage damage in rats with adjuvant-induced arthritis. AB - BACKGROUND: Cartilage damage is a crucial step in rheumatoid arthritis (RA) disease progress while its molecular mechanisms are not fully understood. Here we investigated the expression of hedgehog (Hh) signal pathway in articular cartilage of adjuvant-induced arthritis (AIA) rats and its possible pathological role in cartilage damage. METHODS: 30 rats were divided into sham and AIA group (n = 15). Complete Freund's adjuvant was used to induce AIA. Secondary paw swelling was measured on day 10, 14, 18, 22 and 26 after induction. Rats were sacrificed on day 26 and knee joints and cartilage tissues were collected. Paw swelling, cartilage histopathologic changes and OARSI scores were used to evaluate AIA in rats. The protein expression of Hh signal related genes (Shh, Ptch1, Smo and Gli1) in cartilage were assayed by immunohistochemistry. The mRNA levels of Shh, Ptch1, Smo, Gli1, type-II collagen (COII) and aggrecan in cartilage were assayed by real-time PCR. In vitro study, cultured AIA chondrocytes were treated with cyclopamine (a specific inhibitor of Hh signal) and the mRNA levels of Hh signal and ECM components (COII and aggrecan) were measured by real-time PCR. RESULTS: Immunohistochemical results revealed that Shh, Ptch1, Smo and Gli1 proteins showed higher expression in the articular cartilage of AIA rats than those of sham rats. Real-time PCR results confirmed that Shh, Ptch1, Smo and Gli1 mRNA levels in cartilage tissues of AIA rats were significantly increased compared with those of sham rats (1.6, 1.4, 1.6, 2.0 fold, respectively). The mRNA levels of Shh, Ptch1, Smo, and Gli1 were associated with the severity of cartilage damage (indicated by OARSI scores, COII and aggrecan mRNA levels in cartilage). In vitro, cyclopamine effectively decreased the mRNA levels of Shh, Ptch1, Smo and Gli1, and increased the mRNA levels of COII and aggrecan in AIA chondrocytes, suggesting Hh signal inhibition might directly promote ECM production. CONCLUSIONS: Our findings present certain experimental evidence that Hh signal pathway is involved in the pathogenesis of cartilage damage in RA. PMID- 25821411 TI - Effects of a health information system data quality intervention on concordance in Mozambique: time-series analyses from 2009-2012. AB - BACKGROUND: We assessed the effects of a three-year national-level, ministry-led health information system (HIS) data quality intervention and identified associated health facility factors. METHODS: Monthly summary HIS data concordance between a gold standard data quality audit and routine HIS data was assessed in 26 health facilities in Sofala Province, Mozambique across four indicators (outpatient consults, institutional births, first antenatal care visits, and third dose of diphtheria, pertussis, and tetanus vaccination) and five levels of health system data aggregation (daily facility paper registers, monthly paper facility reports, monthly paper district reports, monthly electronic district reports, and monthly electronic provincial reports) through retrospective yearly audits conducted July-August 2010-2013. We used mixed-effects linear models to quantify changes in data quality over time and associated health system determinants. RESULTS: Median concordance increased from 56.3% during the baseline period (2009-2010) to 87.5% during 2012-2013. Concordance improved by 1.0% (confidence interval [CI]: 0.60, 1.5) per month during the intervention period of 2010-2011 and 1.6% (CI: 0.89, 2.2) per month from 2011-2012. No significant improvements were observed from 2009-2010 (during baseline period) or 2012-2013. Facilities with more technical staff (abeta: 0.71; CI: 0.14, 1.3), more first antenatal care visits (abeta: 3.3; CI: 0.43, 6.2), and fewer clinic beds (abeta: -0.94; CI: -1.7, -0.20) showed more improvements. Compared to facilities with no stock-outs, facilities with five essential drugs stocked out had 51.7% (CI: -64.8 -38.6) lower data concordance. CONCLUSIONS: A data quality intervention was associated with significant improvements in health information system data concordance across public-sector health facilities in rural and urban Mozambique. Concordance was higher at those facilities with more human resources for health and was associated with fewer clinic-level stock-outs of essential medicines. Increased investments should be made in data audit and feedback activities alongside targeted efforts to improve HIS data in low- and middle income countries. PMID- 25821412 TI - Direct Machining of Low-Loss THz Waveguide Components With an RF Choke. AB - We present results for the successful fabrication of low-loss THz metallic waveguide components using direct machining with a CNC end mill. The approach uses a split-block machining process with the addition of an RF choke running parallel to the waveguide. The choke greatly reduces coupling to the parasitic mode of the parallel-plate waveguide produced by the split-block. This method has demonstrated loss as low as 0.2 dB/cm at 280 GHz for a copper WR-3 waveguide. It has also been used in the fabrication of 3 and 10 dB directional couplers in brass, demonstrating excellent agreement with design simulations from 240-260 GHz. The method may be adapted to structures with features on the order of 200 MUm. PMID- 25821410 TI - Pancreatic cystic neoplasms: Review of current knowledge, diagnostic challenges, and management options. AB - Pancreatic cystic lesions are being detected with increasing frequency, largely due to advances in cross-sectional imaging. The most common neoplasms include serous cystadenomas, mucinous cystic neoplasms, intraductal papillary mucinous neoplasms, solid pseudopapillary neoplasms, and cystic pancreatic endocrine neoplasms. Computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS) are currently used as imaging modalities. EUS-guided fine needle aspiration has proved to be a useful diagnostic tool, and enables an assessment of tumor markers, cytology, chemistries, and DNA analysis. Here, we review the current literature on pancreatic cystic neoplasms, including classification, diagnosis, treatment, and recommendations for surveillance. Data for this manuscript was acquired via searching the literature from inception to December 2014 on PubMed and Ovid MEDLINE. PMID- 25821413 TI - Patients in the radiology department may be at increased risk of developing critical instability. AB - The purpose of this study was to calculate the event rate for in-patients in the Radiology Department (RD) developing instability leading to calls for Medical Emergency Team assistance (MET-RD) compared to general ward (MET-W) patients. A retrospective comparison was done of MET-RD and MET-W calls in 2009 in a U.S. tertiary hospital with a well-established MET system. MET-RD and MET-W event rates represented as MET calls/hour/1000 admissions, adjusted for length of stay (LOS); rates also calculated for RD modalities. There were 31,320 hospital ward admissions had 1,230 MET-W, and among 149,569 radiology admissions there were 56 MET-RD. When adjusted for LOS, the MET-RD event rate was 2 times higher than the MET-W rate (0.48 vs. 0.24 events/hour/1000 admissions). Event rates differed by procedure: computed tomography (CT) had 38% of MET-RDs (event rate 0.89); magnetic resonance imaging (MRI) accounted for 27% (event rate 1.56). Nuclear medicine had 1% of RD admissions but these patients accounted for 5% of MET-RD (event rate 1.53). Interventional radiology (IR) had 6% of RD admissions but 16% of MET-RD (event rate 0.61). While general x-ray comprised 63% of RD admissions, only 11% of MET-RD involved their care (event rate 0.09). In conclusion, the overall MET-RD event rate was twice the MET-W event rate; CT, MRI and IR rates were 3.7-6.5 times higher than on wards. RD patients are at increased risk for a MET call compared to ward patients when the time at risk is considered. Increased surveillance of RD patients is warranted. PMID- 25821414 TI - Quantum Monte Carlo Treatment of the Charge Transfer and Diradical Electronic Character in a Retinal Chromophore Minimal Model. AB - The penta-2,4-dieniminium cation (PSB3) displays similar ground state and first excited state potential energy features as those of the retinal protonated Schiff base (RPSB) chromophore in rhodopsin. Recently, PSB3 has been used to benchmark several electronic structure methods, including highly correlated multireference wave function approaches, highlighting the necessity to accurately describe the electronic correlation in order to obtain reliable properties even along the ground state (thermal) isomerization paths. In this work, we apply two quantum Monte Carlo approaches, the variational Monte Carlo and the lattice regularized diffusion Monte Carlo, to study the energetics and electronic properties of PSB3 along representative minimum energy paths and scans related to its thermal cis trans isomerization. Quantum Monte Carlo is used in combination with the Jastrow antisymmetrized geminal power ansatz, which guarantees an accurate and balanced description of the static electronic correlation thanks to the multiconfigurational nature of the antisymmetrized geminal power term, and of the dynamical correlation, due to the presence of the Jastrow factor explicitly depending on electron-electron distances. Along the two ground state isomerization minimum energy paths of PSB3, CASSCF calculations yield wave functions having either charge transfer or diradical character in proximity of the two transition state configurations. Here, we observe that at the quantum Monte Carlo level of theory, only the transition state with charge transfer character can be located. The conical intersection, which becomes highly sloped, is observed only if the path connecting the two original CASSCF transition states is extended beyond the diradical one, namely by increasing the bond-length alternation (BLA). These findings are in good agreement with the results obtained by MRCISD+Q calculations, and they demonstrate the importance of having an accurate description of the static and dynamical correlation when studying isomerization and transition states of conjugated systems. PMID- 25821415 TI - Open-Ended Recursive Approach for the Calculation of Multiphoton Absorption Matrix Elements. AB - We present an implementation of single residues for response functions to arbitrary order using a recursive approach. Explicit expressions in terms of density-matrix-based response theory for the single residues of the linear, quadratic, cubic, and quartic response functions are also presented. These residues correspond to one-, two-, three- and four-photon transition matrix elements. The newly developed code is used to calculate the one-, two-, three- and four-photon absorption cross sections of para-nitroaniline and para nitroaminostilbene, making this the first treatment of four-photon absorption in the framework of response theory. We find that the calculated multiphoton absorption cross sections are not very sensitive to the size of the basis set as long as a reasonably large basis set with diffuse functions is used. The choice of exchange-correlation functional, however, significantly affects the calculated cross sections of both charge-transfer transitions and other transitions, in particular, for the larger para-nitroaminostilbene molecule. We therefore recommend the use of a range-separated exchange-correlation functional in combination with the augmented correlation-consistent double-zeta basis set aug cc-pVDZ for the calculation of multiphoton absorption properties. PMID- 25821416 TI - Theoretical Investigation of the Electronic Structure of Fe(II) Complexes at Spin State Transitions. AB - The electronic structure relevant to low spin (LS)<->high spin (HS) transitions in Fe(II) coordination compounds with a FeN6 core are studied. The selected [Fe(tz)6]2+ (1) (tz = 1H-tetrazole), [Fe(bipy)3]2+ (2) (bipy = 2,2'-bipyridine), and [Fe(terpy)2]2+ (3) (terpy = 2,2':6',2"-terpyridine) complexes have been actively studied experimentally, and with their respective mono-, bi-, and tridentate ligands, they constitute a comprehensive set for theoretical case studies. The methods in this work include density functional theory (DFT), time dependent DFT (TD-DFT), and multiconfigurational second order perturbation theory (CASPT2). We determine the structural parameters as well as the energy splitting of the LS-HS states (DeltaEHL) applying the above methods and comparing their performance. We also determine the potential energy curves representing the ground and low-energy excited singlet, triplet, and quintet d6 states along the mode(s) that connect the LS and HS states. The results indicate that while DFT is well suited for the prediction of structural parameters, an accurate multiconfigurational approach is essential for the quantitative determination of DeltaEHL. In addition, a good qualitative agreement is found between the TD-DFT and CASPT2 potential energy curves. Although the TD-DFT results might differ in some respect (in our case, we found a discrepancy at the triplet states), our results suggest that this approach, with due care, is very promising as an alternative for the very expensive CASPT2 method. Finally, the two-dimensional (2D) potential energy surfaces above the plane spanned by the two relevant configuration coordinates in [Fe(terpy)2]2+ were computed at both the DFT and CASPT2 levels. These 2D surfaces indicate that the singlet-triplet and triplet quintet states are separated along different coordinates, i.e., different vibration modes. Our results confirm that in contrast to the case of complexes with mono- and bidentate ligands, the singlet-quintet transitions in [Fe(terpy)2]2+ cannot be described using a single configuration coordinate. PMID- 25821417 TI - On Predicting Mossbauer Parameters of Iron-Containing Molecules with Density Functional Theory. AB - The performance of six frequently used density functional theory (DFT) methods (RPBE, OLYP, TPSS, B3LYP, B3LYP*, and TPSSh) in the prediction of Mossbauer isomer shifts(delta) and quadrupole splittings (DeltaEQ) is studied for an extended and diverse set of Fe complexes. In addition to the influence of the applied density functional and the type of the basis set, the effect of the environment of the molecule, approximated with the conducting-like screening solvation model (COSMO) on the computed Mossbauer parameters, is also investigated. For the isomer shifts the COSMO-B3LYP method is found to provide accurate delta values for all 66 investigated complexes, with a mean absolute error (MAE) of 0.05 mm s-1 and a maximum deviation of 0.12 mm s-1. Obtaining accurate DeltaEQ values presents a bigger challenge; however, with the selection of an appropriate DFT method, a reasonable agreement can be achieved between experiment and theory. Identifying the various chemical classes of compounds that need different treatment allowed us to construct a recipe for DeltaEQ calculations; the application of this approach yields a MAE of 0.12 mm s-1 (7% error) and a maximum deviation of 0.55 mm s-1 (17% error). This accuracy should be sufficient for most chemical problems that concern Fe complexes. Furthermore, the reliability of the DFT approach is verified by extending the investigation to chemically relevant case studies which include geometric isomerism, phase transitions induced by variations of the electronic structure (e.g., spin crossover and inversion of the orbital ground state), and the description of electronically degenerate triplet and quintet states. Finally, the immense and often unexploited potential of utilizing the sign of the DeltaEQ in characterizing distortions or in identifying the appropriate electronic state at the assignment of the spectral lines is also shown. PMID- 25821418 TI - The Effect of a Mobile Health Decision Support System on Diagnosis and Management of Obesity, Tobacco Use, and Depression in Adults and Children. PMID- 25821419 TI - Cell-free eukaryotic systems for the production, engineering, and modification of scFv antibody fragments. AB - Open cell-free translation systems based on Escherichia coli cell lysates have successfully been used to produce antibodies and antibody fragments. In this study, we demonstrate the cell-free expression of functional single-chain antibody variable fragments (scFvs) in a eukaryotic and endotoxin-free in vitro translation system based on Spodoptera frugiperda (Sf21) insect cell extracts. Three scFv candidates with different specificities were chosen as models. The first scFv candidate SH527-IIA4 specifically discriminates between its phosphorylated (SMAD2-P) and nonphosphorylated antigens (SMAD2) (where SMAD is mothers against decapentaplegic homolog 2), whereas the second scFv candidate SH527-IIC10 recognizes both, SMAD2-P and SMAD2. The third scFv candidate SH855 C11 binds specifically to a linear epitope of the CXC chemokine receptor type 5. The translocation of antibody fragments into the lumen of endogenous microsomal vesicles, which are contained in the lysate, was facilitated by fusion of scFv genes to the insect cell specific signal sequence of honeybee melittin. We compared the binding capabilities of scFv fragments with and without melittin signal peptide and detected that translocated scFv fragments were highly functional, whereas scFvs synthesized in the cytosol of the cell extract showed strongly decreased binding capabilities. Additionally, we describe a cell-free protein synthesis method for the incorporation of noncanonical amino acids into scFv molecules in eukaryotic cell lysates. We demonstrate the successful cotranslational labeling of de novo synthesized scFv molecules with fluorescent amino acids, using residue-specific as well as site-specific labeling. PMID- 25821420 TI - Atopic dermatitis is a serious health problem in Poland. Epidemiology studies based on the ECAP study. AB - INTRODUCTION: Global epidemiological studies have revealed considerable geographical differences in prevalence of atopic dermatitis (AD). AIM: To present the epidemiology of AD, risk factors and co-occurrence of allergic diseases in the Polish population. MATERIAL AND METHODS: The present paper is a part of the Epidemiology of Allergic Disorders in Poland study. We studied 22 703 participants by ECRHS/ISAAC questionnaire; 18 617 (53.8% female, 24.2% 6-7 y.o., 25.4% 13-14 y.o., 50.4% 20-44 y.o.) completed questionnaires were accepted. Four thousand seven hundred and eighty-three participants (25.7%) have undergone a medical examination. RESULTS: Atopic dermatitis was diagnosed in 3.91% (6-7 y.o. 5.34%, 13-14 y.o. 4.3%, adults 3.02%), more often in females (OR = 1.52; 95% CI: 0.56-0.77), in the cities (OR = 2.23; 95% CI: 1.61-3.09), in mothers (OR = 2.07; 95% CI: 1.72-2.48) and fathers (OR = 2.00; 95% CI: 1.61-2.49) with atopy, higher education (OR = 1.61; 95% CI: 1.11-2.32) and economic status (OR = 1.35; 95% CI: 1.04-1.74). The highest prevalence was found in Katowice (4.89%) and lowest in rural areas (1.9%). Coexisting AD and allergic rhinitis (AR) was found in 26.17%, AR and asthma in 9.09% and AD, AR and asthma in 14.6%. Atopic dermatitis was diagnosed by allergologists in 6.5% (6-7 y.o. 8.7%, 13-14 y.o. 9.0%, adults 3.6%). Most diagnoses were made in Poznan (16.76%) and smallest in rural area (3.67%). 78.8% of subjects were diagnosed with AD for the first time although they had earlier experienced its symptoms. CONCLUSIONS: Atopic dermatitis prevalence in Poland is below the mean rate for Europe, but the risk factor profile is similar to other countries. Atopic dermatitis is more frequent in well educated females with atopic parents and high socioeconomic status and who live in a city. PMID- 25821421 TI - Comparison of detection of Borrelia burgdorferi DNA and anti-Borrelia burgdorferi antibodies in patients with erythema migrans in north-eastern Poland. AB - INTRODUCTION: Diagnostic methods in erythema migrans are still not standardized. AIM: To evaluate the frequency of Borrelia burgdorferi s.l. DNA presence in patients with erythema migrans (EM); to assess the polymerase chain reaction (PCR) procedure for detecting B. burgdorferi s.l. DNA in patients with the skin form of Lyme borreliosis; and to compare the results of the PCR-based method with the traditional ELISA method. MATERIAL AND METHODS: Skin biopsy and blood samples from 93 patients with EM were examined for B. burgdorferi s.l. DNA detection (PCR). Seventy-one of these patients were examined for the presence of anti-B. burgdorferi s.l. antibodies (ELISA). RESULTS: Borrelia burgdorferi s.l. DNA was detected in 48% of the skin biopsy specimens and in 2% of blood samples. Only 1 patient was PCR positive in both blood and skin samples. Seventy percent of patients whose PCR results were positive were bitten by a tick less than 14 days before. IgM anti-B. burgdorferi s.l - specific antibodies were present in the serum of 35% of patients and IgG antibodies - in 30% of patients. Seventeen percent were positive in both IgM and IgG. CONCLUSIONS: Polymerase chain reaction of skin biopsy specimens seems to be currently the most sensitive and specific test for the diagnosis of patients with EM, especially in patients with a short duration of the disease (< 14 days) but still its effectiveness is much lower than expected. Polymerase chain reaction of blood samples cannot be recommended at the present time for the routine diagnostic of patients with EM. PMID- 25821422 TI - Relationship between Helicobacter pylori and idiopathic chronic urticaria: effectiveness of Helicobacter pylori eradication. AB - INTRODUCTION: Chronic urticaria (CU) is defined as the presence of urticaria on most days of the week for a period of 6 weeks or longer. Some studies have reported an association between CU and Helicobacter pylori (H. pylori) infection. AIM: To determine the prevalence of H. pylori infection using the stool antigen test in patients with idiopathic CU and to investigate the infected patients with CU following eradication of H. pylori. MATERIAL AND METHODS: One hundred patients with idiopathic CU and 100 healthy controls were referred to our clinic between May 2012 and June 2013 and were tested for H. pylori antigen. The patients infected with H. pylori received quadruple therapy for 2 weeks. To assess eradication efficacy, a repeated H. pylori stool antigen test was performed in each patient 6 weeks after the end of anti-H. pylori therapy. The effectiveness of eradication therapy on CU was assessed 3 months after treatment. RESULTS: Thirty-six percent patients with idiopathic CU were infected with H. pylori while 23% of the controls were infected. Response to eradication therapy was evident in 33 (91.67%) patients in whom H. pylori was eradicated while 3 (8.33%) patients showed no response despite eradication of H. pylori. Clinical follow-up of 33 successfully treated patients 3 months later revealed complete remission of urticaria in 54.5%, partial remission in 18.2%, and no improvement in 27.3%. CONCLUSIONS: The results of our study suggest that H. pylori infection should be included in diagnostic workup of patients with no response to habitual treatment for CU or symptomatic gastrointestinal patients. For the diagnosis of H. pylori infection, one should consider the costs and accessibility of the population to the HpSA((r)) stool antigen test and Urea breath test (UBT). PMID- 25821423 TI - The effect of clary sage oil on staphylococci responsible for wound infections. AB - INTRODUCTION: The spreading of bacterial antibiotic resistance among clinical strains of pathogenic bacteria has made investigators to search for other active antibacterial agents which could provide a valuable complement to the existing therapies. AIM: To determine the antibacterial activity of clary sage oil (Salvia sclarea L.) against Staphylococcus clinical strains which were isolated from patients with wound infections. MATERIAL AND METHODS: A comprehensive evaluation of Staphylococcus clinical strain resistance to antibiotics was performed. The constituents of clary sage oil were assayed by GC-FID-MS analysis. The minimal inhibitory concentration (MIC) of the tested essential oil against staphylococci by the micro-dilution broth method was determined. RESULTS: The clary sage oil was active against Staphylococcus aureus, S. epidermidis and S. xylosus with MIC values ranging from 3.75 to 7.00 ul/ml. CONCLUSIONS: The results of the in vitro tests encourage to use formulations containing sage oil as the active natural antimicrobial agent. Because of its antimicrobial properties clary sage oil may be applied to treat wounds and skin infections. PMID- 25821425 TI - The most common mistakes on dermatoscopy of melanocytic lesions. AB - Dermatoscopy is a method of in vivo evaluation of the structures within the epidermis and dermis. Currently, it may be the most precise pre-surgical method of diagnosing melanocytic lesions. Diagnostic errors may result in unnecessary removal of benign lesions or what is even worse, they can cause early and very early melanomas to be overlooked. Errors in assessment of dermatoscopy can be divided into those arising from failure to maintain proper test procedures (procedural and technical errors) and knowledge based mistakes related to the lack of sufficient familiarity and experience in dermatoscopy. The article discusses the most common mistakes made by beginner or inexperienced dermatoscopists. PMID- 25821424 TI - The role of selectins in alopecia areata. AB - INTRODUCTION: One of the main histopathological features of alopecia areata (AA) is a lymphocytic infiltration that surrounds hair follicles. Soluble forms of E, L, P-selectins are known indicators of ongoing inflammation. There are no studies regarding the assessment of their contribution in AA. AIM: To assess serum concentrations of selectins (E-selectin, L-selectin and P-selectin) in patients with AA in relation to selected clinical parameters, including disease severity and activity. MATERIAL AND METHODS: Sixty-four patients with AA were involved in the study. The diagnosis was based on physical examination and photodermoscopy. The control group consisted of 40 healthy subjects. The serum concentrations of soluble E-selectin, L-selectin and P-selectin were detected with ELISA method. RESULTS: Statistically significantly higher levels of E, P, L-selectins were found in AA patients as compared with the healthy group. Serum concentrations of soluble forms of E- and L-selectins correlated with the severity of the disease, while E-selectin with activity of AA. CONCLUSIONS: This study shows that selectins may play an important role in the pathogenesis of AA and may be a target of future therapies in this disease. PMID- 25821426 TI - Amorolfine vs. ciclopirox - lacquers for the treatment of onychomycosis. AB - Amorolfine 5% and ciclopirox 8% nail lacquers are commonly used in topical treatment of onychomycosis. These formulations may be used alone or in combination with oral antifungal agents. Amorolfine and ciclopirox are valuable therapeutic options, however, their usage in monotherapy should be limited. Proper amorolfine and ciclopirox penetration through the nail plate is provided by transungual drug delivery systems. Although amorolfine and ciclopirox have a different mode of action, they both exhibit a broad antifungal activity. The use of antifungal nail lacquers in combination with oral agents, such as terbinafine and itraconazole, improves efficacy of antifungal therapy. PMID- 25821428 TI - Ultrasound findings in cutaneous sarcoidosis. AB - The diagnosis of cutaneous sarcoidosis relies mainly on the patient's history, presence of characteristic skin lesions and histological examination that shows a granulomatous, non-necrotizing dermal infiltration. The aim of the study was to assess the ultrasonographic features of cutaneous lesions of sarcoidosis before and after treatment. A 38-year-old woman with systemic sarcoidosis and specific cutaneous lesions was treated with systemic steroids followed by hydroxychloroquine. Ultrasonographic examination of the cutaneous sarcoidosis lesions was performed with a Philips iU 22 and Siemens Acuson S 2000 device, with the use of linear 15 MHz and 17 MHz transducers. Histological examination of skin lesions showed characteristic, naked, non-necrotizing granulomas in the upper dermis. Ultrasound examination revealed well-demarcated, hypoechogenic changes. Power-Doppler scan revealed increased vascularity within the lesions and the surrounding tissue. Clinical improvement of the skin lesions was confirmed by ultrasound examination, which showed a decrease in their size and normalization of dermal echogenicity and vascularity. Ultrasound examination can show cutaneous sarcoidosis lesions and their regression after appropriate treatment. PMID- 25821427 TI - Extensive phlegmon and pyoderma gangrenosum: diagnostic difficulties. AB - Pyoderma gangrenosum (PG) is a relatively rare neutrophilic dermatosis, characterized by progressive skin necrosis. It typically has a chronic course, of unknown etiology. Pyoderma gangrenosum diagnosis can be difficult because both histopathological examination and results of additional laboratory tests are not specific and the clinical state is conclusive, as for other physicians it poses a number of diagnostic dilemmas. Therefore, this condition should be treated interdisciplinary. We present a case of a 40-year-old patient with a diagnosis of PG, which in the early stages of the disease was treated as an extensive phlegmon by physicians of other specialties and it presented a serious diagnostic as well as therapeutic problem. PMID- 25821429 TI - Lymphoepithelioma-like carcinoma of the skin in a Polish patient. AB - Lymphoepithelioma-like carcinoma of the skin (LELCS) is a very rare cutaneous neoplasm with limited metastatic potential. It presents distinctive histopathologic features similar to undifferentiated nasopharyngeal carcinoma and clinical similarities with other skin neoplasms. We present the first case of LELCS in Polish patients. A 72-year-old woman presented with a 12 months' history of painless, solitary tumor on the nose. A wide local excision was performed. There was no evidence of local recurrence 24 months after surgical treatment. PMID- 25821430 TI - Case report on a patient with lupus panniculitis. AB - Lupus panniculitis is a rare variant of lupus erythematosus. It may occur as a separate disease or coexist with systemic or discoid lupus erythematosus. It is characterized by persistent, tender and hard nodules localised on the face, arms, shoulders, breast and buttocks. Healing of lesions is associated with scarring, lipoatrophy and rarely ulceration. Treatment of lupus panniculitis depends on disease advancement or concomitance of additional lupus erythematosus symptoms. We report a case of a 44-year-old patient with lupus panniculitis treated with chloroquine and glucocorticosteroids, including high dose infusions. Despite intense treatment, the patient developed symptoms that suggested a diagnosis of systemic lupus erythematosus. PMID- 25821431 TI - Sturge-Weber syndrome type II treated with PDL 595 nm laser. AB - Sturge-Weber syndrome (SWS) is rare congenital disorder presenting facial port wine stains (PWS) eye abnormalities and cerebrovascular malformations. The frequency of SWS is estimated at 1 in 50 000. Cerebrovascular abnormalities can be responsible for seizures, hemiparesis, mental retardation and ophthalmologic abnormalities cause intraocular pressure, glaucoma. Etiopathogenesis of SWS remains elusive. We present a case of a 7-year-old girl with SWS type II. A port wine stain involves the upper right part of half face and has been associated with glaucoma of both eyes. In the Department of Dermatology in 2009-2012 we performed 23 procedures within 2 months. We have been using PDL laser at wavelength 595 nm and very good cosmetic results were achieved. Given positive treatment effects, the laser therapy of port-wine stains is a method of selection. Port-wine stains in the course of SWS requires a large number of laser treatment. PMID- 25821432 TI - Hydrophilic bile acids protect human blood-brain barrier endothelial cells from disruption by unconjugated bilirubin: an in vitro study. AB - Ursodeoxycholic acid and its main conjugate glycoursodeoxycholic acid are bile acids with neuroprotective properties. Our previous studies demonstrated their anti-apoptotic, anti-inflammatory, and antioxidant properties in neural cells exposed to elevated levels of unconjugated bilirubin (UCB) as in severe jaundice. In a simplified model of the blood-brain barrier, formed by confluent monolayers of a cell line of human brain microvascular endothelial cells, UCB has shown to induce caspase-3 activation and cell death, as well as interleukin-6 release and a loss of blood-brain barrier integrity. Here, we tested the preventive and restorative effects of these bile acids regarding the disruption of blood-brain barrier properties by UCB in in vitro conditions mimicking severe neonatal hyperbilirubinemia and using the same experimental blood-brain barrier model. Both bile acids reduced the apoptotic cell death induced by UCB, but only glycoursodeoxycholic acid significantly counteracted caspase-3 activation. Bile acids also prevented the upregulation of interleukin-6 mRNA, whereas only ursodeoxycholic acid abrogated cytokine release. Regarding barrier integrity, only ursodeoxycholic acid abrogated UCB-induced barrier permeability. Better protective effects were obtained by bile acid pre-treatment, but a strong efficacy was still observed by their addition after UCB treatment. Finally, both bile acids showed ability to cross confluent monolayers of human brain microvascular endothelial cells in a time-dependent manner. Collectively, data disclose a therapeutic time-window for preventive and restorative effects of ursodeoxycholic acid and glycoursodeoxycholic acid against UCB-induced blood brain barrier disruption and damage to human brain microvascular endothelial cells. PMID- 25821433 TI - Auditory and motion metaphors have different scalp distributions: an ERP study. AB - While many links have been established between sensory-motor words used literally (kick the ball) and sensory-motor regions of the brain, it is less clear whether metaphorically used words (kick the habit) also show such signs of "embodiment." Additionally, not much is known about the timing or nature of the connection between language and sensory-motor neural processing. We used stimuli divided into three figurativeness conditions-literal, metaphor, and anomalous-and two modality conditions-auditory (Her limousine was a privileged snort) and motion (The editorial was a brass-knuckle punch). The conditions were matched on a large number of potentially confounding factors including cloze probability. The electroencephalographic response to the final word of each sentence was measured at 64 electrode sites on the scalp of 22 participants and event-related potentials (ERPs) calculated. Analysis revealed greater amplitudes for metaphorical than literal sentences in both 350-500 ms and 500-650 ms timeframes. Results supported the possibility of different neural substrates for motion and auditory sentences. Greater differences for motion sentences were seen in the left posterior and left central electrode sites than elsewhere on the scalp. These findings are consistent with a sensory-motor neural categorization of language and with the integration of modal and amodal information during the N400 and P600 timeframes. PMID- 25821434 TI - (-)-Epicatechin combined with 8 weeks of treadmill exercise is associated with increased angiogenic and mitochondrial signaling in mice. AB - The purpose of this study was to conduct an 8 week endurance training program with and without (-)-epicatechin treatment and to determine whether there is a possible cumulative effect on protein markers of angiogenesis and mitochondrial biogenesis. Thirty-four 14-month old male mice (C57BL/6N) were randomized into four groups: control (C); (-)-epicatechin only ((-)-Epi); control with endurance training (CE); and (-)-epicatechin with endurance training ((-)-Epi-Ex). Mice in the training groups performed treadmill exercise for 8 weeks (5 * /week for 60 min/session), whereas mice in the (-)-epicatechin group received 1.0 mg/kg of body mass twice daily during the training period. At 8 weeks, distance ran on the treadmill increased by 46, 69, and 84% in the (-)-Epi, CE, and (-)-Epi-Ex groups, respectively compared to the control group (p < 0.001 for all comparisons). Furthermore, the (-)-Epi-Ex group had significantly higher exercise capacity than the (-)-Epi and CE group. For angiogenic regulators, the (-)-Epi-Ex group had significantly higher VEGF-R2 protein expression with a concomitant reduction in TSP-1 protein expression than the exercise group. Interestingly, FoxO1 protein expression was significantly reduced for all three experimental groups compared to the control group. Protein markers such as PGC-1beta and TFAM were significantly higher in the (-)-Epi-Ex group compared to the three other groups. These findings suggest that (-)-epicatechin treatment combined with 8 weeks of endurance training provide a cumulative effect on a number of angiogenic and mitochondrial signaling which functionally translates to enhanced exercise tolerance. PMID- 25821435 TI - Nonlinear digital signal processing in mental health: characterization of major depression using instantaneous entropy measures of heartbeat dynamics. AB - Nonlinear digital signal processing methods that address system complexity have provided useful computational tools for helping in the diagnosis and treatment of a wide range of pathologies. More specifically, nonlinear measures have been successful in characterizing patients with mental disorders such as Major Depression (MD). In this study, we propose the use of instantaneous measures of entropy, namely the inhomogeneous point-process approximate entropy (ipApEn) and the inhomogeneous point-process sample entropy (ipSampEn), to describe a novel characterization of MD patients undergoing affective elicitation. Because these measures are built within a nonlinear point-process model, they allow for the assessment of complexity in cardiovascular dynamics at each moment in time. Heartbeat dynamics were characterized from 48 healthy controls and 48 patients with MD while emotionally elicited through either neutral or arousing audiovisual stimuli. Experimental results coming from the arousing tasks show that ipApEn measures are able to instantaneously track heartbeat complexity as well as discern between healthy subjects and MD patients. Conversely, standard heart rate variability (HRV) analysis performed in both time and frequency domains did not show any statistical significance. We conclude that measures of entropy based on nonlinear point-process models might contribute to devising useful computational tools for care in mental health. PMID- 25821436 TI - Dysregulated hypothalamic-pituitary-adrenal axis function contributes to altered endocrine and neurobehavioral responses to acute stress. AB - Organisms react to environmental challenges by activating a coordinated set of brain-body responses known as the stress response. These physiological and behavioral countermeasures are, in large part, regulated by the neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis. Normal functioning of the HPA axis ensures that an organism responds appropriately to altered environmental demands, representing an essential system to promote survival. Over the past several decades, increasing evidence supports the hypothesis that disruption of the HPA axis can lead to dysregulated stress response phenotypes, exacting a physiological cost on the organism commonly referred to as allostatic load. Furthermore, it has been recognized that high allostatic load can contribute to increased vulnerability of the organism to further challenges. This observation leads to the notion that disrupted HPA function and resulting inappropriate responses to stressors may underlie many neuropsychiatric disorders, including depression and anxiety. In the present set of studies, we investigate the role of both the normally functioning and disrupted HPA axis in the endocrine, neural, and behavioral responses to acute stress. Using a model of non-invasive chronic corticosterone treatment in mice, we show that dysregulating the normal function of the HPA leads to a mismatch between the hormonal and neural response to acute stress, resulting in abnormal behavioral coping strategies. We believe this model can be leveraged to tease apart the mechanisms by which altered HPA function contributes to neurobehavioral dysregulation in response to acute stress. PMID- 25821437 TI - Clearing the smokescreen: the current evidence on cannabis use. PMID- 25821438 TI - The Oculus Rift: a cost-effective tool for studying visual-vestibular interactions in self-motion perception. AB - For years now, virtual reality devices have been applied in the field of vision science in an attempt to improve our understanding of perceptual principles underlying the experience of self-motion. Some of this research has been concerned with exploring factors involved in the visually-induced illusory perception of self-motion, known as vection. We examined the usefulness of the cost-effective Oculus Rift in generating vection in seated observers. This device has the capacity to display optic flow in world coordinates by compensating for tracked changes in 3D head orientation. We measured vection strength in three conditions of visual compensation for head movement: compensated, uncompensated, and inversely compensated. During presentation of optic flow, the observer was instructed to make periodic head oscillations (+/-22 degrees horizontal excursions at approximately 0.53 Hz). We found that vection was best in the compensated condition, and was weakest in the inversely compensated condition. Surprisingly, vection was always better in passive viewing conditions, compared with conditions where active head rotations were performed. These findings suggest that vection is highly dependent on interactions between visual, vestibular and proprioceptive information, and may be highly sensitive to limitations of temporal lag in visual-vestibular coupling using this system. PMID- 25821439 TI - Stimulus-category competition, inhibition, and affective devaluation: a novel account of the uncanny valley. AB - Stimuli that resemble humans, but are not perfectly human-like, are disliked compared to distinctly human and non-human stimuli. Accounts of this "Uncanny Valley" effect often focus on how changes in human resemblance can evoke different emotional responses. We present an alternate account based on the novel hypothesis that the Uncanny Valley is not directly related to 'human-likeness' per se, but instead reflects a more general form of stimulus devaluation that occurs when inhibition is triggered to resolve conflict between competing stimulus-related representations. We consider existing support for this inhibitory-devaluation hypothesis and further assess its feasibility through tests of two corresponding predictions that arise from the link between conflict resolving inhibition and aversive response: (1) that the pronounced disliking of Uncanny-type stimuli will occur for any image that strongly activates multiple competing stimulus representations, even in the absence of any human-likeness, and (2) that the negative peak of an 'Uncanny Valley' should occur at the point of greatest stimulus-related conflict and not (in the presence of human-likeness) always closer to the 'human' end of a perceptual continuum. We measured affective responses to a set of line drawings representing non-human animal-animal morphs, in which each continuum midpoint was a bistable image (Experiment 1), as well as to sets of human-robot and human-animal computer-generated morphs (Experiment 2). Affective trends depicting classic Uncanny Valley functions occurred for all continua, including the non-human stimuli. Images at continua midpoints elicited significantly more negative affect than images at endpoints, even when the continua included a human endpoint. This illustrates the feasibility of the inhibitory-devaluation hypothesis and the need for further research into the possibility that the strong dislike of Uncanny-type stimuli reflects the negative affective consequences of cognitive inhibition. PMID- 25821440 TI - Talking with consumers about energy reductions: recommendations from a motivational interviewing perspective. AB - Reduction of energy costs has become a concern for many organizations. First, we review energy-saving studies in organizations in which consumers showed resistance to change their behavior. Second, we relate resistance to change to the psycholinguistic construct "sustain talk" that describes verbal arguments against behavior change (e.g., "Work processes have priority here"). Third, we argue how Motivational Interviewing (MI)-an interaction-approach to facilitate behavior change-might be helpful in dealing with this behavior. We transfer MI to interactions about energy-savings in organizations and demonstrate how qualification in MI for energy managers may affect these interactions. Therefore, we present three short case scenarios (i.e., video vignettes) that demonstrate socio-interactional mechanisms underlying energy-relevant decisions and behaviors. Consumer' verbal responses are graphed as one single time-variant index of readiness versus resistance (R-index) in order to illustrate interactional dynamics. In sum, we combine theoretical and empirical perspectives from multiple disciplines and discuss an innovative socio-interaction approach that may facilitate energy-efficient behavior in organizations. PMID- 25821442 TI - The relation between language and arithmetic in bilinguals: insights from different stages of language acquisition. AB - Solving arithmetic problems is a cognitive task that heavily relies on language processing. One might thus wonder whether this language-reliance leads to qualitative differences (e.g., greater difficulties, error types, etc.) in arithmetic for bilingual individuals who frequently have to solve arithmetic problems in more than one language. The present study investigated how proficiency in two languages interacts with arithmetic problem solving throughout language acquisition in adolescents and young adults. Additionally, we examined whether the number word structure that is specific to a given language plays a role in number processing over and above bilingual proficiency. We addressed these issues in a German-French educational bilingual setting, where there is a progressive transition from German to French as teaching language. Importantly, German and French number naming structures differ clearly, as two-digit number names follow a unit-ten order in German, but a ten-unit order in French. We implemented a transversal developmental design in which bilingual pupils from grades 7, 8, 10, 11, and young adults were asked to solve simple and complex additions in both languages. The results confirmed that language proficiency is crucial especially for complex addition computation. Simple additions in contrast can be retrieved equally well in both languages after extended language practice. Additional analyses revealed that over and above language proficiency, language specific number word structures (e.g., unit-ten vs. ten-unit) also induced significant modulations of bilinguals' arithmetic performances. Taken together, these findings support the view of a strong relation between language and arithmetic in bilinguals. PMID- 25821441 TI - Independence of face identity and expression processing: exploring the role of motion. AB - According to the classic Bruce and Young (1986) model of face recognition, identity and emotional expression information from the face are processed in parallel and independently. Since this functional model was published, a growing body of research has challenged this viewpoint and instead support an interdependence view. In addition, neural models of face processing emphasize differences in terms of the processing of changeable and invariant aspects of faces. This article provides a critical appraisal of this literature and discusses the role of motion in both expression and identity recognition and the intertwined nature of identity, expression and motion processing. We conclude by discussing recent advancements in this area and research questions that still need to be addressed. PMID- 25821443 TI - A cross-cultural comparison between South African and British students on the Wechsler Adult Intelligence Scales Third Edition (WAIS-III). AB - There is debate regarding the appropriate use of Western cognitive measures with individuals from very diverse backgrounds to that of the norm population. Given the dated research in this area and the considerable socio-economic changes that South Africa has witnessed over the past 20 years, this paper reports on the use of the Wechsler Adult Intelligence Scale Third Edition (WAIS-III), the most commonly used measure of intelligence, with an English second language, multilingual, low socio-economic group of black, South African university students. Their performance on the WAIS-III was compared to that of a predominantly white, British, monolingual, higher socio-economic group. A multi group confirmatory factor analysis showed that the WAIS-III lacks measurement invariance between the two groups, suggesting that it may be tapping different constructs in each group. The UK group significantly outperformed the SA group on the knowledge-based verbal, and some non-verbal subtests, while the SA group performed significantly better on measures of Processing Speed (PS). The groups did not differ significantly on the Matrix Reasoning subtest and on those working memory subtests with minimal reliance on language, which appear to be the least culturally biased. Group differences were investigated further in a set of principal components analyses, which revealed that the WAIS-III scores loaded differently for the UK and SA groups. While the SA group appeared to treat the PS subtests differently to those measuring perceptual organization and non-verbal reasoning, the UK group seemed to approach all of these subtests similarly. These results have important implications for the cognitive assessment of individuals from culturally, linguistically, and socio-economically diverse circumstances. PMID- 25821445 TI - Characterization of pressure distribution in penetrating traumatic brain injuries. AB - Severe impacts to the head commonly lead to localized brain damage. Such impacts may also give rise to temporary pressure changes that produce secondary injuries in brain volumes distal to the impact site. Monitoring pressure changes in a clinical setting is difficult; detailed studies into the effect of pressure changes in the brain call for the development and use of animal models. The aim of this study is to characterize the pressure distribution in an animal model of penetrating traumatic brain injuries (pTBI). This data may be used to validate mathematical models of the animal model and to facilitate correlation studies between pressure changes and pathology. Pressure changes were measured in rat brains while subjected to pTBI for a variety of different probe velocities and shapes; pointy, blunt, and flat. Experiments on ballistic gel samples were carried out to study the formation of any temporary cavities. In addition, pressure recordings from the gel experiments were compared to values recorded in the animal experiments. The pTBI generated short lasting pressure changes in the brain tissue; the pressure in the contralateral ventricle (CLV) increased to 8 bar followed by a drop to 0.4 bar when applying flat probes. The pressure changes in the periphery of the probe, in the Cisterna Magna, and the spinal canal, were significantly less than those recorded in the CLV or the vicinity of the skull base. High-speed videos of the gel samples revealed the formation of spherically shaped cavities when flat and spherical probes were applied. Pressure changes in the gel were similar to those recorded in the animals, although amplitudes were lower in the gel samples. We concluded cavity expansion rate rather than cavity size correlated with pressure changes in the gel or brain secondary to probe impact. The new data can serve as validation data for finite element models of the trauma model and the animal and to correlate physical measurements with secondary injuries. PMID- 25821444 TI - Non-Coding RNAs in Stroke and Neuroprotection. AB - This review will focus on the current state of knowledge regarding non-coding RNAs (ncRNA) in stroke and neuroprotection. There will be a brief introduction to microRNAs (miRNA), long ncRNAs (lncRNA), and piwi-interacting RNAs (piRNA), followed by evidence for the regulation of ncRNAs in ischemia. This review will also discuss the effect of neuroprotection induced by a sublethal duration of ischemia or other stimuli given before a stroke (preconditioning) on miRNA expression and the role of miRNAs in preconditioning-induced neuroprotection. Experimental manipulation of miRNAs and/or their targets to induce pre- or post stroke protection will also be presented, as well as discussion on miRNA responses to current post-stroke therapies. This review will conclude with a brief discussion of future directions for ncRNAs studies in stroke, such as new approaches to model complex ncRNA datasets, challenges in ncRNA studies, and the impact of extracellular RNAs on human diseases such as stroke. PMID- 25821446 TI - Identification and mutational analyses of phosphorylation sites of the calcineurin-binding protein CbpA and the identification of domains required for calcineurin binding in Aspergillus fumigatus. AB - Calcineurin is a key protein phosphatase required for hyphal growth and virulence in Aspergillus fumigatus, making it an attractive antifungal target. However, currently available calcineurin inhibitors, FK506 and cyclosporine A, are immunosuppressive, limiting usage in the treatment of patients with invasive aspergillosis. Therefore, the identification of endogenous inhibitors of calcineurin belonging to the calcipressin family is an important parallel strategy. We previously identified the gene cbpA as the A. fumigatus calcipressin member and showed its involvement in hyphal growth and calcium homeostasis. However, the mechanism of its activation/inhibition through phosphorylation and its interaction with calcineurin remains unknown. Here we show that A. fumigatus CbpA is phosphorylated at three distinct domains, including the conserved SP repeat motif (phosphorylated domain-I; PD-I), a filamentous fungal-specific domain (PD-II), and the C-terminal CIC motif (Calcipressin Inhibitor of Calcineurin; PD-III). While mutation of three phosphorylated residues (Ser208, Ser217, Ser223) in the PD-II did not affect CbpA function in vivo, mutation of the two phosphorylated serines (Ser156, Ser160) in the SP repeat motif caused reduced hyphal growth and sensitivity to oxidative stress. Mutational analysis in the key domains in calcineurin A (CnaA) and proteomic interaction studies confirmed the requirement of PxIxIT motif-binding residues (352-NIR-354) and the calcineurin B (CnaB)-binding helix residue (V371) for the binding of CbpA to CnaA. Additionally, while the calmodulin-binding residues (442-RVF-444) did not affect CbpA binding to CnaA, three mutations (T359P, H361L, and L365S) clustered between the CnaA catalytic and the CnaB-binding helix were also required for CbpA binding. This is the first study to analyze the phosphorylation status of calcipressin in filamentous fungi and identify the domains required for binding to calcineurin. PMID- 25821447 TI - Tales from the crypt and coral reef: the successes and challenges of identifying new herpesviruses using metagenomics. AB - Herpesviruses are ubiquitous double-stranded DNA viruses infecting many animals, with the capacity to cause disease in both immunocompetent and immunocompromised hosts. Different herpesviruses have different cell tropisms, and have been detected in a diverse range of tissues and sample types. Metagenomics encompassing viromics-analyses the nucleic acid of a tissue or other sample in an unbiased manner, making few or no prior assumptions about which viruses may be present in a sample. This approach has successfully discovered a number of novel herpesviruses. Furthermore, metagenomic analysis can identify herpesviruses with high degrees of sequence divergence from known herpesviruses and does not rely upon culturing large quantities of viral material. Metagenomics has had success in two areas of herpesvirus sequencing: firstly, the discovery of novel exogenous and endogenous herpesviruses in primates, bats and cnidarians; and secondly, in characterizing large areas of the genomes of herpesviruses previously only known from small fragments, revealing unexpected diversity. This review will discuss the successes and challenges of using metagenomics to identify novel herpesviruses, and future directions within the field. PMID- 25821448 TI - Antimicrobial photodynamic therapy: an effective alternative approach to control fungal infections. AB - Skin mycoses are caused mainly by dermatophytes, which are fungal species that primarily infect areas rich in keratin such as hair, nails, and skin. Significantly, there are increasing rates of antimicrobial resistance among dermatophytes, especially for Trichophyton rubrum, the most frequent etiologic agent worldwide. Hence, investigators have been developing new therapeutic approaches, including photodynamic treatment. Photodynamic therapy (PDT) utilizes a photosensitive substance activated by a light source of a specific wavelength. The photoactivation induces cascades of photochemicals and photobiological events that cause irreversible changes in the exposed cells. Although photodynamic approaches are well established experimentally for the treatment of certain cutaneous infections, there is limited information about its mechanism of action for specific pathogens as well as the risks to healthy tissues. In this work, we have conducted a comprehensive review of the current knowledge of PDT as it specifically applies to fungal diseases. The data to date suggests that photodynamic treatment approaches hold great promise for combating certain fungal pathogens, particularly dermatophytes. PMID- 25821449 TI - Microbiota and mucosal immunity in amphibians. AB - We know that animals live in a world dominated by bacteria. In the last 20 years, we have learned that microbes are essential regulators of mucosal immunity. Bacteria, archeas, and viruses influence different aspects of mucosal development and function. Yet, the literature mainly covers findings obtained in mammals. In this review, we focus on two major themes that emerge from the comparative analysis of mammals and amphibians. These themes concern: (i) the structure and functions of lymphoid organs and immune cells in amphibians, with a focus on the gut mucosal immune system; and (ii) the characteristics of the amphibian microbiota and its influence on mucosal immunity. Lastly, we propose to use Xenopus tadpoles as an alternative small-animal model to improve the fundamental knowledge on immunological functions of gut microbiota. PMID- 25821450 TI - Human Milk Blocks DC-SIGN-Pathogen Interaction via MUC1. AB - Beneficial effects of breastfeeding are well-recognized and include both immediate neonatal protection against pathogens and long-term protection against allergies and autoimmune diseases. Although several proteins have been identified to have anti-viral or anti-bacterial effects like secretory IgA or lactoferrin, the mechanisms of immune modulation are not fully understood. Recent studies identified important beneficial effects of glycans in human milk, such as those expressed in oligosaccharides or on glycoproteins. Glycans are recognized by the carbohydrate receptors C-type lectins on dendritic cell (DC) and specific tissue macrophages, which exert important functions in immune modulation and immune homeostasis. A well-characterized C-type lectin is dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), which binds terminal fucose. The present study shows that in human milk, MUC1 is the major milk glycoprotein that binds to the lectin domain of DC-SIGN and prevents pathogen interaction through the presence of Lewis x-type oligosaccharides. Surprisingly, this was specific for human milk, as formula, bovine or camel milk did not show any presence of proteins that interacted with DC-SIGN. The expression of DC-SIGN is found in young infants along the entire gastrointestinal tract. Our data thus suggest the importance of human milk glycoproteins for blocking pathogen interaction to DC in young children. Moreover, a potential benefit of human milk later in life in shaping the infants immune system through DC-SIGN cannot be ruled out. PMID- 25821451 TI - Intravital and whole-organ imaging reveals capture of melanoma-derived antigen by lymph node subcapsular macrophages leading to widespread deposition on follicular dendritic cells. AB - Aberrant antigens expressed by tumor cells, such as in melanoma, are often associated with humoral immune responses, which may in turn influence tumor progression. Despite recent data showing the central role of adaptive immune responses on cancer spread or control, it remains poorly understood where and how tumor-derived antigen (TDA) induces a humoral immune response in tumor-bearing hosts. Based on our observation of TDA accumulation in B cell areas of lymph nodes (LNs) from melanoma patients, we developed a pre-metastatic B16.F10 melanoma model expressing a fluorescent fusion protein, tandem dimer tomato, as a surrogate TDA. Using intravital two-photon microscopy (2PM) and whole-mount 3D LN imaging of tumor-draining LNs in immunocompetent mice, we report an unexpectedly widespread accumulation of TDA on follicular dendritic cells (FDCs), which were dynamically scanned by circulating B cells. Furthermore, 2PM imaging identified macrophages located in the subcapsular sinus of tumor-draining LNs to capture subcellular TDA-containing particles arriving in afferent lymph. As a consequence, depletion of macrophages or genetic ablation of B cells and FDCs resulted in dramatically reduced TDA capture in tumor-draining LNs. In sum, we identified a major pathway for the induction of humoral responses in a melanoma model, which may be exploitable to manipulate anti-TDA antibody production during cancer immunotherapy. PMID- 25821452 TI - Lipid and Protein Co-Regulation of PI3K Effectors Akt and Itk in Lymphocytes. AB - The phosphoinositide 3-kinase (PI 3-kinase, PI3K) pathway transduces signals critical for lymphocyte function. PI3K generates the phospholipid PIP3 at the plasma membrane to recruit proteins that contain pleckstrin homology (PH) domains - a conserved domain found in hundreds of mammalian proteins. PH domain-PIP3 interactions allow for rapid signal propagation and confer a spatial component to these signals. The kinases Akt and Itk are key PI3K effectors that bind PIP3 via their PH domains and mediate vital processes - such as survival, activation, and differentiation - in lymphocytes. Here, we review the roles and regulation of PI3K signaling in lymphocytes with a specific emphasis on Akt and Itk. We also discuss these and other PH domain-containing proteins as they relate more broadly to immune cell function. Finally, we highlight the emerging view of PH domains as multifunctional protein domains that often bind both lipid and protein substrates to exert their effects. PMID- 25821453 TI - Chemical diversity of microbial volatiles and their potential for plant growth and productivity. AB - Microbial volatile organic compounds (MVOCs) are produced by a wide array of microorganisms ranging from bacteria to fungi. A growing body of evidence indicates that MVOCs are ecofriendly and can be exploited as a cost-effective sustainable strategy for use in agricultural practice as agents that enhance plant growth, productivity, and disease resistance. As naturally occurring chemicals, MVOCs have potential as possible alternatives to harmful pesticides, fungicides, and bactericides as well as genetic modification. Recent studies performed under open field conditions demonstrate that efficiently adopting MVOCs may contribute to sustainable crop protection and production. We review here the chemical diversity of MVOCs by describing microbial-plants and microbial microbial interactions. Furthermore, we discuss MVOCs role in inducing phenotypic plant responses and their potential physiological effects on crops. Finally, we analyze potential and actual limitations for MVOC use and deployment in field conditions as a sustainable strategy for improving productivity and reducing pesticide use. PMID- 25821454 TI - Cullin-RING ubiquitin ligases in salicylic acid-mediated plant immune signaling. AB - Plant immune responses against biotrophic pathogens are regulated by the signaling hormone salicylic acid (SA). SA establishes immunity by regulating a variety of cellular processes, including programmed cell death (PCD) to isolate and kill invading pathogens, and development of systemic acquired resistance (SAR) which provides long-lasting, broad-spectrum resistance throughout the plant. Central to these processes is post-translational modification of SA regulated signaling proteins by ubiquitination, i.e., the covalent addition of small ubiquitin proteins. Emerging evidence indicates SA-induced protein ubiquitination is largely orchestrated by Cullin-RING ligases (CRLs), which recruit specific substrates for ubiquitination using interchangeable adaptors. Ligation of ubiquitin chains interlinked at lysine 48 leads to substrate degradation by the 26S proteasome. Here we discuss how CRL-mediated degradation of both nucleotide-binding/leucine-rich repeat domain containing immune receptors and SA-induced transcription regulators are critical for functional PCD and SAR responses, respectively. By placing these recent findings in context of knowledge gained in other eukaryotic model species, we highlight potential alternative roles for processive ubiquitination in regulating the activity of SA-mediated immune responses. PMID- 25821455 TI - Cd and Ni transport and accumulation in the halophyte Sesuvium portulacastrum: implication of organic acids in these processes. AB - The implication of organic acids in Cd and Ni translocation was studied in the halophyte species Sesuvium portulacastrum. Citric, fumaric, malic, and ascorbic acids were separated and quantified by HPLC technique in shoots, roots and xylem saps of plants grown on nutrient solutions added with 50 MUM Cd, 100 MUM Ni and the combination of 50 MUM Cd + 100 MUM Ni. Results showed that Cd had no significant impact on biomass production while Ni and the combination of both metals drastically affected plant development. Cadmium and Ni concentrations in tissues and xylem sap were higher in plants subjected to individual metal application than those subjected to the combined effect of Cd and Ni suggesting a possible competition between these metals for absorption. Both metals applied separately or in combination induced an increase in citrate concentration in shoots and xylem sap but a decrease of this concentration in the roots. However, a minor relationship was observed between metal application and fumaric, malic, and ascorbic acids. Both observations suggest the implication of citric acid in Cd, Ni translocation and shoot accumulation in S. portulacastrum. The relatively high accumulation of citric acid in xylem sap and shoot of S. portulacastrum could be involved in metal chelation and thus contributes to heavy metal tolerance in this species. PMID- 25821456 TI - Omic research in termites: an overview and a roadmap. AB - Many recent breakthroughs in our understanding of termite biology have been facilitated by "omics" research. Omic science seeks to collectively catalog, quantify, and characterize pools of biological molecules that translate into structure, function, and life processes of an organism. Biological molecules in this context include genomic DNA, messenger RNA, proteins, and other biochemicals. Other permutations of omics that apply to termites include sociogenomics, which seeks to define social life in molecular terms (e.g., behavior, sociality, physiology, symbiosis, etc.) and digestomics, which seeks to define the collective pool of host and symbiont genes that collaborate to achieve high-efficiency lignocellulose digestion in the termite gut. This review covers a wide spectrum of termite omic studies from the past 15 years. Topics covered include a summary of terminology, the various kinds of omic efforts that have been undertaken, what has been revealed, and to a degree, what the results mean. Although recent omic efforts have contributed to a better understanding of many facets of termite and symbiont biology, and have created important new resources for many species, significant knowledge gaps still remain. Crossing these gaps can best be done by applying new omic resources within multi-dimensional (i.e., functional, translational, and applied) research programs. PMID- 25821457 TI - Genomic prediction of traits related to canine hip dysplasia. AB - Increased concern for the welfare of pedigree dogs has led to development of selection programs against inherited diseases. An example is canine hip dysplasia (CHD), which has a moderate heritability and a high prevalence in some large sized breeds. To date, selection using phenotypes has led to only modest improvement, and alternative strategies such as genomic selection (GS) may prove more effective. The primary aims of this study were to compare the performance of pedigree- and genomic-based breeding against CHD in the UK Labrador retriever population and to evaluate the performance of different GS methods. A sample of 1179 Labrador Retrievers evaluated for CHD according to the UK scoring method (hip score, HS) was genotyped with the Illumina CanineHD BeadChip. Twelve functions of HS and its component traits were analyzed using different statistical methods (GBLUP, Bayes C and Single-Step methods), and results were compared with a pedigree-based approach (BLUP) using cross-validation. Genomic methods resulted in similar or higher accuracies than pedigree-based methods with training sets of 944 individuals for all but the untransformed HS, suggesting that GS is an effective strategy. GBLUP and Bayes C gave similar prediction accuracies for HS and related traits, indicating a polygenic architecture. This conclusion was also supported by the low accuracies obtained in additional GBLUP analyses performed using only the SNPs with highest test statistics, also indicating that marker-assisted selection (MAS) would not be as effective as GS. A Single-Step method that combines genomic and pedigree information also showed higher accuracy than GBLUP and Bayes C for the log-transformed HS, which is currently used for pedigree based evaluations in UK. In conclusion, GS is a promising alternative to pedigree-based selection against CHD, requiring more phenotypes with genomic data to improve further the accuracy of prediction. PMID- 25821459 TI - DNA damage in BALB/c mice infected with Lacazia loboi and its relation to nutritional status. AB - BACKGROUND: Jorge Lobo's disease, also known as lacaziosis, is a cutaneous subcutaneous mycosis with chronic evolution. It is caused by the fungus Lacazia loboi. Herein we report a study that relates the genotoxicity caused by L. loboi in isogenic mice with nutritional status, through a normal or restricted diet. METHODS: DNA damage was assessed in the peripheral blood by the comet assay (tail intensity). RESULTS: The results for leukocytes showed increases in the mean tail intensity in mice under dietary restriction, in infected mice under dietary restriction and in infected mice ingesting a normal diet. CONCLUSION: These results indicate that dietary restriction and L. loboi infection may increase DNA damage levels in mice, as detected by the comet assay. PMID- 25821460 TI - The interplay of the gut microbiome, bile acids, and volatile organic compounds. AB - Background. There has been an increasing interest in the use of volatile organic compounds (VOCs) as potential surrogate markers of gut dysbiosis in gastrointestinal disease. Gut dysbiosis occurs when pathological imbalances in gut bacterial colonies precipitate disease and has been linked to the dysmetabolism of bile acids (BA) in the gut. BA metabolites as a result of microbial transformations act as signaling molecules and have demonstrated regulation of intestinal homeostasis through the TGR5 and FXR receptors by inhibiting inflammation, preventing pathogen invasion, and maintaining cell integrity. The presence of VOC footprints is the resultant effect to gut microbiome substrate fermentation. Aim. To review the role of the gut microbiome and bile acid signaling in intestinal homeostasis and the resultant use of VOCs as potential noninvasive surrogate biomarkers in gut dysbiosis. Methods. A systematic search on PubMed and Medline databases was performed to identify articles relevant to gut dysbiosis, BA metabolism, and VOCs. Conclusions. The host and presence of the gut microbiome appear to regulate the BA pool size. A dysbiotic gut microbiome results in disrupted intestinal homeostasis, which may be reflected by VOCs, differentiating those who are healthy and those with disease. PMID- 25821461 TI - Analysis of the serum bile Acid composition for differential diagnosis in patients with liver disease. AB - Objectives. We determined the serum bile acid (BA) composition in patients with liver diseases and healthy volunteers to investigate the relationship between the etiologies of liver disease and BA metabolism. Material and Methods. Sera from 150 patients with liver diseases and 46 healthy volunteers were obtained. The serum concentrations of the 16 different BAs were determined according to the LC MS/MS method and were compared between the different liver diseases. Results. A total of 150 subjects, including patients with hepatitis C virus (HCV) (n = 44), hepatitis B virus (HBV) (n = 23), alcoholic liver disease (ALD) (n = 21), biliary tract disease (n = 20), nonalcoholic fatty liver disease (NAFLD) (n = 13), and other liver diseases (n = 29), were recruited. The levels of UDCA and GUDCA were significantly higher in the ALD group, and the levels of DCA and UDCA were significantly lower in the biliary tract diseases group than in viral hepatitis group. In the UDCA therapy (-) subgroup, a significantly lower level of TLCA was observed in the ALD group, with lower levels of CDCA, DCA, and GLCA noted in biliary tract diseases group compared to viral hepatitis group. Conclusions. Analysis of the BA composition may be useful for differential diagnosis in liver disease. PMID- 25821462 TI - Bypass during Liver Transplantation: Anachronism or Revival? Liver Transplantation Using a Combined Venovenous/Portal Venous Bypass-Experiences with 163 Liver Transplants in a Newly Established Liver Transplantation Program. AB - Introduction. The venovenous/portal venous (VVP) bypass technique has generally become obsolete in liver transplantation (LT) today. We evaluated our experience with 163 consecutive LTs that used a VVP bypass. Patients and Methods. The liver transplant program was started in our center in 2010. LTs were performed using an extracorporal bypass device. Results. Mean operative time was 269 minutes and warm ischemic time 43 minutes. The median number of transfusion of packed cells and plasma was 7 and 14. There was no intraoperative death, and the 30-day mortality was 3%. Severe bypass-induced complications did not occur. Discussion. The introduction of a new LT program requires maximum safety measures for all of the parties involved. Both surgical and anaesthesiological management (reperfusion) can be controlled very reliably using a VVP bypass device. Particularly when using marginal grafts, this approach helps to minimise both surgical and anaesthesiological complications in terms of less volume overload, less use of vasopressive drugs, less myocardial injury, and better peripheral blood circulation. Conclusion. Based on our experiences while establishing a new liver transplantation program, we advocate the reappraisal of the extracorporeal VVP bypass. PMID- 25821458 TI - Transcriptional regulation of secretory capacity by bZip transcription factors. AB - Cells of specialized secretory organs expand their secretory pathways to accommodate the increased protein load necessary for their function. The endoplasmic reticulum (ER), the Golgi apparatus and the secretory vesicles, expand not only the membrane components but also the protein machinery required for increased protein production and transport. Increased protein load causes an ER stress response akin to the Unfolded Protein Response (UPR). Recent work has implicated several bZip transcription factors in the regulation of protein components of the early secretory pathway necessary to alleviate this stress. Here, we highlight eight bZip transcription factors in regulating secretory pathway component genes. These include components of the three canonical branches of the UPR-ATF4, XBP1, and ATF6, as well as the five members of the Creb3 family of transcription factors. We review findings from both invertebrate and vertebrate model systems suggesting that all of these proteins increase secretory capacity in response to increased protein load. Finally, we propose that the Creb3 family of factors may have a dual role in secretory cell differentiation by also regulating the pathways necessary for cell cycle exit during terminal differentiation. PMID- 25821463 TI - HOMA, BMI, and Serum Leptin Levels Variations during Antiviral Treatment Suggest Virus-Related Insulin Resistance in Noncirrhotic, Nonobese, and Nondiabetic Chronic Hepatitis C Genotype 1 Patients. AB - Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype. PMID- 25821464 TI - Survey of Accepted Practice following Failed Intubation for Emergency Caesarean Delivery. AB - Background. There is no consensus on the optimum management of failed tracheal intubation in emergency cesarean delivery performed for fetal compromise. The decision making process on whether to wake the patient or continue anesthesia with a supraglottic airway device is an underexplored area. This survey explores perceptions and experiences of obstetric anesthetists managing failed intubation. Methods. Anesthetists attending the Group of Obstetric Anaesthetists London (GOAL) Meeting in April 2014 were surveyed. Results. Ninety-three percent of anesthetists surveyed would not always wake the patient in the event of failed intubation for emergency cesarean delivery performed for fetal compromise. The median (interquartile range) of perceived acceptability of continuing anesthesia with a well-fitting supraglottic airway device, assessed using a visual analogue scale (0-100; 0 completely unacceptable; 100 completely acceptable), was 90 [22.5]. Preoperative patient consent regarding the use of a supraglottic airway device for surgery in the event of failed intubation would affect the decision making of 40% of anaesthetists surveyed. Conclusion. These results demonstrate that a significant body of anesthetists with a subspecialty interest in obstetric anesthesia in the UK would not always wake up the patient and would continue with anesthesia and surgery with a supraglottic airway device in this setting. PMID- 25821466 TI - Islets and glucose homeostasis. PMID- 25821465 TI - Effects of levothyroxine replacement therapy on parameters of metabolic syndrome and atherosclerosis in hypothyroid patients: a prospective pilot study. AB - The aim of this study was to investigate the effect of levothyroxine (LT4) replacement therapy during three months on some parameters of metabolic syndrome and atherosclerosis in patients with increased thyroid-stimulating hormone (TSH) level. This study included a group of 30 female patients with TSH level >4 mIU/L and 15 matched healthy controls. Intima media complex thickness (IMCT) and peak systolic flow velocity (PSFV) of superficial femoral artery were determined by Color Doppler scan. In hypothyroid subjects, BMI, SBP, DBP, and TSH were significantly increased versus controls and decreased after LT4 administration. FT4 was significantly lower in hypothyroid subjects compared with controls and significantly higher by treatment. TC, Tg, HDL-C, and LDL-C were similar to controls at baseline but TC and LDL-C were significantly decreased by LH4 treatment. IMCT was significantly increased versus controls at baseline and significantly reduced by treatment. PSFV was similar to controls at baseline and significantly decreased on treatment. In this study, we have demonstrated the effects of LT4 replacement therapy during three months of treatment on correction of risk factors of metabolic syndrome and atherosclerosis. PMID- 25821467 TI - Negative energy balance induced by paradoxical sleep deprivation causes multicompartmental changes in adipose tissue and skeletal muscle. AB - Objective. Describe multicompartmental changes in the fat and various muscle fiber types, as well as the hormonal profile and metabolic rate induced by SD in rats. Methods. Twenty adult male Wistar rats were equally distributed into two groups: experimental group (EG) and control group (CG). The EG was submitted to SD for 96 h. Blood levels of corticosterone (CORT), total testosterone (TESTO), insulin like growth factor-1 (IGF-1), and thyroid hormones (T3 and T4) were used to assess the catabolic environment. Muscle trophism was measured using a cross sectional area of various muscles (glycolytic, mixed, and oxidative), and lipolysis was inferred by the weight of fat depots from various locations, such as subcutaneous, retroperitoneal, and epididymal. The metabolic rate was measured using oxygen consumption ([Formula: see text]O2) measurement. Results. SD increased CORT levels and decreased TESTO, IGF-1, and T4. All fat depots were reduced in weight after SD. Glycolytic and mixed muscles showed atrophy, whereas atrophy was not observed in oxidative muscle. Conclusion. Our data suggest that glycolytic muscle fibers are more sensitive to atrophy than oxidative fibers during SD and that fat depots are reduced regardless of their location. PMID- 25821468 TI - Determination of Glucocorticoids in UPLC-MS in Environmental Samples from an Occupational Setting. AB - Occupational exposures to glucocorticoids are still a neglected issue in some work environments, including pharmaceutical plants. We developed an analytical method to quantify simultaneously 21 glucocorticoids using UPLC coupled with mass spectrometry to provide a basis to carry out environmental monitoring. Samples were taken from air, hand-washing tests, pad-tests and wipe-tests. This paper reports the contents of the analytical methodology, along with the results of this extensive environmental and personal monitoring of glucocorticoids. The method in UPLC-MS turned out to be suitable and effective for the aim of the study. Wipe-test and pad-test desorption was carried out using 50 mL syringes, a simple technique that saves time without adversely affecting analyte recovery. Results showed a widespread environmental pollution due to glucocorticoids. This is of particular concern. Evaluation of the dose absorbed by each worker and identification of a biomarker for occupational exposure will contribute to assessment and prevention of occupational exposure. PMID- 25821469 TI - The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis. AB - Background. Autoantibodies to citrullinated peptides have been shown to be valuable in the diagnosis of rheumatoid arthritis (RA). The expanding repertoire of antibodies to citrullinated peptide antigens (ACPA) has been a topic of great interest in recent reviews and research studies, as has the ability of these autoantibodies to predict disease outcome. Objectives. The aim of this review was to provide an update on the relevance of ACPA as prognostic markers in RA. The ability to identify patients predisposed to an aggressive outcome at the time of initial diagnosis greatly facilitates the selection of appropriate and cost effective treatment. Methods. A systematic review of the literature was carried out. Studies from 1967 up to June 2014 with data on prognostic value of ACPA were included. Quality assessment was done by using the modified Hayden list for prognostic studies. Meta-analysis was performed using BioStat software. Results. The results of 25 studies were selected for the final review. A total of 6421 patients with RA were included, mainly in inception cohorts, with follow-up duration ranging from one year to ten years. All studies carried prognostic data on all available isotypes of anticyclic citrullinated protein (CCP), while four had data on antimutated citrullinated vimentin (MCV). There was a single relevant study each on anticitrullinated enolase peptide 1 (CEP1) and antichimaeric fibrin/filaggrin citrullinated peptide 1 (CFFCP1). All studies showed ACPA to be strong predictors of joint erosions in RA. Other factors, particularly baseline erosions, showed an additive effect. Anti-MCV appeared to be a marker of a more aggressive form of disease. Ten studies had data on which a meta-analysis could be performed. This gave an overall odds ratio of 4.85 for ACPA (anti-CCP/MCV) positivity being predictive for the development of joint erosions. Two studies with data on anti-CEP1 and anti-CFFCP1 also showed this positive predictive role of ACPA for joint erosions. Conclusions. ACPA are strong predictors of severity in RA. Their use should be part of routine rheumatology practice. PMID- 25821471 TI - PEComa in a Young Patient with Known Li-Fraumeni Syndrome. AB - Perivascular epithelioid cells neoplasms (PEComas) constitute a family of rare tumours which have been reported virtually in all anatomic sites. The histological clarification of the malignant potential of these tumours is still problematic despite the proposed risk stratification systems. Li-Fraumeni syndrome (LFS) is caused by a germline mutation in the TP53 tumour suppressor gene. It is a rare but well-characterized cancer predisposition syndrome leading to the development of a variety of different tumour types. To the best of our knowledge, an association between this syndrome and PEComas has not been previously documented. A 24-year-old lady with known LFS presented with two uncertain-in-nature lesions, one within the right part of the liver and one within the upper pole of the right kidney. The patient underwent an uncomplicated open simultaneous right partial nephrectomy and resection of segment 7 of the liver. The morphological and immunohistochemical features of both lesions were of epithelioid angiomyolipoma (PEComa). Although the obvious scenario was that the liver lesion was a metastasis from the renal lesion, the assessment of their malignant potential according to the existing risk stratification systems was rather in favour of two synchronous primary PEComas, pointing out that the histological assessment of malignant potential of PEComas is still problematic. PMID- 25821470 TI - Circadian System and Melatonin Hormone: Risk Factors for Complications during Pregnancy. AB - Pregnancy is a complex and well-regulated temporal event in which several steps are finely orchestrated including implantation, decidualization, placentation, and partum and any temporary alteration has serious effects on fetal and maternal health. Interestingly, alterations of circadian rhythms (i.e., shiftwork) have been correlated with increased risk of preterm delivery, intrauterine growth restriction, and preeclampsia. In the last few years evidence is accumulating that the placenta may have a functional circadian system and express the clock genes Bmal1, Per1-2, and Clock. On the other hand, there is evidence that the human placenta synthesizes melatonin, hormone involved in the regulation of the circadian system in other tissues. Moreover, is unknown the role of this local production of melatonin and whether this production have a circadian pattern. Available information indicates that melatonin induces in placenta the expression of antioxidant enzymes catalase and superoxide dismutase, prevents the injury produced by oxidative stress, and inhibits the expression of vascular endothelial growth factor (VEGF) a gene that in other tissues is controlled by clock genes. In this review we aim to analyze available information regarding clock genes and clock genes controlled genes such as VEGF and the possible role of melatonin synthesis in the placenta. PMID- 25821472 TI - Comparisons of mouse mesenchymal stem cells in primary adherent culture of compact bone fragments and whole bone marrow. AB - The purification of mouse bone marrow mesenchymal stem cells (BMSCs) by using the standard method of whole bone marrow adherence to plastic still remains ineffective. An increasing number of studies have indicated compact bone as an alternative source of BMSCs. We isolated BMSCs from cultured compact bone fragments and investigated the proliferative capacity, surface immunophenotypes, and osteogenic and adipogenic differentiations of the cells after the first trypsinization. The fragment culture was based on the fact that BMSCs were assembled in compact bones. Thus, the procedure included flushing bone marrow out of bone cavity and culturing the fragments without any collagenase digestion. The cell yield from cultured fragments was slightly less than that from cultured bone marrow using the same bone quantity. However, the trypsinized cells from cultured fragments exhibited significantly higher proliferation and were accompanied with more CD90 and CD44 expressions and less CD45 expression. The osteogenic and adipogenic differentiation capacity of cells from cultured fragments were better than those of cells from bone marrow. The directly adherent culture of compact bone is suitable for mouse BMSC isolation, and more BMSCs with potentially improved proliferation capacity can be obtained in the primary culture. PMID- 25821473 TI - Methane and nitrous oxide exchange over a managed hay meadow. AB - The methane (CH4) and nitrous oxide (N2O) exchange of a temperate mountain grassland near Neustift, Austria, was measured during 2010-2012 over a time period of 22 months using the eddy covariance method. Exchange rates of both compounds at the site were low, with 97% of all half-hourly CH4 and N2O fluxes ranging between +/-200 and +/-50 ng m-2 s-1, respectively. The meadow acted as a sink for both compounds during certain time periods, but was a clear source of CH4 and N2O on an annual timescale. Therefore, both gases contributed to an increase of the global warming potential (GWP), effectively reducing the sink strength in terms of CO2 equivalents of the investigated grassland site. In 2011, our best guess estimate showed a net greenhouse gas (GHG) sink of -32 g CO2 equ. m-2 yr-1 for the meadow, whereby 55% of the CO2 sink strength of -71 g CO2m-2 yr 1 was offset by CH4 (N2O) emissions of 7 (32) g CO2 equ. m-2 yr-1. When all data were pooled, the ancillary parameters explained 27 (42)% of observed CH4 (N2O) flux variability, and up to 62 (76)% on shorter timescales in-between management dates. In the case of N2O fluxes, we found the highest emissions at intermediate soil water contents and at soil temperatures close to 0 or above 14 degrees C. In comparison to CO2, H2O and energy fluxes, the interpretation of CH4 and N2O exchange was challenging due to footprint heterogeneity regarding their sources and sinks, uncertainties regarding post-processing and quality control. Our results emphasize that CH4 and N2O fluxes over supposedly well-aerated and moderately fertilized soils cannot be neglected when evaluating the GHG impact of temperate managed grasslands. PMID- 25821474 TI - Dystrophic-Anagen Effluvium Occurring During Pegylated Interferon-alpha 2a/Ribavirin Therapy. AB - INTRODUCTION: Various types of dermatological manifestations have been reported due to hepatitis C virus (HCV) infection and anti-HCV therapy. Some of them have been described during IFN-based therapies. PEG-IFN-alpha-2a/RBV combination is used as the international standard of treatment for HCV infection for a long time. The combination therapy yields an adverse-event profile similar to standard interferon (IFN) therapy. Some of these adverse effects are rheumatologic, neuropsychiatric and dermatological manifestations including alopecia. CASE PRESENTATION: We reported a 43-year-old woman with dystrophic anagen effluvium (DAE), rheumatoid arthritis and Hashimoto thyroiditis, which were developed under the combination therapy for chronic HCV infection. CONCLUSIONS: Although some cases of alopecia areata (AA) and telogen effluvium (TE) were reported in literature, no case of DAE associated with PEG-INF-alpha-2a /RBV combination therapy was reported previously. PMID- 25821475 TI - Effect of Powdered Shells of the Snail Megalobulimus lopesi on Secondary Intention Wound Healing in an Animal Model. AB - Topical administration of powdered shells of the land snail Megalobulimus lopesi was evaluated in Wistar rats for their healing activity in an excision wound model. The animals were distributed into three groups-G1 (control): no therapeutic intervention; G2 (vehicle controls): Lanette cream once daily; G3 (experimental animals): treated with powdered shells. Variables investigated were: wound area contraction, angiogenic activity, morphometric data, leukocytic inflammatory infiltrate, and total leukocyte count in peripheral blood. Thermogravimetric analysis and quantification and characterization of powdered shell proteins were also performed. Wound area on days 3, 7, and 14 was smaller in G3, besides presenting wound closure on day 21 for all these animals. Topical administration of the powdered shells also led to an increased number of vessels at the wound site, higher leukocyte counts in peripheral blood, and increased leukocytic inflammatory infiltrate. The results lend support to the southern Brazilian folk use of M. lopesi powdered shells, as shown by the enhanced secondary-intention healing achieved with their topical administration to wounds in rats. Topical administration caused inflammatory response modulation, crucial to accelerating the healing process, the chronification of which increases the risks of wound contamination by opportunistic pathogens. PMID- 25821476 TI - The Synergistic Beneficial Effects of Ginkgo Flavonoid and Coriolus versicolor Polysaccharide for Memory Improvements in a Mouse Model of Dementia. AB - This study reports the combination of Ginkgo flavonoid (GF) and Coriolus versicolor polysaccharide (CVP) in the prevention and treatment of a mouse model of Alzheimer's disease (AD). GF is a traditional health product, and CVP is the main active ingredient of the medicinal fungus Coriolus versicolor. The Morris water maze test, the Y maze, and the step-through test showed that the combinational use of CVP and GF synergistically improved memory in a mouse model of AD. Based on H&E staining analysis, the combination of CVP and GF decreased the severity of the pathological findings in the brain. Given that the expression of IL-1beta, IL-6, and TNF-alpha was downregulated, the inflammation response in AD mice was considered to be inhibited. The downregulation of GFAP further demonstrated that inflammation was reduced in the brain of AD mice following treatment. Moreover, the expression levels of superoxide dismutase (SOD) and catalase (CAT) were elevated in the brains of treated mice, indicating that oxidation levels were reduced upon the combination treatment. Our results provide new insights into the efficient utilization of traditional medicine for preventing dementia. PMID- 25821477 TI - Electroacupuncture Treatment Improves Learning-Memory Ability and Brain Glucose Metabolism in a Mouse Model of Alzheimer's Disease: Using Morris Water Maze and Micro-PET. AB - Introduction. Alzheimer's disease (AD) causes progressive hippocampus dysfunctions leading to the impairment of learning and memory ability and low level of uptake rate of glucose in hippocampus. What is more, there is no effective treatment for AD. In this study, we evaluated the beneficial and protective effects of electroacupuncture in senescence-accelerated mouse prone 8 (SAMP8). Method. In the electroacupuncture paradigm, electroacupuncture treatment was performed once a day for 15 days on 7.5-month-old SAMP8 male mice. In the normal control paradigm and AD control group, 7.5-month-old SAMR1 male mice and SAMP8 male mice were grabbed and bandaged while electroacupuncture group therapy, in order to ensure the same treatment conditions, once a day, 15 days. Results. From the Morris water maze (MWM) test, we found that the treatment of electroacupuncture can improve the spatial learning and memory ability of SAMP8 mouse, and from the micro-PET test, we proved that after the electroacupuncture treatment the level of uptake rate of glucose in hippocampus was higher than normal control group. Conclusion. These results suggest that the treatment of electroacupuncture may provide a viable treatment option for AD. PMID- 25821478 TI - Protective effects of tao-Hong-si-wu decoction on memory impairment and hippocampal damage in animal model of vascular dementia. AB - Tao-Hong-Si-Wu decoction (TSD) as a traditional chinese medicine (TCM) has been developed to treat thrombotic diseases for hundreds of years, and vascular dementia (VD) is a cognitive dysfunction syndrome caused by cerebral embolism. In this study, the protective effect of TSD on memory impairment and brain damage in rat model of VD induced by middle cerebral artery occlusion (MCAO) was investigated. The study showed that rats in MCAO treatment with TSD for 14 days significantly improved behavioral function, increased densities of neuron, and induced angiogenesis in the brain compared with model rats. TSD also adjusted the neurotransmitter levels, reduced the content of endothelin-1 (ET-1), and induced the activities of vascular endothelial growth factor (VEGF) in hippocampus. Moreover, the immunohistochemical staining and western blotting results also revealed that TSD decreased apoptosis via upregulated B-cell lymphoma-2 (Bcl 2)/Bcl-2 associated X protein (Bax) ratio. These results demonstrated TSD possesses neuroprotective and antidementia properties by preventing the loss of neural cells, adjusting brain neurotransmitter, promoting cerebral blood circulation, and decreasing apoptosis. These results suggested that TSD might be developed as an effective drug for the prevention of VD. PMID- 25821479 TI - Dry Needling Related Short-Term Vasodilation in Chronic Sciatica under Infrared Thermovision. AB - Vasomotor responses to dry needling (DN) of trigger points (TrPs) under infrared thermovision (IRT) camera control and TrPs coexistence in chronic sciatica patients have never been studied. Materials and Methods. Fifty consecutive chronic sciatica patients were enrolled in the study. DN under IRT control was performed for all patients regardless of gluteus minimus (GM) active TrPs examination. Then, the vasomotor response and its agreement with TrPs examination were evaluated. Results. The prevalence of GM active TrPs was 32%. DN provokes intensive vasodilatation for TrPs-positive patients only, with the localization dependent on referred pain during the procedure (r = 0.896; P = 0.000) not the daily complaint. The increase of vasodilatation was, for example, for thigh, TrPs positive +30.29% (P < 0.05) versus TrPs-negative +4.08%. Additionally, a significant skin temperature increase was observed for TrPs-positive only, for example, thigh +1.5 +/- 1.3 degrees C (maximum) and +1.2 +/- 1.0 degrees C (average) (both P < 0.05). Conclusion. GM active TrPs prevalence among chronic sciatica patients was around one in three. Every TrPs-positive subject presented with vasodilatation under IRT in the area of DN related referred pain. Although TrPs involvement in chronic sciatica patients is possible, further studies on a bigger group of patients are still required. PMID- 25821480 TI - Chemical Constituents and an Alternative Medicinal Veterinary Herbal Soap Made from Senna macranthera. AB - Upon undergoing biomonitoring, the most active dichloromethane extract retrieved from Senna macranthera roots led to the isolation of three main compounds: emodine, physione, and chrysophanol. In this sequence, these compounds revealed a potential antibacterial activity against Staphylococcus aureus strains isolated from animals with mastitis infections with minimum inhibitory concentration (MIC) values of 20, 90, and 90 MUg mL(-1), respectively. Therefore, an herbal soap was also produced from this same active extract. This soap was tested in vitro using gloves contaminated by animals with bovine mastitis that had been discarded after use by milkers and showed similar results to previously tested compounds. These results indicate the potential of this plant as an alternative veterinary medicine for the production of antibacterial soaps that aimed at controlling bovine mastitis infections in small Brazilian farms. PMID- 25821481 TI - NaoXinTong Inhibits the Development of Diabetic Retinopathy in db/db Mice. AB - Buchang NaoXinTong capsule (NXT) is a Chinese Materia Medica standardized product extracted from 16 Chinese traditional medical herbs and widely used for treatment of patients with cerebrovascular and cardiovascular diseases in China. Formation of microaneurysms plays an important role in the development of diabetic retinopathy. In this study, we investigated if NXT can protect diabetic mice against the development of diabetic retinopathy. The db/db mice (~6 weeks old), a diabetic animal model, were divided into two groups and fed normal chow or plus NXT for 14 weeks. During the treatment, fasting blood glucose levels were monthly determined. After treatment, retinas were collected to determine retinal thickness, accumulation of carbohydrate macromolecules, and caspase-3 (CAS-3) expression. Our results demonstrate that administration of NXT decreased fasting blood glucose levels. Associated with the decreased glucose levels, NXT blocked the diabetes-induced shrink of multiple layers, such as photoreceptor layer and outer nuclear/plexiform layers, in the retina. NXT also inhibited the diabetes induced expression of CAS-3 protein and mRNA, MMP-2/9 and TNFalpha mRNA, accumulation of carbohydrate macromolecules, and formation of acellular capillaries in the retina. Taken together, our study shows that NXT can inhibit the development of diabetic retinopathy and suggests a new potential application of NXT in clinic. PMID- 25821483 TI - Korean studies on blood stasis: an overview. AB - Blood stasis is one of the important pathological concepts in Korean medicine. We analyzed the Korean studies concerning blood stasis. We searched for articles in eight electronic databases from their inception to September, 2014. We included reviews, clinical studies, and preclinical studies that had studied blood stasis and excluded articles in which blood stasis was not mentioned or in which the original authors had not explained blood stasis. Of 211 total included studies, 19 were reviews, 52 were clinical studies, and 140 were preclinical articles. "Stagnant blood within the body" was the most frequently mentioned phrase of the traditional concept of blood stasis. Traumatic injury was the most frequently studied disease/condition in the clinical studies. In the preclinical studies, coagulopathy was studied most frequently, followed by hyperviscosity, hyperlipidemia, inflammation, neoplasm, ischemic brain injury, and atherosclerosis. Hyeolbuchukeo-tang and Angelicae Gigantis Radix were the most frequent formula and single herb, respectively, used in the blood stasis researches. The results showed that blood stasis was mainly recognized as disorder of circulation and many studies showed the effectiveness of activating blood circulating herbs for diseases and pathologies such as traumatic injury or coagulopathy. Further studies are needed in the pathologic mechanisms and various diseases of blood stasis. PMID- 25821482 TI - Survival of AIDS patients treated with traditional chinese medicine in rural central china: a retrospective cohort study, 2004-2012. AB - This study aimed to explore the survival of AIDS patients treated with traditional Chinese medicine (TCM) in addition to combined antiretroviral therapy (cART) and of AIDS patients treated with cART. Data of patients taking cART between 30 October 2003 and 30 October 2004 in the National TCM HIV Treatment Trial Program area were retrospectively analyzed, with follow-up from 30 October 2004 to 30 October 2012. The log-rank test was used to compare survival between the two groups. A Cox proportional hazards model was used to determine hazard ratios to identify prognostic factors. The study included 521 patients in the TCM + cART group followed up for 3548 person-years and 375 patients in the cART group followed up for 2523 person-years. Mortality rates were 3.2/100 person-years and 4.2/100 person-years in the TCM + cART and cART groups, respectively. The difference in survival was significant. After adjusting for explanatory variables, the mortality rate of AIDS patients in the cART group was 1.7 times higher than in the TCM + cART group. Male sex, older age, little education, and lower CD4 cell count were risk factors for mortality. TCM intervention in addition to cART could increase survival of AIDS patients. PMID- 25821484 TI - Pharmacogenomics and herb-drug interactions: merge of future and tradition. AB - The worldwide using of herb products and the increasing potential herb-drug interaction issue has raised enthusiasm on discovering the underlying mechanisms. Previous review indicated that the interactions may be mediated by metabolism enzymes and transporters in pharmacokinetic pathways. On the other hand, an increasing number of studies found that genetic variations showed some influence on herb-drug interaction effects whereas these genetic factors did not draw much attention in history. We highlight that pharmacogenomics may involve the pharmacokinetic or pharmacodynamic pathways to affect herb-drug interaction. We are here to make an updated review focused on some common herb-drug interactions in association with genetic variations, with the aim to help safe use of herbal medicines in different individuals in the clinic. PMID- 25821485 TI - Acupuncture for low back pain: an overview of systematic reviews. AB - Objective. As evidence of the effectiveness of acupuncture for low back pain (LBP) is inconsistent, we aimed to critically appraise the evidence from relevant systematic reviews. Methods. Systematic reviews of randomized controlled trials (RCTs) concerning acupuncture and LBP were searched in seven databases. Internal validity and external validity of systematic reviews were assessed. Systematic reviews were categorized and high quality reviews assigned greater weightings. Conclusions were generated from a narrative synthesis of the outcomes of subgroup comparisons. Results. Sixteen systematic reviews were appraised. Overall, the methodological quality was low and external validity weak. For acute LBP, evidence that acupuncture has a more favorable effect than sham acupuncture in relieving pain was inconsistent; it had a similar effect on improving function. For chronic LBP, evidence consistently demonstrated that acupuncture provides short-term clinically relevant benefits for pain relief and functional improvement compared with no treatment or acupuncture plus another conventional intervention. Conclusion. Systematic reviews of variable quality showed that acupuncture, either used in isolation or as an adjunct to conventional therapy, provides short-term improvements in pain and function for chronic LBP. More efforts are needed to improve both internal and external validity of systematic reviews and RCTs in this area. PMID- 25821486 TI - Connectivity Study of the Neuromechanism of Acute Acupuncture Needling during fMRI in "Overweight" Subjects. AB - This functional connectivity study depicts how acupoints ST 36 and SP 9 and their sham acupoints acutely act on blood glucose (GLU), core body temperature (CBT), hunger, and sensations pertaining to needling (De-qi) via the limbic system and dopamine (DA) to affect various brain areas in fasting, adult, and "overweight" Chinese males using functional magnetic resonance imaging. Functional connectivity (FC) analysis utilized the amygdala (AMY) and hypothalamus (HYP) as regions of interest (ROIs) in the discrete cosine transform and seed correlation analysis methods. There was a significant difference in the spatial patterns of the distinct brain regions between groups. Correlation results showed that increased HYP-hippocampus FC after ACU was positively correlated with ACU-induced change in CBT; increased HYP-putamen-insula FC after ACU was positively correlated with ACU-induced change in GLU; and increased HYP-anterior cingulate cortex FC after ACU was positively correlated with ACU-induced change in HUNGER suggesting that increased DA modulation during ACU was probably associated with increased poststimulation limbic system and spinothalamic tract connectivity. Decreased HYP-thalamus FC after ACU was negatively correlated or anticorrelated with ACU-induced change in HUNGER suggesting that increased DA modulation during ACU was possibly associated with decreased poststimulation limbic system and spinothalamic tract connectivity. No correlation was found for min SHAM. This was an important study in addressing acute acupuncture effects and neural pathways involving physiology and appetite regulation in overweight individuals. PMID- 25821487 TI - Classic and Modern Meridian Studies: A Review of Low Hydraulic Resistance Channels along Meridians and Their Relevance for Therapeutic Effects in Traditional Chinese Medicine. AB - Meridian theory is one of the core components of the theory of traditional Chinese medicine (TCM). It gives an integral explanation for how human life works, how a disease forms, and how a therapy acts to treat a disease. If we do not understand the meridians, it is hard to understand the TCM. People in China and abroad had been working hard for 50 years, trying to understand the meridians; then 15 years ago a breakthrough idea appeared when we realized that they are low resistance fluid channels where various chemical and physical transports take place. The channel is called low hydraulic resistance channel (LHRC) and the chemical transport is named volume transmission (VT). This review aims to give a full understanding of the essence of meridian and its works on the therapies of TCM. PMID- 25821488 TI - Possible Involvement of u Opioid Receptor in the Antidepressant-Like Effect of Shuyu Formula in Restraint Stress-Induced Depression-Like Rats. AB - Recently MU opioid receptor (MOR) has been shown to be closely associated with depression. Here we investigated the action of Shuyu, a Chinese herbal prescription, on repeated restraint stress induced depression-like rats, with specific attention to the role of MOR and the related signal cascade. Our results showed that repeated restraint stress caused significant depressive-like behaviors, as evidenced by reduced body weight gain, prolonged duration of immobility in forced swimming test, and decreased number of square-crossings and rearings in open field test. The stress-induced depression-like behaviors were relieved by Shuyu, which was accompanied by decreased expression of MOR in hippocampus. Furthermore, Shuyu upregulated BDNF protein expression, restored the activity of CREB, and stimulated MEK and ERK phosphorylation in hippocampus of stressed rats. More importantly, MOR is involved in the effects of Shuyu on these depression-related signals, as they can be strengthened by MOR antagonist CTAP. Collectively, these data indicated that the antidepressant-like properties of Shuyu are associated with MOR and the corresponding CREB, BDNF, MEK, and ERK signal pathway. Our study supports clinical use of Shuyu as an effective treatment of depression and also suggests that MOR might be a target for treatment of depression and developing novel antidepressants. PMID- 25821490 TI - Catalpol Modulates Lifespan via DAF-16/FOXO and SKN-1/Nrf2 Activation in Caenorhabditis elegans. AB - Catalpol is an effective component of rehmannia root and known to possess various pharmacological properties. The present study was aimed at investigating the potential effects of catalpol on the lifespan and stress tolerance using C. elegans model system. Herein, catalpol showed potent lifespan extension of wild type nematode under normal culture condition. In addition, survival rate of catalpol-fed nematodes was significantly elevated compared to untreated control under heat and oxidative stress but not under hyperosmolality conditions. We also found that elevated antioxidant enzyme activities and expressions of stress resistance proteins were attributed to catalpol-mediated increased stress tolerance of nematode. We further investigated whether catalpol's longevity effect is related to aging-related factors including reproduction, food intake, and growth. Interestingly, catalpol exposure could attenuate pharyngeal pumping rate, indicating that catalpol may induce dietary restriction of nematode. Moreover, locomotory ability of aged nematode was significantly improved by catalpol treatment, while lipofuscin levels were attenuated, suggesting that catalpol may affect age-associated changes of nematode. Our mechanistic studies revealed that mek-1, daf-2, age-1, daf-16, and skn-1 are involved in catalpol mediated longevity. These results indicate that catalpol extends lifespan and increases stress tolerance of C. elegans via DAF-16/FOXO and SKN-1/Nrf activation dependent on insulin/IGF signaling and JNK signaling. PMID- 25821489 TI - Novel Mechanisms of Herbal Therapies for Inhibiting HMGB1 Secretion or Action. AB - High mobility group box 1 (HMGB1) is an evolutionarily conserved protein and is constitutively expressed in virtually all types of cells. In response to microbial infections, HMGB1 is secreted from activated immune cells to orchestrate rigorous inflammatory responses. Here we review the distinct mechanisms by which several herbal components inhibit HMGB1 action or secretion, such as by modulating inflammasome activation, autophagic degradation, or endocytic uptake. In light of the reciprocal interactions between these cellular processes, it is possible to develop more effective combinational herbal therapies for the clinical management of inflammatory diseases. PMID- 25821491 TI - Hepatoprotective Effect of Silymarin (Silybum marianum) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats. AB - This study was aimed to investigate the effect of Silymarin (SLM) on the hypertension state and the liver function changes induced by acetaminophen (APAP) in spontaneously hypertensive rat (SHR). Animals normotensive (N) or hypertensive (SHR) were treated or not with APAP (3 g/kg, oral) or previously treated with SLM. Twelve hours after APAP administration, plasmatic levels of liver function markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), gamma glutamyl transferase (gamma-GT), and alkaline phosphatase (ALP) of all groups, were determined. Liver injury was assessed using histological studies. Samples of their livers were then used to determine the myeloperoxidase (MPO) activity and nitric oxide (NO) production and were also sectioned for histological analysis. No differences were observed for ALT, gamma GT, and GLU levels between SHR and normotensive rats groups. However, AST and ALP levels were increased in hypertensive animals. APAP treatment promoted an increase in ALT and AST in both SHR and N. However, only for SHR, gamma-GT levels were increased. The inflammatory response evaluated by MPO activity and NO production showed that SHR was more susceptible to APAP effect, by increasing leucocyte infiltration. Silymarin treatment (Legalon) restored the hepatocyte functional and histopathological alterations induced by APAP in normotensive and hypertensive animals. PMID- 25821492 TI - Inhibitory Effects of Chemical Compounds Isolated from the Rhizome of Smilax glabra on Nitric Oxide and Tumor Necrosis Factor- alpha Production in Lipopolysaccharide-Induced RAW264.7 Cell. AB - The rhizome of Smilax glabra has been used for a long time as both food and folk medicine in many countries. The present study focused on the active constituents from the rhizome of S. glabra, which possess potential anti-inflammatory activities. As a result, nine known compounds were isolated from the rhizome of S. glabra with the bioassay-guiding, and were identified as syringaresinol (1), lasiodiplodin (2), de-O-methyllasiodiplodin (3), syringic acid (4), 1,4-bis(4 hydroxy-3,5-dimethoxyphenyl)-2,3-bis(hydroxymethyl)-1,4-butanediol (5), lyoniresinol (6), trans-resveratrol (7), trans-caffeic acid methyl ester (8), and dihydrokaempferol (9). Among these compounds, 2 and 3 were isolated for the first time from S. glabra. In addition, the potential anti-inflammatory activities of the isolated compounds were evaluated in vitro in lipopolysaccharide- (LPS-) induced RAW264.7 cells. Results indicated that 4 and 7 showed significant inhibitory effects on NO production of RAW264.7 cells, and 1, 2, 3, and 5 showed moderate suppression effects on induced NO production. 1, 7, and 5 exhibited high inhibitory effects on TNF-alpha production, with the IC50 values less than 2.3, 4.4, and 16.6 MUM, respectively. These findings strongly suggest that compounds 1, 2, 3, 4, 5, 7, and 9 were the potential anti-inflammatory active compositions of S. glabra. PMID- 25821493 TI - The effect of electroacupuncture with different frequencies on muscle oxygenation in humans. AB - The aim of the present study was to investigate the effect of electroacupuncture (EA) with different frequencies on muscle oxygenation in humans. The subjects were 8 healthy male volunteers. Muscle oxygenation was measured using near infrared spectroscopy (NIRS). Blood pressure (BP) and heart rate (HR) were monitored simultaneously. After baseline recording, EA was given for 15 min and recovery was measured for 20 minutes. The procedure of EA at 1 Hz, at 20 Hz, and at control followed in the same subjects. Tissue oxygenation index (TOI) decreased during EA at 20 Hz (P < 0.05) and increased during the recovery period. Normalized tissue hemoglobin index (nTHI) also decreased during EA at 20 Hz and increased during the recovery period (P < 0.05), whereas TOI and nTHI in the EA at 1 Hz did not change significantly throughout the experiment. The peak TOI and nTHI values at 20 Hz during the recovery period were higher than the values at 1 Hz and in the control (P < 0.05). BP and HR remained constant. These data suggest that the supply of oxygen to muscle decreased during EA at 20 Hz and increased after EA at 20 Hz, without any changes in HR and BP. PMID- 25821494 TI - Antinociceptive Effect of the Essential Oil Obtained from the Leaves of Croton cordiifolius Baill. (Euphorbiaceae) in Mice. AB - Croton cordiifolius Baill. is a shrub known as "quebra-faca" and is used to treat inflammation, pain, wounds, and gastrointestinal disturbances in the semiarid region in the northeast of Brazil. In an ethnobotanical survey in the state of Pernambuco, "quebra-faca" use was cited in 33% of the interviews. Thus, we decided to evaluate the antinociceptive effects of the essential oil from C. cordiifolius (CcEO). Chemical analysis by gas chromatography-mass spectrometry revealed 1,8-cineole (25.09%) and alpha-phellandrene (15.43%) as major constituents. Antinociceptive activity was evaluated using murine models of chemically induced pain (writhing induced by acetic acid, formalin, capsaicin, and glutamate tests). Opioid and central nervous systems (CNS) involvement were also investigated. Regarding antinociceptive activity, CcEO (50 and 100 mg/kg) reduced the number of writhing responses induced by acetic acid and decreased the licking times in both phases of the formalin test. CcEO also was evaluated in capsaicin- and glutamate-induced nociception. While no effect was observed in the capsaicin test, CcEO (100 mg/kg) was effective in the glutamate test. Naloxone, an opioid antagonist, did not affect the antinociceptive activity of CcEO in writhing test. In conclusion, the antinociceptive effect of CcEO could be explained, at least in part, by inhibition of the glutamatergic system. PMID- 25821495 TI - Maslinic Acid enhances signals for the recruitment of macrophages and their differentiation to m1 state. AB - The inflammatory process is involved in the genesis and evolution of different diseases like obesity, cardiovascular disease, and cancer. Macrophages play a central role in inflammation. In addition, they can regulate some stages of cancer development. Macrophages can polarize into M1 or M2 functional phenotype depending on the cytokines present in the tissue microenvironment. On the other hand, triterpenes found in virgin olive oil are described to present different properties, such as antitumoral and anti-inflammatory activity. The present study was designed to elucidate if the four major triterpenes found in virgin olive oil (oleanolic acid, maslinic acid, uvaol, and erythrodiol) are able to enhance M1 macrophage response which represents an important defense mechanism against cancer. Our results indicated that maslinic acid modulated the inflammatory response by enhancing the production of IL-8, IL-1alpha, and IL-1beta; it promoted M1 response through the synthesis of IFN-gamma; and finally it did not modify significantly the levels of NFkappabeta or NO. Overall, our results showed that maslinic acid could prevent chronic inflammation, which represents a crucial step in the development of some cancers. PMID- 25821496 TI - Xueshuan Xinmaining Tablet Treats Blood Stasis through Regulating the Expression of F13a1, Car1, and Tbxa2r. AB - Xueshuan Xinmaining Tablet (XXT), the Chinese formula, has long been administered in clinical practice for the treatment of cerebral thrombosis and coronary heart disease. In this study, we aimed to study the effect and the molecular mechanism of activating blood circulation and removing blood stasis. Rat models of cold coagulation blood stasis were induced with ice-water bath and epinephrine to assess the amelioration of blood stasis by XXT. Microarray technique was used to identify gene expression from the model and XXT-treated rats. In addition, Quantitative Real-Time PCR (qPCR) was performed to verify the microarray results. The results showed that XXT had a good therapeutic effect on blood stasis by reducing the whole blood viscosity (WBV), plasma viscosity (PV), increasing PT, APTT and TT, and by inhibiting platelet aggregation. Genes were differentially expressed in rats among the model group and the XXT-pretreated groups. XXT ameliorated blood stasis by regulating the expressions of F13a1, Car1, and Tbxa2r. PMID- 25821497 TI - Evaluation of Antiradical and Anti-Inflammatory Activities of Ethyl Acetate and Butanolic Subfractions of Agelanthus dodoneifolius (DC.) Polhill & Wiens (Loranthaceae) Using Equine Myeloperoxidase and Both PMA-Activated Neutrophils and HL-60 Cells. AB - The ethyl acetate and n-butanolic subfractions of Agelanthus dodoneifolius were investigated for their antioxidant and antimyeloperoxidase (MPO) activities. The reactive oxygen species (ROS) generation was assessed by lucigenin-enhanced chemiluminescence (CL) and dichlorofluorescein- (DCF-) induced fluorescence techniques from phorbol myristate acetate- (PMA-) stimulated equine neutrophils and human myeloid cell line HL-60, respectively. In parallel, the effects of the tested subfractions were evaluated on the total MPO release by stimulated neutrophils and on the specific MPO activity by means of immunological assays. The results showed the potent activity of the butanolic subfraction, at least in respect of the chemiluminescence test (IC50 = 0.3 +/- 0.1 ug/mL) and the ELISA and SIEFED assays (IC50 = 2.8 +/- 1.2 ug/mL and 1.3 +/- 1.0 ug/mL), respectively. However, the ethyl acetate subfraction was found to be the most potent in the DCF assay as at the highest concentration, DCF fluorescence intensity decreases of about 50%. Moreover, we demonstrated that the ethyl acetate subfraction was rich in catechin (16.51%) while it was not easy to identify the main compounds in the butanolic subfraction using the UPLC-MS/MS technique. Nevertheless, taken together, our results provide evidence that Agelanthus dodoneifolius subfractions may represent potential sources of natural antioxidants and of antimyeloperoxidase compounds. PMID- 25821498 TI - Effects of Electroacupuncture with Dominant Frequency at SP 6 and ST 36 Based on Meridian Theory on Pain-Depression Dyad in Rats. AB - Epidemic investigations reveal an intimate interrelationship between pain and depression. The effect of electroacupuncture (EA) on pain or depression has been demonstrated individually, but its effect on pain-depression dyad is unknown. Our study aimed to screen a dominant EA frequency on pain-depression dyad and determine the validity of acupoint selection based on meridian theory. The pain depression dyad rat model was induced by reserpine and treated using EA with different frequencies at identical acupoints to extract a dominant frequency and then administrated dominant-frequency EA at different acupoints in the above models. Paw withdrawal latency (PWL), emotional behavior of elevated zero maze (EZM) test, and open field (OF) test were conducted. We found that 100 Hz EA at Zusanli (ST 36) and Sanyinjiao (SP 6) (classical acupoints for spleen-deficiency syndrome) were the most effective in improving PWL, travelling distance in the EZM, and maximum velocity in OF compared to EA with other frequencies; ST 36 and SP 6 were proved more effective than other acupoints beyond the meridian theory and nonacupoints under the same administration of EA. Therefore, we concluded that 100 Hz is the dominant frequency for treating the pain-depression dyad with EA, and acupoints on spleen and stomach meridians are preferable choices. PMID- 25821499 TI - A network-based approach to investigate the pattern of syndrome in depression. AB - In Traditional Chinese Medicine theory, syndrome is essential to diagnose diseases and treat patients, and symptom is the foundation of syndrome differentiation. Thus the combination and interaction between symptoms represent the pattern of syndrome at phenotypic level, which can be modeled and analyzed using complex network. At first, we collected inquiry information of 364 depression patients from 2007 to 2009. Next, we learned classification models for 7 syndromes in depression using naive Bayes, Bayes network, support vector machine (SVM), and C4.5. Among them, SVM achieves the highest accuracies larger than 0.9 except for Yin deficiency. Besides, Bayes network outperforms naive Bayes for all 7 syndromes. Then key symptoms for each syndrome were selected using Fisher's score. Based on these key symptoms, symptom networks for 7 syndromes as well as a global network for depression were constructed through weighted mutual information. Finally, we employed permutation test to discover dynamic symptom interactions, in order to investigate the difference between syndromes from the perspective of symptom network. As a result, significant dynamic interactions were quite different for 7 syndromes. Therefore, symptom networks could facilitate our understanding of the pattern of syndrome and further the improvement of syndrome differentiation in depression. PMID- 25821500 TI - Complex networks approach for analyzing the correlation of traditional chinese medicine syndrome evolvement and cardiovascular events in patients with stable coronary heart disease. AB - This is a multicenter prospective cohort study to analyze the correlation of traditional Chinese medicine (TCM) syndrome evolvement and cardiovascular events in patients with stable coronary heart disease (CHD). The impact of syndrome evolvement on cardiovascular events during the 6-month and 12-month follow-up was analyzed using complex networks approach. Results of verification using Chi square test showed that the occurrence of cardiovascular events was positively correlated with syndrome evolvement when it evolved from toxic syndrome to Qi deficiency, blood stasis, or sustained toxic syndrome, when it evolved from Qi deficiency to blood stasis, toxic syndrome, or sustained Qi deficiency, and when it evolved from blood stasis to Qi deficiency. Blood stasis, Qi deficiency, and toxic syndrome are important syndrome factors for stable CHD. There are positive correlations between cardiovascular events and syndrome evolution from toxic syndrome to Qi deficiency or blood stasis, from Qi deficiency to blood stasis, or toxic syndrome and from blood stasis to Qi deficiency. These results indicate that stable CHD patients with pathogenesis of toxin consuming Qi, toxin leading to blood stasis, and mutual transformation of Qi deficiency and blood stasis are prone to recurrent cardiovascular events. PMID- 25821501 TI - Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice. AB - Xuebijing (XBJ) injection, a traditional Chinese medicine, has been reported as a promising approach in the treatment of sepsis in China. However, its actual molecular mechanisms in sepsis-induced lung injury are yet unknown. Therefore, this study aimed to investigate the beneficial effects of XBJ on inflammation and the underlying mechanisms in a model of caecal ligation and puncture-(CLP-) induced lung injury. The mice were divided into CLP group, CLP+XBJ group (XBJ, 4 mL/kg per 12 hours), and sham group. The molecular and histological examinations were performed on the lung, serum, and bronchoalveolar lavage (BAL) fluid samples of mice at the points of 6, 24, and 48 hours after CLP. The results show that XBJ reduces morphological destruction and neutrophil infiltration in the alveolar space and lung wet/dry weight ratio, which improves mortality of CLP-induced lung injury. Meanwhile, XBJ treatment downregulates high mobility group box protein 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) expression, as well as neutrophil counts, production of IL-1beta, IL-6, and TNF-alpha in the BAL fluids. In conclusion, these results indicate that XBJ may reduce the mortality through inhibiting proinflammatory cytokines secretion mediated by HMGB1/RAGE axis. PMID- 25821502 TI - Effects of abnormal savda munzip on the proliferation activity and migration ability of fibroblasts derived from hypertrophic scar in vitro. AB - Background. To explore the effect of ASMq on proliferation and migration ability of the fibroblast derived from HS of donor (HSFbs) in vitro. Methods. The HSFbs were cultured from tissue specimens and passaged to the 3~4 generation, which were treated with the different concentrations of ASMq and 5-Fu from 1 to 11 days. The difference of HSFbs proliferation activity was analyzed by the CCK-8 method. The HSFbs migration ability in ASMq (0.4 mg/mL) was analyzed by the Cell Scratch method. Results. Transmission electron microscope result shows ASMq concentration significantly increases and fibroblast cell structure markedly change in the experimental group. The proliferation activity of the HSFbs was obviously weakened in ASMq groups than those of the group A (P < 0.05) at seven days. The group C (0.4 mg/mL) is better suitable than other three ASMq treatment groups. Cell Migration Assay shows that the migration ability HSFbs was significantly reduced in ASMq (0.4 mg/mL) treatment group compared with those of blank control group at both 24 h and 48 h (P < 0.05). Conclusions. These results suggest that ASMq effectively restrains the proliferation and migration ability of the HTSFbs in vitro, which can be one of the mechanisms for the prevention and treatment of HS. PMID- 25821503 TI - The Effect of Essential Oils and Bioactive Fractions on Streptococcus mutans and Candida albicans Biofilms: A Confocal Analysis. AB - The essential oils (EO) and bioactive fractions (BF) from Aloysia gratissima, Baccharis dracunculifolia, Coriandrum sativum, Cyperus articulatus, and Lippia sidoides were proven to have strong antimicrobial activity on planktonic microorganisms; however, little is known about their effects on the morphology or viability of oral biofilms. Previously, we determined the EO/fractions with the best antimicrobial activity against Streptococcus mutans and Candida spp. In this report, we used a confocal analysis to investigate the effect of these EO and BF on the morphology of S. mutans biofilms (thickness, biovolume, and architecture) and on the metabolic viability of C. albicans biofilms. The analysis of intact treated S. mutans biofilms showed no statistical difference for thickness in all groups compared to the control. However, a significant reduction in the biovolume of extracellular polysaccharides and bacteria was observed for A. gratissima and L. sidoides groups, indicating that these BF disrupt biofilm integrity and may have created porosity in the biofilm. This phenomenon could potentially result in a weakened structure and affect biofilm dynamics. Finally, C. sativum EO drastically affected C. albicans viability when compared to the control. These results highlight the promising antimicrobial activity of these plant species and support future translational research on the treatment of dental caries and oral candidiasis. PMID- 25821504 TI - Self-reported efficacy of cannabis and other complementary medicine modalities by Parkinson's disease patients in colorado. AB - Introduction. Complementary and alternative medicine (CAM) is frequently used by Parkinson's disease (PD) patients. We sought to provide information on CAM use and efficacy in PD patients in the Denver metro area with particular attention to cannabis use given its recent change in legal status. Methods. Self-administered surveys on CAM use and efficacy were completed by PD patients identified in clinics and support groups across the Denver metro area between 2012 and 2013. Results. 207 patients (age 69 +/- 11; 60% male) completed the survey. Responses to individual CAM therapy items showed that 85% of respondents used at least one form of CAM. The most frequently reported CAMs were vitamins (66%), prayer (59%), massage (45%), and relaxation (32%). Self-reported improvement related to the use of CAM was highest for massage, art therapy, music therapy, and cannabis. While only 4.3% of our survey responders reported use of cannabis, it ranked among the most effective CAM therapies. Conclusions. Overall, our cross-sectional study was notable for a high rate of CAM utilization amongst PD patients and high rates of self-reported efficacy across most CAM modalities. Cannabis was rarely used in our population but users reported high efficacy, mainly for nonmotor symptoms. PMID- 25821505 TI - Effect of da-cheng-qi decoction on pancreatitis-associated intestinal dysmotility in patients and in rat models. AB - The impairment of intestinal motility and related infectious complications are the predominant clinical phenomenon in patients with severe acute pancreatitis (SAP). We aimed to investigate the effects of Da-Cheng-Qi decoction (DCQD) on the gastrointestinal injury in SAP patients and the potential mechanism involved in rats. DCQD was enema administered to 70 patients for 7 days in West China Hospital. Mortality and organ failure during admission were observed and blood samples for laboratory analysis were collected. We also experimentally examined plasma inflammatory cytokines in rat serum and carried the morphometric studies of the gut. Intestinal propulsion index and serum and tissue vasoactive intestinal peptide (VIP) were also detected. Though DCQD did not affect the overall incidence of organ failure, it shortened the average time of paralytic intestinal obstruction and decreased the morbidity of infectious complications in patients with SAP. Compared with untreated rats, the DCQD lowered the levels of proinflammatory cytokine and decreased the mean pathological intestinal lesion scores. The VIP level in intestinal tissue or serum in DCQD group was obviously lowered and intestinal propulsion index was significantly improved. In conclusion, DCQD has good effect on pancreatitis-associated intestinal dysmotility in patients and in rat models. PMID- 25821506 TI - Tinospora crispa Ameliorates Insulin Resistance Induced by High Fat Diet in Wistar Rats. AB - The antidiabetic properties of Tinospora crispa, a local herb that has been used in traditional Malay medicine and rich in antioxidant, were explored based on obesity-linked insulin resistance condition. Male Wistar rats were randomly divided into four groups, namely, the normal control (NC) which received standard rodent diet, the high fat diet (HFD) which received high fat diet only, the high fat diet treated with T. crispa (HFDTC), and the high fat diet treated with orlistat (HFDO). After sixteen weeks of treatment, blood and organs were harvested for analyses. Results showed that T. crispa significantly (p < 0.05) reduced the body weight (41.14 +/- 1.40%), adiposity index serum levels (4.910 +/ 0.80%), aspartate aminotransferase (AST: 161 +/- 4.71 U/L), alanine aminotransferase (ALT: 100.95 +/- 3.10 U/L), total cholesterol (TC: 18.55 +/- 0.26 mmol/L), triglycerides (TG: 3.70 +/- 0.11 mmol/L), blood glucose (8.50 +/- 0.30 mmo/L), resistin (0.74 +/- 0.20 ng/mL), and leptin (17.428 +/- 1.50 ng/mL) hormones in HFDTC group. The insulin (1.65 +/- 0.07 pg/mL) and C-peptide (136.48 pmol/L) hormones were slightly decreased but within normal range. The histological results showed unharmed and intact liver tissues in HFDTC group. As a conclusion, T. crispa ameliorates insulin resistance-associated with obesity in Wistar rats fed with high fat diet. PMID- 25821507 TI - Windowed multitaper correlation analysis of multimodal brain monitoring parameters. AB - Although multimodal monitoring sets the standard in daily practice of neurocritical care, problem-oriented analysis tools to interpret the huge amount of data are lacking. Recently a mathematical model was presented that simulates the cerebral perfusion and oxygen supply in case of a severe head trauma, predicting the appearance of distinct correlations between arterial blood pressure and intracranial pressure. In this study we present a set of mathematical tools that reliably detect the predicted correlations in data recorded at a neurocritical care unit. The time resolved correlations will be identified by a windowing technique combined with Fourier-based coherence calculations. The phasing of the data is detected by means of Hilbert phase difference within the above mentioned windows. A statistical testing method is introduced that allows tuning the parameters of the windowing method in such a way that a predefined accuracy is reached. With this method the data of fifteen patients were examined in which we found the predicted correlation in each patient. Additionally it could be shown that the occurrence of a distinct correlation parameter, called scp, represents a predictive value of high quality for the patients outcome. PMID- 25821508 TI - Knowledge mining from clinical datasets using rough sets and backpropagation neural network. AB - The availability of clinical datasets and knowledge mining methodologies encourages the researchers to pursue research in extracting knowledge from clinical datasets. Different data mining techniques have been used for mining rules, and mathematical models have been developed to assist the clinician in decision making. The objective of this research is to build a classifier that will predict the presence or absence of a disease by learning from the minimal set of attributes that has been extracted from the clinical dataset. In this work rough set indiscernibility relation method with backpropagation neural network (RS-BPNN) is used. This work has two stages. The first stage is handling of missing values to obtain a smooth data set and selection of appropriate attributes from the clinical dataset by indiscernibility relation method. The second stage is classification using backpropagation neural network on the selected reducts of the dataset. The classifier has been tested with hepatitis, Wisconsin breast cancer, and Statlog heart disease datasets obtained from the University of California at Irvine (UCI) machine learning repository. The accuracy obtained from the proposed method is 97.3%, 98.6%, and 90.4% for hepatitis, breast cancer, and heart disease, respectively. The proposed system provides an effective classification model for clinical datasets. PMID- 25821509 TI - A sparse representation based method to classify pulmonary patterns of diffuse lung diseases. AB - We applied and optimized the sparse representation (SR) approaches in the computer-aided diagnosis (CAD) to classify normal tissues and five kinds of diffuse lung disease (DLD) patterns: consolidation, ground-glass opacity, honeycombing, emphysema, and nodule. By using the K-SVD which is based on the singular value decomposition (SVD) and orthogonal matching pursuit (OMP), it can achieve a satisfied recognition rate, but too much time was spent in the experiment. To reduce the runtime of the method, the K-Means algorithm was substituted for the K-SVD, and the OMP was simplified by searching the desired atoms at one time (OMP1). We proposed three SR based methods for evaluation: SR1 (K-SVD+OMP), SR2 (K-Means+OMP), and SR3 (K-Means+OMP1). 1161 volumes of interest (VOIs) were used to optimize the parameters and train each method, and 1049 VOIs were adopted to evaluate the performances of the methods. The SR based methods were powerful to recognize the DLD patterns (SR1: 96.1%, SR2: 95.6%, SR3: 96.4%) and significantly better than the baseline methods. Furthermore, when the K-Means and OMP1 were applied, the runtime of the SR based methods can be reduced by 98.2% and 55.2%, respectively. Therefore, we thought that the method using the K Means and OMP1 (SR3) was efficient for the CAD of the DLDs. PMID- 25821511 TI - Method for detecting core malware sites related to biomedical information systems. AB - Most advanced persistent threat attacks target web users through malicious code within landing (exploit) or distribution sites. There is an urgent need to block the affected websites. Attacks on biomedical information systems are no exception to this issue. In this paper, we present a method for locating malicious websites that attempt to attack biomedical information systems. Our approach uses malicious code crawling to rearrange websites in the order of their risk index by analyzing the centrality between malware sites and proactively eliminates the root of these sites by finding the core-hub node, thereby reducing unnecessary security policies. In particular, we dynamically estimate the risk index of the affected websites by analyzing various centrality measures and converting them into a single quantified vector. On average, the proactive elimination of core malicious websites results in an average improvement in zero-day attack detection of more than 20%. PMID- 25821510 TI - Transmission dynamics of resistant bacteria in a predator-prey system. AB - This paper discusses the impact on human health caused by the addition of antibiotics in the feed of food animals. We use the established transmission rule of resistant bacteria and combine it with a predator-prey system to determine a differential equations model. The equations have three steady equilibrium points corresponding to three population dynamics states under the influence of resistant bacteria. In order to quantitatively analyze the stability of the equilibrium points, we focused on the basic reproduction numbers. Then, both the local and global stability of the equilibrium points were quantitatively analyzed by using essential mathematical methods. Numerical results are provided to relate our model properties to some interesting biological cases. Finally, we discuss the effect of the two main parameters of the model, the proportion of antibiotics added to feed and the predation rate, and estimate the human health impacts related to the amount of feed antibiotics used. We further propose an approach for the prevention of the large-scale spread of resistant bacteria and illustrate the necessity of controlling the amount of in-feed antibiotics used. PMID- 25821512 TI - Handling diagnosis of schizophrenia by a hybrid method. AB - Psychotics disorders, most commonly known as schizophrenia, have incapacitated professionals in different sectors of activities. Those disorders have caused damage in a microlevel to the individual and his/her family and in a macrolevel to the economic and production system of the country. The lack of early and sometimes very late diagnosis has provided reactive measures, when the professional is already showing psychological signs of incapacity to work. This study aims to help the early diagnosis of psychotics' disorders with a hybrid proposal of an expert system that is integrated to structured methodologies in decision support (multicriteria decision analysis: MCDA) and knowledge structured representations into production rules and probabilities (artificial intelligence: AI). PMID- 25821513 TI - Projecting the spatiotemporal carbon dynamics of the Greater Yellowstone Ecosystem from 2006 to 2050. AB - BACKGROUND: Climate change and the concurrent change in wildfire events and land use comprehensively affect carbon dynamics in both spatial and temporal dimensions. The purpose of this study was to project the spatial and temporal aspects of carbon storage in the Greater Yellowstone Ecosystem (GYE) under these changes from 2006 to 2050. We selected three emission scenarios and produced simulations with the CENTURY model using three General Circulation Models (GCMs) for each scenario. We also incorporated projected land use change and fire occurrence into the carbon accounting. RESULTS: The three GCMs showed increases in maximum and minimum temperature, but precipitation projections varied among GCMs. Total ecosystem carbon increased steadily from 7,942 gC/m2 in 2006 to 10,234 gC/m2 in 2050 with an annual rate increase of 53 gC/m2/year. About 56.6% and 27% of the increasing rate was attributed to total live carbon and total soil carbon, respectively. Net Primary Production (NPP) increased slightly from 260 gC/m2/year in 2006 to 310 gC/m2/year in 2050 with an annual rate increase of 1.22 gC/m2/year. Forest clear-cutting and fires resulted in direct carbon removal; however, the rate was low at 2.44 gC/m2/year during 2006-2050. The area of clear cutting and wildfires in the GYE would account for 10.87% of total forested area during 2006-2050, but the predictive simulations demonstrated different spatial distributions in national forests and national parks. CONCLUSIONS: The GYE is a carbon sink during 2006-2050. The capability of vegetation is almost double that of soil in terms of sequestering extra carbon. Clear-cutting and wildfires in GYE will affect 10.87% of total forested area, but direct carbon removal from clear cutting and fires is 109.6 gC/m2, which accounts for only 1.2% of the mean ecosystem carbon level of 9,056 gC/m2, and thus is not significant. PMID- 25821514 TI - Time Use as Cause and Consequence of Youth Development. AB - From an ecological perspective, daily activities are both causes and consequences of youth development. As causes, daily activities represent distinct sets of socialization experiences that afford opportunities to acquire new competencies and behavioral patterns. As consequences, daily activities reflect youth's force and resource characteristics, including developmental status, temperament and motivation, and pre-existing levels of adjustment. An ecological perspective also highlights the role of the larger sociocultural context in shaping and conditioning the links between daily activities and youth development. In this article, we draw on research with children and adolescents to consider how an ecological perspective can provide a flexible framework for studying time use as a developmental phenomenon. We also discuss methodological issues and suggest research that should be conducted in this broad area. PMID- 25821515 TI - Unpacking Self-Control. AB - Self-controlled behavior refers to actions aligned with valued, longer-term goals in the face of conflicting impulses to seek immediate gratification. In this article, we argue that the psychological processes that contribute to self controlled behavior can be grouped into two functionally distinct categories: Volitional processes facilitate self-controlled behavior and include executive functions as well as learned metacognitive strategies like planning, attention deployment, and psychological distancing. In contrast, impulsigenic processes undermine self-controlled behavior and include reward sensitivity, sensation seeking, and domain-specific cravings. A disproportionate amount of research has addressed the former at the expense of understanding individual and developmental differences in the latter. This imbalance is now being rectified. Distinguishing between self-controlled behavior and its antecedent psychological processes helps illuminate normative developmental changes in self-control and points to directions for measurement and intervention. PMID- 25821516 TI - Pupillary responses during a joint attention task are associated with nonverbal cognitive abilities and sub-clinical symptoms of autism. AB - Measures of pupillary dilation provide a temporally sensitive, quantitative indicator of cognitive resource allocation. The current study included 39 typically developing children between 3 and 9 years of age. Children completed a free-viewing task designed to elicit gaze following, a core deficit of Autism Spectrum Disorders (ASD). Results revealed a negative association between children's pupil dilation and a standardized measure of nonverbal intelligence, suggesting that children with lower intelligence allocated more cognitive resources than children with higher intelligence. In addition, the results revealed a negative association between pupil dilation and a parent-report measure of sub-clinical symptoms of ASD, suggesting that children with fewer ASD related symptoms allocated more cognitive resources than children who showed more sub-clinical symptoms of ASD. Both associations were independent of each other and could not be explained by variation in chronological age. These findings extend previous research demonstrating associations between basic aspects of visual processing and intelligence. In addition, these findings comport with recent theories of ASD that emphasize reduced sensitivity to the reward value of social situations. When confronted with social ambiguity, children with more ASD related symptoms allocated fewer cognitive resources to resolving this ambiguity than children who showed fewer sub-clinical symptoms of ASD. PMID- 25821518 TI - Phenotypic and genetic characterization of a family carrying two Xq21.1-21.3 interstitial deletions associated with syndromic hearing loss. AB - BACKGROUND: Sensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability. RESULTS: Clinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia. CONCLUSIONS: In this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved. PMID- 25821521 TI - Hypermutation takes the driver's seat. AB - Most pediatric tumors have only very few somatic mutations. However, a recent study revealed that a subset of tumors from children with congenital biallelic deficiency of DNA mismatch repair exhibits a mutational load surpassing almost all other cancers. In these ultra-hypermutated tumors, somatic mutations in the proofreading DNA polymerases complement the congenital mismatch repair deficiency to completely abolish replication repair, thereby driving tumor development. These findings open several possibilities for exploiting ultra-hypermutation for cancer therapy. PMID- 25821520 TI - Activation of an endogenous retrovirus-associated long non-coding RNA in human adenocarcinoma. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are emerging as molecules that significantly impact many cellular processes and have been associated with almost every human cancer. Compared to protein-coding genes, lncRNA genes are often associated with transposable elements, particularly with endogenous retroviral elements (ERVs). ERVs can have potentially deleterious effects on genome structure and function, so these elements are typically silenced in normal somatic tissues, albeit with varying efficiency. The aberrant regulation of ERVs associated with lncRNAs (ERV-lncRNAs), coupled with the diverse range of lncRNA functions, creates significant potential for ERV-lncRNAs to impact cancer biology. METHODS: We used RNA-seq analysis to identify and profile the expression of a novel lncRNA in six large cohorts, including over 7,500 samples from The Cancer Genome Atlas (TCGA). RESULTS: We identified the tumor-specific expression of a novel lncRNA that we have named Endogenous retroViral-associated ADenocarcinoma RNA or 'EVADR', by analyzing RNA-seq data derived from colorectal tumors and matched normal control tissues. Subsequent analysis of TCGA RNA-seq data revealed the striking association of EVADR with adenocarcinomas, which are tumors of glandular origin. Moderate to high levels of EVADR were detected in 25 to 53% of colon, rectal, lung, pancreas and stomach adenocarcinomas (mean = 30 to 144 FPKM), and EVADR expression correlated with decreased patient survival (Cox regression; hazard ratio = 1.47, 95% confidence interval = 1.06 to 2.04, P = 0.02). In tumor sites of non-glandular origin, EVADR expression was detectable at only very low levels and in less than 10% of patients. For EVADR, a MER48 ERV element provides an active promoter to drive its transcription. Genome-wide, MER48 insertions are associated with nine lncRNAs, but none of the MER48 associated lncRNAs other than EVADR were consistently expressed in adenocarcinomas, demonstrating the specific activation of EVADR. The sequence and structure of the EVADR locus is highly conserved among Old World monkeys and apes but not New World monkeys or prosimians, where the MER48 insertion is absent. Conservation of the EVADR locus suggests a functional role for this novel lncRNA in humans and our closest primate relatives. CONCLUSIONS: Our results describe the specific activation of a highly conserved ERV-lncRNA in numerous cancers of glandular origin, a finding with diagnostic, prognostic and therapeutic implications. PMID- 25821524 TI - A simple approach to hybrid inorganic-organic step-growth hydrogels with scalable control of physicochemical properties and biodegradability. AB - We prepared new and scalable, hybrid inorganic-organic step-growth hydrogels with polyhedral oligomeric silsesquioxane (POSS) network knot construction elements and hydrolytically degradable poly(ethylene glycol) (PEG) di-ester macromonomers by in situ radical-mediated thiol-ene photopolymerization. The physicochemical properties of the gels are fine-tailored over orders of magnitude including functionalization of their interior, a hierarchical gel structure, and biodegradability. PMID- 25821525 TI - International perspectives on the development of research-guided practice in community-based arts in health: Thinking the World of Arts in Health. PMID- 25821523 TI - High-risk alcohol use and anxiety and depression symptoms in adolescents and adults with type 1 diabetes mellitus: a cross-sectional study. AB - BACKGROUND: The medical literature shows that alcohol consumption is common among diabetic individuals and is associated with poor adherence to treatment, resulting in increased morbidity and mortality. However, no study has assessed the association between high-risk alcohol consumption and the presence of anxiety and depression in individuals with type 1 diabetes mellitus (1DM). METHODS: The present cross-sectional study was conducted in Uberlandia, Brazil, and it assessed 209 outpatients in relation to alcohol consumption and the presence of anxiety and depression symptoms, using the Alcohol Use Disorders Identification Test (AUDIT), the Hospital Anxiety and Depression (HAD) scale, and glycemic control, according to the levels of glycated hemoglobin (HbA1c). The chi-square test and logistic regression analysis were used to investigate the association between the investigated variables. RESULTS: The prevalence of high-risk alcohol consumption (AUDIT >= 8) among individuals with 1DM was high, specifically 24.9% among the entire group of subjects, 12.9% among the adolescents, 14.7% among the females, and 34.6% among the males. In comparisons based on gender and age, the odds of high-risk drinking were higher among males and participants aged 30 to 40 years (33.9%). The frequency of high-risk alcohol consumption did not differ as a function of gender among adolescents (females: 9.0%, males: 16.2%; p = 0.374). There was a linear trend in proportions related to the scores of anxiety and depression symptoms with high-risk alcohol consumption scores, indicating the association of these variables (p = 0.0229 and p = 0.0262, respectively). Moreover, the odds of female subjects exhibiting anxiety and depression symptoms were higher (odds ratio - OR: 4.4 and OR: 7.4, respectively). Glycemic control did not exhibit an association between high-risk alcohol consumption and the presence of anxiety and depression symptoms. CONCLUSIONS: The frequency of high risk drinking increased along with age and was greater among males; however, this frequency did not exhibit differences in terms of gender among adolescents. There was a positive association between high risk alcohol consumption and anxiety and depression symptoms, although glycemic control was inadequate in most of the sample independent of alcohol consumption and the presence of anxiety and depression symptoms. PMID- 25821526 TI - LED pumped polymer laser sensor for explosives. AB - A very compact explosive vapor sensor is demonstrated based on a distributed feedback polymer laser pumped by a commercial InGaN light-emitting diode. The laser shows a two-stage turn on of the laser emission, for pulsed drive currents above 15.7 A. The 'double-threshold' phenomenon is attributed to the slow rise of the ~30 ns duration LED pump pulses. The laser emits a 533 nm pulsed output beam of ~10 ns duration perpendicular to the polymer film. When exposed to nitroaromatic model explosive vapors at ~8 ppb concentration, the laser shows a 46% change in the surface-emitted output under optimized LED excitation. PMID- 25821527 TI - Polarized actin structural dynamics in response to cyclic uniaxial stretch. AB - Endothelial cell (EC) alignment to directional flow or stretch supports anti inflammatory functions, but mechanisms controlling polarized structural adaptation in response to physical cues remain unclear. This study aimed to determine whether factors associated with early actin edge ruffling implicated in cell polarization are prerequisite for stress fiber (SF) reorientation in response to cyclic uniaxial stretch. Time-lapse analysis of EGFP-actin in confluent ECs showed that onset of either cyclic uniaxial or equibiaxial stretch caused a non-directional increase in edge ruffling. Edge activity was concentrated in a direction perpendicular to the stretch axis after 60 min, consistent with the direction of SF alignment. Rho-kinase inhibition caused reorientation of both stretch-induced edge ruffling and SF alignment parallel to the stretch axis. Arp2/3 inhibition attenuated stretch-induced cell elongation and disrupted polarized edge dynamics and microtubule organizing center reorientation, but it had no effect on the extent of SF reorientation. Disrupting localization of p21-activated kinase (PAK) did not prevent stretch-induced SF reorientation, suggesting that this Rac effector is not critical in regulating stretch-induced cytoskeletal remodeling. Overall, these results suggest that directional edge ruffling is not a primary mechanism that guides SF reorientation in response to stretch; the two events are coincident but not causal. PMID- 25821528 TI - Efficacy of Extended Valganciclovir Prophylaxis in Preventing Cytomegalovirus Infection in Pediatric Kidney Transplantation. AB - Cytomegalovirus (CMV) is one of the most frequent opportunistic infection in renal transplant (RTx) recipients. Valganciclovir (VGC) has been showed to be safe and highly effective in prophylaxis of CMV infection in RTx recipients. Recently, an increase in delayed onset CMV disease has been noted with some arguing that longer prophylaxis may decrease the late-onset disease. We retrospectively tested the hypothesis that extended term prophylaxis (ETP) of VGC for 12 months is more effective than short term prophylaxis (STP) of 6 months in preventing CMV infection and disease in pediatric RTx performed at the University of Florida from July 2003 to December 2010. In this period, all recipients underwent prospective CMV PCR (Polymerase Chain Reaction) monitoring and were maintained on similar immunosuppression. Eighty six patients received RTx during that period. All eligible subjects had to have at least 12 months of graft survival and 18 months of follow up, leaving 73 eligible subjects in final study group. CMV infection or disease occurred in 6/29 (20%) in the STP group vs 6/44 (14%) in the ETP group with no statistical significant difference (P= 0.42). Donor positive/recipients negative CMV serology status (D+/R-) were associated with a higher risk of CMV infection in both univariate and multivariate analysis (P=0.01). Anemia and Leucopenia directly associated with VGC were similar in both groups (P=0.58 and P=0.2 respectively). Biopsy-proven acute rejection was also non-significant in both groups (P=0.39). Although ETP for CMV from 6 months to 12 months is safe and has minimal adverse effect, it did not reduce CMV infection or disease. Further controlled studies in pediatrics age group are considered to compare longer versus shorter periods of prophylaxis and their impact on prevention of CMV infection, resistance, cost, and toxicity. PMID- 25821529 TI - Awareness of Memory Ability and Change: (In)Accuracy of Memory Self-Assessments in Relation to Performance. AB - Little is known about subjective assessments of memory abilities and decline among middle-aged adults or their association with objective memory performance in the general population. In this study we examined self-ratings of memory ability and change in relation to episodic memory performance in two national samples of middle-aged and older adults from the Midlife in the United States study (MIDUS II in 2005-06) and the Health and Retirement Study (HRS; every two years from 2002 to 2012). MIDUS (Study 1) participants (N=3,581) rated their memory compared to others their age and to themselves five years ago; HRS (Study 2) participants (N=14,821) rated their current memory and their memory compared to two years ago, with up to six occasions of longitudinal data over ten years. In both studies, episodic memory performance was the total number of words recalled in immediate and delayed conditions. When controlling for demographic and health correlates, self-ratings of memory abilities, but not subjective change, were related to performance. We examined accuracy by comparing subjective and objective memory ability and change. More than one third of the participants across the studies had self-assessments that were inaccurate relative to their actual level of performance and change, and accuracy differed as a function of demographic and health factors. Further understanding of self-awareness of memory abilities and change beginning in midlife may be useful for identifying early warning signs of decline, with implications regarding policies and practice for early detection and treatment of cognitive impairment. PMID- 25821530 TI - Convergent Lines of Descent: Symptoms, Patterns, Constellations, and the Emergent Interface of Systems Biology and Chinese Medicine. AB - During the first decade of the twenty-first century, a network composed of politicians, regulators, bioscientists, clinical researchers, and Chinese medicine specialists has emerged that seeks to bridge an imagined gulf between the modern West and ancient China in order to create a new type of personalized medicine. The central building block of this bridge is the Chinese medical concept of zheng /, variously translated into English as syndrome, pattern, or type. My paper places side by side two different genealogies of how zheng assumed this central role. The first genealogy examines the process by means of which zheng came to be considered as something shared by both ancient China and cutting edge biological science and, by extension, how it manages to hold together the entire institutional, political, and economic framework into which this bridge is embedded and which it co-creates. The second genealogy shows zheng to be central to a much older series of redefinitions of Chinese medicine and Chinese medical practice that extend from the eleventh century to the present. Read together, these two genealogies-neither of which should be seen as exhaustive-raise three important issues that are further discussed in the conclusion of the paper. First, I explore how the concept of zheng has come to tie a medical tradition derided by its adversaries for being a pseudoscience to one of the most cutting edge fields of bioscience research. I ask what is at stake in this synthesis, for whom, and why, and how it transforms Chinese medicine and/or systems biology along the way. Second, I am interested in finding out how and why the very same concept can be at the heart of two apparently agonistic visions of Chinese medicine's future as it is popularly imagined in China today. Finally, I insist that the medical humanities need to become actively involved in the construction of emergent articulations such as the ones I am exploring. Merely writing a history of the present will not be productive unless its critique can somehow be articulated into the very processes of emergence that historians or anthropologists seek to examine. PMID- 25821531 TI - Exploring a Culturally Relevant Model of Cancer Prevention Involving Traditional Chinese Medicine Providers in a Chinese American Community. AB - INTRODUCTION: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in all racial and ethnic groups. Although CRC screening is very cost-effective, screening rates are low among most ethnic groups, including Asian Americans. Given the high use of traditional Chinese medicine (TCM) among Chinese Americans one potentially useful approach to promote CRC screening in these communities could involve TCM providers in outreach efforts. METHODS: A two-phase study was conducted. The perceived suitability of TCM providers in CRC prevention was explored in Phase 1. Guided by Phase 1 findings, in Phase 2, a 38-page integrative educational flipchart was developed and tested. Focus groups and observations were conducted with TCM providers (acupuncturists and herbalists) and with limited English proficient Chinese American immigrants living in San Francisco, California. RESULTS: In Phase 1, the role of TCM providers as CRC screening educators was deemed acceptable by both providers and community members, although some providers had reservations about engaging in CRC outreach activities due to lack of expertise. The majority of providers were not aware of regular CRC screening as a preventive measure, and most were not up-to-date in their own screening. In Phase 2, the integrative CRC education flipchart was perceived as culturally appropriate based on stakeholder input and feedback. CONCLUSION: This study shows that TCM providers have the potential to be a valuable and culturally appropriate community resource for providing information on CRC screening. It suggests a potential role for traditional healers as change agents in the immigrant community health network. PMID- 25821532 TI - The Role of Complex Sentence Knowledge in Children with Reading and Writing Difficulties. PMID- 25821533 TI - Training Cameroonian researchers on pragmatic knowledge translation trials: a workshop report. AB - Limited health research capacity in one of the factors that prevents developing countries from attaining optimal health outcomes and achieving the Millennium Development Goals. We report here, the details of a workshop on pragmatic knowledge translation trials for Cameroonian researchers, the material covered and additional resources to support capacity development. At the end of this workshop, knowledge gains were noted and participants were able to initiate proposals for funding. These proposals were aimed at improving the clinical management of diabetes, hypertension and malaria. PMID- 25821534 TI - [Iridocorneal adhesions revealing ankylosing spondylitis]. PMID- 25821535 TI - [Genital pigmented Bowen disease]. PMID- 25821537 TI - [Appendiculo subcutaneous fistula: a rare complication of acute appendicitis]. PMID- 25821536 TI - [Spinal anesthesia for cesarean section: risk factors for emergence of Apgar scores below 7 in Malagasy newborns]. PMID- 25821538 TI - [Meckel diverticulum complicated by retroperitoneal abscess: report of a rare case]. PMID- 25821539 TI - [Dermatofibrosarcoma protuberans, particular skin tumor: report of 32 cases and review of the literature]. PMID- 25821540 TI - Unrecognized psychiatric disorders among adult patients admitted into a general hospital in Maiduguri, Northeastern Nigeria. AB - INTRODUCTION: Patients with unrecognized psychiatric disorders in general hospitals, suffer economic and psycho-social difficulties. This study aimed to determine (i) prevalence and pattern of psychiatric disorders, and (ii) prevalence of unrecognized psychiatric disorders among adult in-patients of a general hospital. METHODS: In this two-stage, cross-sectional study, we used (i) General Health Questionnaire (GHQ) and Composite International Diagnostic Interview (CIDI) to assess the prevalence of psychiatric disorders, and (ii) Patient Encounter Form to determine unrecognized psychiatric disorders, among patients admitted into a general hospital. RESULTS: Of the 283 respondents, 174 (61.5%) had GHQ scores of <= 4. Eighty seven respondents (31%) had psychiatric disorders of which 85 (98%) were not recognized. The frequency of Depression and Anxiety disorders were 61.5% and 26.2% respectively. Unmarried (2.3, 1.2-4.3; p < 0.00), females (2.1, 1.1-4.05; p = 0.01) and patients with "unexplained symptoms" (<= = 8.4, p< 0.00, df = 1) were more likely to have diagnosis of depression and anxiety disorder. CONCLUSION: We conclude that one-third of the patients in the general hospital, had co-morbid psychiatric diagnoses, mostly unrecognized by their physicians. Unmarried, females and respondents with unexplained symptoms were associated with depression and anxiety disorders. We recommend the posting of psychiatric trainees to general hospitals, and training of general practitioners on the use of simple depression and anxiety screening instruments. PMID- 25821542 TI - [Cecal volvulus on appendiceal tumor: report of a rare case]. PMID- 25821541 TI - Rectal atresia: a rare cause of failure to pass meconium. AB - Rectal atresia or stenosis is an extremely rare anorectal malformation associating a normal anal canal with a stricture or a complete rectal atresia. We describe a case of rectal atresia in a newborn female presenting with an abdominal distension and failure of passing meconium. PMID- 25821543 TI - [Primary tuberculous pyomyositis in an immunocompetent patient: report of a case]. PMID- 25821544 TI - [Pneumocephalus complicating a blood patch for post cesarean headache]. PMID- 25821546 TI - [Small pits of the lower lip: think paramedian fistula lip]. PMID- 25821545 TI - [Pulmonary tuberculosis and tobacco: about 100 cases]. PMID- 25821547 TI - [Corneal abscess: serious complication of neglected and poorly managed corneal trauma]. PMID- 25821548 TI - [Lifesaving bilateral nephrectomy complicating Bourneville tuberous sclerosis]. PMID- 25821549 TI - [Bladder metastasis of signet ring gastric adenocarcinoma]. PMID- 25821550 TI - [The interest of addiction to first line anti-TB drugs]. PMID- 25821551 TI - Advances in the pathogenesis of cardiorenal syndrome type 3. AB - Cardiorenal syndrome (CRS) type 3 is a subclassification of the CRS whereby an episode of acute kidney injury (AKI) leads to the development of acute cardiac injury or dysfunction. In general, there is limited understanding of the pathophysiologic mechanisms involved in CRS type 3. An episode of AKI may have effects that depend on the severity and duration of AKI and that both directly and indirectly predispose to an acute cardiac event. Experimental data suggest that cardiac dysfunction may be related to immune system activation, inflammatory mediators release, oxidative stress, and cellular apoptosis which are well documented in the setting of AKI. Moreover, significant derangements, such as fluid and electrolyte imbalance, metabolic acidosis, and uremia, which are typical features of acute kidney injury, may impair cardiac function. In this review, we will focus on multiple factors possibly involved in the pathogenesis issues regarding CRS type 3. PMID- 25821552 TI - Enhancement of the acrolein-induced production of reactive oxygen species and lung injury by GADD34. AB - Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2alpha in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury. PMID- 25821553 TI - Cardioprotective effect of propofol against oxygen glucose deprivation and reperfusion injury in H9c2 cells. AB - BACKGROUND: The intravenous anesthetic propofol is reported to be a cardioprotective agent against ischemic-reperfusion injury in the heart. However, the regulatory mechanism still remains unclear. METHODS: In this study, we used H9c2 cell line under condition of oxygen glucose deprivation (OGD) followed by reperfusion (OGD/R) to induce in vitro cardiomyocytes ischemia-reperfusion injury. Propofol (5, 10, and 20 MUM) was added to the cell cultures before and during the OGD/R phases to investigate the underlying mechanism. RESULTS: Our data showed that OGD/R decreased cell viability, and increased lactate dehydrogenase leakage, and reactive oxygen species and malondialdehyde production in H9c2 cells, all of which were significantly reversed by propofol. Moreover, we found that propofol increased both the activities and protein expressions of superoxide dismutase and catalase. In addition, propofol increased FoxO1 expression in a dose-dependent manner and inhibited p-AMPK formation significantly. CONCLUSIONS: These results indicate that the propofol might exert its antioxidative effect through FoxO1 in H9c2 cells, and it has a potential therapeutic effect on cardiac disorders involved in oxidative stress. PMID- 25821556 TI - Design and Analysis of a Novel Articulated Drive Mechanism for Multifunctional NOTES Robot. AB - This paper presents a novel articulated drive mechanism (ADM) for a multifunctional natural orifice transluminal endoscopic surgery (NOTES) robotic manipulator. It consists mainly of three major components including a snakelike linkage, motor housing, and an arm connector. The ADM can articulate into complex shapes for improved access to surgical targets. A connector provides an efficient and convenient modularity for insertion and removal of the robot. Four DC motors guide eight cables to steer the robot. The workspace, cable displacement and force transmission relationships are derived. Experimental results give preliminary validation of the feasibility and capability of the ADM system. PMID- 25821555 TI - Antioxidant capacity of "Mexican arnica" Heterotheca inuloides Cass natural products and some derivatives: their anti-inflammatory evaluation and effect on C. elegans life span. AB - It has been suggested that the accumulation of biomolecular damage caused by reactive oxygen species (ROS) contributes to aging. The antioxidant activity is related to the ability of certain compounds to protect against the potentially harmful effect of processes or reactions involving ROS. This ability is associated with the termination of free radical propagation in biological systems. From Heterotheca inuloides various compounds which have shown to possess antioxidant capacity and scavenging ROS. The aim of this study was to determine the antioxidant capacity of additional natural components isolated from H. inuloides and some semisynthetic derivatives, their anti-inflammatory activity and the effect on Caenorhabditis elegans nematode life span. Compounds showed ability to inhibit various biological processes such as lipid peroxidation, scavenge nonbiological important oxidants such as (1)O2, OH(?), H2O2, and HOCl and scavenge non biological stable free radicals (DPPH). Some cadinane type compounds showed possess antioxidant, ROS scavenging capacity, anti-inflammatory activity, and effect on the C. elegans life span. Flavonoid type compounds increased the life of the nematode and quercetin was identified as the compound with the greatest activity. The modification of chemical structure led to a change in the antioxidant capacity, the anti-inflammatory activity, and the survival of the worm. PMID- 25821554 TI - Oxidative stress: dual pathway induction in cardiorenal syndrome type 1 pathogenesis. AB - Cardiorenal Syndrome Type 1 (Type 1) is a specific condition which is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Even though its pathophysiology is complex and not still completely understood, oxidative stress seems to play a pivotal role. In this study, we examined the putative role of oxidative stress in the pathogenesis of CRS Type 1. Twenty-three patients with acute heart failure (AHF) were included in the study. Subsequently, 11 patients who developed AKI due to AHF were classified as CRS Type 1. Quantitative determinations for IL-6, myeloperoxidase (MPO), nitric oxide (NO), copper/zinc superoxide dismutase (Cu/ZnSOD), and endogenous peroxidase activity (EPA) were performed. CRS Type 1 patients displayed significant augmentation in circulating ROS and RNS, as well as expression of IL-6. Quantitative analysis of all oxidative stress markers showed significantly lower oxidative stress levels in controls and AHF compared to CRS Type 1 patients (P < 0.05). This pilot study demonstrates the significantly heightened presence of dual oxidative stress pathway induction in CRS Type 1 compared to AHF patients. Our findings indicate that oxidative stress is a potential therapeutic target, as it promotes inflammation by ROS/RNS-linked pathogenesis. PMID- 25821557 TI - The BRAF kinase domain promotes the development of gliomas in vivo. AB - In-frame BRAF fusions have been observed in over 80% of sporadic pilocytic astrocytomas. In each fusion, the N-terminal autoinhibitory domain of BRAF is lost, which results in constitutive activation via the retained C-terminal kinase domain (BRAF-KD). We set out to determine if the BRAF-KD is sufficient to induce gliomas alone or in combination with Ink4a/Arf loss. Syngeneic cell lines demonstrated the transforming ability of the BRAF-KD following Ink4a/Arf loss. In vivo, somatic cell gene transfer of the BRAF-KD did not cause tumors to develop; however, gliomas were detected in 21% of the mice following Ink4a/Arf loss. Interestingly, these mice demonstrated no obvious symptoms. Histologically the tumors were highly cellular and atypical, similar to BRAF(V600E) tumors reported previously, but with less invasive borders. They also lacked the necrosis and vascular proliferation seen in BRAFV600E-driven tumors. The BRAF-KD-expressing astrocytes showed elevated MAPK signaling, albeit at reduced levels compared to the BRAF(V600E) mutant. Pharmacologic inhibition of MEK and PI3K inhibited cell growth and induced apoptosis in astrocytes expressing BRAF-KD. Our findings demonstrate that the BRAF-KD can cooperate with Ink4a/Arf loss to drive the development of gliomas and suggest that glioma development is determined by the level of MAPK signaling. PMID- 25821558 TI - HSP90 inhibitor AUY922 induces cell death by disruption of the Bcr-Abl, Jak2 and HSP90 signaling network complex in leukemia cells. AB - The Bcr-Abl protein is an important client protein of heat shock protein 90 (HSP90). We evaluated the inhibitory effects of the HSP90 ATPase inhibitor AUY922 on 32D mouse hematopoietic cells expressing wild-type Bcr-Abl (b3a2, 32Dp210) and mutant Bcr-Abl imatinib (IM)-resistant cell lines. Western blotting results of fractions from gel filtration column chromatography of 32Dp210 cells showed that HSP90 together with Bcr-Abl, Jak2 Stat3 and several other proteins co-eluted in peak column fractions of a high molecular weight network complex (HMWNC). Co-IP results showed that HSP90 directly bound to Bcr-Abl, Jak2, Stat 3 and Akt. The associations between HSP90 and Bcr-Abl or Bcr-Abl kinase domain mutants (T315I and E255K) were interrupted by AUY922 treatment. Tyrosine phosphorylation of Bcr Abl showed a dose-dependent decrease in 32Dp210T315I following AUY922 treatment for 16h. AUY922 also markedly inhibited cell proliferation of both IM-sensitive 32Dp210 (IC50 =6 nM) and IM-resistant 32Dp210T315I cells (IC50 ~6 nM) and human KBM-5R/KBM-7R cell lines (IC50 =50 nM). AUY922 caused significant G1 arrest in 32Dp210 cells but not in T315I or E255K cells. AUY922 efficiently induced apoptosis in 32Dp210 (IC50 =10 nM) and T315I or E255K lines with IC50 around 20 to 50 nM. Our results showed that Bcr-Abl and Jak2 form HMWNC with HSP90 in CML cells. Inhibition of HSP90 by AUY922 disrupted the structure of HMWNC, leading to Bcr-Abl degradation, nhibiting cell proliferation and inducing apoptosis. Thus, inhibition of HSP90 is a powerful way to inhibit not only IM-sensitive CML cells but also IM-resistant CML cells. PMID- 25821559 TI - The adenovirus E1A oncoprotein N-terminal transcriptional repression domain enhances p300 autoacetylation and inhibits histone H3 Lys18 acetylation. AB - Expression of the adenovirus E1A N-terminal transcription repression domain alone (E1A 1-80) represses transcription from specific promoters such as HER2 [1] and from reconstituted chromatin [2]. Significantly, E1A 1-80 can induce the death of human breast cancer cells over-expressing the HER2 oncogene [1] as well as other cancer cells. Here, we report that E1A 1-80 alone is sufficient to inhibit H3K18 acetylation in vivo and p300-mediated H3K18 acetylation in reconstituted chromatin. Of interest, hypoacetylation of H3K18 has been correlated with the survival of tumor cells and the poor prognosis of many cancers [3, 4]. E1A 1-80 enhances p300 autoacetylation and concurrently inhibits H3K18 acetylation in chromatin in a dose-dependent manner. Pre-acetylation of p300 by incubation with acetyl-CoA alone reduces p300's ability to acetylate H3K18 in chromatin. Additional acetylation of p300 in the presence of E1A 1-80 produces stronger inhibition of H3K18 acetylation. These findings indicate that autoacetylation of p300 greatly reduces its ability to acetylate H3K18. The results reported here combined with our previous findings suggest that E1A can repress transcription by multiple strategies, including altering the chromatin modifying activity of p300 and dissociating TFIID from the TATA box thus disrupting formation of the transcription pre-initiation complex [5, 6]. PMID- 25821560 TI - Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there was an increased fraction of CHFR-methylated cells in S and G2/M phases (p<0.05). In conclusion, CHFR is frequently methylated in ESCC and the expression of CHFR is regulated by promoter region methylation. CHFR methylation is a late stage event in ESCC. Methylation of CHFR sensitized ESCC cells to taxanes. 5-AZ may re-sensitize chemotherapy resistant in refractory tumors by inducing cell cycle phase re-distribution. PMID- 25821561 TI - Polyphenols from green tea inhibit the growth of melanoma cells through inhibition of class I histone deacetylases and induction of DNA damage. AB - Melanoma is the leading cause of skin cancer-related deaths. We have examined the effect of green tea polyphenols (GTPs), a natural mixture of epicatechin monomers, on melanoma cancer cell growth and the molecular mechanism underlying these effects using different human melanoma cell lines as an in vitro model. Treatment of melanoma cell lines (A375, Hs294t, SK-Mel28 and SK-Mel119) with GTPs significantly inhibited the cell viability as well as colony formation ability of melanoma cells in a dose-dependent manner. These effects of GTPs were associated with a significant inhibition of histone deacetylase (HDAC) activity, reduction in the levels of class I HDAC proteins, enhancement of histone acetyltransferase (HAT) activity and induction of DNA damage, as detected by Comet assay, in melanoma cells. GTPs-induced decrease in the levels of class I HDAC proteins is mediated through proteasomal degradation. Valproic acid, an inhibitor of HDACs, exhibited a similar pattern of reduced viability and induction of death of melanoma cells. Treatment of A375 and Hs294t cells with GTPs resulted in a decrease in the levels of cyclins and cyclin dependent kinases of G1 phase of cell cycle whereas upregulated the levels of tumor suppressor proteins (Cip1/WAF1/p21, p16 and p53). PMID- 25821562 TI - Microarray profile of human kidney from diabetes, renal cell carcinoma and renal cell carcinoma with diabetes. AB - Recent study from our laboratory showed that patients with diabetes are at a higher risk of developing kidney cancer. In the current study, we have screened whole human DNA genome from healthy control, patients with diabetes or renal cell carcinoma (RCC) or RCC+diabetes. We found that 883 genes gain/163 genes loss of copy number in RCC+diabetes group, 669 genes gain/307 genes loss in RCC group and 458 genes gain/38 genes loss of copy number in diabetes group, after removing gain/loss genes obtained from healthy control group. Data analyzed for functional annotation enrichment pathways showed that control group had the highest number (280) of enriched pathways, 191 in diabetes+RCC group, 148 in RCC group, and 81 in diabetes group. The overlap GO pathways between RCC+diabetes and RCC groups showed that nine were enriched, between RCC+diabetes and diabetes groups was four and between diabetes and RCC groups was eight GO pathways. Overall, we observed majority of DNA alterations in patients from RCC+diabetes group. Interestingly, insulin receptor (INSR) is highly expressed and had gains in copy number in RCC+diabetes and diabetes groups. The changes in INSR copy number may use as a biomarker for predicting RCC development in diabetic patients. PMID- 25821563 TI - Mobilization of LINE-1 in irradiated mammary gland tissue may potentially contribute to low dose radiation-induced genomic instability. AB - It is known that cellular stresses such as ionizing radiation activate LINE-1 (long interspersed nuclear element type 1, L1), but the molecular mechanisms of LINE-1 activation have not been fully elucidated. There is a possibility that DNA methylation changes induced by genotoxic stresses might contribute to LINE-1 activation in mammalian cells. L1 insertions usually cause major genomic rearrangements, such as deletions, transductions, the intrachromosomal homologous recombination between L1s, and the generation of pseudogenes, which could lead to genomic instability. The purpose of this study was to evaluate the effects of low and high doses of ionizing radiation on the DNA methylation status of LINE-1 transposable elements in rat mammary glands. Here we describe radiation-induced hypomethylation and activation of LINE-1 ORF1 in rat mammary gland tissues. We show that radiation exposure has also led to the translation of the LINE-1 element, whereby the 148 kDa LINE-1 protein level was increased 96 hours after treatment with a low dose and low energy level radiation and remained elevated for 24 weeks after treatment. The mobilization of LINE-1 in irradiated tissue may potentially contribute to genomic instability. The observed activation of mobile elements in response to radiation exposure is consistently discussed as a plausible mechanism of cancer etiology and development. PMID- 25821564 TI - Targeting Intracellular Cholesterol is a Novel Therapeutic Strategy for Cancer Treatment. AB - Substantial data from cell culture and animal studies evidence the preventive effect of statins, cholesterol lowering-drugs, in regulation of cancer cell proliferation and metastasis. Various clinical studies also support this correlation between use of statin and the reduction of cancer incidence. However, in some cases, statins have failed to decrease the risk of cancer. Since, instead of serum cholesterol, intracellular cholesterol may play a crucial role in the regulation of tumorigenesis and metastasis. The mechanism by which cholesterol is stored within cancer cells may differ among cancer types and also in different individuals. This paper discusses the molecular detail to speculate the statin sensitive cancer. It also highlights that statins may work better as anticancer therapy if it is used with the combination of a specific microRNA (miR). PMID- 25821565 TI - Evaluating resident physicians' knowledge, attitude, and practice regarding the pain control in cancer patients. AB - BACKGROUND: Pain has been one of the most debilitating symptoms of cancer. The aim of this study was to evaluate residents' knowledge, attitude, and practice regarding pain control in cancer patients. METHODS: In a descriptive study, 69 randomly selected third-year various residents practicing in teaching hospitals of Shahid Beheshti School of medicine participated in this study. They have provided their demographic characteristics and completed a questionnaire, based on their "knowledge", "attitude" and "practice" regarding cancer pain and its management. Data analysis has performed using SPSS v.19. A p value of less than 0.05 has considered as significant. RESULTS: Obtained Data from 69 participants including 32 anesthesiology residents has included to our study. The average scores were 35.8+/-6.1 (ranging from 20 to 49) for the residents' attitude, 25.1+/-9.1 (ranging from 0 to 53) for their knowledge and 11.2+/-4.1 (ranging from 0 to 17) for their practice. The overall scores of the questions have related to attitude and knowledge were higher for residents of anesthesiology but the difference was not statistically significant (A: 37.1+/-4.9 vs. 34.7+/-6.8, p=0.106, K: 27.2+/-11.8 vs. 23.3+/-5.6, p=0.076). The average score for questions on physician' practice was significantly higher in residents of anesthesiology (P: 12.8+/-3.2 vs. 9.7+/-4.2, p=0.001). CONCLUSION: In order to provide patients with adequate pain relief, it has seemed advisable for medical schools to focus on improving the educational curriculum and integrating it into clinical practice. PMID- 25821566 TI - Immunohistochemical analysis of mismatch repair proteins in Iranian colorectal cancer patients at risk for lynch syndrome. AB - BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is a common hereditary cancer predisposing syndrome has molecular and clinicopathological features still have remained ambiguous within Iranian populations. We discuss in this article some molecular and clinicopathological features of the condition. METHODS: The study was a descriptive retrospective and designed on 1659 colorectal cancer (CRC) patients were screened based on early-onset disease and Amsterdam II criteria during 14 years (2000-2013). Immunohistochemistry (IHC) staining was set up to detect expression of mismatch repair (MMR) genes on paraffin-embedded tissue sections of 31 HNPCC-CRC tumors. SPSS 19 software was used to analyze the data. RESULTS: IHC-MMR staining was absent in 7/31 individuals (22.6%) of which 4 cases showed IHC-Absent (IHC-A) in both MSH2 and MSH6 (57.1%), in 2 cases both MLH1 and PMS2 had negative staining (28.6%), and just in one case, MSH6 was defective (14.3%). The frequency of CRC among IHC-A and IHC-Present (IHC-P) families was 67.5% and 27.9%, respectively. Also the most frequent extracolonic cancers in IHC-A group were: stomach (10%), small bowel (5%), and prostate (5%); and in IHC-P group: stomach (18.4%), lung (10.9%), and breast (7.5%). Average age of IHC-A individuals at diagnosis was 38.0 versus 45.3 years in IHC-P individuals. Overall, 20.8% and 57.1% of our index CRCs were localized proximal to the splenic flexure in IHC-P and IHC-A groups, respectively. CONCLUSION: Given the lack of enough information about molecular aspects of hereditary cancer syndromes like HNPCC in Iran, more evaluations are necessary on larger samples using complementary techniques such as MSI-testing and mutation analyses. PMID- 25821567 TI - Further Stimulation of Cellular Immune Responses through Association of HPV-16 E6, E7 and L1 Genes in order to produce more Effective Therapeutic DNA Vaccines in Cervical Cancer Model. AB - BACKGROUND: Cervical cancer has been shown to be highly associated with human papillomavirus (HPV) infection. The viral oncogenes E6 and E7 are constantly expressed by the tumor cells and are therefore potent targets for therapeutic genetic vaccination. In the present study, it was investigated the potential effect of HPV-16 E6, E7 and L1 co-administration to activate specific cytotoxic T lymphocytes in tumor mice models. METHODS: The HPV-16 E6, E7 and L1 genes from Iranian isolate were separately inserted into the mammalian expression vector, pcDNA3, to construct the DNA vaccine candidates. Tumor-bearing Animals (C57BL/6 mice) were immunized with the vaccine candidate; then, Lymphocyte Proliferation Assay (LPA) and relative tumor volume measurements were carried out in order to examine the immunological effects of the vaccine. RESULTS: Obtained results showed that co-administration of the HPV-16 E6, E7 and L1 DNA induced HPV-16 specific cellular immune responses and also protected against TC-1-induced tumor in vivo compared with negative controls. CONCLUSION: The results showed that mixed delivery systems might be valuable to improve the magnitude of the induced immune responses and confirmed therapeutic effects of HPV-16 E6, E7 through cytotoxic T lymphocyte induction and illustrate the new promising role for HPV-16 L1 CTL epitopes as a suitable CTL inducer. PMID- 25821568 TI - High Body Mass Index and Young Age Are not Associated with Post-Mastectomy Pain Syndrome in Breast Cancer Survivors: A Case-Control Study. AB - BACKGROUND: Surgery is usually the first treatment for breast cancer which is followed by some complications such as chronic pain. Post mastectomy pain syndrome (PMPS) is a common complication among breast cancer survivors and is considered as a chronic neuropathic pain in the side of surgery which persists more than three months. The exact mechanisms and related risk factors of the chronic pain after breast surgery are unknown. The aim of this study was to investigate the association of body mass index (BMI) and age with PMPS. METHODS: In this case-control study, a total of 122 women were assessed; of these, 61 women were diagnosed with PMPS and selected as cases and 61 pain-free patients were selected as controls. The demographic and clinical characteristics of participants were collected through questionnaires and medical record of patients. Logistic regression model was used to determine the association of BMI and age with PMPS, adjusted for demographic and clinical characteristics. RESULTS: No significant differences were found in means of weight (68.02+/-8.80 vs. 68.67+/-11.82, p=0.726), BMI (26.38+/-3.28 vs. 27.10+/-6.03, p=0.410), and age (46.34+/-11.67 vs. 48.54+/-12.57, p=0.319) between those with PMPS and those not reporting PMPS. A non-significant slight increase in odds ratio of PMPS was observed in obese category compared to normal weight category [OR=1.152 (95% CI 0.405-3.275), p=0.908], but after adjusting the confounding factors, the risk of pain development was attenuated in obese subjects [OR=0.748 (95% CI 0.228-2.459), p=0.633]. Also, non-significant decrease in odds ratios of PMPS was found in 20 39 y, 40-49 y, and 50-59 y ages categories compared to oldest age category [adjusted OR= 0.781 (95% CI 0.213-2.866), p=0.576; adjusted OR=0.485 (95% CI 0.152- 1.554), p=0.183; adjusted OR=0.735 (95% CI 0.206-2.627), p=0.628; respectively]. CONCLUSION: In contrast with some observational studies, present study showed that high BMI and younger age might not be associated with increased risk of PMPS development. Further research is necessary to determine the main risk factors and directionality and causal mechanisms for associations of these risk factors with chronic pain after mastectomy. PMID- 25821569 TI - Evaluation of emotional distress in breast cancer patients. AB - BACKGROUND: Cancer has been known as a class of dangerous diseases which cause tremendous physical and emotional problems to both patients and their families. In spite of medical advances, cancer is still considered to be equal with death and pain. This study aims to analyze the emotional distress and the causes in breast cancer patients. METHODS: This study was a quantitative study which tries to analyze the emotional distress in 82 breast cancer patients referred to the Radiotherapy and Oncology Department of Razi Hospital in Rasht, northern Iran. In this study, the emotional distress is analyzed based on a standard questionnaire which contains demographic information, distress thermometer, and a section devoted to the probable causes. RESULTS: Among the 82 patients that participated in this study, 32 patients (39%) suffered from severe emotional distress which had a statistically significant relationship (p<0.009) with the functional status of the patients. Taking care of children, fear, anxiety, difficulties of taking bath and wearing clothes, family problems, fever and nasal dryness are the most common issued related to emotional distress. CONCLUSION: Emotional distress can affect the quality of life of breast cancer patients. Therefore, oncology specialists should utilize mental health services to improve their patients' mental health as well as to control the consequences of the disease. PMID- 25821570 TI - The Prognostic Role of Tumor Marker CA-125 in B-Cell non-Hodgkin's Lymphoma. AB - BACKGROUND: B-cell non-Hodgkin's lymphoma (NHL) is a common malignancy of lymphoid tissues. Different types of NHL show various behaviors, prognoses, and responses to treatment. Evaluation of disease activity in NHL can be helpful in managing and even increasing the patient's survey. METHODS AND RESULTS: In total, 121 patients (76 males and 45 females), and their age range were 18-53 years, were evaluated in this study. The mean level of serum carbohydrate antigen 125 (CA-125) was 89.3+/-18.5 u/ml, ranging from 27 to 135 u/ml. There were significant differences in International Prognostic Index (IPI) score (p=0.002), stage of the disease (p=0.006), mortality rate (p=0.02), and relapse rate (p=0.04) between patients with serum CA-125 level <35 u/ml and patients with CA 125 level >35 u/ml. CONCLUSION: CA-125 seems to be a useful and reliable tumor marker for monitoring a patient with NHL. It might be the time to consider CA-125 in staging, prognostic scoring, or decision making about NHL treatment. PMID- 25821571 TI - Evaluation of Organs at Risk's Dose in External Radiotherapy of Brain Tumors. AB - BACKGROUND: Radiotherapy plays an important role in the management of most malignant and many benign primary central nervous system (CNS) tumors. Radiotherapy affects both tumor cells and uninvolved normal cells; so, it is important to estimate absorbed dose to organs at risk in this kind of treatment. The aim of this study was to determine the absorbed dose to chiasma, lens, optic nerve, retina, parotid, thyroid and submandibular gland in frontal lobe brain tumors radiotherapy based on treatment planning system (TPS) calculation and direct measurement on the phantom. METHODS: A head and neck phantom was constructed using natural human bone and combination of paraffin wax and Sodium Chloride (NaCl) as tissue-equivalent material. Six cylinders were made of phantom material which had cavities to insert Thermoluminescent Dosimeters (TLDs) at several depths in order to measure absorbed dose to chiasma, lens, optic nerve, retina, parotid, thyroid and submandibular gland. Three routine conventional plans associated with tumors of this region and a new purposed technique were performed on the phantom and dose distribution and absorbed dose to critical organs were compared using treatment planning system (TPS) calculation and direct measurement on the phantom. RESULTS: Absorbed doses were measured with calibrated TLDs and are expressed in centigray (cGy). In all techniques absorbed dose to all organs except the lenses were at their tolerance dose levels and in the new purposed technique, absorbed dose to chiasma was significantly reduced. CONCLUSION: Our findings showed differences in the range of 1-5% in all techniques between TPS calculation and direct measurements for all organs except submandibular glands and thyroid. Because submandibular glands and thyroid are far from primary radiation field, TLD reading in these regions although small but differs from TPS calculation which shows very smaller doses. This might be due to scattered radiation which is not well considered in the TPS. In the new technique, because the chiasma is out of the radiation field, absorbed dose was reduced significantly. PMID- 25821572 TI - Relationships between Family Levels of Socioeconomic Status and Distribution of Breast Cancer Risk Factors. AB - BACKGROUND: Not only the expand development of knowledge for reducing risk factors, but also the improvement in early diagnosis and treatment of cancer, and socioeconomic inequalities could affect cancer incidence, diagnosis stage, and mortality. The aim of this study was investigation the relationships between family levels of socioeconomic status and distribution of breast cancer risk factors. METHODS: This descriptive cross-sectional study has conducted on 526 patients who were suffering from breast cancer, and have registered in Cancer Research Center of Shahid Beheshti University of Medical Sciences from March 2008 to December 2013. A reliable and valid questionnaire about family levels of socioeconomic status has filled by interviewing the patients via phone. For analyzing the data, Multinomial logistic regression, Kendal tau-b correlation coefficient and Contingency Coefficient tests have executed by SPSS19. RESULTS: The mean age of the patients was 48.30 (SD=11.41). According to the results of this study, there was a significant relationship between family socioeconomic status and patient's age at diagnosis of breast cancer (p value<0.001). Also, the relationships between socioeconomic status and number of pregnancies, and duration of breast feeding were significant (p value> 0.001). In the multiple logistic regressions, the relationship between excellent socioeconomic status and number of abortions was significant (p value> 0.007). Furthermore, the relationships between moderate and good socioeconomic statuses and smoking were significant (p value=0.05 and p value=0.02, respectively). CONCLUSION: The results have indicated that among those patients having better socioeconomic status, age at cancer diagnosis, number of pregnancies and duration of breast feeding was lower, and then number of abortions was more than the others. According to the results of this study, it was really important to focus on family socioeconomic status as a critical and effective variable on breast cancer risk factors among the Iranian women. PMID- 25821573 TI - A report of a rare gastric cancer case: leptomeningeal carcinomatosis. AB - Leptomeningeal carcinomatosis (LMC) from gastrointestinal cancer would be rare. A 56-years old man with complaint of dyspepsia and histopathologic examination of the biopsy specimens has shown: adenocarcinoma. At the end of adjuvant chemo radiation therapy, the patient has affected by headache and mild confusion. In cerebrospinal fluid (CSF) cytology, a plenty of malignant cells have seen and unfortunately after a short time for about 4 days after ICU admission, the patient has died. This could be due to heavy burden of disease in central nervous system. PMID- 25821575 TI - Incidence of Seminoma Cancer in Staffs that Worked in Electromagnetic Waves Station; Three Cases Report. AB - Physical agents such as ultraviolet or ionizing radiation and repetitive trauma have been related to the causation of cancer in humans. Much less clear is the association between exposure to radiofrequency, such as radar and microwave radiation to the development of cancer. Sporadic case reports and small series suggest that this type of radiation might lead to cancer or contribute to its evolution. The association between radiofrequency and testicular damage and cancer is unproved, but clinical and experimental data are suggestive of such possibility. In this paper we have reported three cases of seminoma in person who worked in the same place that exposed to radio frequency (RF) waves. PMID- 25821574 TI - Malignant mesenchymal tumor of male breast: primary chondrosarcoma. AB - Breast Sarcomas have relatively been rare and accounted for 1% of all primary malignant tumors of the breast. Pure and primary chondrosarcoma of the male breast would be an extremely rare tumor. It might arise either from the breast stroma itself, or from underlying bone or cartilage. A 65-year-old man has presented with a rapidly growing breast mass since 5 months. Physical examination has established a large firm to hard mass with regular margins in the region of right breast. There was no axillary lymphadenopathy. Contrast enhanced MRI of breasts has shown a mixed-signal intensity multi lobulated cystic-solid mass (10.4 cm * 10.3 cm *9.9 cm) appearing predominantly hyper intense on T2W and hypo intense on T1W. The tumor has diagnosed as a low-grade chondrosarcoma of the breast by histopathological and immunohistochemistry analysis. Right sided radical mastectomy with grafting has done. It has seemed to be very important to identify the mammary primary sarcomas as entity separated from the carcinomas of the breast. PMID- 25821576 TI - Radio Frequency as the Risk Factor of Cancer, yes? No? PMID- 25821577 TI - Effects of phylogenetic reconstruction method on the robustness of species delimitation using single-locus data. AB - Coalescent-based species delimitation methods combine population genetic and phylogenetic theory to provide an objective means for delineating evolutionarily significant units of diversity. The generalised mixed Yule coalescent (GMYC) and the Poisson tree process (PTP) are methods that use ultrametric (GMYC or PTP) or non-ultrametric (PTP) gene trees as input, intended for use mostly with single locus data such as DNA barcodes. Here, we assess how robust the GMYC and PTP are to different phylogenetic reconstruction and branch smoothing methods. We reconstruct over 400 ultrametric trees using up to 30 different combinations of phylogenetic and smoothing methods and perform over 2000 separate species delimitation analyses across 16 empirical data sets. We then assess how variable diversity estimates are, in terms of richness and identity, with respect to species delimitation, phylogenetic and smoothing methods. The PTP method generally generates diversity estimates that are more robust to different phylogenetic methods. The GMYC is more sensitive, but provides consistent estimates for BEAST trees. The lower consistency of GMYC estimates is likely a result of differences among gene trees introduced by the smoothing step. Unresolved nodes (real anomalies or methodological artefacts) affect both GMYC and PTP estimates, but have a greater effect on GMYC estimates. Branch smoothing is a difficult step and perhaps an underappreciated source of bias that may be widespread among studies of diversity and diversification. Nevertheless, careful choice of phylogenetic method does produce equivalent PTP and GMYC diversity estimates. We recommend simultaneous use of the PTP model with any model-based gene tree (e.g. RAxML) and GMYC approaches with BEAST trees for obtaining species hypotheses. PMID- 25821578 TI - A method for calculating minimum biodiversity offset multipliers accounting for time discounting, additionality and permanence. AB - Biodiversity offsetting, which means compensation for ecological and environmental damage caused by development activity, has recently been gaining strong political support around the world. One common criticism levelled at offsets is that they exchange certain and almost immediate losses for uncertain future gains. In the case of restoration offsets, gains may be realized after a time delay of decades, and with considerable uncertainty. Here we focus on offset multipliers, which are ratios between damaged and compensated amounts (areas) of biodiversity. Multipliers have the attraction of being an easily understandable way of deciding the amount of offsetting needed. On the other hand, exact values of multipliers are very difficult to compute in practice if at all possible. We introduce a mathematical method for deriving minimum levels for offset multipliers under the assumption that offsetting gains must compensate for the losses (no net loss offsetting). We calculate absolute minimum multipliers that arise from time discounting and delayed emergence of offsetting gains for a one dimensional measure of biodiversity. Despite the highly simplified model, we show that even the absolute minimum multipliers may easily be quite large, in the order of dozens, and theoretically arbitrarily large, contradicting the relatively low multipliers found in literature and in practice. While our results inform policy makers about realistic minimal offsetting requirements, they also challenge many current policies and show the importance of rigorous models for computing (minimum) offset multipliers. The strength of the presented method is that it requires minimal underlying information. We include a supplementary spreadsheet tool for calculating multipliers to facilitate application. PMID- 25821579 TI - Three layers of working memory: Focus-switch costs and retrieval dynamics as revealed by the N-count task. AB - Two experiments explored the process of switching items in and out of the focus of attention using a new paradigm, the N count task (adapted from Garavan, 1998; N varied from 1 to 4). This task yielded a focus size of one, indicated by a substantial focus switch cost for 2 count. Additionally, the focus switch costs in response time increased with working memory load, indicating an effortful search process occurring at a speed of about 240 ms/item. Maintaining and switching to and from a passive load did not increase the focus switch costs or decrease memory accuracy, indicating that there is no crosstalk between passive and active items. The results support a concentric theory of working memory: a small focus at its core, a surrounding area of (at least) three readily available items referred to as the outer store, and a still wider region of passive storage, possibly more long term memory than working memory. PMID- 25821580 TI - The redesign of the medical intern assignment mechanism in Israel. AB - A collaboration of medical professionals with economists and computer scientists involved in "market design" had led to the redesign of the clearinghouse assigning medical students to internships in Israel. The new mechanism presents significant efficiency gains relative to the previous one, and almost all students get a better chance of getting what they want. Continued monitoring of the new mechanism is required to verify that it is not abused, and explore whether it can be improved. Other organizations in Israel may also be able to profit from the experience that accumulates from market design, both in Israel and abroad. PMID- 25821581 TI - Assessment of knowledge and practice of health workers towards tuberculosis infection control and associated factors in public health facilities of Addis Ababa, Ethiopia: A cross-sectional study. AB - BACKGROUND: Tuberculosis is the leading causes of mortality among infectious diseases worldwide. The risk of transmission from patients to health workers is doubles that of the general population. The close contact to the infectious case before diagnosis is the major risk for tuberculosis infection. The aim of the study was to assess knowledge and practice of health professionals towards tuberculosis infection control and its associated factors in health facilities of Addis Ababa, Ethiopia. METHODS: A cross-sectional study was conducted from February 29 to April 15/2014 in selected health facilities in Addis Ababa. Five hundred ninety health workers were included in the study. The sample size was assigned to each health facility proportional to their number of health workers. Study subjects were selected from each stratum by simple random sampling technique. Interviewer administered structured questionnaire was used to collect information. Logistic regression was used to identify factors associated with knowledge and practice of health workers towards tuberculosis infection control. RESULT: Five hundred eighty two participants with 98.6% response rate were involved in the study. Of these, 36.1% had poor knowledge and 51.7% unsatisfactory practice score towards tuberculosis infection control. Having more than six years working experience in health facility (AOR = 2.51; 95% CI: 1.5 4.1) and tuberculosis related training (AOR = 2.51 95% CI; 1.5, 4.1) were significantly associated with knowledge on tuberculosis infection control. Having experience in tuberculosis clinic (AOR =1.93; 95% CI: 1.12, 3.34) and tuberculosis related training (AOR = 1.48; 95% CI: 1.87, 2.51) were significantly associated with practice on tuberculosis infection control. CONCLUSION: One third of health workers had relatively poor knowledge and nearly half of them had unsatisfactory practice on tuberculosis infection control. Tuberculosis training and work experiences in health facility are determinant factor to knowledge. Whereas tuberculosis related training and experience in tuberculosis clinic are predictor to practice. So, training of the health professionals, on job orientations of junior health workers, and farther study including private health workers are recommended. PMID- 25821583 TI - A Highly Efficient and Extremely Selective Intracellular Copper Detoxifying Agent Based on Nanoparticles of ZnMoS4. AB - Biocompatible ZnMoS4 NPs can selectively remove intracellular copper ions via ion exchange rather than chelation. This strategy represents a paradigm shift in designing new-generation intracellular metal detoxifying drugs. PMID- 25821584 TI - beta-Blockers in hypertension, diabetes, heart failure and acute myocardial infarction: a review of the literature. AB - beta-Blockers (BBs) are an essential class of cardiovascular medications for reducing morbidity and mortality in patients with heart failure (HF). However, a large body of data indicates that BBs should not be used as first-line therapy for hypertension (HTN). Additionally, new data have questioned the role of BBs in the treatment of stable coronary heart disease (CHD). However, these trials mainly tested the non-vasodilating beta1 selective BBs (atenolol and metoprolol) which are still the most commonly prescribed BBs in the USA. Newer generation BBs, such as the vasodilating BBs carvedilol and nebivolol, have been shown not only to be better tolerated than non-vasodilating BBs, but also these agents do not increase the risk of diabetes mellitus (DM), atherogenic dyslipidaemia or weight gain. Moreover, carvedilol has the most evidence for reducing morbidity and mortality in patients with HF and those who have experienced an acute myocardial infarction (AMI). This review discusses the cornerstone clinical trials that have tested BBs in the settings of HTN, HF and AMI. Large randomised trials in the settings of HTN, DM and stable CHD are still needed to establish the role of BBs in these diseases, as well as to determine whether vasodilating BBs are exempt from the disadvantages of non-vasodilating BBs. PMID- 25821586 TI - Sentinel events in ophthalmology: experience from Hong Kong. AB - Purpose. To arouse ophthalmologists' awareness in patient safety by reviewing sentinel events in Ophthalmology submitted to a web-based incident reporting system involving all public hospitals in Hong Kong. Methods. Sentinel events in Ophthalmology reported from November 2007 to October 2014 were identified and classified into different categories for further presentation and analysis. Key contributing factors attributing to the occurrence of the incidents were described. Suggestions aiming to prevent future occurrence of similar events were made. Relevant literature and case law were discussed. Results. Twelve sentinel events were included in this observational case series. They were classified into 4 main categories, namely "wrong eye" (5 cases, 41%), "wrong prescription" (3 cases, 25%), "wrong patient and surgery" (2 cases, 17%), and "retained surgical items" (2 cases, 17%). The key contributing factor leading to the occurrence of the incidents was largely human error. Increased staff awareness and proper time out procedures were recommended to help prevent occurrence of these errors. Conclusion. Sentinel events in Ophthalmology do occur. Many of these incidents were attributed to human error. Surgeon's awareness and willingness to prevent occurrence of sentinel events are warranted. PMID- 25821585 TI - Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age Related Macular Degeneration: Beyond Anti-VEGF Therapy. AB - Age-related macular degeneration (AMD) is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or "wet") form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF). However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly), potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins. PMID- 25821587 TI - Correlation of papillomacular nerve fiber bundle thickness with central visual function in open-angle glaucoma. AB - Purpose. To determine the correlation of reduced retinal thickness in the central papillomacular bundle (CPB) to central visual function, including central retinal sensitivity and visual acuity, in glaucoma patients. Methods. This study enrolled 50 eyes of 50 patients with open-angle glaucoma who were carefully screened for comorbid conditions that can cause decreased central visual function, such as cataracts or macular diseases. We used a novel CPB analysis comprising a program for optical coherence tomography that measured RNFL thickness and GCC thickness in the CPB and divided lengthwise into three parts (upper, middle, and lower CPB). The relationship of these parameters, including conventional macular thickness, to visual field sensitivity in four central standard automated perimetry points (the central four thresholds) and BCVA was analyzed. Results. The two parameters most highly correlated with central four thresholds were macular GCCT and macular RNFLT. The two parameters most highly correlated with BCVA were middle CPB (mid-CPB) GCCT and mid-CPB RNFLT. A multiple regression analysis revealed that mid-CPB GCCT was an independent factor impacting central retinal thresholds and BCVA. Conclusions. Our results suggest that mid-CPB RNFLT and GCCT, parameters of a novel papillomacular bundle analysis, are candidate biomarkers of decreased central visual function in glaucomatous eyes. PMID- 25821588 TI - Proteomic study of retinal proteins associated with transcorneal electric stimulation in rats. AB - Background. To investigate how transcorneal electric stimulation (TES) affects the retina, by identifying those proteins up- and downregulated by transcorneal electric stimulation (TES) in the retina of rats. Methods. Adult Wistar rats received TES on the left eyes at different electrical currents while the right eyes received no treatment and served as controls. After TES, the eye was enucleated and the retina was isolated. The retinas were analyzed by proteomics. Results. Proteomics showed that twenty-five proteins were upregulated by TES. The identified proteins included cellular signaling proteins, proteins associated with neuronal transmission, metabolic proteins, immunological factors, and structural proteins. Conclusions. TES induced changes in expression of various functional proteins in the retina. PMID- 25821589 TI - Clinical applications of anterior segment optical coherence tomography. AB - Anterior segment optical coherence tomography (AS-OCT) was recently developed and has become a crucial tool in clinical practice. AS-OCT is a noncontact imaging device that provides the detailed structure of the anterior part of the eyes. In this review, the author will discuss the various clinical applications of AS-OCT, such as the normal findings, tear meniscus measurement, ocular surface disease (e.g., pterygium, pinguecula, and scleromalacia), architectural analysis after cataract surgery, post-LASIK keratectasia, Descemet's membrane detachment, evaluation of corneal graft after keratoplasty, corneal deposits (corneal dystrophies and corneal verticillata), keratitis, anterior segment tumors, and glaucoma evaluation (angle assessment, morphological analysis of the filtering bleb after trabeculectomy, or glaucoma drainage device implantation surgery). The author also presents some interesting cases demonstrated via AS-OCT. PMID- 25821590 TI - Blockade of vascular endothelial growth factor receptor 1 prevents inflammation and vascular leakage in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. The objective of this study is to investigate the effects of vascular endothelial growth factor receptor 1 (VEGFR1) blockade on the complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ) treatment or Insulin2 gene mutation (Akita) in mice. Protein expression and localization were examined by western blots (WB) and immunofluorescence (IF). mRNA expression was quantified by PCR array and real-time PCR. The activity of VEGFR1 signaling was blocked by a neutralizing antibody called MF1. Vascular leakage was evaluated by measuring the leakage of [(3)H]-mannitol tracer into the retina and the IF staining of albumin. VEGFR1 blockade significantly inhibited diabetes-related vascular leakage, leukocytes-endothelial cell (EC) adhesion (or retinal leukostasis), expression of intercellular adhesion molecule- (ICAM-) 1 protein, abnormal localization and degeneration of the tight junction protein zonula occludens- (ZO-) 1, and the cell adhesion protein vascular endothelial (VE) cadherin. In addition, VEGFR1 blockade interfered with the gene expression of 10 new cytokines and chemokines: cxcl10, il10, ccl8, il1f6, cxcl15, ccl4, il13, ccl6, casp1, and ccr5. These results suggest that VEGFR1 mediates complications of DR and targeting this signaling pathway represents a potential therapeutic strategy for the prevention and treatment of DR. PMID- 25821591 TI - Retinal Neurodegeneration in db/db Mice at the Early Period of Diabetes. AB - Purpose. To describe both the functional and pathological alternations in neurosensory retina in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods. db/db (BKS/DB-/-) mice and heterozygous littermates (as control group) at various ages (12, 16, 20, 24, and 28 weeks) were inspected with pattern electroretinogram (PERG), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT). Histological markers of neuroinflammation (IBA-1 and F4/80) were evaluated by immunohistochemistry. In addition, levels of retinal ganglion cell death were measured by terminal dUTP nick-end labeling (TUNEL). Results. Significant alternations of PERG responses and increased retinal ganglion cells (RGCs) apoptosis were observed in diabetic db/db mice for 20-week period when compared with control group. IBA-1 and F4/80 expression in microglia/macrophages became evidently for 24-week period, thus supporting the PERG findings. Furthermore, obvious thinning of nasal and dorsal retina in 28 week-old db/db mice was also revealed by OCT. No visible retinal microvascular changes were detected by FFA throughout the experiments on db/db mice. Conclusions. Diabetic retina underwent neurodegenerative changes in db/db mice, which happened at retinal ganglion cell layer and inner nuclear layer. But there was no obvious abnormality in retinal vasculature on db/db mice. PMID- 25821593 TI - Prognostic factors of early morphological response to treatment with ranibizumab in patients with wet age-related macular degeneration. AB - Aim. To assess the significance of age, gender, baseline best corrected visual acuity, baseline macula thickness, and type and size of choroidal neovascularization in early morphological therapeutic response to ranibizumab treatment in patients with the wet form of age-related macular degeneration. Methods. From 09/2008 to 06/2013 we evaluated 1153 newly diagnosed, treatment naive patients treated with ranibizumab. Based on the morphological findings in the macula following the initial 3 injections of ranibizumab, the patients were divided into two groups based on active and inactive choroidal neovascularization. Results. After the initial 3 injections of ranibizumab, we examined the sample of 841 eyes with active CNV and 312 eyes with inactive CNV. In the inactive group, we found a statistically higher proportion of occult CNV (P < 0.001) and lower incidence of CNV greater than 5DA (P < 0.001) compared with the active group. We found no statistically significant difference in age, gender, baseline best corrected visual acuity, or baseline macula thickness between the inactive and active groups. Conclusion. Occult CNV and CNV smaller than 5DA are optimistic factors for a better morphological therapeutic response at the beginning of ranibizumab treatment. PMID- 25821592 TI - A review of current management of vitreomacular traction and macular hole. AB - The paper presents a review of the sequence of events of posterior vitreous detachment (PVD), vitreomacular adhesion (VMA), vitreomacular traction (VMT), and macular hole (MH) from their pathophysiological aspects, clinical features, diagnostic implications, and current management strategies. A treatment algorithm to be used in clinical practice in patients with VMA, VMT, and MH based on the presence of symptoms, visual acuity, associated epiretinal membrane, and width of the vitreous attachment is presented. Observation, pharmacologic vitreolysis with ocriplasmin, and surgical treatment are positioned as treatment options in the different steps of the therapeutic algorithm, with clear indications of the paths to be followed according to the initial presenting manifestations and the patient's clinical course. PMID- 25821596 TI - Predictors of Mortality among Adult Antiretroviral Therapy Users in Southeastern Ethiopia: Retrospective Cohort Study. AB - Background. Although efforts have been made to reduce AIDS-related mortality by providing antiretroviral therapy (ART) services, still people are dying while they are on treatment due to several factors. This study aimed to investigate the predictors of mortality among adult antiretroviral therapy (ART) users in Goba Hospital, Southeast Ethiopia. Methods. The medical records of 2036 ART users who enrolled at Goba Hospital between 2007 and 2012 were reviewed and sociodemographic, clinical, and ART-related data were collected. Multivariable Cox proportional hazards regression model was used to measure risk of death and identify the independent predictors of mortality. Results. The overall mortality incidence rate was 20.3 deaths per 1000 person-years. Male, bedridden, overweight/obese, and HIV clients infected with TB and other infectious diseases had higher odds of death compared with their respective counterparts. On the other hand, ART clients with primary and secondary educational level and early and less advanced WHO clinical stage had lower odds of death compared to their counterparts. Conclusion. The overall mortality incidence rate was high and majority of the death had occurred in the first year of ART initiation. Intensifying and strengthening early ART initiation, improving nutritional status, prevention and control of TB, and other opportunistic infections are recommended interventions. PMID- 25821594 TI - Sleep as a mediator in the pathway linking environmental factors to hypertension: a review of the literature. AB - Environmental factors, such as noise exposure and air pollution, are associated with hypertension. These environmental factors also affect sleep quality. Given the growing evidence linking sleep quality with hypertension, the purpose of this review is to investigate the role of sleep as a key mediator in the association between hypertension and environmental factors. Through this narrative review of the extant literature, we highlight that poor sleep quality mediates the relationship between environmental factors and hypertension. The conceptual model proposed in this review offers opportunities to address healthcare disparities in hypertension among African Americans by highlighting the disparate impact that the predictors (environmental factors) and mediator (sleep) have on the African American community. Understanding the impact of these factors is crucial since the main outcome variable (hypertension) severely burdens the African-American community. PMID- 25821595 TI - A study of the relationship between food group recommendations and perceived stress: findings from black women in the Deep South. AB - Black women in the Deep South experience excess morbidity/mortality from obesity related diseases, which may be partially attributable to poor diet. One reason for poor dietary intake may be high stress, which has been associated with unhealthy diets in other groups. Limited data are available regarding dietary patterns of black women in the Deep South and to our knowledge no studies have been published exploring relationships between stress and dietary patterns among this group. This cross-sectional study explored the relationship between stress and adherence to food group recommendations among black women in the Deep South. Participants (n = 355) provided demographic, anthropometric, stress (PSS-10), and dietary (NCI ASA-24 hour recall) data. Participants were obese (BMI = 36.5 kg/m(2)) and reported moderate stress (PSS-10 score = 16) and minimal adherence to Dietary Guidelines for Americans food group recommendations (1/3 did not meet recommendations for any food group). Participants reporting higher stress had higher BMIs than those reporting lower stress. There was no observed relationship between stress and dietary intake in this sample. Based on these study findings, which are limited by potential misreporting of dietary intake and limited variability in stress measure outcomes, there is insufficient evidence to support a relationship between stress and dietary intake. PMID- 25821597 TI - Prevalence of and Risk Factors for Lipoatrophy in Patients with HIV Infection in Nigeria. AB - Background. Although the association between lipoatrophy and highly active antiretroviral therapy (HAART) is well known, other nondrug factors may be associated with lipoatrophy in people living with HIV/AIDS (PLWHA). There are no reports of lipoatrophy from Nigeria, a country with the second largest number of PLWHA. We aimed to determine the prevalence, characteristics, and factors associated with lipoatrophy in a cohort of patients attending the HIV clinic in Lagos University Teaching Hospital, Nigeria. Methods. Two hundred and eighty eight patients with HIV infection were recruited for the study. The study protocol involved administration of a questionnaire, targeted physical examination (including anthropometric indices and skin fold thickness), and bioelectrical impedance analysis measurements. Lipoatrophy was defined clinically. Results. Lipoatrophy was present in 75 (26.0%) persons. It was associated with lower body circumferences, skin fold thicknesses, and lower % body fat with preservation of skeletal muscle mass (all P < 0.05). Male gender and HAART use were the factors associated with lipoatrophy on multivariate analysis (P < 0.05). Conclusion. Lipoatrophy is frequently encountered in patients with HIV infection in Nigeria, with HAART use conferring an added factor in its development. There is need for more physician and patient awareness of this condition. PMID- 25821598 TI - The versatility of autologous fat transplantation in correction of facial deformities: a single-center experience. AB - Deformities in the craniofacial region are of great social and functional importance. Several surgical techniques have been used to treat such pathologies often with high morbidity and lacking the ability to address smaller contour defects. The minimally invasive technique of fat transplantation has evolved rapidly within the last few decades. The objective of this paper is to present the versatility and applicability of fat transplantation in a wide range of contour deformities in the craniofacial region. We share our experiences in treating 13 patients with autoimmune disorders, congenital malformations, and acquired defects. Future perspectives of fat transplantation in the field of craniofacial reconstruction are discussed. PMID- 25821599 TI - Identification of Putative Molecular Markers Associated with Root Traits in Coffea canephora Pierre ex Froehner. AB - Coffea canephora exhibit poor root system and are very sensitive to drought stress that affects growth and production. Deeper root system has been largely empirical as better avoidance to soil water limitation in drought condition. The present study aimed to identify molecular markers linked to high root types in Coffea canephora using molecular markers. Contrasting parents, L1 valley with low root and S.3334 with high root type, were crossed, and 134 F1 individuals were phenotyped for root and associated physiological traits (29 traits) and genotyped with 41 of the 320 RAPD and 9 of the 55 SSR polymorphic primers. Single marker analysis was deployed for detecting the association of markers linked to root associated traits by SAS software. There were 13 putative RAPD markers associated with root traits such as root length, secondary roots, root dry weight, and root to shoot ratio, in which root length associated marker OPS1850 showed high phenotypic variance of 6.86%. Two microsatellite markers linked to root length (CPCM13400) and root to shoot ratio (CM211300). Besides, 25 markers were associated with more than one trait and few of the markers were associated with positively related physiological traits and can be used in marker assisted trait selection. PMID- 25821600 TI - Knowledge and confidence of a convenience sample of australasian emergency doctors in managing dental emergencies: results of a survey. AB - Background. We aimed to determine Australasian Specialist Emergency Physicians' and Emergency Physicians in Training (Trainees') level of knowledge of common dental emergencies. We also explored confidence in managing dental emergencies; predictors of confidence and knowledge; and preferences for further dental education. Methods. A questionnaire was distributed electronically (September 2011) and directly (November 2011) to Fellows and Trainees of the Australasian College for Emergency Medicine. It explored demographics, confidence, knowledge of dental emergencies, and educational preferences. Results. Response rate was 13.6% (464/3405) and college members were proportionally represented by region. Fewer than half (186/446; 42%) had received dental training. Sixty-two percent (244/391, 95% CI 57.5-67.1) passed (>50%) a knowledge test. More than 60% incorrectly answered questions on dental fracture, periodontal abscess, tooth eruption dates, and ulcerative gingivitis. Forty percent (166/416) incorrectly answered a question about Ludwig's Angina. Eighty-three percent (360/433) were confident in the pharmacological management of toothache but only 26% (112/434) confident in recognizing periodontal disease. Knowledge was correlated with confidence (r = 0.488). Interactive workshops were preferred by most (386/415, 93%). Conclusions. The knowledge and confidence of Australasian Emergency Physicians and Trainees in managing dental emergencies are varied, yet correlated. Interactive training sessions in dental emergencies are warranted. PMID- 25821601 TI - Early maternal deprivation enhances voluntary alcohol intake induced by exposure to stressful events later in life. AB - In the present study, we aimed to assess the impact of early life stress, in the form of early maternal deprivation (MD, 24 h on postnatal day, pnd, 9), on voluntary alcohol intake in adolescent male and female Wistar rats. During adolescence, from pnd 28 to pnd 50, voluntary ethanol intake (20%, v/v) was investigated using the two-bottle free choice paradigm. To better understand the relationship between stress and alcohol consumption, voluntary alcohol intake was also evaluated following additional stressful events later in life, that is, a week of alcohol cessation and a week of alcohol cessation combined with exposure to restraint stress. Female animals consumed more alcohol than males only after a second episode of alcohol cessation combined with restraint stress. MD did not affect baseline voluntary alcohol intake but increased voluntary alcohol intake after stress exposure, indicating that MD may render animals more vulnerable to the effects of stress on alcohol intake. During adolescence, when animals had free access to alcohol, MD animals showed lower body weight gain but a higher growth rate than control animals. Moreover, the higher growth rate was accompanied by a decrease in food intake, suggesting an altered metabolic regulation in MD animals that may interact with alcohol intake. PMID- 25821602 TI - Age-related alterations in the expression of genes and synaptic plasticity associated with nitric oxide signaling in the mouse dorsal striatum. AB - Age-related alterations in the expression of genes and corticostriatal synaptic plasticity were studied in the dorsal striatum of mice of four age groups from young (2-3 months old) to old (18-24 months of age) animals. A significant decrease in transcripts encoding neuronal nitric oxide (NO) synthase and receptors involved in its activation (NR1 subunit of the glutamate NMDA receptor and D1 dopamine receptor) was found in the striatum of old mice using gene array and real-time RT-PCR analysis. The old striatum showed also a significantly higher number of GFAP-expressing astrocytes and an increased expression of astroglial, inflammatory, and oxidative stress markers. Field potential recordings from striatal slices revealed age-related alterations in the magnitude and dynamics of electrically induced long-term depression (LTD) and significant enhancement of electrically induced long-term potentiation in the middle-aged striatum (6-7 and 12-13 months of age). Corticostriatal NO-dependent LTD induced by pharmacological activation of group I metabotropic glutamate receptors underwent significant reduction with aging and could be restored by inhibition of cGMP hydrolysis indicating that its age-related deficit is caused by an altered NO-cGMP signaling cascade. It is suggested that age-related alterations in corticostriatal synaptic plasticity may result from functional alterations in receptor-activated signaling cascades associated with increasing neuroinflammation and a prooxidant state. PMID- 25821603 TI - Intensity sensitive modulation effect of theta burst form of median nerve stimulation on the monosynaptic spinal reflex. AB - The effects of electrical stimulation of median nerve with a continuous theta burst pattern (EcTBS) on the spinal H-reflex were studied. Different intensities and durations of EcTBS were given to the median nerve to 11 healthy individuals. The amplitude ratio of the H-reflex to maximum M wave (H/M ratio), corticospinal excitability and inhibition measured using motor evoked potentials (MEPs), short interval intracortical inhibition and facilitation (SICI/ICF), spinal reciprocal inhibition (RI), and postactivation depression (PAD) were measured before and after EcTBS. In result, the H/M ratio was reduced followed by EcTBS at 90% H reflex threshold, and the effect lasted longer after 1200 pulses than after 600 pulses of EcTBS. In contrast, EcTBS at 110% threshold facilitated the H/M ratio, while at 80% threshold it had no effect. Maximum M wave, MEPs, SICI/ICF, RI, and PAD all remained unchanged after EcTBS. In conclusion, EcTBS produced lasting effects purely on the H-reflex, probably, through effects on postsynaptic plasticity. The effect of EcTBS depends on the intensity and duration of stimulation. EcTBS is beneficial to research on mechanisms of human plasticity. Moreover, its ability to modulate spinal excitability is expected to have therapeutic benefits on neurological disorders involving spinal cord dysfunction. PMID- 25821604 TI - Cerebellar transcranial direct current stimulation effects on saccade adaptation. AB - Saccade adaptation is a cerebellar-mediated type of motor learning in which the oculomotor system is exposed to repetitive errors. Different types of saccade adaptations are thought to involve distinct underlying cerebellar mechanisms. Transcranial direct current stimulation (tDCS) induces changes in neuronal excitability in a polarity-specific manner and offers a modulatory, noninvasive, functional insight into the learning aspects of different brain regions. We aimed to modulate the cerebellar influence on saccade gains during adaptation using tDCS. Subjects performed an inward (n = 10) or outward (n = 10) saccade adaptation experiment (25% intrasaccadic target step) while receiving 1.5 mA of anodal cerebellar tDCS delivered by a small contact electrode. Compared to sham stimulation, tDCS increased learning of saccadic inward adaptation but did not affect learning of outward adaptation. This may imply that plasticity mechanisms in the cerebellum are different between inward and outward adaptation. TDCS could have influenced specific cerebellar areas that contribute to inward but not outward adaptation. We conclude that tDCS can be used as a neuromodulatory technique to alter cerebellar oculomotor output, arguably by engaging wider cerebellar areas and increasing the available resources for learning. PMID- 25821605 TI - Acute Spontaneous Coronary Artery Thrombosis as Initial Presentation of HIV Infection in a Young Man. AB - Introduction. The presentation of acute coronary syndrome (ACS) in young HIV patients may be atypical with different pathophysiological and clinical features. Acute coronary thrombosis, as a presentation of acute coronary syndrome in young patients with HIV, raises diagnostic and treatment challenges. Case Presentation. We describe a case of a 33-year-old African man, without traditional atherosclerotic risk factors, who presented with chest pain of acute onset. Emergent coronary angiography revealed extensive thrombus in the left anterior descending coronary artery with no evidence of atherosclerosis in this or other coronary vessels. Plaque and/or thrombus prolapse through the stent was noted following percutaneous coronary intervention (PCI). Resolution of chest pain and improvement in ST-segment elevation was noted after the procedure. A diagnosis of HIV infection was made during the workup for HIV infection. Conclusion. In young patients without traditional risk factors, HIV infection is a possible etiological factor for spontaneous coronary artery thrombosis. Percutaneous coronary intervention in patients with this presentation may be compounded with atherothrombotic complications. The likely pathophysiological pathway is superficial endothelial cell denudation as a result of chronic inflammation and immune activation. PMID- 25821606 TI - Warthin-Like Papillary Thyroid Carcinoma Associated with Lymphadenopathy and Hashimoto's Thyroiditis. AB - Defining the histologic variant of thyroid carcinoma is an important clinical implication as their progression, recurrence, aggressiveness, and prognosis differ. Warthin-like variant is one of the rarest histologic variants of papillary thyroid cancer. A 36-year-old female sought consult for assessment of a painless right neck tumor. High-resolution neck ultrasound revealed a right hypoechoic, 1.71 * 1.05 cm thyroid nodule. Ultrasound-guided fine-needle aspiration biopsy report was a Bethesda grade III. Thyroid function tests showed Hashimoto's thyroiditis. The patient underwent right hemithyroidectomy. Microscopically, the tumor was composed of papillae lined by cells with eosinophilic cytoplasm, nuclear chromatin clearing, grooves, and pseudoinclusions and a characteristic lymphoplasmacytic infiltrate of the papillae cores. Extension into the perithyroidal soft tissue and 3 ipsilateral lymph nodes was found to be positive for cancer. Warthin-like variant is an uncommon and relatively unknown variant of papillary thyroid carcinoma that has been usually associated with an excellent prognosis. Interestingly, BRAF mutations have been reported to be present in up to 75% of the patients. It is frequently associated with Hashimoto's thyroiditis and presents unique morphological features that make it recognizable on histologic examination. The cytological diagnosis is difficult to assess due to the overlap in its findings with the classical variant and Hashimoto's thyroiditis. PMID- 25821607 TI - Autoimmune polyendocrine syndrome 3 onset with severe ketoacidosis in a 74-year old woman. AB - Type 1 diabetes mellitus (T1D), autoimmune thyroid disease, and autoimmune gastritis often occur together forming the so-called autoimmune polyendocrine syndrome type 3 (APS3). We here report a clinical case of a 74-year-old woman who presented for the first time with severe hyperglycemia and ketoacidosis diagnosed as T1D. Further clinical investigations revealed concomitant severe hypothyroidism with autoimmune thyroid disease and severe cobalamin deficiency due to chronic atrophic gastritis. The diagnosis of type 1 diabetes mellitus was confirmed by the detection of autoantibodies against glutamic acid decarboxylase 65, islet cell antibodies, and anti-insulin autoantibodies. Anti-thyroperoxidase, anti-thyroglobulin, and anti-gastric parietal cell antibodies were also clearly positive. The case emphasized that new onset diabetic ketoacidosis, hypothyroidism, and cobalamin deficiency may simultaneously occur, and one disease can mask the features of the other, thereby making diagnosis difficult. It is noteworthy that an APS3 acute episode occurred in an asymptomatic elder woman for any autoimmune diseases. PMID- 25821608 TI - A Complicated Case of Acute Promyelocytic Leukemia in the Second Trimester of Pregnancy Successfully Treated with All-trans-Retinoic Acid. AB - A 40-year-old female at 26-week gestation was diagnosed with acute promyelocytic leukemia (APL) after an abnormal prenatal lab workup showed pancytopenia. She was treated with all-trans-retinoic acid (ATRA), idarubicin, and dexamethasone. After day one of treatment, she developed differentiation syndrome, which was treated with dexamethasone. At 30-week gestation, she had preterm premature rupture of membranes and delivered by cesarean section because of the fetus' breech presentation. Despite ATRA's potential for teratogenicity, a viable infant was born without apparent anomalies. Postpartum, she underwent consolidation treatment with ATRA and arsenic trioxide (ATO). The patient continued ATRA therapy after delivery and is currently in remission. PMID- 25821609 TI - Fulminant Shigellosis in a HIV Patient. AB - Infectious enterocolitis caused by shigella is usually self-limiting and seldom requires antibiotics treatment. It is uncommon to develop fulminant shigellosis requiring surgery. We report a rare case of fulminant shigellosis in a HIV patient with recurring infection which could not be managed with intravenous antibiotics. CT reviewed extensive colonic wall thickening and stranding with evidence of pneumatosis coli. The patient eventually required a Hartmann procedure. Although fulminant shigellosis is uncommon, thorough assessment and vigilant management are warranted in immunosuppressed patient. PMID- 25821610 TI - Brain abscess after percutaneous therapy for trigeminal neuralgia. AB - We report a case of brain abscess following the percutaneous treatment for trigeminal neuralgia. This procedure envisages the access with a needle into the middle cranial fossa through the oral cavity. Thus, in this case, the bacterial infection can be more likely ascribed to the possible contamination of the needle inside the oral cavity rather than to other frequent and more controllable causes of infection like an imperfect sterilization of surgical instruments or an inadequate antiseptic preparation of both operator's hands and patient's skin. The subsequent brain abscess was treated with antibiotic therapy (Vancomycin 2 gr a day and Meropenem 8 g a day for 22 days before the surgical procedure and 30 days after, until complete normalization of laboratory parameters, clinical parameters, and neurological symptoms) and surgical drainage, although the culture of the abscess capsule and the purulent material resulted sterile. In conclusion, the percutaneous therapy for trigeminal neuralgia can be objectively related to risks, even if performed by expert hands. Therefore, it is important that the patient should be advised regarding risks/benefits and/or septic complications of such procedures, even if they occur very seldom. An association of surgery and antibiotic therapy results as effective treatment for this pathologic condition. PMID- 25821611 TI - Disseminated Nocardiosis: A Successful Blind Strategy of Treatment in an HIV Infected Patient. AB - Background. Nocardiosis is a rare disease that mainly affects severely immunocompromised patients. Symptoms are nonspecific and microbiological isolation is difficult, hiding the diagnosis. Treatment should be guided by species and susceptibility testing. Findings. We report a clinical case of a disseminated nocardiosis in a patient with HIV and HVB infections. Interpretation. Diagnosis should be presumed early and microbiological conditions should be optimized, in order to identify the species and achieve antibiotic susceptibility testing. This is a very important step to choose an effective therapeutic regimen or alternative options. PMID- 25821612 TI - Lichen planus induced by pegylated interferon alfa-2a therapy in a patient monitored for delta hepatitis. AB - Interferons are used for treatment of chronic hepatitis B. They can induce or exacerbate some skin disorders, such as lichen planus. In this study, as we know, we presented the first case developing lichen planus while receiving interferon treatment due to delta hepatitis. A 31-year-old male patient presented to our outpatient clinic with HBsAg positivity. With his analyses, HBV DNA was negative, anti-delta total was positive, ALT was 72 U/L (upper limit 41 U/L), and platelet was 119 000/mm(3). He was therefore started on subcutaneous pegylated interferon alfa-2a therapy at 180 mcg/week for delta hepatitis. At month 4 of therapy, the patient developed diffuse eroded lace-like lesions in oral mucosa, white plaques on lips, and itchy papular lesions in the hands and feet. Lichen planus was considered by the dermatology clinic and topical treatment (mometasone furoate) was given. The lesions persisted at month 5 of therapy and biopsy samples were obtained from oral mucosal lesions and interferon dose was reduced to 135 mcg/week. Biopsy demonstrated nonkeratinized stratified squamous epithelium; epithelial acanthosis, spongiosis, and apoptotic bodies were observed in the epidermis and therefore lichen planus was considered. At month 6 of therapy, lesions did not improve and even progressed and interferon treatment was therefore discontinued. PMID- 25821613 TI - Family Outbreaks of Nontyphoidal Salmonellosis following a Meal of Guinea Pigs. AB - Salmonella outbreaks have been linked to a wide variety of foods, including recent nationwide outbreaks. Guinea pig (Cavia porcellus), also known as cuy or cobayo, has long been a popular delicacy and ceremonial food in the Andean region in South America. This case report describes three family outbreaks of nontyphoidal salmonellosis, each occurring after a meal of guinea pigs. We believe this case report is the first to describe a probable association between the consumption of guinea pig meat and human salmonellosis. Physicians should be aware of the association of Salmonella and the consumption of guinea pigs, given the increasing immigration of people from the Andean region of South America and the increasing travel to this region. PMID- 25821614 TI - The impact of intensified hemodialysis on pruritus in an end stage renal disease patient with biliary ductopenia. AB - We report a unique observation characterized by the coexistence of idiopathic adulthood ductopenia (IAD), a rare cholestatic disease, and end stage renal failure treated by conventional hemodialysis in a patient awaiting double renal and liver transplantation. As pruritus gradually worsened, we hypothesized that intensified dialysis could alleviate the symptoms. Conventional hemodialysis following 3 hours/3 times a week regimen was initiated in December 2013. Due to increasing pruritus not responding to standard medical therapy, intensified hemodialysis following 2.5 hours/5 times a week regimen was started in May 2014. During two weeks, a temporary decrease in bilirubin levels was observed. No major changes on other liver function tests and inflammatory markers occurred. Nevertheless, a persistent improvement on pruritus and general wellbeing was obtained during the four weeks' study period. The pathogenesis of itch encompasses multiple factors, and, in our case, both uremic and cholestatic pruritus are involved, although the latter is likely to account for a greater proportion. By improving itch intensity, through better clearance of uremic and cholestatic toxins which we detail further, intensive dialysis appears to be an acceptable short-term method for patients with hepatic cholestasis and moderate pruritus not responding to conventional therapy. Additional studies are needed to assess and differentiate precisely factors contributing to pruritus of both origins. PMID- 25821615 TI - Acute dysphasia and reversible cognitive decline in a patient with probable cerebral amyloid angiopathy-related inflammation. AB - Cerebral amyloid angiopathy related inflammation (CAAri) is becoming increasingly recognised as a subset of cerebral amyloid angiopathy (CAA). CAAri generally presents with subacute cognitive decline, headaches, seizures, behavioral changes, and focal neurological deficits. We describe a patient who developed acute dysphasia and reversible cognitive decline due to probable CAAri. CT brain showed bilateral vasogenic edema in the cerebral hemispheres, predominantly involving the parietal and temporal lobes, left greater than right without enhancement. Magnetic resonance brain imaging showed extensive multifocal areas of subcortical white matter T2 hyperintensity in the frontal and temporal regions with associated mass effect, negligible enhancement, and multiple foci of microhemorrhage on susceptibility weighted imaging sequences consistent with a diagnosis of probable CAAri. She responded dramatically to a course of intravenous methylprednisolone followed by further immunosuppression with pulse intravenous cyclophosphamide. Her dysphasia resolved within 5 days of intravenous methylprednisolone therapy. Her MMSE improved from 11/30 at day 5 of admission to 28/30 at 6-month follow-up. The notable features of our case were the unusual CT findings, which were inconsistent with stroke and diagnostic utility of susceptibility-weighted magnetic resonance imaging in confirming the diagnosis which allowed for prompt institution of immunosuppression. PMID- 25821616 TI - Tracheal agenesis: a challenging prenatal diagnosis-contribution of fetal MRI. AB - Tracheal agenesis is a rare congenital anomaly. The prevalence is less than 1 : 50 000 with a male to female ratio of 2 : 1. This anomaly may be isolated but, in 93% of cases, it is part of polymalformative syndrome. The most evocative diagnosis situation is the ultrasonographic congenital high airway obstruction syndrome. Dilated airways, enlarged lungs with flattened diaphragm, fetal ascites and severe nonimmune hydrops can be observed. In the absence of a congenital high airway obstruction syndrome, the antenatal diagnosis of tracheal agenesis is difficult. Tracheal agenesis should be suspected in the presence of an unexplained polyhydramnios associated with congenital malformations. The fetal airway exploration should then be systematically performed by fetal thoracic magnetic resonance imaging. A case of Floyd's type II tracheal agenesis, detected during the postnatal period, is reported here. The retrospective reexamination of fetal magnetic resonance images showed that the antenatal diagnosis would have been easy if a systematical examination of upper airways had been performed. Prenatal diagnosis of tracheal agenesis is possible with fetal MRI but the really challenge is to think about this pathology. PMID- 25821617 TI - Drug resistant fetal arrhythmia in obstetric cholestasis. AB - Obstetric cholestasis (OC) is a pregnancy specific liver disease characterized by increased levels of bile acid (BA) and pruritus. Raised maternal BA levels could be associated with intrauterine death, fetal distress, and preterm labor and also alter the rate and rhythm of cardiomyocyte contraction and may cause fetal arrhythmic events. We report a case of drug resistant fetal supraventricular tachycardia and concomitant OC. Conclusion. If there are maternal OC and concomitant fetal arrhythmia, possibility of the resistance to antiarrhythmic treatment should be kept in mind. PMID- 25821618 TI - Primary borderline mucinous tumors of the testis: a case report and literature review. AB - Ovarian-type epithelial tumors of the testes and paratestes are very rare. Mucinous subtypes of such tumors are extremely rare; only 25 cases have been reported to date. Ovarian-type epithelial tumors are histologically classified into cystadenomas, borderline tumors, and carcinomas. We herein report a case involving a 60-year-old man with a primary borderline mucinous tumor of the testis. He underwent orchiectomy and has developed no recurrence for 4 years. This is the 26th report of a mucinous tumor of the testis in the literature. We also herein review the literature and discuss the etiology, prognosis, and treatment of mucinous tumors of the testes. PMID- 25821619 TI - Intravitreal aflibercept injection and photodynamic treatment of a patient with unilateral subretinal neovascular membrane associated with fundus flavimaculatus. AB - We report the good outcome of combined intravitreal aflibercept injection and photodynamic treatment in a case with fundus flavimaculatus (FFM) and unilateral subretinal neovascular membrane (SRNM). A 57-year-old man with FFM and unilateral SRNM who was treated with two consecutive ranibizumab injections with no improvement at another institution was referred to us. He was treated successfully with three aflibercept injections three months apart and a single photodynamic treatment performed a week after the initial aflibercept injection. Six weeks after the last aflibercept injection visual acuity was improved and submacular exudation exhibited dramatic resolution with a moderate degree of residual scarring. SRNM formation is rarely observed in eyes with FFM and a satisfactory outcome can be achieved with a proper treatment. PMID- 25821620 TI - Massive temporal lobe cholesteatoma. AB - Introduction. Intracranial extension of cholesteatoma is rare. This may occur de novo or recur some time later either contiguous with or separate to the site of the original cholesteatoma. Presentation of Case. A 63-year-old female presented to a tertiary referral hospital with a fluctuating level of consciousness, fever, headache, and right-sided otorrhoea, progressing over several days. Her past medical history included surgery for right ear cholesteatoma and drainage of intracranial abscess 23 years priorly. There had been no relevant symptoms in the interim until 6 weeks prior to this presentation. Imaging demonstrated a large right temporal lobe mass contiguous with the middle ear and mastoid cavity with features consistent with cholesteatoma. The patient underwent a combined transmastoid/middle fossa approach for removal of the cholesteatoma and repair of the tegmen dehiscence. The patient made an uneventful recovery and remains well over 12 months later. Conclusion. This case presentation details a large intracranial cholesteatoma which had extended through a tegmen tympani dehiscence from recurrent right ear cholesteatoma treated by modified radical mastoidectomy over two decades priorly. There was a completely asymptomatic progression of disease until several weeks prior to this presentation. PMID- 25821621 TI - Acute traumatic injury of the larynx. AB - Laryngeal trauma is rare but serious and potentially deadly injury. The prompt diagnosis and management of acute laryngeal trauma is necessary because the clinical presentation is variable depending on the location, severity, and mechanism of injury. Two case histories are presented: (1) case history A: a 53 year-old male, after motor vehicle accident, fractured the mid anterior thyroid cartilage and both aspects of the cricoid cartilage; however, this patient was asymptomatic from the above fractures; and (2) case history B: a 41-year-old male who sustained trauma to the chest, neck, and left arm after being struck by a large lead pipe which fractured the left aspect of the cricoid cartilage was symptomatic. The type rather than the severity of acute laryngeal injury and the mechanism of injury may be related to symptomatology. Acute laryngeal trauma should be recognized by trauma radiologists and emergency room physicians. Early diagnosis and management of acute laryngeal trauma may prevent unnecessary specialty consults and long-term complications. PMID- 25821622 TI - Robust and sustained effect of ketamine infusions coadministered with conventional antidepressants in a patient with refractory major depression. AB - Antidepressant treatments show low capacity to achieve full clinical remissions. Electroconvulsive therapy is an alternative treatment which has been shown to be more effective but it is not well tolerated and there are concerns regarding its safety. We present the case of a patient with resistant depression and modest and transient response to ECT and who showed a robust and maintained response after six i.v. ketamine (0.5 mg/kg) infusions without withdrawing her antidepressant regimen. Ketamine was very well tolerated. This case illustrates the potential role of ketamine as a booster to standard antidepressants. PMID- 25821623 TI - Transcatheter Arterial Coil Embolization of Ruptured Common Hepatic Artery Aneurysm in a Patient with Behcet's Disease. AB - Hepatic artery aneurysm is a rare and potentially life-threatening entity. We report a case of ruptured common hepatic artery aneurysm in a patient with Behcet's disease. The ruptured aneurysm was treated successfully with transcatheter arterial coil embolization. Transcatheter arterial embolization is the preferred treatment modality in patients at high risk of surgical intervention. PMID- 25821624 TI - Bullous systemic lupus erythematosus associated with esophagitis dissecans superficialis. AB - Bullous systemic lupus erythematosus is one of the rare autoantibody mediated skin manifestation of systemic lupus erythematosus (SLE) demonstrating subepidermal blistering with neutrophilic infiltrate histologically. We present a case of a 40-year-old Hispanic female who presented with a several months' history of multiple blistering pruritic skin lesions involving the face and trunk, a photosensitive rash over the face and neck, swelling of the right neck lymph node, and joint pain involving her elbows and wrist. Her malady was diagnosed as bullous systemic lupus erythematosus based on the immunological workup and biopsy of her skin lesions. The patient also complained of odynophagia and endoscopy revealed esophagitis dissecans superficialis which is a rare endoscopic finding characterized by sloughing of the esophageal mucosa. The bullous disorders typically associated with esophagitis dissecans superficialis are pemphigus and rarely bullous pemphigoid. However, this is the first reported case of bullous systemic lupus erythematosus associated with esophagitis dissecans superficialis. PMID- 25821625 TI - Congenital agenesis of the internal jugular vein: an extremely rare anomaly. AB - Vascular anomalies of major venous vessels are rarely seen. Moreover, congenital absence of internal jugular vein is extremely uncommon. In our case, a female patient presented with primary unknown left cervical mass. Cervical ultrasonography demonstrated absence of right internal jugular vein. In addition, computed tomography and dynamic magnetic resonance imaging scans confirmed this diagnosis. Compensatory left internal jugular vein enlargement mimicked sort of cervical mass. Venous magnetic resonance imaging images revealed the absence of right internal jugular vein with compensatory left internal jugular vein dominance. In the literature, the agenesis of IJV was mentioned in a case with concomitant multiple problems. Here, an asymptomatic case is reported with an incident diagnosis. No interventions were planned upon the patient's request. It should be kept in mind that any kind of anomalies can be seen during venous access and neck surgery. PMID- 25821626 TI - Limy bile syndrome complicated with primary hyperparathyroidism. AB - Limy bile is a relatively rare condition, in which a radiopaque material is visible in the gallbladder on plain radiography or computerized tomography. Cases of complicated hyperparathyroidism are extremely rare. We report a patient with right upper quadrant and epigastric pain and extremity weakness in whom abdominal tomography showed limy bile in the gallbladder and laboratory values showed high levels of serum calcium and parathormone. PMID- 25821627 TI - Prostate cancer metastatic to the cervical lymph nodes. AB - Prostate cancer is the most common cancer in men, often presenting with regional lymph node or bone metastasis and rarely with supradiaphragmatic lymph node involvement. Most metastatic cancers involving the cervical lymph nodes are from cancers of the upper aerodigestive tract. In this report, we describe two cases with cervical lymph node enlargement due to metastatic prostate cancer as the initial clinical presentation: a 43-year-old male, initially misdiagnosed with a tumor of the upper aerodigestive tract and an 87-year-old male with right lobe pneumonia and cervical lymph node enlargement, initially attributed to be an acute inflammatory lymph node reaction. To the best of our knowledge, there are less than 50 cases reported in the literature of adenocarcinoma of prostate metastatic to the cervical lymph nodes and only one case presenting in men younger than 45 years. The authors intend to highlight the importance of digital rectal exam and PSA test in case of persistent left cervical lymph node enlargement, including men younger than 45 years of age. PMID- 25821628 TI - Mediastinal B-cell lymphoma presenting with jugular-subclavian deep vein thrombosis as the first presentation. AB - Jugular venous thrombosis infrequently could be secondary to malignancy and has seldom been reported secondary to mediastinal large B-cell lymphomas. The postulated mechanisms are mechanical compression that leads to stagnation of blood in the venous system of the neck and/or an increase in the circulating thrombogenic elements that could cause venous thromboembolism as a paraneoplastic phenomenon. We report the case of a middle aged male presenting with right sided neck pain and arm swelling secondary to ipsilateral jugular-subclavian deep vein thrombosis. Investigations revealed it to be secondary to a mediastinal mass shown on CT scan of the chest. PMID- 25821629 TI - Predictors of intention to quit waterpipe smoking: a survey of arab americans in houston, Texas. AB - Waterpipe smoking has been described as "the second global tobacco epidemic since the cigarette." Both Middle Eastern ethnicity and having a friend of Middle Eastern ethnicity have been reported as significant predictors of waterpipe smoking. Addressing waterpipe smoking in this ethnic minority is essential to controlling this growing epidemic in the US. We investigated the predictors of an intention to quit waterpipe smoking by surveying 340 Arab American adults in the Houston area. Primary analyses were conducted using stepwise logistic regression. Only 27% of participants reported having an intention to quit waterpipe smoking. Intention to quit waterpipe smoking was significantly higher with history of cigar use, a prior attempt to quit, and not smoking when seriously ill and significantly lower with increasing age, medium cultural acceptability of using waterpipe among family, high cultural acceptability of using waterpipe among friends, longer duration of smoking sessions, and perceiving waterpipe smoking as less harmful than cigarettes. Educational programs that target Arab Americans in general, and specifically older adults, those who smoke waterpipe for more than 60 minutes, those whose family and friends approve waterpipe smoking, and those with no former attempts to quit, may be necessary to increase the intention to quit waterpipe smoking. PMID- 25821630 TI - Inhibitory effects of sodium arsenite and acacia honey on acetylcholinesterase in rats. AB - This study was conducted to investigate the effect of sodium arsenite and Acacia honey on acetylcholinesterase (AChE) activity and electrolytes in the brain and serum of Wistar rats. Male Wistar albino rats in four groups of five rats each were treated with distilled water, sodium arsenite (5 mg/kg body weight), Acacia honey (20% v/v), and sodium arsenite and Acacia honey, daily for one week. The sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the brain with the combined treatment being more potent. Furthermore, sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the serum. Strong correlation was observed between the sodium and calcium ion levels with acetylcholinesterase activity in the brain and serum. The gas chromatography mass spectrometry analysis of Acacia honey revealed the presence of a number of bioactive compounds such as phenolics, sugar derivatives, and fatty acids. These findings suggest that sodium arsenite and/or Acacia honey modulates acetylcholinesterase activities which may be explored in the management of Alzheimer's diseases but this might be counteracted by the hepatotoxicity induced by arsenics. PMID- 25821631 TI - Serum levels of proinflammatory cytokines in painful knee osteoarthritis and sensitization. AB - Osteoarthritis (OA) is the most common joint disorder in the world. Among the mechanisms involved in osteoarthritis, biomarkers (cytokines profile) may be related to pain and pain intensity, functional capacity, and pressure pain thresholds (PPT). Thus, the study of these relationships may offer useful information about pathophysiology and associated mechanisms involved in osteoarthritis. Therefore, the objective of this study was to investigate the seric concentration of pro (IL-6, IL-8, and TNF-alpha) and anti-inflammatory (IL 10) cytokines in patients with painful knee osteoarthritis and to correlate the levels of these biomarkers with the patients' functional capacity and pressure pain threshold (PPT) values. PMID- 25821632 TI - Quantitative determination of lercanidipine enantiomers in commercial formulations by capillary electrophoresis. AB - An enantioselective method based on capillary electrophoresis (CE) using cyclodextrin (CD) as chiral selector was developed and validated for determination of lercanidipine (LER) enantiomers, a drug calcium channel blocker which exerts antihypertensive effects of long duration, in a pharmaceutical formulation. Optimum separation of LER enantiomers was obtained on a 50 cm * 50 MUm id capillary using a sodium acetate buffer solution 200 mmol/L pH 4.0 containing 10 mmol/L of 2,3,6-o-methyl-beta-cyclodextrin (TM-beta-CD) as background electrolyte. The capillary temperature and voltage were 15 degrees C and 25 kV, respectively, hydrodynamic injection and detection at 237 nm. Linearity was obtained in the range 12.5-100 MUg/mL for both enantiomers (r >= 0.995). The RSD (%) and relative errors (E, %) obtained in precision and accuracy studies (intraday and interday) were lower than 5%. After validation, the method was applied to quantify the enantiomers of LER in commercial tablets and the results were satisfactory in terms of accuracy and precision, both less than 5%. Therefore, this method was found to be appropriate for enantioselective quality control of LER enantiomers in pharmaceutical formulations. PMID- 25821633 TI - Behaviour of silica and florisil as solid supports in the removal process of as(v) from aqueous solutions. AB - In this study two solid supports, silica and florisil, were impregnated with crown ether (dibenzo-18-crown-6) and Fe(III) ions and their efficiency was compared in the adsorption process of As(V) from aqueous solutions. The solid supports were impregnated with crown ether due to their ability to build complexes with positives ions. Fe(III) was used because of As(V) affinity for it. The impregnated solid supports were characterized by energy dispersive X-ray analysis, scanning electron microscopy, Fourier transform infrared spectroscopy, and the specific surface area. The influence of the solid : liquid ratio on the adsorption process, kinetic studies for the pseudo-first-order and pseudo-second order, and activation energy were studied. Thermodynamic studies as well as equilibrium studies were carried out. The obtained results showed that, from the two considered materials, impregnated silica presents a higher efficiency with a good selectivity, able to remove As(V) from aqueous solutions containing trace concentrations. PMID- 25821634 TI - Robust PLS Prediction Model for Saikosaponin A in Bupleurum chinense DC. Coupled with Granularity-Hybrid Calibration Set. AB - This study demonstrated particle size effect on the measurement of saikosaponin A in Bupleurum chinense DC. by near infrared reflectance (NIR) spectroscopy. Four types of granularity were prepared including powder samples passed through 40 mesh, 65-mesh, 80-mesh, and 100-mesh sieve. Effects of granularity on NIR spectra were investigated, which showed to be wavelength dependent. NIR intensity was proportional to particle size in the first combination-overtone and combination region. Local partial least squares model was constructed separately for every kind of samples, and data-preprocessing techniques were performed to optimize calibration model. The 65-mesh model exhibited the best prediction ability with root mean of square error of prediction (RMSEP) = 0.492 mg.g(-1), correlation coefficient (R P ) = 0.9221, and relative predictive determinant (RPD) = 2.58. Furthermore, a granularity-hybrid calibration model was developed by incorporating granularity variation. Granularity-hybrid model showed better performance than local model. The model performance with 65-mesh samples was still the most accurate with RMSEP = 0.481 mg.g(-1), R P = 0.9279, and RPD = 2.64. All the results presented the guidance for construction of a robust model coupled with granularity-hybrid calibration set. PMID- 25821637 TI - Stop Aging Disease! ICAD 2014. AB - On November 1-2, 2014, there took place in Beijing, China, the first International Conference on Aging and Disease (ICAD 2014) of the International Society on Aging and Disease (ISOAD). The conference participants presented a wide and exciting front of work dedicated to amelioration of aging-related conditions, ranging from regenerative medicine through developing geroprotective substances, elucidating a wide range of mechanisms of aging and aging-related diseases, from energy metabolism through genetics and immunomodulation to systems biology. The conference further emphasized the need to intensify and support research on aging and aging-related diseases to provide solutions for the urgent health challenges of the aging society. PMID- 25821635 TI - Non-coding RNA: a new frontier in regulatory biology. AB - A striking finding in the past decade is the production of numerous non-coding RNAs (ncRNAs) from mammalian genomes. While it is entirely possible that many of those ncRNAs are transcription noises or by-products of RNA processing, increasing evidence suggests that a large fraction of them are functional and provide various regulatory activities in the cell. Thus, functional genomics and proteomics are incomplete without understanding functional ribonomics. As has been long suggested by the 'RNA world' hypothesis, many ncRNAs have the capacity to act like proteins in diverse biochemical processes. The enormous amount of information residing in the primary sequences and secondary structures of ncRNAs makes them particularly suited to function as scaffolds for molecular interactions. In addition, their functions appear to be stringently controlled by default via abundant nucleases when not engaged in specific interactions. This review focuses on the functional properties of regulatory ncRNAs in comparison with proteins and emphasizes both the opportunities and challenges in future ncRNA research. PMID- 25821636 TI - Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se] Methylselenocysteine. AB - : The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunochemotherapeutics that possess properties of selective "targeted" delivery. The simultaneous dual selective "targeted" delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition; prolong chemotherapeutic plasma half-life (reduces administration frequency); minimize innocent exposure of normal tissues and healthy organ systems; and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. MATERIALS AND METHODS: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354 nm) resulting in the synthesis of covalent immunochemotherapeutics, gemcitabine (C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu]. Cytotoxic anti neoplastic potency of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4 amide)-[anti-HER2/neu] between gemcitabine-equivalent concentrations of 10-12 M and 10-6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunochemotherapeutics. RESULTS: Gemcitabine-(C4-amide) [anti-EGFR], gemcitabine-(C4-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide) [anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide) [anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10-9 M and 10 6 M. Dual simultaneous combinations of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine (C4-amide)-[anti-HER2/neu] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se] methylsele-nocysteine. PMID- 25821638 TI - Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri. AB - Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its deletion retards aging in mice. Recently, new insights in the molecular mechanisms involving p66Shc and the p53 tumor suppressor genes were given: a specific p66Shc/p53 transcriptional regulation pathway was uncovered as determinant in oxidative stress response and, likely, in aging. p53, in a p66Shc-dependent manner, negatively downregulates the expression of 200 genes which are involved in the G2/M transition of mitotic cell cycle and are downregulated during physiological aging. p66Shc modulates the response of p53 by activating a p53 isoform (p44/p53, also named Delta40p53). Based on these latest results, several developments are expected in the future, as the generation of animal models to study aging and the evaluation of the use of the p53/p66Shc target genes as biomarkers in aging related diseases. The aim of this review is to investigate the conservation of the p66Shc and p53 role in oxidative stress between fish and mammals. We propose to approach this study trough a new model organism, the annual fish Nothobranchius furzeri, that has been demonstrated to develop typical signs of aging, like in mammals, including senescence, neurodegeneration, metabolic disorders and cancer. PMID- 25821640 TI - Suicide in the global chinese aging population: a review of risk and protective factors, consequences, and interventions. AB - As one of the leading causes of death around the world, suicide is a global public health threat. In the Chinese population, suicides constitute one-fifth of all recorded suicides in the world. Despite the factual data on suicide rates, the understanding of various causal factors behind suicide, including risk and protective factors and adverse health care, remained incomplete among the global Chinese aging population. To fill in the knowledge void, this paper reviews the epidemiology of suicide among Chinese older adults globally as well as explores the existing intervention strategies. Using the PRISMA statement, we performed a systematic review of exiting research on the topic, including studies describing suicide among Chinese older adults in communities outside of Asia. A literature search was conducted online by using both medical and social science data-bases. Our findings highlighted that elderly suicide in Chinese populations is significantly affected by the social, cultural, and familial contexts within which the individual lived prior to committing suicide. Reviewing such research indicated that while reducing risk factors may contribute to lowering suicides amongst Chinese older adults, measures to improve protective factors are also critical. Support through ongoing family and community care relationships is necessary to improve resilience in older adults and positive aging. Future longitudinal studies on the risk factors and protective factors, and adverse health consequences are called for to devise culturally and linguistically appropriate prevention and intervention programs in global Chinese aging populations. PMID- 25821639 TI - Metabolic syndrome, aging and involvement of oxidative stress. AB - The prevalence of the metabolic syndrome, a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart diseases. One of the defects in metabolic syndrome and its associated diseases is excess of reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process. In this article we review current understandings of oxidative stress in metabolic syndrome related disease and its possible contribution to accelerated senescence. PMID- 25821642 TI - Laparoscopic surgery in the elderly: a review of the literature. AB - Laparoscopic techniques are gradually replacing many common surgical procedures that are performed in an increasingly aging population. Laparoscopy places different physiologic demands on the body than in open surgery. PubMed was searched for evidence related to the use of laparoscopy in the elderly population to treat common surgical pathologies. Randomized trials, systematic reviews, and meta-analyses were preferred. Currently, over 40% of all surgeries performed in the U.S. are on patients older than 65 years. By the end of the 21st century, Americans are expected to live 20 years longer than the current average. However, elderly patients clearly show higher rates of surgical morbidity and mortality overall. Laparoscopic techniques show decreased wound complications, post operative ileus, intraoperative blood loss, and reduced need for post-operative rehabilitation. In conclusion, laparoscopic surgery is safe in the elderly population and affords multiple advantages including decreased pain and convalescence. However, the physiology of laparoscopy places demands on elderly patients that typically present with more medical comorbidities. PMID- 25821643 TI - Hypoglycemia in older people - a less well recognized risk factor for frailty. AB - Recurrent hypoglycemia is common in older people with diabetes and is likely to be less recognized and under reported by patients and health care professionals. Hypoglycemia in this age group is associated with significant morbidities leading to both physical and cognitive dysfunction. Repeated hospital admissions due to frequent hypoglycemia are also associated with further deterioration in patients' general health. This negative impact of hypoglycemia is likely to eventually lead to frailty, disability and poor outcomes. It appears that the relationship between hypoglycemia and frailty is bidirectional and mediated through a series of influences including under nutrition. Therefore, attention should be paid to the management of under nutrition in the general elderly population by improving energy intake and maintaining muscle mass. Increasing physical activity and having a more conservative approach to glycemic targets in frail older people with diabetes may be worthwhile. PMID- 25821641 TI - The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Abeta) and tau. Both Abeta and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Abeta) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N methyl-D-aspartate (NMDA) as a possible convergence point for Abeta and tau toxicity. PMID- 25821645 TI - Correction: a randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy. AB - [This corrects the article DOI: 10.1371/currents.md.2cc69a1dae4be7dfe2bcb420024ea865.]. PMID- 25821644 TI - Parametrial fat tissue from high fat diet-treated SKH-1 mice stimulates transformation of mouse epidermal JB6 cells. AB - : Our previous studies indicated that decreasing visceral adipose tissue by surgical removal of the parametrial fat pads inhibited UVB-induced carcinogenesis in SKH-1 mice fed a high fat diet (HFD), but not a low fat diet (LFD) indicating that the parametrial fat tissue from mice fed a HFD played a role in skin carcinogenesis. OBJECTIVE: In the present study, we sought to investigate how a HFD may influence the intrinsic properties of the parametrial fat tissue to influence UVB-induced skin tumor formation. METHODS AND RESULTS: Immunohistochemical staining, adipokine array, and flow cytometry showed that parametrial fat tissue from mice fed a HFD had a higher density of macrophage fused dead adipocytes (crown-like structures), more adipokines, and stimulated the production of more reactive oxygen species compared with parametrial fat tissue from mice fed a LFD. These differences between parametrial fat tissue from mice fed a HFD and LFD were associated with their effect on the in vitro transformation of mouse epidermal JB6 cells. Our results indicated that fat tissue filtrate (an aqueous filtrate made from the parametrial fat pad) from mice fed a HFD enhanced the conversion of JB6 cells from an epithelial-like morphology to cells with a fibroblast-like morphology to a greater extent than fat tissue filtrate from mice fed a LFD. Studies indicated that the fibroblast-like cells had decreased levels of E-cadherin, increased levels of Twist as assayed by western blot. Fat tissue filtrate made from the parametrial fat tissue of mice fed a HFD had 160% more transforming activity than that from mice fed a LFD and formed malignant mesenchymal tumors in vivo. CONCLUSION: These studies provide the first in vitro demonstration of a parametrial fat tissue-induced transformation of an epidermal cell. PMID- 25821646 TI - Correction: building a phylogenomic pipeline for the eukaryotic tree of life - addressing deep phylogenies with genome-scale data. AB - [This corrects the article DOI: 10.1371/currents.tol.c24b6054aebf3602748ac042ccc8f2e9.]. PMID- 25821647 TI - The humanitarian situation in syria: a snapshot in the third year of the crisis. AB - Between April and June 2014, International Orthodox Christian Charities (IOCC), an International NGO, and the Greek Orthodox Patriarchate of Antioch and All the East (GOPA) conducted a needs assessment of Syrians affected by the crisis with the objective of gaining a better understanding of humanitarian needs and assistance priorities. Findings suggest that interventions that increase access to non-food items, food, medication and education should be prioritized where cost was the primary barrier to accessing goods and services. Cash transfer programs and direct provision of material assistance should be considered, though the most appropriate assistance modality is likely to vary by sector, location and the preferences and prior experience of donors and implementing organizations. Renewed international commitment to funding humanitarian assistance efforts in Syria and neighboring countries where the burden of refugees is greatest is essential from both a human rights perspective and in terms of maintaining stability in the region. PMID- 25821648 TI - Correction: challenges for resuming normal life after earthquake: a qualitative study on rural areas of iran. AB - [This corrects the article DOI: 10.1371/currents.dis.b4e84b942500e2f8f260f3471b7ee815.]. PMID- 25821649 TI - Adapting SugarWatch to manage metabolic syndrome in a partial hospitalization program: a feasibility study. AB - A successful worksite diabetes prevention program, SugarWatch,was adapted for a seriously mentally ill patient population in a partial hospitalization program in Hawai'i. A feasibility study was implemented using an intervention with 3 components: SugarWatch curriculum, structured physical activity,and Create a Plate lunch. Twenty participants completed the three month intervention. Only systolic blood pressure showed statistically significant improvement. However, trends in improvement were also seen with diastolic blood pressure and total cholesterol. Despite minimal improvement in physiological measures, the project changed practice in the setting to align with the 2004 American Diabetes Association and American Psychiatric Association Guidelines for the prevention of metabolic syndrome and better management of patients taking second generation antipsychotic medications. PMID- 25821650 TI - A discrete system simulation study in scheduling and resource allocation for the John A. Burns School of Medicine Clinical Skills Center. AB - The Center for Clinical Skills (CCS) at the University of Hawai'i's John A. Burns School of Medicine (JABSOM) trains medical students in a variety of medical practice education experiences aimed at improving patient care skills of history taking, physical examination, communication, and counseling. Increasing class sizes accentuate the need for efficient scheduling of faculty and students for clinical skills examinations. This research reports an application of a discrete simulation methodology, using a computerized commercial business simulation optimization software package Arena(r) by Rockwell Automation Inc, to model the flow of students through an objective structure clinical exam (OSCE) using the basic physical examination sequence (BPSE). The goal was to identify the most efficient scheduling of limited volunteer faculty resources to enable all student teams to complete the OSCE within the allocated 4 hours. The simulation models 11 two-person student teams, using resources of 10 examination rooms where physical examination skills are demonstrated on fellow student subjects and assessed by volunteer faculty. Multiple faculty availability models with constrained time parameters and other resources were evaluated. The results of the discrete event simulation suggest that there is no statistical difference in the baseline model and the alternative models with respect to faculty utilization, but statistically significant changes in student wait times. Two models significantly reduced student wait times without compromising faculty utilization. PMID- 25821651 TI - Comparing the utility of the non-mydriatic fundus camera to the direct ophthalmoscope for medical education. AB - Visualization of the fundus is an important component of any ophthalmologic exam. Students are taught to visualize the fundus using a direct handheld ophthalmoscope. However, this device has many limitations, which may be a detriment to medical education and patient care. The invention of the non mydriatic automatic fundus camera could significantly improve medical education. Our study examined the ability of a group of 5 medical students to visualize pathology and form a diagnosis with a traditional handheld ophthalmoscope and an automatic fundus camera. With the direct ophthalmoscope, none of the students were able to visualize the macula, a crucial aspect of the ophthalmologic exam. With the automatic fundus camera, all students were able to visualize the fundus. The latter modality also increased the proportion of students that was able to correctly diagnose the patients with diabetic retinopathy, 100% vs 40%. On average, students were also more confident in their ability to visualize basic retinal anatomy with the automatic fundus camera, 9.6/10 vs 6.4/10. Thus, incorporating the non-mydriatic automatic fundus camera into medical education, alongside the handheld ophthalmoscope, has the potential to improve both learning outcomes and patient care. PMID- 25821652 TI - The evolution of the Japanese medical education system: a historical perspective. AB - The Japanese Medical Education system has been influenced by political events throughout the country's history. From long periods of isolation from the western world to the effect of world wars, Japan's training system for physicians has had to adapt in many ways and will continue to change. The Japanese medical education system was recently compared to the "Galapagos Islands" for its unusual and singular evolution, in a speech by visiting professor Dr. Gordon L. Noel at the University of Tokyo International Research center.1 Japanese medical schools are currently working to increase their students' clinical hours or else these students may not be able to train in the United States for residencies. Knowing the history of the Japanese Medical education system is paramount to understanding the current system in place today. Studying the historical foundation of this system will also provide insight on how the system must change in order to produce better clinicians. This article provides a glimpse into the medical system of another nation that may encourage needed reflection on the state of current healthcare training in the United States. PMID- 25821653 TI - Healthy Mothers Healthy Babies: awareness and perceptions of existing breastfeeding and postpartum depression support among parents and perinatal health care providers in Hawai'i. AB - Healthy Mothers, Healthy Babies Coalition of Hawai'i (HMHB) is a local nonprofit organization dedicated to eliminating health disparities and improving Hawai'i's maternal, child, and family health though collaborative efforts in public education, advocacy, and partner development. A review of HMHB services revealed overwhelming requests for both breastfeeding and postpartum depression (PPD) support. The purpose of this article is to present the findings of two surveys that highlight the awareness of existing breastfeeding and PPD resources based on both parents and health care providers; perceptions of where and how care is accessed; and whether mothers throughout Hawai'i have equitable access to support. Results helped assess gaps in resources and determine barriers to care, as well as provide suggestions for new services or resources. Web-based surveys were sent to 450 providers and 2,955 parents with response rates of 8.9% and 4.0%, respectively. Less than half of parent participants reported that their health provider discussed PPD with them. Participants identified a number of barriers to increasing access and utilization of PPD support resources, including: not feeling like symptoms were server enough, feeling embarrassed to seek help, not knowing where to find support/information, and not able to afford or insurance wouldn't cover PPD support. Only 40% of providers reported screening for PPD and 33% felt they had not received adequate training. Barriers identified by providers were a lack of trained providers, lack of PPD specific support groups, cultural stigma, and lack of PPD awareness among providers. Of the women who did not exclusively breastfeed for the full six-month recommendation, the most common breastfeeding concerns included: perceptions of low milk supply; lack of lactation support; medical reasons; and pain. Providers described an environment of uneven distribution of resources, general lack of awareness of available resources, along with a widespread lack of support for breastfeeding efforts. Recommendations for future efforts include comprehensive breastfeeding and PPD training for health care providers enhanced support groups, and improving awareness and access to information and support resources. PMID- 25821655 TI - Academic pharmacy strikes Hawai'i. Part 2. AB - In partnership with the Hawai'i Journal of Medicine & Public Health, the Daniel K. Inouye College of Pharmacy (DKICP) is pleased to provide Scripts on a regular basis. In the inaugural "Script," a brief history of the profession in Hawai'i was presented up to the founding of the DKICP, Hawai'i's only academic pharmacy program. In this second part of the inaugural article, we describe some key accomplishments to date. The mission of the College is to educate pharmacy practitioners and leaders to serve as a catalyst for innovations and discoveries in pharmaceutical sciences and practice for promoting health and well-being, and to provide community service, including quality patient care. Examples are given to support the stated goals of the mission. With 341 graduates to date, and a 96% pass rate on the national licensing board exams, the college has played a significant role in improving healthcare in Hawai'i and throughout the Pacific Region. Additionally, a PhD program with substantial research programs in both pharmacy practice and the pharmaceutical science has been launched. Considerable extramural funding has been garnered from organizations such as the National Institutes of Health and Centers for Medicare and Medicaid Services. The economic impact of the College is estimated to be over $50 million each year. With over 200 signed clinical affiliation agreements within the state as well as nationally and internationally, the DKICP has helped to ameliorate the shortage of pharmacists in the state, and has enhanced the profile and practice standard of the pharmacist's role on interprofessional health care teams. PMID- 25821654 TI - Pilot study for the establishment of biomarkers for radiation damage after computed tomography in children. AB - Computed tomography (CT) is an imaging modality that exposes patients to ionizing radiation (IR). We review and report findings from our pilot study evaluating whether blood markers are altered in 17 children undergoing medically indicated CT scans. Blood was drawn before ('pre-CT') and 1 hour after ('post-CT' CT scans. Plasma carotenoids, tocopherols, Q10, ascorbic acid (AA) and uric acid (UA) were analyzed by RP-HPLC with diode-array and electrochemical detection. Dehydroascorbic acid (DHAA) was calculated by subtraction from total AA. Total antioxidant capacity (TAC) was measured using the ORAC assay. Cytokines were quantified using a multiplex immunoassay. gamma-H2AX foci were visualized using immunofluorescence. Mean pre- and post-CT changes were compared using t-tests; P levels < .05 indicated significance. All major plasma lipid soluble antioxidant levels were lower post- vs pre-CT (P < .05) possibly from the scavenging of free radicals formed by CT-induced IR. Average AA levels increased (134%) while DHAA levels were decreased (29%) post-CT, probably due to intracellular recycling of AA from DHAA. TAC levels in lipophilic and hydrophilic extracts were unchanged, suggesting that other antioxidants may have assisted in free radical quenching, which would corroborate their lower concentrations post-CT. Cytokine levels were unchanged and dose-dependent increases in gamma-H2AX foci, a measure of double strand DNA breaks, were observed (P = .046, n = 3 children). Our results suggest that CT-derived IR can influence the antioxidant system and may elicit detrimental responses on the cellular level of young children. When possible and if appropriate non-IR based techniques such as ultrasound or magnetic resonance imaging should be used. PMID- 25821657 TI - Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency. AB - Hematopoietic stem cell transplantation (HSCT) is an effective approach for the treatment of severe combined immunodeficiency (SCID). However, SCID is not a homogeneous disease, and the treatment required for successful transplantation varies significantly between SCID subtypes and the degree of HLA mismatch between the best available donor and the patient. Recent studies are beginning to more clearly define this heterogeneity and how outcomes may vary. With a more detailed understanding of SCID, new approaches can be developed to maximize immune reconstitution, while minimizing acute and long-term toxicities associated with chemotherapy conditioning. PMID- 25821658 TI - Reenvisioning Clinical Science: Unifying the Discipline to Improve the Public Health. AB - We present a vision of clinical science, based on a conceptual framework of intervention development endorsed by the Delaware Project. This framework is grounded in an updated stage model that incorporates basic science questions of mechanisms into every stage of clinical science research. The vision presented is intended to unify various aspects of clinical science toward the common goal of developing maximally potent and implementable interventions, while unveiling new avenues of science in which basic and applied goals are of equally high importance. Training in this integrated, translational model may help students learn how to conduct research in every domain of clinical science and at each stage of intervention development. This vision aims to propel the field to fulfill the public health goal of producing implementable and effective treatment and prevention interventions. PMID- 25821659 TI - Affective and Self-Esteem Instability in the Daily Lives of People with Generalized Social Anxiety Disorder. AB - Research on affect and self-esteem in social anxiety disorder (SAD) has focused on trait or average levels, but we know little about the dynamic patterns of these experiences in the daily lives of people with SAD. We asked 40 adults with SAD and 39 matched healthy controls to provide end-of-day reports on their affect and self-esteem over two weeks. Compared to healthy adults, participants with SAD exhibited greater instability of negative affect and self-esteem, though the self esteem effect was driven by mean level differences. The SAD group also demonstrated a higher probability of acute changes in negative affect and self esteem (i.e., from one assessment period to the next), as well as difficulty maintaining positive states and improving negative states (i.e., dysfunctional self-regulation). Our findings provide insights on the phenomenology of SAD, with particular attention to the temporal dependency, magnitude of change, and directional patterns of psychological experiences in everyday life. PMID- 25821661 TI - Land and cryosphere products from Suomi NPP VIIRS: Overview and status. AB - [1] The Visible Infrared Imaging Radiometer Suite (VIIRS) instrument was launched in October 2011 as part of the Suomi National Polar-Orbiting Partnership (S-NPP). The VIIRS instrument was designed to improve upon the capabilities of the operational Advanced Very High Resolution Radiometer and provide observation continuity with NASA's Earth Observing System's Moderate Resolution Imaging Spectroradiometer (MODIS). Since the VIIRS first-light images were received in November 2011, NASA- and NOAA-funded scientists have been working to evaluate the instrument performance and generate land and cryosphere products to meet the needs of the NOAA operational users and the NASA science community. NOAA's focus has been on refining a suite of operational products known as Environmental Data Records (EDRs), which were developed according to project specifications under the National Polar-Orbiting Environmental Satellite System. The NASA S-NPP Science Team has focused on evaluating the EDRs for science use, developing and testing additional products to meet science data needs, and providing MODIS data product continuity. This paper presents to-date findings of the NASA Science Team's evaluation of the VIIRS land and cryosphere EDRs, specifically Surface Reflectance, Land Surface Temperature, Surface Albedo, Vegetation Indices, Surface Type, Active Fires, Snow Cover, Ice Surface Temperature, and Sea Ice Characterization. The study concludes that, for MODIS data product continuity and earth system science, an enhanced suite of land and cryosphere products and associated data system capabilities are needed beyond the EDRs currently available from the VIIRS. PMID- 25821660 TI - Polygenic risk for externalizing disorders: Gene-by-development and gene-by environment effects in adolescents and young adults. AB - In this project, we aimed to bring large-scale gene identification findings into a developmental psychopathology framework. Using a family-based sample, we tested whether polygenic scores for externalizing disorders-based on single nucleotide polymorphism weights derived from genome-wide association study results in adults (n = 1,249)-predicted externalizing disorders, subclinical externalizing behavior, and impulsivity-related traits adolescents (n = 248) and young adults (n = 207), and whether parenting and peer factors in adolescence moderated polygenic risk to predict externalizing disorders. Polygenic scores predicted externalizing disorders in adolescents and young adults, even after controlling for parental externalizing disorder history. Polygenic scores also predicted subclinical externalizing behavior and impulsivity traits in the adolescents and young adults. Adolescent parental monitoring and peer substance use moderated polygenic scores to predict externalizing disorders. This illustrates how state of the science genetics can be integrated with psychological science to identify how genetic risk contributes to the development of psychopathology. PMID- 25821662 TI - North-south cross sections of the vertical aerosol distribution over the Atlantic Ocean from multiwavelength Raman/polarization lidar during Polarstern cruises. AB - Shipborne aerosol lidar observations were performed aboard the research vessel Polarstern in 2009 and 2010 during three north-south cruises from about 50 degrees N to 50 degrees S. The aerosol data set provides an excellent opportunity to characterize and contrast the vertical aerosol distribution over the Atlantic Ocean in the polluted northern and relatively clean southern hemisphere. Three case studies, an observed pure Saharan dust plume, a Patagonian dust plume east of South America, and a case of a mixed dust/smoke plume west of Central Africa are exemplarily shown and discussed by means of their optical properties. The meridional transatlantic cruises were used to determine the latitudinal cross section of the aerosol optical thickness (AOT). Profiles of particle backscatter and extinction coefficients are presented as mean profiles for latitudinal belts to contrast northern- and southern-hemispheric aerosol loads and optical effects. Results of lidar observations at Punta Arenas (53 degrees S), Chile, and Stellenbosch (34 degrees S), South Africa, are shown and confirm the lower frequency of occurrence of free-tropospheric aerosol in the southern hemisphere than in the northern hemisphere. The maximum latitudinal mean AOT of 0.27 was found in the northern tropics (0- 15 degrees N) in the Saharan outflow region. Marine AOT is typically 0.05 +/- 0.03. Particle optical properties are presented separately for the marine boundary layer and the free troposphere. Concerning the contrast between the anthropogenically influenced midlatitudinal aerosol conditions in the 30- 60 degrees N belt and the respective belt in the southern hemisphere over the remote Atlantic, it is found that the AOT and extinction coefficients for the vertical column from 0-5km (total aerosol column) and 1-5km height (lofted aerosol above the marine boundary layer) are a factor of 1.6 and 2 higher at northern midlatitudes than at respective southern midlatitudes, and a factor of 2.5 higher than at the clean marine southern-hemispheric site of Punta Arenas. The strong contrast is confined to the lowermost 3km of the atmosphere. PMID- 25821663 TI - Recent climate tendencies on an East Antarctic ice shelf inferred from a shallow firn core network. AB - : Nearly three decades of stable isotope ratios and surface mass balance (SMB) data from eight shallow firn cores retrieved at Fimbul Ice Shelf, East Antarctica, in the Austral summers 2009-2011 have been investigated. An additional longer core drilled in 2000/2001 extends the series back to the early eighteenth century. Isotope ratios and SMB from the stacked record of all cores were also related to instrumental temperature data from Neumayer Station on Ekstrom Ice Shelf. Since the second half of the twentieth century, the SMB shows a statistically significant negative trend, whereas the delta18O of the cores shows a significant positive trend. No trend is found in air temperature at the nearest suitable weather station, Neumayer (available since 1981). This does not correspond to the statistically significant positive trend in Southern Annular Mode (SAM) index, which is usually associated with a cooling of East Antarctica. SAM index and SMB are negatively correlated, which might be explained by a decrease in meridional exchange of energy and moisture leading to lower precipitation amounts. Future monitoring of climate change on the sensitive Antarctic ice shelves is necessary to assess its consequences for sea level change. KEY POINTS: Mass balance and stable oxygen isotope ratios from shallow firn coresDecreasing trend in surface mass balance, no trend in stable isotopesNegative correlation between SAM and SMB. PMID- 25821664 TI - Remote sensing of aerosols in the Arctic for an evaluation of global climate model simulations. AB - : In this study Moderate Resolution Imaging Spectroradiometer (MODIS) Aqua retrievals of aerosol optical thickness (AOT) at 555 nm are compared to Sun photometer measurements from Svalbard for a period of 9 years. For the 642 daily coincident measurements that were obtained, MODIS AOT generally varies within the predicted uncertainty of the retrieval over ocean (DeltaAOT = +/-0.03 +/- 0.05 . AOT). The results from the remote sensing have been used to examine the accuracy in estimates of aerosol optical properties in the Arctic, generated by global climate models and from in situ measurements at the Zeppelin station, Svalbard. AOT simulated with the Norwegian Earth System Model/Community Atmosphere Model version 4 Oslo global climate model does not reproduce the observed seasonal variability of the Arctic aerosol. The model overestimates clear-sky AOT by nearly a factor of 2 for the background summer season, while tending to underestimate the values in the spring season. Furthermore, large differences in all-sky AOT of up to 1 order of magnitude are found for the Coupled Model Intercomparison Project phase 5 model ensemble for the spring and summer seasons. Large differences between satellite/ground-based remote sensing of AOT and AOT estimated from dry and humidified scattering coefficients are found for the subarctic marine boundary layer in summer. KEY POINTS: Remote sensing of AOT is very useful in validation of climate models. PMID- 25821665 TI - View angle dependence of MODIS liquid water path retrievals in warm oceanic clouds. AB - : We investigated the view angle dependence of domain mean Moderate Resolution Imaging Spectroradiometer (MODIS) liquid water path (LWP) and that of corresponding cloud optical thickness, effective radius, and liquid cloud fraction as proxy for plane-parallel retrieval biases. Independent Advanced Microwave Scanning Radiometer-EOS LWP was used to corroborate that the observed variations with sun-view geometry were not severely affected by seasonal/latitudinal changes in cloud properties. Microwave retrievals showed generally small (<10%) cross-swath variations. The view angle (cross-swath) dependence of MODIS optical thickness was weaker in backscatter than forward scatter directions and transitioned from mild ? shape to stronger ? shape as heterogeneity, sun angle, or latitude increased. The 2.2 um effective radius variations always had a ? shape, which became pronounced and asymmetric toward forward scatter in the most heterogeneous clouds and/or at the lowest sun. Cloud fraction had the strongest and always ?-shaped view angle dependence. As a result, in-cloud MODIS cloud liquid water path (CLWP) showed surprisingly good view angle (cross-swath) consistency, usually comparable to that of microwave retrievals, due to cancelation between optical thickness and effective radius biases. Larger (20-40%) nadir-relative increases were observed in the most extreme heterogeneity and sun angle bins, that is, typically in the polar regions, which, however, constituted only 3-8% of retrievals. The good consistency of MODIS in-cloud CLWP was lost for gridbox mean LWP, which was dominated by the strong cloud fraction increase with view angle. More worryingly, MODIS LWP exhibited significant and systematic absolute increases with heterogeneity and sun angle that is not present in microwave LWP. KEY POINTS: Microwave LWP shows small overall and cross-swath variationsMODIS in-cloud LWP also shows good view angle consistency in most casesMODIS retrievals show strong overall increase with heterogeneity and sun angle. PMID- 25821666 TI - The effect of surface charge on nonspecific uptake and cytotoxicity of CdSe/ZnS core/shell quantum dots. AB - In this work, cytotoxicity and cellular impedance response was compared for CdSe/ZnS core/shell quantum dots (QDs) with positively charged cysteamine-QDs, negatively charged dihydrolipoic acid-QDs and zwitterionic D-penicillamine-QDs exposed to canine kidney MDCKII cells. Pretreatment of cells with pharmacological inhibitors suggested that the uptake of nanoparticles was largely due to receptor independent pathways or spontaneous entry for carboxylated and zwitterionic QDs, while for amine-functionalized particles involvement of cholesterol-enriched membrane domains is conceivable. Cysteamine-QDs were found to be the least cytotoxic, while D-penicillamine-QDs reduced the mitochondrial activity of MDCKII by 20-25%. Although the cell vitality appeared unaffected (assessed from the changes in mitochondrial activity using a classical MTS assay after 24 h of exposure), the binding of QDs to the cellular interior and their movement across cytoskeletal filaments (captured and characterized by single-particle tracking), was shown to compromise the integrity of the cytoskeletal and plasma membrane dynamics, as evidenced by electric cell-substrate impedance sensing. PMID- 25821667 TI - Green preparation and spectroscopic characterization of plasmonic silver nanoparticles using fruits as reducing agents. AB - Chemicals typically available in plants have the capability to reduce silver and gold salts and to create silver and gold nanoparticles. We report the preparation of silver nanoparticles with sizes between 10 and 300 nm from silver nitrate using fruit extract collected from pineapples and oranges as reducing agents. The evolvement of a characteristic surface plasmon extinction spectrum in the range of 420 nm to 480 nm indicates the formation of silver nanoparticles after mixing silver nitrate solution and fruit extract. Shifts in plasmon peaks over time indicate the growth of nanoparticles. Electron microscopy shows that the shapes of the nanoparticles are different depending on the fruit used for preparation. The green preparation process can result in individual nanoparticles with a very poor tendency to form aggregates with narrow gaps even when aggregation is forced by the addition of NaCl. This explains only modest enhancement factors for near infrared-excited surface enhanced Raman scattering. In addition to the surface plasmon band, UV-visible absorption spectra show features in the UV range which indicates also the presence of small silver clusters, such as Ag4 (2+). The increase of the plasmon absorption correlates with the decrease of absorption band in the UV. This confirms the evolution of silver nanoparticles from silver clusters. The presence of various silver clusters on the surface of the "green" plasmonic silver nanoparticles is also supported by a strong multicolor luminesce signal emitted by the plasmonic particles during 473 nm excitation. PMID- 25821669 TI - Tunable white light emission by variation of composition and defects of electrospun Al2O3-SiO2 nanofibers. AB - Composite nanofibers consisting of Al2O3-SiO2 were prepared by electrospinning in combination with post-calcination in air. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy were used to investigate the crystalline phase and microstructure of the composite nanofibers. Photoluminescence experiments indicated that the resulting white light emission can be tuned by the relative intensity of the individual spectral components, which are related to the individual defects such as: violet-blue emission from O defects, green emission from =Si(Al)-O-C?=O, and red emission from intersystem radiative crossing. White light emission was realized at a Al/(Al-Si) ratio of 40 and 60 mol %. This research may offer a deeper understanding of the preparation of efficient and environmentally friendly, white luminescence materials. PMID- 25821668 TI - Comparative evaluation of the impact on endothelial cells induced by different nanoparticle structures and functionalization. AB - In the research field of nanoparticles, many studies demonstrated a high impact of the shape, size and surface charge, which is determined by the functionalization, of nanoparticles on cell viability and internalization into cells. This work focused on the comparison of three different nanoparticle types to give a better insight into general rules determining the biocompatibility of gold, Janus and semiconductor (quantum dot) nanoparticles. Endothelial cells were subject of this study, since blood is the first barrier after intravenous nanoparticle application. In particular, stronger effects on the viability of endothelial cells were found for nanoparticles with an elongated shape in comparison to spherical ones. Furthermore, a positively charged nanoparticle surface (NH2, CyA) leads to the strongest reduction in cell viability, whereas neutral and negatively charged nanoparticles are highly biocompatible to endothelial cells. These findings are attributed to a rapid internalization of the NH2-functionalized nanoparticles in combination with the damage of intracellular membranes. Interestingly, the endocytotic pathway seems to be a size-dependent process whereas nanoparticles with a size of 20 nm are internalized by caveolae-mediated endocytosis and nanoparticles with a size of 40 nm are taken up by clathrin-mediated internalization and macropinocytosis. Our results can be summarized to formulate five general rules, which are further specified in the text and which determine the biocompatibility of nanoparticles on endothelial cells. Our findings will help to design new nanoparticles with optimized properties concerning biocompatibility and uptake behavior with respect to the respective intended application. PMID- 25821670 TI - Strain distribution due to surface domains: a self-consistent approach with respect to surface elasticity. AB - Elastically mediated interactions between surface domains are classically described in terms of point forces. Such point forces lead to local strain divergences that are usually avoided by introducing a poorly defined cut-off length. In this work, we develop a self-consistent approach in which the strain field induced by the surface domains is expressed as the solution of an integral equation that contains surface elastic constants, S ij . For surfaces with positive S ij the new approach avoids the introduction of a cut-off length. The classical and the new approaches are compared in case of 1-D periodic ribbons. PMID- 25821671 TI - Synthesis, characterization, monolayer assembly and 2D lanthanide coordination of a linear terphenyl-di(propiolonitrile) linker on Ag(111). AB - As a continuation of our work employing polyphenylene-dicarbonitrile molecules and in particular the terphenyl derivative 1 (TDCN), we have synthesized a novel ditopic terphenyl-4,4"-di(propiolonitrile) (2) linker for the self-assembly of organic monolayers and metal coordination at interfaces. The structure of the organic linker 2 was confirmed by single crystal X-ray diffraction analysis (XRD). On the densely packed Ag(111) surface, the terphenyl-4,4" di(propiolonitrile) linkers self-assemble in a regular, molecular chevron arrangement exhibiting a Moire pattern. After the exposure of the molecular monolayer to a beam of Gd atoms, the propiolonitrile groups get readily involved in metal-ligand coordination interactions. Distinct coordination motifs evolve with coordination numbers varying between three and six for the laterally-bound Gd centers. The linker molecules retain an overall flat adsorption geometry. However, only networks with restricted local order were obtained, in marked contrast to previously employed, simpler polyphenylene-dicarbonitrile 1 linkers. PMID- 25821672 TI - Nanoporous Ge thin film production combining Ge sputtering and dopant implantation. AB - In this work a novel process allowing for the production of nanoporous Ge thin films is presented. This process uses the combination of two techniques: Ge sputtering on SiO2 and dopant ion implantation. The process entails four successive steps: (i) Ge sputtering on SiO2, (ii) implantation preannealing, (iii) high-dose dopant implantation, and (iv) implantation postannealing. Scanning electron microscopy and transmission electron microscopy were used to characterize the morphology of the Ge film at different process steps under different postannealing conditions. For the same postannealing conditions, the Ge film topology was shown to be similar for different implantation doses and different dopants. However, the film topology can be controlled by adjusting the postannealing conditions. PMID- 25821673 TI - Carrier multiplication in silicon nanocrystals: ab initio results. AB - One of the most important goals in the field of renewable energy is the development of original solar cell schemes employing new materials to overcome the performance limitations of traditional solar cell devices. Among such innovative materials, nanostructures have emerged as an important class of materials that can be used to realize efficient photovoltaic devices. When these systems are implemented into solar cells, new effects can be exploited to maximize the harvest of solar radiation and to minimize the loss factors. In this context, carrier multiplication seems one promising way to minimize the effects induced by thermalization loss processes thereby significantly increasing the solar cell power conversion. In this work we analyze and quantify different types of carrier multiplication decay dynamics by analyzing systems of isolated and coupled silicon nanocrystals. The effects on carrier multiplication dynamics by energy and charge transfer processes are also discussed. PMID- 25821674 TI - Exploiting the hierarchical morphology of single-walled and multi-walled carbon nanotube films for highly hydrophobic coatings. AB - Self-assembled hierarchical solid surfaces are very interesting for wetting phenomena, as observed in a variety of natural and artificial surfaces. Here, we report single-walled (SWCNT) and multi-walled carbon nanotube (MWCNT) thin films realized by a simple, rapid, reproducible, and inexpensive filtration process from an aqueous dispersion, that was deposited at room temperature by a dry transfer printing method on glass. Furthermore, the investigation of carbon nanotube films through scanning electron microscopy (SEM) reveals the multi-scale hierarchical morphology of the self-assembled carbon nanotube random networks. Moreover, contact angle measurements show that hierarchical SWCNT/MWCNT composite surfaces exhibit a higher hydrophobicity (contact angles of up to 137 degrees ) than bare SWCNT (110 degrees ) and MWCNT (97 degrees ) coatings, thereby confirming the enhancement produced by the surface hierarchical morphology. PMID- 25821675 TI - Nanoparticle shapes by using Wulff constructions and first-principles calculations. AB - BACKGROUND: The majority of complex and advanced materials contain nanoparticles. The properties of these materials depend crucially on the size and shape of these nanoparticles. Wulff construction offers a simple method of predicting the equilibrium shape of nanoparticles given the surface energies of the material. RESULTS: We review the mathematical formulation and the main applications of Wulff construction during the last two decades. We then focus to three recent extensions: active sites of metal nanoparticles for heterogeneous catalysis, ligand-protected nanoparticles generated as colloidal suspensions and nanoparticles of complex metal hydrides for hydrogen storage. CONCLUSION: Wulff construction, in particular when linked to first-principles calculations, is a powerful tool for the analysis and prediction of the shapes of nanoparticles and tailor the properties of shape-inducing species. PMID- 25821677 TI - Biological responses to nanoscale particles. PMID- 25821676 TI - Dynamic force microscopy simulator (dForce): A tool for planning and understanding tapping and bimodal AFM experiments. AB - We present a simulation environment, dForce, which can be used for a better understanding of dynamic force microscopy experiments. The simulator presents the cantilever-tip dynamics for two dynamic AFM methods, tapping mode AFM and bimodal AFM. It can be applied for a wide variety of experimental situations in air or liquid. The code provides all the variables and parameters relevant in those modes, for example, the instantaneous deflection and tip-surface force, velocity, virial, dissipated energy, sample deformation and peak force as a function of time or distance. The simulator includes a variety of interactions and contact mechanics models to describe AFM experiments including: van der Waals, Hertz, DMT, JKR, bottom effect cone correction, linear viscoelastic forces or the standard linear solid viscoelastic model. We have compared two numerical integration methods to select the one that offers optimal accuracy and speed. The graphical user interface has been designed to facilitate the navigation of non experts in simulations. Finally, the accuracy of dForce has been tested against numerical simulations performed during the last 18 years. PMID- 25821678 TI - Hematopoietic and mesenchymal stem cells: polymeric nanoparticle uptake and lineage differentiation. AB - The combination of stem cell therapy and nanoparticles promises to enhance the effect of cellular therapies by using nanocarriers as drug delivery devices to guide the further differentiation or homing of stem cells. The impact of nanoparticles on primary cell types remains much more elusive as most groups study the nanoparticle-cell interaction in malignant cell lines. Here, we report on the influence of polymeric nanoparticles on human hematopoietic stem cells (hHSCs) and mesenchymal stem cells (hMSCs). In this study we systematically investigated the influence of polymeric nanoparticles on the cell functionality and differentiation capacity of hHSCs and hMSCs to obtain a deeper knowledge of the interaction of stem cells and nanoparticles. As model systems of nanoparticles, two sets of either bioinert (polystyrene without carboxylic groups on the surface) or biodegradable (PLLA without magnetite) particles were analyzed. Flow cytometry and microscopy analysis showed high uptake rates and no toxicity for all four tested particles in hMSCs and hHSCs. During the differentiation process, the payload of particles per cell decreased. The PLLA-Fe particle showed a significant increase in the IL-8 release in hMSCs but not in hHSCs. We assume that this is due to an increase of free intracellular iron ions but obviously also depends on the cell type. For hHSCs and hMSCs, lineage differentiation into erythrocytes, granulocytes, and megakaryocytes or adipocytes, osteocytes and chondrocytes, was not influenced by the particles when analyzed with lineage specific cluster of differentiation markers. On the other hand qPCR analysis showed significant changes in the expression of some (but not all) investigated lineage markers for both primary cell types. PMID- 25821679 TI - Electrical response of liquid crystal cells doped with multi-walled carbon nanotubes. AB - The inclusion of nanoparticles modifies a number of fundamental properties of many materials. Doping of nanoparticles in self-organized materials such as liquid crystals may be of interest for the reciprocal interaction between the matrix and the nanoparticles. Elongated nanoparticles and nanotubes can be aligned and reoriented by the liquid crystal, inducing noticeable changes in their optical and electrical properties. In this work, cells of liquid crystal doped with high aspect ratio multi-walled carbon nanotubes have been prepared, and their characteristic impedance has been studied at different frequencies and excitation voltages. The results demonstrate alterations in the anisotropic conductivity of the samples with the applied electric field, which can be followed by monitoring the impedance evolution with the excitation voltage. Results are consistent with a possible electric contact between the coated substrates of the LC cell caused by the reorientation of the nanotubes. The reversibility of the doped system upon removal of the electric field is quite low. PMID- 25821680 TI - Influence of size, shape and core-shell interface on surface plasmon resonance in Ag and Ag@MgO nanoparticle films deposited on Si/SiO x. AB - Ag and Ag@MgO core-shell nanoparticles (NPs) with a diameter of d = 3-10 nm were obtained by physical synthesis methods and deposited on Si with its native ultrathin oxide layer SiO x (Si/SiO x ). Scanning electron microscopy and transmission electron microscopy (TEM) images of bare Ag NPs revealed the presence of small NP aggregates caused by diffusion on the surface and agglomeration. Atomic resolution TEM gave evidence of the presence of crystalline multidomains in the NPs, which were due to aggregation and multitwinning occurring during NP growth in the nanocluster source. Co-deposition of Ag NPs and Mg atoms in an oxygen atmosphere gave rise to formation of a MgO shell matrix surrounding the Ag NPs. The behaviour of the surface plasmon resonance (SPR) excitation in surface differential reflectivity (SDR) spectra with p-polarised light was investigated for bare Ag and Ag@MgO NPs. It was shown that the presence of MgO around the Ag NPs caused a red shift of the plasmon excitation, and served to preserve its existence after prolonged (five months) exposure to air, realizing the possibility of technological applications in plasmonic devices. The Ag NP and Ag@MgO NP film features in the SDR spectra could be reproduced by classical electrodynamics simulations by treating the NP-containing layer as an effective Maxwell Garnett medium. The simulations gave results in agreement with the experiments when accounting for the experimentally observed aggregation. PMID- 25821681 TI - A surface acoustic wave-driven micropump for particle uptake investigation under physiological flow conditions in very small volumes. AB - Static conditions represent an important shortcoming of many in vitro experiments on the cellular uptake of nanoparticles. Here, we present a versatile microfluidic device based on acoustic streaming induced by surface acoustic waves (SAWs). The device offers a convenient method for introducing fluid motion in standard cell culture chambers and for mimicking capillary blood flow. We show that shear rates over the whole physiological range in sample volumes as small as 200 MUL can be achieved. A precise characterization method for the induced flow profile is presented and the influence of flow on the uptake of Pt-decorated CeO2 particles by endothelial cells (HMEC-1) is demonstrated. Under physiological flow conditions the particle uptake rates for this system are significantly lower than at low shear conditions. This underlines the vital importance of the fluidic environment for cellular uptake mechanisms. PMID- 25821682 TI - Influence of spurious resonances on the interaction force in dynamic AFM. AB - The quantification of the tip-sample interaction in amplitude modulation atomic force microscopy is challenging, especially when measuring in liquid media. Here, we derive formulas for the tip-sample interactions and investigate the effect of spurious resonances on the measured interaction. Highlighting the differences between measuring directly the tip position or the cantilever deflection, and considering both direct and acoustic excitation, we show that the cantilever behavior is insensitive to spurious resonances as long as the measured signal corresponds to the tip position, or if the excitation force is correctly considered. Since the effective excitation force may depend on the presence of such spurious resonances, only the case in which the frequency is kept constant during the measurement is considered. Finally, we show the advantages that result from the use of a calibration method based on the acquisition of approach-retract curves. PMID- 25821683 TI - Palladium nanoparticles anchored to anatase TiO2 for enhanced surface plasmon resonance-stimulated, visible-light-driven photocatalytic activity. AB - Freely assembled palladium nanoparticles (Pd NPs) on titania (TiO2) nano photocatalysts were successfully synthesized through a photodeposition method using natural sunlight. This synthesized heterogeneous photocatalyst (Pd/TiO2) was characterized through field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), BET surface area, UV-vis diffuse reflectance spectra (UV-DRS), Raman and photoluminescence (PL) analyses. The simple and smart synthesis anchored well the deposition with controlled Pd NPs size ranging between 17 and 29 nm onto the surface of TiO2. Thus, it gives the characteristic for Pd NPs to absorb light in the visible region obtained through localized surface plasmon resonance (LSPRs). Apparently, the photocatalytic activity of the prepared photocatalysts was evaluated by degrading the endocrine disrupting compound (EDC) amoxicillin (AMX) excited under an artificial visible light source. In the preliminary run, almost complete degradation (97.5%) was achieved in 5 h with 0.5 wt % Pd loading and the degradation followed pseudo-first-order kinetics. The reusability trend proved the photostability of the prepared photocatalysts. Hence, the study provides a new insight about the modification of TiO2 with noble metals in order to enhance the absorption in the visible-light region for superior photocatalytic performance. PMID- 25821684 TI - In situ scanning tunneling microscopy study of Ca-modified rutile TiO2(110) in bulk water. AB - Despite the rising technological interest in the use of calcium-modified TiO2 surfaces in biomedical implants, the Ca/TiO2 interface has not been studied in an aqueous environment. This investigation is the first report on the use of in situ scanning tunneling microscopy (STM) to study calcium-modified rutile TiO2(110) surfaces immersed in high purity water. The TiO2 surface was prepared under ultrahigh vacuum (UHV) with repeated sputtering/annealing cycles. Low energy electron diffraction (LEED) analysis shows a pattern typical for the surface segregation of calcium, which is present as an impurity on the TiO2 bulk. In situ STM images of the surface in bulk water exhibit one-dimensional rows of segregated calcium regularly aligned with the [001] crystal direction. The in situ-characterized morphology and structure of this Ca-modified TiO2 surface are discussed and compared with UHV-STM results from the literature. Prolonged immersion (two days) in the liquid leads to degradation of the overlayer, resulting in a disordered surface. X-ray photoelectron spectroscopy, performed after immersion in water, confirms the presence of calcium. PMID- 25821685 TI - Electrical properties of single CdTe nanowires. AB - Ion track, nanoporous membranes were employed as templates for the preparation of CdTe nanowires. For this purpose, electrochemical deposition from a bath containing Cd and Te ions was employed. This process leads to high aspect ratio CdTe nanowires, which were harvested and placed on a substrate with lithographically patterned, interdigitated electrodes. Focused ion beam-induced metallization was used to produce individual nanowires with electrical contacts and electrical measurements were performed on these individual nanowires. The influence of a bottom gate was investigated and it was found that surface passivation leads to improved transport properties. PMID- 25821686 TI - A scanning probe microscope for magnetoresistive cantilevers utilizing a nested scanner design for large-area scans. AB - We describe an atomic force microscope (AFM) for the characterization of self sensing tunneling magnetoresistive (TMR) cantilevers. Furthermore, we achieve a large scan-range with a nested scanner design of two independent piezo scanners: a small high resolution scanner with a scan range of 5 * 5 * 5 MUm(3) is mounted on a large-area scanner with a scan range of 800 * 800 * 35 MUm(3). In order to characterize TMR sensors on AFM cantilevers as deflection sensors, the AFM is equipped with a laser beam deflection setup to measure the deflection of the cantilevers independently. The instrument is based on a commercial AFM controller and capable to perform large-area scanning directly without stitching of images. Images obtained on different samples such as calibration standard, optical grating, EPROM chip, self-assembled monolayers and atomic step-edges of gold demonstrate the high stability of the nested scanner design and the performance of self-sensing TMR cantilevers. PMID- 25821687 TI - Fundamental edge broadening effects during focused electron beam induced nanosynthesis. AB - The present study explores lateral broadening effects of 3D structures fabricated through focused electron beam induced deposition using MeCpPt(IV)Me3 precursor. In particular, the scaling behavior of proximity effects as a function of the primary electron energy and the deposit height is investigated through experiments and validated through simulations. Correlated Kelvin force microscopy and conductive atomic force microscopy measurements identified conductive and non conductive proximity regions. It was determined that the highest primary electron energies enable the highest edge sharpness while lower energies contain a complex convolution of broadening effects. Moreover, it is demonstrated that intermediate energies lead to even more complex proximity effects that significantly reduce lateral edge sharpness and thus should be avoided if desiring high lateral resolution. PMID- 25821688 TI - Conformal SiO2 coating of sub-100 nm diameter channels of polycarbonate etched ion-track channels by atomic layer deposition. AB - Polycarbonate etched ion-track membranes with about 30 um long and 50 nm wide cylindrical channels were conformally coated with SiO2 by atomic layer deposition (ALD). The process was performed at 50 degrees C to avoid thermal damage to the polymer membrane. Analysis of the coated membranes by small angle X-ray scattering (SAXS) reveals a homogeneous, conformal layer of SiO2 in the channels at a deposition rate of 1.7-1.8 A per ALD cycle. Characterization by infrared and X-ray photoelectron spectroscopy (XPS) confirms the stoichiometric composition of the SiO2 films. Detailed XPS analysis reveals that the mechanism of SiO2 formation is based on subsurface crystal growth. By dissolving the polymer, the silica nanotubes are released from the ion-track membrane. The thickness of the tube wall is well controlled by the ALD process. Because the track-etched channels exhibited diameters in the range of nanometres and lengths in the range of micrometres, cylindrical tubes with an aspect ratio as large as 3000 have been produced. PMID- 25821689 TI - Raman spectroscopy as a tool to investigate the structure and electronic properties of carbon-atom wires. AB - Graphene, nanotubes and other carbon nanostructures have shown potential as candidates for advanced technological applications due to the different coordination of carbon atoms and to the possibility of pi-conjugation. In this context, atomic-scale wires comprised of sp-hybridized carbon atoms represent ideal 1D systems to potentially downscale devices to the atomic level. Carbon atom wires (CAWs) can be arranged in two possible structures: a sequence of double bonds (cumulenes), resulting in a 1D metal, or an alternating sequence of single-triple bonds (polyynes), expected to show semiconducting properties. The electronic and optical properties of CAWs can be finely tuned by controlling the wire length (i.e., the number of carbon atoms) and the type of termination (e.g., atom, molecular group or nanostructure). Although linear, sp-hybridized carbon systems are still considered elusive and unstable materials, a number of nanostructures consisting of sp-carbon wires have been produced and characterized to date. In this short review, we present the main CAW synthesis techniques and stabilization strategies and we discuss the current status of the understanding of their structural, electronic and vibrational properties with particular attention to how these properties are related to one another. We focus on the use of vibrational spectroscopy to provide information on the structural and electronic properties of the system (e.g., determination of wire length). Moreover, by employing Raman spectroscopy and surface enhanced Raman scattering in combination with the support of first principles calculations, we show that a detailed understanding of the charge transfer between CAWs and metal nanoparticles may open the possibility to tune the electronic structure from alternating to equalized bonds. PMID- 25821690 TI - Hollow plasmonic antennas for broadband SERS spectroscopy. AB - The chemical environment of cells is an extremely complex and multifaceted system that includes many types of proteins, lipids, nucleic acids and various other components. With the final aim of studying these components in detail, we have developed multiband plasmonic antennas, which are suitable for highly sensitive surface enhanced Raman spectroscopy (SERS) and are activated by a wide range of excitation wavelengths. The three-dimensional hollow nanoantennas were produced on an optical resist by a secondary electron lithography approach, generated by fast ion-beam milling on the polymer and then covered with silver in order to obtain plasmonic functionalities. The optical properties of these structures have been studied through finite element analysis simulations that demonstrated the presence of broadband absorption and multiband enhancement due to the unusual geometry of the antennas. The enhancement was confirmed by SERS measurements, which showed a large enhancement of the vibrational features both in the case of resonant excitation and out-of-resonance excitation. Such characteristics indicate that these structures are potential candidates for plasmonic enhancers in multifunctional opto-electronic biosensors. PMID- 25821691 TI - Correction: Carbon-based smart nanomaterials in biomedicine and neuroengineering. AB - [This corrects the article DOI: 10.3762/bjnano.5.196.]. PMID- 25821692 TI - Synergic combination of the sol-gel method with dip coating for plasmonic devices. AB - Biosensing technologies based on plasmonic nanostructures have recently attracted significant attention due to their small dimensions, low-cost and high sensitivity but are often limited in terms of affinity, selectivity and stability. Consequently, several methods have been employed to functionalize plasmonic surfaces used for detection in order to increase their stability. Herein, a plasmonic surface was modified through a controlled, silica platform, which enables the improvement of the plasmonic-based sensor functionality. The key processing parameters that allow for the fine-tuning of the silica layer thickness on the plasmonic structure were studied. Control of the silica coating thickness was achieved through a combined approach involving sol-gel and dip coating techniques. The silica films were characterized using spectroscopic ellipsometry, contact angle measurements, atomic force microscopy and dispersive spectroscopy. The effect of the use of silica layers on the optical properties of the plasmonic structures was evaluated. The obtained results show that the silica coating enables surface protection of the plasmonic structures, preserving their stability for an extended time and inducing a suitable reduction of the regeneration time of the chip. PMID- 25821693 TI - Filling of carbon nanotubes and nanofibres. AB - The reliable production of carbon nanotubes and nanofibres is a relatively new development, and due to their unique structure, there has been much interest in filling their hollow interiors. In this review, we provide an overview of the most common approaches for filling these carbon nanostructures. We highlight that filled carbon nanostructures are an emerging material for biomedical applications. PMID- 25821694 TI - Pulmonary surfactant augments cytotoxicity of silica nanoparticles: Studies on an in vitro air-blood barrier model. AB - The air-blood barrier is a very thin membrane of about 2.2 um thickness and therefore represents an ideal portal of entry for nanoparticles to be used therapeutically in a regenerative medicine strategy. Until now, numerous studies using cellular airway models have been conducted in vitro in order to investigate the potential hazard of NPs. However, in most in vitro studies a crucial alveolar component has been neglected. Before aspirated NPs encounter the cellular air blood barrier, they impinge on the alveolar surfactant layer (10-20 nm in thickness) that lines the entire alveolar surface. Thus, a prior interaction of NPs with pulmonary surfactant components will occur. In the present study we explored the impact of pulmonary surfactant on the cytotoxic potential of amorphous silica nanoparticles (aSNPs) using in vitro mono- and complex coculture models of the air-blood barrier. Furthermore, different surface functionalisations (plain-unmodified, amino, carboxylate) of the aSNPs were compared in order to study the impact of chemical surface properties on aSNP cytotoxicity in combination with lung surfactant. The alveolar epithelial cell line A549 was used in mono- and in coculture with the microvascular cell line ISO HAS-1 in the form of different cytotoxicity assays (viability, membrane integrity, inflammatory responses such as IL-8 release). At a distinct concentration (100 ug/mL) aSNP-plain displayed the highest cytotoxicity and IL-8 release in monocultures of A549. aSNP-NH2 caused a slight toxic effect, whereas aSNP-COOH did not exhibit any cytotoxicity. In combination with lung surfactant, aSNP-plain revealed an increased cytotoxicity in monocultures of A549, aSNP-NH2 caused a slightly augmented toxic effect, whereas aSNP-COOH did not show any toxic alterations. A549 in coculture did not show any decreased toxicity (membrane integrity) for aSNP-plain in combination with lung surfactant. However, a significant augmented IL-8 release was observed, but no alterations in combination with lung surfactant. The augmented aSNP toxicity with surfactant in monocultures appears to depend on the chemical surface properties of the aSNPs. Reactive silanol groups seem to play a crucial role for an augmented toxicity of aSNPs. The A549 cells in the coculture seem to be more robust towards aSNPs, which might be a result of a higher differentiation and polarization state due the longer culture period. PMID- 25821695 TI - Structural, optical, opto-thermal and thermal properties of ZnS-PVA nanofluids synthesized through a radiolytic approach. AB - This work describes a fast, clean and low-cost approach to synthesize ZnS-PVA nanofluids consisting of ZnS nanoparticles homogeneously distributed in a PVA solution. The ZnS nanoparticles were formed by the electrostatic force between zinc and sulfur ions induced by gamma irradiation at a dose range from 10 to 50 kGy. Several experimental characterizations were conducted to investigate the physical and chemical properties of the samples. Fourier transform infrared spectroscopy (FTIR) was used to determine the chemical structure and bonding conditions of the final products, transmission electron microscopy (TEM) for determining the shape morphology and average particle size, powder X-ray diffraction (XRD) for confirming the formation and crystalline structure of ZnS nanoparticles, UV-visible spectroscopy for measuring the electronic absorption characteristics, transient hot wire (THW) and photoacoustic measurements for measuring the thermal conductivity and thermal effusivity of the samples, from which, for the first time, the values of specific heat and thermal diffusivity of the samples were then calculated. PMID- 25821696 TI - Silica micro/nanospheres for theranostics: from bimodal MRI and fluorescent imaging probes to cancer therapy. AB - Nano-theranostics offer remarkable potential for future biomedical technology with simultaneous applications for diagnosis and therapy of disease sites. Through smart and careful chemical modifications of the nanoparticle surface, these can be converted to multifunctional tiny objects which in turn can be used as vehicle for delivering multimodal imaging agents and therapeutic material to specific target sites in vivo. In this sense, bimodal imaging probes that simultaneously enable magnetic resonance imaging and fluorescence imaging have gained tremendous attention because disease sites can be characterized quick and precisely through synergistic multimodal imaging. But such hybrid nanocomposite materials have limitations such as low chemical stability (magnetic component) and harsh cytotoxic effects (fluorescent component) and, hence, require a biocompatible protecting agent. Silica micro/nanospheres have shown promise as protecting agent due to the high stability and low toxicity. This review will cover a full description of MRI-active and fluorescent multifunctional silica micro/nanospheres including the design of the probe, different characterization methods and their application in imaging and treatment in cancer. PMID- 25821697 TI - Chains of carbon atoms: A vision or a new nanomaterial? AB - Linear strings of sp(1)-hybridized carbon atoms are considered as a possible phase of carbon since decades. Whereas the debate about the stability of the corresponding bulk phase carbyne continues until today, the existence of isolated chains of carbon atoms has meanwhile been corroborated experimentally. Since graphene, as the two-dimensional sp(2)-bonded allotrope of carbon, has become a vast field, the question about the importance of one-dimensional carbon became of renewed interest. The present article gives an overview of the work that has been carried out on chains of carbon atoms in the past one or two decades. The review concentrates on isolated chains of carbon atoms and summarizes the experimental observations to date. While the experimental information is still very limited, many calculations of the physical and chemical properties have been published in the past years. Some of the most important theoretical studies and their importance in the present experimental situation are reviewed. PMID- 25821698 TI - Novel ZnO:Ag nanocomposites induce significant oxidative stress in human fibroblast malignant melanoma (Ht144) cells. AB - The use of photoactive nanoparticles (NPs) such as zinc oxide (ZnO) and its nanocomposites has become a promising anticancer strategy. However, ZnO has a low photocatalytic decomposition rate and the incorporation of metal ions such as silver (Ag) improves their activity. Here different formulations of ZnO:Ag (1, 3, 5, 10, 20 and 30% Ag) were synthesized by a simple co-precipitation method and characterized by powder X-ray diffraction, scanning electron microscopy, Rutherford back scattering and diffuse reflectance spectroscopy for their structure, morphology, composition and optical band gap. The NPs were investigated with regard to their different photocatalytic cytotoxic effects in human malignant melanoma (HT144) and normal (HCEC) cells. The ZnO:Ag nanocomposites killed cancer cells more efficiently than normal cells under daylight exposure. Nanocomposites having higher Ag content (10, 20 and 30%) were more toxic compared to low Ag content (1, 3 and 5%). For HT144, under daylight exposure, the IC50 values were ZnO:Ag (10%): 23.37 MUg/mL, ZnO:Ag (20%): 19.95 MUg/mL, and ZnO:Ag (30%): 15.78 MUg/mL. ZnO:Ag (30%) was toxic to HT144 (IC50: 23.34 MUg/mL) in dark as well. The three nanocomposites were further analyzed with regard to their ability to generate reactive oxygen species (ROS) and induce lipid peroxidation. The particles led to an increase in levels of ROS at cytotoxic concentrations, but only HT144 showed strongly induced MDA level. Finally, NPs were investigated for the ROS species they generated in vitro. A highly significant increase of (1)O2 in the samples exposed to daylight was observed. Hydroxyl radical species, HO(*), were also generated to a lesser extent. Thus, the incorporation of Ag into ZnO NPs significantly improves their photo-oxidation capabilities. ZnO:Ag nanocomposites could provide a new therapeutic option to selectively target cancer cells. PMID- 25821699 TI - Entropy effects in the collective dynamic behavior of alkyl monolayers tethered to Si(111). AB - Dynamic properties of n-alkyl monolayers covalently bonded to Si(111) were studied by broadband admittance spectroscopy as a function of the temperature and the applied voltage using rectifying Hg/C12H25/n-type Si junctions. Partial substitution of methyl end groups by polar (carboxylic acid) moieties was used to enhance the chain end relaxation response. Two thermally activated dissipation mechanisms (B1 and B2, with f B1 < f B2) are evidenced for all reverse bias values. The strong decrease of both relaxation frequencies with increasing reverse dc bias reveals increasing motional constraints, attributed to electrostatic pressure applied to the densely-packed nanometer-thick monolayer. Spectral decomposition of the frequency response shows a power-law dependence of their activation energies on |V DC|. A large reverse bias reversibly increases the B2 response attributed to the distribution of gauche defects, in contrast with the constant strength of the acid dipole loss (B1). A trans-gauche isomerization energy of 50 meV is derived from the temperature dependence of the B2 dipolar strength. For both dissipation mechanisms, the observed linear correlation between activation energy and logarithm of pre-exponential factor is consistent with a multi-excitation entropy model, in which the molecular reorientation path is strongly coupled with a large number of low energy excitations (here the n-alkyl bending vibrational mode) collected from the thermal bath. This collective dynamic behavior of alkyl chains tethered to Si is also confirmed by the asymmetric relaxation peak shape related to many-body interactions in complex systems. PMID- 25821700 TI - Overview of nanoscale NEXAFS performed with soft X-ray microscopes. AB - Today, in material science nanoscale structures are becoming more and more important. Not only for the further miniaturization of semiconductor devices like carbon nanotube based transistors, but also for newly developed efficient energy storage devices, gas sensors or catalytic systems nanoscale and functionalized materials have to be analysed. Therefore, analytical tools like near-edge X-ray absorption fine structure (NEXAFS) spectroscopy has to be applied on single nanostructures. Scanning transmission X-ray microscopes (STXM) as well as full field transmission X-ray microscopes (TXM) allow the required spatial resolution to study individual nanostructures. In the soft X-ray energy range only STXM was used so far for NEXAFS studies. Due to its unique setup, the TXM operated by the Helmholtz-Zentrum Berlin (HZB) at the electron storage ring BESSY II is the first one in the soft X-ray range which can be used for NEXAFS spectroscopy studies which will be shown in this review. Here we will give an overview of the different microscopes used for NEXAFS studies and describe their advantages and disadvantages for different samples. PMID- 25821701 TI - Tm-doped TiO2 and Tm2Ti2O7 pyrochlore nanoparticles: enhancing the photocatalytic activity of rutile with a pyrochlore phase. AB - Tm-doped TiO2 nanoparticles were synthesized using a water-controlled hydrolysis reaction. Analysis was performed in order to determine the influence of the dopant concentration and annealing temperature on the phase, crystallinity, and electronic and optical properties of the resulting material. Various characterization techniques were utilized such as X-ray diffraction, Raman spectroscopy, X-ray photoelectron spectroscopy and UV-vis spectroscopy. For the samples annealed at 773 and 973 K, anatase phase TiO2 was obtained, predominantly internally doped with Tm(3+). ICP-AES showed that a doping concentration of up to 5.8 atom % was obtained without reducing the crystallinity of the samples. The presence of Tm(3+) was confirmed by X-ray photoelectron spectroscopy and UV-vis spectroscopy: the incorporation of Tm(3+) was confirmed by the generation of new absorption bands that could be assigned to Tm(3+) transitions. Furthermore, when the samples were annealed at 1173 K, a pyrochlore phase (Tm2Ti2O7) mixed with TiO2 was obtained with a predominant rutile phase. The photodegradation of methylene blue showed that this pyrochlore phase enhanced the photocatalytic activity of the rutile phase. PMID- 25821703 TI - A versatile strategy towards non-covalent functionalization of graphene by surface-confined supramolecular self-assembly of Janus tectons. AB - Two-dimensional (2D), supramolecular self-assembly at surfaces is now well mastered with several existing examples. However, one remaining challenge to enable future applications in nanoscience is to provide potential functionalities to the physisorbed adlayer. This work reviews a recently developed strategy that addresses this key issue by taking advantage of a new concept, Janus tecton materials. This is a versatile, molecular platform based on the design of three dimensional (3D) building blocks consisting of two faces linked by a cyclophane type pillar. One face is designed to steer 2D self-assembly onto C(sp(2))-carbon based flat surfaces, the other allowing for the desired functionality above the substrate with a well-controlled lateral order. In this way, it is possible to simultaneously obtain a regular, non-covalent paving as well as supramolecular functionalization of graphene, thus opening interesting perspectives for nanoscience applications. PMID- 25821702 TI - Self-assembled anchor layers/polysaccharide coatings on titanium surfaces: a study of functionalization and stability. AB - Composite materials based on a titanium support and a thin, alginate hydrogel could be used in bone tissue engineering as a scaffold material that provides biologically active molecules. The main objective of this contribution is to characterize the activation and the functionalization of titanium surfaces by the covalent immobilization of anchoring layers of self-assembled bisphosphonate neridronate monolayers and polymer films of 3-aminopropyltriethoxysilane and biomimetic poly(dopamine). These were further used to bind a bio-functional alginate coating. The success of the titanium surface activation, anchoring layer formation and alginate immobilization, as well as the stability upon immersion under physiological-like conditions, are demonstrated by different surface sensitive techniques such as spectroscopic ellipsometry, infrared reflection absorption spectroscopy and X-ray photoelectron spectroscopy. The changes in morphology and the established continuity of the layers are examined by scanning electron microscopy, surface profilometry and atomic force microscopy. The changes in hydrophilicity after each modification step are further examined by contact angle goniometry. PMID- 25821704 TI - Simple approach for the fabrication of PEDOT-coated Si nanowires. AB - The synthesis of a conformal poly(3,4-ethylenedioxythiophene) (PEDOT) layer on Si nanowires was demonstrated using a pulsed electrodeposition technique. N-type Si nanowire (SiNWs) arrays were synthesized using an electroless metal-assisted chemical etching technique. The dependence of the SiNW reflection on the concentration of the AgNO3 solution was identified. A reflection of less than 2% over the entire visible spectral range was obtained for these structures, evidencing their excellent antireflective properties. The etched SiNWs nanostructures can be further modified by using a tapering technique, which further preserves the strong light trapping effect. P-type PEDOT was grown on these SiNWs using electrochemical methods. Since the polymerization reaction is a very fast process with regards to monomer diffusion along the SiNW, the conformal deposition by classical, fixed potential deposition was not favored. Instead, the core-shell heterojunction structure was finally achieved by a pulsed deposition method. An extremely large shunt resistance was exhibited and determined to be related to the diffusion conditions occurring during polymerization. PMID- 25821706 TI - In situ observation of biotite (001) surface dissolution at pH 1 and 9.5 by advanced optical microscopy. AB - Laser confocal differential interference contrast microscopy (LCM-DIM) allows for the study of the reactivity of surface minerals with slow dissolution rates (e.g., phyllosilicates). With this technique, it is possible to carry out in situ inspection of the reacting surface in a broad range of pH, ionic strength and temperature providing useful information to help unravel the dissolution mechanisms of phyllosilicates. In this work, LCM-DIM was used to study the mechanisms controlling the biotite (001) surface dissolution at pH 1 (11 and 25 degrees C) and pH 9.5 (50 degrees C). Step edges are the preferential sites of dissolution and lead to step retreat, regardless of the solution pH. At pH 1, layer swelling and peeling takes place, whereas at pH 9.5 fibrous structures (streaks) form at the step edges. Confocal Raman spectroscopy characterization of the reacted surface could not confirm if the formation of a secondary phase was responsible for the presence of these structures. PMID- 25821705 TI - Influence of gold, silver and gold-silver alloy nanoparticles on germ cell function and embryo development. AB - The use of engineered nanoparticles has risen exponentially over the last decade. Applications are manifold and include utilisation in industrial goods as well as medical and consumer products. Gold and silver nanoparticles play an important role in the current increase of nanoparticle usage. However, our understanding concerning possible side effects of this increased exposure to particles, which are frequently in the same size regime as medium sized biomolecules and accessorily possess highly active surfaces, is still incomplete. That particularly applies to reproductive aspects, were defects can be passed onto following generations. This review gives a brief overview of the most recent findings concerning reprotoxicological effects. The here presented data elucidate how composition, size and surface modification of nanoparticles influence viablility and functionality of reproduction relevant cells derived from various animal models. While in vitro cultured embryos displayed no toxic effects after the microinjection of gold and silver nanoparticles, sperm fertility parameters deteriorated after co-incubation with ligand free gold nanoparticles. However, the effect could be alleviated by bio-coating the nanoparticles, which even applies to silver and silver-rich alloy nanoparticles. The most sensitive test system appeared to be in vitro oocyte maturation showing a dose-dependent response towards protein (BSA) coated gold-silver alloy and silver nanoparticles leading up to complete arrest of maturation. Recent biodistribution studies confirmed that nanoparticles gain access to the ovaries and also penetrate the blood-testis and placental barrier. Thus, the design of nanoparticles with increased biosafety is highly relevant for biomedical applications. PMID- 25821707 TI - Mandibular gnathobases of marine planktonic copepods - feeding tools with complex micro- and nanoscale composite architectures. AB - Copepods are dominant members of the marine zooplankton. Their diets often comprise large proportions of diatom taxa whose silicified frustules are mechanically stable and offer protection against grazers. Despite of this protection, many copepod species are able to efficiently break even the most stable frustule types. This ability requires specific feeding tools with mechanically adapted architectures, compositions and properties. When ingesting food, the copepods use the gnathobases of their mandibles to grab and, if necessary, crush and mince the food items. The morphology of these gnathobases is related to the diets of the copepods. Gnathobases of copepod species that mainly feed on phytoplankton feature compact and stable tooth-like structures, so-called teeth. In several copepod species these gnathobase teeth have been found to contain silica. Recent studies revealed that the siliceous teeth are complex microscale composites with silica-containing cap-like structures located on chitinous exoskeleton sockets that are connected with rubber-like bearings formed by structures with high proportions of the soft and elastic protein resilin. In addition, the silica-containing cap-like structures exhibit a nanoscale composite architecture. They contain some amorphous silica and large proportions of the crystalline silica type alpha-cristobalite and are pervaded by a fine chitinous fibre network that very likely serves as a scaffold during the silicification process. All these intricate composite structures are assumed to be the result of a coevolution between the copepod gnathobases and diatom frustules in an evolutionary arms race. The composites very likely increase both the performance of the siliceous teeth and their resistance to mechanical damage, and it is conceivable that their development has favoured the copepods' dominance of the marine zooplankton observed today. PMID- 25821708 TI - Electromagnetic enhancement of ordered silver nanorod arrays evaluated by discrete dipole approximation. AB - The enhancement factor (EF) of surface-enhanced Raman scattering (SERS) from two dimensional (2D) hexagonal silver nanorod (AgNR) arrays were investigated in terms of electromagnetic (EM) mechanism by using the discrete dipole approximation (DDA) method. The dependence of EF on several parameters, i.e., structure, length, excitation wavelength, incident angle and polarization, and gap size has been investigated. "Hotspots" were found distributed in the gaps between adjacent nanorods. Simulations of AgNR arrays of different lengths revealed that increasing the rod length from 374 to 937 nm (aspect ratio from 2.0 to 5.0) generated more "hotspots" but not necessarily increased EF under both 514 and 532 nm excitation. A narrow lateral gap (in the incident plane) was found to result in strong EF, while the dependence of EF on the diagonal gap (out of the incident plane) showed an oscillating behavior. The EF of the array was highly dependent on the angle and polarization of the incident light. The structure of AgNR and the excitation wavelength were also found to affect the EF. The EF of random arrays was stronger than that of an ordered one with the same average gap of 21 nm, which could be explained by the exponential dependence of EF on the lateral gap size. Our results also suggested that absorption rather than extinction or scattering could be a good indicator of EM enhancement. It is expected that the understanding of the dependence of local field enhancement on the structure of the nanoarrays and incident excitations will shine light on the optimal design of efficient SERS substrates and improved performance. PMID- 25821709 TI - Manipulation of magnetic vortex parameters in disk-on-disk nanostructures with various geometry. AB - Magnetic nanostructures in the form of a sandwich consisting of two permalloy (Py) disks with diameters of 600 and 200 nm separated by a nonmagnetic interlayer are studied. Magnetization reversal of the disk-on-disk nanostructures depends on the distance between centers of the small and big disks and on orientation of an external magnetic field applied during measurements. It is found that manipulation of the magnetic vortex chirality and the trajectory of the vortex core in the big disk is only possible in asymmetric nanostructures. Experimentally studied peculiarities of a motion path of the vortex core and vortex parameters by the magneto-optical Kerr effect (MOKE) magnetometer are supported by the magnetic force microscopy imaging and micromagnetic simulations. PMID- 25821710 TI - Observation of a photoinduced, resonant tunneling effect in a carbon nanotube silicon heterojunction. AB - A significant resonant tunneling effect has been observed under the 2.4 V junction threshold in a large area, carbon nanotube-silicon (CNT-Si) heterojunction obtained by growing a continuous layer of multiwall carbon nanotubes on an n-doped silicon substrate. The multiwall carbon nanostructures were grown by a chemical vapor deposition (CVD) technique on a 60 nm thick, silicon nitride layer, deposited on an n-type Si substrate. The heterojunction characteristics were intensively studied on different substrates, resulting in high photoresponsivity with a large reverse photocurrent plateau. In this paper, we report on the photoresponsivity characteristics of the device, the heterojunction threshold and the tunnel-like effect observed as a function of applied voltage and excitation wavelength. The experiments are performed in the near-ultraviolet to near-infrared wavelength range. The high conversion efficiency of light radiation into photoelectrons observed with the presented layout allows the device to be used as a large area photodetector with very low, intrinsic dark current and noise. PMID- 25821711 TI - Electroburning of few-layer graphene flakes, epitaxial graphene, and turbostratic graphene discs in air and under vacuum. AB - Graphene-based electrodes are very promising for molecular electronics and spintronics. Here we report a systematic characterization of the electroburning (EB) process, leading to the formation of nanometer-spaced gaps, on different types of few-layer graphene (namely mechanically exfoliated graphene on SiO2, graphene epitaxially grown on the C-face of SiC and turbostratic graphene discs deposited on SiO2) under air and vacuum conditions. The EB process is found to depend on both the graphene type and on the ambient conditions. For the mechanically exfoliated graphene, performing EB under vacuum leads to a higher yield of nanometer-gap formation than working in air. Conversely, for graphene on SiC the EB process is not successful under vacuum. Finally, the EB is possible with turbostratic graphene discs only after the creation of a constriction in the sample using lithographic patterning. PMID- 25821712 TI - Morphological and structural characterization of single-crystal ZnO nanorod arrays on flexible and non-flexible substrates. AB - We report a facile synthesis of zinc oxide (ZnO) nanorod arrays using an optimized, chemical bath deposition method on glass, PET and Si substrates. The morphological and structural properties of the ZnO nanorod arrays were investigated using various techniques such as field emission scanning electron microscopy (FESEM) and X-ray diffraction (XRD) measurements, which revealed the formation of dense ZnO nanorods with a single crystal, hexagonal wurtzite structure. The aspect ratio of the single-crystal ZnO nanorods and the growth rate along the (002) direction was found to be sensitive to the substrate type. The lattice constants and the crystallite size of the fabricated ZnO nanorods were calculated based on the XRD data. The obtained results revealed that the increase in the crystallite size is strongly associated with the growth conditions with a minor dependence on the type of substrate. The Raman spectroscopy measurements confirmed the existence of a compressive stress in the fabricated ZnO nanorods. The obtained results illustrated that the growth of high quality, single-crystal ZnO nanorods can be realized by adjusting the synthesis conditions. PMID- 25821713 TI - Graphene quantum interference photodetector. AB - In this work, a graphene quantum interference (QI) photodetector was simulated in two regimes of operation. The structure consists of a graphene nanoribbon, Mach Zehnder interferometer (MZI), which exhibits a strongly resonant transmission of electrons of specific energies. In the first regime of operation (that of a linear photodetector), low intensity light couples two resonant energy levels, resulting in scattering and differential transmission of current with an external quantum efficiency of up to 5.2%. In the second regime of operation, full current switching is caused by the phase decoherence of the current due to a strong photon flux in one or both of the interferometer arms in the same MZI structure. Graphene QI photodetectors have several distinct advantages: they are of very small size, they do not require p- and n-doped regions, and they exhibit a high external quantum efficiency. PMID- 25821714 TI - Production, detection, storage and release of spin currents. AB - BACKGROUND: Quantum rings connected to ballistic circuits couple strongly to external magnetic fields if the connection is not symmetric. Moreover, properly connected rings can be used to pump currents in the wires giving raise to a number of interesting new phenomena. At half filling using a time-dependent magnetic field in the plane of the ring one can pump a pure spin current, excited by the the spin-orbit interaction in the ring. RESULTS: Such a magnetic current is even under time reversal and produces an electric field instead of the usual magnetic field. Numerical simulations show that one can use magnetizable bodies as storage units to concentrate and save the magnetization in much the same way as capacitors operating with charge currents store electric charge. The polarization obtained in this way can then be used on command to produce spin currents in a wire. These currents show interesting oscillations while the storage units exchange their polarizations. CONCLUSION: The magnetic production of spin currents can be a useful alternative to optical excitation and electric field methods. PMID- 25821715 TI - Recreational Water and Infection: A Review of Recent Findings. AB - This paper reviews the latest evidence provided by epidemiological studies and quantitative microbial risk assessments (QMRAs) of infection risk from recreational water use. Studies for review were selected following a PubMed search for articles published between January 2010 and April 2014. Epidemiological studies show a generally elevated risk of gastrointestinal illness in bathers compared to non-bathers but often no clear association with water quality as measured by faecal indicator bacteria; this is especially true where study sites are impacted by non-point source pollution. Evidence from QMRAs support the lack of a consistent water quality association for non-point source impacted beaches. It is suggested that source attribution, through quantified microbial source apportionment, linked with appropriate use of microbial source tracking methods should be employed as an integral part of future epidemiological surveys. PMID- 25821716 TI - Microbial Contamination of Drinking Water and Human Health from Community Water Systems. AB - A relatively short list of reference viral, bacterial and protozoan pathogens appears adequate to assess microbial risks and inform a system-based management of drinking waters. Nonetheless, there are data gaps, e.g. human enteric viruses resulting in endemic infection levels if poorly performing disinfection and/or distribution systems are used, and the risks from fungi. Where disinfection is the only treatment and/or filtration is poor, cryptosporidiosis is the most likely enteric disease to be identified during waterborne outbreaks, but generally non-human-infectious genotypes are present in the absence of human or calf fecal contamination. Enteric bacteria may dominate risks during major fecal contamination events that are ineffectively managed. Reliance on culture-based methods exaggerates treatment efficacy and reduces our ability to identify pathogens/indicators; however, next-generation sequencing and polymerase chain reaction approaches are on the cusp of changing that. Overall, water-based Legionella and non-tuberculous mycobacteria probably dominate health burden at exposure points following the various societal uses of drinking water. PMID- 25821717 TI - Sleep and oligodendrocyte functions. AB - Transcriptomic studies have revealed that the brains of sleeping and awake animals differ significantly at the molecular level, with hundreds of brain transcripts changing their expression across behavioral states. However, it was unclear how sleep affects specific cells types, such as oligodendrocytes, which make myelin in the healthy brain and in response to injury. In this review, I summarize the recent findings showing that several genes expressed at higher levels during sleep are involved in the synthesis/maintenance of all membranes and of myelin in particular. In addition, I will discuss the effect of sleep and wake on oligodendrocyte precursor cells (OPCs), providing a working hypothesis on the function of REM sleep and acetylcholine in OPC proliferation. PMID- 25821718 TI - Molecular Imaging in Optical Coherence Tomography. AB - Optical coherence tomography (OCT) is a medical imaging technique that provides tomographic images at micron scales in three dimensions and high speeds. The addition of molecular contrast to the available morphological image holds great promise for extending OCT's impact in clinical practice and beyond. Fundamental limitations prevent OCT from directly taking advantage of powerful molecular processes such as fluorescence emission and incoherent Raman scattering. A wide range of approaches is being researched to provide molecular contrast to OCT. Here we review those approaches with particular attention to those that derive their molecular contrast directly from modulation of the OCT signal. We also provide a brief overview of the multimodal approaches to gaining molecular contrast coincident with OCT. PMID- 25821719 TI - Detecting Significant Changes in Protein Abundance. AB - We review and demonstrate how an empirical Bayes method, shrinking a protein's sample variance towards a pooled estimate, leads to far more powerful and stable inference to detect significant changes in protein abundance compared to ordinary t-tests. Using examples from isobaric mass labeled proteomic experiments we show how to analyze data from multiple experiments simultaneously, and discuss the effects of missing data on the inference. We also present easy to use open source software for normalization of mass spectrometry data and inference based on moderated test statistics. PMID- 25821720 TI - Are hospitals "keeping up with the Joneses"?: Assessing the spatial and temporal diffusion of the surgical robot. AB - BACKGROUND: The surgical robot has been widely adopted in the United States in spite of its high cost and controversy surrounding its benefit. Some have suggested that a "medical arms race" influences technology adoption. We wanted to determine whether a hospital would acquire a surgical robot if its nearest neighboring hospital already owned one. METHODS: We identified 554 hospitals performing radical prostatectomy from the Healthcare Cost and Utilization Project Statewide Inpatient Databases for seven states. We used publicly available data from the website of the surgical robot's sole manufacturer (Intuitive Surgical, Sunnyvale, CA) combined with data collected from the hospitals to ascertain the timing of robot acquisition during year 2001 to 2008. One hundred thirty four hospitals (24%) had acquired a surgical robot by the end of 2008. We geocoded the address of each hospital and determined a hospital's likelihood to acquire a surgical robot based on whether its nearest neighbor owned a surgical robot. We developed a Markov chain method to model the acquisition process spatially and temporally and quantified the "neighborhood effect" on the acquisition of the surgical robot while adjusting simultaneously for known confounders. RESULTS: After adjusting for hospital teaching status, surgical volume, urban status and number of hospital beds, the Markov chain analysis demonstrated that a hospital whose nearest neighbor had acquired a surgical robot had a higher likelihood itself acquiring a surgical robot. (OR=1.71, 95% CI: 1.07-2.72, p=0.02). CONCLUSION: There is a significant spatial and temporal association for hospitals acquiring surgical robots during the study period. Hospitals were more likely to acquire a surgical robot during the robot's early adoption phase if their nearest neighbor had already done so. PMID- 25821721 TI - Whole Exome Sequencing Reveals DYSF, FKTN, and ISPD Mutations in Congenital Muscular Dystrophy Without Brain or Eye Involvement. AB - BACKGROUND: Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. OBJECTIVE: We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. METHODS: Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. RESULTS: Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to absence of dysferlin protein in patient muscle. Mutations in ISPD led to impaired ISDP function, as demonstrated by deficiency of alpha-dystroglycan glycosylation in patient muscle. CONCLUSIONS: This study highlights the benefit of unbiased genomic approaches in molecular diagnosis of neuromuscular disorders with high clinical heterogeneity, such as the phenotypes observed in our patients. Our results suggest that dysferlin deficiency should be in the differential diagnosis of congenital and rapidly progressive muscular dystrophy, and therefore dysferlin antibody should be in the standard immunohistochemistry panel for muscle biopsies in cases with suspected CMD. PMID- 25821722 TI - Short-term, daily exposure to cold temperature may be an efficient way to prevent muscle atrophy and bone loss in a microgravity environment. AB - Microgravity induces less pressure on muscle/bone, which is a major reason for muscle atrophy as well as bone loss. Currently, physical exercise is the only countermeasure used consistently in the U.S. human space program to counteract the microgravity-induced skeletal muscle atrophy and bone loss. However, the routinely almost daily time commitment is significant and represents a potential risk to the accomplishment of other mission operational tasks. Therefore, development of more efficient exercise programs (with less time) to prevent astronauts from muscle atrophy and bone loss are needed. Consider the two types of muscle contraction: exercising forces muscle contraction and prevents microgravity-induced muscle atrophy/bone loss, which is a voluntary response through the motor nervous system; and cold temperature exposure-induced muscle contraction is an involuntary response through the vegetative nervous system, we formed a new hypothesis. The main purpose of this pilot study was to test our hypothesis that exercise at 4 degrees C is more efficient than at room temperature to prevent microgravity-induced muscle atrophy/bone loss and, consequently reduces physical exercise time. Twenty mice were divided into two groups with or without daily short-term (10 min * 2, at 12 h interval) cold temperature (4 degrees C) exposure for 30 days. The whole bodyweight, muscle strength and bone density were measured after terminating the experiments. The results from the one-month pilot study support our hypothesis and suggest that it would be reasonable to use more mice, in a microgravity environment and observe for a longer period to obtain a conclusion. We believe that the results from such a study will help to develop efficient exercise, which will finally benefit astronauts' heath and NASA's missions. PMID- 25821723 TI - Frameless single-isocenter intensity modulated stereotactic radiosurgery for simultaneous treatment of multiple intracranial metastases. AB - PURPOSE: Stereotactic radiosurgery (SRS) is well accepted treatment for patients with intracranial metastases, but the role of frameless radiosurgery is not well defined. Here, we describe our clinical experience applying a novel single isocenter technique to frameless intensity modulated stereotactic radiosurgery (IMRS) for simultaneous treatment of multiple intracranial metastases. METHODS AND MATERIALS: Between 2006 and 2012, 100 consecutive patients received frameless IMRS for multiple intracranial metastases using a single, centrally-located isocenter. Among these, 29 patients were treated for progressive or recurrent intracranial disease. A total of 465 metastases (median, 4 per patient, range, 2 18) were treated to a median dose of 20 Gy (range, 15-50 Gy). Follow-up including clinical examination and magnetic resonance imaging (MRI) occurred every 3 months. RESULTS: Median follow-up for all patients was 4.3 months (range, 0.2 58.3 months), with 83 patients (83.0%) followed until their death. For the remaining 17 patients alive at the time of analysis, median follow-up was 9.2 months (range, 2.2-58.3 months). Overall survival at 6 months was 49.5% [95% confidence interval (CI), 35.3-63.6%]. Local control at 6 and 12 months was 88.9% (95% CI, 79.1-98.6%) and 81.5% (95% CI, 65.2-97.7%), respectively. Regional failure was observed in 39 patients (39%), and 25 patients (25%) received salvage therapy. Grade 3 or greater treatment-related toxicity was observed in 4 patients (4%) and included intracranial hemorrhage, seizure, and radionecrosis. Median total treatment time was 17.2 minutes (range, 2.8-55.3 minutes). CONCLUSIONS: Single-isocenter IMRS for multiple intracranial metastases can produce clinical outcomes comparable to those of conventional radiosurgery techniques. PMID- 25821724 TI - Nail as a window of systemic diseases. AB - Certain nail changes are specific for various dermatological disorders. In addition, examination of nails may also provide an insight into more sinister systemic manifestations in the form of both subtle as well as specific changes. These findings may present as a defect of various anatomical components of the nail unit; nail matrix, nail plate and/or nail bed or vasculature. This article is an attempt to equip the dermatologists with a foresight to suspect and diagnose the unapparent systemic connotations that may be possible by a simple but detailed nail examination. PMID- 25821725 TI - A comparative study of 10% KOH solution and 5% imiquimod cream for the treatment of Molluscum contagiosum in the pediatric age group. AB - BACKGROUND: Although Molluscum contagiosum (MC) is a self-limiting condition, active therapy could prevent further spread and improve cosmesis. Most of the available treatment modalities traumatize the lesions and have to be undertaken in the hospital, therefore evoking panic in children. In the quest for an alternative therapy, this study comparing 10% potassium hydroxide (KOH) solution and 5% imiquimod cream was taken up. AIMS AND OBJECTIVES: To compare the efficacy and tolerability of 10% KOH and 5% imiquimod in the treatment of MC. MATERIALS AND METHODS: This comparative study was conducted over a period of 18 months from October 2011 to March 2013, 40 patients between the age group of 1-18 years with clinically diagnosed MC were divided into two groups (lottery method), 20 patients were treated with 5% imiquimod cream (Group A) and the other 20 were treated with 10% KOH solution (Group B). Patients were followed up on the 4(th), 8(th) and 12(th) week of treatment. RESULTS: At the end of 12 weeks, out of 20 patients who received 10% KOH, 17 patients showed complete disappearance, whereas out of 20 patients who received 5% imiquimod, only 10 patients showed total clearance of the lesions. Adverse events were more frequent with 10% KOH, pigmentary disturbances being the most common. CONCLUSION: With only minor adverse effects, 10% KOH is an inexpensive and efficient modality for the treatment of MC in the pediatric age group. Although 5% imiquimod was effective in clearing the lesions with minimal adverse effects, the longer duration required for its efficacy may deter its wider use. PMID- 25821726 TI - Comparison of levels of serum copper, zinc, albumin, globulin and alkaline phosphatase in psoriatic patients and controls: A hospital based casecontrol study. AB - BACKGROUND: Psoriasis is a chronic, immune-mediated skin disease with unknown etiology, with an epidermal turnover time of <10 days compared to a normal turnover time of 4-8 weeks. This epidermal hyperproliferation accounts for many of the metabolic abnormalities including alteration in the serum levels of proteins and some trace elements. AIM: The aim was to detect any statistically significant difference in the serum levels of zinc, copper, albumin, globulin and alkaline phosphatase between psoriasis patients and healthy controls. MATERIALS AND METHODS: Hundred cases of psoriasis and 100 age and sex matched controls were enrolled in a hospital based case-control study. The serum levels of zinc, copper, albumin, globulin and alkaline phosphatase were calculated and compared among the cases and controls and evaluated statistically. RESULTS: Serum zinc levels were significantly low in the psoriasis group as compared with controls (mean 80.028 MUg/dl vs. 109.179 MUg/dl, P < 0.0001). Serum copper levels were significantly raised among cases as compared with controls (mean 167.317 MUg/dl vs. 133.884 MUg/dl P < 0.0001). Serum albumin levels were significantly decreased (3.762 g/dl vs. 4.103 g/dl, P < 0.001), whereas serum globulin levels were raised (3.296 g/dl vs. 2.596 g/dl, P = 0.0014) among cases as compared with controls, respectively. Serum alkaline phosphatase levels were comparable between the two groups. CONCLUSION: The results of this study show significant alterations in the serum levels of copper, zinc, albumin, and globulin in psoriatic patients. This paper aims at highlighting the possible role of trace metals copper and zinc in the aetiopathogenesis of psoriasis and also provides a proposed interplay of factors involved in the pathogenesis of psoriasis. PMID- 25821727 TI - Retinoic acid and glycolic acid combination in the treatment of acne scars. AB - INTRODUCTION: Acne is a prevalent condition in society affecting nearly 80-90% of adolescents often resulting in secondary damage in the form of scarring. Retinoic acid (RA) is said to improve acne scars and reduce postinflammatory hyperpigmentation while glycolic acid (GA) is known for its keratolytic properties and its ability to reduce atrophic acne scars. There are studies exploring the combined effect of retinaldehyde and GA combination with positive results while the efficacy of retinoic acid and GA (RAGA) combination remains unexplored. AIM: The aim of this study remains to retrospectively assess the efficacy of RAGA combination on acne scars in patients previously treated for active acne. MATERIALS AND METHODS: A retrospective assessment of 35 patients using topical RAGA combination on acne scars was done. The subjects were 17-34 years old and previously treated for active acne. Case records and photographs of each patient were assessed and the acne scars were graded as per Goodman and Baron's global scarring grading system (GSGS), before the start and after 12 weeks of RAGA treatment. The differences in the scar grades were noted to assess the improvement. RESULTS: At the end of 12 weeks, significant improvement in acne scars was noticed in 91.4% of the patients. CONCLUSION: The RAGA combination shows efficacy in treating acne scars in the majority of patients, minimizing the need of procedural treatment for acne scars. PMID- 25821728 TI - Association of anti-phospholipid antibodies with connective tissue diseases. AB - BACKGROUND: The antiphospholipid antibodies (APLA) are directed against phospholipids and their binding proteins and are frequently found in association with connective tissue disorders. Systemic lupus erythematoses (SLE) with APLA may cause a diagnostic dilemma as there are several manifestations like haemolytic anemia, thrombocytopenia, neurologic manifestations, leg ulcerations, serositis proteinuria which overlap in both these conditions. We conducted a study to find out the association of antiphospholipid antibodies with connective tissue diseases and compared the clinical and laboratory parameters between antiphoshpolipid antibody positive and antiphoshpolipid antibody negative group. MATERIALS AND METHODS: This study was carried out in 102 patients diagnosed with connective tissue diseases. APLA testing was done at baseline and for those positive, the test was repeated after 12 weeks. RESULTS: 14.7 % of patients with connective tissue diseases tissue had positive antiphoshpolipid antibodies. Positive antiphoshpolipid antibody was detected in 73.3% of patients with SLE group, 13.3% of patients with mixed connective tissue disease (MCTD) and 13.3% of patients with systemic sclerosis. APLA positivity was seen in SLE patients with leg ulcers (87.2%), neurologic manifestation (72.7%), hemolytic anemia (62.3%), thrombocytopenia (72.7%), serositis (27.8%) and proteinuria(19.6%). CONCLUSIONS: Antiphoshpolipid antibodies should be tested in all patients with connective tissue disease. PMID- 25821729 TI - The nondermatophyte molds: Emerging as leading cause of onychomycosis in south east Rajasthan. AB - BACKGROUND: Onychomycosis is a fungal disease of the nail apparatus caused by both dermatophytic and nondermatophytic strains. Treatment involves long duration antifungal therapy. However, long treatment duration without identifying the causative species may lead to resistance. Confirmation of diagnosis and speciation by culture before administering antifungal therapy is ideal. AIMS: To study the clinical and epidemiological aspects of onychomycosis in Hadoti region (south-east Rajasthan) and identify various mycological strains and predisposing factors causing onychomycosis. MATERIALS AND METHODS: A prospective study of clinically diagnosed cases of onychomycosis attending the outpatient Department of Dermatology in our institute conducted from June 2012 to May 2013. The clippings were subjected to potassium hydroxide (KOH) examination and culture in the appropriate medium. RESULTS: A total of 150 cases were enrolled in our study. There were 110 males (73.33%) and 40 females (26.66%) and male to female ratio was 2.75:1. The total dystrophic onychomycosis was the most common presentation seen in the majority of cases (46%) followed by distal lateral subungual onychomycosis in 52 cases (34.6%), mixed onychomycosis in 16 cases (10.66%), superficial white onychomycosis in 11 cases (7.33%), and proximal subungual onychomycosis in 2 cases. None had the endonyx variant. Direct microscopic examination of the nail clipping mounted with 40% KOH demonstrated fungal elements in 83 (55.33%) cases. Rate of isolation of organisms by culture was 64%. Nondermatophytes were isolated in 53 (35.33%), dermatophytes in 28 (18.66%), and yeasts in 15 (10%) of cases. The most commonly isolated species was Aspergillus in 45 (30%) cases. Aspergillus flavus was more commonly isolated compared to Aspergillus niger. CONCLUSION: The nondermatophyte molds appear to be more common causative agents of onychomycosis compared to usual dermatophyte species in south east Rajasthan. Our study re-emphasizes the importance of culture for diagnosis of onychomycosis in every suspected case prior to therapy. PMID- 25821730 TI - Fibromatosis over the dorsa of both feet: An unusual presentation. AB - Fibromatosis is benign fibrous tissue condition intermediate between benign fibroma and metastasizing fibrosarcoma. The lesion tends to infiltrate and recur when removed, but do not metastasize. The lesion may be single or multiple, and the likelihood of recurrence after surgical removal varies with location of the lesion and age. A 40-year-old female presented with multiple raised lesions over both feet since 4 years, they were multiple well-defined firm nodules coalescing to form lobulated plaques distributed in a symmetrical pattern over the dorsum of both feet. Histopathology of skin showed epidermis with hyperkeratosis, acanthosis, mild parakeratosis, and prominent granular layer. Superficial dermis was unremarkable and deep dermis showed thick bundles of irregular collagen and fibroblastic proliferation, suggestive of fibromatosis. This case is being reported for its unusual presentation of fibromatosis over the dorsum of both feet. PMID- 25821731 TI - Porokeratosis - Head to toe: An unusual presentation. AB - Porokeratosis is a disorder of epidermal proliferation in which many different clinical variants can be distinguished. Herein we report a rare case of porokeratosis involving almost all parts of the body with simultaneous occurrence of various forms of the disease in the same individual (classical porokeratosis of Mibelli, disseminated superficial actinic porokeratosis, hypertrophic porokeratosis, and genital porokeratosis). PMID- 25821732 TI - A case of dyschromatosis universalis hereditaria with adermatoglyphia: A rare association. AB - Dyschromatosis universalis hereditaria (DUH) is a rare, autosomal dominant genodermatosis with a peculiar reticulate pigmentary change, consisting of hyperpigmented macules mingled with hypopigmented lesions to give an overall impression of mottling. We herein report a case of DUH with adermatoglyphia in a young male with family history of the disorder. PMID- 25821733 TI - Nonfamilial acrokeratosis verruciformis of Hopf. AB - Acrokeratosis verruciformis (AKV) of Hopf is an autosomal dominant genodermatosis with unknown etiology. It is characterized by multiple flat-topped keratotic papules resembling planar warts located mainly on the dorsum of hands and feet. Superficial ablation is the treatment of choice. A 41-year-old female presented with multiple hyperpigmented, hyperkeratotic papules and plaques over flexor aspect of both forearms, extensors of both legs and dorsum of the feet. Histopathology showed changes of AKV. Patient was treated with a combination of topical corticosteroids and cryotherapy with no visible improvement. PMID- 25821734 TI - Palpable purpura with foot drop: Common presentations in an uncommon disease. AB - Churg-Strauss syndrome is a rare disease manifested by hypereosinophilia, vasculitis and tissue infiltration. This report describes the case of a 45-year old man who presented with a history of fever, difficulty in breathing, reddish lesions over the extremities and inability to walk since two weeks. The cutaneous features prompted us to conduct serial lab investigations which led to an early, potentially life saving diagnosis. PMID- 25821735 TI - Porokeratotic eccrine ostial and dermal duct nevus. AB - Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare nevoid condition characterized by asymptomatic grouped keratotic papules and plaques with a linear pattern on the extremities, having distinct porokeratotic histopathological features. The lesions usually present at birth or in childhood. We present here a case of late-onset PEODDN in a 23-year-old man who had lesions on the palm, forearm, arm and the chest along the lines of Blaschko, strictly localized to the left side of the body. PMID- 25821736 TI - Sporotrichoid lupus vulgaris: A rare presentation. AB - Lupus vulgaris is the most common presentation of cutaneous tuberculosis in India and can present as papular, nodular, plaque, ulcerative, vegetating, and tumid forms. Unusual variants include the frambesiform, gangrenous, ulcerovegetating, lichen simplex chronicus, myxomatous, and sporotrichoid types. We describe a rare sporotrichoid presentation of lupus vulgaris on the leg of a 28-year-old female of 12 years duration. PMID- 25821737 TI - Porocarcinoma with perineural invasion. AB - Herein we present the case of a 58 year old woman with porocarcinoma of the left forehead with perineural invasion, diagnosed after recurrence of previously excised benign poroma. This case serves as a reminder of the potential of malignant degeneration within long-standing benign adnexal tumors as well as the spectrum of histological features that may be seen in porocarcinoma. PMID- 25821738 TI - A lady presenting with segmental anhidrosis and heat intolerance. PMID- 25821739 TI - Bier spots: An uncommon cause of mottled skin. PMID- 25821740 TI - Porokeratotic eccrine ostial and dermal duct nevus: A noteworthy presentation. PMID- 25821741 TI - Solitary painful ulcerated plaque on the sole. PMID- 25821742 TI - Linear dermatoses over the hand and foot. PMID- 25821743 TI - Hypohidrotic ectodermal dysplasia. PMID- 25821745 TI - Crusted scabies presenting as palmoplantar psoriasis in Down's syndrome. PMID- 25821744 TI - Dermatitis neglecta-to be remembered, not neglected! PMID- 25821746 TI - Tuberous sclerosis. PMID- 25821747 TI - Development and validation of osteoporosis prescreening model for Iranian postmenopausal women. AB - BACKGROUND: Studies have indicated that the commonly used osteoporosis prescreening tools are not appropriate for use in every nation. This study was designed to develop and validate a prescreening model for bone mineral densitometry among Iranian postmenopausal women. METHODS: From 13613 individuals who were referred for bone mineral densitometry in Shariati hospital in Tehran, 8644 postmenopausal women were considered for the study after excluding men and premenopausal women. Questionnaires regarding the risk factors for osteoporosis were filled for each individual. Bone mineral density at the lumbar vertebrae (L2 L4), femoral neck and total femur was measured by dual X-ray absorptiometry. Using holdout validation, the study sample was divided into two parts; training set (5705) and test set (2939). Logistic regression analysis was performed on the training set. A scoring model was developed and tested in the test set. RESULTS: Based on the training set, a seven-variable model named OPMIP (Osteoporosis Prescreening Model for Iranian Postmenopausal women) was developed with C statistics (area under curve) of 0.72. Using a cut-off of -2.5 for the model, the sensitivity, specificity, positive predictive value and negative predictive value were 72%, 59.5%, 64% and 69% respectively. The model performance was tested in the test set. OPMIP correctly classified 67.10% of cases with a sensitivity and specificity of 73.2% and 61%. CONCLUSIONS: In order to appropriately refer patients for a bone mineral densitometry, OPMIP can be used as a prescreening tool in Iranian Postmenopausal women. PMID- 25821748 TI - Fixed drug eruption to sitagliptin. AB - Fixed drug eruption is a common adverse effect seen with various drugs notably antibiotics, antiepileptics and non-steroidal anti-inflammatory drugs. Herein we report a case of Sitagliptin induced fixed drug eruption in a 46 year old female who developed circumscribed, erythematous macules all over the body within one week of initiation of Sitagliptin. The lesions resolved with residual hyperpigmentation on cessation of the drug. The diagnosis was confirmed by an oral provocation test which led to a reactivation of the lesions. To the best of our knowledge, this is the first case of fixed drug eruption to Sitagliptin reported in the literature. PMID- 25821749 TI - Transition zone prostate specific antigen density improves prostate cancer detection in Iranian men. AB - BACKGROUND: Prostate specific antigen (PSA) as a tumor marker has extensively changed the diagnosis of prostate cancer (PCa). With the advent of PSA, the majority of patients are diagnosed with nonpalpable early stage PCa. However, PSA lacks specificity and many patients undergo unnecessary biopsies due to an elevated serum PSA level. OBJECTIVES: This study aimed to assess the sensitivity and specificity of transition zone PSA density (TZPSAD) in detection of PCa. PATIENTS AND METHODS: This study was performed on 1712 men underwent trans-rectal ultrasound guided prostate biopsy in our institution between March 2008 and March 2013. A total of 1120 men with PSA < 20 ng/mL and normal digital rectal exam were selected for evaluation. Transition zone PSA density was calculated in all patients and the receiver operating characteristic (ROC) curve was used to analyze the accuracy of TZPSAD for the diagnosis of PCa. RESULTS: Among 1120 men who were eligible for enrolment, prostate cancer was detected in 265 patients. Mean serum PSA levels were 9.7 +/- 4.3 ng/mL and 8.5 +/- 3.7 ng/mL in patients with and without PCa, respectively (P < 0.001). Mean value for TZPSAD was 1.18 +/ 1.19 ng/mL/mL in patients with PCa, whereas it was 0.55 +/- 0.84 ng/mL in men without cancer (P < 0.001). Optimal cut-off value for TZPSAD was 0.32 ng/mL. At this cut-off value, the sensitivity and specificity values for TZPSAD were 85% and 45%, respectively. Applying the TZPSAD for PCa screening decreased 50% of unnecessary biopsies. CONCLUSIONS: Using TZPSAD as an adjunct to PSA may improve the specificity of PSA in the diagnosis of PCa and decrease the number of unnecessary prostatic biopsies in Iranian men with serum PSA level < 20 ng/mL. PMID- 25821750 TI - Prescription drugs, alcohol, and illicit substance use and their correlations among medical sciences students in iran. AB - BACKGROUND: Substance use among young people is a major public health problem in Iran. OBJECTIVES: The aims of the present study were to determine the prevalence of substance misuse and its determinants in medical sciences students in Tehran, Iran. PATIENTS AND METHODS: A cross-sectional study was performed on a randomly selected sample of 1992 medical sciences students during 2012-2013. Anonymous, structured questionnaires were distributed among the students in each selected class. Substance misuse was defined according to cultural and epidemiological features. Data analysis was performed using chi-squared test, Fisher's exact test, and binary logistic regression. RESULTS: The prevalence of prescription drug misuse, last year alcohol use, and ever illicit substance use was 4.9%, 6.9%, and 2.9%, respectively. The result of multiple logistic regression model showed that being a male (OR = 4.0), hookah use in the last year (OR = 3.2), prescription drug misuse (OR = 3.2), and alcohol use in the last year (OR = 3.3) were associated with the students' illicit substance use. Last year alcohol use (OR = 5.3), ever illicit substance use (OR = 3.2), and illicit substance use in friends (OR = 2.6) were associated with prescription drug misuse. CONCLUSIONS: Our results suggested that the prevalence of prescription drugs, alcohol and illicit substance use was relatively low, though still significant, among Iranian students, which was strongly associated with family and friends' use. The findings of this research can be used for planning and evaluating interventions by considering the risk factors and protective factors in Universities. PMID- 25821752 TI - Adult dental patients with avoidance behaviours. PMID- 25821751 TI - The effect of methadone-maintenance therapy with and without interactive treatment on improving emotion-regulation strategies and resilience among opiate dependent clients. AB - BACKGROUND: Due to the chronic and recurrent nature of addiction, many people who quit drug addiction may slip back into the pattern of using drugs shortly after the detoxification period. Emotion-regulation strategies and resilience play an important role in preventing the recurrences of substance abuse. OBJECTIVES: This study aimed to compare the effects of methadone-maintenance therapy (MMT) and interactive therapy (a combination of MMT and cognitive-behavioral therapy) on improving emotion-regulation strategies and resilience among opiate-dependent clients. PATIENTS AND METHODS: This pretest-posttest quasi-experimental study was performed on 60 patients with substance abuse admitted to Methadone Addiction Treatment Centers and Detox Centers in Sari within three months of therapy for their addiction (from October to December 2013). Then, the participants were randomly assigned to two different groups (n = 30) were examined in two groups of 30 people targeted to be available in the selected population. Participants in all three groups, before and after the intervention, filled out the questionnaires of Schutte emotional intelligence scale and Connor-Davidson resiliency questionnaire. Data were analyzed using the analysis of covariance method. RESULTS: The results showed that an interactive therapy would be significantly more effective than the MMT on improving emotion-regulation strategies and promoting the resilience level among opiate-dependent clients. Moreover, the results showed that cognitive- behavior therapy combined with MMT may improve emotion-regulation strategies, and promote the amount of resiliency and recovery. CONCLUSIONS: The cognitive-behavior therapy combined with MMT can improve emotion-regulation strategies and resiliency and thus prevent the substance-abuse relapse. PMID- 25821753 TI - Mechanical ventilation in chest trauma. PMID- 25821754 TI - Factors affecting the decision to quit smoking of the participants of a hospital based smoking cessation program in Greece. AB - INTRODUCTION: The purpose of this study was to investigate the factors that affect people who are in the process of quitting smoking. METHODS: A randomly selected sample of 110 participants in a smoking cessation program (SCP) of a hospital in Thessaloniki Greece. Instruments of data collection were: i) the Demographic Data Lifestyle Questionnaire and ii) the Fragerstrom Tolerance Questionnaire. ANOVA tests between the Demographic Data Lifestyle Questionnaire and the Fagerstrom Tolerance Questionnaire relating to the smokers' determination to quit smoking applied. RESULTS: Work satisfaction was related to whether the participants had difficulty to smoke in places that prohibited smoking and to how many cigarettes they smoked per day. If a non-smoker partner was urging the participant to quit smoking, it affected the hours of the day when the respondents smoked more cigarettes. Pressure from a non-smoking spouse was a deterrent from smoking many cigarettes during morning hours. Those participants who consumed alcohol smoked cigarettes containing higher levels of nicotine. CONCLUSION: Smoking cessation is a difficult process which is influenced by many factors such as educational level, work satisfaction and the presence of a partner. PMID- 25821755 TI - Mothers' strategies in handling the prematurely born infant: a qualitative study. AB - INTRODUCTION: Family, especially mother, is faced with numerous challenges by experiencing a premature birth. Since knowing about mother's efforts regarding prematurely born infant helps us in our comprehensive understanding of the impact of this incident on the family system and its performance. The present study was carried out to explore the mothers' strategies regarding prematurely born infant. METHODS: In a conventional qualitative content analysis, data was collected through purposive sampling by semi-structured deep interviews with 18 mothers who had prematurely born infant during 2012-2013 in the teaching hospitals of the north and northwest of Iran. All the interviews were recorded, typed, and finally analyzed. RESULTS: Data analysis resulted in the extraction of categories of "asking for help, elevating capacity and reducing personal responsibilities and commitments". These categories were revealed in mothers respectively by the different sub-categories of "religious appeal and relying on beliefs, seeking information from the treatment and caring team, participating in infant's care, companionship and support of family and friends","focusing on positive thinking and imagination, patience and strength " and "ignoring some routine affairs and reducing role-related activities and duties". CONCLUSION: Considering the uniqueness of the mother's role in responding to the needs of infants, healthcare system should consider mothers as real target in the intervention strategies in order to promote health and quality of life, so maybe this way, the burden of care and management of critical situations caused by a premature birth on the mother can be reduced. PMID- 25821756 TI - Going beyond-the-routines view in nursing: a qualitative study. AB - INTRODUCTION: Nurses' practice of beyond-the-routine view leads to a better treatment process and higher professional status for nurses. However, most studies show that such care is ignored in nursing. The objective of the present study is to analyze nurses' experiences with regard to beyond-the-routine care in order to know this type of better care and encourage nurses to practice it. METHODS: This is a qualitative study based on conventional content analysis. Eighteen nurses participated in the study. Data collection was based on purposive, snowball and theoretical sampling. The data was collected through comprehensive interviews conducted in various wards at the university hospitals of Urmia and Tabriz, Iran. The collected data was analyzed according to qualitative content analysis and by using the software MAXQDA. RESULTS: The results showed that the categories of attempting to identify the patients' problems and listening to one's inner voice are effective factors in going beyond the routines in providing care which can in turn lead to more satisfactory care plans. CONCLUSION: Effective communicative skills, sufficient nursing knowledge, strong religious and professional principles will encourage nurses to provide beyond-the-routine care. Accordingly, it is necessary to emphasize these factors during education in order for nurses to practice this type of caring. PMID- 25821757 TI - The Effect of Vitamin D and Calcium plus Vitamin D during Pregnancy on Pregnancy and Birth Outcomes: a Randomized Controlled Trial. AB - INTRODUCTION: Evidence suggests a high prevalence of calcium and vitamin D deficiencies exists in both pregnant women and babies. Adequate intake of micronutrients has great importance especially during pregnancy and lactation period. Thus, the present study aimed at assessing the effect of vitamin D and calcium-vitamin D on pregnancy and birth outcomes (including duration of pregnancy, type of delivery and infant anthropometric indicators). METHODS: A randomized, controlled, clinical, triple-blind trial conducted on 126 pregnant women referring to Tabriz health centers in 2013-14. Subjects were allocated into three groups using block randomization. Interventional groups received vitamin D, calcium-vitamin D and placebo pills daily for 60 days. ANCOVA and Chi-square tests were used for data analysis. RESULTS: By controlling BMI before and during pregnancy, there were no significant differences between the group in average neonatal weight, height and head circumference, duration of pregnancy, type of delivery and gestational age at the time of delivery. CONCLUSION: The results show that calcium-vitamin D and vitamin D have no effect on duration of pregnancy, type of delivery and infant anthropometric indicators. PMID- 25821758 TI - Nurses' knowledge regarding hand hygiene and its individual and organizational predictors. AB - INTRODUCTION: Based on recommendations from World Health Organization, hand hygiene is the most important way to control the hospital infections. Due to the critical role of nurses in patient care, they should have essential and updated information regarding hand hygiene. So this study aims at determining the knowledge of hand hygiene and its individual and organizational predictors among nurses in neonatal units. METHODS: This descriptive and cross-sectional study was conducted in neonatal units in the hospitals affiliated to Tabriz University of Medical Sciences. The participants surveyed in this study were 150 nurses who were invited by census sampling method. A researcher prepared questionnaire that investigated the knowledge of participants about hand hygiene and was used after approving its validity and reliability. The quantitative analysis of this study used Statistical Package for Social Sciences SPSS version 13 by descriptive statistics and pearson correlation test, independent samples t-test, One-way ANOVA. For multivariable explanation of nurses' knowledge based on independent variables multiple linear regressions was used. RESULTS: Most of participants have an acceptable level of knowledge regarding hand hygiene. The highest score was for infection control domain and the lowest score was for definition of hand hygiene domain. Multivariable analysis showed that work experience and history of previous training were the most important predictors of participants' knowledge about hand hygiene. CONCLUSION: It is recommended that infection control committees should revise their educational methods and give more emphasis on update guidelines regarding hand hygiene. Also, more experienced nurses should be employed in neonatal units. PMID- 25821759 TI - Nursing students' perception of instructors' caring behaviors in tabriz university of medical sciences. AB - INTRODUCTION: Caring behaviors of clinical teachers is one of the most important and influential factors in the process of clinical instruction, so far has not been paid enough attention. In other words, there has been so little research done in this area, so that the researchers couldn't present the clear image of caring dimensions. Therefore, the present study was conducted to determine nursing students' perception of instructors' caring behavior. METHODS: This descriptive study was performed on 240 nursing students in Tabriz University of Medical Sciences, Iran. The participants were selected through stratified random sampling method. The data were collected using Wade's inventory for nursing students' perception of instructor caring (NSPIC). Data were analyzed using descriptive statistics in SPSS13 software. RESULTS: The level of nursing instructors' caring behavior during teaching students was medium to high with the mean and standard deviation of 4.65 (0.93), as the highest level belonged to the respectful sharing, and then respectively, instill confidence through caring, appreciation of life meanings, supportive learning climate, and control versus flexibility. CONCLUSION: The results obtained in this study demonstrate that there is a gap in some dimension in order to achieve optimum about instructors' caring behaviors. Examining and identifying the influential factors in this regard, and applying effective strategies by relevant authorities will be effective in qualitative promotion of clinical teaching. PMID- 25821760 TI - Effect of Lavender Cream with or without Foot-bath on Anxiety, Stress and Depression in Pregnancy: a Randomized Placebo-Controlled Trial. AB - INTRODUCTION: Psychological disorders are associated with maternal and neonatal morbidities. We aimed to evaluate the effect of Lavender cream with or without foot-bath on depression, anxiety and stress of pregnant women. METHODS: In this trial, 141 women at 25 to 28 weeks gestation were randomly assigned into three groups (47 at each group); receiving Lavender cream with foot-bath, only Lavender cream, or placebo, 2g every night for two months. Depression, anxiety and stress were assessed at baseline, and 4(th) and 8(th) weeks after intervention, using DASS-21. General linear model was used to compare the groups. RESULTS: There were three losses to follow-up at the 4(th) and one more at the 8(th) week. Scores of all three outcomes in both Lavender and foot-bath and only Lavender groups were significantly lower than those in the placebo group at the 8(th) week; adjusted difference of depression score -3.3, 95% confidence interval -4.6 to -1.9;-2.4, 3.7 to -1.0, respectively, anxiety score -1.4, -2.6 to -0.2; -1.7,-2.9 to -0.5 and stress score -3.1, -4.7 to -1.5; -2.7, -4.3 to -1.1. At the 4(th) week, only score of anxiety in the lavender group (-2.3, -3.9 to -0.8) and stress in the both groups (-2.3, -4.1 to -0.5; -1.9, -3.7 to -0.1) were significantly less than those in the placebo group. There were not statistically significant differences between the two experimental groups in terms of the outcomes. CONCLUSION: Lavender cream with foot-bath or alone can be used for pregnant women for reducing their stress, anxiety and depression. PMID- 25821761 TI - Attitude toward Child Abuse among Mothers Referring Health Centers of Tabriz. AB - INTRODUCTION: Parental attitude is an important factor in prediction of child abuse. Awareness of people's attitudes is important in the prediction of their behavior and controlling it. This study was conducted to determine the mothers' attitudes toward child abuse. METHODS: In this cross-sectional study, 261 mothers referred to the 13 health centers of Tabriz with children aged 2-12, they were selected by a multistage method and their attitudes were assessed using a questionnaire within 2 months. Higher score were representing more negative attitudes. RESULTS: The results showed that the mean score of total attitude toward child abuse was significantly higher than the middle and was significantly associated with mothers' educational level, employment status, attendance status, number of children they have, and economic status. CONCLUSION: The results showed that although the mothers' attitudes toward child abuse were negative, because of the relationship between mothers' attitudes with their demographic characteristics, it is necessary to enhance mothers' quality of life, and their social and spiritual support to improve their attitudes and prevent the child abuse. PMID- 25821762 TI - The effect of two educational methods on knowledge and adherence to treatment in hemodialysis patients: clinical trial. AB - INTRODUCTION: Patients with chronic renal disease (CRD) deal with many potential problems with hemodialysis for all their life. Regarding the importance of preventing dialysis adverse effects, which are in close connection with lack of knowledge and report on how to train the patients? This study aims at comparing the impact of two methods of face to face training and training pamphlet on complying and informing of hemodialysis treatments. METHODS: This clinical trial study was conducted on 58 hemodialysis patients who visited Shahid Rahnemun Teaching hospital, Yazd, Iran, and had required conditions of the research. Data were collected through a questionnaire including personal-social information, several questions to assess the level of compliance and to inform the treatment method. The quantitative analysis of this study used the Statistical Package for Social Sciences SPSS version 13 and descriptive (frequency, mean, standard deviation) and inferential (Chi-square, paired t-test, ANOVA, ANCOVA) statistics were employed. RESULTS: The mean scores for informing both groups (face to face and training pamphlet) were significantly increased. The mean score for adherence to treatments was also significant. CONCLUSION: In this research, face to face training was found to be more effective than training pamphlet. It seemed to have more strong effect on increasing the level of information and adherence to treatment. To train these people, face to face training should be, thus, preferred. PMID- 25821763 TI - Toxic epidermal necrolysis in hemodialysis patient. AB - Toxic epidermal necrolysis (TEN) is a rare and life-threatening allergic drug reaction. We report a 26-year-old young female with end-stage renal disease on maintenance hemodialysis developing TEN while on filgrastim and phenytoin. It was successfully treated with intravenous immunoglobulins and steroids. PMID- 25821764 TI - Comparison the effects of paracetamol with sufentanil infusion on postoperative pain control after craniotomy in patients with brain tumor. AB - BACKGROUND: Patients experience severe pain after craniotomy surgery that leads to discomfort. Our target in this study that performed in interventional method is an evaluation of sufentanil and paracetamol effect on postoperative pain control in patients undergone craniotomy surgery at Urmia Imam Khomeini Hospital. MATERIALS AND METHODS: Totally, 45 patients between the ages 18 and 65 were studied. The effect of sufentanil and paracetamol medicines in pain management, hemodynamic stability, and side effects compared with control group that were receiving morphine (subcutaneous [SC]) in 3 groups of 15 people at time 0, 2, 4, 12 and 24-h were evaluated. Collected data were included and monitoring blood pressure, O2 Sat, heart rate (HR) and pain, nausea, vomiting and use of morphine. RESULTS: According to the analysis of results, there was a significant difference between 3 groups on postoperative pain (P < 0.05). In patients that used sufentanil, pain score of visual analog scale (VAS) is lowest and in the paracetamol group the highest VAS score was seen. There was a significant difference in HR between 3 groups (P < 0.05). Maximum average of HR was observed in the paracetamol group. There was a significant difference in mean arterial pressure between 3 groups (P < 0.05). In paracetamol group, there was the highest value (99.3). There was no significant difference in Glasgow Coma scale and SPO2 between 3 groups (P > 0.05). CONCLUSION: Sufentanil compared to morphine (which is routinely used for patients pain control after craniotomy surgery) has better pain control, less nausea and vomiting, and better hemodynamic stability. Although paracetamol has the least nausea and vomiting, it has the lowest quality of pain relief. PMID- 25821765 TI - Surgically assisted rapid palatal expansion with tent screws and a custom-made palatal expander: a case report. AB - Rapid palatal expansion(RPE) with the tooth-born appliance is not sufficient to apply to the patients with periodontal problem or insufficient tooth anchorage, and it leads to tipping of the anchorage teeth and increasing teeth mobility and root resorption. To avoid these disadvantages, we present the case using palatal screws and custommade palatal expander. A 23-year-old patient underwent surgically assisted rapid maxillary expansion with the Hyrax expansion using 4 tent screws. The study models were used to measure the pre-/-post surgical width of the anterior and posterior dental arches with a digital sliding caliper. In the result, the custom-made palatal expander with 4 tent screws is suitable for delivering a force to the mid-palatal suture expansion. And it is low cost, small sized and simply applied. The results indicated that maxillary expansion with the custom-made palatal anchorage device is predictable and stable technique without significant complications in patients. PMID- 25821766 TI - Evaluating the effect of polytetrafluoroethylene and extractum cepae-heparin allantoin gel in peripheral nerve injuries in a rat model. AB - BACKGROUND: Peripheral nerves can be injured by congenital, mechanical, thermal or chemical causes. Peripheral nerve injuries are increasing in frequency, particularly in countries that are becoming more industrialized. Nerve and extremity injuries result in work loss and high treatment costs, and can lead to separation of patients from their social environment. Failure of nerve repair causes muscle functional losses, sensory losses and painful neuropathies. OBJECTIVES: To compare the effects of condensed polytetrafluoroethylene (cPTFE) and cPTFE-extractum cepae-heparin-allantoin (cPTFE-EHA) gel compound on nerve and functional recovery, and the prevention of adhesion and scar tissue formation after total peripheral nerve injury repaired by primary suture in a rat model. RESULTS: cPTFE alone and cPTFE-EHA gel was found to provide better functional recovery and nerve regeneration compared with primary repair only. In the macroscopic evaluation, the cPTFE-EHA gel was found to have no negative effect on wound healing and, despite increasing extra-neural scar tissue and adhesions, it had no negative effect on nerve function; in addition, it facilitated functional recovery. CONCLUSIONS: Compared with the cPTFE application alone, the application of perineural cPTFE-EHA gel during peripheral nerve surgery appeared to provide better functional recovery without causing any significant changes in epineural and extraneural scar tissue formation. PMID- 25821767 TI - Impact of liposome bupivacaine on the adequacy of pain management and patient experiences following aesthetic surgery: Results from an observational study. AB - BACKGROUND: Despite the efficacy of opioid analgesics for postsurgical pain, they are associated with side effects that may complicate recovery. Liposome bupivacaine is a prolonged-release formulation of bupivacaine approved for intraoperative administration at the surgical site for postsurgical analgesia. OBJECTIVES: To evaluate the effect of a single intraoperative administration of liposome bupivacaine on postsurgical pain, opioid use and opioid-related side effects in subjects undergoing breast surgery and/or abdominoplasty. METHODS: In the present phase IV, multicentre, prospective observational study, subjects received a single intraoperative administration (266 mg) of liposome bupivacaine. Rescue analgesia was available to all subjects as needed. Outcome measures, assessed through postoperative day 3, included postsurgical pain intensity (11 point numerical rating scale), opioid consumption and overall benefit of analgesic score. Results were evaluated comparing investigators' previous experience with similar surgeries. RESULTS: Forty-nine subjects entered the study: 34 underwent breast surgery only and 15 underwent abdominoplasty with or without breast surgery (six underwent breast surgery in addition to abdominoplasty). Mean numerical rating scale pain scores remained <=4.3 from discharge through postoperative day 3. Median daily oral opioid consumption was approximately 1.0 tablet postoperatively on the day of surgery and was approximately 2.0 tablets by postoperative day 3. Mean overall benefit of analgesic score ranged between 2.8 and 4.9 throughout the study. CONCLUSION: In this particular subject population, liposome bupivacaine was associated with low pain intensity scores and reduced opioid consumption compared with the investigators' previous experiences. Subjects' satisfaction with postsurgical analgesia was high, with a low burden of opioid-related side effects. PMID- 25821768 TI - Intraoperative tissue expansion in the surgical correction of craniosynostosis. AB - BACKGROUND: Wound healing complications can occur after calvarial vault expansion due to tension on the scalp flaps. OBJECTIVES: To compare wound healing outcomes in patients with craniosynostosis undergoing calvarial vault expansion with and without intraoperative tissue expansion of the scalp. METHODS: The present analysis was an institutional review board-approved, retrospective cohort study involving 40 consecutive patients at the University of Missouri Hospitals and Clinics (Columbia, Missouri, USA) who underwent calvarial vault expansion for nonsyndromic craniosynostosis between June 1, 2009 and June 30, 2012. Patients were divided into two sequential cohorts: the first 20 underwent calvarial vault expansion without intraoperative tissue expansion; the second 20 underwent calvarial vault expansion with intraoperative tissue expansion. The main outcome measures included presence or absence of wound healing complications (persistent scabbing or slow-healing wounds, hardware exposure, need for operative wound revision or healed but widened scars), with documented postoperative follow-up of at least three months. The primary end point was the presence of a well-healed scar; the secondary end point was the need for an operative revision. RESULTS: Patients in the intraoperative tissue expansion group had a higher percentage of well-healed scars (73.6%) than those in the nonexpansion group (42.1%) (P=0.0487). This difference was primarily due to scar widening in the nonexpansion group. CONCLUSIONS: The present study demonstrated that the use of intraoperative tissue expansion in patients with nonsyndromic craniosynostosis who underwent calvarial vault expansion resulted in a greater likelihood of a well-healed incision with a lower rate of poor scarring. PMID- 25821769 TI - Isolated limb infusion: Efficacy, toxicity and an evolution in the management of in-transit melanoma. AB - BACKGROUND: Isolated limb infusion (ILI) delivers low-flow chemotherapy via percutaneous catheters to treat melanoma in-transit metastases. OBJECTIVE: To describe the experience of two regional referral centres with ILI. METHODS: A retrospective review of patients who underwent ILI between 2002 and 2012 was performed. Outcomes were measured using the WHO criteria for response, the Wieberdink toxicity score and long-term limb function using the Toronto Extremity Salvage Score (TESS). RESULTS: Fifty-two patients (mean age 66 years [range 27 to 90 years], female sex 65%, and lower [treated] limb in 86%) with 54 ILIs were reviewed. Wieberdink toxicity score was >=3 in 21 (39%) procedures. Median follow up was 18 months (range one to 117 months). Initial complete response (CR) was 29%, partial response 27%, stable disease 18% and progressive disease 27%. Predictors of better initial response were low disease burden and previous treatment. One or more treatments after ILI were common (65%). At 12 months, 19% of ILI patients had died from melanoma but 44% of surviving patients experienced limb CR. At 24 months, 57% of surviving patients experienced limb CR. The quality of life in the surviving, contactable patients according to the Toronto Extremity Salvage Score was 89%. CONCLUSION: Even if ILI does not result in CR for melanoma intransit metastases. it may slow disease progression as a single therapy, but more frequently in combination with other modalities. PMID- 25821770 TI - Analysis of individualized education programs to quantify long-term educational needs following surgical intervention for single-suture craniosynostosis. AB - BACKGROUND: Single-suture craniosynostosis (SSC) is a common craniofacial condition with potential neurocognitive sequelae. OBJECTIVE: To quantify any long term functional academic and behavioural difficulties of children with SSC as indicated by the need for individualized education programs (IEPs), despite having undergone surgical treatment. METHODS: Records of all school-age patients from 1992 to 2011 who underwent operative intervention for SSC were identified. Fifty-nine patients' guardians were contacted by telephone to provide informed consent for completion of a mailed standardized questionnaire querying demographic information as well as information regarding the patient's health, family and educational history; specifically whether the patient had ever been provided educational support as delineated in an IEP. The primary outcome measure was the history of the patient being assigned educational support as delineated in an IEP. RESULTS: Thirty-seven consenting guardians completed and returned the standardized questionnaire (response rate 62.7%). Twenty-one patients were male and 16 were female, with an age range of five to 14 years (mean age 10.2 years). Eleven (29.7%) patients had a previous history of or currently were receiving educational support delineated in an IEP. CONCLUSIONS: A higher proportion of school-age patients with a history of SSC (status postsurgical intervention) in the present study received educational support delineated in an IEP than the proportion of IEPs in the general student population of the United States (11.3%). PMID- 25821771 TI - Inhibitory effects of low-level laser therapy on skin-flap survival in a rat model. AB - BACKGROUND: Although several studies have demonstrated the effects of low-level laser therapy (LLLT) on skin flap viability, the role of higher doses has been poorly investigated. OBJECTIVE: To investigate the inhibitory effect of the LLLT (lambda=670 nm) on the viability of random skin flaps in a rat model using an irradiation energy of 2.79 J at each point. METHODS: Sixteen Wistar rats were randomly assigned into two groups: sham laser irradiation (n=8); and active laser irradiation (n=8). Animals in the active laser irradiation group were irradiated with a 670 nm diode laser with an energy of 2.79 J/point, a power output 30 mW, a beam area of 0.028 cm(2), an energy density of 100 J/cm(2), an irradiance of 1.07 W/cm(2) for 93 s/point. Irradiation was performed in 12 points in the cranial skin flap portion. The total energy irradiated on the tissue was 33.48 J. The necrotic area was evaluated on postoperative day 7. RESULTS: The sham laser irradiation group presented a mean (+/- SD) necrotic area of 47.96+/-3.81%, whereas the active laser irradiation group presented 62.24+/-7.28%. There was a significant difference in skin-flap necrosis areas between groups (P=0.0002). CONCLUSION: LLLT (lambda=670 nm) increased the necrotic area of random skin flaps in rats when irradiated with an energy of 2.79 J (100 J/cm(2)). PMID- 25821772 TI - The Le Fort system revisited: Trauma velocity predicts the path of Le Fort I fractures through the lateral buttress. AB - OBJECTIVE: To examine the effect of trauma velocity on the pattern of Le Fort I facial fractures. METHOD: A retrospective medical record review was conducted on a consecutive cohort of craniofacial traumas surgically treated by a single surgeon between 2007 and 2011 (n=150). Of these cases, 39 Le Fort fractures were identified. Patient demographic information, method of trauma and velocity of impact were reviewed for these cases. Velocity of impact was expressed categorically as either 'high' or 'low': high-velocity fractures were those caused by a fall from >1 story or a motor vehicle collision; low-velocity fractures were the result of assaults with a blunt weapon, closed fist or falls from standing height. The vertical position of each fracture was measured at its point of entry on the lateral buttress and its point of exit on the piriform aperture. To allow for comparison across individuals, values were expressed as ratios based on their location on the face relative to these landmarks. A Wilcoxon rank-sum test was used to compare the fracture heights caused by high- and low-velocity trauma. RESULTS: The results revealed that high-velocity traumas to the face create Le Fort I fractures at a higher point in the lateral buttress compared with low-velocity traumas. There was no difference between heights at the piriform aperture. CONCLUSION: High-velocity trauma resulted in higher Le Fort I fracture patterns compared with low-velocity trauma. PMID- 25821773 TI - Exposure to plastic surgery during undergraduate medical training: A single institution review. AB - BACKGROUND: Applications to surgical residency programs have declined over the past decade. Even highly competitive programs, such as plastic surgery, have begun to witness these effects. Studies have shown that early surgical exposure has a positive influence on career selection. OBJECTIVE: To review plastic surgery application trends across Canada, and to further investigate medical student exposure to plastic surgery. METHODS: To examine plastic surgery application trends, national data from the Canadian Resident Matching Service database were analyzed, comparing 2002 to 2007 with 2008 to 2013. To evaluate plastic surgery exposure, a survey of all undergraduate medical students at the University of Toronto (Toronto, Ontario) during the 2012/2013 academic year was conducted. RESULTS: Comparing 2002 to 2007 and 2008 to 2013, the average number of national plastic surgery training positions nearly doubled, while first-choice applicants decreased by 15.3%. The majority of Canadian academic institutions experienced a decrease in first-choice applicants; 84.7% of survey respondents indicated they had no exposure to plastic surgery during their medical education. Furthermore, 89.7% believed their education had not provided a basic understanding of issues commonly managed by plastic surgeons. The majority of students indicated they receive significantly less plastic surgery teaching than all other surgical subspecialties. More than 44% of students not considering plastic surgery as a career indicated they may be more likely to with increased exposure. CONCLUSION: If there is a desire to grow the specialty through future generations, recruiting tactics to foster greater interest in plastic surgery must be altered. The present study suggests increased and earlier exposure for medical students is a potential solution. PMID- 25821774 TI - Accuracy and completeness of electronic medical records obtained from referring physicians in a Hamilton, Ontario, plastic surgery practice: A prospective feasibility study. AB - OBJECTIVE: To assess the feasibility of auditing electronic medical records (EMRs) in plastic surgery for future large-scale research studies. The secondary objective was to ascertain the accuracy and completeness of EMRs accompanying referral requests by physicians for plastic surgery consultation between July and December 2013. METHODS: EMRs of 30 patients were reviewed and crosschecked independently by two reviewers and subsequently verified by a third reviewer using predefined criteria to determine whether they were accurate and/or complete. Descriptive analysis was performed to calculate the frequency of inaccuracies and incompleteness for each EMR information field. Information fields were compared to assess whether the frequency of inaccuracies and incompleteness varied. RESULTS: Of the 270 information fields reviewed, four (1.48%) were inaccurate and 66 (24.4%) were incomplete. The most common field of inaccuracy was current medications, followed by medical history and medical allergies. The most common field of incompleteness was history of presenting illness followed by surgical history. CONCLUSION: Despite their purported benefits, inaccuracies and incompleteness are a frequently occurring problem in EMRs. A large-scale study may be beneficial in determining the efficacy of EMRs in the future. PMID- 25821775 TI - Long-term outcomes and patient satisfaction following wrist ganglion aspiration. AB - BACKGROUND: There is a strong body of evidence addressing short-term outcomes following wrist ganglion aspiration; however, few studies have investigated long term outcomes and patient satisfaction. OBJECTIVE: To evaluate patient satisfaction and the long-term rate of recurrence following wrist ganglion aspiration. METHODS: Charts of all patients with a wrist ganglion treated by a single surgeon from 2001 to 2011 were reviewed. Demographic and clinical data were retrieved from patient charts. Patients were contacted by telephone and asked to complete a questionnaire addressing recurrence, satisfaction and symptom improvement. Improvement was assessed using a Likert scale, with 1 indicating 'significantly worse' and 5 indicating 'significantly improved'. Statistical analysis was performed using Pearson chi(2), Mann-Whitney-Wilcoxon and Fisher's exact tests. RESULTS: Forty-one consecutive patients were identified using hospital records; 21 (51%) consented to the telephone questionnaire. There were no differences in demographic or clinical data between patients who completed the telephone questionnaire and those who did not. The mean age at treatment was 45.3 years, mean time to follow-up was 6.3 years and 52.4% of ganglions recurred. Overall, 95% (20 of 21) of patients were satisfied with their treatment and would proceed again given the option; satisfaction was independent of recurrence. Following treatment, there was improvement in pain, function, range of motion and appearance; improvement in symptoms was independent of recurrence. CONCLUSIONS: Long-term recurrence of ganglions treated with aspiration appeared to be similar to the short-term rates reported in the literature. Independent of recurrence, patients remained satisfied with aspiration and reported improvement in symptoms. PMID- 25821776 TI - Trochanteric pressure sore / Intra-oral squamous cell carcinoma. PMID- 25821777 TI - The current decline in oil: Investment and macroeconomic considerations. PMID- 25821778 TI - The Impact of Emotional Intelligence on Conditions of Trust among Leaders at the Kentucky Department for Public Health. AB - There has been limited leadership research on emotional intelligence and trust in governmental public health settings. The purpose of this study was to identify and seek to understand the relationship between trust and elements of emotional intelligence, including stress management, at the Kentucky Department for Public Health (KDPH). The KDPH serves as Kentucky's state governmental health department. KDPH is led by a Commissioner and composed of seven primary divisions and 25 branches within those divisions. The study was a non-randomized cross sectional study utilizing electronic surveys that evaluated conditions of trust among staff members and emotional intelligence among supervisors. Pearson correlation coefficients and corresponding p-values are presented to provide the association between emotional intelligence scales and the conditions of trust. Significant positive correlations were observed between supervisors' stress management and the staff members' trust or perception of supervisors' loyalty (r = 0.6, p = 0.01), integrity (r = 0.5, p = 0.03), receptivity (r = 0.6, p = 0.02), promise fulfillment (r = 0.6, p = 0.02), and availability (r = 0.5, p = 0.07). This research lays the foundation for emotional intelligence and trust research and leadership training in other governmental public health settings, such as local, other state, national, or international organizations. This original research provides metrics to assess the public health workforce with attention to organizational management and leadership constructs. The survey tools could be used in other governmental public health settings in order to develop tailored training opportunities related to emotional intelligence and trust organizations. PMID- 25821779 TI - The emerging role of complex modifications of tRNALysUUU in signaling pathways. PMID- 25821780 TI - Phylogenomic and molecular demarcation of the core members of the polyphyletic pasteurellaceae genera actinobacillus, haemophilus, and pasteurella. AB - The genera Actinobacillus, Haemophilus, and Pasteurella exhibit extensive polyphyletic branching in phylogenetic trees and do not represent coherent clusters of species. In this study, we have utilized molecular signatures identified through comparative genomic analyses in conjunction with genome based and multilocus sequence based phylogenetic analyses to clarify the phylogenetic and taxonomic boundary of these genera. We have identified large clusters of Actinobacillus, Haemophilus, and Pasteurella species which represent the "sensu stricto" members of these genera. We have identified 3, 7, and 6 conserved signature indels (CSIs), which are specifically shared by sensu stricto members of Actinobacillus, Haemophilus, and Pasteurella, respectively. We have also identified two different sets of CSIs that are unique characteristics of the pathogen containing genera Aggregatibacter and Mannheimia, respectively. It is now possible to demarcate the genera Actinobacillus sensu stricto, Haemophilus sensu stricto, and Pasteurella sensu stricto on the basis of discrete molecular signatures. The other members of the genera Actinobacillus, Haemophilus, and Pasteurella that do not fall within the "sensu stricto" clades and do not contain these molecular signatures should be reclassified as other genera. The CSIs identified here also provide useful diagnostic targets for the identification of current and novel members of the indicated genera. PMID- 25821781 TI - Reduced Representation Libraries from DNA Pools Analysed with Next Generation Semiconductor Based-Sequencing to Identify SNPs in Extreme and Divergent Pigs for Back Fat Thickness. AB - The aim of this study was to identify single nucleotide polymorphisms (SNPs) that could be associated with back fat thickness (BFT) in pigs. To achieve this goal, we evaluated the potential and limits of an experimental design that combined several methodologies. DNA samples from two groups of Italian Large White pigs with divergent estimating breeding value (EBV) for BFT were separately pooled and sequenced, after preparation of reduced representation libraries (RRLs), on the Ion Torrent technology. Taking advantage from SNAPE for SNPs calling in sequenced DNA pools, 39,165 SNPs were identified; 1/4 of them were novel variants not reported in dbSNP. Combining sequencing data with Illumina PorcineSNP60 BeadChip genotyping results on the same animals, 661 genomic positions overlapped with a good approximation of minor allele frequency estimation. A total of 54 SNPs showing enriched alleles in one or in the other RRLs might be potential markers associated with BFT. Some of these SNPs were close to genes involved in obesity related phenotypes. PMID- 25821783 TI - Inhibitory and apoptosis-inducing effects of Newcastle disease virus strain AF2240 on mammary carcinoma cell line. AB - Breast cancer is the malignant tumour that developed from cells of the breast and is the first leading cause of cancer death among women worldwide. Surgery, radiotherapy, and chemotherapy are the available treatments for breast cancer, but these were reported to have side effects. Newcastle disease virus (NDV) known as Avian paramyxovirus type-1 (APMV1) belongs to the genus Avulavirus in a family Paramyxoviridae. NDV is shown to be a promising anticancer agent, killing tumour cells while sparing normal cells unharmed. In this study, the oncolytic and cytotoxic activities of NDV AF2240 strain were evaluated on MDA-MB-231, human mammary carcinoma cell line, using MTT assay, and its inhibitory effects were further studied using proliferation and migration assays. Morphological and apoptotic-inducing effects of NDV on MD-MB-231 cells were observed using phase contrast and fluorescence microscopes. Detection of DNA fragmentation was done following terminal deoxyribonucleotide transferase-mediated Br-dUTP nick end labeling staining (TUNEL) assay, which confirmed that the mode of death was through apoptosis and was quantified by flow cytometry. Furthermore, analysis of cellular DNA content demonstrated that the virus caused an increase in the sub-G1 phase (apoptotic peak) of the cell cycle. It appears that NDV AF2240 strain is a potent anticancer agent that induced apoptosis in time-dependent manner. PMID- 25821784 TI - Comparative myocardial deformation in 3 myocardial layers in mice by speckle tracking echocardiography. AB - BACKGROUND: Speckle tracking echocardiography (STE) using dedicated high resolution ultrasound is a relatively new technique that is useful in assessing myocardial deformation in 3 myocardial layers in small animals. However, comparative studies of STE parameters acquired from murine are limited. METHODS: A high-resolution rodent ultrasound machine (VSI Vevo 2100) and a clinically validated ultrasound machine (GE Vivid 7) were used to consecutively acquire echocardiography images from standardized parasternal long axis and short axis at midpapillary muscle level from 13 BALB/c mice. Speckle tracking strain (longitudinal, circumferential, and radial) from endocardial, myocardial, and epicardial layers was analyzed using vendor-specific offline analysis software. RESULTS: Intersystem differences were not statistically significant in the global peak longitudinal strain (-16.8 +/- 1.7% versus -18.7 +/- 3.1%) and radial strain (46.8 +/- 14.2% versus 41.0 +/- 9.5%), except in the global peak circumferential strain (-16.9 +/- 3.1% versus 27.0 +/- 5.2%, P < 0.05). This was corroborated by Bland Altman analysis that revealed a weak agreement in circumferential strain (mean bias +/- 1.96 SD of -10.12 +/- 6.06%) between endocardium and midmyocardium. However, a good agreement was observed in longitudinal strain between midmyocardium/endocardium (mean bias +/- 1.96 SD of -1.88 +/- 3.93%) and between midmyocardium/epicardium (mean bias +/- 1.96 SD of 3.63 +/- 3.91%). Radial strain (mean bias +/- 1.96 SD of -5.84 +/- 17.70%) had wide limits of agreement between the two systems that indicated an increased variability. CONCLUSIONS: Our study shows that there is good reproducibility and agreement in longitudinal deformation of the 3 myocardial layers between the two ultrasound systems. Directional deformation gradients at endocardium, myocardium, and epicardium observed in mice were consistent to those reported in human subjects, thus attesting the clinical relevance of STE findings in murine cardiovascular disease models. PMID- 25821785 TI - Recent developments of carbonic anhydrase inhibitors as potential drugs. PMID- 25821782 TI - Roles of autophagy induced by natural compounds in prostate cancer. AB - Autophagy is a homeostatic mechanism through which intracellular organelles and proteins are degraded and recycled in response to increased metabolic demand or stress. Autophagy dysfunction is often associated with many diseases, including cancer. Because of its role in tumorigenesis, autophagy can represent a new therapeutic target for cancer treatment. Prostate cancer (PCa) is one of the most common cancers in aged men. The evidence on alterations of autophagy related genes and/or protein levels in PCa cells suggests a potential implication of autophagy in PCa onset and progression. The use of natural compounds, characterized by low toxicity to normal tissue associated with specific anticancer effects at physiological levels in vivo, is receiving increasing attention for prevention and/or treatment of PCa. Understanding the mechanism of action of these compounds could be crucial for the development of new therapeutic or chemopreventive options. In this review we focus on the current evidence showing the capacity of natural compounds to exert their action through autophagy modulation in PCa cells. PMID- 25821787 TI - An open-label uncontrolled, multicenter study for the evaluation of the efficacy and safety of the dermal filler Princess VOLUME in the treatment of nasolabial folds. AB - The dermal filler Princess VOLUME is a highly cross-linked, viscoelastic hyaluronic acid injectable gel implant used for aesthetic treatment. To evaluate the efficacy and safety of Princess VOLUME in the treatment of nasolabial folds, an open-label uncontrolled, multicenter study was conducted. Forty-eight subjects were recruited who had moderate to deep wrinkles, according to the Modified Fitzpatrick Wrinkle Scale (MFWS). Subjects received Princess VOLUME in both nasolabial folds at Day 0. Nasolabial fold severity was evaluated at 30, 90, 180, and 270 days after treatment, using the MFWS and the Global Aesthetic Improvement Scale (GAIS). Adverse events and treatment site reactions were recorded. Among the 48 subjects, 93.8% were female with a median age of 52 years. There were significant improvements (P < 0.0001) in the MFWS scores at 30, 180, and 270 days after treatment compared with those at baseline, with a mean decrease of 1.484 (+/-0.408), 1.309 (+/-0.373), and 1.223 (+/-0.401), respectively; hence the primary endpoint was achieved and clinical efficacy demonstrated. Princess VOLUME was well tolerated, and most adverse events were injection site reactions of mild to moderate severity. Subject satisfaction (97.9%), subject recommendation of the treatment (93.6%), and investigators GAIS scores (97.9% improvement) were high. PMID- 25821786 TI - Ox-LDL induces dysfunction of endothelial progenitor cells via activation of NF kappaB. AB - Dyslipidemia increases the risks for atherosclerosis in part by impairing endothelial integrity. Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. Oxidized low-density lipoprotein (ox-LDL) can induce EPC dysfunction, but the underlying mechanism is not well understood. Human EPCs were cultured in endothelial growth medium supplemented with VEGF (10 ng/mL) and bFGF (10 ng/mL). The cells were treated with ox-LDL (50 ug/mL). EPC proliferation was assayed by using CCK8 kits. Expression and translocation of nuclear factor-kabba B (NF-kappaB) were evaluated. The level of reactive oxygen species (ROS) in cells was measured using H2DCF-DA as a fluorescence probe. The activity of NADPH oxidase activity was determined by colorimetric assay. Ox-LDL significantly decreased the proliferation, migration, and adhesion capacity of EPCs, while significantly increased ROS production and NADPH oxidase expression. Ox-LDL induced NF-kappaB P65 mRNA expression and translocation in EPCs. Thus ox-LDL can induce EPC dysfunction at least by increasing expression and translocation of NF-kappaB P65 and NADPH oxidase activity, which represents a new mechanism of lipidemia-induced vascular injury. PMID- 25821788 TI - Cytotoxicity of cyclodipeptides from Pseudomonas aeruginosa PAO1 leads to apoptosis in human cancer cell lines. AB - Pseudomonas aeruginosa is an opportunistic pathogen of plants and animals, which produces virulence factors in order to infect or colonize its eukaryotic hosts. Cyclodipeptides (CDPs) produced by P. aeruginosa exhibit cytotoxic properties toward human tumor cells. In this study, we evaluated the effect of a CDP mix, comprised of cyclo(L-Pro-L-Tyr), cyclo(L-Pro-L-Val), and cyclo(L-Pro-L-Phe) that were isolated from P. aeruginosa, on two human cancer cell lines. Our results demonstrated that the CDP mix promoted cell death in cultures of the HeLa cervical adenocarcinoma and Caco-2 colorectal adenocarcinoma cell lines in a dose dependent manner, with a 50% inhibitory concentration (IC50) of 0.53 and 0.66 mg/mL, for HeLa and Caco-2 cells, respectively. Flow cytometric analysis, using annexin V and propidium iodide as apoptosis and necrosis indicators, respectively, clearly showed that HeLa and Caco-2 cells exhibited apoptotic characteristics when treated with the CDP mix at a concentration <0.001 mg/mL. IC50 values for apoptotic cells in HeLa and Caco-2 cells were 6.5 * 10(-5) and 1.8 * 10(-4) mg/mL, respectively. Our results indicate that an apoptotic pathway is involved in the inhibition of cell proliferation caused by the P. aeruginosa CDP mix. PMID- 25821789 TI - Combined epidermal growth factor receptor and Beclin1 autophagic protein expression analysis identifies different clinical presentations, responses to chemo- and radiotherapy, and prognosis in glioblastoma. AB - Dysregulated EGFR in glioblastoma may inactivate the key autophagy protein Beclin1. Each of high EGFR and low Beclin1 protein expression, independently, has been associated with tumor progression and poor prognosis. High (H) compared to low (L) expression of EGFR and Beclin1 is here correlated with main clinical data in 117 patients after chemo- and radiotherapy. H-EGFR correlated with low Karnofsky performance and worse neurological performance status, higher incidence of synchronous multifocality, poor radiological evidence of response, shorter progression disease-free (PDFS), and overall survival (OS). H-Beclin1 cases showed better Karnofsky performance status, higher incidence of objective response, longer PDFS, and OS. A mutual strengthening effect emerges in correlative power of stratified L-EGFR and H-Beclin1 expression with incidence of radiological response after treatment, unifocal disease, and better prognosis, thus identifying an even longer OS group (30 months median OS compared to 18 months in L-EGFR, 15 months in H-Beclin1, and 11 months in all GBs) (P = 0.0001). Combined L-EGFR + H-Beclin1 expression may represent a biomarker in identifying relatively favorable clinical presentations and prognosis, thus envisaging possible EGFR/Beclin1-targeted therapies. PMID- 25821790 TI - A low-dose combination of fluvastatin and valsartan: a new "drug" and a new approach for decreasing the arterial age. AB - We have developed a new "drug" and approach that appear to be effective in reducing arterial age. This "drug" represents a low, subtherapeutic dose of statin and sartan and particularly their low-dose combination. The improvement of arterial wall characteristics, also reflecting in a decrease of arterial age, was achieved after a short period of treatment (one month) with the above-mentioned drugs. In addition, we have also implemented a new, innovative therapeutic approach, consisting of intermittent (cyclic) treatment-alternating short "treatment" periods and much longer "rest" periods (when the beneficial effects are still present but gradually decline). This new "drug" and approach both merit further investigation in order to confirm their antiaging efficacy. PMID- 25821791 TI - Incidence and risk factors of postoperative pulmonary complications in noncardiac Chinese patients: a multicenter observational study in university hospitals. AB - PURPOSE: To assess the incidence of postoperative pulmonary complications (PPCs) in Chinese inpatients, and to develop a brief predictive risk index. METHODS: Between August 6, 2012, and August 12, 2012, patients undergoing noncardiac operations in four university hospitals were enrolled. The cohort was divided into two subsamples, cohort 1 to develop a predictive risk index of PPCs and cohort 2 to validate it. RESULTS: 1673 patients were enrolled. PPCs were recorded for 163 patients (9.7%), of whom the hospital length of stay (LOS) was longer (P < 0.001). The mortality was 1.84% in patients with PPCs and 0.07% in those without. Logistic Regression modeling in cohort 1 identified nine independent risk factors, including smoking, respiratory infection in the last month, preoperative antibiotic use, preoperative saturation of peripheral oxygen, surgery site, blood lost, postoperative blood glucose, albumin, and ventilation. The model was validated within cohort 2 with an area under the receiver operating characteristic curve of 0.90 (95% CI 0.86 to 0.94). CONCLUSIONS: PPCs are common in noncardiac surgical patients and are associated with prolonged LOS in China. The current study developed a risk index, which can be used to assess individual risk of PPCs and guide individualized perioperative respiratory care. PMID- 25821792 TI - Recent development in production and biotechnological application of microbial enzymes. PMID- 25821794 TI - Validation of new and existing decision rules for the estimation of beat-to-beat pulse transit time. AB - Pulse transit time (PTT) is a pivotal marker of vascular stiffness. Because the actual PTT duration in vivo is unknown and the complicated variation in waveform may occur, the robust determination of characteristic point is still a very difficult task in the PTT estimation. Our objective is to devise a method for real-time estimation of PTT duration in pulse wave. It has an ability to reduce the interference caused by both high- and low-frequency noise. The reproducibility and performance of these methods are assessed on both artificial and clinical pulse data. Artificial data are generated to investigate the reproducibility with various signal-to-noise ratios. For all artificial data, the mean biases obtained from all methods are less than 1 ms; collectively, this newly proposed method has minimum standard deviation (SD, <1 ms). A set of data from 33 participants together with the synchronously recorded continuous blood pressure data are used to investigate the correlation coefficient (CC). The statistical analysis shows that our method has maximum values of mean CC (0.5231), sum of CCs (17.26), and median CC (0.5695) and has the minimum SD of CCs (0.1943). Overall, the test results in this study indicate that the newly developed method has advantages over traditional decision rules for the PTT measurement. PMID- 25821793 TI - Predictors of mortality for nursing home-acquired pneumonia: a systematic review. AB - BACKGROUND: Current risk stratification tools, primarily used for CAP, are suboptimal in predicting nursing home acquired pneumonia (NHAP) outcome and mortality. We conducted a systematic review to evaluate current evidence on the usefulness of proposed predictors of NHAP mortality. METHODS: PubMed (MEDLINE), EMBASE, and CINAHL databases were searched for articles published in English between January 1978 and January 2014. The literature search elicited a total of 666 references; 580 were excluded and 20 articles met the inclusion criteria for the final analysis. RESULTS: More studies supported the Pneumonia Severity Index (PSI) as a superior predictor of NHAP severity. Fewer studies suggested CURB-65 and SOAR (especially for the need of ICU care) as useful predictors for NHAP mortality. There is weak evidence for biomarkers like C-reactive protein and copeptin as prognostic tools. CONCLUSION: The evidence supports the use of PSI as the best available indicator while CURB-65 may be an alternative prognostic indicator for NHAP mortality. Overall, due to the paucity of information, biomarkers may not be as effective in this role. Larger prospective studies are needed to establish the most effective predictor(s) or combination scheme to help clinicians in decision-making related to NHAP mortality. PMID- 25821795 TI - Macrophage migration inhibitory factor polymorphism is associated with susceptibility to inflammatory coronary heart disease. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. This study explored the association of 173G/C polymorphism of the MIF gene with coronary heart disease (CHD). METHODS: Sequencing was carried out after polymerase chain reaction with DNA specimens from 186 volunteers without CHD and 70 patients with CHD. Plasma MIF levels on admission were measured by ELISA. Patients were classified into either stable angina pectoris (SAP) or unstable angina pectoris (UAP). Genotype distribution between cases and controls and the association of patients' genotypes with MIF level and plaque stability were statistically evaluated (ethical approval number: 2012-01). RESULTS: The frequency of the C genotype was higher in CHD patients than in the control (P = 0.014). The frequency of the 173*CC genotype was higher in CHD patients than in the control (P = 0.005). The plasma MIF level was higher in MIF173*C carriers than in MIF173*G carriers (P = 0.033). CHD patients had higher plasma MIF levels than the control (P = 0.000). Patients with UAP had higher plasma MIF levels than patients with SAP (P = 0.014). CONCLUSIONS: These data suggest that MIF -173G/C polymorphism may be related to the development of CHD in a Chinese population. Plasma MIF level is a predictor of plaque stability. This trial is registered with NCT01750502. PMID- 25821796 TI - Serum levels of anticyclic citrullinated peptide antibodies, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein are associated with increased carotid intima-media thickness: a cross-sectional analysis of a cohort of rheumatoid arthritis patients without cardiovascular risk factors. AB - The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients. METHODS: Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P < 0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFalpha and IL-6 (P < 0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P = 0.02). The cIMT correlated with levels of anti-CCP (r = 0.513, P = 0.001), CRP (r = 0.799, P < 0.001), TNFalpha (r = 0.642, P = 0.001), and IL-6 (r = 0.751, P < 0.001). In multiple regression analysis, cIMT was associated with CRP (P < 0.001) and anti-CCP levels (P = 0.03). CONCLUSIONS: Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events. PMID- 25821797 TI - Calcium homeostasis and ER stress in control of autophagy in cancer cells. AB - Autophagy is a basic catabolic process, serving as an internal engine during responses to various cellular stresses. As regards cancer, autophagy may play a tumor suppressive role by preserving cellular integrity during tumor development and by possible contribution to cell death. However, autophagy may also exert oncogenic effects by promoting tumor cell survival and preventing cell death, for example, upon anticancer treatment. The major factors influencing autophagy are Ca(2+) homeostasis perturbation and starvation. Several Ca(2+) channels like voltage-gated T- and L-type channels, IP3 receptors, or CRAC are involved in autophagy regulation. Glucose transporters, mainly from GLUT family, which are often upregulated in cancer, are also prominent targets for autophagy induction. Signals from both Ca(2+) perturbations and glucose transport blockage might be integrated at UPR and ER stress activation. Molecular pathways such as IRE 1-JNK Bcl-2, PERK-eIF2alpha-ATF4, or ATF6-XBP 1-ATG are related to autophagy induced through ER stress. Moreover ER molecular chaperones such as GRP78/BiP and transcription factors like CHOP participate in regulation of ER stress-mediated autophagy. Autophagy modulation might be promising in anticancer therapies; however, it is a context-dependent matter whether inhibition or activation of autophagy leads to tumor cell death. PMID- 25821798 TI - Hydroxyapatite whisker reinforced 63s glass scaffolds for bone tissue engineering. AB - Bioactive glass (BG) is widely used for bone tissue engineering. However, poor mechanical properties are the major shortcomings. In the study, hydroxyapatite nanowhisker (HANw) was used as a reinforcement to improve the mechanical properties. 63s glass/HANw scaffolds were successfully fabricated by selective laser sintering (SLS). It was found that the optimal compressive strength and fracture toughness were achieved when 10 wt.% HANw was added. This led to 36% increase in compressive strength and 83% increase in fracture toughness, respectively, compared with pure 63s glass scaffolds. Different reinforcement mechanisms were analyzed based on the microstructure investigation. Whisker bridging and whisker pulling-out were efficient in absorbing crack propagating energy, resulting in the improvement of the mechanical properties. Moreover, bioactivity and biocompatibility of the scaffolds were evaluated in vitro. The results showed that composite scaffolds with 10 wt.% HANw exhibited good apatite forming ability and cellular affinity. PMID- 25821799 TI - Is visual registration equivalent to semiautomated registration in prostate biopsy? AB - In magnetic resonance iimaging- (MRI-) ultrasound (US) guided biopsy, suspicious lesions are identified on MRI, registered on US, and targeted during biopsy. The registration can be performed either by a human operator (visual registration) or by fusion software. Previous studies showed that software registration is fairly accurate in locating suspicious lesions and helps to improve the cancer detection rate. Here, the performance of visual registration was examined for ability to locate suspicious lesions defined on MRI. This study consists of 45 patients. Two operators with differing levels of experience (<1 and 18 years) performed visual registration. The overall spatial difference by the two operators in 72 measurements was 10.6 +/- 6.0 mm. Each operator showed a spatial difference of 9.4 +/- 5.1 mm (experienced; 39 lesions) and 12.1 +/- 6.6 mm (inexperienced; 33 lesions), respectively. In a head-to-head comparison of the same 16 lesions from 12 patients, the spatial differences were 9.7 mm +/- 4.9 mm (experienced) and 13.4 mm +/- 7.4 mm (inexperienced). There were significant differences between the two operators (unpaired, P value = 0.042; paired, P value = 0.044). The substantial differences by the two operators suggest that visual registration could improperly and inaccurately target many tumors, thereby potentially leading to missed diagnosis or false characterization on pathology. PMID- 25821800 TI - Controversial indications for sentinel lymph node biopsy in breast cancer patients. AB - Sentinel lymph node biopsy (SLNB) emerged in the 1990s as a new technique in the surgical management of the axilla for patients with early breast cancer, resulting in lower complication rates and better quality of life than axillary lymph node dissection (ALND). Today SLNB is firmly established in the armamentarium of clinicians treating breast cancer, but several questions remain. The goal of this paper is to review recent work addressing 4 questions that have been the subject of debate in the use of SLNB in the past few years: (a) What is the implication of finding micrometastases in the sentinel nodes? (b) Is ALND necessary in all patients who have a positive SLNB? (c) How accurate is SLNB after neoadjuvant therapy? (d) Can SLNB be used to stage the axilla in locally recurrent breast cancer following breast surgery with or without prior axillary surgery? PMID- 25821801 TI - Elevated serum levels of cysteine and tyrosine: early biomarkers in asymptomatic adults at increased risk of developing metabolic syndrome. AB - As there is effective intervention for delaying or preventing metabolic diseases, which are often present for years before becoming clinically apparent, novel biomarkers that would mark metabolic complications before the onset of metabolic disease should be identified. We investigated the role of fasting serum amino acids and their associations with inflammatory markers, adipokines, and metabolic syndrome (MetS) components in subjects prior to the onset of insulin resistance (IR). Anthropometric measurements, food records, adipokines, biochemical markers, and serum levels of amino acids were determined in 96 asymptomatic subjects aged 25-49 years divided into three groups according to the number of MetS components present. Cysteine and tyrosine were significantly higher already in group with one component of MetS present compared to subjects without MetS components. Serum amino acid levels correlated with markers of inflammation and adipokines. Alanine and glycine explained 10% of insulin resistance variability. The role of tyrosine and cysteine, that were higher already with 1 component of MetS present, should be further investigated as they might point to future insulin disturbances. PMID- 25821802 TI - Gene network exploration of crosstalk between apoptosis and autophagy in chronic myelogenous leukemia. AB - BACKGROUND: Gene expression levels change to adapt the stress, such as starvation, toxin, and radiation. The changes are signals transmitted through molecular interactions, eventually leading to two cellular fates, apoptosis and autophagy. Due to genetic variations, the signals may not be effectively transmitted to modulate apoptotic and autophagic responses. Such aberrant modulation may lead to carcinogenesis and drug resistance. The balance between apoptosis and autophagy becomes very crucial in coping with the stress. Though there have been evidences illustrating the apoptosis-autophagy interplay, the underlying mechanism and the participation of the regulators including transcription factors (TFs) and microRNAs (miRNAs) remain unclear. RESULTS: Gene network is a graphical illustration for exploring the functional linkages and the potential coordinate regulations of genes. Microarray dataset for the study of chronic myeloid leukemia was obtained from Gene Expression Omnibus. The expression profiles of those genes related to apoptosis and autophagy, including MCL1, BCL2, ATG, beclin-1, BAX, BAK, E2F, cMYC, PI3K, AKT, BAD, and LC3, were extracted from the dataset to construct the gene networks. CONCLUSION: The network analysis of these genes explored the underlying mechanisms and the roles of TFs and miRNAs for the crosstalk between apoptosis and autophagy. PMID- 25821803 TI - Localized and sustained delivery of erythropoietin from PLGA microspheres promotes functional recovery and nerve regeneration in peripheral nerve injury. AB - Erythropoietin (EPO) has been demonstrated to exert neuroprotective effects on peripheral nerve injury recovery. Though daily intraperitoneal injection of EPO during a long period of time was effective, it was a tedious procedure. In addition, only limited amount of EPO could reach the injury sites by general administration, and free EPO is easily degraded in vivo. In this study, we encapsulated EPO in poly(lactide-co-glycolide) (PLGA) microspheres. Both in vitro and in vivo release assays showed that the EPO-PLGA microspheres allowed sustained release of EPO within a period of two weeks. After administration of such EPO-PLGA microspheres, the peripheral nerve injured rats had significantly better recovery compared with those which received daily intraperitoneal injection of EPO, empty PLGA microspheres, or saline treatments. This was supported by the functional, electrophysiological, and histological evaluations of the recovery done at week 8 postoperatively. We conclude that sustained delivery of EPO could be achieved by using EPO-PLGA microspheres, and such delivery method could further enhance the recovery function of EPO in nerve injury recovery. PMID- 25821804 TI - Use of a robotic device for the rehabilitation of severe upper limb paresis in subacute stroke: exploration of patient/robot interactions and the motor recovery process. AB - This pioneering observational study explored the interaction between subacute stroke inpatients and a rehabilitation robot during upper limb training. 25 stroke survivors (age 55 +/- 17 years; time since stroke, 52 +/- 21 days) with severe upper limb paresis carried out 16 sessions of robot-assisted shoulder/elbow training (InMotion 2.0, IMT, Inc., MA, USA) combined with standard therapy. The values of 3 patient/robot interaction parameters (a guidance parameter: Stiffness, a velocity-related parameter: Slottime, and Robotic Power) were compared between sessions 1 (S1), 4 (S4), 8 (S8), 12 (S12), and 16 (S16). Pre/post Fugl-Meyer Assessment (FMA) scores were compared in 18 patients. Correlations between interaction parameters and clinical and kinematic outcome measures were evaluated. Slottime decreased at S8 (P = 0.003), while Guidance decreased at S12 (P = 0.008). Robotic Power tended to decrease until S16. FMA scores improved from S1 to S16 (+49%, P = 0.002). Changes in FMA score were correlated with the Stiffness parameter (R = 0.4, P = 0.003). Slottime was correlated with movement velocity. This novel approach demonstrated that a robotic device is a useful and reliable tool for the quantification of interaction parameters. Moreover, changes in these parameters were correlated with clinical and kinematic changes. These results suggested that robot-based recordings can provide new insights into the motor recovery process. PMID- 25821805 TI - Thermal tomography imaging in photonic traditional Chinese medicine information therapy with holistic effect for health whole nursing. AB - A photonic traditional Chinese medicine (TCM) information therapy was developed that has applications in whole health nursing including the prevention and treatment of ischemic cardiovascular and cerebrovascular diseases as well as the conditioning of the subhealth state. This therapy utilizes the beam of a 630 nm LED light to irradiate the oropharynx, while simultaneously employing two beams of 650 nm LED light to irradiate corresponding acupuncture points resulting in a synergistic outcome. This method was named "1 + 2 phototherapy." The principle mechanism of the therapy is a series of photon induced biological effects that are triggered by stimulating the photosensitive tissues of the oropharynx. This tissue includes the oral mucosa, capillaries, lymph nodes, saliva glands, nerves, and Jingluo and is stimulated by light beams of certain photon energy and imitative acupuncture information. Thermal tomography imaging shows that the average temperature of the upper-body was improved significantly after oropharyngeal irradiation under irradiation of "Futu point": the heat radiation of the spine, as well as chest, shoulders, arms, and clavicle, increased under irradiation of "Hoku," whereas the overall average temperature was below the temperature before irradiation. The experiment indicates that this therapy can promote blood circulation, regulate varied physiological parameters, and have holistic effects in whole health nursing. PMID- 25821806 TI - The relationship of CSF and plasma cytokine levels in HIV infected patients with neurocognitive impairment. AB - Although HAD is now rare due to HAART, the milder forms of HAND persist in HIV infected patients. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. The levels of cytokines in CSF were associated with neurocognitive impairment in HIV infection. However, the changes of cytokines involved in cognition impairment in plasma have not been shown, and their relationships between CSF and plasma require to be addressed. We compared cytokine levels in paired CSF and plasma samples from HIV-infected individuals with or without neurocognitive impairment. Cytokine concentrations were measured by Luminex xMAP. In comparing the expression levels of cytokines in plasma and CSF, IFN-alpha2, IL-8, IP-10, and MCP-1 were significantly higher in CSF. Eotaxin was significantly higher in plasma, whereas G-CSF showed no difference between plasma and CSF. G-CSF (P = 0.0079), IL-8 (P = 0.0223), IP-10 (P = 0.0109), and MCP-1 (P = 0.0497) in CSF showed significant difference between HIV-CI and HIV-NC group, which may indicate their relationship to HIV associated neurocognitive impairment. In addition, G-CSF (P = 0.0191) and IP-10 (P = 0.0377) in plasma were significantly higher in HIV-CI than HIV-NC. The consistent changes of G-CSF and IP-10 in paired plasma and CSF samples might enhance their potential for predicting HAND. PMID- 25821807 TI - The epidemiology and economic burden of Clostridium difficile infection in Korea. AB - The prevalence of Clostridium difficile infection and the associated burden have recently increased in many countries. While the main risk factors for C. difficile infection include old age and antibiotic use, the prevalence of this infection is increasing in low-risk groups. These trends highlight the need for research on C. difficile infection. This study pointed out the prevalence and economic burden of C. difficile infection and uses the representative national data which is primarily from the database of the Korean Health Insurance Review and Assessment Service, for 2008-2011. The annual economic cost was measured using a prevalence approach, which sums the costs incurred to treat C. difficile infection. C. difficile infection prevalence was estimated to have increased from 1.43 per 100,000 in 2008 to 5.06 per 100,000 in 2011. Moreover, mortality increased from 69 cases in 2008 to 172 in 2011. The economic cost increased concurrently, from $2.4 million in 2008 to $7.6 million, $10.5 million, and $15.8 million in 2009, 2010, and 2011, respectively. The increasing economic burden of C. difficile infection over the course of the study period emphasizes the need for intervention to minimize the burden of a preventable illness like C. difficile infection. PMID- 25821810 TI - Prediction of cardiovascular disease risk among low-income urban dwellers in metropolitan Kuala Lumpur, Malaysia. AB - We aimed to predict the ten-year cardiovascular disease (CVD) risk among low income urban dwellers of metropolitan Malaysia. Participants were selected from a cross-sectional survey conducted in Kuala Lumpur. To assess the 10-year CVD risk, we employed the Framingham risk scoring (FRS) models. Significant determinants of the ten-year CVD risk were identified using General Linear Model (GLM). Altogether 882 adults (>=30 years old with no CVD history) were randomly selected. The classic FRS model (figures in parentheses are from the modified model) revealed that 20.5% (21.8%) and 38.46% (38.9%) of respondents were at high and moderate risk of CVD. The GLM models identified the importance of education, occupation, and marital status in predicting the future CVD risk. Our study indicated that one out of five low-income urban dwellers has high chance of having CVD within ten years. Health care expenditure, other illness related costs and loss of productivity due to CVD would worsen the current situation of low income urban population. As such, the public health professionals and policy makers should establish substantial effort to formulate the public health policy and community-based intervention to minimize the upcoming possible high mortality and morbidity due to CVD among the low-income urban dwellers. PMID- 25821809 TI - Antioxidant strategies in the management of diabetic neuropathy. AB - Chronic hyperglycaemia (an abnormally high glucose concentration in the blood) resulting from defects in insulin secretion/action, or both, is the major hallmark of diabetes in which it is known to be involved in the progression of the condition to different complications that include diabetic neuropathy. Diabetic neuropathy (diabetes-induced nerve damage) is the most common diabetic complication and can be devastating because it can lead to disability. There is an increasing body of evidence associating diabetic neuropathy with oxidative stress. Oxidative stress results from the production of oxygen free radicals in the body in excess of its ability to eliminate them by antioxidant activity. Antioxidants have different mechanisms and sites of actions by which they exert their biochemical effects and ameliorate nerve dysfunction in diabetes by acting directly against oxidative damage. This review will examine different strategies for managing diabetic neuropathy which rely on exogenous antioxidants. PMID- 25821811 TI - Protective and curative effects of the sea cucumber Holothuria atra extract against DMBA-induced hepatorenal diseases in rats. AB - Oxidative stress is a common mechanism contributing to the initiation and progression of hepatic damage. Hence there is a great demand for the development of agents with potent antioxidant effect. The aim of the present study is to evaluate the efficacy of Holothuria atra extract (HaE) as an antioxidant against 7,12-dimethylbenz[a]anthracene- (DMBA-) induced hepatorenal dysfunction. Experimental animals were divided into two main groups: protective and curative. Each group was then divided into five subgroups pre- or posttreated either with distilled water (DMBA subgroups) or with HaE (200 mg/kg body weight) for seven and fourteen days. Single oral administration of DMBA (15 mg/kg body weight) to Wistar rats resulted in a significant increase in the serum liver enzymes and kidney function's parameters. DMBA increased level of liver malondialdehyde (MDA), decreased levels of reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) in the liver tissue, and induced liver histopathological alterations. Pre- or posttreatment with HaE orally for 14 days significantly reversed the hepatorenal alterations induced following DMBA administration. In conclusion, HaE exhibits good hepatoprotective, curative, and antioxidant potential against DMBA-induced hepatorenal dysfunction in rats that might be due to decreased free radical generation. PMID- 25821808 TI - Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. AB - Suicidal erythrocyte death or eryptosis is characterized by erythrocyte shrinkage, cell membrane blebbing, and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include Ca(2+) entry, ceramide formation, stimulation of caspases, calpain activation, energy depletion, oxidative stress, and dysregulation of several kinases. Eryptosis is triggered by a wide variety of xenobiotics. It is inhibited by several xenobiotics and endogenous molecules including NO and erythropoietin. The susceptibility of erythrocytes to eryptosis increases with erythrocyte age. Phosphatidylserine exposing erythrocytes adhere to the vascular wall by binding to endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor for phosphatidylserine and oxidized low density lipoprotein (CXCL16). Phosphatidylserine exposing erythrocytes are further engulfed by phagocytosing cells and are thus rapidly cleared from circulating blood. Eryptosis eliminates infected or defective erythrocytes thus counteracting parasitemia in malaria and preventing detrimental hemolysis of defective cells. Excessive eryptosis, however, may lead to anemia and may interfere with microcirculation. Enhanced eryptosis contributes to the pathophysiology of several clinical disorders including metabolic syndrome and diabetes, malignancy, cardiac and renal insufficiency, hemolytic uremic syndrome, sepsis, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose 6-phosphate dehydrogenase deficiency, and Wilson's disease. Facilitating or inhibiting eryptosis may be a therapeutic option in those disorders. PMID- 25821812 TI - Prokinetic activity of Prunus persica (L.) Batsch flowers extract and its possible mechanism of action in rats. AB - The peach tree, Prunus persica (L.) Batsch, is widely cultivated in China, and its flowers have been used for centuries in traditional Chinese medicine to treat gut motility disorders. But few studies have explored the pharmacological effect of Prunus persica (L.) Batsch flowers on gastrointestinal motility. In this study, the activities of different extracts from Prunus persica (L.) Batsch flowers on the smooth muscle contractions were evaluated using isolated colon model, and the ethyl acetate extract (EAE) showed the strongest effects in vitro. EAE (10(-8)-10(-5) g/mL) caused a concentration-dependent stimulatory effect in rat colonic tissue. Additionally, ketotifen (100 uM), cimetidine (10 uM), and pyrilamine (1 uM) produced a significant inhibition of contractions caused by EAE. Furthermore, immunofluorescence and toluidine blue staining revealed increased numbers of mast cells in the EAE group, and EAE increased histamine release from the colonic tissues. These data indicate that EAE has significant prokinetic activity and acts by a mechanism that mainly involves mast cell degranulation. Our study provides a pharmacological basis for the use of an extract of Prunus persica (L.) Batsch flowers in the treatment of gut motility disorders. PMID- 25821813 TI - Prediction of drug indications based on chemical interactions and chemical similarities. AB - Discovering potential indications of novel or approved drugs is a key step in drug development. Previous computational approaches could be categorized into disease-centric and drug-centric based on the starting point of the issues or small-scaled application and large-scale application according to the diversity of the datasets. Here, a classifier has been constructed to predict the indications of a drug based on the assumption that interactive/associated drugs or drugs with similar structures are more likely to target the same diseases using a large drug indication dataset. To examine the classifier, it was conducted on a dataset with 1,573 drugs retrieved from Comprehensive Medicinal Chemistry database for five times, evaluated by 5-fold cross-validation, yielding five 1st order prediction accuracies that were all approximately 51.48%. Meanwhile, the model yielded an accuracy rate of 50.00% for the 1st order prediction by independent test on a dataset with 32 other drugs in which drug repositioning has been confirmed. Interestingly, some clinically repurposed drug indications that were not included in the datasets are successfully identified by our method. These results suggest that our method may become a useful tool to associate novel molecules with new indications or alternative indications with existing drugs. PMID- 25821814 TI - Substance P receptor antagonism: a potential novel treatment option for viral myocarditis. AB - Viral-myocarditis is an important cause of heart failure for which no specific treatment is available. We previously showed the neuropeptide substance P (SP) is associated with the pathogenesis of murine myocarditis caused by encephalomyocarditis virus (EMCV). The current studies determined if pharmacological inhibition of SP-signaling via its high affinity receptor, NK1R and downstream G-protein, Ras homolog gene family, member-A (RhoA), will be beneficial in viral-myocarditis. Aprepitant (1.2 mg/kg), a SP-receptor antagonist, or fasudil (10 mg/kg), a RhoA inhibitor, or saline control was administered daily to mice orally for 3 days, prior to, or 5 days following, intraperitoneal infection with and without 50 PFU of EMCV, following which disease assessment studies, including echocardiogram and cardiac Doppler were performed in day 14 after infection. Pretreatment and posttreatment with aprepitant significantly reduced mortality, heart and cardiomyocyte size, and cardiac viral RNA levels (P < 0.05 all, ANOVA). Only aprepitant pretreatment improved heart functions; it significantly decreased end systolic diameter, improved fractional shortening, and increased peak aortic flow velocity (P < 0.05 all, ANOVA). Pre- or posttreatment with fasudil did not significantly impact disease manifestations. These findings indicate that SP contributes to cardiac remodeling and dysfunction following ECMV infection via its high affinity receptor, but not through the Rho-A pathway. These studies suggest that SP receptor antagonism may be a novel therapeutic-option for patients with viral myocarditis. PMID- 25821815 TI - Expression of MMP-9 and VEGF in meningiomas and their correlation with peritumoral brain edema. AB - Meningiomas constitute up to 13% of all intracranial tumors. The predictive factors for meningioma have not been unambiguously defined; however some limited data suggest that the expression of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) may be associated with the presence of peritumoral brain edema (PTBE) and worse clinical outcome. The aim of this study was to analyze the expressions of MMP-9 and VEGF in a group of meningiomas of various grades and to study associations between these two markers and PTBE. The study included patients with supratentorial meningiomas. The patients were divided into low- (G1) and high-grade meningiomas (G2 and G3). PTBE was assessed on MRI. The expressions of VEGF and MMP-9 were determined immunohistochemically. The expression of MMP-9 was observed significantly more often in G3 meningiomas than in lower grade tumors. The presence of stage II or III PTBE was associated with a significant increase in MMP-9 expression. The expression of VEGF did not differ across the PTBE stages. Our findings point to a significant role of MMP-9 and VEGF in the pathogenesis of peritumoral brain edema in low- and high-grade meningiomas. PMID- 25821816 TI - Evaluating LRRK2 genetic variants with unclear pathogenicity. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) have been known to be a major genetic component affecting Parkinson's disease (PD). However, the pathogenicity of many of the LRRK2 variants is unclear because they have been detected in single patients or also in patients and controls. Here, we selected 5 exonic variants (L1165P, T1410M, M1646T, L2063X, and Y2189C) from each of the protein domain of LRRK2 and analysed their possible association with pathogenicity using in vitro functional assays. Point mutations representing each of these variants were incorporated into the LRRK2 gene, and functional aspects such as the percentage of cell survival upon application of stress and kinase activity were measured. Our results showed that all 5 variants had a significantly negative effect on the survival of cells, in both presence and absence of stress, as compared to the wild-type. In addition, there was also a slight increase in kinase activity in most of the variants in comparison to the wild-type. A negative correlation between cell survival and kinase activity was observed. These data suggest that most of the variants despite being located in different domains of LRRK2 appear to exert a potential pathogenic effect possibly through an increased kinase activity, supporting a gain of function mechanism. PMID- 25821817 TI - Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model. AB - Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs. PMID- 25821818 TI - Nucleofection of rat pheochromocytoma PC-12 cells with human mutated beta-amyloid precursor protein gene (APP-sw) leads to reduced viability, autophagy-like process, and increased expression and secretion of beta amyloid. AB - Pheochromocytoma PC-12 cells are immune to physiological stimuli directed to evoke programmed cell death. Besides, metabolic inhibitors are incapable of sensitizing PC-12 cells to extrinsic or intrinsic apoptosis unless they are used in toxic concentrations. Surprisingly, these cells become receptive to cell deletion after human APP-sw gene expression. We observed reduced cell viability in GFP vector + APP-sw-nucleofected cells (drop by 36%) but not in GFP vector - or GFP vector + APP-wt-nucleofected cells. Lower viability was accompanied by higher expression of Abeta 1-16 and elevated secretion of Abeta 1-40 (in average 53.58 pg/mL). At the ultrastructural level autophagy-like process was demonstrated to occur in APP-sw-nucleofected cells with numerous autophagosomes and multivesicular bodies but without autolysosomes. Human APP-sw gene is harmful to PC-12 cells and cells are additionally driven to incomplete autophagy-like process. When stimulated by TRAIL or nystatin, CLU protein expression accompanies early phase of autophagy. PMID- 25821819 TI - Effectiveness of the lower eyelid suspension using fascia lata graft for the treatment of lagophthalmos due to facial paralysis. AB - PURPOSE: To evaluate of functional and cosmetic effectiveness of lower eyelid sling technique with fascia lata graft in patients with lagophthalmos due to facial paralysis. MATERIAL AND METHOD: Ten patients with a mean age of 55.1 +/- 19.77 years who underwent lower eyelid sling surgery with a fascia lata graft between September 2011 and January 2014 were included in this prospective study. Preoperatively and postoperatively patients were evaluated in terms of corneal epithelial defects, Schirmer's test, and tear break-up time (TBUT). Cosmetically, vertical eyelid aperture, margin reflex distances 1 and 2 (MRD1 and MRD2) and scleral show were evaluated preoperatively and postoperatively. RESULTS: One patient had facial paralysis on the right side whereas the other 9 patients had facial paralysis on the left side. Preoperatively, 3 patients were detected with corneal ulcer, whereas 7 patients were detected with persistent corneal epithelial defects localized in the lower half of the cornea. In the 3 patients with preoperative corneal ulcer, the ulcer recovered with corneal opacity, whereas in the 7 patients with punctate epitheliopathy, postoperative corneal transparency was obtained. DISCUSSION: Lower eyelid sling technique with fascia lata graft is an effective technique for the repositioning of the lower eyelid and preventing the corneal complications. PMID- 25821820 TI - Cloning and expression of synthetic genes encoding the broad antimicrobial spectrum bacteriocins SRCAM 602, OR-7, E-760, and L-1077, by recombinant Pichia pastoris. AB - We have evaluated the cloning and functional expression of previously described broad antimicrobial spectrum bacteriocins SRCAM 602, OR-7, E-760, and L-1077, by recombinant Pichia pastoris. Synthetic genes, matching the codon usage of P. pastoris, were designed from the known mature amino acid sequence of these bacteriocins and cloned into the protein expression vector pPICZalphaA. The recombinant derived plasmids were linearized and transformed into competent P. pastoris X-33, and the presence of integrated plasmids into the transformed cells was confirmed by PCR and sequencing of the inserts. The antimicrobial activity, expected in supernatants of the recombinant P. pastoris producers, was purified using a multistep chromatographic procedure including ammonium sulfate precipitation, desalting by gel filtration, cation exchange-, hydrophobic interaction-, and reverse phase-chromatography (RP-FPLC). However, a measurable antimicrobial activity was only detected after the hydrophobic interaction and RP FPLC steps of the purified supernatants. MALDI-TOF MS analysis of the antimicrobial fractions eluted from RP-FPLC revealed the existence of peptide fragments of lower and higher molecular mass than expected. MALDI-TOF/TOF MS analysis of selected peptides from eluted RP-FPLC samples with antimicrobial activity indicated the presence of peptide fragments not related to the amino acid sequence of the cloned bacteriocins. PMID- 25821821 TI - Recent developments in vascular imaging techniques in tissue engineering and regenerative medicine. AB - Adequate vascularisation is key in determining the clinical outcome of stem cells and engineered tissue in regenerative medicine. Numerous imaging modalities have been developed and used for the visualization of vascularisation in tissue engineering. In this review, we briefly discuss the very recent advances aiming at high performance imaging of vasculature. We classify the vascular imaging modalities into three major groups: nonoptical methods (X-ray, magnetic resonance, ultrasound, and positron emission imaging), optical methods (optical coherence, fluorescence, multiphoton, and laser speckle imaging), and hybrid methods (photoacoustic imaging). We then summarize the strengths and challenges of these methods for preclinical and clinical applications. PMID- 25821822 TI - Phytochemical analysis and modulation of antibiotic activity by Luehea paniculata Mart. & Zucc. (Malvaceae) in multiresistant clinical isolates of Candida spp. AB - The high incidence of fungal infections has led to the continuous search for new drugs. Extracts of Luehea paniculata, a tree of multiple medicinal uses, were evaluated for anti-Candida activity, as well as its modulator potential of the Fluconazole antibiotic. Chemical prospecting of ethanol extracts of leaf and bark was carried out, the quantification of total phenols and flavonoids, characterized by the HPLC-DAD technique. The rosmarinic acid and the vitexin flavonoid were observed as major constituents in ELELP and ESWELP, respectively. Antioxidant activity was also evaluated by the method of scavenging the free radical DPPH, and quercetin was used as standard, obtaining IC50 values: 0.341 (mg/mL) for ELELP and 0.235 (mg/mL) for ESWELP. The microdilution assay was performed for antifungal activity against strains of Candida albicans, C. krusei, and C. tropicalis and showed minimum inhibitory concentrations values >=1024 MUg/mL. In the modulator action of extracts on Fluconazole against multiresistant clinical isolates of Candida (subinhibitory concentration minimum of 128 MUg/mL), a significant synergism was observed, indicating that the extracts potentiated the antifungal effect against C. tropicalis, where antioxidant flavonoids could be responsible. This is the first report about modifying activity of the antibiotic action of a species of the genus Luehea. PMID- 25821823 TI - Topical anti-inflammatory effects of isorhamnetin glycosides isolated from Opuntia ficus-indica. AB - Opuntia ficus-indica (OFI) has been widely used in Mexico as a food and for the treatment of different health disorders such as inflammation and skin aging. Its biological properties have been attributed to different phytochemicals such as the isorhamnetin glycosides which are the most abundant flavonoids. Moreover, these compounds are considered a chemotaxonomic characteristic of OFI species. The aim of this study was to evaluate the effect of OFI extract and its isorhamnetin glycosides on different inflammatory markers in vitro and in vivo. OFI extract was obtained by alkaline hydrolysis of OFI cladodes powder and pure compounds were obtained by preparative chromatography. Nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor- (TNF-) alpha, and interleukin- (IL-) 6 production were measured. NO production was tested in lipopolysaccharide stimulated RAW 264.7 cells while in vivo studies were carried on croton oil induced ear edema model. OFI extract and diglycoside isorhamnetin-glucosyl rhamnoside (IGR) at 125 ng/mL suppressed the NO production in vitro (73.5 +/- 4.8% and 68.7 +/- 5.0%, resp.) without affecting cell viability. Likewise, IGR inhibited the ear edema (77.4 +/- 5.7%) equating the indomethacin effects (69.5 +/- 5.3%). Both IGR and OFI extract significantly inhibited the COX-2, TNF-alpha, and IL-6 production. IGR seems to be a suitable natural compound for development of new anti-inflammatory ingredient. PMID- 25821824 TI - Proteomic analysis of human brain microvascular endothelial cells reveals differential protein expression in response to enterovirus 71 infection. AB - 2D DIGE technology was employed on proteins prepared from human brain microvascular endothelial cells (HBMEC), to study the differentially expressed proteins in cells at 0 h, 1 h, 16 h, and 24 h after infection. Proteins found to be differentially expressed were identified with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDITOF/TOF MS) analysis. We identified 43 spots showing changes of at least 2.5 fold up- or downregulated expressions in EV71-infected cells at different time when comparing to control, and 28 proteins could be successfully identified by MALDI TOF/TOF mass spectrometry analysis. 4 proteins were significantly upregulated, and 6 proteins were downregulated, another 18 proteins were different expression at different incubation time. We identified changes in the expression of 12 cellular metabolism-related proteins, 5 molecules involved in cytoskeleton, 3 molecules involved in energy metabolism, 2 molecules involved in signal transduction, 1 molecule involved in the ubiquitin-proteasome pathway, 1 molecule involved in cell cycle, 1 molecule involved in apoptosis-related protein, 1 molecular chaperone, and 2 unknown proteins. These findings build up a comprehensive profile of the HBMEC proteome and provide a useful basis for further analysis of the pathogenic mechanism that underlies EV71 infections to induce severe neural complications. PMID- 25821825 TI - Aging and cardiovascular risk. PMID- 25821826 TI - Morphological study of the lingula in adult human mandibles of Brazilians individuals and clinical implications. AB - OBJECTIVES: The purpose of this research was to study, in macerated adult human mandibles, the height of the lingula and provide morphometric data for its location considering aspects such as shape of the lingula, gender, and race. MATERIAL AND METHODS: 132 macerated mandibles of Brazilian adult individuals, both sexes, Amerindian and Caucasian, were used. The distances: from mandibular notch to lingula; from anterior margin of ramus of mandible to lingula; from posterior margin of ramus of mandible to lingula; from mandibular base to lingula, and the height of lingula were obtained. To perform these measurements we used a digital caliper. The variables such as gender and race were analyzed. RESULTS: The mean values found for the height of lingula and its location were determined according to the gender, race, and the lingula shape. CONCLUSION: This research provides additional data on height of the lingula and morphometric data for its location considering aspects such as shape of the lingula, gender, and race, information that had not been reported in the literature to date. We emphasize that a careful study considering gender and ethnic group makes procedures involving the region of lingula safer. PMID- 25821827 TI - Alterations of dendritic cells in sepsis: featured role in immunoparalysis. AB - Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies. PMID- 25821828 TI - Retrograde intrarenal surgery versus percutaneous lithotripsy to treat renal stones 2-3 cm in diameter. AB - OBJECTIVE: Retrograde intrarenal surgery (RIRS) performed using a flexible ureterorenoscope marked the beginning of a new era in urology. Today, even staghorn stones are successfully treated via RIRS. The recommended treatment for larger stones is percutaneous nephrolithotomy (PNL). However, the question of whether PNL or RIRS should be the first-line treatment option for larger stones remains controversial. In this study, we contribute to the debate by comparing the success and complication rates of PNL and RIRS that were used to treat renal pelvis stones 2-3 cm in diameter. MATERIALS AND METHODS: The medical records of 154 patients (74 PNL, 80 RIRS) were retrospectively evaluated. PNL patients were placed in Group 1 and RIRS patients in Group 2. RESULTS: The complete stone-free rates were 95.5% in the PNL group and 80.6% in the RIRS group 1 month postoperatively (P = 0.061). The respective complication rates (evaluated using the Clavien system) were 13.5% and 8.8% (P = 0.520). CONCLUSIONS: RIRS affords a comparable success rate, causes fewer complications than PNL, and seems to be a promising alternative to PNL when larger stones are to be treated. Prospective randomized controlled trials are needed to confirm these findings. PMID- 25821829 TI - Elaborating the role of natural products-induced autophagy in cancer treatment: achievements and artifacts in the state of the art. AB - Autophagy is a homeostatic process that is highly conserved across different types of mammalian cells. Autophagy is able to relieve tumor cell from nutrient and oxidative stress during the rapid expansion of cancer. Excessive and sustained autophagy may lead to cell death and tumor shrinkage. It was shown in literature that many anticancer natural compounds and extracts could initiate autophagy in tumor cells. As summarized in this review, the tumor suppressive action of natural products-induced autophagy may lead to cell senescence, provoke apoptosis-independent cell death, and complement apoptotic cell death by robust or target-specific mechanisms. In some cases, natural products-induced autophagy could protect tumor cells from apoptotic death. Technical variations in detecting autophagy affect data quality, and study focus should be made on elaborating the role of autophagy in deciding cell fate. In vivo study monitoring of autophagy in cancer treatment is expected to be the future direction. The clinical-relevant action of autophagy-inducing natural products should be highlighted in future study. As natural products are an important resource in discovery of lead compound of anticancer drug, study on the role of autophagy in tumor suppressive effect of natural products continues to be necessary and emerging. PMID- 25821830 TI - Survival of Mexican children with acute myeloid leukaemia who received early intensification chemotherapy and an autologous transplant. AB - BACKGROUND: In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist. Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment. PROCEDURE: This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients), diagnosed in the period 2005-2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients), diagnosed in the period 1999-2004, was treated as Group A, but without the early intensified chemotherapy. RESULTS: Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P = 0.041). Overall survival for Group A (18, 90%) was higher than that for Group B (60%). Complete remission continued for two years of follow-up. CONCLUSIONS: Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy. PMID- 25821831 TI - Ankylosing spondylitis and posture control: the role of visual input. AB - OBJECTIVES: To assess the motor control during quiet stance in patients with established ankylosing spondylitis (AS) and to evaluate the effect of visual input on the maintenance of a quiet posture. METHODS: 12 male AS patients (mean age 50.1 +/- 13.2 years) and 12 matched healthy subjects performed 2 sessions of 3 trials in quiet stance, with eyes open (EO) and with eyes closed (EC) on a baropodometric platform. The oscillation of the centre of feet pressure (CoP) was acquired. Indices of stability and balance control were assessed by the sway path (SP) of the CoP, the frequency bandwidth (FB1) that includes the 80% of the area under the amplitude spectrum, the mean amplitude of the peaks (MP) of the sway density curve (SDC), and the mean distance (MD) between 2 peaks of the SDC. RESULTS: In severe AS patients, the MD between two peaks of the SDC and the SP of the center of feet pressure were significantly higher than controls during both EO and EC conditions. The MP was significantly reduced just on EC. CONCLUSIONS: Ankylosing spondylitis exerts negative effect on postural stability, not compensable by visual inputs. Our findings may be useful in the rehabilitative management of the increased risk of falling in AS. PMID- 25821832 TI - cspA influences biofilm formation and drug resistance in pathogenic fungus Aspergillus fumigatus. AB - The microbial cell wall plays a crucial role in biofilm formation and drug resistance. cspA encodes a repeat-rich glycophosphatidylinositol-anchored cell wall protein in the pathogenic fungus Aspergillus fumigatus. To determine whether cspA has a significant impact on biofilm development and sensitivity to antifungal drugs in A. fumigatus, a DeltacspA mutant was constructed by targeted gene disruption, and we then reconstituted the mutant to wild type by homologous recombination of a functional cspA gene. Deletion of cspA resulted in a rougher conidial surface, reduced biofilm formation, decreased resistance to antifungal agents, and increased internalization by A549 human lung epithelial cells, suggesting that cspA not only participates in maintaining the integrity of the cell wall, but also affects biofilm establishment, drug response, and invasiveness of A. fumigatus. PMID- 25821833 TI - Pituitary adenylate cyclase-activating polypeptide protects glomerular podocytes from inflammatory injuries. AB - Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease; however, there are few treatment options. Inflammation plays a crucial role in the initiation and/or progression of DN. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide, which was originally isolated from the ovine hypothalamus and reportedly has diverse biological functions. It has been reported that PACAP has renoprotective effects in different models of kidney pathology. However, the specific cell types within the kidney that are protected by PACAP have not yet been reported. In this study, we localized VPAC1, one of the PACAP receptors, to glomerular podocytes, which also reportedly has crucial roles not only in glomerular physiology but also in pathology. PACAP was effective in the downregulation of proinflammatory cytokines, such as monocyte chemoattractant protein-1 (MCP-1) and interleukin-6, which had been induced by the activation of toll-like receptor (TLR) with lipopolysaccharide. PACAP also had downregulated the expression of MCP-1 through the protein kinase A signaling pathway; this led to the attenuation of the activation of extracellular signal regulated kinase and nuclear factor-kappa B signaling. Our results suggested that PACAP could be a possible treatment option for DN through the use of anti inflammation effects on glomerular podocytes. PMID- 25821834 TI - Use of Drosophila as an evaluation method reveals imp as a candidate gene for type 2 diabetes in rat locus Niddm22. AB - Type 2 diabetes (T2D) is one of the most common human diseases. QTL analysis of the diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats has identified numerous hyperglycemic loci. However, molecular characterization and/or gene identification largely remains to be elucidated due mostly to the weak genetic variances contributed by each locus. Here we utilized Drosophila melanogaster as a secondary model organism for functional evaluation of the candidate gene. We demonstrate that the tissue specific knockdown of a homologue of igf2bp2 RNA binding protein leads to increased sugar levels similar to that found in the OLETF rat. In the mutant, the expression of two of the insulin-like peptides encoded in the fly genome, dilp2 and dilp3, were found to be downregulated. Consistent with previous reports of dilp mutants, the imp mutant flies exhibited an extension of life span; in contrast, starvation tolerance was reduced. These results further reinforce the possibility that imp is involved in sugar metabolism by modulating insulin expression. PMID- 25821835 TI - Intestinal microbiota as modulators of the immune system. PMID- 25821836 TI - Significance of circulating and crevicular matrix metalloproteinase-9 in rheumatoid arthritis-chronic periodontitis association. AB - In the recent years, statistically significant associations between rheumatoid arthritis (RA) and periodontal disease have been identified. Emerging as a chronic inflammatory joint disease, RA displays various features and pathogenetic events similar to chronic periodontitis (CP). The purpose of this study was to evaluate the utility of determining systemic and crevicular levels of metalloproteinase-9 (MMP-9) as potential biomarkers for association between RA and CP. A total of fifty-six patients were included in the study. The subjects were categorized into four groups as follows: healthy-control (n = 21), active RA (n = 16), CP (n = 14), and RA-CP association (n = 12). Assessment of serum and crevicular concentrations of total MMP-9 (active and pro-MMP-9) was based on ELISA technique. The results of this study showed statistically significant differences of serum MMP-9 between patients groups and control. Serum levels of MMP-9 were similar in RA and RA-CP associated patients. Gingival crevicular fluid (GCF) recorded increased MMP-9 levels in RA-CP association subjects as compared to CP. Considering that RA-CP association is characterized by a disregulation of the inflammatory response, MMP-9 may play a role in the pathogenesis of RA-CP association. MMP-9 is therefore a sensitive tool in the diagnosis and management of patients affected by this binomial association. PMID- 25821838 TI - How the provenance of electronic health record data matters for research: a case example using system mapping. AB - INTRODUCTION: The use of electronic health records (EHRs) for research is proceeding rapidly, driven by computational power, analytical techniques, and policy. However, EHR-based research is limited by the complexity of EHR data and a lack of understanding about data provenance, meaning the context under which the data were collected. This paper presents system flow mapping as a method to help researchers more fully understand the provenance of their EHR data as it relates to local workflow. We provide two specific examples of how this method can improve data identification, documentation, and processing. BACKGROUND: EHRs store clinical and administrative data, often in unstructured fields. Each clinical system has a unique and dynamic workflow, as well as an EHR customized for local use. The EHR customization may be influenced by a broader context such as documentation required for billing. METHODS: We present a case study with two examples of using system flow mapping to characterize EHR data for a local colorectal cancer screening process. FINDINGS: System flow mapping demonstrated that information entered into the EHR during clinical practice required interpretation and transformation before it could be accurately applied to research. We illustrate how system flow mapping shaped our knowledge of the quality and completeness of data in two examples: (1) determining colonoscopy indication as recorded in the EHR, and (2) discovering a specific EHR form that captured family history. DISCUSSION: Researchers who do not consider data provenance risk compiling data that are systematically incomplete or incorrect. For example, researchers who are not familiar with the clinical workflow under which data were entered might miss or misunderstand patient information or procedure and diagnostic codes. CONCLUSIONS: Data provenance is a fundamental characteristic of research data from EHRs. Given the diversity of EHR platforms and system workflows, researchers need tools for evaluating and reporting data availability, quality, and transformations. Our case study illustrates how system mapping can inform researchers about the provenance of their data as it pertains to local workflows. PMID- 25821837 TI - Viruses and the Microbiota. AB - Every surface of the human body is colonized by a diverse microbial community called the microbiota, yet the impact of microbiota on viruses is unclear. Recent research has advanced our understanding of how microbiota influence viral infection. Microbiota inhibit infection of some viruses and promote infection of other viruses. These effects can occur through direct and/or indirect effects on the host and/or virus. This review examines the known effects and mechanisms by which the microbiota influence mammalian virus infections. Furthermore, we suggest strategies for future research on how microbiota impact viruses. Overall, microbiota may influence a wide array of viruses through diverse mechanisms, making the study of virus-microbiota interactions a fertile area for future investigation. PMID- 25821839 TI - Erratum: Recurrent ZFX mutations in human sporadic parathyroid adenomas. AB - [This corrects the article on p. 360 in vol. 1, PMID: 25594030.]. PMID- 25821840 TI - The "virgin birth", polyploidy, and the origin of cancer. AB - Recently, it has become clear that the complexity of cancer biology cannot fully be explained by somatic mutation and clonal selection. Meanwhile, data have accumulated on how cancer stem cells or stemloids bestow immortality on tumour cells and how reversible polyploidy is involved. Most recently, single polyploid tumour cells were shown capable of forming spheroids, releasing EMT-like descendents and inducing tumours in vivo. These data refocus attention on the centuries-old embryological theory of cancer. This review attempts to reconcile seemingly conflicting data by viewing cancer as a pre-programmed phylogenetic life-cycle-like process. This cycle is apparently initiated by a meiosis-like process and driven as an alternative to accelerated senescence at the DNA damage checkpoint, followed by an asexual syngamy event and endopolyploid-type embryonal cleavage to provide germ-cell-like (EMT) cells. This cycle is augmented by genotoxic treatments, explaining why chemotherapy is rarely curative and drives resistance. The logical outcome of this viewpoint is that alternative treatments may be more efficacious - either those that suppress the endopolyploidy associated 'life cycle' or, those that cause reversion of embryonal malignant cells into benign counterparts. Targets for these opposing strategies are components of the same molecular pathways and interact with regulators of accelerated senescence. PMID- 25821841 TI - Exosomal lipids induce human pancreatic tumoral MiaPaCa-2 cells resistance through the CXCR4-SDF-1alpha signaling axis. AB - We previously reported that exosomes secreted by human pancreatic tumor cells induce cell death through the inhibition of the Notch-1 survival pathway (Ristorcelli et al., 2009). We demonstrated that exosomal lipids evoked apoptosis of human pancreatic cancer SOJ-6 cells. Based on the lipid composition of efficient exosomes we designed Synthetic Exosome-Like Nanoparticles (SELN) in which the ratio ordered lipids versus disordered lipids was equal to 6.0 (SELN6.0). These SELN decreased SOJ-6 cells survival by inhibiting the Notch-1 pathway. However MiaPaCa-2 cells were resistant to exosomes (Ristorcelli et al., 2008) and to SELN6.0 (Beloribi et al.,2012). In this paper we aimed at deciphering the reason(s) of this resistance. We observed, in presence of SELN6.0, that the expression of the Notch IntraCytoplasmic Domain (NICD) decreases in MiaPaCa-2 cells but neither Hes-1, the nuclear target of NICD, nor the ratio Bax/Bcl-2 were affected. We further showed that in MiaPaCa-2 cells SELN6.0 induced the activation of NF-kB, which promotes the expression and the secretion of SDF-1alpha. This chemokine interacts with its receptor CXCR4 on MiaPaCa-2 cells and activates the Akt survival pathway protecting cells from death. This activation process promoted by exosomal lipids could have implications in tumor progression and drug resistance. PMID- 25821842 TI - P2Y12 expression and function in alternatively activated human microglia. AB - OBJECTIVE: To investigate and measure the functional significance of altered P2Y12 expression in the context of human microglia activation. METHODS: We performed in vitro and in situ experiments to measure how P2Y12 expression can influence disease-relevant functional properties of classically activated (M1) and alternatively activated (M2) human microglia in the inflamed brain. RESULTS: We demonstrated that compared to resting and classically activated (M1) human microglia, P2Y12 expression is increased under alternatively activated (M2) conditions. In response to ADP, the endogenous ligand of P2Y12, M2 microglia have increased ligand-mediated calcium responses, which are blocked by selective P2Y12 antagonism. P2Y12 antagonism was also shown to decrease migratory and inflammatory responses in human microglia upon exposure to nucleotides that are released during CNS injury; no effects were observed in human monocytes or macrophages. In situ experiments confirm that P2Y12 is selectively expressed on human microglia and elevated under neuropathologic conditions that promote Th2 responses, such as parasitic CNS infection. CONCLUSION: These findings provide insight into the roles of M2 microglia in the context of neuroinflammation and suggest a mechanism to selectively target a functionally unique population of myeloid cells in the CNS. PMID- 25821843 TI - A 41-year-old woman with acute weakness and encephalopathy associated with MOG antibodies. PMID- 25821845 TI - The equivalency between logic Petri workflow nets and workflow nets. AB - Logic Petri nets (LPNs) can describe and analyze batch processing functions and passing value indeterminacy in cooperative systems. Logic Petri workflow nets (LPWNs) are proposed based on LPNs in this paper. Process mining is regarded as an important bridge between modeling and analysis of data mining and business process. Workflow nets (WF-nets) are the extension to Petri nets (PNs), and have successfully been used to process mining. Some shortcomings cannot be avoided in process mining, such as duplicate tasks, invisible tasks, and the noise of logs. The online shop in electronic commerce in this paper is modeled to prove the equivalence between LPWNs and WF-nets, and advantages of LPWNs are presented. PMID- 25821844 TI - MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. AB - OBJECTIVE: To optimize sensitivity and disease specificity of a myelin oligodendrocyte glycoprotein (MOG) antibody assay. METHODS: Consecutive sera (n = 1,109) sent for aquaporin-4 (AQP4) antibody testing were screened for MOG antibodies (Abs) by cell-based assays using either full-length human MOG (FL-MOG) or the short-length form (SL-MOG). The Abs were initially detected by Alexa Fluor goat anti-human IgG (H + L) and subsequently by Alexa Fluor mouse antibodies to human IgG1. RESULTS: When tested at 1:20 dilution, 40/1,109 sera were positive for AQP4-Abs, 21 for SL-MOG, and 180 for FL-MOG. Only one of the 40 AQP4-Ab positive sera was positive for SL-MOG-Abs, but 10 (25%) were positive for FL-MOG Abs (p = 0.0069). Of equal concern, 48% (42/88) of sera from controls (patients with epilepsy) were positive by FL-MOG assay. However, using an IgG1-specific secondary antibody, only 65/1,109 (5.8%) sera were positive on FL-MOG, and AQP4 Ab- positive and control sera were negative. IgM reactivity accounted for the remaining anti-human IgG (H + L) positivity toward FL-MOG. The clinical diagnoses were obtained in 33 FL-MOG-positive patients, blinded to the antibody data. IgG1 Abs to FL-MOG were associated with optic neuritis (n = 11), AQP4-seronegative neuromyelitis optica spectrum disorder (n = 4), and acute disseminated encephalomyelitis (n = 1). All 7 patients with probable multiple sclerosis (MS) were MOG-IgG1 negative. CONCLUSIONS: The limited disease specificity of FL-MOG Abs identified using Alexa Fluor goat anti-human IgG (H + L) is due in part to detection of IgM-Abs. Use of the FL-MOG and restricting to IgG1-Abs substantially improves specificity for non-MS demyelinating diseases. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of serum IgG1- MOG-Abs in AQP4-Ab-negative patients distinguishes non-MS CNS demyelinating disorders from MS (sensitivity 24%, 95% confidence interval [CI] 9%-45%; specificity 100%, 95% CI 88%-100%). PMID- 25821846 TI - Study of research and development processes through Fuzzy Super FRM model and optimization solutions. AB - The aim of this study is to measure resources for R&D (research and development) at the regional level in Romania and also obtain primary data that will be important in making the right decisions to increase competitiveness and development based on an economic knowledge. As our motivation, we would like to emphasize that by the use of Super Fuzzy FRM model we want to determine the state of R&D processes at regional level using a mean different from the statistical survey, while by the two optimization methods we mean to provide optimization solutions for the R&D actions of the enterprises. Therefore to fulfill the above mentioned aim in this application-oriented paper we decided to use a questionnaire and for the interpretation of the results the Super Fuzzy FRM model, representing the main novelty of our paper, as this theory provides a formalism based on matrix calculus, which allows processing of large volumes of information and also delivers results difficult or impossible to see, through statistical processing. Furthermore another novelty of the paper represents the optimization solutions submitted in this work, given for the situation when the sales price is variable, and the quantity sold is constant in time and for the reverse situation. PMID- 25821847 TI - A two-stage method to determine optimal product sampling considering dynamic potential market. AB - This paper develops an optimization model for the diffusion effects of free samples under dynamic changes in potential market based on the characteristics of independent product and presents a two-stage method to figure out the sampling level. The impact analysis of the key factors on the sampling level shows that the increase of the external coefficient or internal coefficient has a negative influence on the sampling level. And the changing rate of the potential market has no significant influence on the sampling level whereas the repeat purchase has a positive one. Using logistic analysis and regression analysis, the global sensitivity analysis gives a whole analysis of the interaction of all parameters, which provides a two-stage method to estimate the impact of the relevant parameters in the case of inaccuracy of the parameters and to be able to construct a 95% confidence interval for the predicted sampling level. Finally, the paper provides the operational steps to improve the accuracy of the parameter estimation and an innovational way to estimate the sampling level. PMID- 25821848 TI - Understanding transferable supply chain lessons and practices to a "high-tech" industry using guidelines from a primary sector industry: a case study in the food industry supply chain. AB - Flexibility and innovation at creating shapes, adapting processes, and modifying materials characterize composites materials, a "high-tech" industry. However, the absence of standard manufacturing processes and the selection of materials with defined properties hinder the configuration of the composites materials supply chain. An interesting alternative for a "high-tech" industry such as composite materials would be to review supply chain lessons and practices in "low-tech" industries such as food. The main motivation of this study is to identify lessons and practices that comprise innovations in the supply chain of a firm in a perceived "low-tech" industry that can be used to provide guidelines in the design of the supply chain of a "high-tech" industry, in this case composite materials. This work uses the case study/site visit with analogy methodology to collect data from a Spanish leading producer of fresh fruit juice which is sold in major European markets and makes use of a cold chain. The study highlights supply base management and visibility/traceability as two elements of the supply chain in a "low-tech" industry that can provide guidelines that can be used in the configuration of the supply chain of the composite materials industry. PMID- 25821849 TI - Salivary fluoride levels after use of high-fluoride dentifrice. AB - The aim of the study was to evaluate salivary fluoride (F) availability after toothbrushing with a high-F dentifrice. Twelve adult volunteers took part in this crossover and blind study. F concentration in saliva was determined after brushing with a high-F dentifrice (5000 ug F/g) or with a conventional F concentration dentifrice (1100 ug F/g) followed by a 15 mL distilled water rinse. Samples of nonstimulated saliva were collected on the following times: before (baseline), and immediately after spit (time = 0) and after 1, 2, 3, 4, 5, 10, 15, 20, 30, 45, 60, 90, and 120 min. F analysis was performed with a fluoride sensitive electrode and the area under curve of F salivary concentration * time (ug F/mL * min(-1)) was calculated. At baseline, no significant difference was found among dentifrices (P > 0.05). After brushing, both dentifrices caused an elevated fluoride level in saliva; however salivary F concentration was significantly higher at all times, when high-F dentifrice was used (P < 0.01). Even after 120 min, salivary F concentration was still higher than the baseline values for both dentifrices (P < 0.001). High-F dentifrice enhanced the bioavailability of salivary F, being an option for caries management in patients with high caries risk. PMID- 25821850 TI - Prospective evaluation of cases of discharge against medical advice in Abuja, Nigeria. AB - BACKGROUND: Discharge against medical advice (DAMA) is a global clinical phenomenon contributing significantly to adverse patients' outcome. Literatures abound on self-discharges in specific medical subpopulations. However, multidisciplinary studies on this subject in our region are few. AIM: To prospectively evaluate cases of DAMA in a wholesale multidisciplinary perspective at Federal Staff Medical Centre, Abuja, and suggest strategies to reduce it. PATIENTS AND METHODS: All consecutive patients who DAMA from our medical centre between June 2013 and May 2014 were included in the study. Data harvested from the standard proforma were analyzed using IBM SPSS version 19.0. RESULTS: We recorded an overall DAMA rate of 2.1%. The majority of the patients were paediatric cases (n = 63, 44.6%) while closed long bone fractures represented the leading diagnosis (n = 35, 24.8%). The most commonly cited reasons for leaving the hospital were financial constraints (n = 46, 32.6%) and seeking alternative therapy (n = 25, 17.7%). CONCLUSION: The DAMA rate in our study is comparable to some urban hospitals elsewhere. However, the leading reasons for this phenomenon are unacceptable in the current medical best practice. Thus, strengthening the Health Insurance Scheme, strict control of traditional medical practices, and focused health education are recommended strategies to reduce DAMA. PMID- 25821852 TI - FPGA techniques based new hybrid modulation strategies for voltage source inverters. AB - This paper corroborates three different hybrid modulation strategies suitable for single-phase voltage source inverter. The proposed method is formulated using fundamental switching and carrier based pulse width modulation methods. The main tale of this proposed method is to optimize a specific performance criterion, such as minimization of the total harmonic distortion (THD), lower order harmonics, switching losses, and heat losses. The proposed method is articulated using fundamental switching and carrier based pulse width modulation methods. Thus, the harmonic pollution in the power system will be reduced and the power quality will be augmented with better harmonic profile for a target fundamental output voltage. The proposed modulation strategies are simulated in MATLAB r2010a and implemented in a Xilinx spartan 3E-500 FG 320 FPGA processor. The feasibility of these modulation strategies is authenticated through simulation and experimental results. PMID- 25821851 TI - Performance of PRP associated with porous chitosan as a composite scaffold for regenerative medicine. AB - This study aimed to evaluate the in vitro performance of activated platelet-rich plasma associated with porous sponges of chitosan as a composite scaffold for proliferation and osteogenic differentiation of human adipose tissue-derived mesenchymal stem cells. The sponges were prepared by controlled freezing (-20, 80, or -196 degrees C) and lyophilization of chitosan solutions (1, 2, or 3% w/v). The platelet-rich plasma was obtained from controlled centrifugation of whole blood and activated with calcium and autologous serum. The composite scaffolds were prepared by embedding the sponges with the activated platelet-rich plasma. The results showed the performance of the scaffolds was superior to that of activated platelet-rich plasma alone, in terms of delaying the release of growth factors and increased proliferation of the stem cells. The best preparation conditions of chitosan composite scaffolds that coordinated the physicochemical and mechanical properties and cell proliferation were 3% (w/v) chitosan and a -20 degrees C freezing temperature, while -196 degrees C favored osteogenic differentiation. Although the composite scaffolds are promising for regenerative medicine, the structures require stabilization to prevent the collapse observed after five days. PMID- 25821853 TI - An extended EPQ-based problem with a discontinuous delivery policy, scrap rate, and random breakdown. AB - In real supply chain environments, the discontinuous multidelivery policy is often used when finished products need to be transported to retailers or customers outside the production units. To address this real-life production shipment situation, this study extends recent work using an economic production quantity- (EPQ-) based inventory model with a continuous inventory issuing policy, defective items, and machine breakdown by incorporating a multiple delivery policy into the model to replace the continuous policy and investigates the effect on the optimal run time decision for this specific EPQ model. Next, we further expand the scope of the problem to combine the retailer's stock holding cost into our study. This enhanced EPQ-based model can be used to reflect the situation found in contemporary manufacturing firms in which finished products are delivered to the producer's own retail stores and stocked there for sale. A second model is developed and studied. With the help of mathematical modeling and optimization techniques, the optimal run times that minimize the expected total system costs comprising costs incurred in production units, transportation, and retail stores are derived, for both models. Numerical examples are provided to demonstrate the applicability of our research results. PMID- 25821854 TI - Integrated DEA models and grey system theory to evaluate past-to-future performance: a case of Indian electricity industry. AB - The growth of economy and population together with the higher demand in energy has created many concerns for the Indian electricity industry whose capacity is at 211 gigawatts mostly in coal-fired plants. Due to insufficient fuel supply, India suffers from a shortage of electricity generation, leading to rolling blackouts; thus, performance evaluation and ranking the industry turn into significant issues. By this study, we expect to evaluate the rankings of these companies under control of the Ministry of Power. Also, this research would like to test if there are any significant differences between the two DEA models: Malmquist nonradial and Malmquist radial. Then, one advance model of MPI would be chosen to see these companies' performance in recent years and next few years by using forecasting results of Grey system theory. Totally, the realistic data 14 are considered to be in this evaluation after the strict selection from the whole industry. The results found that all companies have not shown many abrupt changes on their scores, and it is always not consistently good or consistently standing out, which demonstrated the high applicable usability of the integrated methods. This integrated numerical research gives a better "past-present-future" insights into performance evaluation in Indian electricity industry. PMID- 25821855 TI - Association between polymorphism of interleukin-1 beta and interleukin-1 receptor antagonist gene and asthma risk: a meta-analysis. AB - BACKGROUND: Asthma is a complex polygenic disease in which gene-environment interactions are important. A number of studies have investigated the polymorphism of IL-1beta -511C/T and IL-1RA genes in relation to asthma susceptibility in different populations. However, the results of individual studies have been inconsistent. Accordingly, we conducted a comprehensive meta analysis to investigate the association between the IL-1beta -511C/T and IL-1RA polymorphism and asthma risk. METHODS: Data were collected from the following electronic databases: Pub Med, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), ISI Web of Knowledge, and Google Scholar Search databases with the last report up to July 2013. Finally, 15 studies were included in our meta-analysis. We summarized the data on the association between IL-1beta -511C/T and IL-1RA polymorphism and risk of asthma in the overall population and performed subgroup analyses by ethnicity, mean of age, and source of controls. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the associations between IL-1beta -511C/T and IL-1RA polymorphism and asthma risk. Statistical analysis was performed with Review Manager 5.1. RESULTS: A total of 15 case-control studies were included in the meta-analysis of IL-1beta -511C/T (1,385 cases and 1,964 controls) and IL-1RA (2,800 cases and 6,359 controls) genotypes. No association was found between IL 1beta -511C/T polymorphism and asthma risk (dominant model: OR = 1.11, 95% CI: 0.99-1.25, P = 0.07, P Heterogeneity = 0.06; recessive model: OR = 1.04, 95% CI: 0.91-1.20, P = 0.55, P Heterogeneity = 0.11). Subgroup analysis based on ethnicity (Asian and Caucasian), source of controls (population-based controls and hospital-based controls), and mean of age (adulthood and childhood) did not present any significant association. The overall results showed that the IL-1RA polymorphism was related to an increased risk of asthma (homozygote model: OR = 1.32, 95% CI: 1.12-1.56, P = 0.0009, P Heterogeneity = 0.87; recessive model: OR = 1.39, 95% CI: 1.18-1.63, P = 0.0001, P Heterogeneity = 0.82). Similar results were found in the subgroup analyses by ethnicity, mean of age, and source of controls. Sensitivity analysis did not perturb the results. CONCLUSIONS: This meta-analysis provided strong evidence that the IL-1RA polymorphism was a risk factor of asthma, especially in Caucasian populations. However, no association was found for IL-1beta -511C/T genotype carriers. Larger scale studies are needed for confirmation. PMID- 25821856 TI - HT-Paxos: high throughput state-machine replication protocol for large clustered data centers. AB - Paxos is a prominent theory of state-machine replication. Recent data intensive systems that implement state-machine replication generally require high throughput. Earlier versions of Paxos as few of them are classical Paxos, fast Paxos, and generalized Paxos have a major focus on fault tolerance and latency but lacking in terms of throughput and scalability. A major reason for this is the heavyweight leader. Through offloading the leader, we can further increase throughput of the system. Ring Paxos, Multiring Paxos, and S-Paxos are few prominent attempts in this direction for clustered data centers. In this paper, we are proposing HT-Paxos, a variant of Paxos that is the best suitable for any large clustered data center. HT-Paxos further offloads the leader very significantly and hence increases the throughput and scalability of the system, while at the same time, among high throughput state-machine replication protocols, it provides reasonably low latency and response time. PMID- 25821857 TI - A novel ontology approach to support design for reliability considering environmental effects. AB - Environmental effects are not considered sufficiently in product design. Reliability problems caused by environmental effects are very prominent. This paper proposes a method to apply ontology approach in product design. During product reliability design and analysis, environmental effects knowledge reusing is achieved. First, the relationship of environmental effects and product reliability is analyzed. Then environmental effects ontology to describe environmental effects domain knowledge is designed. Related concepts of environmental effects are formally defined by using the ontology approach. This model can be applied to arrange environmental effects knowledge in different environments. Finally, rubber seals used in the subhumid acid rain environment are taken as an example to illustrate ontological model application on reliability design and analysis. PMID- 25821858 TI - A seed-based plant propagation algorithm: the feeding station model. AB - The seasonal production of fruit and seeds is akin to opening a feeding station, such as a restaurant. Agents coming to feed on the fruit are like customers attending the restaurant; they arrive at a certain rate and get served at a certain rate following some appropriate processes. The same applies to birds and animals visiting and feeding on ripe fruit produced by plants such as the strawberry plant. This phenomenon underpins the seed dispersion of the plants. Modelling it as a queuing process results in a seed-based search/optimisation algorithm. This variant of the Plant Propagation Algorithm is described, analysed, tested on nontrivial problems, and compared with well established algorithms. The results are included. PMID- 25821859 TI - A study of the strategic alliance for EMS industry: the application of a hybrid DEA and GM (1, 1) approach. AB - Choosing a partner is a critical factor for success in international strategic alliances, although criteria for partner selection vary between developed and transitional markets. This study aims to develop effective methods to assist enterprise to measure the firms' operation efficiency, find out the candidate priority under several different inputs and outputs, and forecast the values of those variables in the future. The methodologies are constructed by the concepts of Data Envelopment Analysis (DEA) and grey model (GM). Realistic data in four consecutive years (2009-2012) a total of 20 companies of the Electronic Manufacturing Service (EMS) industry that went public are completely collected. This paper tries to help target company-DMU1-to find the right alliance partners. By our proposed approach, the results show the priority in the recent years. The research study is hopefully of interest to managers who are in manufacturing industry in general and EMS enterprises in particular. PMID- 25821860 TI - Royal Jelly and its dual role in TNBS colitis in mice. AB - Royal Jelly (RJ) is widely consumed in diets throughout the world due to its beneficial effects: antioxidant, antitumor and anti-inflammatory. We have investigated the role of RJ in the development of TNBS colitis in mice. Colitis was induced by a rectal instillation of TNBS at 0.1 mL per mouse. Intestine samples of the animals orally treated with RJ (100, 150, and 200 mg/kg) were collected for antioxidant assays (GSH and GSH-Px), proinflammatory protein quantification (COX-2 and NF-kappaB), and histological analyses. RJ 100 mg/kg maintained GSH levels and increased the activity of GSH-Px, downregulated key inflammatory mediators (COX-2 and NF-kappaB), and decreased the lesions caused by TNBS as shown by the histological analyses. In conclusion, RJ showed anti inflammatory and antioxidant properties in experimental colitis, resulting in the amelioration of the macroscopic and histological analyses. These results corroborate with the RJ supplementation in diets. PMID- 25821861 TI - Are We There Yet? Feasibility of Continuous Stress Assessment via Wireless Physiological Sensors. AB - Stress can lead to headaches and fatigue, precipitate addictive behaviors (e.g., smoking, alcohol and drug use), and lead to cardiovascular diseases and cancer. Continuous assessment of stress from sensors can be used for timely delivery of a variety of interventions to reduce or avoid stress. We investigate the feasibility of continuous stress measurement via two field studies using wireless physiological sensors - a four-week study with illicit drug users (n = 40), and a one-week study with daily smokers and social drinkers (n = 30). We find that 11+ hours/day of usable data can be obtained in a 4-week study. Significant learning effect is observed after the first week and data yield is seen to be increasing over time even in the fourth week. We propose a framework to analyze sensor data yield and find that losses in wireless channel is negligible; the main hurdle in further improving data yield is the attachment constraint. We show the feasibility of measuring stress minutes preceding events of interest and observe the sensor-derived stress to be rising prior to self-reported stress and smoking events. PMID- 25821862 TI - Editorial: medicine and dentistry: different entities? PMID- 25821863 TI - More conservative dentistry: clinical long-term results of direct composite resin restorations. AB - Current treatment protocols and recent developments in composite resin technology allow for extended indication of direct composite resin restorations. This article presents clinical longterm observations of direct composite resin restorations indicated for primary and replacement therapy, repair restorations, direct crowns, and composite buildups for the correction of tooth form. PMID- 25821865 TI - [Rare diseases on the trail--the registry for refractory sprue]. PMID- 25821866 TI - [The clinically and scientifically active doctors--current status and perspectives]. PMID- 25821867 TI - [Joint opinion of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the German Society for Internal Medicine (DGIM) to Daclatasvir-benefit assessment according to S 35a SGB V the G-BA]. PMID- 25821868 TI - [Statement of the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) for teduglutide-benefit assessment according to S 35a SGB V the G BA]. PMID- 25821869 TI - Metabonomics: methods and protocols: preface. PMID- 25821871 TI - Postobstructive diuresis: pay close attention to urinary retention. AB - OBJECTIVE: To educate primary health care professionals about the diagnosis and treatment of postobstructive diuresis (POD), a rare but potentially lethal complication associated with the relief of urinary obstructions. SOURCES OF INFORMATION: The main concepts and clinical evidence reviewed in this article were derived from a literature search of PubMed and Google Scholar. Expert opinion was used to supplement recommendations in areas with little evidence. MAIN MESSAGE: Urinary retention is a frequently encountered presentation seen by all physicians. Most family physicians are comfortable treating these patients, initiating investigations, and organizing appropriate follow-up. This article reviews a rare but potentially lethal complication known as POD. Postobstructive diuresis is a polyuric response initiated by the kidneys after the relief of a substantial bladder outlet obstruction. In severe cases this condition can become pathologic, resulting in dehydration, electrolyte imbalances, and death if not adequately treated. Primary care physicians should be familiar with this potential clinical entity, especially as they are generally the first to encounter and treat these patients. CONCLUSION: Physicians aware of POD will be able to identify patients at risk and arrange the appropriate monitoring after relieving a urinary obstruction. Early diagnosis and treatment of pathologic POD will prevent mortality. PMID- 25821870 TI - Targeted temperature management after out-of-hospital cardiac arrest: who, when, why, and how? AB - OBJECTIVE: To provide a succinct review of the evidence, framed for the emergency department clinician, for the application of targeted temperature management (TTM) for patients after out-of-hospital cardiac arrest (OHCA). SOURCES OF INFORMATION: MEDLINE, EMBASE, and the Cochrane database were searched for prospective and retrospective studies relevant to the indications of TTM, optimal timing of TTM initiation, method of cooling, and target temperature. MAIN MESSAGE: Two prospective interventional trials reported improved neurologically intact survival with the use of TTM (goal temperatures of 32 degrees C to 34 degrees C) compared with no temperature management in comatose OHCA patients with shockable initial cardiac arrest rhythms. A more recent, high-quality randomized controlled trial including OHCA patients with shockable and nonshockable initial rhythms compared TTM at 33 degrees C versus TTM at 36 degrees C. Despite the study being well powered, superiority of one target temperature over the other was not demonstrated. The benefit of TTM in patients with initial nonshockable rhythms is not clear; however, some observational studies have suggested benefit. There is no evidence that any particular method of temperature regulation is superior. The relationship between time and TTM initiation has not been well established. CONCLUSION: Targeted temperature management, with a target temperature between 32 degrees C and 36 degrees C, as a component of comprehensive critical care is a beneficial intervention for comatose patients with return of spontaneous circulation after OHCA. PMID- 25821872 TI - The MUN Med Gateway Project: marrying medical education and social accountability. AB - PROBLEM ADDRESSED: Access to a continuum of care from a family physician is an essential component of health and well-being; however, refugees have particular barriers in accessing medical care. OBJECTIVE OF PROGRAM: To provide access to family physicians and continuity of care for newly arrived refugees; to provide opportunities for medical students to practise cross-cultural health care; and to mentor medical students in advocacy for underserved populations. PROGRAM DESCRIPTION: The MUN Med Gateway Project, based at Memorial University of Newfoundland in St John's, is a medical student initiative that partners with the local refugee settlement agency to provide health care for new refugees to the province. Medical students conduct in-depth medical histories, with provision of some basic physical screening, while working through an interpreter with supervision by a family doctor and settlement public health nurse. Each patient or family is matched with a family physician. CONCLUSION: The project's adaptation of student-run clinics, which connects refugees with the existing mainstream medical system, has been an overwhelming success, making it a model for community action as an educational strategy. PMID- 25821873 TI - Narcotic tapering in pregnancy using long-acting morphine: an 18-month prospective cohort study in northwestern Ontario. AB - OBJECTIVE: To document the management of and outcomes for patients receiving narcotic replacement and tapering with long-acting morphine preparations during pregnancy. DESIGN: A prospective cohort study over 18 months. SETTING: Northwestern Ontario. PARTICIPANTS: All 600 births at Meno Ya Win Health Centre in Sioux Lookout, Ont, from January 1, 2012, to June 30, 2013, including 166 narcotic-exposed pregnancies. INTERVENTION: Narcotic replacement and tapering of narcotic use with long-acting morphine preparations. MAIN OUTCOME MEASURES: Prenatal management of maternal narcotic use, incidence of neonatal abstinence syndrome, and other neonatal outcomes. RESULTS: The incidence of neonatal abstinence syndrome fell significantly to 18.1% of pregnancies exposed to narcotics (from 29.5% in a previous 2010 study, P = .003) among patients using narcotic replacement and tapering with long-acting morphine preparations. Neonatal outcomes were otherwise equivalent to those of the nonexposed pregnancies. CONCLUSION: In many patients, long-acting morphine preparations can be safely used and tapered in pregnancy, with a subsequent decrease in observed neonatal withdrawal symptoms. PMID- 25821874 TI - Community-wide measures of wellness in a remote First Nations community experiencing opioid dependence: evaluating outpatient buprenorphine-naloxone substitution therapy in the context of a First Nations healing program. AB - OBJECTIVE: To document the development of unique opioid-dependence treatment in remote communities that combines First Nations healing strategies and substitution therapy with buprenorphine-naloxone. DESIGN: Quantitative measurements of community wellness and response to community-based opioid dependence treatment. SETTING: Remote First Nations community in northwestern Ontario. PARTICIPANTS: A total of 140 self-referred opioid-dependent community members. INTERVENTION: Community-developed program of First Nations healing, addiction treatment, and substitution therapy. MAIN OUTCOME MEASURES: Community wide measures of wellness: number of criminal charges, addiction-related medical evacuations, child protection agency cases, school attendance, and attendance at community events. RESULTS: The age-adjusted adult rate of opioid-dependence treatment was 41%. One year after the development of the in-community healing and substitution therapy program for opioid dependence, police criminal charges had fallen by 61.1%, child protection cases had fallen by 58.3%, school attendance had increased by 33.3%, and seasonal influenza immunizations had dramatically gone up by 350.0%. Attendance at community events is now robust, and sales at the local general store have gone up almost 20%. CONCLUSION: Community-wide wellness measures have undergone dramatic public health changes since the development of a First Nations healing program involving opioid substitution therapy with buprenorphine-naloxone. Funding for such programs is ad hoc and temporary, and this threatens the survival of the described program and other such programs developing in this region, which has been strongly affected by an opioid dependence epidemic. PMID- 25821875 TI - Busting top trauma myths. Exploring best practices for prehospital trauma care. AB - Evidence-based medicine will continually change the paradigm in which emergency medicine is practiced. Fifteen years ago tourniquets were a last resort and often considered a guaranteed way to lose a limb; today they are a gold standard in hemorrhage control. Believing in, and having practiced, medicine we later learn to be false doesn't make someone a bad provider, nor does it make them wrong. It simply means emergency medicine and EMS will continue to develop as a profession, and our body of evidence will continue to grow as we learn more about prehospital care. As we prepare to retire MAST, backboards and lidocaine, and realize the golden hour as a concept rather than a definitive 60 minutes, it's important to keep a critical eye out for the next intervention that truly will help patients during their prehospital care. PMID- 25821876 TI - Earlier than too late: stopping stress & suicide among emergency personnel. First responders keep killing themselves--why is that, and what can we do about it? PMID- 25821877 TI - The state of pediatric transport. PMID- 25821878 TI - A strong test of the maximum entropy theory of ecology. AB - The maximum entropy theory of ecology (METE) is a unified theory of biodiversity that predicts a large number of macroecological patterns using information on only species richness, total abundance, and total metabolic rate of the community. We evaluated four major predictions of METE simultaneously at an unprecedented scale using data from 60 globally distributed forest communities including more than 300,000 individuals and nearly 2,000 species.METE successfully captured 96% and 89% of the variation in the rank distribution of species abundance and individual size but performed poorly when characterizing the size-density relationship and intraspecific distribution of individual size. Specifically, METE predicted a negative correlation between size and species abundance, which is weak in natural communities. By evaluating multiple predictions with large quantities of data, our study not only identifies a mismatch between abundance and body size in METE but also demonstrates the importance of conducting strong tests of ecological theories. PMID- 25821879 TI - Orange-colored Russell bodies by Papanicolaou stain. PMID- 25821880 TI - Harry A. Fozzard, MD: 1931-2014. PMID- 25821882 TI - Building student community in a hybrid program. AB - The concept of student community has been shown to enhance learning, empower students, and increase engagement in the learning process. An occupational therapy program transformed classroom-based learning to a hybrid platform with over 70% of the course content online and expanded from one to two learning sites. Based on faculty concerns about occupational therapy students' experience of belonging to a community, this study compared student-perceived sense of community in the first and final didactic semesters of a hybrid Master's program. Using the Classroom and School Community Inventory and a Checklist of 24 Points of Contact, faculty found over 90% of students reported a sense of community with no significant differences from start to finish of the didactic program, or between learning sites. Furthermore, students reported informal, out-of-classroom interactions with colleagues, group assignments, and face-to-face classroom sessions as the strongest points of contact contributing to a sense of student community. PMID- 25821881 TI - Exploring the complexity of the academic fieldwork coordinator role. AB - A nation-wide survey was conducted of occupational therapy and occupational therapy assistant academic fieldwork coordinators (AFWCs) to describe demographic characteristics and tasks of the role. From the data, 10 clusters of role tasks of the AFWC are described. AFWCs view the position as a final career goal although the majority of respondents reported 5 years or less experience. Administrative assistant support and hours dedicated to fieldwork tasks are higher at the professional level than for occupational therapy assistant AFWCs. AFWCs reported difficulty accomplishing tasks in a 40-h work week and limited time for research and scholarship. Recommendations are provided for recruitment and retention through development of a systematic training program and establishment of a national fieldwork education research agenda. PMID- 25821883 TI - The nature, perception, and impact of e-mentoring on post-professional occupational therapy doctoral students. AB - This retrospective study employed a descriptive, quantitative design to investigate the nature, perception, and impact of the e-mentoring experiences of 29 graduates of an online post-professional Doctor of Occupational Therapy (OTD) program. Study results highlight positive features of electronic mentoring (e mentoring); how multi-modal e-mentoring supports the accessibility needs of participants; and students' preferences to engage in real-time e-mentoring communication by web camera or telephone, supplemented with e-mail. E-mentoring positively impacted the professional development of participants during and after the online OTD program. As online education continues to grow, a better understanding of e-mentoring will assist in providing exemplary education to meet the needs of adult learners. PMID- 25821884 TI - Candidates' and interviewers' perceptions of multiple-mini interviews for admission to an occupational therapy professional program. AB - Multiple-Mini Interviews (MMIs) were used to assess professional attributes of candidates seeking admission to an occupational therapy professional entry-level master's program. Candidates and interviewers were invited to complete a questionnaire comprised of quantitative and open-ended questions following the MMIs. The MMIs were perceived to be fair, enjoyable, and capable of capturing professional attributes. Descriptive analysis of candidates' data revealed perceptions regarding logistics, interview station content, process, and interviewers. Interviewers commented on the positive and challenging aspects of the scenarios and the MMI process. Admissions committees need to consider several logistical, content, and process issues when designing and implementing MMIs as a selection tool. PMID- 25821885 TI - Interprofessional educational experience to assist in student readiness toward neurorehabilitation. AB - Occupational and physical therapy professionals are natural partners in neurorehabilitation especially in the acute stages of recovery. To enhance student-learning experiences from both disciplines, we have developed an interprofessional (IP) learning unit that was embedded in neurorehabilitation tracks of each respective program. The primary goal of this project was to examine interprofessional attitudes and perception toward interprofessional learning and practice. A total of 117 occupational therapy (53) and physical therapy (64) students completed an IP case-based learning module with the goal of developing an IP care plan typically seen in neurorehabilitation. Using a sequential explanatory mixed methods design, we collected data pre- and postintervention using the Readiness for Interprofessional Learning Survey (RIPLS). We also utilized a postintervention questionnaire and focus groups intended to solicit information regarding IP competencies. At pretest, students had high ratings on the RIPLS that led to minimal changes at posttest (p = .157). However, common threads from the questionnaire and focus groups showed positive effects on student learning and attitudes toward interprofessionalism. Students reported positive experiences with the IP module. An IP case-based educational module has the potential to facilitate professional development and readiness for future IP practice. Students from different disciplines appreciate the value of IP education (IPE) in reinforcing their professional identity and understanding the professional contributions of others. Our findings are consistent with literature on best practices for IPE. PMID- 25821886 TI - Bridging the gap: evaluation of a pilot project to facilitate use of psychosocial strategies across an occupational therapy curriculum. AB - The integration of psychosocial strategies into pediatric and physical disabilities coursework presents an issue of importance to advancing the outcomes for both occupational therapy education and practice. After curriculum mapping and modification to course content, a retrospective student survey and review of educational outcomes were undertaken in one curriculum. The programmatic formative evaluation results demonstrated that all students felt moderately prepared to use cognitive-behavioral strategies in their future practices, preferring behavioral strategies over cognitive strategies for changing client thinking. Implications for the importance of integration of psychosocial content across curricula and for future study of effective teaching methods within classroom learning activities and fieldwork are included. PMID- 25821887 TI - The collaborative model of fieldwork education: a blueprint for group supervision of students. AB - Historically, occupational therapists have used a traditional one-to-one approach to supervision on fieldwork. Due to the impact of managed care on health-care delivery systems, a dramatic increase in the number of students needing fieldwork placement, and the advantages of group learning, the collaborative supervision model has evolved as a strong alternative to an apprenticeship supervision approach. This article builds on the available research to address barriers to model use, applying theoretical foundations of collaborative supervision to practical considerations for academic fieldwork coordinators and fieldwork educators as they prepare for participation in group supervision of occupational therapy and occupational therapy assistant students on level II fieldwork. PMID- 25821888 TI - Instructing occupational therapy students in use of theory to guide practice. AB - We investigated the effectiveness of instructing students in occupational therapy practice models to facilitate their competence in applying theory in clinical practice. Course evaluation data were gathered and analyzed retrospectively. We found that perceived understanding of theory and its application improved significantly after instruction. The students' perceived competence in theory use predicted their level of confidence in their assessment and intervention skills. We concluded that emphasis on instruction of students in the use of occupational therapy practice models could be a viable method of improving practice through consistent use of theoretical guidelines in clinical reasoning. PMID- 25821889 TI - The entry-level occupational therapy clinical doctorate: advantages, challenges, and international issues to consider. AB - Internationally, occupational therapy education has gone through several paradigm shifts during the last few decades, moving from certificate to diploma to bachelors to masters and now in some instances to clinical doctorate as the entry level professional credential to practice. In the United States there is a recommendation under consideration by the American Occupational Therapy Association (AOTA) that by 2025, all occupational therapy university programs will move to the clinical doctorate level. It should be noted, however, that the AOTA Board can only make recommendations and it is the Accreditation Council for Occupational Therapy Education (ACOTE) who has regulatory authority to approve such a change. What are the potential implications for the profession, our clients, and funders of occupational therapy services? What are the primary drivers for the move towards the clinical doctorate being the educational entry point? Is the next step in the evolution of occupational therapy education globally a shift to the entry-level clinical doctorate? This article reviews current literature and discusses issues about the occupational therapy entry level clinical doctorate. The published evidence available about the occupational therapy entry-level clinical doctorate is summarized and the perceived or frequently cited pros and cons of moving to the clinical doctorate as the singular entry point to occupational therapy practice are considered. The potential impacts of the introduction of the clinical doctorate as the entry-to practice qualification across the United States on the occupational therapy community internationally will be briefly discussed. If the United States moves toward the entry-level clinical doctorate as the only educational starting point for the profession, will other jurisdictions follow suit? Further discourse and investigation of this issue both inside and outside of the United States is needed so that informed decisions can be made. PMID- 25821890 TI - Teaching interprofessional collaboration: using online education across institutions. AB - Interdisciplinary courses among students in occupational therapy, physical therapy, and speech-language pathology are important for addressing teamwork, communication, and understanding of professional roles, especially in pre-service training for early intervention and school-based practice where collaboration is essential. Although interprofessional education (IPE) as a part of higher education in the health sciences has been strongly encouraged, IPE courses are difficult to schedule and implement. This article discusses the challenges of developing and delivering two IPE courses in an online format, specifically the innovation that addresses logistics, time factors, and social presence for the IPE courses across two institutions. PMID- 25821892 TI - Capstone projects as scholarship of application in entry-level occupational therapy education. AB - Capstone projects are integrative student learning experiences used in higher education. This article describes the value and merit of capstone projects as scholarship of application within an entry-level occupational therapy education program. The capstone process is outlined and roles and responsibilities of student, faculty members, and community mentors described. Summative curricular evaluation from 5 years of capstone projects indicated that project characteristics and objectives aligned with the theory and desired outcomes of applied scholarship in the areas of student learning, faculty practice and development, and community service. Challenges identified can further inform development of the capstone experience in occupational therapy education. PMID- 25821891 TI - Process-oriented guided-inquiry learning: a natural fit for occupational therapy education. AB - After a brief review of the major group cooperative learning strategies, this article presents the format and use of Process-Oriented Guided-Inquiry Learning (POGIL) as a recommended teaching strategy for occupational therapy classes. This recommendation is based upon evidence of effectiveness of this strategy for enhancing critical thinking, content retention, and teamwork. Strategies for learning the process and suggestions for its use are based upon literature evidence and the authors' experiences with this strategy over 4 years in a class on evidence-based practice. PMID- 25821893 TI - Zn-catalyzed enantio- and diastereoselective formal [4 + 2] cycloaddition involving two electron-deficient partners: asymmetric synthesis of piperidines from 1-azadienes and nitro-alkenes. AB - We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners. PMID- 25821894 TI - Clinical characterization of asymptomatic or minimally symptomatic young patients showing signs compatible with dry eye: a pilot study. AB - PURPOSE: To evaluate and characterize the clinical profile of young asymptomatic or minimally symptomatic patients without diagnosis of dry eye but showing signs compatible with dry eye syndrome (DES). METHODS: Prospective study including a total of 50 consecutive subjects with ages ranging from 18 to 40 years that were identified as asymptomatic or minimally symptomatic by means of the Ocular Surface Disease Index (OSDI) (score of <22). In all patients, a complete battery of tests for the diagnosis of DES was performed including the evaluation of the tear film break-up time (TFBUT), the level of corneal and conjunctival staining, and the eyelid and Meibomian morphology. RESULTS: The OSDI score was significantly higher in women than in men (median: 12.5 vs. 5.3, P=0.01). Low grades of ocular surface staining, dysfunction of Meibomian gland expression, and alteration of quality of Meibomian secretions were observed in 56%, 58%, and 84% of eyes, respectively. More eyes with some dysfunction of Meibomian gland expressibility had a TFBUT less than 5 sec (P=0.033). A statistically significant difference in the OSDI score was found between patients with and without systemic allergies (P=0.036) and between male and female (P=0.01). Likewise, the OSDI score was significantly higher in those women wearing contact lenses compared with those not wearing them (P=0.012). CONCLUSIONS: Asymptomatic or minimally symptomatic young subjects may present low grades of clinical signs compatible with DES, with a trend to more symptomatology in women and allergic patients. These outcomes should be confirmed in future studies with larger samples. PMID- 25821895 TI - Biotransformation of Curcumenol by Mucor polymorphosporus. AB - Biocatalysis of curcumenol (1) was performed by Mucor polymorphosporus AS 3.3443. Six metabolites including five new compounds were obtained, and their structures were elucidated as 10beta-hydroxy-9,10-dihydrocurcumenol (2), 2beta hydroxycurcumenol (3), 15-hydroxycurcumenol (4), 12-hydroxycurcumenol (5), 1 hydroxy-4alphaH-guai-1,6,9-triene-2,8-dione (6), and 5-hydroxycarbonyl-1-oxo-3,7 dimethylindane (7) by spectroscopic analysis. M. polymorphosporus catalyzed unusual degradation and rearrangement reactions to generate a ring-contracted metabolite (7) of curcumenol (1). Curcumenol (1) and metabolites 4-7 exhibited inhibitory activities against lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages, with 7 exhibiting more potent activity than curcumenol. PMID- 25821896 TI - The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats. AB - The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-alpha) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-alpha, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues. PMID- 25821897 TI - Molecular selectivity of graphene-enhanced Raman scattering. AB - Graphene-enhanced Raman scattering (GERS) is a recently discovered Raman enhancement phenomenon that uses graphene as the substrate for Raman enhancement and can produce clean and reproducible Raman signals of molecules with increased signal intensity. Compared to conventional Raman enhancement techniques, such as surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS), in which the Raman enhancement is essentially due to the electromagnetic mechanism, GERS mainly relies on a chemical mechanism and therefore shows unique molecular selectivity. In this paper, we report graphene-enhanced Raman scattering of a variety of different molecules with different molecular properties. We report a strong molecular selectivity for the GERS effect with enhancement factors varying by as much as 2 orders of magnitude for different molecules. Selection rules are discussed with reference to two main features of the molecule, namely its molecular energy levels and molecular structures. In particular, the enhancement factor involving molecular energy levels requires the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies to be within a suitable range with respect to graphene's Fermi level, and this enhancement effect can be explained by the time-dependent perturbation theory of Raman scattering. The enhancement factor involving the choice of molecular structures indicates that molecular symmetry and substituents similar to that of the graphene structure are found to be favorable for GERS enhancement. The effectiveness of these factors can be explained by group theory and the charge-transfer interaction between molecules and graphene. Both factors, involving the molecular energy levels and structural symmetry of the molecules, suggest that a remarkable GERS enhancement requires strong molecule-graphene coupling and thus effective charge transfer between the molecules and graphene. These conclusions are further experimentally supported by the change of the UV visible absorption spectra of molecules when in contact with graphene and these conclusions are theoretically corroborated by first-principles calculations. These research findings are important for gaining fundamental insights into the graphene-molecule interaction and the chemical mechanism in Raman enhancement, as well as for advancing the role of such understanding both in guiding chemical and molecule detection applications and in medical and biological technology developments. PMID- 25821899 TI - Polymer Stabilized Fe3O4-Graphene as an Amphiphilic Drug Carrier for Thermo Chemotherapy of Cancer. AB - In light of the growing interest in the search for cheap and effective solutions for cancer treatment, we report a simple one pot synthesis of polymer stabilized iron oxide-graphene (PIG) that could be realized on a large scale. The structural (Fe3O4 particle size of ~11 nm), functional (various oxygen containing moieties), and magnetic (moment of ~43 emu/g) properties of PIG are explored using various characterization techniques for possible biomedical applications. PIG shows good colloidal stability and is biocompatible even at higher concentrations (2.5 mg/mL) by virtue of cross-linking polymers. The biocompatibility of the composite has been tested using HeLa cell lines by computing the percentage of the reactive oxygen species through the 2,7-dichlorofluorescein (DCF) intensity level. PIG has the ability to load and release both hydrophobic and hydrophilic drugs with a good loading efficiency and capacity. The dug loading efficiency of PIG is measured to be ~87% and ~91% for doxorubicin (DOX) and paclitaxel (PTXL), respectively. Under an AC magnetic field, superparamagnetic PIG (2.5 mg/mL) takes less than 16 min to reach the stable hyperthermia temperature, suggesting it as a good anticancer material. A time-dependent cellular uptake of doxorubicin conjugated PIG has been studied to optimize the parameters for thermo chemotherapy of cancer. The synergetic effect of both the drug and hyperthermia is observed in the killing of the cancerous cells, verified by computing the cell apoptotic population using a flow cytometer. However, it has been noticed that, even in the absence of chemotherapy, PIG shows good antiproliferative activity with thermotherapy alone. PMID- 25821898 TI - Validation of Diagnostic Groups Based on Health Care Utilization Data Should Adjust for Sampling Strategy. AB - OBJECTIVE: Valid measurement of outcomes such as disease prevalence using health care utilization data is fundamental to the implementation of a "learning health system." Definitions of such outcomes can be complex, based on multiple diagnostic codes. The literature on validating such data demonstrates a lack of awareness of the need for a stratified sampling design and corresponding statistical methods. We propose a method for validating the measurement of diagnostic groups that have: (1) different prevalences of diagnostic codes within the group; and (2) low prevalence. METHODS: We describe an estimation method whereby: (1) low-prevalence diagnostic codes are oversampled, and the positive predictive value (PPV) of the diagnostic group is estimated as a weighted average of the PPV of each diagnostic code; and (2) claims that fall within a low prevalence diagnostic group are oversampled relative to claims that are not, and bias-adjusted estimators of sensitivity and specificity are generated. APPLICATION: We illustrate our proposed method using an example from population health surveillance in which diagnostic groups are applied to physician claims to identify cases of acute respiratory illness. CONCLUSIONS: Failure to account for the prevalence of each diagnostic code within a diagnostic group leads to the underestimation of the PPV, because low-prevalence diagnostic codes are more likely to be false positives. Failure to adjust for oversampling of claims that fall within the low-prevalence diagnostic group relative to those that do not leads to the overestimation of sensitivity and underestimation of specificity. PMID- 25821900 TI - Development and evaluation of a database of dietary bioaccumulation test data for organic chemicals in fish. AB - Dietary bioaccumulation tests for fish have been conducted for about 40 years. Standardized test guidance has recently been developed. Test metrics of primary scientific and regulatory interest are the whole body depuration rate constant (kT), whole body growth corrected depuration rate constant (kTg), and corresponding chemical half-lives (t1/2 and t1/2g), dietary chemical absorption efficiency (AE), and biomagnification factor (BMF). A database of 3032 measurement end points for 477 discrete organic chemicals including 964 half lives, 1199 AEs and 869 BMFs from 19 species (primarily trout and carp) was developed from the literature. Biological properties (e.g., organism weight, lipid content) and exposure conditions (e.g., temperature, feeding rate, dietary lipid content, exposure duration) are documented. Test chemicals range in molar mass from 120 to 1423 g.mol(-1) with log octanol-water partition coefficients (KOW) ranging from 0.8 to 14.3; 50% of the database entries are for polychlorinated biphenyls. The measured end points are derived from various protocols and sources of variability are described. The data are evaluated and categorized using proposed data quality (confidence) criteria derived from the standardized test protocol providing initial guidance for data users. Half-lives range from 0.13 to 2600 days; however, approximately 54% have an identifiable source of uncertainty. The data suggest that chemicals absorbed from the gastrointestinal tract with a log KOW >= ~5 and at least as high as ~9 have biomagnification potential in fish. A mechanistic bioaccumulation model is compared to the measured data and used to illustrate the influence of growth and biotransformation rates on the BMF. PMID- 25821901 TI - Copper(II)-catalyzed direct dioxygenation of alkenes with air and N hydroxyphthalimide: synthesis of beta-keto-N-alkoxyphthalimides. AB - Copper(II)-catalyzed direct dioxygenation of alkenes using air and a simple N hydroxyphthalimide leading to beta-keto-N-alkoxyphthalimides has been developed. The reaction system is mild, efficient, and effective at room temperature with broad substrate scope and substantial steric hindrance. The radical-trapping and (18)O-labeling experiments have been demonstrated. PMID- 25821902 TI - Why have we not yet developed a simple blood test for TBI? AB - In recent years, traumatic brain injury (TBI) has emerged as a rapidly growing public health challenge. Annually, approximately 1.7 million people will sustain a TBI in the USA and WHO has named TBI the leading cause of death and disability in young adults worldwide, predicting it will become the third leading cause of death in the general population by 2020. The medical community currently relies on clinical examination and various neuroimaging modalities for the diagnosis of TBI; however, these methodologies are often confounded by altered patient mental status and are particularly poor at identifying mild-to-moderate injury. Despite decades of basic and clinical research, and the identification of hundreds of biochemical markers, presently there is no blood test to objectively assess TBI severity. Recent work suggests treatment-induced variance in the brain's glymphatic clearance may be responsible for the breakdown between biomarker discovery and clinical translation. PMID- 25821903 TI - Ventilator-associated pneumonia prevention: the issue is the control of oropharyngeal and gut overgrowth. PMID- 25821904 TI - Ventilator-associated pneumonia prevention: response to Silvestri et al. PMID- 25821905 TI - Response to Spindelboek et al. Oxygen and cardiac arrest: the timepoint matters. PMID- 25821906 TI - Predictors of noninvasive ventilation success in children with acute respiratory failure. PMID- 25821907 TI - Single ion conducting, polymerized ionic liquid triblock copolymer films: high capacitance electrolyte gates for n-type transistors. AB - There has been impressive progress in the fabrication and characterization of p type organic electrolyte-gated transistors (EGTs). Unfortunately, despite the importance of n-type organic transistors for complementary circuits, fewer investigations have focused on developing electrolytes as gate dielectrics for n type organic semiconductors. Here, we present a novel single ion conductor, a polymerized ionic liquid (PIL) triblock copolymer (PS-PIL-PS) composed of styrene (PS) and 1-[(2-acryloyloxy)ethyl]-3-butylimidazolium bis(trifluoromethylsulfonyl)imide (PIL), that conducts only the TFSI anion. This triblock copolymer acts as a gate dielectric to allow low-voltage n-type organic EGT operation. Impedance characterization of PS-PIL-PS reveals that there are three polarization regions: (1) dipolar relaxation, (2) ion migration, and (3) electric double layer (EDL) formation. These polarization regions are controlled by film thickness, and rapid EDL formation can be obtained in thinner polyelectrolyte films. In particular, a 500 nm-thick polyelectrolyte film exhibits a large capacitance of ~1 MUF/cm(2) at 10 kHz. Employing this single ion conducting PIL triblock copolymer as the gate insulator, we achieved low voltage operation (<1 V supply) of poly{[N,N'-bis(2-octyldodecyl)-naphthalene-1,4,5,8 bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2OD-T2)) n-type organic EGTs (electron mobility of ~0.008 cm(2)/(V.s) and ON/OFF current ratio of ~2 * 10(3)) by preventing electrochemical doping. Furthermore, the recognition that the performance of n-type organic EGTs is diminished by 3D electrochemical doping suggests that it may be necessary to have a unipolar electrolyte to gate n type organic semiconductors. Finally, we highlight that the use of PIL block copolymer electrolytes as gate insulators opens unique opportunities to explore the role of ion penetration in n-type organic EGTs by tuning the extent of electrochemical doping. PMID- 25821908 TI - Correction to Catalino, Algoe, & Fredrickson (2014). AB - Reports an error in "Prioritizing positivity: An effective approach to pursuing happiness" by Lahnna I. Catalino, Sara B. Algoe and Barbara L. Fredrickson (Emotion, 2014[Dec], Vol 14[6], 1155-1161). There was an error in Table 2 of the Results. There was a negative sign added to .51 in Table 2. The corrected table is shown in the erratum. (The following abstract of the original article appeared in record 2014-48826-003.) A decade of research reveals the benefits of positive emotions for mental and physical health; however, recent empirical work suggests the explicit pursuit of happiness may backfire. The present study hypothesized that the pursuit of happiness is not inherently self-defeating; in particular, individuals who seek positivity, as exemplified by how they make decisions about how to organize their day-to-day lives, may be happier. This individual difference is labeled prioritizing positivity. In a community sample of young to older adults (N = 233), prioritizing positivity predicted a host of well-being outcomes (positive emotions, depressive symptomology). In addition, people high in prioritizing positivity have greater resources, and these links are explained by more frequent experiences of positive emotions. In sum, the present study suggests that seeking happiness, although a delicate art, may be a worthwhile pursuit. PMID- 25821909 TI - Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. AB - Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders, including schizophrenia. DISC1 has been implicated in neurodevelopment in relation to scaffolding signal complexes. Here we used proteomic analysis to screen for DISC1 interactors and identified several RNA binding proteins, such as hematopoietic zinc finger (HZF), that act as components of RNA-transporting granules. HZF participates in the mRNA localization of inositol-1,4,5-trisphosphate receptor type 1 (ITPR1), which plays a key role in synaptic plasticity. DISC1 colocalizes with HZF and ITPR1 mRNA in hippocampal dendrites and directly associates with neuronal mRNAs, including ITPR1 mRNA. The binding potential of DISC1 for ITPR1 mRNA is facilitated by HZF. Studies of Disc1 knockout mice have revealed that DISC1 regulates the dendritic transport of Itpr1 mRNA by directly interacting with its mRNA. The DISC1-mediated mRNA regulation is involved in synaptic plasticity. We show that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity. PMID- 25821910 TI - Slowly dividing neural progenitors are an embryonic origin of adult neural stem cells. AB - The mechanism by which adult neural stem cells (NSCs) are established during development is unclear. In this study, analysis of cell cycle progression by examining retention of a histone 2B (H2B)-GFP fusion protein revealed that, in a subset of mouse embryonic neural progenitor cells (NPCs), the cell cycle slows between embryonic day (E) 13.5 and E15.5 while other embryonic NPCs continue to divide rapidly. By allowing H2B-GFP expressed at E9.5 to become diluted in dividing cells until the young adult stage, we determined that a majority of NSCs in the young adult subependymal zone (SEZ) originated from these slowly dividing embryonic NPCs. The cyclin-dependent kinase inhibitor p57 is highly expressed in this embryonic subpopulation, and the deletion of p57 impairs the emergence of adult NSCs. Our results suggest that a substantial fraction of adult SEZ NSCs is derived from a slowly dividing subpopulation of embryonic NPCs and identify p57 as a key factor in generating this embryonic origin of adult SEZ NSCs. PMID- 25821911 TI - Family income, parental education and brain structure in children and adolescents. AB - Socioeconomic disparities are associated with differences in cognitive development. The extent to which this translates to disparities in brain structure is unclear. We investigated relationships between socioeconomic factors and brain morphometry, independently of genetic ancestry, among a cohort of 1,099 typically developing individuals between 3 and 20 years of age. Income was logarithmically associated with brain surface area. Among children from lower income families, small differences in income were associated with relatively large differences in surface area, whereas, among children from higher income families, similar income increments were associated with smaller differences in surface area. These relationships were most prominent in regions supporting language, reading, executive functions and spatial skills; surface area mediated socioeconomic differences in certain neurocognitive abilities. These data imply that income relates most strongly to brain structure among the most disadvantaged children. PMID- 25821912 TI - GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury. AB - Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. NG2-expressing oligodendrocyte precursor cells (NG2 cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2 cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor-mediated synaptic input to NG2 cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2 cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2 cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI. PMID- 25821913 TI - Brain feminization requires active repression of masculinization via DNA methylation. AB - The developing mammalian brain is destined for a female phenotype unless exposed to gonadal hormones during a perinatal sensitive period. It has been assumed that the undifferentiated brain is masculinized by direct induction of transcription by ligand-activated nuclear steroid receptors. We found that a primary effect of gonadal steroids in the highly sexually dimorphic preoptic area (POA) is to reduce activity of DNA methyltransferase (Dnmt) enzymes, thereby decreasing DNA methylation and releasing masculinizing genes from epigenetic repression. Pharmacological inhibition of Dnmts mimicked gonadal steroids, resulting in masculinized neuronal markers and male sexual behavior in female rats. Conditional knockout of the de novo Dnmt isoform, Dnmt3a, also masculinized sexual behavior in female mice. RNA sequencing revealed gene and isoform variants modulated by methylation that may underlie the divergent reproductive behaviors of males versus females. Our data show that brain feminization is maintained by the active suppression of masculinization via DNA methylation. PMID- 25821915 TI - Internet-based group contingency management to promote smoking abstinence. AB - Internet-based group contingencies have been shown to promote brief periods of abstinence from cigarette smoking. Under a group contingency, small teams of smokers must collectively meet abstinence goals to receive monetary consequences. The present study investigated 2 arrangements, 1 in which all team members had to meet group treatment goals to receive monetary consequences (full group), and 1 in which team members had to meet some group goals and some individual goals to receive these consequences (mixed group). Motiv8 Systems, an Internet-based remote monitoring platform, was used to collect video-recorded breath carbon monoxide (CO) samples. All team members could communicate with each other via an online discussion forum. During baseline conditions, only 3.3% of CO samples were negative for smoking, which suggests that self-monitoring and access to the online discussion forum were insufficient to initiate abstinence. When the group contingencies were instituted 41.3% of CO samples were negative. There were no statistically significant differences between the 2 arrangements in the percentage of negative CO samples or point prevalence at the end of treatment or at the 3-month follow-up. Participants posted an average of 25 comments on the discussion forum, most of which were rated as positive by independent observers. The mean cost of vouchers per participant was lower in the full group ($33) relative to the mixed group ($190). The present results replicate and extend previous findings on group contingencies to promote abstinence and social support. PMID- 25821916 TI - Direct Measurements of Colloidal Solvophoresis under Imposed Solvent and Solute Gradients. AB - We describe a microfluidic system that enables direct visualization and measurement of diffusiophoretic migration of colloids in response to imposed solution gradients. Such measurements have proven difficult or impossible in macroscopic systems due to difficulties in establishing solution gradients that are sufficiently strong yet hydrodynamically stable. We validate the system with measurements of the concentration-dependent diffusiophoretic mobility of polystyrene colloids in NaCl gradients, confirming that diffusiophoretic migration velocities are proportional to gradients in the logarithm of electrolyte concentration. We then perform the first direct measurement of the concentration-dependent "solvophoretic" mobility of colloids in ethanol-water gradients, whose dependence on concentration and gradient strength was not known either theoretically or experimentally, but which our measurements reveal to be proportional to the gradient in the logarithm of ethanol mole fraction. Finally, we examine solvophoretic migration under a variety of qualitatively distinct chemical gradients, including solvents that are miscible or have finite solubility with water, an electrolyte for which diffusiophoresis proceeds down concentration gradients (unlike for most electrolytes), and a nonelectrolyte (sugar). Our technique enables the direct characterization of diffusiophoretic mobilities of various colloids under various solvent and solute gradients, analogous to the electrophoretic zeta-potential measurements that are routinely used to characterize suspensions. We anticipate that such measurements will provide the feedback required to test and develop theories for solvophoretic and diffusiophoretic migration and ultimately to the conceptual design and engineering of particles that respond in a desired way to their chemical environments. PMID- 25821914 TI - Synaptic diversity enables temporal coding of coincident multisensory inputs in single neurons. AB - The ability of the brain to rapidly process information from multiple pathways is critical for reliable execution of complex sensory-motor behaviors, yet the cellular mechanisms underlying a neuronal representation of multimodal stimuli are poorly understood. Here we explored the possibility that the physiological diversity of mossy fiber (MF) to granule cell (GC) synapses in the mouse vestibulocerebellum may contribute to the processing of coincident multisensory information at the level of individual GCs. We found that the strength and short term dynamics of individual MF-GC synapses can act as biophysical signatures for primary vestibular, secondary vestibular and visual input pathways. Most GCs receive inputs from different modalities, which, when coactivated, produced enhanced GC firing rates and distinct first spike latencies. Thus, pathway specific synaptic response properties permit temporal coding of correlated multisensory inputs by single GCs, thereby enriching sensory representation and facilitating pattern separation. PMID- 25821917 TI - Questionnaires on Family Satisfaction in the Adult ICU: A Systematic Review Including Psychometric Properties. AB - OBJECTIVES: To perform a systematic review of the literature to determine which questionnaires are currently available to measure family satisfaction with care on the ICU and to provide an overview of their quality by evaluating their psychometric properties. DATA SOURCES: We searched PubMed, Embase, The Cochrane Library, Web of Science, PsycINFO, and CINAHL from inception to October 30, 2013. STUDY SELECTION: Experimental and observational research articles reporting on questionnaires on family satisfaction and/or needs in the ICU were included. Two reviewers determined eligibility. DATA EXTRACTION: Design, application mode, language, and the number of studies of the tools were registered. With this information, the tools were globally categorized according to validity and reliability: level I (well-established quality), II (approaching well-established quality), III (promising quality), or IV (unconfirmed quality). The quality of the highest level (I) tools was assessed by further examination of the psychometric properties and sample size of the studies. DATA SYNTHESIS: The search detected 3,655 references, from which 135 articles were included. We found 27 different tools that assessed overall or circumscribed aspects of family satisfaction with ICU care. Only four questionnaires were categorized as level I: the Critical Care Family Needs Inventory, the Society of Critical Care Medicine Family Needs Assessment, the Critical Care Family Satisfaction Survey, and the Family Satisfaction in the Intensive Care Unit. Studies on these questionnaires were of good sample size (n >= 100) and showed adequate data on face/content validity and internal consistency. Studies on the Critical Care Family Needs Inventory, the Family Satisfaction in the Intensive Care Unit also contained sufficient data on inter-rater/test-retest reliability, responsiveness, and feasibility. In general, data on measures of central tendency and sensitivity to change were scarce. CONCLUSIONS: Of all the questionnaires found, the Critical Care Family Needs Inventory and the Family Satisfaction in the Intensive Care Unit were the most reliable and valid in relation to their psychometric properties. However, a universal "best questionnaire" is indefinable because it depends on the specific goal, context, and population used in the inquiry. PMID- 25821918 TI - Mortality in Multicenter Critical Care Trials: An Analysis of Interventions With a Significant Effect. AB - OBJECTIVES: We aimed to identify all treatments that affect mortality in adult critically ill patients in multicenter randomized controlled trials. We also evaluated the methodological aspects of these studies, and we surveyed clinicians' opinion and usual practice for the selected interventions. DATA SOURCES: MEDLINE/PubMed, Scopus, and Embase were searched. Further articles were suggested for inclusion from experts and cross-check of references. STUDY SELECTION: We selected the articles that fulfilled the following criteria: publication in a peer-reviewed journal; multicenter randomized controlled trial design; dealing with nonsurgical interventions in adult critically ill patients; and statistically significant effect in unadjusted landmark mortality. A consensus conference assessed all interventions and excluded those with lack of reproducibility, lack of generalizability, high probability of type I error, major baseline imbalances between intervention and control groups, major design flaws, contradiction by subsequent larger higher quality trials, modified intention to treat analysis, effect found only after adjustments, and lack of biological plausibility. DATA EXTRACTION: For all selected studies, we recorded the intervention and its comparator, the setting, the sample size, whether enrollment was completed or interrupted, the presence of blinding, the effect size, and the duration of follow-up. DATA SYNTHESIS: We found 15 interventions that affected mortality in 24 multicenter randomized controlled trials. Median sample size was small (199 patients) as was median centers number (10). Blinded trials enrolled significantly more patients and involved more centers. Multicenter randomized controlled trials showing harm also involved significantly more centers and more patients (p = 0.016 and p = 0.04, respectively). Five hundred fifty-five clinicians from 61 countries showed variable agreement on perceived validity of such interventions. CONCLUSIONS: We identified 15 treatments that decreased/increased mortality in critically ill patients in 24 multicenter randomized controlled trials. However, design affected trial size and larger trials were more likely to show harm. Finally, clinicians view of such trials and their translation into practice varied. PMID- 25821919 TI - Coreactivation of Human Herpesvirus 6 and Cytomegalovirus Is Associated With Worse Clinical Outcome in Critically Ill Adults. AB - OBJECTIVES: Human herpesvirus 6 is associated with a variety of complications in immunocompromised patients, but no studies have systematically and comprehensively assessed the impact of human herpesvirus 6 reactivation, and its interaction with cytomegalovirus, in ICU patients. DESIGN: We prospectively assessed human herpesvirus 6 and cytomegalovirus viremia by twice-weekly plasma polymerase chain reaction in a longitudinal cohort study of 115 adult, immunocompetent ICU patients. The association of human herpesvirus 6 and cytomegalovirus reactivation with death or continued hospitalization by day 30 (primary endpoint) was assessed by multivariable logistic regression analyses. SETTING: This study was performed in trauma, medical, surgical, and cardiac ICUs at two separate hospitals of a large tertiary care academic medical center. PATIENTS: A total of 115 cytomegalovirus seropositive, immunocompetent adults with critical illness were enrolled in this study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Human herpesvirus 6 viremia occurred in 23% of patients at a median of 10 days. Human herpesvirus 6B was the species detected in eight samples available for testing. Most patients with human herpesvirus 6 reactivation also reactivated cytomegalovirus (70%). Severity of illness was not associated with viral reactivation. Mechanical ventilation, burn ICU, major infection, human herpesvirus 6 reactivation, and cytomegalovirus reactivation were associated with the primary endpoint in unadjusted analyses. In a multivariable model adjusting for mechanical ventilation and ICU type, only coreactivation of human herpesvirus 6 and cytomegalovirus was significantly associated with the primary endpoint (adjusted odds ratio, 7.5; 95% CI, 1.9-29.9; p = 0.005) compared to patients with only human herpesvirus 6, only cytomegalovirus, or no viral reactivation. CONCLUSIONS: Coreactivation of both human herpesvirus 6 and cytomegalovirus in ICU patients is associated with worse outcome than reactivation of either virus alone. Future studies should define the underlying mechanism(s) and determine whether prevention or treatment of viral reactivation improves clinical outcome. PMID- 25821920 TI - Sperm mRNAs and microRNAs as candidate markers for the impact of toxicants on human spermatogenesis: an application to tobacco smoking. AB - Spermatozoa contain a complex population of RNAs including messenger RNAs (mRNAs) and small RNAs such as microRNAs (miRNA). It has been reported that these RNAs can be used to understand the mechanisms by which toxicological exposure affects spermatogenesis. The aim of our study was to compare mRNA and miRNA profiles in spermatozoa from eight smokers and eight non-smokers, and search for potential relationships between mRNA and miRNA variation. All men were selected based on their answers to a standard toxic exposure questionnaire, and sperm parameters. Using mRNA and miRNA microarrays, we showed that mRNAs from 15 genes were differentially represented between smokers and non-smokers (p<0.01): five had higher levels and 10 lower levels in the smokers. For the microRNAs, 23 were differentially represented: 16 were higher and seven lower in the smokers (0.004<=p<0.01). Quantitative RT-PCR confirmed the lower levels in smokers compared to non-smokers for hsa-miR-296-5p, hsa-miR-3940, and hsa-miR-520d-3p. Moreover, we observed an inverse relationship between the levels of microRNAs and six potential target mRNAs (B3GAT3, HNRNPL, OASL, ODZ3, CNGB1, and PKD2). Our results indicate that alterations in the level of a small number of microRNAs in response to smoking may contribute to changes in mRNA expression in smokers. We conclude that large-scale analysis of spermatozoa RNAs can be used to help understand the mechanisms by which human spermatogenesis responds to toxic substances including those in tobacco smoke. PMID- 25821921 TI - Dielectric and phase behavior of dipolar spheroids. AB - The Stockmayer fluid, composed of dipolar spheres, has a well-known isotropic ferroelectric phase transition at high dipole densities. However, there has been little investigation of the ferroelectric transition in nearly spherical fluids at dipole densities corresponding to those found in many polar solvents and in guest-host organic electro-optic materials. In this work, we examine the transition to ordered phases of low-aspect-ratio spheroids under both unperturbed and poled conditions, characterizing both the static dielectric response and thermodynamic properties of spheroidal systems. Spontaneous ferroelectric ordering was confined to a small region of aspect ratios about unity, indicating that subtle changes in sterics can have substantial influence on the behavior of coarse-grained liquid models. Our results demonstrate the importance of molecular shape in obtaining even qualitatively correct dielectric responses and provide an explanation for the success of the Onsager model as a phenomenological representation for the dielectric behavior of polar organic liquids. PMID- 25821922 TI - Treatment escalation in the intensive care unit among patients with preexisting treatment limitations: best-laid plans gone awry? PMID- 25821923 TI - Glyburide for gestational diabetes: time for a pause for thought. PMID- 25821924 TI - Facial expression recognition in crested macaques (Macaca nigra). AB - Facial expressions are a main communication channel used by many different species of primate. Despite this, we know relatively little about how primates discriminate between different facial expressions, and most of what we do know comes from a restricted number of well-studied species. In this study, three crested macaques (Macaca nigra) took part in matching-to-sample tasks where they had to discriminate different facial expressions. In a first experiment, the macaques had to match a photograph of a facial expression to another exemplar of the same expression produced by a different individual, against examples of one of three other types of expressions and neutral faces. In a second experiment, they had to match a dynamic video recording of a facial expression to a still photograph of another exemplar of the same facial expression produced by another individual, also against one of four other expressions. The macaques performed above chance in both tasks, identifying expressions as belonging to the same category regardless of individual identity. Using matrix correlations and multidimensional scaling, we analysed the pattern of errors to see whether overall similarity between facial expressions and/or specific morphological features caused the macaques to confuse facial expressions. Overall similarity, measured with the macaque facial action coding system (maqFACS), did not correlate with performances. Instead, functional similarities between facial expressions could be responsible for the observed pattern of error. These results expand previous findings to a novel primate species and highlight the potential of using video stimuli to investigate the perception and categorisation of visual signals in primates. PMID- 25821925 TI - Making Inferences: Comprehension of Physical Causality, Intentionality, and Emotions in Discourse by High-Functioning Older Children, Adolescents, and Adults with Autism. AB - Studies investigating inferential reasoning in autism spectrum disorder (ASD) have focused on the ability to make socially-related inferences or inferences more generally. Important variables for intervention planning such as whether inferences depend on physical experiences or the nature of social information have received less consideration. A measure of bridging inferences of physical causation, mental states, and emotional states was administered to older children, adolescents, and adults with and without ASD. The ASD group had more difficulty making inferences, particularly related to emotional understanding. Results suggest that individuals with ASD may not have the stored experiential knowledge that specific inferences depend upon or have difficulties accessing relevant experiences due to linguistic limitations. Further research is needed to tease these elements apart. PMID- 25821926 TI - Incorporating Preliminary Mental Health Assessment in the Initial Healthcare for Refugees in New Jersey. AB - The study aims to assess the feasibility of introducing a mental health screening tool into the initial health care assessment for refugees in New Jersey, US. A semi-structured interview was conducted with a convenience sample of professionals providing refugee health care in New Jersey and in a number of other states. There is a widespread appreciation of the need to consider the mental and emotional issues of the refugees as a priority in healthcare services. A mental health screening tool is required for practice in NJ. Community resources should be coupled with early screening for better refugee mental health outcomes. PMID- 25821927 TI - Access to and Use of the Internet by Veterans with Serious Mental Illness. AB - This study evaluated internet use among 239 veterans with serious mental illness who completed questionnaires assessing demographics and internet use in 2010 2011. The majority of individuals (70 %) reported having accessed the internet and among those, 79 % had accessed it within the previous 30 days. Those who were younger and more educated were more likely to have accessed the internet, as were those with a schizophrenia spectrum disorder, bipolar disorder, or major depressive disorder, compared to individuals with PTSD. Veterans with serious mental illness commonly use the internet, including to obtain health information, though use varies across demographic characteristics and clinical diagnosis. PMID- 25821928 TI - Investigating Vulnerability for Developing Eating Disorders in a Multi confessional Population. AB - The present study aimed to examine the vulnerability to eating disorders (ED) among 949 Lebanese female young adults as well as its association with stress, anxiety, depression, body image dissatisfaction (BID), dysfunctional eating, body mass index, religious affiliation (Christian, Muslim, Druze or Other), religiosity and activity level. Results showed that anxiety had the greatest effect on increasing the predisposition to ED, followed by stress level, BID, depression and restrained eating. Affiliating as Christian was found to significantly decrease the vulnerability to developing an ED. Furthermore, the interaction of anxiety with intrinsic religiosity was found to have a protective role on reducing ED. The current study emphasized a buffering role of intrinsic religiosity against anxiety and ED vulnerability. PMID- 25821929 TI - Automated multiplexed ECL Immunoarrays for cancer biomarker proteins. AB - Point-of-care diagnostics based on multiplexed protein measurements face challenges of simple, automated, low-cost, and high-throughput operation with high sensitivity. Herein, we describe an automated, microprocessor-controlled microfluidic immunoarray for simultaneous multiplexed detection of small protein panels in complex samples. A microfluidic sample/reagent delivery cassette was coupled to a 30-microwell detection array to achieve sensitive detection of four prostate cancer biomarker proteins in serum. The proteins are prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), platelet factor-4 (PF 4), and interlukin-6 (IL-6). The six channel system is driven by integrated micropumps controlled by an inexpensive programmable microprocessor. The reagent delivery cassette and detection array feature channels made by precision-cut 0.8 mm silicone gaskets. Single-wall carbon nanotube forests were grown in printed microwells on a pyrolytic graphite detection chip and decorated with capture antibodies. The detection chip is housed in a machined microfluidic chamber with a steel metal shim counter electrode and Ag/AgCl reference electrode for electrochemiluminescent (ECL) measurements. The preloaded sample/reagent cassette automatically delivers samples, wash buffers, and ECL RuBPY-silica-antibody detection nanoparticles sequentially. An onboard microcontroller controls micropumps and reagent flow to the detection chamber according to a preset program. Detection employs tripropylamine, a sacrificial reductant, while applying 0.95 V vs Ag/AgCl. Resulting ECL light was measured by a CCD camera. Ultralow detection limits of 10-100 fg mL(-1) were achieved in simultaneous detection of the four protein in 36 min assays. Results for the four proteins in prostate cancer patient serum gave excellent correlation with those from single protein ELISA. PMID- 25821930 TI - Cutaneous Chromoblastomycosis Caused by Veronaea botryosa in a Patient with Pemphigus Vulgaris and Review of Published Reports. AB - Chromoblastomycosis and phaeohyphomycosis represent two poles of a disease spectrum caused by melanized fungi. Veronaea botryosa belongs to a small genus of saprobic fungi that occasionally cause human infections. To date, 11 cases of V. botryosa-induced cutaneous phaeohyphomycosis have been actually reported since 1990 after exclusion of 2 duplicated cases. We report the first case to our knowledge of cutaneous chromoblastomycosis caused by V. botryosa in a patient with pemphigus vulgaris. A 61-year-old man with 5-year history of pemphigus vulgaris and long-term treatment of corticosteroids and immunosuppressive agents developed multiple nodules on the dorsum of right wrist and hand after wrist trauma. Skin biopsy showed numerous brown muriform cells and a few septate hyphae in the tissue. Veronaea botryosa was isolated from the biopsy samples and then identified based on morphologic observation and DNA sequencing. The patient underwent immediate withdrawal of cyclophosphamide and gradual decrease in prednisone. Skin lesions healed after 5-month itraconazole therapy with an interval of 1-month terbinafine and one cycle of liquid nitrogen cryotherapy. Our results demonstrate that V. botryosa could induce both chromoblastomycosis and phaeohyphomycosis. Combined use of itraconazole and cryotherapy may be preferable to treat this infection. PMID- 25821931 TI - Estimated human absorbed dose for (68)Ga-ECC based on mice data: comparison with (67)Ga-ECC. AB - OBJECTIVE: Nowadays, the efficacies of (68)Ga-based tracers are comparable to that of (18)F-based agents and have stimulated researchers to investigate the potential of (68)Ga-based positron emission tomography (PET) imaging agents. In this study, the human absorbed dose of (68)Ga labeled with ethylenecysteamine cysteine (68)Ga-ECC and (67)Ga-ECC was estimated based on biodistribution data in mice by the medical internal radiation dose (MIRD) method. METHODS: For biodistribution of (67)Ga/(68)Ga-ECC, three mice were killed by CO2 asphyxiation at each selected times after injection (15, 30, 45, 60, 120 min for (68)Ga-ECC and 0.5, 2 and 48 h for (67)Ga-ECC), and then the tissue (heart, lung, brain, intestine, skin, stomach, kidneys, liver, muscle and bone) was removed. RESULTS: (68)Ga-ECC as a new PET renal imaging agent was prepared with radiochemical purity of >97 % in less than 30 min. The biodistribution data for (68)Ga-ECC showed that the most of the activity extracted from the urinary tract very fast. Comparison between human absorbed dose estimation for these two agents indicated that the absorbed dose of the most organs after injection of (67)Ga-ECC is approximately tenfold higher than the amount after (68)Ga-ECC injection. CONCLUSION: The results showed that (68)Ga-ECC is a more appropriate agent rather than (67)Ga-ECC and generally can be a good candidate for PET renal imaging applications. PMID- 25821932 TI - Prediction of the maximum temperature for life based on the stability of metabolites to decomposition in water. AB - The components of life must survive in a cell long enough to perform their function in that cell. Because the rate of attack by water increases with temperature, we can, in principle, predict a maximum temperature above which an active terrestrial metabolism cannot function by analysis of the decomposition rates of the components of life, and comparison of those rates with the metabolites' minimum metabolic half-lives. The present study is a first step in this direction, providing an analytical framework and method, and analyzing the stability of 63 small molecule metabolites based on literature data. Assuming that attack by water follows a first order rate equation, we extracted decomposition rate constants from literature data and estimated their statistical reliability. The resulting rate equations were then used to give a measure of confidence in the half-life of the metabolite concerned at different temperatures. There is little reliable data on metabolite decomposition or hydrolysis rates in the literature, the data is mostly confined to a small number of classes of chemicals, and the data available are sometimes mutually contradictory because of varying reaction conditions. However, a preliminary analysis suggests that terrestrial biochemistry is limited to environments below ~150-180 degrees C. We comment briefly on why pressure is likely to have a small effect on this. PMID- 25821933 TI - Bending elasticity modulus of giant vesicles composed of aeropyrum pernix k1 archaeal lipid. AB - Thermally induced shape fluctuations were used to study elastic properties of giant vesicles composed of archaeal lipids C25,25-archetidyl (glucosyl) inositol and C25,25-archetidylinositol isolated from lyophilised Aeropyrum pernix K1 cells. Giant vesicles were created by electroformation in pure water environment. Stroboscopic illumination using a xenon flash lamp was implemented to remove the blur effect due to the finite integration time of the camera and to obtain an instant picture of the fluctuating vesicle shape. The mean weighted value of the bending elasticity modulus kc of the archaeal membrane determined from the measurements meeting the entire set of qualification criteria was (1.89 +/- 0.18) * 10-19 J, which is similar to the values obtained for a membrane composed of the eukaryotic phospholipids SOPC (1.88 +/- 0.17) * 10-19 J and POPC (2.00 +/- 0.21) ' 10-19 J. We conclude that membranes composed of archaeal lipids isolated from Aeropyrum pernix K1 cells have similar elastic properties as membranes composed of eukaryotic lipids. This fact, together with the importance of the elastic properties for the normal circulation through blood system, provides further evidence in favor of expectations that archaeal lipids could be appropriate for the design of drug delivery systems. PMID- 25821934 TI - Enhancing alkane production in cyanobacterial lipid droplets: a model platform for industrially relevant compound production. AB - Cyanobacterial lipid droplets (LDs) are packed with hydrophobic energy-dense compounds and have great potential for biotechnological expression and the compartmentalization of high value compounds. Nostoc punctiforme normally accumulates LDs containing neutral lipids, and small amounts of heptadecane, during the stationary phase of growth. In this study, we further enhanced heptadecane production in N. punctiforme by introducing extrachromosomal copies of aar/adc genes, and report the discovery of a putative novel lipase encoded by Npun_F5141, which further enhanced alkane production. Extra copies of all three genes in high light conditions resulted in a 16-fold higher accumulation of heptadecane compared to the wild type strain in the exponential phase. LD accumulation during exponential phase also increased massively to accommodate the heptadecane production. A large number of small, less fluorescent LDs were observed at the cell periphery in exponential growth phase, whereas fewer number of highly fluorescent, much larger LDs were localized towards the center of the cell in the stationary phase. These advances demonstrate that cyanobacterial LDs are an ideal model platform to make industrially relevant compounds, such as alkanes, during exponential growth, and provide insight into LD formation in cyanobacteria. PMID- 25821935 TI - A histological evaluation of development and axis formation in freshwater fish ectoparasite Argulus bengalensis Ramakrishna, 1951 (Crustacea: Branchiura). AB - The present investigation was carried out to underscore the developmental events of a crustacean ectoparasite of fish, Argulus bengalensis. Serial histological sections of the embryo were made at lateral, sagittal and longitudinal planes to explain its cleavage, gastrulation and axis specification. The centrolecithal egg of A. bengalensis underwent meroblastic superficial cleavage. The cleavage initiated at the future dorsal side of the egg within 5 h to 5 h and 30 min of incubation. Consequently, a small mass of energids appeared superficially at the future dorsal side within 6 h. Later, energids were found at the future ventral and lateral sides. A syncytial blastoderm was formed around the centrally placed yolk material which was transformed into a cellular blastoderm within 30 h of incubation. In the blastoderm, two cell masses were formed at the dorsal and ventral part which initially extended towards each other and later spread out though future anterior-posterior direction. The pressure exerted by the cell flow displaced the entire yolk material at the future postero-ventral side. At the time of egg laying, a prototype of the embryonic axes is determined. The substratum side of the egg formed the dorsal part, whilst the side facing water turned to the ventral part. The broader end of the egg formed the anterior side and the narrow end formed the posterior side of the embryo. The anterior posterior axis formation was initiated within 72 to 96 h of incubation when the blastodermal cells displaced the yolk material at the future posterior end. Within 120 h of incubation, the germ layers of the embryo were determined. The study reveals that the cleavage pattern of A. bengalensis shows close similarities with that of the Malacostraca amongst the crustaceans and dipteran and hymenopteran amongst the insects. PMID- 25821936 TI - Mineral trioxide aggregate (MTA): its history, composition, and clinical applications. AB - Mineral trioxide aggregate (MTA) has been a revolutionary material in endodontics. Since its introduction in the 1990s several studies have demonstrated its use in various clinical applications. MTA has been extensively studied and is currently used for perforation repairs, apexifications, regenerative procedures, apexogenesis, pulpotomies, and pulp capping. This article will review the history, composition, research findings, and clinical applications of this versatile endodontic material. PMID- 25821937 TI - Root canal irrigants: a review of their interactions, benefits, and limitations. AB - Endodontic treatment success depends on a combination of appropriate instrumentation, effective irrigation and decontamination of root canal spaces to apices, and obturation of the root canals. Irrigation of the root canal is paramount in determining periapical tissue healing. This article reviews presently available root canal irrigants, their interactions, advantages, and limitations. For this review, the authors performed a Medline search for all English language articles published through January 2014 with "root canal irrigants" and "endodontic irrigants" as keywords. PMID- 25821938 TI - Transitional bonding for segmented treatment: a two-phase restorative approach. AB - When extensive dental therapy is needed, as in cases of severe attrition, interim restorations are useful in determining whether or not the proposed treatment will be successful. Transitional resin bonding is one type of interim method. In this case report, a 60-year-old patient presented with severely worn maxillary and mandibular anterior teeth; he desired treatment to be done in a timely fashion so as to be ready to attend an important wedding. Due to the urgency in timing and the complexity of the case, the treatment plan was a two-phase approach that included an initial esthetic and occlusal design to create a diagnostic wax-up followed by placement of transitional composite resin bonding, and then placement of indirect porcelain restorations. This transitional bonding approach allowed comprehensive treatment to be completed at a pace suitable to the patient's needs. PMID- 25821939 TI - Minimizing shrinkage of interdental papilla height when treating multiple Miller Class III gingival recession defects. AB - Miller Class III and IV gingival recession defects have interdental bone and soft tissue loss that limit root coverage. Given the importance of the interdental papilla, protecting the integrity of this structure would seem prudent. Tunnel techniques have been successfully used to protect the interdental papilla. This article discusses the results of two cases in which multiple Miller Class III gingival recession defects were treated using tunnel-grafting techniques and an acellular dermal matrix. In both cases, root coverage was achieved while protecting the interdental papilla height. PMID- 25821940 TI - Vonlays: a conservative esthetic alternative to full-coverage crowns. AB - Porcelain veneers have long been a popular restorative option that have evolved into a well-accepted treatment that can be fabricated in various ways. Onlays are another common treatment modality used in contemporary dentistry to restore large areas of decay and to replace old restorations. With the availability of newer high-strength materials such as lithium disilicate and processing technologies like CAD/CAM and heat pressing, dental professionals are now able to produce highly esthetic, high-strength restorations that blend seamlessly with the natural dentition while also withstanding posterior occlusal forces. This has resulted in innovative methods of providing minimally invasive dentistry. One such approach is a combination restoration the authors call a "vonlay," which, as demonstrated in this case report, can be used as an alternative to coverage crowns to restore damaged posterior teeth. PMID- 25821941 TI - Dental implant uncovering techniques with emphasis on increasing keratinized mucosa. AB - The focus in implantology today is on the need to achieve results that are not only functional but also long-lasting and highly esthetic. Increased width and thickness of keratinized mucosa (KM) around dental implants, which is now widely recognized to be associated with better long-term success than implants without KM, addresses these goals. This is especially important in the esthetic zone, where marginal recession can be of concern. The author describes the following methods of implant uncovering that emphasize enhancement of the keratinized mucosa: the punch technique; buccally advanced flap; roll flap; tissue preservation technique; free connective tissue graft; and pedicle flap. PMID- 25821942 TI - The dental handpiece: technology continues to impact everyday practice. AB - One of the most fundamental devices used in dentistry, the handpiece can enhance the efficiency of everyday dental tasks. Through the years, handpieces have gradually been redesigned and upgraded to become the highly accurate and sophisticated tools they are today. Technological advances continue to improve these indispensable instruments. PMID- 25821943 TI - Dengue virus infection in Croatia: seroprevalence and entomological study. AB - During 2011-2012, a total of 1,180 sera samples were collected from residents of seven Croatian counties located on the Adriatic Coast and four counties in northeastern Croatia and tested for the presence of dengue virus (DENV) IgG antibodies using ELISA. Reactive samples were further tested by IFA. Seven samples (0.59%) tested positive for DENV antibodies. Seroprevalence rates by county varied from 0-2.21%. The highest seropositivity rate (2.21%) was found in the Dubrovnik-Neretva County where autochthonous dengue cases were recorded in 2010. Additionally,3,699 mosquitoes were collected from 126 localities along the Adriatic coast in August-September, 2011. Aedes albopictus was the most prevalent species (81.37%). No evidence of DENV RNA was detected by RT-PCR among 1,748 female mosquitoes. PMID- 25821944 TI - Maternal dietary patterns and gestational diabetes mellitus: a large prospective cohort study in China. AB - Few studies have explored the relationship between dietary patterns and the risk of gestational diabetes mellitus (GDM). Evidence from non-Western areas is particularly lacking. In the present study, we aimed to examine the associations between dietary patterns and the risk of GDM in a Chinese population. A total of 3063 pregnant Chinese women from an ongoing prospective cohort study were included. Data on dietary intake were collected using a FFQ at 24-27 weeks of gestation. GDM was diagnosed using a 75 g, 2 h oral glucose tolerance test. Dietary patterns were determined by principal components factor analysis. A log binomial regression model was used to examine the associations between dietary pattern and the risk of GDM. The analysis identified four dietary patterns: vegetable pattern; protein-rich pattern; prudent pattern; sweets and seafood pattern. Multivariate analysis showed that the highest tertile of the vegetable pattern was associated with a decreased risk of GDM (relative risk (RR) 0.79, 95% CI 0.64, 0.97), compared with the lowest tertile, whereas the highest tertile of the sweets and seafood pattern was associated with an increased risk of GDM (RR 1.23, 95% CI 1.02, 1.49). No significant association was found for either the protein-rich or the prudent pattern. The protective effect of a high vegetable pattern score was more evident among women who had a family history of diabetes (P for interaction=0.022). These findings suggest that the vegetable pattern was associated with a decreased risk of GDM, while the sweets and seafood pattern was associated with an increased risk of GDM. These findings may be useful in dietary counselling during pregnancy. PMID- 25821945 TI - Performance of synchronized fins in biomimetic propulsion. AB - By using a two-dimensional model of ray fins, we numerically investigate the thrust generation by closely-coupled fins with an immersed boundary approach. The concentration is on the performance enhancement through fin-fin interactions and the underlying vortex control mechanisms in three representative systems, a two fin tandem configuration, a two-fin parallel configuration, and a three-fin triangular configuration. In all these systems the thrust generation can be significantly increased in comparison with single fins. Unlike previous studies of tandem fins, in which the gap and phase lag between the two fins were considered separately, our study shows that the dynamics of the system is determined by a parameter that combines these two (the global phase difference). The optimal performance occurs as this parameter is around pi (destructive mode), and the worst performance occurs when it is around 0 (constructive mode). Interestingly, contrary to the vorticity cancellation scenario implied by its name, our simulations show that in the destructive mode there is in fact a wake re-organization mechanism, during which vortices with the same rotational direction shed from the two fins are attracted towards each other and merge. Subsequently, the wake downstream becomes a strong and well-organized reverse Karman vortex street, which explains the increased thrust. In the parallel system, the best performance occurs in cases when the two fins are in opposites phases. Both the thrust and efficiency increase as the gap between the fins decreases, until a symmetry-breaking instability occurs in the wake and the efficiency starts plunging due to the increase in lateral force generation. In the triangular formation, the highest thrust generation also occurs in the destructive mode. However, no further increase in performance is observed compared with the tandem system. PMID- 25821946 TI - Rap1 is indispensable for TRF2 function in etoposide-induced DNA damage response in gastric cancer cell line. AB - The telomeric protein TRF2, involving in telomeric and extratelomeric DNA damage response, has been previously reported to facilitate multidrug resistance (MDR) in gastric cancer cells by interfering ATM-dependent DNA damage response induced by anticancer drugs. Rap1 is the TRF2-interacting protein in the shelterin complex. Complex formation between Rap1 and TRF2 is essential for their function in telomere and end protection. Here we focus on the effects of Rap1 on TRF2 function in DNA damage response induced by anticancer drugs. Both Rap1 and TRF2 expression were upregulated in SGC7901 and its MDR variant SGC7901/VCR after etoposide treatment, which was more marked in SGC7901/VCR than in SGC7901. Rap1 silencing by siRNA in SGC7901/VCR partially reversed the etoposide resistance. And Rap1 silencing partially reversed the TRF2-mediated resistance to etoposide in SGC7901. Rap1 silencing did not affect the TRF2 upregulation induced by etoposide, but eliminated the inhibition effect of TRF2 on ATM expression and ATM phosphorylation at serine 1981 (ATM pS1981). Furthermore, phosphorylation of ATM targets, including gammaH2AX and serine 15 (S15) on p53, were increased in Rap1 silencing cells in response to etoposide. Thus, we confirm that Rap1, interacting with TRF2 in the shelterin complex, also has an important role in TRF2-mediated DNA damage response in gastric cancer cells treated by etoposide. PMID- 25821947 TI - Inhibiting phosphorylation of the oncogenic PAX3-FOXO1 reduces alveolar rhabdomyosarcoma phenotypes identifying novel therapy options. AB - Patients with translocation-positive alveolar rhabdomyosarcoma (ARMS), an aggressive childhood tumor primarily characterized by the PAX3-FOXO1 oncogenic fusion protein, have a poor prognosis because of lack of therapies that specifically target ARMS tumors. This fact highlights the need for novel pharmaceutical interventions. Posttranslational modifications such as phosphorylation are becoming attractive biological targets for the development of such interventions. Along these lines, we demonstrated that PAX3-FOXO1 is phosphorylated at three specific sites and that its pattern of phosphorylation is altered relative to wild-type Pax3 throughout early myogenesis and in ARMS tumor cells. However, little work has been performed examining the effect of directly inhibiting phosphorylation at these sites on ARMS development. To address this gap in knowledge, we used small molecule inhibitors or mutational analysis to specifically inhibit phosphorylation of PAX3-FOXO1 to investigate how altering phosphorylation of the oncogenic fusion protein affects ARMS phenotypes. We found that inhibiting the phosphorylation of PAX3-FOXO1 at Ser201 significantly reduced migration, invasion and proliferation in two independent ARMS tumor cell lines. Further, we found that inhibition of phosphorylation at Ser205 also decreased proliferation and anchorage-independent growth. Consistent with these in vitro results, we demonstrate for the first time that PAX3-FOXO1 is phosphorylated at Ser201 and Ser205 in a primary tumor sample and in tumor cells actively invading the surrounding normal tissue. This report is the first to demonstrate that the direct inhibition of PAX3-FOXO1 phosphorylation reduces ARMS tumor phenotypes in vitro and that these phosphorylation events are present in primary human ARMS tumors and invading tumor cells. These results identify phosphorylation of PAX3 FOXO1, especially at Ser201, as a novel biological target that can be explored as a promising avenue for ARMS therapies. PMID- 25821948 TI - Single-destination navigation in a multiple-destination environment: a new "later destination attractor" bias in route choice. AB - People choose different routes depending on the size of the environment. However, the size of the environment is often confounded by cognitive load. The current study investigated whether changes in route choice varied as a function of memory load while keeping the size of the environment constant. Also, a new situation was used: route choice to a single destination as a function of the location of follow-up destinations. Critically, there were two routes of equal length to the first destination. The results showed that route choice to the first destination was influenced by the locations of later destinations. This (new) "later destination attractor" bias is the tendency to take a route to the first destination that begins in the direction of subsequent destinations even when the route to the first destination is logically independent of the locations of subsequent destinations. In Experiment 1, all destinations were visible, and the bias was seen for both second and third subsequent destinations. In Experiments 2 and 3, only the first destination was visible, and the locations of the subsequent destinations were indicated on a diagram and had to be remembered by participants. In Experiment 3, the diagrams were misaligned by 180 degrees. Route choice to the first destination was still influenced by later destinations, but only by the nearer, second destination, and the extent of the bias was reduced as memory load increased. Indications are that differences in route choice between small- and large-scale environments may be due more to cognitive load than to environmental size. PMID- 25821950 TI - One Example of a Model Humanitarian Mission. AB - This paper describes a model humanitarian mission to Guyana; it illustrates the value of excellent ongoing care in collaboration with local physicians and surgeons, cooperation with local government and medical officials, and frequent periodic follow-up missions (always to the same hospital, working with the same staff). This effort has largely avoided the so-called "Seven Sins of Humanitarian Medicine". PMID- 25821951 TI - Invitation and a warm welcome to the 41th Annual Meeting of the Society for Neuropediatrics. PMID- 25821949 TI - Patterns of Use and Short-Term Outcomes of Minimally Invasive Surgery for Malignant Pheochromocytoma: A Population-Level Study. AB - BACKGROUND: Malignant pheochromocytoma is rare, and there is a scarcity of data on the use of minimally invasive surgery (MIS) for treatment. The aims of this study were to analyze patterns of use of MIS for malignant pheochromocytoma in the U.S. and compare short-term outcomes to those of open adrenalectomy. METHODS: Patients with malignant pheochromocytoma undergoing MIS, including laparoscopy, robotic assisted, laparoscopy converted to open, or open adrenalectomy, were culled from the National Cancer Database, from 1998 to 2011. Data were examined using simple summary statistics, Chi2 and student's t tests, Mann-Whitney test, and logistic regression. RESULTS: A total of 36 MIS and 67 open adrenalectomies were identified in 2010-2011. No significant differences were observed between the two treatment groups in demographic characteristics or comorbidities. Preoperative diagnosis of malignancy was made in 52.8% of MIS and 48.5% of open patients (p=NS). MIS and open adrenalectomies did not differ with respect to lymph node metastases, vascular invasion, extra-adrenal-extension, and distant metastases (all p=NS). MIS tended to more often be used to perform partial adrenalectomy (38.9 vs. 20.4% open, p=0.061); surgical margins, 30-day readmission and mortality rates were similar to open adrenalectomy (all p=NS). Tumors removed via MIS were smaller (48.7 vs. 73.3 mm open, p=0.003) and associated with a shorter length of stay. CONCLUSIONS: A significant proportion of patients with malignant pheochromocytomas underwent MIS, with short-term outcomes which are comparable to those of open surgery. Further studies focused on long-term survival and recurrence are needed to assess the role of MIS in the management of these rare tumors. PMID- 25821952 TI - Correction: Discovery of a novel, monocationic, small-molecule inhibitor of scrapie prion accumulation in cultured sheep microglia and Rov cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0051173.]. PMID- 25821954 TI - A new method to quantify and compare the multiple components of fitness--a study case with kelp niche partition by divergent microstage adaptations to temperature. AB - POINT 1: Management of crops, commercialized or protected species, plagues or life-cycle evolution are subjects requiring comparisons among different demographic strategies. The simpler methods fail in relating changes in vital rates with changes in population viability whereas more complex methods lack accuracy by neglecting interactions among vital rates. POINT 2: The difference between the fitness (evaluated by the population growth rate lambda) of two alternative demographies is decomposed into the contributions of the differences between the pair-wised vital rates and their interactions. This is achieved through a full Taylor expansion (i.e. remainder = 0) of the demographic model. The significance of each term is determined by permutation tests under the null hypothesis that all demographies come from the same pool. POINT 3: An example is given with periodic demographic matrices of the microscopic haploid phase of two kelp cryptic species observed to partition their niche occupation along the Chilean coast. The method provided clear and synthetic results showing conditional differentiation of reproduction is an important driver for their differences in fitness along the latitudinal temperature gradient. But it also demonstrated that interactions among vital rates cannot be neglected as they compose a significant part of the differences between demographies. POINT 4: This method allows researchers to access the effects of multiple effective changes in a life-cycle from only two experiments. Evolutionists can determine with confidence the effective causes for changes in fitness whereas population managers can determine best strategies from simpler experimental designs. PMID- 25821953 TI - Lpg0393 of Legionella pneumophila is a guanine-nucleotide exchange factor for Rab5, Rab21 and Rab22. AB - Legionella pneumophila, a human intracellular pathogen, encodes about 290 effector proteins that are translocated into host cells through a secretion machinery. Some of these proteins have been shown to manipulate or subvert cellular processes during infection, but functional roles of a majority of them remain unknown. Lpg0393 is a newly identified Legionella effector classified as a hypothetical protein. Through X-ray crystallographic analysis, we show that Lpg0393 contains a Vps9-like domain, which is structurally most similar to the catalytic core of human Rabex-5 that activates the endosomal Rab proteins Rab5, Rab21 and Rab22. Consistently, Lpg0393 exhibited a guanine-nucleotide exchange factor activity toward the endosomal Rabs. This work identifies the first example of a bacterial guanine-nucleotide exchange factor that is active towards the Rab5 sub-cluster members, implying that the activation of these Rab proteins might be advantageous for the intracellular survival of Legionella. PMID- 25821955 TI - Polarity-dependent asymmetric distribution and MEX-5/6-mediated translational activation of the Era-1 mRNA in C. elegans embryos. AB - The early C. elegans embryo is an attractive model system to investigate fundamental developmental processes. With the exception of mex-3 mRNA, maternally contributed mRNAs are thought to be distributed uniformly in the one-cell embryo. Here, we report and characterize the striking distribution of the mRNA encoding the novel protein ERA-1. We found that era-1 mRNA is enriched in the anterior of the one-cell embryo and present solely in anterior blastomeres thereafter. Although era-1 is not an essential gene, we uncovered that era-1 null mutant embryos are sensitive to slight impairment of embryonic polarity. We found that the asymmetric distribution of era-1 mRNA depends on anterior-posterior polarity cues and on the era-1 3'UTR. Similarly to the era-1 mRNA, the YFP-ERA-1 protein is enriched in anterior blastomeres. Interestingly, we found that the RNA-binding protein MEX-5 is required for era-1 mRNA asymmetry. Furthermore, we show that MEX 5, together with its partially redundant partner MEX-6, are needed to activate era-1 mRNA translation in anterior blastomeres. These findings lead us to propose that MEX-5/6-mediated regulation of era-1 mRNA contributes to robust embryonic development. PMID- 25821956 TI - Baseline survey of root-associated microbes of Taxus chinensis (Pilger) Rehd. AB - Taxol (paclitaxel) a diterpenoid is one of the most effective anticancer drugs identified. Biosynthesis of taxol was considered restricted to the Taxus genera until Stierle et al. discovered that an endophytic fungus isolated from Taxus brevifolia could independently synthesize taxol. Little is known about the mechanism of taxol biosynthesis in microbes, but it has been speculated that its biosynthesis may differ from plants. The microbiome from the roots of Taxus chinensis have been extensively investigated with culture-dependent methods to identify taxol synthesizing microbes, but not using culture independent methods.,Using bar-coded high-throughput sequencing in combination with a metagenomics approach, we surveyed the microbial diversity and gene composition of the root-associated microbiomefrom Taxus chinensis (Pilger) Rehd. High throughput amplicon sequencing revealed 187 fungal OTUs which is higher than any previously reported fungal number identified with the culture-dependent method, suggesting that T. chinensis roots harbor novel and diverse fungi. Some operational taxonomic units (OTU) identified were identical to reported microbe strains possessing the ability to synthesis taxol and several genes previously associated with taxol biosynthesis were identified through metagenomics analysis. PMID- 25821957 TI - Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats. AB - Stroke triggers a systemic inflammatory response that exacerbates the initial injury. Immunizing with peptides derived from CNS proteins can stimulate protective autoimmunity (PA). The most renowned of these peptides is copolymer-1 (Cop-1) also known as glatiramer acetate. This peptide has been approved for use in the treatment of multiple sclerosis. Cop-1-specific T cells cross the blood brain barrier and secrete neurotrophins and anti-inflammatory cytokines that could stimulate proliferation of neural precursor cells and recruit them to the injury site; making it an ideal therapy for acute ischemic stroke. The aim of this work was to evaluate the effect of Cop-1 on neurogenesis and neurological recovery during the acute phase (7 days) and the chronic phase of stroke (60 days) in a rat model of transient middle cerebral artery occlusion (tMCAo). BDNF and NT-3 were quantified and infarct volumes were measured. We demonstrated that Cop-1 improves neurological deficit, enhances neurogenesis (at 7 and 60 days) in the SVZ, SGZ, and cerebral cortex through an increase in NT-3 production. It also decreased infarct volume even at the chronic phase of tMCAo. The present manuscript fortifies the support for the use of Cop-1 in acute ischemic stroke. PMID- 25821958 TI - Impact of cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus on the amyloid cascade. AB - The aim of this study was to determine whether the improvement of cerebrospinal fluid (CSF) flow dynamics by CSF shunting, can suppress the oligomerization of amyloid beta-peptide (Abeta), by measuring the levels of Alzheimer's disease (AD) related proteins in the CSF before and after lumboperitoneal shunting. Lumbar CSF from 32 patients with idiopathic normal pressure hydrocephalus (iNPH) (samples were obtained before and 1 year after shunting), 15 patients with AD, and 12 normal controls was analyzed for AD-related proteins and APLP1-derived Abeta-like peptides (APL1beta) (a surrogate marker for Abeta). We found that before shunting, individuals with iNPH had significantly lower levels of soluble amyloid precursor proteins (sAPP) and Abeta38 compared to patients with AD and normal controls. We divided the patients with iNPH into patients with favorable (improvement >= 1 on the modified Rankin Scale) and unfavorable (no improvement on the modified Rankin Scale) outcomes. Compared to the unfavorable outcome group, the favorable outcome group showed significant increases in Abeta38, 40, 42, and phosphorylated-tau levels after shunting. In contrast, there were no significant changes in the levels of APL1beta25, 27, and 28 after shunting. After shunting, we observed positive correlations between sAPPalpha and sAPPbeta, Abeta38 and 42, and APL1beta25 and 28, with shifts from sAPPbeta to sAPPalpha, from APL1beta28 to 25, and from Abeta42 to 38 in all patients with iNPH. Our results suggest that Abeta production remained unchanged by the shunt procedure because the levels of sAPP and APL1beta were unchanged. Moreover, the shift of Abeta from oligomer to monomer due to the shift of Abeta42 (easy to aggregate) to Abeta38 (difficult to aggregate), and the improvement of interstitial-fluid flow, could lead to increased Abeta levels in the CSF. Our findings suggest that the shunting procedure can delay intracerebral deposition of Abeta in patients with iNPH. PMID- 25821959 TI - The role of zinc and iron-folic acid supplementation on early child temperament and eating behaviors in rural Nepal: a randomized controlled trial. AB - Child eating behaviors play an important role in nutrient intake, ultimately affecting child growth and later outcomes in adulthood. The study assessed the effects of iron-folic acid and zinc supplementation on child temperament and child eating behaviors in rural Nepal. Children (N = 569) aged 4-17 months in Sarlahi district, southern Nepal were randomized to receive daily supplements of placebo, iron-folic acid, zinc, or zinc plus iron-folic acid and followed for approximately 1 year. At baseline and four follow-up visits mothers completed questionnaires including information on demographic characteristics and child temperament and eating behaviors. The main effects of zinc and iron-folic acid supplementation on temperament and eating behaviors were assessed through crude and adjusted differences in mean cumulative score changes between visits 1 and 5. The adjusted rate-of-change for these outcomes was modeled using generalized estimating equations. Mean changes in temperament scores and in eating behavior scores between visits 1 and 5 were not significant in either the zinc or non-zinc group. Children in the iron-folic acid group increased temperament scores by 0.37 points over 5 visits (95% CI 0.02, 0.7), which was not significant after adjustment. Neither the adjusted rate-of-change in temperament scores between zinc and non-zinc (beta = -0.03, 95% CI -0.3, 0.2) or iron-folic acid and non iron-folic acid (beta = 0.08, 95% CI -0.2, 0.3) were significantly different. Adjusted rate of change analysis showed no significant difference between zinc and non-zinc (beta = -0.14, 95% CI -0.3, 0.04) or between iron and non-iron eating behavior scores (beta = -0.11, 95% CI -0.3, 0.1). Only among children with iron-deficiency anemia at baseline was there a significant decrease in eating behavior score, indicating better eating behaviors, when supplemented with zinc (beta = -0.3, 95% CI -0.6, -0.01), Ultimately, this effect of zinc on eating behaviors was the only effect we observed after approximately one year of micronutrient supplementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00109551. PMID- 25821960 TI - A comparison between multiple regression models and CUN-BAE equation to predict body fat in adults. AB - BACKGROUND: Because the accurate measure of body fat (BF) is difficult, several prediction equations have been proposed. The aim of this study was to compare different multiple regression models to predict BF, including the recently reported CUN-BAE equation. METHODS: Multi regression models using body mass index (BMI) and body adiposity index (BAI) as predictors of BF will be compared. These models will be also compared with the CUN-BAE equation. For all the analysis a sample including all the participants and another one including only the overweight and obese subjects will be considered. The BF reference measure was made using Bioelectrical Impedance Analysis. RESULTS: The simplest models including only BMI or BAI as independent variables showed that BAI is a better predictor of BF. However, adding the variable sex to both models made BMI a better predictor than the BAI. For both the whole group of participants and the group of overweight and obese participants, using simple models (BMI, age and sex as variables) allowed obtaining similar correlations with BF as when the more complex CUN-BAE was used (rho = 0:87 vs. rho = 0:86 for the whole sample and rho = 0:88 vs. rho = 0:89 for overweight and obese subjects, being the second value the one for CUN-BAE). CONCLUSIONS: There are simpler models than CUN-BAE equation that fits BF as well as CUN-BAE does. Therefore, it could be considered that CUN BAE overfits. Using a simple linear regression model, the BAI, as the only variable, predicts BF better than BMI. However, when the sex variable is introduced, BMI becomes the indicator of choice to predict BF. PMID- 25821961 TI - Hemodynamic changes of the middle hepatic vein in patients with pulmonary hypertension using echocardiography. AB - The aim of this study was to analyze the changes of the middle hepatic vein (MHV) spectra in patients with pulmonary hypertension (PH) caused by congenital heart disease (CHD) and determine the proper parameters of MHV to predict PH. Eighty patients with CHD were included, whose pulmonary artery pressure was measured via right heart catheterization, and the MHV spectra were detected via echocardiography. The peak value of velocity (V) and velocity time integral (VTI) of the waves, including S wave, D wave and A wave, were measured at the end of inspiration. The values of the MHV parameters that were predictive of PH were evaluated and their cut-off points were determined. Compared with the control group, V of S wave (S), VTI of S wave (SVTI), V of D wave (D), VTI of D wave (DVTI) decreased and V of A wave (A), VTI of A wave (AVTI), A/S, AVTI/SVTI, A/(S+D), AVTI/ (SVTI+DVTI) increased in the PH group. These differences were statistically significant (P<0.05). A correlation analysis determined that the ratios of A/S, A/(S+D), AVTI/(SVTI+DVTI) were positively correlated with pulmonary artery mean pressure (r=0.529,0.575,0.438,P<0.001). An ROC curve analysis determined that the diagnostic effect of A/(S+D) was superior to the other two parameters. On the ROC curve, when the ratio of A/(S+D) was 0.30, the sensitivity was 85.37% and specificity was 75.00% for predicting PH. The spectral parameters of MHV, including the ratios of A/S, A/(S+D) and AVTI/(SVTI+DVTI), increased with increasing pulmonary pressure in CHD patients. When the ratio of A/(S+D) was 0.30 in MHV spectra, it had sufficient sensitivity and specificity for diagnosing PH, and this method could be used as a new non-invasive complementary echocardiographic parameter for predicting PH. PMID- 25821962 TI - Comparison of oral microbial profiles between children with severe early childhood caries and caries-free children using the human oral microbe identification microarray. AB - OBJECTIVE: Early childhood caries (ECC) has become a prevalent public health problem among Chinese preschool children. The bacterial microflora is considered to be an important factor in the formation and progress of dental caries. However, high-throughput and large-scale studies of the primary dentition are lacking. The present study aimed to compare oral microbial profiles between children with severe ECC (SECC) and caries-free children. METHODS: Both saliva and supragingival plaque samples were obtained from children with SECC (n = 20) and caries-free children (n = 20) aged 3 to 4 years. The samples were assayed using the Human Oral Microbe Identification Microarray (HOMIM). RESULTS: A total of 379 bacterial species were detected in both the saliva and supragingival plaque samples from all children. Thirteen (including Streptococcus) and two (Streptococcus and Actinomyces) bacterial species in supragingival plaque and saliva, respectively, showed significant differences in prevalence between the two groups. Of these, the frequency of Streptococcus mutans detection was significantly higher in both saliva (p = 0.026) and plaque (p = 0.006) samples from the SECC group than in those from the caries-free group. CONCLUSIONS: The findings of our study revealed differences in the oral microbiota between the SECC and caries-free groups Several genera, including Streptococcus, Porphyromonas, and Actinomyces, are strongly associated with SECC and can be potential biomarkers of dental caries in the primary dentition. PMID- 25821963 TI - Week 120 efficacy of tenofovir, lamivudine and lopinavir/r-based second-line antiretroviral therapy in treatment-experienced HIV patients. AB - BACKGROUND: Tenofovir (TDF) and ritonavir-boosted lopinavir (LPV/r) were not introduced to China as second-line medications until 2009. The efficacy and safety of TDF/3TC/LPV/r based second-line regimen have not been evaluated in Chinese HIV patients who failed first-line regimens. METHODS: This was a multicenter cohort study recruiting patients from Beijing, Shanghai, Guangdong, and Henan provinces between November 2008 and January 2010. Eighty HIV infected patients failing first-line regimens with serum creatinine lower than 1.5 times the upper limit of normal received TDF+ lamivudine (3TC)+ LPV/r were followed up for 120 weeks. CD4 cell count, viral load, and estimated glomerular filtration rate (eGFR) were monitored at each visit. RESULTS: At baseline, 31.2% and 48.8% of patients had moderate/high-level resistance to TDF and 3TC, respectively; while 2.5% of patients had only low-level resistance to LPV/r. During 120 weeks of follow-up, virological suppression rate reached over 70% (<40 copies/ml) and 90% (<400 copies/ml), and median CD4 cell count increased from 157 cells/MUL at baseline to 307 cells/MUL at week 120. Baseline drug-resistance mutations had no impact on the efficacy of second-line antiretroviral therapy. Median eGFR dropped from 104.7 ml/min/1.73m2 at baseline to 95.6 ml/min/1.73m2 at week 24 and then recovered after week 96. CONCLUSION: This study for the first time demonstrated that TDF+ 3TC+ LPV/r was efficacious as second-line regimen with acceptable nephrotoxicity profiles in patients who failed zidovudine or stavudine based first-line regimens in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT00872417. PMID- 25821964 TI - Hedging your bets: intermediate movements as optimal behavior in the context of an incomplete decision. AB - Existing theories of movement planning suggest that it takes time to select and prepare the actions required to achieve a given goal. These theories often appeal to circumstances where planning apparently goes awry. For instance, if reaction times are forced to be very low, movement trajectories are often directed between two potential targets. These intermediate movements are generally interpreted as errors of movement planning, arising either from planning being incomplete or from parallel movement plans interfering with one another. Here we present an alternative view: that intermediate movements reflect uncertainty about movement goals. We show how intermediate movements are predicted by an optimal feedback control model that incorporates an ongoing decision about movement goals. According to this view, intermediate movements reflect an exploitation of compatibility between goals. Consequently, reducing the compatibility between goals should reduce the incidence of intermediate movements. In human subjects, we varied the compatibility between potential movement goals in two distinct ways: by varying the spatial separation between targets and by introducing a virtual barrier constraining trajectories to the target and penalizing intermediate movements. In both cases we found that decreasing goal compatibility led to a decreasing incidence of intermediate movements. Our results and theory suggest a more integrated view of decision-making and movement planning in which the primary bottleneck to generating a movement is deciding upon task goals. Determining how to move to achieve a given goal is rapid and automatic. PMID- 25821965 TI - Pre-existing mutations in reverse transcriptase of hepatitis B virus in treatment naive Chinese patients with chronic hepatitis B. AB - High rate of viral replication and lacking of proofreading activity in hepatitis B virus (HBV) polymerase lead to the generation of mutations in HBV virus. Mutations in the reverse transcriptase (RT) region of HBV polymerase are demonstrated to be strongly associated with drug resistance during antiviral treatment. However, the presence of mutations as well as its clinical significance in treatment-naive hepatitis patients (defined as pre-existing mutations) need to be further investigated. In the present study, a total of 168 serum samples from treatment-naive chronic hepatitis B (CHB) patients were collected, and the RT region of HBV polymerase was sequenced. The results showed that pre-existing mutations in the RT region of HBV polymerase were detected in 43 of 168 (25.6%) treatment-naive CHB patients within which there were no well characterized primary nucleotide analogs (NAs) resistance sites. Three dominant sites at rt191, rt207 and rt226 were found mutant in 7(16.28%), 8(18.60%), and 14(32.56%) samples respectively among these 43 patients. No significant correlation was found between pre-existing mutations and gender, age, HBV genotype, ALT, HBeAg or HBV DNA loads. However, patients with pre-existing RT mutations under HBeAg sero-negative status exhibited decreased HBV DNA loads, which contributed to the decreased HBV DNA loads in the total HBeAg sero-negative patients. The above investigation indicated that there was a prevalence of pre existing mutations in RT region of HBV polymerase which might affect the serum HBV DNA level in treatment-naive CHB patients. Its effects on the occurrence of NAs resistance and the prognosis after treatment need to be further investigated. PMID- 25821966 TI - Effect of anti-ApoA-I antibody-coating of stents on neointima formation in a rabbit balloon-injury model. AB - BACKGROUND AND AIMS: Since high-density lipoprotein (HDL) has pro-endothelial and anti-thrombotic effects, a HDL recruiting stent may prevent restenosis. In the present study we address the functional characteristics of an apolipoprotein A-I (ApoA-I) antibody coating in vitro. Subsequently, we tested its biological performance applied on stents in vivo in rabbits. MATERIALS AND METHODS: The impact of anti ApoA-I- versus apoB-antibody coated stainless steel discs were evaluated in vitro for endothelial cell adhesion, thrombin generation and platelet adhesion. In vivo, response to injury in the iliac artery of New Zealand white rabbits was used as read out comparing apoA-I-coated versus bare metal stents. RESULTS: ApoA-I antibody coated metal discs showed increased endothelial cell adhesion and proliferation and decreased thrombin generation and platelet adhesion, compared to control discs. In vivo, no difference was observed between ApoA-I and BMS stents in lumen stenosis (23.3+/-13.8% versus 23.3+/-11.3%, p=0.77) or intima surface area (0.81+/-0.62 mm2 vs 0.84+/-0.55 mm2, p=0.85). Immunohistochemistry also revealed no differences in cell proliferation, fibrin deposition, inflammation and endothelialization. CONCLUSION: ApoA-I antibody coating has potent pro-endothelial and anti-thrombotic effects in vitro, but failed to enhance stent performance in a balloon injury rabbit model in vivo. PMID- 25821967 TI - Sustained endothelial expression of HoxA5 in vivo impairs pathological angiogenesis and tumor progression. AB - HoxA5 is expressed in quiescent endothelial cells (EC), but absent in activated angiogenic EC. To examine the efficacy of targeting HoxA5 therapeutically to quell pathologic or tumor angiogenesis, we generated an inducible, transgenic mouse model of sustained HoxA5 expression in ECs. During pathologic angiogenesis, sustained HoxA5 regulates expression several angiogenic effector molecules, notably increased expression of TSP-2 and reduced expression of VEGF, thus leading to inhibition of pathological angiogenesis in tissues. To evaluate if this impressive reduction of vascularization could also impact tumor angiogenesis, HoxA5 mice were bred with a mouse model of de novo squamous carcinogenesis, e.g., K14-HPV16 mice. Activation of EC-HoxA5 significantly reduced infiltration by mast cells into neoplastic skin, an early hallmark of progression to dysplasia, reduced angiogenic vasculature, and blunted characteristics of tumor progression. To evaluate HoxA5 as a therapeutic, topical application of a HoxA5 transgene onto early neoplastic skin of K14-HPV16 mice similarly resulted in a significant impairment of angiogenic vasculature and progression to dysplasia to a similar extent as observed with genetic delivery of HoxA5. Together these data indicate that HoxA5 represents a novel molecule for restricting pathological and tumorigenic angiogenesis. PMID- 25821968 TI - Structural and immunological effects of skin cryoablation in a mouse model. AB - Cryoablation is therapeutically applied for various disorders in several organs, and skin diseases are typical targets as this cryotherapy has been widely used for viral warts, benign tumors, and actinic keratosis. The main mechanisms of cryoablation consist of direct freezing effect on skin constituents, thrombosis formation in microcirculation, and subsequent immunological responses. Among them, however, the immunological mechanism remains unelucidated, and it is an issue how the direct freezing injury induces immunological consequences. We established a mouse cryoablation model with liquid nitrogen applied to the shaved back skin, and used this system to study the immunological excitement. After application of liquid nitrogen, the thermal decrease ratio was -25 degrees C/sec or less and the lowest temperature was less than -100 degrees C, which was sufficient to induce ulceration. Destruction of cornified layer and necrosis of epidermal cells were observed in transmission electron microscopy image, and increased transepidermal water loss and skin permeability were detected by the functional measurements. By flow cytometry, antigen-presenting dendritic cells (DCs), including PDCA1+B220+CD19- plasmacytoid DCs (pDCs) and CD11c+ myeloid DCs, as well as neutrophils and macrophages were increased in subcutaneous tissue. In parallel, the mRNA expressions of interferon alpha1 which are known as pDC producing cytokines, was elevated. We also found marked degranulation of mast cells, providing a possibility that released histamine attracts pDCs. Finally, FITC migration assay revealed that pDCs and CD11c+ DCs emigrated from the cryoablated skin to the draining lymph nodes. Our study suggests that cryoablation induces destruction of the barrier/epidermis, accumulation of pDCs and CD11c+ DCs to the skin, and migration of DCs to regional lymph nodes. Viral elements or tumor cell lysates released from damaged keratinocytes may stimulate the DCs, thereby leading to antiviral or antitumor effect. PMID- 25821969 TI - Methylation levels of SLC23A2 and NCOR2 genes correlate with spinal muscular atrophy severity. AB - Spinal muscular atrophy (SMA) is a monogenic neurodegenerative disorder subdivided into four different types. Whole genome methylation analysis revealed 40 CpG sites associated with genes that are significantly differentially methylated between SMA patients and healthy individuals of the same age. To investigate the contribution of methylation changes to SMA severity, we compared the methylation level of found CpG sites, designed as "targets", as well as the nearest CpG sites in regulatory regions of ARHGAP22, CDK2AP1, CHML, NCOR2, SLC23A2 and RPL9 in three groups of SMA patients. Of notable interest, compared to type I SMA male patients, the methylation level of a target CpG site and one nearby CpG site belonging to the 5'UTR of SLC23A2 were significantly hypomethylated 19-22% in type III-IV patients. In contrast to type I SMA male patients, type III-IV patients demonstrated a 16% decrease in the methylation levels of a target CpG site, belonging to the 5'UTR of NCOR2. To conclude, this study validates the data of our previous study and confirms significant methylation changes in the SLC23A2 and NCOR2 regulatory regions correlates with SMA severity. PMID- 25821970 TI - A framework for the monitoring and evaluation of international surgical initiatives in low- and middle-income countries. AB - BACKGROUND: An estimated two billion people worldwide lack adequate access to surgical care. To address this humanitarian emergency, an increasing number of international surgical partnerships are emerging between developed and low- and middle-income countries (LMICs). At present, there are no clear indicators that may be used to assess the effectiveness of such initiatives. STUDY DESIGN: We conducted an international qualitative study of 31 surgeons from developed and LMICs involved in international partnerships across a variety of subspecialties. Thematic analysis and grounded theory were applied in order to develop a practical framework that may be applied to monitor and evaluate global surgical initiatives. RESULTS: Several themes emerged from the study: (i) there is a large unmet need to establish and maintain prospective databases in LMICs to inform the monitoring and evaluation of international surgical partnerships; (ii) assessment of initiatives must occur longitudinally over the span of several years; (ii) the domains of assessment are contextual and encompass cultural, institutional and regional factors; and (iv) evaluation strategies should explore broader impact within the community and country. Based on thematic analysis within the domains of inputs, outputs and outcomes, a framework for the monitoring and evaluation of international surgical initiatives, the Framework for the Assessment of InteRNational Surgical Success (FAIRNeSS) is proposed. CONCLUSIONS: In response to the increasing number of surgical partnerships between developed and LMICs, we propose a framework to monitor and evaluate international surgical initiatives. PMID- 25821971 TI - Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. AB - Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-alpha) levels along with nuclear factor kappa B (NF-kappaB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase 3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses. PMID- 25821972 TI - Transcriptome analysis of post-hatch breast muscle in legacy and modern broiler chickens reveals enrichment of several regulators of myogenic growth. AB - Agriculture provides excellent model systems for understanding how selective pressure, as applied by humans, can affect the genomes of plants and animals. One such system is modern poultry breeding in which intensive genetic selection has been applied for meat production in the domesticated chicken. As a result, modern meat-type chickens (broilers) exhibit enhanced growth, especially of the skeletal muscle, relative to their legacy counterparts. Comparative studies of modern and legacy broiler chickens provide an opportunity to identify genes and pathways affected by this human-directed evolution. This study used RNA-seq to compare the transcriptomes of a modern and a legacy broiler line to identify differentially enriched genes in the breast muscle at days 6 and 21 post-hatch. Among the 15,945 genes analyzed, 10,841 were expressed at greater than 0.1 RPKM. At day 6 post hatch 189 genes, including several regulators of myogenic growth and development, were differentially enriched between the two lines. The transcriptional profiles between lines at day 21 post-hatch identify 193 genes differentially enriched and still include genes associated with myogenic growth. This study identified differentially enriched genes that regulate myogenic growth and differentiation between the modern and legacy broiler lines. Specifically, differences in the ratios of several positive (IGF1, IGF1R, WFIKKN2) and negative (MSTN, ACE) myogenic growth regulators may help explain the differences underlying the enhanced growth characteristics of the modern broilers. PMID- 25821975 TI - Rhizodeposition of nitrogen and carbon by mungbean (Vigna radiata L.) and its contribution to intercropped oats (Avena nuda L.). AB - Compounds released by mungbean roots potentially represent an enormous source of nitrogen (N) and carbon (C) in mungbean-oat intercropping systems. In this study, an in situ experiment was conducted using a 15N - 13C double stem-feeding method to measure N and C derived from the rhizodeposition (NdfR and CdfR) of mungbean and their transfer to oats in an intercropping system. Mungbean plants were sole cropped (S) or intercropped (I) with oat. The plants were labeled 5 weeks after planting and were harvested at the beginning of pod setting (Ip and Sp) and at maturity (Im and Sm). More than 60% and 50% of the applied 15N and 13C, respectively, were recovered in each treatment, with 15N and 13C being quite uniformly distributed in the different plant parts. NdfR represented 9.8% (Sp), 9.2% (Ip), 20.1% (Sm), and 21.2% (Im) of total mungbean plant N, whereas CdfR represented 13.3% (Sp), 42.0% (Ip), 15.4% (Sm), and 22.6% (Im) of total mungbean plant C. When considering the part of rhizodeposition transferred to associated oat, intercropping mungbean released more NdfR and CdfR than mungbean alone. About 53.4-83.2% of below-ground plant N (BGP-N) and 58.4-85.9% of BGP-C originated from NdfR and CdfR, respectively. The N in oats derived from mungbean increased from 7.6% at the pod setting stage to 9.7% at maturity, whereas the C in oats increased from 16.2% to 22.0%, respectively. Only a small percentage of rhizodeposition from mungbean was transferred to oats in the intercropping systems, with a large percentage remaining in the soil. This result indicates that mungbean rhizodeposition might contribute to higher N and C availability in the soil for subsequent crops. PMID- 25821973 TI - Transgenic expression of the dicotyledonous pattern recognition receptor EFR in rice leads to ligand-dependent activation of defense responses. AB - Plant plasma membrane localized pattern recognition receptors (PRRs) detect extracellular pathogen-associated molecules. PRRs such as Arabidopsis EFR and rice XA21 are taxonomically restricted and are absent from most plant genomes. Here we show that rice plants expressing EFR or the chimeric receptor EFR::XA21, containing the EFR ectodomain and the XA21 intracellular domain, sense both Escherichia coli- and Xanthomonas oryzae pv. oryzae (Xoo)-derived elf18 peptides at sub-nanomolar concentrations. Treatment of EFR and EFR::XA21 rice leaf tissue with elf18 leads to MAP kinase activation, reactive oxygen production and defense gene expression. Although expression of EFR does not lead to robust enhanced resistance to fully virulent Xoo isolates, it does lead to quantitatively enhanced resistance to weakly virulent Xoo isolates. EFR interacts with OsSERK2 and the XA21 binding protein 24 (XB24), two key components of the rice XA21 mediated immune response. Rice-EFR plants silenced for OsSERK2, or overexpressing rice XB24 are compromised in elf18-induced reactive oxygen production and defense gene expression indicating that these proteins are also important for EFR mediated signaling in transgenic rice. Taken together, our results demonstrate the potential feasibility of enhancing disease resistance in rice and possibly other monocotyledonous crop species by expression of dicotyledonous PRRs. Our results also suggest that Arabidopsis EFR utilizes at least a subset of the known endogenous rice XA21 signaling components. PMID- 25821974 TI - Identification of real microRNA precursors with a pseudo structure status composition approach. AB - Containing about 22 nucleotides, a micro RNA (abbreviated miRNA) is a small non coding RNA molecule, functioning in transcriptional and post-transcriptional regulation of gene expression. The human genome may encode over 1000 miRNAs. Albeit poorly characterized, miRNAs are widely deemed as important regulators of biological processes. Aberrant expression of miRNAs has been observed in many cancers and other disease states, indicating they are deeply implicated with these diseases, particularly in carcinogenesis. Therefore, it is important for both basic research and miRNA-based therapy to discriminate the real pre-miRNAs from the false ones (such as hairpin sequences with similar stem-loops). Particularly, with the avalanche of RNA sequences generated in the postgenomic age, it is highly desired to develop computational sequence-based methods in this regard. Here two new predictors, called "iMcRNA-PseSSC" and "iMcRNA-ExPseSSC", were proposed for identifying the human pre-microRNAs by incorporating the global or long-range structure-order information using a way quite similar to the pseudo amino acid composition approach. Rigorous cross-validations on a much larger and more stringent newly constructed benchmark dataset showed that the two new predictors (accessible at http://bioinformatics.hitsz.edu.cn/iMcRNA/) outperformed or were highly comparable with the best existing predictors in this area. PMID- 25821976 TI - Oxidative stress as a pharmacological target for medicinal chemistry: synthesis and evaluation of compounds with redox activity - part 4. PMID- 25821978 TI - Correction: Temporal evolution of ischemic lesions in nonhuman primates: a diffusion and perfusion MRI study. PMID- 25821979 TI - Correction: transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutatmatergic- and insulin-mediated neuronal processes. PMID- 25821977 TI - Influence of a non-hospital medical care facility on antimicrobial resistance in wastewater. AB - The global widespread use of antimicrobials and accompanying increase in resistant bacterial strains is of major public health concern. Wastewater systems and wastewater treatment plants are considered a niche for antibiotic resistance genes (ARGs), with diverse microbial communities facilitating ARG transfer via mobile genetic element (MGE). In contrast to hospital sewage, wastewater from other health care facilities is still poorly investigated. At the instance of a nursing home located in south-west Germany, in the present study, shotgun metagenomics was used to investigate the impact on wastewater of samples collected up- and down-stream in different seasons. Microbial composition, ARGs and MGEs were analyzed using different annotation approaches with various databases, including Antibiotic Resistance Ontologies (ARO), integrons and plasmids. Our analysis identified seasonal differences in microbial communities and abundance of ARG and MGE between samples from different seasons. However, no obvious differences were detected between up- and downstream samples. The results suggest that, in contrast to hospitals, sewage from the nursing home does not have a major impact on ARG or MGE in wastewater, presumably due to much less intense antimicrobial usage. Possible limitations of metagenomic studies using high-throughput sequencing for detection of genes that seemingly confer antibiotic resistance are discussed. PMID- 25821980 TI - Building trust with people receiving supported employment and housing first services. AB - OBJECTIVES: The developing literature on supported employment for people who have a mental illness and recent history of homelessness has yet to explore the relationship between clients and their employment specialists. The objective of the present article is to explore and understand the way in which service users experience supported employment services and how these experiences differ from those receiving usual services. METHOD: Semistructured qualitative interviews were conducted with 27 people from a randomized controlled trial of supported employment, 14 receiving supported employment, and 13 receiving usual services. Thematic content analysis was used to generate themes and compare experiences between the 2 groups. RESULTS: Trust emerged as an important facilitator to development of a collaborative relationship. It developed with time and featured in the narratives of participants who found jobs. Lack of trust and communication was associated with greater difficulty finding work. People receiving usual services rarely had repeated contact with service providers and therefore did not develop working alliances to the same extent as people receiving supported employment. CONCLUSIONS AND IMPLICATIONS: Without the support of an employment specialist, participants receiving usual services relied more on internal motivation to search for employment opportunities. Programs assisting people to reach their employment goals must be sensitive to homelessness-specific experiences that may make establishing trust difficult. Vocational services should be designed to allow clients to deal exclusively with 1 service provider to permit the development of a working alliance. PMID- 25821981 TI - Stigma of taking psychiatric medications among psychiatric outpatient veterans. AB - OBJECTIVE: Service members and veterans underutilize mental health services due to stigma. The study investigated stigma of taking psychiatric medications, and its relationship to internalized stigma of mental illness, gender, age, service era, duration of taking medications, and their perceived helpfulness. METHOD: Of the 200 veterans completing an anonymous questionnaire in an outpatient mental health waiting room, data are presented on the 159 who reported taking psychiatric medications. RESULTS: Medication stigma was related to internalized stigma and was common: over one half reported feeling uncomfortable disclosing or feeling judged, and about one fifth reported feeling embarrassed. Medication stigma was not related to gender, duration, or helpfulness. Younger age was associated with feeling judged, and more recent service era was associated with shame. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Medication stigma among veterans is common and warrants further study. Discomfort disclosing and feeling judged might be particularly worthy targets of discussion in shared decisions about medication. PMID- 25821982 TI - Modeling stigma, help-seeking attitudes, and intentions to seek behavioral healthcare in a clinical military sample. AB - OBJECTIVE: This study examined the relationship between public and self-stigma of seeking behavioral health services, and help-seeking attitudes and intent in a sample of active duty military personnel currently being assessed for traumatic brain injuries in a military health center. Although it has been suggested that many military personnel in need of care do not seek services due to concerns with stigma it is not fully clear what role different types of stigma play in the process. METHOD: Using previously collected data from a clinical sample of 97 military personnel, we conducted path analyses to test the mediation effects of self-stigma on the relationship between public stigma and attitudes toward and intentions to seek behavioral health care. RESULTS: In contrast to a model of military stigma but in line with research with civilian samples, results from this study indicate that self-stigma fully mediates the relationship between public stigma and help-seeking attitudes and intentions. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These results indicate that programming aimed at increasing mental health care use in the military might best focus on reducing self-stigma associated with seeking mental health services. PMID- 25821983 TI - The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism. AB - ISWI family chromatin remodelers typically organize nucleosome arrays, while SWI/SNF family remodelers (RSC) typically disorganize and eject nucleosomes, implying an antagonism that is largely unexplored in vivo. Here, we describe two independent genetic screens for rsc suppressors that yielded mutations in the promoter-focused ISW1a complex or mutations in the 'basic patch' of histone H4 (an epitope that regulates ISWI activity), strongly supporting RSC-ISW1a antagonism in vivo. RSC and ISW1a largely co-localize, and genomic nucleosome studies using rsc isw1 mutant combinations revealed opposing functions: promoters classified with a nucleosome-deficient region (NDR) gain nucleosome occupancy in rsc mutants, but this gain is attenuated in rsc isw1 double mutants. Furthermore, promoters lacking NDRs have the highest occupancy of both remodelers, consistent with regulation by nucleosome occupancy, and decreased transcription in rsc mutants. Taken together, we provide the first genetic and genomic evidence for RSC-ISW1a antagonism and reveal different mechanisms at two different promoter architectures. PMID- 25821984 TI - Oxyntomodulin regulates resetting of the liver circadian clock by food. AB - Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light-dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues. PMID- 25821985 TI - Rab6 regulation of the kinesin family KIF1C motor domain contributes to Golgi tethering. AB - Most kinesins transport cargoes bound to their C-termini and use N-terminal motor domains to move along microtubules. We report here a novel function for KIF1C: it transports Rab6A-vesicles and can influence Golgi complex organization. These activities correlate with KIF1C's capacity to bind the Golgi protein Rab6A directly, both via its motor domain and C-terminus. Rab6A binding to the motor domain inhibits microtubule interaction in vitro and in cells, decreasing the amount of motile KIF1C. KIF1C depletion slows protein delivery to the cell surface, interferes with vesicle motility, and triggers Golgi fragmentation. KIF1C can protect Golgi membranes from fragmentation in cells lacking an intact microtubule network. Rescue of fragmentation requires sequences that enable KIF1C to bind Rab6A at both ends, but not KIF1C motor function. Rab6A binding to KIF1C's motor domain represents an entirely new mode of regulation for a kinesin motor, and likely has important consequences for KIF1C's cellular functions. PMID- 25821986 TI - Genetic basis of sRNA quantitative variation analyzed using an experimental population derived from an elite rice hybrid. AB - We performed a genetic analysis of sRNA abundance in flag leaf from an immortalized F2 (IMF2) population in rice. We identified 53,613,739 unique sRNAs and 165,797 sRNA expression traits (s-traits). A total of 66,649 s-traits mapped 40,049 local-sQTLs and 30,809 distant-sQTLs. By defining 80,362 sRNA clusters, 22,263 sRNA cluster QTLs (scQTLs) were recovered for 20,249 of all the 50,139 sRNA cluster expression traits (sc-traits). The expression levels for most of s traits from the same genes or the same sRNA clusters were slightly positively correlated. While genetic co-regulation between sRNAs from the same mother genes and between sRNAs and their mother genes was observed for a portion of the sRNAs, most of the sRNAs and their mother genes showed little co-regulation. Some sRNA biogenesis genes were located in distant-sQTL hotspots and showed correspondence with specific length classes of sRNAs suggesting their important roles in the regulation and biogenesis of the sRNAs. PMID- 25821987 TI - Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. AB - Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit(+) hematopoietic progenitors, megakaryocytes, and Leptin Receptor(+) (LepR(+)) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR(+) cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR(+) stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery. PMID- 25821989 TI - The self-organization of grid cells in 3D. AB - Do we expect periodic grid cells to emerge in bats, or perhaps dolphins, exploring a three-dimensional environment? How long will it take? Our self organizing model, based on ring-rate adaptation, points at a complex answer. The mathematical analysis leads to asymptotic states resembling face centered cubic (FCC) and hexagonal close packed (HCP) crystal structures, which are calculated to be very close to each other in terms of cost function. The simulation of the full model, however, shows that the approach to such asymptotic states involves several sub-processes over distinct time scales. The smoothing of the initially irregular multiple fields of individual units and their arrangement into hexagonal grids over certain best planes are observed to occur relatively quickly, even in large 3D volumes. The correct mutual orientation of the planes, though, and the coordinated arrangement of different units, take a longer time, with the network showing no sign of convergence towards either a pure FCC or HCP ordering. PMID- 25821990 TI - Chemistry and anticarcinogenic mechanisms of glycoalkaloids produced by eggplants, potatoes, and tomatoes. AB - Inhibition of cancer can occur via apoptosis, a genetically directed process of cell self-destruction that involves numerous biomarkers and signaling pathways. Glycoalkaloids are nitrogen-containing secondary plant metabolites found in numerous Solanaceous plants including eggplants, potatoes, and tomatoes. Exposure of cancer cells to glycoalkaloids produced by eggplants (alpha-solamargine and alpha-solasonine), potatoes (alpha-chaconine and alpha-solanine), and tomatoes (alpha-tomatine) or their hydrolysis products (mono-, di-, and trisaccharide derivatives and the aglycones solasodine, solanidine, and tomatidine) inhibits the growth of the cells in culture (in vitro) as well as tumor growth in vivo. This overview comprehensively surveys and consolidates worldwide efforts to define the following aspects of these natural compounds: (a) their prevalence in the three foods; (b) their chemistry and structure-activity relationships; (c) the reported factors (biomarkers, signaling pathways) associated with apoptosis of bone, breast, cervical, colon, gastric, glioblastoma, leukemia, liver, lung, lymphoma, melanoma, pancreas, prostate, and squamous cell carcinoma cell lines in vitro and the in vivo inhibition of tumor formation and growth in fish and mice and in human skin cancers; and (d) future research needs. The described results may make it possible to better relate the structures of the active compounds to their health-promoting function, individually, in combination, and in food, and allow the consumer to select glycoalkaloid-containing food with the optimal content of nontoxic beneficial compounds. The described findings are expected to be a valuable record and resource for further investigation of the health benefits of food-related natural compounds. PMID- 25821988 TI - G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L. AB - Autophagy is an important intracellular catabolic mechanism involved in the removal of misfolded proteins. Atg14L, the mammalian ortholog of Atg14 in yeast and a critical regulator of autophagy, mediates the production PtdIns3P to initiate the formation of autophagosomes. However, it is not clear how Atg14L is regulated. In this study, we demonstrate that ubiquitination and degradation of Atg14L is controlled by ZBTB16-Cullin3-Roc1 E3 ubiquitin ligase complex. Furthermore, we show that a wide range of G-protein-coupled receptor (GPCR) ligands and agonists regulate the levels of Atg14L through ZBTB16. In addition, we show that the activation of autophagy by pharmacological inhibition of GPCR reduces the accumulation of misfolded proteins and protects against behavior dysfunction in a mouse model of Huntington's disease. Our study demonstrates a common molecular mechanism by which the activation of GPCRs leads to the suppression of autophagy and a pharmacological strategy to activate autophagy in the CNS for the treatment of neurodegenerative diseases. PMID- 25821991 TI - Charge-enhanced acidity and catalyst activation. AB - Acidities are commonly measured in polar solvents but catalytic reactions are typically carried out in nonpolar media. IR spectra of a series of phenols in CCl4 and 1% CD3CN/CCl4 provide relative acidities. Nonprotonated charged substituents with an appropriate counterion are found to enhance their Bronsted acidities and improve catalyst performance by orders of magnitude. PMID- 25821992 TI - Meeting abstracts - 27th annual meeting expo. AB - Abstracts provide a forum through which authors can share their insights and outcomes of advanced managed care practice through publication in AMCP's Journal of Managed Care Specialty Pharmacy (JMCP). Of the abstracts accepted for publication, most are presented as posters, so interested AMCP meeting attendees can review the findings and query authors. The main poster presentation is Thursday, April 9, 2015; posters are also displayed on Friday, April 10, 2015. The AMCP 2015 Annual Meeting Expo in San Diego, California, is expected to attract more than 3,500 managed care pharmacists and other health care professionals who manage and evaluate drug therapies, develop and manage networks, and work with medical managers and information specialists to improve the care of all individuals enrolled in managed care programs. PMID- 25821993 TI - Femtosecond laser ablation molecular isotopic spectrometry for zirconium isotope analysis. AB - Laser ablation molecular isotopic spectrometry (LAMIS) for rapid isotopic analysis of zirconium at atmospheric pressure was studied with a femtosecond laser system operated under high repetition rate (1 kHz) and low pulse energy (160 MUJ). The temporal evolution of zirconium neutral-atomic and ionic lines, as well as zirconium oxide molecular bands, were studied. Six molecular bands, belonging to the d(3)Delta-a(3)Delta (i.e., the alpha system) and E(1)Sigma(+) X(1)Sigma(+) transitions, were observed with appreciable isotopic shifts. The assignments of the isotopic bandheads were first based on theoretical predictions of the band origins and the associated isotopic shifts of various dipole-allowed ZrO electronic transitions, followed by an experimental confirmation with a (94)Zr-enriched ZrO2 sample. In this work, the alpha(0,1) band from the d(3)Delta3-a(3)Delta3 subsystem was utilized for Zr isotope analysis based on a compromise between the magnitude of isotopic shifts in emission wavelengths, emission strengths, signal-to-background ratios, and spectral interferences. The analysis was performed in a standardless calibration approach; the isotopic information was extracted from the experimentally measured molecular spectra through theoretical spectral fitting. The results demonstrate the feasibility to obtain isotopic information for a spectrally complicated element like zirconium, without the need to use isotopically labeled calibration standards. The availability of comprehensive molecular constants will further improve the analytical accuracy of this standardless calibration approach. PMID- 25821994 TI - A highly tunable and fully biocompatible silk nanoplasmonic optical sensor. AB - Novel concepts for manipulating plasmonic resonances and the biocompatibility of plasmonic devices offer great potential in versatile applications involving real time and in vivo monitoring of analytes with high sensitivity in biomedical and biological research. Here we report a biocompatible and highly tunable plasmonic bio/chemical sensor consisting of a natural silk protein and a gold nanostructure. Our silk plasmonic absorber sensor (SPAS) takes advantage of the strong local field enhancement in the metal-insulator-metal resonator in which silk protein is used as an insulating spacer and substrate. The silk insulating spacer has hydrogel properties and therefore exhibits a controllable swelling when exposed to water-alcohol mixtures. We experimentally and numerically show that drastic spectral shifts in reflectance minima arise from the changing physical volume and refractive index of the silk spacer during swelling. Furthermore, we apply this SPAS device as a glucose sensor with a very high sensitivity of 1200 nm/RIU (refractive index units) and high relative intensity change. PMID- 25821995 TI - Staphylococcus epidermidis Affinity for Fibrinogen-Coated Surfaces Correlates with the Abundance of the SdrG Adhesin on the Cell Surface. AB - Staphylococcus epidermidis is a world-leading pathogen in healthcare facilities, mainly causing medical device-associated infections. These nosocomial diseases often result in complications such as bacteremia, fibrosis, or peritonitis. The virulence of S. epidermidis relies on its ability to colonize surfaces and develop thereupon in the form of biofilms. Bacterial adherence on biomaterials, usually covered with plasma proteins after implantation, is a critical step leading to biofilm infections. The cell surface protein SdrG mediates adhesion of S. epidermidis to fibrinogen (Fg) through a specific "dock, lock, and latch" mechanism, which results in greatly stabilized protein-ligand complexes. Here, we combine single-molecule, single-cell, and whole population assays to investigate the extent to which the surface density of SdrG determines the ability of S. epidermidis clinical strains HB, ATCC 35984, and ATCC 12228 to bind to Fg-coated surfaces. Strains that showed enhanced adhesion on Fg-coated polydimethylsiloxane (PDMS) were characterized by increased amounts of SdrG proteins on the cell surface, as observed by single-molecule analysis. Consistent with previous reports showing increased expression of SdrG following in vivo exposure, this work provides direct evidence that abundance of SdrG on the cell surface of S. epidermidis strains dramatically improves their ability to bind to Fg-coated implanted medical devices. PMID- 25821996 TI - Work modification as a treatment for low-back pain. PMID- 25821997 TI - Exposure of Microcystis aeruginosa to Hydrogen Peroxide under Light: Kinetic Modeling of Cell Rupture and Simultaneous Microcystin Degradation. AB - The effect of hydrogen peroxide on the cell integrity of a cyanobacterium, Microcystis aeruginosa, and on the release and degradation of microcystins (MCs) under simulated sunlight was investigated. The cyanobacterium was exposed to H2O2 in the range of 0-60 mg.L(-1) for 3.5 h. Production of OH radical in the solution was estimated by a chemical probe method. More than 99% (2 log) of the M. aeruginosa cells were ruptured or damaged by 3 h for all the treatments. Loss of cell integrity over time revealed two distinct phases. Cells retained their integrity during the initial lag phase and rapidly ruptured following first-order reaction afterward. A linear relationship was found between the duration of the lag phase and the steady-state concentration of OH radical. Release of MCs was closely correlated with the loss of cell integrity. Sequential reaction models were developed to simulate the release and degradation of MCs. These models were able to quantitatively describe the kinetics of all reactions under different H2O2 doses and extended exposure time. In particular, the models successfully predicted the concentration change of MCs using independently measured parameters. These models provide a simple and quantitative means to estimate the interaction of oxidants and cells and the consequent release of metabolites during oxidation treatment of cyanobacterium-laden waters. PMID- 25821998 TI - Transition-metal-catalyzed C-N bond forming reactions using organic azides as the nitrogen source: a journey for the mild and versatile C-H amination. AB - Owing to the prevalence of nitrogen-containing compounds in functional materials, natural products and important pharmaceutical agents, chemists have actively searched for the development of efficient and selective methodologies allowing for the facile construction of carbon-nitrogen bonds. While metal-catalyzed C-N cross-coupling reactions have been established as one of the most general protocols for C-N bond formation, these methods require starting materials equipped with functional groups such as (hetero)aryl halides or their equivalents, thus generating stoichiometric amounts of halide salts as byproducts. To address this aspect, a transition-metal-catalyzed direct C-H amination approach has emerged as a step- and atom-economical alternative to the conventional C-N cross-coupling reactions. However, despite the significant recent advances in metal-mediated direct C-H amination reactions, most available procedures need harsh conditions requiring stoichiometric external oxidants. In this context, we were curious to see whether a transition-metal-catalyzed mild C H amination protocol could be achieved using organic azides as the amino source. We envisaged that a dual role of organic azides as an environmentally benign amino source and also as an internal oxidant via N-N2 bond cleavage would be key to develop efficient C-H amination reactions employing azides. An additional advantage of this approach was anticipated: that a sole byproduct is molecular nitrogen (N2) under the perspective catalytic conditions. This Account mainly describes our research efforts on the development of rhodium- and iridium catalyzed direct C-H amination reactions with organic azides. Under our initially optimized Rh(III)-catalyzed amination conditions, not only sulfonyl azides but also aryl- and alkyl azides could be utilized as facile amino sources in reaction with various types of C(sp(2))-H bonds bearing such directing groups as pyridine, amide, or ketoxime. More recently, a new catalyst system using Ir(III) species was developed for the direct C-H amidation of arenes and alkenes with acyl azides under exceptionally mild conditions. As a natural extension, amidation of primary C(sp(3))-H bonds could also be realized on the basis of the superior activity of the Cp*Ir(III) catalyst. Mechanistic investigations revealed that a catalytic cycle is operated mainly in three stages: (i) chelation-assisted metallacycle formation via C-H bond cleavage; (ii) C-N bond formation through the in situ generation of a metal-nitrenoid intermediate followed by the insertion of an imido moiety to the metal carbon bond; (iii) product release via protodemetalation with the concomitant catalyst regeneration. In addition, this Account also summarizes the recent advances in the ruthenium- and cobalt catalyzed amination reactions using organic azides, developed by our own and other groups. Comparative studies on the relative performance of those catalytic systems are briefly described. PMID- 25821999 TI - Polydiacetylene-embedded microbeads for colorimetric and volumetric sensing of hydrocarbons. AB - Rational design of a hydrocarbon sensor that enables visual differentiation of saturated aliphatic hydrocarbons (SAHCs) is very difficult owing to the lack of useful functional groups that can interact with the sensor system. Here, we report a microbead embedded with polydiacetylene that undergoes faster swelling and faster blue-to-red color change in response to the hydrocarbons of shorter alkyl chains. Accordingly, visual differentiation among n-pentane, n-heptane, n nonane, and n-undecane was readily achieved. By taking advantage of the collective effect, construction of a sensor system with amplified response was possible. Combination of microfluidic technology (for bead preparation), PDMS (swellable polymeric matrix), and polydiacetylene (colorimetric material) was key to enabling this unique hydrocarbon sensor. PMID- 25822000 TI - Electron-induced growth mechanism of conducting polymers: a coupled experimental and computational investigation. AB - Pulse radiolysis was used to study the mechanism of HO(*)-induced polymerization of poly(3,4-ethylenedioxythiophene), PEDOT, in aqueous solution. A step-by-step mechanism has been found which involves a recurrent oxidation process by HO(*) hydroxyl radicals produced by water radiolysis. Furthermore, the cation radical, EDOT(*)(+), has been proposed as the promoter of the first step of polymerization. The determination of rate constants values and the attribution of transient and stable species were confirmed by molecular simulations and spectrokinetic analysis. Moreover, applying a series of electron pulses enabled in situ PEDOT polymerization. These polymers, which were characterized in solution or after deposition, form globular self-assembled structures with interesting conducting properties. Such a synthesis initiated for the first time by an electron accelerator gives us a glimpse of future promising industrial applications in the field of conducting polymers synthesis. PMID- 25822001 TI - Rh(III) and Ru(II)-catalyzed site-selective C-H alkynylation of quinolones. AB - C2- and C5-alkynylated quinolone scaffolds are core structures of numerous biologically active molecules. Utilizing TIPS-EBX as an alkynylating agent, we have developed an efficient and site-selective C5 alkynylation of 4-quinolones that is directed by the weakly coordinating carbonyl group. In addition, Ru(II) catalyzed C2-selective alkynylation was successfully realized via N-pyrimidyl group-directed cross-couplings to access valuable C2-alkynylated 4-quinolones. This strategy provides direct access to the C2 or C5 alkynylated 4-quinolones. Furthermore, the reaction was applied to isoquinolones for C3-selective alkynylation. PMID- 25822002 TI - Intakes of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis: Results from five cohort studies. AB - Caffeine is thought to be neuroprotective by antagonizing the adenosine A2A receptors in the brain and thereby protecting motor neurons from excitotoxicity. We examined the association between consumption of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis (ALS). Longitudinal analyses based on over 1,010,000 males and females in five large cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study). Cohort-specific multivariable-adjusted risk ratios (RR) and 95% confidence intervals (CI) estimates of ALS incidence or death were estimated by Cox proportional hazards regression and pooled using random effects models. Results showed that a total of 1279 cases of ALS were documented during a mean of 18 years of follow-up. Caffeine intake was not associated with ALS risk; the pooled multivariable-adjusted RR comparing the highest to the lowest quintile of intake was 0.96 (95% CI 0.81-1.16). Similarly, neither coffee nor tea was associated with ALS risk. In conclusion, the results of this large study do not support associations of caffeine or caffeinated beverages with ALS risk. PMID- 25822003 TI - Epidemiology and surveillance of amyotrophic lateral sclerosis in two large metropolitan areas in California. AB - Our objective was to provide demographic profiles and incidence estimates of amyotrophic lateral sclerosis (ALS) in two diverse California metropolitan areas: Los Angeles County (LA) and the San Francisco Bay Area (SFBA). Data were retrospectively collected from multiple sources. Case eligibility criteria included residency in SFBA or LA, and treatment for or diagnosis of ALS between 1 January 2009 and 31 December 2011. Overall incidence rates as well as age-, gender-, race- and ethnicity-specific rates were calculated. We identified 539 ALS cases in SFBA and 545 in LA; 618 were incident cases. Cases were more likely to be male and white. There were considerably more cases (p < 0.05) in LA who were foreign-born (LA, 22%; SFBA, 15%), black (LA, 10%; SFBA, 6%) or Hispanic (LA, 19%; SFBA, 10%). Conversely, the age adjusted incidence rates (per 100,000) were higher in SFBA for whites (LA, 1.40; SFBA, 2.49) and Hispanics (LA, 0.66; SFBA, 1.57) compared with LA. General case demographics and incidence rates in these two areas were similar to published studies. However, the differences between the two areas raise questions about how factors such as geography, access to care, and referral patterns may affect case ascertainment and diagnosis. PMID- 25822004 TI - Identification of factors integral to designing community-based CPR interventions for high-risk neighborhood residents. AB - BACKGROUND: High-risk neighborhoods can be identified as census tracts in which cardiac arrest incidence is high and bystander cardiopulmonary resuscitation (CPR) prevalence is low. However, little is known about how best to tailor community CPR training to high-risk neighborhood residents. The objective of this study was to identify factors integral to the design and implementation of community-based CPR intervention programs targeted to these areas. METHODS: Using qualitative methods, six focus groups with 42 participants were conducted in high risk neighborhoods in Columbus, Ohio during January and February 2011 to elicit resident views on how best to design community-based CPR educational programs for these neighborhoods. Snowball and purposeful sampling by community liaisons was used to recruit participants. Three reviewers analyzed the data in an iterative process to identify recurrent and unifying themes. RESULTS: Focus group participants identified four principal considerations for the design of community based CPR interventions: 1) identifying lay people to serve as motivated leaders while targeting both senior citizens and school children to increase reach, 2) finding appropriate community-based locations to hold CPR training, 3) providing incentives to encourage more people to participate, and 4) identifying and addressing barriers to participation. CONCLUSION: Out-of-hospital cardiac arrest is a particular risk for minority and low-income communities. By working together with the community key factors integral to designing community-based CPR within these high-risk communities can be identified and implemented. PMID- 25822005 TI - Effect of Lactobacillus plantarum NCU116 on loperamide-induced constipation in mice. AB - Lactobacillus plantarum, as a probiotic, has many functional properties in human intestinal tract. This study examined the effects of L. plantarum NCU116 on loperamide-induced constipation in a mouse model. Loperamide (5 mg kg(-1)) was injected subcutaneously to induce constipation. Animals were divided to five groups: normal group, constipation group, constipation plus three doses of L. plantarum NCU116 groups (NCU116-L, 10(7) CFU/mL; NCU116-M, 10(8) CFU/mL; NCU116 H, 10(9) CFU/mL; respectively). Mice were treated with the probiotic for 15 d to assess the anti-constipation effects. Fecal parameters, intestinal transit ratio and the production of fecal short chain fatty acids, histological of colon and immunohistochemical in colonic interstitial cells of Cajal (ICC) by c-kit were all improved in L. plantarum NCU116-treated mice as compared to the constipation group. These results demonstrate that L. plantarum NCU116 enhanced gastrointestinal transit and alleviated in mice with loperamide-induced constipation. PMID- 25822006 TI - Activity of 30 different cheeses on cholesterol plasma levels and Oxidative Balance Risk Index (OBRI) in a rat model. AB - BACKGROUND: Cheese is considered to increase the total cholesterol levels (CH) due to the high-saturated fat content. New models are needed to measure the relationship between cholesterol and cheese. METHODS: Thirty different cheeses produced in Val Brembana, Italy ("furmai da mut", "caprino" and "stracchino"), were added to the diet of 30 groups of 4 rats. Cheeses were analyzed to differentiate the volatile organic compounds (VOCs) and the cholesterol content (Ch(f)). The body weight, CH, urine volume and oxidative balance were measured. Three new indexes in relation to CH were calculated: OI (oxidative index), PI (protective index) and OBRI (oxidative balance risk index). RESULTS: None of the cheeses increased CH. Some of the "furmai de mut" were significantly decreasing CH and improved the oxidative balance. Ch(f) was not affecting the CH levels in plasma. In terms of VOCs, the acetic acid content was correlated (p < 0.05) with the CH reduction and PI improvement. OBRI was reduced mainly in the "stracchino group". CONCLUSIONS: The model shows that some cheese can reduce significantly CH levels and improve the antioxidant capacity. PMID- 25822007 TI - Antinociceptive and anti-inflammatory activities of a pomegranate (Punica granatum L.) extract rich in ellagitannins. AB - Pomegranate (Punica granatum L.) has been used for centuries for the treatment of inflammatory diseases. However, there is a lack of comprehensive information focused on the properties of a certain pomegranate (poly)phenolic profile to cure pain and gastric injury induced by anti-inflammatory drugs. This study investigated the systemic effects of different doses of a HPLC-characterized pomegranate extract on the formalin-induced nociceptive behavior in mice. The effect of the extract against gastric injury caused by non-steroidal anti inflammatory drugs and ethanol was also assessed. Pomegranate reduced nociception in both phases of the formalin test, suggesting central and peripheral activities to inhibit nociception. Indomethacin-induced gastric injury was not produced in the presence of pomegranate, which also protected against ethanol-induced gastric lesions. The present results reinforce the benefits of pomegranate (poly)phenolics in the treatment of pain as well as their anti-inflammatory properties. PMID- 25822008 TI - [Quality of Care in Certified Lung Cancer Centers]. AB - BACKGROUND: Since 2008, lung cancer centers can be certified in accordance with the criteria set out by the German Cancer Society (Deutsche Krebsgesellschaft). This paper reports on the certification program for lung cancer centers and presents data on 18 quality indicators collected during certification. METHODS: After checks for plausibility and completeness, data on quality indicators for the 2011 and 2012 patient cohorts as well as data of the treating centers were analyzed descriptively (relative/absolute frequencies, means, site medians). PATIENTS: 23,222 patients with ICD-10 diagnoses C33 und C34 from 35 (2012) and 24 operating sites (2011), respectively. RESULTS: From 2011 to 2012, both the number of certified sites and the number of patients treated increased. Fulfillment of the certification requirements is already high and improved slightly from 2011 to 2012. The implementation of indicators without target values is less advanced. CONCLUSION: Thanks to the medical and professional associations as well as the oncologic medical experts, the lung cancer certification program is evolving continuously. There has been a steady increase both in the number of patients treated and the number of lung cancer centers; certification requirements are also being increasingly fulfilled. PMID- 25822009 TI - [Gender-Specific Differences in Obstructive Lung Diseases]. AB - Asthma is a common disease with increasing prevalence worldwide. Sex differences in asthma vary with age. The prevalence of chronic obstructive pulmonary disease (COPD) in females appears to be increasing.There is increasing clinical evidence for sex differences in incidence, morbidity, and mortality of obstructive lung disease. The purpose of this review is to define sex differences in epidemiology, symptom profiles, and management. This provides valuable information which could aid the management of asthma and COPD. There is still a high amount of research in gender medicine to do. PMID- 25822010 TI - Effect of 2 psychotherapies on depression and disease activity in pediatric Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) is associated with depression. It is unclear if psychosocial interventions offer benefit for depressive symptoms during active CD. In this secondary analysis of a larger study of treating depression in pediatric inflammatory bowel disease, we assessed whether cognitive behavioral therapy (CBT) would differentiate from supportive nondirective therapy in treating depression and disease activity in youth with CD. We also explored whether somatic depressive symptoms showed a different pattern of response in the overall sample and the subset with active inflammatory bowel disease. METHODS: Youth with depression and CD (n = 161) were randomized to 3 months of CBT (teaching coping skills) or supportive nondirective therapy (supportive listening). Depressive severity was measured using the Children's Depression Rating Scale-Revised (CDRS-R) with the somatic depressive subtype consisting of those CDRS-R items, which significantly correlated with CD activity. Disease activity was measured by the Pediatric Crohn's disease Activity Index. Given the potential confound of higher dose steroids, subanalyses excluded subjects on >20 mg/d prednisone equivalent (n = 34). RESULTS: Total CDRS-R scores in the overall sample significantly decreased over time after both treatments (P < 0.0001). Treatment with CBT was associated with a significantly greater improvement in the Pediatric Crohn's disease Activity Index (P = 0.05) and somatic depressive subtype (P = 0.03) in those with active inflammatory bowel disease (n = 95) compared with supportive nondirective therapy. After excluding those on steroids (n = 34), there was a significant improvement in total CDRS-R (P = 0.03) and in Pediatric Crohn's disease Activity Index (P = 0.03) after CBT. CONCLUSIONS: Psychotherapy may be a useful adjunct to treat depression in the context of CD related inflammation in youth who are not concurrently on higher dose steroids. PMID- 25822011 TI - Body fat composition assessment using analytic morphomics predicts infectious complications after bowel resection in Crohn's disease. AB - BACKGROUND: Decisions between medical and surgical management of Crohn's disease (CD) incorporate risk assessments for potential complications of each therapy. Analytic morphomics is a novel method of image analysis providing quantifiable measurements of body tissue composition, characterizing body fat more comprehensively than body mass index alone. The aim of this study was to determine the risk factors associated with postoperative complications in CD, incorporating fat composition analysis using analytic morphomics. METHODS: We performed a retrospective review of adults undergoing bowel resection for CD between 2004 and 2011 at a single center. Computed tomography obtained within 30 days prior to surgery underwent morphomic analysis for fat characterization. Postoperative infectious complications were defined as the need for a postoperative abdominal drain, intravenous antibiotics, or reoperation within 30 days. Bivariate and multivariate analyses using logistic regression were used to generate a prediction model of infectious complications. RESULTS: A total of 269 subjects met selection criteria; 27% incurred postoperative infectious complications. Bivariate analysis showed hemoglobin, albumin, surgical urgency, high-dose prednisone use, and subcutaneous-to-visceral fat volume distribution as predictors of complications. Body mass index, anti-tumor necrosis factor alpha therapies, and immunomodulator use were not predictors of complication. Multivariate modeling demonstrated a c-statistic of 0.77 and a negative predictive value of 81.1% with surgical urgency (odds ratio = 2.78; 95% confidence interval, 1.46-6.02; P = 0.004), subcutaneous-to-visceral fat distribution (odds ratio = 2.01; 95% confidence interval, 1.20-3.19; P = 0.006), and hemoglobin (odds ratio = 0.69; 95% confidence interval, 0.55-0.85; P = 0.001) as predictors of infectious complication. CONCLUSIONS: Fat subtype and distribution are predictive of postoperative infectious complications after bowel resection for CD. Analytic morphomics provides additional body composition detail not captured by body mass index. PMID- 25822012 TI - Downregulation of FoxC2 Increased Susceptibility to Experimental Colitis: Influence of Lymphatic Drainage Function? AB - BACKGROUND: Although inflammation-induced expansion of the intestinal lymphatic vasculature (lymphangiogenesis) is known to be a crucial event in limiting inflammatory processes, through clearance of interstitial fluid and immune cells, considerably less is known about the impact of an impaired lymphatic clearance function (as seen in inflammatory bowel diseases) on this cascade. We aimed to investigate whether the impaired intestinal lymphatic drainage function observed in FoxC2 mice would influence the course of disease in a model of experimental colitis. METHODS: Acute dextran sodium sulfate colitis was induced in wild-type and haploinsufficient FoxC2 mice, and survival, disease activity, colonic histopathological injury, neutrophil, T-cell, and macrophage infiltration were evaluated. Functional and structural changes in the intestinal lymphatic vessel network were analyzed, including submucosal edema, vessel morphology, and lymphatic vessel density. RESULTS: We found that FoxC2 downregulation in FoxC2 mice significantly increased the severity and susceptibility to experimental colitis, as displayed by lower survival rates, increased disease activity, greater histopathological injury, and elevated colonic neutrophil, T-cell, and macrophage infiltration. These findings were accompanied by structural (dilated torturous lymphatic vessels) and functional (greater submucosal edema, higher immune cell burden) changes in the intestinal lymphatic vasculature. CONCLUSIONS: These results indicate that sufficient lymphatic clearance plays a crucial role in limiting the initiation and perpetuation of experimental colitis and those disturbances in the integrity of the intestinal lymphatic vessel network could intensify intestinal inflammation. Future therapies might be able to exploit these processes to restore and maintain adequate lymphatic clearance function in inflammatory bowel disease. PMID- 25822013 TI - Escherichia coli LF82 differentially regulates ROS production and mucin expression in intestinal epithelial T84 cells: implication of NOX1. AB - BACKGROUND: Increased reactive oxygen species (ROS) production is associated with inflamed ileal lesions in Crohn's disease colonized by pathogenic adherent invasive Escherichia coli LF82. We investigated whether such ileal bacteria can modulate ROS production by epithelial cells, thus impacting on inflammation and mucin expression. METHODS: Ileal bacteria from patients with Crohn's disease were incubated with cultured epithelial T84 cells, and ROS production was assayed using the luminol-amplified chemiluminescence method. The gentamicin protection assay was used for bacterial invasion of T84 cell. The expression of NADPH oxidase (NOX) subunits, mucin, and IL-8 was analyzed by quantitative real-time PCR and Western blots. Involvement of NOX and ROS was analyzed using diphenyleneiodonium (DPI) and N-acetylcysteine (NAC). RESULTS: Among different bacteria tested, only LF82 induced an increase of ROS production by T84 cells in a dose-dependent manner. This response was inhibited by DPI and NAC. Heat- or ethanol-attenuated LF82 bacteria and the mutant LF82DeltaFimA, which does not express pili type 1 and poorly adheres to epithelial cells, did not induce the oxidative response. The LF82-induced oxidative response coincides with its invasion in T84 cells, and both processes were inhibited by DPI. Also, we observed an increased expression of NOX1 and NOXO1 in response to LF82 bacteria versus the mutant LF82DeltaFimA. Furthermore, LF82 inhibited mucin gene expression (MUC2 and MUC5AC) in T84 cells while increasing the chemotactic IL-8 expression, both in a DPI-sensitive manner. CONCLUSIONS: Adherent-invasive E. coli LF82 induced ROS production by intestinal NADPH oxidase and altered mucin and IL-8 expression, leading to perpetuation of inflammatory lesions in Crohn's disease. PMID- 25822014 TI - Beneficial Effects of Probiotics, Prebiotics, Synbiotics, and Psychobiotics in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a group of diseases characterized by inflammation of the small and large intestine and primarily includes ulcerative colitis and Crohn's disease. Although the etiology of IBD is not fully understood, it is believed to result from the interaction of genetic, immunological, and environmental factors, including gut microbiota. Recent studies have shown a correlation between changes in the composition of the intestinal microbiota and IBD. Moreover, it has been suggested that probiotics and prebiotics influence the balance of beneficial and detrimental bacterial species, and thereby determine homeostasis versus inflammatory conditions. In this review, we focus on recent advances in the understanding of the role of prebiotics, probiotics, and synbiotics in functions of the gastrointestinal tract and the induction and maintenance of IBD remission. We also discuss the role of psychobiotics, which constitute a novel class of psychotropic agents that affect the central nervous system by influencing gut microbiota. PMID- 25822015 TI - Reliability and reproducibility of a handheld videorefractor. AB - PURPOSE: To assess the performance of the 2Win eccentric videorefractor in relation to subjective refraction and table-mounted autorefraction. METHODS: Eighty-six eyes of 86 adults (46 male and 40 female subjects) aged between 20 and 25 years were examined. Subjective refraction and autorefraction using the table mounted Topcon KR8800 and the handheld 2Win videorefractor were carried out in a randomized fashion by three different masked examiners. Measurements were repeated about 1 week after to assess instrument reproducibility, and the intertest variability was compared between techniques. Agreement of the 2Win videorefractor with subjective refraction and autorefraction was assessed for sphere and for cylindrical vectors at 0 degrees (J0) and 45 degrees (J45). RESULTS: Reproducibility coefficients for sphere values measured by subjective refraction, Topcon KR8800, and 2Win (+/-0.42, +/-0.70, and +/-1.18, respectively) were better than their corresponding J0 (+/-1.0, +/-0.85, and +/-1.66) and J45 (+/-1.01, +/-0.87, and +/-1.31) vector components. The Topcon KR8800 showed the most reproducible values for mean spherical equivalent refraction and the J0 and J45 vector components, whereas reproducibility of spherical component was best for subjective refraction. The 2Win videorefractor measurements were the least reproducible for all measures. All refractive components measured by the 2Win videorefractor did not differ significantly from those of subjective refraction, in both sessions (p > 0.05). The Topcon KR8800 autorefractometer and the 2Win videorefractor measured significantly more positive spheres and mean spherical equivalent refraction (p < 0.0001), but the J0 and J45 vector components were similar (p > 0.05), in both sessions. CONCLUSIONS: The 2Win videorefractor compares well, on average, with subjective refraction. The reproducibility values for the 2Win videorefractor were considerably worse than either subjective refraction or autorefraction. The wide limits of reproducibility of the 2Win videorefractor probably limit its usefulness as a primary screening device. PMID- 25822016 TI - Posterior segment toxicity after gemcitabine and docetaxel chemotherapy. AB - PURPOSE: To report outer retinal disruption and uveal effusion after gemcitabine and docetaxel combination therapy. CASE REPORT: A 78-year-old woman presented with blurry vision after two cycles of gemcitabine and docetaxel combination chemotherapy for stage IV sarcoma. At presentation, visual acuity was finger counting and 20/25 in the right and left eyes, respectively. Slit-lamp examination and B-scan ultrasonography revealed severe uveal effusion in the right eye and choroidal folds in the left eye. Spectral domain optical coherence tomography showed disruption of photoreceptor inner segment ellipsoid band in the right eye. The patient was monitored weekly with ophthalmic examination and B scan ultrasonography, while continuing with gemcitabine monotherapy. At 8 weeks follow-up, uveal effusion improved considerably and visual acuity was 20/40 and 20/20 in the right and left eyes, respectively. CONCLUSIONS: Uveal effusion and outer retinal disruption were reported after gemcitabine and docetaxel chemotherapy. Early detection and close ophthalmic monitoring may allow concurrent cancer treatment and prevention of possible chemotherapy-induced ocular side effects. PMID- 25822017 TI - Early-Onset Candida glabrata Interface Keratitis after Deep Anterior Lamellar Keratoplasty. AB - PURPOSE: Fungal interface keratitis by Candida species can occur several weeks to several months after deep anterior lamellar keratoplasty (DALK). Here, we report a case of early-onset fungal interface keratitis by Candida glabrata after DALK. CASE REPORT: A 31-year-old Chinese man complained of decreased vision 4 days after an uneventful DALK for keratoconus. White to cream-colored interface deposits were identified under slit-lamp examination. The confocal scan disclosed clusters of hyperreflective granular deposits of 2 to 4 MUm at the interface, without evidence of inflammation or hyphae-like structures. The graft was then removed, along with interface irrigation, and another graft was sutured. Finally, a penetrating keratoplasty was performed because the interface opacities recurred and deteriorated after graft replacement. Histopathological examination disclosed yeast-like structures at the retrocorneal side. The microbiologic results of both corneal scrapings taken from the recipient stromal bed and the removed half cornea button showed C. glabrata. CONCLUSIONS: Candida glabrata interface keratitis can occur early after DALK, which can only be effectively treated with penetrating keratoplasty. Confocal microscopy is a promising tool to diagnose this rare complication. The importance of donor corneoscleral rim cultures should be emphasized during DALK. PMID- 25822019 TI - Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. AB - BACKGROUND: The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluation and detection of Mycobacterium tuberculosis (Mtb) in the patient's sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes several weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that immune activation markers on Mtb-specific CD4+ T cells would be associated with Mtb load in vivo and could thus provide a gauge of Mtb infection. METHODS: Using polychromatic flow cytometry, we evaluated the expression of immune activation markers on Mtb specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) and ATB as well as from ATB patients undergoing anti-TB treatment. RESULTS: Frequencies of Mtb-specific IFN-gamma+CD4+ T cells that expressed immune activation markers CD38 and HLA-DR as well as intracellular proliferation marker Ki-67 were substantially higher in subjects with ATB compared with those with LTBI. These markers accurately classified ATB and LTBI status, with cutoff values of 18%, 60%, and 5% for CD38+IFN-gamma+, HLA-DR+IFN-gamma+, and Ki-67+IFN-gamma+, respectively, with 100% specificity and greater than 96% sensitivity. These markers also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment. CONCLUSION: We have identified host blood based biomarkers on Mtb-specific CD4+ T cells that discriminate between ATB and LTBI and provide a set of tools for monitoring treatment response and cure. TRIAL REGISTRATION: Registration is not required for observational studies. FUNDING: This study was funded by Emory University, the NIH, and the Yerkes National Primate Center. PMID- 25822018 TI - Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. AB - Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable, with few means to predict which patients will benefit. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next generation sequencing. These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance. PMID- 25822020 TI - Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration. AB - Parkin and the glial cell line-derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson's disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-kappaB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD. PMID- 25822021 TI - MEL-18 loss mediates estrogen receptor-alpha downregulation and hormone independence. AB - The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-alpha (ER alpha, encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-alpha-positive breast cancer. Furthermore, whereas MEL 18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-alpha and the progesterone receptor (PR), MEL-18 overexpression restored ER-alpha expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI 1/RING1B-mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer. PMID- 25822022 TI - Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations. AB - Reversal of HIV-1 latency by small molecules is a potential cure strategy. This approach will likely require effective drug combinations to achieve high levels of latency reversal. Using resting CD4+ T cells (rCD4s) from infected individuals, we developed an experimental and theoretical framework to identify effective latency-reversing agent (LRA) combinations. Utilizing ex vivo assays for intracellular HIV-1 mRNA and virion production, we compared 2-drug combinations of leading candidate LRAs and identified multiple combinations that effectively reverse latency. We showed that protein kinase C agonists in combination with bromodomain inhibitor JQ1 or histone deacetylase inhibitors robustly induce HIV-1 transcription and virus production when directly compared with maximum reactivation by T cell activation. Using the Bliss independence model to quantitate combined drug effects, we demonstrated that these combinations synergize to induce HIV-1 transcription. This robust latency reversal occurred without release of proinflammatory cytokines by rCD4s. To extend the clinical utility of our findings, we applied a mathematical model that estimates in vivo changes in plasma HIV-1 RNA from ex vivo measurements of virus production. Our study reconciles diverse findings from previous studies, establishes a quantitative experimental approach to evaluate combinatorial LRA efficacy, and presents a model to predict in vivo responses to LRAs. PMID- 25822023 TI - CCN1 induces hepatic ductular reaction through integrin alphavbeta5-mediated activation of NF-kappaB. AB - Liver cholestatic diseases, which stem from diverse etiologies, result in liver toxicity and fibrosis and may progress to cirrhosis and liver failure. We show that CCN1 (also known as CYR61), a matricellular protein that dampens and resolves liver fibrosis, also mediates cholangiocyte proliferation and ductular reaction, which are repair responses to cholestatic injury. In cholangiocytes, CCN1 activated NF-kappaB through integrin alphavbeta5/alphavbeta3, leading to Jag1 expression, JAG1/NOTCH signaling, and cholangiocyte proliferation. CCN1 also induced Jag1 expression in hepatic stellate cells, whereupon they interacted with hepatic progenitor cells to promote their differentiation into cholangiocytes. Administration of CCN1 protein or soluble JAG1 induced cholangiocyte proliferation in mice, which was blocked by inhibitors of NF-kappaB or NOTCH signaling. Knock-in mice expressing a CCN1 mutant that is unable to bind alphavbeta5/alphavbeta3 were impaired in ductular reaction, leading to massive hepatic necrosis and mortality after bile duct ligation (BDL), whereas treatment of these mice with soluble JAG1 rescued ductular reaction and reduced hepatic necrosis and mortality. Blockade of integrin alphavbeta5/alphavbeta3, NF-kappaB, or NOTCH signaling in WT mice also resulted in defective ductular reaction after BDL. These findings demonstrate that CCN1 induces cholangiocyte proliferation and ductular reaction and identify CCN1/alphavbeta5/NF-kappaB/JAG1 as a critical axis for biliary injury repair. PMID- 25822024 TI - Noninvasive detection of tumor-infiltrating T cells by PET reporter imaging. AB - Adoptive transfer of tumor-reactive T cells can successfully reduce tumor burden; however, in rare cases, lethal on-target/off-tumor effects have been reported. A noninvasive method to track engineered cells with high sensitivity and resolution would allow observation of correct cell homing and/or identification of dangerous off-target locations in preclinical and clinical applications. Human deoxycytidine kinase triple mutant (hdCK3mut) is a nonimmunogenic PET reporter that was previously shown to be an effective tool to monitor whole-body hematopoiesis. Here, we engineered a construct in which hdCK3mut is coexpressed with the anti-melanoma T cell receptor F5, introduced this construct into human CD34 cells or PBMCs, and evaluated this approach in multiple immunotherapy models. Expression of hdCK3mut allowed engrafted cells to be visualized within recipient bone marrow, while accumulation of [18F]-L-FMAU in hdCK3mut-expressing T cells permitted detection of intratumoral homing. Animals that received T cells coexpressing hdCK3mut and the anti-melanoma T cell receptor had demonstrably higher signals in HLA-matched tumors compared with those in animals that received cells solely expressing hdCK3mut. Engineered T cells caused cytotoxicity in HLA/antigen-matched tumors and induced IFN-gamma production and activation. Moreover, hdCK3mut permitted simultaneous monitoring of engraftment and tumor infiltration, without affecting T cell function. Our findings suggest that hdCK3mut reporter imaging can be applied in clinical immunotherapies for whole body detection of engineered cell locations. PMID- 25822025 TI - IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF kappaB signaling. AB - Osteosarcoma is a common malignant bone tumor with a propensity to metastasize to the lungs. Epigenetic abnormalities have been demonstrated to underlie osteosarcoma development; however, the epigenetic mechanisms that are involved in metastasis are not yet clear. Here, we analyzed 2 syngeneic primary human osteosarcoma cell lines that exhibit disparate metastatic potential for differences in epigenetic modifications and expression. Using methylated DNA immunoprecipitation (MeDIP) and microarray expression analysis to screen for metastasis-associated genes, we identified Iroquois homeobox 1 (IRX1). In both human osteosarcoma cell lines and clinical osteosarcoma tissues, IRX1 overexpression was strongly associated with hypomethylation of its own promoter. Furthermore, experimental modulation of IRX1 in osteosarcoma cell lines profoundly altered metastatic activity, including migration, invasion, and resistance to anoikis in vitro, and influenced lung metastasis in murine models. These prometastatic effects of IRX1 were mediated by upregulation of CXCL14/NF kappaB signaling. In serum from osteosarcoma patients, the presence of IRX1 hypomethylation in circulating tumor DNA reduced lung metastasis-free survival. Together, these results identify IRX1 as a prometastatic gene, implicate IRX1 hypomethylation as a potential molecular marker for lung metastasis, and suggest that epigenetic reversion of IRX1 activation may be beneficial for controlling osteosarcoma metastasis. PMID- 25822026 TI - Multiple genome segments determine virulence of bluetongue virus serotype 8. AB - Bluetongue virus (BTV) causes bluetongue, a major hemorrhagic disease of ruminants. In order to investigate the molecular determinants of BTV virulence, we used a BTV8 strain minimally passaged in tissue culture (termed BTV8L in this study) and a derivative strain passaged extensively in tissue culture (BTV8H) in in vitro and in vivo studies. BTV8L was pathogenic in both IFNAR(-/-) mice and in sheep, while BTV8H was attenuated in both species. To identify genetic changes which led to BTV8H attenuation, we generated 34 reassortants between BTV8L and BTV8H. We found that partial attenuation of BTV8L in IFNAR(-/-) mice was achieved by simply replacing genomic segment 2 (Seg2, encoding VP2) or Seg10 (encoding NS3) with the BTV8H homologous segments. Fully attenuated viruses required at least two genome segments from BTV8H, including Seg2 with either Seg1 (encoding VP1), Seg6 (encoding VP6 and NS4), or Seg10 (encoding NS3). Conversely, full reversion of virulence of BTV8H required at least five genomic segments of BTV8L. We also demonstrated that BTV8H acquired an increased affinity for glycosaminoglycan receptors during passaging in cell culture due to mutations in its VP2 protein. Replication of BTV8H was relatively poor in interferon (IFN) competent primary ovine endothelial cells compared to replication of BTV8L, and this phenotype was determined by several viral genomic segments, including Seg4 and Seg9. This study demonstrated that multiple viral proteins contribute to BTV8 virulence. VP2 and NS3 are primary determinants of BTV pathogenesis, but VP1, VP5, VP4, VP6, and VP7 also contribute to virulence. IMPORTANCE: Bluetongue is one of the major infectious diseases of ruminants, and it is listed as a notifiable disease by the World Organization for Animal Health (OIE). The clinical outcome of BTV infection varies considerably and depends on environmental and host- and virus-specific factors. Over the years, BTV serotypes/strains with various degrees of virulence (including nonpathogenic strains) have been described in different geographical locations. However, no data are available to correlate the BTV genotype to virulence. This study shows that BTV virulence is determined by different viral genomic segments. The data obtained will help to characterize thoroughly the pathogenesis of bluetongue. The possibility to determine the pathogenicity of virus isolates on the basis of their genome sequences will help in the design of control strategies that fit the risk posed by new emerging BTV strains. PMID- 25822027 TI - HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+ T Lymphocytes. AB - Leukocyte recirculation between blood and lymphoid tissues is required for the generation and maintenance of immune responses against pathogens and is crucially controlled by the L-selectin (CD62L) leukocyte homing receptor. CD62L has adhesion and signaling functions and initiates the capture and rolling on the vascular endothelium of cells entering peripheral lymph nodes. This study reveals that CD62L is strongly downregulated on primary CD4(+) T lymphocytes upon infection with human immunodeficiency virus type 1 (HIV-1). Reduced cell surface CD62L expression was attributable to the Nef and Vpu viral proteins and not due to increased shedding via matrix metalloproteases. Both Nef and Vpu associated with and sequestered CD62L in perinuclear compartments, thereby impeding CD62L transport to the plasma membrane. In addition, Nef decreased total CD62L protein levels. Importantly, infection with wild-type, but not Nef- and Vpu-deficient, HIV-1 inhibited the capacity of primary CD4(+) T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1 infection impaired the signaling pathways and costimulatory signals triggered in primary CD4(+) T cells by CD62L ligation. We propose that HIV-1 dysregulates CD62L expression to interfere with the trafficking and activation of infected T cells. Altogether, this novel HIV-1 function could contribute to virus dissemination and evasion of host immune responses. IMPORTANCE: L-selectin (CD62L) is an adhesion molecule that mediates the first steps of leukocyte homing to peripheral lymph nodes, thus crucially controlling the initiation and maintenance of immune responses to pathogens. Here, we report that CD62L is downmodulated on the surfaces of HIV-1-infected T cells through the activities of two viral proteins, Nef and Vpu, that prevent newly synthesized CD62L molecules from reaching the plasma membrane. We provide evidence that CD62L downregulation on HIV-1-infected primary T cells results in impaired adhesion and signaling functions upon CD62L triggering. Removal of cell surface CD62L may predictably keep HIV-1-infected cells away from lymph nodes, the privileged sites of both viral replication and immune response activation, with important consequences, such as systemic viral spread and evasion of host immune surveillance. Altogether, we propose that Nef- and Vpu-mediated subversion of CD62L function could represent a novel determinant of HIV-1 pathogenesis. PMID- 25822028 TI - The efficacy of physiotherapy for the prevention and treatment of prenatal symptoms: a systematic review. AB - Several studies have described the evidence of prenatal physiotherapy for one symptom, but none has made an overview. We provided a systematic review on the effectiveness of prenatal physiotherapy. A full search was conducted in three electronic databases (Embase, PubMed/MEDLINE and PEDro), selecting randomized controlled trials concerning prenatal physiotherapy. Methodological quality was assessed using the PEDro scale. We identified 1,249 studies and after exclusions 54 studies were included concerning the evidence of prenatal physiotherapy. The majority of studies indicated a preventative effect for low back pain/pelvic girdle pain, weight gain, incontinence, and perineal massage. For leg edema, fear, and prenatal depression, the efficacy was only based on one study per symptom. No preventative effect was found for gestational diabetes, while literature concerning gestational hypertensive disorders was inconclusive. Regarding the treatment of low back pain/pelvic girdle pain and weight gain, most therapies reduced pain and weight respectively. Evidence regarding exercises for diabetes was contradictory and only minimally researched for incontinence. Foot massage and stockings reduced leg edema and leg symptoms respectively. Concerning gestational hypertensive disorders, perineal pain, fear, and prenatal depression no treatment studies were performed. The majority of studies indicated that prenatal physiotherapy played a preventative role for low back pain/pelvic girdle pain, weight gain, incontinence, and pelvic pain. Evidence for the remaining symptoms was inclusive or only minimally investigated. Regarding treatment, most studies indicated a reduction of low back pain/pelvic girdle pain, weight gain, incontinence, and the symptoms of leg edema. PMID- 25822029 TI - Can 3D power Doppler identify levator ani vascularization at its pubic insertion? AB - INTRODUCTION AND HYPOTHESIS: The levator ani is the most important muscle in the pelvic floor. This pilot study using 3D power Doppler aimed to identify normal vascularization of the puborectalis/pubovisceralis muscle at its insertion in nulliparous and premenopausal women. METHODS: Forty nulliparous and premenopausal women were evaluated at the Gynecological Unit of a tertiary hospital. All women underwent a translabial ultrasound (US) with 3D power Doppler. Pubic insertion of the puborectalis/pubovisceralis muscle was assessed in the axial plane, and vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were calculated bilaterally. Volumes were analyzed offline by two independent observers, and interobserver agreement and correlation between variables was calculated. RESULTS: A high, statistically significant, correlation was found between the three US indices on each side (p < 0.005). No correlation was found between the US index and either of the demographic parameters of body mass index [(BMI), p > 0.241], or age (p > 0.398). The degree of correlation between the same index on the different sides was not statistically significant. CONCLUSION: Puborectalis/pubovisceralis muscle vascularization at its insertion can be identified using 3D Doppler US, but values differ substantially from those of the contralateral side. PMID- 25822030 TI - An integrative approach to slow pathway modulation in AVNRT using a novel ultra high-density electroanatomical mapping system. PMID- 25822031 TI - Intracranial hemorrhage during extracorporeal membrane oxygenation: does family history play a role? PMID- 25822032 TI - Volitional personality trait change: Can people choose to change their personality traits? AB - Previous research has found that most people want to change their personality traits. But can people actually change their personalities just because they want to? To answer this question, we conducted 2, 16-week intensive longitudinal randomized experiments. Across both studies, people who expressed goals to increase with respect to any Big Five personality trait at Time 1 tended to experience actual increases in their self-reports of that trait-as well as trait relevant daily behavior-over the subsequent 16 weeks. Furthermore, we tested 2 randomized interventions designed to help participants attain desired trait changes. Although 1 of the interventions was inefficacious, a second intervention that trained participants to generate implementation intentions catalyzed their ability to attain trait changes. We also tested several theoretical processes through which volitional changes might occur. These studies suggest that people may be able to change their self-reported personality traits through volitional means, and represent a first step toward understanding the processes that enable people to do so. PMID- 25822033 TI - Psychosocial effects of perceived emotional synchrony in collective gatherings. AB - In a classic theory, Durkheim (1912) predicted that because of the social sharing of emotion they generate, collective gatherings bring participants to a stage of collective effervescence in which they experience a sense of union with others and a feeling of empowerment accompanied by positive affect. This would lead them to leave the collective situation with a renewed sense of confidence in life and in social institutions. A century after Durkheim's predictions of these effects, though, they remained untested as a whole. This article reports 4 studies, 2 correlational, 1 semilongitudinal, and 1 experimental, assessing the positive effects of participation in either positively valenced (folkloric marches) or negatively valenced (protest demonstrations) collective gatherings. Results confirmed that collective gatherings consistently strengthened collective identity, identity fusion, and social integration, as well as enhancing personal and collective self-esteem and efficacy, positive affect, and positive social beliefs among participants. In line with a central tenet of the theory, emotional communion, or perceived emotional synchrony with others mediated these effects. Higher perceived emotional synchrony was associated with stronger emotional reactions, stronger social support, and higher endorsement of social beliefs and values. Participation in symbolic collective gatherings also particularly reinforced identity fusion when perceived emotional synchrony was high. The respective contributions of perceived emotional synchrony and flow, or optimal experience, were also assessed. Whereas perceived emotional synchrony emerged as strongly related to the various social outcomes, flow was observed to be related first to collective efficacy and self-esteem, and thus, to encompass mainly empowerment effects. PMID- 25822034 TI - Not all inequality is created equal: Effects of status versus power hierarchies on competition for upward mobility. AB - Although hierarchies are thought to be beneficial for groups, empirical evidence is mixed. We argue and find in 7 studies spanning methodologies and samples that different bases of hierarchical differentiation have distinct effects on lower ranking group members' disruptive competitive behavior because status hierarchies are seen as more mutable than are power hierarchies. Greater mutability means that more opportunity exists for upward mobility, which motivates individuals to compete in hopes of advancing their placement in the hierarchy. This research provides further evidence that different bases of hierarchy can have different effects on individuals and the groups of which they are a part and explicates a mechanism for those effects. PMID- 25822035 TI - Narcissism and the use of personal pronouns revisited. AB - [Correction Notice: An Erratum for this article was reported in Vol 109(3) of Journal of Personality and Social Psychology (see record 2015-37773-002). The authors erroneously reported the overall correlation, first stated in the abstract, between Narcissism and total first-person-singular use as .02 (.017) instead of .01 (.010). The misreporting of the overall correlation between Narcissism and total use of first-person singular does not change the results or interpretation in any way (i.e., the near-zero association between Narcissism and I-talk). The online version of this article has been corrected.] Among both laypersons and researchers, extensive use of first-person singular pronouns (i.e., I-talk) is considered a face-valid linguistic marker of narcissism. However, the assumed relation between narcissism and I-talk has yet to be subjected to a strong empirical test. Accordingly, we conducted a large-scale (N = 4,811), multisite (5 labs), multimeasure (5 narcissism measures) and dual language (English and German) investigation to quantify how strongly narcissism is related to using more first-person singular pronouns across different theoretically relevant communication contexts (identity-related, personal, impersonal, private, public, and stream-of-consciousness tasks). Overall (r = .02, 95% CI [-.02, .04]) and within the sampled contexts, narcissism was unrelated to use of first-person singular pronouns (total, subjective, objective, and possessive). This consistent near-zero effect has important implications for making inferences about narcissism from pronoun use and prompts questions about why I-talk tends to be strongly perceived as an indicator of narcissism in the absence of an underlying actual association between the 2 variables. (PsycINFO Database Record PMID- 25822036 TI - Deployment of a Short, Single-Opening Endoscopic Clip Versus a Long, Reopening Endoscopic Clip in Clinical Practice. AB - BACKGROUND: Endoscopic clips vary in their designs and costs. Clip wastage is a common problem, and this is dependent on the success of its deployment. AIMS: The aim of this study is to compare the rates of successful deployment between two different commonly used endoscopic clips. METHODS: A single-center, retrospective study was conducted. Endoscopy reports of patients with clips deployed over 24 months were reviewed. We compared a long-pronged, reopening endoscopic clip (type A: Resolution clip; Boston Scientific, Natick, MA, USA) versus a short-pronged, single-opening clip (type B: QuickClip2; Olympus Medical Systems Corp, Japan). The main outcome was clip deployment success rate. Secondary outcomes were predictors of successful deployment, cost, and wastage. RESULTS: Of 14,690 endoscopic cases, 472 clips (171 type A and 301 type B) were deployed in 262 procedures. Type A clips had a significantly higher successful deployment rate (147/171, 86.0 %) than type B clips (221/301, 73.4 %) (p = 0.002). On multivariate analysis, variables independently associated with successful deployment included using type A clips (OR 2.07, 95 % CI 1.20-3.55; p = 0.009) and clips placed in the lower gastrointestinal tract (OR 3.48, 95 % CI 1.64-7.40; p = 0.001). The cost of using type A clips was higher than type B clips (p < 0.001). Type B clips were associated with more wastage (p = 0.049). CONCLUSIONS: Long-pronged, reopening clips (type A) have a better deployment rate than short pronged, single-opening clips (type B). Although type A clips had less wastage, the cost per procedure was higher. PMID- 25822037 TI - The impact of chronic opioid use on colonoscopy outcomes. AB - BACKGROUND: Endoscopic procedures are frequently performed on patients chronically on opioids, raising concerns about the safety and efficacy of conventional sedation. AIMS: We hypothesized that chronic opioid use is associated with longer procedure times, higher dosages of sedation medications, and an increase in adverse effects. METHODS: This is a retrospective review from June 2012 to June 2013. Patients on chronic opioids (opioids use >= 12 weeks) were compared to randomly selected patients matched for age, race, and sex. Multivariate regression analysis was performed to identify factors that were independently predictive of longer procedure times. RESULTS: Patients on chronic opioids required higher doses of fentanyl (122.0 +/- 45.3 vs. 105.8 +/- 47.2 ug; P < 0.0001) and midazolam (5.3 +/- 5.3 vs. 4.4 +/- 2 mg; P = 0.0037) and were more likely to receive diphenhydramine (42.8 vs. 22.6 %; P < 0.001). The induction period (11.3 +/- 8.8 vs. 7.5 +/- 4.0 min), duration of procedure (39.1 +/- 17.5 vs. 33.4 +/- 14.1 min), and recovery times (38.7 +/- 15.3 vs. 33.8 +/- 12.1 min) were significantly longer for patients on chronic opioids. In the multivariate regression analysis, opioid use was an independent predictor of longer procedure duration (P < 0.05). Hypotensive episodes did not differ between groups (2.8 vs. 2.7 %; P = 0.8). However, patients on chronic opioids experienced more pain (13.4 vs. 5.9 %; P 0.001) and hypertensive episodes (8.1 vs. 2.8 %; P 0.002). CONCLUSION: Patients on chronic opioids represent a high-risk population with longer procedural times and more discomfort, despite higher dosages of sedative agents. Prospective studies are required to define the risks and benefits of more costly alternative sedation strategies for patients on chronic opioids. PMID- 25822038 TI - Diagnostic evaluation and risk factors for drug allergies in children: from clinical history to skin and challenge tests. AB - BACKGROUND: Parent or self-reported drug allergy claims frequently overestimate the real incidence of hypersensitivity reactions. A detailed and algorithmic diagnostic evaluation of drug reactions may allow a proper diagnosis. OBJECTIVE: The aim of this study was to determine the confirmation rates and risk factors for confirmed allergic drug reactions in children. SETTING: Mersin University Hospital in Turkey. METHOD: The study consisted of children between ages of 8 months and 18 years with the history of suspected drug allergy as reported by the clinician or the patients. Parents were interviewed by a clinician to complete questionnaires that included questions about demographic data and characteristics of index drug reaction. Immediate reactions (IRs) were assessed with immediate reading skin prick (SPT) and intradermal tests (IDT). Nonimmediate reactions (NIRs) were assessed with SPT, both early and delayed reading of IDT and patch tests. In case of negative skin tests, drug provocation tests were performed. The possible risk factors for confirmed drug allergy in univariate analysis (p < 0.1) were entered into the multivariate logistic regression analysis to determine independent predictors. MAIN OUTCOME MEASURE: (1) Confirmation rates of drug allergy (2) Risk factors related to confirmed drug allergy in children. RESULTS: We evaluated a total of 180 suspected drug allergy reactions in 97 children, mainly to antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants. Among all suspected allergic drug reactions, 97 (53.9 %) were immediate type and 83 (46.1 %) were non-immediate type. The average time interval between the reaction and allergologic work-up was 5 months. Drug allergy confirmation rates were 30.1 % for beta-lactams, 27.2 % for non-betalactams, 21.1 % for NSAIDs and 30 % for anticonvulsants. Eight of 54 confirmed NIRs showed positivity on immediate skin tests. Regulatory T cells, TGF-beta and IL-10 levels were not different between groups with and without confirmed drug allergy. A strong family and personal history of drug allergy were found to be significantly related to the confirmed allergic drug reactions. CONCLUSION: Parent or self reported drug allergy should be evaluated with a standardized diagnostic work-up before strict prohibitions are made. In addition, family and personal histories of drug allergy were significant risk factors related to allergic drug reactions in children. PMID- 25822040 TI - South Asian and Middle Eastern patients' perspectives on medicine-related problems in the United Kingdom. AB - BACKGROUND: There has been little research which specifically examines medicine use among South Asian (SA) and Middle Eastern (ME) groups, although evidence suggests that medicine-related needs may be poorly met for these groups. OBJECTIVE: To describe medicine-related problems (MRPs) experienced by SA and ME patients from their perspectives and identify possible contributory factors that may be specific to their cultures. SETTING: The data were collected in seven pharmacies in London, United Kingdom (UK). METHOD: The study was a qualitative study. Patients were from SA and ME origins, aged over 18 and prescribed three or more regular medicines. Patients were identified when presenting with a prescription. The data were collected in 80 face-to-face semi-structured interviews using Gordon's MRPs tool. Interviews were audiotaped, transcribed verbatim and analysed thematically using Gordon's coding frame and Nvivo 10 software. MAIN OUTCOME MEASURE: Describing MRPs experienced by SA and ME patients from their perspectives and identifying possible contributory factors that may be specific to their cultures. Results Eighty participants (61 % male) had mean (SD) age 58 (13.4) years and a mean (SD) of 8 (4) medicines. Interviews revealed that several factors contributed to the development of MRPs; some appeared to be specific to SA and ME cultures and others were similar to the general population. The factors that were reported to be specific to SA and ME groups comprised religious practices and beliefs, use of non-prescription medicines, extent of family support, and travelling abroad--to patient's homeland or to take religious journeys. Illiteracy, language and communication barriers, lack of translated resources, perceptions of healthcare providers, and difficulty consulting a doctor of the same gender may also contribute to the problems. Many of these factors could be expected to influence patient's safety, adherence, and informed decision-making. CONCLUSION: This study demonstrated that SA and ME patients have their own problems and needs regarding both medicine use and service access. By uncovering particular problems experienced by these groups, the study can inform healthcare professionals to support SA and ME patients in the use of their medicines. PMID- 25822039 TI - Promoting weight management services in community pharmacy: perspectives of the pharmacy team in Scotland. AB - BACKGROUND: Obesity has reached pandemic levels with more than 1.4 billion adults affected worldwide. While there is a need to systematically develop and evaluate community pharmacy based models of weight management, it is imperative to describe and understand the perspectives of pharmacy staff. In the UK, trained and accredited community pharmacy medicines counter assistants (MCAs) are commonly the front line staff involved in patient consultations and sale of over the-counter medicines. OBJECTIVE: To explore the beliefs and experiences of pharmacists and MCAs in the North-East of Scotland on community pharmacy weight management. SETTING: All 135 community pharmacies in the North-East of Scotland. METHOD: A qualitative approach of semi-structured telephone interviews with 31 pharmacists and 20 MCAs in the North-East of Scotland. The semi-structured interview schedule was developed with reference to key domains describing professional practice (i.e. awareness and knowledge, skills, practicalities, motivation, acceptance and beliefs) and contextualised with policy documents and published research on community pharmacy based weight management. Interviews were audio-recorded, transcribed and analysed thematically. MAIN OUTCOME MEASURE: Pharmacists' and MCAs' beliefs and experiences with delivering weight management services in community pharmacy. RESULTS: There were mixed responses from pharmacists and MCAs around pharmacy based weight management services from positive views of providing the service in community pharmacy to those more reticent who would always favour patients visiting their physician. While all described similar services e.g. measurement of weight, healthy eating advice, supply of products, they acknowledged that support was often opportunistic at the request of customers, with little integration of other providers. Roles described varied from pharmacist only functions to any staff member. While pharmacists generally felt comfortable and confident, MCAs gave more diverse responses. Both Pharmacist and MCAs highlighted the need for a practice model which is systematically developed and suggested a scheme akin to the successful smoking cessation 12-week nicotine replacement therapy service already available in community pharmacies in Scotland. CONCLUSION: Pharmacists and MCAs interviewed in this study reported their perceptions of benefits to providing community pharmacy based weight management as part of a wider public health function. They described services as opportunistic and customer driven based on ease of access. There was a notable variation in pharmacist and MCA training, reflected in their levels of comfort and confidence. There is a clear need to systematically develop and provide evidence of effectiveness and cost effectiveness for a pharmacy based practice model with key roles and functions for the full pharmacy team. PMID- 25822041 TI - Role of high-dose levetiracetam as add-on therapy for intractable epilepsy: case report and brief review of the literature. AB - CASE: We discuss the case of a 5-year-old long-standing epileptic woman, who received oxcarbazepine 2.1 g/day, and levetiracetam 3 g/day (started in 2005 and up-titrated according to response). In October/2008, due to poor seizure control, patient consent was obtained and levetiracetam up-titrated to 6 g/day, remaining invariable for 72 months; zonisamide was added in July/2009 and up-titrated to 500 mg/day. This combination achieved seizure frequency reduction >=50 %, however, the patient ultimately necessitated temporal lobectomy for complete remission. Occasional agitation and moderate depression were the main side effects. CONCLUSION: Three anti-epileptic drugs (including levetiracetam 6 g/day) achieved statistically-significant seizure frequency reduction >=50 % compared with lower doses, but not seizure freedom. Low-dose risperidone was initiated due to transient dose-dependent agitation, although it did not lead to discontinuation. This report provides insightful information on the use of high dose levetiracetam in focal refractory epilepsy. The concomitance of anti epileptics may have contributed to both efficacy and toxicity. Therefore, the risk/benefit ratio must be individually weighed until larger studies are available. PMID- 25822042 TI - Pharmacists' role in handling problems with prescriptions for antithrombotic medication in Belgian community pharmacies. AB - BACKGROUND: Community pharmacists have an important task in the follow-up of patients treated with antithrombotics. When delivering these medicines, pharmacists can encounter drug-related problems (DRPs) with substantial clinical and economic impact. OBJECTIVE: To investigate the amount and type of antithrombotic related DRPs as well as how community pharmacists handled these DRPs. SETTING: Belgian community pharmacies. METHODS: MSc pharmacy students of six Belgian universities collected data about all DRPs encountered by a pharmacist during ten half days of their pharmacy internship. Data were registered about DRPs detected at delivery and in an a posteriori setting, when consulting the medical history of the patient. Classification of the DRP, cause of the DRP, intervention and result of the intervention were registered. MAIN OUTCOME MEASURE: Amount and type of antotrombitocs related DRPs occurring in community pharmacies, as well as how community pharmacists handled these DRPs. RESULTS: 3.1 % of the 15,952 registered DRPs concerned antithrombotics. 79.3 % of these DRPs were detected at delivery and 20.7 % were detected a posteriori. Most antithrombotic-related DRPs concerned problems with the choice of the drug (mainly because of drug-drug interactions) or concerned logistic problems. Almost 80 % of the antithrombotic-related DRPs were followed by an intervention of the pharmacist, mainly at the patient's level, resulting in 90.1 % of these DRPs partially or totally solved. CONCLUSION: Different DRPs with antithrombotic medication occurred in Belgian community pharmacies. About 20 % was detected in an a posteriori setting, showing the benefit of medication review. Many of the encountered DRPs were of technical nature (60.7 %). These DRPs were time consuming for the pharmacist to resolve and should be prevented. Most of the DRPs could be solved, demonstrating the added value of the community pharmacist as first line healthcare provider. PMID- 25822044 TI - A step towards mobile arsenic measurement for surface waters. AB - Surface modified quantum dots (QDs) are studied using a bio-inspired cysteine rich ligand (glutathione, GSH) and their quenching response and selectivity to arsenic examined. As predicted from As(3+) binding with highly crosslinked phytochelatin-(PCn)-like molecules, better arsenic selectivity is obtained for a thicker more 3-dimensional GSH surface layer, with exposed sulfhydryl groups. A detection limit of at least 10 MUM can be achieved using CdSe/ZnS core-shell QDs capped with this GSH structure. The system is also demonstrated using a mobile phone camera to record the measurement, producing a detection limit of 5 MUM. However, copper remains the main interferent of concern. Water-soluble CdTe QDs show little sensitivity to As(3+) even with a GSH surface, but they remain sensitive to Cu(2+), allowing a copper baseline to be established from the CdTe measurement. Despite anticipating that spectrally non overlapping fluorescence would be required from the two types of QDs to achieve this, a method is demonstrated using RGB channels from a mobile phone and processing the raw data for CdTe QDs, with an emission wavelength of 600 nm, and CdSe/ZnS QDs, with emission maximum of 630 nm. It is shown that As(3+) measurement remains feasible at the WHO guideline value of 10 MUg L(-1) up to a copper concentration of around 0.3 MUM Cu(2+), which corresponds to the highest recorded level in a selection of large rivers world-wide. PMID- 25822043 TI - Impact of Japanese regulatory action on metformin-associated lactic acidosis in type II diabetes patients. AB - BACKGROUND: The March 2012 regulatory action issued by the Japanese government signalled the rare but serious complication of lactic acidosis that can occur during metformin treatment, especially with the high dose formulation, h metformin, and in those above 75 years old. OBJECTIVE: To assess quantitatively the impact of this regulatory action on patient management using a medical information database (MID). SETTING: Eight hospitals in Japan. METHOD: Using a commercial MID, we collected data on adult outpatients treated with metformin, including h-metformin, during a 2-year study period between April 1, 2011 and March 31, 2013. The 2-year study period spanned 1 year before and after the regulatory action. The frequencies of lactate measurement in all metformin users, h-metformin users, and new users (started on metformin during the study period) were compared between the periods before and after the regulatory action, using generalized estimating equations. Trends in metformin prescription for elderly patients were analysed month-wise by regression analysis using an interrupted time series design. MAIN OUTCOME MEASURE: The rate ratios (RR) of lactate testing before and after the regulatory action. RESULTS: Of 4347 metformin users, 784 patients were >75 years old. A significant increase in lactate measurement was observed after the regulatory action than before in the overall study population, with an adjusted RR of 2.14 (95 % confidence interval 1.24-3.68). No significant change was found in h-metformin users and new users because lactate measurements were being performed as frequently in these subgroups before the regulatory action. There were no meaningful changes in the proportion of elderly metformin users in the overall population. CONCLUSION: The regulatory action led to increased lactate measurement in the overall metformin users, but did not affect metformin prescription rate in the elderly patients. Our findings probably reflect the doctors' judgement that the benefits of metformin use outweigh the risk of lactic acidosis if lactate testing is performed regularly. PMID- 25822045 TI - Emergency Health Care Use among Sociodemographic Groups of Children Presenting to Emergency Departments for Self-Harm in Alberta. AB - OBJECTIVE: To examine sociodemographic variations among children <18 years in (1) rates of self-harm visits to emergency departments (EDs) and (2) physician follow up after the self-harm visit in Alberta. METHODS: A retrospective, population based cohort (2002-2011) of ED visits for self-harm by individuals <18 years was conducted using administrative databases from Alberta, Canada. Individuals were grouped by First Nations status or type of health care premium subsidy (family receipt of government subsidy, human services program subsidy, no subsidy received). Visits from 104 EDs were summarized by crude and directly standardized visit rates (DSVRs) per 100,000 individuals. Kaplan-Meier estimates for median estimated time to physician follow-up were calculated with 95% confidence intervals (CIs). RESULTS: During the study period, visit rates decreased with the exception of children from families receiving government-sponsored program subsidy (DSVRs 163/100,000 to 250/100,000; p=0.032). First Nations children had disproportionately fewer follow-up visits compared to other children. The median time to follow-up for First Nations children was 39 days (95% CI: 32, 48) compared to 16 days for children from families receiving no subsidy (95% CI: 14, 19), who had the shortest follow-up time after an ED visit. CONCLUSIONS: Sociodemographic differences were evident in ED visit rates as well as the number of and time to physician follow-up visit. The disparities experienced by First Nations children in the follow-up period highlight an opportunity for culturally grounded risk and needs assessment in the ED to determine and facilitate timely and appropriate follow-up care. PMID- 25822047 TI - The fate of patients with acute myeloid leukemia not undergoing induction chemotherapy. AB - Advances in chemotherapy for acute myeloid leukemia (AML) have resulted in the exclusion of patients not undergoing induction chemotherapy from research studies. To examine in detail the clinical experience of such patients, we retrospectively analyzed the outcomes of consecutive patients diagnosed with AML at our hospital from 2004 to 2012. Of 158 AML patients, 43 (27 %) did not undergo induction chemotherapy. Their median survival duration was 1.5 months, with 11, six, and four patients surviving more than 3, 6, and 12 months, respectively. As expected, their survival was worse than that of those treated with intensive or less-intensive induction therapy (14, 74, and 47 % at 1 year, and 0, 40, and 10 % at 4 years, respectively). Low white blood cell count at AML diagnosis and prior history of myelodysplastic syndrome were significantly associated with longer survival. Our findings suggest that modern supportive care measures do not prolong survival for AML patients not undergoing induction chemotherapy, although certain patients show relatively long survival. These data should prove helpful in discussing treatment pathways with patients for cases in which palliative or supportive therapy alone may be a viable treatment option. PMID- 25822048 TI - Qualitative health psychology research: diversity, power, and impact. AB - This special issue showcases a range of qualitative research projects conducted by health psychologists with a view to promoting greater uptake and development of qualitative research methods in the field. It is timely because qualitative methods have become prominent across psychology and health research and because major health research funders are now inviting qualitative research to help give voice to patient experiences. As a whole, the papers demonstrate the diversity, power, and impact of qualitative research conducted in health-related settings and show how traditional health psychology methods and concepts can be enriched in the process. PMID- 25822046 TI - Computational and biophysical approaches to protein-protein interaction inhibition of Plasmodium falciparum AMA1/RON2 complex. AB - Invasion of the red blood cell by Plasmodium falciparum parasites requires formation of an electron dense circumferential ring called the Moving Junction (MJ). The MJ is anchored by a high affinity complex of two parasite proteins: Apical Membrane Antigen 1 (PfAMA1) displayed on the surface of the parasite and Rhoptry Neck Protein 2 that is discharged from the parasite and imbedded in the membrane of the host cell. Structural studies of PfAMA1 revealed a conserved hydrophobic groove localized to the apical surface that coordinates RON2 and invasion inhibitory peptides. In the present work, we employed computational and biophysical methods to identify competitive P. falciparum AMA1-RON2 inhibitors with the goal of exploring the 'druggability' of this attractive antimalarial target. A virtual screen followed by molecular docking with the PfAMA1 crystal structure was performed using an eight million compound collection that included commercial molecules, the ChEMBL malaria library and approved drugs. The consensus approach resulted in the selection of inhibitor candidates. We also developed a fluorescence anisotropy assay using a modified inhibitory peptide to experimentally validate the ability of the selected compounds to inhibit the AMA1 RON2 interaction. Among those, we identified one compound that displayed significant inhibition. This study offers interesting clues to improve the throughput and reliability of screening for new drug leads. PMID- 25822049 TI - Social networking and young adults' drinking practices: innovative qualitative methods for health behavior research. AB - OBJECTIVES: Understandings of health behaviors can be enriched by using innovative qualitative research designs. We illustrate this with a project that used multiple qualitative methods to explore the confluence of young adults' drinking behaviors and social networking practices in Aotearoa, New Zealand. METHOD: Participants were 18-25 year old males and females from diverse ethnic, class, and occupational backgrounds. In Stage 1, 34 friendship focus group discussions were video-recorded with 141 young adults who talked about their drinking and social networking practices. In Stage 2, 23 individual interviews were conducted using screen-capture software and video to record participants showing and discussing their Facebook pages. In Stage 3, a database of Web-based material regarding drinking and alcohol was developed and analyzed. RESULTS: In friendship group data, young adults co-constructed accounts of drinking practices and networking about drinking via Facebook as intensely social and pleasurable. However, this pleasure was less prominent in individual interviews, where there was greater explication of unpleasant or problematic experiences and practices. The pleasure derived from drinking and social networking practices was also differentiated by ethnicity, gender, and social class. Juxtaposing the Web-based data with participants' talk about their drinking and social media use showed the deep penetration of online alcohol marketing into young people's social worlds. CONCLUSIONS: Multiple qualitative methods, generating multimodal datasets, allowed valuable nuanced insights into young adults' drinking practices and social networking behaviors. This knowledge can usefully inform health policy, health promotion strategies, and targeted health interventions. PMID- 25822050 TI - Responsible men, blameworthy women: Black heterosexual men's discursive constructions of safer sex and masculinity. AB - OBJECTIVE: Although Black heterosexual men (BHM) in the United States rank among those most affected by HIV, research about how safer sex messages shape their safer sex behaviors is rare, highlighting the need for innovative qualitative methodologies such as critical discursive psychology (CDP). This CDP study examined how: (a) BHM construct safer sex and masculinity; (b) BHM positioned themselves in relation to conventional masculinity; and (c) discursive context (individual interview vs. focus group) shaped talk about safer sex and masculinity. METHOD: Data included individual interviews (n = 30) and 4 focus groups (n = 26) conducted with 56 self-identified Black/African American heterosexual men, ages 18 to 44. RESULTS: Analyses highlighted 5 main constructions: (a) condoms as signifiers of "safe" women; (b) blaming women for STI/responsibility for safer sex; (c) relationship/trust/knowledge; (d) condom mandates; and (e) public health safer sex. Discourses positioned BHM in terms of conventional masculinity when talk denied men's agency for safer sex and/or contraception, or positioned women as deceitful, or apathetic about sexual risk and/or pregnancy. Notably, discourses also spotlighted alternative masculinities relevant to taking responsibility for safer sex or sexual exclusivity. Discursive context, namely the homosocial nature of focus group discussions, shaped how participants conversed about safer sex, and masculinity but not the content of that talk. CONCLUSION: In denying BHM's responsibility for safer sex, BHM's discourses about safer sex and masculinity often mirror public health messages, underscoring a critical need to sync these discourses to reduce sexual risk, and develop gender-transformative safer sex interventions for BHM. PMID- 25822051 TI - Using qualitative methods within a mixed-methods approach to developing and evaluating interventions to address harmful alcohol use among young people. AB - OBJECTIVE: This article illustrates how qualitative methods can be used in the development and evaluation of behavior change interventions. Although many campaigns advise young people to drink responsibly, few clarify how to convert this general advice into specific behavioral strategies. Resilience-based approaches argue that treating young non-drinkers and moderate drinkers as "experts" in responsible alcohol use may facilitate co-creation of acceptable interventions that focus on how to change behavior. METHOD: Four distinct phases of intervention development were linked to past research and future developments. RESULTS: First, analysis of correlates of alcohol use using data from a survey of 1,412 people aged 16-21 indicated that alcohol harm-reduction interventions should help young people to develop skills and strategies to resist alcohol. Second, interpretative phenomenological analysis of 25 interviews with people purposively selected from among the survey sample identified general strategies and specific tactics used by young people to manage opportunities to drink. Third, insights from the first 2 phases and past qualitative research guided development of video resources to be use in school-based alcohol education to illustrate strategies and tactics for moderate or non-use of alcohol. Fourth, 18 focus groups with students and teachers were used to evaluate the video: structured thematic analysis indicated that after revision the video would be a valuable addition to school-based alcohol education. CONCLUSIONS: Findings from the 4 phases highlight the value of using different qualitative and quantitative methods as part of a program of work designed to inform the development, refinement, and evaluation of health psychology interventions. PMID- 25822052 TI - Developing an intervention to equip nurses for acute life threatening events (ALTEs) in hospital: a phenomenological approach to healthcare research. AB - OBJECTIVES: To understand staff's experiences of acute life threatening events (ALTEs) in a pediatric hospital setting. These data will inform an intervention to equip nurses with clinical and emotional skills for dealing with ALTEs. METHOD: A mixed design was used in the broader research program; this paper focuses on phenomenon-focused interviews analyzed using interpretative phenomenological analysis (IPA). RESULTS: Emerging themes included staff's relationships with patients and the impact of personhood on their ability to perform competently in an emergency. More experienced nurses described "automatic" competence generated through increased exposure to ALTEs and were able to recognize "fumbling and shaking" as a normal stress response. Designating a role was significant to staff experience of effectiveness. Key to nurses' learning experience was reflection and identifying experiences as "teachable moments." Findings were considered alongside existing theories of self-efficacy, reflective thought, and advocacy inquiry to create an experiential learning intervention involving a series of clinical and role-related scenarios. CONCLUSION: The phenomenological work facilitated an in-depth reading of experience. It accentuated the importance of exposure to ALTEs giving nurses experiential knowledge to prepare them for the impact of these events. Challenges included bracketing the personhood of child patients, shifting focus to clinical tasks during the pressured demands of managing an ALTE, normalizing the physiological stress response, and the need for a forum and structure for reflection and learning. An intervention will be designed to provide experiential learning and encourage nurses to realize and benefit from their embodied knowledge. PMID- 25822053 TI - Applying discursive approaches to health psychology. AB - OBJECTIVE: The aim of this paper is to outline the contribution of two strands of discursive research, glossed as 'macro' and 'micro,' to the field of health psychology. A further goal is to highlight some contemporary debates in methodology associated with the use of interview data versus more naturalistic data in qualitative health research. METHOD: Discursive approaches provide a way of analyzing talk as a social practice that considers how descriptions are put together and what actions they achieve. RESULTS: A selection of recent examples of discursive research from one applied area of health psychology, studies of diet and obesity, are drawn upon in order to illustrate the specifics of both strands. 'Macro' discourse work in psychology incorporates a Foucauldian focus on the way that discourses regulate subjectivities, whereas the concept of interpretative repertoires affords more agency to the individual: both are useful for identifying the cultural context of talk. Both 'macro' and 'micro' strands focus on accountability to varying degrees. 'Micro' Discursive Psychology, however, pays closer attention to the sequential organization of constructions and focuses on naturalistic settings that allow for the inclusion of an analysis of the health professional. CONCLUSION: Diets are typically depicted as an individual responsibility in mainstream health psychology, but discursive research highlights how discourses are collectively produced and bound up with social practices. PMID- 25822055 TI - Painting pain: an interpretative phenomenological analysis of representations of living with chronic pain. AB - OBJECTIVE: This study examines patients' pictorial representations of their chronic pain, alongside their accounts of those images, in order to help our understanding of their lived experience of the condition. METHOD: The sample comprises 7 women in middle adulthood from southern England. They began by drawing what their pain felt like and were then interviewed about their portrayals. The interviews were analyzed with interpretative phenomenological analysis. RESULTS: The participants produce strong, vivid, abstract pictures. In many of the pictures, the pain is objectified as punitive and sinister. This is enhanced through the use of stark colors of red and black. Paintings also often have a temporal element, showing either the movement from self before pain to self since the pain had started, or pointing to aspirations for the possible relief of pain in the future. The analysis of the images is grounded in the participants' accounts of them. CONCLUSION: The images and accounts provide a powerful insight into the internal world of the pain sufferer and the subjective experience of chronic pain. We link this work to other attempts to represent patients' pain and point to the particular contribution our work makes. We make some suggestions for subsequent research following on from what is presented here and we also argue that the methodology outlined in the article offers considerable potential for research on other health conditions. PMID- 25822054 TI - Reducing youth screen time: qualitative metasynthesis of findings on barriers and facilitators. AB - OBJECTIVE: An integrated perspective on the relevant qualitative findings on the experience of screen time in youth can inform the development of hypotheses to be tested in future research and can guide the development of interventions to decrease sedentary behavior. The purpose of this qualitative metasynthesis was to explore parent, youth, and educational professionals' perceptions of barriers to, and facilitators of, reducing youth screen time. METHOD: Qualitative metasynthesis techniques were used to analyze and synthesize 15 qualitative studies of screen time among youth (11-18 years) meeting inclusion criteria. The phrases, quotes, and/or author interpretations (i.e., theme or subtheme) were recorded in a data display matrix to facilitate article comparisons. Codes were collapsed into 23 categories of similar conceptual meaning and 3 overarching themes were derived using thematic analysis procedures. RESULTS: Study sample sizes ranged from 6 to 270 participants from 6 countries. Data collection methods included focus groups (n = 6), interviews (n = 4), focus group and interviews (n = 4), and naturalistic observation (n = 1) with youth and/or parents. Data analysis techniques included thematic analysis (n = 9), content analysis (n = 3), grounded theory (n = 1), observation (n = 1), and interpretive phenomenological analysis (n = 1). Three thematic categories were identified: (a) youth's norms screen time is an integral part of daily life, and facilitates opportunities for entertainment, social interaction, and escapism; (b) family dynamics and parental roles-parents are conflicted and send mixed messages about the appropriate uses and amounts of screen time; and, (c) resources and environment-engagement in screen time is dependent on school, community, neighborhood, and home environmental contexts. CONCLUSIONS: Screen time is an established norm in many youth cultures, presenting barriers to behavior change. Parents recognize the importance of reducing youth screen time, but model and promote engagement themselves. For youth and parents, mutually agreed rules, limits, and parental monitoring of screen time were perceived as likely to be effective. PMID- 25822056 TI - "My bus is here": a phenomenological exploration of "living-with-dying". AB - OBJECTIVES: This article has 2 aims. The first is to demonstrate how the application of an innovative qualitative methodology generated novel insights into the experience of living with advanced cancer. The article's second aim is to challenge the idea that the identification of shared themes provides the researcher with access to the meaning and significance of the experience of "living-with-dying." METHOD: The research used object elicitation together with existentially informed hermeneutic phenomenological analysis. The analysis is based on 10 semistructured interviews with people who are living with advanced cancer. RESULTS: Three brief case studies demonstrate the variability in accounts that characterizes the data set as a whole. This is followed by reflections on the way in which, despite striking individual differences, all participants seemed to experience living-with-dying as an existential challenge that demands that the individual concerned finds a way of coming to terms with the very parameters of human existence. CONCLUSION: A thoroughly idiographic approach that advocates staying with the diversity that characterizes the experience of living with advanced cancer. It is argued that to make sense of the remarkable differences between the research participants' accounts of their experiences of living with a diagnosis of advanced cancer, a focus on process (i.e., What happens when people encounter their mortality?) and meaning (i.e., What does it mean to them?) helps us to understand these as different responses to the challenge of death awareness. PMID- 25822057 TI - Renegotiating sexual intimacy in the context of altered embodiment: the experiences of women with breast cancer and their male partners following mastectomy and reconstruction. AB - OBJECTIVE: Breast cancer diagnosis and treatments can have a profound impact upon women's well-being, body image, and sexual functioning, but less is known about the relational context of their coping and the impact upon their intimate partners. Our study focuses upon couples' experiences of breast cancer surgery, and its impact on body image and sexual intimacy. METHOD: Utilizing a dyadic design, we conducted 8 semistructured individual interviews, with 4 long-term heterosexual couples, after the women had undergone mastectomy with reconstruction. Interviews explored both partners' experiences of diagnosis, decision-making, and experiences of body image and sexual intimacy. Interpretative phenomenological analysis (IPA) was adopted; this is a qualitative research approach characterized by in-depth analysis of the personal meaning of experiences. RESULTS: Findings illustrate the positive acceptance that partners may express toward their wives' postsurgical bodies. They illuminate ways in which gendered coping styles and normative sexual scripts may shape couples' negotiations of intimacy around "altered embodiment." Reciprocal communication styles were important for couples' coping. The management of expectations regarding breast reconstruction may also be helpful. CONCLUSIONS: The insights from the dyadic, multiple perspective design suggest that psychologists must situate the meaning of supportive relationships and other protective factors in the context of complex life events and histories, in order to understand and support people's developing responses to distress. PMID- 25822058 TI - The parents' ability to attend to the "voice of their child" with incurable cancer during the palliative phase. AB - OBJECTIVE: In pediatric oncology, parents want, and are expected, to act and decide in the best interest of their child. A recent qualitative study (PRESENCE study) indicated that parents had difficulty in doing so. The aim of this subanalysis was to describe and offer an explanation for the parents' actions in expressing and handling of "the voice of the child." METHOD: A multicenter, qualitative research study comprising 37 interviews conducted with 34 parents of 17 children with incurable cancer, cared for at home, during the palliative phase. A thematic analysis was conducted. RESULTS: The "voice of the child" becomes manifest in the parents' expressions of the child's needs and perceptions. Parents who actively searched to understand their child's inner perspective used direct and indirect strategies. Parents preferred indirect strategies when their child avoided talking or when they considered the conversation as threatening for the child, or for themselves. Even if the parents show an intense involvement in the care and support of their child; they can still have difficulty acknowledging the child's perspective. An inability to take into account the child's perspective was largely due to the parents' own struggle to cope with loss. CONCLUSIONS: Whether or not the voice of children approaching the end-of- life is heard, often depends on their parents' ability to give them a voice. Professional caregivers have a difficult task in supporting parents in giving their child his or her voice, while at the same time preserving their, and their parents', ability to cope. PMID- 25822059 TI - Meaning making during parent-physician bereavement meetings after a child's death. AB - OBJECTIVE: Our goal was to identify and describe types of meaning-making processes that occur among parents during bereavement meetings with their child's intensive care physician after their child's death in a pediatric intensive care unit. METHODS: Fifty-three parents of 35 deceased children participated in a bereavement meeting with their child's physician 14.5 +/- 6.3 weeks after the child's death. One meeting was conducted per family. Meetings were video recorded and transcribed verbatim. Using a directed content analysis, an interdisciplinary team analyzed the transcripts to identify and describe meaning-making processes that support and extend extant meaning-making theory. RESULTS: Four major meaning making processes were identified: (1) sense making, (2) benefit finding, (3) continuing bonds, and (4) identity reconstruction. Sense making refers to seeking biomedical explanations for the death, revisiting parents' prior decisions and roles, and assigning blame. Benefit finding refers to exploring positive consequences of the death, including ways to help others, such as giving feedback to the hospital, making donations, participating in research, volunteering, and contributing to new medical knowledge. Continuing bonds refers to parents' ongoing connection with the deceased child manifested by reminiscing about the child, sharing photographs and discussing personal rituals, linking objects, and community events to honor the child. Identity reconstruction refers to changes in parents' sense of self, including changes in relationships, work, home, and leisure. CONCLUSIONS: Parent-physician bereavement meetings facilitate several types of meaning-making processes among bereaved parents. Further research should evaluate the extent to which meaning making during bereavement meetings affects parents' health outcomes. PMID- 25822060 TI - A conceptual model of morphogenesis and regeneration. AB - This paper is devoted to computer modelling of the development and regeneration of multicellular biological structures. Some species (e.g. planaria and salamanders) are able to regenerate parts of their body after amputation damage, but the global rules governing cooperative cell behaviour during morphogenesis are not known. Here, we consider a simplified model organism, which consists of tissues formed around special cells that can be interpreted as stem cells. We assume that stem cells communicate with each other by a set of signals, and that the values of these signals depend on the distance between cells. Thus the signal distribution characterizes location of stem cells. If the signal distribution is changed, then the difference between the initial and the current signal distribution affects the behaviour of stem cells-e.g. as a result of an amputation of a part of tissue the signal distribution changes which stimulates stem cells to migrate to new locations, appropriate for regeneration of the proper pattern. Moreover, as stem cells divide and form tissues around them, they control the form and the size of regenerating tissues. This two-level organization of the model organism, with global regulation of stem cells and local regulation of tissues, allows its reproducible development and regeneration. PMID- 25822061 TI - Impact of anatomic location on locally recurrent rectal cancer: superior outcome for intraluminal tumour recurrence. AB - BACKGROUND: Local recurrence of rectal cancer after curative surgery predicts patients' prognosis. The correlation between the exact anatomic location of tumour recurrence and patients' survival is still under debate. Thus, this study aimed to investigate the impact of the exact location of recurrent rectal cancer on post-operative morbidity and survival. METHODS: This is a retrospective study including 90 patients with locally recurrent rectal cancer. The location of tumour recurrence was classified into intraluminal and extraluminal recurrence. Univariate and multivariable Cox regression analyses were used to determine the impact on post-operative morbidity and survival. RESULTS: Patients' survival with intraluminal recurrence was significantly longer compared to patients with extraluminal recurrence (p = 0.027). Curative resection was associated with prolonged survival in univariate and multivariable analyses (p = 0.0001) and was more often achieved in patients with intraluminal recurrence (p = 0.024). Survival of curative resected patients with intraluminal recurrence was significantly longer compared to curatively resected patients with extraluminal recurrence (p = 0.0001). The rate of post-operative morbidity between intraluminal and extraluminal recurrence was not statistically different (p = 0.59). CONCLUSION: Based on the present investigation, intraluminal recurrence is associated with superior outcome. Post-operative morbidity did not differ significantly between both groups. PMID- 25822062 TI - Transcatheter Arterial Embolization of Ruptured Inferior Phrenic Artery Pseudoaneurysm Following Completion Gastrectomy. AB - A 56-year-old man underwent completion gastrectomy and regional lymphadenectomy for adenocarcinoma of the remnant stomach. Postoperatively, he developed an esophagojejunal anastomotic insufficiency associated with leakage of activated pancreatic juice, resulting in pseudoaneurysm arising from the inferior phrenic artery (IPA) with massive bleeding. Emergency angiography was performed, and the artery was successfully embolized using N-butyl cyanoacrylate. Pseudoaneurysm of the IPA is an extremely rare entity, and transcatheter arterial embolization is an effective treatment method because of its advantages over surgery. PMID- 25822063 TI - Outcome for Asymptomatic Recurrence Following Laparoscopic Repair of Very Large Hiatus Hernia. AB - BACKGROUND: Radiological follow-up following repair of large hiatus hernias have identified recurrence rates of 20-30%, although most are small and asymptomatic. Whether patients will eventually develop clinical problems is uncertain. This study evaluated the outcome for individuals identified with an asymptomatic hiatus hernia following previous repair vs. asymptomatic controls. METHODS: One hundred fifteen asymptomatic patients who had previously undergone sutured repair of a large hiatus hernia and then underwent barium meal X-ray 6-60 months after surgery within a clinical trial were identified and divided into two cohorts: with (n = 41) vs. without (n = 74) an asymptomatic hernia. Heartburn, dysphagia, and satisfaction with surgery were assessed prospectively using a standardized questionnaire applying analogue scales. Consumption of antisecretory medication and revision surgery were also determined. To determine the natural history of asymptomatic recurrent hiatus hernia, outcomes for the two groups were compared at 1 and 5 years and at most recent (late) follow-up. RESULTS: Outcomes were available at 1 year for 98.2% and 5 years or the latest follow-up (range 6-237 months) for 100%. Heartburn and dysphagia scores were low and satisfaction scores high in both groups at all follow-up points, but heartburn scores and medication use were higher in the recurrent hernia group. At late follow-up, 94.6% of the recurrent hernia group vs. 98.5% without a hernia regarded their original decision for surgery to be correct. Two patients in recurrent hernia group underwent revision surgery. CONCLUSIONS: Patients with an initially asymptomatic recurrent hiatus hernia are more likely to report heartburn and use antisecretory medication at later follow-up than controls. However, overall clinical outcomes remain good, with high satisfaction and low surgical revision rates. Additional interventions to reduce the risk of recurrence might not be warranted. PMID- 25822064 TI - Patients with ocular symptoms referred for electrodiagnosis: how many of them suffer from myasthenia gravis? AB - The aim of this study was the diagnosis of patients with isolated ocular manifestations (ptosis and/or diplopia) referred for electrophysiological evaluation to the electrodiagnostic laboratory of a University Neurological Department. Examination was performed either in inpatient status or in outpatient basis. We analyzed the clinical, electrophysiological and other laboratory data in 79 subjects. Myasthenia gravis (MG) was diagnosed in 38 %, 45.6 % in other diseases (Graves disease, blepharospasm, IIId cranial verve palsy, multiple sclerosis, stroke, etc.), while in 16.5 %, the cause remained unidentified. Symptoms fluctuation was significantly more frequent in the myasthenic patients, compared to patients with other diseases. The presence of both diplopia and ptosis are more likely due to MG rather than other pathology. PMID- 25822065 TI - A 90 day safety assessment of genetically modified rice expressing Cry1Ab/1Ac protein using an aquatic animal model. AB - In fields of transgenic Bt rice, frogs are exposed to Bt proteins through consumption of both target and nontarget insects. In the present study, we assessed the risk posed by transgenic rice expressing a Cry1Ab/1Ac fusion protein (Huahui 1, HH1) on the development of Xenopus laevis. For 90 days, froglets were fed a diet with 30% HH1 rice, 30% parental rice (Minghui 63, MH63), or no rice as a control. Body weight and length were measured every 15 days. After sacrificing the froglets, we performed a range of biological, clinical, and pathological assessments. No significant differences were found in body weight (on day 90: 27.7 +/- 2.17, 27.4 +/- 2.40, and 27.9 +/- 1.67 g for HH1, MH63, and control, respectively), body length (on day 90: 60.2 +/- 1.55, 59.3 +/- 2.33, and 59.7 +/- 1.64 mm for HH1, MH63, and control, respectively), animal behavior, organ weight, liver and kidney function, or the microstructure of some tissues between the froglets fed on the HH1-containing diet and those fed on the MH63-containing or control diets. This indicates that frog development was not adversely affected by dietary intake of Cry1Ab/1Ac protein. PMID- 25822067 TI - Cognitive predictors and age-based adverse impact among business executives. AB - Age differences on measures of general mental ability and specific cognitive abilities were examined in 2 samples of job applicants to executive positions as well as a mix of executive/nonexecutive positions to determine which predictors might lead to age-based adverse impact in making selection and advancement decisions. Generalizability of the pattern of findings was also investigated in 2 samples from the general adult population. Age was negatively related to general mental ability, with older executives scoring lower than younger executives. For specific ability components, the direction and magnitude of age differences depended on the specific ability in question. Older executives scored higher on verbal ability, a measure most often associated with crystallized intelligence. This finding generalized across samples examined in this study. Also, consistent with findings that fluid abilities decline with age, older executives scored somewhat lower on figural reasoning than younger executives, and much lower on a letter series test of inductive reasoning. Other measures of inductive reasoning, such as Raven's Advanced Progressive Matrices, also showed similar age group mean differences across settings. Implications for employee selection and adverse impact on older job candidates are discussed. PMID- 25822066 TI - C. elegans outside the Petri dish. AB - The roundworm Caenorhabditis elegans has risen to the status of a top model organism for biological research in the last fifty years. Among laboratory animals, this tiny nematode is one of the simplest and easiest organisms to handle. And its life outside the laboratory is beginning to be unveiled. Like other model organisms, C. elegans has a boom-and-bust lifestyle. It feasts on ephemeral bacterial blooms in decomposing fruits and stems. After resource depletion, its young larvae enter a migratory diapause stage, called the dauer. Organisms known to be associated with C. elegans include migration vectors (such as snails, slugs and isopods) and pathogens (such as microsporidia, fungi, bacteria and viruses). By deepening our understanding of the natural history of C. elegans, we establish a broader context and improved tools for studying its biology. PMID- 25822068 TI - Stargazing: an integrative conceptual review, theoretical reconciliation, and extension for star employee research. AB - Stars--employees with disproportionately high and prolonged (a) performance, (b) visibility, and (c) relevant social capital--have garnered attention in economics, sociology, and management. However, star research is often isolated within these research disciplines. Thus, 3 distinct star research streams are evolving, each disconnected from the others and each bringing siloed theoretical perspectives, terms, and assumptions. A conceptual review of these perspectives reveals a focus on the expost effects that stars exert in organizations with little explanation of who a star is and how one becomes a star. To synthesize the stars literature across these 3 disciplines, we apply psychological theories, specifically motivation theories, to create an integrative framework for stars research. Thus, we present a unified stars definition and extend theory on the making, managing, and mobility of stars. We extend research about how and why employees may be motivated to become stars, how best to manage stars and their relationships with colleagues, and how to motivate star retention. We then outline directions for future research. PMID- 25822069 TI - Taking it to another level: do personality-based human capital resources matter to firm performance? AB - Drawing on the attraction-selection-attrition perspective, strategic human resource management (SHRM) scholarship, and recent human capital research, this study explores organization-level emergence of personality (i.e., personality based human capital resources) and its direct, interactive, and (conditional) indirect effects on organization-level outcomes based on data from 6,709 managers across 71 firms. Results indicate that organization-level mean emotional stability, extraversion, and conscientiousness are positively related to organization-level managerial job satisfaction and labor productivity but not to financial performance. Furthermore, organization-level mean and variance in emotional stability interact to predict all three organization-level outcomes, and organization-level mean and variance in extraversion interact to predict firm financial performance. Specifically, the positive effects of organization-level mean emotional stability and extraversion are stronger when organization-level variance in these traits is lower. Finally, organization-level mean emotional stability, extraversion, and conscientiousness are all positively related to firm financial performance indirectly via labor productivity, and the indirect effects are more positive when organization-level variance in those personality traits is lower. Overall, the findings suggest that personality-based human capital resources demonstrate tangible effects on organization-level outcomes. Theoretical and practical implications of these findings are discussed along with study limitations and future research directions. PMID- 25822070 TI - Understanding organizational commitment: A meta-analytic examination of the roles of the five-factor model of personality and culture. AB - We examined the relationships between the Five-Factor Model (FFM) of personality traits and three forms of organizational commitment (affective, normative, and continuance commitment) and their variability across individualistic and collectivistic cultures. Meta-analytic results based on 55 independent samples from 50 studies (N = 18,262) revealed that (a) all FFM traits had positive relationships with affective commitment; (b) all FFM traits had positive relationships with normative commitment; and (c) Emotional Stability, Extraversion, and Openness to Experience had negative relationships with continuance commitment. In particular, Agreeableness was found to be the trait most strongly related to both affective and normative commitment. The results also showed that Agreeableness had stronger relationships with affective and normative commitment in collectivistic cultures than in individualistic cultures. We provide theoretical and practical implications of these findings for personality, job attitudes, and employee selection and retention. PMID- 25822071 TI - Ideal, nonideal, and no-marker variables: The confirmatory factor analysis (CFA) marker technique works when it matters. AB - A persistent concern in the management and applied psychology literature is the effect of common method variance on observed relations among variables. Recent work (i.e., Richardson, Simmering, & Sturman, 2009) evaluated 3 analytical approaches to controlling for common method variance, including the confirmatory factor analysis (CFA) marker technique. Their findings indicated significant problems with this technique, especially with nonideal marker variables (those with theoretical relations with substantive variables). Based on their simulation results, Richardson et al. concluded that not correcting for method variance provides more accurate estimates than using the CFA marker technique. We reexamined the effects of using marker variables in a simulation study and found the degree of error in estimates of a substantive factor correlation was relatively small in most cases, and much smaller than error associated with making no correction. Further, in instances in which the error was large, the correlations between the marker and substantive scales were higher than that found in organizational research with marker variables. We conclude that in most practical settings, the CFA marker technique yields parameter estimates close to their true values, and the criticisms made by Richardson et al. are overstated. PMID- 25822073 TI - Charge Transport across DNA-Based Three-Way Junctions. AB - DNA-based molecular electronics will require charges to be transported from one site within a 2D or 3D architecture to another. While this has been shown previously in linear, pi-stacked DNA sequences, the dynamics and efficiency of charge transport across DNA three-way junction (3WJ) have yet to be determined. Here, we present an investigation of hole transport and trapping across a DNA based three-way junction systems by a combination of femtosecond transient absorption spectroscopy and molecular dynamics simulations. Hole transport across the junction is proposed to be gated by conformational fluctuations in the ground state which bring the transiently populated hole carrier nucleobases into better aligned geometries on the nanosecond time scale, thus modulating the pi-pi electronic coupling along the base pair sequence. PMID- 25822072 TI - Lactobacillus rhamnosus lowers zebrafish lipid content by changing gut microbiota and host transcription of genes involved in lipid metabolism. AB - The microbiome plays an important role in lipid metabolism but how the introduction of probiotic communities affects host lipid metabolism is poorly understood. Using a multidisciplinary approach we addressed this knowledge gap using the zebrafish model by coupling high-throughput sequencing with biochemical, molecular and morphological analysis to evaluate the changes in the intestine. Analysis of bacterial 16S libraries revealed that Lactobacillus rhamnosus was able to modulate the gut microbiome of zebrafish larvae, elevating the abundance of Firmicutes sequences and reducing the abundance of Actinobacteria. The gut microbiome changes modulated host lipid processing by inducing transcriptional down-regulation of genes involved in cholesterol and triglycerides metabolism (fit2, agpat4, dgat2, mgll, hnf4alpha, scap, and cck) concomitantly decreasing total body cholesterol and triglyceride content and increasing fatty acid levels. L. rhamnosus treatment also increased microvilli and enterocyte lengths and decreased lipid droplet size in the intestinal epithelium. These changes resulted in elevated zebrafish larval growth. This integrated system investigation demonstrates probiotic modulation of the gut microbiome, highlights a novel gene network involved in lipid metabolism, provides an insight into how the microbiome regulates molecules involved in lipid metabolism, and reveals a new potential role for L. rhamnosus in the treatment of lipid disorders. PMID- 25822074 TI - Dual colorimetric and fluorescent sensor based on semiconducting polymer dots for ratiometric detection of lead ions in living cells. AB - Recently, semiconducting polymer dots (Pdots) have become a novel type of ultrabright fluorescent probes which hold great promise in biological imaging and analytical detection. Here we developed a visual sensor based on Pdots for Pb(2+) detection. We first embedded near-infrared (NIR) dyes into the matrix of poly[(9,9-dioctylfluorene)-co-2,1,3-benzothiadiazole-co-4,7-di(thiophen-2-yl) 2,1,3-benzothiadiazole] (PFBT-DBT) polymer and then capped the Pdots with polydiacetylenes (PDAs), in which parts of the PDAs were prefunctionalized with 15-crown-5 moieties to form Pdots. The high selectivity of these Pdots for lead ions is attributed to the formation of 2:1 15-crown-5-Pb(2+)-carboxylate sandwich complex on the Pdot surface. After Pb(2+) chelation, the conjugation system of the PDA was perturbed and strained, causing a chromatic change of the PDA from blue to red. At the same time, the encapsulated NIR dyes were liable to leach out that resulted in an emission variation of the Pdots. Accordingly, lead ions can be recognized by either color change or emission variation of the Pdots. We also loaded these nanoprobes into live HeLa cells through endocytosis, and then monitored changes in Pb(2+) levels within cells, demonstrating their utility for use in cellular and bioimaging applications. In addition, we fabricated easy-to prepare test strips impregnated with Pdot-poly(vinyl alcohol) films to identify Pb(2+) in real samples, which proved their applicability for in situ on-site detection. Our results suggest that this Pdot-based visual sensor shows promising potential for advanced environmental and biological applications. PMID- 25822076 TI - Long- versus Short-Range Scattering in Doped Epitaxial Graphene. AB - Tuning the electronic properties of graphene by adatom deposition unavoidably introduces disorder into the system, which directly affects the single-particle excitations and electrodynamics. Using angle-resolved photoemission spectroscopy (ARPES) we trace the evolution of disorder in graphene by thallium adatom deposition and probe its effect on the electronic structure. We show that the signatures of quasiparticle scattering in the photoemission spectral function can be used to identify thallium adatoms, although charged, as efficient short-range scattering centers. Employing a self-energy model for short-range scattering, we are able to extract a delta-like scattering potential delta = -3.2 +/- 1 eV. Therefore, isolated charged scattering centers do not necessarily act just as good long-range (Coulomb) scatterers but can also act as efficient short-range (delta-like) scatterers; in the case of thallium, this happens with almost equal contributions from both mechanisms. PMID- 25822077 TI - Colorectal cancer incidence by age among patients undergoing surveillance colonoscopy. PMID- 25822075 TI - Protolytic cleavage of Hg-C bonds induced by 1-methyl-1,3-dihydro-2H benzimidazole-2-selone: synthesis and structural characterization of mercury complexes. AB - Multinuclear ((1)H, (77)Se, and (199)Hg) NMR spectroscopy demonstrates that 1 methyl-1,3-dihydro-2H-benzimidazole-2-selone, H(sebenzim(Me)), a structural analogue of the selenoamino acid, selenoneine, binds rapidly and reversibly to the mercury centers of HgX2 (X = Cl, Br, I), while X-ray diffraction studies provide evidence for the existence of adducts of composition [H(sebenzim(Me))]xHgX2 (X = Cl, x = 2, 3, 4; X = I, x = 2) in the solid state. H(sebenzim(Me)) also reacts with methylmercury halides, but the reaction is accompanied by elimination of methane resulting from protolytic cleavage of the Hg-C bond, an observation that is of relevance to the report that selenoneine demethylates CysHgMe, thereby providing a mechanism for mercury detoxification. Interestingly, the structures of [H(sebenzim(Me))]xHgX2 exhibit a variety of different hydrogen bonding patterns resulting from the ability of the N-H groups to form hydrogen bonds with chlorine, iodine, and selenium. PMID- 25822078 TI - Anti-inflammatory screening and molecular modeling of some novel coumarin derivatives. AB - Coumarin and their derivatives have drawn much attention in the pharmacological and pharmaceutical fields due to their broad range and diverse biological activities. In the present work, starting from the 6-amino-7-hydroxy-4-methyl-2H chromen-2-one, a series of 6-(substituted benzylamino)-7-hydroxy-4-methyl-2H chromen-2-ones 1-11 was synthesized and assessed for their anti-inflammatory activity using the carrageenan-induced hind paw edema method. Compounds 2, 3, 4 and 9 showed significant (p < 0.001) reduction of rat paw edema volume after 1 h from the administration of the carrageenan compared to the reference drug, indomethacin. On the other hand, compounds 4 and 8 showed the highest anti inflammatory activity, surpassing indomethacin after 3 h with 44.05% and 38.10% inhibition, respectively. Additionally, a molecular docking study was performed against the COX enzyme using the MOE 10.2010 software. PMID- 25822079 TI - New 1-(3-nitrophenyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepines: synthesis and computational study. AB - Triazole derivatives constitute an important group of heterocyclic compounds have have been the subject of extensive study in the recent past. These compounds have shown a wide range of biological and pharmacological activities. In this work, new fused tricyclic 1-(3-nitrophenyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5] benzodiazepines have been synthesized by the thermal cyclization of N'-(2,3 dihydro-1H-1,5-benzodiazepin-4-yl)-3-nitrobenzohydrazides. After screening ethanol, toluene and 1-butanol as solvents, butanol-1 was found to be the best choice for the cyclization reaction in order to obtain the highest yields of tricyclic derivatives. The chemical structures of the synthesized compounds were elucidated by the analysis of their IR, 1H- and 13C-NMR spectral data. For tentative rationalization of the reaction processes, the global and local reactivity indices of certain compounds, taking part in the reaction pathway, were assessed by means of quantum mechanical calculations using the conceptual density functional theory (DFT) approach. This work could be useful for the synthesis of new heterocyclic compounds bearing a fused triazole ring. PMID- 25822080 TI - Formylation of electron-rich aromatic rings mediated by dichloromethyl methyl ether and TiCl4: scope and limitations. AB - Here the aromatic formylation mediated by TiCl4 and dichloromethyl methyl ether previously described by our group has been explored for a wide range of aromatic rings, including phenols, methoxy- and methylbenzenes, as an excellent way to produce aromatic aldehydes. Here we determine that the regioselectivity of this process is highly promoted by the coordination between the atoms present in the aromatic moiety and those in the metal core. PMID- 25822082 TI - Correction: Huang, W.-H., et al. Anticancer activities of polyynes from the root bark of Oplopanax horridus and their acetylated derivatives. Molecules 2014, 19, 6142-6162. PMID- 25822081 TI - Dereplication of known nucleobase and nucleoside compounds in natural product extracts by capillary electrophoresis-high resolution mass spectrometry. AB - Nucleobase and nucleoside compounds exist widely in various organisms. An often occurring problem in the discovery of new bioactive compounds from natural products is reisolation of known nucleobase and nucleoside compounds. To resolve this problem, a capillary electrophoresis-high resolution mass spectrometry (CE HR-MS) method providing both rapid separation and accurate mass full-scan MS data was developed for the first time to screen and dereplicate known nucleobase and nucleoside compounds in crude extracts of natural products. Instrumental parameters were optimized to obtain optimum conditions for CE separation and electrospray ionization-time-of-flight mass spectrometry (ESI-TOF/MS) detection. The proposed method was verified to be precise, reproducible, and sensitive. Using this method, known nucleobase and nucleoside compounds in different marine medicinal organisms including Syngnathus acus Linnaeus; Hippocampus japonicus Kaup and Anthopleura lanthogrammica Berkly were successfully observed and identified. This work demonstrates that CE-HR-MS combined with an accurate mass database may be used as a powerful tool for dereplicating known nucleobase and nucleoside compounds in different types of natural products. Rapid dereplication of known nucleobase and nucleoside compounds allows researchers to focus on other leads with greater potential to yield new substances. PMID- 25822083 TI - Parental absence from clinic predicts human immunodeficiency virus treatment failure in adolescents. PMID- 25822084 TI - Linear Dependence of Photoluminescence in Mixed Ln-MOFs for Color Tunability and Barcode Application. AB - Multicolored photoluminescence tuning in a single-phase material has invaluable potential in display and security applications. By deliberate design of a multifunctional antenna ligand and precise control of mixed metal ionic compositions in lanthanide metal-organic frameworks (Ln-MOFs), we achieved dichromatic fine-tuning among red, green, or blue primary colors through growth of a series of isomorphous Ln-MOF crystals.solvents of formula [LnnLn'1 n(TTP)2.H2O]Cl3 (Ln = Ln' = Eu, Tb, and Gd, 1-3; Ln = Eu, Ln' = Tb, 4-8; Ln = Gd, Ln' = Eu, 9-11; Ln = Gd, Ln' = Tb, 12-14; 0 < n < 1; TTP = 1',1"-(2,4,6 trimethylbenzene-1,3,5-triyl)tris(methylene)tris(pyridine-4(1H)-one)). The linear dependence of the emissions were analyzed, and the mathematical matrix models were established, which are useful to control the synthetic conditions and to predict the color chromaticity coordinates under varied excitation wavelengths. The potential relevance of these multicolored photoluminescent Ln-MOFs to barcoded materials was demonstrated. PMID- 25822085 TI - Photovoltaic Conversion Enhancement of a Carbon Quantum Dots/p-Type CuAlO2/n-Type ZnO Photoelectric Device. AB - Carbon quantum dots (C QDs)/p-type CuAlO2/n-type ZnO photoelectric bilayer film composites were prepared by a simple route, through which ZnO films were sputtered on crystal quartz substrates and CuAlO2 films were prepared by sol-gel on ZnO films and then these bilayer films were composited with C QDs on their surface. The characterization results indicated that C QDs were well combined with the surface of the CuAlO2 films. The photovoltage and photocurrent of these bilayer film composites were investigated under illumination and darkness switching, which demonstrated to be significantly enhanced compared with those of the CuAlO2/ZnO bilayer films. Through analysis, this enhancement of the photoconductivity was mainly attributed to C QDs with unique up-converted photoluminescence behavior. PMID- 25822086 TI - Enzyme-mimetic activity of Ce-intercalated titanate nanosheets. AB - Colloidal solutions of Ce-doped titanate nanosheets (Ce-TNS) with tiny dimensions (<10 nm) were fabricated through a hydrolysis reaction of titanium tetraisopropoxide and Ce(NO3)3, and their annihilation activity for reactive oxygen species (ROS) was investigated. The obtained Ce-TNS had an akin crystal structure to layered tetratitanate (Ti4O9(2-)) and Ce ions occupied interlayer space between the host layers with a negative charge. The Ce-TNS possessed a superoxide dismutase (SOD) mimetic activity for disproportionation of superoxide anion radicals (O2(-)) as target ROS. It was explained that the annihilation of O2(-) caused a valence fluctuation of Ce ions existing in the interlayer. Moreover, the activity of Ce-TNS exceeded that of CeO2 nanoparticles recently attracting much attention as an inorganic SOD mimic. The superior performance was explained mainly by a high dispersion stability of the Ce-TNS bringing about a huge reaction area. Moreover, the Ce-TNS protected DNA molecules from ultraviolet light induced oxidative damage, demonstrating effectiveness as one of the new inorganic protecting agents for biomolecules and tissues. PMID- 25822087 TI - Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. AB - RAS network activation is common in human cancers, and in acute myeloid leukemia (AML) this activation is achieved mainly through gain-of-function mutations in KRAS, NRAS or the receptor tyrosine kinase FLT3. We show that in mice, premalignant myeloid cells harboring a Kras(G12D) allele retained low levels of Ras signaling owing to negative feedback involving Spry4 that prevented transformation. In humans, SPRY4 is located on chromosome 5q, a region affected by large heterozygous deletions that are associated with aggressive disease in which gain-of-function mutations in the RAS pathway are rare. These 5q deletions often co-occur with chromosome 17 alterations involving the deletion of NF1 (another RAS negative regulator) and TP53. Accordingly, combined suppression of Spry4, Nf1 and p53 produces high levels of Ras signaling and drives AML in mice. Thus, SPRY4 is a tumor suppressor at 5q whose disruption contributes to a lethal AML subtype that appears to acquire RAS pathway activation through a loss of negative regulators. PMID- 25822088 TI - Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. AB - Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy. PMID- 25822090 TI - Testing for genetic associations in arbitrarily structured populations. AB - We present a new statistical test of association between a trait and genetic markers, which we theoretically and practically prove to be robust to arbitrarily complex population structure. The statistical test involves a set of parameters that can be directly estimated from large-scale genotyping data, such as those measured in genome-wide association studies (GWAS). We also derive a new set of methodologies, called a 'genotype-conditional association test' (GCAT), shown to provide accurate association tests in populations with complex structures, manifested in both the genetic and non-genetic contributions to the trait. We demonstrate the proposed method on a large simulation study and on the Northern Finland Birth Cohort study. In the Finland study, we identify several new significant loci that other methods do not detect. Our proposed framework provides a substantially different approach to the problem from existing methods, such as the linear mixed-model and principal-component approaches. PMID- 25822089 TI - Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. AB - DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Here we inactivated all three catalytically active DNA methyltransferases (DNMTs) in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing to further investigate the roles and genomic targets of these enzymes. Disruption of DNMT3A or DNMT3B individually as well as of both enzymes in tandem results in viable, pluripotent cell lines with distinct effects on the DNA methylation landscape, as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to findings in mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome this immediate lethality, we generated a doxycycline-responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1-mutant lines. However, doxycycline-mediated repression of exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death. Our data provide a comprehensive characterization of DNMT-mutant ESCs, including single-base genome-wide maps of the targets of these enzymes. PMID- 25822091 TI - Electrostatic kinetic barriers in the threading/dethreading motion of a rotaxane like complex. AB - A new rigid cationic thread, based on the 1,2-bis(bipyridinium)ethane motif, and a 24-crown-8 anionic macrocycle self-assemble into a pseudo-rotaxane complex in aqueous solution. The presence of pH-responsive end groups on the thread, remote from the recognition motif, allows controlling the threading/dethreading rate without perturbing the complex structure or stability. The difference in the rate is attributed to the activation or deactivation of electrostatic barriers on the thread during the sliding process at different pH values. PMID- 25822092 TI - Patient dependant on ventriculo-atrial shunt after 49 years. AB - The insertion of ventriculo-atrial (VA) shunts has been performed for the treatment of hydrocephalus since the 1950s. Thrombosis, infection, pulmonary hypertension, tricuspid stenosis, shunt nephritis, intra-cardiac migration due to displacement or fracture are reported complications. (1) We present the case of a 49-year-old female who had a VA shunt as a baby, that was never revised, who presented with a neck abscess related to the shunt tubing. PMID- 25822093 TI - 3D printing of patient-specific anatomy: A tool to improve patient consent and enhance imaging interpretation by trainees. AB - We report the use of three-dimensional or 3D printed, patient-specific anatomy as a tool to improve informed patient consent and patient understanding in a case of posterior lumbar fixation. Next, we discuss its utility as an educational tool to enhance imaging interpretation by neurosurgery trainees. PMID- 25822094 TI - Intermittent visual field defects caused by a dilated Virchow-Robin space close to the optic radiation: Therapeutic and pathomechanical considerations. AB - OBJECTIVE: Virchow-Robin spaces (VRSs) are extensions of subarachnoid spaces that accompany vessels entering the brain. T2-weighted magnetic resonance imaging detects VRS in about 95 percent of patients in a recent study. VRSs are considered a normal variant with benign prognosis. Occasionally, VRS might become symptomatic causing neurological deficits depending on their location. CASE DESCRIPTION: We report the case of a 55-year-old female patient with dilated VRS presenting with visual field disturbances and cognitive deficits. The patient underwent endoscopic fenestration of a large periventricular VRS located next to the visual radiation into the posterior horn of the right lateral ventricle. During the postoperative course, visual field disturbances were resolved but cognitive deficits remained unchanged. CONCLUSION: Dilated VRSs can cause a variety of neurological deficits depending on their size and location. Therefore, patients harboring dilated VRS should undergo early close inspection and in case of progressive neurological deficits, an operative therapy should be done; as valve mechanisms can cause a reduction of size when brain scans are conducted and later lead to occurrence of severe neurological deficits during phase of dilation. PMID- 25822096 TI - A vaccine against an explosively spreading virus. PMID- 25822095 TI - Detection of Rheumatoid Arthritis-Interstitial Lung Disease Is Enhanced by Serum Biomarkers. AB - RATIONALE: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. OBJECTIVES: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. METHODS: Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. MEASUREMENTS AND MAIN RESULTS: A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. CONCLUSIONS: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality. PMID- 25822097 TI - Pre-entry screening for tuberculosis: the need for better evidence. PMID- 25822098 TI - Enrolment trends in a comprehensive HIV programme in rural north-central Nigeria: improved care indices, but declining quality of clinical data over time. AB - BACKGROUND: Vanderbilt University affiliate Friends in Global Health was funded in 2008 to support comprehensive HIV/AIDS services in north-central Nigeria. We summarise programme characteristics and trends in enrolment and quality of data collection in this rural, resource-limited environment. METHODS: We used routinely collected programme data in supported sites from June 1 2009 to September 30, 2013.Baseline characteristics were defined as those collected closest to a 90-day window period before and after enrolment. Summary characteristics were compared by site and enrolment year. RESULTS: We enrolled 3,960 HIV-infected patients into care (68% women), median age of 32 years [interquartile range (IQR): 27-40]. Most clients were married (79%) and unemployed (60%). At enrolment, median CD4+ cell count was 230 cells/MUL (IQR: 114-390) and haemoglobin was 10.7 g/dL (IQR: 9.3-11.9). Advanced clinical disease [World Health Organization (WHO) clinical stage III/IV] at enrolment was documented in 29% of clients. Cumulative enrolment increased from 377 patients in 2009 to 3,960 patients by 2013.With each successive year, more clients were enrolled at earlier stages of disease; in 2009, 37% of patients were identified as WHO clinical stage I, while in 2013, 55% of patients were so classified. While documentation of clinical staging remained stable, the completeness of CD4+ cell count and haemoglobin data declined with time. CONCLUSION: Expanded testing in a comprehensive HIV programme in rural Nigeria brought persons to care at earlier stages of illness. Yet, as clinical services expanded, data collection quality declined. The paradox of successful scaling up HIV services but deteriorating quality of data underscores the importance of data management training and quality improvement efforts. PMID- 25822099 TI - Simultaneous modulated accelerated radiotherapy in cervical cancer with retroperitoneal lymph node metastasis after radical hysterectomy and pelvic lymphadenectomy. AB - OBJECTIVE: To compare the dosimetry, toxicity, and efficacy of simultaneous modulated accelerated radiotherapy (SMART) with 3-dimensional conformal radiotherapy (3DCRT) in cervical cancer with retroperitoneal lymph node metastasis after radical hysterectomy and pelvic lymphadenectomy. METHODS: Total 32 patients who underwent SMART were retrospectively evaluated. Daily fractions of 2.2 to 2.4 Gy and 1.8 to 2 Gy were prescribed and delivered to gross tumor volume and clinical target volume to a total dose of 63.8 and 52.2 Gy, respectively. A 3DCRT plan was designed for the SMART group and planned to deliver the same prescribed dose. The doses of organs at risk (OARs) were compared. Thirty-six patients who received 3DCRT were used to compare the target dose, toxicities, and efficacy with 32 cases who received SMART. RESULTS: The mean doses delivered to gross tumor volume and clinical target volume were significantly higher in the SMART group than in the 3DCRT group (63.8 vs 55.2 Gy [P < 0.01] and 52.5 vs 48.6 Gy [P < 0.01], respectively). For SMART plan, the doses of OARs were significantly lower than that of 3DCRT plans (small intestine: 25.1 vs 30.9 Gy [P < 0.01], bladder: 35.3 vs 46.3 [P < 0.01], and rectum: 31.7 vs 43.7 [P = 0.002], respectively). The patients experienced less acute and late toxicities in the SMART group (acute toxicities: enteroproctitis, P = 0.019; cystitis, P = 0.013; leukopenia, P = 0.025; late toxicities: enteroproctitis, P = 0.007; and cystitis, P = 0.026, respectively). No significant difference was found for 1-year survival (78.7% vs 67.7%, P = 0.222), but SMART group had a higher 2-year survival rate (2-year: 63.1% vs 39.1%, P = 0.029). CONCLUSIONS: Simultaneous modulated accelerated radiotherapy plans yielded higher dose to the targets and better sparing of OARs than did 3DCRT in cervical cancer with retroperitoneal lymph node metastasis after radical hysterectomy and pelvic lymphadenectomy. Simultaneous modulated accelerated radiotherapy provided better clinical outcomes than did 3DCRT. Long-term follow-up and studies involving more patients are needed to confirm our results. PMID- 25822100 TI - Changes of Dietary Fat and Carbohydrate Content Alter Central and Peripheral Clock in Humans. AB - CONTEXT: The circadian clock coordinates numerous metabolic processes with light dark and feeding regimens. However, in humans it is unknown whether dietary patterns influence circadian rhythms. OBJECTIVE: We examined the effects of switching from a high-carbohydrate, low-fat diet to a low-carbohydrate, high fat (LC/HFD) isocaloric diet on the central and peripheral circadian clocks in humans. DESIGN: Diurnal patterns of salivary cortisol and gene expression were analyzed in blood monocytes of 29 nonobese healthy subjects before and 1 and 6 weeks after the dietary switch. For this, we established a method of rhythm prediction by 3-time point data. RESULTS: The centrally driven cortisol rhythm showed a phase delay 1 and 6 weeks after the dietary switch to a LC/HFD as well as an amplitude increase. The dietary switch altered diurnal oscillations of core clock genes (PER1, PER2, PER3, and TEF) and inflammatory genes (CD14, CD180, NFKBIA, and IL1B). The LC/HFD also affected the expression of nonoscillating genes contributing to energy metabolism (SIRT1) and fat metabolism (ACOX3 and IDH3A). Expression of clock genes but not of salivary cortisol in monocytes tightly correlated with levels of blood lipids and with expression of metabolic and inflammatory genes. CONCLUSIONS: Our results suggest that the modulation of the dietary fat and carbohydrate content alters the function of the central and peripheral circadian clocks in humans. PMID- 25822101 TI - Clinical Outcome, Hormonal Status, Gonadotrope Axis, and Testicular Function in 219 Adult Men Born With Classic 21-Hydroxylase Deficiency. A French National Survey. AB - CONTEXT: Outcomes of congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) have been widely studied in children and women, but less so in men. OBJECTIVE: The objective was to analyze data from a network of metropolitan French teaching hospitals on the clinical outcome of classic 21OHD in a large sample of congenital adrenal hyperplasia/21OHD-genotyped adult men, and particularly the impact of 21OHD on the gonadotrope axis, testicular function, and fertility. METHODS: From April 2011 to June 2014, tertiary endocrinology departments provided data for 219 men with 21OHD (ages, 18-70 y; 73.6% salt wasters, 26.4% simple virilizers). Testicular sonography was performed in 164 men, and sperm analysis was performed in 71 men. RESULTS: Mean final height was 7.8 cm lower than in a reference population. Obesity was more common, and mean blood pressure was lower than in the reference population. None of the patients were diabetic, and lipid status was generally normal. Blood electrolyte status was normal in the vast majority of men, despite markedly elevated ACTH and renin levels. Serum progesterone, 17-hydroxyprogesterone, and androstenedione levels were above normal in the vast majority of cases. Hormonal profiling variously showed a normal gonadotrope-testicular axis, gonadotropin deficiency, or primary testicular insufficiency. Testicular sonography revealed testicular adrenal rest tumors (TARTs) in 34% of 164 men. Serum inhibin B and FSH levels were significantly lower and higher, respectively, in patients with TARTs. Severe oligospermia or azoospermia was found in 42% of patients and was significantly more prevalent in men with TARTs (70%) than in men with normal testes (3.6%; P < .0001). Among men living with female partners, TARTs were significantly more prevalent in those who had not fathered children. CONCLUSION: We report the spectrum of testicular/gonadotrope axis impairment in the largest cohort of 21OHD men studied to date. Our results suggest that French men with 21OHD managed in specialized centers frequently have impaired exocrine testicular function but that its reproductive implications are often overlooked. PMID- 25822102 TI - Primary Aldosteronism and ARMC5 Variants. AB - CONTEXT: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia. OBJECTIVE: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects. METHODS: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods. RESULTS: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023). CONCLUSIONS: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension. PMID- 25822103 TI - [Adjustment to a Stressful Event in the Couple: Depression of the Partner as Risk for Adjustment Disorder]. AB - Maladaptive reactions on stressful experiences justifying a diagnosis of adjustment disorder have high prevalence. Little is known about the possible risk for clinically significant maladaptation that results from the social context. The literature on the effects of depression on communication and altered support conditions in couples is suggesting this. Aim of this study was to investigate whether clinically significant depression in the romantic partner is a risk factor for adjustment disorder following a concept of stress-response disorder. Furthermore, from a dimensional point of view a possible positive association between depressive symptoms in the partner and own adjustment symptom was studied. Thereby, own depressive symptoms were controlled for in order to exclude mere depressive contagion and isolate stress-related responses. In an online couple-study N=294 participants (N=147 couples) reported whether or not they had experienced a stressful event that is still bothering them. N=152 participants reported such an event. N=28 of this group reached the threshold of a possible diagnosis with the screening questionnaire "Adjustment disorder New Module". N=14 romantic partners reported depressive symptoms above the cut-off of the CES-D. The risk for an adjustment disorder is elevated if the female partner reports a clinically significant level of depressive symptoms (OR 7.13). This was only true when female partners were depressed, the depression of male partners did not show any significant associations. Accordingly, dimensionally there is a positive association between depressive symptoms of the female partner and adjustment symptoms of preoccupation (stressor-related repetitive negative thoughts). Depression of the romantic partner seems to be a significant risk factor for maladaptive reactions on a stressful event. This was particularly true for male participants of the study. To sum up, results encourage taking up an interpersonal perspective in research and clinical interventions. PMID- 25822104 TI - Long-term persistence with anti-osteoporosis drugs after fracture. AB - Long-term persistence with anti-osteoporosis drugs and determinants for discontinuation among fracture patients were examined. Persistence was 75.0 and 45.3 % after 1 and 5 years, respectively. Those aged >=80 years were at increased risk of early discontinuation. Within 1 year after discontinuation, 24.3 % restarted therapy, yet 47.0 % persisted for 1 year. INTRODUCTION: The risk of osteoporotic fracture can effectively be reduced with use of anti-osteoporosis drugs. However, little is known about persistence with these drugs after fracture where subsequent fracture risk is high. The aims were to determine long-term persistence with anti-osteoporosis drugs among fracture patients, including its determinants, and to describe restart and subsequent persistence. METHODS: A cohort study was conducted within the Dutch PHARMO Database Network. Patients aged >=50 years (n = 961) who received anti-osteoporosis drugs within 1 year after fracture, but not in the preceding year, were included (2002-2011). Persistence (defined as the proportion on treatment) and the proportion restarting after discontinuation were estimated using Kaplan-Meier analyses. Time dependent Cox regression was used to identify determinants of non-persistence including age, sex, initial dosage regime, fracture type, comorbidities, and drug use. RESULTS: Persistence with anti-osteoporosis drugs was 75.0 % (95 % confidence interval (CI) 72.0-77.7) and 45.3 % (95 % CI 40.4-50.0) after 1 and 5 years, respectively. A significant determinant of non-persistence was age >=80 years (reference 50-59 years: adjusted hazard ratio [adj. HR] 1.65; 95 % CI 1.15 2.38). This effect was not constant over time (<=360 days following initiation: adj. HR 2.07; 95 % CI 1.27-3.37; >360 days: adj. HR 1.08; 95 % CI 0.62-1.88). Within 1 year after discontinuation, 24.3 % (95 % CI 20.1-29.2) restarted therapy, yet 47.0 % persisted for 1 year. CONCLUSIONS: This study identified suboptimal persistence with anti-osteoporosis drugs among fracture patients. Major target groups for measures aimed to improve persistence may be those aged >80 years and those restarting therapy. PMID- 25822105 TI - Simple and rapid in vitro assay for detecting human thyroid peroxidase disruption. AB - A simple and rapid luminometric assay for the detection of chemical inhibitors of human thyroid peroxidase (hTPO) activity was developed and validated with 10 model compounds. hTPO was derived from the human thyroid follicular cell line Nthy-ori 3-1 and its activity was quantified by measuring the oxidation of luminol in the presence of hydrogen peroxide (H2O2), which results in the emission of light at 428 nm. In this assay,hTPO activity was shown to be inhibited by 5 known TPO inhibitors and not inhibited by 5 non-inhibitors. Similar results were obtained with porcine TPO (pTPO).The inhibition of hTPO by the model compounds was also tested with guaiacol and Ampliflu Red as alternative indicator substrates. While all substrates allowed the detection of pTPO activity and its inhibition, only the Ampliflu Red and luminol-based methods were sensitive enough to allow the quantification of hTPO activity from Nthy-ori 3-1 cell lysates. Moreover, luminol gave results with a narrower 95% confidence interval and therefore more reliable data.Whole extracts of fast-growing Nthy-ori 3-1 cells circumvent the need for animal-derived thyroid organs,thereby reducing costs, eliminating potential contamination and providing the possibility to study human instead of porcine TPO. Overall, the application of luminol and Nthy-ori 3 1 cell lysate for the detection of the disruption of hTPO activity was found to represent a valuable in vitro alternative and a possible candidate for inclusion within a high throughput integrated testing strategy for the detection of compounds that potentially interfere with normal thyroid function in vivo. PMID- 25822106 TI - Efficacy of palonosetron and 1-day dexamethasone in moderately emetogenic chemotherapy compared with fosaprepitant, granisetron, and dexamethasone: a prospective randomized crossover study. AB - BACKGROUND: Although palonosetron (PALO) and NK1 receptor antagonist both reduce chemotherapy-induced nausea and vomiting, no comparison trial in moderately emetogenic chemotherapy (MEC) had been reported. The purpose of this study was to find out which drug combinations are preferable for patients receiving MEC. METHODS: Chemotherapy-naive patients receiving MEC were randomized to two groups; group A first received PALO therapy [PALO plus 1-day dexamethasone (DEX)], and group B first received fosaprepitant (FAPR) therapy [FAPR, granisetron (GRAN), and DEX]. Patients were re-allocated to the other therapy, respectively, for the second cycle of chemotherapy. We administered intravenous PALO (0.75 mg) and DEX (9.9 mg) to the PALO therapy group, and FAPR (150 mg), DEX (4.95 mg), and GRAN (3 mg) to the FAPR therapy group, on Day 1. Complete response (CR) was the primary endpoint; complete control (CC), total control (CT), and the therapy chosen by the patients for their third and following cycles of antiemetic therapy were the secondary endpoints. We evaluated CR, CC, and TC in the acute phase, in the delayed phase, and over the whole period. RESULTS: A total of 35 patients and 70 cycles of therapy was evaluable for analysis. No significant difference was found at all evaluation points. Overall CR rates for PALO and FAPR therapy were 74 vs 69 % (P = 0.567), CC rates 66 vs 69 % (P = 0.521), and TC rates 46 vs 60 % (P = 0.235), respectively. Patients also showed no clear preference for their third and following cycles of chemotherapy, choosing both regimens almost equally often (PALO 10 vs FAPR 13). CONCLUSIONS: PALO and 1-day DEX is almost equivalent to FAPR, GRAN, and DEX for MEC. PMID- 25822107 TI - Nutritional profile and obesity: results from a random-sample population-based study in Cordoba, Argentina. AB - INTRODUCTION: Obesity is a chronic, heterogeneous, multifactorial disease, which has sharply increased in prevalence in both developed and developing countries. This study aimed to estimate the prevalence of obesity and to identify socio demographic risk factors associated with it, with special emphasis on diet. METHODS: Nutritional status, demographic characteristics, lifestyle habits, and food consumption patterns derived from a Food Frequency Questionnaire were investigated. Exhaustive exploratory analyses were performed in order to describe dietary patterns, and logistic regression models were used for odds ratio estimation. RESULTS: The study included 4328 subjects, over 18 years old and resident in Cordoba city. The prevalence of overweight and obesity was 34 and 17 %, respectively, with 60 % in men and 45 % in women of BMI >= 25. Obesity risk factors were high intake of sodium, refined grains, starchy vegetables, and snacks. A lower risk of overweight and obesity was associated with an adequate, moderate intake of meats, eggs, alcoholic beverages, sugar and sweets, milk, yogurt, and pulses. CONCLUSIONS: A high intake of snacks, refined grains, starchy vegetables and sodium and low intake of yogurt, milk, pulses, and whole grains seem to be associated with the emergence and high prevalence of obesity in Cordoba, Argentina. PMID- 25822108 TI - Attachment history as a moderator of the alliance outcome relationship in adolescents. AB - The role of the alliance in predicting treatment outcome is robust and long established. However, much less attention has been paid to mechanisms of change, including moderators, particularly for youth. This study examined the moderating role of pretreatment adolescent-caregiver attachment and its impact on the working alliance-treatment outcome relationship. One hundred adolescents and young adults with primary substance dependence disorders were treated at a residential facility, with a cognitive-behavioral emphasis. The working alliance and clinical symptoms were measured at regular intervals throughout treatment. A moderator hypothesis was tested using a path analytic approach. Findings suggested that attachment to the primary caregiver moderated the impact of the working alliance on treatment outcome, such that for youth with the poorest attachment history, working alliance had a stronger relationship with outcome. Conversely, for those with the strongest attachment histories, alliance was not a significant predictor of symptom reduction. This finding may help elucidate alliance-related mechanisms of change, lending support for theories of corrective emotional experience as one function of the working alliance in youth psychotherapy. PMID- 25822109 TI - Xilonix, a novel true human antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer. AB - BACKGROUND: Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1alpha (Xilonix), which is intended to modulate the malignant phenotype-inhibiting tumor growth, spread and offering relief of symptoms. METHODS: Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy. Disease progression was evaluated using a multi-modal approach: tumor response, patient reported outcomes (EORTC-QLQC30), and lean body mass (LBM). Patients received infusions every 2 or 3 weeks until progression, and were followed 24 months to assess survival. RESULTS: There were no infusion reactions, dose-limiting toxicities, or deaths due to therapy. Albeit not statistically significant, there was a trend in IL-6 (-2.6 +/- 18.5 (0.1 [-2.8-2.4]), platelet counts (-11 +/- 54 (-4[-36.0-1.0]), CRP (-3.3 +/- 30.2 (0.4 [-10.7-1.8]) and LBM (1.0 +/- 2.5 (0.4 [ 0.5-2.6]). Self-reported outcomes revealed reductions in pain, fatigue and improvement in appetite. Median survival was 7.6 (IQR 4.4-11.5) months, stratification based on prior anti-EGFR therapy revealed a median survival of 9.4 months (IQR 7.6-12.5) for those pretreated (N = 10) versus a survival of 4.8 months (IQR 4.3-5.7) for those without (N = 6, logrank p = 0.187). CONCLUSION: Xilonix was well tolerated, with gains in LBM and improvement in symptoms suggesting a clinically important response. Although not statistically significant, the survival outcomes observed for patients with and without prior anti-EGFR therapy raises intriguing questions about the potential synergy of IL 1alpha blockade and anti-EGFR therapy. Further study for this agent in NSCLC is warranted. PMID- 25822110 TI - Inhibition of human vascular endothelial cell migration and capillary-like tube formation by the microtubule-stabilizing agent peloruside A. AB - Peloruside A is a microtubule-stabilizing agent that is currently under investigation as a potential anticancer agent. Peloruside A binds to a site on beta-tubulin that is distinct to that of the taxanes (paclitaxel and docetaxel) and the epothilones. An attractive clinical quality of microtubule-stabilizing agents is their ability to target multiple mechanisms of tumour growth. In addition to inducing tumour cell apoptosis by arresting cells in mitosis, microtubule-stabilizing agents also inhibit angiogenesis, a process needed by tumor cells for growth and metastasis. In this study, the effects of peloruside A on endothelial cell processes important for angiogenesis were assessed in comparison to docetaxel. Both peloruside A and docetaxel potently inhibited the proliferation of human umbilical vein endothelial cells, with IC50 values of 1.4 and 1.7 nM, respectively. Peloruside also potently blocked endothelial cell migration during wound closure and the three-dimensional organization of the endothelial cells into capillary-like tubes. In the wound scratch assay, peloruside A inhibited wound recovery with an IC50 of 6.3 nM after 18 h. Docetaxel was approximately 3-fold more potent than peloruside A. The number of capillary-like tubes that formed after 16 h culture in MatrigelTM was also inhibited in a dose-dependent manner with an IC50 of 4.5 nM. Docetaxel was about 2-fold more potent than peloruside A in preventing tube formation. This inhibition of endothelial cell function occurred at relatively non-cytotoxic concentrations over the 16-18 h incubations for both stabilizing agents, suggesting that anti-angiogenic effects are likely to occur before therapeutically relevant doses begin to inhibit tumor growth or adverse side effects develop. PMID- 25822111 TI - A diagnostic pitfall in IgG4-related hypophysitis: infiltration of IgG4-positive cells in the pituitary of granulomatosis with polyangiitis. AB - INTRODUCTION: Immunoglobulin (Ig) G4-related hypophysitis is an emerging clinical entity, which is characterized by an elevated serum IgG4 concentration and infiltration of IgG4-positive plasma cells in the pituitary. Although some criteria for its diagnosis have been proposed, they have not been fully established. In particular, differential diagnosis from secondary chronic inflammation including granulomatosis with polyangiitis (GPA) is difficult in some cases. We describe central diabetes insipidus with pituitary swelling exhibiting infiltration of IgG4-positive cells. PATIENT: A 43-year-old woman in the remission stage of GPA presented with sudden-onset polyuria and polydipsia. Pituitary magnetic resonance imaging revealed swelling of the anterior and posterior pituitary and stalk, with heterogeneous gadolinium enhancement and disappearance of the high signal intensity of the posterior pituitary. Evaluation of biochemical markers for GPA suggested that the disease activity was well controlled. Endocrinological examination revealed the presence of central diabetes insipidus and growth hormone deficiency. Pituitary biopsy specimen showed IgG4-positive cells, with a 43% IgG4(+)/IgG(+) ratio, which met the criteria for IgG4-related hypophysitis. However, substantial infiltration of polymorphonuclear neutrophils with giant cells was also noted, resulting in a final diagnosis of pituitary involvement of GPA. CONCLUSION: These results suggest that pituitary involvement of GPA should be taken into account for the differential diagnosis of IgG4-related hypophysitis. PMID- 25822113 TI - Community psychology and the capabilities approach. AB - What makes for a good life? The capabilities approach to this question has much to offer community psychology, particularly with respect to marginalized groups. Capabilities are freedoms to engage in valued social activities and roles-what people can do and be given both their capacities, and environmental opportunities and constraints. Economist Amartya Sen's focus on freedoms and agency resonates with psychological calls for empowerment, and philosopher Martha Nussbaum's specification of requirements for a life that is fully human provides an important guide for social programs. Community psychology's focus on mediating structures has much to offer the capabilities approach. Parallels between capabilities, as enumerated by Nussbaum, and settings that foster positive youth development, as described in a National Research Council Report (Eccles and Gootman (Eds) in Community programs to promote youth development. National Academy Press, Washington, 2002) suggest extensions of the approach to children. Community psychologists can contribute to theory about ways to create and modify settings to enhance capabilities as well as empowerment and positive youth development. Finally, capabilities are difficult to measure, because they involve freedoms to choose but only choices actually made or enacted can be observed. The variation in activities or goals across members of a setting provides a measure of the capabilities that the setting fosters. PMID- 25822112 TI - Post-Discharge Adverse Events Among Urban and Rural Patients of an Urban Community Hospital: A Prospective Cohort Study. AB - BACKGROUND: There has been little research to examine post-discharge adverse events (AEs) in rural patients discharged from community hospitals. OBJECTIVE: We aimed to determine the rate of post-discharge AEs, classify the types of post discharge AEs, and identify risk factors for post-discharge AEs in urban and rural patients. DESIGN: This was a prospective cohort study of patients at risk for post-discharge adverse events from December 2011 through October 2012. PATIENTS: Six hundred and eighty-four patients who were under the care of hospitalist physicians and were being discharged home, spoke English, and could be contacted after discharge, were admitted to the medical service. Patients were stratified as urban/rural using zip code of residence. Rural patients were oversampled to ensure equal enrollment of urban and rural patients. MAIN MEASURES: The main outcome of the study was post-discharge AEs based on structured telephone interviews, health record review, and adjudication by two blinded, trained physicians using a previously established methodology. RESULTS: Over 28% of 684 patients experienced post-discharge AEs, most of which were either preventable or ameliorable. There was no difference in the incidence of post-discharge AEs in urban versus rural patients (ARR 1.04 95% CI 0.82-1.32 ), but post-discharge AEs were associated with hypertension, type 2 diabetes mellitus, and number of secondary discharge diagnoses only in urban patients. CONCLUSIONS: Post-discharge AEs were common in both urban and rural patients and many were preventable or ameliorable. Potentially different risk factors for AEs in urban versus rural patients suggests the need for further research into the underlying causes. Different interventions may be required in urban versus rural patients to improve patient safety during transitions in care. PMID- 25822114 TI - Detecting mismatches of bird migration stopover and tree phenology in response to changing climate. AB - Migratory birds exploit seasonal variation in resources across latitudes, timing migration to coincide with the phenology of food at stopover sites. Differential responses to climate in phenology across trophic levels can result in phenological mismatch; however, detecting mismatch is sensitive to methodology. We examined patterns of migrant abundance and tree flowering, phenological mismatch, and the influence of climate during spring migration from 2009 to 2011 across five habitat types of the Madrean Sky Islands in southeastern Arizona, USA. We used two metrics to assess phenological mismatch: synchrony and overlap. We also examined whether phenological overlap declined with increasing difference in mean event date of phenophases. Migrant abundance and tree flowering generally increased with minimum spring temperature but depended on annual climate by habitat interactions. Migrant abundance was lowest and flowering was highest under cold, snowy conditions in high elevation montane conifer habitat while bird abundance was greatest and flowering was lowest in low elevation riparian habitat under the driest conditions. Phenological synchrony and overlap were unique and complementary metrics and should both be used when assessing mismatch. Overlap declined due to asynchronous phenologies but also due to reduced migrant abundance or flowering when synchrony was actually maintained. Overlap declined with increasing difference in event date and this trend was strongest in riparian areas. Montane habitat specialists may be at greatest risk of mismatch while riparian habitat could provide refugia during dry years for phenotypically plastic species. Interannual climate patterns that we observed match climate change projections for the arid southwest, altering stopover habitat condition. PMID- 25822115 TI - Light-level geolocators reveal covariation between winter plumage molt and phenology in a trans-Saharan migratory bird. AB - Contingent individual performance can depend on the environment experienced at previous life-stages. Migratory birds are especially susceptible to such carry over effects as they periodically travel between breeding ranges and 'wintering' areas where they may experience broadly different ecological conditions. However, the study of carry-over effects is hampered by the difficulty of tracking vagile organisms throughout their annual life-cycle. Using information from light-level geolocators on the barn swallow (Hirundo rustica), we tested if feather growth bar width (GBW), a proxy of feather growth rate which depends on individual condition, and wing isometric size and shape predict the phenology of subsequent migration. GBW did not predict duration of wintering but negatively predicted the duration of spring migration and arrival date to the breeding sites, suggesting that migration phenology is not constrained by molt, and individuals in prime condition achieve both faster molt and earlier arrival. Wing morphology did not predict migration duration, as expected if wing shape were optimized for foraging, rather than migration performance, in this aerially foraging, insectivorous bird. Thus, we showed for the first time that migration phenology in a long-distance migratory bird covaries with body condition during wintering, as reflected by the growth rate of feathers. PMID- 25822116 TI - Impact of melanoma genetic test reporting on perceived control over melanoma prevention. AB - To determine whether receiving melanoma genetic test results undermines perceived control over melanoma prevention, control-related beliefs were examined among 60 adults from melanoma-prone families receiving CDKN2A/p16 test results (27 unaffected noncarriers, 15 unaffected carriers, 18 affected carriers; response rate at 2 years = 64.9 % of eligible respondents). Multilevel modeling of perceived control ratings over a 2-year period revealed significant variation in individual trajectories: most participants showed increases (45 %) or no change (38.3 %), while 16.7 % showed decreases. At the group level, noncarriers reported sustained increases through the 2-year follow-up (ps < .05); unaffected carriers reported significant short-term increases (ps < .05); and affected carriers reported no change. Participants in all groups continued to rate photoprotection as highly effective in reducing melanoma risk and reported decreased beliefs that carrying the p16 mutation would inevitably lead to the development of melanoma. Qualitative responses immediately following counseling and test reporting corroborated these findings, as 93 % indicated it was possible to either prevent (64.9 %) or decrease the likelihood (28.1 %) of future melanomas. Thus, genetic test reporting does not generally undermine perceived control over melanoma prevention, though variability in response to positive results warrants future study. PMID- 25822117 TI - Field experiment of a very brief worksite intervention to improve nutrition among health care workers. AB - Despite the potential of worksite interventions to boost productivity and save insurance costs, they tend to be costly and tested in nonrandomized trials. The aim of the present study was to test the ability of a very brief worksite intervention based on implementation intentions to improve nutrition among health care workers. Seventy-nine health care workers were randomly allocated to a control condition or to form implementation intentions using standard instructions or with a supporting tool. Fruit intake and metacognitive processing (operationalized as awareness of standards, self-monitoring and self-regulatory effort) were measured at baseline and follow-up. Participants who formed implementation intentions ate significantly more fruit and engaged in significantly more metacognitive processing at follow-up than did participants in the control condition (ds > .70). The findings support the efficacy of implementation intentions for increasing fruit intake in health care workers and preliminary support for the utility of a tool to support implementation intention formation. PMID- 25822118 TI - Purpose in life and incidence of sleep disturbances. AB - Purpose in life has been linked with better mental health, physical health, and health behaviors, but the association between purpose and sleep is understudied. Sleep disturbances increase with age and as the number of older adults rapidly increases, it is ever more important to identify modifiable factors that are associated with reduced incidence of sleep disturbances. We used multiple logistic regression models and data from the Health and Retirement Study, a nationally representative panel study of American adults over the age of 50, to examine whether higher purpose was linked with a reduced incidence of sleep disturbances. Among 4144 respondents reporting minimal or no sleep disturbances at baseline, higher purpose was associated with a lower incidence of sleep disturbances over the 4-year follow-up. After adjusting for sociodemographic factors, each unit increase in purpose (on a six-point scale) was associated with a 16 % reduced odds of developing sleep disturbances (OR 0.84, 95 % CI 0.77 0.92). The association between purpose and sleep disturbances remained after adjusting for sociodemographic, behavioral, psychological, and health covariates. Should future research replicate our findings, this area of research may lead to innovative efforts that improve the quality of sleep in older adults. PMID- 25822119 TI - Cellular signaling in sinecatechins-treated external genital and perianal warts: unraveling the mechanism of action of a botanical therapy. PMID- 25822120 TI - Rolling back malaria. PMID- 25822121 TI - The issue of 'informed consent' in medical student introductions. PMID- 25822122 TI - Who can do without patients? PMID- 25822123 TI - User reception of a simple online multisource feedback tool for residents. AB - Receiving feedback on daily clinical activities, in whatever form, is crucial for the development of clinical proficiency. Multisource or 360-degree feedback procedures have been recommended to include various co-workers as sources of feedback. In 2008, a web-based multisource feedback (MSF) tool for medical residents was developed at the University Medical Center Utrecht and launched nationally in the Netherlands and has been widely used since then. In 2012, an evaluation was carried out to collect opinions on its use, on the quality of the instrument and on its experienced effectiveness. We approached 408 residents and 59 residency programme directors with an anonymous online survey.Completed surveys were received from 108 residents (26 %) and 22 programme directors (37 %). The tool was well received among the respondents and proved to be a simple, efficient and effective instrument to prepare for information-rich progress interviews of programme directors with their residents. Despite a relatively low response rate, indications were found for the effectiveness of MSF use at four levels of Kirkpatrick's hierarchy based on user impressions: reaction, learning, behaviour change, and impact. This MSF tool, designed for effective formative feedback, was found to meet its purpose and was well received. PMID- 25822124 TI - What is more effective: a daily or a weekly formative test? AB - BACKGROUND: Exams in anatomy courses are traditionally summative. Formative testing induces retrieval practice, provides feedback and enhances learning results. We investigated the optimal frequency for retrieval practice during an anatomy course. METHOD: During a first-year course, students were offered four online daily quizzes a week that assessed thoracic anatomy. Once a week they received a quiz about abdominal anatomy. Students immediately received feedback afterwards. In the fourth course week, a survey about participation and satisfaction was taken. 424 students participated in the final summative exam. Trunk wall questions were used as a control. Relationship between participation and test results was investigated with a one-way ANOVA. RESULTS: More frequent participation in formative tests was correlated to higher scores in the summative exam with no difference between daily and weekly quizzes. This effect was found for thorax-abdomen and 'control' trunk wall questions. Participation in weekly quizzes was higher (p < 0.001). All survey responses showed a significant difference in favour of the weekly quiz (p < 0.001). DISCUSSION AND CONCLUSION: Participation in formative quizzes was correlated to summative exam scores. This correlation was not specific for the material tested, probably because of diligence. Student participation and preference were much higher in weekly quizzes. PMID- 25822125 TI - Room temperature quantum spin Hall insulators with a buckled square lattice. AB - Two-dimensional (2D) topological insulators (TIs), also known as quantum spin Hall (QSH) insulators, are excellent candidates for coherent spin transport related applications because the edge states of 2D TIs are robust against nonmagnetic impurities since the only available backscattering channel is forbidden. Currently, most known 2D TIs are based on a hexagonal (specifically, honeycomb) lattice. Here, we propose that there exists the quantum spin Hall effect (QSHE) in a buckled square lattice. Through performing global structure optimization, we predict a new three-layer quasi-2D (Q2D) structure, which has the lowest energy among all structures with the thickness less than 6.0 A for the BiF system. It is identified to be a Q2D TI with a large band gap (0.69 eV). The electronic states of the Q2D BiF system near the Fermi level are mainly contributed by the middle Bi square lattice, which are sandwiched by two inert BiF2 layers. This is beneficial since the interaction between a substrate and the Q2D material may not change the topological properties of the system, as we demonstrate in the case of the NaF substrate. Finally, we come up with a new tight-binding model for a two-orbital system with the buckled square lattice to explain the low-energy physics of the Q2D BiF material. Our study not only predicts a QSH insulator for realistic room temperature applications but also provides a new lattice system for engineering topological states such as quantum anomalous Hall effect. PMID- 25822126 TI - Interligand Interactions Dictate the Regioselectivity of trans-Hydrometalations and Related Reactions Catalyzed by [Cp*RuCl]. Hydrogen Bonding to a Chloride Ligand as a Steering Principle in Catalysis. AB - Reactions of internal alkynes with R3M-H (M = Si, Ge, Sn) follow an unconventional trans-addition mode in the presence of [Cp*Ru(MeCN)3]PF6 (1) as the catalyst; however, the regioselectivity is often poor with unsymmetrical substrates. This problem can be solved upon switching to a catalyst comprising a [Ru-Cl] bond, provided that the acetylene derivative carries a protic functional group. The R3M unit is then delivered with high selectivity to the alkyne-C atom proximal to this steering substituent. This directing effect originates from the ability of the polarized [Ru-Cl] bond to engage in hydrogen bonding with the protic substituent, which helps upload, activate, and lock the alkyne within the coordination sphere. An additional interligand contact of the chloride with the MR3 center positions the incoming reagent in a matching orientation that translates into high regioselectivity. The proposed secondary interactions within the loaded catalyst are in line with a host of preparative and spectral data and with the structures of the novel ruthenium pi-complexes 10 and 11 in the solid state. Moreover, the first X-ray structure of a [Ru(sigma-stannane)] complex (12a) is presented, which indeed features peripheral Ru-Cl...MR3 contacts; this adduct also corroborates that alkyne trans-addition chemistry likely involves sigma-complexes as reactive intermediates. Finally, it is discussed that interligand cooperativity might constitute a more general principle that extends to mechanistically distinct transformations. The presented data therefore make an interesting case for organometallic chemistry that provides inherently better results when applied to substrates containing unprotected rather than protected OH, -NHR, or -COOH groups. PMID- 25822129 TI - Low-temperature conditioning alleviates chilling injury in loquat fruit and regulates glycine betaine content and energy status. AB - The influence of low-temperature conditioning (LTC) treatment on chilling injury, glycine betaine content, and energy metabolism in loquat fruit at 1 degrees C storage was investigated. The results indicated that LTC treatment significantly reduced chilling injury index, ion leakage, and malondialdehyde content in loquat fruit. Betaine aldehyde hydrogenase (BADH) activity and endogenous glycine betaine (GB) content in loquats treated with LTC were significantly higher than those in control fruit. Moreover, LTC treatment induced activities of energy metabolism-associated enzymes, including H(+)-adenosine triphosphatase, Ca(2+) adenosine triphosphatase, succinic dehydrogenase, and cytochrome c oxidase. LTC treatment triggered obviously higher levels of adenosine triphosphate (ATP) content and energy charge in loquat fruit. These results showed that LTC possibly alleviated chilling injury and enhanced chilling tolerance of loquat fruit by enhancing endogenous GB content and energy status. PMID- 25822130 TI - Sleep and motor learning: Is there room for consolidation? AB - It is widely believed that sleep is critical to the consolidation of learning and memory. In some skill domains, performance has been shown to improve by 20% or more following sleep, suggesting that sleep enhances learning. However, recent work suggests that those performance gains may be driven by several factors that are unrelated to sleep consolidation, inviting a reconsideration of sleep's theoretical role in the consolidation of procedural memories. Here we report the first comprehensive investigation of that possibility for the case of motor sequence learning. Quantitative meta-analyses involving 34 articles, 88 experimental groups and 1,296 subjects confirmed the empirical pattern of a large performance gain following sleep and a significantly smaller gain following wakefulness. However, the results also confirm strong moderating effects of 4 previously hypothesized variables: averaging in the calculation of prepost gain scores, build-up of reactive inhibition over training, time of testing, and training duration, along with 1 supplemental variable, elderly status. With those variables accounted for, there was no evidence that sleep enhances learning. Thus, the literature speaks against, rather than for, the enhancement hypothesis. Overall there was relatively better performance after sleep than after wakefulness, suggesting that sleep may stabilize memory. That effect, however, was not consistent across different experimental designs. We conclude that sleep does not enhance motor learning and that the role of sleep in the stabilization of memory cannot be conclusively determined based on the literature to date. We discuss challenges and opportunities for the field, make recommendations for improved experimental design, and suggest approaches to data analysis that eliminate confounds due to averaging over online learning. (PsycINFO Database Record PMID- 25822131 TI - Cognitive aspects of young children's experience of economic disadvantage. AB - Economic disadvantage is a well-studied risk factor for poorer behavioral and academic functioning in young children. Although the mechanisms by which disadvantage impacts children have long been of interest to researchers, studies to date have predominantly focused on mechanisms that are external to the child (e.g., parental depression, marital conflict). Very few studies have examined the internal, cognitive aspects of the experience of economic disadvantage, and almost none have considered how the effects of disadvantage on children's functioning might be mediated through cognitive processes. This article provides a framework for research into cognitive and social-cognitive mediators of economic disadvantage operating in early-to-middle childhood. The initial section of the article briefly reviews and summarizes the extant literature on childhood poverty and its effects. The second section reviews the evidence that preschool aged children have the requisite cognitive abilities to recognize social inequality in their environments, to be aware of stereotypes related to social class, and to connect these social concepts to their own experience. The third section reviews and evaluates the small literature on children's appraisals, attributions, stereotypes, and perceptions of or about poverty and inequality. The fourth section defines and evaluates the literature on 2 social-cognitive processes-stereotype threat and status anxiety-that are hypothesized to mediate the effects of economic disadvantage on children's functioning. The article concludes with a series of proposed questions and hypotheses for future research, and elaborates on the potential implications of the proposed area of research. (PsycINFO Database Record PMID- 25822132 TI - Divisions of the physical world: Concepts of objects and substances. AB - Our concepts of the physical world distinguish objects, such as chairs, from substances, such as quantities of wood, that constitute them. A particular chair might consist of a single chunk of wood, yet we think about the chair and the wood in different ways. For example, part of the wood is still wood, but part of the chair is not a chair. In this article we examine the basis of the object/substance distinction. We draw together for the first time relevant experiments widely dispersed in the cognitive literature, and view these findings in the light of theories in linguistics and metaphysics. We outline a framework for the difference between objects and substances, based on earlier ideas about form and matter, describing the psychological evidence surrounding it. The framework suggests that concepts of objects include a relation of unity and organization governing their parts, whereas concepts of substances do not. We propose, as a novel twist on this framework, that unity and organization for objects is a function of causal forces that shape the objects. In agreement with this idea, results on the identification of an item as an object depend on clues about the presence of the shaping relation, clues provided by solidity, repetition of shape, and other factors. We also look at results from human infants about the source of the object/substance distinction and conclude that the data support an early origin for both object and substance knowledge. (PsycINFO Database Record PMID- 25822133 TI - The relation between short-term emotion dynamics and psychological well-being: A meta-analysis. AB - Not only how good or bad people feel on average, but also how their feelings fluctuate across time is crucial for psychological health. The last 2 decades have witnessed a surge in research linking various patterns of short-term emotional change to adaptive or maladaptive psychological functioning, often with conflicting results. A meta-analysis was performed to identify consistent relationships between patterns of short-term emotion dynamics-including patterns reflecting emotional variability (measured in terms of within-person standard deviation of emotions across time), emotional instability (measured in terms of the magnitude of consecutive emotional changes), and emotional inertia of emotions over time (measured in terms of autocorrelation)-and relatively stable indicators of psychological well-being or psychopathology. We determined how such relationships are moderated by the type of emotional change, type of psychological well-being or psychopathology involved, valence of the emotion, and methodological factors. A total of 793 effect sizes were identified from 79 articles (N = 11,381) and were subjected to a 3-level meta-analysis. The results confirmed that overall, low psychological well-being co-occurs with more variable (overall rho = -.178), unstable (overall rho = -.205), but also more inert (overall rho = -.151) emotions. These effect sizes were stronger when involving negative compared with positive emotions. Moreover, the results provided evidence for consistency across different types of psychological well-being and psychopathology in their relation with these dynamical patterns, although specificity was also observed. The findings demonstrate that psychological flourishing is characterized by specific patterns of emotional fluctuations across time, and provide insight into what constitutes optimal and suboptimal emotional functioning. (PsycINFO Database Record PMID- 25822134 TI - Types of subtalar joint facets. AB - Articular facets of the clinical subtalar joint (CSTJ) were analyzed using a total of 118 (right 57, left 61) dry, paired calcanei and tali from 68 Korean adult cadavers. The CSTJ facets were classified into the following three types depending on their continuity: type A, all three facets are separated; type B, the anterior and middle facets are partially connected; and type C, the anterior and middle facets are fused to form a single facet. The continuity between the anterior and middle facets was represented by the degree of separation (DS), which ranged between 2.00 (type A) and 1.00 (type C). Type A was most common (39.0 %) in calcanei and rarest (11.0 %) in tali. Matching of calcaneus-talus pairs yielded five combined types: A-A (11.0 %), A-B (28.0 %), B-B (18.6 %), B-C (13.6 %), and C-C (28.8 %). The mean DS was slightly greater in calcanei (1.53) than in tali (1.32), and decreased in the order of types A-A, A-B, B-B, B-C, and C-C. The intersecting angles between the anterior and middle facets, which are related to the mobility of the CSTJ, were inversely related to the DS. These findings indicate that the anterior and middle facets are fused more frequently in tali than in calcanei, and combinations of different CSTJ facet types (A-B, B C) exist over 40 % of feet. Our results indicate that types with a smaller DS (such as B-C and C-C) are relatively mobile but less stable compared to those with a greater DS (such as A-A and A-B). PMID- 25822135 TI - Breakdown of Bose-Einstein distribution in photonic crystals. AB - In the last two decades, considerable advances have been made in the investigation of nano-photonics in photonic crystals. Previous theoretical investigations of photon dynamics were carried out at zero temperature. Here, we investigate micro/nano cavity photonics in photonic crystals at finite temperature. Due to photonic-band-gap-induced localized long-lived photon dynamics, we discover that cavity photons in photonic crystals do not obey Bose Einstein statistical distribution. Within the photonic band gap and in the vicinity of the band edge, cavity photons combine the long-lived non-Markovain dynamics with thermal fluctuations together to form photon states that memorize the initial cavity state information. As a result, Bose-Einstein distribution is completely broken down in these regimes, even if the thermal energy is larger or much larger than the cavity detuning energy. In this investigation, a crossover phenomenon from equilibrium to nonequilibrium steady states is also revealed. PMID- 25822136 TI - Semisynthetic tRNA complement mediates in vitro protein synthesis. AB - Genetic code expansion is a key objective of synthetic biology and protein engineering. Most efforts in this direction are focused on reassigning termination or decoding quadruplet codons. While the redundancy of genetic code provides a large number of potentially reassignable codons, their utility is diminished by the inevitable interaction with cognate aminoacyl-tRNAs. To address this problem, we sought to establish an in vitro protein synthesis system with a simplified synthetic tRNA complement, thereby orthogonalizing some of the sense codons. This quantitative in vitro peptide synthesis assay allowed us to analyze the ability of synthetic tRNAs to decode all of 61 sense codons. We observed that, with the exception of isoacceptors for Asn, Glu, and Ile, the majority of 48 synthetic Escherichia coli tRNAs could support protein translation in the cell free system. We purified to homogeneity functional Asn, Glu, and Ile tRNAs from the native E. coli tRNA mixture, and by combining them with synthetic tRNAs, we formulated a semisynthetic tRNA complement for all 20 amino acids. We further demonstrated that this tRNA complement could restore the protein translation activity of tRNA-depleted E. coli lysate to a level comparable to that of total native tRNA. To confirm that the developed system could efficiently synthesize long polypeptides, we expressed three different sequences coding for superfolder GFP. This novel semisynthetic translation system is a powerful tool for tRNA engineering and potentially enables the reassignment of at least 9 sense codons coding for Ser, Arg, Leu, Pro, Thr, and Gly. PMID- 25822138 TI - Hydration Enthalpies of Ba(2+)(H2O)x, x = 1-8: A Threshold Collision-Induced Dissociation and Computational Investigation. AB - The sequential bond dissociation energies (BDEs) of Ba(2+)(H2O)x complexes, where x = 1-8, are determined using threshold collision-induced dissociation (TCID) in a guided ion beam tandem mass spectrometer. The electrospray ionization source generates complexes ranging in size from x = 6 to x = 8 with smaller complexes, x = 1-5, formed by an in-source fragmentation technique. The only products observed result from sequential loss of water ligands. Charge separation, a process in which both hydrated singly charged barium hydroxide and hydronium ion are formed, was not observed except for Ba(2+)(H2O)3 yielding BaOH(+) + H5O2(+). Modeling of the kinetic energy-dependent cross sections, taking into account the number of collisions, energy distributions, and lifetime effects for both primary and secondary water loss, provides 0 K BDEs. Experimental thermochemistry for the x = 1-3 complexes is obtained here for the first time. Hydration enthalpies and reaction coordinate pathways for charge separation are also examined computationally at several levels of theory. Our experimental and computational work are in excellent agreement in the x = 1-6 range. The present experimental values and theoretical calculations are also in reasonable agreement with the available literature values for experiment, x = 4-8, and theory, x = 1-6. Of the numerous calculations performed in the current study, B3LYP/DHF/def2-TZVPP calculations including counterpoise corrections reproduce our experimental values the best, although MP2(full)/DHF/def2-TZVPP//B3LYP/DHF/def2-TZVPP results are comparable. PMID- 25822137 TI - Association between apple consumption and physician visits: appealing the conventional wisdom that an apple a day keeps the doctor away. AB - IMPORTANCE: Fruit consumption is believed to have beneficial health effects, and some claim, "An apple a day keeps the doctor away." OBJECTIVE: To examine the relationship between eating an apple a day and keeping the doctor away. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study of a nationally representative sample of the noninstitutionalized US adult population. A total of 8728 adults 18 years and older from the 2007-2008 and 2009-2010 National Health and Nutrition Examination Survey completed a 24-hour dietary recall questionnaire and reported that the quantity of food they ate was reflective of their usual daily diet. EXPOSURES: Daily apple eaters (consuming the equivalent of at least 1 small apple daily, or 149 g of raw apple) vs non-apple eaters, based on the reported quantity of whole apple consumed during the 24-hour dietary recall period. MAIN OUTCOMES AND MEASURES: The primary outcome measure was success at "keeping the doctor away," measured as no more than 1 visit (self-reported) to a physician during the past year; secondary outcomes included successful avoidance of other health care services (ie, no overnight hospital stays, visits to a mental health professional, or prescription medications). RESULTS: Of 8399 eligible study participants who completed the dietary recall questionnaire, we identified 753 adult apple eaters (9.0%)--those who typically consume at least 1 small apple per day. Compared with the 7646 non-apple eaters (91.0%), apple eaters had higher educational attainment, were more likely to be from a racial or ethnic minority, and were less likely to smoke (P<.001 for each comparison). Apple eaters were more likely, in the crude analysis, to keep the doctor (and prescription medications) away: 39.0% of apple eaters avoided physician visits vs 33.9% of non apple eaters (P=.03). After adjusting for sociodemographic and health-related characteristics, however, the association was no longer statistically significant (OR, 1.19; 95% CI, 0.93-1.53; P=.15). In the adjusted analysis, apple eaters also remained marginally more successful at avoiding prescription medications (odds ratio, 1.27; 95% CI, 1.00-1.63). There were no differences seen in overnight hospital stay or mental health visits. CONCLUSIONS AND RELEVANCE: Evidence does not support that an apple a day keeps the doctor away; however, the small fraction of US adults who eat an apple a day do appear to use fewer prescription medications. PMID- 25822139 TI - A noncontact FMCW radar sensor for displacement measurement in structural health monitoring. AB - This paper investigates the Frequency Modulation Continuous Wave (FMCW) radar sensor for multi-target displacement measurement in Structural Health Monitoring (SHM). The principle of three-dimensional (3-D) displacement measurement of civil infrastructures is analyzed. The requirements of high-accuracy displacement and multi-target identification for the measuring sensors are discussed. The fundamental measuring principle of FMCW radar is presented with rigorous mathematical formulas, and further the multiple-target displacement measurement is analyzed and simulated. In addition, a FMCW radar prototype is designed and fabricated based on an off-the-shelf radar frontend and data acquisition (DAQ) card, and the displacement error induced by phase asynchronism is analyzed. The conducted outdoor experiments verify the feasibility of this sensing method applied to multi-target displacement measurement, and experimental results show that three targets located at different distances can be distinguished simultaneously with millimeter level accuracy. PMID- 25822140 TI - A distributed transmission rate adjustment algorithm in heterogeneous CSMA/CA networks. AB - Distributed transmission rate tuning is important for a wide variety of IEEE 802.15.4 network applications such as industrial network control systems. Such systems often require each node to sustain certain throughput demand in order to guarantee the system performance. It is thus essential to determine a proper transmission rate that can meet the application requirement and compensate for network imperfections (e.g., packet loss). Such a tuning in a heterogeneous network is difficult due to the lack of modeling techniques that can deal with the heterogeneity of the network as well as the network traffic changes. In this paper, a distributed transmission rate tuning algorithm in a heterogeneous IEEE 802.15.4 CSMA/CA network is proposed. Each node uses the results of clear channel assessment (CCA) to estimate the busy channel probability. Then a mathematical framework is developed to estimate the on-going heterogeneous traffics using the busy channel probability at runtime. Finally a distributed algorithm is derived to tune the transmission rate of each node to accurately meet the throughput requirement. The algorithm does not require modifications on IEEE 802.15.4 MAC layer and it has been experimentally implemented and extensively tested using TelosB nodes with the TinyOS protocol stack. The results reveal that the algorithm is accurate and can satisfy the throughput demand. Compared with existing techniques, the algorithm is fully distributed and thus does not require any central coordination. With this property, it is able to adapt to traffic changes and re-adjust the transmission rate to the desired level, which cannot be achieved using the traditional modeling techniques. PMID- 25822141 TI - A naked eye refractive index sensor with a visible multiple peak metamaterial absorber. AB - We report a naked eye refractive index sensor with a visible metamaterial absorber. The visible metamaterial absorber consisting of a silver dendritic/dielectric/metal structure shows multiple absorption peaks. By incorporating a gain material (rhodamine B) into the dielectric layer, the maximal magnitude of the absorption peak can be improved by about 30%. As the metamaterial absorber is sensitive to the refractive index of glucose solutions, it can function as a sensor that quickly responds to variations of the refractive index of the liquid. Meanwhile, since the response is presented via color changes, it can be clearly observed by the naked eyes. Further experiments have confirmed that the sensor can be used repeatedly. PMID- 25822142 TI - A survey on the feasibility of sound classification on wireless sensor nodes. AB - Wireless sensor networks are suitable to gain context awareness for indoor environments. As sound waves form a rich source of context information, equipping the nodes with microphones can be of great benefit. The algorithms to extract features from sound waves are often highly computationally intensive. This can be problematic as wireless nodes are usually restricted in resources. In order to be able to make a proper decision about which features to use, we survey how sound is used in the literature for global sound classification, age and gender classification, emotion recognition, person verification and identification and indoor and outdoor environmental sound classification. The results of the surveyed algorithms are compared with respect to accuracy and computational load. The accuracies are taken from the surveyed papers; the computational loads are determined by benchmarking the algorithms on an actual sensor node. We conclude that for indoor context awareness, the low-cost algorithms for feature extraction perform equally well as the more computationally-intensive variants. As the feature extraction still requires a large amount of processing time, we present four possible strategies to deal with this problem. PMID- 25822143 TI - Synthesis and charge-transfer dynamics in a ferrocene-containing organoboryl aza BODIPY donor-acceptor triad with boron as the hub. AB - A N,N'-bis(ferroceneacetylene)boryl complex of 3,3' diphenylazadiisoindolylmethene was synthesized by the reaction of an N,N' difluoroboryl complex of 3,3'-diphenylazadiisoindolylmethene and ferroceneacetylene magnesium bromide. The novel diiron complex was characterized by a variety of spectroscopic techniques, electrochemistry, and ultrafast time resolved methods. Spectroscopy and redox behavior was correlated with the density functional theory (DFT) and time-dependent DFT calculations. An unexpected degree of coupling between the two Fc ligands was observed. Despite a lack of conjugation between the donor and acceptor, the complex undergoes very rapid (tau = 1.7 +/- 0.1 ps) photoinduced intramolecular charge separation followed by subpicosecond charge recombination to form a triplet state with a lifetime of 4.8 +/- 0.1 MUs. PMID- 25822144 TI - Trends in Energy Intakes by Type of Fast Food Restaurant Among US Children From 2003 to 2010. PMID- 25822145 TI - Comparative Study of Potential Applications of Graphene, MoS2, and Other Two Dimensional Materials in Energy Devices, Sensors, and Related Areas. AB - Novel properties of graphene have been well documented, whereas the importance of nanosheets of MoS2 and other chalcogenides is increasingly being recognized over the last two to three years. Borocarbonitrides, BxCyNz, with insulating BN and conducting graphene on either side are new materials whose properties have been attracting attention. These two-dimensional (2D) materials contain certain common features. Thus, graphene, MoS2, and borocarbonitrides have all been used in supercapacitor applications, oxygen reduction reactions (ORRs), and lithium-ion batteries. It is instructive, therefore, to make a comparative study of some of the important properties of these layered materials. In this article, we discuss properties related to energy devices at length. We examine the hydrogen evolution reaction facilitated by graphene, MoS2, and related materials. We also discuss gas and radiation sensors based on graphene and MoS2 as well as gas storage properties of graphene and borocarbonitrides. The article should be useful in making a judicious choice of which 2D material to use for a particular application. PMID- 25822146 TI - Apocytolysis, a proposed mechanism of blister formation in epidermolysis bullosa simplex. AB - Epidermolysis bullosa simplex (EBS) is caused by keratin 5 and 14 mutations. In vitro studies revealed that susceptibility to caspase 8-mediated apoptosis is increased in keratin 14 mutated keratinocytes. We aimed to investigate the role of apoptotic/inflammatory pathways in the pathogenesis of EBS by studying the expression of caspase 8 in lesional and non-lesional skin compared to controls. Ten EBS patients proved by electron microscopy and five age and sex matched healthy volunteers were the subjects of this case control study. Caspase 8 expression was studied by immunohistochemistry. Caspase 8 expression in lesional and non-lesional skin was significantly higher than in controls (p < 0.01 and p = 0.013, respectively) with no significant difference between lesional and non lesional skin. Lesional skin had significantly higher density of dermal infiltrate (p = 0.02). Caspase 8 expression in lesional skin was significantly correlated with the extent of the disease, rate of blistering, and density of dermal infiltrate (r = 0.835; p = 0.003, r = 0.889; p = 0.001 and r = 0.776; p = 0.008 respectively). Caspase 8-mediated apoptosis is an integral component of an orchestra of events conducted by keratin mutation. Apo-cytolysis is proposed to better describe the mechanism of blistering in EBS. The small number of cases is a limitation. PMID- 25822148 TI - A stochastic model for detecting overlapping and hierarchical community structure. AB - Community detection is a fundamental problem in the analysis of complex networks. Recently, many researchers have concentrated on the detection of overlapping communities, where a vertex may belong to more than one community. However, most current methods require the number (or the size) of the communities as a priori information, which is usually unavailable in real-world networks. Thus, a practical algorithm should not only find the overlapping community structure, but also automatically determine the number of communities. Furthermore, it is preferable if this method is able to reveal the hierarchical structure of networks as well. In this work, we firstly propose a generative model that employs a nonnegative matrix factorization (NMF) formulization with a l(2,1) norm regularization term, balanced by a resolution parameter. The NMF has the nature that provides overlapping community structure by assigning soft membership variables to each vertex; the l(2,1) regularization term is a technique of group sparsity which can automatically determine the number of communities by penalizing too many nonempty communities; and hence the resolution parameter enables us to explore the hierarchical structure of networks. Thereafter, we derive the multiplicative update rule to learn the model parameters, and offer the proof of its correctness. Finally, we test our approach on a variety of synthetic and real-world networks, and compare it with some state-of-the-art algorithms. The results validate the superior performance of our new method. PMID- 25822149 TI - Canakinumab: a review of its use in the management of systemic juvenile idiopathic arthritis. AB - Subcutaneous canakinumab (Ilaris((r))) is a human monoclonal anti-human interleukin (IL)-1beta antibody of the immunoglobulin G1/kappa isotype that binds with high affinity and specificity to human IL-1beta, blocking its interaction with IL-1 receptors. It is approved in the EU as monotherapy or in combination with methotrexate for the treatment of patients aged >=2 years with active systemic juvenile idiopathic arthritis (SJIA) who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs and systemic corticosteroids. In the USA, it is indicated for the treatment of patients aged >=2 years with active SJIA. In two placebo-controlled, multinational, phase III studies in patients aged 2-19 years with SJIA, canakinumab rapidly reduced disease activity, permitted the tapering of glucocorticoid therapy and delayed the time to disease flare. The efficacy of canakinumab was sustained at a median follow-up of 49 weeks in an ongoing extension study. In clinical studies, canakinumab had an acceptable tolerability profile that was comparable with that observed in patients with cryopyrin-associated periodic syndromes. In general, adverse events were mild or moderate in intensity, with nasopharyngitis, cough, pyrexia, vomiting, diarrhoea and upper respiratory tract infection the most frequently reported treatment-emergent adverse events. Thus, current evidence suggests subcutaneous canakinumab extends the treatment options currently available for patients aged >=2 years with SJIA. PMID- 25822147 TI - Properties of neurons derived from induced pluripotent stem cells of Gaucher disease type 2 patient fibroblasts: potential role in neuropathology. AB - Gaucher disease (GD) is caused by insufficient activity of acid beta-glucosidase (GCase) resulting from mutations in GBA1. To understand the pathogenesis of the neuronopathic GD, induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from three GD type 2 (GD2) and 2 unaffected (normal and GD carrier) individuals. The iPSCs were converted to neural precursor cells (NPCs) which were further differentiated into neurons. Parental GD2 fibroblasts as well as iPSCs, NPCs, and neurons had similar degrees of GCase deficiency. Lipid analyses showed increases of glucosylsphingosine and glucosylceramide in the GD2 cells. In addition, GD2 neurons showed increased alpha-synuclein protein compared to control neurons. Whole cell patch-clamping of the GD2 and control iPSCs derived neurons demonstrated excitation characteristics of neurons, but intriguingly, those from GD2 exhibited consistently less negative resting membrane potentials with various degree of reduction in action potential amplitudes, sodium and potassium currents. Culture of control neurons in the presence of the GCase inhibitor (conduritol B epoxide) recapitulated these findings, providing a functional link between decreased GCase activity in GD and abnormal neuronal electrophysiological properties. To our knowledge, this study is first to report abnormal electrophysiological properties in GD2 iPSC-derived neurons that may underlie the neuropathic phenotype in Gaucher disease. PMID- 25822150 TI - Scale-dependence of processes structuring dung beetle metacommunities using functional diversity and community deconstruction approaches. AB - Community structure is driven by mechanisms linked to environmental, spatial and temporal processes, which have been successfully addressed using metacommunity framework. The relative importance of processes shaping community structure can be identified using several different approaches. Two approaches that are increasingly being used are functional diversity and community deconstruction. Functional diversity is measured using various indices that incorporate distinct community attributes. Community deconstruction is a way to disentangle species responses to ecological processes by grouping species with similar traits. We used these two approaches to determine whether they are improvements over traditional measures (e.g., species composition, abundance, biomass) for identification of the main processes driving dung beetle (Scarabaeinae) community structure in a fragmented mainland-island landscape in southern Brazilian Atlantic Forest. We sampled five sites in each of four large forest areas, two on the mainland and two on the island. Sampling was performed in 2012 and 2013. We collected abundance and biomass data from 100 sampling points distributed over 20 sampling sites. We studied environmental, spatial and temporal effects on dung beetle community across three spatial scales, i.e., between sites, between areas and mainland-island. The gamma-diversity based on species abundance was mainly attributed to beta-diversity as a consequence of the increase in mean alpha- and beta-diversity between areas. Variation partitioning on abundance, biomass and functional diversity showed scale-dependence of processes structuring dung beetle metacommunities. We identified two major groups of responses among 17 functional groups. In general, environmental filters were important at both local and regional scales. Spatial factors were important at the intermediate scale. Our study supports the notion of scale-dependence of environmental, spatial and temporal processes in the distribution and functional organization of Scarabaeinae beetles. We conclude that functional diversity may be used as a complementary approach to traditional measures, and that community deconstruction allows sufficient disentangling of responses of different trait-based groups. PMID- 25822151 TI - Correlation between decrease of CRP and resolution of airway inflammatory response, improvement of health status, and clinical outcomes during severe acute exacerbation of chronic obstructive pulmonary disease. AB - Circulating C-reactive protein (CRP) plays an important role in mediating extra pulmonary complications of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the relationship between changes in high sensitivity (hs)-CRP levels and the resolution of airway inflammatory markers and clinical health status during the recovery period after an acute exacerbation of COPD (AECOPD). Consecutive patients hospitalized for AECOPD were recruited. Serum hs-CRP, airway inflammatory markers, and COPD Assessment Test (CAT) score were evaluated at admission prior to treatment and at days 4, 7, and 14. Adverse outcomes were recorded. The relationship between changes in airway inflammatory markers, CAT score, and hs-CRP during the recovery period was studied. A total of 135 patients were enrolled. Serum hs-CRP levels at admission of patients with adverse outcomes were marginally higher than those without an adverse outcome (7.6 [4.8, 16.7] vs. 6.6 [4.7, 9.3], p = 0.061). Compared with patients without cardiovascular complications, patients with cardiovascular complications had higher serum hs-CRP levels at admission (11.6 [6.7, 16.7] vs. 6.6 [4.4, 10.0], p = 0.001). Sputum neutrophils were positively correlated to hs-CRP at admission (r = 0.474, p < 0.001). A decreasing hs-CRP level was positively related to decreasing sputum neutrophils at day 4 and 7 (r = 0.455, p < 0.001; r = 0.504, p < 0.001, respectively). Significant correlations between decreasing hs-CRP and CAT at all time-points were noted. Hs-CRP may be useful in monitoring airway inflammation resolution and improvement of health status during AECOPD treatment. PMID- 25822152 TI - Overexpression of TFAM or twinkle increases mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. AB - BACKGROUND: Mitochondrial DNA (mtDNA) copy number decreases in animal and human heart failure (HF), yet its role in cardiomyocytes remains to be elucidated. Thus, we investigated the cardioprotective function of increased mtDNA copy number resulting from the overexpression of human transcription factor A of mitochondria (TFAM) or Twinkle helicase in volume overload (VO)-induced HF. METHODS AND RESULTS: Two strains of transgenic (TG) mice, one overexpressing TFAM and the other overexpressing Twinkle helicase, exhibit an approximately 2-fold equivalent increase in mtDNA copy number in heart. These TG mice display similar attenuations in eccentric hypertrophy and improved cardiac function compared to wild-type (WT) mice without any deterioration of mitochondrial enzymatic activities in response to VO, which was accompanied by a reduction in matrix metalloproteinase (MMP) activity and reactive oxygen species after 8 weeks of VO. Moreover, acute VO-induced MMP-2 and MMP-9 upregulation was also suppressed at 24 h in both TG mice. In isolated rat cardiomyocytes, mitochondrial reactive oxygen species (mitoROS) upregulated MMP-2 and MMP-9 expression, and human TFAM (hTFAM) overexpression suppressed mitoROS and their upregulation. Additionally, mitoROS were equally suppressed in H9c2 rat cardiomyoblasts that overexpress hTFAM or rat Twinkle, both of which exhibit increased mtDNA copy number. Furthermore, mitoROS and mitochondrial protein oxidation from both TG mice were suppressed compared to WT mice. CONCLUSIONS: The overexpression of TFAM or Twinkle results in increased mtDNA copy number and facilitates cardioprotection associated with limited mitochondrial oxidative stress. Our findings suggest that increasing mtDNA copy number could be a useful therapeutic strategy to target mitoROS in HF. PMID- 25822153 TI - Nafamostat mesilate for prevention of post-ERCP pancreatitis: a meta-analysis of prospective, randomized, controlled trials. AB - OBJECTIVES: We aimed to evaluate the efficacy of nafamostat on the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS: Medline, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched until April 18, 2014. RESULTS: Seven randomized controlled trials and 2956 patients met the search criteria. When compared with nonnafamostat, the incidence of PEP was reduced to 53% in the patients who received nafamostat (risk ratio [RR], 0.47; 95% confidence interval [CI], 0.34 0.63). Further analyses were conducted based on the different risk classifications (n = 641 in patients with high risks: RR, 0.54; 95% CI, 0.30-0.96 and n = 944 with low risks: RR, 0.31; 95% CI, 0.17-0.56), PEP severities (n = 1654: RR, 0.38; 95% CI, 0.25-0.59 for mild; RR, 0.37; 95% CI, 0.15-0.96 for moderate; RR, 0.92; 95% CI, 0.13-6.38 for severe), and nafamostat doses (n = 1902: RR, 0.42; 95% CI, 0.28-0.63 for 20 mg; n = 1150: RR, 0.40; 95% CI, 0.25 0.63 for 50 mg). However, there was no reduction of the incidence of post-ERCP hyperamylasemia (n = 1585; 95% CI, 0.68-1.45) or cannulation difficulty (n = 1585; 95% CI, 0.91-1.23). CONCLUSIONS: Pooled analyses from current randomized controlled trials support the effectiveness of nafamostat for prophylaxis of PEP. PMID- 25822154 TI - Circulating tumor cells found in patients with localized and advanced pancreatic cancer. AB - OBJECTIVES: Isolation of circulating tumor cells (CTCs) holds the promise of diagnosing and molecular profiling cancers from a blood sample. Here, we test a simple new low-cost filtration device for CTC isolation in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Peripheral blood samples drawn from healthy donors and PDAC patients were filtered using ScreenCell devices, designed to capture CTCs for cytologic and molecular analysis. Giemsa-stained specimens were evaluated by a pancreatic cytopathologist blinded to the histological diagnosis. Circulating tumor cell DNA was subjected to KRAS mutational analysis. RESULTS: Spiking experiments demonstrated a CTC capture efficiency as low as 2 cells/mL of blood. Circulating tumor cells were identified by either malignant cytology or presence of KRAS mutation in 73% of 11 patients (P = 0.001). Circulating tumor cells were identified in 3 of 4 patients with early (<=American Joint Committee on Cancer stage IIB) and in 5 of 7 patients with advanced (>= American Joint Committee on Cancer stage III) PDAC. No CTCs were detected in blood from 9 health donors. CONCLUSIONS: Circulating tumor cells can be found in most patients with PDAC of any stage, whether localized, locally advanced, or metastatic. The ability to capture, cytologically identify, and genetically analyze CTCs suggests a possible tool for the diagnosis and characterization of genetic alterations of PDAC. PMID- 25822155 TI - Calcium signaling in a genetically engineered human pancreatic beta-cell line. AB - OBJECTIVES: The use of primary human beta-cells for studying Ca signaling is limited by the scarcity of human pancreatic islets. Rodent insulinoma cell lines are widely used, but it is difficult to extrapolate results obtained from rodent cells to human. Recently, a genetically engineered human beta-cell line EndoC-BH1 has been developed. We have examined whether the EndoC-BH1 cells could be used as a model for studying Ca signaling in the beta-cells. METHODS: We used microscope based fluorometry to measure cytoplasmic-free Ca concentration from fura-2-loaded single EndoC-BH1 cells cultured on glass cover slips. Ca responses to different agonists of insulin secretion were studied. Insulin secretion was measured by radioimmunoassay. RESULTS: EndoC-BH1 cells secreted insulin in response to glucose in a dose-dependent manner, and the secretion was enhanced by GLP-1 (glucagon-like peptide 1). Glucose, potassium chloride, carbachol, L-arginine, and tolbutamide increased cytoplasmic-free Ca concentration in the EndoC-BH1 cells. We found that GLP-1 was essential for Ca response to glucose and tolbutamide. CONCLUSIONS: We concluded that the EndoC-BH1 cells can be used as model cells to study Ca signaling and stimulus-secretion coupling in the human beta-cells. PMID- 25822156 TI - Acyl azolium fluorides for room temperature nucleophilic aromatic fluorination of chloro- and nitroarenes. AB - The reaction of acid fluorides with N-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature SNAr fluorination of a variety of aryl chlorides and nitroarenes. PMID- 25822157 TI - Hymenobacter humi sp. nov., a bacterium isolated from soil. AB - A red-pink coloured, Gram-negative, rod-shaped bacterium designated as strain DG31A(T) was isolated from soil collected in Seoul, South Korea. The isolate was found to grow optimally at 25 degrees C on R2A agar. The highest degrees of 16S rRNA gene sequence similarities of the strain were found with Hymenobacter arizonensis JCM 13504(T) (98.0 %), Hymenobacter glaciei VUG-A130(T) (96.1 %), Hymenobacter soli PB17(T) (95.2 %), Hymenobacter antarcticus VUG-A42aa(T) (94.7 %) and Hymenobacter chitinivorans Txc1(T) (92.8 %). The DNA G+C content of the novel strain, DG31A(T), was determined to be 60.8 mol%. Chemotaxonomic data revealed that the major fatty acids were summed feature 3 (C16:1 omega7c and/or C16:1 omega6c; 26.7 %), C16:1 omega5c (18.9 %) and anteiso-C15:0 (12.9 %); the major polar lipid was identified as phosphatidylethanolamine; the polyamine pattern was found to contain sym-homospermidine; and the major quinone was identified as MK-7. The DNA-DNA relatedness of strain DG31A(T) with respect to H. arizonensis JCM 13504(T) was 19.5 +/- 2.9 % (reciprocal, 19.3 +/- 0.6 %). Based on these data, strain DG31A(T) should be classified within the genus Hymenobacter as a novel species for which the name Hymenobacter humi sp. nov. is proposed, with the type strain DG31A(T) (=KCTC 32523(T) = JCM 19635(T)). PMID- 25822158 TI - Simultaneous determination of chlorantraniliprole and cyantraniliprole in fruits, vegetables and cereals using ultra-high-performance liquid chromatography-tandem mass spectrometry with the isotope-labelled internal standard method. AB - A reliable and sensitive isotope-labelled internal standard method for simultaneous determination of chlorantraniliprole and cyantraniliprole in fruits (apple and grape), vegetables (cucumber and tomato) and cereals (rice and wheat) using ultra-high-performance liquid chromatography-tandem mass spectrometry was developed. Isotope-labelled internal standards were effective in compensating for the loss in the pretreatment and overcoming the matrix effect. The analytes were extracted with acetonitrile and cleaned up with different kinds of sorbents. The determination of the target compounds was achieved in less than 4 min using a T3 column combined with an electrospray ionization source in positive mode. The overall average relative recoveries in all matrices at three spiking levels (10, 20 and 50 MUg kg(-1)) ranged from 95.5 to 106.2 %, with all relative standard deviations being less than 14.4 % for all analytes. The limits of detection did not exceed 0.085 MUg kg(-1) and the limits of quantification were below 0.28 MUg kg(-1) in all matrices. The method was demonstrated to be convenient and accurate for the routine monitoring of chlorantraniliprole and cyantraniliprole in fruits, vegetables and cereals. PMID- 25822159 TI - Quantification of tocopherols and tocotrienols in soybean oil by supercritical fluid chromatography coupled to high-resolution mass spectrometry. AB - For the most effective analytical strategies, development and validation include optimization of such analytical variables as resolution, detectability, sensitivity, simplicity, cost effectiveness, flexibility, and speed. However, other aspects concerning operator safety and environmental impact are not considered at the same level. The result has been many unintended negative effects of analytical methods developed to investigate different kinds of sample, especially hydrophobic compounds that generate a large amount of chemical waste and have a strong negative environmental impact. In this context, quantification of tocopherols and tocotrienols, i.e. the vitamin E family, is usually achieved by normal-phase liquid chromatography using large volumes of toxic organic solvents, or reversed-phase liquid chromatography using a high percentage of methanol for elution. We propose here a "greener" analytical strategy, including the hyphenation of supercritical-fluid chromatography, using CO2 and ethanol as mobile phase, NH2 as stationary phase, and mass spectrometry for the detection and quantification of vitamin E congeners in soybean oil. An atmospheric-pressure photoionization (APPI) source seemed significantly more sensitive and robust than electrospray or atmospheric-pressure chemical ionization (APCI). This method led to shortened analysis time (less than 5 min) and was revealed to be as sensitive as more traditional approaches, with limits of detection and quantification in the tens of MUg L(-1). PMID- 25822160 TI - Semi-quantitative determination of monocarboxylate forms of ginkgolide B in plasma by UPLC-MS. AB - Ginkgolide B (GB) has a unique structure incorporating three gamma-lactones that may be hydrolyzed in aquae as carboxylate forms. However, the determinations of them are challenging because there is no way to prepare the standards of any hydrolyzed products of GB in the solid state. In this report, a semi-quantitative method was developed to determine the monocarboxylate forms of GB in plasma. UPLC coupled with selected ion monitoring (SIR) of m/z 423 and m/z 441 were employed to detect the trilactone and monocarboxylates in assistances with the frozen method and the recovered method, which were, respectively, used to stabilize the hydrolyzed states and fully recover the monocarboxylates as the trilactone in samples. Two monocarboxylates were detected in pH 7.4 potassium phosphate buffers (PPB) after incubations, while only one was found in plasma in vitro and in vivo. The identifications of them require further studies. Following the bioanalytical validation of the trilactone, critical issues of the relative responses of the monocarboxylates in contrast to the trilactone, matrix effects, and stabilities were carefully investigated with subtly designed measures. The validation results supported the quantifications of monocarboxylates in PPB or plasma directly by using the corresponding calibration curve of the trilactone. The applications of this method presented a clear disparity between the hydrolysis kinetics of GB in plasma and PPB. Based on the quantification results and method applications, it was concluded that the present method was suitable to study the complex hydrolysis mechanisms of GB in vitro and in vivo. PMID- 25822161 TI - Enzyme-free and isothermal detection of microRNA based on click-chemical ligation assisted hybridization coupled with hybridization chain reaction signal amplification. AB - An enzyme-free and isothermal microRNA (miRNA) detection method has been developed based on click-chemical ligation-assisted hybridization coupled with hybridization chain reaction (HCR) on magnetic beads (MBs). The click-chemical ligation between an azide-modified probe DNA and a dibenzocyclooctyne-modified probe DNA occurred through the hybridization of target miRNA (miR-141). HCR on MBs was performed by the addition of DNA hairpin monomers (H1 and H2). After magnetic separation and denaturation/rehybridization of HCR products ([H1/H2] n ), the resulting HCR products were analyzed by the fluorescence emitted from an intercalative dye, allowing amplification of the fluorescent signal. The proposed assay had a limit of detection of 0.55 fmol, which was 230-fold more sensitive than that of the HCR on the MBs coupled with a conventional sandwich hybridization assay (without click-chemical ligation) (limit of detection 127 fmol). Additionally, the proposed assay could discriminate between miR-141 and other miR-200 family members. In contrast to quantitative reverse transcription polymerase chain reaction techniques using enzymes and thermal cycling, this is an enzyme-free assay that can be conducted under isothermal conditions and can specifically detect miR-141 in fetal bovine serum. PMID- 25822162 TI - Multidimensional mass spectrometry-based shotgun lipidomics analysis of vinyl ether diglycerides. AB - Diglycerides play a central role in lipid metabolism and signaling in mammalian cells. Although diacylglycerol molecular species comprise the majority of cellular diglycerides that are commonly measured using a variety of approaches, identification of extremely low abundance vinyl ether diglycerides has remained challenging. In this work, representative molecular species from the three diglyceride subclasses (diacyl, vinyl ether, and alkyl ether diglycerides; hereafter referred to as diradylglycerols) were interrogated by mass spectrometric analysis. Product ion mass spectra of the synthesized diradylglycerols with varied chain lengths and degrees of unsaturation demonstrated diagnostic fragmentation patterns indicative of each subclass. Multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) analysis of mouse brain and heart lipid extracts were performed using the identified informative signature product ions. Through an array of tandem mass spectrometric analyses utilizing the orthogonal characteristics of neutral loss scanning and precursor ion scanning, the differential fragmentation of each subclass was exploited for high-yield structural analyses. Although molecular ion mass spectra readily identified diacylglycerol molecular species directly from the hexane fractions of tissue extracts enriched in nonpolar lipids, molecular ion peaks corresponding to ether-linked diglycerides were not observable. The power of MDMS SL utilizing the tandem mass spectrometric array analysis was demonstrated by identification and profiling of individual molecular species of vinyl ether diglycerides in mouse brain and heart from their undetectable molecular ion peaks during MS(1) analysis. Collectively, this technology enabled the identification and profiling of previously inaccessible vinyl ether diglyceride molecular species in mammalian tissues directly from extracts of biologic tissues. PMID- 25822163 TI - GMO detection in food and feed through screening by visual loop-mediated isothermal amplification assays. AB - Isothermal DNA/RNA amplification techniques are the primary methodology for developing on-spot rapid nucleic acid amplification assays, and the loop-mediated isothermal amplification (LAMP) technique has been developed and applied in the detection of foodborne pathogens, plant/animal viruses, and genetically modified (GM) food/feed contents. In this study, one set of LAMP assays targeting on eight frequently used universal elements, marker genes, and exogenous target genes, such as CaMV35S promoter, FMV35S promoter, NOS, bar, cry1Ac, CP4 epsps, pat, and NptII, were developed for visual screening of GM contents in plant-derived food samples with high efficiency and accuracy. For these eight LAMP assays, their specificity was evaluated by testing commercial GM plant events and their limits of detection were also determined, which are 10 haploid genome equivalents (HGE) for FMV35S promoter, cry1Ac, and pat assays, as well as five HGE for CaMV35S promoter, bar, NOS terminator, CP4 epsps, and NptII assays. The screening applicability of these LAMP assays was further validated successfully using practical canola, soybean, and maize samples. The results suggested that the established visual LAMP assays are applicable and cost-effective for GM screening in plant-derived food samples. PMID- 25822164 TI - Does diabetes prevention pay for itself? Evaluation of the M.O.B.I.L.I.S. program for obese persons. AB - In response to the growing burden of obesity, public primary prevention programs against obesity have been widely recommended. Several studies have estimated the cost-effectiveness of diabetes-prevention trials for different countries. Nevertheless, it is still controversial if prevention conducted in more real world settings and among people with increased risk but not yet exhibiting increased glucose tolerance can be a cost-saving strategy to cope with the obesity epidemic. We examine this question in a simulation model based on the results of the M.O.B.I.L.I.S program, a German lifestyle intervention to reduce obesity, which is directed on the high-risk group of people who are already obese. The contribution of this paper is the use of 4-year follow-up data on the intervention group and a comparison with a control group formed by SOEP respondents as inputs in a Markov model of the long-term cost savings through this intervention due to the prevention of type 2 diabetes. We show that from the point of view of a health insurer, these programs can pay for themselves. PMID- 25822165 TI - Investigating the effects of ICT on innovation and performance of European hospitals: an exploratory study. AB - Hospitals are making big investments in various types of ICT, so it is important to investigate their effects on innovation and performance. This paper presents an empirical study in this direction, based on data for 743 hospitals from 18 European countries. We specified and estimated econometrically five equations: one for product innovation, one for process innovation and three equations for the three different dimensions of (ICT-enabled) hospital performance. All five equations included various ICT-related variables reflecting ICT infrastructure and a series of important ICT applications, some of them hospital-specific, and some others of general business use, and also ICT personnel (viewed as a kind of 'soft' ICT investment), while the performance equations also included the two innovation measures. PMID- 25822166 TI - Correction: the relationship between bipolar disorder and cannabis use in daily life: an experience sampling study. PMID- 25822167 TI - Effect of rhizosphere enzymes on phytoremediation in PAH-contaminated soil using five plant species. AB - A pot experiment was performed to study the effectiveness of remediation using different plant species and the enzyme response involved in remediating PAH contaminated soil. The study indicated that species Echinacea purpurea, Festuca arundinacea Schred, Fire Phoenix (a combined F. arundinacea), and Medicago sativa L. possess the potential for remediation in PAH-contaminated soils. The study also determined that enzymatic reactions of polyphenol oxidase (except Fire Phoenix), dehydrogenase (except Fire Phoenix), and urease (except Medicago sativa L.) were more prominent over cultivation periods of 60d and 120d than 150d. Urease activity of the tested species exhibited prominently linear negative correlations with alkali-hydrolyzable nitrogen content after the tested plants were cultivated for 150d (R2 = 0.9592). The experiment also indicated that alkaline phosphatase activity in four of the five tested species (Echinacea purpurea, Callistephus chinensis, Festuca arundinacea Schred and Fire Phoenix) was inhibited during the cultivation process (at 60d and 120d). At the same time, the study determined that the linear relationship between alkaline phosphatase activity and effective phosphorus content in plant rhizosphere soil exhibited a negative correlation after a growing period of 120d (R2 = 0.665). Phytoremediation of organic contaminants in the soil was closely related to specific characteristics of particular plant species, and the catalyzed reactions were the result of the action of multiple enzymes in the plant rhizosphere soil. PMID- 25822168 TI - The biochemical properties of the Arabidopsis ecto-nucleoside triphosphate diphosphohydrolase AtAPY1 contradict a direct role in purinergic signaling. AB - The Arabidopsis E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase) AtAPY1 was previously shown to be involved in growth and development, pollen germination and stress responses. It was proposed to perform these functions through regulation of extracellular ATP signals. However, a GFP-tagged version was localized exclusively in the Golgi and did not hydrolyze ATP. In this study, AtAPY1 without the bulky GFP-tag was biochemically characterized with regard to its suggested role in purinergic signaling. Both the full-length protein and a soluble form without the transmembrane domain near the N-terminus were produced in HEK293 cells. Of the twelve nucleotide substrates tested, only three--GDP, IDP and UDP--were hydrolyzed, confirming that ATP was not a substrate of AtAPY1. In addition, the effects of pH, divalent metal ions, known E-NTPDase inhibitors and calmodulin on AtAPY1 activity were analyzed. AtAPY1-GFP extracted from transgenic Arabidopsis seedlings was included in the analyses. All three AtAPY1 versions exhibited very similar biochemical properties. Activity was detectable in a broad pH range, and Ca(2+), Mg(2+) and Mn(2+) were the three most efficient cofactors. Of the inhibitors tested, vanadate was the most potent one. Surprisingly, sulfonamide-based inhibitors shown to inhibit other E-NTPDases and presumed to inhibit AtAPY1 as well were not effective. Calmodulin stimulated the activity of the GFP-tagless membranous and soluble AtAPY1 forms about five-fold, but did not alter their substrate specificities. The apparent Km values obtained with AtAPY1 GFP indicate that AtAPY1 is primarily a GDPase. A putative three-dimensional structural model of the ecto-domain is presented, explaining the potent inhibitory potential of vanadate and predicting the binding mode of GDP. The found substrate specificity classifies AtAPY1 as a nucleoside diphosphatase typical of N-terminally anchored Golgi E-NTPDases and negates a direct function in purinergic signaling. PMID- 25822169 TI - The experience of pain and redness in patients with moderate to severe plaque psoriasis. AB - INTRODUCTION: The Psoriasis Symptom Inventory is a patient-reported outcome instrument that assesses severity of psoriasis signs and symptoms. In early qualitative research, patients reported pain related to psoriasis skin lesions and redness of affected areas of skin as key symptoms. METHODS: Individual concept elicitation interviews and cognitive interviews were conducted in adults with moderate to severe plaque psoriasis. Interviews were audio-recorded and transcribed. Concepts were identified, coded and grouped by similar content using Atlas.ti software. Results were evaluated using qualitative research methods. RESULTS: Of 30 patients recruited, 20 patients participated in concept elicitation interviews and 10 participated in cognitive interviews. Concept codes for skin pain and descriptions of color comprised 11% and 15%, respectively, of all symptom-related expressions. Of 90 pain-related expressions, 22 were about pain related to unconscious scratching and 68 were about pain from the psoriasis lesions. Of 199 color-related expressions, 72 were about red or reddish lesion color. Patients with darker skin tones were found to interpret redness consistently. DISCUSSION: These results provide further support to content validity of pain and redness concepts in the Psoriasis Symptom Inventory. CONCLUSIONS: Symptoms of skin pain and redness are highly relevant to patients with psoriasis. PMID- 25822170 TI - Trends in the use of percutaneous ventricular assist devices: analysis of national inpatient sample data, 2007 through 2012. AB - IMPORTANCE: Percutaneous ventricular assist devices (PVADs) provide robust hemodynamic support compared with intra-aortic balloon pumps (IABPs), but clinical use patterns are unknown. OBJECTIVE: To examine contemporary patterns in PVAD use in the United States and compare them with use of IABPs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of adults older than 18 years who received a PVAD or IABP while hospitalized in the United States (2007-2012). MAIN OUTCOMES AND MEASURES: Temporal trends in utilization, patient and hospital characteristics, in-hospital mortality, and cost of PVAD use compared with IABP. RESULTS: During 2007 through 2012, utilization of PVADs increased 30-fold (4.6 per million discharges in 2007 to 138 per million discharges in 2012; P for trend < .001) while utilization of IABPs decreased from 1738 per million discharges in 2008 to 1608 per million discharges in 2012 (P for trend = .02). In 2007, an estimated 72 hospitals used PVADs, increasing to 477 in 2011 (P for trend < .001). The number of hospitals with an annual volume of 10 or more PVAD procedures per year increased from 0 in 2007 to 102 in 2011 (21.4% of PVAD-using hospitals; P for trend < .001). Among PVAD recipients, 67.3% had a diagnosis of cardiogenic shock or acute myocardial infarction (AMI). There was a temporal increase in the use of PVADs in older patients and patients with AMI, hypertension, diabetes mellitus, and chronic kidney disease (P for trend < .001 for all). Overall, mortality in PVAD recipients was 28.8%, and mean (SE) hospitalization cost was $85,580 ($4165); both were significantly higher in PVAD recipients with cardiogenic shock (mortality, 47.5%; mean [SE] cost, $113,695 [$6260]; P < .001 for both). The PVAD recipients were less likely than IABP recipients to have cardiogenic shock (34.3% vs 41.2%; P = .001), AMI (48.0% vs 68.6%; P < .001), and undergo coronary artery bypass graft surgery (6.2% vs 43.2%; P < .001), but more likely to undergo percutaneous coronary intervention (70.9% vs 40.4%; P < .001). In propensity-matched analysis, PVADs were associated with higher mortality compared with IABP (odds ratio, 1.23 [95% CI, 1.06-1.43]; P = .007). CONCLUSIONS AND RELEVANCE: There has been a substantial increase in the use of PVADs in recent years with an accompanying decrease in the use of IABPs. Given the high mortality, associated cost, and uncertain evidence for a clear benefit, randomized clinical trials are needed to determine whether use of PVADs leads to improved patient outcomes. PMID- 25822171 TI - Strategies to increase the ownership and use of insecticide-treated bednets to prevent malaria. AB - BACKGROUND: Malaria is a life-threatening parasitic disease and 40% of the world's population lives in areas affected by malaria. Insecticide-treated bednets (ITNs) effectively prevent malaria, however, barriers to their use have been identified. OBJECTIVES: To assess the evidence on the effectiveness of available strategies that focus on delivery and appropriate use of ITNs. SEARCH METHODS: We searched the EPOC Register of Studies, CENTRAL, MEDLINE, EMBASE, HealthStar, CINAHL, PubMed, Science Citation Index, ProQuest Dissertations and Theses, African Index Medicus (AIM), World Health Organization Library and Information Networks for Knowledge (WHOLIS), LILACS, Virtual Health Library (VHL), and the World Health Organization Library Information System (WHOLIS). Initial searches were conducted in May 2011, updated in March 2012 and February 2013. Authors contacted organizations and individuals involved in ITN distribution programs or research to identify current initiatives, studies or unpublished data, and searched reference lists of relevant reviews and studies. SELECTION CRITERIA: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series evaluating interventions focused on increasing ITN ownership and use were considered. The populations of interest were individuals in malaria-endemic areas. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies to be included. They extracted data from the selected studies and assessed the risk of bias. When consensus was not reached, any disagreements were discussed with a third author. The magnitude of effect and quality of evidence for each outcome was assessed. MAIN RESULTS: Of the 3032 records identified, 10 studies were included in this review. Effect of ITN cost on ownership:Four studies including 4566 households and another study comprising 424 participants evaluated the effect of ITN price on ownership. These studies suggest that providing free ITNs probably increases ITN ownership when compared to subsidized ITNs or ITNs offered at full market price. Effect of ITN Cost on appropriate use of ITNs:Three studies including 9968 households and another study comprising 259 individuals found that there is probably little or no difference in the use of ITNs when they are provided free, compared to providing subsidized ITNs or ITNs offered at full market price. Education:Five studies, including 12,637 households, assessed educational interventions regarding ITN use and concluded that education may increase the number of adults and children using ITNs (sleeping under ITNs) compared to no education.One study, including 519 households, assessed the effects of providing an incentive (an undisclosed prize) to promote ITN ownership and use, and found that incentives probably lead to little or no difference in ownership or use of ITNs, compared to not receiving an incentive.None of the included studies reported on adverse effects. AUTHORS' CONCLUSIONS: Five studies examined the effect of price on ITN ownership and found moderate-certainty evidence that ownership was highest among the groups who received the ITN free versus those who purchased the ITN at any cost. In economic terms, this means that demand for ITNs is elastic with regard to price. However, once the ITN is supplied, the price paid for the ITN probably has little to no effect on its use; the four studies addressing this outcome failed to confirm the hypothesis that people who purchase nets will use them more than those who receive them at no cost. Educational interventions for promoting ITN use have an additional positive effect. However, the impact of different types or intensities of education is unknown. PMID- 25822173 TI - Correction: Characterization of the RelBbu regulon in Borrelia burgdorferi reveals modulation of glycerol metabolism by (p)ppGpp. PMID- 25822172 TI - Remodeling of the residual gastric mucosa after roux-en-y gastric bypass or vertical sleeve gastrectomy in diet-induced obese rats. AB - Whereas the remodeling of intestinal mucosa after bariatric surgeries has been the matter of numerous studies to our knowledge, very few reported on the remodeling of the residual gastric mucosa. In this study, we analyzed remodeling of gastric mucosa after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) in rats. Diet-induced obese rats were subjected to RYGB, VSG or sham surgical procedures. All animals were assessed for food intake, body-weight, fasting blood, metabolites and hormones profiling, as well as insulin and glucose tolerance tests before and up to 5 weeks post-surgery. Remodeling of gastric tissues was analyzed by routine histology and immunohistochemistry studies, and qRT-PCR analyses of ghrelin and gastrin mRNA levels. In obese rats with impaired glucose tolerance, VSG and RYGB caused substantial weight loss and rats greatly improved their oral glucose tolerance. The remaining gastric mucosa after VSG and gastric pouch (GP) after RYGB revealed a hyperplasia of the mucous neck cells that displayed a strong immunoreactivity for parietal cell H+/K+-ATPase. Ghrelin mRNA levels were reduced by 2-fold in remaining fundic mucosa after VSG and 10 fold in GP after RYGB. In the antrum, gastrin mRNA levels were reduced after VSG in line with the reduced number of gastrin positive cells. This study reports novel and important observations dealing with the remaining gastric mucosa after RYGB and VSG. The data demonstrate, for the first time, a hyperplasia of the mucous neck cells, a transit cell population of the stomach bearing differentiating capacities into zymogenic and peptic cells. PMID- 25822174 TI - Correction: Tractography of the spider monkey (Ateles geoffroyi) corpus callosum using diffusion tensor magnetic resonance imaging. PMID- 25822175 TI - Development of a rapid, simple method for detecting Naegleria fowleri visually in water samples by loop-mediated isothermal amplification (LAMP). AB - Naegleria fowleri is the causative agent of the fatal disease primary amebic meningoencephalitis. Detection of N. fowleri using conventional culture and biochemical-based assays is time-consuming and laborious, while molecular techniques, such as PCR, require laboratory skills and expensive equipment. We developed and evaluated a novel loop-mediated isothermal amplification (LAMP) assay targeting the virulence-related gene for N. fowleri. Time to results is about 90 min and amplification products were easily detected visually using hydroxy naphthol blue. The LAMP was highly specific after testing against related microorganisms and able to detect one trophozoite, as determined with spiked water and cerebrospinal fluid samples. The assay was then evaluated with a set of 80 water samples collected during the flooding crisis in Thailand in 2011, and 30 natural water samples from border areas of northern, eastern, western, and southern Thailand. N. fowleri was detected in 13 and 10 samples using LAMP and PCR, respectively, with a Kappa coefficient of 0.855. To the best of our knowledge, this is the first report of a LAMP assay for N. fowleri. Due to its simplicity, speed, and high sensitivity, the LAMP method described here might be useful for quickly detecting and diagnosing N. fowleri in water and clinical samples, particularly in resource-poor settings. PMID- 25822177 TI - Bradykinin release avoids high molecular weight kininogen endocytosis. AB - Human H-kininogen (120 kDa) plays a role in many pathophysiological processes and interacts with the cell surface through protein receptors and proteoglycans, which mediate H-kininogen endocytosis. In the present work we demonstrate that H kininogen containing bradykinin domain is internalized and different endogenous kininogenases are present in CHO-K1 cells. We used CHO-K1 (wild type) and CHO-745 (mutant deficient in proteoglycans biosynthesis) cell lines. H-kininogen endocytosis was studied using confocal microscopy, and its hydrolysis by cell lysate fraction was determined by immunoblotting. Bradykinin release was also measured by radioimmunoassay. H-kininogen interaction with the cell surface of CHO-745 cells resulted in bradykinin release by serine proteases. In CHO-K1 cells, which produce heparan and chondroitin sulfate proteoglycans, internalization of H-kininogen through its bradykinin domain can occur on lipid raft domains/caveolae. Nevertheless bradykinin-free H-kininogen was not internalized by CHO-K1 cells. The H-kininogen present in acidic endosomal vesicles in CHO-K1 was approximately 10-fold higher than the levels in CHO-745. CHO-K1 lysate fractions were assayed at pH 5.5 and intact H-kininogen was totally hydrolyzed into a 62 kDa fragment. By contrast, at an assay pH 7.4, the remained fragments were 115 kDa, 83 kDa, 62 kDa and 48 kDa in size. The antipain-Sepharose chromatography separated endogenous kininogenases from CHO-K1 lysate fraction. No difference was detected in the assays at pH 5.5 or 7.4, but the proteins in the fraction bound to the resin released bradykinin from H-kininogen. However, the proteins in the unbound fraction cleaved intact H-kininogen at other sites but did not release bradykinin. H-kininogen can interact with extravascular cells, and is internalized dependent on its bradykinin domain and cell surface proteoglycans. After internalization, H-kininogen is proteolytically processed by intracellular kininogenases. The present data also demonstrates that serine or cysteine proteases in lipid raft domains/caveolae on the CHO cell can hydrolyze H kininogen, thus releasing kinins. PMID- 25822176 TI - Lower mutation frequency of BCP/precore regions in e antigen-negative chronic HBV infected children instead of adults patients. AB - To describe the Hepatitis B e antigen(HBeAg) seroconversion related mutation profiles of the basal core promoter(BCP)/precore regions in e antigen seroconverted child patients, a cohort of 245 child patients with CHB and a control patients group of 92 adult patients with CHB were recruited. The mutation frequencies of six nucleotides or nucleotide combinations including nucleotide (nt)1896, nt1762/1764, nt1752, nt1846, nt1899 and nt1753 showed significant differences between HBeAg positive and HBeAg-negative child patients groups. The frequencies of these HBeAg seroconversion-related mutations were significantly lower in HBeAg-negative children with CHB than in HBeAg-negative adults with CHB, especially for the mutation G1896A (41.1% vs 91.7%, P<0.001), and the average number of BCP/precore region mutations in samples from HBeAg-negative child patients was also obviously lower than in HBeAg-negative adult patients(3.62+/ 3.03 vs 4.89+/-2.09, P<0.001), suggesting less impact of mutations in the BCP/precore region on HBeAg seroconversion in child patients than adult patients. PMID- 25822179 TI - The Role of Ubiquitination in Regulation of Innate Immune Signaling. AB - Ubiquitination, also denoted ubiquitylation, is a posttranslational modification that has been implicated in the regulation of both innate and adaptive immune responses. Ubiquitination plays crucial roles in innate immune signaling by ensuring the proper orchestration of several signaling mediators that constitute a functional immune response. Herein, we briefly summarize the latest discoveries concerning the molecular ubiquitination-related machinery that senses, assembles, and disassembles innate immune signaling mediators. PMID- 25822178 TI - Dose-dependent dual role of PIT-1 (POU1F1) in somatolactotroph cell proliferation and apoptosis. AB - To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death. Expression of PIT271 induced a strong dose-dependent decrease of cell proliferation accompanied by a very pronounced cell death. These actions of PIT271 are independent of its interaction/competition with endogenous PIT-1, as they were unchanged when expression of endogenous PIT-1 was blocked. All these actions are specific for somatolactotroph cells, and could not be observed in heterologous cells. Cell death induced by PITWT or by PIT271 was accompanied by DNA fragmentation, but was not inhibited by inhibitors of caspases, autophagy or necrosis, suggesting that this cell death is a caspase-independent apoptosis. Altogether, our results indicate that under normal conditions PIT-1 is important for the maintenance of cell proliferation, while when expressed at supra-normal levels it induces cell death. Through this dual action, PIT-1 may play a role in the expansion/regression cycles of pituitary lactotroph population during and after lactation. Our results also demonstrate that the so-called "dominant-negative" action of PIT271 is independent of its competition with PIT-1 or a blockade of the actions of the latter, and are actions specific to this mutant variant of PIT 1. PMID- 25822180 TI - The role of psychological resilience and mTBI as predictors of postconcussional syndrome symptomatology. AB - OBJECTIVE: Resilience is 1 of several factors that are thought to contribute to outcome following mild traumatic brain injury (mTBI). This study explored the predictors of the postconcussional syndrome (PCS) symptoms that can occur following mTBI. We hypothesized that a reported recent mTBI and lower psychological resilience would predict worse reported PCS symptomatology. METHOD: 233 participants completed the Neurobehavioral Symptom Inventory (NSI) and the Brief Resilience Scale (BRS). Three NSI scores were used to define PCS symptomatology. A total of 35 participants reported an mTBI (as operationally defined by the World Health Organization) that was sustained between 1 and 6 months prior to their participation (positive mTBI history); the remainder reported having never had an mTBI. RESULTS: Regression analyses revealed that a positive reported recent mTBI history and lower psychological resilience were significant independent predictors of reported PCS symptomatology. These results were found for the 3 PCS scores from the NSI, including using a stringent caseness criterion, p < .05. Demographic variables (age and gender) were not related to outcome, with the exception of education in some analyses. CONCLUSION: The results demonstrate that: (a) both perceived psychological resilience and mTBI history play a role in whether or not PCS symptoms are experienced, even when demographic variables are considered, and (b) of these 2 variables, lower perceived psychological resilience was the strongest predictor of PCS-like symptomatology. PMID- 25822181 TI - Coping among individuals with multiple sclerosis: Evaluating a goodness-of-fit model. AB - OBJECTIVE: Multiple sclerosis (MS) is a chronic illness involving both controllable and uncontrollable stressors. The goodness-of-fit hypothesis posits that managing stressors effectively requires the use of different coping approaches in the face of controllable and uncontrollable stressors. To test the applicability of the goodness-of-fit model in a sample of adults with MS, we evaluated the ratio of 2 types of coping (an active problem-solving approach and an emotion-based meaning-focused approach) as a moderator of the relations between stress uncontrollability and mental health outcomes. METHODS: Participants were veterans with MS (N = 90) receiving medical services through the Veterans Health Administration who completed telephone-based interviews. Regression analyses tested the interaction of stress uncontrollability and the problem- and meaning-focused coping ratio on anxious and depressive symptoms. Significant interactions were probed at 1 SD above the mean of coping (use of predominantly problem-focused coping) and 1 SD below the mean of coping (use of predominantly meaning-focused coping). RESULTS: Findings largely supported the goodness-of-fit hypothesis. Anxiety and depressive symptoms were elevated when participants used more problem-focused strategies relative to meaning-focused strategies in the face of perceived uncontrollable stress. Conversely, symptoms of anxiety and depression were lower when uncontrollable stress was met with predominantly meaning-focused coping; however, the relations did not reach statistical significance. CONCLUSIONS: The impact of uncontrollable stressors on mental health outcomes for individuals with MS may vary depending on the degree to which problem-focused versus meaning-focused coping strategies are employed, lending support to the goodness-of-fit model. PMID- 25822182 TI - New toxicity mechanism of silver nanoparticles: promoting apoptosis and inhibiting proliferation. AB - Silver nanoparticles are increasingly recognized for their utility in biological applications, especially antibacterial effects. Herein, we confirmed the antibacterial effect of silver nanoparticles on Escherichia coli using the conventional optical density (OD) and colony-forming units (CFU) method and used flow cytometry (FC), TEM and BrdU ELISA to investigate the mechanisms of this effect. From the results, we conclude that AgNPs can simultaneously induce apoptosis and inhibit new DNA synthesis in the cells in a positive concentration dependent manner. This study presents the first induction of apoptosis in these bacteria by AgNPs in this field. Our findings may provide a new strategy for the use of silver nanoparticles in antibacterial applications. PMID- 25822183 TI - Biological, Serological, and Molecular Characterization of a Highly Divergent Strain of Grapevine leafroll-associated virus 4 Causing Grapevine Leafroll Disease. AB - The complete genome sequence of a highly divergent strain of Grapevine leafroll associated virus 4 (GLRaV-4) was determined using 454 pyrosequencing technology. This virus, designated GLRaV-4 Ob, was detected in Vitis vinifera 'Otcha bala' from our grapevine virus collection at Agroscope. The GLRaV-4 Ob genome length and organization share similarities with members of subgroup II in the genus Ampelovirus (family Closteroviridae). Otcha bala was graft-inoculated onto indicator plants of cultivar Gamay to evaluate the biological properties of this new strain, and typical leafroll symptoms were induced. A monoclonal antibody for the rapid detection of GLRaV-4 Ob by enzyme-linked immunosorbent assay is available, thus facilitating large-scale diagnostics of this virus. Based on the relatively small size of the coat protein, the reduced amino acid identity and the distinct serological properties, our study clearly shows that GLRaV-4 Ob is a divergent strain of GLRaV-4. Furthermore, molecular and serological data revealed that the AA42 accession from which GLRaV-7 was originally reported is in fact co infected with GLRaV-4 Ob and GLRaV-7. This finding challenges the idea that GLRaV 7 is a leafroll-causing agent. PMID- 25822184 TI - Predicting Cereal Root Disease in Western Australia Using Soil DNA and Environmental Parameters. AB - Root diseases have long been prevalent in Australian grain-growing regions, and most management decisions to reduce the risk of yield loss need to be implemented before the crop is sown. The levels of pathogens that cause the major root diseases can be measured using DNA-based services such as PreDicta B. Although these pathogens are often studied individually, in the field they often occur as mixed populations and their combined effect on crop production is likely to vary across diverse cropping environments. A 3-year survey was conducted covering most cropping regions in Western Australia, utilizing PreDicta B to determine soilborne pathogen levels and visual assessments to score root health and incidence of individual crop root diseases caused by the major root pathogens, including Rhizoctonia solani (anastomosis group [AG]-8), Gaeumannomyces graminis var. tritici (take-all), Fusarium pseudograminearum, and Pratylenchus spp. (root lesion nematodes) on wheat roots for 115, 50, and 94 fields during 2010, 2011, and 2012, respectively. A predictive model was developed for root health utilizing autumn and summer rainfall and soil temperature parameters. The model showed that pathogen DNA explained 16, 5, and 2% of the variation in root health whereas environmental parameters explained 22, 11, and 1% of the variation in 2010, 2011, and 2012, respectively. Results showed that R. solani AG-8 soil pathogen DNA, environmental soil temperature, and rainfall parameters explained most of the variation in the root health. This research shows that interactions between environment and pathogen levels before seeding can be utilized in predictive models to improve assessment of risk from root diseases to assist growers to plan more profitable cropping programs. PMID- 25822186 TI - Winter Conditions Correlate with Phytophthora alni Subspecies Distribution in Southern Sweden. AB - During the last century, the number of forest pathogen invasions has increased substantially. Environmental variables can play a crucial role in determining the establishment of invasive species. The objective of the present work was to determine the correlation between winter climatic conditions and distribution of two subspecies of the invasive forest pathogen Phytophthora alni: P. alni subspp. alni and uniformis killing black alder (Alnus glutinosa) in southern Sweden. It is known from laboratory experiments that P. alni subsp. alni is more pathogenic than P. alni subsp. uniformis, and that P. alni subsp. alni is sensitive to low temperatures and long frost periods. By studying the distribution of these two subspecies at the northern limit of the host species, we could investigate whether winter conditions can affect the geographical distribution of P. alni subsp. alni spreading northward. Sixteen major river systems of southern Sweden were systematically surveyed and isolations were performed from active cankers. The distribution of the two studied subspecies was highly correlated with winter temperature and duration of periods with heavy frost. While P. alni subsp. uniformis covered the whole range of temperatures of the host, P. alni subsp. alni was recovered in areas subjected to milder winter temperatures and shorter frost periods. Our observations suggest that winter conditions can play an important role in limiting P. alni subsp. alni establishment in cold locations, thus affecting the distribution of the different subspecies of P. alni in boreal regions. PMID- 25822185 TI - Maize Lethal Necrosis (MLN), an Emerging Threat to Maize-Based Food Security in Sub-Saharan Africa. AB - In sub-Saharan Africa, maize is a staple food and key determinant of food security for smallholder farming communities. Pest and disease outbreaks are key constraints to maize productivity. In September 2011, a serious disease outbreak, later diagnosed as maize lethal necrosis (MLN), was reported on maize in Kenya. The disease has since been confirmed in Rwanda and the Democratic Republic of Congo, and similar symptoms have been reported in Tanzania, Uganda, South Sudan, and Ethiopia. In 2012, yield losses of up to 90% resulted in an estimated grain loss of 126,000 metric tons valued at $52 million in Kenya alone. In eastern Africa, MLN was found to result from coinfection of maize with Maize chlorotic mottle virus (MCMV) and Sugarcane mosaic virus (SCMV), although MCMV alone appears to cause significant crop losses. We summarize here the results of collaborative research undertaken to understand the biology and epidemiology of MLN in East Africa and to develop disease management strategies, including identification of MLN-tolerant maize germplasm. We discuss recent progress, identify major issues requiring further research, and discuss the possible next steps for effective management of MLN. PMID- 25822187 TI - Species or Genotypes? Reassessment of Four Recently Described Species of the Ceratocystis Wilt Pathogen, Ceratocystis fimbriata, on Mangifera indica. AB - Ceratocystis wilt is among the most important diseases on mango (Mangifera indica) in Brazil, Oman, and Pakistan. The causal agent was originally identified in Brazil as Ceratocystis fimbriata, which is considered by some as a complex of many cryptic species, and four new species on mango trees were distinguished from C. fimbriata based on variation in internal transcribed spacer sequences. In the present study, phylogenetic analyses using DNA sequences of mating type genes, TEF-1alpha, and beta-tubulin failed to identify lineages corresponding to the four new species names. Further, mating experiments found that the mango isolates representing the new species were interfertile with each other and a tester strain from sweet potato (Ipomoea batatas), on which the name C. fimbriata is based, and there was little morphological variation among the mango isolates. Microsatellite markers found substantial differentiation among mango isolates at the regional and population levels, but certain microsatellite genotypes were commonly found in multiple populations, suggesting that these genotypes had been disseminated in infected nursery stock. The most common microsatellite genotypes corresponded to the four recently named species (C. manginecans, C. acaciivora, C. mangicola, and C. mangivora), which are considered synonyms of C. fimbriata. This study points to the potential problems of naming new species based on introduced genotypes of a pathogen, the value of an understanding of natural variation within and among populations, and the importance of phenotype in delimiting species. PMID- 25822188 TI - Genomes of 'Candidatus Liberibacter solanacearum' Haplotype A from New Zealand and the United States Suggest Significant Genome Plasticity in the Species. AB - 'Candidatus Liberibacter solanacearum' contains two solanaceous crop-infecting haplotypes, A and B. Two haplotype A draft genomes were assembled and compared with ZC1 (haplotype B), revealing inversion and relocation genomic rearrangements, numerous single-nucleotide polymorphisms, and differences in phage-related regions. Differences in prophage location and sequence were seen both within and between haplotype comparisons. OrthoMCL and BLAST analyses identified 46 putative coding sequences present in haplotype A that were not present in haplotype B. Thirty-eight of these loci were not found in sequences from other Liberibacter spp. Quantitative polymerase chain reaction (qPCR) assays designed to amplify sequences from 15 of these loci were screened against a panel of 'Ca. L. solanacearum'-positive samples to investigate genetic diversity. Seven of the assays demonstrated within-haplotype diversity; five failed to amplify loci in at least one haplotype A sample while three assays produced amplicons from some haplotype B samples. Eight of the loci assays showed consistent A-B differentiation. Differences in genome arrangements, prophage, and qPCR results suggesting locus diversity within the haplotypes provide more evidence for genetic complexity in this emerging bacterial species. PMID- 25822189 TI - Population Structure, Pathogenicity, and Mating Type Distribution of Magnaporthe oryzae Isolates from East Africa. AB - Rice blast, caused by Magnaporthe oryzae, is one of the emergent threats to rice production in East Africa (EA), where little is known about the population genetics and pathogenicity of this pathogen. We investigated the genetic diversity and mating type (MAT) distribution of 88 isolates of M. oryzae from EA and representative isolates from West Africa (WA) and the Philippines (Asia) using amplified fragment length polymorphism markers and mating-type-specific primer sets. In addition, the aggressiveness of each isolate was evaluated by inoculating on the susceptible Oryza sativa indica 'Co39', scoring the disease severity and calculating the disease progress. Hierarchical analysis of molecular variance revealed a low level of genetic differentiation at two levels (FST 0.12 and FCT 0.11). No evidence of population structure was found among the 65 isolates from EA, and gene flow among EA populations was high. Moreover, pairwise population differentiation (GST) in EA populations ranged from 0.03 to 0.04, suggesting that >96% of genetic variation is derived from within populations. However, the populations from Asia and WA were moderately differentiated from EA ones. The spatial analysis of principal coordinates and STRUCTURE revealed overlapping between individual M. oryzae isolates from EA, with limited distinctness according to the geographic origin. All the populations were clonal, given the positive and significant index of association (IA) and standardized index of association (rd), which indicates a significant (P<0.001) departure from panmixia (IA and rd=0). Both MAT1-1 and MAT1-2 were detected. However, MAT1-1 was more prevalent than MAT1-2. Pathogenicity analysis revealed variability in aggressiveness, suggesting a potential existence of different races. Our data suggest that either M. oryzae populations from EA could be distributed as a single genetic population or gene flow is exerting a significant influence, effectively swamping the action of selection. This is the first study of genetic differentiation of rice-infecting M. oryzae strains from EA, and may guide further studies on the pathogen as well as resistance breeding efforts. PMID- 25822191 TI - Synthesis, Photophysical and Redox Properties of the D-pi-A Type Pyrimidine Dyes Bearing the 9-Phenyl-9H-Carbazole Moiety. AB - Novel donor-pi-acceptor dyes bearing the pyrimidine unit as an electron withdrawing group have been synthesized by using combination of two processes, based on the microwave-assisted Suzuki cross-coupling reaction and nucleophilic aromatic substitution of hydrogen. Spectral properties of the obtained dyes in six aprotic solvents of various polarities have been studied by ultraviolet visible and fluorescence spectroscopy. In contrast to the absorption spectra, fluorescence emission spectra displayed a strong dependence from their solvent polarities. The nature of the observed long wavelength maxima has been elucidated by means of quantum chemical calculations. The electrochemical properties of these dyes have been investigated by using cyclic voltammetry, while their photovoltaic performance was evaluated by a device fabrication study. The experimental and calculation data show that all of the dyes can be regarded as potentially good photosensitizers for dye-sensitized solar cells. PMID- 25822190 TI - Highly Selective and Sensitive Detection of Hg(II) from HgCl2 by a Simple Rhodamine-Based Fluorescent Sensor. AB - N-acryloyl rhodamine B hydrazide, a non-responsive control of a colorimetric Cu(2+) sensor, was used as a turn-on fluorescent sensor for Hg(II) from HgCl2 in the presence of AgNO3. The detection was highly selective and sensitive, and a large number of environmentally and biologically relevant metal ions, such as Na(+), K(+), Ca(2+), Mg(2+), Fe(3+), Cu(2+), Zn(2+), Cr(3+), Pb(2+), Ni(2+), Fe(2+), Mn(2+), Co(2+), Cd(2+), including Hg(II) from the easy dissociated salts, did not show significant interference. The fluorescence of the sensor (10 MUM) was enhanced 74 folds by 10 equiv. of Hg(II) from HgCl2 in THF/HAc-NaAc (1/1, v/v, pH = 6) aqueous buffer solution containing 20 equiv. of AgNO3. The maximal fluorescence intensity increased linearly with the concentration of Hg(II) in the range of 0-70 MUM. The detection limit of Hg(II) was 0.59 MUM. The sensing mechanism was explored by Job's plot experiment, reversible experiment, mass spectrum analysis, spectroscopic analysis, and thin-layer chromatography. PMID- 25822192 TI - Correction: Sensitivity of genome-wide-association signals to phenotyping strategy: the PROP-TAS2R38 taste association as a benchmark. PMID- 25822193 TI - Genomic DNA hypomethylation is associated with neural tube defects induced by methotrexate inhibition of folate metabolism. AB - DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5 formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs. PMID- 25822194 TI - Inhibition of telomere recombination by inactivation of KEOPS subunit Cgi121 promotes cell longevity. AB - DNA double strand break (DSB) is one of the major damages that cause genome instability and cellular aging. The homologous recombination (HR)-mediated repair of DSBs plays an essential role in assurance of genome stability and cell longevity. Telomeres resemble DSBs and are competent for HR. Here we show that in budding yeast Saccharomyces cerevisiae telomere recombination elicits genome instability and accelerates cellular aging. Inactivation of KEOPS subunit Cgi121 specifically inhibits telomere recombination, and significantly extends cell longevity in both telomerase-positive and pre-senescing telomerase-negative cells. Deletion of CGI121 in the short-lived yku80(tel) mutant restores lifespan to cgi121Delta level, supporting the function of Cgi121 in telomeric single stranded DNA generation and thus in promotion of telomere recombination. Strikingly, inhibition of telomere recombination is able to further slow down the aging process in long-lived fob1Delta cells, in which rDNA recombination is restrained. Our study indicates that HR activity at telomeres interferes with telomerase to pose a negative impact on cellular longevity. PMID- 25822195 TI - Functional lung MRI in chronic obstructive pulmonary disease: comparison of T1 mapping, oxygen-enhanced T1 mapping and dynamic contrast enhanced perfusion. AB - PURPOSE: Monitoring of regional lung function in interventional COPD trials requires alternative endpoints beyond global parameters such as FEV1. T1 relaxation times of the lung might allow to draw conclusions on tissue composition, blood volume and oxygen fraction. The aim of this study was to evaluate the potential value of lung Magnetic resonance imaging (MRI) with native and oxygen-enhanced T1 mapping for the assessment of COPD patients in comparison with contrast enhanced perfusion MRI. MATERIALS AND METHODS: 20 COPD patients (GOLD I-IV) underwent a coronal 2-dimensional inversion recovery snapshot flash sequence (8 slices/lung) at room air and during inhalation of pure oxygen, as well as dynamic contrast-enhanced first-pass perfusion imaging. Regional distribution of T1 at room air (T1), oxygen-induced T1 shortening (DeltaT1) and peak enhancement were rated by 2 chest radiologists in consensus using a semi quantitative 3-point scale in a zone-based approach. RESULTS: Abnormal T1 and DeltaT1 were highly prevalent in the patient cohort. T1 and DeltaT1 correlated positively with perfusion abnormalities (r = 0.81 and r = 0.80; p&0.001), and with each other (r = 0.80; p<0.001). In GOLD stages I and II DeltaT1 was normal in 16/29 lung zones with mildly abnormal perfusion (15/16 with abnormal T1). The extent of T1 (r = 0.45; p<0.05), DeltaT1 (r = 0.52; p<0.05) and perfusion abnormalities (r = 0.52; p<0.05) showed a moderate correlation with GOLD stage. CONCLUSION: Native and oxygen-enhanced T1 mapping correlated with lung perfusion deficits and severity of COPD. Under the assumption that T1 at room air correlates with the regional pulmonary blood pool and that oxygen-enhanced T1 reflects lung ventilation, both techniques in combination are principally suitable to characterize ventilation-perfusion imbalance. This appears valuable for the assessment of regional lung characteristics in COPD trials without administration of i.v. contrast. PMID- 25822196 TI - Defining the catalytic activity of nanoceria in the P23H-1 rat, a photoreceptor degeneration model. AB - PURPOSE: Inorganic catalytic nanoceria or cerium oxide nanoparticles (CeNPs) are bona fide antioxidants that possess regenerative radical scavenging activities in vitro. Previously, we demonstrated that CeNPs had neuroprotective and anti angiogenic properties in rodent retinal degeneration and neovascularization models. However, the cellular mechanisms and duration of the catalytic activity of CeNPs in preventing photoreceptor cell loss are still unknown. In this study, we sought to answer these questions using the P23H-1 rat, an autosomal dominant retinitis pigmentosa (adRP) model. METHODS: A single dose of either saline or CeNPs was delivered intravitreally into the eyes of P23H-1 rats at 2-3 weeks of age. Retinal functions were examined at 3 to 7 weeks post injection. We quantified retinal proteins by Western blot analyses and counted the number of apoptotic (TUNEL+) profiles in the outer nuclear layer (ONL) of retinal sections. We measured free 8-isoprostanes to quantify lipid peroxidation in retinal tissues. RESULTS: We observed increased rod and cone cell functions up to three weeks post injection. Apoptotic cells were reduced by 46%, 56%, 21%, and 24% at 3, 7, 14, 21 days, respectively, after CeNPs injection compared to saline. Additionally, reduction of lipid peroxidation in the retinas of CeNPs-treated vs saline-treated animals was detected 14 days post injection. CONCLUSIONS: We validated that CeNPs were effective in delaying loss of photoreceptor cell function in an adRP rat model. This represents the fourth rodent retinal disease model that shows delay in disease progression after a single application of CeNPs. We further demonstrated that CeNPs slowed the rate of photoreceptor cell death. We deduced that the catalytic activity of CeNPs in vivo in this rat model to be undiminished for at least 7 days and then declined over the next 14 days after CeNPs administration. PMID- 25822197 TI - Early functional postoperative therapy of distal radius fracture with a dynamic orthosis: results of a prospective randomized cross-over comparative study. AB - INTRODUCTION: This study was conducted according to GCP criteria as a prospective randomized cross-over study. The primary goal of the study was to determine clinical findings and patient satisfaction with postoperative treatment. 29 patients with a distal radius fracture that was surgically stabilized from volar and who met the inclusion criteria were enrolled over a 12-month period. Each patient randomly received either a dorsal plaster splint or a vacuum-fit flexible but blocked orthosis applied postoperatively in the operating theatre to achieve postoperative immobilization. After one week all patients were crossed over to the complementary device maintaining the immobilization until end of week 2. After week 2 both groups were allowed to exercise wrist mobility with a physiotherapist, in the orthosis group the device was deblocked, thus allowing limited wrist mobility. After week 4 the devices were removed in both groups. Follow-up exams were performed after postoperative weeks 1, 2, 4 and 12. RESULTS AND DISCUSSION: Results were determined after week 1 and 2 using SF 36 and a personally compiled questionnaire; after weeks 4 and 12 with a clinical check-up, calculation of ROM and the DASH Score. Comparison of the two groups showed a significant difference in ROM for volar flexion after 4 weeks, but no significant differences in DASH Score, duration of disability or x-ray findings. With regard to satisfaction with comfort and hygiene, patients were significantly more satisfied with the dynamic orthosis, and 23 of the 29 patients would prefer the flexible vacuum orthosis in future. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00006097. PMID- 25822198 TI - Ligand-enabled cross-coupling of C(sp(3))-H bonds with arylsilanes. AB - Pd(II)-catalyzed cross-coupling of C(sp(3))-H bonds with organosilicon coupling partners has been achieved for the first time. The use of a newly developed quinoline-based ligand is essential for the cross-coupling reactions to proceed. PMID- 25822200 TI - Heavy metals in wild marine fish from South China Sea: levels, tissue- and species-specific accumulation and potential risk to humans. AB - Heavy metal pollution in marine fish has become an important worldwide concern, not only because of the threat to fish in general, but also due to human health risks associated with fish consumption. To investigate the occurrence of heavy metals in marine fish species from the South China Sea, 14 fish species were collected along the coastline of Hainan China during the spring of 2012 and examined for species- and tissue-specific accumulation. The median concentrations of Cd, Cr, Cu, Zn, Pb and As in muscle tissue of the examined fish species were not detectable (ND), 2.02, 0.24, 2.64, 0.025, and 1.13 mg kg(-1) wet weight, respectively. Levels of Cu, Zn, Cd and Cr were found to be higher in the liver and gills than in muscle, while Pb was preferentially accumulated in the gills. Differing from other heavy metals, As did not exhibit tissue-specific accumulation. Inter-species differences of heavy metal accumulation were attributed to the different habitat and diet characteristics of marine fish. Human dietary exposure assessment suggested that the amounts of both Cr and As in marine wild fish collected from the sites around Hainan, China were not compliant with the safety standard of less than 79.2 g d(-1) for wild marine fish set by the Joint FAO/WHO Expert Committee on Food Additives. Further research to identify the explicit sources of Cr and As in marine fish from South China Sea should be established. PMID- 25822199 TI - Transcriptomic profiling of Arabidopsis thaliana mutant pad2.1 in response to combined cold and osmotic stress. AB - The contribution of glutathione (GSH) in stress tolerance, defense response and antioxidant signaling is an established fact. In this study transcriptome analysis of pad2.1, an Arabidopsis thaliana mutant, after combined osmotic and cold stress treatment has been performed to explore the intricate position of GSH in the stress and defense signaling network in planta. Microarray data revealed the differential regulation of about 1674 genes in pad2.1 amongst which 973 and 701 were significantly up- and down-regulated respectively. Gene enrichment, functional pathway analysis by DAVID and MapMan analysis identified various stress and defense related genes viz. members of heat shock protein family, peptidyl prolyl isomerase (PPIase), thioredoxin peroxidase (TPX2), glutathione-S transferase (GST), NBS-LRR type resistance protein etc. as down-regulated. The expression pattern of the above mentioned stress and defense related genes and APETALA were also validated by comparative proteomic analysis of combined stress treated Col-0 and pad2.1. Functional annotation noted down-regulation of UDP glycosyl transferase, 4-coumarate CoA ligase 8, cinnamyl alcohol dehydrogenase 4 (CAD4), ACC synthase and ACC oxidase which are the important enzymes of phenylpropanoid, lignin and ethylene (ET) biosynthetic pathway respectively. Since the only difference between Col-0 (Wild type) and pad2.1 is the content of GSH, so, this study suggested that in addition to its association with specific stress responsive genes and proteins, GSH provides tolerance to plants by its involvement with phenylpropanoid, lignin and ET biosynthesis under stress conditions. PMID- 25822201 TI - Distribution, diversity and abundance of bacterial laccase-like genes in different particle size fractions of sediments in a subtropical mangrove ecosystem. AB - This study investigated the diversity and abundance of bacterial lacasse-like genes in different particle size fractions, namely sand, silt, and clay of sediments in a subtropical mangrove ecosystem. Moreover, the effects of nutrient conditions on bacterial laccase-like communities as well as the correlation between nutrients and, both the abundance and diversity indices of laccase-like bacteria in particle size fractions were also studied. Compared to bulk sediments, Bacteroidetes, Caldithrix, Cyanobacteria and Chloroflexi were dominated in all 3 particle-size fractions of intertidal sediment (IZ), but Actinobacteria and Firmicutes were lost after the fractionation procedures used. The diversity index of IZ fractions decreased in the order of bulk > clay > silt > sand. In fractions of mangrove forest sediment (MG), Verrucomicrobia was found in silt, and both Actinobacteria and Bacteroidetes appeared in clay, but no new species were found in sand. The declining order of diversity index in MG fractions was clay > silt > sand > bulk. Furthermore, the abundance of lacasse like bacteria varied with different particle-size fractions significantly (p < 0.05), and decreased in the order of sand > clay > silt in both IZ and MG fractions. Additionally, nutrient availability was found to significantly affect the diversity and community structure of laccase-like bacteria (p < 0.05), while the total organic carbon contents were positively related to the abundance of bacterial laccase-like genes in particle size fractions (p < 0.05). Therefore, this study further provides evidence that bacterial laccase plays a vital role in turnover of sediment organic matter and cycling of nutrients. PMID- 25822202 TI - Characterization and expression of genes involved in the ethylene biosynthesis and signal transduction during ripening of mulberry fruit. AB - Although ethylene is well known as an essential regulator of fruit development, little work has examined the role ethylene plays in the development and maturation of mulberry (Morus L.) fruit. To study the mechanism of ethylene action during fruit development in this species, we measured the ethylene production, fruit firmness, and soluble solids content (SSC) during fruit development and harvest. By comparing the results with those from other climacteric fruit, we concluded that Morus fruit are probably climacteric. Genes associated with the ethylene signal transduction pathway of Morus were characterized from M. notabilis Genome Database, including four ethylene receptor genes, a EIN2-like gene, a CTR1-like gene, four EIN3-like genes, and a RTE1-like gene. The expression patterns of these genes were analyzed in the fruit of M. atropurpurea cv. Jialing No.40. During fruit development, transcript levels of MaETR2, MaERS, MaEIN4, MaRTE, and MaCTR1 were lower at the early stages and higher after 26 days after full bloom (DAF), while MaETR1, MaEIL1, MaEIL2, and MaEIL3 remained constant. In ripening fruit, the transcripts of MaACO1 and MaACS3 increased, while MaACS1 and MaACO2 decreased after harvest. The transcripts of MaACO1, MaACO2, and MaACS3 were inhibited by ethylene, and 1-MCP (1 methylcyclopropene) upregulated MaACS3. The transcripts of the MaETR-like genes, MaRTE, and MaCTR1 were inhibited by ethylene and 1-MCP, suggesting that ethylene may accelerate the decline of MaETRs transcripts. No significant changes in the expression of MaEIN2, MaEIL1, and MaEIL3 were observed during ripening or in response to ethylene, while the expressions of MaEIL2 and MaEIL4 increased rapidly after 24 h after harvest (HAH) and were upregulated by ethylene. The present study provides insights into ethylene biosynthesis and signal transduction in Morus plants and lays a foundation for the further understanding of the mechanisms underlying Morus fruit development and ripening. PMID- 25822203 TI - Novel mechanism of arenavirus-induced liver pathology. AB - Viral hemorrhagic fevers (VHFs) encompass a group of diseases with cardinal symptoms of fever, hemorrhage, and shock. The liver is a critical mediator of VHF disease pathogenesis and high levels of ALT/AST transaminases in plasma correlate with poor prognosis. In fact, Lassa Fever (LF), the most prevalent VHF in Africa, was initially clinically described as hepatitis. Previous studies in non-human primate (NHP) models also correlated LF pathogenesis with a robust proliferative response in the liver. The purpose of the current study was to gain insight into the mechanism of liver injury and to determine the potential role of proliferation in LF pathogenesis. C57Bl/6J mice were infected with either the pathogenic (for NHPs) strain of lymphocytic choriomeningitis virus (LCMV, the prototypic arenavirus), LCMV-WE, or with the non-pathogenic strain, LCMV-ARM. As expected, LCMV-WE, but not ARM, caused a hepatitis-like infection. LCMV-WE also induced a robust increase in the number of actively cycling hepatocytes. Despite this increase in proliferation, there was no significant difference in liver size between LCMV-WE and LCMV-ARM, suggesting that cell cycle was incomplete. Indeed, cells appeared arrested in the G1 phase and LCMV-WE infection increased the number of hepatocytes that were simultaneously stained for proliferation and apoptosis. LCMV-WE infection also induced expression of a non-conventional virus receptor, AXL-1, from the TAM (TYRO3/AXL/MERTK) family of receptor tyrosine kinases and this expression correlated with proliferation. Taken together, these results shed new light on the mechanism of liver involvement in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation contributes to expansion of the infection to parenchymal cells. Elevated levels of plasma transaminases are likely explained, at least in part, by abortive cell cycle arrest induced by the infection. These results may lead to the development of new therapies to prevent VHF progression. PMID- 25822204 TI - Lower inter-partum interval and unhealthy life-style factors are inversely associated with n-3 essential fatty acids changes during pregnancy: a prospective cohort with Brazilian women. AB - OBJECTIVE: To analyze serum fatty acids concentrations during healthy pregnancy and evaluate whether socioeconomic, demographic, obstetric, nutritional, anthropometric and lifestyle factors are associated with their longitudinal changes. STUDY DESIGN: A prospective cohort of 225 pregnant women was followed in the 5th-13th, 20th-26th and 30th-36th weeks of gestation. Serum samples were collected in each trimester of pregnancy and analyzed to determine the fatty acids composition using a high-throughput robotic direct methylation method coupled with fast gas-liquid chromatography. The independent variables comprised the subjects' socioeconomic and demographic status, obstetric history, early pregnancy body mass index (BMI), dietary and lifestyle parameters. Analyses were performed using linear mixed-effects models. RESULTS: The overall absolute concentrations of fatty acids increased from the 1st to the 2nd trimester and slightly increased from the 2nd to the 3rd trimester. Early pregnancy BMI, inter partum interval and weekly fish intake were the factors associated with changes in eicosapentaenoic + docosahexaenoic acids (EPA+DHA) and total n-3 polyunsaturated fatty acids (PUFAs). Early pregnancy BMI, age and monthly per capita income were inversely associated with the changes in the n-6/n-3 ratio. Alcohol consumption was positively associated with the n-6/n-3 ratio. CONCLUSION: Early pregnancy BMI was positively associated with EPA+DHA and total n-3 PUFAs, while presenting a reduced weekly fish intake and a lower inter-partum interval were associated with lower levels of n-3 PUFAs. A lower per-capita family income and a drinking habit were factors that were positively associated with a higher n 6/n-3 ratio. PMID- 25822206 TI - On disaggregating between-person and within-person effects with longitudinal data using multilevel models. AB - This article extends current discussion of how to disaggregate between-person and within-person effects with longitudinal data using multilevel models. Our main focus is on the 2 issues of centering and detrending. Conceptual and analytical work demonstrates the similarities and differences among 3 centering approaches (no centering, grand-mean centering, and person-mean centering) and the relations and differences among various detrending approaches (no detrending, detrending X only, detrending Y only, and detrending both X and Y). Two real data analysis examples in psychology are provided to illustrate the differences in the results of using different centering and detrending methods for the disaggregation of between- and within-person effects. Simulation studies were conducted to further compare the various centering and detrending approaches under a wider span of conditions. Recommendations of how to perform centering, whether detrending is needed or not, and how to perform detrending if needed are made and discussed. PMID- 25822205 TI - Mutations of the SL2 dimerization sequence of the hepatitis C genome abrogate viral replication. AB - Stem-loop SL2 is a self-interacting palindromic sequence that has been identified within the hepatitis C virus genome (HCV). While, RNA dimerization of the HCV genome has been observed in vitro with short RNA sequences, the role of a putative RNA dimerization during viral replication has not been elucidated. To determine the effect of genomic dimerization on viral replication, we introduced mutations into SL2 predicted to disrupt genomic dimerization. Using surface plasmon resonance, we show that mutations within the SL2 bulge impact dimerization in vitro. Transfection of Huh7 cells with luciferase-encoding full length genomes containing SL2 mutations abolishes viral replication. Luciferase expression indicates that viral translation is not or slightly affected and that the viral RNA is properly encapsidated. However, RT-qPCR analysis demonstrates that viral RNA synthesis is drastically decreased. In vitro synthesis experiments using the viral recombinant polymerase show that modifications of intra-molecular interactions have no effect on RNA synthesis, while impairing inter-molecular interactions decreases polymerase activity. This confirms that dimeric templates are preferentially replicated by the viral polymerase. Altogether, these results indicate that the dimerization of the HCV genomic RNA is a crucial step for the viral life cycle especially for RNA replication. RNA dimerization could explain the existence of HCV recombinants in cell culture and patients reported recently in other studies. PMID- 25822207 TI - Meaningful aspects of change as novel random coefficients: a general method for reparameterizing longitudinal models. AB - A fundamental goal of longitudinal modeling is to obtain estimates of model parameters that reflect meaningful aspects of change over time. Often, a linear or nonlinear model may be sensible from a theoretical perspective, yet may have parameters that are difficult to interpret in a way that sheds light on substantive hypotheses. Fortunately, such models may be reparameterized to yield more easily interpretable parameters. This article has 3 goals. First, we provide theoretical background and elaboration on Preacher and Hancock's (2012) 4-step method for reparameterizing growth curve models. Second, we extend this method by providing a user-friendly modification of the structured latent curve model in the third step that enables fitting models that are not estimable with the original method. This modification also allows researchers to specify the mean structure without having to determine which parameters enter nonlinearly and without needing to solve complex matrix expressions. Third, we illustrate how this general reparameterization method allows researchers to treat the average rate of change, half-life, and knot (transition point) as random coefficients; these aspects of change have not before been treated as random coefficients in structural equation modeling. We supply Mplus code for illustrative examples in an online supplement. Our core message is that growth curve models are considerably more flexible than most researchers may suspect. Virtually any parameter can be treated as a random coefficient that varies across individuals. Alternative parameterizations of a given model may yield unique insights that are not available with traditional parameterizations. PMID- 25822208 TI - A critique of the cross-lagged panel model. AB - The cross-lagged panel model (CLPM) is believed by many to overcome the problems associated with the use of cross-lagged correlations as a way to study causal influences in longitudinal panel data. The current article, however, shows that if stability of constructs is to some extent of a trait-like, time-invariant nature, the autoregressive relationships of the CLPM fail to adequately account for this. As a result, the lagged parameters that are obtained with the CLPM do not represent the actual within-person relationships over time, and this may lead to erroneous conclusions regarding the presence, predominance, and sign of causal influences. In this article we present an alternative model that separates the within-person process from stable between-person differences through the inclusion of random intercepts, and we discuss how this model is related to existing structural equation models that include cross-lagged relationships. We derive the analytical relationship between the cross-lagged parameters from the CLPM and the alternative model, and use simulations to demonstrate the spurious results that may arise when using the CLPM to analyze data that include stable, trait-like individual differences. We also present a modeling strategy to avoid this pitfall and illustrate this using an empirical data set. The implications for both existing and future cross-lagged panel research are discussed. PMID- 25822210 TI - Correction to Imai et al. (2014). PMID- 25822209 TI - The cusp catastrophe model as cross-sectional and longitudinal mixture structural equation models. AB - Catastrophe theory (Thom, 1972, 1993) is the study of the many ways in which continuous changes in a system's parameters can result in discontinuous changes in 1 or several outcome variables of interest. Catastrophe theory-inspired models have been used to represent a variety of change phenomena in the realm of social and behavioral sciences. Despite their promise, widespread applications of catastrophe models have been impeded, in part, by difficulties in performing model fitting and model comparison procedures. We propose a new modeling framework for testing 1 kind of catastrophe model-the cusp catastrophe model-as a mixture structural equation model (MSEM) when cross-sectional data are available; or alternatively, as an MSEM with regime-switching (MSEM-RS) when longitudinal panel data are available. The proposed models and the advantages offered by this alternative modeling framework are illustrated using 2 empirical examples and a simulation study. PMID- 25822211 TI - Effect of ultrafiltration on sleep apnea and sleep structure in patients with end stage renal disease. AB - RATIONALE: In end-stage renal disease (ESRD), a condition characterized by fluid overload, both obstructive and central sleep apnea (OSA and CSA) are common. This observation suggests that fluid overload is involved in the pathogenesis of OSA and CSA in this condition. OBJECTIVES: To test the hypothesis that fluid removal by ultrafiltration (UF) will reduce severity of OSA and CSA in patients with ESRD. METHODS: At baseline, on a nondialysis day, patients with ESRD on thrice weekly hemodialysis underwent overnight polysomnography along with measurement of total body extracellular fluid volume (ECFV), and ECFV of the neck, thorax, and right leg before and after sleep. The following week, on a nondialysis day, subjects with an apnea-hypopnea index (AHI) greater than or equal to 20 had fluid removed by UF, followed by repeat overnight polysomnography with fluid measurements. MEASUREMENTS AND MAIN RESULTS: Fifteen patients (10 men) with an AHI greater than or equal to 20 (10 OSA; 5 CSA) participated. Mean age was 53.5 +/- 10.4 years and mean body mass index was 25.3 +/- 4.8 kg/m(2). Following removal of 2.17 +/- 0.45 L by UF, the AHI decreased by 36% (43.8 +/- 20.3 to 28.0 +/- 17.7; P < 0.001) without affecting uremia. The reduction in AHI correlated with the reduction in total body ECFV (r = 0.567; P = 0.027) and was associated with reductions in ECFV of the right leg (P = 0.001), overnight change in ECFV of the right leg (P = 0.044), ECFV of the thorax (P = 0.001), and ECFV of the neck (P = 0.003). CONCLUSIONS: These findings indicate that fluid overload contributes to the pathogenesis of OSA and CSA in ESRD, and that fluid removal by UF attenuates sleep apnea without altering uremic status. PMID- 25822212 TI - Bupropion injection resulting in tissue necrosis and psychosis: previously undocumented complications of intravenous bupropion use disorder. AB - INTRODUCTION: There have been several reports of bupropion insufflation since 2002 and 2 cases of intravenous bupropion use disorder since 2013. There are no documented cases of bupropion injection associated with tissue necrosis or psychosis. CASE PRESENTATION: We report 2 cases of habitual intravenous bupropion injection by individuals with polysubstance use disorder and comorbid mental illness. The patients obtained bupropion as a result of physician deception, diversion or crime, and injected it to achieve a high. Both individuals experienced tissue and vascular complications, including tissue necrosis, cellulitis, and compartment syndrome in 1 patient. The other patient reported visual hallucinations and persecutory ideation that persisted for 3 days after his last use of the drug. DISCUSSION: Bupropion seems to have addictive effects, particularly when administered intravenously or intranasally. Individuals who inject high doses of bupropion may be at risk of tissue necrosis, seizures, or psychosis. Prescribers should be aware of uncontrolled medications with emerging potential for abuse and popularity among recreational drug users. We identify a need for policy on clinical strategies to minimize the abuse and diversion of bupropion and other uncontrolled prescription drugs. PMID- 25822213 TI - Abuse and Intentional Misuse of Promethazine Reported to US Poison Centers: 2002 to 2012. AB - OBJECTIVE: Promethazine abuse has been reported. The objective was to investigate promethazine abuse/misuse in the United States. METHODS: An 11-year retrospective review was conducted of promethazine abuse and intentional misuse cases without co-ingestants in persons 10 years and older reported to the National Poison Data System. Data were stratified by product (promethazine-alone [PA] or co formulation [PC]) and evaluated for demographics, toxicity, management sites, and outcomes. RESULTS: There were 354 single product abuse or misuse exposures-95 PA and 259 PC. Over the 11-year timeframe, the annual exposure rate per 100,000 population doubled. Exposures were most prevalent among 10 to 19 years old and young adults (20s), accounting for 69.5% of PA and 57.5% of PC cases. Clinical effects due to PA included drowsiness (43.2%), tachycardia (7.4%), agitation (13.7%), confusion (13.7%), slurred speech (12.6%), hallucinations (7.4%), dizziness (7.4%), and hypertension (5.3%). Drowsiness (53.4%) and tachycardia (20.8%) were more frequent with PC. There were significant differences between PA and PC in management site (P = 0.0078). Management sites for PA and PC, respectively, were emergency department (37.9%, 55.6%), non-health care facility (33.7%, 14.7%), critical care unit (8.4%, 11.2%), non-critical care unit (7.4%, 7.3%), psychiatry (2.1%, 4.2%), and other/unknown (10.5%, 7.0%). Outcomes for PA and PC, respectively, were no effect (21.0%, 12.4%), minor (58.9%, 53.7%), moderate (17.9%, 32.0%), and major effects (2.1%, 1.9%). CONCLUSIONS: Promethazine-alone abuse/misuse most frequently resulted in minor outcomes, and less than 20% required medical admission. Abuse/misuse of PC resulted in a higher frequency of health care facility treatment and a trend toward more moderate outcomes. These differences are most likely attributed to the co-formulate. PMID- 25822214 TI - A step forward in the understanding of prefrontal cortical functions. PMID- 25822215 TI - Dopaminergic modulation of synaptic plasticity in rat prefrontal neurons. AB - The prefrontal cortex (PFC) is thought to store the traces for a type of long term memory - the abstract memory that determines the temporal structure of behavior often termed a "rule" or "strategy". Long-term synaptic plasticity might serve as an underlying cellular mechanism for this type of memory. We therefore studied the induction of synaptic plasticity in rat PFC neurons, maintained in vitro, with special emphasis on the functionally important neuromodulator dopamine. First, the induction of long-term potentiation (LTP) was facilitated in the presence of tonic/background dopamine in the bath, and the dose-dependency of this background dopamine followed an "inverted-U" function, where too high or too low dopamine levels could not facilitate LTP. Second, the induction of long-term depression (LTD) by low-frequency stimuli appeared to be independent of background dopamine, but required endogenous, phasically-released dopamine during the stimuli. Blockade of dopamine receptors during the stimuli and exaggeration of the effect of this endogenously-released dopamine by inhibition of dopamine transporter activity both blocked LTD. Thus, LTD induction also followed an inverted-U function in its dopamine-dependency. We conclude that PFC synaptic plasticity is powerfully modulated by dopamine through inverted-U-shaped dose dependency. PMID- 25822216 TI - What can atypical language hemispheric specialization tell us about cognitive functions? AB - Recent studies have made substantial progress in understanding the interactions between cognitive functions, from language to cognitive control, attention, and memory. However, dissociating these functions has been hampered by the close proximity of regions involved, as in the case in the prefrontal and parietal cortex. In this article, we review a series of studies that investigated the relationship between language and other cognitive functions in an alternative way - by examining their functional (co-)lateralization. We argue that research on the hemispheric lateralization of language and its link with handedness can offer an appropriate starting-point to shed light on the relationships between different functions. Besides functional interactions, anatomical asymmetries in non-human primates and those underlying language in humans can provide unique information about cortical organization. Finally, some open questions and criteria are raised for an ideal theoretical model of the cortex based on hemispheric specialization. PMID- 25822217 TI - Prefrontal cortical alpha2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder. AB - Attention deficit and hyperactivity disorder (ADHD), a prevalent syndrome in children worldwide, is characterized by impulsivity, inappropriate inattention, and/or hyperactivity. It seriously afflicts cognitive development in childhood, and may lead to chronic under-achievement, academic failure, problematic peer relationships, and low self-esteem. There are at least three challenges for the treatment of ADHD. First, the neurobiological bases of its symptoms are still not clear. Second, the commonly prescribed medications, most showing short-term therapeutic efficacy but with a high risk of serious side-effects, are mainly based on a dopamine mechanism. Third, more novel and efficient animal models, especially in nonhuman primates, are required to accelerate the development of new medications. In this article, we review research progress in the related fields, focusing on our previous studies showing that blockade of prefrontal cortical alpha2A-adrenoceptors in monkeys produces almost all the typical behavioral symptoms of ADHD. PMID- 25822218 TI - Prefrontal dysfunction and a monkey model of schizophrenia. AB - The prefrontal cortex is implicated in cognitive functioning and schizophrenia. Prefrontal dysfunction is closely associated with the symptoms of schizophrenia. In addition to the features typical of schizophrenia, patients also present with aspects of cognitive disorders. Based on these relationships, a monkey model mimicking the cognitive symptoms of schizophrenia has been made using treatment with the non-specific competitive N-methyl-D-aspartate receptor antagonist, phencyclidine. The symptoms are ameliorated by atypical antipsychotic drugs such as clozapine. The beneficial effects of clozapine on behavioral impairment might be a specific indicator of schizophrenia-related cognitive impairment. PMID- 25822221 TI - Enhanced Hydrate Nucleation Near the Limit of Stability. AB - Clathrate hydrates are crystalline structures composed of small guest molecules trapped into cages formed by hydrogen-bonded water molecules. In hydrate nucleation, water and the guest molecules may stay in a metastable fluid mixture for a long period. Metastability is broken if the concentration of the guest is above certain limit. We perform molecular dynamics (MD) simulations of supersaturated water-propane solutions close to the limit of stability. We show that hydrate nucleation can be very fast in a very narrow range of composition at moderate temperatures. Propane density fluctuations near the fluid-fluid demixing are coupled with crystallization producing en- hanced nucleation rates. This is the first report of propane-hydrate nucleation by MD simulations. We observe motifs of the crystalline structure II in line with experiments and new hydrate cages not reported in the literature. Our study relates nucleation to the fluid fluid spinodal decomposition and demonstration that the enhanced nucleation phenomenon is more general than short range attractive interactions as suggested in nucleation of proteins. PMID- 25822220 TI - Endurance training inhibits insulin clearance and IDE expression in Swiss mice. AB - INTRODUCTION: Endurance training improves peripheral insulin sensitivity in the liver and the skeletal muscle, but the mechanism for this effect is poorly understood. Recently, it was proposed that insulin clearance plays a major role in both glucose homeostasis and insulin sensitivity. Therefore, our goal was to determine the mechanism by which endurance training improves insulin sensitivity and how it regulates insulin clearance in mice. METHODS: Mice were treadmill trained for 4 weeks at 70-80% of maximal oxygen consumption (VO2 max) for 60 min, 5 days a week. The glucose tolerance and the insulin resistance were determined using an IPGTT and an IPITT, respectively, and the insulin decay rate was calculated from the insulin clearance. Protein expression and phosphorylation in the liver and the skeletal muscle were ascertained by Western blot. RESULTS: Trained mice exhibited an increased VO2 max, time to exhaustion, glucose tolerance and insulin sensitivity. They had smaller fat pads and lower plasma concentrations of insulin and glucose. Endurance training inhibited insulin clearance and reduced expression of IDE in the liver, while also inhibiting insulin secretion by pancreatic islets. There was increased phosphorylation of both the canonical (IR-AKT) and the non-canonical (CaMKII-AMPK-ACC) insulin pathways in the liver of trained mice, whereas only the CaMKII-AMPK pathway was increased in the skeletal muscle. CONCLUSION: Endurance training improved glucose homeostasis not only by increasing peripheral insulin sensitivity but also by decreasing insulin clearance and reducing IDE expression in the liver. PMID- 25822222 TI - Single-donor granulocyte transfusions for improving the outcome of high-risk pediatric patients with known bacterial and fungal infections undergoing stem cell transplantation: a 10-year single-center experience. AB - Bacterial and fungal infections remain a significant cause of transplant-related mortality following allogeneic stem cell transplantation (SCT). Granulocyte transfusions (GTs) may reduce the neutropenic period after SCT and prevent further progression of the existing infection (that is, therapeutic GT) in addition to standard antibacterial and antifungal therapy. A retrospective analysis was performed on 28 consecutive pediatric SCT recipients who received at least one dose of GT between March 2003 and November 2013 at a single institution. All donors were conditioned with G-CSF+dexamethasone with harvest performed 12-18 h later. Indications for SCT were acute leukemia in 46% (13/28) and severe aplastic anemia in 21% (6/28). The main indications for GT were invasive fungal disease in 50%, bacterial infection in 21% and co-morbidities with predicted reduced tolerance to sepsis in 18% (5/28). The median number of GT was 6 (range 1-14) with a median dose of 3.56 * 10(10) granulocytes infused. The median increment in ANC was 1.06 * 10(9)/L and correlated with the granulocyte dose infused. Adverse reactions observed were mild and infrequent. Sixty-four percent of patients (18/28) are alive with only 2 of the 10 deaths being related to progression of infection. In addition there was a low overall incidence of grade 3-4 acute mucositis and a very low incidence (7%) of acute GvHD grade 3-4. Single-donor GTs afford protection to children undergoing SCT at additional risk of infection and may reduce the overall incidence of severe GvHD. PMID- 25822224 TI - Cardiac QTc interval characteristics before and after hematopoietic stem cell transplantation: an analysis of 995 consecutive patients at a single center. AB - Hematopoietic stem cell transplantation (HSCT) treats disorders affecting patients of all ages. We studied the rate-corrected cardiac QT interval (QTc) in 995 consecutive children and adults undergoing HSCT at the University of Minnesota. We sought to (1) describe QTc before and after HSCT; (2) describe the change in QTc after HSCT; (3) identify factors affecting QTc and its change; and (4) scrutinize an 'at risk' sub-cohort with a long QTc before HSCT. Pre HSCT: 952 (96%) patients had an evaluable electrocardiography (ECG); median QTc was 426 ms and depended upon disease necessitating transplant. Post HSCT: 506 (51%) patients had an evaluable ECG; median QTc was 441 ms. Intrapatient QTc change: 490 (49%) evaluable patients showed median QTc change (pre to post HSCT) of +16 ms (P<0.0001). At risk group: 68 patients were 'at risk' (long pre-HSCT QTc). In some, 'at-risk' status trended toward predictive of post-transplant nonrelapse mortality. QTc interval prolongation is evident in a large, diverse cohort undergoing HSCT at our institution. Prospective studies of this patient population may be warranted, particularly for 'at-risk' patients who demonstrate significant QTc prolongation both pre and post HSCT. PMID- 25822223 TI - Secondary solid cancer screening following hematopoietic cell transplantation. AB - Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients. PMID- 25822225 TI - Immortal person-time bias in the association between herpes zoster and survival following autologous stem cell transplantation. PMID- 25822226 TI - Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission. AB - Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups. PMID- 25822227 TI - Hematopoietic stem cell transplantation in relapsed ALK+ anaplastic large cell lymphoma in children and adolescents: a study on behalf of the SFCE and SFGM-TC. AB - Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a treatment option for relapsed anaplastic large cell lymphoma (ALCL) in children, but reports on its efficacy in this disease are still limited. We analyzed data concerning 34 patients under 18 years of age prospectively registered in the French SFGM-TC database, who had undergone an allo-SCT for the treatment of ALK+ ALCL between 1993 and 2011. At transplant, 28 patients (82.4%) were in CR, whereas 6 exhibited detectable disease. Conditioning regimens were mostly myelo ablative (n=31). With a median follow-up of 6 years, 5-year overall and event free survival rates were 70% (SE=8%) and 58% (SE=9%), respectively. The 5-year cumulative incidence of relapse and treatment-related mortality was 18% (SE=7%) and 24% (SE=8%), respectively. Six patients had relapsed (median time, 141 days (35-235)). A durable CR had been obtained in 4/6 patients after injection of donor lymphocytes (n=1) or vinblastine-corticosteroid therapy (n=3). Ten patients had died, eight due to transplant toxicity and two due to progressive disease. Allo-SCT is an efficient treatment for pediatric patients with high-risk relapsed ALK+ ALCL. However, the overall morbidity of allo-SCT raises questions about its place, given the efficacy of targeted agents currently under development in this disease. PMID- 25822228 TI - Adult non-cystic fibrosis bronchiectasis is characterised by airway luminal Th17 pathway activation. AB - BACKGROUND: Non-cystic fibrosis (CF) bronchiectasis is characterised by chronic airway infection and neutrophilic inflammation, which we hypothesised would be associated with Th17 pathway activation. METHODS: Th17 pathway cytokines were quantified in bronchoalveolar lavage fluid (BALF), and gene expression of IL-17A, IL-1beta, IL-8 and IL-23 determined from endobronchial biopsies (EBx) in 41 stable bronchiectasis subjects and 20 healthy controls. Relationships between IL 17A levels and infection status, important clinical measures and subsequent Pseudomonas aeruginosa infection were determined. RESULTS: BALF levels of all Th17 cytokines (median (IQR) pg/mL) were significantly higher in bronchiectasis than control subjects, including IL-17A (1.73 (1.19, 3.23) vs. 0.27 (0.24, 0.35), 95% CI 1.05 to 2.21, p<0.0001) and IL-23 (9.48 (4.79, 15.75) vs. 0.70 (0.43, 1.79), 95% CI 4.68 to 11.21, p<0.0001). However, BALF IL-17A levels were not associated with clinical measures or airway microbiology, nor predictive of subsequent P. aeruginosa infection. Furthermore, gene expression of IL-17A in bronchiectasis EBx did not differ from control. In contrast, gene expression (relative to medians of controls) in bronchiectasis EBx was significantly higher than control for IL1beta (4.12 (1.24, 8.05) vs 1 (0.13, 2.95), 95% CI 0.05 to 4.07, p = 0.04) and IL-8 (3.75 (1.64, 11.27) vs 1 (0.54, 3.89), 95% CI 0.32 to 4.87, p = 0.02) and BALF IL-8 and IL-1alpha levels showed significant relationships with clinical measures and airway microbiology. P. aeruginosa infection was associated with increased levels of IL-8 while Haemophilus influenzae was associated with increased IL-1alpha. CONCLUSIONS AND CLINICAL RELEVANCE: Established adult non-CF bronchiectasis is characterised by luminal Th17 pathway activation, however this pathway may be relatively less important than activation of non-antigen-specific innate neutrophilic immunity. PMID- 25822229 TI - Polysialylation of NCAM characterizes the proliferation period of contractile elements during postnatal development of the epididymis. AB - Polysialic acid (polySia) attached to the neural cell adhesion molecule (NCAM) regulates inter alia the proliferation and differentiation via the interactions with neurotrophins. Since in postnatal epididymis neurotrophins and their receptors like the Low-Affinity Nerve Growth Factor Receptor p75 and TrK B receptor are expressed, we wanted to analyze if the polysialylation of NCAM is also involved during the development of the epididymis. To this end, we monitored the developmental changes in the expression of the polysialyltransferases and NCAM polysialylation using murine epididymis at different time points during postnatal development. Our results revealed that during postnatal development of the epididymis both polysialyltransferases, ST8SiaII and ST8SiaIV, were expressed and that the expression levels dropped with increasing age. In agreement with the expression levels of the polysialyltransferases the highest content of polysialylated NCAM was present during the first 10 days after birth. Interestingly, proliferating smooth muscle cell populations prevalently expressed polysialylated NCAM. Furthermore, we observed that inverse to the decrease in polysialylation of smooth muscle cells a strong up-regulation of collagen takes place suggesting a functional relationship since collagen was recently described to induce the turnover of polysialylated NCAM via an induction of endocytosis in cellulo. The same time course of polySia and collagen synthesis was also observed in other regions of the male reproductive system e.g. vas deferens and tunica albuginea (testis). Together, we identified a spatio-temporal expression pattern of polySia-NCAM characterized by high proliferation rate of smooth muscle cells and low collagen content. PMID- 25822231 TI - Brachytherapy-based Accelerated Partial Breast Irradiation Provides Equivalent 10 Year Outcomes to Whole Breast Irradiation: A Matched-Pair Analysis. AB - INTRODUCTION: Although whole breast irradiation (WBI) represents the standard radiotherapy technique in breast conserving therapy, accelerated partial breast irradiation (APBI) has emerged as an option to reduce treatment duration with comparable clinical outcomes. The purpose of this analysis is to present long term clinical outcomes between WBI and APBI. METHODS: A total of 3009 patients were treated with breast conserving therapy at a single institution between 1980 and 2012. Among them, 2528 patients received WBI and 481 received APBI (interstitial or balloon based). A matched-pair analysis was performed with patients matched by age (+/-3 years), stage (T-stage vs. T1 vs. T2), and estrogen receptor status (+/-). All patients had a minimum of 12 months follow-up. A total of 274 matches (ratio 1:1) were made. RESULTS: No differences between groups were noted with respect to clinicopathologic features; WBI patients demonstrated a trend for slightly larger tumors (1.3 vs. 1.1 cm, P=0.06). At 10 years, no differences were noted with respect to rates of ipsilateral breast tumor recurrence (4% vs. 4%, P=0.11), regional recurrence (1% vs. 1%, P=0.20), contralateral breast failure (9% vs. 3%, P=0.06), or distant metastases (3% vs. 6%, P=0.47) for WBI and APBI, respectively. In addition, 10-year disease-free survival (93% vs. 91%, P=0.10) and overall survival (83% vs. 75%, P=0.34) were similar. Long-term cosmesis was good to excellent in 94% of WBI patients versus 95% of APBI patients (P=0.78). CONCLUSIONS: At 10 years, no differences in recurrence or survival were found between patients undergoing WBI or brachytherapy-based APBI. PMID- 25822230 TI - Selective microRNA-Offset RNA expression in human embryonic stem cells. AB - Small RNA molecules, including microRNAs (miRNAs), play critical roles in regulating pluripotency, proliferation and differentiation of embryonic stem cells. miRNA-offset RNAs (moRNAs) are similar in length to miRNAs, align to miRNA precursor (pre-miRNA) loci and are therefore believed to derive from processing of the pre-miRNA hairpin sequence. Recent next generation sequencing (NGS) studies have reported the presence of moRNAs in human neurons and cancer cells and in several tissues in mouse, including pluripotent stem cells. In order to gain additional knowledge about human moRNAs and their putative development related expression, we applied NGS of small RNAs in human embryonic stem cells (hESCs) and fibroblasts. We found that certain moRNA isoforms are notably expressed in hESCs from loci coding for stem cell-selective or cancer-related miRNA clusters. In contrast, we observed only sparse moRNAs in fibroblasts. Consistent with earlier findings, most of the observed moRNAs derived from conserved loci and their expression did not appear to correlate with the expression of the adjacent miRNAs. We provide here the first report of moRNAs in hESCs, and their expression profile in comparison to fibroblasts. Moreover, we expand the repertoire of hESC miRNAs. These findings provide an expansion on the known repertoire of small non-coding RNA contents in hESCs. PMID- 25822232 TI - Slr2019, lipid A transporter homolog, is essential for acidic tolerance in Synechocystis sp. PCC6803. AB - Living organisms must defend themselves against various environmental stresses. Extracellular polysaccharide-producing cells exhibit enhanced tolerance toward adverse environmental stress. In Synechocystis sp. PCC6803 (Synechocystis), lipopolysaccharide (LPS) may play a role in this protection. To examine the relationship between stress tolerance of Synechocystis and LPS, we focused on Slr2019 because Slr2019 is homologous to MsbA in Escherichia coli, which is related to LPS synthesis. First, to obtain a defective mutant of LPS, we constructed the slr2019 insertion mutant (slr2019) strain. Sodium deoxycholate polyacrylamide gel electrophoresis indicated that slr2019 strain did not synthesize normal LPS. Second, to clarify the participation of LPS in acid tolerance, wild type (WT) and slr2019 strain were grown under acid stress; slr2019 strain growth was significantly weaker than WT growth. Third, to examine influences on stress tolerance, slr2019 strain was grown under various stresses. Under salinity and temperature stress, slr2019 strain grew significantly slower than WT. To confirm cell morphology, cell shape and envelope of slr2019 strain were observed by transmission electron microscopy; slr2019 cells contained more electron-transparent bodies than WT cells. Finally, to confirm whether electron transparent bodies are poly-3-hydroxybutyrate (PHB), slr2019 strain was stained with Nile Blue A, a PHB detector, and observed by fluorescence microscopy. The PHB granule content ratio of WT and slr2019 strain grown at BG-11 pH 8.0 was each 7.18 and 8.41 %. At pH 6.0, the PHB granule content ratio of WT and slr2019 strain was 2.99 and 2.60 %. However, the PHB granule content ratio of WT and slr2019 strain grown at BG-11N-reduced was 10.82 and 0.56 %. Because slr2019 strain significantly decreased PHB under BG-11N-reduced compared with WT, LPS synthesis may be related to PHB under particular conditions. These results indicated that Slr2019 is necessary for Synechocystis survival in various stresses. PMID- 25822233 TI - Factors associated with participation in research conducted in a pediatric emergency department. AB - OBJECTIVE: To examine the association of demographic and study characteristics in eligible subjects who agree to participate compared with those who did not participate in clinical research studies in a pediatric emergency department (PED). METHODS: Information for all families approached for participation in PED based clinical research studies during a 6-year period was recorded in an electronic database. This included demographic factors, decision to participate, primary reason for not participating, and study characteristics. Forty studies were included in this analysis. Differences in participation rate among demographic and study characteristics were examined. Multivariable logistic regression was used to predict the likelihood of participation. RESULTS: Participation rates were similar with respect to sex (50.1% in male vs 49.9% in female), whereas families with younger children were more likely to participate (mean age, 8.5 years vs 10.2 years among nonparticipants P < 0.001). White patients were more likely to participate than African American patients (54.7% vs 45.6% in African Americans, P < 0.001). The presence of compensation, brief time requirement, and older children was negatively associated with participation for moderate to very invasive studies. However, for noninvasive and mildly invasive studies, the presence of compensation and the time required were not associated with participation. CONCLUSIONS: Study characteristics including invasiveness, time required of patients, and whether compensation is offered, along with demographic factors, influence participation in clinical studies conducted in the PED. When designing a research study in the PED, these, along with novel approaches to including all races and ethnicities in PED research, should be considered. PMID- 25822234 TI - Factors Influencing the Decision to Attend a Pediatric Emergency Department for Nonemergent Complaints. AB - OBJECTIVE: The objective of this study was to explore the factors associated with parents' decisions to bring their children to the pediatric emergency department (PED) for nonemergent concerns. METHODS: We conducted a cross-sectional survey at a tertiary-care, pediatric referral center emergency department. We surveyed caregivers of children triaged to low-acuity levels using the Pediatric Canadian Triage and Acuity Scale. We used descriptive statistics to report the proportion of patients who have a primary care physician, who attempted to contact any health care providers prior to coming to the PED, and other factors surrounding the decision to come to the PED. RESULTS: We approached 340 families, of which 300 were enrolled (uptake rate, 88.2%). We found that 32% (95% confidence interval, 0.26-0.37) attempted to contact another health care provider prior to coming to the PED, and 59% (95% confidence interval, 0.48-0.69) of those respondents were specifically instructed to come to the PED. The top 3 reasons for coming to the British Columbia Children's Hospital PED were (1) that it specializes in children, (2) child has medical issues previously managed at the same hospital, and (3) closest location to patient. CONCLUSIONS: Despite the majority of patients having a primary care physician, less than half of them actually contacted these providers (or another health care provider) before presenting to the PED for their nonurgent illness or injury. Of these, nearly two thirds were specifically instructed to come to the PED by the health care provider in the community. PMID- 25822235 TI - Empiric Antibiotics for Serious Bacterial Infection in Young Infants: Opportunities for Stewardship. AB - OBJECTIVES: To evaluate the causative agents of serious bacterial infection (SBI) in young infants and the optimal approach to empiric antibiotic therapy for infants with SBI. METHODS: From May 1, 2011, to December 1, 2013, pertinent clinical data were collected on previously well infants 60 days or younger with SBI as defined by a positive bacterial culture from a sterile site. Infants were identified by prospective surveillance of admissions and daily review of microbiology records. RESULTS: Two hundred sixty-five infants with SBI were identified. Mean age was 32 days (SD +/-16.6 days). Twenty-nine infants had meningitis, 66 had bacteremia (37 with concomitant urinary tract infection), and 170 had urinary tract infection alone. No methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus sp., or penicillin-resistant Streptococcus pneumoniae were identified. Four extended-spectrum beta-lactamase producing gram-negative bacilli were seen. Empiric therapy was ampicillin and gentamicin (n = 116, 44%) or third-generation cephalosporin based (n = 149, 56%). Ampicillin and gentamicin, with third-generation cephalosporins reserved for cases where meningitis is suspected, would have provided effective coverage for 98.5% of infants and unnecessarily broad therapy for 4.3%. Third-generation cephalosporins with ampicillin would have been effective for 98.5% of infants and unnecessarily broad for 83.8%. Third-generation cephalosporin monotherapy was less effective than either combination (P < 0.001). Fifty-seven percent of broad spectrum empiric therapy was continued despite culture results allowing de escalation. CONCLUSIONS: Ampicillin/gentamicin remains an effective empiric regimen for infants 60 days or younger with suspected SBI. Use of a third generation cephalosporin for suspected meningitis is appropriate, but cerebrospinal fluid must be obtained promptly to guide appropriate therapy. PMID- 25822237 TI - Protocol for Reducing Time to Antibiotics in Pediatric Patients Presenting to an Emergency Department With Fever and Neutropenia: Efficacy and Barriers. AB - OBJECTIVES: Patients with febrile neutropenia are at high risk of morbidity and mortality from infectious causes. Decreasing time to antibiotic (TTA) administration is associated with improved patient outcomes. We sought to reduce TTA for children presenting to the emergency department with fever and neutropenia. METHODS: In a prospective cohort study with historical comparison, TTA administration was evaluated in patients with neutropenia presenting to the Children's of Alabama Emergency Department. A protocol was established to reduce delays in antibiotic administration and increase the percentage of patients who receive treatment within 60 minutes of presentation. One hundred pre-protocol patient visits between August 2010 and December 2011 were evaluated and 153 post protocol visits were evaluated between August 2012 and September 2013. We reviewed individual cases to determine barriers to rapid antibiotic administration. RESULTS: Antibiotics were administered in 96.9 +/- 57.8 minutes in the pre-protocol patient group, and only 35% of patients received antibiotics within 60 minutes of presentation and 70% received antibiotics within 120 minutes. After implementation of the protocol, TTA for neutropenic patients was decreased to 64.3 +/- 28.4 minutes (P < 0.0001) with 51.4% receiving antibiotics within 60 minutes and 93.2% within 120 minutes. CONCLUSIONS: Implementing a standard approach to patients at risk for neutropenia decreased TTA. There are numerous challenges in providing timely antibiotics to children with febrile neutropenia. Identified delays included venous access (time to effect of topical anesthetics, and difficulty obtaining access), physicians waiting on laboratory results, and antibiotic availability. PMID- 25822236 TI - Blood Pressure Directed Booster Trainings Improve Intensive Care Unit Provider Retention of Excellent Cardiopulmonary Resuscitation Skills. AB - OBJECTIVES: Brief, intermittent cardiopulmonary resuscitation (CPR) training sessions, "Booster Trainings," improve CPR skill acquisition and short-term retention. The objective of this study was to incorporate arterial blood pressure (ABP) tracings into Booster Trainings to improve CPR skill retention. We hypothesized that ABP-directed CPR "Booster Trainings" would improve intensive care unit (ICU) provider 3-month retention of excellent CPR skills without need for interval retraining. METHODS: A CPR manikin creating a realistic relationship between chest compression depth and ABP was used for training/testing. Thirty-six ICU providers were randomized to brief, bedside ABP-directed CPR manikin skill retrainings: (1) Booster Plus (ABP visible during training and testing) versus (2) Booster Alone (ABP visible only during training, not testing) versus (3) control (testing, no intervention). Subjects completed skill tests pretraining (baseline), immediately after training (acquisition), and then retention was assessed at 12 hours, 3 and 6 months. The primary outcome was retention of excellent CPR skills at 3 months. Excellent CPR was defined as systolic blood pressure of 100 mm Hg or higher and compression rate 100 to 120 per minute. RESULTS: Overall, 14 of 24 (58%) participants acquired excellent CPR skills after their initial training (Booster Plus 75% vs 50% Booster Alone, P = 0.21). Adjusted for age, ABP-trained providers were 5.2* more likely to perform excellent CPR after the initial training (95% confidence interval [95% CI], 1.3 21.2; P = 0.02), and to retain these skills at 12 hours (adjusted odds ratio, 4.4; 95% CI, 1.3-14.9; P = 0.018) and 3 months (adjusted odds ratio, 4.1; 95% CI, 1.2-13.9; P = 0.023) when compared to baseline performance. CONCLUSIONS: The ABP directed CPR booster trainings improved ICU provider 3-month retention of excellent CPR skills without the need for interval retraining. PMID- 25822238 TI - Lack of Accuracy of Biomarkers and Physical Examination to Detect Bacterial Infection in Febrile Infants. AB - OBJECTIVES: The aim of this study was to analyze the usefulness of physical examination, C-reactive protein (CRP), procalcitonin (PCT), white blood cell (WBC) count, and absolute neutrophils counts (ANCs) for the diagnosis of invasive bacterial infections (IBIs) and potentially serious bacterial infections in infants younger than the age of 3 months presenting with fever without source (FWS) to the emergency department (ED). METHODS: A descriptive retrospective study that includes all infants aged younger than 3 months who presented with FWS to the ED between July 2008 and January 2012. We evaluated diagnostic performance for each test by receiver operating characteristic curve analysis. Sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were also calculated. RESULTS: Three hundred eighteen patients met the inclusion criteria. Eleven bacteremia (3.5%) and 76 urinary tract infections (23.9%) were diagnosed. To detect IBI, the areas under the curve for the different tests were as follows: PCT, 0.77 (95% confidence interval [CI], 0.57-0.96); CRP, 0.54 (95% CI, 0.36 0.73); ANC, 0.53 (95% CI, 0.34-0.71); and WBC, 0.42 (0.24-0.61). To detect potentially serious bacterial infections, the areas under the curve were as follows: PCT, 0.66 (95% CI, 0.59-0.74); CRP, 0.68 (0.60-0.76); ANC, 0.64 (0.56 0.71); and WBC, 0.66 (0.58-0.72). CONCLUSIONS: Procalcitonin is better than CRP, WBC, and ANC to confirm or dismiss the presence of an IBI in infants aged younger than 3 months presenting with FWS to the ED. However, it could not identify almost 30% of infants with IBI. Most patients diagnosed with IBI (10 of 11) presented abnormal values in at least one of the analytical parameters and/or physical appearance. Four of 5 patients with IBI and well appearing presented abnormal results in at least one of the analytical parameters. Therefore, the development of tools combining different tests including the new biomarkers could increase the reliability of the tests for the diagnosis of IBI in these patients. PMID- 25822240 TI - Correction: Cerebral circulation time is prolonged and not correlated with EDSS in multiple sclerosis patients: a study using digital subtracted angiography. PMID- 25822239 TI - Risk profiles for weight gain among postmenopausal women: a classification and regression tree analysis approach. AB - PURPOSE: Risk factors for obesity and weight gain are typically evaluated individually while "adjusting for" the influence of other confounding factors, and few studies, if any, have created risk profiles by clustering risk factors. We identified subgroups of postmenopausal women homogeneous in their clustered modifiable and non-modifiable risk factors for gaining >= 3% weight. METHODS: This study included 612 postmenopausal women 50-79 years old, enrolled in an ancillary study of the Women's Health Initiative Observational Study between February 1995 and July 1998. Classification and regression tree and stepwise regression models were built and compared. RESULTS: Of 27 selected variables, the factors significantly related to >= 3% weight gain were weight change in the past 2 years, age at menopause, dietary fiber, fat, alcohol intake, and smoking. In women younger than 65 years, less than 4 kg weight change in the past 2 years sufficiently reduced risk of >= 3% weight gain. Different combinations of risk factors related to weight gain were reported for subgroups of women: women 65 years or older (essential factor: < 9.8 g/day dietary factor), African Americans (essential factor: currently smoking), and white women (essential factor: >= 5 kg weight change for the past 2 years). CONCLUSIONS: Our findings suggest specific characteristics for particular subgroups of postmenopausal women that may be useful for identifying those at risk for weight gain. The study results may be useful for targeting efforts to promote strategies to reduce the risk of obesity and weight gain in subgroups of postmenopausal women and maximize the effect of weight control by decreasing obesity-relevant adverse health outcomes. PMID- 25822241 TI - A diary-based modification of symptom attributions in pathological health anxiety: effects on symptom report and cognitive biases. AB - OBJECTIVE: To examine whether a 2-week attribution modification training (AMT) changes symptom severity, emotional evaluation of health-threatening stimuli, and cognitive biases in pathological health anxiety. METHOD: We randomized 85 patients with pathological health anxiety into an electronic diary-based AMT group (AMTG; n = 42) and a control group without AMT (CG; n = 43). Self-report symptom measures, emotional evaluation, attentional bias, and memory bias toward symptom and illness words were assessed with an emotional Stroop task, a recognition task, and an emotional rating task for valence and arousal. RESULTS: After the 2-week period, the AMTG compared with the CG reported lower symptoms of pathological health anxiety, F(1, 82) = 10.94, p < .01, eta2p = .12, rated symptom, F(1, 82) = 5.56, p = .02, eta2p = .06, and illness words, F(1, 82) = 4.13, p = .045, eta2p = .05, as less arousing, and revealed a smaller memory response bias toward symptom words in the recognition task F(1, 82) = 12.32, p < .01, eta2p = .13. However, no specific AMT effect was observed for the attentional bias. CONCLUSION: The results support the efficacy of a comparatively short cognitive intervention in pathological health anxiety as a possible add-on intervention to existing treatment approaches to reduce symptom severity, as well as abnormalities in health-related emotional evaluation and memory processes. PMID- 25822242 TI - Randomized comparative efficacy study of parent-mediated interventions for toddlers with autism. AB - OBJECTIVE: This study compared effects of two parent-mediated interventions on joint engagement outcomes as augmentations of an early intervention program for toddlers with autism spectrum disorder (ASD). METHOD: Participants included 86 toddlers (range 22-36 months) with ASD and their primary caregiver. Caregiver child dyads were randomized to receive 10 weeks of hands-on parent training in a naturalistic, developmental behavioral intervention (joint attention, symbolic play, engagement and regulation-JASPER) or a parent-only psychoeducational intervention (PEI). Dose was controlled in terms of researcher-parent contact and early intervention services received by the child. RESULTS: Results yielded significant effects of the JASPER intervention on the primary outcome of joint engagement. The treatment effect was large (Cohen's f2 = .69) and maintained over the 6-month follow-up. JASPER effects were also found on secondary outcomes of play diversity, highest play level achieved, and generalization to the child's classroom for child-initiated joint engagement. The PEI intervention was found to be effective in reducing parenting stress associated with child characteristics. All secondary effects were generally small to moderate. CONCLUSIONS: These data highlight the benefit of a brief, targeted, parent-mediated intervention on child outcomes. Future studies may consider the combination of JASPER and PEI treatments for optimal parent and child outcomes. Trial registry no. NCT00999778. PMID- 25822243 TI - The sleeper effect: Artifact or phenomenon-A brief comment on Bell et al. (2013). AB - OBJECTIVE: Bell, Marcus, and Goodlad (2013) recently conducted a meta-analysis of randomized controlled additive trials and found that adding an additional component to an existing treatment vis-a-vis the existing treatment produced larger effect sizes on targeted outcomes at 6-months follow-up than at termination, an effect they labeled as a sleeper effect. One of the limitations with Bell et al.'s detection of the sleeper effect was that they did not conduct a statistical test of the size of the effect at follow-up versus termination. METHOD: To statistically test if the differences of effect sizes between the additive conditions and the control conditions at follow-up differed from those at termination, we used a restricted maximum-likelihood random-effect model with known variances to conduct a multilevel longitudinal meta-analysis (k = 30). RESULTS: Although the small effects at termination detected by Bell et al. were replicated (ds = 0.17-0.23), none of the analyses of growth from termination to follow-up produced statistically significant effects (ds < 0.08; p > .20), and when asymmetry was considered using trim-and-fill procedure or the studies after 2000 were analyzed, magnitude of the sleeper effect was negligible (d = 0.00). CONCLUSION: There is no empirical evidence to support the sleeper effect. (PsycINFO Database Record PMID- 25822245 TI - Mark-recapture and mark-resight methods for estimating abundance with remote cameras: a carnivore case study. AB - Abundance estimation of carnivore populations is difficult and has prompted the use of non-invasive detection methods, such as remotely-triggered cameras, to collect data. To analyze photo data, studies focusing on carnivores with unique pelage patterns have utilized a mark-recapture framework and studies of carnivores without unique pelage patterns have used a mark-resight framework. We compared mark-resight and mark-recapture estimation methods to estimate bobcat (Lynx rufus) population sizes, which motivated the development of a new "hybrid" mark-resight model as an alternative to traditional methods. We deployed a sampling grid of 30 cameras throughout the urban southern California study area. Additionally, we physically captured and marked a subset of the bobcat population with GPS telemetry collars. Since we could identify individual bobcats with photos of unique pelage patterns and a subset of the population was physically marked, we were able to use traditional mark-recapture and mark-resight methods, as well as the new "hybrid" mark-resight model we developed to estimate bobcat abundance. We recorded 109 bobcat photos during 4,669 camera nights and physically marked 27 bobcats with GPS telemetry collars. Abundance estimates produced by the traditional mark-recapture, traditional mark-resight, and "hybrid" mark-resight methods were similar, however precision differed depending on the models used. Traditional mark-recapture and mark-resight estimates were relatively imprecise with percent confidence interval lengths exceeding 100% of point estimates. Hybrid mark-resight models produced better precision with percent confidence intervals not exceeding 57%. The increased precision of the hybrid mark-resight method stems from utilizing the complete encounter histories of physically marked individuals (including those never detected by a camera trap) and the encounter histories of naturally marked individuals detected at camera traps. This new estimator may be particularly useful for estimating abundance of uniquely identifiable species that are difficult to sample using camera traps alone. PMID- 25822246 TI - Determinants of performance of health systems concerning maternal and child health: a global approach. AB - AIMS: To assess the association of social determinants on the performance of health systems around the world. METHODS: A transnational ecological study was conducted with an observation level focused on the country. In order to research on the strength of the association between the annual maternal and child mortality in 154 countries and social determinants: corruption, democratization, income inequality and cultural fragmentation, we used a mixed linear regression model for repeated measures with random intercepts and a conglomerate-based geographical analysis, between 2000 and 2010. RESULTS: Health determinants with a significant association on child mortality(<1year): higher access to water (betaa Quartile 4(Q4) vs Quartile 1(Q1) = -6,14; 95%CI: -11,63 to -0,73), sanitation systems, (Q4 vs Q1 = -25,58; 95%CI: -31,91 to -19,25), % measles vaccination coverage (Q4 vs Q1 = -7.35; 95%CI: -10,18 to -4,52), % of births attended by a healthcare professional (Q4 vs Q1 = -7,91; 95%CI: -11,36 to -4,52) and a % of the total health expenditure (Q3 vs Q1 = -2,85; 95%CI: -4,93 to -0,7). Ethnic fragmentation (Q4 vs Q1 = 9,93; 95%CI: -0.03 to 19.89) had a marginal effect. For child mortality<5 years, an association was found for these variables and democratization (not free vs free = 11,23; 95%CI: -0,82 to 23,29), out-of-pocket expenditure (Q1 vs Q4 = 17,71; 95%CI: 5,86 to 29,56). For MMR (Maternal mortality ratio), % of access to water for all the quartiles, % of access to sanitation systems, (Q3 vs Q1 = -171,15; 95%CI: -281,29 to -61), birth attention by a healthcare professional (Q4 vs Q1 = -231,23; 95%CI: -349,32 to -113,15), and having corrupt government (Q3 vs Q1 = 83,05; 95%CI: 33,10 to 133). CONCLUSIONS: Improving access to water and sanitation systems, decreasing corruption in the health sector must become priorities in health systems. The ethno-linguistic cultural fragmentation and the detriment of democracy turn out to be two factors related to health results. PMID- 25822247 TI - Correction: Rapid, accurate, and non-invasive measurement of zebrafish axial length and other eye dimensions using SD-OCT allows longitudinal analysis of myopia and emmetropization. AB - [This corrects the article DOI: 10.1371/journal.pone.0110699.]. PMID- 25822248 TI - Warm ischemic injury is reflected in the release of injury markers during cold preservation of the human liver. AB - BACKGROUND: Liver transplantation plays a pivotal role in the treatment of patients with end-stage liver disease. Despite excellent outcomes, the field is strained by a severe shortage of viable liver grafts. To meet high demands, attempts are made to increase the use of suboptimal livers by both pretransplant recovery and assessment of donor livers. Here we aim to assess hepatic injury in the measurement of routine markers in the post-ischemic flush effluent of discarded human liver with a wide warm ischemic range. METHODS: Six human livers discarded for transplantation with variable warm and cold ischemia times were flushed at the end of preservation. The liver grafts were flushed with NaCl or Lactated Ringer's, 2 L through the portal vein and 1 L through the hepatic artery. The vena caval effluent was sampled and analyzed for biochemical markers of injury; lactate dehydrogenase (LDH), alanine transaminase (ALT), and alkaline phosphatase (ALP). Liver tissue biopsies were analyzed for ATP content and histologically (H&E) examined. RESULTS: The duration of warm ischemia in the six livers correlated significantly to the concentration of LDH, ALT, and ALP in the effluent from the portal vein flush. No correlation was found with cold ischemia time. Tissue ATP content at the end of preservation correlated very strongly with the concentration of ALP in the arterial effluent (P<0.0007, R2 = 0.96). CONCLUSION: Biochemical injury markers released during the cold preservation period were reflective of the duration of warm ischemic injury sustained prior to release of the markers, as well as the hepatic energy status. As such, assessment of the flush effluent at the end of cold preservation may be a useful tool in evaluating suboptimal livers prior to transplantation, particularly in situations with undeterminable ischemic durations. PMID- 25822249 TI - Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008-2013: results from population-based surveillance. AB - BACKGROUND: Recent reports have demonstrated a decline in bacterial bloodstream infections (BSIs) following adherence to central line insertion practices; however, declines have been less evident for BSIs due to Candida species. METHODS: We conducted active, population-based laboratory surveillance for candidemia in metropolitan Atlanta, GA and Baltimore, MD over a 5-year period. We calculated annual candidemia incidence and antifungal drug resistance rates. RESULTS: We identified 3,848 candidemia cases from 2008-2013. Compared with 2008, candidemia incidence per 100,000 person-years decreased significantly by 2013 in both locations (GA: 14.1 to 9.5, p<0.001; MD: 30.9 to 14.4, p<0.001). A total of 3,255 cases (85%) had a central venous catheter (CVC) in place within 2 days before the BSI culture date. In both locations, the number of CVC-associated cases declined (GA: 473 to 294; MD: 384 to 151). Candida albicans (CA, 36%) and Candida glabrata (CG, 27%) were the most common species recovered. In both locations, the proportion of cases with fluconazole resistance decreased (GA: 8.0% to 7.1%, -10%; MD: 6.6% to 4.9%, -25%), while the proportion of cases with an isolate resistant to an echinocandin increased (GA: 1.2% to 2.9%, +147%; MD: 2.0% to 3.5%, +77%). Most (74%) echinocandin-resistant isolates were CG; 17 (<1%) isolates were resistant to both drug categories (multidrug resistant [MDR], 16/17 were CG). The proportion of CG cases with MDR Candida increased from 1.8% to 2.6%. CONCLUSIONS: We observed a significant decline in the incidence of candidemia over a five-year period, and increases in echinocandin-resistant and MDR Candida. Efforts to strengthen infection control practices may be preventing candidemia among high-risk patients. Further surveillance for resistant Candida is warranted. PMID- 25822250 TI - Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis. AB - The human helicase senataxin (SETX) has been linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2). Here we identified a role for SETX in controlling the antiviral response. Cells that had undergone depletion of SETX and SETX-deficient cells derived from patients with AOA2 had higher expression of antiviral mediators in response to infection than did wild-type cells. Mechanistically, we propose a model whereby SETX attenuates the activity of RNA polymerase II (RNAPII) at genes stimulated after a virus is sensed and thus controls the magnitude of the host response to pathogens and the biogenesis of various RNA viruses (e.g., influenza A virus and West Nile virus). Our data indicate a potentially causal link among inborn errors in SETX, susceptibility to infection and the development of neurologic disorders. PMID- 25822251 TI - E-cigarettes and smoking cessation: evidence from a systematic review and meta analysis. AB - BACKGROUND: E-cigarettes are currently being debated regarding their possible role in smoking cessation and as they are becoming increasingly popular, the research to date requires investigation. OBJECTIVES: To investigate whether the use of e-cigarettes is associated with smoking cessation or reduction, and whether there is any difference in efficacy of e-cigarettes with and without nicotine on smoking cessation. DATA SOURCES: A systematic review of articles with no limit on publication date was conducted by searching PubMed, Web of Knowledge and Scopus databases. METHODS: Published studies, those reported smoking abstinence or reduction in cigarette consumption after the use of e-cigarettes, were included. Studies were systematically reviewed, and meta-analyses were conducted using Mantel-Haenszel fixed-effect and random-effects models. Degree of heterogeneity among studies and quality of the selected studies were evaluated. RESULTS: Six studies were included involving 7,551 participants. Meta-analyses included 1,242 participants who had complete data on smoking cessation. Nicotine filled e-cigarettes were more effective for cessation than those without nicotine (pooled Risk Ratio 2.29, 95%CI 1.05-4.97). Amongst 1,242 smokers, 224 (18%) reported smoking cessation after using nicotine-enriched e-cigarettes for a minimum period of six months. Use of such e-cigarettes was positively associated with smoking cessation with a pooled Effect Size of 0.20 (95%CI 0.11-0.28). Use of e-cigarettes was also associated with a reduction in the number of cigarettes used. LIMITATIONS: Included studies were heterogeneous, due to different study designs and gender variation. Whilst we were able to comment on the efficacy of nicotine vs. non-nicotine e-cigarettes for smoking cessation, we were unable to comment on the efficacy of e-cigarettes vs. other interventions for cessation, given the lack of comparator groups in the studies included in this meta analysis. CONCLUSIONS: Use of e-cigarettes is associated with smoking cessation and reduction. More randomised controlled trials are needed to assess effectiveness against other cessation methods. PMID- 25822253 TI - Association of Adverse Pregnancy Outcomes With Glyburide vs Insulin in Women With Gestational Diabetes. AB - IMPORTANCE: Glyburide is thought to be safe for use during pregnancy for treatment of gestational diabetes mellitus (GDM). However, there are limited data on the effectiveness of glyburide when compared with insulin as used in a real world setting. OBJECTIVE: To estimate the risk of adverse maternal and neonatal outcomes in women with GDM treated with glyburide compared with insulin. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of a population-based cohort from a nationwide US employer-based insurance claims database from January 1, 2000, to December 31, 2011. We identified women with GDM and their newborns. We excluded those with type 1 or 2 diabetes and those younger than 15 years or older than 45 years. EXPOSURES: Treatment with glyburide or insulin during pregnancy within 150 days before delivery. MAIN OUTCOMES AND MEASURES: We used binomial regression to estimate risk ratios (RRs) and risk differences with 95% confidence intervals for the association of glyburide with diagnosis codes for obstetric trauma, cesarean delivery, birth injury, preterm birth, hypoglycemia, respiratory distress, jaundice, large for gestational age, and hospitalization in the neonatal intensive care unit. Inverse probability of treatment weights were used to adjust for maternal characteristics that differed between the treatment groups. RESULTS: Among 110,879 women with GDM, 9173 women (8.3%) were treated with glyburide (n = 4982) or insulin (n = 4191). After adjusting for differences at baseline, newborns of women treated with glyburide were at increased risk for neonatal intensive care unit admission (RR = 1.41; 95% CI, 1.23-1.62), respiratory distress (RR = 1.63; 95% CI, 1.23-2.15), hypoglycemia (RR = 1.40; 95% CI, 1.00-1.95), birth injury (RR = 1.35; 95% CI, 1.00-1.82), and large for gestational age (RR = 1.43; 95% CI, 1.16-1.76) compared with those treated with insulin; they were not at increased risk for obstetric trauma (RR = 0.92; 95% CI, 0.71-1.20), preterm birth (RR = 1.06; 95% CI, 0.93-1.21), or jaundice (RR = 0.96; 95% CI, 0.48-1.91). The risk of cesarean delivery was 3% lower in the glyburide group (adjusted RR = 0.97; 95% CI, 0.93-1.00). The risk difference associated with glyburide was 2.97% (95% CI, 1.82-4.12) for neonatal intensive care unit admission, 1.41% (95% CI, 0.61-2.20) for large for gestational age, and 1.11% (95% CI, 0.50-1.72) for respiratory distress. CONCLUSIONS AND RELEVANCE: Newborns from privately insured mothers treated with glyburide were more likely to experience adverse outcomes than those from mothers treated with insulin. Given the widespread use of glyburide, further investigation of these differences in pregnancy outcomes is a public health priority. PMID- 25822252 TI - Preservation of the blood brain barrier and cortical neuronal tissue by liraglutide, a long acting glucagon-like-1 analogue, after experimental traumatic brain injury. AB - Cerebral edema is a common complication following moderate and severe traumatic brain injury (TBI), and a significant risk factor for development of neuronal death and deterioration of neurological outcome. To this date, medical approaches that effectively alleviate cerebral edema and neuronal death after TBI are not available. Glucagon-like peptide-1 (GLP-1) has anti-inflammatory properties on cerebral endothelium and exerts neuroprotective effects. Here, we investigated the effects of GLP-1 on secondary injury after moderate and severe TBI. Male Sprague Dawley rats were subjected either to TBI by Controlled Cortical Impact (CCI) or sham surgery. After surgery, vehicle or a GLP-1 analogue, Liraglutide, were administered subcutaneously twice daily for two days. Treatment with Liraglutide (200 MUg/kg) significantly reduced cerebral edema in pericontusional regions and improved sensorimotor function 48 hours after CCI. The integrity of the blood-brain barrier was markedly preserved in Liraglutide treated animals, as determined by cerebral extravasation of Evans blue conjugated albumin. Furthermore, Liraglutide reduced cortical tissue loss, but did not affect tissue loss and delayed neuronal death in the thalamus on day 7 post injury. Together, our data suggest that the GLP-1 pathway might be a promising target in the therapy of cerebral edema and cortical neuronal injury after moderate and severe TBI. PMID- 25822254 TI - Ocular inflammation associated with antivascular endothelial growth factor treatment. AB - PURPOSE OF REVIEW: To describe the diagnosis and management of intraocular inflammation following antivascular endothelial growth factor (VEGF) injections. RECENT FINDINGS: Inflammation following intravitreal anti-VEGF injections can cause a dramatic reduction in acuity. Differentiating factors from truly infectious endophthalmitis include a lack of pain, redness, or hypopyon, although none of these factors is diagnostic. A high suspicion of infectious endophthalmitis should trigger a prompt vitreous tap and injection of intravitreal antibiotics. Conversely, if noninfectious endophthalmitis is suspected, close observation with frequent topical steroids is warranted. SUMMARY: Most eyes with noninfectious endophthalmitis following anti-VEGF injection recover within 1 month to baseline acuity with topical corticosteroid treatment. Mechanisms hypothesized to explain postinjection inflammation include patient-specific, delivery-specific, and medication-specific factors. PMID- 25822255 TI - Current phase 1/2 research for neovascular age-related macular degeneration. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an update of phase 1 and 2 clinical trials in neovascular age-related macular degeneration that are either currently underway or recently completed by the end of 2014. RECENT FINDINGS: Three gene therapy options are currently in early clinical trials, administered via intravitreal (AAV2-sFLT01) or subretinal (AVA-101 and RetinoStat) injection to express angiogenesis inhibitors. Several eye drops are being developed for topical administration for various angiogenic inhibitors, including regorafenib, squalamine lactate, and PAN-90806. Early development of systemic administration options may be intravenous (iSONEP) or oral (X-82). Initial study of local radiation therapy may be via proton beam irradiation or stereotactic radiotherapy. Several intravitreal injections are being studied including human immuno-conjugate molecule (hl-con1), abicipar pegol, PF582, DE 120, ESBA 1008, and REGN2176-3. SUMMARY: Numerous treatment options of neovascular age-related macular degeneration are in phase 1/2 clinical trials including gene therapy, eye drops, systemic dosing, localized irradiation, and various intravitreal injections. Future phase 3 trial results will be observed closely to determine which of these therapies will be the next novel treatment of neovascular age-related macular degeneration. PMID- 25822256 TI - Four-Coordinate Iron(II) Diaryl Compounds with Monodentate N-Heterocyclic Carbene Ligation: Synthesis, Characterization, and Their Tetrahedral-Square Planar Isomerization in Solution. AB - The salt elimination reactions of (IPr2Me2)2FeCl2 (IPr2Me2 = 1,3-diisopropyl-4,5 dimethylimidazol-2-ylidene) with the corresponding aryl Grignard reagents afford [(IPr2Me2)2FeAr2] (Ar = Ph, 3; C6H4-p-Me, 4; C6H4-p-(t)Bu, 5; C6H3-3,5-(CF3)2, 6) in good yields. X-ray crystallographic studies revealed the presence of both tetrahedral and trans square planar isomers for 3 and 6 and the tetrahedral structures for 4 and 5. Magnetic susceptibility and (57)Fe Mossbauer spectrum measurements on the solid samples indicated the high-spin (S = 2) and intermediate-spin (S = 1) nature of the tetrahedral and square planar structures, respectively. Solution property studies, including solution magnetic susceptibility measurement, variable-temperature (1)H and (19)F NMR, and absorption spectroscopy, on 3-6, as well as an (57)Fe Mossbauer spectrum study on a frozen tetrahydrofuran solution of tetrahedral [(IPr2Me2)2(57)FePh2] suggest the coexistence of tetrahedral and trans square planar structures in solution phase. Density functional theory calculations on (IPr2Me2)2FePh2 disclosed that the tetrahedral and trans square planar isomers are close in energy and that the geometry isomerization can occur by spin-change-coupled geometric transformation on four-coordinate iron(II) center. PMID- 25822257 TI - Tetraphenylethene-based star shaped porphyrins: synthesis, self-assembly, and optical and photophysical study. AB - Supramolecular self-assembly and self-organization are simple and convenient ways to design and create controlled assemblies with organic molecules, and they have provoked great interest due to their potential applications in various fields, such as electronics, photonics, and light-energy conversion. Herein, we describe the synthesis of two pi-conjugated porphyrin molecules bearing tetraphenylethene moieties with high fluorescence quantum yield. Photophysical and electrochemical studies were conducted to understand the physical and redox properties of these new materials, respectively. Furthermore, these derivatives were used to investigate self-assembly via the solvophobic effect. The self-assembled aggregation was performed in nonpolar and polar organic solvents and forms nanospheres and ring-like nanostructures, respectively. The solution based aggregation was studied by means of UV-vis absorption, emission, XRD, and DLS analyses. Self-assembled ring-shape structures were visualized by SEM and TEM imaging. This ring-shape morphology of nanosized macromolecules might be a good candidate for the creation of artificial light-harvesting nanodevices. PMID- 25822258 TI - The use of global rating scales for OSCEs in veterinary medicine. AB - OSCEs (Objective Structured Clinical Examinations) are widely used in health professions to assess clinical skills competence. Raters use standardized binary checklists (CL) or multi-dimensional global rating scales (GRS) to score candidates performing specific tasks. This study assessed the reliability of CL and GRS scores in the assessment of veterinary students, and is the first study to demonstrate the reliability of GRS within veterinary medical education. Twelve raters from two different schools (6 from University of Calgary [UCVM] and 6 from Royal (Dick) School of Veterinary Studies [R(D)SVS] were asked to score 12 students (6 from each school). All raters assessed all students (video recordings) during 4 OSCE stations (bovine haltering, gowning and gloving, equine bandaging and skin suturing). Raters scored students using a CL, followed by the GRS. Novice raters (6 R(D)SVS) were assessed independently of expert raters (6 UCVM). Generalizability theory (G theory), analysis of variance (ANOVA) and t tests were used to determine the reliability of rater scores, assess any between school differences (by student, by rater), and determine if there were differences between CL and GRS scores. There was no significant difference in rater performance with use of the CL or the GRS. Scores from the CL were significantly higher than scores from the GRS. The reliability of checklist scores were .42 and .76 for novice and expert raters respectively. The reliability of the global rating scale scores were .7 and .86 for novice and expert raters respectively. A decision study (D-study) showed that once trained using CL, GRS could be utilized to reliably score clinical skills in veterinary medicine with both novice and experienced raters. PMID- 25822259 TI - Thyroxine differentially modulates the peripheral clock: lessons from the human hair follicle. AB - The human hair follicle (HF) exhibits peripheral clock activity, with knock-down of clock genes (BMAL1 and PER1) prolonging active hair growth (anagen) and increasing pigmentation. Similarly, thyroid hormones prolong anagen and stimulate pigmentation in cultured human HFs. In addition they are recognized as key regulators of the central clock that controls circadian rhythmicity. Therefore, we asked whether thyroxine (T4) also influences peripheral clock activity in the human HF. Over 24 hours we found a significant reduction in protein levels of BMAL1 and PER1, with their transcript levels also decreasing significantly. Furthermore, while all clock genes maintained their rhythmicity in both the control and T4 treated HFs, there was a significant reduction in the amplitude of BMAL1 and PER1 in T4 (100 nM) treated HFs. Accompanying this, cell-cycle progression marker Cyclin D1 was also assessed appearing to show an induced circadian rhythmicity by T4 however, this was not significant. Contrary to short term cultures, after 6 days, transcript and/or protein levels of all core clock genes (BMAL1, PER1, clock, CRY1, CRY2) were up-regulated in T4 treated HFs. BMAL1 and PER1 mRNA was also up-regulated in the HF bulge, the location of HF epithelial stem cells. Together this provides the first direct evidence that T4 modulates the expression of the peripheral molecular clock. Thus, patients with thyroid dysfunction may also show a disordered peripheral clock, which raises the possibility that short term, pulsatile treatment with T4 might permit one to modulate circadian activity in peripheral tissues as a target to treat clock related disease. PMID- 25822260 TI - Mitochondrial dynamics protein Drp1 is overexpressed in oncocytic thyroid tumors and regulates cancer cell migration. AB - Oncocytic cell tumors are characterized by the accumulation of morphologically abnormal mitochondria in their cells, suggesting a role for abnormal mitochondrial biogenesis in oncocytic cell transformation. Little is known about the reason for the dysmorphology of accumulated mitochondria. The proteins regulating the morphology of mitochondria, the "mitochondria-shaping" proteins, can modulate their size and number; however, nothing is known hitherto about a possible involvement of mitochondrial dynamics in oncocytic cell transformation in tumors. Our aim was to assess the status of the mitochondria morphology and its role in oncocytic cell transformation. We therefore evaluated the expression pattern of the main mitochondrial fusion and fission proteins in a series of thyroid cell tumor samples, as well as in thyroid tumor cell lines, with and without oncocytic cell features. The expression of mitochondrial fusion (Opa1, Mfn1 and Mfn2) and fission (Drp1 and Fis1) proteins were evaluated by immunohistochemistry (IHC) in a series of 88 human thyroid tumors. In vitro studies, for comparative purposes and to deepen the study, were performed using TPC1--a papillary thyroid carcinoma derived cell line--and XTC.UC1, an oncocytic follicular thyroid carcinoma-derived cell line. Both IHC and in vitro protein analyses showed an overall increase in the levels of "mitochondrial-shaping" proteins in oncocytic thyroid tumors. Furthermore, overexpression of the pro fission protein Drp1 was found to be associated with malignant oncocytic thyroid tumors. Interestingly, genetic and pharmacological blockage of Drp1 activity was able to influence thyroid cancer cells' migration/invasion ability, a feature of tumor malignancy. In this study we show that unbalanced mitochondrial dynamics characterize the malignant features of thyroid oncocytic cell tumors, and participate in the acquisition of the migrating phenotype. PMID- 25822261 TI - Sex ratio meiotic drive as a plausible evolutionary mechanism for hybrid male sterility. AB - Biological diversity on Earth depends on the multiplication of species or speciation, which is the evolution of reproductive isolation such as hybrid sterility between two new species. An unsolved puzzle is the exact mechanism(s) that causes two genomes to diverge from their common ancestor so that some divergent genes no longer function properly in the hybrids. Here we report genetic analyses of divergent genes controlling male fertility and sex ratio in two very young fruitfly species, Drosophila albomicans and D. nasuta. A majority of the genetic divergence for both traits is mapped to the same regions by quantitative trait loci mappings. With introgressions, six major loci are found to contribute to both traits. This genetic colocalization implicates that genes for hybrid male sterility have evolved primarily for controlling sex ratio. We propose that genetic conflicts over sex ratio may operate as a perpetual dynamo for genome divergence. This particular evolutionary mechanism may largely contribute to the rapid evolution of hybrid male sterility and the disproportionate enrichment of its underlying genes on the X chromosome--two patterns widely observed across animals. PMID- 25822262 TI - Measuring and overcoming limits of the Saffman-Delbruck model for soap film viscosities. AB - We observe tracer particles diffusing in soap films to measure the two dimensional (2D) viscous properties of the films. Saffman-Delbruck type models relate the single-particle diffusivity to parameters of the film (such as thickness h) for thin films, but the relation breaks down for thicker films. Notably, the diffusivity is faster than expected for thicker films, with the crossover at h/d = 5.2 +/- 0.9 using the tracer particle diameter d. This indicates a crossover from purely 2D diffusion to diffusion that is more three dimensional. We demonstrate that measuring the correlations of particle pairs as a function of their separation overcomes the limitations of the Saffman-Delbruck model and allows one to measure the viscosity of a soap film for any thickness. PMID- 25822263 TI - Propagation of damage in brain tissue: coupling the mechanics of oedema and oxygen delivery. AB - Brain tissue swelling, or oedema, is a dangerous consequence of traumatic brain injury and stroke. In particular, a locally swollen region can cause the injury to propagate further through the brain: swelling causes mechanical compression of the vasculature in the surrounding tissue and so can cut off that tissue's oxygen supply. We use a triphasic mathematical model to investigate this propagation, and couple tissue mechanics with oxygen delivery. Starting from a fully coupled, finite elasticity, model, we show that simplifications can be made that allow us to express the volume of the propagating region of damage analytically in terms of key parameters. Our results show that performing a craniectomy, to alleviate pressure in the brain and allow the tissue to swell outwards, reduces the propagation of damage; this finding agrees with experimental observations. PMID- 25822266 TI - Improving quality by doing less: overdiagnosis. PMID- 25822264 TI - Mechanical microenvironments and protein expression associated with formation of different skeletal tissues during bone healing. AB - Uncovering the mechanisms of the sensitivity of bone healing to mechanical factors is critical for understanding the basic biology and mechanobiology of the skeleton, as well as for enhancing clinical treatment of bone injuries. This study refined an experimental method of measuring the strain microenvironment at the site of a bone injury during bone healing. This method used a rat model in which a well-controlled bending motion was applied to an osteotomy to induce the formation of pseudarthrosis that is composed of a range of skeletal tissues, including woven bone, cartilage, fibrocartilage, fibrous tissue, and clot tissue. The goal of this study was to identify both the features of the strain microenvironment associated with formation of these different tissues and the expression of proteins frequently implicated in sensing and transducing mechanical cues. By pairing the strain measurements with histological analyses that identified the regions in which each tissue type formed, we found that formation of the different tissue types occurs in distinct strain microenvironments and that the type of tissue formed is correlated most strongly to the local magnitudes of extensional and shear strains. Weaker correlations were found for dilatation. Immunohistochemical analyses of focal adhesion kinase and rho family proteins RhoA and CDC42 revealed differences within the cartilaginous tissues in the calluses from the pseudarthrosis model as compared to fracture calluses undergoing normal endochondral bone repair. These findings suggest the involvement of these proteins in the way by which mechanical stimuli modulate the process of cartilage formation during bone healing. PMID- 25822267 TI - Alpha blockers to speed ureteral stone passage. PMID- 25822268 TI - Buprenorphine Maintenance vs. Methadone Maintenance or Placebo for Opioid Use Disorder. PMID- 25822269 TI - Teaching Health Center GME Funding Instability Threatens Program Viability. PMID- 25822270 TI - Common questions about the initial management of hypertension. AB - Hypertension is the most common chronic condition treated by family physicians. Elevated blood pressure is associated with an increased risk of heart failure, myocardial infarction, cerebrovascular disease, and death. Treatment of hypertension reduces the risk of these events. Several lifestyle modifications are associated with improvements in blood pressure, including the Dietary Approaches to Stop Hypertension diet, sodium restriction, regular exercise, and moderate weight loss. There is strong evidence that reducing diastolic blood pressure to less than 90 mm Hg is beneficial in adults older than 30 years. Although there is good evidence to support reducing systolic blood pressure to less than 150 mm Hg in adults older than 60 years, the evidence in younger adults is insufficient to recommend a specific goal. Black patients with chronic kidney disease who are treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to a blood pressure of less than 140/90 mm Hg experience slower declines in glomerular filtration rates than patients treated with other medications. A blood pressure goal of less than 140/90 mm Hg is recommended in patients with chronic kidney disease and in those with diabetes mellitus. Thiazide diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers are the preferred medications in nonblack patients; thiazide diuretics and calcium channel blockers are preferred in black patients. PMID- 25822271 TI - Cesarean delivery: counseling issues and complication management. AB - Nearly one-third of all deliveries in the United States are cesarean deliveries. Compared with spontaneous vaginal delivery, cesarean delivery is associated with increased maternal and neonatal morbidity and mortality. Interventions that decrease the chance of a cesarean delivery include avoiding non-medically indicated induction of labor, avoiding amniotomy, and having a doula present. In North America, the most common reasons for cesarean delivery include elective repeat cesarean delivery, dystocia or failure to progress, malpresentation, and fetal heart rate tracings that suggest fetal distress. Post-cesarean delivery complications include pain, endomyometritis, wound separation/infection, urinary tract infection, gastrointestinal problems, deep venous thrombosis, and septic thrombophlebitis. Women with no risk factors for deep venous thrombosis other than the postpartum state and the operative delivery do not require thromboembolism prophylaxis other than early ambulation. A pregnant woman's decision to attempt a trial of labor after cesarean delivery or have a planned repeat cesarean delivery involves a balancing of maternal and neonatal risks, as well as personal preference after counseling by her physician. Approximately 75% of attempted trials of labor after cesarean delivery are successful. Provision of advanced maternity care practices by family physicians, including serving as primary surgeons for cesarean deliveries, is consistent with the goals of the patient-centered medical home. PMID- 25822272 TI - Diagnosis and treatment of seborrheic dermatitis. AB - Seborrheic dermatitis is a common skin condition in infants, adolescents, and adults. The characteristic symptoms-scaling, erythema, and itching-occur most often on the scalp, face, chest, back, axilla, and groin. Seborrheic dermatitis is a clinical diagnosis based on the location and appearance of the lesions. The skin changes are thought to result from an inflammatory response to a common skin organism, Malassezia yeast. Treatment with antifungal agents such as topical ketoconazole is the mainstay of therapy for seborrheic dermatitis of the face and body. Because of possible adverse effects, anti-inflammatory agents such as topical corticosteroids and calcineurin inhibitors should be used only for short durations. Several over-the-counter shampoos are available for treatment of seborrheic dermatitis of the scalp, and patients should be directed to initiate therapy with one of these agents. Antifungal shampoos (long-term) and topical corticosteroids (short-term) can be used as second-line agents for treatment of scalp seborrheic dermatitis. PMID- 25822273 TI - Benzodiazepines and Alzheimer disease. PMID- 25822274 TI - Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Blockers. PMID- 25822275 TI - Vesicular rash in a college student. PMID- 25822276 TI - Planning for Labor and Vaginal Birth After Cesarean Delivery: Guidelines from the AAFP. PMID- 25822277 TI - Prevention of dental caries in children from birth through five years of age: recommendation statement. PMID- 25822278 TI - Screening for suicide risk in adolescents, adults, and older adults in primary care: recommendation statement. PMID- 25822279 TI - Treating newly diagnosed high blood pressure. PMID- 25822280 TI - Involvement of large-conductance Ca2+-activated K+ channels in chloroquine induced force alterations in pre-contracted airway smooth muscle. AB - The participation of large-conductance Ca2+ activated K+ channels (BKs) in chloroquine (chloro)-induced relaxation of precontracted airway smooth muscle (ASM) is currently undefined. In this study we found that iberiotoxin (IbTx, a selective inhibitor of BKs) and chloro both completely blocked spontaneous transient outward currents (STOCs) in single mouse tracheal smooth muscle cells, which suggests that chloro might block BKs. We further found that chloro inhibited Ca2+ sparks and caffeine-induced global Ca2+ increases. Moreover, chloro can directly block single BK currents completely from the intracellular side and partially from the extracellular side. All these data indicate that the chloro-induced inhibition of STOCs is due to the blockade of chloro on both BKs and ryanodine receptors (RyRs). We also found that low concentrations of chloro resulted in additional contractions in tracheal rings that were precontracted by acetylcholine (ACH). Increases in chloro concentration reversed the contractile actions to relaxations. In the presence of IbTx or paxilline (pax), BK blockers, chloro-induced contractions were inhibited, although the high concentrations of chloro-induced relaxations were not affected. Taken together, our results indicate that chloro blocks BKs and RyRs, resulting in abolishment of STOCs and occurrence of contraction, the latter will counteract the relaxations induced by high concentrations of chloro. PMID- 25822281 TI - Serum levels of caspase-cleaved cytokeratin-18 in patients with severe traumatic brain injury are associated with mortality: a pilot study. AB - OBJECTIVE: There have been found apoptotic changes in brain tissue samples from animals and humans after a traumatic brain injury (TBI). The protein cytokeratin 18 (CK-18), present in epithelial cells, is cleaved by the action of caspases during apoptosis, and the resulting fragments are released into the blood as caspase-cleaved CK (CCCK)-18. Circulating levels of CCCK-18, as biomarker of apoptosis, have been determined in patients with different processes; however, it has not been explored in TBI patients. Thus, the objective of this study was to determine whether there is an association between serum CCCK-18 levels and mortality and whether such levels could be used as a biomarker to predict outcomes in TBI patients. METHODS: A prospective, observational, multicenter study carried out in six Spanish Intensive Care Units. We included patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9; and were excluded those patients with Injury Severity Score (ISS) in non-cranial aspects higher than 9. We measured serum CCCK-18 levels at admission. The end-point of the study was 30-day mortality. RESULTS: Surviving patients (n = 73) showed lower serum CCCK-18 levels (P = 0.003) than non-survivors (n = 27). On ROC analysis, the area under the curve (AUC) for serum CCCK-18 levels as predictor of 30-day mortality was 0.69 (95% CI = 0.59-0.78; P = 0.006). We found in survival analysis that patients with serum CCCK-18 higher than 201 u/L had higher 30-day mortality than patients with lower levels (Hazard ratio = 3.9; 95% CI = 1.81-8.34; P<0.001). Regression analyses showed that serum CCCK-18 levels higher than 201 u/L were associated with 30-day mortality (OR = 8.476; 95% CI = 2.087-34.434; P = 0.003) after controlling for age and GCS. CONCLUSIONS: The novel finding of our study was that serum CCCK-18 levels are associated with 30-day mortality and could be used as a prognostic biomarker in patients with severe TBI. PMID- 25822282 TI - Polymer nanofiber-guided uniform lithium deposition for battery electrodes. AB - Lithium metal is one of the most promising candidates as an anode material for next-generation energy storage systems due to its highest specific capacity (3860 mAh/g) and lowest redox potential of all. The uncontrolled lithium dendrite growth that causes a poor cycling performance and serious safety hazards, however, presents a significant challenge for the realization of lithium metal based batteries. Here, we demonstrate a novel electrode design by placing a three dimensional (3D) oxidized polyacrylonitrile nanofiber network on top of the current collector. The polymer fiber with polar surface functional groups could guide the lithium ions to form uniform lithium metal deposits confined on the polymer fiber surface and in the 3D polymer layer. We showed stable cycling of lithium metal anode with an average Coulombic efficiency of 97.4% over 120 cycles in ether-based electrolyte at a current density of 3 mA/cm(2) for a total of 1 mAh/cm(2) of lithium. PMID- 25822283 TI - Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. AB - Sofosbuvir (SOVALDI((r))), a potent, once-daily, orally administered nucleotide analog prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase is approved in the USA, EU, Canada, and other regions for the treatment of HCV infection as a component of an antiviral treatment regimen. Sofosbuvir undergoes intracellular activation to form GS-461203 (active triphosphate, not detected in plasma), and ultimately the inactive, renally eliminated metabolite GS-331007. GS 331007 was identified as the primary analyte of interest for clinical pharmacology studies as it accounted for >90 % of systemic drug-related material exposure, and provided comparable exposure-response relationships for viral kinetics as observed for sofosbuvir. GS-331007 and sofosbuvir exhibit linear pharmacokinetics with minimal accumulation upon multiple dosing. Compared to healthy subjects, HCV-infected patients had modestly lower (39 %) GS-331007 area under the plasma concentration-time curve (AUC) and higher sofosbuvir AUC (60 %). Sofosbuvir can be administered without dose modification in HCV-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. Sofosbuvir has a low propensity for clinically significant drug interactions with common concomitant medications used by HCV-infected patients. Clinically significant alterations in GS-331007 or sofosbuvir exposures are limited to potent inducers of intestinal P-glycoprotein that may lower exposure. In HCV infected patients, demographic variables do not significantly influence GS-331007 and sofosbuvir exposures and no consistent exposure-response relationships were observed for efficacy or safety. This review focuses on the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic-pharmacodynamic relationships of sofosbuvir, and summarizes a number of drug interaction studies with important concomitant medications commonly used by HCV-infected patients. PMID- 25822284 TI - Primary Results of the Patient-Centered Disease Management (PCDM) for Heart Failure Study: A Randomized Clinical Trial. AB - IMPORTANCE: Heart failure (HF) has a major effect on patients' health status, including their symptom burden, functional status, and health-related quality of life. OBJECTIVE: To determine the effectiveness of a collaborative care patient centered disease management (PCDM) intervention to improve the health status of patients with HF. DESIGN, SETTING, AND PARTICIPANTS: The Patient-Centered Disease Management (PCDM) trial was a multisite randomized clinical trial comparing a collaborative care PCDM intervention with usual care in patients with HF. A population-based sample of 392 patients with an HF diagnosis from 4 Veterans Affairs centers who had a Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of less than 60 (heavy symptom burden and impaired functional status and quality of life) were enrolled between May 2009 and June 2011. INTERVENTIONS: The PCDM intervention included collaborative care by a multidisciplinary care team consisting of a nurse coordinator, cardiologist, psychiatrist, and primary care physician; home telemonitoring and patient self management support; and screening and treatment for comorbid depression. MAIN OUTCOMES AND MEASURES: The primary outcome was change in the KCCQ overall summary score at 1 year (a 5-point change is clinically significant). Mortality, hospitalization, and depressive symptoms (Patient Health Questionnaire 9) were secondary outcomes. RESULTS: There were no significant differences in baseline characteristics between patients randomized to the PCDM intervention (n=187) vs usual care (n=197); baseline mean KCCQ overall summary scores were 37.9 vs 36.9 (P=.48). There was significant improvement in the KCCQ overall summary scores in both groups after 1 year (mean change, 13.5 points in each group), with no significant difference between groups (P=.97). The intervention was not associated with greater improvement in the KCCQ overall summary scores when the effect over time was estimated using 3-month, 6-month, and 12-month data (P=.74). Among secondary outcomes, there were significantly fewer deaths at 1 year in the intervention arm (8 of 187 [4.3%]) than in the usual care arm (19 of 197 [9.6%]) (P = .04). Among those who screened positive for depression, there was a greater improvement in the Patient Health Questionnaire 9 scores after 1 year in the intervention arm than in the usual care arm (2.1 points lower, P=.01). There was no significant difference in 1-year hospitalization rates between the intervention arm and the usual care arm (29.4% vs 29.9%, P=.87). CONCLUSIONS AND RELEVANCE: This multisite randomized trial of a multifaceted HF PCDM intervention did not demonstrate improved patient health status compared with usual care. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00461513. PMID- 25822285 TI - The dynamic conformational cycle of the group I chaperonin C-termini revealed via molecular dynamics simulation. AB - Chaperonins are large ring shaped oligomers that facilitate protein folding by encapsulation within a central cavity. All chaperonins possess flexible C-termini which protrude from the equatorial domain of each subunit into the central cavity. Biochemical evidence suggests that the termini play an important role in the allosteric regulation of the ATPase cycle, in substrate folding and in complex assembly and stability. Despite the tremendous wealth of structural data available for numerous orthologous chaperonins, little structural information is available regarding the residues within the C-terminus. Herein, molecular dynamics simulations are presented which localize the termini throughout the nucleotide cycle of the group I chaperonin, GroE, from Escherichia coli. The simulation results predict that the termini undergo a heretofore unappreciated conformational cycle which is coupled to the nucleotide state of the enzyme. As such, these results have profound implications for the mechanism by which GroE utilizes nucleotide and folds client proteins. PMID- 25822286 TI - Rational synthesis of AB-type N-substituted core-functionalized naphthalene diimides (cNDIs). AB - Acid-mediated transformation of tetraethyl 2,6-diethoxynaphthalene-1,4,5,8 tetracarboxylate selectively affords the core-substituted naphthalene-anhydride ester (cNAE) in quantitative yield. This anhydride can be selectively converted into hetero-N-substituted core-functionalized naphthalene diimides (cNDIs) through sequential condensation reactions in the presence of the precursor amine with very high isolated yields over four steps. The approach can be applied to prepare a large variety of heterocyclic, aromatic, and aliphatic heterodiimides. PMID- 25822287 TI - Enhanced photocatalytic activity and charge carrier dynamics of hetero-structured organic-inorganic nano-photocatalysts. AB - P3HT-coupled CdS heterostructured nanophotocatalysts have been synthesized by an inexpensive and scalable chemical bath deposition approach followed by drop casting. The presence of amorphous regions corresponding to P3HT in addition to the lattice fringes [(002) and (101)] corresponding to hexagonal CdS in the HRTEM image confirm the coupling of P3HT onto CdS. The shift of pi* (C?C) and sigma* (C C) peaks toward lower energy losses and prominent presence of sigma* (C-H) in the case of P3HT-CdS observed in electron energy loss spectrum implies the formation of heterostructured P3HT-CdS. It was further corroborated by the shifting of S 2p peaks toward higher binding energy (163.8 and 164.8 eV) in the XPS spectrum of P3HT-CdS. The current density recorded under illumination for the 0.2 wt % P3HT CdS photoelectrode is 3 times higher than that of unmodified CdS and other loading concentration of P3HT coupled CdS photoelectrodes. The solar hydrogen generation studies show drastic enhancement in the hydrogen generation rate i.e. 4108 MUmol h(-1)g(-1) in the case of 0.2 wt % P3HT-CdS. The improvement in the photocatalytic activity of 0.2 wt % P3HT-CdS photocatalyst is ascribed to improved charge separation lead by the unison of shorter lifetime (tau1=0.25 ns) of excitons, higher degree of band bending, and increased donor density as revealed by transient photoluminescence studies and Mott-Schottky analysis. PMID- 25822288 TI - Azaphilones inhibit tau aggregation and dissolve tau aggregates in vitro. AB - The aggregation of the microtubule-associated protein tau is a seminal event in many neurodegenerative diseases, including Alzheimer's disease. The inhibition or reversal of tau aggregation is therefore a potential therapeutic strategy for these diseases. Fungal natural products have proven to be a rich source of useful compounds having wide varieties of biological activities. We have previously screened Aspergillus nidulans secondary metabolites for their ability to inhibit tau aggregation in vitro using an arachidonic acid polymerization protocol. One aggregation inhibitor identified was asperbenzaldehyde, an intermediate in azaphilone biosynthesis. We therefore tested 11 azaphilone derivatives to determine their tau assembly inhibition properties in vitro. All compounds tested inhibited tau filament assembly to some extent, and four of the 11 compounds had the advantageous property of disassembling preformed tau aggregates in a dose dependent fashion. The addition of these compounds to the tau aggregates reduced both the total length and number of tau polymers. The most potent compounds were tested in in vitro reactions to determine whether they interfere with tau's normal function of stabilizing microtubules (MTs). We found that they did not completely inhibit MT assembly in the presence of tau. These derivatives are very promising lead compounds for tau aggregation inhibitors and, more excitingly, for compounds that can disassemble pre-existing tau filaments. They also represent a new class of anti-tau aggregation compounds with a novel structural scaffold. PMID- 25822289 TI - Observation and partial targeted surgery in the management of tympano-jugular paraganglioma: a contribution to the multioptional treatment. AB - The objective of this study was to assess the value of a limited tumor excision in tympano-jugular paragangliomas treated with observation with the goal of preventing, or repairing, a neural (VII cranial nerve) or brain damage and continue an otherwise correct observation. This is a retrospective case review. Each patient was submitted to a complete neuro-radiological work-up for diagnosis including CT, MRI, and angiography if needed of tympano-jugular paraganglioma class C. All the cases were submitted to observation and in 16 cases partial targeted surgery was performed. In 10 cases, the procedure involved a targeted removal of the tumor growing in contact with, or invading, the Fallopius. In four cases, the procedure was a petro-occipital trans-sigmoid approach to remove the intradural portion of tumor producing the picture of brain stem compression. In two cases, there was the excision of the bleeding tumor surfaces in the outer ear canal. Follow-up ranged from 4 to 20 years. Success was considered the maintenance of observation without the change of class of tumor extension. In 13 over 16 cases, the observation could be continued, as it still was the more favorable option between natural and surgical morbidity. In the other three cases, a newly installed paralysis of the 9-10 cranial nerves due to tumor growth involved a correction of the strategy to a radical procedure. Partial targeted surgery was directed to cases submitted to observation. It allowed to prevent, or repair, an impending, or actual damage to the facial nerve or the brain stem and to continue the abstentional treatment by keeping the balance between natural and therapy morbidity in favor of observation. PMID- 25822290 TI - Totally endoscopic stapes surgery without packing: novel technique bringing most comfort to the patients. AB - Many difficulties might be encountered during conventional stapes surgery. However, the good exposure provided by the endoscope can facilitate this procedure. The present study addresses the effectiveness of endoscopic stapes surgery with regard to the operation time and patients' convenience and satisfaction. 19 patients underwent endoscopic stapes surgery without packing. 15 patients who experienced the microscopic stapes surgery served as the comparison group. Audiometric results and the patients' satisfaction as measured by visual analog scale in both group were compared. Audiometric results were similar in both groups. Nevertheless, the endoscopic method was accompanied by shorter operation time and more comfort for the patients. Totally endoscopic stapes surgery can be done in much shorter time without major difficulties and without need to pack ear canal after surgery. Far less dissection and incision as well as patients' more satisfaction make this technique as a good alternative to the microscopic approach to stapes surgery. PMID- 25822291 TI - Primary definitive radiotherapy with or without chemotherapy for squamous cell carcinoma of the temporal bone. AB - We aimed to evaluate the impact of concurrent chemoradiotherapy (CCRT) on the survival of patients with squamous cell carcinoma of the temporal bone. We retrospectively analyzed the data of 13 consecutive patients who were treated by definitive radiation therapy (RT) or CCRT as the initial treatment between 1999 and 2012. There were 5 patients with stage II disease, 5 with stage III, and 3 with stage IV, as classified according to the University of Pittsburgh system. Among these, 2, 4, and 3 patients, respectively, were treated by CCRT; whereas the remaining (3 patients with stage II and 1 with stage III) were treated by RT alone. Median follow-up duration was 39 months (12-106 months) in all cases, and 61.5 months (17-70 months) in censored cases. The 5-year overall survival (OS) rates were 51 % in all patients, and 40, 100, and 0 % in patients with stage II, stage III, and stage IV disease, respectively. In patients with stage II and III disease, the 5-year OS rates were 80 % in the CCRT group and 50 % in the RT-alone group. We found better prognosis in patients with stage II and III disease who were treated by CCRT. Only 2 patients treated by CCRT experienced adverse events more than grade 3, which were neutropenia and dermatitis. There was no late adverse event of bony necrosis. Our study results indicate that CCRT is safe and very effective as a first-line treatment for stage II and III squamous cell carcinoma of the temporal bone. PMID- 25822292 TI - Physiologic and pathophysiologic changes in the right heart in highly trained athletes. AB - Exercise causes changes in the heart in response to the hemodynamic demands of increased systemic and pulmonary requirements during exercise. Understanding these adaptations is of great importance, since they may overlap with those caused by pathological conditions. Initial descriptions of athlete's heart focused mainly on chronic adaptation of the left heart to training. In recent years, the substantial structural and functional adaptations of the right heart have been documented, highlighting the complex interplay with left heart. Moreover, there is evolving evidence of acute and chronic cardiac damage, mainly involving the right heart, which may predispose subjects to atrial and ventricular arrhythmias, configuring an exercise-induced cardiomyopathy. The aim of this article is to review the current knowledge on the physiologic and pathophysiologic changes in the right heart in highly trained athletes. PMID- 25822293 TI - Exercise and sports in cardiac patients and athletes at risk: Balance between benefit and harm. AB - Physical training has a well-established role in the primary and secondary prevention of coronary artery disease. Moderate exercise has been shown to be beneficial in chronic stable heart failure. Competitive sports, however, is contraindicated in most forms of hypertrophic cardiomyopathy (HCM), in myocarditis, in pericarditis, and in right ventricular cardiomyopathy/dysplasia. In most European countries, the recommendations of medical societies or public bodies state that these diseases have to be ruled out by prescreening before an individual can take up competitive sports. But the intensity and quality of this health check vary considerably from country to country, from the type of sports activity, and from the individuals who want to participate in sports. Prescreening on an individual basis should also be considered for leisure sports, particularly in people who decide to start training in middle age after years of physical inactivity to regain physical fitness. In leisure sports the initiative for a medical check-up lies primarily in the hands of the "healthy" individual. If she or he plans to participate in extreme forms of endurance sports with excessive training periods such as a marathon or ultramarathon and competitive cycling or rowing, they should be aware that high-intensity endurance sports can lead to structural alterations of the heart muscle even in healthy individuals. Physical exercise in patients with heart disease should be accompanied by regular medical check-ups. Most rehabilitation programs in Europe perform physical activity and training schedules according to current guidelines. Little is known about athletes who are physically handicapped and participate in competitive sports or the Paralympics, and even less is known about individuals with intellectual disabilities (ID) who participate in local, regional, international competitions or the Special Olympics or just in leisure sport activities. PMID- 25822294 TI - Neuroplasticity and the edentulous patient- toward a paradigm shift in oral rehabilitation. PMID- 25822295 TI - Digitally planned and fabricated mandibular fixed complete dentures. Part 2. Prosthodontic phase. AB - Part 1 of this patient report described a prosthetically driven protocol that used computer-aided engineering for the fabrication of a mandibular conversion denture and maxillary provisional complete denture using the AvaDent Digital Denture system. The report demonstrated that this system combined with NobelClinician implant-planning software can be used to efficiently convert a digital denture into an immediately loaded provisional implant-supported fixed complete denture (hybrid prosthesis). Part 2 of the patient report describes the technique and steps involved in the fabrication of a digitally planned and fabricated mandibular fixed complete denture with incorporated titanium milled bar opposed by a definitive computer-aided design/computer-assisted manufacture milled maxillary complete denture. PMID- 25822296 TI - First diagnosis of rheumatoid arthritis in a patient with temporomandibular disorder: a case report. AB - Rheumatoid arthritis (RA) is a chronic disease of unknown etiology, characterized by synovitis of the diarthroidal joints, gradual bone erosion, and cartilage destruction. Temporomandibular joint (TMJ) arthritis is frequent in patients with RA, but it is seldom the first joint to be affected. This report presents a case of a female patient with undiagnosed RA who first presented with signs and symptoms of the disease in the TMJs. It highlights the importance of professional awareness and provides a roadmap for clinical and radiologic examination followed by biochemical and genetic monitoring for early diagnosis of RA. PMID- 25822297 TI - Screw- versus cement-retained implant prostheses: a systematic review of prosthodontic maintenance and complications. AB - PURPOSE: This systematic review aimed to identify different prosthodontic outcomes between screw- and cement-retained implant prostheses. MATERIALS AND METHODS: The relevant articles were retrieved from the following electronic databases: MEDLINE, EMBASE, PubMed (using medical subject headings), and the Cochrane Central Register of Controlled Trials (CENTRAL). The search was performed up to December 31, 2013, and was restricted to studies on human subjects reported in English. A further search was conducted through the reference lists of the articles found as well as from early online articles. Reviewed studies were those on fixed implant prostheses using different retention mechanisms such as screws or cement. Information on types of screws and mechanisms of preloading, as well as different luting cements, was collected in correlation with prosthodontic maintenance/complication issues seen in the clinical studies. RESULTS: Sixty-two papers met the review criteria. There were only six randomized controlled trials and none of them included an equivalent number of screw- and cement-retained single implant crowns for comparison. Studies used different types of screws and only a few reported the preloading procedure for the prosthetic screws. Other studies involving cement-retained implant prostheses used a range of dental cements; however, some did not specify the type used. Studies reported various prosthodontic maintenance/complication issues such as screw loosening, porcelain fracture, loss of retention, and esthetic concerns. Five studies did not report any prosthodontic maintenance issues during their observation periods. More recent studies also did not report any incidence of screw loosening. Only two studies stated the standardized criteria for reporting their prosthodontic maintenance/ complication issues. CONCLUSIONS: With inadequate information and various study designs, it was difficult to compare the prosthodontic outcomes between screw and cement-retained fixed implant prostheses. Both retention mechanisms showed prosthodontic maintenance/complication issues that must be considered and this review showed that the introduction of newer implant components may assist in minimizing these issues. It is also recommended that standardized criteria be used when reporting prosthodontic maintenance/complication issues to allow better comparison of data. PMID- 25822298 TI - The oral health of institutionalized older adults in Malta. AB - PURPOSE: Studies on the oral health status of institutionalized older adults are less prevalent than those of community-dwelling older adults, as institutionalized older adults tend to be frailer. Poor oral health in older adults has a negative impact on the quality of life and self-confidence of older people and potentially poses a financial burden on both the older adult and society in general. The objective of this study was to assess and compare the oral health status of state institutionalized older adults in Malta with that of their European counterparts. MATERIALS AND METHODS: A total of 278 older adults with an average age of 83.6 +/- 6.5 years from nine state institutions in Malta were randomly selected. Participants were clinically examined for caries, periodontal disease, oral mucosal lesions, and prosthetic status. RESULTS: The oral health status of state institutionalized older adults was poor, with a very low routine dental attendance (29.3%) and, consequently, a high level of treatment need (44.4% of dentate individuals required extractions and 42.1% of dentate individuals required restorations). Only 2% of dentate individuals had healthy periodontal tissues with no clinical attachment loss over 4 mm. Edentulism among state institutionalized older adults stood at 41%. CONCLUSIONS: Institutionalized older adults from Malta have a poor oral health status comparable to institutionalized older adults from Europe in general, which poses fiscal and cultural challenges that need to be addressed by the dental community. PMID- 25822299 TI - The effectiveness of polishing kits: influence on surface roughness of zirconia. AB - This study investigated the effectiveness of intraoral and technical polishing kits. Zirconia specimens were sintered, ground, and polished with 14 different two-step or three-step polishing kits. Surface roughness (Ra, Rz) after each treatment step was determined, and scanning electron micrographs were made. Except for one system, all polishing kits were effective in reducing the surface roughness of ground zirconia. Differences in surface roughness were high after the first polishing step but were reduced to Ra/Rz values similar to or lower than those of the sintered reference after the final polishing step. Achieving smooth surfaces depended on a sequential application of all polishing steps. PMID- 25822300 TI - Zirconia-based crowns up to 5 years in function: a retrospective clinical study and evaluation of prosthetic restorations and failures. AB - PURPOSE: The purpose of this retrospective study was to evaluate the 5-year clinical performance and failure rate of single- or multiple-unit zirconia-based crowns. MATERIALS AND METHODS: A total of 148 patients (39 men and 109 women, mean age: 46.9 +/- 10.6 years) treated in university and private practices with 618 single- or multiple-unit zirconia-based (Lava) crowns made on natural teeth from January 2007 to December 2008 were included. Two hundred fifty-nine anterior and 359 posterior crowns were examined. A core and/or veneer fracture that required replacement of the restoration was considered to be a failure. The cumulative survival rate (CSR) was described with Kaplan-Meier survival functions. The crowns replaced for other reasons were deemed lost to follow-up, and esthetic, functional, and biologic complications were rated. RESULTS: At the 5-year follow-up, no zirconia core fractures were observed. Twelve veneer fractures that required crown replacement were detected. The CSR was 98.1%. There was a statistically significant difference between survival of the anterior and posterior restorations (P < .001). In total, 116 crowns experienced biologic and technical complications. The most common complications were smooth veneer fracture (4, 0.6%), loss of retention (7, 1%), staining because of smoking (24, 4%), and gingival recession (48, 8%). CONCLUSIONS: According to the 5-year CSR (98.1%) observed in this study, zirconia-based single or multiple crowns may be considered an acceptable treatment modality for the replacement of anterior and posterior teeth. RESULTS from the current study should be supported by additional randomized clinical trials. PMID- 25822301 TI - Loss of teeth in positions mesially adjacent to implant-supported fixed dentures: a retrospective clinical survey. AB - The aim of this study was to investigate the loss of teeth in positions mesially adjacent to implant-supported fixed dentures (IFDs) after insertion of IFDs in unilateral free-end edentulous spaces in the mandible at dental clinics. There were a total of 157 adjacent teeth. Nine adjacent teeth (5.73%, 9 of 157), 9 opposing teeth (2.59%, 9 of 348), 38 posterior teeth (1.93%, 38 of 1,964), and 3 anterior teeth (0.22%, 3 of 1,380) were lost during the observation period. The percentage of lost adjacent teeth was higher than that of posterior teeth (P = .002). Teeth in positions adjacent to the IFDs require more attention than other remaining teeth. PMID- 25822302 TI - Does case severity make a difference to clinical improvement following complete denture treatment? AB - PURPOSE: The aim of this study was to investigate the effect of case severity on clinical outcomes when fabricating new complete dentures. MATERIALS AND METHODS: Participants were separated into severe and moderate groups using the index of case difficulty for edentulous patients developed by the Japan Prosthodontic Society. Before and after treatment, self-assessed masticatory ability and oral health-related quality of life (OHRQoL) were examined, and the authors compared them according to case severity using the Mann-Whitney U test. To compare findings before and after treatment, the authors used the Wilcoxon signed rank test. RESULTS: In the severe group, both scores were significantly improved after treatment (P < .01). However, in the moderate group, there was no significant difference in self-assessed masticatory ability as measured by the food acceptance score before and after treatment (P = .11). Before treatment, OHRQoL as measured by the Oral Health Impact Profile score was significantly higher in the severe group than in the moderate group (P < .01). However, after treatment, there was no significant difference between the two groups (P = .92). CONCLUSIONS: The authors concluded that case severity makes a difference in the edentulous patient's OHRQoL and self-assessed masticatory ability during complete denture treatment. Evaluating case severity with the index before treatment is a useful tool for patients and clinicians to predict clinical outcomes. PMID- 25822303 TI - Decision making for residual palatoalveolar cleft defects: a new classification. AB - Oral rehabilitation of adult patients with cleft lip and palate is related to the severity of the anatomical and functional alterations that hamper the proper closure of the nasopharynx. The ideal treatment is closure by bone graft and orthodontics. However, when surgery is not possible or when the patient does not wish to undergo surgery, a palatal prosthesis may offer the best solution in most clinical situations. The authors of this article propose a new classification to help the practitioner with decision making and prosthetic treatment planning for residual palatoalveolar cleft defects. PMID- 25822304 TI - The combination of digital surface scanners and cone beam computed tomography technology for guided implant surgery using 3Shape implant studio software: a case history report. AB - The incorporation of virtual engineering into dentistry and the digitization of information are providing new perspectives and innovative alternatives for dental treatment modalities. The use of digital surface scanners with surgical planning software allows for the combination of the radiographic, prosthetic, surgical, and laboratory fields under a common virtual scenario, permitting complete digital treatment planning. In this article, the authors present a clinical case in which a guided implant surgery was performed based on a complete digital surgical plan combining the information from a cone beam computed tomography scan and the virtual simulation obtained from the 3Shape TRIOS intraoral surface scanner. The information was imported to and combined in the 3Shape Implant Studio software for guided implant surgery planning. A surgical guide was obtained by a 3D printer, and the surgical procedure was done using the Biohorizons Guided Surgery Kit and its protocol. PMID- 25822305 TI - Reliability of the impression replica technique. AB - The aim of this study was to evaluate the reliability of the impression replica technique with a four-unit zirconia fixed dental prosthesis (FDP). Marginal and internal fit were measured by repeatedly placing the FDP on an epoxy cast using light-body silicone material corresponding to cement. All measured marginal and internal fit points showed varying values. The greatest variations were seen at the most distal margin (33 MUm) and at the distal abutment of the FDP (77 MUm). The results showed that the technique gives moderate variations and is a useful method to evaluate marginal and internal fit. PMID- 25822306 TI - Effects of dentifrices on subsurface dentin tubule occlusion: an in situ study. AB - PURPOSE: To evaluate, in situ, the penetration of deposits formed within the subsurface of dentin samples treated with desensitizing dentifrices designed to occlude dentin tubules compared to two controls. MATERIALS AND METHODS: Twenty eight healthy participants wore left and right intraoral appliances, each retaining four human dentin samples, for two periods of 4 days. Samples were power-brushed, outside the mouth, twice daily with test products (dentifrices containing 8% strontium or 8% arginine) or control (1,450 ppm NaF or water) and subjected to an agitated grapefruit juice acid challenge on days 3 and 4. Eighteen dentin samples were randomly selected from each treatment group and were dry fractured for scanning electron microscopy and energy-dispersive x-ray spectroscopy analysis. RESULTS: The proportion of cross-sectioned dentin tubules with subsurface occlusion (occluded to a mean of 5 +/- 2 MUm, range: 1 to 9 MUm below the surface) for the 8% strontium group on days 1 and 2 (pre-acid) was 82% (SD: 9%, 95% confidence interval [CI] = 78% to 86%) and on days 3 and 4 (post acid) was 88% (SD: 10%, CI = 83% to 93%). For 8% arginine on days 3 and 4 (post acid), the proportion was 78% (SD: 8%, CI = 74% to 82%). These results were statistically significant compared to those for controls (P < .01). The 8% arginine on days 1 and 2 (pre-acid) and water and control paste on all days revealed no subsurface deposit. CONCLUSIONS: Within the limitations of this study, cross-sectional SEM analysis suggested strontium and arginine dentifrices occlude tubules subsurface in dentin compared to negative controls following acid challenge. The desensitizing dentifrices elicit subsurface changes that may potentiate their effects for the management of dentin hypersensitivity, particularly for patients who consume acidic beverages. PMID- 25822307 TI - Metal reinforcement of a complete maxillary denture without a palate: a preliminary report. AB - This preliminary study examined laboratory-simulated differences between maxillary complete dentures with and without a palate (palateless) as well as the effect of reinforcement of the latter design. Five types of experimental dentures and three types of reinforcements were made. Strain gauges were attached, and a vertical load was applied. The strain was statistically compared using analysis of variance (P = .05). Strain recordings on the palatal side of palateless dentures without reinforcement were significantly higher than in complete dentures and palateless dentures with reinforcement (P < .05). These preliminary observations suggest that such reinforcement with a palatal bar or metal-based palate may reduce the risk of fracture and deformation. PMID- 25822308 TI - Bending properties of Ce-TZP/A nanocomposite clasps for removable partial dentures. AB - PURPOSE: Ceria-stabilized zirconia/alumina nanocomposite (Ce-TZP/A) has excellent fracture toughness and bending strength that could be useful for partial denture framework application. The aim of this study was to investigate the effects of three-dimensional (3D) geometry on the bending and fatigue properties of a model simulation of Ce-TZP/A clasps. MATERIALS AND METHODS: Half oval-shaped Ce-TZP/A rods were prepared in six 3D designs. Specimens were either of standard (width divided by thickness: 2.0/1.0 mm) or flat type (2.5/0.8 mm) cross-sectional areas with taper ratios of 1.0, 0.8, or 0.6. As a comparison, cobalt-chromium (Co-Cr) alloy rods of the same shape as the Ce-TZP/A standard shape rod were prepared. All specimens were subjected to the cantilever test and loaded until fracture. They were also cyclically loaded 106 times with various constant displacements, and the maximum displacement prior to fracture was determined for each specimen. Three-dimensional finite element analysis (3D FEA), simulating the cantilever test, was performed to determine the stress distribution during loading. RESULTS: Specimens with the standard cross-sectional shape exhibited higher rigidity and higher fracture loads than the flat specimens by the cantilever test. In addition, lower taper ratios were consistently associated with larger displacements at fracture. Fatigue tests revealed that the maximum displacement prior to fracture of Ce-TZP/A specimens was comparable to that of Co-Cr alloy specimens. The 3D FEA showed that specimens with a taper ratio of 0.6 had the least stress concentration. CONCLUSIONS: Ce-TZP/A clasp specimens with a standard cross-sectional shape and a 0.6 taper ratio exhibited the best bending properties among those tested. PMID- 25822309 TI - Prosthetic rehabilitation of edentulism prevents malnutrition in nursing home residents. AB - To investigate the association between prosthetic rehabilitation and malnutrition in institutionalized elders, 255 nursing home residents were recruited for this study and underwent a comprehensive dental examination. The body mass index (BMI) was administered to estimate the nutritional condition. Participants with BMI < 20 kg/mc were categorized as malnourished (n = 33), whereas all others were categorized as adequately nourished (n = 222). The number of teeth present and the prevalence of prosthetic rehabilitation were significantly lower in malnourished participants (P < .05). Malnutrition risk was 4.6 times higher for participants who were edentulous and did not wear dentures. Adequate replacement of teeth is important to prevent malnutrition in institutionalized older people. PMID- 25822310 TI - Phase II study of capecitabine and the oral mTOR inhibitor everolimus in patients with advanced pancreatic cancer. AB - PURPOSE: The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patients. METHODS: Patients with advanced adenocarcinoma of the pancreas were enrolled. Eligible patients had a WHO performance status 0-2 and adequate hepatic and renal functions. The treatment regimen consisted of capecitabine 1000 mg/m(2) BID day 1-14 and everolimus 10 mg daily (5 mg BID) in a continuous 21-day schedule. Tumor assessment was performed with CT-scan every three cycles. Primary endpoint was response rate (RR) according to RECIST 1.0. Secondary endpoints were progression-free survival, overall survival and 1-year survival rate. RESULTS: In total, 31 patients were enrolled. Median (range) treatment duration with everolimus was 76 days (1-431). Principal grade 3/4 toxicities were hyperglycemia (45 %), hand-foot syndrome (16 %), diarrhea (6 %) and mucositis (3 %). Prominent grade 1/2 toxicities were anemia (81 %), rash (65 %), mucositis (58 %) and fatigue (55 %). RR was 6 %. Ten patients (32 %) had stable disease resulting in a disease control rate of 38 %. Median overall survival was 8.9 months (95 % CI 4.6-13.1). Progression-free survival was 3.6 months (95 % CI 1.9-5.3). CONCLUSIONS: The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer, with an acceptable toxicity profile at the applied dose level. PMID- 25822311 TI - Multidimensional clinical phenotyping of an adult cystic fibrosis patient population. AB - BACKGROUND: Cystic Fibrosis (CF) is a multi-systemic disease resulting from mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene and has major manifestations in the sino-pulmonary, and gastro-intestinal tracts. Clinical phenotypes were generated using 26 common clinical variables to generate classes that overlapped quantiles of lung function and were based on multiple aspects of CF systemic disease. METHODS: The variables included age, gender, CFTR mutations, FEV1% predicted, FVC% predicted, height, weight, Brasfield chest xray score, pancreatic sufficiency status and clinical microbiology results. Complete datasets were compiled on 211 subjects. Phenotypes were identified using a proximity matrix generated by the unsupervised Random Forests algorithm and subsequent clustering by the Partitioning around Medoids (PAM) algorithm. The final phenotypic classes were then characterized and compared to a similar dataset obtained three years earlier. FINDINGS: Clinical phenotypes were identified using a clustering strategy that generated four and five phenotypes. Each strategy identified 1) a low lung health scores phenotype, 2) a younger, well-nourished, male-dominated class, 3) various high lung health score phenotypes that varied in terms of age, gender and nutritional status. This multidimensional clinical phenotyping strategy identified classes with expected microbiology results and low risk clinical phenotypes with pancreatic sufficiency. INTERPRETATION: This study demonstrated regional adult CF clinical phenotypes using non-parametric, continuous, ordinal and categorical data with a minimal amount of subjective data to identify clinically relevant phenotypes. These studies identified the relative stability of the phenotypes, demonstrated specific phenotypes consistent with published findings and identified others needing further study. PMID- 25822313 TI - The effects of chronological age and size on toxicity of zinc to juvenile brown trout. AB - A series of toxicity tests were conducted to investigate the role of chronological age on zinc tolerance in juvenile brown trout (Salmo trutta). Four different incubation temperatures were used to control the maturation of the juveniles before zinc exposures. These 96-h exposures used flow-through conditions and four chronological ages of fish with weights ranging from 0.148 to 1.432 g. Time-to-death (TTD) data were collected throughout the exposure along with the final mortality. The results indicate that chronological age does not play a predictable role in zinc tolerance for juvenile brown trout. However, a relationship between zinc tolerance and fish size was observed in all chronological age populations, which prompted us to conduct additional exploratory data analysis to quantify how much of an effect size had during this stage of development. The smallest fish (0.148-0.423 g) were shown to be less sensitive than the largest fish (0.639-1.432 g) with LC50 values of 868 and 354 ug Zn/L, respectively. The Kaplan-Meier product estimation method was used to determine survival functions from the TTD data and supports the LC50 results with a greater median TTD for smaller fish than larger juvenile fish. These results indicate that fish size or a related characteristic may be a significant determinant of susceptibility and should be considered in acute zinc toxicity tests with specific attention paid to the expected exposure scenario in the field. PMID- 25822312 TI - Probing the protective mechanism of poly-beta-hydroxybutyrate against vibriosis by using gnotobiotic Artemia franciscana and Vibrio campbellii as host-pathogen model. AB - The compound poly-beta-hydroxybutyrate (PHB), a polymer of the short chain fatty acid beta-hydroxybutyrate, was shown to protect experimental animals against a variety of bacterial diseases, (including vibriosis in farmed aquatic animals), albeit through undefined mechanisms. Here we aimed at unraveling the underlying mechanism behind the protective effect of PHB against bacterial disease using gnotobiotically-cultured brine shrimp Artemia franciscana and pathogenic Vibrio campbellii as host-pathogen model. The gnotobiotic model system is crucial for such studies because it eliminates any possible microbial interference (naturally present in any type of aquatic environment) in these mechanistic studies and furthermore facilitates the interpretation of the results in terms of a cause effect relationship. We showed clear evidences indicating that PHB conferred protection to Artemia host against V. campbellii by a mechanism of inducing heat shock protein (Hsp) 70. Additionally, our results also showed that this salutary effect of PHB was associated with the generation of protective innate immune responses, especially the prophenoloxidase and transglutaminase immune systems - phenomena possibly mediated by PHB-induced Hsp70. From overall results, we conclude that PHB induces Hsp70 and this induced Hsp70 might contribute in part to the protection of Artemia against pathogenic V. campbellii. PMID- 25822314 TI - Serum-free suspension culturing of human cells: adaptation, growth, and cryopreservation. AB - Human cell lines have attracted great interest because they are capable of producing glycosylated proteins that are more similar to native human proteins, thereby reducing the potential for immune responses. However, these cells have not been extensively characterized and cultured under serum-free suspension conditions. In this work, we describe the adaptation, growth, and cryopreservation of the human cell lines SK-Hep-1, HepG2, and HKB-11 under serum free suspension conditions. The results showed that both HKB-11 and SK-Hep-1 adapted to serum-free suspension cultures in FreeStyle and SFM II, respectively. Kinetic characterization showed that the HKB-11 and SK-Hep-1 cells reached cell densities as high as 8.6 * 10(6) and 1.9 * 10(6) cells/mL, respectively. The maximum specific growth rates (MU max) were similar for both cells (0.0159/h for HKB-11 and 0.0186/h for SK-Hep-1). The growth limitation of adapted cells does not appear to be associated with glucose or glutamine depletion, nor with the formation of lactate in inhibitory concentrations. However, in both cases, ammonia production reached concentrations that are considered inhibitory to mammalian cells (2-5 mM). The adapted cells were also successfully cryopreserved under serum-free formulations. The SK-HEP-1 and HKB-11 cells that were adapted to serum-free suspension conditions might be suitable for use in the manufacturing of recombinant proteins, thereby eliminating the potential for the introduction of adventitious process contamination and greatly simplifying downstream protein purification. PMID- 25822315 TI - Correction to Fox, Meyer, and Vogt (2015). AB - Reports an error in "Attitudes about the VA health-care setting, mental illness, and mental health treatment and their relationship with VA mental health service use among female and male OEF/OIF veterans" by Annie B. Fox, Eric C. Meyer and Dawne Vogt (Psychological Services, 2015[Feb], Vol 12[1], 49-58). The institutional affiliation in the byline for Annie B. Fox and Dawne Vogt did not include the National Center for Posttraumatic Stress Disorder. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2014-45062-001.) In the present study, the authors explored gender differences in attitudinal barriers to and facilitators of care for Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans and examined the relationship of those factors with VA mental health service use among female and male veterans with probable mental health conditions. Data were collected as part of a national cross-sectional survey of OEF/OIF veterans; the current sample was limited to participants with a probable diagnosis of posttraumatic stress disorder, depression, or alcohol abuse (N = 278). Although negligible gender differences were observed in attitudes about VA care and perceived fit in the VA setting, men reported slightly more negative beliefs about mental illness and mental health treatment than women. In addition, logistic regressions revealed different associations with VA mental health service use for women and men. For women only, positive perceptions of VA care were associated with increased likelihood of seeking mental health treatment. For men only, perceived similarity to other VA care users and negative beliefs about mental health treatment were associated with increased likelihood of service use, whereas negative beliefs about mental illness were associated with lower likelihood of service use. For both women and men, perceived entitlement to VA care was associated with increased likelihood of service use and negative beliefs about treatment-seeking were associated with a reduced likelihood of seeking mental health care in the past 6 months. Results support the need for tailored outreach to address unique barriers to mental health treatment for female and male OEF/OIF veterans. PMID- 25822316 TI - African American and European American veterans' perspectives on receiving mental health treatment. AB - Little is known about client attitudes, especially veterans', toward the types of structured interventions that are increasingly being offered in public sector and U.S. Department of Veterans Affairs mental health clinics, nor is the possible impact these attitudes may have on treatment engagement well understood. Previous work indicates that attitudes of African Americans and European Americans toward treatment may differ in important ways. Attitudes toward treatment have been a proposed explanation for lower treatment engagement and higher dropout rates among African Americans compared with European Americans. Yet to date, the relationship between race and attitudes toward treatment and treatment outcomes has been understudied and the findings inconclusive. The purpose of this study was to explore African American and European American veteran attitudes toward mental health care, especially as they relate to structured treatments. Separate focus groups were conducted with 24 African American and 37 European American military veterans. In general, both groups reported similar reasons for seeking 0treatment and similar thoughts regarding the purpose of therapy. Differences emerged primarily regarding therapist preferences. In both groups, some participants expressed favorable opinions of structured treatments and others expressed negative views; treatment preferences did not appear to be influenced by race. PMID- 25822317 TI - Gender, Ethnicity and Environmental Risk Perception Revisited: The Importance of Residential Location. AB - Studies in the U.S. have found that white men are less concerned about pollution than are women or people of other ethnicity. These studies have not assessed respondents' proximity to localized sources of pollution. Our objective was to assess lay perceptions of risk from air pollution in an ethnically diverse sample in which proximity to a major perceptible source of pollution is known. Cross sectional interview study of combined area probability and convenience sample of individuals 40 and older in the Boston area, selected according to proximity to high traffic controlled access highways. Of 697 respondents 46% were white, 37% Asian (mostly Chinese), 6.3% African-American, 6.3% Latino, and 7.6% other ethnicity. While white respondents, and particularly white men, were less concerned about air pollution than others, this effect disappeared when controlling for distance from the highway. White men were slightly less supportive than others of government policy to control pollution. The "white male" effect may in part be accounted for by the greater likelihood of minority respondents to live near perceptible localized sources of pollution. PMID- 25822318 TI - Exposure to and health effects of volatile PCBs. AB - INTRODUCTION: Polychlorinated biphenyls (PCBs) are persistent, lipophilic contaminants that are known to increase risk of a number of human diseases. Although ingestion of animal fats is a major route of exposure, there is increasing evidence that inhalation of vapor-phase PCBs is also important and may be as or even more important than ingestion under some circumstances. METHODS: The evidence that inhalation of PCBs may cause cancer, heart disease, hypertension, and diabetes is reviewed and presented in this report. RESULTS: PCBs are known human carcinogens. A husband and wife, occupationally required to 'smell' PCB-containing oils, both developed thyroid cancer, malignant melanoma/severely melanocytic dysplastic nevus (a precursor to malignant melanoma) and the husband, a non-smoker, developed and died of lung cancer. The serum of both had highly elevated concentrations of lower chlorinated, volatile PCB congeners. In other studies, residents living near PCB-containing hazardous waste sites, and thus breathing PCB-contaminated air, have elevated rates of hospitalization for cardiovascular disease, hypertension, diabetes and reduced cognitive performance, whereas other studies in defined populations show that there is an elevated risk of all of these diseases in individuals with elevated serum PCBs. CONCLUSIONS: These results are consistent with the conclusion that inhaled PCBs can increase risk of cancer, cardiovascular disease, hypertension, diabetes and reduce cognitive function. PMID- 25822319 TI - Development of banana-based weaning food mixes for infants and its nutritional quality evaluation. AB - Banana-based weaning food mixes were developed from the Nendran variety to study the nutritional quality of the mixes and feasibility of marketing on a commercial scale. Chemical composition viz., moisture, acid, pH, reducing and total sugars, protein and beta-carotene of the developed banana-based weaning mixes were analysed. The trypsin inhibitor activity reduced during cooking, and the flatus compound could not be measured due to its very meagre gas production. The alpha amylase activity and in vitro protein and carbohydrate digestibilities were also analysed. A feeding trial of the developed mixes was conducted in infants as a supplement to study the nutritional quality of the developed banana-based weaning food mixes. Results showed an increase in all the anthropometric measurements during the feeding period, and the developed mixes can be prepared on a commercial scale to prevent malnutrition and undernutrition during the rapid growing period of infants. PMID- 25822320 TI - Association of DDT and heptachlor epoxide in human blood with diabetic nephropathy. AB - Six organochlorine pesticides and pesticide metabolites in human blood were tested to determine their relationships with diabetic nephropathy. The data were derived from the National Health and Nutrition Examination Survey (NHANES) 1999 2004 (unweighted, n=2992, population estimate=133,088,752). The six chemicals were p,p'-DDT (dichlorodiphenyltrichloroethane), p,p'-DDE (dichlorodiphenyltrichloroethylene), beta-hexachlorocyclohexane, oxychlordane, trans-nonachlor and heptachlor epoxide. In this research, total diabetes included diagnosed and undiagnosed diabetes (glycohemoglobin, A1c >=6.5%), and nephropathy was defined as a urinary albumin to creatinine ratio >30 mg/g, representing microalbuminuria and macroalbuminuria. The pesticide p,p'-DDT and pesticide metabolite heptachlor epoxide were significantly associated with total diabetes with nephropathy, with odds ratios of 2.08 (95% CI 1.06-4.11) and 1.75 (95% CI 1.05-2.93), respectively. Organochlorine pesticides are thought to act through the constitutive androstane receptor/pregnane X receptor disease pathway, but this is not well established. When p,p'-DDT and heptachlor epoxide were both elevated, the odds ratio for diabetic nephropathy was 2.76 (95% CI 1.31-5.81), and when six of six organochlorine pesticides and pesticide metabolites, were elevated, the odds ratio for diabetic nephropathy was 3.00 (95% CI 1.08-8.36). The differences in the odds ratios for these groups appear to be due to differences in the mean heptachlor epoxide concentration of each category. Organochlorine pesticides and pesticide metabolites are known to have estrogenic, antiestrogenic or antiandrogenic activity. The constitutive androstane receptor/pregnane X receptor pathway is thought to interact with the aryl hydrocarbon receptor pathway, and the associations noted may be due to that interaction. PMID- 25822321 TI - The association of first trimester bleeding with preterm delivery. AB - INTRODUCTION: Preterm birth (PTB) is a predictor of perinatal morbidity and mortality, and prematurity continues to burden public healthcare with growing expenses. First trimester bleeding (FTB) has a well-known association with PTB; however, the relationship with severity of PTB is less obvious. AIM: The primary aim of the study was to analyze the influence of FTB on the risk and severity of PTB, as well as to assess the connection of FTB and other pregnancy complications. METHODS: It was an observational case control study. The material consisted of medical records of patients who delivered between 2010 and 2013. Two groups were formed - 497 women with FTB and 500 women without bleeding. RESULTS: Women with FTB were more likely to deliver preterm in general (OR=2.11; 95% CI 1.43-3.10). The risk of extremely PTB (<28 weeks) was almost four-fold (OR=3.76; 95% CI 0.97-17.06) and very PTB (28-31 weeks) more than three-fold (OR=3.41; 95% CI 0.86-15.69). FTB increased the risk of placenta previa (OR=4.81; 95% CI 1.29 20.53; P=0.007). CONCLUSION: FTB is a risk factor of PTB and is associated with greater risk of PTB-related pregnancy complications. Management of FTB pregnancies should include thorough screening for both preterm delivery and placental pathologies. PMID- 25822322 TI - A study examining the bias of albumin and albumin/creatinine ratio measurements in urine. AB - BACKGROUND: The objective of the study was to examine the bias of albumin and albumin/creatinine (ACR) measurements in urine. METHODS: Pools of normal human urine were augmented with purified human serum albumin to generate a series of 12 samples covering the clinical range of interest for the measurement of ACR. Albumin and creatinine concentrations in these samples were analyzed three times on each of 3 days by 24 accredited laboratories in Canada and the USA. Reference values (RV) for albumin measurements were assigned by a liquid chromatography tandem mass spectrometry (LC-MS/MS) comparative method and gravimetrically. Ten random urine samples (check samples) were analyzed as singlets and albumin and ACR values reported according to the routine practices of each laboratory. RESULTS: Augmented urine pools were shown to be commutable. Gravimetrically assigned target values were corrected for the presence of endogenous albumin using the LC-MS/MS comparative method. There was excellent agreement between the RVs as assigned by these two methods. All laboratory medians demonstrated a negative bias for the measurement of albumin in urine over the concentration range examined. The magnitude of this bias tended to decrease with increasing albumin concentrations. At baseline, only 10% of the patient ACR values met a performance limit of RV +/- 15%. This increased to 84% and 86% following post analytical correction for albumin and creatinine calibration bias, respectively. CONCLUSIONS: International organizations should take a leading role in the standardization of albumin measurements in urine. In the interim, accuracy based urine quality control samples may be used by clinical laboratories for monitoring the accuracy of their urinary albumin measurements. PMID- 25822323 TI - Selective synthesis of ruthenium(II) Metalla[2]catenane via solvent and guest dependent self-assembly. AB - The coordination-driven self-assembly of an anthracene-functionalized ditopic pyridyl donor and a tetracene-based dinuclear Ru(II) acceptor resulted in an interlocked metalla[2]catenane, [M2L2]2, in methanol and a corresponding monorectangle, [M2L2], in nitromethane. Subsequently, guest template, solvent, and concentration effects allowed the self-assembly to be reversibly fine-tuned among monorectangle and catenane structures. PMID- 25822324 TI - The History of US: From Bats and Boats to the Bedside and Beyond: RSNA Centennial Article. PMID- 25822325 TI - Which patients require or can skip biopsy for breast clustered microcysts? Predictive findings of breast cancer and mucocele-like tumor. AB - BACKGROUND: In order to determine the patients who require biopsy for breast clustered microcysts, we retrospectively investigated cases of clustered microcysts that were detected by ultrasonography (US) examinations. METHODS: We investigated 52 patients in whom clustered microcysts were detected by US and who underwent biopsy at our institution between January 2011 and March 2014. These patients were divided into two groups according to histopathological findings: those with invasive carcinoma (IC), ductal carcinoma in situ (DCIS), or mucocele like tumor (MLT) (Group 1), and those with benign lesions (Group 2). Mammography (MG) and magnetic resonance imaging (MRI) findings were assessed in these two groups. RESULTS: There were 12 patients in Group 1 (IC:2, DCIS:6, and MLT:4) and 40 patients in Group 2. In 51 of the 52 patients, MG was performed before biopsy. Since 11 of 12 patients in Group 1 exhibited MG findings (mass, focal asymmetry, coarse heterogeneous calcifications and fine pleomorphic calcifications) at the same site as the clustered microcysts, and that MG findings had a significant probability of detecting clustered microcysts categorized into Group 1 with a sensitivity of 91.7 % and negative predictive value (NPV) of 96.8 % (p < 0.001). In contrast, MRI was performed in 39 of the 52 patients, and only 3 of the 9 Group 1 patients (33.3 %) for whom MRI was performed were detected as MRI Category 4 or 5 enhancement. CONCLUSION: The patients who exhibit clustered microcysts with MG findings (mass, focal asymmetry, coarse heterogeneous calcifications and fine pleomorphic calcifications) appear to require biopsy. PMID- 25822326 TI - Mental Health Clinicians' Participation in Web-Based Training for an Evidence Supported Intervention: Signs of Encouragement and Trouble Ahead. AB - Comprehensive scalable clinician training is needed to increase the impact of evidence-supported psychotherapies. This study was designed to ascertain clinician participation in different low-cost training activities, what predicts their training participation, and how participation can be increased. The study enrolled 163 clinicians. Of these, 105 completed a follow-up survey and 20 completed a more in-depth qualitative interview. Some activities (web training) attracted greater participation than others (e.g., discussion boards, role playing). Key findings include the desirability of self-paced learning and the flexibility it afforded practicing clinicians. However, some found the lack of accountability insurmountable. Many desired in-person training as a way to introduce accountability and motivation. While low-cost, relevant, self-paced learning appeals to practicing clinicians, it may need to be combined with opportunities for in-person training and accountability mechanisms in order to encourage large numbers of clinicians to complete training. PMID- 25822327 TI - Cost-minimization analysis of panitumumab compared with cetuximab for first-line treatment of patients with wild-type RAS metastatic colorectal cancer. AB - OBJECTIVE: To compare the costs of first-line treatment with panitumumab + FOLFOX in comparison to cetuximab + FOLFIRI among patients with wild-type (WT) RAS metastatic colorectal cancer (mCRC) in the US. METHODS: A cost-minimization model was developed assuming similar treatment efficacy between both regimens. The model estimated the costs associated with drug acquisition, treatment administration frequency (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions. Average anti-EGFR doses were calculated from the ASPECCT clinical trial, and average doses of chemotherapy regimens were based on product labels. Using the medical component of the consumer price index, adverse event costs were inflated to 2014 US dollars, and all other costs were reported in 2014 US dollars. The time horizon for the model was based on average first-line progression-free survival of a WT RAS patient, estimated from parametric survival analyses of PRIME clinical trial data. RESULTS: Relative to cetuximab + FOLFIRI in the first-line treatment of WT RAS mCRC, the cost minimization model demonstrated lower projected drug acquisition, administration, and adverse event costs for patients who received panitumumab + FOLFOX. The overall cost per patient for first-line treatment was $179,219 for panitumumab + FOLFOX vs $202,344 for cetuximab + FOLFIRI, resulting in a per-patient saving of $23,125 (11.4%) in favor of panitumumab + FOLFOX. CONCLUSIONS: From a value perspective, the cost-minimization model supports panitumumab + FOLFOX instead of cetuximab + FOLFIRI as the preferred first-line treatment of WT RAS mCRC patients requiring systemic therapy. PMID- 25822329 TI - Critical factors and their effects on product maturity in food waste composting. AB - Product maturity represents the efficiency of composting performance, and it calls for high attention in food waste composting. In this study, a 2(4-1) fractional factorial design method combined with well-controlled experiments was introduced to characterize the effects of system factors (i.e., C/N ratio, aeration rate, starting culture amount, and coal ash amendment) on product maturity of food waste composting. The compost maturity was synthetically evaluated by developing a Mamdani fuzzy rule-based inference system. Temperature index, O2 uptake rate, ammonium, OM loss, C/N ratio, and ash content were chosen as indicators of the fuzzy multicriterion maturity evaluation. Evaluation results of compost maturity for the eight experiment runs demonstrated that the proposed method is capable of evaluating the compost maturity in food waste composting. The effect analyses indicated that the starting culture amount and aeration rate contributed the most to the compost maturity in this study. The results could provide decision support for the process control in food waste composting management. PMID- 25822330 TI - Heavy metals in fish from the Red Sea, Arabian Sea, and Indian Ocean: effect of origin, fish species and size and correlation among the metals. AB - This study determined the levels of As, Cu, Pb, and Cd in fish from Red Sea, Arabian Sea, and Indian Ocean by graphite furnace atomic absorption spectrophotometry. Metal levels were compared with international standards. The levels among fish types and origin, the relationship among metals, and the correlation between the levels and fish size were statistically tested. Fish type and origin significantly affected the levels. None of the fish contained As, Cu, and Pb above the FAO and EU codes. However, Cd exceeded the Jordanian, FAO, and EC codes from the three origins. As and Cd positively correlated with each other in Arabian Sea fish. As and Pb correlated negatively, but Cu and Cd did not correlate with fish size. This study indicates that Cd is common in fish from the three origins regardless the fish size. This warrants continuous monitoring for heavy metals, especially Cd, in internationally traded fish. PMID- 25822331 TI - Cisplatin release from dual-responsive magnetic nanocomposites. AB - BACKGROUND: The combination of hyperthermia and controlled drug delivery is a very promising recent effort in cancer therapy. The aim of this study is to synthesize and characterize a dual pH/thermal-responsive composite nanoparticle that acts as a cisplatin carrier, and to evaluate its release profile at different pH and temperature conditions relevant to the physiological and cancerous environment during hyperthermia. METHODS: Poly (n-isopropyl acrylamide methacrylic acid-hydroxy ethyl methacrylate) (P (NIPAAM-MAA-HEM)) was synthesized by emulsion polymerization. Fe3O4 magnetic nanoparticles (MNPs) and cisplatin were loaded onto the nanogel, by the swelling method and the conjugation of cisplatin with the -COOH group of MAA, respectively. The chemical and morphological properties of the drug-loaded composite nanoparticle and its profile of drug release at pH levels of 7.4 (physiological pH), 6.8 (tumor extracellular pH), and 5.3 (endosomal pH), and at temperatures of 37 degrees C (physiological) and 43 degrees C (hyperthermia), were studied. RESULTS: The result shows that the synthesized nanogel and nanocomposite were almost pure and were of an appropriate size and stability. Magnetic saturation was at a position appropriate for the production of enough heat during hyperthermia. A high level of drug release under conditions of low pH and high temperature was observed. CONCLUSION: This result suggests that the dual pH/temperature-responsive P (NIPAAM-MAA-HEM) magnetic nanocomposite can be very effective in hyperthermia and controlled cisplatin delivery. PMID- 25822333 TI - Characteristics and mid-term follow-up of a single-center population affected by Tako-Tsubo cardiomyopathy. AB - INTRODUCTION: Tako-Tsubo cardiomyopathy (TTC) is an acute cardiomyopathy mimicking acute myocardial infarction. The aim of our study was to define clinical and instrumental features of an Italian population of patients with TTC and to report their short and mid-term outcome. METHODS: We retrospectively evaluated 42 patients admitted to our Department with diagnosis of TTC (100% women, age 67 +/- 11 years) using Mayo Clinic-modified criteria. In this population, we analyzed the stressful event (if present), the clinical presentation, the ECG and echocardiogram at admission and the markers of myocardial cytonecrosis, such as troponin I, at admission and during the hospitalization. All the patients have been clinically evaluated after 6 months and 1 year of follow-up. RESULTS: In this population, a stressful event before TTC has been detected in 59% of patients. The most common clinical presentation was chest pain (81%) and the major sign was dyspnea (17%). ECG showed negative T waves and ST elevation, respectively, in 45 and 38%. Only 10% had a ST depression and 7% developed a newly acquired complete left bundle branch block. All of these abnormalities disappeared within 1.8 +/- 0.9 days. The mean ejection fraction at admission was 35 +/- 7% associated with apical (40%), mid-apical (56%) and mid ventricular (4%) wall motion abnormalities. The recovery of these abnormalities occurred within 10 +/- 3 days. At 6-month and 1-year follow-up, no patients had TTC recurrence, and 10 patients at 6 months and 20 patients at 1 year were re hospitalized for a non-cardiac cause. CONCLUSION: Our data describe the characteristics of TTC in a small Italian population, which are similarly described in Japanese and North American people. TTC was related to a very low mortality, both in the short and mid term, but the risk of acute heart failure in the acute phase could not be neglected. PMID- 25822332 TI - Three-dimensional numerical model of cell morphology during migration in multi signaling substrates. AB - Cell Migration associated with cell shape changes are of central importance in many biological processes ranging from morphogenesis to metastatic cancer cells. Cell movement is a result of cyclic changes of cell morphology due to effective forces on cell body, leading to periodic fluctuations of the cell length and cell membrane area. It is well-known that the cell can be guided by different effective stimuli such as mechanotaxis, thermotaxis, chemotaxis and/or electrotaxis. Regulation of intracellular mechanics and cell's physical interaction with its substrate rely on control of cell shape during cell migration. In this notion, it is essential to understand how each natural or external stimulus may affect the cell behavior. Therefore, a three-dimensional (3D) computational model is here developed to analyze a free mode of cell shape changes during migration in a multi-signaling micro-environment. This model is based on previous models that are presented by the same authors to study cell migration with a constant spherical cell shape in a multi-signaling substrates and mechanotaxis effect on cell morphology. Using the finite element discrete methodology, the cell is represented by a group of finite elements. The cell motion is modeled by equilibrium of effective forces on cell body such as traction, protrusion, electrostatic and drag forces, where the cell traction force is a function of the cell internal deformations. To study cell behavior in the presence of different stimuli, the model has been employed in different numerical cases. Our findings, which are qualitatively consistent with well-known related experimental observations, indicate that adding a new stimulus to the cell substrate pushes the cell to migrate more directionally in more elongated form towards the more effective stimuli. For instance, the presence of thermotaxis, chemotaxis and electrotaxis can further move the cell centroid towards the corresponding stimulus, respectively, diminishing the mechanotaxis effect. Besides, the stronger stimulus imposes a greater cell elongation and more cell membrane area. The present model not only provides new insights into cell morphology in a multi-signaling micro-environment but also enables us to investigate in more precise way the cell migration in the presence of different stimuli. PMID- 25822336 TI - Correction: What happened if various kinds of postconditioning working on the preconditioned ischemic skin flaps. PMID- 25822334 TI - Establishment and characterization of rat portal myofibroblast cell lines. AB - The major sources of scar-forming myofibroblasts during liver fibrosis are activated hepatic stellate cells (HSC) and portal fibroblasts (PF). In contrast to well-characterized HSC, PF remain understudied and poorly defined. This is largely due to the facts that isolation of rodent PF for functional studies is technically challenging and that PF cell lines had not been established. To address this, we have generated two polyclonal portal myofibroblast cell lines, RGF and RGF-N2. RGF and RGF-N2 were established from primary PF isolated from adult rat livers that underwent culture activation and subsequent SV40-mediated immortalization. Specifically, Ntpdase2/Cd39l1-sorted primary PF were used to generate the RGF-N2 cell line. Both cell lines were functionally characterized by RT-PCR, immunofluorescence, immunoblot and bromodeoxyuridine-based proliferation assay. First, immortalized RGF and RGF-N2 cells are positive for phenotypic myofibroblast markers alpha smooth muscle actin, type I collagen alpha-1, tissue inhibitor of metalloproteinases-1, PF-specific markers elastin, type XV collagen alpha-1 and Ntpdase2/Cd39l1, and mesenchymal cell marker ecto-5' nucleotidase/Cd73, while negative for HSC-specific markers desmin and lecithin retinol acyltransferase. Second, both RGF and RGF-N2 cell lines are readily transfectable using standard methods. Finally, RGF and RGF-N2 cells attenuate the growth of Mz-ChA-1 cholangiocarcinoma cells in co-culture, as previously demonstrated for primary PF. Immortalized rat portal myofibroblast RGF and RGF-N2 cell lines express typical markers of activated PF-derived myofibroblasts, are suitable for DNA transfection, and can effectively inhibit cholangiocyte proliferation. Both RGF and RGF-N2 cell lines represent novel in vitro cellular models for the functional studies of portal (myo)fibroblasts and their contribution to the progression of liver fibrosis. PMID- 25822338 TI - Accurate Time-Dependent Wave Packet Calculations for the O(+) + H2 -> OH(+) + H Ion-Molecule Reaction. AB - Accurate quantum reactive scattering time-dependent wave packet close-coupling calculations have been carried out to determine total reaction probabilities and integral cross sections for the O(+) + H2 -> OH(+) + H reaction in a range of collision energies from 10(-3) eV up to 1.0 eV for the H2 rovibrational states (v = 0; j = 0, 1, 2) and (v = 1; j = 0) using the potential energy surface (PES) by Martinez et al. As expected for a barrierless reaction, the reaction cross section decays rapidly with collision energy, Ec, following a behavior that nearly corresponds to that predicted by the Langevin model. Rotational excitation of H2 into j = 1, 2 has a very moderate effect on reactivity, similarly to what happens with vibrational excitation below Ec ~ 0.3 eV. However, at higher collision energies the cross section increases notably when H2 is promoted to v = 1. This effect is explained by resorting to the effective potentials in the entrance channel. The integral cross sections have been used to calculate rate constants in the temperature range 200-1000 K. A good overall agreement has been found with the available experimental data on integral cross sections and rate constants. In addition, time-independent quantum mechanical and quasi-classical trajectory (QCT) calculations have been performed on the same PES aimed to compare the various methodologies and to discern the detailed mechanism of the title reaction. In particular, the analysis of individual trajectories has made it possible to explain, in terms of the coupling between reagent relative velocity and the topography of the PES, the presence of a series of alternating maxima and minima in the collision energy dependence of the QCT reaction probabilities for the reactions with H2(v=0,1,j=0), which are absent in the quantum mechanical calculations. PMID- 25822337 TI - Conantokin-G attenuates detrimental effects of NMDAR hyperactivity in an ischemic rat model of stroke. AB - The neuroprotective activity of conantokin-G (con-G), a naturally occurring antagonist of N-methyl-D-aspartate receptors (NMDAR), was neurologically and histologically compared in the core and peri-infarct regions after ischemia/reperfusion brain injury in male Sprague-Dawley rats. The contralateral regions served as robust internal controls. Intrathecal injection of con-G, post middle carotid artery occlusion (MCAO), caused a dramatic decrease in brain infarct size and swelling at 4 hr, compared to 26 hr, and significant recovery of neurological deficits was observed at 26 hr. Administration of con-G facilitated neuronal recovery in the peri-infarct regions as observed by decreased neurodegeneration and diminished calcium microdeposits at 4 hr and 26 hr. Intact Microtubule Associated Protein (MAP2) staining and neuronal cytoarchitecture was observed in the peri-infarct regions of con-G treated rats at both timepoints. Con-G restored localization of GluN1 and GluN2B subunits in the neuronal soma, but not that of GluN2A, which was perinuclear in the peri-infarct regions at 4 hr and 26 hr. This suggests that molecular targeting of the GluN2B subunit has potential for reducing detrimental consequences of ischemia. Overall, the data demonstrated that stroke-induced NMDAR excitoxicity is ameliorated by con-G mediated repair of neurological and neuroarchitectural deficits, as well as by reconstituting neuronal localization of GluN1 and GluN2B subunits in the peri infarct region of the stroked brain. PMID- 25822339 TI - Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma. AB - Liposarcoma (LPS) is a type of soft tissue sarcoma that mostly occurs in adults, and in humans is characterized by amplifications of MDM2 and CDK4. The molecular pathogenesis of this malignancy is still poorly understood and, therefore, we developed a mouse model with conditional inactivation of PTEN and p53 to investigate these pathways in the progression of the disease. We show that deletion of these two tumor suppressors cooperate in the formation of multiple subtypes of LPS (from well-differentiated LPS to pleomorphic LPS). In addition, progression of the tumors is further characterized by the expression of D cyclins and CDK4/6, which allow for continued cell division. Microarray analysis also revealed novel genes that are differentially expressed between different subtypes of LPS, which could aid in understanding the disease and to unravel potential new therapeutic targets. PMID- 25822340 TI - Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry. AB - Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3beta pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR. PMID- 25822342 TI - Differential response of fish assemblages to coral reef-based seaweed farming. AB - As the global demand for seaweed-derived products drives the expansion of seaweed farming onto shallow coral ecosystems, the effects of farms on fish assemblages remain largely unexplored. Shallow coral reefs provide food and shelter for highly diverse fish assemblages but are increasingly modified by anthropogenic activities. We hypothesized that the introduction of seaweed farms into degraded shallow coral reefs had potential to generate ecological benefits for fish by adding structural complexity and a possible food source. We conducted 210 transects at 14 locations, with sampling stratified across seaweed farms and sites adjacent to and distant from farms. At a seascape scale, locations were classified by their level of exposure to human disturbance. We compared sites where (1) marine protected areas (MPAs) were established, (2) neither MPAs nor blast fishing was present (hence "unprotected"), and (3) blast fishing occurred. We observed 80,186 fish representing 148 species from 38 families. The negative effects of seaweed farms on fish assemblages appeared stronger in the absence of blast fishing and were strongest when MPAs were present, likely reflecting the positive influence of the MPAs on fish within them. Species differentiating fish assemblages with respect to seaweed farming and disturbance were typically small but also included two key target species. The propensity for seaweed farms to increase fish diversity, abundance, and biomass is limited and may reduce MPA benefits. We suggest that careful consideration be given to the placement of seaweed farms relative to MPAs. PMID- 25822341 TI - Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy. AB - Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. PMID- 25822343 TI - Inferring social status and rich club effects in enterprise communication networks. AB - Social status, defined as the relative rank or position that an individual holds in a social hierarchy, is known to be among the most important motivating forces in social behaviors. In this paper, we consider the notion of status from the perspective of a position or title held by a person in an enterprise. We study the intersection of social status and social networks in an enterprise. We study whether enterprise communication logs can help reveal how social interactions and individual status manifest themselves in social networks. To that end, we use two enterprise datasets with three communication channels--voice call, short message, and email--to demonstrate the social-behavioral differences among individuals with different status. We have several interesting findings and based on these findings we also develop a model to predict social status. On the individual level, high-status individuals are more likely to be spanned as structural holes by linking to people in parts of the enterprise networks that are otherwise not well connected to one another. On the community level, the principle of homophily, social balance and clique theory generally indicate a "rich club" maintained by high-status individuals, in the sense that this community is much more connected, balanced and dense. Our model can predict social status of individuals with 93% accuracy. PMID- 25822345 TI - Shrinking the gap between research and practice: tailoring and testing youth psychotherapies in clinical care contexts. AB - Most youth psychotherapy research involves conditions quite unlike the clinical practice it is designed to strengthen. Most studies have not tested interventions with clinically referred youths and practicing clinicians in clinical care settings, nor have they tested whether new treatments produce better outcomes than usual practice. Limited exposure to real-world conditions and questions may partially explain why empirically supported treatments show such modest effects when tested under more representative conditions, against usual care. Our deployment-focused model calls for intervention development and testing with the kinds of participants (e.g., clients and clinicians) and in the contexts (e.g., clinics) for which the interventions are ultimately intended, and for randomized comparisons to usual clinical care. Research with the Child STEPs (system and treatment enhancement projects) treatment approach illustrates the methods and potential benefits of the deployment-focused model. Findings supporting Child STEPs are but one part of a rich research matrix needed to shrink the gap between intervention research and clinical practice. PMID- 25822346 TI - Surgical interventions for treating distal tibial metaphyseal fractures in adults. AB - BACKGROUND: The distal tibial metaphysis is located in the lower (distal) part of the tibia (shin bone). Fractures of this part of the tibia are most commonly due to a high energy injury in young men and to osteoporosis in older women. The optimal methods of surgical intervention for a distal tibial metaphyseal fracture remain uncertain. OBJECTIVES: To assess the effects (benefits and harms) of surgical interventions for distal tibial metaphyseal fractures in adults. We planned to compare surgical versus non-surgical (conservative) treatment, and different methods of surgical intervention. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (9 December 2014), the Cochrane Central Register of Controlled Trials (2014, Issue 12), MEDLINE (1946 to November Week 3 2014), EMBASE (1980 to 2014 Week 48), the Airiti Library (1967 to 2014 Week 8), China Knowledge Resource Integrated Database (1915 to 2014 Week 8), ClinicalTrials.gov (February 2014) and reference lists of included studies. SELECTION CRITERIA: We included randomised and quasi-randomised controlled clinical studies comparing surgical versus non-surgical (conservative) treatment or different surgical interventions for treating distal tibial metaphyseal fractures in adults. Our primary outcomes were patient-reported function and the need for secondary or revision surgery or substantive physiotherapy because of adverse outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, assessed the risk of bias in each study and extracted data. We resolved disagreement by discussion and, where necessary, in consultation with a third author. Where appropriate we pooled data using the fixed-effect model. MAIN RESULTS: We included three randomised trials that evaluated intramedullary nailing versus plating in 213 participants, with useable data from 173 participants of whom 112 were male. The mean age of participants in individual studies ranged from 41 to 44 years. There were no trials comparing surgery with non-surgical treatment. The three included trials were at high risk of performance bias, with one trial also being at high risk of selection, detection and attrition bias. Overall, the quality of available evidence was rated as very low for all outcomes, meaning that we are very unsure about the estimates for all outcomes.The results of two large ongoing trials of nailing versus plating are likely to provide sufficient evidence to address this issue in a future update. AUTHORS' CONCLUSIONS: Overall, there is either no or insufficient evidence to draw definitive conclusions on the use of surgery or the best surgical intervention for distal tibial metaphyseal fractures in adults. The available evidence, which is of very low quality, found no clinically important differences in function or pain, and did not confirm a difference in the need for re-operation or risk of complications between nailing and plating.The addition of evidence from two ongoing trials of nailing versus plating should inform this question in future updates. Further randomised trials are warranted on other issues, but should be preceded by research to identify priority questions. PMID- 25822347 TI - Role of swi7H4 mutant allele of DNA polymerase alpha in the DNA damage checkpoint response. AB - Besides being a mediator of initiation of DNA replication, DNA polymerase alpha plays a key role in chromosome maintenance. Swi7H4, a novel temperature sensitive mutant of DNA polymerase alpha was shown to be defective in transcriptional silencing at the mating type centromere and telomere loci. It is also required for the establishment of chromatin state that can recruit the components of the heterochromatin machinery at these regions. Recently the role of DNA polymerase alpha in the S-phase alkylation damage response in S. pombe has also been studied. Here we investigate whether defects generated by swi7H4, a mutant allele of DNA polymerase alpha can activate a checkpoint response. We show that swi7H4 exhibit conditional synthetic lethality with chk1 null mutant and the double mutant of swi7H4 with chk1 deletion aggravate the chromosome segregation defects. More importantly swi7H4 mutant cells delay the mitotic progression at non permissive temperature that is mediated by checkpoint protein kinase Chk1. In addition we show that, in the swi7H4 mutant background, cells accumulate DNA damage at non permissive temperature activating the checkpoint kinase protein Chk1. Further, we observed synthetic lethality between swi7H4 and a number of genes involved in DNA repair pathway at semi permissive temperature. We summarize that defects in swi7H4 mutant results in DNA damage that delay mitosis in a Chk1 dependent manner that also require the damage repair pathway for proper recovery. PMID- 25822348 TI - Collecting psycholinguistic response time data using Amazon mechanical Turk. AB - Researchers in linguistics and related fields have recently begun exploiting online crowd-sourcing tools, like Amazon Mechanical Turk (AMT), to gather behavioral data. While this method has been successfully validated for various offline measures--grammaticality judgment or other forced-choice tasks--its use for mainstream psycholinguistic research remains limited. This is because psycholinguistic effects are often dependent on relatively small differences in response times, and there remains some doubt as to whether precise timing measurements can be gathered over the web. Here we show that three classic psycholinguistic effects can in fact be replicated using AMT in combination with open-source software for gathering response times client-side. Specifically, we find reliable effects of subject definiteness, filler-gap dependency processing, and agreement attraction in self-paced reading tasks using approximately the same numbers of participants and/or trials as similar laboratory studies. Our results suggest that psycholinguists can and should be taking advantage of AMT and similar online crowd-sourcing marketplaces as a fast, low-resource alternative to traditional laboratory research. PMID- 25822349 TI - Appropriate measures. PMID- 25822350 TI - 2014 section on pediatrics knowledge translation lecture: clinicians and researchers on the same path toward facilitating family goals for mobility and participation. AB - BACKGROUND: The knowledge translation (KT) lecture at the Combined Sections Meeting 2014 was a personal perspective from a researcher who had been a therapist and a longtime clinician, now a PhD candidate. OBJECTIVE: To better integrate research and clinical care, KT is a seamless rather than separate process. KEY POINTS: Knowledge translation can be enhanced by improved receptivity to evidence, and increasing use of research designs that encourage and even require clinician involvement, from single-subject designs to large scale pragmatic trials. Clinical practice databases and hiring therapists to provide intervention in research efforts also serve to integrate research and clinical care. Limitations of applying mean group research results to an individual patient were also discussed and suggest an important unanswered topic for future research. CONCLUSION: We all need to assume responsibility for the researcher-clinician partnership, making our jobs more joyful and fulfilling, and hopefully the biggest beneficiaries will be our current and future patients. PMID- 25822344 TI - Biological and psychosocial predictors of postpartum depression: systematic review and call for integration. AB - Postpartum depression (PPD) adversely affects the health and well being of many new mothers, their infants, and their families. A comprehensive understanding of biopsychosocial precursors to PPD is needed to solidify the current evidence base for best practices in translation. We conducted a systematic review of research published from 2000 through 2013 on biological and psychosocial factors associated with PPD and postpartum depressive symptoms. Two hundred fourteen publications based on 199 investigations of 151,651 women in the first postpartum year met inclusion criteria. The biological and psychosocial literatures are largely distinct, and few studies provide integrative analyses. The strongest PPD risk predictors among biological processes are hypothalamic-pituitary-adrenal dysregulation, inflammatory processes, and genetic vulnerabilities. Among psychosocial factors, the strongest predictors are severe life events, some forms of chronic strain, relationship quality, and support from partner and mother. Fully integrated biopsychosocial investigations with large samples are needed to advance our knowledge of PPD etiology. PMID- 25822351 TI - Measuring joint hypermobility using the Beighton scale in children with intellectual disability. AB - PURPOSE: To determine the feasibility and reliability of using the 9-point Beighton Hypermobility Score (9-BHS) with youth with intellectual disabilities using a least to most prompting technique. METHOD: One hundred one youth (5-18 years old) enrolled in the study. Two separate evaluations, separated by 3 to 4 weeks, were performed on 25 participants. RESULTS: Ninety assented to the test, and 85 performed all 9-BHS maneuvers. Scores were not significantly different for age and gender, but participants with Down syndrome had significantly higher scores. Test-retest scores showed 80% to 90% agreement (n = 25). Cohen kappa ranged from moderate (0.41-0.60) to perfect (1.0) for the 9 maneuvers, and an ICC of 0.88 was found for total scores. CONCLUSION: The results demonstrate that the use of the 9-BHS in youth with intellectual disabilities in the manner described is feasible and reliable. PMID- 25822352 TI - Commentary on "Measuring joint hypermobility using the Beighton scale in children with intellectual disability". PMID- 25822353 TI - PT graduates' perceptions of a higher education early intervention training program on employment and practice. AB - PURPOSE: The purpose of this study was to describe physical therapist graduates' perceptions of a higher education early intervention (EI) training program on postgraduation employment and practice. METHODS: Using a mixed methods approach, 13 graduates responded to an online survey and 14 participated in a telephone interview. Descriptive statistics and qualitative methods were used for analysis. RESULTS: More than 80% of survey respondents pursued state EI certification following graduation and had practiced in EI. Participants reported that the EI training increased their marketability for employment and preparation for EI practice. Reported challenges included embracing the diverse role of an EI service provider and limited mentoring by another PT. CONCLUSIONS: Results provide important program feedback and highlight the need for curriculum review. This study further informs the national discussion about EI training, pediatric physical therapy curriculum, new graduate practice in EI, and entry-level versus advanced practice. PMID- 25822354 TI - Commentary on "PT graduates' perceptions of a higher education early intervention training program on employment and practice". PMID- 25822355 TI - Provision of school-based physical therapy services: a survey of current practice patterns. AB - PURPOSE: To compare current patterns of school system practice with "best practice" recommendations in the literature. Additional variables examined were the effects of perceived barriers to inclusion, years of practice, and rural location. METHOD/SUBJECTS: A survey was developed, and a link was e-mailed to members of the APTA's Section on Pediatrics members of the School-Based Special Interest Group, and to personal contacts of the researchers. RESULTS: A total of 226 clinicians responded to more than 50% of survey questions. Respondents reported they practiced inclusively and integrated/inclusive practice patterns were beneficial, yet a high incidence of "private therapy room" use was reported. Wide variability was noted in use of standardized assessments as well as inconsistencies in clinician definition of inclusive/integrated services. CONCLUSION: Further research is needed to examine aide/teacher training; clinicians' understanding of "inclusion"; as well as practice patterns versus years of experience, rural versus urban/suburban districts; and private therapy room use. PMID- 25822356 TI - Commentary on "Provision of school-based physical therapy services: a survey of current practice patterns". PMID- 25822357 TI - A therapeutic skating intervention for children with autism spectrum disorder. AB - PURPOSE: The purpose of this study was to evaluate the effects of a highly structured therapeutic skating intervention on motor outcomes and functional capacity in 2 boys with autism spectrum disorder aged 7 and 10 years. METHODS: This multiple-baseline, single-subject study assigned participants to three 1 hour skating sessions per week for 12 weeks focusing on skill and motor development. Multiple data points assessed (a) fidelity to the intervention and (b) outcomes measures including the Pediatric Balance Scale, Timed Up and Go, floor to stand, Six-Minute Walk Test, goal attainment, and weekly on-ice testing. RESULTS: Improvements were found in balance, motor behavior, and functional capacity by posttest with gains remaining above pretest levels at follow-up. CONCLUSIONS: Therapeutic skating may produce physical benefits for children with autism spectrum disorder and offer a viable, inexpensive community-based alternative to other forms of physical activity. PMID- 25822358 TI - Commentary on "A therapeutic skating intervention for children with autism spectrum disorder". PMID- 25822359 TI - Innovation in pediatric clinical education: application of the essential competencies. AB - BACKGROUND: At the Section on Pediatrics Education Summit in July 2012, consensus was achieved on 5 essential core competencies (ECCs) that represent a knowledge base essential to all graduates of professional physical therapist education programs. KEY POINTS: This article offers suggestions for how clinical instructors (CIs) might use the ECCs to identify student needs and guide student learning during a pediatric clinical education experience. Pediatric CIs potentially might choose to use the ECCs as a reference tool in clinical education to help (1) organize and develop general, clinic-specific clinical education objectives, (2) develop and plan individualized student learning experiences, (3) identify student needs, and (4) show progression of student learning from beginner to intermediate to entry level. CONCLUSIONS: The ECCs may offer CIs insights into the role of pediatric clinical education in professional physical therapist education. PMID- 25822360 TI - Update of the core set of exercise tests for children and adolescents with cerebral palsy. PMID- 25822361 TI - Gait recovery in a girl with ischemic spinal cord stroke. AB - BACKGROUND AND PURPOSE: This case report describes an aggressive, task-specific program for the recovery of gait in a girl with a spinal cord stroke. CASE DESCRIPTION: The 11-year-old girl sustained a spinal cord stroke resulting in a T4 motor-incomplete lesion. Therapy was initiated 6 months after onset when she was not ambulating. INTERVENTION: The focus of all interventions was on the restoration of gait. Locomotor treadmill training and over ground walking were the primary practice interventions. Walking was facilitated by orthoses, neuromuscular electrical stimulation, laser treatments, and strengthening. Treatment continued for 18 months. OUTCOMES: At the conclusion of therapy, the client was able to walk independently in the community with a single ankle foot orthosis and reverse rolling walker. DISCUSSION: The outcome was not anticipated for this client, given the type and level of her injury and the delay in starting gait training. PMID- 25822362 TI - Functional movement, strength, and intervention for an adolescent with cerebral palsy. AB - BACKGROUND AND PURPOSE: This case report describes the examination, intervention, and outcome of a 3-month episode of physical therapy (PT) using combined functional training and progressive resistance exercise for an adolescent with cerebral palsy. SUMMARY OF KEY POINTS: The patient presented with a long history of PT intervention and strength impairments that limited functional and transitional movement, agility, and peer-level participation in school and the community. Functional strength, aerobic conditioning, and anaerobic power were examined and addressed during intervention. STATEMENT OF CONCLUSIONS: Lower extremity strength was improved. Improvements in functional strength, agility, and anaerobic power generation were clinically insignificant. Most importantly, patient defined participation improved and was accompanied by achievement of new transitional and functional movements. RECOMMENDATIONS FOR CLINICAL PRACTICE: Outcomes described support the use of progressive resistance exercise and functional training to improve strength and functional mobility in an adolescent with cerebral palsy. PMID- 25822364 TI - Do social networks influence small-scale fishermen's enforcement of sea tenure? AB - Resource systems with enforced rules and strong monitoring systems typically have more predictable resource abundance, which can confer economic and social benefits to local communities. Co-management regimes demonstrate better social and ecological outcomes, but require an active role by community members in management activities, such as monitoring and enforcement. Previous work has emphasized understanding what makes fishermen comply with rules. This research takes a different approach to understand what influences an individual to enforce rules, particularly sea tenure. We conducted interviews and used multiple regression and Akaike's Information Criteria model selection to evaluate the effect of social networks, food security, recent catch success, fisherman's age and personal gear investment on individual's enforcement of sea tenure. We found that fishermen's enforcement of sea tenure declined between the two time periods measured and that social networks, age, food security, and changes in gear investment explained enforcement behavior across three different communities on Nicaragua's Atlantic Coast, an area undergoing rapid globalization. PMID- 25822363 TI - Metabolite responses to exogenous application of nitrogen, cytokinin, and ethylene inhibitors in relation to heat-induced senescence in creeping bentgrass. AB - The exogenous application of ethylene inhibitors, cytokinins, or nitrogen has previously been shown to suppress heat-induced senescence and improve heat tolerance in cool-season grasses. The objectives of this study were to examine metabolic profiles altered by exogenous treatment of creeping bentgrass with an ethylene inhibitor, cytokinin or nitrogen under heat stress and to determine metabolic pathways regulated by those compounds in association with their effectiveness for improving heat tolerance. Creeping bentgrass (Agostis stolonifera) plants (cv. Penncross) were foliar sprayed with 18 mM carbonyldiamide (N source), 25 MUM aminoethoxyvinylglycine (AVG, ethylene inhibitor), 25 MUM zeatin riboside (ZR, cytokinin), or a water control, and then exposed to 20/15 degrees C (day/night) or 35/30 degrees C (heat stress) in growth chambers. All three exogenous treatments suppressed leaf senescence, as manifested by increased turf quality and chlorophyll content, and reduced electrolyte leakage under heat stress. Polar metabolite profiling identified increases in the content of certain organic acids (i.e. citric and malic acid), sugar alcohols, disaccharides (sucrose), and decreased accumulations of monosaccharides (i.e. glucose and fructose) with exogenous treatment of N, AVG, or ZR at the previously mentioned concentrations when compared to the untreated control under heat stress. Nitrogen stimulated amino acid accumulation whereas AVG and ZR reduced amino acid accumulation compared to the untreated control under heat stress. These results revealed that the alleviation of heat-induced leaf senescence by N, AVG, and ZR could be due to changes in the accumulation of metabolites involved in osmoregulation, antioxidant metabolism, carbon and nitrogen metabolism, as well as stress signaling molecules. PMID- 25822365 TI - Correction: Analysis of structural flexibility of damaged DNA using thiol tethered oligonucleotide duplexes. PMID- 25822366 TI - DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. AB - Rearrangements of MLL (encoding lysine-specific methyltransferase 2A and officially known as KMT2A; herein referred to as MLL to denote the gene associated with mixed-lineage leukemia) generate MLL fusion proteins that bind DNA and drive leukemogenic gene expression. This gene expression program is dependent on the disruptor of telomeric silencing 1-like histone 3 lysine 79 (H3K79) methyltransferase DOT1L, and small-molecule DOT1L inhibitors show promise as therapeutics for these leukemias. However, the mechanisms underlying this dependency are unclear. We conducted a genome-scale RNAi screen and found that the histone deacetylase SIRT1 is required for the establishment of a heterochromatin-like state around MLL fusion target genes after DOT1L inhibition. DOT1L inhibits chromatin localization of a repressive complex composed of SIRT1 and the H3K9 methyltransferase SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation and minimal H3K9 methylation at MLL fusion target genes. Furthermore, the combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against MLL-rearranged leukemia cells. These results indicate that the dynamic interplay between chromatin regulators controlling the activation and repression of gene expression could provide novel opportunities for combination therapy. PMID- 25822367 TI - Targeting the MLL complex in castration-resistant prostate cancer. AB - Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer. PMID- 25822368 TI - Transcriptomic analysis of the primary roots of Alhagi sparsifolia in response to water stress. AB - BACKGROUND: Alhagi sparsifolia is a typical desert phreatophyte and has evolved to withstand extreme dry, cold and hot weather. While A. sparsifolia represents an ideal model to study the molecular mechanism of plant adaption to abiotic stress, no research has been done in this aspect to date. Here we took advantage of Illumina platform to survey transcriptome in primary roots of A. sparsifolia under water stress conditions in aim to facilitate the exploration of its genetic basis for drought tolerance. METHODOLOGY AND PRINCIPAL FINDINGS: We sequenced four primary roots samples individually collected at 0, 6, 24 and 30h from the A. sparsifolia seedlings in the course of 24h of water stress following 6h of rehydration. The resulting 38,763,230, 67,511,150, 49,259,804 and 54,744,906 clean reads were pooled and assembled into 33,255 unigenes with an average length of 1,057 bp. All-unigenes were subjected to functional annotation by searching against the public databases. Based on the established transcriptome database, we further evaluated the gene expression profiles in the four different primary roots samples, and identified numbers of differently expressed genes (DEGs) reflecting the early response to water stress (6h vs. 0h), the late response to water stress (24h vs. 0h) and the response to post water stress rehydration (30h vs. 24h). Moreover, the DEGs specifically regulated at 6, 24 and 30h were captured in order to depict the dynamic changes of gene expression during water stress and subsequent rehydration. Functional categorization of the DEGs indicated the activation of oxidoreductase system, and particularly emphasized the significance of the 'Glutathione metabolism pathway' in response to water stress. CONCLUSIONS: This is the first description of the genetic makeup of A. sparsifolia, thus providing a substantial contribution to the sequence resources for this species. The identified DEGs offer a deep insight into the molecular mechanism of A. sparsifolia in response to water stress, and merit further investigation. PMID- 25822369 TI - Normalized lactate load is associated with development of acute kidney injury in patients who underwent cardiopulmonary bypass surgery. AB - BACKGROUND AND OBJECTIVE: Cardiac surgery associated acute kidney injury is a major postoperative complication and has long been associated with adverse outcomes. However, the association of lactate and AKI has not been well established. The study aimed to explore the association of normalized lactate load with AKI in patients undergoing cardiac surgery. METHODS: This was a prospective observational cohort study conducted in a 47-bed ICU of a tertiary academic teaching hospital from July 2012 to January 2014. All patients undergoing cardiopulmonary bypass surgery were included. Normalized lactate load (L) was calculated by the equation: [Formula: see text], where ti was time point for lactate measurement and vi was the value of lactate. L was transformed by natural log (Lln) to improve its normality. Logistic regression model was fitted by using stepwise method. Scale of Lln was examined by using fractional polynomial approach and potential interaction terms were explored. RESULTS: A total of 117 patients were included during study period, including 17 AKI patients and 100 non-AKI patients. In univariate analysis Lln was significantly higher in AKI as compared with non-AKI group (1.43+/-0.38 vs 1.01+/-0.45, p = 0.0005). After stepwise selection of covariates, the main effect logistic model contained variables of Lln (odds ratio: 11.1, 95% CI: 1.22-101.6), gender, age, baseline serum creatinine and fluid balance on day 0. Although the two-term fractional polynomial model was the best-fitted model, it was not significantly different from the linear model (Deviance difference = 6.09, p = 0.107). There was no significant interaction term between Lln and other variables in the main effect model. CONCLUSIONS: Our study demonstrates that Lln is independently associated with postoperative AKI in patients undergoing CPB. There is no significant interaction with early postoperative fluid balance. PMID- 25822370 TI - Protocols and programs for high-throughput growth and aging phenotyping in yeast. AB - In microorganisms, and more particularly in yeasts, a standard phenotyping approach consists in the analysis of fitness by growth rate determination in different conditions. One growth assay that combines high throughput with high resolution involves the generation of growth curves from 96-well plate microcultivations in thermostated and shaking plate readers. To push the throughput of this method to the next level, we have adapted it in this study to the use of 384-well plates. The values of the extracted growth parameters (lag time, doubling time and yield of biomass) correlated well between experiments carried out in 384-well plates as compared to 96-well plates or batch cultures, validating the higher-throughput approach for phenotypic screens. The method is not restricted to the use of the budding yeast Saccharomyces cerevisiae, as shown by consistent results for other species selected from the Hemiascomycete class. Furthermore, we used the 384-well plate microcultivations to develop and validate a higher-throughput assay for yeast Chronological Life Span (CLS), a parameter that is still commonly determined by a cumbersome method based on counting "Colony Forming Units". To accelerate analysis of the large datasets generated by the described growth and aging assays, we developed the freely available software tools GATHODE and CATHODE. These tools allow for semi-automatic determination of growth parameters and CLS behavior from typical plate reader output files. The described protocols and programs will increase the time- and cost-efficiency of a number of yeast-based systems genetics experiments as well as various types of screens. PMID- 25822371 TI - Melanopsin-derived visual responses under light adapted conditions in the mouse dLGN. AB - A direct projection from melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) reaches the primary visual thalamus (dorsal lateral geniculate nucleus; dLGN). The significance of this melanopsin input to the visual system is only recently being investigated. One unresolved question is the degree to which neurons in the dLGN could use melanopsin to track dynamic changes in light intensity under light adapted conditions. Here we set out to address this question. We were able to present full field steps visible only to melanopsin by switching between rod-isoluminant 'yellow' and 'blue' lights in a mouse lacking cone function (Cnga3-/-). In the retina these stimuli elicited melanopsin-like responses from a subset of ganglion cells. When presented to anaesthetised mice, we found that ~25-30% of visually responsive neurones in the contralateral dLGN responded to these melanopsin-isolating steps with small increases in firing rate. Such responses could be elicited even with fairly modest increases in effective irradiance (32% Michelson contrast for melanopsin). These melanopsin-driven responses were apparent at bright backgrounds (corresponding to twilight-daylight conditions), but their threshold irradiance was strongly dependent upon prior light exposure when stimuli were superimposed on a spectrally neutral ramping background light. While both onset and offset latencies were long for melanopsin-derived responses compared to those evoked by rods, there was great variability in these parameters with some cells responding to melanopsin steps in <1 s. These data indicate that a subset of dLGN units can employ melanopsin signals to detect modest changes in irradiance under photopic conditions. PMID- 25822372 TI - Smoking, antioxidant supplementation and dietary intakes among older adults with age-related macular degeneration over 10 years. AB - We aimed to compare the micronutrient usage and other lifestyle behaviors over 10 years among those with and without age-related macular degeneration (AMD). 1612 participants aged 49+ years at baseline were re-examined over 10 years, west of Sydney, Australia. AMD was assessed from retinal photographs. Dietary data were collected using a semi-quantitative food frequency questionnaire. Smoking status was self-reported. 56 participants had any AMD at baseline, of these 25% quit smoking at 5 years and were still not smoking at 10-year follow-up. Among participants who had below the recommended intake of vitamins A, C or E supplements at baseline, those who did compared to those who did not develop late AMD over 10 years were more likely to report vitamins A (total), C or E supplement intake above the recommended intake at 10-year follow-up: multivariable-adjusted OR 4.21 (95% CI 1.65-10.73); OR 6.52 (95% CI 2.76-15.41); and OR 5.71 (95% CI 2.42-13.51), respectively. Participants with compared to without AMD did not appreciably increase fish, fruit and vegetable consumption and overall diet quality. Adherence to smoking and dietary recommendations was poor among older adults with AMD. However, uptake of antioxidant supplements increased significantly among those with late AMD. PMID- 25822373 TI - Hip fracture in the elderly: a re-analysis of the EPIDOS study with causal Bayesian networks. AB - OBJECTIVES: Hip fractures commonly result in permanent disability, institutionalization or death in elderly. Existing hip-fracture predicting tools are underused in clinical practice, partly due to their lack of intuitive interpretation. By use of a graphical layer, Bayesian network models could increase the attractiveness of fracture prediction tools. Our aim was to study the potential contribution of a causal Bayesian network in this clinical setting. A logistic regression was performed as a standard control approach to check the robustness of the causal Bayesian network approach. SETTING: EPIDOS is a multicenter study, conducted in an ambulatory care setting in five French cities between 1992 and 1996 and updated in 2010. The study included 7598 women aged 75 years or older, in which fractures were assessed quarterly during 4 years. A causal Bayesian network and a logistic regression were performed on EPIDOS data to describe major variables involved in hip fractures occurrences. RESULTS: Both models had similar association estimations and predictive performances. They detected gait speed and mineral bone density as variables the most involved in the fracture process. The causal Bayesian network showed that gait speed and bone mineral density were directly connected to fracture and seem to mediate the influence of all the other variables included in our model. The logistic regression approach detected multiple interactions involving psychotropic drug use, age and bone mineral density. CONCLUSION: Both approaches retrieved similar variables as predictors of hip fractures. However, Bayesian network highlighted the whole web of relation between the variables involved in the analysis, suggesting a possible mechanism leading to hip fracture. According to the latter results, intervention focusing concomitantly on gait speed and bone mineral density may be necessary for an optimal prevention of hip fracture occurrence in elderly people. PMID- 25822374 TI - Formation mechanism of nanostructured metal carbides via salt-flux synthesis. AB - Nanostructured metal carbides are of particular interest because of their potential as high surface area, low-cost catalysts. By taking advantage of a salt flux synthesis method, multiple carbide compounds were synthesized at low temperatures providing a pathway to nanosized materials. To better understand the reaction mechanism, vanadium carbide (V8C7) synthesis was monitored by quenching samples at 100 degrees C intervals and analyzed by multiple spectroscopic methods. The reaction was determined to occur through the formation of metal halide and acetylide carbide intermediates, which were repeatedly observed by X ray diffraction and further supported by IR and Raman spectroscopies. Control experiments were also employed to further verify this mechanism of formation by using different salt compositions and a solid-state metathesis reaction. The reaction mechanism was also verified by applying these techniques to other metal carbide systems, which produced similar intermediate compounds. PMID- 25822375 TI - Treatment of elderly patients with glioblastoma: a systematic evidence-based analysis. AB - IMPORTANCE: Despite improvements in survival with aggressive chemoradiation, outcomes for patients diagnosed as having glioblastoma multiforme (GBM) remain poor. Survival is further limited in elderly patients, who are often unable to tolerate multimodality therapy. The appropriate treatment approach for elderly patients (aged >65 years) with GBM remains unclear. While the literature supports the use of standard radiotherapy (60 Gy), several recent studies have suggested that treatment with temozolomide monotherapy or short-course radiotherapy may be a reasonable alternative. OBJECTIVE: To review literature reporting survival data related to treatment of elderly patients with GBM using either temozolomide alone or radiotherapy alone. EVIDENCE REVIEW: We performed a systematic review to identify articles from the temozolomide era (2005-present) that reported survival data related to treatment of elderly patients with GBM using either temozolomide alone or radiotherapy alone, with consideration of O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation status. PubMed was searched for articles between January 1, 2005, and August 31, 2013, using the search terms glioblastoma, elderly, temozolomide, radiation, hypofractionated, and survival, and references from relevant articles were searched. Selected articles reported overall survival data associated with either temozolomide alone or radiotherapy alone in elderly patients (aged >=60 years) with GBM; articles were excluded if they did not report survival data from radiotherapy alone or temozolomide alone, were not restricted to an elderly population, did not report original data, were not restricted to patients with primary GBM, were a subgroup analysis of a prior article, were a case report, or could not be located in entirety. Articles were interrogated as per the criteria designated by the Oxford Centre for Evidence Based Medicine to determine the level of evidence presented, and data from level 1 and 2 studies were used for analysis. From a review of 185 articles, 23 were selected for inclusion and final analysis. From these, we identified 2 level 1 studies and 1 level 2 study that reported overall survival in elderly patients treated with temozolomide alone, and 4 level 1 studies and 2 level 2 studies that reported overall survival in elderly patients treated with radiotherapy alone. FINDINGS: This review of the literature revealed several limitations. First, there is a paucity of randomized clinical studies comparing temozolomide alone with radiotherapy alone in elderly patients with GBM. Second, there is a lack of coherence in the literature for the definition of elderly. Third, the treatment paradigms used are not consistent from study to study. Regardless, the available data did allow the formulation of a recommendation based on level 1 and 2 data. CONCLUSIONS AND RELEVANCE: The literature supports the use of hypofractionated radiotherapy or temozolomide monotherapy in the treatment of elderly patients with GBM. In patients with MGMT promoter methylation, temozolomide monotherapy may have greater benefit than radiotherapy. PMID- 25822376 TI - Reply: To PMID 25393092. PMID- 25822377 TI - Electron-rich triphenylamine-based sensors for picric acid detection. AB - This paper demonstrates the role of solvent in selectivity and sensitivity of a series of electron-rich compounds for the detection of trace amounts of picric acid. Two new electron-rich fluorescent esters (6, 7) containing a triphenylamine backbone as well as their analogous carboxylic acids (8, 9) have been synthesized and characterized. Fluorescent triphenylamine coupled with an ethynyl moiety constitutes pi-electron-rich selective and sensitive probes for electron deficient picric acid (PA). In solution, the high sensitivity of all the sensors toward PA can be attributed to a combined effect of the ground-state charge transfer complex formation and resonance energy transfer between the sensor and analyte. The acids 8 and 9 also showed enhanced sensitivity for nitroaromatics in the solid state, and their enhanced sensitivity could be attributed to exciton migration due to close proximity of the neighboring acid molecules, as evident from the X-ray diffraction study. The compounds were found to be quite sensitive for the detection of trace amount of nitroaromatics in solution, solid, and contact mode. PMID- 25822378 TI - Large-scale hydrological modeling for calculating water stress indices: implications of improved spatiotemporal resolution, surface-groundwater differentiation, and uncertainty characterization. AB - Physical water scarcities can be described by water stress indices. These are often determined at an annual scale and a watershed level; however, such scales mask seasonal fluctuations and spatial heterogeneity within a watershed. In order to account for this level of detail, first and foremost, water availability estimates must be improved and refined. State-of-the-art global hydrological models such as WaterGAP and UNH/GRDC have previously been unable to reliably reflect water availability at the subbasin scale. In this study, the Soil and Water Assessment Tool (SWAT) was tested as an alternative to global models, using the case study of the Mississippi watershed. While SWAT clearly outperformed the global models at the scale of a large watershed, it was judged to be unsuitable for global scale simulations due to the high calibration efforts required. The results obtained in this study show that global assessments miss out on key aspects related to upstream/downstream relations and monthly fluctuations, which are important both for the characterization of water scarcity in the Mississippi watershed and for water footprints. Especially in arid regions, where scarcity is high, these models provide unsatisfying results. PMID- 25822379 TI - Cancer risk should prompt hepatitis B surveillance for patients. PMID- 25822380 TI - Lidocaine is an option for treating postmenopausal dyspareunia. PMID- 25822383 TI - Risk of venous thromboembolism with use of combined oral contraceptives. PMID- 25822384 TI - Improving quality by doing less: overtreatment. PMID- 25822385 TI - Practical selection of antiemetics in the ambulatory setting. AB - Nausea and vomiting are mediated primarily by three neurotransmitter pathways: visceral stimulation releases dopamine and serotonin; vestibular and central nervous system activation release histamine and acetylcholine; and chemoreceptor trigger zone activation releases dopamine and serotonin. Clinicians can improve the effectiveness and cost-effectiveness of treatments by targeting the appropriate pathways. Antihistamines and anticholinergics are most effective in patients with vestibular-mediated nausea secondary to vertigo. Serotonin antagonists block serotonin in the intestines and chemoreceptor trigger zone, and are most effective for treating gastroenteritis. Dopamine antagonists block dopamine in the intestines and chemoreceptor trigger zone; indications for these agents are similar to those for serotonin antagonists. For treatment of mild pregnancy-induced nausea, pyridoxine with or without doxylamine is recommended, and ginger may also be effective. In patients with migraine headache-associated nausea, metoclopramide improves response to oral anti-migraine agents. Ondansetron reduces nausea and vomiting in children with acute gastroenteritis and in women with hyperemesis gravidarum. PMID- 25822386 TI - Diagnosis and management of sodium disorders: hyponatremia and hypernatremia. AB - Hyponatremia and hypernatremia are common findings in the inpatient and outpatient settings. Sodium disorders are associated with an increased risk of morbidity and mortality. Plasma osmolality plays a critical role in the pathophysiology and treatment of sodium disorders. Hyponatremia and hypernatremia are classified based on volume status (hypovolemia, euvolemia, and hypervolemia). Sodium disorders are diagnosed by findings from the history, physical examination, laboratory studies, and evaluation of volume status. Treatment is based on symptoms and underlying causes. In general, hyponatremia is treated with fluid restriction (in the setting of euvolemia), isotonic saline (in hypovolemia), and diuresis (in hypervolemia). A combination of these therapies may be needed based on the presentation. Hypertonic saline is used to treat severe symptomatic hyponatremia. Medications such as vaptans may have a role in the treatment of euvolemic and hypervolemic hyponatremia. The treatment of hypernatremia involves correcting the underlying cause and correcting the free water deficit. PMID- 25822387 TI - Evaluation and treatment of infertility. AB - Infertility is defined as the inability to achieve pregnancy after one year of regular, unprotected intercourse. Evaluation may be initiated sooner in patients who have risk factors for infertility or if the female partner is older than 35 years. Causes of infertility include male factors, ovulatory dysfunction, uterine abnormalities, tubal obstruction, peritoneal factors, or cervical factors. A history and physical examination can help direct the evaluation. Men should undergo evaluation with a semen analysis. Abnormalities of sperm may be treated with gonadotropin therapy, intrauterine insemination, or in vitro fertilization. Ovulation should be documented by serum progesterone level measurement at cycle day 21. Evaluation of the uterus and fallopian tubes can be performed by hysterosalpingography in women with no risk of obstruction. For patients with a history of endometriosis, pelvic infections, or ectopic pregnancy, evaluation with hysteroscopy or laparoscopy is recommended. Women with anovulation may be treated in the primary care setting with clomiphene to induce ovulation. Treatment of tubal obstruction generally requires referral for subspecialty care. Unexplained infertility in women or men may be managed with another year of unprotected intercourse, or may proceed to assisted reproductive technologies, such as intrauterine insemination or in vitro fertilization. PMID- 25822388 TI - FPIN's Clinical Inquiries. Obesity and joint injuries in children. PMID- 25822389 TI - Blisters over the buttocks. PMID- 25822395 TI - Information from Your Family Doctor. Infertility: what women should know. PMID- 25822396 TI - Comparison of Two Deformable Registration Algorithms in the Presence of Radiologic Change Between Serial Lung CT Scans. AB - We evaluated the image registration accuracy achieved using two deformable registration algorithms when radiation-induced normal tissue changes were present between serial computed tomography (CT) scans. Two thoracic CT scans were collected for each of 24 patients who underwent radiation therapy (RT) treatment for lung cancer, eight of whom experienced radiologically evident normal tissue damage between pre- and post-RT scan acquisition. For each patient, 100 landmark point pairs were manually placed in anatomically corresponding locations between each pre- and post-RT scan. Each post-RT scan was then registered to the pre-RT scan using (1) the Plastimatch demons algorithm and (2) the Fraunhofer MEVIS algorithm. The registration accuracy for each scan pair was evaluated by comparing the distance between landmark points that were manually placed in the post-RT scans and points that were automatically mapped from pre- to post-RT scans using the displacement vector fields output by the two registration algorithms. For both algorithms, the registration accuracy was significantly decreased when normal tissue damage was present in the post-RT scan. Using the Plastimatch algorithm, registration accuracy was 2.4 mm, on average, in the absence of radiation-induced damage and 4.6 mm, on average, in the presence of damage. When the Fraunhofer MEVIS algorithm was instead used, registration errors decreased to 1.3 mm, on average, in the absence of damage and 2.5 mm, on average, when damage was present. This work demonstrated that the presence of lung tissue changes introduced following RT treatment for lung cancer can significantly decrease the registration accuracy achieved using deformable registration. PMID- 25822397 TI - Detection of Hard Exudates in Colour Fundus Images Using Fuzzy Support Vector Machine-Based Expert System. AB - Diabetic retinopathy is a major cause of vision loss in diabetic patients. Currently, there is a need for making decisions using intelligent computer algorithms when screening a large volume of data. This paper presents an expert decision-making system designed using a fuzzy support vector machine (FSVM) classifier to detect hard exudates in fundus images. The optic discs in the colour fundus images are segmented to avoid false alarms using morphological operations and based on circular Hough transform. To discriminate between the exudates and the non-exudates pixels, colour and texture features are extracted from the images. These features are given as input to the FSVM classifier. The classifier analysed 200 retinal images collected from diabetic retinopathy screening programmes. The tests made on the retinal images show that the proposed detection system has better discriminating power than the conventional support vector machine. With the best combination of FSVM and features sets, the area under the receiver operating characteristic curve reached 0.9606, which corresponds to a sensitivity of 94.1% with a specificity of 90.0%. The results suggest that detecting hard exudates using FSVM contribute to computer-assisted detection of diabetic retinopathy and as a decision support system for ophthalmologists. PMID- 25822398 TI - Poly(vinyl alcohol)/cellulose nanofibril hybrid aerogels with an aligned microtubular porous structure and their composites with polydimethylsiloxane. AB - Superhydrophobic poly(vinyl alcohol) (PVA)/cellulose nanofibril (CNF) aerogels with a unidirectionally aligned microtubular porous structure were prepared using a unidirectional freeze-drying process, followed by the thermal chemical vapor deposition of methyltrichlorosilane. The silanized aerogels were characterized using various techniques including scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and contact angle measurements. The structure of the aerogels fully filled with polydimethylsiloxane (PDMS) was confirmed by SEM and optical microscopy. The mechanical properties of the resulting PDMS/aerogel composites were examined using both compressive and tensile tests. The compressive and tensile Young's moduli of the fully filled PDMS/aerogel composites were more than 2-fold and 15-fold higher than those of pure PDMS. This study provides a novel alternative approach for preparing high performance polymer nanocomposites with a bicontinuous structure. PMID- 25822399 TI - Polarity-Driven Quasi-3-Fold Composition Symmetry of Self-Catalyzed III-V-V Ternary Core-Shell Nanowires. AB - A quasi-3-fold composition symmetry has for the first time been observed in self catalyzed III-V-V core-shell nanowires. In GaAsP nanowires, phosphorus-rich sheets on radial {110} planes originating at the corners of the hexagonal core were observed. In a cross section, they appear as six radial P-rich bands that originate at the six outer corners of the hexagonal core, with three of them higher in P content along ?112?A direction and others along ?112?B, forming a quasi-3-fold composition symmetry. We propose that these P-rich bands are caused by a curvature-induced high surface chemical potential at the small corner facets, which drives As adatoms away more efficiently than P adatoms. Moreover, their polarity related P content difference can be explained by the different adatom bonding energies at these polar corner facets. These results provide important information on the further development of shell growth in the self catalyzed core-shell NW structure and, hence, device structure for multicomponent material systems. PMID- 25822400 TI - Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. AB - Adverse drug reactions (ADRs) cause considerable mortality and morbidity but no recent reviews are currently available for the European region. Therefore, we performed a review of all epidemiological studies quantifying ADRs in a European setting that were published between 1 January 2000 and 3 September 2014. Included studies assessed the number of patients who were admitted to hospital due to an ADR, studies that assessed the number of patients who developed an ADR during hospitalization, and studies that measured ADRs in the outpatient setting. In total, 47 articles were included in the final review. The median percentage of hospital admissions due to an ADR was 3.5 %, based on 22 studies, and the median percentage of patients who experienced an ADR during hospitalization was 10.1 %, based on 13 studies. Only five studies were found that assessed ADRs occurring in the outpatient setting. These results indicate that the occurrence of ADRs in the European hospital setting-both ADRs that result in hospitalization and ADRs that occur during the hospital stay-is significant. Furthermore, the limited number of studies that were performed in the outpatient setting identify a lack of information regarding the epidemiology of ADRs in this setting. PMID- 25822401 TI - Hands-off preparation of monodisperse emulsion droplets using a poly(dimethylsiloxane) microfluidic chip for droplet digital PCR. AB - A fully autonomous method of creating highly monodispersed emulsion droplets with a low sample dead volume was realized using a degassed poly(dimethylsiloxane) (PDMS) microfluidic chip possessing a simple T-junction channel geometry with two inlet reservoirs for oil and water to be loaded and one outlet reservoir for the collection of generated droplets. Autonomous transport of oil and water phases in the channel was executed by permeation of air confined inside the outlet reservoir into the degassed PDMS. The only operation required for droplet creation was simple pipetting of oil and aqueous solutions into the inlet reservoirs. Long-lasting fluid transport in the current system enabled us to create ca. 51,000 monodispersed droplets (with a coefficient of variation of <3% for the droplet diameter) in 80 min with a maximum droplet generation rate of ca. 12 Hz using a PDMS chip that had been degassed overnight. With multiple time course measurements, the reproducibility in the current method of droplet preparation was confirmed, with tunable droplet sizes achieved simply by changing the cross-sectional dimensions of the microchannel. Furthermore, it was verified that the resultant droplets could serve as microreactors for digital polymerase chain reactions. This hands-free technique for preparing monodispersed droplets in a very facile and inexpensive fashion is intended for, but not limited to, bioanalytical applications and is also applicable to material syntheses. PMID- 25822402 TI - Variability Among US Intensive Care Units in Managing the Care of Patients Admitted With Preexisting Limits on Life-Sustaining Therapies. AB - IMPORTANCE: Although the end-of-life care patients receive is known to vary across nations, regions, and centers, these differences are best explored within a group of patients with presumably similar care preferences. OBJECTIVE: To examine the proportions of patients admitted to the intensive care unit (ICU) with limitations on life-sustaining treatments and the proportions of such patients who receive aggressive care across individual ICUs. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective cohort study using the Project IMPACT database (from April 1, 2001, to December 31, 2008) including 141 ICUs in 105 hospitals in the United States and 277,693 ICU patient visits. We used logistic regression analysis models adjusted for available patient characteristics and clustered visits by individual ICU. The full analysis was last performed in October 2014. MAIN OUTCOMES AND MEASURES: Outcomes included the provision of (1) cardiopulmonary resuscitation, (2) new forms of life support, and the (3) addition or (4) reversal of treatment limitations. RESULTS: Of the ICU admissions evaluated, 4.8% (95% CI, 4.7%-4.9%) had previously established treatment limitations. Patients admitted with treatment limitations were more likely to be older with more functional limitations and comorbidities. Among patients who survived to hospital discharge, more experienced reversals of existing treatment limitations during the ICU stay (17.8% [95% CI, 17.0%-18.7%]) than additions of new limits (11.7% [95% CI, 11.1%-12.4%]) (P < .01). Among patients who died, 15.7% (95% CI, 14.7-16.8%) had received cardiopulmonary resuscitation. After risk adjustment, ICUs varied widely in the proportions of patients admitted with treatment limitations (median, 4.0%; range, <1.0%-20.9%), the proportions of those who received cardiopulmonary resuscitation (37.7% [95% CI, 3.8%-92.4%]), the proportions of new forms of life support (30.0% [95% CI, 6.0%-84.2%]), and, among survivors, the proportion who had new treatment limitations established (11.2% [95% CI, 1.9%-57.3%]) and reversal of treatment limitations during or following ICU admission (20.2% [95% CI, 1.8%-76.2%]). The observed variability could not be consistently explained using measurable center-level characteristics. CONCLUSIONS AND RELEVANCE: Intensive care units vary dramatically in how they manage care for patients admitted with treatment limitations. Among patients who survive, escalations in the aggressiveness of care are more common during the ICU stay than are de-escalations in aggressiveness. This study cannot directly measure whether care received was consistent with patients' preferences but suggests that ICU culture and physicians' practice styles contribute to the aggressiveness of care. PMID- 25822403 TI - Universal adhesives: the next evolution in adhesive dentistry? AB - Every so often a new material, technique, or technological breakthrough spurs a paradigm shift in the way dentistry is practiced. The development and evolution of reliable enamel and dentin bonding agents is one such example. Indeed, the so called "cosmetic revolution" in dentistry blossomed in large part due to dramatic advances in adhesive technology. It is the ability to bond various materials in a reasonably predictable fashion to both enamel and dentin substrates that enables dentists to routinely place porcelain veneers, direct and indirect composites, and a plethora of other restorative and esthetic materials. In fact, the longevity and predictability of many (if not most) current restorative procedures is wholly predicated on the dentist's ability to bond various materials to tooth tissues. Adhesive systems have progressed from the largely ineffective systems of the 1970s and early 1980s to the relatively successful total- and self-etching systems of today. The latest players in the adhesive marketplace are the so called "universal adhesives." In theory, these systems have the potential to significantly simplify and expedite adhesive protocols and may indeed represent the next evolution in adhesive dentistry. But what defines a universal system, and are all these new systems truly "universal" and everything they are claimed to be? This article will examine the origin, chemistry, strengths, weaknesses, and clinical relevance of this new genre of dental adhesives. PMID- 25822404 TI - Current all-ceramic systems in dentistry: a review. AB - This article describes the ceramic systems and processing techniques available today in dentistry. It aims to help clinicians understand the advantages and disadvantages of a myriad of ceramic materials and technique options. The microstructural components, materials' properties, indications, and names of products are discussed to help clarify their use. Key topics will include ceramics, particle-filled glasses, polycrystalline ceramics, CAD/CAM, and adhesive cementation. PMID- 25822405 TI - Use of a resin-modified glass-ionomer (RMGI) liner in conservative direct treatment of deep caries. AB - Liners and bases are a class of dental materials that provide added protection for the health and well-being of a tooth being restored. They help prevent postoperative sensitivity resulting from an incomplete dentinal seal. Some practitioners use them, while others choose not to. In this case report, a resin modified glass-ionomer (RMGI) liner was utilized in deep restorations on premolars that had old, existing amalgam restorations and were experiencing microleakage and sensitivity problems. The materials and technique used allowed for conservative treatment while delivering an esthetic and functionally pleasing result. PMID- 25822406 TI - Bonding a veneered zirconia anterior fixed partial denture. AB - This case report documents the rationale and procedure for bonding a veneered zirconia restoration. A three-unit zirconia fixed partial denture (FPD) was fabricated with facial and incisal porcelain veneering. The intaglio surface of the prosthesis was abraded with 50-MUm aluminum oxide (Al2O3) particles and coated with one layer of a 10-methacryloxydecyl dihydrogen phosphate (MDP) primer. The FPD was tried into the mouth and occlusal adjustment was performed with a fine grit diamond, and then it was polished with zirconia polishing points. The intaglio surfaces of the abutment crowns were cleaned with 37% phosphoric acid and rinsed. A self-etch adhesive was applied to the tooth preparations and light-cured, and the crowns were filled with cement and seated. Excess cement was immediately wiped away with a brush, followed by spot-curing of the margins. The case demonstrates that, when properly designed, veneered zirconia restorations offer acceptable esthetic and mechanical properties for anterior FPDs. PMID- 25822407 TI - Provisional materials: advances lead to extensive options for clinicians. AB - The progression of provisional materials to bis-acrylics has lead to such improvements as easier handling, improved compressive and tensile strength, less water sorption, and less shrinkage. The end-result is more options for clinicians for high-quality chairside provisional restorations. Newer provisional materials are easy to manipulate and bring increased comfort to the patient. This review of current products affirms that the choices of provisional materials available for the dental professional today are quite extensive and have advanced the quality of interim restorations. PMID- 25822408 TI - Dental repair material: a resin-modified glass-ionomer bioactive ionic resin based composite. AB - This report documents treatment and repair of three carious teeth that were restored with a new dental repair material that features the characteristics of both resin-modified glass-ionomer restorative cement (RMGI) and resin-based composite (RBC). The restorative products presented are reported by the manufacturer to be the first bioactive dental materials with an ionic resin matrix, a shock-absorbing resin component, and bioactive fillers that mimic the physical and chemical properties of natural teeth. The restorative material and base/liner, which feature three hardening mechanisms, could prove to be a notable advancement in the adhesive dentistry restorative materials continuum. PMID- 25822409 TI - Dental laser utility expanding as research supports innovation. PMID- 25822410 TI - High prevalence of lower extremity peripheral artery disease in type 2 diabetes patients with proliferative diabetic retinopathy. AB - Little is known about the relationship between lower extremity peripheral arterial disease (PAD) and proliferative diabetic retinopathy (PDR) in type 2 diabetes (T2D). Here, we explored the relationship between sight-threatening PDR and PAD. We screened for diabetic retinopathy (DR) and PAD in hospitalized patients with T2D. Patients with a diabetic duration of more than 10 years, HbA1c >=7.5%, eGFR >=60 mL/min/1.73 m2 and with PDR or with no diabetic retinopathy (NDR) were eligible for this cross-sectional study. Severities of DR were graded by digital retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. We assessed PAD by measuring Ankle Brachial Index (ABI), Toe Brachial Index (TBI) and Doppler ultrasound. Statistical analyses were performed using SPSS 17.0 software. Of the 1544 patients, 169 patients with extreme eye (57 PDR and 112 NDR) phenotypes met the inclusion criteria. Patients with PDR had a significantly higher proportion of low ABI (<=0.99) and high ABI (>=1.3) than patients with NDR (28.1% and 15.8% vs. 14.3% and 6.2% respectively, P<0.05). PDR patients also had lower TBI than NDR patients (0.56+/-0.09 vs. 0.61+/-0.08, P<0.01). The proportion of patients with abnormal duplex ultrasound was higher in PDR than in NDR (21.1% vs. 9.8%, P<0.001). This showed that PDR associated with PAD could be defined in multiple ways: abnormal ABI (<=0.9) (OR = 3.61, 95% CI: 1.15-11.26), abnormal TBI (OR = 2.84, 95% CI: 1.19-6.64), abnormal duplex (OR = 3.28, 95% CI: 1.00-10.71), and critical limb ischemia (OR = 5.52, 95% CI: 2.14-14.26). Moreover, PDR was a stronger independent correlation factor for PAD than a diabetic duration of 10 years. In conclusion, PAD is more common in PDR than in NDR. It implies that PDR and PAD are mostly concomitant in T2D. We should focus on screening PAD in patients with PDR in clinical practice. PMID- 25822411 TI - Combinatorial control of light induced chromatin remodeling and gene activation in Neurospora. AB - Light is an important environmental cue that affects physiology and development of Neurospora crassa. The light-sensing transcription factor (TF) WCC, which consists of the GATA-family TFs WC1 and WC2, is required for light-dependent transcription. SUB1, another GATA-family TF, is not a photoreceptor but has also been implicated in light-inducible gene expression. To assess regulation and organization of the network of light-inducible genes, we analyzed the roles of WCC and SUB1 in light-induced transcription and nucleosome remodeling. We show that SUB1 co-regulates a fraction of light-inducible genes together with the WCC. WCC induces nucleosome eviction at its binding sites. Chromatin remodeling is facilitated by SUB1 but SUB1 cannot activate light-inducible genes in the absence of WCC. We identified FF7, a TF with a putative O-acetyl transferase domain, as an interaction partner of SUB1 and show their cooperation in regulation of a fraction of light-inducible and a much larger number of non light-inducible genes. Our data suggest that WCC acts as a general switch for light-induced chromatin remodeling and gene expression. SUB1 and FF7 synergistically determine the extent of light-induction of target genes in common with WCC but have in addition a role in transcription regulation beyond light-induced gene expression. PMID- 25822412 TI - Galphaq protein carboxyl terminus imitation polypeptide GCIP-27 improves cardiac function in chronic heart failure rats. AB - BACKGROUND: Galphaq protein carboxyl terminus imitation polypeptide (GCIP)-27 has been shown to alleviate pathological cardiomyocyte hypertrophy induced by various factors. Pathological cardiac hypertrophy increases the morbidity and mortality of cardiovascular diseases while it compensates for poor heart function. This study was designed to investigate the effects of GCIP-27 on heart function in rats with heart failure induced by doxorubicin. METHODS AND RESULTS: Forty-eight rats were randomly divided into the following six groups receiving vehicle (control), doxorubicin (Dox), losartan (6 mg/kg, i.g.) and three doses of GCIP-27 (10, 30, 90 MUg/kg; i.p., bid), respectively. Heart failure was induced by Dox, which was administered at a 20 mg/kg cumulative dose. After 10 weeks of treatment, we observed that GCIP-27 (30, 90 MUg/kg) significantly increased ejection fraction, fraction shortening, stroke volume and sarcoplasmic reticulum Ca2+ ATPase activity of Dox-treated hearts. Additionally, GCIP-27 decreased myocardial injury, heart weight index and left ventricular weight index, fibrosis and serum cardiac troponin-I concentration in Dox-treated mice. Immunohistochemistry, western blotting and real-time PCR experiments indicated that GCIP-27 (10-90 MUg/kg) could markedly upregulate the protein expression of myocardial alpha-myosin heavy chain (MHC), Bcl-2, protein kinase C (PKC) epsilon and phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2 as well as the mRNA expression of alpha-MHC, but downregulated the expression of beta-MHC, Bax and PKC betaII, and the mRNA expression levels of beta-MHC in Dox-treated mice. It was also found that GCIP-27 (30, 90 MUg/L) decreased cell size and protein content of cardiomyocytes significantly in vitro by comparison of Dox group. CONCLUSIONS: GCIP-27 could effectively ameliorate heart failure development induced by Dox. PKC-ERK1/2 signaling might represent the underlying mechanism of the beneficial effects of GCIP-27. PMID- 25822414 TI - Elucidating the impact of molecular packing and device architecture on the performance of nanostructured perylene diimide solar cells. AB - The performance of organic photovoltaic devices (OPV) with nanostructured polymer:perylene diimide (PDI) photoactive layers approaches the levels of the corresponding polymer:fullerene systems. Nevertheless, a coherent understanding of the difficulty for PDI-based OPV devices to deliver high power conversion efficiencies remains elusive. Here we perform a comparative study of a set of four different polymer:PDI OPV model systems. The different device performances observed are attributed to differences in the nanostructural motif of these composites, as determined by wide-angle X-ray scattering (WAXS) measurements. Long-range structural order in the PDI domain dictates (i) the stabilization energy and (ii) the concentration of the PDI excimers in the composites. The quenching of the PDI excimer photoluminescence (PL) is found to be insensitive to the former, but it depends on the latter. High PL quenching occurs for the low concentration of PDI excimers that are formed in PDI columns with a length comparable to the PDI excimer diffusion length. The stabilization of the PDI excimer state increases as the long-range order in the PDI domains improves. The structural order of the PDI domains primarily affects charge transport. Electron mobility reduces as the size of the PDI domain increases, suggesting that well ordered PDI domains suffer from poor electronic connectivity. WAXS further reveals the presence of additional intermolecular PDI interactions, other than the direct face-to-face intermolecular coupling, that introduce a substantial energetic disorder in the polymer:PDI composites. Conventional device architectures with hole-collecting ITO/PEDOT:PSS bottom electrodes are compared with inverted device architectures bearing bottom electron-collecting electrodes of ITO/ZnO. In all cases the ZnO-functionalized devices surpass the performance of the conventional device analogues. X-ray photoelectron spectroscopy explains that in PEDOT: PSS-functionalized devices, the PDI component preferentially segregates closer to the hydrophilic PEDOT: PSS electrode, thus impeding the efficient charge extraction and limiting device photocurrent. PMID- 25822413 TI - Higher protein kinase C zeta in fatty rat liver and its effect on insulin actions in primary hepatocytes. AB - We previously showed the impairment of insulin-regulated gene expression in the primary hepatocytes from Zucker fatty (ZF) rats, and its association with alterations of hepatic glucose and lipid metabolism. However, the molecular mechanism is unknown. A preliminary experiment shows that the expression level of protein kinase C zeta (PKCzeta), a member of atypical PKC family, is higher in the liver and hepatocytes of ZF rats than that of Zucker lean (ZL) rats. Herein, we intend to investigate the roles of atypical protein kinase C in the regulation of hepatic gene expression. The insulin-regulated hepatic gene expression was evaluated in ZL primary hepatocytes treated with atypical PKC recombinant adenoviruses. Recombinant adenovirus-mediated overexpression of PKCzeta, or the other atypical PKC member PKCiota/lambda, alters the basal and impairs the insulin-regulated expressions of glucokinase, sterol regulatory element-binding protein 1c, the cytosolic form of phosphoenolpyruvate carboxykinase, the catalytic subunit of glucose 6-phosphatase, and insulin like growth factor binding protein 1 in ZL primary hepatocytes. PKCzeta or PKCiota/lambda overexpression also reduces the protein level of insulin receptor substrate 1, and the insulin-induced phosphorylation of AKT at Ser473 and Thr308. Additionally, PKCiota/lambda overexpression impairs the insulin-induced Prckz expression, indicating the crosstalk between PKCzeta and PKCiota/lambda. We conclude that the PKCzeta expression is elevated in hepatocytes of insulin resistant ZF rats. Overexpressions of aPKCs in primary hepatocytes impair insulin signal transduction, and in turn, the down-stream insulin-regulated gene expression. These data suggest that elevation of aPKC expression may contribute to the hepatic insulin resistance at gene expression level. PMID- 25822415 TI - CRISPathBrick: Modular Combinatorial Assembly of Type II-A CRISPR Arrays for dCas9-Mediated Multiplex Transcriptional Repression in E. coli. AB - Programmable control over an addressable global regulator would enable simultaneous repression of multiple genes and would have tremendous impact on the field of synthetic biology. It has recently been established that CRISPR/Cas systems can be engineered to repress gene transcription at nearly any desired location in a sequence-specific manner, but there remain only a handful of applications described to date. In this work, we report development of a vector possessing a CRISPathBrick feature, enabling rapid modular assembly of natural type II-A CRISPR arrays capable of simultaneously repressing multiple target genes in Escherichia coli. Iterative incorporation of spacers into this CRISPathBrick feature facilitates the combinatorial construction of arrays, from a small number of DNA parts, which can be utilized to generate a suite of complex phenotypes corresponding to an encoded genetic program. We show that CRISPathBrick can be used to tune expression of plasmid-based genes and repress chromosomal targets in probiotic, virulent, and commonly engineered E. coli strains. Furthermore, we describe development of pCRISPReporter, a fluorescent reporter plasmid utilized to quantify dCas9-mediated repression from endogenous promoters. Finally, we demonstrate that dCas9-mediated repression can be harnessed to assess the effect of downregulating both novel and computationally predicted metabolic engineering targets, improving the yield of a heterologous phytochemical through repression of endogenous genes. These tools provide a platform for rapid evaluation of multiplex metabolic engineering interventions. PMID- 25822417 TI - Module-based association analysis for omics data with network structure. AB - Module-based analysis (MBA) aims to evaluate the effect of a group of biological elements sharing common features, such as SNPs in the same gene or metabolites in the same pathways, and has become an attractive alternative to traditional single bio-element approaches. Because bio-elements regulate and interact with each other as part of network, incorporating network structure information can more precisely model the biological effects, enhance the ability to detect true associations, and facilitate our understanding of the underlying biological mechanisms. However, most MBA methods ignore the network structure information, which depicts the interaction and regulation relationship among basic functional units in biology system. We construct the connectivity kernel and the topology kernel to capture the relationship among bio-elements in a module, and use a kernel machine framework to evaluate the joint effect of bio-elements. Our proposed kernel machine approach directly incorporates network structure so to enhance the study efficiency; it can assess interactions among modules, account covariates, and is computational efficient. Through simulation studies and real data application, we demonstrate that the proposed network-based methods can have markedly better power than the approaches ignoring network information under a range of scenarios. PMID- 25822416 TI - Bilaterally reduced claustral volumes in schizophrenia and major depressive disorder: a morphometric postmortem study. AB - Multiple brain structural abnormalities have been reported in schizophrenia and major depressive disorder. A majority of disease-affected brain regions act as relay nodes within neural networks, which are known to be impaired in neuropsychiatric diseases. One of these regions is the claustrum, which has the highest connectivity in the human brain by regional volume. Its possible involvement in disturbed connectivity is yet incompletely explored, however. The present study aimed at searching for possible structural deviations of the claustrum in neuropsychiatric disorders. We found bilaterally reduced claustral volumes both in schizophrenia and in major depressive disorder. These structural impairments may have different, disease-related consequences: In patients with schizophrenia, they may contribute to sensory processing impairments, and in patients with major depressive disorder to disturbances in salience. PMID- 25822418 TI - [Diagnosis and therapy of heart failure]. PMID- 25822419 TI - [Epidemiology and prognosis of heart failure]. AB - Heart failure (HF) is a major and growing health problem in western communities. Recent data indicate that more than 50% of patients with the clinical syndrome of HF have a preserved left ventricular ejection fraction (HF with preserved ejection fraction, HFpEF). In contrast to the calculated expectations, the observed incidence of HF is rising. Despite the fact that the relative proportion of patients with preserved left ventricular function is also increasing, other factors, such as ageing of the population and the concomitant change of compound risk factors may also contribute to the actual rise in the incidence of HF. Patients with HF suffer from reduced exercise capacity, impaired quality of life and also from recurrent hospitalization due to HF. Over the past decades, an increase of recurrent HF events has been documented. In contrast to earlier reports in which HFpEF was considered to be more benign than HF with reduced ejection fraction (HFrEF), recent data suggest that once hospitalized for HF, patients with HFpEF and those with HFrEF have a comparable prognosis in terms of morbidity and mortality. Despite increasing clinical and economic relevance, no treatment has yet been shown to convincingly reduce mortality in HFpEF. In contrast, strategies for improving survival have now been established for HFrEF. The problem of HF will continue to be major challenge for the healthcare systems in western communities; therefore, consolidated clinical research is necessary to further improve therapeutic strategies for HFrEF and to generally establish treatment options for HFpEF. PMID- 25822420 TI - [Interventional therapy of heart valve diseases: future perspectives]. AB - Transcatheter procedures have been adopted as novel treatment strategy for patients with valvular heart disease, particularly for those who are inoperable or at high risk for surgical valve procedures. Significant technological advances have resulted in an improvement of devices for transcatheter aortic valve replacement (TAVI) with downsizing of crossing profiles, reduction in the rate of paravalvular leakage and conduction abnormalities as well as a lower short- and mid-term mortality and a higher patient acceptance. In the near future, TAVI may potentially develop as first-line treatment for the majority of patients with aortic valve disease. For patients with mitral and pulmonary stenosis, balloon valvuloplasty is effective and well established and should be preferred over valve replacement, last but not least also for economic reasons. For treatment of mitral regurgitation, several transcatheter devices aiming to restore or replace mitral valve function are currently under investigation. This review summarizes the current state of interventional treatment of valvular heart disease along with implications for the future. PMID- 25822421 TI - [Ventricular long-term support with implantable continuous flow pumps: on the way to a gold standard in the therapy of terminal heart failure]. AB - Mechanical circulatory support nowadays represents an important option in the treatment of patients with advanced heart insufficiency. Once developed as a bridging to heart transplantation, it is now a valuable option for permanent support in patients for whom a heart transplantation is not possible due to contraindications or a lack of available organs. Furthermore, it can be used as a bridging to myocardial recovery and explantation. The number of implantations of left ventricular assist devices (LVAD) has clearly increased in recent years and approximately one half of these implantations is already carried out in centers not specialized in transplantations. This development necessitates that every practicing physician is aware of the basic principles of mechanical circulatory support and with the possible complications. This article gives a summary of the current state of the technology and treatment of patients with long-term VADs. PMID- 25822422 TI - [Infective endocarditis]. AB - Colonization of native cardiac valves or polymer implants, e.g. valves, conduits, rings, electrode leads and polymer-associated endocarditis (PIE), by microorganisms, primarily gram-positive bacteria (infective endocarditis), constitutes a severe, prognostically unfavorable disease. Fever and in the majority of cases development of a valve regurgitant murmur are clinical landmark findings. The white blood cell count, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) are regularly elevated. With a normal CRP level, infective endocarditis is extremely unlikely. Irrespective of body temperature, at least three blood cultures (aerobic and anaerobic) should be taken and if initiation of antimicrobial therapy is urgent, 1 h apart before therapy is initiated. Identification of the pathogen to the species level and testing antimicrobial susceptibility to antibiotics by a quantitative hemodilution test, not with agar diffusion tests, are obligatory. A minimum inhibitory concentration should be administered for antibiotics and usual combinations of antibiotics with an expected synergistic potential. Streptococci, staphylococci and enterococci are the most frequent causative organisms. Immediate initiation of transthoracic echocardiography (TTE) is mandatory followed by transesophageal echocardiography if imaging quality is poor, involvement of intracardiac implants is possible or TTE is insufficient to establish the diagnosis. An insufficiently long antimicrobial therapy promotes recurrent infections, thus a 4-week treatment is standard, while in special cases (e.g. PIE) treatment for 6 weeks should be the rule. If typical complications of infective endocarditis, such as uncontrolled local infection, systemic thromboembolism, central nervous involvement, development of a severe valve incompetence or mitral kissing vegetation in primary aortic valve endocarditis occur, urgent surgical intervention should be considered. If cardiac implants are involved, early surgical removal followed by a 6-week antimicrobial treatment is the rule. Adequate and timely diagnosis and treatment are the key to improve the overall prognosis. PMID- 25822423 TI - Network catastrophe: self-organized patterns reveal both the instability and the structure of complex networks. AB - Critical events in society or biological systems can be understood as large-scale self-emergent phenomena due to deteriorating stability. We often observe peculiar patterns preceding these events, posing a question of-how to interpret the self organized patterns to know more about the imminent crisis. We start with a very general description - of interacting population giving rise to large-scale emergent behaviors that constitute critical events. Then we pose a key question: is there a quantifiable relation between the network of interactions and the emergent patterns? Our investigation leads to a fundamental understanding to: 1. Detect the system's transition based on the principal mode of the pattern dynamics; 2. Identify its evolving structure based on the observed patterns. The main finding of this study is that while the pattern is distorted by the network of interactions, its principal mode is invariant to the distortion even when the network constantly evolves. Our analysis on real-world markets show common self organized behavior near the critical transitions, such as housing market collapse and stock market crashes, thus detection of critical events before they are in full effect is possible. PMID- 25822424 TI - Malignancy presenting as multiple lesions in a cirrhotic liver: not always hepatocellular carcinoma. PMID- 25822425 TI - Association between chronic HCV hepatitis, membranoproliferative glomerulopathy and cutaneous sarcoidosis. PMID- 25822426 TI - Cocaine capsules in the colon: the internal concealment of illicit drugs. PMID- 25822427 TI - Right upper quadrant pain in a young female. PMID- 25822428 TI - CAP: a novel era to better quantitate fatty liver? PMID- 25822429 TI - Prevalence of anemia and iron deficiency in Romanian patients with inflammatory bowel disease: a prospective multicenter study. AB - BACKGROUND AND AIMS: Anemia is the most frequent systemic complication in inflammatory bowel diseases. It affects the quality of life and can interact with working capacity. Our objectives were to identify the prevalence of anemia, its main causes and its management in patients with inflammatory bowel disease from Romania. METHODS: We conducted a multicenter prospective study from March 2013 to August 2014. We enrolled 291 patients from three referral centers: 115 (39.52%) with Crohn's disease (CD) and 176 (60.48%) with ulcerative colitis (UC). We defined anemia according to the WHO criteria. RESULTS: Median age of the patients was 41 years and the median time period since diagnosis was 3 years (0.75-7). The median activity index for UC (UCAI) was 4 and the median CD activity index (CDAI) was 96. More patients with CD were on antiTNFalpha therapy (p < 0.01), corticosteroids (p =0.18) or azathioprine (p=0.05) and required surgery for their underlying disease at study enrollment (p < 0.01). Anemia was present in 31.27% of the patients, more often in those with CD (35.65%) than with UC (28.41%) (not statistically significant); 53.26% of the patients had iron deficiency while 4.12% had folic acid and 8.59% vitamin B12 deficiency; 9.62% of the patients had received anti-anemic therapy at inclusion in the study or in the last three months prior to study enrollment. CONCLUSIONS: About one in three Romanian patients with inflammatory bowel disease has anemia, which is frequently associated with iron deficiency. About 30% of the patients with anemia are under therapy and the most frequent route for iron supplementation is the oral one. This might contribute to the high prevalence of iron deficiency and the low level of compliance. PMID- 25822430 TI - Saccharomyces boulardii for the prevention of hospital onset Clostridium difficile infection. AB - BACKGROUND AND AIMS: Probiotics, including Saccharomyces boulardii, have been advocated for the prevention of Clostridium difficile infection. The aim of this project was to evaluate the effects of the removal of S. boulardii from an automatic antibiotic order set and hospital formulary on hospital onset C. difficile infection rates. DESIGN: A retrospective chart review was performed on all patients with hospital onset C. difficile infection during the 13 months prior (control group) and the 13 months after (study group) removal of an automatic order set linking S. boulardii capsules to certain broad spectrum antibiotics. SETTING: A large 800+ bed tertiary hospital. RESULTS: Among all hospitalized patients, the rate of hospital onset C. difficile infection was 0.99 per 1000 patient days while the S. boulardii protocol was active compared with 1.04 per 1000 patient days (p=0.10) after S. boulardii was removed from the formulary. No difference in the rate of hospital onset C. difficile infection was detected in patients receiving the linked broad spectrum antibiotics during and after the removal of the protocol (1.25% vs. 1.51%, respectively; p=0.70). CONCLUSIONS: Removal of S. boulardii administration to patients receiving broad spectrum antibiotics and the hospital formulary did not impact the rate of hospital onset C. difficile infection in either the hospital population or patients receiving broad spectrum antibiotics. PMID- 25822431 TI - Autoimmune liver diseases and antiphospholipid antibodies positivity: a meta analysis of literature studies. AB - BACKGROUND AND AIMS: Several studies reported an association between autoimmune liver diseases (AiLD) and antiphospholipid antibodies (aPL) positivity. We performed a meta-analysis of studies evaluating the association of primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC) with aPL positivity and with aPL-related thrombotic events. METHODS: Studies evaluating the association of AiLD with aPL (anticardiolipin [aCL], anti-beta2 glycoprotein-I [anti-beta2GPI], lupus anticoagulant [LA] antibodies) and with aPL-related thrombotic complications were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. RESULTS: A total of 10 studies (750 patients with AiLD and 1,244 healthy controls) were included in the analysis on the prevalence of aPL and showed that AiLD are significantly associated with the presence of aCL and anti-beta2GPI. The association with aCL positivity was consistently confirmed in PBC (OR: 13.93, 95%CI: 4.69-41.38), AIH (OR: 23.50, 95%CI: 4.28-129.13), and PSC (OR: 18.21, 95%CI: 7.05-47.08). Similarly, anti-beta2GPI were found more frequently in PBC (OR: 25.10, 95%CI: 4.77-132.11), AIH (OR: 48.57, 95%CI: 11.07-213.09), and PSC (OR: 36.30, 95%CI: 6.55-201.31). These findings are confirmed when separately analyzing IgM, IgG, and IgA directed against phospholipids. Two of the 10 included articles and 1 further study (67 cases and 75 controls) showed a trend - not achieving statistical significance - towards a higher prevalence of thrombotic complications in AIH patients with aPL as compared to those with only AIH (OR: 1.67, 95%CI: 0.46-6.05). CONCLUSION: PBC, AIH, and PSC are significantly associated with aPL positivity. The association with aPL-related thrombotic complications should be further studied. PMID- 25822432 TI - Diagnostic accuracy of controlled attenuation parameter measured by transient elastography for the non-invasive assessment of liver steatosis: a prospective study. AB - BACKGROUND AND AIMS: A novel non-invasive tool based on the evaluation of ultrasound attenuation using transient elastography (TE) has been developed, called controlled attenuation parameter (CAP). We aim to establish the histopathological parameters that significantly influence CAP, the cutoff values and their performance in predicting each steatosis grade on a group of biopsied patients with chronic liver diseases (CLD) from Romania. METHODS: We prospectively analyzed 201 consecutive CLD patients who underwent CAP measurements using TE. Steatosis, liver fibrosis and necroinflammatory activity were staged and graded during the pathological analysis of bioptic specimens. Univariate and multivariate regression analyses were applied to identify the variables correlated with CAP values. The diagnostic performance of CAP for steatosis prediction was assessed using an AUC analysis. RESULTS: Among the histopathological factors correlating with CAP, the multivariate analysis found steatosis as the only factor independently influencing CAP values (p < 0.001). Maximal diagnostic accuracy (DA) was obtained for the prediction of >= 34-66% (S2) fatty load and of 67-100% (S3) fatty load (82.06%, respectively 81.59%) while, for the prediction of >= 11-33% (S1) fatty load, DA reached only 76.11%. The negative predictive value for the exclusion of >= S2 and S3 was 93.5% and 98.7%, respectively. AUCs calculated between each two steatosis grades were: 0.772 (S0 vs S1), 0.874 (S0 vs S2), 0.904 (S0 vs S3), 0.659 (S1 vs S2), 0.777 (S1 vs S3), and 0.665 (S2 vs S3). CONCLUSION: Steatosis is the only histopathological factor independently influencing CAP. Maximal DA could be obtained for the prediction of >= S2 and S3 (82.06% and 81.59%), while for the prediction of S1, the accuracy reached only 76.11%. PMID- 25822433 TI - Plasma lipidomic fingerprinting to distinguish among hepatitis C-related hepatocellular carcinoma, liver cirrhosis, and chronic hepatitis C using MALDI TOF mass spectrometry: a pilot study. AB - BACKGROUND AND AIMS: Hepatitis C (HC) is a major cause of hepatocellular carcinoma (HCC), and a late diagnosis is the main factor for the poor survival of patients. There is an urgent need for identifying sensitive and specific biomarkers for HCC diagnosis. In the present study, plasma lipid patterns of patients with HC-HCC, HC-liver cirrhosis (LC), and chronic HC (CHC) were assessed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). METHODS: Plasma samples of 25 patients with HC-HCC, 15 patients with HC-LC, and 25 patients with CHC were evaluated by MALDI-MS using a Q-ToF premier (Synapt) mass spectrometer (Waters, Manchester, UK) equipped with a 200-Hz solid-state laser in the mass range between m/z (mass-to-charge ratio) of 700-1200. RESULTS: A total of 2205 ions were initially obtained and 7 ions (m/z) were highlighted as corresponding to the most important lipids to differentiate HCC patients from LC and CHC patients. The specific lipidomic expression signature generated resulted in an overall predictive accuracy of 93% of HC-HCC and HC-LC, and 100% of HC-HCC and CHC. The 7-peak algorithm distinguished HCC from LC with a sensitivity of 96% and a specificity of 87%, and HCC from CHC with both sensitivity and specificity of 100%. CONCLUSION: MALDI-MS-specific signature peaks accurately distinguished patients with HC-HCC from those with HC-LC and CHC. The results indicate the potential of MALDI-MS and the selected peaks to improve HCC surveillance in patients with viral C cirrhosis and chronic hepatitis C. PMID- 25822434 TI - Association between portal vein thrombosis and survival of liver transplant recipients: a systematic review and meta-analysis of observational studies. AB - BACKGROUND AND AIMS: Portal vein thrombosis (PVT) increases the technical complexity of liver transplantation (LT). This systematic review and meta analysis aim to analyze the association of pre-LT PVT with the overall survival after LT. METHODS: PubMed, EMBASE, and Cochrane library databases were used to search for papers related to the association between pre-LT PVT and survival of LT recipients. The differences in the survival rates between the LT recipients with and without pre-LT PVT were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Twenty-seven papers were included. Overall meta-analysis showed that the total LT recipients with pre-LT PVT had a significantly lower 1-year survival rate than those without pre-LT PVT (OR=0.733, 95%CI=0.621-0.865; P=0.0002). But no statistically significant difference was observed in the in-hospital (OR=0.713, 95%CI=0.343-1.482; P=0.365), 1-month (OR=0.679, 95%CI=0.345-1.333; P=0.261), or 5-year survival rate (OR=0.788, 95%CI=0.587-1.058; P=0.113). Additionally, the 1-year survival rate was significantly lower in the LT recipients with complete PVT than in those without PVT (OR=0.503, 95%CI=0.295-0.858; P=0.012). However, no statistically significant difference in the 1-year survival rate between them was observed in the meta analysis of high-quality studies (OR=0.899, 95%CI=0.657-1.230; P=0.505) or that of studies in which LT was performed after 2000 (OR=0.783, 95%CI=0.566-1.083; P=0.140). CONCLUSION: Pre-LT PVT, especially complete PVT, decreased the 1-year survival rate after LT. However, the detrimental effect of pre-LT PVT on the survival of LT recipients became inconclusive in high-quality studies. Additionally, further well-designed cohort studies should validate the association in patients undergoing LT during the latter years. PMID- 25822435 TI - Serum immunoreactive collagen IV detected by monoclonal antibodies as a marker of severe fibrosis in patients with non-alcoholic fatty liver disease. AB - BACKGROUND AND AIMS: The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We evaluated serum collagen IV as a direct non-invasive marker of severe liver fibrosis in NAFLD. METHODS: The study included 148 NAFLD and 187 chronic hepatitis C patients in whom histological severity of liver fibrosis was evaluated. The utility of serum collagen IV measured by immune mediated agglutination using two types of monoclonal antibodies for distinguishing severe fibrosis (>= stage 3 and >= F3) from non-to-moderate fibrosis in NAFLD or chronic hepatitis C was assessed in comparison to serum hyaluronic acid or other indirect fibrosis markers. RESULTS: Multiple logistic regression analysis showed that serum collagen IV was significantly associated with severe fibrosis in NAFLD (odds ratio: 1.21, p<0.001) but not in chronic hepatitis C. For distinguishing severe fibrosis in NAFLD, collagen IV showed the largest area under the receiver-operating characteristic curve (0.827, 95%CI: 0.746-0.908) followed by FIB-4 (0.805, 95%CI: 0.728-0.890); in chronic hepatitis C, those for FIB-4 (0.813, 95%CI: 0.748-0.878) and collagen IV (0.770, 95%CI: 0.683-0.857) were the largest and smallest, respectively. To detect severe fibrosis in NAFLD, a cutoff of collagen IV > 177 exhibited 77.1% sensitivity, 84.0% specificity, 76.5% positive predictive value, and 84.0% negative predictive value. Combined with a cutoff of FIB-4 > 2.09, the negative and positive predictive values, and specificity for detecting severe fibrosis in NAFLD increased further. CONCLUSION: Collagen IV is a reliable marker for distinguishing severe liver fibrosis from non-to-moderate fibrosis in NAFLD but not chronic hepatitis C. PMID- 25822436 TI - Diagnostic performance of endoscopic ultrasound (EUS)/endoscopic ultrasound--fine needle aspiration (EUS-FNA) cytology in solid and cystic pancreatic neuroendocrine tumours. AB - BACKGROUND AND AIMS: Our study aimed to assess the sensitivity of EUS and EUS-FNA for pancreatic neuro-endocrine tumors (pNETs) and compare performance over two consecutive 4 year 2 month periods, to investigate the comparative performance between solid and cystic pNETs and determine the incremental yield of EUS +/- FNA in individuals with a mass not diagnosed as a pNET after cross-sectional imaging. METHODS: A retrospective review of a prospectively maintained database was carried out to identify all pNET patients who underwent EUS-FNA between April 2003 and September 2011. RESULTS: A final diagnosis of solid and cystic pNETs was made in 43 and 10 patients, respectively. Overall, the yield of combined EUS imaging and cytology was significantly higher than that of CT and/or MRI (p< 0.05) across all groups [solid (83.7% vs. 41.8%), cystic (70% vs. 10%) and combined solid-cystic (81.1% vs. 35.8%)]. The yield of combined EUS imaging and cytology was significantly better than EUS imaging alone (p<0.05) in the solid (83.7% vs. 58%) and combined pNET cohort (81.1% vs. 52.8%) of patients. After a non-diagnostic CT and or MRI, EUS/EUS-FNA confirmed pNET in 19 out of 25 patients (76.0%) with solid pNETs and 6 out of 9 patients (66.7%) with cystic pNETs. CONCLUSION: EUS and EUS-FNA had a significant clinical impact in the 25/34 of cases where pNET was not suspected after initial cross-sectional imaging. PMID- 25822438 TI - The role of colonoscopy in managing diverticular disease of the colon. AB - Diverticulosis of the colon is frequently found on routine colonoscopy, and the incidence of diverticular disease and its complications appears to be increasing. The role of colonoscopy in managing this disease is still controversial. Colonoscopy plays a key role in managing diverticular bleeding. Several techniques have been effectively used in this field, but band ligation seems to be the best in preventing rebleeding. Colonoscopy is also effective in posing a correct differential diagnosis with other forms of chronic colitis involving colon harbouring diverticula (in particular with Crohn's disease or Segmental Colitis Associated with Diverticulosis). The role of colonoscopy to confirm diagnosis of uncomplicated diverticulitis is still under debate, since the risk of advanced colonic neoplasia in patients admitted for acute uncomplicated diverticulitis is not increased as compared to the average-risk population. On the contrary, colonoscopy is mandatory if patients complain of persistent symptoms or after resolution of an episode of complicated diverticulitis. Finally, a recent endoscopic classification, called Diverticular Inflammation and Complications Assessment (DICA), has been developed and validated. This classification seems to be a promising tool for predicting the outcome of the colon harboring diverticula, but further, prospective studies have to confirm its predictive role on the outcome of the disease. PMID- 25822437 TI - The Lauren classification highlights the role of epithelial-to-mesenchymal transition in gastric carcinogenesis: an immunohistochemistry study of the STAT3 and adhesion molecules expression. AB - BACKGROUND AND AIMS: Despite some recent advances, gastric cancer remains an important cause of death at world level. This indicates an absence of therapeutic options, stemming from the limited understanding of the molecular mechanisms involved in carcinogenesis. Nearly fifty years ago Lauren classified gastric cancers, according to the morphological aspect, as intestinal or diffuse. The phenotype of the cells indicates the presence of different molecular mechanisms, which can be approached in the light of recent data and identified with the help of current techniques. The best described are the germline/somatic mutations or the hypermethylations of the E-cadherin 1 CDH1 gene promotor. METHODS: We analyzed 195 gastric tumors,120 intestinal and 75 diffuse type, using immunohistochemistry (tissue microarray TMA method) for pStat3Tyr705, E-cadherin, alpha-catenin and beta-catenin; 985 spots of gastric tumors, distributed on 4 TMA blocks were analyzed. For pStat3Tyr705 we took the nuclear staining into account and for the adhesion molecules, membrane staining. RESULTS: In our study, in the diffuse type gastric cancer, pStat3Tyr705 nuclear expression was statistically significantly increased (p=0.003). Also we observed a decreased expression of the adhesion molecules in the same type of gastric cancer (E-cadherin p<0.0001, alpha catenin p<0.0001, beta-catenin p<0.0001), suggesting that epithelial-to mesenchymal transition (EMT) may be involved not only in gastric carcinogenesis, but also in resistance to treatment. CONCLUSION: The Stat3 role has been recently highlighted in carcinogenesis of the diffuse type of gastric cancer. We found that the morphological features of the diffuse type also suggest the involvement of EMT in this type of gastric cancer. Therefore, targeting the key molecules involved in this process may interfere with EMT process in the diffuse type of gastric cancer. PMID- 25822439 TI - A systematic review on drugs absorption modifications after eradication in Helicobacter pylori positive patients undergoing replacement therapy. AB - BACKGROUND AND AIMS: Helicobacter pylori (H. pylori) infection has been suggested as a cause of impaired drug absorption. This infection leads to alteration of the gastric acid secretion that may change the conformational characteristics of drugs and their intestinal absorption leading to uncertainties about the dose to administer and the therapeutic results. A systematic review was undertaken to clarify the implications of drug absorption during the administration of replacement therapies. METHODS: Electronic databases such as MEDLINE/Pubmed, EMBASE and The Cochrane Library [which includes Cochrane Database of Systematic Review (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstract of Reviews of Effect (DARE)] were searched. Grey literature databases (e.g. the International clinical trials registry platform, Trials Register, Clinical Trials.gov, Controlled Trials and TrialsCentral), Theses database, Government publication and LILACS database were also searched. No language restriction was applied. RESULTS: Infection and altered drug absorption were evaluated in patients under replacement therapies with iron, thyroxin and L dopa. In all, seven studies included an improvement in drug absorption after eradication and an existing inverse correlation between the grade of gastric inflammation and indices of drug absorption were noticed. CONCLUSION: This systematic review confirmed the presence of an interaction between infection and drug absorption of orally administered replacement therapies. Gastric acid reduction and subsequent alteration of drug composition seem to lead this mechanism. Clinicians should be aware of this possible interaction when starting a replacement therapy in patients and when evaluating poor clinical response. PMID- 25822440 TI - Primary biliary cirrhosis--autoimmune hepatitis overlap syndrome associated with dermatomyositis, autoimmune thyroiditis and antiphospholipid syndrome. AB - Autoimmune liver diseases may be associated with extrahepatic autoimmune pathology. We report the case of a 52-year old woman who initially presented to the gastroenterology department for extreme fatigue, pale stools, dark urine and pruritus. Laboratory tests showed significant cholestasis and elevation of aminotransferase levels. Immunological tests revealed positive antinuclear (ANA=1:320) and antimitochondrial antibodies (AMA=1:40) with negative anti-smooth muscle and liver kidney microsomal type 1 antibodies. The biopsy was compatible with overlap syndrome type 1. The patient was commenced on immunosuppressive therapy according to standard of care (azathioprine 50mg, ursodeoxycholic acid and prednisone 0.5mg/kg), with moderate biochemical improvement. She subsequently developed proximal symmetrical weakness and cutaneous involvement and was diagnosed with biopsy-proven dermatomyositis. The immunosuppressive regimen was intensified to 150 mg azathioprine. At the three-month follow-up, her symptoms subsided and aminotransferases and muscle enzymes normalized. Upon further investigation the patient was diagnosed with autoimmune thyroiditis and antiphospholipid syndrome. To our knowledge, this is the first case of primary biliary cirrhosis - autoimmune hepatitis overlap syndrome associated with dermatomyositis, autoimmune thyroiditis and antiphospholipid syndrome. PMID- 25822441 TI - Open biopsy guided by endoscopic ultrasonography from a gastric submucosal tumor growing outside the stomach. AB - Submucosal tunneling bloc biopsy for submucosal tumors growing inside the gastric wall is a safe and reliable method. However, it is difficult for an endoscopist to perform submucosal tunneling bloc biopsy and detect the demarcation line between the proper muscular layer and the capsule layer of submucosal tumors growing outside the gastric wall. A submucosal tumor in the lesser curvature of the stomach was identified in a 74-year-old man by esophagogastroduodenoscopy. Computed tomography revealed hetero-density with partial calcification of the tumor growing outside the gastric wall, that connected to approximately 10 mm of the muscular layer. Almost all of the tumor body was located outside the stomach. After the small connecting area was detected by endoscopic ultrasonography, two markings were placed at the opposite ends of the tumor. The tumor was removed via snare resection between the markings located immediately above the top of the tumor. After the biopsy site was reconfirmed using endoscopic ultrasonography, a large bloc biopsy was conducted. This new "open biopsy under endoscopic ultrasonography" is a simple, safe, and reliable method to obtain samples from any type of submucosal tumor growing inside or outside the stomach. PMID- 25822442 TI - Gangliocytic paraganglioma: a rare cause of gastrointestinal bleeding. AB - Duodenal neuroendocrine tumors (NETs) are rare tumors, consisting of five different types of tumors. In many cases, they may be asymptomatic, leading to delay in diagnosis. Clinical symptoms are related to local tumor growth and mucosal ulceration. We report a 38-year old man with duodenal gangliocytic paraganglioma causing overt upper gastrointestinal bleeding and anemia. We describe specific clinical and histopathological features of the tumor, and review the diagnostic and therapeutic strategy. Gangliocytic paragangliomas are regarded as benign tumors. However, the disease recurrence and the malignant potential of the tumor have also been reported. PMID- 25822443 TI - Paroxysmal postprandial atrial fibrilation suppressed by laparoscopic repair of a giant paraesophageal hernia compressing the left atrium. AB - We present the case of a patient with a giant paraesophageal hernia associated with paroxysmal postprandial atrial fibrillation that was suppressed after surgery. The imaging investigations showed the intrathoracic displacement of a large part of the stomach, which pushed the left atrial wall causing atrial fibrillation. The laparoscopic surgical repair acted as sole treatment for this condition. PMID- 25822444 TI - Romanian guidelines on the diagnosis and treatment of exocrine pancreatic insufficiency. AB - In assessing exocrine pancreatic insufficiency (EPI), its diverse etiologies and the heterogeneous population affected should be considered. Diagnosing this condition remains a challenge in clinical practice especially for mild-to moderate EPI, with the support of the time-consuming breath test or the coefficient of fat absorption. The fecal elastase-1 test, less precise for the diagnosis, cannot be useful for assessing treatment efficacy. Pancreatic enzyme replacement therapy (PERT) is the mainstay of treatment, whereby enteric-coated mini-microspheres are taken with every meal, in progressive doses based on an individual's weight and clinical symptoms. The main indication for PERT is chronic pancreatitis, in patients who have clinically relevant steatorrhea, abnormal pancreatic function test or abnormal function tests associated with symptoms of malabsorption such as weight loss or meteorism. While enzyme replacement therapy is not recommended in the initial stages of acute pancreatitis, pancreatic exocrine function should be monitored for at least 6-18 months. In the case of unresectable pancreatic cancer, replacement enzyme therapy helps to maintain weight and improve overall quality of life. It is also indicated in patients with celiac disease, who have chronic diarrhea (in spite of gluten-free diet), and in patients with cystic fibrosis with proven EPI. PMID- 25822445 TI - The relationship between inflammatory bowel disease and type 1 diabetes mellitus: a study of relative prevalence in comparison with population controls. PMID- 25822446 TI - Does anatomical distribution of colorectal polyps show a rightward shift? Analysis of 2,372 colorectal polyps in 1,558 patients from Turkey. PMID- 25822447 TI - Neutrophil-lymphocyte ratio in Crohn's disease patients predicts sustained response to infliximab 52-week therapy. PMID- 25822448 TI - Appendiceal mucocele in ulcerative colitis: a rare association and a crucial preoperative diagnosis. PMID- 25822449 TI - Comment to the article Gastric cat scratch--an upper endoscopy finding? PMID- 25822450 TI - Reply: To PMID 25531988. PMID- 25822451 TI - Territorial pattern formation in the absence of an attractive potential. AB - Territoriality is a phenomenon exhibited throughout nature. On the individual level, it is the processes by which organisms exclude others of the same species from certain parts of space. On the population level, it is the segregation of space into separate areas, each used by subsections of the population. Proving mathematically that such individual-level processes can cause observed population level patterns to form is necessary for linking these two levels of description in a non-speculative way. Previous mathematical analysis has relied upon assuming animals are attracted to a central area. This can either be a fixed geographical point, such as a den- or nest-site, or a region where they have previously visited. However, recent simulation-based studies suggest that this attractive potential is not necessary for territorial pattern formation. Here, we construct a partial differential equation (PDE) model of territorial interactions based on the individual-based model (IBM) from those simulation studies. The resulting PDE does not rely on attraction to spatial locations, but purely on conspecific avoidance, mediated via scent-marking. We show analytically that steady-state patterns can form, as long as (i) the scent does not decay faster than it takes the animal to traverse the terrain, and (ii) the spatial scale over which animals detect scent is incorporated into the PDE. As part of the analysis, we develop a general method for taking the PDE limit of an IBM that avoids destroying any intrinsic spatial scale in the underlying behavioral decisions. PMID- 25822452 TI - beta-Ecdysone Augments Peak Bone Mass in Mice of Both Sexes. AB - BACKGROUND: One of the strongest predictors for osteoporosis is peak bone mass. Interventions to augment peak bone mass have yet to be developed. beta-Ecdysone (betaEcd), a natural steroid-like compound produced by arthropods to initiate metamorphosis, is believed to have androgenic effects and so may be used to augment bone mass. QUESTIONS/PURPOSES: The purpose of this study was to use both male and female (1) gonadal-sufficient; and (2) -insufficient mice to investigate sex differences in terms of bone development and structure after betaEcd administration. METHODS: Two-month-old male and female Swiss-Webster mice were randomized to receive either vehicle or betaEcd (0.5 mg/kg) for 3 weeks. In a separate experiment to evaluate the effects of betaEcd on sex hormone-deficient mice, gonadectomy was performed in male (orchiectomy [ORX]) and female mice (ovariectomy [OVX]). Sham-operated and the ORX/OVX mice were then treated for 3 weeks with betaEcd. Primary endpoints for the study were trabecular bone structure and bone strength. RESULTS: In male mice, the trabecular bone volume was 0.18+/-0.02 in the placebo-treated (PL) and 0.23+/-0.02 in the betaEcd treated group (p<0.05 versus PL); and 0.09+/-0.01 in the ORX group (p<0.05 versus PL) and 0.12+/-0.01 in the ORX+betaEcd group. Vertebral bone strength (maximum load) was 43+/-2 in PL and 51+/-1 in the betaEcd-treated group (p<0.05 versus PL); and 30+/-4 in the ORX group (p<0.05 versus PL) and 37+/-3 in the ORX+betaEcd group. In female mice, trabecular bone volume was 0.23+/-0.02 in PL and 0.26+/ 0.02 in the betaEcd-treated group (p<0.05 versus PL); and 0.15+/-0.01 in the OVX group (p<0.05 versus PL) and 0.14+/-0.01 in the OVX+betaEcd group. Maximum load of the vertebrae was 45+/-2 in PL and 48+/-4 in the betaEcd-treated group; and 39+/-4 in the OVX group (p<0.05 versus PL) and 44+/-4 in the OVX+betaEcd group. CONCLUSIONS: These findings suggest the potential use of betaEcd in the augmentation of bone mass in growing male and female mice. It may also partially prevent the detrimental effects of gonadectomy on trabecular bone. CLINICAL RELEVANCE: Our results support the potential use of betaEcd or nature products that are rich in betaEcd to augment peak bone mass. betaEcd may differ from the other anabolic hormone treatments that may have severe side effects such as serious cardiac complications. However, its effects on humans remain to be determined. PMID- 25822453 TI - To What Degree Do Pain-coping Strategies Affect Joint Stiffness and Functional Outcomes in Patients with Hand Fractures? AB - BACKGROUND: Patients with hand fractures often have pain, swelling, and stiffness in the joints of the hand, which may lead them to protect their hands, resulting in more stiffness and in delayed recovery. However, the effects of pain-coping strategies and catastrophization (the tendency to expect the worst to occur when pain is present, an approach that can be thought of as the opposite of "coping") on functional recovery after hand fractures have not been investigated in depth. QUESTIONS/PURPOSES: Are preoperative catastrophization and anxiety in patients with hand fractures associated with (1) decreased grip strength; (2) decreased range of motion; and (3) increased disability at 3 and 6 months after surgical treatment for a hand fracture? Secondarily, we asked if there are other patient and injury factors that are associated with these outcomes at 3 and 6 months. METHODS: A total of 93 patients with surgically treated hand fractures were enrolled in this prospective study. Preoperative assessments measured coping strategies evaluated by measuring catastrophic thinking with the Pain Catastrophizing Scale and pain anxiety with the Pain Anxiety Symptom Scale. At 3 and 6 months postoperatively, grip strength, total active range of motion, and disability (Quick Disabilities of the Arm, Shoulder, and Hand score) were assessed. Bivariate and multivariate analyses were performed to identify patient demographic, injury, and coping skills factors that accounted for outcomes of strength, motion, and disability. RESULTS: Decreased grip strength was associated with catastrophic thinking (beta = -1.29 [95% confidence interval, -1.67 to 0.89], partial R(2) = 11%, p < 0.001) and anxiety (beta = -0.83 [-1.16 to -0.50], partial R(2) = 7%, p = 0.007) at 3 months, but by 6 months, only anxiety (beta = 0.74 [-1.04 to -0.44], partial R(2) = 7%, p = 0.010) remained an important factor. Decreased total active range of motion was associated with pain catastrophizing (beta = -0.63 [-0.90 to -0.36], partial R(2) = 6 %, p = 0.024) and anxiety (beta = -0.28 [-0.42 to -0.14], partial R(2) = 3%, p = 0.035) at 3 months but not at 6 months. Similarly, increased disability was associated with pain catastrophizing (beta = 1.09 [1.39-0.79], partial R(2) = 12%, p < 0.001) and anxiety (beta = 0.93 [1.21-0.65], partial R(2) = 11%, p = 0.001) at 3 months; these factors failed to be associated for 6-month outcomes. CONCLUSIONS: Preoperative poor coping skills as measured by high catastrophization and anxiety were associated with a weaker grip strength, decreased range of motion, and increased disability after surgical treatment for a hand fracture at 3 months. However, poor coping skills did not show persistent effects beyond 6 months. More research may be needed to show interventions to improve coping skills will enhance treatment outcome in patients after acute hand fractures. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25822454 TI - Bone Regeneration Is Promoted by Orally Administered Bovine Lactoferrin in a Rabbit Tibial Distraction Osteogenesis Model. AB - BACKGROUND: Lactoferrin, an iron-binding glycoprotein which belongs to the transferrin family, has been shown to promote bone growth. However, reports regarding effects of lactoferrin on bone regeneration during distraction osteogenesis are limited. Our study was designed to investigate the effect of bovine lactoferrin treatment on bone formation of the distracted callus. QUESTIONS/PURPOSES: We asked whether bovine lactoferrin enhances bone formation of the distraction callus as determined by (1) radiographic and histologic appearances; (2) dual-energy x-ray absorptiometry (DXA) analysis of bone mineral composition and bone mineral density; (3) micro-CT measures of trabecular architecture; and (4) biomechanical strength of the healing bone. Additionally, serology, reverse transcription (RT)-PCR, and immunohistochemistry were used to explore the possible mechanisms of bovine lactoferrin use on bone formation during distraction osteogenesis. METHODS: Unilateral tibial osteodistraction was performed on 80 New Zealand White rabbits with a distraction rate of 1 mm per day for 10 days. Animals then were divided randomly into two groups: (1) vehicle and (2) bovine lactoferrin. At 4 and 8 weeks after completion of distraction, the animals were sacrificed. Lengthened tibias and serum samples were obtained and subjected to radiologic, DXA, micro-CT, histologic, and biomechanical examinations, and serum, RT-PCR and immunohistochemical analyses. RESULTS: Radiologic, DXA, micro-CT, histologic, and biomechanical examinations indicated that bovine lactoferrin treatment not only accelerated bone formation at early stages of distraction osteogenesis but also promoted bone consolidation at late stages. The ultimate force of the distracted calluses was increased by 37% (118.8 +/- 6.65 N in the lactoferrin group and 86.5 +/- 5.47 N in the vehicle group; p < 0.001) and 84% (384.8 +/- 18.4 N in the lactoferrin group and 209.0 +/- 15.2 N in the vehicle group; p < 0.001) at 4 and 8 weeks, respectively. Moreover, serum analysis showed that bovine lactoferrin treatment significantly increased serum levels of bone alkaline phosphatase and decreased serum levels of tartrate resistant acid phosphatase 5b. In addition, RT-PCR and immunohistochemical analyses suggested that bovine lactoferrin treatment induced a lower receptor activator of nuclear factor-kappaB (RANK) ligand/osteoprotegerin (RANKL/OPG) ratio in the distracted callus. CONCLUSIONS: The results of our study suggest that bovine lactoferrin treatment could promote bone regeneration during distraction osteogenesis in the rabbit. The results indicate that the OPG/RANKL/RANK system might be a major mechanism for increased bone formation and decreased bone resorption in distraction osteogenesis with bovine lactoferrin treatment. CLINICAL RELEVANCE: Oral administration of bovine lactoferrin may provide a feasible approach for promoting osteogenesis during distraction osteogenesis. PMID- 25822455 TI - Bioburden Increases Heterotopic Ossification Formation in an Established Rat Model. AB - BACKGROUND: Heterotopic ossification (HO) develops in a majority of combat related amputations wherein early bacterial colonization has been considered a potential early risk factor. Our group has recently developed a small animal model of trauma-induced HO that incorporates many of the multifaceted injury patterns of combat trauma in the absence of bacterial contamination and subsequent wound colonization. QUESTIONS/PURPOSES: We sought to determine if (1) the presence of bioburden (Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus [MRSA]) increases the magnitude of ectopic bone formation in traumatized muscle after amputation; and (2) what persistent effects bacterial contamination has on late microbial flora within the amputation site. METHODS: Using a blast-related HO model, we exposed 48 rats to blast overpressure, femur fracture, crush injury, and subsequent immediate transfemoral amputation through the zone of injury. Control injured rats (n = 8) were inoculated beneath the myodesis with phosphate-buffered saline not containing bacteria (vehicle) and treatment rats were inoculated with 1 * 10(6) colony-forming units of A baumannii (n = 20) or MRSA (n = 20). All animals formed HO. Heterotopic ossification was determined by quantitative volumetric measurements of ectopic bone at 12-weeks postinjury using micro-CT and qualitative histomorphometry for assessment of new bone formation in the residual limb. Bone marrow and muscle tissue biopsies were collected from the residual limb at 12 weeks to quantitatively measure the bioburden load and to qualitatively determine the species-level identification of the bacterial flora. RESULTS: At 12 weeks, we observed a greater volume of HO in rats infected with MRSA (68.9 +/- 8.6 mm(3); 95% confidence interval [CI], 50.52 85.55) when compared with A baumannii (20.9 +/- 3.7 mm(3); 95% CI, 13.61-28.14; p < 0.001) or vehicle (16.3 +/- 3.2 mm(3); 95% CI, 10.06-22.47; p < 0.001). Soft tissue and marrow from the residual limb of rats inoculated with A baumannii tested negative for A baumannii infection but were positive for other strains of bacteria (1.33 * 10(2) +/- 0.89 * 10(2); 95% CI, -0.42 * 10(2)-3.08 * 10(2) and 1.25 * 10(6) +/- 0.69 * 10(6); 95% CI, -0.13 * 10(6)-2.60 * 10(6) colony-forming units in bone marrow and muscle tissue, respectively), whereas tissue from MRSA infected rats contained MRSA only (4.84 * 10(1) +/- 3.22 * 10(1); 95% CI, -1.47 * 10(1)-11.1 * 10(1) and 2.80 * 10(7) +/- 1.73 * 10(7); 95% CI, -0.60 * 10(7)-6.20 * 10(7) in bone marrow and muscle tissue, respectively). CONCLUSIONS: Our findings demonstrate that persistent infection with MRSA results in a greater volume of ectopic bone formation, which may be the result of chronic soft tissue inflammation, and that early wound colonization may be a key risk factor. CLINICAL RELEVANCE: Interventions that mitigate wound contamination and inflammation (such as early debridement, systemic and local antibiotics) may also have a beneficial effect with regard to the mitigation of HO formation and should be evaluated with that potential in mind in future preclinical studies. PMID- 25822456 TI - Cartilage Thickness and Cyst Volume Are Unchanged 10 Years After Periacetabular Osteotomy in Patients Without Hip Symptoms. AB - BACKGROUND: Periacetabular osteotomy (PAO) may affect cartilage thickness and cyst volume in patients with hip dysplasia. However, as no studies randomizing patients to either PAO or conservative treatment have been performed, to our knowledge, it is unknown if PAO directly affects the development or progression of osteoarthritis in patients with hip dysplasia. QUESTIONS/PURPOSES: We investigated (1) changes of cartilage thickness in the hip after PAO; (2) how many patients had subchondral bone cysts in the acetabulum or femoral head; (3) changes in cyst volume; and (4) patients' hip function and pain after PAO. PATIENTS AND METHODS: In this prospective study, 26 patients (22 women and four men) with hip dysplasia were enrolled with the goal of having MRI of the hip before undergoing PAO and again at 1, 21/2, and 10 years after PAO. Of the 26 patients, 17 (65%) underwent complete followup 10 years after PAO, whereas nine could not be included. Of those nine, three had undergone THA, three had substantial hip symptoms, and three were lost to followup. Thickness of acetabular and femoral cartilage and volume of subchondral bone cysts were estimated in the remaining 17 patients. Ten years postoperatively, the patients' Hip disability and Osteoarthritis Outcome Scores (HOOS) were collected. RESULTS: Preoperatively, the mean thickness of the acetabular cartilage was 1.38+/-0.14 mm compared with 1.43+/-0.07 mm 10 years postoperatively (p=0.73). The mean thickness of the femoral cartilage preoperatively was 1.37+/-0.20 mm compared with 1.30+/-0.07 mm 10 years postoperatively (p=0.24). Seven patients had an increase in cyst volume, six had a decrease, and four had no cysts to start with and remained without cysts. Preoperatively, the median total cyst volume per patient was 6.0 cm3 (range, 1.6-188.3 cm3) compared with 2.9 cm3 (range, 0.7-8.2 cm3) (p=0.18) at 10 years followup. At 10 years, the mean subscores for the HOOS were: pain, 79+/-16; symptoms, 73+/-17; activities of daily living, 85+/-14; sport/recreation, 68+/-22; and quality of life, 61+/-19. CONCLUSIONS: Ten years after PAO, approximately 25% of the patients who have the procedure will have substantial hip pain and/or undergo hip arthroplasty. Of the patients who do not have substantial hip pain or an arthroplasty, cartilage thickness appears to be preserved. Future studies are needed to help us decide which patients are most likely to succeed with PAO at long-term followup. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 25822457 TI - Sequence variation within the KIV-2 copy number polymorphism of the human LPA gene in African, Asian, and European populations. AB - Amazingly little sequence variation is reported for the kringle IV 2 copy number variation (KIV 2 CNV) in the human LPA gene. Apart from whole genome sequencing projects, this region has only been analyzed in some detail in samples of European populations. We have performed a systematic resequencing study of the exonic and flanking intron regions within the KIV 2 CNV in 90 alleles from Asian, European, and four different African populations. Alleles have been separated according to their CNV length by pulsed field gel electrophoresis prior to unbiased specific PCR amplification of the target regions. These amplicons covered all KIV 2 copies of an individual allele simultaneously. In addition, cloned amplicons from genomic DNA of an African individual were sequenced. Our data suggest that sequence variation in this genomic region may be higher than previously appreciated. Detection probability of variants appeared to depend on the KIV 2 copy number of the analyzed DNA and on the proportion of copies carrying the variant. Asians had a high frequency of so-called KIV 2 type B and type C (together 70% of alleles), which differ by three or two synonymous substitutions respectively from the reference type A. This is most likely explained by the strong bottleneck suggested to have occurred when modern humans migrated to East Asia. A higher frequency of variable sites was detected in the Africans. In particular, two previously unreported splice site variants were found. One was associated with non-detectable Lp(a). The other was observed at high population frequencies (10% to 40%). Like the KIV 2 type B and C variants, this latter variant was also found in a high proportion of KIV 2 repeats in the affected alleles and in alleles differing in copy numbers. Our findings may have implications for the interpretation of SNP analyses in other repetitive loci of the human genome. PMID- 25822458 TI - Characterization of calmodulin-free murine inducible nitric-oxide synthase. AB - Nitric-Oxide Synthase (NOS), that produces the biological signal molecule Nitric Oxide (NO), exists in three different isoforms called, neuronal (nNOS), endothelial (eNOS) and inducible (iNOS). All NOS isoforms require post translational interaction with the calcium-binding protein, calmodulin (CaM) for manifesting their catalytic activity. However, CaM has been suggested to control the translational assembly of the enzyme as well, particularly in helping its inducible isoform, iNOS assume a stable, heme-replete, dimeric and active form. Expression of recombinant murine iNOS in E.coli in the absence of CaM has been previously shown to give extremely poor yield of the enzyme which was claimed to be absolutely heme-free, devoid of flavins, completely monomeric and catalytically inactive when compared to the heme-replete, active, dimeric iNOS, generated through co-expression with CaM. In contrast, we found that although iNOS expressed without CaM does produce significantly low amounts of the CaM-free enzyme, the iNOS thus produced, is not completely devoid of heme and is neither entirely monomeric nor absolutely bereft of catalytic activity as reported before. In fact, iNOS synthesized in the absence of CaM undergoes compromised heme incorporation resulting in extremely poor dimerization and activity compared to its counterpart co-expressed with CaM. Moreover, such CaM-free iNOS has similar flavin content and reductase activity as iNOS co-expressed with CaM, suggesting that CaM may not be as much required for the functional assembly of the iNOS reductase domain as its oxygenase domain. LC-MS/MS-based peptide mapping of the CaM-free iNOS confirmed that it had the same full-length sequence as the CaM-replete iNOS. Isothermal calorimetric measurements also revealed high affinity for CaM binding in the CaM-free iNOS and thus the possible presence of a CaM-binding domain. Thus CaM is essential but not indispensible for the assembly of iNOS and such CaM-free iNOS may help in elucidating the role of CaM on iNOS catalysis. PMID- 25822459 TI - The Number of GT(n) Repeats in the Hemeoxygenase-1 Gene Promoter is Increased in Pediatric Heart Failure but is Unrelated to Renal, Antioxidant and Anti inflammatory Markers. AB - Products of hemeoxygenase (HO)-1 have anti-inflammatory and antioxidant functions. The HO-1 promoter has a variable number of GT(n) repeats: A low number (n < 23) is associated with high transcriptional activity in response to oxidative stress. We hypothesized that the frequency of GT(n) repeats in pediatric heart failure (HF) reflects plasma biomarkers of different disease processes: the soluble receptor for advance glycation end products (sRAGE, marking cellular activation), oxLDL (oxidative stress), NGAL (impaired renal function), HIF-1alpha (hypoxia) and hsCRP (inflammation). Sixty HF children [aged 4-14 years, 30 with HF due to idiopathic dilated cardiomyopathy (IDCM), 30 due to chronic renal failure (CRF)] were compared to 20 healthy controls (HC). Leukocyte HO-1 GT(n) repeats were determined by PCR, plasma markers by ELISA or nephelometry. The number of GT(n) repeats in the HF patients was higher than the number of repeats in the controls, with no difference between the patient groups (p < 0.001). sRAGE, oxLDL, HIF-1alpha, NGAL and hsCRP were higher in both HF groups compared to HC (all p < 0.01). IDCM had higher sRAGEs and HIF-1alpha compared to CRF patients (p < 0.01). NGAL was higher in CRF compared to IDCM (p < 0.01). None of the plasma/serum markers correlated with the number of GT(n) repeats in any group. The number of HO-1 promoter GT(n) polymorphism is increased in both IDCM and CRF children with HF, but is unrelated to plasma markers of different pathological processes. This casts doubts on the clinical value of the number of GT(n) repeats in pediatric HF. PMID- 25822460 TI - In-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction. AB - BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. CLINICAL CASE: A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. CONCLUSIONS: The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin. PMID- 25822461 TI - Searching for explanations: How the Internet inflates estimates of internal knowledge. AB - As the Internet has become a nearly ubiquitous resource for acquiring knowledge about the world, questions have arisen about its potential effects on cognition. Here we show that searching the Internet for explanatory knowledge creates an illusion whereby people mistake access to information for their own personal understanding of the information. Evidence from 9 experiments shows that searching for information online leads to an increase in self-assessed knowledge as people mistakenly think they have more knowledge "in the head," even seeing their own brains as more active as depicted by functional MRI (fMRI) images. PMID- 25822462 TI - The propagation of self-control: Self-control in one domain simultaneously improves self-control in other domains. AB - [Correction Notice: An Erratum for this article was reported in Vol 144(3) of Journal of Experimental Psychology: General (see record 2015-24174-008). The affiliations for co-authors Kuangjie Zhang and Steven Sweldens were incorrect. All versions of this article have been corrected.] A rich tradition in self control research has documented the negative consequences of exerting self control in 1 task for self-control performance in subsequent tasks. However, there is a dearth of research examining what happens when people exert self control in multiple domains simultaneously. The current research aims to fill this gap. We integrate predictions from the most prominent models of self-control with recent neuropsychological insights in the human inhibition system to generate the novel hypothesis that exerting effortful self-control in 1 task can simultaneously improve self-control in completely unrelated domains. An internal meta-analysis on all 18 studies we conducted shows that exerting self-control in 1 domain (i.e., controlling attention, food consumption, emotions, or thoughts) simultaneously improves self-control in a range of other domains, as demonstrated by, for example, reduced unhealthy food consumption, better Stroop task performance, and less impulsive decision making. A subset of 9 studies demonstrates the crucial nature of task timing-when the same tasks are executed sequentially, our results suggest the emergence of an ego depletion effect. We provide conservative estimates of the self-control facilitation (d = |0.22|) as well as the ego depletion effect size (d = |0.17|) free of data selection and publication biases. These results (a) shed new light on self-control theories, (b) confirm recent claims that previous estimates of the ego depletion effect size were inflated due to publication bias, and (c) provide a blueprint for how to handle the power issues and associated file drawer problems commonly encountered in multistudy research projects. PMID- 25822463 TI - Movement cues aid face recognition in developmental prosopagnosia. AB - OBJECTIVE: Seeing a face in motion can improve face recognition in the general population, and studies of face matching indicate that people with face recognition difficulties (developmental prosopagnosia; DP) may be able to use movement cues as a supplementary strategy to help them process faces. However, the use of facial movement cues in DP has not been examined in the context of familiar face recognition. This study examined whether people with DP were better at recognizing famous faces presented in motion, compared to static. METHODS: Nine participants with DP and 14 age-matched controls completed a famous face recognition task. Each face was presented twice across 2 blocks: once in motion and once as a still image. Discriminability (A) was calculated for each block. RESULTS: Participants with DP showed a significant movement advantage overall. This was driven by a movement advantage in the first block, but not in the second block. Participants with DP were significantly worse than controls at identifying faces from static images, but there was no difference between those with DP and controls for moving images. CONCLUSIONS: Seeing a familiar face in motion can improve face recognition in people with DP, at least in some circumstances. The mechanisms behind this effect are unclear, but these results suggest that some people with DP are able to learn and recognize patterns of facial motion, and movement can act as a useful cue when face recognition is impaired. PMID- 25822464 TI - An exploratory study of the association of acute posttraumatic stress, depression, and pain to cognitive functioning in mild traumatic brain injury. AB - OBJECTIVE: Few studies have examined whether psychological distress and pain affect cognitive functioning in the acute to subacute phase (up to 30 days postinjury) following mild traumatic brain injury (mTBI). The current study explored whether acute posttraumatic stress, depression, and pain were associated with performance on a task of selective and sustained attention completed under conditions of increasing cognitive demands (standard, auditory distraction, and dual-task), and on tests of working memory, memory, processing speed, reaction time (RT), and verbal fluency. METHOD: At a mean of 2.87 days (SD = 2.32) postinjury, 50 adult mTBI participants, consecutive admissions to a Level 1 trauma hospital, completed neuropsychological tests and self-report measures of acute posttraumatic stress, depression, and pain. A series of canonical correlation analyses was used to explore the relationships of a common set of psychological variables to various sets of neuropsychological variables. RESULTS: Significant results were found on the task of selective and sustained attention. Strong relationships were found between psychological variables and speed (r(c) = .56, p = .02) and psychological variables and accuracy (r(c) = .68, p = .002). Pain and acute posttraumatic stress were associated with higher speed scores (reflecting more correctly marked targets) under standard conditions. Acute posttraumatic stress was associated with lower accuracy scores across all task conditions. Moderate but nonsignificant associations were found between psychological variables and most cognitive tasks. CONCLUSIONS: Acute posttraumatic stress and pain show strong associations with selective and sustained attention following mTBI. PMID- 25822465 TI - Cervical total disc replacement is superior to anterior cervical decompression and fusion: a meta-analysis of prospective randomized controlled trials. AB - BACKGROUND: Despite being considered the standard surgical procedure for symptomatic cervical disc disease, anterior cervical decompression and fusion invariably accelerates adjacent segment degeneration. Cervical total disc replacement is a motion-preserving procedure developed as a substitute to fusion. Whether cervical total disc replacement is superior to fusion remains unclear. METHODS: We comprehensively searched PubMed, EMBASE, Medline, and the Cochrane Library in accordance with the inclusion criteria to identify possible studies. The retrieved results were last updated on December 12, 2014. We classified the studies as short-term and midterm follow-up. RESULTS: Nineteen randomized controlled trials involving 4516 cases were identified. Compared with anterior cervical decompression and fusion, cervical total disc replacement had better functional outcomes (neck disability index [NDI], NDI success, neurological success, neck pain scores reported on a numerical rating scale [NRS], visual analog scales scores and overall success), greater segmental motion at the index level, fewer adverse events and fewer secondary surgical procedures at the index and adjacent levels in short-term follow-up (P < 0.05). With midterm follow-up, the cervical total disc replacement group indicated superiority in the NDI, neurological success, pain assessment (NRS), and secondary surgical procedures at the index level (P < 0.05). The Short Form 36 (SF-36) and segmental motion at the adjacent level in the short-term follow-up showed no significant difference between the two procedures, as did the secondary surgical procedure rates at the adjacent level with midterm follow-up (P > 0.05). CONCLUSIONS: Cervical total disc replacement presented favorable functional outcomes, fewer adverse events, and fewer secondary surgical procedures. The efficacy and safety of cervical total disc replacement are superior to those of fusion. Longer-term, multicenter studies are required for a better evaluation of the long-term efficacy and safety of the two procedures. PMID- 25822466 TI - Hierarchically structured hematite architectures achieved by growth in a silica hydrogel. AB - Biomineralization strategies include the use of hydrogels to direct the formation of composite, single-crystal-like structures with unique structure-property profiles. Application of similar synthetic approaches to transition-metal oxides has the promise to yield low-temperature routes to hierarchically structured crystals that are optimized for a range of applications. Here, growth of hematite (alpha-Fe2O3) within a silica hydrogel resulted in hierarchical, mosaic crystals preferentially expressing catalytically active {110} facets, which are absent in solution-grown controls. Quantitative structural and compositional analysis reveals architectural changes that begin with the incorporation of silicon into the hematite lattice and propagate through to the nanoscale domain structure and assembly, leading to microscale morphologies that show improved photocatalytic performance. This work demonstrates the potential of applying bioinspired crystallization techniques to design functional oxides with multiscale architectural features. PMID- 25822467 TI - A phenomenographic study of students' conception of learning for a written examination. AB - OBJECTIVE: We investigated students' conception of learning for an examination in internal medicine, infectious diseases and dermatology-venereology, in three separate examinations versus a single integrated one. METHODS: The study was carried out during a curricular change, with one cohort belonging to a new integrated examination and the other to the former non-integrated examination. Forty-eight interviews were carried out among medical undergraduates regarding the role of the examination in the learning process. The interviews were analyzed according to the phenomenographic approach to identify the students' conception of learning. RESULTS: The learning approaches could be categorized in 47 of the 48 students into 4 major groups: application directed, holistic, comprehensive and tactical memorizing learning. The result indicated that comprehensive learning was the most common approach among students following either examination form; tactical memorizing learning was more prevalent among students following the non-integrated examination and holistic learning was applied more frequently among students following the integrated examination. Nine of the 47 students changed their approaches over time, the majority switching to a comprehensive approach. No significant gender difference was observed. CONCLUSIONS: Comprehensive learning was the most common strategy employed and students who changed during the course most often switched to this. However, only a minor change in approach was observed after a switching to an integrated examination, i.e. it takes more than just an integrated examination to change the student's conception of learning. PMID- 25822468 TI - Assessing the potential threat landscape of a proposed reintroduction site for carnivores. AB - This study provides a framework to assess the feasibility of reintroducing carnivores into an area, using African wild dogs (Lycaon pictus) as an example. The Great Fish River Nature Reserve in the Eastern Cape Province, South Africa, has been identified as a potential reserve to reintroduce wild dogs, and we applied this framework to provide a threat assessment of the surrounding area to determine potential levels of human-wildlife conflict. Although 56% of neighbouring landowners and local communities were positive about a wild dog reintroduction, data collected from questionnaire surveys revealed that human wild dog conflict is a potential threat to wild dog survival in the area. Additional potential threats include diseases, snaring, poaching and hunting wild dogs for the use of traditional medicine. A threat index was developed to establish which properties harboured the greatest threats to wild dogs. This index was significantly influenced by the respondent's first language (isiXhosa had more positive indices), education level (poorer education was synonymous with more positive threat indices), land use (wildlife ranching being the most negative) and land tenure (community respondents had more positive indices than private landowners). Although threats are present, they can be effectively mitigated through strategies such as carnivore education programs, vaccination campaigns and anti-snare patrols to promote a successful reintroduction of this endangered canid. PMID- 25822469 TI - Stent-assisted Coil Placement for the Treatment of 211 Acutely Ruptured Wide necked Intracranial Aneurysms: A Single-Center 11-Year Experience. AB - PURPOSE: To evaluate the safety and angiographic and clinical outcome of stent assisted coil placement (SACP) for acutely ruptured wide-necked intracranial aneurysms treated in a single center during an 11-year period. MATERIALS AND METHODS: According to an institutional review board-approved protocol, the angiographic and clinical data of 211 patients (52 men, 159 women; median age, 56 years; age range, 31-83 years) with acutely ruptured wide-necked intracranial aneurysms (neck > 4 mm and/or dome-to-neck ratio <= 2) treated with SACP from September 2000 to December 2011 were reviewed retrospectively. Baseline characteristics, procedure-related complications, angiographic follow-up results, and clinical outcome were analyzed statistically. A Mann-Whitney U test was performed for non-normally distributed continuous variables. A Pearson chi(2) or Fisher exact test was performed for categorical variables. Univariate analysis and logistic regression analysis were performed to determine the association of procedure-related complications and clinical outcome with potential risk factors. RESULTS: Procedure-related complications occurred in 30 patients (14.2%). They were more common in the anterior communicating artery (26.7%, 12 of 45) and middle cerebral artery bifurcation (40%, four of 10) aneurysms than in aneurysms at other locations (9.0%, 14 of 156). Clinical outcome (median, 33 months) was good in 175 patients (82.9%) with a modified Rankin Scale score of up to 2. Older age (P = .013, odds ratio = 1.054) and higher Hunt and Hess grade (P < .001, odds ratio = 15.876) were independent risk factors for unfavorable outcome. One hundred fifty-two of 190 patients who survived (80%) underwent angiographic follow-up at least once (median, 12 months). The complete occlusion rate improved from an immediate 45.5% to 75.7% at follow-up (115 of 152 patients). CONCLUSION : Angiographic and clinical outcomes in our series were comparable to those reported by using coil placement alone or balloon-assisted coil placement techniques. SACP for the treatment of acutely ruptured middle cerebral artery bifurcation and anterior communicating artery aneurysms was associated with a significantly higher incidence of complications than was the case for treatment of aneurysms at other locations. PMID- 25822471 TI - Hepatic Parenchymal Heterogeneity on Contrast-enhanced CT Scans Following Oxaliplatin-based Chemotherapy: Natural History and Association with Clinical Evidence of Sinusoidal Obstruction Syndrome. AB - PURPOSE: To evaluate the natural history and contrast material-enhanced computed tomographic (CT) features of postoxaliplatin heterogeneity of liver parenchyma (POHL) and to investigate the association of POHL with clinical factors and biomarkers of sinusoidal obstruction syndrome (SOS). MATERIALS AND METHODS: The retrospective study was approved by the institutional review board, and informed consent was waived. Two hundred seventy patients (159 men, 111 women; age range, 31-92 years) who underwent oxaliplatin-based chemotherapy (OBC) and serial contrast-enhanced CT were consecutively registered. POHL severity was independently scored by two abdominal imagers, who were blinded to the clinical data, using a six-point scale (POHL presence, >=4), followed by a consensus review. Complete radiologic remission was determined by consensus on the disappearance of heterogeneity on CT images. The association of POHL severity score with CT-based quantitative (ie, change in spleen size and blood-free hepatic parenchymal attenuation) and laboratory values (ie, aspartate aminotransferase, alanine transaminase, and platelet count), as well as time to complete radiologic remission, were evaluated with the Spearman rank test. Multivariate analysis was performed to determine the association between clinical factors of SOS (ie, age, sex, number of OBC sessions, chemotherapy regimen, bevacizumab use, and presence of concomitant hepatic metastasis) and POHL development. RESULTS Interobserver agreement was excellent (kappa = 0.90). POHL was present in 167 (61.9%) of 270 patients, and the number of OBC sessions was significantly associated with POHL development (odds ratio, 1.138; 95% confidence interval: 1.039, 1.245; P = .005). POHL severity score was correlated with quantitative CT and laboratory values (P < .05 for all statistical analysis). Peripheral distribution (103 of 167, 61.7%) and right lobar predominance (103 of 165, 62.4%) were the most common POHL features. The mean time to complete radiologic remission, which was correlated with POHL severity score, was 82.5 days +/- 68.8 after OBC discontinuation. CONCLUSION: POHL development is associated with increased number of OBC sessions, and POHL severity was correlated with various biomarkers of SOS. PMID- 25822472 TI - Radiofrequency Ablation: Inflammatory Changes in the Periablative Zone Can Induce Global Organ Effects, including Liver Regeneration. AB - PURPOSE: To determine the kinetics of innate immune and hepatic response to the coagulation necrosis area that remains in situ after radiofrequency (RF) ablation, the cytokine profile of this response, and its local and global effect on the whole organ in a small-animal model. MATERIALS AND METHODS: A standardized RF ablation dose (70 degrees C for 5 minutes) was used to ablate more than 7% of the liver in 91 C57BL6 mice (wild type) according to a protocol approved by the animal care committee. The dynamic cellular response in the border zone surrounding ablation-induced coagulation and in the ablated lobe and an untreated lobe were characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (the time points at which cells migrate to necrotic tissues). After characterization of the cellular populations that reacted to the RF treatment, cytokines secreted by these cells were blocked, either by using interleukin-6 knockout mice (n = 24) or c-met inhibitor PHA 665752 (n = 15), to elucidate the key factors facilitating the wound healing response to RF ablation. Statistical significance was assessed with nonparametric analysis of variance. RESULTS: RF ablation induces a strong time-dependent immunologic response at the perimeter of the necrotic zone. This includes massive accumulation of neutrophils, activated myofibroblasts, and macrophages peaking at 24 hours, 7 days, and 14 days after ablation, respectively. In correlation with myofibroblast accumulation, RF ablation induced hepatocyte proliferation in both the ablated lobe and an untreated lobe (mean, 165.15 and 230.4 cyclin-dependent kinase 47 positive cells per *20 field, respectively, at day 7; P < .02). Blockade of either IL-6 or c-met significantly reduced global hepatocyte proliferation (P < .05 for both), with the former reducing the accumulation of both macrophages and myofibroblasts surrounding the coagulation necrosis area (42.9 and 113.6 vs 7.3 and 46.6 macrophages and activated myofibroblasts per *20 field, respectively; P < .036 for both). CONCLUSION: Hepatic RF ablation induces not only a local periablational inflammatory zone but also more global proliferative effects on the liver. These IL-6- and/or c-met-mediated changes could potentially account for some of the local and distant tumor recurrence observed after treatment. PMID- 25822473 TI - Commentary on "E. Mugnaini and A. Floris, the unipolar brush cell: a neglected neuron of the mammalian cerebellar cortex. J Comp Neurol, 339:174-180, 1994". PMID- 25822474 TI - Beholder and Beheld: A Multilevel Model of Perceived Sexual Appeal. AB - When individuals (observers) assess how appealing they find sexual stimuli (targets), which factors matter and to whom? The present study examined how observer and target characteristics interact and impact perceived sexual appeal. Participants were 302 men (206 heterosexual, 96 gay) and 289 women (196 heterosexual, 93 lesbian) between the ages of 18 and 67 years, who viewed 34 photographs of targets of their preferred gender and rated each target for sexual appeal, masculinity-femininity, and estimated age. Participants also rated their own masculinity-femininity. A baseline model indicated that roughly 30 % of the variance in sexual appeal ratings was at the observer level (between observers) and 70 % of the variance was at the target level (within observers). In the final model, five characteristics of the participant observers (gender, sexual orientation, age, race/ethnicity, and self-described masculinity-femininity) and six characteristics of the target photographs (gender, whether the photographs were taken from heterosexual versus gay/lesbian media, race/ethnicity, perceived masculinity-femininity, and estimated age) were independently and interactively related to observer ratings of target sexual appeal. Observers displayed preferences for similar targets in terms of race/ethnicity and masculinity femininity, while also displaying a general preference for target youth. Variation in the strength of these preferences occurred according to observers' own gender, race/ethnicity, masculinity-femininity, and sexual orientation. PMID- 25822476 TI - Increased risk for colorectal adenomas and cancer in mono-allelic MUTYH mutation carriers: results from a cohort of North-African Jews. AB - Bi-allelic MUTYH gene mutations are associated with a clinical phenotype of multiple colorectal adenomas and an increased risk for colorectal cancer (CRC). It is unclear whether mono-allelic MUTYH gene carriers (heterozygotes) are also at increased risk for even few adenomas or cancer. In order to clarify an association between MUTYH heterozygotes and adenomas, we evaluated the frequency and types of MUTYH mutations and variants in 72 North-African Jews having few (>=3) colorectal adenomas with or without early onset (<50 years) CRC compared to 29 healthy controls. Germ-line DNA was analyzed for a panel of 6 MUTYH mutations and variants, and Sanger sequencing of the entire MUTYH gene was performed for mono-allelic MUTYH mutation carriers. APC gene mutations and Lynch syndrome were excluded in the relevant cases according to accepted clinical criteria. Twenty two of the 72 adenoma subjects (30.5%) had MUTYH mutations or variants. Nine were homozygotes or compound heterozygotes: all had >10 adenomas and one had CRC. Thirteen others were mono-allelic carriers (heterozygotes) of a single MUTYH mutation: six had more than ten adenomas and seven had less than ten adenomas; of these 13 mono-allelic carriers, six had a neoplasm: three CRCs and three extra intestinal tumors. Eleven of the thirteen mono-allelic carriers with adenomas had a family history of cancer in first or second degree relatives. A multivariable model showed positive correlation between G396D, Y179C and 1186 ins GG mutations and number of adenomas (OR 8.6, 10.2 and 14.4, respectively). The Q324H variant was negatively associated with the number of adenomatous polyps (OR -5.23). In conclusion, MUTYH mutations are prevalent among Jews of North-African origin with colorectal adenomas with or without early onset CRC. Mono-allelic MUTYH carriers with a family history of cancer had a clinical phenotype that varied from having only few adenomas to multiple (>10) adenomas. These findings support MUTYH testing in patients with even few adenomas and suggest the consideration of increased surveillance in mono-allelic carriers with a family history of cancer. PMID- 25822477 TI - A Conceptual Framework for Improving Critical Care Patient Flow and Bed Use. AB - RATIONALE: High demand for intensive care unit (ICU) services and limited bed availability have prompted hospitals to address capacity planning challenges. Simulation modeling can examine ICU bed assignment policies, accounting for patient acuity, to reduce ICU admission delays. OBJECTIVES: To provide a framework for data-driven modeling of ICU patient flow, identify key measurable outcomes, and present illustrative analysis demonstrating the impact of various bed allocation scenarios on outcomes. METHODS: A description of key inputs for constructing a queuing model was outlined, and an illustrative simulation model was developed to reflect current triage protocol within the medical ICU and step down unit (SDU) at a single tertiary-care hospital. Patient acuity, arrival rate, and unit length of stay, consisting of a "service time" and "time to transfer," were estimated from 12 months of retrospective data (n = 2,710 adult patients) for 36 ICU and 15 SDU staffed beds. Patient priority was based on acuity and whether the patient originated in the emergency department. The model simulated the following hypothetical scenarios: (1) varied ICU/SDU sizes, (2) reserved ICU beds as a triage strategy, (3) lower targets for time to transfer out of the ICU, and (4) ICU expansion by up to four beds. Outcomes included ICU admission wait times and unit occupancy. MEASUREMENTS AND MAIN RESULTS: With current bed allocation, simulated wait time averaged 1.13 (SD, 1.39) hours. Reallocating all SDU beds as ICU decreased overall wait times by 7.2% to 1.06 (SD, 1.39) hours and increased bed occupancy from 80 to 84%. Reserving the last available bed for acute patients reduced wait times for acute patients from 0.84 (SD, 1.12) to 0.31 (SD, 0.30) hours, but tripled subacute patients' wait times from 1.39 (SD, 1.81) to 4.27 (SD, 5.44) hours. Setting transfer times to wards for all ICU/SDU patients to 1 hour decreased wait times for incoming ICU patients, comparable to building one to two additional ICU beds. CONCLUSIONS: Hospital queuing and simulation modeling with empiric data inputs can evaluate how changes in ICU bed assignment could impact unit occupancy levels and patient wait times. Trade-offs associated with dedicating resources for acute patients versus expanding capacity for all patients can be examined. PMID- 25822478 TI - Fluoxetine associated with thrombocytopenia and treatment with reboxetine: 3 cases. PMID- 25822479 TI - HTR1A Gene Polymorphisms and 5-HT1A Receptor Partial Agonist Antipsychotics Efficacy in Schizophrenia. AB - Individual differences in serotonin 1A (5-HT1A) receptor may result in variable response to antipsychotics with 5-HT1A receptor partial agonism. We investigated the relationship between 5-HT1A receptor gene (HTR1A) single nucleotide polymorphisms (SNPs) and efficacy of antipsychotics with 5-HT1A receptor partial agonism in Japanese patients with schizophrenia. Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. Candidate SNPs were rs6295 (which affects HTR1A expression and function), rs1364043, rs878567, and rs10042486. Efficacy at week 12 of treatment was evaluated using the Positive and Negative Syndrome Scale (PANSS) 5-factor subscales (excitement/hostility, depression/anxiety, cognition, positive, and negative). Rs1364043 T allele was correlated with the percent change in the PANSS 5-factor negative score (P < 0.01). Haplotype analysis showed that the rs10042486 rs6295-rs1364043 T-C-G haplotype was correlated with worse negative score improvement (haplotype frequency, 0.675; P = 0.014), and the relatively rare T-G T haplotype correlated with better efficacy (haplotype frequency, 0.05; P = 0.031). This is the first study to show that rs10042486-rs6295-rs1364043 HTR1A variants may be correlated with the improvement of the PANSS 5-factor negative score during treatment with 5-HT1A partial agonist antipsychotics. Studies with larger sample sizes and in different ethnic groups are warranted. PMID- 25822480 TI - Directional analysis of the storm surge from Hurricane Sandy 2012, with applications to Charleston, New Orleans, and the Philippines. AB - Hurricane Sandy in late October 2012 drove before it a storm surge that rose to 4.28 meters above mean lower low water at The Battery in lower Manhattan, and flooded the Hugh L. Carey automobile tunnel between Brooklyn and The Battery. This study examines the surge event in New York Harbor using the Weather Research and Forecasting (WRF) atmospheric model and the Coupled-Ocean-Atmosphere-Wave- Sediment Transport/Regional Ocean Modeling System (COAWST/ROMS). We present a new technique using directional analysis to calculate and display maps of a coastline's potential for storm surge; these maps are constructed from wind fields blowing from eight fixed compass directions. This analysis approximates the surge observed during Hurricane Sandy. The directional analysis is then applied to surge events at Charleston, South Carolina, New Orleans, Louisiana, and Tacloban City, the Philippines. Emergency managers could use these directional maps to prepare their cities for an approaching storm, on planning horizons from days to years. PMID- 25822481 TI - SIP metagenomics identifies uncultivated Methylophilaceae as dimethylsulphide degrading bacteria in soil and lake sediment. AB - Dimethylsulphide (DMS) has an important role in the global sulphur cycle and atmospheric chemistry. Microorganisms using DMS as sole carbon, sulphur or energy source, contribute to the cycling of DMS in a wide variety of ecosystems. The diversity of microbial populations degrading DMS in terrestrial environments is poorly understood. Based on cultivation studies, a wide range of bacteria isolated from terrestrial ecosystems were shown to be able to degrade DMS, yet it remains unknown whether any of these have important roles in situ. In this study, we identified bacteria using DMS as a carbon and energy source in terrestrial environments, an agricultural soil and a lake sediment, by DNA stable isotope probing (SIP). Microbial communities involved in DMS degradation were analysed by denaturing gradient gel electrophoresis, high-throughput sequencing of SIP gradient fractions and metagenomic sequencing of phi29-amplified community DNA. Labelling patterns of time course SIP experiments identified members of the Methylophilaceae family, not previously implicated in DMS degradation, as dominant DMS-degrading populations in soil and lake sediment. Thiobacillus spp. were also detected in (13)C-DNA from SIP incubations. Metagenomic sequencing also suggested involvement of Methylophilaceae in DMS degradation and further indicated shifts in the functional profile of the DMS-assimilating communities in line with methylotrophy and oxidation of inorganic sulphur compounds. Overall, these data suggest that unlike in the marine environment where gammaproteobacterial populations were identified by SIP as DMS degraders, betaproteobacterial Methylophilaceae may have a key role in DMS cycling in terrestrial environments. PMID- 25822482 TI - Polar freshwater cyanophage S-EIV1 represents a new widespread evolutionary lineage of phages. AB - Cyanobacteria are often the dominant phototrophs in polar freshwater communities; yet, the phages that infect them remain unknown. Here, we present a genomic and morphological characterization of cyanophage S-EIV1 that was isolated from freshwaters on Ellesmere Island (Nunavut, High Arctic Canada), and which infects the polar Synechococcus sp., strain PCCC-A2c. S-EIV1 represents a newly discovered evolutionary lineage of bacteriophages whose representatives are widespread in aquatic systems. Among the 130 predicted open reading frames (ORFs) there is no recognizable similarity to genes that encode structural proteins other than the large terminase subunit and a distant viral morphogenesis protein, indicating that the genes encoding the structural proteins of S-EIV1 are distinct from other viruses. As well, only 19 predicted coding sequences on the 79 178 bp circularly permuted genome have homology with genes encoding proteins of known function. Although S-EIV1 is divergent from other sequenced phage isolates, it shares synteny with phage genes captured on a fosmid from the deep-chlorophyll maximum in the Mediterranean Sea, as well as with an incision element in the genome of Anabaena variabilis (ATCC 29413). Sequence recruitment of metagenomic data indicates that S-EIV1-like viruses are cosmopolitan and abundant in a wide range of aquatic systems, suggesting they have an important ecological role. PMID- 25822484 TI - Dihydrogen bond intermediated alcoholysis of dimethylamine-borane in nonaqueous media. AB - Dimethylamine-borane (DMAB) acid/base properties, its dihydrogen-bonded (DHB) complexes and proton transfer reaction in nonaqueous media were investigated both experimentally (IR, UV/vis, NMR, and X-ray) and theoretically (DFT, NBO, QTAIM, and NCI). The effects of DMAB concentration, solvents polarity and temperature on the degree of DMAB self-association are shown and the enthalpy of association is determined experimentally for the first time (-DeltaH degrees assoc = 1.5-2.3 kcal/mol). The first case of "improper" (blue-shifting) NH...F hydrogen bonds was observed in fluorobenzene and perfluorobenzene solutions. It was shown that hydrogen-bonded complexes are the intermediates of proton transfer from alcohols and phenols to DMAB. The reaction mechanism was examined computationally taking into account the coordinating properties of the reaction media. The values of the rate constants of proton transfer from HFIP to DMAB in acetone were determined experimentally [(7.9 +/- 0.1) * 10(-4) to (1.6 +/- 0.1) * 10(-3) mol(-1).s(-1)] at 270-310 K. Computed activation barrier of this reaction DeltaG(?theor)298 K(acetone) = 23.8 kcal/mol is in good agreement with the experimental value of the activation free energy DeltaG(?exp)270 K = 21.1 kcal/mol. PMID- 25822483 TI - Metatranscriptomic census of active protists in soils. AB - The high numbers and diversity of protists in soil systems have long been presumed, but their true diversity and community composition have remained largely concealed. Traditional cultivation-based methods miss a majority of taxa, whereas molecular barcoding approaches employing PCR introduce significant biases in reported community composition of soil protists. Here, we applied a metatranscriptomic approach to assess the protist community in 12 mineral and organic soil samples from different vegetation types and climatic zones using small subunit ribosomal RNA transcripts as marker. We detected a broad diversity of soil protists spanning across all known eukaryotic supergroups and revealed a strikingly different community composition than shown before. Protist communities differed strongly between sites, with Rhizaria and Amoebozoa dominating in forest and grassland soils, while Alveolata were most abundant in peat soils. The Amoebozoa were comprised of Tubulinea, followed with decreasing abundance by Discosea, Variosea and Mycetozoa. Transcripts of Oomycetes, Apicomplexa and Ichthyosporea suggest soil as reservoir of parasitic protist taxa. Further, Foraminifera and Choanoflagellida were ubiquitously detected, showing that these typically marine and freshwater protists are autochthonous members of the soil microbiota. To the best of our knowledge, this metatranscriptomic study provides the most comprehensive picture of active protist communities in soils to date, which is essential to target the ecological roles of protists in the complex soil system. PMID- 25822486 TI - Lessons learned from implementing a wet laboratory molecular training workshop for beach water quality monitoring. AB - Rapid molecular testing methods are poised to replace many of the conventional, culture-based tests currently used in fields such as water quality and food science. Rapid qPCR methods have the benefit of being faster than conventional methods and provide a means to more accurately protect public health. However, many scientists and technicians in water and food quality microbiology laboratories have limited experience using these molecular tests. To ensure that practitioners can use and implement qPCR techniques successfully, we developed a week long workshop to provide hands-on training and exposure to rapid molecular methods for water quality management. This workshop trained academic professors, government employees, private industry representatives, and graduate students in rapid qPCR methods for monitoring recreational water quality. Attendees were immersed in these new methods with hands-on laboratory sessions, lectures, and one-on-one training. Upon completion, the attendees gained sufficient knowledge and practice to teach and share these new molecular techniques with colleagues at their respective laboratories. Key findings from this workshop demonstrated: 1) participants with no prior experience could be effectively trained to conduct highly repeatable qPCR analysis in one week; 2) participants with different desirable outcomes required exposure to a range of different platforms and sample processing approaches; and 3) the collaborative interaction amongst newly trained practitioners, workshop leaders, and members of the water quality community helped foster a cohesive cohort of individuals which can advocate powerful cohort for proper implementation of molecular methods. PMID- 25822487 TI - Apoptotic cells induce NF-kappaB and inflammasome negative signaling. AB - As they undergo phagocytosis, most early apoptotic cells negatively regulate proinflammatory signaling and were suggested as a major mechanism in the resolution of inflammation. The dextran sulfate sodium model is generally viewed as an epithelial damage model suited to investigate innate immune responses. Macrophages primed with LPS and subsequently exposed to DSS secrete high levels of IL-1beta in an NLRP3-, ASC-, and caspase-1-dependent manner. The aim of this research was to test the therapeutic effect of a single dose of apoptotic cells in a DSS-colitis model and to explore possible mechanisms. Primary peritoneal macrophages, the DSS mice model, and Nlrp3-deficient mice, were used to assess the effect apoptotic cells on colitis. Immunohistochemistry, flow-cytometer, and western blots helped to explore the effect and mechanisms. Using a variety of NLRP3 triggering mechanisms, we show that apoptotic cells negatively regulate NF kappaB and NLRP3 activation in primary peritoneal macrophages, at pre- and post transcription levels, via inhibition of reactive oxygen species, lysosomal stabilization, and blocking K+ efflux. This property of apoptotic cells is demonstrated in a dramatic clinical, histological, and immunological amelioration of DSS colitis in Balb/c and B6 mice following a single administration of apoptotic cells. PMID- 25822488 TI - Multicolor whole-cell bacterial sensing using a synchronous fluorescence spectroscopy-based approach. AB - The wide collection of currently available fluorescent proteins (FPs) offers new possibilities for multicolor reporter gene-based studies of bacterial functions. However, the simultaneous use of multiple FPs is often limited by the bleed through of their emission spectra. Here we introduce an original approach for detection and separation of multiple overlapping fluorescent signals from mixtures of bioreporters strains. The proposed method relies on the coupling of synchronous fluorescent spectroscopy (SFS) with blind spectral decomposition achieved by the Canonical Polyadic (CP) decomposition (also known as Candecomp/Parafac) of three-dimensional data arrays. Due to the substantial narrowing of FP emission spectra and sensitive detection of multiple FPs in a one step scan, SFS reduced spectral overlap and improved the selectivity of the CP unmixing procedure. When tested on mixtures of labeled E. coli strains, the SFS/CP approach could easily extract the contribution of at least four overlapping FPs. Furthermore, it allowed to simultaneously monitor the expression of three iron responsive genes and pyoverdine production in P. aeruginosa. Implemented in a convenient microplate format, this multiplex fluorescent reporter method provides a useful tool to study complex processes with different variables in bacterial systems. PMID- 25822489 TI - Minutia tensor matrix: a new strategy for fingerprint matching. AB - Establishing correspondences between two minutia sets is a fundamental issue in fingerprint recognition. This paper proposes a new tensor matching strategy. First, the concept of minutia tensor matrix (simplified as MTM) is proposed. It describes the first-order features and second-order features of a matching pair. In the MTM, the diagonal elements indicate similarities of minutia pairs and non diagonal elements indicate pairwise compatibilities between minutia pairs. Correct minutia pairs are likely to establish both large similarities and large compatibilities, so they form a dense sub-block. Minutia matching is then formulated as recovering the dense sub-block in the MTM. This is a new tensor matching strategy for fingerprint recognition. Second, as fingerprint images show both local rigidity and global nonlinearity, we design two different kinds of MTMs: local MTM and global MTM. Meanwhile, a two-level matching algorithm is proposed. For local matching level, the local MTM is constructed and a novel local similarity calculation strategy is proposed. It makes full use of local rigidity in fingerprints. For global matching level, the global MTM is constructed to calculate similarities of entire minutia sets. It makes full use of global compatibility in fingerprints. Proposed method has stronger description ability and better robustness to noise and nonlinearity. Experiments conducted on Fingerprint Verification Competition databases (FVC2002 and FVC2004) demonstrate the effectiveness and the efficiency. PMID- 25822490 TI - Exploration of the association between obesity and semen quality in a 7630 male population. AB - This study aimed to explore the association between body mass index (BMI), other anthropometric indexes and semen quality in a general male population in Taiwan. In this cross-sectional cohort study, the study cohort consisted of 7941 healthy male individuals aged 18 years or older who participated in a standard medical screening program run by a private firm from January 2008 to May 2013. Semen parameters including sperm concentration (SC), total sperm motility (TSM), progressive motility (PRM), and normal sperm morphology (NSM) were recorded. Anthropometric indexes including BMI, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and body fat percentage were measured. A total of 7630 men were enrolled for the final analysis, of whom 68.5% had a normal weight distribution and 31.4% were overweight or obese. Total sperm motility, progressive motility, normal sperm morphology and sperm concentration showed a statistically linear decline with increasing age (p < 0.001, p < 0.001, p < 0.001 and p = 0.004). Sperm concentration showed a significantly negatively linear association with BMI (p = 0.005), and normal sperm morphology showed an inverse association with BMI and waist-to-height ratio (p < 0.001 and p = 0.004). The prevalence of abnormal total sperm motility, progressive motility, normal sperm morphology and sperm concentration increased with increasing age (p = 0.011, p < 0.001, p < 0.001 and p = 0.002). Lower normal sperm morphology and sperm concentration were associated with increasing body adiposity (p<0.05). No relationship between obesity and sperm motility was identified. PMID- 25822491 TI - Correction: morphometry, bite-force, and paleobiology of the late miocene caiman Purussaurus brasiliensis. PMID- 25822493 TI - Correction: First clinical experience of intra-operative high intensity focused ultrasound in patients with colorectal liver metastases: a phase I-IIa study. PMID- 25822492 TI - Moving towards routine evaluation of quality of inpatient pediatric care in Kenya. AB - BACKGROUND: Regular assessment of quality of care allows monitoring of progress towards system goals and identifies gaps that need to be addressed to promote better outcomes. We report efforts to initiate routine assessments in a low income country in partnership with government. METHODS: A cross-sectional survey undertaken in 22 'internship training' hospitals across Kenya that examined availability of essential resources and process of care based on review of 60 case-records per site focusing on the common childhood illnesses (pneumonia, malaria, diarrhea/dehydration, malnutrition and meningitis). RESULTS: Availability of essential resources was 75% (45/61 items) or more in 8/22 hospitals. A total of 1298 (range 54-61) case records were reviewed. HIV testing remained suboptimal at 12% (95% CI 7-19). A routinely introduced structured pediatric admission record form improved documentation of core admission symptoms and signs (median score for signs 22/22 and 8/22 when form used and not used respectively). Correctness of penicillin and gentamicin dosing was above 85% but correctness of prescribed intravenous fluid or oral feed volumes for severe dehydration and malnutrition were 54% and 25% respectively. Introduction of Zinc for diarrhea has been relatively successful (66% cases) but use of artesunate for malaria remained rare. Exploratory analysis suggests considerable variability of the quality of care across hospitals. CONCLUSION: Quality of pediatric care in Kenya has improved but can improve further. The approach to monitoring described in this survey seems feasible and provides an opportunity for routine assessments across a large number of hospitals as part of national efforts to sustain improvement. Understanding variability across hospitals may help target improvement efforts. PMID- 25822494 TI - Estimating annual soil carbon loss in agricultural peatland soils using a nitrogen budget approach. AB - Around the world, peatland degradation and soil subsidence is occurring where these soils have been converted to agriculture. Since initial drainage in the mid 1800s, continuous farming of such soils in the California Sacramento-San Joaquin Delta (the Delta) has led to subsidence of up to 8 meters in places, primarily due to soil organic matter (SOM) oxidation and physical compaction. Rice (Oryza sativa) production has been proposed as an alternative cropping system to limit SOM oxidation. Preliminary research on these soils revealed high N uptake by rice in N fertilizer omission plots, which we hypothesized was the result of SOM oxidation releasing N. Testing this hypothesis, we developed a novel N budgeting approach to assess annual soil C and N loss based on plant N uptake and fallow season N mineralization. Through field experiments examining N dynamics during growing season and winter fallow periods, a complete annual N budget was developed. Soil C loss was calculated from SOM-N mineralization using the soil C:N ratio. Surface water and crop residue were negligible in the total N uptake budget (3 - 4 % combined). Shallow groundwater contributed 24 - 33 %, likely representing subsurface SOM-N mineralization. Assuming 6 and 25 kg N ha-1 from atmospheric deposition and biological N2 fixation, respectively, our results suggest 77 - 81 % of plant N uptake (129 - 149 kg N ha-1) was supplied by SOM mineralization. Considering a range of N uptake efficiency from 50 - 70 %, estimated net C loss ranged from 1149 - 2473 kg C ha-1. These findings suggest that rice systems, as currently managed, reduce the rate of C loss from organic delta soils relative to other agricultural practices. PMID- 25822495 TI - Stably expressed housekeeping genes across developmental stages in the two spotted spider mite, Tetranychus urticae. AB - Quantitative real-time PCR (qRT-PCR) is a reliable and reproducible technique for measuring mRNA expression. To facilitate gene expression studies and obtain more accurate qRT-PCR analysis, normalization relative to stable housekeeping genes is mandatory. In this study, ten housekeeping genes, including beta-actin (Actin) , elongation factor 1 alpha (EF1A) , glyceralde hyde-3-phosphate dehydrogenase (GAPDH) , ribosomal protein L13 (RPL13) , ribosomal protein 49 (RP49) , alpha tubulin (Tubulin) , vacuolar-type H+-ATPase (v-ATPase) , succinate dehydrogenase subunit A (SDHA) , 28S ribosomal RNA (28S) , and 18S ribosomal RNA (18S) from the two-spotted spider mite, Tetranychus urticae, were selected as the candidate reference genes. Four algorithms, geNorm, Normfinder, BestKeeper, and the DeltaCt method, were used to evaluate the performance of these candidates as endogenous controls across different developmental stages. In addition, RefFinder, which integrates the above-mentioned software tools, provided the overall ranking of the stability/suitability of these candidate reference genes. Among them, PRL13 and v-ATPase were the two most stable housekeeping genes across different developmental stages. This work is the first step toward establishing a standardized qRT-PCR analysis in T. urticae following the MIQE guideline. With the recent release of the T. urticae genome, results from this study provide a critical piece for the subsequent genomics and functional genomics research in this emerging model system. PMID- 25822497 TI - Correction: A cell-based systems biology assessment of human blood to monitor immune responses after influenza vaccination. PMID- 25822496 TI - Identification and analysis of the paulomycin biosynthetic gene cluster and titer improvement of the paulomycins in Streptomyces paulus NRRL 8115. AB - The paulomycins are a group of glycosylated compounds featuring a unique paulic acid moiety. To locate their biosynthetic gene clusters, the genomes of two paulomycin producers, Streptomyces paulus NRRL 8115 and Streptomyces sp. YN86, were sequenced. The paulomycin biosynthetic gene clusters were defined by comparative analyses of the two genomes together with the genome of the third paulomycin producer Streptomyces albus J1074. Subsequently, the identity of the paulomycin biosynthetic gene cluster was confirmed by inactivation of two genes involved in biosynthesis of the paulomycose branched chain (pau11) and the ring A moiety (pau18) in Streptomyces paulus NRRL 8115. After determining the gene cluster boundaries, a convergent biosynthetic model was proposed for paulomycin based on the deduced functions of the pau genes. Finally, a paulomycin high producing strain was constructed by expressing an activator-encoding gene (pau13) in S. paulus, setting the stage for future investigations. PMID- 25822498 TI - The punctum fixum-punctum mobile model: a neuromuscular principle for efficient movement generation? AB - According to the "punctum fixum-punctum mobile model" that was introduced in prior studies, for generation of the most effective intentional acceleration of a body part the intersegmental neuromuscular onset succession has to spread successively from the rotation axis (punctum fixum) toward the body part that shall be accelerated (punctum mobile). The aim of the present study was to investigate whether this principle is, indeed, fundamental for any kind of efficient rotational accelerations in general, independent of the kind of movements, type of rotational axis, the current body position, or movement direction. Neuromuscular onset succession was captured by surface electromyography of relevant muscles of the anterior and posterior muscle chain in 16 high-level gymnasts during intentional accelerating movement phases while performing 18 different gymnastics elements (in various body positions to forward and backward, performed on high bar, parallel bars, rings and trampoline), as well as during non-sport specific pivot movements around the longitudinal axis. The succession patterns to generate the acceleration phases during these movements were described and statistically evaluated based on the onset time difference between the muscles of the corresponding muscle chain. In all the analyzed movement phases, the results clearly support the hypothesized succession pattern from punctum fixum to punctum mobile. This principle was further underlined by the finding that the succession patterns do change their direction running through the body when the rotational axis (punctum fixum) has been changed (e.g., high bar or rings [hands] vs. floor or trampoline [feet]). The findings improve our understanding of intersegmental neuromuscular coordination patterns to generate intentional movements most efficiently. This could help to develop more specific methods to facilitate such patterns in particular contexts, thus allowing for shorter motor learning procedures of context-specific key movement sequences in different disciplines of sports, as well as during non sport specific movements. PMID- 25822499 TI - Dose- and time-dependent association of smoking and its cessation with glycemic control and insulin resistance in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry. AB - OBJECTIVE: Cigarette smoking is an important modifiable risk factor for cardiovascular diseases. However, the effect of smoking and its cessation on glycemic control in diabetic patients has not been fully examined yet. The aim of the present study was to examine the association of smoking status with glycemic level and markers of insulin resistance and secretion in patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: A total of 2,490 Japanese male patients with type 2 diabetes mellitus aged >=20 years were divided according to smoking status, amount of cigarettes smoked and years since quitting. The associations with glycemic level and markers of insulin resistance and secretion were examined cross-sectionally. RESULTS: HbA1c levels increased progressively with increases in both number of cigarettes per day and pack-years of cigarette smoking compared with never smokers (P for trend = 0.001 and <0.001, respectively), whereas fasting plasma glucose did not. On the other hand, HbA1c, but not fasting plasma glucose, decreased linearly with increase in years after smoking cessation (P for trend <0.001). These graded relationships persisted significantly after controlling for the confounders, including total energy intake, current drinking, regular exercise, depressive symptoms, and BMI. In addition, a homeostasis model assessment of insulin resistance and high sensitivity C-reactive protein also showed similar trends. CONCLUSIONS: Smoking and its cessation showed dose- and time-dependent relationship with glycemic control and insulin resistance in patients with type 2 diabetes mellitus. These findings may highlight the importance of smoking cessation in the clinical management of diabetes mellitus. PMID- 25822500 TI - Classifying ten types of major cancers based on reverse phase protein array profiles. AB - Gathering vast data sets of cancer genomes requires more efficient and autonomous procedures to classify cancer types and to discover a few essential genes to distinguish different cancers. Because protein expression is more stable than gene expression, we chose reverse phase protein array (RPPA) data, a powerful and robust antibody-based high-throughput approach for targeted proteomics, to perform our research. In this study, we proposed a computational framework to classify the patient samples into ten major cancer types based on the RPPA data using the SMO (Sequential minimal optimization) method. A careful feature selection procedure was employed to select 23 important proteins from the total of 187 proteins by mRMR (minimum Redundancy Maximum Relevance Feature Selection) and IFS (Incremental Feature Selection) on the training set. By using the 23 proteins, we successfully classified the ten cancer types with an MCC (Matthews Correlation Coefficient) of 0.904 on the training set, evaluated by 10-fold cross validation, and an MCC of 0.936 on an independent test set. Further analysis of these 23 proteins was performed. Most of these proteins can present the hallmarks of cancer; Chk2, for example, plays an important role in the proliferation of cancer cells. Our analysis of these 23 proteins lends credence to the importance of these genes as indicators of cancer classification. We also believe our methods and findings may shed light on the discoveries of specific biomarkers of different types of cancers. PMID- 25822501 TI - Interacted QTL mapping in partial NCII design provides evidences for breeding by design. AB - The utilization of heterosis in rice, maize and rapeseed has revolutionized crop production. Although elite hybrid cultivars are mainly derived from the F1 crosses between two groups of parents, named NCII mating design, little has been known about the methodology of how interacted effects influence quantitative trait performance in the population. To bridge genetic analysis with hybrid breeding, here we integrated an interacted QTL mapping approach with breeding by design in partial NCII mating design. All the potential main and interacted effects were included in one full model. If the number of the effects is huge, bulked segregant analysis were used to test which effects were associated with the trait. All the selected effects were further shrunk by empirical Bayesian, so significant effects could be identified. A series of Monte Carlo simulations was performed to validate the new method. Furthermore, all the significant effects were used to calculate genotypic values of all the missing F1 hybrids, and all these F1 phenotypic or genotypic values were used to predict elite parents and parental combinations. Finally, the new method was adopted to dissect the genetic foundation of oil content in 441 rapeseed parents and 284 F1 hybrids. As a result, 8 main-effect QTL and 37 interacted QTL were found and used to predict 10 elite restorer lines, 10 elite sterile lines and 10 elite parental crosses. Similar results across various methods and in previous studies and a high correlation coefficient (0.76) between the predicted and observed phenotypes validated the proposed method in this study. PMID- 25822503 TI - Comparison of newly diagnosed and relapsed patients with acute promyelocytic leukemia treated with arsenic trioxide: insight into mechanisms of resistance. AB - There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens. PMID- 25822504 TI - Energy and cost associated with ventilating office buildings in a tropical climate. AB - Providing sufficient amounts of outdoor air to occupants is a critical building function for supporting occupant health, well-being and productivity. In tropical climates, high ventilation rates require substantial amounts of energy to cool and dehumidify supply air. This study evaluates the energy consumption and associated cost for thermally conditioning outdoor air provided for building ventilation in tropical climates, considering Singapore as an example locale. We investigated the influence on energy consumption and cost of the following factors: outdoor air temperature and humidity, ventilation rate (L/s per person), indoor air temperature and humidity, air conditioning system coefficient of performance (COP), and cost of electricity. Results show that dehumidification of outdoor air accounts for more than 80% of the energy needed for building ventilation in Singapore's tropical climate. Improved system performance and/or a small increase in the indoor temperature set point would permit relatively large ventilation rates (such as 25 L/s per person) at modest or no cost increment. Overall, even in a thermally demanding tropical climate, the energy cost associated with increasing ventilation rate up to 25 L/s per person is less than 1% of the wages of an office worker in an advanced economy like Singapore's. This result implies that the benefits of increasing outdoor air ventilation rate up to 25 L/s per person--which is suggested to provide for productivity increases, lower sick building syndrome symptom prevalence, and reduced sick leave--can be much larger than the incremental cost of ventilation. PMID- 25822502 TI - A role for the budding yeast separase, Esp1, in Ty1 element retrotransposition. AB - Separase/Esp1 is a protease required at the onset of anaphase to cleave cohesin and thereby enable sister chromatid separation. Esp1 also promotes release of the Cdc14 phosphatase from the nucleolus to enable mitotic exit. To uncover other potential roles for separase, we performed two complementary genome-wide genetic interaction screens with a strain carrying the budding yeast esp1-1 separase mutation. We identified 161 genes that when mutated aggravate esp1-1 growth and 44 genes that upon increased dosage are detrimental to esp1-1 viability. In addition to the expected cell cycle and sister chromatid segregation genes that were identified, 24% of the genes identified in the esp1-1 genetic screens have a role in Ty1 element retrotransposition. Retrotransposons, like retroviruses, replicate through reverse transcription of an mRNA intermediate and the resultant cDNA product is integrated into the genome by a conserved transposon or retrovirus encoded integrase protein. We purified Esp1 from yeast and identified an interaction between Esp1 and Ty1 integrase using mass spectrometry that was subsequently confirmed by co-immunoprecipitation analysis. Ty1 transposon mobility and insertion upstream of the SUF16 tRNA gene are both reduced in an esp1-1 strain but increased in cohesin mutant strains. Securin/Pds1, which is required for efficient localization of Esp1 to the nucleus, is also required for efficient Ty1 transposition. We propose that Esp1 serves two roles to mediate Ty1 transposition - one to remove cohesin and the second to target Ty1-IN to chromatin. PMID- 25822505 TI - Mapping forest fuels through vegetation phenology: the role of coarse-resolution satellite time-series. AB - Traditionally fuel maps are built in terms of 'fuel types', thus considering the structural characteristics of vegetation only. The aim of this work is to derive a phenological fuel map based on the functional attributes of coarse-scale vegetation phenology, such as seasonality and productivity. MODIS NDVI 250 m images of Sardinia (Italy), a large Mediterranean island with high frequency of fire incidence, were acquired for the period 2000-2012 to construct a mean annual NDVI profile of the vegetation at the pixel-level. Next, the following procedure was used to develop the phenological fuel map: (i) image segmentation on the Fourier components of the NDVI profiles to identify phenologically homogeneous landscape units, (ii) cluster analysis of the phenological units and post-hoc analysis of the fire-proneness of the phenological fuel classes (PFCs) obtained, (iii) environmental characterization (in terms of land cover and climate) of the PFCs. Our results showed the ability of coarse-resolution satellite time-series to characterize the fire-proneness of Sardinia with an adequate level of accuracy. The remotely sensed phenological framework presented may represent a suitable basis for the development of fire distribution prediction models, coarse scale fuel maps and for various biogeographic studies. PMID- 25822506 TI - Laplacian Estrada and normalized Laplacian Estrada indices of evolving graphs. AB - Large-scale time-evolving networks have been generated by many natural and technological applications, posing challenges for computation and modeling. Thus, it is of theoretical and practical significance to probe mathematical tools tailored for evolving networks. In this paper, on top of the dynamic Estrada index, we study the dynamic Laplacian Estrada index and the dynamic normalized Laplacian Estrada index of evolving graphs. Using linear algebra techniques, we established general upper and lower bounds for these graph-spectrum-based invariants through a couple of intuitive graph-theoretic measures, including the number of vertices or edges. Synthetic random evolving small-world networks are employed to show the relevance of the proposed dynamic Estrada indices. It is found that neither the static snapshot graphs nor the aggregated graph can approximate the evolving graph itself, indicating the fundamental difference between the static and dynamic Estrada indices. PMID- 25822507 TI - Transcriptome analysis of the Capra hircus ovary. AB - BACKGROUND: Capra hircus is an important economic livestock animal, and therefore, it is necessary to discover transcriptome information about their reproductive performance. In this study, we performed de novo transcriptome sequencing to produce the first transcriptome dataset for the goat ovary using high-throughput sequencing technologies. The result will contribute to research on goat reproductive performance. METHOD AND RESULTS: RNA-seq analysis generated more than 38.8 million clean paired end (PE) reads, which were assembled into 80,069 unigenes (mean size = 619 bp). Based on sequence similarity searches, 64,824 (60.6%) genes were identified, among which 29,444 and 11,271 unigenes were assigned to Gene Ontology (GO) categories and Clusters of Orthologous Groups (COG), respectively. Searches in the Kyoto Encyclopedia of Genes and Genomes pathway database (KEGG) showed that 27,766 (63.4%) unigenes were mapped to 258 KEGG pathways. Furthermore, we investigated the transcriptome differences of goat ovaries at two different ages using a tag-based digital gene expression system. We obtained a sequencing depth of over 5.6 million and 5.8 million tags for the two ages and identified a large number of genes associated with reproductive hormones, ovulatory cycle and follicle. Moreover, many antisense transcripts and novel transcripts were found; clusters with similar differential expression patterns, enriched GO terms and metabolic pathways were revealed for the first time with regard to the differentially expressed genes. CONCLUSIONS: The transcriptome provides invaluable new data for a functional genomic resource and future biological research in Capra hircus, and it is essential for the in-depth study of candidate genes in breeding programs. PMID- 25822508 TI - Differential responses to virus challenge of laboratory and wild accessions of australian species of nicotiana, and comparative analysis of RDR1 gene sequences. AB - Nicotiana benthamiana is a model plant utilised internationally in plant virology because of its apparent hyper-susceptibility to virus infection. Previously, others showed that all laboratory accessions of N. benthamiana have a very narrow genetic basis, probably originating from a single source. It is unknown if responses to virus infection exhibited by the laboratory accession are typical of the species as a whole. To test this, 23 accessions of N. benthamiana were collected from wild populations and challenged with one to four viruses. Additionally, accessions of 21 other Nicotiana species and subspecies from Australia, one from Peru and one from Namibia were tested for susceptibility to the viruses, and for the presence of a mutated RNA-dependent RNA polymerase I allele (Nb-RDR1m) described previously from a laboratory accession of N. benthamiana. All Australian Nicotiana accessions tested were susceptible to virus infections, although there was symptom variability within and between species. The most striking difference was that plants of a laboratory accession of N. benthamiana (RA-4) exhibited hypersensitivity to Yellow tailflower mild mottle tobamovirus infection and died, whereas plants of wild N. benthamiana accessions responded with non-necrotic symptoms. Plants of certain N. occidentalis accessions also exhibited initial hypersensitivity to Yellow tailflower mild mottle virus resembling that of N. benthamiana RA-4 plants, but later recovered. The mutant Nb-RDR1m allele was identified from N. benthamiana RA-4 but not from any of 51 other Nicotiana accessions, including wild accessions of N. benthamiana, demonstrating that the accession of N. benthamiana used widely in laboratories is unusual. PMID- 25822511 TI - Seeing is believing: why including tables and figures matters to the effectiveness of your publications. PMID- 25822510 TI - An exploration of parent-child dyadic asthma management influences on quality of life. AB - Most studies of childhood asthma management use data from a single family reporter and fail to capture the parent-child dyadic influences. In this descriptive exploratory study with 183 parent-child dyads, data were collected from both parents and children. Using structural equation modeling, the relationships of parents' and children's asthma knowledge, self-efficacy to manage asthma, and asthma management on the child's quality of life were examined. Direct significant relationships from knowledge to self-efficacy to asthma management were found for each member of the dyad. The associations between parents' and children's self-efficacy and asthma management were not statistically significant. Only the children's self-efficacy to manage asthma was significantly associated with children's asthma-related quality of life. PMID- 25822509 TI - Properties of protein drug target classes. AB - Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein's sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein's sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins' hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID- 25822512 TI - End-of-life-care in the NICU. PMID- 25822514 TI - Newborn physiological immaturity: a concept analysis. AB - BACKGROUND: Most standardized nursing care plans for healthy neonates include multiple nursing diagnoses to reflect nurses' judgments on the infant's status; however scientific literature concerning this issue is scarce. Newborn physiological immaturity is a concept in the ATIC terminology (architecture, terminology, interface, information, nursing [infermeria], and knowledge [coneixement]) to represent the natural status of vulnerability of the healthy neonate. PURPOSE: To identify the essential attributes of the concept and provide its conceptual and operational definition, using the Wilsonian approach. FINDINGS: The concept under analysis embeds a natural cluster of vulnerabilities and environmental interactions that enhance the evolving maturation process. IMPLICATIONS FOR PRACTICE: The use of this diagnosis may simplify the process of charting the nursing care plans and reduce time needed for documentation while maintaining the integrity of the information. IMPLICATIONS FOR RESEARCH: Consistent development and use of nursing concepts is essential for knowledge building. Studies on the actual use of nursing diagnoses are needed to inform decision making. PMID- 25822515 TI - Oxygen administration to preterm neonates in the delivery room: minimizing oxidative stress. AB - BACKGROUND: Neonatal resuscitation continues to be challenged by evolving research on the best approach to resuscitating preterm infants while minimizing potential health risks. The actions of the resuscitation team in the first minutes of transition to extrauterine life can have a lasting impact on the growth and development of the preterm infant. PURPOSE: This article reviews the most current literature on the use of oxygen in the delivery room and discusses the implications related to nursing and the multidisciplinary care team. FINDINGS: Oxygen saturation monitoring in the delivery room through the use of pulse oximetry in conjunction with oxygen titration via a blended oxygen source is an appropriate intervention to decrease the risk of free radical damage to the tissues. IMPLICATIONS FOR PRACTICE: Ensure delivery room providers are educated to resuscitation standards and ensure delivery rooms are appropriately supplied with a compressed air source, oxygen blenders, and pulse oximeters to minimize the free radical damage to the tissues. IMPLICATIONS FOR RESEARCH: Future studies should be focused on pulse oximetry use in the delivery room and its effect on long-term outcomes for preterm infants, safe oxygen saturation target ranges for the preterm infant in the delivery room, and effective resuscitation procedures for extremely preterm infants. PMID- 25822516 TI - Promoting family-centered care in the NICU through a parent-to-parent manager position. AB - BACKGROUND: The Family-Centered Care (FCC) committee had formulated multiple ideas for projects but was unable to fully carry out and sustain many of the initiatives. The committee felt that to implement the proposed FCC projects someone would need to devote full attention to the task. The parent-to-parent (PTP) position was created to develop and sustain initiatives of our institution's NICU Family Support Program. PURPOSE: The purpose of this article is to describe the process of creating a PTP manager position and the effects it can have in the NICU for the family. Program outcomes were assessed in 3 areas that align with core principles of FCC: (1) emotional support and parent empowerment, (2) a welcoming environment with supportive policies, and (3) education for staff and families. The assessment of the program included review and attendance of parent support offerings, review and revision of parent material, and survey evaluation of staff education. FINDINGS/RESULTS: In the first year, the program reached over 800 families, provided 136 parent education hours, and organized social activities that reached 847 families. IMPLICATIONS FOR PRACTICE: The creation of a PTP manager position has been instrumental in the development and management of multiple initiatives to offer families and staff continued support and education. IMPLICATIONS FOR RESEARCH: Further evaluation of programs and strategies for PTP support in the NICU setting is needed. PMID- 25822517 TI - Evidence of developmental continuity from birth to 1 year: sleep, temperament, problem solving, and recognition memory. AB - BACKGROUND: Research evidence is limited regarding developmentally appropriate care. Variations exits with respect to test procedure type, infant age at testing, and test relatedness. PURPOSE: To assess developmental continuity using multiple developmental measures from birth to 12 months in a single cohort of term infants. METHODS: A secondary analysis, longitudinal, correlational design was used to assess developmental continuity in a single cohort of infants (n 27). Measures included: sleep, using the Motility Monitoring System (first 48 hours of life); temperament, using the Infant Characteristics Questionnaire (ICQ, 6 months) and the Revised Infant Temperament Questionnaire (RITQ, 12 months); problem-solving, using the Willatts Infant Planning Test (PS, 9 and 12 months); and the Fagan Test of Infant Intelligence (FTII, 6 and 9 months). RESULTS: Using Spearmen correlation, significant correlations included: (1) Sleep and ICQ: transitional sleep and "unpredictable" (r 0.455, P .017), "unadaptable" (r 0.420, P .026), and "dull" (r 0.416, P .028); (2) ICQ and FTII 6 months (r -0.512, P .008); (3) RITQ "approachability" and quiet sleep (r 0.662, P .005); (4) arousals in active sleep and PS at 9 months (r -0.528, P .016). IMPLICATIONS FOR PRACTICE: Given our reported continuity between early sleep and later developmental measures, sleep-wake state should be considered in caregiving and environmental control to support sleep. Parental education on facilitating sleep-wake regulation in the home environment is essential. IMPLICATIONS FOR RESEARCH: These data support the existence of continuity between early sleep and later developmental milestones warranting a larger-scale investigation. Specific focus on development of care strategies for facilitating sleep immediately following birth is warranted. PMID- 25822518 TI - When is it safe to initiate breastfeeding for preterm infants? AB - BACKGROUND: Breast milk is the gold standard of nutrition for preterm infants. Yet, initiation of direct breastfeeding before 32 weeks' postconceptional age (PCA) is not common practice in many neonatal intensive care units (NICUs). Our clinical question was, "In preterm infants, when is it safe to initiate breastfeeding in infants <32 weeks PCA receiving enteral feedings?" SEARCH STRATEGY: A review of the literature was compiled between February 2013 and January 2015 by using the following databases: CINAHL, Cochrane Systematic Review, Scopus, and PubMed. Articles found were written in English and published after 1985. Key words were utilized during searches and references were hand checked. RESULTS: Our review revealed that stable preterm infants maintain their physiological status during exposure to the breast as early as 27 to 28 weeks' PCA. Several studies demonstrated infants during breastfeeding compared with bottle-feeding experienced minimal variation in oxygen saturation and heart rate during feeding. Some infants exposed to the breast before 30 weeks' PCA were exclusively breastfeeding (direct breastfeeding and breast milk) at 32.8 weeks' PCA. Skin-to-skin mother-infant contact is crucial to the successful transition to direct breastfeeding. IMPLICATIONS FOR PRACTICE AND RESEARCH: The transition from enteral feedings to direct, exclusive breastfeeding should involve frequent mother-infant skin-to-skin contact requiring support and guidance from the NICU staff. Future research should involve creating standard protocols within NICUs to facilitate breastfeeding transition and exploring barriers that may prevent the preterm infant from achieving direct, exclusive breastfeeding. PMID- 25822519 TI - Multisensory intervention for preterm infants improves sucking organization. AB - BACKGROUND: Premature infants are at risk for difficulties in feeding, social interaction, and growth. Many premature infants exhibit a lower capacity for self regulation, resulting in less behavioral alertness and hypersensitivity to stimulation. Feeding is critically important because it is a primary factor for infant growth and a major concern for both parents and clinicians. PURPOSE: The aim of this randomized controlled trial was to evaluate sucking organization in premature infants following a preterm infant multisensory intervention, the Auditory, Tactile, Visual, and Vestibular (ATVV) intervention. METHODS: A convenience sample of 183 healthy premature infants born 29-34 weeks postmenstrual age (PMA) enrolled. Sucking organization was measured at baseline, then weekly, during the infant's hospital stay. RESULTS: A quadratic trend was observed for number of sucks, sucks per burst, and maturity index with the intervention group increasing significantly faster by day 7 (model estimates for group * day: beta= 13.69, P < .01; beta = 1.16, P < .01; and beta= 0.12, P < .05, respectively). Sucking pressure increased linearly over time, with significant between-group differences at day 14 (beta= 45.66, P < .01). IMPLICATIONS FOR PRACTICE: The ATVV infants exhibited improved sucking organization during hospitalization, suggesting that the ATVV intervention improves maturation of oral feeding. IMPLICATIONS FOR RESEARCH: Further research that includes 2 or more tests, delivered the same day and/or over consecutive days, will provide researchers and clinicians a more sensitive indicator of maturational changes in feeding behaviors. PMID- 25822521 TI - An efficiently cleaved HIV-1 clade C Env selectively binds to neutralizing antibodies. AB - An ideal HIV-1 Env immunogen is expected to mimic the native trimeric conformation for inducing broadly neutralizing antibody responses. The native conformation is dependent on efficient cleavage of HIV-1 Env. The clade B isolate, JRFL Env is efficiently cleaved when expressed on the cell surface. Here, for the first time, we report the identification of a native clade C Env, 4 2.J41 that is naturally and efficiently cleaved on the cell surface as confirmed by its biochemical and antigenic characteristics. In addition to binding to several conformation-dependent neutralizing antibodies, 4-2.J41 Env binds efficiently to the cleavage-dependent antibody PGT151; thus validating its native cleaved conformation. In contrast, 4-2.J41 Env occludes non-neutralizing epitopes. The cytoplasmic-tail of 4-2.J41 Env plays an important role in maintaining its conformation. Furthermore, codon optimization of 4-2.J41 Env sequence significantly increases its expression while retaining its native conformation. Since clade C of HIV-1 is the prevalent subtype, identification and characterization of this efficiently cleaved Env would provide a platform for rational immunogen design. PMID- 25822524 TI - Territory tenure increases with repertoire size in brownish-flanked bush warbler. AB - Song repertoire size is often cited as a classic example of a secondary sexual trait in birds. Models of sexual selection and empirical tests of their predictions have often related secondary sexual traits to longevity. However, the relationship between repertoire size and longevity is unclear. Using capture-mark recapture studies in two populations of the brownish-flanked bush warbler Cettia fortipes, we found that males with a repertoire size of three maintained territory tenure for a longer duration than did males with a repertoire size of two. These results provide evidence that even a minimal difference in repertoire size can serve as a potential signal of territory tenure capability. PMID- 25822522 TI - Differential gene expression in the liver of the African lungfish, Protopterus annectens, after 6 months of aestivation in air or 1 day of arousal from 6 months of aestivation. AB - The African lungfish, Protopterus annectens, can undergo aestivation during drought. Aestivation has three phases: induction, maintenance and arousal. The objective of this study was to examine the differential gene expression in the liver of P. annectens after 6 months (the maintenance phase) of aestivation as compared with the freshwater control, or after 1 day of arousal from 6 months aestivation as compared with 6 months of aestivation using suppression subtractive hybridization. During the maintenance phase of aestivation, the mRNA expression of argininosuccinate synthetase 1 and carbamoyl phosphate synthetase III were up-regulated, indicating an increase in the ornithine-urea cycle capacity to detoxify ammonia to urea. There was also an increase in the expression of betaine homocysteine-S-transferase 1 which could reduce and prevent the accumulation of hepatic homocysteine. On the other hand, the down-regulation of superoxide dismutase 1 expression could signify a decrease in ROS production during the maintenance phase of aestivation. In addition, the maintenance phase was marked by decreases in expressions of genes related to blood coagulation, complement fixation and iron and copper metabolism, which could be strategies used to prevent thrombosis and to conserve energy. Unlike the maintenance phase of aestivation, there were increases in expressions of genes related to nitrogen, carbohydrate and lipid metabolism and fatty acid transport after 1 day of arousal from 6 months aestivation. There were also up-regulation in expressions of genes that were involved in the electron transport system and ATP synthesis, indicating a greater demand for metabolic energy during arousal. Overall, our results signify the importance of sustaining a low rate of waste production and conservation of energy store during the maintenance phase, and the dependence on internal energy store for repair and structural modification during the arousal phase, of aestivation in the liver of P. annectens. PMID- 25822526 TI - Menopausal status and physical performance in middle aged women: a cross sectional community-based study in Northeast Brazil. AB - OBJECTIVE: To examine associations between menopausal status and physical performance in middle-aged women from the Northeast region of Brazil. METHODS: Cross-sectional study of women between 40 to 65 years old living in Parnamirim. Women were recruited by advertisements in primary care neighborhood centers across the city. Physical performance was assessed by grip strength, gait speed and chair stands. Menopausal status was determined using the Stages of Reproductive Aging Workshop classification and women were classified in: premenopausal, perimenopausal or postmenopausal. Multiple linear regression analyses were performed to model the effect of menopausal status on each physical performance measure, adjusting for covariates (age, family income, education, body mass index, parity and age at first birth). RESULTS: The premenopausal women were significantly stronger and performed better in chair stands than perimenopausal and postmenopausal women. Gait speed did not vary significantly by menopausal status. In multivariate analyses, menopausal status remained statistically significant only for grip strength. In fully adjusted analyses, premenopausal women had grip strength mean of 2.226 Kgf (95% CI: 0.361 - 4.091) higher than the postmenopausal group. CONCLUSIONS: This study provides further evidence for the associations between menopause and physical performance in middle-aged women, since grip strength is weaker in peri and postmenopausal women compared to premenopausal, even adjusted for age and other covariates. PMID- 25822523 TI - Vinpocetine reduces carrageenan-induced inflammatory hyperalgesia in mice by inhibiting oxidative stress, cytokine production and NF-kappaB activation in the paw and spinal cord. AB - Vinpocetine is a safe nootropic agent used for neurological and cerebrovascular diseases. The anti-inflammatory activity of vinpocetine has been shown in cell based assays and animal models, leading to suggestions as to its utility in analgesia. However, the mechanisms regarding its efficacy in inflammatory pain treatment are still not completely understood. Herein, the analgesic effect of vinpocetine and its anti-inflammatory and antioxidant mechanisms were addressed in murine inflammatory pain models. Firstly, we investigated the protective effects of vinpocetine in overt pain-like behavior induced by acetic acid, phenyl p-benzoquinone (PBQ) and formalin. The intraplantar injection of carrageenan was then used to induce inflammatory hyperalgesia. Mechanical and thermal hyperalgesia were evaluated using the electronic von Frey and the hot plate tests, respectively, with neutrophil recruitment to the paw assessed by a myeloperoxidase activity assay. A number of factors were assessed, both peripherally and in the spinal cord, including: antioxidant capacity, reduced glutathione (GSH) levels, superoxide anion, tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1beta) levels, as well as nuclear factor kappa B (NF-kappaB) activation. Vinpocetine inhibited the overt pain-like behavior induced by acetic acid, PBQ and formalin (at both phases), as well as the carrageenan-induced mechanical and thermal hyperalgesia and associated neutrophil recruitment. Both peripherally and in the spinal cord, vinpocetine also inhibited: antioxidant capacity and GSH depletion; increased superoxide anion; IL 1beta and TNF-alpha levels; and NF-kappaB activation. As such, vinpocetine significantly reduces inflammatory pain by targeting oxidative stress, cytokine production and NF-kappaB activation at both peripheral and spinal cord levels. PMID- 25822525 TI - Secoisolariciresinol diglucoside abrogates oxidative stress-induced damage in cardiac iron overload condition. AB - Cardiac iron overload is directly associated with cardiac dysfunction and can ultimately lead to heart failure. This study examined the effect of secoisolariciresinol diglucoside (SDG), a component of flaxseed, on iron overload induced cardiac damage by evaluating oxidative stress, inflammation and apoptosis in H9c2 cardiomyocytes. Cells were incubated with 50 MU5M iron for 24 hours and/or a 24 hour pre-treatment of 500 MU M SDG. Cardiac iron overload resulted in increased oxidative stress and gene expression of the inflammatory mediators tumor necrosis factor-alpha, interleukin-10 and interferon gamma, as well as matrix metalloproteinases-2 and -9. Increased apoptosis was evident by increased active caspase 3/7 activity and increased protein expression of Forkhead box O3a, caspase 3 and Bax. Cardiac iron overload also resulted in increased protein expression of p70S6 Kinase 1 and decreased expression of AMP-activated protein kinase. Pre-treatment with SDG abrogated the iron-induced increases in oxidative stress, inflammation and apoptosis, as well as the increased p70S6 Kinase 1 and decreased AMP-activated protein kinase expression. The decrease in superoxide dismutase activity by iron treatment was prevented by pre-treatment with SDG in the presence of iron. Based on these findings we conclude that SDG was cytoprotective in an in vitro model of iron overload induced redox-inflammatory damage, suggesting a novel potential role for SDG in cardiac iron overload. PMID- 25822528 TI - Correction: The extracellular loop 2 (ECL2) of the human histamine H4 receptor substantially contributes to ligand binding and constitutive activity. PMID- 25822527 TI - Single domain antibodies as a powerful tool for high quality surface plasmon resonance studies. AB - Single domain antibodies are recombinantly expressed functional antibodies devoid of light chains. These binding elements are derived from heavy chain antibodies found in camelids and offer several distinctive properties for applications in biotechnology such as small size, stability, solubility, and expression in high yields. In this study we demonstrated the potential of using single domain antibodies as capturing molecules in biosensing applications. Single domain antibodies raised against green fluorescent protein were anchored onto biosensor surfaces by using several immobilization strategies based on Ni2+:nitrilotriacetic acid-polyhistidine tag, antibody-antigen, biotin streptavidin interactions and amine-coupling chemistry. The interaction with the specific target of the single domain antibodies was characterized by surface plasmon resonance. The immobilized single domain antibodies show high affinities for their antigens with KD = 3-6 nM and outperform other antibody partners as capturing molecules facilitating also the data analysis. Furthermore they offer high resistance and stability to a wide range of denaturing agents. These unique biophysical properties and the production of novel single domain antibodies against affinity tags make them particularly attractive for use in biosensing and diagnostic assays. PMID- 25822530 TI - Computational studies of ion pairing. 10. Ion pairing between tetrabutylammonium ion and inorganic ions: a general motif confirmed. AB - Until recently, little has been known about the nature of the factors governing the stereochemistry of the interactions between organic ions, even though such information should be directly relative to issues of molecular recognition and supermolecular self-assembly. The present study of the preferred structures of the ion pairs between tetrabutylammonium and 22 common inorganic ions, a continuation of previous studies in this series, brings to 93 the number of such species that have been examined in this way. In every one of these ion pairs, the minimum energy orientation of the cation relative to the anion is the same, reinforcing the conclusion that this structural motif is completely general. This is the first such pattern to be identified for the mode of association between organic cations and polar species in solution. PMID- 25822529 TI - A color-coded tape for uterine height measurement: a tool to identify preterm pregnancies in low resource settings. AB - INTRODUCTION: Neonatal mortality associated with preterm birth can be reduced with antenatal corticosteroids (ACS), yet <10% of eligible pregnant women in low middle income countries. The inability to accurately determine gestational age (GA) leads to under-identification of high-risk women who could receive ACS or other interventions. To facilitate better identification in low-resource settings, we developed a color-coded tape for uterine height (UH) measurement and estimated its accuracy identifying preterm pregnancies. METHODS: We designed a series of colored-coded tapes with segments corresponding to UH measurements for 20-23.6 weeks, 24.0-35.6 weeks, and >36.0 weeks GA. In phase 1, UH measurements were collected prospectively in the Democratic Republic of Congo, India and Pakistan, using distinct tapes to address variation across regions and ethnicities. In phase 2, we tested accuracy in 250 pregnant women with known GA from early ultrasound enrolled at prenatal clinics in Argentina, India, Pakistan and Zambia. Providers masked to the ultrasound GA measured UH. Receiver operating characteristics (ROC) analysis was conducted. RESULTS: 1,029 pregnant women were enrolled. In all countries the tapes were most effective identifying pregnancies between 20.0-35.6 weeks, compared to the other GAs. The ROC areas under the curves and 95% confidence intervals were: Argentina 0.69 (0.63, 0.74); Zambia 0.72 (0.66, 0.78), India 0.84 (0.80, 0.89), and Pakistan 0.83 (0.78, 0.87). The sensitivity and specificity (and 95% confidence intervals) for identifying pregnancies between 20.0-35.6 weeks, respectively, were: Argentina 87% (82%-92%) and 51% (42%-61%); Zambia 91% (86%-95%) and 50% (40%-60%); India 78% (71%-85%) and 89% (83%-94%); Pakistan 63% (55%-70%) and 94% (89%-99%). CONCLUSIONS: We observed moderate-good accuracy identifying pregnancies <= 35.6 weeks gestation, with potential usefulness at the community level in low-middle income countries to facilitate the preterm identification and interventions to reduce preterm neonatal mortality. Further research is needed to validate these findings on a population basis. PMID- 25822531 TI - Exploring new gene integration sites for gene knock-in by gene-trapping strategy. AB - The knock-in mouse is a powerful tool for biological research, but the stability of expression of an integrated gene strongly depends on where it is integrated in the mouse genome. At present, there are an insufficient number of loci suitable for gene knock-in, such as the Rosa26 locus. Therefore, in this study, we developed an efficient strategy for identifying genome loci suitable for gene knock-in and characterized the properties of such loci for gene integration. For efficient discovery and characterization, we constructed a new gene-trapping vector that enables monitoring of the expression of both trapped and integrated genes using fluorescence. We successfully obtained fluorescent-positive mouse embryonic stem cell (mESC) clones with the vector. Thorough analysis of the expression of fluorescent proteins in chimera embryos generated with the obtained mESC clones, some of the gene-trapped chimera embryos showed stable and ubiquitous expression of the integrated gene. Furthermore, adult mice derived from one of the gene-trapped mESC clones showed ubiquitous expression of the integrated gene in various tissues without any unusual phenotype. This indicated that the identified locus possesses high potential for foreign gene integration. Our strategy allows for efficient discovery and characterization of mouse genome loci for gene integration. PMID- 25822533 TI - Correction: Local and global limits on visual processing in schizophrenia. PMID- 25822532 TI - Transgenic tobacco simultaneously overexpressing glyphosate N-acetyltransferase and 5-enolpyruvylshikimate-3-phosphate synthase are more resistant to glyphosate than those containing one gene. AB - 5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS) and glyphosate N acetyltransferase (GAT) can detoxify glyphosate by alleviating the suppression of shikimate pathway. In this study, we obtained transgenic tobacco plants overexpressing AM79 aroA, GAT, and both of them, respectively, to evaluate whether overexpression of both genes could confer transgenic plants with higher glyphosate resistance. The transgenic plants harboring GAT or AM79 aroA, respectively, showed good glyphosate resistance. As expected, the hybrid plants containing both GAT and AM79 aroA exhibited improved glyphosate resistance than the transgenic plants overexpressing only a single gene. When grown on media with high concentration of glyphosate, seedlings containing a single gene were severely inhibited, whereas plants expressing both genes were affected less. When transgenic plants grown in the greenhouse were sprayed with glyphosate, less damage was observed for the plants containing both genes. Metabolomics analysis showed that transgenic plants containing two genes could maintain the metabolism balance better than those containing one gene after glyphosate treatment. Glyphosate treatment did not lead to a huge increase of shikimate contents of tobacco leaves in transgenic plants overexpressing two genes, whereas significant increase of shikimate contents in transgenic plants containing only a single gene was observed. These results demonstrated that pyramiding both aroA and GAT in transgenic plants can enhance glyphosate resistance, and this strategy can be used for the development of transgenic glyphosate-resistant crops. PMID- 25822534 TI - What drives farmers to make top-down or bottom-up adaptation to climate change and fluctuations? A comparative study on 3 cases of apple farming in Japan and South Africa. AB - Agriculture is one of the most vulnerable sectors to climate change. Farmers have been exposed to multiple stressors including climate change, and they have managed to adapt to those risks. The adaptation actions undertaken by farmers and their decision making are, however, only poorly understood. By studying adaptation practices undertaken by apple farmers in three regions: Nagano and Kazuno in Japan and Elgin in South Africa, we categorize the adaptation actions into two types: farmer initiated bottom-up adaptation and institution led top down adaptation. We found that the driver which differentiates the type of adaptation likely adopted was strongly related to the farmers' characteristics, particularly their dependence on the institutions, e.g. the farmers' cooperative, in selling their products. The farmers who rely on the farmers' cooperative for their sales are likely to adopt the institution-led adaptation, whereas the farmers who have established their own sales channels tend to start innovative actions by bottom-up. We further argue that even though the two types have contrasting features, the combinations of the both types of adaptations could lead to more successful adaptation particularly in agriculture. This study also emphasizes that more farm-level studies for various crops and regions are warranted to provide substantial feedbacks to adaptation policy. PMID- 25822535 TI - Complex of rutin with beta-cyclodextrin as potential delivery system. AB - This study aimed to obtain and characterize an RU-beta-CD complex in the context of investigating the possibility of changes in the solubility, stability, antioxidative and microbiological activity as well as permeability of complexated rutin as against its free form. The formation of the RU-beta-CD complex via a co grinding technique was confirmed by using DSC, SEM, FT-IR and Raman spectroscopy, and its geometry was assessed through molecular modeling. It was found that the stability and solubility of the so-obtained complex were greater compared to the free form; however, a slight decrease was observed inits antibacterial potency. An examination of changes in the EPR spectra of thecomplex excluded any reducing effect of complexation on the antioxidative activity of rutin. Considering the prospect of preformulation studies involving RU-beta-CD complexes, of significance is also the observed possibility of prolongedly releasing rutin from the complex at a constant level over along period of 20 h, and the fact that twice as much complexated rutin was able topermeate compared to its free form. PMID- 25822537 TI - Coligand and solvent effects on the architectures and spin-crossover properties of (4,4)-connected Iron(II) coordination polymers. AB - The self-assemblies of 1,4-bis(pyrid-4-yl)benzene (bpb) and Fe(NCX)2 (X = S, Se, BH3) afforded six coordination polymers with the general formula of [Fe(bpb)2(NCX)2].Y (X = S and Y = 3C2H5OH.2.5H2O for complex 4, X = S and Y = 2C2H5OH for 5, X = Se and Y = 2C2H5OH.H2O for 6, X = Se and Y = 0.67CH2Cl2.1.33C2H5OH.0.67H2O for 7, X = BH3 and Y = 3C2H5OH.2H2O for 8, X = BH3 and Y = 2CH2Cl2.2C2H5OH for 9). The frameworks of complexes 4 and 5 with the NCS( ) anion as coligand are supramolecular isomers, of which complex 4 features a threefold self-interpenetrated three-dimensional (3D) CdSO4-type topological structure with a Schlafli symbol of 6(5).8, and complex 5 is a two-dimensional (2D) 4(4) rhombic grid network. These two complexes are purely high-spin systems. Complexes 6 and 7 with the NCSe(-) anion as coligand, both having the 3D 6(5).8 CdSO4-type framework, show gradual and incomplete spin-crossover behaviors with transition temperature T1/2 being equal to 86 and 96 K, respectively. The usage of NCBH3(-) anion as coligand leads to the formation of 2D 4(4) rhombic grid networks for both complexes 8 and 9, which undergo relatively abrupt, complete spin crossover with T1/2 being equal to 247 and 189 K, respectively. The structural divergences are attributed to the coligands NCX(-) (X = S, Se, BH3) and solvent molecules. Meanwhile, a significant coligand effect is observed on the spin-crossover behaviors of these complexes, and the completeness and transition temperature of spin-state conversion depends on the nature of the coligand, that is, T1/2(NCS(-)) < T1/2(NCSe(-)) < T1/2(NCBH3(-)). These results further facilitate the design and synthesis of spin-crossover complexes with spin state conversion. PMID- 25822538 TI - Personality change and gait dysfunction. PMID- 25822536 TI - Protection against Mycobacterium tuberculosis infection offered by a new multistage subunit vaccine correlates with increased number of IFN-gamma+ IL-2+ CD4+ and IFN-gamma+ CD8+ T cells. AB - Protein subunit vaccines present a compelling new area of research for control of tuberculosis (TB). Based on the interaction between Mycobacterium tuberculosis and its host, five stage-specific antigens of M. tuberculosis that participate in TB pathogenesis--Rv1813, Rv2660c, Ag85B, Rv2623, and HspX--were selected. These antigens were verified to be recognized by T cells from a total of 42 whole blood samples obtained from active TB patients, patients with latent TB infections (LTBIs), and healthy control donors. The multistage polyprotein A1D4 was developed using the selected five antigens as a potentially more effective novel subunit vaccine. The immunogenicity and protective efficacy of A1D4 emulsified in the adjuvant MTO [monophosphoryl lipid A (MPL), trehalose-6,6'-dibehenate (TDB), components of MF59] was compared with Bacillus Calmette-Guerin (BCG) in C57BL/6 mice. Our results demonstrated that A1D4/MTO could provide more significant protection against M. tuberculosis infection than the PBS control or MTO adjuvant alone judging from the A1D4-specific Th1-type immune response; however, its efficacy was inferior to BCG as demonstrated by the bacterial load in the lung and spleen, and by the pathological changes in the lung. Antigen-specific single IL-2-secreting cells and different combinations with IL-2-secreting CD4+ T cells were beneficial and correlated with BCG vaccine-induced protection against TB. Antigen-specific IFN-gamma+ IL-2+ CD4+ T cells were the only effective biomarker significantly induced by A1D4/MTO. Among all groups, A1D4/MTO immunization also conferred the highest number of antigen-specific single IFN-gamma+ and IFN-gamma+ TNF-alpha+ CD4+ T cells, which might be related to the antigen load in vivo, and single IFN-gamma+ CD8+ T cells by mimicking the immune patterns of LTBIs or curable TB patients. Our strategy seems promising for the development of a TB vaccine based on multistage antigens, and subunit antigen A1D4 suspended in MTO adjuvant warrants preclinical evaluation in animal models of latent infection and may boost BCG vaccination. PMID- 25822539 TI - An Atomically Layered InSe Avalanche Photodetector. AB - Atomically thin photodetectors based on 2D materials have attracted great interest due to their potential as highly energy-efficient integrated devices. However, photoinduced carrier generation in these media is relatively poor due to low optical absorption, limiting device performance. Current methods for overcoming this problem, such as reducing contact resistances or back gating, tend to increase dark current and suffer slow response times. Here, we realize the avalanche effect in a 2D material-based photodetector and show that avalanche multiplication can greatly enhance the device response of an ultrathin InSe-based photodetector. This is achieved by exploiting the large Schottky barrier formed between InSe and Al electrodes, enabling the application of a large bias voltage. Plasmonic enhancement of the photosensitivity, achieved by patterning arrays of Al nanodisks onto the InSe layer, further improves device efficiency. With an external quantum efficiency approaching 866%, a dark current in the picoamp range, and a fast response time of 87 MUs, this atomic layer device exhibits multiple significant advances in overall performance for this class of devices. PMID- 25822540 TI - Environment-friendly cathodes using biopolymer chitosan with enhanced electrochemical behavior for use in lithium ion batteries. AB - The biopolymer chitosan has been investigated as a potential binder for the fabrication of LiFePO4 cathode electrodes in lithium ion batteries. Chitosan is compared to the conventional binder, polyvinylidene fluoride (PVDF). Dispersion of the active material, LiFePO4, and conductive agent, Super P carbon black, is tested using a viscosity analysis. The enhanced structural and morphological properties of chitosan are compared to the PVDF binder using X-ray diffraction analysis (XRD) and field emission scanning electron microscopy (FE-SEM). Using an electrochemical impedance spectroscopy (EIS) analysis, the LiFePO4 electrode with the chitosan binder is observed to have a high ionic conductivity and a smaller increase in charge transfer resistance based on time compared to the LiFePO4 electrode with the PVDF binder. The electrode with the chitosan binder also attains a higher discharge capacity of 159.4 mAh g(-1) with an excellent capacity retention ratio of 98.38% compared to the electrode with the PVDF binder, which had a discharge capacity of 127.9 mAh g(-1) and a capacity retention ratio of 85.13%. Further, the cycling behavior of the chitosan-based electrode is supported by scrutinizing its charge-discharge behavior at specified intervals and by a plot of dQ/dV. PMID- 25822541 TI - Germline-transmitted genome editing in Arabidopsis thaliana Using TAL-effector nucleases. AB - Transcription activator-like effector nucleases (TALENs) are custom-made bi partite endonucleases that have recently been developed and applied for genome engineering in a wide variety of organisms. However, they have been only scarcely used in plants, especially for germline-modification. Here we report the efficient creation of small, germline-transmitted deletions in Arabidopsis thaliana via TALENs that were delivered by stably integrated transgenes. Using meristem specific promoters to drive expression of two TALEN arms directed at the CLV3 coding sequence, we observed very high phenotype frequencies in the T2 generation. In some instances, full CLV3 loss-of-function was already observed in the T1 generation, suggesting that transgenic delivery of TALENs can cause highly efficient genome modification. In contrast, constitutive TALEN expression in the shoot apical meristem (SAM) did not cause additional phenotypes and genome re sequencing confirmed little off-target effects, demonstrating exquisite target specificity. PMID- 25822542 TI - Bulk-fill materials: simplify restorations, reduce chairtime. AB - Newer bulk-fill composite materials are being developed for preparation depths of up to 5 mm in an effort to simplify and improve placement of direct composite posterior restorations. Depth of cure for any dental composite is a critical issue, and especially so for bulk-fill composites. This article discusses factors involved in determining adequate depth of cure. Additionally, a case report depicting occlusal decay describes how a highly filled bulk-fill material was used to achieve an esthetic and functional restoration while eliminating incremental composite layering, thereby saving considerable time. PMID- 25822543 TI - KAST Study: The Kiva System As a Vertebral Augmentation Treatment-A Safety and Effectiveness Trial: A Randomized, Noninferiority Trial Comparing the Kiva System With Balloon Kyphoplasty in Treatment of Osteoporotic Vertebral Compression Fractures. AB - STUDY DESIGN: The KAST (Kiva Safety and Effectiveness Trial) study was a pivotal, multicenter, randomized control trial for evaluation of safety and effectiveness in the treatment of patients with painful, osteoporotic vertebral compression fractures (VCFs). OBJECTIVE: The objective was to demonstrate noninferiority of the Kiva system to balloon kyphoplasty (BK) with respect to the composite primary endpoint. SUMMARY OF BACKGROUND DATA: Annual incidence of osteoporotic VCFs is prevalent. Optimal treatment of VCFs should address pain, function, and deformity. Kiva is a novel implant for vertebral augmentation in the treatment of VCFs. METHODS: A total of 300 subjects with 1 or 2 painful osteoporotic VCFs were randomized to blindly receive Kiva (n = 153) or BK (n = 147). Subjects were followed through 12 months. The primary endpoint was a composite at 12 months defined as a reduction in fracture pain by at least 15 mm on the visual analogue scale, maintenance or improvement in function on the Oswestry Disability Index, and absence of device-related serious adverse events. Secondary endpoints included cement usage, extravasation, and adjacent level fracture. RESULTS: A mean improvement of 70.8 and 71.8 points in the visual analogue scale score and 38.1 and 42.2 points in the Oswestry Disability Index was noted in Kiva and BK, respectively. No device-related serious adverse events occurred. Despite significant differences in risk factors favoring the control group at baseline, the primary endpoint demonstrated noninferiority of Kiva to BK. Analysis of secondary endpoints revealed superiority with respect to cement use and site reported extravasation and a positive trend in adjacent level fracture warranting further study. CONCLUSION: The KAST study successfully established that the Kiva system is noninferior to BK based on a composite primary endpoint assessment incorporating pain-, function-, and device-related serious adverse events for the treatment of VCFs due to osteoporosis. Kiva was shown to be noninferior to BK and revealed a positive trend in several secondary endpoints. LEVEL OF EVIDENCE: 1. PMID- 25822544 TI - Pathogenesis of Vertebral Anterior Wedge Deformity: A 2-Stage Process? AB - STUDY DESIGN: Biomechanical and radiographical study on cadaveric spines. OBJECTIVE: To explain the pathogenesis of vertebral "anterior wedge" deformity, which causes senile kyphosis. SUMMARY OF BACKGROUND DATA: This deformity arises with minimal trauma and is difficult to reproduce in cadaveric spines. We hypothesize that wedging is created by a 2-stage process. First, excessive loading damages a vertebral endplate and decompresses the adjacent intervertebral disc. This alters load sharing between the vertebral body cortex and trabeculae so that subsequent cyclic loading causes progressive collapse of the unsupported anterior cortex. METHODS: Thirty-four cadaveric thoracolumbar "motion segments," aged 70 to 98 years, were positioned in flexion and overloaded in compression. Physiologically reasonable cyclic compressive loading was then applied to each flexed specimen, at progressively higher loads, for up to 2 hours. Before and after initial overload and again after cyclic loading, the distribution of loading on the vertebra was assessed from measurements of compressive stress within the adjacent disc. These "stress profiles" were repeated in the neutral, flexed, and extended postures. Progressive vertebral body deformity was assessed radiographically. RESULTS: Compressive overload induced endplate fracture at an average force of 2.31 kN. There was minimal anterior wedging, but pressure in the adjacent disc nucleus (in flexion) fell by an average of 55% and neural arch load bearing increased by 166%. Subsequent cyclic loading exaggerated these changes and concentrated compressive stress within the anterior annulus. After both stages, height of the anterior and posterior vertebral cortexes was reduced by 32% and 12%, respectively, so that anterior wedging of the vertebral body increased from 5.0 degrees to 11.4 degrees on average. All changes were highly significant (P < 0.001). CONCLUSION: Anterior wedge deformities can be created consistently by a 2-stage process involving initial endplate damage, followed by progressive collapse of the anterior cortex. Detecting initial endplate damage may be important to minimize vertebral deformity in patients with osteoporosis. LEVEL OF EVIDENCE: N/A. PMID- 25822546 TI - Medicare Charges and Payments for Cervical Spine Surgery: Association With Hospital Characteristics. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To determine the association of hospital and patient population characteristics with charges and payments for Medicare patients undergoing cervical spine surgery. SUMMARY OF BACKGROUND DATA: Third-party payers such as Medicare pay negotiated rates for health care services that represent a substantial savings from hospitals' list prices. Previous research has shown geographical variation in hospital charges. However, the association with other hospital and patient population characteristics is poorly understood. METHODS: We determined the association of hospital characteristics (hospital size, ownership, location, teaching status, procedure volume, and geographical region) and patient population characteristics (proportion female, nonwhite, or with >=1 comorbid conditions) with excess charges (difference between hospital charges and payments) and cost-to-charge ratio (ratio of payments to hospital charges) for Medicare patients undergoing cervical spine fusion without complication (MS-DRG 473). Significance levels were set at a P value less than 0.05. RESULTS: The median excess charge was $59,799 (interquartile range, $41,668, $69,576) and cost-to-charge ratio was 25.8% (interquartile range, 20.4%, 32.7%). Higher excess charges were observed for urban hospitals (P = 0.003). There was an association between excess charges and procedure volume (P = 0.034) and proportion of patients with 1 or more comorbid conditions (P = 0.008). There were no differences based on hospital size, ownership, teaching status, geographical region, or proportion of female or nonwhite patients.Private hospitals had higher cost-to-charge ratios than government hospitals (P = 0.017). There was no association with hospital size, teaching status, geographical region, procedure volume, or proportion of patients who were female, nonwhite, or who had 1 or more comorbid conditions. CONCLUSION: The relationship between hospital charges and payments for cervical spine surgery without complication is associated with certain hospital and patient population characteristics. Further study is needed to determine whether these differences are associated with health outcomes. LEVEL OF EVIDENCE: 3. PMID- 25822547 TI - Arabidopsis BREVIPEDICELLUS interacts with the SWI2/SNF2 chromatin remodeling ATPase BRAHMA to regulate KNAT2 and KNAT6 expression in control of inflorescence architecture. AB - BREVIPEDICELLUS (BP or KNAT1), a class-I KNOTTED1-like homeobox (KNOX) transcription factor in Arabidopsis thaliana, contributes to shaping the normal inflorescence architecture through negatively regulating other two class-I KNOX genes, KNAT2 and KNAT6. However, the molecular mechanism of BP-mediated transcription regulation remains unclear. In this study, we showed that BP directly interacts with the SWI2/SNF2 chromatin remodeling ATPase BRAHMA (BRM) both in vitro and in vivo. Loss-of-function BRM mutants displayed inflorescence architecture defects, with clustered inflorescences, horizontally orientated pedicels, and short pedicels and internodes, a phenotype similar to the bp mutants. Furthermore, the transcript levels of KNAT2 and KNAT6 were elevated in brm-3, bp-9 and brm-3 bp-9 double mutants. Increased histone H3 lysine 4 tri methylation (H3K4me3) levels were detected in brm-3, bp-9 and brm-3 bp-9 double mutants. Moreover, BRM and BP co-target to KNAT2 and KNAT6 genes, and BP is required for the binding of BRM to KNAT2 and KNAT6. Taken together, our results indicate that BP interacts with the chromatin remodeling factor BRM to regulate the expression of KNAT2 and KNAT6 in control of inflorescence architecture. PMID- 25822548 TI - Pain Management in Patients with ADPKD. PMID- 25822549 TI - Vitamin D supplementation in premature infants. PMID- 25822553 TI - What to Do at Well-Child Visits: The AAFP's Perspective. PMID- 25822554 TI - Diagnosis and management of kawasaki disease. AB - Kawasaki disease is an acute, systemic vasculitis that predominantly affects patients younger than five years. It represents the most prominent cause of acquired coronary artery disease in childhood. In the United States, 19 per 100,000 children younger than five years are hospitalized with Kawasaki disease annually. According to U.S. and Japanese guidelines, Kawasaki disease is a clinical diagnosis. Classic (typical) Kawasaki disease is diagnosed based on the presence of a fever lasting five or more days, accompanied by four out of five findings: bilateral conjunctival injection, oral changes such as cracked and erythematous lips and strawberry tongue, cervical lymphadenopathy, extremity changes such as erythema or palm and sole desquamation, and polymorphous rash. Incomplete (atypical) Kawasaki disease occurs in persons with fever lasting five or more days and with two or three of these findings. Transthoracic echocardiography is the diagnostic imaging modality of choice to screen for coronary aneurysms, although other techniques are being evaluated for diagnosis and management. Treatment for acute disease is intravenous immunoglobulin and aspirin. If there is no response to treatment, patients are given a second dose of intravenous immunoglobulin with or without corticosteroids or other adjunctive treatments. The presence and severity of coronary aneurysms and obstruction at diagnosis determine treatment options and the need, periodicity, and intensity of long-term cardiovascular monitoring for potential atherosclerosis. PMID- 25822555 TI - Common questions about infectious mononucleosis. AB - Epstein-Barr is a ubiquitous virus that infects 95% of the world population at some point in life. Although Epstein-Barr virus (EBV) infections are often asymptomatic, some patients present with the clinical syndrome of infectious mononucleosis (IM). The syndrome most commonly occurs between 15 and 24 years of age. It should be suspected in patients presenting with sore throat, fever, tonsillar enlargement, fatigue, lymphadenopathy, pharyngeal inflammation, and palatal petechiae. A heterophile antibody test is the best initial test for diagnosis of EBV infection, with 71% to 90% accuracy for diagnosing IM. However, the test has a 25% false-negative rate in the first week of illness. IM is unlikely if the lymphocyte count is less than 4,000 mm3. The presence of EBV specific immunoglobulin M antibodies confirms infection, but the test is more costly and results take longer than the heterophile antibody test. Symptomatic relief is the mainstay of treatment. Glucocorticoids and antivirals do not reduce the length or severity of illness. Splenic rupture is an uncommon complication of IM. Because physical activity within the first three weeks of illness may increase the risk of splenic rupture, athletic participation is not recommended during this time. Children are at the highest risk of airway obstruction, which is the most common cause of hospitalization from IM. Patients with immunosuppression are more likely to have fulminant EBV infection. PMID- 25822556 TI - Diagnosis and treatment of temporomandibular disorders. AB - Temporomandibular disorders (TMD) are a heterogeneous group of musculoskeletal and neuromuscular conditions involving the temporomandibular joint complex, and surrounding musculature and osseous components. TMD affects up to 15% of adults, with a peak incidence at 20 to 40 years of age. TMD is classified as intra articular or extra-articular. Common symptoms include jaw pain or dysfunction, earache, headache, and facial pain. The etiology of TMD is multifactorial and includes biologic, environmental, social, emotional, and cognitive triggers. Diagnosis is most often based on history and physical examination. Diagnostic imaging may be beneficial when malocclusion or intra-articular abnormalities are suspected. Most patients improve with a combination of noninvasive therapies, including patient education, self-care, cognitive behavior therapy, pharmacotherapy, physical therapy, and occlusal devices. Nonsteroidal anti inflammatory drugs and muscle relaxants are recommended initially, and benzodiazepines or antidepressants may be added for chronic cases. Referral to an oral and maxillofacial surgeon is indicated for refractory cases. PMID- 25822557 TI - Screening for oral cancer. PMID- 25822558 TI - Asymptomatic, evolving lesion on the upper arm. PMID- 25822565 TI - Temporomandibular disorders. PMID- 25822566 TI - Detachable strong cation exchange monolith, integrated with capillary zone electrophoresis and coupled with pH gradient elution, produces improved sensitivity and numbers of peptide identifications during bottom-up analysis of complex proteomes. AB - A detachable sulfonate-silica hybrid strong cation-exchange monolith was synthesized in a fused silica capillary, and used for solid phase extraction with online pH gradient elution during capillary zone electrophoresis-tandem mass spectrometry (CZE-MS/MS) proteomic analysis. Tryptic digests were prepared in 50 mM formic acid and loaded onto the strong cation-exchange monolith. Fractions were eluted using a series of buffers with lower concentration but higher pH values than the 50 mM formic acid background electrolyte. This combination of elution and background electrolytes results in both sample stacking and formation of a dynamic pH junction and allows use of relatively large elution buffer volumes while maintaining reasonable peak efficiency and resolution. A series of five pH bumps were applied to elute E. coli tryptic peptides from the monolith, followed by analysis using CZE coupled to an LTQ-Orbitrap Velos mass spectrometer; 799 protein groups and 3381 peptides were identified from 50 ng of the digest in a 2.5 h analysis, which approaches the identification rate for this organism that was obtained with an Orbitrap Fusion. We attribute the improved numbers of peptide and protein identifications to the efficient fractionation by the online pH gradient elution, which decreased the complexity of the sample in each elution step and improved the signal intensity of low abundance peptides. We also performed a comparative analysis using a nanoACQUITY UltraPerformance LCH system. Similar numbers of protein and peptide identifications were produced by the two methods. Protein identifications showed significant overlap between the two methods, whereas peptide identifications were complementary. PMID- 25822567 TI - A Review of Barriers to Minorities' Participation in Cancer Clinical Trials: Implications for Future Cancer Research. AB - To enhance nurses' awareness and competencies in practice and research by reporting the common barriers to participation of minorities in cancer clinical trials and discussing facilitators and useful strategies for recruitment. Several databases were searched for articles published in peer reviewed journals. Some of the barriers to minorities' participation in clinical trials were identified within the cultural social-context of cancer patients. The involvement of community networking was suggested as the most effective strategy for the recruitment of minorities in cancer clinical trials. Using culturally sensitive approaches to enhance ethnic minorities' participation is important for advancing cancer care and eliminating health disparities. Awareness of barriers and potential facilitators to the enrollment of ethnic minority cancer patients may contribute to enhancing nurses' competencies of recruiting ethnic minorities in nursing research, playing efficient roles in cancer clinical trials team, and providing culturally competent quality care. PMID- 25822568 TI - Erratum to: Acculturation and Depressive Symptoms in Hispanic Older Adults: Does Perceived Ethnic Density Moderate their Relationship? PMID- 25822569 TI - Prevalence of Sleep-disordered Breathing in Obese Patients with Chronic Hypoxemia. A Cross-Sectional Study. AB - RATIONALE: Hypoxemia in obese patients is likely to be associated with a high prevalence of sleep-disordered breathing. Supplemental oxygen is commonly used to treat chronic hypoxemia but carries some risk in obese individuals due to unrecognized comorbid obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS). OBJECTIVES: The first step in the estimation of this risk is to determine the prevalence of OSA and OHS in obese individuals with chronic, awake hypoxemia. METHODS: A single-center retrospective cohort study was performed to assess the prevalence and severity of OSA and OHS among obese individuals with hypoxemia. One hundred eighty-four individuals underwent arterial blood gas testing and polysomnography. One hundred fifty-eight of these individuals also had spirometry. MEASUREMENTS AND MAIN RESULTS: The prevalence of OSA was 80%, and the prevalence of OHS was 51%. Chronic obstructive pulmonary disease (COPD) was confirmed by spirometry in 49% of the cohort, and OSA was found in 69% of those individuals. The severity of hypoxemia in this cohort was not statistically related to COPD, OSA, or OHS. CONCLUSIONS: OSA and OHS are highly prevalent in obese patients with chronic awake hypoxemia, and OSA frequently coexists with COPD. Evaluation of chronic, awake hypoxemia solely based on arterial blood gas measurements and pulmonary function testing is not sufficient to identify OSA and OHS. Further diagnostic sleep testing should be performed to identify those who could benefit from alternative therapies and to avoid potential harm from treatment with supplemental oxygen alone. PMID- 25822570 TI - Correction to Armenta et al. (2013). AB - Reports an error in "Where are you from? A validation of the Foreigner Objectification Scale and the psychological correlates of foreigner objectification among Asian Americans and Latinos" by Brian E. Armenta, Richard M. Lee, Stephanie T. Pituc, Kyoung-Rae Jung, Irene J. K. Park, Jose A. Soto, Su Yeong Kim and Seth J. Schwartz (Cultural Diversity and Ethnic Minority Psychology, 2013[Apr], Vol 19[2], 131-142). There were errors in the author note and the Measures section. The omitted information in the author note and the corrected version of the last sentence in paragraph two of the Measures section are provided. (The following abstract of the original article appeared in record 2013-14946-002.) Many ethnic minorities in the United States consider themselves to be just as American as their European American counterparts. However, there is a persistent cultural stereotype of ethnic minorities as foreigners (i.e., the perpetual foreigner stereotype) that may be expressed during interpersonal interactions (i.e., foreigner objectification). The goal of the present study was to validate the Foreigner Objectification Scale, a brief self-report measure of perceived foreigner objectification, and to examine the psychological correlates of perceived foreigner objectification. Results indicated that the Foreigner Objectification Scale is structurally (i.e., factor structure) and metrically (i.e., factor loadings) invariant across foreign-born and U.S.-born Asian Americans and Latinos. Scalar (i.e., latent item intercepts) invariance was demonstrated for the two foreign-born groups and the two U.S.-born groups, but not across foreign-born and U.S.-born individuals. Multiple-group structural equation models indicated that, among U.S.-born individuals, perceived foreigner objectification was associated with less life satisfaction and more depressive symptoms, and was indirectly associated with lower self-esteem via identity denial, operationalized as the perception that one is not viewed by others as American. Among foreign-born individuals, perceived foreigner objectification was not significantly associated directly with self-esteem, life satisfaction, or depressive symptoms. However, perceived foreigner objectification was positively associated with identity denial, and identity denial was negatively associated with life satisfaction. This study illustrates the relevance of perceived foreigner objectification to the psychological well-being of U.S.-born Asian Americans and Latinos. PMID- 25822571 TI - Comprehensive mapping infection-enhancing epitopes of dengue pr protein using polyclonal antibody against prM. AB - Dengue vaccine development is considered a global public health priority, but the antibody-dependent enhancement (ADE) issues have critically restricted vaccine development. Recent findings have demonstrated that pre-membrane (prM) protein was involved in dengue virus (DENV) infection enhancement. Although the importance of prM antibodies have been well characterized, only a few epitopes in DENV prM protein have ever been identified. In this study, we screened five potential linear epitopes located at positions pr1 (1-16aa), pr3 (13-28aa), pr4 (19-34aa), pr9 (49-64aa), and pr10 (55-70aa) in pr protein using peptide scanning and comprehensive bioinformatics analysis. Then, we found that only pr4 (19-34aa) could elicit high-titer antibodies in Balb/c mice, and this epitope could react with sera from DENV2-infected patients, suggesting that specific antibodies against epitope peptide pr4 were elicited in both DENV-infected mice and human. In addition, our data demonstrated that anti-pr4 sera showed limited neutralizing activity but significant ADE activity toward standard DENV serotypes and imDENV. Hence, it seems responsible to hypothesize that anti-pr4 serum was infection enhancing antibody and pr4 was infection-enhancing epitope. In conclusion, we characterized a novel infection-enhancing epitope on dengue pr protein, a finding that may provide new insight into the pathogenesis of DENV infection and contribute to dengue vaccine design. PMID- 25822572 TI - Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial. AB - IMPORTANCE: Osteoarthritis (OA) of the knee is the most frequent form of arthritis and a cause of pain and disability. Combined nonpharmacologic and pharmacologic treatments are recommended as the optimal treatment approach, but no evidence supports the recommendation. OBJECTIVE: To assess the clinical benefits of an intra-articular corticosteroid injection given before exercise therapy in patients with OA of the knee. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, blinded, placebo-controlled clinical trial evaluating the benefit of intra-articular corticosteroid injection vs placebo injection given before exercise therapy at an OA outpatient clinic from October 1, 2012, through April 2, 2014. The participants had radiographic confirmation of clinical OA of the knee, clinical signs of localized inflammation in the knee, and knee pain during walking (score >4 on a scale of 0 to 10). INTERVENTIONS: Participants were randomly allocated (1:1) to an intra-articular 1-mL injection of the knee with methylprednisolone acetate (Depo-Medrol), 40 mg/mL, dissolved in 4 mL of lidocaine hydrochloride (10 mg/mL) (corticosteroid group) or a 1-mL isotonic saline injection mixed with 4 mL of lidocaine hydrochloride (10 mg/mL) (placebo group). Two weeks after the injections, all participants started a 12-week supervised exercise program. MAIN OUTCOMES AND MEASURES: The primary outcome was change in the Pain subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire (range, 0-100; higher scores indicate greater improvement) at week 14. Secondary outcomes included the remaining KOOS subscales and objective measures of physical function and inflammation. Outcomes were measured at baseline, week 2 (exercise start), week 14 (exercise stop), and week 26 (follow-up). RESULTS: One hundred patients were randomized to the corticosteroid group (n = 50) or the placebo group (n = 50); 45 and 44 patients, respectively, completed the trial. The mean (SE) changes in the KOOS Pain subscale score at week 14 were 13.6 (1.8) and 14.8 (1.8) points in the corticosteroid and placebo groups, respectively, corresponding to a statistically insignificant mean difference of 1.2 points (95% CI, -3.8 to 6.2; P = .64). We found no statistically significant group differences in any of the secondary outcomes at any time point. CONCLUSIONS AND RELEVANCE: No additional benefit results from adding an intra-articular injection of 40 mg of corticosteroid before exercise in patients with painful OA of the knee. Further research is needed to establish optimal and potentially synergistic combinations of conservative treatments. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2012-002607-18; clinicaltrials.gov Identifier: NCT01945749. PMID- 25822573 TI - Tobacco smoking, family history, and the risk of nasopharyngeal carcinoma: a case referent study in Hong Kong Chinese. AB - PURPOSE: This study aimed to investigate the associations of tobacco smoking and family history of nasopharyngeal carcinoma (NPC) with the risk of NPC in Hong Kong Chinese. METHODS: Between June 2010 and December 2012, we conducted a case referent study with 352 incident cases and 410 referents in Hong Kong. We collected information on tobacco smoking and family history of NPC via face-to face interviews. RESULTS: There were 174 (49.4%) and 131 (32.0%) ever-smokers among cases and referents, respectively. The adjusted odds ratio (OR) for NPC related to current smoking was 1.67 [95% confidence interval (CI) 1.06, 2.61]. Exposure-response relationships were observed between years and total pack-years of smoking, and NPC risk (p = 0.001 and p = 0.018, respectively). History of NPC in first-degree relatives was associated with an increased NPC risk (adjusted OR = 4.52, 95% CI 2.39, 8.55). The increased NPC risk associated with sibling history (adjusted OR = 6.80, 95% CI 2.63, 17.56) was higher than that for parental history (adjusted OR = 3.04, 95% CI 1.27, 7.25). The adjusted OR for ever-smokers with family history using never-smokers without family history as the reference was 4.54 (95% CI 1.67, 12.34). CONCLUSIONS: This study verified the important roles of tobacco smoking and family history on NPC risk among Hong Kong Chinese. The provided evidence supported the knowledge that both environmental exposures and inherited susceptibility contributed to the risk of NPC. PMID- 25822574 TI - Prostate cancer screening: contrasting trends. AB - PURPOSE: Our previously published data showed rapidly increasing rates of prostate cancer screening in men aged 50-74, which rose from 36% in 2005 to 48% in 2008. Based on men's reported intentions at that time, this was expected to rise to 70% in 2011. Here we report the actual rate of prostate cancer screening. METHOD: Three nationwide observational telephone surveys (EDIFICE opinion polls) were conducted in 2005, 2008, and 2011. The overall target was a representative sample of > 1,500 individuals living in France and aged 40-75 years, including 481 men aged 50-74 years. RESULTS: Within this male population, the rate of screening reported remained stable between 2008 and 2011 (48 and 49%, respectively). However, comparison of privileged versus disadvantaged populations showed significant differences, with a relative decrease in screening among those of higher socioprofessional status (p = 0.03) and from higher-income groups (p = 0.02). For households with a monthly income above 2,500?, the screening rate decreased from 61% in 2008 to 51% in 2011 (p = 0.05), while for those with an income below 2,500?, it increased from 36% in 2008 to 44 % in 2011 (p = 0.18). CONCLUSION: A plateau or even a reduction in prostate cancer screening is currently being observed; this is possibly due to progressive recognition among the population at large of the controversy surrounding prostate cancer screening, whereas this speculation was formerly limited to health-care professionals. After previously being more likely to undergo prostate cancer screening, it is the younger, wealthier populations that are currently showing the most noteworthy step backwards. PMID- 25822575 TI - Optical coherence tomography errors in glaucoma: preanalytical errors. PMID- 25822576 TI - Response to comment on the article entitled "effect of improper scan alignment on retinal nerve fiber layer thickness measurements using stratus optical coherence tomograph" by Vizzeri G, et al published in J Glaucoma. 2008;17: 341-349. PMID- 25822578 TI - Experimental and Kinetic Modeling Study of 2-Methyl-2-Butene: Allylic Hydrocarbon Kinetics. AB - Two experimental studies have been carried out on the oxidation of 2-methyl-2 butene, one measuring ignition delay times behind reflected shock waves in a stainless steel shock tube, and the other measuring fuel, intermediate, and product species mole fractions in a jet-stirred reactor (JSR). The shock tube ignition experiments were carried out at three different pressures, approximately 1.7, 11.2, and 31 atm, and at each pressure, fuel-lean (phi = 0.5), stoichiometric (phi = 1.0), and fuel-rich (phi = 2.0) mixtures were examined, with each fuel/oxygen mixture diluted in 99% Ar, for initial postshock temperatures between 1330 and 1730 K. The JSR experiments were performed at nearly atmospheric pressure (800 Torr), with stoichiometric fuel/oxygen mixtures with 0.01 mole fraction of 2M2B fuel, a residence time in the reactor of 1.5 s, and mole fractions of 36 different chemical species were measured over a temperature range from 600 to 1150 K. These JSR experiments represent the first such study reporting detailed species measurements for an unsaturated, branched hydrocarbon fuel larger than iso-butene. A detailed chemical kinetic reaction mechanism was developed to study the important reaction pathways in these experiments, with particular attention on the role played by allylic C-H bonds and allylic pentenyl radicals. The results show that, at high temperatures, this olefinic fuel reacts rapidly, similar to related alkane fuels, but the pronounced thermal stability of the allylic pentenyl species inhibits low temperature reactivity, so 2M2B does not produce "cool flames" or negative temperature coefficient behavior. The connections between olefin hydrocarbon fuels, resulting allylic fuel radicals, the resulting lack of low-temperature reactivity, and the gasoline engine concept of octane sensitivity are discussed. PMID- 25822577 TI - Serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) improves voiding efficiency in the diabetic rat. AB - OBJECTIVES: To examine the effects of the serotonin (5-HT)2A/2C receptor agonist (2,5-dimethoxy-4-idophenyl)-2-aminopropane hydrochloride (DOI) on micturition in rats with diabetes mellitus (DM). METHODS: Female Sprague-Dawley rats (n = 16) were divided into two groups: rats with Type 1 DM and age-matched control rats. DM was induced by i.p. injection of streptozotocin (65 mg/kg) and detailed cystometrogram (CMG) studies were performed 8 weeks post-injection in all rats under urethane anaesthesia. The selective 5-HT2A antagonist ketanserin was administered after each DOI dose-response curve was plotted. All drugs were administered i.v. RESULTS: Compared with controls, comprehensive urodynamic studies showed that DM rats had a higher bladder capacity and post-void residual urine volume (PVR), and a markedly lower voiding efficiency. In DM rats, DOI (0.01-0.3 mg/kg) induced significant dose-dependent increases in micturition volume and reductions in PVR, resulting in greater voiding efficiency. CMG measurements showed a dose-dependent increase in high-frequency oscillation (HFO) activity, evidenced by an increased duration of HFOs per voiding. This correlated with the improved voiding efficiency. Ketanserin (0.1 mg/kg) partially or completely reversed the DOI-induced changes. CONCLUSIONS: The HFOs observed in the present study seem to correlate with external urethral sphincter bursting activity during voiding. Bladder voiding efficiency was reduced in DM rats. The 5 HT2A receptor agonist can enhance HFO activity and improves voiding efficiency, and so may represent a new strategy to improve voiding efficiency after DM in experimental studies. PMID- 25822579 TI - Narrow Band Ultraviolet B Treatment for Human Vitiligo Is Associated with Proliferation, Migration, and Differentiation of Melanocyte Precursors. AB - In vitiligo, the autoimmune destruction of epidermal melanocytes produces white spots that can be repigmented by melanocyte precursors from the hair follicles, following stimulation with UV light. We examined by immunofluorescence the distribution of melanocyte markers (C-KIT, DCT, PAX3, and TYR) coupled with markers of proliferation (KI-67) and migration (MCAM) in precursors and mature melanocytes from the hair follicle and the epidermis of untreated and narrow band UVB (NBUVB)-treated human vitiligo skin. NBUVB was associated with a significant increase in the number of melanocytes in the infundibulum and with restoration of the normal melanocyte population in the epidermis, which was lacking in the untreated vitiligo. We identified several precursor populations (melanocyte stem cells, melanoblasts, and other immature phenotypes), and progressively differentiating melanocytes, some with putative migratory and/or proliferative abilities. The primary melanocyte germ was present in the untreated and treated hair follicle bulge, whereas a possible secondary melanocyte germ composed of C KIT+ melanocytes was found in the infundibulum and interfollicular epidermis of UV-treated vitiligo. This is an exceptional model for studying the mobilization of melanocyte stem cells in human skin. Improved understanding of this process is essential for designing better treatments for vitiligo, ultimately based on melanocyte stem cell activation and mobilization. PMID- 25822580 TI - Interferon-Gamma Enhances TLR3 Expression and Anti-Viral Activity in Keratinocytes. AB - Toll-like receptors (TLRs) recognize specific microbial products in the innate immune response. TLR3, a double-stranded RNA sensor, is thought to have an important role in viral infections, but the regulation of TLR3 expression and its function in keratinocytes are not fully understood. Here we show the Th1 cytokine IFN-gamma increased the TLR3 expression via STAT1 in cultured normal human epidermal keratinocytes (NHEKs). Co-stimulation with IFN-gamma and the TLR3 ligand poly (I:C) synergistically increased the expression of IFN-beta, IL-6, IL 8, and human beta-defensin-2 in NHEKs compared with poly (I:C) or IFN-gamma alone. These synergistic inductions were significantly inhibited by an endosomal acidification inhibitor, chloroquine, and by TLR3 siRNA. Co-stimulation with IFN gamma and poly (I:C) also significantly enhanced the anti-viral activity against herpes simplex virus type-1 in NHEKs compared with poly (I:C) or IFN-gamma alone. In addition to the in vitro findings, an immunohistochemical analysis revealed IFN-gamma-positive cells surrounding herpetic vesicles. These findings indicate that IFN-gamma might contribute to the innate immune response to cutaneous viral infections by enhancing TLR3 expression and function in keratinocytes. PMID- 25822581 TI - Transient global amnesia and broken heart syndrome: two faces of one pathology. AB - We present a case of a 57-year-old female patient with transient global amnesia, who later developed broken heart syndrome also known as takotsubo cardiomyopathy. The present case underlines that co-occurrence of both pathologies might still be an under-recognized clinical problem. PMID- 25822582 TI - Correction to Kyllingsbaek, Markussen, and Bundesen (2012). PMID- 25822583 TI - Versatile wedge-based system for the construction of unidirectional collagen scaffolds by directional freezing: practical and theoretical considerations. AB - Aligned unidirectional collagen scaffolds may aid regeneration of those tissues where alignment of cells and extracellular matrix is essential, as for instance in cartilage, nerve bundles, and skeletal muscle. Pores can be introduced by ice crystal formation followed by freeze-drying, the pore architecture reflecting the ice crystal morphology. In this study we developed a wedge-based system allowing the production of a wide range of collagen scaffolds with unidirectional pores by directional freezing. Insoluble type I collagen suspensions were frozen using a custom-made wedge system, facilitating the formation of a horizontal as well as a vertical temperature gradient and providing a controlled solidification area for ice dendrites. The system permitted the growth of aligned unidirectional ice crystals over a large distance (>2.5 cm), an insulator prolonging the freezing process and facilitating the construction of crack-free scaffolds. Unidirectional collagen scaffolds with tunable pore sizes and pore morphologies were constructed by varying freezing rates and suspension media. The versatility of the system was indicated by the construction of unidirectional scaffolds from albumin, poly(vinyl alcohol) (a synthetic polymer), and collagen-polymer blends producing hybrid scaffolds. Macroscopic observations, temperature measurements, and scanning electron microscopy indicated that directed horizontal ice dendrite formation, vertical ice crystal nucleation, and evolutionary selection were the basis of the aligned unidirectional ice crystal growth and, hence, the aligned unidirectional pore structure. In conclusion, a simple, highly adjustable freezing system has been developed allowing the construction of large (hybrid) bioscaffolds with tunable unidirectional pore architecture. PMID- 25822584 TI - [Panorama of dermatological practice]. PMID- 25822585 TI - [Music dermatology]. PMID- 25822586 TI - [Quality of life in dermatology. From measurement to practical implementation]. AB - Health-related quality of life has not only been established as an important patient-reported outcome measure in patient care but has been defined as an evaluation criterion for therapies in the German Code of Social Law as well as in the guidelines of the American Food and Drug Administration and of the European Medicines Agency (EMA). Quality of life can be measured in a standardised manner. Validated questionnaires are available for recording specific problems of patients with, for example, skin diseases. Measuring quality of life has not yet been implemented into daily dermatological routine, although (1) studies have confirmed that the measurement of quality of life offers major benefits for the treatment of skin diseases, and (2) first experiences in implementing quality of life measurement into practice have been positive. The further implementation of systemically measuring quality of life requires advancements in automated measurement and the assumption of cost by social health insurances. PMID- 25822587 TI - Comparative pharmacokinetics of oxytetracycline in blunt-snout bream (Megalobrama amblycephala) with single and multiple-dose oral administration. AB - Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 degrees C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration. PMID- 25822588 TI - Regulation of Bacterial Gene Expression by Protease-Alleviated Spatial Sequestration (PASS). AB - In natural microbial systems, conditional spatial sequestration of transcription factors enables cells to respond rapidly to changes in their environment or intracellular state by releasing presynthesized regulatory proteins. Although such a mechanism may be useful for engineering synthetic biology technologies ranging from cell-based biosensors to biosynthetic platforms, to date it remains unknown how or whether such conditional spatial sequestration may be engineered. In particular, based upon seemingly contradictory reports in the literature, it is not clear whether subcellular spatial localization of a transcription factor within the cytoplasm is sufficient to preclude regulation of cognate promoters on plasmid-borne or chromosomal loci. Here, we describe a modular, orthogonal platform for investigating and implementing this mechanism using protease alleviated spatial sequestration (PASS). In this system, expression of an exogenous protease mediates the proteolytic release of engineered transcriptional regulators from the inner face of the Escherichia coli cytoplasmic membrane. We demonstrate that PASS mediates robust, conditional regulation of either transcriptional repression, via tetR, or transcriptional activation, by the lambda phage CI protein. This work provides new insights into a biologically important facet of microbial gene expression and establishes a new strategy for engineering conditional transcriptional regulation for the microbial synthetic biology toolbox. PMID- 25822589 TI - Computational analysis of kilohertz frequency spinal cord stimulation for chronic pain management. AB - BACKGROUND: Kilohertz frequency spinal cord stimulation (KHFSCS) is an emerging therapy for treating refractory neuropathic pain. Although KHFSCS has the potential to improve the lives of patients experiencing debilitating pain, its mechanisms of action are unknown and thus it is difficult to optimize its development. Therefore, the goal of this study was to use a computer model to investigate the direct effects of KHFSCS on specific neural elements of the spinal cord. METHODS: This computer model consisted of two main components: (1) finite element models of the electric field generated by KHFSCS and (2) multicompartment cable models of axons in the spinal cord. Model analysis permitted systematic investigation into a number of variables (e.g., dorsal cerebrospinal fluid thickness, lead location, fiber collateralization, and fiber size) and their corresponding effects on excitation and conduction block thresholds during KHFSCS. RESULTS: The results of this study suggest that direct excitation of large-diameter dorsal column or dorsal root fibers require high stimulation amplitudes that are at the upper end or outside of the range used in clinical KHFSCS (i.e., 0.5 to 5 mA). Conduction block was only possible within the clinical range for a thin dorsal cerebrospinal fluid layer. CONCLUSIONS: These results suggest that clinical KHFSCS may not function through direct activation or conduction block of dorsal column or dorsal root fibers. Although these results should be validated with further studies, the authors propose that additional concepts and/or alternative hypotheses should be considered when examining the pain relief mechanisms of KHFSCS. PMID- 25822590 TI - An unknown enemy: Drugs sought against EV-68 as paralysis link is explored. PMID- 25822591 TI - Internal in vitro dosimetry for fish using hydroxyapatite-based EPR detectors. AB - A number of aquatic ecosystems were exposed to ionizing radiation as a result of the activities of the Mayak Production Association in the Southern Urals, former Soviet Union, in the 1950s. Currently, fishes inhabiting contaminated lakes are being actively studied. These investigations need dosimetric support. In the present paper the results of a pilot study for elaborating an EPR dosimeter which can be used for internal dosimetry in vitro are described. Biological hydroxyapatite is proposed here to be used as a detecting substance. More specifically, small hydroxyapatite grains are proposed for use as point detectors fixed in a solid matrix. After having been pelletized, the detectors were covered by Mylar and placed in the body of a fish to be stored in the fridge for several months. Application of the detectors for internal fish dosimetry demonstrated that the enamel sensitivity is sufficient for passive detection of ionizing radiation in fishes inhabiting contaminated lakes in the Southern Urals. PMID- 25822592 TI - Letter to the Editor concerning "A less invasive surgical approach in the lumbar lateral recess stenosis: direct approach to the medial wall of the pedicle" by A. Colak et al. (2008) Eur Spine J;17:1745-51. PMID- 25822593 TI - Answer to the Letter to the Editor of Hue Zhang concerning "A less invasive surgical approach in the lumbar lateral recess stenosis: direct approach to the medial wall of the pedicle" by A. Colak et al. (2008) Eur Spine J; 17:1745-1751. PMID- 25822594 TI - A mechanism for nano-titanium dioxide-induced cytotoxicity in HaCaT cells under UVA irradiation. AB - Nano-TiO2 has been reported to be an efficient photocatalyst, which is able to produce reactive oxygen species (ROS) under UVA irradiation. In this study, we investigated the effects of nano-TiO2 on the cytotoxicity, induction of apoptosis, and the putative pathways of its actions in HaCaT cells. We show that nano-TiO2 is a potent inducer of apoptosis and that it transduces the apoptotic signal via ROS generation, thereby inducing mitochondrial permeability transition (MPT) and activating Caspase-3 from HaCaT cells. ROS production, mitochondrial alteration, and subsequent apoptotic cell death in nano-TiO2-treated cells were blocked by the MPT pore-blocker cyclosporin A. Taken together, our data indicate that nano-TiO2 induces the ROS-mediated MPT and resultant Caspase-3 activation. PMID- 25822595 TI - A laser-engraved glass duplicating the structure, mechanics and performance of natural nacre. AB - Highly mineralized biological materials such as nacre (mother of pearl), tooth enamel or conch shell boast unique and attractive combinations of stiffness, strength and toughness. The structures of these biological materials and their associated mechanisms are now inspiring new types of advanced structural materials. However, despite significant efforts, no bottom up fabrication method could so far match biological materials in terms of microstructural organization and mechanical performance. Here we present a new 'top down' strategy to tackling this fabrication problem, which consists in carving weak interfaces within a brittle material using a laser engraving technique. We demonstrate the method by fabricating and testing borosilicate glasses containing nacre-like microstructures infiltrated with polyurethane. When deformed, these materials properly duplicate the mechanisms of natural nacre: combination of controlled sliding of the tablets, accompanied with geometric hardening, strain hardening and strain rate hardening. The nacre-like glass is composed of 93 volume % (vol%) glass, yet 700 times tougher and breaks at strains as high as 20%. PMID- 25822596 TI - [Molecular pathology of soft tissue tumors: Contribution to diagnosis and therapy prediction]. AB - Soft tissue tumors are often challenging for pathologists on the basis of morphology alone; therefore, tumor-specific chromosomal aberrations, such as translocations and fusions, amplifications or deletions can be diagnostically useful. Fluorescence in situ hybridization is widely used for the detection of most aberrations in routine diagnostics. Furthermore, reverse transcriptase PCR, sequencing and specific immunohistochemical assays are also applied. Next generation sequencing has already contributed to the identification of hitherto unknown aberrations. Molecular pathology is mainly used in sarcomas to discriminate between different tumor entities. In terms of personalized therapy and targeted treatment, molecular pathology can be utilized to detect predictive markers. PMID- 25822597 TI - Dephosphorization of High-Phosphorus Iron Ore Using Different Sources of Aspergillus niger Strains. AB - High-phosphorus iron ore is traditionally dephosphorized by chemical process with inorganic acids. However, this process is not recommended nowadays because of its high cost and consequent environmental pollution. With the current tendency for development of a low-cost and eco-friendly process, dephosphorization of high phosphorus iron ore through microbial process with three different sources of Aspergillus niger strains was studied in this study. Results show that the three strains of A. niger could grow well in the broth, and effectively remove phosphate from high-phosphorus iron ore during the experiments. Meanwhile, the total iron in the broth was also increased. Acidification of the broth seemed to be the major mechanism for the dephosphorization by these strains. High-pressure liquid chromatography analysis indicated that various organic acids were secreted in the broth, which caused a significant drop of the broth pH. Scanning electron microscopy of ore residues revealed that the high-phosphorus iron ore was obviously destroyed by the actions of these strains. Ore residues by energy dispersive X-ray microanalysis and Fourier transform infrared spectroscopy indicated that the phosphate was obviously removed from the high-phosphorus iron ore. The optimization of the dephosphorization by these strains was also investigated, and the maximum percentages of phosphate removal were recorded at temperature 27-30 degrees C, initial pH 5.0-6.5, particle size 0.07-0.1 mm, and pulp density of 2-3% (w/v), respectively. The fungus A. niger was found to have good potential for the dephosphorization of high-phosphorus iron ore, and this microbial process seems to be economic and effective in the future industrial application. PMID- 25822598 TI - The ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation) trial - a pragmatic multicentre randomised controlled trial evaluating the clinical effectiveness and cost-effectiveness of surgical compared with non-surgical treatment for proximal fracture of the humerus in adults. AB - BACKGROUND: Proximal humeral fractures account for 5-6% of all fractures in adults. There is considerable variation in whether or not surgery is used in the management of displaced fractures involving the surgical neck. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of surgical compared with non-surgical treatment of the majority of displaced fractures of the proximal humerus involving the surgical neck in adults. DESIGN: A pragmatic parallel-group multicentre randomised controlled trial with an economic evaluation. Follow-up was for 2 years. SETTING: Recruitment was undertaken in the orthopaedic departments of 33 acute NHS hospitals in the UK. Patient care pathways included outpatient and community-based rehabilitation. PARTICIPANTS: Adults (aged >= 16 years) presenting within 3 weeks of their injury with a displaced fracture of the proximal humerus involving the surgical neck. INTERVENTIONS: The choice of surgical intervention was left to the treating surgeons, who used techniques with which they were experienced. Non-surgical treatment was initial sling immobilisation followed by active rehabilitation. Provision of rehabilitation was comparable in both groups. MAIN OUTCOME MEASURES: The primary outcome was the Oxford Shoulder Score (OSS) assessed at 6, 12 and 24 months. Secondary outcomes were the 12-item Short Form health survey, surgical and other shoulder fracture-related complications, secondary surgery to the shoulder or increased/new shoulder-related therapy, medical complications during inpatient stay and mortality. European Quality of Life-5 Dimensions data and treatment costs were also collected. RESULTS: The mean age of the 250 trial participants was 66 years and 192 (77%) were female. Independent assessment using the Neer classification identified 18 one-part fractures, 128 two-part fractures and 104 three- or four-part fractures. OSS data were available for 215 participants at 2 years. We found no statistically or clinically significant differences in OSS scores between the two treatment groups (scale 0-48, with a higher score indicating a better outcome) over the 2-year period [difference of 0.75 points in favour of the surgery group, 95% confidence interval (CI) -1.33 to 2.84; p = 0.479; data from 114 surgery and 117 non-surgery participants] or at individual time points. We found no statistically significant differences between surgical and non-surgical group participants in SF-12 physical or mental component summary scores; surgical or shoulder fracture-related complications (30 vs. 23 respectively); those undergoing further shoulder-related therapy, either surgery (11 vs. 11 respectively) or other therapy (seven vs. four respectively); or mortality (nine vs. five respectively). The base-case economic analysis showed that, at 2 years, the cost of surgical intervention was, on average, L1780.73 more per patient (95% CI L1152.71 to L2408.75) than the cost of non-surgical intervention. It was also slightly less beneficial in terms of utilities, although this difference was not statistically significant. The net monetary benefit associated with surgery is negative. There was only a 5% probability of surgery achieving the criterion of costing < L20,000 to gain a quality-adjusted life-year, which was confirmed by extensive sensitivity analyses. CONCLUSIONS: Current surgical practice does not result in a better outcome for most patients with displaced fractures of the proximal humerus involving the surgical neck and is not cost-effective in the UK setting. Two areas for future work are the setting up of a national database of these fractures, including the collection of patient-reported outcomes, and research on the best ways of informing patients with these and other upper limb fractures about initial self-care. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50850043. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 24. See the NIHR Journals Library website for further project information. PMID- 25822602 TI - Overcoming the educational disadvantages of poor children: How much do teacher preparation, workload, and expectations matter. AB - This article reviews data on aspects of the learning environment most closely associated with successful development of early academic competence, compares children from low socioeconomic backgrounds to children with higher socioeconomic status (SES) on access to academically auspicious environments, and uses the findings to identify promising targets for social innovations aimed at improving the educational prospects of poor children. PMID- 25822599 TI - Pyrosequencing reveals a shift in symbiotic bacteria populations across life stages of Bactrocera dorsalis. AB - Bactrocera dorsalis is one of the most economically important fruit flies around the world. In this study, 454 pyrosequencing was used to identify the bacteria associated with different developmental stages of B. dorsalis. At >= 97% nucleotide similarity, total reads could be assigned to 172 Operational Taxonomic Units belonging to six phyla. Proteobacteria dominated in immature stages while Firmicutes dominated in adult stages. The most abundant families were Enterococcaceae and Comamondaceae. The genus Comamonas was most abundant in pupae whereas completely absent in adults. Some identified species had low sequence similarity to reported species indicating the possibility of novel taxa. However, a majority sequence reads were similar to sequences previously identified to be associated with Bactrocera correcta, suggesting a characteristic microbial fauna for this insect genus. The type and abundance of different bacterial groups varied across the life stages of B. dorsalis. Selection pressure exerted by the host insect as a result of its habitat and diet choices could be the reason for the observed shift in the bacteria groups. These findings increase our understanding of the intricate symbiotic relationships between bacteria and B. dorsalis and provide clues to develop potential biocontrol techniques against this fruit fly. PMID- 25822603 TI - Examining the role of methamphetamine in permanency: A competing risks analysis of reunification, guardianship, and adoption. AB - Parental methamphetamine use has drawn significant attention in recent years. Despite prior research that shows that parental substance abuse is a risk factor for lengthy foster care stay, little is known about the effect of specific types of substance use on permanency. This study sought to compare the impact of parental methamphetamine use to alcohol use, other drug use, and polysubstance use on the timing of 3 types of permanency: reunification, guardianship, and adoption. Using an entry cohort of 16,620 children who had entered foster care during a 5-year period, competing risks event history models were conducted for each permanency type. Findings showed that, after controlling for several case characteristics, parent illicit drug use significantly impacted the timing of the 3 types of permanency, but alcohol use did not. Methamphetamine, other drug, and polysubstance with methamphetamine use were associated with lower rates of reunification and higher rates of adoption. Guardianship was also predicted by other drug and polysubstance use without methamphetamine; however, methamphetamine use was not associated with guardianship. Notably, the methamphetamine groups comprised the youngest children and had the shortest median time to adoption. Results suggest that type of parental substance use is predictive of permanency exits and that parental illicit drug use may require tailored strategies for improving permanency outcomes. Further implications of the findings are discussed. PMID- 25822604 TI - How people evaluate others with social anxiety disorder: A comparison to depression and general mental illness stigma. AB - Despite the availability of effective interventions, most individuals with social anxiety disorder do not seek treatment. Given their fear of negative evaluation, socially anxious individuals might be especially susceptible to stigma concerns, a recognized barrier for mental health treatment. However, very little is known about the stigma specific to social anxiety disorder. In a design similar to Feldman and Crandall (2007), university undergraduate students read vignettes about target individuals with a generic mental illness label, major depressive disorder, and social anxiety disorder. Subjects rated each of 3 people in the vignettes on social distance and 17 dimensions including dangerousness, heritability and prevalence of the disorder, and gender ratio. Results indicated that being male and not having experience with mental health treatment was associated with somewhat greater preferred social distance. Multiple regression analyses revealed that being embarrassed by the disorder and dangerousness predicted social distance across all 3 vignettes. The vignette for social anxiety disorder had the most complex model and included work impairment, more common among women, and more avoidable. These results have implications for understanding the specific aspects of the stigma associated with social anxiety disorder. Public service messages to reduce stigma should focus on more accurate information about dangerousness and mental illness, given this is an established aspect of mental illness stigma. More nuanced messages about social anxiety might be best incorporated into the treatment referral process and as part of treatment. PMID- 25822605 TI - University students' identification of stigmatizing schizophrenia in Italian newspapers. AB - Stigma associated with mental disorders represents one main obstacle to receive appropriate care for people with mental disorders. Compared to adults, university students have higher levels of stigmatizing attitudes toward patients with schizophrenia. The primary aim of this case-control study was to assess university students' ability to identify stigma toward schizophrenia in Italian newspapers. Secondary aims were: a) to explore differences in stigmatizing attitudes among two different groups of university students (health professionals [HP] and nonhealth professionals [n-HP]) and b) to compare the attitudes of these two groups with those of a sample of expert psychiatrists. The electronic archives of two Italian newspapers were searched using the term "schizo" (as a word or part of it). One hundred seventy articles published between January and December 2011 were identified. Students from the HP group and expert psychiatrists had a higher ability to detect stigmatizing attitudes in newspapers. Students from the n-HP group had a higher concordance with the experts on the topics "characteristics of the article" and "services and rights." Our findings highlight the importance of targeting university students with correct and updated information about schizophrenia and its psychosocial consequences. PMID- 25822606 TI - Childhood victimization, attachment, psychological distress, and substance use among women on probation and parole. AB - The present analysis was guided by a gendered pathways-based theoretical model and examined relationships between childhood victimization and current attachment, psychological distress, and substance use among 406 women with histories of victimization who were on probation and parole in an urban Kentucky county. Structural equation modeling examined relationships among childhood victimization, attachment, psychological distress, and substance use. Additionally, we examined the mediational role that attachment plays in relationships between childhood victimization and both psychological distress and substance use. The data fit the models properly. Psychological distress was significantly predicted by childhood victimization, and adult attachment partially mediated this relationship. Childhood victimization did not significantly predict substance use; however, attachment did. The findings suggest that attachment may be an important factor to further understand and address in relation to psychological distress and substance use among women with histories of victimization who are involved in the criminal justice system. PMID- 25822607 TI - Normative identity construction among women diagnosed with a gambling disorder. AB - Women with a gambling problem bear a negative social stigma. Based on the theory of symbolic interactionism, this study examined the construction of social identities by 17 Israeli women diagnosed with a gambling disorder. Interpretive interactionist analysis revealed how they construct their identity through correspondence with patterns of behavior that are perceived as normative, and identified 3 major themes: "I'm not actually a gambler" (the presentation of a multidimensional identity comprising other identities besides that of a gambler); "Staying normative during gambling"; and "I have changed" (reformed gamblers' presentation of themselves as having changed for the better). The findings underscore the complex dialogue behind the identity construction put forward by women with a gambling problem, their yearning to be perceived by society as normative women and to fit in despite their stigmatized behavior, and the tension they feel in society's relationship toward them. The findings also suggest that practitioners who work with women gamblers may want to pay attention to the power relations shaping identity construction in an interview setting, and look more closely at the women's awareness of the stigma they bear and the complex processes that make up their multidimensional identity. PMID- 25822608 TI - Respecting our elders: Evaluation of an educational program for adolescent students to promote respect toward older adults. AB - The current project explored issues related to respect for older people, and then developed, implemented, and evaluated an educational intervention program for adolescents to raise understanding and improve attitudes toward older people. In Study 1, 46 focus groups were conducted, with participants (n = 211) drawn from older people, carers of older people, and adolescents to inform on issues related to the expression of respect to older people. The emergent themes were used to inform the design of the educational program delivered to adolescents and evaluated in Study 2. A total of 118 year-9 students were allocated to an intervention or control condition. The intervention group participated in 4 educational sessions focused on developing understanding of and respect for older adults, and promoting positive interactions with older people. Participants in both conditions completed measures of knowledge and attitudes to aging to determine whether the intervention had effected change at post-program and at 6 months follow-up. Analyses indicated significant improvements in knowledge, attitudes, and social skills related to older people in the intervention group compared to the control group. The findings from these studies provide a better understanding of what constitutes respect for older people, and a method for improving this in adolescents. PMID- 25822609 TI - Family functioning and posttraumatic growth among parents and youth following wildfire disasters. AB - A conceptual model was used to investigate how demographic characteristics, perceived fire stress, aspects of the recovery environment (life stressors since the disaster, social support), mental health, and coping influences parent and youth reports of family functioning and posttraumatic growth (PTG) following multiple wildfires. Participants included 50 parent-youth dyads (M = 14.5 years) who had been evacuated because of the fire, many of whom had homes that were damaged (60%) or destroyed (30%). For youth, younger age, being female, greater fire stress, more life stressors, and those using more positive reappraisal coping reported greater PTG. For parents, family type and perceived fire stress were positively related to PTG, and positive reappraisal approached significance. For family functioning, only the youth model was significant. Younger age and more life stressors were negatively related, and positive reappraisal coping was positively related, to family functioning. Overall, the results support the important role of positive reappraisal in postdisaster outcomes. PMID- 25822610 TI - Modified Regulatory Pathways to Approve Generic Drugs in the US and a Systematic Review of Their Outcomes. AB - BACKGROUND: Generic drugs are approved on the basis of pharmaceutical equivalence and bioequivalence. Some drug products have unique structural or functional attributes, necessitating modified approaches to bioequivalence determinations. OBJECTIVE: The aim of this systematic review was to identify studies that evaluated laboratory or clinical outcomes of six drugs approved via modified bioequivalence approaches. DATA SOURCES: We conducted a systematic review of articles published through February 2014 in MEDLINE, EMBASE, and International Pharmaceutical Abstracts related to six recent drugs subject to modified regulatory approaches: venlafaxine extended release tablet (Effexor XR), acarbose (Precose), enoxaparin (Lovenox), vancomycin capsules (Vancocin), sodium ferric gluconate (Ferrlecit), and calcitonin salmon nasal spray (Miacalcin NS). We included all empirical evaluations (whether in vivo or in vitro) and excluded case studies, qualitative analyses, and pharmacoeconomic evaluations. Studies were summarized and evaluated on their methodological quality and assessed for bias using the Cochrane Risk of Bias Assessment Tool. Articles were divided into studies of US FDA-approved generics and non-FDA-approved generics available in non-US locations. DATA EXTRACTION: We extracted drug(s) studied, study design, setting, sample size, population characteristics, study endpoints and results, and source of funding. DATA SYNTHESIS: After retrieving 1408 articles and searching through the full text of 106 articles, we found 26 articles that met our inclusion criteria-8 examining FDA-approved versions and 18 examining non-FDA approved versions. Among FDA-approved generics, five studies of enoxaparin showed minor variations in biologic activities of unclear clinical importance, and no publications involved acarbose, venlafaxine ER, or vancomycin capsules. Among non FDA-approved generics, nine studies of enoxaparin supported generic bioequivalence, despite three showing minor variations in drug activity. Four of six studies of venlafaxine ER supported generic bioequivalence, while two found a lack of bioequivalence with a Canadian generic version of the drug. Most studies were either highly susceptible to bias (12/26) or were not able to be assessed for bias (13/26), in part because eight studies were abstracts/posters without full reports. CONCLUSIONS: Pharmaceutical manufacturers sometimes raise scientific concerns related to potential generic versions of their drugs; however, in the six cases we reviewed, these companies did not follow up the pre approval concerns they raised with any methodologically rigorous post-approval testing using clinical endpoints. Despite their pre-approval controversy, experience with these generic drugs provides reassurance of their clinical interchangeability. Systematized post-approval study of certain generic drug bioequivalence determinations is needed. PMID- 25822611 TI - Human gastroenteropancreatic expression of melatonin and its receptors MT1 and MT2. AB - BACKGROUND AND AIM: The largest source of melatonin, according to animal studies, is the gastrointestinal (GI) tract but this is not yet thoroughly characterized in humans. This study aims to map the expression of melatonin and its two receptors in human GI tract and pancreas using microarray analysis and immunohistochemistry. METHOD: Gene expression data from normal intestine and pancreas and inflamed colon tissue due to ulcerative colitis were analyzed for expression of enzymes relevant for serotonin and melatonin production and their receptors. Sections from paraffin-embedded normal tissue from 42 individuals, representing the different parts of the GI tract (n=39) and pancreas (n=3) were studied with immunohistochemistry using antibodies with specificity for melatonin, MT1 and MT2 receptors and serotonin. RESULTS: Enzymes needed for production of melatonin are expressed in both GI tract and pancreas tissue. Strong melatonin immunoreactivity (IR) was seen in enterochromaffin (EC) cells partially co-localized with serotonin IR. Melatonin IR was also seen in pancreas islets. MT1 and MT2 IR were both found in the intestinal epithelium, in the submucosal and myenteric plexus, and in vessels in the GI tract as well as in pancreatic islets. MT1 and MT2 IR was strongest in the epithelium of the large intestine. In the other cell types, both MT2 gene expression and IR were generally elevated compared to MT1. Strong MT2, IR was noted in EC cells but not MT1 IR. Changes in gene expression that may result in reduced levels of melatonin were seen in relation to inflammation. CONCLUSION: Widespread gastroenteropancreatic expression of melatonin and its receptors in the GI tract and pancreas is in agreement with the multiple roles ascribed to melatonin, which include regulation of gastrointestinal motility, epithelial permeability as well as enteropancreatic cross-talk with plausible impact on metabolic control. PMID- 25822613 TI - Delocalization of charge and electron density in the humulyl cation-implications for terpene biosynthesis. AB - The stabilizing features of a macrocyclic sesquiterpene-derived cation were explored using quantum mechanical calculations. The monocyclic humulyl cation, the product of 11,1-cyclization of farnesyl diphosphate, is the product of the first committed step in the enzymatic synthesis of a range of structurally diverse sesquiterpenes, including humulene (monocyclic); caryophyllene (bicyclic); and protoilludene, pentalenene, and isocomene (tricyclic). These natural products are formed via carbocation cascades that are directed in part by the conformation of the humulyl cation. Understanding the mechanistic details of product formation requires an understanding of the conformational preferences of this fundamental intermediate. Replacing the carbocation with borane (preserving pi-accepting capabilities), ammonium (preserving positive charge), and methylene (preserving neither pi-accepting capabilities nor charge) provides a systematic method to distinguish electrostatic and orbital effects on structure and internal stabilization. Several modes of internal stabilization-hyperconjugation, transannular pi(alkene)...C(+) and transannular C-H...C(+) interactions-were uncovered, confirming and extending previous studies on this and similar systems. PMID- 25822612 TI - Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer: a retrospective review. AB - BACKGROUND: Docetaxel, a lipophilic drug, is indicated for castration-resistant metastatic prostate cancer. Most men with such disease would have had androgen deprivation therapy, which decreases muscle and increases body fat. Obesity and body composition changes may influence the outcomes of docetaxel therapy. METHODS: We conducted a retrospective review of 333 patients with metastatic prostate cancer treated with docetaxel at a comprehensive cancer center between October 7, 2004 and December 31, 2012. Body composition parameters were measured based on the areas of muscle and adipose tissues in the visceral and subcutaneous compartments on CT images at L3-4 levels. Dose calculations, toxicity and adverse reaction profiles, and overall survival were analyzed. RESULTS: Obese patients were younger at the diagnosis of prostate cancer and had a shorter duration from diagnosis to docetaxel therapy. Analysis of body composition found that a high visceral fat-to-subcutaneous fat area ratio (VSR) was associated with poor prognosis but a high visceral fat-to-muscle area ratio (VMR) and high body mass index were associated with increased duration from starting docetaxel to death, allowing such men to catch up with patients with normal body mass index in overall survival from cancer diagnosis to death. Cox proportional hazard regression showed that age >=65 years, high VSR, abnormal serum alkaline phosphatase, and >10% reduction of initial dosage were significant predictors of shorter time between starting docetaxel and death, and that high VMR, obesity, and weekly regimens were significant predictors of longer survival after docetaxel. CONCLUSION: Obese and overweight patients may benefit more from weekly docetaxel regimens using the reference dosage of 35 mg/m2 without empirical dosage reduction. PMID- 25822614 TI - Antipyretic therapy in critically ill patients with sepsis: an interaction with body temperature. AB - BACKGROUND AND OBJECTIVE: The effect of antipyretic therapy on mortality in patients with sepsis remains undetermined. The present study aimed to investigate the role of antipyretic therapy in ICU patients with sepsis by using a large clinical database. METHODS: The multiparameter intelligent monitoring in intensive care II (MIMIC- II) database was employed for the study. Adult patients with sepsis were included for analysis. Antipyretic therapy included antipyretic medication and external cooling. Multivariable model with interaction terms were employed to explore the association of antipyretic therapy and mortality risk. MAIN RESULTS: A total of 15,268 patients fulfilled inclusion criteria and were included in the study. In multivariable model by treating temperature as a continuous variable, there was significant interaction between antipyretic therapy and the maximum temperature (Tmax). While antipyretic therapy had no significant effect on mortality in low temperature quintiles, antipyretic therapy was associated with increased risk of death in the quintile with body temperature >39 degrees C (OR: 1.29, 95% CI: 1.04-1.61). CONCLUSION: Our study shows that there is no beneficial effect on reducing mortality risk with the use of antipyretic therapy in ICU patients with sepsis. External cooling may even be harmful in patients with sepsis. PMID- 25822616 TI - Should simultaneous ureteral reimplantation be performed during sigmoid bladder augmentation to reduce vesicoureteral reflux in neurogenic bladder cases? AB - PURPOSE: To assess the necessity of performing simultaneous collateral reimplantation during sigmoid bladder augmentation (SBA) to reduce vesicoureteral reflux (VUR) in low-compliance neuropathic bladder with associated VUR. METHODS: We retrospectively identified 31 patients who underwent SBA alone or with simultaneous ureteral reimplantation at our hospital. The video urodynamics data, VUR status, renal function, and clinical symptoms were studied during follow-up. RESULTS: The mean follow-up time was 57 months (range 12-117). All patients displayed significantly increased safe cystometric capacity (P < 0.001) and bladder compliance (P < 0.001) and decreased creatinine (P < 0.01) and urea nitrogen (P < 0.05) compared with preoperative levels. High-grade VUR was resolved in only 7 of 15 patients (47%) in Group A (simultaneous ureteral reimplantation), whereas low-grade VUR was resolved in 13 of 16 patients (81%) in Group B (SBA alone). The other 11 patients still displaying VUR after SBA had larger safe bladder volumes due to augmentation. The patients' improving renal function benefited most from the enlarged bladder and partly from increased antireflux resistance of vesico-ureter anastomosis. Twelve (38.7%) had recurrent febrile urinary tract infection after SBA, and one (3.2%) suffered from vesico ureter anastomosis contracture after ureteral reimplantation. CONCLUSIONS: A preoperative intravesical VUR pressure of 20 cmH2O is not an effective cutoff point for whether ureteral reimplantation should be simultaneously performed during SBA. Augmentation appears to be more important than reimplantation for protecting kidney from damage due to febrile urinary tract infection after SBA. Simultaneous reimplantation may be not necessary during SBA in neurogenic bladder. PMID- 25822615 TI - Effects of cyclic tensile strain on chondrocyte metabolism: a systematic review. AB - Chondrocytes reorganize the extracellular matrix of articular cartilage in response to externally applied loads. Thereby, different loading characteristics lead to different biological responses. Despite of active research in this area, it is still unclear which parts of the extracellular matrix adapt in what ways, and how specific loading characteristics affect matrix changes. This review focuses on the influence of cyclic tensile strain on chondrocyte metabolism in vitro. It also aimed to identify anabolic or catabolic chondrocyte responses to different loading protocols. The key findings show that loading cells up to 3% strain, 0.17 Hz, and 2 h, resulted in weak or no biological responses. Loading between 3-10% strain, 0.17-0.5 Hz, and 2-12 h led to anabolic responses; and above 10% strain, 0.5 Hz, and 12 h catabolic events predominated. However, this review also discusses that various other factors are involved in the remodeling of the extracellular matrix in response to loading, and that parameters like an inflammatory environment might influence the biological response. PMID- 25822618 TI - Correction: Ewing sarcoma Ewsa protein regulates chondrogenesis of Meckel's cartilage through modulation of Sox9 in zebrafish. PMID- 25822617 TI - Statistical detection of EEG synchrony using empirical bayesian inference. AB - There is growing interest in understanding how the brain utilizes synchronized oscillatory activity to integrate information across functionally connected regions. Computing phase-locking values (PLV) between EEG signals is a popular method for quantifying such synchronizations and elucidating their role in cognitive tasks. However, high-dimensionality in PLV data incurs a serious multiple testing problem. Standard multiple testing methods in neuroimaging research (e.g., false discovery rate, FDR) suffer severe loss of power, because they fail to exploit complex dependence structure between hypotheses that vary in spectral, temporal and spatial dimension. Previously, we showed that a hierarchical FDR and optimal discovery procedures could be effectively applied for PLV analysis to provide better power than FDR. In this article, we revisit the multiple comparison problem from a new Empirical Bayes perspective and propose the application of the local FDR method (locFDR; Efron, 2001) for PLV synchrony analysis to compute FDR as a posterior probability that an observed statistic belongs to a null hypothesis. We demonstrate the application of Efron's Empirical Bayes approach for PLV synchrony analysis for the first time. We use simulations to validate the specificity and sensitivity of locFDR and a real EEG dataset from a visual search study for experimental validation. We also compare locFDR with hierarchical FDR and optimal discovery procedures in both simulation and experimental analyses. Our simulation results showed that the locFDR can effectively control false positives without compromising on the power of PLV synchrony inference. Our results from the application locFDR on experiment data detected more significant discoveries than our previously proposed methods whereas the standard FDR method failed to detect any significant discoveries. PMID- 25822619 TI - Assessing human diet and movement in the Tongan maritime chiefdom using isotopic analyses. AB - The rise of stratified societies fundamentally influences the interactions between status, movement, and food. Using isotopic analyses, we assess differences in diet and mobility of individuals excavated from two burial mounds located at the 'Atele burial site on Tongatapu, the main island of the Kingdom of Tonga (c. 500 - 150 BP). The first burial mound (To-At-1) was classified by some archaeologists as a commoner's mound while the second burial mound (To-At-2) was possibly used for interment of the chiefly class. In this study, stable isotope analyses of diet (delta13C, delta15N, and delta34S; n = 41) are used to asses paleodiet and 87Sr/86Sr ratios (n = 30) are analyzed to investigate individual mobility to test whether sex and social status affected these aspects of life. Our results show significant differences in diet between burial mounds and sexes. Those interred in To-At-2 displayed lower delta13C values, indicating they ate relatively more terrestrial plants (likely starchy vegetable staples) compared with To-At-1 individuals. Females displayed significantly lower delta15N values compared with males within the entire assemblage. No differences in delta34S values were observed between sexes or burial mound but it is possible that sea spray or volcanism may have affected these values. One individual displayed the strontium isotopic composition representative of a nonlocal immigrant (outside 2SD of the mean). This suggests the hegemonic control over interisland travel, may have prevented long-term access to the island by non-Tongans exemplifying the political and spiritual importance of the island of Tongatapu in the maritime chiefdom. PMID- 25822620 TI - Correction: Effects of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma in plasminogen activator inhibitor-1 deficient and wild-type mice. AB - [This corrects the article DOI: 10.1371/journal.pone.0110869.]. PMID- 25822621 TI - Genetic structure of capelin (Mallotus villosus) in the northwest Atlantic Ocean. AB - Capelin (Mallotus villosus) is a commercially exploited, key forage-fish species found in the boreal waters of the North Pacific and North Atlantic Oceans. We examined the population structure of capelin throughout their range in the Canadian northwest Atlantic Ocean using genetic-based methods. Capelin collected at ten beach and five demersal spawning locations over the period 2002 through 2008 (N = 3,433 fish) were genotyped using six polymorphic microsatellite loci. Temporally distinct samples were identified at three beach spawning locations: Chance Cove, Little Lawn and Straitsview, Newfoundland. Four capelin stocks are assumed for fisheries management in the northwest Atlantic Ocean based on meristics, morphometrics, tag returns, and seasonal distribution patterns. Our results suggested groupings that were somewhat different than the assumed structure, and indicate at least seven genetically defined populations arising from two ancestral populations. The spatial mosaic of capelin from each of the two basal cluster groups explains much of the observed geographic variability amongst neighbouring samples. The genetic-defined populations were resolved at Jost's Dest >= 0.01 and were composed of fish collected 1) in the Gulf of St. Lawrence, 2) along the south and east coasts of Newfoundland, 3) along coastal northern Newfoundland and southern Labrador, 4) along coastal northern Labrador, 5) near the Saguenay River, and at two nearshore demersal spawning sites, 6) one at Grebes Nest off Bellevue Beach on the east coast of Newfoundland, and 7) one off the coast of Labrador at Domino Run. Moreover, the offshore demersal spawners on the Scotian Shelf and Southeast Shoal appeared to be related to the inshore demersal spawners at Grebes Nest and in Domino Run and to beach spawners from the Gulf of St. Lawrence. PMID- 25822622 TI - The effect of exon 7 deletion during the evolution of TRIMCyp fusion proteins on viral restriction, cytoplasmic body formation and multimerization. AB - TRIMCyp is a fusion protein consisting of the TRIM5 gene product and retrotransposed Cyclophilin A (CypA). Two primate TRIMCyp fusion proteins with varying anti-HIV-1 activities independently evolved in owl monkeys and Old World monkeys. In addition, Old World monkey TRIMCyps lack exon7, which encodes amino acids in the Linker2 region. Previous studies on TRIM5alpha indicated that this region affects anti-retroviral activity, cytoplasmic body formation, and multimerization. The effects of exon7 deletion on the functions of the TRIMCyp are unclear. In this study, we found that the cytoplasmic bodies and multimers of owl monkey TRIMCyp (omTRIMCyp) are different from those of northern pig-tailed macaque TRIMCyp (npmTRIMCyp). In addition, we demonstrated that exon7 deletion affected cytoplasmic body formation and multimerization. Moreover, we unexpectedly found two chimeric proteins of omTRIMCyp and npmTRIMCyp that failed to block HIV-1 replication, despite the presence of CypA in omTRIMCyp. Further studies indicated that the cytoplasmic bodies and spontaneous multimerization were not responsible for TRIMCyp anti-HIV-1 activity. Moreover, potent viral restriction is associated with higher amounts of monomeric TRIMCyp when the CypA domain is able to recognize and bind to the HIV-1 capsid. Our results suggested that the deletion of exon7 during the evolution of TRIMCyp affected its function. PMID- 25822623 TI - DUPA conjugation of a cytotoxic indenoisoquinoline topoisomerase I inhibitor for selective prostate cancer cell targeting. AB - Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3 dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice. PMID- 25822624 TI - Effect of endobronchial valve therapy on pulmonary perfusion and ventilation distribution. AB - INTRODUCTION: Endoscopic lung volume reduction (ELVR) is an emerging therapy for emphysematous COPD. However, any resulting changes in lung perfusion and ventilation remain undetermined. Here, we report ELVR-mediated adaptations in lung perfusion and ventilation, as investigated by means of pulmonary scintigraphy. METHODS: In this observational study, we enrolled 26 patients (64.9 +/- 9.4 yrs, 57.7% male) with COPD heterogeneous emphysema undergoing ELVR with endobronchial valves (Zephyr, Pulmonx, Inc.). Mean baseline FEV1 and RV were 32.9% and 253.8% predicted, respectively. Lung scintigraphy was conducted prior to ELVR and eight weeks thereafter. Analyses of perfusion and ventilation shifts were performed and complemented by correlation analyses between paired zones. RESULTS: After ELVR, target zone perfusion showed a mean relative reduction of 43.32% (p<0.001), which was associated with a significant decrease in target zone ventilation (p<0.001). Perfusion of the contralateral untreated zone and of the contralateral total lung exhibited significant increases post-ELVR (p = 0.002 and p = 0.005, respectively); both correlated significantly with the corresponding target zone perfusion adaptations. Likewise, changes in target zone ventilation correlated significantly with ventilatory changes in the contralateral untreated zone and the total contralateral lung (Pearson's r: -0.42, p = 0.04 and Pearson's r: -0.42, p = 0.03, respectively). These effects were observed in case of clinical responsiveness to ELVR, as assessed by changes in the six-minute walk test distance. DISCUSSION: ELVR induces a relevant decrease in perfusion and ventilation of the treated zone with compensatory perfusional and ventilatory redistribution to the contralateral lung, primarily to the non-concordant, contralateral zone. PMID- 25822625 TI - Is radon emission in caves causing deletions in satellite DNA sequences of cave dwelling crickets? AB - The most stable isotope of radon, 222Rn, represents the major source of natural radioactivity in confined environments such as mines, caves and houses. In this study, we explored the possible radon-related effects on the genome of Dolichopoda cave crickets (Orthoptera, Rhaphidophoridae) sampled in caves with different concentrations of radon. We analyzed specimens from ten populations belonging to two genetically closely related species, D. geniculata and D. laetitiae, and explored the possible association between the radioactivity dose and the level of genetic polymorphism in a specific family of satellite DNA (pDo500 satDNA). Radon concentration in the analyzed caves ranged from 221 to 26,000 Bq/m3. Specimens coming from caves with the highest radon concentration showed also the highest variability estimates in both species, and the increased sequence heterogeneity at pDo500 satDNA level can be explained as an effect of the mutation pressure induced by radon in cave. We discovered a specific category of nuclear DNA, the highly repetitive satellite DNA, where the effects of the exposure at high levels of radon-related ionizing radiation are detectable, suggesting that the satDNA sequences might be a valuable tool to disclose harmful effects also in other organisms exposed to high levels of radon concentration. PMID- 25822626 TI - Carbapenem-resistant Acinetobacter baumannii from Serbia: revision of CarO classification. AB - Carbapenem-resistant A. baumannii present a significant therapeutic challenge for the treatment of nosocomial infections in many European countries. Although it is known that the gradient of A. baumannii prevalence increases from northern to southern Europe, this study provides the first data from Serbia. Twenty-eight carbapenem-resistant A. baumannii clinical isolates were collected at a Serbian pediatric hospital during a 2-year period. The majority of isolates (67.68%) belonged to the sequence type Group 1, European clonal complex II. All isolates harbored intrinsic OXA-51 and AmpC cephalosporinase. OXA-23 was detected in 16 isolates (57.14%), OXA-24 in 23 isolates (82.14%) and OXA-58 in 11 isolates (39.29%). Six of the isolates (21.43%) harbored all of the analyzed oxacillinases, except OXA-143 and OXA-235 that were not detected in this study. Production of oxacillinases was detected in different pulsotypes indicating the presence of horizontal gene transfer. NDM-1, VIM and IMP were not detected in analyzed clinical A. baumannii isolates. ISAba1 insertion sequence was present upstream of OXA-51 in one isolate, upstream of AmpC in 13 isolates and upstream of OXA-23 in 10 isolates. In silico analysis of carO sequences from analyzed A. baumannii isolates revealed the existence of two out of six highly polymorphic CarO variants. The phylogenetic analysis of CarO protein among Acinetobacter species revised the previous classification CarO variants into three groups based on strong bootstraps scores in the tree analysis. Group I comprises four variants (I-IV) while Groups II and III contain only one variant each. One half of the Serbian clinical isolates belong to Group I variant I, while the other half belongs to Group I variant III. PMID- 25822628 TI - Bifunctional reactivity of amidoximes observed upon nucleophilic addition to metal-activated nitriles. AB - Treatment of the aromatic nitrile complexes trans-[PtCl2(RC6H4CN)2] (R = p-CF3 NC1, H NC2, o-Cl NC3) with the aryl amidoximes p-R'C6H4C(NH2)=NOH (R' = Me AO1, H AO2, Br AO3, CF3 AO4, NO2 AO5) in all combinations, followed by addition of 1 equiv of AgOTf and then 5 equiv of Et3N, leads to the chelates [PtCl{HN=C(RC6H4)ON=C(C6H4R'-p)NC(RC6H4)?NH}] (1-15; 15 examples; yields 71-88% after column chromatography) derived from the platinum(II)-mediated coupling between metal-activated nitriles and amidoximes. The mechanism of this reaction was studied experimentally by trapping and identification of the reaction intermediates, and it was also investigated theoretically at the DFT level of theory. The combined experimental and theoretical results indicate that the coupling with the nitrile ligands involves both the HON and monodeprotonated NH2 groups of the amidoximes, whereas in the absence of the base, the NH2 functionality is inactive toward the coupling. The observed reaction represents the first example of bifunctional nucleophilic behavior of amidoximes. The complexes 1-16 were characterized by elemental analyses (C, H, N), high resolution ESI(+)-MS, FTIR, and (1)H NMR techniques, whereas unstable 17 was characterized by HRESI(+)-MS and FTIR. In addition, 8.C4H8O2, 12, and 16.CHCl3 were studied by single-crystal X-ray diffraction. PMID- 25822627 TI - Diagnostic performance of echocardiography for the detection of acute cardiac allograft rejection: a systematic review and meta-analysis. AB - OBJECTIVE: Many studies have addressed the diagnostic performance of echocardiography to evaluate acute cardiac allograft rejection compared with endomyocardial biopsy. But the existence of heterogeneity limited its clinical application. Thus, we conducted a comprehensive, systematic literature review and meta-analysis for the purpose. METHODS: Studies prior to September 1, 2014 identified by Medline/PubMed, EMBASE and Cochrance were examined by two independent reviews. We conducted meta-analysis by using Meta-DiSc 1.4 software. An assessment tool of QUADAS-2 was applied to evaluate the risk of bias and applicability of the studies. RESULTS: Thirty studies met the inclusion criteria of meta-analysis. The four parameters of pressure half time, isovolumic relaxation time, index of myocardial performance and late diastolic mitral annular motion velocity were included in the meta-analysis, with a pooled diagnostic odds ratio of 10.43, 6.89, 15.95 and 5.68 respectively, and the area under the summary receiver operating characteristic curves value of 0.829, 0.599, 0.871 and 0.685 respectively. CONCLUSION: The meta-analysis and systematic review demonstrate that no single parameter of echocardiography showed a reliable diagnostic performance for acute cardiac allograft rejection. A result of echocardiography for ACAR should be comprehensively considered by physicians in the context of clinical presentations and imaging feature. PMID- 25822629 TI - Probing the interactions of intrinsically disordered proteins using nanoparticle tags. AB - The structural plasticity of intrinsically disordered proteins serves as a rich area for scientific inquiry. Such proteins lack a fix three-dimensional structure but can interact with multiple partners through numerous weak bonds. Nevertheless, this intrinsic plasticity possesses a challenging hurdle in their characterization. We underpin the intermolecular interactions between intrinsically disordered neurofilaments in various hydrated conditions, using grafted gold nanoparticle (NP) tags. Beyond its biological significance, this approach can be applied to modify the surface interaction of NPs for the creation of future tunable "smart" hybrid biomaterials. PMID- 25822630 TI - DJ-1 knockout augments disease severity and shortens survival in a mouse model of ALS. AB - Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson's disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN 1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS. PMID- 25822631 TI - Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults. AB - IMPORTANCE: Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. OBJECTIVES: To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (>=80 years of age), and examine the relationship between pulse pressure and progression to dementia. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and beta-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia. MAIN OUTCOMES AND MEASURES: Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure * age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use. RESULTS: Individuals with a P tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and beta-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for beta-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04). CONCLUSIONS AND RELEVANCE: Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants. PMID- 25822632 TI - Hydrogen sulfide promotes adipogenesis in 3T3L1 cells. AB - The effect of hydrogen sulfide (H2S) on differentiation of 3T3L1-derived adipocytes was examined. Endogenous H2S was increased after 3T3L1 differentiation. The expression of the H2S-synthesising enzymes, cystathionine gamma-lyase (CSE), cystathionine beta-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), was increased in a time-dependent manner during 3T3L1 differentiation. Expression of genes associated with adipogenesis related genes including fatty acid binding protein 4 (FABP4/aP2), a key regulator of this process, was increased by GYY4137 (a slow-releasing H2S donor compound) and sodium hydrosulfide (NaHS, a classical H2S donor) but not by ZYJ1122 or time expired NaHS. Furthermore expression of these genes were reduced by aminooxyacetic acid (AOAA, CBS inhibitor), DL-propargylglycine (PAG, CSE inhibitor) as well as by CSE small interference RNA (siCSE) and siCBS. The size and number of lipid droplets in mature adipocytes was significantly increased by both GYY4137 and NaHS, which also impaired the ability of CL316,243 (beta3 agonist) to promote lipolysis in these cells. In contrast, AOAA and PAG had the opposite effect. Taken together, we show that the H2S-synthesising enzymes CBS, CSE and 3-MST are endogenously expressed during adipogenesis and that both endogenous and exogenous H2S modulate adipogenesis and adipocyte maturation. PMID- 25822633 TI - Corrugated paraffin nanocomposite films as large stroke thermal actuators and self-activating thermal interfaces. AB - High performance active materials are of rapidly growing interest for applications including soft robotics, microfluidic systems, and morphing composites. In particular, paraffin wax has been used to actuate miniature pumps, solenoid valves, and composite fibers, yet its deployment is typically limited by the need for external volume constraint. We demonstrate that compact, high performance paraffin actuators can be made by confining paraffin within vertically aligned carbon nanotube (CNT) films. This large-stroke vertical actuation is enabled by strong capillary interaction between paraffin and CNTs and by engineering the CNT morphology by mechanical compression before capillary driven infiltration of the molten paraffin. The maximum actuation strain of the corrugated CNT-paraffin films (~0.02-0.2) is comparable to natural muscle, yet the maximum stress is limited to ~10 kPa by collapse of the CNT network. We also show how a CNT-paraffin film can serve as a self-activating thermal interface that closes a gap when it is heated. These new CNT-paraffin film actuators could be produced by large-area CNT growth, infiltration, and lamination methods, and are attractive for use in miniature systems due to their self-contained design. PMID- 25822634 TI - The development of a novel Mycobacterium-Escherichia coli shuttle vector system using pMyong2, a linear plasmid from Mycobacterium yongonense DSM 45126T. AB - The Mycobacterium-Escherichia coli shuttle vector system, equipped with the pAL5000 replicon, is widely used for heterologous gene expression and gene delivery in mycobacteria. Despite its extensive use, this system has certain limitations, which has led to the development of alternative mycobacterial vector systems. The present study describes the molecular structure and expression profiles of a novel 18-kb linear plasmid, pMyong2, from Mycobacterium yongonense. Sixteen open reading frames and a putative origin of replication were identified, and the compatibility of the pMyong2 and pAL5000 vector systems was demonstrated. In recombinant Mycobacterium smegmatis (rSmeg), the pMyong2 vector system showed a copy number that was approximately 37 times greater than that of pAL5000. Furthermore, pMyong2 increased the mRNA and protein expression of the human macrophage migration inhibitory factor (hMIF) over pAL5000 levels by approximately 10-fold and 50-fold, respectively, demonstrating the potential utility of the pMyong2 vector system in heterologous gene expression in mycobacteria. Successful delivery of the EGFP gene into mammalian cells via rSmeg carrying the pMyong2 vector system was also observed, demonstrating the feasibility of this system for DNA delivery. In conclusion, the pMyong2 vector system could be effectively used not only for the in vivo delivery of recombinant protein and DNA but also for mycobacterial genetic studies as an alternative or a complement to the pAL5000 vector system. PMID- 25822636 TI - Clinical management of acute orofacial infections. AB - Management of acute dental infections requires an understanding of microbiology, anatomy, pharmacology, wound healing, and oral surgery. Recognizing early signs of inflammation and differentiating them from characteristics of an infection facilitates timely intervention and avoids further complications. This article addresses various aspects of the diagnosis and treatment of acute oral infections. Suggestions are made to help differentiate between swelling associated with an infection and edema related to inflammation of nonpathogenic origin. In addition, discussion focuses on how to distinguish between an abscess and cellulitis, when to culture, and which antibiotics to select to resolve an infection. Protocols for managing an infection with and without fluctuance are reviewed. Finally, the consequences of spreading cellulitis are discussed, and signs indicating the need for referral of a patient are delineated. PMID- 25822637 TI - Use of opioid pain relievers following extraction of third molars. AB - Following extraction of third molars, it is common practice for oral and maxillofacial surgeons to provide a prescription for an opioid-containing analgesic such as hydrocodone with acetaminophen. Because the instructions for use most often indicate that these analgesics are to be taken "as needed for pain," it is unknown how many of the prescribed postoperative analgesic tablets are needed and actually taken. Therefore, an assessment of patient pain experiences and actual opioid analgesic usage was carried out using structured telephone interviews of patients performed 1 and 7 days following their thirdmolar extraction surgery. Forty-eight adolescents and young adults, ages 15 to 30 years, participated in this assessment. A review of the surgeon's notes indicated that the median number of prescribed opioid-containing analgesics (ie, Vicodin(r), Norco(r), Lorcet(r), Percocet(r)) was 20 tablets (range 10 to 40). The median consumption during the first 24 hours was reported to be three tablets (range 0 to 10), and the total consumption for all 7 days was eight tablets (range 0 to 34). Four patients reported nausea or vomiting in the first 24 hours, and six patients reported nausea or vomiting during the following 6 days of recovery. The initial prescriptions provided adequate relief for 45 of the 48 patients. Higher consumption of opioid pain relievers (OPRs) was associated with a longer duration of surgery and the occurrence of postoperative infections. PMID- 25822635 TI - Chemical and thermal unfolding of a global staphylococcal virulence regulator with a flexible C-terminal end. AB - SarA, a Staphylococcus aureus-specific dimeric protein, modulates the expression of numerous proteins including various virulence factors. Interestingly, S. aureus synthesizes multiple SarA paralogs seemingly for optimizing the expression of its virulence factors. To understand the domain structure/flexibility and the folding/unfolding mechanism of the SarA protein family, we have studied a recombinant SarA (designated rSarA) using various in vitro probes. Limited proteolysis of rSarA and the subsequent analysis of the resulting protein fragments suggested it to be a single-domain protein with a long, flexible C terminal end. rSarA was unfolded by different mechanisms in the presence of different chemical and physical denaturants. While urea-induced unfolding of rSarA occurred successively via the formation of a dimeric and a monomeric intermediate, GdnCl-induced unfolding of this protein proceeded through the production of two dimeric intermediates. The surface hydrophobicity and the structures of the intermediates were not identical and also differed significantly from those of native rSarA. Of the intermediates, the GdnCl generated intermediates not only possessed a molten globule-like structure but also exhibited resistance to dissociation during their unfolding. Compared to the native rSarA, the intermediate that was originated at lower GdnCl concentration carried a compact shape, whereas, other intermediates owned a swelled shape. The chemical-induced unfolding, unlike thermal unfolding of rSarA, was completely reversible in nature. PMID- 25822638 TI - Guided full-arch immediate-function treatment modality for the edentulous and terminal dentition patient. AB - This article reviews the rationale, techniques, and advantages of a guided full arch immediatefunction implant treatment modality that includes placement of a prefabricated, bar-supported, monolithic polymethyl methacrylate acrylic (PMMA) prosthesis for edentulous and terminal dentition patients. A case presentation depicting the protocol shows it to be an effective and predictable approach to providing fullarch immediate fixed teeth, particularly when compared to conventional denture conversion techniques. PMID- 25822639 TI - Post-traumatic treatment of maxillary incisors by immediate dentoalveolar restoration with long-term follow-up. AB - Replacing both missing maxillary anterior teeth is particularly challenging, especially in compromised sockets. This case report describes the management of an 18-year-old female patient, who suffered avulsion of both maxillary central incisors at 7 years of age. This multidisciplinary implant technique, called Immediate Dentoalveolar Restoration (IDR), included extraction of the injured teeth and a single procedure for immediate implant placement and restoration of the compromised sockets after root fracture and periapical lesion development were detected during orthodontic treatment. Successful esthetic and functional outcomes and reestablishment of the alveolar process after bone reconstruction were observed during the 3-year follow-up period. The predictable esthetic outcomes and soft- and hard-tissue stability that can be achieved following IDR are demonstrated. PMID- 25822640 TI - Using functional analysis to determine if esthetically driven treatment requires comprehensive care for long-term success. AB - This article reviews the case of a male patient with esthetic concerns about a large diastema between teeth Nos. 8 and 9. Through functional analysis, the clinician determined that the patient had a mild temporomandibular disorder, as well as a constriction in his anterior envelope of function. These issues will affect the prognosis of treatment if only orthodontics is used to close the diastema. The clinician determined that implementing a systematic treatment planning approach was critical in achieving a successful outcome, which was accomplished with a combination of orthodontics, occlusal deprogramming, and complex prosthodontics restorations. PMID- 25822641 TI - A two-dimensional gauge and protocol for fitting oral appliances used in treating sleep breathing disorders. AB - The authors tested whether a novel dental gauge that adjusts the mandibular position in both anterior-posterior (A-P) and vertical directions would improve the airway opening. A pilot study of nine patients with sleep breathing disorder used a snoring sound to guide mandibular vertical and protrusion positions with an adjustable mandibular positioning gauge (AMPG). Volumetric airway changes were confirmed by 2-dimensional (2-D) and 3-dimensional (3-D) measurements taken from cone-beam computed tomography (CBCT) scans. Patients experienced a significant average improvement in airway volumetric increase of 50%. The authors concluded that the AMPG device along with employing a snore sound technique as feedback can be used to ensure an improved awake state airway patency and may prove to be a means to optimize fit for oral appliances in treating obstructive sleep apnea. PMID- 25822642 TI - Safety of a water flosser: a literature review. AB - Since their introduction more than 50 years ago, water flossers (also known as oral irrigators) have been subject to numerous studies on their safety, efficacy, and delivery of antimicrobial agents, particularly in relation to their ability to impact clinical parameters such as plaque, bleeding, gingivitis, pocket depth, and calculus. Evidence based on such studies and decades of use by the public continues to support their safety and efficacy and disproves suggestions of possible detrimental effects on the attachment, junctional epithelium, or pocket depth. PMID- 25822643 TI - Clinicians reaping benefits of new concepts in impressioning. AB - While conventional elastomeric impression materials are still being used to generate excellent impressions, the future of impression-taking is undoubtedly with digital intraoral scanners. Advances in scanning systems are making this technology easier to use and more practical for dentists. PMID- 25822644 TI - Correction: Towards a quantitative theory of epidermal calcium profile formation in unwounded skin. PMID- 25822646 TI - Comparison of Psychophysical and Physical Measurements of Real Ear to Coupler Differences. AB - OBJECTIVES: The purpose of the study is to compare real ear to coupler difference (RECD) curves based on physical and psychophysical measures. For the physically measured RECD, the RECD was measured with real ear and coupler measurements for the ear simulator and HA1- and HA2 2-cc couplers. The psychophysically measured RECDs were derived from audiogram measures. DESIGN: RECDs were measured in 19 normally hearing subjects. The coupler measurement was done with the probe microphone and the coupler microphone itself. Psychophysically measured RECDs were derived for all subjects by measuring the audiogram in sound field and with an ER-3A insert phone. RESULTS: Reference data were obtained for the three coupler types. It was possible to derive the RECD curve with psychophysical methods. There was no overall statistical difference between the physically and psychophysically measured RECD curves for the HA2 2-cc coupler and the ear simulator. The standard deviation was, however, much higher for the psychophysically derived RECD, indicating that physically measured RECDs are more precise than psychophysically derived RECDs. CONCLUSIONS: For the physical RECD measurements, the coupler microphone should be used for the coupler measurement. Physically measured RECDs were validated on group level by the reliable derivation of the RECD curve from audiogram measures. PMID- 25822645 TI - BILBO1 is a scaffold protein of the flagellar pocket collar in the pathogen Trypanosoma brucei. AB - The flagellar pocket (FP) of the pathogen Trypanosoma brucei is an important single copy structure that is formed by the invagination of the pellicular membrane. It is the unique site of endo- and exocytosis and is required for parasite pathogenicity. The FP consists of distinct structural sub-domains with the least explored being the annulus/horseshoe shaped flagellar pocket collar (FPC). To date the only known component of the FPC is the protein BILBO1, a cytoskeleton protein that has a N-terminus that contains an ubiquitin-like fold, two EF-hand domains, plus a large C-terminal coiled-coil domain. BILBO1 has been shown to bind calcium, but in this work we demonstrate that mutating either or both calcium-binding domains prevents calcium binding. The expression of deletion or mutated forms of BILBO1 in trypanosomes and mammalian cells demonstrate that the coiled-coil domain is necessary and sufficient for the formation of BILBO1 polymers. This is supported by Yeast two-hybrid analysis. Expression of full length BILBO1 in mammalian cells induces the formation of linear polymers with comma and globular shaped termini, whereas mutation of the canonical calcium binding domain resulted in the formation of helical polymers and mutation in both EF-hand domains prevented the formation of linear polymers. We also demonstrate that in T. brucei the coiled-coil domain is able to target BILBO1 to the FPC and to form polymers whilst the EF-hand domains influence polymers shape. This data indicates that BILBO1 has intrinsic polymer forming properties and that binding calcium can modulate the form of these polymers. We discuss whether these properties can influence the formation of the FPC. PMID- 25822647 TI - The Gap Detection Test: Can It Be Used to Diagnose Tinnitus? AB - OBJECTIVES: Animals with induced tinnitus showed difficulties in detecting silent gaps in sounds, suggesting that the tinnitus percept may be filling the gap. The main purpose of this study was to evaluate the applicability of this approach to detect tinnitus in human patients. The authors first hypothesized that gap detection would be impaired in patients with tinnitus, and second, that gap detection would be more impaired at frequencies close to the tinnitus frequency of the patient. DESIGN: Twenty-two adults with bilateral tinnitus, 20 age-matched and hearing loss-matched subjects without tinnitus, and 10 young normal-hearing subjects participated in the study. To determine the characteristics of the tinnitus, subjects matched an external sound to their perceived tinnitus in pitch and loudness. To determine the minimum detectable gap, the gap threshold, an adaptive psychoacoustic test was performed three times by each subject. In this gap detection test, four different stimuli, with various frequencies and bandwidths, were presented at three intensity levels each. RESULTS: Similar to previous reports of gap detection, increasing sensation level yielded shorter gap thresholds for all stimuli in all groups. Interestingly, the tinnitus group did not display elevated gap thresholds in any of the four stimuli. Moreover, visual inspection of the data revealed no relation between gap detection performance and perceived tinnitus pitch. CONCLUSIONS: These findings show that tinnitus in humans has no effect on the ability to detect gaps in auditory stimuli. Thus, the testing procedure in its present form is not suitable for clinical detection of tinnitus in humans. PMID- 25822648 TI - Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. AB - BACKGROUND: Osteoarthritis is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. Conventional treatments demonstrate only modest clinical benefits without lesion reversal. Autologous mesenchymal stromal cell (MSC) treatments have shown feasibility, safety, and strong indications for clinical efficacy. We performed a randomized, active control trial to assess the feasibility and safety of treating osteoarthritis with allogeneic MSCs, and we obtain information regarding the efficacy of this treatment. METHODS: We randomized 30 patients with chronic knee pain unresponsive to conservative treatments and showing radiological evidence of osteoarthritis into 2 groups of 15 patients. The test group was treated with allogeneic bone marrow MSCs by intra-articular injection of 40 * 10(6) cells. The control group received intra-articular hyaluronic acid (60 mg, single dose). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. RESULTS: Feasibility and safety were confirmed and indications of clinical efficacy were identified. The MSC-treated patients displayed significant improvement in algofunctional indices versus the active controls treated with hyaluronic acid. Quantification of cartilage quality by T2 relaxation measurements showed a significant decrease in poor cartilage areas, with cartilage quality improvements in MSC-treated patients. CONCLUSIONS: Allogeneic MSC therapy may be a valid alternative for the treatment of chronic knee osteoarthritis that is more logistically convenient than autologous MSC treatment. The intervention is simple, does not require surgery, provides pain relief, and significantly improves cartilage quality. PMID- 25822649 TI - Freeze enrichment protocol based on voltammetric probing of liquid-phase growth in frozen aqueous electrolyte solutions. AB - Voltammetry of the reversible redox couple, Fe(CN)6(4-)/Fe(CN)6(3-), using a microdisc electrode, is employed to probe the dynamic process of the growth of the liquid phase (LP) in frozen aqueous NaCl solutions. Critical factors are the temperature history of a frozen sample and a freeze-concentration ratio. When the temperature is directly set to the working temperature after freezing at -25.0 degrees C, CV measurements are often impossible at high concentration ratios. Even if measurements are possible, the shapes of the CVs and the currents change with time over 3 h. Combined measurements of CV and chronoamperometry clearly indicate that the growth of the LP near the working electrode is responsible for these phenomena. The development of an LP along the electrode surface leads to a change in the shape of the CV due to an increase in the contribution from the radial diffusion. When the LP mainly grows orthogonal to the electrode surface, the peak-shaped CV representing linear diffusion is maintained over several hours. In contrast, when the temperature of a frozen sample increases up to -2.0 degrees C for annealing, reproducible cyclic voltammograms (CVs) are always measured at temperatures higher than -18 degrees C. This procedure allows us to handle frozen solutions as a deterministic system rather than a stochastic one. The present results strongly suggest that annealing of frozen samples is critical for successful uses of the freeze enrichment of trace solutes. Up to 1000-fold enrichments for voltammetric measurements are demonstrated by the proposed procedure involving an annealing step. PMID- 25822650 TI - Erratum to "Adipokines at the crossroad between obesity and cardiovascular disease" (Thromb Haemost 2015; 113: 553-566). PMID- 25822651 TI - PDF-based heterogeneous multiscale filtration model. AB - Motivated by modeling of gasoline particulate filters (GPFs), a probability density function (PDF) based heterogeneous multiscale filtration (HMF) model is developed to calculate filtration efficiency of clean particulate filters. A new methodology based on statistical theory and classic filtration theory is developed in the HMF model. Based on the analysis of experimental porosimetry data, a pore size probability density function is introduced to represent heterogeneity and multiscale characteristics of the porous wall. The filtration efficiency of a filter can be calculated as the sum of the contributions of individual collectors. The resulting HMF model overcomes the limitations of classic mean filtration models which rely on tuning of the mean collector size. Sensitivity analysis shows that the HMF model recovers the classical mean model when the pore size variance is very small. The HMF model is validated by fundamental filtration experimental data from different scales of filter samples. The model shows a good agreement with experimental data at various operating conditions. The effects of the microstructure of filters on filtration efficiency as well as the most penetrating particle size are correctly predicted by the model. PMID- 25822652 TI - Model-based assessment of erlotinib effect in vitro measured by real-time cell analysis. AB - Real time cell analysis (RTCA) is an impedance-based technology which tracks various living cell characteristics over time, such as their number, morphology or adhesion to the extra cellular matrix. However, there is no consensus about how RTCA data should be used to quantitatively evaluate pharmacodynamic parameters which describe drug efficacy or toxicity. The purpose of this work was to determine how RTCA data can be analyzed with mathematical modeling to explore and quantify drug effect in vitro. The pharmacokinetic-pharmacodynamic erlotinib concentration profile predicted by the model and its effect on the human epidermoid carcinoma cell line A431 in vitro was measured through RTCA output, designated as cell index. A population approach was used to estimate model parameter values, considering a plate well as the statistical unit. The model related the cell index to the number of cells by means of a proportionality factor. Cell growth was described by an exponential model. A delay between erlotinib pharmacokinetics and cell killing was described by a transit compartment model, and the effect potency, by an E max function of erlotinib concentration. The modeling analysis performed on RTCA data distinguished drug effects in vitro on cell number from other effects likely to modify the relationship between cell index and cell number. It also revealed a time dependent decrease of erlotinib concentration over time, described by a mono exponential pharmacokinetic model with nonspecific binding. PMID- 25822653 TI - The effectiveness of the problem-based learning teaching model for use in introductory Chinese undergraduate medical courses: a systematic review and meta analysis. AB - BACKGROUND: Although the problem-based learning (PBL) emerged in 1969 and was soon widely applied internationally, the rapid development in China only occurred in the last 10 years. This study aims to compare the effect of PBL and lecture based learning (LBL) on student course examination results for introductory Chinese undergraduate medical courses. METHODS: Randomized and nonrandomized controlled trial studies on PBL use in Chinese undergraduate medical education were retrieved through PubMed, the Excerpta Medica Database (EMBASE), Chinese National Knowledge Infrastructure (CNKI) and VIP China Science and Technology Journal Database (VIP-CSTJ) with publication dates from 1st January 1966 till 31 August 2014. The pass rate, excellence rate and examination scores of course examination were collected. Methodological quality was evaluated based on the modified Jadad scale. The I-square statistic and Chi-square test of heterogeneity were used to assess the statistical heterogeneity. Overall RRs or SMDs with their 95% CIs were calculated in meta-analysis. Meta-regression and subgroup meta analyses were also performed based on comparators and other confounding factors. Funnel plots and Egger's tests were performed to assess degrees of publication bias. RESULTS: The meta-analysis included 31studies and 4,699 subjects. Fourteen studies were of high quality with modified Jadad scores of 4 to 6, and 17 studies were of low quality with scores of 1 to 3. Relative to the LBL model, the PBL model yielded higher course examination pass rates [RR = 1.09, 95%CI (1.03, 1.17)], excellence rates [RR = 1.66, 95%CI (1.33, 2.06)] and examination scores [SMD = 0.82, 95%CI (0.63, 1.01)]. The meta-regression results show that course type was the significant confounding factor that caused heterogeneity in the examination-score meta-analysis (t = 0.410, P<0.001). The examination score SMD in "laboratory course" subgroup [SMD = 2.01, 95% CI: (1.50, 2.52)] was higher than that in "theory course" subgroup [SMD = 0.72, 95% CI: (0.56, 0.89)]. CONCLUSIONS: PBL teaching model application in introductory undergraduate medical courses can increase course examination excellence rates and scores in Chinese medical education system. It is more effective when applied to laboratory courses than to theory-based courses. PMID- 25822654 TI - The Relationship of Educational Attainment with Pulmonary Emphysema and Airway Wall Thickness. AB - RATIONALE: Low educational attainment is a risk factor of chronic obstructive pulmonary disease (COPD). There is limited knowledge on the relationship between educational level and computed tomography measures of emphysema and airway wall thickness (AWT). OBJECTIVES: We hypothesized that low educational attainment is associated with increased emphysema and AWT in ever-smokers with and without COPD. METHODS: We included 462 and 485 ever-smokers with and without COPD in a cross-sectional study, aged 40-86 years. The sample was divided into groups reflecting educational attainment: primary, secondary, and university. We performed linear regression to examine associations between educational attainment and both emphysema and AWT separately for those with and without COPD. We adjusted for sex, age, smoking status, age of onset of smoking, pack-years, height, and body mass index. MEASUREMENTS AND MAIN RESULTS: Compared with university education, in subjects with COPD, primary education was associated with a 68.1% (95% confidence interval = 14.2-147.6%; P = 0.01) relative increase in emphysema and secondary education was associated with a 50.6% (95% confidence interval = 5.7-114.6%; P = 0.02) relative increase. There was a nonsignificant trend toward an association between lower educational attainment and increased emphysema among those without COPD (P = 0.18), yet greater age appeared to modify this association (P = 0.01). We did not detect significant linear relationships between educational attainment and AWT in subjects with or without COPD. CONCLUSIONS: Lower educational attainment was associated with increased emphysema among adults with COPD. Among those without COPD, this association was more pronounced with increasing age. No significant linear relationship between educational attainment and AWT was found. Clinicians treating adults with emphysema should keep in mind that factors related to low education beyond that of smoking and occupational dust exposure might be of importance to the disease. PMID- 25822655 TI - Peptide receptor radionuclide therapy with (90)Y/ (177)Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours). AB - PURPOSE: Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT. METHODS: Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using (90)Y/(177)Lu-labelled peptides after positive confirmation of SSTR expression on (68)Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with (68)Ga-DOTATOC PET/CT was carried out every 6 months to assess response to treatment. Clinical (symptomatic) response was also assessed. RESULTS: Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUVmax, accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUVmax. The three asymptomatic patients showed no new lesions or symptomatic worsening. CONCLUSION: PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or distant spread. Though these are preliminary results, PRRT shows promise as a good treatment option for HNPGL, and hence study in a larger patient cohort is essential to establish its place in the management algorithm. PMID- 25822656 TI - Delivering medical abortion at scale: a study of the retail market for medical abortion in Madhya Pradesh, India. AB - BACKGROUND: Medical abortion (mifepristone and misoprostol) has the potential to contribute to reduced maternal mortality but little is known about the provision or quality of advice for medical abortion through the private retail sector. We examined the availability of medical abortion and the practices of pharmacists in India, where abortion has been legal since 1972. METHODS: We interviewed 591 pharmacists in 60 local markets in city, town and rural areas of Madhya Pradesh. One month later, we returned to 359 pharmacists with undercover patients who presented themselves unannounced as genuine customers seeking a medical abortion. RESULTS: Medical abortion was offered to undercover patients by 256 (71.3%) pharmacists and 24 different brands were identified. Two thirds (68.5%) of pharmacists stated that abortion was illegal in India. Only 106 (38.5%) pharmacists asked clients the timing of the last menstrual period and 38 (13.8%) requested to see a doctor's prescription - a legal requirement in India. Only 59 (21.5%) pharmacists correctly advised patients on the gestational limit for medical abortion, 97 (35.3%) provided correct information on how many and when to take the tablets in a combination pack, and 78 (28.4%) gave accurate advice on where to seek care in case of complications. Advice on post-abortion family planning was almost nonexistent. CONCLUSIONS: The retail market for medical abortion is extensive, but the quality of advice given to patients is poor. Although the contribution of medical abortion to women's health in India is poorly understood, there is an urgent need to improve the practices of pharmacists selling medical abortion. PMID- 25822657 TI - Intra-aortic Balloon Pump Therapy for Acute Myocardial Infarction: A Meta analysis. AB - IMPORTANCE: Intra-aortic balloon pump (IABP) therapy is a widely used intervention for acute myocardial infarction with cardiogenic shock. Guidelines, which previously strongly recommended it, have recently undergone substantial change. OBJECTIVE: To assess IABP efficacy in acute myocardial infarction. DATA SOURCES: Human studies found in Pubmed, Embase, and Cochrane libraries through December 2014 and in reference lists of selected articles. Search strings were "myocardial infarction" or "acute coronary syndrome" and "intra-aortic balloon pump" or "counterpulsation." STUDY SELECTION: Randomized clinical trials (RCTs) and observational studies comparing use of IABP with no IABP in patients with acute myocardial infarction. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted the data, and risk of bias in RCTs was assessed using the Cochrane risk of bias tool. We conducted separate meta-analyses of the RCTs and observational studies. Data were quantitatively synthesized using random-effects meta-analysis. MAIN OUTCOMES AND MEASURES: Thirty-day mortality. RESULTS: There were 12 eligible RCTs randomizing 2123 patients. In the RCTs, IABP use had no statistically significant effect on mortality (odds ratio [OR], 0.96 [95% CI, 0.74-1.24]), with no significant heterogeneity among trials (I2 = 0%; P = .52). This result was consistent when studies were stratified by the presence (OR, 0.94 [95% CI, 0.69-1.28]; P = .69, I2 = 0%) or absence (OR, 0.98 [95% CI, 0.57-1.69]; P = .95, I2 = 17%) of cardiogenic shock. There were 15 eligible observational studies totaling 15 530 patients. Their results were mutually conflicting (heterogeneity I2 = 97%; P < .001), causing wide uncertainty in the summary estimate for the association with mortality (OR, 0.96 [95% CI, 0.54-1.70]). A simple index of baseline risk marker imbalance in the observational studies appeared to explain much of the heterogeneity in the observational data (R2meta = 46.2%; P < .001). CONCLUSIONS AND RELEVANCE: Use of IABP was not found to improve mortality among patients with acute myocardial infarction in the RCTs, regardless of whether patients had cardiogenic shock. The observational studies showed a variety of mutually contradictory associations between IABP therapy and mortality, much of which was explained by the differences between studies in the balance of risk factors between IABP and non-IABP groups. PMID- 25822658 TI - Long-distance interdisciplinarity leads to higher scientific impact. AB - Scholarly collaborations across disparate scientific disciplines are challenging. Collaborators are likely to have their offices in another building, attend different conferences, and publish in other venues; they might speak a different scientific language and value an alien scientific culture. This paper presents a detailed analysis of success and failure of interdisciplinary papers--as manifested in the citations they receive. For 9.2 million interdisciplinary research papers published between 2000 and 2012 we show that the majority (69.9%) of co-cited interdisciplinary pairs are "win-win" relationships, i.e., papers that cite them have higher citation impact and there are as few as 3.3% "lose lose" relationships. Papers citing references from subdisciplines positioned far apart (in the conceptual space of the UCSD map of science) attract the highest relative citation counts. The findings support the assumption that interdisciplinary research is more successful and leads to results greater than the sum of its disciplinary parts. PMID- 25822659 TI - Imaging unruptured giant aneurysm of right sinus of Valsalva by 320-row dynamic volume computed tomography (CT): a case report. AB - Multi-detector computed tomography with ECG-synchronized data acquisition allows detailed analysis of cardiac anatomy of the heart with excellent spatial resolution. Sinus of Valsalva aneurysms occurs rarely in the western world, but the incidence in Asian populations is higher (Goldberg and Krasnow in Clin Cardiol 13:831-836, 1990). We present the case of a patient with an unruptured giant aneurysm of right sinus of Valsalva. PMID- 25822660 TI - Ocular Myasthenia Gravis Associated With Thymic Amyloidosis. AB - A 45-year-old woman with ptosis and diplopia was found to have myasthenia gravis (MG) associated with amyloidosis of the thymus gland. Systemic MG is frequently associated with thymomas or thymic hyperplasia but has only once previously been reported in association with amyloidosis of the thymus. This case demonstrates that isolated ocular MG rarely may also be associated with amyloidosis of the thymus. PMID- 25822661 TI - Keratin dynamics: modeling the interplay between turnover and transport. AB - Keratin are among the most abundant proteins in epithelial cells. Functions of the keratin network in cells are shaped by their dynamical organization. Using a collection of experimentally-driven mathematical models, different hypotheses for the turnover and transport of the keratin material in epithelial cells are tested. The interplay between turnover and transport and their effects on the keratin organization in cells are hence investigated by combining mathematical modeling and experimental data. Amongst the collection of mathematical models considered, a best model strongly supported by experimental data is identified. Fundamental to this approach is the fact that optimal parameter values associated with the best fit for each model are established. The best candidate among the best fits is characterized by the disassembly of the assembled keratin material in the perinuclear region and an active transport of the assembled keratin. Our study shows that an active transport of the assembled keratin is required to explain the experimentally observed keratin organization. PMID- 25822662 TI - Mechanism and kinetics of low-temperature oxidation of a biodiesel surrogate: methyl propanoate radicals with oxygen molecule. AB - This paper presents a computational study on the low-temperature mechanism and kinetics of the reaction between molecular oxygen and alkyl radicals of methyl propanoate (MP), which plays an important role in low-temperature oxidation and/or autoignition processes of the title fuel. Their multiple reaction pathways either accelerate the oxidation process via chain branching or inhibit it by forming relatively stable products. The potential energy surfaces of the reactions between three primary MP radicals and molecular oxygen, namely, C(*)H2CH2COOCH3 + O2, CH3C(*)HCOOCH3 + O2, and CH3CH2COOC(*)H2 + O2, were constructed using the accurate composite CBS-QB3 method. Thermodynamic properties of all species as well as high-pressure rate constants of all reaction channels were derived with explicit corrections for tunneling and hindered internal rotations. Our calculation results are in good agreement with a limited number of scattered data in the literature. Furthermore, pressure- and temperature dependent rate constants for all reaction channels on the multiwell-multichannel potential energy surfaces were computed with the quantum Rice-Ramsperger-Kassel (QRRK) and the modified strong collision (MSC) theories. This procedure resulted in a thermodynamically consistent detailed kinetic submechanism for low temperature oxidation governed by the title process. A simplified mechanism, which consists of important reactions, is also suggested for low-temperature combustion at engine-like conditions. PMID- 25822663 TI - Unsaturation of very-long-chain ceramides protects plant from hypoxia-induced damages by modulating ethylene signaling in Arabidopsis. AB - Lipid remodeling is crucial for hypoxic tolerance in animals, whilst little is known about the hypoxia-induced lipid dynamics in plants. Here we performed a mass spectrometry-based analysis to survey the lipid profiles of Arabidopsis rosettes under various hypoxic conditions. We observed that hypoxia caused a significant increase in total amounts of phosphatidylserine, phosphatidic acid and oxidized lipids, but a decrease in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Particularly, significant gains in the polyunsaturated species of PC, PE and phosphatidylinositol, and losses in their saturated and mono-unsaturated species were evident during hypoxia. Moreover, hypoxia led to a remarkable elevation of ceramides and hydroxyceramides. Disruption of ceramide synthases LOH1, LOH2 and LOH3 enhanced plant sensitivity to dark submergence, but displayed more resistance to submergence under light than wild type. Consistently, levels of unsaturated very-long-chain (VLC) ceramide species (22:1, 24:1 and 26:1) predominantly declined in the loh1, loh2 and loh3 mutants under dark submergence. In contrast, significant reduction of VLC ceramides in the loh1-1 loh3-1 knockdown double mutant and lacking of VLC unsaturated ceramides in the ads2 mutants impaired plant tolerance to both dark and light submergences. Evidence that C24:1-ceramide interacted with recombinant CTR1 protein and inhibited its kinase activity in vitro, enhanced ER-to-nucleus translocation of EIN2-GFP and stabilization of EIN3-GFP in vivo, suggests a role of ceramides in modulating CTR1-mediated ethylene signaling. The dark submergence sensitive phenotypes of loh mutants were rescued by a ctr1-1 mutation. Thus, our findings demonstrate that unsaturation of VLC ceramides is a protective strategy for hypoxic tolerance in Arabidopsis. PMID- 25822664 TI - Social inhibitory control in five lemur species. AB - We tested five lemur species-ring-tailed lemurs, ruffed lemurs, mongoose lemurs, black lemurs, and Coquerel's sifakas-(N = 52) in an experiment that evaluated skills for inhibitory control in a social context. First, two human experimenters presented identical food rewards; the "generous" experimenter allowed the subject to eat from her hand, whereas the "competitive" experimenter always withheld the reward. Lemurs quickly learned to approach the generous experimenter and avoid the competitive one. In the inhibition test phase, we endowed the competitive experimenter with a more valuable food reward but the competitive experimenter continued to withhold food from the subject. Thus, lemurs were required to inhibit approaching the more desirable reward in favor of the lesser but obtainable reward presented by the generous experimenter. In test trials, lemurs' tendency to approach the competitive experimenter increased from the reputation phase, demonstrating sensitivity to the experimental manipulation. However, subjects approached the larger reward less frequently in test trials compared with pretest food-preference trials, evidencing some capacity for inhibitory control in this context. Despite differences in sociality and ecology, the five lemur species did not differ in this ability. Although the study did not uncover species differences, this experimental task may provide a useful measure of social inhibition in broader comparative studies. PMID- 25822665 TI - Short-term costs and benefits of grooming in Japanese macaques. AB - This study investigated the short-term consequences of giving grooming in Japanese macaques (Macaca fuscata) in order to obtain information on its immediate costs and benefits. Giving grooming was associated with increased aggression received from groomees and decreased aggression received from third parties (but only as long as the groomer maintained proximity to the groomee). Grooming was also associated with decreased scratching rates. These results emphasize the unpredictable outcome of individual grooming interactions and the difficulties of social decision-making for monkeys living in despotic societies. PMID- 25822668 TI - Assessing the Sporicidal Activity of Oligo-p-phenylene Ethynylenes and Their Role as Bacillus Germinants. AB - A wide range of oligo-p-phenylene ethynylenes has been shown to exhibit good biocidal activity against both Gram-negative and Gram-positive bacteria. While cell death may occur in the dark, these biocidal compounds are far more effective in the light as a result of their ability to sensitize the production of cell damaging reactive oxygen species. In these studies, the interactions of a specific cationic oligo-p-phenylene ethynylene with spore-forming Bacillus atrophaeus and Bacillus anthracis Sterne have been investigated. Flow cytometry assays are used to rapidly monitor cell death as well as spore germination. This compound effectively killed Bacillus anthracis Sterne vegetative cells (over 4 log reduction), presumably by severe perturbations of the bacterial cell wall and cytoplasmic membrane, while also acting as an effective spore germinant in the dark. While 2 log reduction of B. anthracis Sterne spores was observed, it is hypothesized that further killing could be achieved through enhanced germination. PMID- 25822669 TI - Polymer-Enriched 3D Graphene Foams for Biomedical Applications. AB - Graphene foams (GFs) are versatile nanoplatforms for biomedical applications because of their excellent physical, chemical, and mechanical properties. However, the brittleness and inflexibility of pristine GF (pGF) are some of the important factors restricting their widespread application. Here, a chemical vapor-deposition-assisted method was used to synthesize 3D GFs, which were subsequently spin-coated with polymer to produce polymer-enriched 3D GFs with high conductivity and flexibility. Compared to pGF, both poly(vinylidene fluoride)-enriched GF (PVDF/GF) and polycaprolactone-enriched GF (PCL/GF) scaffolds showed improved flexibility and handleability. Despite the presence of the polymers, the polymer-enriched 3D GF scaffolds retained high levels of electrical conductivity because of the presence of microcracks that allowed for the flow of electrons through the material. In addition, polymer enrichment of GF led to an enhancement in the formation of calcium phosphate (Ca-P) compounds when the scaffolds were exposed to simulated body fluid. Between the two polymers tested, PCL enrichment of GF resulted in a higher in vitro mineralization nucleation rate because the oxygen-containing functional group of PCL had a higher affinity for Ca-P deposition and formation compared to the polar carbon fluorine (C-F) bond in PVDF. Taken together, our current findings are a stepping stone toward future applications of polymer-enriched 3D GFs in the treatment of bone defects as well as other biomedical applications. PMID- 25822667 TI - Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane. In particular, the coexpression and plasma membrane interaction between Cavin-1 and Cav-1 characterized the proliferation of human and mouse RMS cell cultures, while a downregulation of their expression levels was observed during the myogenic differentiation. Knockdown of Cavin-1 or Cav-1 in the human RD and RH30 cells led to impairment of cell proliferation and migration. Moreover, loss of Cavin-1 in RD cells impaired the anchorage independent cell growth in soft agar. While the loss of Cavin-1 did not affect the Cav-1 protein levels in RMS cells, Cav-1 overexpression and knockdown triggered a rise or depletion of Cavin-1 protein levels in RD cells, respectively, in turn reflecting on increased or decreased cell proliferation, migration and anchorage-independent cell growth. Collectively, these data indicate that the interaction between Cavin-1 and Cav-1 underlies the cell growth and migration in myogenic tumors. PMID- 25822670 TI - Obesity as a Socially Defined Disease: Philosophical Considerations and Implications for Policy and Care. AB - Obesity has generated significant worries amongst health policy makers and has obtained increased attention in health care. Obesity is unanimously defined as a disease in the health care and health policy literature. However, there are pragmatic and not principled reasons for this. This warrants an analysis of obesity according to standard conceptions of disease in the literature of philosophy of medicine. According to theories and definitions of disease referring to (abnormal functioning of) internal processes, obesity is not a disease. Obesity undoubtedly can result in disease, making it a risk factor for disease, but not a disease per se. According to several social conceptions of disease, however, obesity clearly is a disease. Obesity can conflict with aesthetic, moral, or other social norms. Making obesity a "social disease" may very well be a wise health policy, assuring and improving population health, especially if we address the social determinants of obesity, such as the food supply and marketing system. However, applying biomedical solutions to social problems may also have severe side effects. It can result in medicalization and enhance stigmatization and discrimination of persons based on appearance or behavior. Approaching social problems with biomedical means may also serve commercial and professionals' interests more than the health and welfare of individuals; it may make quick fix medical solutions halt more sustainable structural solutions. This urges health insurers, health care professionals, and health policy makers to be cautious. Especially if we want to help and respect persons that we classify and treat as obese. PMID- 25822666 TI - Hepatitis B virus genotype distribution and genotype-specific BCP/preCore substitutions in acute and chronic infections in Argentina. AB - AIM: In order to assess Hepatitis B Virus genotype (g) and subgenotype (sg) implications in the course of infection, 234 HBsAg positive patients in different infection stages were characterized (66 acute infections, 63 HBeAg positive chronic infections and 105 anti-HBe positive chronic infections). RESULTS: Overall, sgA2 (17.9%), gD (20.9%), sgF1b (34.2%) and sgF4 (19.7%) were the most prevalent. Subgenotype F1b was overrepresented in acute and chronic HBeAg infections (56.1%), whereas gD was the most frequent (40.0%) in anti-HBe positive chronic infections. Among chronic infections, HBeAg positivity rates were 50.0, 12.5, 62.8 and 35.3% for sgA2, gD, sgF1b and sgF4, respectively (p <0.05). A bias toward BCP/preCore mutations was observed among genotypes. In anti-HBe positive chronic infections, sgF1b was more prone to have A1762T/G1764A mutation than sgA2, sgF4 and gD (75.0, 40.0, 33.3 and 31.8%, p<0.005), whereas in the pC region, gD and sgF4 were more likely to have G1896A than sgA2 and sgF1b (81.0, 72.7, 0.0 and 31.3%, p <0.001). The unexpected low frequency of the G1896A mutation in the sgF1b (despite carrying 1858T) prompted us to perform a further analysis in order to identify genotype-specific features that could justify the pattern mutations observed. A region encompassing nucleotides 1720 to 1920 showed the higher dissimilarity between sgF1b and sgF4. Genotypes and subgenotypes carrying the 1727G, 1740C and 1773T polymorphisms were prevented to mutate position 1896. DISCUSSION: HBeAg seroconversion is a critical event in the natural history of HBV infection. Differences in the HBeAg positivity rate might be relevant since different studies have observed that delayed HBeAg seroconversion is associated with a more severe clinical course of infection, highlighting the critical role that genotypes/subgenotypes might play in the progression of HBV infection. Polymorphisms in the regions 1720 to 1920 could be involved in the molecular mechanisms underlying seroconversion of each genotype/subgenotype. PMID- 25822671 TI - Generating Systems Biology Markup Language Models from the Synthetic Biology Open Language. AB - In the context of synthetic biology, model generation is the automated process of constructing biochemical models based on genetic designs. This paper discusses the use cases for model generation in genetic design automation (GDA) software tools and introduces the foundational concepts of standards and model annotation that make this process useful. Finally, this paper presents an implementation of model generation in the GDA software tool iBioSim and provides an example of generating a Systems Biology Markup Language (SBML) model from a design of a 4 input AND sensor written in the Synthetic Biology Open Language (SBOL). PMID- 25822673 TI - Organ Failure and Infection in Necrotizing Pancreatitis: What Are the Predictors of Mortality? PMID- 25822672 TI - Prospective Validation of a Low Rectal Cancer Magnetic Resonance Imaging Staging System and Development of a Local Recurrence Risk Stratification Model: The MERCURY II Study. AB - OBJECTIVE: This study aimed to validate a magnetic resonance imaging (MRI) staging classification that preoperatively assessed the relationship between tumor and the low rectal cancer surgical resection plane (mrLRP). BACKGROUND: Low rectal cancer oncological outcomes remain a global challenge, evidenced by high pathological circumferential resection margin (pCRM) rates and unacceptable variations in permanent colostomies. METHODS: Between 2008 and 2012, a prospective, observational, multicenter study (MERCURY II) recruited 279 patients with adenocarcinoma 6 cm or less from the anal verge. MRI assessed the following: mrLRP "safe or unsafe," venous invasion (mrEMVI), depth of spread, node status, tumor height, and tumor quadrant. MRI-based treatment recommendations were compared against final management and pCRM outcomes. RESULTS: Overall pCRM involvement was 9.0% [95% confidence interval (CI), 5.9-12.3], significantly lower than previously reported rates of 30%. Patients with no adverse MRI features and a "safe" mrLRP underwent sphincter-preserving surgery without preoperative radiotherapy, resulting in a 1.6% pCRM rate. The pCRM rate increased 5-fold for an "unsafe" compared with "safe" preoperative mrLRP [odds ratio (OR) = 5.5; 95% CI, 2.3-13.3)]. Posttreatment MRI reassessment indicated a "safe" ymrLRP in 33 of 113 (29.2%), none of whom had ypCRM involvement. In contrast, persistent "unsafe" ymrLRP posttherapy resulted in 17.5% ypCRM involvement. Further independent MRI assessed risk factors were EMVI (OR = 3.8; 95% CI, 1.5-9.6), tumors less than 4.0 cm from the anal verge (OR = 3.4; 95% CI, 1.3-8.8), and anterior tumors (OR = 2.8; 95% CI, 1.1-6.8). CONCLUSIONS: The study validated MRI low rectal plane assessment, reducing pCRM involvement and avoiding overtreatment through selective preoperative therapy and rationalized use of permanent colostomy. It also highlights the importance of posttreatment restaging. PMID- 25822674 TI - The Value of Isosulfan Blue Dye in Addition to Isotope Scanning in the Identification of the Sentinel Lymph Node in Breast Cancer Patients With a Positive Lymphoscintigraphy: A Randomized Controlled Trial (ISRCTN98849733). AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) has become the gold standard for axillary staging. Debate remains as to the optimal method of SLN detection. OBJECTIVES: Determine whether patients undergoing an SLNB required the addition of isosulfan blue dye to radioisotope when an SLN was identified on a preoperative lymphoscintigram. METHODS: A prospective randomized controlled trial comparing the combination of radioisotope and blue dye versus radioisotope alone was performed between March 2010 and September 2012. The trial protocol was registered with Current Controlled Trials. Women with clinically and radiologically node-negative breast cancer with a positive preoperative lymphoscintigram were eligible for inclusion. RESULTS: A total of 667 patients were included in the analysis with 342 patients receiving the combination (blue dye and radioisotope) and 325 patients receiving radioisotope alone. The groups were evenly matched both demographically and pathologically. The mean age was 48 years (48.3 vs 47.7 years; P = 0.47), the mean tumour size was 24.2 mm (24.3 mm vs 24.1 mm; P = 0.7) and there was no statistically significant difference in the grade of the tumors between the 2 groups (P = 0.58). There was no difference in the identification rate, nor was that in the number of nodes retrieved between the 2 groups (P = 0.30). There was no difference in the number of positive lymph nodes that were identified between the 2 groups (23.8% vs 22.1%; P = 0.64). CONCLUSIONS: This study failed to demonstrate an advantage with the addition of isosulfan blue dye to radioisotope in the identification of the SLN in the presence of a positive preoperative lymphoscintigram. PMID- 25822677 TI - Primary Hyperparathyroidism With Negative Imaging: A Significant Clinical Problem. PMID- 25822675 TI - Prospective Study of Surgical Decision-making Processes for Contralateral Prophylactic Mastectomy in Women With Breast Cancer. AB - OBJECTIVE: We prospectively examined the psychosocial predictors and the decision making process regarding contralateral prophylactic mastectomy (CPM) among women with sporadic breast cancer. BACKGROUND: Increasing numbers of women with breast cancer are seeking CPM. Data are limited about the surgical decision-making process and the psychosocial factors that influence interest in CPM. METHODS: Women with early-stage unilateral breast cancer (n = 117) were recruited before their first surgical visit at MD Anderson and completed questionnaires assessing knowledge of and interest in CPM and associated psychosocial factors. After the appointment, women and their surgeons completed questions about the extent that various surgical options (including CPM) were discussed; also, the women rated their perceived likelihood of having CPM and the surgeons rated the appropriateness of CPM. RESULTS: Before their first visit, 50% of women were moderately to extremely interested in CPM and 12 (10%) of women had CPM at the time of their primary breast cancer surgery. Less knowledge about breast cancer (P = 0.02) and greater cancer worry (P = 0.03) predicted interest in CPM. Greater cancer worry predicted who had CPM (P = 0.02). Interest in CPM before surgical visit and the likelihood of having CPM after the visit differed (P <= 0.001). Surgeons' rating of the appropriateness of CPM and the patient's reported likelihood of having CPM were not significantly different (P = 0.49). CONCLUSIONS: Interest in CPM is common among women with sporadic breast cancer. The informational and emotional aspects of CPM may affect the decision to have CPM and should be addressed when discussing surgical options. PMID- 25822678 TI - Oncologic Outcomes of Single-incision Laparoscopic Surgery Compared With Conventional Laparoscopy for Colon Cancer. AB - OBJECTIVE: The aim of this study is to document perioperative results and mid term oncologic outcomes of single-incision laparoscopic (SIL) colectomy compared to conventional laparoscopic (CL) colectomy. BACKGROUND: SIL surgery is an advance in minimally invasive operative techniques and is widely accepted for various types of surgery. METHODS: We prospectively collected data from 767 patients who underwent radical colectomy (250 SIL colectomy and 517 CL colectomy) between 2010 and 2011 due to primary colon cancer and retrospectively analyzed these patients with propensity score matching. RESULTS: Before matching, patients with CL surgery had a significantly higher percentage of comorbidities (49.2% vs 57.8%, P = 0.024). Tumor location significantly differed between 2 groups: SIL surgery was performed more frequently in patients with right colon cancer. After propensity score matching, each group included 239 patients, and there was no difference between the SIL and CL surgery groups. Estimated blood loss was more in the patients with SIL colectomy, but the rate itself of intraoperative complications was not statistically different (P = 0.662). The median follow-up period was 37 months. There were 20 recurrences in the SIL surgery group (8.4%), including 3 locoregional recurrences and 18 (7.5%) in the CL surgery group. Disease-free survival at 48 months did not differ significantly between the SIL and CL surgery groups (89.8% vs 89.9%, P = 0.548). CONCLUSIONS: SIL colectomy for colon cancer shows probably higher, but an acceptable complication rate and can provide resection and oncologic outcomes equal to those of CL colectomy. PMID- 25822684 TI - Rat Reflux Model of Esophageal Cancer and Its Implication in Human Disease. AB - OBJECTIVES: The epidemiologic shift in esophageal cancer from squamous cell carcinoma to esophageal adenocarcinoma coincided with popularization of proton pump inhibitors and has focused attention on gastroesophageal reflux disease as a causative factor in this shift. The aim of this study is to review the literature on the rat reflux model in an effort to elucidate this phenomenon. METHODS: An extensive online literature review (PubMed) was carried out to identify all seminal contributions to the study of esophageal adenocarcinoma using the rat reflux model. RESULTS: The rat reflux model is a validated reproducible model for the development of Barrett's esophagus and esophageal adenocarcinoma. Esophageal reflux of an admixture of gastric acid and duodenal juice induces Barrett's esophagus followed by adenocarcinoma. A high-pH environment created by surgical gastrectomy or proton pump inhibitor therapy in combination with a high-fat diet seems to potentiate the development of Barrett's esophagus and adenocarcinoma. Early surgical intervention to prevent reflux reduces the progression toward esophageal adenocarcinoma. Anti-inflammatory, antioxidant, and nitrate-trapping agents reduce the incidence of tumorigenesis. CONCLUSIONS: As in the rat so also in humans, reflux of an admixture of gastric acid and duodenal juice in a high-pH environment induces the development of Barrett's esophagus followed by esophageal adenocarcinoma. This has led to the hypothesis that to prevent Barrett's esophagus and subsequent esophageal adenocarcinoma in humans, the reflux of an admixture of acid and bile must be controlled before the development of Barrett's esophagus by methods other than acid-suppression therapy. PMID- 25822687 TI - Validation of the 2012 International Consensus Guidelines Using Computed Tomography and Magnetic Resonance Imaging: Branch Duct and Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas. AB - OBJECTIVE: To validate the 2012 guidelines for intraductal papillary mucinous neoplasm (IPMN) of the pancreas and to compare diagnostic performances of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiating malignant from benign IPMN. BACKGROUND: As IPMN has variable risks of malignancy and management of this entity is closely related to its malignant potential, it is important to predict risks of IPMN malignancy. METHODS: This retrospective study included 158 patients with surgically confirmed IPMN of the pancreas who underwent both preoperative CT and MRI. Two radiologists evaluated the "high-risk stigmata" and "worrisome features" of the 2012 guidelines for branch duct (BD) IPMN and main duct (MD)-IPMN. Univariate and multivariable analyses were used to identify significant predictors of malignancy in IPMN. The diagnostic performance was compared between CT and MRI. RESULTS: Malignant IPMN was seen in 8 of 60 patients (13.3%) with BD-IPMN and 44 of 98 patients (44.9%) with MD-IPMN. Presence of mural nodule was the most important predictor in BD-IPMN and MD-IPMN (odds ratios, 9.2 and 7.6, respectively, P = 0.01 on CT; and odds ratios, 5.7 and 13.3, respectively, P <= 0.04 on MRI), whereas mural nodule size and lymphadenopathy were significant only in MD-IPMN (P < 0.05). The diagnostic performance of CT and MRI for significant findings was not statistically different in both types of IPMN (P > 0.34). CONCLUSIONS: The presence of mural nodule was the most important predictor of malignancy in both types of IPMN. Mural nodule size and lymphadenopathy were also significant predictors in MD IPMN. Computed tomography and MRI showed similar diagnostic performances for differentiating malignant from benign IPMN. PMID- 25822686 TI - IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers. AB - OBJECTIVES: To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts. BACKGROUND: The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown. METHODS: IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics. RESULTS: Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low- and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04-4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10-5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence. CONCLUSIONS: Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence. PMID- 25822689 TI - Reduced Hospital Mortality With Surgical Ligation of Patent Ductus Arteriosus in Premature, Extremely Low Birth Weight Infants: A Propensity Score-matched Outcome Study. AB - OBJECTIVES: To evaluate outcomes after surgical ligation (SL) of patent ductus arteriosus (PDA) in premature, extremely low birth weight (ELBW) infants. BACKGROUND: Optimal management of PDA in this specialized population remains undefined. Currently, surgical therapy is largely reserved for infants failing medical management. To date, a large-scale, risk-matched population-based study has not been performed to evaluate differences in mortality and resource utilization. METHODS: Data on identified premature (<37 weeks) and ELBW (<1000 g) infants with PDA (International Classification of Diseases, 9th revision, Clinical Modification, 747.0) and respiratory distress (769) were obtained from Kids' Inpatient Database (2003-2009). RESULTS: Overall, 12,470 cases were identified, with 3008 undergoing SL. Propensity score-matched analysis of 1620 SL versus 1584 non-SL found reduced mortality (15% vs 26%) and more routine disposition (48% vs 41%) for SL (P < 0.001). SL had longer length of stay and higher total cost (P < 0.001). On multivariate analysis, SL mortality predictors were necrotizing enterocolitis (NEC; surgical odds ratio, 5.95; medical odds ratio, 4.42) and sepsis (3.43) (P < 0.006). Length of stay increased with bronchopulmonary dysplasia (BPD; 1.77), whereas total cost increased with surgical NEC (1.82) and sepsis (1.26) (P < 0.04). Non-SL mortality predictors were NEC (surgical, 76.3; medical, 6.17), sepsis (2.66), and intraventricular hemorrhage (1.97) (P < 0.005). Length of stay increased with BPD (2.92) and NEC (surgical, 2.04; medical, 1.28) (P < 0.03). Total cost increased with surgical NEC (2.06), medical NEC (1.57), sepsis (1.43), and BPD (1.30) (P < 0.001). CONCLUSIONS: Propensity score-matched analysis demonstrates reduced mortality in premature/ELBW infants with SL for PDA. NEC and sepsis are predictors of mortality and resource utilization. PMID- 25822691 TI - Comprehensive Surgical Coaching Enhances Surgical Skill in the Operating Room: A Randomized Controlled Trial. AB - OBJECTIVES: The aim of the study was to determine whether individualized coaching improved surgical technical skill in the operating room to a higher degree than current residency training. BACKGROUND: Clinical training in the operating room is a valuable opportunity for surgeons to acquire skill and knowledge; however, it often remains underutilized. Coaching has been successfully used in various industries to enhance performance, but its role in surgery has been insufficiently investigated. METHODS: This randomized controlled trial was conducted at one surgical training program. Trainees undergoing a minimally invasive surgery rotation were randomized to either conventional training (CT) or comprehensive surgical coaching (CSC). CT included ward and operating room duties, and regular departmental teaching sessions. CSC comprised performance analysis, debriefing, feedback, and behavior modeling. Primary outcome measures were technical performance as measured on global and procedure-specific rating scales, and surgical safety parameters, measured by error count. Operative performance was assessed by blinded video analysis of the first and last cases recorded by the participants during their rotation. RESULTS: Twenty residents were randomized and 18 completed the study. At posttraining the CSC group (n = 9) scored significantly higher on a procedure-specific skill scale compared with the CT group (n = 9) [median, 3.90 (interquartile range, 3.68-4.30) vs 3.60 (2.98 3.70), P = 0.017], and made fewer technical errors [10 (7-13) vs 18 (13-21), P = 0.003]. Significant within-group improvements for all skill metrics were only noted in the CSC group. CONCLUSIONS: Comprehensive surgical coaching enhances surgical training and results in skill acquisition superior to conventional training. PMID- 25822692 TI - Memoryless self-reinforcing directionality in endosomal active transport within living cells. AB - In contrast to Brownian transport, the active motility of microbes, cells, animals and even humans often follows another random process known as truncated Levy walk. These stochastic motions are characterized by clustered small steps and intermittent longer jumps that often extend towards the size of the entire system. As there are repeated suggestions, although disagreement, that Levy walks have functional advantages over Brownian motion in random searching and transport kinetics, their intentional engineering into active materials could be useful. Here, we show experimentally in the classic active matter system of intracellular trafficking that Brownian-like steps self-organize into truncated Levy walks through an apparent time-independent positive feedback such that directional persistence increases with the distance travelled persistently. A molecular model that allows the maximum output of the active propelling forces to fluctuate slowly fits the experiments quantitatively. Our findings offer design principles for programming efficient transport in active materials. PMID- 25822693 TI - Biodegradable silicon nanoneedles delivering nucleic acids intracellularly induce localized in vivo neovascularization. AB - The controlled delivery of nucleic acids to selected tissues remains an inefficient process mired by low transfection efficacy, poor scalability because of varying efficiency with cell type and location, and questionable safety as a result of toxicity issues arising from the typical materials and procedures employed. High efficiency and minimal toxicity in vitro has been shown for intracellular delivery of nuclei acids by using nanoneedles, yet extending these characteristics to in vivo delivery has been difficult, as current interfacing strategies rely on complex equipment or active cell internalization through prolonged interfacing. Here, we show that a tunable array of biodegradable nanoneedles fabricated by metal-assisted chemical etching of silicon can access the cytosol to co-deliver DNA and siRNA with an efficiency greater than 90%, and that in vivo the nanoneedles transfect the VEGF-165 gene, inducing sustained neovascularization and a localized sixfold increase in blood perfusion in a target region of the muscle. PMID- 25822694 TI - The impact of intensified training with a high or moderate carbohydrate feeding strategy on resting and exercise-induced oxidative stress. AB - PURPOSE: This study investigated the impact of intensified training (IT) and carbohydrate (CHO) supplementation on resting and exercise-induced oxidative stress. METHODS: Male cyclists (n = 13, mean +/- SD: age 25 +/- 6 years; [Formula: see text] 72 +/- 5 ml/kg/min) undertook two 9 day periods of endurance based IT. In a counter-balanced, crossover and double-blinded study design, participants completed IT whilst ingesting high (H-CHO) or moderate (M-CHO) CHO beverages before (H-CHO: 24 g vs. M-CHO: 2 g), during (H-CHO: 60 g/h vs. M-CHO: 20 g/h) and after training sessions (H-CHO: 44 g vs. M-CHO: 10 g). Participants completed fasted performance trials without CHO on days 2, 6 and 10. Blood samples were taken before and immediately after exercise to assess plasma oxidative stress. RESULTS: Resting thiol (-SH) and catalase (CAT) activities decreased following 6 days of IT, independent of CHO condition [-SH (MUM oxidised NADPH): H-CHO-14.0 +/- 18.8, M-CHO-20.4 +/- 20.3 and CAT (nmol/min/ml): H-CHO 12.5 +/- 12.5, M-CHO 6.0 +/- 4.5; all p < 0.05]. Resting total antioxidant capacity (TAC) was reduced after IT in M-CHO. All exercise bouts elicited significant increases in CAT, TAC, protein carbonylation (PC) and lipid hydroperoxides (LOOH), independent of CHO condition (p < 0.05). The magnitude of increase in PC and LOOH was greater on days 6 and 10 compared to day 2 in both conditions. CONCLUSIONS: Short-term IT caused reductions in resting antioxidant capacity in trained cyclists. Exercise-induced increases in PC and LOOH were exaggerated as a result of IT; however, these responses were independent of carbohydrate intake before, during and after the preceding IT sessions. PMID- 25822695 TI - Rapid detection of copper chlorophyll in vegetable oils based on surface-enhanced Raman spectroscopy. AB - The addition of copper chlorophyll and its derivatives (Cu-Chl) to vegetable oils to disguise them as more expensive oils, such as virgin olive oils, would not only create public confusion, but also disturb the olive oil market. Given that existing detection methods of Ch-Chl in oils, such as LC-MS are costly and time consuming, it is imperative to develop economical and fast analytical techniques to provide information quickly. This paper demonstrates a rapid analytical method based on surface-enhanced Raman spectroscopy (SERS) to detect Cu-Chl in vegetable oils; the spectroscopic markers of Cu-Chl are presented and a detection limit of 5 mg kg(-1) is demonstrated. The analysis of a series of commercial vegetable oils is undertaken with this method and the results verified by a government agency. This study shows that a SERS-based assessment method holds high potential for quickly pinpointing the addition of minute amounts of Cu-Chl in vegetable oils. PMID- 25822696 TI - Ultra-HPLC method for quality and adulterant assessment of steviol glycosides sweeteners - Stevia rebaudiana and stevia products. AB - Stevia products are advertised as a zero-calorie sweetener. Glucose should not be an intrinsic component of this product, but it has been identified from some of stevia products in a preliminary study. An UHPLC-UV method was developed for the quantitative determination of glucose from stevia products. After stevia products reacted with 1-phenyl-3-methyl-5-pyrazolone (PMP), PMP derivatives were analysed and glucose was found in seven out of 35 products in the range 0.3-91.5% (w/w). Two products, SPR-12 and SPR-27, showed remarkable amounts of glucose at 61.6% and 91.5%, respectively. In addition, an UHPLC-UV-evaporative light-scattering detector (ELSD) method was developed for the quantitative determination of rebaudioside A, stevioside, rebaudioside D, dulcoside A and steviolbioside from Stevia rebaudiana and related products. In a 12 min run, five steviol glycosides were baseline-separated. ELSD and ultraviolet (UV) detections showed comparable results. The LC methods were validated for linearity, repeatability, accuracy, limits of detection (LOD) and limits of quantification (LOQ). For steviol glycosides, the LODs and LOQs were found to be less than 10 and 30 MUg ml(-1), respectively. The RSD for intra- and inter-day analyses was less than 2.5%, and the recovery was 90-94%. For PMP derivative of glucose, the LOD and LOQ were 0.01 and 0.05 MUg ml(-1), respectively. Repeatability (RSD) was less than 2.6%; recovery was 98.6-101.7%. The methods are useful for the identification, quality assurance, and adulterant assessment of S. rebaudiana and steviol glycosides sweeteners (stevia products). PMID- 25822697 TI - A quantum dot-based immunoassay for screening of tylosin and tilmicosin in edible animal tissues. AB - A rapid, indirect competitive fluorescence-linked immunosorbent assay (ic-FLISA) based on quantum dots (QDs) as the fluorescent marker was developed for the detection of tylosin and tilmicosin in edible animal tissues. The end point fluorescent detection system was carried out using QDs conjugated with goat anti mouse secondary antibody. The limits of detection (LODs) for the determination of tylosin and tilmicosin were 0.02 and 0.04 MUg kg(-1), respectively. This detection method was used to analyse spiked samples and the recoveries ranged from 83.5% to 98.7% for tylosin and from 81.8% to 98.2% for tilmicosin. In real porcine tissue sample analysis, the results of ic-FLISA were similar to those obtained from an indirect competitive enzyme-linked immunosorbent assay (ic ELISA) to an HPLC method indicating its potential for tylosin and tilmicosin screening in edible animal tissues. PMID- 25822698 TI - Onward. PMID- 25822699 TI - Acute fractures of the pediatric foot and ankle. AB - BACKGROUND: Injuries around the foot and ankle are challenging. There is a paucity of literature, outside that of specialist orthopedic journals, that focuses on this subject in the pediatric population. DATA SOURCES: In this review, we outline pediatric foot and ankle fractures in an anatomically oriented manner from the current literature. Our aim is to aid the emergency department doctor to manage these challenging injuries more effectively in the acute setting. RESULTS: These injuries require a detailed history and examination to aid the diagnosis. Often, plain radiographs are sufficient, but more complex injuries require the use of magnetic resonance imaging. Treatment is dependent on the proximity to skeletal maturity and the degree of displacement of fracture. Children have a marked ability to remodel after fractures and therefore mainstay treatment is immobilization by a cast or splint. Operative fixation, although uncommon in this population, may be necessary with adolescents, certain unstable injuries or in cases with displaced articular surface. In the setting of severe foot trauma, skin compromise and compartment syndrome of the foot must be excluded. CONCLUSION: The integrity of the physis, articular surface and soft tissues are all equally important in treating these injuries. PMID- 25822700 TI - Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T cells to podocytes. AB - BACKGROUND: Nephrotic syndrome is the most common cause of kidney disease in children, but its pathogenesis remains unclear. This article reviews the novel aspects of the mechanisms underlying massive proteinuria in minimal-change disease, which is the most common form of childhood nephrotic syndrome. DATA SOURCES: This article integrates the findings of a PubMed database search for English language articles published in the past 40 years (from September 1974 to February 2014) using the key words "pathogenesis", "minimal change nephrotic syndrome" or "idiopathic nephrotic syndrome". RESULTS: Unknown humoral factors associated with T-cell dysfunction have been thought to play an important role in the pathogenesis of minimal-change disease. However, recent findings are changing this paradigm, i.e., visceral glomerular epithelial cells (podocytes) may be involved via expression of molecules such as CD80 and angiopoietin-like 4. CONCLUSIONS: Recent evidence suggests that minimal-change disease results from interactions between humoral factors and dysfunctional podocytes. In addition to immunosuppressant drugs that target lymphocytes, a biological agent such as an antibody against the abnormal molecule(s) expressed by podocytes may provide novel drug treatment for minimal-change disease. PMID- 25822702 TI - Double trisomy 48,XXX,+18 with multiple dysmorphic features. AB - BACKGROUND: Chromosomal abnormality is a common cause of congenital anomalies, psychiatric disorders, and mental retardation. However, the double trisomy 48,XXX,+18 is a rare chromosome abnormality. METHODS: Case report and literature review. RESULTS: A 7-hour-old girl presented to our unit because of poor response after birth. She presented with multiple dysmorphic features, including small for gestational age infant, flat nasal bridge, widely-spaced eyes, the left thumb deformities, flat facial profile, raised sternum, ventricular septal defect, the third lateral brain ventricle enlargement, and small liver. This case expands the spectrum of malformations reported in association with the double trisomy 48,XXX,+18. The literature on 16 fetuses or infants with the 48,XXX,+18 were also reviewed. CONCLUSION: These data suggested that in patients with clinical features similar to trisomy 18, especially with anomalies of the ears and/or reproductive malformations, double trisomy (48,XXX,+18) should be considered and karyotyping should be performed although it is a rare disease. PMID- 25822701 TI - Investigation of the status of interhospital transport of critically ill pediatric patients. AB - BACKGROUND: With the unequal distribution of medical resources in developing countries, critically ill children need to be transferred to tertiary hospitals from primary hospitals with limited resources. Although a large number of critically ill children are transferred each day in China, the standard process of inter-hospital transport is not formulated. METHODS: We retrospectively analyzed the data collected during transport. A total number of 9231 patients (<=14 years) who had been transferred to the Hunan Children's Hospital by a specialized team from primary hospitals from January 1, 2009 to June 30, 2012 were included in the study. RESULTS: Nearly half of the critically ill children were neonates (48.72%) and two thirds of the children were suffering from respiratory, neurological and cardiac diseases. Multivariate adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. Mobilization time in non-working hours was longer than the working hours (OR=1.186, 95% CI=1.059-1.329). Our study showed that mobilization time for neonates was shorter than that for older children (OR=0.801, 95% CI=0.692-0.928). The mobilization time of referral cases was shorter in areas within a radius of 50 km than in those within a radius of over 250 km (OR=0.427, 95% CI=0.350-0.521). Referred patients in summer needed a significantly shorter mobilization time than in winter (OR=0.705, 95% CI=0.616-0.806). CONCLUSION: Standardized processes and guidelines for inter-hospital transport would be essential to ensure effective transport of patients and reduce the mobilization activation time. PMID- 25822703 TI - Aluminum exposure and toxicity in neonates: sources, absorption, and retention. PMID- 25822704 TI - Aluminum exposure and toxicity inneonates: sources, absorption, and retention. PMID- 25822705 TI - Predictive role of free prostate-specific antigen in a prospective active surveillance program (PRIAS). AB - PURPOSE: To evaluate the utility of percentage of free serum PSA (%fPSA) as a predictor of adverse rebiopsy findings, treatment change and radical prostatectomy (RP) findings in a prospective active surveillance (AS) trial. METHODS: Patients enrolled in the global PRIAS study with baseline %fPSA available were included. Putative baseline predictors (e.g. PSA, %fPSA) of adverse rebiopsy findings were explored using logistic regression analysis. Association of variables with treatment change and RP findings over time were evaluated with Cox regression analysis. Active treatment-free survival was assessed with a Kaplan-Meier method. RESULTS: Of 3701 patients recruited to PRIAS, 939 had %fPSA measured at study entry. Four hundred and thirty-eight of them had %fPSA available after 1 year. Median follow-up was 17.2 months. First rebiopsy results were available for 595 patients and of those, 144 (24.2 %) had adverse findings. A total of 283 (30.1 %) patients discontinued surveillance, of those 181 (64.0 %) due to protocol-based reasons. Although median %fPSA values were significantly lower in patients who changed treatment, according to the multivariate regression analysis, initial %fPSA value was not predictive for treatment change or adverse rebiopsy findings. However, the probability of discontinuing AS was significantly lower in patients with "favourable" initial %fPSA characteristics and %fPSA during follow-up (initial %fPSA >=15 and positive %fPSA velocity) compared to those with "adverse" %fPSA characteristics (initial %fPSA <15 and negative %fPSA velocity). CONCLUSIONS: Diagnostic %fPSA provides no additional prognostic value when compared to other predictors already in use in AS protocols. However, %fPSA velocity during surveillance may aid in predicting the probability for future treatment change. PMID- 25822706 TI - Differences in practice patterns between urologists and radiation oncologists in the management of localized prostate cancer: a cross-sectional survey. AB - INTRODUCTION: Through a cross-sectional survey, we tried to assess whether practices of urologists and radiation oncologists are uniform when faced with similar clinical situations. MATERIALS AND METHODS: A self-administered questionnaire was mailed to all French urologists and radiation oncologists. Respondents were asked about their practices through 11 case scenarios. The scenarios cover most of localized prostate cancer situations and were gradually organized depending on prostate cancer progression risk and the age of the patient. The eight first scenarios address the situation of treatment-naive patients, and the last cases were about the management of patients after radical prostatectomy. Physicians were asked to choose a treatment modality for each case. The responses were first stratified according to the intention to treat: either curative-intent treatment or palliative. The curative-treatment modality chosen were afterward assessed. The responses to clinical scenarios were compared between the two specialties. RESULTS: Concerning the intention to treat, practice patterns were overall consistent except in one case. Indeed, a higher rate of radiation oncologists prefer curative-intent treatment for intermediate-risk prostate cancer in aged patients: 57.4 versus 14.6 % (p < 0.001). Each medical specialist prefers the treatment that he himself delivers (p < 0.005). For intermediate-risk prostate cancer in 65-year-old patient: 96.5 % of urologists chose radical prostatectomy versus 37.7 % of radiation oncologists (p < 0.001). Fewer urologists (almost 14 %) compared to radiation oncologists (47.5 %) would prescribe adjuvant treatment after radical prostatectomy for T3a R0 prostate cancer with post-operative PSA undetectable (p < 0.001). CONCLUSION: Significant differences were found in therapeutic approach between the two main specialties that deal with localized prostate cancer. PMID- 25822707 TI - Retroperitoneal laparoscopic ureterolithotomy in comparison with ureteroscopic lithotripsy in the management of impacted upper ureteral stones larger than 12 mm. AB - OBJECTIVE: To compare the results of ureteroscopic lithotripsy (URSL) with retroperitoneal laparoscopic ureterolithotomy (RPLU) as two minimally invasive techniques in the management of proximal ureteral stones larger than 12 mm. PATIENTS AND METHODS: From January 2009 to October 2013, patients with impacted unilateral upper ureteral stones larger than 12 mm were enrolled including 182 males and 93 females with a medium age of 40 years (22-72 years). Patients were randomized to receive URSL (139 cases) with semirigid ureteroscope or RPLU (136 cases). RESULTS: Stone size was similar in RPLU and URSL groups (13.8 +/- 1.9 vs 13.6 +/- 1.4 mm, P = 0.312). Operating time and hospitalizing days in URSL group were significantly shorter than those in RPLU group (P < 0.001), whereas stone clearance rate was significantly higher in RPLU group (97.1 vs 89.9 %, P = 0.017). Ureteral strictures happened higher in URSL group (5 patients, 3.6 %) than RPLU group (2 patients, 1.5 %) with no statistical significance, while the strictures requiring surgical intervention were significantly higher in URSL group (4 cases) (2.9 vs 0 %, P = 0.046). CONCLUSION: RPLU could provide better stone clearance rate than semirigid URSL for upper ureteral impacted stones larger than 12 mm. It may also reduce the chance of surgical intervention for postoperative ureteral stricture. PMID- 25822708 TI - Mechatronic design and locomotion control of a robotic thunniform swimmer for fast cruising. AB - This paper presents mechatronic design and locomotion control of a biomimetic robotic fish that swims using thunniform kinematics for fast cruising. Propulsion of the robotic fish is realized with a parallel four-bar propulsive mechanism that delivers combined translational and rotational motion to a lunate caudal fin. A central pattern generator controller, composed of two unidirectionally coupled Hopf oscillators, is employed to generate robust, smooth and coordinated oscillatory control signals for the tail joints. In order to maintain correct phase relation between joints during fast tail beating, a novel phase adjusting mechanism is proposed and incorporated into the controller. The attitude of the robotic fish in fast swimming is stabilized using an attitude and heading reference system unit and a pair of pitching pectoral fins. The maximum speed of the robotic fish can reach 2.0 m s(-1), which is the fastest speed that robotic fishes have achieved. Its outstanding swimming performance presents possibilities for deployment to real-world exploration, probe and survey missions. PMID- 25822709 TI - Homocysteine and cognitive disorders of postmenopausal women measured by a battery of computer tests--central nervous system vital signs. AB - The purpose of the study was the analysis of cognitive functions in postmenopausal women having different status of homocysteine levels by a battery of computer tests-central nervous system vital signs (CNS-VS). We examined whether homocysteine increases the risk of cognitive decline and which cognitive domains are more affected. We showed that the considerably better neurocognitive index was obtained by women with low homocysteine levels in comparison with those with hyperhomocysteinemia (p = 0.0017). Similarly, results were obtained in the field of executive functioning (p = 0.0011), complex attention (p = 0.0106), cognitive flexibility (p = 0.0016), and memory (p = 0.0145). Verbal memory and visual memory did not differ considerably among the studied groups. Also, we demonstrated that epsilon4/epsilon4 genotype was the most common (15.5 %) in women with hyperhomocysteinemia than in groups of patients with low (0 %) or normal (1.9 %) homocysteine levels. In summary, hyperhomocysteinemia was related with increased risk of decline in executive functioning, complex attention, cognitive flexibility, and memory in postmenopausal women. PMID- 25822710 TI - Different perceptions of stress, coping styles, and general well-being among pregnant Chinese women: a structural equation modeling approach. AB - Few studies have examined different perceptions of stress or explored the positive aspects of well-being among pregnant Chinese women, so there is a need to explore these phenomena in order to fill the research gap. The aim of this study was to examine the relationships among the different perceptions of stress, coping styles, and general well-being using a structural equation modeling approach. We examined a hypothetical model among 755 pregnant Chinese women based on the integration of theoretical models. The Perceived Stress Scale (PSS), the Trait Coping Styles Questionnaire (TCSQ), and the General Well-Being Schedule (GWB) were used to measure perceived stress, coping styles, and general well being, respectively. A structural equation model showed that positive and negative perceptions of stress significantly influenced positive and negative coping styles, respectively. Different perceptions of stress were significantly associated with general well-being, but different coping styles had no significant effects on general well-being. The model had a good fit to the data (IFI = 0.910, TLI = 0.904, CFI = 0.910, and RMSEA = 0.038). Different perception of stress was able to predict significant differences in coping styles and general well-being. PMID- 25822711 TI - Novel role of mitochondrial manganese superoxide dismutase in STAT3 dependent pluripotency of mouse embryonic stem cells. AB - Leukemia Inhibitory Factor (LIF)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway maintains the stemness and pluripotency of mouse embryonic stem cells (mESCs). Detailed knowledge on key intermediates in this pathway as well as any parallel pathways is largely missing. We initiated our study by investigating the effect of small molecule Curcumin on various signalling pathways essential for self-renewal. Curcumin sustained the LIF independent self-renewal of mESCs and induced pluripotent stem cells (miPSCs) in a STAT3 activity dependent manner. Gene expression analysis showed LIF/STAT3 and redox signaling components to be majorly modulated. Amongst ROS genes, expression of Manganese Superoxide Dismutase (MnSOD) specifically relied on STAT3 signaling as evidenced by STAT3 inhibition and reporter assay. The silencing of MnSOD, but not Cu-ZnSOD expression, resulted in the loss of mESC pluripotency in presence of LIF, and the overexpression of MnSOD is sufficient for maintaining the expression of pluripotent genes in the absence of STAT3 signaling. Finally, we demonstrate MnSOD to stabilize the turnover of pluripotent proteins at the post-translational level by modulating proteasomal activity. In conclusion, our findings unravel a novel role of STAT3 mediated MnSOD in the self-renewal of mESCs. PMID- 25822712 TI - Why Can dl-Sotalol Prolong the QT Interval In Vivo Despite Its Weak Inhibitory Effect on hERG K(+) Channels In Vitro? Electrophysiological and Pharmacokinetic Analysis with the Halothane-Anesthetized Guinea Pig Model. AB - In order to bridge the gap of action of dl-sotalol between the human ether-a-go go-related gene (hERG) K(+) channel inhibition in vitro and QT-interval prolongation in vivo, its electropharmacological effect and pharmacokinetic property were simultaneously studied in comparison with those of 10 drugs having potential to prolong the QT interval (positive drugs: bepridil, haloperidol, dl sotalol, terfenadine, thioridazine, moxifloxacin, pimozide, sparfloxacin, diphenhydramine, imipramine and ketoconazole) and four drugs lacking such property (negative drugs: enalapril, phenytoin, propranolol or verapamil) with the halothane-anesthetized guinea pig model. A dose of each drug that caused 10 % prolongation of Fridericia-corrected QT interval (QTcF) was calculated, which was compared with respective known hERG K(+) IC50 value and currently obtained heart/plasma concentration ratio. Each positive drug prolonged the QTcF in a dose related manner, whereas such effect was not observed by the negative drugs. Drugs with more potent hERG K(+) channel inhibition showed higher heart/plasma concentration ratio, resulting in more potent QTcF prolongation in vivo. The potency of dl-sotalol for QTcF prolongation was flat middle, although its hERG K(+) channel inhibitory property as well as heart/plasma concentration ratio was the smallest among the positive drugs, which may be partly explained by its lack of binding to plasma protein. PMID- 25822713 TI - Lysophosphatidic acid alters the expression profiles of angiogenic factors, cytokines, and chemokines in mouse liver sinusoidal endothelial cells. AB - BACKGROUND AND AIMS: Lysophosphatidic acid (LPA) is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR) expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs) play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs. METHODS: Mouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR's and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA). Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor. RESULTS: LPAR1 and LPAR3 mRNA's were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1), cytokines (C5/C5a, M-CSF, and SDF-1), and chemokines (MCP-5, gp130, CCL28, and CXCL16). The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism. CONCLUSION: LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration. PMID- 25822714 TI - Pharmacological and Morphological Evidence of AMPK-Mediated Energy Sensing in the Lower Brain Stem Ependymocytes to Control Reproduction in Female Rodents. AB - Ependymocytes are one of the energy-sensing cells that regulate animal reproduction through their responsiveness to changes in extracellular glucose levels and the expression of pancreatic-type glucokinase and glucose transporter 2, which play a critical role in sensing blood glucose levels in pancreatic beta cells. Molecular mechanisms underlying glucose sensing in the ependymocytes remain poorly understood. The AMP-activated protein kinase (AMPK), a serine/threonine kinase highly conserved in all eukaryotic cells, has been suggested to be an intracellular fuel gauge that detects cellular energy status. The present study aims to clarify the role AMPK of the lower brainstem ependymocytes has in sensing glucose levels to regulate reproductive functions. First, we will show that administration of 5-aminoimidazole-4-carboxamide-1-beta D-ribofuranoside, an AMPK activator, into the 4th ventricle suppressed pulsatile LH release in female rats. Second, we will demonstrate the presence of AMPK catalytic subunit immunoreactivities in the rat lower brainstem ependymocytes. Third, transgenic mice were generated to visualize the ependymocytes with Venus, a green fluorescent protein, expressed under the control of the mouse vimentin promoter for further in vitro study. The Venus-labeled ependymocytes taken from the lower brainstem of transgenic mice revealed that AMPK activation by 5 aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an AMPK activator, increased in vitro intracellular calcium concentrations. Taken together, malnutrition-induced AMPK activation of ependymocytes of the lower brainstem might be involved in suppression of GnRH/LH release and then gonadal activities. PMID- 25822715 TI - The GHKL ATPase MORC1 Modulates Species-Specific Plant Immunity in Solanaceae. AB - The microrchidia (MORC) proteins, a subset of the GHKL ATPase superfamily, were recently described as components involved in transcriptional gene silencing and plant immunity in Arabidopsis. To assess the role of MORC1 during resistance to Phytophthora infestans in solanaceous species, we altered the expression of the corresponding MORC1 homologs in potato, tomato, and Nicotiana benthamiana. Basal resistance to P. infestans was compromised in StMORC1-silenced potato and enhanced in overexpressing lines, indicating that StMORC1 positively affects immunity. By contrast, silencing SlMORC1 expression in tomato or NbMORC1 expression in N. benthamiana enhanced basal resistance to this oomycete pathogen. In addition, silencing SlMORC1 further enhanced resistance conferred by two resistance genes in tomato. Transient expression of StMORC1 in N. benthamiana accelerated cell death induced by infestin1 (INF1), whereas SlMORC1 or NbMORC1 suppressed it. Domain-swapping and mutational analyses indicated that the C terminal region dictates the species-specific effects of the solanaceous MORC1 proteins on INF1-induced cell death. This C-terminal region also was required for homodimerization and phosphorylation of recombinant StMORC1 and SlMORC1, and its transient expression induced spontaneous cell death in N. benthamiana. Thus, this C-terminal region likely plays important roles in both determining and modulating the biological activity of MORC1 proteins. PMID- 25822716 TI - Evaluation of health promotion training for the Western Australian Aboriginal maternal and child health sector. AB - ISSUE ADDRESSED: The evaluation of health promotion training for the Western Australian (WA) Aboriginal maternal and child health (MCH) sector. METHODS: Fifty one MCH professionals from five regions in WA who attended one of three health promotion short courses in 2012-2013 were invited to complete an online survey or a telephone interview, between 4 to 17 months post-course. Respondents were asked how they had utilised the information and resources from the training and to identify the enabling factors or barriers to integrating health promotion into their work practices subsequently. RESULTS: Overall response rate was 33% (n=17); 94% of respondents reported they had utilised the information and resources from the course and 76% had undertaken health promotion activities since attending the course. Building contacts with other MCH providers and access to planning tools were identified as valuable components of the course. Barriers to translating knowledge into practice included financial constraints and lack of organisational support for health promotion activity. CONCLUSIONS: Health promotion training provides participants with the skills and confidence to deliver health promotion strategies in their communities. The training presents an opportunity to build health professionals' capacity to address some determinants of poor health outcomes among pregnant Aboriginal women and their babies. SO WHAT?: Training would be enhanced if accompanied by ongoing support for participants to integrate health promotion into their work practice, organisational development including health promotion training for senior management, establishing stronger referral pathways among partner organisations to support continuity of care and embedding training into MCH workforce curricula. PMID- 25822717 TI - Macrophages support splenic erythropoiesis in 4T1 tumor-bearing mice. AB - Anemia is a common complication of cancer; a role of spleen in tumor-stress erythropoiesis has been suggested. However, the molecular mechanisms involved in the splenic erythropoiesis following tumor maintenance remain poorly understood. Here we show that tumor development blocks medullar erythropoiesis by granulocyte colony-stimulating factor (G-CSF) and then causes anemia in murine 4T1 breast tumor-bearing mice. Meanwhile, tumor-stress promotes splenic erythropoiesis. Splenectomy worsened tumor-induced anemia, and reduced tumor volume and tumor weight, indicating the essential role of spleen in tumor-stress erythropoiesis and tumor growth. Tumor progression of these mice led to increased amounts of bone morphogenetic protein 4 (BMP4) in spleen. The in vivo role of macrophages in splenic erythropoiesis under tumor-stress conditions was investigated. Macrophage depletion by injecting liposomal clodronate decreased the expression of BMP4, inhibited splenic erythropoiesis, aggravated the tumor-induced anemia and suppressed tumor growth. Our results provide insight that macrophages and BMP4 are positive regulators of splenic erythropoiesis in tumor pathological situations. These findings reveal that during the tumor-stress period, the microenvironment of the spleen is undergoing changes, which contributes to adopt a stress erythropoietic fate and supports the expansion and differentiation of stress erythroid progenitors, thereby replenishing red blood cells and promoting tumor growth. PMID- 25822718 TI - Lesion of the olfactory epithelium accelerates prion neuroinvasion and disease onset when prion replication is restricted to neurons. AB - Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain. PMID- 25822719 TI - Evaluation of two influenza surveillance systems in South Africa. AB - BACKGROUND: The World Health Organisation recommends outpatient influenza-like illness (ILI) and inpatient severe acute respiratory illness (SARI) surveillance. We evaluated two influenza surveillance systems in South Africa: one for ILI and another for SARI. METHODOLOGY: The Viral Watch (VW) programme has collected virological influenza surveillance data voluntarily from patients with ILI since 1984 in private and public clinics in all 9 South African provinces. The SARI surveillance programme has collected epidemiological and virological influenza surveillance data since 2009 in public hospitals in 4 provinces by dedicated personnel. We compared nine surveillance system attributes from 2009-2012. RESULTS: We analysed data from 18,293 SARI patients and 9,104 ILI patients. The annual proportion of samples testing positive for influenza was higher for VW (mean 41%) than SARI (mean 8%) and generally exceeded the seasonal threshold from May to September (VW: weeks 21-40; SARI: weeks 23-39). Data quality was a major strength of SARI (most data completion measures >90%; adherence to definitions: 88-89%) and a relative weakness of the VW programme (62% of forms complete, with limited epidemiologic data collected; adherence to definitions: 65-82%). Timeliness was a relative strength of both systems (e.g. both collected >93% of all respiratory specimens within 7 days of symptom onset). ILI surveillance was more nationally representative, financially sustainable and expandable than the SARI system. Though the SARI programme is not nationally representative, the high quality and detail of SARI data collection sheds light on the local burden and epidemiology of severe influenza-associated disease. CONCLUSIONS: To best monitor influenza in South Africa, we propose that both ILI and SARI should be under surveillance. Improving ILI surveillance will require better quality and more systematic data collection, and SARI surveillance should be expanded to be more nationally representative, even if this requires scaling back on information gathered. PMID- 25822721 TI - Molecular and quantitative genetic differentiation in Sitobion avenae populations from both sides of the Qinling Mountains. AB - Quantitative trait differences are often assumed to be correlated with molecular variation, but the relationship is not certain, and empirical evidence is still scarce. To address this issue, we sampled six populations of the cereal aphid Sitobion avenae from areas north and south of the Qinling Mountains, and characterized their molecular variation at seven microsatellite loci and quantitative variation at nine life-history traits. Our results demonstrated that southern populations had slightly longer developmental times of nymphs but much higher lifetime fecundity, compared to northern populations. Of the nine tested quantitative characters, eight differed significantly among populations within regions, as well as between northern and southern regions. Genetic differentiation in neutral markers was likely to have been caused by founder events and drift. Increased subdivision for quantitative characters was found in northern populations, but reduced in southern populations. This phenomenon was not found for molecular characters, suggesting the decoupling between molecular and quantitative variation. The pattern of relationships between FST and QST indicated divergent selection and suggested that local adaptation play a role in the differentiation of life-history traits in tested S. avenae populations, particularly in those traits closely related to reproduction. The main role of natural selection over genetic drift was also supported by strong structural differences in G-matrices among S. avenae populations. However, cluster analyses did not result in two groups corresponding to northern and southern regions. Genetic differentiation between northern and southern populations in neutral markers was low, indicating considerable gene flow between them. The relationship between molecular and quantitative variation, as well as its implications for differentiation and evolution of S. avenae populations, was discussed. PMID- 25822720 TI - Short-term heart rate variability--influence of gender and age in healthy subjects. AB - In the recent years, short-term heart rate variability (HRV) describing complex variations of beat-to-beat interval series that are mainly controlled by the autonomic nervous system (ANS) has been increasingly analyzed to assess the ANS activity in different diseases and under various conditions. In contrast to long term HRV analysis, short-term investigations (<30 min) provide a test result almost immediately. Thus, short-term HRV analysis is suitable for ambulatory care, patient monitoring and all those applications where the result is urgently needed. In a previous study, we could show significant variations of 5-min HRV indices according to age in almost all domains (linear and nonlinear) in 1906 healthy subjects from the KORA S4 cohort. Based on the same group of subjects, general gender-related influences on HRV indices are to be determined in this study. Short-term 5-min HRV indices from linear time and frequency domain and from nonlinear methods (compression entropy, detrended fluctuation analysis, traditional and segmented Poincare plot analysis, irreversibility analysis, symbolic dynamics, correlation and mutual information analysis) were determined from 782 females and 1124 males. First, we examined the gender differences in two age clusters (25-49 years and 50-74 years). Secondly, we investigated the gender specific development of HRV indices in five age decade categories, namely for ages 25-34, 35-44, 45-54, 55-64 and 65-74 years. In this study, significant modifications of the indices according to gender could be obtained, especially in the frequency domain and correlation analyses. Furthermore, there were significant modifications according to age in nearly all of the domains. The gender differences disappeared within the last two age decades and the age dependencies disappeared in the last decade. To summarize gender and age influences need to be considered when performing HRV studies even if these influences only partly differ. PMID- 25822722 TI - Transcriptome analysis of resistant and susceptible alfalfa cultivars infected with root-knot nematode Meloidogyne incognita. AB - Nematodes are one of the major limiting factors in alfalfa production. Root-knot nematodes (RKN, Meloidogyne spp.) are widely distributed and economically important sedentary endoparasites of agricultural crops and they may inflict significant damage to alfalfa fields. As of today, no studies have been published on global gene expression profiling in alfalfa infected with RKN or any other plant parasitic nematode. Very little information is available about molecular mechanisms that contribute to pathogenesis and defense responses in alfalfa against these pests and specifically against RKN. In this work, we performed root transcriptome analysis of resistant (cv. Moapa 69) and susceptible (cv. Lahontan) alfalfa cultivars infected with RKN Meloidogyne incognita, widespread root-knot nematode species and a major pest worldwide. A total of 1,701,622,580 pair-end reads were generated on an Illumina Hi-Seq 2000 platform from the roots of both cultivars and assembled into 45,595 and 47,590 transcripts in cvs Moapa 69 and Lahontan, respectively. Bioinformatic analysis revealed a number of common and unique genes that were differentially expressed in susceptible and resistant lines as a result of nematode infection. Although the susceptible cultivar showed a more pronounced defense response to the infection, feeding sites were successfully established in its roots. Characteristically, basal gene expression levels under normal conditions differed between the two cultivars as well, which may confer advantage to one of the genotypes toward resistance to nematodes. Differentially expressed genes were subsequently assigned to known Gene Ontology categories to predict their functional roles and associated biological processes. Real-time PCR validated expression changes in genes arbitrarily selected for experimental confirmation. Candidate genes that contribute to protection against M. incognita in alfalfa were proposed and alfalfa-nematode interactions with respect to resistance are discussed. PMID- 25822723 TI - Generating Inner Ear Organoids from Mouse Embryonic Stem Cells. AB - This protocol describes a three-dimensional culture method for generating inner ear sensory epithelia, which comprises sensory hair cells and a concurrently arising neuronal population. Mouse embryonic stem cells are initially plated in 96-well plates with differentiation media; following aggregation, Matrigel is added in order to promote epithelialization. A series of small molecule applications is then used over the first 14 days of culture to guide differentiation towards an otic lineage. After 16-20 days, vesicles containing inner ear sensory hair cells and supporting cells arise from the cultured aggregates. Aggregates may be analyzed using immunohistochemistry and electrophysiology techniques. This system serves as a simple and relatively inexpensive in vitro model of inner ear development. PMID- 25822724 TI - Definitive Endoderm Differentiation of Human Embryonic Stem Cells Combined with Selective Elimination of Undifferentiated Cells by Methionine Deprivation. AB - Human embryonic stem cells (ESCs) show a characteristic feature in that they are highly dependent on methionine metabolism. Undifferentiated human ESCs cannot survive under the condition that methionine is deprived from culture medium. We describe here a procedure for definitive endoderm differentiation from human ESCs, in which human ESCs are subject to 10 days (d) differentiation combined with methionine deprivation between differentiation day (d) 8 to d10. Methionine deprivation results in elimination of undifferentiated cells from the culture with no significant loss of definitive endoderm cells, as compared to those cultured under complete condition throughout the whole culture period. PMID- 25822725 TI - Delivering Antisense Morpholino Oligonucleotides to Target Telomerase Splice Variants in Human Embryonic Stem Cells. AB - Morpholino oligonucleotides (MO) are an innovative tool that provides a means for examining and modifying gene expression outcomes by antisense interaction with targeted RNA transcripts. The site-specific nature of their binding facilitates focused modulation to alter splice variant expression patterns. Here we describe the steric-blocking of human telomerase reverse transcriptase (hTERT) Deltaalpha and Deltabeta splice variants using MO to examine cellular outcomes related to pluripotency and differentiation in human embryonic stem cells. PMID- 25822727 TI - No-needle, single-visit adult male circumcision with Unicirc: a multi-centre field trial. AB - BACKGROUND: Voluntary medical male circumcision (VMMC) is a priority HIV preventive intervention. Current adult circumcision methods need improvement. METHODS: Field trial in 3 primary care centres. Minimally invasive VMMC using the Unicirc instrument following topical lidocaine/prilocaine anesthetic. Men were followed up at 1 and 4 weeks. RESULTS: We circumcised 110 healthy volunteers. Two men complained of transient burning pain during circumcision, but none required injectable anaesthesia. Median blood loss was 1ml and median procedure time was 9.0 min. There were 7 (6.3%) moderate complications (5 (4.5%) post-operative bleeds requiring suture and 2 (1.8%) post-operative infections) affecting 7 men. No men experienced significant wound dehiscence. 90.4% of men were fully healed at 4 weeks of follow-up and all were highly satisfied. CONCLUSIONS: Use of topical anaesthesia obviates the need for injectable anesthetic and makes the Unicirc procedure nearly painless. Unicirc is rapid, easy to learn, heals by primary intention with excellent cosmetic results, obviates the need for a return visit for device removal, and is potentially cheaper and safer than other methods. Use of this method will greatly facilitate scale-up of mass circumcision programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02091726. PMID- 25822726 TI - Biosorption of Cr(VI) by Ceratocystis paradoxa MSR2 using isotherm modelling, kinetic study and optimization of batch parameters using response surface methodology. AB - This study is focused on the possible use of Ceratocystis paradoxa MSR2 native biomass for Cr(VI) biosorption. The influence of experimental parameters such as initial pH, temperature, biomass dosage, initial Cr(VI) concentration and contact time were optimized using batch systems as well as response surface methodology (RSM). Maximum Cr(VI) removal of 68.72% was achieved, at an optimal condition of biomass dosage 2 g L(-1), initial Cr(VI) concentration of 62.5 mg L(-1) and contact time of 60 min. The closeness of the experimental and the predicted values exhibit the success of RSM. The biosorption mechanism of MSR2 biosorbent was well described by Langmuir isotherm and a pseudo second order kinetic model, with a high regression coefficient. The thermodynamic study also revealed the spontaneity and exothermic nature of the process. The surface characterization using FT-IR analysis revealed the involvement of amine, carbonyl and carboxyl groups in the biosorption process. Additionally, desorption efficiency of 92% was found with 0.1 M HNO3. The Cr(VI) removal efficiency, increased with increase in metal ion concentration, biomass concentration, temperature but with a decrease in pH. The size of the MSR2 biosorbent material was found to be 80 MUm using particle size analyzer. Atomic force microscopy (AFM) visualizes the distribution of Cr(VI) on the biosorbent binding sites with alterations in the MSR2 surface structure. The SEM-EDAX analysis was also used to evaluate the binding characteristics of MSR2 strain with Cr(VI) metals. The mechanism of Cr(VI) removal of MSR2 biomass has also been proposed. PMID- 25822728 TI - Correction: Integrated analysis of residue coevolution and protein structures capture key protein sectors in HIV-1 proteins. PMID- 25822729 TI - Conservation and losses of non-coding RNAs in avian genomes. AB - Here we present the results of a large-scale bioinformatics annotation of non coding RNA loci in 48 avian genomes. Our approach uses probabilistic models of hand-curated families from the Rfam database to infer conserved RNA families within each avian genome. We supplement these annotations with predictions from the tRNA annotation tool, tRNAscan-SE and microRNAs from miRBase. We identify 34 lncRNA-associated loci that are conserved between birds and mammals and validate 12 of these in chicken. We report several intriguing cases where a reported mammalian lncRNA, but not its function, is conserved. We also demonstrate extensive conservation of classical ncRNAs (e.g., tRNAs) and more recently discovered ncRNAs (e.g., snoRNAs and miRNAs) in birds. Furthermore, we describe numerous "losses" of several RNA families, and attribute these to either genuine loss, divergence or missing data. In particular, we show that many of these losses are due to the challenges associated with assembling avian microchromosomes. These combined results illustrate the utility of applying homology-based methods for annotating novel vertebrate genomes. PMID- 25822730 TI - Effectiveness of surgery for lumbar spinal stenosis: a systematic review and meta analysis. AB - BACKGROUND: The management of spinal stenosis by surgery has increased rapidly in the past two decades, however, there is still controversy regarding the efficacy of surgery for this condition. Our aim was to investigate the efficacy and comparative effectiveness of surgery in the management of patients with lumbar spinal stenosis. METHODS: Electronic searches were performed on MEDLINE, EMBASE, AMED, CINAHL, Web of Science, LILACS and Cochrane Library from inception to November 2014. Hand searches were conducted on included articles and relevant reviews. We included randomised controlled trials evaluating surgery compared to no treatment, placebo/sham, or to another surgical technique in patients with lumbar spinal stenosis. Primary outcome measures were pain, disability, recovery and quality of life. The PEDro scale was used for risk of bias assessment. Data were pooled with a random-effects model, and the GRADE approach was used to summarise conclusions. RESULTS: Nineteen published reports (17 trials) were included. No trials were identified comparing surgery to no treatment or placebo/sham. Pooling revealed that decompression plus fusion is not superior to decompression alone for pain (mean difference -3.7, 95% confidence interval -15.6 to 8.1), disability (mean difference 9.8, 95% confidence interval -9.4 to 28.9), or walking ability (risk ratio 0.9, 95% confidence interval 0.4 to 1.9). Interspinous process spacer devices are slightly more effective than decompression plus fusion for disability (mean difference 5.7, 95% confidence interval 1.3 to 10.0), but they resulted in significantly higher reoperation rates when compared to decompression alone (28% v 7%, P < 0.001). There are no differences in the effectiveness between other surgical techniques for our main outcomes. CONCLUSIONS: The relative efficacy of various surgical options for treatment of spinal stenosis remains uncertain. Decompression plus fusion is not more effective than decompression alone. Interspinous process spacer devices result in higher reoperation rates than bony decompression. PMID- 25822731 TI - Tunable collagen I hydrogels for engineered physiological tissue micro environments. AB - Collagen I hydrogels are commonly used to mimic the extracellular matrix (ECM) for tissue engineering applications. However, the ability to design collagen I hydrogels similar to the properties of physiological tissues has been elusive. This is primarily due to the lack of quantitative correlations between multiple fabrication parameters and resulting material properties. This study aims to enable informed design and fabrication of collagen hydrogels in order to reliably and reproducibly mimic a variety of soft tissues. We developed empirical predictive models relating fabrication parameters with material and transport properties. These models were obtained through extensive experimental characterization of these properties, which include compression modulus, pore and fiber diameter, and diffusivity. Fabrication parameters were varied within biologically relevant ranges and included collagen concentration, polymerization pH, and polymerization temperature. The data obtained from this study elucidates previously unknown fabrication-property relationships, while the resulting equations facilitate informed a priori design of collagen hydrogels with prescribed properties. By enabling hydrogel fabrication by design, this study has the potential to greatly enhance the utility and relevance of collagen hydrogels in order to develop physiological tissue microenvironments for a wide range of tissue engineering applications. PMID- 25822732 TI - MicroPET Evaluation of a Hydroxamate-Based MMP Inhibitor, [(18)F]FB-ML5, in a Mouse Model of Cigarette Smoke-Induced Acute Airway Inflammation. AB - Matrix metalloproteinases (MMPs) are the main proteolytic enzymes involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). A radiolabeled MMP inhibitor, [(18)F]FB-ML5, was prepared, and its in vivo kinetics were tested in a mouse model of pulmonary inflammation. BALB/c mice were exposed for 4 days to cigarette smoke (CS) or air. On the fifth day, a dynamic microPET scan was made with [(18)F]FB-ML5. Standardized uptake values (PET-SUVmean) were 0.19 +/- 0.06 in the lungs of CS-exposed mice (n = 6) compared to 0.11 +/- 0.03 (n = 5) in air exposed controls (p < 0.05), 90 min post-injection MMP-9 levels in bronchoalveolar lavage fluid (BALF) were increased from undetectable level to 4615 +/- 1963 pg/ml by CS exposure. Increased MMP expression in a COPD mouse model was shown to lead to increased retention of [(18)F]FB-ML5. PMID- 25822733 TI - Co-inheritance of G6PD and PK deficiencies in a neonate carrying a Novel UGT1A1 genotype associated to Crigler-Najjar type II syndrome. PMID- 25822734 TI - Changed clonal growth form induced by sand burial facilitates the acclimation of Carex brevicuspis to competition. AB - Both competition and burial are important factors that influence plant growth and structuring plant communities. Competition intensity may decline with increased burial stress. However, experimental evidence is scarce. The aim of this study was to elucidate the role of burial stress in influencing plant competition by investigating biomass accumulation, biomass allocation, and clonal growth performance of Carex brevicuspis, one of the dominant species in the Dongting Lake wetland in China. The experiment was conducted with two typical wetland species, C. brevicuspis (target plant) and Polygonum hydropiper (neighbor plant), in a target-neighbor design containing three densities (0, 199, and 398 neighbor plants m-2) and two burial depths (0 and 12 cm). The biomass accumulation of C. brevicuspis decreased with increment of P. hydropiper density in the 0 cm burial treatment. However, in the 12 cm burial treatment, biomass accumulation of C. brevicuspis did not change under medium and high P. hydropiper densities. The relative neighbor effect index (RNE) increased with enhancement of P. hydropiper density but decreased with increasing burial depth. The shoot mass fraction decreased with P. hydropiper density in the 12 cm burial treatments, but the root mass fraction was only affected by burial depth. However, the rhizome mass fraction increased with both P. hydropiper density and burial depth. The number of ramets decreased with increasing P. hydropiper density. With increasing burial depth and density, the proportion of spreading ramets increased from 34.23% to 80.44%, whereas that of clumping ramets decreased from 65.77% to 19.56%. Moreover, increased P. hydropiper density and burial depth led to greater spacer length. These data indicate that the competitive effect of P. hydropiper on C. brevicuspis was reduced by sand burial, which was reflected by different patterns of biomass accumulation and RNE at the two burial depth treatments. A change from a phalanx to a guerrilla growth form and spacer elongation induced by sand burial helped C. brevicuspis to acclimate to competition. PMID- 25822735 TI - Phototautomerization in pyrrolylphenylpyridine terphenyl systems. AB - [4-(2-Pyrrolyl)phenyl]pyridines 2-4 were synthesized and their photophysical properties and reactivity in phototautomerization reactions investigated by fluorescence spectroscopy and laser flash photolysis (LFP). The pKa for the protonation of the pyridine nitrogen in 2-4 was determined by UV-vis and fluorescence titration (pKa = 5.5 for 4). On excitation in polar protic solvents, 2-4 populate charge-transfer states leading to an enhanced basicity of the pyridine (pKa* ~ 12) and enhanced acidity of pyrrole (pKa* ~ 8-9) enabling excited-state proton transfer (ESPT). ESPT gives rise to phototautomers and significantly quenches the fluorescence of 2-4. Phototautomers 2-T and 4-T were detected by LFP with strong transient absorption maxima at 390 nm. Phototautomers 2-T and 4-T decayed by competing uni- and bimolecular reactions. However, at pH 11 the decay of 4-T followed exponential kinetics with a rate constant of 4.2 * 10(6) s(-1). The pyridinium salt 4H(+) forms a stable complex with cucurbit[7]uril (CB[7]) with 1:1 stoichiometry (beta11 = (1.0 +/- 0.2) * 10(5) M( 1), [Na(+)] = 39 mM). Complexation to CB[7] increased the pKa for 4H(+) (pKa = 6.9) and changed its photochemical reactivity. Homolytic cleavage of the pyrrole NH leads to the formation of an N-radical because of the decreased acidity of the pyrrole in the inclusion complex. PMID- 25822736 TI - Bespoke SnAP reagents for the synthesis of C-substituted spirocyclic and bicyclic saturated N-heterocycles. AB - The precise placement of C-substituents on bicyclic and spirocyclic N heterocycles is readily achieved by the combination of aldehydes and new SnAP reagents. The substituted SnAP reagents are readily prepared from simple starting materials and couple with a variety of aromatic and heteroaromatic aldehydes at room temperature under operationally simple conditions to deliver substituted morpholine and piperazine products. PMID- 25822738 TI - The identification of loci for immune traits in chickens using a genome-wide association study. AB - The genetic improvement of disease resistance in poultry continues to be a challenge. To identify candidate genes and loci responsible for these traits, genome-wide association studies using the chicken 60k high density single nucleotide polymorphism (SNP) array for six immune traits, total serum immunoglobulin Y (IgY) level, numbers of, and the ratio of heterophils and lymphocytes, and antibody responses against Avian Influenza Virus (AIV) and Sheep Red Blood Cell (SRBC), were performed. RT-qPCR was used to quantify the relative expression of the identified candidate genes. Nine significantly associated SNPs (P < 2.81E-06) and 30 SNPs reaching the suggestively significant level (P < 5.62E 05) were identified. Five of the 10 SNPs that were suggestively associated with the antibody response to SRBC were located within or close to previously reported QTL regions. Fifteen SNPs reached a suggestive significance level for AIV antibody titer and seven were found on the sex chromosome Z. Seven suggestive markers involving five different SNPs were identified for the numbers of heterophils and lymphocytes, and the heterophil/lymphocyte ratio. Nine significant SNPs, all on chromosome 16, were significantly associated with serum total IgY concentration, and the five most significant were located within a narrow region spanning 6.4kb to 253.4kb (P = 1.20E-14 to 5.33E-08). After testing expression of five candidate genes (IL4I1, CD1b, GNB2L1, TRIM27 and ZNF692) located in this region, changes in IL4I1, CD1b transcripts were consistent with the concentrations of IgY, while abundances of TRIM27 and ZNF692 showed reciprocal changes to those of IgY concentrations. This study has revealed 39 SNPs associated with six immune traits (total serum IgY level, numbers of, and the ratio of heterophils and lymphocytes, and antibody responses against AIV and SRBC) in Beijing-You chickens. The narrow region spanning 247kb on chromosome 16 is an important QTL for serum total IgY concentration. Five candidate genes related to IgY level validated here are novel and may play critical roles in the modulation of immune responses. Potentially useful candidate SNPs for marker assisted selection for disease resistance are identified. It is highly likely that these candidate genes play roles in various aspects of the immune response in chickens. PMID- 25822739 TI - Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents. AB - Cyclin G associated kinase (GAK) emerged as a promising drug target for the treatment of viral infections. However, no potent and selective GAK inhibitors have been reported in the literature to date. This paper describes the discovery of isothiazolo[5,4-b]pyridines as selective GAK inhibitors, with the most potent congeners displaying low nanomolar binding affinity for GAK. Cocrystallization experiments revealed that these compounds behaved as classic type I ATP competitive kinase inhibitors. In addition, we have demonstrated that these compounds exhibit a potent activity against hepatitis C virus (HCV) by inhibiting two temporally distinct steps in the HCV life cycle (i.e., viral entry and assembly). Hence, these GAK inhibitors represent chemical probes to study GAK function in different disease areas where GAK has been implicated (including viral infection, cancer, and Parkinson's disease). PMID- 25822742 TI - Interpreting effects of structure variations induced by temperature and pressure on luminescence spectra of platinum(II) bis(dithiocarbamate) compounds. AB - Luminescence spectra of two square-planar dithiocarbamate complexes of platinum(II) with different steric bulk, platinum(II) bis(dimethyldithiocarbamate) (Pt(MeDTC)2) and platinum(II) bis(di(o pyridyl)dithiocarbamate) (Pt(dopDTC)2), are presented at variable temperature and pressure. The spectra show broad d-d luminescence transitions with maxima at approximately 13500 cm(-1) (740 nm). Variations of the solid-state spectra with temperature and pressure reveal intrinsic differences due to subtle variations of molecular and crystal structures, reported at 100 and 296 K for Pt(dopDTC)2. Luminescence maxima of Pt(MeDTC)2 shift to higher energy as temperature increases by +320 cm(-1) for an increase by 200 K, mainly caused by a bandwidth increase from 3065 to 4000 cm(-1) on the high-energy side of the band over the same temperature range. Luminescence maxima of Pt(dopDTC)2 shift in the opposite direction by -460 cm(-1) for a temperature increase by 200 K. The bandwidth of approximately 2900 cm(-1) does not vary with temperature. Both ground and emitting-state properties and subtle structural differences between the two compounds lead to this different behavior. Luminescence maxima measured at variable pressure show shifts to higher energy by +47 +/- 3 and +11 +/- 1 cm( 1)/kbar, for Pt(MeDTC)2 and Pt(dopDTC)2, respectively, a surprising difference by a factor of 4. The crystal structures indicate that decreasing intermolecular interactions with increasing pressure are likely to contribute to the exceptionally high shift for Pt(MeDTC)2. PMID- 25822741 TI - Effects of puerarin on lipid accumulation and metabolism in high-fat diet-fed mice. AB - In order to investigate the mechanisms by which puerarin from kudzu root extract regulates lipid metabolism, fifty mice were randomly assigned to five groups: normal diet, high-fat diet (HFD), and HFD containing 0.2%, 0.4% or 0.8% puerarin for 12 weeks. Body weight, intraperitioneal adipose tissue (IPAT) weight, serum biochemical parameters, and hepatic and feces lipids were measured. Activity and mRNA and protein expressions of hepatic lipid metabolism-related enzymes were analyzed. Compared with HFD, 0.4% and 0.8% puerarin significantly decreased body and IPAT weight. There was a significant decrease in the serum and hepatic concentrations of total cholesterol, triglycerides and leptin in mice fed the 0.4% and 0.8% puerarin diets compared with HFD. Fatty acid synthase activity was suppressed in mice fed the 0.4% and 0.8% puerarin diets, while the activities of AMP-activated protein kinase (AMPK), carnitine acyltransferase (CAT) and hormone sensitive lipase (HSL) were increased. mRNA expression of peroxisome proliferator activated receptor gamma 2 (PPARgamma 2) was down-regulated in liver of mice fed the 0.8% diet compared with HFD, while mRNA expression of CAT and HSL was considerably up-regulated by 0.4% and 0.8% puerarin diets. The protein expression of PPARgamma2 in liver was decreased and those of p-AMPK, HSL and p-HSL were increased in mice fed 0.4% and 0.8% puerarin diets. These results suggest that > 0.4% puerarin influenced the activity, mRNA and protein levels of hepatic lipid metabolism-related enzymes, decreasing serum and liver lipids, body weight gain and fat accumulation. Puerarin might be beneficial to prevent lifestyle-related diseases. PMID- 25822740 TI - Telomerase inhibition decreases alpha-fetoprotein expression and secretion by hepatocellular carcinoma cell lines: in vitro and in vivo study. AB - Alpha-fetoprotein (AFP) is a diagnostic marker for hepatocellular carcinoma (HCC). A direct relationship between poor prognosis and the concentration of serum AFP has been observed. Telomerase, an enzyme that stabilizes the telomere length, is expressed by 90% of HCC. The aim of this study was to investigate the effect of telomerase inhibition on AFP secretion and the involvement of the PI3K/Akt/mTOR signaling pathway. Proliferation and viability tests were performed using tetrazolium salt. Apoptosis was determined through the Annexin V assay using flow cytometry. The concentrations of AFP were measured using ELISA kits. The AFP mRNA expression was evaluated using RT-PCR, and cell migration was evaluated using a Boyden chamber assay. The in vivo effect of costunolide on AFP production was tested in NSG mice. Telomerase inhibition by costunolide and BIBR 1532 at 5 and 10 MUM decreased AFP mRNA expression and protein secretion by HepG2/C3A cells. The same pattern was obtained with cells treated with hTERT siRNA. This treatment exhibited no apoptotic effect. The AFP mRNA expression and protein secretion by PLC/PRF/5 was decreased after treatment with BIBR1532 at 10 MUM. In contrast, no effect was obtained for PLC/PRF/5 cells treated with costunolide at 5 or 10 MUM. Inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP concentration. In contrast, the MAPK/ERK pathway appeared to not be involved in HepG2/C3A cells, whereas ERK inhibition decreased the AFP concentration in PLC/PRF/5 cells. Modulation of the AFP concentration was also obtained after the inhibition or activation of PKC. Costunolide (30 mg/kg) significantly decreased the AFP serum concentration of NSG mice bearing HepG2/C3A cells. Both the inhibition of telomerase and the inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP production of HepG2/C3A and PLC/PRF/5 cells, suggesting a relationship between telomerase and AFP expression through the PI3K/Akt/mTOR pathway. PMID- 25822743 TI - Changes in patient satisfaction and masticatory efficiency during adaptation to new dentures. AB - Because adapting to new conventional dentures is highly variable, there is uncertainty as to how long dissatisfied patients should wait before choosing a treatment with dental implants. The authors investigated whether changes in patient satisfaction and masticatory efficiency may be observed between 3 and 6 months after the insertion of new conventional complete dentures. The study included 24 edentulous patients requiring new complete dentures. Masticatory efficiency and patient satisfaction were evaluated at 3 and 6 months post insertion. Masticatory efficiency was evaluated through the colorimetric method, with the beads as the artificial test food. A method for quantifying overall satisfaction of complete-denture wearers was used. Subjects were asked to respond to questions with three-grade answers concerning 12 factors: chewing, tasting, speech, esthetics, pain, fit, retention, and comfort (maxillary and mandibular evaluations were done for each of the last four factors). The results of patient satisfaction and masticatory efficiency at 3 and 6 months post-insertion were compared using the paired-samples t test (alpha = 0.05). Significant reductions in mandibular pain (P less than 0.05) and improvements in mandibular fit (P less than 0.05) were observed at 6 months. No difference was found for patient overall satisfaction, chewing, tasting, speech, maxillary pain, esthetics, maxillary fit, retention, comfort, and masticatory efficiency. The authors concluded that reduction in pain and improvements in adaptation of the lower denture may be observed between 3 and 6 months after insertion of new conventional complete dentures. This period of adaptation should be considered before choosing a treatment with dental implants. PMID- 25822744 TI - Prosthetic management of gingival recession around implants: lessons learned from staged-approach treatment planning. AB - Complex implant rehabilitations can include procedures requiring multiple phases of treatment, commonly referred to as staged approaches. The reasons for staged approaches are varied but usually involve serial extraction of hopeless teeth. These treatment plans both enable the patient to avoid removable prostheses by keeping natural teeth during healing phases, and circumvent the immediate loading of some implants placed in grafted bone. One major disadvantage to serial extraction in a staged approach is the potential for gingival changes. These changes include gingival recession around abutments that can affect the gingival profile around the finished case. This article discusses varying approaches for dealing with these gingival changes and suggests protocol modifications during the implant treatment-planning phase. PMID- 25822737 TI - Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 beta Amyloid Measures Across the Spectrum of Alzheimer Disease. AB - IMPORTANCE: Cerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study. OBJECTIVE: To determine the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)-PET scan and at least 1 CSF beta-amyloid 1-42 (Abeta1 42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Abeta1-42 measurements). Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database. MAIN OUTCOMES AND MEASURES: Four different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures. RESULTS: The values of the CSF Abeta1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Abeta1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOE genotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Abeta1-42 cutoff levels. There was no association between longitudinal Abeta1-42 levels and standardized uptake value ratios during follow up. CONCLUSIONS AND RELEVANCE: The association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Abeta cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Abeta pathology. PMID- 25822745 TI - Case report using the "H" abutment: achieving esthetics, strength, and predictability for the anterior implant. AB - Replacing an anterior tooth using a dental implant has long been a challenge for most clinicians. Implant abutment selection is a crucial aspect of maximizing esthetics, strength, and customization. The author has experienced significant success in this regard over a period of more than 7 years using a lithium disilicate "H" ("Hybrid") abutment. In this case presentation, a procedure is described for providing these highly esthetic abutment-supported restorations, which may offer significant advantages over traditional options. PMID- 25822746 TI - Multidisciplinary treatment of anterior worn dentition: a staged approach. AB - This case involving a male patient with long-standing wear on his anterior teeth demonstrates the importance of an accurate risk profile and prognosis. It also shows an example of a patient who, as is frequently the case, was aware of his problem but chose not to address it until after many years, being finally motivated by a change in marital status. Upon examination, it was determined that the severe attrition was due to the position of the teeth, and the functional diagnosis was a constricted chewing pattern. Orthodontic therapy was a central aspect of the treatment plan, followed initially by a composite trial restoration of the anterior teeth, and, finally, placement of porcelain crowns. Careful communication among the treating dentist, orthodontist, and the dental laboratory at specific phases of the treatment proved to play a pivotal role in achieving an exceptional esthetic result and stable functional bite. PMID- 25822747 TI - Effect of curing light and restoration location on energy delivered. AB - This study determined how long it would take skilled operators to deliver 16 J/cm2 to an anterior or a posterior restoration using different light-curing units (LCUs). Three skilled operators used the following LCUs at two locations in the MARC-patient simulator: Optilux 501 standard mode for 20 s; Sapphire Supreme for 5 s; EliparTM S10 for 5 s and 20 s; DemiTM Plus standard mode for 5 s; SmartLite(r) Max boost mode for 5 s and continuous mode for 20 s; Radii Plus for 30 s; Valo (main version) in standard mode for 20 s and Xtra Power mode for 3 s; and Valo Cordless in standard mode for 20 s and Xtra Power mode for 3 s. The three MARCtrained operators made 30 readings with each light over 7 days. The energy (J/cm2) delivered to the anterior Class III and posterior Class I simulated restorations in MARC was recorded using a laboratory-grade spectroradiometer, and the time each light would take to deliver 16 J/cm2 calculated. ANOVA and Fisher's PLSD tests compared differences in the time to deliver 16 J/cm2 of energy, alpha = 0.05. Three-way ANOVA showed there was no significant difference between the operators, but there was a difference between the lights and locations. The Valo main and Valo Cordless in the Xtra Power mode delivered 16 J/cm2 in the shortest time at both locations. The Radii Plus took the longest to deliver 16 J/cm2, taking twice as long in the posterior location. PMID- 25822748 TI - Dental unit waterline contamination: a review of research and findings from a clinic setting. AB - The interior of small-diameter tubing in dental unit waterlines (DUWLs) creates an attractive environment for the growth of biofilm and bacteria. Substantial research shows that troublesome and potentially pathogenic bacteria have been found in DUWLs, and scant peer-reviewed information from which to evaluate chemical treatment options has been historically available. The authors' research compares three DUWL cleaners-an alkaline peroxide product, a freshly mixed chlorine dioxide product, and a buffer-stabilized chlorine dioxide product-in 16 dental units with self-contained water systems over a 10-day working period to determine the optimal chemical treatment option. The study found chlorine dioxide waterline cleaners to be most effective in containing DUWL contaminations. PMID- 25822749 TI - Today's CAD/CAM: flexible digital technologies expanding workflow options. AB - CAD/CAM and digital scanning technologies have become essential components of dentistry. Digital impression scanning, restoration design, and manufacturing techniques yield greater treatment predictability, high-level esthetics, and functional accuracy using a variety of materials. PMID- 25822750 TI - Aleutian mink disease virus in free-ranging mink from Sweden. AB - Aleutian mink disease (AMD) is a chronic viral disease in farmed mink and the virus (AMDV) has been found in many free-ranging mink (Neovison vison) populations in Europe and North America. In this study, AMDV DNA and AMDV antibodies were analysed in 144 free-ranging mink hunted in Sweden. Associations between being AMDV infected (defined as positive for both viral DNA and antibodies) and the weight of the spleen, liver, kidneys, adrenal glands and body condition were calculated and the sequences of ten AMDV isolates were analysed in order to characterize the genetic relationships. In total, 46.1% of the mink were positive for AMDV antibodies and 57.6% were positive for AMDV DNA. Twenty-two percent of the mink tested on both tests (n = 133) had dissimilar results. The risk of having AMDV antibodies or being positive for AMDV DNA clearly increased with age and the majority of the mink that were two years or older were infected. Few macroscopic changes were found upon necropsy. However, the relative weight of the spleen was sexually dimorphic and was found to be slightly, but significantly (p = 0.006), heavier in AMDV infected male mink than uninfected. No association between AMDV infection and body condition, weight of the kidneys, liver or adrenal glands were found. Several different strains of AMDV were found across the country. Two of the AMDV sequences from the very north of Sweden did not group with any of the previously described groups of strains. In summary, AMDV seems to be prevalent in wild mink in Sweden and may subtly influence the weight of the spleen. PMID- 25822751 TI - Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation. AB - Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-beta, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-beta1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, beta1-integrin, calponin and alpha-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-beta signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-beta-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-beta-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation. PMID- 25822752 TI - Statistical analysis methods for meta-analysis of times to emergence. PMID- 25822754 TI - Impacts of discarded plastic bags on marine assemblages and ecosystem functioning. AB - The accumulation of plastic debris is a global environmental problem due to its durability, persistence, and abundance. Although effects of plastic debris on individual marine organisms, particularly mammals and birds, have been extensively documented (e.g., entanglement and choking), very little is known about effects on assemblages and consequences for ecosystem functioning. In Europe, around 40% of the plastic items produced are utilized as single-use packaging, which rapidly accumulate in waste management facilities and as litter in the environment. A range of biodegradable plastics have been developed with the aspiration of reducing the persistence of litter; however, their impacts on marine assemblages or ecosystem functioning have never been evaluated. A field experiment was conducted to assess the impact of conventional and biodegradable plastic carrier bags as litter on benthic macro- and meio-faunal assemblages and biogeochemical processes (primary productivity, redox condition, organic matter content, and pore-water nutrients) on an intertidal shore near Dublin, Ireland. After 9 weeks, the presence of either type of bag created anoxic conditions within the sediment along with reduced primary productivity and organic matter and significantly lower abundances of infaunal invertebrates. This indicates that both conventional and biodegradable bags can rapidly alter marine assemblages and the ecosystem services they provide. PMID- 25822755 TI - Detection of the carcinogenic water pollutant benzo[a]pyrene with an electro switchable biosurface. AB - The toxic nature of polycyclic aromatic hydrocarbons (PAHs), in particular benzo[a]pyrene (B[a]P), neccessitates the monitoring of PAH contamination levels in food and the environment. Here we introduce an indirect immunoassay format using electro-switchable biosurfaces (ESB) for the detection of B[a]P in water. The association of anti-B[a]P antibodies to microelectrodes is analyzed in real time by measuring changes in the oscillation dynamics of DNA nanolever probes, which are driven to switch their orientations by high-frequency electrical actuation. From the association kinetics, the active concentration of anti-B[a]P, and hence the B[a]P contamination of the sample, can be determined with picomolar sensitivity. The detection limit of the assay improves with measurement time because increasingly accurate analyses of the binding kinetics become possible. It is demonstrated that an exceedance of the permissible 10 ng/L (40 pM) limit for B[a]P is detectable in an unprecedented short assay time (<1 h), using a simple three-step workflow involving minimal sample preparation. The reproducibility was satisfying with standard deviations below 5%. Further, the utility of the assay for practical applications is exemplified by analyzing a river water sample. PMID- 25822757 TI - Hyperbranched quasi-1D TiO2 nanostructure for hybrid organic-inorganic solar cells. AB - The performance of hybrid solar cells is strongly affected by the device morphology. In this work, we demonstrate a poly(3-hexylthiophene-2,5-diyl)/TiO2 hybrid solar cell where the TiO2 photoanode comprises an array of tree-like hyperbranched quasi-1D nanostructures self-assembled from the gas phase. This advanced architecture enables us to increase the power conversion efficiency to over 1%, doubling the efficiency with respect to state of the art devices employing standard mesoporous titania photoanodes. This improvement is attributed to several peculiar features of this array of nanostructures: high interfacial area; increased optical density thanks to the enhanced light scattering; and enhanced crystallization of poly(3-hexylthiophene-2,5-diyl) inside the quasi-1D nanostructure. PMID- 25822756 TI - A signal-on fluorosensor based on quench-release principle for sensitive detection of antibiotic rapamycin. AB - An antibiotic rapamycin is one of the most commonly used immunosuppressive drugs, and also implicated for its anti-cancer activity. Hence, the determination of its blood level after organ transplantation or tumor treatment is of great concern in medicine. Although there are several rapamycin detection methods, many of them have limited sensitivity, and/or need complicated procedures and long assay time. As a novel fluorescent biosensor for rapamycin, here we propose "Q'-body", which works on the fluorescence quench-release principle inspired by the antibody-based quenchbody (Q-body) technology. We constructed rapamycin Q'-bodies by linking the two interacting domains FKBP12 and FRB, whose association is triggered by rapamycin. The fusion proteins were each incorporated position-specifically with one of fluorescence dyes ATTO520, tetramethylrhodamine, or ATTO590 using a cell free translation system. As a result, rapid rapamycin dose-dependent fluorescence increase derived of Q'-bodies was observed, especially for those with ATTO520 with a lowest detection limit of 0.65 nM, which indicates its utility as a novel fluorescent biosensor for rapamycin. PMID- 25822753 TI - Identification of a peptide-pheromone that enhances Listeria monocytogenes escape from host cell vacuoles. AB - Listeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen that invades mammalian cells and escapes from membrane-bound vacuoles to replicate within the host cell cytosol. Gene products required for intracellular bacterial growth and bacterial spread to adjacent cells are regulated by a transcriptional activator known as PrfA. PrfA becomes activated following L. monocytogenes entry into host cells, however the signal that stimulates PrfA activation has not yet been defined. Here we provide evidence for L. monocytogenes secretion of a small peptide pheromone, pPplA, which enhances the escape of L. monocytogenes from host cell vacuoles and may facilitate PrfA activation. The pPplA pheromone is generated via the proteolytic processing of the PplA lipoprotein secretion signal peptide. While the PplA lipoprotein is dispensable for pathogenesis, bacteria lacking the pPplA pheromone are significantly attenuated for virulence in mice and have a reduced efficiency of bacterial escape from the vacuoles of nonprofessional phagocytic cells. Mutational activation of PrfA restores virulence and eliminates the need for pPplA-dependent signaling. Experimental evidence suggests that the pPplA peptide may help signal to L. monocytogenes its presence within the confines of the host cell vacuole, stimulating the expression of gene products that contribute to vacuole escape and facilitating PrfA activation to promote bacterial growth within the cytosol. PMID- 25822758 TI - Salience Effects: L2 Sentence Production as a Window on L1 Speech Planning. AB - Salience influences grammatical structure during production in a language dependent manner because different languages afford different options to satisfy preferences. During production, speakers may always try to satisfy all syntactic encoding preferences (e.g., salient entities to be mentioned early, themes to be assigned the syntactic function of object) and adjust when this is not possible (e.g., a salient theme in English) or, alternatively, they may learn early on to associate particular conceptual configurations with particular syntactic frames (e.g., salient themes with passives). To see which of these alternatives is responsible for the production of passives when dealing with a salient theme, we looked at the second language effects of salience for English-speaking learners of Spanish, where the two preferences can be satisfied simultaneously by fronting the object (Prat-Sala and Branigan in J Mem Lang 42:168-182, 2000). In accordance with highly incremental models of language production, English speakers appear to quickly make use of the alternatives in the second language that allow observance of more processing preferences. PMID- 25822759 TI - Utility of ADAMTS13 assays in diagnosing thrombotic thrombocytopenic purpura. PMID- 25822760 TI - Utility of ADAMTS13 assays in diagnosing thrombotic thrombocytopenic purpura. In reply. PMID- 25822761 TI - The essential role of pathologists in health care and health policy. PMID- 25822762 TI - A new ever-evolving paradigm. PMID- 25822763 TI - A triple stain of reticulin, glypican-3, and glutamine synthetase: a useful aid in the diagnosis of liver lesions. AB - CONTEXT: The correct histologic diagnosis of mass lesions of the liver can be difficult, especially in biopsy samples. Reticulin, glypican-3, and glutamine synthetae are stains that can help distinguish hepatocellular carcinoma, hepatic adenoma, and focal nodular hyperplasia. OBJECTIVE: To evaluate the utility of a triple stain of reticulin, glypican-3, and glutamine synthetae in distinguishing hepatocellular carcinoma, hepatic adenoma, and focal nodular hyperplasia. DESIGN: Whole tissue sections and tissue microarrays were evaluated with a triple stain of reticulin, followed by glutamine synthetae (diaminobenzidine, brown chromogen) and glypican-3 (alkaline phosphatase, red chromogen). The 109 cases evaluated included whole tissue section hepatocellular carcinoma (n = 16), tissue microarray hepatocellular carcinoma (n = 19), whole tissue section hepatic adenoma (n = 15), tissue microarray hepatic adenoma (n = 13), whole tissue section focal nodular hyperplasia (n = 13; 12%), tissue microarray focal nodular hyperplasia (n = 13), as well as nonmalignant liver parenchyma adjacent to hepatocellular carcinoma (n = 20). All cases were scored for reticulin being intact or lost, positive or negative staining for glypican-3, and diffuse, maplike, perivenular, or negative staining for glutamine synthetae. RESULTS: The combination of intact reticulin with either glypican-3 negativity or negative glutamine synthetae was 92% sensitive and 95% specific in the distinction of tissue microarray hepatic adenoma from hepatocellular carcinoma. For the distinction of tissue microarray focal nodular hyperplasia and hepatic adenoma, maplike glutamine synthetae was most useful and was 85% sensitive and 100% specific. CONCLUSIONS: The triple stain of reticulin, glypican-3, and glutamine synthetae is useful in the differentiation of hepatocellular carcinoma, hepatic adenoma, and focal nodular hyperplasia on biopsy specimens. Furthermore, this triple stain is advantageous to single stains and can help when aberrant staining patterns are observed. PMID- 25822764 TI - Diagnostic utility of PHOX2B in primary and treated neuroblastoma and in neuroblastoma metastatic to the bone marrow. AB - CONTEXT: Neuroblastoma (NB) is the most common extracranial tumor of childhood. Although most cases have a distinctive histology, a subset of primitive cases require immunohistochemical studies to distinguish them from other small round blue cell tumors of childhood. Immunohistochemistry is also used to detect small amounts of tumor metastatic to the bone marrow and in posttreatment samples with obscuring fibrosis, calcification, or inflammation. The transcription factor PHOX2B is essential for the differentiation and survival of sympathetic neurons and chromaffin cells, and therefore is highly specific for the peripheral autonomic nervous system. OBJECTIVE: To determine the diagnostic utility of PHOX2B immunohistochemistry as a marker of primary, treated, and metastatic NB. DESIGN: Neuroblastoma tissue microarrays were stained with PHOX2B, CD57, and synaptophysin. Arrays containing rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor were stained with PHOX2B, and negative bone marrow samples were stained with PHOX2B and CD57. RESULTS: PHOX2B and CD57 were similar to synaptophysin in their ability to detect NB. PHOX2B and CD57 similarly showed robust staining in posttreatment NB and NB metastatic to the bone marrow. In contrast to the cytoplasmic staining pattern seen with synaptophysin and CD57, clear and strong nuclear PHOX2B permitted identification of individual tumor cells. PHOX2B staining was absent in all cases of rhabdomyosarcoma, Ewing sarcoma, and Wilms tumor, and in the negative bone marrow. CONCLUSIONS: PHOX2B and CD57 are useful markers of NB. PHOX2B is specific for NB in its differential diagnosis with other small round cell tumors, and its nuclear staining may be helpful for accurate bone marrow tumor quantification. PMID- 25822765 TI - Renal dysplasia. AB - Renal dysplasia is an aberrant developmental disease usually diagnosed during the perinatal and childhood years. Prevalence is estimated at 0.1% of infants (via ultrasound screening) and 4% of fetuses and infants (via autopsy study). Occurrences may be combined with abnormalities in the collecting system or associated with complex syndromes. Histopathology shows primitive tubules surrounded by a fibromuscular collar. The differential diagnosis includes renal dysplasia, hypoplasia, and renal atrophy. Immunohistochemical expression of the paired box genes 2 and 8 (PAX2/8) and Wilms tumor 1 (WT1) is increased in the primitive ducts and fibromuscular collar, respectively. Renal dysplasia pathogenesis is not well understood, but may be caused by a nephron-inductive deficit due to ampullary inactivity or abnormal budding of the ureteric bud from the mesonephric duct. Either the PAX2 mutation only or cross-talk with the p53 pathway is involved in this deficit. Nephrectomy is the treatment of choice for symptomatic renal dysplasia. PMID- 25822766 TI - Low-grade fibromatosis-like spindle cell carcinoma of the breast. AB - Low-grade fibromatosis-like spindle cell carcinoma is a rare tumor in the breast, and represents a variant of the very heterogeneous group of metaplastic carcinomas of the breast. These tumors warrant distinction because of their resemblance to pure fibromatosis, their propensity for local recurrence, and their favorable prognosis among the metaplastic carcinomas of the breast. The diagnosis is potentially challenging, particularly on core needle biopsies, because of the morphologic overlap with other low-grade spindle cell lesions. Recognition of a proliferation of cytologically bland spindle cells with areas of epithelial differentiation in combination with immunohistochemistry using antibodies against cytokeratins and myoepithelial markers should aid in producing a definitive diagnosis. These tumors can be locally aggressive with an increased incidence of local recurrence, but the potential for lymph node or distant metastasis is low. Complete excision with adequate margins is considered curative in the majority of cases. PMID- 25822767 TI - A combined approach of human leukocyte antigen ligandomics and immunogenicity analysis to improve peptide-based cancer immunotherapy. AB - The breakthrough development of immune checkpoint inhibitors as clinically effective novel therapies demonstrates the potential of cancer immunotherapy. The identification of suitable targets for specific immunotherapy, however, remains a challenging task. Most peptides previously used for vaccination in clinical trials were able to elicit strong immunological responses but failed with regard to clinical benefit. This might, at least partly, be caused by an inadequate peptide selection, usually derived from established tumor-associated antigens which are not necessarily presented as human leukocyte antigen (HLA) ligands. Recently, HLA ligandome analysis revealed cancer-associated peptides, which have been used in clinical trials showing encouraging impact on survival. To improve peptide-based cancer immunotherapy, our group established a combined approach of HLA ligandomics and immunogenicity analysis for the identification of vaccine peptides. This approach is based on the identification of naturally presented HLA ligands on tumor samples, the selection of tumor-associated/tumor-specific HLA ligands and their subsequent testing for immunogenicity in vitro. In this review, we want to present our pipeline for the identification of vaccine peptides, focusing on ovarian cancer, and want to discuss differences to other approaches. Furthermore, we want to give a short outlook of a potential multi-peptide vaccination trial using the novel identified peptides. PMID- 25822768 TI - Impairment of lymphocyte function following yttrium-90 DOTATOC therapy. AB - The radiolabeled somatostatin analogue, yttrium-90 DOTA-D-Phe(1)-Tyr(3) octreotide (DOTATOC), is currently applied to treat advanced somatostatin receptor-positive tumors, e.g., neuroendocrine tumors of the pancreas, lung or gut. However, effects of this treatment on antimicrobial immune responses are not yet defined. In 20 patients treated with DOTATOC, cellular in vitro immune function was determined. Their antimicrobial lymphocyte responses were assessed by lymphocyte transformation test and enzyme-linked immunospot-measuring lymphocyte proliferation and on a single cell level production of pro- and anti inflammatory cytokines (interferon-gamma and interleukin-10)-prior to therapy, at day 1, day 7 and day 90 post-therapy. Proliferative lymphocyte responses and interferon-gamma production after in vitro stimulation with microbial antigens were non-significantly suppressed at day 1 and significantly (p < 0.05) at day 7 versus pre-therapy. In vitro immune responses did not fully recover until day 90. In contrast, at day 1 interleukin-10 production was significantly (p < 0.05) increased. Taken together, we observed a decrease in pro-inflammatory immune responses after DOTATOC therapy. Patients with versus without bone metastases displayed significantly (p < 0.05) lower cellular immune responses toward several microbial antigens. Progressive disease and higher tumor burden could also be defined as factors associated with impaired immune function. Spearman correlation analysis indicated that cellular in vitro immunity was positively correlated with kidney function; better kidney function led to stronger immune responses. In conclusion, DOTATOC therapy caused a decrease in in vitro immune responses against microorganisms. The clinical impact needs to be evaluated in further studies. PMID- 25822769 TI - Temporal coherence for complex signals in budgerigars (Melopsittacus undulatus) and humans (Homo sapiens). AB - The auditory scene is filled with an array of overlapping acoustic signals, yet relatively little work has focused on how animals are able to perceptually isolate different sound sources necessary for survival. Much of the previous work on auditory scene analysis has investigated how sequential pure tone stimuli are perceived, but how temporally overlapping complex communication signals are segregated has been largely ignored. In this study, budgerigars and humans were tested using psychophysical procedures to measure their perception of synchronous, asynchronous, and partially overlapping complex signals, including bird calls and human vowels. Segregation thresholds for complex stimuli were significantly lower than those for pure tone stimuli in both humans and birds. Additionally, a species effect was discovered such that relative to humans, budgerigars required significantly less temporal separation between 2 sounds in order to segregate them. Overall, and similar to previous behavioral results investigating temporal coherence, the results from this experiment illustrate that temporal cues are particularly important for auditory scene analysis across multiple species and for both simple and complex acoustic signals. PMID- 25822770 TI - The importance of cognitive assessment before ventricular device placement: a teachable moment. PMID- 25822771 TI - Ginkgo Biloba Extract Enhances Differentiation and Performance of Neural Stem Cells in Mouse Cochlea. AB - Ginkgo biloba extract (GBE) has been widely used for treatment of neural damage and disorders. Neural stem cells (NSCs) hold promise as a treatment of hearing loss caused by neural damage. However, the biological functions of GBE in modulating NSC behaviors in the cochlea are still largely elusive. In this study, we sought to explore the effects of GBE on the differentiation and performance of NSCs from mouse cochlea. Our data showed that GBE treatment promotes cell survival and NSC proliferation. In addition, GBE treatment also increases NSC differentiation to neurons and enhances the performance of mature neural networks evident by the increased frequency of calcium oscillation. Moreover, neurite outgrowth is also dramatically increased upon GBE treatment. Overall, our study demonstrates the positive regulatory role of GBE in NSC proliferation and differentiation into functional neurons in vitro, supporting the potential therapeutic use of GBE in hearing loss recovery. PMID- 25822772 TI - Single cell transcriptome amplification with MALBAC. AB - Recently, Multiple Annealing and Looping-Based Amplification Cycles (MALBAC) has been developed for whole genome amplification of an individual cell, relying on quasilinear instead of exponential amplification to achieve high coverage. Here we adapt MALBAC for single-cell transcriptome amplification, which gives consistently high detection efficiency, accuracy and reproducibility. With this newly developed technique, we successfully amplified and sequenced single cells from 3 germ layers from mouse embryos in the early gastrulation stage, and examined the epithelial-mesenchymal transition (EMT) program among cells in the mesoderm layer on a single-cell level. PMID- 25822773 TI - Feeding soy protein isolate and n-3 PUFA affects polycystic liver disease progression in a PCK rat model of autosomal polycystic kidney disease. AB - OBJECTIVE: In polycystic liver disease (PCLD), multiple cysts cause liver enlargement, structural damage, and loss of function. Soy protein and dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been found to decrease cyst proliferation and inflammation in polycystic kidney disease. Therefore, the aim of the study was to investigate whether soy protein and n-3 PUFA supplementation attenuates PCLD. METHODS: Young (age 28 days) female PCK rats were fed (n = 12 per group) either casein + corn oil (casein + CO), casein + soybean oil (casein + SO), soy protein isolate + soybean oil (SPI + SO), or SPI + 1:1 soybean/salmon oil blend (SPI + SB) diet for 12 weeks. Liver histology, gene expression by real time quantitative polymerase chain reaction, and serum markers of liver injury were determined. RESULTS: Diet had no effect on PCLD progression as indicated by no significant differences in liver weight and hepatic proliferation gene expression between diet groups. PCK rats fed SPI + SB diet, however, had the greatest (P < 0.05) histological evidence of hepatic cyst obstruction, portal inflammation, steatosis, and upregulation (P = 0.03) of fibrosis-related genes. Rats fed SPI + SB diet also had the lowest (P < 0.001) serum cholesterol and higher (P < 0.05) serum alkaline phosphatase and bilirubin concentrations. CONCLUSIONS: Feeding young female PCK rats SPI and n-3 PUFA failed to attenuate PCLD progression. Furthermore, feeding SPI + SB diet resulted in complications of hepatic steatosis attributable to cysts obstruction of bile duct and hepatic vein. Based on the results, it was concluded that diet intervention alone was not effective at attenuating PCLD associated with autosomal recessive polycystic kidney disease. PMID- 25822774 TI - A methodological approach to fecal microbial transplant via nasogastric tube for active pediatric ulcerative colitis. PMID- 25822775 TI - Author's Response. PMID- 25822776 TI - Adding alpha-1 antitrypsin deficiency to the newborn screen. PMID- 25822777 TI - Author's response. PMID- 25822778 TI - Prediction model for critically ill patients with acute respiratory distress syndrome. AB - BACKGROUND AND OBJECTIVES: Acute respiratory distress syndrome (ARDS) is a major cause respiratory failure in intensive care unit (ICU). Early recognition of patients at high risk of death is of vital importance in managing them. The aim of the study was to establish a prediction model by using variables that were readily available in routine clinical practice. METHODS: The study was a secondary analysis of data obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center. Patients were enrolled between August 2007 and July 2008 from 33 hospitals. Demographics and laboratory findings were extracted from dataset. Univariate analyses were performed to screen variables with p<0.3. Then these variables were subject to automatic stepwise forward selection with significance level of 0.1. Interaction terms and fractional polynomials were examined for variables in the main effect model. Multiple imputations and bootstraps procedures were used to obtain estimations of coefficients with better external validation. Overall model fit and logistic regression diagnostics were explored. MAIN RESULT: A total of 282 ARDS patients were included for model development. The final model included eight variables without interaction terms and non-linear functions. Because the variable coefficients changed substantially after exclusion of most poorly fitted and influential subjects, we estimated the coefficient after exclusion of these outliers. The equation for the fitted model was: g(Chi)=0.06*age(in years)+2.23(if on vasopressor)+1.37*potassium (mmol/l)-0.007*platelet count (*109)+0.03*heart rate (/min)-0.29*Hb(g/dl)-0.67*T( degrees C)+0.01*PaO_2+13, and the probability of death pi(Chi)=eg(Chi)/(1+eg(Chi)). CONCLUSION: The study established a prediction model for ARDS patients requiring mechanical ventilation. The model was examined with rigorous methodology and can be used for risk stratification in ARDS patients. PMID- 25822779 TI - The quality analysis of literature retrievals of systematic reviews for traditional Chinese medicine. AB - BACKGROUND: The literature retrievals are still the main problems which limit the quality of systematic review (SR) for traditional Chinese medicine (TCM), and there were still no comprehensive analyses for these problems. The aim of this study is to analyze these problems to guide future SRs for TCM. METHODS: The Cochrane Library (Issue 2, 2009) and the Chinese BioMedical Database (CBM, 1978- 2009.7.31) were comprehensively searched to identify the SRs of TCM. The native literature retrieval rate of the first author, the characteristics of the included databases, the number of the included database, the reporting of literature retrieval strategy, and the reporting of adjuvant search for both the SRs from the CBM and Cochrane Library were analyzed. RESULTS: A total of 341 SRs were included in our analyses, including 245 from the CBM and 96 from the CL. The Chinese-authored SRs ranked the first in median retrieval rate (100%). The Cochrane SRs were significantly superior than the CBM SRs: more searched databases (media: 4 vs. 6, P < 0.001), more precision of retrieval time, more conducting gray literatures searches (47.92% vs. 20.41%) and handing searches (57.29% vs. 54.69%), and more reported retrieval strategies (66.67% vs. 8.16%). CONCLUSIONS: There were significant problems in the literature retrieval of SRs for TCM. In future, when performing any SRs for TCM, sufficient and proper databases, clearly searching strategies and times, proper adjuvant retrievals should be reported. Cochrane SRs might be a better choice. PMID- 25822780 TI - Superior orthonasal but not retronasal olfactory skills in congenital blindness. AB - Sight is undoubtedly important for finding and appreciating food, and cooking. Blind individuals are strongly impaired in finding food, limiting the variety of flavours they are exposed to. We have shown before that compared to sighted controls, congenitally blind individuals have enhanced olfactory but reduced taste perception. In this study we tested the hypothesis that congenitally blind subjects have enhanced orthonasal but not retronasal olfactory skills. Twelve congenitally blind and 14 sighted control subjects, matched in age, gender and body mass index, were asked to identify odours using grocery-available food powders. Results showed that blind subjects were significantly faster and tended to be better at identifying odours presented orthonasally. This was not the case when odorants were presented retronasally. We also found a significant group x route interaction, showing that although both groups performed better for retronasally compared to orthonasally presented odours, this gain was less pronounced for blind subjects. Finally, our data revealed that blind subjects were more familiar with the orthonasal odorants and used the retronasal odorants less often for cooking than their sighted counterparts. These results confirm that orthonasal but not retronasal olfactory perception is enhanced in congenital blindness, a result that is concordant with the reduced food variety exposure in this group. PMID- 25822781 TI - Hemodynamic Stability During Pheochromocytoma Resection: Lessons Learned Over the Last Two Decades. AB - BACKGROUND: Ideal perioperative management of pheochromocytomas/paragangliomas (pheo) is a subject of debate and can be highly variable. The purpose of this study was to identify potential predictive factors of hemodynamic instability during pheo resection. METHODS: A retrospective review of pheo resections from 1992 to 2013 was undertaken. Intraoperative hemodynamics, patient demographics, tumor characteristics, and perioperative management were examined. Postoperative intensive-care admission, myocardial infarction, stroke, and 30-day mortality were reviewed. Linear regression was used to analyze factors influencing intraoperative hemodynamics. RESULTS: During the 20-year study period, 100 patients underwent pheo resection. Postoperative morbidity and mortality was significantly reduced (p = 0.003) in the last 10 years of practice, and there was a trend towards greater morbidity and mortality with intraoperative hemodynamic instability (p = 0.06). The preoperative dose of phenoxybenzamine and the number of laparoscopic procedures has increased in the last decade [59 mg (95 % CI 32 108) to 106 mg (95 % CI 91-124), p = 0.008, and 27 vs. 54 %, p = 0.05, respectively]. Increased preoperative phenoxybenzamine dose was a significant predictor of improved intraoperative hemodynamic stability (p = 0.01). Lack of intraoperative magnesium use resulted in greater hemodynamic instability as preoperative systolic blood pressure increased (p = 0.002). CONCLUSIONS: Postoperative outcomes following pheo resection have improved over the last two decades. Preoperative alpha-blockade plays a significant role in improving intraoperative hemodynamics and post-op outcomes. Increased doses of phenoxybenzamine and utilization of laparoscopic approaches have likely contributed to improved outcomes in the last decade. Intraoperative magnesium use may provide protection against hemodynamic instability and warrants further study. PMID- 25822782 TI - Outcomes of Gastric Cancer Resection in Octogenarians: A Multi-institutional Study of the U.S. Gastric Cancer Collaborative. AB - BACKGROUND: As the U.S. population ages, an increasing number of elderly patients with gastric adenocarcinoma are being evaluated for surgical resection. This study aimed to describe the short- and long-term outcomes after gastric cancer resection for patients 80 years of age or older. METHODS: Patients who underwent gastrectomy for gastric adenocarcinoma from 2000 to 2012 at seven U.S. academic institutions were analyzed. The main outcome measures included postoperative morbidity, mortality, survival, and failure to rescue (defined as death after any complication). RESULTS: Of 953 patients who underwent distal or total gastrectomy during the 12-year study period, 127 (13 %) were 80 years of age or older. Although the type of postoperative complications did not differ between the two groups, octogenarians had a higher incidence of any (54 vs 41 %; p = 0.006) and of major (28 vs 17 %; p = 0.006) postoperative complications. This translated into higher 30-day (10.2 vs 3.6 %; p = 0.001) and 90-day mortality (19.7 vs 7.9 %; p = 0.001) rates, with correspondingly higher failure-to-rescue rates (17.4 vs 8 %; p = 0.015). However, disease-specific survival after resection was equivalent between the two groups (5-year survival: 46 vs 53 %; p = 0.676). In the multivariate analysis, age of 80 years or older, blood transfusion, and albumin and creatinine levels all were independent predictors of 90-day mortality. Stage, tumor grade, race, blood transfusion, and adjuvant therapy, but not age, were independently associated with disease-specific survival. CONCLUSION: Perioperative mortality and failure-to-rescue from complications is substantial for octogenarians undergoing gastric cancer resection. However, if the operation can be performed safely, the long-term cancer-specific outcome appears similar to that for younger patients. PMID- 25822784 TI - Liquid Crystal Foams Generated by Pressure-Driven Microfluidic Devices. AB - Thermotropic liquid crystals possess superior foaming capability without the aid of surfactants because of the anisotropic molecular structures. We developed a T junction microfluidic device to inject gas bubbles of uniform size into a liquid crystal in the nematic and the smectic phases. The bubble size is primarily determined by the dimension of microfluidic channel regardless of the phase, and air bubbles of a few tens of micrometer diameter were stably injected at the rate up to 110 Hz to the close packing density with a polydispersity less than 4%. It is shown that an efficient path to fabricate stable liquid crystal foams is to inject bubbles in the nematic phase, where the highest injection rate is possible, and promptly cool it down to the smectic phase. PMID- 25822783 TI - Truthiness and falsiness of trivia claims depend on judgmental contexts. AB - When people rapidly judge the truth of claims presented with or without related but nonprobative photos, the photos tend to inflate the subjective truth of those claims--a "truthiness" effect (Newman et al., 2012). For example, people more often judged the claim "Macadamia nuts are in the same evolutionary family as peaches" to be true when the claim appeared with a photo of a bowl of macadamia nuts than when it appeared alone. We report several replications of that effect and 3 qualitatively new findings: (a) in a within-subjects design, when people judged claims paired with a mix of related, unrelated, or no photos, related photos produced truthiness but unrelated photos had no significant effect relative to no photos; (b) in a mixed design, when people judged claims paired with related (or unrelated) and no photos, related photos produced truthiness and unrelated photos produced "falseness;" and (c) in a fully between design, when people judged claims paired with either related, unrelated, or no photos, neither truthiness nor falsiness occurred. Our results suggest that photos influence people's judgments when a discrepancy arises in the expected ease of processing, and also support a mechanism in which-against a backdrop of an expected standard related photos help people generate pseudoevidence to support claims. PMID- 25822785 TI - Improving axial resolution in confocal microscopy with new high refractive index mounting media. AB - Resolution, high signal intensity and elevated signal to noise ratio (SNR) are key issues for biologists who aim at studying the localisation of biological structures at the cellular and subcellular levels using confocal microscopy. The resolution required to separate sub-cellular biological structures is often near to the resolving power of the microscope. When optimally used, confocal microscopes may reach resolutions of 180 nm laterally and 500 nm axially, however, axial resolution in depth is often impaired by spherical aberration that may occur due to refractive index mismatches. Spherical aberration results in broadening of the point-spread function (PSF), a decrease in peak signal intensity when imaging in depth and a focal shift that leads to the distortion of the image along the z-axis and thus in a scaling error. In this study, we use the novel mounting medium CFM3 (Citifluor Ltd., UK) with a refractive index of 1.518 to minimize the effects of spherical aberration. This mounting medium is compatible with most common fluorochromes and fluorescent proteins. We compare its performance with established mounting media, harbouring refractive indices below 1.500, by estimating lateral and axial resolution with sub-resolution fluorescent beads. We show furthermore that the use of the high refractive index media renders the tissue transparent and improves considerably the axial resolution and imaging depth in immuno-labelled or fluorescent protein labelled fixed mouse brain tissue. We thus propose to use those novel high refractive index mounting media, whenever optimal axial resolution is required. PMID- 25822786 TI - Trends, correlates, and disease patterns of antidepressant use among elderly persons in Taiwan. AB - PURPOSE: The population-based National Health Insurance database was used to investigate the trends, correlates, and disease patterns for elderly people in Taiwan who use antidepressants. METHODS: The National Health Research Institute provided a database of 1000,000 random subjects for study. We created a sample of subjects who were older than 65 years from 1997 to 2005. Trends, prevalence, and associated factors of antidepressant use were detected. We also examined the proportion of antidepressant use for psychiatric and medical disorders. RESULTS: The one-year prevalence of antidepressant use in elderly persons increased from 5.8 % in 1997 to 9.8 % in 2005. The one-year prevalence rates of tricyclic antidepressant (TCA), selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), serotonin modulator, and other antidepressant use in 2005 were 5.3, 2.6, 0.4, 2.9, and 0.6 %, respectively. Overall antidepressant use was higher for those in the 75- to 84-year-old age group, females, and those with higher Charlson Comorbidity Index scores. Among subjects using TCAs, 77.6 % users did not have a psychiatric diagnosis. Psychiatric disorders were commonly found in most SSRI and SNRI users (85.1 and 90.1 %, respectively). Subjects using SSRIs and SNRIs had higher proportions of psychiatric disorders such as neurotic depression, major depression, senile and presenile organic psychotic conditions, and anxiety. CONCLUSION: The prevalence of antidepressant use among elderly persons increased greatly from 1997 to 2005. SSRIs, SNRIs, and other antidepressants were used mostly by subjects with psychiatric disorders, whereas TCAs were used mostly by subjects with nonpsychiatric disorders. PMID- 25822787 TI - Delithation, Exfoliation, and Transformation of Rock-Salt-Structured Li2TiO3 to Highly Exposed {010}-Faceted Anatase. AB - {010}-Facet-exposed anatase TiO2 crystals exhibit the highest photoreactivity among the exposed facets. To obtain a higher exposure rate of this facet, the work investigated the transformation of the nanosheets with cavities within the layers derived from a rock-salt-structured Li2TiO3 precursor. All the lithium ions were extracted from the precursor by H+/Li+ ion exchange in HCl aqueous solutions, and after tetramethylammonium ions were intercalated, the precursor can delaminated into the nanosheets. The [TiO3]2- nanosheets were hydrothermally treated under different temperatures and pH values. The results showed that the anatase phase was formed in a wider range of pH and temperature, compared with using nanoribbons of [Ti4O9]2- and nanosheets of [Ti1.73O4]1.07-. At low pH, [111]-faceted nanorod-shaped anatase nanocrystals were formed preferentially, and the nanocrystals preferentially grow along the [001] direction with the increase of solution pH, leading to a large percentage of {010} facets on their surface. The photocatalytic activity increases with the increase of exposure rate of {010} facets. PMID- 25822788 TI - IL-17-producing gammadelta T cells and neutrophils conspire to promote breast cancer metastasis. AB - Metastatic disease remains the primary cause of death for patients with breast cancer. The different steps of the metastatic cascade rely on reciprocal interactions between cancer cells and their microenvironment. Within this local microenvironment and in distant organs, immune cells and their mediators are known to facilitate metastasis formation. However, the precise contribution of tumour-induced systemic inflammation to metastasis and the mechanisms regulating systemic inflammation are poorly understood. Here we show that tumours maximize their chance of metastasizing by evoking a systemic inflammatory cascade in mouse models of spontaneous breast cancer metastasis. We mechanistically demonstrate that interleukin (IL)-1beta elicits IL-17 expression from gamma delta (gammadelta) T cells, resulting in systemic, granulocyte colony-stimulating factor (G-CSF)-dependent expansion and polarization of neutrophils in mice bearing mammary tumours. Tumour-induced neutrophils acquire the ability to suppress cytotoxic T lymphocytes carrying the CD8 antigen, which limit the establishment of metastases. Neutralization of IL-17 or G-CSF and absence of gammadelta T cells prevents neutrophil accumulation and downregulates the T-cell suppressive phenotype of neutrophils. Moreover, the absence of gammadelta T cells or neutrophils profoundly reduces pulmonary and lymph node metastases without influencing primary tumour progression. Our data indicate that targeting this novel cancer-cell-initiated domino effect within the immune system--the gammadelta T cell/IL-17/neutrophil axis--represents a new strategy to inhibit metastatic disease. PMID- 25822789 TI - Branch-specific dendritic Ca(2+) spikes cause persistent synaptic plasticity. AB - The brain has an extraordinary capacity for memory storage, but how it stores new information without disrupting previously acquired memories remains unknown. Here we show that different motor learning tasks induce dendritic Ca(2+) spikes on different apical tuft branches of individual layer V pyramidal neurons in the mouse motor cortex. These task-related, branch-specific Ca(2+) spikes cause long lasting potentiation of postsynaptic dendritic spines active at the time of spike generation. When somatostatin-expressing interneurons are inactivated, different motor tasks frequently induce Ca(2+) spikes on the same branches. On those branches, spines potentiated during one task are depotentiated when they are active seconds before Ca(2+) spikes induced by another task. Concomitantly, increased neuronal activity and performance improvement after learning one task are disrupted when another task is learned. These findings indicate that dendritic-branch-specific generation of Ca(2+) spikes is crucial for establishing long-lasting synaptic plasticity, thereby facilitating information storage associated with different learning experiences. PMID- 25822790 TI - Two disparate ligand-binding sites in the human P2Y1 receptor. AB - In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 A resolution, and with a non-nucleotide antagonist BPTU at 2.2 A resolution. The structures reveal two distinct ligand binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects. PMID- 25822792 TI - Self-similar fragmentation regulated by magnetic fields in a region forming massive stars. AB - Most molecular clouds are filamentary or elongated. For those forming low-mass stars (<8 solar masses), the competition between self-gravity and turbulent pressure along the dynamically dominant intercloud magnetic field (10 to 100 parsecs) shapes the clouds to be elongated either perpendicularly or parallel to the fields. A recent study also suggested that on the scales of 0.1 to 0.01 parsecs, such fields are dynamically important within cloud cores forming massive stars (>8 solar masses). But whether the core field morphologies are inherited from the intercloud medium or governed by cloud turbulence is unknown, as is the effect of magnetic fields on cloud fragmentation at scales of 10 to 0.1 parsecs. Here we report magnetic-field maps inferred from polarimetric observations of NGC 6334, a region forming massive stars, on the 100 to 0.01 parsec scale. NGC 6334 hosts young star-forming sites where fields are not severely affected by stellar feedback, and their directions do not change much over the entire scale range. This means that the fields are dynamically important. The ordered fields lead to a self-similar gas fragmentation: at all scales, there exist elongated gas structures nearly perpendicular to the fields. Many gas elongations have density peaks near the ends, which symmetrically pinch the fields. The field strength is proportional to the 0.4th power of the density, which is an indication of anisotropic gas contractions along the field. We conclude that magnetic fields have a crucial role in the fragmentation of NGC 6334. PMID- 25822791 TI - Defining fundamental steps in the assembly of the Drosophila RNAi enzyme complex. AB - Small RNAs such as small interfering RNAs (siRNAs) and microRNAs (miRNAs) silence the expression of their complementary target messenger RNAs via the formation of effector RNA-induced silencing complexes (RISCs), which contain Argonaute (Ago) family proteins at their core. Although loading of siRNA duplexes into Drosophila Ago2 requires the Dicer-2-R2D2 heterodimer and the Hsc70/Hsp90 (Hsp90 also known as Hsp83) chaperone machinery, the details of RISC assembly remain unclear. Here we reconstitute RISC assembly using only Ago2, Dicer-2, R2D2, Hsc70, Hsp90, Hop, Droj2 (an Hsp40 homologue) and p23. By following the assembly of single RISC molecules, we find that, in the absence of the chaperone machinery, an siRNA bound to Dicer-2-R2D2 associates with Ago2 only transiently. The chaperone machinery extends the dwell time of the Dicer-2-R2D2-siRNA complex on Ago2, in a manner dependent on recognition of the 5'-phosphate on the siRNA guide strand. We propose that the chaperone machinery supports a productive state of Ago2, allowing it to load siRNA duplexes from Dicer-2-R2D2 and thereby assemble RISC. PMID- 25822793 TI - The 39th international conference of the EURO working group on operational research applied to health services: ORAHS 2013 special issue. PMID- 25822794 TI - Risk profiling of hookworm infection and intensity in southern Lao People's Democratic Republic using Bayesian models. AB - BACKGROUND: Among the common soil-transmitted helminth infections, hookworm causes the highest burden. Previous research in the southern part of Lao People's Democratic Republic (Lao PDR) revealed high prevalence rates of hookworm infection. The purpose of this study was to predict the spatial distribution of hookworm infection and intensity, and to investigate risk factors in the Champasack province, southern Lao PDR. METHODOLOGY: A cross-sectional parasitological and questionnaire survey was conducted in 51 villages. Data on demography, socioeconomic status, water, sanitation, and behavior were combined with remotely sensed environmental data. Bayesian mixed effects logistic and negative binomial models were utilized to investigate risk factors and spatial distribution of hookworm infection and intensity, and to make predictions for non surveyed locations. PRINCIPAL FINDINGS: A total of 3,371 individuals were examined with duplicate Kato-Katz thick smears and revealed a hookworm prevalence of 48.8%. Most infections (91.7%) were of light intensity (1-1,999 eggs/g of stool). Lower hookworm infection levels were associated with higher socioeconomic status. The lowest infection levels were found in preschool-aged children. Overall, females were at lower risk of infection, but women aged 50 years and above harbored the heaviest hookworm infection intensities. Hookworm was widespread in Champasack province with little evidence for spatial clustering. Infection risk was somewhat lower in the lowlands, mostly along the western bank of the Mekong River, while infection intensity was homogeneous across the Champasack province. CONCLUSIONS/SIGNIFICANCE: Hookworm transmission seems to occur within, rather than between villages in Champasack province. We present spatial risk maps of hookworm infection and intensity, which suggest that control efforts should be intensified in the Champasack province, particularly in mountainous areas. PMID- 25822795 TI - Role of Interleukin-1 in Radiation-Induced Cardiomyopathy. AB - Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO-or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening. PMID- 25822796 TI - Genetic Determinants of Epigenetic Patterns: Providing Insight into Disease. AB - The field of epigenetics and our understanding of the mechanisms that regulate the establishment, maintenance and heritability of epigenetic patterns continue to grow at a remarkable rate. This information is providing increased understanding of the role of epigenetic changes in disease, insight into the underlying causes of these epigenetic changes and revealing new avenues for therapeutic intervention. Epigenetic modifiers are increasingly being pursued as therapeutic targets in a range of diseases, with a number of agents targeting epigenetic modifications already proving effective in diseases such as cancer. Although it is well established that DNA mutations and aberrant expression of epigenetic modifiers play a key role in disease, attention is now turning to the interplay between genetic and epigenetic factors in complex disease etiology. The role of genetic variability in determining epigenetic profiles, which can then be modified by environmental and stochastic factors, is becoming more apparent. Understanding the interplay between genetic and epigenetic factors is likely to aid in identifying individuals most likely to benefit from epigenetic therapies. This goal is coming closer to realization because of continual advances in laboratory and statistical tools enabling improvements in the integration of genomic, epigenomic and phenotypic data. PMID- 25822797 TI - CD40-CD40 Ligand Pathway is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis. AB - Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis. PMID- 25822798 TI - Diversity of the expression profiles of late embryogenesis abundant (LEA) protein encoding genes in the anhydrobiotic midge Polypedilum vanderplanki. AB - MAIN CONCLUSION: In the anhydrobiotic midge Polypedilum vanderplanki , LEA family proteins are likely to play distinct temporal and spatial roles in the larvae throughout the process of desiccation and rehydration. The larvae of the anhydrobiotic midge, P. vanderplanki, which can tolerate almost complete desiccation, accumulate late embryogenesis abundant (LEA) proteins in response to drying. Using complete genome data of the midge, we have identified 27 PvLea1 like genes based on the similarity to previously characterized PvLea1 gene belonging to group 3 LEA proteins. Generally, group 3 LEA proteins are characterized by several repetitions of an 11-mer motif. However, some PvLea genes lack the canonical motif in their sequences. We performed the detailed characterization of all 27 PvLea genes in terms of biochemical and biophysical properties and conserved motifs. The motif analysis among their amino acid sequences revealed that all 27 PvLEA proteins have at least one of two types of motifs (motif 1: G AKDTTKEKLGE AKDATAEKLG or motif 2: KD ILExAKDKLxD AKDAVKEKL), indicating the presence of at least two repeated 11-mer LEA motifs. Most of PvLEA proteins were localized to the cytosol. We also performed quantitative real-time PCR of all 27 PvLea genes in detail during the process of desiccation and rehydration. The expression of these genes was upregulated at the beginning of dehydration, the latter phase of the desiccation process and on rehydration process. These data suggested that each LEA protein is likely to play distinct temporal and spatial roles in the larvae throughout the process of desiccation and rehydration. PMID- 25822799 TI - High-speed label-free functional photoacoustic microscopy of mouse brain in action. AB - We present fast functional photoacoustic microscopy (PAM) for three-dimensional high-resolution, high-speed imaging of the mouse brain, complementary to other imaging modalities. We implemented a single-wavelength pulse-width-based method with a one-dimensional imaging rate of 100 kHz to image blood oxygenation with capillary-level resolution. We applied PAM to image the vascular morphology, blood oxygenation, blood flow and oxygen metabolism in both resting and stimulated states in the mouse brain. PMID- 25822801 TI - The Chhattisgarh state screening programme for the sickle cell gene: a cost effective approach to a public health problem. AB - In India, the Chhattisgarh State screening programme for sickle haemoglobin focuses on children aged 3-15 years and has screened over 1,050,440 subjects over the last 6 years. Commencing in the District around the capital Raipur, this programme has now completed screening in 7 of the 27 Districts of Chhattisgarh State. Screening is initially performed by solubility tests on fingerprick samples in the field and those with positive tests have venipunctures for haemoglobin electrophoresis. The frequency of the sickle cell trait was 9.64 % and of the SS phenotype 0.29 % with only two Districts in Hardy-Weinberg equilibrium, most Districts showing an excess of the SS 'phenotype' most readily explained by symptomatic selection. The estimated costs were US$0.28 (solubility tests alone) and US$0.60 (haemoglobin electrophoresis). Of the social groupings commonly used in India, the OBC's (other backward classes) had the highest frequencies of the sickle cell gene mutations, followed by the Scheduled Tribes and the Scheduled Castes. The objectives of the programme were the detection of sickle cell disease for prospective clinical management and of the sickle cell trait for purposes of genetic counselling. The former objective is being met for diagnosis although the success of referral to clinic services requires audit. The objective of genetic counselling is compromised by the failure of the screening test to detect other genes of potential clinical significance such as HbD Punjab and the beta thalassaemia trait. Despite these exceptions, the detection of HbS appears relatively robust and could be another condition factored into the traditions of partner selection amongst the underprivileged communities of this state. Overall, the Chhattisgarh programme seeks to address the daunting challenges of large populations carrying the sickle cell gene and maybe a useful model for elsewhere. PMID- 25822800 TI - Robust enumeration of cell subsets from tissue expression profiles. AB - We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content and closely related cell types. CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersort.stanford.edu/). PMID- 25822803 TI - Editorial. PMID- 25822802 TI - Down-regulated E-cadherin expression is associated with poor five-year overall survival in bone and soft tissue sarcoma: results of a meta-analysis. AB - PURPOSE: To conduct a meta-analysis to evaluate the prognostic role of E-cadherin expression in bone and soft tissue sarcomas. METHODS: The PubMed, EMBASE, and Web of Science databases were searched using terms related to E-cadherin, sarcoma, and prognosis for all articles published in English before March 2014. Pooled effect was calculated from the available data to evaluate the association between negative E-cadherin expression and 5-year overall survival and tumor clinicopathological features in sarcoma patients. Pooled odds ratios (OR) and risk ratios (RR) with 95% confidence intervals (CI) were calculated using a fixed effects model. RESULT: Eight studies met the selection criteria and reported on 812 subjects. A total of 496 subjects showed positive E-cadherin expression (59.9%). Negative E-cadherin expression in bone and soft tissue sarcomas was correlated with lower 5-year overall survival (OR = 3.831; 95% CI: 2.246-6.534), and was associated with higher clinical stage (RR = 1.446; 95% CI: 1.030-2.028) and with male sex (RR = 0.678; 95% CI: 0.493-0.933). CONCLUSION: In the E cadherin negative group, 5-year overall survival was significantly worse than in the E-cadherin positive group. However, further studies are required to confirm these results. PMID- 25822805 TI - Effect of resveratrol and orchidectomy on the vasorelaxing influence of perivascular adipose tissue. AB - Perivascular adipose tissue (PVAT) releases several adipo(cyto)kines. Some are vasoactive substances that elicit a net beneficial anticontractile effect. Resveratrol and testosterone are known to modulate adipo(cyto)kine release from adipose tissue and could therefore influence the anticontractile effect of PVAT. In vitro tension measurements were performed using thoracic aorta segments with and without adipose tissue from sham-operated or orchidectomized male Swiss mice. Concentration-response curves to norepinephrine (NOR) were constructed in the presence and absence of resveratrol (10 MUM, 15 min) or the relaxant effect of resveratrol (10-100 MUM) was investigated after inducing tone with NOR (5 MUM). Aortas with PVAT displayed significantly attenuated contractions to NOR compared with aortas without PVAT. In aortas without PVAT, resveratrol (10 MUM) significantly decreased NOR responses and elicited concentration-dependent (10 100 uM) relaxations. However, in aortas with adherent PVAT, resveratrol (10 MUM) neither decreased NOR responses, nor did resveratrol (10-100 uM) induce arterial relaxations. The anticontractile effect of PVAT was less pronounced in the presence of resveratrol and unaltered by orchidectomy. Orchidectomy did not influence contractions induced by NOR. Orchidectomy does not modulate the anticontractile capacity of PVAT, while resveratrol decreases the vasorelaxing influence of PVAT. The positive effects associated with resveratrol addition are neutralized by the presence of PVAT. This is thought to result from a dual effect of resveratrol: (1) inhibition of the influence of vasodilatory adipo(cyto)kines and (2) a direct relaxant effect on the vascular smooth muscle. Overall, the beneficial relaxing effect of resveratrol is lost in mice thoracic aorta surrounded by PVAT. PMID- 25822804 TI - World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Schizophrenia. Part 3: Update 2015 Management of special circumstances: Depression, Suicidality, substance use disorders and pregnancy and lactation. AB - These updated guidelines are based on the first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in the years 2005 and 2006. For this 2015 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations which are clinically and scientifically relevant. They are intended to be used by all physicians diagnosing and treating patients with schizophrenia. Based on the first version of these guidelines a systematic review, as well as a data extraction from national guidelines have been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and subsequently categorised into six levels of evidence (A-F) and five levels of recommendation (1-5). This third part of the updated guidelines covers the management of the following specific treatment circumstances: comorbid depression, suicidality, various comorbid substance use disorders (legal and illegal drugs), and pregnancy and lactation. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of patients with schizophrenia. PMID- 25822806 TI - Diabetes is a predictor of coronary artery stenosis in patients hospitalized with heart failure. AB - In patients with heart failure, coronary artery disease is the most common underlying heart disease, and is associated with increased mortality. However, estimating the presence or absence of coronary artery disease in patients with heart failure is sometimes difficult without coronary imaging. We reviewed 155 consecutive patients hospitalized with heart failure who underwent coronary angiography. The patients were divided into two groups: patients with (N = 59) and without (N = 96) coronary artery stenosis. The clinical characteristics and blood sampling data were compared between the two groups. The patients with coronary artery stenosis were older than those without. The prevalence of diabetes mellitus (DM), dyslipidemia and a history of revascularization was higher in the patients with coronary artery stenosis. Patients with coronary artery stenosis tended to have wall motion asynergy more frequently than those without. On the other hand, the prevalence of atrial fibrillation (AF) was lower in patients with coronary artery stenosis. The serum hemoglobin level and estimated glomerular filtration rate were lower in patients with coronary artery stenosis than in those without. In the multivariate analysis, DM (odds ratio 3.517, 95 % CI 1.601-7.727) was found to be the only the predictor of the presence of coronary artery stenosis in patients with heart failure. In conclusion, coronary imaging is strongly recommended for heart failure patients with DM to confirm the presence of coronary artery stenosis. PMID- 25822807 TI - The development of a MU-biomimetic uncooled IR-Sensor inspired by the infrared receptors of Melanophila acuminata. AB - The beetle Melanophila acuminata uses a specialized organ to detect infrared radiation. The organ consists of about 100 individual sensilla. The main component of the sensillum is a pressure chamber. Upon absorption of radiation, the pressure increases, and the tip of a dendrite is deformed. A unique feature of the organ is a compensation mechanism that prevents large pressures. The beetle uses this organ to detect forest fires and to navigate inside burning woods. However, the sensitivity is part of a long-lasting discussion, providing thresholds between [Formula: see text] and [Formula: see text]. To end the decade long discussion and to provide a novel type of infrared sensor, we are developing an uncooled MU-biomimetic infrared (IR) sensor inspired by Melanophila acuminata using MEMS technology. Here, we present the development of a MU-capacitor that is used to detect pressure changes and the characterization of the compensation mechanism. We describe the microtechnological fabrication process for air-filled capacitors with a ratio of diameter-to-electrode distance of 1000 and a technique to fill the sensor bubble-free with water. Finally, we estimate the sensitivity of the beetle using a theoretical model of the sensillum. PMID- 25822808 TI - EPR and NMR spectroscopies provide input on the coordination of Cu(I) and Ag(I) to a disordered methionine segment. AB - Methionine motifs are methionine-rich metal-binding segments found in many human, yeast, and bacterial proteins involved in the transportation of copper ion to other cellular pathways, and in protecting copper from oxidation. Methionine motifs are found to bind Ag(I) and Cu(I) ions. Proteins or peptides that can bind different metal ions should have the ability to differentiate between them, to be able to shuttle them to various pathways in the cell. This study utilizes electron paramagnetic resonance spectroscopy together with circular dichroism and nuclear magnetic resonance to probe structural changes in the methionine segment upon coordinating Cu(I) and Ag(I) metal ions. The data collected here indicate that methionine segments experience structural changes while coordinating Cu(I) and Ag(I), however, the differences between the coordination of Cu(I) vs. Ag(I) to the methionine segment are mild. Since Cu(I) and Ag(I) metal ions are pretty similar in their nature and charge, the minor structural changes reported here are significant towards the understanding of the differences in the transport mechanism of these two metal ions in prokaryotic and eukaryotic cells. PMID- 25822809 TI - Fullerene mixing effect on carrier formation in bulk-hetero organic solar cell. AB - Organic solar cells (OSCs) with a bulk-heterojunction (BHJ) are promising energy conversion devices, because they are flexible and environmental-friendly, and can be fabricated by low-cost roll-to-roll process. Here, we systematically investigated the interrelations between photovoltaic properties and the domain morphology of the active layer in OSCs based on films of poly-(9,9 dioctylfluorene-co-bithiophene) (F8T2)/[6,6]-phenyl C71-butyric acid methyl ester (PC71BM) blend annealed at various temperatures (Tan). The scanning transmission X-ray microscopy (STXM) revealed that fullerene mixing (PhiFullerene) in the polymer matrix decreases with increase in Tan while the domain size (L) is nearly independent of Tan. The TEM-S mapping image suggests that the polymer matrix consist of polymer clusters of several nm and fullerene. We found that the charge formation efficiency (PhiCF), internal quantum efficiency (PhiIQ), and power conversion efficiency (PCE) are dominantly determined by PhiFullerene. We interpreted these observations in terms of the polymer clusters within the polymer matrix. PMID- 25822810 TI - Modelling and Analysis of Electrical Potentials Recorded in Microelectrode Arrays (MEAs). AB - Microelectrode arrays (MEAs), substrate-integrated planar arrays of up to thousands of closely spaced metal electrode contacts, have long been used to record neuronal activity in in vitro brain slices with high spatial and temporal resolution. However, the analysis of the MEA potentials has generally been mainly qualitative. Here we use a biophysical forward-modelling formalism based on the finite element method (FEM) to establish quantitatively accurate links between neural activity in the slice and potentials recorded in the MEA set-up. Then we develop a simpler approach based on the method of images (MoI) from electrostatics, which allows for computation of MEA potentials by simple formulas similar to what is used for homogeneous volume conductors. As we find MoI to give accurate results in most situations of practical interest, including anisotropic slices covered with highly conductive saline and MEA-electrode contacts of sizable physical extensions, a Python software package (ViMEAPy) has been developed to facilitate forward-modelling of MEA potentials generated by biophysically detailed multicompartmental neurons. We apply our scheme to investigate the influence of the MEA set-up on single-neuron spikes as well as on potentials generated by a cortical network comprising more than 3000 model neurons. The generated MEA potentials are substantially affected by both the saline bath covering the brain slice and a (putative) inadvertent saline layer at the interface between the MEA chip and the brain slice. We further explore methods for estimation of current-source density (CSD) from MEA potentials, and find the results to be much less sensitive to the experimental set-up. PMID- 25822811 TI - Estimating Intracranial Volume in Brain Research: An Evaluation of Methods. AB - Intracranial volume (ICV) is a standard measure often used in morphometric analyses to correct for head size in brain studies. Inaccurate ICV estimation could introduce bias in the outcome. The current study provides a decision aid in defining protocols for ICV estimation across different subject groups in terms of sampling frequencies that can be optimally used on the volumetric MRI data, and type of software most suitable for use in estimating the ICV measure. Four groups of 53 subjects are considered, including adult controls (AC, adults with Alzheimer's disease (AD), pediatric controls (PC) and group of pediatric epilepsy subjects (PE). Reference measurements were calculated for each subject by manually tracing intracranial cavity without sub-sampling. The reliability of reference measurements were assured through intra- and inter- variation analyses. Three publicly well-known software packages (FreeSurfer Ver. 5.3.0, FSL Ver. 5.0, SPM8 and SPM12) were examined in their ability to automatically estimate ICV across the groups. Results on sub-sampling studies with a 95 % confidence showed that in order to keep the accuracy of the inter-leaved slice sampling protocol above 99 %, sampling period cannot exceed 20 mm for AC, 25 mm for PC, 15 mm for AD and 17 mm for the PE groups. The study assumes a priori knowledge about the population under study into the automated ICV estimation. Tuning of the parameters in FSL and the use of proper atlas in SPM showed significant reduction in the systematic bias and the error in ICV estimation via these automated tools. SPM12 with the use of pediatric template is found to be a more suitable candidate for PE group. SPM12 and FSL subjected to tuning are the more appropriate tools for the PC group. The random error is minimized for FS in AD group and SPM8 showed less systematic bias. Across the AC group, both SPM12 and FS performed well but SPM12 reported lesser amount of systematic bias. PMID- 25822812 TI - Genetic association study of phosphodiesterase 8B gene with subclinical hypothyroidism in pregnant women. AB - OBJECTIVE: To explore whether phosphodiesterase 8B (PDE8B) gene is involved in the etiology of subclinical hypothyroidism (SCH) in pregnant women. METHODS: A total of 180 pregnant patients with SCH and 311 healthy, pregnant control subjects were recruited in this study to detect 4 (rs4704397, rs6885099, rs2046045, and rs12514694 in PDE8B) single nucleotide polymorphisms (SNPs). Univariate associations were studied using Pearson's chi(2) test for categorical variables and Student t/ANOVA tests for continuous ones. Nonparametric Kruskal Wallis test were used to study the associations of TSH level in different genotypes. Genotyping of SNPs was performed by the MassARRAY((r)) iPLEX((r)) Gold SNP genotyping analysis technique. The SHEsis program was used to analyze the genotyping data. RESULTS: There was a significant difference in the rate of high TSH in three genotypes of rs4704397 in all pregnant women. After adjusting for multiple testing by the program SNPSpD, allelic frequencies of rs4704397 (p = 0.016, OR = 1.692), rs6885099 (p = 0.031, OR = 0.621), and rs2046045 (p = 0.023, OR = 0.602) in PDE8B gene showed significant differences between patients with SCH and control subjects. There were no significant differences of genotype frequencies between patients and controls at any of the analyzed SNPs (p > 0.05).The haplotypes ''A G C G'' (p = 0.002; OR, 1.533; 95% CI, 1.172-2.006) and "G A A G" (p = 0.014; OR, 0.576; 95% CI, 0.369-0.899) in PDE8B were observed to be significantly associated with SCH in pregnant women. CONCLUSION: Genetic variation of the PDE8B gene may be involved in the etiology of SCH in pregnant women. PMID- 25822813 TI - Anxiolytic effects of sesamin in mice with chronic inflammatory pain. AB - OBJECTIVE: Sesamin is known for its role in antioxidant, antiproliferative, antihypertensive, and neuroprotective activities. However, little is known about the role of sesamin in the development of emotional disorders. Here we investigated persistent inflammatory pain hypersensitivity and anxiety-like behaviors in the mouse suffering chronic pain. METHODS: Chronic inflammatory pain was induced by hind paw injection of complete Freund's adjuvant (CFA). Levels of protein were detected by Western blot. RESULTS: Administration of sesamin could induce anxiolytic activities but had no effect on analgesia. In the basolateral amygdala, a structure involving the anxiety development, sesamin attenuated the up-regulation of NR2B-containing N-methyl-d-aspartate receptors, GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor as well as phosphorylation of GluR1 at Ser831 (p-GluR1-Ser831), and Ca(2+)/calmodulin dependent protein kinase II (CaMKII-alpha) in the hind paw CFA-injected mice. In the same model, we found that the sesamin blocked the down-regulation of gamma aminobutyric acid A (GABAA-alpha-2) receptors. CONCLUSION: Our findings show that sesamin reduces anxiety-like behaviors induced by chronic pain at least partially through regulating the GABAergic and glutamatergic transmission in the amygdala of mice. PMID- 25822814 TI - [Excess mortality of schizophrenia]. AB - Patients with schizophrenia have a diminished life expectancy of 15-20 years compared to the general population. Over the last decades excess mortality of suicide has decreased, whereas excess mortality of physical illness, especially cardiovascular disease has increased. Focus attends current somatic co-morbidity, side effects to medication and poor lifestyle. Further actions to prevent excess mortality of physical illness are needed. PMID- 25822815 TI - [Autoimmune hepatitis preceded by hepatitis A]. AB - Autoimmune hepatitis is characterized by unresolving inflammation and fibrosis of the liver, which untreated may lead to cirrhosis. The pathogenesis remains unclear and reflects a complex interaction between autoantigens, genetic predisposition, triggering factors and immune regulation. In rare cases, acute hepatitis A has been suspected as a triggering factor. We describe a case of a 66 year-old woman who two months after a resolving acute hepatitis A presented with fatigue, pale stools and elevated levels of transaminases. A liver biopsy showed histological changes compatible with autoimmune hepatitis. PMID- 25822816 TI - [Frovatriptan possibly causing acute myocardial infarction]. AB - Globally migraine affects more than 10% of the adult population and it is treated with simple analgesics, combined with a triptan for a stronger treatment effect. Triptans cause arterial vasoconstriction, and this is a case report of vasospasm induced acute myocardial infarction in a 61-year-old woman with frequent episodic migraine attacks treated with triptans. She was possibly also suffering from medication overuse headache. We suggest that regular frovatriptan use may have contributed to the myocardial infarction and that long-term triptan use may have caused the medication overuse headache. PMID- 25822817 TI - [Metastatic adenocarcinoma in preputium of a patient with oesophageal cancer]. AB - Secondary or acquired phimosis usually occurs as part of a benign disease. We present a case of secondary phimosis caused by metastasis from a newly diagnosed oesophageal adenocarcinoma. The patient presented with clinical suspicion of infection in the preputial space, but histopathology revealed dilated lymphatic vessels with peripheral embolisms of epithelial tumour cells. This case report emphasizes the importance of establishing the cause of secondary phimosis by histopath-ological examination for possible malignancy. PMID- 25822818 TI - [Spontaneous bilateral tubal pregnancy following caesarean section]. AB - We describe a rare case of bilateral tubal pregnancy following natural conception in a woman with no other known risk factor than two former caesarean sections. Intraabdominal adhesions following the caesarean sections complicated the salpingectomy thus diminishing certainty of a healthy contralateral tube. The woman was readmitted three weeks later and had an additional salpingectomy on behalf of an unrecognized tubal pregnancy. Considering the rising caesarean section rates clinicians need to be certain of no additional ectopic pregnancy while performing the primary operation. PMID- 25822819 TI - Investigation of hydrogen sulfide exposure and lung function, asthma and chronic obstructive pulmonary disease in a geothermal area of New Zealand. AB - BACKGROUND: Results have been conflicting whether long-term ambient hydrogen sulfide (H2S) affects lung function or is a risk factor for asthma or chronic obstructive pulmonary disease (COPD). Rotorua city, New Zealand, has the world's largest population exposed to ambient H2S-from geothermal sources. OBJECTIVES: We investigated associations of H2S with lung function, COPD and asthma in this population. METHODS: 1,204 of 1,639 study participants, aged 18-65 years during 2008-2010, provided satisfactory spirometry results. Residences, workplaces and schools over the last 30 years were geocoded. Exposures were estimated from data collected by summer and winter H2S monitoring networks across Rotorua. Four metrics for H2S exposure, representing both current and long-term (last 30 years) exposure, and also time-weighted average and peak exposures, were calculated. Departures from expected values for pre-bronchodilator lung function, calculated from prediction equations, were outcomes for linear regression models using quartiles of the H2S exposure metrics. Separate models examined participants with and without evidence of asthma or COPD, and never- and ever-smokers. Logistic regression was used to investigate associations of COPD (a post-bronchodilator FEV1/FVC < 70% of expected) and asthma (doctor-diagnosed or by FEV1 response to bronchodilator) with H2S exposure quartiles. RESULTS: None of the exposure metrics produced evidence of lung function decrement. The logistic regression analysis showed no evidence that long-term H2S exposure at Rotorua levels was associated with either increased COPD or asthma risk. Some results suggested that recent ambient H2S exposures were beneficially associated with lung function parameters. CONCLUSIONS: The study found no evidence of reductions in lung function, or increased risk of COPD or asthma, from recent or long-term H2S exposure at the relatively high ambient concentrations found in Rotorua. Suggestions of improved lung function associated with recent ambient H2S exposures require confirmation in other studies. PMID- 25822820 TI - Effect and Tolerability of Agalsidase Alfa in Patients with Fabry Disease Who Were Treatment Naive or Formerly Treated with Agalsidase Beta or Agalsidase Alfa. AB - OBJECTIVES: In a multicenter, open-label, treatment protocol (HGT-REP-059; NCT01031173), clinical effects and tolerability of agalsidase alfa (agalalpha; 0.2 mg/kg every other week) were evaluated in patients with Fabry disease who were treatment naive or switched from agalsidase beta (switch). Over 24 months, data were collected on the safety profile; renal and cardiac parameters were assessed using estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and midwall fractional shortening (MFS). RESULTS: Enrolled patients included 71 switch (median [range] age, 46.6 [5-84] years; male to female [M:F], 40:31) and 29 treatment naive (38.7 [12-74] years; M:F, 14:15). Adverse events (AEs) were consistent with the known safety profile of agalalpha. Two switch patients had hospitalization due to possibly/probably drug-related serious AEs (one with transient ischemic attack, one with infusion-related AEs). One switch and two treatment-naive patients discontinued treatment because of AEs. Three patients (one each switch, treatment naive, and previous agalalpha) died; no deaths were considered drug-related. There was no significant change from baseline in LVMI or MFS in either group. Similarly, eGFR remained stable; mean +/ standard error annualized change in eGFR (mL/min/1.73 m(2)) was -2.40 +/- 1.04 in switch and -1.68 +/- 2.21 in treatment-naive patients. CONCLUSIONS: This is the largest cohort of patients with Fabry disease who were started on or switched to agalalpha in an FDA-accepted protocol during a worldwide supply shortage of agalsidase beta. Because this protocol was primarily designed to provide access to agalalpha, there were limitations, including not having stringent selection criteria and the lack of a placebo group. PMID- 25822821 TI - The Kuvan((r)) Adult Maternal Paediatric European Registry (KAMPER) Multinational Observational Study: Baseline and 1-Year Data in Phenylketonuria Patients Responsive to Sapropterin. AB - INTRODUCTION: Sapropterin dihydrochloride (Kuvan((r))), a synthetic 6R diastereoisomer of tetrahydrobiopterin (BH4), is approved in Europe for the treatment of patients aged >=4 years with hyperphenylalaninaemia (HPA) due to BH4 responsive phenylalanine hydroxylase (PAH) deficiency, in conjunction with a phenylalanine-restricted diet, and also for the treatment of patients with BH4 deficiency. AIMS/METHODS: KAMPER is an ongoing, observational, multicentre registry with the primary objective of providing information over 15 years on long-term safety of sapropterin dihydrochloride treatment in patients with HPA. Here we report initial data on characteristics from patients recruited by the time of the third interim analysis and results at 1 year. RESULTS: Overall, 325 patients from 55 sites in seven European countries were included in the analysis: 296 (91.1%) patients with PAH deficiency (median [Q1, Q3] age, 10.3 [7.2, 15.0] years) and 29 (8.9%) with BH4 deficiency (12.8 [6.6, 18.9] years). Fifty-nine patients (18.2%) were aged >=18 years; 4 patients were pregnant. No elderly patients (aged >=65 years) or patients with renal or hepatic insufficiency were enroled in the study. Twelve-month data were available for 164 patients with PAH deficiency and 16 with BH4 deficiency. No new safety concerns were identified as of May 2013. CONCLUSIONS: Initial data from KAMPER show that sapropterin dihydrochloride has a favourable safety profile. Registry data collected over time will provide insight into the management and outcomes of patients with PAH deficiency and BH4 deficiency, including long-term safety, impact on growth and neurocognitive outcomes and the effect of sapropterin dihydrochloride treatment on populations of special interest. PMID- 25822822 TI - Pyrroloquinoline-quinone suppresses liver fibrogenesis in mice. AB - Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injuries, and its progression toward cirrhosis is the major cause of liver-related morbidity and mortality worldwide. However, anti-fibrotic treatment remains an unconquered area for drug development. Accumulating evidence indicate that oxidative stress plays a critical role in liver fibrogenesis. In this study, we found that PQQ, a natural anti-oxidant present in a wide variety of human foods, exerted potent anti-fibrotic and ROS-scavenging activity in Balb/C mouse models of liver fibrosis. The antioxidant activity of PQQ was involved in the modulation of multiple steps during liver fibrogenesis, including chronic liver injury, hepatic inflammation, as well as activation of hepatic stellate cells and production of extracellular matrix. PQQ also suppressed the up regulation of RACK1 in activated HSCs in vivo and in vitro. Our data suggest that PQQ suppresses oxidative stress and liver fibrogenesis in mice, and provide rationale for the clinical application of PQQ in the prevention and treatment of liver fibrosis. PMID- 25822823 TI - Expression of 1N3R-Tau isoform inhibits cell proliferation by inducing S phase arrest in N2a cells. AB - Tau is a microtubule-associated protein implicated in neurodegenerative tauopathies. Six tau isoforms are generated from a single gene through alternative splicing of exons 2, 3 and 10 in human brain. Differential expression of tau isoforms has been detected in different brain areas, during neurodevelopment and in neurodegenerative disorders. However, the biological significance of different tau isoforms is not clear. Here, we investigated the individual effect of six different isoforms of tau on cell proliferation and the possible mechanisms by transient expression of eGFP-labeled tau isoform plasmid in N2a cells. Our study showed the transfection efficiency was comparable between different isoforms of tau by examining GFP expression. Compared with other isoforms, we found expression of 1N3R-tau significantly inhibited cell proliferation by Cell Counting Kit-8 assay and BrdU incorporation. Flow cytometry analysis further showed expression of 1N3R-tau induced S phase arrest. Compared with the longest isoform of tau, expression of 1N3R-tau induced cyclin E translocation from the nuclei to cytoplasm, while it did not change the level of cell cycle checkpoint proteins. These data indicate that 1N3R-tau inhibits cell proliferation through inducing S phase arrest. PMID- 25822824 TI - Milk matrix effects on antibody binding analyzed by enzyme-linked immunosorbent assay and biolayer interferometry. AB - Biolayer interferometry (BLI) was employed to study the impact of the milk matrix on the binding of ricin to asialofetuin (ASF) and to antibodies. This optical sensing platform used ligands immobilized covalently or via biotin-streptavidin linkage, and the results were compared to those obtained by enzyme-linked immunosorbent assay (ELISA). In sandwich ELISA, the binding of ricin to ASF was dramatically decreased when galactose was present during the analyte or detection antibody binding step. Low concentrations of milk (1%, v/v) produced a similar reduction in ricin binding to ASF but not to a high-affinity monoclonal antibody (mAb), increasing the dissociation rate of ASF-ricin complexes up to 100-fold. The effect of milk on the binding of ricin to ASF was ascribable to dialyzable factors, and milk sugar can account for these effects. The use of high-affinity mAbs in ELISA effectively limits the milk matrix effect on ricin analysis. PMID- 25822825 TI - "Selling" value: the influence of language on willingness-to-accept. AB - In behavioral economics, the "endowment effect" describes the robust finding that prices people are willing to accept (WTA) for a good exceed prices people are willing to pay (WTP) for the same good. The increase in WTA values is often explained by the sellers' negative hedonic response to losing their item. Recent studies, however, show that subtle cues may change participants' perspective, influencing their valuations. We hypothesized that implicit connotations of instructional language may be one of those cues. To test this hypothesis we manipulated the wording of instructions in two conditions: in the Sell condition, subjects were endowed with a set of pens and asked to select an amount of money for which they would sell the pens back and in the Take condition, subjects were endowed with the pens and asked to select an amount of money they would take for the pens. Participants in each condition also estimated the market value of the pens. Consistent with our hypothesis, WTA in the Sell condition was higher than in the Take condition, though there were no differences in market values between conditions. These findings show that instructional language does influence participant valuations. Furthermore, we suggest that those being asked to "sell" use their market estimations as the salient reference point in the transaction. PMID- 25822826 TI - Correction: New insights into phosphorus mobilisation from sulphur-rich sediments: time-dependent effects of salinisation. AB - [This corrects the article DOI: 10.1371/journal.pone.0111106.]. PMID- 25822827 TI - The cost of perfection with apparent ease: Theoretical foundations and development of the Effortless Perfectionism Scale. AB - Effortless perfection is a term used to describe an intense pressure to be perfect without visible effort (Yee, 2003), and is thought to be linked to several indicators of maladjustment among college-age youth (Ruane, 2012; Yee, 2003). Although effortless perfectionism (EP) is a phenomenon referenced in popular culture, empirical support for this construct is needed. In addition to conceptualizing and discussing the theoretical underpinnings of EP, this paper describes the development of an instrument to assess EP: the 10-item Effortless Perfectionism scale (EPS). The responses of a large sample of students from a Midwestern university (N = 1,270) were used to develop a 1-factor measurement model for the EPS. The EPS showed good internal consistency and test-retest reliability, and demonstrated convergent, discriminant, and incremental validity in relation to other perfectionism scales, as a predictor of psychosocial adjustment, and as a mediator of the effects of gender on adjustment. The present study supports the reliability and construct validity of the EPS as a self-report measure of EP, a distinct type of perfectionism that warrants future investigation. PMID- 25822828 TI - Self-regulation assessment among preschoolers with externalizing behavior problems. AB - This study examined the construct validity and clinical utility of a brief self regulation assessment (Head-Toes-Knees-Shoulders, HTKS) among a clinical sample of children with externalizing behavior problems (EBP). Participants for this study included 101 preschool children (72% male; Mage = 5.10 years; 79% Hispanic) with at-risk or clinically elevated levels of EBP. Self-regulation measures included the HTKS task, 4 standardized subtests from the Automated Working Memory Assessment (AWMA), parent and teacher reports of children's executive functioning (EF), and children's self-regulation performance across a series of executive functioning classroom games conducted as part of a summer treatment camp. Additional outcomes included school readiness as measured by standardized achievement tests, and parent and teacher reports of kindergarten readiness and behavioral impairment related to academic functioning. Performance on the HTKS task was moderately correlated with children's performance on the standardized working memory tasks and observed self-regulation performance in the classroom. Low to moderate correlations were observed between performance on the HTKS task and parent report of children's EF difficulties, as well as parent and teacher reports of children's kindergarten readiness and behavioral impairment related to academic functioning. Moderate to high correlations were observed between performance on the HTKS task and standardized academic outcomes. These findings highlight the promise of the HTKS task as a brief, ecologically valid, and integrative EF task tapping into both behavioral and cognitive aspects of self regulation that are important for children with EBP's success in school. PMID- 25822829 TI - Associations between DSM-5 section III personality traits and the Minnesota Multiphasic Personality Inventory 2-Restructured Form (MMPI-2-RF) scales in a psychiatric patient sample. AB - Our aim in the current study was to evaluate the convergence between Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) Section III dimensional personality traits, as operationalized via the Personality Inventory for DSM-5 (PID-5), and Minnesota Multiphasic Personality Inventory 2-Restructured Form (MMPI-2-RF) scale scores in a psychiatric patient sample. We used a sample of 346 (171 men, 175 women) patients who were recruited through a university affiliated psychiatric facility in Toronto, Canada. We estimated zero-order correlations between the PID-5 and MMPI-2-RF substantive scale scores, as well as a series of exploratory structural equation modeling (ESEM) analyses to examine how these scales converged in multivariate latent space. Results generally showed empirical convergence between the scales of these two measures that were thematically meaningful and in accordance with conceptual expectations. Correlation analyses showed significant associations between conceptually expected scales, and the highest associations tended to be between scales that were theoretically related. ESEM analyses generated evidence for distinct internalizing, externalizing, and psychoticism factors across all analyses. These findings indicate convergence between these two measures and help further elucidate the associations between dysfunctional personality traits and general psychopathology. PMID- 25822831 TI - A Bayesian approach to mixed group validation of performance validity tests. AB - Mental health professionals often use structured assessment tools to help detect individuals who are feigning or exaggerating symptoms. Yet estimating the accuracy of these tools is problematic because no "gold standard" establishes whether someone is malingering or not. Several investigators have recommended using mixed group validation (MGV) to estimate the accuracy of malingering measures, but simulation studies show that typical implementations of MGV may yield vague, biased, or logically impossible results. In this article we describe a Bayesian approach to MGV that addresses and avoids these limitations. After explaining the concepts that underlie our approach, we use previously published data on the Test of Memory Malingering (TOMM; Tombaugh, 1996) to illustrate how our method works. Our findings concerning the TOMM's accuracy, which include insights about covariates such as study population and litigation status, are consistent with results that appear in previous publications. Unlike most investigations of the TOMM's accuracy, our findings neither rely on possibly flawed assumptions about subjects' intentions nor assume that experimental simulators can duplicate the behavior of real-world examinees. Our conceptual approach may prove helpful in evaluating the accuracy of many assessment tools used in clinical contexts and psycholegal determinations. PMID- 25822830 TI - Is the Short Form of the Mini-Mental State Examination (MMSE) a better screening instrument for dementia in older primary care patients than the original MMSE? Results of the German study on ageing, cognition, and dementia in primary care patients (AgeCoDe). AB - The aim of the study was to investigate the psychometric properties of a Short Form of the Mini-Mental State Examination (SMMSE) for the screening of dementia in older primary care patients. Data were obtained from a large longitudinal cohort study of initially nondemented individuals recruited via primary care chart registries and followed at 18-month intervals. Item and scale parameters for MMSE and SMMSE scores were analyzed and cross-validated for 2 follow-up assessments (n1 = 2,657 and n2 = 2,274). Binary logistic regression and receiver operating-characteristic (ROC) curve analyses were conducted in order to assess diagnostic accuracy parameters for MMSE and SMMSE scores. Cross-sectional differentiation between dementia-free and dementia patients yielded moderate to good results for MMSE and SMMSE scores. With regard to most diagnostic accuracy parameters, SMMSE scores did not outperform the MMSE scores. The current study provides first evidence regarding the psychometric properties of the SMMSE score in a sample of older primary care patients. However, our findings do not confirm previous findings that the SMMSE is a more accurate screening instrument for dementia than the original MMSE. Further studies are needed in order to assess and to develop short, reliable and valid instruments for routine cognitive screening in clinical practice and primary care settings. PMID- 25822832 TI - Cross-cultural validation of a behavioral screener for executive functions: Guidelines for clinical use among Colombian children with and without ADHD. AB - Garcia-Barrera, Kamphaus, and Bandalos (2011) derived a 25-item executive functioning screener from the Behavior Assessment System for Children (BASC), measuring 4 latent executive constructs: problem solving, attentional control, behavioral control, and emotional control. The current study included a cross cultural examination of this screener in Colombian children with and without attention-deficit/hyperactivity disorder (ADHD). BASC teacher ratings were collected for Colombian children ages 6-11 years (848 healthy children [53% boys] and 155 children with ADHD [76% boys]). To examine the psychometric properties of the screener, a multistep procedure was implemented, including (a) confirmatory factor analysis (CFA) and factorial invariance testing across gender, age group (6-8 years, 9-11 years), and ADHD status to replicate and extend the original derivation; (b) item response theory (IRT) analysis to evaluate the information provided by individual items; and (c) given IRT results, a repeated CFA and invariance testing after the exclusion of 1 item from the problem-solving factor. The 24-item 4-factor model fit was adequate for controls and for ADHD participants. Results support the use of the 24-item executive functioning screener in a cross-cultural context. In turn, in supplemental material, normative data for the Colombian sample are reported along with bilingual guidelines (i.e., Spanish/English) for implementing the screener in clinical practice. Even though the screener is useful when examining executive functions, it was not designed as a diagnostic measure for developmental disorders such as ADHD; as such, it should only inform about status of executive functioning. PMID- 25822833 TI - Parsing the heterogeneity of impulsivity: A meta-analytic review of the behavioral implications of the UPPS for psychopathology. AB - The construct of impulsivity is implicated in a wide variety of psychopathology. However, the heterogeneous factors or subcomponents that differentially predict outcomes are still in the process of being parsed. The present review and meta analysis focuses on the psychopathological correlates of the Negative Urgency, (lack of) Premeditation, (lack of) perseverance, Sensation Seeking, and Positive Urgency (UPPS/UPPS-P; Whiteside & Lynam, 2001). which provides a relatively new model of impulsivity that posits 5 potentially overlapping pathways to impulsive action. The present meta-analysis included 115 studies that used the UPPS, with a total of 40,432 participants. Findings suggested that the Negative Urgency pathway to impulsivity demonstrated the greatest correlational effect sizes across all forms of psychopathology, with the Positive Urgency pathway demonstrating a pattern of correlations similar to that of Negative Urgency. These findings raise questions regarding the conceptual and practical separability of these pathways. Lack of Premeditation and Lack of Perseverance also demonstrated similar correlational patterns, suggesting that further investigation of the distinctiveness of these pathways is warranted. PMID- 25822835 TI - Test-retest reliability of the Tower of London Planning Task (TOL-F). AB - Test-retest reliability is difficult to establish for measures of executive functioning that rely on task novelty. Correspondingly, evidence on the test retest reliability of the commonly used Tower of London (TOL) planning task is, as yet, equivocal and only based on indices of relative consistency, rather than absolute agreement of individual scores. Further, the stability of planning latencies over repeated testing has not been investigated. The present study assessed test-retest reliability of planning performance measures using a structurally balanced problem set implemented in the TOL-Freiburg version (TOL F). The TOL-F was administered in 2 structurally identical versions to a sample of young, healthy adults over a 1-week interval. For planning accuracy, the Pearson correlation and intraclass correlation coefficient for relative consistency were adequate (r = .739 and .734), with the intraclass correlation coefficient for absolute agreement only slightly decreased (r = .690). For initial thinking and movement execution times, relative consistency and absolute agreement reliability indices were uniformly low (all r between .274 and .519). Given adequate planning accuracy test-retest reliability, the TOL-F can be reliably used to measure planning ability in group-based studies and with individual participants, as is important for clinical testing. Planning latencies, however, should only be used as complementary, but not sole measures of planning ability, particularly for normative evaluations in clinical assessment. In sum, TOL-F planning accuracy possesses adequate absolute and relative test-retest reliability for experimental utility. Future studies should assess whether this indeed translates into clinical utility of the TOL-F for measuring planning ability in patients. PMID- 25822834 TI - Development of an abbreviated form of the Penn Line Orientation Test using large samples and computerized adaptive test simulation. AB - Visuospatial processing is a commonly assessed neurocognitive domain with deficits linked to dysfunction in right posterior regions of the brain. With the growth of large-scale clinical research studies, there is an increased need for efficient and scalable assessments of neurocognition, including visuospatial processing. The purpose of the current study was to use a novel method that combines item response theory (IRT) and computerized adaptive testing (CAT) approaches to create an abbreviated form of the computerized Penn Line Orientation Test (PLOT). The 24-item PLOT was administered to 8,498 youths (aged 8-21 years) as part of the Philadelphia Neurodevelopmental Cohort study and, by Web-based data collection, in an independent sample of 4,593 adults from Great Britain as part of a TV documentary. IRT-based CAT simulations were used to select the best PLOT items for an abbreviated form by performing separate simulations in each group and choosing only items that were selected as useful (i.e., high item discrimination and in the appropriate difficulty range) in at least 1 of the simulations. Fifteen items were chosen for the final, short form of the PLOT, indicating substantial agreement among the models in how they evaluated each item's usefulness. Moreover, this abbreviated version performed comparably to the full version in tests of sensitivity to age and sex effects. This abbreviated version of the PLOT cuts administration time by 50% without detectable loss of information, which points to its feasibility for large-scale clinical and genomic studies. PMID- 25822836 TI - Home mechanical ventilation in childhood-onset hereditary neuromuscular diseases: 13 years' experience at a single center in Korea. AB - INTRODUCTION: Children with hereditary neuromuscular diseases (NMDs) are at a high risk of morbidity and mortality related to respiratory failure. The use of home mechanical ventilation (HMV) has saved the lives of many children with NMD but, due to a lack of studies, dependable guidelines are not available. We drew upon our experience to compare the various underlying NMDs and to evaluate HMV with regard to respiratory morbidity, the proper indications and timing for its use, and to develop a policy to improve the quality of home noninvasive ventilation (NIV). METHODS: We retrospectively analyzed the medical records of 57 children with childhood-onset hereditary NMDs in whom HMV was initiated between January 2000 and May 2013 at Seoul National University Children's Hospital. The degree of respiratory morbidity was estimated by the frequency and duration of hospitalizations caused by respiratory distress. RESULTS: The most common NMD was spinal muscular atrophy (SMA, n = 33). Emergent mechanical ventilation was initiated in 44% of the patients before the confirmed diagnosis, and the indicators of pre-HMV respiratory morbidity (e.g., extubation trials, hypoxia, hospitalizations, and intensive care unit stay) were greater in these patients than in others. The proportion of post-HMV hospitalizations (range, 0.00-0.52; median, 0.01) was lower than that of pre-HMV hospitalizations (0.02-1.00; 0.99) (P < 0.001). Eight patients were able to maintain home NIV. The main causes of NIV failure were air leakage and a large amount of airway secretions. CONCLUSIONS: The application of HMV helped reduce respiratory morbidity in children with childhood-onset hereditary NMD. Patients with SMA type I can benefit from an early diagnosis and the timely application of HMV. The choice between invasive and noninvasive HMV should be based on the patient's age and NIV trial tolerance. Systematic follow-up guidelines provided by a multidisciplinary team are needed. PMID- 25822837 TI - Embryonic and larval development and early behavior in grass carp, Ctenopharyngodon idella: implications for recruitment in rivers. AB - With recent findings of grass carp Ctenopharyngodon idella in tributaries of the Great Lakes, information on developmental rate and larval behavior is critical to efforts to assess the potential for establishment within the tributaries of that region. In laboratory experiments, grass carp were spawned and eggs and larvae reared at two temperature treatments, one "cold" and one "warm", and tracked for developmental rate, egg size, and behavior. Developmental rate was quantified using Yi's (1988) developmental stages and the cumulative thermal units method. Grass carp had a thermal minimum of 13.5 degrees C for embryonic stages and 13.3 degrees C for larval stages. Egg size was related to temperature and maternal size, with the largest eggs coming from the largest females, and eggs were generally larger in warmer treatments. Young grass carp larvae exhibited upward and downward swimming interspersed with long periods of lying on the bottom. Swimming capacity increased with ontogeny, and larvae were capable of horizontal swimming and position holding with gas bladder emergence. Developmental rates, behavior, and egg attributes can be used in combination with physical parameters of a river to assess the risk that grass carp are capable of reproduction and recruitment in rivers. PMID- 25822838 TI - Use of composite protein database including search result sequences for mass spectrometric analysis of cell secretome. AB - Mass spectrometric (MS) data of human cell secretomes are usually run through the conventional human database for identification. However, the search may result in false identifications due to contamination of the secretome with fetal bovine serum (FBS) proteins. To overcome this challenge, here we provide a composite protein database including human as well as 199 FBS protein sequences for MS data search of human cell secretomes. Searching against the human-FBS database returned more reliable results with fewer false-positive and false-negative identifications compared to using either a human only database or a human-bovine database. Furthermore, the improved results validated our strategy without complex experiments like SILAC. We expect our strategy to improve the accuracy of human secreted protein identification and to also add value for general use. PMID- 25822840 TI - Correction: Analysis of the transient response of a dual-fed RC transmission line. PMID- 25822839 TI - Cognitive functions and stereopsis in patients with Parkinson's disease and Alzheimer's disease using 3-dimensional television: a case controlled trial. AB - Stereopsis or depth perception is an awareness of the distances of objects from the observer, and binocular disparity is a necessary component of recognizing objects through stereopsis. In the past studies, patients with neurodegenerative disease (Alzheimer dementia, AD; Parkinson's disease IPD) have problems of stereopsis but they did not have actual stimulation of stereopsis. Therefore in this study, we used a 3-dimensional (3D) movie on 3D television (TV) for actual stereopsis stimulation. We propose research through analyzing differences between the three groups (AD, IPD, and Controls), and identified relations between the results from the Titmus Stereo Fly Test, and the 3D TV test. The study also looked into factors that affect the 3D TV test. Before allowing the patients to watch TV, we examined Titmus stereo Fly Test and cognitive test. We used the 3D version of a movie, of 17 minutes 1 second duration, and carried out a questionnaire about stereopsis. The scores of the stereopsis questionnaire were decreased in AD patients, compared with in IPD and controls, although they did not have any difference of Titmus Stereo Fly Test scores. In IPD patients, cognitive function (Montreal cognitive assessment, MoCA) scores were correlated with the scores of the stereopsis questionnaire. We could conclude that Titmus fly test could not distinguish between the three groups and cognitive dysfunction contributes to actual stereopsis perception in IPD patients. Therefore the 3D TV test of AD and IPD patients was more effective than Titmus fly test. PMID- 25822841 TI - Calculation of permissible load capacity and establishment of total amount control in the Wujin River Catchment--a tributary of Taihu Lake, China. AB - The deterioration of water quality in Taihu Lake, China, has caused widespread concern in recent years. The primary pollution sources of Taihu Lake are its inflow rivers. Effective environmental water management strategies need to be implemented in these rivers to improve the water quality of Taihu Lake and to promote sustainable development in the region. In this study, the QUAL2K model is used in conjunction with the trial and error approach to assess permissible load capacities for the Wujin River (a major tributary of Taihu Lake) in terms of COD, NH3-N, TN, and TP. Results show that permissible annual loads for these pollutants are 5216.31, 491.71, 948.53, and 104.38 t, respectively. This suggests that COD, NH3-N, TN, and TP loads in the Wujin River catchment need to be reduced by 13.35, 27.26, 47.75, and 37.08 %, respectively, to satisfy national water quality objectives. Total amount control measures are proposed to control and reduce pollution loads of the Wujin River catchment. The method applied in this study should provide a sound basis for water environmental management decision making. PMID- 25822842 TI - Fast formation of supergene Mn oxides/hydroxides under acidic conditions in the oxic/anoxic transition zone of a shallow aquifer. AB - Extensive uranium mining in the former German Democratic Republic (GDR) in eastern Thuringia and Saxony took place during the period of 1946-1990. During mining activities, pelitic sediments rich in organic carbon and uranium were processed and exposed to oxygen. Subsequent pyrite oxidation and acidic leaching lead to partial contamination of the area with heavy metals and acid mine drainage (AMD) even few years after completion of remediation. One of those areas is the former heap Gessen (Ronneburg, Germany) were the residual contamination can be found 10 m under the base of the former heap containing partly permeable drainage channels. Actually, in such a system, a rapid but locally restricted mineralization of Mn oxides takes place under acidic conditions. This formation can be classified as a natural attenuation process as certain heavy metals, e.g., Cd (up to 6 MUg/g), Ni (up to 311 MUg/g), Co (up to 133 MUg/g), and Zn (up to 104 MUg/g) are bound to this phases. The secondary minerals occur as colored layers close to the shallow aquifer in glacial sediments and could be identified as birnessite and todorokite as Mn phase. The thermodynamic model shows that even small changes in the system are sufficient to shift either the pH or the Eh in the direction of stable Mn oxide phases in this acidic system. As a consequence of 9-15-year-long formation process (or even less), the supergene mineralization provides a cost-efficient contribution for remediation (natural attenuation) strategies of residual with heavy metals (e.g., Cd, Co, Ni, Zn) contaminated substrates. PMID- 25822843 TI - Comparison of the antennal sensilla ultrastructure of two cryptic species in Bemisia tabaci. AB - Bemisia tabaci is an important agricultural pest with worldwide distribution and host preference. Therefore, understanding the biology of this pest is important to devise specific pest control strategies. The antennae of herbivorous insects play an important role in the identification of hosts using plant volatiles. To understand the features of antennae in B. tabaci MEAM 1(formerly known as biotype 'B') and MED (formerly known as biotype 'Q'), the morphology and distribution of the antennal sensilla were examined using scanning electron micrographs. The results showed that the average antennae length in MEAM 1 was longer than MED. No differences were observed in the number and distribution of antennal sensilla in MEAM 1 and MED antennae; each antenna had nine different types of sensilla. Both cryptic species possessed Microtrichia, Grooved surface trichodea sensilla, Chaetae sensilla, Coeloconic sensillaIandII, Basiconic sensilla I, II and III and Finger-like sensilla. This is the first report of Grooved surface trichodea sensilla and Basiconic sensilla II on B. tabaci flies. The numbers of Chaetae sensilla were different in the females and males of MEAM 1 and MED, which females having 5 and males containing 7. The surface structure of Basiconic sensilla I was different with MEAM 1 showing a multiple-pitted linen surface and MED showing a multiple-pitted pocking surface. Basiconic sensillaII were double in one socket with the longer one having a multiple-pitted surface and the shorter one with a smooth surface. Basiconic III and Finger-like sensillae were longer in MEAM 1 antennae than in MED antennae. Our results are expected to further the studies that link morphological characteristics to insect behavior and help devise strategies to control insect pests. PMID- 25822844 TI - Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. AB - The present and future live birth prevalence of Down syndrome (DS) is of practical importance for planning services and prioritizing research to support people living with the condition. Live birth prevalence is influenced by changes in prenatal screening technologies and policies. To predict the future impact of these changes, a model for estimating the live births of people with DS is required. In this study, we combine diverse and robust datasets with validated estimation techniques to describe the non-selective and live birth prevalence of DS in the United States from 1900-2010. Additionally, for the period 1974-2010, we estimate the impact of DS-related elective pregnancy terminations (following a prenatal diagnosis of DS) on the live births with DS. The live birth prevalence for DS in the most recent years (2006-2010) was estimated at 12.6 per 10,000 (95% CI 12.4-12.8), with around 5,300 births annually. During this period, an estimated 3,100 DS-related elective pregnancy terminations were performed in the U.S. annually. As of 2007, the estimated rates at which live births with DS were reduced as a consequence of DS-related elective pregnancy terminations were 30% (95% CI: 27.3-31.9) for the U.S. as a whole. Our results and our model provide data on the impact of elective pregnancy terminations on live births with DS and may provide a baseline from which future trends for live births with DS can be estimated. PMID- 25822845 TI - Inverse association of serum vitamin D in relation to carotid intima-media thickness in Chinese postmenopausal women. AB - OBJECTIVE: This study aimed to investigate the relationship between serum vitamin D level and carotid intima-media thickness (C-IMT) in Chinese postmenopausal women. METHODS: Nine hundred and twenty six Chinese postmenopausal women without carotid artery plaque or history of cardiovascular disease were selected for analysis. Measurements of serum 25 hydroxyvitamin D3 (25(OH)D3) concentration and C-IMT were made by electrochemiluminescence immunoassay and B-mode ultrasound, respectively. Trend analysis was conducted according to tertiles of C-IMT. RESULTS: The median serum 25(OH)D3 level was 11.03 ng/mL, with an interquartile range of 8.22-14.70. A decreasing trend of serum 25(OH)D3 level was accompanied by increased C-IMT tertiles (P for trend = 0.001). Correlation analysis found an inverse relationship between serum 25(OH)D3 level and C-IMT (r = -0.113, P = 0.001). After adjustment for confounding factors, multiple regression analysis showed that serum 25(OH)D3 level independently and negatively associated with C IMT (Standard beta = -0.112, P < 0.001). Moreover, the inverse correlation of serum 25(OH)D3 with C-IMT was also found in a subgroup of women with normal glucose tolerance, blood pressure and body mass index, and without undergoing lipid-lowering therapy (standard beta = -0.140, P = 0.018). CONCLUSIONS: Serum 25(OH)D3 level was inversely correlated with C-IMT in Chinese postmenopausal women. PMID- 25822846 TI - Synthesis of a Tight Intramolecular OH...Olefin Interaction, Probed by IR, (1)H NMR, and Quantum Chemistry. AB - We have synthesized a molecule containing a tight hydrogen-bonding interaction between an alcohol and a nonconjugated pi-system. The strength of this hydrogen bond results in a large red shift, nearly 189 cm(-1), on the alcohol stretching frequency in the IR spectrum in comparison to a free alcohol control. The interaction is notable in that it possesses a better defined intramolecular hydrogen bond compared to the usual molecules for which it is noted, such as syn 7-norbornenol. This interaction was studied through the use of IR and NMR spectroscopy, X-ray crystallography, and molecular modeling calculations. PMID- 25822847 TI - Nickel-catalyzed direct thiolation of C(sp(3))-H bonds in aliphatic amides. AB - Nickel-catalyzed thiolation of the inactivated methyl C(sp(3))-H bonds of aliphatic amides with disulfide is described. It is a novel strategy for the synthesis of thioethers with the ultimate goal of generating thioether carboxylic acids with various functional groups. PMID- 25822848 TI - Improving the safety of epidural steroid injections. PMID- 25822849 TI - Invertebrate and vertebrate class III myosins interact with MORN repeat containing adaptor proteins. AB - In Drosophila photoreceptors, the NINAC-encoded myosin III is found in a complex with a small, MORN-repeat containing, protein Retinophilin (RTP). Expression of these two proteins in other cell types showed NINAC myosin III behavior is altered by RTP. NINAC deletion constructs were used to map the RTP binding site within the proximal tail domain of NINAC. In vertebrates, the RTP ortholog is MORN4. Co-precipitation experiments demonstrated that human MORN4 binds to human myosin IIIA (MYO3A). In COS7 cells, MORN4 and MYO3A, but not MORN4 and MYO3B, co localize to actin rich filopodia extensions. Deletion analysis mapped the MORN4 binding to the proximal region of the MYO3A tail domain. MYO3A dependent MORN4 tip localization suggests that MYO3A functions as a motor that transports MORN4 to the filopodia tips and MORN4 may enhance MYO3A tip localization by tethering it to the plasma membrane at the protrusion tips. These results establish conserved features of the RTP/MORN4 family: they bind within the tail domain of myosin IIIs to control their behavior. PMID- 25822850 TI - Lung cancer incidence trends by gender, race and histology in the United States, 1973-2010. AB - BACKGROUND: Lung cancer (LC) incidence in the United States (US) continues to decrease but with significant differences by histology, gender and race. Whereas squamous, large and small cell carcinoma rates have been decreasing since the mid 80s, adenocarcinoma rates remain stable in males and continue to increase in females, with large racial disparities. We analyzed LC incidence trends by histology in the US with an emphasis on gender and racial differences. METHODS: LC incidence rates from 1973-2010 were obtained from the SEER cancer registry. Age-adjusted incidence trends of five major histological types by gender and race were evaluated using joinpoint regression. Trends of LC histology and stage distributions from 2005-2010 were analyzed. RESULTS: US LC incidence varies by histology. Squamous, large and small cell carcinoma rates continue to decrease for all gender/race combinations, whereas adenocarcinoma rates remain relatively constant in males and increasing in females. An apparent recent increase in the incidence of squamous cell carcinoma and adenocarcinoma since 2005 can be explained by a concomitant decrease in the number of cases classified as other non-small cell carcinoma. Black males continue to be disproportionally affected by squamous LCs, and blacks continue to be diagnosed with more advanced cancers than whites. CONCLUSIONS: LC incidence by histology continues to change over time. Additional variations are expected as screening becomes disseminated. It is important to continue to monitor LC rates to evaluate the impact of screening on current trends, assess the continuing benefits of tobacco control, and focus efforts on reducing racial disparities. PMID- 25822852 TI - Discovery of Small Molecules for Up-Regulating the Translation of Antiamyloidogenic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10), by Binding to the G-Quadruplex-Forming Sequence in the 5' Untranslated Region (UTR) of Its mRNA. AB - Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of beta-amyloid (Abeta) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5'-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPPalpha, consequently decreasing the Abeta40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10. PMID- 25822853 TI - Alkane C-H functionalization and oxidation with molecular oxygen. AB - The application of environmentally benign, cheap, and economically viable oxidation procedures is a key challenge of homogeneous, oxidative alkane functionalization. The typically harsh reaction conditions and the propensity of dioxygen for radical reactivity call for extraordinary robust catalysts. Mainly three strategies have been applied. These are (1) the combination of a catalyst responsible for C-H activation with a cocatalyst responsible for dioxygen activation, (2) transition-metal catalysts, which react with both hydrocarbons and molecular oxygen, and (3) the introduction of very robust main-group element catalysts for C-H functionalization chemistry. Herein, these three approaches will be assessed and exemplified by the reactivity of chelated palladium (N heterocyclic carbene) catalysts in combination with a vanadium cocatalyst, the methane functionalization by cobalt catalysts, and the reaction of group XVII compounds with alkanes. PMID- 25822851 TI - MRI-based intelligence quotient (IQ) estimation with sparse learning. AB - In this paper, we propose a novel framework for IQ estimation using Magnetic Resonance Imaging (MRI) data. In particular, we devise a new feature selection method based on an extended dirty model for jointly considering both element-wise sparsity and group-wise sparsity. Meanwhile, due to the absence of large dataset with consistent scanning protocols for the IQ estimation, we integrate multiple datasets scanned from different sites with different scanning parameters and protocols. In this way, there is large variability in these different datasets. To address this issue, we design a two-step procedure for 1) first identifying the possible scanning site for each testing subject and 2) then estimating the testing subject's IQ by using a specific estimator designed for that scanning site. We perform two experiments to test the performance of our method by using the MRI data collected from 164 typically developing children between 6 and 15 years old. In the first experiment, we use a multi-kernel Support Vector Regression (SVR) for estimating IQ values, and obtain an average correlation coefficient of 0.718 and also an average root mean square error of 8.695 between the true IQs and the estimated ones. In the second experiment, we use a single kernel SVR for IQ estimation, and achieve an average correlation coefficient of 0.684 and an average root mean square error of 9.166. All these results show the effectiveness of using imaging data for IQ prediction, which is rarely done in the field according to our knowledge. PMID- 25822854 TI - Oral rehabilitation and psychosocial evaluation of a patient with bulimia nervosa following Teeth in a Day(r) immediate loading protocol. AB - PURPOSE: The purpose of this patient report is to accurately portray the clinical experience of treating an active bulimic patient by employing an immediately loaded dental implant protocol to provide the patient with an expedited esthetic and functional result. Implementation of a psychometric component statistically quantifies the psychological effects of the oral rehabilitation. MATERIALS AND METHODS: A 34-year-old woman presented with severe dental perimolysis (erosion) resulting from a 28-year history of bulimic behaviors. Clinical and radiographic evaluation of the existing dentition indicated advanced dental erosion and previous restoration attempts in a state of failure. The patient's existing teeth were extracted and treated with full maxillary and mandibular implant-supported prostheses, following the Teeth in a Day(r) (TIAD) immediate functional loading protocol. Psychometric assessment was conducted through administration of a 20 item questionnaire, as seen in previous literature. RESULTS: Radiographic and clinical analysis suggested all implant fixtures to be viable and accompanied by normal levels of alveolar bone 7 months into treatment. Questionnaire results at the new-patient presentation (T1) resulted in a composite score of 4.0 (SD = 2.9; P = 0.004), indicating severe body-image dysphoria. At 3 months postoperative (T2), the questionnaire score was 0.4 (SD = -1.7; P = 0.09). The final psychometric questionnaire at 7 months (T3) resulted in a score of 0.5 (SD = 1.5; P = 0.12). The patient was followed for a total of 7 years following implant placement. CONCLUSION: In this patient report, oral rehabilitation using the TIAD protocol provided an expedited and predictable alternative method for restoring functional abilities, esthetics, and self-esteem to a severely depressed bulimic patient. Psychometrically, at the postoperative (T2) and final testing period (T3), the patient's body image profile was no longer considered to be significantly different from established normative values. PMID- 25822855 TI - Acute gastrointestinal bleeding - a new approach to clinical and endoscopic management. AB - Overt or occult gastrointestinal bleeding is a frequently observed condition in routine gastroenterological practice. Occult gastrointestinal bleeding is usually a purely incidental finding, based on the discovery of iron deficiency anemia in the laboratory or blood in stool (a positive Hemoccult test). However, overt bleeding accompanied by the clinical features of tarry stool, hematemesis, or hematochezia may be a life-threatening condition, calling for immediate emergency management. In contrast to traumatology, algorithms of emergency and intensive medicine are not sufficiently validated yet for acute life-threatening bleeding. The purpose of this review was to present all established and new endoscopic hemostasis techniques and to evaluate their efficacy, as well as to provide the treating endoscopist with practical advice on how he/she could incorporate these procedures into acute medical management. The recommendations are based on inspection of the study results in the recent published literature, as well as emergency medicine algorithms in traumatology. PMID- 25822856 TI - Adenocarcinomas at different positions at the gastro-oesophageal junction show distinct association with gastritis and gastric preneoplastic conditions. AB - OBJECTIVE: Adenocarcinomas at the gastro-oesophageal junction (GOJ) are currently stratified by tumour location. This retrospective study examines the association of preneoplastic conditions and inflammation of the gastric mucosa with GOJ cancer at different locations and compares them with nonjunctional gastric cancers. PATIENTS AND METHODS: A total of 520 patients with junctional and nonjunctional gastric cancer were assessed for the presence and degree of intestinal metaplasia, glandular atrophy and inflammation in the stomach. Histopathological data were complete for 428 patients (68.9% men, median age 67.7 years), including 172 patients with GOJ cancer (GOJ1: 1-5 cm proximal to the junction, GOJ2: 'true' junctional, GOJ3: 2-5 cm distal to the junction). Gastric inflammation and preneoplastic conditions were scored according to the updated Sydney classification and further stratified into respective operative link on gastritis assessment (OLGA) and operative link on gastritis assessment on intestinal metaplasia (OLGIM) stages. RESULTS: The prevalence and degree of gastric atrophy and intestinal metaplasia were significantly lower in GOJ1 than GOJ3 (P<0.01). Preneoplastic conditions in the stomach were similar in GOJ3 compared with nonjunctional gastric cancer. GOJ1 were almost exclusively (98.4%) of the intestinal type, whereas GOJ2 and GOJ3 were the diffuse type in 22.6 and 22.4% of the patients (P<0.001). Of all patients, only 8.5 and 12.7% presented with stage III/IV according to OLGA and OLGIM, respectively. However, data for OLGA and OLGIM staging were only available in 61.2 and 67.9% of patients, respectively. CONCLUSION: GOJ1 are less likely to be associated with gastric pathology compared with GOJ3 or nonjunctional gastric cancer. OLGA or OLGIM staging in patients with advanced gastro-oesophageal cancer seems to be of limited value. PMID- 25822857 TI - Long-term dynamics of gastric biomarkers after eradication of Helicobacter pylori infection. AB - BACKGROUND: Secretion of pepsinogen I (PgI), pepsinogen II (PgII), fasting gastrin-17 (fG-17) and stimulated gastrin-17 (sG-17) changes after Helicobacter pylori eradication. Few data are available on the long-term dynamics of gastric biomarkers after H. pylori eradication.The aim of this study was to investigate the dynamics of gastric biomarkers in H. pylori-positive patients after eradication over a 3-year period and to compare the levels with initially H. pylori-negative patients. MATERIALS AND METHODS: Blood samples for the detection of gastric biomarkers were obtained from dyspeptic patients coming for upper gastrointestinal endoscopy. In H. pylori-positive patients, after eradication therapy, three follow-up blood samples were drawn after 12, 24 and 36 months; in H. pylori-negative patients, two samples were taken - at 12 and after 30 months. Median values of biomarkers in follow-up samples were compared with the baseline sample. RESULTS: The final sample included 110 patients (median age 67 years, M/F ratio 27/83). In patients after H. pylori eradication (n=83) PgI, PgII, fG-17 and sG-17 had decreased significantly during a 36-month period, whereas the PgI/PgII ratio had increased significantly from 5.59 to 11.64. CONCLUSION: In H. pylori positive dyspeptic patients, after eradication therapy, a decrease in PgI, PgII, fG-17 and sG-17 was observed after 36 months whereas an increase in the PgI/II ratio suggested an improvement in gastric atrophy. The median levels of gastric biomarkers in patients after H. pylori eradication therapy may become similar to biomarker levels among initially H. pylori-negative individuals. PMID- 25822858 TI - PPI-responsive esophageal eosinophilia cannot be distinguished from eosinophilic esophagitis by endoscopic signs. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease histologically characterized by eosinophil-predominant inflammation. One-third of patients respond to proton pump inhibitor (PPI) treatment; this group is identified as having PPI-responsive esophageal eosinophilia (PPI-REE). If we could predict the response to PPIs on the basis of endoscopic signs, futile treatment efforts and additional endoscopies to assess treatment response can be prevented. OBJECTIVE: To determine whether endoscopic signs can distinguish PPI REE from EoE. METHODS: Endoscopic images of 30 EoE and 30 PPI-REE patients were included. Baseline characteristics were compared between groups. Complete clinical remission after a PPI trial for at least 8 weeks was classified as PPI REE. Per patient, at least three depersonalized images were incorporated into a slideshow. These images were scored by two experienced endoscopists according to a validated classification system. RESULTS: Characteristics were highly comparable between EoE and PPI-REE patients. Endoscopic signs were similar and did not enable differentiation between EoE and PPI-REE [presence of: rings (P=0.893), white exudates (P=0.209), furrows (P=0.371), edema (P=0.554), crepe paper esophagus (P=1.000), and strictures (P=0.071)]. CONCLUSION: Endoscopic signs at baseline endoscopy cannot distinguish EoE from PPI-REE before a PPI trial; the demographic and clinical characteristics in both groups are similar. Endoscopic features do not enable differentiation between PPI-REE and EoE. PMID- 25822859 TI - Outpatient management of low-risk patients with upper gastrointestinal bleeding: can we safely extend the Glasgow Blatchford Score in clinical practice? AB - BACKGROUND AND AIM: The Glasgow Blatchford Score (GBS) is a validated prognostic score for patients presenting with upper gastrointestinal (GI) bleeding (UGIB). The score predicts the need for therapeutic intervention or death, and studies have suggested that outpatient management is safe for patients with a GBS of zero. Our aim was to assess whether we could safely extend the threshold for outpatient management to patients with GBS<=1. METHODS: Following assessment of our historical data, our UGIB protocol was changed to recommend outpatient management for patients with a GBS<=1, unless required for other reasons. Data on all patients presenting with UGIB over the following 12 months were prospectively recorded, including GBS and clinical Rockall scores. Adverse outcomes were defined by a 30-day combined endpoint of death, endotherapy, interventional radiology, surgery or transfusion. Negative predictive value (NPV) of GBS<=1 for adverse outcomes in UGIB was calculated. RESULTS: A total of 514 patients presented with UGIB in the 12 month study period. Of the patients, 183 (35.6%) had GBS<=1 (111, GBS=0; 72, GBS=1). Of these, 88 (48.1%) were managed as outpatients, and none had an adverse outcome. Of the 95 (51.9%) patients with GBS<=1 managed as inpatients, 80 (84.2%) had comorbidities requiring inpatient care. Within this admitted group with GBS<=1, one patient required transfusion and one died from a nongastrointestinal malignancy. GBS<=1 had an NPV of 99.45% (95% confidence interval 95.53-99.97%) in predicting adverse outcomes within 30 days. CONCLUSION: GBS<=1 has a high NPV for adverse outcomes in UGIB. This suggests outpatient management of patients with UGIB and that GBS<=1 is safe in our population. PMID- 25822860 TI - Clinical, metabolic, and psychological characteristics in patients with gastroesophageal reflux disease overlap with irritable bowel syndrome. AB - OBJECTIVES: Gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS) are highly prevalent in the general population, with significant symptom overlap, whereas the interaction between both remains poorly understood. We aim to identify the clinical and psychological factors that contribute toward the overlap of GERD and IBS. PATIENTS AND METHODS: We carried out a case-control study among 806 GERD and 176 IBS patients from a health check-up cohort (n=2604). All participants were evaluated using the Reflux Disease Questionnaire score, the Pittsburgh Sleep Quality Index score, the Taiwanese Depression Questionnaire score, and the State-Trait Anxiety Inventory score. Endoscopic findings were classified according to the Los Angeles classification. IBS was diagnosed on the basis of Rome III criteria, and metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel III definition. RESULTS: Among the study population, 727 individuals had GERD, 97 individuals had IBS, and 79 individuals had a diagnosis of both GERD and IBS (GERD-I). GERD-I patients had more severe GERD symptoms compared with patients with GERD or IBS alone (P<0.0001). Moreover, GERD-I patients had more frequent healthcare-seeking behavior, decreased quality of sleep, and higher depression scores than patients with GERD (P<0.0001) or IBS alone (P<0.05). In addition, GERD-I patients had lower blood pressure, waist-to-hip ratio, and higher serum high-density lipoprotein levels than those with GERD alone (P<0.05). CONCLUSION: GERD patients overlapping with IBS have different clinical and psychological profiles than those with GERD or IBS alone. Our study suggests that awareness of these symptom presentations will help optimize the treatment of these conditions. PMID- 25822861 TI - Acceptability and efficacy of a gel hypotonic oral rehydration solution in children with acute gastroenteritis. AB - OBJECTIVE: Oral rehydration solution remains the mainstay of acute gastroenteritis therapy. The aim of this study was to investigate the acceptability of a new zinc-containing hypotonic super-oral rehydration solution (ORS) in a gel formulation and its efficacy in reducing the duration and severity of diarrhea in children. METHODS: This was a randomized-controlled trial of children (5-36 months of age) observed for diarrhea lasting less than 24 h. Children were randomized to receive standard hypotonic ORS (group 1) or a gel hypotonic super-ORS containing zinc (group 2). The main study outcome was ORS intake in the first 24 h. ORS intake at 4 h, rate of diarrhea resolution at 72 h of treatment, total duration and severity of diarrhea, hospitalization, and adverse effects were also evaluated. RESULTS: Eighty-three children were enrolled (group 1: 40; group 2: 43). The amount of ORS consumed at 24 h was significantly higher in group 2 than in group 1. A similar result was observed at 4 h. The number of children who refused ORS (<10 ml/kg/day) was lower in group 2 versus group 1 (P=0.001). The number of children presenting diarrhea after 72 h of treatment was lower in group 2 versus group 1 (P=0.028). Also, the mean duration of diarrhea was shorter in group 2 than in group 1 (P=0.001). The hypotonic super ORS containing zinc in a gel formulation had a positive effect on the severity of diarrhea. No patient required hospitalization. No adverse events were observed in either of the two study groups. CONCLUSION: The new zinc-containing hypotonic super-ORS in a gel formulation is effective in the management of childhood acute gastroenteritis. PMID- 25822862 TI - The value of serum chromogranin A as a predictor of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors with liver metastases. AB - OBJECTIVE: To investigate the usefulness of serum chromogranin A (CgA) for the prediction of tumor burden, therapeutic response, and nomogram-based survival in well-moderate nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) with liver metastases (LMs). MATERIALS AND METHODS: This prospective study included 51 NF-PNETs of LMs patients, 134 other neuroendocrine tumors, and 125 controls. Serum CgA levels were determined by enzyme-linked immunosorbent assay at baseline and after treatment. LMs tumor burden was computed simultaneously from computed tomography/MRI scan with thin slices using a semiquantitative three-dimensional reconstruction approach. Predictive CgA for therapeutic response was assessed using the response evaluation criteria in solid tumors criteria. A nomogram to predict the prognostic value of CgA with variables selected in the multivariate Cox proportional hazards model was constructed; the accuracy of the nomogram was quantified by the (concordance index) C-index and a calibration plot. RESULTS: Considering NF-PNETs, CgA correlated with the tumor grade and differentiation (P<0.05). There was a nonlinear exponential regression between LMs tumor burden and CgA levels (P<0.001). The alteration in CgA correlated with therapeutic response (P<0.001). Increased CgA presented significantly lower progression-free survival than the stable/decreased CgA subgroup (P<0.001). For overall survival, a baseline CgA increase greater than 2.5 upper limit of normal level was predictive of a poor prognosis (P<0.001). Baseline CgA level, LMs tumor burden, and Ki-67 were selected as independent factors for the nomogram to predict overall survival; the nomogram showed fitting calibration with a C-index of 0.87 (95% confidence interval, 0.82-0.92). CONCLUSION: Serum CgA could be used to reflect tumor burden, evaluate the therapeutic response, and predict the survival outcomes for NF-PNETs with LMs. An effective nomogram including CgA was proposed for prediction. PMID- 25822864 TI - Nationwide large survey on hepatitis B surface antigen quantification use in real life clinical practice. AB - BACKGROUND AND AIM: Hepatitis B surface antigen quantification (qHBsAg) is a relevant biomarker assay in the therapeutic management of hepatitis B virus infected patients; however, little is known about its use in France. The aim of this study was to describe the knowledge of qHBsAg use and the indications for the prescription of qHBsAg in France. METHODS: From March 2014 to May 2014, 135 questionnaires were sent to hepatologists and gastroenterologists from several health centers (private practice, public practice, and outlying health centers). There were 20 items in each questionnaire on the use of qHBsAg. RESULTS: Seventy six percent of the practitioners had previously used qHBsAg, among whom 88% had prescribed the use of qHBsAg before treatment, 73% had prescribed the use of qHBsAg in combination with hepatitis B virus viral load, 64% had prescribed the use of qHBsAg at week 12 or week 24 of treatment, 62% had prescribed the use of qHBsAg for stopping rules, and 49% had prescribed the use of qHBsAg to identify inactive carriers. The reason for nonprescription of qHBsAg was mainly because of difficulty accessing the test (50% of the practitioners), followed by nonreimbursement of the test (27%); 97% of the practitioners who did not prescribe qHBsAg indicated an interest in accessing the test. CONCLUSION: This survey describes the characteristics of the prescription of qHBsAg in France. More than three out of four practitioners have previously used qHBsAg. The use of the qHBsAg just before treatment was the main reason for prescription. The main reason for nonprescription was because of difficulty in accessing the test. PMID- 25822865 TI - Hepatic progenitor cells in children with chronic hepatitis C: correlation with histopathology, viremia, and treatment response. AB - OBJECTIVE: Hepatic progenitor cells (HPCs) are bipotential stem cells that can differentiate towards the hepatocytic and cholangiocytic lineages. Many studies have investigated HPCs in adults with hepatitis C virus infection; however, none has been carried out in the pediatric population. Therefore, this work aimed to investigate HPCs expansion in children with chronic hepatitis C (CHC) and its correlation with histopathology, viremia, and treatment response. PATIENTS AND METHODS: Eighty children with CHC, 73 of whom received interferon-based therapy, were recruited. Sections of their liver biopsies were prepared for immunostaining of HPCs using cytokeratin-7 antibody. RESULTS: HPCs were expanded in most children (81.3%) with CHC. Expansion occurred in two forms: intraparenchymal isolated hepatic progenitor cell form and periportal ductular reaction form. There was a significant increase in HPCs expansion in higher stages of fibrosis (50, 81.8, and 100% in no, mild, and moderate fibrosis, respectively, with P=0.029). Also, HPCs expansion increased with increased grade of necroinflammatory activity (0, 77.8, 81.8, and 100%, in no, minimal, mild, and moderate activity, respectively), although this was statistically insignificant. Moreover, a significant positive correlation was found between the isolated hepatic progenitor cell number and ductular reaction grade (r=0.755, P<0.0001), and both were significantly correlated with the level of viremia and the grade of necroinflammatory activity. Finally, HPCs expansion was not related to the treatment response. CONCLUSION: The relationship of HPCs with both the severity of hepatitis and the stage of fibrosis may be because of a role of HPCs in their pathogenesis. PMID- 25822866 TI - Effect of long-term acid gastric inhibition on bacterial translocation in cirrhotic rats. AB - BACKGROUND: Bacterial translocation (BT) related to intestinal bacterial overgrowth (IBO) plays an important role in the pathogenesis of bacterial infections in cirrhosis. Inhibition of acid gastric secretion promotes IBO and might favor BT. We evaluated the effect of long-term inhibition of acid gastric secretion on BT in cirrhotic rats. METHODS: Cirrhotic rats with and without ascites induced by oral CCl4 and controls were randomized to treatment with a daily subcutaneous injection of placebo, ranitidine (50 mg/kg), or pantoprazole (8 mg/kg) during 2 weeks. Continuous pH-metry was performed for 2 h before and at the end of treatment; thereafter, a laparotomy to obtain samples of blood, mesenteric lymph nodes, ascites, spleen, liver, and cecal stools was performed. RESULTS: Ranitidine and pantoprazole increased gastric pH as compared with placebo (P<0.001). However, antisecretory drugs increased the incidence of BT only in ascitic rats treated with ranitidine (P<0.05) or pantoprazole (P=0.07) when compared with placebo-treated ascitic rats or cirrhotic rats without ascites treated with the same drug. Cirrhotic ascitic rats treated with pantoprazole showed a trend toward an increased incidence of IBO (P=0.08), a higher ileal malondialdehyde level (P<0.01), and an increased production of tumor necrosis factor-alpha (P<0.05). CONCLUSION: Although inhibition of acid gastric secretion increased gastric pH in all animals, the incidence of BT increased only in ascitic rats, and it was associated with a trend toward an increase in IBO incidence, a higher ileal malondialdehyde level, and an increased production of serum tumor necrosis factor-alpha. Therefore, antisecretory drugs should be carefully administered to cirrhotic ascitic patients. PMID- 25822868 TI - Risk factors for first-year hospital readmission after liver transplantation. AB - OBJECTIVE: To investigate the frequency of and the risk factors for hospital readmission within the first year after liver transplantation (LT). MATERIALS AND METHODS: Between January 1999 and August 2013, LTs were performed in 890 adult patients at our center. We collected medical data from the Chinese Liver Transplant Registry and performed a retrospective review of the medical records of these patients. We aimed to identify the factors that contribute toward readmission during the first year after LT. We also first investigated the relationship between the number and severity of post-transplant complications and the risk of readmission. The survival outcomes of patients with and without readmission were also studied. RESULTS: A total of 165 rehospitalizations occurred in 142 patients (18.0%) within 1 year after discharge from their index admissions. The risk factors included hepatic malignancy as an indication for LT (P=0.01), previous abdominal surgery (P=0.03), the occurrence of any complications (P<0.001), biliary complications (P<0.001), vascular complications (P=0.005), rejection (P<0.001), pulmonary complications (P<0.001), infection (P<0.001), returning to the operating room (P<0.001), and other complications (P<0.001). First-year readmission rates increased as the number (P<0.01) and severity (P<0.01) of post-LT complications increased. Patients requiring readmission had decreased survival compared with those not requiring readmission during the first year of discharge after LT (P<0.001). CONCLUSION: Our study identified the factors that place LT recipients at a high risk for readmission. This knowledge could help prevent and minimize rehospitalizations during the first year after LT. PMID- 25822867 TI - Reappraisal of upper age limit for adult living-donor liver transplantation using right lobe grafts: an outcome analysis. AB - BACKGROUND: Increasingly more elderly recipients are being evaluated for liver transplant nowadays. Reported outcomes of deceased donor liver transplant in elderly recipients have varied in different eras. Little was reported on the outcome of living donor liver transplant (LDLT) in elderly patients, and the upper age limit for consideration for LDLT is variable from center to center. PATIENTS AND METHODS: We retrospectively reviewed our database for LDLT procedures performed for recipients 60 years of age or older. Procedures performed for retransplantation or left lobe liver transplants were excluded. Patients were divided into two groups: group A included recipients at least 60 and younger than 65 years old and group B included recipients at least 65 years old. RESULTS: A total of 55 liver transplants were included in our study. Group A included 30 patients, whereas group B included 25 patients. There was a trend toward more vascular complications, more frequent rejections, and hepatitis B virus recurrence in younger patients. This was only significant for hepatitis B virus recurrence. However, there was a trend toward more biliary complications, incisional hernias, and longer ICU/hospital stay in older patients. None of the latter variables reached statistical significance. Older recipients had better patient survival, which was more evident at 3 and 5 years of follow-up. However, graft and disease-free survivals did not differ significantly between both groups. CONCLUSION: LDLT using right lobe grafts for recipients aged 65 years or older is safe and feasible. PMID- 25822869 TI - Regression tree for choledocholithiasis prediction. AB - OBJECTIVES: The aim of this study was to develop and compare the predictive accuracy of classification and regression tree (CART) analysis with logistic regression (LR) for predicting common bile duct stones (CBDS) in patients subjected to laparoscopic cholecystectomy. PATIENTS AND METHODS: We prospectively collected preoperative (demographic, biochemical, ultrasonographic) and intraoperative (intraoperative cholangiography, cystic duct diameter) data for 154 patients considered for elective laparoscopic cholecystectomy at the department of General Surgery at Gornji Milanovac from 2013 through 2014. Univariate and multivariate regression analyses were used to determine independent predictors of CBDS. The CART analysis was carried out using the predictors identified by LR analysis. Various measures for the assessment of risk prediction models were determined, such as predictive ability, accuracy, the area under the receiver operating characteristic curve, and clinical utility using decision curve analysis. RESULTS: The most decisive variable at the time of classification was the cystic duct diameter category, the alkaline phosphatase, and dangerous stones. The CART model was shown to have good discriminatory ability (93.9%). Accuracy was similar in both models, ranging from 92.9% in the CART model and 93.5% in the LR model. In decision curve analysis, the CART model outperformed the LR model. CONCLUSION: We developed a user-friendly risk model that can successfully predict the presence of choledocholithiasis in patients planned for elective cholecystectomy. However, before recommending its use in clinical practice, a larger and more complete database should be used to further clarify the differences between models in terms of prediction of the CBDS. PMID- 25822863 TI - Hepatogastroenterologists' knowledge of inactive carriers and immunotolerant hepatitis B virus patients in France: results of a practice survey. AB - BACKGROUND: Before the 2012 revision of the EASL guidelines for the management of hepatitis B virus infection, we conducted a survey to determine how French nonacademic hepatogastroenterologists defined inactive hepatitis B virus carriers and immunotolerant patients. METHODS: We asked 680 hepatogastroenterologists to complete a simple survey consisting of 11 multiple-choice questions. RESULTS: The participation rate was 32%. HBeAg positivity was not identified as a key criterion for the diagnosis of immunotolerance by 61.9% of the respondents. A total of 82.5 and 75.9% of the respondents identified repeatedly normal alanine transaminase levels and repeatedly low viremia (<2000 IU/ml), respectively, as relevant criteria for the HBsAg inactive carrier state. The question on the biological monitoring of inactive carriers and immunotolerant patients was answered by 78% of the respondents, 97% of whom considered determinations of alpha-fetoprotein concentration and viremia every 6 (n=58, 35%) or 12 months (n=105, 63%) to be useful. Overall, 19% of the respondents declared never having treated an immunotolerant patient; 81% reported that they had treated such patients under some circumstances: 73% before immunosuppression or chemotherapy, 54% treated pregnant women in their third trimester when viremia was greater than 7 log IU/ml, 49% treated health professionals to prevent contamination, and 31% before medically assisted procreation. CONCLUSION: The definition of 'inactive carrier state' seems to have been well assimilated, but immunotolerance remains poorly understood. Biological monitoring was frequently carried out for inactive carriers and immunotolerant patients, but the diversity of the responses obtained highlights the lack of clear recommendations for the follow-up of these populations. PMID- 25822871 TI - Deposition of Mercury in Forests along a Montane Elevation Gradient. AB - Atmospheric mercury (Hg) deposition varies along elevation gradients and is influenced by both orographic and biological factors. We quantified total Hg deposition over a 2 year period at 24 forest sites at Whiteface Mountain, NY, USA, that ranged from 450 to 1450 m above sea level and covered three distinct forest types: deciduous/hardwood forest (14.1 MUg/m2-yr), spruce/fir forest (33.8 MUg/m2-yr), and stunted growth alpine/fir forest (44.0 MUg/m2-yr). Atmospheric Hg deposition increased with elevation, with the dominant deposition pathways shifting from litterfall in low-elevation hardwoods to throughfall in midelevation spruce/fir to cloudwater in high-elevation alpine forest. Soil Hg concentrations (ranging from 69 to 416 ng/g for the Oi/Oe and 72 to 598 ng/g for the Oa horizons) were correlated with total Hg deposition, but the weakness of the correlations suggests that additional factors such as climate and tree species also contribute to soil Hg accumulation. Meteorological conditions influenced Hg deposition pathways, as cloudwater Hg diminished in 2010 (dry conditions) compared to 2009 (wet conditions). However, the dry conditions in 2010 led to increased Hg dry deposition and subsequent significant increases in throughfall Hg fluxes compared to 2009. These findings suggest that elevation, forest characteristics, and meteorological conditions are all important drivers of atmospheric Hg deposition to montane forests. PMID- 25822872 TI - Resistance training regulates cardiac function through modulation of miRNA-214. AB - AIMS: To determine the effects of resistance training (RT) on the expression of microRNA (miRNA)-214 and its target in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), and on the morphological and mechanical properties of isolated left ventricular myocytes. MAIN METHODS: Male Wistar rats were divided into two groups (n = 7/group): Control (CO) or trained (TR). The exercise-training protocol consisted of: 4 * 12 bouts, 5*/week during 8 weeks, with 80% of one repetition maximum. KEY FINDINGS: RT increased the left ventricular myocyte width by 15% and volume by 12%, compared with control animals (p < 0.05). The time to half relaxation and time to peak were 8.4% and 4.4% lower, respectively, in cells from TR group as compared to CO group (p < 0.05). RT decreased miRNA-214 level by 18.5% while its target SERCA2a expression were 18.5% higher (p < 0.05). SIGNIFICANCE: Our findings showed that RT increases single left ventricular myocyte dimensions and also leads to faster cell contraction and relaxation. These mechanical adaptations may be related to the augmented expression of SERCA2a which, in turn, may be associated with the epigenetic modification of decreased miRNA-214 expression. PMID- 25822873 TI - Exploring the balance between folding and functional dynamics in proteins and RNA. AB - As our understanding of biological dynamics continues to be refined, it is becoming clear that biomolecules can undergo transitions between ordered and disordered states as they execute functional processes. From a computational perspective, studying disorder events poses a challenge, as they typically occur on long timescales, and the associated molecules are often large (i.e., hundreds of residues). These size and time requirements make it advantageous to use computationally inexpensive models to characterize large-scale dynamics, where more highly detailed models can provide information about individual sub-steps associated with function. To reduce computational demand, one often uses a coarse grained representation of the molecule or a simplified description of the energetics. In order to use simpler models to identify transient disorder in RNA and proteins, it is imperative that these models can accurately capture structural fluctuations about folded configurations, as well as the overall stability of each molecule. Here, we explore a class of simplified model for which all non-hydrogen atoms are explicitly represented. We find that this model can provide a consistent description of protein folding and native-basin dynamics for several representative biomolecules. We additionally show that the native basin fluctuations of tRNA and the ribosome are robust to variations in the model. Finally, the extended variable loop in tRNAIle is predicted to be very dynamic, which may facilitate biologically-relevant rearrangements. Together, this study provides a foundation that will aid in the application of simplified models to study disorder during function in ribonucleoprotein (RNP) assemblies. PMID- 25822874 TI - Tumour cell membrane poration and ablation by pulsed low-intensity electric field with carbon nanotubes. AB - Electroporation is a physical method to increase permeabilization of cell membrane by electrical pulses. Carbon nanotubes (CNTs) can potentially act like "lighting rods" or exhibit direct physical force on cell membrane under alternating electromagnetic fields thus reducing the required field strength. A cell poration/ablation system was built for exploring these effects of CNTs in which two-electrode sets were constructed and two perpendicular electric fields could be generated sequentially. By applying this system to breast cancer cells in the presence of multi-walled CNTs (MWCNTs), the effective pulse amplitude was reduced to 50 V/cm (main field)/15 V/cm (alignment field) at the optimized pulse frequency (5 Hz) of 500 pulses. Under these conditions instant cell membrane permeabilization was increased to 38.62%, 2.77-fold higher than that without CNTs. Moreover, we also observed irreversible electroporation occurred under these conditions, such that only 39.23% of the cells were viable 24 h post treatment, in contrast to 87.01% cell viability without presence of CNTs. These results indicate that CNT-enhanced electroporation has the potential for tumour cell ablation by significantly lower electric fields than that in conventional electroporation therapy thus avoiding potential risks associated with the use of high intensity electric pulses. PMID- 25822875 TI - Anti-inflammatory effect of Streptochlorin via TRIF-dependent signaling pathways in cellular and mouse models. AB - Streptochlorin, a small compound derived from marine actinomycete, has been shown to have anti-angiogenic, anti-tumor, and anti-allergic activities. However, the anti-inflammatory effects and underlying mechanisms have not yet been reported. In the present study, we investigated the effect of streptochlorin on lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Streptochlorin attenuated the production of proinflammatory mediators such as nitric oxide, cyclooxygenase-2, pro-interleukin (IL)-1beta, and IL-6 in LPS stimulated RAW264.7 cells through inhibition of the Toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-beta (TRIF)-dependent signaling pathway. Furthermore, streptochlorin suppressed the infiltration of immune cells such as neutrophils into the lung and proinflammatory cytokine production such as IL-6 and TNF-alpha in broncho-alveolar lavage fluid (BALF) in the LPS-induced acute lung injury (ALI) mouse model. Streptochlorin has potent anti-inflammatory effects through regulating TRIF-dependent signaling pathways, suggesting that streptochlorin may provide a valuable therapeutic strategy in treating various inflammatory diseases. PMID- 25822876 TI - Functionalization of magnetite nanoparticles as oil spill collector. AB - In the present study, a new magnetic powder based on magnetite can be used as a petroleum crude oil collector. Amidoximes based on rosin as a natural product can be prepared from a reaction between hydroxylamine and rosin/acrylonitrile adducts. The produced rosin amidoximes were used as capping agents for magnetite nanoparticles to prepare hydrophobic coated magnetic powders. A new class of monodisperse hydrophobic magnetite nanoparticles was prepared by a simple and inexpensive co-precipitation method. Iron ions and iodine were prepared by the reaction between ferric chloride and potassium iodide. The structure and morphology of magnetite capped with rosin amidoxime were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential, thermogravimetric analysis (TGA) and dynamic light scattering (DLS). The magnetic properties were determined from vibrating sample magnetometer (VSM) analyses. These prepared magnetite nanoparticles were tested as bioactive nanosystems and their antimicrobial effects were investigated. The prepared nanomaterials were examined as a crude oil collector using magnetic fields. The results show promising data for the separation of the petroleum crude oil from aqueous solution in environmental pollution cleanup. PMID- 25822878 TI - Virtual colorimetric sensor array: single ionic liquid for solvent discrimination. AB - There is a continuing need to develop high-performance sensors for monitoring organic solvents, primarily due to the environmental impact of such compounds. In this regard, colorimetric sensors have been a subject of intense research for such applications. Herein, we report a unique virtual colorimetric sensor array based on a single ionic liquid (IL) for accurate detection and identification of similar organic solvents and mixtures of such solvents. In this study, we employ eight alcohols and seven binary mixtures of ethanol and methanol as analytes to provide a stringent test for assessing the capabilities of this array. The UV visible spectra of alcoholic solutions of the IL used in this study show two absorption bands. Interestingly, the ratio of absorbance for these two bands is found to be extremely sensitive to alcohol polarity. A virtual sensor array is created by using four different concentrations of IL sensor, which allowed identification of these analytes with 96.4-100% accuracy. Overall, this virtual sensor array is found to be very promising for discrimination of closely related organic solvents. PMID- 25822877 TI - Multi-layer electrospun membrane mimicking tendon sheath for prevention of tendon adhesions. AB - Defect of the tendon sheath after tendon injury is a main reason for tendon adhesions, but it is a daunting challenge for the biomimetic substitute of the tendon sheath after injury due to its multi-layer membrane-like structure and complex biologic functions. In this study, a multi-layer membrane with celecoxib loaded poly(l-lactic acid)-polyethylene glycol (PELA) electrospun fibrous membrane as the outer layer, hyaluronic acid (HA) gel as middle layer, and PELA electrospun fibrous membrane as the inner layer was designed. The anti-adhesion efficacy of this multi-layer membrane was compared with a single-layer use in rabbit flexor digitorum profundus tendon model. The surface morphology showed that both PELA fibers and celecoxib-loaded PELA fibers in multi-layer membrane were uniform in size, randomly arrayed, very porous, and smooth without beads. Multi-layer membrane group had fewer peritendinous adhesions and better gliding than the PELA membrane group and control group in gross and histological observation. The similar mechanical characteristic and collagen expression of tendon repair site in the three groups indicated that the multi-layer membrane did not impair tendon healing. Taken together, our results demonstrated that such a biomimetic multi-layer sheath could be used as a potential strategy in clinics for promoting tendon gliding and preventing adhesion without poor tendon healing. PMID- 25822879 TI - Tunable and robust phosphite-derived surface film to protect lithium-rich cathodes in lithium-ion batteries. AB - A thin, uniform, and highly stable protective layer tailored using tris(trimethylsilyl) phosphite (TMSP) with a high tendency to donate electrons is formed on the Li-rich layered cathode, Li1.17Ni0.17Mn0.5Co0.17O2. This approach inhibits severe electrolyte decomposition at high operating voltages during cycling and dramatically improves the interfacial stability of the cathode. The TMSP additive in the LiPF6-based electrolyte is found to preferentially eliminate HF, which promotes the dissolution of metal ions from the cathode. Our investigation revealed that the TMSP-derived surface layer can overcome the significant capacity fading of the Li-rich cathode by structural instability ascribed to an irreversible phase transformation from layered to spinel-like structures. Moreover, the superior rate capability of the Li-rich cathode is achieved because the TMSP-originated surface layer allows facile charge transport at high C rates for the lithiation process. PMID- 25822880 TI - The Influence of God and Providence on Happiness and the Quality of Life of Patients Benefiting from Aesthetic Medicine Treatments in Poland. AB - The research reveals the impact of a belief in god and god's Providence on the happiness and quality of life of patients benefiting from aesthetic medicine treatments in Poland (country where over 90 % of society declare to be deeply devout). The work also examines age and sex of the patients benefiting from beauty treatments (botulinum toxin, fillers, medical peels and needle mesotherapy), their quality of life and also the impact of various factors, including God and Divine Providence on their happiness. The research shows the analysis of factors influencing the successes or failures in the past year and presents the comparison of patients who have benefited from the aesthetic medicine treatments (cosmetic medicine) to the common average Polish citizens. PMID- 25822881 TI - A Model of Spirituality for Ageing Muslims. AB - Spirituality's influence on general well-being and its association with healthy ageing has been studied extensively. However, a different perspective has to be brought in when dealing with spirituality issues of ageing Muslims. Central to this perspective is the intertwining of religion and spirituality in Islam. This article will contribute to the understanding of the nature of Islamic spirituality and its immense importance in the life of a practicing ageing Muslim. Consequently, it will help care providers to include appropriate spiritual care in the care repertoire of a Muslim care recipient. It is assumed that the framework for a model of spirituality based on Islamic religious beliefs would help contextualise the relationship between spirituality and ageing Muslims. Not only challenges, but also the opportunities that old age provides for charting the spiritual journey have underpinned this model. PMID- 25822883 TI - The role of statins in inflammatory vasculitides. AB - While the statins are best known for their cholesterol lowering capabilities, they also appear to have anti-inflammatory, anti-oxidant and endothelial repairing properties that have raised the question as to whether this class of drugs can be of benefit in non-atherosclerotic, acute and chronic vasculitides. These effects, independent of the lipid-lowering effects, make the statins a class of drugs that are primed for repurposing and being used in disease states where innate and adaptive immunity and endothelial damage play a key role. Thus far, statins have been used in Behcet's, rheumatoid arthritis and Kawasaki disease with some promising results. Further study is needed to better understand the innate and adaptive immunological response to statins in cardiovascular diseases as well as the full potential of statins in acute and chronic inflammatory vasculitides. PMID- 25822884 TI - Correction: Proteomic profile and in silico analysis in metastatic melanoma with and without BRAF mutation. PMID- 25822882 TI - Fine specificities of natural regulatory T cells after IVIG therapy in patients with Kawasaki disease. AB - The activation of natural regulatory T cells (nTreg) recognizing the heavy constant region (Fc) of IgG is an important mechanism of action of intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). Lack of circulating Fc specific nTreg in the sub-acute phase of KD is correlated with the development of coronary artery abnormalities (CAA). Here, we characterize the fine specificity of nTreg in sub-acute (2- to 8-week post-IVIG) and convalescent (1- to 10-year post-IVIG) KD subjects by testing the immunogenicity of 64 peptides, 15 amino acids in length with a 10 amino acid-overlap spanning the entire Fc protein. About 12 Fc peptides (6 pools of 2 consecutive peptides) were recognized by nTreg in the cohorts studied, including two patients with CAA. To test whether IVIG expands the same nTreg populations that maintain vascular homeostasis in healthy subjects, we compared these results with results obtained in healthy adult controls. Similar nTreg fine specificities were observed in KD patients after IVIG and in healthy donors. These results suggest that T cell fitness rather than T cell clonal deletion or anergy is responsible for the lack of Fc-specific nTreg in KD patients who develop CAA. Furthermore, we found that adolescents and adults who had KD during childhood without developing CAA did not respond to the Fc protein in vitro, suggesting that the nTreg response induced by IVIG in KD patients is short-lived. Our results support the concept that peptide epitopes may be a viable therapeutic approach to expand Fc-specific nTreg and more effectively prevent CAA in KD patients. PMID- 25822886 TI - Drivers of coastal shoreline change: case study of hon dat coast, Kien Giang, Vietnam. AB - Coastal shorelines are naturally dynamic, shifting in response to coastal geomorphological processes. Globally, land use change associated with coastal urban development and growing human population pressures is accelerating coastal shoreline change. In southern Vietnam, coastal erosion currently is posing considerable risks to shoreline land use and coastal inhabitants. The aim of this paper is to quantify historical shoreline changes along the Hon Dat coast between 1995 and 2009, and to document the relationships between coastal mangrove composition, width and density, and rates of shoreline change. The generalized linear mixed-effects models were used to quantify the major biophysical and land use factors influencing shoreline change rates. Most significant drivers of the rates of change are cutting of mangroves, the dominant mangrove genus, changes in adjacent shoreline land use, changes of shoreline land cover, and width of fringing mangroves. We suggest that a possible and inexpensive strategy for robust mangrove shoreline defense is direct mangrove planting to promote mangrove density with the presence of breakwater structures. In the shorter term, construction of coastal barriers such as fence-structured melaleuca poles in combination with mangrove restoration schemes could help retain coastal sediments and increase the elevation of the accretion zone, thereby helping to stabilize eroding fringe shorelines. It also is recommended that implementation of a system of payments for mangrove ecosystem services and the stronger regulation of mangrove cutting and unsustainable land-use change to strengthen the effectiveness of mangrove conservation programs and coastal land-use management. PMID- 25822885 TI - The clinical and etiological characteristics of influenza-like illness (ILI) in outpatients in Shanghai, China, 2011 to 2013. AB - INTRODUCTION: Clinical and etiological characteristics of influenza-like illness (ILI) in outpatients is poorly understood in the southern temperate region of China. We conducted laboratory-based surveillance of viral etiology for ILI outpatients in Shanghai from January 2011 to December 2013. MATERIALS AND METHODS: Clinical and epidemiological data from ILI outpatients, both children and adults, were collected. A total of 1970 nasopharyngeal swabs were collected and tested for 12 respiratory viruses using multiplex RT-PCR, and the data were analyzed anonymously. RESULTS: All 12 respiratory viruses were detected in the specimens. At least one virus was detected in 32.4% of 1970 specimens analyzed, with 1.1% showing co-infections. The most frequently detected agents were influenza A (11.7%), influenza B (9.6%), and rhinoviruses (3.1%).Other viruses were present at a frequency less than 3.0%. We observed a winter peak in the detection rate in ILI patients during 3 years of surveillance and a summer peak in 2012. HCoV, HADV, and HMPV were detected more frequently in children than in adults. Patients infected with influenza virus experienced higher temperatures, more coughs, running noses, headaches and fatigue than patients infected with other viruses and virus-free patients (p<0.001). CONCLUSIONS: The spectrum, seasonality, age distribution and clinical associations of respiratory virus infections in children and adults with influenza-like illness were analyzed in this study for the first time. To a certain extent, the findings can provide baseline data for evaluating the burden of respiratory virus infection in children and adults in Shanghai. It will also provide clinicians with helpful information about the etiological patterns of outpatients presenting with complaints of acute respiratory syndrome, but further studies should be conducted, and longer-term laboratory-based surveillance would give a better picture of the etiology of ILI. PMID- 25822887 TI - More of the same: high functional redundancy in stream fish assemblages from tropical agroecosystems. AB - In this study, we investigated the influence of environmental variables (predictor variables) on the species richness, species diversity, functional diversity, and functional redundancy (response variables) of stream fish assemblages in an agroecosystem that harbor a gradient of degradation. We hypothesized that, despite presenting high richness or diversity in some occasions, fish communities will be more functionally redundant with stream degradation. Species richness, species diversity, and functional redundancy were predicted by the percentage of grass on the banks, which is a characteristic that indicates degraded conditions, whereas the percentage of coarse substrate in the stream bottom was an important predictor of all response variables and indicates more preserved conditions. Despite being more numerous and diverse, the groups of species living in streams with an abundance of grass on the banks perform similar functions in the ecosystem. We found that riparian and watershed land use had low predictive power in comparison to the instream habitat. If there is any interest in promoting ecosystem functions and fish diversity, conservation strategies should seek to restore forests in watersheds and riparian buffers, protect instream habitats from siltation, provide wood debris, and mitigate the proliferation of grass on stream banks. Such actions will work better if they are planned together with good farming practices because these basins will continue to be used for agriculture and livestock in the future. PMID- 25822888 TI - What is Novel About Novel Ecosystems: Managing Change in an Ever-Changing World. AB - Influenced by natural climatic, geological, and evolutionary changes, landscapes and the ecosystems within are continuously changing. In addition to these natural pressures, anthropogenic drivers have increasingly influenced ecosystems. Whether affected by natural or anthropogenic processes, ecosystems, ecological communities, and ecosystem functioning are dynamic and can lead to "novel" or "emerging" ecosystems. Current literature identifies several definitions of these ecosystems but lacks an unambiguous definition and framework for categorizing what constitutes a novel ecosystem and for informing decisions around best management practices. Here we explore the various definitions used for novel ecosystems, present an unambiguous definition, and propose a framework for identifying the most appropriate management option. We identify and discuss three approaches for managing novel ecosystems: managing against, tolerating, and managing for these systems, and we provide real-world examples of each approach. We suggest that this framework will allow managers to make thoughtful decisions about which strategy is most appropriate for each unique situation, to determine whether the strategy is working, and to facilitate decision-making when it is time to modify the management approach. PMID- 25822889 TI - Changes in Microbial Community Structure and Soil Biological Properties in Mined Dune Areas During Re-vegetation. AB - The aim of this study was to describe the impact of re-vegetation on the restoration of microbial community structure and soil microbiological properties in sand dunes that had been affected by mining activity. Soil samples were collected during the dry and rainy seasons from a chronosequence (1, 9, 21 years) of re-vegetated dunes using a single preserved dune as a reference. The composition of the fatty acid methyl esters and soil microbial properties were evaluated. The results showed that the changes in microbial community structure were related to seasonal variations: biomarkers of Gram-positive bacteria were higher than Gram-negative bacteria during the dry season, showing that this group of organisms is more tolerant to these stressful conditions. The microbial community structure in the natural dune was less affected by seasonal variation compared to the re-vegetated areas, whereas the opposite was observed for microbiological properties. Thus, in general, the proportion of saprobic fungi was higher in the natural dune, whereas Gram-negative bacteria were proportionally more common in the younger areas. Although over time the re vegetation allows the recovery of the microbial community and the soil functions, these communities and functions are different from those found in the undisturbed areas. PMID- 25822890 TI - The burden and etiology of community-onset pneumonia in the aging Japanese population: a multicenter prospective study. AB - BACKGROUND: The increasing burden of pneumonia in adults is an emerging health issue in the era of global population aging. This study was conducted to elucidate the burden of community-onset pneumonia (COP) and its etiologic fractions in Japan, the world's most aged society. METHODS: A multicenter prospective surveillance for COP was conducted from September 2011 to January 2013 in Japan. All pneumonia patients aged >= 15 years, including those with community-acquired pneumonia (CAP) and health care-associated pneumonia (HCAP), were enrolled at four community hospitals on four major islands. The COP burden was estimated based on the surveillance data and national statistics. RESULTS: A total of 1,772 COP episodes out of 932,080 hospital visits were enrolled during the surveillance. The estimated overall incidence rates of adult COP, hospitalization, and in-hospital death were 16.9 (95% confidence interval, 13.6 to 20.9), 5.3 (4.5 to 6.2), and 0.7 (0.6 to 0.8) per 1,000 person-years (PY), respectively. The incidence rates sharply increased with age; the incidence in people aged >= 85 years was 10-fold higher than that in people aged 15-64 years. The estimated annual number of adult COP cases in the entire Japanese population was 1,880,000, and 69.4% were aged >= 65 years. Aspiration-associated pneumonia (630,000) was the leading etiologic category, followed by Streptococcus pneumoniae-associated pneumonia (530,000), Haemophilus influenzae-associated pneumonia (420,000), and respiratory virus-associated pneumonia (420,000), including influenza-associated pneumonia (30,000). CONCLUSIONS: A substantial portion of the COP burden occurs among elderly members of the Japanese adult population. In addition to the introduction of effective vaccines for S. pneumoniae and influenza, multidimensional approaches are needed to reduce the pneumonia burden in an aging society. PMID- 25822892 TI - The role of states in improving price transparency in health care. PMID- 25822891 TI - Spatiotemporal analysis of hepatitis C virus infection. AB - Hepatitis C virus (HCV) entry, translation, replication, and assembly occur with defined kinetics in distinct subcellular compartments. It is unclear how HCV spatially and temporally regulates these events within the host cell to coordinate its infection. We have developed a single molecule RNA detection assay that facilitates the simultaneous visualization of HCV (+) and (-) RNA strands at the single cell level using high-resolution confocal microscopy. We detect (+) strand RNAs as early as 2 hours post-infection and (-) strand RNAs as early as 4 hours post-infection. Single cell levels of (+) and (-) RNA vary considerably with an average (+):(-) RNA ratio of 10 and a range from 1-35. We next developed microscopic assays to identify HCV (+) and (-) RNAs associated with actively translating ribosomes, replication, virion assembly and intracellular virions. (+) RNAs display a defined temporal kinetics, with the majority of (+) RNAs associated with actively translating ribosomes at early times of infection, followed by a shift to replication and then virion assembly. (-) RNAs have a strong colocalization with NS5A, but not NS3, at early time points that correlate with replication compartment formation. At later times, only ~30% of the replication complexes appear to be active at a given time, as defined by (-) strand colocalization with either (+) RNA, NS3, or NS5A. While both (+) and (-) RNAs colocalize with the viral proteins NS3 and NS5A, only the plus strand preferentially colocalizes with the viral envelope E2 protein. These results suggest a defined spatiotemporal regulation of HCV infection with highly varied replication efficiencies at the single cell level. This approach can be applicable to all plus strand RNA viruses and enables unprecedented sensitivity for studying early events in the viral life cycle. PMID- 25822893 TI - Examining the associations between daily caregiving discontinuity and children's social-emotional outcomes. AB - Many child care centers temporarily move children and teachers in and out of their assigned classrooms throughout the day. Such practices create frequent discontinuity in children's experiences in child care, including discontinuity in their peer and teacher relationships. This study examined the prevalence and patterns of teacher and child movement between classrooms, the characteristics of teachers and children who were more likely to move between classrooms on a daily basis, and the associations between children's and teachers' rate of daily movement between classrooms with children's social-emotional outcomes. A moderate to high prevalence of child and teacher movement between classrooms was observed (29% and 83%, respectively). Children who were younger, considered solitary, and who had been enrolled in their classroom for shorter periods of time were less likely to transition between classrooms. Children's rate of movement was a positive predictor of teachers' perceived conflict with children in their care, and a negative predictor of teachers' perceived closeness. In addition, the more frequently teachers moved, the less children were inclined to indicate liking their teachers or centers. However, the more frequently children moved, the more likely children were to indicate liking their peers and for their peers to indicate liking them. Results are interpreted in light of additional research avenues that can inform sensible daily teacher continuity practices. PMID- 25822894 TI - The utility of the prototype/willingness model in predicting alcohol use among North American Indigenous adolescents. AB - In the present study, we considered the utility of the prototype/willingness model in predicting alcohol use among North-American Indigenous adolescents. Specifically, using longitudinal data, we examined the associations among subjective drinking norms, positive drinker prototypes, drinking expectations (as a proxy of drinking willingness), and drinking behavior among a sample of Indigenous adolescents from ages 12 to 14 years. Using an autoregressive cross lagged analysis, our results showed that subjective drinking norms and positive drinker prototypes at 12 years of age were associated with increased drinking expectations at 13 years of age, and that greater drinking expectations at 13 years of age were associated with increased drinking behavior at 14 years of age. Our results provide initial evidence that the prototype/willingness model may generalize to Indigenous adolescents, a population that has received little attention within the psychological sciences. Our results also highlight some potential ways in which existing prevention efforts aimed at reducing substance use among Indigenous adolescents may be enhanced. PMID- 25822895 TI - Predictors of child-to-parent aggression: A 3-year longitudinal study. AB - Although we rarely hear about it, children sometimes aggress against their parents. This is a difficult topic to study because abused parents and abusive children are both reluctant to admit the occurrence of child-to-parent aggression. There are very few research studies on this topic, and even fewer theoretical explanations of why it occurs. We predicted that exposure to violence in the home (e.g., parents aggressing against each other) and ineffective parenting (i.e., parenting that is overly permissive or lacks warmth) influences cognitive schemas of how children perceive themselves and the world around them (i.e., whether aggression is normal, whether they develop grandiose self-views, and whether they feel disconnected and rejected), which, in turn, predicts child to-parent aggression. In a 3-year longitudinal study of 591 adolescents and their parents, we found that exposure to violence in Year 1 predicted child-to-parent aggression in Year 3. In addition, parenting characterized by lack of warmth in Year 1 was related to narcissistic and entitled self-views and disconnection and rejection schemas in Year 2, which, in turn, predicted child-to-mother and child to-father aggression in Year 3. Gender comparisons indicated that narcissism predicted child-to-parent aggression only in boys and that exposure to violence was a stronger predictor of child-to-father violence in boys. This longitudinal study increases our understanding of the understudied but important topic of child-to-parent aggression, and will hopefully stimulate future research. PMID- 25822896 TI - Cognitive control of speech perception across the lifespan: A large-scale cross sectional dichotic listening study. AB - The ability to use cognitive-control functions to regulate speech perception is thought to be crucial in mastering developmental challenges, such as language acquisition during childhood or compensation for sensory decline in older age, enabling interpersonal communication and meaningful social interactions throughout the entire life span. Although previous studies indicate that cognitive control of speech perception is subject to developmental changes, its exact developmental trajectory has not been described. Thus, examining a sample of 2,988 participants (1,119 women) with an age range from 5 to 89 years, the aim of the present cross-sectional study was to examine the development of cognitive control of speech perception across the life span using age as continuous predictor. Based on data collected with the forced-attention consonant-vowel dichotic listening paradigm, the data analysis revealed an inverted U-shaped association of age and performance level: A steep increase in performance level was seen throughout childhood and adolescence, reaching highest performance in the early 20s, and was followed by a monotonous, continuous decline into late adulthood. Thus, cognitive control of speech perceptions shows similar life span developmental trajectories as observed regarding cognitive-control functions in other domains, for example, as assessed in the visual domain. PMID- 25822897 TI - Further examination of the immediate impact of television on children's executive function. AB - Three studies examined the short-term impact of television (TV) on children's executive function (EF). Study 1 (N = 160) showed that 4- and 6-year-olds' EF is impaired after watching 2 different fast and fantastical shows, relative to that of children who watched a slow, realistic show or played. In Study 2 (N = 60), 4 year-olds' EF was as depleted after watching a fast and fantastical educational show as it was after a fast and fantastical entertainment 1, relative to that of children who read a book based on the educational show. Study 3 (N = 80) examined whether show pacing or fantasy was more influential, and found that only fantastical shows, regardless of their pacing, disrupted 4-year-olds' EF. Taken together, these studies show that 10-20 min watching televised fantastical events, relative to other experiences, results in lower EF in young children. PMID- 25822898 TI - Correction: Polymorphisms of renin-angiotensin-aldosterone system gene in Chinese Han patients with nonfamilial atrial fibrillation. PMID- 25822899 TI - Growth pattern of colorectal liver metastasis as a marker of recurrence risk. AB - Despite improved therapy of advanced colorectal cancer, the median overall survival (OS) is still low. A surgical removal has significantly improved survival, if lesions are entirely removed. The purpose of this retrospective explorative study was to evaluate the prognostic value of histological growth patterns (GP) in chemonaive and patients receiving neo-adjuvant therapy. Two hundred-fifty-four patients who underwent liver resection of colorectal liver metastases between 2007 and 2011 were included in the study. Clinicopathological data and information on neo-adjuvant treatment were retrieved from patient and pathology records. Histological GP were evaluated and related to recurrence free and OS. Kaplan-Meier curves, log-rank test and Cox regression analysis were used. The 5-year OS was 41.8% (95% CI 33.8-49.8%). Growth pattern evaluation of the largest liver metastasis was possible in 224 cases, with the following distribution: desmoplastic 63 patients (28.1%); pushing 77 patients (34.4%); replacement 28 patients (12.5%); mixed 56 patients (25.0%). The Kaplan-Meier analyses demonstrated that patients resected for liver metastases with desmoplastic growth pattern had a longer recurrence free survival (RFS) than patients resected for non-desmoplastic liver metastases (p=0.05). When patients were stratified according to neo-adjuvant treatment in the multivariate Cox regression model, hazard ratios for RFS compared to desmoplastic were: pushing (HR=1.37, 95% CI 0.93-2.02, p=0.116), replacement (HR=2.16, 95% CI 1.29-3.62, p=0.003) and mixed (HR=1.70, 95% CI 1.12-2.59, p=0.013). This was true for chemonaive patients as well as for patients who received neo-adjuvant treatment. PMID- 25822900 TI - Vitamin D deficiency and its predictors in a country with thirteen months of sunshine: the case of school children in central Ethiopia. AB - Studies examining vitamin D status among children living in sunny climates indicated that children did not receive adequate vitamin D, however, this has not been looked at among children living in Ethiopia. In this study, we determined vitamin D deficiency and its predictors among school children aged 11-18 years, examining circulating 25-hydroxy vitamin D [25(OH)D]. The school-based cross sectional study was conducted in schools in Adama Town (n = 89) and in rural Adama (n = 85) for a total sample of 174. Students were randomly selected using multi-stage stratified sampling method from both settings. Socioeconomic status of parents and demographic, anthropometric, sun exposure status and blood 25(OH)D levels were obtained. Vitamin D deficiency, defined as circulating levels of 25(OH)D <50 nmol/L, was found in 42% of the entire study participants. Prevalence of deficiency was significantly higher among students in urban setting compared to rural (61.8% vs 21.2%, respectively, p<0.001). After controlling for potential confounders using multivariable logistic regression model, duration of exposure to sunlight, amount of body part exposed to sunlight, place of residence, maternal education, body fatness, having TV/computer at home and socioeconomic status were significant predictors of vitamin D deficiency. The findings suggest that Vitamin D deficiency was prevalent in healthy school children living both in urban and rural areas of a country with abundant year round sunshine providing UVB, with the prevalence of deficiency being significantly higher among urban school children who were less exposed to sunlight. Behaviour change communication to enhance exposure to ultraviolet light is critical to prevent vitamin D deficiency in tropical country like Ethiopia. Further study is required to assess the deleterious effect of its deficiency on bone mineral homeostasis of growing children in Ethiopia during their most critical period of bone development. PMID- 25822901 TI - Prevalence of Elevated Blood Lead Levels and Risk Factors Among Residents Younger Than 6 Years, Puerto Rico--2010. AB - CONTEXT: Limited data exist about blood lead levels (BLLs) and potential exposures among children living in Puerto Rico. The Puerto Rico Department of Health has no formal blood lead surveillance program. OBJECTIVES: We assessed the prevalence of elevated BLLs (>=5 micrograms of lead per deciliter of blood), evaluated household environmental lead levels, and risk factors for BLL among children younger than 6 years of age living in Puerto Rico in 2010. METHODS: We used a population-based, cross-sectional sampling strategy to enroll an island representative sample of Puerto Rican children younger than 6 years. We estimated the island-wide weighted prevalence of elevated BLLs and conducted bivariable and multivariable linear regression analyses to ascertain risk factors for elevated BLLs. RESULTS: The analytic data set included 355 households and 439 children younger than 6 years throughout Puerto Rico. The weighted geometric mean BLL of children younger than 6 years was 1.57 MUg/dL (95% confidence interval [CI], 1.27 1.88). The weighted prevalence of children younger than 6 years with BLLs of 5 MUg/dL or more was 3.18% (95% CI, 0.93-5.43) and for BLLs of 10 MUg/dL or more was 0.50% (95% CI, 0-1.31). Higher mean BLLs were significantly associated with data collection during the summer months, a lead-related activity or hobby of anyone in the residence, and maternal education of less than 12 years. Few environmental lead hazards were identified. CONCLUSIONS: The prevalence of elevated BLLs among Puerto Rican children younger than 6 years is comparable with the most recent (2007-2010) US national estimate (BLLs >=5 MUg/dL = 2.6% [95% CI = 1.6-4.0]). Our findings suggest that targeted screening of specific higher-risk groups of children younger than 6 years can replace island-wide or insurance specific policies of mandatory blood lead testing in Puerto Rico. PMID- 25822902 TI - The Tobacco Control Network's Policy Readiness and Stage of Change Assessment: What the Results Suggest for Moving Tobacco Control Efforts Forward at the State and Territorial Levels. AB - CONTEXT: The Tobacco Control Network (TCN) is comprised of the tobacco control programs in the health departments of states, territories, and the District of Columbia. During the assessment period, the TCN was managed by the Tobacco Technical Assistance Consortium at Emory University. OBJECTIVE: To assess the readiness of state and territory tobacco control programs to work on evidence based, promising policy and system change strategies aimed at preventing and reducing tobacco use and secondhand smoke exposure. DESIGN: The Policy Readiness and Stage of Change Assessment was a Web-based survey fielded in September 2013, which was based on the Community Readiness Model. SETTING: Fifty-nine comprehensive tobacco control programs. PARTICIPANTS: State and territory tobacco control program managers and their internal and external partners. INTERVENTION: The TCN's 2012 Policy Platform recommendations were used as the basis to assess state/territory readiness to adopt and implement evidence-based and promising tobacco control policy/system change strategies. MAIN OUTCOME MEASURES: Sixteen tobacco control strategies were rated on: (1) implementation status, (2) readiness, (3) stage of change, and (4) the appropriate level of action for work on the strategy. RESULTS: The 3 strategies with the highest readiness scores were as follows: (1) 100% smoke-free air in workplaces (64%), (2) tobacco-free schools (61%), and (3) $1.50 or less cigarette tax with funds to tobacco control (53%). The 3 strategies with lowest readiness scores were: 1) coupon redemption (17%), 2) tobacco mitigation fee (14%), and 3) disclosure or sunshine laws (8%). CONCLUSION: Readiness to work on tobacco control strategies varied by region and strategy. Many states/territories are ready to work on strategies for which there is less evidence of a population-level impact for reducing tobacco use, but which contribute to denormalizing tobacco use. Working toward less impactful policies may build support, capacity, and policy success, laying an important foundation to achieve more impactful strategies. PMID- 25822903 TI - Learning from New York City : a case study of public health policy practice in the Bloomberg administration. AB - OBJECTIVES: To ascertain any lessons learned about how public health reforms undertaken in New York City during the Bloomberg Administration were shepherded through the public policy and administration gauntlet. The question is, how feasible is this approach and would it work outside of New York City? DESIGN/SETTING/PARTICIPANTS: Using a theoretically grounded case study approach, 3 initiatives were examined that were proposed and/or implemented during a 10 year period of the Mayoralty of Michael Bloomberg (2002-2011): transfats restrictions, clean bus transportation policies, and a sugar-sweetened beverages tax (as a counterfactual). The investigation began by performing a comprehensive public documents search and was followed with interviews of 27 individuals involved in the selected policy initiatives. Interviews were coded in Nvivo using an iterative, grounded methodology. RESULTS: Using a theoretical lens, the case study illustrates that the multifaceted role of leadership was not confined to the executives in the City or the Agency. Instead, leadership extended to other administrative officials within the agency and the Board of Health. Second, New York City used reorganization and coordinative mechanisms strategically to ensure achievement of their goals. This included creation of new departments/bureaus and coordinating structures across the City. Evidence of the explicit use of incentives, as initially anticipated from the theoretical framework, was not found. CONCLUSIONS: While some aspects of this case study are unique to the context of New York City, 2 approaches used in New York City are feasible for other jurisdictions: harnessing the full scope and breadth of authority of the agency and its associated boards and commissions, and remobilizing existing workforce to explicitly focus on and coordinate targeted policies for issues of concern. Questions for further consideration are posed at the conclusion of the article. PMID- 25822904 TI - Public health initiatives in New York City during the Bloomberg administration. PMID- 25822906 TI - Deficiency of angulin-2/ILDR1, a tricellular tight junction-associated membrane protein, causes deafness with cochlear hair cell degeneration in mice. AB - Tricellular tight junctions seal the extracellular spaces of tricellular contacts, where the vertices of three epithelial cells meet, and are required for the establishment of a strong barrier function of the epithelial cellular sheet. Angulins and tricellulin are known as specific protein components of tricellular tight junctions, where angulins recruit tricellulin. Mutations in the genes encoding angulin-2/ILDR1 and tricellulin have been reported to cause human hereditary deafness DFNB42 and DFNB49, respectively. To investigate the pathogenesis of DFNB42, we analyzed mice with a targeted disruption of Ildr1, which encodes angulin-2/ILDR1. Ildr1 null mice exhibited profound deafness. Hair cells in the cochlea of Ildr1 null mice develop normally, but begin to degenerate by two weeks after birth. Tricellulin localization at tricellular contacts of the organ of Corti in the cochlea was retained in Ildr1 null mice, but its distribution along the depth of tricellular contacts was affected. Interestingly, compensatory tricellular contact localization of angulin-1/LSR was observed in the organ of Corti in Ildr1 null mice although it was hardly detected in the organ of Corti in wild-type mice. The onset of hair cell degeneration in Ildr1 null mice was earlier than that in the reported Tric mutant mice, which mimic one of the tricellulin mutations in DFNB49 deafness. These results indicate that the angulin-2/ILDR1 deficiency causes the postnatal degenerative loss of hair cells in the cochlea, leading to human deafness DFNB42. Our data also suggest that angulin family proteins have distinct functions in addition to their common roles of tricellulin recruitment and that the function of angulin-2/ILDR1 for hearing cannot be substituted by angulin-1/LSR. PMID- 25822905 TI - Micronutrient intakes and potential inadequacies of community-dwelling older adults: a systematic review. AB - Micronutrient deficiencies and low dietary intakes among community-dwelling older adults are associated with functional decline, frailty and difficulties with independent living. As such, studies that seek to understand the types and magnitude of potential dietary inadequacies might be beneficial for guiding future interventions. We carried out a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Observational cohort and longitudinal studies presenting the habitual dietary intakes of older adults (>=65 years) were included. Sex-specific mean (and standard deviation) habitual micronutrient intakes were extracted from each article to calculate the percentage of older people who were at risk for inadequate micronutrient intakes using the estimated average requirement (EAR) cut-point method. The percentage at risk for inadequate micronutrient intakes from habitual dietary intakes was calculated for twenty micronutrients. A total of thirty-seven articles were included in the pooled systematic analysis. Of the twenty nutrients analysed, six were considered a possible public health concern: vitamin D, thiamin, riboflavin, Ca, Mg and Se. The extent to which these apparent inadequacies are relevant depends on dynamic factors, including absorption and utilisation, vitamin and mineral supplement use, dietary assessment methods and the selection of the reference value. In light of these considerations, the present review provides insight into the type and magnitude of vitamin and mineral inadequacies. PMID- 25822908 TI - Self-Assembling of Tetradecylammonium Chain on Swelling High Charge Micas (Na Mica-3 and Na-Mica-2): Effect of Alkylammonium Concentration and Mica Layer Charge. AB - A family of tetradecylammonium micas is synthesized using synthetic swelling micas with high layer charge (Na(n)Si(8-n)Al(n)Mg6F4O20.XH2O, where n = 2 and 3) exchanged with tetradecylammonium cations. The molecular arrangement of the surfactant is elucidated on the basis of XRD patterns and DTA. The ordering conformation of the surfactant molecules into the interlayer space of micas is investigated by IR/FT, (13)C, (27)Al, and (29)Si MAS NMR. The structural arrangement of the tetradecylammonium cation in the interlayer space of high charge micas is more sensitive to the effect of the mica layer charge at high concentration. The surfactant arrangement is found to follow the bilayer-paraffin model for all values of layer charge and surfactant concentration. However, at initial concentration below the mica CEC, a lateral monolayer is also observed. The amount of ordered conformation all-trans is directly proportional to the layer charge and surfactant concentration. PMID- 25822907 TI - Hockey STAR: A Methodology for Assessing the Biomechanical Performance of Hockey Helmets. AB - Optimizing the protective capabilities of helmets is one of several methods of reducing brain injury risk in sports. This paper presents the experimental and analytical development of a hockey helmet evaluation methodology. The Summation of Tests for the Analysis of Risk (STAR) formula combines head impact exposure with brain injury probability over the broad range of 227 head impacts that a hockey player is likely to experience during one season. These impact exposure data are mapped to laboratory testing parameters using a series of 12 impact conditions comprised of three energy levels and four head impact locations, which include centric and non-centric directions of force. Injury risk is determined using a multivariate injury risk function that incorporates both linear and rotational head acceleration measurements. All testing parameters are presented along with exemplar helmet test data. The Hockey STAR methodology provides a scientific framework for manufacturers to optimize hockey helmet design for injury risk reduction, as well as providing consumers with a meaningful metric to assess the relative performance of hockey helmets. PMID- 25822909 TI - [Individualized knee arthroplasty]. PMID- 25822910 TI - [Morphological and functional cartilage imaging]. AB - Excellent morphological imaging of cartilage is now possible and allows the detection of subtle cartilage pathologies. Besides the standard 2D sequences, a multitude of 3D sequences are available for high-resolution cartilage imaging. The first part therefore deals with modern possibilities of morphological imaging. The second part deals with functional cartilage imaging with which it is possible to detect changes in cartilage composition and thus early osteoarthritis as well as to monitor biochemical changes after therapeutic interventions. Validated techniques such as delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T2 mapping as well the latest techniques, such as the glycosaminoglycan chemical exchange-dependent saturation transfer (gagCEST) technique will be discussed. PMID- 25822911 TI - Improved Dielectric Properties and Energy Storage Density of Poly(vinylidene fluoride-co-hexafluoropropylene) Nanocomposite with Hydantoin Epoxy Resin Coated BaTiO3. AB - Energy storage materials are urgently demanded in modern electric power supply and renewable energy systems. The introduction of inorganic fillers to polymer matrix represents a promising avenue for the development of high energy density storage materials, which combines the high dielectric constant of inorganic fillers with supernal dielectric strength of polymer matrix. However, agglomeration and phase separation of inorganic fillers in the polymer matrix remain the key barriers to promoting the practical applications of the composites for energy storage. Here, we developed a low-cost and environmentally friendly route to modifying BaTiO3 (BT) nanoparticles by a kind of water-soluble hydantoin epoxy resin. The modified BT nanoparticles exhibited homogeneous dispersion in the ferroelectric polymer poly(vinylidene fluoride-co-hexafluoropropylene) (P(VDF HFP)) matrix and strong interfacial adhesion with the polymer matrix. The dielectric constants of the nanocomposites increased significantly with the increase of the coated BT loading, while the dielectric loss of the nanocomposites was still as low as that of the pure P(VDF-HFP). The energy storage density of the nanocomposites was largely enhanced with the coated BT loading at the same electric field. The nanocomposite with 20 vol % BT exhibited an estimated maximum energy density of 8.13 J cm(-3), which was much higher than that of pure P(VDF-HFP) and other dielectric polymers. The findings of this research could provide a feasible approach to produce high energy density materials for practical application in energy storage. PMID- 25822912 TI - Dissociated roles of the inferior frontal gyrus and superior temporal sulcus in audiovisual processing: top-down and bottom-up mismatch detection. AB - Visual inputs can distort auditory perception, and accurate auditory processing requires the ability to detect and ignore visual input that is simultaneous and incongruent with auditory information. However, the neural basis of this auditory selection from audiovisual information is unknown, whereas integration process of audiovisual inputs is intensively researched. Here, we tested the hypothesis that the inferior frontal gyrus (IFG) and superior temporal sulcus (STS) are involved in top-down and bottom-up processing, respectively, of target auditory information from audiovisual inputs. We recorded high gamma activity (HGA), which is associated with neuronal firing in local brain regions, using electrocorticography while patients with epilepsy judged the syllable spoken by a voice while looking at a voice-congruent or -incongruent lip movement from the speaker. The STS exhibited stronger HGA if the patient was presented with information of large audiovisual incongruence than of small incongruence, especially if the auditory information was correctly identified. On the other hand, the IFG exhibited stronger HGA in trials with small audiovisual incongruence when patients correctly perceived the auditory information than when patients incorrectly perceived the auditory information due to the mismatched visual information. These results indicate that the IFG and STS have dissociated roles in selective auditory processing, and suggest that the neural basis of selective auditory processing changes dynamically in accordance with the degree of incongruity between auditory and visual information. PMID- 25822913 TI - One-step site-specific modification of native proteins with 2 pyridinecarboxyaldehydes. AB - The chemical modification of proteins is an enabling technology for many scientific fields, including chemical biology, biophysics, bioengineering and materials science. These methods allow the attachment of strategically selected detection probes, polymers, drug molecules and analysis platforms. However, organic reactions that can proceed under conditions mild enough to maintain biomolecular function are limited. Even more rare are chemical strategies that can target a single site, leading to products with uniform properties and optimal function. We present a versatile method for the selective modification of protein N termini that does not require any genetic engineering of the protein target. This reaction is demonstrated for 12 different proteins, including the soluble domain of the human estrogen receptor. The function of this protein was confirmed through the binding of a fluorescent estrogen mimic, and the modified protein was explored as a prototype for the detection of endocrine-disrupting chemicals in water. PMID- 25822914 TI - Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation. AB - Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-kappaB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the kappaB element. However, this function of Nur77 is countered by the LPS-activated p38alpha phosphorylation of Nur77. Dampening the interaction between Nur77 and p38alpha would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38alpha interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF kappaB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38alpha substrate to modulate p38alpha-regulated functions. PMID- 25822915 TI - A pentose bisphosphate pathway for nucleoside degradation in Archaea. AB - Owing to the absence of the pentose phosphate pathway, the degradation pathway for the ribose moieties of nucleosides is unknown in Archaea. Here, in the archaeon Thermococcus kodakarensis, we identified a metabolic network that links the pentose moieties of nucleosides or nucleotides to central carbon metabolism. The network consists of three nucleoside phosphorylases, an ADP-dependent ribose 1-phosphate kinase and two enzymes of a previously identified NMP degradation pathway, ribose-1,5-bisphosphate isomerase and type III ribulose-1,5-bisphosphate carboxylase/oxygenase. Ribose 1,5-bisphosphate and ribulose 1,5-bisphosphate are intermediates of this pathway, which is thus designated the pentose bisphosphate pathway. PMID- 25822916 TI - Bioconjugation: How to pick a single amine? PMID- 25822917 TI - Preventing the Development of Observationally Learnt Fears in Children by Devaluing the Model's Negative Response. AB - Vicarious learning has become an established indirect pathway to fear acquisition. It is generally accepted that associative learning processes underlie vicarious learning; however, whether this association is a form of conditioned stimulus-unconditioned stimulus (CS-US) learning or stimulus-response (CS-CR) learning remains unclear. Traditionally, these types of learning can be dissociated in a US revaluation procedure. The current study explored the effects of post-vicarious learning US revaluation on acquired fear responses. Ninety-four children (46 males and 48 females) aged 6 to 10 years first viewed either a fear vicarious learning video or a neutral vicarious learning video followed by random allocation to one of three US revaluation conditions: inflation; deflation; or control. Inflation group children were presented with still images of the adults in the video and told that the accompanying sound and image of a very fast heart rate monitor belonged to the adult. The deflation group were shown the same images but with the sound and image of a normal heart rate. The control group received no US revaluation. Results indicated that inflating how scared the models appeared to be did not result in significant increases in children's fear beliefs, avoidance preferences, avoidance behavior or heart rate for animals above increases caused by vicarious learning. In contrast, US devaluation resulted in significant decreases in fear beliefs and avoidance preferences. Thus, the findings provide evidence that CS-US associations underpin vicarious learning and suggest that US devaluation may be a successful method for preventing children from developing fear beliefs following a traumatic vicarious learning episode with a stimulus. PMID- 25822919 TI - The prescription is laughter. PMID- 25822918 TI - Refugia persistence of Qinghai-Tibetan plateau by the cold-tolerant bird Tetraogallus tibetanus (Galliformes: Phasianidae). AB - Most of the temperate species are expected to have moved to lower altitudes during the glacial periods of the Quaternary. Here we tested this hypothesis in a cold-tolerant avian species Tibetan snowcock (Tetraogallus tibetanus) using two segments of mitochondrial gene (a 705bp Cytochrome-b; abbrev. Cyt-b and an 854 bp Control Region; abbrev. CR) and eight microsatellite loci by characterizing population differentiation and gene flow across its range. Combined (Cyt-b + CR) datasets detected several partially lineages with poor support. Microsatellite data, however, identified two distinct lineages congruent with the geographically separated western and central regions of Qinghai-Tibetan Plateau (QTP). The phylogeographic patterns that we observed might be explained by a combination of vicariance events that led to local isolation of T. tibetanus during warm periods and range expansions and population intermixing during cold periods. The results of this study add to our knowledge of population differentiation and connectivity in high altitude mountain ecosystems. PMID- 25822920 TI - Cue-type manipulation dissociates two types of task set inhibition: backward inhibition and competitor rule suppression. AB - Backward inhibition (BI) reflects the suppression of a recently abandoned task set to allow for smooth transition to a new task even when the rules do not generate a response conflict. Competitor rule suppression (CRS) reflects the inhibition/suppression of irrelevant task rules when these rules generate a response conflict even if they have not recently been abandoned. We assessed whether BI and CRS are differentially affected by the difficulty in retrieving category-response mappings from memory. Retrieval demands were manipulated via the information provided by the task cues, which either indicated the relevant dimension (dimension cues; "color") or the relevant dimension with its category to-key mapping (mapping cues; "red green", indicating that "red" and "green" go with the left/right responses, respectively). CRS was larger with dimension compared to mapping cues when cue-type varied between groups and was larger after trials involving dimension cues when cue-type varied on a trial-by-trial basis. In contrast, BI was not influenced by cue-type. These results suggest that task switching involve at least two distinct inhibitory processes, with CRS being related to the ease of retrieval of category-response mappings from memory. PMID- 25822921 TI - An exploratory cohort study comparing prothrombin complex concentrate and fresh frozen plasma for the treatment of coagulopathy after complex cardiac surgery. AB - BACKGROUND: Administration of coagulation factor concentrates to treat bleeding after cardiac surgery with cardiopulmonary bypass might be a strategy for reducing allogeneic blood transfusions, particularly for patients treated with warfarin preoperatively. We performed an exploratory analysis on whether the use of prothrombin complex concentrate (PCC) is safe and effective compared with fresh frozen plasma (FFP) to treat coagulopathy after pulmonary endarterectomy surgery with deep hypothermic circulatory arrest. METHODS: Consecutive adult patients who underwent pulmonary endarterectomy surgery between January 2010 and September 2012 and received PCC or FFP to treat coagulopathy were studied. Blood loss during the first 12 hours of admission to the intensive care unit and patient outcomes were compared with propensity score adjustment. RESULTS: Three hundred fifty-one patients underwent pulmonary endarterectomy surgery, all of whom had warfarin discontinued for up to 5 days before surgery; bleeding complications requiring transfusion of blood products were observed in 108 (31%) patients. Of those, 55 received only FFP and 45 received only PCC, whereas 8 received both. Blood loss was significantly greater in the FFP group compared with the PCC group after 12 hours (median [interquartile range], 650 mL [325 1075] vs 277 mL [175-608], P = 0.008). However, there was no difference in the frequency of patients receiving a red blood cell transfusion (number [percent], 44 [80%] vs 34 [76%], P = 0.594) or in the number of units of red blood cells transfused (median [interquartile range], 2 [1-4] vs 3 [1-5] units, P = 0.181). The final propensity score included preoperative international normalized ratio, postoperative activated partial thromboplastin time, and postoperative platelet count. After inclusion of the propensity score in the regression analyses, there were no differences between patients receiving only PCC and patients receiving only FFP in the need for renal replacement therapy (odds ratio [OR] 2.39, 95% confidence interval [CI] 0.51-11.20, P = 0.27), 30-day-mortality (OR 0.32, 95% CI 0.03-3.36, P = 0.35), intracranial hemorrhage (OR 0.73, 95% CI 0.14-3.89, P = 0.71), hospital length of stay (hazard ratio 0.77, 95% CI 0.50-1.19, P = 0.24), or duration of intensive care stay (hazard ratio 0.91, 95% CI 0.59-1.40, P = 0.66). CONCLUSIONS: This retrospective analysis suggests that PCC may be an alternative to FFP in patients previously treated with warfarin who are coagulopathic after major cardiac surgery. Randomized controlled studies powered to evaluate efficacy and important postoperative outcomes for patients receiving PCC versus FFP for coagulopathic bleeding after cardiopulmonary bypass are warranted. PMID- 25822922 TI - The Contractile Effects of Oxytocin, Ergonovine, and Carboprost and Their Combinations: an In Vitro Study on Human Myometrial Strips. AB - BACKGROUND: The objective of this study was to compare the in vitro contractile effects of the combination of oxytocin (low dose and high dose) with either ergonovine or carboprost in myometrial strips from women undergoing cesarean delivery (CD), and to study the effect of oxytocin pretreatment on these contractions. We hypothesized that the use of ergonovine or carboprost in combination with oxytocin would improve contractility compared with oxytocin alone. METHODS: Myometrial samples obtained from women undergoing elective CD were pretreated in organ bath chambers with either oxytocin 10 M (experimental) or physiological salt solution (control) for 2 hours. They were then washed and subjected to dose-response testing with oxytocin, ergonovine, or carboprost (10 to 10 M), either alone or in combination with a fixed low-dose (10 M) (LDOx) or high-dose (10 M) (HDOx) oxytocin. The amplitude, frequency, area under the curve, and motility index (amplitude * frequency) of contractions during the dose response period were analyzed with linear regression models, and compared among the groups. The primary outcome was the motility index across the study groups. RESULTS: One hundred sixty-nine experiments were done in samples obtained from 56 women. The mean square root of the motility index [standard error] (?g.contractions/10 min) of oxytocin was significantly higher in the control (3.40 [0.24]) versus experimental group (2.02 [0.15]) (P < 0.001). When all control groups were compared, the motility index of oxytocin (3.21 [0.25]) was higher than that of ergonovine (2.13 [0.30], P < 0.001 [multiple comparisons adjusted P value, P < 0.001]), carboprost (1.88 [0.10], P < 0.001 [P < 0.001]), ergonovine + LDOx (2.07 [0.15], P < 0.001 [P < 0.001]), and carboprost + LDOx (1.82 [0.15], P < 0.001 [P < 0.001]) and was not different than that of ergonovine + HDOx (3.39 [0.32], P = 0.68 [P = 0.99]) and carboprost + HDOx (2.68 [0.30], P = 0.20 [P = 0.60]). However, in oxytocin-pretreated groups, carboprost + LDOx (motility index: 2.53 [0.08], P = 0.001 [multiple comparisons adjusted P value, P = 0.002]) and ergonovine + HDOx (2.82 [0.15], P < 0.001 [P < 0.001]) exhibited significantly superior contractility response compared with oxytocin alone, while ergonovine + LDOx (2.47 [0.13], P = 0.01 [P = 0.08]) and carboprost + HDOx (2.51 [0.20], P = 0.05 [P = 0.24]) showed higher mean contractility response compared with oxytocin alone but failed to reach statistical significance in adjusted analyses. CONCLUSIONS: The attenuation of oxytocin induced contractility in oxytocin-pretreated myometrial strips is in keeping with the previously established oxytocin-receptor desensitization phenomenon. Oxytocin is the most effective of the uterotonics tested if the myometrium is not preexposed to oxytocin. However, in the oxytocin-pretreated myometrium, a synergistic response is evident, and the combination of oxytocin with either ergonovine or carboprost produces superior response compared with oxytocin alone. Further in vivo studies in humans are necessary to determine whether these differences identified in vitro are clinically significant. PMID- 25822923 TI - Will the Real Benefits of Single-Shot Interscalene Block Please Stand Up? A Systematic Review and Meta-Analysis. AB - BACKGROUND: Interscalene block (ISB) can provide pain relief after shoulder surgery, but a reliable quantification of its analgesic benefits is lacking. This meta-analysis examines the effect of single-shot ISB on analgesic outcomes during the first 48 hours after shoulder surgery. METHODS: We retrieved randomized and quasirandomized controlled trials examining the analgesic benefits of ISB compared with none in shoulder surgery. Severity of postoperative pain measured on a visual analog scale (10 cm scale, 0 = no pain, 10 = worst pain) at rest at 24 hours was the designated primary outcome. Secondary outcomes included pain severity at rest and with motion at 2, 4, 6, 8, 12, 16, 32, 36, 40, and 48 hours postoperatively. Opioid consumption, postoperative nausea and vomiting, patient satisfaction with pain relief, and postanesthesia care unit and hospital discharge time were also assessed. RESULTS: A total of 23 randomized controlled trials, including 1090 patients, were analyzed. Patients in the ISB group had more severe postoperative pain at rest by a weighed mean difference (95% confidence interval) of 0.96 cm (0.08-1.83; P = 0.03) at 24 hours compared with no ISB, but there was no difference in pain severity beyond that point. The duration of pain relief at rest and with motion after ISB were 8 and 6 hours, respectively, with a corresponding weighed mean difference in visual analog scale pain scores (99% confidence interval) of -1.59 cm (-2.60 to -0.58) and -2.20 cm ( 4.34 to -0.06), respectively, with no additional pain relief benefits beyond these points. ISB reduced postoperative opioid consumption up to 12 hours, decreased postoperative nausea and vomiting at 24 hours, and expedited postanesthesia care unit and hospital discharge. The type, dose, and volume of local anesthetic used did not affect the results. CONCLUSIONS: ISB can provide effective analgesia up to 6 hours with motion and 8 hours at rest after shoulder surgery, with no demonstrable benefits thereafter. Patients who receive an ISB can suffer rebound pain at 24 hours but later experience similar pain severity compared with those who do not receive an ISB. ISB can also provide an opioid sparing effect and reduce opioid-related side effects in the first 12 and 24 hours postoperatively, respectively. These findings are useful to inform preoperative risk-benefit discussions regarding ISB for shoulder surgery. PMID- 25822924 TI - A comparative evaluation of nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication for outpatient pediatric dental surgery. AB - BACKGROUND: This study was designed to evaluate and compare the efficacy and safety of nebulized dexmedetomidine, nebulized ketamine, and the combination of these drugs for premedication in pediatric outpatient dental surgeries. METHODS: A prospective, randomized, double-blinded study was conducted in the Alexandria Main University Hospital after approval of the Medical Ethics Committee. Informed written consent was obtained from the patient's parents. Sixty children classified as ASA physical status I and II and aged 3 to 6 years were enrolled in the study. Patients were randomly categorized into 3 equal groups. Group K was premedicated with nebulized ketamine (2 mg/kg), group D was premedicated with nebulized dexmedetomidine (2 MUg/kg), and group DK was premedicated with combined nebulized dexmedetomidine and ketamine (1 MUg/kg + 1 mg/kg). The primary end point was the level of sedation when the child was first seen in the operating room 30 minutes after sedation. The secondary end points were tolerance of mask induction, hemodynamic changes, analgesia, sedation at emergence, and wake-up behavior. RESULTS: Studied groups were comparable as regards demographic data (age, weight, sex, and ASA physical status, all P > 0.226) and patients' acceptance of drugs (P = 0.968). Level of sedation at 30 minutes was significantly greater in group DK than in either group K (P = 0.003) or group D (P = 0.009). Group DK had the briefest recovery times, followed in order by group K and group D with progressively longer recovery times. Recovery times were significantly briefer in group DK than in either group K (P = 0.039) or group D (P < 0.001). Group DK had significantly briefer discharge times than group D (P < 0.001). Postoperative analgesia was significantly better in group DK compared with group K (P = 0.008). CONCLUSIONS: A nebulized combination of low-dose ketamine and dexmedetomidine produced more satisfactory sedation and provided a smoother induction of general anesthesia than nebulized ketamine or dexmedetomidine alone, with more rapid recovery and no significant side effects. PMID- 25822925 TI - Development of Rapidly Metabolized and Ultra-Short-Acting Ketamine Analogs. AB - BACKGROUND: Ketamine is a well-established, rapidly acting dissociative anesthetic. Clinical use is limited by prolonged psychotomimetic phenomena on emergence, often requiring the coadministration of additional hypnotic drugs. We hypothesized that the development of ketamine ester analogs with ultrashort offset times might markedly reduce the dysphoric emergence phenomena and, hence, increase the utility of a ketamine-like hypnotic and analgesic. Here, we describe the results of studies that seek to define the pharmacology of 5 esters of ((1-(2 chlorophenyl)-2-oxocyclohexyl)amino)pentanoate hydrochloride, the first ketamine analogs designed to be susceptible to ultrarapid metabolism. METHODS: Five norketamine ester analogs (R1-R5) were compared by ability to produce loss of righting and nociceptive blunting in rats. Toxicity testing was performed for 2 analogs (R1, R5) with 50% lethal dose (LD50) estimation in rats. In vitro metabolic stability was tested in rabbit plasma and whole blood by high performance liquid chromatography. Behavioral and hemodynamic effects were observed in rabbits. We estimated the pharmacokinetics of these analogs in rabbits. RESULTS: All 5 norketamine esters produced rapid loss of righting reflex and diminished pedal withdrawal with ultrarapid offset in the models studied (return of righting reflex 87 seconds [interquartile range (IQR) 78-131] R1 vs 996 seconds [IQR 840-1304] ketamine in rats; P < 0.01). The LD50 was comparable to that of ketamine (LD50 R1 50.2 mg/kg [95% confidence interval, 30-63]). For all analogs, hydrolysis to sole carboxylic acid derivatives was most rapid in vivo (clearance 1.61 L/kg/min R1 [IQR 0.40-2.42]), followed by whole blood and then plasma. Analog R5 demonstrated relatively greater nociceptive blunting than hypnotic effect (P < 0.001; pedal withdrawal score comparison with R1). CONCLUSIONS: The 5 norketamine ester analogs retain the hypnotic characteristics of the parent compound, yet display rapid offset due to ultrarapid metabolism. PMID- 25822926 TI - Guiding principles in the design of molecular bioconjugates for vaccine applications. AB - Antigen- and adjuvant-based bioconjugates that can stimulate the immune system play an important role in vaccine applications. Bioconjugates have demonstrated unique physicochemical and biological properties, enabling vaccines to be delivered to key immune cells, to target specific intracellular pathways, or to mimic immunogenic properties of natural pathogens. In this Review we highlight recent advances in such molecular immunomodulators, with an emphasis on the structure-function relationships that provide the foundation for rational design of safe and effective vaccines and immunotherapies. PMID- 25822927 TI - Mass Spectrometry Imaging and GC-MS Profiling of the Mammalian Peripheral Sensory Motor Circuit. AB - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) has evolved to become an effective discovery tool in science and clinical diagnostics. Here, chemical imaging approaches are applied to well-defined regions of the mammalian peripheral sensory-motor system, including the dorsal root ganglia (DRG) and adjacent nerves. By combining several MSI approaches, analyte coverage is increased and 195 distinct molecular features are observed. Principal component analysis suggests three chemically different regions within the sensory-motor system, with the DRG and adjacent nerve regions being the most distinct. Investigation of these regions using gas chromatography-mass spectrometry corroborate these findings and reveal important metabolic markers related to the observed differences. The heterogeneity of the structurally, physiologically, and functionally connected regions demonstrates the intricate chemical and spatial regulation of their chemical composition. PMID- 25822928 TI - Profiling and Imaging Ion Mobility-Mass Spectrometry Analysis of Cholesterol and 7-Dehydrocholesterol in Cells Via Sputtered Silver MALDI. AB - Profiling and imaging of cholesterol and its precursors by mass spectrometry (MS) are important in a number of cholesterol biosynthesis disorders, such as in Smith Lemli-Opitz syndrome (SLOS), where 7-dehydrocholesterol (7-DHC) is accumulated in affected individuals. SLOS is caused by defects in the enzyme that reduces 7-DHC to cholesterol. However, analysis of sterols is challenging because these hydrophobic olefins are difficult to ionize for MS detection. We report here sputtered silver matrix-assisted laser desorption/ionization (MALDI)-ion mobility MS (IM-MS) analysis of cholesterol and 7-DHC. In comparison with liquid-based AgNO3 and colloidal Ag nanoparticle (AgNP), sputtered silver NP (10-25 nm) provided the lowest limits-of-detection based on the silver coordinated [cholesterol + Ag](+) and [7-DHC + Ag](+) signals while minimizing dehydrogenation products ([M + Ag-2H](+)). When analyzing human fibroblasts that were directly grown on poly-L-lysine-coated ITO glass plates with this technique, in situ, the 7-DHC/cholesterol ratios for both control and SLOS human fibroblasts are readily obtained. The m/z of 491 (specific for [7-DHC + (107)Ag](+)) and 495 (specific for [cholesterol + (109)Ag](+)) were subsequently imaged using MALDI-IM MS. MS images were co-registered with optical images of the cells for metabolic ratio determination. From these comparisons, ratios of 7-DHC/cholesterol for SLOS human fibroblasts are distinctly higher than in control human fibroblasts. Thus, this strategy demonstrates the utility for diagnosing/assaying the severity of cholesterol biosynthesis disorders in vitro. PMID- 25822929 TI - In situ conversion of porphyrin microbubbles to nanoparticles for multimodality imaging. AB - Converting nanoparticles or monomeric compounds into larger supramolecular structures by endogenous or external stimuli is increasingly popular because these materials are useful for imaging and treating diseases. However, conversion of microstructures to nanostructures is less common. Here, we show the conversion of microbubbles to nanoparticles using low-frequency ultrasound. The microbubble consists of a bacteriochlorophyll-lipid shell around a perfluoropropane gas. The encapsulated gas provides ultrasound imaging contrast and the porphyrins in the shell confer photoacoustic and fluorescent properties. On exposure to ultrasound, the microbubbles burst and form smaller nanoparticles that possess the same optical properties as the original microbubble. We show that this conversion is possible in tumour-bearing mice and could be validated using photoacoustic imaging. With this conversion, our microbubble can potentially be used to bypass the enhanced permeability and retention effect when delivering drugs to tumours. PMID- 25822930 TI - Theranostic agents: From micro to nano in seconds. PMID- 25822931 TI - Inertial imaging with nanomechanical systems. AB - Mass sensing with nanoelectromechanical systems has advanced significantly during the last decade. With nanoelectromechanical systems sensors it is now possible to carry out ultrasensitive detection of gaseous analytes, to achieve atomic-scale mass resolution and to perform mass spectrometry on single proteins. Here, we demonstrate that the spatial distribution of mass within an individual analyte can be imaged--in real time and at the molecular scale--when it adsorbs onto a nanomechanical resonator. Each single-molecule adsorption event induces discrete, time-correlated perturbations to all modal frequencies of the device. We show that by continuously monitoring a multiplicity of vibrational modes, the spatial moments of mass distribution can be deduced for individual analytes, one-by-one, as they adsorb. We validate this method for inertial imaging, using both experimental measurements of multimode frequency shifts and numerical simulations, to analyse the inertial mass, position of adsorption and the size and shape of individual analytes. Unlike conventional imaging, the minimum analyte size detectable through nanomechanical inertial imaging is not limited by wavelength-dependent diffraction phenomena. Instead, frequency fluctuation processes determine the ultimate attainable resolution. Advanced nanoelectromechanical devices appear capable of resolving molecular-scale analytes. PMID- 25822932 TI - Mapping protein binding sites on the biomolecular corona of nanoparticles. AB - Nanoparticles in a biological milieu are known to form a sufficiently long-lived and well-organized 'corona' of biomolecules to confer a biological identity to the particle. Because this nanoparticle-biomolecule complex interacts with cells and biological barriers, potentially engaging with different biological pathways, it is important to clarify the presentation of functional biomolecular motifs at its interface. Here, we demonstrate that by using antibody-labelled gold nanoparticles, differential centrifugal sedimentation and various imaging techniques it is possible to identify the spatial location of proteins, their functional motifs and their binding sites. We show that for transferrin-coated polystyrene nanoparticles only a minority of adsorbed proteins exhibit functional motifs and the spatial organization appears random, which is consistent, overall, with a stochastic and irreversible adsorption process. Our methods are applicable to a wide array of nanoparticles and can offer a microscopic molecular description of the biological identity of nanoparticles. PMID- 25822933 TI - Infratentorial ependymomas--a study of the centre in Katowice. AB - The aim of the study was to assess the correlation of the results of the treatment of infratentorial ependymomas with the degree of resection and histopathological diagnosis. The study was conducted on a group of 19 patients, 13 boys and 6 girls aged 3 months to 16 years, with infratentorial ependymoma treated at the Department of Paediatric Neurosurgery of the Medical University of Silesia in Katowice from January 2000 until December 2008. The most significant factor having an impact on overall survival and progression-free survival was totality of tumour resection. There has been no statistically significant influence of the histopathological type of ependymoma on the result of treatment. The tendency to report better results of treatment of non-anaplastic ependymoma seems to derive from a statistically higher frequency of total removal of tumours of this type. PMID- 25822934 TI - Spinal extradural arachnoid cyst presenting as recurrent abdominal pain. AB - INTRODUCTION: Spinal arachnoid cysts are an infrequently reported cause of abdominal pain in children. In this report, we describe the unusual case of an extradural arachnoid cyst presenting as recurrent abdominal pain in a pediatric patient without any signs of cord or nerve root compression. CASE REPORT: A 14 year-old girl with recurrent abdominal pain as the only symptom of a spinal extradural arachnoid cyst is reported. The patient was incidentally diagnosed with an intraspinal mass on abdominal computed tomography (CT) during the course of investigating her abdominal pain. Magnetic resonance (MR) imaging confirmed the diagnosis of a T11-L2 extradural arachnoid cyst. After resection of the T11 L2 arachnoid cyst, the patient's abdominal pain resolved. To our knowledge, this is the first report describing abdominal pain as the sole presenting feature of a spinal arachnoid cyst in the pediatric population. CONCLUSION: This case illustrates that abdominal pain may be the first and only presentation of spinal arachnoid cysts in children. Spinal pathology should be considered in the differential diagnosis of unexplained abdominal pain, even when there are no other symptoms of spinal disease. PMID- 25822935 TI - Application of the polystyrene model made by 3-D printing rapid prototyping technology for operation planning in revision lumbar discectomy. AB - OBJECTIVE: The objective was to evaluate the effectiveness of 3-D rapid prototyping technology in revision lumbar discectomy. 3-D rapid prototyping technology has not been reported in the treatment of revision lumbar discectomy. METHODS: Patients with recurrent lumbar disc herniation who were preparing to undergo revision lumbar discectomy from a single center between January 2011 and 2013 were included in this analysis. Patients were divided into two groups. In group A, 3-D printing technology was used to create subject-specific lumbar vertebral models in the preoperative planning process. Group B underwent lumbar revision as usual. Preoperative and postoperative clinical outcomes were compared between groups included operation time, perioperative blood loss, postoperative complications, Oswestry Disability Index (ODI), Japan Orthopaedics Association (JOA) scores, and visual analogue scale (VAS) scores for back pain and leg pain. RESULTS: A total of 37 patients were included in this study (Group A = 15, Group B = 22). Group A had a significantly shorter operation time (106.53 +/- 11.91 vs. 131.92 +/- 10.81 min, P < 0.001) and significantly less blood loss (341.67 +/- 49.45 vs. 466.77 +/- 71.46 ml, P < 0.001). There was no difference between groups for complication rate. There were also no differences between groups for any clinical metric. CONCLUSION: Using the 3-D printing technology before revision lumbar discectomy may reduce the operation time and the perioperative blood loss. There does not appear to be a benefit to using the technology with respect to clinical outcomes. Future prospective studies are needed to further elucidate the efficacy of this emerging technology. PMID- 25822937 TI - Differential network analysis with multiply imputed lipidomic data. AB - The importance of lipids for cell function and health has been widely recognized, e.g., a disorder in the lipid composition of cells has been related to atherosclerosis caused cardiovascular disease (CVD). Lipidomics analyses are characterized by large yet not a huge number of mutually correlated variables measured and their associations to outcomes are potentially of a complex nature. Differential network analysis provides a formal statistical method capable of inferential analysis to examine differences in network structures of the lipids under two biological conditions. It also guides us to identify potential relationships requiring further biological investigation. We provide a recipe to conduct permutation test on association scores resulted from partial least square regression with multiple imputed lipidomic data from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, particularly paying attention to the left censored missing values typical for a wide range of data sets in life sciences. Left-censored missing values are low-level concentrations that are known to exist somewhere between zero and a lower limit of quantification. To make full use of the LURIC data with the missing values, we utilize state of the art multiple imputation techniques and propose solutions to the challenges that incomplete data sets bring to differential network analysis. The customized network analysis helps us to understand the complexities of the underlying biological processes by identifying lipids and lipid classes that interact with each other, and by recognizing the most important differentially expressed lipids between two subgroups of coronary artery disease (CAD) patients, the patients that had a fatal CVD event and the ones who remained stable during two year follow-up. PMID- 25822936 TI - Changes in rodent abundance and weather conditions potentially drive hemorrhagic fever with renal syndrome outbreaks in Xi'an, China, 2005-2012. AB - BACKGROUND: Increased risks for hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus have been observed since 2005, in Xi'an, China. Despite increased vigilance and preparedness, HFRS outbreaks in 2010, 2011, and 2012 were larger than ever, with a total of 3,938 confirmed HFRS cases and 88 deaths in 2010 and 2011. METHODS AND FINDINGS: Data on HFRS cases and weather were collected monthly from 2005 to 2012, along with active rodent monitoring. Wavelet analyses were performed to assess the temporal relationship between HFRS incidence, rodent density and climatic factors over the study period. Results showed that HFRS cases correlated to rodent density, rainfall, and temperature with 2, 3 and 4-month lags, respectively. Using a Bayesian time-series Poisson adjusted model, we fitted the HFRS outbreaks among humans for risk assessment in Xi'an. The best models included seasonality, autocorrelation, rodent density 2 months previously, and rainfall 2 to 3 months previously. Our models well reflected the epidemic characteristics by one step ahead prediction, out-of sample. CONCLUSIONS: In addition to a strong seasonal pattern, HFRS incidence was correlated with rodent density and rainfall, indicating that they potentially drive the HFRS outbreaks. Future work should aim to determine the mechanism underlying the seasonal pattern and autocorrelation. However, this model can be useful in risk management to provide early warning of potential outbreaks of this disease. PMID- 25822938 TI - Preferred supramolecular organization and dimer interfaces of opioid receptors from simulated self-association. AB - Substantial evidence in support of the formation of opioid receptor (OR) di /oligomers suggests previously unknown mechanisms used by these proteins to exert their biological functions. In an attempt to guide experimental assessment of the identity of the minimal signaling unit for ORs, we conducted extensive coarse grained (CG) molecular dynamics (MD) simulations of different combinations of the three major OR subtypes, i.e., MU-OR, delta-OR, and kappa-OR, in an explicit lipid bilayer. Specifically, we ran multiple, independent MD simulations of each homomeric MU-OR/MU-OR, delta-OR/delta-OR, and kappa-OR/kappa-OR complex, as well as two of the most studied heteromeric complexes, i.e., delta-OR/MU-OR and delta OR/kappa-OR, to derive the preferred supramolecular organization and dimer interfaces of ORs in a cell membrane model. These simulations yielded over 250 microseconds of accumulated data, which correspond to approximately 1 millisecond of effective simulated dynamics according to established scaling factors of the CG model we employed. Analysis of these data indicates similar preferred supramolecular organization and dimer interfaces of ORs across the different receptor subtypes, but also important differences in the kinetics of receptor association at specific dimer interfaces. We also investigated the kinetic properties of interfacial lipids, and explored their possible role in modulating the rate of receptor association and in promoting the formation of filiform aggregates, thus supporting a distinctive role of the membrane in OR oligomerization and, possibly, signaling. PMID- 25822939 TI - Tight junction protein claudin-6 inhibits growth and induces the apoptosis of cervical carcinoma cells in vitro and in vivo. AB - Claudin-6, a member of claudin family integral membrane proteins, has recently been reported to be a tumor suppressor for breast cancer. However, whether it plays a role in other types of cancer remains unclear. In the present study, we showed that the expression of claudin-6 is down-regulated in cervical carcinoma tissues as revealed by immunohistochemistry. Through over-expressing claudin-6 in HeLa and C33A cervical carcinoma cells, we found that claudin-6 is localized at plasma membrane and it increases transepithelial electrical resistance of the cells. Gain of claudin-6 expression suppresses cell proliferation, colony formation in vitro, and tumor growth in vivo. The effects are accompanied and potentially caused by promotion of tumor cell apoptosis. Taken together, these results suggest that claudin-6 may function as a tumor suppressor and loss of claudin-6 contributes to enhanced tumorigenic properties of cervical carcinoma cells. PMID- 25822940 TI - High prevalence of Hashimoto's thyroiditis in patients with polycystic ovary syndrome: does the imbalance between estradiol and progesterone play a role? AB - OBJECTIVE: Some similar factors, such as genetic susceptibility and subinflammation/autoimmunity, contribute to development of both polycystic ovary syndrome (PCOS) and Hashimoto's thyroiditis (HT), suggesting a potential pathogenic link between the two common disorders. In this study, we investigated the relationship between PCOS and HT, considering the possible effect of PCOS related hormonal and metabolic factors on thyroid autoimmunity. METHODS: Eighty six reproductive-age women diagnosed with PCOS according to Rotterdam criteria and 60 age-BMI matched control women were included in the study. All subjects had thyroid function tests, thyroid peroxidase anti-body (anti-TPO), thyroglobulin anti-body (anti-Tg), LH, FSH, estradiol, progesterone, androgens, fasting glucose, insulin, lipid, homeostasis model assessment insulin resistance (HOMA IR) levels, thyroid and pelvic ultrasounds. RESULTS: TSH, anti-TPO (p = 0.017), anti-Tg (p = 0.014), LH, DHEAS, testosterone, and HOMA-IR levels were significantly higher and progesterone were lower in PCOS women than in controls. Free T4, free T3, FSH, estradiol levels and thyroid volume were similar between the two groups. A higher percentage of PCOS patients had elevated TSH (26.7 and 5%; p = 0.001), anti-TPO (26.7 and 6.6%; p = 0.002), and anti-Tg (16.2 and 5%; p = 0.039). HT was more common in PCOS patients compared to controls (22.1 and 5%; p = 0.004). Estradiol (p = 0.003) were higher in anti-TPO positive PCOS women than anti-TPO negative ones. Anti-TPO was correlated positively with estradiol, estradiol/progesterone ratio, and TSH. CONCLUSIONS: This study demonstrated a higher prevalence of HT, elevated TSH, anti-TPO, and anti-Tg levels in PCOS patients. Increased estrogen and estrogen/progesterone ratio seem to be directly involved in high anti-TPO levels in PCOS patients. PMID- 25822941 TI - Different Resistance-Training Regimens Evoked a Similar Increase in Myostatin Inhibitors Expression. AB - The aim of the present study was to investigate the effect of different resistance-training regimens (S or P) on the expression of genes related to the MSTN signaling pathway in physically-active men. 29 male subjects with at least 2 years of experience in strength training were assigned to either a strength training group (S; n=11) or a power-training group (P; n=11). The control group (C; n=7) was composed of healthy physically-active males. The S and the P groups performed high- and low-intensity squats, respectively, 3 times per week, for 8 weeks. Muscle biopsies from the vastus lateralis muscle were collected before and after the training period. No change was observed in MSTN, ACTIIB, GASP-1 and FOXO-3 A gene expression after the training period. A similar increase in the gene expression of the inhibitory proteins of the MSTN signaling pathway, FLST (S: 4.2 fold induction and P: 3.7 fold induction, p<0.01) and FL-3 (S: 5.6 fold induction and P: 5.6 fold induction, p<0.01), was detected after the training period. SMAD-7 gene expression was similarly augmented after both training protocols (S: 2.5 fold induction; P: 2.8 fold induction; p<0.05). In conclusion, the resistance-training regimens (S and P) activated the expression of inhibitors of the MSTN signaling pathway in a similar manner. PMID- 25822942 TI - [In Process Citation]. PMID- 25822943 TI - [In Process Citation]. PMID- 25822944 TI - [In Process Citation]. PMID- 25822945 TI - [In Process Citation]. PMID- 25822946 TI - [Constructive learning theories and clinical apprenticeship]. AB - The article introduces how constructive learning theories as Constructive Alignment, Situated Learning and Cognitive Apprenticeship can explain learning during medical students' clinical placements and points out why Cognitive Apprenticeship can be particularly applicable in clinical psychiatry. This results in a discussion of the time frame, the organization of the placement in psychiatry at University of Copenhagen. PMID- 25822947 TI - [Emphysematous pyelonephritis in a non-diabetic patient with a kidney tumour]. AB - Emphysematous pyelonephritis (EPN) is a potentially life-threatening infection, where gas produced by bacteria accumulates in the kidney and the surrounding tissue. Although EPN usually presents in diabetic women, it is also associated with urinary tract obstruction and kidney tumours in non-diabetic patients. We present a case of EPN in a non-diabetic patient with a known kidney tumour, successfully treated with double-J catheter, antibiotics and delayed nephrectomy. PMID- 25822948 TI - [Hepato-pericardial fistula caused by radiofrequency ablation of colorectal liver metastases]. AB - Radiofrequency ablation (RFA) of colorectal liver metastases is a well tolerated minimally invasive procedure. Various complications can occur but most of these are self-limiting if diagnosed and treated in time. This case report describes a serious and rare complication following RFA treatment: hepato-pericardial fistula caused by several RFA procedures aiming to cure colorectal liver metastases. Complications to RFA treatment vary and can be difficult to diagnose. We recommend that RFA procedures and management of complications take place in highly specialised multidisciplinary departments. PMID- 25822949 TI - [A large abdomen can camouflage the symptoms of an ovarian tumour]. AB - Mucinous cystadenomas of the ovaries are benign tumours which can grow to sometimes gigantic proportions. Symptoms may be vague and due to complications hence the tumour can go undiagnosed for several years. This is a case report of a 48-year-old woman with a 40-kg ovarian tumour developed through 19 years. In spite of discomfort and complaints of the very large abdomen she had not received thorough examination previously. A large abdomen and discomfort should always lead to transabdominal ultrasound when transvaginal ultrasound - as in this case does not diagnose the condition. PMID- 25822950 TI - [Tuberculous meningitis presented by altered mental state and hydrocephalus]. AB - Tuberculous meningitis (TBM) denotes infection of the meninges with Mycobacterium tuberculosis complex. In Denmark, TBM is rare, but requires correct handling and rapid treatment. We describe a case of TBM in a previously healthy 19-year-old man from Somalia, whose primary symptoms were fever, headache and altered mental state. PMID- 25822951 TI - Development of an in vitro assay and demonstration of Plasmodium berghei liver stage inhibition by TRAP-specific CD8+ T cells. AB - The development of an efficacious vaccine against the Plasmodium parasite remains a top priority. Previous research has demonstrated the ability of a prime-boost virally vectored sub-unit vaccination regimen, delivering the liver-stage expressed malaria antigen TRAP, to produce high levels of antigen-specific T cells. The liver-stage of malaria is the main target of T cell-mediated immunity, yet a major challenge in assessing new T cell inducing vaccines has been the lack of a suitable pre-clinical assay. We have developed a flow-cytometry based in vitro T cell killing assay using a mouse hepatoma cell line, Hepa1-6, and Plasmodium berghei GFP expressing sporozoites. Using this assay, P. berghei TRAP specific CD8+ T cell enriched splenocytes were shown to inhibit liver-stage parasites in an effector-to-target ratio dependent manner. Further development of this assay using human hepatocytes and P. falciparum would provide a new method to pre-clinically screen vaccine candidates and to elucidate mechanisms of protection in vitro. PMID- 25822952 TI - Dissociation of eIF4E-binding protein 2 (4E-BP2) from eIF4E independent of Thr37/Thr46 phosphorylation in the ischemic stress response. AB - Eukaryotic initiation factor (eIF) 4E-binding proteins (4E-BPs) are translational repressors that bind specifically to eIF4E and are critical in the control of protein translation. 4E-BP2 is the predominant 4E-BP expressed in the brain, but their role is not well known. Here, we characterized four forms of 4E-BP2 detected by two-dimensional gel electrophoresis (2-DGE) in brain. The form with highest electrophoretic mobility was the main form susceptible to phosphorylation at Thr37/Thr46 sites, phosphorylation that was detected in acidic spots. Cerebral ischemia and subsequent reperfusion induced dephosphorylation and phosphorylation of 4E-BP2 at Thr37/Thr46, respectively. The induced phosphorylation was in parallel with the release of 4E-BP2 from eIF4E, although two of the phosphorylated 4E-BP2 forms were bound to eIF4E. Upon long-term reperfusion, there was a decrease in the binding of 4E-BP2 to eIF4E in cerebral cortex, demonstrated by cap binding assays and 4E-BP2-immunoprecipitation experiments. The release of 4E-BP2 from eIF4E was without changes in 4E-BP2 phosphorylation or other post-translational modification recognized by 2-DGE. These findings demonstrated specific changes in 4E-BP2/eIF4E association dependent and independent of 4E-BP2 phosphorylation. The last result supports the notion that phosphorylation may not be the uniquely regulation for the binding of 4E-BP2 to eIF4E under ischemic stress. PMID- 25822953 TI - Accuracy of contrast-enhanced ultrasound (CEUS) in the identification and characterization of traumatic solid organ lesions in children: a retrospective comparison with baseline US and CE-MDCT. AB - INTRODUCTION: Localized low-energy abdominal trauma is very frequent in the pediatric population. The findings of several studies have shown that ultrasonography (US) can represent a useful and cost-effective tool in the evaluation of blunt abdominal trauma both in adults and children. However, many parenchymal injuries are not correctly visualized at baseline US examination. The introduction of specific US contrast agents contrast-enhanced ultrasound (CEUS) has enabled a better identification of traumatic organ injuries. The correct use of CEUS could therefore identify and select the children who need further diagnostic investigation computed tomography (CT), avoiding unnecessary radiation and iodinated contrast medium exposure. The purpose of our study was to assess the sensibility and feasibility of CEUS in the assessment of low-energy abdominal trauma compared to baseline US in pediatric patients, using contrast-enhanced MDCT as the reference standard. MATERIALS AND METHODS: We retrospectively reviewed 73 children (51 M and 22 F; mean age 8.7 +/- 2.8 years) who presented in our Emergency Department between October 2012 and October 2013, with history of minor abdominal trauma according to the Abbreviated Injury Scale and who underwent US, CEUS, and CE-MDCT. Inclusion criteria were: male or female, aged 0 16, hemodynamically stable patients with a history of minor blunt abdominal trauma. Exclusion criteria were adulthood, hemodynamical instability, history of major trauma. Sensitivity, specificity, PPV, NPV, and accuracy were determined for US and CEUS compared to MDCT. RESULTS: 6/73 patients were negative at US, CEUS, and MDCT for the presence of organ injuries. In the remaining 67 patients, US depicted 26/67 parenchymal lesions. CEUS identified 67/67 patients (67/67) with parenchymal lesions: 21 lesions of the liver (28.8 %), 26 lesions of the spleen (35.6 %), 7 lesions of right kidney (9.6 %), 13 lesions of left kidney. MDCT confirmed all parenchymal lesions (67/67). Thus, the diagnostic performance of CEUS was better than that of US, as sensitivity, specificity, PPV, NPV, and accuracy were 100, 100, 100, 100, and 100 % for CEUS and 38.8, 100, 100, 12.8, and 44 % for US. In some patients CEUS identified also prognostic factors as parenchymal active bleeding in 8 cases, partial devascularization in 1 case; no cases of vascular bleeding, no cases of urinoma. MDCT confirmed all parenchymal lesions. Parenchymal active bleeding was identified in 16 cases, vascular bleeding in 2 cases, urinoma in 2 cases, partial devascularization in 1 case. CONCLUSIONS: CEUS is more sensitive and accurate than baseline US and almost as sensitive as CT in the identification and characterization of solid organs lesions in blunt abdominal trauma. CT is more sensitive and accurate than CEUS in identifying prognostic indicators, as active bleeding and urinoma. CEUS should be considered as a useful tool in the assessment and monitoring of blunt abdominal trauma in children. PMID- 25822954 TI - Performance of computer vision in vivo flow cytometry with low fluorescence contrast. AB - Detection and enumeration of circulating cells in the bloodstream of small animals are important in many areas of preclinical biomedical research, including cancer metastasis, immunology, and reproductive medicine. Optical in vivo flow cytometry (IVFC) represents a class of technologies that allow noninvasive and continuous enumeration of circulating cells without drawing blood samples. We recently developed a technique termed computer vision in vivo flow cytometry (CV IVFC) that uses a high-sensitivity fluorescence camera and an automated computer vision algorithm to interrogate relatively large circulating blood volumes in the ear of a mouse. We detected circulating cells at concentrations as low as 20 cells/mL. In the present work, we characterized the performance of CV-IVFC with low-contrast imaging conditions with (1) weak cell fluorescent labeling using cell-simulating fluorescent microspheres with varying brightness and (2) high background tissue autofluorescence by varying autofluorescence properties of optical phantoms. Our analysis indicates that CV-IVFC can robustly track and enumerate circulating cells with at least 50% sensitivity even in conditions with two orders of magnitude degraded contrast than our previous in vivo work. These results support the significant potential utility of CV-IVFC in a wide range of in vivo biological models. PMID- 25822955 TI - Imaging of nanoparticle-labeled stem cells using magnetomotive optical coherence tomography, laser speckle reflectometry, and light microscopy. AB - Cell transplantation and stem cell therapy are promising approaches for regenerative medicine and are of interest to researchers and clinicians worldwide. However, currently, no imaging technique that allows three-dimensional in vivo inspection of therapeutically administered cells in host tissues is available. Therefore, we investigate magnetomotive optical coherence tomography (MM-OCT) of cells labeled with magnetic particles as a potential noninvasive cell tracking method. We develop magnetomotive imaging of mesenchymal stem cells for future cell therapy monitoring. Cells were labeled with fluorescent iron oxide nanoparticles, embedded in tissue-mimicking agar scaffolds, and imaged using a microscope setup with an integrated MM-OCT probe. Magnetic particle-induced motion in response to a pulsed magnetic field of 0.2 T was successfully detected by OCT speckle variance analysis, and cross-sectional and volumetric OCT scans with highlighted labeled cells were obtained. In parallel, fluorescence microscopy and laser speckle reflectometry were applied as two-dimensional reference modalities to image particle distribution and magnetically induced motion inside the sample, respectively. All three optical imaging modalities were in good agreement with each other. Thus, magnetomotive imaging using iron oxide nanoparticles as cellular contrast agents is a potential technique for enhanced visualization of selected cells in OCT. PMID- 25822956 TI - The Year that Was-commentaries. PMID- 25822957 TI - Growth, maturation and exercise. PMID- 25822958 TI - Aerobic fitness and training in children. PMID- 25822959 TI - Resistance training in children. PMID- 25822960 TI - Elite youth sports. PMID- 25822961 TI - Physical activity, inactivity, and health. PMID- 25822962 TI - Psychosocial aspects of exercise and physical activity in childhood. PMID- 25822963 TI - Endocrinology and metabolism. PMID- 25822964 TI - Biomechanics and exercise. PMID- 25822965 TI - Cardiovascular physiology and disease in youth. PMID- 25822966 TI - Childhood obesity, physical activity, and exercise. PMID- 25822967 TI - Chronic diseases, exercise, and physical activity in childhood: off the beaten track. PMID- 25822968 TI - PYY3-36 and hunger responses to exercise in obese adolescent girls: which effects on effective energy intake? PMID- 25822969 TI - Lipopolysaccharide does not alter small airway reactivity in mouse lung slices. AB - The bacterial endotoxin, lipopolysaccharide (LPS) has been associated with occupational airway diseases with asthma-like symptoms and in acute exacerbations of COPD. The direct and indirect effects of LPS on small airway reactivity have not been fully elucidated. We tested the hypothesis that both in vitro and in vivo LPS treatment would increase contraction and impair relaxation of mouse small airways. Lung slices were prepared from naive Balb/C mice and cultured in the absence or presence of LPS (10 MUg/ml) for up to 48 h for measurement of TNFalpha levels in conditioned media. Alternatively, mice were challenged with PBS or LPS in vivo once a day for 4 days for preparation of lung slices or for harvest of lungs for Q-PCR analysis of gene expression of pro-inflammatory cytokines and receptors involved in airway contraction. Reactivity of small airways to contractile agonists, methacholine and serotonin, and bronchodilator agents, salbutamol, isoprenaline and rosiglitazone, were assessed using phase contrast microscopy. In vitro LPS treatment of slices increased TNFalpha release 6-fold but did not alter contraction or relaxation to any agonists tested. In vivo LPS treatment increased lung gene expression of TNFalpha, IL-1beta and ryanodine receptor isoform 2 more than 5-fold. However there were no changes in reactivity in lung slices from these mice, even when also incubated with LPS ex vivo. Despite evidence of LPS-induced inflammation, neither airway hyperresponsiveness or impaired dilator reactivity were evident. The increase in ryanodine receptor isoform 2, known to regulate calcium signaling in vascular smooth muscle, warrants investigation. Since LPS failed to elicit changes in small airway reactivity in mouse lung slices following in vitro or in vivo treatment, alternative approaches are required to define the potential contribution of this endotoxin to altered small airway reactivity in human lung diseases. PMID- 25822970 TI - Evaluation of Hs-CRP levels and interleukin 18 (-137G/C) promoter polymorphism in risk prediction of coronary artery disease in first degree relatives. AB - BACKGROUND: Coronary Artery Disease (CAD) is clearly a multifactorial disease that develops from childhood and ultimately leads to death. Several reports revealed having a First Degree Relatives (FDRS) with premature CAD is a significant autonomous risk factor for CAD development. C - reactive protein (CRP) is a member of the pentraxin family and is the most widely studied proinflammatory biomarker. IL-18 is a pleiotrophic and proinflammatory cytokine which is produced mainly by macrophages and plays an important role in the inflammatory cascade. METHODS AND RESULTS: Hs-CRP levels were estimated by ELISA and Genotyping of IL-18 gene variant located on promoter -137 (G/C) by Allele specific PCR in blood samples of 300 CAD patients and 300 controls and 100 FDRS. Promoter Binding sites and Protein interacting partners were identified by Alibaba 2.1 and Genemania online tools respectively. Hs-CRP levels were significantly high in CAD patients followed by FDRS when compared to controls. In IL-18 -137 (G/C) polymorphism homozygous GG is significantly associated with occurrence of CAD and Hs-CRP levels were significantly higher in GG genotype subjects when compared to GC and CC. IL-18 was found to be interacting with 100 protein interactants. CONCLUSION: Our results indicate that Hs-CRP levels and IL 18-137(G/C) polymorphism may help to identify risk of future events of CAD in asymptomatic healthy FDRS. PMID- 25822972 TI - The effect of iron ion on the specificity of photodynamic therapy with 5 aminolevulinic acid. AB - Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects. PMID- 25822971 TI - Transcriptomics of maternal and fetal membranes can discriminate between gestational-age matched preterm neonates with and without cognitive impairment diagnosed at 18-24 months. AB - BACKGROUND: Neurocognitive impairment among children born preterm may arise from complex interactions between genes and the intra-uterine environment. OBJECTIVES: (1) To characterize the transcriptomic profiles of chorioamniotic membranes in preterm neonates with and without neurocognitive impairment via microarrays and (2) to determine if neonates with neurocognitive impairment can be identified at birth. MATERIALS/METHODS: A retrospective case-control study was conducted to examine the chorioamniotic transcriptome of gestational-age matched very preterm neonates with and without neurocognitive impairment at 18-24 months' corrected age defined by a Bayley-III Cognitive Composite Score <80 (n = 14 each). Pathway analysis with down-weighting of overlapping genes (PADOG) was performed to identify KEGG pathways relevant to the phenotype. Select differentially expressed genes were profiled using qRT-PCR and a multi-gene disease prediction model was developed using linear discriminant analysis. The model's predictive performance was tested on a new set of cases and controls (n = 19 each). RESULTS: 1) 117 genes were differentially expressed among neonates with and without subsequent neurocognitive impairment (p<0.05 and fold change >1.5); 2) Gene ontology analysis indicated enrichment of 19 biological processes and 3 molecular functions; 3)PADOG identified 4 significantly perturbed KEGG pathways: oxidative phosphorylation, Parkinson's disease, Alzheimer's disease and Huntington's disease (q-value <0.1); 4) 48 of 90 selected differentially expressed genes were confirmed by qRT-PCR, including genes implicated in energy metabolism, neuronal signaling, vascular permeability and response to injury (e.g., up-regulation of SEPP1, APOE, DAB2, CD163, CXCL12, VWF; down-regulation of HAND1, OSR1)(p<0.05); and 5) a multi-gene model predicted 18-24 month neurocognitive impairment (using the ratios of OSR1/VWF and HAND1/VWF at birth) in a larger, independent set (sensitivity = 74%, at specificity = 83%). CONCLUSIONS: Gene expression patterns in the chorioamniotic membranes link neurocognitive impairment in preterm infants to neurodegenerative disease pathways and might be used to predict neurocognitive impairment. Further prospective studies are needed. PMID- 25822973 TI - Idealized computational models for auditory receptive fields. AB - We present a theory by which idealized models of auditory receptive fields can be derived in a principled axiomatic manner, from a set of structural properties to (i) enable invariance of receptive field responses under natural sound transformations and (ii) ensure internal consistency between spectro-temporal receptive fields at different temporal and spectral scales. For defining a time frequency transformation of a purely temporal sound signal, it is shown that the framework allows for a new way of deriving the Gabor and Gammatone filters as well as a novel family of generalized Gammatone filters, with additional degrees of freedom to obtain different trade-offs between the spectral selectivity and the temporal delay of time-causal temporal window functions. When applied to the definition of a second-layer of receptive fields from a spectrogram, it is shown that the framework leads to two canonical families of spectro-temporal receptive fields, in terms of spectro-temporal derivatives of either spectro-temporal Gaussian kernels for non-causal time or a cascade of time-causal first-order integrators over the temporal domain and a Gaussian filter over the logspectral domain. For each filter family, the spectro-temporal receptive fields can be either separable over the time-frequency domain or be adapted to local glissando transformations that represent variations in logarithmic frequencies over time. Within each domain of either non-causal or time-causal time, these receptive field families are derived by uniqueness from the assumptions. It is demonstrated how the presented framework allows for computation of basic auditory features for audio processing and that it leads to predictions about auditory receptive fields with good qualitative similarity to biological receptive fields measured in the inferior colliculus (ICC) and primary auditory cortex (A1) of mammals. PMID- 25822974 TI - The influence of diabetes, glycemic control, and diabetes-related comorbidities on pulmonary tuberculosis. AB - BACKGROUND: To assess the influence of diabetes mellitus (DM), glycemic control, and diabetes-related comorbidities on manifestations and outcome of treatment of pulmonary tuberculosis (TB). METHODOLOGY/PRINCIPAL FINDINGS: Culture positive pulmonary TB patients notified to health authorities in three hospitals in Taiwan from 2005-2010 were investigated. Glycemic control was assessed by glycated haemoglobin A1C (HbA1C) and diabetic patients were categorized into 3 groups: HbA1C<7%, HbA1C 7-9%, HbA1C>9%. 1,473 (705 with DM and 768 without DM) patients were enrolled. Of the 705 diabetic patients, 82 (11.6%) had pretreatment HbA1C<7%, 152 (21.6%) 7%-9%, 276 (39.2%) >9%, and 195 (27.7%) had no information of HbA1C. The proportions of patients with any symptom, cough, hemoptysis, tiredness and weight loss were all highest in diabetic patients with HbA1C>9%. In multivariate analysis adjusted for age, sex, smoking, and drug resistance, diabetic patients with HbA1C>9% (adjOR 3.55, 95% CI 2.40-5.25) and HbA1C 7-9% (adjOR 1.62, 95% CI 1.07-2.44) were significantly more likely to be smear positive as compared with non-diabetic patients, but not those with HbA1C<7% (adjOR 1.16, 95% CI 0.70-1.92). The influence of DM on outcome of TB treatment was not proportionately related to HbA1C, but mainly mediated through diabetes related comorbidities. Patients with diabetes-related comorbidities had an increased risk of unfavorable outcome (adjOR 3.38, 95% CI 2.19-5.22, p<0.001) and one year mortality (adjOR 2.80, 95% CI 1.89-4.16). However, diabetes was not associated with amplification of resistance to isoniazid (p = 0.363) or to rifampicin (p = 0.344). CONCLUSIONS/SIGNIFICANCE: Poor glycemic control is associated with poor TB treatment outcome and improved glycemic control may reduce the influence of diabetes on TB. PMID- 25822975 TI - High prevalence of nickel allergy in an overweight female population: a pilot observational analysis. AB - CONTEXT: In our Allergy Unit, we incidentally observed that a low Nickel diet, prescribed for delayed allergy to Nickel sulfate, reduced body mass index (BMI) and waist circumference in overweight patients. OBJECTIVES: This pilot cross sectional analysis was undertaken to compare the prevalence of Nickel allergy of overweight individuals versus the general population. We also had the chance to report the efficacy of a low Nickel diet on BMI and waist circumference in Nickel sensitive overweight subjects. METHODS: Eighty-seven overweight subjects, with a BMI > 26 Kg/m2, were consecutively enrolled in a health prevention program, and screened for the presence of Nickel allergy. The enrolled population was mostly females (72/87) (82.8%). Forty-three overweight women and two men showed a Nickel allergy and started a low Nickel diet. After 6-months of dieting, 24 overweight allergic women could be traced and changes in BMI and waist circumference were calculated. MAIN OUTCOME MEASUREMENTS: Prevalence of Nickel allergy in overweight. RESULTS: Prevalence of Nickel allergy in overweight female was 59.7%, compared with a prevalence rate of 12.5% in the general population. A significant reduction in BMI was observed in 24 out of 43 overweight females with Nickel allergy after 24 weeks of a low Nickel diet. Relative to baseline, mean BMI decrease was 4.2 +/- 0.5 (P < 0.001) and the mean decline in waist circumference was 11.7 +/- 0.6 cm (P < 0.001). CONCLUSIONS: This pilot observational analysis showed a substantially higher prevalence of Nickel allergy among overweight females, especially those with metabolic syndrome and fatty liver disease. A normocaloric low Nickel diet was effective in reducing BMI in this population. Further research is strongly needed to confirm these preliminary findings. PMID- 25822976 TI - Correction: Deep mRNA sequencing of the Tritonia diomedea brain transcriptome provides access to gene homologues for neuronal excitability, synaptic transmission and peptidergic signalling. PMID- 25822977 TI - Effect of C282Y genotype on self-reported musculoskeletal complications in hereditary hemochromatosis. AB - OBJECTIVE: Arthropathy that mimics osteoarthritis (OA) and osteoporosis (OP) is considered a complication of hereditary hemochromatosis (HH). We have limited data comparing OA and OP prevalence among HH patients with different hemochromatosis type 1 (HFE) genotypes. We investigated the prevalence of OA and OP in patients with HH by C282Y homozygosity and compound heterozygosity (C282Y/H63D) genotype. METHODS: A total of 306 patients with HH completed a questionnaire. Clinical and demographic characteristics and presence of OA, OP and related complications were compared by genotype, adjusting for age, sex, body mass index (BMI), current smoking and menopausal status. RESULTS: In total, 266 of the 306 patients (87%) were homozygous for C282Y, and 40 (13%) were compound heterozygous. The 2 groups did not differ by median age [60 (interquartile range [IQR] 53 to 68) vs. 61 (55 to 67) years, P=0.8], sex (female: 48.8% vs. 37.5%, P=0.18) or current smoking habits (12.4% vs. 10%, P=0.3). As compared with compound heterozygous patients, C282Y homozygous patients had higher median serum ferritin concentration at diagnosis [1090 (IQR 610 to 2210) vs. 603 (362 to 950) ug/L, P<0.001], higher median transferrin saturation [80% (IQR 66 to 91%) vs. 63% (55 to 72%), P<0.001]) and lower median BMI [24.8 (22.1 to 26.9) vs. 26.2 (23.5 to 30.3) kg/m2, P<0.003]. The overall prevalence of self-reported OA was significantly higher with C282Y homozygosity than compound heterozygosity (53.4% vs. 32.5%; adjusted odds ratio [aOR] 2.4 [95% confidence interval 1.2-5.0]), as was self-reported OP (25.6% vs. 7.5%; aOR 3.5 [1.1-12.1]). CONCLUSION: Patients with C282Y homozygosity may be at increased risk of musculoskeletal complications of HH. PMID- 25822978 TI - Patient characteristics associated with measurement of routine diabetes care: an observational study. AB - BACKGROUND: Non-modifiable patient characteristics, including age, gender, ethnicity as well as the occurrence of multi-morbidities, are associated with processes and outcomes of diabetes care. Information on these factors can be used in case mix adjustment of performance measures. However, the practical relevance of such adjustment is not clear. The aim of this study was to assess the strength of associations between patient factors and diabetes care processes and outcomes. METHODS: We performed an observational study based on routinely collected data of 12,498 diabetes patients in 59 Dutch primary care practices. Data were collected on patient age, gender, whether the patient lived in a deprived area, body mass index and the co-occurrence of cardiovascular disease, chronic obstructive pulmonary disease, depression or anxiety. Outcomes included 6 dichotomous measures (3 process and 3 outcome related) regarding glycosylated hemoglobin, systolic blood pressure and low density lipoprotein-cholesterol. We performed separate hierarchical logistic mixed model regression models for each of the outcome measures. RESULTS: Each of the process measure models showed moderate effect sizes, with pooled areas under the curve that varied between 0.66 and 0.76. The frequency of diabetes related consultations as a measure of patient compliance to treatment showed the strongest association with all process measures (odds ratios between 5.6 and 14.5). The effect sizes of the outcome measure models were considerably smaller than the process measure models, with pooled areas under the curve varying from 0.57 to 0.61. CONCLUSIONS: Several non modifiable patient factors could be associated with processes and outcomes of diabetes care. However, associations were small. These results suggest that case mix correction or stratification in assessing diabetes care has limited practical relevance. PMID- 25822979 TI - Chronic testosterone replacement exerts cardioprotection against cardiac ischemia reperfusion injury by attenuating mitochondrial dysfunction in testosterone deprived rats. AB - BACKGROUND: Although testosterone deficiency is associated with increased risks of heart disease, the benefits of testosterone therapy are controversial. Moreover, current understanding on the cardiac effect of testosterone during cardiac ischemia-reperfusion (I/R) periods is unclear. We tested the hypothesis that testosterone replacement attenuates the impairment of left ventricular (LV) function and heart rate variability (HRV), and reduces the infarct size and arrhythmias caused by I/R injury in orchiectomized (ORX) rats. METHODOLOGY: ORX or sham-operated male Wistar rats (n = 24) were randomly divided and received either testosterone (2 mg/kg, subcutaneously administered) or the vehicle for 8 weeks. The ejection fraction (EF) and HRV were determined at baseline and the 4th and 8th week. I/R was performed by left anterior descending coronary artery ligation for 30 minutes, followed by a 120-minute reperfusion. LV pressure, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. RESULTS: Prior to I/R, EF and HRV were impaired in the ORX group, but were restored in the testosterone-treated group. During I/R, arrhythmia scores and the infarct size were greater, and cardiac mitochondrial function was impaired, whereas the time to 1st VT/VF onset and the LV end-systolic pressure were decreased in the ORX group when compared to the sham group. Testosterone replacement attenuated the impairment of these parameters in ORX rats during I/R injury, but did not show any benefit or adverse effect in non-ORX rats. CONCLUSIONS: Testosterone replacement restores cardiac function and autonomic regulation, and exerts cardioprotective effects during the I/R period via mitochondrial protection in ORX rats. PMID- 25822980 TI - Overexpression of AtTTP affects ARF17 expression and leads to male sterility in Arabidopsis. AB - Callose synthesis is critical for the formation of the pollen wall pattern. CalS5 is thought to be the major synthethase for the callose wall. In the Arabidopsis anther, ARF17 regulates the expression of CalS5 and is the target of miR160. Plants expressing miR160-resistant ARF17 (35S:5mARF17 lines) with increased ARF17 mRNA levels display male sterility. Here we report a zinc finger family gene, AtTTP, which is involved in miR160 maturation and callose synthesis in Arabidopsis. AtTTP is expressed in microsporocytes, tetrads and tapetal cells in the anther. Over-expression lines of AtTTP (AtTTP-OE line) exhibited reduced male fertility. CalS5 expression was tremendously reduced and the tetrad callose wall became much thinner in the AtTTP-OE line. Northern blotting hybridization and quantitative RT-PCR analysis revealed that miR160 was decreased, while the expression of ARF17 was increased in the AtTTP-OE line. Based on these results, we propose that AtTTP associates with miR160 in order to regulate the ARF17 expression needed for callose synthesis and pollen wall formation. PMID- 25822982 TI - Nonaqueous System of Iron-Based Ionic Liquid and DMF for the Oxidation of Hydrogen Sulfide and Regeneration by Electrolysis. AB - To improve the hydrogen sulfide removal efficiency with the application of an iron-based imidazolium chloride ionic liquid (Fe(III)-IL) as desulfurizer, Fe(II) and N,N-dimethylformamide (DMF) are introduced to Fe(III)-IL to construct a new nonaqueous desulfurization system (Fe(III/II)-IL/DMF). Following desulfurization, the system can be regenerated using the controlled-potential electrolysis method. The addition of Fe(II) in Fe(III)-IL is beneficial for the hydrogen sulfide removal and the electrochemical regeneration of the desulfurizer. The addition of DMF in Fe(III/II)-IL does not change the structure of Fe(III/II)-IL but clearly decreases the acidity, increases the electrolytic current, and decreases the stability of the Fe-Cl bond in Fe(III/II)-IL. Fe(III/II)-IL/DMF can remove hydrogen sulfide and can be regenerated through an electrochemical method more efficiently than can Fe(III/II)-IL. After six cycles, the desulfurization efficiency remains higher than 98%, and the average conversion rate of Fe(II) is essentially unchanged. No sulfur peroxidation occurs, and the system remains stable. Therefore, this new nonaqueous system has considerable potential for removing H2S in pollution control applications. PMID- 25822981 TI - Examining the species-specificity of rhesus macaque cytomegalovirus (RhCMV) in cynomolgus macaques. AB - Cytomegalovirus (CMV) is a highly species-specific virus that has co-evolved with its host over millions of years and thus restricting cross-species infection. To examine the extent to which host restriction may prevent cross-species research between closely related non-human primates, we evaluated experimental infection of cynomolgus macaques with a recombinant rhesus macaque-derived CMV (RhCMV eGFP). Twelve cynomolgus macaques were randomly allocated to three groups: one experimental group (RhCMV-eGFP) and two control groups (UV-inactivated RhCMV-eGFP or media alone). The animals were given two subcutaneous inoculations at week 0 and week 8, and a subset of animals received an intravenous inoculation at week 23. No overt clinical or haematological changes were observed and PBMCs isolated from RhCMV-eGFP inoculated animals had comparable eGFP- and IE-1-specific cellular responses to the control animals. Following inoculation with RhCMV-eGFP, we were unable to detect evidence of infection in any blood or tissue samples up to 4 years post-inoculation, using sensitive viral co-culture, qPCR, and Western blot assays. Co-culture of urine and saliva samples demonstrated the presence of endogenous cynomolgus CMV (CyCMV) cytopathic effect, however no concomitant eGFP expression was observed. The absence of detectable RhCMV-eGFP suggests that the CyCMV-seropositive cynomolgus macaques were not productively infected with RhCMV eGFP under these inoculation conditions. In a continued effort to develop CMV as a viral vector for an HIV/SIV vaccine, these studies demonstrate that CMV is highly restricted to its host species and can be highly affected by laboratory cell culture. Consideration of the differences between lab-adapted and primary viruses with respect to species range and cell tropism should be a priority in evaluating CMV as vaccine vector for HIV or other pathogens at the preclinical development stage. PMID- 25822984 TI - Forces and straw cutting performance of double disc furrow opener in no-till paddy soil. AB - Conservation tillage is an energy efficient and low cost tillage system to improve soil environment compared with conventional tillage systems. However, the rice residue management becomes an "impossible to achieve" task due to high soil moisture content at harvest time and the thickness of rice straw. Disc type furrow openers are used for both seed drilling as well as straw cutting during no tillage sowing. A study was conducted to evaluate the draft requirement and straw cutting performances of different sized furrow openers in no-till paddy soil conditions. Double disc furrow opener was tested on an in-field traction bench for three working depths, i.e. 30, 60 and 90 mm, and three forwarding speeds, i.e. 0.1, 0.2 and 0.3 m/s. The draft and vertical forces on the disc were recorded with load cells. These sensors were connected to a data acquisition system developed with hardware and software. The results revealed that the size of the furrow opener, operating depth and the forwarding speed had significant effects (P<0.05) on the horizontal and vertical forces, and the straw cutting performance. Mean values of the draft were 648.9, 737.2 and 784.6 N for the opener with diameters of 330, 450 and 600 mm respectively, and the vertical forces for similar openers were 904.7, 1553.9 and 1620.4 N, respectively. Furthermore, the mean straw cutting efficiencies for the double disc opener with diameters of 330, 450 and 600 mm were 39.36, 78.47 and 65.46%, respectively. The opener with 450 mm diameter provided higher straw cutting efficiency as compared to 600 mm diameter disc, while lowest straw cutting efficiency was observed with 330 mm diameter disc. The 450 mm diameter opener provided the highest straw cutting efficiency (88.6%) at 90 mm working depth and expressed optimum performance compared with other furrow openers. PMID- 25822983 TI - Development of colloidal gold immunochromatographic strips for detection of Riemerella anatipestifer. AB - Riemerella anatipestifer is one of the most important bacterial pathogen of ducks and causes a contagious septicemia. R. anatipestifer infection causes serositis syndromes similar to other bacterial infections in ducks, including infection by Escherichia coli, Salmonella enterica and Pasteurella multocida. Clinically differentiating R. anatipestifer infections from other bacterial pathogen infections is usually difficult. In this study, MAb 1G2F10, a monoclonal antibody against R. anatipestifer GroEL, was used to develop a colloidal gold immunochromatographic strip. Colloidal gold particles were prepared by chemical synthesis to an average diameter of 20 +/- 5.26 nm by transmission electron microscope imaging. MAb 1G2F10 was conjugated to colloidal gold particles and the formation of antibody-colloidal gold conjugates was monitored by UV/Vis spectroscopy. Immunochromatographic strips were assembled in regular sequence through different accessories sticked on PVC plate. Strips specifically detected R. anatipestifer within 10 min, but did not detect E. coli, S. enterica and P. multocida. The detection limit for R. anatipestifer was 1 * 10(6) colony forming units, which was 500 times higher than a conventional agglutination test. Accuracy was 100% match to multiplex PCR. Assay stability and reproducibility were excellent after storage at 4 degrees C for 6 months. The immunochromatographic strips prepared in this study offer a specific, sensitive, and rapid detection method for R. anatipestifer, which is of great importance for the prevention and control of R. anatipestifer infections. PMID- 25822985 TI - Sulcus-based MR analysis of focal cortical dysplasia located in the central region. AB - OBJECTIVE: Focal cortical dysplasias (FCDs) are mainly located in the frontal region, with a particular tropism for the central sulcus. Up to 30% of lesions are undetected (magnetic resonance [MR]-negative FCD patients) or belatedly diagnosed by visual analysis of MR images. We propose an automated sulcus-based method to analyze abnormal sulcal patterns associated with central FCD, taking into account the normal interindividual sulcal variability. METHODS: We retrospectively studied 29 right-handed patients with FCD in the central region (including 12 MR negative histologically-confirmed cases) and 29 right-handed controls. The analysis of sulcal abnormalities from T1-weighted MR imaging (MRI) was performed using a graph-based representation of the cortical folds and an automated sulci recognition system, providing a new quantitative criterion to describe sulcal patterns, termed sulcus energy. RESULTS: Group analysis showed that the central sulcus in the hemisphere ipsilateral to the FCD exhibited an abnormal sulcal pattern compared with controls (p = 0.032). FCDs were associated with abnormal patterns of the central sulci compared with controls (p = 0.006), a result that remained significant when MR-negative and MR-positive patients were considered separately, while the effects of sex, age and MR-field were not significant. At the individual level, sulcus energy alone failed to detect the FCD lesion. We found, however, a significant association between maximum z-scores and the site of FCD (p = 0.0046) which remained significant in MR-negative (p = 0.024) but not in MR-positive patients (p = 0.058). The maximum z-score pointed to an FCD sulcus in four MR-negative and five MR-positive patients. CONCLUSIONS: We identified abnormal sulcal patterns in patients with FCD of the central region compared with healthy controls. The abnormal sulcal patterns ipsilateral to the FCD and the link between sulcus energy and the FCD location strengthen the interest of sulcal abnormalities in FCD patients. PMID- 25822987 TI - Relative abundance of and composition within fungal orders differ between cheatgrass (Bromus tectorum) and sagebrush (Artemisia tridentata)-associated soils. AB - Nonnative Bromus tectorum (cheatgrass) is decimating sagebrush steppe, one of the largest ecosystems in the Western United States, and is causing regional-scale shifts in the predominant plant-fungal interactions. Sagebrush, a native perennial, hosts arbuscular mycorrhizal fungi (AMF), whereas cheatgrass, a winter annual, is a relatively poor host of AMF. This shift is likely intertwined with decreased carbon (C)-sequestration in cheatgrass-invaded soils and alterations in overall soil fungal community composition and structure, but the latter remain unresolved. We examined soil fungal communities using high throughput amplicon sequencing (ribosomal large subunit gene) in the 0-4 cm and 4-8 cm depth intervals of six cores from cheatgrass- and six cores from sagebrush-dominated soils. Sagebrush core surfaces (0-4 cm) contained higher nitrogen and total C than cheatgrass core surfaces; these differences mirrored the presence of glomalin related soil proteins (GRSP), which has been associated with AMF activity and increased C-sequestration. Fungal richness was not significantly affected by vegetation type, depth or an interaction of the two factors. However, the relative abundance of seven taxonomic orders was significantly affected by vegetation type or the interaction between vegetation type and depth. Teloschistales, Spizellomycetales, Pezizales and Cantharellales were more abundant in sagebrush libraries and contain mycorrhizal, lichenized and basal lineages of fungi. Only two orders (Coniochaetales and Sordariales), which contain numerous economically important pathogens and opportunistic saprotrophs, were more abundant in cheatgrass libraries. Pleosporales, Agaricales, Helotiales and Hypocreales were most abundant across all libraries, but the number of genera detected within these orders was as much as 29 times lower in cheatgrass relative to sagebrush libraries. These compositional differences between fungal communities associated with cheatgrass- and sagebrush-dominated soils warrant future research to examine soil fungal community composition across more sites and time points as well as in association with native grass species that also occupy cheatgrass-invaded ecosystems. PMID- 25822986 TI - Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity. AB - Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens. PMID- 25822988 TI - The A allele of cluster of differentiation 36 (CD36) SNP 1761667 associates with decreased lipid taste perception in obese Tunisian women. AB - Recent studies have suggested that excessive intake of dietary fat is associated with obesity. Some obese subjects have been reported to exhibit high thresholds for the gustatory detection of lipids via lipid receptors, such as cluster of differentiation 36 (CD36). We studied lingual detection thresholds for emulsions containing oleic acid in obese Tunisian women (n 203) using a three-alternative forced choice (3-AFC) method. Genotyping of the TNF-alpha (rs1800629), IL-6 (rs1800795) and CD36 (rs1761667) genes was performed to associate with lipid taste perception thresholds. The CD36 genotype distribution was as follows: GG (n 42), AG (n 102) and AA (n 59). Women with the CD36 GG genotype exhibited oral detection thresholds for oleic acid that were more than three times lower than those with the CD36 AA genotype. The present study confirms a high threshold of gustatory fat detection in obese women with the CD36 AA genotype, but there is no significant association with the IL-6 and TNF-alpha gene polymorphisms. PMID- 25822990 TI - High-risk medical devices: why do we not better understand effectiveness and safety? PMID- 25822989 TI - Sprouty2 in the dorsal hippocampus regulates neurogenesis and stress responsiveness in rats. AB - Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress related disorders. PMID- 25822991 TI - Elicitation of expert prior opinion: application to the MYPAN trial in childhood polyarteritis nodosa. AB - OBJECTIVES: Definitive sample sizes for clinical trials in rare diseases are usually infeasible. Bayesian methodology can be used to maximise what is learnt from clinical trials in these circumstances. We elicited expert prior opinion for a future Bayesian randomised controlled trial for a rare inflammatory paediatric disease, polyarteritis nodosa (MYPAN, Mycophenolate mofetil for polyarteritis nodosa). METHODS: A Bayesian prior elicitation meeting was convened. Opinion was sought on the probability that a patient in the MYPAN trial treated with cyclophosphamide would achieve disease remission within 6-months, and on the relative efficacies of mycophenolate mofetil and cyclophosphamide. Expert opinion was combined with previously unseen data from a recently completed randomised controlled trial in ANCA associated vasculitis. RESULTS: A pan-European group of fifteen experts participated in the elicitation meeting. Consensus expert prior opinion was that the most likely rates of disease remission within 6 months on cyclophosphamide or mycophenolate mofetil were 74% and 71%, respectively. This prior opinion will now be taken forward and will be modified to formulate a Bayesian posterior opinion once the MYPAN trial data from 40 patients randomised 1:1 to either CYC or MMF become available. CONCLUSIONS: We suggest that the methodological template we propose could be applied to trial design for other rare diseases. PMID- 25822992 TI - Atomic structure of the Y complex of the nuclear pore. AB - The nuclear pore complex (NPC) is the principal gateway for transport into and out of the nucleus. Selectivity is achieved through the hydrogel-like core of the NPC. The structural integrity of the NPC depends on ~15 architectural proteins, which are organized in distinct subcomplexes to form the >40-MDa ring-like structure. Here we present the 4.1-A crystal structure of a heterotetrameric core element ('hub') of the Y complex, the essential NPC building block, from Myceliophthora thermophila. Using the hub structure together with known Y-complex fragments, we built the entire ~0.5-MDa Y complex. Our data reveal that the conserved core of the Y complex has six rather than seven members. Evolutionarily distant Y-complex assemblies share a conserved core that is very similar in shape and dimension, thus suggesting that there are closely related architectural codes for constructing the NPC in all eukaryotes. PMID- 25822993 TI - Atomic structures of a bactericidal contractile nanotube in its pre- and postcontraction states. AB - R-type pyocins are representatives of contractile ejection systems, a class of biological nanomachines that includes, among others, the bacterial type VI secretion system (T6SS) and contractile bacteriophage tails. We report atomic models of the Pseudomonas aeruginosa precontraction pyocin sheath and tube, and the postcontraction sheath, obtained by cryo-EM at 3.5-A and 3.9-A resolutions, respectively. The central channel of the tube is negatively charged, in contrast to the neutral and positive counterparts in T6SSs and phage tails. The sheath is interwoven by long N- and C-terminal extension arms emanating from each subunit, which create an extensive two-dimensional mesh that has the same connectivity in the extended and contracted state of the sheath. We propose that the contraction process draws energy from electrostatic and shape complementarities to insert the inner tube through bacterial cell membranes to eventually kill the bacteria. PMID- 25822994 TI - Genome-wide survey and expression analysis of Chlamydomonas reinhardtii U-box E3 ubiquitin ligases (CrPUBs) reveal a functional lipid metabolism module. AB - E3 ubiquitin ligases determine the substrate specificity of ubiquitination. Plant U-box (PUB) E3 ligases, with a typical 70-amino acid U-box domain, participate in plant developmental processes and environmental responses. Thus far, 64 PUB proteins have been identified in Arabidopsis and 77 PUB proteins have been identified in Oryza. However, detailed studies on U-box genes in the model microalgae Chlamydomonas reinhardtii are lacking. Here, we present a comprehensive analysis of the genes encoding U-box family proteins in C. reinhardtii. Following BLASTP analysis, 30 full-length U-box genes were identified in the C. reinhardtii genome sequence. Bioinformatics analyses of CrPUB genes were performed to characterize the phylogenetic relationships, chromosomal locations and gene structures of each member. The 30 identified CrPUB proteins are clustered into 3 distinct subfamilies, and the genes for these proteins are unevenly distributed among 14 chromosomes. Furthermore, the quantitative real-time RT-PCR or semi-quantitative RT-PCR analysis of 30 CrPUB mRNA abundances under nitrogen starvation showed that 18 CrPUB genes were induced by N starvation and that 7 genes were repressed in the N-poor environment. We selected five CrPUB genes exhibiting marked changes in expression under N-free conditions for further analysis in RNAi experiments and examined the oil content of these gene-silenced transgenic strains. The silencing of CrPUB5 and CrPUB14, which are typically down-regulated under N starvation, induced 9.8%-45.0% and 14.4%-61.8% lipid accumulation, respectively. In contrast, the silencing of CrPUB11, CrPUB23 and CrPUB28, which are markedly up-regulated under N-free conditions, decreased the lipid content by 5.5%-27.8%, 8.1%-27.3% and 6.6%-27.9%, respectively. These results provide a useful reference for the identification and functional analysis of this gene family and fundamental information for microalgae lipid metabolism research. PMID- 25822995 TI - Individual polyp detection rate in routine daily endoscopy practice depends on case-mix. AB - INTRODUCTION: The adenoma detection rate (ADR), a marker of endoscopic quality, is confounded by selection bias. It is not known what the ADR is in normal daily practice. AIM: To study the polyp detection rate (PDR) in different endoscopists in the course of years. PATIENTS AND METHODS: All consecutive endoscopies of the colon done in 11 years were included. Endoscopies in the regular surveillance programme after polyp removal and after surgery because of colorectal cancer or diverticular disease were scored separately. The number of yearly procedures per endoscopist and presence of polyps, anastomoses, surveillance and cancer were noted. RESULTS: In the period of 11 years, 14,908 consecutive endoscopies of colon and rectum were done by four endoscopists. Two endoscopists had a significantly lower PDR than the other two (p < 0.001), these two had the longest careers in endoscopy. The two younger endoscopists did significantly less often procedures in patients with anastomoses and because of surveillance (p < 0.001, respectively). One endoscopist detected significantly less colorectal cancers than the other three endoscopists (p < 0.001). CONCLUSION: This study presents the PDR in normal routine daily endoscopy practice. It can be concluded that the PDR, implicating the ADR, in unselected patients can be lower in individual endoscopists than recommended in the literature. This highly depends on the case mix of patients presented for endoscopy. This result debates the use of the ADR as quality indicator for individual endoscopists. PMID- 25822996 TI - Patient-reported outcomes in ANCA-associated vasculitis. A comparison between Birmingham Vasculitis Activity Score and routine assessment of patient index data 3. AB - The objective of this study was to determine health-related quality of life (HRQoL) in patients with ANCA-associated vasculitis (AAV) as measured by the "routine assessment of patient index data 3" (RAPID3) and whether RAPID3 is correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). Data from patients at an academic institution vasculitis clinic seen between Jan 2010 and Jan 2012 were collected using chart review. BVAS and RAPID3 scores were calculated at each patient visit. RAPID3 was compared between patients in remission (BVAS = 0) and patients with active disease (BVAS > =1) at all visits for four consecutive visits, when data available, at least 3 months apart during the period mentioned. Robust generalized estimating equations (GEE) in linear regression models evaluated associations between the RAPID3 and BVAS over all available observations, adjusting for intra-subject correlations. Thirty-four patients were included in the study, 26 had granulomatosis with polyangiitis (GPA), five microscopic polyangiitis (MPA), and three eosinophilic granulomatosis with polyangiitis (EGPA). Patients at first visit had impaired HRQoL as measured by RAPID3 [6.8 (3.1-12.6)]. The median RAPID3 scores were higher in patients with active disease as compared to patients in remission (7.0 vs. 3.0, p = 0.115; 8.8 vs. 1.0, p = 0.011; 6.1 vs. 2.0, p = 0.032; and 11.7 vs. 2.0, p = 0.128 for visits 1, 2, 3, and 4, respectively). In longitudinal GEE models incorporating all observations there was a strong association between the RAPID3 (per 1 unit) and BVAS (per 1 unit) [beta 0.21 (0.10, 0.32) p < 0.001]. RAPID3 can be used to measure HRQoL in patients with AAV. RAPID3 correlated significantly with BVAS. RAPID3 can discriminate between disease states in AAV. This instrument may help document patient experience and add to clinical decisions. PMID- 25822997 TI - Commercial cow milk contains physically stable extracellular vesicles expressing immunoregulatory TGF-beta. AB - SCOPE: Extracellular vesicles, including exosomes, have been identified in all biological fluids and rediscovered as an important part of the intercellular communication. Breast milk also contains extracellular vesicles and the proposed biological function is to enhance the antimicrobial defense in newborns. It is, however, unknown whether extracellular vesicles are still present in commercial milk and, more importantly, whether they retained their bioactivity. Here, we characterize the extracellular vesicles present in semi-skimmed cow milk available for consumers and study their effect on T cells. METHODS AND RESULTS: Extracellular vesicles from commercial milk were isolated and characterized. Milk derived extracellular vesicles contained several immunomodulating miRNAs and membrane protein CD63, characteristics of exosomes. In contrast to RAW 267.4 derived extracellular vesicles the milk-derived extracellular vesicles were extremely stable under degrading conditions, including low pH, boiling and freezing. Milk-derived extracellular vesicles were easily taken up by murine macrophages in vitro. Furthermore, we found that they can facilitate T cell differentiation towards the pathogenic Th17 lineage. Using a (CAGA)12-luc reporter assay we showed that these extracellular vesicles carried bioactive TGF beta, and that anti-TGF-beta antibodies blocked Th17 differentiation. CONCLUSION: Our findings show that commercial milk contains stable extracellular vesicles, including exosomes, and carry immunoregulatory cargo. These data suggest that the extracellular vesicles present in commercial cow milk remains intact in the gastrointestinal tract and exert an immunoregulatory effect. PMID- 25822998 TI - Insights into the skeletonization, lifestyle, and affinity of the unusual Ediacaran fossil Corumbella. AB - The Ediacaran fossil Corumbella is important because it is hypothesized to be a scyphozoan cnidarian, and thus might be one of the rare examples of bona fide Neoproterozoic animals. Unfortunately, its mode of life, style of skeletonization, and taxonomic affinity have been very controversial. Here, we use X-ray micro-CT, SEM, and taphonomic analysis to compare preservational modes of Corumbella, in order to better understand the symmetry, mode of construction, preservational style, and taxonomy of this group. Results suggest that articulated and disarticulated specimens of Corumbella from the Ediacaran of Brazil, Paraguay, and the United States, although sometimes preserved very differently, represent the same taxon--Corumbella werneri. Corumbellids had a thick but flexible theca and probably lived with their basalmost part anchored in the sediment, much like Conotubus. When considered together, these results suggest that Corumbella was one of the first animals to build a skeleton, employing a lamellar microfabric similar to conulariids. PMID- 25822999 TI - Coiled coil rich proteins (Ccrp) influence molecular pathogenicity of Helicobacter pylori. AB - Pathogenicity of the human pathogen Helicobacter pylori relies on its capacity to adapt to a hostile environment and to escape the host response. Although there have been great advances in our understanding of the bacterial cytoskeleton, major gaps remain in our knowledge of its contribution to virulence. In this study we have explored the influence of coiled coil rich proteins (Ccrp) cytoskeletal elements on pathogenicity factors of H. pylori. Deletion of any of the ccrp resulted in a strongly decreased activity of the main pathogenicity factor urease. We further investigated their role using in vitro co-culture experiments with the human gastric adenocarcinoma cell line AGS modeling H. pylori - host cell interactions. Intriguingly, host cell showed only a weak "scattering/hummingbird" phenotype, in which host cells are transformed from a uniform polygonal shape into a severely elongated state characterized by the formation of needle-like projections, after co-incubation with any ccrp deletion mutant. Furthermore, co-incubation with the ccrp59 mutant resulted in reduced type IV secretion system associated activities, e.g. IL-8 production and CagA translocation/phosphorylation. Thus, in addition to their role in maintaining the helical cell shape of H. pylori Ccrp proteins influence many cellular processes and are thereby crucial for the virulence of this human pathogen. PMID- 25823000 TI - Identifying and tracking simulated synaptic inputs from neuronal firing: insights from in vitro experiments. AB - Accurately describing synaptic interactions between neurons and how interactions change over time are key challenges for systems neuroscience. Although intracellular electrophysiology is a powerful tool for studying synaptic integration and plasticity, it is limited by the small number of neurons that can be recorded simultaneously in vitro and by the technical difficulty of intracellular recording in vivo. One way around these difficulties may be to use large-scale extracellular recording of spike trains and apply statistical methods to model and infer functional connections between neurons. These techniques have the potential to reveal large-scale connectivity structure based on the spike timing alone. However, the interpretation of functional connectivity is often approximate, since only a small fraction of presynaptic inputs are typically observed. Here we use in vitro current injection in layer 2/3 pyramidal neurons to validate methods for inferring functional connectivity in a setting where input to the neuron is controlled. In experiments with partially-defined input, we inject a single simulated input with known amplitude on a background of fluctuating noise. In a fully-defined input paradigm, we then control the synaptic weights and timing of many simulated presynaptic neurons. By analyzing the firing of neurons in response to these artificial inputs, we ask 1) How does functional connectivity inferred from spikes relate to simulated synaptic input? and 2) What are the limitations of connectivity inference? We find that individual current-based synaptic inputs are detectable over a broad range of amplitudes and conditions. Detectability depends on input amplitude and output firing rate, and excitatory inputs are detected more readily than inhibitory. Moreover, as we model increasing numbers of presynaptic inputs, we are able to estimate connection strengths more accurately and detect the presence of connections more quickly. These results illustrate the possibilities and outline the limits of inferring synaptic input from spikes. PMID- 25823001 TI - Fatigue performance of medical Ti6Al4V alloy after mechanical surface treatments. AB - Mechanical surface treatments have a long history in traditional engineering disciplines, such as the automotive or aerospace industries. Today, they are widely applied to metal components to increase the mechanical performance of these. However, their application in the medical field is rather rare. The present study aims to compare the potential of relevant mechanical surface treatments on the high cycle fatigue (R = 0.1 for a maximum of 10 million cycles) performance of a Ti6Al4V standard alloy for orthopedic, spinal, dental and trauma surgical implants: shot peening, deep rolling, ultrasonic shot peening and laser shock peening. Hour-glass shaped Ti6Al4V specimens were treated and analyzed with regard to the material's microstructure, microhardness, residual stress depth profiles and the mechanical behavior during fatigue testing. All treatments introduced substantial compressive residual stresses and exhibited considerable potential for increasing fatigue performance from 10% to 17.2% after laser shock peening compared to non-treated samples. It is assumed that final mechanical surface treatments may also increase fretting wear resistance in the modular connection of total hip and knee replacements. PMID- 25823002 TI - Imbalance of pro- vs. anti-coagulation factors in Chinese patients with Budd Chiari syndrome and non-cirrhotic portal vein thrombosis. AB - BACKGROUND AND AIM: The coagulation abnormalities in non-cirrhotic Budd-Chiari syndrome (NC-BCS) and non-cirrhotic portal vein thrombosis (NC-PVT) are unclear. We conducted this case-control study to investigate the coagulation profile of NC BCS and NC-PVT in Chinese patients. METHODS: We measured the levels of factors II, V, VII, VIII, IX, X, XI, XII, protein C (PC), protein S (PS) and antithrombin (AT) in blood samples from 37 NC-BCS patients, 74 NC-PVT patients, and 100 healthy controls. The levels and ratios of pro- and anti-coagulation factors were compared between patients with NC-BCS and healthy controls, between different types of NC-BCS and between NC-PVT and healthy controls. RESULTS: In patients with NC-BCS, factor VIII (P<0.001) was significantly elevated; factor V (P<0.001), VII (P<0.001), IX (P = 0.003), X (P<0.001), XI (P<0.001), XII (P<0.001), PC (P<0.001) and AT (P<0.001) were significantly decreased; and no difference was observed for factor II (P = 0.088) and PS (P = 0.199) compared with healthy controls. Factor VIII-to-PC (P = 0.008), factor VIII-to-PS (P = 0.037) and factor VIII-to-AT (P = 0.001) were significantly increased; other ratios were significantly reduced or did not show any difference. No differences were observed between different types of NC-BCS for individual pro- and anti coagulation factors or the ratios between them. Among patients with NC-PVT, factor VIII (P<0.001) was significantly elevated and other factors were significantly decreased. Factor II-to-PC (P<0.001), factor VIII-to-PC (P<0.001), factor IX-to-PC (P<0.001), factor VIII-to-PS (P<0.001), factor II-to-AT (P<0.001), factor VIII-to-AT (P<0.001) and factor IX-to-AT (P<0.001) were significantly increased; all other ratios for NC-PVT were significantly reduced or did not show any significant difference. CONCLUSIONS: NC-BCS and NC-PVT are associated with elevated levels of factor VIII and the decreased levels of PC and AT were probably the most significant features of coagulation imbalance. Additionally, NC-PVT was associated with decreased levels of PS. PMID- 25823003 TI - Hierarchical gene selection and genetic fuzzy system for cancer microarray data classification. AB - This paper introduces a novel approach to gene selection based on a substantial modification of analytic hierarchy process (AHP). The modified AHP systematically integrates outcomes of individual filter methods to select the most informative genes for microarray classification. Five individual ranking methods including t test, entropy, receiver operating characteristic (ROC) curve, Wilcoxon and signal to noise ratio are employed to rank genes. These ranked genes are then considered as inputs for the modified AHP. Additionally, a method that uses fuzzy standard additive model (FSAM) for cancer classification based on genes selected by AHP is also proposed in this paper. Traditional FSAM learning is a hybrid process comprising unsupervised structure learning and supervised parameter tuning. Genetic algorithm (GA) is incorporated in-between unsupervised and supervised training to optimize the number of fuzzy rules. The integration of GA enables FSAM to deal with the high-dimensional-low-sample nature of microarray data and thus enhance the efficiency of the classification. Experiments are carried out on numerous microarray datasets. Results demonstrate the performance dominance of the AHP-based gene selection against the single ranking methods. Furthermore, the combination of AHP-FSAM shows a great accuracy in microarray data classification compared to various competing classifiers. The proposed approach therefore is useful for medical practitioners and clinicians as a decision support system that can be implemented in the real medical practice. PMID- 25823004 TI - Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease: a prospective cohort study. AB - BACKGROUND: Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function. PATIENTS AND METHODS: In 131 patients, CKD stage 4 5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates. RESULTS: During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1. CONCLUSION: sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease. PMID- 25823005 TI - A standardized method for the construction of tracer specific PET and SPECT rat brain templates: validation and implementation of a toolbox. AB - High-resolution anatomical image data in preclinical brain PET and SPECT studies is often not available, and inter-modality spatial normalization to an MRI brain template is frequently performed. However, this procedure can be challenging for tracers where substantial anatomical structures present limited tracer uptake. Therefore, we constructed and validated strain- and tracer-specific rat brain templates in Paxinos space to allow intra-modal registration. PET [18F]FDG, [11C]flumazenil, [11C]MeDAS, [11C]PK11195 and [11C]raclopride, and SPECT [99mTc]HMPAO brain scans were acquired from healthy male rats. Tracer-specific templates were constructed by averaging the scans, and by spatial normalization to a widely used MRI-based template. The added value of tracer-specific templates was evaluated by quantification of the residual error between original and realigned voxels after random misalignments of the data set. Additionally, the impact of strain differences, disease uptake patterns (focal and diffuse lesion), and the effect of image and template size on the registration errors were explored. Mean registration errors were 0.70 +/- 0.32 mm for [18F]FDG (n = 25), 0.23 +/- 0.10mm for [11C]flumazenil (n = 13), 0.88 +/- 0.20 mm for [11C]MeDAS (n = 15), 0.64 +/- 0.28 mm for [11C]PK11195 (n = 19), 0.34 +/- 0.15 mm for [11C]raclopride (n = 6), and 0.40 +/- 0.13 mm for [99mTc]HMPAO (n = 15). These values were smallest with tracer-specific templates, when compared to the use of [18F]FDG as reference template (p<0.001). Additionally, registration errors were smallest with strain-specific templates (p<0.05), and when images and templates had the same size (p <= 0.001). Moreover, highest registration errors were found for the focal lesion group (p<0.005) and the diffuse lesion group (p = n.s.). In the voxel-based analysis, the reported coordinates of the focal lesion model are consistent with the stereotaxic injection procedure. The use of PET/SPECT strain- and tracer-specific templates allows accurate registration of functional rat brain data, independent of disease specific uptake patterns and with registration error below spatial resolution of the cameras. The templates and the SAMIT package will be freely available for the research community [corrected]. PMID- 25823007 TI - Correction to tailoring the interface quality between HfO2 and GaAs via in situ ZnO passivation using atomic layer deposition. PMID- 25823006 TI - Impact of routine cerebral CT angiography on treatment decisions in infective endocarditis. AB - BACKGROUND: Infective endocarditis (IE) is commonly complicated by cerebral embolization and hemorrhage secondary to intracranial mycotic aneurysms (ICMAs). These complications are associated with poor outcome and may require diagnostic and therapeutic plans to be modified. However, routine screening by brain CT and CT angiography (CTA) is not standard practice. We aimed to study the impact of routine cerebral CTA on treatment decisions for patients with IE. METHODS: From July 2007 to December 2012, we prospectively recruited 81 consecutive patients with definite left-sided IE according to modified Duke's criteria. All patients had routine brain CTA conducted within one week of admission. All patients with ICMA underwent four-vessel conventional angiography. Invasive treatment was performed for ruptured aneurysms, aneurysms >= 5 mm, and persistent aneurysms despite appropriate therapy. Surgical clipping was performed for leaking aneurysms if not amenable to intervention. RESULTS: The mean age was 30.43 +/- 8.8 years and 60.5% were males. Staph aureus was the most common organism (32.3%). Among the patients, 37% had underlying rheumatic heart disease, 26% had prosthetic valves, 23.5% developed IE on top of a structurally normal heart and 8.6% had underlying congenital heart disease. Brain CT/CTA revealed that 51 patients had evidence of cerebral embolization, of them 17 were clinically silent. Twenty-six patients (32%) had ICMA, of whom 15 were clinically silent. Among the patients with ICMAs, 11 underwent endovascular treatment and 2 underwent neurovascular surgery. The brain CTA findings prompted different treatment choices in 21 patients (25.6%). The choices were aneurysm treatment before cardiac surgery rather than at follow-up, valve replacement by biological valve instead of mechanical valve, and withholding anticoagulation in patients with prosthetic valve endocarditis for fear of aneurysm rupture. CONCLUSIONS: Routine brain CT/CTA resulted in changes in the treatment plan in a significant proportion of patients with IE, even those without clinically evident neurological disease. Routine brain CT/CTA may be indicated in all hospitalized patients with IE. PMID- 25823009 TI - Correction: Ecological change, sliding baselines and the importance of historical data: lessons from combing observational and quantitative data on a temperate reef over 70 years. PMID- 25823008 TI - Leukocyte inclusion within a platelet rich plasma-derived fibrin scaffold stimulates a more pro-inflammatory environment and alters fibrin properties. AB - One of the main differences among platelet-rich plasma (PRP) products is the inclusion of leukocytes that may affect the biological efficacy of these autologous preparations. The purpose of this study was to evaluate whether the addition of leukocytes modified the morphological, biomechanical and biological properties of PRP under normal and inflammatory conditions. The release of pro inflammatory cytokines from plasma rich in growth factors (PRGF) and leukocyte platelet rich plasma (L-PRP) scaffolds was determined by enzyme-linked immunosorbent assay (ELISA) and was significantly increased under an inflammatory condition when leukocytes were included in the PRP. Fibroblasts and osteoblasts treated with L-PRP, under an inflammatory situation, underwent a greater activation of NFKB pathway, proliferated significantly less and secreted a higher concentration of pro-inflammatory cytokines. These cellular events were assessed through Western blot and fluorimetric and ELISA methods, respectively. Therefore, the inclusion of leukocytes induced significantly higher pro-inflammatory conditions. PMID- 25823010 TI - Fault diagnosis for the heat exchanger of the aircraft environmental control system based on the strong tracking filter. AB - The aircraft environmental control system (ECS) is a critical aircraft system, which provides the appropriate environmental conditions to ensure the safe transport of air passengers and equipment. The functionality and reliability of ECS have received increasing attention in recent years. The heat exchanger is a particularly significant component of the ECS, because its failure decreases the system's efficiency, which can lead to catastrophic consequences. Fault diagnosis of the heat exchanger is necessary to prevent risks. However, two problems hinder the implementation of the heat exchanger fault diagnosis in practice. First, the actual measured parameter of the heat exchanger cannot effectively reflect the fault occurrence, whereas the heat exchanger faults are usually depicted by utilizing the corresponding fault-related state parameters that cannot be measured directly. Second, both the traditional Extended Kalman Filter (EKF) and the EKF-based Double Model Filter have certain disadvantages, such as sensitivity to modeling errors and difficulties in selection of initialization values. To solve the aforementioned problems, this paper presents a fault-related parameter adaptive estimation method based on strong tracking filter (STF) and Modified Bayes classification algorithm for fault detection and failure mode classification of the heat exchanger, respectively. Heat exchanger fault simulation is conducted to generate fault data, through which the proposed methods are validated. The results demonstrate that the proposed methods are capable of providing accurate, stable, and rapid fault diagnosis of the heat exchanger. PMID- 25823011 TI - Toll-like receptor 4 mediates the inflammatory responses and matrix protein remodeling in remote non-ischemic myocardium in a mouse model of myocardial ischemia and reperfusion. AB - The signaling mechanism that mediates inflammatory responses in remote non ischemic myocardium following regional ischemia/reperfusion (I/R) remains incompletely understood. Myocardial Toll-like receptor 4 (TLR4) can be activated by multiple proteins released from injured cells and plays a role in myocardial inflammation and injury expansion. We tested the hypothesis that TLR4 occupies an important role in mediating the inflammatory responses and matrix protein remodeling in the remote non-ischemic myocardium following regional I/R injury. METHODS AND RESULTS: TLR4-defective (C3H/HeJ) and TLR4-competent (C3H/HeN) mice were subjected to coronary artery ligation (30 min) and reperfusion for 1, 3, 7 or 14 days. In TLR4-competent mice, levels of monocyte chemoattractant protein -1 (MCP-1), keratinocyte chemoattractant (KC), intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were elevated in the remote non-ischemic myocardium at day 1, 3, and 7 of reperfusion. Levels of collagen I, collagen IV, matrix metalloproteinase (MMP) 2 and MMP 9 were increased in the remote non-ischemic myocardium at day 7 and 14 of reperfusion. MMP 2 and MMP 9 activities were also increased. TLR4 deficiency resulted in a moderate reduction in myocardial infarct size. However, it markedly downgraded the changes in the levels of chemokines, adhesion molecules and matrix proteins in the remote non-ischemic myocardium. Further, left ventricular function at day 14 was significantly improved in TLR4-defective mice. In conclusion, TLR4 mediates the inflammatory responses and matrix protein remodeling in the remote non-ischemic myocardium following regional myocardial I/R injury and contributes to the mechanism of adverse cardiac remodeling. PMID- 25823012 TI - Identifying the association of contrast enhancement with vascular endothelia growth factor expression in anaplastic gliomas: a volumetric magnetic resonance imaging analysis. AB - Contrast enhancement is a crucial radiologic feature of malignant brain tumors, which are associated with genetic changes of the tumor. The purpose of the current study was to investigate the potential relationship among tumor contrast enhancement with MR imaging, vascular endothelial growth factor (VEGF) expression, and survival outcome in anaplastic gliomas. MR images from 240 patients with histologically confirmed anaplastic gliomas were retrospectively analyzed. The volumes of T2 hyperintense, contrast enhanced regions and necrotic regions on postcontrast T1-weighted images were measured. The ratio of the enhanced volume to necrotic volume was compared between patients with high versus low levels of VEGF expression and was further used in the survival analysis. The volumetric ratio of enhancement to necrosis was significantly higher in patients with low VEGF expression than in those with high VEGF expression (Mann-Whitney, p = 0.009). In addition, the enhancement/necrosis ratio was identified as a significant predictor of progression-free survival (Cox regression model, p = 0.004) and overall survival (Cox regression model, p = 0.006) in the multivariate analysis. These results suggest that the volumetric ratio of enhancement to necrosis could serve as a noninvasive radiographic marker associated with VEGF expression and that this ratio is an independent predictor for progression-free survival and overall survival in patients with anaplastic gliomas. PMID- 25823013 TI - A system for creating stable cell lines that express a gene of interest from a bidirectional and regulatable herpes simplex virus type 1 promoter. AB - Expression systems used to study the biological function of a gene of interest can have limited utility due to three major factors: i) weak or heterogeneous gene expression; ii) poorly controlled gene expression; and iii) low efficiencies of stable integration and persistent expression. We envisioned that the ideal system should be tightly controlled and coupled with the ability to efficiently create and identify stable cell lines. Herein, we describe a system based upon a bidirectional Herpes simplex virus type 1 promoter that is naturally responsive to the VP16 transactivator and modified to permit tetracycline-regulated transcription on one side while maintaining constitutive activity on the other side. Incorporation of this element into the Sleeping Beauty transposon resulted in a novel bidirectional system with the capacity for high-efficiency stable integration. Using this system, we created stable cell lines in which expression of a gene of interest was tightly and uniformly controlled across a broad range of levels via a novel combination of doxycycline-sensitive de-repression and VP16 mediated sequence-specific induction. The unique characteristics of this system address major limitations of current methods and provide an excellent strategy to investigate the effects of gene dosing in mammalian models. PMID- 25823015 TI - Correction: The acetate/ACSS2 switch regulates HIF-2 stress signaling in the tumor cell microenvironment. PMID- 25823014 TI - An in vivo metabolic approach for deciphering the product specificity of glycerate kinase proves that both E. coli's glycerate kinases generate 2 phosphoglycerate. AB - Apart from addressing humanity's growing demand for fuels, pharmaceuticals, plastics and other value added chemicals, metabolic engineering of microbes can serve as a powerful tool to address questions concerning the characteristics of cellular metabolism. Along these lines, we developed an in vivo metabolic strategy that conclusively identifies the product specificity of glycerate kinase. By deleting E. coli's phosphoglycerate mutases, we divide its central metabolism into an 'upper' and 'lower' metabolism, each requiring its own carbon source for the bacterium to grow. Glycerate can serve to replace the upper or lower carbon source depending on the product of glycerate kinase. Using this strategy we show that while glycerate kinase from Arabidopsis thaliana produces 3 phosphoglycerate, both E. coli's enzymes generate 2-phosphoglycerate. This strategy represents a general approach to decipher enzyme specificity under physiological conditions. PMID- 25823016 TI - Preoperative axillary staging with 3.0-T breast MRI: clinical value of diffusion imaging and apparent diffusion coefficient. AB - The axillary staging in newly diagnosed breast cancer is under major evolution. The aims of this study were to define the diagnostic performance of 3.0-T diffusion-weighted imaging (DWI) in the detection of axillary metastases in newly diagnosed breast cancer, to assess apparent diffusion coefficients (ADCs) for histopathologically confirmed metastatic lymph nodes in a clinical setting. Altogether 52 consecutive breast cancer patients underwent magnetic resonance imaging and DWI in addition to axillary ultrasound. ADCs of axillary lymph nodes were analysed by two breast radiologists and ultrasound-guided core biopsies were taken. In a separate reading by one radiologist two types of region of interests were used for a smaller group of patients. Altogether 56 axillae (121 lymph nodes) were included in the statistical analysis. Metastatic axillae (51.8%) had significantly lower ADCs (p<0.001). Mean ADCs were 0.663-0.676 x 10(-3) mm2/s for the histologically confirmed metastatic LNs and 1.100-1.225 x 10(-3) mm2/s for the benign. The sensitivity, specificity, and accuracy of DWI were 72.4%, 79.6%, and 75.9%, respectively with threshold ADC 0.812 x 10(-3) mm2/s. Region of interest with information on the minimum value increased the diagnostic performance (area under the curve 0.794 vs. 0.619). Even though ADCs are significantly associated with histopathologically confirmed axillary metastases the diagnostic performance of axillary DWI remains moderate and ultrasound-guided core biopsies or sentinel lymph node biopsies cannot be omitted. PMID- 25823017 TI - Pre-analytical sample quality: metabolite ratios as an intrinsic marker for prolonged room temperature exposure of serum samples. AB - Advances in the "omics" field bring about the need for a high number of good quality samples. Many omics studies take advantage of biobanked samples to meet this need. Most of the laboratory errors occur in the pre-analytical phase. Therefore evidence-based standard operating procedures for the pre-analytical phase as well as markers to distinguish between 'good' and 'bad' quality samples taking into account the desired downstream analysis are urgently needed. We studied concentration changes of metabolites in serum samples due to pre-storage handling conditions as well as due to repeated freeze-thaw cycles. We collected fasting serum samples and subjected aliquots to up to four freeze-thaw cycles and to pre-storage handling delays of 12, 24 and 36 hours at room temperature (RT) and on wet and dry ice. For each treated aliquot, we quantified 127 metabolites through a targeted metabolomics approach. We found a clear signature of degradation in samples kept at RT. Storage on wet ice led to less pronounced concentration changes. 24 metabolites showed significant concentration changes at RT. In 22 of these, changes were already visible after only 12 hours of storage delay. Especially pronounced were increases in lysophosphatidylcholines and decreases in phosphatidylcholines. We showed that the ratio between the concentrations of these molecule classes could serve as a measure to distinguish between 'good' and 'bad' quality samples in our study. In contrast, we found quite stable metabolite concentrations during up to four freeze-thaw cycles. We concluded that pre-analytical RT handling of serum samples should be strictly avoided and serum samples should always be handled on wet ice or in cooling devices after centrifugation. Moreover, serum samples should be frozen at or below -80 degrees C as soon as possible after centrifugation. PMID- 25823018 TI - Bursting regimes in a reaction-diffusion system with action potential-dependent equilibrium. AB - The equilibrium Nernst potential plays a critical role in neural cell dynamics. A common approximation used in studying electrical dynamics of excitable cells is that the ionic concentrations inside and outside the cell membranes act as charge reservoirs and remain effectively constant during excitation events. Research into brain electrical activity suggests that relaxing this assumption may provide a better understanding of normal and pathophysiological functioning of the brain. In this paper we explore time-dependent ionic concentrations by allowing the ion specific Nernst potentials to vary with developing transmembrane potential. As a specific implementation, we incorporate the potential-dependent Nernst shift into a one-dimensional Morris-Lecar reaction-diffusion model. Our main findings result from a region in parameter space where self-sustaining oscillations occur without external forcing. Studying the system close to the bifurcation boundary, we explore the vulnerability of the system with respect to external stimulations which disrupt these oscillations and send the system to a stable equilibrium. We also present results for an extended, one-dimensional cable of excitable tissue tuned to this parameter regime and stimulated, giving rise to complex spatiotemporal pattern formation. Potential applications to the emergence of neuronal bursting in similar two-variable systems and to pathophysiological seizure-like activity are discussed. PMID- 25823019 TI - Dietary Njavara rice bran oil reduces experimentally induced hypercholesterolaemia by regulating genes involved in lipid metabolism. AB - The present study was carried out to evaluate the anti-atherogenic effect of Njavara rice bran oil (NjRBO) on atherosclerosis by modulating enzymes and genes involved in lipid metabolism in rats fed a high-cholesterol diet (HCD). Adult male rats (Sprague-Dawley strain, weighing 100-120 g) were divided into three groups of nine animals each. Group I served as the control, group II were fed a HCD and group III were fed a HCD and NjRBO (100 mg/kg body weight). The study duration was 60 d. Serum and tissue lipid profile, atherogenic index, enzymes of lipid metabolism, plasma C-reactive protein levels, serum paraoxonase and arylesterase activities, thiobarbituric acid-reactive substances, gene and protein expression of paraoxonase 1 (PON1), PPARalpha, ATP-binding cassette transporter A1 (ABCA1), apoB and apoA1 in the liver were quantified. Total cholesterol, TAG, phospholipid, NEFA, LDL-cholesterol concentrations in the serum and liver, lipogenic enzyme activities, hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity and atherogenic index were significantly increased in HCD-fed rats, but they decreased after treatment with NjRBO. HDL-cholesterol level and lecithin cholesterol acyl transferase activity were increased in the NjRBO treated group, but decreased in the HCD-fed group. The expression levels of ABCA1, apoA1, PON1 and PPARalpha were found to be significantly increased in NjRBO-treated group compared with the HCD-fed group; however, the expression level of apoB was found to be higher in HCD-fed group and lower in the NjRBO treated group. These data suggest that NjRBO possesses an anti-atherogenic property by modulating lipid metabolism and up-regulating genes involved in reverse cholesterol transport and antioxidative defence mechanism through the induction of the gene expression PON1. PMID- 25823020 TI - Cancer whole-genome sequencing: present and future. AB - Recent explosive advances in next-generation sequencing technology and computational approaches to massive data enable us to analyze a number of cancer genome profiles by whole-genome sequencing (WGS). To explore cancer genomic alterations and their diversity comprehensively, global and local cancer genome sequencing projects, including ICGC and TCGA, have been analyzing many types of cancer genomes mainly by exome sequencing. However, there is limited information on somatic mutations in non-coding regions including untranslated regions, introns, regulatory elements and non-coding RNAs, and rearrangements, sometimes producing fusion genes, and pathogen detection in cancer genomes remain widely unexplored. WGS approaches can detect these unexplored mutations, as well as coding mutations and somatic copy number alterations, and help us to better understand the whole landscape of cancer genomes and elucidate functions of these unexplored genomic regions. Analysis of cancer genomes using the present WGS platforms is still primitive and there are substantial improvements to be made in sequencing technologies, informatics and computer resources. Taking account of the extreme diversity of cancer genomes and phenotype, it is also required to analyze much more WGS data and integrate these with multi-omics data, functional data and clinical-pathological data in a large number of sample sets to interpret them more fully and efficiently. PMID- 25823021 TI - Fibulin-3 is a novel TGF-beta pathway inhibitor in the breast cancer microenvironment. AB - Transforming growth factor-beta (TGF-beta) is an important regulator of breast cancer progression. However, how the breast cancer microenvironment regulates TGF beta signaling during breast cancer progression remains largely unknown. Here, we identified fibulin-3 as a secreted protein in the breast cancer microenvironment, which efficiently inhibits TGF-beta signaling in both breast cancer cells and endothelial cells. Mechanistically, fibulin-3 interacts with the type I TGF-beta receptor (TbetaRI) to block TGF-beta induced complex formation of TbetaRI with the type II TGF-beta receptor (TbetaRII) and subsequent downstream TGF-beta signaling. Fibulin-3 expression decreases during breast cancer progression, with low fibulin-3 levels correlating with a poorer prognosis. Functionally, high fibulin-3 levels inhibited TGF-beta-induced epithelial-mesenchymal transition (EMT), migration, invasion and endothelial permeability, while loss of fibulin-3 expression/function promoted these TGF-beta-mediated effects. Further, restoring fibulin-3 expression in breast cancer cells inhibited TGF-beta signaling, breast cancer cell EMT, invasion and metastasis in vivo. These studies provide a novel mechanism for how TGF-beta signaling is regulated by the tumor microenvironment, and provide insight into targeting the TGF-beta signaling pathway in human breast cancer patients. PMID- 25823022 TI - Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis promoting protein. AB - AAA domain containing 3A (ATAD3A) is an integral mitochondrial membrane protein with unknown function, although we now show that high-level expression is associated with poor survival in breast cancer patients. Using a mass spectrometry approach we have demonstrated that ATAD3A interacts with the WASF3 metastasis-promoting protein. Knockdown of ATAD3A leads to decreased WASF3 protein levels in breast and colon cancer cells. Silencing ATAD3A also results in loss of both cell anchorage-independent growth and invasion and suppression of tumor growth and metastasis in vivo using immuno-compromised mice. HSP70 is responsible for stabilizing WASF3 in the cytoplasm, but inactivation of HSP70 does not lead to the loss of WASF3 stability at the mitochondrial membrane, where presumably it is protected through its interaction with ATAD3A. In response to endoplasmic reticulum (ER) stress, increases in the GRP78 protein level leads to increased WASF3 protein levels. We also show that ATAD3A was present in a WASF3 GRP78 complex, and suppression of GRP78 led to destabilization of WASF3 at the mitochondrial membrane, which was ATAD3A dependent. Furthermore, ATAD3A-mediated suppression of CDH1/E-cadherin occurs through its regulation of GRP78-mediated WASF3 stability. Proteolysis experiments using isolated mitochondria demonstrates the presence of the N-terminal end of WASF3 within the mitochondria, which is the interaction site with the N-terminal end of ATAD3A. It appears, therefore, that stabilization of WASF3 function occurs through its interaction with ATAD3A and GRP78, which may provide a bridge between the ER and mitochondria, allowing communication between the two organelles. These findings also suggest that pharmacologic inhibition of ATAD3A could be an effective therapeutic strategy to treat human cancer. PMID- 25823024 TI - ATM-mediated KDM2A phosphorylation is required for the DNA damage repair. AB - The ataxia-telangiectasia mutated (ATM) protein is a key signaling molecule that modulates the DNA damage response. However, the exact mechanism by which ATM regulates DNA damage repair has not yet been elucidated. Here, we report that ATM regulates the DNA damage response by phosphorylating lysine-specific demethylase 2A (KDM2A), a histone demethylase that acts at sites of H3K36 dimethylation. ATM interacts with KDM2A, and their interaction significantly increases in response to DNA double-stranded, but not single-stranded, breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage, as demonstrated by a mutagenesis assay and mass spectrometric analysis. Although KDM2A phosphorylation does not alter its own demethylase activity, T632 phosphorylation of KDM2A largely abrogates its chromatin-binding capacity, and H3K36 dimethylation near DNA damage sites is significantly increased. Consequently, enriched H3K36 dimethylation serves as a platform to recruit the MRE11 complex to DNA damage sites by directly interacting with the BRCT2 domain of NBS1, which results in efficient DNA damage repair and enhanced cell survival. Collectively, our study reveals a novel mechanism for ATM in connecting histone modifications with the DNA damage response. PMID- 25823023 TI - Lineage factors and differentiation states in lung cancer progression. AB - Lung cancer encompasses a heterogeneous group of malignancies. Here we discuss how the remarkable diversity of major lung cancer subtypes is manifested in their transforming cell of origin, oncogenic dependencies, phenotypic plasticity, metastatic competence and response to therapy. More specifically, we review the increasing evidence that links this biological heterogeneity to the deregulation of cell lineage-specific pathways and the transcription factors that ultimately control them. As determinants of pulmonary epithelial differentiation, these poorly characterized transcriptional networks may underlie the etiology and biological progression of distinct lung cancers, while providing insight into innovative therapeutic strategies. PMID- 25823025 TI - Oncogenic c-Myc-induced lymphomagenesis is inhibited non-redundantly by the p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways. AB - The multifaceted oncogene c-Myc plays important roles in the development and progression of human cancer. Recent in vitro and in vivo studies have shown that the p19Arf-Mdm2-p53 and the ribosomal protein (RP)-Mdm2-p53 pathways are both essential in preventing oncogenic c-Myc-induced tumorigenesis. Disruption of each pathway individually by p19Arf deletion or by Mdm2(C305F) mutation, which disrupts RP-Mdm2 binding, accelerates EMU-myc transgene-induced pre-B/B-cell lymphoma in mice at seemingly similar paces with median survival around 10 and 11 weeks, respectively, compared to 20 weeks for EMU-myc transgenic mice. Because p19Arf can inhibit ribosomal biogenesis through its interaction with nucleophosmin (NPM/B23), RNA helicase DDX5 and RNA polymerase I transcription termination factor (TTF-I), it has been speculated that the p19Arf-Mdm2-p53 and the RP-Mdm2-p53 pathways might be a single p19Arf-RP-Mdm2-p53 pathway, in which p19Arf activates p53 by inhibiting RP biosynthesis; thus, p19Arf deletion or Mdm2(C305F) mutation would result in similar consequences. Here, we generated mice with concurrent p19Arf deletion and Mdm2(C305F) mutation and investigated the compound mice for tumorigenesis in the absence and the presence of oncogenic c-Myc overexpression. In the absence of EMU-myc transgene, the Mdm2(C305F) mutation did not elicit spontaneous tumors in mice, nor did it accelerate spontaneous tumors in mice with p19Arf deletion. In the presence of EMU-myc transgene, however, Mdm2(C305F) mutation significantly accelerated p19Arf deletion-induced lymphomagenesis and promoted rapid metastasis. We found that when p19Arf-Mdm2-p53 and RP-Mdm2-p53 pathways are independently disrupted, oncogenic c-Myc-induced p53 stabilization and activation is only partially attenuated. When both pathways are concurrently disrupted, however, c-Myc-induced p53 stabilization and activation are essentially obliterated. Thus, the p19Arf Mdm2-p53 and the RP-Mdm2-p53 are non-redundant pathways possessing similar capabilities to activate p53 upon c-Myc overexpression. PMID- 25823026 TI - PPM1D phosphatase, a target of p53 and RBM38 RNA-binding protein, inhibits p53 mRNA translation via dephosphorylation of RBM38. AB - PPM1D phosphatase, also called wild-type p53-induced phosphatase 1, promotes tumor development by inactivating the p53 tumor suppressor pathway. RBM38 RNA binding protein, also called RNPC1 and a target of p53, inhibits p53 messenger RNA (mRNA) translation, which can be reversed by GSK3 protein kinase via phosphorylation of RBM38 at serine 195. Here we showed that ectopic expression of RBM38 increases, whereas knockdown of RBM38 inhibits, PPM1D mRNA translation. Consistent with this, we found that RBM38 directly binds to PPM1D 3'-untranslated region (3'-UTR) and promotes expression of a heterologous reporter gene that carries PPM1D 3'-UTR in a dose-dependent manner. Interestingly, we showed that PPM1D directly interacts with and dephosphorylates RBM38 at serine 195. Furthermore, we showed that PPM1D modulates p53 mRNA translation and p53 dependent growth suppression through dephosphorylation of RBM38. These findings provide evidence that the crosstalk between PPM1D and RBM38, both of which are targets and modulators of p53, has a critical role in p53 expression and activity. PMID- 25823027 TI - Disruption of NCOA2 by recurrent fusion with LACTB2 in colorectal cancer. AB - Whole-genome and transcriptome sequencing were used to discover novel gene fusions in a case of colon cancer. A tumor-specific LACTB2-NCOA2 fusion originating from intra-chromosomal rearrangement of chromosome 8 was identified at both DNA and RNA levels. Unlike conventional oncogenic chimeric proteins, the fusion product lacks functional domain from respective genes, indicative of an amorphic rearrangement. This chimeric LACTB2-NCOA2 transcript was detected in 6 out of 99 (6.1%) colorectal cancer (CRC) cases, where NCOA2 was significantly downregulated. Enforced expression of wild-type NCOA2 but not the LACTB2-NCOA2 fusion protein impaired the pro-tumorigenic phenotypes of CRC cells, whereas knockdown of endogenous NCOA2 in normal colonocytes had opposite effects. Mechanistically, NCOA2 inhibited Wnt/beta-catenin signaling through simultaneously upregulating inhibitors and downregulating stimulators of Wnt/beta catenin pathway. Collectively, our data supports that NCOA2 is a novel negative growth regulatory gene repressing the Wnt/beta-catenin pathway in CRC, where recurrent fusion with LACTB2 contributes to its disruption. PMID- 25823028 TI - CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-kappaB pathway in multidrug-resistant glioblastoma cells in vitro. AB - Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF) kappaB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-kappaB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-kappaB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma. PMID- 25823030 TI - Optimization of Single-Trial Detection of Event-Related Potentials Through Artificial Trials. AB - GOAL: Many brain-computer interface (BCI) classification techniques rely on a large number of labeled brain responses to create efficient classifiers. A large database representing all of the possible variability in the signal is impossible to obtain in a short period of time, and prolonged calibration times prevent efficient BCI use. We propose to improve BCIs based on the detection of event related potentials (ERPs) in two ways. METHODS: First, we increase the size of the training database by considering additional deformed trials. The creation of the additional deformed trials is based on the addition of Gaussian noise, and on the variability of the ERP latencies. Second, we exploit the variability of the ERP latencies by combining decisions across multiple deformed trials. These new methods are evaluated on data from 16 healthy subjects participating in a rapid serial visual presentation task. RESULTS: The results show a significant increase in the performance of single-trial detection with the addition of artificial trials, and the combination of decisions obtained from altered trials. When the number of trials to train a classifier is low, the proposed approach allows us improve performance from an AUC of 0.533+/-0.080 to 0.905+/-0.053. This improvement represents approximately an 80% reduction in classification error. CONCLUSION: These results demonstrate that artificially increasing the training dataset leads to improved single-trial detection. SIGNIFICANCE: Calibration sessions can be shortened for BCIs based on ERP detection. PMID- 25823029 TI - Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer. AB - Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or gamma-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy. PMID- 25823031 TI - Diseased Region Detection of Longitudinal Knee Magnetic Resonance Imaging Data. AB - Magnetic resonance imaging (MRI) has become an important imaging technique for quantifying the spatial location and magnitude/direction of longitudinal cartilage morphology changes in patients with osteoarthritis (OA). Although several analytical methods, such as subregion-based analysis, have been developed to refine and improve quantitative cartilage analyses, they can be suboptimal due to two major issues: the lack of spatial correspondence across subjects and time and the spatial heterogeneity of cartilage progression across subjects. The aim of this paper is to present a statistical method for longitudinal cartilage quantification in OA patients, while addressing these two issues. The 3D knee image data is preprocessed to establish spatial correspondence across subjects and/or time. Then, a Gaussian hidden Markov model (GHMM) is proposed to deal with the spatial heterogeneity of cartilage progression across both time and OA subjects. To estimate unknown parameters in GHMM, we employ a pseudo-likelihood function and optimize it by using an expectation-maximization (EM) algorithm. The proposed model can effectively detect diseased regions in each OA subject and present a localized analysis of longitudinal cartilage thickness within each latent subpopulation. Our GHMM integrates the strengths of two standard statistical methods including the local subregion-based analysis and the ordered value approach. We use simulation studies and the Pfizer longitudinal knee MRI dataset to evaluate the finite sample performance of GHMM in the quantification of longitudinal cartilage morphology changes. Our results indicate that GHMM significantly outperforms several standard analytical methods. PMID- 25823033 TI - Approximation and compression with sparse orthonormal transforms. AB - We propose a new transform design method that targets the generation of compression-optimized transforms for next-generation multimedia applications. The fundamental idea behind transform compression is to exploit regularity within signals such that redundancy is minimized subject to a fidelity cost. Multimedia signals, in particular images and video, are well known to contain a diverse set of localized structures, leading to many different types of regularity and to nonstationary signal statistics. The proposed method designs sparse orthonormal transforms (SOTs) that automatically exploit regularity over different signal structures and provides an adaptation method that determines the best representation over localized regions. Unlike earlier work that is motivated by linear approximation constructs and model-based designs that are limited to specific types of signal regularity, our work uses general nonlinear approximation ideas and a data-driven setup to significantly broaden its reach. We show that our SOT designs provide a safe and principled extension of the Karhunen-Loeve transform (KLT) by reducing to the KLT on Gaussian processes and by automatically exploiting non-Gaussian statistics to significantly improve over the KLT on more general processes. We provide an algebraic optimization framework that generates optimized designs for any desired transform structure (multiresolution, block, lapped, and so on) with significantly better n -term approximation performance. For each structure, we propose a new prototype codec and test over a database of images. Simulation results show consistent increase in compression and approximation performance compared with conventional methods. PMID- 25823032 TI - Persistent Homology in Sparse Regression and Its Application to Brain Morphometry. AB - Sparse systems are usually parameterized by a tuning parameter that determines the sparsity of the system. How to choose the right tuning parameter is a fundamental and difficult problem in learning the sparse system. In this paper, by treating the the tuning parameter as an additional dimension, persistent homological structures over the parameter space is introduced and explored. The structures are then further exploited in drastically speeding up the computation using the proposed soft-thresholding technique. The topological structures are further used as multivariate features in the tensor-based morphometry (TBM) in characterizing white matter alterations in children who have experienced severe early life stress and maltreatment. These analyses reveal that stress-exposed children exhibit more diffuse anatomical organization across the whole white matter region. PMID- 25823034 TI - Robust representation and recognition of facial emotions using extreme sparse learning. AB - Recognition of natural emotions from human faces is an interesting topic with a wide range of potential applications, such as human-computer interaction, automated tutoring systems, image and video retrieval, smart environments, and driver warning systems. Traditionally, facial emotion recognition systems have been evaluated on laboratory controlled data, which is not representative of the environment faced in real-world applications. To robustly recognize the facial emotions in real-world natural situations, this paper proposes an approach called extreme sparse learning, which has the ability to jointly learn a dictionary (set of basis) and a nonlinear classification model. The proposed approach combines the discriminative power of extreme learning machine with the reconstruction property of sparse representation to enable accurate classification when presented with noisy signals and imperfect data recorded in natural settings. In addition, this paper presents a new local spatio-temporal descriptor that is distinctive and pose-invariant. The proposed framework is able to achieve the state-of-the-art recognition accuracy on both acted and spontaneous facial emotion databases. PMID- 25823035 TI - Density maximization for improving graph matching with its applications. AB - Graph matching has been widely used in both image processing and computer vision domain due to its powerful performance for structural pattern representation. However, it poses three challenges to image sparse feature matching: 1) the combinatorial nature limits the size of the possible matches; 2) it is sensitive to outliers because its objective function prefers more matches; and 3) it works poorly when handling many-to-many object correspondences, due to its assumption of one single cluster of true matches. In this paper, we address these challenges with a unified framework called density maximization (DM), which maximizes the values of a proposed graph density estimator both locally and globally. DM leads to the integration of feature matching, outlier elimination, and cluster detection. Experimental evaluation demonstrates that it significantly boosts the true matches and enables graph matching to handle both outliers and many-to-many object correspondences. We also extend it to dense correspondence estimation and obtain large improvement over the state-of-the-art methods. We further demonstrate the usefulness of our methods using three applications: 1) instance level image retrieval; 2) mask transfer; and 3) image enhancement. PMID- 25823036 TI - PM-PM: PatchMatch with Potts Model for object segmentation and stereo matching. AB - This paper presents a unified variational formulation for joint object segmentation and stereo matching, which takes both accuracy and efficiency into account. In our approach, depth-map consists of compact objects, each object is represented through three different aspects: 1) the perimeter in image space; 2) the slanted object depth plane; and 3) the planar bias, which is to add an additional level of detail on top of each object plane in order to model depth variations within an object. Compared with traditional high quality solving methods in low level, we use a convex formulation of the multilabel Potts Model with PatchMatch stereo techniques to generate depth-map at each image in object level and show that accurate multiple view reconstruction can be achieved with our formulation by means of induced homography without discretization or staircasing artifacts. Our model is formulated as an energy minimization that is optimized via a fast primal-dual algorithm, which can handle several hundred object depth segments efficiently. Performance evaluations in the Middlebury benchmark data sets show that our method outperforms the traditional integer valued disparity strategy as well as the original PatchMatch algorithm and its variants in subpixel accurate disparity estimation. The proposed algorithm is also evaluated and shown to produce consistently good results for various real world data sets (KITTI benchmark data sets and multiview benchmark data sets). PMID- 25823037 TI - Online temporally consistent indoor depth video enhancement via static structure. AB - In this paper, we propose a new method to online enhance the quality of a depth video based on the intermediary of a so-called static structure of the captured scene. The static and dynamic regions of the input depth frame are robustly separated by a layer assignment procedure, in which the dynamic part stays in the front while the static part fits and helps to update this structure by a novel online variational generative model with added spatial refinement. The dynamic content is enhanced spatially while the static region is otherwise substituted by the updated static structure so as to favor the long-range spatiotemporal enhancement. The proposed method both performs long-range temporal consistency on the static region and keeps necessary depth variations in the dynamic content. Thus, it can produce flicker-free and spatially optimized depth videos with reduced motion blur and depth distortion. Our experimental results reveal that the proposed method is effective in both static and dynamic indoor scenes and is compatible with depth videos captured by Kinect and time-of-flight camera. We also demonstrate that excellent performance can be achieved by the proposed method in comparison with the existing spatiotemporal approaches. In addition, our enhanced depth videos and static structures can act as effective cues to improve various applications, including depth-aided background subtraction and novel view synthesis, showing satisfactory results with few visual artifacts. PMID- 25823038 TI - Using Functional Electrical Stimulation Mediated by Iterative Learning Control and Robotics to Improve Arm Movement for People With Multiple Sclerosis. AB - Few interventions address multiple sclerosis (MS) arm dysfunction but robotics and functional electrical stimulation (FES) appear promising. This paper investigates the feasibility of combining FES with passive robotic support during virtual reality (VR) training tasks to improve upper limb function in people with multiple sclerosis (pwMS). The system assists patients in following a specified trajectory path, employing an advanced model-based paradigm termed iterative learning control (ILC) to adjust the FES to improve accuracy and maximise voluntary effort. Reaching tasks were repeated six times with ILC learning the optimum control action from previous attempts. A convenience sample of five pwMS was recruited from local MS societies, and the intervention comprised 18 one-hour training sessions over 10 weeks. The accuracy of tracking performance without FES and the amount of FES delivered during training were analyzed using regression analysis. Clinical functioning of the arm was documented before and after treatment with standard tests. Statistically significant results following training included: improved accuracy of tracking performance both when assisted and unassisted by FES; reduction in maximum amount of FES needed to assist tracking; and less impairment in the proximal arm that was trained. The system was well tolerated by all participants with no increase in muscle fatigue reported. This study confirms the feasibility of FES combined with passive robot assistance as a potentially effective intervention to improve arm movement and control in pwMS and provides the basis for a follow-up study. PMID- 25823039 TI - A Non-Magnetic Rotating Disk Stimulator for the Study of Neuromagnetic Correlates of Sensorimotor Interaction. AB - Fine motor skills in humans require close interaction between the motor and the sensory systems. It is still not fully understood, how sensory feedback modulates motor commands. This is due to the fact, that there is no approach for investigating the sensorimotor cortical-interaction in sufficient detail. The fast and precise communication between the sensory and motor-systems requires measurements of cortical activity with high temporal and spatial resolution. Magnetoencephalography (MEG) is capable of both. Previously, we showed that sensory responses, can be observed by repetitive tactile stimulation. Further, motor cortex responses can be generated by periodical increase and decrease of muscle tone. Utilizing both observations we have designed an MEG and magnetic resonance imaging (MRI) compatible stimulator allowing for the study of brain activity related to sensorimotor integration. The stimulator consists of a rotating disk with an elevation such that subject senses with his finger the speed of the disk. With the force applied by the finger onto the disk, the subject can control its speed. During the experiment the subject is asked to keep the speed of the disk constant while the driving torque is systematically manipulated. This closed-loop design is especially useful to analyze the fast and continuous information flow between the two systems. In a single case pilot study using MEG, we could show that a detailed analysis of the sensorimotor-network is possible. In contrast to existing paradigms this setup allows separate time locked analysis of the sensory- and motor-component independently and therefore the calculation of latency parameters for both systems. In the future this method will help to understand the interaction between the two systems in much greater detail. PMID- 25823040 TI - Nanowire-imposed geometrical control in studies of actomyosin motor function. AB - Recently, molecular motor gliding assays with actin and myosin from muscle have been realized on semiconductor nanowires coated with Al2O3. This opens for unique nanotechnological applications and novel fundamental studies of actomyosin motor function. Here, we provide a comparison of myosin-driven actin filament motility on Al2O3 to both nitrocellulose and trimethylchlorosilane derivatized surfaces. We also show that actomyosin motility on the less than 200 nm wide tips of arrays of Al2O3-coated nanowires can be used to control the number, and density, of myosin-actin attachment points. Results obtained using nanowire arrays with different inter-wire spacing are consistent with the idea that the actin filament sliding velocity is determined both by the total number and the average density of attached myosin heads along the actin filament. Further, the results are consistent with buckling of long myosin-free segments of the filaments as a factor underlying reduced velocity. On the other hand, the findings do not support a mechanistic role in decreasing velocity, of increased nearest neighbor distance between available myosin heads. Our results open up for more advanced studies that may use nanowire-based structures for fundamental investigations of molecular motors, including the possibility to create a nanowire-templated bottom up assembly of 3D, muscle-like structures. PMID- 25823041 TI - Optimal Communication Network-Based Hinfinity Quantized Control With Packet Dropouts for a Class of Discrete-Time Neural Networks With Distributed Time Delay. AB - This paper is concerned with optimal communication network-based Hinfinity quantized control for a discrete-time neural network with distributed time delay. Control of the neural network (plant) is implemented via a communication network. Both quantization and communication network-induced data packet dropouts are considered simultaneously. It is assumed that the plant state signal is quantized by a logarithmic quantizer before transmission, and communication network-induced packet dropouts can be described by a Bernoulli distributed white sequence. A new approach is developed such that controller design can be reduced to the feasibility of linear matrix inequalities, and a desired optimal control gain can be derived in an explicit expression. It is worth pointing out that some new techniques based on a new sector-like expression of quantization errors, and the singular value decomposition of a matrix are developed and employed in the derivation of main results. An illustrative example is presented to show the effectiveness of the obtained results. PMID- 25823042 TI - Learning Subspace-Based RBFNN Using Coevolutionary Algorithm for Complex Classification Tasks. AB - Many real-world classification problems are characterized by samples of a complex distribution in the input space. The classification accuracy is determined by intrinsic properties of all samples in subspaces of features. This paper proposes a novel algorithm for the construction of radial basis function neural network (RBFNN) classifier based on subspace learning. In this paper, feature subspaces are obtained for every hidden node of the RBFNN during the learning process. The connection weights between the input layer and the hidden layer are adjusted to produce various subspaces with dominative features for different hidden nodes. The network structure and dominative features are encoded in two subpopulations that are cooperatively coevolved using the coevolutionary algorithm to achieve a better global optimality for the estimated RBFNN. Experimental results illustrate that the proposed algorithm is able to obtain RBFNN models with both better classification accuracy and simpler network structure when compared with other learning algorithms. Thus, the proposed model provides a more flexible and efficient approach to complex classification tasks by employing the local characteristics of samples in subspaces. PMID- 25823043 TI - Robust Adaptive Neural Tracking Control for a Class of Stochastic Nonlinear Interconnected Systems. AB - In this paper, an adaptive neural decentralized control approach is proposed for a class of multiple input and multiple output uncertain stochastic nonlinear strong interconnected systems. Radial basis function neural networks are used to approximate the packaged unknown nonlinearities, and backstepping technique is utilized to construct an adaptive neural decentralized controller. The proposed control scheme can guarantee that all signals of the resulting closed-loop system are semiglobally uniformly ultimately bounded in the sense of fourth moment, and the tracking errors eventually converge to a small neighborhood around the origin. The main feature of this paper is that the proposed approach is capable of controlling the stochastic systems with strong interconnected nonlinearities both in the drift and diffusion terms that are the functions of all states of the overall system. Simulation results are used to illustrate the effectiveness of the suggested approach. PMID- 25823044 TI - Observer-Based Adaptive Neural Network Control for Nonlinear Systems in Nonstrict Feedback Form. AB - This paper focuses on the problem of adaptive neural network (NN) control for a class of nonlinear nonstrict-feedback systems via output feedback. A novel adaptive NN backstepping output-feedback control approach is first proposed for nonlinear nonstrict-feedback systems. The monotonicity of system bounding functions and the structure character of radial basis function (RBF) NNs are used to overcome the difficulties that arise from nonstrict-feedback structure. A state observer is constructed to estimate the immeasurable state variables. By combining adaptive backstepping technique with approximation capability of radial basis function NNs, an output-feedback adaptive NN controller is designed through backstepping approach. It is shown that the proposed controller guarantees semiglobal boundedness of all the signals in the closed-loop systems. Two examples are used to illustrate the effectiveness of the proposed approach. PMID- 25823045 TI - Synchronization and State Estimation of a Class of Hierarchical Hybrid Neural Networks With Time-Varying Delays. AB - This paper addresses the problems of synchronization and state estimation for a class of discrete-time hierarchical hybrid neural networks (NNs) with time varying delays. The hierarchical hybrid feature consists of a higher level nondeterministic switching and a lower level stochastic switching. The latter is used to describe the NNs subject to Markovian modes transitions, whereas the former is of the average dwell-time switching regularity to model the supervisory orchestrating mechanism among these Markov jump NNs. The considered time delays are not only time-varying but also dependent on the mode of NNs on the lower layer in the hierarchical structure. Despite quantization and random data missing, the synchronized controllers and state estimators are designed such that the resulting error system is exponentially stable with an expected decay rate and has a prescribed Hinfinity disturbance attenuation level. Two numerical examples are provided to show the validity and potential of the developed results. PMID- 25823046 TI - Symmetrical compression distance for arrhythmia discrimination in cloud-based big data services. AB - The current development of cloud computing is completely changing the paradigm of data knowledge extraction in huge databases. An example of this technology in the cardiac arrhythmia field is the SCOOP platform, a national-level scientific cloud based big data service for implantable cardioverter defibrillators. In this scenario, we here propose a new methodology for automatic classification of intracardiac electrograms (EGMs) in a cloud computing system, designed for minimal signal preprocessing. A new compression-based similarity measure (CSM) is created for low computational burden, so-called weighted fast compression distance, which provides better performance when compared with other CSMs in the literature. Using simple machine learning techniques, a set of 6848 EGMs extracted from SCOOP platform were classified into seven cardiac arrhythmia classes and one noise class, reaching near to 90% accuracy when previous patient arrhythmia information was available and 63% otherwise, hence overcoming in all cases the classification provided by the majority class. Results show that this methodology can be used as a high-quality service of cloud computing, providing support to physicians for improving the knowledge on patient diagnosis. PMID- 25823047 TI - Instrumental Assessment of Bradykinesia: A Comparison Between Motor Tasks. AB - Bradykinesia, a common symptom in psychiatry, is characterized by reduced movement speed and amplitude. Monitoring for bradykinesia is important, as it has been associated with reductions in quality of life and medication compliance. Subtle forms of bradykinesia have been associated with treatment response in antipsychotic-naive first episode patients. Therefore, accurate and reliable assessment is of clinical importance. Several mechanical and electronic instruments have been developed for this purpose. However, their content validity is limited. This study investigated which tasks, or combinations thereof, are most suitable for assessing bradykinesia instrumentally. Eleven motor tasks were assessed using inertial sensors. Their capability of distinguishing bradykinetic patients with schizophrenia ( n = 6) from healthy controls ( n = 5) was investigated. Seven tasks significantly discriminated patients from controls. The combination of tasks considered most feasible for the instrumental assessment of bradykinesia was the gait, pronation/supination, leg agility and flexion/extension of elbow tasks (effect size = 2.9). PMID- 25823048 TI - Infant Brain Extraction in T1-Weighted MR Images Using BET and Refinement Using LCDG and MGRF Models. AB - In this paper, we propose a novel framework for the automated extraction of the brain from T1-weighted MR images. The proposed approach is primarily based on the integration of a stochastic model [a two-level Markov-Gibbs random field (MGRF)] that serves to learn the visual appearance of the brain texture, and a geometric model (the brain isosurfaces) that preserves the brain geometry during the extraction process. The proposed framework consists of three main steps: 1) Following bias correction of the brain, a new three-dimensional (3-D) MGRF having a 26-pairwise interaction model is applied to enhance the homogeneity of MR images and preserve the 3-D edges between different brain tissues. 2) The nonbrain tissue found in the MR images is initially removed using the brain extraction tool (BET), and then the brain is parceled to nested isosurfaces using a fast marching level set method. 3) Finally, a classification step is applied in order to accurately remove the remaining parts of the skull without distorting the brain geometry. The classification of each voxel found on the isosurfaces is made based on the first- and second-order visual appearance features. The first order visual appearance is estimated using a linear combination of discrete Gaussians (LCDG) to model the intensity distribution of the brain signals. The second-order visual appearance is constructed using an MGRF model with analytically estimated parameters. The fusion of the LCDG and MGRF, along with their analytical estimation, allows the approach to be fast and accurate for use in clinical applications. The proposed approach was tested on in vivo data using 300 infant 3-D MR brain scans, which were qualitatively validated by an MR expert. In addition, it was quantitatively validated using 30 datasets based on three metrics: the Dice coefficient, the 95% modified Hausdorff distance, and absolute brain volume difference. Results showed the capability of the proposed approach, outperforming four widely used BETs: BET, BET2, brain surface extractor, and infant brain extraction and analysis toolbox. Experiments conducted also proved that the proposed framework can be generalized to adult brain extraction as well. PMID- 25823049 TI - An Implantable RFID Sensor Tag toward Continuous Glucose Monitoring. AB - This paper presents a wirelessly powered implantable electrochemical sensor tag for continuous blood glucose monitoring. The system is remotely powered by a 13.56-MHz inductive link and utilizes an ISO 15693 radio frequency identification (RFID) standard for communication. This paper provides reliable and accurate measurement for changing glucose level. The sensor tag employs a long-term glucose sensor, a winding ferrite antenna, an RFID front-end, a potentiostat, a 10-bit sigma-delta analog to digital converter, an on-chip temperature sensor, and a digital baseband for protocol processing and control. A high-frequency external reader is used to power, command, and configure the sensor tag. The only off-chip support circuitry required is a tuned antenna and a glucose microsensor. The integrated chip fabricated in SMIC 0.13-MUm CMOS process occupies an area of 1.2 mm *2 mm and consumes 50 MUW. The power sensitivity of the whole system is -4 dBm. The sensor tag achieves a measured glucose range of 0-30 mM with a sensitivity of 0.75 nA/mM. PMID- 25823050 TI - Wireless gigabit data telemetry for large-scale neural recording. AB - Implantable wireless neural recording from a large ensemble of simultaneously acting neurons is a critical component to thoroughly investigate neural interactions and brain dynamics from freely moving animals. Recent researches have shown the feasibility of simultaneously recording from hundreds of neurons and suggested that the ability of recording a larger number of neurons results in better signal quality. This massive recording inevitably demands a large amount of data transfer. For example, recording 2000 neurons while keeping the signal fidelity ( > 12 bit, > 40 KS/s per neuron) needs approximately a 1-Gb/s data link. Designing a wireless data telemetry system to support such (or higher) data rate while aiming to lower the power consumption of an implantable device imposes a grand challenge on neuroscience community. In this paper, we present a wireless gigabit data telemetry for future large-scale neural recording interface. This telemetry comprises of a pair of low-power gigabit transmitter and receiver operating at 60 GHz, and establishes a short-distance wireless link to transfer the massive amount of neural signals outward from the implanted device. The transmission distance of the received neural signal can be further extended by an externally rendezvous wireless transceiver, which is less power/heat-constraint since it is not at the immediate proximity of the cortex and its radiated signal is not seriously attenuated by the lossy tissue. The gigabit data link has been demonstrated to achieve a high data rate of 6 Gb/s with a bit-error-rate of 10( 12) at a transmission distance of 6 mm, an applicable separation between transmitter and receiver. This high data rate is able to support thousands of recording channels while ensuring a low energy cost per bit of 2.08 pJ/b. PMID- 25823051 TI - Toward noninvasive quantification of brain radioligand binding by combining electronic health records and dynamic PET imaging data. AB - Quantitative analysis of positron emission tomography (PET) brain imaging data requires a metabolite-corrected arterial input function (AIF) for estimation of distribution volume and related outcome measures. Collecting arterial blood samples adds risk, cost, measurement error, and patient discomfort to PET studies. Minimally invasive AIF estimation is possible with simultaneous estimation (SIME), but at least one arterial blood sample is necessary. In this study, we describe a noninvasive SIME (nSIME) approach that utilizes a pharmacokinetic input function model and constraints derived from machine learning applied to an electronic health record database consisting of "long tail" data (digital records, paper charts, and handwritten notes) that were collected ancillary to the PET studies. We evaluated the performance of nSIME on 95 [(11)C]DASB PET scans that had measured AIFs. The results indicate that nSIME is a promising alternative to invasive AIF measurement. The general framework presented here may be expanded to other metabolized radioligands, potentially enabling quantitative analysis of PET studies without blood sampling. A glossary of technical abbreviations is provided at the end of this paper. PMID- 25823052 TI - Understanding user intents in online health forums. AB - Online health forums provide a convenient way for patients to obtain medical information and connect with physicians and peers outside of clinical settings. However, large quantities of unstructured and diversified content generated on these forums make it difficult for users to digest and extract useful information. Understanding user intents would enable forums to find and recommend relevant information to users by filtering out threads that do not match particular intents. In this paper, we derive a taxonomy of intents to capture user information needs in online health forums and propose novel pattern-based features for use with a multiclass support vector machine (SVM) classifier to classify original thread posts according to their underlying intents. Since no dataset existed for this task, we employ three annotators to manually label a dataset of 1192 HealthBoards posts spanning four forum topics. Experimental results show that a SVM using pattern-based features is highly capable of identifying user intents in forum posts, reaching a maximum precision of 75%, and that a SVM-based hierarchical classifier using both pattern and word features outperforms its SVM counterpart that uses only word features. Furthermore, comparable classification performance can be achieved by training and testing on posts from different forum topics. PMID- 25823053 TI - Finite Time Control Design for Bilateral Teleoperation System With Position Synchronization Error Constrained. AB - Due to the cognitive limitations of the human operator and lack of complete information about the remote environment, the work performance of such teleoperation systems cannot be guaranteed in most cases. However, some practical tasks conducted by the teleoperation system require high performances, such as tele-surgery needs satisfactory high speed and more precision control results to guarantee patient' health status. To obtain some satisfactory performances, the error constrained control is employed by applying the barrier Lyapunov function (BLF). With the constrained synchronization errors, some high performances, such as, high convergence speed, small overshoot, and an arbitrarily predefined small residual constrained synchronization error can be achieved simultaneously. Nevertheless, like many classical control schemes only the asymptotic/exponential convergence, i.e., the synchronization errors converge to zero as time goes infinity can be achieved with the error constrained control. It is clear that finite time convergence is more desirable. To obtain a finite-time synchronization performance, the terminal sliding mode (TSM)-based finite time control method is developed for teleoperation system with position error constrained in this paper. First, a new nonsingular fast terminal sliding mode (NFTSM) surface with new transformed synchronization errors is proposed. Second, adaptive neural network system is applied for dealing with the system uncertainties and the external disturbances. Third, the BLF is applied to prove the stability and the nonviolation of the synchronization errors constraints. Finally, some comparisons are conducted in simulation and experiment results are also presented to show the effectiveness of the proposed method. PMID- 25823054 TI - Control Synthesis of Discrete-Time T-S Fuzzy Systems via a Multi-Instant Homogenous Polynomial Approach. AB - This paper deals with the problem of control synthesis of discrete-time Takagi Sugeno fuzzy systems by employing a novel multiinstant homogenous polynomial approach. A new multiinstant fuzzy control scheme and a new class of fuzzy Lyapunov functions, which are homogenous polynomially parameter-dependent on both the current-time normalized fuzzy weighting functions and the past-time normalized fuzzy weighting functions, are proposed for implementing the object of relaxed control synthesis. Then, relaxed stabilization conditions are derived with less conservatism than existing ones. Furthermore, the relaxation quality of obtained stabilization conditions is further ameliorated by developing an efficient slack variable approach, which presents a multipolynomial dependence on the normalized fuzzy weighting functions at the current and past instants of time. Two simulation examples are given to demonstrate the effectiveness and benefits of the results developed in this paper. PMID- 25823055 TI - Optimized Assistive Human-Robot Interaction Using Reinforcement Learning. AB - An intelligent human-robot interaction (HRI) system with adjustable robot behavior is presented. The proposed HRI system assists the human operator to perform a given task with minimum workload demands and optimizes the overall human-robot system performance. Motivated by human factor studies, the presented control structure consists of two control loops. First, a robot-specific neuro adaptive controller is designed in the inner loop to make the unknown nonlinear robot behave like a prescribed robot impedance model as perceived by a human operator. In contrast to existing neural network and adaptive impedance-based control methods, no information of the task performance or the prescribed robot impedance model parameters is required in the inner loop. Then, a task-specific outer-loop controller is designed to find the optimal parameters of the prescribed robot impedance model to adjust the robot's dynamics to the operator skills and minimize the tracking error. The outer loop includes the human operator, the robot, and the task performance details. The problem of finding the optimal parameters of the prescribed robot impedance model is transformed into a linear quadratic regulator (LQR) problem which minimizes the human effort and optimizes the closed-loop behavior of the HRI system for a given task. To obviate the requirement of the knowledge of the human model, integral reinforcement learning is used to solve the given LQR problem. Simulation results on an x - y table and a robot arm, and experimental implementation results on a PR2 robot confirm the suitability of the proposed method. PMID- 25823056 TI - [Protocol of the 500th jubilee meeting of the Society of Oncologists, devoted to the theme of "Hormone-dependent tumors -- pathogenesis and therapy," May 12, 2014]. PMID- 25823057 TI - [Jubilee of Iu. S. Sidorenko, member of the Russian National Academy of Sciences]. PMID- 25823058 TI - [Sergei Fedorovich Goncharov]. PMID- 25823059 TI - [Igor' Borisovich Ushakov]. PMID- 25823060 TI - [Vladimir Petrovich Kharchenko]. PMID- 25823061 TI - [Anastasiya Pavlovna Shitskova]. PMID- 25823062 TI - [Laureates of the Palladin Prize of the National Academy of Sciences of Ukraine (2005, 2007 years)]. PMID- 25823063 TI - [Laureates of the Palladin Prize of the National Academy of Sciences of Ukraine (2008, 2011)]. PMID- 25823064 TI - Foreword. Medical accidents. PMID- 25823065 TI - Preface.Patients with end-stage renal disease. PMID- 25823066 TI - Enrollment tops HHS goal as consumers face tax penalties. PMID- 25823067 TI - Colleagues in disaster recovery. Hospital CEO humbled by outpouring of support following tornado. PMID- 25823068 TI - Excellence in governance 2015. Using lessons from Disney, board chair leads Orlando Health turnaround. PMID- 25823069 TI - Board chair puts practice on hold to steer hospital. PMID- 25823070 TI - Seasoned executive guides staff through ownership changes. PMID- 25823071 TI - Leader forges partnerships to improve care. PMID- 25823073 TI - Round 2: no win for the ACA. PMID- 25823072 TI - Geisinger's second century of innovation. Health system spreading best practices through new company. PMID- 25823074 TI - Lessons from 'Main Street' doc practices. PMID- 25823075 TI - Using volunteers to improve discharges. PMID- 25823076 TI - 'Imagine if healthcare were priced to consumers'. PMID- 25823077 TI - Largest behavioral-health providers. Ranked by net patient revenue in 2013, based on CMS Hospital Cost Report data. PMID- 25823078 TI - Jewish dermatologists in Nazi Germany. PMID- 25823080 TI - Radiation-associated atypical vascular lesions: vascular lesions with endothelial cell atypia presenting in the radiation port of breast cancer patients. AB - Atypical vascular lesions are an uncommon adverse sequela to the radiotherapy of tumors. Many characteristics are shared between atypical vascular lesions caused by radiation port and well-differentiated radiation-induced angiosarcomas. The authors retrospectively reviewed the medical literature using PubMed, searching the terms acquired, atypical, benign, lymphangioma, lymphangioendothelioma, lymphangiomatous, lesion, papules, progressive, and vascular. Patient reports and previous reviews of the subject were critically assessed and the salient features are presented. Atypical vascular lesions associated with the radiation port present as clinically innocuous flesh-colored to erythematous papules or plaques. The condition presents within the radiation field, approximately 3 years after initial treatment. While the exact me chanism remains to be elucidated, growing evidence supports an association between radiation-associated atypical vascular lesions and radiation-induced angiosarcomas. Atypical vascular lesions within a radiation port are suggested to be in a state of morphologic continuum, which may progress into the more aggressive, malignant angiosarcoma. The authors recommend consideration for biopsy of new skin lesions within or adjacent to radiation. While it is clear that atypical vascular lesions caused by radiation are not equivalent to angiosarcoma, growing evidence supports that radiation-associated atypical vascular lesions may progress to angiosarcoma in some patients; therefore, the authors recommend excision of the lesion with margins depending on clinical judgment and the lesion encountered. PMID- 25823079 TI - Scleredema Adultorum of Buschke. PMID- 25823081 TI - Cutaneous inflammatory lipid mediators. AB - Inflammation is the physiological response of the organism to different stimuli such as infection, trauma, or immunological mechanisms. Lipid mediators play a major role in skin inflammation and are known as "local mediators" acting in the intercellular microenvironments, where they reach considerable levels. A complex family of lipid mediators regulates a wide variety of physiological responses and pathological processes. Lipid mediators are produced by all human tissues, differing widely in the amounts of the various enzymes they contain and, therefore, in the relative proportions and amounts of products. The authors emphasize the effects and roles of lipid mediators in skin inflammation, focusing particularly on evidence provided by recently published studies. In the future, pharmacologic manipulation of lipid mediators and their receptors may provide a novel approach for controlling inflammation. PMID- 25823083 TI - Dalbavancin (Dalvance) for the treatment of acute bacterial skin infection. PMID- 25823082 TI - Footwear dermatitis: historical background, epidemiology, clinical connotation Part II. AB - Footwear dermatitis is a disabling condition that is identified by blistering and/or weeping feet that may become secondarily infected and painful. Fissuring is a common feature, resulting in an inability to walk, and it may prevent the wearing of footwear, especially when shoes are the cause of the dermatosis. In the absence of adequate care and therapy, footwear dermatitis may turn into a chronic distressing disease that largely effects the daily quality of life of patients. PMID- 25823084 TI - Don't blow your top: protecting the information trail in epidermis--fragile skin biopsies. PMID- 25823085 TI - Eosinophilic annular erythema: attention must be paid. PMID- 25823086 TI - Physical modalities in dermatology: 1870-1975. PMID- 25823087 TI - Centrally located acquired bilateral nevus of ota-like macules: a bizarre pattern. AB - A 22-year-old woman was referred to our hospital for pigmented lesions located on her face. These had gradually increased during the past 4 years. Computed tomography (CT) of her head revealed no significant parenchymal abnormalities of temporal, maxillary and sphenoid bones or of either parietal bone. Further screening, including neurologic, ophthalmologic, orthopedic, and visceral investigations, did not reveal any abnormalities. There was no family history of abnormal cutaneous pigmentation. PMID- 25823088 TI - The clinical challenges in the management of deep lymphangioma of the foot. AB - A 12-year-old girl presented with swelling on the lateral aspect of the left foot since early childhood, progressively increasing in size and now causing pain on walking. Pain was relieved with medication only. There was also history of a single episode of blood-tinged discharge from the swelling 3 years prior. There was no history of trauma, diabetes, or hypertension. PMID- 25823089 TI - The preterminal arterioles in the pulmonary circulation of high-altitude natives. PMID- 25823090 TI - Some hemodynamic problems in transposition of the great vessels. PMID- 25823091 TI - Adaptation to exercise in angina pectoris. The electrocardiogram during treadmill walking and coronary angiographic findings. AB - Twelve patients with angina pectoris manifested an ability to adapt to exercise during treadmill stress testing with electrocardiographic monitoring. Three patterns of adaptation were seen. Nine subjects had the ability to continue walking after the onset of angina with eventual disappearance or lessening of anginal pain and the associated ischemic ST-segment depression; anginal pain and ST depression began to diminish during a steady state of blood pressure and heart rate in those cases in which these factors were measured. Four subjects were able to continue walking for long periods of time during a state of angina and ischemic ST depression. Three subjects demonstrated an increase in exercise capacity after being warmed up by a preceding bout of exercise-induced angina; blood pressures and heart rates during the initial, "warming-up" effort tended to be higher than those during the early stages of the second effort. In three subjects more than one of these patterns of adaptation were demonstrated. Five of the subjects showed striking subjective and objective improvement in exercise tolerance while on a program of regular walking exercise. Selective coronary cineangiography was performed in eight of these patients and two patterns of coronary disease were seen: (1) occlusion of a major coronary vessel with good collateral channels circumventing the obstruction; (2) strategically placed, proximal, stenotic lesions in major coronary vessels without frank occlusion and without discernible collateral development. Some diagnostic and therapeutic implications of these findings are discussed. PMID- 25823092 TI - Infarction patterns in endocardial fibroelastosis. AB - Three cases of endocardial fibroelastosis with vectorcardiographic findings suggestive of an anterior myocardial infarct are presented. It had been previously reported that such vectorcardiographic features were diagnostic of anomalous origin of the left coronary artery. We conclude that the two diseases can not be differentiated on the basis of electrocardiography or vectorcardiography alone. Two of the cases presented were in identical twins; serial scalar electrocardiograms and vectorcardiograms were obtained during the development and progression of endocardial fibroelastosis. PMID- 25823093 TI - Bacterial endocarditis following aortic valve replacement. Clinical and pathologic correlations. AB - The clinical and pathologic findings in three patients with bacterial infection at the sites of prosthetic aortic valves are described. Each presented typical clinical features of acute bacterial endocarditis followed by the sudden development of severe and ultimately fatal aortic regurgitation. Pathologically the infectious process was characterized by extensive necrosis of the aortic annulus, disruption of the aortic wall, and the formation of abscesses in the periaortic tissues. In two patients the prosthetic valve was partially detached from the annulus, whereas in the other it was totally dislodged and impacted in the aortic arch shortly before death. In all, secondary operative intervention would have been fruitless because of the extent of the infection and the character of the tissue at the aortic root. In one patient fatal staphylococcal endocarditis followed dental extractions despite penicillin prophylaxis. A more comprehensive antibiotic regimen for patients with prosthetic cardiac valves is suggested. PMID- 25823094 TI - Evaluation of the severity of mitral stenosis and regurgitation. AB - Indices have been developed that provide an improved means for evaluation of the degrees of severity of mitral stenosis and regurgitation. The severity of anatomic mitral valve disease found at surgery or autopsy was considered to be the determinant of the state of the valve. An index of the time for the diastolic atrioventricular pressure gradient to fall to half its value multiplied by 100 and divided by the cardiac index was shown to be comparable to the severity of anatomic stenosis. This index ranged from 5.7 to 10 in mitral stenosis, 0.4 to 0.8 in normal subjects, and 0.6 to 2.0 in patients with predominant mitral regurgitation. Mitral regurgitation was estimated by an index of the rate of the atrial pressure rise during ventricular systole in mm. Hg/0.02 second multiplied by 10, and divided by the cardiac index. In predominant mitral regurgitation, this index ranged from 8.0 to 15; in mitral stenosis these values were 3.7 to 6.3, and normal subjects had an index varying from 2.5 to 3.7. Both indices were significantly elevated in patients in whom stenosis and regurgitation were present at surgery. Mitral stenosis complicated by a mild degree of regurgitation gave significantly elevated stenotic indices, while the regurgitation indices were normal or slightly elevated. These indices facilitate the evaluation of either mitral stenosis or regurgitation even when both processes are present together. The significance of these indices in the evaluation of the degree of invalidism in patients with valvular disease is also discussed. PMID- 25823095 TI - Intercoronary anastomoses in congenital heart disease. AB - Thirty-five cases of congenital heart disease were investigated for the frequency and size of intercoronary anastomoses. Studies of control hearts showed normal intercoronary anastomoses to range to 74 MU in diameter. In those congenital hearts not subjected to surgical procedures, the anastomoses did not differ in size from the control group, even in the presence of anemia, cardiac hypertrophy, and cyanosis. However, the mean age of the cyanotic group was significantly less than the acyanotic group. Even though the size and frequency of the anastomoses were significantly increased in the operated group, surgical trauma alone was an unlikely stimulus, since the size and frequency of anastomoses in those dying within 48 hours of operation and in those surviving for more than 5 weeks were similar. There was also a significant increase in the frequency and size of the intercoronary anastomoses in cases greater than 5 years of age, implying that intercoronary communications in congenital heart disease increase in size with increasing age. PMID- 25823096 TI - Transposition of the great vessels. Pathophysiologic considerations based upon a study of the lungs. AB - A microscopic study of the lungs of 106 patients with transposition of the great vessels has revealed early and severe hypertensive alterations in the pulmonary arteries. These striking changes, associated in almost all instances with normal pulmonary veins, indicate a state of high resistance of the arterial bed. Pulmonary arterial damage was, in general, most advanced in the patients with a large ventricular septal defect, but in spite of this these were the patients who lived longest. It seemed obvious, therefore, that their relatively favorable course was due to a greater beneficial than damaging effect of the ventricular septal defect. Consideration of these findings in the light of known physiologic data has led to a clarification of the physiologic variations of the transposition circulation. Using the recognized physiologic definitions of flows and shunts the transposition circulation is characterized by a diminished effective flow and a bidirectional but predominantly left-to-right shunt. The effect of a large intracardiac communication is to increase the effective flow and to lessen the shunts. With increasing size of the intracardiac communication the spectrum is completed when the circulatory characteristics of a single ventricle are reached in which the anatomic position of the great vessels becomes physiologically insignificant. The effect of a common systolic ejectile force in patients with a large ventricular septal defect will be similar in the transposition circulation and in the normal circulation. Three physiologic states are possible which depend upon the relative magnitude of the systemic and pulmonary resistances. The early appearance and malignant nature of the hypertensive alterations in the pulmonary arteries of patients with transposition of the great vessels suggest that the impact upon the lungs of high blood flow and pressure is aggravated by arterial vasoconstriction. This may be initiated by anoxia and a lowered blood pH. Elevation of pulmonary venous pressure and the increased viscosity of the blood due to polycythemia may add to the damage. Prominence of the bronchial arteries noted in the lung sections suggests that an expanded bronchial circulation augments the effective flow in these patients. If the bronchial venous drainage leads to systemic veins, the bronchial circulation could act as an accessory pulmonary circulation and could improve the effective flow without having to cross the already overloaded intracardiac communications. The anatomic findings and physiologic considerations reported in this study reveal several aspects of the early and severely damaging cardiopulmonary effect of transposition of the great vessels and indicate an urgent necessity of surgical therapy in early life. PMID- 25823097 TI - Percutaneous suprasternal puncture (Radner technique) of the pulmonary artery in transposition of the great vessels. AB - Introduction of a cardiac catheter into the pulmonary artery from the right heart is not possible in a substantial proportion of patients with transposition of the great vessels. It is necessary to obtain the pulmonary artery pressure and oxygen saturation value to evaluate the degree of pulmonary stenosis and the pulmonary vascular resistance. Twenty-three patients are described in whom this was accomplished by percutaneous suprasternal puncture. There was no mortality and there were no significant complications. The technique appears to be safe and reliable. PMID- 25823098 TI - Pulmonary pressure, cardiac output, and arterial oxygen saturation during exercise at high altitude and at sea level. AB - The response elicited by exercise on pulmonary pressure, cardiac output, and arterial oxygen saturation in 35 lifetime residents of high altitude has been studied at high altitude (14,900 feet above sea level), and 22 residents of low altitude have been studied at sea level. A procedure combining cardiac catheterization, arterial cannulation, and spirometry was carried out. The exercise was moderate and was performed in supine position using a bicycle ergometer, the work load being 300 kg-m/min/m2 and the average increase of the oxygen uptake being 4.7 times at sea level and 4.8 times at high altitude. Both at .sea level and at high altitude the cardiac output augmented during exercise proportionally to the increase in oxygen uptake, and thus followed the pattern of response described by other authors. The cardiac output as well as the oxygen intake, for the magnitude of exertion performed in this study, was almost the same at sea level and at high altitude. The cardiac output rose during exercise almost exclusively as a result of an increase in the heart rate, with the stroke volume remaining practically constant. Despite similar increase in cardiac output, the response of pulmonary pressure was smaller for sea-level subjects than for the high-altitude subjects. Increments of mean pulmonary pressure bf nearly 50% and 100% were observed on exercise at sea level and at high altitude, respectively. During exercise the arterial oxygen saturation did not change in the sea-level studies, but decreased significantly in the high-altitude studies. The decrement observed in high-altitude residents is related to a fall in arterial pO2 which at resting conditions is placed on the steep part of the oxygen dissociation curve. PMID- 25823099 TI - The assessment of operative results in congenital heart disease by intraoperative indicator-dilution curves. AB - In 260 patients with intracardiac shunts, indicator-dilution curves were recorded immediately after corrective operations. In every patient, the effectiveness of the repair was also determined at late postoperative cardiac catheterization or necropsy. In 248 patient (96 per cent) the presence or absence of a shunt, determined from the intraoperative curves, was confirmed by the findings at post operative study. The intraoperative curves were normal in 213 patients, 209 of whom had no residual communication at late evaluation; in four patients, the studies indicated initial complete correction followed by recurrence of the shunt. Abnormal intraoperative curves were recorded in 47 patients, eight of whom died. In 17 of the 39 surviving patients, postoperative catheterization revealed persistent residual shunts comparable in magnitude to those present before operation. Fourteen patients had residual shunts that did not necessitate reoperation, and in eight patients, shunts present at the conclusion of the operation were shown to close in the postoperative period. The study indicates that the recording of intraoperative indicator-dilution curves provides a reliable objective method for evaluating the effectiveness of operation in patients with circulatory shunts. If normal curves are recorded, no residual shunt may be expected in 98 per cent of patients, and postoperative catheterization may be unnecessary unless other hemodynamic data are required. If abnormal intraoperative curves are recorded, however, postoperative study is mandatory, since the shunt will persist in 80 per cent of patients, in many of whom a second operation will be indicated. PMID- 25823100 TI - Epidemiological study of the electrocardiographic diagnosis of left ventricular hypertrophy. AB - Electrocardiograms from 5,129 examined persons, 2,449 men and 2,680 women, 16 years of age or older, were classified according to the Minnesota code of Blackburn and associates. The R wave amplitude criteria for possible left ventricular hypertrophy were fulfilled in 193 tracings from 135 men and 58 women. Age and sex matched controls were randomly selected from the remainder of the examined population for similar measurement. Those with high amplitude R waves and their controls were grouped according to age, sex, and possible cause for anatomical left ventricular enlargement. Precise measurements were made of all the amplitudes and intervals necessary for the application of a variety of other differential items from current diagnostic criteria. The prevalence of the various differential items in the high amplitude and control groups and the frequency with which each was associated with a cause for enlargement indicated their relative sensitivity and specificity. Among the individuals with electrocardiographic evidence of left ventricular hypertrophy according to the Minnesota criteria, there were more persons in the upper and lower quintiles of the relative weight distributions, more hypertensives, more persons with roentgenographic evidence of cardiomegaly, and fewer persons in congestive heart failure than among the controls, but the differences were slight. Most QRS amplitude items were too nonspecific to be of much diagnostic value among young men, and the same items apparently lack sensitivity when applied to the tracings from older women. The items which constitute the Minnesota criteria are useful for screening purposes. Single items are unreliable for the detection of left ventricular hypertrophy and certain combinations are suggested to improve diagnostic accuracy. Still the electrocardiogram is often an inexact method for the recognition of left ventricular hypertrophy and the diagnosis should be based on careful physical and roentgenographic examinations as well. PMID- 25823101 TI - Recurrent "pericardial pain" after pericardiectomy for recurrent acute benign pericarditis. AB - Two cases-of recurrent acute benign pericarditis are presented. Both were characterized by recurrent "pericardial type" pain after nearly total pericardiectomy, a previously unreported occurrence. A plausible explanation for this paradox is presented. PMID- 25823102 TI - Plasma cephalins of patients with acute myocardial infarction. AB - In the plasma of patients with acute myocardial infarction the values for phosphatidyl ethanolamine are on the average 50% to 100% higher than in patients with chronic coronary heart disease and up to 400% higher than in normal individuals. Those for phosphatidyl serine are about 50% higher than in patients with chronic coronary heart disease and up to 300% higher than in normal individuals. Expressed in percentages of total phospholipids, the share of phosphatidyl ethanolamine in acute myocardial infarction is about twice as high as in chronic coronary heart disease and three times as high as in healthy persons. The share of phosphatidyl serine is about 50% higher than in patients with chronic coronary heart disease and also almost 300% higher than in healthy persons. Following the acute incident the values for the cephalins, both phosphatidyl ethanolamine and phosphatidyl serine, decrease slowly. Phosphatidyl ethanolamine reaches the level found in patients with chronic coronary heart disease in about 4 weeks, phosphatidyl serine in about 1 week. PMID- 25823103 TI - Fistula from circumflex coronary artery to superior vena cava. PMID- 25823104 TI - Studies of the retinal circulation in man. Observations on vessel diameter, arteriovenous oxygen difference, and mean circulation time. AB - By photographic techniques measurements have been made in the human retina of vessel size, arteriovenous oxygen difference across the retina, and mean retinal circulation time. By combination of these methods estimates can be made of relative changes in retinal blood flow rate and in the rate of oxygen delivery from the retinal vascular system. Observations are presented on the response of the normal and diseased retinal circulation to a variety of stimuli, particularly changes in blood oxygen and carbon dioxide tensions. PMID- 25823105 TI - Congenital anomalies involving the coronary sinus. AB - A classification is presented of anomalies involving the coronary sinus. These anomalies are classified into four anatomic groups on the basis of (1) enlargement of the coronary sinus, (2) absence of the coronary sinus, (3) atresia of the right atrial coronary sinus ostium, and (4) hypoplasia of the coronary sinus. Anomalies involving the coronary sinus often are associated with other venous anomalies, either of the systemic or the pulmonary circulation. In some there is no basic disturbance of the circulation. Those conditions involving the coronary sinus which are of major functional significance participate in shunts, either left-to-right or right-to-left in nature. Enlargement of the coronary sinus in the absence of a shunt usually indicates that a systemic venous channel joins the coronary sinus anomalously. PMID- 25823106 TI - Lung cancer screening in India: along way to go. PMID- 25823107 TI - Pulmonary rehabilitation in chronic respiratory diseases. PMID- 25823108 TI - Clinical experience on use of oral EGFR-TKIs as first-line treatment of advanced NSCLC from a tertiary care centre in North India and implications of skin rash. AB - BACKGROUND: Limited data are available from India on treatment outcomes with oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in newly diagnosed non-small cell lung cancer (NSCLC). We studied the demographic profile and treatment outcomes of patients with NSCLC, receiving first-line treatment with oral EGFR-TKIs. METHODS: Retrospective study of newly diagnosed NSCLC patients treated with oral EGFR-TKIs over a 4-year period at a tertiary care institute in North India. RESULTS: Of 76 patients studied, females and non smokers constituted 32.9% and 48.7%, respectively. Majority of patients had adenocarcinoma (59.2%), stage IV (64.5%) disease and Karnofsky performance status <= 70 (74.5%). Gefitinib was the most frequently used EGFR-TKI (92.1%). Most common indication for the use of EGFR-TKIs was poor performance status (65.8%). Among assessable patients, disease control and progressive disease were evident in 66% and 34%, respectively. Most common side effects were skin rash (17%) and diarrhoea (10.6%). Patients with and without skin rash differed significantly in relation to objective response to treatment (100% versus 23.1%) and overall survival (median not reached versus 178 days). On multivariate logistic regression analysis, malignant pleural effusion was associated with occurrence of rash (odds ratio = 0.19; 95% confidence interval = 0.04-0.95; p = 0.04). CONCLUSIONS: Oral EGFR-TKIs appear to be useful for the treatment of clinically selected patients with advanced NSCLC. Occurrence of skin rash was independently associated with treatment response and better survival in the current study. PMID- 25823109 TI - Community acquired pneumonia and cardiac diseases: a fatal association. AB - BACKGROUND: Community acquired pneumonia (CAP) remains a common disease condition attributing to a significant mortality and morbidity worldwide. Acute cardiac events (ACEs) are one of the most life-threatening complications in patients with severe pneumonia. METHODS: Retrospective study of burden of ACE in 105 patients admitted with CAP. RESULTS: Twenty-five patients with (CURB-65) score ranging between 0 - 2 did not require intensive care unit (ICU) admission and were admitted in the ward and high dependency unit. Of these, 12 developed ACE and 4 required to be shifted to the ICU for further management. Eighty patients with a CURB-65 score of greater than 3 were admitted to the ICU. Of the patients admitted to the ICU, 10 with ACE died; 2 patients without ACE also died. CONCLUSIONS: Our observations suggest that ACE constitute an important cause of morbidity and mortality in patients with CAP requiring hospitalisition. PMID- 25823110 TI - Role of magnetic resonance imaging cephalometry in obstructive sleep apnoea. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is one of the most common public health problems in adults. Patients with OSA are prone for excessive adipose tissue deposition in the neck, which in turn, increases the upper airway narrowing. Of the imaging modalities available for assessing the upper airway, magnetic resonance imaging (MRI) is found to be useful technique for defining soft tissue abnormalities. METHODS: We prospectively studied 50 patients presenting with OSA and 50 normal controls to evaluate the role of MRI cephalometry in the diagnosis of OSA and compared the cross-sectional area and antero-posterior diameter of the upper airway in the retro-palatal airway and retro-glossal areas by MRI cephalometry. RESULTS: In comparison with controls, cases had a significantly lower cross-sectional area and antero-posterior diameter of the upper airway in the retro-palatal airway and retro-glossal areas. CONCLUSIONS: Our observations suggest that MRI cephalometry is a sensitive technique for the diagnosis of OSA. PMID- 25823111 TI - Smoking cessation: an update. AB - Intervention for smoking cessation has become on urgent need because of increasing tobacco use and health hazards, especially in developing countries. Smoking cessation will be at different states of readiness. The states may be: (i) not ready (pre-contemplation), (ii) unsure (contemplation), (iii) ready (preparation), (iv) action, and (v) maintenance. Counselling and behavioural management is important. The '5 A's-based intervention in the form of Ask, Advise, Assess, Assist and Arrange is implemented. Pharmacologic management is based on first-line treatment in the form of nicotine replacement therapy, bupropion and varinicline and second-line treatment as clonidine and nortriptalin. Every health professional has obligation to help their patients to quit and the intervention should be diagnostic and therapeutic. The best results are obtained by behavioural and social support combined with pharmacotherapy whenever needed. The paper highlights the important component of intervention in smoking cessation. PMID- 25823112 TI - Congenital cystic adenomatoid malformation of the left lung presenting in an adult. PMID- 25823113 TI - Spontaneous oesophago-pleural fistula. PMID- 25823114 TI - A rare case of primary adenoid cystic carcinoma of lung. AB - A 33-year-old male presented with repeated episodes of blood-streaked sputum for last one-and half-year. Chest radiograph showed consolidation in the right lower zone. Fibreoptic bronchoscopy revealed an endoluminal growth in the right lower lobe bronchus. Histopathological examination of bronchoscopic biopsy specimen confirmed adenoid cystic carcinoma. PMID- 25823115 TI - Giant mediastinal haemangiopericytoma: an uncommon case. AB - Haemangiopericytoma is a rare soft tissue tumour characterised by tightly packed tumour cells situated around thin walled endothelial lined vascular channels, ranging from capillary sized vessels to large gaping sinusoidal spaces. The tumour cells are surrounded by reticulin and are negative for muscle, nerve and epithelial markers. The diagnosis of extra-pulmonary intra-thoracic, extra pleural mediastinal mass is difficult. It constitutes only 6% of all primary tumours and cysts of the mediastinum. We report the rare occurrence of primary intra-thoracic, extra-pulmonary mediastinal haemangiopericytoma of mesenchymal origin with perivascular localisation. The patient underwent right postero lateral thoracotomy and post-operatively received chemotherapy with adriamycin (60 mg/m2) on day 1 and ifosfamide (1.5 g/m2) on day 1 to 3. Thirty-seven months after the operation, the patient has been well with evidence of a single recurrence in the left lower lobe. PMID- 25823116 TI - Ancient schwannoma of vagus nerve mimicking hamartoma. AB - Schwannomas arising from vagus nerve sheath are rare mediastinal neurogenic tumours. Schwannomas usually arise from left hemithorax. Unlike a hamartoma, radiologically, calcification is rarely seen in schwannomas. We present the rare case of an ancient schwannoma arising from vagus nerve sheath from the right hemithorax presenting with gross calcification. PMID- 25823117 TI - Tracheobronchopathia osteochondroplastica: a rare cause of difficult intubation. AB - Tracheobronchopathia osteochondroplastica is a rare benign airway disorder which is characterised by submucosal nodules projecting into the tracheo-bronchial lumen usually involving the cartilaginous portions of the tracheo-bronchial tree or larynx. The condition is usually asymptomatic but can rarely present with difficulty during endotracheal intubation or rarely with obstructive airway complications. Bronchoscopic appearance is usually sufficient to make the diagnosis, and tissue biopsies are seldom required. No specific treatment is required in asymptomatic patients. However, interventional bronchoscopy procedures or surgery may be helpful in symptomatic cases. PMID- 25823118 TI - Poland's syndrome with unusual hand and chest anomalies: a rare case report. AB - Poland's syndrome is a rare congenital anomaly consisting of a unilateral absence of the pectoralis major, ipsilateral muscle, hand anomaly and occasionally associated other malformations of the chest wall and breast. Many structural and functional abnormalities have been described in association with this syndrome. We report an incidentally diagnosed case in a 27-year-old male patient who presented to us with symbrachydactyly. In addition to this, anterior depression of 2nd, 3rd and 4th ribs and bifid (forked) 5th rib was present on radiological investigations. The body of sternum was short and deformed on the right side with absence of xiphoid process. All middle phalanges were absent on righthand. It is a rare variant of Poland's syndrome. PMID- 25823119 TI - Clinical profile of pneumonia and its association with rain wetting in patients admitted at a tertiary care institute during pandemic of influenza A (H1N1) pdm09 virus infection. PMID- 25823120 TI - The Author's reply. PMID- 25823121 TI - [Focus in the diagnosis and treatment of thoracolumbar spine fracture]. PMID- 25823122 TI - [Semicircular decompression for the treatment of old thoracolumbar fractures and intractable neuropathic pain]. AB - OBJECTIVE: To investigate the clinical outcomes of semicircular decompression in treating old thoracolumbar fractures and intractable neuropathic pain. METHODS: From September 2009 to September 2013, 21 patients with old thoracolumbar fracture and intractable neuropathic pain were treated with semicircular decompression. Among initial surgery, posterior pedicle screw fixation was used in these patients, with or without laminectomy. All patients were male, range in age from 20 to 28 years old with an average of (25.00+/-2.38) years. Vertebral body residual bone block resulted in intra-spinal placeholder more than 50%. All patients were complete spinal cord injury (ASIA grade) or cauda equina injury. VAS scores was from 6 to 10 points with the mean of 7.14+/-0.91. In these patients, MRI, CT, X-rays were performed; denomination and dosage of analgesics were recorded; nerve function and pain status were respectively evaluated by ASIA grade and VAS score before and after operation. RESULTS: All patients were followed up from 8 to 32 months with an average of (17.29+/-6.02) months. All bone fragments of spinal canal were removed and spinal cord decompressions were achieved. At final follow-up, VAS scores were from 0 to 8 points with an average of (2.43+/-2.46) points, and were obviously reduced than peroperative data (P<0.05). Eleven cases of them stopped analgesic intake and 7 cases reduced using. Three patients' symptoms and VAS scores were not improved. CONCLUSION: Old thoracolumbar fractures and intractable neuropathic pain need receive imaging examination as soon as possible and consider semicircular decompression therapy if bone fragments were in vertebral canal and spinal canal stenosis existed. This therapy can effectively relieve pain and profit nerve functional recovery. PMID- 25823123 TI - [Short-segment posterior pedicle screw combined with vertebral arch bone grafting for thoracolumbar burst fractures]. AB - OBJECTIVE: To analyze the clinical effects of short-segment posterior pedicle screw combined with transpedicle vertebral bone grafting in treating thoracolumbar burst fractures. METHODS: From March 2008 to March 2013, 62 patients with thoracolumbar burst fractures were treated with short-segment posterior pedicle screw combined with transpedicle vertebral bone grafting. Including 40 males and 22 females, the age from 17 to 65 years old with an average of 38 years. According to AO classification, 34 cases were type A3.1, 7 cases were type A3.2 and 21 cases were type A3.3. Load-sharing scores were from 4 to 6 points with an average of 5.4 points. According to ASIA grade, 2 cases were grade C, 5 cases were grade D and 55 cases were grade E. Preoperative, postoperative at 3 d and final follow-up, the Cobb angle, the relative height of anterior vertebral body and the encroachment rate of spinal canal were measured by X-ray films and computed tomography (CT) scan, meanwhile, the information of bone healing and spinal nerves recovery were observed. RESULTS: All patients were followed up from 11 to 14 months with an average of 12.2 months. The duration of removing internal fixation were from 9 to 13 months (averaged, 11.5 months). One suffered from infection and was cured by debridement. Two cases had mild pain of back. At 6 months after operation, according to ASIA grade to evaluate never function, 1 case was grade C, 3 cases were grade D and 58 cases were grade E. X ray and CT showed the fractures obtained good union at final follow-up. The Cobb angle, the relative height of anterior vertebral body and the encroachment rate of spinal canal had obviously improved at 3 days after operation (P<0.05); but there was no significant differences between postoperative at 3 d and final follow-up (P>0.05). CONCLUSION: Short-segment posterior pedicle screw combined with transpedicle vertebral bone grafting is an effective method to treat thoracolumbar burst fractures. It can reduce the loss of postoperative correction and prevent the internal fixation failure. PMID- 25823124 TI - [Long-term effects on health-related quality of life after short-segment pedicle fixation of thoracolumbar fractures without neurologic injury]. AB - OBJECTIVE: To evaluate the effects on health-related quality of life after short segment pedicle fixation of thoracolumbar fractures without neurologic injury. METHODS: A total of 55 patients suffered from thoracolumbar fractures without neurological deficit from January 2007 to October 2010 were included in this retrospective study. Of the 55 patients, 35 were male and 20 were female. The mean age was (44.0+/-10.5) years old (ranged, 7 to 75). Preoperatively, the main clinical symptoms in patients were thoracolumbar pain without neurologic injury and the imaging findings mainly showed that the injured vertebra became wedging or flat with the loss of height. Three questionnaires (ODI, EQ-5D and SF-36) were applied to follow-up in this study. RESULTS: All operations were successful and incisions got primary healing. The function of thoracolumbar spine fully or basiclly restored and postoperative imagings showed fractures healed without loose screws, broken screws or broken rods. The completion rates of all the queasionnaires were 100% while the mean follow-up period was 4.2 years (ranged, 3 to 6). The ODI scores were 25.8+/-18.7, which were statistically higher than those of the general population in our country (P<0.05). The EQ-5D index scores were 0.70, which were statistically lower than those of the normal Chinese population (P<0.05). Compared with the normal scores in our country, the scores of 8 items in the SF-36 questionnaire were obviously lower with significant difference (P<0.05). CONCLUSION: Compared with the normal Chinese population, it should be paid more attention to that the health-related quality of life in patients after short-segment pedicle fixation of thoracolumbar fractures without neurologic injury because of lower scores. PMID- 25823125 TI - [Internal fixation combined with bone grafting through the injured pedicle for the treatment of thoracolumbar burst fractures via a paraspinal intermuscular approach under MAST Quadrant retractor]. AB - OBJECTIVE: To study clinical effects of short-segment fixation and injured vertebra bone grafting through injured pedicle for the treatment of thoracolumbar burst fractures under MAST Quadrant retractor via a paraspinal muscle approach. METHODS: The data of 42 patients with thoracolumbar burst fractures treated from June 2009 to September 2012 were reviewed. There were 19 males and 23 females, with an average age of (55.2+/-11.9) years old. The mean injury time was (5.8+/ 4.3) days. Fracture segments included T10 in 3 cases, T11 in 6 cases, T12 in 13 cases, L1 in 9 cases, L2 in 7 cases, and L3 in 4 cases. According to Denis classification, 9 patients were type A, 21 patients were type B, 5 patiens were type C, 5 patients were type D, and 2 patients were type E. All the patients were treated with short-segment pedicle screw-rod system fixation under MAST Quadrant via the paraspinal muscle approach. The operative time, blood loss, complications and the height of vertebra, kyphosis Cobb angle, VAS scores, JOA scores were measured before and after treatment. RESULTS: After treatment, the vertebral height and kyphosis Cobb angle were restored. Compared with preoperative results, postoperative vertebral height and kyphosis Cobb angle, VAS scores and JOA scores were all improved. But there was no statistically significance in vertebral height, kyphosis Cobb angle between postoperative at 1 week and 1 year. CONCLUSION: Internal fixation combined with injured vertebra bone grafting through the injured pedicle for the treatment of thoracolumbar burst fractures via the paraspinal intermuscular approach under MAST Quadrant is a safe, minimally invasive, effective and satisfactory method. PMID- 25823126 TI - [Analysis of clinical effects of cervical artificial disc replacement or anterior cervical decompression and fusion for the treatment of single cervical disc herniation]. AB - OBJECTIVE: To explore the clinical effects of Mobi-C cervical artificial disc replacement (CADR) and anterior cervical decompression and fusion (ACDF) in treating single cervical disc herniation. METHODS: From June 2009 to June 2012, the clinical data of 27 patients with single cervical disc herniation were retrospectively analyzed. There were 18 males and 9 females, aged from 30 to 62 years old with an average of 46.7 years. Of them, 12 patients were treated with CADR (CADR group) and 15 patients with ACDF (ACDF group). All patients had pain and numbness in neck, shoulder and upper limbs, and courses of disease was from 1 to 13 months with an average of 2.4 months. The data of clinical evaluation and questionnaire survey about quality of life were collected before operation, postoperative at 1 week and final follow-up. Odom criterion was used to evaluate postoperative effect. Visual analogue scale (VAS) was used to record pain levels. Neck disability index (NDI) and health questionnaire SF-36 were used to assess the quality of life. RESULTS: No complications about nerve and blood vessel were found and the patients were followed up from 6 to 30 months, with an average of 16 months. One week after operation, 10 cases got excellent results and 2 good in CADR group; 5 cases got excellent results and 10 good in ACDF group; there was significant difference between two groups (P<0.05). At final follow-up, 10 cases got excellent results and 2 good in CADR group; 12 cases got excellent results and 3 good in ACDF group; there was no significant difference between two groups (P> 0.05). Pain of upper limbs had obviously relieved between two groups at 1 week after operation and final follow-up (P<0.05). VAS of neck and NDI in CADR group had decreased respectively from preoperative 3.58+/-0.79, 23.42+/-6.36 to 0.58+/-0.51, 5.42+/-1.68 at 1 week after operation (P<0.05); but the index in ACDF group was no obvious at 1 week after operation. At final follow-up, VAS of neck and NDI and SF-36 score were obviously improved than preoperation (P<0.05) between two groups. CONCLUSION: Mobi-C CADR retains the movement unit in the decompression segment and can quickly recover normal action for patients. Using CADR method has a good curative effect in the early phase, and the clinical effect is reliable, may improve the quality of life. PMID- 25823127 TI - [Clinical study of a cervical anterior Hybrid technique with posterior longitudinal ligament retained for cervical spondylosis]. AB - OBJECTIVE: To explore the clinical effects and significances of a cervical anterior Hybrid technique with posterior longitudinal ligament retained in treating cervical spondylosis. METHODS: The clinical data of 138 patients with cervical spondylosis underwent cervical anterior Hybrid surgery were retrospectively analyzed from March 2009 to March 2013. There were 52 males and 86 females,the age ranged from 36 to 58 years old with an average of 45.3 years. Course of disease was from 3 to 16 months. Cervical spondylosis classification included 22 cases with nerve root type, 68 cases with myelopathic type, 48 cases with mixed type. All patients were treated with the primary Hybrid surgery and their cervical posterior longitudinal ligaments were retained in anterior decompression. JOA score and image examination were used to evaluate clinical effect, and image examination included range of motion of the replacement segment, range of motion of the whole cervical spine, the sagittal diameter of the spinal cord before and after operation. RESULTS: All operations were successful and operation time was 60 to 125 min (averaged 90.6 min), perioperative bleeding was 10 to 60 ml (averaged 30.1 ml). All patients were followed up from 12 to 48 months with an average of 22.2 months. All pathological segments obtained fully decompression, reserved posterior longitudinal ligament had no obvious hypertrophy, proliferation and calcification. The prosthesis had good location and the incision healed well without complications. Upper limbs root symptoms were completely relieved in the patients with cervical spondylotic radiculopathy, muscle strengths and sensations got different recovery in the patients with cervical spondylotic myelopathy. JOA score was increased from preoperative 8.62+/-1.22 to final follow-up 14.26+/-1.47 (P<0.05). Artificial intervertebral discs were stabilized in the patients, the replacement segment and range of motion of whole cervical spine were respectively (14.2+/- 5.6) degrees and (33.8+/-10.3) degrees , there was no significant differences between preoperative and postoperative (P>0.05). Spinal cord sagittal diameter was increased from preoperative (5.2+/-1.3) mm to postoperative (8.8+/-0.5) mm (P<0.05). CONCLUSION: Anterior cervical Hybrid surgery with posterior longitudinal ligament retained can achieve fully decompression and good clinical efficacy, we recommend retaining the normal posterior longitudinal ligament in surgery as complete as possible. PMID- 25823128 TI - [Sustentaculum tali screw fixation for the treatment of Sanders type II and III calcaneal fractures]. AB - OBJECTIVE: To explore the clinical outcomes of open reduction and internal fixation with calcaneal locking plates in treating Sanders type II and III calcaneal fractures. METHODS: From January 2010 and October 2012, 38 calcaneal fractures with Sanders type II or III were treated with open reduction and internal fixation with calcaneal locking plate. According to the Sanders classification, 15 fractures were classified as type II, 23 fractures as type III. The patients were divided into two groups (group A and B) according to the different fixed methods. Sustentaculum tali was fixed with one screw in group A, including 13 males and 5 females, with a mean age of (38.56+/-8.03) years old (ranged, 25 to 55). And sustentaculum tali was not fixed in group B, including 16 males and 4 females, with a mean age of (42.35+/-8.29) years old (ranged, 29 to 53). Clinical effects were evaluated according to the changes of Bohler's angle and the Maryland Foot Score and VAS score. RESULTS: All patients were followed up from 12 to 20 months with a mean of 14 months. Bohler's angles and subtalar joints obtained satisfactory reconstruction in all patients. One year after operation, the mean Maryland Foot Score was 88.61+/-7.59 in group A; and was 82.40+/-9.24 in group B; Maryland Foot Score of group A was higher and foot functional rehabilitation was better than group B. The mean VAS score was 13.39+/ 11.47 in group A; and was 22.50+/-13.10 in group B; VAS score of group A was lower and foot pain was less than group B. CONCLUSION: Sustentaculum tall screw fixation has advantages of strong fixed strength, high stability, less postoperative pain, rapid functional recovery in treating Sanders type II and III calcaneal fractures. PMID- 25823129 TI - [Anterior cervical intervertebral space decompression under microscope for cervical spondylotic myelopathy in elderly patients]. AB - OBJECTIVE: To investigate the clinical effects of anterior cervical intervertebral space decompression under microscope in treating cervical spondylotic myelopathy in elderly patients. METHODS: From June 2009 to March 2012, 43 patients with cervical spondylotic myelopathy were treated with anterior cervical intervertebral space decompression and intervertebral fusion under microscope. There were 26 males and 17 females, aged from 60 to 72 years old with an average of (64.9+/-3.7) years. Japanese Orthopaedic Association System (JOA) score was from 7 to 12 points with an average of (9.5+/-1.8) points before operation. The function of nerves was assessed before and after operation according to JOA. RESULTS: All patients were followed up from 10 to 18 months with an average of (14.7+/-1.6) months. Postoperative JOA score was (13.81+/ 1.44) points (ranged, 10 to 16), had significantly higher than preoperative (P<0.01). According to the rate of the improved JOA score, 9 cases got excellent results, 26 good, 7 fair, 1 poor. CONCLUSION: Anterior cervical intervertebral space decompression under microscope for cervical spondylotic myelopathy in elderly patients is safe and effective. PMID- 25823130 TI - [Pathomorphological change of the atlanto-occipital segment of vertebral artery related with cervical vertigo]. AB - OBJECTIVE: To explore the pathomorphological change of the atlanto-occipital segment of vertebral artery (V3 part) related with cervical vertigo. METHODS: From June 1999 to November 2011, the pathomorphological change of the atlanto occipital segment of vertebral artery were observed in 1680 patients with cervical vertigo using 3D-CTA technology. The clinical data of these patients were analyzed. There were 783 males and 897 females, aged from 22 to 70 years old with an average of 52.8 years old. Doppler examination showed vertebral basilar artery flow velocity to speed up or slow down. RESULTS: The blood vessel of 3360 branches were detected in 1680 patients and 2778 branches were detected out vascular anomaly. And 829 branches were in V1 segment, 421 were in V2, 328 were in V3, 1190 were in V4. The pathomorphological changes in the atlanto-occipital segment (V3) of vertebral artery included angiospasm, congenital absence, abnormal exit, localized stenosis. CONCLUSION: There are 4 kinds of pathomorphological changes in the atlanto-occipital segment of vertebral artery related with cervical vertigo. The 3D-CTA result can be used to judge prognosis and adopt reasonable treatment for the patients. PMID- 25823131 TI - [Early effect of induced membrane technique for the reconstruction of chronic osteomyelitis defects in limbs of adult patients]. AB - OBJECTIVE: To investigate the early clinical efficacy of induced membrane technique for reconstruction of large bone defects after debridement in adults with chronic osteomyelitis of limbs. METHODS: From March 2010 to March 2012,a total of 23 adult patients with chronic osteomyelitis of limbs were treated in our department. There were 15 males and 8 females, with a mean age 35.2 years old (ranged from 26 to 49 years old). Sixteen patients had open fracture history. According to the lesion site, there were 12 cases of tibia, 7 cases of femur, 3 cases of humerus, and 1 case of both radius and ulna. Among them, 19 patients had diseases in diaphysis and 4 patients in the metaphysis. The mean interval from infection to operation was 6.9 months (ranged from 4 to 13 months). All the patients were treated by using induced membrane technique. The follow-up evaluation included clinical complications, time of bone healing and limbs function. The Chinese version of SF-36 scores was used in the assessment of quality of life pre- and post-operation. RESULTS: The average duration of follow up was (27.6 +/- 5.3) months (ranged from 18 to 43 months). Two patients had postoperative flap edge necrosis, 1 patient had superficial iliac incision infection, no obvious complications were recorded. Twenty patients obtained radiological union at a mean time of 4.6 months (ranged from 3 to 7 months). Among them, 16 patients treated with lower limbs surgery achieved full weight bearing at about 5.2 months (ranged from 4 to 8 months) postoperatively. Four patients suffered from reinfection during follow-up, but 3 of them achieved complete bone healing after the second surgeries with induced membrane technique. At the final follow-up, there was a substantial improvement in each dimension scores and total scores of SF-36 as compared with those before surgery. CONCLUSION: When treating with adult chronic osteomyelitis of limbs, the induced membrane technique can effectively reconstruct large bone defects after debridement, significantly shorten treatment cycle, provide satisfactory results with minimal complications, promote good recovery of limbs function and require relatively simple operation technique. PMID- 25823132 TI - [Treatment of tibial avulsion fracture at the insertion of the posterior cruciate ligament through a minimally posteromedial transverse incision in the hip knee flexion]. AB - OBJECTIVE: To explore the methods and outcomes of a minimally posteromedial transverse incision in the hip knee flexion for the treatment of tibial avulsion fracture at the insertion of posterior cruciate ligament (PCL). METHODS: Twenty one patients with tibial avulsion fracture at the insertion of PCL treated with a minimally posteromedial transverse incision in the hip knee flexion by cannulated screw fixation from March 2010 to March 2013 were retrospectively analyzed. There were 13 males and 8 females with an average age of 35.1 years old (ranged, 20 to 56 years). Eleven cases caused by traffic accident, 3 caused by falling, 4 caused by sport, 3 caused by heavy pounds. The injury duration ranged from 3 hours to 9 days with a mean of 3.5 days. The results of posterior drawer test were positive in all patients. Lysholm score was used to evaluated knee joint function. RESULTS: All operations were successful without infection, vessel and nerve injuries and all incisions healed by first intention with the mean length of 5.8 cm (ranged, 5 to 6 cm). All patients were followed up from 7 to 23 months with an average of 12.7 months. The results of posterior drawer test were negative in all patients. X-ray films showed that all fractures healed. The Lysholm score was improved from preoperative 40.76+/-9.55 to 95.86+/-2.33 final follow-up (t=30.07, P=0.000). CONCLUSION: Treatment of tibial avulsion fracture at the insertion of the posterior cruciate ligament through a minimally posteromedial transverse incision in the hip knee flexion with cannulated screw fixation is a better surgical procedure with the advantages of minimal incision, sufficient exposure, effective fixation, small scar and satisfactory effects. PMID- 25823133 TI - [The impingement of sciatic nerve by acetabular prosthesis after revision hip arthroplasty: a case report]. PMID- 25823134 TI - [Delayed postoperative infection in deep site of fracture of lumbar vertebrae treated through anterior approach: a case report]. PMID- 25823135 TI - [Clinical study of cervical anterior and posterior decompression and internal fixation in the revision of anterior cervical fixation failure]. AB - OBJECTIVE: To investigate the clinical effects and prevent the complications of posterior and anterior decompression and internal fixation in the revision of cervical anterior internal fixation failure. METHODS: From 2008 January to 2011 December, 17 patients with cervical anterior internal fixation failure were treated with posterior and anterior decompression and internal fixation. There were 12 males and 5 females, aged from 26 to 68 years old with an average of 44.1 years. The lower screw loosening was found in 6 cases, the upper screw loosening in 5 cases, titanium mesh caving in 3 cases, the upper screw breakage in 2 cases, the lower screw breakage in 1 case. Informations of bone fusion were observed by X-ray, CT, MRI. Clinical effects were evaluated by modified JOA score. RESULTS: All the revision operations were successfully completed. One case with poor blood coagulation function before operation resulted in postoperative hematoma and occurred neurological symptoms; after hematoma removal and fresh frozen plasma infusion later, neurological symptoms of the patient disappeared. All patients were followed up from 6 to 38 months with an average of (22.4+/-10.0) months. Postoperative at 2 weeks, 3 months, and final follow-up, JOA score had obviously improved and respectively was 13.1+/-1.6, 13.4+/-1.6, 14.2+/-1.5. All internal fixation locations were good after revision,and obtained bone fusion at 10 months after operation, with an average fusion time of 6 months. CONCLUSION: The combined posterior and anterior decompression and internal fixation in the revision of cervical anterior internal fixation failure is safe, can achieve thoroughly decompression, maintain the cervical curvature, reconstruct the three column stability, and it may be used for the patients of cervical anterior fixation failure. PMID- 25823136 TI - [A randomized controlled trials on treatment of cervicogenic sudden hearing loss with chiropractic]. AB - OBJECTIVE: To investigate the clinical effect and safety of chiropractic in treating cervicogenic sudden hearing loss. METHODS: From January 2011 to October 2013, 90 patients with cervicogenic sudden hearing loss were randomly divided into treatment group and control group according to the random number table produced by SPSS 19.0 software. In the treatment group, there were 17 males and 28 females, aged from 31 to 62 years old with an average of (47.57+/-9.43) years; course of disease was from 1 to 3 days with an average of (1.43+/-0.68) days; pure-tone audiometry score was from 46.5 to 77.8 dB with the mean of (61.20+/ 9.83) dB; Northwick Park Neck Pain Questionnaire (NPQ) score was from 17 to 31 scores with an average of (23.46+/-7.18) scores. In the control group, there were 15 males and 30 females, aged from 28 to 64 years old with an average of (45.77+/ 6.99) years; course of disease was from 1 to 3 days with an average of (1.50+/ 0.73) days; pure-tone audiometry score was from 48.1 to 75.0 dB with the mean of (63.91+/-8.05) dB; Northwick Park Neck Pain Questionnaire (NPQ) score was from 20 to 29 scores with an average of (25.61+/-10.43) scores. The patients of control group were treated with dexamethasone intravenous drip of 10 mg, 3 days later, decreased to 5 mg, 3 days again. And with the methycobal intravenous drip of 500 MUg, treatment continued for 10 days. The patients of treatment group were treated with chiropractic additionally except for the therapeutic methods of control group. Chiropractic included local muscle loosening, attacking point, bilateral pulling atlanto-axial joint, and continuous treatment for 10 days. The pure-tone audiometry score and NPQ score were compared between two groups after treatment. RESULTS: After the treatment, pure-tone audiometry score and NPQ score in treatment group improved to (40.23+/- 8.14) dB and (12.70+/-8.29) scores respectively, which were obviously better than that of control group's (37.70+/ 10.61) dB and (21.24+/-11.13) scores (P<0.05). CONCLUSION: Compared with routine method for cervicogenic sudden hearing loss, additional chiropractic can improve hearing and relieve neck pain effectively. PMID- 25823137 TI - [Clinical significance of PCT, CRP, ESR, WBC count as predictors in postoperative early infectious complications with fever after posterior lumbar internal fixation]. AB - OBJECTIVE: To evaluate the role of serum level of procalcitonin (PCT), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell count (WBC) as predictors in postoperative early infectious complications with fever after posterior lumbar internal fixation (PLIF). METHODS: A retrospective study was conducted from January 2012 to January 2014. Fifty-two patients with fever in the early stage(within 10 days) after the PLIF were collected in the study. They were divided into infection group and non-infection group (group A and group B) according to the results of postoperative blood culture. There were 26 patients in group A and 32 patients in group B. The values of PCT, CRP, ESR, and WBC count were compared and analyzed between two groups. RESULTS: The values of PCT, CRP, and ESR in group A were higher than those of group B. Meanwhile, CRP and ESR in group B were still higher than the normal range. Among the 26 patients with infections (group A), PCT was superior to CRP and ESR, had a good ability in discriminating different kinds of postoperative infections. The area under the ROC curve of serum PCT levels was the largest (CI 95% was 0.81 to 0.98) in the indexs; and ROC curve of WBC count was no statistically significant. When the cut off points of each predictors were evaluated, the higher sensitive was CRP and reached at 90.27% and the higher specific was ESR and reached at 88.50%. CONCLUSION: For the patients with fever at the early stage after the PLIF should be paid attention and reasonable choosing predictors are helpful to identify postoperative infection in the early stage. The CRP and ESR may be influenced by the surgery, and the PCT level is helpful to differentiate infection type. PMID- 25823138 TI - [Relations of synovial angiogenesis and PTEN/PI3K/AKT signaling pathway in rats with adjuvant arthritis]. AB - OBJECTIVE: To observe the change of PTEN/PI3K/AKT pathway hypoxia-inducible factor (HIF-1alpha), vascular endothelial growth factor (VEGF) in rats with adjuvant arthritis and to explore the mechanism of neovasculization in rheumatoid arthritis. METHODS: Thirty rats were randomly divided into normal control group and model control group. The model control group were established the model of adjuvant arthritis using Freund's complete adjuvant. At 19 days after modeling, the expression of microvascular density (MVD), HIF-1alpha, VEGF were detected by ELISA assay and PTEN, PI3K, AKT were detected by Werstern Blotting. RESULTS: Compared with the normal control group, paw swelling, arthritic index were increased, and the expression of MVD, VEGF, HIF-1alpha of serum, PI3K, AKT of synovial tissue were significantly increased, PTEN was significantly decreased in model control group. PI3K, HIF-1alpha were positively correlated with MVD; VEGF, AKT were positively correlated with paw swelling; PTEN was negatively correlated with the arthritis index; HIF-1alpha was positively correlated with VEGF; PI3K was positively correlated with AKT, PTEN was negatively correlated with PI3K, AKT, VEGF. CONCLUSION: Imbalance of PTEN/PI3K/AKT pathway in rats with adjuvant arthritis is one of the mechanisms of synovial neovasculization. PMID- 25823139 TI - [Experimental research on substance P content of hypothalamus and dorsal root ganglia in rats with lumbar vertebrae Gucuofeng model]. AB - OBJECTIVE: To detect the effects of lumbar vertebrae Gucuofeng on the substance P content of hypothalamus and dorsal root ganglia in rat models. METHODS: A hundred and twenty SPF level SD male rats with the weight of 350 to 450 g were randomly divided into rotary fixation group (RF group), simple fixation group (SF group) and sham-operation group (Sham group). The external link fixation system was implanted into the L4-L6 of rats in RF group and SF group; and in RF group, that the L5 spinous process was rotated to the right resulted in L4, L5, L6 spinous process not collinear; in SF group, the external link fixation system was simply implanted and not rotated. The rats of Sham group were not implanted the external link fixation system and only open and suture. The substance P content of hypothalamus and dorsal root ganglia were detected at 1, 4, 8, 12 weeks after operation. RESULTS: Substance P content of hypothalamus in RF group and SF group was lower than Sham group at 1, 4, 8 weeks after operation (P<0.05). Substance P content of dorsal root ganglia was higher than Sham group at 1, 4, 8, 12 weeks after operation (P<0.05). There was no significant differences in the substance P content of hypothalamus among three groups at 12 weeks after operation (P>0.05). CONCLUSION: Lumbar vertebrae Gucuofeng can inhibit the analgesic activity of substance P in hypothalamus and promote the synthesis and transmission of substance P in dorsal root ganglia, so as to cause or aggravate the pain. PMID- 25823140 TI - [Surgical treatment for Forestier disease: a report of 8 cases]. AB - OBJECTIVE: To investigate the clinical effects and operative options for the treatment of Forestier disease. METHODS: From June 2005 to May 2012, 8 patients with progressive dysphagia due to Forestier disease were treated through anterior approach, their clinical data were retrospective analyzed. There were 6 males and 2 females, aged from 65 to 83 years old with an average of 73 years. Among the patients, osteophytes removal was performed in 3 cases, osteophytes removal with discectomy and fusion was performed in 2 cases, osteophytes removal with corpectomy and fusion was performed in 3 cases. According to Bazaz dysphagia score to assess the improvement of the patients' symptoms before and after operation. RESULTS: All patients were followed up from 12 to 40 months with the mean of 18.5 months. Seven cases were asymptomatic and 1 case had mild symptom in the last follow-up. Radiographs showed the space enlargement between vertebral body and trachea. CONCLUSION: It is effective to treat patients with progressive dysphagia due to Forestier disease through surgical method. And the operative options depend on the stability of cervical spine and the neurological symptoms of the patients. PMID- 25823141 TI - [Progress on early diagnosis of spinal tuberculosis]. AB - Researching on a large relevant literature of spinal tuberculosis, this paper discussed characteristics of spinal tuberculosis and its early diagnosis method. If spinal tuberculosis can be found and treated earlier, prognosis will be better. The early diagnosis of spinal tuberculosis has become hot spot at present. There are many different diagnostic methods including clinical manifestation, laboratory examination, imaging examination, etc. The newest standpoint showed that immunization has closely correlation with tuberculosis and it will become the focus and developmental direction of future research in spinal tuberculosis. In addition, we should know the differential diagnosis of spinal tuberculosis to avoid the misdiagnosis. PMID- 25823142 TI - [Progress on pain control during the perioperative period of shoulder arthroscopy]. AB - Successful pain management of perioperative shoulder arthroscopy may allow patients to go home earlier, improve the quality of life in perioperative period, and facilitate rehabilitation. A comprehensive method to perioperative pain control has three stages including preoperative, intraoperative and postoperative phase. Successful pain reduction should begin preoperatively because of an excellent communication between patient and physician, moreover, preoperative analgesia also should be administered. Intraoperative efforts should include local wound infiltration and the administration of anesthetic medication intra articularly. Postoperative management should include oral analgesics, constant infusion devices, Patient Controlled Analgesia (PCA), sedative-hypnotic drug, continuous cryotherapy and vicarious treatment. PMID- 25823143 TI - [Progress on establishment of animal model of osteoarthritis by intra-articular injection]. AB - Osteoarthritis (Osteoarthritis, OA) is a common clinical degenerative joint disease with increased incidence rate in recent years. Animal experiment is one of the important ways to explore pathogenesis and treatment of OA, while induced animal model is the most important part in animal experiment. Intra-articular injection of drugs is a classical method for establishing animal model of OA. Choose of animal should follows the principle of correlation, appropriateness and practicability, injections should perform in accordance with experimental purposes and subject, detections means and evaluation methods also should corresponding to experimental reality. The gold standard of OA animal model and intra-articular injections has not build, need further study. PMID- 25823144 TI - The Frax tool: still under utilized. PMID- 25823145 TI - Differential expression of phophatase and tensin homologue in normal, hyperplastic and neoplastic endometrium. AB - OBJECTIVES: To observe the differential expression of phophatase and tensin homologue in normal proliferative, hyperplastic and malignant endometrial lesions. METHODS: .The retrospective study was based on the analysis of endometrial samples, both hysterectomies and curettage, received at the department of pathology Basic Medical Sciences Institute at the Jinnah Postgraduate Medical Centre, Karachi, from January 1, 2006 to December 31, 2010. A total of 55 endometrial samples were analysed for morphological features and results of immunohistochemical staining. RESULTS: Of the 55 samples, 25 (45.45%) were malignant endometrial lesions, 6 (10.9%) complex hyperplasias with atypia, 14(25.45%) complex hyperplasias without atypia hyperplasia, 6 (10.9%) simple hyperplasias without atypia, and 4 (7.27%) normal proliferative endometrium. Among malignant endometrial lesions, 12 (48%) showed complete loss of phophotase and tensin homologue expression out of which majority were endometroid adenocarcinoma. Five (83.3%) cases of complex hyperplasias with atypia and 9 (64.28%) cases of complex hyperplasia without atypia showed complete loss of or diminished expression of phophotase and tensin homologue. CONCLUSION: Loss of phophotase and tensin homologue expression was seen in a significant number of well differentiated endometrial adenocarcinomas and complex hyperplasias with atypia suggesting loss of PTEN expression as an early event in endometrial carcinogenesis. PMID- 25823146 TI - The role of neutrophil gelatinase-associated lipocalin in identifying contrast induced nephropathy development in the emergency department. AB - OBJECTIVE: To evaluate the diagnostic significance of neutrophil gelatinase associated lipocalin in detecting the development of contrast-induced nephropathy in patients undergoing contrast imaging in an emergency department setting. METHODS: The case-control study was conducted at the emergency department of Uludag University, Turkey, between January 1 and July 1, 2012, and comprised patients who underwent a diagnostic thoracic or abdominal Computed Tomography examination with contrast agent. At 2 hours and 72 hours after the scan, control urea, creatinine, and neutrophil gelatinase-associated lipocalin values were recorded. Plasma lipocalin measurement was performed using fluorescence-detected immunoassay method. An increase in serum creatinine of more than 0.5 mg/dl or 25% elevation from the basal level was considered to be a marker for the occurrence of contrast-induced nephropathy. SPSS 13 was used for statistical analysis. RESULTS: Of the 80 subjects in the study, 60 (75%) were cases and 20 (25%) were controls. Contrast-induced nephropathy did not develop in any of the patients, and, accordingly, no significant increase of plasma urea, creatinine, or neutrophil gelatinase-associated lipocalin levels was observed. A significant positive relationship was found between urea and creatinine levels at 2 hours (p < 0.009) and at 72 hours (p < 0.001). CONCLUSIONS: Diagnostic contrast computed tomography examination in patients with normal renal function did not lead to Contrast-induced nephropathy or increased neutrophil gelatinase-associated lipocalin levels, an accepted early indicator of kidney injury. PMID- 25823147 TI - Study guide usability survey: perception of students and teachers of an undergraduate medical college. AB - OBJECTIVES: To explore the perception about usability of study guide from students and teachers of an undergraduate medical college. METHODS: The cross sectional study was done at Bahria University Medical and Dental College, Karachi, in May 2012 and comprised 2nd, 3rd and 4th year medical students and faculty members. Data was analysed on SPSS 16. Analysis of variance was used for looking at differences in perceptions of the three groups of students and among different cadres of faculty, while tukeys test was used for individual differences. RESULTS: Of the 300 students initially enrolled, 257 (85.6%) represented the final study sample. There were 147 (57.2%) females and 110 (42.8%) males. Reliability of the questionnaire by Cronbach's alpha was 0.889. Besides, 150 (58.3%) students agreed that layout and content of the study guide helped in self-directed learning, while 128 (50%) said that information about books and resources was not mentioned in it. The faculty overall appreciated the study guide except on information about identification of resources in it. CONCLUSION: The perception about the usability of study guide was well appreciated by both students and teachers Their content will be reviewed and improved based on the results of this study. PMID- 25823148 TI - Effect of age on uterine and ovarian morphology with polycystic ovaries. AB - OBJECTIVE: To measure the outcome of age on ovarian and uterine morphology in primary infertile women with polycystic ovaries. METHODS: The observational cross sectional study was conducted from January 2009 to March 2010, and the subjects were recruited from Ziauddin Hospital, Nazimabad, Karachi. The primary infertile subjects with polycystic ovaries were subdivided into two age groups: 20-30 years (group I), and 31-40 years (group II). Both groups had equal number of subjects. The ovarian volume, follicles count and size, uterine area and endometrial thickness were determined by transabdominal and transvaginal scans. Shapiro Wilk's test and Mann-Whitney test were applied, with p < 0.05 being significant. RESULTS: There were 200 female subjects in the study who were divided into two equal age-based groups of 100 (50%) each. The mean age of group I was 26.46 +/- 3.55 years and that of group II was 36.73 +/- 3.19. An increase in uterine area from 89.99 +/- 5.83 to 119.0 +/- 23.33 (p < 0.03) and endometrial thickness from 0.48 +/- 0.11 to 0.59 +/- 0.13 (p = 0.01) was observed in group II. A decline in follicular count and size was also noticed in group II (p < 0.02, p = 0.001). Ovarian volume declined from 15.36 +/- 2.56 to 10.57 +/- 1.29 (p = 0.001) in group II. A positive correlation of age with uterine area (r = 0.202; p < 0.003) and endometrial thickness (r = 0153; p < 0.025) was noticed. CONCLUSION: Ovarian morphology decreased in the elder infertile group of women with polycystic ovaries, but the uterine morphology variables showed an increase in area with thickening of the endometrium in the elder group. PMID- 25823149 TI - A multivariate analysis of factors associated with infant mortality in South-East of Iran. AB - OBJECTIVES: To determine the causes and risk factors of infant mortality. METHODS: The population-based case-control study in 2011 comprised infants under one-year-old who had died at Ali-ebn-Abitaleb Hospital in Zahedan, Iran, during 2011 who were taken as the case group, while infants selected randomly through multistage sampling from various health centres formed the control group. Data were analysed using logistic regression model. RESULTS: There were 186 cases including 103 (55.7%) boys, and 29 (15.6%) incidents of multiple births. The other group had 300 healthy infants including 139 (46.5%) boys, and 4 (1.3%) incidents of multiple births. According to the multivariate model, chance of death in neonates with birth weight under 2500 gram, less than 4 antenatal visits, lack of exclusive breast feeding, delivering at home and abortion history among mothers was 46.3%, 27.4%, 13.2%, 9.4% and 7.0% respectively compared to 42.1%, 15.3%, 4.5%, 5.8% and 3.0% respectively in the post-neonatal period. For post-neonatal period, lack of complete vaccination also increased the chance of death by 14.9%. CONCLUSION: Most of the factors related to infant mortality can be controlled by providing sufficient information and healthcare to pregnant mothers which will result in reduced infant mortality rate. PMID- 25823150 TI - Effects of hepatitis C virus gene NS2 on the expressions of Bcl-2 and Bax in HepG2 cells. AB - OBJECTIVE: To study the effects of hepatitis C virus gene nonstructural protein 2 on the expressions of Bcl-2 and Bax in liver hepatocellular cells. METHOD: The study was conducted at the Department of Infectious Diseases, the First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China, from March 2012 to April 2013. Negative controls pEGFP-C3-NS2, pEGFP-C3-C and pEGFP-C3 were transiently transfected into liver hepatocellular cells and expressions of Bcl-2 and Bax were detected by Western blot 24 h post transfection. SPSS 13 was used for statistical analysis. RESULTS: After transfected with NS2 gene, expression of Bcl-2 in liver hepatocellular cells was slightly higher than the non-transfected cells, and the expression of Bax was significantly higher than the non-transfected cells. CONCLUSION: Hepatitis C virus non-structural protein 2 gene plays a role in adjusting the proto-oncogene Bcl-2 and tumour suppressor gene Bax. PMID- 25823151 TI - Predictive validity of medical and dental colleges' entrance test in Punjab: the way forward. AB - OBJECTIVE: To identify the strengths and weaknesses of the current selection process for admissions to public medical colleges being followed in the province of Punjab and to suggest changes. METHODS: The prospective study comprised candidates sitting the Medical and Dental Colleges Entrance Tests administered by the University of Health Sciences, Lahore, from 2008 to 2011. The marks of pre- and post-admission examinations were entered in SPSS 17 and performance of candidates in different examinations up to 2012 was compared using parametric statistical tests. P <= 0.05 was considered statistically significant. Reliability of the entrance test question paper was calculated through Cronbach's Alpha. RESULTS: Overall 1,01,273 candidates sat in the entrance test during the study period, and of them 14, 995 (14.8%) students were admitted to public and private medical colleges in Punjab affiliated with the University of Health Sciences, Lahore. Cronbach's Alpha showed excellent internal consistency reliability of the question paper of 220 items for all these four years. Overall, students scored significantly lower marks (p < 0.05) in all their MBBS Professional Examinations than their pre-admission tests. A similar pattern of difference was seen in entrance test marks in different geographical localities as in the case with MBBS Professional Examination. Students from Islamabad and Rawalpindi regions scored significantly higher marks in all MBBS examinations as well as in the entrance test and aptitude test, but lower in the Higher Secondary School Certificate examination. Internal consistency reliability of the aptitude test was found to be 0.83. Linear regression analysis showed that Estimated Regression Coefficient of the Higher Secondary School Certificate marks was negative, but positive for entrance test and indicated that the latter results were a good positive predictor for the post-selection performance. In the sub components, only the Biology and Chemistry regression coefficient section was found to be positive. CONCLUSIONS: Entrance and aptitude tests in Punjab were found to be valid and reliable with incremental predictive validity at least for performance in the pre-clinical years. It is suggested that Higher Secondary School Certificate-marks should have little, if any, weightage in the selection process. PMID- 25823152 TI - Frequency of severe vitamin-D deficiency in patients presenting to a tertiary care hospital in Islamabad. AB - OBJECTIVES: To determine the frequency of severe vitamin D deficiency in patients presenting in a tertiary care hospital in Islamabad and its possible causes. METHODS: The cross-sectional study involving 351 consecutive patients was conducted at the out-patient department of General Medicine, Federal Government Services Hospital, Islamabad, from September 2011 to June 2012.Both male and female patients between the ages of 13 and 65 were included in the study, while those having renal or liver failure and using drugs that could potentially cause a decrease in vitamin D3 were excluded. SPSS 17 was used for statistical analyses. RESULTS: Of the 351 subjects, 221 (62.9%) were females and 123 (37.1%) were male. The overall mean age was 46.03 +/- 16.18 years. There were 251 (71.5) subjects from Islamabad, followed by 51 (14.6%) from Peshawar, 26 (7.3%) from Rawalpindi, 7(2%) from Abbottabad while 16 (4.6%)were from other parts of Pakistan. Overall, 225 (64%) were aware of the importance of vitamin D, whereas 126 (36%) were not; 246 (70%) knew about the role of vitamin D in normal bone development, and 105 (30%) did not know; 344 (98%) didn't know what was meant by fortified food containing vitamin D, while 168 (48%)experienced generalised body aches and pains and none of the patients had a fracture in the preceding one year. Vitamin D3 levels were decreased in 291 (82.8%) subjects and the mean vitamin D3 level was 14.09 +/- 12.93 ng/dL. CONCLUSION: Undiagnosed vitamin D deficiency is prevalent in the community. With the magnitude of deficiency that is seen in our healthy population, fortification of food items is required. PMID- 25823153 TI - Magnetic resonance spectroscopy of enhancing cerebral lesions: analysis of 78 histopathology proven cases. AB - OBJECTIVES: To investigate the efficacy of magnetic resonance spectroscopy in differentiating various types of neoplastic and non-neoplastic enhancing cerebral lesions. METHODS: The prospective study was conducted from January 2007 to December 2009 at the Department of Radiology, Aga Khan University Hospital, Karachi. All patients with enhancing brain lesions on magnetic resonance imaging who underwent magnetic resonance spectroscopy and a biopsy with histopathological analysis were included in study. The lesions were categorised into neoplastic and non-neoplastic lesions on the basis of spectroscopy findings. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of magnetic resonance spectroscopy were calculated. Predicted probabilities were computed and comparison of median values of metabolites and their ratios was analysed using non-parametric Mann Whitney U test to differentiate between neoplastic and non-neoplastic lesions. RESULTS: Of the 102 patients enrolled, 78 (76.5%) comprised the final study sample. There were 53 (68%) male and 25 (32%) female patients with an overall mean age of 40.21 +/- 17.69 years (range: 4-76 years). The mean overall size of the lesion was 4.01 +/- 1.79 cm, and 61(78%) lesions were neoplastic and 17 (22%) were non-neoplastic. The sensitivity, specificity, positive predictive value and negative predictive value and diagnostic accuracy of magnetic resonance spectroscopy in differentiating neoplastic and non-neoplastic lesions were 90.16%, 64.70%, 90.16%, 64.70% and 78.20% respectively. A cut-off value of 2.55 of Choline/N Acetyl Aspartate ratio depicted sensitivity of 70% in differentiating the lesions. CONCLUSION: Magnetic resonance spectroscopy is a highly sensitive technique in addition to conventional magnetic resonance imaging in characterising and differentiating between neoplastic and non-neoplastic cerebral lesions. PMID- 25823154 TI - Risk factors for intraventricular haemorrhage in preterm infants from a tertiary care hospital of Karachi, Pakistan. AB - OBJECTIVE: To determine the incidence of Intraventricular Haemorrhage in pre-term infants, along with adverse neonatal outcomes associated with the disease. METHODS: The retrospective case control study was conducted at Aga Khan University Hospital, Karachi, and comprised patients' records from January 2004 to December 2009 of preterm babies from 26-35 weeks of gestation who had Intraventricular Haemorrhage of any grade. The diagnosis was confirmed by ultrasound scan. Controls were preterm births matched with the cases according to gestational age (+/-1 week) and birth weight (+/-150 grams). SPSS 19 was used for statistical analysis. RESULT: Of the total 201 preterm babies in the study, there were 67(33.33%) cases and 134(66.66%) controls; the respective ratio being 1:2.The incidence of Intraventricular Haemorrhage in the study population was 22.1 per 1000 live births.The odds of developing Intraventricular Haemorrhage was substantially higher in babies with respiratory distress syndrome (odds ratio: 3.77; 95% Confidence Interval: 1.52-9.37; p < 0.004) and who were given mechanical ventilation (odds ratio: 23.6; 95% Confidence Interval: 5.09-109.5; p < 0.001). There was a four-fold increase in risk of Intraventricular Haemorrhage in babies who received surfactant administration (odds ratio: 4.26; 95% Confidence Interval: 1.77-10.22; p < 0.001). Out of 67 cases, 50 (74.6%) re demonstrated the same grade, 13 (19.4%) were resolved, and 4 (6%) progressed. Overall, there were 38 death; the mortality rate being 56.71. CONCLUSION: The risk of Intraventricular Haemorrhage was substantially higher in preterm neonates with respiratory distress syndrome, etc., and the mortality rate was higher in babies with severe disease. PMID- 25823155 TI - The effects of magnesium sulphate on succinylcholine-induced fasciculation during induction of general anaesthesia. AB - OBJECTIVES: To investigate the effects of magnesium sulphate on succinylcholine induced fasciculation in patients during the induction of general anaesthesia. METHODS: The double-blind randomised clinical trial was conducted in 2012 at Tohid and Besat Hospitals in Sanandaj, Iran, on patients who were candidates for surgery under general anaesthesia. Patients were selected and divided into two equal groups of cases and controls using block randomisation. The cases received magnesium sulphate, while the controls received normal saline. SPSS 18 was used for statistical analysis. RESULTS: Of the 100 subjects in the study, 49 (49%) were men and 51 (51%) were women (p < 0.072). The mean age of the two groups were 37.5 +/- 12.2 years and 37.7 +/- 12 years (p < 0.9). There was significant difference between the two groups in terms of the degree of fasciculation and muscle fasciculation (p< 0.001). The difference between potassium levels in the two groups was not significant before anaesthesia (p > 0.05), but it was significant after anaesthesia (p < 0.001). CONCLUSIONS: Magnesium sulphate can prevent and reduce the degree of fasciculation after anaesthesia. Therefore it can be used to prevent fasciculation. PMID- 25823156 TI - Four-site skinfolds and body fat percentage references in 6-to-17-year old Turkish children and adolescents. AB - OBJECTIVE: As skinfolds from four-sites (triceps, biceps, subscapular, suprailiac) and body fat percentage in 6-17 years is lacking in Turkey. This study was undertaken to produce references for four-site skinfolds and body fat percentage in children and adolescents. METHODS: The cross-sectional study was conducted between September 2007-May 2008 in Kayseri, Turkey, after approval by ethics committee of Erciyes University and local educational authority. Data were obtained from the Determination of Anthropometric Measures of Turkish Children and Adolescents Study-II. Using multistage sampling method, 4285 children were selected from the schools representing city centre, rural and urban areas of the province. Skinfolds were measured from four sites and body fat percentage was calculated according to Westrate and Deurenberg equation. LMS Chart Maker Pro version 2.3 software was used to obtain skinfold references. RESULTS: There were 1914 (44.6%) boys, 2371 (55.3%) girls in the study; the age range being 6-17 years. The peripheral skinfolds increased with age for girls (7.2 mm at age 10 versus 8.7 mm at age 17), while this was true for boys until 10 years (6.2 mm at age 10 versus 4.2 mm at age 17) after which the values gradually decreased. In terms of central skinfolds, girls had higher numbers in each age (11.7 mm for boys versus 12.8 mm for girls at age 6; 24.9 mm versus 26.3 mm at age 17). CONCLUSION: Skinfolds and body fat percentage provide information that helps monitor secular trends in obesity in Turkey and may be used to make national and international comparisons in the future. PMID- 25823157 TI - Pedestrian injuries and fatalities by patterns in reported road traffic crashes- Islamabad. AB - OBJECTIVE: To find the main cause behind pedestrian injuries and fatalities and to categorise the information on the basis of key indicators. METHODS: The retrospective study was conducted in Islamabad, Pakistan, and was based on the officially-lodged First Information Reports of roadside accidents involving pedestrians over a period of 3 years from January 1, 2008, to December 31, 2010. The reports were collected from the Islamabad Police Department and relevant information was extracted on a pre-designed questionnaire having 40 kinds of variables. This study is limited only to causative factors and presentation of data according to age, gender, day and month which was analysed using simple descriptive percentage technique in SPSS 17. RESULTS: During the period covered by the study, there were 250 reported fatal traffic accidents causing 270 fatalities. Pedestrians were involved in 141 (56%) of these accidents in which there were 144 (53.3%) fatalities. Among the fatalities, there were 114 (79%) males and 30 (21%) females. Fatal accidents on midweek Wednesday were 27 (19%) which was more than the other days of the week. The highest number of pedestrian related fatal accidents occurred in December 19 (13.5%). Over-speeding was the major causing factor 42 (29.8%) behind the fatalities. CONCLUSION: Drivers are not giving the right of way to pedestrians and the pedestrians also did not use facilities like footpaths, zebra crossings etc. PMID- 25823158 TI - Patterns of care and outcomes of adult osteosarcoma in a tertiary care cancer centre in Pakistan. AB - OBJECTIVE: To present our experience of treatment outcomes in adult osteosarcoma patients. METHODS: The retrospective study was conducted at the Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised data related to 74 adult patients with osteosarcoma from 1995 to 2009. The treatment plan consisted of surgery preceded by neo-adjuvant chemotherapy followed by adjuvant chemotherapy. SPSS 16 was used for statistical analysis. RESULTS: Of the 74 patients in the study, 58 (78%) were in the 18-29 age group with an overall male-to-female ratio of 3:1. The commonest site of disease was femur, 30 (43%). Of the 66 (89%) patients undergoing definitive surgery, 59 (89.4%) had amputation. The remaining 7 (10.6%) limb salvage operations were in the neo-adjuvant chemotherapy group. Good histopathological response rates in high-dose methotrexate containing regimens and other regimens were similar with an overall good response rate of 18/51 (35%). The commonest site of relapse was lung.Twelve out of 27 (44%) patients with lung-only metastases underwent successful metastatectomy. For patients with localised disease at presentation 3 year event-free survival was 30%, and 3-year overall survival was 71%. For patients with metastases at presentation 3-year overall survival was 45%. Median overall survival for patients receiving high-dose methotrexate and other regimens was 1.7 years vs 2.9 years. CONCLUSION: Adult osteosarcoma treated with cisplatin/doxorubicin based chemotherapy and surgery had good outcomes. The role of high-dose methotrexate in adult osteosarcoma remains uncertain. PMID- 25823159 TI - Clinically significant Coagulase Negative Staphylococci and their antibiotic resistance pattern in a tertiary care hospital. AB - OBJECTIVES: To identify various species of coagulase negative staphylococci involved in neonatal septicaemia and determine their antimicrobial resistance pattern. METHODS: The prospective descriptive study was carried out from January 2012 to October 2013, at Umm Al-Qura University, Makkah, Saudi Arabia, and comprised clinical isolates of coagulase negative staphylococci recovered from the blood of neonates at Maternity and Children Hospital, Makkah..The identification of species and antibiotic sensitivity for each isolate was done using Microscan Walk Away system. RESULTS: Of the 190 clinical isolates S. epidermidis was the most common species found 144(75.8%).The overall drug resistance among the species ranged from 1.6% to 99.5% to all the drugs tested, except to vancomycin and linezolid which were 100% sensitive.The highest drug resistance was exhibited by penicillin 189 (99.5%), ampicillin 188 (99%), oxacillin 178 (93.6%) and augmentin 177 (93%). The minimum drug resistance was shown by synercid 4 (2.2%) and daptomycin 3 (1.6%). All species were 100% resistant to penicillin and ampicillin, except S. hyicus and one isolate of S. hominis-homin which was sensitive to ampicillin. CONCLUSION: High rates of antibiotic resistance was seen among coagulase negative staphylococci to commonly used antibiotics and majority of them were methicillin-resistant. The newer drugs tested can be used as an alternative. PMID- 25823160 TI - Determinants of caesarean section in a tertiary hospital. AB - OBJECTIVE: To analyse the different indications and frequency of caesarean sections in order to reduce such deliveries in a tertiary hospital. METHODS: The retrospective study was conducted at the Department of Obstetrics and Gynaecology, Liaquat National Hospital, Karachi, from January 1 to December 31, 2011. It comprised review of clinical records of all patients who underwent caesarean section during the period. This included booked, un-booked or referred cases and data regarding the indications, type of caesarean deliveries and demographic features as well as outcomes. SPSS 13 was used statistical analysis. RESULTS: During the study period, there were 1491 deliveries out of which 669 (44.8) were caesarean. Emergency caesarean section was performed on 392 (58.5%) and elective caesarean section was performed on 277 (41.4%) patients. Overall, 523 (78.2%) cases were booked and 146 (21.8%) were un-booked or referred cases. Most of the caesarean sections were carried out due to previous caesarean sections 207 (30.9%) followed by foetal distress 102 (15.2%), non-progress of labour 93 (13.9%), malpresentation 44 (6.57%), placental abruption 21 (3.13%) and placenta previa 19 (2.84%). CONCLUSION: Audit and feedback is the best way to judge clinical practice and to reduce the frequency of caesarean section in any tertiary setup. Previous caesareans were the most common indication of repeat procedure in the study. PMID- 25823161 TI - Changes in brain metabolites in experimental cerebral malaria infection with plasmodium berghei ANKA: a literature review. AB - In this paper, we have collected the findings of available literature focusing on brain metabolites by spectroscopy in the murine model of cerebral malaria disease. The literature search for experimental cerebral malaria (ECM) and spectroscopy using National Institute of Health's PubMed database provided us with 9 peer-reviewed publications. These publications have used mice infected with Plasmodium Berghei (PbA) Antwerpen-Kasapa (ANKA) strain to mimic the human infection with Plasmodium falciparum. Brain ischaemia, as depicted by increased lactate and alanine concentrations, as well as decreased aspartate and adenosine triphosphate levels, play a key role in ECM. Lowering the lactate levels by using dichloroacetate has been shown to improve survival. Significant cellular injury has also been documented through decreased N-acetylaspartate and glycerophosphocholine levels. The advantage of using spectroscopic technique provide important functional information which helps determine the aetiology, pathogenesis, progression, and monitoring of treatment as well as predicting prognosis in the clinical setting of cerebral malaria. PMID- 25823162 TI - Serum adiponectin levels in diabetes, obesity and gender in Punjabi subjects from Faisalabad, Pakistan. AB - Adiponectin has been associated with common metabolic disorders. The current study was conducted to measure and compare levels of adiponectin with obesity, type 2 diabetes mellitus (T2DM) and gender in Punjabi subjects from Faisalabad, Pakistan. Serum adiponectin was measured by enzyme-linked immunosorbent assay (ELISA) along with measurements of some clinically important analytes (fasting blood glucose, cholesterol, triglycerides) as well as body mass index (BMI) in 80 subjects. The main results were significantly (p < 0.003) decreased serum adiponectin level in T2DM patients (n = 40) compared to non-diabetic controls (n = 40). In obese subjects, (n = 40) also, there was a decrease, but it was not significant. Adiponectin levels in the subgroups of diabetic and obese patients were also observed, but no significant gender-based differences were found. PMID- 25823163 TI - Hepatotoxicity associated with the ingestion of Papaver Rhoease. AB - Liver injury appears to be associated with the use of herbal products and wild plants.This paper presents what is to our knowledge the first case report in the world of acute liver toxicity caused by Papaver Rhoease. A 17-year- old woman from eastern Turkey ingested Papaver Rhoease which is known as "poppy flower" among the local inhabitants. Her liver function tests were initially 10- 15 fold higher than normal. She was hospitalised in intensive care unit and on day 2 of hospitalisation, the results of her liver function tests showed about a hundred fold increase compared to the normal level. Her general status deteriorated and she was transferred to another medical centre for liver transplantation. PMID- 25823164 TI - A chronic eosinophilic pneumonia case with long exposure to isocyanates. AB - Chronic eosinophilic pneumonia (CEP) is a disease with unknown etiology, characterized by peripheral blood eosinophilia and abnormal eosinophil accumulation in the lungs. A 43-year-old male with 30 years history of exposure to isocyanates was admitted with the complaint of sputum, cough, progressive dyspnoea, and weight loss. Physical examination revealed bilaterally decreased breath sounds and extensive rales. On laboratory analysis; leukocytosis (12.3 10(3)/proportional variant L), hypereosinophilia (30%), elevated CRP and RF (1000 IU/ml), and IgE levels (1160 IU/ml) in the serum were observed. Chest radiograph and computed tomography on admission showed reticulonodular pattern at both lung fields. Pulmonary function tests assumed a restrictive pattern and a low diffusing capacity. Bronchoalveolar lavage revealed a marked eosinophilia (50%). Transbronchial lung biopsy indicated eosinophilic pneumonia. In this case we aimed to describe a rare case of CEP probably caused by exposure to isocyanate. PMID- 25823166 TI - Prolonged mania in a case of bipolar affective disorder. AB - Bipolar disorder, which often has its onset in adolescence or early adulthood, is characterised by marked variations in mood, ranging from major depressive episodes to manic exacerbations. Compared to depressive episodes, manic recurrences are often brief and usually respond to anti-manic medications within a few weeks. Infrequently bipolar patients get badly affected by protracted manic symptoms that exhibit resistance to the usual anti-manic agents. As mania is a very disruptive condition with severe and adverse consequences for the patient, every effort should be made to bring it under control as soon as possible. Nonetheless, an occasional patient may require prolonged and persistent treatment to attain remission. In a case where manic symptoms are showing resistance, an evidence-based pharmacotherapuetic approach by the treating physician is essential. The provision of psychological and social support to the patient is vital in conjunction with biological measures for optimal management. PMID- 25823165 TI - Transient cortical blindness: a benign but devastating complication after coronary angiography and graft study. AB - Transient cortical blindness after coronary angiography and bypass graft is a very rare complication. In this report we present the case of a 63-year-old man who developed transient cortical blindness within 30 minutes of coronary angioplasty and graft study, but subsequently recovered within 72 hours without any neurological deficit. A plain computed tomography brain scan showed bilateral symmetrical subarachnoid hyperdensities in the posterior cerebral circulation area suspicious of subarachnoid bleed. However, magnetic resonance imaging and magnetic resonance angiography scans were normal. Excess contrast volume causing direct neurotoxicity seems to be the most probable cause, but the exact mechanism is unclear. PMID- 25823167 TI - Anthrax: a case report. AB - Anthrax is a zoonotic disease caused by a bacterium called Bacillus Anthracis. In humans, it causes a cutaneous, gastro-intestinal and inhalation form of disease. The in-cutaneous form progresses along with skin necrosis and oedema. Since the necroses in the skin are not quite superficial, they can affect the tendon sheaths progressing close to the skin. Therefore, in surgical treatment, the closure in the areas where tendons are surfaced must be provided by a flap instead of a graft.The repair on the existing patient was performed with a graft since the flap repair was not accepted, and thus, restrictions in hand movements occurred during the post-operative period. PMID- 25823168 TI - Sodium glucose transporter 2 (sglt2) inhibitors: Current status in clinical practice. AB - Sodium glucose transporter 2 (SGLT2) inhibitors including dapagliflozin, canagliflozin and empagliflozin act by a novel insulin-independent mechanism by blocking glucose reabsorption in the proximal convoluted tubules resulting in markedly increased glycosuria, a mechanism not limited by the degree of insulin resistance or beta-cell dysfunction, and which results in weight loss due to loss of 300 to 400kcal/day. Currently dapagliflozin, canagliflozin and empagliflozin are the three primary drugs, which represent this group. They have comparable efficacy in HbA1c reduction as compared to metformin, sulfonylureas and slightly better than gliptins. They have additional beneficial effects on blood pressure and lipids. Their use is not limited by the degree of insulin resistance or beta cell dysfunction, and hence can be used at any stage of diabetes, along with a potential for use in type-1 diabetes. Long term safety and impact on microvascular and macrovascular complications is likely to be favourable, data on which should be available in the next few years. PMID- 25823169 TI - Early magnetic resonance imaging in transient ischaemic attack and minor stroke. PMID- 25823170 TI - How to write an introduction and methods of a systematic review of literature. PMID- 25823171 TI - Rotavirus vaccine--a new hope. AB - Diarrhoea due to Rotavirus is the leading cause of mortality among children less than 5 years of age in developing countries. Though Rotavirus vaccine has been approved by FDA since 2006 it has not been incorporated in the EPI schedule of Pakistan. Objective of our study was to explore the clinical efficacy, cost effectiveness and safety of Rotavirus vaccine in infants and children against diarrhoea caused by Rotavirus. Online search yielded a total of 103 articles out of which 31 articles were included for perusal. Newly-developed vaccines have been found to have combined efficacy of 61.2-64.6% in African Countries and 82.1 84.7% in Europe and Latin America against Rotavirus-induced diarrhoea. Rotavirus vaccine is a very effective option in terms of efficacy, cost and safety against viral diarrhoea caused by Rotavirus. Consideration should be given to include this vaccine in EPI programme of developing countries. PMID- 25823172 TI - The decrepit state of trauma care in under-developed healthcare settings. PMID- 25823173 TI - Nanotechnology and its implication in medical science. PMID- 25823174 TI - Effect of an intervention on attitudes towards domestic violence among Iranian girls. AB - OBJECTIVE: To evaluate the effect of an intervention based on the Precede-Proceed Model on attitudes towards prevention of Domestic Violence among Iranian girls. METHODS: The randomised controlled trial was conducted during 2010-11 at 10 high schools in District 17 ofTehran Municipality in Iran. The subjects were divided into two equal groups of cases and controls. Components of the Precede-Proceed Model for planning, implementation and evaluation of the study. After need assessment, an appropriate environmental and educational intervention was implemented in the intervention group. Changes in predisposing, reinforcing, enabling factors and especially attitudes towards prevention of Domestic Violence immediately and two months after the intervention were assessed in by questionnaires based on the Precede-Proceed Model. SPSS 18 was used for statistical analyses. RESULTS: There were 510 students who comprised the study population, with 255 individuals in each of the two groups. The intervention had significantly positive effect on predisposing, enabling and reinforcing factors immediately and two months after the intervention (p < 0.05). Repeated measures analysis of variance showed a significant positive increase in attitude score in the intervention group from baseline to two months (p < 0.001). CONCLUSION: The Precede-Proceed Model is one of the most widely used health planning models for identifying factors that influence health behaviours associated with domestic violence. Implementation of an educational programme based on the model among young girls was effective in changing attitude towards domestic violence. PMID- 25823175 TI - Intellectual wellness awareness: a neglected area in medical universities of Pakistan. AB - OBJECTIVE: To compare the presence of intellectual wellness awareness in students of public and private sector medical colleges in a metropolitan city. METHODS: The cross-sectional questionnaire-based survey was conducted from March to November 2011 at Bahria University Medical and Dental College, Karachi, and overall covered five private and 3 public sector medical colleges of the city.The study randomly selected 800 medical students.The responses - never, sometimes, mostly and always (numbered 0-4)--were analysed in terms of frequency, proportion and percentages using Predictive Analysis Software version 18. RESULTS: Of the 800 forms distributed, 736 (92%) completed forms were analysed. Among the respondents, 526 (71.5%) were females. Besides, 450 (61%) belonged to private medical colleges and 236 (39) were from public medical colleges. The participants of private medical colleges had taken part in intellectual discussions actively compared to those from public colleges (p < 0.001). Habit of reading books to acquire knowledge was found in 126 (44%) private college students compared to 149 (33%) in public colleges (p < 0.004). The importance of creative mental activities (p = 0.954) and current information about local and international affairs (p < 0.564) was deficient in both sets of students. CONCLUSION: Students of private medical colleges were better in terms of presence of intellectual wellness awareness, took active participation in class discussions, had good reading habits and carefully selected television programmes and movies. PMID- 25823176 TI - Assessment of internet addiction and loneliness in secondary and high school students. AB - OBJECTIVE: To determine the frequency of Internet addiction and loneliness in secondary and high school students. METHODS: The cross-sectional study was conducted between May 7 and June 8, 2012, among secondary and high school students in Sivrihisar, which is a district in rural part of Anatolia, Turkey. The study group consisted of 1157 students. Young Internet Addiction Scale was used to assess the internet addiction. University of California, Los Angeles Loneliness Scale was used for the evaluation of the level of loneliness. SPSS 15 was used for statistical analysis. RESULTS: Of the 1157 students, there were 636 (55.0%) male and 521 (45.0%) female aged 11 to 19 years (mean: 15.13 +/- 1.71 years). According to the Internet Addiction Scale, 91 (7.9%) of the subjects were addicted to the internet. Obesity (odds ratio: 9.57), "Type A" personality (odds ratio: 1.83), first time usage of internet before age 12 (odds ratio: 2.18), using the internet every day (odds ratio: 2.47) and use the internet more than 2 hours a day (odds ratio: 4.96) were risk factors of internet addiction (p < 0.05). A positive correlation was found between the internet addiction and loneliness (rs = 0.121; p < 0.001). CONCLUSION: Internet addiction was found to be a major health problem in middle and high school students. A positive correlation between loneliness and internet addiction was also found. PMID- 25823177 TI - Intralesional triamcinolone alone and in combination with 5-fluorouracil for the treatment of keloid and hypertrophic scars. AB - OBJECTIVE: To compare the use of intralesional triamcinolone acetonide and its combination with 5 flourouracil in the treatment of keloid and hypertrophic scars in terms of reduction in initial height of the scar. METHODS: The randomised controlled trial was conducted at the Department of Plastic Surgery, King Edward Medical University, Lahore, from March 2011 to December 2012. It comprised patients of both genders having keloids or hypertrophic scars (1 cm to 5 cm in size) having no history of treatment for the scars in preceding 6 months. Those who were pregnant, planning pregnancy or lactating were excluded. The subjects were divided into two groups: Group A received intralesional triamcinolone acetonide alone; and Group B received triamcinolone acetonide + 5 flourouracil. Eight injections were given at weekly interval. Scars were assessed 4 weeks after the completion of treatment on a five-point scale. SPSS 16 was used for statistical analysis. RESULTS: The 150 subjects in the study were divided into two equal groups of 75 (50%) each. Good to excellent results were seen in 51 (68%) cases in Group A compared to 63 (84%) in Group B. Frequency of complications was 18 (24%) and 6 (8%) in Group A and Group B respectively. CONCLUSION: Combination of triamcinolone acetonide and 5 flourouracil is superior to triamcinolone acetonide therapy in the treatment of keloids and hypertrophic scars. PMID- 25823178 TI - Pre-natal genetic counseling in a resource limited country--a single center geneticist's perspectives. AB - OBJECTIVE: To assess the needs related to prenatal genetic counselling in a developing country. METHODS: The prospective observational study was conducted at the Prenatal-Genetic Counselling Clinic of Aga Khan University Hospital, Karachi, from October 2007 to September 2010. In-depth interviews were conducted and the data was stored in the form of patient charts. Information was then extracted from the charts and entered into a structured questionnaire. RESULTS: Of the 93 couples in the study, 49 (53%) were in the self-referral group and 44 (47%) were in the physician- referral group. Diagnosis was not given for previously affected children by the paediatrician or by obstetrician for recurrent miscarriages in 68 (73%)cases. Besides, 20 (22%) couples had voluntarily terminated a pregnancy without any tests because of the fear of having a diseased child. Eleven (12%) couples were looking for amniocentensis or chorionic villus sampling. Death in previous children was the main reason to seek genetic counselling and was seen in 57 (61%) couples. Consanguinity was seen in 77 (83%) couples. CONCLUSION: A clear deficiency of knowledge of genetics was seen among the non-genetic healthcare providers. Demand of antenatal genetic testing among the public was also seen, highlighting the need of diagnostic facility for genetic and metabolic disorders. However, this needs to be explored in the context of the existing healthcare infrastructure. PMID- 25823179 TI - Outcome of primigravida with high head at term. AB - OBJECTIVE: To determine the progress of labour, need of medical and surgical intervention and foetal and maternal outcome in primigravida with high head at term METHODS: The prospective descriptive study was conducted at the Department of Obstetrics and Gynaecology, Peoples University of Medical and Health Sciences, Nawabshah, Pakistan, from Jan 1 to June30, 2011, and comprised 100 primigravida with unengaged head at term and at onset of labour. Detailed history was taken in each case and general, systemic and obstetric examination was done. Pelvic assessment and ultrasonography was performed. SPSS 16 was used for statistical analysis. RESULT: Of the 100 women in the study, 70 (70%) were aged between 20-30 years.The most common identified cause of non-engaged head was deflexed head in 28 (28%), while no cause was found in 45(45%) women. Further, 45 (45%) women presented with spontaneous labour, while labour had to be induced with prostaglandin in the rest. Vaginal delivery occurred in 59 (59%) cases and caesarean section was performed in 41 (41%).The duration of labour was < 12 hours in 32 (32%) cases. Postpartum haemorrhage affected 10 (10%) patients, wound infection was seen in 7 (7%), and perineal tear in 2 (2%). Apgar score at 5 minutes was 7-10 in 75 (75%), 4-6 in (20%), 3 and below in 5 (5%) of neonates. PMID- 25823180 TI - Outcome of one stage combined open reduction, pelvic and derotation femoral osteotomy in congenital dislocated hips of children younger than three years age. AB - OBJECTIVE: To determine the outcome of one-stage combined operative management of congenital dislocation of hips in children aged 18-36 months. METHODS: The descriptive case series study was conducted at the Department of Orthopaedic Surgery, Jinnah Postgraduate Medical Centre, Karachi, from January 2005 to December 2011. Children aged 18-36 months suffering from congenital dislocation of hips were included. Those with Tonnis stage III and IV were managed with one stage operative procedure without preliminary traction. The operative procedure included adductor tenotomy, open reduction, capsulorraphy, Salter's osteotomy and a femoral derotation osteotomy. Catteral's 'Test of Stability' was used after open reduction as an indicator for need of pelvic and femoral osteotomies. Follow up ranged between 1 and 7 years. The patients were evaluated clinically on McKay's criteria and radiologically on Severin's criteria. Klisic's overall rating was used to know mean of the assessments. RESULTS: There were 38 patients with 50 congenital dislocations of hip. There were 26 (68.42%) females and 12 (31.57%) males with a female-to-male ratio of 2:1. Mean age at the time of operation was 24.26 +/- 7.6 months. Of the total, 12 (31.57%) patients had bilateral involvement, 11 (28.94%) had right-sided and 15 (39.47%) had left-sided involvement. Right side to Left ratio was 1:1.2. At the time of last follow-up, 25 (50%) hips behaved excellent on McKay's criteria. According to radiographic classification on Severin's criteria, 24 (48%) hips were in excellent class. Avascular necrosis of femoral head was noted in 3 (6%) hips, re-subluxation/re dislocations were observed in 3 (6%) hips and 1 (2.6%) patient had 1 cm femoral lengthening. CONCLUSION: One-stage open reduction, capsulorrapyhy, Salter's osteotomy and femoral derotation osteotomy without preliminary traction to re locate congenital dislocation of hips in late presenting children is a safe and highly effective method. It produces a low rate of complication and need for repeat surgery. It reduces the cost of treatment, minimises socio-economic burden and psychological trauma incurred by lengthy hospitalisation of treatment with traction followed by closed reduction. PMID- 25823181 TI - Role of dissection in light of students' perceptions. AB - OBJECTIVE: To observe students' perception of gross anatomy dissection. METHODS: The qualitative study comprised second year medical students of Army Medical College, Rawalpindi, and was conducted in July, 2013. Data was collected over three weeks through quota sampling. Focus group discussions were held with four groups having 15 students each.The sessions were audio-recorded which were transcribed and interpreted. RESULTS: On the basis of FGDs, four themes were identified: Prossected specimen as an introductory teaching tool; emotional reaction on specimen handling; practical concerns during specimen handling; and experience of learning anatomy. Trends were identified within these broader themes. CONCLUSION: There were differences in terms of attitudes and dissection hall experiences of medical students connected with the learning. PMID- 25823182 TI - Evaluation of the awareness and perception of professional students in medicine, business and law schools of Karachi, regarding the use of (recreational) cannabis. AB - OBJECTIVE: To assess the awareness and perception of students attending professional medicine, law and business schools regarding recreational use of cannabis. METHODS: The cross-sectional study was conducted between June 2010 and November 2010. Using convenience sampling, 150 students from medical, business and law schools from both private and public sectors were enrolled. Government institutions included, Sindh Medical College, Institute of Business Administration and S.M. Law College, private schools were Ziauddin Medical College, SZABIST and Lecole for advanced studies. Data was collected through self administered questionnaire. SPSS 17 was used for statistical analysis. RESULTS: A total of 250 students were approached out of which 150(60%) filled the questionnaire. Of them 91(60.7%) were males and the overall mean age of the respondents was 22 +/- 2 years. A total of 68 (45.3%) students were from the medical field, 53 (35.3%) from business and 29 (19.3%) from law. The private and public sectors were equally represented at 75 (50%) each. Overall, 93 (62%) agreed that hashish is a serious problem concerning student population. When asked to identify factors encouraging abstinence, 67 (44.7%) respondents each cited religion and health risks. CONCLUSION: Our youth is not only concerned about the menace of hashish and but want proper awareness to be provided. PMID- 25823183 TI - A qualitative study on menopause described from the man's perspective. AB - OBJECTIVE: To look at menopause from men's point of view and to provide a better understanding of this phase to improve the care delivered to menopausal women. METHODS: The study was conducted at the health centre of a single district of Istanbul, from April 2013 to June 2013, which serves as the research and training area of the Marmara University and which receives migrations from mainly southern and eastern regions of Turkey.The study sample included 33 married men. Qualitative in-depth interviews were performed individually and main themes were noted down for analysis. RESULTS: The age range of the study population was 40-77 years. The subjects lacked basic knowledge about both menstruation and menopause. Most of the participants defined menopause as loss of fecundity, increased weight, and loss of beauty.The most important concern voiced was men's own sexual life. None of the men had heard about treatment modalities available for menopause. CONCLUSION: Interventions are needed to increase men's awareness regarding menopause in order to help these men to be able to better support their spouses so that they can both have a smooth transition into postmenopausal years. PMID- 25823184 TI - Determining the diagnostic value of endogenous carbon monoxide in chronic obstructive pulmonary disease exacerbations. AB - OBJECTIVE: To determine whether endogenous carbon monoxide levels in exacerbations of Chronic Obstructive Pulmonary Disease patients were higher compared to healthy individuals and to investigate alteration of carbon monoxide levels across the three different severity stages of Global Initiative for Chronic Obstructive Lung Disease criteria related to Chronic Obstructive Pulmonary Disease exacerbations. METHODS: The prospective study was conducted from January to March 2011 at two medical institutions in Ankara, Turkey, and comprised patients of acute Chronic Obstructive Pulmonary Disease exacerbations. The severity of the exacerbations was based on the Global Initiative for Chronic Obstructive Lung Disease criteria. Patients with active tobacco smoking, suspicious carbon monoxide poisoning and uncertain diagnosis were excluded. healthy control subjects who did not have any comorbid diseases and smoking habitus were also enrolled to compare the differences between carboxyhaemoglobin levels A two-tailed Mann-Whitney U test with Bonferroni correction was done following a Kruskal-Wallis test for statistical purposes. RESULTS: There were 90 patients and 81 controls in the study. Carboxyhaemoglobin levels were higher in the patients than the controls (p < 0.001). As for the three severity stages, Group 1 had a median carboxyhaemoglobin of 1.6 (0.95- 2.00). The corresponding levels in Group 2 (1.8 [1.38-2.20]) and Group 3 (1.9 [1.5-3.0]) were higher than the controls (p < 0.001 and p < 0.005 respectively). No statistically significant difference between Group 1 and the controls (1.30 [1.10-1.55]) was observed (p < 0.434). CONCLUSION: Carboxyhaemoglobin levels were significantly higher in exacerbations compared with the normal population. Also, in more serious exacerbations, carboxyhaemoglobin levels were significantly increased compared with healthy individuals and mild exacerbations. PMID- 25823185 TI - Causes of poisoning in patients evaluated in a hospital emergency department in Konya, Turkey. AB - OBJECTIVES: To evaluate demographic and clinical characteristics of patients with poisoning at a community hospital. METHODS: The retrospective study comprised records of patients who were admitted to the emergency department of Konya Numune Hospital, Turkey, because of poisoning between January 1, 2009, and December 31, 2011. Data was evaluated for age, gender, educational status, occupation, arrival time, mechanism of intoxication , body temperature, pulse, respiratory rate, Glasgow Coma Scale score, treatment applied, duration of hospital stay, duration of follow-up, test results, final diagnosis, clinical disposition, and outcome. Agents causing the poisoning were also determined. RESULTS: Records of 1036 patients were evaluated. Of them, 764(74%) were female and 272(26%) were male. The predominant age range was 15-24 years in 617(60%) patients. The median time from substance exposure to admission to the emergency department was 2 hours. The most common cause of poisoning was attempted suicide in 955 [92%] patients and drug intoxication was the agent involved in 932 (90%). In the 15-24 year age range, there were 469 (76%) female patients. Of the total female population in the study, 716 (94%) attempted suicide. The median hospital stay was 24 hours. There were 908 (88%) patients who were advised to seek further evaluation at the psychiatry clinic, and 9 (0.9%) patients were admitted to the psychiatry inpatient units after medical treatment. In patients who were hospitalized and followed up, 1 (0.1%) died because of multiple drug poisoning. CONCLUSION: Most admissions to the emergency department for poisoning related to young women had used drugs during a suicide attempt. PMID- 25823186 TI - Dyslipidaemia in woman with polycystic ovarian syndrome: a case control study in tertiary care hospital of Karachi. AB - OBJECTIVE: To compare lipid profile in lean and obese women with polycystic ovary syndrome with normal weight and obese controls. METHOD: The case-control study was conducted at the Department of Chemical Pathology, Liaquat National Hospital, Karachi, from March 2006 to April 2007. It comprised 50 cases of polycystic ovary syndrome along with 50 healthy controls matching for age, gender and weight. SPSS 14 was used for statistical analysis. RESULT: The mean fasting levels of triglyceride and Low density lipoprotein cholesterol were considerably higher in women with polycystic ovary syndrome than those in the control group (p < 0.05), while high-density lipoprotein cholesterolwas significantly low in patients than the controls (p <0.001). Obese patients had high triglyceride value (p < 0.05). There was significant interaction between polycystic ovary syndrome, obesity and triglyceride levels (p < 0.05). CONCLUSION: Polycystic ovary syndrome is associated with a more pronounced atherogenic lipid profile. Lipid parameters were adversely affected in a subgroup that was obese. As such, women with polycystic ovary syndrome are at high risk of developing cardiovascular disease due to the presence of dyslipidaemia. PMID- 25823187 TI - Effects of aerobic exercise training on maternal and neonatal outcome: a randomized controlled trial on pregnant women in Iran. AB - OBJECTIVE: To assess the effect of aerobic exercise training on maternal and neonatal outcome METHODS: The case-control study was conducted between January and July, 2011 . It was approved by the Research Ethics Committee of Toyserkan Azad University, and data was collected at prenatal clinics and delivery centres located in Hamedan, Iran. It comprised 80 pregnant women between 20-26 weeks of gestation randomly assigned to two equal and matching groups of cases and controls. The intervention group did exercise continuously on a bicycle ergometre for 15 minutes, three times a week; the intensity being 50-60% of maximal heart rate. The control group did not do any exercise training. All information was obtained from the clinics, delivery centres, and from the reports of delivery room midwives. RESULTS: No statistically significant difference was found between the two groups in gestational weight gain, pregnancy length, mode of delivery, first and second stage of labour, perineal tear, and 1st and 5th min Apgar score. Mean neonatal weight was significantly less in the intervention group than the control group (p < 0.001). CONCLUSION: Exercising on a bicycle ergometer during pregnancy seems to be safe for the mother and the neonate. PMID- 25823188 TI - Farsi version of the multidimensional health locus of control and God locus of health control scales: validity and reliability study among Iranian women with a family history of breast cancer. AB - OBJECTIVE: To determine the Persian version's reliability and validity of the Multidimensional Health Locus of Control and God Health Locus of Control scales among women with family history of breast cancer. METHODS: The cross-sectional study was conducted in Sabzevar, Iran, in 2012. It randomly selected women with family members affected by breast cancer. Predesigned questionnaires were completed through interviews. Content and face validity was evaluated using the opinions of a panel of experts, and construct validity was confirmed by applying confirmatory factor analysis.The instruments' reliability was assessed using Cronbach's alpha and test-retest reliability. RESULTS: There were 200 women in the study with their age ranging between 18 and 69 years and revealed the following; root mean square error of approximation for Multidimensional Health Locus of Control Scale = 0.013, and God Locus of Health Control Scale = 0.077; comparative fit index = 0.999, 0.998; incremental fit index = 0.999, 0.998;Tucker Lewis fit index = 0.998, 0.998; and normed fit index = 0.983, 0.997 respectively. Cronbach's alpha was 0.61 for Internal Health Locus of Control, 0.8 for Chance Health Locus of Control, 0.68 for Power Health Locus of Control and 0.9 for God Locus Health Control. CONCLUSION: The Persian version of the subscales supported the main version. PMID- 25823189 TI - Frequency of hyper-homocysteinaemia in ischaemic stroke patients of Karachi. AB - OBJECTIVE: To find out the frequency of hyper-homocysteinaemia in ischaemic stroke patients and its relation with other risk factors. METHODS: The cross sectional study based on convenience sampling was conducted at the Civil Hospital, Karachi, from May to July 2012. It comprised ischaemic stroke patients selected from the Out Patient Department and Emergency Department. An overnight 8 hour fasting venous blood sample (4 ml in ethylenediamminetetraacetate) was drawn for analysis. Rest of the data was collected through a structured proforma and was analysed using SPSS 17.0. RESULTS: The mean age of the 96 patients in the study was 64.9 +/- 10.9 years (range: 40-85). Overall, 56 (58.3%) cases had hyper homocysteinemia.The frequency was significantly high in the age 60-79 age group (p < 0.007). CONCLUSION: Hyper-homocysteinaemia, a modifiable risk factor, is associated with a high number of ischaemic stroke patients. Hence, steps should be taken to minimise this risk factor by screening and early intervention. PMID- 25823190 TI - Pender's health promotion model in medical research. AB - This review shows how researchers use pander's health promotion model. We included all articles in which Pender's health promotion has been used for theoretical framework. Eligible articles were selected according to review of abstracts. Search was conducted using the electronic database from 1990 to 2012. Based on our search, 74 articles with various methodologies were relevant for review. Their aims of these studies were to predict effective factors/barriers in health promotion behaviours, to detect effects of intervention programme for improving health promotion behaviours, test the model, identify quality of life and health promotion behaviour, predict stage of change in related factors that affect health promotion behaviour, prevent the events that interfere with health promotion behaviour, develop another model similar to this model, compare this model with another model, determine the relationship of variables associated to health promotion behaviours. PMID- 25823191 TI - Coexistence of hepatocelluler carcinoma and cyst hydatid disease of the liver. AB - The evidence suggests that both delta hepatitis-related hepatocellular carcinoma (HCC) and cyst hydatid disease (CHD) are frequently seen separately in people who live in the rural areas of Asia. However, there are still a few case reports about coexistence of these different diseases in the same liver. The current case illustrates a number of clinical problems that physicians face in the diagnosis of patients with basically different liver masses. PMID- 25823192 TI - Mad honey intoxication mimicking acute coronary syndrome. AB - Mad honey intoxication or grayanotoxin poisoning is caused by consumption of grayanotoxin-containing toxic honey produced from leaves and flowers of the Rhododendron family. Despite the rarity of intoxication cases, the correct diagnosis and treatment are required because of the significance of haemodynamic disturbance and confounding of symptoms for disease identification. We report herein a case of a patient with mad honey intoxication mimicking acute non-ST segment elevation myocardial infarction and review the pathophysiology and diagnostic considerations. PMID- 25823193 TI - Persistent metabolic acidosis and severe diarrhoea due to Artemisia absinthium poisoning. AB - Herbs have long been used in the treatment of various disorders in traditional medicine since ancient age. Artemisia absinthium, one of these herbs, has traditionally been used in different societies for antibiotic, antiparasitic, antifungal and antipyretic purposes. Here, we report a poisoning case of a 10 month-old male infant progressing with severe diarrhoea and persistent metabolic acidosis after ingesting home-prepared Artemisia absinthium extract which was given for the treatment of common cold. PMID- 25823194 TI - Mediastinal enteric cyst. AB - A 20-year-old female presented with complaints of right-sided chest pain, cough, fever and shortness of breath for the preceding one-and-a-half year. Air entry was decreased over the middle and lower chest. Computed tomography scan of the chest revealed a cystic lesion with thick margins present in the right hemi thorax. The cyst was excised by posterolateral thoracotomy. Histopathology revealed it to be mediastinal enteric cyst with intestinal and pancreatic tissue. PMID- 25823195 TI - A rare cause of lower urinary tract symptoms: retrovesical hydatid cyst. AB - Retrovesical cysts are extremely rare. For differential diagnosis radiologic findings and serologic tests can be used. In this article, we aimed to report our approach to diagnose and to treat a primary huge hydatid cyst in retrovesical space, between sigmoid colon and bladder. A 34-year old patient presented to our hospital with lower urinary tract symptoms (LUTS). Abdominal ultrasound reported a 14x8 cm cystic lesion adjacent to the posterior wall of the bladder. Computerized tomography revealed a 14 x 8 cm cystic mass adjacent to bladder posteriorly and prostate and seminal vesicle anteriorly in the retrovesical space. Patient received albendazole prophylaxis and intervention was planned by transperitoneal approach. In a two-year of follow-up patient did not encounter any recurrences. Retrovesical cysts may cause LUTS. With patients suffering from LUTS, hydatid cyst should be kept in mind. PMID- 25823196 TI - Hypoglycaemia in diabetes. AB - Hypoglycaemia is perhaps the most common complication of diabetes management. Often fatal, this condition can easily be prevented and managed. This paper reviews recent advances in understanding the causes of iatrogenic hypoglycaemia in diabetes, and the clinical risk factors associated with it. It provides a simple framework to help classify and asses these causative and risk factors. Also discussed are relevant non- pharmacological and pharmacological strategies to help prevent and manage hypoglycaemia. PMID- 25823197 TI - The impact of green tea and coffee consumption on risk of stroke in Japanese population. PMID- 25823198 TI - Clinical trials--discussing your findings. AB - Discussing findings of a clinical trial gives an opportunity to the investigator to elaborate the meaning of the findings of the trial. It should consist of the major findings, interpretation of the results in light of the available literature, theory and practice, limitations, generalizability of the findings and its implication, and way forwards for future research. One should avoid repetition of results in the discussion and give critical appraisal of the findings in such a way as to give a true picture of the internal and external validity of the clinical trial. PMID- 25823199 TI - Choroidal neo-vascularization presentation in younger age group (pre-senile). AB - Age-related macular degeneration (ARMD) is the most common cause of permanent visual loss in the elderly. Advancing age, as the name suggests, is a major risk factor. Vascular endothelial growth factor. (VEGF) along with other factors could be responsible for the dramatic damage in the eyes. Although uncommon in pre senile group, this disorder can also occur unrelated to age, such as pathologic myopia in which Fuch's spots can classically be seen. It can also occur following traumatic disruption of the Bruch's membrane. Herein we report a case of a 20 year-old healthy female with no known co-morbidities who presented with complaints of sudden central visual loss in her left eye over the course of a few days (one week) with no preceding history of traumatic event or predisposing factor. To investigate the cause, Optical Coherence Tomography/Fluorescein angiography (OCT/FFA) was ordered which exhibited the classical signs of choroidal neo-vascularization. PMID- 25823200 TI - IORT: possible change in early breast cancer management? PMID- 25823201 TI - Hospitals face closures as 'a new day in healthcare' dawns. PMID- 25823202 TI - Endoscope contagion raises questions about FDA oversight. PMID- 25823203 TI - Plaintiffs avoid legal standing issue in King case. PMID- 25823205 TI - Hospital prices drop for the first time. PMID- 25823204 TI - Rate battle peaks as Advantage plans grow. PMID- 25823206 TI - Telehealth services surging despite questions about value. PMID- 25823207 TI - The rise of the specialty emergency department. PMID- 25823208 TI - Drug firms and insurers move to center stage in the cost debate. PMID- 25823209 TI - Health entrepreneurship's moment. PMID- 25823210 TI - Kaiser tests video visits to cut waits. PMID- 25823211 TI - Troubled by health plans' high cost-sharing for drugs. PMID- 25823212 TI - Largest children's hospitals. Ranked by number of staffed beds in 2013. PMID- 25823213 TI - Preface. London tap water experiment. PMID- 25823214 TI - Mechanisms for the defects in phospholipid signal transduction in diabetic cardiomyopathy. AB - Although diabetic cardiomyopathy is associated with heart dysfunction and disturbance in cardiac sarcolemmal membrane phospholipid composition, the role of the different phospholipases and their related signaling mechanisms to altered function of the heart in diabetes is not completely understood. Thus, understanding the pathophysiology of cardiovascular abnormalities in diabetes, as well as identifying defects in various components of the phospholipid signaling pathways, that could serve as therapeutic targets, is warranted. Accordingly, this review provides an outline of the role of and the mechanisms for the defects in phospholipase A2, C and D-mediated signal transduction in the diabetic heart. In addition, the potential of different phospholipases as targets for drug development for the prevention/treatment of heart disease in diabetes is discussed. PMID- 25823215 TI - Implications of fundamental signalling alterations in diabetes mellitus associated cardiovascular disease . AB - The chronic diabetes mellitus (DM) is a major risk factor for cardiovascular disease. The incidence of cardiovascular disease might be a foremost cause of morbidity and mortality in patients afflicted with DM. In fact, DM is associated with multi-factorial cardiovascular signalling alterations via significant modulation of expression pattern, activation or release of PI3K, PKB, eNOS, EDRF, NADPH oxidase, EDHF, CGRP, adenosine, iNOS, ROCK, PKC-beta2, CaMKII, microRNA (miR)-126 and miR-130a, which could result in inadequate maintenance of cardiovascular physiology and subsequent development of cardiovascular pathology. This review highlights the possible adverse implications of fundamental cardiovascular signalling alteration in DM-associated cardiovascular disease pathology. PMID- 25823216 TI - Vascular aneurysms: a perspective. AB - Aneurysms develop as a result of chronic inflammation of vascular bed, where progressive destruction of structural proteins, especially elastin and collagen of smooth muscle cells has been shown to manifest. The underlying mechanisms are an increase in local production of proinflammatory cytokines and subsequent increase in proteases, especially matrix metalloproteinases (MMPs) that degrade the structural proteins. The plasminogen system: urokinase-type PA (u-PA), tissue type PA (t-PA) and plasminogen activator inhibitor-1 (PAI-1) and the MMPs system MMPs and TIMPs contribute to the progression and development of aneurysms. Recent studies suggest that aneurysms may be genetically determined. To date, most observable candidate genes for aneurysm (elastin, collagen, fibrillin, MMPs and TIMPs) have been explored with little substantiation of the underlying cause and effect. Recently, overexpression of the MMP-2 gene has been suggested as an important phenomenon for aneurysm formation. Along with MMPs, matrix formation also depends on JNK (c-Jun N-terminal kinase) as its activation plays important role in downregulating several genes of matrix production. Under stress, activation of JNK by various stimuli, such as angiotensin II, tumor necrosis factor-alpha and interleukin-1beta has been noted significantly in vascular smooth muscle cells. Several therapeutic indications corroborate that inhibition of MMP-2 and JNK is useful in preventing progression of vascular aneurysms. This review deals with the role of proteases in the progression of vascular aneurysm. PMID- 25823217 TI - Involvement of the early growth response protein 1 in vascular pathophysiology: an overview. AB - Hyperactivation of proliferative and growth promoting pathways underlies the progression of vessel remodeling, leading to vascular dysfunction. An upregulation of early growth response protein 1 (Egr-1), a zinc finger transcription factor has been observed in several models of vascular diseases. In the vasculature, Egr-1 expression can be induced by multiple hormonal, metabolic and external stimuli, such as growth factors, cytokines, reactive oxygen species, hyperglycaemia and stretch-induced stress. The structure of the Egr-1 promoter allows both its auto-regulation and its binding with several regulatory transcription cofactors like the serum response factor and the cAMP response element binding protein. Pharmacological and genetic studies have revealed the involvement of several signaling pathways that contribute to the expression of Egr-1. Among them, the mitogen-activated protein kinase pathway has emerged as a predominant signaling cascade that regulates Egr-1 transcription in response to various stimuli. Moreover, targeted deletion of Egr-1 by DNAzymes, antisense oligonucleotides or RNA interference has also helped in defining the importance of Egr-1 in the pathophysiology of vascular diseases. Neointimal formation and expression of genes directly linked with proinflammatory processes have been demonstrated to be enhanced by Egr-1 expression and activity. This review provides an overview on the signaling components implicated in Egr-1 expression and discusses its potential involvement in vascular pathophysiology. PMID- 25823218 TI - Regulation of Gialpha protein expression by vasoactive peptides in hypertension: molecular mechanisms. AB - Guanine nucleotide regulatory proteins (G proteins) play a key role in the regulation of various signal transduction systems, including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol (PI) turnover, which are implicated in the modulation of a variety of physiological functions, such as platelet functions, including platelet aggregation, secretion, and clot formation and cardiovascular functions, including arterial tone and reactivity. Several abnormalities in adenylyl cyclase activity, cAMP levels and G proteins have been shown to be responsible for the altered cardiac performance and vascular functions observed in cardiovascular disease states. The enhanced or unaltered levels of inhibitory G proteins (Gialpha) and mRNA have been reported in different models of hypertension, whereas Gsalpha levels are shown to be unaltered. The enhanced levels of Gialpha proteins precede the development of blood pressure and suggest that overexpression of Gi proteins may be one of the contributing factors for the pathogenesis of hypertension. The levels of vasoactive peptides including ET-1 and Ang II and growth factors are augmented in hypertension and contribute to the enhanced expression of Gialpha proteins in hypertension. In addition, oxidative stress due to enhanced levels of Ang II and ET-1 is enhanced in hypertension and may also be responsible for the enhanced expression of Gialpha proteins observed in hypertension. Furthermore, Ang II- and ET-1-induced transactivation of growth factor receptor through the activation of MAP kinase signaling is also shown to contribute to the augmented levels of Gialpha in hypertension. Thus, it appears that the enhanced levels of vasoactive peptides by increasing oxidative stress and transactivation growth factor receptors enhance MAP kinase activity that contribute to the enhanced expression of Gialpha proteins responsible for the pathogenesis of hypertension. In this review, we describe the role of vasoactive peptides and the signaling mechanisms responsible for the enhanced expression of Gialpha proteins in hypertension. PMID- 25823219 TI - Signaling mechanisms regulating fibroblast activation, phenoconversion and fibrosis in the heart. AB - Cardiac fibroblasts (CFs) maintain the cardiac extracellular matrix (ECM) through myocardial remodelling. The remodelling process can become dysregulated during various forms of heart disease which leads to an overall accumulation of ECM. This results in cardiac fibrosis which increases the risk of heart failure in many patients. During heart disease, quiescent CFs undergo phenoconversion to an activated cell type called cardiac myofibroblasts (CMFs). Factors influencing phenoconversion include transforming growth factor beta (TGF-beta) which via SMADs (small mothers against decapentaplegic) activates the myofibroblast marker gene alphaSMA (alpha smooth muscle actin). Signaling molecules as diverse as NAD(P)H oxidase 4 (Nox4) and Wnt have been found to interact with TGF-beta signalling via SMADs. Pathways, including FAK/TAK/JNK and PI3K/Akt/rac have also been implicated in activating phenoconversion of fibroblasts. Another major contributor is mechanical stress exerted on CFs by ECM changes, which involves activation of ERK and subsequent alphaSMA expression. Other factors, such as the mast cell protease tryptase and the seeding density also affect the phenoconversion of fibroblast cultures in vitro. Further, reversal of myofibroblast phenotype has been reported by a negative regulator of TGF-beta, Ski, as well as the hormone relaxin and the second messenger cAMP. Targeting the signaling molecules involved in promoting phenoconversion of CFs to CMFs presents a possible method of controlling cardiac fibrosis. Here, we provide a brief review of signaling mechanisms responsible for phenoconversion and identify critical targets for the treatment of cardiac fibrosis. PMID- 25823220 TI - Regulation of cardiac beta3-adrenergic receptors in hyperglycemia. AB - Beta-adrenoceptors (beta-AR), members of the G protein-coupled receptors play important roles in the regulation of heart function. A positive inotropic action of catecholamines is mediated through their interaction with beta-AR, located on the sarcolemma, while they can also mediate some deleterious effects, such as cardiac arrhythmias or myocardial apoptosis. The well-known beta-AR-associated signaling in heart is composed of a coupled mechanism among both beta1- and beta2 AR and stimulatory G protein (G(s)). This coupled mechanism further leads to the activation of adenylyl cyclase and thereby increases in intracellular cAMP level. However, recent studies have emphasized the contribution of constitutive beta3-AR coupling to G(i) proteins, thereby initiating additional signal transduction pathways, particularly under physiopathological conditions. Diabetic cardiomyopathy, as a distinct entity is recognized due to its diminished responsiveness to beta1-AR agonist stimulation in the heart from diabetic rats with no important changes in the responses mediated with beta2-AR. Furthermore, an upregulation of beta3-AR has been shown in diabetic rat heart with a strong negative inotropic effect on left ventricular function. Experimental data provide evidences that the mechanisms for the negative inotropic effect with beta3-AR activation appear to involve a pertussis toxin (PTX)-sensitive G protein and the activation of a nitric oxide synthase pathway. On the other hand, beta-blockers demonstrate marked beneficial effects in heart dysfunction with scavenging free radicals and/or acting as an antioxidant with both sex- and dose-dependent manner. However, further investigations are needed to clarify the roles of both altered expression and/or responsiveness of beta-AR and the benefits with beta blocker treatment in diabetes. This review discusses the role of beta-AR activation, particularly beta3-AR in cardiac pathological remodeling under hyperglycemia. PMID- 25823221 TI - Insulin signaling network in cancer. AB - The primary function of insulin is viewed as a hormone that controls blood glucose level. However, there is growing evidence that aberrant insulin level and insulin-mediated signaling can lead to cancer development and progression. The insulin-cancer relationship has stemmed from various observational and epidemiological studies, which linked higher incidence of cancer with central obesity, type II diabetes and other conditions associated with increased levels of circulating insulin, insulin resistance and hyperinsulinemic states. Increased risk of developing a range of cancers is also seen with a certain treatment options used to lower blood glucose level in diabetic patients. While metformin monotherapy has the lowest risk of developing cancer, in comparison, treatment with insulin or insulin secretagogues shows more likelihood to develop solid cancers. Cellular signaling initiated by insulin provides a clue regarding these diverse cellular outcomes. This review discusses how the insulin enacts such diverse physiological effects and the insulin-cancer relationship, with focus on the role of insulin signaling in cancer. PMID- 25823222 TI - Lung retinoid metabolism and signaling in chronic obstructive pulmonary disease. AB - There are a number of sites that are required for the production and/or action of all-trans retinoic acid (ATRA). In particular, interruption of different components of the chain of trafficking and metabolism has been associated with cancers arising in numerous organs of the body. Preliminary work suggests that such interruptions may be a factor in lung disorders induced by the smoke exposure. The active metabolite of retinoid, ATRA offers a therapeutic strategy to protect against functional abnormality in the lung, including chronic obstructive pulmonary disease (COPD). This review deals with the lung retinoid metabolism and mediators of retinoid trafficking and signaling with special emphasis on their roles in health and disease. PMID- 25823223 TI - Regulation of N-myristoyltransferase by the calpain and caspase systems. AB - N-myristoyltransferase (NMT) is an essential eukaryotic enzyme which catalyzes the transfer of the myristoyl group to the terminal glycine residue of a number of proteins including those involved in signal transduction and apoptotic pathways. In higher eukaryotes, two isoforms of NMT have been identified (NMT1 and NMT2) which share about 76% amino acid sequence identity in humans. Protein protein interactions of NMTs reveal that m-calpain interacts with NMT1 whereas caspase-3 interacts with NMT2. These findings reveal differential interactions of both isoforms of NMT with various signaling molecules. This minireview provides an overview of the regulation of N-myristoyltransferase by calpain and caspase systems. PMID- 25823224 TI - Phospholipid remodeling and eicosanoid signaling in colon cancer cells. AB - Phospholipid remodeling and eicosanoid synthesis are central to lipid-based inflammatory reactions. Studies have revealed that membrane phospholipid remodeling by fatty acids through deacylation/reacylation reactions increases the risk of colorectal cancers (CRC) by allowing the cells to produce excess inflammatory eicosanoids, such as prostaglandins, thromboxanes and leukotrienes. Over the years, efforts have been made to understand the lipid remodeling pathways and to design anti-cancer drugs targeting the enzymes of eicosanoid biosynthesis. Here, we discuss the recent progress in phospholipid remodeling and eicosanoid biosynthesis in CRC. PMID- 25823225 TI - Signaling pathways in insulin- and IGF-I mediated oocyte maturation in lower vertebrates. AB - The endocrine control of oocyte maturation in fish and amphibians has proved to be a valuable model for investigating the rapid and non-genomic steroid actions at the cell surface. Considerable progress has made over the last decade in elucidating signaling pathways in steroid-induced oocyte maturation. In addition to steroids, various growth factors have also been reported to be involved in this process and progress being made to elucidate their mechanism of actions. Exposure of fully-grown oocytes to steroids or growth factors (insulin/IGFs) initiates various signaling cascade, leading to formation and activation of maturation-promoting factor (MPF), a key enzyme that catalyzes entry into M-phase of meiosis I and II. Whereas the function of MPF in promoting oocyte maturation is ubiquitous, there are differences in signaling pathways between steroids- and growth factors-induced oocyte maturation in amphibian and fish. Here, we have reviewed the recent advances on the signaling pathways in insulin- and IGF-I induced oocyte maturation in these two groups of non-mammalian vertebrates. New findings demonstrating the involvement of PI3 kinase and MAP kinase in induction of oocyte maturation by insulin and IGF-I are presented. PMID- 25823226 TI - Challenges of ionizing radiation in tumor treatment and role of angiogenesis. AB - Ionizing radiation is a non-specific, but most widely used therapeutic method for cancer treatment. However, a minor fraction of tumor cell population manages to survive after radiation. Radiation efficacy depends on adequate oxygen supply. Rapid growing tumors cause hypoxia that upregulates many pro-survival pathways. At clinical doses, radiation activates inflammatory pathways and causes oxidative stress that plays a positive role during angiogenesis. Selective targeting of signaling mechanisms may radiosensitize tumors. PMID- 25823227 TI - TLR4-mediated activation of MyD88 signaling induces protective immune response and IL-10 down-regulation in Leishmania donovani infection. AB - In visceral leishmaniasis, a fragmentary IL-12 driven type 1 immune response along with the expansion of IL-10 producing T-cells correlates with parasite burden and pathogenesis. Successful immunotherapy involves both suppression of IL 10 production and enhancement of IL-12 and nitric oxide (NO) production. As custodians of the innate immunity, the toll-like receptors (TLRs) constitute the first line of defense against invading pathogens. The TLR-signaling cascade initiated following innate recognition of microbes shapes the adaptive immune response. Whereas numerous studies have correlated parasite control to the adaptive response in Leishmania infection, growing body of evidence suggests that the activation of the innate immune response also plays a pivotal role in disease pathogenicity. In this study, using a TLR4 agonist, a Leishmania donovani (LD) derived 29 kDa beta 1,4 galactose terminal glycoprotein (GP29), we demonstrated that the TLR adaptor myeloid differentiation primary response protein-88 (MyD88) was essential for optimal immunity following LD infection. Treatment of LD infected cells with GP29 stimulated the production of IL-12 and NO while suppressing IL-10 production. Treatment of LD-infected cells with GP29 also induced the degradation of IKB and the nuclear translocation of NF-kappaB, as well as rapid phosphorylation of p38 MAPK and p54/56 JNK. Knockdown of TLR4 or MYD88 using siRNA showed reduced inflammatory response to GP29 in LD-infected cells. Biochemical inhibition of p38 MAPK, JNK or NF-kappaB, but not p42/44 ERK, reduced GP29-induced IL-12 and NO production in LD-infected cells. These results suggested a potential role for the TLR4-MyD88-IL-12 pathway to induce adaptive immune responses to LD infection that culminated in an effective control of intracellular parasite replication. PMID- 25823229 TI - Influence of ultraviolet C bystander effect on inflammatory response in A375 cell on subsequent exposure to ultraviolet C or hydrogen peroxide. AB - Ultraviolet C (UVC) irradiation (lambda: 200-280 nm) causes release of several secretory cytokines responsible for inflammation. Our objective was to investigate whether inflammatory response was also induced in bystander cells. For this purpose, the conditioned medium containing the released factors from UVC irradiated A375 cells was used in this study to evaluate the expression of inflammatory markers, such as tumour necrosis factor alpha (TNFalpha), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) and p38 mitogen activated protein kinase (p38 MAPK) in its bystander cells. Inflammatory responses in bystander cells subjected to further irradiation by UVC or other damaging agent like H2O2 were also examined. It was observed that TNFalpha, NFkappaB and p38 MAPK were not induced in UVC-bystander cells, but their expression was suppressed in the UVC-bystander cells treated with UVC or H2O2. This lowering in inflammatory response might be due to smaller depletion in the reduced glutathione (GSH) content present in these treated bystander cells. The study indicated that UVC-induced bystander effect was an intrinsic protective response in cells, capable of suppressing inflammation induced in cells on exposure to damaging agents. PMID- 25823228 TI - Leishmania donovani secretory serine protease alters macrophage inflammatory response via COX-2 mediated PGE-2 production. AB - Leishmania parasites determine the outcome of the infection by inducing inflammatory response that suppresses macrophage's activation. Defense against Leishmania is dependent on Th1 inflammatory response by turning off macrophages' microbicidal property by upregulation of COX-2, as well as immunosuppressive PGE 2 production. To understand the role of L. donovani secretory serine protease (pSP) in these phenomena, pSP was inhibited by its antibody and serine protease inhibitor, aprotinin. Western blot and TAME assay demonstrated that pSP antibody and aprotinin significantly inhibited protease activity in the live Leishmania cells and reduced infection index of L. donovani-infected macrophages. Additionally, ELISA and RT-PCR analysis showed that treatment with pSP antibody or aprotinin hold back COX-2-mediated immunosuppressive PGE-2 secretion with enhancement of Th1 cytokine like IL-12 expression. This was also supported in Griess test and NBT assay, where inhibition of pSP with its inhibitors elevated ROS and NO production. Overall, our study implies the pSP is involved in down regulation of macrophage microbicidal activity by inducing host inflammatory responses in terms of COX-2-mediated PGE-2 release with diminished reactive oxygen species generation and thus suggests its importance as a novel drug target of visceral leishmaniasis. PMID- 25823230 TI - Lys-413 of S-phase mRNA cycling sequence binding protein from Leishmania donovani (LdCSBP) is modified through monoubiquitination that is responsible for inhibition of its riboendonuclease activity. AB - In addition to well-known process of proteasome-mediated degradation of polyubiquitinated proteins, monoubiquitination of proteins is also an important post-translational modification that regulates various non-degradative cellular processes like protein trafficking, cellular signalling, DNA replication and DNA repair. We have previously characterized a multi-domain cycling sequence binding protein LdCSBP from Leishmania donovani, which binds specifically to a conserved CAUAGAAG octamer containing RNAs via its uniquely arranged CCCH type Zn-fingers and degrades them using its Smr endonuclease domain, indicative of its potential role in the turnover of the S-phase mRNAs. Remarkably, its riboendonuclease activity is inhibited due to the incorporation of a monoubiquitin residue in the ZnF domain, though the target Lys residue remains unknown. Here, we report through systematic mutation of Lys residue to Ala that Lys-413 in LdCSBP is the site of monoubiquitination. However, the amino acid motif around the target Lys in LdCSBP is not consensus with any previously known monoubiquitination site, though partial homology is observed with a subset of recently identified mammalian ubiquitination target sites. Interestingly, Lys-413 of LdCSBP is conserved in the homologous annotated proteins from the related kinetoplastida parasites, suggesting similar monoubiquitination-mediated regulation of RNA endonuclease activity in the organisms. PMID- 25823231 TI - Herbicide paraquat induces sex-specific variation of neuroinflammation and neurodegeneration in Drosophila melanogaster. AB - There are several reports on herbicide paraquat (PQ)-induced Parkinsonian-like pathology in different animal models, including Drosophila melanogaster. Also, the role of some inflammatory factors, such as nitric oxide is reported in PQ induced neuroinflammation of Drosophila. Although invertebrate model is valuable to study the conserved inflammatory pathway at the time of neurodegeneration, but neuroinflammation during PQ-mediated neurodegeneration has not been studied explicitly in Drosophila. In this study, the inflammatory response was examined in Drosophila model during PQ-induced neurodegeneration. We found that after exposure to PQ, survivability and locomotion ability were affected in both sexes of Drosophila. Behavioural symptoms indicated similar physiological features of Parkinson's disease (PD) in different animal models, as well as in humans. Our study revealed alteration in proinflamatory factor, TNF-alpha and Eiger (the Drosophila homologue in TNF superfamily) was changed in PQ-treated Drosophila both at protein and mRNA level during neurodegeneration. To ensure the occurrence of neurodegeneration, tyrosine hydroxylase (TH) positive neuronal cell loss was considered as a hallmark of PD in the fly brain. Thus, our result revealed the conserved inflammatory events in terms of expression of TNF-alpha and Eiger present during a sublethal dose of PQ-administered neurodegeneration in male and female Drosophila with significant variation in proinflammatory factor level among both the sexes. PMID- 25823232 TI - [Polymorphism frequency of fibrinogen Bbeta-chain 448Arg and Lys, and the differences of plasma fibrinogen level and clotting function with three genotypes in Japanese]. AB - The 448th residue in the fibrinogen Bbeta-chain molecule is known to be polymorphic (Arg/Lys, R/K), and its allele frequency was previously estimated to be R: 0.85 and K: 0.15 in the US. In the present study, we collected blood samples from 64 healthy individuals and examined the frequency of the fibrinogen Bbeta-chain 448 polymorphism in the Japanese population as well as the relationship between polymorphic types and the function and levels of fibrinogen. The polymorphic site was confirmed by MnlI restriction analysis and direct sequencing analysis for amplified 860 bp PCR products containing the Bbeta 448 residue. Fibrinogen plasma levels were estimated based on functional and immunological methods. Functional analyses were performed on the R/R, R/K, and K/K types using thrombin-catalyzed fibrin polymerization. The R/R type was detected in 48 out of 64 subjects, R/K in 15, and K/K in one. Therefore, the allele frequency was found to be R: 0.87 and K: 0.13 for the Bbeta 448 site, which was similar to that reported previously in the US. The polymorphism did not affect fibrinogen plasma levels. The results of the analysis on fibrin polymerization of the three types suggested that lateral aggregation may be significantly slower in the fibrinogen Bbeta-chain 448R/K and K/K types than in the R/R type. (Original). PMID- 25823233 TI - Detection of metallo-beta-lactamase genes in clinically isolated Klebsiella pneumoniae and Klebsiella oxytoca. AB - We detected and characterized metallo-beta-lactamase genes (blaIMP-1 and blaIMP 11) in third generation cephalosporin-resistant Klebsiella pneumoniae and Klebsiella oxytoca isolated at Showa University Hospital between January 1, 2011 and December 31, 2012. The cephalosporin-resistant K pneumoniae strains were frequently isolated from the urine, while one strain of K. pneumoniae, which was resistant to carbapenem, was isolated from the stool. We analyzed the phenotypes and genotypes of the metallo-beta-lactamase genes from the 16 strains of cephalosporin-resistant-K pneumoniae and 6 strains of -K. oxytoca isolated from the same ward. The minimum inhibitory concentrations of imipenem were below 4 ug/ml in 21 out of the 22 isolated strains. The double disc synergy test using ceftazidime and sodium mercaptoacetic acid revealed enlargements in the inhibitory zones of 14 of the 16 strains of K. pneumoniae and all 6 strains of K. oxytoca. Metallo-beta-lactamase genes were detected in all of the tested strains, with blaIMP-1 in 3 K. pneumoniae and 1 K. oxytoca, blaIMP-11 in 13 K pneumoniae and 4 K. oxytoca, and both blaIMP-1 and blaIMP-11 in one K. oxytoca. Our results indicate that third generation cephalosporin-resistant and imipenem-susceptible K. pneumoniae and K. oxytoca possess the metallo-beta-lactamase gene. The active surveillance of metallo-beta-lactamase genes should be performed in clinical laboratories. (Original). PMID- 25823234 TI - [A first case report of empyema caused by Tetratrichomonas species in Japan]. AB - Trichomonad is a type of flagellate that parasitizes the human oral cavity, intestine, or vagina. However, respiratory infection is rare. We report a patient with pyothorax related to Tetratrichomonas species, which is the first reported case in Japan. The patient was a 66-year-old female. She consulted the Emergency Outpatient Unit of our hospital with fever, dyspnea, and the retention of pleural effusion. The appearance of the pleural effusion collected by thoracic drainage was brown, fetid pus. On microscopy, Trichomonad was detected in the pleural effusion. On a gene test, Tetratrichomonas sp. was identified. Based on this experience, we propose that non-stained specimens should be examined to detect Trichomonad on a puncture fluid test. (Case report). PMID- 25823235 TI - [Clinical laboratory tests supporting respiratory disease treatment--chairman's introductory remarks]. AB - The symposium consisted of four parts: history of lung function tests, nitric oxide for diagnosis and monitoring of bronchial asthma, radiological and functional changes of the lung in COPD, and combined pulmonary fibrosis and emphysema (CPFE) occasionally showing almost normal results in lung function tests. The history of lung function tests was presented by Dr. Naoko Tojo of the Tokyo Medical and Dental University. Nitric oxide tests in clinical use for diagnosis and monitoring of bronchial asthma were presented by Dr. Hiroyuki Nagase of Teikyo University. Radiological and functional changes of the lung in COPD were presented by Dr. Shigeo Muro of Kyoto University. Clinical features of combined pulmonary fibrosis and emphysema and their associated lung function were presented by Dr. Daiya Takai of the University of Tokyo. I hope that discussing the history of lung function tests until the present was useful for many medical technologists. (Review). PMID- 25823236 TI - [Pulmonary function testing: history up to the present]. AB - The main roles of pulmonary function testing are: aiding in the diagnosis, assessing disease severity, and monitoring the progress and effects of treatment. The spirometric measurements of highest clinical value are the vital capacity(VC) and forced expiratory volume in one second(FEV1). Measurements of VC were reported in both healthy subjects and patients with respiratory disease during the mid-19th century. The VC, however, was little used in clinical medicine until the second half of the 20th century. The FEV1, FEV1/VC ratio, and/or FEV1/forced vital capacity (FVC) ratio all came into existence after 1950. Pulmonary function testing evolved over time into a more complex set of lung function measurements using various techniques and devices. If the variability of the results can be minimized and the measurement accuracy can be improved, abnormalities will be more easily detected. In 2005, the American Thoracic Society (ATS) and European Respiratory Society (ERS) together published an updated set of standards for pulmonary function testing that could be applied more widely. These standards are structured to cover definitions, equipment, and patient-related procedures commonly applied for many methods of lung function testing. In 2004, the Japanese Respiratory Society issued an initial set of recommendations for the standardized measurement of VC, FVC, and the single-breath carbon monoxide-diffusing capacity. These recommendations have not been updated, and the prediction equations for pulmonary function testing have not been fully established. The statements need to be periodically updated in accordance with new developments. (Review). PMID- 25823237 TI - [The role of pulmonary function and computer-assisted tomography imaging in COPD clinics]. AB - Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow limitation caused by a loss of elastic recoil of the lung and/or small airway remodeling. Emphysema is the major pathological lesion in COPD, defined as the abnormal and permanent enlargement of distal airspaces and destruction of alveolar walls. Emphysema correlates most closely with a loss of elastic recoil of the lung and is associated with both airflow limitation and loss of diffusion capacity, while the airway component contributes mainly to airflow limitation. Pulmonary functions reflect these pathological changes and are standard indices for "lung physiological abilities", so that these seem to be appropriate to evaluate the general lung status in vivo. In CT, emphysema is identified as low attenuation and airway wall thickening, and airway lumen narrowing can also be quantified. These CT indices shows the morphological changes/abnormalities that correspond to pathological changes. Thus, CT indices reflect pathological abnormality more precisely and have several advantages over pulmonary functions because those can give us regional information that pulmonary function tests cannot offer. Through the rigorous investigation of COPD pathophysiology using these CT indices, some aspects of the COPD course, such as emphysema progression, and the relationship between COPD pathophysiology and systemic manifestations are becoming clear. (Review). PMID- 25823238 TI - [Combined pulmonary fibrosis and emphysema (CPFE)--limitation of usual lung function test and challenge at practice]. AB - Spirometry and the flow-volume curve test are commonly performed lung function tests. However, a unique clinical entity occasionally shows almost normal data in these tests, and is therefore missed on screening tests. The clinical entity of combined pulmonary emphysema and pulmdoary fibrosis was recognized and documented in the 90's in Japan, the USA, and Europe. Typical emphysema shows obstructive disorders, and pulmonary fibrosis shows restrictive disorders. Thus, the combination of both should lead to a combined disorder pattern in lung function tests, but this is not the case. In 2005, Cottin reported and redefined this combination of emphysema and fibrosis of the lung as "Combined Pulmonary Fibrosis and Emphysema" (CPFE). The patients are typically heavily smoking males who show an almost normal lung function. The upper lobe of these patients usually shows severe emphysema, which contributes to a static volume and a late phase in the forced volume test. On the other hand their lower lobe shows fibrotic change. The fibrotic portion contributes to early phase flow in the flow-volume curve. These mechanisms are a reason for the normal pattern appearance in lung function tests in CPFE patients. As a matter of course, these patients have damaged upper and lower lobes: their diffusing capacity of the lung shows a low performance, their saturation of blood hemoglobin decreases soon after light exercise, and their KL 6 (a blood marker of pulmonary fibrosis) usually shows a high value. They are considered a high risk group regarding complications of post-surgical treatment. Thus, when medical technologists identify suspicious cases, they should advise doctors to add diffusing capacity and KL-6 tests. (Review). PMID- 25823239 TI - [The role of fractional nitric oxide in exhaled breath (FeNO) in clinical practice of asthma]. AB - The measurement of FeNO (fractional nitric oxide concentration in exhaled breath) is a noninvasive method to assess airway inflammation. The elevated level of FeNO in asthma patients was first reported in 1993, and measurement has been covered by insurance in Japan since April 2013. NO is generated through the conversion of L-arginine to L-citrulline by the action of nitric oxide synthase (NOS) and iNOS is highly expressed in asthmatic airways. FeNO is expiratory flow-ependent, and measurement at 50 mL/s is recommended. As a nitrate-rich diet and the contamination of nasal NO increase, and smoking and spirometry decrease FeNO, these factors should be avoided or taken into account when measuring FeNO. For clinical application, FeNO may be used for the diagnosis or as a guide to treat asthma. Although FeNO correlates well with eosinophilic airway inflammation, it is not present in all asthma patients, and eosinophilic bronchitis or a part of COPD also shows eosinophilic inflammation. Thus, FeNO may be used as an adjunct for asthma diagnosis, and in ATS guideline, it is recommended to use FeNO for the diagnosis of eosinophilic airway inflammation and determining the likelihood of responsiveness to steroids. Several studies attempted to use FeNO to determine the dose of ICS (inhaled corticosteroids) and compared FeNO with traditional guideline-based management. The results were inconsistent, and the Cochrane review found that FeNO-based treatment did not lead to a reduction in the ICS dose or improved asthma outcomes. Nevertheless, a study of a pregnant woman showed reduced exacerbations with a refined algorithm, and further research will shed light on the appropriate application of FeNO measurement for asthma management. In this paper, the mechanism of NO generation, background and method of FeNO measurement, and clinical application will be reviewed and an outline of the official ATS clinical practice guideline will be introduced. PMID- 25823240 TI - [Laboratory tests of serum lipid molecules using mass spectrometry]. AB - Serum lipids have a variety of molecular frameworks and fatty acid side chains, and these molecules include various metabolites and derivatives. Lipid molecules influence the physicochemical properties of the plasma membrane and intracellular transport, and their metabolites are often bioactive substances. Fatty acid molecules are also precursors of lipid mediators, and are involved in the regulation of inflammatory reactions. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is used in various fields in the clinical laboratory. Serum phosphatidylcholine (PC), lysoPCGSphingomyelin, triglycerides, cholesterol ester, sulfatide, phosphatidylethanolamine, and phosphatidylglycerol can be analyzed by MALDI-TOF MS. We devised an analytical procedure for serum ceramide and glycolipids from partially purified serum lipids. Investigation of lipid molecular species is used for the characterization of disorders of lipid metabolism. MS methods for use in routine laboratory tests require both precise and accurate measurement, and sample preparation procedures should be both simple and quick. (Review). PMID- 25823241 TI - ["How can hospitals develop a beneficial relationship with laboratory testing companies?" - Chairmen's introductory remarks]. AB - The symposium was held with the Japanese Society of Laboratory Medicine and JACLaP to discuss the way to develop a beneficial relationship between hospitals and laboratory testing companies with co-chairing by Seiji Kawano, Kobe University and Toshisuke Morita, Toho University. Clinical testing is considered to be essential for medical diagnosis and treatment; however, it is difficult for a hospital to perform all clinical testing for various reasons, including cost effectiveness. In this session, 4 guest speakers gave a talk from their viewpoints. Doctor Kawano talked about the results of a questionnaire filled out by 114 university hospitals on how to develop a beneficial relationship between hospitalsoand laboratory testing companies. Next, Mr. Shinji Ogawa, president and CEO of SRL, talked about favorable ways to utilize laboratory testing companies, sayingthat such companies, which have a variety of skills, are expected to offer new and advanced technologies to hospitals continuously, and abundant data which laboratory testing companies have should be used for the advancement of community medicine. Professor Koshiba, Hyogo Medical School, expressed his apprehension to develop a so-called branch lab. in university hospitals from his own experience, and concluded that a beneficial relationship with companies to perform tasks required by hospitals should be sought. The last speaker, Yuichi Setoyama, Mitsubishi Chemical Medience, talked about the new relationship between hospitals and laboratory testing companies, and emphasized that hospitals and such companies should know the strong and weak points of each other and build a mutually complementary system. After all presentations were over, a discussion with participants was held. Doctors of clinics said that the role of laboratory testing companies for large hospitals is different from that for small clinics, and such companies are indispensable for his everyday medical activities. Each medical institute has its own medical mission, and, therefore, what constitutes a beneficial relationship varies with each medical institute. The key to the success of building a win-win relationship with laboratory testing companies is held by each hospital. (Review). PMID- 25823242 TI - [How do hospital clinical laboratories and laboratory testing companies cooperate and build reciprocal relations?]. AB - As the 2nd Joint Symposium of the Japanese Society of Laboratory Medicine and the Japanese Association of Laboratory Pathologists, the symposium on clinical test out-sourcing and branch laboratories was held at the 60th General Meeting of the Japanese Society of Laboratory Medicine on November 2nd, 2013 in Kobe. For the symposium, we conducted a questionnaire survey on the usage of clinical test out sourcing and the introduction of branch laboratories to clinical laboratories of Japanese university hospitals, both private and public, between July 25th and August 20th, 2013. Seventy-two hospitals responded to the questionnaire survey, consisting of 41 public medical school hospitals and 31 private ones. According to the survey, the selection of each clinical test for out-sourcing was mainly determined by the capacities of hospital clinical laboratories and their equipment, as well as the profitability of each test. The main concerns of clinical laboratory members of university hospitals involved the continuity of measurement principles, traceability, and standardization of reference values for each test. They strongly requested the interchangeability and computerization of test data between laboratory testing companies. A branch laboratory was introduced to six hospitals, all of which were private medical college hospitals, out of 72 university hospitals, and eight of the other hospitals were open to its introduction. The merits and demerits of introducing a branch laboratory were also discussed. (Review). PMID- 25823243 TI - [Quality use of commercial laboratory for clinical testing services - considering laboratory's role]. AB - The number of commercial laboratories for clinical testing in Japan run privately has decreased to about 30 companies, and their business is getting tougher. Branch Lab. and FMS businesses have not expanded recently due to the new reimbursement system which adds an additional sample management fee, becoming effective in 2010. This presentation gives an outline of each role for hospital and commercial laboratories, and their pros & cons considering the current medical situation. Commercial laboratories have investigated how to utilize ICT systems for sharing test information between hospitals and our facilities. It would be very helpful to clarify issues for each hospital. We will develop and create new values for clinical laboratory testing services and forge mutually beneficial relationships with medical institutions. (Review). PMID- 25823244 TI - [Discussing the usefulness of companion diagnostics - introductory remarks by chairpersons]. AB - Personalized medicine has been expected to be utilized in daily practice since the international human genome project completed sequencing of the entire genome in 2003. The aim of personalized medicine is to treat patients effectively and safely based on the genome characteristics of each patient, or to choose the right drug for the right patient at the right time and at the right dose. Regulatory agencies such as the United States Food and Drug Administration(FDA) and Pharmaceuticals and Medical Devices Agency (PMDA), Japan implemented guidance to facilitate the co-development of drugs and companion diagnostics. For the practice of personalized medicine, companion diagnostic tests are essential, although their availability is limited. PMID- 25823245 TI - [Team approaches to critical bleeding (massive bleeding and transfusion) - chairmen's introductory remarks. Questionnaire survey on current status of hospital clinical laboratories evaluating critical hemorrhage]. AB - In 2007, "the Guidelines for Actions against Intraoperative Critical Hemorrhage" were established by the Japanese Society of Anaesthesiologists and the Japanese Society of Blood transfusion and Cell Therapy. The documentation of in-hospital procedures for critical hemorrhage, especially about how to select RBC units, has widely standardized hospital practice. Patients with intraoperative critical hemorrhage sometimes suffer from massive blood loss. In this situation, some patients develop coagulopathy. To treat them, we need to evaluate their coagulation status based on laboratory test results. So, we performed a nationwide questionnaire survey on the current status of hospital clinical laboratories evaluating critical hemorrhage. From the results of this survey, it was recommended that central hospital laboratories should try to reduce the turn around time required to test for coagulation parameters as much as possible for appropriate substitution therapy. (Review). PMID- 25823246 TI - [Present status of critical hemorrhage and its management in the operating room]. AB - Hemorrhage is a major cause of cardiac arrest in the operating room. Many human factors, including surgical procedures, transfusion practices, blood supply, and anesthetic management, are involved in the process that leads to hemorrhage developing into a critical situation. It is desirable for hospital transfusion committees to prepare hospital-based regulations on 'actions to be taken to manage critical hemorrhage', and practice the implementation of these regulations with simulated drills. If intraoperative hemorrhage may become critical, a state of emergency should immediately be declared to the operating room staff, the blood transfusion service staff, and blood bank staff in order to organize a systematic approach to the ongoing problem and keep all responsible staff working outside the operating room informed of events developing in the room. To rapidly deal with critical hemorrhage, not only cooperation between anesthesiologists and surgeons but also linkage of operating rooms with blood transfusion services and a blood bank are important. When time is short, cross-matching tests are omitted, and ABO-identical red blood cells are used. When supplies of ABO-identical red blood cells are not available, ABO-compatible, non-identical red blood cells are used. Because a systematic, not individual, approach is required to prevent and manage critical hemorrhage, whether or not a hospital can establish a procedure to deal with it depends on the overall capability of critical and crisis management of the hospital. (Review). PMID- 25823247 TI - [Management of massive transfusion - the role of the blood transfusion service]. AB - Massive transfusion (hemorrhage) is defined as blood transfusion exceeding the circulatory blood volume within 24 hours. Here, we investigated cases of massive transfusion, defined as transfusion of more than 21 units of red blood cells within 24 hours, in our institution in the period from August 2005 to March 2013. Massive transfusion accounted for approximately 1% of all blood transfusions in our institution, and the majority were cardiac surgery cases (75%), with 80% of the cases receiving blood transfusion irtfhe operating theater. Brain-dead heart and liver transplantations were started in our hospital in 2006. Due to the revision of the Organ Transplantation Law in July 2010, brain-dead organ donations increased in Japan. Massive transfusion was required in approximately 47% of heart and 41% of liver transplants, with 44% of the transplants being conducted on holidays, and 47% at night. Therefore, the implementation of a 24 hour duty system for medical technologists, including holidays, is essential for the prompt testing and supply of blood products. For improvement of the safety of blood supply, a computer network system, connecting the blood control system of the blood transfusion service, the anesthetic system of the operating theater, and the hospital general medical system, was implemented in our hospital in March 2007. In the operating theater, anesthetists can request blood products, order new blood products, cross-check the provided blood products, and register their use, using this system. At the blood transfusion service, the blood products to be provided are cross- checked against the anesthetists' requests. Through this system, the anesthetists and blood transfusion service staff can check the list of blood products available for the surgical patient as well as those already transfused, on a real-time basis. For analysis of the improvements achieved, we compared the number of non-used blood units, i.e., the number of those provided minus the number of transfused units in the surgical theater, in the period after (2009-2012) and before (2005-2006) the implementation of this computer network system. In the period after its implementation, the number of non-used units decreased from 17.4 units to 7.5 units (P<0.001), leading us to conclude that this system helped avoid the excessive ordering of blood products by the anesthetists. (Review). PMID- 25823248 TI - [Contribution of central hospital laboratory to critical bleeding]. AB - It has been reported that fibrinogen products, such as fibrinogen concentrates, cryoprecipitate (CRYO), and fresh frozen plasma, are beneficial for treating coagulopathy due to massive blood transfusion. For the appropriate use of these products, it is necessary to evaluate the status of coagulopathy and determine the trigger level of the fibrinogen concentration for the administration of fibrinogen products. In our institution, we established a treatment procedure for coagulopathy due to massive transfusion in 2011. This procedure includes determination of the trigger level for administration of CRYO (150 mg/dL), timing of sample collection for the evaluation of coagulation parameters (prothrombin time, activated partial thromboplastin time, and fibrinogen) and concentration status during the operation, and a method for rapid coagulation testing (turnaround time within 15 minutes) in critical bleeding. Since 2011, we have performed 56 rapid coagulation tests for patients suffering from critical bleeding. The average turnover time was 13 minutes. According to the rapid coagulation test results, CRYO was administered to 27 patients. These results are satisfactory for treating critical bleeding patients. We stress the need for the establishment of a rapid coagulation test system in the central hospital laboratory. (Review). PMID- 25823249 TI - [How to establish a medical team for patients with critical bleeding]. AB - The medical guidelines for critical bleeding were published by several medical societies, and they declared the importance of approaches by teams composed of various kinds of medical staff. A medical team dealing with critical bleeding is characterized as an ad hoc type team, since the team is inactivated after its individual work is finished. Its characteristics are: 1)it is hard to predict when to be organized, 2) extremely rapid responses are required, and 3) staff outside the hospital,such as the Red Cross Society, are involved. To promote medical teams, it is very important: 1)to standardize the public guidelines for individual hospitals, 2) to define the roles of staff with their affiliations, posts, and phone numbers, 3) to simulate events, and 4) to have irregular but continuous meetings. Furthermore, it is important to involve manufacturers in our activities for innovating new test apparatuses or systems, and also to stress the significance of such team approaches to the nation and government, such as the Ministry of Health, Labour and Welfare, in order to secure additional points in the health insurance payment system. (Review). PMID- 25823250 TI - Push to modify payment must overcome strong fee-for-service legacy system. PMID- 25823251 TI - Endoscope infections at Virginia Mason prompt broader safety fears. PMID- 25823252 TI - CMS' dialysis-clinic ratings won't help patients, critics charge. PMID- 25823253 TI - 2017 is new goal for interoperability. PMID- 25823254 TI - Enrollers bank on late Obamacare surge. PMID- 25823255 TI - Indiana Medicaid expansion may spur other state cost-sharing proposals. PMID- 25823256 TI - Backers of mental health overhaul see bigger role for inpatient care. Re institutionalization push. PMID- 25823257 TI - Making healthcare environments safer for seniors. PMID- 25823258 TI - Beware vaporware on value-based care. PMID- 25823259 TI - Data-driven medicine requires infrastructure investment and regulatory reform. PMID- 25823260 TI - Dedicated panel sets executive pay. PMID- 25823261 TI - Partnerships can be effective in building your network. PMID- 25823262 TI - Largest U.S. teaching hospitals. Ranked by total number of residents and interns based on Medicare cost report data, 2013. PMID- 25823263 TI - [Prevention of noncommunicable diseases in a local therapist's practice: content, problems, solution ways, and prospects]. AB - High-risk and secondary prevention strategies for noncommunicable diseases in primary health care are mainly implemented by local therapists. The large-scale clinical examination of an adult population (a high-risk strategy), which has been launched in the country since 2013 to solve the problems of detecting people with noncommunicable diseases and their risk factors and making a prevention counseling, is simultaneously a mechanism for the formation of a full therapeutic area passport to identify follow-up groups (a secondary prevention strategy). Currently, there is an obviously insufficient follow-up of inadequate quality. The reasons for this situation are a lack of regular training of local doctors in follow-up in addition to staff shortages. Medical teachers and professional communities working on the basis of common guidelines must be attracted to solve this problem. The actual introduction of a local therapist's efficient performance measures, the setting up of special structures in charge of primary care prevention in the health authorities, and the active involvement of medical prevention and health centers (for people at high risk in the absence of proven non-communicable diseases) in this process will be able to enhance the efficiency of a follow-up. Information technologies, including a tele-follow-up, are an important reserve in implementing the high-risk and secondary prevention strategies. PMID- 25823264 TI - [Russian and regional performance indices of local therapists]. AB - AIM: To analyze the statistical indicators of a local therapist's performance in the Russian Federation and its districts in the 2008- 2012 period. MATERIALS AND METHODS: The authors analyzed staffing and understaffing in the federal districts with respect to the Russian Federation, a doctor's actual function and its deviation ratio, staffing of local therapists, secondary employment coefficient, and the total number of physician visits with the ratio of the number of home/polyclinic ones. RESULTS: The staffing of local therapists was steady-state in the country as a whole in the period analyzed. At the same time, there was a decline in staffing. The performance of doctors everywhere is greater than the recommended one since 2009. There was a reduction in the number of visits to local therapists in both the country as a whole and its regions, with more visits being made by rural dwellers. CONCLUSION: The current approach to the standards for the load and number of physicians should determine needs for specialists of this profile and become a major part to solve the problem of delivering available and high-quality primary outpatient care to the population of Russia. PMID- 25823265 TI - [Gender differences in health awareness and attitudes as a subjective-objective health index in the population of Russia/Siberia (WHO MONICA-psychosocial program, HAPIEE project)]. AB - AIM: To establish gender differences in health attitudes and awareness of risk factors for cardiovascular diseases in an open 25-64-year-old population of Russia/Siberia. SUBJECTS AND METHODS: A representative sample from the population of a Novosibirsk district was examined using the 1988 WHO MONICA-MOPSY (847 women and 739 men aged 25-64 years) and the 2003 HAPIEE (1074 women and 576 men aged 45 64 years) programs. The health awareness and attitudes questionnaire was used. RESULTS: The number of persons who considered perfectly healthy was minimal (2%) in the open Siberian population aged 25-64 years. The view of health in the women proved to be more pessimistic than that in the men. The fact that two thirds of the population could fall ill with a serious disease in the coming 5-10 years was accepted. Mainly the men took the view that modern medicine might prevent heart disease. The men were regularly examined 2 to 3 times more often than the women. The latter versus the men were less frequently inclined to stop work if they felt not quite well on-site, with the difference being more marked in old age groups. The majority of the study participants considered preventive examination to be useful for health. At the same time only a small portion of the population itself undergoes examination. CONCLUSION: The changed socioeconomic situation in the country leads to the need to alter the established stereotypes of conscience and behavior of the population in health and to realize the need for personal responsibility for health. PMID- 25823266 TI - [The frequency of potentially inappropriate medication use according to the Beers' criteria in elderly people at the therapy departments of a multidisciplinary hospital]. AB - AIM: To analyze the frequency of potentially inappropriate medication use according to the Beers' criteria in elderly people at the therapy departments of a hospital. SUBJECTS AND METHODS: Case histories of 150 patients over 65 years of age (47 men and 103 women at the age of 79.0 +/- 15.5 years) treated at the therapy department of a multidisciplinary hospital were analyzed to estimate the frequency of potentially inappropriate medication use in elderly people according to the Beers' criteria in the 4-month period: from March to June 2013. Each treatment sheet was checked against the so-called Beers' list (supported by the American Geriatric Associated in 2012) to reveal the use of potentially inappropriate medications. RESULTS: An average of 6.4 +/- 4.0 drugs was simultaneously used in the patients. In 61 (40.67%) patients, the treatment sheets showed 78 potentially inappropriate medications that should be avoided by the elderly. Twenty-one (14%) patients were noted to use 24 potentially inappropriate drugs that should be avoided by elderly patients with definite diseases and syndromes. Fifty (33.3%) patients were observed to have taken the drugs that should be used with great caution. CONCLUSION: The findings suggest that the elderly patients frequently receive potentially inappropriate medications; as a result their benefits can be overweighed by the risk. PMID- 25823267 TI - [Identification of circulatory diseases and their risk during medical examination of an adult population: methodological aspects]. AB - AIM: To study the efficiency of a methodology for the active detection of coronary heart disease (CHD) and cerebrovascular diseases (CVD) during medical examination and to determine the need and possible ways of its improvement. SUBJECTS AND METHODS: The medical examinations of 19.4 million people (94.6% of all the citizens who had undergone medical examinations in all the regions of Russia in 2013) were analyzed and the methodological aspects of identification of the circulatory diseases (CDs) that were induced by coronary and cerebral vessel atherosclerosis and had common risk factors, primarily CHD and CVD, were assessed. RESULTS: The medical examinations revealed 2,915,445 cases of CDs and their suspicions, during which its clinical diagnosis was established in 57.2%. The suspected disease requiring that its diagnosis should be further specified; off-medical examinations revealed hypertension in more than 770,000 cases, CHD in 232,000, and CVD in 146,000. The proportion of stable angina pectoris of all angina cases was much higher at a young age (25.6%) than at middle (15.6%) and elderly (11.3%) ages. Brachiocephalic artery stenoses were detected in almost 13,000 cases. According to the official health statistics, within the years preceding the introduction of large-scale medical examinations, there was a slight rise in new CD cases among the adult population of Russia, which was more significant in 2013 (according to the preliminary data) than in 2012. CONCLUSION: The methodology for the active detection of CDs through a two-step medical examination, which is used during a follow-up, makes it possible to substantially increase detection rates for CDs. There has been shown to be a need for the better quality and completeness of diagnostic examination in real practice. PMID- 25823268 TI - [Refralon (niferidil) is a new class III antiarrhythmic agent for pharmacological cardioversion for persistent atrial fibrillation and atrial flutter]. AB - AIM: To evaluate the efficacy and safety of refralon (niferidil), a new class III antiarrhythmic agent whose activity is related to the block of delayed rectifying potassium current and to the prolongation of atrial and ventricular action potential and refractory periods, when it is used as an agent for pharmacological cardioversion for atrial fibrillation (AF) and atrial flutter (AFL). SUBJECTS AND METHODS: The efficacy of the drug as 3 intravenous boluses of 10 MUg/kg was evaluated in 134 patients (90 men; 57.8 +/- 11 years) with a mean AF duration of 3 (1.5; 6) months. Its effect was controlled by 24-hour Holter ECG monitoring. The criterion for its antiarrhythmic effect was 24-hour sinus rhythm (SR) recovery. RESULTS: Niferidil restored SR in 47.7% of the patients with AF after administration of bolus 1, in 62% after bolus 2, and in 84.6% after bolus 3. SR was restored in all 100% patients with AFL. With the AF duration of less than 3 months, the efficacy of niferidil was 91.8%. There was nonsustained polymorphic ventricular tachycardia (VT) (torsade de pointes) in 1 (0.7%) patient and nonsustained monomorphic VT was stated in 5 (3.7%) patients. CONCLUSION> Pharmacological cardioversion with niferidil for persistent AF and VT may be regarded as a possible alternative to electrical cardioversion. PMID- 25823269 TI - [Impact of bosentan therapy on stress-induced pulmonary hypertension in patients with systemic sclerosis]. AB - AIM: To describe hemodynamic and clinical changes in patients with elevated mean pulmonary artery pressure (MPAP) > 30 mm Hg during exercise and the impact of bosentan therapy on stress-induced pulmonary hypertension (SIPH). SUBJECTS AND METHODS: The study included 19 patients with systemic sclerosis (SDS) in whom possible causes of pulmonary hypertension (PH) (lung and left heart injuries and thromboembolism) were excluded. All the patients underwent pulmonary artery catheterization at rest and during exercise. The hemodynamic (right atrial pressure (RAP), systolic and diastolic pressure, MPAP, pulmonary artery wedge pressure (PAWP), cardiac output (CO) by a thermodilution technique), clinical (demographic, immunological, and instrumental) parameters were analyzed and the risk of pulmonary arterial hypertension (PAH) was also calculated; 5 patients with SIPH received 16-week bosentan therapy according to the conventional regimen. RESULTS: Ten of the 19 patients were at increased risk for PAH in accordance with the DETECT scale, but no signs of PH at resting catheterization were found in anybody. In 5 patients, MPAP, was in the range from 21 to 24 mm Hg; in 9 (47%) patients were found to have SIPH, a median MPAP of 35 (32; 41) mm Hg. Seven patients had no diagnostic changes during exercise; 3 patients could not perform an exercise test. There were correlations between MPAP and DETECT risk scores (p < 0.05). The patients with SIPH had significantly higher levels of resting MPAP and exercise pulmonary vascular resistance (PVR) and PAWP. The calculated DETECT risk was significantly higher in the SIPH group. The level of uric acid was also higher in the SIPH group (p < 0.05). There were no changes in NT-proBNP levels, telangiectasias and anti-centromere antibodies, and EchoCG and lung test results. During 16-week bosentan therapy, there was a significant decrease in MPAP and transpulmonary gradient during exercise, but PVR, MPAP/CO ratio and NT-proBNP levels tended to decrease. CONCLUSION: In the patients with SDS, SIPH may be a stage of pulmonary vasculopathy that precedes the development of clinical PAH. The use of current PAH-specific drugs used at the preclinical stage of the disease may substantially improve lifetime prognosis in patients with SDS-associated PAH. PMID- 25823270 TI - [Prevalence of some modified cardiovascular risk factors among young students]. AB - AIM: To estimate the prevalence of some modified cardiovascular risk factors (RFs) among the students of two Moscow higher education institutions to further test the technology of individual medical prevention counseling. SUBJECTS AND METHODS: A questionnaire survey was conducted among 1912 first-year students (boys and girls, mean age 17.7 years) from 2 Moscow higher education institutions to reveal physical activity levels, smoking status, alcohol abuse, and food addictions. RESULTS: Almost one third of the students (mainly girls) lead a sedentary lifestyle. The mean age at onset of smoking is 14.8 years. At the moment, the smoking students are 22% (28% of boys and 18% of girls). 12.2% of the respondents have moderate and high nicotine dependence. Most smokers demonstrate low motivation to give up smoking. The mean age for alcohol consumption is 15.8 years. 60% of the students use alcohol. There are no great differences in the drinking of alcoholic beverages between the girls and boys. 18% of the study sample students eat irregularly. Nearly 50% of the students add salt to cooked foods. 17% of the students eat too much sugar; more than 50% take sugar- and fat laden foods. 54% of the students use vegetables and fruits insufficiently. CONCLUSION: Among all the modified cardiovascular RFs, alcohol use and irrational nutrition are most common among the students. Smoking and low physical activity are also relevant problems although these indicators among the students of Moscow are lower than among those in other regions of the Russian Federation. The found patterns call for the increased attention of the administrations of higher education institutions. PMID- 25823271 TI - [Clinicoeconomic effectiveness of using psychotherapy to treat patients with essential hypertension]. AB - AIM: To assess the expediency of psychotherapy in patients with essential hypertension (EH) from clinical and economic standpoints. SUBJECTS AND METHODS: Seventy-five (37 men, 38 women) with grades 1-2 EH (blood pressure (BP) was 140/90 to 179/109 mm Hg) and the verified psychosomatic background of the disease) were examined and randomized into 2 groups (the mean age in Groups 1 and 2 was 48.5 +/- 3.69 and 47.5 +/- 4.2 years, respectively). All the patients received medical therapy using the same regimen; however, Group 1 patients had additionally psychotherapy. The decrease in BP and the average number of visits required to reach goal BP were estimated as a criterion for therapeutic effectiveness. A pharmacoeconomic analysis of antihypertensive therapy was made in each group. RESULTS: The average cost for 24 weeks was 349.67 rbl per person in Group 1 and 435.9 rbl in Group 2, which was 19.78% cheaper. The costs of reductions in systolic-BP (SBP) and diastolic BP (DBP) were also lower in Group 1 (-22.108 and -39.534 rbl, respectively). At the same time, goal BP was achieved more rapidly in Group 1 (in Groups 1 and 2, the reduction in SBP was 5.28 and 3.38 mm Hg weekly and that in DBP was 2.51 and 1.73 mm Hg weekly, respectively). This makes it possible to lower a physicians' load and to save timing budget (p > 0.032). CONCLUSION: The treatment policy in Group 1 surpassed that in Group 2 in the rate of BP normalization and the number of required visits to a physician and showed significant economic benefits. PMID- 25823272 TI - [Association of cognitive impairments with carbohydrate and lipid metabolic parameters in type 2 diabetes mellitus patients undergoing coronary bypass surgery]. AB - AIM. To comparatively analyze neuropsychological parameters in patients with coronary artery disease (CAD) depending on the presence of type 2 diabetes mellitus (DM) and to evaluate their relationship to carbohydrate and lipid metabolic parameters. SUBJECTS AND METHODS: Fifty-two male patients with type 2 DM (mean age 58.0 +/- 5.7 years) and 46 male patients without this condition (mean age 57.1 +/- 6.2 years) were examined. Besides standard clinical examination, neurophysiological testing and determinations of glycated hemoglobin (HbA(1c),) and insulin concentrations, QUICKI index, and blood lipid profile were made. RESULTS: The patients with DM differed from those without DM in the lower speeds of sensorimotor reactions during neurodynamic testing and in worse attention values. In the patients with type 2 DM, the worse neuropsychological status was associated with the higher plasma concentrations of glucose, insulin, HbA(1c), total cholesterol, low-density lipoproteins, and triglycerides and with the lower levels of high-density lipoproteins. These relationships were not observed in the patients without DM. CONCLUSION: The patients with CAD concurrent with DM had a worse neurophysiological status than those without DM. Only the DM group demonstrated a relationship between cognitive impairments and carbohydrate metabolic markers. Carbohydrate and lipid metabolic disturbances may be assumed to make a negative contribution to the development of cognitive impairments in patients with CAD concurrent with type 2 DM. PMID- 25823273 TI - [Cardiovascular diseases in the population of industrial towns and environmental factors]. AB - AIM: To study the influence of environmental factors (EFs) on the development of cardiovascular diseases in the population of industrial towns of the Republic of Kazakhstan. SUBJECTS AND METHODS: The investigation covered an 18-59-year-old adult population who had been living in the urbanized areas of the Republic of Kazakhstan for at least 10 years, who worked in harmless conditions and were unregistered as having chronic diseases. At Stage 1, screening (a therapist's examination, blood general and immunological tests, and electrocardiography) was carried out for risk group persons who underwent in-depth clinical examination (blood biochemical test) at Stage 2. RESULTS: Multivariate statistical analysis has revealed that the development of hypertension is associated with the high concentration of sulfur dioxide in atmospheric air, copper in dust sediments, and zinc in soil and that of coronary heart disease (CHD) is related to the high levels of nitrogen dioxide in atmospheric air and zinc in dust sediments. CONCLUSION: Based on pathogenetic and statistical data and information available in the literature, hypertension and CHD are referred to as the diseases that may result from the influence of EFs. PMID- 25823274 TI - [Lung ultrasonography for the diagnosis of pneumonia in pregnant women with blood system tumors]. AB - AIM: To estimate the informative value of ultrasonography (USG) in the diagnosis of lung injuries in pregnant women with blood system tumors. SUBJECTS AND METHODS: Lung ultrasound was performed in 5 pregnant patients with blood cancers. The women's age was 29-38 years; gestational age was 14-33 weeks. Four women had different types of acute leukemia; one had primary mediastinal large B-cell lymphoma. All the women received chemotherapy for blood cancer. When there were signs of lung injury, USG was conducted, the results of which necessitated therapy or bronchoalveolar lavage (BAL). RESULTS: Three patients developed acute respiratory failure; 2 of them required noninvasive ventilation. Based on the detection of consolidation with a dynamic air bronchogram and pleural effusion, the authors diagnosed bilateral pneumonia and alveolar-interstitial syndrome in 1 patient, right-sided pneumonia in 1, left-sided one in 1, and transfusion-related pulmonary edema in 1. Lung ultrasound did not verify the diagnosis of pneumonia in 1 patient. According to USG data, BAL procedures were performed in 2 patients; one of them was diagnosed as having Pneumocystis pneumonia; the other was found to have no pathogens in lavage fluid. Treatment resulted in clinical improvements and normalization of the lung ultrasound pattern in all the pregnant women. Later on, 4 women delivered via cesarean section done at 32-34 weeks' gestation and gave birth to healthy babies. One patient died from infectious complications after chemotherapy. CONCLUSION: Lung sound may be used to diagnose lung injury in pregnant women with blood cancers. PMID- 25823275 TI - [Clinical efficacy of arbidol (umifenovir) in the therapy of influenza in adults: preliminary results of the multicenter double-blind randomized placebo-controlled study ARBITR]. AB - AIM: To evaluate the efficacy and safety of Arbidol (umifenovir) in adult patients with influenza. SUBJECTS AND METHODS: The analysis of the preliminary results of the multicenter double-blind randomized placebo-controlled post marketing study ARBITR was performed. A total of 293 adults aged 18 to 65 years with influenza or acute respiratory tract infection of no more than 36 hours' duration were enrolled in the study. Individuals were randomized into 2 treatment groups: oral umifenovir 200 mg four times daily for 5 days or placebo four times daily for 5 days. The efficacy endpoints were time to resolution of all symptoms, severity of symptoms and illness, durations of virus shedding. RESULTS: The efficacy of umifenovir was evaluated in the group of 119 (40.6%) patients with influenza: 45 patients with laboratory-confirmed influenza and 74 patients whom diagnosis of influenza was made based on clinical and epidemiological data. Umifenovir had influence on the time to resolution of all symptoms. All symptoms were resolved within the first 60 hours after therapy initiation in 23.8% patients with laboratory-confirmed influenza in the umifenovir group and it was 5.7 times greater compared to placebo group (4.2%) (p < 0.05). Severity of illness, catarrhal symptoms and intoxication was reduced with umifenovir compared to placebo, reducing of severity was most evidently observed within the first 2-3 days following the therapy initiation. Umifenovir had a significant effect on viral shedding. The proportion of patients still shedding influenza virus on day 4 was significantly reduced in the umifenovir group compared to placebo (25 vs 53%, respectively; p < 0.05). CONCLUSION: It was found that the effect of umifenovir in the treatment of influenza in adults is most pronounced in the acute stage of the disease and appears in the reduction of time to resolution of all symptoms of the disease, reducing the severity of symptoms of the disease and durations of virus shedding. PMID- 25823276 TI - [Common variable hypogammaglobulinemia: the author's observation]. AB - The paper gives a case history of a patient with common variable hypogammaglobulinemia (CVHGG). Its clinical picture was characterized by frequent inflammatory airway diseases, pansinusitis, and periodic rises in temperature up to febrile ones. The diagnosis was established on the basis of the decreased serum concentrations of immunoglobulins (IG) A, M, and G, the unusual small intestinal (SI) wall relief created by large lymphoid follicles, as well as the characteristic sign of CVHGG, namely, the lack of plasma cells in the lamina propria of the SI mucosa. Antibacterial therapy was noted to have a good effect that confirmed the leading role of excessive bacterial growth in the pathogenesis of chronic diarrhea and fever, which are the major clinical manifestations of CVHGG in this patient. PMID- 25823277 TI - [Arterial hypertension: an expanding pathogenic continuum and therapeutic limitations]. AB - The paper considers the role of the immune system, endoplasmic network stress, metabolic dysregulation, and epigenetic mechanisms in the pathogenesis of essential hypertension, as well as the limited possibilities of therapy with existing antihypertensive agents. PMID- 25823278 TI - [Renal dysfunction in patients with myocardial infarction concurrent with type 2 diabetes mellitus]. AB - Carbohydrate metabolic disturbances are an independent risk factor for not only the development, but also poor course of cardiovascular diseases, particularly those concurrent with renal dysfunction (RD). This factor acquires particular relevance due to the fact that the incidence of type 2 diabetes mellitus significantly continues to rise worldwide. The review considers the main mechanisms and common components of the pathogenesis of RD, as well as the constituents forming its basis in the presence of carbohydrate metabolic disturbances. Moreover, it highlights the timely detection of RD, a search for new biomarkers of prognostic value for cardiovascular events, and the early diagnosis of RD. The review unveils the present view of optimal diagnostic and management tactics for patients with myocardial infarction concurrent with background diseases. PMID- 25823279 TI - [Specific features of neurological complications developing in patients with type 2 diabetes mellitus and metabolic syndrome: possibility for correction and prevention]. AB - The prevalence of type 2 diabetes mellitus (DM) and preceding metabolic disturbances has reached epidemic proportions. Oxidative stress plays a significant role in the development of micro- and macrovascular complications in patients with DM. The accumulation of free radicals is responsible for the development of systemic and vascular inflammation, endothelial dysfunction, and hypercoagulable and ischemic states. Since vascular and nervous system damages do not level off even under adequate glycemic control, there is a need for complex pathogenetic treatment strategies. Antioxidant therapy using mexidol is one of the compulsory components of combination therapy for complications of DM. PMID- 25823280 TI - [Significance of surfactant proteins in the diagnosis of therapeutic diseases]. AB - The lung provides not only respiration, but also the functioning of innate immunity mechanisms. The hydrophilic proteins SP-A and SP-D are responsible for the regulation of the latter. In the literature, there is evidence for elevated serum SP-A and SP-D levels in respiratory diseases accompanied by enhanced mucosal inflammation of the lung or its parenchymal injury and their association with age and cardiovascular diseases has been recently found. Studies of the efficiency of using SP-A and SP-D as specific markers for inflammatory lung diseases are presently worthwhile. PMID- 25823281 TI - [An important stage in the development of field therapy (on the 70th anniversary of victory in the Great Patriotic War)]. AB - Much previous experience accumulated by physicians in various wars and local military conflicts provides strong evidence that it is necessary to set up a harmonious system to deliver therapeutic care during wartime, which is based on the unity of views on the origin, course, and treatment of pathological processes having regard to the specific conditions under which armed forces are involved in combat operations. This all has given rise to the new branch of therapy--field therapy. The Great Patriotic War was the most important stage in the development of Russian field therapy, which was characterized by the setting up of the effective and scientifically ground system to deliver therapeutic care to the wounded and patients, which was based on the tenets of a uniform field medical doctrine. PMID- 25823282 TI - [Changes in the expression of Bcl-2 antiapoptotic protein in rat neocortex and hippocampus under the influence of various modes of hypobaric hypoxia]. AB - Using immunocytochemical method, the level of expression of Bcl-2 antiapoptotic factor was studied in neurons of the neocortex and hippocampus in 72 male Wistar rats exposed to damaging severe hypoxia (SH), moderate hypobaric hypoxia (MHH), as well as their combination. After SH (180 mmHg) Bcl-2 expression in the neurons of the brain regions examined was reduced or. unchanged. The effect of preconditioning with one trial of MHH (360 mmHg) on Bcl-2 expression was similar to that seen after SH. In contrast, preconditioning with repeated exposures to MHH significantly up-regulated Bcl-2 expression levels 3-24 h after SH that apparently protected neurons from SH-induced injury. MHH alone, not followed by SH, significantly increased Bcl-2 expression only after multiple (three or six) exposures whereas single MHH exposure had no effect on Bcl content. Hence, up regulation of Bcl-2 seen in response to multiple MHH trials appears to be important for the formation of the mechanisms of brain neuronal tolerance to damaging factors. PMID- 25823283 TI - [Expression of BDNF neurotrophin in the hippocampus and neocortex of rats during the development of post-stress anxiety and its correction by hypoxic postconditioning]. AB - Using quantitative immunohistochemistry, changes in the expression of the BDNF (Brain-Derived Neurotrophic Factor) were studied in the hippocampus and neocortex of 24 male Wistar rats during the development of post-stress-related anxiety state in the experimental model of posttraumatic stress disorder, and its correction by hypoxic postconditioning (PC). For the induction of anxiety state, combined severe psychoemotional stress was applied (immobilization, forced swimming, ether stress followed 7 days later by repeated immobilization - restress). Correction of the anxiety state was achieved by application of hypoxic PC, which included three sessions of mild hypobaric hypoxia (360 mm Hg, 2 h, daily). The formation of the anxiety pathology was accompanied by a significant reduction in the expression of immunoreactive BDNF in dorsal (CA1) and ventral (dentate gyrus) hippocampus and neocortex, while hypoxic PC resulted in partial (hippocampus) or complete (neocortex) restoration of BDNF expression. The results indicate that the neurotrophic factors, and BDNF in particular, seem to play an important role in the pathogenesis of the anxiety-depressive disorders as well as in mechanisms of proadaptive and neuroprotective effects of hypoxic PC. PMID- 25823284 TI - [Ultrastructural changes in brain histaminergic neurons under the influence of alcohol]. AB - The aim of the present study was to investigate the ultrastructural changes developing in histaminergic neurons of the brain of 24 outbred albino male rats after administration of ethanol in the acute experiment (single intraperitoneal dose of 1 and 4 g/kg), subacute exposure (as the sole source of drinking at a dose of 4 g/kg for 7 days), or chronic administration (at a dose of 2-3 g/kg/day for 6 months). After alcohol administration histaminergic neurons were found to develop various ultrastructural changes of their nucleus and organelles. They reflect the processes of neuron destruction, as well as adaptive changes aimed at restoring and maintaining their functions. These changes were nonspecific and depended on the dose, time after injection and duration of alcohol administration. In general they corresponded to the structural and histochemical changes observed at light-microscopic level. PMID- 25823285 TI - [Organization of the pallidal projections of the rostromedial tegmental nucleus in the dog brain]. AB - The method of retrograde and anterograde transport of horse-radish peroxidase was used to study the organization of the projections of the rostromedial tegmental nucleus (RMTN) to functionally distinct regions of pallidal structures of brain in dogs (n = 13). It was found that the fibers formed by the neurons of the limbic medial segments of RMTN rostral and caudal regions projected to the limbic pallidal regions--ventral globus pallidus and ventral pallidum. The reciprocal projections were detected between the ventral pallidum and medial segment of the rostral RMTN. These data indicate the possibility of the segregated conduction of the limbic information in the examined projection systems. However, in the majority of the pallidal structures, the convergence of the projection fibers originating from the neurons of functionally different parts of RMTN was observed. Thus, the projection fibers formed by the neurons of motor lateral and limbic medial parts of RMTN are directed to the limbic ventral segment of the globus pallidus and to the entopeduncular nucleus, which is innervated by the fibers formed by the neurons of functionally diverse structures. The possible pathways for conduction of functionally different information and its integration in the projection systems investigated are discussed. PMID- 25823286 TI - [Architectonics of gastric arterial bed in norm, after Nissen fundoplication, and its different combination with splenectomy and left gastric artery ligation]. AB - A comparative study of the effect of the combination of Nissen fundoplication, different variants of splenectomy ligation of left gastric artery on stomach wall arterial bed blood fillability was carried out on 40 human corpses in 6 research series. The red lead paint suspension was used for the injection of arterial bed. It was shown that combination of Nissen operation andligation of stomach short arteries during splenectomy and left gastric artery trunk in its intraligamental part resulted in the impairment of the stomach wall blood supply. In the gastric fundus area avascular zones measuring from 2.5 x 3.0 to 5.0 x 10.0 cm and larger, were detected. The stomach wall of the given areas is potentially prone to necrosis. Avascular zones in the stomach wall were not observed when short gastric arteries were preserved. PMID- 25823287 TI - [Morphological and immunohistochemical characteristics of the thymus during chemical carcinogenesis induced by 1,2-dimethylhydrazine administration]. AB - The aim of the study was to examine the histological and immunohistochemical characteristics of the thymus 5 months after the intraperitoneal administration of the carcinogen (1,2-dimethylhydrazine in the dose of 20 mg/kg once a week for 2 weeks). The study was conducted on 50 outbred albino male rats. Paraffin sections of the thymus were stained with hematoxylin-eosin and were processed by an immunohistochemical method using antibodies against CD3, CD30, CD68, synaptophysin, S-100 protein, p53, bcl-2, Ki-67, as well as against IgM and IgG. It was found that carcinogen administration resulted in the increased number of thymic cells expressing bcl-2, S-100 and Ki-67, active T-lymphocytes and thymopoietic microenvironment cells, as well as in the change of the correlation between medullary and cortical CD3(+)-thymocytes with a predominance of the latter. Thus, the malignant tumor, developing in the colon, on the one hand, inhibits the supply of the precursors of thymopoiesis to the thymus, while on the other--enhances the proliferation and differentiation of thymocytes into mature forms. PMID- 25823288 TI - [Liver, lung, kidney and spleen macrophages in rats after intravenous administration of the modified magnetite nanoparticles]. AB - Using the immunohistochemical method, mononuclear phagocytes (MNPs) were detected in the liver, lung, kidneys and spleen of rats after a single intravenous injection of a suspension of magnetoliposomes and magnetic microspheres prepared on the basis of nanoscale magnetite particles of (NMPs). The dynamics of the of the number and topography of CD68(+)- and CD163(+)-cells in liver, lung and kidneys was characterized during 120 days after the intravenous injection of the suspension of modified NMPs. It was shown that NMPs surface modification reduced the degree and duration of macrophage activation. Signs of MNPs activation after the infusion of nanomaterial decreased in the following series: unmodified NMPs, magnetoliposomes, magnetic microspheres. PMID- 25823289 TI - [Structural reorganization of the dermis of dog tibia during its elongation by the method of transosseous distraction osteosynthesis]. AB - Using the methods of light, scanning and transmission electron microscopy, immunohistochemistry and morphometry the status of the various components of the dermis was studied in the experiment performed on 16 adult mongrel dogs that had their shank extended by 17% of its original length using the method of transosseous distraction osteosynthesis with a daily rate of 1 mm for 4 steps. During the period of distraction, a reduction in the thickness of the dermis, change of the architectonics of its fibrous component, active collageno- and elastogenesis, cell proliferation, and the expressiveness of heteromorphism of fibroblast and macrophage cell populations were detected. In postdistraction period, all the indices were gradually approaching the norm. The data obtained may serve as criteria for the estimation of the stages of the reparative process developing under the created conditions and should be considered in the development of new technologies aimed at optimizing reparative-regenerative processes during tibial lengthening. PMID- 25823290 TI - [Peculiarities of the morphological structure of the inorganic component of human dental enamel and dentin at nano-level]. AB - Using the polished sections of 20 permanent human molars and premolars, the regimes of probe atomic force microscopy were assessed that permit the definition of the size, shape, spatial configuration of the structure-forming hydroxyapatite crystals of enamel and dentin inorganic component. It was found that the major part of enamel crystals had the size of 40-60 nm and were more flattened. Dentin crystal average size was equal to 60-80 nm. Microspaces between them had the shape of rotational ellipsoid sized 120 nm by 60 nm. PMID- 25823291 TI - [Comparative characteristics of the morphometric peculiarities of the structure of bone tissue of the dentoalveolar segments of maxillary premolars]. AB - The morphometric parameters of bone tissue structure were studied in 168 dentoalveolar segments of maxillar premolars relative to the conventional median vertical median line. It was found that height, width and area indices were not significantly different in the 1st and the 2nd premolar dentoalveolar segments. At the same time, the dependence of the thickness of compact and cancellous bone on the side (vestibular, palatal) and part (upper, middle, base) of the segment was detected. It was also found that while the thickness of the compact substance increased from the upper part of the segments toward the base independently on their part, the thickness of the cancellous substance, conversely, was significantly decreased on vestibular side, and was increased on the palatal side. PMID- 25823292 TI - [Structural reorganization of the main joint components during the experimental modeling of osteoarthrosis with reduced blood supply]. AB - The reactive changes in the knee synovium, articular cartilage, and subchondral bone during osteoarthrosis modeling were studied in dogs (n = 5). The results of histomorphometry, scanning electron microscopy, and electron probe microanalysis have demonstrated that the osteoarthrosis model used (femoral artery ligation and the knee immobilization) lead to marked synovitis, axonal atrophy and nerve fiber degeneration in subsynovial nerves, as well as synovial membrane hypovascularization. Subchondral bone vascularization was shown to deteriorate, while calcium content was reduced. Destructive changes were detected in the articular cartilage. Chondrocytes of the intermediate zone which were equidistant from vascular and synovial sources of supply appeared to be the most vulnerable. The changes described are the consequences of the disturbed interactions of the main joint components indicating the reduction of synthesis with a predominance of catabolic processes. PMID- 25823293 TI - [The relationship between the parameters of mineral density of bone tissue and somatotype in women residing in the Republic of Karelia]. AB - Comprehensive anthropometric and densitometric study using the dual x-ray absorptiometry was conducted to determine the relationship between the mineral density of bone tissue and somatotype in 360 women aged 20 to 87 years, permanently residing in the Republic of Karelia. Significant direct correlation was detected between the somatotype and the amount of mineral substances in the vertebrae, bone mineral density and the area of the lumbar vertebrae. Bone mineral density level of the lumbar vertebrae was higher in women with europlastic and athletic somatotypes, which were characterized by high values of body mass and length, body muscle and fat mass. Low values of bone mineral density of vertebrae were identified in women belonging to subathletic, mesoplastic and stenoplastic somatotypes. The risk of developing osteopenia and osteoporosis is increased in women with low body muscle mass. PMID- 25823294 TI - [Nestin expression in ependymal cells of lateral ventricles of the rat brain in aging]. AB - It is known that during development of the brain, with the progress of ependendymocyte differentiation from radial gliocytes, the synthesis of nestin is stopped. However, it was shown that in the ependyma of the lateral brain ventricles nestin synthesis was resumed in response to ischemic injury. The aim of the present study was to test the hypothesis of possible re-expression of nestin in the ependyma in aging. The study was performed on male Wistar rats aged 4 (n = 4) and 28 months (n = 3). In older animals the expression of nestin was demonstrated in the ependyma of the lateral ventricles of the brain. It was also found that the area of the medial and upper walls of the lateral ventricle contained the regions of ependyma, in which all cells had intense cytoplasmic staining. The causes of the phenomenon described remain unclear. PMID- 25823295 TI - [Demonstration of the glomeruli in human cerebellum using synaptophysin immunohistochemistry and confocal laser microscopy]. AB - The aim of the study was to develop the methodologic approaches for the demonstration of the complex synaptic groups (glomeruli) in human cerebellum using synaptophysin immunocytochemistry. The protocols presented in the paper allow to obtain of high qualify prepartaions for conventional light and confocal laser microscopy in which individual glomeruli and intraglomerular axonal terminals could be distinctly identified. The preparations obtained are suitable for a quantitative analysis. PMID- 25823296 TI - [The role of E-cadherin cell adhesion molecule in human ontogenesis in norm and pathology]. AB - E-cadherin is one of the most important cell adhesion molecules, which plays a key role in embryogenesis and adult tissues under normal conditions and during tumor development. Molecules of E-cadherin are located at the epitheliocyte surface and take part in the adhesion contacts formation which are a characteristic feature of epithelial tissues. The role of E-cadherin is not only in the maintenance of intercellular adhesion, but also in provision of cell proliferation and differentiation through participation in the realization of a number of signaling pathways, the main of which is the canonical Wnt signaling pathway. This review provides basic information regarding the role of E-cadherin in human ontogenesis in norm and pathology. PMID- 25823297 TI - [Regulation of hair follicle cycle]. AB - This review is devoted to the control of hair growth. The hair follicle undergoes cyclic transformation from the resting phase (telogen) to the growth phase (anagen). The latter phase is characterized by rapid proliferation of follicular keratinocytes and elongation and thickening of the hair shaft. The regression phase (catagen) leads to the involution of the hair follicle. These cyclic changes include rapid remodeling of both the epithelial and the dermal components. They are controlled by numerous different factors: sex hormones, neurotrophins, FGF, TGF, BMP, VEGF, Sonic Hedgehog, and other signaling pathways. PMID- 25823298 TI - [250 years of the Department of Human Anatomy of the I. M. Sechenov First Moscow State Medical University (1764-2014)]. PMID- 25823299 TI - [70 years of S.S. Mikhailov Department of Operative Surgery and Clinical Anatomy of Orenburg State Medical Academy]. PMID- 25823300 TI - [United XII Congress of the International Association of Morphologists and VII Congress of Russian Scientific Medical Society of Anatomists, Histologists and Embryologists (Tiumen', May, 28-31, 2014)]. PMID- 25823301 TI - [Problems of Theoretical and Medical Embryology (Inter-University Conference, St. Petersburg, April 24, 2014)]. PMID- 25823302 TI - [Yakov Vasil'evich Villie (1768-1854)--surgeon-public health official of Russian medical corps]. PMID- 25823303 TI - [Dopplerographic predictors of cognitive status dynamics of patients after carotid angioplasty with stenting]. AB - The authors present dopplerographic predictors of cognitive status dynamics of patients undergoing carotid angioplasty with stenting. It was stated that the cognitive status dynamics depended on the initial condition of patients and reactivity coefficient on hypercapnia in target vascular pool. PMID- 25823304 TI - [Prevalence of esophageal syndromes of gastroesophageal reflux disease in population of Leningrad region (according to esophagogastroduodenoscopy findings)]. AB - The article presents an analysis of 34.903 esophagoscopy results performed for population of Leningrad region at the period from 2007 to 2013. A prevalence of erosive esophagitis was 4.9%, peptic strictures--0.18%, columnar-celled metaplasias--1.43% and esophageal adenocarcinoma--0.645%. The data obtained showed a high prevalence of GERD-associated syndromes with injury of mucous coat of esophagus in the local population of Russians. PMID- 25823305 TI - [Endoscopic and roentgenovascular interventions in treatment of patients with bleeding from a gastroduodenal ulcer]. AB - The authors analyzed the results of treatment of 965 patients with bleeding from gastroduodenal ulcers. The endoscopic hemostasis was carried out in 20.2% patients, however a recurrence of bleeding was noted in 12.8% cases. The combined endoscopic hemostasis was performed in 76.9% patients, though the relapse of bleeding had only 4.2% and 49 patients were safe. A surgery was required for 3.2% patients. PMID- 25823306 TI - [Choice of the way of pancreaticodigestive fistula in pancreaticoduodenal resection]. AB - The author offered an algorithm of definition of optimal ways of pancreaticodigestive fistula formation in pancreaticoduodenal resection. It is based on the following factors such as tissue conditions of the pancreas gland stump, a diameter of pancreatic duct and compliance with cut dimensions of gland stump of anastomotic loop of the jejunum. A comparative analysis of pancreaticodigestive fistulas performance was made in 2 groups. An algorithm of choice of pancreaticodigestive anastomosis was applied in the main group (n = 35). An inconsistency of pancreaticodigestive fistula was noted in the main group (5.7%) and in the comparative group (n = 59)--17% (p = 0.205). There weren't any cases of destructive pancreatitis and lethality, which were directly specified by pancreaticodigestive anastomosis in the main group. Destructive pacreatitis developed in 10.1% cases in the comparative group. The lethality consisted of 5.1%. The results obtained confirmed the efficacy of individualized approach to formation of pancreaticodigestive fistulas and showed the practical value of investigation in this way. PMID- 25823307 TI - [Ways of stump processing of appendix vermiformis in modern conditions]. AB - The authors analyzed the experience of 517 appendectomies during last three years. There weren't any differences in postoperative course in patients with immersion and ligature methods of stump processing of appendix vermiformis. The ligature method should be considered as leading method in appendectomy in consideration of long-term experience in surgery. The immersion method would be used in presence of contraindications to the ligature method. PMID- 25823308 TI - [Treatment of the parastomal hernias]. AB - The article presents the results of 16 operations for the parastomal hernias. The operations were differentiated: the colostomy was relocated to the left retroperitoneal space and in case of hernioplasty it was performed with use of mesh transplant. The fascial defects were closed using the mesh transplant. There weren't any complications in early postoperative period. Long-term five-year results showed no recurrence. PMID- 25823309 TI - [Exenteration of the small pelvis in treatment of local tumors]. AB - The authors analyzed the experience at the period from September 2000 to January 2014. The total exenterations of the small pelvis were performed on 23 patients (12 men and 11 women) at the age from 37 to 71 years old. Supralevator total exenterations with full visceral reconstruction were carried out in 13 cases out of 23. Total infralevator pelvic exenterations were used in 10 cases. There wasn't the intraoperative lethality. Patients (3 cases) died in postoperative period. Postoperative complications developed in 10 patients, though serious complications, which required an application of surgical strategy were noted only in 3 cases. The mean life span consisted of 29 months. The performance of total exenteration of the small pelvis considerably increased the life span of the patients and in case of application of reconstructive methods allowed restoration of quality of life to high level and obtaining moral, psychological and social rehabilitation. PMID- 25823310 TI - [Surgical correction of dislipodemia in patients with obesity]. AB - The results of surgical treatment of 139 patients with metabolic syndrome, obesity and dislipodemia were analyzed. Modern bariatric operations (4 types) were performed by using laparoscopic method. There were regulated bandages of the stomach (RBS), lengthwise gastric resections (LGR), biliopancreatic and stomach bypass surgeries (BBS, SBS). Results of five-year follow-up indicated that restrictive operations on the stomach (RBS, LGR) aimed to correct overweight and dislipodemia had some limitations to application in a varying degree. The RBS operation should be appropriate to use for women of the young age group, when an initial body-weight index wasn't more than 43 kg/m2. The LGR operation was effective for men of the young age group and women in case of moderately expressed dislipodemia and in case when the initial body-weight index didn't exceed more than 45 kg/m2. Combined bariatric operations (BBS, SBS) were most likely effective on body weight and dislipodemia. PMID- 25823311 TI - [Clinical picture and treatment results in patients with secondary hyperparathyroidism]. AB - The secondary hyperparathyroidism was observed in 23 patients using a program hemodialysis. The parathyroidectomy was applied as a medical aid. A relapse was noted in one case. Clinical signs of hyperparathyroidism were completely terminated by 6 months. PMID- 25823312 TI - [Long-term results of surgical treatment of secondary hyperparathyroidism in patients using a program hemodialysis]. AB - The efficacy of total parathyroidectomy was shown in 18 patients with renal hyperparathyroidism after 6-12 years period after operation. The authors accepted the total parathyroidectomy as a reasonable way for treatment of secondary hyperthyroidism in patients with long-term dialysis therapy. PMID- 25823313 TI - [Experience of the use of endovideotechnology in surgical treatment of esophageal cancer]. AB - An investigation included 33 patients with cancer of thoracal section of the esophagus at the age from 42 to 74 years old. A surgical method of treatment was applied as only one in 13 patients and methods of nonadjuvant chemoradiation therapy were used for 20 patients. A hybrid minimally invasive esophagectomy (laparoscopic mobilization of the stomach and right-side thoracotomy) was performed on 16 patients. The rate of postoperative complications consisted of 31%. The minimally invasive esophagectomy (performed by totally endovideosurgical approach) was carried out in 15 cases. Postoperative complications developed in 53% of follow-up patients. There weren't cases of lethality. The experience of minimally invasive methods indicated the satisfactory results of application of given methods in patient treatment of esophageal cancer. The use of endovideosurgical approaches allowed performing oncologically adequate volume of operative interventions. PMID- 25823314 TI - [Antibiotic prophylaxis and therapy of pancreatonecrosis in multifield surgical hospital]. AB - The article is based on an analysis of results of complex treatment of 497 patients with pancreatonecrosis at the period from 2010 to 2014. All patients were admitted to the surgical departments of Republican hospital No 2 and Centre of Emergency Medicine of Republic of Sakha (Yakutia). The investigation allowed adaptation and development of antibiotic prophylaxis and therapy management in pancreatonecrosis in multifield surgical hospital. More than 80% of patients avoided a contamination of necrotic destruction zones. The level of lethality was reduced in group of patients with infectious complications of pancreatonecrosis from 45.8% to 37.7%. PMID- 25823315 TI - [Rare observation of giant Askin's tumor with localization in anterior mediastinum]. PMID- 25823316 TI - [Experience of treatment of female with disseminated cancer of the colon in consideration of predictive markers of sensitivity to cytostatic agent and bevatsizumab]. PMID- 25823317 TI - [Favorable result of the use of bioplastic material for closing an ulcerous defect in patient with diabetic foot syndrome]. PMID- 25823318 TI - [Emergency oncology--ways of solving the problem]. PMID- 25823319 TI - [Discovery of intravenous anaesthesia]. PMID- 25823320 TI - [Professors A. A. Kiter and S.M. Yanovich-Chainskiy--founders of phlebosclerosing therapy in Russia (to 150th anniversary of history of the question)]. PMID- 25823321 TI - [Modern approach to problem of diagnostics and treatment of patients with thyroid cancer]. PMID- 25823322 TI - [Features of spontaneous pneumothorax in female]. PMID- 25823323 TI - [Simultaneous operations on abdominal organs: controversial and obvious aspects of the problem]. PMID- 25823324 TI - [Organ-preserving and segmental resections of the head of the pancreas: anatomic substantiation and surgical technique]. PMID- 25823325 TI - [In commemoration of professor Vladimir Viktorovich Gritsenko (1938-2014) (collective of authors)]. PMID- 25823326 TI - [In commemoration of professor Igor Aleksandrovich Eryukhin (1936-2014) (Samokhvalov I.M., Tynyankin N.A]. PMID- 25823327 TI - [Academician Fedor Grigorevich Uglov. Patriarch of national and world surgery (commemorating the 110th anniversary of birthday) (collective of authors)]. PMID- 25823328 TI - [Optimization of prophylaxis of hypercoagulation complications in oncological surgery]. AB - The authors investigate the results of prophylaxis of venous thromboembolic complications (VTC) during 24 years in onco- logical surgery. The multicentric study shows that common frequency of occurrence of such VTC was reduced due to period of routine prophylaxis of VTC to 3.4%. The strategy of active revision and escalation of preventive measures in the third period of study in comparison with the second period resulted in the decrease of VTC. Patients with moderate risk degree had the results from 3.2% to 1%, patients with high risk degree moved from 4.1% to 13%. The fatal thromboembolism of the lung artery was 0.1%. PMID- 25823329 TI - [Complex approach to assessment of condition severity in patients with pyoinflammatory odontogenous diseases]. AB - Dynamics of mean value indices and mean dispersion doesn't exclude the feedback (Mayanskiy D.N., 2008) in process of study the disease according to cooperative processes using system leukocyte-monocyte-lymphocyte (L+M+LM). The authors investigated a dynamic balance between these cell substratums and collagen formation. Acute inflammatory processes in tissues of maxillofacial area accompanied by leukemoid response of peripheral blood in the form of leukocytosis (10 x 10(9)-15 x 10(9)/l and more). The authors completely agree with the opinion of M.M. Solov'yov (2012) and N.K. Artyushenko (2008) that mechanism of this reaction is associated with both the leukocyte redistribution in the inflammation zone and with changes of hematopoietic rostock which aimed to balance the affected compensatory mechanisms of nonspecific resistance. PMID- 25823330 TI - [Electrocardiotherapy using pericardoscopy]. AB - The standard transvenous electrocardiostimulation (ECS) is currently used in many specialized hospitals. The authors offered and launched systematic application of simple but available technique of epymiocardiac ECS using pericardoscopy since middle of 80th. According to this principle, the authors developed some diversities of manipulation which are distinctive due to their availability, reliability and supersafety. The method could be recommended for wide-spread usage in practice because of high efficacy, few complications and absence of fatal outcomes in correct intervention. Described methods used in treatment of considerable quantity of patients and adapted to real work conditions of public health hospitals. PMID- 25823331 TI - [Genetical aspects of surgical treatment in patients with hereditary breast cancer]. AB - Numerous available results of investigations confirmed the important role of prophylactic bilateral laparoscopic salpingo-oophorectomy and contralateral prophylactic subcutaneous mastectomy in decrease of risks of malignant tumors of the reproductive system when mutation carriers of BRCA1 and BRCA2 presented. Recommendations to surgical treatment of hereditary breast cancer are considered as a very difficult task which should be based on risks and advantages of prophylactic surgical interventions. Presented surgical operations could be applied in mutation carriers of reparation DNA genes and patients with hereditary breast cancer aimed to improve the indices of general survival rate and quality of life. PMID- 25823332 TI - [Assessment of risk factors of operations on the lung and pulmonary arteries in patients with accompanied diseases]. PMID- 25823333 TI - [Choice of the method of surgical treatment of chronic pancreatitis]. AB - An analysis of surgical treatment of 187 patients with chronic pancreatitis was made during 3-year period in the department of surgery clinic of Byelorussian Medical Academy of Post-Graduate Education. Drainage operations were performed on 28 patients, resection-drainage operations were carried out on 130 patients and resection operations had 19 patients. The laser beam technologies were successfully applied during operations on the pancreas in 43 patients. Postoperative complications (14.8%) were analyzed and structured. Methods of corrections and ways of prophylaxis of complication development were provided. On the basis of the complication analysis and new conception concerning peripheral pancreatic hypertension the authors offered the rational approaches to choice of operations on the pancreas in case of chronic pancreatitis. The authors developed the classification of pancreatoductolitiasis, pancreatic hypertension and a new strategy of surgical management of chronic pancreatitis. PMID- 25823334 TI - [Comparative rate of regional metastasis of high differentiated carcinoma of the thyroid gland]. AB - The rate of metastasis of high differentiated carcinoma of the thyroid glands to the neck lymph nodes was studied in people of Kemerovo Region. The metastatic lesions of pretracheal lymph nodes (VI group) were detected in 49.5% patients with papillary carcinoma and 21.0% of patients with follicular cancer. Metastases in jungular lymph nodes were revealed in 37.3% patients with papillary carcinoma. It was noted that an extension of metastatic lesions of regional lymph nodes was observed in the case of primary tumour foci spread beyond borders of the capsula glandularis in patients with papillary carcinoma. There wasn't such a relation in a case of follicular cancer. Metastases in regional lymph nodes were detected more often (67.6%) in the case of papillary carcinoma in uncontaminated zone of the thyroid gland compared with other thyroid pathology (31.7%). PMID- 25823335 TI - [Early enteral infussions in complex treatment of severe combined chest trauma]. AB - On the basis of study and treatment of 98 victims it was stated that the absorption of isotonic glucose electrolytes solutions in the small intestine was saved even increased in case of large hemorrhage in severe polytrauma with chest, abdominal injury and other regions trauma. An application of early enteral infusions allowed reducing of the volume of parenteral introduction solutions and facilitated to a reliable decrease of development frequency of nosocomial pneumonia of attributive lethality. PMID- 25823336 TI - [Optimization of surgical strategy in complications after thoracic operations demanding recurrent surgical interventions]. AB - A frequency of postoperative complications varied from 1-2% after endoscopic thoracal operations to 4-12% after open operations using thoracotomic access. There isn't any common approach to indications and terms of the recurrent endoscopic intervention. An analysis of postoperative complications was made after 2795 thoracothomies and 3632 videothoracoscopies required the recurrent operation in 139 patients (2.2%). The rethoracoscopies were performed on 62 patients (44.6%), thoracoscopies were carried out after thoracotomies in 40 cases (28.8%) and rethoracotomies were in 37 cases (26.6%). The more frequent indication to recurrent operation was bleeding (26.6%), pleural empyema (20.9%), fragmented pleuritis (11.5%). It was shown that thoracoscopy was an alternative to rethoracotomy as the rethoracoscopy in case of nonmassive intrapleural bleeding, clotted hemothorax, postoperative fragmented pleuritis, non-sanitized empyema region, the presence of sequestrums in this area, limited postoperative pleuritis, chylothorax, bronchopleural fistula of the size of 1-2 mm, leakage of the lung, a foreign body in pleural cavity. The lethality consisted of 35.1% after rethoracotomies and it was 12.7% after recurrent endoscopic operations. PMID- 25823337 TI - [Laparoscopic interventions in left sections colon cancer complicated by obturation intestinal obstruction]. AB - On the basis of an analysis of 2200 cases of left sections colon cancer complicated by obturation intestinal obstruction the authors showed the possibility and reasonability of two-step operation performance. The first operation formed unloading part and the second was the radical operation in one hospitalization. Given method allowed improvement of the results and quality of life of the patients. PMID- 25823338 TI - [Features of angenesis against the background of negative pressure wound therapy in patients with neuropathic and neuroischemic forms of diabetic foot ulcers]. AB - The authors analyzed clinical (size, tissue oxygenation), histological (light microscopy) and immunohistochemical (CD68, MMP-9, TIMP-1) features of reparative processes of soft tissue of lower extremities in patients with diabetes mellitus against the background of vacuum therapy in comparison with standard local treatment. Patients (31 cases) with diabetic foot ulcers were followed-up after surgical d-bridement and before plastic closure of the wound. During perioperative period 13 patients obtained the negative pressure wound therapy (NPWT of 90-120 mmHg) and 18 patients had the standard care. Given results supported higher efficacy of NPWT as compared with standard local care. The therapy caused rapid reduction of wound and its depth, increased local microcirculation and reduced inflammation. These data were confirmed by the histological and immunohistochemical studies. The high efficacy of the method of local treatment could significantly reduce the time of wound preparation for the next step of surgical treatment. PMID- 25823339 TI - [Apparatus for external fixation of the hand]. AB - The authors offered the apparatus for external fixation of the hand. A medical plastic is used for making the support of an improvised apparatus. The pins "sealed" in plastic and fixed bone fragments. The proposed apparatus has a number of advantages in comparison with analogous devices and could be useful for surgeons who provide emergency care for the patients with hand injuries. PMID- 25823340 TI - [Method of detection of residual tissues in recurrent operations on the thyroid gland]. AB - A search of residual tissues is complicated in recurrent operations on the thyroid gland. The Saint-Petersburg Centre of Surgery of the Endocrine System and Oncology developed the method of detection of residual tissues of the thyroid gland with the aim of preoperative chromothyroidolymphography under control of ultrasound. The method consisted of US performance during 15-20 minutes before the operation and an introduction of 1% sterile water solution of methylene blue in revealed residual tissues of the thyroid gland. The volume of injected coloring agent was 0.5-2 ml in the residual tissue volume smaller than 9 cm3 and 2-3 ml injected in case of more than 9 cm3. The residual tissues of the thyroid gland accurately visualized during the following operation. Described method gives the possibility to detect all regions of residual tissues which should be removed and at the same time it shortens a revision and surgery trauma. PMID- 25823341 TI - [False incarceration of hernia of linea alba with phlegmon of hernia sac caused by acute gangrenous appendicitis]. PMID- 25823342 TI - [Vladimir Nikolaevich Derevenko (1879-1936). Perm' period of work (commemorating the 135th anniversary of birthday)]. PMID- 25823343 TI - [Influence of structural features on clinical results of transcatheter aortic valve implantation]. PMID- 25823344 TI - [Surgery of chronic pancreatitis]. PMID- 25823345 TI - [Recent clinical developments in prophylaxis of postoperative intra-abdominal adhesions]. PMID- 25823347 TI - [Professor Valeriy Mikhailovich Sedov (to the 70th anniversary of birthday)]. PMID- 25823348 TI - [Pathways from initial symptoms to psychiatric treatment in patients with schizophrenia]. AB - Early intervention is essential for improving the long-term prognosis of schizophrenic patients. With the objective of contributing to early treatment in communities in the future, we retrospectively investigated patient data, including the pathway to psychiatric care, the course prior to consultation, and initial symptoms. An interview survey was conducted involving a total of 125 patients receiving treatment for a diagnosis of schizophrenia and 74 family members using two questionnaire sheets to collect data on the pathway to psychiatric care, age at onset, time between onset and the initiation of treatment, initial symptoms, and the necessary information. For the pathway to psychiatric care, facilities were classified into : psychiatric clinic, psychiatric hospital, psychiatric department of a general hospital, and general practices, and tendencies were investigated. As for the initial symptoms, differences between those recognized by the patients themselves and their families were investigated. The results showed that approximately 80% of patients had first visited medical facilities, while the remaining patients had consulted psychologists, school nurses, teachers, or public health centers. The mean time from onset to initial psychiatric consultation was 24.7 +/- 3.3 months, with a median period of 6.0 months. This duration was particularly long among patients who first visited general practitioners. As the initial symptoms, 70% of patients had psychiatric symptoms as subjective symptoms, and more than 70% of family members equally noticed psychiatric symptoms. On the other hand, 40% of patients had positive symptoms, but only 20% of family members had noticed the positive symptoms. A total of 30% of patients had been aware of somatic symptoms, and these patients were significantly more likely to initially visit physicians in a department other than the psychiatric department. As for delay in consultation, patients who had onsets at an early age tended to take longer to make the initial visit. The above findings confirmed the necessity of disease education at schools, given that onset can occur in school-age children, as well as the establishment of a mental health network, understanding of psychiatric diseases among primary care physicians and their cooperation with psychiatrists, and increased public awareness regarding psychiatric diseases. PMID- 25823349 TI - [Introduction of British guidelines in perinatal mental healthcare--towards enhancing the function of perinatal mental healthcare in Japan]. AB - Professionals in many different occupations, from psychiatrists, obstetricians, and pediatricians to nurses, midwives, pharmacists, clinical psychologists, public health nurses, and psychiatric social workers, are involved in perinatal mental healthcare. In order to enhance the function of such healthcare, it is necessary both to provide specialized training in each occupation and form a system and to smoothly conduct medical collaboration between different occupations. A deficiency in the medical function of perinatal mental healthcare greatly influences the mother and child's health, mental hygiene, and social life later in life. Therefore, a demand is seen for specialized staff and system formation capable of the following: 1) responding with appropriate perinatal management of female patients taking psychotropic drugs; 2) providing support and pregnancy consultation to female patients who wish to have children; and 3) properly handling postpartum mental disorder management, possibility of breastfeeding, and various issues that arise in mother-child relationships during upbringing. In the UK, the clinical guideline (NICE Clinical Guideline 45) for perinatal mental healthcare, which was created by the National Institute for Clinical Excellence (NICE), provides important guidelines on how to handle perinatal mental health. Aside from the NICE guideline, the Maudsley Prescribing Guidelines in Psychiatry indicates basic guidelines on prescribing perinatal drug therapy. In Japan, however, the current situation of perinatal mental healthcare is such that it has yet to be systemically developed. In this paper, we introduce the basic content in these British guidelines that should be noted. In addition, we consider the current status and future disposition of Japan's perinatal mental healthcare, with consideration for the differences in healthcare circumstances between Japan and the UK. PMID- 25823350 TI - [Comparison of care for perinatal mental health between Japan and other countries]. AB - Various types of mood, anxiety, and psychotic disorder are seen in the perinatal period. Recently, evidence regarding risk factors and the onset time of such psychiatric disorders has been reported. Local care service systems that can predict or detect high-risk women early are desirable. Furthermore, a specialist multidisciplinary perinatal mental health service should be established in each locality, providing regular services, consultation, and advice to promote maternity, other mental health, and community services. PMID- 25823351 TI - [Current evaluation of teratogenic and fetotoxic effects of psychotropic drugs]. AB - Psychiatric disorders are equally common among pregnant and non-pregnant women, and many of these conditions are treated with psychotropic medications. The use of psychotropic medicines during pregnancy, especially antidepressants, became increasingly prevalent in the early 2000's, although many physicians prefer not to prescribe drugs for pregnant women due to concerns about teratogenicity. Current data on the risks of in utero exposure to psychotropic medications are limited, leaving women and physicians to make difficult decisions regarding the initiation or maintenance of treatment during pregnancy without a complete knowledge of the risks. Of all the psychotropics, antidepressant use in pregnancy has been relatively well studied. However, available studies have not yet adequately controlled for other factors that may influence birth outcomes, including maternal illness or problematic health-related behaviors such as smoking and alcohol use during pregnancy. This review focuses on the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, the antidepressants most commonly used to treat depression. In the evaluation of medication during pregnancy, teratogenicity and fetotoxicity must be considered. Most studies on the use of SSRIs during the first trimester of pregnancy have not shown an increase in the overall risk of major malformations, although several studies have suggested that SSRIs may be associated with a small increased risk of cardiovascular malformations, mainly involving ventricular and atrial septal defects. In addition to structural malformations, drugs were also observed to induce other adverse effects. Since SSRIs readily cross the placenta, concern has been raised about the short- or long-term effects of prenatal exposure to SSRIs on the developing offspring. Epidemiological studies have documented that 10-30% of neonates exposed to SSRIs near term had poor neonatal adaptation syndrome (PNAS). Some studies reported that persistent pulmonary hypertension of the newborn (PPHN) is weakly associated with in utero antidepressant exposure, while no association has been reported in other studies. Recent studies have raised questions about possible associations with antidepressant use during pregnancy and long-term effects on neurobehavioral development. Some individual studies have suggested associations between prenatal exposure to antidepressants and autism spectrum disorder; however, other studies identified no associations. On the other hand, depressive symptoms during pregnancy are also associated with increased risks of preterm delivery, fetal growth retardation, and postpartum depression. Therefore, the effects of untreated maternal depression on both maternal and child outcomes must be taken into consideration when making treatment decisions. Future research needs to focus on large prospective studies with adequate adjustments for key potential confounding factors, including maternal mental illness, other exposures, and an adequate length of follow-up, in order to obtain accurate child developmental outcomes. PMID- 25823352 TI - [Psychosocial aspects of perinatal mental health: research and clinical settings]. AB - The perinatal period is not free from psychological maladjustment. A variety of mood and anxiety disorders are seen in this period. In addition, psychological problems specific to this life stage are also observed, including bonding disorders and infant abuse. Psychosocial aetiologies have been identified. Psychological treatment is more important than pharmacotherapy. In recent years, efforts for the prevention of postnatal depression heve increased. PMID- 25823353 TI - [Impact of psychotropic drugs on breast-fed Infants: international perspective]. AB - The benefit of breast-feeding has been established, and it has recently been strongly encouraged internationally. However, new mothers have more risks of developing psychiatric symptoms than in any other period of their life, and some of them require psychopharmacotherapy. There are some clinical dilemmas regarding the benefit of such therapy and possible adverse effects on infants when mothers want to breast-feed their infants. Most drugs are transferred to breast-milk and, eventually, low levels of maternal daily doses can be taken by breast-fed infants. Having considered this issue and based on several studies, the authors of studies report that breast-feeding can be carried out by mothers who take psychotropic drugs. More research data accumulation, including individual case observations and follow-ups, is necessary to guarantee the safety of breast feeding by a mother on medication; however, in the current clinical setting, decision-making is essential to plan treatment. Such mothers are allowed to breast-feed infants who can be monitored by pediatricians. The critical matter is that clinicians should not hesitate to prescribe optimal doses to mothers for effective treatment. PMID- 25823354 TI - [Specified expectant mother, Child Welfare Act, and community cooperation: the role of psychiatrists]. AB - In 2009, the amended provisions of Article 6 of the Child Welfare Act defined "Specified Expectant Mother" (Tokutei-ninpu) as an expectant mother with the need for potential support in nurturing her baby before its delivery. This term was subsequently supplemented with relevant notices and manuals of the Ministry of Health, Labor, and Welfare; it then became a new target of the community network built for the prevention of child abuse. The two notices issued on November 30, 2012 are of great significance. One notice indicates that pregnant females should be screened for psychiatric disorders as well as some other risk factors by officers of their municipalities as a precaution against child abuse. The other states that in the context of Article 5 of the Child Abuse Prevention Law, medical service workers are immunized from sanctions if they divulge privileged information about a "Specified Expectant Mother" with the potential risk for child abuse to municipalities without patient approval. As a result of the latter notice, medical staff must judge whether the privacy of a parent or health of an unborn child with potential risk is more worthy of protection. However, the official criteria for judging the potential for child abuse and those who fall into the category of "Specified Expectant Mother" have yet to be specified. Fetal abuse, as defined by Condon in 1986, serves as a suitable surrogate marker for possible harmful actions that would justify public community cooperation without patient approval. Parenting capacity has rarely been discussed in the field of child abuse and neglect in Japan. The capacity is a legal requirement for custody. Considering the capacity of a "Specified Expectant Mother" to prevent child abuse and neglect, health care workers supporting pregnant women with psychiatric disorders or intellectual disabilities should deliberate, first, their capacities to appreciate their situations and, then, their parenting capacities. A custody substitution system for children of incompetent parents is clearly indicated for minors in the Civil Code (Article 833 and 867); however, it ignores psychiatric disorders and intellectual disabilities. The rights of children, which are lost in this omission, must be guaranteed by competent persons, usually by child guardians. Contributions of psychiatrists are essential for applying legal protections. Without these contributions, their rights are voided of all substance. Advocacy for such pregnant females requires wide and precise knowledge of relevant laws and ethics. PMID- 25823355 TI - Pneumocephalus, hearing loss, and vertigo after airline flight in a patient with superior canal dehiscence. In reply. PMID- 25823356 TI - Silencing the double-stranded RNA binding protein DGCR8 inhibits ovarian cancer cell proliferation, migration, and invasion. AB - PURPOSE: To evaluate the role of DiGeorge Critical Region 8 (DGCR8), a key component of miRNA biogenesis pathway in ovarian cancer. METHODS: The expression of DGCR8 in ovarian cancer was detected by immunostaining and DGCR8 knockdown in ovarian cancer cells was achieved using lentiviral shRNA. Differential expression of miRNAs was determined using Nanostring miRNA arrays and validated by real-time RT-PCR. RESULTS: DGCR8 was highly expressed in ovarian cancer. Knockdown of DGCR8 expression inhibits cell proliferation, migration, and invasion, as well as sensitizes cells to apoptosis induced by the chemotherapeutic drug cisplatin. Cellular survival pathways including ERK1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT were attenuated in DGCR8 knockdown cells. DGCR8 knockdown results in dysregulated miRNA gene expression. miR-27b was identified as the most highly down-regulated miRNA in DGCR8 knockdown cells and promoted cell proliferation in ovarian cancer cells. CONCLUSIONS: DGCR8 functions as an oncogene in ovarian cancer, which is in part mediated by miR-27b. PMID- 25823357 TI - [Vitreoretinal interface/vascular tumors]. PMID- 25823358 TI - Author's response. PMID- 25823359 TI - Mary Frances Lyon (1925-2014). PMID- 25823360 TI - Dietary sodium modulation of aldosterone activation and renal function during the progression of experimental heart failure. AB - AIMS: Aldosterone activation is central to the sodium-fluid retention that marks the progression of heart failure (HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of experimental HF. METHODS AND RESULTS: Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity (PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. CONCLUSIONS: Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression. PMID- 25823361 TI - Reduced inotropic reserve is predictive of further degradation in left ventricular ejection fraction in patients with Duchenne muscular dystrophy. AB - AIMS: Duchenne muscular dystrophy (DMD), an inherited X-linked muscular disease, is associated with dilated cardiomyopathy that is responsible for death in 40% of patients. Our objective was to determine whether inotropic reserve is predictive of LV trend over time. METHODS AND RESULTS: A total of 69 DMD patients (age 12.2+/-2.3 years) were investigated. At baseline, LVEF and the presence of inotropic reserve (defined as an increase in LVEF >10% during dobutamine infusion) were investigated using radionuclide ventriculography. During follow-up (FU), LVEF was remeasured after a mean 29+/-19 months delay. In the whole population, mean LVEF was 58+/-8% at baseline and declined to 54+/-11% during FU (P =0.004). At baseline, 21 patients (30.4%) had LVEF <55% and 38 had no LV inotropic reserve. LVEF declined in the 38 patients (55.1%) without LV inotropic reserve (58+/-8% to 52+/-10%, P =0.001), and not in the other patients (58+/-8% to 57+/-11%, P =0.516) (P =0.042 for trends in LVEF between groups after adjustment for age, FU duration, and baseline LVEF). Fewer patients with vs. without inotropropic reserve at baseline show a depressed LVEF <55% during follow up(35.5% vs. 63.2%, respectively, P =0.030). Similar findings were observed in the subgroups of patients with LVEF >45% or 55% at baseline. CONCLUSION: Inotropic reserve assessment allows the distinction of DMD patients who will vs. those who will not show a deterioration in LVEF, thus offering a sensitive approach for delineating the presence and progression of cardiovascular disease in these patients. PMID- 25823362 TI - [Not Available]. PMID- 25823363 TI - [Treatment of coma in diabetic ketoacidosis. Author reply]. PMID- 25823364 TI - Response: research-enriching your journey. PMID- 25823365 TI - Bone marrow aspiration in resource poor environment: our experience in Kenya. AB - Bone marrow aspiration examination is performed mainly to evaluate haematological disorders. Several bone marrow aspiration needles are available that include the Salah, Klima, Jamshidi and Islam. However, cost is an issue in our local environment as most of our patients are not medically insured. We describe our experience of bone marrow aspiration using an 18-gauge lumbar puncture needle at the posterior superior iliac spine. The technique is safe and cost effective and the site is easily accessible, even in obese patients. The crush preparations provide good morphology, therefore avoiding repeats. Additional training is not required for the procedural technique. We recommend this technique for use in resource challenged settings. PMID- 25823367 TI - Which whistleblower is more vulnerable: the Indian doctor or nurse? PMID- 25823366 TI - Identification of acquired coagulation disorders and effects of target-controlled coagulation factor substitution on the incidence and severity of spontaneous intracranial bleeding during veno-venous ECMO therapy. AB - INTRODUCTION: Intracranial haemorrhage is a redoubtable complication during extracorporeal membrane oxygenation (ECMO) therapy. The underlying mechanisms of haemorrhagic diathesis are still not completely understood. This study was performed to evaluate a coagulation protocol for the regular analysis of acquired coagulation disorders and the systematic substitution of coagulation factors to reach predefined target values. We hypothesised that using this strategy would lead to the identification of acquired bleeding disorders which cannot be monitored with standard coagulation tests and that substitution of the respective factors in a target-controlled approach could have an impact on the incidence and severity of intracranial haemorrhage. METHODS: A protocol for the analysis of acquired coagulation disorders and the subsequent administration of associated factor concentrates was introduced. Previously, coagulation management was mainly based on clinical bleeding signs as the trigger for the administration of blood products. In this investigation, nineteen consecutive patients before (control group) and twenty consecutive patients after the implementation of the protocol (intervention group) have been included in the study. RESULTS: Eighty-eight percent of the patients developed factor XIII deficiency, 79% acquired von Willebrand syndrome, 40% fibrinogen deficiency and 54% of the patients showed a decline in platelet count >20% within the first 24 hours of ECMO therapy. In 6 out of 19 (31%) patients in the control group and in 2 patients out of 20 (10%) in the intervention group, intracranial haemorrhage was detected. Whilst 5 of 6 patients in the control group died because of fatal bleeding, both of the patients in the intervention group recovered with a favourable neurologic outcome. CONCLUSIONS: Veno-venous ECMO therapy leads to thrombocytopenia, factor XIII and fibrinogen deficiency as well as acquired von Willebrand syndrome. The implementation of a coagulation protocol including a standardized determination and target-controlled substitution of coagulation factors may have a beneficial impact on the incidence and severity of intracranial haemorrhage. PMID- 25823368 TI - A novel operant-based behavioral assay of mechanical allodynia in the orofacial region of rats. AB - BACKGROUND: Detecting behaviors related to orofacial pain in rodent models often relies on subjective investigator grades or methods that place the animal in a stressful environment. In this study, an operant-based behavioral assay is presented for the assessment of orofacial tactile sensitivity in the rat. NEW METHODS: In the testing chamber, rats are provided access to a sweetened condensed milk bottle; however, a 360 degrees array of stainless steel wire loops impedes access. To receive the reward, an animal must engage the wires across the orofacial region. Contact with the bottle triggers a motor, requiring the animal to accept increasing pressure on the face during the test. To evaluate this approach, tolerated bottle distance was measured for 10 hairless Sprague Dawley rats at baseline and 30 min after application of capsaicin cream (0.1%) to the face. The experiment was repeated to evaluate the ability of morphine to reverse this effect. RESULTS: The application of capsaicin cream reduced tolerated bottle distance measures relative to baseline (p<0.05). As long as morphine did not cause reduced participation due to sedation, subcutaneous morphine dosing reduced the effects of capsaicin (p<0.001). Comparison with existing method: For behavioral tests, experimenters often make subjective decisions of an animal's response. Operant methods can reduce these effects by measuring an animal's selection in a reward-conflict decision. Herein, a method to measure orofacial sensitivity is presented using an operant system. CONCLUSIONS: This operant device allows for consistent measurement of heightened tactile sensitivity in the orofacial regions of the rat. PMID- 25823369 TI - Airbrush Formation of Liquid Crystal/Polymer Fibers. AB - A homogeneous solution of a low-molecular-weight liquid crystal and a polymer spontaneously phase separates during airbrushing to form uniform fibers with a fluid liquid-crystal core surrounded by a solid polymer sheath. This structure forms because it effectively minimizes the interfacial energy of the phase separated components while minimizing the elastic energy of the liquid-crystal core. These fibers incorporate the sensitive stimuli response of liquid crystals while maintaining the structural integrity, flexibility, and large surface-area to-volume ratios inherent in fibers. We demonstrate the electro- and thermo optical response of the resulting fibers. They may find use as biological and chemical sensors. The resulting fibers have the potential to shape the future of flexible/wearable electronics and sensors. PMID- 25823370 TI - Mechanical force-induced specific MicroRNA expression in human periodontal ligament stem cells. AB - It remains unclear how the expression of microRNAs (miRNAs) in human periodontal ligament stem cells (PDLSCs) might respond to mechanical stretch. To investigate specific miRNA expression in stretched PDLSCs, we used a Flexcell(r) FX-5000TM tension system to achieve external mechanical stimulation. Then, a custom designed microarray assay was performed to investigate and describe the genome wide differential expression of miRNAs in normal and stretched PDLSCs. Finally, we implemented integrative miRNA target prediction and network analysis approaches to construct an interaction network of the key miRNAs and their putative targets. We found that stretching induced morphological changes and increased alkaline phosphatase (ALP) activity, runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and bone sialoprotein (BSP) expression in PDLSCs. The microarray data showed that 53 miRNAs were differentially expressed with stretching. With an interaction network, we examined the connections between 10 selected key miRNAs and their putative target genes, which were related to mechanical force. The results from the interaction network provided a basis for postulating the functional roles of miRNAs in PDLSCs. PMID- 25823371 TI - The effect of maternal hypothyroidism on cardiac function and tolerance to ischemia-reperfusion injury in offspring male and female rats. AB - PURPOSE: Accumulating evidence indicates that intrauterine evolution disturbance can contribute to myocardial ischemia reperfusion (IR) injury; in addition, thyroid hormones (THs) have a crucial role in the development of different systems during fetal life. The aim of this study was to determine the effect of TH deficiency during fetal life on tolerance of isolated heart to ischemia during adulthood in both genders. METHODS: Hypothyroidism was induced in pregnant Wistar rats by administrating 0.025 % 6-propyl-2-thiouracil in drinking water throughout pregnancy. Offspring of rats with maternal hypothyroidism (MH) and control groups were tested in adulthood. Isolated hearts were perfused with Langendorff setup and exposed to 30 min of ischemia, followed by 45 min of reperfusion. Baseline values of the left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), heart rate (HR), and peak rates of positive and negative changes in left ventricular pressure (+/-dp/dt) were recorded. RESULTS: In the MH groups the baseline levels of LVDP (male: 23 %, female: 33 %), HR (male: 31 %, female: 26 %), and +/-dp/dt were significantly (p < 0.01) lower, compared to controls. After ischemia, hearts from male rats with MH had less tolerance to IR injury as assessed in terms of reductions in recovery of hemodynamic parameters compared to controls, while in female rats there were no significant differences between MH and controls. CONCLUSIONS: MH decreases hemodynamic parameters in the heart of both male and female offspring in adulthood; in addition, hearts of male rats with MH show less tolerance to ischemia, compared to those of females. PMID- 25823372 TI - Multifocal extraparotid Warthin's tumours mimicking metastatic squamous cell carcinoma of the upper neck. AB - BACKGROUND: Warthin's tumours can show features of pseudo-neoplasia. They do not usually cause problems for diagnosis and management when present within the parotid gland. However, extraparotid Warthin's tumours that are associated with pseudo-neoplasia upon cytological analysis can mimic metastatic malignant disease. The case of a patient presenting with multifocal extraparotid Warthin's tumours is described. CASE REPORT: A 57-year-old male smoker presented with rapidly growing upper neck lumps. Fine needle aspiration cytology, magnetic resonance imaging and positron emission tomography findings were compatible with metastatic squamous cell carcinoma secondary to either an unknown primary upper aerodigestive or a parotid malignancy. The patient subsequently underwent total conservative parotidectomy and modified radical neck dissection. Final histology findings revealed multifocal benign Warthin's tumours with four extraparotid components. CONCLUSION: Warthin's tumours may present outside the parotid gland, present with multifocal lesions and mimic metastatic disease. Frozen section examination prior to radical resection should be considered to guide management. PMID- 25823373 TI - MR CLEAN: past the tipping point of clinical equipoise. PMID- 25823374 TI - Prostate cancer: CYP17A1 inhibitor failure-lessons for future drug development. PMID- 25823375 TI - Prostate cancer: Platelet-to-lymphocyte ratio predicts prostate cancer prognosis. PMID- 25823376 TI - Prostate cancer: New ligand-receptor targets. PMID- 25823378 TI - Utilisation of water soluble iridium catalysts for signal amplification by reversible exchange. AB - The catalytic hyperpolarisation of pyridine, 3-hydroxypyridine and oxazole by the Signal Amplification By Reversible Exchange (SABRE) process is achieved by a series of water soluble iridium phosphine and N-heterocyclic carbene dihydride complexes. While the efficiency of the SABRE process in methanol-d4 solution or ethanol-d6 solution is high, with over 400-fold (1)H polarisation of pyridine being produced by [Ir(H)2(NCMe)(py)(IMes)(monosulfonated-triphenylphosphine)]BF4, changing to a D2O or a D2O-ethanol solvent mixture leads to dramatically reduced activity which is rationalised in terms of low H2 solubility. PMID- 25823377 TI - ERK7 regulates ciliogenesis by phosphorylating the actin regulator CapZIP in cooperation with Dishevelled. AB - Cilia are essential for embryogenesis and maintenance of homeostasis, but little is known about the signalling pathways that regulate ciliogenesis. Here, we identify ERK7, an atypical mitogen-activated protein kinase, as a key regulator of ciliogenesis. ERK7 is strongly expressed in ciliated tissues of Xenopus embryos. ERK7 knockdown markedly diminishes both the number and the length of cilia in multiciliated cells, and it inhibits the apical migration of basal bodies. Moreover, ERK7 knockdown results in a loss of the apical actin meshwork, which is required for the proper migration of basal bodies. We find that the actin regulator CapZIP, which has been shown to regulate ciliogenesis in a phosphorylation-dependent manner, is an ERK7 substrate, and that Dishevelled, which has also been shown to regulate ciliogenesis, facilitates ERK7 phosphorylation of CapZIP through binding to both ERK7 and CapZIP. Collectively, these results identify an ERK7/Dishevelled/CapZIP axis that regulates ciliogenesis. PMID- 25823379 TI - Striking a balance. PMID- 25823380 TI - Partial kilovoltage cone beam computed tomography, complete kilovoltage cone beam computed tomography, and electronic portal images for breast radiation therapy: A dose-comparison study. AB - PURPOSE: The purpose of this study was to compare absorbed dose with the treated breast and organs at risks (OARs) with weekly image guidance using electronic portal imaging (EPI), complete kilovoltage cone beam computed tomography (kV CBCT), and partial kV CBCT. METHODS AND MATERIALS: Using a thorax female phantom, we determined absorbed doses to treated and contralateral breast, ipsilateral and contralateral lung, heart, and skin for tangential EPI, complete kV CBCT, and partial kV CBCT. Doses were measured by use of ionization chambers and compared with treatment planning system calculations. With simulation of breast tangential irradiation to a standard dose of 50 Gy in 25 fractions, dose to each organ was measured for each image guidance technique. RESULTS: Use of weekly EPI was associated with a significantly increased dose to the treated breast compared with weekly complete and partial kV CBCT (4.44 +/- 0.04 vs 1.00 +/- 0.07 vs 0.576 +/- 0.003 cGy, respectively). Dose to the contralateral breast, ipsilateral and contralateral lung, heart, and contralateral skin was lower with EPI than with either complete or partial kV CBCT (0.042 +/- 0.004 vs 0.36 +/- 0.01 vs 0.23 +/- 0.01 cGy, 0.06 +/- 0.04 vs 0.42 +/- 0.02 vs 0.31 +/- 0.01 cGy, 0.004 +/- 0.002 vs 0.29 +/- 0.01 vs 0.22 +/- 0.01 cGy, 0.03 +/- 0.08 vs 0.36 +/- 0.02 vs 0.25 +/- 0.01 cGy, and 0.20 +/- 0.02 vs 0.80 +/- 0.06 vs 0.40 +/- 0.03 cGy, respectively). Compared with complete CBCT, the use of partial CBCT allowed dose reductions of 42%, 37%, 27%, 24%, and 28% to the ipsilateral breast, contralateral breast, ipsilateral lung, contralateral lung, and heart, respectively. Additional dose from weekly CBCT was significantly lower than treatment-related scatter dose for all OARs. CONCLUSIONS: Use of CBCT was associated with decreased dose to ipsilateral breast and increased dose to all OARs compared with EPI. Significant dose reduction can be achieved with the use of partial CBCT, while generally maintaining image quality. PMID- 25823381 TI - Utility and validation of biomechanical deformable image registration in low contrast images. AB - PURPOSE: The application of a biomechanical deformable image registration algorithm has been demonstrated to overcome the potential limitations in the use of intensity-based algorithms on low-contrast images that lack prominent features. Because validation of deformable registration is particularly challenging on such images, the dose distribution predicted via a biomechanical algorithm was evaluated using the measured dose from a deformable dosimeter. METHODS AND MATERIALS: A biomechanical model-based image registration algorithm registered computed tomographic (CT) images of an elastic radiochromic dosimeter between its undeformed and deformed positions. The algorithm aligns the external boundaries of the dosimeter, created from CT contours, and the internal displacements are solved by modeling the physical material properties of the dosimeter. The dosimeter was planned and irradiated in its deformed position, and subsequently, the delivered dose was measured with optical CT in the undeformed position. The predicted dose distribution, created by applying the deformable registration displacement map to the planned distribution, was then compared with the measured optical CT distribution. RESULTS: Compared with the optical CT distribution, biomechanical image registration predicted the position and size of the deformed dose fields with mean errors of <=1 mm (maximum, 3 mm). The accuracy did not differ between cross sections with a greater or lesser deformation magnitude despite the homogenous CT intensities throughout the dosimeter. The overall 3-dimensional voxel passing rate of the predicted distribution was gamma3%/3mm = 91% compared with optical CT. CONCLUSIONS: Biomechanical registration accurately predicted the deformed dose distribution measured in a deformable dosimeter, whereas previously, evaluations of a commercial intensity based algorithm demonstrated substantial errors. The addition of biomechanical algorithms to the collection of adaptive radiation therapy tools would be valuable for dose accumulation, particularly in feature-poor images such as cone beam CT and organs such as the liver. PMID- 25823382 TI - Early palliative radiation therapy in patients with newly diagnosed cancer: Reasons, clinical practice, and survival. AB - PURPOSE: To analyze indications for early palliative radiation therapy (RT) (ie, start within 1 month from cancer diagnosis), regimens used in clinical practice, rate of treatment completion and treatment in the last 30 days of life, and overall survival. METHODS AND MATERIALS: Retrospective uni- and multivariate analyses covering a 4.5-year inclusion period. RESULTS: Seventeen percent of all palliative RT courses were administered in the specified time frame (n = 100 patients, 30 Gy in 10 fractions in 49%). Common indications were bone and brain metastases, whereas metastatic spinal cord compression or other emergencies comprised a minority. Only 14% of patients had no distant metastases. Most patients had non-small cell lung cancer (51%), whereas other high-incidence primary tumors such as breast, prostate, and colorectal cancer combined comprised 10%. Failure to complete RT occurred in 6%. Median survival was 3.6 months. A startling high rate of RT in the last 30 days of life was observed (19%). Risk correlated significantly with performance status and extent of metastatic disease. CONCLUSIONS: The study population of patients who received early palliative RT is not identical to the general population described in previous studies, which covered the entire disease trajectory. Median survival was relatively short and rate of RT in the last 30 days of life higher than expected. Need for early palliative RT might be caused by large symptom burden and/or contraindication(s) for other management options, and might in many cases also be associated with adverse prognostic features and aggressive disease. PMID- 25823383 TI - Feasibility of magnetic resonance imaging-guided liver stereotactic body radiation therapy: A comparison between modulated tri-cobalt-60 teletherapy and linear accelerator-based intensity modulated radiation therapy. AB - PURPOSE: The purpose of this study was to investigate the dosimetric feasibility of liver stereotactic body radiation therapy (SBRT) using a teletherapy system equipped with 3 rotating (60)Co sources (tri-(60)Co system) and a built-in magnetic resonance imager (MRI). We hypothesized tumor size and location would be predictive of favorable dosimetry with tri-(60)Co SBRT. METHODS AND MATERIALS: The primary study population consisted of 11 patients treated with SBRT for malignant hepatic lesions whose linear accelerator (LINAC)-based SBRT plans met all mandatory Radiation Therapy Oncology Group (RTOG) 1112 organ-at-risk (OAR) constraints. The secondary study population included 5 additional patients whose plans did not meet the mandatory constraints. Patients received 36 to 60 Gy in 3 to 5 fractions. Tri-(60)Co system SBRT plans were planned with ViewRay system software. RESULTS: All patients in the primary study population had tri-(60)Co SBRT plans that passed all RTOG constraints, with similar planning target volume coverage and OAR doses to LINAC plans. Mean liver doses and V10Gy to the liver, although easily meeting RTOG 1112 guidelines, were significantly higher with tri (60)Co plans. When the 5 additional patients were included in a univariate analysis, the tri-(60)Co SBRT plans were still equally able to pass RTOG constraints, although they did have inferior ability to pass more stringent liver and kidney constraints (P < .05). A multivariate analysis found the ability of a tri-(60)Co SBRT plan to meet these constraints depended on lesion location and size. Patients with smaller or more peripheral lesions (as defined by distance from the aorta, chest wall, liver dome, and relative lesion volume) were significantly more likely to have tri-(60)Co plans that spared the liver and kidney as well as LINAC plans did (P < .05). CONCLUSIONS: It is dosimetrically feasible to perform liver SBRT with a tri-(60)Co system with a built-in MRI. Patients with smaller or more peripheral lesions are more likely to have optimal liver and kidney sparing, with the added benefit of MRI guidance, when receiving tri-(60)Co-based SBRT. PMID- 25823385 TI - MISUNDERSTANDING, THREATS, AND FEAR, OF THE LAW IN CONFLICTS OVER CHILDREN'S HEALTHCARE: IN THE MATTER OF ASHYA KING [2014] EWHC 2964. AB - This commentary critically examines the role of the law in the conflict over the post-operative care of five-year-old Ashya King. It argues that misunderstanding, threats, and fear of the law contributed to the deteriorating relationship between his parents and the professionals caring for him. The commentary analyses the judgment, in wardship proceedings, of Baker J arguing that too much weight was placed upon the responsibilities of Ashya's parents and an insufficient account provided of his best interests or of the principled basis for preferring innovative and, as yet, unproven therapy only available, privately funded, abroad to conventional treatment for a child with a life-threatening condition. PMID- 25823386 TI - Licochalcone F alleviates glucose tolerance and chronic inflammation in diet induced obese mice through Akt and p38 MAPK. AB - BACKGROUND & AIMS: Licochalcone (lico) F is a novel synthetic retrochalcone. In this study, we investigated the anti-inflammatory effects of lico F in vitro, and its effects on obesity-induced chronic inflammation, glucose intolerance, and fatty liver in vivo. METHODS: The inhibitory effects of lico F on TNFalpha induced inflammation were investigated using NF-kappaB luciferase reporter assay and RT-PCR. Diet-induced obese mice were treated orally, once per day, with vehicle or lico F (10 mg/kg/day), for 3 weeks, and blood, liver, and adipose tissues were analyzed. RESULTS: Lico F inhibited TNFalpha-induced NF-kappaB activation and mRNA expression of TNFalpha, COX-2, IL-6, IL-1beta, and NOS2. In obese mice, lico F administration significantly alleviated glucose tolerance without changes in body weight gain and food intake. Lico F reduced adipocyte size and macrophage infiltration into white adipose tissue and improved hepatic lesions, by decreasing fat droplets and glycogen deposition. The mRNA expression levels of TNFalpha, MCP-1, and CD68 in white adipose tissue also decreased markedly. Moreover, lico F enhanced Akt signaling, but reduced p38 MAPK signaling in white adipose tissue. CONCLUSIONS: Lico F had anti-inflammatory effects and showed beneficial effects on glucose metabolism, which could be partially caused by activation of the Akt signal pathway and obesity-induced chronic inflammation, probably by downregulating p38 signal pathway. Moreover, lico F could be used as a potential novel therapeutic compound against type 2 diabetes and obesity induced chronic inflammation without the deleterious effects of body weight gain and fatty liver. PMID- 25823388 TI - A comparative study of 18F-FDG PET/CT and ultrasonography in the diagnosis of breast cancer and axillary lymph node metastasis. AB - BACKGROUND: The aim of this study was to compare the diagnostic value of 18F-FDG PET/CT (PET/CT) with ultrasonography (US) in detection of primary breast cancer and axillary lymph nodes (ALN) metastasis of breast cancer. METHODS: One hundred and sixty four patients with breast carcinoma were recruited and analyzed retrospectively. All patients underwent PET-CT and US. The PET/CT scan results for the diagnosis of primary breast cancer were compared with US. The diagnostic accuracy of PET/CT in detecting ALN metastasis was compared with histopathology. RESULTS: In 164 patients with cytologically established breast carcinoma, the sensitivity of PET/CT and US in the diagnosis of breast cancer were 86% (141/164), 91% (149/164), respectively. The sensitivity, specificity of PET/CT and US in ALN staging were 46% and 54%, 91% and 91%, respectively. The diagnostic accuracy of PET/CT correlated with the ALN size, the SUVmax of primary breast cancer (P=0.02 and 0.04). CONCLUSIONS: PET/CT is very expensive, and not superior to US in detection of primary breast cancer and in ALN staging, but superior in detecting distant metastases. PET/CT cannot be recommended as a primary diagnostic procedure in early breast cancer. US should still remain the first line for the diagnosis of stage I breast cancer. In relation to the detection of axillary node metastases, both PET/CT and ultrasonography have poor sensitivity, and cannot replace staging by using the sentinel node procedure. PMID- 25823387 TI - Higher visceral adiposity is associated with an enhanced early thermogenic response to carbohydrate-rich food. AB - BACKGROUND: Studies examining the dynamics of the thermic effect of feeding (TEF) of specific food items and the relationship of TEF to visceral adiposity are limited. METHODS: We measured resting energy expenditure (REE) and early-TEF (40 min postprandial, e-TEF) after 8-h fast by indirect calorimetry in 40 obese men, and imaged abdominal fat tissues by magnetic resonance imaging. Each participant was examined on two occasions, 3-weeks apart. At each examination we measured fasting REE and then postprandial REE following the isocaloric [~380 kcal] consumption of either 56 gr walnuts [(8% carbohydrates; 84% fat, of which 72% polyunsaturated fat)], or 5-slices (150gr) of whole-grain bread (48% carbohydrates; 32% fat). e-TEF was calculated as the area under the curve between the fasting and postprandial tests. RESULTS: Participants had a mean age of 45 +/ 8 years, body-mass-index (BMI) = 31.1 +/- 3.8 kg/m(2), total abdominal fat area = 901.4 +/- 240 cm(2), visceral fat area (VAT) = 260 +/- 102.9 cm(2), fasting REE = 1854 +/- 205 kcal, REE/kg = 19.39 +/- 1.73 kcal/kg, and respiratory quotient (RQ, CO2 eliminated/O2 consumed) = 0.82 +/- 0.04. Individuals who exhibited increased e-TEF (top DeltaAUC median) to bread had higher VAT (299 cm(2) vs. 223 cm(2); p = 0.024) and higher BMI (32.4 kg/m(2) vs. 30.0 kg/m(2); p = 0.013), compared to their peers with the lower e-TEF response (DeltaAUC below median). As expected, postprandial e-TEF was higher after whole-grain bread consumption [DeltaAUC = +14 kcal/40min] compared to walnuts [DeltaAUC = -2 kcal/40 min; p < 0.001]. CONCLUSIONS: Higher early thermic effect of high-carbohydrate food, likely reflecting digestion, early absorption and/or sympathetic tone (rather than metabolic utilization (oxidation)), associates with visceral adiposity. Future studies are required to determine if this association represents an added causality between early carbohydrate processing and visceral fat accumulation. PMID- 25823389 TI - Is there a role for a handheld gamma camera (TReCam) in the SNOLL breast cancer procedure? AB - BACKGROUND: Sentinel node and occult lesion localization (SNOLL) calls for a combination of two specific procedures: intraoperative detection of sentinel lymph node (SLN) and radio--guided occult lesion localization (ROLL). The safety and benefits of radio--guided localization in the surgical treatment of non- palpable breast cancer have been confirmed. The aim of this study was to evaluate the potential role for an intra--operative handheld gamma camera (TreCam) in the SNOLL procedure. METHODS: Fifteen patients were enrolled. The SNOLL procedure was performed in all patients with conventional lymphoscintigraphy (LS). TReCam was used to obtain nuclear imaging in the operating theater. Concordance between LS and TreCam images, duration of use and assessment of difficulties in data acquisition with TReCam were reported. RESULTS: Concordance for tumor localization between single--detector gamma probe and TReCam was excellent (15/15). The number of radioactive SLNs visualized between LS and TReCam was equivalent in 53.3% of cases (8/15). TreCam was considered to be very easy--to- use (12/15) or easy--to--use (3/15). Average duration of acquisition with TReCam was 4 min 45 s for the SLN procedure and 2 min 10 s for lumpectomy. CONCLUSION: This study suggests that TReCam is easy--to--use and does not increase operative time. Its exact role in radio--guided surgery needs to be clearly defined in a larger study. However, its usefulness and benefits in radio--guided breast surgery seem to be promising. PMID- 25823390 TI - Molecular dynamics simulation and conformational analysis of some catalytically active peptides. AB - The design of stable and inexpensive artificial enzymes with potent catalytic activity is a growing field in peptide science. The first step in this design process is to understand the key factors that can affect the conformational preference of an enzyme and correlate them with its catalytic activity. In this work, molecular dynamics simulations in explicit water of two catalytically active peptides (peptide 1: Fmoc-Phe1-Phe2-His-CONH2; peptide 2: Fmoc-Phe1-Phe2 Arg-CONH2) were performed at temperatures of 300, 400, and 500 K. Conformational analysis of these peptides using Ramachandran plots identified the secondary structures of the amino acid residues involved (Phe1, Phe2, His, Arg) and confirmed their conformational flexibility in solution. Furthermore, Ramachandran maps revealed the intrinsic preference of the constituent residues of these compounds for a helical conformation. Long-range interaction distances and radius of gyration (R g) values obtained during 20 ns MD simulations confirmed their tendency to form folded conformations. Results showed a decrease in side-chain (Phe1, Phe2, His ring, and Arg) contacts as the temperature was raised from 300 to 400 K and then to 500 K. Finally, the radial distribution functions (RDF) of the water molecules around the nitrogen atoms in the catalytically active His and Arg residues of peptide 1 and peptide 2 revealed that the strongest water-peptide interaction occurred with the arginine nitrogen atoms in peptide 2. Our results highlight differences in the secondary structures of the two peptides that can be explained by the different arrangement of water molecules around the nitrogen atoms of Arg in peptide 2 as compared to the arrangement of water molecules around the nitrogen atoms of His in peptide 1. The results of this work thus provide detailed insight into peptide conformations which can be exploited in the future design of peptide analogs. PMID- 25823391 TI - Symmetric nested complexes of fullerenes. AB - Large fullerenes such as C180 and C116 can be used as hosts for other molecules of the same family. Based on this idea, two complexes were designed, one in which C180 accepts a C60 molecule as a guest and the other in which C20 was placed inside C116. The behavior of these new assemblies was closer to that of a large endohedral complex rather than onion-like. There were marked differences between the systems. In the first system, there was minor interaction between the two cages but the association resulted in a more stable thermodynamic state. In the second system, there was strong electronic interchange between the cages, and the thermodynamic results suggest that such a combination might be useful for forming stable C20. PMID- 25823392 TI - Synthesis and evaluation of 7alpha-(3-[(18)F]fluoropropyl) estradiol. AB - INTRODUCTION: Several lines of evidence suggest that C-7alpha-substituted estradiol derivatives are well tolerated by estrogen receptor (ER). In line with this hypothesis, we are interested in the design and synthesis of C-7alpha substituted estrogens as molecular probes to visualize ER function. METHODS: We have synthesized 7alpha-(3-[(18)F]fluoropropyl) estradiol (C3-7alpha-[(18)F]FES) as a potential radiopharmaceutical for ER imaging by positron emission tomography (PET). In vitro receptor binding and in vivo biodistribution and blocking studies in mature female mice, and in vivo metabolite analysis were carried out. Furthermore, in vivo ER-selective uptake was confirmed using ER-positive T-47D and ER-negative MDA-MB-231 tumor-bearing mice. We also compared the in vivo biodistribution of C3-7alpha-[(18)F]FES with 16alpha-[(18)F]FES. RESULTS: C3 7alpha-[(18)F]FES was produced in moderate yields (30.7%+/-15.1%, decay corrected) with specific activity of 32.0+/-18.1GBq/MUmol (EOS). The in vitro binding affinity of C3-7alpha-FES to the ERalpha isoform was sufficient and equivalent to that of estradiol. C3-7alpha-[(18)F]FES showed selective uptake in ER-rich tissues, such as the uterus (4.7%ID/g+/-1.2%ID/g at 15minutes) and ovary (4.0%ID/g+/-1.0%ID/g at 5minutes). The tissue time activity curves of these organs showed reversible kinetics, indicating suitability for quantitative analysis. The highest contrast was obtained at 120minutes after injection of C3 7alpha-[(18)F]FES in the uterus (uterus/blood=18, uterus/muscle=17.3) and ovary (ovary/blood=6.3, ovary/muscle=6.0). However, the level of selective uptake of C3 7alpha-[(18)F]FES was significantly lower than that of 16alpha-[(18)F]FES. Most radioactivity in the uterus was detected in unchanged form, although peripherally C3-7alpha-[(18)F]FES was rapidly degraded to hydrophilic metabolites. In accordance with this peripheral metabolism, gradual increases in bone radioactivity were observed, indicating defluorination. Coinjection with estradiol dose-dependently inhibited C3-7alpha-[(18)F]FES uptake in the uterus and ovary. The in vivo IC50 values of estradiol in the uterus and ovary were 34.4 and 38.5nmol/kg, respectively. Furthermore, in vivo tumor uptake of C3-7alpha [(18)F]FES was significantly higher (unpaired t test with Welch's correction; p=0.015) in ER-positive T-47D tumors (2.3%ID/g+/-0.4%ID/g) than ER-negative MDA MB-231 tumors (0.9%ID/g+/-0.1%ID/g). CONCLUSIONS: Although extensive metabolism was observed in rodents, C3-7alpha-[(18)F]FES showed promising results for quantitative analysis of ER density in vivo. However, the selective uptake of C3 7alpha-[(18)F]FES was lower than that of 16alpha-[(18)F]FES. Further optimizations and structure-activity relationship studies of the C-7alpha substituted estradiol are needed. PMID- 25823393 TI - [(18)F]FDG is not transported by P-glycoprotein and breast cancer resistance protein at the rodent blood-brain barrier. AB - INTRODUCTION: Transport of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) by the multidrug efflux transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier (BBB) may confound the interpretation of [(18)F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of [(18)F]FDG in vivo by performing [(18)F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in [(18)F]FDG brain distribution after transporter inhibition. METHODS: Dynamic small-animal PET experiments (60min) were performed with [(18)F]FDG in groups of wild-type and transporter knockout mice (Abcb1a/b((-/-)), Abcg2((-/-)) and Abcb1a/b((-/-))Abcg2((-/-))) and in wild-type rats without and with i.v. pretreatment with the known ABCB1 inhibitor tariquidar (15mg/kg, given at 2h before PET). Blood was sampled from animals from the orbital sinus vein at the end of the PET scans and measured in a gamma counter. Brain uptake of [(18)F]FDG was expressed as the brain-to-blood radioactivity concentration ratio in the last PET time frame (Kb,brain). RESULTS: Kb,brain values of [(18)F]FDG were not significantly different between different mouse types both without and with tariquidar pretreatment. The blood-to-brain transfer rate constant of [(18)F]FDG was significantly lower in tariquidar-treated as compared with vehicle treated rats (0.350+/-0.025mL/min/g versus 0.416+/-0.024mL/min/g, p=0.026, paired t-test) but Kb,brain values were not significantly different between both rat groups. CONCLUSION: Our results show that [(18)F]FDG is not transported by Abcb1 at the mouse and rat BBB in vivo. In addition we found no evidence for Abcg2 transport of [(18)F]FDG at the mouse BBB. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Our findings imply that functional activity of ABCB1 and ABCG2 at the BBB does not need to be taken into account when interpreting brain [(18)F]FDG PET data. PMID- 25823394 TI - Role of calcium in the regulation of bone morphogenetic protein 2, runt-related transcription factor 2 and Osterix in primary renal tubular epithelial cells by the vitamin D receptor. AB - The aim of the present study was to investigate the effect of 1,25(OH)2D3/vitamin D receptor (VDR) and calcium on the expression levels of osteogenic factors in primary renal tubular epithelial cells (RTECs) using genetic hypercalciuric rats. The basal levels of osteogenic factors were detected in Sprague Dawley and genetic hypercalciuric rats. The gene and protein levels of bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (Runx2) and osterix were detected in the RTECs transduced with Lenti-VDR-sh and were incubated with calcium. Using the o-cresolphthalein complexone method, the calcium levels of the primary RTECs cultured with Lenti-VDR-sh and with 1,25(OH)2D3 were assessed. The basal levels of BMP2, Runx2 and Osterix in the cells were significantly higher in the genetic hypercalciuric rats compared with the control rats. VDR knockdown in the RTECs reduced the expression levels of BMP2, Runx2 and Osterix. The calcium depositions in the primary RTECs were also decreased following exposure to Lenti VDR-sh, but increased following treatment with 1,25(OH)2D3. The expression levels of BMP2, Runx2 and Osterix were markedly increased in the cells incubated with calcium compared with the cells treated with normal saline and the untreated cells. These findings indicated that osteogenic factors, including BMP2, Runx2 and Osterix may be important in renal stone formation in idiopathic hypercalciuria. VDR may mediate the increased expression levels of BMP2, Runx2 and Osterix by positively regulating calcium levels in primary RTECs. PMID- 25823395 TI - Accuracy of in vivo palpation-guided acromioclavicular joint injection assessed with contrast material and fluoroscopic evaluations. AB - OBJECTIVE: The purpose of this study was to evaluate the accuracy of in vivo acromioclavicular (AC) joint injections without fluoroscopic guidance and assess whether patient demographics affected the accuracy of injections. MATERIALS AND METHODS: A consecutive cohort of patients who presented with painful acromioclavicular joints was prospectively evaluated. All patients had clinical and radiographic evidence of AC arthritis, had failed conservative measures, and thus had received intraarticular corticosteroid injections. All injections were performed by experienced fellowship-trained musculoskeletal radiologists and by blinded digital palpation technique. Accuracy of injections was assessed with biplanar fluoroscopic views. RESULTS: Forty-one AC injections in 22 males and 16 females with a mean age of 51 years (range 18 to 78) were identified. Twenty three injections were in the right shoulder and 18 in the left. Only 15 injections were confirmed to be in the intraarticular AC joint, yielding an accuracy of 36.5%. There were no significant differences in the mean age (54 vs. 52 years; p = 0.58), male-to-female ratio (p = 0.73), and side of the injection between the accurate and inaccurate injections, respectively. CONCLUSION: Based on the findings of the present study, the authors encourage the use of image guidance for corticosteroid treatment of the AC joint. LEVEL OF EVIDENCE: Level IV Therapeutic Case Series. PMID- 25823396 TI - CALU polymorphism A29809G affects calumenin availability involving vascular calcification. AB - Calumenin inhibits gamma-carboxylation of matrix-Gla-protein preventing BMP2 dependent calcification. Our aim was to explore the clinical relevance and functionality of the CALU polymorphism rs1043550, and the relationship of calumenin time-dependent expression profile with the active calcification of human vascular smooth muscle cells (hVSMC). Coronary artery calcium score and lesion severity were assessed by cardiac computed tomography in 139 consecutive low-risk patients genotyped for rs1043550. Polymorphic (G) allele carriage was associated with lower calcium (OR: 6.19, p=0.042). Calcified arteries from CALU 'A' allele carriers undergoing cardiovascular surgery exhibited higher residual calcification, higher calumenin immunostaining and lower matrix-Gla-protein, contrary to 'G' allele carriers. In a luciferase reporter system in vascular cells, polymorphic 'G' allele reduced the mRNA stability by 30% (p < 0.05). Osteogenic high-phosphate media induced active differentiation of hVSMC onto functional osteoblast-like cells as demonstrated by extracellular matrix mineralization and osteoblast markers expression. Calumenin was early over expressed at day 3 (p < 0.05), but decreased thereafter (mRNA and protein) with implications on gamma-carboxylation system. Calumenin was found released and co localizing with extracellular matrix calcifications. The CALU polymorphism rs1043550 affects mRNA stability and tissue availability of calumenin thus supporting the protective clinical significance. Calumenin shows a time-dependent profile during induced calcification. These data demonstrate a novel association of vascular calcification with the VSMC phenotypic transition into osteoblast like cells. Moreover, hyperphosphatemic stimuli render calumenin accumulation in the mineralized extracellular matrix. PMID- 25823397 TI - A comparison of high-frequency jet ventilation and synchronised intermittent mandatory ventilation in preterm lambs. AB - PURPOSE: Synchronised intermittent mandatory ventilation (SIMV) and high frequency jet ventilation (HFJV) are accepted ventilatory strategies for treatment of respiratory distress syndrome (RDS) in preterm babies. We hypothesised that SIMV and HFJV both facilitate adequate oxygenation and ventilation but that HFJV is associated with less lung injury. RESULTS: There were no differences in arterial oxygenation or partial pressure of carbon dioxide despite lower mean airway pressure during SIMV for most of the study. There were no consistent significant differences in end systolic and end diastolic PBF, lung injury data and static lung compliance. METHODS: Preterm lambs of anaesthetised ewes were instrumented, intubated and delivered by caesarean section after intratracheal suction and instillation of surfactant. Each lamb was managed for 3 hr according to a predetermined algorithm for ventilatory support consistent with open lung ventilation. Pulmonary blood flow (PBF) was measured continuously and pulsatility index was calculated. Ventilatory parameters were recorded and arterial blood gases were measured at intervals. At postmortem, in situ pressure volume deflation curves were recorded, and bronchoalveolar lavage fluid and lung tissue were obtained to assess inflammation. CONCLUSIONS: SIMV and HFJV have comparable clinical efficacy and ventilator pressure requirements when applied with a targeted lung volume recruitment strategy. PMID- 25823398 TI - Glycinamide prevents MK-801-induced hyperactivity and deficits in object recognition memory in an animal model of positive and cognitive symptoms of schizophrenia. PMID- 25823399 TI - Creativity and positive symptoms in schizophrenia revisited: Structural connectivity analysis with diffusion tensor imaging. AB - Both creativity and schizotypy are suggested to be manifestations of the hyperactivation of unusual or remote concepts/words. However, the results of studies on creativity in schizophrenia are diverse, possibly due to the multifaceted aspects of creativity and difficulties of differentiating adaptive creativity from pathological schizotypy/positive symptoms. To date, there have been no detailed studies comprehensively investigating creativity, positive symptoms including delusions, and their neural bases in schizophrenia. In this study, we investigated 43 schizophrenia and 36 healthy participants using diffusion tensor imaging. We used idea, design, and verbal (semantic and phonological) fluency tests as creativity scores and Peters Delusions Inventory as delusion scores. Subsequently, we investigated group differences in every psychological score, correlations between fluency and delusions, and relationships between these scores and white matter integrity using tract-based spatial statistics (TBSS). In schizophrenia, idea and verbal fluency were significantly lower in general, and delusion score was higher than in healthy controls, whereas there were no group differences in design fluency. We also found positive correlation between phonological fluency and delusions in schizophrenia. By correlation analyses using TBSS, we found that the anterior part of corpus callosum was the substantially overlapped area, negatively correlated with both phonological fluency and delusion severity. Our results suggest that the anterior interhemispheric dysconnectivity might be associated with executive dysfunction, and disinhibited automatic spreading activation in the semantic network was manifested as uncontrollable phonological fluency or delusions. This dysconnectivity could be one possible neural basis that differentiates pathological positive symptoms from adaptive creativity. PMID- 25823400 TI - Insight in paranoia: The role of experiential avoidance and internalized stigma. AB - Evidence suggests that insight in psychosis has been related to treatment adherence, recovery and good prognosis, but also to depression, low self-esteem, and diminished quality of life. Thus, insight might not be advantageous under all circumstances. Internalized-stigma (i.e. self-acceptance of stigmatizing images of illness) and experiential avoidance (i.e. unwillingness to experience negative private events) have been proposed as moderating variables between insight, and psychological health variables and/or distress. We investigated the patterns of association of insight with satisfaction with life, self-esteem, depression, anxiety and psychotic psychopathology as moderated by self-stigmatizing beliefs and experiential avoidance, in a sample of 47 participants with persecutory beliefs and diagnosed with schizophrenia or other psychotic disorder. Moderation analyses confirm the importance of internalized-stigma and experiential avoidance. The presence of insight was associated with more depression when there were high levels of self-stigma. Whereas, the absence of insight was associated with a greater life satisfaction when there were high levels of experiential avoidance. To summarize, our results help understand the complex relationship between insight, psychological health variables and emotional distress, pointing to a differential pattern of moderation for negative and positive outcomes. We discuss the implications of these results for research and treatment of paranoia. PMID- 25823401 TI - Spanish version of the social network questionnaire in schizophrenia patients' caregivers. PMID- 25823402 TI - Management of Apical Periodontitis: Healing of Post-treatment Periapical Lesions Present 1 Year after Endodontic Treatment. AB - INTRODUCTION: Post-treatment periapical lesions present 1 year after treatment may heal during the second year or later. The aim of this study was to assess second-year volumetric changes in post-treatment periapical radiolucencies detected 1 year after treatment. METHODS: Post-treatment periapical radiolucencies were detected on cone-beam computed tomographic (CBCT) scans obtained from 93 single-rooted teeth 1 year after endodontic treatment. The outcome of these teeth was evaluated 2 years after treatment. Two examiners independently measured the volume of the radiolucencies on CBCT images twice. A Wilcoxon signed rank test was used to assess the 1- and 2-year post-treatment volumes. RESULTS: The intraclass correlation coefficients for the CBCT volumetric measurements were 0.971 and 0.998 for the 2 examiners, and the interexaminer correlation coefficient was 0.998. Of the 93 teeth with post-treatment radiolucencies at 1 year, 61were examined at the second-year evaluation. The overall size of the radiolucencies significantly decreased during the second year (P = .01); the volume decreased in 38 teeth (63%), remained unchanged in 20 (33%), and increased in 2 (3%). CONCLUSIONS: The volume of post-treatment periapical radiolucencies detected 1 year after treatment was significantly reduced after the second year in 63% of teeth. PMID- 25823403 TI - Effect of different endodontic regeneration protocols on wettability, roughness, and chemical composition of surface dentin. AB - INTRODUCTION: We investigated the changes in physiochemical properties of dentin surfaces after performing different endodontic regeneration protocols. METHODS: Human dentin slices were randomized into 4 treatment groups and 1 untreated control group (n = 10). One treatment group was irrigated with sodium hypochlorite (NaOCl) for 5 minutes followed by EDTA for 10 minutes. The other 3 treatment groups were irrigated with NaOCl; treated for 4 weeks with triple antibiotic paste (TAP), diluted triple antibiotic paste (DTAP), or calcium hydroxide (Ca[OH]2); and then irrigated with EDTA. After treatment, contact angles between a blood analog and dentin surfaces were evaluated. Surface roughness and chemical composition were characterized using optical profilometry and energy-dispersive X-ray spectroscopy, respectively. One-way analysis of variance followed by Fisher least significant difference tests were used for statistical analyses. RESULTS: All treatment groups showed a significant reduction in wettability and a significant increase in surface roughness when compared with untreated dentin. Dentin treated with Ca(OH)2 had significantly lower wettability compared with all other groups. No significant difference in wettability was found between dentin treated with DTAP and TAP protocols. Dentin treated with TAP had significantly higher surface roughness compared with all other groups. Untreated dentin and NaOCl + EDTA-treated dentin had significantly higher calcium and phosphorus as well as significantly lower carbon compared with dentin treated with Ca(OH)2, DTAP, and TAP. CONCLUSIONS: Endodontic regeneration protocols had a significant effect on wettability, surface roughness, and chemical composition of surface dentin. The Ca(OH)2 protocol caused a significant reduction in dentin wettability compared with TAP or DTAP protocols. PMID- 25823404 TI - [A rare cause of abdominal pain in a healthy child]. PMID- 25823405 TI - [It's not pneumonia, it's a diaphragmatic hernia]. PMID- 25823406 TI - [Comfort and noise level in infants with helmet interface]. AB - OBJECTIVES: To evaluate comfort and noise intensity using the COMFORT scale in infants who receive respiratory support with a helmet interface. PATIENTS AND METHODS: An observational descriptive study was conducted on all infants (1 to 12 months of age) admitted to a PICU from November 1st 2013 to March 31st 2014 and who received non-invasive ventilation with a helmet interface. Tolerance to the interface was assessed by use of the COMFORT scale. The intensity of the noise to which the infants were exposed was measured with a TES1350A HIBOK 412 sound-level meter. Three measurements were made every day. RESULTS: Twenty seven patients with bronchiolitis (median age: 54 days; range: 10 to 256) were included. Median COMFORT score in the first day was 21 points (14 - 28). An increase in patient comfort was found with a gradual decrease in the scores, with a maximum reduction of 22% from the first hours (score of 22) to the fifth day (score of 18). The minimum sound intensity registered was 42dB, and the maximum was 78dB. Background noise intensity was associated with noise intensity in the helmet. No differences were observed in COMFORT score and noise intensity between ventilator devices. CONCLUSIONS: Helmet interface was well tolerated by infants. COMFORT score results are an indicator that infants were comfortable or very comfortable. The measured noise intensity was in the safe range permitted by World Health Organization. PMID- 25823407 TI - Pandemic influenza: an evolutionary concept analysis. AB - AIM: The aim of this paper was to provide a concept analysis of 'pandemic influenza'. BACKGROUND: Pandemic influenza can have a devastating impact as individuals have little to no immunity towards the newly encountered virus. It is a persistent societal threat due to the advancement of multiple technological processes. Nurses work in multiple roles in pandemics. As such, a thorough understanding of the concept and its implications from a nursing perspective is required. DESIGN: Rodgers' Evolutionary Method was used to conduct the concept analysis of the term 'pandemic influenza'. DATA SOURCES: Forty-nine papers were examined from the disciplines of public health, medicine, law, bioethics and healthcare policy. Papers were found from the PubMed, CINAHL and Google Scholar databases all dates up to December 2013. Limits were set to include peer reviewed, English language articles. METHODS: Identified papers were critically analyzed to explore the concept's antecedents, attributes and consequences. Surrogate and related terms, and an exemplar, were identified. RESULTS: Attributes of pandemic include original viral structure, increased human susceptibility, younger vulnerable populations and unpredictable time frames. Antecedents include processes that enable the increased geographical transmission of a newly created influenza. Consequences include higher morbidity and mortality rates and the need for an efficient pandemic response. CONCLUSIONS: This analysis identified the attributes of pandemic influenza through a synthesis of the current pandemic literature. However, no articles were identified as specifically nursing in nature. Therefore, more research is required to examine the impact of a pandemic declaration on the nursing profession. PMID- 25823408 TI - The colon shuffle: A modified urinary diversion. AB - AIM: To assess the results of a urinary diversion in patients who already have a colostomy or simultaneously require a (rectum) colon resection. The diversion is created from the distal part of the transected colon with a simultaneously created new colostomy contra-laterally (if necessary). This procedure is known in our institute as the 'colon shuffle'. MATERIALS AND METHODS: All patients who underwent a colon shuffle in the period of 2003 and 2013 in our institute (Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital) were identified. Comorbidity was scored using the Charlson comorbidity index. Local or systemic treatment prior to surgery was reported (e.g. external beam radiotherapy, systemic chemotherapy). Surgical complications were reported according to the Clavien-Dindo classification. RESULTS: Twenty-one patients (14 male; 7 female) underwent a colon shuffle procedure in our institute, with a mean age of 61.5 years. The majority (90.4%) of these patients had been subjected to radiotherapy on the pelvic region in the past. Although short-term complications (<30 days) were seen in 52.4% of these patients, major complications such as anastomotic leakage of the bowel and fecal peritonitis were not seen in this high-risk group of patients. CONCLUSION: The colon shuffle offers an elegant solution for patients who require a urinary diversion simultaneously with a colostomy or for patients who already have a colostomy from previous surgery. PMID- 25823409 TI - How gene expression in fast-proliferating cells keeps pace. AB - The development of living organisms requires a precise coordination of all basic cellular processes, in space and time. Early embryogenesis of most species with externally deposited eggs starts with a series of extremely fast cleavage cycles. These divisions have a strong influence on gene expression as mitosis represses transcription and pre-mRNA processing. In this review, we will describe the distinct adaptations for efficient gene expression and discuss the emerging role of the multifunctional NineTeen Complex (NTC) in gene expression and genomic stability during fast proliferation. PMID- 25823410 TI - Proteomics beyond trypsin. AB - Peptide-centered shotgun analysis of proteins has been the core technology in mass spectrometry based proteomics and has enabled numerous biological discoveries, such as the large-scale charting of protein-protein interaction networks, the quantitative analysis of protein post-translational modifications and even the first drafts of the human proteome. The conversion of proteins into peptides in these so-called bottom-up approaches is nearly uniquely done by using trypsin as a proteolytic reagent. Here, we argue that our view of the proteome still remains incomplete and this is partially due to the nearly exclusive use of trypsin. Newly emerging alternative proteases and/or multi-protease protein digestion aim to increase proteome sequence coverage and improve the identification of post-translational modifications, through the analysis of complementary and often longer peptides, introducing an approach termed middle down proteomics. Of pivotal importance for this purpose is the identification of proteases beneficial for use in proteomics. Here, we describe some of the shortcomings of the nearly exclusive use of trypsin in proteomics and review the properties of other proteomics-appropriate proteases. We describe favorable protease traits with an emphasis on middle-down proteomics and suggest potential sources for the discovery of new proteases. We also highlight a few examples wherein the use of other proteases than trypsin enabled the generation of more comprehensive data sets leading to previously unexplored knowledge of the proteome. PMID- 25823411 TI - Identification of pivotal markers in vascular dementia based on proteomics data. AB - OBJECTIVE: The aim of this study was to analyze protein expression profiles of vascular dementia (VaD) subjects for investigating the underlying therapeutic markers. METHODS: Protein expression profile data were acquired from a quantitative clinical proteomic study, including 10 nondemented elderly controls and 10 age-matched VaD subjects. Differentially expressed proteins (DEPs) were identified between VaD subjects and controls, followed by function prediction using DAVID (Database for Annotation, Visualization, and Integrated Discovery). Then, a protein-protein interaction (PPI) network was constructed by comparing it with the STRING (Search Tool for the Retrieval of Interacting Genes) database, and the pathway crosstalk analysis was conducted based on overlapping PPI network and enriched pathways. Furthermore, the subpathway was screened and analyzed by the iSubpathwayMiner package in R. RESULTS: A total of 144 DEPs were screened from VaD subjects and the controls. They were significantly enriched in many pathways. High-degree proteins were detected in the PPI network, such as ATP5B (ATP synthase subunit beta). Furthermore, 'metabolic pathways' and 'Alzheimer's disease' were the significant pathways screened in the crosstalk analysis. At last, upregulated proteins were enriched in 2 subpathways of 1 pathway, while downregulated proteins were enriched in 162 subpathways of 36 pathways. CONCLUSION: By analyzing the differential expressions of proteins, the potential underlying therapeutic markers and mechanism of VaD might be elucidated. PMID- 25823412 TI - Alcohol intake measured by phosphatidylethanol in blood and the lifetime drinking history interview are correlated with the extent of psoriasis. AB - BACKGROUND: Psoriasis has been reported to be associated with alcohol consumption. OBJECTIVE: To investigate the level of alcohol intake in individuals with psoriasis and correlate intake with the extent of disease and pruritus. METHODS: Twenty-nine outpatients (15 females and 14 males) with stable chronic plaque psoriasis of moderate severity were recruited. The Psoriasis Area and Severity Index (PASI) and the degree of pruritus (visual analogue scale) were compared with measures of drinking habits as determined by the Lifetime Drinking History (LDH), the Alcohol Use Disorders Identification Test and whole-blood phosphatidylethanol (PEth), an alcohol-specific biomarker. RESULTS: The majority of patients were social drinkers with moderate alcohol consumption as determined by PEth and LDH. Alcohol consumption correlated significantly with the PASI score. There was no correlation between alcohol use and pruritus. CONCLUSION: The level of alcohol consumption is correlated with the extent of psoriasis. PMID- 25823413 TI - Long-Term Outcomes and Patterns of Failure After Surgical Resection of Small-Cell Lung Cancer. AB - BACKGROUND: The role of surgical resection as a treatment option for early-stage small-cell lung cancer (SCLC) is controversial, and few data exist regarding the patterns of treatment failure in these patients. PATIENTS AND METHODS: The medical records of all patients receiving definitive surgical management of SCLC at Mayo Clinic (Rochester, MN) from January 1, 1985 to December 31, 2012 were reviewed. Estimates of survival and recurrence risk were recorded using the Kaplan-Meier method, and comparative analyses were performed with Cox regression analysis. RESULTS: A total of 54 patients were identified. The median follow-up period was 5.9 years. At 5 years, overall survival was 37% and recurrence-free survival 44%. Intrathoracic recurrence, the most frequent treatment failure, occurred in 14 patients, with an estimated intrathoracic recurrence-free survival at 3 years of 64.4%. Patients undergoing wedge resection or segmentectomy, rather than lobectomy or pneumonectomy, had an increased risk of intrathoracic recurrence (hazard ratio, 3.5; P = .01). Overall survival was improved at 5 years after lobectomy or pneumonectomy compared with wedge resection or segmentectomy (48% vs. 15%, respectively; P = .03). CONCLUSION: Surgical resection of SCLC can achieve reasonable treatment outcomes and can be considered for well-selected patients with clinical early-stage disease. Intrathoracic recurrence is the most common site of treatment failure. Caution should be taken with patients who are unable to tolerate at least lobectomy, because they are at a high risk of local recurrence. PMID- 25823414 TI - Microtubule teardrop patterns. AB - Several strategies for controlling microtubule patterns are developed because of the rigidity determined from the molecular structure and the geometrical structure. In contrast to the patterns in co-operation with motor proteins or associated proteins, microtubules have a huge potential for patterns via their intrinsic flexural rigidity. We discover that a microtubule teardrop pattern emerges via self-assembly under hydrodynamic flow from the parallel bundles without motor proteins. In the growth process, the bundles ultimately bend according to the critical bending curvature. Such protein pattern formation utilizing the intrinsic flexural rigidity will provide broad understandings of self-assembly of rigid rods, not only in biomolecules, but also in supramolecules. PMID- 25823415 TI - Hearing function after intratympanic application of gadolinium-based contrast agent: A long-term evaluation. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to evaluate the long-term influence of intratympanic gadolinium-based contrast agent on hearing function in patients with possible Meniere's disease and normal auditory thresholds who were undergoing locally enhanced magnetic resonance imaging scans. STUDY DESIGN: Prospective observational cohort study in a tertiary referral university hospital ear, nose, and throat department. METHODS: Between 2009 and 2012, 17 patients with possible or probable Meniere's disease and a four-tone pure-tone average baseline of <25 dB were recruited for our study. Before undergoing intratympanic injection of gadolinium-based contrast agent, all patients underwent a complete audiological evaluation. The study population was then invited back after at least 6 months postinjection for a follow-up auditory evaluation. This consisted of comprehensive clinical and audiological tests on both sides and were evaluated according to the ototoxicity guidelines. RESULTS: A long-term evaluation of our study group revealed no significant difference in the air-conduction pure-tone average. Furthermore, no statistical difference at individual frequencies compared to baseline was found. There was no evidence of ototoxicity in the injected ear. CONCLUSIONS: Long-term hearing function assessment after intratympanic application of gadolinium-based agent showed no evidence of ototoxicity. The use of intratympanic gadolinium-based agent in the diagnosis of Menieres disease is currently a helpful tool, and seems to be a safe method, especially with regard to auditory function. LEVEL OF EVIDENCE: 4. PMID- 25823416 TI - Crystal growth of four oxovanadium(IV) tartrates prepared via a mild two-step hydrothermal method: observation of spin-dimer behavior and second harmonic generation. AB - Four new oxovanadium(IV) tartrates, namely, A2[(VO)2(C4H4O6)(C4H2O6)(H2O)2].(H2O)2, where A = Cs, 1, Rb, 2; K2[(VO)2(C4H2O6)2(H2O)2].(H2O)2, 3; and Na2[(VO)2(C4H4O6)(C4H2O6)(H2O)7].(H2O)2, 4, were prepared utilizing a two-step, mild hydrothermal route involving l-(+) tartaric acid as the reducing agent. All four compounds were structurally characterized by single-crystal and powder X-ray diffraction methods and were found to crystallize in the non-centrosymmetric orthorhombic space groups P212121 for 1, 2, and 4 and C2221 for 3. The temperature dependence of the magnetic susceptibility of these compounds was measured, and 1, 2, and 4 were found to be paramagnetic down to 2 K, while 3 was found to exhibit spin-dimer behavior. Compounds 1, 2, and 3 were found to be second harmonic generation active. All compounds were further characterized by IR and UV-vis spectroscopies. PMID- 25823417 TI - Which is worse in psoriasis - skin or joints? PMID- 25823418 TI - Additional evidence that PGAP1 loss of function causes autosomal recessive global developmental delay and encephalopathy. PMID- 25823419 TI - Potential Motivators and Barriers for Encouraging Health Screening for Cardiovascular Disease Among Latino Men in Rural Communities in the Northwestern United States. AB - Cardiovascular disease (CVD) is the leading cause of death across all races and ethnicities. In particular, Latino men suffer disproportionately from conditions that lead to CVD such as hypertension, high cholesterol, and diabetes. There are easy and inexpensive ways to screen for certain cardiovascular conditions, yet Latino men are not benefiting from these. It is important to identify motivators and barriers to screening among this population. The purpose of this qualitative, descriptive study was to determine what motivates Latino men to participate in health screening for diabetes, high blood pressure, and high cholesterol. Self identified Latino men (n = 17) were interviewed following a community health screening targeting Latinos. Individual semi-structured interviews were conducted in either Spanish or English after giving written consent. Trained interpreters were used for Spanish interviews. Emerging themes include motivating factors and barriers to participate in screening. Data findings direct future studies and provide culturally meaningful and relevant strategies to reduce health disparities. PMID- 25823420 TI - Facile synthesis of benzoindoles and naphthofurans through carbonaceous material catalyzed cyclization of naphthylamines/naphthols with nitroolefins in water. AB - A facile and efficient approach has been established for the synthesis of benzoindole and naphthofuran derivatives via the metal-free cyclization reaction of nitroolefins with naphthylamines/naphthols. Various substituted benzoindoles and naphthofurans are obtained in good to excellent yields. Moreover, the ability to recycle the carbonaceous material makes this method quite cost-effective and environmentally benign compared to traditional acid-catalyzed methods. Theoretical studies indicated that the reaction between naphthylamine and nitroolefin catalyzed by this solid acid was thermodynamically controlled at 60 degrees C, resulting in the formation of the benzoindoles. PMID- 25823421 TI - Structure and mechanism leading to formation of the cysteine sulfinate product complex of a biomimetic cysteine dioxygenase model. AB - Cysteine dioxygenase is a unique nonheme iron enzyme that is involved in the metabolism of cysteine in the body. It contains an iron active site with an unusual 3-His ligation to the protein, which contrasts with the structural features of common nonheme iron dioxygenases. Recently, some of us reported a truly biomimetic model for this enzyme, namely a trispyrazolylborato iron(II) cysteinato complex, which not only has a structure very similar to the enzyme substrate complex but also represents a functional model: Treatment of the model with dioxygen leads to cysteine dioxygenation, as shown by isolating the cysteine part of the product in the course of the work-up. However, little is known on the conversion mechanism and, so far, not even the structure of the actual product complex had been characterised, which is also unknown in case of the enzyme. In a multidisciplinary approach including density functional theory calculations and X ray absorption spectroscopy, we have now determined the structure of the actual sulfinato complex for the first time. The Cys-SO2 (-) functional group was found to be bound in an eta(2) -O,O-coordination mode, which, based on the excellent resemblance between model and enzyme, also provides the first support for a corresponding binding mode within the enzymatic product complex. Indeed, this is again confirmed by theory, which had predicted a eta(2) -O,O-binding mode for synthetic as well as the natural enzyme. PMID- 25823422 TI - Genetic variation and effects of candidate-gene polymorphisms on coagulation properties, curd firmness modeling and acidity in milk from Brown Swiss cows. AB - The aims of this study were to estimate the genetic variation of traditional milk coagulation properties (MCPs), milk acidity, curd firmness (CF) modeled on time t (CF(t) ; comprising: RCT(eq), rennet coagulation time estimated from the equation; CF(P), the asymptotic potential curd firmness; k(CF), the curd firming instant rate constant; and k(SR), the syneresis instant rate constant) and maximum CF traits (MCF; comprising CF(max), the maximum CF value; and tmax, the time of attainment). Furthermore, we investigated 96 single nucleotide polymorphisms (SNPs) from 54 candidate genes, testing their associations with the above-listed traits. Milk and blood samples were collected from 1271 cows (each sampled once) from 85 herds. Genotyping was performed using a custom Illumina VeraCode GoldenGate approach. A Bayesian linear animal model (including the effects of herd, days in milk, parity and additive polygenic effects) was used to estimate the genetic parameters of the studied traits. The same model with the addition of the SNP genotype effect was used for our association analysis. The heritability estimates of CF t and the MCF traits (RCT(eq)=0.258; k(CF)=0.230; CF(max)=0.191; t(max)=0.278) were similar to those obtained using traditional MCPs (0.187 to 0.267), except for the lower estimates for CF(P) (0.064) and k(SR) (0.077). A total of 13 of the 51 tested SNPs had relevant additive effects on at least one trait. We observed associations between MCPs and SNPs in the genes encoding ATP-binding cassette sub-family G member 2 (ABCG2), chemokine ligand 2 (CCL2), growth hormone 1 (GH1), prolactin (PRL) and toll-like receptor 2 (TLR2). Whereas, CF(t) and the MCF traits were associated with polymorphisms in the alpha s1-casein (CSN1S1), beta-casein (CSN2), GH1, oxidized low-density lipoprotein receptor 1 (OLR1), phospholipase C beta1 (PLCB1), PRL and signal transducer and activator of transcription 5A (STAT5A) genes. PMID- 25823423 TI - Pilot study comparing multi-family therapy to single family therapy for adults with anorexia nervosa in an intensive eating disorder program. AB - Multi-family therapy (MFT) has yet to be evaluated in families of adults with anorexia nervosa (AN). The study aims were: (i) assess the feasibility of MFT for AN; and, (ii) assess whether MFT is associated with improved outcomes for families compared with single-family therapy (SFT). Adult patients with AN consecutively referred to an eating disorder treatment program were assigned (non randomly) to receive eight sessions of SFT or MFT. Assessment occurred pre therapy, immediately post-therapy, and at 3-month follow-up. A total of 37 female patients (13 SFT, 24 MFT) and 45 family members (16 SFT, 29 MFT) completed treatment. There were significant time effects for patients' BMI, eating disorder related psychopathology and multiple family outcome measures. There were no differences between MFT and SFT on family outcome measures at end of treatment and 3 months post treatment. MFT is a feasible intervention that can be used in adult intensive treatment for those with AN. PMID- 25823425 TI - The urokinase lock-therapy for hemodialysis occluded central venous catheters. PMID- 25823424 TI - FK-3000 isolated from Stephania delavayi Diels. inhibits MDA-MB-231 cell proliferation by decreasing NF-kappaB phosphorylation and COX-2 expression. AB - The World Health Organization (WHO) has reported that cancer is one of the most prevalent diseases and a leading cause of death worldwide. Many anticancer drug development studies have been pursued over the last few decades and several viable drugs have been discovered, such as paclitaxel, topotecan and irinotecan. Previously, our research group uncovered the cytocidal and cytostatic effects of the plant Stephania delavayi Diels. In this study, we determined the active chemical to be 6,7-di-O-acetylsinococuline (FK-3000). The FK-3000 half maximal inhibitory concentration (IC50) in MDA-MB-231 breast carcinoma cells at 48 h was 0.52 ug/ml and it induced apoptosis in a dose- and time-dependent manner. FK-3000 suppressed NF-kappaB nuclear translocation, decreased NF-kappaB phosphorylation, and decreased COX-2 protein expression. MDA-MB-231 xenografted mice were treated with FK-3000, Taxol, or their combination for 21 days. The tumor size was smallest in the co-treatment group, indicating that FK-3000 may have a synergistic effect with Taxol. FK-3000 treatment showed no adverse effects on blood cell counts, serum protein levels, or pathology. These studies demonstrate that FK-3000, isolated from S. delavayi Diels., is a promising, pathway-specific anticancer agent that exhibits low toxicity. PMID- 25823426 TI - Fatigue in immune thrombocytopenia. AB - Fatigue is an important aspect of health-related quality of life from the patient perspective and can have significant socio-economic consequences. It is a common feature of chronic illnesses and a significant number of both adults and children with immune thrombocytopenia (ITP) suffer from fatigue. Reliable, validated fatigue scales have been developed for use in ITP. These will facilitate future investigation of its pathogenesis and the effectiveness of intervention. Acute inflammation acts on neural and endocrine systems resulting in 'sickness behaviour', an adaptive response to infection and injury. Inflammation is also thought to cause fatigue in chronic disease and immune dysregulation in ITP appears to have a number of pro-inflammatory components. Clinicians should consider fatigue when assessing the burden of disease. Although effective ITP directed therapy can improve fatigue, a number of fatigue-directed strategies may also need to be considered. PMID- 25823428 TI - Smart tools and orthogonal click-like reactions onto small unilamellar vesicles. AB - Click-based reactions were conducted at the surface of small unilamellar vesicles (SUVs) to provide onto-vesicle chemistry with efficient innovative ready-for-use tools. For that purpose, four amphiphilic molecules were designed to insert into bilayers while presenting a reactive functional head. In this manner, a dioleylglycero-ethoxy-ethoxy-ethoxy-ethanamine (DOG-PEG4-NH2) was chosen as a common platform while the reactive amine head was converted into several electrophilic functions. Thus, two dioleylglycerol-based cyclooctyne anchors were prepared: cyclooct-1-yn-3-glycolic acid-based anchor (DOG-COA) and 1 fluorocyclooct-2-ynecarboxylic acid-based anchor (DOG-FCOA). The last one differed from the first one in that a fluorine atom reinforces the electrophilic properties of the unsaturated bond. In addition, a third dioleylglycerol-based triphenylphosphine (DOG-PPh3) was synthesized for the first time. These three innovative amphiphilic anchors were designed to react with any azide-based biomolecule following copper-free Huisgen 1,4-cycloaddition and Staudinger ligation, respectively. A fourth anchor bearing a 3,4-dibromomaleimide ring (DOG DBM) was also unprecedentedly synthesized, to be further substituted by two thiols. Model reactions conducted in solution with either model biotinyl azide or model biotinyl disulfide gave good to total conversions and excellent isolated yields. The four new anchors were inserted into SUVs whose formula is classically used in in vivo biology. Stability and surface overall electrostatic charge were in the expected range and constant over the study. Then, the functionalized liposomes were ligated to biotin-based reagents and the experimental conditions were finely tuned to optimize the conversion. The biotinyl liposomes were demonstrated functional and totally accessible in an affinity test based on biotin scaffold quantification. Finally, DOG-FCOA's reactivity was confronted to that of DOG-DBM in a 'one-pot' orthogonal reaction. (Biotin-S)2 and TAMRA-N3 (tetramethylcarboxyrhodamine azide) were successively conjugated to the liposome suspension in a successful manner. These data implement and reinforce the interest of bioorthogonal click-like reactions onto lipid nanoparticles. PMID- 25823429 TI - Lyle T. Sinor, PhD: May 24, 1957-January 12, 2015. PMID- 25823427 TI - Does Caspase-6 Have a Role in Perinatal Brain Injury? AB - Apoptotic mechanisms are centre stage for the development of injury in the immature brain, and caspases have been shown to play a pivotal role during brain development and in response to injury. The inhibition of caspases using broad spectrum agents such as Q-VD-OPh is neuroprotective in the immature brain. Caspase-6, an effector caspase, has been widely researched in neurodevelopmental disorders and found to be important following adult stroke, but its function in the neonatal brain has yet to be detailed. Furthermore, caspases may be important in microglial activation; microglia are required for optimal brain development and following injury, and their close involvement during neuronal cell death suggests that apoptotic cues such as caspase activation may be important in microglial activation. Therefore, in this study we aimed to investigate the possible apoptotic and non-apoptotic functions caspase-6 may have in the immature brain in response to hypoxia-ischaemia. We examined whether caspases are involved in microglial activation. We assessed cleaved caspase-6 expression following hypoxia-ischaemia and conducted primary microglial cultures to assess whether the broad-spectrum inhibitor Q-VD-OPh or caspase-6 gene deletion affected lipopolysaccharide (LPS)-mediated microglial activation and phenotype. We observed cleaved caspase-6 expression to be low but present in the cell body and cell processes in both a human case of white matter injury and 72 h following hypoxia-ischaemia in the rat. Gene deletion of caspase-6 did not affect the outcome of brain injury following mild (50 min) or severe (60 min) hypoxia ischaemia. Interestingly, we did note that cleaved caspase-6 was co-localised with microglia that were not of apoptotic morphology. We observed that mRNA of a number of caspases was modulated by low-dose LPS stimulation of primary microglia. Q-VD-OPh treatment and caspase-6 gene deletion did not affect microglial activation but modified slightly the M2b phenotype response by changing the time course of SOCS3 expression after LPS administration. Our results suggest that the impact of active caspase-6 in the developing brain is subtle, and we believe there are predominantly other caspases (caspase-2, -3, -8, -9) that are essential for the cell death processes in the immature brain. PMID- 25823430 TI - Evaluation of Treatment Integrity: The Treatment Specificity Index. AB - OBJECTIVE: To differentiate between treatments in a randomized controlled trial (RCT), therapies need to display not only high purity but also high specificity. The aim of this study was to demonstrate the benefits of calculating a treatment specificity index for the evaluation of treatment differentiation. METHOD: Based on an RCT of relapse prevention in depression, comparing a cognitive with a psychoeducational treatment, the specificity and the purity index were calculated. RESULTS: As indicated by the specificity index, both conditions differed in their levels of implemented specific and common interventions. A significant relationship was found between symptom change before a therapy session and treatment specificity. CONCLUSIONS: The specificity index is an appropriate method for enhancing the internal validity of RCTs in evaluating treatment integrity. PMID- 25823431 TI - Regional radiotherapy in high-risk breast cancer: is the issue solved? AB - Adjuvant radiotherapy is the treatment standard for breast cancer with lymph node metastases after breast-conserving surgery or mastectomy. The inclusion of regional lymph nodes into the treatment volumes has been a question in recent clinical trials. Their impact on treatment standards and open questions is discussed. PMID- 25823433 TI - Resultant vertical prism in toric soft contact lenses. AB - PURPOSE: Rotational stability of toric soft contact lenses (TSCLs) is achieved using a range of designs. Designs utilising prism or peripheral ballast may result in residual prism in the optic zone. This study quantifies the vertical prism in the central 6mm present in TSCLs with various stabilisation methods. METHOD: Vertical prism was computed using published refractive index and vertical thickness changes in the central optic zone on a full lens thickness map. Thickness maps were measured using scanning transmission microscopy. Designs tested were reusable, silicone hydrogel and hydrogel TSCLs: SofLens((r)) Toric, PureVision((r))2 for Astigmatism, PureVision((r)) Toric, Biofinity((r)) Toric, Avaira((r)) Toric, clariti((r)) toric, AIR OPTIX((r)) for ASTIGMATISM and ACUVUE OASYS((r)) for ASTIGMATISM; with eight parameter combinations for each lens ( 6.00DS to +3.00DS, -1.25DC, 90 degrees and 180 degrees axes). RESULTS: All TSCL designs evaluated had vertical prism in the optic zone except one which had virtually none (0.01Delta). Mean prism ranged from 0.52Delta to 1.15Delta, with three designs having prism that varied with sphere power. Vertical prism in ACUVUE OASYS((r)) for ASTIGMATISM was significantly lower than all other TSCLs tested. CONCLUSIONS: TSCL designs utilising prism-ballast and peri-ballast for stabilisation have vertical prism in the central optic zone. In monocular astigmats fitted with a TSCL or those wearing a mix of toric designs, vertical prism imbalance could create or exacerbate disturbances in binocular vision function. Practitioners should be aware of this potential effect when selecting which TSCL designs to prescribe, particularly for monocular astigmats with pre existing binocular vision anomalies, and when managing complaints of asthenopia in monocular astigmats. PMID- 25823434 TI - Hemodynamic and Arterial Stiffness Parameters in Ambulatory Blood Pressure Phenotypes and the Clinical Scenario of Polypharmacy and Comorbidities. PMID- 25823435 TI - Single perforator greater saphenous neuro-veno-fasciocutaneous propeller flaps for lower extremity reconstructions. AB - BACKGROUND: The lack of soft tissue that is available for medial leg and foot defect reconstructions presents a challenge for plastic surgeons. The saphenous neurofasciocutaneous perforator flap application presents an effective alternative to local flap transfers. However, the venous flow and pedicle twisting problems are still disputed. Here, we present our experiences with modified cutaneous pedicles with a single perforator pedicle, which improves the venous flow and the pedicle twisting problem. METHODS: This study was conducted from June 2007 through September 2011, and a total of 15 patients with lower medial leg and foot defects were included. There were 11 men and four women. An asymmetric 'propeller' flap was planned around a perforator that was adjacent to the defects, which was preoperatively confirmed by Doppler. The perforator was sufficiently dissociated to allow for the flap to be turned towards the defects. We preserved some distal skin and subcutaneous tissue from the short side of the 'propeller' to cover some donor site regions, and other regions were covered with split thickness skin grafts. The follow-up period ranged from 3 to 12 months. RESULTS: An infection occurred in one case. Partial flap necrosis was noted in two cases. The other 12 flaps completely survived and matched the recipient sites with regard to colour, texture and thickness. CONCLUSION: The single perforator greater saphenous neuro-veno-fasciocutaneous propeller flap is an effective solution for medial leg and foot defects, and it has a large rotation arc and a satisfactory aesthetic result. PMID- 25823436 TI - Trunk Muscle Coordination During Upward and Downward Reaching in Stroke Survivors. AB - In this study, we investigated deficits in coordination of trunk muscle modes involved in the stabilization of the trunk's trajectory for reaching upward and downward beyond functional arm length. Trunk muscle activity from 10 stroke survivors (8 men, 2 women; 64.1 +/- 10.5 years old) and 9 healthy control subjects (7 men, 2 women; 59.3 +/- 9.3 years old) was analyzed. Coordination of trunk muscle modes to stabilize the trunk trajectory was investigated using the uncontrolled manifold (UCM) analysis. The UCM analysis decomposes the variability of muscle modes into good and bad variability. The good variability does not affect the control of trunk motion, whereas the bad variability does. In stroke survivors, deficits in the ability to flexibly combine trunk muscle modes was associated with reduced ability to minimize those combinations of trunk muscle modes that led to an error in trunk trajectory (bad variability), and this had a greater effect on reaching upward. This reduced coordination of trunk muscle modes during reaching was correlated with a clinical measure of trunk impairment. PMID- 25823437 TI - Dominant and Protective Role of the CYTH4 Primate-Specific GTTT-Repeat Longer Alleles Against Neurodegeneration. AB - Primate-specific genes and regulatory mechanisms could provide insight into human brain functioning and disease. In a genome-scale analysis of the entire protein coding genes listed in the GeneCards database, we have recently reported human genes that contain "exceptionally long" short tandem repeats (STRs) in their core promoter, which may be of adaptive/selective evolutionary advantage in this species. The longest tetra-nucleotide repeat identified in a human gene core promoter belongs to the CYTH4 gene. This GTTT-repeat is specific to Hominidae and Old World monkeys, and the shortest allele of this repeat, (GTTT)6, is linked with neural dysfunction and type I bipolar disorder in human. In the present study, we sought a possibly broader role for the CYTH4 gene core promoter GTTT repeat in neural functioning and investigated its allelic distribution in a total of 949 human subjects, consisting of two neurodegenerative disorders, multiple sclerosis (MS) (n = 272) and Alzheimer's disease (AD) (n = 257), and controls (n = 420). The range of the alleles of this GTTT-repeat in the human sample studied was between 6- and 9-repeats. The shortest allele, (GTTT)6, was significantly in excess in the MS and AD patients in comparison with the controls (p < 0.004). The 6/6, 6/7, and 7/7 genotypes were in excess in the MS and AD patients, whereas the overall frequency of all other genotypes (consisting of at least one longer allele, i.e., 8- or 9-repeat) was higher in the controls (p < 0.005), indicating a dominant and protective effect for the longer alleles against neurodegeneration. This is the first indication of the involvement of a primate specific STR in neurodegeneration in humans. We propose an adaptive evolutionary role for the expansion of the CYTH4 gene core promoter GTTT-repeat in the human brain, which is supported by a link between the shortest allele of this repeat with neuropsychiatric disorders. PMID- 25823438 TI - The Unexposed Secrets of Prion Protein Oligomers. AB - According to the "protein-only" hypothesis, the misfolding and conversion of host derived cellular prion protein (PrP(C)) into pathogenically misfolded PrP are believed to be the key procedure in the pathogenesis of prion diseases. Intermediate, soluble oligomeric prion protein (PrP) aggregates were considered a critical process for prion diseases. Several independent studies on PrP oligomers gained insights into oligomers' formation, biophysical and biochemical characteristics, structure conversion, and neurotoxicity. PrP oligomers are rich in beta-sheet structure and slightly resistant to proteinase K digestion. PrP oligomers exhibited more neurotoxicity and induced neuronal apoptosis in vivo and/or in vitro. In this review, we summarized recent studies regarding PrP oligomers and the relationship between misfolded PrP aggregates and neuronal death in the course of prion diseases. PMID- 25823439 TI - Regulation of atherosclerotic plaque inflammation. AB - The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of chemotactic cytokines that mediate immune cell recruitment and control cell homeostasis and activation of different immune cell types and subsets. Chemokine production and activation of chemokine receptors form a positive feedback mechanism to recruit monocytes, neutrophils and lymphocytes into the atherosclerotic plaque. In addition, chemokine signalling affects immune cell mobilization from the bone marrow. Targeting several of the chemokines and/or chemokine receptors reduces experimental atherosclerosis, whereas specific chemokine pathways appear to be involved in plaque regression. Leukotrienes are lipid mediators that are formed locally in atherosclerotic lesions from arachidonic acid. Leukotrienes mediate immune cell recruitment and activation within the plaque as well as smooth muscle cell proliferation and endothelial dysfunction. Antileukotrienes decrease experimental atherosclerosis, and recent observational data suggest beneficial clinical effects of leukotriene receptor antagonism in cardiovascular disease prevention. By contrast, other lipid mediators, such as lipoxins and metabolites of omega-3 fatty acids, have been associated with the resolution of inflammation. Costimulatory molecules play a central role in fine-tuning immunological reactions and mediate crosstalk between innate and adaptive immunity in atherosclerosis. Targeting these interactions is a promising approach for the treatment of atherosclerosis, but immunological side effects are still a concern. In summary, targeting chemokines, leukotriene receptors and costimulatory molecules could represent potential therapeutic strategies to control atherosclerotic plaque inflammation. PMID- 25823440 TI - New scoring system for the differentiation of chronic obstructive pulmonary disease and asthma. AB - BACKGROUND AND OBJECTIVE: It remains difficult to differentiate between chronic obstructive pulmonary disease (COPD) and asthma in clinical practice, especially in a primary care setting. The purpose of this study was to develop a new scoring system for differentiating between COPD and asthma, and to evaluate its effectiveness. METHODS: First, to identify important variables differentiating COPD from asthma, the data of 197 patients with COPD and 138 patients with asthma were assessed retrospectively. Secondly, a scoring system that was based on these variables was then developed, and its performance was internally validated using a bootstrapping-based method. Thirdly, the scoring system was externally validated using prospectively collected data from patients with COPD (n = 104) or asthma (n = 96). RESULTS: The final scoring system was composed of the four variables: age of onset of breathlessness (<40 years, 0 points; 40-60 years, 2 points; >60 years, 4 points), continuous breathlessness (no, 0 points; yes, 1 point), diurnal variation of breathlessness (yes, 0 points; no, 1 point) and emphysematous change in chest X-ray (no, 0 points; yes, 1 point). The patients were classified by their total score into three categories: 0-2 points, probable asthma; 3-4 points, difficult-to-differentiate; 5-7 points, probable COPD. The new scoring system performed well in the external validation dataset (area under the curve, 0.86; 95% confidence interval: 0.813-0.911; P < 0.001). CONCLUSIONS: The new scoring system that was developed in this study may be a useful tool for differentiating between COPD and asthma in primary care. PMID- 25823441 TI - Long-Term (24 Months) Carcinogenicity Study of D-004, a Lipid Extract From Roystonea regia Fruits, in Sprague Dawley Rats. PMID- 25823442 TI - Clinical Aspects of Syphilis Reinfection in HIV-Infected Patients. AB - BACKGROUND: The incidence of HIV-syphilis co-infection has risen since 2000, especially among men having sex with men (MSM). Syphilis reinfection can occur, but the clinical features of such events remain poorly characterized. OBJECTIVE: To compare the cutaneous lesions seen with syphilis reinfections with those of first episodes in HIV-infected patients. METHODS: In a cohort of HIV-infected patients, syphilis reinfection was established both clinically and biologically by evaluating changes in Venereal Disease Research Laboratory titers. Photographs and medical records were studied in order to determine the type of skin lesions and their quantification. RESULTS: Among 533 HIV-infected patients, 42 (8%) experienced a first syphilis infection. Thirteen episodes of reinfection occurred in 12/42 (28%) patients, all MSM. In 78% of cases, reinfections were less symptomatic than first episodes. All patients presented classical syphilis lesions. CONCLUSIONS: We observed a high rate of reinfection, but with less severe skin manifestations during reinfection episodes. PMID- 25823443 TI - Pain reduction in patients after applying a nitrous oxide/oxygen mixture (Livopan) during photodynamic therapy: study protocol for an observational study (Livopan study). AB - INTRODUCTION: Photodynamic therapy (PDT) is an effective treatment option for extensively photodamaged skin with multiple actinic kerastosis. However, the main drawback of PDT is the intensive pain experienced during its application, which makes it frequently necessary to interrupt or even terminate the process resulting in incomplete treatment. Several strategies for controlling pain during PDT have been studied but few effective methods are currently available. Alternative options are urgently needed. Livopan, a nitrous oxide/oxygen mixture, is indicated for the treatment of short-term pain conditions when rapid analgesic onset and offset effects are wanted. But so far, there are no studies evaluating the effect of Livopan on pain intensity during PDT. Therefore, it remains unclear whether patients benefit from this inhalation analgesia. Within the Livopan study, this issue will be evaluated for the first time. METHODS AND ANALYSIS: The Livopan study is a prospective, single-centre, explorative, controlled, observational study to investigate the pain reduction in patients after applying a nitrous oxide/oxygen mixture (Livopan) during PDT according to the visual analogue scale in 60 patients. ETHICS AND DISSEMINATION: Ethics approval was provided by the ethics committee of the medical faculty of the University of Heidelberg. Ethics approval number S-169/2014. TRIAL REGISTRATION NUMBER: German Clinical Trial Register (DRKS): DRKS00006054. PMID- 25823444 TI - Practice guidelines for sedation and analgesia management of critically ill children: a pilot study evaluating guideline impact and feasibility in the PICU. AB - AIMS: The aim of this study was to develop and implement guidelines for sedation and analgesia management in the paediatric intensive care unit (PICU) and evaluate the impact, feasibility and acceptability of these as part of a programme of research in this area and as a prelude to future trial work. METHOD: This pilot study used a pre-post design using a historical control. SETTING: Two PICUs at different hospitals in an Australian metropolitan city. PARTICIPANTS: Patients admitted to the PICU and ventilated for >=24 h, aged more than 1 month and not admitted for seizure management or terminal care. INTERVENTION: Guidelines for sedation and analgesia management for critically ill children including algorithm and assessment tools. OUTCOME VARIABLES: In addition to key outcome variables (ventilation time, medication dose and duration, length of stay), feasibility outcomes data (recruitment, data collection, safety) were evaluated. Guideline adherence was assessed through chart audit and staff were surveyed about merit and the use of guidelines. RESULTS: The guidelines were trialled for a total of 12 months on 63 patients and variables compared with the historical control group (n=75). Analysis revealed differences in median Morphine infusion duration between groups (pretest 3.63 days (87 h) vs post-test 2.83 days (68 h), p=0.05) and maximum doses (pretest 120 MUg/kg/h vs post-test 97.5 MUg/kg/h) with no apparent change to ventilation duration. Chart audit revealed varied use of tools, but staff were positive about the guidelines and their use in practice. CONCLUSIONS: The sedation guidelines impacted on the duration and dosage of agents without any apparent impact on ventilation duration or length of stay. Furthermore, the guidelines appeared to be feasible and acceptable in clinical practice. The results of the study have laid the foundation for follow up studies in withdrawal from sedation, point prevalence and longitudinal studies of sedation practices as well as drug trial work. PMID- 25823445 TI - The Chromatin and Transcriptional Landscape of Native Saccharomyces cerevisiae Telomeres and Subtelomeric Domains. AB - Saccharomyces cerevisiae telomeres have been a paradigm for studying telomere position effects on gene expression. Telomere position effect was first described in yeast by its effect on the expression of reporter genes inserted adjacent to truncated telomeres. The reporter genes showed variable silencing that depended on the Sir2/3/4 complex. Later studies examining subtelomeric reporter genes inserted at natural telomeres hinted that telomere position effects were less pervasive than previously thought. Additionally, more recent data using the sensitive technology of chromatin immunoprecipitation and massively parallel sequencing (ChIP-Seq) revealed a discrete and noncontinuous pattern of coenrichment for all three Sir proteins at a few telomeres, calling the generality of these conclusions into question. Here we combined the ChIP-Seq of the Sir proteins with RNA sequencing (RNA-Seq) of messenger RNAs (mRNAs) in wild type and in SIR2, SIR3, and SIR4 deletion mutants to characterize the chromatin and transcriptional landscape of all native S. cerevisiae telomeres at the highest achievable resolution. Most S. cerevisiae chromosomes had subtelomeric genes that were expressed, with only ~6% of subtelomeric genes silenced in a SIR dependent manner. In addition, we uncovered 29 genes with previously unknown cell type-specific patterns of expression. These detailed data provided a comprehensive assessment of the chromatin and transcriptional landscape of the subtelomeric domains of a eukaryotic genome. PMID- 25823446 TI - Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. AB - Interpreting variants of uncertain significance (VUS) is a central challenge in medical genetics. One approach is to experimentally measure the functional consequences of VUS, but to date this approach has been post hoc and low throughput. Here we use massively parallel assays to measure the effects of nearly 2000 missense substitutions in the RING domain of BRCA1 on its E3 ubiquitin ligase activity and its binding to the BARD1 RING domain. From the resulting scores, we generate a model to predict the capacities of full-length BRCA1 variants to support homology-directed DNA repair, the essential role of BRCA1 in tumor suppression, and show that it outperforms widely used biological effect prediction algorithms. We envision that massively parallel functional assays may facilitate the prospective interpretation of variants observed in clinical sequencing. PMID- 25823447 TI - Shortening delivery times of intensity modulated proton therapy by reducing proton energy layers during treatment plan optimization. AB - PURPOSE: To shorten delivery times of intensity modulated proton therapy by reducing the number of energy layers in the treatment plan. METHODS AND MATERIALS: We have developed an energy layer reduction method, which was implemented into our in-house-developed multicriteria treatment planning system "Erasmus-iCycle." The method consisted of 2 components: (1) minimizing the logarithm of the total spot weight per energy layer; and (2) iteratively excluding low-weighted energy layers. The method was benchmarked by comparing a robust "time-efficient plan" (with energy layer reduction) with a robust "standard clinical plan" (without energy layer reduction) for 5 oropharyngeal cases and 5 prostate cases. Both plans of each patient had equal robust plan quality, because the worst-case dose parameters of the standard clinical plan were used as dose constraints for the time-efficient plan. Worst-case robust optimization was performed, accounting for setup errors of 3 mm and range errors of 3% + 1 mm. We evaluated the number of energy layers and the expected delivery time per fraction, assuming 30 seconds per beam direction, 10 ms per spot, and 400 Giga-protons per minute. The energy switching time was varied from 0.1 to 5 seconds. RESULTS: The number of energy layers was on average reduced by 45% (range, 30%-56%) for the oropharyngeal cases and by 28% (range, 25%-32%) for the prostate cases. When assuming 1, 2, or 5 seconds energy switching time, the average delivery time was shortened from 3.9 to 3.0 minutes (25%), 6.0 to 4.2 minutes (32%), or 12.3 to 7.7 minutes (38%) for the oropharyngeal cases, and from 3.4 to 2.9 minutes (16%), 5.2 to 4.2 minutes (20%), or 10.6 to 8.0 minutes (24%) for the prostate cases. CONCLUSIONS: Delivery times of intensity modulated proton therapy can be reduced substantially without compromising robust plan quality. Shorter delivery times are likely to reduce treatment uncertainties and costs. PMID- 25823448 TI - ZRBA1, a Mixed EGFR/DNA Targeting Molecule, Potentiates Radiation Response Through Delayed DNA Damage Repair Process in a Triple Negative Breast Cancer Model. AB - PURPOSE: ZRBA1 is a combi-molecule designed to induce DNA alkylating lesions and to block epidermal growth factor receptor (EGFR) TK domain. Inasmuch as ZRBA1 downregulates the EGFR TK-mediated antisurvival signaling and induces DNA damage, we postulated that it might be a radiosensitizer. The aim of this study was to further investigate the potentiating effect of ZRBA1 in combination with radiation and to elucidate the possible mechanisms of interaction between these 2 treatment modalities. METHODS AND MATERIALS: The triple negative human breast MDA MB-468 cancer cell line and mouse mammary cancer 4T1 cell line were used in this study. Clonogenic assay, Western blot analysis, and DNA damage analysis were performed at multiple time points after treatment. To confirm our in vitro findings, in vivo tumor growth delay assay was performed. RESULTS: Our results show that a combination of ZRBA1 and radiation increases the radiation sensitivity of both cell lines significantly with a dose enhancement factor of 1.56, induces significant numbers of DNA strand breaks, prolongs higher DNA damage up to 24 hours after treatment, and significantly increases tumor growth delay in a syngeneic mouse model. CONCLUSIONS: Our data suggest that the higher efficacy of this combination could be partially due to increased DNA damage and delayed DNA repair process and to the inhibition of EGFR. The encouraging results of this combination demonstrated a significant improvement in treatment efficiency and therefore could be applicable in early clinical trial settings. PMID- 25823449 TI - Submandibular gland transfer for the prevention of postradiation xerostomia in patients with head and neck cancer: a systematic review and meta-analysis. AB - BACKGROUND: Submandibular gland transfer has been widely used to prevent postradiation xerostomia in head-and-neck cancers. However, there are still some controversies. METHODS: Six databases were searched, data extraction was performed and the risk of bias was assessed by 2 reviewers independently. The meta-analysis was performed using Review Manager, version 5.2. RESULTS: A total of 7 trials (12 articles) and 369 participants were included. CONCLUSIONS: The present clinical evidence suggests that submandibular gland transfer might be highly effective to prevent postradiation xerostomia in head-and-neck cancers without serious adverse events. However, more randomized controlled trials are still needed to confirm this conclusion. PMID- 25823450 TI - Immune response to gut Escherichia coli and susceptibility to adjuvant arthritis in the rats. AB - We have investigated the humoral immune response to antigens of predominant gut aerobic bacterial strains (i.e. Escherichia coli) over the course of adjuvant arthritis and oil-induced arthritis in two inbred rat strains: Dark Agouti (DA) and Albino Oxford (AO). We report the presence of antibodies specific to proteins of E. coli in molecular weight range between 20-30 kDa in sera of diseased DA rats, and the absence of these antibodies in the sera of AO rats. In DA rats, CFA and IFA provoked a stronger antibody response to E. coli, especially of the IgG2b antibody class. Intramuscular administration of E. coli preceding the adjuvant arthritis induction had no effect on the development and course of disease, as well as on the activation of T cells in the draining inguinal lymph nodes. Higher serum levels of natural and induced IgA antibodies, combined with a higher CD3+CD26+ cell percentage were found in AO rats. The observed correlation between the serologic response to commensal flora and rats' genetic background as a defining factor for arthritis susceptibility may contribute to the process of creating a favorable (or less favorable) milieu for arthritis development. PMID- 25823451 TI - Retrovesical hydatidosis associated with urinary tract pathology - case report. AB - Cystic hydatidosis (CH) is a worldwide distributed parasitic zoonosis. It is considered one of the 17 neglected parasitic tropical diseases, among cysticercosis and soil transmitted helminthiases. CH is caused by the larval stage of Echinococcus granulosus, a tapeworm that usually infects dogs and other carnivorous animals as definitive hosts and herbivorous animals and rarely humans as intermediate hosts. Main primary localizations are the liver and the lung. In less than 3% they can primarily be present in the spleen. Treatment is mainly surgical, in some cases resulting in reoccurrence. In this paper we present the case of a male 55 years old patient who underwent a surgical intervention on his spleen for a solitary hydatid cyst as primary localization. Fifteen years after the operation the patient presented macroscopic haematuria; routine laboratory findings presented soft eosinophilia, 5%, without any other modification. There was found no palpable tumour in the pelvis by rectal examination. Abdominal ultrasound investigation revealed a 2*1 cm formation in the urinary bladder at the base of the left bladder-wall and a retrovesical, inhomogeneous 10*10 cm tumour with multiple septa and transonic zones. Computed tomography (CT) scan strongly suggested the presence of a bladder tumour and a hydatid cyst. The symptoms caused by the bladder tumour revealed the co-existing non-symptomatic retrovesical secondary CH, which is a rare complication of splenic Echinococcus granulosus infection. Close follow-up and a proper pre- and postoperative anti parasitic medication of the patient could have prevented reoccurrence of CH. PMID- 25823452 TI - Infections and antimicrobial use among institutionalized residents in Hungary: increasing need of microbiological surveillance. AB - As a result of the age-related changes, more elders live in long-term care facilities (LTCFs). Due to their susceptibility, infections and excess use of antimicrobials are common. The aim was to estimate the burden of infections and antimicrobial use in Hungarian LTCFs in order to increase the attention given to the prevention. European-wide point prevalence survey was conducted between April and May 2013. For each resident who had a signs and symptoms of an infection and/or treated with an antibacterial for systemic use a resident questionnaire was completed. Descriptive statistics were used to present the data. In total, 91 LTCFs with 11,823 residents were selected in this survey. The 252 residents had a sign/symptom of an infection (2.1%) and 156 received antimicrobial (1.3%). Skin and soft tissues (36.5%) was the most frequent infection. However, antimicrobials were mostly prescribed for respiratory tract infections (40.4%). The most common therapeutic antimicrobial agent (97.5%) belonged to the quinolone antibacterials (34.2%). Our results emphasise the need for targeted improvement of antimicrobial use including: reducing the use of quinolone antibacterials in order to prevent the spread of Clostridium difficile and other antimicrobial resistant microorganisms among institutionalized residents. PMID- 25823453 TI - Evaluating synergy between marbofloxacin and gentamicin in Pseudomonas aeruginosa strains isolated from dogs with otitis externa. AB - The aim of this study was to determine antimicrobial susceptibility of Pseudomonas aeruginosa strains to marbofloxacin and gentamicin, and investigate the possible synergistic, additive, indifferent or antagonistic effects between the two agents. P. aeruginosa strains can develop resistance quickly against certain antibiotics if used alone, thus the need emerges to find synergistic combinations. A total of 68 P. aeruginosa strains isolated from dogs were examined. In order to describe interactions between marbofloxacin and gentamicin the checkerboard microdilution method was utilized. The MICs (minimum inhibitory concentrations) for marbofloxacin and gentamicin were in the range 0.25-64 mg/L and 0.25-32 mg/L, respectively. The combination of marbofloxacin and gentamicin was more effective with a MIC range of 0.031-8 mg/L and a MIC90 of 1 mg/L, compared to 16 mg/L for marbofloxacin alone and 8 mg/L for gentamicin alone. The FIC (fractional inhibitory concentration) indices ranged from 0.0945 (pronounced synergy) to 1.0625 (indifference). Synergy between marbofloxacin and gentamicin was found in 33 isolates. The mean FIC index is 0.546, which represents a partial synergistic/additive effect close to the full synergy threshold. In vitro results indicate that marbofloxacin and gentamicin as partially synergistic agents may prove clinically useful in combination therapy against P. aeruginosa infections. Although marbofloxacin is not used in the human practice, the interactions between fluoroquinolones and aminoglycosides may have importance outside the veterinary field. PMID- 25823454 TI - Ubiquiter circovirus sequences raise challenges in laboratory diagnosis: the case of honey bee and bee mite, reptiles, and free living amoebae. AB - Circoviruses of pigs and birds are established pathogens, however, the exact role of other, recently described circoviruses and circovirus-like viruses remains to be elucidated. The aim of this study was the detection of circoviruses in neglected host species, including honey bees, exotic reptiles and free-living amoebae by widely used broad-spectrum polymerase chain reaction (PCR) assays specific for the replication initiation protein coding gene of these viruses. The majority of sequences obtained from honey bees were highly similar to canine and porcine circoviruses, or, were distantly related to dragonfly cycloviruses. Other rep sequences detected in some honey bees, reptiles and amoebae showed similarities to various rep sequences deposited in the GenBank. Back-to-back PCR primers designed for the amplification of whole viral genomes failed to work that suggested the existence of integrated rep-like elements in many samples. Rolling circle amplification and exonuclease treatment confirmed the absence of small circular DNA genomes in the specimens analysed. In case of honey bees Varroa mite DNA contamination might be a source of the identified endogenous rep-like elements. The reptile and amoebae rep-like sequences were nearly identical with each other and with sequences detected in chimpanzee feces raising the possibility that detection of novel or unusual rep-like elements in some host species might originate from the microbial community of the host. Our results indicate that attention is needed when broad-spectrum rep gene specific polymerase chain reaction is chosen for laboratory diagnosis of circovirus infections. PMID- 25823455 TI - Comparative study of antibody levels developed by vaccination against polio virus in population after vaccine type alteration. AB - During clinical trials, samples from Hungarian patients of different age groups were tested for antibodies against all 3 serotypes of poliovirus, a member of Picornaviridae family. During the virus neutralization serological test, blood samples were titrated using permanent virus concentration. Based on the cythopathic effect observed under a light microscope, the antibody level of the patient was assessed. The 100 people examined were classified into 5 groups based on age and type of original vaccine: I. Newborns, no vaccination given; II. Immunosuppressed patients; III. Born before 1986, received only OPV vaccine; IV. Born between 1992-2005, received a combination of OPV and IPV vaccines; V. Born after 2006, received only IPV vaccine. Results show that vaccination coverage meets all the criteria. None of the immunized persons was seronegative to all three polioviruses. Both IPV and OPV vaccines are effective against poliovirus. Blood samples from newborn babies with no immunization were also examined. Results show that most newborns have maternal antibodies in their blood. Results of group II show that immunosuppression does not have a negative influence on blood antibody levels against polioviruses. In spite of the low number of samples, our results show that seroconversion after immunization in the Hungarian population is adequate. For more accurate results about vaccination coverage in the population, further trials would be necessary. PMID- 25823456 TI - Modulation of ConA-induced inflammatory ascites by histamine - short communication. AB - The early phase of the ConA-induced inflammatory ascites was studied, with special reference to histamine. Concanavalin A (ConA), a cell-surface binding lectin was injected i.p. (25 mg/kg bw) to mice. After 1 h the animals were killed, the ascitic fluid collected and measured. Other agents were injected s.c., 10 min before the ConA-challenge. Exogenous histamine markedly inhibited the ConA-induced ascites. Release of endogenous vasoactive agents from the mast cells by Compound 48/80 had a similar, but slight effect. Cromolyn, a mast cell stabilizing agent, and chloropyramine, a histamine H1 receptor antagonist was ineffective. Although histamine increases endothelial permeability, it did not enhance the formation of ascitic fluid, on the contrary, it inhibited the ConA induced ascites, presumably due to its known hypotonic effect. It is concluded that ConA-induced ascites is not mediated by mast cell histamine. PMID- 25823457 TI - Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to beta blocker therapy in hypertension. AB - OBJECTIVE: To investigate the associations between beta1-adrenergic receptor (ADRB1) and cytochrome P450 2D6 (CYP2D6) gene polymorphisms and beta-blocker treatment outcomes in patients with hypertension. METHODS: Chinese patients with essential hypertension were treated with the beta-blocker metoprolol and followed up for 12 weeks. xTAG(r) liquid-chip technology was used for CYP2D6 100 C > T and ADRB1 1165G > C genotyping. Associations between gene polymorphisms and antihypertensive therapy outcomes were assessed by generalized linear model fitting. A decrease of >= 10 mmHg in systolic blood pressure indicated an effective treatment outcome. RESULTS: A total of 93 patients were included in the study. Mutant allele frequencies of 61.29% and 58.60% were obtained for ADRB1 and CYP2D6, respectively. There was no significant interaction between the effects of ADRB1 and CYP2D6 gene polymorphisms on treatment outcome. Patients homozygous for the mutant ADRB1 genotype (CC) had better treatment outcomes than those heterozygous for the mutation (GC). Interestingly, beta-blocker treatment duration was an independent factor associated with treatment outcome. CONCLUSIONS: The ADRB1 1165G > C gene polymorphism and beta-blocker treatment duration are independent factors associated with beta-blocker treatment outcome. These findings suggest that the selection of antihypertensive therapy should take into consideration the patient's genotype. PMID- 25823458 TI - Cerebral perivascular spaces visible on magnetic resonance imaging: development of a qualitative rating scale and its observer reliability. AB - BACKGROUND: Perivascular spaces (PVS) are an important component of cerebral small vessel disease (SVD), several inflammatory disorders, hypertension and blood-brain barrier breakdown, but are difficult to quantify. A recent international collaboration of SVD experts has highlighted the need for a robust, easy-to-use PVS rating scale for the effective investigation of the diagnostic and prognostic significance of PVS. The purpose of the current study was to develop and extend existing PVS scales to provide a more comprehensive scale for the measurement of PVS in the basal ganglia, centrum semiovale and midbrain, and to test its intra- and inter-rater agreement, assessing reasons for discrepancy. METHODS: We reviewed previously published PVS scales, including site of PVS assessed, rating method, and size and morphological criteria. Retaining key features, we devised a more comprehensive scale in order to improve the reliability of PVS rating. Two neuroradiologists tested the new scale in MRI brain scans of 60 patients from two studies (stroke, ageing population), chosen to represent a full range of PVS, and demonstrating concomitant features of SVD such as lacunes and white matter hyperintensities. We rated basal ganglia, centrum semiovale, and midbrain PVS. Basal ganglia and centrum semiovale PVS were rated 0 (none), 1 (1-10), 2 (11-20), 3 (21-40) and 4 (>40), and midbrain PVS were rated 0 (none visible) or 1 (visible). We calculated kappa statistics for rating, assessed consistency in use of PVS categories (Bhapkar test) and reviewed sources of discrepancy. RESULTS: Intra- and inter-rater kappa statistics were highest for basal ganglia PVS (range 0.76-0.87 and 0.8-0.9, respectively) than for centrum semiovale PVS (range 0.68-0.75 and 0.61-0.8, respectively) or midbrain PVS (inter rater range 0.51-0.52). Inter-rater consistency was better for basal ganglia compared to centrum semiovale PVS (Bhapkar statistic 2.49-3.72, compared to 6.79 21.08, respectively). Most inter-rater disagreements were due to very faint PVS, coexisting extensive white matter hyperintensities (WMH) or the presence of lacunes. CONCLUSIONS: We developed a more inclusive and robust visual PVS rating scale allowing rating of all grades of PVS severity on structural brain imaging. The revised PVS rating scale has good observer reliability for basal ganglia and centrum semiovale PVS, best for basal ganglia PVS, and moderate reliability for midbrain PVS. Agreement is influenced by PVS severity and the presence of background features of SVD. The current scale can be used in further studies to assess the clinical implications of PVS. PMID- 25823459 TI - Plasma and ovarian oestradiol and the variability in the LH surge induced in ewes by the ram effect. AB - The proportion of anoestrous ewes ovulating after exposure to a sexually active ram is variable mainly due to whether an LH surge is induced. The aim of this study was to determine the role of oestradiol (E2) in the ram-induced LH surge. In one study, we measured the plasma concentrations of E2 in ewes of different breeds before and after the 'ram effect' and related these patterns to the presence and latency of the LH surge, while another compared ovarian responses with the 'ram effect' following exposure to rams for 2 or 12 h. In all ewes, the concentration of E2 increased 2-4 h after rams were introduced and remained elevated for 14.5 +/- 0.86 h. The quantity of E2 secreted before the LH surge varied among breeds as did the mean concentration of E2. The granulosa cells of IF ewes collected after 12 h exposure to rams secreted more E2 and progesterone and had higher levels of StAR than the 2 h group but in MV ewes there was no differences between these groups for any of these parameters. These results demonstrate that the LH surge induced by the rams is a result of increased E2 secretion associated with increased levels of STAR in granulosa cells and that these responses varied among breeds. The results suggest that the variable occurrence of a LH surge and ovulation may be the result of variable ovarian responses to the 'ram effect' and insensitivity of the hypothalamus to the E2 positive feedback signal. PMID- 25823461 TI - Immigrant patients with dementia and memory impairment in primary health care in Norway: a national registry study. AB - BACKGROUND: Immigrants comprise a growing proportion of the elderly population. However, knowledge about the diagnosis and management of dementia and memory impairment among immigrants is scarce in Norway and elsewhere. AIMS: To compare proportions of Norwegians and immigrants aged >=50 years with a diagnosis of dementia or memory impairment in primary health care and to study the demographic characteristics, utilization of primary health care services and pharmacological treatment of Norwegians and immigrants with either of the two diagnoses in 2008. METHOD: This is a registry-based study using linked data at the individual level from 4 national Norwegian registers. RESULTS: A significantly lower proportion of immigrants, especially those from other than high-income countries, had a diagnosis of dementia or memory impairment. Among patients with such diagnoses, anti-dementia medication was purchased 20-50% more often by Norwegians than by immigrants, although the differences remained significant only for immigrants from other than high-income countries after adjustment for several variables. CONCLUSION: The lower proportions of immigrants with a dementia diagnosis and lower proportions of patients receiving treatment might indicate a lower prevalence or milder forms of dementia among immigrants. However, the cultural validity of the assessment tools, linguistic barriers and challenges for general practitioners should be further investigated. PMID- 25823463 TI - Transfusion strategies in patients with traumatic brain injury: which is the optimal hemoglobin target? AB - Robertson et al. (JAMA 2014; 312:36-47) investigated the effects of two different thresholds of hemoglobin (Hb) to guide red blood cells transfusions (RBCT; 7 g/dL vs. 10 g/dL) in patients suffering from traumatic brain injury (TBI). In a two center, controlled, open-label trial (from May 2006 and August 2012), comatose patients with a closed TBI were randomized within 6 hours since initial resuscitation to one of the two RBCT strategies and, in a factorial design (2x2), to receive erythropoietin (EPO) or placebo. Patients were excluded if they had a Glasgow Coma Scale (GCS) score of 3 with fixed and dilated pupils, penetrating trauma, pregnancy, life-threatening systemic injuries and severe preexisting diseases. A total of 200 patients (7 g/dL with [N.=49] or without EPO [N. =50]; 10 g/dL with [N.=53] or without EPO [N.=48]) were enrolled among 598 who were screened. There was no interaction between EPO and Hb thresholds on the primary outcome, which was the occurrence of favorable neurological outcome, assessed using the Glasgow Outcome Scale (GOS) at 6 months after the injury (favorable=GOS 4-5). Favorable outcome was similar between patients included in the 7 g/dL (37/87-43%) and the 10 g/dL group (31/94-33%) as if receiving EPO or placebo, even after adjustment for several covariates. Thromboembolic events were significantly more frequent in the group transfused at 10 g/dL (22/101 [22%] vs. 8/99 [8%]; P=0.009). We discussed how theses results might influence the management of such patients as well as the methodological limitations that underline the need for further investigations. PMID- 25823462 TI - 2'-O-Methylation within Bacterial RNA Acts as Suppressor of TLR7/TLR8 Activation in Human Innate Immune Cells. AB - Microbial RNA is an important stimulator of innate immune responses. Differences in posttranscriptional RNA modification profiles enable the immune system to discriminate between self and non-self nucleic acids. This principle may be exploited by certain bacteria to circumvent immune cell activation. In this regard, 2'-O-methylation of Escherichia coli tRNATyr at position 18 (Gm18) has recently been described to inhibit TLR7-mediated IFN-alpha production in human plasmacytoid dendritic cells (pDCs). Extending these findings, we now demonstrate that Gm18 also potently inhibits TLR7-independent human monocyte activation by RNA derived from a variety of bacterial strains. The half minimal inhibitory concentration values were similar to those found for IFN-alpha inhibition in pDCs. Mechanistically, 2'-O-methylated RNA impaired upstream signalling events, including MAP kinase and NFx03BA;B activation. Our results suggest that antagonizing effects of Gm18-modified RNA are due to competition with stimulatory RNA for receptor binding. The antagonistic effect was specific for RNA because the small molecule TLR7/8 agonist R848 was not inhibited. Despite the striking phenotype in human cells, 2'-O-methylated RNA did not interfere with TLR13 activation by bacterial 23S rRNA in murine DC and BMDM. Thus, we identify here Gm18 in E. coli tRNA(Tyr) as a universal suppressor of innate immune activation in the human but not the murine system. PMID- 25823460 TI - Accurate typing of short tandem repeats from genome-wide sequencing data and its applications. AB - Short tandem repeats (STRs) are implicated in dozens of human genetic diseases and contribute significantly to genome variation and instability. Yet profiling STRs from short-read sequencing data is challenging because of their high sequencing error rates. Here, we developed STR-FM, short tandem repeat profiling using flank-based mapping, a computational pipeline that can detect the full spectrum of STR alleles from short-read data, can adapt to emerging read-mapping algorithms, and can be applied to heterogeneous genetic samples (e.g., tumors, viruses, and genomes of organelles). We used STR-FM to study STR error rates and patterns in publicly available human and in-house generated ultradeep plasmid sequencing data sets. We discovered that STRs sequenced with a PCR-free protocol have up to ninefold fewer errors than those sequenced with a PCR-containing protocol. We constructed an error correction model for genotyping STRs that can distinguish heterozygous alleles containing STRs with consecutive repeat numbers. Applying our model and pipeline to Illumina sequencing data with 100-bp reads, we could confidently genotype several disease-related long trinucleotide STRs. Utilizing this pipeline, for the first time we determined the genome-wide STR germline mutation rate from a deeply sequenced human pedigree. Additionally, we built a tool that recommends minimal sequencing depth for accurate STR genotyping, depending on repeat length and sequencing read length. The required read depth increases with STR length and is lower for a PCR-free protocol. This suite of tools addresses the pressing challenges surrounding STR genotyping, and thus is of wide interest to researchers investigating disease-related STRs and STR evolution. PMID- 25823464 TI - Preschool oscillometry and lung function at adolescence in asthmatic children. AB - INTRODUCTION: Reduced lung function in early childhood is associated with persistent symptoms and low lung function later in life. Impulse oscillometry (IOS) is feasible for assessing lung function also in preschool children, and some of the parameters, such as respiratory resistance at 5 Hz (Rrs5) and the frequency dependence of resistance (dRrs/df), have been suggested to reflect small airway dysfunction. Whether changes in preschool IOS predict later lung function remains unknown. METHODS: The medical data of 154 asthmatic children with IOS performed at 2-7 years and spirometry at 12-18 years were analyzed. IOS and post-bronchodilator spirometry parameters were compared, and the association was estimated in a multivariate model. RESULTS: Measured at preschool age, particularly Rrs5 and dRrs/df were significantly correlated with post bronchodilator forced expiratory volume in 1 sec (FEV1) at adolescence (Rrs5: r = -0.223, P = 0.005; dRrs/df: r = 0.234, P = 0.004). Although the number of children with decreased FEV1 was low, associations of increased Rrs5 (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.7; 20.9) and decreased dRrs/df (OR 8.2, 95% CI 1.7; 39.6) with decreased FEV1 remained significant in multivariate analyses. Similar findings were observed also with other spirometric parameters. CONCLUSION: In asthmatic children, preschool IOS is associated with spirometric lung function at adolescence, but the scatter is wide. Normal preschool IOS seems to indicate favourable lung function outcome, whereas in some individuals IOS could potentially be of clinical use, at a younger age than spirometry, to screen lung function deficits and increased risk for later lung function impairment. PMID- 25823465 TI - Galectin-9 suppresses the growth of hepatocellular carcinoma via apoptosis in vitro and in vivo. AB - Galectin-9, a soluble beta-galactoside-binding animal lectin, evokes apoptosis in various human cancer cell lines. The galectin-9 antitumor effect against hepatocellular carcinoma (HCC) is, however, unknown. We investigated whether galectin-9 suppresses HCC growth in vitro and in vivo. We assessed the antitumor effect of galectin-9 on HCC cells by conducting WST-8 assay in vitro and xenograft model analysis in vivo. Galectin-9-induced apoptosis was evaluated by FACS and ELISA in vitro and by TUNEL stain in vivo. Cell cycle alteration was profiled by FACS. Caspases were profiled by colorimetry. MicroRNAs related to the galectin-9 antitumor effects were determined using microarrays, and their antitumor effect was confirmed in a transfection study in vitro. The expression levels of the target proteins of the miRNAs extracted above were analyzed by western blot analysis. To summarize the results, galectin-9 inhibited the growth of the HCC cell lines HLE and Li-7 in vitro and Li-7 in vivo inducing apoptosis. Cell cycle turnover was not arrested in HLE and Li-7 cells in vitro. miR-1246 was similarly extracted both in vitro and in vivo, which sensitized Li-7 cells to apoptosis when transfected into the cells. DYRK1A, a target protein of miR-1246 was downregulated in Li-7 cells. Caspase-9 was upregulated in Li-7 cells in vitro and in vivo. In conclusion, galectin-9 inhibited the growth of HCC cells by apoptosis, but not cell cycle arrest, in vitro and in vivo. miR-1246 mediated signals of galectin-9, possibly through miR-1246-DYRK1A-caspase-9 axis. Galectin 9 might be a candidate agent for HCC chemotherapy. PMID- 25823466 TI - Impact of vascular calcifications on arteriovenous fistula survival in hemodialysis patients: a five-year follow-up. AB - BACKGROUND/AIMS: Vascular calcifications are frequently found among dialysis patients, and the calcification process may influence the patient's outcome. The aim of the present study was to determine the role that vascular calcifications may have on autologous arteriovenous fistula (AVF) survival. METHODS: This study included 90 patients (49 males, mean age 62 +/- 11) with a native AVF treated by chronic hemodialysis (HD) for more than one year. The overall vascular calcification scores ranged from 0-11 (Adragao score + vascular access calcification score); patients were categorized into mild (score 0-3; n = 36), moderate (score 4-7; n = 24) and severe (score 8-11; n = 30) calcification groups. AVF survival was then followed for 5 years after calcification measurement or until the patient's death/transplantation. RESULTS: Patients with more pronounced vascular calcifications were more frequently diabetic and male. Multiple linear regression analysis showed a significant relationship between calcification score and male gender, diabetes mellitus, previous duration of AVF, low dialysis flow rate and intact parathormone (iPTH) values. After multivariate adjustment for basal differences, Cox proportional analysis revealed a graded impact of calcification scores on AVF failure: moderate scores (were associated with a hazard rate (HR) of 3.82 (95% confidence interval (CI) 1.10-13.23) and severe scores with an HR of 4.65 (CI 0.97-22.38). CONCLUSION: Vascular calcifications are associated with worse survival of native arteriovenous hemodialysis fistulas. PMID- 25823467 TI - BDNF Val66Met is Associated With Performance in a Computerized Visual-Motor Tracking Test In Healthy Adults. AB - The brain-derived neurotrophic factor gene (BDNF) is known to play an important role in neuroplasticity and cognitive processes. We explored the association of BDNF Val66Met polymorphism with performance in a visual-motor tracking test. One hundred and sixty-seven young, healthy Colombian adults completed a computerized version of the Pursuit Rotor Task, using the Psychology Experiment Building Language (PEBL) platform. DNA genotyping was performed by allele-specific polymerase chain reaction. We found that BDNF Val/Met and Met/Met subjects performed better in the pursuit rotor task (p = .03). Our findings suggest that the BDNF gene is essential to understand differences in motor performance in healthy participants in different populations. This approach could be useful for future fine mapping of genetic modifiers for neuropsychiatric diseases. PMID- 25823468 TI - The stem cell potential and multipotency of human adipose tissue-derived stem cells vary by cell donor and are different from those of other types of stem cells. AB - Human adipose tissue-derived mesenchymal stem cells (AT-MSCs) from various sites are applied in tissue engineering and cell therapy. The condition of AT-MSCs depends on the donor's age, body mass index (BMI), and gender. AT-MSCs from 66 human donors were analyzed, and the cells were sorted according to donor age (10 19 years: n = 1; 20-29 years: n = 5; 30-39 years: n = 12; 40-49 years: n = 22; 50 59 years: n = 12; 60-69 years: n = 9, and 70 years or older: n = 5), BMI (under 25, 25-30, and over 30), and gender (19 males and 48 females). Additionally, AT MSCs were compared to bone marrow MSCs and chorionic tissue-derived MSCs. We measured the MSC yield, growth rate, colony-forming units, multipotency, and surface antigens. AT-MSC proliferation was greater in cells isolated from individuals aged less than 30 years compared to the proliferation of AT-MSCs from those over 50 years old. BMI was correlated with osteogenic differentiation potency; increased BMI enhanced osteogenesis. Adipogenic differentiation was more strongly induced in cells isolated from donors aged less than 30 years compared to those isolated from other age groups. Also, a BMI above 30 was associated with enhanced adipogenic differentiation compared to cells isolated from individuals with a BMI below 25. Bone marrow MSCs were strongly induced to differentiate along both osteogenic and adipogenic lineages, whereas AT-MSCs predominantly differentiated into the chondrogenic lineage. Therefore, the type of regeneration required and variations among potential donors must be carefully considered when selecting MSCs for use in applied tissue engineering or cell therapy. PMID- 25823470 TI - Catching genomic rearrangements in the act: Integrating DNA breakage models and functional genomics data: (comment on DOI 10.1002/bies.201400174). PMID- 25823469 TI - Adipocyte hypoxia promotes epithelial-mesenchymal transition-related gene expression and estrogen receptor-negative phenotype in breast cancer cells. AB - The development of breast cancer is linked to the loss of estrogen receptor (ER) during the course of tumor progression, resulting in loss of responsiveness to hormonal treatment. The mechanisms underlying dynamic ERalpha gene expression change in breast cancer remain unclear. A range of physiological and biological changes, including increased adipose tissue hypoxia, accompanies obesity. Hypoxia in adipocytes can establish a pro-malignancy environment in breast tissues. Epidemiological studies have linked obesity with basal-like breast cancer risk and poor disease outcome, suggesting that obesity may affect the tumor phenotype by skewing the microenvironment toward support of more aggressive tumor phenotypes. In the present study, human SGBS adipocytes were co-cultured with ER positive MCF7 cells for 24 h. After co-culture, HIF1alpha, TGF-beta, and lectin type oxidized LDL receptor 1 (LOX1) mRNA levels in the SGBS cells were increased. Expression levels of the epithelial-mesenchymal transition (EMT)-inducing transcription factors FOXC2 and TWIST1 were increased in the co-cultured MCF7 cells. In addition, the E-cadherin mRNA level was decreased, while the N-cadherin mRNA level was increased in the co-cultured MCF7 cells. ERalpha mRNA levels were significantly repressed in the co-cultured MCF7 cells. ERalpha gene expression in the MCF7 cells was decreased due to increased HIF1alpha in the SGBS cells. These results suggest that adipocytes can modify breast cancer cell ER gene expression through hypoxia and also can promote EMT processes in breast cancer cells, supporting an important role of obesity in aggressive breast cancer development. PMID- 25823471 TI - Cribriform adenocarcinoma of the tongue and minor salivary gland: transoral robotic surgical resection. AB - BACKGROUND/AIMS: Cribriform adenocarcinoma of the tongue and minor salivary gland (CATMSG) is a rare, locally invasive, and poorly recognized tumor, typically occurring on the base of the tongue. This case report describes the previously unreported use of transoral robotic surgery (TORS) for the local resection of CATMSG in a novel location, the palatine tonsil, and leverages follow-up information to compare TORS to conventional surgical approaches. METHODS: We performed transoral radical tonsillectomy, limited pharyngectomy, and base-of tongue resection with staged left selective neck dissection. RESULTS: Tumor pathology revealed an infiltrating salivary gland carcinoma with perineural invasion and a histologically similar adenocarcinoma in 1 of 64 left neck lymph nodes. TORS was performed with no perioperative complications, and the patient was subsequently discharge on postoperative day 3 with a Dobhoff tube. Postoperatively, the Dobhoff tube was removed at 1 month, the patient was advanced to soft foods by mouth at 2 months, and 3-month positron emission tomography-computed tomography scan showed no evidence of distant metastases and evolving postsurgical changes in the left tonsillectomy bed. CONCLUSIONS: This case report highlights the use of TORS resection with minimal acute and long-term morbidity compared to conventional approaches for the resection of this rare, locally invasive salivary gland carcinoma in the palatine tonsil. PMID- 25823472 TI - Introducing robotic surgery into an endometrial cancer service--a prospective evaluation of clinical and economic outcomes in a UK institution. AB - BACKGROUND: We have assessed how the introduction of robotics in a publicly funded endometrial cancer service affects clinical and economic outcomes. METHODS: The study included 196 women. Costs were divided into those for wards, high dependency, staffing, theatres, pharmacy, blood products, imaging, pathology and rehabilitation. Capital depreciation was included. RESULTS: Prior to the introduction of robotics, 78/130 (60.0%) cases were performed open, compared to 17/66 (25.8%) afterwards (p < 0.0001). The median operative time increased 37 min (95% CI 17-55 min; p = 0.0002); the median blood loss was 55 ml lower (95% CI 0 150 ml; p = 0.0181); the stay was 2 days shorter (95% CI 1-3; p < 0.0001). Complications reduced from 64/130 (49.2%) to 19/66 (28.8%) (p = 0.0045). Costs reduced from L11 476 to L10 274 (p = 0.0065). Conversions for 'straight stick' surgery were 18.2% (14/77) compared to 0.0% (0/24) for robotics (p = 0.0164). CONCLUSIONS: Introducing robotics resulted in fewer laparotomies, shorter stays, fewer complications and lower costs. PMID- 25823473 TI - Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis. AB - C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis that serves as a direct regulator of the human leukocyte antigen class II pathway in antigen-presenting cells. These findings are a first step in coupling multiple sclerosis-associated genes to the regulation of the strongest genetic factor in multiple sclerosis, human leukocyte antigen class II. PMID- 25823475 TI - Magnetization transfer ratio measures in normal-appearing white matter show periventricular gradient abnormalities in multiple sclerosis. AB - In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken. The present study investigates this relationship in vivo using quantitative magnetic resonance imaging and compares the abnormalities between secondary progressive and relapsing remitting multiple sclerosis. Forty-three patients with relapsing remitting and 28 with secondary progressive multiple sclerosis, and 38 healthy control subjects were included in this study. T1-weighted volumetric, magnetization transfer and proton density/T2-weighted scans were acquired for all subjects. From the magnetization transfer data, magnetization transfer ratio maps were prepared. White matter tissue masks were derived from SPM8 segmentations of the T1-weighted images. Normal-appearing white matter masks were generated by subtracting white matter lesions identified on the proton density/T2 scan, and a two-voxel perilesional ring, from the SPM8 derived white matter masks. White matter was divided in concentric bands, each ~1-mm thick, radiating from the ventricles toward the cortex. The first periventricular band was excluded from analysis to mitigate partial volume effects, and normal-appearing white matter and lesion magnetization transfer ratio values were then computed for the 10 bands nearest to the ventricles. Compared with controls, magnetization transfer ratio in the normal-appearing white matter bands was significantly lower in patients with multiple sclerosis. In controls, magnetization transfer ratio was highest in the band adjacent to the ventricles and declined with increasing distance from the ventricles. In the multiple sclerosis groups, relative to controls, reductions in magnetization transfer ratio were greater in the secondary progressive multiple sclerosis compared with relapsing remitting multiple sclerosis group, and these reductions were greatest next to the ventricles and became smaller with distance from them. White matter lesion magnetization transfer ratio reductions were also more apparent adjacent to the ventricle and decreased with distance from the ventricles in both the relapsing remitting and secondary progressive multiple sclerosis groups. These findings suggest that in people with multiple sclerosis, and more so in secondary progressive than relapsing remitting multiple sclerosis, tissue structural abnormalities in normal-appearing white matter and white matter lesions are greatest near the ventricles. This would be consistent with a cerebrospinal fluid or ependymal mediated pathogenesis. PMID- 25823477 TI - How should unmatched otolaryngology applicants proceed? AB - OBJECTIVES/HYPOTHESIS: To determine the attitudes of otolaryngology residency program directors and chairpersons toward unmatched residency applicants, including whether a surgical internship or research year is preferred in considering repeat applicants. STUDY DESIGN: Cross-sectional survey. METHODS: Approval was obtained from the Colorado Multiple Institution Review Board. A 12 question Web-based survey was sent to otolaryngology residency program directors and chairpersons three times over a 6-week period. Responses collected from respondents were anonymous, with no identifying characteristics. RESULTS: Forty five percent of those contacted responded to the survey. The most commonly recommended course of action for an unmatched applicant was completion of a general surgery intern year (43%) or a year of research (31%). Program directors were more likely than chairpersons to recommend a year of research (P value 0.014). Ninety-seven percent of the respondents felt it was important or essential to obtain new letters of recommendation. Respondents ranked poor interview skills as the most common reason for applicants remaining unmatched (29%). CONCLUSION: Otolaryngology residency match is even more competitive for previously unmatched applicants. Unmatched applicants should be advised to proceed with either a research year or postgraduate year 1 general surgery year. Before applying again, applicants should obtain new letters of recommendation, and the importance of improving poor interviewing skills should be emphasized by advisors. LEVEL OF EVIDENCE: N/A. PMID- 25823476 TI - Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis. AB - The in vitro leishmanicidal activity of a series of imidazole-containing phthalazine derivatives 1-4 was tested on Leishmania infantum, Leishmania braziliensis and Leishmania donovani parasites, and their cytotoxicity on J774.2 macrophage cells was also measured. All compounds tested showed selectivity indexes higher than that of the reference drug glucantime for the three Leishmania species, and the less bulky monoalkylamino substituted derivatives 2 and 4 were clearly more effective than their bisalkylamino substituted counterparts 1 and 3. Both infection rate measures and ultrastructural alterations studies confirmed that 2 and 4 were highly leishmanicidal and induced extensive parasite cell damage. Modifications to the excretion products of parasites treated with 2 and 4 were also consistent with substantial cytoplasmic alterations. On the other hand, the most active compounds 2 and 4 were potent inhibitors of iron superoxide dismutase enzyme (Fe-SOD) in the three species considered, whereas their impact on human CuZn-SOD was low. Molecular modelling suggests that 2 and 4 could deactivate Fe-SOD due to a sterically favoured enhanced ability to interact with the H-bonding net that supports the antioxidant features of the enzyme. PMID- 25823478 TI - Pd/C-Catalyzed Cyclizative Cross-Coupling of Two ortho-Alkynylanilines under Aerobic Conditions: Synthesis of 2,3'-Bisindoles. AB - A palladium-catalyzed cyclizative cross-coupling of two o-alkynylanilines to 2,3' bisindoles under aerobic oxidative conditions was developed. Mechanistic studies suggested that the two catalytic cycles, namely the formation of 3-alkynylindoles 8 and their subsequent cyclization to bisindoles 5, are temporally separated. The aminopalladation of 3-alkynylindoles 8 occurred only after all the N,N-dialkyl-o alkynylanilines were consumed. The solid support (activated charcoal) played a crucial role in the second intramolecular aminopalladation process. PMID- 25823474 TI - Roles of microglia in brain development, tissue maintenance and repair. AB - The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease. PMID- 25823479 TI - Oral Health Knowledge of Pregnant Women on Pregnancy Gingivitis and Children's Oral Health. AB - OBJECTIVE: Pregnancy gingivitis and early childhood caries remain prevalent in Hong Kong. The aim of this study was to assess pregnant women's knowledge and beliefs related to pregnancy gingivitis and children's oral health. STUDY DESIGN: An outreach survey was carried out in a clinic that provided antenatal examination. A written oral health questionnaire related to pregnancy gingivitis and early childhood caries was administered to pregnant women. Of the 106 pregnant women who enrolled in the study, 100 completed the questionnaires. RESULTS: Among the 100 subjects, only 39% correctly identified that hormonal changes contribute to pregnancy gingivitis. Only 36% identified red and swollen gums as signs of gingivitis. Furthermore, 53% of the surveyed pregnant women were not sure about the amount of toothpaste to administer to a child aged 18 months to 5 years. Almost 50% assumed that a replanted avulsed tooth would probably not survive within a short extra-alveolar period of less than 60 minutes. CONCLUSION: Prenatal women generally lack knowledge of a common oral disease that occurs during pregnancy and of what constitutes adequate oral health care for children. Oral health care education should be implemented as part of a prenatal care program. PMID- 25823481 TI - Energy dispersive x-ray spectroscopy evaluation of demineralized human enamel after titanium tetrafluoride application. AB - OBJECTIVE: Evaluate the presence of a titanium dioxide layer after application of titanium tetrafluoride on human permanent tooth enamel. STUDY DESIGN: The sample consisted of unerupted third molars. After the removal of the roots, each tooth was mesiodistally divided into 2 fragments, one reserved for the experimental group and the other for the control group. Before the treatments the fragments were artificially demineralized. The experimental group (n=5) received an application of 4% titanium tetrafluoride, for one minute and the control group (n=5) did not receive any treatment. The samples were sputter-coated with a 20 30nm gold layer as the energy dispersive x-ray spectrometer analysis was carried out in a scanning electron microscope and the results were descriptively analyzed. RESULTS: The titanium dioxide layer was present on all experimental samples with a titanium peak varying between 6.82 and 26.37%. This layer was not found in the control group. Fluoride and calcium fluoride precipitates were present in the samples treated with titanium tetrafluoride. CONCLUSION: Titanium dioxide layer was formed after one titanium tetrafluoride application, but it was not uniform. Further studies should be carried out so that both the morphology and thickness of such layers can be better understood. PMID- 25823480 TI - Efficacy and tolerance of papain gel with conventional drilling method: a clinico microbiological study. AB - BACKGROUND: Conventional methods of caries removal are commonly associated with pain, fear and discomfort. Chemomechanical methods were introduced to instill a positive dental attitude. Agents like GK-101, Caridex, Carisolv did not prove effective alternatives owing to their high cost, need of special instruments and taste of chlorine. A new chemomechanical agent, Papacarie(r), has been introduced to overcome these deficiencies. OBJECTIVE: This study was aimed to compare the effectiveness and tolerance of Papacarie(r) with the conventional method. METHOD: 25 children with at least two primary teeth with broad cavitated occlusal or cervical lesion were selected. One carious tooth from each patient was randomly treated with each of Papacarie(r) and conventional drilling method, one after the other. Time taken for caries excavation, child's pain perception, change in anxiety levels, microbial flora and child's preference of treatment were recorded separately for both the methods. RESULT: Although the mean time taken for caries removal by the Papacarie(r) method was slightly longer (P?0.05) but it led to reduction in pain and anxiety (p<0.05). The viable bacterial counts were significantly reduced by either of the two methods (P <0?0001). More patients preferred Papacarie(r) over conventional method of treatment (P<0.05). CONCLUSION: Papacarie(r) method seems to be a better alternative to conventional method of caries removal. PMID- 25823482 TI - Salivary Cortisol Levels and its Implication on Behavior In Children with Autism during Dental Treatment. AB - The aim of the study was to estimate the diurnal variations of salivary cortisol in children with autism and healthy children and it's implication on behavior during non-invasive dental procedures. STUDY DESIGN: 50 children with autism and 50 healthy children in the age group between 6 to 12 years of both genders with the need for dental treatment were included in the study. Whole unstimulated saliva was collected from them during early hours of the day and during evenings for 2 consecutive days . The collected saliva was then subjected to electrochemiluminescence assay . Minimum invasive dental procedures like hand scaling, pit and fissure sealants and glass ionomer cement restorations were performed for the participants each time after the saliva sample collection and their behavior during the procedures was rated using Frankl's Behavior Rating Scale. RESULTS: Significant correlation was seen between cortisol levels and behavior in children with autism. As cortisol levels increased in children with autism, behavior worsened and as the cortisol levels decreased they showed positive behaviour. CONCLUSION: Cortisol acts as a stress marker and studying the diurnal variations of salivary cortisol can help us in attaining better knowledge about the behavior pattern and thereby assist us in modifying the behavior modification procedures and treatment planning in this group of special children. PMID- 25823483 TI - Effect of ethanol wet bonding technique on the durability of resin- dentin bond with contemporary adhesive systems. AB - OBJECTIVE: To evaluate the effect of ethanol wet bonding technique on the immediate and long term bond strength of simplified etch and rinse adhesive systems to dentin. STUDY DESIGN: 96 extracted human permanent molars were ground to expose the flat dentin surface. The teeth were divided into four groups (n=24) according to the adhesives used, either Tetric N Bond or Solobond M and bonding techniques i.e. water wet bonding or ethanol wet bonding (EWB). Composite cylinder was bonded to each specimen using the respective adhesive technique. Ten samples from each group were then tested immediately for shear bond strength evaluation and two samples for SEM analysis. The remaining samples (12) were tested after 6 month storage in distilled water. RESULTS: Upon immediate testing, there was no significant difference in the mean shear bond strength of the groups regardless of the bonding technique or adhesive used. The bond strength fell dramatically in the water wet bonded specimens after 6 months water storage, while the bond strength of both the adhesives was maintained when EWB technique was used. SEM observation revealed good interfacial adaptation in EWB groups even after six months. CONCLUSION: For both simplified etch and rinse adhesives used, ethanol wet bonding technique led to significant preservation of the resin dentin bond over 6 months. PMID- 25823484 TI - Bond strength of different restorative materials to light-curable mineral trioxide aggregate. AB - The aim of the present study was to evaluate the bond strength of methacrylate based (MB) composites, silorane-based (SB) composites, and glass-ionomer cement (GIC) in comparison to TheraCal and to compare those findings with the reference pulp capping material (MTA). STUDY DESIGN: A total of 90 acrylic blocks were prepared. Each of the blocks were prepared as 15 mm high and 10 mm diameter and the blocks had a 2 mm high and a 5 mm diameter central hole. In 45 of the samples, the holes were fully filled with TheraCal and in the other 45 samples, the holes were fully filled with MTA. The TheraCal and the MTA samples were randomly divided into 3 subgroups of 15 specimens each: Group-1: Methacrylate based (MB) composite; Group-2: Silorane-based (SB) composite; and Group-3: Glass ionomer cement (GIC). For the shear bond strength (SBS) test, each block was secured in a universal testing machine. After the SBS test, the fractured surfaces were examined under a stereomicroscope at *25 magnification. RESULTS: The analysis of variance that compared the experimental groups revealed the presence of significant differences among the groups (P < 0.001). The highest (19.3 MPa) and the lowest (3.4 MPa) bond strength value were recorded for the MB composite-TheraCal and the GIC-TheraCal, respectively.There were significant differences in bond strength between the TheraCal and the MTA groups for the MB composite subgroup (P < 0.001) and the SB composite subgroup (P < 0.05); however, there was no significant difference in bond strength for the GIC subgroup (P ? 0.05). Conlusions: The results from this in vitro study suggest that the new pulp capping material, known as light-curable MTA, showed clinically acceptable and higher shear bond scores compared to MTA when used with the MB composite. PMID- 25823485 TI - Effect of three different pastes on remineralization of initial enamel lesion: an in vitro study. AB - OBJECTIVE: Dental caries in enamel is unique as enamel is both acellular and avascular. Fluoride is one of the most effective remineralizing agents in caries prevention. The purpose of the study was to assess whether nano-hydroxyapatite and CPP-ACP can be used as an alternative to fluoride for remineralization of early carious lesions. STUDY DESIGN: Initial artificial carious lesions were prepared in enamel with demineralization solution. The treatment materials used as remineralizing agents were Nano-hydroxyapatite (10%), CPP - ACP (10%), NaF (1000 ppm) and Deionized water (negative control). Surface microhardness (SMH) measurements were performed before/after demineralization and after 3, 6, 9 and 12 days of pH cycling and the percentage surface microhardness recovery (%SMHR) was calculated. The specimens were then examined by scanning electron microscope. RESULTS: Percentage surface microhardness recovery of nano-hydroxyapatite and fluoride was significantly greater than CPP - ACP and negative control. There was no significant difference of %SMHR between n-HA and fluoride at different time periods in the pH cycling. SEM analysis revealed n-HA particles were deposited on the demineralized enamel surface which formed a new surface layer. When observed under SEM CPP - ACP failed to show any significant surface remineralization while surface globular crystal depositions with multiple discrete porosities were evident with fluoride. CONCLUSION: It was concluded that nano-hydroxyapatite and fluoride had the potential to remineralize initial enamel lesions. CPP - ACP can be used as an effective adjunct to fluoride therapy but cannot be used as an alternative to fluoride. PMID- 25823486 TI - A spectroscopic and surface microhardness study on enamel exposed to beverages supplemented with lower iron concentrations. AB - OBJECTIVES: This study aimed to compare the in vitro mineral loss and surface microhardness (SMH) changes in human enamel specimens following supplementation of acidic carbonated beverages with low iron concentrations than when treated without. STUDY DESIGN: 180 enamel blocks each from primary and permanent teeth were prepared and equally subdivided (n=10) for their respective treatments in Group 1 (Coca Cola and Sprite without iron supplementation) and Group 2 (beverages supplemented with 2/5 mmol/L FeSO4.7H2O). Following initial SMH estimation, the blocks were subjected to 3 treatment cycles of 5/20 minute incubation periods, equally interspaced by a 5-min treatment in artificial saliva. The calcium and phosphate released after each cycle were analyzed spectrophotometrically and the final SMH was recorded. The results were tested using student's T test, One-way ANOVA and Kruskal Walli's test (p<0.05). RESULTS: Two and five mmol/L FeSO4.7H2O supplementation produced a highly significant SMH change and calcium and phosphate reduction than when treated without (p<.0005). Both the enamel specimens showed similar patterns of mineral loss and SMH reduction, with pronounced effects in the twenty minute incubation cycles. CONCLUSION: Our results suggest that 2 mmol/L FeSO4.7H2O supplementation to acidic beverages is beneficial in reducing mineral loss and preserving surface microhardness of human enamel. PMID- 25823487 TI - Oral manifestations of neurofibromatosis type 1 in children with facial plexiform neurofibroma: report of three cases. AB - Neurofibromatosis type 1 (NF1) is a common autosomal genetic disorder with a prevalence of 1 in 3,000 births. NF1 is a complex syndrome characterized by many abnormalities and may affect all organ systems. Oral manifestations of NF1 occur frequently, but reports including NF1 children with facial plexiform neurofibromas and oral alterations are scant. Facial plexiform neurofibroma may cause asymmetry, disfigurement and usually arises from the trigeminal nerve. The aim of this paper is to to report three pediatric NF1 cases with facial plexiform neurofibroma presenting with oral manifestations, which were evaluated clinically and radiographically, and also to briefly review the literature. Patients presented with changes in the oral soft tissues, jaws, and teeth ipsilateral to the tumor. PMID- 25823488 TI - Treatment considerations in hutchinson-gilford progeria syndrome: a case report. AB - Hutchinson-Guilford progeria syndrome is an extremely rare condition classified as one of the premature ageing syndromes. This case presents a 16-year-old Israeli female patient, suffering from a variant of Hutchinson-Guilford progeria with a history of treatment with oral biphosphnates. The patient presented with typical cranial and facial features of the syndrome including delayed teeth eruption and root development probably due to insufficient jaw growth and severs retrognatic position of the maxilla and mandible. Orthodontic treatment considerations are described along with those required in light of the previous treatment by oral biphosphonates.All primary teeth were extracted in three appointments while creating as minimal trauma as possible to the surrounding tissue and alveolar bone. For now, the patient refuses to begin the orthodontic treatment course. There are no limitations to conduct any dental procedures in progeria patients, however, extreme caution must be exercised during oral surgery due to the inelasticity of tissues and dermal atrophy. Orthodontic procedure commencement should be early enough to manage the delayed development and eruption of teeth. Patients taking oral biphosphonates should be advised of this potential complication. If orthodontic treatment is considered appropriate, plans should be assessed and modified to include compromises. PMID- 25823489 TI - Clinical Usefulness of Proseal Laryngeal Mask Airway for Anesthesia during Dental Procedures in Children. AB - AIM: Although the Proseal laryngeal mask airway (PLMA) has been widely used in anesthesia, little is known about its clinical effectiveness during dental procedures. We describe the clinical feasibility of the PLMA for managing airways in the field of pediatric dentistry. . STUDY DESIGN: We reviewed the medical records of children who underwent airway management with the use of the PLMA from January 2011 to December 2012 at an outpatient facility at Seoul National Dental University Hospital. RESULTS: During the study period, the airways of 19 children were managed with the PLMA for dental procedures. During its placement, blood pressure and heart rate were stably maintained. There were no interruptions of the dental procedures. None of the children experienced oxygen desaturation or ventilation difficulty. In one patient, the PLMA was dislodged for a short time, but the problem was easily solved with repositioning. After transferring to the post-anesthetic care unit, there were no incidences of oxygen desaturation or vomiting. All of the children were discharged from the hospital without complications. CONCLUSION: The PLMA can be successfully used in airway management during dental treatment in children. PMID- 25823491 TI - Orthodontic Treatment of Skeletal Class II Adolescent with Anterior Open Bite using Mini-Screws and Modified Palatal Anchorage Plate. AB - This article presents a non-extraction orthodontic treatment case using mini screws and a modified palatal anchorage plate (MPAP) to intrude the maxillary posterior teeth, and distalize the whole arch dentition and control the extrusion of the maxillary posterior dentition during distalization. PMID- 25823490 TI - Maxillary dental anomalies in patients with cleft lip and palate: a cone beam computed tomography study. AB - OBJECTIVE: To compare the frequency of maxillary dental anomalies in patients affected by unilateral (UCLP) and bilateral (BCLP) cleft lip with palate and to determine whether statistical differences were present or not between cleft and normal sides in UCLP group by using cone beam computed tomography (CBCT). In addition, the frequency of those dental anomalies was compared with previous studies presenting the same population without cleft Study Design: Fifty non syndromic patients affected by UCLP (28 patients) and BCLP (22 patients) were selected for analysis of dental anomalies by means of CBCT. The frequency of maxillary dental anomalies including tooth agenesis, microdontia of lateral incisor, ectopic eruption and impaction of canine and supernumerary tooth were examined. Pearson chi-square and Fisher's exact tests were performed for statistical comparisons. RESULTS: All patients affected by UCLP and BCLP were found to have at least one maxillary dental anomaly. The most frequently observed dental anomaly was tooth agenesis (92.5% and 86.4%, respectively) in UCLP and BCLP groups. Tooth agenesis and canine impaction were observed more commonly in the cleft side (75.0% and 35.7%, respectively) than in the normal side (57.1% and 14.3%, respectively) in UCLP group (p?0.05). All dental anomalies were found to be higher in both cleft groups than in general populations not affected by cleft. CONCLUSION: Since patients affected by UCLP and BCLP had at least one dental anomaly and higher dental anomaly frequency as compared to patients without cleft, those patients should be examined carefully prior to orthodontic treatment. PMID- 25823492 TI - Synthesis of polybenzoquinolines as precursors for nitrogen-doped graphene nanoribbons. AB - Graphene nanoribbons (GNRs) represent promising materials for the next generation of nanoscale electronics. However, despite substantial progress towards the bottom-up synthesis of chemically and structurally well-defined all-carbon GNRs, strategies for the preparation of their nitrogen-doped analogs remain at a nascent stage. This scarce literature precedent is surprising given the established use of substitutional doping for tuning the properties of electronic materials. Herein, we report the synthesis of a previously unknown class of polybenzoquinoline-based materials, which have potential as GNR precursors. Our scalable and facile approach employs few synthetic steps, inexpensive commercial starting materials, and straightforward reaction conditions. Moreover, due to the importance of quinoline derivatives for a variety of applications, the reported findings may hold implications across a diverse range of chemical and physical disciplines. PMID- 25823493 TI - Contralesional thalamic surface atrophy and functional disconnection 3 months after ischemic stroke. AB - BACKGROUND: Remote structural and functional changes have been previously described after stroke and may have an impact on clinical outcome. We aimed to use multimodal MRI to investigate contralesional subcortical structural and functional changes 3 months after anterior circulation ischemic stroke. METHODS: Fifteen patients with acute ischemic stroke had multimodal MRI imaging (including high resolution structural T1-MPRAGE and resting state fMRI) within 1 week of onset and at 1 and 3 months. Seven healthy controls of similar age group were also imaged at a single time point. Contralesional subcortical structural volume was assessed using an automated segmentation algorithm in FMRIB's Integrated Registration and Segmentation Tool (FIRST). Functional connectivity changes were assessed using the intrinsic connectivity contrast (ICC), which was calculated using the functional connectivity toolbox for correlated and anticorrelated networks (Conn). RESULTS: Contralesional thalamic volume in the stroke patients was significantly reduced at 3 months compared to baseline (median change -2.1%, interquartile range [IQR] -3.4-0.4, p = 0.047), with the predominant areas demonstrating atrophy geometrically appearing to be the superior and inferior surface. The difference in volume between the contralesional thalamus at baseline (mean 6.41 ml, standard deviation [SD] 0.6 ml) and the mean volume of the 2 thalami in controls (mean 7.22 ml, SD 1.1 ml) was not statistically significant. The degree of longitudinal thalamic atrophy in patients was correlated with baseline stroke severity with more severe strokes being associated with a greater degree of atrophy (Spearman's rho -0.54, p = 0.037). There was no significant difference between baseline contralesional thalamic ICC in patients and control thalamic ICC. However, in patients, there was a significant linear reduction in the mean ICC of the contralesional thalamus over the imaging time points (p = 0.041), indicating reduced connectivity to the remainder of the brain. CONCLUSIONS: These findings highlight the importance of remote brain areas, such as the contralesional thalamus, in stroke recovery. Similar methods have the potential to be used in the prediction of stroke outcome or as imaging biomarkers of stroke recovery. PMID- 25823494 TI - Case formulation and the therapeutic alliance in contemporary problem-solving therapy (PST). AB - In addition to providing psychoeducation and sharing clinical explanations and treatment goals, case formulation serves as a potential mechanism by which therapists may facilitate an alliance with their patients. This article illustrates how a case formulation shared with a patient early in the process of contemporary problem-solving therapy (PST) may yield both a road map to treatment and a means to build and adapt a therapeutic alliance based on patient attributes. We provide a description of a clinical case in which PST was carried out with a woman who, in the midst of alcohol recovery, experienced symptoms of anxiety, depression, and binge eating. PMID- 25823495 TI - Response to Disodium Etidronate Treatment in Three Siblings with Pulmonary Alveolar Microlithiasis. AB - Pulmonary alveolar microlithiasis (PAM) is a rare chronic genetic lung disease in childhood with no proven therapy. It is characterized by the deposition of calcium phosphate microliths within the alveolar air spaces. The effect of disodium etidronate (DE) treatment on PAM is controversial. We report 3 siblings (an 11-year-old boy and 4-year-old twin girls) with PAM diagnosed by chest X-ray, thoracic high-resolution computed tomography, technetium-99m bone scan and bronchoalveolar lavage fluid findings. After the administration of DE (200 mg/day) for a 1-year period, 2 siblings showed radiological improvement, while 1 sibling did not. No drug side effects were observed within the treatment period. PMID- 25823496 TI - The algorithmic level is the bridge between computation and brain. AB - Every scientist chooses a preferred level of analysis and this choice shapes the research program, even determining what counts as evidence. This contribution revisits Marr's (1982) three levels of analysis (implementation, algorithmic, and computational) and evaluates the prospect of making progress at each individual level. After reviewing limitations of theorizing within a level, two strategies for integration across levels are considered. One is top-down in that it attempts to build a bridge from the computational to algorithmic level. Limitations of this approach include insufficient theoretical constraint at the computation level to provide a foundation for integration, and that people are suboptimal for reasons other than capacity limitations. Instead, an inside-out approach is forwarded in which all three levels of analysis are integrated via the algorithmic level. This approach maximally leverages mutual data constraints at all levels. For example, algorithmic models can be used to interpret brain imaging data, and brain imaging data can be used to select among competing models. Examples of this approach to integration are provided. This merging of levels raises questions about the relevance of Marr's tripartite view. PMID- 25823497 TI - Aboriginal and Torres Strait Islander community governance of health research: Turning principles into practice. AB - PROBLEM: Gaps exist in researchers' understanding of the 'practice' of community governance in relation to research with Aboriginal and Torres Strait Islander peoples. DESIGN: We examine Aboriginal community governance of two rural NSW research projects by applying principles-based criteria from two independent sources. SETTING: One research project possessed a strong Aboriginal community governance structure and evaluated a 2-year healthy lifestyle program for children; the other was a 5-year cohort study examining factors influencing the mental health and well-being of participants. KEY MEASURES FOR IMPROVEMENT: The National Health and Medical Research Council of Australia's 'Values and ethics: guidelines for ethical conduct in Aboriginal and Torres Strait Islander research' and 'Ten principles relevant to health research among Indigenous Australian populations' described by experts in the field. STRATEGIES FOR CHANGE: Adopt community-based participatory research constructs. Develop clear governance structures and procedures at the beginning of the study and allow sufficient time for their establishment. Capacity-building must be a key component of the research. Ensure sufficient resources to enable community engagement, conduct of research governance procedures, capacity-building and results dissemination. EFFECTS OF CHANGE: The implementation of governance structures and procedures ensures research addresses the priorities of the participating Aboriginal and Torres Strait Islander communities, minimises risks and improves outcomes for the communities. LESSONS LEARNT: Principles-based Aboriginal and Torres Strait Islander community governance of research is very achievable. Next steps include developing a comprehensive evidence base for appropriate governance structures and procedures, and consolidating a suite of practical guides for structuring clear governance in health research. PMID- 25823498 TI - Does Dopamine Replacement Medication Affect Postural Sequence Learning in Parkinson's Disease? AB - Deficits in sequence-specific learning (SSL) may be a product of Parkinson's disease (PD) but this deficit could also be related to dopamine replacement. The purpose of this study was to determine whether dopamine replacement affected acquisition and retention of a standing Continuous Tracking Task in individuals with PD. SSL (difference between random/repeated Root Mean Square Error across trials) was calculated over 2 days of practice and 1 day of retention for 4 groups; 10 healthy young (HY), 10 healthy elders, 10 individuals with PD on, 9 individuals with PD off their usual dosage of dopamine replacement. Improvements in acquisition were observed for all groups; however, only the HY demonstrated retention. Therefore, age appeared to have the largest effect on SSL with no significant effect of medication. Additional research is needed to understand the influence of factors such as practice amount, task difficulty, and dopamine replacement status on SSL deficits during postural tasks. PMID- 25823499 TI - Long-term outcome of endoscopic radiofrequency ablation for ingrowth thyroglossal duct cyst. AB - AIMS: To evaluate the effectiveness and safety of endoscopic radiofrequency (RF) ablation to treat ingrowth thyroglossal duct cysts (TGDCs). METHODS: Between September 2008 and October 2013, 9 patients with ingrowth TGDCs underwent endoscopic RF ablation at our hospital. Their operative time, blood loss, time until recovery of normal diet, postoperative hospitalization time, and recurrence were retrospectively analyzed. RESULTS: In the study, 8 patients underwent an RF procedure of less than 60 min. All patients resumed a normal diet within 48 h after the operation. The operative blood loss was <10 ml in 2 patients, and between 10 and 20 ml in 7 patients. The postoperative pain value was 2 (n = 2) and 3 or 4 (n = 7). Seven patients were discharged home on postoperative day 2 or 3, and 2 patients on postoperative day 4. The postoperative follow-up period was from 14 to 32 months. Only 1 patient suffered recurrence and underwent a modified Sistrunk procedure as a remedy. All patients reported complete resolution of the symptoms in their last follow-up. CONCLUSIONS: Endoscopic RF ablation can be considered the preferred choice for treating ingrowth TGDCs because of minimal morbidity and rapid postoperative recovery. However, for lesions involving complicated branches, the modified Sistrunk procedure may be necessary. PMID- 25823500 TI - Advantages of fecal lactoferrin measurement during granulocyte and monocyte adsorptive apheresis therapy in ulcerative colitis. AB - BACKGROUND: Fecal lactoferrin has been introduced as a useful tool for the diagnosis and monitoring of inflammatory bowel disease (IBD). The aim of this study was to assess if fecal lactoferrin can be employed to predict or estimate the effect of granulocyte and monocyte adsorptive apheresis (GMA) in ulcerative colitis (UC). METHODS: This was a prospective study involving 21 patients with UC. Patients with moderately-to-severely active UC who were scheduled to undergo GMA were recruited. Changes in fecal lactoferrin concentration were compared between the GMA-responder and -nonresponder groups. RESULTS: In the GMA-responder group, fecal lactoferrin significantly increased 1 week after the introduction of GMA and then significantly decreased after GMA sessions. Fecal lactoferrin concentrations were significantly higher in the GMA-responder group than in the GMA-nonresponder group at 1 and 2 weeks after the introduction of GMA. Multivariate logistic regression analysis revealed that fecal lactoferrin concentration 1 week after the introduction of GMA was the most contributing factor for the effectiveness of GMA in patients with UC. CONCLUSIONS: In the GMA responder group, fecal lactoferrin concentration significantly increased 1 week after the introduction of GMA. Fecal lactoferrin may be beneficial for predicting clinical response of GMA in patients with UC at an early stage of GMA treatment. PMID- 25823502 TI - Semi-automatic cone beam CT segmentation of in vivo pre-clinical subcutaneous tumours provides an efficient non-invasive alternative for tumour volume measurements. AB - OBJECTIVE: To evaluate the feasibility and accuracy of using cone beam CT (CBCT) scans obtained in radiation studies using the small-animal radiation research platform to perform semi-automatic tumour segmentation of pre-clinical tumour volumes. METHODS: Volume measurements were evaluated for different anatomical tumour sites, the flank, thigh and dorsum of the hind foot, for a variety of tumour cell lines. The estimated tumour volumes from CBCT and manual calliper measurements using different volume equations were compared with the "gold standard", measured by weighing the tumours following euthanasia and tumour resection. The correlation between tumour volumes estimated with the different methods, compared with the gold standard, was estimated by the Spearman's rank correlation coefficient, root-mean-square deviation and the coefficient of determination. RESULTS: The semi-automatic CBCT volume segmentation performed favourably compared with manual calliper measures for flank tumours <=2 cm(3) and thigh tumours <=1 cm(3). For tumours >2 cm(3) or foot tumours, the CBCT method was not able to accurately segment the tumour volumes and manual calliper measures were superior. CONCLUSION: We demonstrated that tumour volumes of flank and thigh tumours, obtained as a part of radiation studies using image-guided small-animal irradiators, can be estimated more efficiently and accurately using semi-automatic segmentation from CBCT scans. ADVANCES IN KNOWLEDGE: This is the first study evaluating tumour volume assessment of pre-clinical subcutaneous tumours in different anatomical sites using on-board CBCT imaging. We also compared the accuracy of the CBCT method to manual calliper measures, using various volume calculation equations. PMID- 25823501 TI - Evolutionary dynamics of metazoan TRP channels. AB - Transient receptor potential (TRP) channels are unusual among cation channels because of their diverse cation selectivities and activation mechanisms. TRP channels thus play major roles in various sensory perceptions by functioning as multimodal signal integrators. Some TRP subfamily members are also implicated in acute and chronic pain and inflammation. So far, most TRP channel studies have been targeted to human and model organisms within a limited evolutionary context. Classification of TRP channels in various animal genomes has revealed extensive gene gain and loss events across animal species. Furthermore, the chemical activation profiles of some orthologous TRP channels were different between species such as human and mouse. Amino acid substitutions must underlie such differences, and the crucial amino acid residues have been identified in some cases. These changes represent the evolution of TRP channels at the amino acid sequence level. There is also evidence that TRP channels have obtained species diversity through alternative splicing and possibly cis-regulatory element mutations. All of the above demonstrate the dynamic and plastic evolutionary history of metazoan TRP channels at multiple levels, possibly in conjunction with the specific habitats and life histories of individual species. PMID- 25823503 TI - Eukaryotic initiation factor 3C silencing inhibits cell proliferation and promotes apoptosis in human glioma. AB - Eukaryotic initiation factor 3, subunit c (eIF3c), an oncogene overexpressed in human cancers, plays an important role in cell tumorigenesis and proliferation. However, studies assessing its function in gliomas are scarce. The present study evaluated for the first time, the role of eIF3c in gliomas. Immunohistochemistry was carried out to assess eIF3c expression in 95 human glioma samples and normal brain tissues. Then, the eIF3c mRNA levels were detected in tumor and normal brain specimens by quantitative RT-PCR. In addition, eIF3c mRNA levels were assessed in four glioma cell lines (U87, U251, A172 and U373) by semi quantitative RT-PCR. The RNA interference (RNAi) technology was employed to knock down the eIF3c gene in the U251 cells. Western blot analysis, BrdU assay and flow cytometry were used to measure eIF3c protein levels, cell proliferation, cell apoptosis and cell cycle, respectively. The eIF3c protein was overexpressed in the human glioma specimens. In agreement, the eIF3c mRNA expression levels were significantly higher in the human glioma tissues compared with the normal brain samples (P<0.0001). In addition, eIF3c mRNA was detected in all the glioma cell lines. Silencing the eIF3c gene in the U251 cells by RNAi significantly suppressed cell proliferation (P<0.01) and increased apoptosis (P<0.01). Finally, a stark decrease was observed in the G1 phase cell number (P<0.01), while the S and G2 phase cells were significantly increased (P<0.01) after eIF3c knockdown. These findings suggest that eIF3c is overexpressed in human gliomas and essential for their proliferation and survival. Therefore, inhibiting eIF3c expression may constitute an effective therapy for human glioma. PMID- 25823504 TI - Timing of cholecystectomy in acute biliary pancreatitis: is it still reasonable to wait? AB - BACKGROUND: Acute gallstone-related pancreatitis is a potentially life threatening condition, and its adequate therapy is represented by cholecystectomy. The aim of this study was to analyze the best surgical strategy, and the optimal timing. METHODS: All cases of acute pancreatitis of biliary origin occurred between January 2007 and December 2013 in Gradenigo Hospital (Turin, Italy) undergone to a surgical procedure, were reviewed. Patients were divided in two groups, based on the timing of cholecystectomy, and compared. RESULTS: Out of 2233 cholecystectomies performed in the mentioned time interval, we have identified 79 patients that fulfill the selection criteria. 24 patients were treated with an index-stay procedure, while 55 with a delayed approach. Length of stay was significantly lower in patients that underwent to an early laparoscopic cholecystectomy (9 vs. 13 days, P=0.003), while no differences were found in terms of length of intervention, intraoperative complications, postoperative stay and mortality. Patients treated with delayed surgery had a 28.6% recurrence rate of acute pancreatitis, with an odds ratio of 10.28 (P=0.02). CONCLUSIONS: Early laparoscopic cholecystectomy should be performed in suitable patients in the index admission, reducing overall risks, avoiding or at least minimizing recurrencies, and rationalizing the scarce economic resources. PMID- 25823505 TI - A Modified Nerve-Sparing Panhysterectomy for Benign Uterine Diseases: Techniques and Evaluation of Postoperative Pelvic Dysfunctions. AB - OBJECTIVE: To describe a modified nerve-sparing panhysterectomy and to investigate the feasibility and impact of this nerve-sparing technique in improving postoperative pelvic visceral dysfunctions of benign uterine disease patients. METHODS: From January 2008 to January 2010, a total of 300 patients diagnosed with benign uterine diseases at the Second Affiliated Hospital of Nantong University were enrolled. Of those, 150 randomly selected patients underwent modified panhysterectomy (research group), while the other 150 patients underwent conventional panhysterectomy (control group). The surgery-related parameters, including operation time, intraoperative blood loss, length of hospital stay, postoperative indwelling catheter time, and first voiding and defecation time were compared between the two groups. The extent of nerve damage in both groups was examined using the nerve-specific marker S-100 via immunohistochemistry. Besides, postoperative assessments of bladder and bowel functions were conducted within 1 year after the operation. RESULTS: The surgery related parameters in the two groups showed no significant difference (p > 0.05). Immunohistochemistry results showed significantly reduced damage of the nerves in the research group. We also found a better bladder and bowel function in the research group (p < 0.05) and in younger patients (p < 0.05) compared with that in the control group. Recovery trends of the bladder and bowel function were found in both groups (chi(2) = 7.512, p = 0.006 in the research group; chi(2) = 7.299, p = 0.007 in the control group). CONCLUSION: Modified panhysterectomy for benign uterine diseases seems feasible and safe, with the main advantage of improving postoperative urocystic and rectal dysfunctions through the preservation of the pelvic autonomic nerves. PMID- 25823507 TI - Evaluation of Blood Alcohol Concentrations after Oral Administration of a Fixed Combination of Thyme Herb and Primrose Root Fluid Extract to Children with Acute Bronchitis. AB - BACKGROUND: The application of alcohol-containing medicinal products to children has been a subject of discussion for many years. A safety threshold of 0.1250/00 blood alcohol concentration following the administration of a single dose has been recommended by the European Medicines Agency.The aim of this clinical study was to prove the safety of administering a fixed combination of thyme herb and primrose root fluid extract (Bronchicum((r)) Elixir) containing 4.9% ethanol. METHODS: The herbal drug was administered for a period of 7-9 days to 16 children (ages 1-12 years) suffering from acute bronchitis for <= 48 h. After 3-5 days, a blood sample was taken 45 min (children >= 5 years: also 0 and 90 min) after application of the drug. The efficacy was assessed using the Bronchitis Severity Score. Global efficacy and tolerability were rated by the investigator and patients. RESULTS: All measured blood ethanol concentrations were below the threshold (mean value after 45 min: 0.0029 +/- 0.00570/00 and after 90 min: 0.0051 +/- 0.00780/00). The Bronchitis Severity Score decreased from 6.6 +/- 1.0 to 0.9 +/- 1.6 points. Global efficacy was assessed as "very good" and "good" in 60% (investigator) and 80% (patients) of cases. Global tolerability was rated as "very good" and "good" in more than 90% of cases. CONCLUSION: In conclusion, oral administration of the drug containing 4.9% ethanol to children (age 1-12 years) demonstrated a favourable risk/benefit ratio of the drug. PMID- 25823508 TI - Tricyclic Neovibsanin Scaffold (TCNS) as an Effective Antidepressant Agent. AB - Neovibsanin type natural products were found to display neurite outgrowth activity in PC12 cells. This suggests that such type of compounds could be promising candidates for the development of novel therapeutic agents to treat neurological diseases. In the present study rats after chronic mild stress (CMS) were treated with tricyclic neovibsanin scaffold (TCNS) to study its effect on depression. The results revealed that 15 mg/kg doses of TCNS reduced the duration of immobility in CMS model of depression. It led to a significant increase in neurite outgrowths which increased the synaptic and structural plasticity of neurons. Treatment with TCNS decreased the levels of MAO-A and caspase-3 expression both of which were found to be higher in CMS. TCNS also led to an increase in expression of heat shock protein 70 (Hsp70) in the hippocampus. These findings suggest that TCNS possesses antidepressant activity in CMS model of depression. Therefore the relief in depression by TCNS may be due to suppression of MAO-A expression and the apoptosis cascade by increased expression of Hsp70. PMID- 25823509 TI - Toxicity Study of a Self-nanoemulsifying Drug Delivery System Containing N-methyl pyrrolidone. AB - Recently within the lipid based formulation category, Self-nanoemulsifying drug delivery system (SNEDDS) has received considerable attention in the enhancement of bioavailability of poorly water-soluble drugs. Self-emulsifying formulation should have good solvent properties to allow appropriate solubility of the drug in the formulation. Drug incorporated in the formulation should also be readily dissolved as clear and monophasic liquid at ambient temperature when introduced to aqueous phase. N-methyl pyrrolidone (NMP) is one of the main pharmaceutical cosolvents and is a solubilizing excipient used in parenteral and oral medications. Marketed Leuprolide acetate (Sanofi-aventis, Quebec, Canada) is formulated as a solution composed of 55-66% NMP and 34-45% poly(DL-lactide-co glycolide). Self-emulsifying oral formulation of fenofibrate containing NMP as solubilizer has been patented. Based on these reports we successfully developed SNEDDS formulation using NMP as cosolvent and found ~ 4 fold improvement in apparent permeability coefficient of model drug. To ensure the safety of the developed SNEDDS formulation, in the present study we further investigated its toxicity studies in mice and evaluated for various parameter. From the results it can be concluded that oral administration of SNEDDS formulation containing NMP did not exhibit significant toxicity in mice and further detail toxicity study is required so as to ensure the safety of this system in oral drug delivery. PMID- 25823510 TI - Participants' Perceptions of a Violence Prevention Curriculum for Middle School Students: Was It Relevant and Useful? AB - School-based youth violence prevention programs, particularly those focused on middle school students, have generally had limited effects that are often not sustained over time. Although many interventions focus on teaching social cognitive skills, few studies have explored the extent to which students master these skills, actually use them, and find them effective in dealing with problem situations. This study examined these issues based on interviews with 141 students attending one county and two urban middle schools in classrooms where the Second Step violence prevention program had been implemented. We coded interviews to assess participants' general reactions to the interventions, use of skills, and effectiveness of skills. We also asked participants to describe outcomes they experienced when they used specific skills taught in the intervention in response to problem situations. Participants had generally positive reactions to the intervention. Their suggestions for improving the intervention primarily concerned improving its relevance. Participants described changes they had made based on the intervention, particularly controlling anger and improving relations with others. Their responses indicated that they sometimes misunderstood or misused specific intervention skills, especially problem solving and empathy. Students' descriptions of the outcomes they experienced when using intervention skills were not uniformly positive. This was especially true for situations involving peers such as peer pressure and bullying. These results underscore the need for more intensive efforts to ensure that students master intervention skills and are able to use them correctly. In addition, interventions should address the broader social context (e.g., peers, school) to maximize the effectiveness of skills. PMID- 25823511 TI - Stability and Reproducibility Underscore Utility of RT-QuIC for Diagnosis of Creutzfeldt-Jakob Disease. AB - Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP(Sc)). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, "blinded" ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluorescence units (rfu), we obtained a sensitivity of 85% and a specificity of 99%. The multi-centre inter-laboratory reproducibility of RT-QuIC revealed a Fleiss' kappa value of 0.83 (95% CI: 0.40-1.00) indicating an almost perfect agreement. Moreover, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP(Sc) seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/MUL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days) can be rescued by removal of erythrocytes. The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT QuIC as an innovative and robust diagnostic method. PMID- 25823512 TI - Streptozotocin Induced Neurotoxicity Involves Alzheimer's Related Pathological Markers: a Study on N2A Cells. AB - Intracerebroventricular (icv) injection of streptozotocin (STZ) in rat brain causes prolonged impairment of brain energy metabolism and oxidative damage and leads to cognitive dysfunction; however, its mechanistic specific effects on neurons are not known. The present study was conducted to investigate the STZ induced cellular and molecular alterations in mouse neuronal N2A cells. The N2A cells were treated with STZ (10, 50, 100, 1000 MUM) for 48 h, and different assays were performed. STZ treatment caused significant decrease in cell viability, choline levels, increased acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation. STZ treatment also led to low levels of glucose uptake, elevated mitochondrial stress, translocation of cytochrome c in cytosol, phosphatidylserine externalization, increased expression of caspase-3 and DNA damage. Co-treatment of clinically used drug donepezil (1 MUM) offered significant protection against STZ induced neurotoxicity. Donepezil treatment significantly inhibited the STZ induced neurotoxicity, altered choline level, AChE activity, lowered glucose uptake and mitochondrial stress. However, the caspase-3 expression remains unaltered with co-treatment of donepezil. In conclusion, findings showed that STZ treated N2A cells exhibited the Alzheimer's disease (AD) related pathological markers which are attenuated with co-treatment of donepezil. Findings of the study suggested the potent use of STZ treated N2A cells as in vitro experimental test model to study the disease mechanism at cellular level. PMID- 25823513 TI - Role of MicroRNA Let-7 in Modulating Multifactorial Aspect of Neurodegenerative Diseases: an Overview. AB - The multifactorial aspect of neurodegenerative diseases has posed challenges in terms of understanding various mechanistic cues behind these ailments. The fact that single microRNA (miRNA) molecules can regulate multiple genes and associated pathways makes these molecules interesting for studies within the area of age associated neurodegenerative diseases. miRNAs are endogenous, evolutionarily conserved, 20-23 nucleotide non-coding RNAs, which were first discovered in Caenorhabditis elegans. They play a key role in gene regulation and are known to be deregulated in many disease conditions. Steady regulations of miRNAs are required for normal biological processes. One of the crucial miRNA molecules let 7 is highly conserved and is known to be required for development and viability. It acts as a regulator for oncogenes and insulin-PI3K-mTOR pathway genes. Upregulation of let-7 impairs glucose homeostasis and results in degeneration of neurons, while its downregulation leads to cancer. Maturation of let-7 in cancer subjects is inhibited by lin-28, an RNA-binding protein inhibitor. This highlights the importance of let-7 miRNAs in various diseases and developmental processes. This article provides an overview on the functions of let-7 and its probable association with various neurodegenerative diseases. PMID- 25823514 TI - Revisiting the Serotonin Hypothesis: Implications for Major Depressive Disorders. AB - Major depressive disorder (MDD) is a heritable neuropsychiatric disease associated with severe changes at cellular and molecular levels. Its diagnosis mainly relies on the characterization of a wide range of symptoms including changes in mood and behavior. Despite the availability of antidepressant drugs, 10 to 30 % of patients fail to respond after a single or multiple treatments, and the recurrence of depression among responsive patients is very high. Evidence from the past decades suggests that the brain neurotransmitter serotonin (5-HT) is incriminated in MDD, and that a dysfunction of 5-HT receptors may play a role in the genesis of this disease. The 5-HT membrane transporter protein (SERT), which helps regulate the serotonergic transmission, is also implicated in MDD and is one of the main targets of antidepressant therapy. Although a number of behavioral tests and animal models have been developed to study depression, little is known about the neurobiological bases of MDD. Understanding the role of the serotonergic pathway will significantly help improve our knowledge of the pathophysiology of depression and may open up avenues for the development of new antidepressant drugs. The overarching goal of this review is to present recent findings from studies examining the serotonergic pathway in MDD, with a focus on SERT and the serotonin 1A (5-HT1A), serotonin 1B (5-HT1B), and serotonin 2A (5 HT2A) receptors. This paper also describes some of the main molecules involved in the internalization of 5-HT receptors and illustrates the changes in 5-HT neurotransmission in knockout mice and animal model of depression. PMID- 25823515 TI - Sex chromosome conservation, DMRT1 phylogeny and gonad morphology in diploid Palearctic green toads (Bufo viridis subgroup). AB - Due to the prevailing sex chromosome homomorphy and large genome size, the knowledge on sex determination systems, sex chromosomes and sex-determining genes in amphibians remains scarce. Using 3 cross-amplifying sex-linked microsatellite markers, we uncover sex determination systems and sex chromosomes in purebred, diploid Palearctic green toads (Bufo viridis subgroup), which had so far only been characterized in laboratory-bred hybrids. Our data support an XY system in B. balearicus, B. viridis and B. variabilis. While females show recombination, it is strongly suppressed (or not detectable) in males. Markers corroborate the largest chromosome pair 1 (homologous to linkage group 1 of Xenopus tropicalis) to represent the sex chromosomes in diploid species of the B. viridis subgroup (B. siculus, B. shaartusiensis, B. balearicus, B. turanensis, B. variabilis, B. viridis, and probably B. boulengeri). This chromosome harbors DMRT1, a key gene of the sexual pathway in deeply divergent animal taxa. However, our phylogenetic analysis of a 600-bp fragment of that gene in diploid green toad taxa reveals that X and Y alleles cluster by species and not by gametolog. This suggests that XY-sequence similarity stems from occasional XY recombination within DMRT1, and we preliminarily reject its role as the master sex determination gene, pending future extension of this evidence to the entire DMRT1 gene. We further create a chain of evidence, which supports the hypothesis that linkage group 1 of X. tropicalis appears to be maintained as the largest chromosome (1), and thus is homologous in anuran karyotype evolution from pipid to hylid, bufonid and ranid anurans. PMID- 25823516 TI - Does varus alignment adversely affect implant survival and function six years after kinematically aligned total knee arthroplasty? AB - PURPOSE: We report the six year implant survivorship, tibial component alignment and knee and limb function measured by the Oxford Knee Score and Western Ontario and McMaster Universities Osteoarthritis Index ((WOMAC) score after kinematically aligned total knee arthroplasty (TKA) and tested the hypothesis that varus alignment of the tibial component, knee, or limb does not adversely affect implant survival and function. METHODS: We prospectively followed 214 consecutive patients (219 knees) treated with a kinematically aligned TKA in 2007. Kaplan Meier survival analysis and revision rate per 100 component years determined implant failure. The Oxford Knee Score (0 worst, 48 best) and WOMAC score (0 worst, 100 best) were used to measure function. We categorised tibial component alignment as in-range (<= 0 degrees ) or varus (>0 degrees ), knee alignment as in-range (between -2.5 degrees and -7.4 degrees ), varus (>-2.5 degrees ), or valgus (<-7.4 degrees ), and limb alignment as in-range (0 degrees +/- 3 degrees ), varus (>3 degrees ) or valgus (<-3 degrees ). RESULTS: At a mean of 6.3 years (range, 5.8-7.2), implant survivorship was 97.5 % and revision-rate per 100 component years 0.40. Three implants had been revised (deep infection one, loose tibial component one and patella instability [1); two loose patella components were pending revision and considered failures. The average Oxford Knee Score was 43 and WOMAC 91. Function of tibial components (80 %), knees (31 %) and limbs (7 %) that were aligned in varus was similar to patients aligned in-range. CONCLUSIONS: At a mean of 6.3 years after kinematically aligned TKA, varus alignment of the tibial component, knee and limb did not adversely affect implant survival or function, which supports the consideration of kinematic alignment as an alternative to mechanical alignment for performing primary TKA. Level of evidence, III; therapeutic study. PMID- 25823517 TI - Predictors of pain and disability outcomes in one thousand, one hundred and eight patients who underwent lumbar discectomy surgery. AB - BACKGROUND: A key component toward improving surgical outcomes is proper patient selection. Improved selection can occur through exploration of prognostic studies that identify variables which are associated with good or poorer outcomes with a specific intervention, such as lumbar discectomy. To date there are no guidelines identifying key prognostic variables that assist surgeons in proper patient selection for lumbar discectomy. The purpose of this study was to identify baseline characteristics that were related to poor or favourable outcomes for patients who undergo lumbar discectomy. In particular, we were interested in prognostic factors that were unique to those commonly reported in the musculoskeletal literature, regardless of intervention type. METHODS: This retrospective study analysed data from 1,108 patients who underwent lumbar discectomy and had one year outcomes for pain and disability. All patient data was part of a multicentre, multi-national spine repository. Ten relatively commonly captured data variables were used as predictors for the study: (1) age, (2) body mass index, (3) gender, (4) previous back surgery history, (5) baseline disability, unique baseline scores for pain for both (6) low back and (7) leg pain, (8) baseline SF-12 Physical Component Summary (PCS) scores, (9) baseline SF 12 Mental Component Summary (MCS) scores, and (10) leg pain greater than back pain. Univariate and multivariate logistic regression analyses were run against one year outcome variables of pain and disability. RESULTS: For the multivariate analyses associated with the outcome of pain, older patients, those with higher baseline back pain, those with lesser reported disability and higher SF-12 MCS quality of life scores were associated with improved outcomes. For the multivariate analyses associated with the outcome of disability, presence of leg pain greater than back pain and no previous surgery suggested a better outcome. CONCLUSIONS: For this study, several predictive variables were either unique or conflicted with those advocated in general prognostic literature, suggesting they may have value for clinical decision making for lumbar discectomy surgery. In particular, leg pain greater than back pain and older age may yield promising value. Other significant findings such as quality of life scores and prior surgery may yield less value since these findings are similar to those that are considered to be prognostic regardless of intervention type. PMID- 25823518 TI - Open reduction and internal fixation versus radial head arthroplasty in the treatment of adult closed comminuted radial head fractures (modified Mason type III and IV). AB - BACKGROUND: The purpose of our study was to compare the outcome of radial head fractures (modified Mason type III and IV) treated by open reduction and internal fixation (ORIF) versus radial head arthroplasty (RHA). PATIENTS AND METHODS: A retrospective review of 36 patients with closed comminuted radial head fractures treated either by ORIF or RHA with an average of 15-months' follow-up was undertaken. The primary outcome was the QuickDASH, the shortened version of the Dissabilities of the Arm, Shouler and Hand score. Other outcomes included regain of functional range of motion (ROM) of the elbow and duration of surgery. Surgical complications were noted. RESULTS: Thirty-six patients with a mean age of 36 years were evaluated. Nineteen patients underwent ORIF and 17 RHA. The two treatment groups were comparable with regards to gender, side of injury, Mason type and mechanism of injury. Patients who underwent RHA were slightly older (p < 0.001). At follow-up, the QuickDASH score was similar between groups (p = 0.58). Regain of functional ROM of the elbow (p = 0.13) and complication rate (p = 0.57) were similar. CONCLUSION: The treatment of closed comminuted radial head fracture (modified Mason type III and IV) with ORIF and RHA demonstrates similar findings despite less surgical time for performing RHA. PMID- 25823519 TI - Reliability and Validity of the Intensive Care Delirium Screening Checklist in Turkish. AB - PURPOSE: The aim was to investigate and evaluate validity and reliability of the Intensive Care Delirium Screening Checklist (ICDSC) in Turkey. METHODS: A cross sectional study design was used. Fifty-nine patients in an intensive care unit for longer than 24 hr were included in this study. RESULTS: Cronbach's alpha coefficient indicated that the ICDSC was a reliable test with high internal consistency (specialist nurse min: 0.720, max: 0.855; primary nurse min: 0.728, max: 0.830). The sensitivity and specificity were high. CONCLUSION: The findings showed that the sensitivity and specificity of the ICDSC are high for Turkish patients. IMPLICATIONS FOR NURSING PRACTICE: The ICDSC provides fast and effective evaluations of the patients for delirium. So, ICDSC may be easily integrated into routine nursing practice. PMID- 25823520 TI - Youth physical activity self-efficacy: a concept analysis. AB - AIM: To report an analysis of the concept of youth physical activity self efficacy. BACKGROUND: Physical activity self-efficacy is a concept that has been frequently examined as a key variable in research aimed at increasing physical activity among youth. Different conceptual definitions and empirical measures indicate the need for concept analysis to advance knowledge of the concept. DESIGN: Rodger's evolutionary method of concept analysis was used to collect and analyse the data. Social cognitive theory guided the analysis. DATA SOURCES: The PubMed, Cumulative Index of Nursing and Allied Health Literature, PsychInfo, Educational Resources Information Center and Sociological Abstracts databases were searched for publications from 1990-2013. Search terms included self efficacy, physical activity, youth, children, adolescent and teen. REVIEW METHODS: A total of 276 articles were identified. Fifty-five articles meeting inclusion criteria were included in the review. Data were analysed with particular focus on the attributes, antecedents and consequences of the concept. RESULTS: Defining attributes of physical activity self-efficacy were identified as personal cognition/perception, self-appraisal process, related action, power to choose physical activity, dynamic state and bi-dimensional nature. Antecedents and consequences were consistent with social cognitive theory. Youth physical activity self-efficacy is defined as a youth's belief in his/her capability to participate in physical activity and to choose physical activity despite existing barriers. CONCLUSIONS: This concept analysis provided an in-depth analysis and clarification of youth physical activity self-efficacy. Future research should be aimed at establishing consistency in conceptual definitions and empirical measurement to further develop the concept across disciplines. PMID- 25823521 TI - Oxidative stress damage in the protozoan parasite Trypanosoma cruzi is inhibited by Cyclosporin A. AB - Cyclosporin A (CsA) specifically inhibits the mitochondrial permeability transition pore (mPTP). Opening of the mPTP, which is triggered by high levels of matrix [Ca2+] and/or oxidative stress, leads to mitochondrial dysfunction and thus to cell death by either apoptosis or necrosis. In the present study, we analysed the response of Trypanosoma cruzi epimastigote parasites to oxidative stress with 5 mm H2O2, by studying several features related to programmed cell death and the effects of pre-incubation with 1 MU m of CsA. We evaluated TcPARP cleavage, DNA integrity, cytochrome c translocation, Annexin V/propidium iodide staining, reactive oxygen species production. CsA prevented parasite oxidative stress damage as it significantly inhibited DNA degradation, cytochrome c translocation to cytosol and TcPARP cleavage. The calcein-AM/CoCl2 assay, used as a selective indicator of mPTP opening in mammals, was also performed in T. cruzi parasites. H2O2 treatment decreased calcein fluorescence, but this decline was partially inhibited by pre-incubation with CsA. Our results encourage further studies to investigate if there is a mPTP-like pore and a mitochondrial cyclophilin involved in this protozoan parasite. PMID- 25823523 TI - Medically unexplained dyspnoea and panic. AB - Medically unexplained dyspnoea in the pulmonary setting is often accompanied by considerable levels of anxiety, suggestive of psychopathology, in particular panic disorder (PD). This pilot study investigates the value of the Multidimensional Dyspnea Profile as a tool to facilitate identification of a specific dyspnoea profile suggestive of comorbid PD. The verbal descriptors, feeling depressed, air hunger and concentrating on breathing, significantly differentiated between the two groups of patients with pulmonary disease with and without PD. PMID- 25823524 TI - Sarcoidosis presenting as non-scarring non-scalp alopecia. AB - In this article we describe a 39-year-old man who presented with non-scarring non scalp alopecia of his limbs as the initial presentation of sarcoidosis. Alopecia is a rare cutaneous manifestation of sarcoidosis. A literature review has found only one other example of sarcoidosis presenting as non-scarring non-scalp alopecia in an area other than the scalp in a patient who was otherwise asymptomatic. Several reported cases have described scarring alopecia of the scalp, which is the area of skin most commonly affected by sarcoidosis. There has been one documented case of sarcoidosis manifesting as total body non-scarring alopecia in a patient who had systemic symptoms of sarcoidosis. Other cases have presented rare cutaneous manifestations of sarcoidosis but in all these cases several other organ systems have been involved, and the patient has had systemic symptoms on presentation or the cutaneous presentation did not include non-scalp non-scarring alopecia. PMID- 25823525 TI - Elevated whole blood viscosity is associated with insulin resistance and non alcoholic fatty liver. AB - BACKGROUND: Accumulating evidences demonstrate that abnormalities in whole blood viscosity (WBV) have been implicated in insulin resistance which may lead to non alcoholic fatty liver disease (NAFLD). However, epidemiological studies exploring the association between WBV and NAFLD were not available. OBJECTIVE: Our objective was to evaluate the association between WBV levels and risk of prevalent NAFLD. DESIGN: This was a cross-sectional population-based study performed in Shanghai, China. PATIENTS: A total of 8673 participants aged 40 years or older were included. MEASUREMENTS: WBV was calculated from haematocrit and plasma protein concentration, at a shear rate of 208(-1) s, by a validated equation. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases. Insulin resistance (IR) was assessed by homeostasis model assessment (HOMA-IR). RESULTS: The overall prevalence of NAFLD was 30.2% in this population. With the increase of WBV level, participants have larger waist circumference (WC), more severe insulin resistance and the prevalence of NAFLD increased significantly with elevated WBV quartiles. Compared with those in the lowest quartiles, adults in the highest quartile of WBV levels have higher prevalence of NAFLD (adjusted odds ratio 1.77, 95% confidence interval [CI] 1.48-2.13) and IR (2.72, 95% CI 2.26-3.27). CONCLUSIONS: Elevated WBV is associated with prevalence of NAFLD and IR in middle-aged and elderly Chinese population. PMID- 25823526 TI - From respiratory adaptation at birth to early markers of childhood respiratory health. AB - Assessing lung function in the newborn relates to the need for early markers of chronic respiratory diseases such as cystic fibrosis or asthma. Non-invasive respiratory measurements of forced oscillations mechanics are recently shown to be possible in unsedated babies. The bronchodilator effect of catecholamine release at birth, and the respiratory muscle contribution to respiratory mechanical impedance resulting in sometimes excessive variability suggest that measurements should be performed beyond the first 24 hr of life. PMID- 25823527 TI - A highly sensitive room temperature H2S gas sensor based on SnO2 multi-tube arrays bio-templated from insect bristles. AB - A tin oxide multi-tube array (SMTA) with a parallel effect was fabricated through a simple and promising method combining chemosynthesis and biomimetic techniques; a biomimetic template was derived from the bristles on the wings of the Alpine Black Swallowtail butterfly (Papilio maackii). SnO2 tubes are hollow and porous structures with micro-pores regularly distributed on the wall. The morphology, the delicate microstructure and the crystal structure of this SMTA were characterized by super resolution digital microscopy, scanning electron microscopy, transmission electron microscopy and X-ray diffraction. The SMTA exhibits a high sensitivity to H2S gas at room temperature. It also exhibits a short response/recovery time, with an average value of 14/30 s at 5 ppm. In particular, heating is not required for the SMTA in the gas sensitivity measurement process. On the basis of these results, SMTA is proposed as a suitable new material for the design and fabrication of room-temperature H2S gas sensors. PMID- 25823522 TI - Making thawed universal donor plasma available rapidly for massively bleeding trauma patients: experience from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial. AB - BACKGROUND: The Pragmatic, Randomized Optimal Platelets and Plasma Ratios (PROPPR) trial was a randomized clinical trial comparing survival after transfusion of two different blood component ratios for emergency resuscitation of traumatic massive hemorrhage. Transfusion services supporting the study were expected to provide thawed plasma, platelets, and red blood cells within 10 minutes of request. STUDY DESIGN AND METHODS: At the 12 Level 1 trauma centers participating in PROPPR, blood components transfused and delivery times were tabulated, with a focus on universal donor (UD) plasma management. The adequacy of site plans was assessed by comparing the bedside blood availability times to study goals and the new American College of Surgeons guidelines. RESULTS: Eleven of 12 sites were able to consistently deliver 6 units of thawed UD plasma to their trauma-receiving unit within 10 minutes and 12 units in 20 minutes. Three sites used blood group A plasma instead of AB for massive transfusion without complications. Approximately 4700 units of plasma were given to the 680 patients enrolled in the trial. No site experienced shortages of AB plasma that limited enrollment. Two of 12 sites reported wastage of thawed AB plasma approaching 25% of AB plasma prepared. CONCLUSION: Delivering UD plasma to massively hemorrhaging patients was accomplished consistently and rapidly and without excessive wastage in high-volume trauma centers. The American College of Surgeons Trauma Quality Improvement Program guidelines for massive transfusion protocol UD plasma availability are practicable in large academic trauma centers. Use of group A plasma in trauma resuscitation needs further study. PMID- 25823528 TI - Self-Assembly of a Designed Alternating Arginine/Phenylalanine Oligopeptide. AB - A model octapeptide peptide consisting of an alternating sequence of arginine (Arg) and phenylalanine (Phe) residues, namely, [Arg-Phe]4, was prepared, and its self-assembly in solution studied. The simple alternating [Arg-Phe]4 peptide sequence allows for unique insights into the aggregation process and the structure of the self-assembled motifs. Fluorescence and UV-vis assays were used to determine critical aggregation concentrations, corresponding to the formation of oligomeric species and beta-sheet rich structures organized into both spheroidal aggregates and highly ordered fibrils. Electron and atomic force microscopy images show globular aggregates and long unbranched fibers with diameters ranging from ~4 nm up to ~40 nm. Infrared and circular dichroism spectroscopy show the formation of beta-sheet structures. X-ray diffraction on oriented stalks show that the peptide fibers have an internal lamellar structure, with an orthorhombic unit cell with parameters a ~ 27.6 A, b ~ 9.7 A, and c ~ 9.6 A. In situ small-angle X-ray scattering (SAXS) shows the presence of low molecular weight oligomers in equilibrium with mature fibers which are likely made up from 5 or 6 intertwined protofilaments. Finally, weak gel solutions are probed under gentle shear, suggesting the ability of these arginine-rich fibers to form networks. PMID- 25823529 TI - Re-evaluation casts doubt on the pathogenicity of homozygous USH2A p.C759F. AB - Mutations in USH2A are a common cause of Retinitis Pigmentosa (RP). Among the most frequently reported USH2A variants, c.2276G>T (p.C759F) has been found in both affected and healthy individuals. The pathogenicity of this variant remains controversial since it was detected in homozygosity in two healthy siblings of a Spanish family (S23), eleven years ago. The fact that these individuals remain asymptomatic today, prompted us to study the presence of other pathogenic variants in this family using targeted resequencing of 26 retinal genes in one of the affected individuals. This approach allowed us to identify one novel pathogenic homozygous mutation in exon 13 of PDE6B (c.1678C>T; p.R560C). This variant cosegregated with the disease and was absent in 200 control individuals. Remarkably, the identified variant in PDE6B corresponds to the mutation responsible of the retinal degeneration in the naturally occurring rd10 mutant mice. To our knowledge, this is the first report of the identification of the rd10 mice mutation in a RP family. These findings, together with a review of the literature, support the hypothesis that homozygous p.C759F mutations are not pathogenic and led us to exclude the implication of p.C759F in the RP of family S23. Our results indicate the need of re-evaluating all families genetically diagnosed with this mutation. PMID- 25823530 TI - Robotic vs laparoscopic radical hysterectomy for cervical cancer: a meta analysis. AB - BACKGROUND: To evaluate whether the safety and efficacy of robotic radical hysterectomy (RRH) in patients with cervical cancer (CC) are equivalent to those of laparoscopic radical hysterectomy (LRH). METHODS: The Pubmed, Embase, Cochrane Library, Ovid and Web of Science databases were searched. Studies documenting a comparison of RRH with LRH for CC were selected. Operative and recovery outcomes, common morbidity, and oncological parameters were evaluated. RESULTS: Compared with LRH, RRH was associated with less blood loss and shorter hospital stay. There were no significant differences in operative time, complications, mortality, transfusion, conversions, number of retrieved lymph nodes, recurrence or disease-free survival between the two groups. CONCLUSION: RRH for CC is safe and feasible and may be an alternative treatment for CC. More multicentre randomized controlled trials investigating the long-term oncological outcomes are required to determine the advantages of RRH over LRH in CC. PMID- 25823531 TI - Historical classics. PMID- 25823532 TI - Vapor-phase transport deposition, characterization, and applications of large nanographenes. AB - Recently, chemical synthesis of a range of large nanographene molecules with various shapes and sizes opened a new path to utilize them in various applications and devices. However, due to their extended aromatic cores and high molecular weight, film formation of large nanographene molecules, bearing more than 90 sp(2) carbon atoms in aromatic cores, is very challenging, which has prevented their applications such as in thin-film transistors. Here, we developed an effective approach to prepare films of such large nanographene molecules using a vapor-phase transport (VPT) technique based on molecule sublimation. The VPT of these molecules was made possible by combining the molecules and the target substrate in a small confinement of vacuum-sealed glass tube, so that a small amount of sublimation can be utilized to create films. Surprisingly, such heavy and large molecules can be deposited on any substrate by this method to create films of assembled large nanographene molecules while maintaining their aromatic cores intact, which was confirmed using mass spectrometry measurements. Moreover, field-effect transistors based on these films are depleted and show significantly improved current on/off ratio compared to previous large nanographene-based transistors fabricated using liquid-phase-based process. Our work shows that VPT deposition can be a viable technique to prepare films based on large nanographene molecules and potentially other high molecular weight compounds, which may find exciting applications in electronics and optoelectronics. PMID- 25823533 TI - Reply: To PMID 24954365. PMID- 25823534 TI - Dipeptidyl peptidase-4 inhibitor improves cardiac function by attenuating adverse cardiac remodelling in rats with chronic myocardial infarction. AB - NEW FINDINGS: What is the central question of this study? Although cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated, their cardiac effects in chronic myocardial infarction (MI) are unclear. We determined the effects of a DPP-4 inhibitor on cardiac function and remodelling in rats with chronic MI. What is the main finding and its importance? We demonstrated, for the first time, that DPP-4 inhibitor, but not metformin, exerted similar efficacy in improving cardiac function and attenuating cardiac fibrosis compared with enalapril in rats with chronic MI. These findings reveal benefits additional to the glycaemic control by the DPP-4 inhibitor in chronic MI, and it might become the new drug of choice for MI in patients with diabetes mellitus. Adverse cardiac remodelling after myocardial infarction (MI) leads to progressive heart failure. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new antidiabetic drugs that exert cardioprotection. However, their role in cardiac function and remodelling in chronic MI is unclear. We hypothesized that the DPP-4 inhibitor vildagliptin reduces adverse cardiac remodelling and improves cardiac function in rats with chronic MI. These effects were also compared with enalapril and metformin. Male Wistar rats (n = 36) with chronic MI induced by ligation of the left anterior descending coronary artery were divided into six groups to receive vehicle, vildagliptin (3 mg kg(-1) day(-1) ), metformin (30 mg kg(-1) day(-1) ), enalapril (10 mg kg(-1) day(-1) ), combined metformin and enalapril or combined vildagliptin and enalapril for 8 weeks. At the end of the study, plasma malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, pathological and biochemical studies of cardiac remodelling were investigated. Our study demonstrated that rats with chronic MI had increased oxidative stress levels, depressed HRV, adverse cardiac remodelling, indicated by cardiac fibrosis, and LV dysfunction. Treatment with vildagliptin or enalapril significantly decreased oxidative stress, attenuated cardiac fibrosis and improved HRV and LV function. We conclude that vildagliptin exerts similar cardioprotective effects to enalapril in attenuating oxidative stress and cardiac fibrosis and improving cardiac function in rats with chronic MI. Metformin does not provide these benefits in this model. Moreover, addition of either metformin or vildagliptin to enalapril does not provide additional benefit in attenuating cardiac remodelling or improving LV function compared with enalapril alone. PMID- 25823535 TI - Carbonic anhydrase-IX score is a novel biomarker that predicts recurrence and survival for high-risk, nonmetastatic renal cell carcinoma: Data from the phase III ARISER clinical trial. AB - INTRODUCTION AND OBJECTIVE: With a limited number of prognostic and predictive biomarkers available, carbonic anhydrase-IX (CAIX) has served as an important prognostic biomarker for patients with clear cell renal cell carcinoma (ccRCC). However, studies have recently called into question the role of CAIX as a biomarker for ccRCC. To investigate this uncertainty, we quantified the association of CAIX with lymphatic involvement and survival using data from ARISER study (WX-2007-03-HR)--a prospective trial involving subjects with high risk nonmetastatic ccRCC. METHODS AND MATERIALS: We reviewed the records of 813 patients enrolled in the ARISER study. Central review of histology, grade, and CAIX staining (frequency and intensity) was performed. CAIX score was derived by multiplying the staining intensity (1-3) by percent positive cells (0%-100%), yielding a range of 0 to 300. We quantified the association of CAIX expression and score with lymphatic spread and survival (disease-free survival [DFS] and overall survival [OS]) using Kaplan-Meier and multivariable propensity score adjusted Cox regression analyses. RESULTS: Median follow-up of the cohort was 54.2 months. Although 56% of subjects with lymphatic involvement had CAIX>85%, only 33% had CAIX score >= 200. On multivariable analysis, CAIX>85% was not a statistically significant predictor of DFS and OS (P = 0.06 and P = 0.15, respectively). However, CAIX score >= 200, when compared with CAIX score <= 100, was associated with improved DFS and OS (P = 0.01 and P = 0.01, respectively) on multivariable analysis. CONCLUSIONS: The largest, multicenter, prospective analysis of patients with high-risk nonmetastatic ccRCC demonstrates the utility of CAIX score as a statistically significant prognostic biomarker for survival. We recommend that CAIX score be quantified for all patients with high-risk disease after nephrectomy. PMID- 25823536 TI - Hot water-promoted cyclopropylcarbinyl rearrangement facilitates construction of homoallylic alcohols. AB - In refluxing 9 : 1 (v/v) H2O-1,4-dioxane and without an additional catalyst, the rearrangements of various types of cyclopropyl carbinols were attempted. It was found that the reactions generally gave homoallylic alcohols in good to very high chemical yields. Rearrangements of bicyclic or tricyclic cyclopropyl carbinols readily gave the desired ring-expanded cyclic homoallylic alcohols which are difficult to synthesize by other means. PMID- 25823537 TI - Is fluid resuscitation with high-volume hydroxyethyl starch safe for the kidney in trauma patients? PMID- 25823540 TI - Understanding and using enactments to further clinical work: a case study of a man unable to experience intimacy. AB - This article examines the value of working within enactments-affectively charged, unconscious remnants of painful, past experiences played out in the novel context of the therapeutic relationship-to further the work of psychodynamically oriented therapy in the treatment of a HIV-positive Hispanic gay male in his early 30s with a history of relational trauma. Through clinical vignettes, I highlight how relational uncertainty and its vicissitudes-vulnerability, doubt, safety, and trust-have triggered mutual dissociation in the context of enactment. At times, this has disrupted our ability to communicate honestly and relate intersubjectively. By working within affectively charged enactments, we have expanded our capacities to accommodate to relational uncertainty and used the tension of ambiguity within our relationship to permit the emergence of a shared space for recognition and self-discovery. PMID- 25823539 TI - Visual deficits in Nepalese patients with oculocutaneous albinism. AB - BACKGROUND: Albinism poses a significant threat to visual functions and causes remarkable ocular morbidity often resulting in visual disabilities. The study aimed at describing the visual status in patients with diagnosed cases of complete oculocutaneous albinism (OCA) attending to a tertiary eye hospital in Nepal. METHODS: This was a cross-sectional descriptive hospital-based study of all diagnosed oculocutaneous albinotic cases (16 males and 9 females; mean age of 16 years) who visited the Department of Ophthalmology at the Institute of Medicine, for ocular consultation between September 1, 2011 and December 1, 2013. RESULTS: Twenty-five cases (50 eyes) with OCA were enrolled in the study. All the participants had maximally reduced visual acuity (mean: 1.24+/-0.50logMAR). Myopic astigmatism was the most common refractive error (n=17; 34%). 58% of all participants had with-the-rule astigmatism. Considering the spherical equivalent power, most of the eyes (n=30; 60%) had myopia, with overall mean SE refractive error of -1.59+/-5.39D. Visual acuity improved significantly with refractive correction in place (paired sample t-test, p<0.05). Horizontal pendular nystagmus was the most common nystagmus (n=34 eyes; 68%). Alternating esotropia and alternating exotropia each were observed in 16% of participants who had strabismus (40% of all cases). The diaphanous iris, foveal hypoplasia and poliosis were the most consistent clinical features. CONCLUSION: Patients with OCA present with a broad spectrum of visual deficits that impair the visual functions. Significant improvement in visual acuity following optical correction serves as an impetus to the reduction of visual disabilities in individuals with albinism. PMID- 25823541 TI - Volatile sedation with sevoflurane in intensive care patients with acute stroke or subarachnoid haemorrhage using AnaConDa(r): an observational study. AB - BACKGROUND: The anaesthetic conserving device, AnaConDa((r)), allows use of inhaled anaesthetics for sedation in the intensive care unit. We prospectively measured cerebral and cardiopulmonary parameters in patients with acute stroke or subarachnoid haemorrhage during a switch from i.v. to inhalative sedation. METHODS: 25 patients were switched from i.v. to an indefinite period of inhaled sedation with sevoflurane. Mean arterial (MAP), intracranial (ICP), and cerebral perfusion pressure (CPP), middle cerebral artery mean flow velocity (MFV) and fractional tissue oxygen extraction (FTOE), systemic cardiopulmonary parameters, and administered drugs were assessed before and after the change (-6 to +12 h). RESULTS: In 8 patients, critically reduced MAP or ICP crisis led to premature termination of sevoflurane sedation. In the other 17 patients, after the first hour, mean ICP increased [2.4 (4.5) mm Hg; P=0.046], MAP decreased [7.8 (14.1) mm Hg; P=0.036] and thus CPP decreased also [-10.2 (15.1) mm Hg; P=0.014]. MFV and FTOE did not change. Over a 12 hour post switch observational period, [Formula: see text] increased slightly [0.3 (0.8) kPa; P=0.104], ICP did not change [0.2 (3.9) mm Hg; P=0.865], but MAP [-6 (6.9) mm Hg; P=0.002] and thus CPP decreased [ 6 (8.5) mm Hg; P=0.010]. CONCLUSION: Sevoflurane led to sufficient sedation, but decreased MAP and CPP in a selected cerebrovascular neurocritical care population. In about a third of these patients, severe adverse reactions, including intolerable ICP increases, were observed. PMID- 25823542 TI - The humanistic and economic burden of providing care for a patient with schizophrenia. AB - BACKGROUND: Schizophrenia is a debilitating disorder that often requires the affected individual to receive part- or full-time care from a caregiver. AIMS: The purpose of this study was to examine the humanistic and economic burden of caring for an individual with Schizophrenia with regard to the measures of quality of life (QoL), work productivity, healthcare resource use and estimated economic costs. METHODS: Data for this study came from the 2012 US National Health and Wellness Survey (NHWS; n = 71,149). Specifically, this analysis focused on those individuals in the survey who indicated that they were currently the primary caregiver for an individual with Schizophrenia (C-SCZ; n = 174). These individuals were matched via two separate 1:2 propensity score matches with both caregivers of other disorders (C-Other; n = 294) and non-caregivers (Non-C; n = 294) on significant covariates. Individuals were then compared across the outcomes of QoL, work productivity, healthcare resource use and estimated economic costs. RESULTS: C-SCZ respondents had worse outcomes on all outcomes measured than C-Other respondents and Non-C respondents even when controlling for significant differences between the groups on sociodemographic characteristics. However, due to the small sample sizes, these comparisons were only significant in most cases for the C-SCZ to Non-C comparisons. CONCLUSION: Results indicate that caregivers of those with Schizophrenia experience a heightened humanistic and economic burden, especially relative to the burden experienced by non caregivers. The fact that Schizophrenia not only affects the individual but also those who care for that individual is underscored by these results. PMID- 25823543 TI - Pulmonary oedema: an unusual aetiology. PMID- 25823545 TI - The Nursing Diagnosis Disturbed Thought Processes in Psychiatric Patients: Prevalence and Associated Characteristics. AB - PURPOSE: To analyze the frequency of the nursing diagnosis disturbed thought processes (DTP) (00130) in a sample of psychiatric and psychogeriatric patients in medium- and long-term units and to describe those factors associated with its presence. METHODS: A secondary analysis of the data obtained in a multicentric and cross-sectional study developed in Spain was undertaken. FINDINGS: The total sample was 624 patients, from which 39.4% (n = 246) had the nursing diagnosis DTP. A statistically significant relationship between the presence of DTP and different variables was found. CONCLUSIONS: The nursing diagnosis DTP is very frequent among psychiatric and psychogeriatric institutionalized patients. IMPLICATIONS FOR NURSING PRACTICE: Patients with DTP may require a more complex nursing attention as its presence is associated with specific care needs. PMID- 25823544 TI - Rapid Blood Pressure Lowering According to Recovery at Different Time Intervals after Acute Intracerebral Hemorrhage: Pooled Analysis of the INTERACT Studies. AB - BACKGROUND AND PURPOSE: Early intensive blood pressure (BP) lowering has been shown to improve functional outcome in acute intracerebral hemorrhage (ICH), but the treatment effect is modest and without a clearly defined underlying explanatory mechanism. We aimed at more reliably quantifying the benefits of this treatment according to different time periods in the recovery of participants in the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies. METHODS: Pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2,839) involving patients with spontaneous ICH (<6 h) and elevated systolic BP (SBP 150-220 mm Hg) who were randomized to intensive (target SBP <140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) BP lowering treatment. Treatment effects were examined according to repeated measures analysis of an ordinal ('shift') across all 7 levels of the modified Rankin Scale (mRS) assessed during follow-up at 7, 28, and 90 days, post-randomization. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov, NCT00226096 and NCT00716079. RESULTS: Intensive BP lowering resulted in a significant favorable distribution of mRS scores for better functioning (odds ratio 1.13, 95% confidence interval 1.00-1.26; p = 0.042) over 7, 28 and 90 days, and the effect was consistency for early (7-28 days) and later (28-90 days) time periods (p homogeneity 0.353). Treatment effects were also consistent across several pre-specified patient characteristic subgroups, with trends favoring those randomized early, and with higher SBP and milder neurological severity at baseline. CONCLUSIONS: Intensive BP lowering provides beneficial effects on physical functioning that manifests consistently through the early and later phases of recovery from ICH. PMID- 25823546 TI - Electrochemical assay to detect influenza viruses and measure drug susceptibility. AB - An electrochemical assay has been designed to rapidly diagnose influenza viruses. Exposure of a glucose-bearing substrate to influenza viruses or its enzyme, neuraminidase (NA), releases glucose, which was detected amperometrically. Two methods were used to detect released glucose. First, we used a standard glucose blood meter to detect two viral NAs and three influenza strains. We also demonstrated drug susceptibility of two antivirals, Zanamivir and Oseltamivir, using the assay. Finally, we used disposable test strips to detect nineteen H1N1 and H3N2 influenza strains using this assay in one hour. The limit and range of detection of this first generation assay is 10(2) and 10(2)-10(8) plaque forming units (pfu), respectively. Current user-friendly glucose meters can be repurposed to detect influenza viruses. PMID- 25823547 TI - Bladder Tumor Heterogeneity: The Impact on Clinical Treatment. AB - Bladder cancer relapse and treatment failure in most patients have often been attributed to chemoresistance in tumor cells and metastasis. Emerging evidence indicates that tumor heterogeneity may play an equally important role and extends to virtually all measurable properties of cancer cells. Although the idea of tumor heterogeneity is not new, little attention has been paid to applying it to understand and control bladder cancer progression. With the development of biotechnology, such as Gene sequencing, recent advances in understanding its generation model, original basis, consequent problems, and derived therapies provide great potential for tumor heterogeneity to be considered a new insight in the treatment of bladder cancers. PMID- 25823548 TI - A real time Taqman RT-PCR for the detection of rabbit hemorrhagic disease virus 2 (RHDV2). AB - A specific real time RT-PCR for the detection of RHDV2 was developed and validated using RHDV and RHDV2 RNA preparations from positive field samples. The system was designed to amplify a 127 nucleotide-long RNA region located within the vp60 gene, based on the alignment of six sequences originated in Portugal, obtained in our laboratory, and 11 sequences from France and Italy. The primers and probe target sequences are highly conserved in the vast majority of the RHDV2 sequences presently known. In the sequences showing variability, only one mismatch is found per strain, usually outlying the 3' end of the primer or probe hybridization sequences. The specificity of the method was demonstrated in vitro with a panel of common rabbit pathogens. Standardization was performed with RNA transcripts obtained from a recombinant plasmid harboring the target sequence. The method was able to detected nine RNA molecules with an efficiency of 99.4% and a R(2) value of 1. Repeatability and reproducibility of the method were very high, with coefficients of variation lower than 2.40%. The assay was proven a valuable tool to diagnose most of RDVH2 circulating strains, and may be also useful to monitor viral loads, and consequently, disease progression and vaccination efficacy. PMID- 25823549 TI - Imaging of omphalomesenteric duct remnants and related pathologies in children. AB - The omphalomesenteric duct (OMD) or the vitelline duct (VD) is the embryologic communication between the yolk sac and the primitive midgut. OMD or VD anomalies are a group of defects resulting from failure of involution of the OMD. Meckel diverticulum is the most common anomaly that results from failure of resorption of the OMD. Other less common anomalies seen in children include OMD fibrous band, fistula, sinus tract, cyst, and umbilical polyps. These OMD remnants can have variable clinical manifestations such as umbilical discharge, small bowel obstruction, gastrointestinal tract bleeding, or acute abdomen. This pictorial essay reviews the clinical presentation and imaging findings of the common and not so common complications of OMD remnants in the pediatric population. PMID- 25823550 TI - Atypical magnetic resonance imaging findings in hepatocellular carcinoma. AB - Magnetic resonance imaging (MRI) is currently the modality of choice to evaluate liver lesions in patients with cirrhosis and hepatitis B and C. Hepatocellular carcinoma demonstrates typical imaging findings on contrast-enhanced MRI, which are usually diagnostic. Unfortunately, a subgroup of hepatocellular carcinoma presents with atypical imaging features, and awareness of these atypical presentations is important in ensuring early diagnosis and optimal patient outcomes. Herein, we review some of the more common atypical presentations with a focus on MRI. PMID- 25823551 TI - Integrating telehealth services into a remote allied health service: A pilot study. AB - PROBLEM: The continuity of care for people with neurological conditions in a remote northwest Queensland town as services are currently only available intermittently. DESIGN: Mixed methods design using questionnaires and staff review of the program and processes. SETTING: Intermittent community rehabilitation service for clients with neurological conditions has been offered in Mount Isa and is supported by a similar fulltime service in Townsville. Both services use a unique client-centred, student-assisted, interprofessional model of care. KEY MEASURES FOR IMPROVEMENT: Understanding participant experiences by obtaining feedback from clients, students and allied health professionals (AHPs) regarding their experiences of using telehealth in this setting. STRATEGY FOR CHANGE: Previous clients of the North West Community Rehabilitation service were offered a review assessment using telehealth by an interprofessional team. EFFECTS OF CHANGE: Using telehealth enabled the client, remote AHP and students in Mount Isa to be connected to expert assistance in Townsville. LESSONS LEARNT: The findings suggest that telehealth was useful in a community rehabilitation setting to provide review services for clients. This improved continuity of care for these clients because without this telehealth assessment, the clients would have had to wait up to 12 months for the next service period in Mount Isa or travel to a major urban centre to access a similar service. Feedback from clients, students and AHPs was positive; however, some challenges were identified. Recommendations for future service delivery using telehealth are outlined in the paper. PMID- 25823552 TI - Incompleteness, aesthetic sensitivity, and the obsessive-compulsive need for symmetry. AB - BACKGROUND AND OBJECTIVES: The "need for symmetry" is a well recognized yet little understood feature of obsessive-compulsive (OC) experience. In light of the strong associations between the OC-related trait of incompleteness and symmetry-related behaviors and symptoms, and between perceptual symmetry and aesthetic judgments, this study examined whether trait incompleteness is associated with enhanced natural aesthetic skill and/or aesthetic sensitivity, particularly as they pertain to visual symmetry. METHODS: A quasi-experimental design was used to compare the responses of nonclinical individuals with high versus average levels of trait incompleteness on self-report measures and two performance measures of aesthetic judgment. RESULTS: Compared to controls, participants high in incompleteness reported higher levels of self-perceived symmetry-related concerns and behaviors, and displayed greater aesthetic sensitivity in the form of substantially heightened preferences for symmetry in images. Contrary to the hypothesis relating to aesthetic skill, however, the two groups did not differ in their capacity to estimate accurately the objective aesthetic value of images. Nor did they differ in self-reported aesthetics interests and background. LIMITATIONS: A clinical sample was not included. CONCLUSIONS: Findings provide evidence that high trait incompleteness is associated not just with symptomatic symmetry-related concerns but with a nonspecific heightened preference for visual symmetry. Conceptual implications are discussed, particularly the potential value of the perceptual fluency theory of symmetry and aesthetic response for explaining the association between incompleteness and symmetry preferences and symptoms. PMID- 25823553 TI - An ATPase-deficient variant of the SNF2 family member HELLS shows altered dynamics at pericentromeric heterochromatin. AB - The HELLS (helicase, lymphoid specific, also known as lymphoid-specific helicase) protein is related to the SNF2 (sucrose non-fermentable 2) family of chromatin remodeling ATPases. It is required for efficient DNA methylation in mammals, particularly at heterochromatin-located repetitive sequences. In this study, we investigated the interaction of HELLS with chromatin and used an ATPase-deficient HELLS variant to address the role of ATP hydrolysis in this process. Chromatin fractionation experiments demonstrated that, in the absence of the ATPase activity, HELLS is retained at the nuclear matrix compartment, defined in part by lamin B1. Microscopy studies revealed a stronger association of the ATPase deficient mutant with heterochromatin. These results were further supported by fluorescence recovery after photobleaching measurements, which showed that, at heterochromatic sites, wild-type HELLS is very dynamic, with a recovery half-time of 0.8s and a mobile protein fraction of 61%. In contrast, the ATPase-deficient mutant displayed 4.5-s recovery half-time and a reduction in the mobile fraction to 30%. We also present evidence suggesting that, in addition to the ATPase activity, a functional H3K9me3 signaling pathway contributes to an efficient release of HELLS from pericentromeric chromatin. Overall, our results show that a functional ATPase activity is not required for the recruitment of HELLS to heterochromatin, but it is important for the release of the enzyme from these sites. PMID- 25823554 TI - The secretion patterns and roles of cardiac and circulating arginine vasopressin during the development of heart failure. AB - OBJECTIVE: The aim of this study is to investigate local cardiac and circulating AVP secretion during heart failure and to determine whether AVP mediates ventricular remodeling. METHODS: We assessed cardiac function and AVP levels of post-myocardial infarction (MI) heart-failure rats 3 weeks (n = 10), 4 weeks (n = 10), 6 weeks (n = 10), 9 weeks (n = 15) after the proximal left anterior descending coronary artery (LAD) ligation. Ten sham-operated rats were used as the control group. In vitro, cardiac microvascular endothelial cells (CMECs) were initiated from isolated Wistar rat hearts and subjected to Ang II to induce AVP expression and secretion. Besides, the effects of AVP stimulation on CMECs and cardiac fibroblasts (CFs) were studied using methylthiazol tetrazolium assay, Western blotting and real-time PCR. RESULTS: With cardiac dysfunction, plasma and local cardiac AVP, aldosterone levels increased over time, peaking at 9 weeks post-MI. AVP levels were negatively correlated with serum Na(+) and LVEF but positively correlated with LVEDD and myocardial hydroxyproline. In CMECs treated with Ang II, AVP mRNA and protein expression increased. In addition, AVP promoted CFs proliferation and up-regulated the expression of endothelin-1 and connective tissue growth factor. CONCLUSION: CMECs are the cellular sources of elevated local heart AVP stimulated with Ang II/AT1. An intrinsic cardiac AVP system exists. Local cardiac and circulating AVP secretion were enhanced by deteriorating cardiac function. AVP may promote ventricular remodeling. Thus, AVP could be an important mediator of myocardial fibrosis in late-stage heart failure. PMID- 25823555 TI - HMGA2 expression pattern and TERT mutations in tumors of the vulva. AB - Malignant tumors of the vulva account for only 5% of cancers of the female genital tract in the USA. The most frequent cancers of the vulva are squamous cell carcinoma (SCC) and malignant melanoma (MM). Little is known about the genetic aberrations carried by these tumors. We report a detailed study of 25 vulva tumors [22 SCC, 2 MM, 1 atypical squamous cell hyperplasia (AH)] analyzed for expression of the high-mobility group AT-hook family member genes HMGA2 and HMGA1, for mutations in the IDH1, IDH2 and TERT genes, and for methylation of the MGMT promoter. The RT-PCR and immunohistochemistry analyses showed that HMGA2 was expressed in the great majority of analyzed samples (20 out of 24; SCC as well as MM) but not in the normal controls. HMGA1, on the other hand, was expressed in both tumors and normal tissues. Five of the 24 tumors (all SCC) showed the C228T mutation in the TERT promoter. Our results showed that HMGA2 and TERT may be of importance in the genesis and/or the progression of tumors of the vulva. PMID- 25823556 TI - Sarcocystis chloropusae (protozoa: Sarcocystidae) n. sp. from the common moorhen (Gallinula chloropus) from Egypt. AB - A new name Sarcocystis chloropusae is proposed for a parasite previously found in two of 25 common moorhen (Gallinula chloropus) from Brolos Lake, Egypt. Sarcocysts were microscopic, up to 650 MUm long, the cyst wall was up to 4.5 MUm thick, and contained villar protrusions that were up to 4 MUm long and up to 2 MUm wide. The villar protrusions were crowded, contained vesicles but lacked microtubules. The ground substance layer was smooth. The bradyzoites were up to 12 MUm long and up to 2 MUm wide. Molecular characterization and phylogenetic analysis of the (ITS-1) supported the conclusion that the Sarcocystis in G. chloropus is a distinct species. PMID- 25823557 TI - A new performance measurement system for maternal and child health in the United States. AB - OBJECTIVE: The Title V Maternal and Child Health (MCH) Block Grant is the linchpin for US MCH services. The first national performance measures (NPMs) for MCH were instituted in 1997. Changing trends in MCH risk factors, outcomes, health services, data sources, and advances in scientific knowledge, in conjunction with budgetary constraints led the Maternal and Child Health Bureau (MCHB) to design a new performance measurement system. METHODS: A workgroup was formed to develop a new system. The following guiding principles were used: (1) Afford States more flexibility and reduce the overall reporting burden; (2) Improve accountability to better document Title V's impact; (3) Develop NPMs that encompass measures in: maternal and women's health, perinatal health, child health, children with special health care needs, adolescent health, and cross cutting areas. RESULTS: A three-tiered performance measurement system was proposed with national outcome measures (NOMs), NPMs and evidence-based/informed strategy measures (ESMs). NOMs are the ultimate goals that MCHB and States are attempting to achieve. NPMs are measures, generally associated with processes or programs, shown to affect NOMs. ESMs are evidence-based or informed measures that each State Title V program develops to affect the NPMs. There are 15 NPMs from which States select eight, with at least one from each population area. MCHB will provide the data for the NOMs and NPMs, when possible. CONCLUSIONS: The new performance measurement system increases the flexibility and reduces the reporting burden for States by allowing them to choose 8 NPMs to target, and increases accountability by having States develop actionable ESMs. SIGNIFICANCE: The new national performance measure framework for maternal and child health will allow States more flexibility to address their areas of greatest need, reduce their data reporting burden by having the Maternal and Child Health Bureau provide data for the National Outcome and Performance Measures, yet afford States the opportunity to develop measurable strategies to address their selected performance measures. PMID- 25823558 TI - Ureteroscopy for Paediatric Renal Tract Stones - Outcomes from a Tertiary European Centre. AB - AIMS: The use of ureteroscopy in treating paediatric stone disease has risen in recent years. We retrospectively reviewed the results of ureteroscopic stone management for our regional paediatric stone service. MATERIAL AND METHODS: Between April 2010 and October 2013, consecutive patients undergoing ureteroscopy and stone fragmentation were identified. Data were recorded from electronic records for patient demographics, pre-operative assessment, stone characteristics, and intra- and post-operative complications. RESULTS: Twenty-one patients (mean age 8.6 years; range: 1.4-16) had 32 procedures in our series (13 males and 8 females). Five (24%) had a metabolic abnormality and 8 (38%) had an anatomical abnormality. The mean initial stone size was 9.6 mm (range: 5-20) and 10 were left sided. Of the 32 procedures, 18 (56%) had a pre-operative stent. A positive pre-operative urine culture was seen in 4 (13%). CT was used in 6 (19%) with the rest having a combination of USS and/or plain KUB. Of these 21 patients, 13 (62%) were stone free after the first procedure, 17 (81%) after a second and 20 (95%) after a third (mean 1.5 procedures/patient). One patient with a 6-mm residual fragment chose to have surveillance. Eighteen (50%) had post-operative stent insertion. The mean length of stay was 1.5 days (range: 0-5). A minor complication (Clavien 1) was observed in 1 patient. No other complications were recorded. CONCLUSIONS: Ureteroscopy for stone disease in children is feasible with a low complication rate and high stone-free rate. PMID- 25823559 TI - The fusion of Toxoplasma gondii SAG1 vaccine candidate to Leishmania infantum heat shock protein 83-kDa improves expression levels in tobacco chloroplasts. AB - Chloroplast transformation technology has emerged as an alternative platform offering many advantages over nuclear transformation. SAG1 is the main surface antigen of the intracellular parasite Toxoplasma gondii and a promising candidate to produce an anti-T. gondii vaccine. The aim of this study was to investigate the expression of SAG1 using chloroplast transformation technology in tobacco plants. In order to improve expression in transplastomic plants, we also expressed the 90-kDa heat shock protein of Leishmania infantum (LiHsp83) as a carrier for the SAG1 antigen. SAG1 protein accumulation in transplastomic plants was approximately 0.1-0.2 MUg per gram of fresh weight (FW). Fusion of SAG1 to LiHsp83 significantly increased the level of SAG1 accumulation in tobacco chloroplasts (by up to 500-fold). We also evaluated the functionality of the chLiHsp83-SAG1. Three human seropositive samples reacted with SAG1 expressed in transplastomic chLiHsp83-SAG1 plants. Oral immunization with chLiHsp83-SAG1 elicited a significant reduction of the cyst burden that correlated with an increase of SAG1-specific antibodies. We propose the fusion of foreign proteins to LiHsp83 as a novel strategy to increase the expression level of the recombinant proteins using chloroplast transformation technology, thus addressing one of the current challenges for this approach in antigen protein production. PMID- 25823560 TI - The Effect of Cognitive-Task Type and Walking Speed on Dual-Task Gait in Healthy Adults. AB - In a number of studies in which a dual-task gait paradigm was used, researchers reported a relationship between cognitive function and gait. However, it is not clear to what extent these effects are dependent on the type of cognitive and walking tasks used in the dual-task paradigm. This study examined whether stride time variability (STV) and trunk range of motion (RoM) are affected by the type of cognitive task and walking speed used during dual-task gait. Participants walked at both their preferred walking speed and at 25% of their preferred walking speed and performed a serial subtraction and a working memory task at both speeds. Although both tasks significantly reduced STV at both walking speeds, there was no difference between the two tasks. Trunk RoM was affected by the walking speed and type of cognitive task used during dual-task gait: Mediolateral trunk RoM was increased at the slow walking speed, and anterior posterior trunk RoM was higher only when performing the serial subtraction task at the slow walking speed. The reduction of STV, regardless of cognitive-task type, suggests that healthy adults may redirect cognitive processes away from gait toward cognitive-task performance during dual-task gait. PMID- 25823561 TI - Evaluation of the efficacy of an exercise program for pregnant women with low back and pelvic pain: a prospective randomized controlled trial. AB - AIM: To evaluate the effect of exercise programs on pregnant women with pregnancy related low back and pelvic pain. BACKGROUND: Low back and pelvic pain during pregnancy is a major health problem due to its frequent occurrence and such pain can limit pregnant women in many of their daily activities. DESIGN: A randomized trial with a control group (n = 48) and an intervention group (n = 48). Trial registration number NCT02189356. METHODS: Department of Obstetrics and Gynecology, between December 2011-May 2012, an Education and Research Hospital in Turkey. Based on the intention-to-treat principle, all pregnant women were analysed according to the group they were assigned to, regardless of whether they received the intervention or not. Participants in the intervention group received health counselling and exercised regarding low back and pelvic pain for four weeks. The pregnant women in the control group received usual care, comprised of routine clinical practice for pregnancy-related low back and pelvic pain. RESULTS: According to Mann-Whitney U test analysis results, there was a statistically significant difference between the control and intervention groups' Visual Analogue Scale during relaxation scores and Visual Analogue Scale during activity scores at the end of the study. According to Mann-Whitney U test analysis results, the change in the mean Oswestry Disability Index score for the intervention group and the difference in the mean scores between the two groups was statistically significant. CONCLUSIONS: A four-week exercise program including individualized health counselling to relieve low back and pelvic pain improved the functional status in pregnant women. PMID- 25823562 TI - PLAGL1 protein is differentially expressed in the nephron segments and collecting ducts in human kidney. AB - INTRODUCTION: PLAGL1 (pleiomorphic adenoma gene-like 1) is a C2H2-type zinc finger transcription factor associated with the regulation of cell growth and development. Although PLAGL1 expression in kidney was assessed by biochemical methods, the exact localization of the PLAGL1 protein in human kidney has not yet been described. MATERIAL AND METHODS: Macroscopically unchanged specimens of kidney tissue were collected from 39 patients undergoing nephrectomy due to renal cell carcinoma. H & E staining of paraffin sections was used to assess histology of the kidney whereas immunohistochemistry was used to localize PLAGL1 protein in kidney compartments. In addition, database sequences search for putative PLAGL1 binding sites among the kidney-related genes was performed. RESULTS: PLAGL1 staining intensity differed depending on the kidney compartment. Strong PLAGL1 immunoreactivity was found in thick ascending limbs of Henle's loop, distal tubules and collecting ducts, whereas PLAGL1 expression in proximal tubules and renal corpuscles (including podocytes) was moderate and weak, respectively. By the in sillico screening of promoter sequences for PLAGL1 specific DNA-binding sites GGG-GCCCC we designated 43 candidate genes for PLAGL1-regulated genes. Analysis of their functional annotations identified three significantly over represented gene sets: inositol phosphate metabolic processes (GO), endocrine and other factor-regulated calcium reabsorption (KEGG) and calcium signaling pathways (KEGG). CONCLUSION: Differences in the renal expression of PLAGL1 suggest that this protein may be involved in the regulation of several cellular pathways both as transcriptional factor and coactivator/corepressor of other tran-scription factors reflecting its role in the cell type-specific control of gene expression. PMID- 25823563 TI - Low-pH-induced apoptosis: role of endoplasmic reticulum stress-induced calcium permeability and mitochondria-dependent signaling. AB - The acidic microenvironment around tumor cells is a major determinant in cancer growth, metabolism, and metastasis. However, its role in cancer physiology is still not clearly understood. In the present investigation, an attempt has been made to explore the effect of acidic environment on physiology of cancer cells. Exposure of Raji cells to extracellular acidic environment was associated with enhanced cytosolic calcium level and endoplasmic reticulum stress response. X-box binding protein 1 (XBP1) splicing, CCAAT/enhancer-binding protein homologous protein (CHOP), and glucose-regulated protein 78 kDa (GRP78) upregulation suggested endoplasmic reticulum stress generation. On the other hand, real-time based upregulation of Bax gene expression and flow cytometric analysis of cytochrome c release as well as enhanced active caspase-3 further confirmed mitochondrion-mediated events leading to induction of apoptosis. The expression of TP53 and p21 was upregulated. These observations collectively strongly suggest that both endoplasmic reticulum stress-mediated calcium release and Bax targeting might be altering mitochondrion membrane potential which in turn could induce secondary apoptotic signals; subsequently, endoplasmic reticulum stress can also lead to nuclear localization of Nuclear factor-kappaB (NF-kappaB) which in turn favors p53 mediated apoptotic signals. PMID- 25823564 TI - Association of single nucleotide polymorphisms in MPO and COX genes with oral lichen planus. AB - Oral lichen planus (OLP) is an intractable, chronic inflammatory disorder, and its pathogenesis is still largely unknown. Some literatures supported that genes involved in both oxidative stress and prostaglandin metabolism play an important role in the process of inflammation. To explore their association with OLP, we investigated four single nucleotide polymorphisms (SNPs) from myeloperoxidase (MPO) and cyclooxygenase (COX) genes in 475 Chinese individuals (242 case and 233 controls) by MassArray. Although the genotype distributions had no significant differences between the patients and controls, we found that in different gender, rs2243828 from MPO displayed the statistically significant variance genotype frequencies between patients and controls (P = 0.018 in females, P = 0.035 in males). Moreover, for the major allele recessive model, this SNP also showed a significant difference between case and control groups in males (P = 0.015). In this study, we first observed significant association with MPO polymorphism and OLP risk in different gender groups in Chinese, suggesting MPO polymorphism is a gender-specific risk factor of OLP probably by influencing sex hormone-sensitive elements to regulate inflammatory gene expression networks, and we further revealed that oxidative stress was actually involved in the pathogenesis of this disease. Moreover, these findings inspire us some constructive solutions to the treatment of this disease. PMID- 25823565 TI - Education programs are likely to improve health, but will they improve health equity? PMID- 25823566 TI - A survey of intestinal parasites including associated risk factors in humans in Panama. AB - BACKGROUND: Intestinal parasitic infections are among the most common infections worldwide, leading to illness with serious and long lasting implications in children and immunocompromised people. Transmission of intestinal parasites is more frequent in tropical and sub-tropical areas where sanitation is poor and socioeconomic conditions are deficient. Panama is a country where climate and social conditions could be reflected in a high number of people infected with intestinal parasites. The presence, prevalence, and distribution of intestinal parasites in this country have been approached to date only in very restricted areas and population groups, but the impact of intestinal parasite infections at the national level is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional survey between 2008 and 2010 to determine the prevalence of intestinal parasites across Panama. Overall, 14 municipalities in seven provinces of Panama were surveyed. The presence of eggs, cysts, and larvae was assessed by microscopy in 1123 human fecal samples using a concentration technique. A questionnaire to identify risk factors associated with the frequency of intestinal parasites in the study population was also prepared and performed. Overall, 47.4% of human samples presented parasites. Variables including community type, age group, occupation, co-presence of commensals and socioeconomic factors (use of shoes and type of sanitation) were significantly associated with intestinal parasites (p<0.05). CONCLUSIONS/SIGNIFICANCE: The preliminary data obtained in the current study, showing a high prevalence of fecal-oral transmitted parasites in Panama, place intestinal parasitism as a major health problem in this country. Specific interventions should be planned for the indigenous population, the group most afflicted by intestinal parasites. PMID- 25823567 TI - Regulation of the oncogenic function of distal-less 4 by microRNA-122 in hepatocellular carcinoma. AB - Distal-less 4 (DLX4) is a member of the DLX family of homeobox genes. Recent reports have suggested that abnormal expression of DLX4 is present in several types of human tumors, including breast cancer, leukemia and colon cancer. However, the function and the mechanistic regulation of DLX4 in hepatocellular carcinoma (HCC) are elusive. In the present study, a proportion of hepatocellular carcinomas were identified to exhibit upregulated DLX4 expression. This study proposed that the overexpression of DLX4 is associated with the downregulation of miR-122, an underexpressed miRNA in human HCC. Functional studies have demonstrated that the downregulation of DLX4 in hepatocellular carcinoma cell lines is regulated by miR-122 through binding to its 3'UTR. Furthermore, a DLX4 overexpression vector lacking the 3'UTR was shown to abolish miR-122-induced inhibition of proliferation in the HCC cell line Hep3B. These results gave new insight into the mechanism of the miR-122/DLX4 axis in HCC. PMID- 25823568 TI - Cutaneous Sarcoidosis: Preamble of a Paucisymptomatic Systemic Disease. AB - Sarcoidosis is a systemic granulomatous disease with a wide range of clinical manifestations. Skin involvement is an early, frequent and accessible location for a histopathological study. Several risk factors have been described to determine the likelihood of systemic involvement of an apparent cutaneous condition. Early diagnosis and systemic treatment could prevent future complications. A series of three cases is presented in which the initial diagnosis was cutaneous sarcoidosis, but it was actually the first manifestation of a systemic disease. A review of this topic is also presented. PMID- 25823569 TI - Chemotherapeutic effects on circulating tumor cells in bladder cancer. PMID- 25823571 TI - Correlative in-resin super-resolution and electron microscopy using standard fluorescent proteins. AB - We introduce a method for correlative in-resin super-resolution fluorescence and electron microscopy (EM) of biological structures in mammalian culture cells. Cryo-fixed resin embedded samples offer superior structural preservation, performing in-resin super-resolution, however, remains a challenge. We identified key aspects of the sample preparation procedure of high pressure freezing, freeze substitution and resin embedding that are critical for preserving fluorescence and photo-switching of standard fluorescent proteins, such as mGFP, mVenus and mRuby2. This enabled us to combine single molecule localization microscopy with transmission electron microscopy imaging of standard fluorescent proteins in cryo fixed resin embedded cells. We achieved a structural resolution of 40-50 nm (~17 nm average single molecule localization accuracy) in the fluorescence images without the use of chemical fixation or special fluorophores. Using this approach enabled the correlation of fluorescently labeled structures to the ultrastructure in the same cell at the nanometer level and superior structural preservation. PMID- 25823570 TI - Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia. AB - Myopia can cause severe visual impairment. Here, we report a two-stage genome wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 * 10(-13)) and corneal curvature (Pmeta=2.9 * 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia. PMID- 25823572 TI - Combination therapy with infliximab and thiopurine compared to infliximab monotherapy in maintaining remission of postoperative Crohn's disease. AB - BACKGROUND AND AIMS: Infliximab is an efficacious agent used for the induction and maintenance of remission in Crohn's disease (CD), and recent studies suggested that it may also prevent the recurrence of this disease after surgery. The present study was performed to assess the efficacy and safety of infliximab in the postoperative setting, and to identify whether combination treatment with thiopurines had any additional beneficial effect as compared to mono-therapy. METHODS: We performed a retrospective cohort study to compare the efficacy of infliximab mono-therapy and combination treatment with a thiopurine in preventing recurrence after surgery. RESULTS: Forty-one patients who received infliximab as maintenance treatment following surgery from May 2002 to April 2010 were identified. Twenty-four were naive to infliximab, and 17 who underwent surgery during infliximab treatment were continued on it following surgery. The median follow-up period was 27 months (range 12-66 months). All patients continued infliximab as maintenance treatment, but 10 required dose intensification due to clinical recurrence. Kaplan-Meier analysis demonstrated that the use of concomitant thiopurine was correlated with the continuation of infliximab treatment at an 8-week interval (log-rank test p = 0.018). The rate of adverse event was 9.8% with no patient experiencing severe adverse reactions. CONCLUSION: Infliximab appears to be safe and it prevented clinical recurrence after surgery. Concomitant thiopurine use predicted response toward continuation of therapy at an 8-week interval. Prospective controlled studies to assess the efficacy of combination treatment in the postoperative setting are warranted. PMID- 25823573 TI - Initial Results of Image-Guided Percutaneous Ablation as Second-Line Treatment for Symptomatic Vascular Anomalies. AB - PURPOSE: The purpose of this study was to determine the feasibility, safety, and early effectiveness of percutaneous image-guided ablation as second-line treatment for symptomatic soft-tissue vascular anomalies (VA). MATERIALS AND METHODS: An IRB-approved retrospective review was undertaken of all patients who underwent percutaneous image-guided ablation as second-line therapy for treatment of symptomatic soft-tissue VA during the period from 1/1/2008 to 5/20/2014. US/CT or MRI-guided and monitored cryoablation or MRI-guided and monitored laser ablation was performed. Clinical follow-up began at one-month post-ablation. RESULTS: Eight patients with nine torso or lower extremity VA were treated with US/CT (N = 4) or MRI-guided (N = 2) cryoablation or MRI-guided laser ablation (N = 5) for moderate to severe pain (N = 7) or diffuse bleeding secondary to hemangioma-thrombocytopenia syndrome (N = 1). The median maximal diameter was 9.0 cm (6.5-11.1 cm) and 2.5 cm (2.3-5.3 cm) for VA undergoing cryoablation and laser ablation, respectively. Seven VA were ablated in one session, one VA initially treated with MRI-guided cryoablation for severe pain was re-treated with MRI guided laser ablation due to persistent moderate pain, and one VA was treated in a planned two-stage session due to large VA size. At an average follow-up of 19.8 months (range 2-62 months), 7 of 7 patients with painful VA reported symptomatic pain relief. There was no recurrence of bleeding at five-year post-ablation in the patient with hemangioma-thrombocytopenia syndrome. There were two minor complications and no major complications. CONCLUSION: Image-guided percutaneous ablation is a feasible, safe, and effective second-line treatment option for symptomatic VA. PMID- 25823574 TI - Use of Spider Filter Embolic Protection Device During Endovascular Revascularization of Acute Thromboembolic Occlusion of Superficial Femoral Artery. AB - OBJECTIVE: To retrospectively evaluate the safety and efficacy of the Spider filter embolic protection device (EPD) in protecting patients from distal migration of thromboemboli during revascularization of acute superficial femoral artery (SFA) occlusion secondary to thromboemboli. METHODS: Data from all patients at our institution who had EPD placement for embolic protection during endovascular revascularization for acute thromboembolic occlusion of the SFA were analyzed. RESULTS: From April 2007 to June 2014, a total of 14 patients had EPD placement during endovascular revascularization for acute SFA occlusion secondary to thromboemboli. All patients presented with acute onset of limb ischemia, and further work-up with imaging studies demonstrated thromboembolic occlusions. The duration from onset of symptoms to revascularization was 7.0 +/- 2.7 h (range 2 14 h). An aspiration technique for thrombectomy was used in all 14 cases (aspiration alone, 6 cases; aspiration plus urokinase, 7 cases; additional angioplasty after urokinase, 1 case). Spider filter EPDs were successfully placed at the target in all 14 cases, and the thromboemboli were captured in 13/14 (92.9%) cases. Successful reestablishment of the SFA flow without distal branch embolism occurred in all 14 cases. There were no EPD-related complications. During a mean 32.2 +/- 20.2 months of follow-up, 13 patients remained asymptomatic; one patient who underwent PTA during the procedure reported limb coolness and fatigue 6 months later because of recurrent atherosclerotic stenosis. CONCLUSION: The Spider filter EPD can be safe and effective in protecting patients from distal branch embolism when they undergo an endovascular thrombectomy procedure. PMID- 25823575 TI - Prophylactic embolization of the cystic artery prior to radioembolization of liver malignancies--an evaluation of necessity. AB - PURPOSE: Prior to radioembolization (RE) of hepatic tumors, many centers prophylactically occlude the cystic artery (CA) during evaluation angiography (EVA) to prevent radiation-induced cholecystitis. There is no conclusive evidence for the protective effect of CA embolization and it bears the risk of inducing ischemic cholecystitis. The aim of this study is to evaluate the justification for CA embolization by comparing clinical and morphologic imaging parameters between patients undergoing coil occlusion of the cystic artery (COCA) and those with uncoiled CA (UCCA). MATERIALS AND METHODS: Retrospective comparison of 37 patients with UCCA versus 68 patients with COCA in terms of clinical findings (CRP, leukocyte count, body temperature, upper abdominal pain) and morphologic imaging parameters associated with cholecystitis (gallbladder (GB) wall thickness, free fluid in GB bed, bremsstrahlung SPECT) after EVA, after RE, and at 6-week follow-up. RESULTS: At none of the 3 time points (EVA, RE, 6-week follow-up) was there any significant difference in CRP, leukocyte count, body temperature, or upper abdominal pain between the UCCA and COCA group. There was also no significant difference between the two groups with regard to GB wall thickness, fluid in the GB bed, and bremsstrahlung in SPECT. One patient of the UCCA group and two patients of the COCA developed cholecystitis requiring treatment. CONCLUSION: Comparison of clinical and imaging findings between patients with and without CA embolization prior to RE identified no predictors of radiogenic or ischemic cholecystitis after RE. Our study provides no evidence for a benefit of prophylactic CA embolization before RE. PMID- 25823576 TI - Th2 cytokines enhance TrkA expression, upregulate proliferation, and downregulate differentiation of keratinocytes. AB - BACKGROUND: Nerve growth factor (NGF), a neurotrophin that plays a critical role in developmental neurobiology, is released by proliferating keratinocytes and induces proliferation. OBJECTIVE: The aim of this study was to investigate the role of tyrosine kinase receptor A (TrkA), a high-affinity receptor of NGF, in human keratinocytes. METHODS: Expression of TrkA and NGF in skin diseases was investigated by immunohistochemistry. Expression of TrkA in cells was examined by Western blotting and RT-PCR. Cell proliferation was assessed by BrdU assay. RESULTS: We first determined the expression of TrkA and NGF in skin samples from patients with atopic dermatitis, prurigo nodularis, psoriasis vulgaris, and seborrheic keratosis. TrkA was only expressed in proliferating basal cells, and its expression was enhanced in atopic dermatitis samples. NGF expression was enhanced in atopic dermatitis and prurigo nodularis samples and in some samples from seborrheic keratosis patients. Investigation of the role of TrkA in vitro using normal human epidermal keratinocytes (NHEK) revealed that TrkA was significantly enhanced by the T helper type 2 (Th2) cytokines interleukin (IL)-4 and IL-13 but not by other inflammatory cytokines, such as IL-1beta, tumor necrosis factor alpha, interferon gamma, or epidermal growth factor. On the other hand, expression of NGF was not altered by Th2 cytokines. Notably, inhibition of TrkA significantly reversed the effects of IL-4 on proliferation and differentiation. Furthermore, overexpression of TrkA enhanced proliferation of NHEK. These results indicate that IL-4-induced TrkA expression in keratinocytes modulates proliferation and differentiation of these cells. CONCLUSION: Increased TrkA expression in keratinocytes in atopic dermatitis may contribute to the observed epidermal hyperproliferation in these patients. PMID- 25823577 TI - Incentivising effort in governance of public hospitals: Development of a delegation-based alternative to activity-based remuneration. AB - This paper is a first examination of the development of an alternative to activity-based remuneration in public hospitals, which is currently being tested at nine hospital departments in a Danish region. The objective is to examine the process of delegating the authority of designing new incentive schemes from the principal (the regional government) to the agents (the hospital departments). We adopt a theoretical framework where, when deciding about delegation, the principal should trade off an initiative effect against the potential cost of loss of control. The initiative effect is evaluated by studying the development process and the resulting incentive schemes for each of the departments. Similarly, the potential cost of loss of control is evaluated by assessing the congruence between focus of the new incentive schemes and the principal's objectives. We observe a high impact of the effort incentive in the form of innovative and ambitious selection of projects by the agents, leading to nine very different solutions across departments. However, we also observe some incongruence between the principal's stated objectives and the revealed private interests of the agents. Although this is a baseline study involving high uncertainty about the future, the findings point at some issues with the delegation approach that could lead to inefficient outcomes. PMID- 25823579 TI - [Title Unavailable]. PMID- 25823578 TI - Adoption of health information technologies by physicians for clinical practice: The Andalusian case. AB - OBJECTIVES: We investigated the level of adoption of Health Information Technologies (HIT) services, and the factors that influence this, amongst specialised and primary care physicians; in Andalusia, Spain. METHODS: We analysed the physicians' responses to an online survey. First, we performed a statistical descriptive analysis of the data; thereafter, a principal component analysis; and finally an order logit model to explain the effect of the use in the adoption and to analyse which are the existing barriers. RESULTS: The principal component analysis revealed three main uses of Health Information Technologies: Electronic Health Records (EHR), ePrescription and patient management and telemedicine services. Results from an ordered logit model showed that the frequency of use of HIT is associated with the physicians' perceived usefulness. Lack of financing appeared as a common barrier to the adoption of the three types of services. For ePrescription and patient management, the physician's lack of skills is still a barrier. In the case of telemedicine services, lack of security and lack of interest amongst professionals are the existing barriers. CONCLUSIONS: EHR functionalities are fully adopted, in terms of perceived usefulness. EPrescription and patient management are almost fully adopted, while telemedicine is in an early stage of adoption. PMID- 25823580 TI - Research priorities in epilepsy for the Asia-Oceanian region. AB - The Asia-Oceanian region is the most populous region in the world. Although there has been substantial economic development and improvement in health services in recent years, epilepsy remains generally an underrecognized and understudied condition. To help promote research in the region, the Commission on Asian and Oceanian Affairs (CAOA) of the International League Against Epilepsy (ILAE) appointed the Research Task Force (RTF) to facilitate the development of research priorities for the region. Research that focuses on issues that are unique or of particular importance in the Asia-Oceanian region is encouraged, and that captures the impact of the dynamic socioeconomic changes taking place in the region is emphasized. Based on these considerations, we propose research "dimensions" as priorities within the Asia-Oceanian region. These are studies (1) that would lead to fuller appreciation of the health burden of epilepsy, particularly the treatment gap; (2) that would lead to better understanding of the causes of epilepsy; (3) that would alleviate the psychosocial consequences of epilepsy; (4) that would develop better therapies and improved therapeutic outcomes; and (5) that would improve the research infrastructure. PMID- 25823581 TI - Propensity of red blood cells to undergo P2X7 receptor-mediated phosphatidylserine exposure does not alter during in vivo or ex vivo aging. AB - BACKGROUND: Phosphatidylserine (PS) exposure facilitates the removal of red blood cells (RBCs) from the circulation, potentially contributing to the loss of stored RBCs after transfusion, as well as senescent RBCs. Activation of the P2X7 receptor by extracellular adenosine 5'-triphosphate (ATP) can induce PS exposure on freshly isolated human RBCs, but whether this process occurs in stored RBCs or changes during RBC aging is unknown. STUDY DESIGN AND METHODS: RBCs were processed and stored according to Australian blood banking guidelines. PS exposure was determined by annexin V binding and flow cytometry. Efficacy of P2X antagonists was assessed by flow cytometric measurements of ATP-induced ethidium+ uptake in RPMI 8226 cells. Osmotic fragility was assessed by lysis in hypotonic saline. RBCs were fractionated by discontinuous density centrifugation. RESULTS: ATP (1 mmol/L) induced PS exposure on RBCs stored for less than 1 week. This process was near-completely inhibited by the P2X7 antagonists A438079 and AZ10606120 and the P2X1/P2X7 antagonist MRS2159 but not the P2X1 antagonist NF499. ATP-induced PS exposure on RBCs was not dependent on K+, Na+, or Cl- fluxes. ATP did not alter the osmotic fragility of stored RBCs. ATP-induced PS exposure was similar between RBCs of different densities. ATP-induced PS exposure was also similar between RBCs stored for less than 1 week or for 6 weeks. CONCLUSION: The propensity of RBCs to undergo P2X7-mediated PS exposure does not alter during in vivo and ex vivo aging. Thus, P2X7 activation is unlikely to be involved in the removal of senescent RBCs or stored RBCs after transfusion. PMID- 25823582 TI - Flowering time of butterfly nectar food plants is more sensitive to temperature than the timing of butterfly adult flight. AB - 1. Variation among species in their phenological responses to temperature change suggests that shifts in the relative timing of key life cycle events between interacting species are likely to occur under climate warming. However, it remains difficult to predict the prevalence and magnitude of these shifts given that there have been few comparisons of phenological sensitivities to temperature across interacting species. 2. Here, we used a broad-scale approach utilizing collection records to compare the temperature sensitivity of the timing of adult flight in butterflies vs. flowering of their potential nectar food plants (days per degrees C) across space and time in British Columbia, Canada. 3. On average, the phenology of both butterflies and plants advanced in response to warmer temperatures. However, the two taxa were differentially sensitive to temperature across space vs. across time, indicating the additional importance of nontemperature cues and/or local adaptation for many species. 4. Across butterfly plant associations, flowering time was significantly more sensitive to temperature than the timing of butterfly flight and these sensitivities were not correlated. 5. Our results indicate that warming-driven shifts in the relative timing of life cycle events between butterflies and plants are likely to be prevalent, but that predicting the magnitude and direction of such changes in particular cases is going to require detailed, fine-scale data. PMID- 25823583 TI - Diagnostic evaluation for interventional bronchoscopists and radiologists in lung cancer practice. AB - The global epidemic of lung cancer shows no signs of abating. It is generally accepted that accurate and cost-efficient diagnostic evaluation is the first important step to achieve the best outcomes of treatment. This is true in the context of disease confirmation, treatment planning, treatment monitoring, detection of and management of treatment failure or prognostication. Fortunately, major advances in the diagnostic evaluation of lung cancer have been made in the past three decades allowing more patients to get the appropriate treatment at the right time. This paper outlines how computed tomography, positron emission tomography/computed tomography and endobronchial ultrasound contribute to lung cancer management and discuss their strengths and weaknesses and their complimentary roles at different stages of lung cancer management. Due to financial constraint and reimbursement restrictions, not all clinically important advances in the diagnostic evaluation of lung cancer have been readily accepted into routine clinical care. This enforces the need to maintain ongoing dialogue between cancer clinicians, imaging specialists and health-care economists. PMID- 25823584 TI - Structural and quantitative analysis of Equisetum alkaloids. AB - Equisetum palustre L. is known for its toxicity for livestock. Several studies in the past addressed the isolation and identification of the responsible alkaloids. So far, palustrine (1) and N(5)-formylpalustrine (2) are known alkaloids of E. palustre. A HPLC-ESI-MS/MS method in combination with simple sample work-up was developed to identify and quantitate Equisetum alkaloids. Besides the two known alkaloids six related alkaloids were detected in different Equisetum samples. The structure of the alkaloid palustridiene (3) was derived by comprehensive 1D and 2D NMR experiments. N(5)-Acetylpalustrine (4) was also thoroughly characterized by NMR for the first time. The structure of N(5)-formylpalustridiene (5) is proposed based on mass spectrometry results. Twenty-two E. palustre samples were screened by a HPLC-ESI-MS/MS method after development of a simple sample work-up and in most cases the set of all eight alkaloids were detected in all parts of the plant. A high variability of the alkaloid content and distribution was found depending on plant organ, plant origin and season ranging from 88 to 597mg/kg dried weight. However, palustrine (1) and the alkaloid palustridiene (3) always represented the main alkaloids. For the first time, a comprehensive identification, quantitation and distribution of Equisetum alkaloids was achieved. PMID- 25823585 TI - Unravelling the architecture and dynamics of tropane alkaloid biosynthesis pathways using metabolite correlation networks. AB - The tropane alkaloid spectrum in Solanaceae is highly variable within and between species. Little is known about the topology and the coordination of the biosynthetic pathways leading to the variety of tropine and pseudotropine derived esters in the alkaloid spectrum, or about the metabolic dynamics induced by tropane alkaloid biosynthesis stimulating conditions. A good understanding of the metabolism, including all ramifications, is however necessary for the development of strategies to increase the abundance of pharmacologically interesting compounds such as hyoscyamine and scopolamine. The present study explores the tropane alkaloid metabolic pathways in an untargeted approach involving a correlation-based network analysis. Using GC-MS metabolite profiling, the variation and co-variation among tropane alkaloids and primary metabolites was monitored in 60 Datura innoxia Mill. individuals, of which half were exposed to tropane alkaloid biosynthesis stimulating conditions by co-culture with Agrobacterium rhizogenes. Considerable variation was evident in the relative proportions of the tropane alkaloids. Remodeling of the tropane alkaloid spectrum under co-culture with A. rhizogenes involved a specific and strong increase of hyoscyamine production and revealed that the accumulation of hyoscyamine, 3 tigloyloxy-6,7-epoxytropane, and 3-methylbutyryloxytropane was controlled independently of the majority of tropane alkaloids. Based on correlations between metabolites, we propose a biosynthetic origin of hygrine, the order of esterification of certain di-oxygenated tropanes, and that the rate of acetoxylation contributes to control of hyoscyamine production. Overall, this study shows that the biosynthesis of tropane alkaloids may be far more complex and finely controlled than previously expected. PMID- 25823586 TI - Single-Cell Based Quantitative Assay of Chromosome Transmission Fidelity. AB - Errors in mitosis are a primary cause of chromosome instability (CIN), generating aneuploid progeny cells. Whereas a variety of factors can influence CIN, under most conditions mitotic errors are rare events that have been difficult to measure accurately. Here we report a green fluorescent protein-based quantitative chromosome transmission fidelity (qCTF) assay in budding yeast that allows sensitive and quantitative detection of CIN and can be easily adapted to high throughput analysis. Using the qCTF assay, we performed genome-wide quantitative profiling of genes that affect CIN in a dosage-dependent manner and identified genes that elevate CIN when either increased (icCIN) or decreased in copy number (dcCIN). Unexpectedly, qCTF screening also revealed genes whose change in copy number quantitatively suppress CIN, suggesting that the basal error rate of the wild-type genome is not minimized, but rather, may have evolved toward an optimal level that balances both stability and low-level karyotype variation for evolutionary adaptation. PMID- 25823587 TI - Gene Network Reconstruction by Integration of Prior Biological Knowledge. AB - With the development of high-throughput genomic technologies, large, genome-wide datasets have been collected, and the integration of these datasets should provide large-scale, multidimensional, and insightful views of biological systems. We developed a method for gene association network construction based on gene expression data that integrate a variety of biological resources. Assuming gene expression data are from a multivariate Gaussian distribution, a graphical lasso (glasso) algorithm is able to estimate the sparse inverse covariance matrix by a lasso (L1) penalty. The inverse covariance matrix can be seen as direct correlation between gene pairs in the gene association network. In our work, instead of using a single penalty, different penalty values were applied for gene pairs based on a priori knowledge as to whether the two genes should be connected. The a priori information can be calculated or retrieved from other biological data, e.g., Gene Ontology similarity, protein-protein interaction, gene regulatory network. By incorporating prior knowledge, the weighted graphical lasso (wglasso) outperforms the original glasso both on simulations and on data from Arabidopsis. Simulation studies show that even when some prior knowledge is not correct, the overall quality of the wglasso network was still greater than when not incorporating that information, e.g., glasso. PMID- 25823588 TI - Assessment of attitudes towards sun-protective behaviour in Australians: A cross sectional study. AB - OBJECTIVE: To assess the knowledge, attitudes and behaviour towards sun protection measures in a sample of Australian adults. METHODS: A multicentre, cross-sectional study was undertaken during 2014 using a population-based survey of 416 individuals over the age of 18. The knowledge, behaviour and attitudes towards sun protection measures in this group of adults were assessed. The impact of educational level and employment status on responses was also evaluated. RESULTS: Sunscreen is the most common sun-protective measure. Daily sunscreen use is below 20%. Forgetfulness was the largest barrier to sunscreen use. A total of 85% of respondents did not apply a sufficient amount of sunscreen. Only 32% of individuals reapplied sunscreen every 2 hours and 20% never reapplied it. In the preceding year, one or more sun burns were suffered by 46% of the participants in the survey. In all, 36% of individuals rarely or never check their sunscreens expiry date and less than 50% of individuals replaced their sunscreen each year. Furthermore, 65% were unaware that sunscreens stored above 25 degrees C were less effective than when stored correctly as per manufactures labelling. CONCLUSIONS: This study highlights a number of significant deficiencies that future sun protection programmes could target in order to improve the general public's knowledge and attitudes towards sun protection. There is also a need for this to be translated into the public's sun-protection behaviour. PMID- 25823589 TI - Intermediate-risk differentiated thyroid carcinoma patients who were surgically ablated do not need adjuvant radioiodine therapy: long-term outcome study. AB - OBJECTIVE: The mute question is whether patients with DTC of intermediate risk of recurrence, second most common presentation, who were surgically ablated in the first place, ever needed adjuvant RAI therapy? This study exclusively evaluated the long-term outcome in intermediate-risk patients with DTC. DESIGN: Two-arm retrospective cohort study conducted between years 1991 and 2012. SETTING: Institutional practice. PATIENTS: Intermediate-risk DTC patients, with pathologically proven T1/2 N1 M0, T3 with/without N1 M0 disease, with a minimum follow-up of 12 months, were included. Of 254 patients who fulfilled the inclusion/exclusion criteria, 125 patients were surgically ablated (Gr-I) and 129 patients had significant remnant and/nodal disease (Gr-II). No radioiodine in Gr I and adjuvant RAI therapy was administered in Gr-II patients. MEASUREMENTS: Baseline characteristics were compared and overall survival, event-free survival, disease-free survival/overall remission rates and recurrence rates were calculated for both the groups. RESULTS: All baseline patient characteristics were comparable except 24-h RAIU between two groups. Depending on adjuvant radioiodine therapy outcome, Gr-II patients were subclassified as Gr-IIa (ablated) and Gr-IIb (not ablated). With a median follow-up duration of 10.3 years (range: 1-21 years), 12/125 (9.6%) patients had disease recurrence and 10 (8%) showed persistent disease in Gr-I. In Gr-IIa, 6/102 (5.9%) patients recurred but only one of them was successfully ablated with (131) I, and 5 (4.9%) had persistent disease. However, in Gr-IIb, 27 patients who failed first-dose adjuvant RAI therapy, 8/27 (29.6%) showed persistent disease (P = 0.000). Overall survival was 100%; however, disease-free survival rates were 92% and 90%, in Gr-I and Gr-II, respectively. CONCLUSION: Intermediate-risk surgically ablated patients do not need adjuvant RAI therapy and patients who failed to achieve ablation with first dose of (131) I may be dynamically risk stratified as high risk category and managed aggressively. PMID- 25823590 TI - Predictors of need for mechanical ventilation at discharge after tracheostomy in the PICU. AB - BACKGROUND: The objective of this study was to determine factors predictive of need for mechanical ventilation (MV) upon discharge from the pediatric intensive care unit (PICU) among patients who receive a tracheostomy during their stay. METHODS: This was a retrospective cohort study using the Virtual PICU Systems (VPS) database. Patients <18 years old admitted between 2009-2011 who required MV for at least 3 days and received a tracheostomy during their PICU stay were included. RESULTS: A total of 680 pediatric patients from 74 PICUs were included, of whom 347 (51%) remained on MV at the time of PICU discharge. Neonates (30/38, 79%) and infants (129/203, 64%) required MV at PICU discharge after tracheostomy more often than adolescents (66/141, 47%) and children (122/298, 41%). Time on MV pre-tracheostomy was longer among those who required MV at discharge (median 18.3 vs. 13.8 days, P < 0.0001); however, number of failed extubations was similar (median 1 for both groups, P = 0.97). On mixed-effects multivariable regression analysis, the age categories of neonate (OR 2.9, 95%CI 1.1-7.6, P = 0.03), and infant (OR 1.7, 95%CI 1.1-2.8, P = 0.03), and ventilator days prior to tracheostomy (OR 1.01, 95%CI 1.0-1.02, P = 0.01) were significantly associated with increased odds of MV upon PICU discharge, while being a trauma admission was associated with decreased odds (OR 0.45, 95%CI 0.28-0.73, P = 0.001). CONCLUSIONS: Younger patients and those with prolonged courses of MV prior to tracheostomy are more likely to continue to need MV upon PICU discharge. PMID- 25823592 TI - The advantages of covalently attaching organometallic catalysts to a carbon black support: recyclable Rh(i) complexes that deliver enhanced conversion and product selectivity. AB - Pure carbon black (CB) was covalently attached to a bidentate nitrogen coordination motif with a carbon-carbon bond by spontaneous reaction with an in situ generated ligand precursor. The functionalized support was treated with [Rh(CO)2(MU-Cl)]2 to form a heterogeneous carbon-based support covalently linked to a well defined Rh(i) coordination complex. The hybrid material was characterized using X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), Infrared (IR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS). The CB-supported Rh(i) catalyst was active in both hydroamination and dihydroalkoxylation reactions achieving turnover numbers approaching 1000 and was readily recycled. The selectivity of an intramolecular dihydroalkoxylation reaction was significantly improved by covalently anchoring the catalyst to the CB surface. PMID- 25823591 TI - FIB-SEM tomography of human skin telocytes and their extracellular vesicles. AB - We have shown in 2012 the existence of telocytes (TCs) in human dermis. TCs were described by transmission electron microscopy (TEM) as interstitial cells located in non-epithelial spaces (stroma) of many organs (see www.telocytes.com). TCs have very long prolongations (tens to hundreds micrometers) named Telopodes (Tps). These Tps have a special conformation with dilated portions named podoms (containing mitochondria, endoplasmic reticulum and caveolae) and very thin segments (below resolving power of light microscopy), called podomers. To show the real 3D architecture of TC network, we used the most advanced available electron microscope technology: focused ion beam scanning electron microscopy (FIB-SEM) tomography. Generally, 3D reconstruction of dermal TCs by FIB-SEM tomography revealed the existence of Tps with various conformations: (i) long, flattened irregular veils (ribbon-like segments) with knobs, corresponding to podoms, and (ii) tubular structures (podomers) with uneven calibre because of irregular dilations (knobs) - the podoms. FIB-SEM tomography also showed numerous extracellular vesicles (diameter 438.6 +/- 149.1 nm, n = 30) released by a human dermal TC. Our data might be useful for understanding the role(s) of TCs in intercellular signalling and communication, as well as for comprehension of pathologies like scleroderma, multiple sclerosis, psoriasis, etc. PMID- 25823593 TI - An atypical 0.73 MB microduplication of 22q11.21 and a novel SALL4 missense mutation associated with thumb agenesis and radioulnar synostosis. AB - We describe a 0.73 Mb duplication of chromosome 22q11.21 between LCR-B and LCR-D and a missense mutation in a conserved C2H2 zinc finger domain of SALL4 in a cognitively normal patient with multiple skeletal anomalies including radioulnar synostosis, thumb aplasia, butterfly vertebrae, rib abnormalities, and hypoplasia of the humeral and femoral epiphyses. 22q11.21 is a common site for microdeletions and their reciprocal microduplications as a result of non-allelic homologous recombination between its multiple low copy repeat regions (LCR). DiGeorge /Velocardiofacial syndrome (DG/VCFS) is classically caused by a 3 Mb deletion between LCR-A and LCR-D or a 1.5 Mb deletion between LCR-A and LCR-B. The reciprocal syndrome to DG/VCFS is the recently described 22q11.2 microduplication, which usually presents with the typical 3 Mb or 1.5 Mb duplication. Numerous atypical deletions and duplications have been reported between other LCRs. Typically, SALL4-related Duane-radial ray syndrome is caused by deletions or nonsense mutations; the only missense SALL4 mutation described prior was thought to result in gain of function and produced cranial midline defects. The skeletal anomalies presented in this report have not been previously described in association with 22q11.2 microduplication nor SALL4 mutations. PMID- 25823594 TI - Pain in cochlear implant recipients: an uncommon, yet serious, consequence of cochlear implantation. AB - OBJECTIVES/HYPOTHESIS: We describe pain around the receiver/stimulator [RS] presenting months to years after implantation. STUDY DESIGN: A retrospective chart review. METHODS: We performed a retrospective review of all cochlear implant recipients complaining of pain around their RS through the years 2009 through 2013, with a follow-up of at least 6 months. Excluded from the study were patients with an identifiable cause for their pain such as trauma, local infection, or skin breakdown. The therapy regimen and outcomes were reviewed. RESULTS: Thirty patients complained of delayed pain over their RS, representing 2.8% of 1,044 implantations performed at the Sheba Medical Center, Tel Hashomer, Israel, as of 2013. The time from implantation to the presentation of pain ranged from 3 months to 12 years. The pain was perceptible even when the external magnet and processor were not used, and was usually most obvious in specific points around the RS. Seventy-seven percent of our patients responded well to conservative therapy. Fifteen (50%) responded to prolonged antibiotic treatment. Five patients (17%) responded to antiinflammatories alone. One patient (3%) responded to deactivation of two electrodes. Six patients (20%) required reimplantation, after which the pain resolved in all. At explantation, no signs of infection, foreign body reaction, or obvious device damage were found. CONCLUSION: Delayed pain around the RS that is unrelated to use is a serious consequence of cochlear implantation, and in some cases, those necessitating reimplantation, should be considered a major complication. LEVEL OF EVIDENCE: 4. PMID- 25823595 TI - Self-assembly of molecule-like nanoparticle clusters directed by DNA nanocages. AB - Analogous to the atom-molecule relationship, nanoparticle (NP) clusters (or NP molecules) with defined compositions and directional bonds could potentially integrate the properties of the component individual NPs, leading to emergent properties. Despite extensive efforts in this direction, no general approach is available for assembly of such NP-molecules. Here we report a general method for building this type of structures by encapsulating NPs into self-assembled DNA polyhedral wireframe nanocages, which serve as guiding agents for further assembly. As a demonstration, a series of NP-molecules have been assembled and validated. Such NP-molecules will, we believe, pave a way to explore new nanomaterials with emergent functions/properties that are related to, but do not belong to the individual component nanoparticles. PMID- 25823596 TI - True and false interindividual differences in the physiological response to an intervention. AB - NEW FINDINGS: What is the topic of this review? In 'personalized medicine', various plots and analyses are purported to quantify individual differences in intervention response, identify responders/non-responders and explore response moderators or mediators. What advances does it highlight? We highlight the impact of within-subject random variation, which is inevitable even with 'gold-standard' measurement tools/protocols and sometimes so substantial that it explains all apparent individual response differences. True individual response differences are quantified only by comparing the SDs of changes between intervention and comparator arms. When these SDs are similar, true individual response differences are clinically unimportant and further analysis unwarranted. Within the 'hot topic' of personalized medicine, we scrutinize common approaches for presenting and quantifying individual differences in the physiological response to an intervention. First, we explain how popular plots used to present individual differences in response are contaminated by random within-subject variation and the regression to the mean artefact. Using a simulated data set of blood pressure measurements, we show that large individual differences in physiological response can be suggested by some plots and analyses, even when the true magnitude of response is exactly the same in all individuals. Second, we present the appropriate designs and analysis approaches for quantifying the true interindividual variation in physiological response. It is imperative to include a comparator arm/condition (or derive information from a prior relevant repeatability study) to quantify true interindividual differences in response. The most important statistic is the SD of changes in the intervention arm, which should be compared with the same SD in the comparator arm or from a prior repeatability study in the same population conducted over the same duration as the particular intervention. Only if the difference between these SDs is clinically relevant is it logical to go on to explore any moderators or mediators of the intervention effect that might explain the individual response. To date, very few researchers have compared these SDs before making claims about individual differences in physiological response and their importance to personalized medicine. PMID- 25823598 TI - Effects of Immobilized BMP-2 and Nanofiber Morphology on In Vitro Osteogenic Differentiation of hMSCs and In Vivo Collagen Assembly of Regenerated Bone. AB - Engineering bone tissue is particularly challenging because of the distinctive structural features of bone within a complex biochemical environment. In the present study, we fabricated poly(L-lactic acid) (PLLA) electrospun nanofibers with random and aligned morphology immobilized with bone morphogenic protein-2 (BMP-2) and investigated how these signals modulate (1) in vitro osteogenic differentiation of human mesenchymal stem cells (hMSCs) and (2) in vivo bone growth rate, mechanical properties, and collagen assembly of newly formed bone. The orientation of adherent cells followed the underlying nanofiber morphology; however, nanofiber alignment did not show any difference in alkaline phosphate activity or in calcium mineralization of hMSCs after 14 days of in vitro culture in osteogenic differentiation media. In vivo bone regeneration was significantly higher in the nanofiber implanted groups (approximately 65-79%) as compared to the defect-only group (11.8 +/- 0.2%), while no significant difference in bone regeneration was observed between random and aligned groups. However, nanoindentation studies of regenerated bone revealed Young's modulus and contact hardness with anisotropic feature for aligned group as compared to random group. More importantly, structural analysis of collagen at de novo bone showed the ability of nanofiber morphology to guide collagen deposition. SEM and TEM images revealed regular, highly ordered collagen assemblies on aligned nanofibers as compared to random fibers, which showed irregular, randomly organized collagen deposition. Taken together, we conclude that nanofibers in the presence of osteoinductive signals are a potent tool for bone regeneration, and nanofiber alignment can be used for engineering bone tissues with structurally assembled collagen fibers with defined direction. PMID- 25823599 TI - A rhodium(I)-catalysed formal intramolecular C-C/C-H bond metathesis. AB - Phenylcyclobutanes underwent skeletal reorganisation in the presence of Wilkinson's catalyst to afford indanes through a cascade process involving chelation-assisted C-C bond cleavage and intramolecular C-H bond cleavage. PMID- 25823597 TI - Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes. AB - OBJECTIVES: Disordered eating may negatively impact bone in athletes. However, it is not known whether this effect is independent of the associated amenorrhea and relative hypercortisolemia. We aimed to compare attitudes, feelings, and cognitions associated with disordered eating using the Three-Factor Eating Questionnaire (TFEQ) and Eating Disorder Inventory-2 (EDI-2) in normal-weight oligomenorrheic athletes (OA), eumenorrheic athletes (EA), and nonathletes, and determine the associations with bone independent of confounders. METHOD: 109 OA, 39 EA, and 36 nonathletes (14-25 years) completed the TFEQ and EDI-2. Dual-energy X-ray absorptiometry was used to assess spine bone mineral density (BMD), and high-resolution pQCT to assess radius microarchitecture. We measured integrated cortisol (q 20', 11 PM-7 AM), bone formation (procollagen Type 1 N-terminal propeptide, P1NP), and resorption (C-telopeptide, CTX) markers in a subset. RESULTS: OA had lower spine BMD Z-scores than EA. Cognitive eating restraint (CER), drive for thinness (DT), ineffectiveness, and interoceptive awareness (IA) were higher in OA than EA (p < 0.05); CER was higher in OA versus nonathletes (p = 0.03). Pulsatile cortisol was positively associated with DT, ineffectiveness, and IA (p < 0.03). CER was inversely associated with BMD Z-scores and P1NP, and ineffectiveness with radius cross-sectional area even after controlling for age, BMI, amenorrhea duration, and cortisol (p < 0.03). DISCUSSION: Higher CER in athletes independently predicts lower BMD. PMID- 25823601 TI - Colorectal preOperative Surgical Score (CrOSS) for mortality in major colorectal surgery. AB - BACKGROUND: Colorectal surgery carries a significant mortality risk, with reported rates of 1-6% for elective surgery and up to 22% in the emergency setting. Both clinicians and patients will benefit from being able to predict the likelihood of death before surgery. Recently, we have described and validated two risk stratification models for colorectal surgery, the Barwon Health 2012 and Association Francaise de Chirurgie models. However, these models are not suitable for assessment at patient's bedside. The purpose of this study is to develop a simplified preoperative model capable of predicting mortality following colorectal surgery. METHODS: The new model is termed Colorectal preOperative Surgical Score (CrOSS). The development and internal validation of CrOSS was performed using a prospectively maintained colorectal database. External validation was performed using retrospective data. Univariate and multivariate analyses were performed in model development. Calibration and discrimination were used for model validation. RESULTS: There were 474 and 389 consecutive colorectal surgeries at Geelong Hospital and Western Hospital. Overall mortality rates were 5.16% and 1.03%, respectively. Significant predictors for mortality were as follows: age >=70, urgent operation, albumin <=30 g/L and congestive heart failure (receiver operating characteristic (ROC) = 0.870, calibration P-value = 0.937). The predicted risk of mortality was stratified according to the risk profile of 0.39-66.51%. When validated externally, CrOSS predicted mortality accurately (ROC = 0.847, calibration P-value = 0.199). CONCLUSIONS: A robust and simple preoperative model has been created to risk-stratify patients for colorectal surgery. This was successfully validated at another tertiary hospital. PMID- 25823602 TI - Secondary acute lymphoblastic leukaemia is constitutional and probably not related to prior therapy. AB - Very little is known about secondary acute lymphoblastic leukaemia (s-ALL). This retrospective analysis studied a cohort of s-ALL patients treated at a single centre between 1994 and 2013, while comparing therapy-associated ALL (t-ALL) and antecedent malignancy ALL (am-ALL) patients. Thirty-two patients with s-ALL were identified. The overall incidence was 9.4% among ALL adults while T-cell s-ALL was rare (12% of s-ALLs). The median time interval between two malignant diagnoses was 5.3 years (range: 0.1-28). In contrast to previous reports, most of the s-ALLs were CD10 + and without KMT2A (MLL) abnormalities. The overall survival (OS) rates of the entire cohort at 12 and 24 months from ALL diagnosis was 49% and 25%, respectively. Most patients (n = 23, 72%) received prior chemo /radio-therapy for their first malignancy (t-ALL) and only 9 (28%) did not (am ALL). No significant difference was found in the incidence of B-/T- lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia-positive ALL, nor in the rates of complete remission (P = 0.55) and OS (P = 0.97). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s-ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s-ALL. PMID- 25823600 TI - Analysis of cytokine production by peanut-reactive T cells identifies residual Th2 effectors in highly allergic children who received peanut oral immunotherapy. AB - BACKGROUND: Only limited evidence is available regarding the cytokine repertoire of effector T cells associated with peanut allergy, and how these responses relate to IgE antibodies to peanut components. OBJECTIVE: To interrogate T cell effector cytokine populations induced by Ara h 1 and Ara h 2 among peanut allergic (PA) children in the context of IgE and to evaluate their modulation during oral immunotherapy (OIT). METHODS: Peanut-reactive effector T cells were analysed in conjunction with specific IgE profiles in PA children using intracellular staining and multiplex assay. Cytokine-expressing T cell subpopulations were visualized using SPICE. RESULTS: Ara h 2 dominated the antibody response to peanut as judged by prevalence and quantity among a cohort of children with IgE to peanut. High IgE (> 15 kU(A)/L) was almost exclusively associated with dual sensitization to Ara h 1 and Ara h 2 and was age independent. Among PA children, IL-4-biased responses to both major allergens were induced, regardless of whether IgE antibodies to Ara h 1 were present. Among subjects receiving OIT in whom high IgE was maintained, Th2 reactivity to peanut components persisted despite clinical desensitization and modulation of allergen specific immune parameters including augmented specific IgG4 antibodies, Th1 skewing and enhanced IL-10. The complexity of cytokine-positive subpopulations within peanut-reactive IL-4(+) and IFN-gamma(+) T cells was similar to that observed in those who received no OIT, but was modified with extended therapy. Nonetheless, high Foxp3 expression was a distinguishing feature of peanut reactive IL-4(+) T cells irrespective of OIT, and a correlate of their ability to secrete type 2 cytokines. CONCLUSION: Although total numbers of peanut-reactive IL-4(+) and IFN-gamma(+) T cells are modulated by OIT in highly allergic children, complex T cell populations with pathogenic potential persist in the presence of recognized immune markers of successful immunotherapy. PMID- 25823603 TI - Reduction of Acute Shoulder Dislocations in a Remote Environment: A Prospective Multicenter Observational Study. AB - OBJECTIVE: Acute dislocations of the glenohumeral joint are common in wilderness activities. Emergent reduction should take place at the site of trauma to reduce the patient's pain and the risk of vascular and neurological complications. A limited number of reduction methods are applicable in remote areas. The aim of this study is to present our method of reduction of anterior shoulder luxation that is easily applicable in remote areas without medication, adjuncts, and assistants and is well tolerated by patients. METHODS: A prospective observational study was conducted during a 5-year period. The patients included underwent closed manual reduction with our technique. After each reduction, the physician who performed the reduction completed a standardized detailed history, and reexamined the patient (for acute complications). The patients were contacted 6 months after the trauma to investigate long-term postreduction complications. RESULTS: Reduction was achieved with our method in 39 (100.0%) of 39 patients. The mean pain felt during our reduction procedure was rated 1.7 +/- 1.4 (on a scale of 10) using the visual analog scale scoring system. No complications were noted before or after the reduction attempts. We did not find any long-term complications. CONCLUSIONS: The reduction method presented in the present study is an effective method for the reduction of acute shoulder luxations in remote places. Our data suggest that this method could be applied for safe and effective reduction of shoulder dislocation. PMID- 25823604 TI - Hypothermia Evidence, Afterdrop, and Practical Experience. PMID- 25823605 TI - Synthesis of two new enrichable and MS-cleavable cross-linkers to define protein protein interactions by mass spectrometry. AB - The cross-linking Mass Spectrometry (XL-MS) technique extracts structural information from protein complexes without requiring highly purified samples, crystallinity, or large amounts of material. However, there are challenges to applying the technique to protein complexes in vitro, and those challenges become more daunting with in vivo experiments. Issues include effective detection and identification of cross-linked peptides from complex mixtures. While MS-cleavable cross-linkers facilitate the sequencing and identification of cross-linked peptides, enrichable cross-linkers increase their detectability by allowing their separation from non-cross-linked peptides prior to MS analysis. Although a number of cross-linkers with single functionality have been developed in recent years, an ideal reagent would incorporate both capabilities for XL-MS studies. Therefore, two new cross-linkers have been designed and prepared that incorporate an azide (azide-A-DSBSO) or alkyne (alkyne-A-DSBSO) to enable affinity purification strategies based on click chemistry. The integration of an acid cleavage site next to the enrichment handle allows easy recovery of cross-linked products during affinity purification. In addition, these sulfoxide containing cross-linking reagents possess robust MS-cleavable bonds to facilitate fast and easy identification of cross-linked peptides using MS analysis. Optimized, gram scale syntheses of these cross-linkers have been developed and the azide-A-DSBSO cross-linker has been evaluated with peptides and proteins to demonstrate its utility in XL-MS analysis. PMID- 25823606 TI - A cross-sectional study of tumor markers during normal and high-risk pregnancies. AB - OBJECTIVE: To determine tumor marker concentrations during normal and high-risk pregnancies. METHODS: The present cross-sectional study included women attending the gynecology outpatient department at All India Institute of Medical Sciences, New Delhi, India, between November 1, 2012 and March 31, 2013. Their serum was assayed for carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 15-3 (CA15-3). RESULTS: A total of 251 pregnant women and 31 nonpregnant women were included. Median CEA value was lower among pregnant women than among nonpregnant women (1.2MUg/L vs 1.4MUg/L; P=0.006), whereas that of CA15-3 was higher (16.7U/mL vs 12.3U/mL; P=0.03). CA19-9 concentration was higher among pregnant women aged 25-29years (7.0U/mL) or 30-34years (7.2U/mL) than among those aged 20-24years (4.2U/mL; P=0.01 for both). The CA15-3 level was increased during the second (13.0U/mL) and third (60.5U/mL) trimesters compared with the first trimester (9.5U/mL) (P<=0.01 for both comparisons). It was also raised in high-risk pregnancies (33.7U/mL), specifically pregnancies complicated by gestational diabetes mellitus (39.7U/mL), intrahepatic cholestasis of pregnancy (64.3U/mL), or heart disease (54.0U/mL) (P<0.05 for all). CONCLUSION: CA15-3 concentrations rise during pregnancy, but whether this increase can be attributed to physiological changes in breast tissue needs to be investigated further. PMID- 25823608 TI - Persistent luminescent sub-10 nm Cr doped ZnGa2O4 nanoparticles by a biphasic synthesis route. AB - This communication highlights a simple and facile biphasic synthesis of sub-10 nm Cr doped ZnGa2O4 nanoparticles (NPs) for the first time. These smallest Cr:ZnGa2O4 NPs demonstrate stable persistent luminescence emission more than 40 min after excitation. This synthesis strategy not only enables the controlled synthesis of these mixed metal oxide NPs unprecedentedly with smallest size to date but also allows them to be solution processable, which is advantageous for relevant applications with feasible and economic device fabrication. PMID- 25823609 TI - Hamate fractures. AB - OBJECTIVE: The purpose of this paper is to present our experience in the treatment of the fractures of the hamate and to make a review of the literature on this topic. MATERIAL AND METHOD: We retrospectively reviewed 10 patients treated in our clinic between 2005-2012 suffering from fractures of the hamate. Six cases were fractures of the body and four were fractures of the hamate. Five cases were of associated injuries. Diagnostic delay ranged from 30 days to 2 years. Patient follow-up ranged from 1 to 10 years. Patient satisfaction was evaluated using the DASH questionnaire. Five patients with a fracture of the body underwent surgery, and one was treated conservatively. Two patients with fracture of the hook of the hamate were treated with immobilization, and two more patients had the fragment removed. RESULTS: The grip strength and the digital clip were reduced in 2 cases. Flexion and extension of the wrist was limited in 3 cases. The mobility of the fingers was normal in all the cases, except in one. The results obtained from the DASH questionnaire were normal in all the cases, except in one case of fracture of the hamate, and in two cases of fracture of the body. CONCLUSIONS: The surgical treatment should reduce the dislocation and stabilize the injuries with osteosynthesis. The fractures of the hamate are usually diagnosed late, and the most recommended treatment is removal of the fragment, although it cannot be deduced from this study. PMID- 25823610 TI - Connexin50 couples axon terminals of mouse horizontal cells by homotypic gap junctions. AB - Horizontal cells in the mouse retina are of the axon-bearing B-type and contribute to the gain control of photoreceptors and to the center-surround organization of bipolar cells by providing feedback and feedforward signals to photoreceptors and bipolar cells, respectively. Horizontal cells form two independent networks, coupled by dendro-dendritic and axo-axonal gap junctions composed of connexin57 (Cx57). In Cx57-deficient mice, occasionally the residual tracer coupling of horizontal cell somata was observed. Also, negative feedback from horizontal cells to photoreceptors, potentially mediated by connexin hemichannels, appeared unaffected. These results point to the expression of a second connexin in mouse horizontal cells. We investigated the expression of Cx50, which was recently identified in axonless A-type horizontal cells of the rabbit retina. In the mouse retina, Cx50-immunoreactive puncta were predominantly localized on large axon terminals of horizontal cells. Electron microscopy did not reveal any Cx50-immunolabeling at the membrane of horizontal cell tips invaginating photoreceptor terminals, ruling out the involvement of Cx50 in negative feedback. Moreover, Cx50 colocalized only rarely with Cx57 on horizontal cell processes, indicating that both connexins form homotypic rather than heterotypic or heteromeric gap junctions. To check whether the expression of Cx50 is changed when Cx57 is lacking, we compared the Cx50 expression in wildtype and Cx57-deficient mice. However, Cx50 expression was unaffected in Cx57-deficient mice. In summary, our results indicate that horizontal cell axon terminals form two independent sets of homotypic gap junctions, a feature which might be important for light adaptation in the retina. PMID- 25823612 TI - Risk factors for cytarabine-induced cutaneous toxicity in patients with haematological malignancies. AB - BACKGROUND: The risk factors for cytarabine (Ara-C)-induced cutaneous toxicity are unclear. METHODS: We retrospectively reviewed the medical charts of patients with haematopoietic malignancies treated with Ara-C and examined risk factors for Ara-C-induced cutaneous toxicity. RESULTS: We reviewed 114 patients (76 men, 38 women) and found that 47 patients (41.2%) experienced cutaneous toxicity. In 93 patients (81.6%) with non-Hodgkin's lymphoma (NHL) and acute myeloid leukaemia (AML), the toxicity was significantly associated with the cancer type [AML/NHL: odds ratio (OR) = 4.84; 95% confidence interval (CI) = 1.99-11.81; p = 0.001], age (<50/>=50 years: OR = 2.54; 95% CI = 1.08-5.95; p = 0.032) and concurrent steroid administration (yes/no: OR = 0.22; 95% CI = 0.09-0.56; p = 0.001). AML was the only significant association (OR = 3.83; 95% CI = 1.21-12.06; p = 0.022) in the multivariate logistic analysis. CONCLUSION: AML, age <50 years and no steroid use are considered to be risk factors for Ara-C-induced cutaneous toxicity. PMID- 25823611 TI - Generation of Natural Killer Cell Memory during Viral Infection. AB - Immunological memory is classically regarded as an attribute of antigen-specific T and B lymphocytes of the adaptive immune system. Cells of the innate immune system, including natural killer (NK) cells, have been considered short-lived cytolytic cells that can rapidly respond against pathogens in an antigen independent manner and then die off. However, NK cells have recently been described to possess traits of adaptive immunity, such as clonal expansion after viral antigen exposure to generate long-lived memory cells. In this review, we will discuss the current evidence for viral-induced NK cell memory in both mice and humans. PMID- 25823613 TI - Oocyte zona pellucida dysmorphology is associated with diminished in-vitro fertilization success. AB - BACKGROUND: Although irregularities in human zona pellucida (ZP) morphology are well described, there is scant literature on the clinical significance of ZP dysmorphology. We, therefore, designed a retrospective cohort trial of ZP dysmorphology to assess the clinical significance of ZP dysmorphology and its affect on IVF outcome. Over the same time period a random sample of 77 cycles of 77 subjects with all normal oocyte morphology were selected as controls. METHODS: Between July 2006 and December 2010, all fresh non-donor cases performed at a university hospital IVF center were assessed for ZP dysmorphology. ZP dysmorphology included extracytoplasmic abnormalities (dark ZP and large perivitelline space) and oocyte shape (oval or irregularly shaped ZP). 136 IVF cycles from 119 subjects were identified where a majority of oocytes displayed ZP dysmorphology. Over the same time period a random sample of 77 cycles of 77 subjects with all normal oocyte morphology were selected as controls. IVF prognostic and outcome parameters were compared between the patients with dysmorphic and normal oocytes. RESULTS: 136/1710 (8.0%) cycles of fresh non-donor IVF displayed predominant ZP dysmorphology. Dysmorphic and normal oocytes showed no difference in the oocyte quality predictors such as FSH (6.03+/-2.5 vs. 6.8+/ 2.3 IU/L), or AMH (2.5+/-2.0 vs. 2.30+/-1.5 ng/ml levels). ZP dysmorphology was associated with markedly diminished clinical pregnancy rates (44% vs. 70%; RR:0.62 [0.48, 0.80]; p = 0.0002), implantation rates (.17 vs. .36; IRR: 0.48 [0.34, 0.68]; p < 0.0001) and live birth rates as compared to non dysmorphic oocytes (29% vs. 52%; RR:0.55 [0.39, 0.79]; p = 0.001). CONCLUSIONS: ZP dysmorphology is associated with markedly diminished pregnancy and implantation rates in IVF. The poorer outcome appears to be independent of the usual markers of ovarian reserve. PMID- 25823615 TI - Energetic Materials with Promising Properties: Synthesis and Characterization of 4,4'-Bis(5-nitro-1,2,3-2H-triazole) Derivatives. AB - Using a variety of functionalization strategies, derivatives of 4, 4'-bis(5-nitro 1,2,3-2H-triazole) were designed, synthesized, and characterized. The isomers were separated, their structures were confirmed with single-crystal X-ray analysis, and their properties were determined by differential scanning calorimetry, density, impact sensitivity, heat of formation, and detonation velocity and pressure (calculated by EXPLO5 V6.01). Those materials were found to exhibit superior detonation performance when compared with the other fully carbon nitrated bis(azoles). PMID- 25823614 TI - Management of obstructive salivary disorders by sialendoscopy: a systematic review. AB - Our aim was to assess the effectiveness and safety of sialendoscopy as a diagnostic and therapeutic technique in the management of obstructive salivary disorders. We searched the following databases: MEDLINE, EMBASE, ISI Web of Knowledge, The Cochrane Library, and the National Health Service Centre for Reviews and Dissemination (up to April 2014). References from the studies included and from review articles were scanned. A study was eligible for inclusion if it was a fully published peer-reviewed report with original data, if participants included adult patients with obstructive disease of the major salivary glands, if the outcome variables gave information about the success rates of the procedure in terms of freedom from symptoms and absence of residual obstruction, and if the paper was published in English, French, Italian, Portuguese, or Spanish. The data were extracted and summarised in tables of evidence. We report weighted pooled proportions, 95% CI, and test results for heterogeneity. The weighted pooled proportion of success rates of the obstruction's resolution was 76% (95% CI 71 to 82) for 40 studies involving 2654 patients undergoing sialendoscopy alone, and 91% (95% CI 88 to 94) for the 23 studies and 1480 procedures made with sialendoscopy and a combined surgical approach. In general, few complications were reported and the rate of sialadenectomy was low (4.6%). This systematic review suggests that sialendoscopy is effective and safe for the diagnosis and treatment of patients with obstructive salivary gland disease. PMID- 25823616 TI - Immunostaining of phospho-histone H3 and Ki-67 improves reproducibility of recurrence risk assessment of gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial tumors in the digestive tract. Beyond surgery, therapeutic management depends on risk of recurrence. Risk evaluation of GIST takes into account location and size of the tumor, whether or not the tumor was intact or ruptured and mitotic index. The mitotic index lacks in intra- and interobserver reproducibility. In this study, we evaluated on 61 GISTs, the reproducibility of mitotic counting using classical hematoxylin-eosin-saffron (HES) staining, and its correlation with the mitotic count obtained through immunohistochemical staining for phospho-histone H3 (PHH3) and the proliferation index based upon Ki-67 immunostaining. Mitotic counts by HES and PHH3 staining and Ki-67 proliferation index were evaluated twice by three independent observers taking into account interpretation times per tumor for each technique. HES-based and PHH3-based mitotic counts and Ki-67 proliferation index correlated well and presented good intra- and interobserver reproducibility. PHH3 staining resulted in a slight but statistically significant difference of about two more mitotic figures per 5 mm(2) than the HES-based count, which might have put some borderline tumors in a different risk category. Immunohistochemical staining for PHH3 and Ki-67 allowed more rapid interpretation than mitotic counts based upon HES staining, but only PHH3 staining allows counting of mitoses. Immunostaining using anti-PHH3 and anti-Ki-67 antibodies will eventually provide improved recurrence risk stratification of GIST and may become effective ancillary tools in deciding on optimal therapeutic management. PMID- 25823617 TI - Antiviral activities of 15 dengue NS2B-NS3 protease inhibitors using a human cell based viral quantification assay. AB - The dengue virus is a mosquito-borne pathogen responsible for an estimated 50-100 million human dengue infections annually. There are currently no approved drugs against this disease, resulting in a major unmet clinical need. The dengue viral NS2B-NS3 protease has been identified as a plausible drug target due to its involvement in viral replication in mammalian host cells. In the past decade, at least 20 dengue NS2B-NS3 protease inhibitors have been reported in the literature with a range of inhibitory activities in protease assays. However, such assays do not shed light on an inhibitor's ability to penetrate human cell membranes where the viral protease resides. In this study, we investigated the antiviral activities of 15 small-molecule and peptide-based NS2B-NS3 inhibitors on dengue serotype 2-infected HuH-7 human hepatocarcinoma cells. Experimental results revealed anthraquinone ARDP0006 (compound 5) to be the most potent inhibitor which reduced dengue viral titer by more than 1 log PFU/mL at 1 MUM in our cell based assays involving HuH-7 and K562 cell lines, suggesting that its scaffold could serve as a lead for further medicinal chemistry studies. Compound 5 was also found to be non-cytotoxic at 1 MUM over 3 days incubation on HuH-7 cells using the Alamar Blue cellular toxicity assay. PMID- 25823618 TI - Hepatitis C therapy with interferon-alpha and ribavirin reduces the CD4 cell count and the total, 2LTR circular and integrated HIV-1 DNA in HIV/HCV co infected patients. AB - This study investigated whether treatment with IFN-alpha and ribavirin (RBV) reduces 2LTR circular HIV DNA in addition to the total and integrated HIV DNA. Two groups of patients were enrolled. Group 1 comprised HIV/HCV co-infected patients who were treated with highly active antiretroviral therapy (HAART), IFN alpha and RBV for 48 weeks. After the 48 weeks of treatment, IFN-alpha and RBV treatment was discontinued and HAART was continued. Group 2 comprised HIV infected patients who were treated with HAART. Real-time polymerase chain reaction (RT-PCR) was used to quantify the levels of HIV-1 DNA. We found that compared with Group 2 patients, Group 1 patients exhibited an obvious decrease in the CD4 cell count and the total DNA, 2LTR circular DNA, and integrated HIV DNA after 48 weeks of treatment. After the discontinuation of IFN-alpha and RBV treatment in Group 1 patients, the levels of HIV DNA recovered. Therefore, we concluded that treatment with IFN-alpha and ribavirin (RBV) reduces 2LTR circular HIV DNA. PMID- 25823619 TI - The kinase-inhibitor sorafenib inhibits multiple steps of the Hepatitis C Virus infectious cycle in vitro. AB - Hepatitis C Virus (HCV) chronic infection is a major cause of hepatocellular carcinoma. Sorafenib is the only medical treatment that has been approved for the treatment of this cancer. It is a multikinase inhibitor with anti-tumor activity against a wide variety of cancers. Sorafenib blocks angiogenesis and tumor cell proliferation through inhibition of kinases, such as VEGFR2, PDGFR, or the serine/threonine kinases RAF. Previous studies have reported an anti-HCV effect of sorafenib in vitro, but various mechanisms of action have been described. The aim of this study was to clarify the action of sorafenib on the complete HCV infectious cycle. In order to examine the action of sorafenib on all steps of the HCV infectious cycle, we used a combination of validated cell culture models, based on the HuH-7 reference cell line and primary human hepatocytes. We found that sorafenib blocks HCV infection by altering the viral entry step and the production of viral particles. Moreover, we observed that treatment with sorafenib lead to a modification of Claudin-1 expression and localization, which could partly be responsible for the anti-HCV effect. Collectively, our findings confirm the anti-HCV effect of sorafenib in vitro, while highlighting the complexity of the action of sorafenib on the HCV infectious cycle. PMID- 25823620 TI - Effects of nutrition intervention on the nutritional status and outcomes of pediatric patients with pneumonia. AB - BACKGROUND: This study aims to explore the correlation between nutrient level and pneumonia via the analysis and intervention of nutrient levels in pediatric patients with pneumonia. METHODS: Nutrient deficient children with pneumonia were randomized into intervention and non-intervention groups, and healthy children with the same age served as controls. Serum vitamin and trace element levels were determined. The nutrient levels, average hospital stay and nutrient deficiency rate were compared between groups. RESULTS: The pneumonia group showed significantly higher rates of iron, zinc and vitamin A deficiencies than the control group. The serum vitamin D level in asthmatic pneumonia group was lower than that in non-asthmatic pneumonia group and control group. Serum zinc, iron and vitamin A levels in the pneumonia group distinctly increased after intervention therapy. After vitamin D supplementation, the serum vitamin D level in asthmatic pneumonia group was significantly improved. Children in the intervention group had shorter hospital stays than children in the non intervention group, whose hospital stays were longer than pediatric patients with normal nutrient levels. However, the difference between the intervention and normal nutrient groups was insignificant. CONCLUSION: Clinical nutrition intervention could improve the efficacy of pneumonia in pediatric patients and shorten hospital stay. PMID- 25823621 TI - Informative nursery rhymes: a pilot study of children's satisfaction. AB - BACKGROUND: The aim of this study was to assess, by means of a questionnaire, the level of children's satisfaction relating to three informative charts, including a nursery rhyme, administered to the patient before a medical procedure. METHODS: We created three types of specific informative charts on three medical topics with the double function of informing the child before the medical procedure, and of distracting him/her by means of a nursery rhyme read aloud by the authors. To assess the level of children's satisfaction, we administered the patients a questionnaire. RESULTS: According to children's feedback, the charts were funny and useful. CONCLUSIONS: The charts conceived in this study seem to be an easily applicable and entertaining approach to provide information and distraction to children undergoing surgery. PMID- 25823623 TI - The effect of anesthesia type on nonsurgical operating room time. AB - PURPOSE: To determine the effect of local-only anesthesia on nonsurgical time compared with monitored anesthesia care (MAC)/local and general anesthesia. Our hypothesis was that local-only anesthesia cases would have lower nonsurgical times compared with MAC/local and general anesthesia. METHODS: We retrospectively reviewed the surgical records of 1,179 patients undergoing elective hand surgery. For each case, we recorded the type of anesthesia used (general, MAC/local, or local-only anesthesia) and in-room presurgical time, in-room postsurgical time, and, if relevant, room turnover time. We did not record room turnover times for the first case of the day or for cases after procedures that did not meet inclusion criteria. We also recorded the presence of any anesthesia providers (anesthesiologist vs anesthesia-assistant [certified registered nurse anesthetist]). RESULTS: A total of 566 cases performed on 501 patients met inclusion criteria. Room turnover times were not calculated for 304 cases. The choice of anesthesia had a significant effect on nonsurgical operating room time. Local anesthesia cases had significantly less nonsurgical time compared with general anesthesia and MAC/local. Cases performed under MAC/local anesthesia also had significantly reduced nonsurgical time compared with general anesthesia. The presence of a certified anesthesia assistant had no effect on any time metrics recorded. CONCLUSIONS: Choice of local anesthesia, when appropriate, may facilitate rapid operating room turnover and improve overall facility efficiency with lower costs. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25823622 TI - Reconstruction of fingertip injuries: surgical tips and avoiding complications. AB - The fingertip is the most commonly injured part of the hand. When replantation of a fingertip amputation is not possible, flap reconstruction may be necessary for a functional and aesthetically pleasing outcome. This paper reviews commonly utilized reconstruction techniques with a focus on technical tricks and potential complications and how to avoid them, with illustrative cases. PMID- 25823624 TI - Long-term efficacy and safety outcomes of transplantation of induced pluripotent stem cell-derived neurospheres with bioabsorbable nerve conduits for peripheral nerve regeneration in mice. AB - The induced pluripotent stem cell (iPSc) offers great potential for cell-based therapy in regenerative medicine. We previously developed tissue-engineered bioabsorbable nerve conduits coated with iPSc-derived neurospheres for use in peripheral nerve repair. Here, we examine the long-term efficacy and safety of using nerve conduits with iPSc technology for peripheral nerve repair in mice. The nerve conduit consisted of an outer layer of a poly L-lactide mesh and an inner layer of porous sponge composed of 50% L-lactide and 50% epsilon caprolactone. Secondary neurospheres were derived from mouse iPScs, resuspended and cultured within the conduit for 14 days. Conduits were implanted within surgically administered 5-mm defects in the left sciatic nerve of mice (iPSc group; n = 14). The defects in the control group (n = 13) were reconstructed using the nerve conduit alone. At 4, 8, 12, 24 and 48 weeks postsurgery, motor and sensory functional recovery in the iPSc group had improved significantly more than in the control group. At 24 and 48 weeks, histological analysis revealed axonal regeneration in the nerve conduits of both groups. However, axonal regeneration and myelination were significantly enhanced in the iPSc group. No teratomas were identified in the iPSc group at any time point. Therefore, we here demonstrate that bioabsorbable nerve conduits coated with iPSc-derived neurospheres promote enhanced regeneration of peripheral nerves and functional recovery without teratoma formation in the long term. This combination of iPSc technology and bioabsorbable nerve conduits has the potential to be a safe future tool for the treatment of peripheral nerve defects. PMID- 25823629 TI - Intensive ketamine use for multiple years: A case report. AB - Ketamine is known within the medical field for its anesthetic properties, yet its unique psychedelic and antidepressant properties are being increasingly recognized. We document the case of a patient with bipolar I disorder and an extensive history of substance dependence who used large doses of ketamine (1-3 g) on a daily basis over a period of 5 years, and described acute antidepressant effects as well as diminished cravings for alcohol. While his use was untenable and ultimately led to an inpatient admission, it is notable that he did not experience a withdrawal syndrome nor did he have any observable cognitive deficits upon cessation of use. Such a unique drug profile suggests that further exploration of its risks and therapeutic potential in treating mood and addiction disorders is warranted. PMID- 25823630 TI - Initiating buprenorphine treatment for hospitalized patients with opioid dependence: A case series. AB - BACKGROUND AND OBJECTIVES: Opioid dependent patients are hospitalized frequently. We aimed to determine if initiation of buprenorphine treatment during hospitalization facilitates entry into treatment following discharge. METHODS: Retrospective case series (n = 47). RESULTS: Twenty-two (46.8%) patients successfully initiated buprenorphine treatment within 2 months of discharge. Those patients obtaining a referral to a specific program were more successful in continuing treatment, but this difference did not reach statistical significance (59.1% vs 39.1%, p = 0.18). DISCUSSION AND CONCLUSIONS: Hospitalization may be an important opportunity to engage opioid dependent patients to initiate buprenorphine treatment. SCIENTIFIC SIGNIFICANCE: This study provides provisional support for utilizing buprenorphine for hospitalized patients. PMID- 25823631 TI - The role of opioidergic genes in the treatment outcome of drug addiction pharmacotherapy: A systematic review. AB - BACKGROUND AND OBJECTIVES: Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. METHODS: Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. RESULTS AND CONCLUSIONS: The genetic variability of MU-, delta- and kappa-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. SCIENTIFIC SIGNIFICANCE: Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction. PMID- 25823632 TI - Trends in the use of buprenorphine by office-based physicians in the United States, 2003-2013. AB - BACKGROUND AND OBJECTIVES: Despite buprenorphine's promise as a novel therapy for opioid dependence, little is known about its clinical adoption. We characterized trends in ambulatory use of buprenorphine in the United States. METHODS: Cross sectional, descriptive analyses of buprenorphine utilization from 2003 to 2013 using the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory care. The primary unit of analysis was an office visit where buprenorphine was used for opioid dependence (treatment visit). RESULTS: Between 2003 and 2013, there was significant uptake of buprenorphine in ambulatory treatment visits, from 0.16 million [M] (95% confidence interval [CI] 0.10-0.20) visits in 2003 to 2.1M (CI 1.9-2.3M) treatment visits during 2013. Approximately 90% involved the use of brand name combination buprenorphine/naloxone (Suboxone), although this percentage decreased modestly to 80% by the last quarter of 2013. Buprenorphine prescribing increased among all specialties, but the proportion accounted for by primary care physicians increased significantly from 6.0% in 2003 to 63.5% in 2013 and decreased among psychiatrists from 92.2% to 32.8% over the same time period. CONCLUSIONS: The use of buprenorphine products to treat opioid dependence has increased significantly in the past 10 years and has shifted to greater use by primary care physicians, indicating a rapidly changing face of opioid maintenance therapy in the United States. PMID- 25823633 TI - The prevalence of substance use disorders in American physicians. AB - BACKGROUND: There have been few studies on the prevalence of substance use disorders (SUDS) in the physician population at large nor have any studies compared the prevalence of SUDS in American physicians by specialty. METHODS: We conducted a national study of SUDS in a large sample of U.S. physicians from all specialty disciplines using the AMA Physician Masterfile. Substance Use Disorders (SUDS) were measured using validated instruments. RESULTS: Of the 27,276 physicians who received an invitation to participate, 7,288 (26.7%) completed surveys. 12.9% of male physicians and 21.4% of female physicians met diagnostic criteria for alcohol abuse or dependence. Abuse of prescription drugs and use of illicit drugs was rare. Factors independently associated with alcohol abuse or dependence were age (OR = .985; p < .0001), hours worked (OR = .994; p = .0094), male gender (OR = .597; p < .0001), being married (OR 1.296; p = .0424) or partnered (OR 1.989; p = .0003), having children (OR .745; p = .0049), and being in any specialty other than internal medicine (OR 1.757; p = .0060). Specialty choice was strongly associated with alcohol abuse or dependence (p = .0011). Alcohol abuse or dependence was associated with burnout (p < .0001), depression (p < .0001), suicidal ideation (p = .0004), lower quality of life (p < .0001), lower career satisfaction (p = .0036), and recent medical errors (p = .0011). CONCLUSION: Alcohol abuse or dependence is a significant problem among American physicians. Since prognosis for recovery of physicians from chemical dependency is exceptionally high, organizational approaches for the early identification of problematic alcohol consumption in physicians followed by intervention and treatment where indicated should be strongly supported. PMID- 25823634 TI - Post-traumatic stress disorder symptoms, underlying affective vulnerabilities, and smoking for affect regulation. AB - BACKGROUND AND OBJECTIVES: Post-traumatic stress disorder (PTSD) is overrepresented among cigarette smokers. It has been hypothesized that those with PTSD smoke to alleviate negative affect and counteract deficient positive affect commonly associated with the disorder; however, limited research has examined associations between PTSD symptoms, smoking motives, and affective vulnerability factors. In the current study, we examined (1) whether PTSD symptoms were associated with positive reinforcement and negative reinforcement smoking motives; and (2) whether two affective vulnerability factors implicated in PTSD anxiety sensitivity and anhedonia-mediated relationships between PTSD symptoms and smoking motives. METHODS: Data were drawn from a community sample of non treatment-seeking smokers recruited without regard for trauma history (N = 342; 10+ cig/day). We used the Posttraumatic Stress Disorder Checklist-Civilian Version (PCL-C) to assess overall PTSD symptom severity as well as individual PTSD subfactors. RESULTS: Overall, PTSD symptom severity was significantly associated with negative reinforcement, but not positive reinforcement, smoking motives. Variation in anxiety sensitivity significantly mediated the relation between PTSD symptom severity and negative reinforcement smoking motives, whereas anhedonia did not. Regarding PTSD subfactors, emotional numbing was the only PTSD subfactor associated with smoking rate, while re-experiencing symptoms were uniquely associated with both positive reinforcement and negative reinforcement smoking motives. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Findings suggest that anxiety sensitivity may be an important feature associated with PTSD that enhances motivation to smoke for negative reinforcement purposes. Smoking cessation interventions that alleviate anxiety sensitivity and enhance coping with negative affect may be useful for smokers with elevated PTSD symptoms. PMID- 25823635 TI - Objective and subjective memory ratings in cannabis-dependent adolescents. AB - BACKGROUND AND OBJECTIVES: Cannabis is the most widely used illicit substance worldwide, with an estimated 160 million users. Among adolescents, rates of cannabis use are increasing, while the perception of detrimental effects of cannabis use is declining. Difficulty with memory is one of the most frequently noted cognitive deficits associated with cannabis use, but little data exist exploring how well users can identify their own memory deficits, if present. METHODS: The current secondary analysis sought to characterize objective verbal and visual memory performance via a neurocognitive battery in cannabis-dependent adolescents enrolled in a pharmacotherapeutic cannabis cessation clinical trial (N = 112) and compare this to a single self-reported item assessing difficulties with memory loss. Exploratory analyses also assessed dose-dependent effects of cannabis on memory performance. RESULTS: A small portion of the study sample (10%) endorsed a "serious problem" with memory loss. Those participants reporting "no problem" or "serious problem" scored similarly on visual and verbal memory tasks on the neurocognitive battery. Exploratory analyses suggested a potential relationship between days of cannabis use, amount of cannabis used, and gender with memory performance. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This preliminary and exploratory analysis suggests that a sub-set of cannabis users may not accurately perceive difficulties with memory. Further work should test this hypothesis with the use of a control group, comprehensive self-reports of memory problems, and adult populations that may have more years of cannabis use and more severe cognitive deficits. PMID- 25823640 TI - Concomitant major vessel resection in pancreatic adenocarcinoma. AB - Increasing evidence has contraindicated extended radical dissection of pancreatic adenocarcinoma (PC). With the recent improvement of perioperative management techniques and multimodal treatment strategy for PC, concomitant major vessel resection and reconstruction has thus been aggressively attempted in association with comparatively better pathologically negative surgical margins and postoperative survival. We have discussed the clinical relevance of concomitant major vessel resection mainly focusing on indications for such resection with borderline resectable tumor associated with chemoradiotherapy, distal pancreatectomy with en bloc celiac axis resection for pancreatic body and tail cancer, and adjuvant surgery for initially unresectable pancreatic cancer. PMID- 25823641 TI - Benign prostatic hyperplasia and urinary symptoms: Evaluation and treatment. AB - Benign prostatic hyperplasia (BPH) is one of the most common conditions affecting middle-aged men. This condition can be microscopic, macroscopic, symptomatic, or asymptomatic. Up to 15% to 25% of men aged 50-65 years have lower urinary tract symptoms (LUTS) consisting of nocturia, urgency, frequency, a sensation of not completely emptying the bladder, stop-start urination, straining to urinate, a need to urinate soon after voiding, and weak urinary stream. These symptoms usually are associated with benign enlargement of the prostate gland that is of sufficient severity to interfere with a man's quality of life. Although LUTS is often associated with BPH, LUTS can also be due to various unrelated syndromes such as heart failure, urinary tract infections, and diabetes. Most men will have benign hyperplasia of the prostate gland and this benign growth compresses the urethra resulting in LUTS. This article will discuss the evaluation, pharmacological management, minimally invasive treatment, and surgical therapy of this common condition affecting millions of American men. PMID- 25823642 TI - A numerical study of the benefits of driving jellyfish bells at their natural frequency. AB - A current question in swimming and flight is whether or not driving flexible appendages at their resonant frequency results in faster or more efficient locomotion. It has been suggested that jellyfish swim faster when the bell is driven at its resonant frequency. The goal of this study was to determine whether or not driving a jellyfish bell at its resonant frequency results in a significant increase in swimming velocity. To address this question, the immersed boundary method was used to solve the fully coupled fluid structure interaction problem of a flexible bell in a viscous fluid. Free vibration numerical experiments were used to determine the resonant frequency of the jellyfish bell. The jellyfish bells were then driven at frequencies ranging from above and below the resonant frequency. We found that jellyfish do swim fastest for a given amount of applied force when the bells are driven near their resonant frequency. Nonlinear effects were observed for larger deformations, shifting the optimal frequency to higher than the resonant frequency. We also found that the benefit of resonant forcing decreases for lower Reynolds numbers. PMID- 25823643 TI - Standardized fluorescence in situ hybridization testing based on an appropriate panel of probes more effectively identifies common cytogenetic abnormalities in myelodysplastic syndromes than conventional cytogenetic analysis: a multicenter prospective study of 2302 patients in China. AB - In an attempt to establish the advantages of fluorescence in situ hybridization (FISH) studies over conventional cytogenetic (CC) analysis, a total of 2302 de novo MDS patients from 31 Chinese institutions were prospectively selected in the present study for both CC and standardized FISH analysis for +8, -7/7q-, -5/5q-, 20q- and-Y chromosomal abnormalities. CC analysis was successful in 94.0% of the patients; of these patients, 35.9% of the cases were abnormal. FISH analysis was successful in all 2302 patients and detected at least one type of common cytogenetic abnormality in 42.7% of the cases. The incidences of +8, -7/7q-, 5/5q-, 20q- and-Y chromosomal abnormalities by FISH were 4.1% to 8.7% higher than those by CC. FISH identified abnormalities in 23.6% of the patients exhibiting normal CC results and revealed that 20.7% of the patients with adequate normal metaphases (>=20) had abnormal clones. FISH identified cytogenetic abnormalities in 50.4% of the patients with failed CC analysis. In summary, our multicenter studies emphasised and confirmed the importance of applying standardized FISH testing based on an appropriate panel of probes to detect common cytogenetic abnormalities in Chinese de novo MDS patients, particularly those with normal or failed CC results. PMID- 25823644 TI - Expression of the histone chaperone SET/TAF-Ibeta during the strobilation process of Mesocestoides corti (Platyhelminthes, Cestoda). AB - The histone chaperone SET/TAF-Ibeta is implicated in processes of chromatin remodelling and gene expression regulation. It has been associated with the control of developmental processes, but little is known about its function in helminth parasites. In Mesocestoides corti, a partial cDNA sequence related to SET/TAF-Ibeta was isolated in a screening for genes differentially expressed in larvae (tetrathyridia) and adult worms. Here, the full-length coding sequence of the M. corti SET/TAF-Ibeta gene was analysed and the encoded protein (McSET/TAF) was compared with orthologous sequences, showing that McSET/TAF can be regarded as a SET/TAF-Ibeta family member, with a typical nucleosome-assembly protein (NAP) domain and an acidic tail. The expression patterns of the McSET/TAF gene and protein were investigated during the strobilation process by RT-qPCR, using a set of five reference genes, and by immunoblot and immunofluorescence, using monospecific polyclonal antibodies. A gradual increase in McSET/TAF transcripts and McSET/TAF protein was observed upon development induction by trypsin, demonstrating McSET/TAF differential expression during strobilation. These results provided the first evidence for the involvement of a protein from the NAP family of epigenetic effectors in the regulation of cestode development. PMID- 25823647 TI - Radiation protection in cardiovascular interventions: what can we do? PMID- 25823645 TI - Eprobe-mediated screening system for somatic mutations in the KRAS locus. AB - Activating mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) loci are largely predictive of resistance to epidermal growth factor receptor (EGFR) therapy in colorectal cancer (CRC). A highly sensitive detection system for the KRAS gene mutations is urgently needed; however, conventional methods have issues with feasibility and cost performance. Here, we describe a novel detection system using a fluorescence 'Eprobe' capable of detecting low level KRAS gene mutations, via real-time PCR, with high sensitivity and simple usability. We designed our Eprobes to be complementary to wild-type (WT) KRAS or to the commonly mutated codons 12 and 13. The WT Eprobe binds strongly to the WT DNA template and suppresses amplification by blocking annealing of the primer during PCR. Eprobe-PCR with WT Eprobe shows high sensitivity (0.05-0.1% of plasmid DNA, 1% of genomic DNA) for the KRAS mutation by enrichment of the mutant type (MT) amplicon. Assay performance was compared to Sanger sequencing using 92 CRC samples. Discrepancies were analyzed by mutation genotyping via Eprobe-PCR with full match Eprobes for 7 prevalent mutations and the next generation sequencing (NGS). Significantly, the Eprobe system had a higher sensitivity for detecting KRAS mutations in CRC patient samples; these mutations could not be identified by Sanger sequencing. Thus, the Eprobe approach provides for highly sensitive and convenient mutation detection and should be useful for diagnostic applications. PMID- 25823648 TI - Focused Ultrasound as a Scalable and Contact-Free Method to Manufacture Protein Loaded PLGA Nanoparticles. AB - PURPOSE: Although nanomaterials are under investigation for a very broad range of medical applications, only a small fraction of these are already commercialized or in clinical development. A major challenge for the translation of nanomedicines into the clinic is the missing scalability of the available lab scale preparation methods and, ultimately, non-identical samples during early and late research. METHODS: Protein-loaded PLGA nanoparticles using focused ultrasound in an emulsion solvent diffusion method were prepared in different batch sizes to evaluate achievable mean size, protein loading, and yield. RESULTS: Using the same equipment, nanoparticles could be prepared in batch sizes from 1 mg to 2.5 g. Size and yield were directly controllable by the amount of incident energy with good reproducibility. The nanoparticles displayed similar mean size, protein loading, and nanoparticle yield in batch sizes over three orders of magnitude. A scalable purification method based on diafiltration was established. CONCLUSIONS: The proposed method enables for feasibility studies during early research using just a small amount of polymer and protein, while at the same time it allows for larger scale production at later stages. As the proposed method further relies on contact-free energy transmission, it is especially suited for the preparation of clinical research samples. PMID- 25823649 TI - Production of Highly Charged Pharmaceutical Aerosols Using a New Aerosol Induction Charger. AB - PURPOSE: Properly charged particles can be used for effective lung targeting of pharmaceutical aerosols. The objective of this study was to characterize the performance of a new induction charger that operates with a mesh nebulizer for the production of highly charged submicrometer aerosols to bypass the mouth throat and deliver clinically relevant doses of medications to the lungs. METHODS: Variables of interest included combinations of model drug (albuterol sulfate) and charging excipient (NaCl) as well as strength of the charging field (1-5 kV/cm). Aerosol charge and size were measured using a modified electrical low pressure impactor system combined with high performance liquid chromatography. RESULTS: At the approximate mass median aerodynamic diameter (MMAD) of the aerosol (~0.4 MUm), the induction charge on the particles was an order of magnitude above the field and diffusion charge limit. The nebulization rate was 439.3 +/- 42.9 MUl/min, which with a 0.1% w/v solution delivered 419.5 +/- 34.2 MUg of medication per minute. A new correlation was developed to predict particle charge produced by the induction charger. CONCLUSIONS: The combination of the aerosol induction charger and predictive correlations will allow for the practical generation and control of charged submicrometer aerosols for targeting deposition within the lungs. PMID- 25823650 TI - Reducing the Visibility of the Vector/DNA Nanocomplexes to the Immune System by Elastin-Like Peptides. AB - PURPOSE: One of the major hurdles facing nanomedicines is the antibody production against nanoparticles that subsequently results in their opsonization and clearance by macrophages. The objective of this research was to examine and identify the sequence of a low-immunogenic peptide based on recombinant elastin like polypeptides (ELPs) that does not evoke IgG response and can potentially be used for masking the surfaces of the nanoparticles. METHODS: Biopolymers composed of a DNA condensing domain in fusion with anionic, neutral and cationic elastin like peptides were genetically engineered. The biopolymers were used to complex with plasmid DNA and form ELP-coated nanoparticles. Then, the potential immunogenicity of nanoparticles in terms of IgM/IgG response after repeated injections was evaluated in Balb/c immunocompetent mice. RESULTS: The results revealed the sequence of a non-immunogenic ELP construct that in comparison to control group did not elicit any significant IgG response, whereas the vector/DNA complexes that were coated with polyethylene glycol (PEG) did elicit significant IgG response under the same conditions. CONCLUSIONS: The identification of the sequence of an ELP-based peptide that does not induce IgG response opens the door to more focused in-depth immunotoxicological studies which could ultimately lead to the production of safer and more effective drug/gene delivery systems such as liposomes, micelles, polymeric nanoparticles, viruses and antibodies. PMID- 25823651 TI - Metabolic syndrome, dyslipidemia and prostate cancer recurrence after primary surgery or radiation in a veterans cohort. AB - BACKGROUND: Metabolic syndrome (MetS) has been hypothesized to be associated with cancer, including prostate cancer (PCa), but the relationship is not well characterized. We analyze the relationship between MetS features and localized PCa recurrence after treatment. METHODS: Men having primary treatment for localized PCa were included from a multi-site regional veteran network. Recurrence was defined as nadir PSA +2 ng ml(-1) (radiation) or PSA?0.2 ng ml(-1) (prostatectomy). MetS was based on consensus professional society guidelines from the American Heart Association and International Diabetes Federation (three of: hypertension >130/85 mm Hg, fasting blood glucose ?100 mg dl(-1), waist circumference >102 cm, high-density lipoprotein <40 mg dl(-1), triglycerides ?150 mg dl(-1)). Closely related abnormality in low-density lipoprotein (LDL; >130 mg dl(-1)) was also examined. Analysis of PCa recurrence risk included multivariable Cox proportional hazards regression with propensity adjustment. RESULTS: Of the 1706 eligible men, 279 experienced recurrence over a median follow-up period of 41 months (range 1-120 months). Adjustment variables associated with PCa recurrence included: index PSA, Gleason, and tumor stage. Independent variables of interest associated with PCa recurrence were hyperglycemia and elevated LDL. Elevated LDL was associated with PCa recurrence (multivariable hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.03, 1.74; propensity adjusted HR 1.33, 95% CI 1.03, 1.72). There was also an association between impaired fasting glucose and PCa recurrence in (multivariable HR 1.54, 95% CI 1.10, 2.15; propensity adjusted HR 1.41, 95% CI 1.01, 1.95). MetS was not associated with PCa recurrence (multivariable: HR 0.96, 95% CI 0.61, 1.50; propensity adjusted HR 1.04, 95% CI 0.67, 1.62). CONCLUSIONS: PCa recurrence is not associated with MetS but is associated with elevated LDL and impaired fasting glucose. If confirmed, these data may help provide modifiable targets in preventing recurrence of PCa. PMID- 25823652 TI - Xenopus: An in vivo model for imaging the inflammatory response following injury and bacterial infection. AB - A major goal in regenerative medicine is to identify therapies to facilitate our body's innate abilities to repair and regenerate following injury, disease or aging. In the past decade it has become apparent that the innate immune system is able to affect the speed and quality of the regenerative response through mechanisms that are not entirely clear. For this reason there has been a resurgent interest in investigating the role of inflammation during tissue repair and regeneration. Remarkably, there have only been a handful of such studies using organisms with high regenerative capacity. Here we perform a study of the inflammatory response following injury in Xenopus larvae, which are able to achieve scarless wound healing and to regenerate appendages, as a preamble into understanding the role that inflammation plays during tissue repair and regeneration in this organism. We characterized the morphology and migratory behavior of granulocytes and macrophages following sterile and infected wounding regimes, using various transgenic lines that labeled different types of myeloid lineages, including granulocytes and macrophages. Using this approach we found that the inflammatory response following injury and infection in Xenopus larvae is very similar to that seen in humans, suggesting that this model provides an easily tractable and medically relevant system to investigate inflammation following injury and infection in vivo. PMID- 25823653 TI - Peripheral myeloid-derived suppressor and T regulatory PD-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients. AB - Short-course preoperative radiotherapy (SC-RT) followed by total mesorectal excision (TME) is one therapeutic option for locally advanced rectal cancer (LARC) patients. Since radio-induced DNA damage may affect tumor immunogenicity, Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) were evaluated in 13 patients undergoing SC-RT and TME for LARC. Peripheral Granulocytic-MDSCs (G-MDSC) [LIN-/HLA-DR-/CD11b+/CD14-/CD15+/CD33+], Monocytic (M MDSC) [CD14+/HLA-DR-/lowCD11b+/CD33+] and Tregs [CD4+/CD25hi+/FOXP3+- CTLA-4/PD1] basal value was significantly higher in LARC patients compared to healthy donors (HD). Peripheral MDSC and Tregs were evaluated at time 0 (T0), after 2 and 5 weeks (T2-T5) from radiotherapy; before surgery (T8) and 6-12 months after surgery (T9, T10). G-MDSC decreased at T5 and further at T8 while M-MDSC cells decreased at T5; Tregs reached the lowest value at T5. LARC poor responder patients displayed a major decrease in M-MDSC after SC-RT and an increase of Treg PD-1. In this pilot study MDSCs and Tregs decrease during the SC-RT treatment could represent a biomarker of response in LARC patients. Further studies are needed to confirm that the deepest M-MDSC reduction and increase in Treg-PD1 cells within 5-8 weeks from the beginning of treatment could discriminate LARC patients poor responding to SC-RT. PMID- 25823654 TI - Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer. AB - The clinical significance of Cluster of Differentiation 44 (CD44) remains controversial in human ovarian cancer. The aim of this study is to evaluate the clinical significance of CD44 expression by using a unique tissue microarray, and then to determine the biological functions of CD44 in ovarian cancer. In this study, a unique ovarian cancer tissue microarray (TMA) was constructed with paired primary, metastatic, and recurrent tumor tissues from 26 individual patients. CD44 expression in TMA was assessed by immunohistochemistry. Both the metastatic and recurrent ovarian cancer tissues expressed higher level of CD44 than the patient-matched primary tumor. A significant association has been shown between CD44 expression and both the disease free survival and overall survival. A strong increase of CD44 was found in the tumor recurrence of mouse model. Finally, when CD44 was knocked down, proliferation, migration/invasion activity, and spheroid formation were significantly suppressed, while drug sensitivity was enhanced. Thus, up-regulation of CD44 represents a crucial event in the development of metastasis, recurrence, and drug resistance to current treatments in ovarian cancer. Developing strategies to target CD44 may prevent metastasis, recurrence, and drug resistance in ovarian cancer. PMID- 25823655 TI - miR-93 promotes cell proliferation in gliomas through activation of PI3K/Akt signaling pathway. AB - The PI3K/Akt signaling pathway is frequently activated in various human cancer types and plays essential roles in development and progression of cancers. Multiple regulators, such as phosphatase and tensin homolog (PTEN) and PH domain leucine rich repeat protein phosphatases (PHLPP), have also found to be involved in suppression of the PI3K/Akt signaling pathway. However, how suppressive effects mediated by these regulators are concomitantly disrupted in cancers, which display constitutively activated PI3K/Akt signaling, remains puzzling. In the present study, we reported that the expression of miR-93 was markedly upregulated in glioma cell lines and clinical glioma tissues. Statistical analysis revealed that miR-93 levels significantly correlated with clinicopathologic grade and overall survival in gliomas. Furthermore, we found that overexpressing miR-93 promoted, but inhibition of miR-93 reduced, glioma cell proliferation and cell-cycle progression. We demonstrated that miR-93 activated PI3K/Akt signaling through directly suppressing PTEN, PHLPP2 and FOXO3 expression via targeting their 3'UTRs. Therefore, our results suggest that miR-93 might play an important role in glioma progression and uncover a novel mechanism for constitutive PI3K/Akt activation in gliomas. PMID- 25823656 TI - Loss of beta-catenin in adrenocortical cancer cells causes growth inhibition and reversal of epithelial-to-mesenchymal transition. AB - Adrenal carcinoma (ACC) is a rare neoplasm with a poor outcome. Aberrant expression of beta-catenin has been found in approximatively 30% of ACC. We herein studied its effects on the growth of the human ACC cell line H295R. The cells were infected with short hairpin RNA (shRNA)-mediated silencing beta catenin. Two shRNAs used induced down-regulation of beta-catenin protein levels. The expression of these shRNAs decreased cell growth and increased H295R cells in S and G2/M phases. This cytostatic effect is due to a decrease of phosphorylated MAPK and to an up-regulation expression of the cyclin-dependent kinase inhibitors p57(KIP2), p21(CIP) and p27(KIP1). In addition, the knockdown of beta-catenin decreased phosphorylated Akt and increased apoptosis. Finally, loss of beta catenin was sufficient to induce the reversal of the epithelial-to-mesenchymal transition. We then transplanted these genetically modified H295R cells in Scid mice. Tumor growth suppression was achieved by the two shRNAs showing in vitro efficacy. Proliferation was not reduced in silenced tumors. In contrast, p57, p27 and p21 proteins were found expressed at high levels in silenced tumors along with an increase in apoptotic cells. These findings indicate that beta-catenin loss in H295R cells inhibits tumor growth by inducing transcriptional and functional changes. PMID- 25823657 TI - HOTAIR is a therapeutic target in glioblastoma. AB - HOTAIR is a negative prognostic factor and is overexpressed in multiple human cancers including glioblastoma multiform (GBM). Survival analysis of Chinese Glioma Genome Atlas (CGGA) patient data indicated that high HOTAIR expression was associated with poor outcome in GBM patients. NLK (Nemo-like kinase), a negative regulator of the beta-catenin pathway, was negatively correlated with HOTAIR expression. When the beta-catenin pathway was inhibited, GBM cells became susceptible to cell cycle arrest and inhibition of invasion. Introduction of the HOTAIR 5' domain in human glioma-derived astrocytoma induced beta-catenin. An intracranial animal model was used to confirm that HOTAIR depletion inhibited GBM cell migration/invasion. In the orthotopic model, HOTAIR was required for GBM formation in vivo. In summary, HOTAIR is a potential therapeutic target in GBM. PMID- 25823658 TI - Modulation of TGFbeta 2 levels by lamin A in U2-OS osteoblast-like cells: understanding the osteolytic process triggered by altered lamins. AB - Transforming growth factor beta (TGFbeta) plays an essential role in bone homeostasis and deregulation of TGFbeta occurs in bone pathologies. Patients affected by Mandibuloacral Dysplasia (MADA), a progeroid disease linked to LMNA mutations, suffer from an osteolytic process. Our previous work showed that MADA osteoblasts secrete excess amount of TGFbeta 2, which in turn elicits differentiation of human blood precursors into osteoclasts. Here, we sought to determine how altered lamin A affects TGFbeta signaling. Our results show that wild-type lamin A negatively modulates TGFbeta 2 levels in osteoblast-like U2-OS cells, while the R527H mutated prelamin A as well as farnesylated prelamin A do not, ultimately leading to increased secretion of TGFbeta 2. TGFbeta 2 in turn, triggers the Akt/mTOR pathway and upregulates osteoprotegerin and cathepsin K. TGFbeta 2 neutralization rescues Akt/mTOR activation and the downstream transcriptional effects, an effect also obtained by statins or RAD001 treatment. Our results unravel an unexpected role of lamin A in TGFbeta 2 regulation and indicate rapamycin analogs and neutralizing antibodies to TGFbeta 2 as new potential therapeutic tools for MADA. PMID- 25823659 TI - Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance. AB - Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy available in advanced stages. Nuclear corepressor (NCoR) is an essential regulator of gene transcription, and its function has been found deregulated in different types of cancer. In colorectal cancer cells, loss of nuclear NCoR is induced by Inhibitor of kappa B kinase (IKK) through the phosphorylation of specific serine residues. We here investigate whether NCoR function impacts in MM, which might have important diagnostic and prognostic significance. By IHC, we here determined the subcellular distribution of NCoR in a cohort of 63 primary invasive MM samples, and analyzed its possible correlation with specific clinical parameters. We therefore used a microarray-based strategy to determine global gene expression differences in samples with similar tumor stage, which differ in the presence of cytoplasmic or nuclear NCoR. We found that loss of nuclear NCoR results in upregulation of a specific cancer-related genetic signature, and is significantly associated with MM progression. Inhibition of IKK activity in melanoma cells reverts NCoR nuclear distribution and specific NCoR-regulated gene transcription. Analysis of public database demonstrated that inactivating NCoR mutations are highly prevalent in MM, showing features of driver oncogene. PMID- 25823660 TI - A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis. AB - Here we showed that ursolic acid (UA), a pentacyclic triterpene natural product, and its novel prodrug derivative US597 suppressed cancer cells adhesion, invasion and migration. This effect was accompanied by inhibition of focal adhesion signaling pathway including alterations in ICAM-1, VCAM-1, E-selectin, P selectin, integrin alpha6beta1, FAK, Src, paxillin and PTEN. While oral administration of UA or US597 increases survival rate of melanoma lung metastasis in C57BL/6 mice, US597 treatment extend the survival rate above that of UA. Immunohistochemical analysis revealed that US597 treatment regulates ICAM-1, a biomarker of metastasis. We did not detect side effects with US597 in mice such as weight loss, viscera tissues toxicity and blood cell abnormalities. Thus, UA and US597 are potential drug candidates for preventing cancer metastasis. Molecular and cellular study data suggest that UA and US597 modulate expression of cell adhesion molecules within focal adhesion signaling pathway leading to cancer cell motility. PMID- 25823662 TI - MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma. AB - A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions. PMID- 25823661 TI - The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients. AB - We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway. PMID- 25823663 TI - High expression of small GTPase Rab3D promotes cancer progression and metastasis. AB - Rab GTPases control exocytic and endocytic membrane trafficking such as exosomes release. As a secretory small GTPase, Rab3D is a vital regulator for protein secretion. However, the role of Rab3D in cancer was never systematically studied. The aim of this study is to examine its function and mechanism in cancer, especially metastasis. We detected protein levels of Rab3D in nine cancer cell lines and twelve types of clinical cancer specimens. Subsequently, we established in vitro migration and in vivo orthotopic metastatic mouse models to study the role of Rab3D in tumor metastasis. Here, we reported that the expression levels of Rab3D were dysregulated in cancer cells and highly correlated with tumor malignancies in the clinical samples. Increased expressions of Rab3D led to tumor invasion in vitro and lung metastasis in vivo, whereas Rab3D knockdown suppressed the tumor cell motility. Mechanistic studies revealed that Rab3D activated intracellular the AKT/GSK3beta signaling to induce the EMT process. In addition, it also regulated the extracellular secretion of Hsp90alpha to promote tumor cell migration and invasion. These results prove that Rab3D is a key molecule to regulate tumor metastasis, suggesting that blocking the Rab3D function can be a potential therapeutic approach for cancer metastasis. PMID- 25823664 TI - Ndrg2 promoter hypermethylation triggered by helicobacter pylori infection correlates with poor patients survival in human gastric carcinoma. AB - N-myc downstream regulated gene 2 (Ndrg2) is a candidate suppressor of cancer metastasis. We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues. This resulted in down regulation of Ndrg2 mRNA and protein. Ndrg2 promoter methylation was associated with H. pylori infection and worse prognosis of gastric cancer patients, which is an independent prognostic factor for the disease-free survival (DFS). We found that H. pylori silenced Ndrg2 by activating the NF-kappaB pathway and up regulating DNMT3b, promoting gastric cancer progression. These findings uncover a previously unrecognized role for H. pylori infection in gastric cancer. PMID- 25823665 TI - Ghrelin receptor controls obesity by fat burning. PMID- 25823666 TI - Spontaneous Age-related Changes of Peripheral Nerves in Cattle: Morphological and Biochemical Studies. AB - Peripheral nerve function is significantly affected by ageing. During ageing process, multiple changes occur on tissue cells and extracellular matrix. The aim of this work was to study the ageing-associated changes of peripheral nerves in adult and old regularly slaughtered cattle compared with young calves, and correlate them to the features reported in humans and laboratory animals. Samples of axial dorsal metacarpal nerves from 44 cows were collected immediately after slaughtering. Each nerve was dissected and divided into two fragments: one used for morphological evaluation (n = 43) and the other one for biochemical analysis (n = 31). Axonal degeneration, demyelination, thickness of perineurium and endoneurium and increase of mast cells were the most important features detected. The mean amount of glycosaminoglycan quantitative content recorded in the samples increased with the age. Axonal degeneration, demyelination and thickness of endoneurium were positively and significantly correlated with biochemistry. The presence of changes affecting the different elements of the peripheral nerves, similar to that reported in humans and in laboratory species, the easy availability of the nerve tissue in this species, the considerable size of the samples and the life conditions more similar to humans than to laboratory animals, allows the authors to consider cattle as a potential good model for the comparative study of spontaneous ageing nerve lesions. PMID- 25823667 TI - Rural-urban disparities in incidence and outcomes of neuroendocrine tumors: A population-based analysis of 6271 cases. AB - BACKGROUND: Despite their rising incidence, neuroendocrine tumors (NETs) remain a poorly understood disease. Living in a rural area (RA) affects the incidence and outcomes of other types of cancer. This study compared the incidence and outcomes of NETs for patients in RAs and patients in urban areas (UAs). METHODS: A population-based cohort study of patients with NETs in Ontario, Canada from 1994 to 2011 was conducted. An RA was defined as any community with a population < 10,000 and outside the commuting zone of a metropolitan area. Incidence, advanced stage at presentation, distant recurrence-free survival (dRFS), and overall survival (OS) were compared between patients who lived in RAs and patients who lived in UAs with univariate and multivariate regression analyses. RESULTS: The cohort included 6271 patients diagnosed with NETs, of whom 13.5% (n = 846) resided in RAs. The incidence of NETs was higher in RAs at 3.01 per 100,000 per year versus UAs at 2.82 per 100,000 per year (relative rate, 1.10; P = .04). RA living was not associated with an advanced stage at presentation (odds ratio, 1.15; 95% confidence interval, 0.96-1.38). Patients who lived in RAs had worse 10 year dRFS (62.8% vs 65.9%, P = .03) and OS (44.6% vs 48.8%, P = .004). RAs were independently associated with decreased OS (hazard ratio, 1.16; 95% confidence interval, 1.04-1.30). CONCLUSIONS: Patients are more commonly diagnosed with NETs in RAs, but they do not present at more advanced stages in comparison with patients diagnosed in UAs. Patients living in RAs experience worse cancer recurrence and OS, and this is possibly related to variations in socioeconomic status, rural environmental factors, and access to specialized health care. PMID- 25823668 TI - Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9. AB - RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple subcutaneous doses. Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to explain the antibody PK and LDLc time course data. The PK and PD models based on data from healthy subjects were used to simulate the effects of RG7652 on LDLc levels for a range of potential dose regimens in patients with coronary heart disease. A one-compartment PK model combined with an indirect PD response model was able to adequately describe the PK and LDLc data. Simulations of 400 mg every 4 weeks or 800 mg every 8 weeks regimens show significant LDLc reduction and suggest that dosing RG7652 once every month or once every 2 months is predicted to be optimal for the treatment of hypercholesterolemia. The PK and PD model successfully described the PK and LDLc data from healthy subjects in a Phase 1 study, and the model-based simulations provided useful insights and quantitative understanding for the selection of Phase 2 study doses in patients with coronary heart disease. The approach used in the case study demonstrates the utility of modeling and simulation in designing dose-ranging studies. PMID- 25823669 TI - Molecular Imaging of Membrane Transporters' Activity in Cancer: a Picture is Worth a Thousand Tubes. AB - Molecular imaging allows the non-invasive assessment of membrane transporter expression and function in living subjects. Such technologies have the potential to become diagnostic and prognostic tools, allowing detection, localization, and prediction of response of tumors and their metastases to therapy. Beyond tumors, imaging can also help understand the role of transporters in adverse drug effects and drug clearance. Here, we review molecular imaging technologies that monitor transporter-mediated processes. We emphasize emerging probe substrates and potential clinical applications of imaging the function of membrane transporters in cancer. PMID- 25823670 TI - Peptide Developability at the Discovery-to-Development Interface--Current State and Future Opportunities. PMID- 25823671 TI - Iatrogenic Medial Patellar Instability: An Avoidable Injury. AB - Iatrogenic medial patellar instability is a specific condition that frequently causes incapacitating anterior knee pain, severe disability, and serious psychological problems. The diagnosis should be suspected in a patient who has undergone previous patellar realignment surgery that has made the pain worse. The diagnosis can be established by physical examination and simple therapeutic tests (e.g., "reverse" McConnell taping) and confirmed by imaging techniques. This iatrogenic condition should no longer exist and could almost be eliminated by avoiding over-release of the lateral retinaculum. PMID- 25823672 TI - The Addition of Platelet-Rich Plasma to Scaffolds Used for Cartilage Repair: A Review of Human and Animal Studies. AB - PURPOSE: To review the available literature on studies focusing on platelet-rich plasma (PRP)-enhanced scaffolds for cartilage lesion repair in animals and to analyze the clinical outcomes of similar biologically augmented cartilage regeneration techniques in humans. METHODS: We conducted a literature search and subsequent review investigating the potential of PRP to enhance articular cartilage repair using scaffolds or bioengineered implants. RESULTS: Of the 14 animal model studies reviewed, 10 reported positive effects with PRP whereas only 2 showed negative overall effects. The remaining 2 studies reported no significant differences, or neutral results, with the use of PRP. With the addition of PRP, the gross appearance and histologic analysis of repair cartilage were improved or no difference was seen compared with control (11 of 12 studies that looked at this). Human studies of the knee or talar dome showed improvements in clinical assessment scores as soon as 6 months after surgery. There was great variability in the method of PRP preparation, choice of scaffold, and cell source between studies. CONCLUSIONS: PRP-augmented scaffolds have been shown to be beneficial in the articular cartilage repair process in animals and humans based on macroscopic, histologic, and biochemical analysis and based on clinical outcome scores, respectively. Comparison between studies is difficult because there is great variability in PRP preparation and administration. LEVEL OF EVIDENCE: Level IV, systematic review of Level III and IV studies. PMID- 25823673 TI - The Incidence of Propionibacterium acnes in Shoulder Arthroscopy. AB - PURPOSE: To document the skin colonization and deep tissue inoculation rates associated with arthroscopic shoulder surgery and how these rates differ with procedural and demographic factors. METHODS: We prospectively recruited outpatient shoulder arthroscopy patients who agreed to participate and met the inclusion criteria from February 2013 to May 2014. All patients received routine antibiotic prophylaxis intravenously. Initial cultures were obtained before the skin preparation by swabbing the skin at the 3 standard portal sites: posterior, anterosuperior, and anterolateral. The skin preparation used 4% chlorhexidine scrub and 2% chlorhexidine gluconate/70% isopropyl alcohol paint applied to the entire shoulder. After completion of the arthroscopic procedure, a second culture was obtained through a cannula at the surgical site. All cultures were plated for 21 days using Brucella medium. RESULTS: We enrolled 51 patients over a 15-month period. Cultures showed a 72.5% Propionibacterium acnes superficial colonization rate: 46.1% of female and 81.6% of male patients (P = .027). We identified a deep culture-positive inoculation rate of 19.6%, all with positive P acnes skin colonization. No correlation could be made concerning diagnosis, procedure, suture anchor use, age, or sex. CONCLUSIONS: The rate of skin colonization with P acnes is high at arthroscopic portals, especially in men. Despite standard skin preparation and prophylactic antibiotics, the rate of deep tissue inoculation with P acnes in shoulder arthroscopy is much higher than the rate of infection reported in the literature. CLINICAL RELEVANCE: Shoulder arthroscopy introduces a significant amount of P acnes into the deep tissues. PMID- 25823674 TI - An in Vivo 3D Computed Tomographic Analysis of Femoral Tunnel Geometry and Aperture Morphology Between Rigid and Flexible Systems in Double-Bundle Anterior Cruciate Ligament Reconstruction Using the Transportal Technique. AB - PURPOSE: The aim of this study was to compare femoral tunnel length, femoral graft-bending angle, posterior wall breakage, and femoral aperture morphologic characteristics between rigid and flexible systems after double-bundle (DB) anterior cruciate ligament (ACL) reconstruction using the transportal (TP) technique. METHODS: We evaluated 3-dimensional computed tomography (3D-CT) results for 54 patients who underwent DB ACL reconstruction using the TP technique with either a flexible system (n = 27) or a rigid system (n = 27). The femoral tunnel length, femoral graft-bending angle, posterior wall breakage, femoral tunnel aperture height to width (H:W) ratio, aperture axis angle, and femoral tunnel position were assessed using OsiriX Imaging Software and Geomagic Qualify 2012 (Geomagic, Cary, NC). RESULTS: The mean anteromedial (AM) femoral tunnel length of the flexible group was significantly longer than that of the rigid group (P = .009). The mean femoral graft-bending angles in the flexible group were significantly less acute than those in the rigid group (AM, P < .001; posterolateral [PL], P = .003]. Posterior wall breakage was observed in both groups (P = 1.00). The mean H:W ratios in the rigid group were significantly larger (more elliptical) than those of the flexible group (AM, P < .001; PL, P = .006). The mean aperture axis angle of the PL femoral tunnel in the rigid group was more parallel to the femoral shaft axis than that in the flexible group (P < .001). There were no significant differences in femoral tunnel position between the 2 groups. CONCLUSIONS: The AM femoral tunnel length and the AM/PL femoral graft-bending angle of the flexible system were significantly longer and less acute than those of the rigid system. However, the aperture morphologic characteristics of the AM/PL femoral tunnel and the aperture axis angle of the PL femoral tunnel in the rigid system were significantly more elliptical and closer to parallel to the femoral shaft axis than those of the flexible system. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 25823675 TI - Inclusion and Exclusion Criteria in the Diagnosis of Femoroacetabular Impingement. AB - PURPOSE: The purpose of this study was to clarify the criteria for femoroacetabular impingement (FAI) by way of a systematic review of FAI-related articles, as well as to define more appropriate inclusion or exclusion criteria in the diagnosis of FAI. METHODS: A systematic review of FAI-related articles was performed using Web of Science. Thirty-two articles met the inclusion and exclusion criteria. In these articles we investigated radiographic findings for the diagnosis of FAI and the prevalence of each FAI-related finding. RESULTS: The crossover sign was used in 22 articles (69%); acetabular index, 9 articles (28%); posterior wall sign, 7 articles (22%); and prominence of the ischial spine sign, 3 articles (7%). Regarding acetabular coverage, the lateral center-edge (LCE) angle was described in 13 articles (41%), in which an LCE angle either of more than 40 degrees or of more than 30 degrees combined with an acetabular index of less than 0 degrees was considered an inclusion criterion for pincer impingement. Meanwhile, the alpha angle was used in 28 articles (88%), in which 50 degrees or 55 degrees was recommended as a positive finding of cam impingement. CONCLUSIONS: Common findings of pincer or cam deformity were used to select FAI patients with sufficient coverage of the acetabulum with an LCE angle of more than 25 degrees . Patients with an LCE angle of less than 25 degrees or those with local acetabular deficiency regardless of having a normal LCE angle should be excluded from the FAI criteria, even if the FAI-related findings are positive. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies. PMID- 25823676 TI - Calcitriol ameliorates renal damage in a pre-established proteinuria model. AB - Proteinuria is critical in the tubulointerstitial changes that ultimately lead to renal insufficiency. Increased protein filtration has direct toxic effects on tubular epithelial cells, leading to epithelial mesenchymal transition (EMT) to a myofibroblast phenotype. Angiotensin II and transforming growth factor (TGF) beta1 are the main mediators of EMT. Calcitriol may exert a potential renoprotective effect by reducing the activity of the renin angiotensin system by suppressing renin gene expression and also by inhibiting the proinflammatory nuclear factor-kappaB pathway. The present study investigated the benefits of calcitriol treatment in a puromycin-induced proteinuric nephropathy model. Uninephrectomized adult male Wistar rats received intraperitoneal administration of a single dose of puromycin (100 mg/kg) or vehicle. After eight weeks, the animals were divided into two groups and received vehicle or calcitriol (0.5 ug/kg) for four weeks. The vehicle-treated, proteinuric rats developed progressive proteinuria and tubulointerstitial fibrosis after 12 weeks. Increased collagen deposition and fibrosis were significantly ameliorated by calcitriol treatment. Calcitriol was effective in preventing an increase in the EMT markers, alpha-smooth muscle actin and fibroblast-specific protein 1, reducing macrophage infiltration as evidenced by levels of ED-1. In addition, calcitriol increased the anti-inflammatory cytokine interleukin-10 and reduced the pro-oxidant p47 phox enzyme. These effects were paralleled by a reduction in TGF-beta/Smad3 expression. Calcitriol may have therapeutic potential in the proteinuric nephropathy model used in the present study by inhibiting the TGF-beta1 axis. PMID- 25823677 TI - Acute exacerbation of psychiatric symptoms during influenza treatment with oseltamivir in chronic schizophrenia. AB - Influenza treatment and prophylaxis with oseltamivir are critically important in reducing the morbidity and mortality of patients in chronic psychiatric facilities. Abnormal behavior, delusions, perceptual disturbances, mania, and depression have all been reported as oseltamivir-related psychiatric side effects. We hereby report two chronic schizophrenia patients in Taiwan manifesting psychiatric instability who were being treated with oseltamivir for suspected influenza infection, and further discuss other potential contributing factors. The possibility that oseltamivir can cause psychotic or affective symptoms suggests that additional caution is necessary for its use in patients with an established psychiatric diagnosis. PMID- 25823678 TI - Comparison of balloon-expandable valves versus self-expandable valves in high risk patients undergoing transcatheter aortic valve replacement for severe aortic stenosis. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement for patients with symptomatic severe aortic stenosis (AS) who have a high surgical risk. In Taiwan, this is the first study reporting TAVI outcomes at a single center offering two different transcatheter heart valve technologies via four types of approaches. Our aim was to compare 30-day and 6-month Valve Academic Research Consortium-2 (VARC-2) outcomes of the two valves. METHODS: We reported the procedural, 30-day, and 6 month VARC-2 outcomes of high-risk patients who were consecutively treated with the Medtronic CoreValve (MCV) or with the Edwards SAPIEN valve or SAPIEN XT valve (ESV; Edwards Lifesciences, Irvine, CA, USA) delivered via four types of approaches. RESULTS: From May 2010 to December 2013, 30 consecutive patients with severe AS underwent TAVI: 15 patients were treated with the MCV and 15 patients were treated with the ESV. The transfemoral approach was the most frequently used route (13 MCV and 6 ESV), followed by the transapical approach (9 ESV), trans subclavian approach (1 MCV), and direct aortic approach (1 MCV). There were no procedural deaths. "Device success" was achieved in 29 (96.7%) patients, and is defined as the absence of procedural mortality, correct positioning of one prosthetic heart valve into the proper anatomical location, and intended performance of the heart valve without moderate or severe regurgitation. The VARC 2-defined combined safety endpoint at 30 days was comparable between patients treated with the ESV and the MCV (33.3% vs. 20%, respectively; group, p = 0.409). At the 6-month follow up, the combined efficacy endpoint was not significantly different between the two groups (13.3% in the ESV group vs. 20% in the MCV group; p = 0.624). There was only one (3.3%) patient who required permanent pacemaker implantation. CONCLUSION: For the first time in Taiwan, we have demonstrated that TAVI using either device is complementary and feasible for treating a wide range of patients by using a careful selection of approaches. Favorable overall procedural success rates and 30-day and 6-month outcomes were achieved with both devices. PMID- 25823679 TI - Disseminated Penicillium marneffei mimicking paradoxical response and relapse in a non-HIV patient with pulmonary tuberculosis. AB - Clinical deterioration during the treatment of tuberculosis remains a diagnostic challenge. We describe the case of a 46-year-old man with a history of oral cancer status after a radical operation who had pulmonary tuberculosis with pleura and neck lymph node involvement. The clinical condition improved after antituberculosis therapy. However, the patient suffered from low-grade fever, progressive dyspnea, and cough after 7 weeks of the therapy. The findings of chest plain films were relapse and progression of left lung haziness. The deterioration was caused by disseminated Penicillium marneffei infection. Disseminated P. marneffei in a non-HIV patient with tuberculosis is rarely seen, and the manifestations are similar to a paradoxical response and relapse of pulmonary tuberculosis, thereby making it difficult to establish a diagnosis. PMID- 25823680 TI - Endothelial cell dysfunction and preeclampsia. PMID- 25823681 TI - Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories. AB - Rapid in silico selection of target-focused libraries from commercial repositories is an attractive and cost-effective approach. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compound databases, but the generated library requires further focusing. We report here a combination of the 2D approach with pharmacophore matching which was used for selecting 5-HT6 antagonists. In the first screening round, 12 compounds showed >85% antagonist efficacy of the 91 screened. For the second-round (hit validation) screening phase, pharmacophore models were built, applied, and compared with the routine 2D similarity search. Three pharmacophore models were created based on the structure of the reference compounds and the first-round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking the novelty. To demonstrate the power of the virtual screening cascade, ligand efficiency indices were also calculated and their steady improvement was confirmed. PMID- 25823682 TI - Spermatozoa input concentrations and RNA isolation methods on RNA yield and quality in bull (Bos taurus). AB - Sperm RNA can be used to understand the past spermatogenic process, future successful fertilization, and embryo development. To study the sperm RNA composition and function, isolation of good quality RNA with sufficient quantity is essential. The objective of this study was to assess the influence of sperm input concentrations and RNA isolation methods on RNA yield and quality in bull sperm. The fresh semen samples from bulls (n = 6) were snap-frozen in liquid nitrogen and stored at -80 degrees C. The sperm RNA was isolated using membrane based methods combined with TRIzol (RNeasy+TRIzol and PureLink+TRIzol) and conventional methods (TRIzol, Double TRIzol, and RNAzol RT). Based on fluorometric quantification, combined methods resulted in significantly (P < 0.05) higher total RNA yields (800-900 ng/30-40 * 10(6)) as compared with other methods and yielded 20 to 30 fg of RNA/spermatozoon. The quality of RNA isolated by membrane-based methods was superior to that isolated by conventional methods. The sperm RNA was observed to be intact as well as fragmented (50-2000 bp). The study revealed that the membrane-based methods with a cocktail of lysis solution and an optimal input concentration of 30 to 40 million sperm were optimal for maximum recovery of RNA from bull spermatozoa. PMID- 25823683 TI - Isothermal titration calorimetry determination of individual rate constants of trypsin catalytic activity. AB - Determination of individual rate constants for enzyme-catalyzed reactions is central to the understanding of their mechanism of action and is commonly obtained by stopped-flow kinetic experiments. However, most natural substrates either do not fluoresce/absorb or lack a significant change in their spectra while reacting and, therefore, are frequently chemically modified to render adequate molecules for their spectroscopic detection. Here, isothermal titration calorimetry (ITC) was used to obtain Michaelis-Menten plots for the trypsin catalyzed hydrolysis of several substrates at different temperatures (278-318K): four spectrophotometrically blind lysine and arginine N-free esters, one N substituted arginine ester, and one amide. A global fitting of these data provided the individual rate constants and activation energies for the acylation and deacylation reactions, and the ratio of the formation and dissociation rates of the enzyme-substrate complex, leading also to the corresponding free energies of activation. The results indicate that for lysine and arginine N-free esters deacylation is the rate-limiting step, but for the N-substituted ester and the amide acylation is the slowest step. It is shown that ITC is able to produce quality kinetic data and is particularly well suited for those enzymatic reactions that cannot be measured by absorption or fluorescence spectroscopy. PMID- 25823684 TI - Relationship of leptin with adiposity and inflammation and resistin with disease severity in psoriatic patients undergoing anti-TNF-alpha therapy. AB - BACKGROUND: Altered secretion patterns of proinflammatory adipokines may influence the increased risk of cardiovascular mortality observed in patients with chronic inflammatory diseases. OBJECTIVE: To determine whether two adipokines, leptin and resistin, correlate with metabolic syndrome features and disease severity in psoriatic patients who underwent anti-TNF-alpha therapy. METHODS: Prospective study of consecutive non-diabetic patients with moderate-to severe psoriasis who completed 6 months of therapy with anti-TNF-alpha- adalimumab. Patients with kidney disease, hypertension or body mass index >=35 Kg/m(2) were excluded. Metabolic and clinical evaluation was performed at the onset of anti-TNF-alpha treatment and at month 6. RESULTS: Twenty-nine patients were assessed. A correlation between adiposity and leptin was observed (waist circumference and leptin levels after 6 months of therapy: r = 0.43; P = 0.030). Leptin concentration also correlated with blood pressure before adalimumab onset (systolic: r = 0.48; P = 0.013 and diastolic blood pressure: r = 0.50; P = 0.010 ). A marginally significant negative correlation between insulin sensitivity (QUICKI) and leptin levels was also observed. CRP levels correlated with leptin prior to the onset of adalimumab (r = 0.45; P = 0.020) and with resistin both before (r = 0.45; P = 0.020) and after 6 months of therapy (r = 0.55; P = 0.004). A positive association between parameters of disease activity such as BSA (r = 0.60; P = 0.001) and PASI (r = 0.63; P = 0.001) prior to the onset of adalimumab therapy and resistin concentrations was also disclosed. No significant changes in leptin and resistin concentrations following the 6-month treatment with adalimumab were seen. CONCLUSION: In patients with moderate-to-severe psoriasis leptin correlates with metabolic syndrome features and inflammation whereas resistin correlate with inflammation and disease severity. PMID- 25823685 TI - A Case of Granulocyte-Colony Stimulating Factor-Producing Spindle Cell Carcinoma of the Breast. PMID- 25823687 TI - Genome-wide association study of myelosuppression in non-small-cell lung cancer patients with platinum-based chemotherapy. AB - Platinum-induced myelosuppression severely impedes successful chemotherapy in non small-cell lung cancer (NSCLC) patients. Hence, it is clinically important to identify the patients who are at high risk for severe toxicity to certain chemotherapy. We first carried out a genome-wide scan of 906 703 single nucleotide polymorphisms (SNPs) to identify genetic variants associated with platinum-induced myelosuppression risk in 333 NSCLC patients with chemotherapy. Then, we replicated 24 SNPs that had P<1 * 10(-4) in another independent cohort of 876 NSCLC patients. With P<0.05 as the criterion of statistical significance, we found that rs13014982 at 2q24.3 and rs9909179 at 17p12 exhibited consistently significant associations with myelosuppression risk in both the genome-wide association studies (GWAS) scan and the replication stage (rs13014982: odds ratio (OR)=0.55, 95% confidence intervals (CIs): 0.41-0.74, P=7.29 * 10(-5) for GWAS scan and OR=0.77, 95% CI: 0.65-0.93, P=0.006 for replication stage; rs9909179: OR=0.51, 95% CI: 0.37-0.70, P=4.60 * 10(-5) for GWAS scan and OR=0.82, 95% CI: 0.68-0.99, P=0.040 for replication stage; both in additive model). In combined samples of genome-wide scan and replication samples, the minor alleles of rs13014982 and rs9909179 remained significant associations with the decreased risk of myelosuppression (rs13014982: OR=0.71, 95% CI: 0.61-0.83, P =1.36 * 10( 5); rs9909179: OR=0.76, 95% CI: 0.65-0.89, P=0.001). Rs13014982 at 2q24.3 and rs9909179 at 17p12 might be independent susceptibility markers for platinum induced myelosuppression risk in NSCLC patients. PMID- 25823686 TI - Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. AB - The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development. PMID- 25823689 TI - The impact of a ten-week physical exercise program on health-related quality of life in patients with inflammatory bowel disease: a prospective randomized controlled trial. AB - BACKGROUND: Improving health-related quality of life is a primary target of therapy for patients with inflammatory bowel disease. Physical activity has been demonstrated to improve health-related quality of life in several patient populations with chronic disease. There are very few studies investigating the effects of physical activity on health-related quality of life in inflammatory bowel disease. The primary purpose of this study is to investigate the effects of 10 weeks of moderate physical activity on health-related quality of life in patients with inflammatory bowel disease. METHODS: Thirty patients with mild to moderate IBD (Crohn's Disease Activity Index (CDAI) <220 or Rachmilewitz Index (RI) <11) were randomized 1:1 to either supervised moderate-intensity running thrice a week for 10 weeks or a control group who were not prescribed any exercise. Health-related quality of life, symptoms, and inflammation were assessed at baseline and after 10 weeks. RESULTS: Participants were 41 +/- 14 years (73% female), had a body mass index of 22.8 +/- 4.1 kg/m(2), and an average CDAI or RI of 66.8 +/- 42.4 and 3.6 +/- 3.1. No adverse events occurred during the 10-week training period. Health-related quality of life, reported as IBDQ total score, improved 19% in the intervention group and 8% in the control group. Scores for the IBDQ social sub-scale were significantly improved in the intervention group compared with controls (DeltaIBDQsocial = 6.27 +/- 5.46 vs. 1.87 +/- 4.76, p = 0.023). CONCLUSION: Patients suffering from moderately active IBD are capable of performing symptom-free regular endurance exercise. Our data support the assumption that PA is feasible in IBD patients. PA may furthermore improve quality of life through improvements in social well-being, and may, therefore, be a useful adjunct to IBD therapy. PMID- 25823688 TI - The role of Toll-like receptor 4 polymorphisms in vaccine immune response. AB - Toll-like receptors (TLRs) are a class of pattern recognition receptors that are deputed to recognise a range of molecular structures in pathogens. One of the most studied members of this family is the TLR4, which is essential for the signalling of lipopolysaccharide. The gene encoding for TLR4 is highly polymorphic and this genetic variability may explain in part the interindividual variability observed in several clinical setting, including the response to vaccination. Herein, we review and systematise the available scientific evidence about the effect of TLR4 polymorphisms on vaccine response, including approved prophylactic, new therapeutic cancer vaccines and recently approved vaccine adjuvants. Data reviewed in this analysis indicate that TLR4 polymorphisms significantly affect vaccine response. If these results are confirmed by further analyses, the use of these genetic biomarkers may become a useful tool to tailor vaccination in specific subsets of patients. PMID- 25823690 TI - Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells. AB - Gut microbiota-innate immunity axis is emerging as a key player to guarantee the structural and functional integrity of the enteric nervous system (ENS). Alterations in the composition of the gut microbiota, derangement in signaling of innate immune receptors such as Toll-like receptors (TLRs), and modifications in the neurochemical coding of the ENS have been associated with a variety of gastrointestinal disorders. Indeed, TLR2 activation by microbial products controls the ENS structure and regulates intestinal neuromuscular function. However, the cellular populations and the molecular mechanisms shaping the plasticity of enteric neurons in response to gut microbes are largely unexplored. In this study, smooth muscle cells (SMCs), enteric glial cells (EGCs) and macrophages/dendritic cells (MPhi/DCs) were isolated and cultured from the ileal longitudinal muscle layer of wild-type (WT) and Toll-like receptor-2 deficient (TLR2(-/-)) mice. Quantification of mRNA levels of neurotrophins at baseline and following stimulation with TLR ligands was performed by RT-PCR. To determine the role of neurotrophins in supporting the neuronal phenotype, we performed co culture experiments of enteric neurons with the conditioned media of cells isolated from the longitudinal muscle layer of WT or TLR2(-/-) mice. The neuronal phenotype was investigated evaluating the expression of betaIII-tubulin, HuC/D, and nNOS by immunocytochemistry. As detected by semi-quantitative RT-PCR, SMCs expressed mRNA coding TLR1-9. Among the tested cell populations, un-stimulated SMCs were the most prominent sources of neurotrophins. Stimulation with TLR2, TLR4, TLR5 and TLR9 ligands further increased Gdnf, Ngf, Bdnf and Lif mRNA levels in SMCs. Enteric neurons isolated from TLR2(-/-) mice exhibited smaller ganglia, fewer HuC/D(+ve) and nNOS(+ve) neurons and shorter betaIII-tubulin axonal networks as compared to neurons cultured from WT mice. The co-culture with the conditioned media from WT-SMCs but not with those from WT-EGCs or WT-MPhi/DCs corrected the altered neuronal phenotype of TLR2(-/-) mice. Supplementation of TLR2(-/-) neuronal cultures with GDNF recapitulated the WT-SMC co-culture effect whereas the knockdown of GDNF expression in WT-SMCs using shRNA interference abolished the effect on TLR2(-/-) neurons. These data revealed that by exploiting the repertoire of TLRs to decode gut-microbial signals, intestinal SMCs elaborate a cocktail of neurotrophic factors that in turn supports neuronal phenotype. In this view, the SMCs represent an attractive target for novel therapeutic strategies. PMID- 25823691 TI - Infraorbital canal bilaterally replaced by a lateroantral canal. AB - The infraorbital canal (IOC) normally courses above the maxillary sinus in the orbit floor. During a retrospective study of cone beam computed tomography (CBCT) scans, we found a previously unknown variant of the IOC. The IOCs were absent, being replaced by lateroantral canals coursing around and not above the maxillary sinus to open at infraorbital foramina which were located above the second upper premolar teeth. On coronal multiplanar reconstructions, the lateroantral canals were located anatomically at the outer limit of the zygomatic recess of each maxillary sinus, while the upper wall of the sinus was devoid of any canal. Such rare variant should be kept in mind by dental practitioners and surgeons, as it can determine modifications of common procedures. In this regard, the anatomy of maxilla, as well as mandible, should be evaluated in CBCT on a case-by-case basis. PMID- 25823692 TI - The forgotten foramina: a study of the anterior cribriform plate. AB - PURPOSE: The olfactory cleft has garnered interest since the advent of endoscopic skull base surgery. Its precise anatomy, however, is still partially unknown. According to Rouviere, an "ethmoidal foramen" is located in its antero-medial part and contains a process of the dura mater. In a more lateral and anterior location, a second foramen, the "cribroethmoidal foramen", contains the anterior ethmoidal nerve. The aim of this study was to verify the existence of these elements and to establish landmarks for surgery. METHODS: We performed an anatomical and histological study of eight olfactory clefts in four cadavers using both endonasal endoscopic and endocranial dissection. RESULTS: An ethmoidal and a cribroethmoidal foramen were found in, respectively, 100 and 75% of cases. Their mean length was, respectively, 4.1 and 1.8 mm. They were located, respectively, in mean at 5.3 and 5.8 mm from the anterior ethmoidal artery. CONCLUSION: Our anatomical study demonstrates the existence of both foramina. The ethmoidal foramen clearly represents an area of least resistance in the anterior part of the olfactory cleft, which could predispose to anterior skull base cerebrospinal fluid leaks and meningoceles. PMID- 25823693 TI - No effect of oral L-tryptophan or alpha-lactalbumin on total tryptophan levels in breast milk. AB - Postpartum depression (PPD) is the most common complication of childbearing with a 13% prevalence rate. Sleep disturbances are also common, particularly during early postpartum. In theory, l-tryptophan could improve sleep and reduce depressed mood in early postpartum; however, the first step in clinical development of tryptophan for use in postpartum is to measure the effect of oral l-tryptophan on its concentrations in breast milk, which is presently unknown. The aims were to investigate the effect of oral l-tryptophan and alpha lactalbumin, a protein with high tryptophan concentration, on total and free tryptophan levels in breast milk and plasma, and to compare free tryptophan levels in breast milk with those in common infant formulas. Thirty healthy breastfeeding women were randomly allocated to receive 2g or 4g of l-tryptophan, or, 20g or 40g of alpha-lactalbumin or no supplement. Free tryptophan levels were also measured in 12 different infant formulas. Total tryptophan in breast milk was unaffected by oral administration of l-tryptophan or alpha-lactalbumin (repeated measures of ANOVA (rANOVA), group effect: p=0.93). Both l-tryptophan and alpha-lactalbumin were associated with greater free tryptophan levels in breast milk (rANOVA, group effect: p<0.001) (representing 2% of total tryptophan), but these concentrations were within the range of commonly used infant formulas. In contrast to most sleep inducing medications, l-tryptophan does not affect its total concentration in breast milk. These results support further investigation of dietary l-tryptophan and alpha-lactalbumin as part of a dietary supplementation approach to address sleep disturbances in postpartum and reduce risk of PPD. PMID- 25823694 TI - Olanzapine depot exposure in male rats: Dose-dependent lipogenic effects without concomitant weight gain. AB - Treatment with second-generation antipsychotic agents such as olanzapine frequently results in metabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders. The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies in rodents represent an important approach in their exploration. However, the validity of the rodent model is hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. When administered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of the drug. We recently showed that a single intramuscular injection of long-acting olanzapine formulation yields clinically relevant plasma concentrations accompanied by several dysmetabolic features in the female rat. In the current study, we show that depot injections of 100-250 mg/kg olanzapine yielded clinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia, however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feed efficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue for the highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained. In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantly elevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver. These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raise the possibility that endocrine factors may influence gender specificity of metabolic effects of antipsychotics in the rat. PMID- 25823695 TI - Hyper-responsivity to stress in rats is associated with a large increase in amygdala volume. A 7T MRI study. AB - Stress is known to precipitate psychiatric disorders in vulnerable people. Individual differences in the stress responsivity can dramatically affect the onset of these illnesses. Animal models of repeated stress represent valuable tools to identify region-specific volumetric changes in the brain. Here, using high resolution 7T MRI, we found that amygdala is the most significant parameter for distinction between F344 and SD rats known to have differential response to stress. A significant substantial increase (45%) was found in the amygdala volume of rats that do not habituate to the repeated stress procedure (F344 rats) compared to SD rats. This strain-specific effect of stress was evidenced by a significant strain-by-stress interaction. There were no significant strain differences in the volumes of hippocampi and prefrontal cortices though stress produces significant reductions of smaller amplitude in the medial prefrontal cortex (mPFC) (9% and 12%) and dorsal hippocampus (5% and 6%) in both strains. Our data further demonstrate the feasibility and relevance of high isotropic resolution structural ex vivo 7T MRI in the study of the brain effects of stress in small animals. Neuroimaging is a valuable tool to follow up brain volumetric reorganization during the stress response and could also be easily used to test pharmacological interventions to prevent the deleterious effects of stress. PMID- 25823696 TI - The route to spinal cord cell types: a tale of signals and switches. AB - Understanding the mechanisms that control induction and elaboration of the vertebrate central nervous system (CNS) requires an analysis of the extrinsic signals and downstream transcriptional networks that assign cell fates in the correct space and time. We focus on the generation and patterning of the spinal cord. We summarize evidence that the origin of the spinal cord is distinct from the anterior regions of the CNS. We discuss how this affects the gene regulatory networks and cell state transitions that specify spinal cord cell subtypes, and we highlight how the timing of extracellular signals and dynamic control of transcriptional networks contribute to the correct spatiotemporal generation of different neural cell types. PMID- 25823697 TI - Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy. AB - OBJECTIVE: To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy. METHODS: (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy (N=17) and healthy controls (N=12) were also conducted, and data were interpreted using mathematical modeling. RESULTS: In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes. CONCLUSION: Ih was upregulated after MGO administration in normal mice. SIGNIFICANCE: MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis. PMID- 25823698 TI - Ongoing cumulative effects of single TMS pulses on corticospinal excitability: An intra- and inter-block investigation. AB - OBJECTIVE: To evaluate the effects of several single TMS pulses, delivered at two different inter-trial intervals (ITIs), on corticospinal excitability. METHODS: Twelve healthy volunteers participated in two experimental sessions, during which TMS pulses were delivered at random or at fixed ITIs. The TMS single pulse induced modulation of corticospinal output (motor evoked potential amplitude - MEP) was evaluated on-line. Each session began with a baseline block, followed by 10 blocks, with 20 TMS pulses each. Intra- and inter-block effects were valuated using an ANOVA model, through nested random effect on subjects considering the subject-specific variability. RESULTS: The delivery of successive TMS pulses significantly changed both intra-block and inter-block cortical excitability, as demonstrated by an increase in the amplitude of MEPs (p<0.001) and supported through trend analyses, showing a perfect linear trend for inter-block levels (R(2)=1) and nearly linear trend for intra-block levels (R(2)=0.97). The MEPs significantly increased when the TMS pulses were delivered at both random and fixed ITIs. CONCLUSIONS: Single TMS pulses induce cumulative changes in neural activity during the same stimulation, resulting in a motor cortical excitability increase. SIGNIFICANCE: Particular attention should be taken when several single TMS pulses are delivered in research and clinical settings for diagnostic and therapeutic purposes. PMID- 25823699 TI - Therapeutic options for hydrating airway mucus in cystic fibrosis. AB - BACKGROUND: In cystic fibrosis (CF), genetic mutations in the CF transmembrane conductance regulator (CFTR) gene cause reduced chloride efflux from ciliated airway epithelial cells. This results in a reduction in periciliary liquid (PCL) depth of the airway surface liquid due to associated reduced water efflux. PCL layer dehydration reduces mucociliary clearance (MCC), leading to airway obstruction (reduced airflow and inflammation due to pathogen invasion) with mucus plug formation. SUMMARY: Rehydrating mucus increases MCC. Mucus hydration can be achieved by direct hydration (administering osmotic agents to set up an osmotic gradient), using CFTR modulators to correct dysfunctional CFTR, or it can be achieved pharmacologically (targeting other ion channels on airway epithelial cells). Key Messages: The molecular mechanisms of several therapies are discussed in the context of pre-clinical and clinical trial studies. Currently, only the osmotic agent 7% hypertonic saline and the CFTR 'potentiator' VX-770 (ivacaftor) are used clinically to hydrate mucus. Emerging therapies include the osmotic agent mannitol (Bronchitol), the intracellular Ca(2+)-raising agent Moli1901/lancovutide, the CFTR potentiator sildenafil [phosphodiesterase type 5 (PDE5) inhibitor] and the CFTR 'corrector' VX-809 (lumacaftor). Other CFTR correctors (e.g. 'chemical chaperones') are also showing pre-clinical promise. PMID- 25823700 TI - Distribution of seizures across the menstrual cycle in women with epilepsy. AB - The purpose of this study was to determine whether seizure frequency and cycle days with seizure occurrence vary across the menstrual cycle. The subjects were the first 100 women with intractable focal onset seizures, 13-45 years old, who completed the baseline phase of the National Institutes of Health (NIH) Progesterone Trial. Each subject recorded seizures and menses during a 3-month baseline phase. Data consisted of (1) seizure numbers for each cycle day and (2) cycle days with seizure occurrence. Statistical comparisons of seizure frequency and days with seizures were performed using generalized estimating equation one way analysis of variance (ANOVA) and logistic regression followed by pairwise multiple comparisons of days based on the least square means. Seizure numbers and cycle days with seizure occurrence varied across the menstrual cycle. There was an approximately twofold difference between the highest (day 1) and lowest (day 8) values for both seizure frequency and days with occurrence. The demonstration of variation in seizure frequency and cycle days with seizure occurrence across the menstrual cycle, as well as identification of specific days that have substantially higher or lower frequencies than other days, supports the existence of catamenial epilepsy. PMID- 25823701 TI - Awareness of forensic odontology among dentists in Australia: are they keeping forensically valuable dental records? AB - BACKGROUND: Forensic odontologists provide an important service to the community by identifying unknown deceased people, allowing both legal outcomes and family closure. Non-visual identification may be achieved by comparison of post-mortem data with ante-mortem dental records provided by oral health practitioners. Success is dependent largely on the accuracy and adequacy of data in the dental records. METHODS: An online self-administered questionnaire evaluated Australian dentists' knowledge and behaviours relevant to forensic odontology. Reported record keeping practices were assessed for detail, legibility, accessibility and retention. Behaviours were classified according to the frequency of response. RESULTS: Dentists reported overall reasonable awareness of the major applications of forensic odontology. Personal information and details of restorative treatment were recorded at high levels, while tooth anomalies, photography, additional patient details and denture marking were recorded inadequately. Legible tooth coding was reported at a high level, while other key legibility practices were recorded inadequately. Few of the behaviours related to retention or to maximize accessibility were recorded at a high level. CONCLUSIONS: Australian dentists have high expectations of the forensic value of their dental records; however, many processes that would enhance the diagnostic, medico-legal and forensic value of dental records are not routinely applied. PMID- 25823702 TI - Shape up or ship out: migratory behaviour predicts morphology across spatial scale in a freshwater fish. AB - 1. Migration is a widespread phenomenon, with powerful ecological and evolutionary consequences. Morphological adaptations to reduce the energetic costs associated with migratory transport are commonly documented for migratory species. However, few studies have investigated whether variation in body morphology can be explained by variation in migratory strategy within a species. 2. We address this question in roach Rutilus rutilus, a partially migratory freshwater fish that migrates from lakes into streams during winter. We both compare body shape between populations that differ in migratory opportunity (open vs. closed lakes), and between individuals from a single population that vary in migratory propensity (migrants and residents from a partially migratory population). Following hydrodynamic theory, we posit that migrants should have a more shallow body depth, to reduce the costs associated with migrating into streams with higher flow conditions than the lakes the residents occupy all year round. 3. We find evidence both across and within populations to support our prediction, with individuals from open lakes and migrants from the partially migratory population having a more slender, shallow-bodied morphology than fish from closed lakes and all-year residents. 4. Our data suggest that a shallow body morphology is beneficial to migratory individuals and our study is one of the first to link migratory strategy and intraspecific variation in body shape. PMID- 25823703 TI - Statistical models for respiratory disease diagnosis and prognosis. AB - Risk prediction equations are used in a variety of healthcare settings to provide prognosis for patients with various respiratory conditions. This article provides a review of statistical methods for the development, evaluation and implementation of respiratory disease prediction models. We also consider a second, closely related application of these methods: the creation of equations that describe normal lung function in a particular population and the use of such equations in the diagnosis of abnormal lung function. The methods are illustrated with examples of models that have been developed for use in respiratory medicine and research. PMID- 25823705 TI - Brucellosis control in northeast China: a long way to go. PMID- 25823704 TI - Lessons from collaborative governance and sociobiology theories for reinforcing sustained cooperation: a government food security case study. AB - OBJECTIVES: This research aimed to understand how cooperation and collaboration work in interagency arrangements using a case study of the public management of food security and nutrition in Bogota, Colombia. STUDY DESIGN: This study explored the available scientific literature on Collaborative Governance within the Public Management body of knowledge and the literature on Cooperation from the Sociobiology field. Then, proposals were developed for testing on the ground through an action-research effort that was documented as a case study. Finally, observations were used to test the proposals and some analytical generalizations were developed. METHODS: To document the case study, several personal interviews, file reviews and normative reviews were conducted to generate a case study database. RESULTS: Collaboration and cooperation concepts within the framework of interagency public management can be understood as a shared desirable outcome that unites different agencies in committing efforts and resources to the accomplishment of a common goal for society, as seen in obtaining food and nutrition security for a specific territory. Collaboration emerges when the following conditions exist and decreases when they are absent: (1) a strong sponsorship that may come from a central government policy or from a distributed interagency consensus; (2) a clear definition of the participating agencies; (3) stability of the staff assigned to the coordination system; and (4) a fitness function for the staff, some mechanism to reward or punish the collaboration level of each individual in the interagency effort. CONCLUSIONS: As this research investigated only one case study, the findings must be taken with care and any generalization made from this study needs to be analytical in nature. Additionally, research must be done to accept these results universally. Food security and nutrition efforts are interagency in nature. For collaboration between agencies to emerge, a minimum set of characteristics that were established during the merging of the public management and sociobiology fields of knowledge and validated by means of a case study must be accomplished. PMID- 25823706 TI - Comparing levels of social capital in three northern post-industrial UK cities. AB - OBJECTIVES: A high level of 'excess' mortality (i.e. that seemingly not explained by deprivation) has been shown for Scotland compared to England & Wales and, in particular, for its largest city, Glasgow, compared to the similarly deprived postindustrial English cities of Liverpool and Manchester. The excess has been observed across all social classes, but, for premature mortality, has been shown to be highest in comparison of those of lowest socio-economic status (SES). Many theories have been proposed to explain this phenomenon. One such suggestion relates to potential differences in social capital between the cities, given the previously evidenced links between social capital and mortality. The aim of this study was to ascertain whether any aspects of social capital differed between the cities and whether, therefore, this might be a plausible explanation for some of the excess mortality observed in Glasgow. STUDY DESIGN: Cross-sectional study. METHODS: A representative survey of Glasgow, Liverpool and Manchester was undertaken in 2011. Social capital was measured using an expanded version of the Office for National Statistics (ONS) core 'Social Capital Harmonised Question Set'. Differences between the cities in five sets of social capital topics (views about the local area, civic participation, social networks and support, social participation, and reciprocity and trust) were explored by means of a series of multivariate regression models, while controlling for differences in the characteristics (age, gender, SES, ethnicity etc.) of the samples. RESULTS: Some, but not all, aspects of social capital were lower among the Glasgow sample compared to those in Liverpool and Manchester. A number of these differences were greatest among those of higher, rather than lower, SES. Levels of social participation, trust and (some measures of) reciprocity were lower in Glasgow, particularly in comparison with Liverpool. However, assessment of any potential impact of these differences is limited by the cross-sectional nature of the data. CONCLUSIONS: The analyses suggest it is at least possible that differences in some aspects of social capital could play some part in explaining Glasgow's excess mortality, especially among particular sections of its population (e.g. those of higher SES). However, in the absence of more detailed longitudinal data, this remains speculative. PMID- 25823707 TI - Chronic generalized fibrotic skin lesions from disseminated leishmaniasis caused by Leishmania martiniquensis in two patients from northern Thailand infected with HIV. AB - BACKGROUND: Leishmaniasis is a newly emerging infection in Thailand. Most of the previous human cases have presented with the clinical features of visceral leishmaniasis and were mainly found in southern Thailand. Here we report the first two patients from northern Thailand presenting with disseminated cutaneous leishmaniasis. OBJECTIVES: To determine the nature of the infection of leishmaniasis and to identify the species of parasite responsible. METHODS: Clinical investigations included the taking of biopsy samples and histology. Parasitological diagnosis was performed by establishment of Leishmania promastigote cultures, and identification was performed by DNA sequencing of four independent gene loci (ribosomal RNA internal transcribed spacer 1; large subunit of RNA polymerase II; heat shock protein 70; RPL23a intergenic sequence). RESULTS: Both patients were infected with HIV, and had multiple cutaneous lesions and accompanying visceral leishmaniasis. They had similar cutaneous manifestations characterized by chronic generalized fibrotic lesions, which were more prominent on traumatic areas. In both patients the parasite was identified as Leishmania martiniquensis. This is a recently described species that is distinct and only distantly related to the classical agents of cutaneous leishmaniasis in Asia (Leishmania major and Leishmania tropica) or of visceral leishmaniasis (Leishmania donovani and Leishmania infantum). Each patient responded well to therapy with intravenous amphotericin B followed by oral itraconazole. CONCLUSIONS: Leishmania martiniquensis is a cause of cutaneous leishmaniasis in Thailand. PMID- 25823708 TI - LC-MS/MS-based method for long-term steroid profiling in human scalp hair. AB - BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the method of choice for quantification of steroids. Human scalp hair provides the possibility to measure long-term retrospective steroid concentrations, which is especially useful for steroids with large time-dependent fluctuations in concentration, such as the glucocorticoid cortisol. AIM: We set up and validated a LC-MS/MS-based method for long-term steroid profiling, quantifying cortisol, cortisone, testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS) and 17-alpha-hydroxyprogesterone (17OHP). METHOD: Hair locks were cut from the posterior vertex of healthy male and female volunteers and washed in isopropanol. Steroids were extracted using methanol, and extract was cleaned up by solid-phase extraction and measured on a Waters XEVO-TQ-S LC-MS/MS. Lower limit of quantification, precision, matrix interference and intra-individual variation were determined. RESULTS: The functional sensitivity of our steroid analysis was <1.3, <9.3, 2.3, <1.3, <15.9, 1.87 pg/mg hair for cortisol, cortisone, testosterone, androstenedione, dehydroepiandrosterone sulphate (DHEAS), and 17OHP, respectively. Measured over a 9-month period, the inter-run CVs were below 16% for all steroids. Intra-individual coefficients of variation were below 15% for all steroids, except 17OHP (19.7%). CONCLUSION: The authors present a LC MS/MS-based method for long-term steroid profiling in human scalp hair, potentially providing novel insights by a multitude of clinical and research applications in the field of endocrinology. PMID- 25823709 TI - Implications of modifying membrane fatty acid composition on membrane oxidation, integrity, and storage viability of freeze-dried probiotic, Lactobacillus acidophilus La-5. AB - The aim of this study was to investigate the effect of altering the fatty acid profile of the lipid membrane on storage survival of freeze-dried probiotic, Lactobacillus acidophilus La-5, as well as study the membrane integrity and lipid oxidation. The fatty acid composition of the lipid membrane of L. acidophilus La 5 was significantly different upon growth in MRS (containing Tween 80, an oleic acid source), or in MRS with Tween 20 (containing C12:0 and C14:0), linoleic, or linolenic acid supplemented. Bacteria grown in MRS showed the highest storage survival rates. No indications of loss of membrane integrity could be found, and membrane integrity could therefore not be connected with loss of viability. Survival of bacteria grown with linoleic or linolenic acid was more negatively affected by the presence of oxygen, than bacteria grown in MRS or with Tween 20 supplemented. A small, but significant, loss of linolenic acid during storage could be identified, and an increase of volatile secondary oxidation products during storage was found for bacteria grown in MRS, or with linoleic, or linolenic acid supplemented, but not for bacteria grown with Tween 20. Overall, the results indicate that lipid oxidation and loss of membrane integrity are not the only or most important detrimental reactions which can occur during storage. By altering the fatty acid composition, it was also found that properties of oleic acid gave rise to more robust bacteria than more saturated or unsaturated fatty acids did. PMID- 25823711 TI - A high efficient graphitic-C3N4/BiOI/graphene oxide ternary nanocomposite heterostructured photocatalyst with graphene oxide as electron transport buffer material. AB - It is important to reduce the recombination of electrons and holes and enhance charge transfer through fine controlled interfaces for advanced catalyst design. In this work, graphene oxide (GO) was composited with graphitic-C3N4 (g-C3N4) and BiOI forming GO/g-C3N4 and GO/BiOI heterostructural interfaces, respectively. GO, which has a work function between the conducting bands of g-C3N4 and BiOI, is used as a buffer material to enhance electron transfer from g-C3N4 to BiOI through the GO/g-C3N4 and GO/BiOI interfaces. The increased photocurrent and reduced photoluminescence indicate efficient reduction of electron and hole recombination under the successful heterostructure design. Accordingly, the introduction of GO as a charge transfer buffer material has largely enhanced the photocatalytic performance of the composite. Thus, introducing charge transfer buffer materials for photocatalytic performance enhancement has proved to be a new strategy for advanced photocatalyst design. PMID- 25823710 TI - FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. AB - Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21's effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild-type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP-activated protein kinase and the expression of hexokinase II and peroxisome proliferator-activated receptor gamma co-activator 1alpha in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 up-regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM. PMID- 25823712 TI - Segmentation and tracking of stem cells in time lapse microscopy to quantify dynamic behavioral changes during spheroid formation. PMID- 25823713 TI - Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity. AB - BACKGROUND: Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro. OBJECTIVE: To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC. METHODS: Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4 dinitrophenol (DNP). RESULTS: Selective EP2 agonism attenuated aeroallergen caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation. CONCLUSIONS & CLINICAL RELEVANCE: The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis. PMID- 25823714 TI - OnabotulinumtoxinA Injections for the Treatment of Cyclic Vomiting Syndrome. AB - Cyclic vomiting syndrome (CVS) is a disorder characterized by episodes of nausea and vomiting lasting 1 to 5 days, followed by asymptomatic periods. The etiology and pathophysiology of CVS are unknown, but CVS shares similar characteristics to those of migraine headaches. Tricyclic antidepressants have the most evidence and are generally effective for prophylaxis of further episodes in patients with CVS. Second-line pharmacotherapies typically target specific comorbid symptoms or conditions and may include antiepileptic or antimigraine drugs, benzodiazepines, antispasmodics, proton pump inhibitors, antiemetics, and analgesics. OnabotulinumtoxinA (ONABoNT-A) injections have not been studied in the population with CVS but are regarded as a pharmacotherapeutic option for migraine headaches. We describe a 45-year-old woman with a 5-year history of CVS who had failed previous typical prophylactic migraine and CVS pharmacotherapies and was referred to the neurology clinic for management of both of these conditions. On review, the neurologist noted a correlation of the patient's headaches with her CVS symptoms. ONABoNT-A injections were started at 155 units intramuscularly every 12 weeks for her migraine headaches, which also dramatically improved her CVS. The main adverse effect reported by the patient was numbness and weakness in her left shoulder after the injections, which are symptoms consistent with ONABoNT-A injection use; however, these symptoms typically resolved a few days later. Regarded as a pharmacotherapeutic option for migraine headache prophylaxis, ONABoNT-A injections have demonstrated modest efficacy in preventing migraine headaches. Clinicians should be aware that ONABoNT-A injections may also have a role in the prophylaxis of CVS. PMID- 25823715 TI - Biomimetic Method To Assemble Nanostructured Ag@ZnO on Cotton Fabrics: Application as Self-Cleaning Flexible Materials with Visible-Light Photocatalysis and Antibacterial Activities. AB - A bioinspired mineralization route to prepare self-cleaning cotton fabrics by functionalizing their surface with nanostructured Ag@ZnO is demonstrated herein. In a polyamine-mediated mineralization process, while the nucleation, organization and coating of ZnO is done directly from water-soluble zinc salts under mild conditions, the entrapped polyamine in the ZnO matrix acts as reducing agent to generate Ag(0) from Ag(I) at room temperature. The Ag@ZnO coated cotton fabrics are characterized by FESEM, HRTEM, XRD, and UV-vis-DRS to confirm the formation and coating of Ag@ZnO particles on individual threads of the fabric. The presence of Ag nanoparticles not only enables the ZnO-coated fabrics exhibiting improved photocatalytic property but also allows for visible-light driven activities. Furthermore, it exhibits efficient antimicrobial activity against both Gram-positive and Gram-negative bacteria. Therefore, besides these multifunctional properties, the polyamine-mediated bioinspired approach is expected to pave way for functionalization of flexible substrates under mild conditions as desirable for the development and fabrication of smart, lightweight, and wearable devices for various niche applications. PMID- 25823716 TI - Synthesis of an Amphiphilic Brush Copolymer by a Highly Efficient "Grafting onto" Approach via CO2 Chemistry. AB - A novel and robust route for the synthesis of a new amphiphilic brush copolymer, poly(glycidyl methacrylate)-graft-polyethylene glycol (PGMA-g-PEG), with high grafting densities of 97%-98% through a "grafting onto" method via carbon dioxide chemistry is reported. PGMA-g-PEG can self-assemble and form stable spherical core-shell micelles in aqueous solution. Besides, the obtained PGMA-g-PEG polymer contains hydroxyurethane structures as the junction sites between the PGMA backbone and PEG side chain, which can be used for further modification. PMID- 25823717 TI - Perovskite solar cells prepared by flash evaporation. AB - A simple vacuum deposition method for the preparation of high quality hybrid organic-inorganic methylammonium lead iodide perovskite thin films is reported. When sandwiched in between organic charge transporting layers, such films lead to solar cells with a power conversion efficiency of 12.2%. PMID- 25823718 TI - A tribute to Dr. Raymond Read. PMID- 25823719 TI - Dysmenorrhea Management and Coping among Students in Ghana: A Qualitative Exploration. AB - STUDY OBJECTIVE: The study sought to gain an in-depth understanding of primary dysmenorrhea management and coping strategies for dysmenorrhea among adolescents and young adults who were in school. DESIGN: The study adopted a qualitative exploratory approach using a descriptive phenomenology to explore the phenomenon of interest. SETTING: The study was conducted in two educational institutions in Accra, Ghana: a Senior High School (SHS) and a University. PARTICIPANTS AND DATA COLLECTION: Sixteen participants were purposively recruited (8 SHS and 8 University students) through snowball sampling. Individual interviews were conducted in English, audio-taped, transcribed and analysed using content analysis procedures. Informed consent was obtained from all participants and rigor was ensured through prolonged engagement and member checking. RESULTS: Participants employed both pharmacologic (orthodox and herbal) and nonpharmacologic approaches such as warm compress, exercise, and water and diet therapy for their dysmenorrhea. Students' dysmenorrhea was managed at the school clinic and the hospital. Health professionals demonstrated negative attitudes towards dysmenorrhea management. Students coped with dysmenorrhea by planning activities before the onset of pain, receiving social and spiritual support, and developing a mind-set to bear pain. CONCLUSIONS: Individualized approaches should be employed to enhance dysmenorrhea management. Health professionals should be educated on dysmenorrhea to improve their attitude and skills for dysmenorrhea management. PMID- 25823720 TI - Successful Pregnancy After Sacrectomy Combined With Chemotherapy and Radiation for Ewing Sarcoma: Case Report and Literature Review. AB - BACKGROUND: Ewing sarcoma is considered to have a poor prognosis. Recent advances in multidisciplinary management have resulted in a marked improvement in long term survival. CASE: We describe a case of successful pregnancy in a patient who underwent sacrectomy combined with multi-agent chemotherapy and radiotherapy for Ewing sarcoma. The patient was diagnosed with Ewing sarcoma of the sacrum at the age of 16. The ovaries were transposed, the uterus was shielded, and a gonadotropin-releasing hormone agonist was used during treatment to protect ovarian function. The patient spontaneously conceived at the age of 27. After an uneventful pregnancy, the patient delivered a healthy neonate at term by cesarean section. SUMMARY AND CONCLUSIONS: Successful pregnancy and delivery can be achieved after multi-modality treatment with pretreatment intervention for fertility preservation. PMID- 25823721 TI - Massive Hydronephrosis from Ureteropelvic Junction Obstruction Masquerading as a Paratubal Cyst in an 11-Year-Old Girl. AB - BACKGROUND: The differential diagnosis of a cystic pelvic mass in an adolescent girl is broad, and includes gastrointestinal, urologic, and gynecologic conditions. CASE: A premenarchal 11-year-old girl presented with abdominal pain. On transabdominal ultrasonography, abutting the lateral side of the left ovary was a large mass with an appearance compatible with a large paratubal cyst measuring 16.7 * 11.9 cm. On exploratory laparotomy, the patient's uterus, tubes and ovaries were normal and a massively dilated and displaced left kidney due to an ureteropelvic junction obstruction was ultimately diagnosed. SUMMARY AND CONCLUSION: A cystic pelvic mass in an adolescent girl may not always be of ovarian or mullerian origin. Urinary tract obstruction is often silent; an incidental finding of hydronephrosis on ultrasonography may be the first clue of the possibility of ureteropelvic junction obstruction as the underlying diagnosis. It is always best to know which organ system is involved prior to surgery, so that the correct surgical team is present and the correct surgical approach is utilized. PMID- 25823722 TI - CCR5 gene polymorphism affects the risk of GvHD after haematopoietic stem cell transplantation from an unrelated donor. PMID- 25823723 TI - The effect of the physical properties of the substrate on the kinetics of cell adhesion and crawling studied by an axisymmetric diffusion-energy balance coupled model. AB - In this paper an analytical approach to study the effect of the substrate physical properties on the kinetics of adhesion and motility behavior of cells is presented. Cell adhesion is mediated by the binding of cell wall receptors and substrate's complementary ligands, and tight adhesion is accomplished by the recruitment of the cell wall binders to the adhesion zone. The binders' movement is modeled as their axisymmetric diffusion in the fluid-like cell membrane. In order to preserve the thermodynamic consistency, the energy balance for the cell substrate interaction is imposed on the diffusion equation. Solving the axisymmetric diffusion-energy balance coupled equations, it turns out that the physical properties of the substrate (substrate's ligand spacing and stiffness) have considerable effects on the cell adhesion and motility kinetics. For a rigid substrate with uniform distribution of immobile ligands, the maximum ligand spacing which does not interrupt adhesion growth is found to be about 57 nm. It is also found that as a consequence of the reduction in the energy dissipation in the isolated adhesion system, cell adhesion is facilitated by increasing substrate's stiffness. Moreover, the directional movement of cells on a substrate with gradients in mechanical compliance is explored with an extension of the adhesion formulation. It is shown that cells tend to move from soft to stiff regions of the substrate, but their movement is decelerated as the stiffness of the substrate increases. These findings based on the proposed theoretical model are in excellent agreement with the previous experimental observations. PMID- 25823724 TI - Doped In2O3 inverse opals as photoanode for dye sensitized solar cells. AB - One promising way to improve the power conversion efficiency (PCE) of dye sensitized solar cells (DSSCs), which have attracted great interest due to their low cost, is modifying the working electrode. In this work, Tm and Yb doped as well as undoped In2O3 inverse opals (IOs) were synthesized by the sol-gel method. DSSCs based on In2O3, In2O3:Tm and In2O3:Yb IOs as photoanodes were fabricated and studied. It is observed that the device performance including open-circuit voltage (V(oc)) and short-circuit current (J(sc)) increased largely with the increasing pore size of the IOs and the introduction of Tm and Yb elements in the In2O3 lattices. The PCE of the DSSC was increased from 0.33% to 0.96% when the ln2O3 IOs photoanode was substituted by ln2O3:Yb IOs. The electrochemical impedance spectroscopy (EIS) measurements indicate that the modification of band gap in the Tm and Yb doped In2O3 IOs is significant for the improved performance, which can effectively suppress the charge transfer recombination and improve the electron lifetime. PMID- 25823725 TI - Highly effective Fe-doped TiO2 nanoparticles photocatalysts for visible-light driven photocatalytic degradation of toxic organic compounds. AB - This paper reports the synthesis of various molar concentrations of iron (Fe) doped TiO2 nanoparticles and their efficient use as potential photocatalysts for photocatalytic degradation of toxic and harmful chemical, paranitrophenol. The nanoparticles were synthesized by a novel and facile ultrasonic assisted hydrothermal method and characterized in detail by various analytical techniques in terms of their morphological, structural, compositional, thermal, optical, pore size distribution, etc properties. The photocatalytic activities of the as prepared Fe-doped TiO2 nanoparticles were examined under visible light illumination using para-nitrophenol as target pollutant. By detailed experimental findings revealed that the Fe dopant content crucially determines the catalytic activity of TiO2 nanoparticles. The maximum degradation rate of para-nitrophenol observed was 92% in 5 h when the Fe(3+) molar concentration was 0.05 mol%, without addition of any oxidizing reagents. The prepared nanoparticles demonstrated excellent photocatalytic response because of their small size, excellent crystalline structure, increase in threshold wavelength response and maximum separation of photogenerated charge carriers. Further, the determination of reaction intermediates has also been carried out and plausible mechanism of photocatalytic degradation of para-nitrophenol has been proposed. PMID- 25823726 TI - Cooperative adsorption on solid surfaces. AB - Adsorptions are commonly of monolayer coverage of adsorbate molecules on adsorbent sites, in particular for chemisorptions, where Langmuir adsorption isotherm equation and kinetics are adequate. The Langmuir adsorption is termed ideal adsorption as the surface active centers are uniformly distributed, the molecules are of point-sizes and the interactions between adsorbate molecules and the adsorbent are uniform. However, there are more cases where Langmuir adsorption isotherm and/or kinetics are inadequate in describing the adsorption behavior. Apparent multilayer adsorption has been shown to be descriptive of both physisorptions and chemisorptions as a means of idealization to nonideal adsorptions. The deviation of adsorption isotherm and/or kinetics from (ideal) Langmuir adsorption is due to cooperative adsorption, or interactions between adsorbates or between adsorbate and adsorbent caused deviation from "uniform" interactions. The multi-layer or apparent multilayer behavior of adsorption is an excellent model to describe cooperative adsorption. Adsorption kinetics and isotherms have been derived for adsorptions without differentiating the different types of adsorptions. The simplistic approach can explain majority of the adsorption isotherms and kinetic behaviors. PMID- 25823727 TI - Water defluoridation using a nanostructured diatom-ZrO2 composite synthesized from algal biomass. AB - Frustules or the rigid amorphous silica cell wall of unicellular, photosynthetic microalgae with unique porous architecture has been used to synthesize a composite by immobilizing ZrO2 on its surface and in the pores. This was effective in water defluoridation. The average diameter of the composite was 80+/ 2 nm and surface area was 140 m(2)/g. The adsorption isotherms followed both Langmuir and Freundlich models, and the composite was regenerable. Adsorption kinetics followed second order model and the adsorption capacity was as high as 11.32 mg/g, while the Langmuir maximum adsorption capacity (q(m)) reached 15.53 mg/g. The research findings highlight the potential of diatoms as hosts for nanomaterials for use in water treatment. PMID- 25823728 TI - Heterostructures of Ag3PO4/TiO2 mesoporous spheres with highly efficient visible light photocatalytic activity. AB - Heterostructured Ag3PO4/m-TiO2 (mesoporous sphere) visible-light photocatalyst has been synthesized via a facile method. The resultant composite consists of numerous Ag3PO4 nanoparticles with diameter less than 10nm, and these nanoparticles deposit onto the TiO2 nanoparticles surface forming a heterostructure. N2 adsorption-desorption measurements have suggested that the composite was porous with relative high surface area. Studies of the photocatalytic activity and stability of heterostructured Ag3PO4/m-TiO2 for the degradation of methylene blue (MB) have indicated that its visible light photocatalytic performance was improved compared with pure Ag3PO4 and Ag3PO4/m TiO2, and exhibited excellent photocatalytic stability. The performance was improved attributing to three aspects: (1) the large specific surface area enhanced the adsorption of MB; (2) numerous pores enlarged the contact area between photocatalyst and MB; (3) the most importantly, depositing Ag3PO4 onto the surface of TiO2 facilitated the separation of electron and hole pairs, which also elevates the photocatalytic performance. Furthermore, the photocatalytic mechanism also has been discussed. Compare with Ag3PO4, the Ag weight percent of Ag3PO4/m-TiO2 decreases from 77% to 20.8%, significantly reducing the cost of photocatalyst. PMID- 25823729 TI - Preparation of new ion-selective cross-linked poly(vinylimidazole-co-ethylene glycol dimethacrylate) using a double-imprinting process for the preconcentration of Pb2+ ions. AB - A new ion-selective cross-linked poly(vinylimidazole-co-ethylene glycol dimethacrylate) prepared via a double-imprinting process was developed for the recognition and preconcentration of Pb(2+) from water samples. The sorbent was characterized by FT-IR, SEM, TGA and textural data. The maximum dynamic sorption capacity of Pb(2+) was 42.04 mg Pb(2+) g(-1) of the double-imprinted polymer. The sorption kinetics data were described by a pseudo-second-order model. The double imprinted polymer exhibited a higher sorption efficiency of Pb(2+) than the blank polymer (non-imprinted polymer). The preconcentration procedure involved the loading of a Pb(2+) solution at pH 7.25 through 40.0 mg of the double-imprinted polymer packed in a mini-column at 5.0 mL min(-1). The selective efficiency of proposed method for the Pb(2+) preconcentration was assured by competitive sorption using different proportions of Pb(2+)/cations and Pb(2+)/anions. An analytical curve was obtained in the range 0.0-300.0 MUg L(-1) (r=0.999) and a limit of detection of 2.46 MUg L(-1) was obtained. The preconcentration factor was found to be 21, the consumptive index 0.95 mL and the concentration efficiency 5.25 min(-1). The preconcentration method was successfully applied to the Pb(2+) ions determination in different kinds of water samples with high recovery values (91.3-108.9%). PMID- 25823730 TI - Study on the condensed state physics of poly(epsilon-caprolactone) nano aggregates in aqueous dispersions. AB - Narrowly size distributed spherical, ellipsoid-like and lamellae stacked poly(epsilon-caprolactone) (PCL) nano-aggregates in aqueous dispersions with a diameter ranging from about (~) 50 to 330 nm were prepared via nanoprecipitation method in the present study. Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM) were used to characterize the morphology and size of the PCL nano-aggregates. We investigated the melt behaviors of the original (without any thermal treatment after preparation) PCL nano-aggregates in aqueous dispersions by nano differential scanning calorimetry (nano-DSC). In particular, the condensed state of the original ~50 nm PCL nanospheres was demonstrated to be amorphous as a result of exhibiting no melting peak in the first nano-DSC heating scan. Furthermore, the rubbery<->flow condensed state transition of the amorphous PCL nanospheres was explored by fluorescence measurements. Moreover, the confined crystallization of the ~50 nm PCL nanospheres from rubbery state in aqueous dispersions was investigated via isothermal crystallization process. Enormous supercooling was observed during crystallization due to nanoconfinement effect. In addition, when the diameter of the original PCL aggregates was increased to more than 150 nm, PCL is in semi-crystalline state and the crystallinity increases with the diameter. PMID- 25823731 TI - Does surveillance imaging after treatment for diffuse large B-cell lymphoma really work? PMID- 25823732 TI - Reply to B. O'Sullivan et Al. PMID- 25823733 TI - The night before the first day of school. PMID- 25823734 TI - You have nothing to lose. PMID- 25823735 TI - Cost-effectiveness analysis of routine surveillance imaging of patients with diffuse large B-cell lymphoma in first remission. AB - PURPOSE: Surveillance imaging of asymptomatic patients with diffuse large B-cell lymphoma (DLBCL) in first remission remains controversial. A decision-analytic Markov model was developed to evaluate the cost-effectiveness of follow-up strategies following first-line immunochemotherapy. PATIENTS AND METHODS: Three strategies were compared in 55-year-old patient cohorts: routine clinical follow up without serial imaging, routine follow-up with biannual computed tomography (CT) scans for 2 years, or routine follow-up with biannual [(18)F] fluorodeoxyglucose positron emission tomography-computed tomography (PET/CT) for 2 years. The baseline model favored imaging-based strategies by associating asymptomatic imaging-detected relapses with improved clinical outcomes. Lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each surveillance strategy. RESULTS: Surveillance strategies utilizing 2 years of routine CT or PET/CT scans were associated with minimal survival benefit when compared with clinical follow-up without routine imaging (life-years gained: CT, 0.03 years; PET/CT, 0.04 years). The benefit of imaging-based follow-up remained small after quality-of-life adjustments (CT, 0.020 QALYs; PET/CT, 0.025 QALYs). Costs associated with imaging based surveillance strategies are considerable; ICERs for imaging strategies compared with clinical follow-up were $164,960/QALY (95% CI, $116,510 to $766,930/QALY) and $168,750/QALY (95% CI, $117,440 to 853,550/QALY) for CT and PET/CT, respectively. Model conclusions were robust and remained stable on one way and probabilistic sensitivity analyses. CONCLUSION: Our cost-effectiveness analysis suggests surveillance imaging of asymptomatic DLBCL patients in remission offers little clinical benefit at substantial economic costs. PMID- 25823736 TI - Reply to B. O'Sullivan et Al. PMID- 25823737 TI - Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. AB - PURPOSE: Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer. PATIENTS AND METHODS: Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin. RESULTS: Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238). CONCLUSION: Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted. PMID- 25823739 TI - First Site of Failure Analysis Incompletely Addresses Issues of Late and Unexpected Metastases in p16-Positive Oropharyngeal Cancer. PMID- 25823738 TI - Low Serum Vitamin D Levels Are Associated With Inferior Survival in Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies. AB - PURPOSE: Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome. PATIENTS AND METHODS: SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS). RESULTS: After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort). CONCLUSION: Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting. PMID- 25823740 TI - Organic nanoparticles of malachite green with enhanced far-red emission: size dependence of particle rigidity. AB - In tracing the biological processes using fluorescent probes, it is desirable to shift the excitation/emission energy to a far-red/near-infrared (FR/NIR) region. In this study, we successfully synthesize FR fluorescent organic nanoparticles via ion-association between the malachite green (MG) cations and tetrakis(4 fluorophenyl)borate (TFPB) anions in the presence of a neutral stabilizing polymer. Binding of MG with TFPB results in the prominent appearance of an absorption band that can be assigned to an H-aggregate of MG. The fluorescence intensity as well as the fluorescence lifetime shows a significant increase with a decrease in the nanoparticle size. Since the MG dye is known as a local viscosity or environmental rigidity probe showing a rotational friction dependence of the excited state lifetime, we find that the rigidity of the organic nanoparticle is strongly size-dependent; that is, the smaller the size of the nanoparticle, the greater the rigidity of the nanoparticle. We also reveal that surface regions of the ion-based organic nanoparticles are more rigid than inner regions. The presence of H-aggregates that are almost non-fluorescent is the major origin of aggregation-caused quenching (ACQ) and still avoids the enhancement of the fluorescence quantum yield of the MG nanoparticles, so we develop a new approach to prevent H-aggregation inside the nanoparticle by incorporating photochemically inert, bulky phosphonium cations, which results in a 430-fold enhancement of its fluorescence yield. We believe that such a methodology will open up an avenue in the development of new types of fluorescent nanomaterials for many applications. PMID- 25823741 TI - Processing of Dynamic Affective Information in Adults With ADHD. AB - OBJECTIVE: ADHD has been repeatedly linked to problems in social functioning. Although some theories assume that the emotion recognition deficits are explained by general attentional deficits, mounting evidence suggests that they may actually constitute a distinct impairment. However, it remains unclear whether the deficient processing affects specific emotional categories or may generalize to all basic emotions. The present study aims to investigate these questions by assessing the sensitivity to all six basic emotions in adults with ADHD. METHOD: The participants judged the emotion onset in animated morph clips displaying facial expressions that slowly changed from neutral to emotional. RESULTS: ADHD participants exhibited an impaired recognition of sad and fearful facial expressions. CONCLUSION: The present findings indicate that ADHD is possibly associated with a specific deficit in the recognition of facial emotions signaling negative social feedback. PMID- 25823742 TI - Is the Theta/Beta EEG Marker for ADHD Inherently Flawed? AB - OBJECTIVE: Despite advances in our understanding of ADHD as a neurodevelopmental disorder, robust biomarkers are yet to be established in clinical practice. More than 40 years of electroencephalography (EEG)-based research has culminated in the recent Food and Drug Administration (FDA) approval of the theta/beta (EEG power) ratio (TBR) as a diagnostic marker of ADHD. METHOD: This review article focuses on resting-state EEG power research in ADHD. RESULTS: Inconsistent findings in the literature and suggestions of reduced specificity threaten the utility of TBR as a biomarker of ADHD. The use of fixed EEG bands may be a significant limitation, particularly in youth, and alternative approaches are needed. CONCLUSION: We propose that a personalized theta-to-alpha cut point or "transition frequency" is a better frame of reference for the measurement of TBR. Such an approach is better placed to test maturational lag and cortical hypoarousal models of ADHD and may in turn have greater utility in supporting diagnosis. PMID- 25823743 TI - Attention, Executive Function, Behavior, and Electrocortical Function, Significantly Improved With 19-Channel Z-Score Neurofeedback in a Clinical Setting: A Pilot Study. AB - OBJECTIVE: Neurofeedback (NF) is gaining recognition as an evidence-based intervention grounded in learning theory, and 19-channel z-score NF (19ZNF) is a new NF model. This pilot study sought to evaluate the efficacy of 19ZNF in a clinical setting. METHOD: Outcome measures framed groups such that 19ZNF was evaluated, as it relates to the neuropsychological constructs of attention (n = 10), executive function (n = 12), behavior (n = 14), and electrocortical functioning (n = 21). One-tailed t tests compared pre-post difference scores. RESULTS: For all pre-post comparisons, the direction of change was in the predicted direction, and differences were statistically significant (p = .000 to p = .008, effect sizes 1.29 to 3.42). CONCLUSION: Results suggest 19ZNF improved attention, executive function, behavior, and electrocortical function. This study provides beginning evidence of 19ZNF's efficacy, adds to what is known about 19ZNF, and offers an innovative approach for using quantitative electroencephalographic (QEEG) metrics as outcome measures. PMID- 25823744 TI - Do High and Low Extremes of ADHD and ASD Trait Continua Represent Maladaptive Behavioral and Cognitive Outcomes? A Population-Based Study. AB - OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) are thought to reflect the high, symptomatic extreme of quantitative trait continua. However, extreme deviations in either direction on disorder continua, high and low, may both represent maladaptive behavioral and cognitive outcomes. We aimed to test this hypothesis. METHOD: In a population sample of 378 children, ADHD and ASD traits were rated by parents on questionnaires that provide resolution at high and low extremes of the ADHD and ASD trait continua. ADHD and ASD traits were related to parent-ratings of internalizing and externalizing behavior problems and tests of cognitive functioning using polynomial regression. RESULTS: The low ends of the ADHD and ASD trait continua were related to fewer behavior problems and better cognitive functioning than symptomatic ends. CONCLUSION: Studying the correlates of the low continuum ends may deepen our understanding of the mechanisms underlying adaptive behavioral and cognitive outcomes. PMID- 25823745 TI - Experimental evidence for the effect of habitat loss on the dynamics of migratory networks. AB - Migratory animals present a unique challenge for understanding the consequences of habitat loss on population dynamics because individuals are typically distributed over a series of interconnected breeding and non-breeding sites (termed migratory network). Using replicated breeding and non-breeding populations of Drosophila melanogaster and a mathematical model, we investigated three hypotheses to explain how habitat loss influenced the dynamics of populations in networks with different degrees of connectivity between breeding and non-breeding seasons. We found that habitat loss increased the degree of connectivity in the network and influenced population size at sites that were not directly connected to the site where habitat loss occurred. However, connected networks only buffered global population declines at high levels of habitat loss. Our results demonstrate why knowledge of the patterns of connectivity across a species range is critical for predicting the effects of environmental change and provide empirical evidence for why connected migratory networks are commonly found in nature. PMID- 25823746 TI - Integration of mobile technology in educational materials improves participation: creation of a novel smartphone application for resident education. AB - OBJECTIVE: Traditional education consists of didactics and book learning. Recently, technology has been integrated into graduate medical education, primarily in the form of simulation. The primary aim of this study was to investigate if a novel smartphone application using technology to engage learners would improve participation in an educational activity when compared with a daily e-mail format and how this use translated to performance on standardized testing. DESIGN: The UF Surgery App (App), which is a smartphone application, was developed to deliver 2 questions from a general surgery educational database every weekday from October to February 2013. The App, developed for iOS, featured a notification alarm and a reminder icon to actively engage the learner. Learners who used the App responded to multiple-choice questions and were provided instantaneous feedback in the form of a correct answer with an explanation. The response rate and answers were collected prospectively and compared with the American Board of Surgery In-Training Examination score. SETTING: University of Florida, College of Medicine, Gainesville, Florida, a university teaching hospital. PARTICIPANTS: A total of 46 general surgical residents were enrolled in a university training program. Participation was voluntary. RESULTS: Overall, 26 of 46 (57%) residents participated. Of the users, 70% answered more than 20% of the questions, while 46% responded to more than 70% of questions. The percentage of correct answers on the App was positively correlated with standardized score (p = 0.005), percentage correct (p = 0.02), and percentile (p = 0.034) on the ABSITE examination. CONCLUSIONS: Technology can be used to actively engage residents. Deployment of this novel App improved participation over a daily question-answer e-mail format, and answers correlated with standardized test performance. The effect of the App on overall education is unclear, and a multi institutional study has been initiated. PMID- 25823747 TI - A cadaveric training system for the maintenance of basic microsurgical hand skill: submersible pump perfusion system. PMID- 25823748 TI - Certainty and uncertainty about end of life care nursing practices in New Zealand Intensive Care Units: a mixed methods study. AB - BACKGROUND: With end-of-life (EOL) central to the nursing role in intensive care, few studies have been undertaken to explore EOL care in the context of New Zealand (NZ) intensive care nursing. OBJECTIVE: To investigate NZ intensive care nurses' experiences of, and attitudes towards EOL care. DESIGN: Sequential mixed methods study using cross sectional survey with follow-on focus groups. METHODS: NZ intensive care nurses (N=465) across four large tertiary intensive care units (ICUs) were contacted to complete a 43-item web-based survey. A follow-on focus group was conducted in each of the sites to explore specific aspects of the survey findings. RESULTS: 203 fully completed surveys were returned (response rate 44%) from the four ICUs. Over half of nurses surveyed (55%, n=111) disagreed that withholding and withdrawing life support treatment were ethically the same. 78% (n=159) of nurses stated that withholding treatment was ethically more acceptable than withdrawing it. Whilst nurses generally supported reducing inspired oxygen to air for ventilated patients at EOL (71%, n=139) this was also an area that demonstrated one of the highest levels of uncertainty (21%, n=41). Just under a quarter of respondents were also uncertain about the use of continued nutritional support, continued passive limb exercises and use of deep sedation during EOL. The 18 nurses who participated in follow-on focus groups detailed the supportive, culturally sensitive, collaborative environment that EOL was conducted in. However diverse opinions and understandings were held on the use of passive limb and use of fluids at EOL. CONCLUSIONS: Whilst results from this NZ study broadly align with European studies, uncertainty about specific areas of EOL practices highlight that further guidance for nurses is required. PMID- 25823750 TI - The effect of essential medicines programme on rational use of medicines in China. AB - OBJECTIVE: Irrational use of medicines is a serious problem in China and has been the primary target of China's national essential medicines programme (NEMP). The aim of this study was to evaluate the effect of the NEMP on rational use of medicines in China. METHODS: A nationwide sample of 3 76 700 prescriptions written by primary care providers from 2007 to 2011 was obtained following a multistage sampling process. Six prescribing indicators were measured: average number of drugs prescribed per prescription, average expenditure per prescription, percentage of prescriptions with antibiotics, with injections, with two or more antibiotics and with corticosteroids. The pre-post with control study design and the difference-in-difference (DID) methodology were employed to evaluate the effect of NEMP. RESULTS: Prescriptions from primary care institutions with the NEMP implementation were better than those without NEMP implementation. Adjusting for the institution's sizes, ownership, economic geographic regions and the year of NEMP implementation, the DID estimator was statistically significant in all prescribing indicators except for the percentage of prescriptions with injection. The number of drugs per prescription decreased by 0.2 per prescription [95% confidence interval (CI): -0.3, -0.1] after the NEMP was implemented; the percentages of prescriptions with antibiotics, with corticosteroids and with two or more antibiotics decreased by 7% (95% CI: -10, 4), 1% (95% CI: -2, 0) and 2% (95% CI: -3, 0), respectively; and the average expenditure per prescription decreased by eight Renminbi Yuan (95% CI: -14, -2). The effect of NEMP on reducing irrational prescribing was greater in public institutions than in private institutions (P < 0.05). CONCLUSIONS: China's NEMP is effective in promoting rational use of medicines, and the effect is greater in public institutions than in private institutions. However, the irrational use is still high, pointing to the need for further reforms to tackle the underlying causes, such as clinical guidelines and patient education. PMID- 25823751 TI - Evolution of health coverage in Mexico: evidence of progress and challenges in the Mexican health system. AB - To consolidate an effective and efficient universal health care coverage requires a deep understanding of the challenges faced by the health care system in providing services demanded by population in need. This study analyses the dynamics of health insurance coverage and effective access coverage to some health interventions in Mexico. It examines the evolution of inequalities and heterogeneous performance of the insurance subsystems incorporated under the Mexican health care system. Two types of coverage indicators were selected: health insurance and effective access to preventive health interventions intended for normative population. Data were drawn from National Health and Nutrition Surveys 2006 and 2012. The economic inequality was estimated using the Standardized Concentration Index by household per capita consumption expenditure as socioeconomic-status indicator. Approximately 75% of the population reported being covered by one of the existing insurance schemes, representing a huge step forward from 2006, when as much as 51.62% of the population had no health insurance. About 87% of this growth was attributable to the expansion of Non Contributory Health Insurance whereas 7% emanated from the Social Security subsystem. The results revealed that inequality in access to health insurance was virtually eradicated; however, traces of unequal access persisted in some subpopulations groups. Coverage indicators of effective access showed a slight improvement in the period analysed, but prenatal care and interventions to prevent chronic disease still presented a serious shortage. Furthermore, there was no evidence that inequities in coverage of these interventions have decreased in recent years. The results provided a mixed picture, generalizable to the system as a whole, expansion of insurance status represents one of the most remarkable advances that have not been accompanied by a significant improvement in effective access. In addition, existing inequalities are part of the most important challenges to be faced by the Mexican health system. PMID- 25823752 TI - French Nationwide Cohort Temporary Utilization Authorization Survey of GranuPAS((r)) in MDR-TB patients. AB - BACKGROUND: Para-aminosalicylic acid (PAS) is again needed for the treatment of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB). The study of a new granulated formulation (PAS-GR, 'GranuPAS((r))'), which might have fewer adverse events, was made possible by the statutory requirement that data be collected regarding its use in France in multidrug-resistant TB (MDR-TB) patients under a 'therapeutic utilization' follow-up for safety and efficacy system called 'Autorisation Temporaire d'Utilisation' (ATU). METHODS: In May 2011 an ATU cohort was established to monitor the named patient use of PAS-GR. All patients were included in a follow-up protocol developed by Lucane Pharma and the French Medicines Agency (ANSM) which recorded demographics, dosing characteristics, concomitant medications, adverse events, and outcome. Following EU marketing authorization, the ATU terminated about 3 years after initiation. RESULTS: PAS-GR was used for the treatment of 231 MDR-TB patients. PAS-GR was used at 12 g/day in 114 cases and 8 g/day in 80 cases. PAS-GR-containing combinations resulted in sputum conversion in a median of 94 days (IQR 48-143) in the 55 patients with information after treatment initiation. Adverse effects of PAS-GR-containing combinations were mostly gastrointestinal (GI; 9% of patients experiencing a GI event at any time) and led to interrupt PAS-GR in 6% of cases (2.1% GI). CONCLUSIONS: The efficacy of PAS-GR appears equivalent to that of PAS, and its tolerance improved over earlier PAS formulations, thus supporting the use of PAS GR as part of drug combinations for the treatment of MDR and XDR-TB. PMID- 25823749 TI - Light-evoked S-nitrosylation in the retina. AB - Nitric oxide (NO) synthesis in the retina is triggered by light stimulation. NO has been shown to modulate visual signal processing at multiple sites in the vertebrate retina, via activation of the most sensitive target of NO signaling, soluble guanylate cyclase. NO can also alter protein structure and function and exert biological effects directly by binding to free thiol groups of cysteine residues in a chemical reaction called S-nitrosylation. However, in the central nervous system, including the retina, this reaction has not been considered to be significant under physiological conditions. Here we provide immunohistochemical evidence for extensive S-nitrosylation that takes place in the goldfish and mouse retinas under physiologically relevant light intensities, in an intensity dependent manner, with a strikingly similar pattern in both species. Pretreatment with N-ethylmaleimide (NEM), which occludes S-nitrosylation, or with 1-(2 trifluromethylphenyl)imidazole (TRIM), an inhibitor of neuronal NO synthase, eliminated the light-evoked increase in S-nitrosylated protein immunofluorescence (SNI) in the retinas of both species. Similarly, light did not increase SNI, above basal levels, in retinas of transgenic mice lacking neuronal NO synthase. Qualitative analysis of the light-adapted mouse retina with mass spectrometry revealed more than 300 proteins that were S-nitrosylated upon illumination, many of which are known to participate directly in retinal signal processing. Our data strongly suggest that in the retina light-evoked NO production leads to extensive S-nitrosylation and that this process is a significant posttranslational modification affecting a wide range of proteins under physiological conditions. PMID- 25823753 TI - Growth Hormone Treatment Improves Cognitive Function in Short Children with Growth Hormone Deficiency. AB - BACKGROUND/AIMS: We investigated the association between cognition and growth hormone (GH) status and GH treatment in short prepubertal children with broadly ranging GH secretion. METHODS: A total of 99 children (age 3-11 years), 41 with GH deficiency (GHD) and 58 with idiopathic short stature (ISS), were randomized to a fixed dose (43 ug/kg/day) or a prediction model-guided individualized dose (17-100 ug/kg/day) and followed up for 24 months. In a longitudinal and mixed within- and between-subjects study, we examined clinical effect size changes, measured by Cohen's d, in full-scale IQ (FSIQ) and secondary IQ indices. RESULTS: Significant increases giving medium effect size in FSIQ (p = 0.001, Cohen's d = 0.63), performance IQ (p = 0.001, Cohen's d = 0.65) and processing speed (p = 0.005, Cohen's d = 0.71) were found in the GH-deficient group. In contrast, perceptual organization only increased in the ISS group (p = 0.001, Cohen's d = 0.53). Baseline IQ was normally distributed with small but significant differences between the groups: GH-deficient children had lower FSIQ (p = 0.042) and lower performance IQ (p = 0.021). Using multiple regression analysis, 40% of the variance in delta processing speed scores (0-24 months) was explained by GHmax and IGF-ISDS at baseline. CONCLUSION: IQ, specifically fluid intelligence, increased in the GH-deficient children. The pretreatment status of the GH/IGF-I axis was significantly predictive for these changes. (c) 2015 S. Karger AG, Basel. PMID- 25823754 TI - Risk factors of transient and persistent anxiety during pregnancy. AB - PURPOSE: chronic poor mental health over the course of pregnancy contributes to greater adverse maternal and child outcomes. Identifying women with chronic depressive or anxiety symptoms can provide opportunities to reduce distress and improve pregnancy outcomes. The objective of this study was to determine risk factors of chronic antenatal depressive and anxiety symptoms using a longitudinal pregnancy cohort in Alberta, Canada. METHODS: women with singleton pregnancies were included (N=3021). Anxiety and depressive symptoms were measured in the second and third trimesters using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale, respectively. On the basis of the timing and persistence of symptoms, the following three mutually exclusive subgroups for each anxiety and depressive symptoms were created: never symptomatic, symptomatic only in the second trimester, and symptomatic at both time points. Separate logistic regression models were used to derive risk factors for each subgroup. FINDINGS: women with chronic anxiety or depressive symptoms were distinguished from those with transient symptoms or no symptoms by their optimism scores, in which less optimistic pregnant women had a four-fold increased risk for developing chronic depressive or anxiety symptoms compared with more optimistic women (AOR varied from 4.30 to 4.93). Additionally, high perceived stress, low social support, history of mental health issues were common predictors of chronic anxiety and depressive symptoms in pregnancy. Partner tension was the exclusive predictor of anxiety symptoms (AOR varied from 1.94 to 2.31) and poor physical health (AOR 2.54; 95% CI 1.32-4.89), unplanned pregnancy (AOR 3.05; 95% CI 1.61-5.79), and infertility treatments (AOR 4.98; 95% CI 1.85 13.39) were unique predictors of chronic depressive symptoms. CONCLUSIONS: knowledge of the risk factors of chronic poor mental health during pregnancy might inform the development of effective strategies within the limited resources of health-care systems to target populations with greater needs for interventions. PMID- 25823755 TI - Maternity services are not meeting the needs of immigrant women of non-English speaking background: Results of two consecutive Australian population based studies. AB - BACKGROUND: women of non-English speaking background who migrate by choice or seek refuge in developed countries such as Australia have notably poorer perinatal outcomes than local-born women. Using data collected in two consecutive population-based surveys conducted in 2000 and 2008, the objective of this paper is to compare the views and experiences of immigrant women of non-English speaking background (NESB) giving birth in Victoria, Australia with those of women who were born in Australia. METHODS: consecutive population-based surveys of women giving birth in Victoria, Australia conducted in 2000 and 2008. Questionnaires were distributed to women giving birth in a two-week period in 2000 and a four-week period in 2008 by hospitals and home birth practitioners. Surveys were mailed to women at five to six months post partum. FINDINGS: completed surveys were received from 67% of eligible women in 2000 (1616/2412), and 51.2% in 2008 (2900/5667). Compared to Australian-born women, immigrant women of NESB were more likely to report negative experiences of antenatal, intrapartum and postnatal care. In 2008, 47.1% of immigrant women expressed dissatisfaction antenatal care compared with 26.8% of Australian born women (Adj OR 2.17, 95% CI 1.7-2.7). Similarly, 40.5% of immigrant women were dissatisfied with intrapartum care compared with 25.5% of Australian born women (Adj OR 1.81, 95% CI 1.4-2.3), and 53.5% of immigrant women rated their postnatal care negatively compared with 41.0% of Australian born women (Adj OR 1.52, 95% CI 1.2-1.9). There was no evidence of improvement between the two surveys. Immigrant women were more likely than Australian-born women to say that health professionals did not always remember them between visits, make an effort to get to know the issues that were important to them, keep them informed about what was happening during labour or take their wishes into account. CONCLUSION: data from repeated population-based surveys of recent mothers provides one of the few avenues for gauging whether changes to the organisation of maternity services is making a difference to immigrant women's experiences of care. Our findings showing no change over an eight year period - during which there were major efforts to increase access to midwifery led models of care and provide greater continuity of caregiver - suggest that different approaches, more specifically tailored to the needs of immigrant families are needed to enhance women's experiences of care and improve outcomes. PMID- 25823756 TI - A Highly Efficient Gold-Catalyzed Photoredox alpha-C(sp(3))-H Alkynylation of Tertiary Aliphatic Amines with Sunlight. AB - A new alpha-C(sp(3))H alkynylation of unactivated tertiary aliphatic amines with 1-iodoalkynes as radical alkynylating reagents in the presence of [Au2(MU dppm)2](2+) in sunlight provides propargylic amines. Based on mechanistic studies, a C-C coupling of an alpha-aminoalkyl radical and an alkynyl radical is proposed for the C(sp(3))-C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp(3))-H alkynylation reaction shows excellent regioselectivity and good functional-group compatibility. A scale-up to gram quantities is possible with sunlight used as a clean and sustainable energy source. PMID- 25823757 TI - Less invasive ventilation in extremely low birth weight infants from 1997 to 2011: survey versus evidence. AB - Evidence for target values of arterial oxygen saturation (SaO2), CO2, and pH has changed substantially over the last 20 years. A representative survey concerning treatment strategies in extremely low-birth-weight infants (ELBW) was sent to all German neonatal intensive care units (NICUs) treating ELBW infants in 1997. A follow-up survey was conducted in 2011 and sent to all NICUs in Germany, Austria, and Switzerland. During the observation period, NICUs targeting SaO2 of 80, 85, and 90 % have increased, while units aiming for 94 and 96 % decreased (all p < 0.001). Similarly, NICUs aiming for pH 7.25 or lower increased, while 7.35 or higher decreased (both p < 0.001). Furthermore, more units targeted a CO2 of 50 mmHg (7.3 kPa) or higher (p < 0.001), while fewer targeted 40 or 35 mmHg (p < 0.001). Non-invasive ventilation (NIV) was used in 80.2 % of NICUs in 2011. The most frequently used ventilation modes were synchronized intermittent mandatory ventilation (SIMV) (67.5 %) and intermittent positive pressure ventilation (IPPV) (59.7 %) in 1997 and SIMV (77.2 %) and synchronized intermittent positive pressure ventilation (SIPPV) (26.8 %) in 2011. NICUs reporting frequent or always use of IPPV decreased to 11.0 % (p < 0.001). SIMV (77.2 %) and SIPPV (26.8 %) did not change from 1997 to 2011, while high-frequency oscillation (HFO) increased from 9.1 to 19.7 % (p = 0.018). Differences between countries, level of care, and size of the NICU were minimal. CONCLUSIONS: Target values for SaO2 decreased, while CO2 and pH increased significantly during the observation period. Current values largely reflect available evidence at time of the surveys. WHAT IS KNOWN: * Evidence concerning target values of oxygen saturation, CO 2 , and pH in extremely low-birth-weight infants has grown substantially. * It is not known to which extent this knowledge is transferred into clinical practice and if treatment strategies have changed. WHAT IS NEW: * Target values for oxygen saturation in ELBW infants decreased between 1997 and 2011 while target values for CO 2 and pH increased. * Similar treatment strategies existed in different countries, hospitals of different size, or university versus nonuniversity hospitals in 2011. PMID- 25823758 TI - Preventing deformational plagiocephaly through parent guidance: a randomized, controlled trial. AB - Deformational plagiocephaly (DP) occurs frequently in otherwise healthy infants. Many infants with DP undergo physiotherapy or helmet therapy, and ample treatment related research is available. However, the possibility of preventing DP has been left with little attention. We sought to evaluate the effectiveness of intervention in the newborn's environment, positioning, and handling on the prevalence of DP at 3 months and to investigate the causal relationship between DP and cervical imbalance. We carried out a randomized controlled trial, with healthy newborns randomized into two groups at birth. All families received standard positioning instructions to prevent SIDS. Additionally, the intervention group received detailed instructions regarding the infant's environment, positioning, and handling, with the goal of creating a nonrestrictive environment that promotes spontaneous physical movement and symmetrical motor development. Two- and three-dimensional photogrammetry served to assess cranial shape and goniometry to measure cervical motion. At 3 months, the prevalence of DP was lower in the intervention group in both 2D (11 vs 31 %) and 3D analyses (15 vs 33 %), and the asymmetry was milder in the intervention group. Infants with DP at follow-up had also developed more torticollis. CONCLUSION: An early educational intervention reduces the prevalence and severity of DP at 3 months. WHAT IS KNOWN: *Deformational plagiocephaly, often with associated torticollis, is common in healthy infants. *Parental education is frequently recommended for preventing deformational plagiocephaly, although information regarding the effectiveness of preventive strategies is scarce. WHAT IS NEW: *Early parent guidance effectively reduces the prevalence and severity of DP and improves the cervical range of motion at three months. *Educating both parents and professionals about proper infant positioning on a national scale could help minimize public healthcare costs. PMID- 25823759 TI - Chronic conditions and coexisting ADHD-a complicated combination in adolescents. AB - Adolescents with chronic conditions (CCs) take more health risks than peers. However, coexisting ADHD has not sufficiently been considered. The aim of the present study was to investigate the impact of different CCs on protective factors and health-risk behaviors, taking coexisting ADHD into account. A school based study among 6895 15- and 17-year-old students was performed in the county of Sormland, Sweden in 2011 (response rate 80 %). The questionnaire explored background factors, CCs, protective factors, and health-risk behaviors. CCs were reported by 11 %, while 55 % were healthy. Students with CCs more often reported coexisting ADHD than healthy students. In adolescents with neurological conditions, the odds ratio for having ADHD was 7.34 (95 % CI 3.00-17.99) as compared to healthy peers. Few protective factors (<4) and clustered health-risk behaviors (>=4) were more common among students with CCs, especially if ADHD or a combination including ADHD was reported. CONCLUSION: CCs and coexisting ADHD are associated with few protective factors and clustered-health risk behaviors. Adolescents with ADHD-in addition to a chronic condition-should be specially acknowledged by health care professionals in order to prevent health risk behaviors. ADHD should be considered when studying these outcomes in adolescents. WHAT IS KNOWN: * Youth with chronic conditions (CCs)-especially ADHD-are reported to take more health risks than peers. * In earlier studies of youth with CCs, the presence of coexisting ADHD has not been taken into account. WHAT IS NEW: * In this study, we showed that ADHD was more prevalent among adolescents with different types of CCs. * CCs and coexisting ADHD were associated with few protective factors and clustered health-risk behaviors. PMID- 25823760 TI - Role of basolateral amygdala dopamine D2 receptors in impulsive choice in acute cocaine-treated rats. AB - Psychostimulant substances have been found to either increase or inhibit impulsive choice (preference to choose small immediate reward over large delayed reward) in laboratory animals. Although central dopamine transmission has been demonstrated to be involved in impulsivity and drug addiction, little is known regarding dopaminergic neurotransmission in addictive drug-induced alteration of impulse control. In this study, we used a delay discounting model to measure impulsive choice in rats and found that acute cocaine dose-dependently decreased impulsive choice in rats. Intraperitoneal injection (i.p.) of D1 receptor antagonist SCH23390 (0.02 mg/kg) could increase the impulsive choice but had no effect on the inhibition of impulsive choice induced by acute cocaine exposure. D2 receptor antagonist eticlopride (0.06 mg/kg) had no effect on the choice behavior itself, but it reversed acute cocaine-induced impulse inhibition. Moreover, bilateral microinjection of eticlopride (1 MUg/side) into the basolateral amygdala (BLA) but not the nucleus accumbens (NAc) core reversed the inhibitory effect of acute cocaine on impulsive choice. These data suggest important but dissociable roles of dopamine D1 and D2 receptors in impulse control. The preference of delayed rewards depends on D1 receptors, whereas acute cocaine inhibited impulsive choice by activating D2 receptors in the BLA. PMID- 25823762 TI - Ultrasonic vocalizations during intermittent swim stress forecasts resilience in a subsequent juvenile social exploration test of anxiety. AB - Current behavioral paradigms of stress resilience traditionally employ forms of prior manipulation or subsequent testing. Recent work has reported adult rat ultrasonic vocalizations (USVs) emitted during intermittent swim stress (ISS) may serve as a predictor of resilience. ISS-induced USVs predicted resilience on several endpoints of behavioral depression and may be considered a forecast of innate resilience. However, a potential problem for these previous findings is the lack of generalizability to other contexts, because both the stress induction and post-stress testing occur in water. The current study tests the generalizability of USVs as a predictor of stress resilience in a non-water-based post-test, the juvenile social exploration test of anxiety. The results provide further support that USVs emitted during ISS predict resilience to depression- and anxiety-like behaviors. Extensions of this work to examine the neurobiology of innate resilience associated with ISS-induced USVs are discussed with comparisons to extant models of learned resilience. PMID- 25823761 TI - Role of whiskers in sensorimotor development of C57BL/6 mice. AB - The mystacial vibrissae (whiskers) of nocturnal rodents play a major role in their sensorimotor behaviors. Relatively little information exists on the role of whiskers during early development. We characterized the contribution of whiskers to sensorimotor development in postnatal C57BL/6 mice. A comparison between intact and whisker-clipped mice in a battery of behavioral tests from postnatal day (P) 4-17 revealed that both male and female pups develop reflexive motor behavior even when the whiskers are clipped. Daily whisker trimming from P3 onwards results in diminished weight gain by P17, and impairment in whisker sensorimotor coordination behaviors, such as cliff avoidance and littermate huddling from P4 to P17, while facilitation of righting reflex at P4 and grasp response at P12. Since active whisker palpation does not start until 2 weeks of age, passive whisker touch during early neonatal stage must play a role in regulating these behaviors. Around the onset of exploratory behaviors (P12) neonatal whisker-clipped pups also display persistent searching movements when they encounter cage walls as a compensatory mechanism of sensorimotor development. Spontaneous whisker motion (whisking) is distinct from respiratory fluttering of whiskers. It is a symmetrical vibration of whiskers at a rate of approximately ~8 Hz and begins around P10. Oriented, bundled movements of whiskers at higher frequencies of ~12 Hz during scanning object surfaces, i.e., palpation whisking, emerges at P14. The establishment of locomotive body coordination before eyes open accompanies palpation whisking, indicating an important role in the guidance of exploratory motor behaviors. PMID- 25823763 TI - Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin. AB - Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK 016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus dependent paradigm, though this protection occurs independently of recovery of BDNF expression. PMID- 25823764 TI - Effects of age on cognitive control during semantic categorization. AB - We used event-related potentials (ERPs) to study age effects of perceptual (basic level) vs. perceptual-semantic (superordinate-level) categorization on cognitive control using the go/nogo paradigm. Twenty-two younger (11 M; 21 +/- 2.2 years) and 22 older adults (9 M; 63 +/- 5.8 years) completed two visual go/nogo tasks. In the single-car task (SiC) (basic), go/nogo responses were made based on single exemplars of a car (go) and a dog (nogo). In the object animal task (ObA) (superordinate), responses were based on multiple exemplars of objects (go) and animals (nogo). Each task consisted of 200 trials: 160 (80%) 'go' trials that required a response through button pressing and 40 (20%) 'nogo' trials that required inhibition/withholding of a response. ERP data revealed significantly reduced nogo-N2 and nogo-P3 amplitudes in older compared to younger adults, whereas go-N2 and go-P3 amplitudes were comparable in both groups during both categorization tasks. Although the effects of categorization levels on behavioral data and P3 measures were similar in both groups with longer response times, lower accuracy scores, longer P3 latencies, and lower P3 amplitudes in ObA compared to SiC, N2 latency revealed age group differences moderated by the task. Older adults had longer N2 latency for ObA compared to SiC, in contrast, younger adults showed no N2 latency difference between SiC and ObA. Overall, these findings suggest that age differentially affects neural processing related to cognitive control during semantic categorization. Furthermore, in older adults, unlike in younger adults, levels of categorization modulate neural processing related to cognitive control even at the early stages (N2). PMID- 25823765 TI - A double-blind, randomized, sham-controlled trial of the effect of a radiation attenuating drape on radiation exposure to endoscopy staff during ERCP. AB - OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with radiation exposure to the endoscopist and staff that may be significant in high-volume centers. We investigated whether a radiation-attenuating drape over the fluoroscopy image intensifier reduces radiation exposure during ERCP. METHODS: We performed a prospective, randomized, double-blind trial of 100 therapeutic ERCPs at a tertiary-care university center. Procedures were randomly assigned to groups receiving lead-free radiation-attenuating drapes (n=50) or identical sham drapes (n=50). The drapes were suspended around the fluoroscopy image intensifier during ERCP. The primary end point was the effective dose of radiation measured at the endoscopist's eye and neck, and at the assisting nurse's neck. The cumulative annual radiation exposure was also estimated. RESULTS: Fluoroscopy time, absorbed radiation dose, and dose area product were similar in the study groups. Mean effective dose for sham vs. radiation attenuating drape was 0.21+/-0.27 vs. 0.02+/-0.02 mSv at the endoscopist's eye, 0.35+/-0.44 vs. 0.03+/-0.03 mSv at the endoscopist's neck, and 0.27+/-0.34 vs. 0.02+/-0.02 mSv at the nurse's neck (P<0.0001 for all comparisons). The relative risk reduction in radiation was 90%, 91%, and 93% at the three sites. At a high volume center in which an endoscopist performs 500 therapeutic ERCPs per year, the estimated cumulative annual effective dose at the endoscopist's eye level is 126 mSv with conventional protection and 12 mSv with a radiation-attenuating drape, with the recommended limit being 20 mSv. CONCLUSIONS: The addition of a radiation-attenuating drape around the image intensifier during ERCP significantly decreases radiation exposure to endoscopists and staff by ~90%. PMID- 25823766 TI - Rapid, accurate, and on-site detection of C. difficile in stool samples. AB - OBJECTIVES: A rapid test to diagnose Clostridium difficile infection (CDI) on hospital wards could minimize common but critical diagnostic delay. Field asymmetric ion mobility spectrometry (FAIMS) is a portable mass spectrometry instrument that quickly analyses the chemical composition of gaseous mixtures (e.g., above a stool sample). Can FAIMS accurately distinguish C. difficile positive from -negative stool samples? METHODS: We analyzed 213 stool samples with FAIMS, of which 71 were C. difficile positive by microbiological analysis. The samples were divided into training, test, and validation samples. We used the training and test samples (n=135) to identify which sample characteristics discriminate between positive and negative samples, and to build machine learning algorithms interpreting these characteristics. The best performing algorithm was then prospectively validated on new, blinded validation samples (n=78). The predicted probability of CDI (as calculated by the algorithm) was compared with the microbiological test results (direct toxin test and culture). RESULTS: Using a Random Forest classification algorithm, FAIMS had a high discriminatory ability on the training and test samples (C-statistic 0.91 (95% confidence interval (CI): 0.86-0.97)). When applied to the blinded validation samples, the C-statistic was 0.86 (0.75-0.97). For samples analyzed <=7 days of collection (n=76), diagnostic accuracy was even higher (C-statistic: 0.93 (0.85-1.00)). A cutoff value of 0.32 for predicted probability corresponded with a sensitivity of 92.3% (95% CI: 77.4 98.6%) and specificity of 86.0% (78.3-89.3%). For even fresher samples, discriminatory ability further increased. CONCLUSIONS: FAIMS analysis of unprocessed stool samples can differentiate between C. difficile-positive and negative samples with high diagnostic accuracy. PMID- 25823767 TI - Evaluation of the ESPGHAN Celiac Guidelines in a North American Pediatric Population. AB - OBJECTIVES: We retrospectively examined the performance of the tissue transglutaminase (TTG), endomysial antibody (EMA) tests, and the ESPGHAN (European Society of Paediatric Gastroenterology, Hepatology and Nutrition) nonbiopsy criteria in a pediatric population. METHODS: Consecutive celiac serologies and corresponding intestinal biopsy results were obtained on children <18 years old over 3.5 years. Patients were classified into three categories: positive TTG, negative TTG, and IgA deficiency. RESULTS: Of the 17,505 patients with celiac serology performed, 775 had a positive TTG, 574 with a negative TTG were biopsied, and 25 were IgA deficient. Of the patients with a TTG >=10 * upper limit of normal (ULN), positive EMA, and symptoms, 98.2% had biopsies consistent with celiac disease (CD). Four human leukocyte antigen (HLA) DQ2/DQ8-positive patients who met the ESPGHAN nonbiopsy criteria did not have CD. In the group with a TTG 3-10 * ULN, 75.7% EMA-positive patients and only 40% EMA-negative patients had CD (P<0.001). Of those with a TTG 1-3 * ULN, 52.2% EMA-positive patients vs. only 13.3% EMA-negative patients had CD (P<0.01). Of the patients with bulbar and duodenal biopsies, 9.8% had CD confined only in the bulb, especially those with a low titer TTG (P<0.01). CD prevalence in our cohort was 34.6%. Sensitivity, specificity, and positive predictive value of the TTG were 98.7%, 86.4%, and 79.4%, respectively. CONCLUSIONS: The TTG is a very sensitive screen for CD, but positive predictive value improves with a positive EMA titer. To apply the new ESPGHAN guidelines, clinicians must understand the performance of their celiac serology tests. PMID- 25823768 TI - Randomized controlled trial of transoral incisionless fundoplication vs. proton pump inhibitors for treatment of gastroesophageal reflux disease. AB - OBJECTIVES: Transoral incisionless fundoplication (TIF) was developed in an attempt to create a minimally invasive endoscopic procedure that mimics antireflux surgery. The objective of this trial was to evaluate effectiveness of TIF compared with proton pump inhibition in a population consisting of gastroesophageal reflux disease (GERD) patients controlled with proton pump inhibitors (PPIs) who opted for an endoscopic intervention over lifelong drug dependence. METHODS: Patients with chronic GERD were randomized (2:1) for TIF or continuation of PPI therapy. American Society of Anesthesiologists >2, body mass index >35 kg/m(2), hiatal hernia >2 cm, and esophageal motility disorders were exclusion criteria. Primary outcome measure was GERD-related quality of life. Secondary outcome measures were esophageal acid exposure, number of reflux episodes, PPI usage, appearance of the gastroesophageal valve, and healing of reflux esophagitis. Crossover for the PPI group was allowed after 6 months. RESULTS: A total of 60 patients (TIF n=40, PPI n=20, mean body mass index 26 kg/m(2), 37 male) were included. At 6 months, GERD symptoms were more improved in the TIF group compared with the PPI group (P<0.001), with a similar improvement of distal esophageal acid exposure (P=0.228) compared with baseline. The pH normalization for TIF group and PPI group was 50% and 63%, respectively. All patients allocated for PPI treatment opted for crossover. At 12 months, quality of life remained improved after TIF compared with baseline (P<0.05), but no improvement in esophageal acid exposure compared with baseline was found (P=0.171) and normalization of pH was accomplished in only 29% in conjunction with deteriorated valve appearances at endoscopy and resumption of PPIs in 61%. CONCLUSION: Although TIF resulted in an improved GERD-related quality of life and produced a short-term improvement of the antireflux barrier in a selected group of GERD patients, no long-term objective reflux control was achieved. PMID- 25823769 TI - Evaluation of Mucosal Healing in Ulcerative Colitis by Fecal Calprotectin Vs. Fecal Immunochemical Test. AB - OBJECTIVES: We previously showed that a quantitative fecal immunochemical test (FIT) can predict mucosal healing (MH) in ulcerative colitis (UC). Fecal calprotectin (Fcal) has also been reported as an important biomarker of UC activity. The aim of this study was to compare the predictive ability of these two fecal markers for MH in UC. METHODS: FIT and Fcal were examined in stool samples from consecutive UC patients who underwent colonoscopy. Mucosal status was assessed via the Mayo endoscopic subscore (MES). RESULTS: In total, 105 colonoscopies in 92 UC patients were evaluated in conjunction with the FIT and Fcal results. Both FIT and Fcal results were significantly correlated with MES (Spearman's rank correlation coefficient: 0.61 and 0.58, respectively). The sensitivity and specificity of the FIT values (<100 ng/ml) for predicting MH (MES 0 alone) were 0.95 and 0.62, respectively, whereas those of Fcal (<250 MUg/g) were 0.82 and 0.62, respectively. The sensitivities became similar when MH was defined as MES 0 or 1 (0.86 vs. 0.86). Although the predictability of MH evaluated by the area under the receiver operating characteristics curve was similar for the two fecal markers (FIT 0.83 vs. Fcal 0.82 for MES 0 alone), the FIT results were relatively robust regardless of the cutoff value selected. CONCLUSIONS: Both FIT and Fcal can efficiently predict MH in UC, but FIT appears to be more sensitive than Fcal for predicting MES 0 alone. PMID- 25823770 TI - Chromoendoscopy for Surveillance in Inflammatory Bowel Disease Does Not Increase Neoplasia Detection Compared With Conventional Colonoscopy With Random Biopsies: Results From a Large Retrospective Study. AB - OBJECTIVES: Randomized trials demonstrated that chromoendoscopy is superior to white light endoscopy with random biopsy sampling (WLE) for the detection of dysplasia in patients with inflammatory bowel disease (IBD). Whether implementing chromoendoscopy can increase the detection of dysplasia in clinical practice is unknown. METHODS: Patients with ulcerative colitis (UC) and Crohn's disease (CD) undergoing colonoscopic surveillance between January 2000 and November 2013 in three referral centers were identified using the patients' medical records. In recent years, the use of high-definition chromoendoscopy was adopted in all three centers using segmental pancolonic spraying of 0.1% methylene blue or 0.3% indigo carmine (chromoendoscopy group). Previously, surveillance was performed employing WLE with random biopsies every 10 cm (WLE group). The percentage of colonoscopies with dysplasia was compared between both groups. RESULTS: A total of 440 colonoscopies in 401 patients were performed using chromoendoscopy and 1,802 colonoscopies in 772 patients using WLE. Except for a higher number of CD patients with extensive disease and more patients with a first-degree relative with colorectal cancer (CRC) in the chromoendoscopy group, the known risk factors for IBD-associated CRC were comparable between both groups. Dysplasia was detected during 48 surveillance procedures (11%) in the chromoendoscopy group as compared with 189 procedures (10%) in the WLE group (P=0.80). Targeted biopsies yielded 59 dysplastic lesions in the chromoendoscopy group, comparable to the 211 dysplastic lesions detected in the WLE group (P=0.30). CONCLUSIONS: Despite compelling evidence from randomized trials, implementation of chromoendoscopy for IBD surveillance did not increase dysplasia detection compared with WLE with targeted and random biopsies. PMID- 25823771 TI - Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview. AB - OBJECTIVES: This study provides an overview of the largest and longest-running colonoscopic surveillance program for colorectal cancer (CRC) in patients with long-standing ulcerative colitis (UC). METHODS: Data were obtained from medical records, endoscopy, and histology reports. Primary end points were defined as death, colectomy, withdrawal from surveillance, or censor date (1 January 2013). RESULTS: A total of 1,375 UC patients were followed up for 15,234 patient-years (median, 11 years per patient). CRC was detected in 72 patients (incidence rate (IR), 4.7 per 1,000 patient-years). Time-trend analysis revealed that although there was significant decrease in incidence of colectomy performed for dysplasia (linear regression, R=-0.43; P=0.007), IR of advanced CRC and interval CRC have steadily decreased over past four decades (Pearson's correlation, -0.99; P=0.01 for both trends). The IR of early CRC has increased 2.5-fold in the current decade compared with past decade (chi(2), P=0.045); however, its 10-year survival rate was high (79.6%). The IR of dysplasia has similarly increased (chi(2), P=0.01), potentially attributable to the recent use of chromoendoscopy that was twice more effective at detecting dysplasia compared with white-light endoscopy (chi(2), P<0.001). CRCs were frequently accompanied by synchronous CRC or spatially distinct dysplasia (37.5%). Finally, the risk of CRC was not significantly different between "indefinite" or low-grade dysplasia (log-rank, P=0.78). CONCLUSIONS: Colonoscopic surveillance may have a significant role in reducing the risk of advanced and interval CRC while allowing more patients to retain their colon for longer. Given the ongoing risk of early CRC, patients with any grade of dysplasia who are managed endoscopically should be monitored closely with advanced techniques. PMID- 25823772 TI - Differentiation of benign and malignant lesions of the tongue by using diffusion weighted MRI at 3.0 T. AB - OBJECTIVES: Diffusion-weighted MRI (DWI) has been introduced in head and neck lesions and adds important information to the findings obtained through conventional MRI. The purpose of this study was to assess the role of DWI in differentiating benign and malignant lesions of the tongue at 3.0-T field strength imaging. METHODS: 78 patients with 78 lingual lesions underwent conventional MRI and DWI with b-values of 0 and 1000 s mm(-2) before therapy. The apparent diffusion coefficient (ADC) maps were reconstructed, and the ADC values of the lingual lesions were calculated and compared between benign and malignant lesions of the tongue. RESULTS: The mean ADC values of the malignant tumours, benign solid lesions and cystic lesions were (1.08+/-0.16)*10(-3), (1.68+/ 0.33)*10(-3) and (2.21+/-0.35)*10(-3) mm2 s(-1), respectively. The mean ADC values of malignant tumours were significantly lower (p<0.001) than those of benign solid lesions, and the mean ADC values of benign solid lesions were significantly lower (p<0.001) than those of cystic lesions. Receiver operating characteristic analysis showed that when an ADC value<.31*10(-3) mm2 s(-1) was used for predicting malignancy, the highest accuracy of 95.3%, sensitivity of 92.6% and specificity of 97.3% were obtained. CONCLUSIONS: ADC values of benign and malignant lesions are significantly different at 3.0-T imaging. DWI can be applied as a complementary tool in the differentiation of benign and malignant lesions of the tongue. PMID- 25823773 TI - Clinical images in gastroenterology. Median arcuate ligament syndrome. PMID- 25823774 TI - Clinical images in gastroenterology. Eosinophilic colitis: An unusual case. PMID- 25823775 TI - Simultaneous primary cancers: Atypical Lynch syndrome? PMID- 25823776 TI - Stage-specific effects of fibroblast growth factor 2 on the differentiation of dental pulp cells. AB - Dentinogenesis is a complex and multistep process, which is regulated by various growth factors, including members of the fibroblast growth factor (FGF) family. Both positive and negative effects of FGFs on dentinogenesis have been reported, but the underlying mechanisms of these conflicting results are still unclear. To gain a better insight into the role of FGF2 in dentinogenesis, we used dental pulp cells from various transgenic mice, in which fluorescent protein expression identifies cells at different stages of odontoblast differentiation. Our results showed that the continuous exposure of pulp cells to FGF2 inhibited mineralization and revealed both the stimulatory and inhibitory effects of FGF2 on the expression of markers of dentinogenesis and various transgenes. During the proliferation phase of in vitro growth, FGF2 increased the expression of markers of dentinogenesis and the percentages of dentin matrix protein 1/green fluorescent protein (DMP1-GFP)-positive functional odontoblasts and dentin sialophosphoprotein (DSPP)-Cerulean-positive odontoblasts. Additional exposure to FGF2 during the differentiation/mineralization phase of in vitro growth decreased the extent of mineralization and the expression of markers of dentinogenesis and of the DMP1-GFP and DSPP-Cerulean transgenes. Recovery experiments showed that the inhibitory effects of FGF2 on dentinogenesis were related to the blocking of the differentiation of cells into mature odontoblasts. These observations together showed the stage-specific effects of FGF2 on dentinogenesis by dental pulp cells, and they provide critical information for the development of improved treatments for vital pulp therapy and dentin regeneration. PMID- 25823777 TI - Examination of breath alcohol concentration (BrAC) levels, alcohol use disorders identification test (AUDIT-C) classification, and intended plans for getting home among bar-attending college students. AB - BACKGROUND AND OBJECTIVE: The college student population is one of the heaviest drinking demographic groups in the US and impaired driving is a serious alcohol related problem. The objective of this study is to better understand the relationship between alcohol-related behaviors and "plans to get home" among a sample of college students. METHODS: We conducted four anonymous field studies to examine associations between breath alcohol concentration (BrAC) levels, Alcohol Use Disorders Identification Test (AUDIT-C) classification, and plans for getting home among a sample of bar-attending college students (N = 713). RESULTS, DISCUSSION AND CONCLUSIONS: The vast majority of participants in our sample (approximately 95%) were not intending to drive and the average BrAC% of those intending to drive was .041. Our one-way ANOVAs indicated that (1) participants classified by the AUDIT-C as not having an alcohol problem had a significantly lower BrAC% than those classified as having a potential problem and (2) participants planning to drive had a significantly lower BrAC% than those with a plan that did not involve them driving and those without a plan to get home. Although it is encouraging that most of our sample was not intending to drive, it is important to continue to attempt to reduce impaired driving in this population. SCIENTIFIC SIGNIFICANCE: This study helps college health professionals and administrators to better understand the relationship between alcohol-related behaviors and plans to get home among college students. PMID- 25823778 TI - Potential use of auxiliary labels to promote patient awareness of pharmacogenetic testing. PMID- 25823779 TI - Implementation and evaluation of a CYP2C19 genotype-guided antiplatelet therapy algorithm in high-risk coronary artery disease patients. AB - AIM: An algorithm that uses clinical factors and CYP2C19 genotype to guide P2Y12 inhibitor selection in high-risk patients undergoing percutaneous coronary intervention was implemented at our institution. We sought to evaluate use of this algorithm and identify which factors influenced P2Y12 inhibitor selection. PATIENTS & METHODS: This retrospective cohort study included 264 patients receiving percutaneous coronary intervention from July-December 2012. RESULTS: CYP2C19 genotype was obtained in 229 patients; of these, 30% were intermediate or poor metabolizers. CYP2C19 intermediate or poor metabolizer phenotype was among the strongest predictors for selecting prasugrel or ticagrelor as maintenance therapy (p < 0.001), and was the only significant predictor of a change in therapy (p < 0.001). CONCLUSION: These findings suggest that using CYP2C19 genotype to guide P2Y12 inhibitor selection is feasible. Original submitted 27 October 2014; revision submitted 19 December 2014. PMID- 25823780 TI - Evaluation of a shared pharmacogenomics curriculum for pharmacy students. AB - AIM: This national dissemination study evaluated pharmacy students' self-reported overall ability, self-efficacy and attitudes toward applying pharmacogenomics and perceptions of Pharmacogenomics Education Program, a shared pharmacogenomics curriculum. PATIENTS & METHODS: Following a series of train-the-trainer programs for pharmacy faculty, pre- (n = 2674) and post-training surveys (n = 2542) were administered to Doctor of Pharmacy students (n = 43 pharmacy schools). RESULTS: Students reported increased (pre- vs post-training) overall ability to educate patients about pharmacogenomics (17 vs 63%; p < 0.0001) and pharmacogenomic testing (11 vs 60%; p < 0.0001) and increased self-efficacy for identifying therapeutic areas for which pharmacogenomic testing is required (20 vs 75%; p < 0.0001). Most (92%) agreed that students at other schools would benefit from receiving the same, or similar, pharmacogenomics education. CONCLUSION: A shared curriculum is an effective approach for broadscale curricular dissemination. Original submitted 17 October 2014; Revision submitted 19 December 2014. PMID- 25823781 TI - Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity. AB - AIM: Assuming that genetic variants of the SLC22A2 and SLC31A1 transporter affect patients' susceptibility to cisplatin-induced ototoxicity, we compared the distribution of 11 SLC22A2 variants and the SLC31A1 variant rs10981694 between patients with and without cisplatin-induced ototoxicity. PATIENTS & METHODS: Genotyping was performed in 64 pediatric patients and significant findings were re-evaluated in 66 adults. RESULTS: The SLC22A2 polymorphism rs316019 (c.808G>T; Ser270Ala) was significantly associated with protection from cisplatin-induced ototoxicity in the pediatric (p = 0.022) and the adult cohort (p = 0.048; both: Fisher's exact test). This result was confirmed by multiple logistic regression analysis accounting for age which was identified as a relevant factor for ototoxicity as well (rs316019: OR [G/T vs G/G] = 0.12, p = 0.009; age: OR [per year]: 0.84, p = 0.02). CONCLUSION: These results identified rs316019 as potential pharmacogenomic marker for cisplatin-induced ototoxicity and point to a critical role of SLC22A2 for cisplatin transport in humans and its contribution to the organ specific side effects of this drug. Original submitted 17 September 2014; Revision submitted 19 December 2014. PMID- 25823782 TI - FCGR polymorphisms in the treatment of rheumatoid arthritis with Fc-containing TNF inhibitors. AB - OBJECTIVES: Reproducible association of a functional polymorphism in FCGR2A with response to a TNF inhibitor (TNFi) in patients with rheumatoid arthritis (RA) led us to explore other FcgammaR functional polymorphisms. METHODS: Functional polymorphisms FCGR3A F158V, FCGR2B I223T and promoter VNTR in FCGRT were analyzed in up to 429 patients with RA. Response to TNFi was recorded during standard care at 3, 6 and 12 months of follow-up. Fixed effects meta-analysis of studies addressing FCGR3A F158V polymorphism, which is the most studied of these polymorphisms, was conducted with inverse variance weighting. RESULTS: None of the functional polymorphisms were associated with change in DAS28. Meta-analysis of the seven studies (899 patients) with available data addressing association of FCGR3A F158V with response to TNFi in RA showed no association (OR: 1.11, 95% CI: 0.8-1.5; p = 0.5). CONCLUSION: None of the three functional polymorphisms in FcgammaR genes showed association with response to TNFi in patients with RA. These negative results were obtained in spite of the larger size of this study relative to previous studies addressing the same polymorphisms. In addition, meta analysis of FCGR3A F158V was also negative against the results provided by previous studies. Original submitted 17 September 2014; Revision submitted 9 December 2014. PMID- 25823783 TI - SCN1A, ABCC2 and UGT2B7 gene polymorphisms in association with individualized oxcarbazepine therapy. AB - AIM: Associations between the effects of SCN1A, SCN2A, ABCC2 and UGT2B7 genetic polymorphisms and oxcarbazepine (OXC) maintenance doses in Han Chinese epileptic patients were investigated. PATIENTS & METHODS: Genetic polymorphisms were detected in 184 epileptic patients receiving OXC monotherapy by high-resolution melting curve and TaqMan method. RESULTS: Carriers of the SCN1A IVS5-91G>A, UGT2B7 c.802T>C and ABCC2 c.1249G>A variant alleles required significantly higher OXC maintenance doses than noncarriers (p < 0.05). Corresponding relative ln (concentration-dose ratios) values for SCN1A IVS5-91 variants differed by the genotypic order GG > GA > AA. CONCLUSION: SCN1A, UGT2B7 and ABCC2 genetic polymorphisms are associated with OXC maintenance doses and may be useful for the personalization of OXC therapy in epileptic patients. Further studies are needed. Original submitted 6 June 2014; Revision submitted 5 September 2014. PMID- 25823784 TI - Association of NADPH oxidase polymorphisms with anthracycline-induced cardiotoxicity in the RICOVER-60 trial of patients with aggressive CD20(+) B-cell lymphoma. AB - AIM: To identify gene variants responsible for anthracycline-induced cardiotoxicity. PATIENTS & METHODS: Polymorphisms of the NADPH oxidase subunits and of the anthracycline transporters ABCC1, ABCC2 and SLC28A3 were genotyped in elderly patients (61-80 years) treated for aggressive CD20(+) B-cell lymphomas with CHOP-14 with or without rituximab and followed up for 3 years. RESULTS: The accumulation of RAC2 subunit genotypes TA/AA among cases was statistically significant upon adjustment for gender, age and doxorubicin dose in a multivariate logistic regression analysis (OR: 2.3, p = 0.028; univariate: OR: 1.8, p = 0.077). RAC2 and CYBA genotypes were significantly associated with anthracycline-induced cardiotoxicity in a meta-analysis of this and a similar previous study. CONCLUSION: Our results support the theory that NADPH oxidase is involved in anthracycline-induced cardiotoxicity. Original submitted 9 July 2014; Revision submitted 19 December 2014. PMID- 25823785 TI - FcGR genetic polymorphisms and the response to adalimumab in patients with rheumatoid arthritis. AB - AIM: The aim of our study was to explore the potential of FcGR genetic polymorphisms as a predictor of adalimumab efficacy in rheumatoid arthritis (RA) patients. MATERIALS & METHODS: The study population was composed of 302 Dutch RA patients receiving adalimumab therapy. The FcGR2A (R131>H; rs1801274) and FcGR3A (F158>V; rs396991) genetic variants were genotyped using the TaqMan((r)) allelic discrimination technology. Treatment outcome was evaluated with the use of the 28 joint disease activity score criteria (DAS28) and good response and remission were classified according to European League Against Rheumatism (EULAR) criteria. RESULTS: Comparing allelic frequencies between responders and nonresponders, the presence of the FcGR2A*R allele was associated with EULAR good response at 14 weeks (p = 0.017, odds ratio: 1.53, 95% CI: 1.08-2.17). No significant association was found for FcGR3A, with good response or remission. The combined effect of both FcGR2A and FcGR3A SNPs showed a trend for association with EULAR good response (p-value = 0.041, odds ratio: 1.38, 95% CI: 1.01-1.89). CONCLUSION: Our results indicate that FcGR polymorphisms could be a determinant of adalimumab efficacy in RA patients. Original submitted 28 July 2014; Revision submitted 19 December 2014. PMID- 25823786 TI - Correlation of genetic polymorphisms with clinical outcomes in pemetrexed-treated advanced lung adenocarcinoma patients. AB - AIM: Pemetrexed is a commonly used chemotherapeutic agent for lung adenocarcinoma patients. We investigated the impact of the genetic polymorphisms on the therapeutic efficacy of pemetrexed in lung adenocarcinoma patients. MATERIALS & METHODS: We performed genotying of 51 polymorphisms of 13 genes in 243 lung adenocarcinoma patients treated with pemetrexed as a single agent for second or more line of therapy. RESULTS: Total 12 polymorphisms in six genes were showed statistical significances in univariate analysis. After a false-discovery rate correction, the associations between GGH rs16930092 (p = 0.034) and rs10464903 (p = 0.034), and progression-free survival (PFS) were still conserved. Two polymorphisms in ATIC and GGH genes were associated with therapeutic efficacy in multivariate analysis: ATIC rs12995526 for tumor response (p = 0.014) and for overall survival (p = 0.006), and GGH rs16930092 (p = 0.009) for PFS. CONCLUSION: This study shows that polymorphisms on genes related to the metabolic pathway of pemetrexed, especially, ATIC and GGH genes, would have a therapeutic implication in pemetrexed-treated patients with lung adenocarcinoma. Original submitted 10 May 2013; Revision submitted 27 June 2014. PMID- 25823787 TI - Mechanistic insights into the effect of CYP2C9*2 and CYP2C9*3 variants on the 7 hydroxylation of warfarin. AB - AIM: To evaluate the impact of CYP2C9*2 and CYP2C9*3 variants on binding and hydroxylation of warfarin. MATERIALS & METHODS: Multiple linear regression model of warfarin pharmacokinetics was developed from the dataset of patients (n = 199). Pymol based in silico models were developed for the genetic variants. RESULTS: CYP2C9*2 and CYP2C9*3 variants exhibited high warfarin/7-hydroxywarfarin (multiple linear regression model), dose-dependent disruption of hydrogen bonds with warfarin, dose-dependent increase in the distance between C7 of S-warfarin and Fe-O of CYP2C9, dose-dependent decrease in the glide scores (in silico). CONCLUSION: CYP2C9*2 and CYP2C9*3 variants result in disruption of hydrogen bonding interactions with warfarin and longer distance between C7 and Fe-O thus impairing warfarin 7-hydroxylation due to lower binding affinity of warfarin. Original submitted 7 May 2014; Revision submitted 30 October 2014. PMID- 25823788 TI - Role of dermatology in pharmacogenomics: drug-induced skin injury. AB - Different individuals may respond diversely to the same drug, in terms of efficacy and toxicity. Adverse drug reactions cause about 6% of all hospital admissions and account for up to 9% of hospitalization costs. Drug-induced skin injury (DISI) is the most common presentation of adverse drug reactions, ranging from maculopapular eruptions to severe adverse cutaneous drug reactions (SCARs) with mortality of up to 40%. Specific genetic polymorphisms confer susceptibility to different types of DISI. Identifying patients genetically at risk for SCARs is one of the goals of pharmacogenomics. In this article, the aspects of clinical dermatology relevant to the pharmacogenetics of DISI are reviewed. Many SCARs are now preventable, with consequent reduction of morbidity, mortality and healthcare costs. PMID- 25823789 TI - Evaluation of association studies and meta-analyses of MTHFR gene polymorphisms in colorectal cancer. AB - There is a discrepancy between the results of 89 original studies and 15 meta analyses investigating the association of MTHFR rs1801133 and rs1801131 polymorphisms with colorectal cancer (CRC) risk. We examined this hypothesis through meta-analyses of both loci and their diplotypes as well as evaluation of previous meta-analyses. The present meta-analysis showed that rs1801133 and rs1801131 might be CRC susceptibility variants in Americans and Australians and rs1801133 in Brazilians and Japanese. A strong linkage disequilibrium was observed between both loci and their diplotypes were associated with CRC risk. Evaluation of 15 meta-analyses showed a high discrepancy among their findings, mainly caused by population stratification of original studies and data analysis strategies in meta-analysis. Population stratification was more dominant in the studies from Australia, America and Brazil leading to false positive or negative results. In conclusion, these loci alone might modify the development of CRC in some ethnicities. PMID- 25823790 TI - A Stress-Induced Shift From Trace to Delay Conditioning Depends on the Mineralocorticoid Receptor. AB - BACKGROUND: Fear learning in stressful situations is highly adaptive for survival by steering behavior in subsequent situations, but fear learning can become disproportionate in vulnerable individuals. Despite the potential clinical significance, the mechanism by which stress modulates fear learning is poorly understood. Memory theories state that stress can cause a shift away from more controlled processing depending on the hippocampus toward more reflexive processing supported by the amygdala and striatum. This shift may be mediated by activation of the mineralocorticoid receptor (MR) for cortisol. We investigated how stress shifts processes underlying cognitively demanding learning versus less demanding fear learning using a combined trace and delay fear conditioning paradigm. METHODS: In a pharmacological functional magnetic resonance imaging study, we tested 101 healthy men probing the effects of stress (socially evaluated cold pressor vs. control procedure) and MR-availability (400 mg spironolactone vs. placebo) in a randomized, placebo-controlled, full-factorial, between-subjects design. RESULTS: Effective stress induction and successful conditioning were confirmed by subjective, physiologic, and somatic data. In line with a stress-induced shift, stress enhanced later recall of delay compared with trace conditioning in the MR-available groups as indexed by skin conductance responses. During learning, this was accompanied by a stress-induced reduction of learning-related hippocampal activity for trace conditioning. The stress-induced shift in fear and neural processing was absent in the MR-blocked groups. CONCLUSIONS: Our results are in line with a stress-induced shift in fear learning, mediated by the MR, resulting in a dominance of cognitively less demanding amygdala-based learning, which might be particularly prominent in individuals with high MR sensitivity. PMID- 25823792 TI - Lymph Node Yield in Primary Retroperitoneal Lymph Node Dissection for Nonseminoma Germ Cell Tumors. AB - PURPOSE: The number of lymph nodes removed at surgery for various malignancies has diagnostic and prognostic value. However, there are limited data on the significance of the number of nodes removed at retroperitoneal lymph node dissection performed for testicular nonseminoma germ cell tumors. MATERIALS AND METHODS: From 1979 to 2012 primary open retroperitoneal lymph node dissection was performed by a single experienced surgeon for clinical stage I/II testicular nonseminoma germ cell tumor in 157 patients. Node count was available in 111 cases (71%). Factors associated with total node count and nodes with viable cancer were assessed by linear regression. The association between node count and time to relapse was assessed by multivariate Cox proportional hazards models controlled for adjuvant chemotherapy. RESULTS: The median total lymph node count was 28 (IQR 19-38). Patient age, cancer laterality, body mass index, clinical stage, time from orchiectomy to retroperitoneal lymph node dissection, pathologist and lymph node dissection year were not associated with total lymph node count. A viable germ cell tumor was found in 70 patients (63%). Total node yield was not associated with nodal cancer metastasis. After lymph node dissection 17 patients (16%) received adjuvant chemotherapy. At a median 57-month followup 18 cases (17%) relapsed after primary retroperitoneal lymph node dissection. Increasing total node count was associated with a decreased risk of relapse on univariate and multivariate analysis (HR 0.96, 95% CI 0.92-0.99, p = 0.03 and HR 0.94, 95% CI 0.89-0.99, p = 0.017, respectively). CONCLUSIONS: No analyzed clinical or pathological variable was associated with the node yield of primary retroperitoneal lymph node dissection. However, there may be a relationship between the total node yield at retroperitoneal lymph node dissection and the risk of relapse. PMID- 25823791 TI - Randomized Trial of Studer Pouch versus T-Pouch Orthotopic Ileal Neobladder in Patients with Bladder Cancer. AB - PURPOSE: The need to prevent reflux in the construction of an orthotopic ileal neobladder is controversial. We designed the USC-STAR trial to determine whether the T-pouch neobladder that included an antireflux mechanism was superior to the Studer pouch in patients with bladder cancer undergoing radical cystectomy. MATERIALS AND METHODS: This single center, randomized, controlled trial recruited patients with clinically nonmetastatic bladder cancer scheduled to undergo radical cystectomy with neobladder. Eligible patients were randomly assigned to undergo T-pouch or Studer ileal orthotopic neobladder. Treatment assignment was not masked. The primary end point was change in renal function from baseline to 3 years. The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was used to calculate the estimated glomerular filtration rate. RESULTS: Between February 2002 and November 2009, 237 patients were randomly assigned to T-pouch ileal orthotopic neobladder and 247 to Studer ileal orthotopic neobladder. Baseline characteristics did not differ between the groups. Between baseline and 3 years the estimated glomerular filtration rate decreased by 6.4 ml/minute/1.73 m(2) in the Studer group and 6.6 ml/minute/1.73 m(2) in the T-pouch group (p=0.35). Multivariable analysis showed that type of ileal orthotopic neobladder was not independently associated with 3-year renal function (p=0.63). However, baseline estimated glomerular filtration rate, age and urinary tract obstruction were independently associated with 3-year decline in renal function. Cumulative risk of urinary tract infection and overall late complications were not different between the groups, but the T-pouch was associated with an increased risk of secondary diversion related surgeries. CONCLUSIONS: T-pouch ileal orthotopic neobladder with an antireflux mechanism did not prevent a moderate reduction in renal function observed at 3 years compared to the Studer pouch, but did result in an increase in diversion related secondary surgical procedures. PMID- 25823793 TI - The moderating effect of relationships on intergenerational risk for infant neglect by young mothers. AB - Infant neglect is the form of child maltreatment that occurs most often, yet has been least amenable to prevention. A maternal history of childhood maltreatment is a potent risk factor for child neglect, yet most maltreated mothers break intergenerational cycles of child abuse and neglect. Little is known about what protective factors support discontinuity in intergenerational transmission. This study examined whether certain factors (positive childhood care, older maternal age, social support) buffer intergenerational risk for neglect among the infants of young mothers, a population at high risk of being victimized. For young mothers in the sample (<21 years at birth; n=447), the effect of a maternal history was assessed separately for different maltreatment types according to data on substantiated reports from Child Protective Services. Early risk for neglect was assessed using maternal self-report of parenting empathy. The results revealed that both infants and their mothers experienced neglect more often than any other maltreatment type. However, approximately 77% of maltreated mothers broke the cycle with their infants (<30 months). Maternal age moderated the relation between a maternal history of neglect and infant neglect, and social support moderated the relation between childhood neglect and maternal empathy. Neglected mothers had considerably higher levels of parenting empathy when they had frequent access to social support than when they had less frequent support, whereas the protective effect of social support was not nearly as strong for non maltreated mothers. Study findings highlight resilience in parenting despite risk for infant neglect, but underscore the context specificity of protective processes. PMID- 25823794 TI - Confirmatory test of two factors and four subtypes of bipolar disorder based on lifetime psychiatric co-morbidity. AB - BACKGROUND: The first aim was to use confirmatory factor analysis (CFA) to test a hypothesis that two factors (internalizing and externalizing) account for lifetime co-morbid DSM-IV diagnoses among adults with bipolar I (BPI) disorder. The second aim was to use confirmatory latent class analysis (CLCA) to test the hypothesis that four clinical subtypes are detectible: pure BPI; BPI plus internalizing disorders only; BPI plus externalizing disorders only; and BPI plus internalizing and externalizing disorders. METHOD: A cohort of 699 multiplex BPI families was studied, ascertained and assessed (1998-2003) by the National Institute of Mental Health Genetics Initiative Bipolar Consortium: 1156 with BPI disorder (504 adult probands; 594 first-degree relatives; and 58 more distant relatives) and 563 first-degree relatives without BPI. Best-estimate consensus DSM-IV diagnoses were based on structured interviews, family history and medical records. MPLUS software was used for CFA and CLCA. RESULTS: The two-factor CFA model fit the data very well, and could not be improved by adding or removing paths. The four-class CLCA model fit better than exploratory LCA models or post hoc-modified CLCA models. The two factors and four classes were associated with distinctive clinical course and severity variables, adjusted for proband gender. Co-morbidity, especially more than one internalizing and/or externalizing disorder, was associated with a more severe and complicated course of illness. The four classes demonstrated significant familial aggregation, adjusted for gender and age of relatives. CONCLUSIONS: The BPI two-factor and four-cluster hypotheses demonstrated substantial confirmatory support. These models may be useful for subtyping BPI disorders, predicting course of illness and refining the phenotype in genetic studies. PMID- 25823795 TI - Knockdown of microRNA-1323 restores sensitivity to radiation by suppression of PRKDC activity in radiation-resistant lung cancer cells. AB - Resistance to radiation is a major problem in cancer treatment. The mechanisms of radioresistance remain poorly understood; however, mounting evidence supports a role for microRNAs (miRNAs) in the modulation of key cellular pathways mediating the response to radiation. The present study aimed to identify specific miRNAs and their effect on radioresistant cells. The global miRNA profile of an established radioresistant lung cancer cell line and the corresponding control cells was determined. Differential expression of the miRNAs was confirmed by quantitative real-time PCR (qRT-PCR). The binding effect of identical novel miRNAs and target mRNAs was determined by luciferase assay. Lung cancer cells were transfected with miRNA-specific mimics or inhibitors. The DNA-dependent protein kinase (DNA-PKcs) protein level was tested by western blot analysis. Radiosensitivity of cancer cells was determined using colony formation assay. Among the differentially expressed miRNAs, 25 miRNAs were overexpressed while 18 were suppressed in the radioresistant cells, both basally and in response to radiation compared to their control. An miRNA signature miR-1323 exhibited a >5 fold increase in the radioresistant cells. miR-1323 was demonstrated to bind to PRKDC 3'UTR, which is involved in DNA repair. Ectopic expression of miR-1323 significantly increased the survival fraction of irradiated cancer cells. Inhibition of miR-1323 reversed the radioresistance of cancer cells and subsequently suppressed the expression of miR-1323-regulated DNA-PKcs protein. The present study indicated that miRNAs are involved in the radioresistance of human lung cancer cells. A possible mechanism for resistance to radiation was via enhanced DNA repair. The present study demonstrated a role for miR-1323 in modulating radioresistance and highlights the need for further study investigating the potential role of miR-1323 as both a predictive marker of response and a novel therapeutic agent with which to enhance the efficacy of radiotherapy. PMID- 25823796 TI - Co-Occurence of Reciprocal Translocation and COL2A1 Mutation in a Fetus with Severe Skeletal Dysplasia: Implications for Genetic Counseling. AB - Achondrogenesis type II is an autosomal-dominant disease leading to severe micromelic dwarfism. Here, we report on the postmortem identification of a de novo heterozygous mutation in the COL2A1 gene (c.1529G>A, p.Gly510Asp) in a fetus who presented with generalized hydrops fetalis and severe micromelia during prenatal sonographic examinations. Initially, a reciprocal translocation t(4;17)(q31;p13) was detected in this fetus by chorionic villus sampling. Subsequent chromosomal analysis of maternal and paternal blood showed that the patient's mother was carrier of the same reciprocal translocation. SNP array analysis of the fetus did not provide evidence for chromosomal imbalances or CNVs that could be associated with the fetal phenotype. The coexistence of a cytogenetic (reciprocal translocation) and a molecular genetic (COL2A1 mutation) abnormality in the fetus carries important implications for genetic counseling. PMID- 25823797 TI - Stress-related hormones and glycinebetaine interplay in protection of photosynthesis under abiotic stress conditions. AB - Plants subjected to abiotic stresses such as extreme high and low temperatures, drought or salinity, often exhibit decreased vegetative growth and reduced reproductive capabilities. This is often associated with decreased photosynthesis via an increase in photoinhibition, and accompanied by rapid changes in endogenous levels of stress-related hormones such as abscisic acid (ABA), salicylic acid (SA) and ethylene. However, certain plant species and/or genotypes exhibit greater tolerance to abiotic stress because they are capable of accumulating endogenous levels of the zwitterionic osmolyte-glycinebetaine (GB). The accumulation of GB via natural production, exogenous application or genetic engineering, enhances plant osmoregulation and thus increases abiotic stress tolerance. The final steps of GB biosynthesis occur in chloroplasts where GB has been shown to play a key role in increasing the protection of soluble stromal and lumenal enzymes, lipids and proteins, of the photosynthetic apparatus. In addition, we suggest that the stress-induced GB biosynthesis pathway may well serve as an additional or alternative biochemical sink, one which consumes excess photosynthesis-generated electrons, thus protecting photosynthetic apparatus from overreduction. Glycinebetaine biosynthesis in chloroplasts is up-regulated by increases in endogenous ABA or SA levels. In this review, we propose and discuss a model describing the close interaction and synergistic physiological effects of GB and ABA in the process of cold acclimation of higher plants. PMID- 25823798 TI - Photosynthesis, sucrose metabolism, and starch accumulation in two NILs of winter wheat. AB - The photosynthetic oxygen evolution rate, Hill reaction activity of seedlings and photosynthetic parameter, Pn-Ci curve and some source-sink metabolism-related enzyme activities, and substance content of flag leaves were measured by using two wheat near isogenic lines with significant differences in the photosynthetic rate of the 154 (high photosynthetic rate) and 212 (low photosynthetic rate) lines as materials. The results showed that the maximal carboxylation efficiency (Vcmax) and Hill reaction activity were higher in line 154 than that of line 212. The Pn in flag leaves of line 154 was significantly higher than that of line 212 during the anthesis to grain-filling stage. Higher leaf sucrose phosphate synthase activity, grain sucrose synthase activity, and grain ADPG pyrophosphorylase activity ensured that the photosynthate of line 154 could be transported to grains and translated into starch in a timely and effective manner, which also contributed to the maintenance of its high photosynthetic rate. Eventually, all of these factors of line 154 resulted in its higher grain yield compared with the low photosynthetic rate of line 212. PMID- 25823799 TI - Can combined aerobic and muscle strength training improve aerobic fitness, muscle strength, function and quality of life in people with spinal cord injury? A systematic review. AB - STUDY DESIGN: A systematic review. OBJECTIVES: The aim of this systematic review was to establish whether combined aerobic training and muscle strength training is effective in improving aerobic fitness, muscle strength, function and/or quality of life (QoL) in people with spinal cord injury (SCI). SETTINGS: Faculty of Health Sciences. University of Sydney, NSW, Australia. METHODS: A search was conducted for randomized controlled trials (RCTs), controlled trials, uncontrolled clinical trials, case series and cross-over studies involving exercise interventions that included a combination of aerobic and strength components, either in circuit-mode or in sequence for people with SCI. Methodological quality was independently rated using the PEDro scale and key findings were extracted from trials by two reviewers. RESULTS: The search identified 7981 abstracts, from which nine trials met the inclusion criteria. From the nine selected trials, seven reported aerobic outcomes, two of which showed a statistically significant within-group difference in aerobic fitness. Five studies reported muscle strength outcomes, four of them showed a statistically significant within-group mean difference on at least one outcome measure. Two studies looked at QoL, one of them found a statistically significant between-group difference on one outcome measure. CONCLUSION: Our systematic review showed that literature on SCI population is scarce, of low quality and findings of existing studies are inconsistent. Thus, further RCTs with larger number of participants are needed to make a definite conclusion about the influence of combined aerobic and muscle strength training on aerobic fitness, muscle strength and QoL in people with SCI. PMID- 25823800 TI - Incidence and aetiology of traumatic spinal cord injury in Cape Town, South Africa: a prospective, population-based study. AB - STUDY DESIGN: Prospective, regional population-based study. OBJECTIVES: To provide the incidence, aetiology and injury characteristics of traumatic spinal cord injury (TSCI) in the City of Cape Town, South Africa. SETTING: All government-funded hospitals within the City of Cape Town, South Africa. METHODS: All survivors of acute TSCI, given that they met the inclusion criteria, were prospectively included for a 1-year period. The International Spinal Cord injury Core Data Set was used and systematically completed by specialist doctors. Further, international standards for neurological classification were adhered to. RESULTS: In total, 147 cases of acute TSCI were identified and 145 were included in the study. The male to female ratio was 5.9:1 and the mean age was 33.5 years, ranging from 18 to 93. The crude incidence rate was 75.6 per million (95% CI: 64.3-88.8) with assault as the main cause of injury, accounting for 59.3% of the cases, followed by motor vehicle accidents (26.3%) and falls (11.7%). Most injuries occurred in the cervical spine (53.1%), and American Spinal Injury Association Impairment Scale A severity was most common (39.3%) in the cohort. CONCLUSION: The incidence rate of TSCI in a region of South Africa was high when compared to previously postulated figures for the country. There is a need for primary preventative strategies to target younger men that are exposed to violent activities. A national study is required to learn whether these findings are only locally applicable or generalisable. PMID- 25823801 TI - Sexual activity and sexual satisfaction in Korean men with spinal cord injury. AB - STUDY DESIGN: A cross-sectional survey. OBJECTIVES: The aim of this study was to identify and assess the sexual activity and perceived sexual satisfaction of Korean males with spinal cord injury (SCI) and to identify factors influencing sexuality and satisfaction. SETTING: Community residents with SCI. METHODS: A total of 139 male participants with SCI in Korea were eligible for inclusion in this study. All participants completed a face-to-face interview regarding sexuality and satisfaction, as well as structured questionnaires including items on socioeconomic factors, medical conditions and rehabilitation services. RESULTS: A total of 90 participants (65%) were engaged in sexual activity. A period of 21-25 years since SCI (compared with the initial 5 years since SCI) and an experience of direct sexual rehabilitation education were positively associated with sexual activity. Among 90 sexually active males with SCI, 8 (8.9%) and 56 (62.2%) were sexually satisfied and unsatisfied, respectively. Lower levels of education were strongly correlated with sexual dissatisfaction. CONCLUSION: Korean males with SCI showed low levels of satisfaction regarding sexual activities. Results showed that socioeconomic factors (e.g., state of employment and direct person-to-person sexual counseling services) had a greater impact on sexual activity than the degree of physical impairment. Notably, the educational background was the most influential factor on sexual satisfaction. PMID- 25823802 TI - Assessment of clinical adherence to the international autonomic standards following spinal cord injury. AB - STUDY DESIGN: Retrospective chart analysis. OBJECTIVES: To investigate the use of the International Autonomic Standards (IAS, 2009 edition) for classification of remaining autonomic function following spinal cord injury (SCI) over a 1-year period in a rehabilitation center, to determine clinical adherence to use of the IAS, and to examine the most common autonomic dysfunctions, as determined by using the IAS. SETTING: Tertiary rehabilitation hospital. METHODS: A retrospective study was conducted on the use of the IAS at admission and discharge over a 1-year period on patients admitted to an in-patient SCI unit in a tertiary rehabilitation center. We examined the consistency of the form completion, as well as the completion of separate components of the forms. Finally, we examined the prevalence of each autonomic impairment. RESULTS: A total of 70 patients were admitted to the unit. The clinical adherence to the IAS was lower than the International Standards for Neurological Classification of SCI (ISNCSCI) at both admission (63% and 93%, respectively) and discharge (39% and 78%, respectively). Blood pressure dysfunction was most common among the general autonomic function disorders. However, urinary, bowel and sexual dysfunctions were present in almost all individuals with acute SCI. CONCLUSION: The IAS is in the initial stages of being incorporated into routine admission and discharge clinical examinations of individuals with SCI. The current results suggest that the clinical adherence to the IAS is low; however, it is expected that increased education, experience, and accumulating evidence for the IAS will improve its use. PMID- 25823803 TI - Sexual satisfaction in women with spinal cord injuries. AB - STUDY DESIGN: Structured interview based on a predesigned survey. OBJECTIVE: To examine the factors that affect the degree of sexual satisfaction in a sample of women with spinal cord injury (SCI). SETTING: The study participants were women with SCIs, from the area of the SCI Unit of A Coruna, a reference unit for the Community of Galicia in the northwest of Spain. All study participants were selected consecutively in the outpatient clinic in 2013. METHODS: The study included women with the American Spinal Injury Association (ASIA) A-D spinal injuries, between the ages of 18 and 65 years, who completed rehabilitation therapy and live in the community. A total of 32 women formed the final study group. RESULTS: When comparing the group of women who were sexually active with those who were not, variables such as age, neurological level, time since the SCI, ASIA or Spinal Cord Independence Measure score, urinary incontinence, chronic pain and spasticity were not related to sexual activity. The only factors that we found to be related to sexual activity were not having a stable partner (P=0.017) and a lack of sensation in the genital area (P=0.039). CONCLUSION: The only variables related to sexual activity were not having a partner and a lack of sensation in the genital area. Improving sexual satisfaction, information and specific programs during rehabilitation can help women with SCI explore and investigate new erotic possibilities, thereby improving their self-esteem and social relationships. PMID- 25823804 TI - 3D angioarchitecture changes after spinal cord injury in rats using synchrotron radiation phase-contrast tomography. AB - STUDY DESIGN: A basic experiment study. OBJECTIVES: An understanding of the three dimensional (3D) angioarchitecture changes that occur after SCI will improve our knowledge of the pathogenesis of SCI and aid in the development of valuable therapeutic strategies to improve its poor outcomes. Our aim was to visualize the normal and traumatized spinal angioarchitecture in 3D using a high-resolution synchrotron radiation phase-contrast tomography (SR-PCT) and evaluate its diagnostic capability. SETTING: SCI Center of Xiangya Hospital of Central South University in China. METHODS: SR-PCT was used as novel high-resolution imaging tool to detect 3D morphological alterations in spinal cord microvasculature after injury. RESULTS: In a rat model, the morphology of the microvasculature on 2D digital slices was matched with histological findings in both the normal and injured spinal cord. 3D angioarchitecture changes after SCI were successfully obtained via SR-PCT without the use of a contrast agent. Quantitative analysis on 3D images of the injured spinal cord revealed a significant decrease in the number and volume of vascular networks. This was especially relevant to vessels with a diameter <50 MUm. CONCLUSION: The 3D local blood supply to the spinal cord was severely disrupted after the acute violent injury. Our results indicate that the use of SR-PCT may improve our understanding of the pathogenesis of SCI and provide a new approach to the morphological investigation of neurovascular diseases in preclinical research. PMID- 25823805 TI - Residential Transience, Major Depressive Episodes, and the Risk of Suicidal Thoughts, Plans, and Attempts. AB - The association between past-year residential transience (frequent moving) and suicidal ideation among a nationally representative sample of over 190,000 U.S. adults was evaluated. Suicidal thoughts, plans, and attempts were more prevalent among transient adults. Among adults without major depressive episodes (MDE), transience was associated with 70% to 90% greater odds of suicidal ideation compared to nontransient adults. Among adults with MDE, transience was associated with a 60% to 80% increased odds of suicidal ideation compared to nontransient adults. Residential transience may be an indicator for increased suicide risk even in the absence of depression. PMID- 25823806 TI - The use of EEG parameters as predictors of drug effects on cognition. AB - It has been shown to be difficult to predict whether cognition-enhancing effects of drugs in animal studies have the same effect in humans. Various issues in translating findings from animal to human studies can be identified. Here we discuss whether EEG could be considered as a possible tool to translate the effects of cognition enhancers across species. Three different aspects of EEG measures are evaluated: frequency bands, event-related potentials, and coherence analysis. On basis of the comparison of these measures between species, and effects of drugs that improve or impair memory performance (mainly cholinergic drugs), it appears that event-related potentials and coherence analyses could be considered as potential translational tools to study cognition-enhancing drug effects in rodents and animals. PMID- 25823807 TI - Animal models of Multiple Sclerosis. AB - Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells. Animal modeling has been critical for addressing MS pathogenesis. The three most characterized animal models of MS are (1) the experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally-induced chronic demyelinating disease, known as Theiler's murine encephalomyelitis virus (TMEV) infection and (3) the toxin-induced demyelination. All these models, in a complementary way, have allowed to reach a good knowledge of the pathogenesis of MS. Specifically, EAE is the model which better reflects the autoimmune pathogenesis of MS and is extremely useful to study potential experimental treatments. Furthermore, both TMEV and toxin-induced demyelination models are suitable for characterizing the role of the axonal injury/repair and the remyelination process in MS. In conclusion, animal models, despite their limitations, remain the most useful instrument for implementing the study of MS. PMID- 25823808 TI - Translational value of animal models of asthma: Challenges and promises. AB - Asthma is a heterogeneous disease in which various environmental stimuli as well as different genes, cell types, cytokines and mediators are implicated. This chronic inflammatory disorder of the airways is estimated to affect as many as 300 million people worldwide. Animal models of asthma, despite their limitations, have contributed greatly to our understanding of disease pathology and the identification of key processes, cells and mediators in asthma. However, it is less likely to develop an animal model of asthma that takes into account all aspects of human disease. The focus in current asthma research is increasingly on severe asthma because this group of patients is not well treated today. Recent advances in studies of asthma exacerbation are thus considered. We therefore need to develop translational model systems for pharmacological evaluation and molecular target discovery of severe asthma and asthma exacerbations. In this review we attempted to discuss the different animal models of asthma, with special emphasis on ovalbumin and house dust mite models, their merits and their limitations. PMID- 25823809 TI - DSR-98776, a novel selective mGlu5 receptor negative allosteric modulator with potent antidepressant and antimanic activity. AB - Modulation of monoaminergic systems has been the main stream of treatment for patients with mood disorders. However, recent evidence suggests that the glutamatergic system plays an important role in the pathophysiology of these disorders. This study pharmacologically characterized a structurally novel metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulator, DSR 98776, and evaluated its effect on rodent models of depression and mania. First, DSR-98776 in vitro profile was assessed using intracellular calcium and radioligand binding assays. This compound showed dose-dependent inhibitory activity for mGlu5 receptors by binding to the same allosteric site as 2-methyl-6 (phenylethynyl)-pyridine (MPEP), a known mGlu5 inhibitor. The in vivo therapeutic benefits of DSR-98776 were evaluated in common rodent models of depression and mania. In the rat forced swimming test, DSR-98776 (1-3mg/kg) significantly reduced rats immobility time after treatment for 7 consecutive days, while paroxetine (3 and 10mg/kg) required administration for 2 consecutive weeks to reduce rats immobility time. In the mouse forced swimming test, acute administration of DSR-98776 (10-30 mg/kg) significantly reduced immobility time. This effect was not influenced by 4-chloro-DL-phenylalanine methyl ester hydrochloride-induced 5-HT depletion. Finally, DSR-98776 (30 mg/kg) significantly decreased methamphetamine/chlordiazepoxide-induced hyperactivity in mice, which reflects this compound antimanic-like effect. These results indicate that DSR 98776 acts as an orally potent antidepressant and antimanic in rodent models and can be a promising therapeutic option for the treatment of a broad range of mood disorders with depressive and manic states. PMID- 25823810 TI - Reverse translation of failed treatments can help improving the validity of preclinical animal models. AB - A major challenge in translational research is to reduce the currently high proportion of new candidate treatment agents for neuroinflammatory disease, which fail to reproduce promising effects observed in animal models when tested in patients. This disturbing situation has raised criticism against the currently used animal models in preclinical research and calls for improvement of these models. This seems a difficult task as the cause of failure is often not known. Here we propose a potentially useful strategy for investigating why a promising strategy fails as a guidance for improving the validity of the animal model(s). PMID- 25823811 TI - Rodent models for human diseases. AB - One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. Except in the case of highly controlled and regulated clinical trials, geneticists and scientists do not use humans for their experimental investigations because of the obvious risk to life. Instead, they use various animal, fungal, bacterial, and plant species as model organisms for their studies. Amongst these model organisms, rodent models are the most used due to the easiness for the experiments and the possibility to modify genetically these model animals. Nevertheless, due to the fact that animal models typically do not contract the same genetic diseases as people, so scientists must alter their genomes to induce human disease states and to know what kind of mutation causes the disease. In this brief review, we will discuss the interests of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases. PMID- 25823812 TI - The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease. AB - Ethics on animal use in science in Western society is based on utilitarianism, weighing the harms and benefits to the animals involved against those of the intended human beneficiaries. The 3Rs concept (Replacement, Reduction, Refinement) is both a robust framework for minimizing animal use and suffering (addressing the harms to animals) and a means of supporting high quality science and translation (addressing the benefits). The ambiguity of basic research performed early in the research continuum can sometimes make harm-benefit analysis more difficult since anticipated benefit is often an incremental contribution to a field of knowledge. On the other hand, benefit is much more evident in translational research aimed at developing treatments for direct application in humans or animals suffering from disease. Though benefit may be easier to define, it should certainly not be considered automatic. Issues related to model validity seriously compromise experiments and have been implicated as a major impediment in translation, especially in complex disease models where harms to animals can be intensified. Increased investment and activity in the 3Rs is delivering new research models, tools and approaches with reduced reliance on animal use, improved animal welfare, and improved scientific and predictive value. PMID- 25823813 TI - The transferability from rat subacute 4-week oral toxicity study to translational research exemplified by two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties. AB - Exposure to chemicals may have an influence on the immune system. Often, this is an unwanted effect but in some pharmaceuticals, it is the intended mechanism of action. Immune function tests and in depth histopathological investigations of immune organs were integrated in rodent toxicity studies performed according to an extended OECD test guideline 407 protocol. Exemplified by two immunosuppressive drugs, azathioprine and cyclosporine A, and two environmental chemicals, hexachlorobenzene and benzo[a]pyrene, results of subacute rat studies were compared to knowledge in other species particular in humans. Although immune function has a high concordance in mammalian species, regarding the transferability from rodents to humans various factors have to be taken into account. In rats, sensitivity seems to depend on factors such as strain, sex, stress levels as well as metabolism. The two immunosuppressive drugs showed a high similarity of effects in animals and humans as the immune system was the most sensitive target in both. Hexachlorobenzene gave an inconsistent pattern of effects when considering the immune system of different species. In some species pronounced inflammation was observed, whereas in primates liver toxicity seemed more obvious. Generally, the immune system was not the most sensitive target in hexachlorobenzene-treatment. Immune function tests in rats gave evidence of a reaction to systemic inflammation rather than a direct impact on immune cells. Data from humans are likewise equivocal. In the case of benzo[a]pyrene, the immune system was the most sensitive target in rats. In the in vitro plaque forming cell assay (Mishell-Dutton culture) a direct comparison of cells from different species including rat and human was possible and showed similar reactions. The doses in the rat study had, however, no realistic relation to human exposure, which occurs exclusively in mixtures and in a much lower range. In summary, a case by case approach is necessary when testing immunotoxicity. Improvements for the translation from animals to humans related to immune cells can be expected from in vitro tests which offer direct comparison with reactions of human immune cells. This may lead to a better understanding of results and variations seen in animal studies. PMID- 25823814 TI - Ethological concepts enhance the translational value of animal models. AB - The translational value of animal models is an issue of ongoing discussion. We argue that 'Refinement' of animal experiments is needed and this can be achieved by exploiting an ethological approach when setting up and conducting experiments. Ethology aims to assess the functional meaning of behavioral changes, due to experimental manipulation or treatment, in animal models. Although the use of ethological concepts is particularly important for studies involving the measurement of animal behavior (as is the case for most studies on neuro psychiatric conditions), it will also substantially benefit other disciplines, such as those investigating the immune system or inflammatory response. Using an ethological approach also involves using more optimal testing conditions are employed that have a biological relevance to the animal. Moreover, using a more biological relevant analysis of the data will help to clarify the functional meaning of the modeled readout (e.g. whether it is psychopathological or adaptive in nature). We advocate for instance that more behavioral studies should use animals in group-housed conditions, including the recording of their ultrasonic vocalizations, because (1) social behavior is an essential feature of animal models for human 'social' psychopathologies, such as autism and schizophrenia, and (2) social conditions are indispensable conditions for appropriate behavioral studies in social species, such as the rat. Only when taking these elements into account, the validity of animal experiments and, thus, the translation value of animal models can be enhanced. PMID- 25823815 TI - Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis. AB - Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors. PMID- 25823816 TI - Overexpression of mutant Ptch in rhabdomyosarcomas is associated with promoter hypomethylation and increased Gli1 and H3K4me3 occupancy. AB - Mice with heterozygous loss of the tumor suppressor Patched1 (Ptch) develop rhabdomyosarcoma (RMS)-like tumors. However, Ptch transcripts are consistently overexpressed in these tumors. We have recently shown that the upregulated transcripts are derived from the mutated Ptch allele thus leading to the hypothesis that the wild-type allele is repressed during RMS development. Here we describe epigenetic changes taking place at the Ptch locus during RMS development. We showed a lower degree of DNA-methylation in methylation-sensitive CpG regions of the Ptch promoter in RMS compared to normal muscle from heterozygous Ptch animals. In agreement with these results, treatment of heterozygous Ptch mice with the DNA demethylating agent 5-aza-2-deoxycytidine (5 aza-dC) between embryonic days E9.5-E11.5 significantly accelerated RMS formation. Since Ptch promoter methylation occurs after/around E13.5, the window for RMS initiation during embryogenesis, these results provide additional evidence that Ptch promoter hypomethylation may contribute to RMS formation. We have also demonstrated increased trimethylation of histone H3 lysine 4 (H3K4me3) and preferential binding of Gli1, a known Ptch activator, to the mutant locus in RMS. Together, these findings support an alternative model for RMS formation in heterozygous Ptch mice including loss of methylation and concomitant occupancy by activating histone marks of mutant Ptch. PMID- 25823817 TI - MicroRNA-155 expression is independently predictive of outcome in chordoma. AB - BACKGROUND: Chordoma pathogenesis remains poorly understood. In this study, we aimed to evaluate the relationships between microRNA-155 (miR-155) expression and the clinicopathological features of chordoma patients, and to evaluate the functional role of miR-155 in chordoma. METHODS: The miRNA expression profiles were analyzed using miRNA microarray assays. Regulatory activity of miR-155 was assessed using bioinformatic tools. miR-155 expression levels were validated by reverse transcription-polymerase chain reaction. The relationships between miR 155 expression and the clinicopathological features of chordoma patients were analyzed. Proliferative, migratory and invasive activities were assessed by MTT, wound healing, and Matrigel invasion assays, respectively. RESULTS: The miRNA microarray assay revealed miR-155 to be highly expressed and biologically active in chordoma. miR-155 expression in chordoma tissues was significantly elevated, and this expression correlated significantly with disease stage (p = 0.036) and the presence of metastasis (p = 0.035). miR-155 expression also correlated significantly with poor outcomes for chordoma patients (hazard ratio, 5.32; p = 0.045). Inhibition of miR-155 expression suppressed proliferation, and the migratory and invasive activities of chordoma cells. CONCLUSIONS: We have shown miR-155 expression to independently affect prognosis in chordoma. These results collectively indicate that miR-155 expression may serve not only as a prognostic marker, but also as a potential therapeutic target in chordoma. PMID- 25823818 TI - By activating matrix metalloproteinase-7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization. AB - Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology. However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated. Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1beta (IL-1beta), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7). Specifically, shear-induced cAMP and IL-1beta activate PI3-K, ERK1/2 and p38 signaling pathways, which lead to the synthesis of MMP-7 via transactivating NF-kappaB and c-Jun in human chondrosarcoma cells. Importantly, MMP-7 upregulation in response to shear stress exposure has the ability to promote lung colonization of chondrosarcomas in vivo. These findings offer a better understanding of the mechanisms underlying MMP-7 activation in shear-stimulated chondrosarcoma cells, and provide insights on designing new therapeutic strategies to interfere with chondrosarcoma invasion and metastasis. PMID- 25823819 TI - ANO1/TMEM16A interacts with EGFR and correlates with sensitivity to EGFR targeting therapy in head and neck cancer. AB - The epidermal growth factor receptor (EGFR) contributes to the pathogenesis of head&neck squamous cell carcinoma (HNSCC). However, only a subset of HNSCC patients benefit from anti-EGFR targeted therapy. By performing an unbiased proteomics screen, we found that the calcium-activated chloride channel ANO1 interacts with EGFR and facilitates EGFR-signaling in HNSCC. Using structural mutants of EGFR and ANO1 we identified the trans/juxtamembrane domain of EGFR to be critical for the interaction with ANO1. Our results show that ANO1 and EGFR form a functional complex that jointly regulates HNSCC cell proliferation. Expression of ANO1 affected EGFR stability, while EGFR-signaling elevated ANO1 protein levels, establishing a functional and regulatory link between ANO1 and EGFR. Co-inhibition of EGFR and ANO1 had an additive effect on HNSCC cell proliferation, suggesting that co-targeting of ANO1 and EGFR could enhance the clinical potential of EGFR-targeted therapy in HNSCC and might circumvent the development of resistance to single agent therapy. HNSCC cell lines with amplification and high expression of ANO1 showed enhanced sensitivity to Gefitinib, suggesting ANO1 overexpression as a predictive marker for the response to EGFR-targeting agents in HNSCC therapy. Taken together, our results introduce ANO1 as a promising target and/or biomarker for EGFR-directed therapy in HNSCC. PMID- 25823820 TI - A novel small-form NEDD4 regulates cell invasiveness and apoptosis to promote tumor metastasis. AB - Despite numerous investigations on metastasis, the determinants of metastatic processes remain unclear. We aimed to identify the metastasis-associated genes in hepatocellular carcinoma (HCC). Potent metastatic SK-hep-1 (SK) cells, designated 'SKM', were generated using Transwell assay followed by selection in a mouse model. Genes expressed differentially in SKM and SK cells were identified via microarray analyses. A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography mass spectrometry. In clinical specimens, sNEDD4 was significantly overexpressed in tumors and serves as a poor prognostic factor for male patients with HCC (P = 0.035). Upon subcutaneous introduction of sNEDD4-overexpressing SK cells into flanks of nude mice, tumors grew faster than those of the control group. Furthermore, sNEDD4-mediated promotion of tumor metastasis was demonstrated in the orthotopic mouse model. Overexpression of sNEDD4 increased the invasive ability of SK cells through upregulation of matrix metalloproteinase 9 and inhibited serum deprivation-induced apoptosis via upregulation of myeloid cell leukemia 1. In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions. The present findings clearly support the prognostic potential of sNEDD4 for HCC. PMID- 25823821 TI - Shp2 SUMOylation promotes ERK activation and hepatocellular carcinoma development. AB - Shp2, an ubiquitously expressed protein tyrosine phosphatase, is essential for regulation of Ras/ERK signaling pathway and tumorigenesis. Here we report that Shp2 is modified by SUMO1 at lysine residue 590 (K590) in its C-terminus, which is reduced by SUMO1-specific protease SENP1. Analysis of wild-type Shp2 and SUMOylation-defective Shp2(K590R) mutant reveals that SUMOylation of Shp2 promotes EGF-stimulated ERK signaling pathway and increases anchorage-independent cell growth and xenografted tumor growth of hepatocellular carcinoma (HCC) cell lines. Furthermore, we find that mutant Shp2(K590R) reduces its binding with the scaffolding protein Gab1, and consistent with this, knockdown of SENP1 increased the interaction between Shp2 and Gab1. More surprisingly, we show that human Shp2 (hShp2) and mouse Shp2 (mShp2) have differential effects on ERK activation as a result of different SUMOylation level, which is due to the event of K590 at hShp2 substituted by R594 at mShp2. In summary, our data demonstrate that SUMOylation of Shp2 promotes ERK activation via facilitating the formation of Shp2-Gab1 complex and thereby accelerates HCC cell and tumor growth, which presents a novel regulatory mechanism underlying Shp2 in regulation of HCC development. PMID- 25823822 TI - Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. AB - The hypomethylating agents (HMAs) are standard therapy for patients with higher risk myelodysplastic syndrome (MDS); however, the majority of the patients will lose their response to HMAs over time due to unknown mechanisms. It has recently been shown that T cell expression of the immunoinhibitory receptor PD-1 is regulated by DNA methylation. In 12 of 27 patients (44%) PD-1 promoter demethylation was observed in sorted peripheral blood T cells isolated over consecutive cycles of treatment with 5-azacytidine (5-aza). The PD-1 promoter demethylation correlated with an increase in PD-1 expression. Moreover, demethylation of the PD-1 promoter correlated with a significantly worse overall response rate (8% vs. 60%, p = 0.014), and a trend towards a shorter overall survival (p = 0.11) was observed. A significantly higher baseline methylation level of the PD-1 promoter was observed in T cells of non-responding patients compared to healthy controls (p = 0.023). Accordingly, in addition to their beneficial function, HMAs induce PD-1 expression on T cells in the MDS microenvironment, thereby likely hampering the immune response against the MDS blasts. Thus, we suggest that activation of the PD-1 checkpoint during HMA treatment can be a possible resistance mechanism, which may be overcome by combination therapy with a PD-1 pathway inhibitor. PMID- 25823824 TI - Temporal regulation of HIF-1 and NF-kappaB in hypoxic hepatocarcinoma cells. AB - Regulations between NF-kappaB and HIF-1 have not been adequately addressed in previous research. Here, we report that hypoxia increased NF-kappaB in hepatocellular carcinoma cells. The HIF-1 protein level was rapidly induced by protein stabilization (by 2 hours) and then moderately decreased, whereas mRNA levels were reciprocally increased. We also found that NF-kappaB p50 and p65 (RelA), but not c-Rel, bound the HIF-1a promoter, thus increasing its transcription. In contrast, miR-199a-5p and miR-93, c-Rel downstream targets, decreased HIF-1alpha at both the mRNA and protein levels. Dicer1, a key enzyme in miRNA biogenesis, was decreased by acute hypoxia but was later increased by HIF 1, rather than by the above-mentioned NF-kappaB subunits. Thus, NF-kappaB both positively and negatively fine-tuned HIF-1 in hypoxic hepatocarcinoma cells. PMID- 25823825 TI - Detection of K-ras gene mutation by liquid biopsy in patients with pancreatic cancer. AB - BACKGROUND: Cell-free circulating tumor DNA (ctDNA) in serum has been considered to be a useful candidate for noninvasive cancer diagnosis. The current study was designed to estimate the clinical usefulness of genetic analysis for ctDNA by digital polymerase chain reaction in patients with pancreatic cancer. METHODS: The authors compared K-ras mutations detected in endoscopic ultrasound-guided fine-needle aspiration biopsy tissue DNA and in ctDNA from 75 patients with pancreatic cancer. K-ras mutations in the serum of 66 independent, consecutive patients with pancreatic cancer were also analyzed and the authors compared the results with survival rates. RESULTS: The frequencies of the mutations in tissue samples at G12V, G12D, and G12R in codon 12 were 28 of 75 samples (37.3%), 22 of 75 samples (29.3%), and 6 of 75 samples (8.0%), respectively. Conversely, the rates of the mutations in ctDNA were 26 of 75 samples (34.6%), 29 of 75 samples (38.6%), and 4 of 75 samples (5.3%), respectively. Overall, the K-ras mutation rates in tissue and ctDNA were 74.7% and 62.6%, respectively, and the concordance rate between them was 58 of 75 samples (77.3%). Survival did not appear to differ by the presence of K-ras mutations in tissue DNA, but the survival of patients with K-ras mutations in ctDNA was significantly shorter than that of patients without mutations in both a development set (P = .006) and an independent validation set (P = .002). The difference was especially evident in cases with a G12V mutation. CONCLUSIONS: Analysis of ctDNA is a new useful procedure for detecting mutations in patients with pancreatic cancer. This noninvasive method may have great potential as a new strategy for the diagnosis of pancreatic cancer as well as for predicting survival. PMID- 25823823 TI - CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis. AB - Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs. PMID- 25823826 TI - No evidence of MERS-CoV in Ghanaian Hajj pilgrims: cautious interpretation is needed. PMID- 25823828 TI - Curcumin protects renal tubular epithelial cells from high glucose-induced epithelial-to-mesenchymal transition through Nrf2-mediated upregulation of heme oxygenase-1. AB - Curcumin has been observed to exhibit an anti-fibrotic effect in the liver, lung and gallbladder. However, the mechanisms underlying the cytoprotective effects of curcumin remain to be elucidated. The epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in the kidney is considered to contribute to the renal accumulation of matrix proteins associated with diabetic nephropathy. The EMT is also closely associated with the progression of renal interstitial fibrosis and oxidative stress. This process may occur through abrogation of high glucose (HG)-induced oxidative stress via activation of nuclear factor (erythroid derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) in kidney tubular epithelial cells. In the present study, the effect of curcumin on HG-induced EMT in the NRK 52E normal rat kidney tubular epithelial cell line was investigated, and whether the effect of curcumin was mediated by the induction of Nrf2 and HO-1 expression was examined. The present study revealed that curcumin was able to prevent events associated with EMT, including the downregulation of E-cadherin and the increased expression of alpha-smooth muscle actin. Further analysis revealed that the expression levels of Nrf2 and HO-1 protein were elevated to a greater extent in the curcumin pretreated NRK-52E cells compared with those of the control. Notably, knockdown of Nrf2 with small interfering RNA prevented the curcumin induced elevation in expression of HO-1 and the associated anti-fibrotic effects. In conclusion, the present findings suggested that curcumin may be significant in cellular antioxidant defense, through the activation of Nrf2 and HO-1, thereby protecting the NRK-52E cells from HG-induced EMT. PMID- 25823829 TI - [Nutrition and hydration at the end of life]. AB - At the end of life the pleasure function of alimentation is to be preferred to its nutritive function. Artificial nutrition and hydration in an enteral or parenteral way are artificial life support techniques. Artificial nutrition and hydration are systematically justified for patients in curative phase that require it but not for patients in a terminal or agonal phase. The fear of death from hunger and thirst is not justified. It is more relevant of a symbolic and phantasmic dimension than of an objective reality. The practice of oral care is much more effective than installing an artificial hydration to improve the comfort of a patient at the very end of life. Withdrawing or withholding an artificial nutrition and hydration can prevent an unreasonable obstinacy prohibited by law. PMID- 25823830 TI - Multiple sclerosis: From new concepts to updates on management. PMID- 25823827 TI - Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias. AB - In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias. PMID- 25823831 TI - New insights and current concepts of the oxidative stress theory of aging. PMID- 25823833 TI - Focus on sugar-sweetened beverages. PMID- 25823832 TI - The value of postoperative anticoagulants to improve flap survival in the free radial forearm flap: a systematic review and retrospective multicentre analysis. AB - BACKGROUND: Free radial forearm flap (FRFF) reconstruction is a valuable technique in head and neck surgery, which allows closure of large defects while striving to maintain functionality. Anticoagulative drugs are often administered to improve flap survival, although evidence regarding effectiveness is lacking. OBJECTIVE OF REVIEW: To investigate the effectiveness of postoperative anticoagulants to improve survival of the FRFF in head and neck reconstruction. TYPE OF REVIEW: Systematic review and multicentre, individual patient data meta analysis. SEARCH STRATEGY: MEDLINE, EMBASE, Web of Science and CINAHL were searched for synonyms of 'anticoagulants' and 'free flap reconstruction'. EVALUATION METHOD: Studies were critically appraised for directness of evidence and risk of bias. Authors of the highest quality publications were invited to submit their original data for meta-analysis. RESULTS: Five studies were of adequate quality, and data from four studies (80%) were available for meta analysis, describing 759 FRFF procedures. Anticoagulants used were as follows: aspirin (12%), low molecular weight dextran (18.3%), unfractioned heparin (28.1%), low molecular weight heparin (49%) and prostaglandin-E1 (2.1%). Thirty one per cent did not receive anticoagulants. Flap failure occurred in 40 of 759 patients (5.3%) On univariate analysis, use of unfractioned heparin was associated with a higher rate of flap failure. However, these regimens were often administered to patients who had revision surgery of the anastomosis. In multivariate logistic regression analysis, anticoagulant use was not associated with improved flap survival or flap-related complications. CONCLUSIONS: The studied anticoagulative drugs did not improve FRFF survival or lower the rate of flap-related complications. In addition, some anticoagulants may cause systemic complications. PMID- 25823834 TI - Quantitative genetics, spread of genes and genetic improvement: papers in honour of John James. Introduction. PMID- 25823835 TI - Genetic contributions and their optimization. AB - Genetic contributions were first formalized in 1958 by James and McBride (Journal of Genetics, 56, 55-62) and have since been shown to provide a unifying framework for theories of gain and inbreeding. As such they have underpinned the development of methods that provide the most effective combination of maximizing gain whilst managing inbreeding and loss of genetic variation. It is shown how this optimum contribution technology can be developed from theory and adapted to provide practical selection protocols for a wide variety of situations including overlapping generations and multistage selection. The natural development of the theory to incorporate genomic selection and genomic control of inbreeding is also shown. PMID- 25823836 TI - GRAIN: a computer program to calculate ancestral and partial inbreeding coefficients using a gene dropping approach. AB - GRain is freely available software intended to enable and promote testing of hypotheses with respect to purging and heterogeneity of inbreeding depression. The program is based on a stochastic approach, the gene dropping method, and calculates various coefficients from large and complex pedigrees. GRain calculates, together with the 'classical' inbreeding coefficient, ancestral inbreeding coefficients proposed by Ballou, (1997) J. Hered., 88, 169 and Kalinowski et al., (2000) Conserv. Biol., 14, 1375 as well as an ancestral history coefficient (AHC ), defined here for the first time. AHC is defined as the number that tells how many times during pedigree segregation (gene dropping) a randomly taken allele has been in IBD status. Furthermore, GRain enables testing of heterogeneity and/or purging of inbreeding depression with respect to different founders/ancestors by calculating partial coefficients for all previously obtained coefficients. PMID- 25823837 TI - Managing the rate of increase in average co-ancestry in a rolling front tree breeding strategy. AB - In breeding forest trees, as for livestock, the goal is to capture as much genetic gain as possible for the breeding objective, while limiting long- and short-term inbreeding. The Southern Tree Breeding Association (STBA) is responsible for breeding Australia's two main commercial forest tree species and has adopted algorithms and methods commonly used in animal breeding to achieve this balance. Discrete generation breeding is the norm for most tree breeding programmes. However, the STBA uses an overlapping generation strategy, with a new stream of breeding initiated each year. A feature of the species bred by the STBA (Pinus radiata and Eucalyptus globulus) is the long interval (up to 7 years) between when an individual is mated and when its progeny is first assessed in field trials and performance data included in the national performance database. Mate selection methods must therefore recognize the large pool of unmeasured progeny generated over recent years of crossing. In addition, the substantial delay between when an individual is selected in a field trial and when it is clonally copied into a mating facility (breeding arboretum) means that selection and mating must occur as a two-step process. In this article, we describe modifications to preselection and mate selection algorithms that allow unmeasured progeny (juveniles) to be recognized. We also demonstrate that the addition of hypothetical new progeny to the juvenile pool is important for computing the increase in average co-ancestry in the population. Methods outlined in this article may have relevance to animal breeding programmes where between mating and progeny measurement, new rounds of mating are initiated. PMID- 25823838 TI - How old are quantitative trait loci and how widely do they segregate? AB - The mutations that cause genetic variation in quantitative traits could be old and segregate across many breeds or they could be young and segregate only within one breed. This has implications for our understanding of the evolution of quantitative traits and for genomic prediction to improve livestock. We investigated the age of quantitative trait loci (QTL) for milk production traits identified as segregating in Holstein dairy cattle. We use a multitrait method and found that six of 11 QTL also segregate in Jerseys. Variants identified as Holstein-only QTL were fixed or rare [minor allele frequency (MAF) < 0.05] in Jersey. The age of the QTL mutations appears to vary from perhaps 2000 to 50,000 generations old. The older QTL tend to have high derived allele frequencies and often segregate across both breeds. Holstein-only QTL were often embedded within longer haplotypes, supporting the conclusion that they are typically younger mutations that have occurred more recently than QTL that segregate in both breeds. A reference population for genomic prediction using both Holsteins and Jersey cattle incorrectly predicted a QTL in Jersey cattle when the QTL only segregates in Holsteins. Overcoming this error should help to make genomic prediction more accurate in smaller breeds. PMID- 25823839 TI - Comparison of breeding objectives across countries with application to sheep indexes in New Zealand and Ireland. AB - Breeding objectives and selection indexes underpin the direction, the extent and the economic implications of selection in livestock populations under specific production systems. The objective of this study was to describe the methodology to calculate correlations between national selection indexes and gain a deeper understanding of the factors influencing responses in economically important traits in both the New Zealand and Irish sheep industries. Moderate to strong correlations were calculated among indexes within and between countries, with the strongest correlation (0.86) between the New Zealand and Irish maternal indexes. In both countries, responses to selection in the maternal indexes are largely driven by growth traits; each index, however, has a different balance of traits. Ewe mature weight also accounts for an important proportion of overall response and has significant emphasis in both maternal indexes. The majority of emphasis in terminal indexes of both countries is on growth and meat traits. Results from this study indicate that differences between national breeding objectives are unlikely to be a barrier to exchange of gene stocks among countries. Future research should investigate the extent to which genotype-by-environment (G * E) interactions exist at the level of individual traits. The methodology presented in this study is robust and represents an opportunity to inform the potential merits of international exchange of germplasm. PMID- 25823840 TI - Community-based livestock breeding programmes: essentials and examples. AB - Breeding programmes described as community-based (CBBP) typically relate to low input systems with farmers having a common interest to improve and share their genetic resources. CBBPs are more frequent with keepers of small ruminants, in particular smallholders of local breeds, than with cattle, pigs or chickens with which farmers may have easier access to alternative programmes. Constraints that limit the adoption of conventional breeding technologies in low-input systems cover a range of organizational and technical aspects. The analysis of 8 CBBPs located in countries of Latin-America, Africa and Asia highlights the importance of bottom-up approaches and involvement of local institutions in the planning and implementation stages. The analysis also reveals a high dependence of these programmes on organizational, technical and financial support. Completely self sustained CBBPs seem to be difficult to realize. There is a need to implement and document formal socio-economic evaluations of CBBPs to provide governments and other development agencies with the information necessary for creating sustainable CBBPs at larger scales. PMID- 25823841 TI - Some aspects of design and analysis of selection programmes in aquaculture species. AB - The aquaculture industry is one of the fastest growing animal food-producing sectors in the world, largely driven by an increasing demand for high-quality protein from developing countries. However, the majority of cultured production of aquatic species currently relies heavily on the collection of wild animals for use as broodstock. Aquatic animal domestication and genetic selection programmes in controlled environments are essential to enable the provision of a continued supply of high-quality food for an ever-expanding world population. Professor John James' significant contributions to the genetic improvement of conventional livestock species are well known. By contrast, his contributions to the aquaculture industry are less well known, especially in the areas of design and conduct of selective breeding programmes in aquatic animal species. In this study, we focus on a few aspects of aquaculture genetics to which Professor James made substantial contributions. His outstanding ability to comprehend, clarify and simplify complex problems with easy-to-understand mathematical derivations is clearly demonstrated in the areas of large-scale strain comparisons, genotype-by environment interactions (GxE), transformations and interpretation of selection response, as well as in the treatment of economic aspects of designing breeding programmes. PMID- 25823842 TI - Expected influence of linkage disequilibrium on genetic variance caused by dominance and epistasis on quantitative traits. AB - Linkage disequilibrium (LD) influences the genetic variation in a quantitative trait contributed by two or more loci, with positive LD increasing the variance. The magnitude of LD also affects the relative magnitude of dominance and epistatic variation. We quantify the extent of the non-additive variance expected within populations, deriving analytical expressions for simple models and using numerical simulation in finite population more generally. As LD generates non independence among loci, a simple partition into additive, dominance and epistatic components is not possible, so we merely distinguish between additive and non-additive components based on comparing covariances among close relatives, such as full sibs, half sibs and offspring-parent. As tight linkage is needed to yield substantial LD in outbred populations, we ignore recombination in the generation used to estimate components and it is analogous to a multi-allelic model. The expected magnitude of the non-additive variance is generally increased but not greatly so by the LD in outbred populations. Thus, as found in previous studies for unlinked loci, independent of the type and strength of gene interaction, the epistatic variance contributes little to the total. PMID- 25823843 TI - Quantitative genetics of disease traits. AB - John James authored two key papers on the theory of risk to relatives for binary disease traits and the relationship between parameters on the observed binary scale and an unobserved scale of liability (James Annals of Human Genetics, 1971; 35: 47; Reich, James and Morris Annals of Human Genetics, 1972; 36: 163). These two papers are John James' most cited papers (198 and 328 citations, November 2014). They have been influential in human genetics and have recently gained renewed popularity because of their relevance to the estimation of quantitative genetics parameters for disease traits using SNP data. In this review, we summarize the two early papers and put them into context. We show recent extensions of the theory for ascertained case-control data and review recent applications in human genetics. PMID- 25823844 TI - A lactate and formate transporter in the intraerythrocytic malaria parasite, Plasmodium falciparum. AB - The intraerythrocytic malaria parasite relies primarily on glycolysis to fuel its rapid growth and reproduction. The major byproduct of this metabolism, lactic acid, is extruded into the external medium. In this study, we show that the human malaria parasite Plasmodium falciparum expresses at its surface a member of the microbial formate-nitrite transporter family (PfFNT), which, when expressed in Xenopus laevis oocytes, transports both formate and lactate. The transport characteristics of PfFNT in oocytes (pH-dependence, inhibitor-sensitivity and kinetics) are similar to those of the transport of lactate and formate across the plasma membrane of mature asexual-stage P. falciparum trophozoites, consistent with PfFNT playing a major role in the efflux of lactate and hence in the energy metabolism of the intraerythrocytic parasite. PMID- 25823845 TI - Shame Experiences Underlying Depression of Adult Turkish Women. AB - Shame is a major component of many mental health problems and affects symptoms, coping styles, remission, and therapeutic ruptures. There are few qualitative studies aimed at understanding shame and its role for patients diagnosed with depression. In this research, we explored the origins of shame, and the coping strategies that patients diagnosed with depression employ to cope with shame. This qualitative research aimed at an in-depth analysis of shame experiences of adult women who had been diagnosed with depression and treated with cognitive behavioral psychotherapy in a Women Health Center in Turkey. Purposive sampling yielded nine high shame prone adult women who were married and had children. Four semi-structured interviews were conducted with each of the nine participants, and 36 semi-structured interviews were analyzed by Interpretative Phenomenological Analysis. According to the results of the analysis, four themes emerged. These were "substitution of rage for the feeling of shame and unworthiness," "perfection struggle to overcompensate the belief of being inadequate," "feeling shame for their own body and sexual acts," and "need for individuation." The results were interpreted by considering the social context and culture of Turkey, and the clinical implications were discussed. PMID- 25823846 TI - Viewing Focus Groups Through a Critical Incident Lens. AB - Scholars often do not describe in detail the complex process of conducting focus groups, including what happens when they take unexpected turns. A critical incident lens provides a framework for better analyzing and understanding what actually happens during focus group sessions. Using a critical incident approach, we examine our experiences of carrying out focus groups about the human papillomavirus (HPV) vaccine with vaccine-eligible adolescent girls and parents/caregivers of vaccine-eligible adolescent girls in New Mexico. The critical incident lens allowed us to productively explore the context and interactional dynamics of our focus groups and ultimately pushed us to talk through the challenges of conducting and analyzing them. We hope this serves as a call to qualitative researchers to be attentive to the critical incidents in your own research to enrich your analysis and contribute to a broader discussion of the realities of focus group conduct. PMID- 25823847 TI - A cell type-specific role of protein tyrosine phosphatase non-receptor type 2 in regulating ER stress signalling. AB - BACKGROUND/AIMS: Genetic polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) have been associated with inflammatory bowel disease (IBD). A recent study demonstrated that PTPN2 regulates ER stress signalling in pancreatic beta-cells. Therefore, we investigated whether PTPN2 regulates ER stress pathways, apoptosis and cytokine secretion in human intestinal epithelial cells (IECs) and monocytes. METHODS: THP 1 and HT-29 IECs were stimulated with 2 ug/ml tunicamycin (TNM) for the indicated periods of time. For knockdown experiments, cells were transfected using a mixture of three different PTPN2-specific siRNA oligonucleotides. Cell lysates were analysed by Western blot and real-time PCR. Cytokine secretion was studied by ELISA measurements of cell culture supernatant. RESULTS: TNM treatment reduced PTPN2 protein levels in HT-29 IECs and THP-1 monocytes. Knockdown of PTPN2 in THP 1 monocytes led to an exaggerated induction of phospho-eIF2alpha, enhanced PARP cleavage, indicative of apoptosis, and attenuated IL-8 and TNF secretion upon TNM stimulation. In HT-29 cells PTPN2 deficiency caused reduced phosphorylation of eIF2alpha and PARP cleavage under ER stress conditions. CONCLUSIONS: Whereas the knockdown of PTPN2 made THP-1 cells more susceptible to ER stress, PTPN2 deficiency reduced ER stress responses in HT-29 IECs. This suggests that PTPN2 regulates adaptation to ER stress in a cell type-specific manner. PMID- 25823848 TI - The expression of DBC1/CCAR2 is associated with poor prognosis of ovarian carcinoma. AB - BACKGROUND: Recent reports have shown that deleted in breast cancer 1 (DBC1/CCAR2) is an indicator of poor prognosis of various human cancers. However, its expression in ovarian carcinoma has not been reported. METHODS: We investigated the immunohistochemical expression of DBC1 and BRCA1 and their prognostic significance in 104 ovarian carcinomas. Survival analyses were performed according to the Kaplan-Meier method, as well as univariate and multivariate Cox proportional hazard regression analysis. RESULTS: Positive expression of DBC1 and BRCA1 were seen in 63% (66/104) and 44% (46/104) of overall ovarian carcinomas, respectively. DBC1 expression was significantly associated with advanced clinicopathological factors such as high tumor stage, latent distant metastasis, platinum-resistance, elevated serum levels of CA125, high histologic grade, and BRCA1 expression. In the histological subtypes of ovarian carcinomas, DBC1 expression was more common in serous carcinoma (72%, 54/75) than mucinous carcinoma (15%, 3/20). BRCA1 expression was significantly associated with latent distant metastasis, platinum-resistance, and higher histologic grade. In addition, DBC1 expression was significantly associated with shorter overall survival (OS) and relapse-free survival (RFS) in 104 ovarian carcinomas (OS; P < 0.001, RFS; P < 0.001) and 63 high-grade serous carcinomas (OS; P = 0.008, RFS; P = 0.023) by univariate analysis. BRCA1 expression was significantly associated with OS and RFS in 104 ovarian carcinomas (OS; P = 0.005, RFS; P = 0.002) and 75 serous carcinomas (OS; P = 0.047, RFS; P = 0.038) by univariate analysis. Moreover, DBC1 expression was an independent prognostic indicator for OS in both 104 ovarian carcinomas (P = 0.021) and 63 high-grade serous carcinomas (P = 0.011) by multivariate analysis. CONCLUSIONS: These results indicate that the expression of DBC1 and BRCA1 are closely related with in the progression of ovarian carcinomas and may have clinical utility in the prediction of prognosis of ovarian carcinomas. Especially, DBC1 expression could be employed as a significant prognostic indicator for ovarian carcinomas especially in high-grade serous carcinomas. PMID- 25823849 TI - Coping with artifact in the analysis of flow cytometric data. AB - This article highlights several sources of artifact that interfere with optimal analysis of flow cytometric data. Such problems are compounded when flow cytometry is performed on mechanically and enzymatically disaggregated solid tissues or on cultured cells, where subcellular debris, apoptotic or necrotic cells, and highly autofluorescent cells may comprise a substantial proportion of acquired events. We provide real-world examples of tissues that pose specific analytical challenges (bone marrow, breast cancer, lung cancer and adipose tissue) and suggest approaches to improve data analysis. These include the use of a sequential or hierarchical gating process, which envisions analysis as consisting of three parts: (1) removal of artifact; (2) defining classifying populations; and (3) measuring outcomes on the classifying populations. Tools for removal of artifact include use of the time parameter to detect and remove fluidic perturbations, use of doublet discrimination to avoid analysis of cell clusters, measurement of DNA content to remove subcellular debris and late apoptotic cells, Boolean gating to recognize and remove auto-fluorescent events, and the use of a dump gate (markers known to be negative on the population of interest, but expressed on interfering cells). Implementation of these strategies, as appropriate, extends the usefulness of flow cytometry to a wider range of applications. PMID- 25823850 TI - Physical characterization and profiling of airway epithelial derived exosomes using light scattering. AB - Exosomes and other extracellular vesicles have been gaining interest during the last decade due to their emerging role in biology and, disease pathogenesis and their biomarker potential. Almost all published research related to exosomes and other extracellular vesicles include some form of physical characterization. Therefore, these vesicles should be precisely profiled and characterized physically before studying their biological role as intercellular messengers, biomarkers or therapeutic tools. Using a combination of light scattering techniques, including dynamic light scattering (DLS) and multi-angle laser light scattering combined with size exclusion separation (SEC-MALLS), we physically characterized and compared distinct extracellular vesicles derived from the apical secretions of two different cultured airway epithelial cells. The results indicated that epithelial cells release vesicles with distinct physical properties and sizes. Human primary tracheobronchial cell culture (HTBE) derived vesicles have a hydrodynamic radius (Rh) of approximately 340 nm while their radius of gyration (Rg) is approximately 200 nm. Electron microscopy analysis, however, revealed that their spherical component is 40-100 nm in size, and they carry filamentous, entangled membrane mucins on their surface that increases their overall radius. The mucin decoration on the surface defines their size and charge as measured using light scattering techniques. Their surface properties mirror the properties of the cells from which they are derived. This may provide a unique tool for researchers to elucidate the unanswered questions in normal airway biology and innate and adaptive defense, including the remodeling of airways during inflammation, tumorigenesis and metastasis. PMID- 25823851 TI - A hybrid classifier combining Borderline-SMOTE with AIRS algorithm for estimating brain metastasis from lung cancer: a case study in Taiwan. AB - Classifying imbalanced data in medical informatics is challenging. Motivated by this issue, this study develops a classifier approach denoted as BSMAIRS. This approach combines borderline synthetic minority oversampling technique (BSM) and artificial immune recognition system (AIRS) as global optimization searcher with the nearest neighbor algorithm used as a local classifier. Eight electronic medical datasets collected from University of California, Irvine (UCI) machine learning repository were used to evaluate the effectiveness and to justify the performance of the proposed BSMAIRS. Comparisons with several well-known classifiers were conducted based on accuracy, sensitivity, specificity, and G mean. Statistical results concluded that BSMAIRS can be used as an efficient method to handle imbalanced class problems. To further confirm its performance, BSMAIRS was applied to real imbalanced medical data of lung cancer metastasis to the brain that were collected from National Health Insurance Research Database, Taiwan. This application can function as a supplementary tool for doctors in the early diagnosis of brain metastasis from lung cancer. PMID- 25823852 TI - In vitro and in vivo drug-drug interaction of losartan and glimepiride in rats and its possible mechanism. AB - BACKGROUND: Losartan and glimepiride are commonly used drugs to treat chronic diseases of hypertension and diabetes; they are both substrates of CYP2C9. The aim of the present study was to investigate the possible interaction of losartan and glimepiride both in vitro (rat liver microsomes) and in vivo (healthy Sprague Dawley rats). METHODS: In rat liver microsomes, 1-10 MUmol/l losartan and glimepiride were coincubated, and the inhibitory effect was analyzed. In the subsequent pharmacokinetic study, 15 healthy Sprague-Dawley rats received administrations of 5 mg/kg losartan or 1 mg/kg glimepiride or a coadministration. RESULTS: In the rat liver microsome system, glimepiride showed a slight inhibition of losartan at concentrations of 1-10 MUmol/l, whereas losartan exhibited no inhibitory effect on glimepiride. In vivo, glimepiride did not modify the plasma concentration of losartan and its metabolite E-3174. The alteration of an increased AUC and Cmax was observed in the pharmacokinetic parameters of glimepiride and hydroxy glimepiride. CONCLUSIONS: Glimepiride did not affect losartan pharmacokinetics in rats, while losartan potently altered glimepiride metabolism; this result was inconsistent with the in vitro outcome. The mechanism requires further investigation. In clinical settings, attention should be paid to the interaction of these two drugs in the human body as well as the possible adverse reactions of glimepiride. PMID- 25823853 TI - Microparticle source and tissue factor expression in pregnancy. AB - Microparticles (MPs) bearing tissue factor (TF) are potent activators of the coagulation system. To investigate whether MPs originating from platelets or trophoblast cells contribute to coagulation changes in pregnancy, we aimed to characterize whether pregnancy, labor, and delivery are associated with changes in the origin and composition of circulating maternal MPs. We performed a prospective cohort study. Blood samples were collected in 20 non-pregnant women, 20 term pregnant women not in labor, and 20 term pregnant women in labor. Two samples were collected in the pregnant groups, the first prior to delivery and the second 1 h after delivery. MPs from platelets and trophoblasts and MPs expressing TF were identified using flow cytometry. Comparisons were made among the non-pregnant and pregnant groups, non-laboring and laboring groups, and predelivery and postdelivery values within the pregnant groups. Pregnancy was not associated with changes in MP origin or number of TF-expressing MPs. Neither labor nor delivery was associated with changes in the percentage of trophoblast derived MPs in the pregnant groups. The percentage of platelet-derived MPs among laboring women increased after delivery (8.5 vs. 20.5 %, p = 0.02), although there was no difference with delivery in the non-laboring group. TF expression was not associated with delivery in either laboring or non-laboring women. In conclusion, pregnancy was not associated with changes in cell origin of circulating maternal MPs or in the number of TF-expressing MPs. However, labor and delivery appear to be associated with an increase in the number of platelet derived MPs. PMID- 25823854 TI - Production of bacterial cellulose membranes in a modified airlift bioreactor by Gluconacetobacter xylinus. AB - In this study, a novel bioreactor for producing bacterial cellulose (BC) is proposed. Traditional BC production uses static culture conditions and produces a gelatinous membrane. The potential for using various types of bioreactor, including a stirred tank, conventional airlift, and modified airlift with a rectangular wire-mesh draft tube, in large-scale production has been investigated. The BC obtained from these bioreactors is fibrous or in pellet form. Our proposed airlift bioreactor produces a membrane-type BC from Gluconacetobacter xylinus, the water-holding capacity of which is greater than that of cellulose types produced using static cultivation methods. The Young's modulus of the product can be manipulated by varying the number of net plates in the modified airlift bioreactor. The BC membrane produced using the proposed bioreactor exhibits potential for practical application. PMID- 25823855 TI - Altered organization of face-processing networks in temporal lobe epilepsy. AB - OBJECTIVE: Deficits in social cognition are common and significant in people with temporal lobe epilepsy (TLE), but the functional and structural underpinnings remain unclear. The present study investigated how the side of seizure focus impacts face-processing networks in temporal lobe epilepsy. METHODS: We used functional magnetic resonance imaging (fMRI) of a face-processing paradigm to identify face-responsive regions in 24 individuals with unilateral temporal lobe epilepsy (left = 15; right = 9) and 19 healthy controls. fMRI signals of face responsive regions ipsilateral and contralateral to the side of seizure onset were delineated in TLE and compared to the healthy controls with right and left sides combined. Diffusion tensor images were acquired to investigate structural connectivity between face regions that differed in fMRI signals between the two groups. RESULTS: In TLE, activation of the cortical face-processing networks varied according to side of seizure onset. In temporal lobe epilepsy, the laterality of amygdala activation was shifted to the side contralateral to the seizure focus, whereas controls showed no significant asymmetry. Furthermore, compared to controls, patients with TLE showed decreased activation of the occipital face-responsive region on the ipsilateral side and an increased activity of the anterior temporal lobe in the side contralateral to the seizure focus. Probabilistic tractography revealed that the occipital face area and anterior temporal lobe are connected via the inferior longitudinal fasciculus, which in individuals with TLE showed reduced integrity. SIGNIFICANCE: Taken together, these findings suggest that brain function and white matter integrity of networks subserving face processing are impaired on the side of seizure onset, accompanied by altered responses on the side contralateral to the seizure. PMID- 25823856 TI - EEG biomarkers of target engagement, therapeutic effect, and disease process. AB - Studies suggest that abnormalities in glutamate and GABA signaling contribute to deficits in schizophrenia and related conditions and that these neurochemical abnormalities produce changes in electroencephalographic (EEG) indices, including event-related potentials and event-related power within specific frequency ranges. Furthermore, clinical studies suggest that a subset of EEG biomarkers is associated with symptoms. This review addresses the relationship between EEG and behavior in preclinical models of N-methyl-d-aspartate (NMDA)-receptor hypofunction, as well as how these models can be used to screen therapies. Data from schizophrenia patients are juxtaposed with data from animal models, and EEG and behavioral data from mice with disruption of NMDA receptors in excitatory and/or inhibitory neurons are then compared to the pattern observed in schizophrenia. Also discussed are results following exposure to potential therapeutic agents, including GABAB agonists. Furthermore, evidence demonstrates that elevated resting gamma power is associated with deficits in social interactions. Consistent with elevated baseline noise, excitatory neurons from transgenic mice show increased intrinsic excitability in in vitro-slice patch clamp studies across model systems. GABAB receptor agonists reduce this excitability, improve gamma-band responses, and reverse behavioral deficits in mice. Data suggest that baseline gamma power is associated with social function and GABAB agonists may be useful for schizophrenia. Translational EEG biomarkers reflect target engagement and can contribute to the design of more efficient drug trials, likely accelerating the development of new therapeutics for central nervous system disorders. PMID- 25823857 TI - The Effect of Clothing on the Rate of Decomposition and Diptera Colonization on Sus scrofa Carcasses. AB - Twenty Sus scrofa carcasses were used to study the effect the presence of clothing had on decomposition rate and colonization locations of Diptera species; 10 unclothed control carcasses were compared to 10 clothed experimental carcasses over 58 days. Data collection occurred at regular accumulated degree day intervals; the level of decomposition as Total Body Score (TBSsurf ), pattern of decomposition, and Diptera present was documented. Results indicated a statistically significant difference in the rate of decomposition, (t427 = 2.59, p = 0.010), with unclothed carcasses decomposing faster than clothed carcasses. However, the overall decomposition rates from each carcass group are too similar to separate when applying a 95% CI, which means that, although statistically significant, from a practical forensic point of view they are not sufficiently dissimilar as to warrant the application of different formulae to estimate the postmortem interval. Further results demonstrated clothing provided blow flies with additional colonization locations. PMID- 25823858 TI - Early pulmonary inflammation and lung damage in children with cystic fibrosis. AB - Individuals with cystic fibrosis (CF) suffer progressive airway inflammation, infection and lung damage. Airway inflammation and infection are present from early in life, often before children are symptomatic. CF gene mutations cause changes in the CF transmembrane regulator protein that result in an aberrant airway microenvironment including airway surface liquid (ASL) dehydration, reduced ASL acidity, altered airway mucin and a dysregulated inflammatory response. This review discusses how an altered microenvironment drives CF lung disease before overt airway infection, the response of the CF airway to early infection, and methods to prevent inflammation and early lung disease. PMID- 25823859 TI - Fluorescein gonioangiography of the normal canine eye using a dSLR camera adaptor. AB - The purpose of this study was to describe fluorescein gonioangiography (FGA) of the normal canine eye using a digital single lens reflex (dSLR) camera adaptor. Dogs were anesthetized using intravenous propofol. Imaging was performed using a Lovac Barkan goniolens, dSLR camera, dSLR camera adaptor, camera lens, and accessory flash. Twelve dogs with a mean age of 2.0 +/- 0.8 years were imaged. No characteristic angiographic phases were observed. Leakage from the peri-limbal capillary network was a common finding and occurred 7.7 +/- 2.2 s post injection in 9 (75%) dogs. In 3 (25%) dogs, filling of the circumferential ciliary artery was observed 10.3 +/- 2.8 s post injection. Dye leakage within the iris base and into the aqueous humor was demonstrated in 4 (33%) and 6 dogs (50%) respectively. No adverse events were noted. This study demonstrates FGA findings in normal canine eyes using a cost effective dSLR camera adaptor. PMID- 25823861 TI - Nomenclature for diseases with IgA antikeratinocyte cell surface autoantibodies. PMID- 25823860 TI - Comparative studies on proliferation, molecular markers and differentiation potential of mesenchymal stem cells from various tissues (adipose, bone marrow, ear skin, abdominal skin, and lung) and maintenance of multipotency during serial passages in miniature pig. AB - Mesenchymal stem cells (MSCs) have the ability to differentiate into multi lineage cells, which confers great promise for use in regenerative medicine. In this study, MSCs were isolated from adipose tissue, bone marrow, ear skin, lung, and abdominal skin of miniature pigs (mpMSCs), and the optimal medium (DMEM/F12 Glutamax) was selected for the culturing of mpMSCs. As a result, proliferation of the mpMSCs derived from all tissues was steadily increased when cultured with DMEM/F12-Glutamax during 14 consecutive passages. The cells harbored MSC surface markers (CD34-, CD45-, CD29+, CD44+, CD90+, and CD105+), whose levels of expression differed among the tissue sources and declined over sub-passaging. In addition, the expression of stemness markers (Oct4, Sox2, and Nanog) and differentiation into mesoderm (adipocytes, chondrocytes, and osteoblasts) were clearly represented at early passage; however, expression of stemness markers decreased, and differentiation potential was lost over sequential sub-passaging, which should be considered in the selection of mpMSC for MSC-based application. PMID- 25823862 TI - Introduction to the theme issue 'Cerebral cartography: a vision of its future'. PMID- 25823863 TI - The BRAIN Initiative: developing technology to catalyse neuroscience discovery. AB - The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade. Capitalizing on this momentum, the United States launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to develop and apply new tools and technologies for revolutionizing our understanding of the brain. In this article, we review the scientific vision for this initiative set forth by the National Institutes of Health and discuss its implications for the future of neuroscience research. Particular emphasis is given to its potential impact on the mapping and study of neural circuits, and how this knowledge will transform our understanding of the complexity of the human brain and its diverse array of behaviours, perceptions, thoughts and emotions. PMID- 25823864 TI - Dwelling quietly in the rich club: brain network determinants of slow cortical fluctuations. AB - For more than a century, cerebral cartography has been driven by investigations of structural and morphological properties of the brain across spatial scales and the temporal/functional phenomena that emerge from these underlying features. The next era of brain mapping will be driven by studies that consider both of these components of brain organization simultaneously--elucidating their interactions and dependencies. Using this guiding principle, we explored the origin of slowly fluctuating patterns of synchronization within the topological core of brain regions known as the rich club, implicated in the regulation of mood and introspection. We find that a constellation of densely interconnected regions that constitute the rich club (including the anterior insula, amygdala and precuneus) play a central role in promoting a stable, dynamical core of spontaneous activity in the primate cortex. The slow timescales are well matched to the regulation of internal visceral states, corresponding to the somatic correlates of mood and anxiety. In contrast, the topology of the surrounding 'feeder' cortical regions shows unstable, rapidly fluctuating dynamics likely to be crucial for fast perceptual processes. We discuss these findings in relation to psychiatric disorders and the future of connectomics. PMID- 25823865 TI - Consciousness: here, there and everywhere? AB - The science of consciousness has made great strides by focusing on the behavioural and neuronal correlates of experience. However, while such correlates are important for progress to occur, they are not enough if we are to understand even basic facts, for example, why the cerebral cortex gives rise to consciousness but the cerebellum does not, though it has even more neurons and appears to be just as complicated. Moreover, correlates are of little help in many instances where we would like to know if consciousness is present: patients with a few remaining islands of functioning cortex, preterm infants, non mammalian species and machines that are rapidly outperforming people at driving, recognizing faces and objects, and answering difficult questions. To address these issues, we need not only more data but also a theory of consciousness-one that says what experience is and what type of physical systems can have it. Integrated information theory (IIT) does so by starting from experience itself via five phenomenological axioms: intrinsic existence, composition, information, integration and exclusion. From these it derives five postulates about the properties required of physical mechanisms to support consciousness. The theory provides a principled account of both the quantity and the quality of an individual experience (a quale), and a calculus to evaluate whether or not a particular physical system is conscious and of what. Moreover, IIT can explain a range of clinical and laboratory findings, makes a number of testable predictions and extrapolates to a number of problematic conditions. The theory holds that consciousness is a fundamental property possessed by physical systems having specific causal properties. It predicts that consciousness is graded, is common among biological organisms and can occur in some very simple systems. Conversely, it predicts that feed-forward networks, even complex ones, are not conscious, nor are aggregates such as groups of individuals or heaps of sand. Also, in sharp contrast to widespread functionalist beliefs, IIT implies that digital computers, even if their behaviour were to be functionally equivalent to ours, and even if they were to run faithful simulations of the human brain, would experience next to nothing. PMID- 25823866 TI - Cerebral hierarchies: predictive processing, precision and the pulvinar. AB - This paper considers neuronal architectures from a computational perspective and asks what aspects of neuroanatomy and neurophysiology can be disclosed by the nature of neuronal computations? In particular, we extend current formulations of the brain as an organ of inference--based upon hierarchical predictive coding- and consider how these inferences are orchestrated. In other words, what would the brain require to dynamically coordinate and contextualize its message passing to optimize its computational goals? The answer that emerges rests on the delicate (modulatory) gain control of neuronal populations that select and coordinate (prediction error) signals that ascend cortical hierarchies. This is important because it speaks to a hierarchical anatomy of extrinsic (between region) connections that form two distinct classes, namely a class of driving (first-order) connections that are concerned with encoding the content of neuronal representations and a class of modulatory (second-order) connections that establish context-in the form of the salience or precision ascribed to content. We explore the implications of this distinction from a formal perspective (using simulations of feature-ground segregation) and consider the neurobiological substrates of the ensuing precision-engineered dynamics, with a special focus on the pulvinar and attention. PMID- 25823867 TI - The brain timewise: how timing shapes and supports brain function. AB - We discuss the importance of timing in brain function: how temporal dynamics of the world has left its traces in the brain during evolution and how we can monitor the dynamics of the human brain with non-invasive measurements. Accurate timing is important for the interplay of neurons, neuronal circuitries, brain areas and human individuals. In the human brain, multiple temporal integration windows are hierarchically organized, with temporal scales ranging from microseconds to tens and hundreds of milliseconds for perceptual, motor and cognitive functions, and up to minutes, hours and even months for hormonal and mood changes. Accurate timing is impaired in several brain diseases. From the current repertoire of non-invasive brain imaging methods, only magnetoencephalography (MEG) and scalp electroencephalography (EEG) provide millisecond time-resolution; our focus in this paper is on MEG. Since the introduction of high-density whole-scalp MEG/EEG coverage in the 1990s, the instrumentation has not changed drastically; yet, novel data analyses are advancing the field rapidly by shifting the focus from the mere pinpointing of activity hotspots to seeking stimulus- or task-specific information and to characterizing functional networks. During the next decades, we can expect increased spatial resolution and accuracy of the time-resolved brain imaging and better understanding of brain function, especially its temporal constraints, with the development of novel instrumentation and finer-grained, physiologically inspired generative models of local and network activity. Merging both spatial and temporal information with increasing accuracy and carrying out recordings in naturalistic conditions, including social interaction, will bring much new information about human brain function. PMID- 25823868 TI - The future of human cerebral cartography: a novel approach. AB - Cerebral cartography can be understood in a limited, static, neuroanatomical sense. Temporal information from electrical recordings contributes information on regional interactions adding a functional dimension. Selective tagging and imaging of molecules adds biochemical contributions. Cartographic detail can also be correlated with normal or abnormal psychological or behavioural data. Modern cerebral cartography is assimilating all these elements. Cartographers continue to collect ever more precise data in the hope that general principles of organization will emerge. However, even detailed cartographic data cannot generate knowledge without a multi-scale framework making it possible to relate individual observations and discoveries. We propose that, in the next quarter century, advances in cartography will result in progressively more accurate drafts of a data-led, multi-scale model of human brain structure and function. These blueprints will result from analysis of large volumes of neuroscientific and clinical data, by a process of reconstruction, modelling and simulation. This strategy will capitalize on remarkable recent developments in informatics and computer science and on the existence of much existing, addressable data and prior, though fragmented, knowledge. The models will instantiate principles that govern how the brain is organized at different levels and how different spatio temporal scales relate to each other in an organ-centred context. PMID- 25823870 TI - Cerebral cartography and connectomics. AB - Cerebral cartography and connectomics pursue similar goals in attempting to create maps that can inform our understanding of the structural and functional organization of the cortex. Connectome maps explicitly aim at representing the brain as a complex network, a collection of nodes and their interconnecting edges. This article reflects on some of the challenges that currently arise in the intersection of cerebral cartography and connectomics. Principal challenges concern the temporal dynamics of functional brain connectivity, the definition of areal parcellations and their hierarchical organization into large-scale networks, the extension of whole-brain connectivity to cellular-scale networks, and the mapping of structure/function relations in empirical recordings and computational models. Successfully addressing these challenges will require extensions of methods and tools from network science to the mapping and analysis of human brain connectivity data. The emerging view that the brain is more than a collection of areas, but is fundamentally operating as a complex networked system, will continue to drive the creation of ever more detailed and multi-modal network maps as tools for on-going exploration and discovery in human connectomics. PMID- 25823869 TI - The restless brain: how intrinsic activity organizes brain function. AB - Traditionally studies of brain function have focused on task-evoked responses. By their very nature such experiments tacitly encourage a reflexive view of brain function. While such an approach has been remarkably productive at all levels of neuroscience, it ignores the alternative possibility that brain functions are mainly intrinsic and ongoing, involving information processing for interpreting, responding to and predicting environmental demands. I suggest that the latter view best captures the essence of brain function, a position that accords well with the allocation of the brain's energy resources, its limited access to sensory information and a dynamic, intrinsic functional organization. The nature of this intrinsic activity, which exhibits a surprising level of organization with dimensions of both space and time, is revealed in the ongoing activity of the brain and its metabolism. As we look to the future, understanding the nature of this intrinsic activity will require integrating knowledge from cognitive and systems neuroscience with cellular and molecular neuroscience where ion channels, receptors, components of signal transduction and metabolic pathways are all in a constant state of flux. The reward for doing so will be a much better understanding of human behaviour in health and disease. PMID- 25823872 TI - Brain/MINDS: brain-mapping project in Japan. AB - There is an emerging interest in brain-mapping projects in countries across the world, including the USA, Europe, Australia and China. In 2014, Japan started a brain-mapping project called Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS). Brain/MINDS aims to map the structure and function of neuronal circuits to ultimately understand the vast complexity of the human brain, and takes advantage of a unique non-human primate animal model, the common marmoset (Callithrix jacchus). In Brain/MINDS, the RIKEN Brain Science Institute acts as a central institute. The objectives of Brain/MINDS can be categorized into the following three major subject areas: (i) structure and functional mapping of a non-human primate brain (the marmoset brain); (ii) development of innovative neurotechnologies for brain mapping; and (iii) human brain mapping; and clinical research. Brain/MINDS researchers are highly motivated to identify the neuronal circuits responsible for the phenotype of neurological and psychiatric disorders, and to understand the development of these devastating disorders through the integration of these three subject areas. PMID- 25823873 TI - Evaluation of risk-factor-based screening for thyroid peroxidase antibody positivity in pregnancy. AB - OBJECTIVE: To determine whether risk-factor-based screening for thyroid dysfunction in pregnancy performs well for detecting thyroid peroxidase antibodies (TPOAb), a marker for autoimmune thyroid disease. STUDY DESIGN: We prospectively evaluated pregnant women for thyroid dysfunction using The Endocrine Society's eleven screening questions. Serum was analysed for TPOAb. RESULT: We enrolled 546 women. TPOAb positivity was higher in women with a personal (odds ratio (OR) = 8.0; 95% confidence interval (CI) = 1.7-37.4; P = 0.02) or family history of thyroid disease (OR = 2.7; 95% CI = 1.3-5.7; P = 0.02). There was no association between the number of positive responses and TPOAb positivity (P = 0.41). Risk-factor-based screening missed 18 women (33%) with TPOAb. CONCLUSION: One-third of women with TPOAb were missed by the case finding method. A personal or family history of thyroid disease was most strongly associated with TPOAb positivity. PMID- 25823871 TI - A massively asynchronous, parallel brain. AB - Whether the visual brain uses a parallel or a serial, hierarchical, strategy to process visual signals, the end result appears to be that different attributes of the visual scene are perceived asynchronously--with colour leading form (orientation) by 40 ms and direction of motion by about 80 ms. Whatever the neural root of this asynchrony, it creates a problem that has not been properly addressed, namely how visual attributes that are perceived asynchronously over brief time windows after stimulus onset are bound together in the longer term to give us a unified experience of the visual world, in which all attributes are apparently seen in perfect registration. In this review, I suggest that there is no central neural clock in the (visual) brain that synchronizes the activity of different processing systems. More likely, activity in each of the parallel processing-perceptual systems of the visual brain is reset independently, making of the brain a massively asynchronous organ, just like the new generation of more efficient computers promise to be. Given the asynchronous operations of the brain, it is likely that the results of activities in the different processing perceptual systems are not bound by physiological interactions between cells in the specialized visual areas, but post-perceptually, outside the visual brain. PMID- 25823874 TI - Absolute quantification of DcR3 and GDF15 from human serum by LC-ESI MS. AB - Biomarkers are widely used in clinical diagnosis, prognosis and therapy monitoring. Here, we developed a protocol for the efficient and selective enrichment of small and low concentrated biomarkers from human serum, involving a 95% effective depletion of high-abundant serum proteins by partial denaturation and enrichment of low-abundant biomarkers by size exclusion chromatography. The recovery of low-abundance biomarkers was above 97%. Using this protocol, we quantified the tumour markers DcR3 and growth/differentiation factor (GDF)15 from 100 MUl human serum by isotope dilution mass spectrometry, using (15) N metabolically labelled and concatamerized fingerprint peptides for the both proteins. Analysis of three different fingerprint peptides for each protein by liquid chromatography electrospray ionization mass spectrometry resulted in comparable concentrations in three healthy human serum samples (DcR3: 27.23 +/- 2.49 fmol/ml; GDF15: 98.11 +/- 0.49 fmol/ml). In contrast, serum levels were significantly elevated in tumour patients for DcR3 (116.94 +/- 57.37 fmol/ml) and GDF15 (164.44 +/- 79.31 fmol/ml). Obtained data were in good agreement with ELISA and qPCR measurements, as well as with literature data. In summary, our protocol allows the reliable quantification of biomarkers, shows a higher resolution at low biomarker concentrations than antibody-based strategies, and offers the possibility of multiplexing. Our proof-of-principle studies in patient sera encourage the future analysis of the prognostic value of DcR3 and GDF15 for colon cancer patients in larger patient cohorts. PMID- 25823875 TI - A one-dimensional coordination polymer based on Cu3-oximato metallacrowns bridged by benzene-1,4-dicarboxylato ligands: structure and magnetic properties. AB - A one-dimensional linear coordination polymer {[Cu3(MU3-OH)(2 pyao)3(bdc)].6(H2O)}n () composed of trinuclear [Cu3(MU3-OH)(2-pyao)3](2+) metallacrown cores bridged by bis-carboxylato linkers has been obtained by treatment of copper(ii) fluoride with pyridine-2-aldoxime (2-pyaoH) ligand and benzene-1,4-dicarboxylic acid (H2bdc). Magnetic susceptibility measurements show strong antiferromagnetic interactions between Cu(ii) centers within the trinuclear metallacrown core with J = -430 cm(-1). PMID- 25823876 TI - A novel photochemical cross-linking technology to improve luminal gain, vessel compliance, and buckling post-angioplasty in porcine arteries. AB - Development of substituted 1,8-naphthalimides for photochemical cross-linking of biomolecules is the focus of this research. This study describes limited cross linking of collagen in the artery wall to control recoil and buckling in arteries following balloon angioplasty. Isolated porcine arteries were overstretched (25%) with balloon angioplasty (BA) +/- light-activated naphthalimide treatment (NVS). Lumen size and recoil were measured as retention of stretch after angioplasty. Cross-sectional compliance and distensibility coefficients were measured as slope of cross-sectional area versus increasing hydrostatic pressure. Buckling was measured, with 30% axial pre-stretch and 200 mmHg, as deviation from the center line. Electron microscopy evaluation of collagen fibers was conducted. RESULTS: Uninjured arteries have low compliance and low levels of buckling, whereas the BA injured arteries demonstrated much greater compliance and buckling behavior. Treatment of the injured artery with NVS reduced buckling and demonstrated compliance midway between the two groups while retaining the increased luminal diameter imparted by angioplasty compared to untreated vessels. In summary, limited collagen cross-linking with NVS treatment resulted in lumen retention, as well as improved compliance without the accompanying rigidity and stiffness of conventional stent therapy or current cross-linking materials. This treatment shows great promise for dilation, repair and strengthening of arteries damaged by injury or vascular disease. PMID- 25823877 TI - Successful use of N-acetylcysteine to treat severe hepatic injury caused by a dietary fitness supplement. AB - In the absence of adequate premarketing efficacy and safety evaluations, adverse events from over-the-counter supplements are emerging as a public health concern. Specifically, bodybuilding products are being identified as a frequent cause of drug-induced liver injury. We present a case of a 20-year-old Hispanic male who presented with acute nausea and vomiting accompanied by severe right upper quadrant abdominal pain, shivering, and shortness of breath. Laboratory data pointed to mixed cholestatic and hepatocellular damage, and after exclusion of known alternate etiologies, the patient was diagnosed with acute drug-induced liver injury secondary to the use of "Friction," a bodybuilding supplement. Treatment with N-acetylcysteine (NAC) 20% oral solution was initiated empirically at a dose of 4000 mg [DOSAGE ERROR CORRECTED] (70 mg/kg) every 4 hours and was continued once the diagnosis was made. Within 48 hours of admission to our hospital, the patient began to show clinical resolution of right abdominal pain and tolerance to oral diet associated with a significant decline toward normal in his liver function tests and coagulopathy. The WHO-UMC causality assessment system suggested a "certain causality" between exposure to the supplement and the acute liver injury. In the event of suspected drug-induced liver injury, treatment with NAC should be considered given its favorable risk-benefit profile. PMID- 25823879 TI - Fluorescence resonance energy transfer in a binary organic nanoparticle system and its application. AB - Fluorescent organic nanoparticles have a much better photostability than molecule based probes. Here, we report a simple strategy to detect chemicals and biomolecules by a binary nanoparticle system based on fluorescence resonance energy transfer (FRET). Poly(9,9-di-n-octylfluorenyl-2,7-diyl) (PFO, energy donor) and poly [2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV, energy acceptor) are utilized to prepare the binary nanoparticle system through a reprecipitation method. Since the FRET process is strongly distance-dependent, a change in the interparticle distance between the two kinds of nanoparticles after introduction of analytes will alter the FRET efficiency. The response of the binary nanoparticle system to cationic polyelectrolytes was investigated by monitoring the FRET efficiency from PFO to MEH-PPV nanoparticles and the fluorescence color of the nanoparticle solutions. Furthermore, the cationic polyelectrolyte pretreated binary nanoparticle system can be used to detect DNA by desorption of nanoparticles from the polyelectrolyte's chains and the detection concentration can go down to 10(-14) M. Thus, the binary nanoparticle system shows great promise for applications in chemical sensing or biosensing. PMID- 25823878 TI - Rapid blood group genotyping by allelic discriminative real-time PCR in multiply transfused patients. PMID- 25823880 TI - Single molecule studies of a ladder type conjugated polymer: vibronic spectra, line widths, and energy transfer. AB - Confocal fluorescence microscopy and spectroscopy are employed to investigate single poly(ladder-type pentaphenylene) (LPPentP) molecules dispersed in thin poly(methyl methacrylate) (PMMA) films at 1.2 K. Emission spectra of single chains show single as well as multi-chromophore emission indicating variegated communication along the chains. The vibronic structure in the emission spectra resembles the one found for other ladder-type polymers. Purely electronic zero phonon lines in emission are substantially broadened, most probably due to fast spectral diffusion. By surmounting the limitations of emission spectroscopy, nonemitting donor chromophores, which transfer their excitation energy in a radiationless manner to emitting chromophores, are accessed by excitation spectroscopy. Remarkably, by comparing the data of emitting and nonemitting chromophores a contribution to the zero-phonon excitation line width has to be considered which places a lower limit on the estimated energy transfer time of several picoseconds between adjacent chromophores. Finally, the data indicate qualitatively a restricted flexibility of LPPentP compared to poly[2-methoxy-5 (2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV). PMID- 25823883 TI - Revisiting the assembly of amino ester-based benzene-1,3,5-tricarboxamides: chiral rods in solution. AB - Some benzene-1,3,5-tricarboxamide (BTA) monomers derived from (l) alpha-amino esters self-assemble into long rods at millimolar concentrations, and display a strong chiral amplification effect. These rods are in competition with dimeric species. PMID- 25823882 TI - Analysis of Quality-Related Parameters in Mature Kernels of Polygalacturonase Inhibiting Protein (PGIP) Transgenic Bread Wheat Infected with Fusarium graminearum. AB - Fusarium head blight, caused by the fungus Fusarium graminearum, has a detrimental effect on both productivity and qualitative properties of wheat. To evaluate its impact on wheat flour, we compared its effect on quality-related parameters between a transgenic bread wheat line expressing a bean polygalacturonase inhibiting protein (PGIP) and its control line. We have compared metabolic proteins, the amounts of gluten proteins and their relative ratios, starch content, yield, extent of pathogen contamination, and deoxynivalenol (DON) accumulation. These comparisons showed that Fusarium significantly decreases the amount of starch in infected control plants, but not in infected PGIP plants. The flour of PGIP plants contained also a lower amount of pathogen biomass and DON accumulation. Conversely, both gluten and metabolic proteins were not significantly influenced either by the transgene or by fungal infection. These results indicate that the transgenic PGIP expression reduces the level of infection, without changing significantly the wheat seed proteome and other quality-related parameters. PMID- 25823884 TI - Re-evaluating birds' ability to detect Glass patterns. AB - Glass patterns (GPs) are static stimuli that consist of randomly positioned dot pairs that are spatially integrated to create the perception of a global form. However, when multiple independently generated static GPs are presented sequentially (termed 'dynamic' GP), observers report a percept of coherent motion, and data show an improvement in sensitivity. This increased sensitivity has been attributed to a summation of the form signals provided by the individual GPs. In Experiment 1, we tested whether pigeons also show a heightened sensitivity to dynamic GPs. Our results show that pigeons are significantly better at learning to discriminate dynamic GPs from noise compared with static GPs. However, in contrast to previous research, we found that pigeons did not perform well enough with our static GPs to extract sensitivity measurements. In Experiment 2, we compared our static GPs to those that have been used previously. We show that the difference in the comparison noise patterns is important. We used dipole noise patterns, while previous studies used uniform noise patterns that differ in mean dot spacing to the S+. We argue that prior findings from the use of GPs in pigeons should be re-evaluated using dynamic GP stimuli with noise that consist of dipoles. PMID- 25823886 TI - Ability to work in anaerobic condition is associated with physical performance on the six-minute walk test in older patients receiving cardiac rehabilitation. AB - OBJECTIVE: During maximal incremental exercise, the ability to work in the anaerobic condition, expressed by the respiratory exchange ratio, is associated with physical performance. Further, peak respiratory exchange ratio is regarded as the best non-invasive measure of a patient's actual exercise effort. This study examined whether ability to work in the anaerobic condition is also associated with physical performance in submaximal constant work rate exercise. SUBJECTS AND METHODS: A total of 75 older patients (51 men, 24 women), mean age 71.1 years (standard deviation 6.7 years), who had recently undergone cardiac surgery, performed cardiopulmonary exercise testing in a 6-min walk test before and after rehabilitation. RESULTS: The distance walked, steady-state oxygen uptake, carbon dioxide output and respiratory exchange ratio increased significantly after rehabilitation (p < 0.001 for all). In multivariable models predicting the distance walked before and after rehabilitation, higher steady state respiratory exchange ratio was independently associated with longer distance (p < 0.001 for both). CONCLUSION: In older patients receiving post-acute cardiac rehabilitation the ability to work in the anaerobic condition is associated with physical performance in submaximal constant work rate exercises. Thus the steady-state respiratory exchange ratio might be regarded as a measure of the patient's actual exercise effort. This information may prove useful in customizing exercise prescription and assessing the effects of rehabilitation. PMID- 25823887 TI - In situ investigation of the surface morphology evolution of the bulk ceramic Y2Mo3O12 during crystal water release. AB - The surface morphology evolution of the bulk ceramic Y2Mo3O12 during the release of crystal water is followed in situ for the first time using atomic force microscopy. It is found that both the shape and size of individual grains and the integration morphology of the sample exhibit dynamic changes with increasing temperature. We believe that the surface morphology evolution of the sample with increasing temperature is closely correlated with the forces induced by the contraction and expansion of the lattice during crystal water release in two different stages. PMID- 25823885 TI - Response-adapted therapy for aggressive non-Hodgkin's lymphomas based on early [18F] FDG-PET scanning: ECOG-ACRIN Cancer Research Group study (E3404). AB - A persistently positive positron emission tomography (PET) scan during therapy for diffuse large B-cell lymphoma (DLBCL) is predictive of treatment failure. A response-adapted strategy consisting of an early treatment change to four cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) was studied in the Eastern Cooperative Oncology Group E3404 trial. Previously untreated patients with DLBCL stage III, IV, or bulky II, were eligible. PET scan was performed after three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and scored as positive or negative by central review during the fourth cycle. PET-positive patients received four cycles of R-ICE, PET negative patients received two more cycles of R-CHOP. A >= 45% 2-year progression free survival (PFS) for mid-treatment PET-positive patients was viewed as promising. Of 74 patients, 16% were PET positive, 79% negative. The PET positivity rate was much lower than the 33% expected. Two-year PFS was 70%; 42% [90% confidence interval (CI), 19-63%] for PET-positives and 76% (90% CI 65-84%) for PET-negatives. Three-year overall survival (OS) was 69% (90% CI 43-85%) and 93% (90% CI 86-97%) for PET-positive and -negative cases, respectively. The 2 year PFS for mid-treatment PET-positive patients intensified to R-ICE was 42%, with a wide confidence interval due to the low proportion of positive mid treatment PET scans. Treatment modification based on early PET scanning should remain confined to clinical trials. PMID- 25823888 TI - Estimation of pressure-, temperature- and frictional heating-related effects on proteins' retention under ultra-high-pressure liquid chromatographic conditions. AB - The goal of this work was to evaluate the changes in retention induced by frictional heating, pressure and temperature under ultra high pressure liquid chromatography (UHPLC) conditions, for four model proteins (i.e. lysozyme, myoglobin, fligrastim and interferon alpha-2A) possessing molecular weights between 14 and 20kDa. First of all, because the decrease of the molar volume upon adsorption onto a hydrophobic surface was more pronounced for large molecules such as proteins, the impact of pressure appears to overcome the frictional heating effects. Nevertheless, we have also demonstrated that the retention decrease due to frictional heating was not negligible with such large biomolecules in the variable inlet pressure mode. Secondly, it is clearly shown that the modification of retention under various pressure and temperature conditions cannot be explained solely by the frictional heating and pressure effects. Indeed, some very uncommon van't Hoff plots (concave plots with a maximum) were recorded for our model/therapeutic proteins. These maximum retention factors values on the van't Hoff plots indicate a probable change of secondary structure/conformation with pressure and temperature. Based on these observations, it seems that the combination of pressure and temperature causes the protein denaturation and this folding-unfolding procedure is clearly protein dependent. PMID- 25823889 TI - Patients Older Than 65 Years With Non-Hodgkin Lymphoma Are Suitable for Treatment With (90)Yttrium-Ibritumumab Tiuxetan: A Single-Institution Experience. AB - BACKGROUND: The mean age of patients included in clinical trials does not reflect the current clinical practice for patients with B-cell non-Hodgkin lymphoma (B NHL). We compared our outcomes for patients with B-NHL aged < 65 and > 65 years who were treated with 90-yttrium-ibritumomab tiuxetan therapy ((90)Y-IT). PATIENTS AND METHODS: A total of 108 patients who had received (90)Y-IT according to the hospital protocol (ISCRTN36210045) were eligible. A quality of life (QoL) assessment using the Medical Outcomes Study short form 36-item survey was performed for patients aged > 65 years. RESULTS: Of the 108 patients, 43 were aged > 65 years (mean age, 73.4 years; men 46.15%); 37 had follicular NHL (86.0%). Also, 27 patients had previously undergone < 2 therapy regimens (62.8%). The mean follow-up period was 45.2 months. The mean progression-free survival (PFS) period was 71.3 months, and the mean overall survival was 78.2 months. The median values were not reached. The overall response rate was 90.5%, and a complete response was observed in 36 of the 43 patients aged > 65 years (85.7%). Neutropenia (43.3%) and thrombocytopenia (45.2%) were the most frequent grade 3 and 4 toxicities. Five patients required a red blood cell transfusion and 11, a platelet transfusion. Five patients aged > 65 years (11.6%) developed a second tumor. These outcomes were similar to those for the younger patients. The QoL assessment showed scores similar to those of general population for general health and social functioning. CONCLUSION: This is the largest cohort of NHL treated with RIT in a single institution in Spain. We observed a high response rate and prolonged PFS in patients with B-NHL, independent of patient age. Thus, consolidation RIT offers better outcomes with manageable toxicity. PMID- 25823890 TI - Parallel mechanisms of polypyrrole self-discharge in aqueous media. AB - In this report we investigate the self-discharge in a positively charged polypyrrole-cellulose composite material in water solution. Rate constants for the self-discharge reaction are determined by potential step methods and their dependence on pH, temperature and applied potential are reported. Based on the results, we propose that two fundamentally different self-discharge mechanisms operate in parallel; one of faradaic origin with a rate constant increasing exponentially with applied potential and one mechanism comprising an initial reaction of the charged polymer with hydroxide ions. The second mechanism dominates at high pH as the rate constant for this reaction increases exponentially with pH whilst the faradaic reaction dominates at low pH. With this report we hope to shed light on the complex and elusive nature of self-discharge in conducting polymers to serve as guidance for the construction of electrical energy storage devices with conducting polymer components. PMID- 25823891 TI - Assessment of immune status using blood transcriptomics and potential implications for global health. AB - The immune system plays a key role in health maintenance and pathogenesis of a wide range of diseases. Leukocytes that are present in the blood convey valuable information about the status of the immune system. Blood transcriptomics, which consists in profiling blood transcript abundance on genome-wide scales, has gained in popularity over the past several years. Indeed, practicality and simplicity largely makes up for what this approach may lack in terms of cell population-level resolution. An extensive survey of the literature reveals increasingly widespread use across virtually all fields of medicine as well as across a number of different animal species, including model organisms but also animals of economical importance. Dissemination across such a wide range of disciplines holds the promise of adding a new perspective, breadth or context, to the considerable depth afforded by whole genome profiling of blood transcript abundance. Indeed, it is only through such contextualization that a truly global perspective will be gained from the use of systems approaches. Also discussed are opportunities that may arise for the fields of immunology and medicine from using blood transcriptomics as a common denominator for developing interactions and cooperation across fields of research that have traditionally been and largely remain compartmentalized. Finally, an argument is made for building immunology research capacity using blood transcriptomics platforms in low-resource and high disease burden settings. PMID- 25823892 TI - Postnatal accumulation of intermediate filaments in the cat and human primary visual cortex. AB - A principal characteristic of the mammalian visual system is its high capacity for plasticity in early postnatal development during a time commonly referred to as the critical period. The progressive diminution of plasticity with age is linked to the emergence of a collection of molecules called molecular brakes that reduce plasticity and stabilize neural circuits modified by earlier visual experiences. Manipulation of braking molecules either pharmacologically or though experiential alteration enhances plasticity and promotes recovery from visual impairment. The stability of neural circuitry is increased by intermediate filamentous proteins of the cytoskeleton such as neurofilaments and alpha internexin. We examined levels of these intermediate filaments within cat and human primary visual cortex (V1) across development to determine whether they accumulate following a time course consistent with a molecular brake. In both species, levels of intermediate filaments increased considerably throughout early postnatal life beginning shortly after the peak of the critical period, with the highest levels measured in adults. Neurofilament phosphorylation was also observed to increase throughout development, raising the possibility that posttranslational modification by phosphorylation reduces plasticity due to increased protein stability. Finally, an approach to scale developmental time points between species is presented that compares the developmental profiles of intermediate filaments between cats and humans. Although causality between intermediate filaments and plasticity was not directly tested in this study, their accumulation relative to the critical period indicates that they may contribute to the decline in plasticity with age, and may also constrain the success of treatments for visual disorders applied in adulthood. PMID- 25823893 TI - Liquid-Based Cytology Preparation Can Improve Cytological Assessment of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration. AB - OBJECTIVE: This study investigated whether liquid-based cytology (LBC) can improve diagnostic values of cytological assessment of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). STUDY DESIGN: A cohort of 600 cases in West China Hospital was prospectively studied from June 2012 to September 2013. EBUS-TBNA was carried out in outpatients under local anesthesia and moderate sedation. The procedure was performed with an echobronchoscope (BF UC160F-OL8, Olympus, Tokyo, Japan). Histological cores were stained with hematoxylin and eosin for further study. Additional immunohistological analysis was performed for establishing a reliable diagnosis when necessary. Aspirates were smeared on glass slides and separate aspirates were processed by the monolayer SurePath method. RESULTS: In total, 480 malignant tumors and 120 benign lesions were confirmed by histological examination. The sensitivity of SurePath liquid-based preparations and conventional smears was 82.1 and 56%, and the specificity was 87.5 and 82.5%, respectively. The combined specificity was 100%. Positive predictive values of the two groups were 96.3 and 92.8%, whereas negative predictive values were 54.9 and 31.9%, respectively. The difference between the two groups was significant (p < 0.001). CONCLUSIONS: LBC preparation can improve cytological assessment of EBUS-TBNA. Histological study is necessary in cases in which the cytological diagnosis is obscure. PMID- 25823894 TI - A genetic variant in CHRNB3-CHRNA6 increases risk of esophageal squamous cell carcinoma in Chinese populations. AB - Nicotinic acetylcholine receptors are important regulators of smoking behavior and tobacco carcinogenesis. We studied the association of the CHRNB3-A6 variant rs13280604 in relation to esophageal squamous cell carcinoma (ESCC) in Chinese populations. Two independent case-control studies were conducted. The first case control study, consisted of 866 ESCC patients and 1621 healthy controls from Northern China, and the second case-control study consisted of 853 ESCC patients and 860 unrelated controls from Southern China. A logistic regression model was used to evaluate the associations of rs13280604 with cancer risk. We found that Rs13280604 GG/AG genotypes were significantly associated with increased risk for ESCC in both case-control studies from Northern [odds ratio (OR), 1.42, 95% confidence interval (CI), 1.19-1.70, P = 1.1*10(-4)], Southern China (OR, 1.56, 95% CI, 1.26-1.93, P = 5.2*10(-5)), and the combined population of both studies (OR, 1.44, 95% CI, 1.26-1.65, P = 8.7*10(-8)), respectively. Our results suggest that this CHRNB3-A6 variant confers susceptibility to ESCC risk. However, future larger studies are needed to validate our finding. PMID- 25823895 TI - 17beta-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1. AB - Granulosa cell tumor (GCT) is a rare and severe form of sex-cord stromal ovarian tumor that is characterized by its long natural history and tendency to recur years after surgical ablation. Because there is no efficient curative treatment beyond surgery, ~20% of patients die of the consequences of their tumor. However, very little is known of the molecular etiology of this pathology. About 70% of GCT patients present with elevated circulating estradiol (E2). Because this hormone is known to increase tumor growth and progression in a number of cancers, we investigated the possible role of E2 in GCTs. Cell-based studies with human GCT metastases and primary tumor-derived cells, ie KGN and COV434 cells, respectively, aimed at evaluating E2 effect on cell growth, migration and invasion. Importantly, we found that E2 did not affect GCT cell growth, but that it significantly decreased the migration and matrix invasion of metastatic GCT cells. Noteworthy, our molecular studies revealed that this effect was accompanied by the inhibition through non-genomic mechanisms of extracellular signal-regulated kinase 1/2 (ERK1/2), which is constitutively activated in GCTs. By using pharmacological and RNA silencing approaches, we found that E2 action was mediated by G protein-coupled estrogen receptor 1 (GPER1) signaling pathway. Analyses of GPER1 expression on tissue microarrays from human GCTs confirmed its expression in ~90% of GCTs. Overall, our study reveals that E2 would act via non classical pathways to prevent metastasis spreading in GCTs and also reveals GPER1 as a possible target in this disease. PMID- 25823896 TI - Leukocyte mitochondrial DNA content: a novel biomarker associated with prognosis and therapeutic outcome in colorectal cancer. AB - Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risks of several malignancies in a cancer-specific manner. However, to date, whether leukocyte mtDNA content can predict clinical outcome of cancer patients has never been investigated. In the present study, we measured leukocyte mtDNA content using real-time PCR-based method in a total of 598 colorectal cancer (CRC) patients and explored its prognostic values. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in CRC patients. We found that patients with high mtDNA content showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low mtDNA content in all patient sets. Furthermore, mtDNA content and tumor node metastasis (TNM) stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte mtDNA content significantly improved the prognosis prediction efficacy for CRC. Importantly, patients with high mtDNA content showed OS and RFS benefits from adjuvant chemotherapy. In addition, we found that patients with high mtDNA content had a higher frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells, higher plasma interleukin-2 and transforming growth factor-beta1 and lower tumor necrosis factor-alpha concentration than those with low mtDNA content, suggesting a stronger immunosuppressive phenotype. In conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with immunosuppression in CRC patients. Additionally, leukocyte mtDNA content might serve as a potential biomarker to select CRC patients who will benefit from adjuvant chemotherapy. PMID- 25823897 TI - Phase I/II study of amrubicin and nedaplatin in patients with untreated, advanced, non-small cell lung cancer. AB - A phase I/II study of combination chemotherapy with amrubicin and nedaplatin for patients with untreated, advanced, non-small cell lung cancer (NSCLC) was conducted. Amrubicin was given on days 1-3, with nedaplatin given on day 1. The treatment was repeated every 3 weeks. In the phase I trial, the initial amrubicin dose of 25 mg/m(2) was escalated in 5-mg/m(2) increments until the maximum tolerated dose was reached, with the dose of nedaplatin fixed at 100 mg/m(2). In the phase II trial, the primary endpoint was the overall response rate (ORR), assuming 20% for a standard therapy and 40% for a target therapy (alpha = 0.05 and beta = 0.20), and the estimated required total number of patients was 35. In the phase I study, nedaplatin 100 mg/m(2) and amrubicin 25 mg/m(2) was recommended. In the phase II study, 17 out of 35 patients achieved a partial response, and the ORR was 48.6%. Grade 3/4 neutropenia, grade 3 anemia and grade 3/4 thrombocytopenia occurred in 62.9, 11.4 and 11.4% of cycles, respectively. Febrile neutropenia occurred in 5 cycles (3.9%) and all cases were manageable. The recommended dose of this combination is well tolerated and effective in patients with advanced NSCLC. PMID- 25823898 TI - Functional liposomes in the cancer-targeted drug delivery. AB - Cancer is considered as one of the most severe health problems and is currently the third most common cause of death in the world after heart and infectious diseases. Novel therapies are constantly being discovered, developed and trialed. Many of the current anticancer agents exhibit non-ideal pharmaceutical and pharmacological properties and are distributed non-specifically throughout the body. This results in death of the both normal healthy and malignant cells and substantially leads to accruing a variety of serious toxic side effects. Therefore, the efficient systemic therapy of cancer is almost impossible due to harmful side effects of anticancer agents to the healthy organs and tissues. Furthermore, several problems such as low bioavailability of the drugs, low drug concentrations at the site of action, lack of drug specificity and drug resistance also cause many restrictions on clinical applications of these drugs in the tumor therapy. Different types of the liposomal formulations have been used in medicine due to their distinctive advantages associated with their structural flexibility in the encapsulation of various agents with different physicochemical properties. They can also mediate delivery of the cargo to the appropriate cell type and subcellular compartment, reducing the effective dosage and possible side effects which are related to high systemic concentrations. Therefore, these novel systems were found very promising and encouraging dosage forms for the treatment of different types of cancer by increasing efficiency and reducing the systemic toxicity due to the specific drug delivery and targeting. PMID- 25823899 TI - Mechanophores with a reversible radical system and freezing-induced mechanochemistry in polymer solutions and gels. AB - Visualization and quantitative evaluation of covalent bond scission in polymeric materials are highly important for understanding failure, fatigue, and deterioration mechanisms and improving the lifetime, durability, toughness, and reliability of the materials. The diarylbibenzofuranone-based mechanophore radical system enabled, through electron paramagnetic resonance spectroscopy, in situ quantitative evaluation of scission of the mechanophores and estimation of mechanical energy induced along polymer chains by external forces. The coagulation of polymer solutions by freezing probably generated force but did not cleave the mechanophores. On the other hand, cross-linking led to efficient propagation of the force of more than 80 kJ mol(-1) to some mechanophores, resulting their cleavage and generation of colored stable radicals. This mechanoprobe concept has the potential to elucidate other debated issues in the polymer field as well. PMID- 25823900 TI - Third instar larvae of flesh flies (Diptera: Sarcophagidae) of forensic importance--critical review of characters and key for European species. AB - Necrophagous Sarcophagidae are among the insects most frequently reported from human corpses. The broad forensic application of flesh flies is restricted by the lack of reliable tools for species identification of larval stages and mass breeding of collected flesh fly larvae to the adult stage, and more recently DNA based methods are usually recommended for precise species identification. To overcome this situation, the following study was implemented: (1) original larval material was obtained of the European flesh flies of confirmed or potential forensic importance; (2) larval morphology was studied and documented using a combination of standard light microscopy, image-stacking stereomicroscopy and SEM; and (3) larval characters used in previously published keys were critically revised. The taxonomic value of the following characters was considered insignificant: (1) differences in level of sclerotisation of particular parts of the cephaloskeleton, (2) level of sclerotisation of the posterior spiracular peritreme and (3) the shape of posterior spiracular slits. A high taxonomic value was noticed for the general shape of anterior spiracles, pattern of arrangement of their lobes, and distribution and shape of spines/warts on the inter-band area of segments. Two character states-long window in the dorsal cornu of cephaloskeleton and deep spiracular cavity on anal division-are not found in the Miltogramminae and therefore cannot be considered as family-specific for the entire Sarcophagidae. As a comprehensive result of our studies, an identification key is presented for the third instar larvae of European flesh flies of forensic importance. The key is user-friendly and requires no dissections of larvae, as soaking the material in methyl salicylate will allow observation of all diagnostic details of the cephaloskeleton. A simple stereomicroscope (magnification about *50) is sufficient for the observation of all characters presented in the key. This key may be systematically extended by the addition of species present in adjacent geographical regions. PMID- 25823901 TI - The effect of osteoarthritis on the regional anatomical variation of subchondral trabecular bone in the femoral head. AB - BACKGROUND: The subchondral trabecular bone is located deep inside the articular cartilage, with the subcapital region carrying up to 70% of the diurnal loads occurring in the hip joint. This leads to severe regional anatomical variations of subchondral trabecular bone in the femoral head and the purpose of this study was to examine whether osteoarthritis affects these topographic characteristics. METHODS: 60 femoral heads were harvested during hip replacement and studied by osteopenetration at 8 pre-defined angles, at a penetration rate of 1mm/s. Twenty eight of the donors underwent surgery due to osteoarthritis, whereas the remaining were trauma patients with hip fractures. To correlate these measurements to non-invasive data, all specimens were scanned by micro Computed Tomography (MUCT) prior to experimentation. A cross-sectional area, perpendicular to the needle penetration pathway, was analyzed and the deviations compared to the recorded osteopenetration energy. FINDINGS: The experiments revealed significant topographical deviations in the trabeculae. These were more pronounced in the osteoarthritic samples which also required overall higher osteopenetration energy. A notable dependency of the directional bone strength to its cross-sectional characteristics was observed. Although the effect of "gender" on osteopenetration energy was proven to be significant, gender was not considered an independent variable in a regression model correlating osteopenetration energy to 2D trabecular bone density as this did not improve the value of the adjusted R(2). INTERPRETATION: The investigation provided refined insight into femoral head load-bearing capacity of patients suffering from osteoarthritis, as a comparison of osteoarthritic to healthy samples illustrated that subchondral trabecular bone in the femoral head region is subjected to increased remodeling and demineralization, reflected in higher osteopenetration values. PMID- 25823902 TI - The biomechanical characteristics of wearing FitFlopTM sandals highlight significant alterations in gait pattern: a comparative study. AB - BACKGROUND: The net contribution of all muscles that act about a joint can be represented as an internal joint moment profile. This approach may be advantageous when studying footwear-induced perturbations during walking since the contribution of the smaller deeper muscles that cross the ankle joint cannot be evaluated with surface electromyography. Therefore, the present study aimed to advance the understanding of FitFlopTM footwear interaction by investigating lower extremity joint moment, and kinematic and centre of pressure profiles during gait. METHODS: 28 healthy participants performed 5 walking trials in 3 conditions: a FitFlopTM sandal, a conventional sandal and an athletic trainer. Three-dimensional ankle joint, and sagittal plane knee and hip joint moments, as well as corresponding kinematics and centre of pressure trajectories were evaluated. FINDINGS: FitFlopTM differed significantly to both the conventional sandal and athletic trainer in: average anterior position of centre of pressure trajectory (P<0.0001) and peak hip extensor moment (P=0.001) during early stance; average medial position of centre of pressure trajectory during late stance; peak ankle dorsiflexion and corresponding range of motion; peak plantarflexor moment and total negative work performed at the ankle (all P<0.0001). INTERPRETATION: The present findings demonstrate that FitFlopTM footwear significantly alters the gait pattern of wearers. An anterior displacement of the centre of pressure trajectory during early stance is the primary response to the destabilising effect of the mid-sole technology, and this leads to reductions in sagittal plane ankle joint range of motion and corresponding kinetics. Future investigations should consider the clinical implications of these findings. PMID- 25823903 TI - Prioritizing Highway Safety Manual's crash prediction variables using boosted regression trees. AB - The Highway Safety Manual (HSM) recommends using the empirical Bayes (EB) method with locally derived calibration factors to predict an agency's safety performance. However, the data needs for deriving these local calibration factors are significant, requiring very detailed roadway characteristics information. Many of the data variables identified in the HSM are currently unavailable in the states' databases. Moreover, the process of collecting and maintaining all the HSM data variables is cost-prohibitive. Prioritization of the variables based on their impact on crash predictions would, therefore, help to identify influential variables for which data could be collected and maintained for continued updates. This study aims to determine the impact of each independent variable identified in the HSM on crash predictions. A relatively recent data mining approach called boosted regression trees (BRT) is used to investigate the association between the variables and crash predictions. The BRT method can effectively handle different types of predictor variables, identify very complex and non-linear association among variables, and compute variable importance. Five years of crash data from 2008 to 2012 on two urban and suburban facility types, two-lane undivided arterials and four-lane divided arterials, were analyzed for estimating the influence of variables on crash predictions. Variables were found to exhibit non linear and sometimes complex relationship to predicted crash counts. In addition, only a few variables were found to explain most of the variation in the crash data. PMID- 25823904 TI - Crash risk and aberrant driving behaviors among bus drivers: the role of personality and attitudes towards traffic safety. AB - Several studies have shown that personality traits and attitudes toward traffic safety predict aberrant driving behaviors and crash involvement. However, this process has not been adequately investigated in professional drivers, such as bus drivers. The present study used a personality-attitudes model to assess whether personality traits predicted aberrant self-reported driving behaviors (driving violations, lapses, and errors) both directly and indirectly, through the effects of attitudes towards traffic safety in a large sample of bus drivers. Additionally, the relationship between aberrant self-reported driving behaviors and crash risk was also assessed. Three hundred and one bus drivers (mean age=39.1, SD=10.7 years) completed a structured and anonymous questionnaire measuring personality traits, attitudes toward traffic safety, self-reported aberrant driving behaviors (i.e., errors, lapses, and traffic violations), and accident risk in the last 12 months. Structural equation modeling analysis revealed that personality traits were associated to aberrant driving behaviors both directly and indirectly. In particular altruism, excitement seeking, and normlessness directly predicted bus drivers' attitudes toward traffic safety which, in turn, were negatively associated with the three types of self-reported aberrant driving behaviors. Personality traits relevant to emotionality directly predicted bus drivers' aberrant driving behaviors, without any mediation of attitudes. Finally, only self-reported violations were related to bus drivers' accident risk. The present findings suggest that the hypothesized personality attitudes model accounts for aberrant driving behaviors in bus drivers, and provide the empirical basis for evidence-based road safety interventions in the context of public transport. PMID- 25823905 TI - Performance of the RAPS4/RAPS4-QF for DSM-5 compared to DSM-IV alcohol use disorders in the general population: Data from the 2000-2010 National Alcohol Surveys. AB - BACKGROUND: A number of relatively short screening instruments have been developed for identifying alcohol use disorders (AUD), but performance has been evaluated against the standard Diagnostic and Statistical Manual of Mental and Behavior Disorders (DSM) criteria, and it is not known how screening instruments may perform based on the newly formulated DSM-5 criteria, which is a radical departure from previous versions of the DSM. Analyzed here is the performance of the RAPS4/RAPS4-QF against DSM-5 criteria for AUD compared to DSM-IV dependence and abuse criteria. METHODS: Sensitivity and specificity are analyzed in a merged sample of 21,386 respondents from three National Alcohol Surveys of the U.S. general population (2000, 2005, 2010). RESULTS: Sensitivity of the RAPS4 was lower for DSM-5 AUD (62.5%) than for DSM-IV dependence (88%), while the RAPS4-QF was higher for DSM-5 AUD (90.3%) than for DSM-IV abuse (81.3%), or abuse/dependence (85.8%), while maintaining good specificity (84%). Sensitivity of the RAPS4-QF was higher for males (92%) compared to females (86.6%) and highest for whites (93.8%) followed by Hispanics (84.2%) and blacks (82.4%). CONCLUSIONS: Screening instruments may not perform similarly for DSM-5 as for DSM IV AUD, and data here suggest the RAPS4-QF may be a good instrument choice for identifying those meeting criteria for DSM-5 AUD. These data also suggest the need for additional research and a similar evaluation of other commonly used screening instruments for DSM-5 AUD. PMID- 25823906 TI - Personality and alcohol consumption: Pooled analysis of 72,949 adults from eight cohort studies. AB - BACKGROUND: The role of personality as a determinant of alcohol consumption has long been debated, but prospective evidence is scarce. METHODS: We performed individual participant meta-analysis to examine the association between the Five Factor Model personality traits (extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience) and alcohol consumption using data from eight cohort studies sampled from the USA, UK, Germany, and Australia (total n=72,949; mean age=50 years, 54% female). Alcohol consumption was categorized into abstinence, moderate consumption, and heavy consumption. RESULTS: After adjustment for age, sex, and race, higher extraversion (odds ratio for 1 standard deviation's increase in the score; 95% confidence interval: 1.14; 1.01-1.29) and lower conscientiousness (0.89; 0.79-1.00) were associated with increased risk of transitioning from moderate to heavy alcohol consumption over time, and also with heavy alcohol consumption. Lower extraversion (0.91; 0.85-0.98), higher agreeableness (1.09; 1.02-1.15), and lower openness (0.90; 0.86-0.95) were associated with increased odds of transitioning from moderate consumption to abstinence as well as with alcohol abstinence. CONCLUSION: Findings from this individual-participant meta-analysis suggest that high and increasing alcohol consumption is more common among extraverts and those low on conscientiousness whereas high agreeableness and low openness to experience may increase odds of reducing alcohol consumption and preferring abstinence. PMID- 25823907 TI - Characterizing opioid withdrawal during double-blind buprenorphine detoxification. AB - BACKGROUND: Prescription opioid (PO) abuse has become an urgent public health issue in the United States. Detoxification is one important treatment option, yet relatively little is known about the time course and severity of opioid withdrawal during buprenorphine detoxification. METHODS: This is a secondary analysis of data from a randomized, placebo-controlled, double-blind evaluation of 1, 2, and 4-week outpatient buprenorphine tapers among primary prescription opioid (PO) abusers. The aim is to characterize the time course and severity of buprenorphine withdrawal under rigorous, double-blind conditions, across multiple taper durations, and using multiple withdrawal-related measures (i.e., self report and observer ratings, pupil diameter, ancillary medication utilization). Participants were PO-dependent adults undergoing buprenorphine detoxification and biochemically-verified to be continuously abstinent from opioids during their taper (N = 28). RESULTS: Participants randomly assigned to the 4-week taper regimen experienced a relatively mild and stable course of withdrawal, with few peaks in severity. In contrast, the 1- and 2-week taper groups experienced stark increases in withdrawal severity during the week following the last buprenorphine dose, followed by declines in withdrawal severity thereafter. The 4-week taper group also reported significantly fewer disruptions in sleep compared to the other experimental groups. When predictors of withdrawal were examined, baseline ratings of "Expected Withdrawal Severity" was the most robust predictor of withdrawal experienced during the taper. CONCLUSION: Data from this trial may inform clinicians about the expected time course, magnitude, and pattern of buprenorphine withdrawal and aid efforts to identify patients who may need additional clinical support during outpatient buprenorphine detoxification. PMID- 25823908 TI - Heavy alcohol use and suicidal behavior among people who use illicit drugs: A cohort study. AB - BACKGROUND: People who use illicit drugs (PWUD) are known to experience high rates of suicidal behavior. While heavy alcohol use has been associated with suicide risk, its impact on the suicidal behavior of PWUD has not been well characterized. Therefore, we examined the relationship between heavy alcohol use and suicidal behavior among PWUD in Vancouver, Canada. METHODS: Data are derived from two prospective cohort studies of PWUD in Vancouver, Canada, from 2005 to 2013. Participants completed questionnaires that elicited information regarding sociodemographics, drug use patterns, and mental health problems, including suicidal behavior. We used recurrent event survival analyses to estimate the independent association between at-risk/heavy drinking (based on National Institute of Alcohol Abuse and Alcoholism [NIAAA] criteria) and risk of incident, self-reported suicide attempts. RESULTS: Of 1757 participants, 162 participants (9.2%) reported 227 suicide attempts over the 8-year study period, resulting in an incidence rate of 2.5 cases per 100 person-years. After adjusting for potential confounders, including intensive illicit drug use patterns, heavy alcohol use (adjusted hazard ratio [AHR] = 1.97; 95% confidence interval [CI] = 1.39, 2.78) was positively associated with an increased risk of suicidal behavior. CONCLUSIONS: We observed a high burden of suicidal behavior among a community-recruited sample of PWUD. Heavy alcohol use predicted a higher risk of suicide attempt, independent of other drug use patterns. These findings demonstrate the need for evidence-based interventions to address suicide risk among PWUD, particularly those who are heavy consumers of alcohol. PMID- 25823909 TI - Safety and systemic consequences of pleurodesis with three different doses of silver nitrate in patients with malignant pleural effusion. AB - BACKGROUND: Silver nitrate (SN) is an alternative to talc pleurodesis in patients with malignant pleural effusion (MPE). Nevertheless, SN complications have not been thoroughly investigated so far. OBJECTIVE: To evaluate frequent adverse events (AE) of SN treatment at three different doses for pleurodesis in patients with MPE. The secondary objective was to evaluate systemic inflammation, efficacy and quality of life in these patients. METHODS: A double-blind, randomized, clinical trial was conducted in patients with recurrent MPE at a tertiary university hospital. The study patients underwent pleural catheter insertion and were randomly assigned to one of the three pleurodesis groups treated with 30 ml 0.3%, 30 ml 0.5% or 60 ml 0.3% SN. Patients were discharged 3 days after the procedure, and returned to follow-up visits on days 10 and 30. During follow-up, AE, inflammatory markers, quality of life and CT scans were systematically assessed and documented. RESULTS: Sixty patients (11 males and 49 females, median age 62.13 years) were included. Overall, 199 AE were observed, including 23 serious AE. Grade 1/2 metabolic AE, such as increases in creatinine and liver enzymes, were the most frequent. Grade 3/4 hypoxia was observed in 13 patients. Four patients died, 3 due to disease progression and in 1 patient death was possibly related to pleurodesis. C-reactive protein levels increased in a dose dependent manner and peaked 48 h after pleurodesis. No significant difference was observed among groups regarding quality of life or clinical/radiological recurrence. CONCLUSION: Hypoxia was the most significant AE following SN pleurodesis; mild metabolic events were very common. SN instillation causes substantial dose-dependent systemic inflammatory responses. PMID- 25823910 TI - Three different points of view in stroke rehabilitation: patient, caregiver, and physiotherapist. AB - BACKGROUND: The similarities or differences of the three some (physiotherapists, patients, and caregivers) thought about the process of stroke rehabilitation can play a key role in the success of rehabilitation. OBJECTIVE: The aim of this qualitative study was to investigate the perspectives of the three some, with regard to the two themes of the study: (1) What are the problems faced by the patients after stroke?; and (2) What does recovery after stroke mean to you? METHODS: The qualitative questions and possible answers were prepared by four physiotherapists. The answers were matched to International Classification of Functioning (ICF) components. Seventy patients who were having treatment as in patient rehabilitation centers, their caregivers, and physiotherapists were invited to the study. After the questions were asked and the possible response choices were presented, subjects were asked to prioritize these response choices. RESULTS: One hundred and fifty-nine subjects, including 53 patients, 53 caregivers, and 53 physiotherapists, were included to the study. When the theme 1 were examined, we found that the patients' first priority was functional abilities (ICF: body function and structure) such as using the hands and feet while the caregivers and physiotherapists prioritized self-care problems (ICF: activity and participation). The most common response to the theme 2 was "being in same health condition before the disease" (ICF: activity and participation) among the patients and caregivers and "being able to move arm and leg on the affected side" (body function and structure) among the physiotherapists. CONCLUSION: As a conclusion, problems faced by the patients, caregivers, and physiotherapists were perceived under the same ICF domain and that caregivers' and physiotherapists' priorities were the same. PMID- 25823911 TI - Guatemalan school food environment: impact on schoolchildren's risk of both undernutrition and overweight/obesity. AB - Guatemala suffers the double burden of malnutrition with high rates of stunting alongside increasing childhood overweight/obesity. This study examines the school food environment (SFE) at low-income Guatemalan elementary schools and discusses its potential impact on undernutrition and overweight/obesity. From July through October 2013, direct observations, in-depth interviews with school principals (n = 4) and food kiosk vendors (n = 4, 2 interviews each) and also focus groups (FGs) with children (n = 48, 8 FGs) were conducted. The SFE comprises food from school food kiosks (casetas); food from home or purchased in the street; and food provided by the school (refaccion). School casetas, street vendors and children's parents largely provide sandwiches, calorie-rich snacks and sugar-sweetened beverages. Refaccion typically serves energy dense atol, a traditional beverage. The current school food program (refaccion), the overall SFE and the roles/opinions of vendors and principals reveal persistent anxiety concerning undernutrition and insufficient concern for overweight/obesity. Predominant concern for elementary schoolchildren remains focused on undernutrition. However, by the time children reach elementary school (ages 6-12+), food environments should encourage dietary behaviors to prevent childhood overweight/obesity. PMID- 25823912 TI - Antipsychotic treatment leading to dopamine supersensitivity persistently alters nucleus accumbens function. AB - Chronic exposure to some antipsychotic medications can induce supersensitivity to dopamine receptor stimulation. This is linked to a worsening of clinical outcome and to antipsychotic treatment failure. Here we investigated the role of striatal subregions [nucleus accumbens (NAc) and caudate-putamen (CPu)] in the expression of antipsychotic-induced dopamine supersensitivity. We treated rats with haloperidol (HAL) or olanzapine (OLZ), using regimens that achieve clinically relevant kinetics of striatal D2 receptor occupancy. Under these conditions, HAL produces dopamine supersensitivity whereas OLZ does not. We then assessed behaviors evoked by the dopamine agonist amphetamine (AMPH). We either injected AMPH into the striatum or inhibited striatal function with microinjections of GABA receptor agonists prior to injecting AMPH systemically. HAL-treated rats were dopamine supersensitive, as indicated by sensitization to systemic AMPH induced potentiation of both locomotor activity and operant responding for a conditioned reward (CR). Intra-CPu injections of AMPH had no effect on these behaviors, in any group. Intra-NAc injections of AMPH enhanced operant responding for CR in OLZ-treated and control rats, but not in HAL-treated rats. In HAL treated rats, inhibition of the NAc also failed to disrupt systemic AMPH-induced potentiation of operant responding for CR. Furthermore, while intra-NAc AMPH enhanced locomotion in both HAL-treated and control animals, inhibition of the NAc disrupted systemic AMPH-induced locomotion only in control rats. Thus, antipsychotic-induced dopamine supersensitivity persistently disrupts NAc function, such that some behaviors that normally depend upon NAc dopamine no longer do so. This has implications for understanding dysfunctions in dopamine mediated behaviors in patients undergoing chronic antipsychotic treatment. PMID- 25823913 TI - The cysteine-rich core domain of REIC/Dkk-3 is critical for its effect on monocyte differentiation and tumor regression. AB - Reduced expression in immortalized cells (REIC)/Dickkopf (Dkk)-3 is a tumor suppressor gene and has been studied as a promising therapeutic gene for cancer gene therapy. Intratumoral injection of an adenovirus vector carrying the human REIC/Dkk-3 gene (Ad-REIC) elicits cancer cell-specific apoptosis and anticancer immune responses. The cytokine-like effect of secretory REIC/Dkk-3 on the induction of dendritic cell (DC)-like cell differentiation from monocytes plays a role in systemic anticancer immunity. In the present study, we generated recombinant full-length and N-terminally truncated REIC/Dkk-3 to characterize the biological activity of the protein. During the purification procedure, we identified a 17 kDa cysteine-rich stable product (C17-REIC) showing limited degradation. Further analysis showed that the C17-REIC domain was sufficient for the induction of DC-like cell differentiation from monocytes. Concomitant with the differentiation of DCs, the REIC/Dkk-3 protein induced the phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) and signal transducers and activators of transcription (STAT) at a level comparable to that of granulocyte/macrophage colony-stimulating factor. In a mouse model of subcutaneous renal adenocarcinoma, intraperitoneal injection of full-length and C17-REIC proteins exerted anticancer effects in parallel with the activation of immunocompetent cells such as DCs and cytotoxic T lymphocytes in peripheral blood. Taken together, our results indicate that the stable cysteine-rich core region of REIC/Dkk-3 is responsible for the induction of anticancer immune responses. Because REIC/Dkk-3 is a naturally circulating serum protein, the upregulation REIC/Dkk-3 protein expression could be a promising option for cancer therapy. PMID- 25823914 TI - The effects of Rho-associated kinase inhibitor Y-27632 on primary human corneal endothelial cells propagated using a dual media approach. AB - The global shortage of donor corneas has garnered extensive interest in the development of graft alternatives suitable for endothelial keratoplasty using cultivated primary human corneal endothelial cells (CECs). We have recently described a dual media approach for the propagation of human CECs. In this work, we characterize the effects of a Rho-kinase inhibitor Y-27632 on the cultivation of CECs propagated using the dual media culture system. Seventy donor corneas deemed unsuitable for transplantation were procured for this study. We assessed the use of Y-27632 for its effect at each stage of the cell culture process, specifically for cell attachment, cell proliferation, and during both regular passaging and cryopreservation. Lastly, comparison of donor-matched CEC-cultures expanded with or without Y-27632 was also performed. Our results showed that Y 27632 significantly improved the attachment and proliferation of primary CECs. A non-significant pro-survival effect was detected during regular cellular passage when CECs were pre-treated with Y-27632, an effect that became more evident during cryopreservation. Our study showed that the inclusion of Y-27632 was beneficial for the propagation of primary CECs expanded via the dual media approach, and was able to increase overall cell yield by between 1.96 to 3.36 fold. PMID- 25823915 TI - Synchronization of E. coli O157 shedding in a grass-fed beef herd: a longitudinal study. AB - This study aims to describe in detail the temporal dynamics of E. coli O157 shedding and risk factors for shedding in a grass-fed beef herd. During a 9-month period, 23 beef cows were sampled twice a week (58 sampling points) and E. coli O157 was enumerated from faecal samples. Isolates were screened by PCR for presence of rfbE, stx 1 and stx 2 . The prevalence per sampling day ranged from 0% to 57%. This study demonstrates that many members of the herd were concurrently shedding E. coli O157. Occurrence of rainfall (P < 0.01), feeding silage (P < 0.01) and lactating (P < 0.01) were found to be predictors of shedding. Moving cattle to a new paddock had a negative effect on shedding. This approach, based on short-interval sampling, confirms the known variability of shedding within a herd and highlights that high shedding events are rare. PMID- 25823916 TI - Interferon-lambda: Inters Ferocity or Inter-Ferocities? PMID- 25823917 TI - Integration of the full-length HPV16 genome in cervical cancer and Caski and Siha cell lines and the possible ways of HPV integration. AB - Integration of high-risk human papillomavirus (HPV) into the host genome is a key event for cervical carcinogenesis. Different methods have been used to explore the physical states of the HPV genome to reveal the mechanisms for malignant transformation of the infected cells. Consensus has been reached that, although variable portions of the HPV genome are deleted in the integrated HPV sequences, common disruption of the viral E2 gene has been demonstrated in different studies. The head-to-tail concatemers of the full-length HPV16 genome is another typical integration pattern of HPV16, typically found in Caski cell lines, but its prevalence in cervical cancer has never been tested. Here, by introducing a modified PCR, we identified this head-to-tail concatemers of full-length HPV genomes in advanced cervical cancer with HPV16 single positive. Our results show that more than half of the cases contain this integrated head-to-tail concatemers of full-length HPV16 genomes. Further studies in two cervical cell lines, Caski cells and Siha cells, revealed a correlation between the prevalence of the spliced variants of integrated HPV16 sequences and the full-length transcription of the integrated head-to-tail concatemers of the full-length HPV16 genome. Based on these results, we propose that HPV16 integrated into host cells by two mechanisms: one mechanism is shared by other DNA virus and cause integration of the head-to-tail concatemers of the viral genome; another is related to the reverse transcription process, which the integrated HPV sequence is generated by the reverse transcription of the viral mRNA. PMID- 25823919 TI - Novel Buccal Film Formulation of Buprenorphine-Naloxone for the Maintenance Treatment of Opioid Dependence: A 12-Week Conversion Study. AB - PURPOSE: The purpose of this study was to provide a preliminary assessment of the safety, tolerability, symptom control, and acceptability of buprenorphine naloxone buccal film (BBN) for the maintenance treatment of opioid dependence in patients converted from buprenorphine-naloxone sublingual tablet or film (SLBN), as well as to determine the conversion ratio for switching patients from SLBN to BBN. METHODS: This open-label study included adult opioid-dependent subjects stabilized on 8/2 to 32/8 mg/d of SLBN for a minimum of 30 days. Study subjects were converted to a bioequivalent dose of BBN and maintained for 12 weeks. FINDINGS: A total of 249 subjects (mean age 38.7 years, 65.9% male) were converted from SLBN to a single daily dose of BBN, and 79.1% completed the 12 week study. Adverse events and withdrawal symptoms led to discontinuation in 2.4% and 2.0% of BBN-treated subjects, respectively. Rates of constipation reported at baseline declined from 41% just before the initial BBN dose and within 24 hours of the last SLBN dose to 13% after 12 weeks of BBN treatment; treatment-emergent constipation was reported by 2.8% of BBN-treated subjects. Oral mucosal abnormalities were identified in 5% and 0.6% of systematic oral examinations in SLBN- and BBN-treated subjects, respectively. A total of 34 subjects had Clinical Opiate Withdrawal Scale total scores ranging from 10 to 25 (overall mean, 13.8) within 24 hours of taking their last SLBN dose, and scores for these subjects were reduced to a range of 0 to 3 (overall mean, 0.7) at 3 hours after the initial dose of BBN. Treatment compliance was high (108%); <1% of urine samples were buprenorphine-free, and 92.4% of BBN-treated subjects did not have a urine sample that tested positive for a non-prescribed opioid. A total of 91.3% subjects rated the taste of BBN as pleasant or neutral, and 82.5% rated BBN ease of use as easy or neutral. The overall mean final dose of BBN was 8.0/1.4 mg/d, yielding a 2:1 buprenorphine conversion ratio. IMPLICATIONS: Although these results should be considered preliminary due to the open-label design, BBN was overall safe and well tolerated, and seemed to provide adequate symptom control, in the treatment of opioid-dependent subjects previously controlled on SLBN for a minimum of 30 days. There was good adherence to study medication and favorable patient acceptance of the buccal formulation. The SLBN/BBN buprenorphine conversion ratio was 2:1. ClinicalTrials.gov identifier: NCT01666119. PMID- 25823920 TI - A Multiple-Channel Model of Task-Dependent Ambiguity Resolution in Sentence Comprehension. AB - Traxler, Pickering, and Clifton (1998) found that ambiguous sentences are read faster than their unambiguous counterparts. This so-called ambiguity advantage has presented a major challenge to classical theories of human sentence comprehension (parsing) because its most prominent explanation, in the form of the unrestricted race model (URM), assumes that parsing is non-deterministic. Recently, Swets, Desmet, Clifton, and Ferreira (2008) have challenged the URM. They argue that readers strategically underspecify the representation of ambiguous sentences to save time, unless disambiguation is required by task demands. When disambiguation is required, however, readers assign sentences full structure--and Swets et al. provide experimental evidence to this end. On the basis of their findings, they argue against the URM and in favor of a model of task-dependent sentence comprehension. We show through simulations that the Swets et al. data do not constitute evidence for task-dependent parsing because they can be explained by the URM. However, we provide decisive evidence from a German self-paced reading study consistent with Swets et al.'s general claim about task dependent parsing. Specifically, we show that under certain conditions, ambiguous sentences can be read more slowly than their unambiguous counterparts, suggesting that the parser may create several parses, when required. Finally, we present the first quantitative model of task-driven disambiguation that subsumes the URM, and we show that it can explain both Swets et al.'s results and our findings. PMID- 25823918 TI - The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma. AB - PURPOSE: Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. METHODS: PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. FINDINGS: The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. IMPLICATIONS: This family of immune checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit. PMID- 25823921 TI - Glipizide suppresses embryonic vasculogenesis and angiogenesis through targeting natriuretic peptide receptor A. AB - Glipizide, a second-generation sulfonylurea, has been widely used for the treatment of type 2 diabetes. However, it is controversial whether or not glipizide would affect angiogenesis or vasculogenesis. In the present study, we used early chick embryo model to investigate the effect of glipizide on angiogenesis and vasculogenesis, which are the two major processes for embryonic vasculature formation as well as tumor neovascularization. We found that Glipizide suppressed both angiogenesis in yolk-sac membrane (YSM) and blood island formation during developmental vasculogenesis. Glipizide did not affect either the process of epithelial to mesenchymal transition (EMT) or mesoderm cell migration. In addition, it did not interfere with separation of smooth muscle cell progenitors from hemangioblasts. Moreover, natriuretic peptide receptor A (NPRA) has been identified as the putative target for glipizide's inhibitory effect on vasculogenesis. When NPRA was overexpressed or activated, blood island formation was reduced. NPRA signaling may play a crucial role in the effect of glipizide on vasculogenesis during early embryonic development. PMID- 25823922 TI - Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110alpha subunit of PI3 kinase. AB - The mammalian target of rapamycin (mTOR) and phosphoinositide-3-kinase (PI3K) pathways are often aberrantly activated in acute myeloid leukemia (AML) and play critical roles in proliferation and survival of leukemia cells. We provide evidence that simultaneous targeting of mTOR complexes with the catalytic mTOR inhibitor OSI-027 and of the p110alpha subunit of PI3K with the specific inhibitor BYL-719 results in efficient suppression of effector pathways and enhanced induction of apoptosis of leukemia cells. Importantly, such a combined targeting approach results in enhanced suppression of primitive leukemic progenitors from patients with AML. Taken together, these findings raise the possibility of combination treatments of mTOR and p110alpha inhibitors as a unique approach to enhance responses in refractory AML. PMID- 25823923 TI - WNT5A promotes stemness characteristics in nasopharyngeal carcinoma cells leading to metastasis and tumorigenesis. AB - Nasopharyngeal carcinoma (NPC) has the highest metastasis rate among head and neck cancers with unclear mechanism. WNT5A belongs to the WNT family of cysteine rich secreted glycoproteins. Our previous high-throughput gene expression profiling revealed that WNT5A was up-regulated in highly metastatic cells. In the present study, we first confirmed the elevated expression of WNT5A in metastatic NPC tissues at both the mRNA and protein levels. We then found that WNT5A promoted epithelial-mesenchymal transition (EMT) in NPC cells, induced the accumulation of CD24-CD44+ cells and side population, which are believed to be cancer stem cell characteristics. Moreover, WNT5A promoted the migration and invasion of NPC cells in vitro, while in vivo treatment with recombinant WNT5A promoted lung metastasis. Knocking down WNT5A diminished NPC tumorigenesis in vivo. When elevated expression of WNT5A coincided with the elevated expression of vimentin in the primary NPC, the patients had a poorer prognosis. Among major signaling pathways, protein kinase C (PKC) signaling was activated by WNT5A in NPC cells. A positive feedback loop between WNT5A and phospho-PKC to promote EMT was also revealed. Taken together, these data suggest that WNT5A is an important molecule in promoting stem cell characteristics in NPC, leading to tumorigenesis and metastasis. PMID- 25823924 TI - NF2 blocks Snail-mediated p53 suppression in mesothelioma. AB - Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM. PMID- 25823925 TI - MicroRNA profiling identifies MiR-195 suppresses osteosarcoma cell metastasis by targeting CCND1. AB - Metastasis is a leading cause of mortality for osteosarcoma patients. The molecular pathological mechanism remains to be elucidated. In the previously study, we established two osteosarcoma cell lines with different metastatic potentials. Differential expressed genes and proteins regarding metastatic ability have been identified. MicroRNAs are important regulators in tumorigenesis and tumor progression. In this study, microRNA microarray was used to assess the differential expressed miRNAs level between these two cell lines. One of the top ranked miRNAs-miR-195 was identified highly expressing in lowly metastatic cells. It was showed that over-expression of miR-195 substantially inhibits migration and invasion of osteosarcoma cells in vitro and pulmonary metastasis formation in vivo. Meanwhile, CCND1 was identified as the target gene of miR-195 and further studied. More importantly, using real-time PCR, we evaluated the expression of miR-195 and CCND1 in osteosarcoma samples from 107 frozen biopsy tissues and 99 formalin- or paraformalin-fixed, paraffin-embedded (FFPE) tissues. Results indicated lowly expressed miR-195 or highly CCND1 correlated with positive overall survival and their expression inversely related to each other. In summary, our study suggests miR-195 functions as a tumor metastasis suppressor gene by down-regulating CCND1 and can be used as a potential target in the treatment of osteosarcoma. PMID- 25823926 TI - Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-kappaB and STAT3 signaling in a bionic airway chip culture and in animal models. AB - We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-kappaB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-alpha signaling or inhibition of NF-kappaB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo, macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-kappaB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-alpha/NF-kappaB/cyclinD1 and IL 6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis. PMID- 25823928 TI - Dynamic instability 30 years later: complexities in microtubule growth and catastrophe. AB - Microtubules are not like other polymers. Whereas polymers such as F-actin will grow continuously as long as the subunit concentration is high enough, a steadily growing microtubule can suddenly shrink even when there is ample alphabeta tubulin around. This remarkable behavior was discovered in 1984 when Tim Mitchison and Marc Kirschner deduced that microtubules switch from growth to shrinkage when they lose their GTP caps. Here, I review the canonical explanation of dynamic instability that was fleshed out in the years after its discovery. Many aspects of this explanation have been recently subverted, particularly those related to how GTP-tubulin forms polymers and why GTP hydrolysis disrupts them. I describe these developments and speculate on how our explanation of dynamic instability can be changed to accommodate them. PMID- 25823929 TI - Correction. PMID- 25823927 TI - Aberrant nuclear factor-kappa B activity in acute myeloid leukemia: from molecular pathogenesis to therapeutic target. AB - The overall survival of patients with acute myeloid leukemia (AML) has not been improved significantly over the last decade. Molecularly targeted agents hold promise to change the therapeutic landscape in AML. The nuclear factor kappa B (NF-kappaB) controls a plethora of biological process through switching on and off its long list of target genes. In AML, constitutive NF-kappaB has been detected in 40% of cases and its aberrant activity enable leukemia cells to evade apoptosis and stimulate proliferation. These facts suggest that NF-kappaB signaling pathway plays a fundamental role in the development of AML and it represents an attractive target for the intervention of AML. This review summarizes our current knowledge of NF-kappaB signaling transduction including canonical and non-canonical NF-kappaB pathways. Then we specifically highlight what factors contribute to the aberrant activation of NF-kappaB activity in AML, followed by an overview of 8 important clinical trials of the first FDA approved proteasome inhibitor, Bortezomib (Velcade), which is a NF-kappaB inhibitor too, in combination with other therapeutic agents in patients with AML. Finally, this review discusses the future directions of NF-kappaB inhibitor in treatment of AML, especially in targeting leukemia stem cells (LSCs). PMID- 25823932 TI - A critical care network pressure ulcer prevention quality improvement project. AB - BACKGROUND: Pressure ulcer prevention is an important safety issue, often underrated and an extremely painful event harming patients. Critically ill patients are one of the highest risk groups in hospital. The impact of pressure ulcers are wide ranging, and they can result in increased critical care and the hospital length of stay, significant interference with functional recovery and rehabilitation and increase cost. AIMS: This quality improvement project had four aims: (1) to establish a critical care network pressure ulcer prevention group; (2) to establish baseline pressure ulcer prevention practices; (3) to measure, compare and monitor pressure ulcers prevalence; (4) to develop network pressure ulcer prevention standards. METHODS: The approach used to improve quality included strong critical care nursing leadership to develop a cross organisational pressure ulcer prevention group and a benchmarking exercise of current practices across a well-established critical care Network in the North of England. The National Safety Thermometer tool was used to measure pressure ulcer prevalence in 23 critical care units, and best available evidence, local consensus and another Critical Care Networks' bundle of interventions were used to develop a local pressure ulcer prevention standards document. RESULTS: The aims of the quality improvement project were achieved. This project was driven by successful leadership and had an agreed common goal. The National Safety Thermometer tool was an innovative approach to measure and compare pressure ulcer prevalence rates at a regional level. A limitation was the exclusion of moisture lesions. CONCLUSION: The project showed excellent engagement and collaborate working in the quest to prevent pressure ulcers from many critical care nurses with the North of England Critical Care Network. RELEVANCE TO CLINICAL PRACTICE: A concise set of Network standards was developed for use in conjunction with local guidelines to enhance pressure ulcer prevention. PMID- 25823930 TI - Genome-wide association study identifies common genetic variants associated with salivary gland carcinoma and its subtypes. AB - BACKGROUND: Salivary gland carcinomas (SGCs) are a rare malignancy with unknown etiology. The objective of the current study was to identify genetic variants modifying the risk of SGC and its major subtypes: adenoid cystic carcinoma and mucoepidermoid carcinoma. METHODS: The authors conducted a genome-wide association study in 309 well-defined SGC cases and 535 cancer-free controls. A single-nucleotide polymorphism (SNP)-level discovery study was performed in non Hispanic white individuals followed by a replication study in Hispanic individuals. A logistic regression analysis was applied to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A meta-analysis of the results was conducted. RESULTS: A genome-wide significant association with SGC in non Hispanic white individuals was detected at coding SNPs in CHRNA2 (cholinergic receptor, nicotinic, alpha 2 [neuronal]) (OR, 8.55; 95% CI, 4.53-16.13 [P = 3.6 * 10(-11)]), OR4F15 (olfactory receptor, family 4, subfamily F, member 15) (OR, 5.26; 95% CI, 3.13-8.83 [P = 3.5 * 10(-10)]), ZNF343 (zinc finger protein 343) (OR, 3.28; 95% CI, 2.12-5.07 [P = 9.1 * 10(-8)]), and PARP4 (poly(ADP-ribose) polymerase family, member 4) (OR, 2.00; 95% CI, 1.54-2.59 [P = 1.7 * 10(-7)]). Meta-analysis of the non-Hispanic white and Hispanic cohorts identified another genome-wide significant SNP in ELL2 (meta-OR, 1.86; 95% CI, 1.48-2.34 [P = 1.3 * 10(-7)]). Risk alleles were largely enriched in mucoepidermoid carcinoma, in which the SNPs in CHRNA2, OR4F15, and ZNF343 had ORs of 15.71 (95% CI, 6.59-37.47 [P = 5.2 * 10(-10)]), 15.60 (95% CI, 6.50-37.41 [P = 7.5 * 10(-10)]), and 6.49 (95% CI, 3.36-12.52 [P = 2.5 * 10(-8)]), respectively. None of these SNPs retained a significant association with adenoid cystic carcinoma. CONCLUSIONS: To the best of the authors' knowledge, the current study is the first to identify a panel of SNPs associated with the risk of SGC. Confirmation of these findings along with functional analysis of identified SNPs are needed. PMID- 25823931 TI - Gastric mixed adenoneuroendocrine carcinoma with thyroid transcription factor-1 positive neuroendocrine component. AB - Small cell carcinoma of the stomach, which is considered synonymous with neuroendocrine carcinoma, is rare. We encountered a case of mixed adenoneuroendocrine carcinoma. Gastrointestinal endoscopy revealed a type 0 IIa + IIc lesion in the stomach. Biopsy suggested well-differentiated adenocarcinoma. Endoscopic submucosal dissection was performed and gastric cancer comprising both well to moderately differentiated adenocarcinoma within the mucous membrane and small cell carcinoma invading to the submucosa with accompanying vessel invasion was found. Mixed adenoneuroendocrine carcinoma was diagnosed and the small cell carcinoma was thyroid transcription factor-1 positive. No tumor lesions were apparent in other organs, so distal gastrectomy and lymph node dissection were performed. Lymph node metastases were not observed. The patient is currently alive without recurrence. Thyroid transcription factor-1-positive gastric neuroendocrine carcinoma is very rare, and the thyroid transcription factor-1 positive rate may contribute to the prediction of prognosis and treatment selection. Accumulation of cases is thus very important. PMID- 25823934 TI - [Techniques and strategy of pathological sampling in the diagnostic and therapeutic management of lung cancer]. AB - Histopathology is key to the diagnosis and staging of lung cancer. This analysis requires tissue sampling from primary and/or metastatic lesions. The choice of sampling technique is intended to optimize diagnostic yield while avoiding unnecessarily invasive procedures. Recent developments in targeted therapy require increasingly precise histological and molecular characterization of the tumor. Therefore, pathologists must be economical with tissue samples to ensure that they have the opportunity to perform all the analyses required. More than ever, good communication between clinician, endoscopist or surgeon, and pathologist is essential. This is necessary to ensure that all participants in the process of lung cancer diagnosis collaborate to ensure that the appropriate number and type of biopsies are performed with the appropriate tissue sampling treatment. This will allow performance of all the necessary analyses leading to a more precise characterization of the tumor, and thus the optimal treatment for patients with lung cancer. PMID- 25823933 TI - An integrated analysis of the effects of microRNA and mRNA on esophageal squamous cell carcinoma. AB - Esophageal squamous cell cancer (ESCC) is an aggressive type of cancer with poor prognosis and leading to decreased quality of life. The identification of patients at increased risk of esophageal squamous cell cancer may improve current understanding of the role of micro (mi)RNA in tumorigenesis, since the miRNA pattern of these patients may be associated with tumorigenesis. In the present study, the miRNA and mRNA expression profiles of ESCC tissue samples and adjacent normal control tissue samples were obtained from two dependent GEO series. Bioinformatics analyses, including the use of the Gene Oncology and Kyoto Encyclopedia of Genes and Genomes databases, were used to identify genes and pathways, which were specifically associated with miRNA-associated ESCC oncology. A total of 17 miRNAs and 1,670 probes were differentially expressed in the two groups, and the differentially expressed miRNA and target interactions were analyzed. The mRNA of miRNA target genes were found to be involve 49 GO terms and 14 pathways. Of the genes differentially expressed between the two groups, miRNA 181a, miRNA-202, miRNA-155, FNDC3B, BNC2 and MBD2 were the most significantly altered and may be important in the regulatory network. In the present study, a novel pattern of differential miRNA-target expression was constructed, which with further investigation, may provide novel targets for diagnosing and understanding the mechanism of ESCC. PMID- 25823935 TI - [Continuous positive airways pressure treatment for obstructive sleep apnoea]. AB - Continuous positive airway pressure (CPAP) still remains the most frequently used and the most efficient treatment for obstructive sleep apnea syndrome. However, its efficiency is conditioned by healthcare quality depending on many factors such as medical specificities of the patients as well as the severity of sleep related breathing disorders. In order to optimize CPAP efficiency, it is necessary to be aware of the functional abilities of the different devices, and to perform a close monitoring of the patients, particularly during the first weeks of treatment, by maximally using the data provided by the CPAP apparatus. Some questions remain unsolved, such as the impact of nasal CPAP on glucose metabolism or cardiovascular prognosis. Furthermore, the strategy of CPAP use should be improved according to future results of studies dedicated to the interest of home telemonitoring and taking into account the validated mode of CPAP initiation. PMID- 25823936 TI - [Does exposure to tabouna (oven garden) increase the risk of small-cell lung carcinoma in non-smoking women?]. PMID- 25823937 TI - Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise. AB - With the advances in biomedical research and neonatal intensive care, our understanding of cardiovascular developmental physiology and pathophysiology has significantly improved during the last few decades. Despite this progress, the current management of circulatory compromise depends primarily on experts' opinions rather than high level of evidence. The lack of reliable, accurate, continuous and preferably non-invasive monitoring techniques has further limited our ability to collect the information needed for the design and execution of more sophisticated clinical trials with a better chance to provide the evidence we need. Given the lack of randomized, placebo-controlled trials investigating clinically relevant outcomes of novel treatments of neonatal cardiovascular compromise, we must now use the available lower level of evidence and our present understanding of developmental physiology and pathophysiology when providing cardiovascular supportive care to critically ill neonates. However, with recent advances in cardiovascular monitoring capabilities, direct and more objective assessment of the changes in cardiovascular function, organ blood flow, and tissue oxygenation have become possible. These advances have helped in our clinical assessment and enabled us to start designing more sophisticated interventional clinical trials using clinically relevant endpoints. PMID- 25823938 TI - Predictive monitoring for sepsis and necrotizing enterocolitis to prevent shock. AB - Despite vigilant clinical assessment of infants in the neonatal intensive care unit (NICU), diagnosis of sepsis and necrotizing enterocolitis often does not occur until an infant has significant hemodynamic compromise. Predictive monitoring involves analysis of vital signs and other clinical data to identify infants at highest risk and to detect early-stage illness, leading to timelier treatment and improved outcomes. The first vital-sign predictive monitoring device developed for sepsis detection in babies in the NICU is the heart rate characteristics index (HeRO) monitor, which continuously analyzes the electrocardiogram signal for low heart rate variability and transient decelerations. Use of this monitor in very low birth weight infants (<1500 g) was shown in a large multicenter randomized clinical trial to significantly reduce mortality. The purpose of this review is (1) to summarize the physiologic changes in neonatal sepsis and progression to shock, (2) to review efforts toward risk stratification for sepsis shortly after birth based on demographic and physiologic scoring systems, (3) to describe development and implementation of heart rate characteristics monitoring and other important aspects of sepsis early warning systems, and (4) to provide an overview of current research analyzing multiple vital signs and other clinical variables in an attempt to develop even more effective predictive monitoring devices and systems. PMID- 25823939 TI - Clinical relevance of fetal hemodynamic monitoring: Perinatal implications. AB - Comprehensive assessment of fetal wellbeing involves monitoring of fetal growth, placental function, central venous pressure, and cardiac function. Ultrasound evaluation of the fetus using 2D, color Doppler, and pulse-wave Doppler techniques form the foundation of antenatal diagnosis of structural anomalies, rhythm abnormalities and altered fetal circulation. Accurate and timely prenatal identification of the fetus at risk is critical for appropriate parental counseling, antenatal diagnostic testing, consideration for fetal intervention, perinatal planning, and coordination of postnatal care delivery. Fetal hemodynamic monitoring and serial assessment are vital to ensuring fetal wellbeing, particularly in the setting of complex congenital anomalies. A complete hemodynamic evaluation of the fetus gives important information on the likelihood of a smooth postnatal transition and contributes to ensuring the best possible outcome for the neonate. PMID- 25823940 TI - Factors associated with discharge to home versus discharge to institutional care after inpatient stroke rehabilitation. AB - OBJECTIVE: To examine sociodemographic and clinical characteristics independently associated with discharge home compared with discharge to a skilled nursing facility (SNF) after acute inpatient rehabilitation. DESIGN: Retrospective cohort study. SETTING: Three tertiary accredited acute care rehabilitation facilities. PARTICIPANTS: Adult patients with stroke (N=2085). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Of 2085 patients with stroke treated at 3 centers over a 4-year period, 78.2% (n=1631) were discharged home and 21.8% (n=454) discharged to an SNF. Findings from a multivariable logistic regression analysis indicated that patients were less likely to be discharged home if they were older (odds ratio [OR], .98; 95% confidence interval [CI], .96 .99), separated or divorced (compared with married; OR, .61; 95% CI, .48-.79), or with Medicare health insurance (compared with private insurance; OR, .69; 95% CI, .55-.88), or had dysphagia (OR, .83; 95% CI, .71-.98) or cognitive deficits (OR, .79; 95% CI, .77-.81). The odds of being discharged home were higher for those admitted with a higher motor FIM score (OR, 1.10; 95% CI, 1.09-1.11). The following were not associated with discharge disposition: sex, race, prestroke vocational status, availability of secondary health insurance, number of days from stroke onset to rehabilitation facility admission, stroke type, impairment group, cognitive FIM on admission, other stroke deficits (aphasia, ataxia, neglect, or speech disturbance), stroke complications of hyponatremia or urinary tract infection, or comorbid conditions. CONCLUSIONS: One in 5 patients with stroke were discharged to an SNF after inpatient rehabilitation. On admission, several sociodemographic and clinical characteristics were identified that could be considered as important factors in early discussions for discharge planning. PMID- 25823941 TI - Comparative ex vivo study on humidifying function of three speaking valves with integrated heat and moisture exchanger for tracheotomised patients. AB - OBJECTIVE: Assessment of humidifying function of tracheotomy speaking valves with integrated heat and moisture exchanger. DESIGN: Ex vivo measurement of water exchange and storage capacity of three tracheotomy speaking valves: Humidiphon Plus, Spiro and ProTrach DualCare (with two different heat and moisture exchangers: XtraMoist and Regular). SETTING: Comprehensive Cancer Centre. PARTICIPANT: Healthy volunteer. MAIN OUTCOME MEASURES: Difference between end inspiratory and end-expiratory weight as measure for water exchange capacity, weight after 10 min breathing as measure for water storage capacity, weighing at 1-min intervals to assess residual water exchange potential in speaking mode and absolute humidity in mg/L as measure for environmental and respiratory humidity. RESULTS: None of the tracheotomy speaking valves provides humidification while in speaking mode. Only the ProTrach DualCare allows blocking the speaking valve and breathing through the heat and moisture exchanger during inhalation and exhalation (heat and moisture exchanger mode). This leads to an increase in inspiratory humidity of 2.5 mg (XtraMoist) and 1.6 mg (Regular). There was no measurable water storage in speaking mode in any of the three tracheotomy speaking valves. In breathing mode, water storage in the DualCare heat and moisture exchangers was 47 and 37 mg, respectively. The remaining humidifying potential in speaking mode after 10 min breathing in heat and moisture exchanger mode for XtraMoist was 38%, 15% and 10% at 1, 2 and 3 min, respectively. For Regular, this was 47%, 24% and 13%, respectively. CONCLUSIONS: Tracheostoma valves with integrated heat and moisture exchanger have no humidification function in speaking mode. Only ProTrach DualCare, allowing blocking the speaking mode, in heat and moisture exchanger mode enables a significant increase in humidification. Regular switching between speaking and heat and moisture exchanger mode with this latter device prolongs the humidification in speaking mode. PMID- 25823942 TI - Epigenetic pattern changes in prenatal female Sprague-Dawley rats following exposure to androgen. AB - Androgen excess is generally considered to be one of the major characteristics of polycystic ovary syndrome (PCOS). Evidence from both clinical research and animal studies has revealed that this syndrome may have fetal origins, with epigenetics being proposed as the underlying mechanism. Our PCOS rat model induced by prenatal administration of 3mg testosterone from Embryonic Day (E) 16 to E19 showed polycystic ovaries, irregular oestrous cycles and endocrine disorders in adulthood. The methylation status of 16, 8 and 4 cytosine-phosphate-guanine (CpG) sites in the promoter regions of the androgen receptor (Ar), cytochrome P450 family 11, subfamily A, polypeptide 1 (Cyp11a1) and cytochrome P450, family 17, subfamily A, polypeptide 1 (Cyp17a1) genes, respectively, were measured by pyrosequencing. We identified three hypomethylated sites (CpG +58, +65 and +150) in Ar and one hypomethylated site (CpG +1016) in Cyp11a1 in peripheral blood cells of prenatally androgenised (PNA) rats. In ovarian tissue, five CpG sites of Ar (CpG +87, +91, +93, +98, +150) and one single CpG site in Cyp11a1 (CpG +953) were significantly hypomethylated in PNA rats, but the modified methylation of these two genes may not be sufficient to significantly alter levels of gene expression. Furthermore, tissue-specific methylation analysis revealed that both Ar and Cyp11a1 exhibited significant hypomethylation in testis in contrast with ovary and blood. PNA may lead to methylation pattern changes and the development of PCOS, but further studies are required to reveal causal relationships. PMID- 25823943 TI - The biodiversity and genetic structure of Balearic sheep breeds. AB - The Balearic sheep breeds, Mallorquina, Menorquina, Roja Mallorquina, Ibicenca and one possible new genetic group, Formentera, constitute a unique genetic resource in the Mediterranean farming landscape, displaying high genetic diversity levels and being well differentiated among themselves and with respect to the continental sheep breeds. We used a microsatellite panel of markers to study genetic diversity and relationships with other Spanish breeds. The results reported in this study have important implications for the use, conservation and breeding of Balearic sheep stocks. A mean number of 7.59 alleles was found among the Balearic sheep breeds for the microsatellites scored. The whole mean value of observed heterozygosity amounted to 0.62, whereas the expected heterozygosity value was 0.69, suggesting the presence of a great degree of genetic variability, although a significant deficit of heterozygotes was detected for some markers. Genetic distance estimates showed that Balearic sheep are differentiated from the other Spanish breeds and in particular, from the Merino type. The Ibicenca breed showed the highest distance value from other breeds. The neighbour-net method of analysis clustered the Roja Mallorquina, Menorquina and Mallorquina breeds. The Structure results clearly demonstrated the genetic differentiation among the four Balearic sheep breeds, with the Ibicenca and Formentera races joined, with slight migration among them. Few external genetic influences from the Spanish mainland breeds were detected. PMID- 25823944 TI - Aspects of abuse: commercial sexual exploitation of children. AB - Commercial sexual exploitation of children (CSEC) and adolescents is a serious worldwide problem. It is, in essence, the sexual abuse of a minor for economic gain. In the United States, there is no uniform nationwide database to capture the incidence and prevalence of CSEC. Therefore, there is a great variation in the estimates, but the actual numbers are unknown. Given the clandestine nature of the practice, it is often underreported and underidentified. Healthcare providers will often encounter victims of commercial sexual exploitation due to mental health, physical health, and sexual health consequences, and therefore should be knowledgeable in the signs of possible sexual exploitation. The aim of this article is to educate healthcare providers on how vulnerable children may become sexually exploited, the health consequences involved with sexual exploitation, how to better identify possible victims, and the medical evaluation of a victim of sexual exploitation. PMID- 25823946 TI - Editorial overview: tumour immunology. PMID- 25823945 TI - Small-molecule inhibitor of Bcl-2 (TW-37) suppresses growth and enhances cisplatin-induced apoptosis in ovarian cancer cells. AB - BACKGROUND: Bcl-2 plays a major role in the pathobiology and drug resistance of ovarian cancer, and inhibition of bcl-2 was useful for OC therapy. It has previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in many cancer cells. In the present study,we investigate the effect of TW-37 or / and in combination with cisplain on several ovarian cancer (OC) cell lines with high bcl-2 expression. METHODS: The bcl-2 mRNA and protein expression, and the cisplain (DDP) sensitivity of OC cell lines SKOV3, OVCAR3, OV-90 and 3AO and SKOV3DDP were determined by Quantitative real-time RT-PCR,Western blot, and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and fluorescence-activated cell sorting (MTT) assays. The effects of TW-37 alone or combined with cisplain on growth and apoptosis in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells was detected by MTT,clonogenic assay, ELISA and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay. RESULTS: The cell lines SKOV3 and 3AO were sensitive, whereas OVCAR3, OV-90 and SKOV3DDP were resistant to cisplain. Significant positive correlation was observed between basal bcl-2 mRNA and protein and cisplain sensitivity. Cisplain treatment did not activate bcl-2 in vitro. Treatment with TW-37 inhibited bcl-2 expression in bcl-2 overexpressed OVCAR3, OV-90 and SKOV3DDP cells , and inhibited growth and induced apoptosis ,and increased cisplain killing of the bcl-2 overexpressed cells in a does and time-dependant manner in vitro. CONCLUSION: Bcl-2 level positively correlated with sensitivity to cisplain. Treatment with TW-37 was effective alone and in combination with cisplain in bcl-2 overexpressed OC cell lines in vitro. Thus, TW-37 may be a useful therapeutic agent for OCs. PMID- 25823947 TI - Association between anemia and multiple sclerosis. AB - BACKGROUND/AIMS: The relationship between multiple sclerosis (MS) and anemia has not been clarified sufficiently. In this retrospective, cross-sectional, case control study we evaluated in MS patients: (1) prevalence of anemia relative to sex- and age-matched controls; (2) relationships between patients' demographic, clinical and drug-related characteristics and anemia; (3) effect of anemia on the risk of developing MS. METHODS: 187 consecutive MS patients (51 males, mean age (+/-SD) 44.5 +/- 10.7 years) and 200 controls (56 males, mean age 45.5 +/- 12 years) were included in the study. Anemia was defined as hemoglobin <12 g/dl for females and <13 g/dl for males. RESULTS: There was a significant difference in the prevalence of anemia between MS patients and controls (35 (18.7%) and 19 (9.5%), respectively, p = 0.009). We did not find any association between patients' characteristics and anemia. The occurrence of anemia increased more than twice the risk of developing MS (odds ratio: 2.19, 95% confidence interval 1.19-4.0). CONCLUSION: Our study showed a consistent association between anemia and MS. PMID- 25823948 TI - Increased yield of high purity recombinant human brain natriuretic peptide by acid hydrolysis of short fusion partner in Escherichia coli. AB - Recombinant human B-type natriuretic peptide (rhBNP) is a 32-amino acid peptide used to treat congestive heart failure. In this paper, we report a method for the increased production of rhBNP in Escherichia coli with high purity. hBNP was cloned with a short growth hormone fusion partner coupled with a unique acid labile dipeptide linker to cleave the fusion protein to release the rhBNP. The recombinant fusion protein was expressed as an inclusion body (IB) and the fermentation process was optimized to produce on large scale. The IBs were recovered by cell lysis, and the pure IBs were directly treated with diluted acid to get the target peptide from the fusion protein and the resultant peptide was purified by reversed phase chromatography. The final purity of the rhBNP was more than 99% with yield of 50mg per liter of culture, which is ten times higher than the previous reports. The purified rhBNP exhibited specific biological activity similar to the standard peptide in producing cyclic-guanosine monophosphate. PMID- 25823949 TI - Complementary spin-Hall and inverse spin-galvanic effect torques in a ferromagnet/semiconductor bilayer. AB - Recently discovered relativistic spin torques induced by a lateral current at a ferromagnet/paramagnet interface are a candidate spintronic technology for a new generation of electrically controlled magnetic memory devices. The focus of our work is to experimentally disentangle the perceived two model physical mechanisms of the relativistic spin torques, one driven by the spin-Hall effect and the other one by the inverse spin-galvanic effect. Here, we show a vector analysis of the torques in a prepared epitaxial transition-metal ferromagnet/semiconductor paramagnet single-crystal structure by means of the all-electrical ferromagnetic resonance technique. By choice of our structure in which the semiconductor paramagnet has a Dresselhaus crystal inversion asymmetry, the system is favourable for separating the torques due to the inverse spin-galvanic effect and spin-Hall effect mechanisms into the field-like and antidamping-like components, respectively. Since they contribute to distinct symmetry torque components, the two microscopic mechanisms do not compete but complement each other in our system. PMID- 25823950 TI - 2015 golden helix symposium - next generation pharmacogenomics. March 11-13, 2015, kuala lumpur, malaysia: abstracts. PMID- 25823952 TI - Blood transcriptomic markers for major depression: from animal models to clinical settings. AB - Depression is a heterogeneous disorder and, similar to other spectrum disorders, its manifestation varies by age of onset, severity, comorbidity, treatment responsiveness, and other factors. A laboratory blood test based on specific biomarkers for major depressive disorder (MDD) and its subgroups could increase diagnostic accuracy and expedite the initiation of treatment. We identified candidate blood biomarkers by examining genome-wide expression differences in the blood of animal models representing both the genetic and environmental/stress etiologies of depression. Human orthologs of the resulting transcript panel were tested in pilot studies. Transcript abundance of 11 blood markers differentiated adolescent subjects with early-onset MDD from adolescents with no disorder (ND). A set of partly overlapping transcripts distinguished adolescent patients who had comorbid anxiety disorders from those with only MDD. In adults, blood levels of nine transcripts discerned subjects with MDD from ND controls. Even though cognitive behavioral therapy (CBT) resulted in remission of some patients, the levels of three transcripts consistently signaled prior MDD status. A coexpression network of transcripts seems to predict responsiveness to CBT. Thus, our approach can be developed into clinically valid diagnostic panels of blood transcripts for different manifestations of MDD, potentially reducing diagnostic heterogeneity and advancing individualized treatment strategies. PMID- 25823951 TI - Urinary triclosan concentrations are inversely associated with body mass index and waist circumference in the US general population: Experience in NHANES 2003 2010. AB - BACKGROUND: Humans are extensively exposed to triclosan, an antibacterial and antifungal agent. Triclosan's effects on human health, however, have not been carefully investigated. OBJECTIVE: To examine whether triclosan exposure is associated with obesity traits. METHODS: This study included 2898 children (6-19 years old) and 5066 adults (20 years or older) who participated in the National Health and Nutrition Examination Surveys (NHANES) 2003-2010 and had a detectable level of urinary triclosan. Multiple linear regression models were used to examine the association between urinary triclosan and both body mass index (BMI) and waist circumference. RESULTS: Each standard deviation increase in urinary triclosan was associated with a 0.34 (95% confidence interval, CI: 0.05, 0.64) kg/m2 lower level of BMI (P=0.02) and 0.92 (95% CI: 0.09, 1.74)cm smaller waist circumference (P=0.03) in boys, and a 0.62 (95% CI: 0.31, 0.94) kg/m2 lower level of BMI (P=0.0002) and 1.32 (95% CI: 0.54, 2.09) cm smaller waist circumference in girls (P=0.001); a 0.42 (95% CI: 0.06, 0.77) kg/m2 lower level of BMI (P=0.02) and 1.35 (95% CI: 0.48, 2.22) cm smaller waist circumference (P=0.003) in men, and a 0.71 (95% CI: 0.34, 1.07) kg/m2 lower level of BMI (P=0.0002) and 1.68 (95% CI: 0.86, 2.50) cm smaller waist circumference (P=0.0001) in women. In both children and adults, there was a consistent trend for lower levels of BMI and smaller waist circumference with increasing levels of urinary triclosan, from the lowest to the highest quartile of urinary triclosan (P <= 0.001 in all cases). CONCLUSION: Triclosan exposure is inversely associated with BMI and waist circumference. The biological mechanisms linking triclosan exposure to obesity await further investigation. PMID- 25823953 TI - The diagnostic role of (18)F fluorodeoxyglucose positron emission tomography in patients with fever of unknown origin. AB - BACKGROUND: Identification of aetiology for fever of unknown origin (FUO) is challenging, due to the high rates of undiagnosed cases. The current diagnostic approach includes initially first-line procedures such as general examination and various laboratory tests and basic imaging techniques followed by second-line tests such as more advanced imaging techniques including (18)F fluorodeoxyglucose positron emission tomography (FDG PET) and tissue biopsies. If no diagnosis is obtained, more invasive measures may be in order such as liver biopsy and exploratory laparotomy. MATERIALS AND METHODS: This review article is based on the relative published material found on MEDLINE and PubMed up to August 2014. We looked for the terms 'fever of unknown origin, FDG PET' in combination with 'cancer, infection and autoimmune disease'. RESULTS: Several clinical studies have investigated the utility of the FDG PET during the diagnostic approach of FUO. Recent evidence suggests that FDG PET has the advantage of total body imaging and may depict all common causes of FUO such as infections, noninfectious inflammatory causes and tumours because they all exhibit glucose hypermetabolism. Depiction of an abnormal lesion on FDG PET could guide clinicians to the next diagnostic procedure (another imaging method, culture, biopsy or surgery) to establish the diagnosis. CONCLUSIONS: Emerging evidence suggests that FDG PET, when available, may provide critical diagnostic information early during evaluation of FUO. PMID- 25823955 TI - Investigating the Postmortem Molecular Biology of Cartilage and its Potential Forensic Applications. AB - This study investigated the postmortem molecular changes that articular cartilage undergoes following burial. Fresh pig trotters were interred in 30-cm-deep graves at two distinct locations exhibiting dissimilar soil environments for up to 42 days. Extracts of the metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joint cartilage from trotters disinterred weekly over 6 weeks were analyzed by Western blot against the monoclonal antibody 2-B-6 to assess aggrecan degradation. In both soil conditions, aggrecan degradation by-products of decreasing molecular size and complexity were observed up to 21 days postmortem. Degradation products were undetected after this time and coincided with MCP/MTP joint exposure to the soil environment. These results show that cartilage proteoglycans undergo an ordered molecular breakdown, the analysis of which may have forensic applications. This model may prove useful for use as a human model and for forensic investigations concerning crimes against animals and the mortality of endangered species. PMID- 25823956 TI - Reply: To PMID 25376643. PMID- 25823954 TI - The role of CD8 T lymphocytes in rickettsial infections. AB - Arthropod-borne obligately intracellular bacteria pose a difficult challenge to the immune system. The genera Rickettsia, Orientia, Ehrlichia, and Anaplasma evolved mechanisms of immune evasion, and each interacts differently with the immune system. The roles of CD8 T cells include protective immunity and immunopathology. In Rickettsia infections, CD8 T cells are protective mediated in part by cytotoxicity toward infected cells. In contrast, TNF-alpha overproduction by CD8 T cells is pathogenic in lethal ehrlichiosis by induction of apoptosis/necrosis in hepatocytes. Yet, CD8 T cells, along with CD4 T cells and antibodies, also contribute to protective immunity in ehrlichial infections. In granulocytic anaplasmosis, CD8 T cells impact pathogen control modestly but could contribute to immunopathology by virtue of their dysfunction. While preliminary evidence indicates that CD8 T cells are important in protection against Orientia tsutsugamushi, mechanistic studies have been neglected. Valid animal models will enable experiments to elucidate protective and pathologic immune mechanisms. The public health need for vaccines against these agents of human disease, most clearly O. tsutsugamushi, and the veterinary diseases, canine monocytotropic ehrlichiosis (Ehrlichia canis), heartwater (Ehrlichia ruminantium), and bovine anaplasmosis (A. marginale), requires detailed immunity and immunopathology investigations, including the roles of CD8 T lymphocytes. PMID- 25823957 TI - [Perioperative anemia correction in Patient Blood Management programs: Lights and shadows]. PMID- 25823958 TI - Secukinumab in psoriasis: randomized, controlled phase 3 trial results assessing the potential to improve treatment response in partial responders (STATURE). AB - BACKGROUND: Secukinumab, an anti-interleukin-17A monoclonal antibody, has demonstrated rapid and sustained efficacy in phase 3 psoriasis trials. OBJECTIVES: To examine whether partial responders could achieve improved responses with intravenous (IV) secukinumab vs. the same or a higher subcutaneous (SC) dose. METHODS: Forty-three participants with moderate-to-severe psoriasis and partial response [Psoriasis Area and Severity Index (PASI) score improvement of >= 50% but < 75%] after 12 weeks of 300 or 150 mg SC secukinumab therapy were randomized 1 : 1 to secukinumab 10 mg kg(-1) IV (baseline, weeks 2 and 4, respectively) or secukinumab 300 mg SC (baseline, week 4). All participants subsequently received secukinumab 300 mg SC every 4 weeks (weeks 8-36). Co primary end points were PASI 75 and Investigator's Global Assessment [2011 modified version (IGA mod 2011)] 0/1 response rates at week 8 (IV vs. SC). RESULTS: Higher IGA mod 2011 0/1 response rates (66.7% vs. 33.3%; P = 0.03) and a trend towards higher PASI 75 response rates (90.5% vs. 66.7%; P = 0.06) were observed with secukinumab IV vs. SC at week 8. The primary objective was not met, as the difference was not significant for both co-primary end points. Improved responses in both groups were maintained at week 40 in most participants. Safety profiles for IV and SC secukinumab were similar. The trial was underpowered owing to its small sample size. CONCLUSIONS: Improved response may be attained in patients with psoriasis achieving partial response after 12 weeks of SC secukinumab treatment by continued dosing with 300 mg SC or treatment with higher doses. PMID- 25823959 TI - Psychological aspects of hyperandrogenic states in late adolescent and young women. AB - OBJECTIVE: The psychosocial implications of polycystic ovary syndrome (PCOS) phenotypes have been investigated in different patient populations, but little attention was paid to adolescent and young women. The aim of this study was to evaluate the psychosocial correlates of PCOS and other hyperandrogenic states in a population of late adolescent and young females and to provide a psychological characterization of specific clinical hyperandrogenic phenotypes. DESIGN: This was a cross-sectional study. PATIENTS: High school female students, aged 16-19 years. MEASUREMENTS: The study protocol was designed with three possible levels of participation characterized by an increased level of commitment. For the specific purposes of this investigation, we focused on the subsamples of students whose clinical state was assessed by medical examination (n = 835) and for whom additional laboratory tests were available (n = 394). Psychological evaluation encompassed psychological distress, levels of stress, well-being, illness behaviour and quality of life (as measured by the Symptom Questionnaire, the Psychosocial Index and the Psychological Well-Being scales). RESULTS: Significantly higher levels of psychological distress and impaired well-being and quality of life were found among late adolescent and young women with isolated clinical hyperandrogenism compared to their normal counterparts. Furthermore, females with PCOS showed significantly greater hostility/irritability compared to healthy control subjects. CONCLUSIONS: These findings highlight the importance of early recognizing and adequately managing psychological distress in such patients. PMID- 25823961 TI - Silver intercalation in SPS dense TiS2: staging and thermoelectric properties. AB - Polycrystalline samples in the series AgxTiS2 with x varying from 0 to 0.2 were prepared using solid-liquid-vapor reaction and spark plasma sintering. Depending on the x content, it is found that different stages can occur with intercalation, from the so-called 1T-TiS2 (stage 1) to ordered Ag1/6TiS2 (stage 2). Randomly intercalated Ag cations in the van der Waals gap of stage 1 and stage 2 based TiS2 structures induce a strong decrease of lattice thermal conductivity through structural disorder. A decrease in electrical resistivity and the absolute value of the Seebeck coefficient with increasing Ag content supports also the charge transfer to the Ti 3d conduction band, enhancing the power factor in the specific temperature range. Thus, the combined effects of Ag intercalation are beneficial to the improvement in ZT, reaching around 0.45 at 700 K in Ag intercalated compounds. PMID- 25823960 TI - Novel mechanism of cardiac protection by valsartan: synergetic roles of TGF-beta1 and HIF-1alpha in Ang II-mediated fibrosis after myocardial infarction. AB - Transforming growth factor (TGF)-beta1 is a known factor in angiotensin II (Ang II)-mediated cardiac fibrosis after myocardial infarction (MI). Hypoxia inducible factor-1 (Hif-1alpha) was recently demonstrated to involve in the tissue fibrosis and influenced by Ang II. However, whether Hif-1alpha contributed to the Ang II mediated cardiac fibrosis after MI, and whether interaction or synergetic roles between Hif-1alpha and TGF-beta pathways existed in the process was unclear. In vitro, cardiac cells were incubated under hypoxia or Ang II to mimic ischaemia. In vivo, valsartan was intravenously injected into Sprague-Dawley rats with MI daily for 1 week; saline and hydralazine (another anti-hypertensive agent like valsartan) was used as control. The fibrosis-related proteins were detected by Western blotting. Cardiac structure and function were assessed with multimodality methods. We demonstrated in vitro that hypoxia would induce the up-regulation of Ang II, TGF-beta/Smad and Hif-1alpha, which further induced collagen accumulation. By blocking with valsartan, a blocker of Ang II type I (AT1) receptor, we confirmed that the up-regulation of TGF-beta/Smad and Hif-1alpha was through the Ang II-mediated pathway. By administering TGF-beta or dimethyloxalylglycine, we determined that both TGF-beta/Smad and Hif-1alpha contributed to Ang II-mediated collagen accumulation and a synergetic effect between them was observed. Consistent with in vitro results, valsartan significantly attenuated the expression of TGF-beta/Smad, Hif-1alpha and fibrosis related protein in rats after MI. Heart function, infarcted size, wall thickness as well as myocardial vascularization of ischaemic hearts were also significantly improved by valsartan compared with saline and hydralazine. Our study may provide novel insights into the mechanisms of Ang II-induced cardiac fibrosis as well as into the cardiac protection of valsartan. PMID- 25823962 TI - Design, synthesis, and characterization of SO2-containing azabicyclo[3.n.1]alkanes: promising building blocks for drug discovery. AB - A set of novel SO2-containing azabicyclo[3.n.1]alkanes has been synthesized by the double-Mannich annulation of of the corresponding monocyclic S-ketones. These compounds have been rationally designed as 3D-shaped, conformationally restricted SO2-containing building blocks for drug discovery. PMID- 25823963 TI - Population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients. AB - The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam administered by prolonged infusion in obese and nonobese patients. Twenty-seven patients (total body weight [TBW], 60 to 211 kg; body mass index [BMI], 19.6 to 72.9 kg/m(2) ) received 4.5 or 6.75 g every 8 hours, infused over 4 hours, and serum concentrations were measured at steady state. Population pharmacokinetic parameters were estimated using NONMEM, and Monte Carlo simulations were performed for three 4-hour dosing regimens to calculate probability of target attainment (PTA) at >=50% fT>MIC.A 1 compartment linear-elimination model best fit the pharmacokinetic data for piperacillin and tazobactam. Creatinine clearance (CRCL), TBW, and BMI were significantly associated with piperacillin pharmacokinetics, and CRCL was significantly associated with tazobactam pharmacokinetics. Clearance and volume of distribution for piperacillin and tazobactam were significantly different between obese and nonobese patients (P < .05). At MICs <= 16 mg/L, PTA was >90% for dosing regimens >=3.375 g every 8 hours in nonobese patients and >= 4.5 g every 8 hours in obese patients. Piperacillin and tazobactam pharmacokinetics are altered in obesity, and 4.5 g every 8 hours infused over 4 hours should be recommended for empiric therapy in obese patients. PMID- 25823964 TI - Surface Segregation in Bimetallic Nanoparticles: A Critical Issue in Electrocatalyst Engineering. AB - Bimetallic nanoparticles are a class of important electrocatalyst. They exhibit a synergistic effect that critically depends on the surface composition, which determines the surface properties and the adsorption/desorption behavior of the reactants and intermediates during catalysis. The surface composition can be varied, as nanoparticles are exposed to certain environments through surface segregation. Thermodynamically, this is caused by a difference in surface energy between the two metals. It may lead to the enrichment of one metal on the surface and the other in the core. The external conditions that influence the surface energy may lead to the variation of the thermodynamic steady state of the particle surface and, thus, offer a chance to vary the surface composition. In this review, the most recent and important progress in surface segregation of bimetallic nanoparticles and its impact in electrocatalysis are introduced. Typical segregation inducements and surface characterization techniques are discussed in detail. It is concluded that surface segregation is a critical issue when designing bimetallic catalysts. It is necessary to explore methods to control it and utilize it as a way towards producing robust, bimetallic electrocatalysts. PMID- 25823965 TI - Evolutionary dynamics of retrotransposons following autopolyploidy in the Buckler Mustard species complex. AB - Long terminal repeat retrotransposons (LTR-RTs) represent a major fraction of plant genomes, but processes leading to transposition bursts remain elusive. Polyploidy expectedly leads to LTR-RT proliferation, as the merging of divergent diploids provokes a genome shock activating LTR-RTs and/or genetic redundancy supports the accumulation of active LTR-RTs through relaxation of selective constraints. Available evidence supports interspecific hybridization as the main trigger of genome dynamics, but few studies have addressed the consequences of intraspecific polyploidy (i.e. autopolyploidy), where the genome shock is expectedly minimized. The dynamics of LTR-RTs was thus here evaluated through low coverage 454 sequencing of three closely related diploid progenitors and three independent autotetraploids from the young Biscutella laevigata species complex. Genomes from this early diverging Brassicaceae lineage presented a minimum of 40% repeats and a large diversity of transposable elements. Differential abundances and patterns of sequence divergence among genomes for 37 LTR-RT families revealed contrasted dynamics during species diversification. Quiescent LTR-RT families with limited genetic variation among genomes were distinguished from active families (37.8%) having proliferated in specific taxa. Specific families proliferated in autopolyploids only, but most transpositionally active families in polyploids were also differentiated among diploids. Low expression levels of transpositionally active LTR-RT families in autopolyploids further supported that genome shock and redundancy are non-mutually exclusive triggers of LTR-RT proliferation. Although reputed stable, autopolyploid genomes show LTR-RT fractions presenting analogies with polyploids between widely divergent genomes. PMID- 25823966 TI - Effects of seasonal changes in dietary energy on body weight of captive Japanese macaques (Macaca fuscata). AB - Food availability varies seasonally for wild animals, and body weight fluctuates accordingly in the wild. In contrast, controlling availability of diet under captive condition is difficult from keepers' standpoint, and monotonous diet often causes health problems in captive animals. We evaluated the effects of a seasonally controlled diet on body weight of captive Japanese macaques (Macaca fuscata) in an outside enclosure at Ueno Zoo, Tokyo, Japan. We fed a high-energy diet in spring and fall, and a more restricted diet in summer and winter for 3 years (2011-2013). Seasonal changes in body weight were similar to those that occur in wild macaques: for both sexes, body weight was higher in spring and fall and lower in winter. A decrease in body weight between fall and winter occurred only in adults, which implied that reducing dietary intake in winter had a more severe effect on adults than on juveniles. Different from wild populations, the body weight of captive macaques did not decrease between spring and summer, which we attributed to a lack of movement within the enclosure and to excess energy intake in summer. In addition to controlling dietary composition, providing large enclosure with complex structure and making efforts of giving unpredictability in feeding are necessary to motivate the captive animals to be more active, which would cause the macaques to show seasonal change in body weight, which is found in wild. PMID- 25823967 TI - Torsade de pointes tachycardia in a patient on dronedarone therapy. AB - Dronedarone is a promising, relatively new antiarrhythmic agent characterized by structural similarities to amiodarone but without amiodarone's severe organ toxicity. The proarrhythmic potential of dronedarone, however, is of increasing concern. We describe a 76-year-old woman who had been receiving dronedarone 400 mg twice/day to prevent recurrent atrial tachycardia with rapid ventricular response. Several months later, she came to the emergency department with decompensated congestive heart failure and episodes of atrial tachycardia; digoxin 0.5 mg and furosemide 40 mg were administered intravenously. Thereafter nonsustained torsade de pointes (TdP) tachycardia occurred. She was transferred to the intensive care unit where a dose of amiodarone 150 mg was administered intravenously by mistake. Thereafter, the patient showed sustained TdP necessitating cardiac resuscitation. Dronedarone was discontinued, and digoxin and amiodarone were not administered again. Under dronedarone a relevant QT prolongation was documented that was additionally augmented after concomitant treatment with digoxin and amiodarone. Use of the Naranjo adverse drug reaction probability scale indicated a probable adverse drug reaction to dronedarone (score of 7). To our knowledge, this is the first case report of a patient who experienced TdP tachycardias while receiving dronedarone therapy in connection with a worsening of heart failure and possible drug interactions with digoxin and amiodarone. Clinicians should be aware of this potential adverse drug reaction and perform repeated heart rate-corrected QT (QTc) interval measurements as well as screening for congestive heart failure in patients receiving dronedarone therapy. PMID- 25823968 TI - Oligomer-coated carbon nanotube chemiresistive sensors for selective detection of nitroaromatic explosives. AB - High-performance chemiresistive sensors were made using a porous thin film of single-walled carbon nanotubes (CNTs) coated with a carbazolylethynylene (Tg-Car) oligomer for trace vapor detection of nitroaromatic explosives. The sensors detect low concentrations of 4-nitrotoluene (NT), 2,4,6-trinitrotoluene (TNT), and 2,4-dinitrotoluene (DNT) vapors at ppb to ppt levels. The sensors also show high selectivity to NT from other common organic reagents at significantly higher vapor concentrations. Furthermore, by using Tg-Car/CNT sensors and uncoated CNT sensors in parallel, differential sensing of NT, TNT, and DNT vapors was achieved. This work provides a methodology to create selective CNT-based sensors and sensor arrays. PMID- 25823969 TI - Patient perspectives on radiation dose: reporting a survey of patient opinions. AB - With the marked increase in the number of CT scans, nuclear medicine tests and interventional radiological procedures, it is no longer possible to ignore the patients' increasingly vocal question: how much radiation is too much? The Powerful Patient conducted a survey of patient opinions in March-May 2014 to gather patient input for the International Conference on Radiation Protection in Medicine. Patients are eager to work with their physicians and radiology professionals to gather the data needed to answer their very real concerns. They clearly know and appreciate the value of these applications of radiation but want to use them wisely and without long-term consequences. PMID- 25823970 TI - A Straightforward Method for Preparing Well-Defined Responsive Diselenide Containing Polymers Based on ATRP. AB - Diselenide-containing polymers are facilely synthesized from polymers prepared by atom transfer radical polymerization (ATRP). Benefiting from the ATRP technology, this protocol provides a flexible route for controlling the polymer structure, which allows for a great variety of architectures of selenium-containing polymer materials for applications in various fields. The oxidative and reductive responsive behavior of the obtained diselenide-containing polymers is also investigated. PMID- 25823972 TI - Effect of various levels of dietary curcumin on meat quality and antioxidant profile of breast muscle in broilers. AB - The aim of this study was to determine the effects of curcumin on meat quality and antioxidant profile of breast muscle in broilers. In experiment 1, birds were fed basal diet with an additional 0, 50, 100, or 200 mg/kg curcumin, respectively. The results showed that dietary curcumin significantly increased the redness values of meat, catalase activity, and ABTS radical scavenging activity and decreased drip loss at 48 h. In experiment 2, birds reared under heat stress were assigned to similar treatments as experiment 1. Significant differences in the redox status of breast muscle were observed between the control and heat stress groups. The various levels of curcumin significantly prevented reactive oxygen species overproduction, enhanced the antioxidant defense system, and alleviated the abnormal change of antioxidant-related gene expression of muscle in heat-stressed birds. It was concluded that curcumin, as a potential antioxidant, improved meat quality and oxidant stability of muscle in broilers, whereas the inclusion of 50 and 100 mg/kg would be more efficient. PMID- 25823973 TI - Evidence for hydrophobic catalysis of DNA strand exchange. AB - The catalytic role of hydrophobic co-solutes in DNA strand exchange is demonstrated by FRET kinetics. Two mechanisms that contribute to this are base stacking destabilisation and nucleation-promoted DNA strand invasion. We propose that hydrophobic catalysis is involved in the strand-exchange activity of recombination enzymes. PMID- 25823974 TI - RHOA mutation in diffuse-type gastric cancer: a comparative clinicopathology analysis of 87 cases. AB - BACKGROUND: Recent studies have discovered recurrent RHOA mutations in diffuse type gastric cancers. These reports show mutant RhoA is an important cancer driver and is a potential therapeutic target. This study aims to investigate the clinicopathological features of diffuse-type gastric cancers with RHOA mutation. METHODS: We performed a thorough review of 87 diffuse-type gastric cancers, including 22 RHOA-mutated and 65 RHOA wild-type gastric cancers. RESULTS: Most advanced tumors with RHOA mutation appeared as Borrmann type 3 lesions (81 %) developing in the middle (50 %) or distal (32 %) third of the stomach. Histologically, although all of the tumors were predominantly or exclusively composed of poorly cohesive carcinoma, limited tubular differentiation was also observed in 73 % of the RHOA-mutated tumors. Notably, RHOA-mutated tumors more frequently showed a permeative growth pattern at the edge of the mucosal area (59 %) compared with RHOA wild-type tumors (29 %, P = 0.0202). Additionally, the size ratios of the deeply invasive components to the mucosal components were significantly lower in RHOA-mutated tumors [less than 1.45 (median) in 68 % of cases] than in RHOA wild-type tumors (less than 1.45 in 42 % of cases, P = 0.0482). RHOA mutation did not significantly impact survival in this study. CONCLUSIONS: These observations suggest that RHOA mutation may be associated with the growth patterns of diffuse-type gastric cancer but have a limited prognostic impact in isolation. Further studies, including analyses of the other alterations involving the RhoA pathways, such as CLDN18-ARHGAP fusion, as well as functional studies of mutant RhoA, are necessary to clarify the significance of alterations in the RhoA-signaling pathway in diffuse-type gastric cancers. PMID- 25823976 TI - Detection of phosphatidyl serine on activated platelets' surface by flow cytometry in whole blood: a simpler test for the diagnosis of Scott syndrome. PMID- 25823975 TI - Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study. AB - OBJECTIVE: Assess perampanel's efficacy and safety as adjunctive therapy in adolescents (ages 12-17) with drug-resistant partial seizures. METHODS: Adolescent patients enrolled in multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) completed 19-week, double-blind phase (6-week titration/13-week maintenance) with once-daily perampanel or placebo. Upon completion, patients were eligible for the extension (study 307), beginning with 16-week, blinded conversion, during which placebo patients switched to perampanel. Patients then entered the open-label treatment. RESULTS: Of 1480 patients from the core studies, 143 were adolescents. Pooled adolescent data from these core studies demonstrated median percent decreases in seizure frequency for perampanel 8 mg (34.8%) and 12 mg (35.6%) were approximately twice that of placebo (18.0%). Responder rates increased with perampanel 8 mg (40.9%) and 12 mg (45.0%) versus placebo (22.2%). Adolescents receiving concomitant enzyme-inducing antiepileptic drugs (AEDs) had smaller reductions in seizure frequency (8 mg:31.6%; 12 mg:26.8%) than those taking non-inducing AEDs (8 mg:54.6%; 12 mg:52.7%). Relative to pre-perampanel baseline, seizure frequency and responder rates during the extension (Weeks 1-52) improved with perampanel. Most commonly reported adverse events in adolescents during the core studies were dizziness (20.4%), somnolence (15.3%), aggression (8.2%), decreased appetite (6.1%), and rhinitis (5.1%). Dizziness (13.2%), somnolence (11.6%), and aggression (6.6%) most often led to perampanel interruption/dose adjustment during the extension. SIGNIFICANCE: Data demonstrated adjunctive perampanel treatment in adolescents with drug-resistant partial seizures produced better seizure control versus placebo, sustained seizure frequency improvements, and a generally favorable safety profile. Results were comparable to the overall study population. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifiers: Study 304: NCT00699972; 305: NCT00699582; 306: NCT00700310; Study 307: NCT00735397. PMID- 25823977 TI - Five-day Azithromycin Treatment Regimen for Mycoplasma genitalium Infection Also Effectively Eradicates Chlamydia trachomatis. PMID- 25823978 TI - Infrared spectroscopy of N2 adsorption on size selected cobalt cluster cations in isolation. AB - We report IR active N2 stretching frequencies in isolated and size selected cobalt cluster nitrogen adsorbate complexes, [Con(N2)1](+) as recorded by virtue of InfraRed Photon Dissociation (IRPD) spectroscopy. The observed frequencies of the [Con(N2)1](+) complexes (n = 8-17) are significantly redshifted (2180 to 2290 cm(-1)) with respect to the IR inactive vibrations of free N2 (2359 cm(-1)). These bands are assigned to a MU1 head-on type of coordination of the N2 to the cobalt cluster surface, revealing remarkable cluster size dependent features to interpret. PMID- 25823979 TI - Silica nanoparticle suspensions under confinement of thin liquid films. AB - The paper deals with the effect of geometrical confinement on the structuring of Silica nanoparticle suspensions in thin films. The confinement is produced by a Colloidal Probe AFM. Approaching of the two outer surface leads to oscillatory forces. The force profile reflects the pair correlation function and its period the average distance between the nanoparticles under confinement. The nanoparticle structuring is compared to the particle distribution in bulk by small angle X-ray scattering (SAXS). The SAXS structure factor which presents the Fourier transform of the pair correlation function gives the same interparticle distance for the bulk as the oscillation period of the AFM force curves. The distance scales with particle number density rho as rho(-1/3) and is very robust against different suspension parameters (nanoparticle size, ionic strength) and parameters of the outer surfaces (surface potential, roughness and elasticity). PMID- 25823980 TI - Tumor necrosis after preventive embolization of large renal angiomyolipomas. AB - OBJECTIVES: The purpose of this study was to retrospectively evaluate tumor necrosis following preventive embolization in patients with renal angiomyolipoma (RAML) at high risk of bleeding. PATIENTS AND METHODS: Arterial embolization was performed in 24 patients (22 women, 2 men; mean age, 43+/-13 years) with a total of 30 RAMLs (mean volume, 137 cm(3)+/-163) between 1996 and 2012. Two sub-groups of patients were identified and further compared based on the presence or not of necrosis following arterial embolization. RESULTS: The technical and clinical success rates of arterial embolization of RAMLs were 97% and 87%, respectively. The mean initial volume of RAMLs differed between the two sub-groups with 331 cm(3) in the group with tumor necrosis and 88 cm(3) in the group without tumor necrosis (P=0.0047). High-fat content RAMLs were predominantly observed in the necrosis group and the mean volume reduction observed for high-fat RAMLs was 65% whereas it was 36% for low-fat content RAMLs. The six patients who developed RAML necrosis had arterial embolization using microspheres (one patient with microspheres alone and five with a combination of microspheres and metallic coils). All necrotic RAMLs displayed arterial dysplasia. CONCLUSION: The risk of tumor necrosis is higher for larger RAMLs. The role of distal arterial embolization with microspheres in tumor necrosis in RAML is suggested by the results of our study but could not be definitely demonstrated statistically due to the limited sample size. PMID- 25823981 TI - Primary plasmacytic hepatic lymphoma mimicking hepatocellular tumor on MR imaging. PMID- 25823982 TI - Imaging of adductor-related groin pain. AB - Groin pain is a common condition in athletes and results from various causes. Osteitis pubis, adductor dysfunction, inguinal hernia, or a combination of all three entities, generally explains the onset of symptoms. Adductor longus tendinopathy is the main cause of adductor-related groin pain. It leads to a significant reduction of sports participation and can require surgical management. Diagnosis is based on ultrasonography and magnetic resonance imaging. Asymptomatic findings (tendinosis, calcifications, cortical erosions) are common in athletes and care should be taken when assessing groin pain. The most specific sign of tendinopathy is an intratendinous tear of the adductor longus. PMID- 25823983 TI - Magnetic diffusion anomaly at the Neel temperature of pyrrhotite, Fe(1-x)S. AB - Cation diffusion is an important rate-limiting process in the growth of pyrrhotite (Fe1-xS) in passivating films on steels exposed to sulfidic environments, and for proposed synthetic applications of Fe1-xS, for example single-phase magnetic switching devices. Above the Neel temperature TN of 315 degrees C, where Fe1-xS is paramagnetic and structurally disordered, iron self diffusivity *DFe predictably follows a standard, established Arrhenius law with temperature. However, we report (57)Fe tracer diffusion measurements below TN, obtained using secondary ion mass spectrometry (SIMS), that demonstrate a 100 fold reduction in diffusion coefficient as compared to the extrapolated, paramagnetic Arrhenius trend at 150 degrees C. The results can be described by a magnetic diffusion anomaly, where the vacancy migration energy for the spontaneously-magnetized cation sublattice is increased by approximately 40% over the paramagnetic state. These constitute the first set of consistent diffusivity data obtained in magnetic pyrrhotite, allowing more accurate prediction of pyrrhotite growth rates and determination of magnetic properties for synthetic devices. PMID- 25823984 TI - Glial and axonal perikaryal coverage and somatic spines in the posterodorsal medial amygdala of male and cycling female rats. AB - The posterodorsal medial amygdala (MePD) is a sex-steroid-sensitive area that modulates reproductive behavior in rats. The volume of the neuronal cell body, density of dendritic spines, and glial fibrillary acidic protein immunoreactivity are sexually dimorphic or affected by gonadal hormones in the MePD. Here we add new data to this panorama and describe the ultrastructure of the glial and axonal coverage of the perikaryal membrane and the somatic spines in the MePD of males and cycling females (in diestrus, early proestrus, late proestrus, and estrus). Transmission electron microscopy data (mean values from seven to 11 neurons per rat, five or six animals per group) showed that the rat MePD has most of the perikaryal membrane covered by glial processes and a relatively large amount (up to 40%) of axonal processes contacting the neuronal cell body. No statistically significant difference was found between groups for these somatic coverages (P > 0.5). However, the density of somatic spines along the length of the perikaryal membrane was higher in the late proestrus than in estrus (P < 0.05), and somatic spines in early and late proestrus showed variable shapes with stubby/wide, thin, mushroom-like, ramified, transitional or atypical aspects. These findings add to the rapid adjustable synaptic changes in the MePD and in the integrated neural circuits that control neuroendocrine secretion and the hormonally modulated timely display of social behaviors in rats. PMID- 25823985 TI - High Impact of Histopathological Remission for Prognosis after Perioperative Chemotherapy with ECF and ECF-Like Regimens for Gastric and Gastroesophageal Adenocarcinoma. AB - BACKGROUND: Perioperative chemotherapy with epirubicin, cisplatin and 5 fluorouracil (5-FU) (ECF)-like regimens is the European standard for patients with adenocarcinoma of the gastroesophageal junction (GEJ) or gastric body (GaCa) stage UICC II/III (staged according to the Union for International Cancer Control). However, limited data exist on the histopathological response and relevance of prognosis for patients homogeneously treated with ECF(-like) therapies. METHODS: All patients with GEJ/GaCa treated from September 2004 to September 2008 by perioperative ECF(-like) chemotherapy were retrospectively analyzed. Cisplatin and 5-FU were substituted with oxaliplatin or capecitabine when indicated. The histopathological response was assessed using the Becker score. RESULTS: Seventy-seven patients were analyzed with a median follow-up of 72.3 months. R0 resection was achieved in 53 of 68 operated patients. Recurrence was observed in 25 (32.5%) of these curatively treated patients, whereas 53/77 patients (68.8%) died, 39 (50.6%) of whom tumor related. The 5-year overall survival (OS) for the intention-to-treat population was 36.3%, and the 5-year tumor-specific survival was 42.2%. Pathological complete response (pCR) was seen in 10 patients (13.0%) and near pCR in 3 patients (3.9%). Patients with pCR had a significantly prolonged 5-year OS of 80.0 versus 29.7% compared to the nonhistopathological complete remission group (p = 0.01). CONCLUSION: In our retrospective analysis, ECF(-like) pretreatment resulted in a (near) pCR rate of 16.9%. In line with other regimens, our data suggest that histopathological response predicts the OS in patients treated with ECF(-like) regimens. PMID- 25823986 TI - The effects of the F-actin inhibitor latrunculin A on the pathogenic yeast Cryptococcus neoformans. AB - BACKGROUND: This basic research aimed to investigate the effects of the actin inhibitor latrunculin A (LA) on the human pathogen Cryptococcus neoformans, by freeze-substitution (FS) and electron microscopy (EM), to determine whether the actin cytoskeleton can become a new antifungal target for inhibition of cell division. METHODS: Cells treated with LA for 20 h in yeast-extract peptone dextrose medium were investigated by phase-contrast and fluorescent microscopy, FS and transmission EM, counted in a Burker chamber and the absorbance was then measured. RESULTS: The disappearance of actin patches, actin cables and actin rings demonstrated the response of the cells of C. neoformans to the presence of the actin inhibitor LA. The removal of actin cables and patches arrested proliferation and led to the production of cells that had ultrastructural disorder, irregular morphology of the mitochondria and thick aberrant cell walls. Budding cells lysed in the buds and septa. CONCLUSION: LA exerts fungistatic, fungicidal and fungilytic effects on the human pathogenic yeast C. neoformans. PMID- 25823987 TI - An unusual cause of pink diapers in an infant: Questions and Answers. PMID- 25823988 TI - An unusual cause of "pink diaper" in an infant: Answers. PMID- 25823990 TI - meso,beta-Oligohaloporphyrins as Useful Synthetic Intermediates of Diphenylamine Fused Porphyrin and meso-to-meso beta-to-beta Doubly Butadiyne-Bridged Diporphyrin. AB - The chlorination of beta-halo or beta,beta-dihaloporphyrins with 2-chloro-1,3 bis(methoxycarbonyl)guanidine (Palau'Chlor) proceeded selectively at the neighboring unsubstituted meso position to afford meso,beta-dihalo or meso,beta,beta-trihaloporphyrins. Such oligohaloporphyrins are useful platforms for constructing more-elaborate porphyrin-based extended pi systems. For example, meso-chloro-beta,beta-diiodoporphyrin participated in an efficient single-step synthesis of a diphenylamine-fused porphyrin. In addition, meso-chloro-beta iodoporphyrin was transformed in stepwise fashion into an efficiently conjugated meso-to-meso,beta-to-beta doubly butadiyne-linked porphyrin dimer, a system which was previously difficult to access without such haloporphyrin precursors. PMID- 25823989 TI - Clinical and laboratory approaches in the diagnosis of renal tubular acidosis. AB - In the absence of a gastrointestinal origin, a maintained hyperchloremic metabolic acidosis must raise the diagnostic suspicion of renal tubular acidosis (RTA). Unlike adults, in whom RTA is usually secondary to acquired causes, children most often have primary forms of RTA resulting from an inherited genetic defect in the tubular proteins involved in the renal regulation of acid-base homeostasis. According to their pathophysiological basis, four types of RTA are distinguished. Distal type 1 RTA, proximal type 2 RTA, mixed-type 3 RTA, and type 4 RTA can be differentiated based on the family history, the presenting manifestations, the biochemical profile, and the radiological findings. Functional tests to explore the proximal wasting of bicarbonate and the urinary acidification capacity are also useful diagnostic tools. Although currently the molecular basis of the disease can frequently be discovered by gene analysis, patients with RTA must undergo a detailed clinical study and laboratory work-up in order to understand the pathophysiology of the disease and to warrant a correct and accurate diagnosis. PMID- 25823991 TI - Soluble dietary fiber (Fibersol-2) decreased hunger and increased satiety hormones in humans when ingested with a meal. AB - We hypothesized that a digestion-resistant maltodextrin, Fibersol-2 (Archer Daniels Midland/Matsutani LLC, Decatur, IL, USA) may impact satiety by decreasing hunger, prolonging satiation, and/or increasing peripheral satiety signals. In a randomized, double-blind, placebo-controlled crossover study, healthy subjects (9 men and 10 women) underwent 3 treatments in which they consumed a standardized meal with a tea containing 0, 5, or 10 g of Fibersol-2. A visual analog scale questionnaire was given in 30-minute intervals to measure subjective appetite and satiety. Blood was drawn just before the meal (time 0) and at 30, 60, 90, 120, 180, and 240 minutes after meal for measurements of plasma ghrelin, cholecystokinin, gastrin, peptide YY, gastric inhibitory polypeptide, and glucagon-like peptide-1, all by enzyme-linked immunosorbent assay. There were significant delays in hunger and increased satiety for 1.5 to 2 hours after treatment with 10 g of Fibersol-2. These delays did not occur after ingesting 0 or 5 g Fibersol-2 at any time. Control and 5 g Fibersol-2 treatments did not suppress increases in hunger postmeal; hunger scores increased and satiety scores decreased significantly (P < .05) at all time points relative to the first postmeal assessment. Plasma peptide YY and glucagon-like peptide-1 were significantly increased by the ingestion of meal with tea containing 10 g Fibersol-2 compared with 0 or 5 g Fibersol-2 (P < .05). This study demonstrated that 10 g Fibersol-2 with a meal stimulated production of satiety hormones and enhanced satiety. PMID- 25823992 TI - Effects of reinnervation of the biarticular shoulder-elbow muscles on joint kinematics and electromyographic patterns of the feline forelimb during downslope walking. AB - Full recovery of the forelimb kinematics during level and upslope walking following reinnervation of the biarticular elbow extensor suggests that the proprioceptive loss is compensated by other sensory sources or altered central drive, yet these findings have not been explored in downslope walking. Kinematics and muscle activity of the shoulder and elbow during downslope locomotion following reinnervation of the feline long head of the triceps brachii (TLo) and biceps brachii (Bi) were evaluated (1) during paralysis and (2) after the motor function was recovered but the proprioceptive feedback was permanently disrupted. The step cycle was examined in three walking conditions: level (0%), -25% grade ( 14 degrees downslope) and -50% grade (-26.6 degrees downslope). Measurements were taken prior to and at three time points (2 weeks, and 1 and 12+ months) after transecting and suturing the radial and musculocutaneous nerves. There was an increase in the yield (increased flexion) at the elbow and less extensor activity duration of flexion during stance as the downslope grade increased. There were two notable periods of eccentric contractions (active lengthening) providing an apparent 'braking' action. Paralysis of the TLo and the Bi resulted in uncompensated alterations in shoulder-elbow kinematics and motor activity during the stance phase. However, unlike the case for the level and upslope conditions, during both paralysis and reinnervation, changes in interjoint coordination persisted for the downslope condition. The lack of complete recovery in the long term suggests that the autogenic reflexes contribute importantly to muscle and joint stiffness during active lengthening. PMID- 25823993 TI - The ultimate mix and match: making sense of HLA alleles and peptide repertoires. PMID- 25823994 TI - Activation of TGF-beta-induced non-Smad signaling pathways during Th17 differentiation. AB - Although transforming growth factor-beta (TGF-beta) has been shown to positively regulate the development of murine T helper type 17 (Th17) cells, which of the intracellular signaling pathways are involved is controversial. We examined Smad dependent and -independent signaling molecules downstream of the TGF-beta receptor (TGFbetaR) involved in Th17 differentiation of naive murine CD4(+)CD62L(+) T cells. During Th17 differentiation of wild-type T cells, Smad2/3 was phosphorylated, indicating activation of the canonical Smad pathway. T cells lacking TGFbetaRII did not differentiate into Th17, whereas T cells treated with a TGFbetaRI kinase inhibitor (SB-431542) or overexpression of inhibitory Smad7 retained a low amount of Th17 polarization despite absent Smad2/3 phosphorylation. Using protein antibody arrays we found an increase of expression and phosphorylation of the following Smad-independent signaling molecules in Th17 polarized wild-type T cells: AKT1(Tyr474), AKT2 (Ser474), ERK1-p44/42 MAPK(Tyr204), mTOR(Thr2446), p38 MAPK(Thr180), Rac1/cdc42(Ser71), SAPK/JNK(Tyr185) and SP1(Thr739). Pharmacological inhibition of AKT/mammalian target of rapamycin (mTOR) signaling with rapamycin or LY294002 decreased Th17 differentiation of wild-type T cells, and completely abolished interleukin-17 production in T cells with overexpression of Smad7. Rapamycin and LY294002 also decreased induced regulatory T cell differentiation, but only had minor additive effects to Smad7 overexpression. Finally, inhibitors of mitogen-activated protein kinase (MAPK) blocked in vitro polarization of Th17 cells. Our data show that Smad-dependent and -independent intracellular pathways contribute to murine Th17 differentiation. PMID- 25823996 TI - Primary large cell neuroendocrine carcinoma of the breast, a case report with an unusual clinical course. AB - Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34 years-old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline-containing neo-adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo-adjuvant chemotherapy, the patient underwent breast-conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo-adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options. PMID- 25823995 TI - The functional contribution of calcium ion flux heterogeneity in T cells. AB - The role of intracellular calcium ion oscillations in T-cell physiology is being increasingly appreciated by studies that describe how unique temporal and spatial calcium ion signatures can control different signalling pathways. Within this review, we provide detailed mechanisms of calcium ion oscillations, and emphasise the pivotal role that calcium signalling plays in directing crucial events pertaining to T-cell functionality. We also describe methods of calcium ion quantification, and take the opportunity to discuss how a deeper understanding of calcium signalling combined with new detection and quantification methodologies can be used to better design immunotherapies targeting T-cell responses. PMID- 25823997 TI - Differing ERP patterns caused by suction and puff stimuli. AB - The present study compared event-related potential (ERP) patterns for two stimuli types, puff and suction, by applying these stimuli to the fingers; ERP patterns for the two stimuli were compared at C3, an area related to somatosensory perception, and at FC5, an area related to motor function. Participants were 12 healthy males in their 20s (mean age=23.1+/-2.0 years). One session consisted of a Control Phase (3s), a Stimulation Phase (3s), and a Rest Phase (9s). During the Stimulation Phase, a 4-psi suction or puff stimulus was applied to the first joint of the right index finger. After completion of the session, a subjective magnitude test was presented. In all phases, electroencephalography signals were recorded. We extracted maximum positive amplitude and minimum negative amplitude as well as relevant latency values for C3 and FC5 signals. Suction and puff stimuli had similar subjective magnitude scores. For both C3 and FC5, the maximum and minimum amplitude latency was reached earlier for the suction stimulus than for the puff stimulus. In conclusion, when suction and puff stimuli of the same intensity were applied to the fingers, the suction stimulus caused a more sensitive response in the somatosensory area (C3) and motor area (FC5) than did the puff stimulus. PMID- 25823998 TI - Spontaneous eye blink rate predicts learning from negative, but not positive, outcomes. AB - A large body of research shows that striatal dopamine critically affects the extent to which we learn from the positive and negative outcomes of our decisions. In this study, we examined the relationship between reinforcement learning and spontaneous eye blink rate (sEBR), a cheap, non-invasive, and easy to obtain marker of striatal dopaminergic activity. Based on previous findings from pharmacological and patient studies, our main prediction was that in healthy individuals, low blink rates (and concomitant lower striatal dopamine levels) would be associated with better learning from negative choices, while high blink rates (and concomitant higher striatal dopamine levels) would be associated with learning from positive choices. Behavioral analyses showed that in healthy individuals, lower blink rates were indeed associated with greater learning from negative outcomes, indicating that lower dopamine levels per se may enhance avoidance learning. Yet, higher EBR was not associated with better learning from positive outcomes. These observations support the notion that sEBR reflects tonic dopamine levels, and suggest that sEBR may specifically relate to dopamine D2 receptor function, given the importance of the dopaminergic D2 pathway in avoidance learning. More generally, these findings highlight the usefulness of sEBR as a non-invasive and cheap method for assessing the relationship between striatal dopaminergic function and behavior. PMID- 25823999 TI - "I know your name, but not your number"--Patients with verbal short-term memory deficits are impaired in learning sequences of digits. AB - Studies on verbal learning in patients with impaired verbal short-term memory (vSTM) have revealed dissociations among types of verbal information. Patients with impaired vSTM are able to learn lists of known words but fail to acquire new word forms. This suggests that vSTM is involved in new word learning. The present study assessed both new word learning and the learning of digit sequences in two patients with impaired vSTM. In two experiments, participants were required to learn people's names, ages and professions, or their four digit 'phone numbers'. The STM patients were impaired on learning unknown family names and phone numbers, but managed to acquire other verbal information. In contrast, a patient with a severe verbal episodic memory impairment was impaired across information types. These results indicate verbal STM involvement in the learning of digit sequences. PMID- 25824000 TI - [Therapy of acute respiratory distress syndrome : Survey of German ARDS centers and scientific evidence]. AB - BACKGROUND: In addition to specific treatment of the underlying cause, the therapy of acute respiratory distress syndrome (ARDS) consists of lung protective ventilation and a range of adjuvant and supportive measures. AIM: A survey was conducted to determine the current treatment strategies for ARDS in German ARDS centers. MATERIAL AND METHODS: The 39 centers listed in the German ARDS network in 2011 were asked to complete a questionnaire collecting data on the clinic, epidemiology as well as diagnostic and therapeutic measures regarding ARDS treatment. RESULTS: Of the centers 25 completed the questionnaire. In 2010 each of these centers treated an median of 31 (25-75 percentile range 20-59) patients. Diagnostic measures at admission were computed tomography of the thorax (60 % of the centers), whole body computed tomography (56 %), chest x-ray (52 %), abdominal computed tomography (32 %) and cranial computed tomography (24 %). Transesophageal echocardiography was performed in 64 %, pulmonary artery pressure was measured in 56 % and cerebral oximetry in 12 %. Sedation was regularly interrupted in 92 % of the centers and in 68 % this was attempted at least once a day. A median minimum tidal volume of 4 ml/kg (range 2-6) and a maximum tidal volume of 6 ml/kg (4-8) were used. Methods to determine the optimal positive end expiratory pressure (PEEP) were the best PEEP method (60 %), ARDS network table (48 %), empirical (28 %), pressure volume curve (16 %), computed tomography (8 %), electrical impedance tomography (8 %) and others (8 %). Median minimum and maximum PEEPs were 10 cmH2O (range 5-15) and 21 cmH2O (15-25), respectively. Median plateau pressure was limited to 30 cmH2O (range 26-45). The respiratory rate was set below 20/min in 20 % and below 30/min in 44 %. Controlled ventilator modes were generally preferred with 80 % using biphasic positive airway pressure (BIPAP/BiLevel), 20 % pressure controlled ventilation (PCV) and 4 % airway pressure release ventilation (APRV). Assisted modes were only utilized by 8 % of the centers. Recruitment maneuvers were used by 28 %, particularly during the early phase of the ARDS. Muscle relaxants were administered by 32 % during the early phase of the ARDS. Complete prone positioning was used by 60 % of the centers, whereas 88 % utilized incomplete (135 degrees ) prone positioning. Continuous axial rotation was utilized by 16 %. Spontaneous breathing tests were used in 88 % of the centers with 60 % performing these at least once a day. Supportive therapies were frequently applied and mainly consisted of nitrous oxide (44 %), prostacycline (48 %) and corticosteroids (52 %). A restrictive fluid therapy was used in 48 % and a special nutrition regimen in 28 % of the centers. Of the participating centers 22 were able to offer extracorporeal membrane oxygenation (ECMO). In this case, respiratory therapy was modified by further reducing tidal volumes (91 %), inspiratory pressures (96 %) as well as using lower respiratory rates (<= 8/min in 31 %). Only 9 % reduced PEEP during ECMO. Regular recruitment maneuvers were used by 14 %. Positioning maneuvers during ECMO were used by 82 %. CONCLUSIONS: Lung protective ventilation with reduced tidal volumes as well as inspiratory pressures represents the current standard of care and was utilized in all network centers. Prone positioning was widely used. Promising adjuvant therapies such as the muscle relaxation during the early phase of the ARDS, fluid restriction and corticosteroids were used less frequently. During ECMO respirator therapy was generally continued with ultraprotective ventilator settings. PMID- 25824001 TI - Impact of Previous Somatostatin Analogue Use on the Activity of Everolimus in Patients with Advanced Neuroendocrine Tumors: Analysis from the Phase III RADIANT 2 Trial. AB - BACKGROUND/AIMS: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. METHODS: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. RESULTS: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). CONCLUSION: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure. PMID- 25824002 TI - Removal of carbamazepine from spiked municipal wastewater using electro-Fenton process. AB - The electrochemical degradation of carbamazepine (CBZ) in both synthetic solutions (CBZo = 12 mg/L) and enriched municipal effluents (CBZo = 60-70 MUg/L) was investigated using an electro-Fenton (EF) process. Different operating parameters were investigated, including current intensity, pH, reaction time, ferrous ion concentration, and the type of anode material. The current intensity, the type of anode material, and the concentration of ferrous ions played an important role in the CBZ degradation efficiency. The degradation was mainly attributed to direct anodic oxidation. The best operating conditions for the synthetic sample were obtained at a current density of 0.2 A, a pH of 3.0, and 120 min of treatment using a boron-doped diamond (BDD) anode in the presence of 0.25 mM of Fe(2+). Under these conditions, 52% of total organic carbon (TOC) and 73% of CBZ were removed. The process was also tested as tertiary treatment for a municipal wastewater treatment plant effluent, and CBZ was completely removed. PMID- 25824005 TI - MicroRNA Screening and the Quest for Biologically Relevant Targets. AB - MicroRNAs (miRNAs) are a class of genome-encoded small RNAs that post transcriptionally regulate gene expression by repressing target transcripts containing partially or fully complementary binding sites.Despite their relatively low number, miRNAs have been shown to directly regulate a large fraction of the transcriptome. In agreement with their pervasive role in the regulation of eukaryotic gene expression, miRNAs have been implicated in virtually all biological processes, including different pathologies.The use of screening technologies to systematically analyze miRNA function in cell-based assays offers a unique opportunity to gain new insights into complex biological and disease-relevant processes. Given the low complexity of the miRNome and the similarities to small interfering RNA (siRNA) screening experimental approaches, phenotypic screening using genome-wide libraries of miRNA mimics or inhibitors is not, per se, technically challenging. The identification of miRNA targets and, more importantly, the characterization of their mechanisms of action through the identification of the key targets underlying observed phenotypes remain the major challenges of this approach.This article provides an overview of cell-based screenings for miRNA function that were performed in different biological contexts. The advantages and limitations of computational and experimental approaches commonly used to identify miRNA targets are also discussed. PMID- 25824004 TI - Effect of multiwalled carbon nanotubes on UASB microbial consortium. AB - The continuous rise in production and applications of carbon nanotubes (CNTs) has grown a concern about their fate and toxicity in the environment. After use, these nanomaterials pass through sewage and accumulate in wastewater treatment plants. Since, such plants rely on biological degradation of wastes; their activity may decrease due to the presence of CNTs. This study investigated the effect of multiwalled carbon nanotubes (MWCNTs) on upflow anaerobic sludge blanket (UASB) microbial activity. The toxic effect on microbial viability, extracellular polymeric substances (EPS), volatile fatty acids (VFA), and biogas generation was determined. The reduction in a colony-forming unit (CFU) was 29 and 58 % in 1 and 100 mg/L test samples, respectively, as compared to control. The volatile fatty acids and biogas production was also found reduced. The scanning electron microscopy (SEM) and fluorescent microscopy images confirmed that the MWCNT mediated microbial cell damage. This damage caused the increase in EPS carbohydrate, protein, and DNA concentration. Fourier transform infrared (FTIR) spectroscopy results supported the alterations in sludge EPS due to MWCNT. Our observations offer a new insight to understand the nanotoxic effect of MWCNTs on UASB microflora in a complex environment system. PMID- 25824003 TI - Toxicokinetics of chiral polychlorinated biphenyls across different species--a review. AB - Nineteen polychlorinated biphenyls (chiral or C-PCBs) exist as two stable rotational isomers (atropisomers) that are non-superimposable mirror images of each other. C-PCBs are released into the environment as racemic (i.e., equal) mixtures of both atropisomers and undergo atropisomeric enrichment due to biological, but not abiotic, processes. In particular, toxicokinetic studies provide important initial insights into atropselective processes involved in the disposition (i.e., absorption, distribution, biotransformation, and excretion) of C-PCBs. The toxicokinetic of C-PCBs is highly congener and species dependent. In particular, at lower trophic levels, abiotic processes play a predominant role in C-PCB toxicokinetics. Biotransformation plays an important role in the elimination of C-PCBs in mammals. The elimination of C-PCB follows the approximate order mammals > birds > amphibians > fish, mostly due to a corresponding decrease in metabolic capacity. A few studies have shown differences in the toxicokinetics of C-PCB atropisomers; however, more work is needed to understand the toxicokinetics of C-PCBs and the underlying biological processes. Such studies will not only contribute to our understanding of the fate of C-PCBs in aquatic and terrestrial food webs but also facilitate our understanding of human exposures to C-PCBs. PMID- 25824006 TI - Epidemic outbreak of acute haemorrhagic conjunctivitis caused by coxsackievirus A24 in Thailand, 2014. AB - Acute haemorrhagic conjunctivitis outbreaks are often attributed to viral infection. In 2014, an unprecedented nationwide outbreak of infectious conjunctivitis occurred in Thailand, which affected >300 000 individuals over 3 months. To identify and characterize the virus responsible for the epidemic, eye swab specimens from 119 patients were randomly collected from five different provinces. Conserved regions in the enteroviral 5'-UTR and adenovirus hexon gene were analysed. Enterovirus was identified in 71.43% (85/119) of the samples, while no adenovirus was detected. From enterovirus-positive samples, the coxsackievirus A24 variant (70.59%, 84/119) and echovirus (0.84%, 1/119) were identified. Additional sequencing of full-length VP1 and 3C genes and subsequent phylogenetic analysis revealed that these clinical isolates form a new lineage cluster related to genotype IV-C5. In summary, the coxsackievirus A24 variant was identified as an aetiological agent for the recent acute haemorrhagic conjunctivitis outbreak in Thailand. PMID- 25824008 TI - Effects of Patient-Controlled Epidural Analgesia on Uterine Electromyography During Spontaneous Onset of Labor in Term Nulliparous Women. AB - OBJECTIVE: To investigate the effect of patient-controlled epidural analgesia (PCEA) on uterine electromyography (EMG) activity in term pregnant women during labor. METHODS: Nulliparous pregnant women in spontaneous term labor (N = 30) were enrolled (PCEA group, n = 20 and control group, n = 10). Five time periods (30 minutes each) were defined for noninvasive abdominal recordings and analysis of uterine EMG activity, that is, period I: before PCEA treatment with 2-cm cervical dilation; periods II to IV: each period successively at 30, 60, and 120 minutes after PCEA; and period V: second stage of labor with cervix at 10 cm dilation. Control patients without PCEA were monitored during the same times. The number of bursts/30 min, power density spectrum peak frequency, mean amplitude, and duration of uterine EMG bursts were measured to assess uterine EMG activity. Maternal, fetal, and labor characteristics were also recorded. Data were analyzed by analysis of variance followed by other tests. RESULTS: Electromyography parameters are significantly lower (P < .001) after PCEA (periods II to IV) compared to controls but similar between groups by period V (P > .05). Also, patients with PCEA have a slower rate of cervical dilation (P < .003, period IV only) and longer labor in both stage 1 and stage 2 (P < .05). All patients have similar (P > .05) positive labor outcomes. CONCLUSIONS: Patient-controlled epidural analgesia initially suppresses uterine EMG and slows cervical dilation thereby prolonging labor. However, the EMG activity recovers with labor progress with no effects on delivery outcomes. PMID- 25824007 TI - Autoantibodies targeting glomerular annexin A2 identify patients with proliferative lupus nephritis. AB - PURPOSE: Patients with systemic lupus erythematosus (SLE) frequently develop lupus nephritis (LN), a complication frequently leading to end stage kidney disease. Immune complex deposition in the glomerulus is central to the development of LN. Using a targeted proteomic approach, we tested the hypothesis that autoantibodies targeting glomerular antigens contribute to the development of LN. EXPERIMENTAL DESIGN: Human podocyte and glomerular proteins were separated by SDS-PAGE and immunoblotted with sera from SLE patients with and without LN. The regions of those gels corresponding to reactive bands observed with sera from LN patients were analyzed using LC-MS/MS. RESULTS: LN reactive bands were seen at approximately 50 kDa in podocyte extracts and between 36 and 50 kDa in glomerular extracts. Those bands were analyzed by LC-MS/MS and 102 overlapping proteins were identified. Bioinformatic analysis determined that 36 of those proteins were membrane associated, including a protein previously suggested to contribute to glomerulonephritis and LN, annexin A2. By ELISA, patients with proliferative LN demonstrated significantly increased antibodies against annexin A2. CONCLUSION AND CLINICAL RELEVANCE: Proteomic approaches identified multiple candidate antigens for autoantibodies in patients with LN. Serum antibodies against annexin A2 were significantly elevated in subjects with proliferative LN, validating those antibodies as potential biomarkers. PMID- 25824009 TI - Perinatal Administration of a Selective Serotonin Reuptake Inhibitor Induces Impairments in Reproductive Function and Follicular Dynamics in Female Rat Offspring. AB - INTRODUCTION: Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring. METHODS: Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function. RESULTS: Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P < .001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERbeta (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent. CONCLUSIONS: This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype. PMID- 25824010 TI - Anti-Mullerian Hormone in Peritoneal Fluid and Plasma From Women With and Without Endometriosis. AB - Anti-Mullerian hormone (AMH) has potential local effects on ovarian function and endometrial tissue, including endometriosis, but its presence in peritoneal fluid is not fully understood. This is a cross-sectional study evaluating AMH in peritoneal fluid and plasma from women with endometriosis (N = 61) and from control women without endometriosis (N = 36). There was a significant correlation between AMH in plasma and peritoneal fluid from both patients with endometriosis (r(2) = .767 [P < .001]) and control participants (r(2) = .647 [P < .001]) less than 45 years of age. Anti-Mullerian hormone declined with women's increasing age in both plasma and peritoneal fluid in women with and without endometriosis. There were no differences in the plasma or peritoneal fluid AMH in women with endometriosis versus control women. The strong relationship between plasma and peritoneal fluid may allow plasma AMH to be a marker for peritoneal AMH in studies evaluating the local effects of AMH. PMID- 25824011 TI - Gene Expression in Placentas From Nondiabetic Women Giving Birth to Large for Gestational Age Infants. AB - Gestational diabetes, obesity, and excessive weight gain are known independent risk factors for the birth of a large for gestational age (LGA) infant. However, only 1 of the 10 infants born LGA is born by mothers with diabetes or obesity. Thus, the aim of the present study was to compare placental gene expression between healthy, nondiabetic mothers (n = 22) giving birth to LGA infants and body mass index-matched mothers (n = 24) giving birth to appropriate for gestational age infants. In the whole gene expression analysis, only 29 genes were found to be differently expressed in LGA placentas. Top upregulated genes included insulin-like growth factor binding protein 1, aminolevulinate delta synthase 2, and prolactin, whereas top downregulated genes comprised leptin, gametocyte-specific factor 1, and collagen type XVII alpha 1. Two enriched gene networks were identified, namely, (1) lipid metabolism, small molecule biochemistry, and organismal development and (2) cellular development, cellular growth, proliferation, and tumor morphology. PMID- 25824012 TI - Power, opportunism, racism: Human experiments under American slavery. PMID- 25824013 TI - Identity From Variation: Representations of Faces Derived From Multiple Instances. AB - Research in face recognition has tended to focus on discriminating between individuals, or "telling people apart." It has recently become clear that it is also necessary to understand how images of the same person can vary, or "telling people together." Learning a new face, and tracking its representation as it changes from unfamiliar to familiar, involves an abstraction of the variability in different images of that person's face. Here, we present an application of principal components analysis computed across different photos of the same person. We demonstrate that people vary in systematic ways, and that this variability is idiosyncratic-the dimensions of variability in one face do not generalize well to another. Learning a new face therefore entails learning how that face varies. We present evidence for this proposal and suggest that it provides an explanation for various effects in face recognition. We conclude by making a number of testable predictions derived from this framework. PMID- 25824014 TI - Graphene oxide nanoflakes incorporated gelatin-hydroxyapatite scaffolds enhance osteogenic differentiation of human mesenchymal stem cells. AB - In this study, graphene oxide (GO) nanoflakes (0.5 and 1 wt%) were incorporated into a gelatin-hydroxyapatite (GHA) matrix through a freeze drying technique and its effect to enhance mechanical strength and osteogenic differentiation was studied. The GHA matrix with GO demonstrated less brittleness in comparison to GHA scaffolds. There was no significant difference in mechanical strength between GOGHA0.5 and GOGHA1.0 scaffolds. When the scaffolds were immersed in phosphate buffered saline (to mimic physiologic condition) for 60 days, around 50-60% of GO was released in sustained and linear manner and the concentration was within the toxicity limit as reported earlier. Further, GOGHA0.5 scaffolds were continued for cell culture experiments, wherein the scaffold induced osteogenic differentiation of human adipose derived mesenchymal stem cells without providing supplements like dexamethasone, L-ascorbic acid and beta glycerophosphate in the medium. The level of osteogenic differentiation of stem cells was comparable to those cultured on GHA scaffolds with osteogenic supplements. Thus biocompatible, biodegradable and porous GO reinforced gelatin-HA 3D scaffolds may serve as a suitable candidate in promoting bone regeneration in orthopaedics. PMID- 25824015 TI - I-123 MIBG Cardiac Imaging. PMID- 25824016 TI - Imaging in patients with advanced therapies for heart failure. PMID- 25824017 TI - Optimizing FDG-PET/CT imaging of inflammation in atherosclerosis. PMID- 25824018 TI - Proceedings of the cardiac PET summit meeting 12 may 2014: Cardiac PET and SPECT instrumentation. AB - Advances in PET and SPECT and imaging hardware and software are vastly improving the noninvasive evaluation of myocardial perfusion and function. PET perfusion imaging has benefitted from the introduction of novel detectors that now allow true 3D imaging, and precise attenuation correction (AC). These developments have also resulted in perfusion images with higher spatial and contrast resolution that may be acquired in shorter protocols and/or with less patient radiation exposure than traditional PET or SPECT studies. Hybrid PET/CT cameras utilize transmission computed tomographic (CT) scans for AC, and offer the additional clinical advantages of evaluating coronary calcium and myocardial anatomy but at a higher cost than PET scanners that use (68)Ge radioactive line sources. As cardiac PET systems continue to improve, dedicated cardiac SPECT systems are also undergoing a profound change in their design. The scintillation camera general purpose design is being replaced with systems with multiple detectors focused on the heart yielding 5 to 10 times the sensitivity of conventional SPECT. As a result, shorter acquisition times and/or lower tracer doses produce higher quality SPECT images than were possible before. This article reviews these concepts and compares the attributes of PET and SPECT instrumentation. PMID- 25824019 TI - Mentorship at Distance: A new initiative of the Journal of Nuclear Cardiology. PMID- 25824020 TI - Medical therapy for the treatment of myocardial ischemia. PMID- 25824021 TI - Stress protocol and accuracy of myocardial perfusion imaging: Is it better to start from the end? PMID- 25824022 TI - The significance of automatically measured transient ischemic dilation in identifying severe and extensive coronary artery disease in regadenoson, single isotope technetium-99m myocardial perfusion SPECT. AB - BACKGROUND: The critical threshold and clinical significance of transient ischemic dilation (TID) for regadenoson, single-isotope (99m)Tc SPECT myocardial perfusion imaging (MPI) are not defined. METHODS: From 100 patients with low likelihood of CAD, we derived the abnormal TID threshold (mean + 2 SD). We validated the threshold in a cohort of 547 patients who received one-day, rest/regadenoson-stress, (99m)Tc-tetrofosmin SPECT-MPI followed by coronary angiography within 6 months. Patients were classified into three CAD severity strata: no significant CAD, mild to moderate CAD, and severe and extensive CAD. RESULTS: The abnormal TID threshold was determined to be 1.31. Though mean TID ratios were different between the three CAD severity groups and the derivation cohort (P < .001), there was no difference in the mean TID ratios between the categories of CAD severity or in the prevalence of severe CAD between TID+ and TID- groups (P = .74). By ROC analysis, TID had a poor discriminatory capacity in identifying severe and extensive CAD [AUC of 0.55 (95% CI 0.47-0.62, P = .25)]. Stepwise multivariate logistic analysis demonstrated that adding TID to clinical and perfusion data did not provide incremental diagnostic value (P = .87). CONCLUSIONS: The clinical utility of TID with regadenoson-stress MPI in this era of declining CAD burden is questionable. PMID- 25824023 TI - Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic. AB - STUDY QUESTION: Is consumption of fruits and vegetables with high levels of pesticide residues associated with lower semen quality? SUMMARY ANSWER: Consumption of fruits and vegetables with high levels of pesticide residues was associated with a lower total sperm count and a lower percentage of morphologically normal sperm among men presenting to a fertility clinic. WHAT IS KNOWN ALREADY: Occupational and environmental exposure to pesticides is associated with lower semen quality. Whether the same is true for exposure through diet is unknown. STUDY DESIGN, SIZE, DURATION: Men enrolled in the Environment and Reproductive Health (EARTH) Study, an ongoing prospective cohort at an academic medical fertility center. Male partners (n = 155) in subfertile couples provided 338 semen samples during 2007-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen samples were collected over an 18-month period following diet assessment. Sperm concentration and motility were evaluated by computer aided semen analysis (CASA). Fruits and vegetables were categorized as containing high or low-to-moderate pesticide residues based on data from the annual United States Department of Agriculture Pesticide Data Program. Linear mixed models were used to analyze the association of fruit and vegetable intake with sperm parameters accounting for within-person correlations across repeat samples while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Total fruit and vegetable intake was unrelated to semen quality parameters. High pesticide residue fruit and vegetable intake, however, was associated with poorer semen quality. On average, men in highest quartile of high pesticide residue fruit and vegetable intake (>=1.5 servings/day) had 49% (95% confidence interval (CI): 31%, 63%) lower total sperm count and 32% (95% CI: 7%, 58%) lower percentage of morphologically normal sperm than men in the lowest quartile of intake (<0.5 servings/day) (P, trend = 0.003 and 0.02, respectively). Low-to moderate pesticide residue fruit and vegetable intake was associated with a higher percentage of morphologically normal sperm (P, trend = 0.04). LIMITATIONS, REASONS FOR CAUTION: Surveillance data, rather than individual pesticide assessment, was used to assess the pesticide residue status of fruits and vegetables. CASA is a useful method for clinical evaluation but may be considered less favorable for accurate semen analysis in the research setting. Owing to the observational nature of the study, confirmation is required by interventional studies as well. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the consumption of fruits and vegetables with high levels of pesticide residue in relation to semen quality. Further confirmation of these findings is warranted. STUDY FUNDING/COMPETING INTERESTS: Supported by National Institutes of Health grants ES009718, ES022955, ES000002, P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16. None of the authors has any conflicts of interest to declare. PMID- 25824024 TI - Is dietary pesticide exposure related to semen quality? Positive evidence from men attending a fertility clinic. PMID- 25824025 TI - Adductor Canal Blockade Following Total Knee Arthroplasty-Continuous or Single Shot Technique? Role in Postoperative Analgesia, Ambulation Ability and Early Functional Recovery: A Randomized Controlled Trial. AB - Total knee arthroplasty (TKA) can be associated with severe pain in early postoperative period. Adductor canal block may provide optimal analgesia following TKA. However, ideal regimen for administration whether continuous or single shot is yet undefined. We prospectively randomized 90 patients in continuous and single shot adductor canal blockade groups. Postoperative VAS (visual analog scale for pain) score was significantly better at all times in continuous than single shot technique (P<0.001). However, ambulation ability (Timed Up & Go, 10m walk, 30s chair) and early functional recovery (active SLR, ambulation with walker, staircase competency, ambulation distance and maximal flexion at discharge) showed no statistical significant difference. Continuous adductor canal blockade was superior to single shot block in terms of pain control but was similar for early functional recovery. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25824026 TI - Prevention of Periprosthetic Joint Infection. AB - Periprosthetic joint infection (PJI) has moved into the first place as the cause of failure following total knee arthroplasty (TKA). Recent studies have shown that PJI results in higher mortality in patients than many cancers. The economic burden of treating PJI is likely to exceed $1 billion this year in the US. Thus, it is paramount that all efforts are invested to prevent this dreaded complication after total joint arthroplasty (TJA). This article summarizes some of the most effective and proven strategies for prevention of PJI. It is hoped that the article will be of benefit to the readers of the journal. PMID- 25824027 TI - Arsenic trioxide inhibits breast cancer cell growth via microRNA-328/hERG pathway in MCF-7 cells. AB - Arsenic trioxide (As2O3) has been widely used in the treatment of acute promyelocytic leukemia and has been observed to exhibit therapeutic effects in various types of solid tumor. In a previous study by this group, it was shown that As2O3 induces the apoptosis of MCF-7 breast cancer cells through inhibition of the human ether-a-go-go-related gene (hERG) channel. The present study was designed to further investigate the effect of As2O3 on breast cancer cells and to examine the mechanism underlying the regulation of hERG expression. The present study confirmed that As2O3 inhibited tumor growth in vivo, following MCF-7 cell implantation into nude mice. Using computational prediction , it was identified that microRNA (miR)-328 had a binding site in the 3'-untranslated region of hERG mRNA. A luciferase activity assay demonstrated that hERG is a target gene of miR 328. Further investigation using western blot analysis and reverse transcription quantitative polymerase chain reaction revealed that As2O3 downregulated hERG expression via upregulation of miR-328 expression in MCF-7 cells. In conclusion, As2O3 was observed to inhibit breast cancer cell growth, at least in part, through the miR-328/hERG pathway. PMID- 25824028 TI - Influenza and Other Respiratory Viruses. From the Editor's desk. PMID- 25824029 TI - Relationship between perilipin genes polymorphisms and growth, carcass and meat quality traits in pigs. AB - The perilipins (PLIN) belong to a family of structural proteins that play a role regulating intracellular lipid storage and mobilization. Here, PLIN1 and PLIN2 have been evaluated as candidate genes for growth, carcass and meat quality traits in pigs. A sample of 607 Duroc pigs were genotyped for two single nucleotide polymorphisms, one in intron 2 of the PLIN1 gene (JN860199:g.173G>A) and the other at the 3' untranslated region of the PLIN2 gene (GU461317:g.98G>A). Using a Bayesian approach, we have been able to find evidence of additive, dominant and epistatic associations of the PLIN1 and PLIN2 polymorphisms with early growth rate and carcass length. However, the major effects were produced by the dominant A allele at the PLIN2 polymorphism, which also affected the carcass lean weight. Thus, pigs carrying an additional copy of the A allele at the g.98G>A PLIN2 polymorphism had a probability of at least 98% of producing carcasses with heavier lean weight (+0.41 kg) and ham weight (+0.10 kg). The results obtained indicate that the PLIN2 polymorphism could be a useful marker for lean growth. In particular, it may help to reduce the undesired negative correlated response in lean weight to selection for increased intramuscular fat content, a common scenario in some Duroc lines involved in the production of high quality pork products. PMID- 25824030 TI - Effects of yoga on brain waves and structural activation: A review. AB - Previous research has shown the vast mental and physical health benefits associated with yoga. Yoga practice can be divided into subcategories that include posture-holding exercise (asana), breathing (pranayama, Kriya), and meditation (Sahaj) practice. Studies measuring mental health outcomes have shown decreases in anxiety, and increases in cognitive performance after yoga interventions. Similar studies have also shown cognitive advantages amongst yoga practitioners versus non-practitioners. The mental health and cognitive benefits of yoga are evident, but the physiological and structural changes in the brain that lead to this remain a topic that lacks consensus. Therefore, the purpose of this study was to examine and review existing literature on the effects of yoga on brain waves and structural changes and activation. After a narrowed search through a set of specific inclusion and exclusion criteria, 15 articles were used in this review. It was concluded that breathing, meditation, and posture-based yoga increased overall brain wave activity. Increases in graygray matter along with increases in amygdala and frontal cortex activation were evident after a yoga intervention. Yoga practice may be an effective adjunctive treatment for a clinical and healthy aging population. Further research can examine the effects of specific branches of yoga on a designated clinical population. PMID- 25824031 TI - Analysis of mutants from a genetic screening reveals the control of intestine and liver development by many common genes in zebrafish. AB - Both the intestine and liver develop from the endoderm, yet little is known how these two digestive organs share and differ in their developmental programs, at the molecular level. A classical forward genetic screen, with no gene bias, is an effective way to address this question by examining the defects of the intestine and liver in obtained mutants to assess mutated genes responsible for the development of either organ or both. We report here such a screen in zebrafish. ENU was used as the mutagen because of its high mutagenic efficiency and no site preference. Embryos were collected at 3.5 dpf for RNA whole mount in situ hybridization with a cocktail probe of the intestine marker ifabp and the liver marker lfabp to check phenotypes and determine their parental heterozygosis. A total of 52 F2 putative mutants were identified, and those with general developmental defects were aborted. To rule out non-inheritable phenotypes caused by high mutation background, F2 putative mutants were outcrossed with wild type fish and a re-screen in F3 generations was performed. After complementation tests between F3 mutants with similar phenotypes originating from the same F2 families, a total of 37 F3 mutant lines originated from 22 F2 families were identified after screening 78 mutagenized genomes. Classification of mutant phenotypes indicated that 31 out of the 37 mutants showed defects in both the intestine and liver. In addition, four "intestine specific mutants" and two "liver specific mutants" showed selectively more severe phenotype in the intestine and liver respectively. These results suggested that the intestine and liver share a substantial number of essential genes during both organs development in zebrafish. Further studies of the mutants are likely to shed more insights into the molecular basis of the digestive system development in the zebrafish and vertebrate. PMID- 25824032 TI - Activation of latent metastases in the lung after resection of a metastatic lymph node in a lymph node metastasis mouse model. AB - Iatrogenic induction of regional and distant cancer metastases is a risk associated with clinical resection of tumor-positive sentinel lymph nodes. However, there have been no studies of this risk in a mouse model of cancer metastasis. Here, we report that resection of a tumor-bearing subiliac lymph node (SiLN) enhanced lung metastasis in a mouse model of lymph node metastasis. Bioluminescence imaging revealed that metastatic tumor cells in the secondary lymph node continued to grow after resection of the SiLN, and that the probability of metastasis to the lungs was increased when the interval between SiLN inoculation and resection was reduced. Futhermore, histological analysis demonstrated that latents in the lung were stimulated to grow after resection of the SiLN. Fluorescence imaging indicated that the route of tumor cell dissemination from SiLN to the lung was the venous system located over the SiLN. We speculate that our mouse model will be useful for studying the mechanisms of tumor cell latency, with a view to improving the detection and treatment of latent metastases. PMID- 25824033 TI - Arf6 guanine-nucleotide exchange factor cytohesin-2 regulates myelination in nerves. AB - In postnatal development of the peripheral nervous system (PNS), Schwann cells differentiate to insulate neuronal axons with myelin sheaths, increasing the nerve conduction velocity. To produce the mature myelin sheath with its multiple layers, Schwann cells undergo dynamic morphological changes. While extracellular molecules such as growth factors and cell adhesion ligands are known to regulate the myelination process, the intracellular molecular mechanism underlying myelination remains unclear. In this study, we have produced Schwann cell specific conditional knockout mice for cytohesin-2, a guanine-nucleotide exchange factor (GEF) specifically activating Arf6. Arf6, a member of the Ras-like protein family, participates in various cellular functions including cell morphological changes. Cytohesin-2 knockout mice exhibit decreased Arf6 activity and reduced myelin thickness in the sciatic nerves, with decreased expression levels of myelin protein zero (MPZ), the major myelin marker protein. These results are consistent with those of experiments in which Schwann cell-neuronal cultures were treated with pan-cytohesin inhibitor SecinH3. On the other hand, the numbers of Ki67-positive cells in knockout mice and controls are comparable, indicating that cytohesin-2 does not have a positive effect on cell numbers. Thus, signaling through cytohesin-2 is required for myelination by Schwann cells, and cytohesin-2 is added to the list of molecules known to underlie PNS myelination. PMID- 25824034 TI - Folic acid supplementation rescues anomalies associated with knockdown of parkin in dopaminergic and serotonergic neurons in Drosophila model of Parkinson's disease. AB - parkin loss associated early-onset of Parkinson's disease, involves mitochondrial dysfunction and oxidative stress as the plausible decisive molecular mechanisms in disease pathogenesis. Mitochondrial dysfunction involves several up/down regulation of gene products, one of which being p53 is found to be elevated. Elevated p53 is involved in mitochondrial mediated apoptosis of neuronal cells in Parkinson's patients who are folate deficient as well. The present study therefore attempts to examine the effect of Folic acid (FA) supplementation in alleviation of anomalies associated with parkin knockdown using RNAi approach, specific to Dopaminergic (DA) neurons in Drosophila model system. Here we show that FA supplementation provide protection against parkin RNAi associated discrepancies, thereby improves locomotor ability, reduces mortality and oxidative stress, and partially improves Zn levels. Further, metabolic active cell status and ATP levels were also found to be improved thereby indicating improved mitochondrial function. To corroborate FA supplementation in mitochondrial functioning further, status of p53 and spargel was checked by qRT PCR. Here we show that folic acid supplementation enrich mitochondrial functioning as depicted from improved spargel level and lowered p53 level, which was originally vice versa in parkin knockdown flies cultured in standard media. Our data thus support the potential of folic acid in alleviating the behavioural defects, oxidative stress, augmentation of zinc and ATP levels in parkin knock down flies. Further, folic acid role in repressing mitochondrial dysfunction is encouraging to further explore its possible mechanistic role to be utilized as potential therapeutics for Parkinson's disease. PMID- 25824035 TI - HO-1 expression control in the rat glomerulus. AB - The differential localization of HO-1 in renal cells under conditions of injury, and the demonstration that exaggerated HO-1 expression can have detrimental rather than beneficial effects, raises the question of whether HO-1 expression in these cells is subject to control. The present study identifies a unique HO-1 expression pattern in the renal glomerulus indicative of presence of HO-1 expression control following prolonged HO-1 induction. HO-1 and HO-2 expression in response to the natural HO substrate/inducer Fe(++) protoporphyrin (PP) IX (hemin) was assessed in normal rat glomeruli. Following 18 h incubations with hemin (0-200 MUM), HO-1 expression increased in a concentration-dependent manner and via a hemopexin (HPX) independent mechanism with no effect on HO-2. In incubations with higher hemin concentrations (400 MUM), likely to be encountered in hemolytic disorders, HO-1 expression, decreased. This was preceded by a prolonged and sustained increase in HO-1 protein and was independent of the Fe(++) moiety as incubations with Cobalt protoporphyrin (CoPP) resulted in an identical expression pattern. The decrease of HO-1 protein could not be accounted for by proteasomal degradation since it was not reversed in co-incubations with hemin and the proteasome inhibitor, MG132, at concentrations sufficient to increase HO-1 glomerular content when used alone. Moreover, in the presence of MG132, a decrease of HO-1 expression also occurred at 100 and 200 MUM hemin. The effect of MG132 was mimicked by two additional mechanistically different approaches which also raised HO-1 content: a) co-incubations of hemin with ZnPP which increased HO-1 protein when used alone, and b) glomerular HO-1 over expression achieved by SB transposon mediated transgenesis. In contrast, the decrease in HO-1 levels observed at high hemin concentrations was reversed in co incubations with hemin and SnPP, which reduced HO-1 content when used alone. Expression of NF-E2 related factor 2 (Nrf2) protein, which mediates HO-1 induction in response to hemin, had a similar expression pattern with that of HO 1 protein indicating involvement of Nrf2 in the response of HO-1 to hemin. The above observations indicate presence of a HO-1 expression control mechanism in the glomerulus that may serve to protect it against potentially detrimental effects of exaggerated HO-1 expression. PMID- 25824036 TI - Co-purification of arrestin like proteins with alpha-enolase from bovine myocardial tissues and the possible role in heart diseases as an autoantigen. AB - AIM: Previously, we reported that visual arrestin co-purified with glycolytic enzymes. The aim of this study was to analyze the co-purification of arrestin like proteins (ALP) in bovine cardiac tissues with enolases. METHODS: The soluble extract of bovine myocardial tissues from different regions such as left and right atriums and ventricles of the bovine heart (n = 3) was analyzed by ACA-34 gel filtration, immuno-affinity column, SDS-PAGE, ELISA, western blot and a sandwich immune assay for quantification of ALP and sequence analysis. RESULTS: We observed that; 1) The cardiac muscle contained a 50 kDa ALP at a concentration of 751 pg/mg of soluble protein extract, 2) ALP purified, by immunoaffinity, contained alpha-enolase of 48 kDa confirmed by protein sequence analysis; 3) Cardiomyocyte cells exposed to anti arrestin and anti enolase monoclonal antibodies showed decreased proliferation in vitro, 4) High level of autoantibodies were detected by ELISA (3.57% for arrestin and 9.12% for alpha enolase) in serum of patients with infarcted heart disease. CONCLUSION: We suggest a possible interaction between ALP and alpha-enolases yielding a complex that may be involved in the induction of cardiac autoimmune diseases. PMID- 25824037 TI - Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics. AB - Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III. Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically. PMID- 25824038 TI - 'Super-perfect' enzymes: Structural stabilities and activities of recombinant triose phosphate isomerases from Pyrococcus furiosus and Thermococcus onnurineus produced in Escherichia coli. AB - Triose phosphate isomerases (TIMs) are considered to be 'kinetically perfect' enzymes, limited in their activity only by the rates of diffusion of substrate and product molecules. Most studies conducted thus far have been on mesophile derived TIMs. Here, we report studies of two extremophile-derived TIMs produced in Escherichia coli: (i) TonTIM, sourced from the genome of the thermophile archaeon, Thermococcus onnurineus, and (ii) PfuTIM, sourced from the genome of the hyperthermophile archaeon, Pyrococcus furiosus (PfuTIM). Although these enzymes are presumed to have evolved to function optimally at temperatures close to the boiling point of water, we find that TonTIM and PfuTIM display second order rate-constants of activity (k(cat)/K(m) values) comparable to mesophile derived TIMs, at 25 degrees C. At 90 degrees C, TonTIM and PfuTIM reach maximum velocities of reaction of ~ 10(6)-10(7) MUmol/s/mg, and display k(cat)/K(m) values in the range of ~ 10(10)-10(11) M(-1) s(-1), which are three orders of magnitude higher than those reported for mesophile TIMs. Further, the two enzymes display no signs of having undergone any structural unfolding at 90 degrees C. Such enzymes could thus probably be called 'super-perfect' enzymes. PMID- 25824039 TI - Resolvin D2 recovers neural injury by suppressing inflammatory mediators expression in lipopolysaccharide-induced Parkinson's disease rat model. AB - Activation of microglial cells have been treated as the main role in the pathogenesis of neuropathic inflammation and neurodegenerative disease, including Parkinson's disease (PD), prion disease and Alzheimer's disease (AD). Resolvin D2 (RvD2) is derived from omega-3 polyunsaturated fatty acid and performs potent anti-inflammatory and pro-resolution effects. Here we investigated the effects of intrathecal injection of RvD2 for substantia nigra pars compacta (SNpc) in vivo and primary microglia in vitro experiment on pro-inflammatory cytokine expression and NF-kappaB activation in Lipopolysaccharide (LPS)-induced PD rat model. The total of 30 days experimental period were used for the rats' experiment, the LPS induced inflammation in SNpc increase the expression of NO, iNOS, TNF-alpha, IL 1, IL-18, IL-6, IL-1beta, ROS production, the translocation of NF-kappaB p65, IkappaBalpha, and IKKbeta expression in glial cells. After injection of RvD2, the treatment prevented development of behavioral defects and TLR4/NF-kappaB pathway activation. Therefore, we demonstrated a novel role of RvD2 in treatment of rat PD model and LPS activated microglia inflammation. Given the significant potency of RvD2 and well-known side effects of microglia inflammatory inhibitors, it may represent novel hotspot for treating neurodegenerative disease. PMID- 25824040 TI - Nucleotides maintain the activity of Cav1.2 channels in guinea-pig ventricular myocytes. AB - The activity of Cav1.2 Ca(2+) channels is maintained in the presence of calmodulin and ATP, even in cell-free patches, and thus a channel ATP-binding site has been suggested. In this study, we examined whether other nucleotides, such as GTP, UTP, CTP, ADP and AMP, could be substituted for ATP in guinea-pig ventricular myocytes. We found that all the nucleotides tested could re-prime the Ca(2+) channels in the presence of 1 MUM calmodulin in the inside-out mode. The order of efficacy was ATP > GTP > UTP > ADP > CTP ~ AMP. Thus, the presumed nucleotide-binding site in the channel seemed to favor a purine rather than pyrimidine base and a triphosphate rather than a di- or mono-phosphate group. Furthermore, a high concentration (10 mM) of GTP, UTP, CTP, ADP and AMP had inhibitory effects on the channel activity. These results provide information on the putative nucleotide-binding site(s) in Cav1.2 Ca(2+) channels. PMID- 25824041 TI - An improved flurogenic probe for high-throughput screening of 2-deoxyribose aldolases. AB - 2-Deoxyribose aldolase-catalyzed C-C bond-forming reactions have become 1 more and more important in synthesis of statins and other drug intermediates. Many methods have focused on improving the aldolase properties and harvesting new aldolases, but a good outcome depends on the efficiency of the high-throughput screening system. We have developed a visible green fluorescence probe based on a coumarin derivative, which can be reversibly modulated by a retro-aldol reaction catalyzed by 2-deoxyribose aldolase for selecting aldolase mutants with high activity. This assay system provides a convenient and effective way for high throughput screening aldolases as the green fluorescence is sensitively detected and daylight-viewable without the need for specialist equipment. We used our probe to successfully harvest aldolase mutants with higher activities than the parent from a random mutagenesis library. PMID- 25824042 TI - Glut4 palmitoylation at Cys223 plays a critical role in Glut4 membrane trafficking. AB - Recently, we identified Glut4 as a palmitoylated protein in adipocytes. To understand the role of Glut4 palmitoylation in Glut4 membrane trafficking, a process that is essential for maintenance of whole body glucose homeostasis, we have characterized Glut4 palmitoylation. We found that Glut4 is palmitoylated at Cys223 and Glut4 palmitoylation at Cys223 is essential for insulin dependent Glut4 membrane translocation as substitution of Cys223 with a serine residue in Glut4 (C223S Glut4) diminished Glut4 responsiveness to insulin in membrane translocation in both adipocytes and CHO-IR cells. We have examined C223S Glut4 subcellular localization and observed that it was absence from tubular-vesicle structure, where insulin responsive Glut4 vesicles were presented. Together, our studies uncover a novel mechanism under which Glut4 palmitoylation regulates Glut4 sorting to insulin responsive vesicles, thereby insulin-dependent Glut4 membrane translocation. PMID- 25824043 TI - SphK1 inhibitor II (SKI-II) inhibits acute myelogenous leukemia cell growth in vitro and in vivo. AB - Previous studies have identified sphingosine kinase 1 (SphK1) as a potential drug target for treatment of acute myeloid leukemia (AML). In the current study, we investigated the potential anti-leukemic activity of a novel and specific SphK1 inhibitor, SKI-II. We demonstrated that SKI-II inhibited growth and survival of human AML cell lines (HL-60 and U937 cells). SKI-II was more efficient than two known SphK1 inhibitors SK1-I and FTY720 in inhibiting AML cells. Meanwhile, it induced dramatic apoptosis in above AML cells, and the cytotoxicity by SKI-II was almost reversed by the general caspase inhibitor z-VAD-fmk. SKI-II treatment inhibited SphK1 activation, and concomitantly increased level of sphingosine-1 phosphate (S1P) precursor ceramide in AML cells. Conversely, exogenously-added S1P protected against SKI-II-induced cytotoxicity, while cell permeable short chain ceramide (C6) aggravated SKI-II's lethality against AML cells. Notably, SKI II induced potent apoptotic death in primary human AML cells, but was generally safe to the human peripheral blood mononuclear cells (PBMCs) isolated from healthy donors. In vivo, SKI-II administration suppressed growth of U937 leukemic xenograft tumors in severe combined immunodeficient (SCID) mice. These results suggest that SKI-II might be further investigated as a promising anti-AML agent. PMID- 25824044 TI - ALS-associated P56S-VAPB mutation restrains 3T3-L1 preadipocyte differentiation. AB - Amyotrophic lateral sclerosis (ALS), which is the most common motor neuron disease in adults, is a neurodegenerative disease that involves the selective and systematic death of upper and lower motor neurons. In addition to the motor neuron death, altered metabolic functions, such as dyslipidemia, have also been reported for ALS patients; however, the underlying mechanism remains unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle associated membrane proteinassociated protein B (VAPB), P56S-VAPB on 3T3-L1 preadipocyte differentiation and on the expression of differentiation-associated genes and unfolded protein response (UPR)-related genes. Experiments with 3T3-L1 cells transfected with wild-type (Wt)-VAPB and P56S-VAPB expression vectors showed that the size of lipid droplets was markedly smaller in P56S-VAPB expressing cells, although fat accumulated intracellularly. In P56S-VAPB expressing cells, increased the expression of PPARgamma2, aP2, and C/EBPalpha, the genes deeply involved in adipocyte differentiation, was not observed. Furthermore, the expression levels of the UPR-related ATF4 and CHOP genes were found to be enhanced in the P56S-VAPB-expressing cells. From these results, P56S VAPB was found to suppress adipocyte differentiation by promoting the activation of the ATF4-CHOP pathway. Given previous reports showing increased ATF4 and CHOP expression levels in neurons of ALS patients, results from the present study suggest that dyslipidemia is caused by enhanced ATF4-CHOP pathway in the adipose tissue of ALS patients. PMID- 25824045 TI - miR-107 and miR-25 simultaneously target LATS2 and regulate proliferation and invasion of gastric adenocarcinoma (GAC) cells. AB - Although a series of oncogenes and tumor suppressors were identified in the pathological development of gastric adenocarcinoma (GAC), the underlying molecule mechanism were still not fully understood. The current study explored the expression profile of miR-107 and miR-25 in GAC patients and their downstream regulative network. qRT-PCR analysis was performed to quantify the expression of these two miRNAs in serum samples from both patients and healthy controls. Dual luciferase assay was conducted to verify their putative bindings with LATS2. MTT assay, cell cycle assay and transwell assay were performed to explore how miR-107 and miR-25 regulate proliferation and invasion of gastric cancer cells. Findings of this study demonstrated that total miR-107 or miR-25 expression might be overexpressed in gastric cancer patients and they can simultaneously and synchronically regulate LATS2 expression, thereby affecting gastric cancer cell growth and invasion. Therefore, the miR-25/miR-107-LATS2 axis might play an important role in proliferation and invasion of the gastric cancer cells. PMID- 25824046 TI - Brusatol inhibits the response of cultured beta-cells to pro-inflammatory cytokines in vitro. AB - Brusatol is a natural terpenoid that is capable of inducing a variety of biological effects. We presently report that this substance dramatically improves beta-cell survival when exposed to pro-inflammatory cytokines (IL-1beta and IFNgamma) in vitro. This was observed in insulin producing rat (RIN-5AH), mouse (betaTC6) and human (EndoC-betaH1) beta-cell lines. Brusatol prevented beta-cell oxidative stress in response to cytokines and counteracted induction of iNOS on the protein level. Brusatol, however, block neither the cytokine-induced increase of iNOS mRNA, nor NF-kappaB activation, suggesting that inhibition of iNOS protein expression relies on posttranscriptional mechanism. This indicates that brusatol acts via a novel protective pathway, which may represent a more promising way of improving beta-cell function and survival. PMID- 25824047 TI - The rice ent-KAURENE SYNTHASE LIKE 2 encodes a functional ent-beyerene synthase. AB - The rice genome contains a family of kaurene synthase-like (OsKSL) genes that are responsible for the biosynthesis of various diterpenoids, including gibberellins and phytoalexins. While many OsKSL genes have been functionally characterized, the functionality of OsKSL2 is still unclear and it has been proposed to be a pseudogene. Here, we found that OsKSL2 is drastically induced in roots by methyl jasmonate treatment and we successfully isolated a full-length cDNA for OsKSL2. Sequence analysis of the OsKSL2 cDNA revealed that the open reading frame of OsKSL2 is mispredicted in the two major rice genome databases, IRGSP-RAP and MSU RGAP. In vitro conversion assay indicated that recombinant OsKSL2 catalyzes the cyclization of ent-CDP into ent-beyerene as a major and ent-kaurene as a minor product. ent-Beyerene is an antimicrobial compound and OsKSL2 is induced by methyl jasmonate; these data suggest that OsKSL2 is a functional ent-beyerene synthase that is involved in defense mechanisms in rice roots. PMID- 25824048 TI - Endothelin-1 exacerbates development of hypertension and atherosclerosis in modest insulin resistant syndrome. AB - Endothelin-1 (ET-1) is known as potent vasoconstrictor, by virtue of its mitogenic effects, and may deteriorate the process of hypertension and atherosclerosis by aggravating hyperplasia and migration in VSMCs. Our previous study demonstrated that insulin infusion caused sequential induction of hyperinsulinemia, hyperendothelinemia, insulin resistance, and then hypertension in rats. However, the underlying mechanism of ET-1 interfere insulin signaling in VSMCs remains unclear. To characterize insulin signaling during modest insulin resistant syndrome, we established and monitored rats by feeding high fructose diet (HFD) until high blood pressure and modest insulin resistance occurred. To explore the role of ET-1/ETAR during insulin resistance, ETAR expression, ET-1 binding, and insulin signaling were investigated in the HFD-fed rats and cultured A-10 VSMCs. Results showed that high blood pressure, tunica medial wall thickening, plasma ET-1 and insulin, and accompanied with modest insulin resistance without overweight and hyperglycemia occurred in early-stage HFD-fed rats. In the endothelium-denuded aorta from HFD-fed rats, ETAR expression, but not ETBR, and ET-1 binding in aorta were increased. Moreover, decreasing of insulin-induced Akt phosphorylation and increasing of insulin-induced ERK phosphorylation were observed in aorta during modest insulin resistance. Interestingly, in ET-1 pretreated VSMCs, the increment of insulin-induced Akt phosphorylation was decreased whereas the increment of insulin-induced ERK phosphorylation was increased. In addition, insulin potentiated ET-1-induced VSMCs migration and proliferation due to increasing ET-1 binding. ETAR antagonist reversed effects of ET-1 on insulin-induced signaling and VSMCs migration and proliferation. In summary, modest insulin resistance syndrome accompanied with hyperinsulinemia leading to the potentiation on ET-1-induced actions in aortic VSMCs. ET-1 via ETAR pathway suppressed insulin-induced AKT activation, whereas remained insulin-induced ERK activation. ET-1 and insulin synergistically potentiated migration and proliferation mainly through ETAR/ERK dependent pathway, which is dominant in VSMCs during modest insulin resistance syndrome. Therefore, ET-1 and ETAR are potential targets responsible for the observed synergism effect in the hypertensive atherosclerotic process through enhancement of ET-1 binding, ET-1 binding, ETAR expression, and ET-1-induced mitogenic actions in aortic VSMCs. PMID- 25824049 TI - MiR-520b suppresses proliferation of hepatoma cells through targeting ten-eleven translocation 1 (TET1) mRNA. AB - Accumulating evidence indicates that microRNAs are able to act as oncogenes or tumor suppressor genes in human cancer. We previously reported that miR-520b was down-regulated in hepatocellular carcinoma (HCC) and its deregulation was involved in hepatocarcinogenesis. In the present study, we report that miR-520b suppresses cell proliferation in HCC through targeting the ten-eleven translocation 1 (TET1) mRNA. Notably, we identified that miR-520b was able to target 3'-untranslated region (3'UTR) of TET1 mRNA by luciferase reporter gene assays. Then, we revealed that miR-520b was able to reduce the expression of TET1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blotting analysis. In terms of function, 5-ethynyl-2 deoxyuridine (EdU) incorporation and colony formation assays demonstrated that the forced miR-520b expression remarkably inhibited proliferation of hepatoma cells, but TET1 overexpression could rescue the inhibition of cell proliferation mediated by miR-520b. Furthermore, anti-miR-520b enhanced proliferation of hepatoma cells, whereas silencing of TET1 abolished anti-miR-520b-induced acceleration of cell proliferation. Then, we validated that the expression levels of miR-520b were negatively related to those of TET1 mRNA in clinical HCC tissues. Thus, we conclude that miR-520b depresses proliferation of liver cancer cells through targeting 3'UTR of TET1 mRNA. Our finding provides new insights into the mechanism of hepatocarcinogenesis. PMID- 25824050 TI - Use of aromatase inhibitors in practice of gynecology. AB - PURPOSE: The conversion of androgens into estrogens by aromatase is called aromatization and is inhibited by aromatase inhibitors (AIs). The aim of this article is to evaluate the use of aromatase inhibitors in gynecological diseases such as endometriosis, leiomyoma, estrogen- dependent gynecologic neoplasia and infertility. METHODS: This is a review of literature combined with experience and use of aromatase inhibitors in practice of gynecology. CONCLUSION: AIs are promising agents in treatment of estrogen dependent disease. However lack of experience, side effects and cost are limiting factors for using these agents in infertility treatment. However there is need for larger, well designed randomized trials to generate robust data in order to establish the true potential of aromatase inhibitors. PMID- 25824051 TI - The efficacy of N-methyl-D-aspartate receptor antagonists on improving the postoperative pain intensity and satisfaction after remifentanil-based anesthesia in adults: a meta-analysis. AB - BACKGROUND: Remifentanil could induce opioid-induced hyperalgesia and tolerance, which would increase pain intensity after the operation. N-methyl-d-aspartate (NMDA) receptor antagonists have been used to prevent these adverse effects while the efficacy is still controversial. We evaluated the effectiveness of NMDA receptor antagonists in reducing postoperative pain and analgesic consumption after remifentanil-based anesthesia. METHODS: Full published reports of randomized controlled trials on adults investigating the effects of intravenous administration of NMDA receptor antagonists compared with placebo for preventing remifentanil-induced postoperative hyperalgesia and tolerance were searched in PubMed, Embase, Springer, and the Cochrane Central Register of Controlled Trials. Postoperative pain scores, analgesic consumption, time to first analgesic request, satisfaction scores, and opioid-related and other adverse effects have been evaluated. Results were combined using fix or random-effects model when appropriate. RESULTS: A total of 14 randomized controlled trials with 729 patients were included in the final analysis. Compared with placebo, NMDA receptor antagonists reduced the pain scores at 0, 4, 6, 8, 12, and 24 hours postoperatively (P < .05), reduced the cumulative analgesic consumption of 0-6, 0 24, and 0-48 hours after the operation (P < .05), prolonged the first time to request analgesic (P < .05), and promoted the satisfaction scores (P < .05). There was no difference in the incidence of postoperative nausea and vomiting, psychological adverse effects, and shivering. Subgroup analysis was conducted on different interventions (ketamine and magnesium); the results are in line with general results. CONCLUSIONS: N-methyl-d-aspartate receptor antagonists can prevent the increase of analgesic consumption and pain intensity induced by remifentanil, and it can improve the postoperative satisfaction of patients. PMID- 25824052 TI - Practical regional blocks for nasal fracture in a child: blockade of infraorbital nerve and external nasal branch of anterior ethmoidal nerve. PMID- 25824053 TI - Unbounded number of channel uses may be required to detect quantum capacity. AB - Transmitting data reliably over noisy communication channels is one of the most important applications of information theory, and is well understood for channels modelled by classical physics. However, when quantum effects are involved, we do not know how to compute channel capacities. This is because the formula for the quantum capacity involves maximizing the coherent information over an unbounded number of channel uses. In fact, entanglement across channel uses can even increase the coherent information from zero to non-zero. Here we study the number of channel uses necessary to detect positive coherent information. In all previous known examples, two channel uses already sufficed. It might be that only a finite number of channel uses is always sufficient. We show that this is not the case: for any number of uses, there are channels for which the coherent information is zero, but which nonetheless have capacity. PMID- 25824054 TI - Update on the autoimmune pathology of multiple sclerosis: B-cells as disease drivers and therapeutic targets. AB - BACKGROUND: Collectively, research on the role of B-cells in the pathogenesis of multiple sclerosis (MS) illustrates how translational medicine has given rise to promising therapeutic approaches for one of the most debilitating chronic neurological diseases in young adults. First described in 1935, the experimental autoimmune/allergic encephalomyelitis model is a key animal model that has provided the foundation for important developments in targeted therapeutics. SUMMARY: While additional B-cell therapies for MS are presently being developed by the pharmaceutical industry, much remains to be understood about the role played by B-cells in MS. The goal of this review is to summarize how B-cells may contribute to MS pathogenesis and thereby provide a basis for understanding why B cell depletion is so effective in the treatment of this disease. Key Messages: B cells are key players in the pathogenesis of MS, and their depletion via B-cell targeted therapy ameliorates disease activity. CLINICAL IMPLICATIONS: In 2008, data from the first CD20-targeting B-cell depleting therapeutic trials using rituximab in MS were published. Since then, there has been a large body of evidence demonstrating the effectiveness of B-cell depletion mediated via anti CD20 antibodies. Intense research efforts focusing on the immunopathological relevance of B-cells has gained significant momentum and given rise to a constellation of promising therapeutic agents for this complex B-cell-driven disease, including novel anti-CD20 antibodies, as well as agents targeting CD19 and BAFF-R. PMID- 25824055 TI - Brood care in a 100-million-year-old scale insect. AB - Behavior of extinct organisms can be inferred only indirectly, but occasionally rare fossils document particular behaviors directly. Brood care, a remarkable behavior promoting the survival of the next generation, has evolved independently numerous times among animals including insects. However, fossil evidence of such a complex behavior is exceptionally scarce. Here, we report an ensign scale insect (Hemiptera: Ortheziidae), Wathondara kotejai gen. et sp. nov., from mid Cretaceous Burmese amber, which preserves eggs within a wax ovisac, and several freshly hatched nymphs. The new fossil is the only Mesozoic record of an adult female scale insect. More importantly, our finding represents the earliest unequivocal direct evidence of brood care in the insect fossil record and demonstrates a remarkably conserved egg-brooding reproductive strategy within scale insects in stasis for nearly 100 million years. PMID- 25824056 TI - Flowering time and seed dormancy control use external coincidence to generate life history strategy. AB - Climate change is accelerating plant developmental transitions coordinated with the seasons in temperate environments. To understand the importance of these timing advances for a stable life history strategy, we constructed a full life cycle model of Arabidopsis thaliana. Modelling and field data reveal that a cryptic function of flowering time control is to limit seed set of winter annuals to an ambient temperature window which coincides with a temperature-sensitive switch in seed dormancy state. This coincidence is predicted to be conserved independent of climate at the expense of flowering date, suggesting that temperature control of flowering time has evolved to constrain seed set environment and therefore frequency of dormant and non-dormant seed states. We show that late flowering can disrupt this bet-hedging germination strategy. Our analysis shows that life history modelling can reveal hidden fitness constraints and identify non-obvious selection pressures as emergent features. PMID- 25824057 TI - Inhibition of Hedgehog signaling pathway impedes cancer cell proliferation by promotion of autophagy. AB - Multiple lines of evidence implicate that aberrant activation of Hedgehog (Hh) signaling is involved in a variety of human cancers. However, the molecular mechanisms underlying how cancer cells respond to Hh inhibition remain to be elucidated. In this study, we found that blockade of Hh signaling suppresses cell proliferation in human cancer cells. Microarray analysis revealed that differentially expressed genes (DEGs) in human cancer cells are enriched in autophagy pathway in response to the inhibition of Hh signaling. Interestingly, inhibition of Hh signaling induced autophagy, whereas activation of Hh signaling by ligand treatments prevented the induction of autophagy. In addition, inhibition of autophagy by 3-methyladenine (3-MA) partially suppressed cytotoxicity induced by inhibition of Hh signaling. Finally, in autophagy deficient cells, cytotoxic effect triggered by inhibition of Hh signaling was partially reversed, indicating the modulation of autophagy by Hh signaling is autophagy-specific. These results suggest that inhibition of Hh signaling impedes cancer cell proliferation in part through induction of autophagy. PMID- 25824058 TI - Physiological and psychophysiological responses to an exer-game training protocol. AB - OBJECTIVES: Exer-games and virtual reality offer alternative opportunities to provide neuro-rehabilitation and exercise that are fun. Our goal was to determine how effective they are in achieving motor learning goals and fitness benefits as players gain experience. DESIGN: We employed a repeated measures design to determine changes in physical exertion and engagement with training. METHODS: Fourteen healthy adults trained on the XBOX Kinect video game Dance Central using a skill-based protocol to examine changes in energy expenditure (EE), heart rate (HR), METs, limb movement, game proficiency, and player engagement in initial, post-training, and transfer-testing of a full-body dance exer-game. Data were analyzed using repeated measures analysis of variance, p<0.05. RESULTS: Both EE, HR, and METs increased from initial (EE 4.89+/-1.35, HR 103+/-18, METs 4.25+/ 0.72) to post-training (EE 5.92+/-1.25, HR 110+/-15, METs 5.05+/-0.75) and were greatest during transfer-testing (EE 6.34+/-1.35, HR 115+/-17, METs 5.42+/-0.88, p<=0.001). Proficiency, measured by game scores, also increased from initial to post-training and transfer-testing (p<=0.002). Limb movement and player engagement remained unchanged. CONCLUSIONS: It is important to understand whether player physiological and psychophysiological responses change with continued game play. Although Dance Central involves whole-body movement, physical exertion remained at moderate levels after training. As exer-game and virtual reality systems move from their initial novelty, research about how players react to continued involvement with a game can guide game developers to maintain a freshness through game progression that preserves the participant's attentional focus, minimizes attrition and maintains a prescribed level of energy exertion. PMID- 25824059 TI - Hinchingbrooke revisited. PMID- 25824060 TI - Identifying reasons for delays in acute hospitals using the Day-of-Care Survey method. AB - This paper describes a new tool called 'Day-of-Care Survey', developed to assess inpatient delays in acute hospitals. Using literature review, iterative testing and feedback from professional groups, a national multidisciplinary team developed the survey criteria and methodology. Review teams working in pairs visited wards and used case records and bedside charts to assess the patient's status against severity of illness and service intensity criteria. Patients who did not meet the survey criteria for acute care were identified and delays were categorised. From March 2012 to December 2013, nine acute hospitals across Scotland, Australia and England were surveyed. A total of 3,846 adult general inpatient beds (excluding intensive care and maternity) were reviewed. There were 145 empty beds at the time of surveys across the nine sites, with 270 definite discharges planned on the day of the survey. The total number of patients not meeting criteria for acute care was 798/3,431 (23%, range 18-28%). Six factors accounted for 61% (490/798) of the reasons why patients not meeting acute care criteria remained in hospital. This survey gives important insights into the challenges of managing inpatient flow using system level information as a method to target interventions designed to address delay. PMID- 25824061 TI - Compassion. AB - The term 'compassion' has been much used and little discussed. I argue that compassion is a virtue in the Aristotelian sense, one of a family of other regarding properties and belongs to the affective qualities of a moral agent. Its exercise is an essential component of good medical care in many situations and requires grounding in moral principles. Although our dispositions vary, compassion is a quality that can be developed in all of us. PMID- 25824062 TI - False interpretation of diagnostic serology tests for patients treated with pooled human immunoglobulin G infusions: a trap for the unwary. AB - Therapeutic immunoglobulin G (IgG) products are produced from numerous plasma donations, and are infused in many medical conditions. The serological testing of patients who have received IgG infusions may well produce falsely positive and misleading results from this infused IgG, rather than endogenously produced IgG. We present two example cases of clinical situations where this could cause concern. We tested multiple IgG products with a range of serological tests performed in infective or autoimmune conditions, including hepatitis B, syphilis, human immunodeficiency virus, human T-lymphotropic virus, anti-neutrophil cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), anti-cardiolipin antibodies and anti-double stranded DNA (dsDNA) antibody. We found positivity within these products for hepatitis B surface and core antibody, syphilis, ANCA, ANA, anti-cardiolipin IgG and dsDNA antibody, which may result from specific or non-specific reactivity. The serological testing of patients who have received IgG treatment detects the administered IgG in addition to IgG produced by the patient. PMID- 25824064 TI - Teaching a 'good' ward round. AB - Ward rounds are a vital part of hospital medicine and junior doctors play a key role in their delivery. Despite the importance of ward rounds to patient care and experience, we believe that junior doctors may lack the training and skills to carry them out most effectively. We designed a simulation-based training session focusing on ward round skills themed to key patient safety issues and have delivered the training to over 100 learners (medical students and foundation year one doctors). Few learners had any prior training in ward rounds. The session was highly valued by all participants and surveys completed both before and after the session showed statistically significant improvements in confidence in leading and documenting ward rounds. In addition, 94% of final year medical students and 93% of doctors felt such training should be included in the undergraduate curriculum. We believe there is a current gap in training around ward round skills and would strongly encourage simulation-based ward round training to be developed for undergraduates. Further sessions following qualification may then consolidate and develop ward round skills adapted to the level of the doctor. PMID- 25824063 TI - Cerebral involvement in IgG4-related disease. AB - IgG4-related disease is a recently recognised multi-system disease. Common organ involvement includes the pancreas, biliary tree and salivary glands. Central nervous system involvement has been infrequently reported. In a single-centre cohort of 84 patients, we report cerebral involvement in three (4%) patients. Details of cerebral involvement in these patients are outlined, including pituitary involvement in two patients and a diffuse autoimmune-like encephalopathy in the other. PMID- 25824065 TI - Surveillance for hepatocellular carcinoma in a mixed-aetiology UK cohort with cirrhosis: does alpha-fetoprotein still have a role? AB - Mortality from hepatocellular carcinoma (HCC) in people with cirrhosis is increasing whereas mortality from other causes is declining. Surveillance appears to reduce mortality but the optimal strategy is uncertain. Current guidelines differ by recommending ultrasonography alone or with alpha-fetoprotein (alphaFP). Records in three UK hospitals were analysed from 2006 to 2011. Of 111 HCC cases identified, 24 (47.1%) of those eligible were under surveillance: 21 (87.5%) were under combined ultrasonography-alphaFP, 2 (8.3%) ultrasonography-only and 1 (4.2%) alphaFP-only surveillance. alphaFP was elevated in 19 (86.4%), and alphaFP alone triggered a confirmatory study in 11 (9.9%) overall and 7 (29.1%) under surveillance. Surveillance, but not alphaFP, correlated with smaller tumours. Survival did not differ significantly between groups. Given that alphaFP use is associated with identifying smaller HCCs and that several diagnoses would have been delayed without alphaFP in this real-life cohort, these data support ongoing alphaFP use. However, further work is necessary with regard to whether alphaFP translates into improved clinical outcome and overall cost effects. In our area, stopping alphaFP use would also represent a significant change in practice. PMID- 25824066 TI - Vitamin B12 deficiency - A 21st century perspective . AB - Vitamin B12 deficiency is a common condition which can present with non-specific clinical features, and in severe cases with neurological or haematological abnormalities. Although classically caused by pernicious anaemia, this condition now accounts for a minority of cases and vitamin B12 deficiency occurs most often due to food-bound cobalamin malabsorption. Since missing the diagnosis can result in potentially severe complications, including degeneration of the spinal cord and pancytopaenia, vitamin B12 deficiency must be diagnosed early and managed appropriately. Intramuscular injections have been the mainstay of treatment, but oral replacement therapy can be effective in many cases. There is accumulating evidence that high vitamin B12 levels (values varied from 350-1,200 pmol/l) are associated with haematological and hepatic disorders, in particular with malignancy. This review focuses on the developments in the clinical features and management of vitamin B12 deficiency over the last decade. PMID- 25824067 TI - Mental health in young adults and adolescents - supporting general physicians to provide holistic care. AB - In the era of an ageing population, young adults on medical wards are quite rare, as only 12% of young adults report a long-term illness or disability. However, mental health problems remain prevalent in the younger population. In a recent report, mental health and obesity were listed as the most common problems in young adults. Teams set up specifically for the needs of younger adults, such as early intervention in psychosis services are shown to work better than traditional care and have also proven to be cost effective. On the medical wards, younger patients may elicit strong emotions in staff, who often feel protective and may identify strongly with the young patient's suffering. In order to provide holistic care for young adults, general physicians need to recognise common presentations of mental illness in young adults such as depression, deliberate self-harm, eating disorders and substance misuse. Apart from treating illness, health promotion is particularly important for young adults. PMID- 25824068 TI - Drug therapies in older adults (part 2). AB - In this, the second of two articles, we continue our evaluation of drug therapies in older adults. Having previously described the pharmacokinetic and pharmacodynamic consequences of physiological ageing, along with the challenge of appropriate prescribing, we proposed four key questions which should be considered when prescribing for this cohort of the population. Does this agent reflect the priorities of the patient? Are there alternatives - with greater efficacy, effectiveness or tolerability - that might be considered? Are the dose, frequency and formulation appropriate? How does this prescription relate to concurrent medication? We also highlighted the reliance on subgroup analysis to demonstrate the efficacy of drug therapies for older adults in osteoporosis and the underutilisation of appropriate treatments for patients with Alzheimer's disease as a result of flawed guidelines. Here we describe current drug therapies in systolic heart failure, noting the limited inclusion of older adults in key trials, while also reviewing the pharmacological treatment of orthostatic hypotension. In doing so, we advocate the intermittent use of midodrine as a first-line treatment for orthostasis in older adults, counter to the generic guidelines produced by various learned societies, but in keeping with the scant trial data available. PMID- 25824069 TI - Harveian Oration 2014: Stem cells and cell replacement prospects . PMID- 25824070 TI - FitzPatrick Lecture: King George III and the porphyria myth - causes, consequences and re-evaluation of his mental illness with computer diagnostics. AB - Recent studies have shown that the claim that King George III suffered from acute porphyria is seriously at fault. This article explores some of the causes of this misdiagnosis and the consequences of the misleading claims, also reporting on the nature of the king's recurrent mental illness according to computer diagnostics. In addition, techniques of cognitive archaeology are used to investigate the nature of the king's final decade of mental illness, which resulted in the appointment of the Prince of Wales as Prince Regent. The results of this analysis confirm that the king suffered from bipolar disorder type I, with a final decade of dementia, due, in part, to the neurotoxicity of his recurrent episodes of acute mania. PMID- 25824071 TI - Management of patients with Graves' orbitopathy: initial assessment, management outside specialised centres and referral pathways. AB - Graves' orbitopathy (GO) is uncommon, but responsible for considerable morbidity. A coordinated approach between healthcare professionals is required in order to meet the needs of patients. Early diagnosis can be achieved by a simple clinical assessment. Low-cost effective interventions can be initiated by generalists, which may improve outcomes. Moderate-to-severe GO should be referred to specialised centres. Recommendations for clinical diagnosis, initial management and referral pathways are highlighted. PMID- 25824072 TI - Alcoholic liver disease - the extent of the problem and what you can do about it. AB - It takes upwards of ten years for alcohol-related liver disease to progress from fatty liver through fibrosis to cirrhosis to acute on chronic liver failure. This process is silent and symptom free and can easily be missed in primary care, usually presenting with advanced cirrhosis. At this late stage, management consists of expert supportive care, with prompt identification and treatment of bleeding, sepsis and renal problems, as well as support to change behaviour and stop harmful alcohol consumption. There are opportunities to improve care by bringing liver care everywhere up to the standards of the best liver units, as detailed in the Lancet Commission report. We also need a fundamental rethink of the technologies and approaches used in primary care to detect and intervene in liver disease at a much earlier stage. However, the most effective and cost effective measure would be a proper evidence-based alcohol strategy. PMID- 25824073 TI - Non-alcoholic fatty liver disease: when to intervene and with what. AB - Non-alcoholic fatty liver disease (NAFLD) is increasingly common due to the rising prevalence of obesity in both children and adults. It is associated with metabolic risk factors such as diabetes mellitus, dyslipidaemia and hypertension, and is associated with increased mortality both from cardiovascular-related and liver-related deaths. Identification of those individuals with significant inflammation and fibrosis is a critical part of the patient pathway. Current treatments for NAFLD include weight loss from lifestyle modification or bariatric surgery, management of underlying metabolic risk factors and for those with end stage liver disease, liver transplantation. PMID- 25824074 TI - New insights in the management of chronic hepatitis B. AB - Chronic hepatitis B (CHB) remains a global healthcare challenge, complicated by the development of cirrhosis and hepatocellular carcinoma, accounting for approximately 600,000 deaths per year. Hepatitis B is a DNA virus, which utilises a covalently closed circular (ccc) DNA to act as a transcriptional template for the virus. The persistence of cccDNA in the nucleus of infected hepatocytes accounts for HBV chronicity. Quantitative hepatitis B surface antigen (qHBsAg) acts as a surrogate for the level of cccDNA and therefore may provide useful information around treatment response and viral immune control. Current antiviral therapies are limited in their ability to achieve HBsAg loss, which is considered the 'gold-standard' treatment endpoint. This article focuses on the unmet needs in CHB today; a better definition of disease phase, the timing of therapeutic intervention, optimising treatment strategies with current therapies and the development of novel agents; all with HBsAg loss as the therapeutic goal. PMID- 25824076 TI - Management of patients with decompensated cirrhosis. AB - During the assessment of a patient with liver disease, finding the patient has decompensated cirrhosis, as defined by the presence of jaundice, ascites, variceal haemorrhage or hepatic encephalopathy, has major implications regarding management and prevention of cirrhosis-related complications, as well as consideration for a referral for liver transplantation evaluation. Prognosis is markedly worse in patients with decompensated compared with compensated cirrhosis. In general, any patient with decompensated cirrhosis should receive evaluation and medical care by a hepatologist. Since patients frequently present with more than one facet of liver decompensation, such cases pose a complex management challenge requiring input from a multidisciplinary team and close liaison with a liver transplant centre. PMID- 25824075 TI - Chronic hepatitis C - what do the new drugs offer and who should get them first? AB - Until recently in the UK the treatment of HCV depended on combination regimes of interferon (IFN) and the antiviral drug ribavirin. These regimes required regular injections and were of variable duration (generally for a minimum of 12 weeks), and the use of IFN often caused unacceptable side effects (thrombocytopenia, leukopenia and depression). Of the common HCV genotypes in the UK, genotype 1 responded relatively poorly to these regimes (50-60% viral clearance), while most (80% plus) of genotype 3 patients responded with sustained viral clearance. Patients with severe liver disease (decompensated cirrhosis) tolerated these regimens very poorly and often their liver function deteriorated. The recent introduction of a series of direct anti-viral agents (DAAs) offers the potential to revolutionise treatment, particularly in genotype 1 patients and those with advanced liver disease, as drug regimens avoiding IFN have been developed, and can be curative in, for example, 95% of genotype 1 patients. The DAAs are currently being evaluated and introduced into UK clinical practice. Choice of drug regime, and strategies for identifying patient groups suitable for treatment, are discussed, as are the prospects for eventual complete control of the HCV epidemic. PMID- 25824078 TI - Lesson of the month 1: A rash decision. AB - Cellulitis is a common condition and several mimics exist which should be considered in patients who fail to respond to antibiotics. We describe the case of a patient with anaplastic large cell lymphoma masquerading as a lower leg cellulitis. The patient had failed to respond to intravenous antibiotics and a skin biopsy confirmed her diagnosis. She received radical radiotherapy to the lower leg but later developed shortness of breath and was identified to have pulmonary infiltration of the lymphoma. She died shortly afterwards from lobar pneumonia. This case highlights the importance of regularly reassessing patients with suspected cellulitis and considering alternative diagnoses in cases that fail to respond to treatment. PMID- 25824079 TI - Lesson of the month 2: Cough and right hypochondrial discomfort. AB - Cystic echinococcosis, commonly known as hydatid disease, is caused by the larval stage of the tapeworm Echinococcus granulosus. Humans are an accidental host to this rare disease in the UK, with around 10-20 new cases reported each year. Once suspected, the diagnosis is confirmed through a combination of relevant history, imaging studies and serological testing. This lesson presents a case of hydatid disease and outlines the significant management issues when cysts rupture and the disease becomes disseminated. PMID- 25824080 TI - Myositis and metastatic melanoma. PMID- 25824082 TI - Brucella and Coxiella; if you don't look, you don't find. PMID- 25824083 TI - Myasthenia gravis as a 'stroke mimic'. PMID- 25824084 TI - Myasthenia gravis as a 'stroke mimic'. PMID- 25824085 TI - Diabetes CME. PMID- 25824086 TI - Sudden onset postural livedo reticularis, cyanotic toes and multiorgan failure. PMID- 25824087 TI - At what cost are resuscitation discussions avoided in general practice? PMID- 25824088 TI - Increased risk of ischaemic stroke while initiating warfarin in patients with atrial fibrillation. PMID- 25824089 TI - CARE - A risk-reduction acronym for clinical communications. PMID- 25824090 TI - p-Phenylenediamine exposure in real life - a case-control study on sensitization rate, mode and elicitation reactions in the northern Netherlands. AB - BACKGROUND: The prevalence of p-phenylenediamine (PPD) sensitization is 4% in the patch tested population and varies between zero and 1.5% in the general population. Hair dye is a recognised sensitization source. OBJECTIVES: To define the prevalence rates of PPD sensitization in the general and patch tested populations of The Netherlands, and to gain insights into relationships between patch test strength and exposure sources. METHODS: Patch test database cases were matched with population-based controls. Analyses were performed based on demographic details, patch test reactions, and potential PPD exposure. RESULTS: PPD sensitization occurred in 3.3% of the patch tested population and in 1.3% of the general population. Hairdressers had a 4.4-fold increased chance of being sensitized to PPD (p = 0.041), and black henna tattoos showed a tendency for a 2.3-fold increased chance of sensitization (p = 0.081). Weak elicitation reactions were present in hairdressers and consumers. However, cases who had had black henna tattoos showed significantly more (extremely) strong patch test reactions upon elicitation (p = 0.015). CONCLUSIONS: The prevalence rates in the patch tested and general population of The Netherlands are comparable with the prevalence rates of other mid-European centres. PPD sensitization is often attributed to hair dye. However, this study shows that subjects sensitized by black henna tattoos present with very severe elicitation reactions, emphasizing the need for more strict policing the prohibition. PMID- 25824092 TI - Human Cutaneous Myiasis by the Australian Sheep Blowfly, Lucilia cuprina (Diptera: Calliphoridae), in Oklahoma. AB - This case report describes an incident of myiasis in Oklahoma City, Oklahoma. Paramedics treated a 53-year-old man in the field when he suffered cardiac arrest. He was intubated by the paramedics and transported to an emergency room, where he received two stents and a balloon pump. He was found to have a GCS of three and remained in the hospital for 7 days before passing away. After his death, the breathing tube was removed, revealing the presence of several maggots. On closer inspection, the dipteran larvae were found in both the oral and nasal cavities. Four of these larvae were reared to adulthood and identified as Lucilia cuprina (Weidemann) (Diptera: Calliphoridae), commonly known as the Australian sheep blowfly, by the Biology Department of the University of Oklahoma. Based on the fly's life cycle and rate of development, the infestation is suspected to be hospital acquired. PMID- 25824093 TI - Should safety of non-invasive mechanical ventilation in asthma be considered from the evidence or real practice perspective? PMID- 25824091 TI - Ecologically driven competence for exogenous DNA uptake in yeast. AB - Unlike prokaryotes, eukaryotic organisms do not seem to be equipped with natural cell process(es) designated for exogenous DNA uptake. However, it is barely known that under laboratory circumstances resembling wild fungal environment(s), at least some lower eukaryotes could become naturally competent for exogenous DNA uptake. Thus, apart from the known fact that non-manipulated cells of yeast Saccharomyces cerevisiae take exogenous DNA by conjugation with certain bacteria, there are also mechanical and physiological mechanisms enabling their transformation under environmental conditions. This clearly shows that lower eukaryotes are amenable to transformation without applying man-made technology (i.e., naturally). However, this topic failed to raise critical scientific interest. Therefore, this review aims to scrutinize the overall implication of the phenomenon stressing its fundamental and applicable importance. It also summarizes all axiomatic laboratory circumstances/vehicles hitherto known to provoke yeast competence naturally and critically discusses plausible mechanisms behind. Possible pathways underlying the phenomenon are emphasized and a unifying model is proposed. This story potentially spans several different research fields, from evolutionary genetics to genetic transformation technology. PMID- 25824094 TI - Femtosecond laser will not be a standard method for cataract extraction ten years from now. AB - The femtosecond laser was recently introduced to cataract surgery in order to replace several highly successful and low risk manual surgical techniques with automated laser techniques. Despite the hope that femtosecond laser-assisted cataract surgery (FLACS) would lead to safer and more predictable surgical outcomes, the literature consistently demonstrates that FLACS has provided no advantage over standard phacoemulsification cataract surgery (SP). Yet, the disadvantages of FLACS as compared to SP are clear. FLACS is more expensive and time-consuming, may increase surgical complications during the surgeon's initial learning period, introduces unique risks due to the additional steps of laser docking and treatment, and is limited in its scope of use as compared to SP due to factors including small pupils and orbital anatomy. While FLACS may one day prove to be advantageous for a small subset of patients, such as those with corneal endothelial cell dysfunction or zonular instability, these patients have not been the targets of this technology, and FLACS will not become the standard technique for cataract extraction in the coming decade. PMID- 25824095 TI - Clinical characteristics of polycystic ovary syndrome: investigating differences in White and South Asian women. AB - OBJECTIVE: To understand the phenotypic presentation of women with polycystic ovary syndrome (PCOS) of different ethnicities and at different ages. DESIGN: Cross-sectional, retrospective data analysis (1988 - 2009). SETTING: Specialist clinic in a University Hospital, Leicestershire, UK. PARTICIPANTS: Women with PCOS, n = 1310 (mean age 26.2 years), 70.9% White and 29.1% South Asian (SA) attending a speciality clinic in Leicester UK. MAIN OUTCOMES MEASURES: Clinical and demographic characteristics of women with PCOS including age at first clinic appointment, signs and symptoms, body mass index (BMI) and blood pressure (BP). RESULTS: Compared to White women, the SA were younger (24.3 vs 27.1 years, P < 0.001), less likely to smoke (3.7% vs 17.9% P < 0.001) and had a higher prevalence of acanthosis nigricans (AN) (16.8% vs 3.1% P < 0.001), type 2 diabetes (T2DM) (8.1% vs 5.6%, P < 0.01) and hirsutism (88.5% vs 77.4%, P < 0.001), with lower systolic (126.5 vs 133.0 mmHg, P < 0.001), diastolic BP (71.8 vs 75.1 mmHg P = 0.008) and BMI (29.3 vs 31.5 kg/m(2) P = 0.002). Differences in body weight remained when participants were classified as obese, overweight and normal according to ethnicity-specific cut-off points (P = 0.048). In both ethnicities, those aged >=30 years old had higher rates of obesity, T2DM, hypertension and infertility, and less acne, and oligomenorrhoea. Obesity was associated with increased T2DM, AN, systolic/diastolic BP, hirsutism and infertility. CONCLUSION: The phenotypic and metabolic presentations of women with PCOS appear to be significantly different depending on ethnicity, obesity and age. This has implications for management strategies in these groups. PMID- 25824096 TI - New grand tree of life study shows a clock-like trend in the emergence of new species and diversity. PMID- 25824097 TI - Forming a belief: The contribution of comprehension to the evaluation and persuasive impact of argumentative text. AB - BACKGROUND: Research has shown substantial belief change as a result of reading text and the pervasive influence of prior belief in the evaluation of short arguments. Both outcomes have been attributed to the depth to which the text or the argument has been processed. This study brings together critical thinking and text comprehension research by employing an extended argumentative text and varying the quality of its arguments. AIM: The study examines the contribution of comprehension outcomes to the critical evaluation and persuasive impact of argumentative text. SAMPLE: One hundred and sixteen first-year graduate and third and fourth-year undergraduate university students. METHOD: Measures of initial topic-related beliefs, perceived topic knowledge, and need for cognition were obtained. Students read one of two versions of a two-sided, implicitly persuasive argumentative text (677 words) varying in argument quality. Post-reading tasks included main claim recall, overall recall, inference generation, claim agreement, and text evaluation. RESULTS: The text was positively evaluated and highly persuasive regardless of argument quality, but half of the students either failed to identify the main claim promoted or confused it with individual arguments. Despite a modest but positive association between inference generation and text evaluation, no comprehension measure had a significant main or interactive effect. Need for cognition contributed to positive evaluations in the absence of prior topic knowledge regardless of argument quality. CONCLUSIONS: The findings suggest a dissociation between the elaboration associated with deep comprehension and the elaboration associated with critical evaluation with implications for belief formation and the teaching of thinking. PMID- 25824099 TI - Two novel 3d-4f heterometallic coordination polymers with infinite [Ln4(OH)4]n(8n+) chains involving in situ decarboxylation. AB - Two unique heterometallic {Ln4Co} coordination polymers with infinite Ln4(OH)4]n(8n+) chains have been successfully assembled, which represent the first example of heterometallic Ln-Co coordination polymers containing infinite lanthanide hydroxide chains. PMID- 25824098 TI - Prognostic role of the CDNK1B V109G polymorphism in multiple endocrine neoplasia type 1. AB - CDKN1B encodes the cyclin-dependent kinase inhibitor p27/Kip1. CDKN1B mutations and polymorphisms are involved in tumorigenesis; specifically, the V109G single nucleotide polymorphism has been linked to different tumours with controversial results. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome, characterized by the development of different types of neuroendocrine tumours and increased incidence of other malignancies. A clear genotype-phenotype correlation in MEN1 has not been established yet. In this study, we assessed whether the CDKN1B V109G polymorphism was associated with the development of aggressive tumours in 55 consecutive patients affected by MEN1. The polymorphism was investigated by PCR amplification of germline DNA followed by direct sequencing. Baseline and follow-up data of tumour types and their severity were collected and associated with the genetic data. MEN1-related aggressive and other malignant tumours of any origin were detected in 16.1% of wild-type and 33.3% of polymorphism allele-bearing patients (P = NS). The time interval between birth and the first aggressive tumour was significantly shorter in patients with the CDKN1B V109G polymorphism (median 46 years) than in those without (median not reached; P = 0.03). Similarly, shorter was the time interval between MEN1 diagnosis and age of the first aggressive tumour (P = 0.02). Overall survival could not be estimated as 96% patients were still alive at the time of the study. In conclusion, CDKN1B V109G polymorphism seems to play a role in the development of aggressive tumours in MEN1. PMID- 25824100 TI - Efficient isocyanide-less isocyanide-based multicomponent reactions. AB - Isocyanides are the "Jekyll and Hyde" of organic chemistry allowing for extremely interesting transformations that are not only extremely odorous but also noxious. Therefore, an isocyanide-less isocyanide-based multicomponent reaction (IMCR) has been developed, and this protocol is expected to replace many of the old procedures in the future not only in IMCR but in other areas of organic chemistry as well. PMID- 25824101 TI - Interferometric Detection of Single Gold Nanoparticles Calibrated against TEM Size Distributions. AB - Single nanoparticle analysis: An interferometric optical approach calibrates sizes of gold nanoparticles (AuNPs) from the interference intensities by calibrating their interferometric signals against the corresponding transmission electron microscopy measurements. This method is used to investigate whether size affects the diffusion behavior of AuNPs conjugated to supported lipid bilayer membranes and to multiplex the simultaneous detection of three different AuNP labels. PMID- 25824102 TI - Nanostructured vanadium carbide thin films produced by RF magnetron sputtering. AB - In this paper, nanostructured vanadium carbide thin films were deposited on glass substrates and their optical and surface properties were analyzed. All produced samples were transparent in the optical region. Refractive index values were calculated using the Drude model. According to contact angle measurements of the coated surfaces, the samples show high wettability. The surface free energies of the samples were found to be very similar. The influence of the nitrogen content in the buffer gas mixture was determined; it was concluded that the microstructure, refractive index, surface morphology, surface free energy, and thickness of thin films can change in response to the nitrogen concentration of the radio frequency (RF) buffer gas. PMID- 25824104 TI - Gene targeting by the TAL effector PthXo2 reveals cryptic resistance gene for bacterial blight of rice. AB - Bacterial blight of rice is caused by the gamma-proteobacterium Xanthomonas oryzae pv. oryzae, which utilizes a group of type III TAL (transcription activator-like) effectors to induce host gene expression and condition host susceptibility. Five SWEET genes are functionally redundant to support bacterial disease, but only two were experimentally proven targets of natural TAL effectors. Here, we report the identification of the sucrose transporter gene OsSWEET13 as the disease-susceptibility gene for PthXo2 and the existence of cryptic recessive resistance to PthXo2-dependent X. oryzae pv. oryzae due to promoter variations of OsSWEET13 in japonica rice. PthXo2-containing strains induce OsSWEET13 in indica rice IR24 due to the presence of an unpredicted and undescribed effector binding site not present in the alleles in japonica rice Nipponbare and Kitaake. The specificity of effector-associated gene induction and disease susceptibility is attributable to a single nucleotide polymorphism (SNP), which is also found in a polymorphic allele of OsSWEET13 known as the recessive resistance gene xa25 from the rice cultivar Minghui 63. The mutation of OsSWEET13 with CRISPR/Cas9 technology further corroborates the requirement of OsSWEET13 expression for the state of PthXo2-dependent disease susceptibility to X. oryzae pv. oryzae. Gene profiling of a collection of 104 strains revealed OsSWEET13 induction by 42 isolates of X. oryzae pv. oryzae. Heterologous expression of OsSWEET13 in Nicotiana benthamiana leaf cells elevates sucrose concentrations in the apoplasm. The results corroborate a model whereby X. oryzae pv. oryzae enhances the release of sucrose from host cells in order to exploit the host resources. PMID- 25824103 TI - Transcatheter melody valve placement in large diameter bioprostheses and conduits: What is the optimal "Landing zone"? AB - OBJECTIVES: This study sought to elucidate the optimal bioprosthetic valve (BPV) size prior to Melody valve implantation. BACKGROUND: BPVs provide an ideal "landing zone" for future Melody valve insertion. To guide surgical choice of BPV size, it is important to understand which BPV size can serve consistently as substrates for Melody valve placements. METHODS: A database of all patients who underwent Melody implantation at UCLA or Kaiser Permanente Los Angeles from 2010 to 2014 was analyzed retrospectively. Patients with an existing BPV were stratified into those with a valve diameter of >=27 mm or <27 mm. RESULTS: One hundred and sixty patients underwent catheterization with the intention to implant a Melody valve. Melody valve implantation was performed in the pulmonary position in 52 patients with prior BPVs. The immediate procedural success rate was 100%. Immediately post-Melody, the right ventricular to pulmonary artery gradient was significantly higher in the <27 mm group compared to the >=27 mm group (14.3+/-3 vs. 8.6+/-6.8, P=0.006). There was a significantly shorter time from prior valve replacement to Melody implantation in the <27 mm group. There was one patient in whom transcatheter pulmonary valve implantation was aborted due to inadequate landing zone in the <27 mm group, and no patients in the >=27 mm group (P=NS). CONCLUSIONS: The results of this study indicate that 27 and 29 mm BPV provide a superior landing zone for Melody valve implantation with excellent immediate and intermediate term hemodynamic results when compared to smaller BPVs less than 27 mm. PMID- 25824105 TI - Clinical analysis of 1629 newly diagnosed malignant lymphomas in current residents of Sichuan province, China. AB - Previous studies in other provinces of China (Beijing, Xinjiang, Shanxi, Jiangxi, Shanghai, Guangdong, and Taiwan) suggest that the distributions of lymphoma subtypes differ compared with Western populations. In order to evaluate the characteristics of malignant lymphoma in Sichuan, China, we analyzed case series data from incident lymphoma patients diagnosed in 2008 from three hospitals, including a total of 1629 cases and including only current residents of Sichuan. The median age of diagnosis for cases was 54 years, with a higher proportion of male cases compared with female cases. The most commonly diagnosed subtypes included diffuse large B-cell lymphoma (40.4%), NK/T-cell lymphoma (NKTCL; 11.8%), mixed cellularity Hodgkin lymphoma (7.0%), mantle cell lymphoma (4.8%), and marginal zone B-cell lymphoma (3.9%). Differences in demographic characteristics between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cases were apparent for median age at diagnosis (HL: 34 years; NHL: 57 years), and NHLs accounted for nearly all (99.3%) of the 931 cases of extranodal lymphoma. These findings indicate a higher proportion of NKTCL cases and a lower proportion of follicular lymphoma cases (2.3%) in these hospitals in Sichuan, relative to reports from some other provinces within China (e.g., Shanghai and Shanxi) and the USA. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25824106 TI - Energy expenditure and activity among Hadza hunter-gatherers. AB - OBJECTIVES: Studies of total energy expenditure, (TEE; kcal/day) among traditional populations have challenged current models relating habitual physical activity to daily energy requirements. Here, we examine the relationship between physical activity and TEE among traditional Hadza hunter-gatherers living in northern Tanzania. METHODS: Hadza adults were studied at two camps, with minimal intervention so as to monitor energy expenditure and activity during normal daily life. We measured daily walking distance and walking speed using wearable GPS units for 41 adults. For a subset of 30 adults, we measured TEE using doubly labeled water, three indices of work load (foraging return rate, maternal status, and number of dependent children), and urinary biomarkers of metabolic activity and stress (8-hydroxydeoxyguanosine, cortisol, and testosterone). RESULTS: Fat free mass was the single strongest predictor of TEE among Hadza adults (r(2) = 0.66, P < 0.001). Hadza men used greater daily walking distances and faster walking speeds compared with that of Hadza women, but neither sex nor any measure of physical activity or work load were correlated with TEE in analyses controlling for fat-free mass. Compared with developed, industrial populations, Hadza adults had similar TEE but elevated levels of metabolic stress as measured by 8-hydroxydeoxyguanosine. CONCLUSION: Our results indicate that daily physical activity may not predict TEE within traditional hunter-gatherer populations like the Hadza. Instead, adults with high levels of habitual physical activity may adapt by reducing energy allocation to other physiological activity. PMID- 25824108 TI - Effect of 7H(ch) Hordeum chilense chromosome introgressions on the wheat endosperm proteomic profile. AB - Hordeum chilense is an excellent genetic resource for wheat breeding due to its potential to improve breadmaking quality and nutritional value and provide resistance to some biotic and abiotic stresses. Hexaploid wheat lines carrying chromosome 7H(ch) introgressions, namely, chromosome additions of the whole chromosome 7H(ch) or the 7H(ch)alpha or the 7H(ch)beta chromosome arms, and chromosome substitutions of the homeologous chromosomes 7A, 7B, or 7D by chromosome 7H(ch) were compared by 2D-PAGE analysis to study the effect of these alien introgressions on the wheat endosperm proteome. The addition of the 7H(ch)alpha chromosome arm did not alter the profile of most glutenins and gliadins, but showed higher quantities of puroindolines and lower xylanase inhibitors, which might improve also resistance to plant pathogens. On the other hand, (7A)7H(ch) or (7D)7H(ch) substitution lines showed enhanced avenin-like b proteins and triticin levels but reduced puroindolines, which could be desirable to improve dough properties and nutritional value and increase kernel hardness in wheat. PMID- 25824109 TI - Possible discrepancy of HbA1c values and its assessment among patients with chronic renal failure, hemodialysis and other diseases. AB - BACKGROUND: Glycated hemoglobin (HbA1c) and glycated albumin (GA) are frequently used as glycemic control markers. However, these markers are influenced by alterations in hemoglobin and albumin metabolism. Thus, conditions such as anemia, chronic renal failure, hypersplenism, chronic liver diseases, hyperthyroidism, hypoalbuminemia, and pregnancy need to be considered when interpreting HbA1c or GA values. Using data from patients with normal albumin and hemoglobin metabolism, we previously established a linear regression equation describing the GA value versus the HbA1c value to calculate an extrapolated HbA1c (eHbA1c) value for the accurate evaluation of glycemic control. In this study, we investigated the difference between the measured HbA1c and the eHbA1c values for patients with various conditions. METHODS: Data sets for a total of 2461 occasions were obtained from 731 patients whose HbA1c and GA values were simultaneously measured. We excluded patients with missing data or changeable HbA1c levels, and patients who had received transfusions or steroids within the previous 3 months. Finally, we included 44 patients with chronic renal failure (CRF), 10 patients who were undergoing hemodialysis (HD), 7 patients with hematological malignancies and a hemoglobin level of less than 10 g/dL (HM), and 12 patients with chronic liver diseases (CLD). RESULTS: In all the groups, the eHbA1c values were significantly higher than the measured HbA1c values. The median difference was 0.75 % (95 % CI 0.40-1.10 %, P for the difference is <0.001) in the CRF group, 0.80 % (95 % CI 0.30-1.65 %, P for the difference is 0.041) in the HD group, 0.90 % (95 % CI 0.90-1.30 %, P for the difference is 0.028) in the HM group, and 0.85 % (95 % CI 0.40-1.50 %, P for the difference is 0.009) in the CLD group. CONCLUSIONS: We found that the measured HbA1c values were lower than the eHbA1c values in each of the groups. PMID- 25824110 TI - Bilateral conjunctival follicular lymphoma in a child. AB - Follicular lymphoma is exceedingly rare in children. We present the case of a 10 year-old patient with a conjunctival lesion on the left eye who later developed a similar lesion on the right eye. Excisional biopsy of the left eye lesion revealed follicular lymphoma. The patient was treated with systemic rituximab. To our knowledge, only 4 other cases of pediatric conjunctival follicular lymphoma have been reported, all of which were isolated lesions that were treated with excisional biopsy alone. PMID- 25824111 TI - Proteomic profiling of naive multiple myeloma patient plasma cells identifies pathways associated with favourable response to bortezomib-based treatment regimens. AB - Toward our goal of personalized medicine, we comprehensively profiled pre treatment malignant plasma cells from multiple myeloma patients and prospectively identified pathways predictive of favourable response to bortezomib-based treatment regimens. We utilized two complementary quantitative proteomics platforms to identify differentially-regulated proteins indicative of at least a very good partial response (VGPR) or complete response/near complete response (CR/nCR) to two treatment regimens containing either bortezomib, liposomal doxorubicin and dexamethasone (VDD), or lenalidomide, bortezomib and dexamethasone (RVD). Our results suggest enrichment of 'universal response' pathways that are common to both treatment regimens and are probable predictors of favourable response to bortezomib, including a subset of endoplasmic reticulum stress pathways. The data also implicate pathways unique to each regimen that may predict sensitivity to DNA-damaging agents, such as mitochondrial dysfunction, and immunomodulatory drugs, which was associated with acute phase response signalling. Overall, we identified patterns of tumour characteristics that may predict response to bortezomib-based regimens and their components. These results provide a rationale for further evaluation of the protein profiles identified herein for targeted selection of anti-myeloma therapy to increase the likelihood of improved treatment outcome of patients with newly-diagnosed myeloma. PMID- 25824112 TI - Effective palliation of intractable bleeding from Noonan syndrome-associated lymphatic malformations by radiotherapy. PMID- 25824113 TI - CH3NH3PbI3 from non-iodide lead salts for perovskite solar cells via the formation of PbI2. AB - We report the formation of CH3NH3PbI3 from more soluble, non-iodide lead salts like Pb(SCN)2 and Pb(NO3)2. When exposed to CH3NH3I vapours, the colourless lead salts turned yellow before the formation of the black perovskite. Investigation of this yellow intermediate suggests that anion exchange (converting lead salts to PbI2) precedes the perovskite formation. PCEs of 7.6% and 8.4% were achieved for the devices formed from Pb(SCN)2 and Pb(NO3)2, respectively. PMID- 25824115 TI - Influence of stearic acid coating of the NaCl surface on the reactivity with NO2 under humidity. AB - In the atmosphere, sea salt aerosols, containing mainly NaCl, can accumulate fatty acids and undergo heterogeneous chemistry with atmospheric nitrogen oxides. The effect of stearic acid (SA) coating on the reactivity of the NaCl(100) surface with NO2 under humidity was studied by atomic force microscopy (AFM), Raman mapping and time-of-flight secondary ion mass spectrometry (ToF-SIMS) to highlight processes occurring on NaCl surfaces. The vapor-deposition of SA on the NaCl surface generates heterogeneous coating with discontinuous monolayer islands. The SA molecules with all-trans conformation stick to the NaCl surface through -CO2H groups and are organized in parallel between them and nearly perpendicularly to the surface. The SA coating does not prevent the NaNO3 particle formation when the sample is exposed to NO2 under low humidity conditions. The initial abilities of the NaCl surface coated with SA to pick up NO2 from the gas phase are correlated with the fraction of bare NaCl area evidencing the spatially heterogeneous reactivity of the surface. The role of H2O in the NO2 uptake and the catalytic conversion of NaCl to NaNO3 is shown. Under humidity (RH = 50%), the H2O uptake by NaNO3 particles on the coated-NaCl surface is significantly more important than that adsorbed under analogous conditions without the presence of NaNO3 particles. This unusual water absorption initiates transitions (i) from solid NaNO3 particles to NaNO3 aqueous solution and (ii) from the SA monolayer with well-ordered all trans alkyl chains to the SA gel with completely disordered conformation. This mixed SA/NaNO3 layer on the particle surface may have significant consequences on the hygroscopic properties and reactivity of the sea salt aerosols in the atmosphere. PMID- 25824114 TI - Eating- and weight-related parenting of adolescents in the context of food insecurity. AB - BACKGROUND: Food insecurity is hypothesized to influence mothers' use of parenting strategies to regulate children's eating. Little is known about the parenting practices directed toward adolescents in food-insecure households. OBJECTIVE: Our aim was to examine the differences in use of eating- and weight related parenting practices among mothers of adolescents by household food security status. DESIGN: This was a cross-sectional study. PARTICIPANTS/SETTING: A sociodemographically diverse sample of mothers and adolescents from the Minneapolis/St Paul, MN, metropolitan area who participated in the Eating and Activity Among Teens 2010 and Project Families and Eating and Activity Among Teens studies in 2009 to 2010 (dyad n=2,087). Seventy percent of mothers identified as nonwhite. MAIN OUTCOME MEASURES: We examined mother-reported use of parenting practices, including pressuring children to eat, restricting high calorie foods, and encouraging dieting. STATISTICAL ANALYSES PERFORMED: Logistic regression models were used to determine the predicted probabilities of parenting practices among food-secure, low food-secure, and very-low food-secure households. Sociodemographic characteristics, mothers' body mass index, and adolescents' body mass index-for-age percentile were examined as confounders. RESULTS: In unadjusted models, food-insecure mothers were more likely than food secure mothers to frequently encourage their children to diet, comment on their child's weight, be concerned about their child's weight, use restrictive feeding practices, and use pressured feeding practices. After adjustment for sociodemographic characteristics and mothers' and children's body mass index, compared to food-secure mothers, mothers with low food security were more likely to frequently comment on their sons' weight (41.5% vs 32.9%, prevalence difference=8.6; 95% CI 0.9 to 16.3) and mothers with very low food security were more likely to be concerned about their sons' weight (48.8% vs 35.1%; prevalence difference=13.7; 95% CI 3.5 to 23.9). Mothers with very low food security were more likely to frequently use restrictive feeding practices with their daughters compared to food-secure mothers (33.0% vs 20.5%; prevalence difference=12.4; 95% CI 4.2 to 20.7). CONCLUSIONS: Interventions to improve food-insecure adolescents' eating behaviors may benefit from supporting mothers' use of health-promoting parenting practices. PMID- 25824116 TI - Renal lesions in cetaceans from Brazil. AB - This study reports the occurrence of renal lesions in cetaceans from the coast of Brazil subjected to necropsy examination between 1996 and 2011. The animals (n = 192) were by-caught in fishing nets, were found dead on beaches or died despite attempted rehabilitation. Kidney samples were evaluated grossly and microscopically and, depending on the histopathological findings, immunohistochemical and ultrastructural analyses were conducted. Due to autolysis, a diagnosis was reached in only 128 animals, of which 82 (64.1%) had kidney lesions. Cystic renal disease was the most common lesion observed in 34 cases (26.6%) and these were classified as simple cysts in eight cases (6.3%), polycystic kidney disease in one rough-toothed dolphin (Steno bredanensis), secondary glomerulocystic disease in 16 cases (12.5%) and primary glomerulocystic disease in nine cases (7%). Other lesions included membranous glomerulonephritis (28 cases; 21.9%), membranoproliferative glomerulonephritis (20 cases; 15.6%), lymphoplasmacytic interstitial nephritis (21 cases; 16.4%), lipidosis (19 cases; 14.8%), glomerulosclerosis (8 cases; 6.3%) and pyogranulomatous nephritis(five cases; 3.9%); two of the later were associated with the migration of nematode larvae. Additionally, tubular adenoma was identified in a Franciscana (Pontoporia blainvillei). The pathological implications of these lesions are discussed according the cause of death, age or sex of the animals. Furthermore, the lesions were compared with those of other marine and terrestrial mammals, including man. PMID- 25824117 TI - Dental and Temporomandibular Joint Pathology of the Northern Fur Seal (Callorhinus ursinus). AB - Skulls from 145 northern fur seals (Callorhinus ursinus) were examined macroscopically according to predefined criteria. The museum specimens were acquired from strandings along the west coast of the USA between 1896 and 2008. Seventy-one skulls (49.0%) were from male animals, 56 (38.6%) from female animals and 18 (12.4%) from animals of unknown sex. Their age varied from juvenile to adult, with 58 adult animals (40.0%) and 87 juvenile animals (60.0%). The majority of teeth were available for examination (95.1%); 3.4% of teeth were artefactually absent, 0.8% were deemed absent due to acquired tooth loss and 0.6% were deemed congenitally absent. Males were no more likely than females to have either acquired tooth loss (P = 0.054) or congenitally absent teeth (P = 0.919). Adults had significantly more acquired tooth loss than juveniles (P = 0.0099). Malformations were seen in 11 teeth (0.2% of all 4,699 teeth available for examination). Two roots, instead of the typical one root, were found on 14 teeth (0.3%). Supernumerary teeth were associated with 14 normal teeth (0.3%) in eight specimens (5.5% of the total number of specimens). A total of 22 persistent deciduous teeth were found, 19 of which were associated with the maxillary canine teeth. Attrition/abrasion was seen on 194 teeth (3.9%); the canine teeth were most often affected, accounting for 39.7% of all abraded teeth. Adults were found to have a greater prevalence of abraded teeth than juveniles (P <0.0001). No significant difference was found in the appearance of attrition/abrasion between males and females (P = 0.072). Tooth fractures were found in 24 specimens (16.6%), affecting a total of 54 teeth (1.1%). Periapical lesions were found in two skulls (1.4%). None of the specimens showed signs of enamel hypoplasia. About a fifth (18.6%) of alveoli, either with or without teeth, showed signs of alveolar bony changes consistent with periodontitis. A total of 108 specimens (74.5%) had at least one tooth associated with mild periodontitis. Lesions consistent with temporomandibular joint osteoarthritis (TMJ-OA) were found in 29 specimens (20.0%). Both periodontal disease and TMJ-OA were significantly more common in adults than in juveniles (P <0.0001). Periodontitis was found to be more common in males than in females (P <0.012). Although the significance of the high incidence of periodontitis and TMJ-OA in the northern fur seal remains unknown, the occurrence and severity of these diseases found in this study may play an important role in this species morbidity and mortality. PMID- 25824118 TI - Dental and Temporomandibular Joint Pathology of the Eastern Pacific Harbour Seal (Phoca vitulina richardii). AB - Skulls from 214 Eastern Pacific harbour seals (Phoca vitulina richardii) were examined macroscopically according to predefined criteria. The museum specimens were acquired from strandings along the west coast of the USA between 1909 and 2014. Ninety-eight skulls (45.8%) were from male animals, 108 (50.5%) from female animals and eight (3.7%) from animals of unknown sex. Their age varied from neonate to adult, with 101 adult animals (47.2%), 93 juvenile animals (43.5%) and 20 neonatal animals (9.3%). The majority of teeth were available for examination (90.0%); 7.5% of teeth were absent artefactually, 2.3% were deemed absent due to acquired tooth loss and 0.2% were absent congenitally. Males were no more likely than females to have either acquired tooth loss (P = 0.492) or congenitally absent teeth (P = 0.494). Adults had significantly more acquired tooth loss than juveniles (P <0.0001). All teeth were normal in morphology, except for four teeth from one skull that exhibited macrodontia. An unusual number of roots were found in most maxillary molar teeth; three roots were counted on six maxillary molar teeth and almost all other maxillary molar teeth available for examination had a fused root. Only 26 maxillary molar teeth exhibited two roots. Supernumerary teeth were associated with 13 normal teeth in nine specimens. The most common sites associated with supernumerary teeth were the left and right mandibular first premolar teeth (53.9% of all supernumerary teeth). No persistent deciduous teeth were found in any of the juvenile or adult specimens. Of the total number of teeth available for examination, 22.1% were abraded; six adult specimens showed attrition/abrasion on all of their teeth present. Adults were found to have a greater prevalence of abraded teeth than juveniles (P <0.0001). No significant difference was found in the appearance of attrition/abrasion between males and females (P = 0.518). Tooth fractures were uncommon, affecting 11 teeth (0.2%) in seven animals. Periapical lesions were found in four skulls (2.1% of the total number of specimens). None of the specimens showed signs of enamel hypoplasia. More than half (55.6%) of alveoli, either with or without teeth, showed signs of alveolar bony changes consistent with periodontitis. A total of 178 specimens (91.8%) had at least one tooth associated with mild periodontitis. Lesions consistent with temporomandibular joint osteoarthritis (TMJ-OA) were found in 67 specimens (34.5%). The most common articular surface to be affected was the left mandibular fossa of the temporal bone, with lesions in 44 cases (32.8% of all lesions). In 13 specimens (6.7%) all articular surfaces were affected. Both periodontal disease and TMJ-OA were significantly more common in adults than in juveniles (P <0.0001). Although the significance of the high incidence of periodontitis and TMJ-OA in the Eastern Pacific harbor seal remains unknown, the occurrence and severity of these diseases as found in this study may play an important role in the morbidity and mortality of this species. PMID- 25824119 TI - The Swiss Canine Cancer Registry: a retrospective study on the occurrence of tumours in dogs in Switzerland from 1955 to 2008. AB - Diagnostic records are a key feature of any cancer epidemiology, prevention or control strategy for man and animals. Therefore, the information stored in human and animal cancer registries is essential for undertaking comparative epidemiological, pathogenic and therapeutic research. This study presents the Swiss Canine Cancer Registry, containing case data compiled between 1955 and 2008. The data consist of pathology diagnostic records issued by three veterinary diagnostic laboratories in Switzerland. The tumours were classified according to the guidelines of the International Classification of Oncology for Humans on the basis of tumour type, malignancy and body location. The dogs were classified according to breed, age, sex, neuter status and place of residence. The diagnostic data were correlated with data on the Swiss general dog population and the incidence of cancer in dogs was thus investigated. A total of 67,943 tumours were diagnosed in 121,963 dogs and 47.07% of these were malignant. The most common tumour location was the skin (37.05%), followed by mammary glands (23.55%) and soft tissue (13.66%). The most common tumour diagnoses were epithelial (38.45%), mesenchymal (35.10%) and lymphoid tumours (13.23%). The results are compared with data in other canine registries and similarities in tumour distribution and incidence are noted. It is hoped that this study will mark the beginning of continuous registration of dog tumours in Switzerland, which, in turn, will serve as a reference for research in the fields of animal and human oncology. PMID- 25824120 TI - Authors' reply. PMID- 25824121 TI - Full-dose gemcitabine is a more effective chemotherapeutic agent than 5 fluorouracil for concurrent chemoradiotherapy as first-line treatment in locally advanced pancreatic cancer. AB - OBJECTIVES: To compare the efficacy of full-dose gemcitabine-based concurrent chemoradiotherapy (FG-CCRT) and conventional 5-fluorouracil CCRT (5FU-CCRT) for locally advanced pancreatic cancer (LAPC). METHODS: 109 LAPC cases treated with FG-CCRT (n = 89) or 5FU-CCRT (n = 20) were reviewed retrospectively. The FG-CCRT group was composed of a full-dose gemcitabine monotherapy (1,000 mg/m(2)) arm and a combination therapy with cisplatin (70 mg/m(2)) arm. The 5FU-CCRT group used a radiosensitizing dose of 5-FU (500 mg/m(2)) plus leucovorin (20 mg/m(2)). Concurrent radiotherapy was targeted at the tumor with a 5-mm margin without lymph node irradiation. RESULTS: Objective response rate (ORR) and disease control rate (DCR) was significantly higher in the FG-CCRT group (ORR: 32.6 vs. 5%, p = 0.013; DCR: 79.8 vs. 50.0%, p = 0.006). FG-CCRT showed remarkable superiority to 5FU-CCRT for suppressing distant metastasis (18.0 vs. 45.0%, p = 0.017). Neutropenia (34.8 vs. 10%, p = 0.032) and thrombocytopenia (21.3 vs. 0.0%, p = 0.021) were more frequent in the FG-CCRT group as originally expected. When dividing the FG-CCRT group to gemcitabine monotherapy (GEM) and gemcitabine plus cisplatin, toxicities of the GEM subgroup were not different than those of the 5FU-CCRT group. CONCLUSION: FG-CCRT, especially full-dose gemcitabine monotherapy-based CCRT was more effective for the initial control of LAPC than 5FU-CCRT, and also relatively safe. PMID- 25824122 TI - Rubber yield prediction by meteorological conditions using mixed models and multi model inference techniques. AB - Linear mixed models were developed and used to predict rubber (Hevea brasiliensis) yield based on meteorological conditions to which rubber trees had been exposed for periods ranging from 1 day to 2 months prior to tapping events. Predictors included a range of moving averages of meteorological covariates spanning different windows of time before the date of the tapping events. Serial autocorrelation in the latex yield measurements was accounted for using random effects and a spatial generalization of the autoregressive error covariance structure suited to data sampled at irregular time intervals. Information theoretics, specifically the Akaike information criterion (AIC), AIC corrected for small sample size (AICc), and Akaike weights, was used to select models with the greatest strength of support in the data from a set of competing candidate models. The predictive performance of the selected best model was evaluated using both leave-one-out cross-validation (LOOCV) and an independent test set. Moving averages of precipitation, minimum and maximum temperature, and maximum relative humidity with a 30-day lead period were identified as the best yield predictors. Prediction accuracy expressed in terms of the percentage of predictions within a measurement error of 5 g for cross-validation and also for the test dataset was above 99 %. PMID- 25824123 TI - Self-Immolative Poly(4,5-dichlorophthalaldehyde) and its Applications in Multi Stimuli-Responsive Macroscopic Plastics. AB - End-capped poly(4,5-dichlorophthalaldehyde) (PCl2PA), which is a new self immolative CD(r) polymer with the unique capability of depolymerizing continuously and completely in the solid state when an end cap is cleaved from the polymer by reaction with a specific molecular signal, is described. End capped poly(4,5-dichlorophthalaldehyde) is sufficiently stable to enable patterning of three-dimensional macroscopic polymeric materials by selective laser sintering. These unique materials are capable of 1) autonomously amplifying macroscopic changes in the material in response to specific molecular inputs, and 2) altering their responses depending on the identity of the applied signal. Thus, not only does end-capped PCl2PA provide new and unique capabilities compared to the small subset of existing CD(r) polymers, but it also provides access to a new class of stimuli-responsive materials. PMID- 25824124 TI - Gait Speed and Mortality, Hospitalization, and Functional Status Change Among Hemodialysis Patients: A US Renal Data System Special Study. AB - BACKGROUND: Slow walk (gait) speed predicts functional decline, institutionalization, and mortality risks in the geriatric population. A gait speed evidence base for dialysis patient outcomes is needed. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 752 prevalent hemodialysis (HD) patients aged 20 to 92 years evaluated in 2009 to 2012 in 7 Atlanta and 7 San Francisco clinics in a US Renal Data System special study. PREDICTOR: Usual walk speed in meters per second, categorized as >=0.6 m/s (baseline n=575), <0.6 m/s (baseline n=94), and unable to perform walk test (baseline n=83). OUTCOMES: Survival; hospitalization; activities of daily living (ADL) difficulty; 36-Item Short Form Health Survey (SF-36) Physical Function score. MEASUREMENTS: Cox proportional hazards models investigated gait speed and mortality over a median follow-up of 703 days. Multivariable logistic or linear regression models estimated associations of baseline gait speed with hospitalization, need for ADL assistance, and SF-36 Physical Function score after 12 months. RESULTS: Participants who walked >=0.6 m/s had 53 (9%) deaths, those who walked <0.6 m/s had 19 (20%) deaths, and those unable to walk had 37 (44%) deaths. Adjusted mortality hazard ratios were 2.17 (95% CI, 1.19-3.98) for participants who walked <0.6 m/s and 6.93 (95% CI, 4.01-11.96) for those unable to walk, compared with participants walking >=0.6 m/s. After 12 months, compared with baseline walk speed >= 1.0 m/s (n=169 participants), baseline walk speed of 0.6 to <0.8 m/s (n=116) was associated with increased odds of hospitalization (OR, 2.04; 95% CI, 1.19-3.49) and ADL difficulty (OR, 3.88; 95% CI, 1.46-10.33) and a -8.20 (95% CI, -13.57 to -2.82) estimated change in SF-36 Physical Function score. LIMITATIONS: Cohort not highly representative of overall US in-center HD population. CONCLUSIONS: Because walking challenges the heart, lungs, and circulatory, nervous, and musculoskeletal systems, gait speed provides an informative marker of health status. The association of gait speed with HD patients' risk for functional decline warrants continued study. PMID- 25824125 TI - Association of Adiponectin With Body Composition and Mortality in Hemodialysis Patients. AB - BACKGROUND: In the general population, circulating adiponectin is associated with a favorable cardiovascular risk profile (eg, lower triglycerides and body fat) and decreased mortality. Hemodialysis (HD) patients have comparatively higher adiponectin concentrations, but prior studies examining the adiponectin-mortality association in this population have not accounted for body composition or shown a consistent relationship. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: We examined baseline serum adiponectin concentrations in 501 HD patients across 13 dialysis centers from the prospective MADRAD (Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease) cohort (entry period, October 2011 to February 2013; follow-up through August 2013). PREDICTOR: Serum adiponectin concentration in tertiles (tertiles 1, 2, and 3 defined as <=16.1, >16.1-<30.1, and >=30.1-100.0 MUg/mL, respectively). Adjustment variables included case-mix and laboratory test results (age, sex, race, ethnicity, vintage, diabetes, serum albumin, total iron-binding capacity, serum creatinine, white blood cell count, phosphate, hemoglobin, and normalized protein catabolic rate), body composition surrogates (subcutaneous, visceral, and total-body fat and lean body mass), and serum lipid levels (cholesterol, high-density lipoprotein cholesterol, and triglycerides). OUTCOMES: All-cause mortality using survival (Cox) models incrementally adjusted for case-mix and laboratory test results. RESULTS: Among 501 HD patients, 50 deaths were observed during 631.1 person-years of follow-up. In case-mix- and laboratory-adjusted Cox analyses, the highest adiponectin tertile was associated with increased mortality versus the lowest tertile (HR, 3.35; 95% CI, 1.50-7.47). These associations were robust in analyses that additionally accounted for body composition (HR, 3.18; 95% CI, 1.61 8.24) and lipid levels (HR, 3.64; 95% CI, 1.34-7.58). LIMITATIONS: Residual confounding cannot be excluded. CONCLUSIONS: Higher adiponectin level is associated with a 3-fold higher death risk in HD patients independent of body composition and lipid levels. Future studies are needed to elucidate underlying mechanisms and determine therapeutic targets associated with improved outcomes in HD patients. PMID- 25824126 TI - Glycine-functionalized Fe3O4@TiO2:Er(3+),Yb(3+) nanocarrier for microwave triggered controllable drug release and study on mechanism of loading/release process using microcalorimetry. AB - OBJECTIVES: The current study aimed at developing microwave-triggered controlled release drug delivery systems using glycine-modified Fe3O4@TiO2:Er(3+),Yb(3+) multifunctional core-shell nanoparticles. We also studied the drug loading and release mechanisms by means of microcalorimetry. METHODS: We used hydrothermal method to prepare glycine-functionalized Fe3O4@TiO2:Er(3+),Yb(3+) multifunctional nanoparticles. The controlled release of the Fe3O4@TiO2:Er(3+),Yb(3+)-glycine VP16 triggered by microwave was determined with ultraviolet-visible spectroscopic analysis. We studied the cytotoxicity of the nanocarrier by MTT assay. RESULTS: The thermodynamic parameter values (DeltaH = -17.46 kJ mol(-1), DeltaS = -365.20 kJ mol(-1)) showed that the main interaction between the carrier and drug molecules is hydrogen bonding. The molar enthalpy (DeltaH) of the drug-release process was 72.01 kJ mol(-1), which indicates an endothermic process. This suggests that drug release can be controlled by microwave heating. The release profile can be controlled by the duration and number of cycles of microwave application. The particles also exhibit good magnetization and upconversion luminescence properties, which will allow simultaneous targeting and monitoring of the loaded drug. CONCLUSION: The modification of glycine and the introduction of absorbing material not only increased the load properties of the composite materials but also realized the microwave-stimulated anticancer drug controlled release. PMID- 25824127 TI - Effects of reinnervation of the triceps brachii on joint kinematics and electromyographic patterns of the feline forelimb during level and upslope walking. AB - Nerve injury in the hindlimb of the cat results in locomotor changes, yet these findings have not been explored in a more multifunctional forelimb. Kinematics and muscle activity of the shoulder and elbow during level and upslope locomotion following reinnervation of the feline long head of the triceps brachii (TLo) were evaluated (1) during paralysis [none to minimum motor activity (short-term effects)] and (2) after the motor function was recovered but the proprioceptive feedback was permanently disrupted (long-term effects). The step cycle was examined in three walking conditions: level (0%), 25% grade (14 degrees upslope) and 50% grade (26.6 degrees upslope). Measurements were taken prior to and at three time points (2 weeks, 1 month and 12+ months) after transecting and suturing the radial nerve of TLo. There was less of a yield (increased flexion) at the elbow joint and more extensor activity during elbow flexion during stance (E2) as the grade of walking increased. Substantial short-term effects were observed at the elbow joint (increased flexion during E2) as well as increased motor activity by the synergistic elbow extensors, and greater shoulder extension at paw contact, leading to altered interjoint coordination during stance. Forelimb shoulder and elbow kinematics during level and upslope locomotion progressed back to baseline at 12 months. The short-term effects can be explained by both mechanical and neural factors that are altered by the functional elimination of the TLo. Full recovery of the forelimb kinematics during level and upslope walking suggests that the proprioceptive length feedback loss is compensated by other sensory sources or altered central drive. PMID- 25824128 TI - Three-year duration of immunity for feline herpesvirus and calicivirus evaluated in a controlled vaccination-challenge laboratory trial. AB - Feline vaccination guidelines recommend less frequent boosters for the core vaccines (rhinotracheitis, calicivirosis and infectious panleucopenia). Most guidelines recommend boosters at 3-yearly intervals after a basic vaccination including primary vaccination and revaccination one year later. The objective of this study was to assess the duration of immunity induced by PUREVAX((r)) RCPCh FeLV, a non-adjuvanted vaccine against feline rhinotracheitis, calicivirosis, infectious panleucopenia, chlamydiosis and leukemia. After primary vaccination followed by revaccination one year later with a vaccine formulated at minimum dose, the cats were kept in a confined environment and challenged 3 years later with a virulent heterologous strain of feline calicivirus (FCV) and subsequently a virulent strain of feline herpesvirus (FHV). Clinical signs and viral excretion were recorded for two weeks after each viral inoculation. Contemporary unvaccinated cats and new animals added at the time of challenge were used as controls. The vaccination regimen induced a stable and long-lasting humoral response. Vaccination resulted in a significant reduction in the severity of the disease after FHV challenge and in the frequency of cats showing a severe calicivirosis (defined as a combination of systemic clinical symptoms and oronasal ulcers). As opposed to the significant reduction of excretion observed a few weeks after primo-vaccination or even one year after vaccination for FCV, viral shedding was not reduced 3 years after revaccination. This study showed that primary vaccination and revaccination one year later with PUREVAX((r)) RCPCh FeLV was able to induce 3-year duration of immunity against FCV and FHV. The results and conclusion of this study are consistent with current vaccination guidelines and will allow the veterinarian to adapt the vaccination regimen to the way of life of the cat. PMID- 25824129 TI - Survey on the presence of Mycobacterium avium subsp. paratuberculosis in ground beef from an industrial meat plant. AB - Paratuberculosis of ruminants is characterised by chronic enteritis but, at advanced stages of the disease, a systemic dissemination of Mycobacterium avium subsp. paratuberculosis (MAP) in tissues and organs can occur. MAP has been recovered from lymph nodes and muscles of clinical and sub-clinical cows. In most countries, dairy and beef cattle infected with paratuberculosis are routinely sent to slaughter and the consumption of their meat could be a possible route of human exposure to MAP. However, few studies on MAP in ground beef are currently available. During the period November 2013-March 2014 we carried out a survey on the ground beef produced in an industrial meat processing plant. One-hundred and forty samples of ground meat were analysed by IS900-qPCR and culture (VersaTrek System). The limit of detection (LOD) of qPCR was 630 MAP cells/g (107 CFU/g) while the LOD for culture was 170-230 MAP cells/g (62-115 CFU/g). No samples were positive by direct IS900 qPCR, while two samples were positive by liquid culture. Our data suggest that the presence of live MAP in raw minced meat is possible. In order to avoid exposure for humans through the consumption of contaminated meat, proper cooking of meat is recommended. PMID- 25824130 TI - Virulence, persistence and dissemination of Mycoplasma bovis. AB - Bovine mycoplasmosis due to Mycoplasma bovis causes several important bovine diseases such as pneumonia, mastitis, arthritis, otitis, genital disorders or keratoconjunctivitis. Variable surface lipoproteins, adhesion, invasion of host cells, modulation of the host immune system, biofilm formation and the release of secondary metabolites like hydrogen peroxide, as well as synergistic infections with other bacterial or viral pathogens are among the more significantly studied characteristics of the bacterium. The aim of this review is to summarize the current knowledge regarding the virulence of M. bovis and additionally, factors contributing to the dissemination and persistence of this pathogen in the bovine host will be discussed. PMID- 25824131 TI - About left septal fascicular block. PMID- 25824132 TI - Response to left septal fascicular block. PMID- 25824133 TI - Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma. AB - Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal regulated kinase (pERK), matrix metalloproteinase (MMP)-2 and MMP-9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR-2 and L1CAM mRNA as well as pERK, MMP-2 and MMP-9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP-2 and MMP-9 protein expression. PMID- 25824134 TI - Preparation, characterization and in vitro release of Zein-pectin capsules for target delivery. AB - Targeted drug delivery has been the interest of many researchers to improve drug efficiency and reduce side effects. Because of the potential toxicity and contamination problems of the current gelatin capsules, plant derived materials are selected for the developments of capsules for drug delivery systems. The objective of this work is to develop a target drug delivery system using zein and pectin. Different ratios of zein and pectin were used to achieve target delivery in stomach and small intestine. Zein-pectin capsule for colon-specific delivery was also developed. In vitro performance of zeinpectin capsules was examined and their structural morphology was characterized using scanning electron microscopy (SEM). Chemical interactions between zein and pectin were analyzed using Fourier transform infrared spectroscopy equipped with attenuated total reflectance (FTIR ATR). Zein and pectin formed complex by hydrogen bonding. The swelling behavior of pectin was suppressed by zein in the zein-pectin interacted complex. By adjusting the ratio of zein to pectin, the drug release from the capsule in simulated gastric solution for 2 hours can be controlled in the range of 0% to 38%. Zein-pectin capsule for colon-specific delivery had no release in gastric and intestinal solutions while gradual release from zein-pectin capsule was observed in colonic solution, finally reaching about 80% release. Zein-pectin capsule has a potential in developing targeted drug delivery system. PMID- 25824135 TI - [Health status of people with a migrant background and impact of socio-economic factors: First results of the German Health Interview and Examination Survey for Adults (DEGS1)]. AB - People with a migrant background (PMB) have specific health-related risk factors and resources compared to the non-migrant population (NMP). The analysis focuses on the relationship between migrant background and health and health-related behavior. Moreover, the study analyses whether socio-economic status (SES) contributes to the explanation of differences between PMB and the NMP. The research is based on the German Health Interview and Examination Survey for Adults (DEGS1) (2008-2012, n = 8151). The population for cross-sectional analyses contains 1107 PMB (weighted 19.8 %). The research question is addressed on the basis of nine exemplary health outcomes. All analyses are gender specific and make a distinction between first and second generation PMB. Logistic regression is calculated adjusting for age and SES. The results reveal clear gender-specific patterns: For women, differences are statistically significant mainly for first generation PMB. Compared to the NMP their self-assessed health status is lower, they are less physically active, consume less alcohol, feel less informed about cancer screening programs and make less use of preventive health services. However, daily smoking is more prevalent in second generation women. For men, differences are statistically significant for first and second generation PMB. Men with a migrant background show more symptoms of depression, consume less alcohol and feel less informed about cancer screening programs. After adjusting for SES the impact of migrant background on health status and health-related behavior largely remains stable. The study shows that the DEGS1 data offers valuable results and new insights into the health status of people with a migrant background. The use of this data for further research requires a differentiated approach to the concept of migrant background and a careful interpretation of results. PMID- 25824136 TI - [Not Available]. PMID- 25824137 TI - Influence of music and its genres on respiratory rate and pupil diameter variations in cats under general anaesthesia: contribution to promoting patient safety. AB - OBJECTIVES: The aims of the study were to recognise if there is any auditory sensory stimuli processing in cats under general anaesthesia, and to evaluate changes in respiratory rate (RR) and pupillary diameter (PD) in anaesthetised patients exposed to different music genres, while relating this to the depth of anaesthesia. METHODS: A sample of 12 cats submitted for elective ovariohysterectomy was exposed to 2 min excerpts of three different music genres (classical [CM], pop [PM] and heavy metal [HM]) at three points during surgery (T1 = coeliotomy; T2 = ligature placement and transection of the ovarian pedicle; T3 = ligature placement and transection of the uterine body). A multiparametric medical monitor was used to measure the RR, and a digital calliper was used for PD measurement. Music was delivered through headphones, which fully covered the patient's ears. P values <0.05 were considered to be statistically significant. RESULTS: Statistically significant differences between stimuli conditions for all surgical points were obtained for RR (T1, P = 0.03; T2, P = 0.00; T3, P = 0.00) and for PD (T1, P = 0.03; T2, P = 0.04; T3, P = 0.00). Most individuals exhibited lower values for RR and PD when exposed to CM, intermediate values to PM and higher values to HM. CONCLUSIONS AND RELEVANCE: The results suggest that cats under general anaesthesia are likely to perform auditory sensory stimuli processing. The exposure to music induces RR and PD variations modulated by the genre of music and is associated with autonomic nervous system activity. The use of music in the surgical theatre may contribute to allowing a reduced anaesthetic dose, minimising undesirable side effects and thus promoting patient safety. PMID- 25824138 TI - Incidence of Second Primary Malignancies in Patients with Neuroendocrine Tumours. AB - BACKGROUND: An association between neuroendocrine tumours (NET) and increased risk of developing second primary malignancies (SPM) has been recognised. METHODS: This was a retrospective review of our institutional prospectively maintained database of NET patients. We identified patients who had been diagnosed with both neuroendocrine and any additional malignancies via examination of patient notes. RESULTS: Clinical data for 169 patients were analysed. After exclusion of patients known to have hereditary tumour predisposition syndromes, 29 SPM were identified in 26 patients (15.38%), the commonest being colorectal (n = 6), breast and renal carcinomas (both n = 5). SPM were classified as previous, synchronous or subsequent relative to NET diagnosis. Rates of SPM in pancreatic and small-bowel NET patients were comparable (15.7 vs. 19.6%, p = 0.78). A person-year methodology was used to compare observed numbers of SPM against expected values generated from age- and sex-specific incidence tables, with standardised incidence ratios (SIR) and 95% confidence intervals (CI) calculated. SPM incidence was significantly elevated in the synchronous subset (SIR 2.732, CI 1.177-5.382) whilst significantly fewer NET patients had a cancer history compared to the general population (SIR 0.4, CI 0.241-0.624). No overall differences were evident between observed and expected incidences of subsequent SPM (SIR 0.36, CI 0.044-1.051). The incidence of synchronous colorectal cancers was markedly elevated (SIR 13.079, CI 4.238-30.474). CONCLUSIONS: Our data support the use of colonoscopy in the diagnostic work-up of NET patients in anticipation of a colorectal SPM. The mechanistic underpinnings of this clinical phenomenon require further genetic investigation, and consideration of this knowledge in patient management pathways is warranted. PMID- 25824139 TI - Human umbilical cord mesenchymal stem cell exosomes enhance angiogenesis through the Wnt4/beta-catenin pathway. AB - Human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes have been considered as potential therapeutic tools for tissue regeneration; however, the underlying mechanisms are still not well understood. In this study, we isolated and characterized the exosomes from hucMSCs (hucMSC-Ex) and demonstrated that hucMSC-Ex promoted the proliferation, migration, and tube formation of endothelial cells in a dose-dependent manner. Furthermore, we demonstrated that hucMSC-Ex promoted wound healing and angiogenesis in vivo by using a rat skin burn model. We discovered that hucMSC-Ex promoted beta-catenin nuclear translocation and induced the increased expression of proliferating cell nuclear antigen, cyclin D3, N-cadherin, and beta-catenin and the decreased expression of E-cadherin. The activation of Wnt/beta-catenin is critical in the induction of angiogenesis by hucMSC-Ex, which could be reversed by beta-catenin inhibitor ICG 001. Wnt4 was delivered by hucMSC-Ex, and the knockdown of Wnt4 in hucMSC-Ex abrogated beta-catenin nuclear translocation in endothelial cells. The in vivo proangiogenic effects were also inhibited by interference of Wnt4 expression in hucMSC-Ex. Taken together, these results suggest that hucMSC-Ex-mediated Wnt4 induces beta-catenin activation in endothelial cells and exerts proangiogenic effects, which could be an important mechanism for cutaneous wound healing. PMID- 25824140 TI - Intra-articular transplantation of atsttrin-transduced mesenchymal stem cells ameliorate osteoarthritis development. AB - Osteoarthritis (OA) remains an intractable clinical challenge. Few drugs are available for reversing this degenerative disease, although some promising candidates have performed well in preclinical studies. Tumor necrosis factor alpha (TNFalpha) has been identified as a crucial effector modulating OA pathogenesis. This study aimed to investigate the therapeutic effects of Atsttrin, a novel TNFalpha blocker, on OA treatment. We developed genetically modified mesenchymal stem cells (MSCs) that expressed recombinant Atsttrin (named as MSC-Atsttrin). Expression levels of ADAMTS-5, MMP13, and iNOS of human chondrocytes were analyzed when cocultured with MSC-GFP/Atsttrin. OA animal models were induced by anterior cruciate ligament transection, and MSC GFP/Atsttrin were injected into the articular cavity 1 week postsurgery. The results showed that MSC-Atsttrin significantly suppressed TNFalpha-driven up regulation of matrix proteases and inflammatory factors. Intra-articular injection of MSC-Atsttrin prevented the progression of degenerative changes in the surgically induced OA mouse model. Additionally, levels of detrimental matrix hydrolases were significantly diminished. Compared with nontreated OA samples at 8 weeks postsurgery, the percentages of MMP13- and ADAMTS-5-positive cells were significantly reduced from 91.33% +/- 9.87% to 24.33% +/- 5.7% (p < .001) and from 91.33% +/- 7.1% to 16.67% +/- 3.1% (p < .001), respectively. Our results thus indicated that suppression of TNFalpha activity is an effective strategy for OA treatment and that intra-articular injection of MSCs-Atsttrin could be a promising therapeutic modality. PMID- 25824141 TI - Conditioned medium from human amniotic mesenchymal stromal cells limits infarct size and enhances angiogenesis. AB - The paracrine properties of human amniotic membrane-derived mesenchymal stromal cells (hAMCs) have not been fully elucidated. The goal of the present study was to elucidate whether hAMCs can exert beneficial paracrine effects on infarcted rat hearts, in particular through cardioprotection and angiogenesis. Moreover, we aimed to identify the putative active paracrine mediators. hAMCs were isolated, expanded, and characterized. In vitro, conditioned medium from hAMC (hAMC-CM) exhibited cytoprotective and proangiogenic properties. In vivo, injection of hAMC CM into infarcted rat hearts limited the infarct size, reduced cardiomyocyte apoptosis and ventricular remodeling, and strongly promoted capillary formation at the infarct border zone. Gene array analysis led to the identification of 32 genes encoding for the secreted factors overexpressed by hAMCs. Among these, midkine and secreted protein acidic and rich in cysteine were also upregulated at the protein level. Furthermore, high amounts of several proangiogenic factors were detected in hAMC-CM by cytokine array. Our results strongly support the concept that the administration of hAMC-CM favors the repair process after acute myocardial infarction. PMID- 25824142 TI - Amine-free reversible hydrogen storage in formate salts catalyzed by ruthenium pincer complex without pH control or solvent change. AB - Due to the intermittent nature of most renewable energy sources, such as solar and wind, energy storage is increasingly required. Since electricity is difficult to store, hydrogen obtained by electrochemical water splitting has been proposed as an energy carrier. However, the handling and transportation of hydrogen in large quantities is in itself a challenge. We therefore present here a method for hydrogen storage based on a CO2 (HCO3 (-) )/H2 and formate equilibrium. This amine-free and efficient reversible system (>90 % yield in both directions) is catalyzed by well-defined and commercially available Ru pincer complexes. The formate dehydrogenation was triggered by simple pressure swing without requiring external pH control or the change of either the solvent or the catalyst. Up to six hydrogenation-dehydrogenation cycles were performed and the catalyst performance remained steady with high selectivity (CO free H2 /CO2 mixture was produced). PMID- 25824143 TI - Ultra-thin and smooth transparent electrode for flexible and leakage-free organic light-emitting diodes. AB - A smooth, ultra-flexible, and transparent electrode was developed from silver nanowires (AgNWs) embedded in a colorless polyimide (cPI) by utilizing an inverted film-processing method. The resulting AgNW-cPI composite electrode had a transparency of >80%, a low sheet resistance of 8 Omega/?, and ultra-smooth surfaces comparable to glass. Leveraging the robust mechanical properties and flexibility of cPI, the thickness of the composite film was reduced to less than 10 MUm, which is conducive to extreme flexibility. This film exhibited mechanical durability, for both outward and inward bending tests, up to a bending radius of 30 MUm, while maintaining its electrical performance under cyclic bending (bending radius: 500 MUm) for 100,000 iterations. Phosphorescent, blue organic light-emitting diodes (OLEDs) were fabricated using these composites as bottom electrodes (anodes). Hole-injection was poor, because AgNWs were largely buried beneath the composite's surface. Thus, we used a simple plasma treatment to remove the thin cPI layer overlaying the nanowires without introducing other conductive materials. As a result, we were able to finely control the flexible OLEDs' electroluminescent properties using the enlarged conductive pathways. The fabricated flexible devices showed only slight performance reductions of <3% even after repeated foldings with a 30 MUm bending radius. PMID- 25824144 TI - Two Novel Homozygous Desmoplakin Mutations in Carvajal Syndrome. AB - BACKGROUND: Mutations in various desmosomal proteins were shown to cause inherited forms of cardiomyopathy. Carvajal syndrome (Online Mendelian Inheritance in Man [OMIM] 605676) is characterized by the association of dilated cardiomyopathy, striate palmoplantar keratoderma, and woolly hair. It is caused by homozygous as well as heterozygous mutations in DSP, which encodes the desmosomal plaque protein desmoplakin. An overlapping cardiocutaneous phenotype was also described with homozygous mutations in genes encoding two other desmosomal proteins; plakoglobin (Naxos disease; OMIM 601214) and desmocollin-2 (OMIM 610476). METHODS: We performed clinical and molecular workups in two consanguineous Arab Palestinian families manifesting an autosomal recessive pattern of inheritance of the above mentioned clinical findings. Whole exome sequencing was employed in the search for the causing mutation. RESULTS: Affected family members suffered from biventricular involvement and arrhythmogenic right ventricular dysplasia based on echocardiography and magnetic resonance imaging. One patient who underwent implantation of an implantable cardioverter defibrillator (ICD) is still alive at the age of 59 years. Whole exome sequencing revealed two novel homozygous mutations in DSP, each affecting one family. CONCLUSIONS: The association of woolly hair with palmoplantar keratoderma in a child should lead to a cardiac workup in the search for those at increased risk for sudden cardiac death. Early diagnosis and ICD implantation may be lifesaving. Whole exome sequencing should be utilized for rapid genetic analysis since the cardiocutaneous phenotype may result from mutations in one of several genes. PMID- 25824145 TI - Regulatory T cells in human and angiotensin II-induced mouse abdominal aortic aneurysms. AB - AIMS: Regulatory T cells (Tregs) protect mice from angiotensin II (Ang-II) induced abdominal aortic aneurysms (AAA). This study tested whether AAA patients are Treg-insufficient and the Treg molecular mechanisms that control AAA pathogenesis. METHODS AND RESULTS: ELISA determined the Foxp3 concentration in blood cell lysates from 485 AAA patients and 204 age- and sex-matched controls. AAA patients exhibited lower blood cell Foxp3 expression than controls (P < 0.0001). Pearson's correlation test demonstrated a significant but negative correlation between Foxp3 and AAA annual expansion rate before (r = -0.147, P = 0.007) and after (r = -0.153, P = 0.006) adjustment for AAA risk factors. AAA in apolipoprotein E-deficient (Apoe(-/-)) mice that received different doses of Ang II exhibited a negative correlation of lesion Foxp3(+) Treg numbers with AAA size (r = -0.883, P < 0.0001). Adoptive transfer of Tregs from wild-type (WT) and IL10 deficient (Il10(-/-)) mice increased AAA lesion Treg content, but only WT mice Tregs reduced AAA size, AAA incidence, blood pressure, lesion macrophage and CD4(+) and CD8(+) T-cell accumulation, and angiogenesis with concurrent increase of lesion collagen content. Both AAA lesion immunostaining and plasma ELISA demonstrated that adoptive transfer of WT Tregs, but not Il10(-/-) Tregs, reduced the expression of MCP-1. In vitro cell culture and aortic ring assay demonstrated that only Tregs from WT mice, but not those from Il10(-/-) mice, reduced macrophage MCP-1 secretion, macrophage and vascular cell protease expression and activity, and aortic ring microvessel formation. CONCLUSION: This study supports a protective role of Tregs in human and experimental AAA by releasing IL10 to suppress inflammatory cell chemotaxis, arterial wall remodelling, and angiogenesis. PMID- 25824146 TI - Hypoxia inducible factor-1-dependent up-regulation of BMP4 mediates hypoxia induced increase of TRPC expression in PASMCs. AB - AIMS: Previously we demonstrated that both hypoxia inducible factor-1 (HIF-1) and bone morphogenetic protein-4 (BMP4) up-regulate transient receptor potential canonical (TRPC) 1 and TRPC6, resulting in increased basal intracellular Ca(2+) concentration ([Ca(2+)]i) in pulmonary arterial smooth muscle cells (PASMCs), driving development of chronic hypoxia (CH)-induced pulmonary hypertension (CHPH). This study aims to determine whether HIF-1 regulates BMP4, and whether BMP4 mediates TRPC and basal [Ca(2+)]i increases in hypoxic PASMCs. METHODS AND RESULTS: The level of BMP4 mature protein was increased for ~183% in distal pulmonary arterial smooth muscle (PA) from CH (10% O2 for 21 days; CH) exposed rats, and 143% in PASMCs cultured under prolonged hypoxia (4% O2 for 60 h). In rat PASMCs, HIF-1alpha overexpression up-regulated, whereas HIF-1alpha knockdown under hypoxia decreased BMP4 expression; site-mutation identified two functional HIF-1-binding sites in Bmp4 gene promoter; noggin or BMP4 siRNA treatment blocked hypoxia-induced increases of TRPC1 and TRPC6 expression and basal [Ca(2+)]i. Likewise, in mice, exposure to CH increased BMP4 expression in distal PA for ~80%, which was absent in HIF-1alpha heterozygous mutant mice. Comparing with wild-type littermates, BMP4 heterozygous mutant mice exposed to CH displayed lower BMP4 and TRPC levels in PA, decreased basal [Ca(2+)]i in PASMCs, and attenuated CHPH. In human PASMCs, HIF-1alpha knockdown attenuated hypoxia-induced BMP4 expression and knockdown of either HIF-1alpha or BMP4 abolished hypoxia induced TRPC expression and basal [Ca(2+)]i. CONCLUSIONS: BMP4 acts downstream of HIF-1 and mediates hypoxia-induced up-regulation of TRPC, leading to increased basal [Ca(2+)]i in PASMCs, promoting CHPH pathogenesis. PMID- 25824147 TI - MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death. AB - AIMS: Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs). For example, miR-150 is down-regulated in patients with acute myocardial infarction, atrial fibrillation, dilated and ischaemic cardiomyopathy as well as in various mouse heart failure (HF) models. Circulating miR-150 has been recently proposed as a better biomarker of HF than traditional clinical markers such as brain natriuretic peptide. We recently showed using the beta arrestin-biased beta-blocker, carvedilol that beta-arrestin1-biased beta1 adrenergic receptor cardioprotective signalling stimulates the processing of miR 150 in the heart. However, the potential role of miR-150 in ischaemic injury and HF is unknown. METHODS AND RESULTS: Here, we show that genetic deletion of miR 150 in mice causes abnormalities in cardiac structural and functional remodelling after MI. The cardioprotective roles of miR-150 during ischaemic injury were in part attributed to direct repression of the pro-apoptotic genes egr2 (zinc binding transcription factor induced by ischaemia) and p2x7r (pro-inflammatory ATP receptor) in cardiomyocytes. CONCLUSION: These findings reveal a pivotal role for miR-150 as a regulator of cardiomyocyte survival during cardiac injury. PMID- 25824148 TI - Angiopoietin-1 inhibits toll-like receptor 4 signalling in cultured endothelial cells: role of miR-146b-5p. AB - AIMS: Bacterial lipopolysaccharides (LPS) induce innate immune inflammatory responses in endothelial cells by activating toll-like receptor 4 (TLR4) signalling. Here, we investigate the effects of angiopoietin-1 (Ang-1) on LPS induced TLR4 signalling and the role of the miR-146 family of micro RNAs in the effects of Ang-1 on TRL4 signalling. METHODS AND RESULTS: Leucocyte adhesion to human umbilical vein endothelial cells (HUVECs) was detected using fluorescence microscopy. Adhesion molecule, pro-inflammatory cytokine, miR-146a, and miR-146b 5p expressions in HUVECs were quantified using real-time PCR. TLR4 signalling protein levels were measured using immunoblotting. Exposure of HUVECs to LPS for 4-6 h induces robust inflammatory responses, including enhanced leucocyte adhesion, up-regulation of adhesion molecule expression (VCAM1, ICAM1, E SELECTIN), enhanced cytokine production (TNFalpha, IL1beta, IL6, and IL8), and increased NFkappaB luciferase reporter activity. Addition of Ang-1 to the culture medium for 24 h prior to LPS exposure significantly attenuates these responses. Prolonged Ang-1 exposure significantly decreases IRAK1 and TRAF6 protein levels but has no effect on TLR4, MYD88, IRAK4, or TAK1 expressions. Ang-1 triggers significant up-regulation of miR-146b-5p levels but has no effect on miR-146a or miR-146b-3p expressions. Transfection of HUVECs with a miR-146b-5p mimic significantly attenuates LPS-induced inflammatory responses and IRAK1 and TRAF6 expressions. In HUVECs transfected with a miR-146b-5p inhibitor, Ang-1 has no effect on LPS-induced inflammatory responses or IRAK1 and TRAF6 expressions. CONCLUSION: Ang-1 disrupts TLR4 signalling, resulting in inhibition of LPS induced inflammatory responses in endothelial cells. This inhibition occurs through selective targeting of IRAK1 and TRAF6 proteins by miR-146b-5p. PMID- 25824149 TI - NOD1, a new player in cardiac function and calcium handling. AB - AIMS: Inflammation is a significant contributor to cardiovascular disease and its complications; however, whether the myocardial inflammatory response is harmonized after cardiac injury remains to be determined. Some receptors of the innate immune system, including the nucleotide-binding oligomerization domain like receptors (NLRs), play key roles in the host response after cardiac damage. Nucleotide-binding oligomerization domain containing 1 (NOD1), a member of the NLR family, is expressed in the heart, but its functional role has not been elucidated. We determine whether selective NOD1 activation modulates cardiac function and Ca(2+) signalling. METHODS AND RESULTS: Mice were treated for 3 days with the selective NOD1 agonist C12-iE-DAP (iE-DAP), and cardiac function and Ca(2+) cycling were assessed. We found that iE-DAP treatment resulted in cardiac dysfunction, measured as a decrease in ejection fraction and fractional shortening. Cardiomyocytes isolated from iE-DAP-treated mice displayed a decrease in the L-type Ca(2+) current, [Ca(2+)]i transients and Ca(2+) load, and decreased expression of phospho-phospholamban, sarcoplasmic reticulum-ATPase, and Na(+) Ca(2+) exchanger. Furthermore, iE-DAP prompted 'diastolic Ca(2+) leak' in cardiomyocytes, resulting from increased Ca(2+) spark frequency and RyR2 over phosphorylation. Importantly, these iE-DAP-induced changes in Ca(2+) cycling were lost in NOD1(-/-) mice, indicating that iE-DAP exerts its actions through NOD1. Co-treatment of mice with iE-DAP and a selective inhibitor of NF-kappaB (BAY11 7082) prevented cardiac dysfunction and Ca(2+) handling impairment induced by iE DAP. CONCLUSION: Our data provide the first evidence that NOD1 activation induces cardiac dysfunction associated with excitation-contraction coupling impairment through NF-kappaB activation and uncover a new pro-inflammatory player in the regulation of cardiovascular function. PMID- 25824150 TI - Preemptive antiretroviral therapy modifications for the management of potential clinically significant drug interactions with direct acting hepatitis C therapies. AB - We report a case series of HIV/HCV co-infected patients who underwent preemptive antiretroviral therapy modifications to manage clinically significant drug interactions with HCV therapy. Among the 15 patients reviewed, all changed to a raltegravir-based regimen and none experienced a loss of virologic suppression or increase in HIV-RNA. PMID- 25824151 TI - Using Elecsys(r) HIV Combi PT assay to identify acute and early HIV infection in a teaching hospital of southwest China. AB - This study is the first attempt to evaluate the use of the Elecsys(r) HIV combi PT assay in identifying acute and early HIV infection in southwest China. We also analyzed the extent of cutoff ratios overlap between false-positive and true positive results to aid the identification of HIV infection, using samples from the West China Hospital in Chengdu, Sichuan Province from April 2012 to December 2013. Reactive results from a screening test were retested and all repeatedly reactive samples - if available - were confirmed with Western blot, HIV-1 p24 antigen, or HIV-1 RNA. Of 241,840 samples screened, the Elecsys(r) HIV combi PT assay identified 54 patients with acute and early HIV infection; 99.8% cases with cutoff index ratios >=50 were proved to be true-positive HIV infection and 95.6% cases with cutoff index ratios <15 were falsely positive. In conclusion, the Elecsys(r) HIV combi PT assay can identify acute and early HIV infection, including those who might have been missed by third-generation HIV screening assays and Western blot. However, cutoff index ratios <15 are not always false reactive results; a definitive result cannot be attained without further confirmation. In resource-poor regions where a HIV-1 nucleic acid test may be unaffordable, detection of HIV-1 p24 antigen can be an alternative strategy to diagnose HIV infection in individuals with a negative or indeterminate Western blot. PMID- 25824152 TI - Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma. AB - Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling. IMPLICATIONS: miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets. PMID- 25824153 TI - Teenage mothers of black and minority ethnic origin want access to a range of mental and physical health support: a participatory research approach. AB - BACKGROUND: In high risk, economically disadvantaged neighbourhoods, such as those primarily resident by black and minority ethnic groups (BME), teenage pregnancies are relatively more frequent. Such families often have limited access to and/or knowledge of services, including prenatal and post-partum physical and mental health support. OBJECTIVE: To explore preferences held by vulnerable young mothers of BME origin and those close to them about existing and desired perinatal health services. DESIGN, SETTING AND PARTICIPANTS: Drawing on a community-based participatory approach, a community steering committee with local knowledge and experience of teenage parenthood shaped and managed an exploratory qualitative study. In collaboration with a local agency and academic research staff, community research assistants conducted two focus groups with 19 members and 21 individual semi-structured interviews with young mothers of BME origin and their friends or relatives. These were coded, thematically analysed, interpreted and subsequently triangulated through facilitator and participant review and discussion. RESULTS: Despite perceptions of a prevalent local culture of mistrust and suspicion, a number of themes and accompanying recommendations emerged. These included a lack of awareness by mothers of BME origin about current perinatal health services, as well as programme inaccessibility and inadequacy. There was a desire to engage with a continuum of comprehensive and well-publicized, family focused perinatal health services. Participants wanted inclusion of maternal mental health and parenting support that addressed the whole family. CONCLUSIONS: It is both ethical and equitable that comprehensive perinatal services are planned and developed following consultation and participation of knowledgeable community members including young mothers of BME origin, family and friends. PMID- 25824155 TI - [Frailty in people with intellectual disabilities: operationalization, risks and detection]. AB - Although the population with intellectual disabilities (ID) is increasingly growing older, there seems to be an early onset of functional decline in this group, which could be explained by frailty. We used data from the Healthy Aging and Intellectual Disability study (HA-ID) to measure frailty in people with ID. Frailty was measured with an adapted version of the frailty index, consisting of 50 health and age related deficits. We were the first to measure frailty with a frailty index in this population, and therefore its validity, in terms of predictive value, needed to be established. In the current article we provide an overview of the design of the frailty index and its relation with adverse health outcomes. In a nearly representative study population of 982 50-plus older adults with ID, we studied the prevalence of frailty and its validity over a 3-year follow-up period. Results show that people with ID were earlier and more severely frail than people from the general population. Frailty was related to early mortality, to disabilities in daily functioning and mobility, to increased medication use, and increased care intensity, but not to hospitalization. Using a hypothetical model, we identify possible interventions to increase the healthy life years in people with ID. PMID- 25824156 TI - Editor's briefing. PMID- 25824154 TI - Genomic signatures of human and animal disease in the zoonotic pathogen Streptococcus suis. AB - Streptococcus suis causes disease in pigs worldwide and is increasingly implicated in zoonotic disease in East and South-East Asia. To understand the genetic basis of disease in S. suis, we study the genomes of 375 isolates with detailed clinical phenotypes from pigs and humans from the United Kingdom and Vietnam. Here, we show that isolates associated with disease contain substantially fewer genes than non-clinical isolates, but are more likely to encode virulence factors. Human disease isolates are limited to a single-virulent population, originating in the 1920, s when pig production was intensified, but no consistent genomic differences between pig and human isolates are observed. There is little geographical clustering of different S. suis subpopulations, and the bacterium undergoes high rates of recombination, implying that an increase in virulence anywhere in the world could have a global impact over a short timescale. PMID- 25824157 TI - Boring but important: the community mental health team. PMID- 25824158 TI - Invest in community-based solutions that address individuals' needs: not more beds. PMID- 25824159 TI - Digital mental health services in general practice. PMID- 25824160 TI - Endometriosis in secondary care. PMID- 25824161 TI - A journey into the humanitarian side of general practice. PMID- 25824162 TI - Compassion or empathy? A way forward to reduce GP stress and burnout. PMID- 25824163 TI - How the NCT will bring down the NHS. PMID- 25824164 TI - Paracetamol, ethnic health inequalities, cerebral palsy, and pornography. PMID- 25824165 TI - A revolution in the making: a suggested model for training NHS doctors. PMID- 25824166 TI - International primary care snapshots: Australia and Brazil. PMID- 25824167 TI - My personal diagnostic delay: 'Physician, prevent thyself'. PMID- 25824172 TI - Are we too narcissistic? PMID- 25824173 TI - Setting ground rules for GP trainer groups: potential pitfalls and how to avoid them. PMID- 25824174 TI - Supporting expert generalist practice: the SAGE consultation model. PMID- 25824175 TI - Seeing red in young children: the importance of the red reflex. PMID- 25824176 TI - Child health care in general practice: priorities for education and practice. PMID- 25824177 TI - Prevention of mental illness must start in childhood: growing up feeling safe and protected from harm. PMID- 25824178 TI - Improving the effectiveness of self-monitoring of blood glucose in type 2 diabetes. PMID- 25824179 TI - Tools and tables in cardiovascular risk management: doing more harm than good? PMID- 25824180 TI - Morbidity matters: challenges for research. PMID- 25824181 TI - Childhood urinary tract infection in primary care: a prospective observational study of prevalence, diagnosis, treatment, and recovery. AB - BACKGROUND: The prevalence of targeted and serendipitous treatment for, and associated recovery from, urinary tract infection (UTI) in pre-school children is unknown. AIM: To determine the frequency and suspicion of UTI in children who are acutely ill, along with details of antibiotic prescribing, its appropriateness, and whether that appropriateness impacted on symptom improvement and recovery. DESIGN AND SETTING: Prospective observational cohort study in primary care sites in urban and rural areas in England and Wales. METHOD: Systematic urine sampling from children aged <5 years presenting in primary care with acute illness with culture in NHS laboratories. RESULTS: Of 6079 children's urine samples, 339 (5.6%) met laboratory criteria for UTI and 162 (47.9%) were prescribed antibiotics at the initial consultation. In total, 576/7101 (8.1%) children were suspected of having a UTI prior to urine sampling, including 107 of the 338 with a UTI (clinician sensitivity 31.7%). Children with a laboratory-diagnosed UTI were more likely to be prescribed antibiotics when UTI was clinically suspected than when it was not (86.0% versus 30.3%, P<0.001). Of 231 children with unsuspected UTI, 70 (30.3%) received serendipitous antibiotics (that is, antibiotics prescribed for a different reason). Overall, 176 (52.1%) children with confirmed UTI did not receive any initial antibiotic. Organism sensitivity to the prescribed antibiotic was higher when UTI was suspected than when treated serendipitously (77.1% versus 26.0%; P<0.001). Children with UTI prescribed appropriate antibiotics at the initial consultation improved a little sooner than those with a UTI who were not prescribed appropriate antibiotics initially (3.5 days versus 4.0 days; P = 0.005). CONCLUSION: Over half of children with UTI on culture were not prescribed antibiotics at first presentation. Serendipitous UTI treatment was relatively common, but often inappropriate to the organism's sensitivity. Methods for improved targeting of antibiotic treatment in children who are acutely unwell are urgently needed. PMID- 25824182 TI - Translation of clinical prediction rules for febrile children to primary care practice: an observational cohort study. AB - BACKGROUND: Clinical prediction rules (CPRs) to identify children with serious infections lack validation in low-prevalence populations, which hampers their implementation in primary care practice. AIM: To evaluate the diagnostic value of published CPRs for febrile children in primary care. DESIGN AND SETTING: Observational cohort study among febrile children (<16 years) who consulted five GP cooperatives (GPCs) in the Netherlands. METHOD: Alarm signs of serious infection and clinical management were extracted from routine clinical practice data and manually recoded with a structured electronic data-entry program. Eight CPRs were selected from literature. CPR-variables were matched with alarm signs and CPRs were applied to the GPC-population. 'Referral to emergency department (ED)' was used as a proxy outcome measure for 'serious infection'. CPR performance was assessed by calibration analyses, sensitivity, specificity, and area under the ROC-curve (ROC-area). RESULTS: A total of 9794 GPC-contacts were eligible, 54% male, median age 2.3 years (interquartile range 1.0-4.6 years) and 8.1% referred to ED. Frequencies of CPR-variables varied from 0.5% (cyanosis, drowsy) to 25% (temperature >=40 degrees C). Alarm signs frequently included in CPRs were 'ill appearance', 'inconsolable', and 'abnormal circulatory or respiratory signs'. The height of the CPR's predicted risks generally corresponded with being (or not being) referred to the ED in practice. However, calibration-slopes indicated that three CPRs underestimated the risk of serious infection in the GPC-population. Sensitivities ranged from 42% to 54%, specificities from 68% to 89%. ROC-areas ranged from 0.52 to 0.81, with best performance of CPRs for children aged <3 months. CONCLUSION: Published CPRs performed moderately well in the primary out-of-hours care population. Advice is given on how to improve translation of CPRs to primary care practice. PMID- 25824183 TI - Child obesity cut-offs as derived from parental perceptions: cross-sectional questionnaire. AB - BACKGROUND: Overweight children are at an increased risk of premature mortality and disease in adulthood. Parental perceptions and clinical definitions of child obesity differ, which may lessen the effectiveness of interventions to address obesity in the home setting. The extent to which parental and objective weight status cut-offs diverge has not been documented. AIM: To compare parental perceived and objectively derived assessment of underweight, healthy weight, and overweight in English children, and to identify sociodemographic characteristics that predict parental under- or overestimation of a child's weight status. DESIGN AND SETTING: Cross-sectional questionnaire completed by parents linked with objective measurement of height and weight by school nurses, in English children from five regions aged 4-5 and 10-11 years old. METHOD: Parental derived cut-offs for under- and overweight were derived from a multinomial model of parental classification of their own child's weight status against school nurse measured body mass index (BMI) centile. RESULTS: Measured BMI centile was matched with parent classification of weight status in 2976 children. Parents become more likely to classify their children as underweight when they are at the 0.8th centile or below, and overweight at the 99.7th centile or above. Parents were more likely to underestimate a child's weight if the child was black or South Asian, male, more deprived, or the child was older. These values differ greatly from the BMI centile cut-offs for underweight (2nd centile) and overweight (85th). CONCLUSION: Clinical and parental classifications of obesity are divergent at extremes of the weight spectrum. PMID- 25824184 TI - Obesity in primary care: a qualitative synthesis of patient and practitioner perspectives on roles and responsibilities. AB - BACKGROUND: Obesity is a top-priority global health issue; however, a clear way to address obesity in primary care is not yet in view. AIM: To conduct a meta ethnography of patient and primary care practitioner perspectives of roles and responsibilities in how to address obesity in the UK, to inform evidence-based services that are acceptable to, and appropriate for, patients and practitioners. DESIGN AND SETTING: Qualitative synthesis applying meta-ethnographic methods according to the Noblit and Hare monograph. Database searches in MEDLINE((r)), Social Sciences Citation Index((r)), CINAHL, and Health Management Information Consortium were limited to 1997-2012 to examine recent perspectives. METHOD: Full articles of practitioner and/or patient perspectives on obesity services in primary care were reviewed, and included semi-structured or unstructured interviews and focus groups, and participant observations. RESULTS: Nine studies were synthesised with perspectives from patients (n = 105) and practitioners (n = 144). Practitioners believe that patients are responsible for obesity, and that primary care should not help, or is poorly equipped to do so. Patients 'take responsibility' by 'blaming' themselves, but feel that practitioners should demonstrate more leadership. The empowerment of patients to access health services is reliant on the empowerment of practitioners to take an unambiguous position. CONCLUSION: Primary care has the potential either to perpetuate or counter obesity-related stigma. There needs to be a firm decision as to what role primary care will take in the prevention and treatment of obesity. To remain ambiguous runs the risk of losing patients' confidence and adding to a growing sense of futility. PMID- 25824185 TI - Experiences of a commercial weight-loss programme after primary care referral: a qualitative study. AB - BACKGROUND: Referral to a commercial weight-loss programme is a cost-effective intervention that is already used within the NHS. Qualitative research suggests this community-based, non-medical intervention accords with participants' view of weight management as a lifestyle issue. AIM: To examine the ways in which participants' attitudes and beliefs about accessing a commercial weight management programme via their doctor relate to their weight-loss experience, and to understand how these contextual factors influence motivation and adherence to the intervention. DESIGN AND SETTING: A qualitative study embedded in a randomised controlled trial evaluating primary care referral to a commercial weight-loss programme in adults who are overweight or obese in England. The study took place from June-September 2013. METHOD: Twenty-nine participants (body mass index [BMI] >=28 kg/m(2); age >=18 years), who took part in the WRAP (Weight Loss Referrals for Adults in Primary Care) trial, were recruited at their 3-month assessment appointment to participate in a semi-structured interview about their experience of the intervention and weight management more generally. Interviews were audiorecorded, transcribed verbatim, and analysed inductively using a narrative approach. RESULTS: Although participants view the lifestyle-based, non medical commercial programme as an appropriate intervention for weight management, the referral from the GP and subsequent clinical assessments frame their experience of the intervention as medically pertinent with clear health benefits. CONCLUSION: Referral by the GP and follow-up assessment appointments were integral to participant experiences of the intervention, and could be adapted for use in general practice potentially to augment treatment effects. PMID- 25824186 TI - Reduction in self-monitoring of blood glucose in type 2 diabetes: an observational controlled study in east London. AB - BACKGROUND: Self-monitoring of blood glucose (SMBG) confers no benefit for many people with type 2 diabetes not being treated with insulin. It accounts for 21% of diabetes prescribing costs. AIM: To improve care quality at reduced cost for type 2 diabetes by reducing unnecessary SMBG. DESIGN AND SETTING: Non-randomised, observational controlled study in two intervention clinical commissioning groups (CCGs) and one control CCG in east London. METHOD: In total, 19,602 people with type 2 diabetes not being treated with insulin were recruited from two intervention CCGs; 16,033 were recruited from a control CCG. The intervention (from 2010 to 2013) comprised implementation of a locally developed guideline, including IT support and peer feedback of performance. Data on practice prescribing SMBG testing strips were gathered using GP electronic health records. Information on costs were obtained via the ePACT electronic database. RESULTS: Over 4 years, in all non-insulin type 2 diabetes treatment groups, use of SMBG was reduced in the two intervention CCGs from 42.8% to 16.5%, and in the control CCG from 56.4% to 47.2%. In people on metformin alone or no treatment, intervention CCGs reduced SMBG use from 29.6% to 6.0%, and in the control CCG use dropped from 47.1% to 38.7% (P<0.001). From 2009 to 2012 the total cost of all SMBG prescribing (type 1 and type 2 diabetes, including users of insulin) was reduced by 4.9% (L62,476) in the two intervention CCGs and increased in the control CCG by 5.0% (L42,607); in England, the total cost increased by 13.5% (L19.4 million). In total, 20% (3865 of 19 602) fewer patients used SMBG in the intervention CCGs. CONCLUSION: This low-cost programme demonstrated a major reduction in unnecessary prescribing of SMBG, along with cost savings. If replicated nationally, this would avoid unnecessary testing in 340 000 people and prescribing costs that total L21.8 million. PMID- 25824187 TI - Using quantitative risk information in decisions about statins: a qualitative study in a community setting. AB - BACKGROUND: A large literature informs guidance for GPs about communicating quantitative risk information so as to facilitate shared decision making. However, relatively little has been written about how patients utilise such information in practice. AIM: To understand the role of quantitative risk information in patients' accounts of decisions about taking statins. DESIGN AND SETTING: This was a qualitative study, with participants recruited and interviewed in community settings. METHOD: Semi-structured interviews were conducted with 34 participants aged >50 years, all of whom had been offered statins. Data were analysed thematically, using elements of the constant comparative method. RESULTS: Interviewees drew frequently on numerical test results to explain their decisions about preventive medication. In contrast, they seldom mentioned quantitative risk information, and never offered it as a rationale for action. Test results were spoken of as objects of concern despite an often-explicit absence of understanding, so lack of understanding seems unlikely to explain the non-use of risk estimates. Preventive medication was seen as 'necessary' either to treat test results, or because of personalised, unequivocal advice from a doctor. CONCLUSION: This study's findings call into question the assumption that people will heed and use numerical risk information once they understand it; these data highlight the need to consider the ways in which different kinds of knowledge are used in practice in everyday contexts. There was little evidence from this study that understanding probabilistic risk information was a necessary or valued condition for making decisions about statin use. PMID- 25824188 TI - Views of newly-qualified GPs about their training and preparedness: lessons for extended generalist training. AB - BACKGROUND: General practice is becoming increasingly complex due to an ageing population with multiple morbidities and the shift of services from secondary to primary care, yet GP training remains largely the same. Extended training is now recommended, initially proposed as a fourth GP specialty trainee year, but more recently as a broad-based 4-year specialty training programme. AIM: To explore the views of newly-qualified GPs about their training and preparedness for specific aspects of the GP's role. DESIGN AND SETTING: Qualitative study with newly-qualified GPs who qualified with Severn Deanery between 2007 and 2010. METHOD: Semi-structured interviews with 18 GPs between November 2011 and April 2012. RESULTS: Gaining experience in a variety of primary care environments widens insight into patient populations as well as helping GPs develop adaptability and confidence, although this is not routinely part of GP training. However, alongside variety, having continuity with patients in practice remains important. Opportunities to be involved in the management of a practice or to take on substantial leadership roles also vary widely and this may limit preparedness and development of generalist skills. CONCLUSION: Extended training could help prepare GPs for the current challenges of general practice. It could ensure all trainees are exposed to a greater variety of primary care settings including those outside GP practice, as well as experience of business, finance, and leadership roles. Collectively, these changes have the potential to produce GPs with both generalist and enhanced skills, who are better prepared to work collaboratively across the organisational boundaries between primary, secondary, and community care. PMID- 25824189 TI - Revisiting screening for type 2 diabetes mellitus: the case for and against using HbA1c. PMID- 25824190 TI - Increasing the number of inter-arch contacts improves mastication in adults with Down syndrome: a prospective controlled trial. AB - Feeding difficulties due to their condition have been widely described for babies, children and adults with Down syndrome (DS). A previous study demonstrated that, compared with wearing a placebo appliance, wearing an occlusal appliance increased inter-arch dental contacts, improved the oral health status of adults with DS and normalised their mandibular rest position. This longitudinal prospective controlled trial aimed to evaluate whether increasing inter-arch contacts in adults with DS would lead to improved masticatory efficiency. Fourteen subjects with DS (mean age+/-SD: 28.5+/-9.3years) and twelve controls without DS (24.6+/-1.0years) were video recorded while chewing samples of carrot and peanuts with and without an oral appliance that was designed to equalise the number of posterior functional units (PFUs) in both groups. Three parameters were collected during mastication for 15cycles and until swallowing: food refusals, food bolus granulometry (D50) and kinematic parameters of the chewing process (number of cycles, chewing duration and cycle frequency within the chewing sequence). In the DS group, increasing the number of PFUs led to a decrease in bolus particle size, to fewer masticatory cycles needed to produce a bolus ready for swallowing and to a decrease in the occurrence of food refusal, while mean chewing frequency did not vary. In the control group, bolus granulometry and chewing time increased with appliance wear while mean chewing frequency decreased. These changes clearly indicate a functional improvement in subjects with DS. This study also demonstrated a causal relationship between the number of functional pairs of posterior teeth and improved mastication. Any evaluation of feeding behaviour in persons with DS should consider inter-arch dental contacts as an explicative variable for feeding problems and their nutritional and respiratory consequences. PMID- 25824191 TI - Blunted hypothalamo-pituitary adrenal axis response to predator odor predicts high stress reactivity. AB - Individuals with trauma- and stress-related disorders exhibit increases in avoidance of trauma-related stimuli, heightened anxiety and altered neuroendocrine stress responses. Our laboratory uses a rodent model of stress that mimics the avoidance symptom cluster associated with stress-related disorders. Animals are classified as 'Avoiders' or 'Non-Avoiders' post-stress based on avoidance of predator-odor paired context. Utilizing this model, we are able to examine subpopulation differences in stress reactivity. Here, we used this predator odor model of stress to examine differences in anxiety-like behavior and hypothalamo-pituitary adrenal (HPA) axis function in animals that avoid a predator-paired context relative to those that do not. Rats were exposed to predator odor stress paired with a context and tested for avoidance (24h and 11days), anxiety-like behavior (48h and 5days) and HPA activation following stress. Control animals were exposed to room air. Predator odor stress produced avoidance in approximately 65% of the animals at 24h that persisted 11days post stress. Both Avoiders and Non-Avoiders exhibited a heightened anxiety-like behavior at 48h and 5days post-stress when compared to unstressed Controls. Non Avoiders exhibited significant increases in circulating adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations immediately following predator odor stress compared to Controls and this response was significantly attenuated in Avoiders. There was an inverse correlation between circulating ACTH/CORT concentrations and avoidance, indicating that lower levels of ACTH/CORT predicted higher levels of avoidance. These results suggest that stress effects on HPA stress axis activation predict long-term avoidance of stress-paired stimuli, and build on previous data showing the utility of this model for exploring the neurobiological mechanisms of trauma- and stress-related disorders. PMID- 25824192 TI - Aesthetic outcome after implant and DIEP flap breast reconstruction: An exploratory, prospective comparison of 25 cases. PMID- 25824193 TI - Preoperative CT angiography versus Doppler ultrasound mapping of abdominal perforator in DIEP breast reconstructions: A randomized prospective study. AB - Is there a difference in surgery time and complication rate when Doppler ultrasound (US) is used for the preoperative mapping of perforators in comparison with computer tomography angiography (CTA)? Women who were candidates for breast reconstruction using the deep inferior epigastric perforator (DIEP) free flap were enrolled in a prospective randomized study. The operating time was 249 +/- 62 min (mean +/- SD) in the CTA group (n = 32) and 255 min +/- 75 in the US group (n = 31)--hence a difference of 6 min on average. No flaps were lost. Sixteen complications occurred in 15 patients: seven in the CTA group and nine in the US group. Complications were remedied without delay and all patients came through with a favorable reconstruction. Preoperative mapping of perforators with US is satisfactory enough provided the microsurgery team has proper experience in breast reconstruction with the DIEP flap. PMID- 25824194 TI - Redon drainage bottle as a reservoir for fat cell harvesting. PMID- 25824195 TI - Masseteric nerve transfer for short-term facial paralysis following skull base surgery. AB - BACKGROUND: Nerve transfers have been widely used to reanimate paralyzed facial muscles after irreversible proximal injuries to the facial nerve. The author has developed a technique involving masseteric nerve transfer combined with cross facial nerve grafting for treating skull base surgery-induced facial paralysis. This paper aims to demonstrate that this procedure is effective and causes negligible donor site morbidity. METHODS: Seven patients who developed facial paralysis after the removal of skull base tumors were treated with masseteric nerve transfer combined with cross-facial nerve grafting with the aim of reanimating the midface. The mean period of preoperative paralysis was 6 months. The follow-up period ranged from 22 to 65 months (mean: 46 months). The patients were evaluated with physical examinations and video analysis. RESULTS: Successful reanimation of the midface was achieved in all patients except one, whose muscle tone recovered. On average, facial motion developed 4 months after the nerve transfer. Only minimal coordinated eyelid movement was seen during biting. None of the patients experienced impaired masticatory function or visible wasting of the masseter muscle. All of the patients who recovered the ability to contract their paralyzed muscles were able to close their eyes tightly during biting; however, none of the patients have been able to achieve an effortless spontaneous smile. CONCLUSIONS: Masseteric nerve transfer is an alternative method for selective reanimation of the midface and does not cause donor site morbidity. PMID- 25824196 TI - Reconstructive outcomes of Mohs surgery compared with conventional excision: A 13 month prospective study. AB - Established in 2012, the Mersey Regional Centre for Mohs Surgery is the first UK Mohs service to be led by a Mohs trained Plastic & Reconstructive surgeon. We evaluate the resection requirements and reconstructive techniques of our patient group and compare their surgical outcome to that which would have been gained with conventional excision (CE) and reconstruction for the same lesions. 157 patients were analysed over 13 months. Had CE and reconstruction been used, 56% of patients would have received a more invasive or cosmetically less desirable reconstruction, and 24% of margins would remain incomplete. The outcome was unchanged in 20% of patients. A small but significant subgroup (9%) of patients would have lost fundamental structures e.g. orbital exenteration, or undergone reconstructions unnecessarily crossing aesthetic subunits. Whilst in its infancy, the Plastic & Reconstructive Mohs surgery service has provided a valuable contribution to the care given to patients in the Mersey and Cheshire Skin Cancer Network. Detailed referral criteria, thorough preoperative patient evaluation, and appreciation of the abilities and limits of CE have enabled the service to produce a demonstrable reconstructive benefit in 80% of patients when compared to non-Mohs resection and reconstruction. PMID- 25824197 TI - Free perivascular tissue flap transfer. AB - Local flaps and composite grafting are the procedures of choice for reconstructing relatively small soft tissue defects. However, despite their limited conveyable volume, local flaps sometimes require a wide dissection area and long new incisions. Composite grafts also have serious limitations and require a well-vascularized recipient bed. To overcome these limitations, we used a free vascularized perivascular tissue flap based on the descending branch of the lateral femoral circumflex artery. Using this method, we performed reconstructions for seven patients (four cases in head and neck region and three cases in lower limb) with various soft tissue defects (ranged from 4.0 cm(3) to 40.0 cm(3)). This flap was easily elevated, without the need for precise preoperative flap design, and the flap volume was adjustable regardless of whether deep fascia and muscle were included. The flap has a rich vascular supply, which allows bone and cartilage tissue to be combined with the transfer of soft tissue, and satisfactorily treats chronic wounds with poor blood supply. PMID- 25824198 TI - Preoperative color Doppler ultrasound assessment in planning of SCIP flaps. AB - INTRODUCTION: Superficial circumflex iliac artery perforator (SCIP) flap is based on the perforator of superficial circumflex iliac artery (SCIA) system, and is a highly useful surgical tool with a wide variety of clinical applications. The SCIA system is associated with considerable anatomical variation, however, rendering transfer of a SCIP flap technically difficult. PATIENTS AND METHODS: Using preoperative color Doppler ultrasound (US), we examined a total of 11 flaps of 11 patients who had undergone reconstruction with SCIP flap from April to August of 2014. The origin of SCIA from femoral artery and the bifurcation of its superficial branch and deep branch were easily identifiable in all patients. Perforator courses and their penetration points were marked to guide dissection. RESULTS: Although one patient required secondary revision and skin grafting because of partial necrosis, there were no serious postoperative complications such as total necrosis or resulting absorption of the transferred adiposal flap. In all cases, findings from the preoperative color Doppler US were useful in delineating the dominant vessel within the groin lesion. CONCLUSION: Using the technique described above, difficulties arising from the anatomical variation within the SCIA system are easily overcome, simplifying SCIP flap harvest. In addition to being relatively easy, the technique is also quick to administer and safe. PMID- 25824199 TI - Re: 'Combined clearance of pelvic and superficial nodes for clinical groin melanoma'. PMID- 25824200 TI - Re: 'Enabling the diagnosis of necrotising fasciitis without associated skin changes in a paediatric patient with acute lymphoblastic leukaemia: The LRINEC score'. PMID- 25824202 TI - Emergency department intensive care units-Does the evidence support this model of care? PMID- 25824201 TI - HIV infection is associated with attenuated frontostriatal intrinsic connectivity: a preliminary study. AB - HIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the association of HIV infection with functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection. Fifteen HIV-positive and 15 demographically matched control participants underwent 6 min of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA). HIV - associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (<50 years, N=9). Seropositive participants also demonstrated reductions in dorsal caudate connectivity to frontal and parietal brain regions previously demonstrated to be functionally connected to the DLPFC. Cognitive impairment, but none of the assessed clinical/immunological variables, was also associated with reduced frontostriatal connectivity. In conclusion, our data indicate that HIV is associated with attenuated intrinsic frontostriatal connectivity. Intrinsic connectivity of this network may therefore serve as a marker of the deleterious effects of HIV infection on the brain, possibly via HIV associated dopaminergic abnormalities. These findings warrant independent replication in larger studies. PMID- 25824203 TI - In-situ atomic layer deposition of tri-methylaluminum and water on pristine single-crystal (In)GaAs surfaces: electronic and electric structures. AB - The electronic structure of single-crystal (In)GaAs deposited with tri methylaluminum (TMA) and water via atomic layer deposition (ALD) is presented with high-resolution synchrotron radiation core-level photoemission and capacitance-voltage (CV) characteristics. The interaction of the precursor atoms with (In)GaAs is confined at the topmost surface layer. The Ga-vacant site on the GaAs(111)A-2 * 2 surface is filled with Al, thereby effectively passivating the As dangling bonds. The As-As dimers on the GaAs(001)-2 * 4 surface are entirely passivated by one cycle of TMA and water. The presumed layerwise deposition fails to happen in GaAs(001)-4 * 6. In In0.20Ga0.80As(001)-2 * 4, the edge row As atoms are partially bonded with the Al, and one released methyl then bonds with the In. It is suggested that the unpassivated surface and subsurface atoms cause large frequency dispersions in CV characteristics under the gate bias. We also found that the (In)GaAs surface is immune to water in ALD. However, the momentary exposure of it to air (less than one minute) introduces significant signals of native oxides. This indicates the necessity of in situ works of high kappa/(In)GaAs-related experiments in order to know the precise interfacial atomic bonding and thus know the electronic characteristics. The electric CV measurements of the ALD-Al2O3 on these (In)GaAs surfaces are correlated with their electronic properties. PMID- 25824204 TI - Identification and Optimization of Combinatorial Glucose Metabolism Inhibitors in Hepatocellular Carcinomas. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. The expression of glucose transporter isoform 1, a key factor in transporting glucose into cancer cells, is overexpressed in several human cancers, including HCC. In addition, this has been shown to correlate with a higher proliferation index and more advanced stages in HCC, suggesting that inhibition of glucose metabolism is a promising therapeutic strategy. Our study used high-content screening (HCS) for compounds that target glucose metabolism and effect cell death in HCC cells. Specifically, we showed that a fluorescent 2-deoxyglucose analog, 2-[N-(7 nitrobenz-2- oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose, and CellTrace Calcein Red Orange AM can be used reliably as readouts for glucose uptake and proliferative index, respectively, to identify drug candidates that simultaneously reduce glucose uptake and induce cell death in HCC cells. Thus, fluorescent glucose uptake bioprobes can be implemented in HCS assays to identify previously unknown regulators of glucose metabolism in HCC. In addition, our study also employs the use of feedback system control (FSC.II), a platform that optimizes the combinations of drugs identified through HCS. The coordinated use of HCS and FSC.II can improve the development of drug combinations and uncover previously unidentified signaling pathways that govern HCC as well as other cancers. PMID- 25824205 TI - Fully Automated Quantification of Insulin Concentration Using a Microfluidic Based Chemiluminescence Immunoassay. AB - A fully automated microfluidic-based detection system for the rapid determination of insulin concentration through a chemiluminescence immunoassay has been developed. The microfluidic chip used in the system is a double-layered polydimethylsiloxane device embedded with interconnecting micropumps, microvalves, and a micromixer. At a high injection rate of the developing solution, the chemiluminescence signal can be excited and measured within a short period of time. The integral value of the chemiluminescence light signal is used to determine the insulin concentration of the samples, and the results indicate that the measurement is accurate in the range from 1.5 pM to 391 pM. The entire chemiluminescence assay can be completed in less than 10 min. The fully automated microfluidic-based insulin detection system provides a useful platform for rapid determination of insulin in clinical diagnostics for diabetes, which is expected to become increasingly important for future point-of-care applications. PMID- 25824206 TI - Cone beam computed tomography images fusion in predicting lung ablation volumes: a feasibility study. AB - BACKGROUND: Recently different software with the ability to plan ablation volumes have been developed in order to minimize the number of attempts of positioning electrodes and to improve a safe overall tumor coverage. PURPOSE: To assess the feasibility of three-dimensional cone beam computed tomography (3D CBCT) fusion imaging with "virtual probe" positioning, to predict ablation volume in lung tumors treated percutaneously. MATERIAL AND METHODS: Pre-procedural computed tomography contrast-enhanced scans (CECT) were merged with a CBCT volume obtained to plan the ablation. An offline tumor segmentation was performed to determine the number of antennae and their positioning within the tumor. The volume of ablation obtained, evaluated on CECT performed after 1 month, was compared with the pre-procedural predicted one. Feasibility was assessed on the basis of accuracy evaluation (visual evaluation [VE] and quantitative evaluation [QE]), technical success (TS), and technical effectiveness (TE). RESULTS: Seven of the patients with lung tumor treated by percutaneous thermal ablation were selected and treated on the basis of the 3D CBCT fusion imaging. In all cases the volume of ablation predicted was in accordance with that obtained. The difference in volume between predicted ablation volumes and obtained ones on CECT at 1 month was 1.8 cm(3) (SD +/- 2, min. 0.4, max. 0.9) for MW and 0.9 cm(3) (SD +/- 1.1, min. 0.1, max. 0.7) for RF. CONCLUSION: Use of pre-procedural 3D CBCT fusion imaging could be useful to define expected ablation volumes. However, more patients are needed to ensure stronger evidence. PMID- 25824207 TI - Prediction of hard meningiomas: quantitative evaluation based on the magnetic resonance signal intensity. AB - BACKGROUND: From a surgical perspective, presurgical prediction of meningioma consistency is beneficial. PURPOSE: To quantitatively analyze the correlation between the magnetic resonance (MR) signal intensity (SI) or apparent diffusion coefficient (ADC) and meningioma consistency and to determine which MR sequence could help predicting hard meningiomas. MATERIAL AND METHODS: This study included 43 patients with meningiomas who underwent preoperative MR imaging (MRI), including T1-weighted (T1W) imaging, T2-weighted (T2W) imaging, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), contrast-enhanced (CE)-T1W imaging, and CE-fast imaging employing steady-state acquisition (FIESTA). A neurosurgeon evaluated the tumor consistency using a visual analog scale (VAS) with the anchors "soft" (score = 0) and "hard" (score = 10). The SI ratio (tumor to cerebral cortex SI) and ADC value were compared with the tumor consistency. The sensitivity, specificity, and accuracy for predicting hard meningiomas (VAS score >=8; 9 of 43 patients) were calculated using cutoff values for the SI ratio that were obtained in a receiver operating characteristic curve analysis. RESULTS: A significant negative correlation was observed between the tumor consistency and the SI ratio on T2W imaging, FLAIR, and CE-FIESTA (P < 0.05) but not on T1W imaging, CE-T1W imaging, and the ADC value. The sensitivity, specificity, and accuracy for predicting hard meningiomas were 89%, 79%, and 81% with T2W imaging; 89%, 76%, and 79% with FLAIR; and 100%, 74%, and 79% with CE FIESTA, respectively. CONCLUSION: Our results suggest that a quantitative assessment using conventional T2W imaging or FLAIR may be a simple and useful method for predicting hard meningiomas. PMID- 25824208 TI - In vitro activity of ceftazidime-avibactam against 338 molecularly characterized gentamicin-nonsusceptible Gram-negative clinical isolates obtained from patients in Canadian hospitals. AB - The mechanism of aminoglycoside resistance among 338 gentamicin-nonsusceptible Gram-negative bacteria (207 Enterobacteriaceae and 131 Pseudomonas aeruginosa) was assessed, and the in vitro activity of ceftazidime-avibactam against these isolates was determined. Aminoglycoside-modifying enzymes were detected in 91.8% of Enterobacteriaceae and 13.7% of P. aeruginosa isolates. A single strain of Klebsiella pneumoniae harbored a 16S rRNA methylase (ArmA). The ceftazidime avibactam MIC90 values were 0.5 MUg/ml (MIC, <=8 MUg/ml for 100% of isolates) and 16 MUg/ml (MIC, <=8 MUg/ml for 87.8% of isolates) against gentamicin nonsusceptible Enterobacteriaceae and P. aeruginosa isolates, respectively. PMID- 25824209 TI - Azole drug import into the pathogenic fungus Aspergillus fumigatus. AB - The fungal pathogen Aspergillus fumigatus causes serious illness and often death when it invades tissues, especially in immunocompromised individuals. The azole class of drugs is the most commonly prescribed treatment for many fungal infections and acts on the ergosterol biosynthesis pathway. One common mechanism of acquired azole drug resistance in fungi is the prevention of drug accumulation to toxic levels in the cell. While drug efflux is a well-known resistance strategy, reduced azole import would be another strategy to maintain low intracellular azole levels. Recently, azole uptake in Candida albicans and other yeasts was analyzed using [(3)H]fluconazole. Defective drug import was suggested to be a potential mechanism of drug resistance in several pathogenic fungi, including Cryptococcus neoformans, Candida krusei, and Saccharomyces cerevisiae. We have adapted and developed an assay to measure azole accumulation in A. fumigatus using radioactively labeled azole drugs, based on previous work done with C. albicans. We used this assay to study the differences in azole uptake in A. fumigatus isolates under a variety of drug treatment conditions, with different morphologies and with a select mutant strain with deficiencies in the sterol uptake and biosynthesis pathway. We conclude that azole drugs are specifically selected and imported into the fungal cell by a pH- and ATP independent facilitated diffusion mechanism, not by passive diffusion. This method of drug transport is likely to be conserved across most fungal species. PMID- 25824210 TI - Effect of a high-fat meal on the pharmacokinetics of 300-milligram posaconazole in a solid oral tablet formulation. AB - Posaconazole in oral suspension must be taken multiple times a day with food (preferably a high-fat meal) to ensure adequate exposure among patients. We evaluated the effect of food on the bioavailability of a new delayed-release tablet formulation of posaconazole at the proposed clinical dose of 300 mg once daily in a randomized, open-label, single-dose, two-period crossover study with 18 healthy volunteers. When a single 300-mg dose of posaconazole in tablet form (3 tablets * 100 mg) was administered with a high-fat meal, the posaconazole area under the concentration-time curve from 0 to 72 h (AUC0-72) and maximum concentration in plasma (Cmax) increased 51% and 16%, respectively, compared to those after administration in the fasted state. The median time to Cmax (Tmax) shifted from 5 h in the fasted state to 6 h under fed conditions. No serious adverse events were reported, and no subject discontinued the study due to an adverse event. Six of the 18 subjects reported at least one clinical adverse event; all of these events were mild and short lasting. The results of this study demonstrate that a high-fat meal only modestly increases the mean posaconazole exposure (AUC), ~1.5-fold, after administration of posaconazole tablets, in contrast to the 4-fold increase in AUC observed previously for a posaconazole oral suspension given with a high-fat meal. PMID- 25824211 TI - Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials. AB - Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r(2) = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) and maximum plasma concentration (Cmax) were 1,530 (36.9%) MUg . h/ml and 138 (23%) MUg/ml, respectively. The mean (CV) half-life at alpha phase (t1/2alpha), t1/2beta, and t1/2gamma were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status. PMID- 25824212 TI - Population pharmacokinetics of benznidazole in adult patients with Chagas disease. AB - The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h(-1)). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.). PMID- 25824213 TI - High prevalence of mupirocin resistance in Staphylococcus aureus isolates from a pediatric population. AB - Topical mupirocin is used widely to treat skin and soft tissue infections and to eradicate nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA). Few studies to date have characterized the rates of S. aureus mupirocin resistance in pediatric populations. We retrospectively studied 358 unique S. aureus isolates obtained from 249 children seen in a predominantly outpatient setting by the Division of Pediatric Dermatology at a major academic center in New York City between 1 May 2012 and 17 September 2013. Mupirocin resistance rates and the associated risk factors were determined using a logistic regression analysis. In our patient population, 19.3% of patients had mupirocin-resistant S. aureus isolates at the time of their first culture, and 22.1% of patients with S. aureus infection had a mupirocin-resistant isolate at some time during the study period. Overall, 31.3% of all S. aureus isolates collected during the study period were resistant to mupirocin. Prior mupirocin use was strongly correlated (odds ratio [OR] = 26.5; P = <0.001) with mupirocin resistance. Additional risk factors for mupirocin resistance included methicillin resistance, atopic dermatitis (AD), epidermolysis bullosa (EB), immunosuppression, and residence in northern Manhattan and the Bronx. Resistance to mupirocin is widespread in children with dermatologic complaints in the New York City area, and given the strong association with mupirocin exposure, it is likely that mupirocin use contributes to the increased resistance. Routine mupirocin testing may be important for MRSA decolonization strategies or the treatment of minor skin infections in children. PMID- 25824214 TI - Plasma and epithelial lining fluid pharmacokinetics of ceftolozane and tazobactam alone and in combination in mice. AB - Ceftolozane is a new cephalosporin with activity against Gram-negative and Gram positive microorganisms. However, the compound is susceptible to degradation by extended-spectrum beta-lactamases (ESBLs). Tazobactam is an ESBL inhibitor and is combined with ceftolozane to broaden its activity. Surprisingly, although tazobactam has been available for over 20 years, few if any reliable data exist on the tazobactam pharmacokinetic (PK) properties in mice. To evaluate the PK and pharmacodynamic (PD) relationships in mice, the PK properties of tazobactam and ceftolozane were extensively investigated. Thigh-infected neutropenic CD-1 mice were injected intraperitoneally with a single 0.1-ml dose containing ceftolozane, tazobactam, or both compounds. Ceftolozane was applied in 2-fold-increasing doses of 4 mg/kg of body weight to 64 mg/kg alone or in combination. Tazobactam was combined in reverse doses (thus, 64/4 mg/kg, 32/8 mg/kg, etc.) (n = 2 per time point). In separate validation experiments, ceftolozane-tazobactam was given alone or in combination at 32/8 mg/kg and 8/32 mg/kg (n = 4 per time point). Plasma samples (one per mouse) and bronchoalveolar lavage samples were collected at up to 12 time points until 6 h after administration. There were no significant differences in the ceftolozane and tazobactam PK alone versus combined, indicating no PK interaction. The PKs were linear and dose proportional for both compounds and showed a good penetration in the epithelial lining fluid. The estimated mean (standard deviation) half-life of ceftolozane was 0.287 h (0.031 h), and that of tazobactam was 0.176 h (0.026), and the V was 0.43 liter/kg and 1.14 liter/kg, respectively. The estimates of tazobactam parameters can also be used to (re)interpret PD data. PMID- 25824215 TI - Novel dosing strategies increase exposures of the potent antituberculosis drug rifapentine but are poorly tolerated in healthy volunteers. AB - Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC0-24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC0-24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. NCT01574638.). PMID- 25824216 TI - Small-plasmid-mediated antibiotic resistance is enhanced by increases in plasmid copy number and bacterial fitness. AB - Plasmids play a key role in the horizontal spread of antibiotic resistance determinants among bacterial pathogens. When an antibiotic resistance plasmid arrives in a new bacterial host, it produces a fitness cost, causing a competitive disadvantage for the plasmid-bearing bacterium in the absence of antibiotics. On the other hand, in the presence of antibiotics, the plasmid promotes the survival of the clone. The adaptations experienced by plasmid and bacterium in the presence of antibiotics during the first generations of coexistence will be crucial for the progress of the infection and the maintenance of plasmid-mediated resistance once the treatment is over. Here we developed a model system using the human pathogen Haemophilus influenzae carrying the small plasmid pB1000 conferring resistance to beta-lactam antibiotics to investigate host and plasmid adaptations in the course of a simulated ampicillin therapy. Our results proved that plasmid-bearing clones compensated for the fitness disadvantage during the first 100 generations of plasmid-host adaptation. In addition, ampicillin treatment was associated with an increase in pB1000 copy number. The augmentation in both bacterial fitness and plasmid copy number gave rise to H. influenzae populations with higher ampicillin resistance levels. In conclusion, we show here that the modulations in bacterial fitness and plasmid copy number help a plasmid-bearing bacterium to adapt during antibiotic therapy, promoting both the survival of the host and the spread of the plasmid. PMID- 25824217 TI - Efflux as a glutaraldehyde resistance mechanism in Pseudomonas fluorescens and Pseudomonas aeruginosa biofilms. AB - A major challenge in microbial biofilm control is biocide resistance. Phenotypic adaptations and physical protective effects have been historically thought to be the primary mechanisms for glutaraldehyde resistance in bacterial biofilms. Recent studies indicate the presence of genetic mechanisms for glutaraldehyde resistance, but very little is known about the contributory genetic factors. Here, we demonstrate that efflux pumps contribute to glutaraldehyde resistance in Pseudomonas fluorescens and Pseudomonas aeruginosa biofilms. The RNA-seq data show that efflux pumps and phosphonate degradation, lipid biosynthesis, and polyamine biosynthesis metabolic pathways were induced upon glutaraldehyde exposure. Furthermore, chemical inhibition of efflux pumps potentiates glutaraldehyde activity, suggesting that efflux activity contributes to glutaraldehyde resistance. Additionally, induction of known modulators of biofilm formation, including phosphonate degradation, lipid biosynthesis, and polyamine biosynthesis, may contribute to biofilm resistance and resilience. Fundamental understanding of the genetic mechanism of biocide resistance is critical for the optimization of biocide use and development of novel disinfection strategies. Our results reveal genetic components involved in glutaraldehyde resistance and a potential strategy for improved control of biofilms. PMID- 25824218 TI - Activity of clarithromycin or rifampin alone or in combination against experimental Rhodococcus equi infection in mice. AB - Treatment of mice with the combination of clarithromycin with rifampin resulted in a significantly lower number of Rhodococcus equi CFU in the organs of mice than treatment with either drug alone or placebo. There was no significant difference in the number of R. equi CFU between mice treated with clarithromycin monotherapy, rifampin monotherapy, or placebo. The combination of clarithromycin with rifampin conferred a clear advantage over either drug as monotherapy in this model of chronic R. equi infection. PMID- 25824220 TI - In vitro antibacterial activity of AZD0914 against human Mycoplasmas and Ureaplasmas. AB - In this study, susceptibilities were determined for AZD0914, a spiropyrimidinetrione DNA gyrase inhibitor, azithromycin, doxycycline, and levofloxacin against Mycoplasma and Ureaplasma species. The activity of AZD0914 was comparable to that of levofloxacin and doxycycline against Mycoplasma genitalium and Mycoplasma pneumoniae. The AZD0914 MIC90 against Mycoplasma hominis was 8-fold greater than that for levofloxacin. The AZD0914 MIC90 against Ureaplasma species was 4-fold less than that for azithromycin and 8-fold less than that for levofloxacin and doxycycline. PMID- 25824219 TI - Berberine blocks the relapse of Clostridium difficile infection in C57BL/6 mice after standard vancomycin treatment. AB - Vancomycin is a preferred antibiotic for treating Clostridium difficile infection (CDI) and has been associated with a rate of recurrence of CDI of as high as 20% in treated patients. Recent studies have suggested that berberine, an alternative medical therapy for gastroenteritis and diarrhea, exhibits several beneficial effects, including induction of anti-inflammatory responses and restoration of the intestinal barrier function. This study investigated the therapeutic effects of berberine on preventing CDI relapse and restoring the gut microbiota in a mouse model. Berberine was administered through gavage to C57BL/6 mice with established CDI-induced intestinal injury and colitis. The disease activity index (DAI), mean relative weight, histopathology scores, and levels of toxins A and B in fecal samples were measured. An Illumina sequencing-based analysis of 16S rRNA genes was used to determine the overall structural change in the microbiota in the mouse ileocecum. Berberine administration significantly promoted the restoration of the intestinal microbiota by inhibiting the expansion of members of the family Enterobacteriaceae and counteracting the side effects of vancomycin treatment. Therapy consisting of vancomycin and berberine combined prevented weight loss, improved the DAI and the histopathology scores, and effectively decreased the mortality rate. Berberine prevented CDIs from relapsing and significantly improved survival in the mouse model of CDI. Our data indicate that a combination of berberine and vancomycin is more effective than vancomycin alone for treating CDI. One of the possible mechanisms by which berberine prevents a CDI relapse is through modulation of the gut microbiota. Although this conclusion was generated in the case of the mouse model, use of the combination of vancomycin and berberine and represent a novel therapeutic approach targeting CDI. PMID- 25824221 TI - Clinical epidemiology and molecular analysis of extended-spectrum-beta-lactamase producing Escherichia coli in Nepal: characteristics of sequence types 131 and 648. AB - Recently, CTX-M-type extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli strains have emerged worldwide. In particular, E. coli with O antigen type 25 (O25) and sequence type 131 (ST131), which is often associated with the CTX-M-15 ESBL, has been increasingly reported globally; however, epidemiology reports on ESBL-producing E. coli in Asia are limited. Patients with clinical isolates of ESBL-producing E. coli in the Tribhuvan University teaching hospital in Kathmandu, Nepal, were included in this study. Whole-genome sequencing of the isolates was conducted to analyze multilocus sequence types, phylotypes, virulence genotypes, O25b-ST131 clones, and distribution of acquired drug resistance genes. During the study period, 105 patients with ESBL-producing E. coli isolation were identified, and the majority (90%) of these isolates were CTX-M-15 positive. The most dominant ST was ST131 (n = 54; 51.4%), followed by ST648 (n = 15; 14.3%). All ST131 isolates were identified as O25b-ST131 clones, subclone H30-Rx. Three ST groups (ST131, ST648, and non-ST131/648) were compared in further analyses. ST648 isolates had a proportionally higher resistance to non beta-lactam antibiotics and featured drug-resistant genes more frequently than ST131 or non-ST131/648 isolates. ST131 possessed the most virulence genes, followed by ST648. The clinical characteristics were similar among groups. More than 38% of ESBL-producing E. coli isolates were from the outpatient clinic, and pregnant patients comprised 24% of ESBL-producing E. coli cases. We revealed that the high resistance of ESBL-producing E. coli to multiple classes of antibiotics in Nepal is driven mainly by CTX-M-producing ST131 and ST648. Their immense prevalence in the communities is a matter of great concern. PMID- 25824222 TI - Sphingolipids mediate differential echinocandin susceptibility in Candida albicans and Aspergillus nidulans. AB - The cell wall synthesis-inhibiting echinocandins, including caspofungin and micafungin, play important roles in the treatment of candidiasis and aspergillosis. Previous studies revealed that, in the haploid yeast Candida glabrata, sphingolipid biosynthesis pathway mutations confer caspofungin reduced susceptibility (CRS) but micafungin increased susceptibility (MIS). Here, we describe one Candida albicans strain (of 10 tested) that similarly yields CRS-MIS mutants at relatively high frequency. Mutants demonstrated increased levels of long-chain bases (sphingolipid pathway intermediates) and, unique to this strain, loss of His104/Pro104 heterozygosity in the TSC13-encoded enoyl reductase. CRS MIS was similarly observed in a C. albicans homozygous fen1Delta fen12Delta laboratory strain and in diverse wild-type strains following exogenous long-chain base treatment. Analogous to these results, CRS-MIS was demonstrated in an Aspergillus nidulans basA mutant encoding defective sphingolipid C4-hydroxylase and in its wild-type parent exposed to long-chain bases. Sphingolipids likely modulate echinocandin interaction with their Fks membrane target in all susceptible fungi, with potential implications for optimizing therapy with existing antifungals and the development of novel agents. PMID- 25824223 TI - PBP1a/LpoA but not PBP1b/LpoB are involved in regulation of the major beta lactamase gene blaA in Shewanella oneidensis. AB - beta-Lactamase production is one of the most important strategies for Gram negative bacteria to combat beta-lactam antibiotics. Studies of the regulation of beta-lactamase expression have largely been focused on the class C beta-lactamase AmpC, whose induction by beta-lactams requires LysR-type regulator AmpR and permease AmpG-dependent peptidoglycan recycling intermediates. In Shewanella, which is ubiquitous in aquatic environments and is a reservoir for antibiotic resistance, production of the class D beta-lactamase BlaA confers bacteria with natural resistance to many beta-lactams. Expression of the blaA gene in the genus representative Shewanella oneidensis is distinct from the AmpC paradigm because of the lack of an AmpR homologue and the presence of an additional AmpG independent regulatory pathway. In this study, using transposon mutagenesis, we identify proteins that are involved in blaA regulation. Inactivation of mrcA and lpoA, which encode penicillin binding protein 1a (PBP1a) and its lipoprotein cofactor, LpoA, respectively, drastically enhances blaA expression in the absence of beta-lactams. Although PBP1b and its cognate, LpoB, also exist in S. oneidensis, their roles in blaA induction are dispensable. We further show that the mrcA-mediated blaA expression is independent of AmpG. PMID- 25824226 TI - Identification of a new integron harboring bla(IMP-10) in carbapenem-resistant Acinetobacter baumannii clinical isolates. PMID- 25824225 TI - Polymorphic variation in susceptibility and metabolism of triclosan-resistant mutants of Escherichia coli and Klebsiella pneumoniae clinical strains obtained after exposure to biocides and antibiotics. AB - Exposure to biocides may result in cross-resistance to other antimicrobials. Changes in biocide and antibiotic susceptibilities, metabolism, and fitness costs were studied here in biocide-selected Escherichia coli and Klebsiella pneumoniae mutants. E. coli and K. pneumoniae mutants with various degrees of triclosan susceptibility were obtained after exposure to triclosan (TRI), benzalkonium chloride (BKC), chlorhexidine (CHX) or sodium hypochlorite (SHC), and ampicillin or ciprofloxacin. Alterations in antimicrobial susceptibility and metabolism in mutants were tested using Phenotype MicroArrays. The expression of AcrAB pump and global regulators (SoxR, MarA, and RamA) was measured by quantitative reverse transcription-PCR (qRT-PCR), and the central part of the fabI gene was sequenced. The fitness costs of resistance were assessed by a comparison of relative growth rates. Triclosan-resistant (TRI(r)) and triclosan-hypersusceptible (TRI(hs)) mutants of E. coli and K. pneumoniae were obtained after selection with biocides and/or antibiotics. E. coli TRI(r) mutants, including those with mutations in the fabI gene or in the expression of acrB, acrF, and marA, exhibited changes in susceptibility to TRI, CHX, and antibiotics. TRI(r) mutants for which the TRI MIC was high presented improved metabolism of carboxylic acids, amino acids, and carbohydrates. In TRI(r) mutants, resistance to one antimicrobial provoked hypersusceptibility to another one(s). TRI(r) mutants had fitness costs, particularly marA-overexpressing (E. coli) or ramA-overexpressing (K. pneumoniae) mutants. TRI, BKC, and CIP exposure frequently yielded TRI(r) mutants exhibiting alterations in AraC-like global regulators (MarA, SoxR, and RamA), AcrAB-TolC, and/or FabI, and influencing antimicrobial susceptibility, fitness, and metabolism. These various phenotypes suggest a trade-off of different selective processes shaping the evolution toward antibiotic/biocide resistance and influencing other adaptive traits. PMID- 25824227 TI - Meropenem-clavulanic acid has high in vitro activity against multidrug-resistant Mycobacterium tuberculosis. AB - We investigated the activity of meropenem-clavulanic acid (MEM-CLA) against 68 Mycobacterium tuberculosis isolates. We included predominantly multi- and extensively drug-resistant tuberculosis (MDR/XDR-TB) isolates, since the activity of MEM-CLA for resistant isolates has previously not been studied extensively. Using Middlebrook 7H10 medium, all but four isolates showed an MIC distribution of 0.125 to 2 mg/liter for MEM-CLA, below the non-species-related breakpoint for MEM of 2 mg/liter defined by EUCAST. MEM-CLA is a potential treatment option for MDR/XDR-TB. PMID- 25824224 TI - Prospective multicenter study of carbapenemase-producing Enterobacteriaceae from 83 hospitals in Spain reveals high in vitro susceptibility to colistin and meropenem. AB - The aim of this study was to determine the impact of carbapenemase-producing Enterobacteriaceae (CPE) in Spain in 2013 by describing the prevalence, dissemination, and geographic distribution of CPE clones, and their population structure and antibiotic susceptibility. From February 2013 to May 2013, 83 hospitals (about 40,000 hospital beds) prospectively collected nonduplicate Enterobacteriaceae using the screening cutoff recommended by EUCAST. Carbapenemase characterization was performed by phenotypic methods and confirmed by PCR and sequencing. Multilocus sequencing types (MLST) were determined for Klebsiella pneumoniae and Escherichia coli. A total of 702 Enterobacteriaceae isolates met the inclusion criteria; 379 (54%) were CPE. OXA-48 (71.5%) and VIM-1 (25.3%) were the most frequent carbapenemases, and K. pneumoniae (74.4%), Enterobacter cloacae (10.3%), and E. coli (8.4%) were the species most affected. Susceptibility to colistin, amikacin, and meropenem was 95.5%, 81.3%, and 74.7%, respectively. The most prevalent sequence types (STs) were ST11 and ST405 for K. pneumoniae and ST131 for E. coli. Forty-five (54.1%) of the hospitals had at least one CPE case. For K. pneumoniae, ST11/OXA-48, ST15/OXA-48, ST405/OXA-48, and ST11/VIM-1 were detected in two or more Spanish provinces. ST11 isolates carried four carbapenemases (VIM-1, OXA-48, KPC-2, and OXA-245), but ST405 isolates carried OXA-48 only. A wide interregional spread of CPE in Spain was observed, mainly due to a few successful clones of OXA-48-producing K. pneumoniae (e.g., ST11 and ST405). The dissemination of OXA-48-producing E. coli is a new finding of public health concern. According to the susceptibilities determined in vitro, most of the CPE (94.5%) had three or more options for antibiotic treatment. PMID- 25824228 TI - In vitro activities of amphotericin B, terbinafine, and azole drugs against clinical and environmental isolates of Aspergillus terreus sensu stricto. AB - The antifungal susceptibilities of 40 clinical and environmental isolates of A. terreus sensu stricto to amphotericin B, terbinafine, itraconazole, and voriconazole were determined in accordance with CLSI document M38-A2. All isolates had itraconazole and voriconazole MICs lower than epidemiologic cutoff values, and 5% of the isolates had amphotericin B MICs higher than epidemiologic cutoff values. Terbinafine showed the lowest MICs. No significant differences were found when MICs of clinical and environmental isolates were compared. PMID- 25824229 TI - Encoded library technology screening of hepatitis C virus NS4B yields a small molecule compound series with in vitro replicon activity. AB - To identify novel antivirals to the hepatitis C virus (HCV) NS4B protein, we utilized encoded library technology (ELT), which enables purified proteins not amenable to standard biochemical screening methods to be tested against large combinatorial libraries in a short period of time. We tested NS4B against several DNA-encoded combinatorial libraries (DEL) and identified a single DEL feature that was subsequently progressed to off-DNA synthesis. The most active of the initial synthesized compounds had 50% inhibitory concentrations (IC50s) of 50 to 130 nM in a NS4B radioligand binding assay and 300 to 500 nM in an HCV replicon assay. Chemical optimization yielded compounds with potencies as low as 20 nM in an HCV genotype 1b replicon assay, 500 nM against genotype 1a, and 5 MUM against genotype 2a. Through testing against other genotypes and genotype 2a-1b chimeric replicons and from resistance passage using the genotype 1b replicon, we confirmed that these compounds were acting on the proposed first transmembrane region of NS4B. A single sequence change (F98L) was identified as responsible for resistance, and it was thought to largely explain the relative lack of potency of this series against genotype 2a. Unlike other published series that appear to interact with this region, we did not observe sensitivity to amino acid substitutions at positions 94 and 105. The discovery of this novel compound series highlights ELT as a valuable approach for identifying direct-acting antivirals to nonenzymatic targets. PMID- 25824230 TI - Efficacy of tigecycline for secondary Acinetobacter bacteremia and factors associated with treatment failure. AB - We describe the clinical outcome of 17 patients with secondary Acinetobacter bacteremia whose isolates had a tigecycline MIC of <=2 mg/liter and who received tigecycline within 2 days of bacteremia onset. The 14-day mortality rate of the tigecycline cohort was 41.2% (7/17), which was significantly higher than that of those receiving other appropriate antimicrobial agents (13.8%, 9/65; P = 0.018). However, the percentages of end-stage renal disease and congestive heart failure were higher in the tigecycline cohort. The efficacy of tigecycline was contingent upon the illness severity and bacterial species. Tigecycline should be applied cautiously for treatment of Acinetobacter bacteremia. PMID- 25824231 TI - Reduced viral fitness and lack of cross-class resistance with integrase strand transfer inhibitor and nucleoside reverse transcriptase inhibitor resistance mutations. AB - The most common pattern of emergent resistance in the phase III clinical trials of coformulated elvitegravir (EVG)-cobicistat (COBI)-emtricitabine (FTC) tenofovir disoproxil fumarate (TDF) was the EVG resistance substitution E92Q in integrase (IN) with the FTC resistance substitution M184V in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R. In this study, the effect of these IN and RT substitutions alone and in combination in the same genome on susceptibility to antiretroviral inhibitors and viral replication fitness was characterized. Single resistance substitutions (E92Q in IN [IN-E92Q], M184V in RT [RT-M184V], and K65R in RT [RT-K65R]) specifically affected susceptibility to the corresponding inhibitor classes, with no cross-class resistance observed. The IN-E92Q mutant displayed reduced susceptibility to EVG (50-fold), which was not impacted by the addition of RT M184V or RT-K65R/M184V. Viruses containing RT-M184V had high-level resistance to FTC (>1,000-fold) that was not affected by the addition of IN-E92Q or RT-K65R. During pairwise growth competitions, each substitution contributed to decreased viral fitness, with the RT-K65R/M184V + IN-E92Q triple mutant being the least fit in the absence of drug. In the presence of drug concentrations approaching physiologic levels, however, drug resistance offset the replication defects, resulting in single mutants outcompeting the wild type with one drug present, and double and triple mutants outcompeting single mutants with two drugs present. Taken together, these results suggest that the reduced replication fitness and phenotypic resistance associated with RT and IN resistance substitutions are independent and additive. In the presence of multiple drugs, viral growth is favored for viruses with multiple substitutions, despite the presence of fitness defects. PMID- 25824232 TI - Candida albicans Cek1 mitogen-activated protein kinase signaling enhances fungicidal activity of salivary histatin 5. AB - Candida albicans is a major etiological organism for oropharyngeal candidiasis (OPC), while salivary histatin 5 (Hst 5) is a human fungicidal protein that protects the oral cavity from OPC. C. albicans senses its environment by mitogen activated protein kinase (MAPK) activation that can also modulate the activity of some antifungal drugs, including Hst 5. We found that phosphorylation of the MAPK Cek1, induced either by N-acetylglucosamine (GlcNAc) or serum, or its constitutive activation by deletion of its phosphatase Cpp1 elevated the susceptibility of C. albicans cells to Hst 5. Cek1 phosphorylation but not hyphal formation was needed for increased Hst 5 sensitivity. Interference with the Cek1 pathway by deletion of its head sensor proteins, Msb2 and Sho1, or by addition of secreted aspartyl protease (SAP) cleavage inhibitors, such as pepstatin A, reduced Hst 5 susceptibility under Cek1-inducing conditions. Changes in fungal cell surface glycostructures also modulated Hst 5 sensitivity, and Cek1-inducing conditions resulted in a higher uptake rate of Hst 5. These results show that there is a consistent relationship between activation of Cek1 MAPK and increased Hst 5 susceptibility in C. albicans. PMID- 25824233 TI - Decrease of vancomycin resistance in Enterococcus faecium isolates from bloodstream infections in Italy from 2003 to 2013. PMID- 25824234 TI - Identification of multiresistance gene cfr in methicillin-resistant Staphylococcus aureus from pigs: plasmid location and integration into a staphylococcal cassette chromosome mec complex. AB - The multiresistance gene cfr was found in 8/231 porcine methicillin-resistant Staphylococcus aureus isolates. They were characterized by multilocus sequence typing, spa typing, dru typing, and staphylococcal cassette chromosome mec (SCCmec) typing as ST627-t002-dt12w-IVb, ST6-t304-dt12w-IVb, ST9-t899-dt12w-IVb, ST9-t899-dt12ae-IVb, or ST63-t899-dt12v-IVb. Different cfr gene regions were detected on plasmids of ca. 35 kb in seven isolates. For the first time, an ISEnfa4-cfr-IS256 fragment was found to be inserted upstream of the ccr genes in a chromosomal SCCmec IVb element of the remaining isolate. PMID- 25824235 TI - Reduced ADAMTS13 activity is associated with thrombotic risk in systemic lupus erythematosus. AB - BACKGROUND: Severe deficiency of ADAMTS13 activity leads to von Willebrand factor (VWF) ultralarge multimers with high affinity for platelets, causing thrombotic thrombocytopenic purpura. Other pathological conditions with moderate ADAMTS13 activity exhibit a thrombotic risk. We examined the ADAMTS13 activity in systemic lupus erythematosus (SLE) and its value as a thrombotic biomarker. METHODS: ADAMTS13 activity, VWF antigen and multimeric structure, and vascular cell adhesion molecule 1 (VCAM-1) were measured in plasma samples from 50 SLE patients and 50 healthy donors. Disease activity (systemic lupus erythematosus disease activity index; SLEDAI) and organ damage (systemic lupus international collaborating clinics) scores, thrombotic events, antiphospholipid syndrome (APS) and antiphospholipid antibodies (aPLs) were registered. RESULTS: SLE patients showed decreased ADAMTS13 activity and high VWF levels compared with controls (66 +/- 27% vs. 101 +/- 8%, P < 0.01, and 325 +/- 151% vs. 81 +/- 14%, P < 0.001). VCAM-1 levels were higher in SLE patients (P < 0.05). Considering three groups of SLE patients depending on ADAMTS13 activity (>60%, 60-40% and <40%), comparative analysis showed significant association between ADAMTS13 activity and SLEDAI (P < 0.05), presence of aPLs (P < 0.001), APS (P < 0.01) and thrombotic events (P < 0.01). Reduced ADAMTS13 activity together with increased VWF levels were especially notable in patients with active disease and with aPLs. CONCLUSION: ADAMTS13 activity, in combination with other laboratory parameters, could constitute a potential prognostic biomarker of thrombotic risk in SLE. PMID- 25824236 TI - What are frailty instruments for? AB - Frailty is measured to understand its nature and biology, to aid diagnosis and care planning, to measure outcomes and to stratify risk. Such goals oblige two types of frailty measures - for screening and for assessment - and recognition that not all measures will serve all purposes. When the goal is broad identification of people at risk, a dichotomised approach (frailty is present or absent ) is appropriate. If, however, the degree of risk varies, strategies to test grades of frailty will be required. Frailty measures should be implemented and evaluated in relation to the goal for their use. PMID- 25824237 TI - The effects of glucose-lowering therapies on diabetic kidney disease. AB - Chronic hyperglycemia and its associated metabolic products are key factors responsible for the development and progression of diabetic chronic kidney disease (CKD). Endocrinologists are tasked with detection and management of early CKD before patients need referral to a nephrologist for advanced CKD or dialysis evaluation. Primary care physicians are increasingly becoming aware of the importance of managing hyperglycemia to prevent or delay progression of CKD. Glycemic control is an integral part of preventing or slowing the advancement of CKD in patients with diabetes; however, not all glucose-lowering agents are suitable for this patient population. The availability of the latest information on treatment options may enable physicians to thwart advancement of serious renal complication in patients suffering from diabetes. This review presents clinical data that shed light on the risk/benefit profiles of three relatively new antidiabetes drug classes, the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 analogs, and sodium glucose co-transporter 2 inhibitors, particularly for patients with diabetic CKD, and summarizes the effects of these therapies on renal outcomes and glycemic control for endocrinologists and primary care physicians. Current recommendations for screening and diagnosis of CKD in patients with diabetes are also discussed. PMID- 25824238 TI - Immunosuppression and Post-transplant Hyperglycemia. AB - BACKGROUND: Post-transplant diabetes mellitus is a significant risk factor for cardiovascular disease in solid organ transplantation. The main underlying pathophysiological mechanism of PTDM is pancreatic beta cell dysfunction in the context of insulin resistance, but the relative importance of each of these important components of glycemic metabolism is under intense debate. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials to January 15, 2015. We selected systematic reviews and meta-analyses and randomized clinical trials. When no such reports were found for a given topic or drug, observational studies were included in the assessment. RESULTS: There are agents with known diabetogenic effects: corticosteroids, calcineurin inhibitors including tacrolimus and cyclosporine, as well as the mammalian target of rapamycin inhibitors (sirolimus and everolimus). The association between the use of induction agents and PTDM is very scarce. No diabetogenic effects have been found with the use of azathioprine, mycophenolate mofetil and its derivatives. CONCLUSION: Immunosuppression is the major modifiable risk factor for development of PTDM but risk versus benefit analysis is required to balance risk of developing PTDM versus rejection. Caution is advisable in immunosuppressant adjustments in the event that PTDM develops based on current evidence. Physicians should choose and use immunosuppression regimens shown to have the best outcome for patient and graft survival, irrespective of PTDM risk. PMID- 25824239 TI - Does a Culture of Appalachia Truly Exist? AB - Some disagreement exists about whether an Appalachian culture exists. Common notions about Appalachia's people are tied to myths that disguise truths about those that claim a heritage tied to place. Living in the region is different from having multiple generations of ancestors and a family legacy associated with place. Conclusions suggest that cultural traits of some residents are recognizable as unique from others in the nation's mainstream, but they are not generalizable to all people living in the Appalachian region. PMID- 25824240 TI - Of mice and men: The factor H protein family and complement regulation. AB - For decades immunological research has relied, with variable success, on mouse models to investigate diseases and possible therapeutic interventions. With the approval of the first therapeutic antibody targeting complement, called eculizumab, as therapy in paroxysmal nocturnal hemoglobinuria (PNH) and more recently atypical hemolytic uremic syndrome (aHUS), the viability of targeting the complement system was demonstrated. The potent, endogenous complement regulators have become of increasing interest as templates for designing and developing new therapeutics. Recently, complement inhibitors based on (parts of) the human complement regulator factor H (FH) are being examined for therapeutic intervention in inflammatory conditions. The first step to evaluate the potency of a new drug is often testing it in a mouse model for the target disease. However, translating results to human conditions requires a good understanding of similarities and, more importantly, differences between the human and mouse complement system and particularly regulation. This review will provide a comprehensive overview of the complement regulator FH and its closely related proteins and current views on their role in mice and men. PMID- 25824241 TI - Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells. AB - Growing evidence suggests that the efficacy of sunitinib in breast cancer may be limited by increasing the population of cancer stem-like cells (CSCs). Hence the concurrent use of CSCs-targeting agents is required. Previous results indicated that dopamine receptor (DR) may serve as a potential therapeutic target of anti CSCs therapies. This study focused on evaluating the effect of dopamine (an agonist of DR) on the enhancement of sunitinib's efficacy in the treatment of drug-resistant breast cancer, investigating the involved activation type of DR pathway and exploring the underlying anti-CSCs mechanisms. MCF-7 cells, MCF-7/Adr cells and breast cancer stem-like cells (BCSCs) were used for in vitro study. Moreover, MCF-7/Adr cells and BCSCs were selected as drug-resistant cell lines and further used for in vivo development of the xenograft animal models. Our results showed that dopamine greatly synergized the inhibitory effect of sunitinib in the drug-resistant cells and strikingly enhanced the response of sunitinib in both xenograft models. It was found that dopamine significantly down regulated the expression of BCSCs markers (CD44(+)/CD24(-)) in vitro and in vivo. In addition, dopamine remarkably induced the apoptosis of BCSCs, markedly inhibited the Wnt signaling pathway and activated the apoptotic associated signals. The activation of dopamine receptor D1 (D1DR) pathway may be involved in the underlying mechanism as D1DR's antagonist SCH23390 completely reversed the combined effects. In conclusion, dopamine may eradicate CSCs and it significantly enhances the response of sunitinib in the treatment of drug-resistant breast cancer. PMID- 25824242 TI - Ascorbic acid decomposition into oxalate ions: a simple synthetic route towards oxalato-bridged heterometallic 3d-4f clusters. AB - Two types of oxalato-bridged heterometallic 3d-4f dodeca- and hexanuclear compounds have been obtained by connecting six bi- and, respectively, trinuclear moieties through oxalato bridges arising from the slow decomposition of the L ascorbic acid. PMID- 25824243 TI - Therapeutic effects of growth hormone combined with low-dose stanozolol on growth velocity and final height of girls with Turner syndrome. AB - OBJECTIVE: Turner syndrome (TS), which is characterized by short stature and gonadal dysfunction, is managed by pharmacotherapy. This study aimed to investigate the therapeutic effects of recombinant human growth hormone (rhGH) combined with low-dose stanozolol on the growth and final adult height (FAH) of girls with Turner syndrome (TS). DESIGN: Prospective study. PATIENTS: A total of 44 girls with TS were treated with rhGH (47.6-52.4 MUg/kg/day) and low-dose stanozolol (20-35 MUg/kg/day), starting at a mean age of 12.65 +/- 1.99 year. The control group consisted of 22 girls with TS, who did not receive treatment. MEASUREMENTS: Subjects' growth velocity (GV) was investigated. Height standard deviation score (HtSDS) was calculated relative to healthy Chinese girls (HtSDSN or ) as well as untreated Chinese girls with TS (HtSDSTS ). Post-treatment follow up was performed until the subjects achieved FAH or near FAH. RESULTS: FAH was significantly higher in subjects receiving treatment compared to the untreated controls (151.42 vs 137.75 cm, P < 0.001). GV was significantly higher in the first to fourth years of treatment compared to baseline values (P < 0.001); it was significantly lower in the second to fourth years of treatment compared to the first year (P < 0.001). CONCLUSIONS: In girls with TS, 9-12 years of age, rhGH combined with low-dose stanozolol may effectively increase growth. At least a 2-year course of this treatment may effectively improve FAH with proper delay of oestrogen-induced development. PMID- 25824244 TI - Patient factors contributing to variation in same-hospital readmission rate. AB - The Centers for Medicare & Medicaid Services Hospital Readmission Reduction Program and the Centers for Medicare & Medicaid Innovations Bundled Payments for Care Improvement Initiative hold hospitals accountable for readmissions that occur at other hospitals. A few studies have described the extent to which hospital readmissions occur at the original place of treatment (i.e., same hospital readmissions). This study uses data from 16 states to describe variation in same-hospital readmissions by patient characteristics across multiple conditions. We found that the majority of 30-day readmissions occur at the same hospital, although rates varied considerably by condition. A significant number of hospitals had very low rates of same-hospital readmissions, meaning that the majority of their readmissions went to other hospitals. Future research should examine why some hospitals are able to retain patients for a same-hospital readmission and others are not. PMID- 25824245 TI - Blood pressure responses to renal denervation precede and are independent of the sympathetic and baroreflex effects. AB - It is still largely unknown whether the neuroadrenergic responses to renal denervation (RD) are involved in its blood pressure (BP)-lowering effects and represent predictors of the BP responses to RD. In 15 treated true resistant hypertensives, we measured before and 15 days, 1, 3, and 6 months after RD clinic, ambulatory and beat-to-beat BP. Measurements included muscle sympathetic nerve traffic (MSNA), spontaneous baroreflex-MSNA sensitivity, and various humoral and metabolic variables. Twelve treated hypertensives served as controls. BP, which was unaffected 15 days after RD, showed a significant decrease during the remaining follow-up period. MSNA and baroreflex did not change at 15-day and 1-month follow-up and showed, respectively, a decrease and a specular increase at 3 and 6 months after RD. No relationship, however, was detected between baseline MSNA and baroreflex, MSNA changes and BP changes. At the 6-month follow-up, the MSNA reduction was similar for magnitude in patients displaying a BP reduction greater or lower the median value. Similarly, the BP reduction detected 6 months after RD was similar in patients displaying a MSNA reduction greater or lower median value. No significant BP and MSNA changes were detected in the control group. Thus, the BP reduction associated with RD seems to precede the MSNA changes and not to display a temporal, qualitative, and quantitative relationship with the MSNA and baroreflex effects. Given the small sample size of the present study further investigations are warranted to confirm the present findings. PMID- 25824246 TI - Central aortic blood pressure from ultrasound wall-tracking of the carotid artery in children: comparison with invasive measurements and radial tonometry. AB - Differences between central aortic root (c) and peripheral (p) systolic blood pressure (SBP) may be particularly marked in children, but noninvasive methods for assessing cSBP in children have not been validated. We compared estimates of cSBP obtained from radiofrequency ultrasound wall tracking of the carotid artery (ART.LAB system) with that measured directly by a catheter in the aortic root at the time of arterial cannulation. Carotid waveforms were calibrated from invasive measurements of mean and diastolic pressures. In 9 children aged 10.5 +/- 5.0 years (mean +/- SD), cSBP obtained from carotid wall tracking was highly correlated with invasive measures of cSBP (r=0.99) with mean (+/- SD) difference 3.9 +/- 2.5 mm Hg. Second, we compared values of cSBP obtained from the carotid with those obtained using noninvasive applanation tonometry at the radial artery and a radial-to-aortic transfer function (SphygmoCor). Both carotid and radial tonometric measurements were calibrated from the same peripheral mean and diastolic measurements of blood pressure obtained by sphygmomanometry. In 84 children aged 13.2 +/- 3.2 years, there was excellent agreement between the 2 methods (r=0.95; P<0.001) with mean difference 0.71 +/- 3.7 mm Hg (95% confidence interval =-1.53 to 1.01). This invasive validation study confirms that cSBP as estimated by carotid wall tracking provides an acceptable measurement of true cSBP when calibration is from true mean and diastolic pressures. Close agreement of cSBP obtained by carotid wall tracking and radial tonometry suggests that these provide similar results when calibrated from the same peripheral blood pressure measurements. PMID- 25824247 TI - Independent associations of circulating galectin-3 concentrations with aortic pulse wave velocity and wave reflection in a community sample. AB - Although the profibrotic inflammatory substance galectin-3 predicts outcomes in the general population, the mechanisms responsible for this effect are uncertain. We aimed to determine whether circulating galectin-3 concentrations are associated with carotid femoral (aortic) pulse wave velocity and aortic reflective wave index (applanation tonometry and SphygmoCor software) in 966 randomly selected participants from a community sample. Galectin-3 concentrations were not independently associated with office (n=966) or 24-hour (n=661) systolic (P=0.88-0.92) or diastolic (P=0.65-0.94) blood pressure. In contrast, with adjustments for age, sex (in all participants), office or 24-hour mean arterial pressure (or systolic blood pressure and pulse pressure), pulse rate, body mass index, regular smoking, regular alcohol intake, total cholesterol concentrations, diabetes mellitus or an glycohemoglobin >6.1%, treatment for hypertension, and estimated glomerular filtration rate, galectin-3 was independently associated with aortic pulse wave velocity in all participants (partial r=0.15, P<0.0001) and reflective wave index in men (partial r=0.13, P<0.02). In 745 participants who had never received antihypertensive therapy, galectin-3 concentrations were similarly independently associated with pulse wave velocity in all participants (partial=0.16, P<0.0001) and reflective wave index in men (partial r=0.15, P<0.02). The blood pressure-independent relations between galectin-3 concentrations and aortic hemodynamics persisted with further adjustments for C reactive protein concentrations (pulse wave velocity in all participants: partial r=0.14, P<0.0001; reflective wave index in men: partial r=0.12, P<0.05). In conclusion, despite a lack of independent association with brachial blood pressure, the profibrotic inflammatory substance galectin-3 may contribute toward adverse outcomes through an effect on aortic stiffness, an effect that cannot be attributed to general inflammatory changes. PMID- 25824248 TI - Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. AB - Few data are available with regard to the effectiveness of renal sympathetic denervation in patients with resistant hypertension yet only mildly elevated blood pressure (BP). Patients with resistant hypertension and slightly elevated BP (day-time systolic pressure, 135-149 and diastolic pressure, 90-94 mm Hg on 24 hour ambulatory measurement) were randomized in a 1:1 ratio to renal sympathetic denervation with the Symplicity Flex Catheter (Medtronic) or an invasive sham procedure. The primary efficacy end point was the change in 24-hour systolic BP at 6 months between groups in the intention to treat population. A total of 71 patients underwent randomization. Baseline day-time systolic BP was 144.4+/-4.8 mm Hg in patients assigned to denervation and 143.0+/-4.7 mm Hg in patients randomized to the sham procedure. The mean change in 24-hour systolic BP in the intention to treat cohort at 6 months was -7.0 mm Hg (95% confidence interval, 10.8 to -3.2) for patients undergoing denervation and -3.5 mm Hg (95% confidence interval, -6.7 to -0.2) in the sham group (P=0.15). In the per protocol population, the change in 24-hour systolic BP at 6 months was -8.3 mm Hg (95% confidence interval, -11.7 to -5.0) for patients undergoing denervation and -3.5 mm Hg (95% confidence interval, -6.8 to -0.2) in the sham group (P=0.042). In patients with mild resistant hypertension, renal sympathetic denervation failed to show a significant reduction in the primary end point of 24-hour systolic BP at 6 months between groups in the intention to treat analysis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01656096. PMID- 25824249 TI - The Physicochemical and Pharmacokinetic Relationships of Barbiturates - From the Past to the Future. AB - The pharmacokinetics of different barbiturates have been studied extensively and the relationship of their duration of action to their clinical use has been known for decades. While these particular compounds have largely been displaced by agents with better therapeutic indices, barbiturate use remains relatively common and important in both inpatient and outpatient settings. Their mechanism of action is to bind to inhibitory GABAA receptors in the CNS causing and potentiating the opening of neuronal chloride ion channels thus having a sedative and CNS depressant effect. All psychotropic barbiturates feature di-substitution at the C5 position of the barbituric acid prototype. This is also the primary factor by which physiologically active barbiturates differ from one another and a major mediator of lipophilicity and duration of action. However, in this review, inconsistencies in certain commonly held notions about the structure-activity relationship of barbiturates were found. Commonly accepted chemistry for the structure-activity relationship of barbiturates holds that substitution of larger alkyl groups, alicyclic, and aromatic groups, as well as branching and unsaturation, lead in general to more lipophilic compounds with a shorter biological half-life. This rationale may have limitations in the case of barbiturates as proposed in this review. There is poor correlation between nine clinically used barbiturates' octanol:water partition coefficients (log(P) values) and their respective half-lives. However, a strong correlation between pKa values and half-life was found. The current clinical relevance of these findings is discussed as well as their pertinence to future design and use of barbiturates. PMID- 25824250 TI - Role of Rhizomys pruinosus as a natural animal host of Penicillium marneffei in Guangdong, China. AB - Penicillium marneffei, a dimorphic fungus that can cause penicilliosis marneffei, is endemic in Southeast Asia. The only known hosts of P. marneffei are humans and bamboo rats. The aim of our study was to explore the distribution of P. marneffei in bamboo rats, their associated environment and non-rat-associated environments. Totally, 270 samples were collected in Guangdong province of China in 2012; the prevalence of P. marneffei was much higher in samples collected from surrounding areas of burrows (8.2%) than in the samples obtained from non-rat-associated sites (2%) or artificial farms of bamboo rats (0%). There was no difference in P. marneffei isolated rate from different areas of Guangdong province. The infection is prevalent in all rats, and this fungus could be frequently seen in the rats' lungs. This study confirms that bamboo rat is the ecological niche of P. marneffei and hypothesizes that bamboo rats become infected by inhaling aerosolized conidia originating from environmental sources, rather than by the fecal-oral route or transplacental crossing. According to the result of no detection of P. marneffei in the artificial farm, the activity of bamboo rats might be more relevant to the distribution and dissemination of P. marneffei in natural environment. PMID- 25824251 TI - Persistent untreated Riga-Fede disease for 6 years. AB - Riga-Fede disease is an uncommon, benign, ulcerative condition due to dental trauma that can occur at any age. A 9-year-old boy with a painful tongue is presented. Physicians need to recognize Riga-Fede disease and Riga-Fede-like disease to intervene early. PMID- 25824252 TI - Livedoid vasculopathy and high levels of lipoprotein (a): response to danazol. AB - Livedoid vasculopathy (LV) is a thrombo occlusive disorder presenting with recurrent painful ulcers of lower extremities. Association of LV with increased level of lipoprotein (a) (LP(a)), a risk factor for cardiovascular disease, has been reported. Danazol has been used with success in the management of LV, but none of the previous studies looked at the correlation between response to the treatment and level of LP(a). The aim of this study was to demonstrate the efficacy of low-dose danazol in the treatment of LV and its effects on LP(a). We present four cases with LV who were successfully treated with low-dose danazol, assessing the clinical characteristics and laboratory tests including the level of LP(a). The average age of the patients was 45 years and the mean duration of the disease was 19 years. The treatment regime of danazol 200 mg daily led to complete healing of ulcers and reduction in pain and a 70% (ranging from 52 to 87%) reduction in the level of LP(a). The limitation of this study is "small sample size." In our patients with LV, low-dose danazol led to clinical improvement along with significant reduction in the level of LP(a). PMID- 25824253 TI - Examining the influence of family dynamics on quality of care by informal caregivers of patients with Alzheimer's dementia in Argentina. AB - PURPOSE: This study examined the pattern of family dynamics of Argentinian individuals with dementia that most heavily influences the quality of care provided by family caregivers (CGs). METHOD: One hundred and two CGs of individuals with Alzheimer's disease in Argentina participated in this study. The majority (75%) were female, with an average age of 57.8 years (standard deviation = 13.5) and had spent a median of 48 months (interquartile range [IQR]: 36.00 60.00) providing care to their family member with dementia, devoting a median of 60 hours (IQR: 50.00-80.00) per week to these duties. Caregivers completed Spanish versions of instruments assessing their family dynamics and quality-of care provision. RESULTS: Hierarchical regression analyses suggested that higher quality of informal care (Provide and Respect) was related to greater levels of empathy and reduced levels of overall dysfunction in CGs' families. Higher quality of care-Provide was also related to shorter duration of time (in months) spent providing care. CONCLUSION: Dementia CG interventions in Latino populations would likely benefit from addressing difficulties experienced when providing care for a prolonged period of time, as well as programming or techniques to improve family dynamics, especially family empathy and general functioning, given the strong reciprocal influence of these factors on CG quality of care. PMID- 25824254 TI - ACR Appropriateness Criteria Imaging in the Diagnosis of Thoracic Outlet Syndrome. AB - Thoracic outlet syndrome is a clinical entity characterized by compression of the neurovascular bundle, and may be associated with additional findings such as venous thrombosis, arterial stenosis, or neurologic symptoms. The goal of imaging is to localize the site of compression, the compressing structure, and the compressed organ or vessel, while excluding common mimics. A literature review is provided of current indications for diagnostic imaging, with discussion of potential limitations and benefits of the respective modalities. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. In this document, we provided guidelines for use of various imaging modalities for assessment of thoracic outlet syndrome. PMID- 25824255 TI - Methyl-branched lipids promote the membrane adsorption of alpha-synuclein by enhancing shallow lipid-packing defects. AB - Alpha-synuclein (AS) is a synaptic protein that is directly involved in Parkinson's disease due to its tendency to form protein aggregates. Since AS aggregation can be dependent on the interactions between the protein and the cell plasma membrane, elucidating the membrane binding properties of AS is of crucial importance to establish the molecular basis of AS aggregation into toxic fibrils. Using a combination of in vitro reconstitution experiments based on Giant Unilamellar Vesicles (GUVs), confocal microscopy and all-atom molecular dynamics simulations, we have investigated the membrane binding properties of AS, with a focus on the relative contribution of hydrophobic versus electrostatic interactions. In contrast with previous observations, we did not observe any binding of AS to membranes containing the ganglioside GM1, even at relatively high GM1 content. AS, on the other hand, showed a stronger affinity for neutral flat membranes consisting of methyl-branched lipids. To rationalize these results, we used all-atom molecular dynamics simulations to investigate the influence of methyl-branched lipids on interfacial membrane properties. We found that methyl-branched lipids promote the membrane adsorption of AS by creating shallow lipid-packing defects to a larger extent than polyunsaturated and monounsaturated lipids. Our findings suggest that methyl-branched lipids may constitute a remarkably adhesive substrate for peripheral proteins that adsorb on membranes via hydrophobic insertions. PMID- 25824256 TI - Guideline on the management of acute chest syndrome in sickle cell disease. PMID- 25824257 TI - Spatial dispersion of lone electron pairs?--experimental charge density of cubic arsenic(III) oxide. AB - The first experimental charge density study of arsenolite, a cubic polymorph of arsenic(III) oxide, extended by periodic DFT calculations is reported. The presence of weak AsO interactions is confirmed and their topological characterization based on experimental electron density is provided. Spatial dispersion of arsenic lone electron pairs into three domains is observed in the Laplacian of electron density as well as in the electron localization function. It results from the clustering of As atomic cores in the crystal structure and/or from the presence of strong As-O bonds. A similar phenomenon is recognized in the crystal structures of antimonates(III) and bismuthates(III) of alkaline metals indicating that this could be a more general feature worthy of further investigations. PMID- 25824258 TI - Sensitivity and specificity of the AdenoPlus point-of-care system in detecting adenovirus in conjunctivitis patients at an ophthalmic emergency department: a diagnostic accuracy study. AB - BACKGROUND: To estimate the diagnostic accuracy (sensitivity and specificity) of the AdenoPlus point-of-care adenoviral test compared to PCR in an ophthalmic accident and emergency service. These findings were compared with those of a previous study. METHODS: This was a prospective diagnostic accuracy study on 121 patients presenting to an emergency eye unit with a clinical picture of acute adenoviral conjunctivitis. AdenoPlus testing was carried out on one eye of each patient and a PCR analysis was also performed on a swab taken from the same eye. AdenoPlus and PCR results were interpreted by masked personnel. Sensitivity and specificity for the AdenoPlus test were calculated using PCR results as the reference standard. RESULTS: 121 patients were enrolled and 109 met the inclusion criteria. 43 patients (39.4%) tested positive for adenovirus by PCR analysis. The sensitivity of the AdenoPlus swab in detecting adenovirus was 39.5% (17/43, 95% CI 26% to 54%) and specificity was 95.5% (63/66, 95% CI 87% to 98%) compared to PCR. CONCLUSIONS: The AdenoPlus test has a high specificity for diagnosing adenoviral conjunctivitis, but in this clinical setting, we could not reproduce the high sensitivity that has been previously published. PMID- 25824259 TI - Aqueous penetration of orally and topically administered moxifloxacin. AB - AIM: To assess the intraocular penetration of 0.5% moxifloxacin hydrochloride into aqueous humour after oral and topical administration. METHODS: A prospective, interventional study of 42 patients scheduled to undergo cataract surgery was carried out. Out of the 42 subjects, 21 were randomly categorised into Group I and received one drop of 0.5% topical moxifloxacin four times, at 15 min intervals starting 75 min before the surgery. Another 21 subjects were categorised into Group II and all subjects in this group were administered a single tablet of 400 mg of moxifloxacin, 12 h before the surgery. Estimation of moxifloxacin in aqueous samples was carried out using high-performance liquid chromatography. Results were analysed using Student unpaired 't' test and analysis of variance. The value of p<0.05 was considered to be significant. RESULTS: Mean aqueous concentration of moxifloxacin attained in the oral group (n=21) was 0.504+/-0.30 MUg/mL while that in the topical group (n=21) was 2.04+/ 0.72 MUg/mL, and this difference in levels was statistically significant (p<0.005). The levels attained by both the groups well exceeded the MIC90 (minimum inhibitory concentration of antibiotic required to inhibit growth of 90% of bacteria strains) levels for most of the organisms causing endophthalmitis. Penetration of moxifloxacin in aqueous in both the groups was not affected by gender, intraocular pressure or comorbidities significantly. However, aqueous levels were found to be higher among the younger subjects within the topical group. CONCLUSIONS: Moxifloxacin has an impressive spectrum of coverage and this pharmacokinetic study reinforces its potential as a prophylactic drug against intraocular infections, given the high aqueous levels post topical administration. PMID- 25824260 TI - Comparison of central and peripheral corneal thickness measurements with scanning slit, Scheimpflug and Fourier-domain ocular coherence tomography. AB - PURPOSE: To compare central, regional and relational corneal thickness values obtained with multiple technologies in normal patients and to determine their equivalence and interchangeability. METHODS: Retrospective analysis of 100 eyes from 50 patients evaluated by ultrasound pachymetry (Pachette II), scanning-slit (Orbscan II), Scheimpflug (Pentacam HR) and spectral-domain ocular coherence tomography (OCT) (RTVue-100) obtained as average values (OCT-A) and point measurements (OCT-P). Measurements included central corneal thickness (CCT) for all technologies and thinnest corneal thickness for scanning-slit, Scheimpflug and OCT. Peripheral thickness measurements were obtained at the 3 mm radius in the superior (S), nasal (N), inferior (I) and temporal (T) regions. RESULTS: CCT values were: 563.9+/-36.1MU ultrasound, 570.9+/-36.1MU scanning-slit, 552.8+/ 33.8MU Scheimpflug, 550.5+/-32.7MU (OCT-A), 549.4+/-32.7MU (OCT-P). Ultrasound and scanning-slit were significantly different from each other (p<0.0001), and both were significantly different from all other devices (p<0.0001), while Scheimpflug was similar to OCT-A and OCT-P (p=0.4). Differences between CCT and thinnest corneal thickness were significantly different from all technologies except scanning-slit and OCT-A. For peripheral values, almost all locations' measurements were significantly different from one another (p<0.0001). Superior inferior values and ratios were also significantly different from one another for almost all devices with no consistent patterns detectible. CONCLUSIONS: There are significant clinically relevant differences between regional and relational thickness measurements obtained with ultrasound, scanning-slit, Scheimpflug and OCT devices. Screening metrics devised for one system do not appear directly applicable to other measurement systems. PMID- 25824261 TI - Superfamily of genes encoding G protein-coupled receptors in the diamondback moth Plutella xylostella (Lepidoptera: Plutellidae). AB - G protein-coupled receptors (GPCRs) are the largest and most versatile superfamily of cell membrane proteins, which mediate various physiological processes including reproduction, development and behaviour. The diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae), is one of the most notorious insect pests, preferentially feeding on cruciferous plants. P. xylostella is not only one of the world's most widespread lepidopteran insects, but has also developed resistance to nearly all classes of insecticides. Although the mechanisms of insecticide resistance have been studied extensively in many insect species, few investigations have been carried out on GPCRs in P. xylostella. In the present study, we identified 95 putative GPCRs in the P. xylostella genome. The identified GPCRs were compared with their homologues in Bombyx mori and Drosophila melanogaster. Our results suggest that GPCRs in different insect species may have evolved by a birth-and-death process. One of the differences among compared insects is the duplication of short neuropeptide F receptor and adipokinetic hormone receptors in P. xylostella and B. mori. Another divergence is the decrease in quantity and diversity of the stress-tolerance gene, Mth, in P. xylostella. The evolution by the birth-and-death process is probably involved in adaptation to the feeding behaviour, reproduction and stress responses of P. xylostella. Some of the genes identified in the present study could be potential targets for the development of novel pesticides. PMID- 25824262 TI - Loss of FOXF2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma Patients. AB - BACKGROUND: FOXF2 is a member of the forkhead box (FOX) family of transcription factors. FOXF2 plays an important role in several tumors but its expression and role in hepatocellular carcinoma (HCC) remains unknown. METHODS: Using immunohistochemistry, western blot, and real-time polymerase chain reaction, we analyzed FOXF2 expression in 295 clinicopathologically characterized HCC cases. Using RNA interference (RNAi), we investigated the effects of FOXF2 depletion on tumor cell behavior in vitro. Statistical analyses were used to determine associations between FOXF2 levels, tumor features, and patient outcomes. RESULTS: FOXF2 downregulation was observed in HCC tissues (p < 0.001) compared with peritumorous tissues, and its expression levels were closely correlated with overall survival and recurrence-free survival (p = 0.023 and 0.006, respectively) in patients with HCC. RNAi-mediated silencing of the FOXF2 gene in the MHCC-97H cell line significantly promoted proliferation and anti-apoptosis. CONCLUSIONS: The results of the present study indicate that FOXF2 may serve as a prognostic biomarker for HCC and may be a promising target in the treatment of patients with HCC. PMID- 25824263 TI - The role of endoscopy in the diagnosis of gastric gastrointestinal stromal tumors. PMID- 25824264 TI - Interfacial Electron Transfer Barrier at Compact TiO2 /CH3 NH3 PbI3 Heterojunction. AB - Low-temperature solution-processed CH3 NH3 PbI3 interfaced with TiO2 has recently been demonstrated as a highly successful type-II light harvesting heterojunction with ~20% efficiency. Therefore, an efficient ultrafast photoexcited electron transfer from CH3 NH3 PbI3 to TiO2 is expected. However, by probing the photoexcited charge carrier dynamics in CH3 NH3 PbI3 /quartz, CH3 NH3 PbI3 /TiO2 (compact), and CH3 NH3 PbI3 /PCBM in a comparative study, an electron transfer potential barrier between CH3 NH3 PbI3 and the compact TiO2 (prepared with the spray pyrolysis method) formed by surface states is uncovered. Consequently, the CH3 NH3 PbI3 photoluminescence intensity and lifetime is enhanced when interfaced to compact TiO2 . The electron accumulation within CH3 NH3 PbI3 needed to overcome this interfacial potential barrier results in the undesirable large current-voltage hysteresis observed for CH3 NH3 PbI3 /TiO2 planar heterojunctions. The findings in this study indicate that careful surface engineering to reduce this potential barrier is key to pushing perovskite solar cell efficiencies toward the theoretical limit. PMID- 25824265 TI - Digit ratio (2D:4D), aggression, and dominance in the Hadza and the Datoga of Tanzania. AB - OBJECTIVES: Digit ratio (2D:4D)-a putative marker of prenatal androgen activity has been shown to correlate with self-reported physical aggression and dominance behavior, especially in male children and adolescents. This evidence is derived primarily from the study of Western samples. METHODS: Digit ratios, self-reported aggression, and dominance behavior were collected from men and women in two traditional, small-scale societies, i.e., the Hadza and the Datoga of Tanzania. RESULTS: We found significant differences in physical and verbal aggression, anger, and hostility between the two societies with the Datoga reporting higher scores on all four measures. Moreover, self-reported dominance in the Datoga was higher than in the Hadza. The Datoga showed lower left and right hand 2D:4D ratios than the Hadza. Men reported higher physical and verbal aggression and dominance, and had lower 2D:4D ratios than women. A significant negative association between 2D:4D and dominance was found in Hadza women. CONCLUSIONS: We discuss our findings with reference to differences in mating systems between the two small-scale societies and previous findings of Western and other small-scale societies. PMID- 25824266 TI - Hierarchical Vanadium Pentoxide Spheres as High-Performance Anode Materials for Sodium-Ion Batteries. AB - We report the synthesis of hierarchical vanadium pentoxide (V2 O5 ) spheres as anode materials for sodium-ion batteries (Na-ion batteries). Through field emission scanning electron microscopy, X-ray diffraction, and transmission electron microscopy characterizations, it was found that the as-prepared V2 O5 spheres are composed of primary nanoparticles with pores between them. The as prepared hierarchical V2 O5 spheres achieved a discharge capacity of 271 mA h g( 1) at a current density of 40 mA g(-1) , and 177 mA h g(-1) discharge capacity after 100 cycles. Even at high current densities, V2 O5 spheres still delivered high capacity and superior cyclability (179 and 140 mA h g(-1) discharge capacities at 640 and 1280 mA g(-1) current densities, respectively). The promising electrochemical performances of V2 O5 spheres should be ascribed to the unique architecture of hierarchical spheres and the predominant exposed (110) facets, which provides open interlayers for facile sodium ion intercalation. Each nanoparticle contains predominantly exposed (110) crystal planes. The ex situ FESEM analysis revealed that the pores formed by the primary nanocrystals effectively buffer volume changes in the electrode during cycling, contributing to the excellent cycling performance. PMID- 25824267 TI - Designing a new model for cosmetic adverse reaction monitoring in China. AB - BACKGROUND: The monitoring of cosmetic adverse reactions (CARs) in China has progressed to a new stage of development because of government institutional reforms. OBJECTIVE: To discuss and formulate an appropriate model for CAR monitoring in China. METHODS: The formulation of a new CAR-monitoring model under the administration of the Food and Drug Supervision Department is discussed on the basis of China's current national conditions and with reference to the previous CAR-monitoring and drug-monitoring models of the organization formerly known as the Ministry of Health of the People's Republic of China. RESULTS: The preliminary design of the CAR-monitoring model is considered to be a long-term development goal of CAR monitoring. The monitoring model at this stage was developed on the basis of China's national conditions; specifically, the development of a two-level (national and provincial agencies) monitoring system that relies on CAR-monitoring sentinels, and reports that cover CARs with definite causal associations. CONCLUSION: This model is developed on both theoretical and practical foundations, and can function as a proper monitoring model at the initial stage of current CAR monitoring through an appropriate pilot programme, exploration, and improvement. PMID- 25824268 TI - Changes in Gross Tumor Volume and Organ Motion Analysis During Neoadjuvant Radiochemotherapy in Patients With Locally Advanced Pancreatic Cancer Using an In House Analysis System. AB - BACKGROUND AND PURPOSE: During radiation treatment, movement of the target and organs at risks as well as tumor response can significantly influence dose distribution. This is highly relevant in patients with pancreatic cancer, where organs at risk lie in close proximity to the target. MATERIAL AND METHODS: Data sets of 10 patients with locally advanced pancreatic cancer were evaluated. Gross tumor volume deformation was analyzed. Dose changes to organs at risk were determined with focus on kidneys both without adaptive radiotherapy compensation and with replanning based on weekly acquired computed tomography scans. RESULTS: During irradiation, gross tumor volume changes between 0% and 26% and moves within a radius of 5 to 16 mm. Required maximal dose to organs at risk for kidneys can be met with the current practice of matching computed tomography scans during treatment and adjusting patient position accordingly. Comparison of the mean doses and V15, V20 volumes demonstrated that weekly replanning could bring a significant dose sparing of the left kidney. CONCLUSION: Manual matching with focus on bony structures can lead to overall acceptable positioning of patients during treatment. Thus, tolerance doses of organs at risk, such as the kidneys, can be met. With adequate margins, normal tissue constraints to organs at risk can be kept as well. Adaptive radiotherapy approaches (in this case with weekly rescanning) reduced dose to organs at risk, which may be especially important for hypofractionated approaches. PMID- 25824269 TI - Does Imaging Technology Cause Cancer? Debunking the Linear No-Threshold Model of Radiation Carcinogenesis. AB - In the past several years, there has been a great deal of attention from the popular media focusing on the alleged carcinogenicity of low-dose radiation exposures received by patients undergoing medical imaging studies such as X-rays, computed tomography scans, and nuclear medicine scintigraphy. The media has based its reporting on the plethora of articles published in the scientific literature that claim that there is "no safe dose" of ionizing radiation, while essentially ignoring all the literature demonstrating the opposite point of view. But this reported "scientific" literature in turn bases its estimates of cancer induction on the linear no-threshold hypothesis of radiation carcinogenesis. The use of the linear no-threshold model has yielded hundreds of articles, all of which predict a definite carcinogenic effect of any dose of radiation, regardless of how small. Therefore, hospitals and professional societies have begun campaigns and policies aiming to reduce the use of certain medical imaging studies based on perceived risk:benefit ratio assumptions. However, as they are essentially all based on the linear no-threshold model of radiation carcinogenesis, the risk:benefit ratio models used to calculate the hazards of radiological imaging studies may be grossly inaccurate if the linear no-threshold hypothesis is wrong. Here, we review the myriad inadequacies of the linear no-threshold model and cast doubt on the various studies based on this overly simplistic model. PMID- 25824271 TI - Predicting the optimal entry point for femoral antegrade nailing using a new measurement approach. AB - PURPOSE: To establish a new reliable approach for measuring proximal femoral anatomical parameters and determining the optimal entry point of the antegrade intramedullary (IM) nailing. METHODS: A new method for measuring the proximal femoral anatomy and locating the optimal entry point for the antegrade nailing was developed using Mimics and 3-Matic softwares (Materialise, Haasrode, Belgium). After verifying the reliability of the measurement method using 15 pairs of the femoral models by the intraclass correlation coefficient, the anatomical parameters of 200 Chinese femurs were measured, and statistical analyses were performed to compare the proximal femoral anatomical parameters between different genders or lateralities and determine the most relevant factors of the optimal entry point. RESULTS: Reliability study showed that both intraobserver reliability and interobserver reliability of the current measurement approach were excellent. After independent samples [Formula: see text]-test, the proximal femoral anatomical parameters were shown significant difference between genders. Stepwise regression statistical analyses showed that the most relevant factors of the distances between the optimal entry point and the femoral head centre, the femoral neck axis and the tip of the greater trochanter were the 3D femoral neck-shaft angle (Pearson's [Formula: see text]; the model's [Formula: see text]), the femoral radius (Pearson's [Formula: see text]; the model's [Formula: see text]) and the femoral length (Pearson's r = 0.316; the model's [Formula: see text]), respectively. CONCLUSIONS: The current study provided a new and reliable measurement approach to evaluating the anatomical morphology of the proximal femur and revealed the most influential factors on the locations of the simulated optimal entry point for the proximal femoral antegrade IM nailing. Furthermore, this study was useful for establishing methodological basis for future researches and developments of the custom-made IM nailing and affiliated surgical instruments. PMID- 25824272 TI - Atypical clinicopathologic presentation of primary cutaneous diffuse large B-cell lymphoma, leg type. AB - BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma, leg type (cDLBCL-LT) is a well-defined entity of cutaneous B-cell lymphoma affecting predominantly elderly patients, mostly women. The typical clinical presentation is characterized by solitary or multiple, rapidly growing plaques or tumors on 1 leg (rarely both legs). OBJECTIVE: We sought to describe a new clinical variant of cDLBCL-LT that deviates from the conventional one. METHODS: Clinical, histopathologic, phenotypical, and molecular features of 3 cases of cDLBCL-LT presenting with patches or thin plaques were reviewed (all were women, aged 60, 62, and 87 years; lesions were located on the leg in all patients). RESULTS: These patients presented with patches or thin plaques that represented the first manifestation of cDLBCL-LT. All 3 patients reported a history of long-standing lesions (present for 6, 9, and 18 months, respectively). Histology revealed moderately dense, perivascular infiltrates of small lymphocytes admixed with variable numbers of large cells that were CD20(+), Bcl-2(+), and MUM-1(+). LIMITATIONS: There were only a small number of cases. CONCLUSIONS: We reported an unusual clinical presentation of cDLBCL-LT that deviates from the conventional one and that represents a formidable diagnostic challenge. Biopsy specimens of unusual patches/thin plaques or annular lesions should be obtained from the legs of adult patients if the lesions do not respond to conventional treatment. PMID- 25824273 TI - Genital psoriasis is associated with significant impairment in quality of life and sexual functioning. AB - BACKGROUND: Genital involvement has significant psychosexual implications for psoriasis patients. OBJECTIVE: This study was designed to ascertain factors associated with the development of genital psoriasis and its impact on quality of life and sexual functioning. METHODS: This was an observational, multicenter study of 354 consecutive psoriasis patients. RESULTS: One hundred thirty-four patients (38%) had current genital involvement while 224 (63%) had a current and/or previous history of genital involvement. Eighty-seven percent reported itch, 39% pain, 42% dyspareunia, 32% a worsening of their genital psoriasis after intercourse, and 43% a decreased frequency of intercourse. Younger age of onset of psoriasis, male sex, more severe disease, and involvement of the scalp, flexures, and nails were associated with the presence of genital disease. There was no association with circumcision or obesity. Patients with genital psoriasis had more impairment in quality of life and sexual health as determined by the Dermatology Life Quality Index (P < .0001), the Center for Epidemiological Studies-Depression Scale (P = .01), and the Relationship and Sexuality Scale (P < .0001). LIMITATIONS: This was a descriptive study from 2 tertiary referral centers where patients were likely to have more severe psoriasis. CONCLUSION: This study highlights the high prevalence of genital psoriasis and its profound impact on quality of life and sexual health. PMID- 25824274 TI - National utilization patterns of Mohs micrographic surgery for invasive melanoma and melanoma in situ. AB - BACKGROUND: Although wide local excision continues to be commonly used for melanoma treatment, Mohs micrographic surgery (MMS) for the treatment of melanomas remains controversial. OBJECTIVE: We sought to determine national utilization patterns for MMS in the treatment of invasive melanoma and melanoma in situ. METHODS: A retrospective analysis of patients receiving surgical excision (MMS or wide local excision) for the treatment of invasive melanoma and melanoma in situ was performed using data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. RESULTS: A total of 195,768 melanomas were diagnosed from 2003 through 2009 from the 17 SEER registries. Utilization of MMS for invasive melanoma and melanoma in situ increased by 60% from 2003 to 2008. Of all SEER-captured lesions treated by surgical excision in this time period, 3.5% (6872) were excised by MMS. LIMITATIONS: Patient insurance status, physician reimbursement practices, and health care provider type were not addressed in this article. CONCLUSION: Use of MMS for melanoma appears to be increasing. Future studies should explore whether this is associated with better outcomes. PMID- 25824275 TI - Clinical and dermoscopic characteristics of melanomas on nonfacial chronically sun-damaged skin. AB - BACKGROUND: Melanomas on chronically sun-damaged skin (CSDS) can be difficult to identify and often manifest morphologic features that overlap with benign lesions. OBJECTIVE: We describe and analyze the clinical and dermoscopic characteristics of melanomas on nonfacial CSDS. METHODS: Melanoma cases on nonfacial CSDS were retrospectively identified from the biopsy specimen logs of 6 melanoma clinics. Clinical and dermoscopic images were combined into 1 database. Demographics, clinical, dermoscopic, and histopathologic information were analyzed. Descriptive frequencies were calculated. RESULTS: One hundred eighty six cases met the inclusion criteria: 142 melanomas in situ (76%) and 39 invasive (21%; mean thickness, 0.49 mm). Lentigo maligna was the most common histopathologic subtype (n = 76; 40.9%). The most frequent dermoscopic structures were granularity (n = 126; 67.7%) and angulated lines (n = 82; 44%). Vascular structures were more frequent in invasive melanomas (56% vs 12% of in situ melanomas). Most manifested 1 of 3 dermoscopic patterns: patchy peripheral pigmented islands, angulated lines, and tan structureless with granularity pattern. LIMITATIONS: This was a retrospective study, and evaluators were not blinded to the diagnosis. In addition, interobserver concordance and sensitivity and specificity for dermoscopic structures were not evaluated. CONCLUSION: Outlier lesions manifesting dermoscopic structures, such as granularity, angulated lines, or vessels and any of the 3 described dermoscopic patterns should raise suspicion for melanoma. PMID- 25824276 TI - A Noninvasive and Speculative Method of Visualizing Latent Fingerprint Deposits on Thermal Paper. AB - Latent fingerprint deposits on thermal paper have been visualized noninvasively at visible wavelengths when illuminated with a UV-A light source (peak 365 nm). A higher intensity UV source (250 W/m(2) at 0.38 m) gave superior fingerprint visibility when compared with a 60 W/m(2) (at 0.4 m) source. Removing the visible (blue) component of the light source emission did not adversely affect the visibility of the fingerprint. Sample fingerprints from 100 donors, when examined 24 h after deposition, produced identifiable fingerprints from nearly 34% of fingerprint deposits. A mechanism for the observed visibility is proposed based on low emission of visible wavelengths from areas of thermal paper coincident with the fingerprint deposit, when illuminated with UV. This is likely due to a weak color change in the thermal paper dye arising from protonated amino acid components of the sweat. This effect was not observed on nonthermal paper. PMID- 25824277 TI - Diffuse brain abnormalities in myotonic dystrophy type 1 detected by 3.0 T proton magnetic resonance spectroscopy. AB - Patients with myotonic dystrophy type 1 (DM1) (n = 14) were compared with healthy controls (n = 13) using 3.0 T proton magnetic resonance spectroscopy ((1)H-MRS) to investigate brain pathophysiology. (1)H-MRS imaging revealed reduced N acetylaspartate to creatine ratio (NAA/Cr) in multiple brain regions (average 24%), suggesting diffuse brain abnormalities among patients with DM1. Single voxel (1)H-MRS among patients with DM1 showed (1) reduced NAA in both the frontal cortex (23%) and frontal white matter (31%) and unaltered myo-inositol, suggesting neuronal abnormalities without significant gliosis; and (2) elevated glutamine in the frontal cortex (36%) and reduced glutamate in the frontal white matter (20%) among patients with DM1, suggesting abnormalities in the glutamatergic system in the brain of patients with DM1. We consider that these results reflect brain abnormalities that cannot be detected by neuropathological assessment in patients with DM1. PMID- 25824278 TI - Induction of lcc2 expression and activity by Agaricus bisporus provides defence against Trichoderma aggressivum toxic extracts. AB - Laccases are used by fungi for several functions including defence responses to stresses associated with attack by other fungi. Laccase activity changes and the induction of two laccase genes, lcc1 and lcc2, in Agaricus bisporus were measured in response to toxic extracts of medium in which Trichoderma aggressivum, the cause of green mould disease, was grown. A strain of A. bisporus that shows resistance to the extracts showed higher basal levels and greater enzymatic activity after extract exposure than did a sensitive strain. Furthermore, pre incubation of T. aggressivum extract with laccases reduced toxicity. Faster induction and greater numbers of lcc2 transcripts in response to the extract were noted in the resistant strain than in the sensitive strain. The timing and increase in lcc2 transcript abundance mirrored changes in total laccase activity. No correlation between resistance and lcc1 transcription was apparent. Transcript abundance in transformants with a siRNA construct homologous to both genes varied widely. A strong negative correlation between transcript abundance and sensitivity of the transformant to toxic extract was observed in plate assays. These results indicated that laccase activity and in particular that encoded by lcc2 contributes to toxin metabolism and by extension green mould disease resistance. PMID- 25824279 TI - Frequent visualization of thyroglossal duct remnant on post-ablation 131I SPECT/CT and its clinical implications. AB - AIM: To evaluate the frequency of thyroglossal duct remnant (TGDR) uptake on post therapy (131)I-scintigraphy in thyroid cancer patients, to analyse the rate of persistent TGDR uptake on follow-up combined (131)I-single-photon emission CT/CT (SPECT/CT), and to identify the differential clinical characteristics between patients with positive and negative TGDR uptake on (131)I-SPECT/CT. MATERIALS AND METHODS: A total of 179 patients treated with total thyroidectomy for thyroid cancer were enrolled in the study. At (131)I-whole-body scan (WBS), TGDR uptake was defined as an increase in radioactivity at the midline of the neck versus the thyroid bed. TGDR uptake on (131)I- SPECT/CT was defined as the presence of radioactivity at the expected pathway of the thyroglossal duct without evidence of metastatic foci. Persistent TGDR uptake was confirmed when TGDR uptake on follow-up (131)I-SPECT/CT corresponded to previous TGDR uptake detected by post therapy (131)I-SPECT/CT. RESULTS: At SPECT/CT, TGDR uptake was noted in 86 of 179 patients. Stimulated thyroglobulin (sTg) levels were significantly higher (p = 0.02) in patients with positive TGDR uptake. Persistent TGDR uptake on follow-up (131)I-SPECT/CT was noted in 15 of 86 patients; sTg levels were significantly higher (p = 0.03) in the patients with persistent TGDR uptake. CONCLUSION: TGDR uptake is frequently visualized on post-therapy (131)I-SPECT/CT images and can be resistant to (131)I ablation. TGDR uptake has the potential to result in an elevation of serum thyroglobulin levels. (131)I-SPECT/CT clarifies TGDR uptake without additional invasive procedures or imaging studies, eliminating confusion among clinicians for managing differentiated thyroid cancer patients. PMID- 25824280 TI - Background parenchymal enhancement on breast MRI and mammographic breast density: correlation with tumour characteristics. AB - AIM: To investigate the relationship between mammographic breast density (MGD) and background parenchymal enhancement (BPE) at breast MRI and histopathological features of invasive breast cancers. MATERIALS AND METHODS: A total of 178 women with unilateral invasive breast cancer who preoperatively underwent mammography and breast MRI were included in the study. Two radiologists rated MGD and BPE according to BI-RADS criteria in consensus. The relationship between MGD and BPE was investigated, and compared with histopathological features of invasive breast cancers according to the level of MGD and BPE. RESULTS: At MRI, there is no significant difference in the distribution of MGD and BPE of the contralateral breast in women with invasive breast cancer according to menopausal status (p=0.226, 0.384). Women with high MGD (>50% glandular) were more likely to have oestrogen-receptor (ER)-positive breast cancer (p=0.045) and progesterone receptor (PR)-positive breast cancer (p=0.020). With regard to BPE, PR positivity correlated with moderate or marked BPE with borderline significance (p=0.054). Multivariate logistic regression analyses revealed that women with high MGD were less likely to have triple-negative (i.e., a cancer that is ER negative, PR negative, and human epidermal growth factor receptor type 2 [HER2] negative) breast cancer compared with ER (+)/HER2 (-) cancer (OR=0.231, 95% CI: 0.070, 0.760; p=0.016). No association between the histological tumour characteristics and BPE was observed. CONCLUSION: In women with invasive breast cancer, high MGD is associated with ER positivity of the invasive breast cancer. However, at MRI, BPE of the contralateral breast seems to be independent of tumour characteristics. PMID- 25824281 TI - Transbronchial cryobiopsy in the evaluation of interstitial lung diseases: Time for a positioning in the diagnostic work-up approach? PMID- 25824282 TI - Potential of lees from wine, beer and cider manufacturing as a source of economic nutrients: An overview. AB - Lees are the wastes generated during the fermentation and aging processes of different industrial activities concerning alcoholic drinks such as wine, cider and beer. They must be conveniently treated to avoid uncontrolled dumping which causes environmental problems due to their high content of phenols, pesticides, heavy metals, and considerable concentrations of nitrogen, phosphate and potassium as well as high organic content. The companies involved must seek alternative environmental and economic physicochemical and biological treatments for their revalorization consisting in the recovery or transformation of the components of the lees into high value-added compounds. After describing the composition of lees and market of wine, beer and cider industries in Spain, this work aims to review the recent applications of wine, beer and cider lees reported in literature, with special attention to the use of lees as an endless sustainable source of nutrients and the production of yeast extract by autolysis or cell disruption. Lees and/or yeast extract can be used as nutritional supplements with potential exploitation in the biotechnological industry for the production of natural compounds such as xylitol, organic acids, and biosurfactants, among others. PMID- 25824283 TI - Brightly Luminescent and Color-Tunable Colloidal CH3NH3PbX3 (X = Br, I, Cl) Quantum Dots: Potential Alternatives for Display Technology. AB - Organometal halide perovskites are inexpensive materials with desirable characteristics of color-tunable and narrow-band emissions for lighting and display technology, but they suffer from low photoluminescence quantum yields at low excitation fluencies. Here we developed a ligand-assisted reprecipitation strategy to fabricate brightly luminescent and color-tunable colloidal CH3NH3PbX3 (X = Br, I, Cl) quantum dots with absolute quantum yield up to 70% at room temperature and low excitation fluencies. To illustrate the photoluminescence enhancements in these quantum dots, we conducted comprehensive composition and surface characterizations and determined the time- and temperature-dependent photoluminescence spectra. Comparisons between small-sized CH3NH3PbBr3 quantum dots (average diameter 3.3 nm) and corresponding micrometer-sized bulk particles (2-8 MUm) suggest that the intense increased photoluminescence quantum yield originates from the increase of exciton binding energy due to size reduction as well as proper chemical passivations of the Br-rich surface. We further demonstrated wide-color gamut white-light-emitting diodes using green emissive CH3NH3PbBr3 quantum dots and red emissive K2SiF6:Mn(4+) as color converters, providing enhanced color quality for display technology. Moreover, colloidal CH3NH3PbX3 quantum dots are expected to exhibit interesting nanoscale excitonic properties and also have other potential applications in lasers, electroluminescence devices, and optical sensors. PMID- 25824284 TI - Global analysis of fungal morphology exposes mechanisms of host cell escape. AB - Developmental transitions between single-cell yeast and multicellular filaments underpin virulence of diverse fungal pathogens. For the leading human fungal pathogen Candida albicans, filamentation is thought to be required for immune cell escape via induction of an inflammatory programmed cell death. Here we perform a genome-scale analysis of C. albicans morphogenesis and identify 102 negative morphogenetic regulators and 872 positive regulators, highlighting key roles for ergosterol biosynthesis and N-linked glycosylation. We demonstrate that C. albicans filamentation is not required for escape from host immune cells; instead, macrophage pyroptosis is driven by fungal cell-wall remodelling and exposure of glycosylated proteins in response to the macrophage phagosome. The capacity of killed, previously phagocytized cells to drive macrophage lysis is also observed with the distantly related fungal pathogen Cryptococcus neoformans. This study provides a global view of morphogenetic circuitry governing a key virulence trait, and illuminates a new mechanism by which fungi trigger host cell death. PMID- 25824287 TI - Necrotising fasciitis secondary to perforated rectal adenocarcinoma presenting as a thigh swelling. AB - A 62-year-old man was admitted to the medical admissions ward with right thigh pain presumed to be a deep vein thrombosis (DVT). Subsequent duplex ultrasonography excluded a DVT but noted the presence of a significant amount of subcutaneous gas. A plain film radiograph was performed with the same finding raising the possibility of necrotising fasciitis (NF). Only at this point was digital rectal examination performed revealing a large rectal mass oozing pus and blood. CT imaging showed thickening of the rectum consistent with a tumour with gas and fluid in the perirectal space extending to the anterolateral right femur. Despite aggressive debridement and treatment, the patient deteriorated and died 6 weeks later. This case should serve as a reminder to consider digital rectal examination and the occurrence of a rectal perforation in all patients who present with suspicious thigh swellings. PMID- 25824286 TI - Fulminant necrotising fasciitis by community-acquired methicillin-resistant Staphylococcus aureus. AB - Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a rare cause of necrotising fasciitis (NF), and is usually not fulminant as in group A Streptococcus (GAS), the archetypal aetiology. We report an unusually fulminant case of NF by CA-MRSA in an immunocompetent patient. A 52-year-old man presented to the emergency department with 1 week of progressive left thigh pain and swelling. The patient had ecchymoses, bullae and hypoesthesia of the involved skin, and CT scan revealed extensive fascial oedema. He was immediately started on broad spectrum antibiotics. Within 12 h of presentation, he underwent surgical debridement. Despite aggressive supportive care, the patient died less than 24 h after presentation. MRSA, with an antibiogram suggestive of a community-acquired strain, was recovered from intraoperative specimens and admission blood cultures. This case underscores that CA-MRSA, while rarely reported, can cause a fulminant presentation of NF similar to GAS in immunocompetent patients. PMID- 25824288 TI - A rash during surgery: rounding up the usual suspects. PMID- 25824285 TI - Molecular and physiological effects of environmental UV radiation on fungal conidia. AB - Conidia are specialized structures produced at the end of the asexual life cycle of most filamentous fungi. They are responsible for fungal dispersal and environmental persistence. In pathogenic species, they are also involved in host recognition and infection. Conidial production, survival, dispersal, germination, pathogenicity and virulence can be strongly influenced by exposure to solar radiation, although its effects are diverse and often species dependent. UV radiation is the most harmful and mutagenic waveband of the solar spectrum. Direct exposure to solar radiation for a few hours can kill conidia of most fungal species. Conidia are killed both by solar UV-A and UV-B radiation. In addition to killing conidia, which limits the size of the fungal population and its dispersion, exposures to sublethal doses of UV radiation can reduce conidial germination speed and virulence. The focus of this review is to provide an overview of the effects of solar radiation on conidia and on the major systems involved in protection from and repair of damage induced by solar UV radiation. The efforts that have been made to obtain strains of fungi of interest such as entomopathogens more tolerant to solar radiation will also be reviewed. PMID- 25824289 TI - Clinical efficacy of autologous stem cell transplantation for the treatment of patients with type 2 diabetes mellitus: a meta-analysis. AB - BACKGROUND AIMS: In this study, we investigate whether bone marrow mononuclear cells (BM-MNC) or peripheral blood mononuclear cells (PB-MNC) have therapeutic efficacy in type 2 diabetes (T2D). METHODS: Search terms included stem cell, bone marrow cell, peripheral blood cell, umbilical cord blood and T2D in MEDLINE, the Cochrane Controlled Trials Register, EMBASE, the Wanfang Database, the China Science and Technology Periodical Database and China Journal Net. RESULTS: Fifteen trials met our inclusion criteria (n = 497). One group included 266 cases with BM-MNC therapy and the other group contained 231 cases with PB-MNC treatment. Glycosylated hemoglobin was decreased after BM-MNC or PB-MNC therapy compared with that before (12 months: P < 0.001; 6 months: P < 0.001; 3 months: P < 0.05). Fasting plasma glucose was reduced in BM-MNC therapy group compared with control after 12-month follow-up (P < 0.001) and after BM-MNC therapy compared with that before (9 months: P < 0.001) but was not obvious in other stages. Meanwhile, the analysis showed that C-peptide level increased after BM-MNC and PB MNC therapy compared with the control therapy (12 months: P < 0.001) and with that before therapy (6 months: P < 0.05). Insulin requirement reduction was also observed in patients receiving BM-MNC therapy (3, 6, 9 and 12 months: P < 0.05). CONCLUSIONS: To a certain extent, BM-MNC or PB-MNC therapy for T2D demonstrated superiority of glycemic control, increased insulin biosynthesis and elevated insulin secretion from existing beta-cells and might prevent islet cell loss. PMID- 25824292 TI - Recognizing the importance of new tools and resources for research. PMID- 25824291 TI - CaRuby-Nano: a novel high affinity calcium probe for dual color imaging. AB - The great demand for long-wavelength and high signal-to-noise Ca(2+) indicators has led us to develop CaRuby-Nano, a new functionalizable red calcium indicator with nanomolar affinity for use in cell biology and neuroscience research. In addition, we generated CaRuby-Nano dextran conjugates and an AM-ester variant for bulk loading of tissue. We tested the new indicator using in vitro and in vivo experiments demonstrating the high sensitivity of CaRuby-Nano as well as its power in dual color imaging experiments. PMID- 25824290 TI - A library of MiMICs allows tagging of genes and reversible, spatial and temporal knockdown of proteins in Drosophila. AB - Here, we document a collection of ~7434 MiMIC (Minos Mediated Integration Cassette) insertions of which 2854 are inserted in coding introns. They allowed us to create a library of 400 GFP-tagged genes. We show that 72% of internally tagged proteins are functional, and that more than 90% can be imaged in unfixed tissues. Moreover, the tagged mRNAs can be knocked down by RNAi against GFP (iGFPi), and the tagged proteins can be efficiently knocked down by deGradFP technology. The phenotypes associated with RNA and protein knockdown typically correspond to severe loss of function or null mutant phenotypes. Finally, we demonstrate reversible, spatial, and temporal knockdown of tagged proteins in larvae and adult flies. This new strategy and collection of strains allows unprecedented in vivo manipulations in flies for many genes. These strategies will likely extend to vertebrates. PMID- 25824293 TI - Does low-molecular-weight heparin influence the antimyeloma effects of thalidomide? A retrospective analysis of data from the GIMEMA, Nordic and Turkish myeloma study groups. AB - BACKGROUND/AIM: Low-molecular-weight heparin (LMWH) has been shown to prolong survival among patients with solid tumors, but its role among myeloma patients is unknown. PATIENTS: Data from the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto), Nordic and Turkish myeloma study groups comparing melphalan and prednisolone with (MPT, n: 404) or without thalidomide (MP, n: 393) are analyzed for effects of LMWH. Forty percent (159/394) of the patients on MPT and 7.4% (29/390) in the MP arm received LMWH. RESULTS: Thalidomide improved response and progression-free survival (PFS). Regardless of thalidomide treatment, response rate was higher among those receiving LMWH vs. none vs. other anticoagulants (58.1 vs. 44.9 vs. 50.4%, p = 0.01). PFS was significantly longer (median 32 vs. 21 and 17 vs. 17 months, p = 0.004) only among international scoring system (ISS) I patients receiving MPT +/- LMWH vs. MP +/- LMWH. The group of MPT patients who also received LMWH had a better OS compared to those who did not [45 months, 95% confidence interval (CI) 27.7-62.3, vs. 32 months, 95% CI 26.1-37.9; p = 0.034]. When multivariate analysis was repeated in subgroups, thalidomide was no longer a significant factor (response, PFS) among those receiving LMWH. CONCLUSION: Addition of LMWH to MPT, in particular in patients with low ISS, suggests additive effects, but the results are limited by the retrospective design of our study. PMID- 25824294 TI - Esophageal and Gastric Cancer Pearl: a nationwide clinical biobanking project in the Netherlands. AB - Esophageal and gastric cancer is associated with a poor prognosis since many patients develop recurrent disease. Treatment requires specific expertise and a structured multidisciplinary approach. In the Netherlands, this type of expertise is mainly found at the University Medical Centers (UMCs) and a few specialized nonacademic centers. Aim of this study is to implement a national infrastructure for research to gain more insight in the etiology and prognosis of esophageal and gastric cancer and to evaluate and improve the response on (neoadjuvant) treatment. Clinical data are collected in a prospective database, which is linked to the patients' biomaterial. The collection and storage of biomaterial is performed according to standard operating procedures in all participating UMCs as established within the Parelsnoer Institute. The collected biomaterial consists of tumor biopsies, blood samples, samples of malignant and healthy tissue of the resected specimen and biopsies of recurrence. The collected material is stored in the local biobanks and is encoded to respect the privacy of the donors. After approval of the study was obtained from the Institutional Review Board, the first patient was included in October 2014. The target aim is to include 300 patients annually. In conclusion, the eight UMCs of the Netherlands collaborated to establish a nationwide database of clinical information and biomaterial of patients with esophageal and gastric cancer. Due to the national coverage, a high number of patients are expected to be included. This will provide opportunity for future studies to gain more insight in the etiology, treatment and prognosis of esophageal and gastric cancer. PMID- 25824295 TI - Evaluation of bone regeneration with biphasic calcium phosphate substitute implanted with bone morphogenetic protein 2 and mesenchymal stem cells in a rabbit calvarial defect model. AB - OBJECTIVE: The aim of this study was to evaluate the in vivo osteogenic potential of biphasic calcium phosphate (BCP), bone morphogenetic protein 2 (BMP-2), and/or mesenchymal stem cell (MSC) composites by using a rabbit calvarial defect model. STUDY DESIGN: Bone formation was assessed by using three different kinds of implants in rabbit calvarial defects, BCP alone, BCP/recombinant human (rh) BMP 2, and BCP/rhBMP-2/MSCs composite. The implants were harvested after 2 or 8 weeks, and the area of new bone formation was quantified by micro-computed tomography (micro-CT) and histologic studies. RESULTS: The highest bone formation was achieved with the BCP/rhBMP-2/MSCs treatment, and it was significantly higher than that achieved with the empty or BCP-alone treatment. The quantity of new bone at 8 weeks was greater than at 4 weeks in each group. The relative density of osteocalcin immunoreactivity also increased during this interval. CONCLUSIONS: These results indicate that the combination of BCP, rhBMP-2, and MSCs synergistically enhances osteogenic potential during the early healing period and could be used as a bone graft substitute. PMID- 25824296 TI - Oral Candida carriage among individuals chewing betel-quid with and without tobacco. PMID- 25824297 TI - CXCR4 attenuates cardiomyocytes mitochondrial dysfunction to resist ischaemia reperfusion injury. AB - The chemokine (C-X-C motif) receptor 4 (CXCR4) is expressed on native cardiomyocytes and can modulate isolated cardiomyocyte contractility. This study examines the role of CXCR4 in cardiomyocyte response to ischaemia-reperfusion (I/R) injury. Isolated adult rat ventricular cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) to simulate I/R injury. In response to H/R injury, the decrease in CXCR4 expression was associated with dysfunctional energy metabolism indicated by an increased adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratio. CXCR4-overexpressing cardiomyocytes were used to determine whether such overexpression (OE) can prevent bio-energetic disruption-associated cell death. CXCR4 OE was performed with adenoviral infection with CXCR4 encoding gene or non-translated nucleotide sequence (Control). The increased CXCR4 expression was observed in cardiomyocytes post CXCR4-adenovirus transduction and this OE significantly reduced the cardiomyocyte contractility under basal conditions. Although the same extent of H/R-provoked cytosolic calcium overload was measured, the hydrogen peroxide-induced decay of mitochondrial membrane potential was suppressed in CXCR4 OE group compared with control group, and the mitochondrial swelling was significantly attenuated in CXCR4 group, implicating that CXCR4 OE prevents permeability transition pore opening exposure to overload calcium. Interestingly, this CXCR4-induced mitochondrial protective effect is associated with the enhanced signal transducer and activator of transcription 3 (expression in mitochondria. Consequently, in the presence of H/R, mitochondrial dysfunction was mitigated and cardiomyocyte death was decreased to 65% in the CXCR4 OE group as compared with the control group. I/R injury leads to the reduction in CXCR4 in cardiomyocytes associated with the dysfunctional energy metabolism, and CXCR4 OE can alleviate mitochondrial dysfunction to improve cardiomyocyte survival. PMID- 25824298 TI - Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study. AB - Gamma-butyric acid (GABA) dysfunction has been implicated in the pathophysiology of schizophrenia and its cognitive deficits. Proton magnetic resonance spectroscopy (MRS) was used to test the hypothesis that older participants with schizophrenia have lower anterior cingulate GABA levels compared with older control participants. One-hundred forty-five participants completed this study. For detection of GABA, spectra were acquired from the medial frontal/anterior cingulate cortex using a macromolecule-suppressed MEGA-PRESS sequence. Patients were evaluated for psychopathology and all participants completed neuropsychological tests of working memory, processing speed and functional capacity. GABA levels were significantly lower in the older participants with schizophrenia (n=31) compared with the older control (n=37) group (P=0.003) but not between the younger control (n=40) and schizophrenia (n=29) groups (P=0.994). Age strongly predicted GABA levels in the schizophrenia group accounting for 42% of the variance, but the effect of age was less in the control group accounting for 5.7% of the variance. GABA levels were specifically related to working memory but not processing speed performance, functional capacity, or positive or negative symptom severity. This is the largest MRS study of GABA in schizophrenia and the first to examine GABA without macromolecule contamination, a potentially significant issue in previous studies. GABA levels more rapidly declined with advancing age in the schizophrenia compared with the control group. Interventions targeted at halting the decline or increasing GABA levels may improve functional outcomes and quality of life as patients with schizophrenia age. PMID- 25824299 TI - Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments. AB - Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs. PMID- 25824300 TI - Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome. AB - Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay. Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony stimulating factor 2 and interleukin 17F, without effects on interleukin 1alpha or interleukin 1beta, suggesting a disturbance in interleukin 1 signaling. Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity. PMID- 25824301 TI - Durable fear memories require PSD-95. PMID- 25824302 TI - Whole-genome association analysis of treatment response in obsessive-compulsive disorder. AB - Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 * 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 * 10(-6) and 8.41 * 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed. PMID- 25824303 TI - Kraepelin revisited: schizophrenia from degeneration to failed regeneration. AB - One hundred years after its conceptual definition as 'Dementia Praecox' by Emil Kraepelin, schizophrenia is still a serious psychiatric illness that affects young adults and leads to disability in at least half of patients. The key treatment issue is partial or non-response, especially of negative symptoms. The illness is also associated with different degrees of cognitive dysfunction, particularly in verbal and working memory; the resulting functional impairment may lead to unemployment and an inability to maintain stable relationships. Patients' cognitive dysfunction led Kraepelin to the assumption that schizophrenia is a form of juvenile dementia caused by a degenerative process of the human brain. Postmortem studies and a plethora of imaging studies do not support the notion of a degenerative process, but such a process is supported by the recently published, largest genome-wide association study on schizophrenia. More than a 100 hits were described, converging on pathways that have a significant role in dopamine metabolism in immune modulation, calcium signalling and synaptic plasticity. This review suggests that research should focus on animal models based on risk genes like transcription factor 4 and study the effects of exposure to environmental stressors relevant for schizophrenia. The use of relevant end points like pre-pulse inhibition or cognitive dysfunction will allow us to gain an understanding of the molecular pathways in schizophrenia and consequently result in improved treatment options, especially for the disabling aspects of this illness. PMID- 25824304 TI - Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa. AB - Individuals with anorexia nervosa (AN) restrict eating and become emaciated. They tend to have an aversion to foods rich in fat. Because epoxide hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared with controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment. PMID- 25824306 TI - Telling true from false: cannabis users show increased susceptibility to false memories. AB - Previous studies on the neurocognitive impact of cannabis use have found working and declarative memory deficits that tend to normalize with abstinence. An unexplored aspect of cognitive function in chronic cannabis users is the ability to distinguish between veridical and illusory memories, a crucial aspect of reality monitoring that relies on adequate memory function and cognitive control. Using functional magnetic resonance imaging, we show that abstinent cannabis users have an increased susceptibility to false memories, failing to identify lure stimuli as events that never occurred. In addition to impaired performance, cannabis users display reduced activation in areas associated with memory processing within the lateral and medial temporal lobe (MTL), and in parietal and frontal brain regions involved in attention and performance monitoring. Furthermore, cannabis consumption was inversely correlated with MTL activity, suggesting that the drug is especially detrimental to the episodic aspects of memory. These findings indicate that cannabis users have an increased susceptibility to memory distortions even when abstinent and drug-free, suggesting a long-lasting compromise of memory and cognitive control mechanisms involved in reality monitoring. PMID- 25824305 TI - The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy. AB - Brain-derived neurotrophic factor (BDNF) has a primary role in neuronal development, differentiation and plasticity in both the developing and adult brain. A single-nucleotide polymorphism in the proregion of BDNF, termed the Val66Met polymorphism, results in deficient subcellular translocation and activity-dependent secretion of BDNF, and has been associated with impaired neurocognitive function in healthy adults and in the incidence and clinical features of several psychiatric disorders. Research investigating the Val66Met polymorphism has increased markedly in the past decade, and a gap in integration exists between and within academic subfields interested in the effects of this variant. Here we comprehensively review the role and relevance of the Val66Met polymorphism in psychiatric disorders, with emphasis on suicidal behavior and anxiety, eating, mood and psychotic disorders. The cognitive and molecular neuroscience of the Val66Met polymorphism is also concisely reviewed to illustrate the effects of this genetic variant in healthy controls, and is complemented by a commentary on the behavioral neuroscience of BDNF and the Val66Met polymorphism where relevant to specific disorders. Lastly, a number of controversies and unresolved issues, including small effect sizes, sampling of allele inheritance but not genotype and putative ethnicity-specific effects of the Val66Met polymorphism, are also discussed to direct future research. PMID- 25824308 TI - Evolocumab (AMG 145) for primary hypercholesterolemia. AB - Evolocumab is a fully human monoclonal IgG2 antibody that inhibits proprotein convertase subtilisin/kexin type 9, a protein that targets LDL receptors for degradation and thereby reduces the liver's ability to remove LDL-C from the blood. In Phase II and III trials in more than 6000 subjects with primary hypercholesterolemia, evolocumab reduced LDL-C by 50-75% compared with placebo and by 35-45% compared with ezetimibe. Evolocumab reduced the proatherogenic lipid profile, including Lp(a), and modestly increased HDL-C and ApoA1. In subjects with homozygous familial hypercholesterolemia, evolocumab reduced LDL-C by 30%. Safety and tolerability of evolocumab was similar to that of placebo and ezetimibe. The ongoing FOURIER trial, anticipated to report in 2017, will provide definitive evidence on cardiovascular endpoints and additional long-term safety. PMID- 25824307 TI - Noncoding RNAs and neurobehavioral mechanisms in psychiatric disease. AB - The human genome project has revolutionized our understanding of the underlying mechanisms in psychiatric disease. It is now abundantly clear that neurobehavioral phenotypes are epigenetically controlled by noncoding RNAs (ncRNAs). The microRNA (miRNA) class of ncRNAs are ubiquitously expressed throughout the brain and govern all major neuronal pathways. The attractive therapeutic potential of miRNAs is underscored by their pleiotropic capacities, putatively targeting multiple pathways within a single neuron. Many psychiatric diseases stem from a multifactorial origin, thus conventional drug targeting of single proteins may not prove most effective. In this exciting post-genome sequencing era, many new epigenetic targets are emerging for therapeutic investigation. Here we review the reported roles of miRNAs, as well as other ncRNA classes, in the pathology of psychiatric disorders; there are both common and unique ncRNA mechanisms that influence the various diagnoses. Collectively, these potent epigenetic regulators may clarify the disrupted signaling networks in psychiatric phenotypes. PMID- 25824309 TI - Low-intensity pulsed ultrasound enhances bone formation around miniscrew implants. AB - Miniscrew implants (MSIs) are currently used to provide absolute anchorage in orthodontics; however, their initial stability is an issue of concern. Application of low-intensity pulsed ultrasound (LIPUS) can promote bone healing. Therefore, LIPUS application may stimulate bone formation around MSIs and enhance their initial stability. AIM: To investigate the effect of LIPUS exposure on bone formation after implantation of titanium (Ti) and stainless steel (SS) MSIs. METHODS: MSIs made of Ti-6Al-4V and 316L SS were placed on rat tibiae and treated with LIPUS. The bone morphology around MSIs was evaluated by scanning electron microscopy and three-dimensional micro-computed tomography. MC3T3-E1 cells cultured on Ti and SS discs were treated with LIPUS, and the temporary expression of alkaline phosphatase (ALP) was examined. RESULTS: Bone-implant contact increased gradually from day 3 to day 14 after MSI insertion. LIPUS application increased the cortical bone density, cortical bone thickness, and cortical bone rate after implantation of Ti and SS MSIs (P<0.05). LIPUS exposure induced ALP upregulation in MC3T3-E1 cells at day 3 (P<0.05). CONCLUSION: LIPUS enhanced bone formation around Ti and SS MSIs, enhancing the initial stability of MSIs. PMID- 25824310 TI - Porphyromonas gingivalis-induced alveolar bone loss is accelerated in the stroke prone spontaneously hypertensive rat. AB - Porphyromonas gingivalis (P. gingivalis) is one of the prominent periodontal pathogens and is the most important bacteria involved in the onset and exacerbation of periodontitis. P. gingivalis is an anaerobic, Gram-negative coccobacillus that plays a role in the progression of periodontal disease by promoting alveolar bone resorption. The aim of the present study was to examine P. gingivalis-induced osteoclastic bone resorption in the stroke-prone spontaneously hypertensive rat (SHRSP), in which oxidative stress induced by reactive oxygen species (ROS) is increased. In the present study, we used animals orally challenged with P. gingivalis as a chronic inflammation model. Horizontal bone loss around the maxillary molars was assessed morphometrically. Animals were divided into four groups: (1) P. gingivalis-non-infected Wister Kyoto Rat (WKY), (2) orally challenged with P. gingivalis WKY (WKY + Pg), (3) P. gingivalis-non infected SHRSP, and (4) orally challenged with P. gingivalis SHRSP (SHRSP + Pg). Alveolar bone resorption was significantly increased in the orally challenged with P. gingivalis groups, and was accelerated in the SHRSP group. Histological analysis revealed that the infiltration of inflammatory cells was absent in all groups. However, the infiltration of osteoclasts was observed in the SHRSP + Pg and SHRSP groups. We examined P. gingivalis-induced alveolar bone loss in both the SHRSP and WKY. The results obtained demonstrated that P. gingivalis-induced alveolar bone loss would be involved in hypertension and stroke animal model, such as SHRSP and/or periodontal disease. PMID- 25824311 TI - Frontline therapy of severe aplastic anaemia with fludarabine, cyclophosphamide and ciclosporin. PMID- 25824312 TI - epsilon-Caprolactone is not a 50-kDa molecule when applied in micro-chambered beads. PMID- 25824313 TI - Percutaneous cryoablation of stage T1b renal cell carcinoma: technique considerations, safety, and local tumor control. AB - PURPOSE: To describe the technical methods, safety, and local tumor control rate associated with percutaneous cryoablation of stage T1b renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective review of a percutaneous renal ablation registry was used to identify 46 patients with a total of 46 biopsy proven RCC lesions measuring 4.1-7.0 cm treated with cryoablation between 2003 and 2011. The main outcome parameters investigated were adjunctive maneuvers, complications, and local tumor progression, and cancer-specific survival rates. Complication rates were categorized and recorded using the Clavien-Dindo classification system. Progression-free and cancer-specific survival rates were estimated using the Kaplan-Meier method. RESULTS: The mean treated RCC size was 4.8 cm (range, 4.1-6.4 cm). Prophylactic tumor embolization was performed in 7 patients (15%), ipsilateral ureteral stents were placed in 7 patients (15%), and hydrodisplacement of bowel was performed in the treatment of 16 tumors (35%). A single technical failure (2.2%) was observed at the time of ablation. Thirty-six tumors (78%) had follow-up imaging at 3 months or later following ablation, including a single recurrence at 9 months after ablation. The mean duration of follow-up for the 35 RCC tumors that did not recur was 2.0 years (range, 0.3-6.1 y). Estimated local progression-free survival rate at 3 years was 96.4%. Of the 46 cryoablation procedures, there were 7 complications (15.2%) of grade II or worse. CONCLUSIONS: The results suggest that cryoablation represents a valid treatment alternative for select patients with clinical stage T1b RCC. Complications are frequent enough that multidisciplinary patient management should be considered. PMID- 25824314 TI - Endovascular Management of Deep Vein Thrombosis with Rheolytic Thrombectomy: Final Report of the Prospective Multicenter PEARL (Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths) Registry. AB - PURPOSE: To report procedural and patient outcomes of endovascular treatment for lower-extremity deep vein thrombosis (DVT) with rheolytic thrombectomy (RT). MATERIALS AND METHODS: A total of 32 sites in the United States and Europe enrolled patients with DVT in the Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths (PEARL) registry. Patient characteristics and outcomes data were collected from consenting patients who underwent rheolytic AngioJet thrombectomy at investigative sites from January 2007 through June 2013. Three hundred twenty-nine patients were enrolled, with 67% of patients undergoing an AngioJet procedure within 14 days of the onset of symptoms. RESULTS: Four treatment approaches using AngioJet thrombectomy were identified: RT without lytic agent in 4% of patients (13 of 329), pharmacomechanical catheter-directed thrombolysis (PCDT) in 35% (115 of 329), PCDT and catheter-directed thrombolysis (CDT) in 52% (172 of 329), and RT in combination with CDT in 9% (29 of 329). Median procedure times for RT alone, PCDT, PCDT/CDT, and RT/CDT were 1.4, 2, 22, and 41 hours, respectively (P < .05, Kruskal-Wallis test). Procedures were completed in less than 24 hours for 73% of patients, with 36% of procedures completed within 6 hours; 86% of procedures required no more than 2 catheter laboratory sessions. The 3-, 6-, and 12-month freedom from rethrombosis rates were 94%, 87%, and 83%, respectively. Major bleeding events occurred in 12 patients (3.6%), but none were related to the AngioJet procedure. CONCLUSIONS: PEARL registry data demonstrate that rheolytic PCDT treatment of DVT is safe and effective, and can potentially reduce the need for concomitant CDT and intensive care. PMID- 25824315 TI - The Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Patients with Unresectable Hepatocellular Carcinoma Treated with Radioembolization. AB - PURPOSE: To assess the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with unresectable intermediate- or advanced-stage hepatocellular carcinoma (HCC) treated with yttrium-90 radioembolization (RE). MATERIALS AND METHODS: Retrospective chart review was performed for 176 patients with intermediate- or advanced-stage HCC treated with RE between August 2000 and November 2012. The appropriate NLR cutoff was determined by receiver operating characteristic curves. Demographic, clinical, radiographic, and pathologic parameters were compared between patients with a normal NLR (< 5) and those with an elevated NLR (>= 5) before RE. Barcelona Clinic Liver Cancer (BCLC) stage stratified univariate and multivariate analyses were conducted to determine variables associated with overall survival. RESULTS: Under univariate analyses, patients with a normal NLR were found to have longer survival than individuals with a high NLR in intermediate/advanced-disease and advanced-disease cohorts. A multivariate Cox proportional-hazards model in the advanced-disease group confirmed that elevated NLR, high alpha-fetoprotein level, and low albumin level were independent predictors of worse survival. CONCLUSIONS: This study provides stage-dependent evidence for the prognostic role of NLR in the radioembolized HCC cohort. Patients with BCLC stage C disease with elevated NLR may not derive benefit from RE, and other intervening modalities should be explored in this subpopulation. PMID- 25824316 TI - Comparison of transarterial chemoembolization and hepatic resection for large solitary hepatocellular carcinoma: a propensity score analysis. AB - PURPOSE: To compare long-term survival after hepatic resection and transarterial chemoembolization of large solitary hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: Analysis of 91 and 68 consecutive patients with large (>= 5 cm) solitary HCCs who underwent hepatic resection and transarterial chemoembolization, respectively, was performed. Overall survival and time to progression (TTP) were estimated using the Kaplan-Meier method and compared using the Cox proportional hazards model. To control for treatment-selection bias, matched groups of patients were selected using a propensity score matching method, and survival analysis was repeated. RESULTS: During the follow-up period (median, 60.7 mo; range, 0.5-122.2 mo), 42 (46%) patients in the hepatic resection group and 35 (51%) patients in the transarterial chemoembolization group died. The 1-year, 3-year, and 5-year overall survival rates of the hepatic resection and transarterial chemoembolization groups were 91.1%, 80.0%, and 66.4% (hepatic resection group) and 89.8%, 72.8%, and 49.6% (transarterial chemoembolization group) (P = .023). TTP was significantly longer in patients who underwent hepatic resection (P < .001). Hepatitis B surface antigen positivity and the absence of portal hypertension were independent predictors for favorable overall survival. For patients with platelet counts <= 100,000/mm(3), Child-Pugh score of 6, smaller HCCs (<= 7 cm), or portal hypertension, hepatic resection and transarterial chemoembolization yielded similar overall survival rates. After propensity score matching, transarterial chemoembolization was comparable to hepatic resection in overall survival (P = .293), whereas TTP remained longer in patients who underwent hepatic resection (P = .001). CONCLUSIONS: Transarterial chemoembolization can lead to results comparable to hepatic resection in the treatment of large solitary HCCs, particularly in patients with clinically presumed portal hypertension. PMID- 25824317 TI - Calibrated Bioresorbable Microspheres as an Embolic Agent: An Experimental Study in a Rabbit Renal Model. AB - PURPOSE: To evaluate the time frame of resorption and tissue response of newly developed bioresorbable microspheres (BRMS) and vessel recanalization after renal embolization. MATERIALS AND METHODS: Embolization of lower poles of kidneys of 20 adult rabbits was performed with BRMS (300-500 um). Two rabbits were sacrificed immediately after embolization (day 0). Three rabbits were sacrificed after follow-up angiography at 3, 7, 10, 14, 21, and 30 days. The pathologic changes in the renal parenchyma, BRMS degradation, and vessel recanalization were evaluated histologically and angiographically. RESULTS: Embolization procedures were successfully performed, and all animals survived without complication. Infarcts were observed in all kidneys that received embolization harvested after day 0. Moderate degradation of BRMS (score = 1.07 +/- 0.06) was observed by day 3. Of BRMS, 95% were resorbed before day 10 with scant BRMS materials remaining in the arteries at later time points. Partial vessel recanalization was observed by angiography starting on day 3, whereas new capillary formation was first identified histologically on day 7. Vascular inflammation associated with BRMS consisted of acute, heterophilic infiltrate at earlier time points (day 3 to day 10); this was resolved with the resorption of BRMS. Inflammation and fibrosis within infarcted regions were consistent with progression of infarction. CONCLUSIONS: BRMS were bioresorbable in vivo, and most BRMS were resorbed before day 10 with a mild tissue reaction. Vessel recanalization occurred secondary to the resorption of BRMS. PMID- 25824318 TI - Optical coherence tomography of dialysis graft after angioplasty. PMID- 25824319 TI - Peripherally Inserted Central Catheter Placement into the Lumen of an Extracorporeal Membrane Oxygenation Catheter. PMID- 25824320 TI - Multiple censored data in dentistry: A new statistical model for analyzing lesion size in randomized controlled trials. AB - Caries infiltration is a novel treatment option for proximal caries lesions. The idea is to build a diffusion barrier inside the lesion to slow down or stop the caries progression. If a lesion still reaches a critical size, restorative treatment is required. Clinical trials investigating caries infiltration thus produce multiple censored ordinal data. Standard statistical models do not take into account this censoring, and we therefore propose the Multiple Ordered Tobit (MOT) model. The model is implemented in R and compared with standard approaches. Simulation studies demonstrate that for all sample sizes and scenarios the MOT model has the largest statistical power among all methods compared, and it is robust against heteroscedasticity to some extent. Finally, a comparison with dichotomous and ordinal scaled models shows that the use of metric data for the lesion size reduces the required sample size considerably. PMID- 25824321 TI - Transforming growth factor-beta, insulin-like growth factor I/insulin-like growth factor I receptor and vascular endothelial growth factor-A: prognostic and predictive markers in triple-negative and non-triple-negative breast cancer. AB - In the current study, the prognostic and predictive values of serum transforming growth factor-beta1 (TGF-beta1), insulin-like growth factor I (IGF-I)/IGF-I receptor (IGF-IR) and vascular endothelial growth factor-A (VEGF-A) were evaluated in triple-negative and non-triple-negative breast cancer (TNBC and non TNBC). The aim was to identify a group of serological biomarkers and to identify possible candidates for targeted therapy in patients with TNBC and non-TNBC. Protein levels of TGF-beta1, IGF-I/IGF-IR and VEGF-A in the serum were measured in 43 TNBC, 53 non-TNBC and 20 normal control participants using quantitative ELISA assays. Results were correlated against standard prognostic factors, response to treatment and survival. TNBC was identified to be associated with poor prognosis and serum levels of VEGF-A and IGF/IGF-IR were significantly higher in the TNBC group compared with the non-TNBC group. IGF-IR and VEGF-A overexpression was observed to be correlated with TGF-beta1 expression and all of the markers investigated were associated with metastasis and disease progression. In the multivariate analysis, VEGF-A, IGF-I and IGF-IR were observed to be independent predictors for overall survival, whereas TGF-beta1 and lymph node status were identified as independent predictors for disease-free survival. The overall response rate was significantly lower in patients with TNBC and those with high levels of TGF-beta1, IGF-I/IGF-IR and VEGF-A. In view of the present results, it was concluded that TGF-beta1, IGF-I/IGF-IR and VEGF-A overexpression is associated with the presence of aggressive tumors, which exhibit an increased probability of metastasis, a poor response to treatment and reduced survival rate. This indicates that VEGF-A, IGF-IR and IGF-I have the potential to be used as surrogate biomarkers and are promising candidates for targeted therapy, particularly in patients with TNBC. PMID- 25824322 TI - Noninvasive mathematical analysis of spectral electrocardiographic components for coronary lesions of intermediate to obstructive stenosis severity-relationship with classic and functional SYNTAX score. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between the multifunction cardiogram (MCG), and SYNTAX score (SS) and functional SYNTAX score (FSS) in detecting the presence of intermediate to obstructive coronary lesions. BACKGROUND: Performing coronary angiography (CAG) and measuring fractional flow reserve (FFR) to calculate the SS and FSS is inherently invasive and adds complexity. METHODS: The MCG was obtained and analyzed before performing CAG in 87 consecutive subjects with suspected coronary artery disease who were scheduled for elective CAG. The patients were divided into three groups according to risk based on high, borderline, and low MCG scores. The SS was determined, as well as FSS but only by counting lesions prone to functional ischemia (FFR <= 0.8). The relationship between the MCG and the SS and FSS was evaluated. RESULTS: The MCG was the only test significantly associated with the SS (odds ratio, 2.92 [1.60 - 5.31], P < 0.001) and FSS (odds ratio, 3.66 [1.95 - 6.87], P < 0.001). A high MCG score had a specificity of 92.6% (89.0-96.2%) and 92.3% (89.0-95.6%), and a predictive accuracy of 72.4% (67.6-77.2%) and 82.8% (78.7-86.8%) for the prediction of SS and FSS, respectively. CONCLUSIONS: The MCG showed high specificity and predictive accuracy especially for the FSS, suggesting that it is useful not only in identifying functionally significant ischemia but also in reducing unnecessary CAGs. PMID- 25824323 TI - Noncontrast-enhanced peripheral venography using velocity-selective magnetization preparation and transient balanced SSFP. AB - PURPOSE: To develop a three-dimensional (3D) noncontrast-enhanced (NCE) peripheral magnetic resonance venography (MRV) method and demonstrate its feasibility in vivo. METHODS: The proposed MRV pulse sequence consisted of a velocity-selective (VS) inversion preparation module, inversion delay time (TI), fat inversion pulse, and 3D balanced steady-state free precession (bSSFP) dummy excitations and readout. The VS preparation module inverted arterial blood, which recovered close to zero magnetization during TI. The TI and the number of dummy excitations (Nnum ) were numerically optimized for maximizing vein-to-background contrast and tested in a healthy subject. The proposed MRV of the entire peripheral system, using four-station acquisition, was performed in six healthy subjects and three peripheral artery patients. RESULTS: The numerical optimization yielded TI = 350 ms and Ndum = 40, which was supported by the largest vein contrast among the parameters chosen around the optima on in vivo venograms. Four-station peripheral MRV using the optimized parameters well visualized all major deep veins with high vein-to-background contrast. The relative vein contrast ratios were 0.80 +/- 0.08, 0.75 +/- 0.07, and 0.84 +/- 0.06 against the arteries, muscle, and fat, respectively. CONCLUSION: The proposed NCE MRV using VS preparation and transient bSSFP can generate high contrast peripheral venograms directly with a single acquisition. PMID- 25824324 TI - Synthesis and radical scavenger properties of novel spirochromenes derived from steroid sapogenins. AB - Tandem aldol condensation between steroid sapogenins and hydroxylated benzaldehydes afforded steroidal spirochromenes. Compounds that bear a phenolic hydroxyl group at position C-6', obtained by a reaction with 2,5 dihydroxybenzaldehyde, showed approximately 80% of maximal radical scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay at 288 nM. In contrast, the starting steroid sapogenins and the spirochromenes without a phenolic group in the side chain proved to be inactive. PMID- 25824325 TI - Neuroactive steroids and the peripheral nervous system: An update. AB - In the present review we summarize observations to date supporting the concept that neuroactive steroids are synthesized in the peripheral nervous system, regulate the physiology of peripheral nerves and exert notable neuroprotective actions. Indeed, neuroactive steroids have been recently proposed as therapies for different types of peripheral neuropathy, like for instance those occurring during aging, chemotherapy, physical injury and diabetes. Moreover, pharmacological tools able to increase the synthesis of neuroactive steroids might represent new interesting therapeutic strategy to be applied in case of peripheral neuropathy. PMID- 25824326 TI - Intraoperative fluorescein angiography-guided treatment in children with early Coats' disease. AB - PURPOSE: To review the anatomic and visual outcomes of a series of children diagnosed with Coats' disease and treated on the basis of intraoperative fluorescein angiography (FA) findings. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-five children 2 to 15 years of age diagnosed with early Coats' disease and treated after intraoperative FA. METHODS: Retrospective review of patients who underwent treatment for stage 2 Coats' disease in a tertiary center in the United Kingdom between 2007 and 2012. The children underwent treatment to the telangiectatic vessels and associated areas of retinal nonperfusion identified on intraoperative FA performed with a wide-angle retinal camera (RetCam II). MAIN OUTCOME MEASURES: Anatomic and structural assessment of the retina after treatment, visual acuity (VA), and complications related to treatment. RESULTS: Twenty children with Coats' disease who underwent intraoperative RetCam FA and retinal ablative treatment and who had more than 3 months of follow-up were identified from clinical records. All had unilateral disease. Six eyes were classified as stage 2a, and 14 eyes were classified as stage 2b. The median duration of follow-up was 21 months (mean, 26 months). Fifteen eyes needed 1 treatment to stabilize the disease, and 5 eyes needed a second treatment. None of the patients demonstrated progression of the disease to a more severe stage. Twelve eyes had a final VA of 0.4 logarithm of the minimum angle of resolution (logMAR) or better, 6 patients had VA between 0.4 and 1.0 logMAR, and 2 patients had VA worse than 1.0 logMAR. CONCLUSIONS: The treatment of retinal telangiectasia and areas of retinal nonperfusion identified by wide angle intraoperative FA in children with stage 2 Coats' disease led to good anatomic outcome, with preservation of VA in most cases. PMID- 25824328 TI - Hydroxychloroquine and chloroquine retinopathy: a systematic review evaluating the multifocal electroretinogram as a screening test. AB - PURPOSE: To determine the validity of multifocal electroretinography (mfERG) as a screening tool for detecting chloroquine (Aralen, Sanofi Aventis, Bridgewater, NJ) (CQ) and hydroxychloroquine (Plaquenil, Covis Pharmaceuticals, Inc, Zug, Switzerland) (HCQ) retinal toxicity in patients using these medications. To evaluate the sensitivity and specificity of mfERG when compared with automated visual fields (AVFs), fundus autofluorescence (FAF), and optical coherence tomography (OCT). CLINICAL RELEVANCE: The 2011 American Academy of Ophthalmology recommendations on screening for CQ/HCQ retinopathy recommended a shift toward more objective testing modalities. Multifocal electroretinography may be effective in detecting functional change before irreversible structural damage from CQ/HCQ toxicity. METHODS: We performed a search for records reporting the use of mfERG for screening CQ/HCQ retinopathy in MEDLINE (PubMed and OVID), EMBASE, and Web of Science, and assessed these using the QUADAS-2 risk of bias tool. We conducted an analysis of 23 individual studies and their reported individual patient data (449 eyes of 243 patients) published from January 2000 to December 2014. RESULTS: Multifocal electroretinography had the greatest proportion of positive test results, followed by AVF. The pooled sensitivity and specificity of mfERG were 90% (95% confidence interval [CI], 0.62-0.98) and 52% (CI, 0.29-0.74), respectively, with AVF as reference standard (13 studies). Sensitivity was high, but specificity was variable when OCT, FAF, and the positivity of 2 of 3 tests was used as the reference standard. When verified against AVF as the reference test, patients with a false-positive mfERG result received higher HCQ cumulative doses (1068 g) than patients with true-negative (658 g, P < 0.01) and false-negative (482 g, P < 0.01) results. CONCLUSIONS: Multifocal electroretinography was shown to have a high sensitivity but variable specificity when verified against AVF, OCT, FAF, and a combination of tests. The greater average cumulative dose in the false-positive group compared with the true-negative group when mfERG was verified against AVF suggests that mfERG may have the ability to detect cases of toxicity earlier than other modalities. There is an unclear risk of bias in the available evidence, and future studies should adhere to Standards for Reporting of Diagnostic Accuracy reporting guidelines. PMID- 25824327 TI - Influence of the Vitreomacular Interface on Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials. AB - OBJECTIVE: To assess the association of the vitreomacular interface with outcomes of eyes treated with anti-vascular endothelial growth factor drugs for neovascular age-related macular degeneration (AMD). DESIGN: Prospective cohort study within a multicenter, randomized clinical trial. PARTICIPANTS: Patients enrolled in the Comparison of AMD Treatments Trials (CATT). METHODS: Treatment was assigned randomly as either ranibizumab or bevacizumab and as 3 different regimens for dosing over a 2-year period. Masked readers at a reading center assessed optical coherence tomography (OCT) scans at baseline and follow-up for vitreomacular traction (VMT) and vitreomacular adhesion (VMA), fluid, and central thickness. Visual acuity (VA) was measured by masked, certified examiners. MAIN OUTCOME MEASURES: Anatomic features and VA at baseline and 1 and 2 years and number of treatments. RESULTS: At baseline, 143 patient eyes (12.8%) had VMT or VMA. Compared with those with neither (n = 972), patients with VMT or VMA were younger (mean +/- standard error, 75.5 +/- 0.6 vs. 79.7 +/- 0.24 years; P < 0.0001) and more likely to be male (52.4% vs. 36.2%; P = 0.0003), to be cigarette smokers (68.5% vs. 55.3%; P = 0.003), and to have subretinal fluid on OCT (86.7% vs. 81.0%; P = 0.047). Vitreomacular interface status was not associated with VA at baseline or follow-up. Among eyes treated as needed (n = 598) and followed up for 2 years (n = 516), the mean number of injections was 15.4 +/- 0.9 for eyes having VMT at baseline or during follow-up (n = 60), 13.8 +/- 0.7 for eyes with VMA at baseline or follow-up (n = 79), and 12.9 +/- 0.4 (P = 0.02) for eyes without VMT or VMA (n = 377). In addition, the mean number of injections in eyes treated as needed increased from 13.0 +/- 0.3 when VMT was not observed to 13.6 +/- 1.3 when observed once and to 17 +/- 1.2 when observed more than once during follow-up. At 2 years, geographic atrophy developed in a lower percentage of eyes with VMT or VMA at baseline (11.7%) than with neither condition (22.5%; P = 0.005). CONCLUSIONS: In eyes in the CATT, VMT and VMA were infrequent. At baseline and follow-up, VMT or VMA were not associated with VA. Eyes with VMT or VMA treated as needed required on average 2 more injections over 2 years. PMID- 25824329 TI - Neuroprotection of brain-targeted bioactive dietary artoindonesianin O (AIO) from mulberry on rat neurons as a novel intervention for Alzheimer's disease. AB - The novel effects of artoindonesianin O, a dietary phenolic compound from mulberry, were investigated on oligomer Abeta42-, NMDA- or okadaic-acid-induced neurotoxicity and the restorative effect on the oligomer Abeta42-induced synapses dysfunction using rat hippocampus neuron cells in vitro. The phenolic compound of AIO can exert neuroprotection by blocking oligomer Abeta42- or NMDA-induced neurotoxicity and okadaic-acid-induced tau protein hyperphosphorylation through inhibiting the expression of kinase p-ERK1/2. Meanwhile, it is also beneficial to synaptic plasticity. These interesting results strongly suggest that AIO, which is rich in abundant sources of mulberry and other fruits, is suitable and possible candidate for the development of general food type neuroprotection on AD by protecting against brain damage and memory impairment. PMID- 25824330 TI - Maternal and fetal outcome of pregnancy related hypertension in Mettu Karl Referral Hospital, Ethiopia. AB - BACKGROUND: Hypertensive disorders of pregnancy are the most common causes of adverse maternal & perinatal outcomes. Such investigations in resource limited settings would help to have great design strategies in preventing maternal and perinatal morbidity and mortality. AIM: To determine management outcome and factor associated with pregnancy related hypertensive disorder in Mettu Karl Referral Hospital, Mettu, Ethiopia. METHOD: A retrospective study deign was conducted at Mettu Karl Referral Hospital from 1st January 2010 to December 1st 2013 by reviewing medical records and logbooks. Descriptive, binary and multiple logistic regression analysis were used. A 95% CI and P- value of < 0.05 were considered statistically significant. RESULT: The magnitude of pregnancy related hypertensive disorder was 2.4%. Majority 82.6% of the mothers were in the age range between 18 to 34 year with a mean age and standard deviation (SD) of 24.4 (SD +/- 5.12). Sever preeclampsia was the most prevalent diagnosis made to 35.5% of the mother, followed by 19% cases of eclampsia and 12.4% of HELLP. Fetal management outcomes indicates 120.37 perinatal mortality per 1000 deliveries and a stillbirth rate of 10.2%, low birth weight of 30.5%, and low APGAR score of 18.5%, abortion 10.7% and preterm delivery 31.4%. CONCLUSION: In this study severe preeclampsia is the most common of all pregnancy related hypertension disorders followed by Eclampsia. Fetal complications like low Apgar score and preterm deliveries were statistically significant and associated with fetal management outcomes. PMID- 25824331 TI - Class II functional orthopaedic treatment: a systematic review of systematic reviews. AB - This Systematic Review (SR) aims to assess the quality of SRs and Meta-Analyses (MAs) on functional orthopaedic treatment of Class II malocclusion and to summarise and rate the reported effects. Electronic and manual searches were conducted until June 2014. SRs and MAs focusing on the effects of functional orthopaedic treatment of Class II malocclusion in growing patients were included. The methodological quality of the included papers was assessed using the AMSTAR (Assessment of Multiple Systematic Reviews). The design of the primary studies included in each SR was assessed with Level of Research Design scoring. The evidence of the main outcomes was summarised and rated according to a scale of statements. 14 SRs fulfilled the inclusion criteria. The appliances evaluated were as follows: Activator (2 studies), Twin Block (4 studies), headgear (3 studies), Herbst (2 studies), Jasper Jumper (1 study), Bionator (1 study) and Frankel-2 (1 study). Four studies reviewed several functional appliances, as a group. The mean AMSTAR score was 6 (ranged 2-10). Six SRs included only controlled clinical trials (CCTs), three SRs included only randomised controlled trials (RCTs), four SRs included both CCTs and RCTs and one SR included also expert opinions. There was some evidence of reduction of the overjet, with different appliances except from headgear; there was some evidence of small maxillary growth restrain with Twin Block and headgear; there was some evidence of elongation of mandibular length, but the clinical relevance of this results is still questionable; there was insufficient evidence to determine an effect on soft tissues. PMID- 25824332 TI - Relationship Between Vertebral Fracture Burden, Height Loss, and Pulmonary Function in Postmenopausal Women With Osteoporosis. AB - The purpose of this analysis was to assess the association of osteoporosis related vertebral fracture burden and pulmonary function. This study also examined the relationship between vertebral fracture burden and height loss, estimated by arm span - height. This was a single-site and single-visit study. Patients had a history of at least 1 moderate or severe vertebral fracture. Vertebral fracture burden was quantified using the spinal deformity index (SDI). Pulmonary function during inspiration was determined by spirometry. Forty-one women aged 70-91 completed the study. Vertebral fracture burden negatively correlated with forced inspiratory vital capacity and inspiratory time. For each unit increase in SDI, forced inspiratory vital capacity decreased by 1.62%, and inspiratory time decreased by 2.39%. There was no correlation between SDI and measures of inspiratory flow. For each unit increase in SDI, height decreased by about 0.5 cm. Vertebral fractures were associated with decreased lung volume and height loss. PMID- 25824334 TI - N2 extrusion and CO insertion: a novel palladium-catalyzed carbonylative transformation of aryltriazenes. AB - A novel procedure for the replacement of N2 with CO of aryltriazenes has been developed. Aryltriazenes were converted to the corresponding arylamides catalyzed by 1 mol % of PdCl2/P(o-Tol)3 under CO pressure. In this process, aryldiazonium salts were generated in the presence of 40 mol % of MeSO3H. Nitrogen was released from the substrates and CO formally inserted. Aryl bromides, iodides, alkynes, and free hydroxyl groups can be tolerated in this transformation. PMID- 25824333 TI - Effectiveness and Safety of rhIGF-1 Therapy in Children: The European Increlex(r) Growth Forum Database Experience. AB - BACKGROUND/AIMS: We report data from the EU Increlex(r) Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children. METHODS: Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013. RESULTS: Mean +/- SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 +/- 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naive to treatment, this was 7.3 +/- 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%). CONCLUSION: Safety and effectiveness data on use of rhIGF-1 in a 'real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia. PMID- 25824335 TI - Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer. AB - Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin +/- the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin low); or BRCA-wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (gamma-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin +/- ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of gamma-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin +/- ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation. PMID- 25824337 TI - 1alpha,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling. AB - The aim of this study was to highlight the role of 1alpha,25-dihydroxyvitamin D3 (calcitriol) in esophageal squamous cell carcinoma (SCC). The human esophageal SCC cell lines CE81T and TE2 were selected for cellular and animal experiments to investigate the changes in tumor behavior after calcitriol supplementation and the underlying mechanisms. Moreover, we evaluated the relationship between calcitriol supplementation, myeloid-derived suppressor cell (MDSC) recruitment, IL6 levels, and tumor progression by a 4-nitroquinoline 1-oxide (4-NQO)-induced esophageal tumor animal model. In this study, we demonstrated that calcitriol supplementation inhibited aggressive tumor behavior both in vitro and in vivo. The underlying changes included increased cell death, a lower degree of epithelial-mesenchymal transition, and inhibited IL6 signaling. In the 4-NQO induced esophageal tumor animal model, increased IL6 and MDSC recruitment were linked with invasive esophageal tumors. Supplementation with calcitriol attenuated the level of IL6, the induction of MDSCs, and the incidence of 4-NQO induced invasive tumors. Moreover, the IL6-induced changes in C57 mice, including augmented MDSC recruitment, increased levels of ROS and p-Stat3 in MDSCs, and higher suppressive function of MDSCs in T-cell proliferation, which were abrogated by calcitriol supplementation. On the basis of our results, we concluded that calcitriol abrogated the IL6-induced aggressive tumor behavior and MDSC recruitment to inhibit esophageal tumor promotion. Therefore, we suggest that supplementation with vitamin D3 may be a promising strategy for the prevention and treatment of esophageal SCC. PMID- 25824338 TI - Childhood epidermolysis bullosa acquisita with underlying coeliac disease. PMID- 25824339 TI - New ways to boost molecular dynamics simulations. AB - We describe a set of algorithms that allow to simulate dihydrofolate reductase (DHFR, a common benchmark) with the AMBER all-atom force field at 160 nanoseconds/day on a single Intel Core i7 5960X CPU (no graphics processing unit (GPU), 23,786 atoms, particle mesh Ewald (PME), 8.0 A cutoff, correct atom masses, reproducible trajectory, CPU with 3.6 GHz, no turbo boost, 8 AVX registers). The new features include a mixed multiple time-step algorithm (reaching 5 fs), a tuned version of LINCS to constrain bond angles, the fusion of pair list creation and force calculation, pressure coupling with a "densostat," and exploitation of new CPU instruction sets like AVX2. The impact of Intel's new transactional memory, atomic instructions, and sloppy pair lists is also analyzed. The algorithms map well to GPUs and can automatically handle most Protein Data Bank (PDB) files including ligands. An implementation is available as part of the YASARA molecular modeling and simulation program from www.YASARA.org. PMID- 25824336 TI - Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma. AB - Multiple myeloma pathogenesis is driven by the MYC oncoprotein, its dimerization with MAX, and the binding of this heterodimer to E-Boxes in the vicinity of target genes. The systemic utility of potent small molecule inhibitors of MYC-MAX dimerization was limited by poor bioavailability, rapid metabolism, and inadequate target site penetration. We hypothesized that new lipid-based MYC-MAX dimerization inhibitor prodrugs delivered via integrin-targeted nanoparticles (NP) would overcome prior shortcomings of MYC inhibitor approaches and prolong survival in a mouse model of cancer. An Sn 2 lipase-labile prodrug inhibitor of MYC-MAX dimerization (MI1-PD) was developed which decreased cell proliferation and induced apoptosis in cultured multiple myeloma cell lines alone (P < 0.05) and when incorporated into integrin-targeted lipid-encapsulated NPs (P < 0.05). Binding and efficacy of NPs closely correlated with integrin expression of the target multiple myeloma cells. Using a KaLwRij metastatic multiple myeloma mouse model, VLA-4-targeted NPs (20 nm and 200 nm) incorporating MI1-PD (D) NPs conferred significant survival benefits compared with respective NP controls, targeted (T) no-drug (ND), and untargeted (NT) control NPs (T/D 200: 46 days vs. NT/ND: 28 days, P < 0.05 and T/D 20: 52 days vs. NT/ND: 29 days, P = 0.001). The smaller particles performed better of the two sizes. Neither MI1 nor MI1-PD provided survival benefit when administered systemically as free compounds. These results demonstrate for the first time that a small molecule inhibitor of the MYC transcription factor can be an effective anticancer agent when delivered using a targeted nanotherapy approach. PMID- 25824340 TI - Matched related donor hematopoietic stem cell transplantation results in a long term follow-up of a pediatric acquired severe aplastic anemia subset: A stem cell source perspective. AB - HSCT has substantially improved pediatric acquired SAA patients' outcomes. Retrospectively, we attempted to assess the outcome of MRD HSCT in 65 pediatric patients referred to a single center from 1992 to 2012. We were particularly interested to find out whether source of SC (PB, n = 40 and BM, n = 25) significantly impacts EFS and GVHD incidence. With a median follow-up of 45 months, total EFS was 87.7%; EFS for PB and BM groups was 87.5% and 88%, respectively. Acute GVHD (grades 3-4) occurred in 13 patients (PB, n = 10 [25%] and BM, n = 3 [12%]), acute GVHD (grades 2-4) occurred in 24 (PB, n = 16 [40%] and BM, n = 8 [32%]). Extensive chronic GVHD occurred in five patients (PB, n = 3 [7.5%] and BM, n = 2 [8%]). Cox regression revealed that elapsed time of <10 months between diagnosis and HSCT is associated with improved survival (hazard ratio, 95% CI = 1.204, 1.010-1.434, p = 0.038). SC source did not significantly affect EFS, incidence of acute GVHD (grades 3-4), or extensive chronic GVHD (p = 0.938, 0.121, and 0.487, respectively). Based on our findings, pediatric acquired SAA patients are benefitted most if MRD-HSCT is carried out early in disease process and SC source does not affect outcome of MRD-HSCT in these patients. PMID- 25824341 TI - The non-steroidal mycoestrogen zeranol suppresses luteinizing hormone secretion from the anterior pituitary of cattle via the estradiol receptor GPR30 in a rapid, non-genomic manner. AB - Picomolar concentrations of estradiol produce rapid suppression of GnRH-induced luteinizing hormone (LH) secretion from the anterior pituitary (AP) of cattle via G-protein-coupled receptor 30 (GPR30). Zeranol is a strong estrogenic metabolite derived from zearalenone, a non-steroidal mycoestrogen produced by Fusarium that induces reproductive disorders in domestic animals. The hypothesis was tested that zeranol suppresses GnRH-induced LH release from the AP of cattle via GPR30 in a rapid, non-genomic manner. The AP cells (n=15) were cultured for 3 days in steroid-free conditions and then treated them with estradiol (0.001-10nM) or zeranol (0.001-100nM) for 5min before GnRH stimulation. Pre-treatment with 0.001 0.1nM estradiol suppressed GnRH-stimulated LH secretion. Pre-treatment with zeranol at concentrations of 0.001nM (P<0.01), 0.01nM (P<0.01), 0.1nM (P<0.05), and 1nM (P<0.05), but not at concentrations of 10 and 100nM, also inhibited GnRH stimulated LH secretion from AP cells. Pre-treatment for 5min with a GPR30 specific antagonist, G36, inhibited estradiol or zeranol suppression of LH secretion from cultured AP cells. Cyclic AMP measurements and quantitative PCR analyses revealed that pre-treatment with small amounts of estradiol (P<0.05) or zeranol (P<0.01) decreased cAMP, but not gene expressions of the LHalpha, LHbeta, or FSHbeta subunits in the AP cells. Hence, zeranol may suppress luteinizing hormone secretion from the AP of cattle via GPR30 in a rapid, non-genomic manner. PMID- 25824342 TI - Non-destructive evaluation of anchorage zones by ultrasonics techniques. AB - This work aims to evaluate the efficiency and reliability of two Non-Destructive Testing (NDT) methods for damage assessment in bridges' anchorages. The Acousto Ultrasonic (AU) technique is compared to classical Ultrasonic Testing (UT) in terms of defect detection and structural health classification. The AU technique is firstly used on single seven-wire strands damaged by artificial defects. The effect of growing defects on the waves traveling through the strands is evaluated. Thereafter, three specimens of anchorages with unknown defects are inspected by the AU and UT techniques. Damage assessment results from both techniques are then compared. The structural health conditions of the specimens can be then classified by a damage severity criterion. Finally, a damaged anchorage socket with mastered defects is controlled by the same techniques. The UT allows the detection and localization of damaged wires. The AU technique is used to bring out the effect of defects on acoustic features by comparing a healthy and damaged anchorage sockets. It is concluded that the UT method is suitable for local and crack-like defects, whereas the AU technique enables the assessment of the global structural health of the anchorage zones. PMID- 25824343 TI - Cutaneous Disease in Autism Spectrum Disorder: A Review. AB - Dermatologic comorbid symptoms and conditions in persons with autism spectrum disorder (ASD) are compelling for several reasons, including problems with tactile sensory dysfunction in this population, a large number of syndromes with dermatologic findings and high rates of autism, nutritional and hormonal problems in ASD and their dermatologic manifestations, and the potential for overrepresentation of dermatologic symptoms that are neurobehavioral in nature. The current article reviews the available literature on the prevalence of comorbid dermatologic symptoms and conditions in children with ASD and identifies strategies for diagnosing and managing cutaneous disease in this population. PMID- 25824344 TI - Low dietary diversity and micronutrient adequacy among lactating women in a peri urban area of Nepal. AB - OBJECTIVE: The main objectives were to assess the adequacy of the micronutrient intakes of lactating women in a peri-urban area in Nepal and to describe the relationships between micronutrient intake adequacy, dietary diversity and sociodemographic variables. DESIGN: A cross-sectional survey was performed during 2008-2009. We used 24 h dietary recall to assess dietary intake on three non consecutive days and calculated the probability of adequacy (PA) of the usual intake of eleven micronutrients and the overall mean probability of adequacy (MPA). A mean dietary diversity score (MDDS) was calculated of eight food groups averaged over 3 d. Multiple linear regression was used to identify the determinants of the MPA. SETTING: Bhaktapur municipality, Nepal. SUBJECTS: Lactating women (n 500), 17-44 years old, randomly selected. RESULTS: The mean usual energy intake was 8464 (sd 1305) kJ/d (2023 (sd 312) kcal/d), while the percentage of energy from protein, fat and carbohydrates was 11 %, 13 % and 76 %, respectively. The mean usual micronutrient intakes were below the estimated average requirements for all micronutrients, with the exception of vitamin C and Zn. The MPA across eleven micronutrients was 0.19 (sd 0.16). The diet was found to be monotonous (MDDS was 3.9 (sd 1.0)) and rice contributed to about 60 % of the energy intake. The multiple regression analyses showed that MPA was positively associated with energy intake, dietary diversity, women's educational level and socio-economic status, and was higher in the winter. CONCLUSIONS: The low micronutrient intakes are probably explained by low dietary diversity and a low intake of micronutrient-rich foods. PMID- 25824345 TI - Reply: To PMID 25277410. PMID- 25824346 TI - Succession of duodenal polypoid lesion. PMID- 25824347 TI - Reply: To PMID 24890443. PMID- 25824348 TI - An uncommon cause of abdominal pain and fever in a patient with Crohn's disease. PMID- 25824349 TI - Water-assisted colonoscopy. PMID- 25824351 TI - An unusual cause of ascites. PMID- 25824352 TI - To "B" or not to "B": efficacy of a neonatal hepatitis B vaccination program to prevent primary liver cancer and end-stage liver disease. PMID- 25824353 TI - An unusual giant duodenal mass lesion. PMID- 25824354 TI - Purpura in the duodenum. PMID- 25824355 TI - A 9-year-old girl with poor weight gain and postprandial vomiting. PMID- 25824356 TI - Mitochondrial metabolomics unravel the primordial trigger of ischemia/reperfusion injury. PMID- 25824357 TI - Confocal laser endomicroscopy for membrane-bound tumor necrosis factor predicts response to therapy in Crohn's disease. PMID- 25824358 TI - Unusual chest pain. PMID- 25824359 TI - Intestinal permeability in patients with diarrhea-predominant irritable bowel syndrome: is there a place for glutamine supplementation? PMID- 25824360 TI - An unusual cause of obscure gastrointestinal bleeding. PMID- 25824361 TI - An unusual cause of torrential lower gastrointestinal hemorrhage. PMID- 25824362 TI - Chronic Cough and Reflux: An Ongoing Conundrum Possibly Elucidated by Combined pH Impedance Monitoring. PMID- 25824363 TI - Reply: To PMID 25549238. PMID- 25824364 TI - Reply: To PMID 25109844. PMID- 25824365 TI - The medical history: form and function. PMID- 25824366 TI - Cultural adaptation and validation of the Korean version of the EORTC QLQ-CR29 in patients with colorectal cancer. AB - PURPOSE: We aimed to evaluate the psychometric properties of the Korean version of the European Organization for Research and Treatment of Cancer (EORTC) Colorectal Cancer-Specific Quality of Life Questionnaire (QLQ-CR29), based on a sample of patients with colorectal cancer. METHODS: A total of 123 patients treated for colorectal cancer participated in the validation study. Test-retest reliability was assessed using intra-class correlations from a random sample. Internal consistency reliability was estimated using Cronbach's alpha coefficient. Convergent and discriminant validity was analyzed with multi-trait scaling. Clinical validity was assessed in terms of clinical differences using known-group comparisons. Concurrent validity was determined by correlations with the EORTC QLQ-C30, which was a generic core questionnaire to evaluate issues common to different cancer sites and treatments. RESULTS: The test-retest, administered to 35 patients, showed acceptable reproducibility (0.62-1.00) except the constipation scale of the QLQ-C30 (0.43). Cronbach's alpha coefficient (0.70 0.87) exceeded the 0.7 criterion. Multi-trait scaling analysis showed that multi item scales met standards of convergent and discriminant validity. The known group comparisons showed quality of life (QOL) differences between groups of patients based on tumor location, receipt of neoadjuvant therapy, and with/without a stoma. Correlations between the scales of the QLQ-CR29 and QLQ-C30 were low in most areas, whereas correlations in several areas with related content were higher. CONCLUSION: This study shows that the Korean version of the EORTC QLQ-CR29 is a reliable and valid tool for measuring QOL, as determined by application to a sample of Korean colorectal cancer patients. PMID- 25824367 TI - Luminescent properties of 2-mercaptobenzothiazolates of trivalent lanthanides. AB - A series of lanthanide complexes (Ln = Nd, Sm, Eu, Gd and Yb) with anionic 2 mercaptobenothiazolate (mbt) ligands were synthesized. Depending on the solvents chosen for the synthesis, Ln(mbt)3(THF)2 and Ln(mbt)3(Et2O) complexes were precipitated from THF and Et2O solutions respectively. The structure of Yb(mbt)3(Et2O) was determined by X-ray analysis. Photophysical properties of the complexes were studied. It was found that under photoexcitation Nd and Yb derivatives exhibit bright metal-centered luminescence in the NIR region while Sm(mbt)3(THF)2 demonstrates intensive visible emission corresponding to (4)G5/2 > (6)HJ (J = 5/2, 7/2, 9/2, 11/2) f-f transitions of Sm(3+) along with NIR emission of moderate intensity. In the case of europium compounds as well as Sm(mbt)3(Et2O) no luminescence was detected. It is assumed that the difference in photoluminescence of Yb and Eu complexes can be explained by an intramolecular electron transfer process, which efficiently proceeds in these compounds. PMID- 25824368 TI - An animal-specific FSI model of the abdominal aorta in anesthetized mice. AB - Recent research has revealed that angiotensin II-induced abdominal aortic aneurysm in mice can be related to medial ruptures occurring in the vicinity of abdominal side branches. Nevertheless a thorough understanding of the biomechanics near abdominal side branches in mice is lacking. In the current work we present a mouse-specific fluid-structure interaction (FSI) model of the abdominal aorta in ApoE(-/-) mice that incorporates in vivo stresses. The aortic geometry was based on contrast-enhanced in vivo micro-CT images, while aortic flow boundary conditions and material model parameters were based on in vivo high frequency ultrasound. Flow waveforms predicted by FSI simulations corresponded better to in vivo measurements than those from CFD simulations. Peak-systolic principal stresses at the inner and outer aortic wall were locally increased caudal to the celiac and left lateral to the celiac and mesenteric arteries. Interestingly, these were also the locations at which a tear in the tunica media had been observed in previous work on angiotensin II-infused mice. Our preliminary results therefore suggest that local biomechanics play an important role in the pathophysiology of branch-related ruptures in angiotensin-II infused mice. More elaborate follow-up research is needed to demonstrate the role of biomechanics and mechanobiology in a longitudinal setting. PMID- 25824369 TI - Potential Neurogenesis of Human Adipose-Derived Stem Cells on Electrospun Catalpol-Loaded Composite Nanofibrous Scaffolds. AB - Catalpol, a natural active ingredient extracted from the traditional Chinese medicine, was verified exhibiting beneficial effects on neural differentiation compared with commonly used chemical inducers by our previous studies. The aim of this study was to evaluate the effects of catalpol-loaded scaffold on guiding neuronal differentiation of human adipose tissue-derived stem cells (hASCs). Fabrication technique of catalpol loading into the electrospun poly(lactic-co glycolic acid)/multi-walled carbon nanotubes/silk fibroin nanofibrous scaffolds was successfully established. The topographical and mechanical properties of the nanofibers scaffolds were characterized by scanning electron microscopy and tensile instrument, respectively. In vitro catalpol release was studied in phosphate-buffered solution at 37 degrees C. Immunnocytochemistry, RT-PCR, and western blot assays were performed to estimate hASCs neuronal differentiation, and it was shown that catalpol has significantly upregulated the expressions of betaIII-tubulin and Nissl. Our experiments demonstrated that catalpol, as a traditional Chinese medicine extract, could be encapsulated into composite nanofibers and induce differentiation of hASCs into neural-like cells, which might offer new avenues in nerve regeneration. PMID- 25824370 TI - Emerging Brain Morphologies from Axonal Elongation. AB - Understanding the characteristic morphology of our brain remains a challenging, yet important task in human evolution, developmental biology, and neurosciences. Mathematical modeling shapes our understanding of cortical folding and provides functional relations between cortical wavelength, thickness, and stiffness. Yet, current mathematical models are phenomenologically isotropic and typically predict non-physiological, periodic folding patterns. Here we establish a mechanistic model for cortical folding, in which macroscopic changes in white matter volume are a natural consequence of microscopic axonal growth. To calibrate our model, we consult axon elongation experiments in chick sensory neurons. We demonstrate that a single parameter, the axonal growth rate, explains a wide variety of in vitro conditions including immediate axonal thinning and gradual thickness restoration. We embed our axonal growth model into a continuum model for brain development using axonal orientation distributions motivated by diffusion spectrum imaging. Our simulations suggest that white matter anisotropy as an emergent property from directional axonal growth-intrinsically induces symmetry breaking, and predicts more physiological, less regular morphologies with regionally varying gyral wavelengths and sulcal depths. Mechanistic modeling of brain development could establish valuable relationships between brain connectivity, brain anatomy, and brain function. PMID- 25824371 TI - Current approaches in the management of low risk Hodgkin lymphoma in children and adolescents. AB - The outcome for children and adolescents with low risk Hodgkin lymphoma (HL) is excellent, with event-free survival >85% and overall survival >95%. Historically, however, treatment has come at the cost of significant long-term toxicity from chemotherapy, radiation or a combination of these. Recent treatment strategies have focused on maintaining high event-free and overall survival while minimizing the use of therapy associated with late effects. The strategies used to achieve this vary greatly among paediatric cooperative groups and there is no one standard treatment for children with low risk HL. This review summaries recent clinical trials in paediatric low risk HL and addresses some of the important considerations when comparing trials, including differences in the definition of low risk HL, differences in outcome among histological subtypes and varying approaches to reduce or eliminate radiation therapy. Recommendations are provided for the treatment of children with low risk HL outside the setting of a clinical trial. PMID- 25824372 TI - Inhibition of NKp30- and 2B4-mediated NK cell activation by evolutionary different human and bovine CEACAM1 receptors. AB - Carcinoembryonicantigen-related cell adhesion molecule 1 (CEACAM1) is a receptor involved in the regulation of NK-cell function. In most species, the CEACAM1 cytoplasmic tail possesses a membrane-proximal ITIM paired with a membrane-distal immunoreceptor tyrosine-based switch motif (ITSM) signaling motif. Human CEACAM1 has phylogenetically relatively recently acquired a second ITIM instead of the ITSM and was shown to inhibit NKG2D-mediated NK-cell activation. Here, we compare the function of bovine and human CEACAM1. We show that in addition to NKG2D, human CEACAM1 can inhibit NK-cell activation via NKp30 or 2B4. Bovine CEACAM1, possessing an ITIM and an ITSM signaling motif, is also inhibitory. However, bovine CEACAM1 inhibition of NKp30-mediated lysis is less pronounced compared with its human counterpart. Bovine CEACAM1 inhibition is dependent on the membrane-proximal ITIM and our data suggest that also the membrane distal ITSM motif contributes to inhibitory signaling. Biochemically, human and bovine CEACAM1 can recruit the phosphatases SHP-1 and SHP-2 after receptor phosphorylation to a similar extend. Bovine CEACAM1 can additionally recruit the adapter molecule Ewing's sarcoma virus-activated transcript-2 (EAT-2), but not SLAM-associated protein (SAP). Taken together, we show that although human and bovine CEACAM1 are differentially equipped with ITIM and ITSM motifs, both receptors can inhibit NKp30 and 2B4 activation of NK cells. PMID- 25824374 TI - Laboratory study on OH-initiated degradation kinetics of dehydroabietic acid. AB - Dehydroabietic acid (DHAA) is a specific organic tracer for the pyrolysis of conifer resin. To understand its atmospheric stability, the degradation behavior of particulate DHAA in the presence of hydroxyl radicals (OH) was investigated under different environmental conditions using a stainless steel reactor with volume of 30 cm(3), in the dark. At 25 degrees C and 40% relative humidity (RH), the second-order rate constant (k2) of pure DHAA with OH was measured to be 5.72 +/- 0.87 * 10(-12) cm(3) molecule(-1) s(-1). The influence of temperature, RH and mixing state on the degradation kinetics of DHAA were also investigated. At 40% RH, k2 of pure DHAA increases with increasing temperature and follows the Arrhenius equation k2 = (8.9 +/- 1.9) * 10(-10) exp[-(1508.2 +/- 64.2)/T], while RH does not have significant impact on k2 at 25 degrees C. At 25 degrees C and 40% RH, compared with pure DHAA, the corresponding k2 for DHAA mixed with (NH4)2SO4 decreased to 4.58 +/- 0.95 * 10(-12) cm(3) molecule(-1) s(-1), while the value was 3.30 +/- 0.79 * 10(-12) cm(3) molecule(-1) s(-1) when mixed with soot. The atmospheric lifetime of DHAA varied from 2.3 +/- 0.2 to 4.4 +/- 0.8 days under different environmental conditions. This study indicates that degradation of DHAA by OH radicals is appreciable, and a significant error in source apportionment should be introduced if the contribution of degradation to DHAA concentration is not considered during air mass aging. PMID- 25824373 TI - Enriching a cellulose hydrogel with a biologically active marine exopolysaccharide for cell-based cartilage engineering. AB - The development of biologically and mechanically competent hydrogels is a prerequisite in cartilage engineering. We recently demonstrated that a marine exopolysaccharide, GY785, stimulates the in vitro chondrogenesis of adipose stromal cells. In the present study, we thus hypothesized that enriching our silated hydroxypropyl methylcellulose hydrogel (Si-HPMC) with GY785 might offer new prospects in the development of scaffolds for cartilage regeneration. The interaction properties of GY785 with growth factors was tested by surface plasmon resonance (SPR). The biocompatibility of Si-HPMC/GY785 towards rabbit articular chondrocytes (RACs) and its ability to maintain and recover a chondrocytic phenotype were then evaluated in vitro by MTS assay, cell counting and qRT-PCR. Finally, we evaluated the potential of Si-HPMC/GY785 associated with RACs to form cartilaginous tissue in vivo by transplantation into the subcutis of nude mice for 3 weeks. Our SPR data indicated that GY785 was able to physically interact with BMP-2 and TGFbeta. Our analyses also showed that three-dimensionally (3D) cultured RACs into Si-HPMC/GY785 strongly expressed type II collagen (COL2) and aggrecan transcripts when compared to Si-HPMC alone. In addition, RACs also produced large amounts of extracellular matrix (ECM) containing glycosaminoglycans (GAG) and COL2. When dedifferentiated RACs were replaced in 3D in Si-HPMC/GY785, the expressions of COL2 and aggrecan transcripts were recovered and that of type I collagen decreased. Immunohistological analyses of Si HPMC/GY785 constructs transplanted into nude mice revealed the production of a cartilage-like extracellular matrix (ECM) containing high amounts of GAG and COL2. These results indicate that GY785-enriched Si-HPMC appears to be a promising hydrogel for cartilage tissue engineering. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25824375 TI - Strip patch testing does not affect reaction profiles of standard allergens. AB - BACKGROUND: It has been hypothesized that positive reactions in the strip patch test are irritant rather than allergic. OBJECTIVE: To study reaction profiles of the baseline series patch test substances applied routinely on tape-stripped skin according to the reaction index (RI) and the positivity ratio (PR). PATIENTS AND METHODS: One thousand two hundred and twenty-eight consecutive patients were routinely strip patch tested with the baseline series between January 2011 and June 2013 (intervention group). On the basis of test reactions at D3/D4, the RI, and the PR, 25 standard allergens were analysed, and the results were compared with those obtained in 1161 patients patch tested conventionally from July 2008 to December 2010 (historical control group). RESULTS: Nickel sulfate, fragrance mix I, cobalt chloride, Myroxylon pereirae (balsam of Peru) and colophonium showed the highest frequencies of positive reactions in both groups, without any significant differences. Of 25 patch test substances of the baseline series, 18 showed good reaction profiles in the intervention group, and 16 in the historical control group. CONCLUSIONS: Reaction profiles of baseline series patch test substances remained largely unaffected by tape stripping the skin prior to patch testing. Thus, if conventional patch test results are presumed to be false negative, performance of the strip patch test can be recommended independently of the standard allergen. PMID- 25824378 TI - Slow ligand-induced conformational switch increases the catalytic rate in Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase. AB - P. falciparum (Pf) hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT) exhibits a unique mechanism of activation where the enzyme switches from a low activity (unactivated) to a high activity (activated) state upon pre incubation with substrate/products. Xanthine phosphoribosylation by unactivated PfHGXPRT exhibits a lag phase, the duration of which reduces with an increase in concentration of the enzyme or substrate, PRPP.Mg(2+). Activated PfHGXPRT does not display the lag phase and exhibits a ten-fold drop in the Km value for PRPP.Mg(2+). These observations suggest the involvement of ligand-mediated oligomerization and conformational changes in the process of activation. The dipeptide Leu-Lys in the PPi binding site of human and T. gondii HG(X)PRT that facilitates PRPP.Mg(2+) binding by isomerization from trans to cis conformation is conserved in PfHGXPRT. Free energy calculations using the well-tempered metadynamics technique show the ligand-free enzyme to be more stable when this dipeptide is in the trans conformation than in the cis conformation. The high rotational energy barrier observed for the conformational change from experimental and computational studies permits delineation of the activation mechanism. PMID- 25824377 TI - Metabolic profiling-based data-mining for an effective chemical combination to induce apoptosis of cancer cells. AB - Green tea extract (GTE) induces apoptosis of cancer cells without adversely affecting normal cells. Several clinical trials reported that GTE was well tolerated and had potential anti-cancer efficacy. Epigallocatechin-3-O-gallate (EGCG) is the primary compound responsible for the anti-cancer effect of GTE; however, the effect of EGCG alone is limited. To identify GTE compounds capable of potentiating EGCG bioactivity, we performed metabolic profiling of 43 green tea cultivar panels by liquid chromatography-mass spectrometry (LC-MS). Here, we revealed the polyphenol eriodictyol significantly potentiated apoptosis induction by EGCG in vitro and in a mouse tumour model by amplifying EGCG-induced activation of the 67-kDa laminin receptor (67LR)/protein kinase B/endothelial nitric oxide synthase/protein kinase C delta/acid sphingomyelinase signalling pathway. Our results show that metabolic profiling is an effective chemical mining approach for identifying botanical drugs with therapeutic potential against multiple myeloma. Metabolic profiling-based data mining could be an efficient strategy for screening additional bioactive compounds and identifying effective chemical combinations. PMID- 25824379 TI - A Couple's Colitis. PMID- 25824380 TI - Angiotensin converting enzyme and methylenetetrahydrofolate reductase gene variations in fibromyalgia syndrome. AB - OBJECTIVE: Fibromyalgia syndrome (FM) is a common disease characterized by generalized body pain, sensitivity in certain physical areas (sensitive points), lowered pain threshold, sleep disorder, and fatigue. The study aimed to determine the effects ACE I/D and MTHFR C677T gene polymorphisms in Turkish patients with FM and evaluate if there was an association with clinical features. METHODS: This study included 200 FM patients and 190 healthy controls recruited from the department of Physical Medicine and Rehabilitation at Gaziosmanpasa University in Tokat, Turkey. ACE I/D polymorphism genotypes were determined by using polymerase chain reaction (PCR) by specific primers. The MTHFR C677T mutation was analyzed by PCR-based restriction fragment length polymorphism (RFLP) methods. RESULTS: We found a statistically significant relation between ACE polymorphism and FM (p<0.001, OR: 1.71, 95% CI: 1.28-2.27). However, this was not the case for ACE polymorphism and the clinical characteristics of the disease. There was also no statistically significant relation between MTHFR C677T mutation and FMS (p>0.05, OR: 1.20, 95% CI: 0.82-1.78), but dry eye and feeling of stiffness which are among the clinical characteristics of FMS were significantly related with MTHFR C677T mutation (p<0.05). CONCLUSION: Our findings showed that there are associations of ACE I/D polymorphism with susceptibility of a person for development of fibromyalgia syndrome. Also, it is determined an association between MTHFR C677T polymorphism and feeling of stiffness and dry eye which are among the clinical characteristics of FM. Our study is the first report of ACE I/D and MTHFR C677T polymorphisms in fibromyalgia syndrome. PMID- 25824381 TI - Mutation and new polymorphisms insight in introns 11 to 14a of CFTR gene of northern Iranian cystic fibrosis patients. AB - BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians, caused by mutation in cystic fibrosis transmembrane conductance regulator (CFTR). The type and distribution of mutations vary widely between different countries and ethnic groups. We therefore aimed to perform a comprehensive analysis of the CFTR gene in northern Iranian CF patients. METHODS: Forty northern Iranian CF patients were analyzed for mutations in introns 11 to 14a of their CFTR genes, using sequencing and reverse dot blot methods. Five normal subjects were also analyzed as normal control. RESULTS: One mutation and seven polymorphisms were identified. Of the eighty alleles studied, c.2043delG in exon 13 represented 12.5% of mutant alleles and was associated with two distinct haplotypes. rs1042077T>G, rs4148712delAT, rs4148711T>A and rs3808183 T>C with frequencies varying between 29.2% and 6.9% for the least common allele, as well as three new polymorphisms c.1680-224C>A (11.1%), c.2491-275T>G (14.1%) and c.2491-274C>G (35.9%) were detected. CONCLUSION: These findings suggest a founder effect for c.2043delG in the Middle East and will assist in genetic counseling, prenatal diagnosis and future screening of CF in Iran. PMID- 25824382 TI - Association between hypoxia-inducible factor-1alpha gene polymorphisms and risk of chronic hepatitis B and hepatitis B virus-related liver cirrhosis in a Chinese population: a retrospective case-control study. AB - BACKGROUND: Our recent study demonstrated a significant association between HIF 1alpha polymorphisms and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Since chronic hepatitis B (CHB), liver cirrhosis (LC), and HCC are progressive stages of chronic HBV infection, the aim of this study is to further determine if HIF-1alpha polymorphisms are associated with CHB and HBV-related LC. METHODS: Two HIF-1alpha polymorphisms (rs11549465 and rs115494657) were examined in 173 healthy controls, 153 patients with CHB, and 132 patients with HBV-related LC, using the polymerase chain reaction-restriction fragment length polymorphism method. DNA sequencing was also used to validate the genotype results. RESULTS: There were no significant differences regarding the HIF-1alpha rs11549465 and rs115494657 polymorphisms between the patient groups and the healthy controls, no matter the genotypes, alleles, or haplotypes. To exclude the potential influence of HBV infection in the association between HIF-1a and HBV-related LC, a comparison between the LC patients and HBV infected patients was also conducted, but a similar insignificant result was found. CONCLUSIONS: Our data suggest that the HIF-1alpha gene polymorphisms might not contribute to the development of CHB and HBV-related LC in a Chinese population. PMID- 25824383 TI - Development of a simultaneous high resolution typing method for three SLA class II genes, SLA-DQA, SLA-DQB1, and SLA-DRB1 and the analysis of SLA class II haplotypes. AB - The characterization of the genetic variations of major histocompatibility complex (MHC) is essential to understand the relationship between the genetic diversity of MHC molecules and disease resistance and susceptibility in adaptive immunity. We previously reported the development of high-resolution individual locus typing methods for three of the most polymorphic swine leukocyte antigens (SLA) class II loci, namely, SLA-DQA, SLA-DQB1, and SLA-DRB1. In this study, we extensively modified our previous protocols and developed a method for the simultaneous amplification of the three SLA class II genes and subsequent analysis of individual loci using direct sequencing. The unbiased and simultaneous amplification of alleles from the all three hyper-polymorphic and pseudogene containing genes such as MHC genes is extremely challenging. However, using this method, we demonstrated the successful typing of SLA-DQA, SLA-DQB1, and SLA-DRB1 for 31 selected individuals comprising 26 different SLA class II haplotypes which were identified from 700 animals using the single locus typing methods. The results were identical to the known genotypes from the individual locus typing. The new method has significant benefits over the individual locus typing, including lower typing cost, use of less biomaterial, less effort and fewer errors in handling large samples for multiple loci. We also extensively characterized the haplotypes of SLA class II genes and reported three new haplotypes. Our results should serve as a basis to investigate the possible association between polymorphisms of MHC class II and differences in immune responses to exogenous antigens. PMID- 25824384 TI - Auxin crosstalk to plant immune networks: a plant-pathogen interaction perspective. AB - The plant hormone auxin regulates a whole repertoire of plant growth and development. Many plant-associated microorganisms, by virtue of their auxin production capability, mediate phytostimulation effects on plants. Recent studies, however, demonstrate diverse mechanisms whereby plant pathogens manipulate auxin biosynthesis, signaling and transport pathways to promote host susceptibility. Auxin responses have been coupled to their antagonistic and synergistic interactions with salicylic acid and jasmonate mediated defenses, respectively. Here, we discuss that a better understanding of auxin crosstalk to plant immune networks would enable us to engineer crop plants with higher protection and low unintended yield losses. PMID- 25824385 TI - Abscisic Acid: a versatile phytohormone in plant signaling and beyond. AB - As sessile organisms, plants cannot escape from adverse conditions and, therefore, they have developed complex responses to the changing environment. Plant responses to abiotic cues involve changes in metabolism, photosynthesis, gene expression, ion levels, etc., and must be perfectly coordinated by phytohormones. The abscisic acid (ABA) is the main phytohormone involved in abiotic stress responses although it is nowadays clear that its signaling pathways are not isolated but interconnected with other hormone signals in complex networks. This article revises molecular mechanisms involved in the crosstalks of ABA with other phytohormones in response to different physiological processes. Moreover, ABA is not a molecule exclusive from plants but it can be found in many other organisms including bacteria, algae, fungi, animals, etc. Interestingly, it can be synthesized and secreted by a variety of human cells. These aspects that confer to the ABA a range of ubiquitous molecule will be also revised in this article. PMID- 25824386 TI - Gibberellins - a multifaceted hormone in plant growth regulatory network. AB - Plants tend to acclimatize to unfavourable environs by integrating growth and development to environmentally activated signals. Phytohormones strongly regulate convergent developmental and stress adaptive procedures and synchronize cellular reaction to the exogenous and endogenous conditions within the adaptive signaling networks. Gibberellins (GA), a group of tetracyclic diterpenoids, being vital regulators of plant growth, are accountable for regulating several aspects of growth and development of higher plants. If the element of reproduction is considered as an absolute requisite then for a majority of the higher plants GA signaling is simply indispensable. Latest reports have revealed unique conflicting roles of GA and other phytohormones in amalgamating growth and development in plants through environmental signaling. Numerous physiological researches have detailed substantial crosstalk between GA and other hormones like abscisic acid, auxin, cytokinin, and jasmonic acid. In this review, a number of explanations and clarifications for this discrepancy are explored based on the crosstalk among GA and other phytohormones. PMID- 25824387 TI - Phytohormone crosstalk research: cytokinin and its crosstalk with other phytohormones. AB - As signal molecules produced within the plant, phytohormones (plant hormones) control plant growth and development through the regulation of gene expression. They play also a crucial role in the regulation of cellular activities including elongation, cell division and differentiation, organogenesis, pattern formation, reproduction and responses to abiotic and biotic stress conditions. Cytokinins, auxins, gibberellins, abscisic acid and ethylene are five classic phytohormones that had been discovered by the middle of the twentieth century, while strigolactones, brassinosteroids, jasmonates and salicylates are of more recently characterized phytohormones. Interaction between different phytohormone pathways is essential in coordinating tissue outgrowth in response to environmental changes. In the past decades, hormone research has focused on elucidating signal transduction pathways from hormone perception to response. Such efforts have been well paid off by recent discoveries of almost all receptors for major classes of phytohormones. While receptors and pathways for individual hormones are being illustrated, growing evidence suggests that these signaling pathways are interconnected in a complex network. In these pathways, phytohormones not only coordinate fundamental developmental cues, but also convey environmental inputs by means of synergistic or antagonistic actions referred to as signaling crosstalk. Focusing on hormone action and crosstalk, this work suggested concentrating on phytohormones signaling, particularly cytokinin crosstalk with other hormones, in various plants. Plant responses to biotic and abiotic stresses are also elucidated regarding the dramatic recent progress in understanding the cytokinin-other phytohormones crosstalk. PMID- 25824388 TI - Role of brassinosteroid in plant adaptation to abiotic stresses and its interplay with other hormones. AB - Brassinosteroids (BRs) are ubiquitous plant steroid hormones, playing diverse roles in plant growth, development and stress responses. Defects in BRs biosynthesis or signaling result in physiologic and phenotypic abnormalities. To date, numerous studies have highlighted BRs-induced stress tolerance to various environmental extremes such as high temperature, chilling, drought, salinity and heavy metals in a range of plant species. However, the in-depth mechanisms of BRs induced stress tolerance still remain largely unknown. It is now clear that BRs induced stress responses are strictly concentration dependent and the optimal concentration for improving the plant adaptability may vary depending on the plant species, developmental stages and environmental conditions as well. Conflicting evidences concerning regulation of stress adaptation by BRs demand further elucidation of mechanism of BRs action in response to environmental stresses in plants. Recent advances in phytohormone research suggest that the effect of BRs on stress tolerance relies largely on its interplay with other hormones. In this review, we critically analyze the multifaceted roles of BRs in various abiotic stresses and its potential crosstalk with other hormones in stress adaptation. The discrepancy in the dose and mode of application of BRs analogues for stress management is also discussed. PMID- 25824389 TI - Role of various hormones in photosynthetic responses of green plants under environmental stresses. AB - Environmental stress includes adverse factors like water deficit, high salinity, enhanced temperature and heavy metals etc. These stresses alter the normal growth and metabolic processes of plants including photosynthesis. Major photosynthetic responses under various stresses include inhibition of photosystems (I and II), changes in thylakoid complexes, decreased photosynthetic activity and modifications in structure and functions of chloroplasts etc. Various defense mechanisms are triggered inside the plants in response to these stresses that are regulated by plant hormones or plant growth regulators. These phytohormones include abscisic acid, auxins, cytokinins, ethylene, brassinosteroids, jasmonates and salicylic acid etc. The present review focuses on stress protective effects of plants hormones on the photosynthetic responses. PMID- 25824390 TI - Crosstalk among Jasmonate, Salicylate and Ethylene Signaling Pathways in Plant Disease and Immune Responses. AB - Phytohormone crosstalk is crucial for plant defenses against pathogens and insects in which salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) play key roles. These low molecular mass signals critically trigger and modulate plant resistance against biotrophic as well as necrotrophic pathogens through a complex signaling network that even involves participation of other hormones. Crosstalk among SA, JA and ET is mediated by different molecular players, considered as integral part of these crosscommunicating signal transduction pathways. Recent progress has revealed that the positive versus negative interactions among those pathways ultimately enable a plant to fine-tune its defense against specific aggressors. On the other hand, pathogens have evolved strategies to manipulate the signaling network to their favour in order to intensify virulence on host plant. Here we review recent advances and current knowledge on the role of classical primary defense hormones SA, JA and ET as well as their synergistic and antagonistic interaction in plant disease and immune responses. Crosstalk with other hormones such as abscisic acid, auxin, brassinosteroids, cytokinins and melatonin is also discussed mainly in plant disease resistance. In addition to our keen focus on hormonal crosstalk, this review also highlights potential implication of positive and negative regulatory interactions for developing an efficient disease management strategy through manipulation of hormone signaling in plant. PMID- 25824391 TI - The common molecular players in plant hormone crosstalk and signaling. AB - Plant growth and development is under the control of mutual interactions among plant hormones. The five classical categories of plant hormones include auxins, cytokinins, gibberellins, abscisic acid and ethylene. Additionally, newer classes of plant hormones have been recognized like brassinosteroids, jasmonic acid, salicylic acid and polyamines. These hormones play significant roles in regulating the plant growth and development. Various receptors and key signaling components of these hormones have been studied and identified. At genetic level, crosstalk among the various plant hormones is found to be antagonistic or synergistic. In addition, components of signaling pathway of one plant hormone interact with the signaling components of other hormone. Thus, an attempt has been made to review the literature regarding the role of plant hormones in plant physiology and the common molecular players in their signaling and crosstalk. PMID- 25824392 TI - Lower urinary tract cancer. AB - Lower urinary tract neoplasia is uncommon in dogs and cats, though transitional cell carcinoma (TCC) is the most common tumor of the lower urinary tract in both species. Clinical signs are not specific for neoplasia, but neoplasia should be considered in patients that are older, have specific risk factors, or have persistent, severe, or relapsing signs. Local disease is often the cause of death or euthanasia; local control is challenging owing to tumor size and location. Systemic therapy is the mainstay of treatment. Prognosis is generally guarded, but therapy can result in improvement in clinical signs and quality of life. PMID- 25824393 TI - Micturition disorders. AB - Evaluation of dogs and cats with micturition disorders can be challenging. It is important to determine the duration, timing, and frequency of the disorder, as well as assessing for any additional medical problems, such as neurologic or orthopedic disease, that may be affecting micturition. Observation of the patient during voiding can be particularly helpful in determining the type of disorder. Treatment of micturition disorders is varied and outcome depends on an accurate diagnosis. Patient response is also highly variable, even with appropriate therapy, and owners' expectations must be set accordingly. PMID- 25824394 TI - Urinary tract infections: treatment/comparative therapeutics. AB - Urinary tract infection (UTI) occurs when there is compromise of host defense mechanisms and a virulent microbe adheres, multiplies, and persists in a portion of the urinary tract. Most commonly, UTI is caused by bacteria, but fungi and viruses are possible. Urine culture and sensitivity are the gold standards for diagnosis of bacterial UTI. Identifying the location of infection (eg, bladder, kidney, prostate) as well as comorbidities (eg, diabetes mellitus, immunosuppression) is essential to guide the diagnostic and therapeutic plan. Antimicrobial agents are the mainstay of therapy for bacterial UTI and selected ideally based on culture and sensitivity. PMID- 25824395 TI - Stabilizing Two Classical Antiaromatic Frameworks: Demonstration of Photoacoustic Imaging and the Photothermal Effect in Metalla-aromatics. AB - Antiaromatic species are substantially less thermodynamically stable than aromatic moieties. Herein, we report the stabilization of two classical antiaromatic frameworks, cyclobutadiene and pentalene, by introducing one metal fragment through the first [2+2] cycloaddition reaction of a late-transition metal carbyne with alkynes. Experimental observations and theoretical calculations reveal that the metal fragment decreases the antiaromaticity in cyclobutadiene and pentalene simultaneously, leading to air- and moisture-stable products. These molecules show broad absorption from the UV to the near-IR region, resulting in photoacoustic and photothermal effects for metalla-aromatic compounds for the first time. These results will encourage further efforts into the exploration of organometallic compounds for photoacoustic-imaging-guided photothermal therapy. PMID- 25824396 TI - Development of mature BDNF-specific sandwich ELISA. AB - Mature brain-derived neurotrophic factor (mBDNF) plays a vital role in the nervous system, whereas proBDNF elicits neurodegeneration and neuronal apoptosis. Although current enzyme-linked immunosorbent assay (ELISA) has been widely used to measure BDNF levels, it cannot differentiate mBDNF from proBDNF. As the function of proBDNF differs from mBDNF, it is necessary to establish an ELISA assay specific for the detection of mBDNF. Therefore, we aimed to establish a new mBDNF-specific sandwich ELISA. In this study, we have screened and found a combination of antibodies for a sandwich ELISA. A monoclonal antibody and sheep anti-BDNF were chosen as capture and detection antibody for sandwich ELISA respectively. The new ELISA showed no cross-reactivity to human recombinant NT-3, NT-4, nerve growth factor and negligible cross-reactivity (0.99-4.99%) for proBDNF compared to commercial ELISA kits (33.18-91.09%). The application of the new mBDNF ELISA was shown through the measurement of mBDNF levels in different brain regions of rats and in the brain of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)(-/-) and WT mice and compared to western blot. Overall, this new ELISA will be useful for the measurement of mBDNF levels with high specificity. As the function of proBDNF differs from mBDNF (mature BDNF), it is necessary to establish an ELISA specific for the detection of mBDNF. Here, we present a novel sandwich ELISA which detects mBDNF with high specificity. This new ELISA will be useful for the measurement of mBDNF levels with high specificity in various human and animal tissues. proBDNF, precursor of BDNF; BDNF, brain-derived neurotrophic factor; NT-3, neurotrophin-3; NT-4, neurotrophin 4; NGF, nerve growth factor. PMID- 25824397 TI - [Complementary therapies in the guidelines for the treatment of irritable bowel syndrome]. PMID- 25824398 TI - [Complementary Medicine in Oncology - difficult to claim effectiveness, quality and efficiency]. PMID- 25824399 TI - [Lymphocyte migration under exposure of homeopathic remedies for periodontal inflammation - a controlled pilot study]. AB - BACKGROUND: Several homeopathic remedies are applied in the treatment of periodontal inflammation. However, little is known about their basic active principles. Therefore, we aimed at investigating the effects of homeopathic drugs in periodontal inflammation by observing lymphocyte migration activity in vitro. MATERIAL AND METHODS: Lymphocytes from blood samples of 3 periodontitis patients and 3 matched healthy volunteers were extracted and embedded in collagen matrix migration assays together with highly diluted (D12 and C200) aqueous extracts from Mercurius solubilis, Silicea, Sulphur, Tuberculinum, or placebo. Lymphocyte migration and lymphocyte speed were observed in a 60-min time frame. Statistical analysis was performed using univariate statistics and SiZer time series analysis. RESULTS: While C-dilutions did not reveal clear differences between placebo and substances, strong effects were observed in D-dilutions compared to placebo. The strongest effects were achieved in lymphocytes exposed to Sulfur D12. While most specific effects were observed in Sulphur D12 showing an activating effect on periodontitis patient lymphocytes (mean activity: 11,1% (placebo) vs. 23,8% (verum)), there was no effect in healthy volunteers (25,8% (placebo) vs. 25,6% (verum)). SiZer analysis confirmed this effect to be significant. CONCLUSION: The basic active principles of highly diluted substances are still a matter of controversial debate. Although conclusions are limited due to low sample size, results from our pilot study might encourage further investigations on the role of highly diluted Sulphur in the treatment of periodontitis. Apart from a reproduction study with Sulphur, other immunological experiments, i.e. the investigation of cell limes via flow cytometry, should be performed to underpin these results. PMID- 25824400 TI - Homeopathic complex remedy in the treatment of allergic rhinitis: results of a prospective, multicenter observational study. AB - BACKGROUND: Seasonal allergic rhinitis (SAR), also known as hay fever, is a widespread chronic respiratory disease. In treatment of SAR the use of complementary therapies is increasing, but little has been published about homeopathic complex remedies so far. Therefore, we think it is time to conduct and publish an appropriate observational study. METHODS: Course of single symptoms, impairment of quality of life, general efficacy, and tolerability of a homeopathic complex remedy containing active substances on a low dilution level have been assessed and analyzed. Altogether, 123 patients with a history of allergic rhinitis of up to 45 years have been observed for about 4 weeks. RESULTS: The majority of symptoms were shown to improve substantially and the patients' quality of life increased clearly. The overall symptom score decreased significantly from 10.3 +/- 4.7 to 3.9 +/- 3.1 points (p < 0.0001), and reduction of impairment of quality of life from 5.7 +/- 2.3 to 1.9 +/- 1.8 score points was also significant (p < 0.0001). Rating of efficacy of study medication was markedly better than efficacy rating of previous therapies (p = 0.0193). Apart from one temporary allergic reaction, the treatment was well tolerated. CONCLUSION: The homeopathic complex remedy (Pascallerg(r)) tested in this observational study offers a useful option in treatment of SAR in children and adults. PMID- 25824401 TI - Mind the gap! Lay and medical perceptions of risks associated with the use of alternative treatment and conventional medicine. AB - BACKGROUND: Studies on the widespread use of complementary and alternative medicine (CAM) demonstrate that CAM users base their treatment decisions on both subjective, experience-based knowledge and medical knowledge. The aim of this study was to explore lay and medical risk perceptions associated with CAM and conventional medicine. PATIENTS AND METHODS: In this explorative qualitative study, we conducted in-depth interviews with 25 Norwegian CAM users with cancer or multiple sclerosis and 12 doctors. RESULTS: The interviews revealed fundamental differences in risk perceptions influencing treatment decisions and risk communication in a clinical setting. While CAM users considered conventional medicine as potentially risky and related this to experiences of severe adverse effects, CAM was perceived as natural and safe. Doctors' risk perceptions were quite the contrary, mainly because of lack of scientific evidence for CAM as a safe and beneficial treatment option. CONCLUSION: For the safety of CAM users, such divergent risk perceptions may have far-reaching consequences. CAM users should be taken seriously with their self-perception as decision-makers considering their approaches to experiences, knowledge, and science. An awareness of differing lay and medical risk perceptions associated with CAM and conventional medicine in research, doctor-patient communication, and education of patients and doctors is thus important to optimize patient safety in complex health care systems. PMID- 25824402 TI - How to handle worsening of condition during treatment - risk assessment in homeopathic practice. AB - Even though homeopathy is regarded as a harmless intervention, homeopathic practice may not be entirely risk-free. Risk in homeopathy can be divided into direct and indirect risk. Direct risk refers to traditional adverse effects of an intervention; indirect risk is related to adverse effects in a treatment context, e.g. the practitioner. Available data suggest that the risk profile of homeopathic remedies in ultra-molecular potencies is minor, but there is a potential for indirect risk related to homeopathic practice. The concept of 'homeopathic aggravation' which is unique for homeopathy may impose a particular risk as it allows the health status of the patients to deteriorate before there is a possible improvement. In that respect it is imperative to distinguish homeopathic aggravations from adverse effects. In a general risk evaluation of the homeopathic treatment it may be useful to assess the patient's symptoms in accordance with the natural course of disease and to evaluate any negative deviation from the normal curve as a possible adverse effect of the treatment. It is imperative that more emphasis is placed on patient safety during the education in homeopathy, and that students are trained to identify serious and red flag situations. PMID- 25824403 TI - Complementary medicine for cancer patients in general practice: qualitative interviews with german general practitioners. AB - BACKGROUND: The aim of this study was to investigate how general practitioners react when their cancer patients show interest in complementary medicine, and how their reaction is related to their knowledge in the field. METHODS: We conducted semi-structured interviews with 10 German general practitioners. Interviewees came from 5 different federal states and varied in terms of urban/rural setting, single/joint practice, additional certifications, gender and length of professional experience. Interviews were electronically recorded, transcribed and then analysed using qualitative content analysis according to Mayring. RESULTS: General practitioners feel largely responsible for providing information on complementary medicine to their cancer patients. However, uncertainty and a lack of knowledge concerning CAM lead mainly to reactive responses to patients' needs, and the general practitioners base their recommendations on personal experiences and attitudes. They wish to support their cancer patients and thus, in order to keep their patients' hopes up and maintain a trusting relationship, sometimes support complementary medicine, regardless of their own convictions. CONCLUSION: Although general practitioners see themselves as an important source of information on complementary medicine for their cancer patients, they also speak of their uncertainties and lack of knowledge. General practitioners would profit from training in complementary medicine enabling them to discuss this topic with their cancer patients in a proactive, open and honest manner. PMID- 25824404 TI - Effects of bergamot ( Citrus bergamia (Risso) Wright & Arn.) essential oil aromatherapy on mood states, parasympathetic nervous system activity, and salivary cortisol levels in 41 healthy females. AB - BACKGROUND: Bergamot essential oil (BEO) is commonly used against psychological stress and anxiety in aromatherapy. The primary aim of the present study was to obtain first clinical evidence for these psychological and physiological effects. A secondary aim was to achieve some fundamental understanding of the relevant pharmacological processes. METHODS: Endocrinological, physiological, and psychological effects of BEO vapor inhalation on 41 healthy females were tested using a random crossover study design. Volunteers were exposed to 3 experimental setups (rest (R), rest + water vapor (RW), rest + water vapor + bergamot essential oil (RWB)) for 15 min each. Immediately after each setup, saliva samples were collected and the volunteers rested for 10 min. Subsequently, they completed the Profile of Mood States, State-Trait Anxiety Inventory, and Fatigue Self-Check List. High-frequency (HF) heart rate values, an indicator for parasympathetic nervous system activity, were calculated from heart rate variability values measured both during the 15 min of the experiment and during the subsequent 10 min of rest. Salivary cortisol (CS) levels in the saliva samples were analyzed using ELISA. RESULTS: CS of all 3 conditions R, RW, and RWB were found to be significantly distinct (p = 0.003). In the subsequent multiple comparison test, the CS value of RWB was significantly lower when compared to the R setup. When comparing the HF values of the RWB setup during the 10 min of rest after the experiment to those of RW, this parameter was significantly increased (p = 0.026) in the RWB setup for which scores for negative emotions and fatigue were also improved. CONCLUSION: These results demonstrate that BEO inhaled together with water vapor exerts psychological and physiological effects in a relatively short time. PMID- 25824405 TI - Leech therapy in Iranian traditional medicine. PMID- 25824407 TI - Proteomic analysis of the effect of extracellular calcium ions on human mesenchymal stem cells: Implications for bone tissue engineering. AB - Human mesenchymal stem cells-bone marrow (BM-hMSCs) are considered as the most suitable seed cells for bone tissue engineering. Calcium ions (Ca(2+)) forms an important component of a number of commercial bone substitutes and support materials. For efficient bone tissue engineering, it is crucial to explore the effect of extracellular Ca(2+) on the growth and differentiation of BM-hMSCs, and to understand their molecular mechanisms. Therefore, in the present study, BM hMSCs were cultivated in serum free growth medium or serum free growth medium with additional 4 or 6mM Ca(2+) for 3weeks, following which, the proliferation and osteoblastic differentiation of these cells were evaluated. Differentially expressed proteins were established using iTRAQ labeling coupled with nano-LC MS/MS. Our data revealed that Ca(2+) significantly promoted the proliferation of BM-hMSCs in the early stage. Furthermore, Ca(2+) showed osteoinduction properties. MAPKs signaling pathway might participate in the osteogenic differentiation of BM-hMSCs caused by Ca(2+). Certain newly found proteins could be potentially important for the osteogenic differentiation of BM-hMSCs and may be associated with osteogenesis. PMID- 25824408 TI - Novel roles of ginsenoside Rg3 in apoptosis through downregulation of epidermal growth factor receptor. AB - Ginsenoside Rg3 (Rg3), a pharmacologically active compound from red ginseng, has been reported to induce cell death in various cancer cell lines, although the specific mechanisms have not been well established. In the present study, Rg3 treatment to A549 human lung adenocarcinoma led to cell death via not only apoptotic pathways but also the downregulation of epidermal growth factor receptor (EGFR). We used cross-linker and cell enzyme-linked immunosorbent assays to show that Rg3 inhibited EGFR dimerization by EGF stimulation and caused EGFR internalization from the cell membrane. Among several important phosphorylation sites in cytoplasmic EGFR, Rg3 increased the phosphorylation of tyrosine 1045 (pY1045) and serine 1046/1047 (pS1046/1047) for EGFR degradation and coincidently, attenuated pY1173 and pY1068 for mitogen-activated protein kinase activity. These effects were amplified under EGF-pretreated Rg3 stimulation. In vivo experiments showed that the average volume of the tumors treated with 30 mg/kg of Rg3 was significantly decreased by 40% compared with the control. Through immunohistochemistry, we detected the fragmentation of DNA, the accumulation of Rg3, and the reduction of EGFR expression in the Rg3-treated groups. Here, we provide the first description of the roles of Rg3 in the reduction of cell surface EGFR, the attenuation of EGFR signal transduction, and the eventual activation of apoptosis in A549 human lung adenocarcinoma. PMID- 25824409 TI - Gambogic acid sensitizes resistant breast cancer cells to doxorubicin through inhibiting P-glycoprotein and suppressing survivin expression. AB - The development of resistance to chemotherapeutic agents remains a major challenge to breast cancer chemotherapy. Overexpression of drug efflux transporters like P-glycoprotein (P-gp) and resistance to apoptosis are the two key factors that confer cancer drug resistance. Gambogic acid (GA), a major component of Gamboge resin, has potent anticancer effects and can inhibit the growth of several types of human cancers. However, the potential and underlying mechanisms of GA in reversing cancer resistance remain poorly understood. In the present study, we found that GA can markedly sensitize doxorubicin (DOX) resistant breast cancer cells to DOX-mediated cell death. GA increased the intracellular accumulation of DOX by inhibiting both P-gp expression and activity. Meanwhile, the combination effect was associated with the generation of intracellular reactive oxygen species (ROS) and the suppression of anti-apoptotic protein survivin. Scavenging intracellular ROS or overexpression of survivin blocked the sensitizing effects of GA in DOX-induced apoptosis. Furthermore, ROS mediated activation of p38 MAPK was revealed in GA-mediated suppression of survivin expression. This study gives rise to the possibility of applying GA as an anticancer agent for the purpose of combating DOX-resistant breast cancer. PMID- 25824410 TI - Protection of radiation induced DNA and membrane damages by total triterpenes isolated from Ganoderma lucidum (Fr.) P. Karst. AB - The total triterpenes isolated from the fruiting bodies of Ganoderma lucidum was examined for its potential to prevent gamma-radiation induced membrane damage in rat liver mitochondria and microsomes. The effects of total triterpenes on gamma radiation-induced DNA strand breaks in pBR 322 plasmid DNA in vitro and human peripheral blood lymphocytes ex vivo were evaluated. The protective effect of total triterpenes against gamma-radiation-induced micronuclei formations in mice bone marrow cells in vivo were also evaluated. The results indicated the significant effectiveness of Ganoderma triterpenes in protecting the DNA and membrane damages consequent to the hazardous effects of radiation. The findings suggest the potential use of Ganoderma triterpenes in radio therapy. PMID- 25824411 TI - Antitumor activity of 4-O-(2"-O-acetyl-6"-O-p-coumaroyl-beta-D-glucopyranosyl)-p coumaric acid against lung cancers via mitochondrial-mediated apoptosis. AB - This study was aimed to investigate antitumor activity of 4-O-(2"-O-acetyl-6"-O-p coumaroyl-beta-D-glucopyranosyl)-p-coumaric acid (4-ACGC) against lung cancer and its mechanisms. The anti-proliferative effects of 4-ACGC on lung cancer cell lines including A549, NCI-H1299, HCC827 were evaluated by MTT method and the IC50 values were calculated, and subsequently a mice xenograft model of A549 was established to investigate the antitumor effect of 4-ACGC in vivo. Furthermore, the apoptosis of the A549 cells was determined by fluorescence microscope by staining with Hoechst 33324 and flow cytometer by staining with FITC conjugated Annexin V/PI, and the further mechanisms were investigated by Western blotting. Our results demonstrated that 4-ACGC possessed notable anti-tumor activity on lung cancer in vivo and in vitro; the mechanisms were involved in inducing mitochondria-mediated apoptosis via up-regulations of caspase-3, caspase-9, Bad and Bax, and down-regulation of Bcl-2. Collectively, our results indicated that the 4-ACGC could be treated as a new candidate for treatment of lung cancer in the future. PMID- 25824413 TI - Synthesis and structure of Ag(I), Pd(II), Rh(I), Ru(II) and Au(I) NHC-complexes with a pendant Lewis acidic boronic ester moiety. AB - Bifunctional Ag(I), Pd(II), Rh(I), Ru(II) and Au(I) complexes containing a NHC ligand and a pendant trivalent boron moiety have been synthesized in high yields. Fine-tuned reaction conditions were used to prevent potential ligand self quenching or polymerization due to the eventual co-existence in situ of free NHC (Lewis base) and boronic ester (Lewis acid) in the same molecule. PMID- 25824412 TI - In vitro and in vivo evaluation of novel cinnamyl sulfonamide hydroxamate derivative against colon adenocarcinoma. AB - The potential of cinnamic acid as an anti-inflammatory and anti-cancer agent has been studied previously. In our investigation, novel bio-isosters of cinnamyl sulfonamide hydroxamate were synthesized, characterized and confirmed for their structure and evaluated for cytotoxicity. Three NCEs namely, NMJ-1, -2 and -3 showed cell-growth inhibition in 6 human cancer cell lines with IC50 at the range of 3.3+/-0.15-44.9+/-2.6 MUM. The hydroxamate derivatives of cinnamyl sulfonamide are reported inhibitors of HDAC enzyme. Thus, the effectiveness of these molecules was determined by whole cell HDAC assay in HCT 116 cell line. NMJ-2 (0.41+/-0.01 MUM) exhibited better enzyme inhibition (IC50) compared to SAHA (2.63+/-0.07). In order to evaluate induction of apoptosis by treatment, Hoechst 33342 and AO/EB nuclear staining methods were used. Further, cell cycle analysis, Annexin V binding and caspase 3/7 activation assays were performed by flow cytometry where NMJ-2 significantly arrested the cell cycle at G2/M phase, increased Annexin V binding to the cell surface and activation of caspase-3/7. Bax/Bcl-2 ratio was observed by Western blot and showed an increase with NMJ-2 treatment. This was comparable to standard SAHA. The acute toxicity study (OECD 425) showed that NMJ-2 was safe up to 2000 mg/kg in rats. 1,2-Dimethyl hydrazine (DMH) was used to produce experimental colon adenocarcinoma in Wistar rats. 5-FU and NMJ-2 (100 mg/kg p.o. and 10 mg/kg i.p. once daily for 21 days, respectively) were administered to the respective groups. Both treatments significantly reduced ACFs, adenocarcinoma count, TNF-alpha, IL-6, nitrite and nitrate levels in colonic tissue. Our findings indicate that NMJ-2 has potent anti-cancer activity against colon cancer, by acting through HDAC enzyme inhibition and activation of intrinsic mitochondrial apoptotic pathway, with additional anti-inflammatory activity. PMID- 25824414 TI - n-Order and maximum fuzzy similarity entropy for discrimination of signals of different complexity: Application to fetal heart rate signals. AB - This paper presents two new concepts for discrimination of signals of different complexity. The first focused initially on solving the problem of setting entropy descriptors by varying the pattern size instead of the tolerance. This led to the search for the optimal pattern size that maximized the similarity entropy. The second paradigm was based on the n-order similarity entropy that encompasses the 1-order similarity entropy. To improve the statistical stability, n-order fuzzy similarity entropy was proposed. Fractional Brownian motion was simulated to validate the different methods proposed, and fetal heart rate signals were used to discriminate normal from abnormal fetuses. In all cases, it was found that it was possible to discriminate time series of different complexity such as fractional Brownian motion and fetal heart rate signals. The best levels of performance in terms of sensitivity (90%) and specificity (90%) were obtained with the n-order fuzzy similarity entropy. However, it was shown that the optimal pattern size and the maximum similarity measurement were related to intrinsic features of the time series. PMID- 25824415 TI - Year in review 2014: Interstitial lung disease, physiology, sleep and ventilation, acute respiratory distress syndrome, cystic fibrosis, bronchiectasis and rare lung disease. PMID- 25824416 TI - Normalizing: adolescent experiences living with type 1 diabetes. AB - PURPOSE: The purpose of this research study was to gain a greater understanding of adolescents' experiences living with diabetes and build a theoretical paradigm to inform interventional design. METHODS: Classical grounded theory was utilized; 15 in-depth interviews of 11 subjects were conducted with Caucasian adolescents' ages 11 to 15 with type 1 diabetes. Interviews were recorded and transcribed verbatim. Data were analyzed using constant comparative analysis. Codes were linked to create the paradigm. RESULTS: A theoretical model was developed about the concept of "normalizing." Normalizing is defined as the ability of the adolescents to integrate diabetes into the background of their daily life by creating routines to make diabetes "part of me." Codes identified in normalizing included: (1) recognizing life is changing, (2) taking action to prevent a crisis, (3) disclosing to engage support, (4) taking on the burden of care, (5) accepting the "new normal," and (6) hoping for a normal future. CONCLUSIONS: Normal developmental tasks of adolescence were closely related and contribute to understanding why adolescents struggle with diabetes. These research findings place a different and positive perspective on diabetes management; the focus shifts to supporting wellness and maintaining a normal life rather than on illness. Findings are expected to be of value to health providers working with adolescents with type 1 diabetes, parents, nursing researchers, and adolescents facing the challenge of diabetes management. PMID- 25824417 TI - Exercise-induced oxygen desaturation in chronic obstructive pulmonary disease patients. PMID- 25824418 TI - The Stair-climbing Test. The Quest for Much-needed Simplicity. PMID- 25824419 TI - Work-related Accidents, Absenteeism and Productivity in Patients With Sleep Apnea. A Future Consideration in Occupational Health Assessments? PMID- 25824420 TI - Dose painting to treat single-lobe prostate cancer with hypofractionated high dose radiation using targeted external beam radiation: Is it feasible? AB - Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involved lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V70 (the volume receiving >=70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V70 was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB. PMID- 25824421 TI - Dosimetric feasibility of an "off-target isocenter" technique for cranial intensity-modulated radiosurgery. AB - To evaluate the dosimetric effect of placing the isocenter away from the planning target volume (PTV) on intensity-modulated radiosurgery (IMRS) plans to treat brain lesions. A total of 15 patients who received cranial IMRS at our institution were randomly selected. Each patient was treated with an IMRS plan designed with the isocenter located at the target center (plan A). A second off target isocenter plan (plan B) was generated for each case. In all the plans,100% of the prescription dose covered 99% of the target volume. The plans A and B were compared for the target dosage (conformity index [CI] and homogeneity index) and organs-at-risk (OAR) dose sparing. Peripheral dose falloff was compared by using the metrics volume of normal brain receiving more than 12-Gy dose (V12) and CI at the level of the 50% of the prescription dose (CI 50%). The values found for each metric (plan B vs plan A) were (mean +/- standard deviation [SD]) as follows-CI: 1.28 +/- 0.15 vs 1.28 +/- 0.15, p = 0.978; homogeneity index (HI): 1.29 +/- 0.14 vs 1.34 +/- 0.17, p = 0.079; maximum dose to the brainstem: 2.95 +/- 2.11 vs 2.89 +/- 1.88Gy, p = 0.813; maximum dose to the optical pathway: 2.65 +/- 4.18 vs 2.44 +/- 4.03Gy, p = 0.195; and maximum dose to the eye lens: 0.33 +/- 0.73 vs 0.33 +/ 0.53Gy, p = 0.970. The values of the peripheral dose falloff were (plan B vs plan A) as follows-V12: 5.98 +/- 4.95 vs 6.06 +/- 4.92cm(3), p = 0.622, and CI 50%: 6.08 +/- 2.77 vs 6.28 +/- 3.01, p = 0.119. The off-target isocenter solution resulted in dosimetrically comparable plans as the center-target isocenter technique, by avoiding the risk of gantry-couch collision during the cone beam computed tomography (CBCT) acquisition. PMID- 25824422 TI - Epitaxial Growth of ZSM-5@Silicalite-1: A Core-Shell Zeolite Designed with Passivated Surface Acidity. AB - The design of materials with spatially controlled chemical composition has potential advantages for wide-reaching applications that span energy to medicine. Here, we present a method for preparing a core-shell aluminosilicate zeolite with continuous translational symmetry of nanopores and an epitaxial shell of tunable thickness that passivates Bronsted acid sites associated with framework Al on exterior surfaces. For this study, we selected the commercially relevant MFI framework type and prepared core-shell particles consisting of an aluminosilicate core (ZSM-5) and a siliceous shell (silicalite-1). Transmission electron microscopy and gas adsorption studies confirmed that silicalite-1 forms an epitaxial layer on ZSM-5 crystals without blocking pore openings. Scanning electron microscopy and dynamic light scattering were used in combination to confirm that the shell thickness can be tailored with nanometer resolution (e.g., 5-20 nm). X-ray photoelectron spectroscopy and temperature-programmed desorption measurements revealed the presence of a siliceous shell, while probe reactions using molecules that were either too large or adequately sized to access MFI pores confirmed the uniform shell coverage. The synthesis of ZSM-5@silicalite-1 offers a pathway for tailoring the physicochemical properties of MFI-type materials, notably in the area of catalysis, where surface passivation can enhance product selectivity without sacrificing catalyst activity. The method described herein may prove to be a general platform for zeolite core-shell design with potentially broader applicability to other porous materials. PMID- 25824423 TI - Double Dissociation of the Roles of Metabotropic Glutamate Receptor 5 and Oxytocin Receptor in Discrete Social Behaviors. AB - Social interactions in vertebrates are complex phenomena based on affective and cognitive processes. Multiple brain regions and neurotransmitter systems are involved in the expression of social behaviors, but their individual roles in specific aspects of social interactions are not well understood. Here we investigated how Gq-protein-coupled metabotropic glutamate receptor 5 (mGluR5) and oxytocin receptor (Oxtr) affect social affiliation and social memory. We used conditional genetic approaches in which the genes coding for these receptors were knocked out in the lateral septum by infusion of recombinant adeno-associated viral vectors containing Cre recombinase (AAV-Cre). Social behavior was assessed 2 weeks later using a three-chamber paradigm for sociability and preference for social novelty. Septal deletion of mGluR5 abolished sociability while leaving preference for social novelty intact. In contrast, deletion of Oxtr did not affect sociability but significantly impaired preference for social novelty. Nonsocial behaviors or memories, including novel object recognition or fear conditioning, were not affected by these genetic manipulations. Immunohistochemical analyses of the distribution of mGluR5 and Oxtr revealed non overlapping localization of these receptors within the lateral septum, suggesting that not only different neurotransmitters but also different neuronal types contribute to sociability versus preference for social novelty. Our findings identify highly specialized roles of lateral septal mGluR5 and Oxtr in the the regulation of discrete social behaviors, and suggest that deficits in social interactions, which accompany many mental illnesses, would benefit from comprehensive treatments targeting different components of social functioning. PMID- 25824425 TI - Reading in the operating room. PMID- 25824424 TI - Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT D Trial. AB - Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ?50% symptom improvement on the 17 item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments. PMID- 25824426 TI - Black box audio/video recording in the operating room: time for anesthesiologists to get with the picture. PMID- 25824428 TI - Increased physiologic intensity during walking and running on a non-motorized, curved treadmill. AB - OBJECTIVE: To determine whether exercise performed on a non-motorized, curved treadmill (NMCT) provides greater physiologic stimulus compared to a standard motorized treadmill (SMT). STUDY DESIGN: Crossover. SETTING: Clinical research laboratory. PARTICIPANTS: 10 healthy athletic adults. MAIN OUTCOME MEASURES: Participants walked (1.34 m s(-1)) for 3 min and ran (2.24 m s(-1)) for 4 min on NMCT and SMT (randomized order) while metabolic data and rating of perceived exertion (RPE) were collected. Participants then identified preferred easy and moderate intensity training paces on each treadmill while blinded to speed. Repeated-measures ANOVA and Wilcoxon Signed-Rank tests were used to compare responses between treadmills. RESULTS: Intensity was significantly greater (P < 0.001) for NMCT than SMT [mean (95% confidence interval): Walking = 5.9(5.3,6.4) vs. 3.4(3.0,3.7) METs; Running = 10.7(9,6,11.7) vs. 7.3(6.8,7.8) METs]. Overall RPE was significantly greater (P < 0.01) on NMCT than SMT for walking [median (inter-quartile range): 7(1) vs. 6(0.8)] and running [11.5(3) vs. 8(2.5)]. Preferred speed was significantly slower on NMCT than SMT for easy [2.5(2.3,2.7) vs. 2.8(2.5,3.1) m s(-1)] and moderate [3.2(3.0,3.4) vs. 3.5(3.1,3.9) m s(-1)] intensities. CONCLUSIONS: NMCT elicits greater physiological stimulus than SMT with small, though statistically significant, changes in RPE at matched speeds. Clinicians must be aware of differences in intensity and RPE when prescribing exercise on NMCT. PMID- 25824427 TI - Efficacy of Raynaud's phenomenon and digital ulcer pharmacological treatment in systemic sclerosis patients: a systematic literature review. AB - To evaluate the efficacy of current treatments for the Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc), a systematic literature search was performed using Medline, EMBASE, and Cochrane Central Register of Controlled Trials (from 1961 to October 2011). We included meta-analyses, systematic reviews, clinical trials, and high-quality cohort studies published in English or Spanish. Patient populations had to include adults diagnosed with limited cutaneous or diffuse SSc who had associated RP and/or digital ulcers under pharmacological treatment. Efficacy of treatments was evaluated based on: number of RP episodes, RP severity, episode-free time, ulcer improvement/healing, and appearance of new ulcers. We used the Jadad scale of methodological quality to evaluate the quality of randomized clinical trials, and the 2009 Oxford Centre for Evidence-Based Medicine classification for other studies. Of a total of 1617 studies identified, only 27 fulfilled inclusion criteria. Drugs received the following grade recommendations: Grade A for nifedipine, nicardipine, quinapril, IV iloprost, bosentan, tadalafil, and MQx-503; Grade B for beraprost, cicaprost, DMSO, cyclofenil, and atorvastatin; and Grade C for misoprostol, prazosin, OPC 2826, enalapril, sildenafil, antioxidant, and stanazolol. Calcium channel blockers, prostanoids, tadalafil, and bosentan received the highest recommendation level for their effectiveness. However, most systematic reviews reviewed just a handful of studies with small sample sizes and short follow-ups. Our review shows that the existing evidence on the efficacy of RP treatment in SSc patients is inconclusive which calls for further research, especially in the form of prospective studies of high quality with long-term follow-ups. PMID- 25824429 TI - The efficacy of therapeutic ultrasound for rotator cuff tendinopathy: A systematic review and meta-analysis. AB - A systematic review and meta-analysis on the efficacy of therapeutic ultrasound (US) in adults suffering from rotator cuff tendinopathy. A literature search was conducted in four databases for randomized controlled trials (RCT) published until 12/2013, comparing the efficacy of US to any other interventions in adults suffering from rotator cuff tendinopathy. The Cochrane Risk of Bias tool was used to evaluate the risk of bias of included studies. Data were summarized qualitatively or quantitatively. Eleven RCTs with a low mean methodological score (50.0% +/- 15.6%) were included. Therapeutic US did not provide greater benefits than a placebo intervention or advice in terms of pain reduction and functional improvement. When provided in conjunction with exercise, US therapy is not superior to exercise alone in terms of pain reduction and functional improvement (pooled mean difference of the Constant-Murley score: -0.26 with 95% confidence interval of -3.84 to 3.32). Laser therapy was found superior to therapeutic US in terms of pain reduction. Based on low to moderate level evidence, therapeutic US does not provide any benefit compared to a placebo or advice, to laser therapy or when combined to exercise. More methodologically sound studies on the efficacy of therapeutic US are warranted. PMID- 25824430 TI - Association between circulating thrombopoietin levels and cardiovascular risk prediction scores in renal transplant recipients. AB - BACKGROUND/AIMS: The 7-year Major Adverse Cardiovascular Events Calculator (CRCRTR-MACE) predicts cardiovascular events (CVE) in renal transplant recipients (RTR), and thrombopoietin (TPO) is a humoral inflammatory factor implicated in cardiovascular disease (CVD). The aim of the study was to determine if circulating TPO levels in stable RTR are positively associated with variable(s) in the CRCRTR-MACE score. METHODS: CRCRTR-MACE scores were calculated in 95 stable RTR. TPO levels were measured by multiplexed fluorescent bead-based immunoassay in all patients and 48 controls. Multivariate analysis (MVA) was performed between TPO and CV risk variables and patient demographics. Stepwise regression with backward elimination of insignificant variables estimated the impact of risk variables on TPO levels. Significance was defined at p < 0.05. Normalized data were presented as mean +/- SD and non-normalized data as median (maximum to minimum). RESULTS: The risk of a CVE within 7 years as predicted by the median was 9.97% (range 1.93-84.2). The percentage of patients who were above 20% risk for a CVE was 28.4%. Control TPO level of 170.41 (4.4-995.9) pg/ml was significantly lower than that of 237.90 (32.77-1,386.79) pg/ml in RTR (p = 0.010). TPO level correlated significantly with the total CRCRTR-MACE score (R = 0.310, p = 0.004), smoking (p = 0.009) and eGFR (R = -0.275, p = 0.012) but not with age, diabetes, LDL level or history of CVE. Only the total CRCRTR-MACE score (p = 0.013) and smoking (p = 0.009) remained significant in the MVA. Stepwise regression estimated that smoking increased TPO levels by 206.28 pg/ml and each 10% increase in CRCRTR-MACE score increased TPO levels by an additional 44.4 pg/ml. CONCLUSION: TPO levels are increased in RTR with high CRCRTR-MACE, particularly in smokers with diminished eGFR. Circulating TPO may serve as a biomarker and treatment target for CVD in RTR. PMID- 25824431 TI - Interspecies Transfer and Regulation of Pseudomonas stutzeri A1501 Nitrogen Fixation Island in Escherichia coli. AB - Until now, considerable effort has been made to engineer novel nitrogen-fixing organisms through the transfer of nif genes from various diazotrophs to non nitrogen fixers; however, regulatory coupling of the heterologous nif genes with the regulatory system of the new host is still not well understood. In this work, a 49 kb nitrogen fixation island from P. stutzeri A1501 was transferred into E. coli using a novel and efficient transformation strategy, and a series of recombinant nitrogen-fixing E. coli strains were obtained. We found that the nitrogenase activity of the recombinant E. coli strain EN-01, similar to the parent strain P. stutzeri A1501, was dependent on external ammonia concentration, oxygen tension, and temperature. We further found that there existed a regulatory coupling between the E. coli general nitrogen regulatory system and the heterologous P. stutzeri nif island in the recombinant E. coli strain. We also provided evidence that the E. coli general nitrogen regulator GlnG protein was involved in the activation of the nif-specific regulator NifA via a direct interaction with the NifA promoter. To the best of our knowledge, this work plays a groundbreaking role in increasing understanding of the regulatory coupling of the heterologous nitrogen fixation system with the regulatory system of the recipient host. Furthermore, it will shed light on the structure and functional integrity of the nif island and will be useful for the construction of novel and more robust nitrogen-fixing organisms through biosynthetic engineering. PMID- 25824432 TI - Molecular Analysis of Promoter and Intergenic Region Attenuator of the Vibrio vulnificus prx1ahpF Operon. AB - Prx1, an AhpF-dependent 2-Cys peroxiredoxin (Prx), was previously identified in Vibrio vulnificus, a facultative aerobic pathogen. In the present study, transcription of the V. vulnificus prx1ahpF genes, which are adjacently located on the chromosome, was evaluated by analyzing the promoter and intergenic region of the two genes. Northern blot analyses revealed that transcription of prx1ahpF results in two transcripts, the prx1 and prx1ahpF transcripts. Primer extension analysis and a point mutational analysis of the promoter region showed that the two transcripts are generated from a single promoter. In addition, the 3' end of the prx1 transcript at the prx1ahpF intergenic region was determined by a 3'RACE assay. These results suggested that the prx1ahpF genes are transcribed as an operon, and the prx1 transcript was produced by transcriptional termination in the intergenic region. RNA secondary structure prediction of the prx1ahpF intergenic region singled out a stem-loop structure without poly(U) tract, and a deletion analysis of the intergenic region showed that the atypical stem-loop structure acts as the transcriptional attenuator to result in the prx1 and prx1ahpF transcripts. The combined results demonstrate that the differential expression of prx1 and ahpF is accomplished by the cis-acting transcriptional attenuator located between the two genes and thereby leads to the production of a high level of Prx1 and a low level of AhpF. PMID- 25824433 TI - Asn-Linked Glycosylation Contributes to Surface Expression and Voltage-Dependent Gating of Cav1.2 Ca2+ Channel. AB - The Cav1.2 Ca2+ channel is essential for cardiac and smooth muscle contractility and many physiological functions. We mutated single, double, and quadruple sites of the four potential Asn (N)-glycosylation sites in the rabbit Cav1.2 into Gln (Q) to explore the effects of Nglycosylation. When a single mutant (N124Q, N299Q, N1359Q, or N1410Q) or Cav1.2/WT was expressed in Xenopus oocytes, the biophysical properties of single mutants were not significantly different from Cav1.2/WT. In comparison, the double mutant N124,299Q showed a positive shift in voltage dependent gating. Furthermore, the quadruple mutant (QM; N124,299,1359,1410Q) showed a positive shift in voltage-dependent gating as well as a reduction of current. We tagged EGFP to the QM, double mutants, and Cav1.2/WT to chase the mechanisms underlying the reduced currents of QM. The surface fluorescence intensity of QM was weaker than that of Cav1.2/WT, suggesting that the reduced current of QM arises from its lower surface expression than Cav1.2/WT. Tunicamycin treatment of oocytes expressing Cav1.2/WT mimicked the effects of the quadruple mutations. These findings suggest that Nglycosylation contributes to the surface expression and voltage-dependent gating of Cav1.2. PMID- 25824434 TI - Identification and Characterization of a New Alkaline Thermolysin-Like Protease, BtsTLP1, from Bacillus thuringiensis Serovar Sichuansis Strain MC28. AB - Thermolysin and its homologs are a group of metalloproteases that have been widely used in both therapeutic and biotechnological applications. We here report the identification and characterization of a novel thermolysin-like protease, BtsTLP1, from insect pathogen Bacillus thuringiensis serovar Sichuansis strain MC28. BtsTLP1 is extracellularly produced in Bacillus subtilis, and the active protein was purified via successive chromatographic steps. The mature form of BtsTLP1 has a molecule mass of 35.6 kDa as determined by mass spectrometry analyses. The biochemical characterization indicates that BtsTLP1 has an apparent Km value of 1.57 mg/ml for azocasein and is active between 20 degrees C and 80 degrees C. Unlike other reported neutral gram-positive thermolysin homologs with optimal pH around 7, BtsTLP1 exhibits an alkaline pH optimum around 10. The activity of BtsTLP1 is strongly inhibited by EDTA and a group of specific divalent ions, with Zn(2+) and Cu(2+) showing particular effects in promoting the enzyme autolysis. Furthermore, our data also indicate that BtsTLP1 has potential in cleaning applications. PMID- 25824435 TI - Enhancing Cellulase Production in Thermophilic Fungus Myceliophthora thermophila ATCC42464 by RNA Interference of cre1 Gene Expression. AB - The role of CRE1 in a thermophilic fungus, Myceliophthora thermophila ATCC42464, was studied using RNA interference. In the cre1-silenced strain C88, the filter paper hydrolyzing activity and beta-1,4-endoglucanase activity were 3.76-, and 1.31-fold higher, respectively, than those in the parental strain when the strains were cultured in inducing medium for 6 days. The activities of beta-1,4 exoglucanase and cellobiase were 2.64-, and 5.59-fold higher, respectively, than those in the parental strain when the strains were cultured for 5 days. Quantitative reverse-transcription polymerase chain reaction showed that the gene expression of egl3, cbh1, and cbh2 was significantly increased in transformant C88 compared with the wild-type strain. Therefore, our findings suggest the feasibility of improving cellulase production by modifying the regulator expression, and an attractive approach to increasing the total cellulase productivity in thermophilic fungi. PMID- 25824436 TI - Feasibility and acceptability of esophageal-directed hypnotherapy for functional heartburn. AB - Functional heartburn (FH) is a benign but burdensome condition characterized by painful, burning epigastric sensations in the absence of acid reflux or symptom reflux correlation. Esophageal hypersensitivity and its psychological counterpart, esophageal hypervigilance (EHv) drive symptom experience. Hypnotherapy (HYP) is an established and preferred intervention for refractory symptoms in functional gastrointestinal disorders (FGIDs) and could be applied to FH. The objective of this study was to determine the feasibility, acceptability, and clinical utility of 7 weekly sessions of esophageal-directed HYP (EHYP) on heartburn symptoms, quality of life, and EHv. Similar to other work in FGIDs and regardless of hypnotizability, there were consistent and significant changes in heartburn symptoms, visceral anxiety, and quality of life and a trend for improvement in catastrophizing. We would recommend EHYP in FH patients who are either non-responsive to medications or who would prefer a lifestyle intervention. PMID- 25824437 TI - Direct tracheobronchopexy to correct airway collapse due to severe tracheobronchomalacia: Short-term outcomes in a series of 20 patients. AB - PURPOSE: Tracheobronchomalacia (TBM) is associated with esophageal atresia, tracheoesophageal fistulas, and congenital heart disease. TBM results in chronic cough, poor mucous clearance, and recurrent pneumonias. Apparent life-threatening events or recurrent pneumonias may require surgery. TBM is commonly treated with an aortopexy, which indirectly elevates trachea's anterior wall. However, malformed tracheal cartilage and posterior tracheal membrane intrusion may limit its effectiveness. This study describes patient outcomes undergoing direct tracheobronchopexy for TBM. METHODS: The records of patients that underwent direct tracheobronchopexy at our institution from January 2011 to April 2014 were retrospectively reviewed. Primary outcomes included TBM recurrence and resolution of the primary symptoms. Data were analyzed by McNemar's test for matched binary pairs and logistic regression modeling to account for the endoscopic presence of luminal narrowing over multiple time points per patient. RESULTS: Twenty patients were identified. Preoperative evaluation guided the type of tracheobronchopexy. 30% had isolated anterior and 50% isolated posterior tracheobronchopexies, while 20% had both. Follow-up was 5 months (range, 0.5-38). No patients had postoperative ALTEs, and pneumonias were significantly decreased (p=0.0005). Fewer patients had tracheobronchial collapse at postoperative endoscopic exam in these anatomical regions: middle trachea (p=0.01), lower trachea (p<0.001), and right bronchus (p=0.04). CONCLUSION: The use of direct tracheobronchopexy resulted in ALTE resolution and reduction of recurrent pneumonias in our patients. TBM was also reduced in the middle and lower trachea and right mainstem bronchus. Given the heterogeneity of our population, further studies are needed to ascertain longer-term outcomes and a grading scale for TBM severity. PMID- 25824438 TI - Cytomegalovirus-associated biliary atresia: An aetiological and prognostic subgroup. AB - BACKGROUND AND AIMS: Perinatal cytomegalovirus (CMV) infection is a possible cause or trigger of biliary atresia though clinical evidence is scant. We hypothesised that CMV IgM+ve biliary atresia is a separate clinical entity compared to CMV IgM-ve biliary atresia. METHODS: Prospective single-centre study. 210 infants with histologically confirmed biliary atresia were treated in our institution (Jan. 2004 to Dec. 2011); of these 20 (9.5%) were CMV IgM+ve at presentation. We compared these with 111 infants who were CMV IgM-ve (controls) for clinical features, biochemistry at presentation and outcome following Kasai portoenterostomy (KPE). A blinded comparison of age-matched liver histology was also performed. Data are quoted as median (interquartile range). A P value <= 0.05 was regarded as significant. RESULTS: Infants with CMV IgM+ve biliary atresia were older at Kasai portoenterostomy (or laparotomy) [70 (60-80) days vs. 56 (44-75)days; P = 0.003] and were more jaundiced [175 (147-224) vs. 140 (121 181) MUmol/L; P = 0.002+ with higher AST*287 (157-403) vs. 180 (133-254) IU/L; P = 0.005] and aspartate aminotransferase-to-platelet ratio index [1.1 (0.79-3.0) vs. 0.63 (0.43-0.95)] levels. Liver histology: CMV IgM+ve biliary atresia was characterised by a greater degree of inflammation (P < 0.0001) and fibrosis (P = 0.02), whereas CMV IgM-ve isolated biliary atresia had a higher degree of lobular cholestasis (P = 0.001). This effect was independent of the effects of age at KPE. OUTCOME: CMV IgM+ve biliary atresia had a poorer outcome with a reduced clearance of jaundice (15% vs. 52.2%; P = 0.002), native liver survival (P < 0.0001) and increased mortality (P = 0.002). CONCLUSIONS: CMV IgM+ve biliary atresia is a distinct clinical and pathological entity with a diminished response to Kasai portoenterostomy. PMID- 25824439 TI - A risk calculator predicting postoperative adverse events in neonates undergoing major abdominal or thoracic surgery. AB - PURPOSE: This study sought to demonstrate the feasibility of a risk calculator for neonates undergoing major abdominal or thoracic surgery with good discriminative ability. METHODS: The American College of Surgeons' National Surgical Quality Improvement Program Pediatric (ACS-NSQIP-P) 2011-12 data were queried for neonates who underwent major abdominal or thoracic surgery. The outcome of interest was the occurrence of any adverse event, including mortality, within 30-days postoperatively. The preoperative clinical characteristics significantly associated with any adverse event were used to build a multivariate model. The model's discriminative ability was assessed with the area under the receiver operating characteristic curve (AUROC). The model was split-set validated with 2013 data. RESULTS: A total of 2967 neonates undergoing major abdominal or thoracic surgery were identified. The overall rate of adverse events was 23.3%. Sixteen variables were found to be associated with adverse events. Four variables increased the odds of adverse events at least two-fold: dirty or infected wound class [odds ratio (OR)=2.1] dialysis (OR=3.8), hepatobiliary disease (OR=2.1), and inotropic agent use (OR=2.6). The AUROC=0.79 for development data and 0.77 on split-set validation. CONCLUSION: Preoperatively estimating the probability of postoperative adverse events in neonates undergoing major abdominal or thoracic surgery with good discrimination is feasible. PMID- 25824440 TI - Positive Family History, Infection, Low Absolute Lymphocyte Count (ALC), and Absent Thymic Shadow: Diagnostic Clues for All Molecular Forms of Severe Combined Immunodeficiency (SCID). AB - BACKGROUND: Severe combined immunodeficiency (SCID) is a syndrome uniformly fatal during infancy unless recognized and treated successfully by bone marrow transplantation or gene therapy. Because infants with SCID have no abnormal physical appearance, diagnosis is usually delayed unless newborn screening is performed. OBJECTIVE: In this study, we sought to evaluate the presenting features of all 172 patients with SCID transplanted at this institution over the past 31 years. METHODS: We reviewed original charts from 172 consecutive patients with classic SCID who received either T-cell-depleted HLA-haploidentical (N = 154) or HLA-identical (N = 18) nonablative related marrow transplants at Duke University Medical Center from 1982 to 2013. RESULTS: The mean age at presentation was 4.87 months. When there was a family history of early infant death or known SCID (37%), the mean presentation age was much earlier, 2.0 months compared with 6.6 months. Failure to thrive was common, with 84 patients (50%) having a weight less than the 5th percentile. The leading infections included oral moniliasis (43%), viral infections (35.5%), and Pneumocystis jiroveci (26%) pneumonia. The group mean absolute lymphocyte count (ALC) was 1454/cmm; 88% of the infants had an ALC less than 3000/cmm. An absent thymic shadow was seen in 92% of infants with electronic radiographic data available. An absence of T-cell function was found in all patients. CONCLUSIONS: Infants with SCID appear normal at birth but later present with failure to thrive and/or recurrent fungal, viral, and bacterial infections. Low ALCs and an absent thymic shadow on chest x-ray are key diagnostic clues. The absence of T-cell function confirms the diagnosis. PMID- 25824441 TI - Combining the Mannitol Test and FeNO in the Assessment of Poorly Controlled Asthma. AB - BACKGROUND: International guidelines recommend up-titration of anti-inflammatory treatment in asthmatic patients with poor symptom control, but patients without eosinophilic airway inflammation are less likely to benefit from this. The mannitol bronchoprovocation test and fractional exhaled nitric oxide (FeNO) are increasingly used in the diagnostic assessment of asthma, but the utility of combining these tests has not been evaluated. AIM: The aim of this study was to determine the value of combining FeNO and the mannitol test to assess patients with asthma referred for specialist assessment because of poor symptom control. METHODS: All patients referred consecutively over a 12-month period for the assessment of asthma at the Respiratory Outpatient Clinic at Bispebjerg Hospital in Copenhagen were examined with bronchial provocation to mannitol, FeNO, and induced sputum. RESULTS: Among asthmatic patients with partly controlled or uncontrolled symptoms according to Global Initiative for Asthma criteria, only 23% had sputum eosinophilia (eosinophils >2.99%). A positive mannitol test did not increase the likelihood of airway eosinophilia significantly (positive test: 32% vs negative test: 18%, P = .12). However, a positive mannitol test combined with a FeNO > 25 ppb indicated a high likelihood of airway eosinophilia (73%), compared with FeNO > 25 ppb and a negative mannitol test (29%) (P < .05). In contrast, in patients with FeNO < 25 ppb, a positive mannitol test was not associated with airway eosinophilia (sputum eosinophils > 2.99%: positive mannitol test: 0%, negative test: 11%, ns). CONCLUSION: Combining the mannitol test and FeNO may aid in the differentiation between eosinophilic and noneosinophilic asthma in patients referred for specialist management because of poorly controlled asthma symptoms. PMID- 25824443 TI - Value of cardiac MRI to evaluate ischemia-related ventricular arrhythmia substrates. AB - During the course of and after a myocardial ischemia-reperfusion insult, ventricular arrhythmia (VA) may have several single or overlapping potential substrates. Some of these may not be associated with morphological and functional changes, whereas others may have individual susceptibility. Nevertheless, cardiac magnetic resonance currently offers a comprehensive and highly effective toolset for the evaluation of a risk of VA on a patient basis after a myocardial infarction. Indeed, cardiac magnetic resonance has established itself as a reference for the evaluation of the myocardial function and properties, using respectively, cine and tissue characterization imaging to detect and evaluate the extent of acute myocardial injuries, scars and remodeling. This article describes and discusses imaging strategies used to evaluate the substrates for VA in the setting of a myocardial infarction. PMID- 25824442 TI - Cardiosome mediated regulation of MMP9 in diabetic heart: role of mir29b and mir455 in exercise. AB - 'Cardiosomes' (exosomes from cardiomyocytes) have recently emerged as nanovesicles (30-100 nm) released in the cardiosphere by myocytes and cardiac progenitor cells, though their role in diabetes remains elusive. Diabetic cardiovascular complications are unequivocally benefitted from exercise; however, the molecular mechanisms need exploration. This novel study is based on our observation that exercise brings down the levels of activated (Matrix Metalloprotease 9) in db/db mice in a model of type 2 diabetes. We hypothesize that exosomes that are released during exercise contain microRNAs (mir455, mir29b, mir323-5p and mir466) that bind to the 3' region of MMP9 and downregulate its expression, hence mitigating the deleterious downstream effects of MMP9, which causes extracellular matrix remodeling. First, we confirmed the presence of exosomes in the heart tissue and serum by electron microscopy and flow cytometry, respectively, in the four treatment groups: (i) db/control, (ii) db/control+exercise, (iii) db/db and (iv) db/db+exercise. Use of exosomal markers CD81, Flottilin 1, and acetylcholinesterase activity in the isolated exosomes confirmed enhanced exosomal release in the exercise group. The microRNAs isolated from the exosomes contained mir455, mir29b, mir323-5p and mir466 as quantified by qRTPCR, however, mir29b and mir455 showed highest upregulation. We performed 2D zymography which revealed significantly lowered activity of MMP9 in the db/db exercise group as compared to non-exercise group. The immunohistochemical analysis further confirmed the downregulated expression of MMP9 after exercise. Since MMP9 is involved in matrix degradation and leads to fibrosis and myocyte uncoupling, the present study provides a strong evidence how exercise can mitigate these conditions in diabetic patients. PMID- 25824444 TI - One versus Two Breast Density Measures to Predict 5- and 10-Year Breast Cancer Risk. AB - BACKGROUND: One measure of Breast Imaging Reporting and Data System (BI-RADS) breast density improves 5-year breast cancer risk prediction, but the value of sequential measures is unknown. We determined whether two BI-RADS density measures improve the predictive accuracy of the Breast Cancer Surveillance Consortium 5-year risk model compared with one measure. METHODS: We included 722,654 women of ages 35 to 74 years with two mammograms with BI-RADS density measures on average 1.8 years apart; 13,715 developed invasive breast cancer. We used Cox regression to estimate the relative hazards of breast cancer for age, race/ethnicity, family history of breast cancer, history of breast biopsy, and one or two density measures. We developed a risk prediction model by combining these estimates with 2000-2010 Surveillance, Epidemiology, and End Results incidence and 2010 vital statistics for competing risk of death. RESULTS: The two measure density model had marginally greater discriminatory accuracy than the one measure model (AUC, 0.640 vs. 0.635). Of 18.6% of women (134,404 of 722,654) who decreased density categories, 15.4% (20,741 of 134,404) of women whose density decreased from heterogeneously or extremely dense to a lower density category with one other risk factor had a clinically meaningful increase in 5-year risk from <1.67% with the one-density model to >=1.67% with the two-density model. CONCLUSION: The two-density model has similar overall discrimination to the one density model for predicting 5-year breast cancer risk and improves risk classification for women with risk factors and a decrease in density. IMPACT: A two-density model should be considered for women whose density decreases when calculating breast cancer risk. PMID- 25824445 TI - Is tendinopathy research at a crossroads? PMID- 25824446 TI - Exercise-associated DNA methylation change in skeletal muscle and the importance of imprinted genes: a bioinformatics meta-analysis. AB - BACKGROUND: Epigenetics is the study of processes--beyond DNA sequence alteration -producing heritable characteristics. For example, DNA methylation modifies gene expression without altering the nucleotide sequence. A well-studied DNA methylation-based phenomenon is genomic imprinting (ie, genotype-independent parent-of-origin effects). OBJECTIVE: We aimed to elucidate: (1) the effect of exercise on DNA methylation and (2) the role of imprinted genes in skeletal muscle gene networks (ie, gene group functional profiling analyses). DESIGN: Gene ontology (ie, gene product elucidation)/meta-analysis. DATA SOURCES: 26 skeletal muscle and 86 imprinted genes were subjected to g:Profiler ontology analysis. Meta-analysis assessed exercise-associated DNA methylation change. DATA EXTRACTION: g:Profiler found four muscle gene networks with imprinted loci. Meta analysis identified 16 articles (387 genes/1580 individuals) associated with exercise. Age, method, sample size, sex and tissue variation could elevate effect size bias. DATA SYNTHESIS: Only skeletal muscle gene networks including imprinted genes were reported. Exercise-associated effect sizes were calculated by gene. Age, method, sample size, sex and tissue variation were moderators. RESULTS: Six imprinted loci (RB1, MEG3, UBE3A, PLAGL1, SGCE, INS) were important for muscle gene networks, while meta-analysis uncovered five exercise-associated imprinted loci (KCNQ1, MEG3, GRB10, L3MBTL1, PLAGL1). DNA methylation decreased with exercise (60% of loci). Exercise-associated DNA methylation change was stronger among older people (ie, age accounted for 30% of the variation). Among older people, genes exhibiting DNA methylation decreases were part of a microRNA regulated gene network functioning to suppress cancer. CONCLUSIONS: Imprinted genes were identified in skeletal muscle gene networks and exercise-associated DNA methylation change. Exercise-associated DNA methylation modification could rewind the 'epigenetic clock' as we age. TRIAL REGISTRATION NUMBER: CRD42014009800. PMID- 25824447 TI - Which determinants predict tibiofemoral and patellofemoral osteoarthritis after anterior cruciate ligament injury? A systematic review. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury is an important risk factor for development of knee osteoarthritis (OA). To identify those ACL injured patients at increased risk for knee OA, it is necessary to understand risk factors for OA. AIM: To summarise the evidence for determinants of (1) tibiofemoral OA and (2) patellofemoral OA in ACL injured patients. METHODS: MEDLINE, EMBASE, Web of Science and CINAHL databases were searched up to 20 December 2013. Additionally, reference lists of eligible studies were manually and independently screened by two reviewers. 2348 studies were assessed for the following main inclusion criteria: >=20 patients; ACL injured patients treated operatively or non-operatively; reporting OA as outcome; description of relationship between OA outcome and determinants; and a follow-up period >=2 years. Two reviewers extracted the data, assessed the risk of bias and performed a best-evidence synthesis. RESULTS: Sixty-four publications were included and assessed for quality. Two studies were classified as low risk of bias. Medial meniscal injury/meniscectomy showed moderate evidence for influencing OA development (tibiofemoral OA and compartment unspecified). Lateral meniscal injury/meniscectomy showed moderate evidence for no relationship (compartment unspecified), as did time between injury and reconstruction (tibiofemoral and patellofemoral OA). CONCLUSIONS: Medial meniscal injury/meniscectomy after ACL rupture increased the risk of OA development. In contrast, it seems that lateral meniscal injury/meniscectomy has no relationship with OA development. Our results suggest that time between injury and reconstruction does not influence patellofemoral and tibiofemoral OA development. Many determinants showed conflicting and limited evidence and no determinant showed strong evidence. PMID- 25824448 TI - Piaget and electronic medical record. PMID- 25824449 TI - Acute Effects of Pacing at Different Ventricular Sites on Left Ventricular Rotational Mechanics in a Porcine Model. AB - OBJECTIVE: The purpose of this study was to examine the acute effects of pacing at different ventricular sites on hemodynamics and left ventricular (LV) rotational mechanics using speckle-tracking echocardiography (STE) in a porcine model. DESIGN: A prospective laboratory investigation. SETTING: University research laboratory. PARTICIPANTS: Yorkshire pigs. INTERVENTIONS: In 9 pigs, after midline sternotomy, epicardial pacing was performed from the right ventricular outflow tract (RVOT), right ventricular apex (RVA), and LV free wall. MEASUREMENTS AND MAIN RESULTS: Two-dimensional STE and conductance catheter derived LV pressure-volume measurements were made to determine the impact of pacing from various sites on LV rotational parameters (twist/untwist) and hemodynamics. RVOT pacing caused the least decrease in end-systolic pressure from baseline (-9.5%), when compared with RVA (-19.1%) and LV (-23.4%). Systolic and diastolic parameters (Emax, Tau) also were different among RVOT (4.7+/-0.8 mmHg/mL, 32+/-4 ms), RVA (3.9+/-0.7 mmHg/mL, 37+/-6 ms), and LV sites (3.6+/-0.8 mmHg/mL, 42+/-7 ms). Similar to the effects of pacing on hemodynamics, RVOT pacing better preserved LV twist (11.1+/-1.8 v 8.6+/-1.7, 5.9+/-0.7 degrees ) and untwisting rate (64.6+/-8.5 v 56.2+/-5.3, 48.2+/-8.5 degrees /s) when compared with RV apical pacing and LV pacing. Furthermore, prolongation of conduction from LV lateral to anteroseptal at LV base (26.5+/-3.8 v 13.8+/-3.3 ms, p<0.05) and LV midpapillary muscle level (35.6+/-5.6 v 14.1+/-2.4 ms, p<0.05) was observed with LV pacing compared with RVOT pacing. CONCLUSIONS: The present data showed that the LV twist/untwist and cardiac systolic and diastolic function were least affected by RVOT pacing. This finding may be explained by the proximity of this location to the native ventricular conduction system. PMID- 25824450 TI - Blood Neutrophil to Lymphocyte Ratio as a Predictor of Hypertension. AB - BACKGROUND: Hypertension is a significant global public health challenge. Low grade inflammation is known to facilitate the development of essential hypertension and target-organ hypertensive damage. Neutrophil to lymphocyte ratio (NLR) is a simple and reliable indicator of inflammation that may also be useful in the prediction of hypertension. METHODS: Participants were recruited from Tianjin Medical University's General Hospital-Health Management Centre. A total of 28,850 initially hypertension-free subjects were followed from 2007 to 2013. Adjusted Cox proportional hazards regression models were used to assess relationships between NLR categories and incidence of hypertension. RESULTS: During the ~6-year follow-up period (median duration of follow-up (interquartile range): 2.63 (2.58-2.68)), 1,824 subjects developed hypertension. The hazard ratios of hypertension incidence were evaluated in increasing NLR quintiles. Compared with participants with the lowest NLR levels, the multivariable-adjusted hazard ratios (95% confidence interval) of hypertension were related to increasing NLR quintiles and were as follows: 1.08 (0.92, 1.26), 0.97 (0.83, 1.14), 1.10 (0.94, 1.28), and 1.23 (1.06, 1.43), respectively (P for trend < 0.01). Similar results also were observed in the white blood cell and neutrophil counts, but not lymphocyte counts. CONCLUSIONS: The study is the first to show the elevated NLR levels significantly correlate with an increased risk of developing hypertension. This result may be useful in elucidating the mechanism underlying the development of hypertension. New therapeutic approaches aimed at inflammation might be proposed to control hypertension and hypertensive damage. PMID- 25824452 TI - Exaggerated Exercise Blood Pressure Response During Treadmill Testing as a Predictor of Future Hypertension in Men: A Longitudinal Study. AB - BACKGROUND: The purpose of this study was to evaluate receiver operating characteristic curves to identify optimal cutoff values of exercise systolic blood pressure (SBP) using both peak SBP and relative SBP (peak SBP minus resting SBP) as predictors of future hypertension (HTN). METHODS: Participants were 3,742 healthy normotensive men who underwent symptom-limited treadmill testing at baseline. Incident HTN was defined as SBP/diastolic blood pressure greater than 140/90 mm Hg and/or diagnosed HTN by a physician. RESULTS: During an average 5 year follow-up, 364 (9.7%) new cases of HTN were observed. The most discriminatory cutoff values for peak SBP and relative SBP for predicting incident HTN were 181 mm Hg (areas under the curve (AUC) = 0.644, sensitivity = 54%, and specificity = 69%) and 52 mm Hg (AUC = 0.549, sensitivity = 64.3%, and specificity = 44.6%), respectively. Participants with peak SBP greater than 181 mm Hg and relative SBP greater than 52 mm Hg had 1.54-fold (95% CI: 1.23-1.93) and 1.44-fold (95% CI: 1.16-1.80) risks of developing HTN after adjusting for potential confounding variables. When these 2 variables were entered simultaneously into the Cox proportional hazards regression model with adjustment for potential confounding variables, only peak SBP (relative risk: 1.39, 95% CI: 1.02-1.89) was a predictor of the development of HTN. CONCLUSIONS: The most accurate discriminators for peak and relative SBP during treadmill exercise testing to predict incident HTN were greater than 181 and 52 mm Hg, respectively, in normotensive men. A peak SBP greater than 181 mm Hg during treadmill exercise testing may provide a useful predictor for the development of HTN in clinical practice. PMID- 25824451 TI - Blood Pressure Reactivity to the Cold Pressor Test Predicts Hypertension Among Chinese Adults: The GenSalt Study. AB - BACKGROUND: Blood pressure (BP) hyper-reactivity to the cold pressor test (CPT) has been suggested as a predictor of hypertension. We examined whether BP reactivity to the CPT was associated with hypertension incidence among the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study participants from China. METHODS: A total of 1,961 GenSalt study participants without any antihypertensive treatment completed the CPT at the baseline examination. Hypertension status was assessed at baseline (2003-2005) and 2 follow-up visits (2008-2009 and 2011-2012). RESULTS: After adjustment for multiple covariates, both systolic BP (SBP) and diastolic BP reactivity to the CPT were significantly associated with hypertension incidence. For example, the multivariable adjusted odds ratios (ORs, 95% CI) of developing hypertension were 0.92 (0.66, 1.29), 1.42 (1.03, 1.97), and 1.45 (1.05, 2.00) for participants with maximum SBP responses of 6.7-12.0, 12.1-19.2, and >=19.3mm Hg, respectively, compared to those with responses of <6.7mm Hg (P for trend = 0.006). Likewise, the multivariable adjusted ORs (95% CI) of hypertension were 1.12 (0.79, 1.57), 1.62 (1.15, 2.29), and 1.82 (1.30, 2.55) for participants with the area under the curve of SBP responses of 3.0-16.0, 16.1-29.9, and >= 30.0mm Hg.min, respectively, compared to those with responses of < 3.0mm Hg.min (P for trend = 0.0001). The associations between BP reactivity variables and the risk of hypertension were not different among subgroups of sex, age, and baseline BP levels. CONCLUSIONS: BP hyperreactivity to the cold stimulus may predict the risk of hypertension among Chinese adults. PMID- 25824453 TI - Simultaneous determination of nicotine and its nine metabolites in rat blood utilizing microdialysis coupled with UPLC-tandem mass spectrometry for pharmacokinetic application. AB - To develop a simple and rapid method for the simultaneous determination of nicotine and its nine metabolites in rat blood, an in vivo microdialysis sampling technique coupled with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established for quantitation and characterization of the pharmacokinetics of nicotine and its metabolites. Microdialysis probes were inserted into the jugular vein of Sprague Dawley rats, and dialysates were collected after nicotine (0.5 mg/kg, i.p.) administration. Target analytes and corresponding deuterated internal standards were separated on a hydrophilic interaction liquid chromatography column (HILIC BEH 2.1. * 150 mm, 1.7 MUm) and detected by UPLC-MS/MS under multiple reaction monitoring mode. The limits of quantification for nicotine and its nine metabolites ranged from 0.039 to 0.46 ng/mL. Intra- and inter-day precision and accuracy were well within the predefined limits of acceptability (<11 %). Pharmacokinetic results showed that the mean half-lives of nicotine, cotinine, nornicotine, norcotinine, nicotine-N' oxide, cotinine-N'-oxide, trans-3'-hydroxy-cotinine, nicotine-N-glucuronide, cotinine-N-glucuronide, and trans-3'-hydroxy-cotinine-O-glucuronide in rat plasma were 63, 291, 175, 440, 251, 451, 322, 341, 488, and 516 min, respectively. The blood concentration-time profiles of nicotine and its nine metabolites indicate that nicotine is rapidly consumed after the administration and subsequently cotinine is generated as the main metabolite; meanwhile, cotinine and other eight minor metabolites exhibit longer retention times in rat body. PMID- 25824454 TI - Figure-ground segregation: A fully nonlocal approach. AB - We present a computational model that computes and integrates in a nonlocal fashion several configural cues for automatic figure-ground segregation. Our working hypothesis is that the figural status of each pixel is a nonlocal function of several geometric shape properties and it can be estimated without explicitly relying on object boundaries. The methodology is grounded on two elements: multi-directional linear voting and nonlinear diffusion. A first estimation of the figural status of each pixel is obtained as a result of a voting process, in which several differently oriented line-shaped neighborhoods vote to express their belief about the figural status of the pixel. A nonlinear diffusion process is then applied to enforce the coherence of figural status estimates among perceptually homogeneous regions. Computer simulations fit human perception and match the experimental evidence that several cues cooperate in defining figure-ground segregation. The results of this work suggest that figure ground segregation involves feedback from cells with larger receptive fields in higher visual cortical areas. PMID- 25824455 TI - Immune checkpoint inhibition in lymphoid disease. AB - It has long been understood that the immune system has intrinsic anti-tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this immune surveillance. A number of attempts have been made to harness this anti-tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death-1 (PDCD1, PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA4) 'immune checkpoint' pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti-tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies. PMID- 25824456 TI - Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of Alzheimer's disease. AB - Parkinson's disease and Alzheimer's disease (AD) are recognized to coexist on a spectrum of neurodegeneration, and it has been proposed that molecular interactions among pathogenic proteins are a basis for the overlap between these two diseases. We instead hypothesized that degeneration of the nigrostriatal dopaminergic system enhances the clinical penetrance of early-stage AD. To determine the effect of striatal dopamine (DA) on the pathological effects in an experimental model of AD, APPSWE /PS1DeltaE9 mice received striatal injections of the neurotoxin 6-hydroxydopamine (6OHDA). Animals were tested in a Barnes maze protocol and in a water T-maze protocol at different ages to determine the onset of cognitive impairment. APPSWE /PS1DeltaE9 mice that received 6OHDA injections showed significant impairment in Barnes maze performance at an earlier age than controls. Additionally, at 12 months of age, APPswe /PS1DeltaE9 + 6OHDA mice demonstrated worse behavioral flexibility than other groups in a task-switch phase of the water T-maze. To determine the neuroprotective effects of dopaminergic neurotransmission against amyloid-beta42 (Abeta42 ) toxicity, neuronal branch order and dendrite length were quantified in primary medium spiny neuron (MSN) cultures pretreated with increasing doses of the D1 and D2 receptor agonists before being exposed to oligomerized Abeta42 . Although there were no differences in Abeta peptide levels or plaque burden among the groups, in murine MSN culture dopaminergic agonists prevented a toxic response to Abeta42. Depletion of DA in the striatum exacerbated the cognitive impairment seen in a mouse model of early-stage AD; this may be due to a protective effect of dopaminergic innervation against Abeta striatal neurotoxicity. PMID- 25824458 TI - Anti-fibrotic effect of plumbagin on CCl4-lesioned rats. AB - BACKGROUND/AIMS: Our previous studies have shown that plumbagin effectively inhibits hepatic stellate cell (HSC) proliferation. Thus, plumbagin-mediated anti fibrotic effects in vivo merit further investigation. METHODS: We used rat models to assess the potential benefits of plumbagin against CCl4-induced liver fibrosis. RESULTS: The results showed that plumbagin lowered the serum concentrations of liver functional enzymes (ALT, AST, ALB, TBIL) in CCl4-fibrotic rats while reducing inflammatory cytokine levels (IL-6, TNF-alpha). As reflected in pathological examinations, rats that were administered plumbagin showed decreased collagen markers (HA, LN, PCIII and CIV) in liver tissues and improved hepatocellular impairments. In addition, plumbagin contributed to down-regulating NF-kappaB and TLR-4 mRNA in CCl4-lesioned livers. As revealed in the immunohistochemical assay, plumbagin-administered rats showed reduced levels of alpha-SMA and TNF-alpha immunoreactive cells in liver tissue. CONCLUSION: Collectively, these findings offer appealing evidence that plumbagin may serve as an anti-fibrotic medication through inactivating the NF-kappaB/TLR-4 pathway that is associated with inflammatory reactions, thereby mitigating liver fibrosis. PMID- 25824457 TI - Calcium sensing receptor regulating smooth muscle cells proliferation through initiating cystathionine-gamma-lyase/hydrogen sulfide pathway in diabetic rat. AB - AIMS: Hydrogen sulfide (H2S) inhibits the proliferation of vascular smooth muscle cells (VSMCs). However, how cystathionine-gamma-lyase (CSE), a major enzyme that produces H2S, is regulated remains unknown. Whether calcium-sensing receptor (CaSR) inhibits the proliferation of VSMCs by regulating the endogenous CSE/H2S pathway in diabetic rat has not been previously investigated. METHODS AND RESULTS: The morphological and ultrastructure alterations were tested by transmission electron microscopy, changes in the H2S concentration and the relaxation of the mesenteric secondary artery loop of diabetic rats were determined by Multiskan spectrum microplate spectrophotometer and isometric force transducer. Additionally, the expression levels of CaSR, CSE and Cyclin D1 in the mesenteric arteries of rats were examined by western blotting. The intracellular calcium concentration, the expression of p-CaMK II (phospho-calmodulin kinases II), CSE activity, the concentration of endogenous H2S and the proliferation of cultured VSMCs from rat thoracic aortas were measured by using confocal microscope, western blotting, microplate spectrophotometer, MTT and BrdU, respectively. The VSMC layer thickened, the H2S concentration dropped, the relaxation of the mesenteric secondary artery rings weakened, and the expression of CaSR and CSE decreased whereas the expression of Cyclin D1 increased in diabetic rats compared with the control group. The [Ca(2+)]i of VSMCs increased upon treatment with CaSR agonists (10 uM Calindol and 2.5 mM CaCl2), while it decreased upon administration of calhex231, U73122 and 2-APB. The expression of p CaMK II and CSE increased upon treatment with CaSR agonists in VSMCs. CSE activity and the endogenous H2S concentration decreased in response to high glucose, while it increased with treatment of CaSR agonists. The proliferation rate increased in response to high glucose, and CaSR agonists or NaHS significantly reversed the proliferation of VSMCs caused by high glucose. CONCLUSIONS: Our results demonstrated that CaSR regulated the endogenous CSE/H2S pathway to inhibit the proliferation of VSMCs in both diabetic and high glucose models. PMID- 25824459 TI - Modest decrease in PGC1alpha results in TAG accumulation but not in insulin resistance in L6 myotubes. AB - BACKGROUND/AIMS: PGC-1alpha is an important cellular protein (coactivator) regulating myocyte mitochondria number and function, and therefore whole cellular energy status. The aim of this work was to investigate the effects of modest, temporary PGC-1alpha knock-down on L6 myotubes insulin resistance in a light of cellular lipid metabolism. METHODS: Gas liquid chromatography was applied for assessing FAs content and composition. For the expression of mitochondrial enzymes, as well as FA and glucose transporters, Western Blot technique was adopted. Additionally, radiolabelled glucose and palmitic acid uptake was performed to estimate the nutrients cellular influx. RESULTS: Modest (-24%) PGC 1alpha protein ablation resulted in decreased mitochondrial activity in general (reduced Cyt C content) and FAs oxidation in particular (diminished beta-HAD expression) without increased FAs cellular influx. The aforementioned intervention led to significantly increased TAG cellular level, but not DAG nor CER. Consequently, no changes in cellular insulin responsiveness were noticed. CONCLUSIONS: Modest (-24%) PGC-1alpha protein depletion results in lipid accumulation, without causing insulin resistance. Importantly, it seems that this TAG loading is a result of decreased mitochondrial oxidative capacity and/or possibly increased lipid biosynthesis but not fatty acid cellular influx. PMID- 25824460 TI - TGF-beta regulates hepatocellular carcinoma progression by inducing Treg cell polarization. AB - BACKGROUND/AIMS: TGF-beta plays a key role in the progression of various tumors. The main objective of our study was to investigate whether TGF-beta is able to regulate N-nitrosodiethylamine (DEN)-induced hepatocellular carcinoma (HCC) progression in a mouse model by inducing Treg cell polarization. METHODS: HCC progression, TGF-beta and Foxp3 expression levels, serum TGF-beta, IL10 and GP73 levels as well as percentage of Treg cells were analyzed in healthy, HCC and HCC+SM-16 mouse groups. The effect of TGF-beta on Treg cell polarization in vitro was measured by flow cytometric analysis. The expression of TGF-beta and IL10 was identified by IHC in HCC patients and the correlation between TGF-beta and IL10 was also assessed. RESULTS: TGF-beta expression is up-regulated in a DEN-induced HCC mouse model. TGF-beta can promote the differentiation of Foxp3(+)CD4(+) T cells (Treg cells) in vitro. However, blocking the TGF-beta pathway with a specific TGF-beta receptor inhibitor, SM-16, reduced HCC progression and the percentage of Treg cells in liver tissue. The correlation between TGF-beta and Treg cells was also confirmed in HCC patients and the expression of both TGF-beta and IL-10 was shown to be associated with HCC progression. CONCLUSION: TGF-beta is necessary for HCC progression, acting by inducing Treg cell polarization. PMID- 25824461 TI - Down-regulation of Homer1b/c protects against chemically induced seizures through inhibition of mTOR signaling. AB - BACKGROUND: Homer is a family of post synaptic density proteins functionally and physically attached to target proteins at proline-rich sequences. Reducing Homer1b/c expression has been shown in previous studies to be protective against excitotoxic insults, implicating Homer1b/c in the physiological regulation of aberrant neuronal excitability. METHODS: To test the efficacy of a Homer1b/c reducing therapy for disorders with a detrimental hyperexcitability profile in mice, we used small interfere RNA (siRNA) to decrease endogenous Homer1b/c expression in mouse hippocampus. The baseline motor and cognitive behavior was measured by sensorimotor tests, Morris water maze and elevated plus maze tasks. The anti-epileptic effects of Homer1b/c knockdown were determined in two chemically induced seizure models induced by Picrotoxin (PTX) or pentylenetetrazole (PTZ) administration. RESULTS: The results of sensorimotor tests, Morris water maze and elevated plus maze tasks showed that Homer1b/c reduction had no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced Homerb/c protein had less severe seizures than control mice. Total Homer1b/c protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of Homer1b/c. In addition, the phosphorylation of mammalian target of rapamycin (mTOR) and its target protein S6 was significantly inhibited in Homer1b/c down-regulated mice. Homer1b/c knockdown induced inhibition of mTOR pathway was partially ablated by the metabotropic glutamate receptor 5 (mGluR5) agonist CHPG. CONCLUSION: Our results demonstrate that endogenous Homer1b/c is integral for regulating neuronal hyperexcitability in adult animals and suggest that reduction of Homer1b/c could protect against chemically induced seizures through inhibition mTOR pathway. PMID- 25824462 TI - Activated phosphatidylinositol 3-kinase/Akt inhibits the transition of endothelial progenitor cells to mesenchymal cells by regulating the forkhead box subgroup O-3a signaling. AB - BACKGROUND AND AIMS: Endothelial progenitor cells (EPCs) differentiate into mature endothelial cells and may thus be candidates for ischemic disease therapy; however, the transition of EPCs to mesenchymal cells is not fully understood. We explored the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGF-beta1). METHODS: Rat bone marrow-derived EPCs were isolated by using Ficoll-Isopaque Plus density-gradient centrifugation. EndMT was induced by TGF-beta1 (5 ng/mL). PI3K/Akt signaling was activated by IGF-1 or Lenti-PIK3R2 shRNA. Additionally, FoxO3a expression was suppressed by a lentiviral vector (Lenti-FoxO3a shRNA). Smad3 and FoxO3a co-localization was detected by confocal immunofluorescence microscopy. The expressions of molecules involved in EndMT were exmined by using Western-blot analysis. RESULTS: EndMT of EPCs was fully developed after TGF-beta1 treatment (5 ng/mL) for 7 days. PIK3R2 expression in EPCs was driven by TGF-beta1. Lenti-PIK3R2 shRNA blocked alpha-smooth muscle actin (alpha-SMA) expression in EPCs treated with TGF-beta1, drove PI3K/Akt activation, and increased expression of phosphorylated FoxO3a instead of phosphorylated Smad3. The effect of Lenti-PIK3R2 shRNA was reduced by LY294002, a specific inhibitor of PI3K. IGF-1 attenuated alpha-SMA protein expression in EPCs treated with TGF-beta1. Similar to Lenti-PIK3R2 shRNA, IGF-1 also inhibited and elevated the phosphorylation of Smad3 and FoxO3a, respectively. IGF-1 disrupted the co-localization of these proteins in EPCs treated with TGF-beta1. Lenti FoxO3a shRNA transfection of EPCs suppressed expression of FoxO3a as well as that of the mesenchymal markers SM22alpha and alpha-SMA. CONCLUSIONS: Activation of PI3K/Akt signaling by Lenti-PIK3R2 shRNA or by exogenous IGF-1 inhibits EndMT in EPCs via negative regulation of FoxO3a-dependent signaling. PMID- 25824463 TI - Activation of PAR-1/NADPH oxidase/ROS signaling pathways is crucial for the thrombin-induced sFlt-1 production in extravillous trophoblasts: possible involvement in the pathogenesis of preeclampsia. AB - BACKGROUNDS/AIMS: Preeclampsia was characterized by excessive thrombin generation in placentas and previous researches showed that thrombin could enhance soluble Fms-like tyrosine kinase 1 (sFlt-1) expression in first trimester trophoblasts. However, the detailed mechanism for the sFlt-1 over-production induced by thrombin was largely unknown. The purpose of this study was to explore the possible signaling pathway of thrombin-induced sFlt-1 production in extravillous trophoblasts (EVT). METHODS: An EVT cell line (HRT-8/SVneo) was treated with various concentrations of thrombin. The mRNA expression and protein secretion of sFlt-1 in EVT were detected with real-time polymerase chain reaction and ELISA, respectively. The levels of intracellular reactive oxygen species (ROS) production were determined by DCFH-DA. RESULTS: Exposure of EVT to thrombin induced increased intracellular ROS generation and overexpression of sFlt-1 at both mRNA and protein levels in a dose dependent manner. Short interfering RNA (siRNA) directed against PAR-1 or apocynin (an inhibitor of NADPH oxidase) could decrease the intracellular ROS generation and subsequently suppressed the production of sFlt-1 at mRNA and protein levels. CONCLUSIONS: Our results suggested that thrombin increased sFlt-1 production in EVT via the PAR-1 /NADPH oxidase /ROS signaling pathway. This also highlights the PAR-1 / NADPH oxidase / ROS pathway might be a potential therapeutic target for the prevention of preeclampsia in the future. PMID- 25824464 TI - Design, expression and characterization of single chain Fv, Mms13 and the single chain Fv-mms13 fusion protein. AB - Single chain Fv (scFv) antibodies are attractive as tumor-targeting vehicles due to their smaller size compared with intact antibody molecules. Mms13 is a putative membrane anchor protein of magnetosome. The present study fused the scFV gene of type IV collagenase to mms13 using the splicing by overlap extension polymerase chain reaction technique. The genes of scFv, mms13 and the scFv-mms13 fusion gene were cloned into a pET30a(+) vector to construct pET30a(+)-scFv, pET30a(+)-mms13 and pET30a(+)-scFv-mms13 expression vectors. The three protein compositions were confirmed by DNA sequencing and western blot analysis, and their cellular locations were determined using SDS-PAGE. The results of enzyme linked immunosorbent assays and immunofluorescence demonstrated that the ScFv and ScFv-mms13 fusion proteins bound to the type IV collagenase and the antigen associated cancer cells SMMC-7721, MCF-7 and HepG2 cells, in a dose-dependent and saturable manner. Although the immunoreactivities of ScFv-mms13 to the type IV collagenase and associated tumor cells were marginally lower than the corresponding scFv (3G11), considerable binding ability to the antigen by ScFv mms13 remained. PMID- 25824465 TI - Copper(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid: Structure and biological features. AB - Copper(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid (Htolf) with the oxygen-donor ligands methanol (MeOH) or N,N dimethylformamide (DMF) and/or the nitrogen-donor heterocyclic ligands 2,2' bipyridine (bipy), 2,2'-bipyridylamine (bipyam), 1,10-phenanthroline (phen) or pyridine (py) were synthesized and characterized. The crystal structures of five novel complexes were determined by X-ray crystallography where tolfenamic acid is deprotonated being in different binding modes. Equimolar quantities of CuCl2, tolf(-1) and bipy led to the formation of [Cu(tolf-O,O')(bipy)Cl] (1), while with a 1:2 Cu(II):tolf ratio, complexes [Cu(tolf-O,O')2(bipy)] (2), [Cu(tolf O,O')2(bipyam)] . 0.5MeOH (3 0.5MeOH), [Cu(tolf-O,O')(tolf-O)(phen)(MeOH)] (4) and [Cu(tolf-O)2(py)2(MeOH)2] (5) were isolated. The interaction of the complexes with serum albumin proteins was studied by fluorescence spectroscopy with the determined binding constant bearing relative high values. The scavenging ability of the complexes towards 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals was investigated and the in vitro inhibitory activity against soybean lipoxygenase was evaluated and complexes 4 and 5 were the more active compounds among those tested. Spectroscopic (UV), electrochemical (cyclic voltammetry) and physicochemical (viscosity measurements) techniques were employed in order to study the binding mode and strength of the complexes to calf-thymus (CT) DNA suggesting intercalation as the most possible mode of binding. Competitive studies with ethidium bromide (EB) revealed the ability of the complexes to displace the DNA bound EB. The biological properties of complexes 1-5 were evaluated in regard to previously reported complex [Cu2(tolf-O,O')4(DMF)2] (6). PMID- 25824466 TI - Expanding the family of heteroleptic oxidovanadium(IV) compounds with salicylaldehyde semicarbazones and polypyridyl ligands showing anti-Trypanosoma cruzi activity. AB - Searching for prospective vanadium-based drugs for the treatment of Chagas disease, a new series of heteroleptic [V(IV)O(L-2H)(NN)] compounds was developed by including the lipophilic 3,4,7,8-tetramethyl-1,10-phenanthroline (tmp) NN ligand and seven tridentate salicylaldehyde semicarbazone derivatives (L1-L7). The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligand is bidentate bound through both nitrogen donor atoms in an axial-equatorial mode. The EPR and (51)V-NMR spectra of aerated solutions at room temperature indicate that the compounds are stable to hydrolysis and that no significant oxidation of V(IV) to V(V) takes place at least in 24h. The complexes are more active in vitro against Trypanosoma cruzi, the parasite responsible for Chagas disease, than the reference drug Nifurtimox and most of them are more active than previously reported [V(IV)O(L-2H)(NN)] complexes of other NN co-ligands. Selectivity towards the parasite was analyzed using J-774 murine macrophages as mammalian cell model. Due to both, high activity and high selectivity, L2, L4, L5 and L7 complexes could be considered new hits for further drug development. Lipophilicity probably plays a relevant role in the bioactivity of the new compounds. The [V(IV)O(L-2H)(NN)] compounds were designed aiming DNA as potential molecular target. Therefore, the novel L1 L7 tmp complexes were screened by computational modeling, comparing their DNA binding features with those of previously reported [V(IV)O(L-2H)(NN)] compounds with different NN co-ligands. Whereas all the complexes interact well with DNA, with binding modes and strength tuned in different extents by the NN and semicarbazone co-ligands, molecular docking suggests that the observed anti-T. cruzi activity cannot be explained upon DNA intercalation as the sole mechanism of action. PMID- 25824467 TI - Attitudes and intentions to smoke: a study of young Brazilian children. AB - BACKGROUND: Children at earlier stages tend to be more susceptible towards different types of tobacco messages. These are able to influence attitudes and behaviours around smoking. This study examined how these messages are able to influence 5- and 6-year olds' attitudes about smokers and their smoking intentions. METHODS: Researchers worked one-on-one with 5- and 6-year olds (n = 398) in Brazil. Children could attribute positive and negative characteristics to two different persons in photos as smoker/non-smoker. Children could indicate the attribute as of a smoker, a non-smoker, both or none. Children were asked also about their smoking intentions. Analysis considered parental smoking, sex, age, cigarette and alcohol brand logos, children's location and media characters from cartoons. We conducted a path analysis for a multivariate model of children's attitudes and intentions about smoking. RESULTS: Overall, children had negative attitudes about smokers (M = -4.58, SD = 4.08) and a total of 32 (8.0%) of them reported intentions to smoke. The resulting multivariate model indicates that parental smoking is a source for a positive image of smokers, while being 6 years old, living in rural areas, being aware of alcohol brands and recognizing educational cartoons tended to be negatively correlated to children's attitudes. Further, 6 year olds were found to be less likely to have smoking intentions, while attitude about smokers was positively related with intentions. One's attitudes served as a mediator for all of the variables in the model towards smoking intentions. The path models differed for each sex. CONCLUSION: Shaped by social and environmental influences, very young children have opinions about smokers. In turn, these attitudes significantly predict children's smoking intentions. To corroborate this research, we recommend that longitudinal designs be employed to help model why Brazilian children become smokers. PMID- 25824468 TI - Linking vegetable preferences, health and local food systems through community supported agriculture. AB - OBJECTIVE: The objective of the present study was to explore the influence of participation in community-supported agriculture (CSA) on vegetable exposure, vegetable intake during and after the CSA season, and preference related to locally produced vegetables acquired directly from CSA growers. DESIGN: Quantitative surveys were administered at three time points in two harvest seasons to four groups of CSA participants: new full-paying, returning full paying, new subsidized and returning subsidized members. Questionnaires included a vegetable frequency measure and measures of new and changed vegetable preference. Comparisons were made between new and returning CSA members and between those receiving subsidies and full-paying members. SETTING: The research was conducted in a rural county in New York, USA. SUBJECTS: CSA members who agreed to participate in the study. RESULTS: Analysis was based on 151 usable questionnaires. CSA participants reported higher intake of eleven different vegetables during the CSA season, with a sustained increase in some winter vegetables. Over half of the respondents reported trying at least one, and up to eleven, new vegetables. Sustained preferences for CSA items were reported. CONCLUSIONS: While those who choose to join a CSA may be more likely to acquire new and expanded vegetable preferences than those who do not, the CSA experience has the potential to enhance vegetable exposure, augment vegetable preference and increase overall vegetable consumption. Dietary patterns encouraged through CSA participation can promote preferences and consumer demand that support local production and seasonal availability. Emphasis on fresh and fresh stored locally produced vegetables is consistent with sustainable community-based food systems. PMID- 25824469 TI - Antioxidant status in peri- and postmenopausal women. AB - Menopause is a risk factor for oxidative stress. The aim of our study is to assess antioxidant system parameters (alpha-tocopherol, retinol, reduced glutathione, total antioxidant activity) in peri- and postmenopausal women. The antioxidant defense activity by estimation of total antioxidant activity, alpha tocopherol, retinol, oxidized and reduced glutathione levels was studied in women of reproductive age (n=37), in perimenopausal (n=41) and postmenopausal women (n=41). In our study we used spectrofluorofotometer methods. Statistical analysis was performed by non-parametric tests with p<0.05 as the level of significance. The results of our study showed the decrease of alpha-tocopherol and retinol concentrations and the increase of oxidized glutathione level in blood serum both in perimenopausal and postmenopausal women, the total antioxidant activity of blood serum was decreased in postmenopausal women only. The results of our study demonstrate that decrease of antioxidant defense system resources depends on the menopausal phase. PMID- 25824470 TI - Facile access to novel [60]fullerenyl diethers and [60]fullerene-sugar conjugates via annulation of diol moieties. AB - A general and facile annulation of various diol motifs to [60]fullerene has been developed. This protocol can afford not only 6- to 10-membered-ring fullerenyl diethers in one step from simple acyclic diols but also directly couple [60]fullerene with a variety of structurally diverse sugars. The [60]fullerene sugar conjugates formed do not require any linker moiety and maintain their inherent structural integrity. The electrochemistry of the fullerenyl diethers and [60]fullerene-sugar conjugates has also been investigated. PMID- 25824471 TI - Quadrivalent human papillomavirus vaccination: a promising treatment for recalcitrant cutaneous warts in children. PMID- 25824472 TI - Signal-to-noise ratio-enhancing joint reconstruction for improved diffusion imaging of mouse spinal cord white matter injury. AB - PURPOSE: To assess the capability of signal-to-noise ratio enhancing reconstruction (SER) to reduce the acquisition time for quantitative white matter injury assessment. METHODS: Four single-average diffusion tensor imaging (DTI) datasets were acquired for each animal from four mouse cohorts: two models of spinal cord injury and two control groups. Quantitative parameters (apparent diffusion coefficient, relative anisotropy, axial and radial diffusivities) were computed from (I) single-average data with traditional reconstruction; (II) single-average data with SER; (III) four-average data with traditional reconstruction; and (IV) single-average data with optimized multicomponent nonlocal means (OMNLM) denoising. These approaches were compared based on coefficients of variation (COVs) and whether estimated diffusion parameters were sensitive to injury. RESULTS: SER yielded better COVs for diffusivity and anisotropy than traditional reconstruction of single-average data, and yielded comparable COVs to that achieved with four-average data. In addition, diffusion parameters obtained using SER with single-average data had comparable injury sensitivity to those obtained from four-average data, while diffusion parameters obtained from OMNLM and traditional reconstruction of single-average data had limited sensitivity. CONCLUSION: A four-fold reduction in the number of averages for quantitative diffusion imaging of small animal white matter injury is feasible using SER. Our results also underscore the need to validate nonlinear methods using task-based measures on an application-by-application basis. PMID- 25824473 TI - Expression of the beta-2 adrenergic receptor (ADRB-2) in human and monkey ovarian follicles: a marker of growing follicles? AB - BACKGROUND: ADRB-2 was implicated in rodent ovarian functions, including initial follicular growth. In contrast, ADRB-2 expression and function in nonhuman primate and human ovary were not fully known but innervation and significant levels of norepinephrine (NE), which is a ligand at the ADRB-2, were reported in the ovary. METHODS: We studied expression of ADRB-2 in human and rhesus monkey ovary (RT-PCR, immunohistochemistry; laser micro dissection) and measured levels of norepinephrine (NE; ELISA) in monkey follicular fluid (FF). 3D cultures of monkey follicles (4 animals) were exposed to NE or the ADRB-2 agonist isoproterenol (ISO), and follicular development (size) was monitored. Upon termination expression of ADRB-2, FSH receptor and aromatase genes were examined. RESULTS: Immunohistochemistry and RT-PCR of either human follicular granulosa cells (GCs) obtained by laser micro dissection or isolated monkey follicles revealed ADRB-2 in GCs of primordial, primary, secondary and tertiary follicles. Staining of GCs in primordial and primary follicles was intense. In large preantral and antral follicles the staining was heterogeneous, with positive and negative GCs present but GCs lining the antrum of large follicles were generally strongly immunopositive. Theca, interstitial, and ovarian surface epithelial cells were also positive. NE was detected in FF of preovulatory antral monkey follicles (0.37 + 0.05 ng/ml; n = 7; ELISA) but not in serum. We examined preantral follicles ranging from 152 to 366 MUm in diameter in a 3D culture in media supplemented with follicle stimulating hormone (FSH). Under these conditions, neither NE, nor ISO, influenced growth rate in a period lasting up to one month. Upon termination of the cultures, all surviving follicles expressed aromatase and FSH receptors, but only about half of them also co-expressed ADRB 2. The ADRB-2 expression was not correlated with the treatment but was positively correlated with the follicular size at the beginning and at the end of the culture period. Hence, expression of ADRB-2 was found in the largest and fastest in vitro growing follicles. CONCLUSIONS: The results imply ADRB-2-mediated actions in the development of primate follicles. Drugs interfering with ADRB-2 are used to treat medical conditions and may have unexplored effects in the human ovary. PMID- 25824475 TI - Effect of low-level laser therapy on chemoradiotherapy-induced oral mucositis and salivary inflammatory mediators in head and neck cancer patients. AB - BACKGROUND AND OBJECTIVE: Oral mucositis (OM) is considered a painful and debilitating side effect in patients receiving head and neck cancer treatment. Low-level laser therapy (LLLT) proved to be effective to prevent and treat chemoradiotherapy-induced OM. The aim of this study was to evaluate the effect of LLLT in the severity of OM in patients with head and neck cancer and on the release of salivary inflammatory mediators. Clinical (score of OM severity) and biochemical parameters (concentration of inflammatory mediators, growth factors, and enzymes in saliva) were used. MATERIALS AND METHODS: Thirty patients were randomized into two groups: control and laser. LLLT was performed three times a week in the laser group, while control group received sham irradiation. OM severity was assessed according to the World Health Organization (WHO) and National Cancer Institute (NCI) scales. Pro-inflammatory and anti-inflammatory cytokines (TNF-alpha, IL-6, IL-1beta, IL-10, TGF-beta), growth factors (EGF, FGF, VEGF), and metalloproteinases (MMP2/TIMP2, MMP9/TIMP2) concentrations were assessed using ELISA test. Saliva samples were collected on admission, and at the 7th, 21st, and 35th sessions of radiotherapy. RESULTS: The laser group showed a reduction in the severity of OM, which coursed with significantly diminished salivary concentration of EGF and VEGF in the 7th radiotherapy session and of IL 6 and FGF in the 35th. There was a trend for reduced levels of IL-1beta, TNF alpha, IL-10, TGF-beta, MMP2/TIMP2, MMP9/TIMP2 in the laser group compared to the control, however, no statistically significant differences were found. CONCLUSIONS: These findings demonstrated that LLLT was effective in reducing the severity of chemoradiotherapy-induced OM and was associated with the reduction of inflammation and repair. PMID- 25824474 TI - Preoperative factors and 3-year weight change in the Longitudinal Assessment of Bariatric Surgery (LABS) consortium. AB - BACKGROUND: Limited data guide the prediction of weight loss success or failure after bariatric surgery according to presurgery factors. There is significant variation in weight change after bariatric surgery and much interest in identifying preoperative factors that may contribute to these differences. This report evaluates the associations of a comprehensive set of baseline factors and 3-year weight change. SETTING: Ten hospitals in 6 geographically diverse clinical centers in the United States. METHODS: Adults undergoing a first bariatric surgical procedure as part of clinical care by participating surgeons were recruited between 2006 and 2009. Participants completed research assessments utilizing standardized and detailed data collection on over 100 preoperative and operative parameters for individuals undergoing Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB). Weight was measured 3 years after surgery. Percent weight change for RYGB or LAGB from baseline to 3 years was analyzed as both a continuous and dichotomous outcome with cut points at 25% for RYGB and 10% for LAGB. Multivariable linear and logistic regression models were used to identify independent baseline predictors of the continuous and categorical outcomes, respectively. RESULTS: The median weight loss 3 years after surgery for RYGB (n = 1513) participants was 31.5% (IQR: 24.6%-38.4%; range, 59.2% loss to .9% gain) of baseline weight and 16.0% (IQR: 8.1%-23.1%; range, 56.1% loss to 12.5% gain) for LAGB (n = 509) participants. The median age was 46 years for RYGB and 48 years for LAGB; 80% of RYGB participants and 75% of LAGB participants were female; and the median baseline body mass index (BMI) was 46 kg/m(2) for RYGB and 44 kg/m(2) for LAGB. For RYGB, black participants lost 2.7% less weight compared with whites and participants with diabetes at baseline had 3.7% less weight loss at year 3 than those without diabetes at baseline. There were small but statistically significant differences in weight change for RYGB in those with abnormal kidney function and current or recent smoking. For LAGB participants, those with a large band circumference had 75% greater odds of experiencing less than 10% weight loss after adjusting for BMI and sex. CONCLUSIONS: Few baseline variables were associated with 3-year weight change and the effects were small. These results indicate that baseline variables have limited predictive value for an individual's chance of a successful weight loss outcome after bariatric surgery. TRIAL REGISTRATION: NCT00465829, ClinicalTrials.gov. PMID- 25824476 TI - Acute lobar nephronia in children. PMID- 25824478 TI - Insect vector-mediated transmission of plant viruses. AB - The majority of plant-infecting viruses are transmitted to their host plants by vectors. The interactions between viruses and vector vary in duration and specificity but some common themes in vector transmission have emerged: 1) plant viruses encode structural proteins on the surface of the virion that are essential for transmission, and in some cases additional non-structural helper proteins that act to bridge the virion to the vector binding site; 2) viruses bind to specific sites in or on vectors and are retained there until they are transmitted to their plant hosts; and 3) viral determinants of vector transmission are promising candidates for translational research aimed at disrupting transmission or decreasing vector populations. In this review, we focus on well-characterized insect vector-transmitted viruses in the following genera: Caulimovirus, Crinivirus, Luteovirus, Geminiviridae, Reovirus, Tospovirus, and Tenuivirus. New discoveries regarding these genera have increased our understanding of the basic mechanisms of virus transmission by arthropods, which in turn have enabled the development of innovative strategies for breaking the transmission cycle. PMID- 25824477 TI - Viral quasispecies. AB - New generation sequencing is greatly expanding the capacity to examine the composition of mutant spectra of viral quasispecies in infected cells and host organisms. Here we review recent progress in the understanding of quasispecies dynamics, notably the occurrence of intra-mutant spectrum interactions, and implications of fitness landscapes for virus adaptation and de-adaptation. Complementation or interference can be established among components of the same mutant spectrum, dependent on the mutational status of the ensemble. Replicative fitness relates to an optimal mutant spectrum that provides the molecular basis for phenotypic flexibility, with implications for antiviral therapy. The biological impact of viral fitness renders particularly relevant the capacity of new generation sequencing to establish viral fitness landscapes. Progress with experimental model systems is becoming an important asset to understand virus behavior in the more complex environments faced during natural infections. PMID- 25824479 TI - The RNA synthesis machinery of negative-stranded RNA viruses. AB - The group of Negative-Stranded RNA Viruses (NSVs) includes many human pathogens, like the influenza, measles, mumps, respiratory syncytial or Ebola viruses, which produce frequent epidemics of disease and occasional, high mortality outbreaks by transmission from animal reservoirs. The genome of NSVs consists of one to several single-stranded, negative-polarity RNA molecules that are always assembled into mega Dalton-sized complexes by association to many nucleoprotein monomers. These RNA-protein complexes or ribonucleoproteins function as templates for transcription and replication by action of the viral RNA polymerase and accessory proteins. Here we review our knowledge on these large RNA-synthesis machines, including the structure of their components, the interactions among them and their enzymatic activities, and we discuss models showing how they perform the virus transcription and replication programmes. PMID- 25824480 TI - Generation of Bioartificial Salivary Gland Using Whole-Organ Decellularized Bioscaffold. AB - Salivary gland hypofunction resulting in xerostomia occurs as a result of various pathological conditions such as radiotherapy for head and neck cancers, Sjogren's syndrome or salivary gland tumor resection. It can induce a large number of problems, including dental decay, periodontitis, dysgeusia, difficulty with mastication and swallowing and a reduced quality of life. Current therapies for xerostomia mostly focus on saliva substitutes, oral lubricants and medications which stimulate salivation from residual glands. However, these treatments are not sufficient to restore gland secretory function. Tissue engineering-based organ regeneration has emerged as a potential therapeutic alternative for end- organ failure. Here, we decellularized rat submandibular glands (SMG) by detergent immersion. Histological, immunofluorescent, Western blot, DNA and collagen quantitative analyses demonstrated that our protocol effectively removed cellular components and that extracellular matrix proteins and native structures were well preserved. We then reseeded the decellularized SMG as scaffolds with rat primary SMG cells in a rotary cell culture system. Histological staining and electron microscopy analyses illustrated that the decellularized SMG could support cellular adhesion. Furthermore, with immunofluorescent staining, we proved that bioartificially generated SMG showed some differentiation markers in vitro. Taken together, our findings might provide a potential scaffold for tissue engineered regeneration of the salivary glands. PMID- 25824481 TI - Optical properties of irradiated imidazolium based room temperature ionic liquids: new microscopic insights into the radiation induced mutations. AB - Considering the future perspectives of room temperature ionic liquids (RTILs) in areas involving high radiation fields (such as the nuclear fuel cycle and space applications), it is essential to probe and have a microscopic understanding of the radiation induced perturbations in the molecular structures and the intrinsic bonding interactions existing in the ILs. Herein, a focused investigation concerning the photophysical behavior of post-irradiated FAP (fluoroalkyl phosphate) imidazolium ILs revealed considerable rearrangements and bonding realignments of the ionic moieties in the ILs on irradiation, however, their physicochemical properties do not change significantly even at high absorbed doses. Most interestingly, the well-established excitation wavelength dependent fluorescence (FL) behavior of the ILs was considerably perturbed on irradiation and this is attributed to the radiation induced decoupling of pre-existing different associated structures of ions, and the subsequent formation of oligomers and other species containing multiple bond order groups. This was further substantiated by vibrational studies, where peaks appearing in the range 1600-1800 cm(-1) indicated the formation of double bonded products. Furthermore, for the hydroxyl functionalized (in the alkyl side chain of the imidazolium cation) IL, a blue shift in the O-H stretching frequency was observed for the -OH group H-bonded to the FAP anion (nuOH...[FAP](-)), while a red shift was observed for the H-bonded -OH groups in the cationic clusters. The FL lifetime values were found to increase with irradiation, which clearly indicates the enhancement in the rigidity level in the vicinity of the ions, thereby hindering the non radiative decay processes. Such studies could contribute to the fundamental understanding of the radiation driven perturbations in the structure-property relationships, which eventually affect the radiolytic degradation pathways and the product distribution in RTILs. PMID- 25824482 TI - The learning curve of lateral access lumbar interbody fusion in an Asian population: a prospective study. AB - PURPOSE: Lateral access lumbar interbody fusion (LLIF) is a minimally invasive technique that has an increasing popularity. It offers unique advantages and circumvents risk of certain serious complications encountered in other conventional spinal approaches. This study provides a statistical analysis defining the lateral access learning curve in the Asian population. METHODS: This prospective study included 32 consecutive patients who underwent LLIF from April 2012 to August 2014. The surgeries were performed by two senior spine surgeons and follow-up was conducted at 6 weeks, 3, 6, 9 months and 1 year post-operation. RESULTS: The breakpoint in operating time occurred at the 22nd level operated, from a mean of 71 min in the early phase group to a mean of 42 min in the steady state group. LLIF at L4/5 level is technically more demanding but technically feasible as competency is achieved. CONCLUSIONS: During the learning process, there was no compromise of perioperative or clinical outcomes. It should be feasibly incorporated into a spine surgeon's repertoire of procedures for the lumbar spine. PMID- 25824483 TI - JAK1/2 inhibition impairs T cell function in vitro and in patients with myeloproliferative neoplasms. AB - Ruxolitinib (INCB018424) is the first JAK1/JAK2 inhibitor approved for treatment of myelofibrosis. JAK/STAT-signalling is known to be involved in the regulation of CD4(+) T cells, which critically orchestrate inflammatory responses. To better understand how ruxolitinib modulates CD4(+) T cell responses, we undertook an in depth analysis of CD4(+) T cell function upon ruxolitinib exposure. We observed a decrease in total CD3(+) cells after 3 weeks of ruxolitinib treatment in patients with myeloproliferative neoplasms. Moreover, we found that the number of regulatory T cells (Tregs), pro-inflammatory T-helper cell types 1 (Th1) and Th17 were reduced, which were validated by in vitro studies. In line with our in vitro data, we found that inflammatory cytokines [tumour necrosis factor-alpha (TNF), interleukin (IL)5, IL6, IL1B] were also downregulated in T cells from patients (all P < 0.05). Finally, we showed that ruxolitinib does not interfere with the T cell receptor signalling pathway, but impacts IL2-dependent STAT5 activation. These data provide a rationale for testing JAK inhibitors in diseases triggered by hyperactive CD4(+) T cells, such as autoimmune diseases. In addition, they also provide a potential explanation for the increased infection rates (i.e. viral reactivation and urinary tract infection) seen in ruxolitinib-treated patients. PMID- 25824484 TI - Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer. AB - Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases. PMID- 25824485 TI - IL-3 synergises with basophil-derived IL-4 and IL-13 to promote the alternative activation of human monocytes. AB - Basophil-derived IL-4 is involved in the alternative activation of mouse monocytes, as recently shown in vivo. Whether this applies to human basophils and monocytes has not been established yet. Here, we sought to characterise the interaction between basophils and monocytes and identify the molecular determinants. A basophil-monocyte co-culture model revealed that IL-3 and basophil-derived IL-4 and IL-13 induced monocyte production of CCL17, a marker of alternative activation. Critically, IL-3 and IL-4 acted directly on monocytes to induce CCL17 production through histone H3 acetylation, but did not increase the recruitment of STAT5 or STAT6. Although freshly isolated monocytes did not express the IL-3 receptor alpha chain (CD123), and did not respond to IL-3 (as assessed by STAT5 phosphorylation), the overnight incubation with IL-4 (especially if associated with IL-3) upregulated CD123 expression. IL-3-activated JAK2-STAT5 pathway inhibitors reduced the CCL17 production in response to IL-3 and IL-4, but not to IL-4 alone. Interestingly, monocytes isolated from allergen sensitised asthmatic patients exhibited a higher expression of CD123. Taken together, our data show that the JAK2-STAT5 pathway modulates both basophil and monocyte effector responses. The coordinated activation of STAT5 and STAT6 may have a major impact on monocyte alternative activation in vitro and in vivo. PMID- 25824487 TI - Activating and Inhibitory Functions of WNT/beta-Catenin in the Induction of Cytochromes P450 by Nuclear Receptors in HepaRG Cells. AB - The WNT/beta-catenin signaling pathway has been identified as an important endogenous regulator of hepatic cytochrome P450 (P450) expression in mouse liver. In particular, it is involved in the regulation of P450 expression in response to exposure to xenobiotic agonists of the nuclear receptors constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR), and Nrf2. To systematically elucidate the effect of the WNT/beta-catenin pathway on the regulation and inducibility of major human P450 enzymes, HepaRG cells were treated with either the WNT/beta-catenin signaling pathway agonist, WNT3a, or with small interfering RNA directed against beta-catenin, alone or in combination with a panel of activating ligands for AhR [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)], CAR [6 (4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4 dichlorobenzyl)oxime (CITCO)], pregnane X receptor (PXR) [rifampicin], and peroxisome proliferator-activated receptor (PPAR) alpha [4-chloro-6-(2,3 xylidino)-2-pyrimidinylthioacetic acid (WY14,643)]. Assessment of P450 gene expression and enzymatic activity after downregulation or activation of the WNT/beta-catenin pathway revealed a requirement of beta-catenin in the AhR-, CAR , and PXR-mediated induction of CYP1A, CYP2B6 and CYP3A4 (for CAR and PXR), and CYP2C8 (for PXR) gene expression. By contrast, activation of the WNT/beta-catenin pathway prevented PPARalpha-mediated induction of CYP1A, CYP2C8, CYP3A4, and CYP4A11 genes, suggesting a dominant-negative role of beta-catenin in PPARalpha mediated regulation of these genes. Our data indicate a significant effect of the WNT/beta-catenin pathway on the regulation of P450 enzymes in human hepatocytes and reveal a novel crosstalk between beta-catenin and PPARalpha signaling pathways in the regulation of P450 expression. PMID- 25824486 TI - Assessing allocation of responsibility for health management in pediatric liver transplant recipients. AB - Given the increased risk for non-adherence and poor health outcomes in late adolescence, there is a need for better methods to evaluate and improve the transition process as adolescent patients are prepared to be independent adults. This study assessed the psychometrics and concurrent validity of a newly developed measure of AoR for health management in pediatric liver transplant patients. A total of 48 patients and 37 parents completed a 13-item measure of AoR. We performed an exploratory PCA on survey results and used component scores to assess the relationship between AoR and age, age at transplant, adherence, and health outcomes. Two primary components were identified: communication with the healthcare system and self-management tasks. Parent perception of adolescent responsibility for tasks related to communicating with the healthcare system was correlated, in younger patients, with increased non-adherence while responsibility for tasks related to self-management was correlated, in older patients, with decreased non-adherence. These results support AoR as a two-domain construct, and they provide targets for monitoring and intervention as adolescent patients advance toward transfer. PMID- 25824488 TI - Quantitative tracking of passage and 3D culture effects on chondrocyte and fibrochondrocyte gene expression. AB - Success in cartilage and fibrocartilage tissue engineering relies heavily on using an appropriate cell source. Many different cell sources have been identified, including primary and stem cells, along with experimental strategies to obtain the required number of cells or to induce chondrogenesis. However, no definitive method exists to quantitatively evaluate the similarity of the resulting cell phenotypes to those of the native cells between candidate strategies. In this study, we develop an integrative approach to enable such evaluations by deriving, from gene expression profiles, two quantitative metrics representing the nearest location within the range of native cell phenotypes and the deviation from it. As an example application to evaluating potential cell sources for cartilage or meniscus tissue engineering, we examine phenotypic changes of juvenile and adult articular chondrocytes and fibrochondrocytes across multiple passages and subsequent 3D culture. A substantial change was observed in cell phenotype due to the isolation process itself, followed by a clear progression toward the outer meniscal cell phenotype with passage. The new metrics also indicated that 3D culture moderately reduced the passage-induced deviation from the native meniscal phenotypes for juvenile chondrocytes and adult fibrochondrocytes, which was not obvious through examination of individual gene expressions. However, brief 3D culture alone did not move any of the cells towards an inner meniscal phenotype, the most relevant target for meniscal tissue engineering. This integrative approach of examining and combining multiple gene expressions can be used to evaluate various other tissue-engineering strategies to direct cells toward the desired phenotype. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25824490 TI - Modelling of phase diagrams of nanoalloys with complex metallic phases: application to Ni-Sn. AB - A method for modelling of size-dependent phase diagrams was developed by combining the semiempirical CALPHAD method and ab initio calculations of surface stresses for intermetallic phases. A novel approach was devised for the calculation of surface energy, free of systematic errors from the selection of different parameters of the software (e.g. number of the k-points) and for handling layered structures and off-stoichiometric slabs. Our approach allows the determination of complex size-dependent phase diagrams of systems with intermetallic phases, which was not possible up to now. The method was verified for the modelling of the phase diagram of the Ni-Sn system and basic comparison with rare experimental results was shown. There is reasonable agreement between the calculated and experimental results. The modelling of size-dependent phase diagrams of real systems allows the prediction of phase equilibria existing in nanosystems and possible changes in material properties. There is a need for such knowledge and the existence of reliable data for simpler systems is crucial for further application of this approach. This should motivate future experimental work. PMID- 25824489 TI - Intravenous Iron Sucrose versus Oral Iron in the Treatment of Pregnancy with Iron Deficiency Anaemia: A Systematic Review. AB - BACKGROUND: Intravenous iron sucrose and oral iron therapy are the main therapies for iron deficiency anaemia (IDA), but there is still a debate regarding their efficacy and especially as to which one is the best choice during pregnancy. METHODS: A meta-analysis of randomised controlled trials comparing patients treated with intravenous iron sucrose (intravenous group) with those treated with oral iron (oral group) for IDA during pregnancy was performed. The primary outcomes of interest were mean maternal haemoglobin and serum ferritin levels at the end of treatment. Secondary outcomes were treatment-related adverse events and foetal birth weight. RESULTS: Six randomised controlled trials, involving a total of 576 women, were included in the present review. Significant increases in haemoglobin [mean difference (MD), 0.85; 95% confidence interval (CI), 0.31-1.39; p = 0.002] and ferritin levels (MD, 63.32; 95% CI, 39.46-87.18; p < 0.00001) were observed in the intravenous group. Compared with the oral group, there were fewer adverse events in the intravenous group (risk ratio, 0.50; 95% CI, 0.34-0.73; p = 0.0003). There was no significant difference in birth weight between the two groups. CONCLUSION: For pregnant women who could not tolerate the side effects of oral treatment or required a rapid replacement of iron stores, intravenous iron sucrose was associated with fewer adverse events and was more effective than regular oral iron therapy. PMID- 25824491 TI - Graphene metascreen for designing compact infrared absorbers with enhanced bandwidth. AB - We propose a compact, wideband terahertz and infrared absorber, comprising a patterned graphene sheet on a thin metal-backed dielectric slab. This graphene based nanostructure can achieve a low or negative effective permeability, necessary for realizing the perfect absorption. The dual-reactive property found in both the plasmonic graphene sheet and the grounded high-permittivity slab introduces extra poles into the equivalent circuit model of the system, thereby resulting in a dual-band or broadband magnetic resonance that enhances the absorption bandwidth. More interestingly, the two-dimensional patterned graphene sheet significantly simplifies the design and fabrication processes for achieving resonant magnetic response, and allows the frequency-reconfigurable operation via electrostatic gating. PMID- 25824492 TI - Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper. AB - Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. PMID- 25824494 TI - Childhood obesity: the guideline for primary care should form part of a whole system approach. PMID- 25824493 TI - Quantifying adhesion mechanisms and dynamics of human hematopoietic stem and progenitor cells. AB - Using planar lipid membranes with precisely defined concentrations of specific ligands, we have determined the binding strength between human hematopoietic stem cells (HSC) and the bone marrow niche. The relative significance of HSC adhesion to the surrogate niche models via SDF1alpha-CXCR4 or N-cadherin axes was quantified by (a) the fraction of adherent cells, (b) the area of tight adhesion, and (c) the critical pressure for cell detachment. We have demonstrated that the binding of HSC to the niche model is a cooperative process, and the adhesion mediated by the CXCR4- SDF1alpha axis is stronger than that by homophilic N cadherin binding. The statistical image analysis of stochastic morphological dynamics unraveled that HSC dissipated energy by undergoing oscillatory deformation. The combination of an in vitro niche model and novel physical tools has enabled us to quantitatively determine the relative significance of binding mechanisms between normal HSC versus leukemia blasts to the bone marrow niche. PMID- 25824495 TI - Legislation jeopardizes safe injection sites. PMID- 25824497 TI - CIHR's commitment to basic science questioned. PMID- 25824500 TI - Quebec bill is an attack on doctors' autonomy. PMID- 25824498 TI - Recommendations for growth monitoring, and prevention and management of overweight and obesity in children and youth in primary care. PMID- 25824501 TI - How schools teach our children to be fat. PMID- 25824502 TI - Rickets re-emerges in northern Aboriginal children. PMID- 25824503 TI - Cognitive decline in an older physician. PMID- 25824504 TI - Disentangling mite predator-prey relationships by multiplex PCR. AB - Gut content analysis using molecular techniques can help elucidate predator-prey relationships in situations in which other methodologies are not feasible, such as in the case of trophic interactions between minute species such as mites. We designed species-specific primers for a mite community occurring in Spanish citrus orchards comprising two herbivores, the Tetranychidae Tetranychus urticae and Panonychus citri, and six predatory mites belonging to the Phytoseiidae family; these predatory mites are considered to be these herbivores' main biological control agents. These primers were successfully multiplexed in a single PCR to test the range of predators feeding on each of the two prey species. We estimated prey DNA detectability success over time (DS50), which depended on the predator-prey combination and ranged from 0.2 to 18 h. These values were further used to weight prey detection in field samples to disentangle the predatory role played by the most abundant predators (i.e. Euseius stipulatus and Phytoseiulus persimilis). The corrected predation value for E. stipulatus was significantly higher than for P. persimilis. However, because this 1.5-fold difference was less than that observed regarding their sevenfold difference in abundance, we conclude that P. persimilis is the most effective predator in the system; it preyed on tetranychids almost five times more frequently than E. stipulatus did. The present results demonstrate that molecular tools are appropriate to unravel predator-prey interactions in tiny species such as mites, which include important agricultural pests and their predators. PMID- 25824506 TI - Antiplatelet therapy. Long-term ticagrelor use in patients with history of MI. PMID- 25824507 TI - Valvular disease. RCTs inform on 5-year outcomes with TAVR and its use in patients at low surgical risk. PMID- 25824508 TI - Heart failure. BAT safe and effective in patients with HF. PMID- 25824510 TI - Coronary artery disease. Drug-eluting stents or CABG? PMID- 25824512 TI - Dyslipidaemia. Assessing the efficacy and safety of evolocumab and alirocumab. PMID- 25824515 TI - Imaging. Effect of CT coronary angiography on the diagnosis and outcomes of patients with CAD. PMID- 25824517 TI - Risk factors. Smoking and CAD--what's plaque got to do with it? PMID- 25824518 TI - Hypertension. Folic acid reduces stroke risk. PMID- 25824520 TI - Anticoagulation therapy. Optimal dosages and genotypes for edoxaban therapy. PMID- 25824519 TI - Atrial fibrillation. Weight loss reduces AF burden. PMID- 25824521 TI - Nickel in biology. PMID- 25824522 TI - Tree nut allergy: risk factors for development, mitigation of reaction risk and current efforts in desensitization. AB - Allergy to tree nuts has grown widespread among patients, specifically in the pediatric population, in recent years. In this review, we evaluate and summarize the literature specific to development and treatment of tree nut allergy. The cause of tree nut allergy, such as most food allergies, is unknown; there are theories regarding maternal dietary factors as well as sensitization related to cross-reactivity to peanut allergens. The gold standard for the diagnosis of tree nut allergy is the double-blind, placebo-controlled, oral food challenge; however, simpler and more cost-effective diagnostic methods, such as the skin prick test and serum-specific IgE are often used as a supplement for diagnosis. Management of tree nut allergy consists of dietary avoidance and using epinephrine to manage serious allergic reactions. Alternative therapeutic methods, such as oral and sublingual immunotherapy and modification of allergenic proteins are being explored to develop safer, more effective and long-lasting management of tree nut allergy. We comment on the current studies involving risk factors for sensitization, diagnosis and management of tree nut allergy. PMID- 25824523 TI - A thorium metallacyclopentadiene complex: a combined experimental and computational study. AB - The synthesis, structure, and reactivity of a thorium metallacyclopentadiene were comprehensively studied. The reduction of (eta(5)-C5Me5)2ThCl2 () with potassium graphite (KC8) in the presence of diphenylacetylene (PhC[triple bond, length as m dash]CPh) yields the first thorium metallacyclopentadiene complex (eta(5) C5Me5)2Th(eta(2)-C4Ph4) (). Density functional theory (DFT) studies suggest that the 5f orbitals are involved in the bonding of the metallacyclopentadiene Th (eta(2)-C[double bond, length as m-dash]C-C[double bond, length as m-dash]C) moiety. Compared to the thorium metallacyclopropene, complex shows a distinctively different reactivity towards diazoalkanes and organic azides such as Me3SiCHN2, 9-diazofluorene and p-tolylN3, leading to the formation of the six membered hydrazido complexes (eta(5)-C5Me5)2Th[N(N[double bond, length as m dash]CHSiMe3)(C4Ph4)] () and (eta(5)-C5Me5)2Th[N(N[double bond, length as m dash]C(C12H8))(C4Ph4)] () and the seven-membered bis(triazenido) complex (eta(5) C5Me5)2Th[N(N[double bond, length as m-dash]N(p-tolyl))(C4Ph4)N(N[double bond, length as m-dash]N(p-tolyl))] (), respectively. PMID- 25824524 TI - Biodegradable Poly (Lactic-co-Glycolic Acid)-Polyethylene Glycol Nanocapsules: An Efficient Carrier for Improved Solubility, Bioavailability, and Anticancer Property of Lutein. AB - Lutein bioavailability is limited because of its poor aqueous solubility. In this study, lutein-poly (lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) nanocapsules were prepared to improve the solubility, bioavailability, and anticancer property of lutein. The scanning electron microscopy and dynamic light scattering examination revealed that the nanocapsules are smooth and spherical with size ranging from 80 to 500 nm (mean = 200 nm). In vitro lutein release profile from nanocapsules showed controlled sustainable release (66%) up to 72 h. Aqueous solubility of lutein nanocapsules was much higher by 735-fold than the lutein. Fourier transform infrared spectroscopy analyses showed no chemical interaction among PLGA, PEG, and lutein, indicating possible weak intermolecular forces like hydrogen bonds. X-ray diffraction revealed lutein is distributed in a disordered amorphous state in nanocapsules. Postprandial plasma kinetics (area under the curve) of an oral dose of lutein from nanocapsules was higher by 5.4 fold compared with that of micellar lutein (control). The antiproliferative effect of lutein from nanocapsules (IC50 value, 10.9 MUM) was higher (43.6%) than the lutein (IC50 value, 25 MUM). Results suggest that PLGA-PEG nanocapsule is an efficient carrier for enhancing hydrophilicity, bioavailability, and anticancer property of lipophilic molecules such as lutein. PMID- 25824525 TI - Synthesis of each enantiomer of rocaglamide by means of a palladium(0)-catalyzed Nazarov-type cyclization. AB - A recently reported Pd(0)-catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (-)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents. PMID- 25824526 TI - Tumour lysis syndrome: new territory for a familiar foe? PMID- 25824527 TI - Incidence and impact of postoperative atrial fibrillation after minimally invasive esophagectomy. AB - Atrial fibrillation (AF) following open esophagectomy has been associated with increased rates of pulmonary and anastomotic complications, and mortality. This study seeks to evaluate effects of AF after minimally invasive esophagectomy (MIE). A retrospective review of patients consecutively treated with MIE for esophageal carcinoma, dysplasia. and benign disease from November 2006 to November 2011 was performed. One hundred twenty-one patients underwent MIE. Median age was 65 years (range 26-88) with 85% being male. Thirty-eight (31.4%) patients developed AF postoperatively. Of these 38 patients, 7 (18.4%) had known AF preoperatively. Patients with postoperative AF were significantly older than those without postoperative AF (68.7 vs. 62.8 years, P = 0.008) and more likely to be male (94.7% vs. 80.7%, P = 0.04). Neoadjuvant chemoradiation showed a trend toward increased risk of AF (73.7% vs 56.6%, P = 0.07). Sixty-day mortality was 2 of 38 (5.3%) in patients with AF and 4 of 83 (6.0%) in the no AF cohort (P = 1.00). The group with AF had increased length of hospitalization (13.4 days vs. 10.6 days P = 0.02). No significant differences in rates of pneumonia (31.6% vs. 21.7% P = 0.24), stricture (13.2% vs. 26.5% P = 0.10), or leak requiring return to operating room (13.2% vs. 8.4% P = 0.51) were noted between groups. We did not find an increased rate of AF in our MIE cohort compared with prior reported rates in open esophagectomy populations. AF did result in an increased length of stay but was not a predictor of other short-term morbidities including anastomotic leak, pulmonary complications, stenosis, or 60-day mortality. PMID- 25824528 TI - The role of parkinson's disease-associated receptor GPR37 in the hippocampus: functional interplay with the adenosinergic system. AB - GPR37 is an orphan G protein-coupled receptor mostly enriched in brain areas such as the cerebellum, striatum, and hippocampus. Identified as a substrate of parkin, GPR37 has been suggested to play a role in Parkinson's disease. Distributed throughout the brain, the function of GPR37, however, remains unknown. We now provide the first mapping of GPR37 within the hippocampus, where GPR37 is widely expressed and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts, and axon terminals. GPR37 per se does not appear to play a role in learning and memory, since knocking out GPR37 (GPR37-KO) did not alter the performance in different hippocampal-related memory tasks. This is in agreement with slice electrophysiology experiments showing no differences both in short-term plasticity paired-pulse facilitation and long-term potentiation between WT and GPR37-KO mice. However, we report a potential functional interaction between GPR37 and adenosine A2A receptors (A2 A R) in the hippocampus, with A2 A R modulating the GPR37-associated phenotype. Thus, the absence of GPR37 appeared to sensitize mice to hippocampal A2 A R-mediated signaling, as observed by the effect of the A2 A R antagonist SCH58261 increasing synaptic depotentiation, reducing novel object recognition memory and reverting the anxiolytic effect of GPR37 deletion. Collectively, these findings afford insight into the localization and role of the orphan GPR37 within the hippocampus with potential involvement in A2 A R function (i.e., A2 A R sensitization). GPR37 is an orphan G protein-coupled receptor widely expressed in the hippocampus and localized at the level of the extrasynaptic plasma membrane of dendritic spines, dendritic shafts and axon terminals. This orphan receptor per se does not appear to directly control the learning and memory processes; however knocking-out GPR37 triggers anxiolytic-like effects and sensitizes mice to hippocampal A2A R mediated signalling. PMID- 25824529 TI - Local cooling and warming effects of forests based on satellite observations. AB - The biophysical effects of forests on climate have been extensively studied with climate models. However, models cannot accurately reproduce local climate effects due to their coarse spatial resolution and uncertainties, and field observations are valuable but often insufficient due to their limited coverage. Here we present new evidence acquired from global satellite data to analyse the biophysical effects of forests on local climate. Results show that tropical forests have a strong cooling effect throughout the year; temperate forests show moderate cooling in summer and moderate warming in winter with net cooling annually; and boreal forests have strong warming in winter and moderate cooling in summer with net warming annually. The spatiotemporal cooling or warming effects are mainly driven by the two competing biophysical effects, evapotranspiration and albedo, which in turn are strongly influenced by rainfall and snow. Implications of our satellite-based study could be useful for informing local forestry policies. PMID- 25824530 TI - IL-22 Produced by T helper Cell 22 as a New player in the Pathogenesis of Immune Thrombocytopenia. AB - Idiopathic thrombocytopenic purpura (ITP) as an autoimmune disease is identified by low count platelet due to decreaed platelet production as well as increased platelet destruction by autoimmune mechanisms in which platelet autoantigen(s) react with the patient's immune system. In ITP a shift toward B cells producing autoantibodies together with CD4+ T helper cells have been reported. T helper cell 22 (Th22) as a new subset of CD4+ T cells is distinctly apart from Th17 and other known CD4+ T cell subsets due to the expression of its specific gene and function. Th22 subset show chemokine receptor CCR4+ CCR6+ CCR10+ phenotype and its key transcription factor is aryl hydrocarbon receptor (AHR). In addition, Th22 cells can be recognized by secretion of a distinguished profile of effector cytokines, including interleukin (IL)- 22, IL- 13, and tumor necrosis factor alpha (TNF-alpha). The amount of Th22 and IL-22 is increased in several autoimmune disorders and positively related to disease severity. The purpose of the present review is to discuss the role of Th22 and its cytokine IL-22 in the immunopathogenesis of ITP. PMID- 25824531 TI - Overdiagnosis: epidemiologic concepts and estimation. AB - Overdiagnosis of thyroid cancer was propounded regarding the rapidly increasing incidence in South Korea. Overdiagnosis is defined as 'the detection of cancers that would never have been found were it not for the screening test', and may be an extreme form of lead bias due to indolent cancers, as is inevitable when conducting a cancer screening programme. Because it is solely an epidemiological concept, it can be estimated indirectly by phenomena such as a lack of compensatory drop in post-screening periods, or discrepancies between incidence and mortality. The erstwhile trials for quantifying the overdiagnosis in screening mammography were reviewed in order to secure the data needed to establish its prevalence in South Korea. PMID- 25824532 TI - Packing to tamponade severe intracranial hemorrhage in pediatric patients. AB - The medical records of all children in whom packing was used to control severe intracranial hemorrhage were reviewed. Eight children, with ages ranging from newborn to 4 years, met the inclusion criteria and all survived. Five were victims of severe closed head trauma, 2 had received penetrating cranial injuries, and 1 developed severe bleeding while undergoing surgery for a malignant tumor in the posterior fossa. Blood loss at the time of removal of the packing was minimal in 7 patients and was surgically controllable in the other. Packing is a simple, efficient, and safe maneuver which can very often halt intracranial bleeding that is considered to be otherwise uncontrollable, and can thereby limit the consequences of prolonged or repeated periods of hypotension and possible exsanguination. PMID- 25824533 TI - Change in obsessive-compulsive symptoms mediates subsequent change in depressive symptoms during exposure and response prevention. AB - OBJECTIVE: The current study examines the temporal relationship between changes in obsessive-compulsive symptoms and changes in depressive symptoms during exposure and response prevention (EX/RP) therapy for obsessive-compulsive disorder (OCD). METHOD: Participants were 40 adults (53% female) who received EX/RP in a randomized controlled trial comparing serotonin reuptake inhibitor (SRI) augmentation strategies. Participants completed clinician-administered assessments of OCD (Yale-Brown Obsessive Compulsive Scale) and depressive symptoms (Hamilton Depression Rating Scale) every four weeks from baseline to 32 week follow-up. RESULTS: Lagged multilevel mediational analyses indicated that change in OCD symptoms accounted for 65% of subsequent change in depressive symptoms. In contrast, change in depressive symptoms only partially mediated subsequent change in OCD symptoms, accounting for 20% of the variance in outcome. CONCLUSIONS: These data indicate that reductions in co-morbid depressive symptoms during EX/RP for OCD are largely driven by reductions in obsessive-compulsive symptoms. PMID- 25824534 TI - Protective effect of berberine against myocardial ischemia reperfusion injury: role of Notch1/Hes1-PTEN/Akt signaling. AB - Berberine (BBR) confers cardioprotective effect against myocardial ischemia reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also reduces MI/RI. We hypothesize that BBR may protect against MI/RI by modulating Notch1/Hes1-Phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signaling. In this study, male Sprague-Dawley rats were exposed to BBR treatment (200 mg/kg/d) for 2 weeks and then subjected to MI/RI. BBR significantly improved cardiac function recovery and decreased myocardial apoptosis, infarct size, serum creatine kinase and lactate dehydrogenase levels. Furthermore, in cultured H9c2 cardiomyocytes, BBR (50 MUmol/L) attenuated simulated ischemia/reperfusion-induced myocardial apoptosis. Both in vivo and in vitro study showed that BBR treatment up-regulates Notch1 intracellular domain, Hes1, Bcl-2 expression and p-Akt/Akt ratio, down-regulates Bax Caspase-3 and cleaved Caspase-3 expression. However, the anti-apoptotic effect conferred by BBR was blocked by Notch1 siRNA, Hes1 siRNA or LY294002 (the specific inhibitor of Akt signaling) in the cultured cardiomyocytes. In summary, our results demonstrate that BBR treatment attenuates MI/RI by modulating Notch1/Hes1 PTEN/Akt signaling. PMID- 25824535 TI - GABA-Synthesizing Enzymes in Calbindin and Calretinin Neurons in Monkey Prefrontal Cortex. AB - Non-overlapping groups of cortical gamma-aminobutyric acid-releasing (GABAergic) neurons are identifiable by the presence of calbindin (CB), calretinin (CR), or parvalbumin (PV). Boutons from PV neuron subtypes are also distinguishable by differences in protein levels of the GABA-synthesizing enzymes GAD65 and GAD67. Multilabel fluorescence microscopy was used to determine if this diversity extends to boutons of CB and CR neurons in monkey prefrontal cortex. CB and CR neurons gave rise to 3 subpopulations of GAD-containing boutons: GAD65+, GAD67+, and GAD65/GAD67+. Somatostatin and vasoactive intestinal peptide-expressing neurons, subtypes of CB and CR neurons, respectively, also gave rise to these distinct bouton subpopulations. At the transcript level, CB and CR neurons contained mRNA encoding GAD67-only or both GADs. Thus, the distinct subpopulations of CB/GAD+ and CR/GAD+ boutons arise from 2 unique subtypes of CB and CR neurons. The different CB and CR GAD-expressing neurons targeted the same projection neurons and neuronal structures immunoreactive for PV, CR, or CB. These findings suggest that GABA synthesis from CB/GAD67+ and CR/GAD67+ neurons would presumably be more vulnerable to disease-associated deficits in GAD67 expression, such as in schizophrenia, than neurons that also contain GAD65. PMID- 25824536 TI - Fronto-Parietal Network Reconfiguration Supports the Development of Reasoning Ability. AB - The goal of this fMRI study was to examine how well developmental improvements in reasoning ability can be explained by changes in functional connectivity between specific nodes in prefrontal and parietal cortices. To this end, we examined connectivity within the lateral fronto-parietal network (LFPN) and its relation to reasoning ability in 132 children and adolescents aged 6-18 years, 56 of whom were scanned twice over the course of 1.5 years. Developmental changes in strength of connections within the LFPN were most prominent in late childhood and early adolescence. Reasoning ability was related to functional connectivity between left rostrolateral prefrontal cortex (RLPFC) and inferior parietal lobule (IPL), but only among 12-18-year olds. For 9-11-year olds, reasoning ability was most strongly related to connectivity between left and right RLPFC; this relationship was mediated by working memory. For 6-8-year olds, significant relationships between connectivity and performance were not observed; in this group, processing speed was the primary mediator of improvement in reasoning ability. We conclude that different connections best support reasoning at different points in development and that RLPFC-IPL connectivity becomes an important predictor of reasoning during adolescence. PMID- 25824537 TI - Jikoshu-kyofu in Singapore. AB - OBJECTIVE: Jikoshu-kyofu (JKF), a condition characterised by a fear of offending others through emitting foul body odour, was first described in Japan in the 1960s. Although initially thought to be a culture-bound syndrome, it has been described in other countries. It is well established that there are two variants, a non- delusional and a delusional variant. METHOD: We describe two cases of JKF who sought treatment from a hospital in Singapore, compare and contrast their characteristics, and in view of overlaps with other conditions, discuss differential diagnoses. RESULTS: Both cases involved women with fairly similar symptomatology except that the first case was younger, had overvalued ideas (but not delusions), an earlier age of onset and good treatment response, while the other had delusions, late age of onset, became too distressed to continue working and was initially resistant to treatment. CONCLUSION: It appears that the delusional variant may have a longer symptomatic duration before presentation, poorer insight, more resistance to treatment and multiple physician consultations, as well as greater impairment of socio-occupational functioning in contrast to the non-delusional variant. PMID- 25824538 TI - DNA Methylation Inhibitor Zebularine Confers Stroke Protection in Ischemic Rats. AB - 5-Aza-deoxycytidine (5-aza-dC) confers neuroprotection in ischemic mice by inhibiting DNA methylation. Zebularine is another DNA methylation inhibitor, less toxic and more stable in aqueous solutions and, therefore more biologically suitable. We investigated Zebularine's effects on brain ischemia in a rat middle cerebral artery occlusion (MCAo) model in order to elucidate its therapeutic potential. Male Wistar wild-type (WT) rats were randomly allocated to three treatment groups, vehicle, Zebularine 100 MUg, and Zebularine 500 MUg. Saline (10 MUL) or Zebularine (10 MUL) was administered intracerebroventricularly 20 min before 45-min occlusion of the middle cerebral artery. Reperfusion was allowed after 45-min occlusion, and the rats were sacrificed at 24-h reperfusion. The brains were removed, sliced, and stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC) before measuring infarct size. Zebularine (500 MUg) reduced infarct volumes significantly (p < 0.05) by 61% from 20.7 +/- 4.2% in the vehicle treated to 8.1 +/- 1.6% in the Zebularine treated. Zebularine (100 MUg) also reduced infarct volumes dramatically by 55 to 9.4 +/- 1.2%. The mechanisms behind this neuroprotection is not yet known, but the results agree with previous studies and support the notion that Zebularine-induced inhibition of DNA methyltransferase ameliorates ischemic brain injury in rats. PMID- 25824539 TI - BPH: a tell-tale sign of prostate cancer? Results from the Prostate Cancer and Environment Study (PROtEuS). AB - INTRODUCTION: In a population-based case-control study (PROtEuS), we examined the association between prostate cancer (PCa) and (1) benign prostatic hypertrophy (BPH) history at any time prior to PCa diagnosis, (2) BPH-history reported at least 1 year prior to interview/diagnosis (index date) and (3) exposure to BPH medications. METHODS: Cases were 1933 men with incident prostate cancer diagnosed across Montreal French hospitals between 2005 and 2009. Population controls were 1994 men from the same age distribution and residential area. In-person interviews collected socio-demographic characteristics and medical history, e.g., BPH diagnosis, duration and treatment, as well as on PCa screening. Logistic regression analyses tested overall and grade-specific associations, including subgroup analyses with frequent PSA testing. RESULTS: A BPH-history was associated with an increased risk of PCa (OR 1.37 [95 % CI 1.16-2.61]), more pronounced for low-grade PCa (Gleason <=6: OR 1.54 [1.26-1.87]; Gleason >=7: OR 1.05 [0.86-1.27]). The association was not significant when BPH-history diagnosis was more than 1 year prior to index date, except for low-grade PCa (OR 1.29 [1.05 1.60]). Exposure to 5alpha reductase inhibitors (5alpha-RI) resulted in a decreased risk of overall PCa (OR 0.62 [0.42-0.92]), particularly for intermediate- to high-grade PCa (Gleason <=6: OR 0.70 [0.43-1.14]; Gleason >=7: OR 0.43 [0.26-0.72]). Adjusting for PSA testing frequency or restricting analyses to frequently screened subjects did not affect these results. CONCLUSION: BPH history was associated with an increased PCa risk, which disappeared, when BPH history did not include BPH diagnosis within the previous year. Our results also suggest that 5alpha-RI exposure exerts a protective effect on intermediate and high-grade PCa. PMID- 25824540 TI - (18)F-choline PET/CT for early detection of metastases in biochemical recurrence following radical prostatectomy. AB - PURPOSE: Salvage radiotherapy (SRT) for biochemical recurrence (BCR) following radical prostatectomy (RP) should if possible be added at a prostate-specific antigen (PSA) level of <1-2 ng/mL. The value of positron emission tomography combined with computed tomography (PET/CT) at such low PSA values is not defined. The purpose was to determine what proportion of a well-defined cohort of hormone naive patients who were candidates for early salvage radiotherapy had (18)F choline PET/CT findings suggesting metastases. MATERIALS AND METHODS: Patients with untreated BCR following RP, PSA <2 ng/mL, and Gleason score >=7 or PSA doubling time <=6 months underwent (18)F-choline PET/CT. Focal choline uptake in lymph nodes or skeletal sites was recorded. RESULTS: PET/CT indicated metastases in 16 (28 %) of 58 patients. In five (9 %) patients, the scans suggested bone metastases, and in 11 (19 %) patients, the scans suggested regional lymph node metastases only. For patients with PSA levels <1.0 ng/mL, the PET/CT scans indicated metastatic recurrence in 25 %. CONCLUSIONS: (18)F-choline PET/CT may be valuable for selecting patients with BCR following RP for SRT or experimental treatment of oligometastases, even at low PSA values. PMID- 25824541 TI - The balancing act of GABAergic synapse organizers. AB - GABA (gamma-aminobutyric acid) is the main neurotransmitter at inhibitory synapses in the mammalian brain. It is essential for maintaining the excitation and inhibition (E/I) ratio, whose imbalance underlies various brain diseases. Emerging information about inhibitory synapse organizers provides a novel molecular framework for understanding E/I balance at the synapse, circuit, and systems levels. This review highlights recent advances in deciphering these components of the inhibitory synapse and their roles in the development, transmission, and circuit properties of inhibitory synapses. We also discuss how their dysfunction may lead to a variety of brain disorders, suggesting new therapeutic strategies based on balancing the E/I ratio. PMID- 25824542 TI - Comparison of inhospital mortality, length of hospitalization, costs, and vascular complications of percutaneous coronary interventions guided by ultrasound versus angiography. AB - Despite the valuable role of intravascular ultrasound (IVUS) guidance in percutaneous coronary interventions (PCIs), its impact on clinical outcomes remains debatable. The aim of the present study was to compare the outcomes of PCIs guided by IVUS versus angiography in the contemporary era on inhospital outcomes in an unrestricted large, nationwide patient population. Data were obtained from the Nationwide Inpatient Sample from 2008 to 2011. Hierarchical mixed-effects logistic regression models were used for categorical dependent variables like inhospital mortality, and hierarchical mixed-effects linear regression models were used for continuous dependent variables like length of hospital stay and cost of hospitalization. A total of 401,571 PCIs were identified, of which 377,096 were angiography guided and 24,475 (weighted n = 119,102) used IVUS. In a multivariate model, significant predictors of higher mortality were increasing age, female gender, higher baseline co-morbidity burden, presence of acute myocardial infarction, shock, weekend and emergent admission, or occurrence of any complication during hospitalization. Significant predictors of reduced mortality were the use of IVUS guidance (odds ratio 0.65, 95% confidence interval 0.52 to 0.83; p <0.001) for PCI and higher hospital volumes (third and fourth quartiles). The use of IVUS was also associated with reduced inhospital mortality in subgroup of patients with acute myocardial infarction and/or shock and those with a higher co-morbidity burden (Charlson's co-morbidity index >=2). In one of the largest studies on IVUS-guided PCIs in the drug-eluting stent era, we demonstrate that IVUS guidance is associated with reduced inhospital mortality, similar length of hospital stay, and increased cost of care and vascular complications compared with conventional angiography-guided PCIs. PMID- 25824543 TI - Predictors of stroke associated with coronary artery bypass grafting in patients with diabetes mellitus and multivessel coronary artery disease. AB - This study assesses demographic and clinical variables associated with perioperative and late stroke in diabetes mellitus patients after multivessel coronary artery bypass grafting (CABG). Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) is the largest randomized trial of diabetic patients undergoing multivessel CABG. FREEDOM patients had improved survival free of death, myocardial infarction, or stroke and increased overall survival after CABG compared to percutaneous intervention. However, the stroke rate was greater following CABG than percutaneous intervention. We studied predictors of stroke in CABG-treated patients analyzing separately overall, perioperative (<=30 days after surgery), and late (>30 days after surgery) stroke. For long-term outcomes (overall stroke and late stroke), Cox proportional hazards regression was used, accounting for time to event, and logistic regression was used for perioperative stroke. Independent perioperative stroke predictors were previous stroke (odds ratio [OR] 6.96, 95% confidence interval [CI] 1.43 to 33.96; p = 0.02), warfarin use (OR 10.26, 95% CI 1.10 to 96.03; p = 0.02), and surgery outside the United States or Canada (OR 9.81, 95% CI 1.28 to 75.40; p = 0.03). Independent late stroke predictors: renal insufficiency (hazard ratio [HR] 3.57, 95% CI 1.01 to 12.64; p = 0.048), baseline low-density lipoprotein >=105 mg/dl (HR 3.28, 95% CI 1.19 to 9.02; p = 0.02), and baseline diastolic blood pressure (each 1 mm Hg increase reduces stroke hazard by 5%; HR 0.95, 95% CI 0.91 to 0.99; p = 0.03). There was no overlap between predictors of perioperative versus late stroke. In conclusion, late post-CABG strokes were associated with well-described risk factors. Nearly half of the strokes were perioperative. Independent risk factors for perioperative stroke: previous stroke, previous warfarin use, and CABG performed outside the United States or Canada. PMID- 25824544 TI - Single nucleotide polymorphisms of the Fas gene are associated with papillary thyroid cancer. AB - OBJECTIVES: Fas is the prototypic representative of the death receptor subgroup of the tumor necrosis factor (TNF) receptor family. Recently, single nucleotide polymorphisms (SNPs) of the Fas or Fas ligand (FasL) genes have been shown to be associated with an increased risk of several cancers and with the prognosis of several cancers. The objective of this study was to evaluate the association between the SNPs of the Fas and FasL genes and papillary thyroid cancer (PTC) and to assess the relationship between these SNPs and the clinicopathological characteristics of PTC. METHODS: Five SNPs located within the two genes of Fas and FasL were genotyped using direct sequencing in 94 patients with PTC and 364 healthy controls. Genetic data were analyzed using commercially available software. And, the statistical analyses were performed according to clinicopathologic characteristics of PTC. RESULTS: Genotyping analysis demonstrated that the intron SNP (rs1571013), promoter SNP (rs1800682) and 3'-UTR SNP (rs1468063) of Fas were significantly associated with the development of PTC. We also detected a significant difference between patients with PTC and healthy controls with respect to Fas gene allele frequencies. Furthermore, we found that the 3'-UTR SNP (rs1468063) of Fas was associated with the multifocality of cancer [dominant model, OR 0.28, p=0.028; log-additive model, OR 0.43, p=0.033]. CONCLUSION: We observed a significant association between SNPs of the Fas gene and the development of PTC. In addition, there was a significant association between a Fas SNP and the multifocality of PTC. PMID- 25824545 TI - Surgery for rectal cancer after high-dose radiotherapy for prostate cancer: is sphincter preservation relevant? AB - AIM: The feasibility and outcome of sphincter-saving resection for rectal cancer were assessed in patients previously treated by high-dose radiotherapy for prostate cancer. METHOD: Between 2000 and 2012, 1066 patients underwent rectal excision for rectal cancer. Of these, 236 were treated by conventional radiotherapy (45 Gy) and sphincter-saving resection (Group A) and 12 were treated by external-beam radiotherapy (EBRT) for prostate cancer (70 Gy) and sphincter saving resection (Group B) of whom five had a metachronous and seven a synchronous cancer. The end-points were surgical morbidity, pelvic sepsis, reoperation and definitive stoma. RESULTS: Tumour characteristics were similar in both groups. Surgical morbidity (67% vs 25%, P = 0.004), anastomotic leakage (50% vs 10%, P = 0.001, and reoperation (50% vs 17%, P = 0.011) were significantly higher in Group B. Multivariate analyses showed that EBRT for prostate cancer was the only independent factor for anastomotic leakage (OR = 5.12; 95% CI 1.45 18.08; P = 0.011) and definitive stoma (OR = 10.56; 95% CI 3.02-39.92; P < 0.001). CONCLUSION: High-dose radiotherapy for prostate cancer increases morbidity from rectal surgery and the risk of a permanent stoma. This suggests that a delayed coloanal anastomosis or a Hartmann procedure should be proposed as an alternative to low anterior resection in this population. PMID- 25824547 TI - Is acetylation a metabolic rheostat that regulates skeletal muscle insulin action? AB - Skeletal muscle insulin resistance, which increases the risk for developing various metabolic diseases, including type 2 diabetes, is a common metabolic disorder in obesity and aging. If potential treatments are to be developed to treat insulin resistance, then it is important to fully understand insulin signaling and glucose metabolism. While recent large-scale "omics" studies have revealed the acetylome to be comparable in size to the phosphorylome, the acetylation of insulin signaling proteins and its functional relevance to insulin stimulated glucose transport and glucose metabolism is not fully understood. In this Mini Review we discuss the acetylation status of proteins involved in the insulin signaling pathway and review their potential effect on, and relevance to, insulin action in skeletal muscle. PMID- 25824549 TI - Technological innovations in forensic genetics: social, legal and ethical aspects. AB - This paper discusses the nature of four waves of technological innovations in forensic genetics alongside the social, legal and ethical aspect of these innovations. It emphasises the way in which technological advances and their socio-legal frameworks are co-produced, shaping technology expectations, social identities, and legal institutions. It also considers how imagined and actual uses of forensic genetic technologies are entangled with assertions about social order, affirmations of common values and civil rights, and promises about security and justice. Our comments seek to encourage the participation of scientific actors in the development of anticipatory governance deliberations concerning the widening application of forensic genetics in an increasing number of criminal and civil jurisdictions. PMID- 25824546 TI - Upstream regulators and downstream effectors of NADPH oxidases as novel therapeutic targets for diabetic kidney disease. AB - Oxidative stress has been linked to the pathogenesis of diabetic nephropathy, the complication of diabetes in the kidney. NADPH oxidases of the Nox family, and in particular the homologue Nox4, are a major source of reactive oxygen species in the diabetic kidney and are critical mediators of redox signaling in glomerular and tubulointerstitial cells exposed to the diabetic milieu. Here, we present an overview of the current knowledge related to the understanding of the role of Nox enzymes in the processes that control mesangial cell, podocyte and tubulointerstitial cell injury induced by hyperglycemia and other predominant factors enhanced in the diabetic milieu, including the renin-angiotensin system and transforming growth factor-beta. The nature of the upstream modulators of Nox enzymes as well as the downstream targets of the Nox NADPH oxidases implicated in the propagation of the redox processes that alter renal biology in diabetes will be highlighted. PMID- 25824548 TI - Expression and preliminary functional profiling of the let-7 family during porcine ovary follicle atresia. AB - Most follicles in the mammalian ovary undergo atresia. Granulosa cell apoptosis is a hallmark of follicle atresia. Our previous study using a microRNA (miRNA) microarray showed that the let-7 microRNA family was differentially expressed during follicular atresia. However, whether the let-7 miRNA family members are related to porcine (Sus scrofa) ovary follicular apoptosis is unclear. In the current study, real-time quantitative polymerase chain reaction showed that the expression levels of let-7 family members in follicles and granulosa cells were similar to our microarray data, in which miRNAs let-7a, let-7b, let-7c, and let 7i were significantly decreased in early atretic and progressively atretic porcine ovary follicles compared with healthy follicles, while let-7g was highly expressed during follicle atresia. Furthermore, flow cytometric analysis and Hoechst33342 staining demonstrated that let-7g increased the apoptotic rate of cultured granulosa cells. In addition, let-7 target genes were predicted and annotated by TargetScan, PicTar, gene ontology and Kyoto encyclopedia of genes and genomes pathways. Our data provide new insight into the association between the let-7 miRNA family in granulosa cell programmed death. PMID- 25824550 TI - Kidney-induced cardiac allograft tolerance in miniature swine is dependent on MHC matching of donor cardiac and renal parenchyma. AB - Kidney allografts possess the ability to enable a short course of immunosuppression to induce tolerance of themselves and of cardiac allografts across a full-MHC barrier in miniature swine. However, the renal element(s) responsible for kidney-induced cardiac allograft tolerance (KICAT) are unknown. Here we investigated whether MHC disparities between parenchyma versus hematopoietic-derived "passenger" cells of the heart and kidney allografts affected KICAT. Heart and kidney allografts were co-transplanted into MHC mismatched recipients treated with high-dose tacrolimus for 12 days. Group 1 animals (n = 3) received kidney and heart allografts fully MHC-mismatched to each other and to the recipient. Group 2 animals (n = 3) received kidney and heart allografts MHC-matched to each other but MHC-mismatched to the recipient. Group 3 animals (n = 3) received chimeric kidney allografts whose parenchyma was MHC mismatched to the donor heart. Group 4 animals (n = 3) received chimeric kidney allografts whose passenger leukocytes were MHC-mismatched to the donor heart. Five of six heart allografts in Groups 1 and 3 rejected <40 days. In contrast, heart allografts in Groups 2 and 4 survived >150 days without rejection (p < 0.05). These data demonstrate that KICAT requires MHC-matching between kidney allograft parenchyma and heart allografts, suggesting that cells intrinsic to the kidney enable cardiac allograft tolerance. PMID- 25824551 TI - Improvement of kidney yang syndrome by icariin through regulating hypothalamus pituitary-adrenal axis. AB - OBJECTIVE: To investigate whether Epimedium brevicornu Maxim (EB) and icariin could exert their protective effects on hydrocortisone induced (HCI) rats by regulating the hypothalamus-pituitary-adrenal (HPA) axis and endocrine system and the possible mechanism. METHODS: Male 10-week-old Sprague Dawley (SD) rats were allotted to 6 groups (A-F) with 12 each, group A was injected normal saline (NS) 3 mL/kg day intraperitoneally, group A and B were given NS 6 mL/kg day by gastrogavage, group B-F were injected hydrocortisone 15 mg/kg intraperitoneally, group C and D were given EB 8 or 5 g/(kg day) by gastrogavage, group E and F were given icariin 25 or 50 mg/(kg day) by gastrogavage. Gene expressions of hypothalamus corticotropin releasing hormone (CRH) and pituitary proopiomelanocortin (POMC) were detected by reverse transcription-polymerase chain reaction (RT-PCR), and protein of pituitary POMC by Western-blot. RESULTS: The serum T4, testosterone, cortisol and POMC mRNA expression were increased after treatment with EB or icariin in HCI rats, the serum CRH and the hypothalamus CRH mRNA expression released from hypothalamus corticotropin decreased compared with group B (P<0.05).The treatment with only icariin increased serum adrenocorticotropic hormone (ACTH) compared with group B (P<0.05). CONCLUSION: EB and icariin might be therapeutically beneficial in the treatment of HCI rats through attuning the HPA axis and endocrine system which was involved in the release of CRH in hypothalamic, and the production of POMC derived peptide ACTH in anterior pituitary, the secretion of corticosteroids in adrenal cortex. PMID- 25824552 TI - Jinmaitong alleviates the diabetic peripheral neuropathy by inducing autophagy. AB - OBJECTIVE: To observe the deregulation of autophagy in diabetic peripheral neuropathy (DPN) and investigate whether Jinmaitong ( JMT) alleviates DPN by inducing autophagy. METHODS: DPN models were established by streptozotocin induced diabetic rats and Schwann cells (SCs) cultured in high glucose medium. The pathological morphology was observed by the improved Bielschowsky's nerve fiber axonal staining and the Luxol fast blue-neutral red myelin staining. The ultrastructure was observed by the transmission electron microscopy. Beclin1 level was detected by immunohistochemistry and Western blot. The proliferation of cultured SCs was detected by methylthiazolyldiphenyl-tetrazolium bromide. RESULTS: Diabetic peripheral nerve tissues demonstrated pathological morphology and reduced autophagic structure, accompanied with down-regulation of Beclin1. JMT apparently alleviated the pathological morphology change and increased the autophagy [in vivo, Beclin1 integral optical density (IOD) value of the control group 86.6+/-17.7, DM 43.9+/-8.8, JMT 73.3 +/-17.8, P<0.01 or P<0.05, in vitro Beclin1 IOD value of the glucose group 0.47+/-0.25 vs the control group 0.88+/ 0.29, P<0.05]. Consequently, inhibition of autophagy by 3-methyladenine resulted in a time- and concentration-dependent decrease of the proliferation of SCs (P<0.05, P<0.01). CONCLUSIONS: Down-regulation of autophagy in SCs might contribute to the pathogenesis of DPN. JMT alleviates diabetic peripheral nerve injury at least in part by inducing autophagy. PMID- 25824553 TI - Regional differences in use and outcomes of left ventricular assist devices: Insights from the Interagency Registry for Mechanically Assisted Circulatory Support Registry. AB - BACKGROUND: We examined whether characteristics, implant strategy, and outcomes in patients who receive continuous-flow left ventricular assist devices (CF-LVAD) differ across geographic regions in the United States. METHODS: A total of 7,404 CF-LVAD patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 134 participating institutions were analyzed from 4 distinct regions: Northeast, 2,605 (35%); Midwest, 2,210 (30%); West, 973 (13%); and South, 1,616 (22%). RESULTS: At baseline, patients in the Northeast and South were more likely to have INTERMACS risk profiles 1 and 2. A bridge-to transplant (BTT) strategy was more common in the Northeast (31.7%; West, 18.5%; South, 26.9%; Midwest, 25.5%; p < 0.0001). In contrast, destination therapy (DT) was more likely in the South (40.6%; Northeast, 32.3%; Midwest, 27.3%; West, 27.3%; p < 0.0001). Although all regions showed a high 1-year survival rate, some regional differences in long-term mortality were observed. Notably, survival beyond 1 year after LVAD implant was significantly lower in the South. However, when stratified by device strategy, no significant differences in survival for BTT or DT patients were found among the regions. Finally, with the exception of right ventricular failure, which was more common in the South, no other significant differences in causes of death were observed among the regions. CONCLUSIONS: Regional differences in clinical profile and LVAD strategy exist in the United States. Despite an overall high survival rate at 1 year, differences in mortality among the regions were noted. The lower survival rate in the South may be attributed to patient characteristics and higher use of LVAD as DT. PMID- 25824554 TI - Effect of racial and ethnic differences in heart transplantation with ABO incompatibility. PMID- 25824555 TI - WITHDRAWN: Modulation of the kinetics of 3beta-hydroxy-5-oxo-5,6-secocholestan-6 al/phosphatidylethanolamine Schiff base formation by cholesterol and cholesterol crystallization. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.chemphyslip.2015.01.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25824556 TI - Effect of magnesium on functional outcome and paraclinical parameters of patients undergoing supratentorial craniotomy for brain tumors: a randomized controlled trial. AB - BACKGROUND: Several studies have demonstrated that magnesium (Mg) plays an important role in the prevention and treatment of central nervous system (CNS) insults. In this study, we tested the effect of intravenous magnesium sulfate (MgSO4) on the outcome of patients with brain tumors who underwent craniotomy. The outcome was defined clinically as the Barthel index score and paraclinically as blood levels of NSE (neuron-specific enloase) and S100Beta protein. METHODS: Sixty patients were randomly divided into two groups of 30 patients: the treatment and control groups. In the treatment group, 5 g of MgSO4 in normal saline was infused in 6 h 2 days before surgery, and the same dosage was repeated the day before and during surgery. The control group received placebo. Serum S100Beta and NSE concentrations were measured at baseline before administration of magnesium, before surgery, and on the 2nd postoperative day. The Barthel index score was evaluated and registered before surgery, 3, and 6 months after the operation. RESULTS: The study results showed a significant change in S100Beta protein levels before and after surgery (p < 0.05), but we could not find similar results for NSE protein and the Barthel index score. There was a correlation between NSE protein and the Barthel index. CONCLUSIONS: The results of this study revealed that administration of intravenous MgSO4 before and during surgery is safe and effective in reducing S100B protein levels in patients undergoing supratentorial craniotomy for brain tumors. Further studies to elucidate the pathophysiology of brain injuries and role of magnesium are warranted. PMID- 25824557 TI - Fluorescein sodium-guided resection of cerebral metastases-experience with the first 30 patients. AB - BACKGROUND: Surgical resection is a key element of the multidisciplinary treatment of cerebral metastases (CMs). Recent studies have highlighted the importance of complete resection of CMs for improving recurrence-free and overall survival rates. This study presents the first data on the use of fluorescein sodium (FL) under the dedicated surgical microscope filter YELLOW 560 nm (Zeiss Meditec, Germany) in patients with CM. METHODS: Thirty patients with CMs of different primary cancers were included (15 females, 15 males; mean age 61.1 years); 200 mg of FL was intravenously injected directly before CM resection. A YELLOW 560 nm filter was used for microsurgical tumor resection and resection control. Surgical reports were evaluated regarding the degree of fluorescent staining, postoperative MRIs regarding the extent of resection [gadolinium (Gd) enhanced T1-weighted sequence] and the postoperative courses regarding any adverse effects. RESULTS: Most patients (90.0%, n = 27) showed bright fluorescent staining, which markedly enhanced tumor visibility. Three patients (10.0%) (two with adenocarcinoma of the lung and one with melanoma of the skin) showed no or only insufficient FL staining. Another three patients (10.0%) showed residual tumor tissue in the postoperative MRI examination. In two other patients, radiographic examination could not exclude the possibility of very small areas of residual tumor tissue. Thus, gross-total resection was achieved in 83.3% (n = 25) of patients. No adverse effects were registered over the postoperative course. CONCLUSIONS: FL and the YELLOW 560 nm filter are safe and practical tools for the resection of CM, but further prospective research is needed to confirm that this advanced technique will improve the quality of CM resection. PMID- 25824559 TI - Emphysema and airway disease affect within-breath changes in respiratory resistance in COPD patients. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by a mixture of emphysema and airway disease. The forced oscillation technique (FOT) has been applied to COPD patients to clarify changes in respiratory mechanics; dynamic changes in respiratory resistance (Rrs) during breathing (within-breath changes in Rrs, DeltaRrs) are characteristic of COPD. However, the pathophysiological significance of these changes is unknown. The aim of this study was to assess how emphysema and airway disease influence DeltaRrs in COPD patients. METHODS: In this cross-sectional study, stable COPD patients were recruited and underwent respiratory impedance measurements with a commercially available FOT device. Rrs was recorded during tidal breathing and then analyzed as whole-breath Rrs (Rrs at 5 Hz, R5; Rrs at 20 Hz, R20; and their difference, R5-R20) or as DeltaRrs, the difference between the expiratory and inspiratory Rrs (DeltaR5, DeltaR20 and DeltaR5-R20). The percentage of the low attenuation area (LAA%) and airway wall area (WA%) was quantified by computed tomography analysis, and their contributions to DeltaRrs were examined. RESULTS: Seventy-five COPD patients were recruited. LAA% was negatively correlated with DeltaR5 and DeltaR5-R20 (P = 0.0002 and P = 0.0033, respectively); meanwhile, WA% in B(10) was positively correlated with DeltaR5 and DeltaR5-R20 (P = 0.0057 and P < 0.0001, respectively). Multivariate analysis revealed that the contribution of both LAA% and WA% in B(10) to DeltaRrs was independent of the severity of airflow limitations. CONCLUSION: This study shows that emphysema suppresses DeltaRrs in COPD patients, while airway disease increases DeltaRrs in these patients. PMID- 25824558 TI - Nationwide study on the use of intravascular catheters in internal medicine departments. AB - BACKGROUND: The use of intravascular catheters (IVCs) in intensive care units (ICUs) has been well assessed in recent years. However, a high proportion of these devices are placed in patients outside the ICU, particularly in internal medicine departments (IMDs), where data on the quality of care are scarce. AIM: To assess the use and management of IVCs in IMDs in Spain. METHODS: We performed a point prevalence study of all adult inpatients on 47 IMDs from hospitals of different sizes on one day in June 2013. A local co-ordinator was appointed to assess patients and collect data from each site. FINDINGS: Out of the 2080 adult patients hospitalized on the study day, 1703 (81.9%) had one or more IVCs (95.4% of which were peripheral devices). Infection was detected at the insertion site in 92 catheters (5.0%); 87 patients (5.2%) had signs of sepsis, but only one case was considered to be catheter-related. The local co-ordinators estimated that 19% of the catheters in place were no longer necessary. A daily record of the need for a catheter was available in only 40.6% of cases. CONCLUSION: Our study shows clear opportunities for improvement regarding catheter use and care in Spanish IMDs. Strategies similar to those applied in ICUs should be implemented in IMDs. PMID- 25824562 TI - Faecolith migrating from the appendix to produce liver abscess after subhepatic laparoscopic appendectomy. AB - The subhepatic position of an appendix may lead to difficulty in diagnosis of appendicitis, its surgical management as well as bizarre complications. A 'lost' appendicular faecolith is not an uncommon complication due to spillage during the removal of the appendix or due to perforation. Here we report a case of such a faecolith migrating into the liver parenchyma following intraoperative hepatic injury, and producing a liver abscess. The calcified lesion seen in the liver corresponded to a free-lying faecolith on a preoperative computed tomography scan. Liver abscess was presumed to arise from implantation of this foreign object into the liver parenchyma. Pigtail drainage of abscess was performed with good result. PMID- 25824561 TI - Plasma neutrophil gelatinase-associated lipocalin and kidney function decline and kidney disease-related clinical events in older women. AB - BACKGROUND: It is still unclear whether serum neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of renal tubular injury, is a prognostic marker for the progression of chronic kidney disease (CKD) in the general population. METHODS: A prospective-cohort study of 1,245 women aged >=70 from the general population. Associations between plasma NGAL and change in 5-year estimated glomerular filtration rate (eGFR), rapid renal decline and 10-year risk of acute or chronic renal disease-related hospitalisations and/or mortality were examined. RESULTS: Compared to women with above-median plasma NGAL of 76.5 ng/l, women with below-median plasma NGAL had a 9.3% reduction in eGFR over a 5-year period. Among women with above-median plasma NGAL, there was over a 1.7-fold increased risk of rapid renal decline (eGFR decline of >3 ml/min/year) (adjusted odds ratio 1.76, 95% CI 1.003, 3.102, p = 0.049). Compared to women with baseline eGFR of <60 ml/min/1.73 m(2), women with above-median plasma NGAL experienced over a 2.5-fold increased risk of renal disease events at 10 years (hazard ratio 2.55, 95% CI 1.13, 5.78, p = 0.025) after adjustment of age, hypertension and diabetes. Addition of plasma NGAL in participants with eGFR of <60 ml/min/1.73 m(2) significantly improved the accuracy in predicting the 10-year risk of renal disease events (adjusted area-under-curve receiver operator characteristics without and with NGAL 0.64 and 0.71, respectively; p = 0.027) and reclassified 13% of women who experienced renal disease events into the higher risk categories (p = 0.03). CONCLUSION: Plasma NGAL is of modest clinical utility in predicting the renal function decline and risk of renal disease-related clinical events, particularly those with mild to moderate CKD. PMID- 25824563 TI - Simple adaptation for dynamic Bogota bag. AB - The use of a large Bogota bag tucked well under fascial edges to the colonic gutters and easily made elastic bands from Esmarch bandage provides a dynamic tension system that decreases subsequent trips to theatre and may allow gradual closure of the abdominal wound. PMID- 25824564 TI - Altered mental status is an indicator of mortality and associated with both infectious and non-communicable disease in Lilongwe, Malawi. AB - Little is known about diseases associated with altered mental status (AMS) in resource-limited settings. We studied adult medicine patients presenting with AMS in Lilongwe, Malawi and found that AMS and HIV infection were each significantly associated with mortality. It is therefore critical that evaluation and management in this patient population is improved. PMID- 25824565 TI - PARADIGM - HF: The Rise of the Arnis. AB - Heart failure remains a widespread commonly encountered clinical condition. It is responsible for increased healthcare expenditure, driven by frequent and often prolonged hospital admissions associated with an increased mortality. A clinically useful classification of the syndrome is, patients with left ventricular systolic impairment (Heart Failure and reduced ejection fraction, HFREF) and patients with preserved left ventricular systolic function (HFPEF). The pharmacological treatment for patients with HFREF has evolved over the last twenty five years, focusing on modulation of the neurohormonal activation which represents a hallmark of this condition. This has led to the development of a stepwise treatment algorithm predominately based on inhibition of the renin angiotensin aldosterone pathway and counteracting sympathetic over-activation. In particular since the early trials in chronic heart failure (CHF) demonstrated a significant mortality benefit with ACE-inhibitors, subsequent studies have been conducted in conjunction with these drugs. The rationale being that it would be unethical to trial any new agent without the concomitant use of ACE-inhibitors. The recent publication of the PARADIGM -HF study has challenged this convention by trialling a novel pharmacological agent against an ACE-inhibitor in a landmark trial. The review sets out the current pharmacological treatment for patients with heart failure and discusses the recent findings with this novel class of medication. PMID- 25824566 TI - In vivo measurement reproducibility of femoral neck microarchitectural parameters derived from 3T MR images. AB - PURPOSE: To evaluate the within-day and between-day measurement reproducibility of in vivo 3D MRI assessment of trabecular bone microarchitecture of the proximal femur. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act (HIPPA)-compliant, Institutional Review Board (IRB)-approved study was conducted on 11 healthy subjects (mean age = 57.4 +/- 14.1 years) with written informed consent. All subjects underwent a 3T MRI hip scan in vivo (0.234 * 0.234 * 1.5 mm) at three timepoints: baseline, second scan same day (intrascan), and third scan 1 week later (interscan). We applied digital topological analysis and volumetric topological analysis to compute the following microarchitectural parameters within the femoral neck: total bone volume, bone volume fraction, markers of trabecular number (skeleton density), connectivity (junctions), plate-like structure (surfaces), plate width, and trabecular thickness. Reproducibility was assessed using root-mean-square coefficient of variation (RMS-CV) and intraclass correlation coefficient (ICC). RESULTS: The within-day RMS-CVs ranged from 2.3% to 7.8%, and the between-day RMS-CVs ranged from 4.0% to 7.3% across all parameters. The within-day ICCs ranged from 0.931 to 0.989, and the between-day ICCs ranged from 0.934 to 0.971 across all parameters. CONCLUSION: These results demonstrate high reproducibility for trabecular bone microarchitecture measures derived from 3T MR images of the proximal femur. The measurement reproducibility is within a range suitable for clinical cross sectional and longitudinal studies in osteoporosis. PMID- 25824567 TI - Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer's disease: phase 3 study. AB - BACKGROUND: Evaluation of brain beta-amyloid by positron emission tomography (PET) imaging can assist in the diagnosis of Alzheimer disease (AD) and other dementias. METHODS: Open-label, nonrandomized, multicenter, phase 3 study to validate the (18)F-labeled beta-amyloid tracer florbetaben by comparing in vivo PET imaging with post-mortem histopathology. RESULTS: Brain images and tissue from 74 deceased subjects (of 216 trial participants) were analyzed. Forty-six of 47 neuritic beta-amyloid-positive cases were read as PET positive, and 24 of 27 neuritic beta-amyloid plaque-negative cases were read as PET negative (sensitivity 97.9% [95% confidence interval or CI 93.8-100%], specificity 88.9% [95% CI 77.0-100%]). In a subgroup, a regional tissue-scan matched analysis was performed. In areas known to strongly accumulate beta-amyloid plaques, sensitivity and specificity were 82% to 90%, and 86% to 95%, respectively. CONCLUSIONS: Florbetaben PET shows high sensitivity and specificity for the detection of histopathology-confirmed neuritic beta-amyloid plaques and may thus be a valuable adjunct to clinical diagnosis, particularly for the exclusion of AD. TRIAL REGISTRATION: ClinicalTrials.govNCT01020838. PMID- 25824569 TI - Use of jet ventilation in thoracoscopic tracheo-esophageal fistula repair-can both surgeons and anesthesiologists be happy? AB - Laparoscopic and open thoracic surgery in the neonate typically results in hypercapnea and low cardiac output with often poor surgical visualization as the anesthesiologist attempts to correct the respiratory derangements usually seen. We describe three cases in which jet ventilation provided not only superior ventilation with a return to normocapnea but also ideal operating conditions. In addition, jet ventilation utilizes lower mean airway pressures which typically results in improved cardiac output. PMID- 25824570 TI - Liquid Chromatographic Separation and Thermodynamic Investigation of Mirabegron Enantiomers on a Chiralpak AY-H Column. AB - Liquid chromatographic separation of mirabegron enantiomers on Chiralpak AY-H, a column coated with amylose tris-(5-chloro-2-methylphenylcarbamate) as a chiral stationary phase, was studied under normal phase conditions. The influence of ethanol content (30-45%) and column temperature (20-40 degrees C) on retention, resolution and separation were evaluated. Apparent thermodynamic parameters deduced from Van't Hoff plots were used to understand chiral separation mechanisms, and the chiral separation was enthalpy driven. The optimized chromatographic conditions were using a mixture solution of n-hexane, ethanol and diethyl amine (55 : 45 : 0.1, v/v/v) as a mobile phase at a flow rate of 1.0 mL/min. The column temperature and UV detector were set at 35 degrees C and 254 nm, respectively. The method was validated to be simple, accuracy, sensitive and robust according to the ICH guidelines, and it was suitable for the routine quality control of mirabegron enantiomers for pharmaceutical industries. PMID- 25824571 TI - A Rapid, Robust and Ultra-Sensitive HPLC Enantioseparation of beta-Amino Alcohols. AB - Enantioseparation of amino acid analogues racemic beta-amino alcohols has hitherto been thought impossible without prior derivatization. Method developers of chromatographic enantioseparation often face detection challenge due to low ultraviolet (UV) absorbance of these molecules. A new chiral derivatizing reagent, benzimidazole-(S)-naproxen amide, was synthesized to provide UV detectable chiral moiety for detection of respective diastereomers of eight beta amino alcohols (dl-alaninol, dl-leucinol, dl-prolinol, dl-phenylalaninol, dl phenylglycinol, dl-valinol, dl-homophenylalaninol and dl-methioninol). An HPLC method has been developed and validated and both the diastereomers were separated within 31 min runtime. Excellent resolution to a pmol detection limit level was achieved. The developed HPLC method for enantioseparation of beta-amino alcohols is the first-ever report of its own kind having such a high detection sensitivity. PMID- 25824568 TI - Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo. AB - Blockade of P-selectin (P-sel)/PSGL-1 interactions holds significant potential for treatment of disorders of innate immunity, thrombosis and cancer. Current inhibitors remain limited due to low binding affinity or by the recognized disadvantages inherent to chronic administration of antibody therapeutics. Here we report an efficient approach for generating glycosulfopeptide mimics of N terminal PSGL-1 through development of a stereoselective route for multi-gram scale synthesis of the C2 O-glycan building block and replacement of hydrolytically labile tyrosine sulfates with isosteric sulfonate analogues. Library screening afforded a compound of exceptional stability, GSnP-6, that binds to human P-sel with nanomolar affinity (Kd~22 nM). Molecular dynamics simulation defines the origin of this affinity in terms of a number of critical structural contributions. GSnP-6 potently blocks P-sel/PSGL-1 interactions in vitro and in vivo and represents a promising candidate for the treatment of diseases driven by acute and chronic inflammation. PMID- 25824572 TI - Alluaudite Na2Co2Fe(PO4)3 as an electroactive material for sodium ion batteries. AB - The electroactive orthophosphate Na2Co2Fe(PO4)3 was synthesized using a solid state reaction. Its crystal structure was solved using the combination of powder X-ray- and neutron-diffraction data. This material crystallizes according to the alluaudite structure (S.G. C2/c). The structure consists of edge sharing [MO6] octahedra (M = Fe, Co) resulting in chains parallel to [-101]. These chains are linked together via the [PO4] tetrahedra to form two distinct tunnels in which sodium cations are located. The electrochemical properties of Na2Co2Fe(PO4)3 were evaluated by galvanostatic charge-discharge cycling. During the first discharge to 0.03 V, Na2Co2Fe(PO4)3 delivers a specific capacity of 604 mA h g(-1). This capacity is equivalent to the reaction of more than seven sodium ions per formula unit. Hence, this is a strong indication of a conversion-type reaction with the formation of metallic Fe and Co. The subsequent charge and discharge involved the reaction of fewer Na ions as expected for a conversion reaction. When discharged to 0.9 V, the material intercalated only one Na(+)-ion leading to the formation of a new phase Na3Co2Fe(PO4)3. This phase could then be cycled reversibly with an average voltage of 3.6 V vs. Na(+)/Na and a capacity of 110 mA h g(-1). This result is in good agreement with the theoretical capacity expected from the extraction/insertion of two sodium atoms in Na3Co2Fe(PO4)3. PMID- 25824573 TI - [Childhood-onset systemic polyarteritis nodosa and systemic lupus erythematosus: an overlap syndrome?] AB - We described herein a patient who presented an overlap syndrome of childhood onset systemic polyarteritis nodosa (c-PAN) and childhood-onset systemic lupus erythematosus (c-SLE). A 9-year-old girl presented tender subcutaneous nodules on feet, arterial hypertension, right hemiplegia and dysarthric speech. She was hospitalized due to stroke and left foot drop. Brain computer tomography showed ischemic stroke. Magnetic resonance angiography revealed stenosis in the middle cerebral and internal carotid arteries. Electroneuromyography identified a mononeuropathy of left posterior tibial nerve and she fulfilled the c-PAN validated criteria. She was treated with intravenous methylprednisolone pulse therapy followed by prednisone, that was progressively tapered, six months of intravenous cyclophosphamide and after that she received azathioprine for 19 months. At the age of 14 years and 9 months, she presented malar rash, photosensitivity, edema in lower limbs and arterial hypertension. The proteinuria was 1.7g/day. Antinuclear antibodies (ANA) were 1/1280 (homogeneous nuclear pattern) and anti-dsDNA antibodies were positive. Renal biopsy showed focal proliferative and membranous glomerulonephritis. Therefore, she fulfilled the American College of Rheumatology classification criteria for SLE and she was treated with prednisone, hydroxychloroquine and mycophenolate mofetil. In conclusion, we described herein a possible overlap syndrome of two autoimmune diseases, where c-PAN occurred five years before the c-SLE diagnosis. PMID- 25824574 TI - IL-17 deficiency attenuates allograft injury and prolongs survival in a murine model of fully MHC-mismatched renal allograft transplantation. AB - IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of inflammatory and autoimmune diseases. However the role of IL-17 in renal allograft rejection has not been fully explored. Here, we investigate the impact of IL-17 in a fully MHC-mismatched, life-sustaining, murine model of kidney allograft rejection using IL-17 deficient donors and recipients (IL-17(-/-) allografts). IL-17(-/-) allografts exhibited prolonged survival which was associated with reduced expression of the Th1 cytokine IFN-gamma and histological attenuation of acute and chronic allograft rejection, as compared to wild-type allograft recipients. Results were confirmed in WT allograft recipients treated with an IL-17 blocking antibody. Subsequent experiments using either donors or recipients deficient in IL-17 showed a trend towards prolongation of survival only when recipients were IL-17(-/-) . Administration of a depleting anti-CD25 antibody to IL-17(-/-) recipients abrogated the survival advantage conferred by IL-17 deficiency, suggesting the involvement of a CD4(+) CD25(+) T cell regulatory mechanism. Therefore, IL-17 deficiency or neutralization was protective against the development of kidney allograft rejection, which may be mediated by impairment of Th1 responses and/or enhanced protection by Tregs. PMID- 25824575 TI - Vinexin-beta deficiency protects against cerebral ischaemia/reperfusion injury by inhibiting neuronal apoptosis. AB - Vinexin-beta is an adaptor protein that regulates cell adhesion, cytoskeletal organization and signal transduction. Our previous work showed that Vinexin-beta protects against cardiac hypertrophy. However, its function in stroke is largely unknown. In the present study, we observed a significant increase in Vinexin-beta expression in both human intracerebral haemorrhage and mouse cerebral ischaemia/reperfusion (I/R) injury model, indicating that Vinexin-beta is involved in stroke. Next, using Vinexin-beta knockout mice, we further demonstrated that Vinexin-beta deficiency significantly protected against cerebral I/R injury, as demonstrated by a dramatic decrease in the infarct volume and an improvement in neurological function. Additionally, immunofluorescence and western blotting showed that the deletion of Vinexin-beta attenuated neuronal apoptosis. Mechanically, we found that Akt signalling was up-regulated in the brains of the Vinexin-beta knockout mice compared with those of the WT control mice after ischaemic injury. Taken together, our results demonstrate that the deletion of Vinexin-beta potently protects against ischaemic injury by inhibiting neuronal apoptosis, and this effect may occur via the up-regulation of Akt signalling. Our findings revealed that Vinexin-beta acts as a novel modulator of ischaemic injury, suggesting that Vinexin-beta may represent an attractive therapeutic target for the prevention of stroke. PMID- 25824576 TI - The potential role of benefit and burden finding in school engagement of young leukaemia survivors: an exploratory study. AB - BACKGROUND: Childhood cancer may radically change the daily lives of young survivors, particularly in school. Depending on the sense they derive from the experience of illness, survivors may go through profound transformations in the way they approach life. METHODS: This exploratory study reports on school engagement of cancer survivors by examining their perceptions of benefits and burdens in relation to their illness. Forty-nine young Quebecers, previously diagnosed and treated for leukaemia, completed a questionnaire measuring their school engagement and participated in an interview focusing on the impact of cancer on their lives. Perceptions with regard to the presence and types of benefits and burdens were described and examined in light of participants' characteristics. An analysis of variance explored whether the presence/absence of benefits and burdens were associated with participants' scores regarding school engagement. RESULTS: Most participants mentioned benefits from having had cancer, and in particular benefits at an interpersonal level. Half of the participants mentioned burdens, mainly of a physical and psychological nature. Significant correlations indicated that (i) the older the survivors were, the more likely they were to report benefits in terms of qualities and strengths of character; (ii) the more time had elapsed since their diagnosis, the more survivors were likely to report psychological types of burdens; and (iii) children from single parent families reported more frequently having appreciated social or recreational activities compared with children from two-parent families. One main effect indicated that school engagement was greater for survivors who perceived the presence of benefits. An interaction effect revealed that the perception of both benefits and burdens predicts the highest scores of school engagement. CONCLUSIONS: While the results reveal the promising potential that an optimistic yet realistic disposition has in regard to school engagement, more research is necessary to further our understanding of such a disposition. PMID- 25824577 TI - Governance challenges in the Nepalese primary health care system: time to focus on greater community engagement? AB - Nepal has seen impressive recent health gains through a successful community based health program. However, governance challenges remain within the Nepalese primary health care system that include under-staffing and absenteeism, limited health facility opening hours, poor supervision and monitoring, and insufficient financial management. We propose that these be addressed through expanded community engagement and a power shift towards local communities, enhancing skills of community representatives in co-managing health facilities and of service providers to effectively engage the community, increased quality of community participation, and improved documentation of the process and impact of engagement on health outcomes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25824578 TI - C-H bonds phosphorylation of ketene dithioacetals. AB - C-H bond phosphorylation of ketene dithioacetals was achieved under transition metal-free or AgNO3 mediated conditions. Synthetic transformations of the coupling product provided promising methods for the construction of highly functionalized phosphorylated N-heterocycles and tetrasubstituted alkenes. PMID- 25824579 TI - Synthesis of carbamide derivatives bearing tetrahydroisoquinoline moieties and biological evaluation as analgesia drugs in mice. AB - Transient receptor potential vanilloid 1 (TRPV1) is a ligand-gated non-selective cation channel that is considered to be an important pain integrator. Tetrahydroisoquinoline, the prototypical antagonist of TRPV1, has a clear therapeutic potential. Here, a series of carbamide derivatives of tetrahydroisoquinoline were designed and synthesized. Preliminary biological tests suggested that the compounds I 1, I 2, and I 9 had favorable TRPV1 antagonism activity. In further studies, I 1 exhibited better antinociceptive activity than the positive control BCTC in diverse pain models. All of these results suggested that I 1 can be considered as the lead candidate for the further development of antinociceptive drugs. PMID- 25824580 TI - All-trans retinoic acid and arsenic combination therapy benefits low-to intermediate-risk patients with newly diagnosed acute promyelocytic leukaemia: a long-term follow-up based on multivariate analysis. PMID- 25824582 TI - Confocal Microscopic Analysis of the Spindle and Chromosome Configurations of in vitro-Matured Oocytes from Different Types of Polycystic Ovary Syndrome Patients. AB - OBJECTIVE: To evaluate the meiotic spindle and chromosome distribution of in vitro-matured oocytes from infertile nonobese or obese women with polycystic ovary syndrome (PCOS) and to compare in vitro maturation (IVM) rates between groups. DESIGN: Prospective study. SETTING: Hospital-based IVF center. PATIENTS: A total of 99 patients (26 obese women with PCOS, 25 nonobese women with PCOS, and 48 controls) undergoing stimulated cycles for intracytoplasmic sperm injection had immature oocytes for IVM. INTERVENTIONS: Immature oocytes (germinal vesicle and metaphase I stages) were collected from obese and nonobese PCOS patients and controlled infertile patients. The meiotic spindle and chromosome configurations in oocytes matured in vitro were studied by confocal microscopy, with fluorescent labeling techniques for visualization of both microtubules and chromosomes. MAIN OUTCOME MEASURES: Meiotic spindle and associated chromosome configurations. RESULTS: There were no significant differences between the different types of PCOS and the control group with respect to IVM rates (61.8, 63.8, and 63.2%, respectively), the percentage of spindle abnormalities in metaphase II oocytes (40.6, 42.9, and 37.5%, respectively) or chromosome abnormalities in metaphase II oocytes (31.2, 34.3, and 33.3%, respectively). CONCLUSIONS: In vitro-matured oocytes obtained from stimulated cycles had a high ratio of meiotic abnormalities. The different types of PCOS had the same ratio of meiotic abnormalities. PMID- 25824583 TI - (99m)Tc-MDP SPECT/CT as the one-stop imaging modality for the diagnosis of early setting of Kienbock's disease. AB - (99m)Tc-Methylene diphosphonate (MDP) triple phase bone scintigraphy (BS) has a role in early diagnosis of Kienbock's disease, especially when the X-ray is negative. Early diagnosis can result in prompt management of the patient since wrist pain in older individuals due to aging may go unnoticed or be due to other diagnoses with the production of greater damage and eventually a worse prognosis. Herein, we present a case report of a 29-year-old female with Kienbock's disease in whom the X-ray was negative and MRI incorrect. The (99m)Tc-MDP SPECT/CT BS helped the diagnosis of the disease in an early stage (stage 1) and had a clinical impact on the patient's management. PMID- 25824584 TI - Bile ascites after T-tube removal in liver transplantation: A hepatobiliary scintigraphy finding. PMID- 25824581 TI - The Mineral-Collagen Interface in Bone. AB - The interface between collagen and the mineral reinforcement phase, carbonated hydroxyapatite (cAp), is essential for bone's remarkable functionality as a biological composite material. The very small dimensions of the cAp phase and the disparate natures of the reinforcement and matrix are essential to the material's performance but also complicate study of this interface. This article summarizes what is known about the cAp-collagen interface in bone and begins with descriptions of the matrix and reinforcement roles in composites, of the phases bounding the interface, of growth of cAp growing within the collagen matrix, and of the effect of intra- and extrafibrilar mineral on determinations of interfacial properties. Different observed interfacial interactions with cAp (collagen, water, non-collagenous proteins) are reviewed; experimental results on interface interactions during loading are reported as are their influence on macroscopic mechanical properties; conclusions of numerical modeling of interfacial interactions are also presented. The data suggest interfacial interlocking (bending of collagen molecules around cAp nanoplatelets) and water mediated bonding between collagen and cAp are essential to load transfer. The review concludes with descriptions of areas where new research is needed to improve understanding of how the interface functions. PMID- 25824585 TI - Imprints of function on the folding landscape: functional role for an intermediate in a conserved eukaryotic binding protein. AB - In the computational characterization of single domain protein folding, the effective free energies of numerous microstates are projected onto few collective degrees of freedom that in turn serve as well-defined reaction coordinates. In this regard, one-dimensional (1D) free energy profiles are widely used mainly for their simplicity. Since folding and functional landscapes are interlinked, how well can these reduced representations capture the structural and dynamic features of functional states while being simultaneously consistent with experimental observables? We investigate this issue by characterizing the folding of the four-helix bundle bovine acyl-CoA binding protein (bACBP), which exhibits complex equilibrium and kinetic behaviours, employing an Ising-like statistical mechanical model and molecular simulations. We show that the features of the 1D free energy profile are sufficient to quantitatively reproduce multiple experimental observations including millisecond chevron-like kinetics and temperature dependence, a microsecond fast phase, barrier heights, unfolded state movements, the intermediate structure and average phi-values. Importantly, we find that the structural features of the native-like intermediate (partial disorder in helix 1) are intricately linked to a unique interplay between packing and electrostatics in this domain. By comparison with available experimental data, we propose that this intermediate determines the promiscuous functional behaviour of bACBP that exhibits broad substrate specificity. Our results present evidence to the possibility of employing the statistical mechanical model and the resulting 1D free energy profile to not just understand folding mechanisms but to even extract features of functionally relevant states and their energetic origins. PMID- 25824586 TI - Valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus: an economic perspective. AB - INTRODUCTION: Valganciclovir (vGCV) and valacyclovir (vACV) are used in cytomegalovirus (CMV) prophylaxis in renal transplant recipients. The aim of this study was to compare the economic impact of both regimens during 1-year follow up. METHODS: A total of 117 renal transplant recipients at risk for CMV were randomized to 3-month prophylaxis either with vGCV (900 mg/day, n = 60) or vACV (8 g/day, n = 57) and their data used in a pharmacoeconomic analysis. The pharmacoeconomic evaluation involved all direct CMV-related expenses in the first year after transplantation. Sensitivity analysis was employed to examine the effects of various prices of antiviral drugs and diagnostic procedures on overall CMV-related costs. Simulation of the more expensive US healthcare perspective was performed, and a scenario involving costs of acute rejection (AR) was examined. RESULTS: Overall CMV-related costs were significantly lower in the vACV arm; median United States dollars (USD) 3473 (3108-3745) vs. USD 5810 (4409-6757; P < 0.001) per patient, respectively. Our data showed that the critical determinant of the major disparity between the prophylactic regimens was the prophylaxis price. Median cost of prophylaxis in the vACV group was USD 1729 (1527-2173) compared to USD 3968 (2683-4857) in the vGCV group (P < 0.001). In sensitivity analysis of the overall CMV-related costs, the least and the most expensive pharmacotherapy and diagnostic scenarios were used; nevertheless, the vACV arm remained markedly less expensive. Simulation considering the higher physician/nurse and hospitalization fees of the US healthcare system and the scenario including expenditure associated with AR episodes also favored vACV. CONCLUSION: VACV prophylaxis for CMV is associated with a significant 44% lower cost than vGCV at the first year after renal transplantation. PMID- 25824588 TI - Erratum. PMID- 25824587 TI - Management of immune thrombocytopenia in adults: a population-based analysis of the French hospital discharge database from 2009 to 2012. AB - The present study describes the current clinical practice and hospital management of adults with immune thrombocytopenia (ITP) between 2009 and 2012 in France, based on the national discharge hospital database. Adult ITP patients were managed almost exclusively in public hospitals. A relatively stable number of patients, around 3200 per year, were hospitalized for ITP annually over the 4 year period, about two-thirds of whom were newly-diagnosed ITP. Re hospitalizations tended to decrease over the study period. Intravenous immunoglobulin administration, concerning half of ITP hospitalized patients, and rituximab administration were stable over time, whereas a slight decrease of splenectomies was observed. PMID- 25824590 TI - NF1 loss induces senescence during human melanocyte differentiation in an iPSC based model. AB - Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called cafe-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) -induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage. PMID- 25824591 TI - Impact of cardiovascular complications among patients with Type 2 diabetes mellitus: a systematic review. AB - Macrovascular and microvascular complications that accompany Type 2 diabetes mellitus (T2DM) add to the burden among patients. The purpose of this systematic review is to conduct a comprehensive search of the medical literature investigating the prevalence of cardiovascular (CV) complications and assess their impact on healthcare costs, quality of life and mortality among patients with T2DM in the context of microvascular complications. A total of 76 studies and reports were used in this systematic review. Hypertension was the most prevalent complication among patients with T2DM. The additional cost burden due to CV complications was higher than any other complication except end-stage renal disease. Quality of life was much lower among patients with CV complications and T2DM, and mortality was higher than either illness alone. PMID- 25824592 TI - Regulatory effect of traditional Chinese medicinal formula Zuo-Gui-Wan on the Th17/Treg paradigm in mice with bone loss induced by estrogen deficiency. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bone loss is a common pathological condition induced by estrogen deficiency. The Th17/Treg paradigm, which can be skewed by estrogen, plays an important role in regulating bone metabolism AIM OF THE STUDY: The purpose of this study was to determine the role of the Th17/Treg shift in estrogen deficiency-induced bone loss in mouse models and to elucidate the immunopharmacologic mechanism of Zuo-Gui-Wan (ZGW) in preventing bone loss in this process by regulating Th17/Treg paradigm. MATERIALS AND METHODS: Splenocytes of ovariectomized (Ovx) mice and naturally aged mice were isolated and Flow cytometry was used to detect the Th17/Treg subsets. In addition, serum estrodiol (E2) and serum C-terminal telopeptides of type Iota collagen (CTx) were detected by ELISA assay. Bone mineral density (BMD) of the left tibiae was measured by dual-energy X-ray absorptiometry. Moreover, Ovx mice were administrated with different doses of ZGW for 12 weeks, and BMD and Th17/Treg subsets were determined. Bone histomorphometry was observed by Hematoxylin and eosin (H&E) staining and serum protein levels of IL-6 were analyzed by ELISA assay. In addition, the mRNA and protein expression of RORgammat and Foxp3 were detected by RT-PCR and Western blot respectively. RESULT: The Th17/Treg paradigm shifted to Th17 in estrogen-deficient mice both in the Ovx mice and the naturally aged mice. BMD and E2 levels negatively correlated with the Th17/Treg ratio. After ZGW administration, the BMD was enhanced markedly in the Ovx mice as well as in the naturally aged mice. Both the mRNA and protein expressions of IL-6 and RORgammat were decreased, whereas those of Foxp3 were increased significantly after ZGW administration. CONCLUSION: Th17/Treg shift involved in the bone loss induced by estrogen deficiency. ZGW prevented bone loss efficiently and skewed Th17/Treg paradigm towards Treg without enhancing E2. PMID- 25824593 TI - A network pharmacology approach to determine active ingredients and rationality of herb combinations of Modified-Simiaowan for treatment of gout. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Modified Simiaowan (MSW) is a traditional Chinese medicine (TCM) formula and is widely used as a clinically medication formula for its efficiency in treating gouty diseases.To predict the active ingredients in MSW and uncover the rationality of herb combinations of MSW. MATERIALS AND METHODS: Three drug-target networks including the "candidate ingredient-target network" (cI-cT) that links the candidate ingredients and targets, the "core ingredient-target-pathway network" connecting core potential ingredients and targets through related pathways, and the "rationality of herb combinations of MSW network", which was derived from the cI-cT network, were developed to dissect the active ingredients in MSW and relationship between ingredients in herb combinations and their targets for gouty diseases. On the other hand, herbal ingredients comparisons were also conducted based on six physicochemical properties to investigate whether the herbs in MSW are similar in chemicals. Moreover, HUVEC viability and expression levels of ICAM-1 induced by monosodium urate (MSU) crystals were assessed to determine the activities of potential ingredients in MSW. RESULTS: Predicted by the core ingredient-target-pathway network, we collected 30 core ingredients in MSW and 25 inflammatory cytokines and uric acid synthetase or transporters, which are effective for gouty treatment through some related pathways. Experimental results also confirmed that those core ingredients could significantly increase HUVEC viability and attenuate the expression of ICAM-1, which supported the effectiveness of MSW in treating gouty diseases. Moreover, heat-clearing and dampness-eliminating herbs in MSW have similar physicochemical properties, which stimulate all the inflammatory and uric acid-lowing targets respectively, while the core drug and basic prescription in MSW stimulate the major and almost all the core targets, respectively. CONCLUSION: Our work successfully predicts the active ingredients in MSW and explains the cooperation between these ingredients and corresponding targets through related pathways for gouty diseases, and provides basis for an alternative approach to investigate the rationality of herb combinations of MSW on the network pharmacology level, which might be beneficial to drug development and applications. PMID- 25824594 TI - Purification and characterisation of an acidic and antifungal chitinase produced by a Streptomyces sp. AB - An extremely acidic extracellular chitinase produced by a Streptomyces sp. was purified 12.44-fold by ammonium sulphate precipitation, ion-exchange chromatography and gel-permeation chromatography and further characterised. The molecular mass of the enzyme was estimated to be about 40 kDa by SDS-PAGE. The optimum pH and temperature of the purified enzyme were pH 2 and 6, and 50 degrees C respectively. The enzyme showed high stability in the acidic pH range of 2-6 and temperature stability of up to 50 degrees C. Additionally, the effect of some cations and other chemical compounds on the chitinase activity was studied. The activity of the enzyme was considerably retained under salinity conditions of up to 3%. The Km and Vmax values of the enzyme were determined to be 6.74 mg mL(-1) and 61.3 U mg(-1) respectively using colloidal chitin. This enzyme exhibited antifungal activity against phytopathogens revealing a potential biocontrol application in agriculture. PMID- 25824595 TI - Direct conversion of chicory flour into L(+)-lactic acid by the highly effective inulinase producer Lactobacillus paracasei DSM 23505. AB - Highly effective bio-process for lactic acid (LA) production by simultaneous saccharification and fermentation (SSF) of chicory flour was developed. The strain used, Lactobacillus paracasei DSM 23505 produced natural inulinase (EC 3.2.1.80) with molecular weight ~130 kDa, located in the cell wall fraction. In batch fermentation with optimized medium content and fermentation conditions, a complete conversion of 136 g/L chicory flour (89.3% inulin and 10.7% mix of sucrose, fructose and glucose) into 123.7 g/L LA was achieved. These yield and conversion rate are the highest obtained by SSF for LA production from inulin. The high efficiency, the cheap fermentation broth and the simple process performance disclose the promising use of the chicory flour in industrial biotechnology for LA production. PMID- 25824596 TI - The association between somatization and disability in primary care patients. AB - BACKGROUND: Patient encounters for medically unexplained physical symptoms are common in primary health care. Somatization ('experiencing and reporting unexplained somatic symptoms') may indicate concurrent or future disability but this may also partly be caused by psychiatric disorders. The aim of this study was to examine the cross-sectional and longitudinal association between somatization and disability in primary care patients with and without anxiety or depressive disorder. METHODS: Data were obtained from 1545 primary care patients, participating in the longitudinal Netherlands Study of Depression and Anxiety (NESDA). Somatization was assessed using the somatization scale of the Four Dimensional Symptom Questionnaire (4DSQ). Disability was determined by the WHO Disability Assessment Schedule 2.0 (WHO-DAS II). The relationships between somatization and both the total and subdomain scores of the WHO-DAS II were measured cross-sectionally and longitudinally after one year of follow-up using linear regression analysis. We examined whether anxiety or depressive disorder exerted a modifying effect on the somatization-disability association. RESULTS: Cross-sectionally and longitudinally, somatization was significantly associated with disability. Somatization accounted cross-sectionally for 41.8% of the variance in WHO-DAS disability and, longitudinally, for 31.7% of the variance in disability after one year of follow-up. The unique contribution of somatization to disability decreased to 16.7% cross-sectionally and 15.7% longitudinally, when anxiety and/or depressive disorder was added to the model. CONCLUSION: Somatization contributes to the presence of disability in primary care patients, even when the effects of baseline demographic and health characteristics and anxiety or depressive disorder are taken into account. PMID- 25824597 TI - Effects of reduced time in bed on daytime sleepiness and recovery sleep in fibromyalgia and rheumatoid arthritis. AB - OBJECTIVES: Fibromyalgia (FM) and rheumatoid arthritis (RA) are associated with sleep disturbance and daytime sleepiness. We sought to determine whether sleep homeostatic mechanisms are blunted in FM by assessing the effects of reduced time in bed (4h) on next day sleepiness and recovery sleep. METHODS: Fifty women (18 with FM, 16 with RA, and 16 HC) had a baseline 8h time-in-bed (TIB) and Multiple Sleep Latency Test (MSLT) the following day, and 3-7 days later bedtime was reduced (4h) followed by MSLT and an 8h TIB recovery night. RESULTS: Following reduced bedtime the MSLT was reduced relative to baseline in the FM group by an amount (4.3+/-4.8 min) similar to that of the RA (3.1+/-5.2 min) and HC (4.8 +/ 3.1 min) groups. Relative to the baseline on the recovery night the FM group showed increased sleep efficiency (83.7+/-7.8 to 88.1+/-9.2%) relative to the RA (83.9+/-8.6 to 80.9+/-13.3%) and HC (90.1+/-5.0 to 87.4+/-7.6%) groups due primarily to reduced wake after sleep onset. The groups did not differ in recovery night sleep stages with the exception that the FM group showed REM rebound (21.6+/-6.5 to 25.2+/-6.0%), which was not found in the RA (20.4+/-7.4 to 17.8+/-6.5%) or HC (16.6+/-6.6 to 17.5+/-6.0%) groups. CONCLUSIONS: Compared to RA and HC, people with FM responded to reduced bedtime with a comparable increase in sleepiness and greater recovery sleep efficiency, suggesting that homeostatic sleep mechanisms are functional in FM. People with FM uniquely showed REM rebound on recovery from reduced bedtime suggesting underlying REM pressure. PMID- 25824598 TI - Immunostimulatory potential and proteome profiling of Leishmania donovani soluble exogenous antigens. AB - Isolation of the soluble exogenous antigens (SEAgs), its immune response study and proteome profiling is an essential prerequisite for understanding the molecular pathogenesis of Leishmania donovani. The immunostimulatory potential of L. donovani SEAgs, purified from culture of L. donovani clinical isolate, was evaluated for their ability to induce cellular responses in treated/cured hamsters. SEAgs induced significant proliferative responses in lymphocytes (SI 5.6 +/- 2.3; P < 0.01) isolated from cured hamster. In addition, significant NO production in response to SEAgs was also noticed in macrophages of hamsters, mouse and human cell lines (J774A-1 and THP1). Western blot analyses with antibodies against proteophosphoglycan (PPG; surface-expressed and secreted molecule) of L. donovani revealed that PPG molecules are also present in L. donovani SEAgs. Mass spectrometry (MS)-based proteome analysis of 12 protein bands of SEAgs through MALDI-TOF/TOF endorsed the identification of some Th1 stimulatory immunogenic proteins. These immunogenic proteins may offer increased hope for the discovery of new promising vaccine candidates against visceral leishmaniasis (VL). The overall results suggest that immunostimulatory molecules are present in the SEAgs, which may be further exploited, for developing a subunit vaccine against VL a fatal human disease. PMID- 25824599 TI - Relative validity and reproducibility of an FFQ to determine nutrient intakes of New Zealand toddlers aged 12-24 months. AB - OBJECTIVE: The study objective was to determine the relative validity and reproducibility of a modified FFQ for ranking the nutrient intakes of New Zealand toddlers aged 12-24 months. DESIGN: Cross-sectional study. SETTING: Dunedin, New Zealand. SUBJECTS: One hundred and fifty-two participants completed a ninety-five item FFQ twice, and five days of weighed diet recording (WDR), over one month. Validity and reproducibility were assessed for crude data and for data that were weighted for total fruit and vegetable intake (FV-adjusted). RESULTS: De attenuated correlations between FV-adjusted FFQ data and WDR data ranged from 0.45 (Zn) to 0.77 (Ca). The percentage classified to the correct WDR quartile by the FV-adjusted FFQ data ranged from 34.6% (total fat, Zn) to 50.3% (Fe). Average gross misclassification was 3%. Bland-Altman statistics showed crude data had a range of 128-178% agreement with the WDR and mean FV-adjusted intakes had 112 160% agreement. FV-adjusted intra-class correlations, assessing reproducibility, ranged from 0.65 (vitamin C) to 0.75 (Ca). CONCLUSIONS: The Eating Assessment in Toddlers (EAT) FFQ showed acceptable to good relative validity, and good reproducibility, for ranking participants' nutrient intake and is able to identify toddlers at extremes of the nutrient intake distribution. It will be a useful tool for investigating toddlers' nutrient intakes in studies that require a method of dietary assessment with low respondent burden. PMID- 25824600 TI - Detection of canine astrovirus in dogs with diarrhea in Japan. AB - Canine astrovirus (CAstV) is the causative agent of gastroenteritis in dogs. We collected rectal swabs from dogs with or without diarrhea symptoms in Japan and examined the feces for the presence of CAstV by RT-PCR with primers based on a conserved region of the ORF1b gene. The ORF1b gene of CAstV was not detected in the 42 dogs without clinical illness but was present in three pups out of the 31 dogs with diarrhea symptoms. Based on the full-length capsid protein, the CAstV KU-D4-12 strain that we detected in this study shared high homology with the novel virulent CAstV VM-2011 strain. PMID- 25824601 TI - Epicutaneous Immunization with Collagen Induces TCRalphabeta Suppressor T Cells That Inhibit Collagen-Induced Arthritis. AB - BACKGROUND: We have shown previously, in an animal model of multiple sclerosis and in TNBS-induced colitis, that epicutaneous (EC) immunization with protein antigen induces T suppressor cells that strongly inhibit the inflammatory response in contact hypersensitivity reactions. METHODS: EC immunization was performed by applying to the shaved skin of the mouse dorsum a gauze patch soaked with a solution containing various amounts of type II collagen (COLL II) in a volume of 100 ul of PBS on days 0 and 4. On day 7 the patches were removed and mice were intradermally (i.d.) immunized with COLL II to induce collagen-induced arthritis (CIA). RESULTS: Our study shows that EC immunization with 100 or 30 MUg of COLL II reduces disease severity, whereas lower doses (10 or 3 MUg) do not affect CIA. Decreased disease severity observed after EC immunization with COLL II correlates with reduced myeloperoxidase activity in joint tissue and with reduced production of anti-citrullinated protein and anti-COLL II IgG2a antibodies. Transfer experiments show that EC immunization with COLL II induces suppressor cells that belong to the population of TCRalphabeta lymphocytes and that EC-induced suppression declines with time. Both in vitro and in vivo experiments show that IL-17A plays an important role in EC-induced suppression of CIA. EC application of COLL II at the first signs of CIA also results in disease suppression. CONCLUSIONS: The suppression of inflammatory responses by T suppressor cells induced through EC immunization of a protein antigen may become an attractive noninvasive therapeutic method for a variety of clinical situations. PMID- 25824602 TI - Smoking increases the risk of delirium for older inpatients: a prospective population-based study. AB - OBJECTIVES: To investigate the association between smoking in the older population and the risk of inpatient delirium, which is common and has adverse consequences. METHOD: Participants (N=3754) were insurants aged >=55years of the largest German statutory health insurance company, who enrolled in a 6-year prospective population-based study. Baseline smoking, adjusted for age, sex, depressive symptoms, cognitive impairment and alcohol consumption, was analyzed as risk factor of inpatient delirium. Results are presented as hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Three-hundred seventy three (10.0%) participants were smokers at baseline, 865 (23.0%) were quitters and 2516 (67.0%) were lifelong abstainers. Mean pack-years of smokers and quitters were 23.8 (S.D.=22.4). Sixty-one (1.6%) received a diagnosis of inpatient delirium. Smokers had an increased risk of delirium compared to abstainers in the fully adjusted model (HR=2.87, 95% CI 1.24-6.66). Quitters and abstainers did not differ (HR=0.79, 95% CI 0.37-1.72). Comparing smokers and quitters, current smoking status (HR=3.22, 95% CI 1.20-8.62) but not pack-years [residual chi(2)(1)=0.25, P=.874] were associated with inpatient delirium. CONCLUSION: Only current smoking but not being a quitter and the lifetime amount smoked were associated with inpatient delirium, indicating that acute nicotine withdrawal may represent a relevant pathogenic mechanism. PMID- 25824603 TI - CADASIL presenting as schizophreniform organic psychosis. AB - OBJECTIVE: To describe an Asian patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting with schizophreniform organic psychosis. METHODS: Case report. RESULTS: We report a case of CADASIL in an Asian female presenting with frank psychotic symptoms. After resolution of her psychosis, she showed persistent distractibility, which indicated signs of cognitive impairment. CONCLUSION: Although neuropsychiatric symptoms are commonly present in this disorder, psychotic symptoms are rare and should be recognized. There is a need for timely diagnosis and management of this disorder. PMID- 25824604 TI - WITHDRAWN: Two Novel Heterozygous Mutations of CSA Cause Cockayne Syndrome in a Chinese Family. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25824605 TI - Liver-targeted gene therapy: Approaches and challenges. AB - The liver plays a major role in many inherited and acquired genetic disorders. It is also the site for the treatment of certain inborn errors of metabolism that do not directly cause injury to the liver. The advancement of nucleic acid-based therapies for liver maladies has been severely limited because of the myriad untoward side effects and methodological limitations. To address these issues, research efforts in recent years have been intensified toward the development of targeted gene approaches using novel genetic tools, such as zinc-finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats as well as various nonviral vectors such as Sleeping Beauty transposons, PiggyBac transposons, and PhiC31 integrase. Although each of these methods uses a distinct mechanism of gene modification, all of them are dependent on the efficient delivery of DNA and RNA molecules into the cell. This review provides an overview of current and emerging therapeutic strategies for liver-targeted gene therapy and gene repair. PMID- 25824607 TI - Prognostic factors in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is a clinically aggressive tumor originating from mesothelial cells, which line the serosal cavities. Recent years have seen extensive research aimed at identifying new therapeutic targets, predictive markers and prognostic factors in this disease. These include both serum and tissue markers, and are related to multiple cellular pathways which affect cell survival, proliferation, apoptosis, angiogenesis, interaction with the immune response and DNA repair. Several of these molecules may become relevant for pathologists as part of the effort to select patient sub-populations for targeted therapy in the future. This review summarizes current data in this area and discusses their potential clinical relevance. PMID- 25824608 TI - Independent positioning of magnetic nanomotors. AB - There is considerable interest in powering and maneuvering nanostructures remotely in fluidic media using noninvasive fuel-free methods, for which small homogeneous magnetic fields are ideally suited. Current strategies include helical propulsion of chiral nanostructures, cilia-like motion of flexible filaments, and surface assisted translation of asymmetric colloidal doublets and magnetic nanorods, in all of which the individual structures are moved in a particular direction that is completely tied to the characteristics of the driving fields. As we show in this paper, when we use appropriate magnetic field configurations and actuation time scales, it is possible to maneuver geometrically identical nanostructures in different directions, and subsequently position them at arbitrary locations with respect to each other. The method reported here requires proximity of the nanomotors to a solid surface, and could be useful in applications that require remote and independent control over individual components in microfluidic environments. PMID- 25824606 TI - Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. AB - Pancreatic cancer is expected to be the second deadliest malignancy in the USA by 2020. The survival rates for patients with other gastrointestinal malignancies have increased consistently during the past 30 years; unfortunately, however, the outcomes of patients with pancreatic cancer have not changed significantly. Although surgery remains the only curative treatment for pancreatic cancer, therapeutic strategies based on initial resection have not substantially improved the survival of patients with resectable disease over the past 25 years; presently, more than 80% of patients suffer disease relapse after resection. Preclinical evidence that pancreatic cancer is a systemic disease suggests a possible benefit for early administration of systemic therapy in these patients. In locally advanced disease, the role of chemoradiotherapy is increasingly being questioned, particularly considering the results of the LAP-07 trial. Novel biomarkers are clearly needed to identify subsets of patients likely to benefit from chemoradiotherapy. In the metastatic setting, FOLFIRINOX (folinic acid, 5 fluorouracil, irinotecan, and oxaliplatin), and nab-paclitaxel plus gemcitabine have yielded only modest improvements in survival. Thus, new treatments are urgently needed for patients with pancreatic cancer. Herein, we review the state of-the-art of pancreatic cancer treatment, and the upcoming novel therapeutics that hold promise in this disease are also discussed. PMID- 25824609 TI - Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases. AB - Aging is an inevitable and multifactorial biological process. Free radicals have been implicated in aging processes; it is hypothesized that they cause cumulative oxidative damage to crucial macromolecules and are responsible for failure of multiple physiological mechanisms. However, recent investigations have also suggested that free radicals can act as modulators of several signaling pathways such as those related to sirtuins. Caloric restriction is a non-genetic manipulation that extends lifespan of several species and improves healthspan; the belief that many of these benefits are due to the induction of sirtuins has led to the search for sirtuin activators, especially sirtuin 1, the most studied. Resveratrol, a polyphenol found in red grapes, was first known for its antioxidant and antifungal properties, and subsequently has been reported several biological effects, including the activation of sirtuins. Endogenously-produced melatonin, a powerful free radical scavenger, declines with age and its loss contributes to degenerative conditions of aging. Recently, it was reported that melatonin also activates sirtuins, in addition to other functions, such as regulator of circadian rhythms or anti-inflammatory properties. The fact that melatonin and resveratrol are present in various foods, exhibiting possible synergistic effects, suggests the use of dietary ingredients to promote health and longevity. PMID- 25824610 TI - Development of fluorescent probes specific for parallel-stranded G-quadruplexes by a library approach. AB - A 241-membered cyanine-based library was constructed by the combinatorial chemistry strategy. Combined with high-throughput screening, we successfully discovered a novel fluorescent probe (CyC-M716) capable of identifying a subset of parallel G-quadruplexes with propeller loops stretching across three tetrad layers with high sensitivity and selectivity. PMID- 25824611 TI - Phosphorus-modified tungsten nitride/reduced graphene oxide as a high performance, non-noble-metal electrocatalyst for the hydrogen evolution reaction. AB - Phosphorus-modified tungsten nitride/reduced graphene oxide (P-WN/rGO) is designed as a high-efficient, low-cost electrocatalyst for the hydrogen evolution reaction (HER). WN (ca. 3 nm in size) on rGO is first synthesized by using the H3[PO4(W3O9)4] cluster as a W source. Followed by phosphorization, the particle size increase slightly to about 4 nm with a P content of 2.52 at %. The interaction of P with rGO and WN results in an obvious increase of work function, being close to Pt metal. The P-WN/rGO exhibits low onset overpotential of 46 mV, Tafel slope of 54 mV dec(-1), and a large exchange current density of 0.35 mA cm( 2) in acid media. It requires overpotential of only 85 mV at current density of 10 mA cm(-2), while remaining good stability in accelerated durability testing. This work shows that the modification with a second anion is powerful way to design new catalysts for HER. PMID- 25824612 TI - Prostate Biopsy Core Handling: Comparison of Contemporary Preembedding Methods. AB - INTRODUCTION: The probability of prostate cancer detection is related to the amount of tissue represented. For optimal tissue representation, the specimens should preserve their regular cylindrical shape and avoid artefacts and deformation caused by fixation and preembedding. The aim of our study was to compare contemporary preembedding methods including a new method of using thick cardboard. MATERIALS AND METHODS: To compare the preembedding methods, we took 36 nonfragmented cores from fresh prostatectomy specimens for each method, fixed them in formalin and made histological slides. The comparison criteria were a core section area in the middle section and the number of fragments per core after processing. RESULTS: Two methods (preembedding on the edge of thick cardboard and on biplicated paper) provided a bigger section area of specimens. The differences in amounts of fragments were very small among the methods mentioned above and the preembedding glass with grooves, but preembedding between two sponges in a histological cassette showed higher fragmentation. CONCLUSIONS: Preembedding on the edge of thick cardboard and on biplicated paper can be recommended as effective methods of prostate biopsy core fixation. Paper or cardboard for fixation of prostate biopsy cores should be presoaked with formalin or normal saline. PMID- 25824613 TI - Preservation of mouse ovarian tissue follicle morphology and ultra-structure after vitrifying in biotechnological protocols. AB - BACKGROUND: The aim of the present study was to characterize the morphological and ultrastractural of mouse ovarian tissue with different cryoprotectant solution. OBJECTIVE: Aim of this study, is to demonstrae an improved convetional vitrification method on mouse ovarian tissue using different concentrations of ethylene glycol (EG) and/or dimetyl sulfoxide (DMSO) and EG. MATERIALS AND METHODS: Mouse ovarian tissue dissected and were randomly assigned to three groups: control, conventional vitrification (CV) and toxicity test. Then ovaries were vitrified by 5%, 10% EG or DMSO CV1-CV4, 5%, 10% EG plus DMSO CV5-CV6 and EG plus DMSO in climbing concentrations CV7. The effect of cryoprotectant solutions on ovarian tissue were evaluated by histological examination hematotoxillin & eosin stain, H&E, viability assessment trypan blue stain and ultrastructural analyses transmission electron microscopy, TEM. RESULTS: Ovarian tissue frozen in CV7 solution showed a higher percentage of morphologically normal follicles or viable follicles than other cryoprotectant solutions P < 0.05. Ultrastructural analysis of ovarian tissue showed that less damage was observed in CV7 and it was very similar to the control group. CONCLUSION: Vitrification of ovarian tissue with optimal cryoprotectant solutions such as EG plus DMSO is the most effective for preserving the structural efficiency of ovarian follicles. PMID- 25824614 TI - Enhanced in-plane thermoelectric figure of merit in p-type SiGe thin films by nanograin boundaries. AB - P-Type polycrystalline silicon-germanium (SiGe) thin films are grown by low pressure chemical vapor deposition (LPCVD) and their thermoelectric properties are characterized from 120 K to 300 K for potential application in integrated microscale cooling. The naturally formed grain boundaries are found to play a crucial role in determining both the charge and thermal transport properties of the films. Particularly, the grain boundaries create energy barriers for charge transport which lead to different dependences of charge mobility on doping concentration and temperature from the bulk counterparts. Meanwhile, the unique columnar grain structures result in remarkable thermal conductivity anisotropy with the in-plane thermal conductivities of SiGe films about 50% lower than the cross-plane values. By optimizing the growth conditions and doping level, a high in-plane figure of merit (ZT) of 0.2 for SiGe films is achieved at 300 K, which is about 100% higher than the previous record for p-type SiGe alloys, mainly due to the significant reduction in the in-plane thermal conductivity caused by nanograin boundaries. The low cost and excellent scalability of LPCVD render these high-performance SiGe films ideal candidates for thin-film thermoelectric applications. PMID- 25824615 TI - Irbesartan, an angiotensin II receptor antagonist, with selective PPAR-gamma modulating activity improves function and structure of chemotherapy-damaged ovaries in rats. AB - Cyclophosphamide (CYP) is a chemotherapeutic agent with a potent ovarian toxic effect. CYP induces granulosa cell apoptosis and oxidative stress. Irbesartan (IRB) is a unique ARB with a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonistic activity. As PPAR-gamma activation exerts anti inflammatory effects and reduces ROS production, IRB may further reduce inflammatory chemokine expression and suppress apoptotic cell death. Therefore, this study aimed to evaluate the effects of IRB on the development of CYP-induced ovarian damage. Rats were divided into four groups: control group, IRB group (100 mg/kg, orally), CYP group (100 mg/kg, i.p. single injection), and IRB+CYP group (IRB administered 9 days before and 6 days after CYP administration). Rats sacrificed on day 16 of experiment; estradiol (E2), FSH, and TNF-alpha levels were estimated in serum. Reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and caspase-3 activities, myeloperoxidase (MPO), and IL-10 levels were determined in ovarian tissues. Protein expressions of p53, caspase-3, Ki-67, and Rad-51 were estimated by immunohistochemical and Western blot techniques. CYP produced ovarian damage as indicated from the decline in serum E2; elevation in FSH; unbalance in tissue oxidative stress parameters; increase in MPO, TNF-alpha levels, caspase-3 activity/expression, p53, and Rad-51 expression; and decrease in IL-10 contents, without effect on Ki-67. On the other hand, IRB, significantly reduced the toxic effects of CYP as indicted from normalization of E2, FSH, oxidative stress, apoptotic, and inflammatory mediators. These data were further supported by histopathological studies. Thus, co-administration of IRB may be promising in alleviating the ovarian toxic effects of CYP. PMID- 25824616 TI - HOTAIR is a potential target for the treatment of cisplatin-resistant ovarian cancer. AB - Previous studies have demonstrated that the presence of Hox transcript antisense intergenic RNA (HOTAIR) is correlated with poor survival in several types of cancer, including breast cancer, and promotes tumor metastasis. Currently, little is known regarding the correlation between HOTAIR and chemoresistance in cancer. The current study aimed to investigate the role of HOTAIR in epithelial ovarian cancer, and the correlation between HOTAIR and cisplatin resistance. Reverse transcription-quantitative polymerase chain reaction was conducted to detect HOTAIR expression in the ovarian specimens and ovarian carcinoma cell lines. The results indicated that the expression level of HOTAIR was higher in epithelial ovarian cancer tissues than the level in the benign ovarian tissues. The expression level was also higher in late-stage malignant ovarian tumors compared with the level in early-stage tumors. Levels of HOTAIR were also higher in the SKOV-3CDDP/R cisplatin-resistant ovarian carcinoma cell line than in the SKOV-3 cisplatin-sensitive cell line. The knockdown of HOTAIR using siRNAs with transfection reagent suppressed cell proliferation, reduced the invasion ability of the cells and notably, it restored cisplatin-sensitivity of the cisplatin resistant cells specifically by enhancing cisplatin-induced cytotoxicity and apoptosis in SKOV-3CDDP/R cells. In conclusion, HOTAIR may be used in the development of novel treatments for ovarian cancer, particularly those that are resistant to conventional therapies. PMID- 25824617 TI - Slow-to-fast transition of hydrogen bond dynamics in acetamide hydration shell formation. AB - The formation of a hydration shell in acetamide aqueous solution has been investigated by means of UV Raman spectroscopy. The experimental results reveal the existence of two distinct regimes of water dynamics. At high acetamide concentration water molecules show a structural and dynamical behavior consistent with the so-called iceberg model. Upon increasing the amount of water we observe the formation of a hydration shell marked by fastening of hydrogen-bond dynamics. Such a behavior may help to shed light on the scientific debate on how water rearranges around the hydrophobic portions of solute molecules (iceberg vs. non iceberg models). PMID- 25824619 TI - Dibromoindium(III) cations as a pi-Lewis acid: characterization of [IPr.InBr2][SbF6] and its catalytic activity towards alkynes and alkenes. AB - [IPr.InBr2][SbF6] (2) (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) has been synthesized and characterized in the solid state. This complex proved to be a very active catalyst for hydroarylations, transfer hydrogenations, and cycloisomerizations. PMID- 25824620 TI - HuR keeps interferon-beta mRNA stable. AB - The expression of interferon (IFN) beta is highly induced in immune and nonimmune cells in response to virus infection. This upregulation is mediated at both transcriptional and posttranscriptional levels. Whereas the signaling pathways triggered by innate virus receptors leading to transcription factor activation have been extensively studied, the mechanisms by which IFN-beta mRNA stability is posttranscriptionally controlled are not fully understood. In this issue of the European Journal of Immunology, Herdy et al. [Eur. J. Immunol. 2015 45:1500-1511] show that a human RNA-binding protein, embryonic lethal, abnormal vision, drosophila-like 1 (ELAVL1)/Hu antigen R (HuR), strongly associates with IFN-beta mRNA via AU-rich sequences present in its 3' untranslated region in various human cell lines. The authors show that ELAVL1/HuR is required for the stabilization of IFN-beta mRNA, and suppression of ELAVL1/HuR by its inhibitor MS-444 leads to impaired expression of IFN-beta in response to viral dsRNA treatment. Thus, this study uncovers a novel mechanism of posttranscriptional IFN-beta mRNA regulation in response to virus infection, through IFN-beta stabilization by ELAVL1/HuR. Future studies are expected to identify further regulatory mechanisms of IFN-beta stabilization and destabilization in the course of antiviral responses. PMID- 25824618 TI - Brain atrophy and white-matter hyperintensities are not significantly associated with incidence and severity of postoperative delirium in older persons without dementia. AB - Postoperative delirium is a common complication in older people and is associated with increased mortality, morbidity, institutionalization, and caregiver burden. Although delirium is an acute confusional state characterized by global impairments in attention and cognition, it has been implicated in permanent cognitive impairment and dementia. The pathogenesis of delirium and the mechanisms leading to these disabling consequences remain unclear. The present study is the first to address the potential predisposing role of brain morphologic changes toward postoperative delirium in a large prospective cohort of patients undergoing elective surgery using state-of-the-art magnetic resonance imaging (MRI) techniques conducted before admission. We investigated the association of MRI-derived quantitative measures of white-matter damage, global brain, and hippocampal volume with the incidence and severity of delirium. Presurgical white-matter hyperintensities (WMHs), whole brain, and hippocampal volume were measured in 146 consecutively enrolled subjects, >=70 years old, without dementia who were undergoing elective surgery. These 3 presurgical MRI indices were tested as predictors of incidence and severity of subsequent delirium. Out of 146 subjects, 32 (22%) developed delirium. We found no statistically significant differences in WMH, whole brain, or hippocampal volume between subjects with and without delirium. Both unadjusted and adjusted (age, gender, vascular comorbidity, and general cognitive performance) regression analyses demonstrated no statistically significant association between any of the MRI measures with respect to delirium incidence or severity. In persons without dementia, preexisting cerebral WMHs, general and hippocampal atrophy may not predispose to postoperative delirium or worsen its severity. PMID- 25824621 TI - Macro- and micro-structural white matter differences correlate with cognitive performance in healthy aging. AB - Studies have shown that white matter (WM) volumetric reductions and overall degradation occur with aging. Nonetheless little is known about the WM alterations that may underlie different cognitive status in older individuals. The main goal of the present work was to identify and characterize possible macro and microstructural WM alterations that could distinguish between older healthy individuals with contrasting cognitive profiles (i.e., "poor" vs "good" cognitive performers). Structural and diffusion magnetic resonance imaging was performed in order to quantify local WM volumes, white matter signal abnormalities (WMSA) volume (a measure of lesion burden) and diffusion tensor imaging scalar maps known to probe WM microstructure. A battery of neurocognitive/psychological tests was administered to assess the cognitive performance. Poor performers showed a higher slope for the positive association between WMSA volume and age compared to good performers. Even when controlling for WMSA volume, poor performers also evidenced lower fractional anisotropy, as well as positive associations with age with higher slopes of regression parameters in radial and axial diffusivity. Altogether results suggest that cognitive performance is related to differences in WM, with poor cognitive performers displaying signs of faster aging in WM. PMID- 25824622 TI - Transferrable superhydrophobic TiO2 nanorods on reduced graphene oxide films using block copolymer templates. AB - Superhydrophobic surfaces are normally fixed on the chosen materials. Here, we report transferrable superhydrophobicity which was enabled by fabricating TiO2 nanorods on a reduced graphene oxide (rGO) film. Superhydrophobic TiO2 nanorods were first synthesized from a nanoporous template of block copolymers (BCPs). The controllability over the dimension and shape of nanopores of the BCP template allowed for the adjustment of TiO2 nanostructures for superhydrophobicity. Since the rGO film provided effective transferring, TiO2 nanorods were conveyed onto a flexible polymer film and a metal substrate. Thus, the surface of the designated substrate was successfully changed to a superhydrophobic surface without alteration of its inherent characteristics. PMID- 25824623 TI - Survival of massive mesenteric infarction through midgut resection and duodenocolostomy--a case report. PMID- 25824624 TI - Erythrocyte remodeling by Plasmodium falciparum gametocytes in the human host interplay. AB - The spread of malaria critically relies on the presence of Plasmodium transmission stages - the gametocytes - circulating in the blood of an infected individual, which are taken up by Anopheles mosquitoes. A striking feature of Plasmodium falciparum gametocytes is their long development inside the erythrocytes while sequestered in the internal organs of the human host. Recent studies of the molecular and cellular remodeling of the host erythrocyte induced by P. falciparum during gametocyte maturation are shedding light on how these may affect the establishment and maintenance of sequestration of the immature transmission stages and the subsequent release and circulation of mature gametocytes in the peripheral bloodstream. PMID- 25824625 TI - A possible instance of sexual dimorphism in the tails of two oviraptorosaur dinosaurs. AB - The hypothesis that oviraptorosaurs used tail-feather displays in courtship behavior previously predicted that oviraptorosaurs would be found to display sexually dimorphic caudal osteology. MPC-D 100/1002 and MPC-D 100/1127 are two specimens of the oviraptorosaur Khaan mckennai. Although similar in absolute size and in virtually all other anatomical details, the anterior haemal spines of MPC D 100/1002 exceed those of MPC-D 100/1127 in ventral depth and develop a hitherto unreported "spearhead" shape. This dissimilarity cannot be readily explained as pathologic and is too extreme to be reasonably attributed to the amount of individual variation expected among con-specifics. Instead, this discrepancy in haemal spine morphology may be attributable to sexual dimorphism. The haemal spine form of MPC-D 100/1002 offers greater surface area for caudal muscle insertions. On this basis, MPC-D 100/1002 is regarded as most probably male, and MPC-D 100/1127 is regarded as most probably female. PMID- 25824626 TI - Ignition's glow: Ultra-fast spread of global cortical activity accompanying local "ignitions" in visual cortex during conscious visual perception. AB - Despite extensive research, the spatiotemporal span of neuronal activations associated with the emergence of a conscious percept is still debated. The debate can be formulated in the context of local vs. global models, emphasizing local activity in visual cortex vs. a global fronto-parietal "workspace" as the key mechanisms of conscious visual perception. These alternative models lead to differential predictions with regard to the precise magnitude, timing and anatomical spread of neuronal activity during conscious perception. Here we aimed to test a specific aspect of these predictions in which local and global models appear to differ - namely the extent to which fronto-parietal regions modulate their activity during task performance under similar perceptual states. So far the main experimental results relevant to this debate have been obtained from non invasive methods and led to conflicting interpretations. Here we examined these alternative predictions through large-scale intracranial measurements (Electrocorticogram - ECoG) in 43 patients and 4445 recording sites. Both ERP and broadband high frequency (50-150 Hz - BHF) responses were examined through the entire cortex during a simple 1-back visual recognition memory task. Our results reveal short latency intense visual responses, localized first in early visual cortex followed (at ~200 ms) by higher order visual areas, but failed to show significant delayed (300 ms) visual activations. By contrast, oddball image repeat events, linked to overt motor responses, were associated with a significant increase in a delayed (300 ms) peak of BHF power in fronto-parietal cortex. Comparing BHF responses with ERP revealed an additional peak in the ERP response - having a similar latency to the well-studied P3 scalp EEG response. Posterior and temporal regions demonstrated robust visual category selectivity. An unexpected observation was that high-order visual cortex responses were essentially concurrent (at ~200 ms) with an ultra-fast spread of signals of lower magnitude that invaded selected sites throughout fronto-parietal cortical areas. Our results are compatible with local models in demonstrating a clear task dependence of the 300 ms fronto-parietal activation. However, they also reveal a more global component of low-magnitude and poor content selectivity that rapidly spreads into fronto-parietal sites. The precise functional role of this global "glow" remains to be elucidated. PMID- 25824627 TI - Metal selectivity by the virulence-associated yersiniabactin metallophore system. AB - Uropathogenic Escherichia coli secrete siderophores during human infections. Although siderophores are classically defined by their ability to bind iron(III) ions, the virulence-associated siderophore yersiniabactin was recently found to bind divalent copper ions during urinary tract infections. Here we use a mass spectrometric approach to determine the extent of non-iron(III) metal interactions by yersiniabactin and its TonB-dependent outer membrane importer FyuA. In addition to copper, iron and gallium ions, yersiniabactin was also observed to form stable nickel, cobalt, and chromium ion complexes. In E. coli, copper(II) and all other non-iron(III) yersiniabactin complexes were imported by FyuA in a TonB-dependent manner. Among metal-yersiniabactin complexes, copper(II) yersiniabactin is predicted to be structurally distinctive and was the only complex not to competitively inhibit iron(III) yersiniabactin import. These results are consistent with yersiniabactin as part of a metallophore system able to prioritize iron(III) complex uptake in high copper environments. PMID- 25824628 TI - The structure of WbnH in a near active state. PMID- 25824630 TI - Typical biomechanical bias in the perception of congenitally absent hands. PMID- 25824631 TI - Do non-human primates cooperate? Evidences of motor coordination during a joint action task in macaque monkeys. AB - Humans are intensively social primates, therefore many of their actions are dedicated to communication and interaction with other individuals. Despite the progress in understanding the cognitive and neural processes that allow humans to perform cooperative actions, in non-human primates only few studies have investigated the ability to interact with a partner in order to reach a common goal. These studies have shown that in naturalistic conditions animals engage in various types of social behavior that involve forms of mutual coordination and cooperation. However, little is known on the capacity of non-human primates to actively cooperate in a controlled experimental setting, which allows full characterization of the motor parameters underlying individual action and their change during motor cooperation. To this aim, we analyzed the behavior of three pairs of macaque monkeys trained to perform solo and joint-actions by exerting a force on an isometric joystick, as to move an individual or a common cursor toward visual targets on a screen. We found that during cooperation monkeys reciprocally adapt their behavior by changing the parameters that define the spatial and temporal aspects of their action, as to fine tune their joint effort, and maximize their common performance. Furthermore the results suggest that when acting together the movement parameters that specify each actor's behavior are not only modulated during execution, but also during planning. These findings provide the first quantitative description of action coordination in non-human primates during the performance of a joint action task. PMID- 25824629 TI - The assessment of cytokines in Quantiferon supernatants for the diagnosis of latent TB infection in a tribal population of Melghat, India. AB - The tuberculin skin test (TST) and interferon-gamma release assays (IGRA), namely, the QuantiFERON-TB Gold test (QFT), remain the standard immunological diagnostic tools for latent tuberculosis (TB) infection (LTBI). However, the sub optimal detection rates of both of these tests are major impediments in recognizing the population at risk. This study was aimed at evaluating additional cytokines besides interferon-gamma (IFN-gamma) as biomarkers for improving LTBI diagnosis in the tribal population of Melghat, India. Seventy-four close TB contacts were stratified by QFT and TST results into: (i) QFT+/TST+ (n = 26), (ii) QFT+/TST- (n = 12), (iii) QFT-/TST- (n = 35) and (iv) QFT-/TST+ (n = 1) groups. A panel of cytokines (IL-6, IL-10, TNF-alpha and IL-2R) was then evaluated in antigen-stimulated QFT cell-free culture supernatants using IMMULITE 1000, an automated immunoassay analyzer. Cytokine estimation showed significantly higher levels of IL-6 in the QFT+/TST+ group, while significantly higher levels of IL-10 were found in the QFT-/TST- group. Correlation analysis identified a positive correlation between IL-6 and the QFT response (r = 0.6723, P < 0.0001), while a negative correlation was seen between QFT and IL-10 expression (r = 0.3271, P = 0.0044). Similarly, IL-6 was positively correlated with TST levels (r = 0.6631, P <0 .0001), and conversely, a negative correlation was found between TST and IL-10 expression (r = -0.5698, P < 0.0001). The positive and negative predictive values of IL-6 were found to be 92.59 and 93.33%, respectively, and the positive and negative predictive values of IL-10 were 96.55 and 91.18%, respectively. No significant impact of the demographic characteristics on cytokine positivity was observed. Our preliminary results suggest that the evaluation of additional cytokines in QFT cell-free culture supernatants may be valuable for the identification of LTBI. Combining IL-6 and IL-10 with QFT and/or TST could markedly improve the detection accuracy of LTBI. Our observations require investigation in larger well-characterized cohorts along with follow-up studies to further confirm the study outcome. PMID- 25824632 TI - Sodium nitrite provides angiogenic and proliferative effects in vivo and in vitro. AB - BACKGROUND Angiogenesis is the formation of new blood vessels from pre-existing vasculature. Many factors and substances may stimulate angiogenesis and exhibit proliferative effect. In this study, we aimed to investigate the angiogenic and proliferative effects of sodium nitrite. MATERIAL AND METHODS The angiogenic activity of sodium nitrite was examined in vivo in the chick chorioallantoic membrane (CAM) model and in vitro in tube formation assay of human umbilical vein endothelial cells (HUVECs). The proliferative activity of sodium nitrite was also determined through MTT assay on HUVECs. RESULTS In CAM assay, sodium nitrite had an angiogenic effect especially at high concentrations compared with the control group and this was statistically significant. There was a proliferative effect on HUVECs in the presence of sodium nitrite for 24 and 48 h, and this was statistically significant (p<0.05). Comparing the tube length/area ratio values, there was statistically significant increase in the sodium nitrite group compared to the control group (p<0.05). CONCLUSIONS The results provide evidence that sodium nitrite induces angiogenesis in vitro and in vivo. PMID- 25824633 TI - A pressure-driven column-based technique for the efficient extraction of DNA from respiratory samples. AB - Currently molecular techniques are a broadly accepted tool for diagnosis and are able to benefit patients in clinical practice. The polymerase chain reaction (PCR) has been especially incorporated into practical applications that are already in widespread use across the globe. With regard to the initial DNA extraction from clinically relevant samples, a number of commercially available kits are commonly used and are also designed to be easy to handle and less labor intensive. In this study, the pressure system extracting DNA in column-based kit was developed, and its utility was compared with the centrifuge method using sputum from patients who were diagnosed with pneumonia. Also, due to the compact size and rapid processing time, the practical application of the pressure-based system incorporated into an automated pipetting machine was evaluated through clinical study. Our data suggests that DNA extraction by pressure was capable of serving as a substitute for the centrifuge method, and the compact and automatic nature of the pressure system device provided rapid and valuable information for clinical practice. PMID- 25824634 TI - Possible role of anaerobes in the pathogenesis of nontuberculous mycobacterial infection. AB - BACKGROUND AND OBJECTIVE: Recent advances in cultivation-independent molecular biological modalities for detecting bacterial species have indicated that several bacterial species may play a role in the pathogenesis of certain infectious diseases. The aim of this study was to evaluate the role of bacterial flora in the pathogenesis of nontuberculous mycobacteriosis (NTM) using a bacterial floral analysis of bronchoalveolar lavage fluid (BALF) with 16S rRNA gene sequencing in patients with bronchiectasis. METHODS: Fifty-eight patients with bronchiectasis evaluated using chest computed tomography were enrolled. BALF obtained from the most affected lung lesions was evaluated using culture and culture-independent methodologies. Approximately 600 bp of the bacterial 16S rRNA gene (E341F-E907R) was amplified via polymerase chain reaction using universal primers, and clone libraries were constructed. Nucleotide sequences of 96 randomly chosen clones for each specimen were determined, and the homology was searched using a basic local alignment search tool to determine the bacterial phylotypes and their proportions (bacterial floral analysis) in each specimen. RESULTS: Twenty-nine patients with bronchiectasis were diagnosed with NTM based on culture-based methods using Ogawa medium. The molecular method showed a significantly high rate of anaerobes among the patients with NTM compared with that observed in the bronchiectasis patients without NTM. In addition, findings of collapse/consolidation were significantly related to the proportion of Prevotella species in the BALF samples determined using the molecular method (P < 0.001). CONCLUSION: Given the results of the present study, anaerobes may play an important role in the pathogenesis of bronchiectasis in patients with NTM. PMID- 25824635 TI - Severe hypoglycaemia the "tip of the iceberg": an underestimated risk in both type 1 and type 2 diabetic patients. PMID- 25824636 TI - Maternal peripheral blood natural killer cells incorporate placenta-associated microRNAs during pregnancy. AB - Although recent studies have demonstrated that microRNAs (miRNAs or miRs) regulate fundamental natural killer (NK) cellular processes, including cytotoxicity and cytokine production, little is known about the miRNA-gene regulatory relationships in maternal peripheral blood NK (pNK) cells during pregnancy. In the present study, to determine the roles of miRNAs within gene regulatory networks of maternal pNK cells, we performed comprehensive miRNA and gene expression profiling of maternal pNK cells using a combination of reverse transcription quantitative PCR (RT-qPCR)-based miRNA array and DNA microarray analyses and analyzed the differential expression levels between first- and third trimester pNK cells. Furthermore, we constructed regulatory networks for miRNA mediated gene expression in pNK cells during pregnancy by Ingenuity Pathway Analysis (IPA). PCR-based array analysis revealed that the placenta-derived miRNAs [chromosome 19 miRNA cluster (C19MC) miRNAs] were detected in pNK cells during pregnancy. Twenty-five miRNAs, including six C19MC miRNAs, were significantly upregulated in the third- compared to first-trimester pNK cells. The rapid clearance of C19MC miRNAs also occurred in the pNK cells following delivery. Nine miRNAs, including eight C19MC miRNAs, were significantly downregulated in the post-delivery pNK cells compared to those of the third trimester. DNA microarray analysis identified 69 NK cell function-related genes that were differentially expressed between the first- and third-trimester pNK cells. On pathway and network analysis, the observed gene expression changes of pNK cells likely contribute to the increase in the cytotoxicity, as well as the cell cycle progression of third- compared to first-trimester pNK cells. Thirteen of the 69 NK cell function-related genes were significantly downregulated between the first- and third-trimester pNK cells. Nine of the 13 downregulated NK function-associated genes were in silico target candidates of 12 upregulated miRNAs, including C19MC miRNA miR-512-3p. The results of this study suggest that the transfer of placental C19MC miRNAs into maternal pNK cells occurs during pregnancy. The present study provides new insight into maternal NK cell functions. PMID- 25824637 TI - Supplementation of n-3 Polyunsaturated Fatty Acids for Major Depressive Disorder: A Randomized, Double-Blind, 12-Week, Placebo-Controlled Trial in Korea. AB - BACKGROUND: Controversy over the efficacy of n-3 polyunsaturated fatty acids (PUFAs) in depression continues to this day. The present study investigated the hypothesis that n-3 PUFA supplementation reduces depressive symptoms in Korean patients with major depressive disorder. METHODS: In a randomized, double-blind, placebo-controlled, 12-week, parallel-group trial, 35 patients with Center for Epidemiological Studies Depression Scale Korean version (CES-D-K) scores >=25 and depression confirmed by a psychiatrist were assigned to take either 3 capsules of n-3 PUFAs (1,140 mg of EPA + 600 mg of DHA; n = 18) or placebo (olive oil + safflower oil; n = 17). RESULTS: Supplementation with n-3 PUFAs significantly reduced Clinical Global Impression Improvement (CGI-I) scores as compared with intake of placebo using intention-to-treat analysis with last-observation-carried forward after adjusting for energy, fat, and fish intake. However, the CES-D-K, Hamilton Depression Rating Scale-17, and Clinical Global Impression Scale scores did not significantly differ between the n-3 PUFA and placebo groups. After supplementation with n-3 PUFAs, the erythrocyte levels of n-3 PUFAs were significantly increased, but n-6 PUFA levels were decreased. CONCLUSIONS: n-3 PUFAs demonstrated an advantage over placebo that did not reach clinical significance, although CGI-I score was significantly decreased in the n-3 PUFA group as compared with the placebo group. PMID- 25824638 TI - Diagnostic accuracy of diffusion-weighted MRI for differentiation of cervical cancer and benign cervical lesions at 3.0T: Comparison with routine MRI and dynamic contrast-enhanced MRI. AB - PURPOSE: To compare the diagnostic accuracy of routine magnetic resonance imaging (MRI) (T1 WI and T2 WI), diffusion-weighted MRI (DWI), and DCE-MRI (dynamic contrast-enhanced MRI) at 3.0T for differentiation of cervical cancer and benign cervical lesions. MATERIALS AND METHODS: A cohort of 75 cervical cancer patients, 26 cervical leiomyoma patients, 22 patients with cervical polyps consecutively underwent pelvic MRI scanning on a 3T MR unit. Two radiologists independently evaluated images at three imaging settings; routine MRI alone, DWI combined with routine MRI (DWI+routine MRI), and DCE-MRI. The apparent diffusion coefficients (ADCs) were calculated from b 0, 600 s/mm(2) and b 0, 1000 s/mm(2). RESULTS: DWI+routine MRI was significantly better than routine MRI and obtained high accuracy (0.95); the diagnostic performance was not significantly different between DWI+routine MRI and DCE-MRI. Reader agreement was excellent for both DWI+routine MRI (kappa, 0.90) and DCE-MRI (kappa, 0.92). The ADCs of cervical cancer were significantly lower than those of benign cervical lesions at both ADC maps (P = 0.0001). The diagnostic accuracy was not different at both ADC maps (P = 0.375). CONCLUSION: For differentiation of cervical cancer and benign cervical lesions, unenhanced MRI with combined diffusion-weighted and routine MRI (DWI+routine MRI) at 3T can provide accurate information and may be preferable to DCE. PMID- 25824640 TI - Molecular analysis of isolated tumor glands from endometrial endometrioid adenocarcinomas. AB - We studied the extensive molecular alterations of endometrial endometrioid adenocarcinoma (EEA) using a crypt isolation method. We analyzed copy number variation (CNV) using a single nucleotide polymorphism (SNP) array, genetic mutations (KRAS, BRAF, p53, PIK3CA), DNA methylation and microsatellite instability (MSI) status. In addition, loss of PTEN protein expression was examined. Increased chromosome copy numbers of 1q21.2-44 (22%) and 10q11.21-23.31 (28%) were seen relatively frequently in EEA, and copy-neutral loss of heterozygosity (LOH) was also observed in 10q22.1-26.3 (22%). The CNV patterns of EEA were classified into four groups through hierarchical cluster analysis. Cluster 1 had many CNVs of 10q, and cluster 2 was characterized by MSI status. In cluster 3, increased CNVs of 1q were often seen. In cluster 4, p53 mutations were detected. KRAS and PIK3CA mutations and reduced PTEN protein expression were common to all groups. On the other hand, CpG island methylator phenotype (CIMP) was rare in all groups. The data indicated an association with chromosomal gain of 1q and 10q or 10q copy-neutral LOH in some cases. We suggest that EEA consists of four groups that are characterized with molecular alterations. PMID- 25824639 TI - Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase. AB - The polyketide natural product borrelidin displays antibacterial, antifungal, antimalarial, anticancer, insecticidal and herbicidal activities through the selective inhibition of threonyl-tRNA synthetase (ThrRS). How borrelidin simultaneously attenuates bacterial growth and suppresses a variety of infections in plants and animals is not known. Here we show, using X-ray crystal structures and functional analyses, that a single molecule of borrelidin simultaneously occupies four distinct subsites within the catalytic domain of bacterial and human ThrRSs. These include the three substrate-binding sites for amino acid, ATP and tRNA associated with aminoacylation, and a fourth 'orthogonal' subsite created as a consequence of binding. Thus, borrelidin competes with all three aminoacylation substrates, providing a potent and redundant mechanism to inhibit ThrRS during protein synthesis. These results highlight a surprising natural design to achieve the quadrivalent inhibition of translation through a highly conserved family of enzymes. PMID- 25824641 TI - SERT and uncertainty: serotonin transporter expression influences information processing biases for ambiguous aversive cues in mice. AB - The long allele variant of the serotonin transporter (SERT, 5-HTT) gene-linked polymorphic region (5-HTTLPR) is associated with higher levels of 5-HTT expression and reduced risk of developing affective disorders. However, little is known about the mechanisms underlying this protective effect. One hypothesis is that 5-HTT expression influences aversive information processing, with reduced negative cognitive bias present in those with higher 5-HTT expression. Here we investigated this hypothesis using genetically-modified mice and a novel aversive learning paradigm. Mice with high levels of 5-HTT expression (5-HTT over expressing, 5-HTTOE mice) and wild-type mice were trained to discriminate between three distinct auditory cues: one cue predicted footshock on all trials (CS+); a second cue predicted the absence of footshock (CS-); and a third cue predicted footshock on 20% of trials (CS20%), and was therefore ambiguous. Wild-type mice exhibited equivalently high levels of fear to the CS+ and CS20% and minimal fear to the CS-. In contrast, 5-HTTOE mice exhibited high levels of fear to the CS+ but minimal fear to the CS- and the CS20%. This selective reduction in fear to ambiguous aversive cues suggests that increased 5-HTT expression reduces negative cognitive bias for stimuli with uncertain outcomes. PMID- 25824642 TI - Spinal pain. AB - The spinal pain, and expecially the low back pain (LBP), represents the second cause for a medical consultation in primary care setting and a leading cause of disability worldwide [1]. LBP is more often idiopathic. It has as most frequent cause the internal disc disruption (IDD) and is referred to as discogenic pain. IDD refers to annular fissures, disc collapse and mechanical failure, with no significant modification of external disc shape, with or without endplates changes. IDD is described as a separate clinical entity in respect to disc herniation, segmental instability and degenerative disc desease (DDD). The radicular pain has as most frequent causes a disc herniation and a canal stenosis. Both discogenic and radicular pain also have either a mechanical and an inflammatory genesis. For to be richly innervated, facet joints can be a direct source of pain, while for their degenerative changes cause compression of nerve roots in lateral recesses and in the neural foramina. Degenerative instability is a common and often misdiagnosed cause of axial and radicular pain, being also a frequent indication for surgery. Acute pain tends to extinguish along with its cause, but the setting of complex processes of peripheral and central sensitization may influence its evolution in chronic pain, much more difficult to treat. The clinical assessment of pain source can be a challenge because of the complex anatomy and function of the spine; the advanced imaging methods are often not sufficient for a definitive diagnosis because similar findings could be present in either asymptomatic and symptomatic subjects: a clinical correlation is always mandatory and the therapy cannot rely uniquely upon any imaging abnormalities. Purpose of this review is to address the current concepts on the pathophysiology of discogenic, radicular, facet and dysfunctional pain, focusing on the role of the imaging in the diagnostic setting, to potentially address a correct approach also to minimally invasive interventional techniques. Special attention will be done to the discogenic pain, actually considered as the most frequent cause of chronic low back pain. PMID- 25824643 TI - Feasibility and evaluation of dual-source transmit 3D imaging of the orbits: Comparison to high-resolution conventional MRI at 3T. AB - PURPOSE: To prospectively compare the image quality and diagnostic performance of orbital MR images obtained by using a dual-source parallel transmission (pTX) 3D sequence (Sampling Perfection with Application optimized Contrasts using different flip angle Evolution, SPACE) with the image quality of conventional high-resolution standard protocol for clinical use in patients at 3T. MATERIALS AND METHODS: After obtaining institutional review board approval and patient consent, 32 patients with clinical indication for orbital MRI were examined using a high-resolution conventional sequences and 3D pTX SPACE sequences. Quantitative measurements, image quality of the healthy orbit, incidence of artifacts, and the subjective diagnostic performance to establish diagnosis was rated. Statistical significance was calculated by using a Student's t-test and nonparametric Wilcoxon signed rank test. RESULTS: Length measurements were comparable in the two techniques, 3D pTX SPACE resulted in significant faster image acquisition with higher spatial resolution and less motion artifacts as well as better delineation of the optic nerve sheath. However, estimated contrast-to-noise and signal-to-noise and overall image quality as well as subjective scores of the conventional TSE imaging were rated significantly higher. The conventional MR sequences were the preferred techniques by the readers. CONCLUSION: This study demonstrates the feasibility of 3D pTX SPACE of the orbit resulting in a rapid acquisition of isotropic high-resolution images. Although no pathology was missed in 3D pTX SPACE, conventional MRI techniques showed the higher diagnostic confidence in our study, presumably due to the higher signal-to-noise and contrast-to-noise ratios. We observed high-resolution TSE imaging to be the preferred technique, 3D pTX SPACE cannot replace conventional MRI so far. PMID- 25824644 TI - An unusual case of multiple facial papules? PMID- 25824645 TI - Effect of salt intake and potassium supplementation on urinary renalase and serum dopamine levels in Chinese adults. AB - OBJECTIVE: The aim of our study was to assess the effects of altered salt and potassium intake on urinary renalase and serum dopamine levels in humans. METHODS: Forty-two subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low salt diet for 7 days (3.0 g/day of NaCl), a high-salt diet for an additional 7 days (18.0 g/day of NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day of NaCl + 4.5 g/day of KCl). RESULTS: Urinary renalase excretions were significantly higher during the high-salt diet intervention than during the low-salt diet. During high-potassium intake, urinary renalase excretions were not significantly different from the high-salt diet, whereas they were significantly higher than the low-salt levels. Serum dopamine levels exhibited similar trends across the interventions. Additionally, a significant positive relationship was observed between the urine renalase and serum dopamine among the different dietary interventions. Also, 24-hour urinary sodium excretion positively correlated with urine renalase and serum dopamine in the whole population. CONCLUSIONS: The present study indicates that dietary salt intake and potassium supplementation increase urinary renalase and serum dopamine levels in Chinese subjects. PMID- 25824646 TI - Sequential O-H/C-H bond insertion of phenols initiated by the gold(I)-catalyzed cyclization of 1-bromo-1,5-enynes. AB - The development of a sequential O-H/C-H bond functionalization of phenols initiated by the cationic gold(I)-catalyzed cyclization of 1-bromo-1,5-enynes to produce (2-bromocyclopent-2-en-1-yl)phenols is reported. This unprecedented domino transformation efficiently proceeds under mild conditions (5 mol % of (t Bu)3PAuNTf2, CH2Cl2, 0-23 degrees C) via an intermediate aryl alkyl ether which collapses at ambient temperature to undergo a 1,2-hydride shift followed by C-H insertion of the phenol. PMID- 25824647 TI - Spatio-temporal resolution of primary processes of photosynthesis. AB - Technical progress in laser-sources and detectors has allowed the temporal and spatial resolution of chemical reactions down to femtoseconds and A-units. In photon-excitable systems the key to chemical kinetics, trajectories across the vibrational saddle landscape, are experimentally accessible. Simple and thus well defined chemical compounds are preferred objects for calibrating new methodologies and carving out paradigms of chemical dynamics, as shown in several contributions to this Faraday Discussion. Aerobic life on earth is powered by solar energy, which is captured by microorganisms and plants. Oxygenic photosynthesis relies on a three billion year old molecular machinery which is as well defined as simpler chemical constructs. It has been analysed to a very high precision. The transfer of excitation between pigments in antennae proteins, of electrons between redox-cofactors in reaction centres, and the oxidation of water by a Mn4Ca-cluster are solid state reactions. ATP, the general energy currency of the cell, is synthesized by a most agile, rotary molecular machine. While the efficiency of photosynthesis competes well with photovoltaics at the time scale of nanoseconds, it is lower by an order of magnitude for crops and again lower for bio-fuels. The enormous energy demand of mankind calls for engineered (bio mimetic or bio-inspired) solar-electric and solar-fuel devices. PMID- 25824648 TI - Synthesis and Biological Evaluation of Some New 2,5-Substituted 1-Ethyl-1H benzoimidazole Fluorinated Derivatives as Direct Thrombin Inhibitors. AB - A new series of fluorinated 2,5-substituted 1-ethyl-1H-benzimidazole derivatives were synthesized from starting compounds 3a-i, which were prepared from acrylic acid ethyl ester and the appropriate amines using trifluoromethanesulfonic acid as a catalyst. A total of 9 novel derivatives were synthesized through 9 steps. All of them were evaluated for thrombin inhibition activity in vitro for the first time. We have altered their structures using different substituents on the amines to assess their structure-activity relationships as direct thrombin inhibitors. All the compounds were effective thrombin inhibitors, with IC50 values ranging from 3.39 to 23.30 nM. Among the compounds synthesized, compounds 14a, 14b, 14d, 14e, and 14h exhibited greater anticoagulant activity than argatroban (IC50 = 9.36 nM). Furthermore, compound 14h synthesized starting with 2-amino-pyridine was the most potent thrombin inhibitor with an IC50 value of 3.39 nM. Molecular modeling studies were performed to determine the probable interactions of the most potent compounds 14a, 14e, and 14h with their protein receptor (PDB ID: 1KTS). Docking data show that the active compounds inhibit thrombin in a similar mode to that of the potent anticoagulant dabigatran. PMID- 25824649 TI - H2 O2 activates matrix metalloproteinases through the nuclear factor kappa B pathway and Ca(2+) signals in human periodontal fibroblasts. AB - BACKGROUND: The mechanisms involved in reactive oxygen species and matrix metalloproteinase (MMP)-mediated periodontal tissue breakdown are unknown. OBJECTIVE: To determine the effect of H2 O2 in MMP-2 and MMP-9 activity, and the involvement of nuclear factor kappa B (NFkappaB) and Ca(2+) -mediated signals in human periodontal ligament fibroblasts. MATERIAL AND METHODS: Primary cultures were characterized for their phenotype and exposed for 24 h to sublethal doses (2.5-10 MUm) of H2 O2 or control media. NFkappaB involvement was evaluated through immunofluorescence of p65 subunit, using the NFkappaB blocking peptide SN50 and catalase. Ca(2+) signals were analyzed by loading the cells with Fluo4 AM and recording the fluorescence changes in a confocal microscope before and after the addition of H2 O2 . 1,2-bis(o-aminophenoxy) ethane-N,N,N',N' tetraacetic acid-acetoxymethyl was used to chelate intracellular Ca(2+) . The activity and levels of MMP-2 and MMP-9 were analyzed by gelatin zymogram and densitometric scanning, and enzyme-linked immunosorbent assay, respectively. Statistical analysis was performed with stata V11.1 software using the ANOVA test. RESULTS: H2 O2 at concentrations of 2.5-5 MUm induced Ca(2+) signaling and NFkappaB subunit p65 nuclear translocation, whereas catalase, SN50 and BAPTA-AM prevented p65 nuclear translocation. H2 O2 at 2.5-5 MUm significantly increased MMP-9 and MMP-2 activity, while SN50 resulted in lower MMP-2 and MMP-9 activity rates compared with controls. CONCLUSION: Sublethal H2 O2 induces Ca(2+) dependent NFkappaB signaling with an increase in MMP gelatinolytic activity in human periodontal ligament. PMID- 25824650 TI - Addressing health system barriers to access to and use of skilled delivery services: perspectives from Ghana. AB - Poor access to and use of skilled delivery services have been identified as a major contributory factor to poor maternal and newborn health in sub-Saharan African countries, including Ghana. However, many previous studies that examine norms of childbirth and care-seeking behaviours have focused on identifying the norms of non-use of services, rather than factors, that can promote service use. Based on primary qualitative research with a total of 185 expectant and lactating mothers, and 20 healthcare providers in six communities in Ghana, this paper reports on strategies that can be used to overcome health system barriers to the use of skilled delivery services. The strategies identified include expansion and redistribution of existing maternal health resources and infrastructure, training of more skilled maternity caregivers, instituting special programmes to target women most in need, improving the quality of maternity care services provided, improving doctor-patient relationships in maternity wards, promotion of choice, protecting privacy and patient dignity in maternity wards and building partnerships with traditional birth attendants and other non-state actors. The findings suggest the need for structural changes to maternity clinics and routine nursing practices, including an emphasis on those doctor-patient relational practices that positively influence women's healthcare-seeking behaviours. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25824652 TI - The addition of CD20 monoclonal antibodies to lenalidomide improves response rates and survival in relapsed/refractory patients with chronic lymphocytic leukaemia relative to lenalidomide monotherapy - the MD Anderson Cancer Center experience. PMID- 25824651 TI - Comprehensive data resources and analytical tools for pathological association of aminoacyl tRNA synthetases with cancer. AB - Mammalian cells have cytoplasmic and mitochondrial aminoacyl-tRNA synthetases (ARSs) that catalyze aminoacylation of tRNAs during protein synthesis. Despite their housekeeping functions in protein synthesis, recently, ARSs and ARS interacting multifunctional proteins (AIMPs) have been shown to play important roles in disease pathogenesis through their interactions with disease-related molecules. However, there are lacks of data resources and analytical tools that can be used to examine disease associations of ARS/AIMPs. Here, we developed an Integrated Database for ARSs (IDA), a resource database including cancer genomic/proteomic and interaction data of ARS/AIMPs. IDA includes mRNA expression, somatic mutation, copy number variation and phosphorylation data of ARS/AIMPs and their interacting proteins in various cancers. IDA further includes an array of analytical tools for exploration of disease association of ARS/AIMPs, identification of disease-associated ARS/AIMP interactors and reconstruction of ARS-dependent disease-perturbed network models. Therefore, IDA provides both comprehensive data resources and analytical tools for understanding potential roles of ARS/AIMPs in cancers. PMID- 25824656 TI - Theoretical prediction of Am(iii)/Eu(iii) selectivity to aid the design of actinide-lanthanide separation agents. AB - Selective extraction of minor actinides from lanthanides is a critical step in the reduction of radiotoxicity of spent nuclear fuels. However, the design of suitable ligands for separating chemically similar 4f- and 5f-block trivalent metal ions poses a significant challenge. First-principles calculations should play an important role in the design of new separation agents, but their ability to predict metal ion selectivity has not been systematically evaluated. In this work, we examine the ability of several density functional theory methods to predict selectivity of Am(iii) and Eu(iii) with oxygen, mixed oxygen-nitrogen, and sulfur donor ligands. The results establish a computational method capable of predicting the correct order of selectivities obtained from liquid-liquid extraction and aqueous phase complexation studies. To allow reasonably accurate predictions, it was critical to employ sufficiently flexible basis sets and provide proper account of solvation effects. The approach is utilized to estimate the selectivity of novel amide-functionalized diazine and 1,2,3-triazole ligands. PMID- 25824653 TI - Genome-wide tests for introgression between cactophilic Drosophila implicate a role of inversions during speciation. AB - Models of speciation-with-gene-flow have shown that the reduction in recombination between alternative chromosome arrangements can facilitate the fixation of locally adaptive genes in the face of gene flow and contribute to speciation. However, it has proven frustratingly difficult to show empirically that inversions have reduced gene flow and arose during or shortly after the onset of species divergence rather than represent ancestral polymorphisms. Here, we present an analysis of whole genome data from a pair of cactophilic fruit flies, Drosophila mojavensis and D. arizonae, which are reproductively isolated in the wild and differ by several large inversions on three chromosomes. We found an increase in divergence at rearranged compared to colinear chromosomes. Using the density of divergent sites in short sequence blocks we fit a series of explicit models of species divergence in which gene flow is restricted to an initial period after divergence and may differ between colinear and rearranged parts of the genome. These analyses show that D. mojavensis and D. arizonae have experienced postdivergence gene flow that ceased around 270 KY ago and was significantly reduced in chromosomes with fixed inversions. Moreover, we show that these inversions most likely originated around the time of species divergence which is compatible with theoretical models that posit a role of inversions in speciation with gene flow. PMID- 25824655 TI - Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. AB - OBJECTIVE: To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma. DATA SOURCES: Cytopathologists with an interest in the field involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC) contributed to this update. Reference material includes peer-reviewed publications and textbooks. RATIONALE: This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in Cape Town. PMID- 25824657 TI - A Cell-Based Assay Reveals Nuclear Translocation of Intracellular Domains Released by SPPL Proteases. AB - During regulated intramembrane proteolysis (RIP) a membrane-spanning substrate protein is cleaved by an ectodomain sheddase and an intramembrane cleaving protease. A cytoplasmic intracellular domain (ICD) is liberated, which can migrate to the nucleus thereby influencing transcriptional regulation. Signal peptide peptidase-like (SPPL) 2a and 2b have been implicated in RIP of type II transmembrane proteins. Even though SPPL2a might represent a potential pharmacological target for treatment of B-cell-mediated autoimmunity, no specific and potent inhibitors for this enzyme are currently available. We report here on the first quantitative cell-based assay for measurement of SPPL2a/b activity. Demonstrating the failure of standard Gal4/VP16 reporter assays for SPPL2a/b analysis, we have devised a novel system employing beta-galactosidase (betaGal) complementation. This is based on detecting nuclear translocation of the proteolytically released substrate ICDs, which results in specific restoration of betaGal activity. Utilizing this potentially high-throughput compatible new setup, we demonstrate nuclear translocation of the ICDs from integral membrane protein 2B (ITM2B), tumor necrosis factor (TNF) and CD74 and identify secreted frizzled-related protein 2 (SFRP2) as potential transcriptional downstream target of the CD74 ICD. We show that the presented assay is easily adaptable to other intramembrane proteases and therefore represents a valuable tool for the functional analysis and development of new inhibitors of this class of enzymes. PMID- 25824658 TI - 'Conditioning the heart' - lessons we have learned from the past and future perspectives for new and old conditioning 'drugs'. AB - LINKED ARTICLES: This article is part of a themed section on Conditioning the Heart - Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-8. PMID- 25824654 TI - Evidence for a Revised Ion/Substrate Coupling Stoichiometry of GABA Transporters. AB - Plasma membrane gamma-aminobutyric acid (GABA) transporters (GATs) are electrogenic transport proteins that couple the cotranslocation of Na(+), Cl(-), and GABA across the plasma membrane of neurons and glia. A fundamental property of the transporter that determines its ability to concentrate GABA in cells and, hence, regulate synaptic and extra-synaptic GABA concentrations, is the ion/substrate coupling stoichiometry. Here, we scrutinized the currently accepted 2 Na(+):1 Cl(-):1 GABA stoichiometry because it is inconsistent with the measured net charge translocated per co-substrate (Na(+), Cl(-), and GABA). We expressed GAT1 and GAT3 in Xenopus laevis oocytes and utilized thermodynamic and uptake under voltage-clamp measurements to determine the stoichiometry of the GABA transporters. Voltage-clamped GAT1-expressing oocytes were internally loaded with GABA, and the reversal potential (V rev) of the transporter-mediated current was recorded at different external concentrations of Na(+), Cl(-), or GABA. The shifts in V rev for a tenfold change in the external Na(+), Cl(-), and GABA concentration were 84 +/- 4, 30 +/- 1, and 29 +/- 1 mV, respectively. To determine the net charge translocated per Na(+), Cl(-), and GABA, we measured substrate fluxes under voltage clamp in cells expressing GAT1 or GAT3. Charge flux to substrate flux ratios were 0.7 +/- 0.1 charge/Na(+), 2.0 +/- 0.2 charges/Cl(-), and 2.1 +/- 0.1 charges/GABA. Altogether, our results strongly suggest a 3 Na(+):1 Cl(-):1 GABA coupling stoichiometry for the GABA transporters. The revised stoichiometry has important implications for understanding the contribution of GATs to GABAergic signaling in health and disease. PMID- 25824659 TI - Green Space, Violence, and Crime: A Systematic Review. AB - PURPOSE: To determine the state of evidence on relationships among urban green space, violence, and crime in the United States. METHODS AND RESULTS: Major bibliographic databases were searched for studies meeting inclusion criteria. Additional studies were culled from study references and authors' personal collections. Comparison among studies was limited by variations in study design and measurement and results were mixed. However, more evidence supports the positive impact of green space on violence and crime, indicating great potential for green space to shape health-promoting environments. CONCLUSION: Numerous factors influence the relationships among green space, crime, and violence. Additional research and standardization among research studies are needed to better understand these relationships. PMID- 25824660 TI - Habitual sleeping position and asymmetric structural and functional loss in patients with open angle glaucoma. PMID- 25824662 TI - 2'-Hydroxy flavanone derivatives as an inhibitors of pro-inflammatory mediators: Experimental and molecular docking studies. AB - 2'-Hydroxy flavanone (1) was previously isolated from Mimosa pudica (L.) whole plant and was found to exhibit anti-inflammatory effects in vitro. There are also reports on anti-inflammatory properties of compounds bearing flavanone/chromone nucleus. Taking this into account, fourteen derivatives of 2'-hydroxy flavanone (1) were synthesized and evaluated against pro-inflammatory mediators (TNF-alpha, IL-1beta and NO) in in vitro and in vivo models. Results directed that among the synthesized compounds, four derivatives (11-14) showed profound inhibition of pro inflammatory mediators as compared to the lead molecule. Further, 11-14 demonstrated comparable anti-inflammatory activity with ibuprofen in carrageenan induced rat paw edema assay and appreciable inhibition of lipopolysaccharide (LPS) induced pro-inflammatory mediators (TNF-alpha and IL-1beta) in Sprague Dawley (SD) rats. The synthesized compounds were further subjected to molecular docking analysis and in silico prediction of pharmacokinetic properties. PMID- 25824661 TI - Designing synthetic vaccines for HIV. AB - Despite three decades of intensive research efforts, the development of an effective prophylactic vaccine against HIV remains an unrealized goal in the global campaign to contain the HIV/AIDS pandemic. Recent characterization of novel epitopes for inducing broadly neutralizing antibodies has fueled research in the design and synthesis of new, well-defined antigenic constructs for the development of HIV envelope-directed vaccines. The present review will cover previous and recent efforts toward the design of synthetic vaccines based on the HIV viral envelope glycoproteins, with special emphasis on examples from our own laboratories. The biological evaluation of some of the most representative vaccine candidates, in terms of their antigenicity and immunogenicity, will also be discussed to illustrate the current state-of-the-art toward the development of fully synthetic HIV vaccines. PMID- 25824663 TI - Synthesis and biological evaluation of chalcone analogues as protective agents against cisplatin-induced cytotoxicity in kidney cells. AB - Chalcone analogues were prepared and evaluated for any renoprotective effects on cisplatin-treated cultured kidney cells (LLC-PK1); two chalcone analogues exhibited a potent renoprotective effect. In an additional study, we demonstrated that the blocking of MAPKs-p53-caspase-3 signaling cascade plays an important role in mediating the protective effect of these compounds against oxidative cytotoxicity in cultured LLC-PK1 cells. PMID- 25824664 TI - Three new fusidic acid derivatives and their antibacterial activity. AB - Two steroid acids, cephalosporin P1 and isocephalosporin P1, were isolated from Hapsidospora irregularis FERM BP-2511. These compounds are structurally related to fusidic acid. Their NMR data were completely assigned on the basis of the 2D NMR spectra. Incubation of these two compounds with Microbacterium oxydans CGMCC 1788 in Luria-Bertani broth yielded the same set of three new 3-dehydrogenated products, 3-keto-isocephalosporin P1, 3-keto-cephalosporin P1 and 6-deacetyl-3 keto-cephalosporin P1. The final pH of the bacterial culture was 9.0. Incubation of 3-keto-isocephalosporin P1 or 3-keto-cephalosporin P1 in Tris-HCl buffer (pH 9.0) revealed that these two compounds can convert to each other by shifting the acetyl group between C-6 and C-7. The acetyl group at C-6 or C-7 can also be removed by hydrolysis to yield the minor product 6-deacetyl-3-keto-cephalosporin P1. These fusidic acid derivatives were tested for the antibacterial activity against the Gram-positive pathogen Staphylococcus aureus. 3-Keto-cephalosporin P1 showed the highest activity among the five compounds, with a minimal inhibition concentration (MIC) of 4 MUg/mL, which is more potent than the substrate cephalosporin P1. Both cephalosporin P1 and 3-keto-cephalosporin P1 were active against methicillin-resistant S. aureus, with the same MIC of 8 MUg/mL. PMID- 25824665 TI - Biocompounds from rapeseed oil industry co-stream as active ingredients for skin care applications. AB - OBJECTIVE: Despite the great number of substances produced by the skincare industry, very few of them seem to truly have an effect on the skin. Therefore, given the social implications surrounding physical appearance, the search for new bioactive compounds to prevent or attenuate skin ageing and enhance self-image is a priority of current research. In this context, being rich in valuable compounds, such as proteins, phenolics, lipids and vitamins, this study is focused on the potential activity of rapeseed press cake hydrolysates to be used as raw materials for skincare applications. METHODS: In this study, the protein rich press residue from the rapeseed oil industry was converted enzymatically into short-chain biologically active peptides using four protease products with varying substrate specificity - Alcalase 2.4L FG, Protex 6L, Protamex and Corolase 7089. The antioxidant, anti-wrinkle and anti-inflammatory activities of the obtained hydrolysates were evaluated in vitro while their biocompatibility with human skin fibroblasts was tested. RESULTS: All hydrolysates were biocompatible with skin fibroblasts after 24 h of exposure, while the non hydrolysed extract induced cell toxicity. Alcalase 2,4L FG and Protex 6L-obtained hydrolysates were the most promising extracts showing improved bioactivities suitable for skin anti-ageing formulations, namely antioxidant activity, inhibiting approximately 80% cellular reactive oxidative species, anti inflammatory and anti-wrinkle properties, inhibiting around 36% of myeloperoxidase activity and over 83% of elastase activity. CONCLUSION: The enzymatic technology applied to the rapeseed oil industry costream results in the release of bioactive compounds suitable for skincare applications. PMID- 25824667 TI - Trayless cafeterias lead diners to take less salad and relatively more dessert- ERRATUM. PMID- 25824666 TI - Plasmodium falciparum Werner homologue is a nuclear protein and its biochemical activities reside in the N-terminal region. AB - RecQ helicases, also addressed as a gatekeeper of genome, are an inevitable family of genome scrutiny proteins conserved from prokaryotes to eukaryotes and play a vital role in DNA metabolism. The deficiencies of three RecQ proteins out of five are involved in genetic abnormalities like Bloom syndrome (BS), Werner syndrome (WS), and Rothmund-Thomson syndrome (RTS). It is noteworthy that Plasmodium falciparum contains only two members of the RecQ family as opposed to five members present in the host Homo sapiens. In the present study, we report the biochemical characterization of the homologue of Werner (Wrn) helicase from P. falciparum 3D7 strain. Although there are significant sequence conservations between Wrn helicases of both H. sapiens and P. falciparum as well as among all the other Plasmodium species, they contain some peculiar differences also. In silico studies reveal that PfWrn is evolutionarily close to the bacterial RecQ protein. The N-terminal fragment (PfWrnN) contains all the helicase motifs along with all the functional domains and the predicted structure resembles with the human RecQ1 protein, whereas the C-terminal fragment (PfWrnC) contains no significant domain. Biochemical characterization further revealed that purified recombinant PfWrnN shows ATPase and DNA helicase activity in 3' to 5' direction, but PfWrnC lacks the ATPase and helicase activities. Immunofluorescence study shows that PfWrn is expressed in all the stages of intraerythrocytic development of the P. falciparum 3D7 strain and localizes distinctly in the nucleus. This study can be used for further characterization of RecQ helicases that will aid in understanding the physiological significance of these helicases in the malaria parasite. PMID- 25824668 TI - Antibiotic utilization based on primary treatment of pediatric empyema. AB - BACKGROUND: Chemical fibrinolysis has been shown to be as effective as surgical debridement for the treatment of pediatric empyema. However, no studies effectively evaluate antibiotic treatment. We evaluated antibiotic utilization among different treatments of pediatric empyema. METHODS: This is a retrospective review of 169 empyema patients who underwent chemical and/or mechanical fibrinolysis at a dedicated children's hospital from 2005-2013. Data points included duration of therapy, cultures, presence of necrosis or abscess, and adverse drug reactions. Immunocompromised patients and those with additional foci of infection were excluded. RESULTS: Twenty-seven patients underwent video assisted thoracoscopic surgery (VATS), 123 had chemical fibrinolysis via tube thoracostomy with tissue plasminogen activator (tPA), and 19 had tPA followed by VATS. The mean (+/- standard deviation) duration of total antibiotic therapy was 25.7 +/- 6.5 d; following a 24 h afebrile period of 19.4 +/- 6.3 d. Patients who had tPA had a significantly shorter duration of parenteral antibiotic therapy when compared with primary VATS (9.2 +/- 3.6 d versus 11.6 +/- 5.5 d, P = 0.04) and VATS following tPA (9.2 +/- 3.6 d versus 14.3 +/- 8.1 d, P < 0.01). Patients with necrosis or abscess (n = 26) had an increased total duration of antibiotics (29.3 +/- 5.7 d versus 25.1 +/- 6.4 d, P < 0.01). Seventy patients (41%) had an adverse reaction related to antibiotic use. CONCLUSIONS: Patients with empyema currently receive a protracted variable course of antibiotic therapy influenced by primary treatment and the presence of necrosis or abscess. With a high incidence of adverse reactions, a standardized protocol with truncated treatment duration should be considered. PMID- 25824670 TI - Reactive oxygen species in psoriasis and psoriasis arthritis: relevance to human disease. AB - Psoriasis (Ps) is a chronic, immune-mediated, skin inflammatory disease affecting up to 3% of the population worldwide. Different environmental triggers initiate this complex multifactorial syndrome. Many individuals affected by Ps (6-26%) develop inflammatory disease in other organs, often in the joints as in psoriasis arthritis (PsA). Animal models that reflect the typical Ps syndrome, including both skin and joint pathology as in Ps and PsA, are valuable tools for dissecting disease pathways leading to clinical manifestations. In this context, we developed a new acute Ps and PsA-like disease model that appears after exposure to Saccharomyces cerevisiae mannan in certain mouse strains. The disease was found to be triggered by mannan-activated macrophages, leading to the activation of a pathogenic interleukin-17 pathway involving innate lymphocytes. Interestingly, the production of reactive oxygen species protected the mice from the triggering of this pathway and ameliorated Ps and PsA development. PMID- 25824669 TI - Staging studies have limited utility for newly diagnosed stage I-II breast cancer. AB - BACKGROUND: For stage I-II breast cancer, routine radiologic staging in the absence of symptoms suggesting distant metastasis is not recommended. This study aims to determine the yield of these studies at a National Comprehensive Cancer Network member institution. METHODS: Patients presenting with clinical stage I-II breast cancer between 1998 and 2012 were identified in a prospective database. Charts were reviewed to document staging studies (computed tomography, bone scan, and positron emission tomography) performed within 6 mo of diagnosis. Results and additional diagnostic procedures were recorded. Appropriate statistical tests were used for the analysis. RESULTS: A total of 3291 patients were included (2044 stage I and 1247 stage II). Eight hundred eighty-two patients (27%) received computed tomography, bone scan, or positron emission tomography within 6 mo of diagnosis. Three hundred twelve patients were stage I (15% of the stage I cohort) and 570 patients were stage II (46% of the stage II cohort). Patients receiving staging studies were more often younger and had estrogen receptor/progesterone receptor-negative or HER2/neu-positive tumors. Of the 882 patients, 194 (22%) required additional imaging and/or biopsies to further evaluate abnormalities. Only 11 of those (5%) were confirmed to have metastasis (1.2% of the imaged patients, 0.3% of the total cohort). Of these, 1 was stage I at presentation and 10 were stage II. CONCLUSIONS: Identification of distant metastasis among stage I II patients was rare. Even among patients judged appropriate for staging, only 1.2% were diagnosed with metastatic disease. These findings suggest that even at a National Comprehensive Cancer Network member institution staging studies are overused and lead to additional testing in over 20% of patients. PMID- 25824671 TI - Demystifying computer science for molecular ecologists. AB - In this age of data-driven science and high-throughput biology, computational thinking is becoming an increasingly important skill for tackling both new and long-standing biological questions. However, despite its obvious importance and conspicuous integration into many areas of biology, computer science is still viewed as an obscure field that has, thus far, permeated into only a few of the biology curricula across the nation. A national survey has shown that lack of computational literacy in environmental sciences is the norm rather than the exception [Valle & Berdanier (2012) Bulletin of the Ecological Society of America, 93, 373-389]. In this article, we seek to introduce a few important concepts in computer science with the aim of providing a context-specific introduction aimed at research biologists. Our goal was to help biologists understand some of the most important mainstream computational concepts to better appreciate bioinformatics methods and trade-offs that are not obvious to the uninitiated. PMID- 25824672 TI - Donation after cardiac death liver transplantation: Graft quality evaluation based on pretransplant liver biopsy. AB - Donation after cardiac death (DCD) liver grafts are associated with inferior clinical outcomes and high discard rates because of poor graft quality. We investigated the predictive value of DCD liver biopsy for the pretransplant graft quality evaluation. DCD liver transplants that took place between October 2010 and April 2014 were included (n = 127). Histological features of graft biopsy samples were analyzed to assess risk factors for graft survival. Macrovesicular steatosis >= 20% [hazard ratio (HR) = 2.973; P = 0.045] and sinusoidal neutrophilic infiltrate (HR = 6.969; P = 0.005) were confirmed as independent risk factors for graft survival; hepatocellular swelling, vacuolation, and necrosis failed to show prognostic value. Additionally, a donor serum total bilirubin level >= 34.2 MUmol/L was also associated with a lower probability of graft survival. Our analysis indicates that macrovesicular steatosis >= 20% and sinusoidal neutrophilic infiltrate are novel and useful histological markers for DCD liver grafts with unacceptable quality. This finding can be used by transplant surgeons to improve DCD liver acceptance protocols. PMID- 25824673 TI - Carbon and nitrogen stable isotopes of well-preserved Middle Pleistocene bone collagen from Schoningen (Germany) and their paleoecological implications. AB - Carbon and nitrogen stable isotopes in bone collagen can provide valuable information about the diet and habitat of mammal species. However, bone collagen degrades in normal circumstances very rapidly, and isotope analyses are therefore usually restricted to fossil material with a Late Pleistocene or Holocene age. The Middle Pleistocene site of Schoningen, dated to around 300,000 years ago, yielded bones and teeth with an exceptionally good state of collagen preservation. This allowed us to measure reliable biogenic carbon and nitrogen stable isotope ratios for different herbivorous taxa from the families Elephantidae, Rhinocerotidae, Equidae, Cervidae, and Bovidae. The results provide insights regarding the paleoenvironmental setting in which Middle Pleistocene hominins operated. The vegetation consumed by the herbivores from the famous spear horizon originates from open environments. During the climatic Reinsdorf Interglacial optimum, the landscape seems to have been relatively open as well, but certainly included parts that were forested. The results also indicate some niche partitioning; different herbivore species used different plant resources. For instance, the horses seem to have been predominantly browsers, while the straight-tusked elephants were feeding chiefly on grass. PMID- 25824678 TI - Therapy: Lenvatinib and radioiodine-refractory thyroid cancers. PMID- 25824679 TI - Diabetes: Dextromethorphan stimulates insulin secretion from pancreatic beta cells--a new role for an old drug? PMID- 25824676 TI - Hypothalamic innate immune reaction in obesity. AB - Findings from rodent and human studies show that the presence of inflammatory factors is positively correlated with obesity and the metabolic syndrome. Obesity associated inflammatory responses take place not only in the periphery but also in the brain. The hypothalamus contains a range of resident glial cells including microglia, macrophages and astrocytes, which are embedded in highly heterogenic groups of neurons that control metabolic homeostasis. This complex neural-glia network can receive information directly from blood-borne factors, positioning it as a metabolic sensor. Following hypercaloric challenge, mediobasal hypothalamic microglia and astrocytes enter a reactive state, which persists during diet induced obesity. In established mouse models of diet-induced obesity, the hypothalamic vasculature displays angiogenic alterations. Moreover, proopiomelanocortin neurons, which regulate food intake and energy expenditure, are impaired in the arcuate nucleus, where there is an increase in local inflammatory signals. The sum total of these events is a hypothalamic innate immune reactivity, which includes temporal and spatial changes to each cell population. Although the exact role of each participant of the neural-glial vascular network is still under exploration, therapeutic targets for treating obesity should probably be linked to individual cell types and their specific signalling pathways to address each dysfunction with cell-selective compounds. PMID- 25824681 TI - Dyslipidaemia: Active BAT reduces atherosclerosis. PMID- 25824680 TI - Diabetes: Microvascular complications in T1DM and coeliac disease. PMID- 25824682 TI - Structural basis for incision at deaminated adenines in DNA and RNA by endonuclease V. AB - Deamination of the exocyclic amines in adenine, guanine and cytosine forms base lesions that may lead to mutations if not removed by DNA repair proteins. Prokaryotic endonuclease V (EndoV/Nfi) has long been known to incise DNA 3' to a variety of base lesions, including deaminated adenine, guanine and cytosine. Biochemical and genetic data implicate that EndoV is involved in repair of these deaminated bases. In contrast to DNA glycosylases that remove a series of modified/damaged bases in DNA by direct excision of the nucleobase, EndoV cleaves the DNA sugar phosphate backbone at the second phosphodiester 3' to the lesion without removing the deaminated base. Structural investigation of this unusual incision by EndoV has unravelled an enzyme with separate base lesion and active site pockets. A novel wedge motif was identified as a DNA strand-separation feature important for damage detection. Human EndoV appears inactive on DNA, but has been shown to incise various RNA substrates containing inosine. Inosine is the deamination product of adenosine and is frequently found in RNA. The structural basis for discrimination between DNA and RNA by human EndoV remains elusive. PMID- 25824684 TI - A model system of the dynamic loading occurring in synovial joints: the biological effect of plowing on pristine cartilage. AB - Mechanical stress is listed as a main risk factor for cartilage degradation. The aim of this study was to investigate the biological response of cartilage to dynamic loading such as plowing. Cartilage strips harvested from bovine nasal septum were submitted to plowing using a cylindrical indenter, applying a constant normal force in the vertical axis and moving at constant speed in the horizontal axis. After plowing, cell viability, gene expression and glycosaminoglycan (GAG) release were measured with conventional assays. The cell viability assay and qRT-PCR showed that plowing induces cell death and matrix metalloproteinase 3 (MMP-3) upregulation. The addition of actinomycin D, before or after plowing, confirmed that plowing was responsible for the observed MMP-3 upregulation. Even if the transcriptions of the tissue inhibitor of metalloproteinase (TIMP-1), aggrecan (Agg), collagen type I (Coll1), collagen type II (Coll2) and fibronectin (Fn) were not significantly affected by plowing, actinomycin D treatment revealed that plowing induces a strong increase in TIMP-1 and Coll1 messenger RNA content and influences the gene regulation of Agg, Coll2 and Fn. Furthermore, plowed cartilage explants exhibited enhanced GAG release. Application of hydroxamate MMP inhibitor after loading showed that plowing induces GAG release via the activation of catabolic enzymes. Plowing causes cell death of the chondrocytes closer to the surface as well as matrix damage, observed as GAG loss. Moreover, in healthy chondrocytes, plowing promotes the production and activation of catabolic enzymes like MMP-3. PMID- 25824683 TI - Structural mechanisms of plexin signaling. AB - Signaling through plexin, the major cell surface receptor for semaphorin, plays critical roles in regulating processes such as neuronal axon guidance, angiogenesis and immune response. Plexin is normally kept inactive in the absence of semaphorin. Upon binding of semaphorin to the extracellular region, plexin is activated and transduces signal to the inside of the cell through its cytoplasmic region. The GTPase Activating Protein (GAP) domain in the plexin cytoplasmic region mediates the major intracellular signaling pathway. The substrate specificity and regulation mechanisms of the GAP domain have only been revealed recently. Many intracellular proteins serve as either upstream regulators or downstream transducers by directly interacting with plexin. The mechanisms of action for some of these proteins also start to emerge from recent studies. We review here these advances in the mechanistic understanding of plexin intracellular signaling from a structural perspective. PMID- 25824686 TI - meso-Dibenzoporphycene has a Large Bathochromic Shift and a Porphycene Framework with an Unusual cis Tautomeric Form. AB - meso-Monobenzoporphycene (mMBPc) and meso-dibenzoporphycene (mDBPc), in which one or two benzene moieties are fused at ethylene-bridged positions (meso-positions) of porphycene, were prepared in an effort to further delocalize the pi-electrons within the porphycene molecule. mMBPc and mDBPc were fully characterized by mass spectrometry, (1)H and (13)C NMR spectroscopy, and X-ray crystallography. The longest-wavelength Q-bands of mMBPc and mDBPc are red-shifted by 92 nm and 418 nm, respectively, compared to that of the unsubstituted porphycene (Pc). Electrochemical measurements indicate that the HOMO is destabilized and the LUMO is stabilized by the fused benzene moieties at the meso positions. Furthermore, both XPS and theoretical studies support the presence of a cis tautomeric form in the ground state of mDBPc, despite the fact that essentially all known porphycene derivatives adopt the trans tautomeric form. PMID- 25824685 TI - Very small embryonic-like stem cells are the elusive mouse endometrial stem cells -a pilot study. AB - BACKGROUND: Endometrium undergoes dramatic growth, breakdown and regeneration throughout reproductive period in mammals. Stem cells have been implicated in the process however their origin, nature, anatomical localization and characterization still remain obscure. Classical concept of presence of stem cells in the basal layer of endometrium was recently challenged when side population and label retaining cells were found to be distributed throughout endometrium. We have earlier reported very small embryonic-like stem cells (VSELs) in adult mammalian ovary and testis as a small population of cells with nuclear OCT-4 along with progenitors (spermatogonial stem cells and ovarian germ stem cells) with cytoplasmic OCT-4. Present study was undertaken to gauge presence of VSELs in bilaterally ovariectomized mouse uterus and their modulation by hormones. METHODS: Bilaterally ovariectomized mice were subjected to sequential estradiol and progesterone treatment in order to induce proliferation, differentiation and remodeling (regeneration). Stem cells were studied in tissue smears after H & E staining and after sorting using SCA-1 by immuno-localization and qRT-PCR studies (Oct-4A, Nanog and Sca-1). Flow cytometry studies were also undertaken to confirm the presence of VSELs in mouse uterus. RESULTS: Two distinct populations of stem cells with dark stained nucleus and high nucleo cytoplasmic ratio were detected in ovariectomized mouse uterus. These cells were sorted using SCA-1 and comprised smaller VSELs with nuclear expression of OCT-4 and slightly bigger, more abundant progenitors termed as endometrial stem cells (EnSCs) with cytoplasmic OCT-4. RT-PCR studies showed presence of pluripotent transcripts (Oct-4, Sca-1) and flow cytometry confirmed the presence of 0.069% of LIN-/CD45-/SCA-1+ VSELs. These stem cells were distinctly regulated during endometrial growth, differentiation and regeneration as evidenced by qRT-PCR results. CONCLUSIONS: VSELs are present in normal uterus and also under conditions of atrophy induced by bilateral ovariectomy. Marked increase in EnSCs is associated with endometrial growth and regeneration. Further studies are warranted to define the niche for these stem cells and whether EnSCs arising from the pluripotent VSELs are common progenitors for epithelial and stromal cells or not remains to be addressed. Results of the present study will help in better understanding of endometrial pathologies and their management in the future. PMID- 25824687 TI - Perivascular deletion of murine Rac reverses the ratio of marrow arterioles and sinusoid vessels and alters hematopoiesis in vivo. AB - Hematopoietic stem cells (HSCs) are localized within specialized microenvironments throughout the BM. Nestin-expressing (Nestin(+)) mesenchymal stromal cells (MSCs) are important in the perivascular space. Rac is critical for MSC cell shape in vitro, whereas its function in MSCs in vivo remains poorly characterized. We hypothesized that deletion of Rac in the Nestin(+) cells would perturb the perivascular space, altering HSC localization and hematopoiesis. Nestin-Cre-directed excision of Rac1 in Rac3(-/-) mice reduces Nestin(+) cells in the marrow. We observed a 2.7-fold decrease in homing of labeled wild-type hematopoietic cells into Rac1(Delta/Delta)Rac3(-/-) mice compared with control mice. Rac1(Delta/Delta)Rac3(-/-) mice demonstrated a marked decrease in arterioles and an increase in the number and volume of venous sinusoids in the marrow that was associated with a reduction in the numbers of immunophenotypically and functionally-defined long-term HSCs in the marrow, a decrease in colony-forming cells and a reduction in circulating progenitors. Rac deleted animals demonstrated a significant increase in trabecular bone. These data demonstrate that Rac GTPases play an important role in the integrity of perivascular space. Increased trabecular bone and sinusoidal space and decreased arteriolar volume in this model were associated with decreased HSC, underscoring the complexity of regulation of hematopoiesis in the perivascular space. PMID- 25824688 TI - How I treat and manage strokes in sickle cell disease. AB - Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ~11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is >4 gm/dL and <10 gm/dL. Standard therapy for secondary prevention of strokes and silent cerebral infarcts includes regular blood transfusion therapy and in selected cases, hematopoietic stem cell transplantation. A critical component of the medical care following an infarct is cognitive and physical rehabilitation. We will discuss our strategy of acute and long-term management of strokes in SCD. PMID- 25824689 TI - Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization. AB - Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities in these processes are associated with myeloproliferative disorders, including thrombocytopenia. Megakaryocyte maturation signals through cascades that involve p21-activated kinase (Pak) function; however, the specific role for Pak kinases in megakaryocyte biology remains elusive. Here, we identify Pak2 as an essential effector of megakaryocyte maturation, polyploidization, and proplatelet formation. Genetic deletion of Pak2 in murine bone marrow is associated with macrothrombocytopenia, altered megakaryocyte ultrastructure, increased bone marrow megakaryocyte precursors, and an elevation of mature CD41(+) megakaryocytes, as well as an increased number of polyploid cells. In Pak2(-/-) mice, platelet clearance rate was increased, as was production of newly synthesized, reticulated platelets. In vitro, Pak2(-/-) megakaryocytes demonstrate increased polyploidization associated with alterations in beta1-tubulin expression and organization, decreased proplatelet extensions, and reduced phosphorylation of the endomitosis regulators LIM domain kinase 1, cofilin, and Aurora A/B/C. Together, these data establish a novel role for Pak2 as an important regulator of megakaryopoiesis, polyploidization, and cytoskeletal dynamics in developing megakaryocytes. PMID- 25824690 TI - Molecular insights into regulation of JAK2 in myeloproliferative neoplasms. AB - The critical role of Janus kinase-2 (JAK2) in regulation of myelopoiesis was established 2 decades ago, but identification of mutations in the pseudokinase domain of JAK2 in myeloproliferative neoplasms (MPNs) and in other hematologic malignancies highlighted the role of JAK2 in human disease. These findings have revolutionized the diagnostics of MPNs and led to development of novel JAK2 therapeutics. However, the molecular mechanisms by which mutations in the pseudokinase domain lead to hyperactivation of JAK2 and clinical disease have been unclear. Here, we describe recent advances in the molecular characterization of the JAK2 pseudokinase domain and how pathogenic mutations lead to constitutive activation of JAK2. PMID- 25824693 TI - Robust Ag nanoplate ink for flexible electronics packaging. AB - Nanoinks are currently a topic of heightened interest with respect to low temperature bonding processes and printable electronics. We have developed an innovative polyvinylpyrrolidone (PVP)-stabilized Ag nanoplate ink amenable to very strong low temperature packaging, and investigated the relationship between bonding strength and electrical conductivity post-bonding. PVP shell plastic deformations observed in failure microcracks with the formation of PVP nanofibers, revealed bonding strength at low temperatures (<250 degrees C) was primarily due to adhesive bonding. It is found that, utilizing photonic sintering, ~ 70 degrees C reduction of transformation temperature from adhesive to metallic bonding was achieved compared to that of thermal sintering. A numerical simulation was developed to better understand the influences of the light-induced heat generation, which demonstrated near-infrared light can facilitate sintering. Bonding strengths of 27 MPa were achieved at room temperatures, and 29.4 MPa at 210 degrees C with photonic sintering. Moreover, the anisotropic resistivity was observed with different thermal dependences. These results demonstrate Ag nanoplate inks have potential for low temperature 3D interconnections in lead-free microcircuits, flexible electronic packaging, and diverse sensing applications. PMID- 25824695 TI - Hypoxia regulates the expression and localization of CCAAT/enhancer binding protein alpha by hypoxia inducible factor-1alpha in bladder transitional carcinoma cells. AB - Hypoxia inducible factor-1alpha (HIF-1alpha) is overexpressed in various types of solid tumor in humans, including bladder cancer. HIF-1alpha regulates the expression of a series of genes, which are involved in cell proliferation, differentiation, apoptosis, angiogenesis, migration and invasion and represents a potential therapeutic target for the treatment of human cancer. Despite extensive investigation of the effects of HIF-1alpha in the progression and metastasis of bladder cancer, the possible regulatory mechanisms underlying the effects of HIF 1alpha on bladder cancer cell proliferation and differentiation remain to be elucidated. It has been suggested that the transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) acts as a tumor suppressor in several types of cancer cell, which are involved in regulating cell differentiation, proliferation and apoptosis. The present study confirmed that, in bladder cancer cells, the expression and localization of C/EBPalpha was regulated by hypoxia through an HIF 1alpha -dependent mechanism, which may be significant in bladder cancer cell proliferation and differentiation. The 5637 and T24 bladder cancer cell lines were incubated under normoxic and hypoxic conditions. The expression levels of HIF-1alpha and C/EBPalpha were detected by reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence analysis. The results revealed that, under hypoxic conditions, the protein expression levels of HIF-1alpha were markedly upregulated, but the mRNA levels were not altered. However, the mRNA and protein levels of C/EBPalpha were significantly reduced. The present study further analyzed the subcellular localization of C/EBPalpha, which was markedly decreased in the nuclei under hypoxic conditions. Following HIF-1alpha small interference RNA silencing of HIF-1alpha, downregulation of C/EBPalpha was prevented in the bladder cancer cells cultured under hypoxic conditions. In addition, groups of cells treated with 3-(5'-hydroxymethyl-2' furyl)-1-benzylindazole, which inhibits the expression of HIF-1alpha in hypoxia, contributed to the inhibited expression of HIF-1alpha and enhanced expression of C/EBPalpha in hypoxic bladder cancer cells. These results suggested that C/EBPalpha was a downstream effector regulated by HIF-1alpha in hypoxic bladder cancer cells and that this regulatory pathway may represent a potential therapeutic target in the treatment of bladder cancer. PMID- 25824696 TI - Preparation of Ni@C-Cd(0.8)Zn(0.2)S nanocomposites with highly efficient and stable photocatalytic hydrogen production activity. AB - A series of carbon-coated Ni (Ni@C)-Cd0.8Zn0.2S nanocomposites were fabricated via a facile hydrothermal process using pre-prepared Ni@C as a starting material. The obtained products were characterized by X-ray diffraction, UV-Vis diffuse reflectance absorption spectroscopy, X-ray photoelectron spectroscopy and electron microscopy. It was found that the introduction of Ni@C nanoparticles can improve both the visible light-induced photocatalytic H2 production activity and stability of the Cd0.8Zn0.2S solid solution, and the Ni nanoparticles encapsulated by several graphite-like carbon layers show high chemical and thermal stability. Among those products with various Ni@C contents, the 5 wt% Ni@C-Cd0.8Zn0.2S nanocomposite exhibits the maximum photoactivity (969.5 MUmol h( 1)) for H2 production, which is ~3.10 times higher than that (312.6 MUmol h(-1)) of pristine Cd0.8Zn0.2S. This significant enhancement in the photoactivity by loading Ni@C nanoparticles can be attributed to the metallic Ni in the Ni@C acting as a co-catalyst, while the graphite-like carbon shells acting as the Cd0.8Zn0.2S nanoparticles' support and electron acceptor, which causes an effective photogenerated carrier separation in space and an improvement in the photoactivity and stability for H2 production. The present findings demonstrate a cost reduction strategy by using a non-noble metal co-catalyst for efficient and stable light-to-hydrogen energy conversion. PMID- 25824694 TI - Brain imaging in cooled encephalopathic neonates does not differ between four and 11 days after birth. AB - AIM: The optimal timing of magnetic resonance imaging (MRI) in encephalopathic infants treated with hypothermia is unknown, and this study examined whether early scans differed from later scans. METHODS: We assessed paired MRI scans carried out on 41 cooled encephalopathic infants at a median of four and 11 days using two scoring systems: the Rutherford injury scores for the basal ganglia and thalami (BGT), white matter and the posterior limb of the internal capsule, and the Bonifacio injury scores for the BGT and watershed area. RESULTS: Both systems produced consistent injury severity scores in 37 of 41 infants on both days, with Rutherford scores predicting poor outcome in six early scans and seven later scans (K = 0.91) and Bonifacio doing the same in seven and nine scans (K = 0.85). A white matter/watershed score of two or a BGT score of one indicated severe changes by day 11 in three infants, but lower scores did not. CONCLUSION: Magnetic resonance imaging scans indicated that the Rutherford and Bonifacio systems produced similar scores in 37 of 41 cooled encephalopathic infants at a median of four and 11 days. Infants with an early white matter/watershed scores of two or a BGT score of one may worsen and should be rescanned. PMID- 25824691 TI - Activated protein C: biased for translation. AB - The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC's activation of these G protein-coupled receptors differs completely from thrombin's activation mechanism due to biased signaling via either G proteins or beta-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies. PMID- 25824692 TI - Alternative donor hematopoietic cell transplantation for Fanconi anemia. AB - Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell-depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976. PMID- 25824697 TI - High-resolution determination of human immune cell signatures from fine-needle liver aspirates. PMID- 25824698 TI - An electric field induced reversible single-molecule fluorescence switch. AB - We report that by applying an electric field to a single squaraine-derived rotaxane (SR) molecule on bare glass, the fluorescence can be completely quenched. The molecule undergoes a reversible fluorescence switch between a zero field "on" state and a high-field "off" state, which is attributed to intramolecular electron transfer within the SR molecule. PMID- 25824700 TI - Arrays of templated TiO2 nanofibres as improved photoanodes for water splitting under visible light. AB - Arrays of TiO2 nanofibres (NFs) were successfully prepared by template sol-gel synthesis, using track-etched polycarbonate membranes as structure directing agent. The control of the sol-gel kinetic was crucial in order to homogeneously fill the pores with a continuous framework. For this reason acetylacetone was added to the sol-gel mixture as chelating agent. The band edge positions of TiO2 NFs were determined by a Mott-Schottky plot and diffuse reflectance analysis. The results support the presence of trace dopants which can act favorably with respect to the photoelectrochemical properties. The TiO2 NFs array showed enhanced photoelectrochemical activity both under UV light and visible light when used as photoanodes for the water splitting reaction. PMID- 25824699 TI - The five steps of comprehensive psychosocial distress screening. AB - Despite the growing recognition of the impact psychosocial distress has on the quality of life of patients with cancer, the implementation of the National Comprehensive Cancer Network (NCCN) Distress Management Guidelines and the mandate of evidence-based policy for routine distress screening continue to lag. To speed adoption of the guideline, the American Psychosocial Oncology Society (APOS) and Yale School of Nursing (YSN) launched the Screening for Psychosocial Distress Program in 2014. The program resulted in the development of five steps necessary to carry out routine psychosocial distress screening. The steps are consistent with the NCCN Distress Management Guidelines and the new criterion for accreditation by the American College of Surgeons (ACS) Commission on Cancer as of 2015. These five steps are as follows: (1) screening, (2) evaluating, (3) referring, (4) following up, and (5) documenting and quality improvement. The purpose of this article is to summarize the detailed procedure of the five steps for cancer care professionals-including oncologists, nurses, psychiatrists, psychologists, and social workers-so they can manage psychosocial distress efficiently in their own clinical environments. PMID- 25824702 TI - Recruiting and retaining plasmapheresis donors: A critical belief analysis. AB - This paper identifies critical beliefs underpinning intentions to commence and continue plasmapheresis donation. Whole blood (n = 624) and first-time plasmapheresis (n = 460) donors completed a cross-sectional survey assessing the belief-base of the theory of planned behaviour and rated their plasmapheresis donation intentions. While the idea of red blood cells being returned was a key deterrent for all donors, critical beliefs underlying commencement and continuation in the plasmapheresis donor panel differed and varied as a function of blood donation history. Findings will assist the development of targeted persuasion messages to optimise recruitment and retention of plasmapheresis donors in a non-remunerated context. PMID- 25824703 TI - Update on pathogen inactivation treatment of plasma, with the INTERCEPT Blood System: Current position on methodological, clinical and regulatory aspects. AB - After the INTERCEPT Blood System for pathogen inactivation (PI) of plasma was locally validated and approved and is now in routine use in Portugal, a conference was arranged in Portugal, by the IPST, in Coimbra, on 19th November 2014. One of the presentations informed about the current status of the INTERCEPT technology for plasma and a subsequent round table discussion, focused on the methodological and logistical aspects as well as on the experience from clinical studies and routine therapeutic use of INTERCEPT treated plasma units. Moreover, in view of current interests, both the global regulatory issues and hemovigilance data obtained were highlighted. This manuscript provides a brief summary of what has been discussed during presentations and the Q/A round table session. It was agreed between speaker and the moderator of the session to report a consensus opinion on the importance of INTERCEPT to improve the safety of plasma products in a standardized way in terms of quality indicators of hemostasis and the clinical effectiveness as well as the reliability of the technology for plasma pathogen inactivation, to be reported as part of a theme section from Portugal and to be published in Transfusion Apheresis Science in early 2015. The session started showing the beneficial advantages of the INTERCEPT technology, which has already become the standard of practice in Portugal and in more than 20 other countries, and then highlighted some of the methodological and global quality/clinical aspects, which are not usually discussed. We hope the topic discussed here would be of interest to readers of Transfusion Apheresis Science. PMID- 25824704 TI - Iron depletion in blood donors - Have extended erythrocyte and reticulocyte parameters diagnostic utility? AB - BACKGROUND: Blood donation is associated with iron depletion, but donor iron status is not usually investigated, as such tests are cumbersome and costly. It would therefore be desirable to have simple, fast and inexpensive tests that give information on a donor's risk of developing iron depletion. In a pilot study we investigated whether novel erythrocyte and reticulocyte parameters can serve this goal. METHODS: In regular blood donors extended red cell parameters were measured using the Abbott CELL-DYN Sapphire hematology analyzer and conventional biochemical tests of iron status. Donors were compared with a regionally matched group of non-donating controls. RESULTS: In the controls, the reference ranges of extended RBC parameters were well comparable to published data. Donors had significantly more microcytic RBC than controls (median 0.9 vs 0.6%), lower serum ferritin concentration (median 43 vs 91 mg/L) and higher soluble transferrin receptor/ferritin index (median 1.60 vs 1.27). Overall 18-28% of the donors were iron depleted. Moreover, 3.3% of donors had iron-restricted erythropoiesis. Microcytic RBC and reticulocyte mean cell hemoglobin content predicted iron depletion with 70% and 64% sensitivities and specificities of 72% and 78%, respectively. When combined these two parameters increased the sensitivity to 82%. CONCLUSIONS: Our results in Swedish blood donors confirm a high prevalence of iron depletion, despite iron supplementation used by about half of the donors. Microcytic RBC and MCHr appeared to be helpful in identifying iron-depleted donors, who might benefit from iron supplementation. We recommend larger prospective investigations in order to confirm and extend the findings of this pilot study. PMID- 25824705 TI - Donor notification: Streamlining the existing enigmatic process: An experience from a tertiary care hospital in central Delhi, India. PMID- 25824706 TI - Film bulk acoustic resonators integrated on arbitrary substrates using a polymer support layer. AB - The film bulk acoustic resonator (FBAR) is a widely-used MEMS device which can be used as a filter, or as a gravimetric sensor for biochemical or physical sensing. Current device architectures require the use of an acoustic mirror or a freestanding membrane and are fabricated as discrete components. A new architecture is demonstrated which permits fabrication and integration of FBARs on arbitrary substrates. Wave confinement is achieved by fabricating the resonator on a polyimide support layer. Results show when the polymer thickness is greater than a critical value, d, the FBARs have similar performance to devices using alternative architectures. For ZnO FBARs operating at 1.3-2.2 GHz, d is ~9 MUm, and the devices have a Q-factor of 470, comparable to 493 for the membrane architecture devices. The polymer support makes the resonators insensitive to the underlying substrate. Yields over 95% have been achieved on roughened silicon, copper and glass. PMID- 25824707 TI - Complementing reversed-phase selectivity with porous graphitized carbon to increase the metabolome coverage in an on-line two-dimensional LC-MS setup for metabolomics. AB - Efficient and robust separation methods are indispensable in modern LC-MS based metabolomics, where high-resolution mass spectrometers are challenged by isomeric and isobaric metabolites. The optimization of chromatographic separation hence remains an invaluable tool in the comprehensive analysis of the chemically diverse intracellular metabolome. While it is widely accepted that a single method with comprehensive metabolome coverage does not exist, the potential of combining different chromatographic selectivities in two-dimensional liquid chromatography is underestimated in the field. Here, we introduce a novel separation system combining reversed-phase and porous graphitized carbon liquid chromatography in a heart-cut on-line two-dimensional setup for mass spectrometry. The proposed experimental setup can be readily implemented using standard HPLC equipment with only one additional HPLC pump and a two-position six port valve. The method proved to be robust with excellent retention time stability (average 0.4%) even in the presence of biological matrix. Testing the presented approach on a test mixture of 82 relevant intracellular metabolites, the number of metabolites that are retained could be doubled as compared to reversed-phase liquid chromatography alone. The presented work further demonstrates how the distinct selectivity of porous graphitized carbon complements reversed-phase liquid chromatography and extends the metabolome coverage of conventional LC-MS based methods in metabolomics to biologically important, but analytically challenging compound groups such as sugar phosphates. Both metabolic profiling and metabolic fingerprinting benefit from this method's increased separation capabilities that enhance sample throughput and the biological information content of LC-MS data. An inter-platform comparison with GC- and LC-tandem MS analyses confirmed the validity of the presented two dimensional approach in the analysis of yeast cell extracts from P. pastoris. PMID- 25824708 TI - Letter regarding Li JS et al. entitled "ERCC polymorphisms and prognosis of patients with osteosarcoma". AB - With great interest, we read the article "ERCC polymorphisms and prognosis of patients with osteosarcoma" (by Li JS et al.), which has reached important conclusions about the relationship between ERCC polymorphisms and osteosarcoma prognosis. Through quantitative analysis, the meta-analysis showed that ERCC2 Lys751Gln (ORGG vs. AA = 0.40 (95%CI = 0.1-0.86), P heterogeneity = 0.502; I (2) = 0 %) and ERCC5 His46His (ORCC vs. TT = 0.37 (95%CI = 0.15-0.93), P heterogeneity = 0.569; I (2) = 0 %) polymorphisms might influence the prognosis of patients with osteosarcoma [1]. The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise. PMID- 25824709 TI - Dermatological manifestations resulting from 'sadhana': An acting out of delusion in a patient of schizophrenia. PMID- 25824711 TI - A new method to estimate catheter length for esophageal multichannel intraluminal impedance monitoring in children. AB - BACKGROUND: Multichannel intraluminal impedance combined with pH (MII-pH) is the gold standard test for diagnosing gastro-esophageal reflux disease (GERD). It provides an opportunity to study acid and non-acid GOR and temporal association between symptoms and reflux. Accurate catheter placement is essential to prevent erroneous recording of reflux events. The aims of our study were to assess the accuracy of our devised method in predicting the catheter length for MII-pH in children (Great Ormond Street Hospital (GOSH) Table) and to compare the results with Strobel and Monreau methods. METHODS: Retrospective review of all records of infants and children who underwent MII-pH studies between January to October 2014. Desired catheter position was calculated using Strobel, Monreau and GOSH formulas and compared to X ray position. KEY RESULTS: One hundred and forty-four children were included; mean age was 5.1 (+/-4.5) years, 73 males and 71 females. In the whole group, the correlation between desired catheter position and GOSH Table was 0.95, for Strobel was 0.84, and Monreau was 0.85. In the first group (age <3 years), the correlation was: GOSH Table 0.91, Strobel 0.56, and Monreau 0.6; in the second group (3-10 years): GOSH Table 0.78, Strobel 0.82, and Monreau 0.82; the third group (>10 years): GOSH 0.81, Strobel 0.43, and Monreau 0.43. CONCLUSIONS & INFERENCES: GOSH Table is an accurate method to estimate the insertion length of MII-pH catheters from nares to a point of approximately two vertebral bodies above the diaphragm in children. Although radiography is required to confirm final catheter position, using GOSH Table will reduce the need for repeated catheter manipulation after initial insertion and will reduce the use of a mathematically complicated formulae. PMID- 25824710 TI - Kif18a is specifically required for mitotic progression during germ line development. AB - Genome integrity in the developing germ line is strictly required for fecundity. In proliferating somatic cells and in germ cells, there are mitotic checkpoint mechanisms that ensure accurate chromosome segregation and euploidy. There is growing evidence of mitotic cell cycle components that are uniquely required in the germ line to ensure genome integrity. We previously showed that the primary phenotype of germ cell deficient 2 (gcd2) mutant mice is infertility due to germ cell depletion during embryogenesis. Here we show that the underlying mutation is a mis-sense mutation, R308K, in the motor domain of the kinesin-8 family member, KIF18A, a protein that is expressed in a variety of proliferative tissues and is a key regulator of chromosome alignment during mitosis. Despite the conservative nature of the mutation, we show that its functional consequences are equivalent to KIF18A deficiency in HeLa cells. We also show that somatic cells progress through mitosis, despite having chromosome alignment defects, while germ cells with similar chromosome alignment defects undergo mitotic arrest and apoptosis. Our data provide evidence for differential requirements for chromosome alignment in germ and somatic cells and show that Kif18a is one of a growing number of genes that are specifically required for cell cycle progression in proliferating germ cells. PMID- 25824713 TI - [E. Quarello et F. Jacquemard in reply to the article by M. Constant: Nuchal translucency: not so simple! Gynecol Obstet Fertil 2014;42:820-21]. PMID- 25824712 TI - Comparison of apical microleakage of dual-curing resin cements with fluid filtration and dye extraction techniques. AB - BACKGROUND: Endodontically treated teeth with excessive loss of tooth structure are frequently restored using fiber posts. In this in vitro study, the apical leakage of self- and dual-activated curing modes for dual-curing resins cementing a translucent fiber post was evaluated using computerized fluid filtration meter and dye extraction method. MATERIAL AND METHODS: One hundred and four extracted human maxillary incisors with single root and canal were used. Experimental samples embedded in a closed system were divided into 4 groups (n=20) according to 2 dual-curing luting systems, with 2 different curing modes (either with self- or light-activation): (1) Panavia F 2.0 with self-cure, (2) Panavia F 2.0 with light-activation, (3) Clearfill SA with self-cure, and (4) Clearfill SA with light activation. Twenty-four teeth served as negative and positive controls. Translucent fiber posts were luted in the roots except in the control groups. RESULTS: Statistical analysis indicated no significant difference in leakage among groups (p>0.05) with 4.12 * 10(-4) (Panavia self-cure), 4.55 * 10(-4) (Clearfill SA self-cure), 5.17 * 10(-4) (Panavia dual-cure), and 5.59 * 10(-4) (Clearfill SA dual-cure) in fluid-filtration method. Absorbance values for dye extraction method were 266 nanometer (nm) (Panavia self-cure), 268 nm (Clearfill SA self-cure), 270 nm (Panavia dual-cure), and 271 nm (Clearfill SA dual-cure), in which difference among the groups were not statistically significant (p>0.05). When comparing the leakage, assessment methods results showed no statistically significant difference between the tested evaluation techniques (p>0.05). CONCLUSIONS: Light- and self-activation curing modes of Panavia F 2.0 and Clearfill SA perform similar to each other in a closed system. PMID- 25824714 TI - [Oncogenetics in the management of ovarian cancer: State-of-the art]. PMID- 25824715 TI - [Maternal obesity and pregnancy outcome]. PMID- 25824716 TI - Long-term results of incus vibroplasty in patients with moderate-to-severe sensorineural hearing loss. AB - OBJECTIVES: The principal aim of this study was to assess the safety and effectiveness of the middle ear implant Vibrant Soundbridge (VSB) in patients with moderate-to-severe sensorineural hearing loss up to a mean (+/- standard deviation) duration of 11.1 +/- 2.1 years (min. = 8.2, max. = 13.9, n = 16) after the intervention. DESIGN: This was a retrospective, single-subject repeated measurements study over a long-term period. A total of 104 German-speaking adults (for 122 implants) were included in this study (54 male, 50 female). The mean age at implantation was 54.5 years (min. = 19.0, max. = 80.4). Audiological outcome and speech intelligibility were assessed in all VSB patients at different time points in non-overlapping groups. RESULTS: Bone conduction (BC) thresholds were preserved after the implantation and no indication was found of an increase over time of the small air-bone gaps introduced by the implantation. BC and air conduction thresholds worsened similarly in both implanted and non-implanted ears over time. The decrease in audiological benefit provided by the VSB was moderate and the Word Recognition Score in quiet conditions at 65 dB SPL was still largely improved with the VSB in the longest observed group. CONCLUSIONS: These results confirm that the VSB does not affect the integrity of the inner/middle ear and is still beneficial in long-term follow-up. PMID- 25824717 TI - The utility of mouse models to provide information regarding the pathomolecular mechanisms in human genetic skeletal diseases: The emerging role of endoplasmic reticulum stress (Review). AB - Genetic skeletal diseases (GSDs) are an extremely diverse and complex group of rare genetic diseases that primarily affect the development and homeostasis of the osseous skeleton. There are more than 450 unique and well-characterised phenotypes that range in severity from relatively mild to severe and lethal forms. Although individually rare, as a group of related genetic diseases, GSDs have an overall prevalence of at least 1 per 4,000 children. Qualitative defects in cartilage structural proteins result in a broad spectrum of both recessive and dominant GSDs. This review focused on a disease spectrum resulting from mutations in the non-collagenous glycoproteins, cartilage oligomeric matrix protein (COMP) and matrilin-3, which together cause a continuum of phenotypes that are amongst the most common autosomal dominant GSDs. Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) comprise a disease spectrum characterised by varying degrees of disproportionate short stature, joint pain and stiffness and early-onset osteoarthritis. Over the past decade, the generation and deep phenotyping of a range of genetic mouse models of the PSACH and MED disease spectrum has allowed the disease mechanisms to be characterised in detail. Moreover, the generation of novel phenocopies to model specific disease mechanisms has confirmed the importance of endoplasmic reticulum (ER) stress and reduced chondrocyte proliferation as key modulators of growth plate dysplasia and reduced bone growth. Finally, new insight into related musculoskeletal complications (such as myopathy and tendinopathy) has also been gained through the in-depth analysis of targeted mouse models of the PSACH-MED disease spectrum. PMID- 25824718 TI - Cadherin-11 involves in synovitis and increases the migratory and invasive capacity of fibroblast-like synoviocytes of osteoarthritis. AB - OBJECTIVE: To detect the expression of cadherin-11 and its correlation with synovitis in osteoarthritis (OA), to explore the mechanism of over expression of cadherin-11 and its role in migratory or invasive capacity of fibroblast-like synoviocytes (FLS). METHODS: Synovitis severity was recorded according to Krenn's scoring system in 25 osteoarthritis patients undergoing total knee arthroplasty. Cadherin-11 expression in OA synoviums and its correlation with synovitis score and systemic inflammation markers were explored. After induction with Interleukin 1 beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha),cadherin-11 expression on OA FLS was assessed by qPCR and western blot,the capacity of migration and invasion of OA FLS was tested by transwell assay, and matrix metalloproteinase-2 production was assessed with ELISA as cadherin-11 expression was up regulated after infection with cadherin-11 cDNA-containing lentivirus, also when cadherin-11 expression was knocked down after infection with cadherin 11 shRNA containing lentivirus. RESULTS: Cadherin-11 expression in OA synovium showed significant differences among different grades of synovitis. Cadherin-11 in the lining layer was positively correlated with hyperplasia of the lining layer, density of the resident cells, inflammatory infiltrate, total synovitis score and D-dimer. Cadherin-11 in the sublining layer was positively correlated with the density of the resident cells, inflammatory infiltrate, total synovitis score and erythrocyte sedimentation rate. IL-1beta or TNF-alpha could up-regulate cadherin-11 expression on OA FLS at transcriptional and protein level. Over expression of cadherin-11 increased migratory or invasive capacity of OA FLS, while cadherin-11 knock down reduced migratory or invasive capacity and MMP-2 production in OA FLS. CONCLUSION: The over expression of cadherin-11 in osteoarthritis is positively correlated with synovitis severity, and can be driven by proinflammatory cytokines on OA FLS; cadherin-11 increases migratory or invasive capacity and MMP-2 production of fibroblast-like synoviocytes of osteoarthritis. PMID- 25824721 TI - A Prospective Controlled Nonrandomized Trial of Robotic Versus Open Radical Prostatectomy: On Point but Still Missed? PMID- 25824720 TI - A Systematic Review of Immunotherapy in Urologic Cancer: Evolving Roles for Targeting of CTLA-4, PD-1/PD-L1, and HLA-G. AB - CONTEXT: Overexpression of immune checkpoint molecules affects tumor-specific T cell immunity in the cancer microenvironment, and can reshape tumor progression and metastasis. Antibodies targeting checkpoints could restore antitumor immunity by blocking the inhibitory receptor-ligand interaction. OBJECTIVE: To analyze data and current trends in immune checkpoint targeting therapy for urologic cancers. EVIDENCE ACQUISITION: Systematic literature search for clinical trials in the PubMed and Cochrane databases up to August 2014 according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Endpoints included oncologic results, tumor response rates, safety, and tolerability. EVIDENCE SYNTHESIS: Anti-CTLA-4 monotherapy has demonstrated biochemical responses in prostate cancer. One phase 3 trial assessing ipilimumab efficacy in castration-resistant disease was negative overall. Nevertheless, ipilimumab may significantly improve overall survival compared with placebo in subgroups of patients with favorable prognostic features. In renal cancer, phase 1 trials showed interesting stabilization or long-lasting objective response rates approaching 50% using anti-PD-1/PD-L1 drugs in heavily pretreated metastatic patients. In bladder cancer, one phase 2 trial indicated a good safety profile for ipilimumab as a neoadjuvant drug before radical cystectomy. Overall, immune related effects such as colitis and dermatitis were common and well tolerated. CONCLUSIONS: Our systematic review shows that antibodies blocking immune checkpoints offer interesting and long-lasting response rates in heavily pretreated patients with advanced urologic cancers. More promising results are currently provided by anti-CTLA-4 antibodies in prostate cancer and by PD-1/PD-L1 inhibitors in renal cancer. These should encourage new clinical trials of immune therapy combinations and immunotherapy monotherapy combined with conventional anticancer drugs. In bladder cancer, the use of targeted immunotherapy still remains underevaluated; however, preliminary results reported at recent conferences seem encouraging. PATIENT SUMMARY: Data from studies support the activity and safety of immune checkpoint inhibitors in urologic cancers, alone or in combination with conventional cancer therapies. Encouraging data in other oncologic fields could translate into interesting responses in urological cancers. PMID- 25824719 TI - Immune complexes regulate bone metabolism through FcRgamma signalling. AB - Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss. However, it has been poorly understood whether ICs regulate bone metabolism directly. Here we show that the level of osteoclastogenesis is determined by the strength of FcRgamma signalling, which is dependent on the relative expression of positive and negative FcgammaRs (FcgammaRI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, FcgammaRIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcRgamma. Fcgr2b(-/-) mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through FcgammaRIII. The IgG2 IC activates osteoclastogenesis by binding to FcgammaRI and FcgammaRIV, which is induced under inflammatory conditions. These results demonstrate a link between the adaptive immunity and bone, suggesting a regulatory role for ICs in bone resorption in general, and not only in inflammatory diseases. PMID- 25824722 TI - Microscopic observation of chemical modification in sections using scanning acoustic microscopy. AB - A scanning acoustic microscope (SAM) calculates the speed of sound (SOS) through tissues and plots the data on the screen to form images. Hard tissues result in greater SOS; based on these differences in tissue properties regarding SOS, SAM can provide data on tissue elasticity. The present study evaluated whether tissue modifications, such as formalin fixation, periodic acid-Schiff (PAS) reactions and protein degradation, changed the acoustic properties of the tissues and whether SAM could be a useful tool for following chemical changes in sections. The fixation process was observable by the increased SOS. During the PAS reaction, the glycosylation of tissues was characterized by an increased SOS. Mucous or glycogen distribution was visualized and was found to be statistically comparable among lesions and states. Protease digestion by pepsin led to a decreased SOS. Tissue sensitivity to proteases varied due to the stage, cause and duration of inflammation or ageing. Changes in acoustic properties were more sensitive than those in optical histology. SAM facilitates the visualisation of the time course or distribution of chemical modifications in tissue sections, thus aiding their comparison among tissues. SAM may be an effective tool for studying changes such as protein cross-linkage, tissue repair and ageing. PMID- 25824723 TI - Effect of orthodontic treatment with preadjusted edgewise appliances on the buccolingual inclination of mandibular canines: a CBCT study. AB - OBJECTIVES: To assess the effects of treatment with preadjusted edgewise appliances on the buccolingual inclination of mandibular canines and the intercanine distance. SETTING AND SAMPLE POPULATION: The Division of Orthodontics at the University of Minnesota. Thirty patients whose treatment included extraction of mandibular first premolars and 30 patients whose treatment did not include extractions. MATERIAL AND METHODS: The buccolingual inclination of mandibular canines and their linear distance were measured on cone beam computed tomograms before and after treatment in both patient groups. Differences between extraction and non-extraction groups and between pre- and post-treatment measurements were tested for statistical significance, and the correlation between the buccolingual inclination and the intercanine distance was computed. RESULTS: Post-treatment, the buccolingual inclination of mandibular canines was significantly greater in the non-extraction group than in the extraction group. In both groups, the canines became more lingually inclined with treatment (non extraction group: -2.1 degrees ; extraction group: -4.1 degrees ). The intercanine distance increased significantly in the extraction group (+1.2 mm) but not in the non-extraction group (-0.5 mm). While there was a significant positive correlation between the buccolingual inclination and the mandibular intercanine distance in both groups before treatment, after treatment this correlation was significant only in the non-extraction group. CONCLUSION: Orthodontic treatment with preadjusted edgewise appliances results in more lingually inclined mandibular canines together with an increased intercanine distance, especially in patients whose treatment involves the extraction of mandibular first premolars. PMID- 25824724 TI - Genomic diversification and virulence features in SPM-1-producing Pseudomonas aeruginosa 13 years later. PMID- 25824725 TI - Development and clinical evaluation of a highly accurate dengue NS1 rapid test: from the preparation of a soluble NS1 antigen to the construction of an RDT. AB - Early diagnosis of dengue virus (DENV) is important. There are numerous products on the market claiming to detect DENV NS1, but these are not always reliable. In this study, a highly sensitive and accurate rapid diagnostic test (RDT) was developed using anti-dengue NS1 monoclonal antibodies. A recombinant NS1 protein was produced with high antigenicity and purity. Monoclonal antibodies were raised against this purified NS1 antigen. The RDT was constructed using a capturing (4A6A10, Kd=7.512+/-0.419*10(-9)) and a conjugating antibody (3E12E6, Kd=7.032+/ 0.322*10(-9)). The diagnostic performance was evaluated with NS1-positive clinical samples collected from various dengue endemic countries and compared to SD BioLine Dengue NS1 Ag kit. The constructed RDT exhibited higher sensitivity (92.9%) with more obvious diagnostic performance than the commercial kit (83.3%). The specificity of constructed RDT was 100%. The constructed RDT could offer a reliable point-of-care testing tool for the early detection of dengue infections in remote areas and contribute to the control of dengue-related diseases. PMID- 25824726 TI - beta3-integrin inhibits lipopolysaccharide-induced autophagy in cardiomyocytes via the Akt signaling pathway. AB - OBJECTIVE: To investigate the role of beta 3 -integrin in lipopolysaccharide (LPS)-induced autophagy in cardiomyocytes and its underlying mechanism. METHODS: beta 3 -Integrin expression in cardiomyocytes was up- or downregulated by adenovirus transfection or cyclic arginine-glycine-aspartic acid (cRGD) peptide treatment before LPS stimulation. The expression of autophagy-associated proteins (LC3-II, Beclin-1 and Bcl-2) and the activation of Akt were determined using Western blotting. Autophagosomes and autophagic vacuoles were observed using monodansylcadaverine (MDC) dye and transmission electron microscopy, respectively. RESULTS: Downregulation of beta 3 -integrin with cRGD peptide resulted in enhanced LC3-II and Beclin-1 and decreased Bcl-2 expression. Low Beclin-1 levels were detected after LPS stimulation in adenovirus beta 3 integrin-transfected cardiomyocytes. There was no significant difference in LC3 II levels between control and adenovirus beta 3 -integrin-transfected cardiomyocytes. Enhanced accumulation of MDC dye and autophagosomes, which were inhibited by beta 3 -integrin overexpression, were detected after LPS treatment. The increased phosphorylation of Akt after LPS stimulation was inhibited by cRGD and enhanced by beta 3 -integrin overexpression. Furthermore, the Akt inhibitor triciribine inhibited the negative effect of beta 3 - integrin on autophagy, as shown by LC3-II and Beclin-1 upregulation. CONCLUSIONS: beta 3 -Integrin inhibits LPS-induced autophagy in cardiomyocytes. The inhibition of Akt signaling might be an important mechanism in this process. PMID- 25824727 TI - RET proto oncogene mutation detection and medullary thyroid carcinoma prevention. AB - Thyroid cancer is the most common endocrine neoplasia. The medullary thyroid carcinoma (MTC) is one of the most aggressive forms of thyroid malignancy,accounting for up to 10% of all types of this disease. The mode of inheritance of MTC is autosomal dominantly and gain of function mutations in the RET proto-oncogene are well known to contribute to its development. MTC occurs as hereditary (25%) and sporadic (75%) forms. Hereditary MTC has syndromic (multiple endocrine neoplasia type 2A, B; MEN2A, MEN2B) and non-syndromic (Familial MTC, FMTC) types. Over the last two decades, elucidation of the genetic basis of tumorigenesis has provided useful screening tools for affected families. Advances in genetic screening of the RET have enabled early detection of hereditary MTCs and prophylactic thyroidectomy for relatives who may not show any symptom sof the disease. In this review we emphasize the main RET mutations in syndromic and non syndromic forms of MTC, and focus on the importance of RET genetic screening for early diagnosis and management of MTC patients, based on American Thyroid Association guidelines and genotype-phenotype correlation. PMID- 25824728 TI - Coevolution between human's anticancer activities and functional foods from crop origin center in the world. AB - Cancer is the leading cause of death around the world. Anticancer activities from many functional food sources have been reported in years, but correlation between cancer prevalence and types of food with anticancer activities from crop origin center in the world as well as food source with human migration are unclear. Hunger from food shortage is the cause of early human evolution from Africa to Asia and later into Eurasia. The richest functional foods are found in crop origin centers, housing about 70% in the world populations. Crop origin centers have lower cancer incidence and mortality in the world, especially Central Asia, Middle East, Southwest China, India and Ethiopia. Asia and Africa with the richest anticancer crops is not only the most important evolution base of humans and origin center of anticancer functional crop, but also is the lowest mortality and incidence of cancers in the world. Cancer prevention of early human migrations was associated with functional foods from crop origin centers, especially Asia with four centers and one subcenter of crop origin, accounting for 58% of the world population. These results reveal that coevolution between human's anticancer activities associated with functional foods for crop origin centers, especially in Asia and Africa. PMID- 25824730 TI - Multifaceted usage of HPV related tests and products in the management of cervical cancer--a review. AB - HPV viruses are integral to the development of cervical cancer. The pathogenesis has been extensively studied. To date, numerous HPV tests and products have been developed and successfully utilized in diagnosis, treatment and prevention of cervical cancer. The HPV DNA test, when combined with other routine cervical cancer screening and diagnostic tests namely exfoliative cytology, visual inspection with acetic acid (VIA) and colposcopy has increased the detection rate of cervical cancer. HPV DNA products could also be measured in other body fluids like urine, lymph node tissue, and serum. HPV association could also be quantified by measuring other parameters like HPV mRNA, viral load, viral integration and methylation status. Vaccination against HPV has been found to decrease the incidence of cervical cancer. Further, therapeutic vaccines for cervical cancer against HPV continue to evolve. All these findings pertaining to HPV could possibly decrease the incidence of cervical cancer in the near future. This review aims to give an overview of the HPV tests and products in use and those under trial currently. PMID- 25824729 TI - Molecular mechanisms of apoptosis and roles in cancer development and treatment. AB - Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis. PMID- 25824731 TI - Advances in the management of unresectable or metastatic pancreatic neuroendocrine tumors: chemotherapy, targeted therapy, hormonal treatment, and future directions. AB - Pancreatic neuroendocrine tumors (pNETs) are rare and heterogenous tumors and surgery to remove the primary tumor is the mainstay of treatment for resectable disease. However, curative surgery is often not feasible, because half of patients with pNET have metastases at the time of diagnosis. Palliative dubulking surgery and liver-directed therapies are appropriate options for these patients. Streptozocin-based regimens are standard, although temozolamide-based treatments are rapidly gaining wide clinical application. Somatostatin analogs are mainly indicated in hormonally active tumors to ameliorate symptoms. In addition, anti tumoral activity has been proven in well-differentiated NETs. Recently, there has been tremendous progress in the molecular biology of pNETs; thereby, the efficacy of sunitinib and everolimus in the treatment of patients with metastatic pNETs has been proven by large placebo-controlled phase III trials. Currently, there are no definitively proven predictive biomarkers to evaluate response to medical therapies in patients with pNET. Therefore, further studies are needed to individualize and optimize their management. This article reviews systemic chemotherapy, targeted therapies, and anti-secretory treatments for the management of patients with unresectable or metastatic pNETs, summarized in the light of recent advances. PMID- 25824732 TI - Sequence to structure approach of estrogen receptor alpha and ligand interactions. AB - Estrogen receptors (ERs) are steroid receptors located in the cytoplasm and on the nuclear membrane. The sequence similarities of human ERalpha, mouse ERalpha, rat ERalpha, dog ERalpha, and cat ERalpha are above 90%, but structures of ERalpha may different among species. Estrogen can be agonist and antagonist depending on its target organs. This hormone play roles in several diseases including breast cancer. There are variety of the relative binding affinity (RBA) of ER and estrogen species in comparison to 17beta-estradiol (E2), which is a natural ligand of both ERalpha and ERbeta. The RBA of the estrogen species are as following: diethyl stilbestrol (DES)>hexestrol>dienestrol>17beta-estradiol (E2)>17-estradiol>moxestrol>estriol (E3)>4-OH estradiol>estrone-3-sulfate. Estrogen mimetic drugs, selective estrogen receptor modulators (SERMs), have been used as hormonal therapy for ER positive breast cancer and postmenopausal osteoporosis. In the postgenomic era, in silico models have become effective tools for modern drug discovery. These provide three dimensional structures of many transmembrane receptors and enzymes, which are important targets of de novo drug development. The estimated inhibition constants (Ki) from computational model have been used as a screening procedure before in vitro and in vivo studies. PMID- 25824733 TI - Autophagy in tumorigenesis and cancer treatment. AB - Autophagy is a self-digestion process, wrapping cytoplasmic proteins or organelles to form vesicles for degradation in lysosomes. The process plays an important role in the maintenance of intracellular homostasis. Here we overview articles on autophagy and cancer/tumors in Pubmed and found 327 articles. Autophagy exists in many tumors and is involved in cell malignant transformation and tumor cell growth. In early phases of tumorigenesis, autophagy clears the abnormally folded proteins and dysfunctional organelles such as mitochondria. Autophagy can also inhibit cell stress responses and prevent genetic damage. When a tumor develops, autophagy helps tumor cells survive nutritional deficiencies and hypoxic conditions. Studies of autophagy in the occurrence and progression of tumors should provide new therapeutic strategies for tumors. PMID- 25824734 TI - The spectrum of genetic mutations in breast cancer. AB - Breast cancer is the most common malignancy in women around the world. About one in 12 women in the West develop breast cancer at some point in life. It is estimated that 5%-10% of all breast cancer cases in women are linked to hereditary susceptibility due to mutations in autosomal dominant genes. The two key players associated with high breast cancer risk are mutations in BRCA 1 and BRCA 2. Another highly important mutation can occur in TP53 resulting in a triple negative breast cancer. However, the great majority of breast cancer cases are not related to a mutated gene of high penetrance, but to genes of low penetrance such as CHEK2, CDH1, NBS1, RAD50, BRIP1 and PALB2, which are frequently mutated in the general population. In this review, we discuss the entire spectrum of mutations which are associated with breast cancer. PMID- 25824735 TI - Cellular protrusions--lamellipodia, filopodia, invadopodia and podosomes--and their roles in progression of orofacial tumours: current understanding. AB - BACKGROUND: Protrusive structures formed by migrating and invading cells are termed lamellipodia, filopodia, invadopodia and podosomes. Lamellipodia and filopodia appear on the leading edges of migrating cells and function to command the direction of the migrating cells. Invadopodia and podosomes are special F actin-rich matrix-degrading structures that arise on the ventral surface of the cell membrane. Invadopodia are found in a variety of carcinomatous cells including squamous cell carcinoma of head and neck region whereas podosomes are found in normal highly motile cells of mesenchymal and myelomonocytic lineage. Invadopodia-associated protein markers consisted of 129 proteins belonging to different functional classes including WASP, NWASP, cortactin, Src kinase, Arp 2/3 complex, MT1-MMP and F-actin. To date, our current understanding on the role(s) of these regulators of actin dynamics in tumors of the orofacial region indicates that upregulation of these proteins promotes invasion and metastasis in oral squamous cell carcinoma, is associated with poor/worst prognostic outcome in laryngeal cancers, contributes to the persistent growth and metastasis characteristics of salivary gland adenoid cystic carcinoma, is a significant predictor of increased cancer risk in oral mucosal premalignant lesions and enhances local invasiveness in jawbone ameloblastomas. PMID- 25824736 TI - High-risk human papillomavirus genotypes in cervical lesions and vaccination challenges in China. AB - Cervical cancer, mostly progressing from cervical intraepithelial neoplasia, is a major cause of morbidity and mortality in Chinese women. This is largely due to high prevalence of high-risk human papillomaviruses (hr-HPVs) in the population. The prevalence of hr-HPV DNA in women and in cervical lesions women ranged from 9.9% to 17.% and from 50.5% to 70.9% in different regions of China, respectively. The most common genotypes somewhat differ between regions throughout the country and from those in many other countries. This may be a challenge to cervical cancer screening and prevention in China. Combined detection of particular HPV genotypes should be recommended in all geographical regions in China and greater attention must be paid to specific hr-HPV types during cervical cancer screening and follow-up of cervical lesions. Besides, vaccination for prevention of cervical cancer by particular HPV genotypes, has not been introduced to China so far. Updated knowledge on prevalent HPV genotypes should be provided to public health organizations to help with the development of more effective HPV vaccines, which can protect Chinese women against HPV types prevalent in local China and thus have a substantial impact on the cervical cancer burden. PMID- 25824737 TI - T-786C, G894T, and intron 4 VNTR (4a/b) polymorphisms of the endothelial nitric oxide synthase gene in bladder cancer cases. AB - The aim of the present study was to determine whether endothelial nitric oxide synthase (eNOS) gene polymorphisms play a role in development of bladder cancer in the Turkish population. The study was performed on 75 patients (64 men, 11 women) with bladder cancer and 143 healthy individuals (107 men, 36 women) with any kind of cancer history. Three eNOS gene polymorphisms (T-786C promoter region, G894T and intron 4 VNTR 4a/b) were determined with polymerase chain reaction and restriction fragment lenght polymorphism methods. In our study, GT and TT genotypes for eNOS G894T polymorphism were found to significantly vary among patients with bladder cancer and control group (OR: 0.185, CI: 0.078-0.439, p=0.0001 and OR: 0.324, CI: 0.106-0.990, p=0.026). Also, the frequency of the 894T allele was significantly higher in patients with bladder cancer (51%). No association was identified for eNOS T-786C and intron 4 VNTR 4a/b polymorphisms between patients with bladder cancer and control groups in our Turkish population. PMID- 25824738 TI - Evaluation of factors impacting cosmetic outcome of breast conservative surgery- a study in Iran. AB - BACKGROUND: Breast conservative surgery (BCS) followed by radiotherapy is the standard approach in management of stage I-II breast cancer. Several factors can affect cosmetic outcomes. The aim of this study was to evaluate the cosmetic results of BCS and influencing factors in the Iranian Breast Cancer Research Center. MATERIALS AND METHODS: Patients who had undergone BCS were included. Photographs were taken of both breasts of the patients in three aspects and were evaluated by three specialists. The cosmetic scores were calculated based on a standard questionnaire. The data were analyzed using univariate and multivariate regression for relationships between cosmetic scores and clinical data. RESULTS: A total number of 103 patients were included in the study. Mean age and BMI of the patients were 46.8+/-8.9 and 28.1+/-3.9, respectively. Breast cup sizes C and D accounted for 74.7% of the study group. The mean cosmetic score obtained from three referees was 5.72+2.06, consisting of 35.9% excellent-good, 35% moderate, and 29.1% unsatisfactory results. Patient BMI, volume of the resected tissue and breast cup size (D) showed significant correlation with the cosmetic score. On multivariate regression analysis, cosmetic score and BMI (p=0.022,) as well as breast cup size (p=0.040), remained significant. CONCLUSIONS: Immediate or delayed symmetrization of the breasts is suggested during breast conservative surgery, meanwhile performing oncoplastic techniques to improve the results significantly. Also it is suggested to discuss anticipation of less satisfactory results with patients having higher BMI and large breast cup size. PMID- 25824739 TI - Loss of expression of cyclin d2 by aberrant DNA methylation: a potential biomarker in vietnamese breast cancer patients. AB - DNA methylation of tumor suppressor gene promoters is the most frequent phenomenon leading to inactivation of function, consequently driving malignant cell transformation. Cyclin D2 is implicated in tumor suppression. In our study, we carried out the MSP assay to evaluation the methylation status at CpG islands in the cyclin D2 promoter in breast cancer cases from the Vietnamese population. The results showed that the frequency of methylation reached 62.1% (59 of 95 breast cancer tumors), but was low in non-cancer specimens at 10% (2 of 20 non cancer specimens). Additionally, with an RR (relative risk) and OR (odd ratios) of 6.21 and 14.8, DNA hypermethylation of cyclin D2 increased the possibility of malignant transformation. Our results confirmed the cyclin D2 hypermethylation could be used as the potential biomarker which could be applied in prognosis and early diagnosis of Vietnamese breast cancer patients. PMID- 25824740 TI - Analysis on early detection of lung cancer by PET/CT scan. AB - BACKGROUND: This systemic analysis was conducted to to evaluate the application value of positron emission tomography/computed tomography (PET/CT) in early diagnosis of lung cancer. METHODS: Clinical studies evaluating the application value of PET/CT for patients underwent PET/CT imaging. The histological diagnosis served as the standard of truth. RESULTS: Four clinical studies which including 1330 patients with pulmonary space- occupying lesions were considered eligible for inclusion. Systemic analysis suggested that, in all 1330 patients, pooled sensitivity was 98.7% (1313.2/1330) and specificity was 58.2%(276.85/476). CONCLUSION: This systemic analysis suggests that integrated PET/CT imaging provides high sensitivity, and reasonably high specificity, and could be applied for early diagnosis of lung cancer. PMID- 25824741 TI - Methylated alteration of SHP1 complements mutation of JAK2 tyrosine kinase in patients with myeloproliferative neoplasm. AB - SHP1 negatively regulates the Janus kinase 2/signal transducer and activator of transcription (JAK2/STAT) signaling pathway, which is constitutively activated in myeloproliferative neoplasms (MPNs) and leukemia. Promoter hypermethylation resulting in epigenetic inactivation of SHP1 has been reported in myelomas, leukemias and other cancers. However, whether SHP1 hypermethylation occurs in MPNs, especially in Chinese patients, has remained unclear. Here, we report that aberrant hypermethylation of SHP1 was observed in several leukemic cell lines and bone marrow mononuclear cells from MPN patients. About 51 of 118 (43.2%) MPN patients including 23 of 50 (46%) polycythaemia vera patients, 20 of 50 (40%) essential thrombocythaemia and 8 of 18 (44.4%) idiopathic myelofibrosis showed hypermethylation by methylation-specific polymerase chain reaction. However, SHP1 methylation was not measured in 20 healthy volunteers. Hypermethylation of SHP1 was found in MPN patients with both positive (34/81, 42%) and negative (17/37, 45.9%) JAK2V617F mutation. The levels of SHP1 mRNA were significantly lower in hypermethylated samples than unmethylated samples, suggesting SHP1 may be epigenetically inactivated in MPN patients. Furthermore, treatment with 5-aza-2' deoxycytidine (AZA) in K562 cells showing hypermethylation of SHP1 led to progressive demethylation of SHP1, with consequently increased reexpression of SHP1. Meanwhile, phosphorylated JAK2 and STAT3 were progressively reduced. Finally, AZA increased the expression of SHP1 in primary MPN cells with hypermethylation of SHP1. Therefore, our data suggest that epigenetic inactivation of SHP1 contributes to the constitutive activation of JAK2/STAT signaling. Restoration of SHP1 expression by AZA may contribute to clinical treatment for MPN patients. PMID- 25824742 TI - The Fok1 vitamin D receptor gene polymorphism and 25(OH) D serum levels and prostate cancer among Jordanian men. AB - BACKGROUND: Prostate cancer (PCa) is one of the most commonly diagnosed neoplasms and the second leading cause of cancer death in men in the Western world. Vitamin D (1,25dihydroxy vitamin D) is linked to many biological processes that influence oncogenesis but data on relations between its genetic variants and cancer risk have been inconsistent. The aim of this study was to determine associations between a vitamin D genetic polymorphism and 25-hydroxyvitamin D [25(OH)D] levels and prostate cancer. MATERIALS AND METHODS: Genomic DNA was extracted from 124 Jordanian prostate cancer patients and 100 healthy volunteers. Ethical approval was granted from the ethical committee at Hashemite University and written consent was given by all patients. PCR was used to amplify the vitamin D receptor Fok1 polymorphism fragment. 25(OH)D serum levels were measured by competitive immunoassay. RESULTS: All genotypes were in Hardy-Weinberg equilibrium. Genotype frequency for Fok1 genotypes FF, Ff and ff was 30.7%, 61.3% and 8.06%, for prostate cancer patients, while frequencies for the control group was 28.0%, 66.0% and 6.0%, respectively, with no significant differences. Vitamin D serum level was significantly lower in prostate cancer patients (mean 7.7 ng/ml) compared to the control group (21.8 ng/ml). No significant association was noted between 25(OH)D and VDR Fok1 gene polymorphism among Jordanians overall, but significant associations were evident among prostate cancer patients (FF, Ff and ff : 25(OH)D levels of 6.2, 8.2 and 9.9) and controls (19.0, 22.5 and 26.3, respectively). An inverse association was noted between 25(OH)D serum level less than 10 ng/ml and prostate cancer risk (OR 35.5 and 95% CI 14.3- 88.0). CONCLUSIONS: There is strong inverse association between 25(OH)D serum level less than 10 ng/ml level and prostate cancer risk. PMID- 25824743 TI - A pilot genome-wide association study of breast cancer susceptibility loci in Indonesia. AB - Genome-wide association studies (GWASs) of the entire genome provide a systematic approach for revealing novel genetic susceptibility loci for breast cancer. However, genetic association studies have hitherto been primarily conducted in women of European ancestry. Therefofre we here performed a pilot GWAS with a single nucleotide polymorphism (SNP) array 5.0 platform from Affymetrix(r) that contains 443,813 SNPs to search for new genetic risk factors in 89 breast cancer cases and 46 healthy women of Indonesian ancestry. The case-control association of the GWAS finding set was evaluated using PLINK. The strengths of allelic and genotypic associations were assessed using logistic regression analysis and reported as odds ratios (ORs) and P values; P values less than 1.00x10(-8) and 5.00x10(-5) were required for significant association and suggestive association, respectively. After analyzing 292,887 SNPs, we recognized 11 chromosome loci that possessed suggestive associations with breast cancer risk. Of these, however, there were only four chromosome loci with identified genes: chromosome 2p.12 with the CTNNA2 gene [Odds ratio (OR)=1.20, 95% confidence interval (CI)=1.13-1.33, P=1.08x10(-7)]; chromosome 18p11.2 with the SOGA2 gene (OR=1.32, 95%CI=1.17-1.44, P=6.88x10(-6)); chromosome 5q14.1 with the SSBP2 gene (OR=1.22, 95%CI=1.11-1.34, P=4.00x10(-5)); and chromosome 9q31.1 with the TEX10 gene (OR=1.24, 95%CI=1.12 1.35, P=4.68x10(-5)). This study identified 11 chromosome loci which exhibited suggestive associations with the risk of breast cancer among Indonesian women. PMID- 25824744 TI - Prognostic factors and the role of adjuvant chemotherapy in post-curative surgery for Dukes B and C colon cancers and survival outcomes: a Malaysian experience. AB - BACKGROUND: Adjuvant chemotherapy improves survival in Dukes C colon cancers post curative resection. However, the evidence for a role with Dukes B lesions remains unproven despite frequent use for disease characterized by poor prognostic features. In view of limited Asia-specific data, this study aimed to determine survival outcomes and identify prognostic factors in a tertiary teaching hospital in Malaysia. MATERIALS AND METHODS: A total of 116 subjects who underwent curative surgery with and without adjuvant chemotherapy for Duke B and C primary colon adenocarcinomas diagnosed from 2004-2009 were recruited and data were collected retrospectively. Five-year overall survival (OS) and disease free survival (DFS) were analysed using Kaplan-Meier survival analysis and log-rank (Mantel-Cox) test. Prognostic factors were determined using Cox proportional hazards regression with both univariate and multivariate analyses. RESULTS: The survival analysis demonstrated a 5-year OS of 74.0% for all patients, with 74.9% for Dukes C subjects receiving chemotherapy compared to 28.6% in those not receiving chemotherapy (p=0.001). For Dukes B disease, the 5-year survival rate was 82.6% compared to 75.0% for subjects receiving and not receiving chemotherapy, respectively (p=0.17). Independent prognostic factors identified included a CEA level more than 3.5 ng/ml (hazard ratio (HR)=4.78; p=0.008), serosal involvement (HR=3.75; p=0.028) and completion of chemotherapy (HR= 0.20; p=0.007). CONCLUSIONS: In a regional context, this study supports current evidence from the West that adjuvant chemotherapy improves survival in Dukes C colon cancers post curative surgery. However, although a clear benefit has yet to be proven for Dukes B disease, our results suggest survival improvement in selected cases. PMID- 25824745 TI - Prognostic significance of preoperative lymphocyte-monocyte ratio in patients with resectable esophageal squamous cell carcinoma. AB - BACKGROUND: The interaction between tumor cells and inflammatory cells has not been systematically investigated in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to evaluate whether preoperative the lymphocyte monocyte ratio (LMR), the neutrophil-lymphocyte ratio (NLR), and the platelet lymphocyte ratio (PLR) could predict the prognosis of ESCC patients undergoing esophagectomy. MATERIALS AND METHODS: Records from 218 patients with histologically diagnosed ESCC who underwent attempted curative surgery from January 2007 to December 2008 were retrospectively reviewed. Besides clinicopathological prognostic factors, we evaluated the prognostic value of the LMR, the NLR, and the PLR using Kaplan-Meier curves and Cox regression models. RESULTS: The median follow-up was 38.6 months (range 3-71 months). The cut-off values of 2.57 for the LMR, 2.60 for the NLR and 244 for the PLR were chosen as optimal to discriminate between survival and death by applying receiver operating curve (ROC) analysis. Kaplan-Meier survival analysis of patients with low preoperative LMR demonstrated a significant worse prognosis for DFS (p=0.004) and OS (p=0.002) than those with high preoperative LMR. The high NLR cohort had lower DFS (p=0.004) and OS (p=0.011). Marginally reduced DFS (p=0.068) and lower OS (p=0.039) were found in the high PLR cohort. On multivariate analysis, only preoperative LMR was an independent prognostic factor for both DFS (p=0.009, HR=1.639, 95% CI 1.129-2.381) and OS (p=0.004, HR=1.759, 95% CI 1.201-2.576) in ESCC patients. CONCLUSIONS: Preoperative LMR better predicts cancer survival compared with the cellular components of systemic inflammation in patients with ESCC undergoing esophagectomy. PMID- 25824747 TI - Return to work and its relation to financial distress among Iranian cancer survivors. AB - BACKGROUND: Return to work after treatment completion is important for both cancer survivors and society. Financial distress is one of the factors that may influence the return to work in cancer survivors. However, this relationship has not been well investigated. This study aimed to determine the rate of return to work and its relation to financial distress among Iranian cancer survivors. MATERIALS AND METHODS: This descriptive-correlational study was undertaken among 165 cancer survivors who completed their initial treatments and had no signs of active cancer. The Return to Work questionnaire and Financial Distress/Financial Well-Being Scale were used for data collection. Data were analyzed using SPSS statistical software. RESULTS: After initial treatments, 120 cancer survivors (72%) had returned to work, of which 50 patients (42%) had returned to full-time work and 70 (58%) reduced their work hours and returned to part-time work. Cancer survivors also reported high levels of financial distress. In addition, the financial distress was lower among patients who had returned completely to work, in comparison to patients who had quit working for cancer-related reasons (p=0.001) or returned to work as part-time workers (p=0.001). CONCLUSIONS: The findings showed that a high percent of Iranian cancer survivors had not returned to their jobs or considerably reduced working hours after treatment completion. Accordingly, due to high levels of financial distress experienced by participants and its relation to return to work, designing rehabilitation programs to facilitate cancer survivor return to work should be considered. PMID- 25824746 TI - Inhibition of c-FLIP by RNAi enhances sensitivity of the human osteogenic sarcoma cell line U2OS to TRAIL-induced apoptosis. AB - To study effects of cellular FLICE (FADD-like IL-1beta-converting enzyme) inhibitory protein (c-FLIP) inhibition by RNA interference (RNAi) on sensitivity of U2OS cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, plasmid pSUPER-c-FLIP-siRNA was constructed and then transfected into U2OS cells. A stable transfection cell clone U2OS/pSUPER-c-FLIP siRNA was screened from the c-FLIP-siRNA transfected cells. RT-PCR and Western blotting were applied to measure the expression of c-FLIP at the levels of mRNA and protein. The results indicated that the expression of c-FLIP was significantly suppressed by the c-FLIP-siRNA in the cloned U2OS/pSUPER-c-FLIP siRNA as compared with the control cells of U2OS/pSUPER. The cloned cell line of U2OS/pSUPER-c-FLIP-siRNA was further examined for TRAIL- induced cell death and apoptosis in the presence of a pan-antagonist of inhibitor of apoptosis proteins (IAPs) AT406, with or without 4 hrs pretreatment with rocaglamide, an inhibitor of c-FLIP biosynthesis, for 24 hrs. Cell death effects and apoptosis were measured by the methods of MTT assay with 3-(4,5-dimethylthiazol-2-yl)- 2,5 diphenyltetrazolium bromide and flow cytometry, respectively. The results indicated that TRAIL-induced cell death in U2OS/pSUPER-c-FLIP-siRNA was increased compared with control cells U2OS/pSUPER in the presence or absence of AT406. Flow cytometry indicated that TRAIL-induced cell death effects proceeded through cell apoptosis pathway. However, in the presence of rocaglamide, cell death or apoptotic effects of TRAIL were similar and profound in both cell lines, suggesting that the mechanism of action for both c-FLIP-siRNA and rocaglamide was identical. We conclude that the inhibition of c-FLIP by either c-FLIP-siRNA or rocaglamide can enhance the sensitivity of U2OS to TRAIL-induced apopotosis, suggesting that inhibition of c-FLIP is a good target for anti-cancer therapy. PMID- 25824748 TI - Association between the XRCC3 Thr241Met polymorphism and risk of colorectal cancer: a meta analysis of 5,193 cases and 6,645 controls. AB - BACKGROUND: Many studies have reported associations of the X-ray repair cross complementing group 3 (XRCC3) Thr241Met polymorphism with colorectal cancer (CRC) risk, but the results remained controversial. Hence, we performed the present meta-analysis with different inheritance models. MATERIALS AND METHODS: We searched the PubMed and Google scholar databases for studies relating to associations between XRCC3 Thr241Met polymorphism and risk of CRC. 16 studies with 5,193 cases and 6,645 controls were finally included into the meta-analysis. RESULTS: We found that the XRCC3 Thr241Met polymorphism was associated with increased CRC risk only under a dominant genetic model (CC+CT vs. TT: OR 0.575, 95%CI 0.498-1.665, p<0.001, Pheterogeneity=0.00, I2=83%). There was a significant association between XRCC3 Thr241Met polymorphism and CRC risk in Caucasian in the overall 8 studies under only in the heterozygote genetic model (CT vs. TT: OR=0.929, 95%CI=0.806-1.070, P=0.308, Pheterogeneity=0.002, I2=57%). Four studies evaluated the XRCC3 Thr241Met polymorphism and CRC risk in Asians. Two genetic models of the XRCC3 polymorphism were significantly correlated with increasing risk in Asians (dominant model: CC+CT vs. TT: OR= 0.609, 95%CI=411-0.902, P=0.013, Pheterogeneity=0.54, I2=0.00%; Allele model: C vs. T: OR=0.708, 95 %=CI 0.605-0.829, p=0.000, Pheterogeneity=0.000, I2=92%). The sensitivity analysis suggested stability of this meta-analysis and no publication bias was detected. CONCLUSIONS: In conclusion, this meta-analysis indicates that XRCC3 Thr241Met shows an increased CRC risk, particularly in Asians rather than Caucasians. PMID- 25824749 TI - Preferences and acceptance of colorectal cancer screening in Thailand. AB - Colorectal cancer (CRC) is now common in Thailand with an increase in incidence over time. Health authorities are planning to implement a nationwide CRC screening program using fecal immunochemical test (FIT) as a primary screening tool. This study aimed to estimate preferences and acceptance of FIT and colonoscopy, explore factors influencing the acceptance, and investigate reasons behind choosing and rejecting to screen before the program was implemented. Patients aged 50-69, visiting the primary care unit during the study period, were invited to join this study. Patients with a history of cancer or past CRC screening were excluded. Face-to-face interviews were conducted. Subjects were informed about CRC and the screening tests: FIT and colonoscopy. Then, they were asked for their opinions regarding the screening. The total number of subjects was 437 (86.7% response rate). Fifty-eight percent were females. The median age was 58 years. FIT was accepted by 74.1% of subjects compared to 55.6% for colonoscopy. The acceptance of colonoscopy was associated with perceived susceptibility to CRC and family history of cancer. No symptoms, unwilling to screen, healthy, too busy and anxious about diagnosis were reasons for refusing to screen. FIT was preferred for its simplicity and non-invasiveness compared with colonoscopy. Those rejecting FIT expressed a strong preference for colonoscopy. Subjects chose colonoscopy because of its accuracy; it was refused for the process and complications. If the screening program is implemented for the entire target population in Thailand, we estimate that 106,546 will have a positive FIT, between 8,618 and 12,749 identified with advanced adenoma and between 2,645 and 3,912 identified with CRC in the first round of the program. PMID- 25824750 TI - Overexpression of astrocyte elevated gene-1 (AEG-1) in cervical cancer and its correlation with angiogenesis. AB - OBJECTIVES: To explore the expression of astrocyte elevated gene-1 (AEG-1) in cervical cancer and analyze its correlation with microvascular density (MVD), nuclear factor kappaB (NF-kB p65) and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Immunohistochemical MaxVision method was adopted to detect the expression level of AEG-1, NF-kB p65 and VEGF in 45 samples of invading cervical cancer and 12 samples of cervicitis from The First Affiliated Hospital of Wenzhou Medical University. Tumor microvascular endothelial marker CD34 combined with Weidner was used to determine the MVD in cervical cancer tissue. The positive expression and staining conditions of AEG-1, NF-kB p65 and VEGF in cervical cancer tissues were observed under a light microscope. Correlations between expression of AEG-1 protein and those of NF-Kb p65 and VEGF, as well as MVD, were analyzed using Pearson correlation. RESULTS: The expression levels of AEG-1 were 0.186+/-0.043 in cervical cancer and 0.051+/-0.002 in chronic cervicitis (p<0.01). Moreover, expression of AEG-1 was related to vascular invasion and lymphatic metastasis of cervical cancer (p<0.01), but not with age of the patients, differentiation degree, tumour size, pathological type and parametrial infiltration (p>0.05). Pearson correlation analysis showed that the expression of AEG-1 was linked with NF-kB p65 (r=0.501, p=0.000), VEGF (r=0.718, p=0.000) as well as MVD in cervical cancer tissue (r=0.815, p=0.000). CONCLUSIONS: AEG-1 is highly expressed in cervical cancer and promotes angiogenesis, which might be related to the fact that AEG-1 activating the signal pathway of NF-kB could up-regulate the level of VEGF expression. PMID- 25824752 TI - Malignant tumors of the central nervous system in Kazakhstan: component analysis of incidence dynamics. AB - The paper presents the incidence rates of malignant tumors of the central nervous system assessed by the component analysis. The data on primary registered cases of malignant tumors of the central nervous system in the country were used as the material of the study for the period from 2004 to 2011. A general trend of increase in the number of patients with malignant tumors of the central nervous system in Kazakhstan was determined and the potential of their increase was evaluated, which can be due to changes in the morbidity risk and age specifics, as well as the increase in population. PMID- 25824751 TI - RASSF1A gene methylation is associated with nasopharyngeal carcinoma risk in Chinese. AB - In order to explore the association between RASSF1A methylation and nasopharyngeal carcinoma (NPC) risk of Chinese, we carried out a meta-analysis with searches of PubMed, Web of Science, ProQest and Medline databases. Ultimately, 14 articles were identified and analysised using R Software (R version 3.1.2) including meta packages. Overall, we found a significant relationship between RASSF1A methylation and NPC risk (OR 30.7; 95 % CI, 16.71~56.23; z=11.0591; p<0.0001) in a fixed effects model and (OR 32.1; 95% CI, 14.27~72.01; z=8.3984; p<0.0001) in a random effects model pooled. In tissue and NP brushings groups , similar results were found. Hence, our study identified a strong association between RASSF1A methylation and NPC and highlighted a promising potential for RASSF1A methylation in NPC risk prediction of Chinese. PMID- 25824754 TI - Roles of white blood cells and subtypes as inflammatory markers in skin cancer. AB - OBJECTIVE: Skin tumors are the most commonly seen cancer type worldwide. Regarding pathogenesis, it is thought that disruption of kinetics through T lymphocyte-mediated development of chronic inflammation may be involved. The present study was intended to identify role of inflammatory cells such as neutrophils, monocytes and lymphocytes in the determination of risk for skin cancer. MATERIALS AND METHODS: We retrospectively reviewed charts of 569 cases diagnosed as having primary skin tumors. Data regarding age, gender and histopathological subtype were recorded. Blood parameters studied on the day before surgery including WBCs, neutrophils, and lymphocyte counts, neutrophil:lymphocyte and neutrophil:monocyte ratios were also recorded. Two hundred and two healthy individuals presented for check-up in an outpatient clinic were selected as the control group. Parameters studied in cases with skin cancer were compared to those healthy individuals. FINDINGS: Of the cases with skin cancer, 401 were basal cell carcinoma (BCC) while 144 were squamous cell carcinoma (SCC) and 13 were malignant melanoma (MM). WBC, neutrophil and monocyte counts and the neutrophil:lymphocyte ratio were found to be lower in the patient group than in the healthy control group (p<0.001) while no significant difference was found in other parameters reviewed (p>0.05). No significant difference was found in WBC, neutrophil, neutrophil: monocyte ratio according to gender (p>0.05). Monocyte count was found to be 0.68+/-0.61 in men and 0.55+/-0.25 in women, indicating strong statistical significance (p<0.001). WBC, neutrophil and monocyte values were highest in control group while lowest in BCC. When BCC and SCC groups were compared to controls, significant differences found (p<0.001). There were no significant differences in lymphocyte counts among groups (p=0.976). Neutrophil:lymphocyte ratios were 3.24 in BCC, 3.59 in SCC, 3.44 in MM and 5.06 in control group (p<0.001). CONCLUSIONS: In our study, it was found that there were significant differences in complete blood count, neutrophil, monocyte and neutrophil:lymphocyte levels among groups. Neutrophil: lymphocyte ratio was found to be lowest in BCC among skin cancers. PMID- 25824755 TI - Curcumol induces apoptosis in SPC-A-1 human lung adenocarcinoma cells and displays anti-neoplastic effects in tumor bearing mice. AB - Curcumol is a sesquiterpene originally isolated from curcuma rhizomes, a component of herbal remedies commonly used in oriental medicine. Its beneficial pharmacological activities have attract significant interest recently. In this study, anti-cancer activity of curcumol was examined with both in vitro and in vivo models. It was found that curcumol exhibited time- and concentration dependent anti-proliferative effects in SPC-A-1 human lung adenocarcinoma cells with cell cycle arrest in the G0/G1 phase while apoptosis-induction was also confirmed with flow cytometry and morphological analyses. Interestingly, curcumol did not display growth inhibition in MRC-5 human embryonic lung fibroblasts, suggesting the anti-proliferative effects of curcumol were specific to cancer cells. Anti-neoplastic effects of curcumol were also confirmed in tumor bearing mice. Curcumol (60 mg/kg daily) significantly reduced tumor size without causing notable toxicity. In conclusion, curcumol appears a favorable anti-cancer candidate for further development. PMID- 25824753 TI - Feasibility of photodynamic diagnosis for challenging TUR- Bt cases including muscle invasive bladder cancer, BCG failure or 2nd-TUR. AB - BACKGROUND: Despite widely adopted standard methods for follow-up including cystoscopy plus cytology, recurrence rates of non muscle-invasive bladder cancer (NMIBC) have not improved over the past decades, still ranging from 60% through 70%. Hence, widely acceptable surveillance strategies with excellent sensitivity are needed. Early recurrence has led to the development of a novel cystoscopy technique utilizing photodynamic diagnosis (PDD). Although, no studies have evaluated the efficacy of PDD for patients of MIBC, BCG failure or 2nd transurethelial resection (TUR). MATERIALS AND METHODS: The present study was performed from October 2012 through May 2013. IRB approved 25 patients initially underwent a cystoscopy examination of white light and blue light followed by the resection of tumors identified. Resections were performed from bladder mucosa areas considered suspicious at PDD, along with PDD negative normal bladder mucosa area resected by random biopsy. Specimens were divided into two groups, PDD positive and negative. Primary endpoints were sensitivity and specificity. RESULTS: A total of 147 specimens extracted from 25 patients were included in the analysis. Some 45 out of 92 PDD-positive specimens were confirmed to have bladder cancer, and 51 out of PDD-negative 55 specimens were confirmed to be cancer negative. The sensitivity of PDD was 91.8% (45/49) and specificity was 52.0% (51/98). The sensitivity:specificity was 89.5% (17/19) : 47.6% (30/63) in 12 2nd TUR patients, 90.5% (19/21) : 61.1% (11/18) in seven MIBC patients, and 95.0% (19/20) : 48.5% (16/33) in eight failed BCG cases. CONCLUSIONS: PDD-TURBT has high sensitivity to diagnose BC even for 2nd-TUR, MIBC or BCG failure cases. PMID- 25824756 TI - Study on the correlation between extracellular matrix protein-1 and the growth, metastasis and angiogenesis of laryngeal carcinoma. AB - OBJECTIVE: To investigate the correlation between extracellular matrix protein-1 (ECM1) and the growth, metastasis and angiogenesis of laryngeal carcinoma. MATERIALS AND METHODS: Forty-five samples with laryngeal benign and malignant tumors confirmed by pathology in Laiwu City People's Hospital from March 2006 to March 2011 were collected, in which there were 29 cases with laryngeal carcinoma and 16 with benign tumors. The expression of ECM1 and factor VIII-related antigens in patients with laryngeal carcinoma and those with benign tumors was respectively detected using immunohistochemical method, and the correlation between ECM1 staining grade and microvessel density (MVD) was analyzed. RESULTS: In laryngeal carcinoma tissue, ECM1 was mainly expressed in cytoplasm, less in cytomembrane or intercellular substance. With abundant expression in the tissue of laryngeal benign tumors (benign mesenchymoma and hemangioma), ECM1 was primarily expressed in the connective tissue, which was different from the expression in laryngeal carcinoma tissue. The proportion of positive ECM1 staining (++) in patients with laryngeal carcinoma was dramatically higher than those with benign tumors (p<0.05), and that of strongly-positive ECM1 staining (+++) slightly higher. The results of Spearman nonparametric correlation analysis revealed that ECM1 staining grade in laryngeal carcinoma tissue had a significantly-positive correlation with MVD (r=0.866, p=0.000). CONCLUSIONS: ECM1 expression in laryngeal carcinoma is closely associated with tumor cell growth, metastasis and angiogenesis, which can be considered as an effective predictor in the occurrence and postoperative recurrence of laryngeal carcinoma. PMID- 25824757 TI - Cost-effectiveness analysis of cervical cancer screening strategies based on the Papanicolaou smear test in Korea. AB - BACKGROUND: Despite the increasing number of screening examinations performed for cervical cancer utilizing the Papanicolaou smear test (Pap test), few studies have examined whether this strategy is cost-effective in Korea. OBJECTIVE: This study was conducted to evaluate the cost-effectiveness of cervical cancer screening strategies incorporating the Pap test based on age at the start and end of screening as well as screening interval. MATERIALS AND METHODS: We designed four alternative screening strategies based on patient age when screening was started (20 or 30 years) and discontinued (lifetime, 79 years). Each strategy was assessed at screening intervals of 1, 2, 3, or 5 years. A Markov model was developed to determine the cost-effectiveness of the 16 possible cervical cancer screening strategies, and this was evaluated from a societal perspective. The main outcome measures were average lifetime cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: Compared with various strategies comprising younger starting age, discontinuation age, and longer screening intervals, strategies employing annual screening for cervical cancer starting at a target age of 30 years and above were the most cost effective, with an ICER of 21,012.98 dollars per QALY gained (with a Korean threshold of 30,000,000 KRW or US$27,272). CONCLUSIONS: We found that annual screening for cervical cancer beginning at a target age of 30 years and above is most cost-effective screening strategy. Considering the potential economic advantages, more intense screening policies for cervical cancer might be favorable among countries with high rates of cervical cancer and relatively low screening costs. PMID- 25824758 TI - GIS-based spatial statistical analysis of risk areas for liver flukes in Surin Province of Thailand. AB - It is urgently necessary to be aware of the distribution and risk areas of liver fluke, Opisthorchis viverrini, for proper allocation of prevention and control measures. This study aimed to investigate the human behavior, and environmental factors influencing the distribution in Surin Province of Thailand, and to build a model using stepwise multiple regression analysis with a geographic information system (GIS) on environment and climate data. The relationship between the human behavior, attitudes (<50%; X111), environmental factors like population density (148-169 pop/km2; X73), and land use as wetland (X64), were correlated with the liver fluke disease distribution at 0.000, 0.034, and 0.006 levels, respectively. Multiple regression analysis, by equations OV=-0.599+0.005(population density (148-169 pop/km2); X73)+0.040 (human attitude (<50%); X111)+0.022 (land used (wetland; X64), was used to predict the distribution of liver fluke. OV is the patients of liver fluke infection, R Square=0.878, and, Adjust R Square=0.849. By GIS analysis, we found Si Narong, Sangkha, Phanom Dong Rak, Mueang Surin, Non Narai, Samrong Thap, Chumphon Buri, and Rattanaburi to have the highest distributions in Surin province. In conclusion, the combination of GIS and statistical analysis can help simulate the spatial distribution and risk areas of liver fluke, and thus may be an important tool for future planning of prevention and control measures. PMID- 25824759 TI - Accuracy of visual inspection with acetic acid in detecting high-grade cervical intraepithelial neoplasia in pre- and post-menopausal Thai women with minor cervical cytological abnormalities. AB - PURPOSE: To determine the accuracy of visual inspection with acetic acid (VIA) in detecting high-grade cervical intraepithelial neoplasia (CIN) in pre- and post menopausal women with atypical squamous cells of undetermined significance (ASC US) and low grade squamous intraepithelial lesion (LSIL) Papanicolaou (Pap) smears. MATERIALS AND METHODS: Two hundred women (150 pre-menopausal and 50 post menopausal) with ASC- US and LSIL cytology who attended the colposcopy clinic, Thammasat University Hospital, between March 2013 and August 2014 were included. All women underwent VIA testing and colposcopy by gynecologic oncologists. Diagnostic values of VIA testing including sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting high grade CIN were determined using the histopathology obtained from colposcopic directed biopsy as a gold standard. RESULTS: VIA testing was positive in 54/150 (36%) pre-menopausal women and 5/50 (10%) post-menopausal women. Out of 54 pre menopausal women with positive VIA testing, 15 (27.8%) had high-grade CIN and 39 (72.2%) had either CIN 1 or insignificant pathology. Ten (10.4%), 43 (44.8%) and 43 (44.8%) out of the remaining 96 pre-menopausal women with negative VIA testing had high- grade CIN, CIN 1 and insignificant pathology, respectively. Out of 5 post-menopausal women with positive VIA testing, there were 4 (80%) women with high-grade CIN, and 1 (20%) women with insignificant pathology. Out of 45 VIA negative post-menopausal women, 42 (93.3%) women had CIN 1 and insignificant pathology, and 3 (6.7%) had high-grade CIN. Sensitivity, specificity, PPV and NPV of the VIA testing were 59.4%, 76.2%, 32.2% and 90.8%, respectively (60%, 68.8%, 27.8% and 89.6% in pre-menopausal women and 57.1%, 97.7%, 80% and 93.3% in post menopausal women). CONCLUSIONS: VIA testing may be used as a screening tool for detecting high-grade CIN in women with minor cervical cytological abnormalities in a low-resource setting in order to lower the rate of colposcopy referral. PMID- 25824760 TI - Peroxisome proliferator-activated receptor-gamma Pro12Ala polymorphism could be a risk factor for gastric cancer. AB - BACKGROUND: Due to the strong inhibitory effects of PPARgamma gene on the growth of cancer cells, the role of Pro12Ala polymorphism in PPARgamma gene has been extensively investigated in cancer recently. However, the results were inconsistent according to cancer type. The aim of this study was to comprehensively evaluate the PPARgamma Pro12Ala polymorphism and gastric cancer susceptibility. MATERIALS AND METHODS: Search strategies were conducted in Pubmed, Medline (Ovid), Chinese biomedical database (CBM), China national knowledge infrastructure (CNKI), VIP, and Wanfang database, covering all publications, with the last search up to November 01, 2014. The strength of association between PPARgamma Pro12Ala polymorphism and gastric cancer risk was assessed by OR with 95%CI. RESULTS: A total of 546 cases and 827 controls in 5 case-control studies were included in this meta-analysis. The results indicated that the variant G allele carriers (CG+GG) had a 2.31 times higher risk for gastric cancer when compared with the homozygote CC (odds ratio (OR)=2.31, 95% confidence interval (CI)=1.67- 3.21 for CG+GG vs. CC). In the subgroup analysis by ethnicity, significantly elevated risks were both found in Asians (OR=2.56, 95% CI=1.42-4.64) and Caucasians (OR=2.20, 95% CI=1.48-3.25). Similarly, in the subgroup analysis by H. pylori status, a significantly increased risk was identified in H. pylori (+) populations (OR=3.68, 95%CI=2.07-6.52), but not in H. pylori(-) populations (OR=1.17, 95%CI=0.58-2.39). CONCLUSIONS: This pooled analysis suggested that the PPARgamma Pro12Ala polymorphism could be an independent predictive risk factor for gastric cancer especially in H. pylori infected populations in Asians and Caucasians. Nevertheless, prospectively designed cohort studies are needed to further investigate gene-gene and gene environment interactions to confirm the combined effects of PPARgamma Pro12Ala polymorphisms and H. pylori infection on gastric cancer risk. PMID- 25824761 TI - Survivin gene functions and relationships between expression and prognosis in patients with nasopharyngeal carcinoma. AB - This study aimed to investigate the relationship between prognosis and protein and mRNA expression of an apoptotic inhibitor gene, survivin, in patients with nasopharyngeal carcinoma. Furthermore, functions of the survivin gene in the CNE2 nasopharyngeal carcinoma cell line were assessed. Immunohistochemistry and in situ hybridization were used in detecting the survivin protein and mRNA in 44 nasopharyngeal carcinoma specimens, and 30 chronic nasopharyngitis samples as controls. Survivin gene expression in CNE2 cell line was suppressed with an shRNA (short hairpin RNA). The positive ratios of expression for survivin protein and mRNA in nasopharyngeal carcinoma were 79.5% and 75.0% respectively, obviously higher than in the control group (p<0.01), and there is very good consistency between the two methods. The mean survival time of patients with higher survivin protein or mRNA expression was shorter than in patients with lower levelsv(p<0.01). Proliferation of the CNE2 cell line was distinctly inhibited by the shRNA . The results indicate that overexpression of the survivin gene plays an important role in onset and development of nasopharyngeal carcinoma, and it may be helpful for prognostic appraisal. PMID- 25824763 TI - Effects of metformin on cell kinetic parameters of MCF-7 breast cancer cells in vitro. AB - In this study, the antiproliferative effects of the metformin was evaluated on MCF-7 Cells (human breast adenocarcinoma cell line). For this purpose cell kinetic parameters including cell proliferation assay, mitotic index and labelling index analysis were used. 30 MUM, 65 MUM and 130 MUM Metformin doses were applied to cells for 24, 48 and 72 hours. The results showed that there was a significant decrease in cell proliferation, mitotic index and labelling index for all experimental groups (p<0.05) for all applications. PMID- 25824762 TI - Increased risk of childhood acute lymphoblastic leukemia (ALL) by prenatal and postnatal exposure to high voltage power lines: a case control study in Isfahan, Iran. AB - Childhood acute lymphoblastic leukemia (ALL) is one of the most common hematologic malignancies, accounting for one fourth of all childhood cancer cases. Exposure to environmental factors around the time of conception or pregnancy can increase the risk of ALL in the offspring.This study aimed to evaluted the role of prenatal and postnatal exposure to high voltage power lines on the incidence of childhood ALL.This cross-sectional case control study was carried out on 22 cases and 100 controls who were born and lived in low socioeconomic families in Isfahan and hospitalized for therapeutic purposes in different hospitals from 2013-2014.With regard to the underlying risk factors, familial history and parental factors were noted but in this age, socioeonomic and zonal matched case control study, prenatal and childhood exposure to high voltage power lines was considered as the most important environmental risk factors of ALL (p=0.006, OR=3.651, CI 95%, 1.692-7.878). As the population was of low socioeconomic background, use of mobiles, computers and microwave was negligible. Moreover prenatal and postnatal exposure to indoor electrically charged objects was not determined to be a significant environmental factor. Thus, pre and post natal exposure to high voltage power lines and living in pollutant regions as well as familial influence could be described as risk factors of ALL for the first time in a low socioeconomic status Iranian population. PMID- 25824764 TI - Comparative analysis of the efficacy and safety of oxaliplatin plus 5 fluorouracil/leucovorin (modified FOLFOX6) with advanced gastric cancer patients having a good or poor performance status. AB - BACKGROUND: Combination chemotherapy of 5 fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin, mainly FOLFOX regimens, has shown considerable antitumor activity and a tolerable toxicity profile in gastric cancer. The goal of this study was to retrospectively compare the efficacy and toxicity of modified FOLFOX 6 (mFOLFOX6) regimen in advanced gastric cancer (AGC) patients with good and poor performance status (PS). MATERIALS AND METHODS: AGC patients receiving the mFOLFOX6 regimen including oxaliplatin 85 mg/m2, bolus of 5-FU 400 mg/m2 and LV 400 mg/m2 on the first day, followed by 2400mg/m2 of 5- FU as a continious infusion over 46 hour for first-line treatment were eligible for the study. RESULTS: A total 58 patients with a median age of 59.5 (32-81) were included. The median follow up of the study was 9.2 months. Thirty patients (51.7%) with an ECOG PS 0-1 were assigned to the good PS arm, while 28 patients (48.3%) with ECOG PS 2 were in the poor PS arm. Overall response rates were 36.6 and 28.8%, respectively (p=0.91). Median PFS was 6.7 and 6.3 months in good PS and poor PS arms (p=0.50) and median OS was 9.6 and 10.4 months (p=0.55). As compared with good PS arm, poor PS arm was associated with more grade 3-4 neutropenia and anemia. Dose reduction and dose delays were also significantly higher. CONCLUSIONS: In this study, mFOLFOX6 was similarly effective in both arms. Although hematologic toxicity was significantly higher in patients with poor PS, it remained manageable. Our results suggest that this regimen may be an effective treatment option for AGC patients with poor PS. PMID- 25824765 TI - Value of contrast-enhanced ultrasonography in the differential diagnosis of enlarged lymph nodes: a meta-analysis of diagnostic accuracy studies. AB - OBJECTIVE: To evaluate the diagnostic accuracy of contrast-enhanced ultrasonography (CEUS) in differentiating between benign and malignant enlarged lymph nodes using meta-analysis. MATERIALS AND METHODS: Pubmed, Embase, SCI and Cochrane databases were searched for studies (up to September 1, 2014) reporting the diagnostic performance of CEUS in discriminating between benign and malignant lymph nodes. Inclusion criteria were: prospective study; histopathology as the reference standard; and sufficient data to construct 2?2 contingency tables. Methodological quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Patient clinical characteristics, sensitivity and specificity were extracted. The summary receiver operating characteristic curve was used to examine the accuracy of CEUS. A meta-analysis was performed to evaluate the clinical utility in identification of benign and malignant lymph nodes. Sensitivity analysis was performed after omitting outliers identified in a bivariate boxplot and publication bias was assessed with Egger testing. RESULTS: The pooled sensitivity, specificity and AUROC were 0.92 (95%CI, 0.85-0.96), 0.91 (95%CI, 0.82-0.95) and 0.97 (95%CI, 0.95-0.98), respectively. After omitting 3 outlier studies, heterogeneity decreased. Sensitivity analysis demonstrated no disproportionate influences of individual studies. Publication bias was not significant. CONCLUSIONS: CEUS is a promising diagnostic modality in differentiating between benign and malignant lymph nodes and can potentially reduce unnecessary fine-needle aspiration biopsies of benign nodes. PMID- 25824766 TI - Role of neoadjuvant chemotherapy in the management of advanced ovarian cancer. AB - OBJECTIVE: To analyze efficacy of neoadjuvant chemotherapy for advanced ovarian cancer. MATERIALS AND METHODS: A total of 107 patients with advanced ovarian cancer undergoing cytoreductive surgery were divided into a neoadjuvant chemotherapy group (n=61) and a primary debulking group (n=46) and retrospectively analyzed. Platinum-based adjuvant chemotherapy was applied to both groups after cytoreductive surgery ande overall and progression-free survival times were calculated. RESULTS: No significant difference was observed in duration of hospitalization (20.8+/-6.1 vs. 20.2+/-5.4 days, p>0.05). The operation time of neoadjuvant chemotherapy group was shorter than the initial surgery group (3.1+/-0.7 vs. 3.4+/-0.8 h, p<0.05). There were no significant differences in median overall survival time between neoadjuvant chemotherapy group and surgery group (42 vs. 55 months, p>0.05). Similarly, there was no difference in median progression-free survival between neoadjuvant chemotherapy group and surgery group (16 vs. 17 months, p>0.05). The surgical residual tumor size demonstrated no significant difference between initial surgery and neoadjuvant chemotherapy groups (p>0.05). Multivariate analysis showed that more than 3 cycles of regimen with neoadjuvant chemotherapy was associated with more resistance to chemotherapy compared with patients without receiving neoadjuvant chemotherapy (OR: 5.962, 95%CI: 1.184-30.030, p<0.05). CONCLUSIONS: Neoadjuvant chemotherapy can shorten the operation time. However, it does not improve survival rates of advanced ovarian cancer patients. PMID- 25824767 TI - Case-control study of diet and prostate cancer in a rural population of Faisalabad, Pakistan. AB - BACKGROUND: The effects of diet on epidemiology of prostate cancer are inconclusive. Therefore a hospital- based, case-control study was conducted in a rural population of Faisalabad, Pakistan, to examine the impact of dietary factors on risk of cancer development. MATERIALS AND METHODS: This study was based on 102 confirmed cases of prostate cancer and 204 normal controls. Logistic regression was used to estimate odds ratios and 95% confidence intervals for odds ratios to evaluate the relationship between prostate cancer and diet. RESULTS: Consumption of red meat and fat items significantly increased the prostate cancer risk having odds ratios and 95% confidence intervals of 3.41; 1.46-7.96 and 2.45; 1.17-5.15, respectively. On the other hand, more consumption of vegetables, fluid intake and fruit significantly decreased the prostate cancer risk (odd ratios and corresponding 95% confidence intervals of 0.21; 0.10-0.44, 0.10; 0.05- 0.19 and 0.09; 0.03- 0.23, respectively. CONCLUSIONS: The present study supports the hypothesis that frequent consumption of red meat and fat items may increase prostate cancer risk while more intake of fruit, vegetables and fluid intake may protect against prostate cancer in the relatively low risk group in rural Pakistan. PMID- 25824768 TI - Cancer incidence and mortality data in Aktobe, west Kazakhstan, 2000-2010. AB - The article provides an assessment of the dynamics of cancer incidence and mortality in the territory of Aktobe city for the period 2000-2010. The most common cancers were found in the lungs, stomach, esophagus and breast throughout the period, with slight increase in colon cancer and decrease in esophageal cancer being apparent. In an attempt to cast light on effects of environmental pollution, the authors also compared data on total emissions of chemicals into the air. While preliminary, the findings provide a basic picture of cancer burden in this industrialised city in Kazakhstan which should be followed up by more comprehensive monitoring. PMID- 25824769 TI - Expression of DDR1 and DVL1 in invasive ductal and lobular breast carcinoma does not correlate with histological type, grade and hormone receptor status. AB - BACKGROUND: Invasive ductal (IDC) and lobular (ILC) carcinomas are the common histological types of breast carcinoma which are difficult to distinguish when poorly differentiated. Discoidin domain receptor (DDR1) and Drosophila dishevelled protein (DVL1) were recently suggested to differentiate IDC from ILC. OBJECTIVES: To assess the expression of DDR1 and DVL1 and their association with histological type, grading and hormonal status of IDC and ILC. MATERIALS AND METHODS: This cross sectional study was conducted on IDC and ILC breast tumours. Tumours were immunohistochemically stained for (DDR1) and (DVL1) as well as estrogen receptor (ER), progesterone receptor (PR) and C-erbB2 receptor. Demographic data including age and ethnicity were obtained from patient records. RESULTS: A total of 51 cases (30 IDCs and 21 ILCs) were assessed. DDR1 and DVL1 expression was not significantly associated with histological type (p=0.57 and p=0.66 respectively). There was no association between DDR1 and DVL1 expression and tumour grade (p=0.32 and p=1.00 respectively), ER (p=0.62 and 0.50 respectively), PR (p=0.38 and p=0.63 respectively) and C-erbB2 expression (p=0.19 and p=0.33 respectively) in IDC. There was no association between DDR1 and DVL1 expression and tumour grade (p=0.52 and p=0.33 respectively), ER (p=0.06 and p=0.76 respectively), PR (p=0.61 and p=0.43 respectively) and C-erbB2 expression (p=0.58 and p=0.76 respectively) in ILC. CONCLUSIONS: This study revealed that DDR1 and DVL1 are present in both IDC and ILC regardless of the tumour differentiation. More studies are needed to assess the potential of these two proteins in distinguishing IDC from ILC in breast tumours. PMID- 25824770 TI - Continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for recurrent or refractory osteosarcoma patients in China: a retrospective study. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the feasibility and efficacy of response to continuous-infusion ifosfamide and doxorubicin combination as second-line chemotherapy for patients with recurrent or refractory osteosarcoma. MATERIALS AND METHODS: Eighteen recurrent or refractory osteosarcoma patients who were treated with continuous-infusion ifosfamide and doxorubicin combination between May 1999 and April 2011 were included in the analysis. Ifosfamide at 12 g/m2 was administered by intravenous continuous infusion over 3 days, and doxorubicin 60 mg/m2 was administered as an intravenous bolus injection on day 1. The combination therapy was repeated every 3 weeks. Treatment was continued until evidence of disease progression or unacceptable toxicity. RESULTS: The patients (ages 7-53 years) received a total of 42 cycles of chemotherapy (median: 2 courses; range: 2-5 courses). The overall response rate was 0% and the disease control rate was 22.3%, with four patients having stable disease. The median time to progression and overall survival time were 2 months (range: 2-5 months) and 9 months (range: 3-29 months), respectively. Major severe toxicities were leucopenia 7 (38.9%), nausea and vomiting 3 (16.7%) and alopecia 9 (50%). There were no treatment-related deaths. CONCLUSIONS: In our experience, continuous-infusion ifosfamide and doxorubicin combination therapy at this dosage and schedule was found to be well tolerated and moderate effective, which could be considered as salvage therapy for patients with recurrent or refractory osteosarcoma. Further assessment is necessary to confirm the safety and efficacy of this treatment. PMID- 25824771 TI - MiR-454 prompts cell proliferation of human colorectal cancer cells by repressing CYLD expression. AB - Previous studies have shown that miR-454 plays an important role in a variety of biological processes in various human cancer cells. However, the underlying mechanisms of this microRNA in colorectal cancer (CRC) cells remain largely unknown. In the present study, we investigated the miR-454 role in CRC cell proliferation. We found that miR-454 expression is markedly upregulated in CRC tissues and CRC cells compared with the matched tumor adjacent tissues and the FHC normal colonic cell line. Ectopic expression of miR-454 promoted the proliferation and anchorage-independent growth of CRC cells, whereas inhibition of miR-454 reduced this effect. Bioinformatics analysis further revealed cylindromatosis (CYLD), a putative tumor suppressor as a potential target of miR 454. Data from luciferase reporter assays showed that miR-454 directly binds to the 3'-untranslated region (3'-UTR) of CYLD mRNA and repressed expression at both transcriptional and translational levels. In functional assays, CYLD-silenced in miR-454-in-transfected SW480 cells have positive effect to promote cell proliferation, suggesting that direct CYLD downregulation is required for miR-454 induced CRC cell proliferation. In sum, our data provide compelling evidence that miR-454 functions as an onco-miRNA, playing a crucial role in the promoting cell proliferation in CRC, and its oncogenic effect is mediated chiefly through direct suppression of CYLD expression. PMID- 25824772 TI - Stressful life events and risk of colorectal cancer: a case-control study of Iran. AB - BACKGROUND: Very few analytical studies are available on any association between stressful life events (SLE) and colorectal cancer (CRC), at least in Iran. The aim of this case control study was to determine the association between stressful life events (SLE) and colorectal cancer. MATERIALS AND METHODS: This study was conducted in four hospital colonoscopy units in Tabriz city of Iran including 414 participants aged 40-75 years: 207 cases with CRC confirmed by pathology and colonoscopy findings and 207 controls free of neoplastic conditions were selected (from the same hospitals at the same period for the cases and after matching for age and sex). Stressful life events were assessed using a 43-item Holmes and Rahe Life Events Questionnaire. Multivariate logistic regression was used to estimate adjusted odds ratios for SLE and risk of CRC. RESULTS: The stressful life event mean score in the case group was 141.3, in contrast to 63.8 in the control group (p<0.011). After adjusting for confounders, death of dear ones increased the risk of CRC (OR: 2.49; 95%CI: 1.41-5.13). Other types of stressful life events (family and husband disputes, serious occupational problems, unemployment of >6 months, and Serious financial problems) were also associated with CRC, but without statistical significance. CONCLUSIONS: According to our findings, it seems that SLE may increase the risk of CRC. PMID- 25824773 TI - Utility of peripheral blood parameters in predicting breast cancer risk. AB - PURPOSE: We aimed to study the inflammatory parameters of complete blood count in breast cancer cases. MATERIALS AND METHODS: This retrospective study covered 178 breast cancer patients and 107 age and body mass index matched healthy women. Complete blood count parameters, neutrophil/lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR) and MPV/platelet were analyzed. RESULTS: The leukocyte, neutrophil and neutrophil/ lymphocyte ratio were higher in the patient group (p values 0.001, 0.0001 and 0.0001, respectively) while haemoglobin and hematocrit were higher in the control group (p=0.0001 for both). Logistic regression analysis showed that elevated neutrophils and platelet distribution width (PDW) (OR: 0.627, 95%CI: 0.508-0.774, p=0.001 and OR: 1.191 95%CI: 1.057-1.342 p=0.003) were independent variables for predicting breast cancer. The cut- off value for the neutrophil/lymphocyte ratio was 2.56. CONCLUSIONS: According to our study results, neutrophil levels as part of complete blood count may be used as an independent predictor of breast cancer risk. PMID- 25824774 TI - Adjuvant chemotherapy and prognostic factors in stage II colon cancer--Izmir Oncology Group Study. AB - BACKGROUND: Although adjuvant chemotherapy is a standard treatment in stage III colon cancer, its benefit is not as clear for stage II patients. In this retrospective analysis, we aimed to evaluate the survival of patients with low risk stage II colon cancer, the efficacy of adjuvant chemotherapy in high-risk stage II colon cancer patients, and prognostic factors in stage II disease. MATERIALS AND METHODS: One hundred and seventeen patients who were diagnosed with stage II colon cancer between January 2006 and December 2011 were included in the study. Patients were stratified into two groups as being low-risk and high-risk according to risk factors for stage II disease. Adjuvant 5-fluorouracil-based chemotherapy were administered to the patients with risk factors. RESULTS: Ninety four patients were treated with adjuvant chemotherapy due to high risk factors and 23 were monitored without treatment. Median follow-up time was 43 months. In terms of disease free survival and overall survival, adjuvant chemotherapy did not provide a statistically significant difference. Univariate analysis demonstrated that bowel obstruction was the major risk factor for shortened disease-free survival, while bowel perforation and perineural invasion were both negative prognostic factors for overall survival. CONCLUSIONS: The recommendation of adjuvant chemotherapy for stage II colon cancer is not clear. In our study, it was found that adjuvant chemotherapy did not contribute to survival in high-risk stage II patients. Due to the fact that prognosis of stage II patients is good, many more patients will be needed for statistically significant differences in survival. Adjuvant chemotherapy containing 5 fluorouracil is being used to high risk stage II patients although it is not a standard treatment approach. PMID- 25824775 TI - Continuous DC-CIK infusions restore CD8+ cellular immunity, physical activity and improve clinical efficacy in advanced cancer patients unresponsive to conventional treatments. AB - BACKGROUND: There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients. MATERIALS AND METHODS: A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits. RESULTS: An average of 5.7+/-2.94x10(9) induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic CD8+CD28+T lymphocytes were increased by 74% and suppressive CD8+CD28-T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of CD8+CD28- T cell proportion reflecting a 5% higher risk of progression (p<0.05). CONCLUSIONS: In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment. PMID- 25824776 TI - siRNA silencing EZH2 reverses cisplatin-resistance of human non-small cell lung and gastric cancer cells. AB - Clinical resistance to chemotherapeutic agents is one of the major hindrances in the treatment of human cancers. EHZ2 is involved in drug resistance and is overexpressed in drug-resistant cancer cell lines. In this study, we investigated the effects of EHZ2 on cisplatin -resistance in A549/DDP and AGS/DDP cells. EHZ2 mRNA and protein were found to be significantly overexpressed in A549/DDP and AGS/DDP cells, compared to parental cells. EHZ2 siRNA successfully silenced EHZ2 mRNA and protein expression. Proliferation was inhibited and drug resistance to cisplatin was improved. Flow cytometry showed that silencing of EHZ2 arrested A549/DDP and AGS/DDP cells in the G0/G1 phase, increasing apoptosis, rh-123 fluorescence intensity and caspase-3/8 activities. Silencing of EHZ2 also significantly reduced the mRNA and protein expression levels of cyclin D1 and MDR1,while up-regulating p15, p21, p27 and miR-218 in A549/DPP cells. Furthermore, silencing of EHZ2 also significantly increased the expression level of tumor suppressor factor miR-218. We also found down-regulating EHZ2 expression increased methylation in A549/DDP and AGS/DDP cells. This study demonstrates that drug resistance can be effectively reversed in human cisplatin-resistant lung and gastric cancer cells through delivery of siRNAs targeting EHZ2. PMID- 25824777 TI - Colorectal cancer treatment and survival: the experience of major public hospitals in south Australia over three decades. AB - BACKGROUND: Registry data from four major public hospitals indicate trends in clinical care and survival from colorectal cancer over three decades, from 1980 to 2010. MATERIALS AND METHODS: Kaplan-Meier product- limit estimates and Cox proportional hazards models were used to investigate disease-specific survival and multiple logistic regression analyses to explore first-round treatment trends. RESULTS: Five-year survivals increased from 48% for 1980-1986 to 63% for 2005-2010 diagnoses. Survival increases applied to each ACPS stage (Australian Clinico-Pathological Stage), and particularly stage C (an increase from 38% to 68%). Risk of death from colorectal cancer halved (hazards ratio: 0.50 (0.45, 0.56)) over the study period after adjusting for age, sex, stage, differentiation, primary sub-site, health administrative region, and measures of socioeconomic status and geographic remoteness. Decreases in stage were not observed. Survivals did not vary by sex or place of residence, suggesting reasonable equity in service access and outcomes. Of staged cases, 91% were treated surgically with lower surgical rates for older ages and more advanced stage. Proportions of surgical cases having adjuvant therapy during primary courses of treatment increased for all stages and were highest for stage C (an increase from 5% in 1980-1986 to 63% for 2005-2010). Radiotherapy was more common for rectal than colonic cases. Proportions of rectal cases receiving radiotherapy increased, particularly for stage C where the increase was from 8% in 1980-1986 to 60% in 2005-2010. The percentage of stage C colorectal cases less than 70 years of age having systemic therapy as part of their first treatment round increased from 3% in 1980-1986 to 81% by 1995-2010. Based on survey data on uptake of adjuvant therapy among those offered this care, it is likely that all these younger patients were offered systemic treatment. CONCLUSIONS: We conclude that pronounced increases in survivals from colorectal cancer have occurred at major public hospitals in South Australia due to increases in stage-specific survivals. Use of adjuvant therapies has increased and the patterns of change accord with clinical guideline recommendations. Reasons for sub-optimal use of radiotherapy for rectal cases warrant further investigation, including the potential for limited rural access to impede uptake of treatments at metropolitan based radiotherapy centres. PMID- 25824778 TI - Malignancy risk scoring of hydatidiform moles. AB - BACKGROUND: Several risk factors leading to malignant transformation of hydatidiform moles have been described previously. Many studies showed that prophylactic chemotherapy for high risk hydatidiform moles could significantly decrease the incidence of malignancy. Thus, it is essential to discover a breakthrough to determine patients with high risk malignancy so that prophylactic chemotherapy can be started as soon as possible. OBJECTIVES: Development of a scoring system of risk factors as a predictor of hydatidiform mole malignant transformation. MATERIALS AND METHODS: This research is a case control study with hydatidiform mole and choriocarcinoma patients as subjects. Multiple logistic regression was used to analyze the data. Odds ratios (OR), attributable at risk (AR : OR-1) and risk index (ARxbeta) were calculated for develoipment of a scoring system of malignancy risk. The optimal cut-off point was determined using receiver operating characteristic (ROC) curve. RESULTS: This study analyzed 34 choriocarcinoma cases and 68 benign hydatidiform mole cases. Four factors significantly increased the risk of malignancy, namely age>=35 years old (OR:4.41, 95%CI:1.07- 16.09, risk index 5); gestational age>=12 weeks (OR:11.7, 95%CI:1.8-72.4, risk index 26); uterine size greater than the gestational age (OR:10.2, 95%CI:2.8-36.6, risk index 21); and histopathological grade II-III (OR:3.4, 95%CI:1.1-10.6, risk index 3). The lowest and the highest scores for the risk factors were zero and 55, respectively. The best cut-off point to decide high risk malignancy patients was >=31. CONCLUSIONS: Malignant transformation of hydatidiform moles can be predicted using the risk scoring by analyzing the above four parameters. Score>=31 implies high risk patients so that prophylactic chemotherapy can be promptly administered for prevention. PMID- 25824779 TI - Osteopontin levels in patients with papillary thyroid cancer according to the presence of Hashimoto's thyroiditis. AB - BACKGROUND: Human papillary thyroid carcinoma (PTC) is often associated with Hashimoto's thyroiditis (HT); their coexistence improves PTC prognosis. Osteopontin, a secreted glycoprotein, plays a role in cell survival, immunity, and tumor progression, its expression being associated with a poor prognosis and metastasis in several malignancies. Osteopontin overexpression correlates with aggressive clinicopathological features in PTC. Lymph node metastases and large tumor size positively correlate with osteopontin positivity. This study aimed to: (1) confirm osteopontin overexpression in human PTC samples; (2) compare osteopontin expression levels in PTC cases with and without HT; and (3) identify correlations between tumor aggressiveness and osteopontin expression levels. MATERIALS AND METHODS: Plasma osteopontin was assessed in 45 patients with PTC, 22 patients with PTC and HT, and 24 healthy controls by enzyme-linked immunosorbent assay. Thyroid tissue osteopontin mRNA and protein levels were analyzed by reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: Plasma osteopontin levels were significantly higher in PTC patients than in healthy controls. Plasma osteopontin, tissue osteopontin mRNA, and tissue osteopontin protein levels were significantly lower in patients with PTC and HT than in those with PTC alone. In advanced disease stage cases, osteopontin mRNA and protein expression levels were lower in patients with PTC and HT than in those with PTC alone. However, the osteopontin expression level was not significantly associated with the TNM stage. CONCLUSIONS: Plasma osteopontin, tissue osteopontin mRNA, and tissue osteopontin protein levels were significantly lower in patients with PTC and HT than in those with PTC alone, suggesting that HT attenuates PTC aggressiveness through negative regulation of osteopontin expression. PMID- 25824781 TI - ZNF217 is overexpressed and enhances cell migration and invasion in colorectal carcinoma. AB - BACKGROUND: To investigate the expression and clinical significance of zinc finger protein 217 (ZNF217) in human colorectal carcinoma (CRC). MATERIALS AND METHODS: The expression of ZNF217 in 60 CRC tissues and matched tumor adjacent tissues, collected between January 2013 and June 2014, was assessed immunohistochemically. The relationship between the expression of ZNF217 and clinicopathlogical features was analyzed by Pearson chi-square test. In addition, siRNA was used to down-regulate the expression of ZNF217 in CRC cells. The effects of ZNF217 for cell migration and invasion were measured by wound healing assay and transwell assay, respectively. RESULTS: The expression level of ZNF217 was significantly higher in CRC tissues than in tumor adjacent tissues (p<0.05), positively correlating with tumor size, lymphatic metastasis and advanced TNM stage (p<0.05). Down-regulation of ZNF217 in CRC cells could significantly suppress cell migration and invasion. CONCLUSIONS: ZNF217 is overexpressed in colorectal carcinoma tissues and is associated with tumor malignant clinicopathological features. ZNF217 may promote CRC progression by inducing cell migration and invasion. PMID- 25824780 TI - XIAP associated factor 1 (XAF1) represses expression of X-linked inhibitor of apoptosis protein (XIAP) and regulates invasion, cell cycle, apoptosis, and cisplatin sensitivity of ovarian carcinoma cells. AB - BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) associated factor 1 (XAF1) exhibits aberrantly low or absent expression in various human malignancies, closely associated with anti-apoptosis and overgrowth of cancer cells. However, limited attention has been directed towards the contribution of XAF1 to invasion, apoptosis, and cisplatin (DDP)-resistance of epithelial ovarian cancer (EOC) cells. This study aimed to evaluate the potential effects of XAF1 on invasion, cell cycle, apoptosis, and cisplatin-resistance by overexpressing XAF1 in SKOV-3 and SKOV-3/DDP cells. METHODS AND RESULTS: The pEGFP-C1-XAF1 plasmid was transfected into SKOV-3 and SKOV-3/DDP cells, and the expression of XAF1 at both mRNA and protein levels was analyzed by reverse transcription-PCR and Western blotting. Overexpression of XAF1 suppressed XIAP expression in both SKOV 3 and SKOV-3/DDP cells. Transwell invasion assays demonstrated that XAF1 exerted a strong anti-invasive effect in XAF1-overexpressing cells. Moreover, flow cytometry analysis revealed that XAF1 overexpression arrested the cell cycle at G0/G1 phase, and cell apoptosis analysis showed that overexpression of XAF1 enhanced apoptosis of SKOV-3 and SKOV-3/DDP cells apparently by activating caspase-9 and caspase-3. Furthermore, MTT assay confirmed a dose-dependent inhibitory effect of cisplatin in the tested tumor cells, and overexpression of XAF1 increased the sensitivity of SKOV-3 and SKOV-3/DDP cells to cisplatin mediated anti- proliferative effects. CONCLUSIONS: In summary, our data indicated that overexpression of XAF1 could suppress XIAP expression, inhibit invasion, arrest cell cycle, promote apoptosis, and confer cisplatin-sensitivity in SKOV-3 and SKOV-3/DDP cells. Therefore, XAF1 may be further assessed as a potential target for the treatment of both cisplatin-resistant and non-resistant EOCs. PMID- 25824782 TI - Breast cancer characteristics and survival differences between Maori, Pacific and other New Zealand women included in the Quality Audit program of Breast Surgeons of Australia and New Zealand. AB - BACKGROUND: The Quality Audit (BQA) program of the Breast Surgeons of Australia and New Zealand (NZ) collects data on early female breast cancer and its treatment. BQA data covered approximately half all early breast cancers diagnosed in NZ during roll-out of the BQA program in 1998-2010. Coverage increased progressively to about 80% by 2008. This is the biggest NZ breast cancer database outside the NZ Cancer Registry and it includes cancer and clinical management data not collected by the Registry. We used these BQA data to compare socio demographic and cancer characteristics and survivals by ethnicity. MATERIALS AND METHODS: BQA data for 1998-2010 diagnoses were linked to NZ death records using the National Health Index (NHI) for linking. Live cases were followed up to December 31st 2010. Socio-demographic and invasive cancer characteristics and disease-specific survivals were compared by ethnicity. RESULTS: Five-year survivals were 87% for Maori, 84% for Pacific, 91% for other NZ cases and 90% overall. This compared with the 86% survival reported for all female breast cases covered by the NZ Cancer Registry which also included more advanced stages. Patterns of survival by clinical risk factors accorded with patterns expected from the scientific literature. Compared with Other cases, Maori and Pacific women were younger, came from more deprived areas, and had larger cancers with more ductal and fewer lobular histology types. Their cancers were also less likely to have a triple negative phenotype. More of the Pacific women had vascular invasion. Maori women were more likely to reside in areas more remote from regional cancer centres, whereas Pacific women generally lived closer to these centres than Other NZ cases. CONCLUSIONS: NZ BQA data indicate previously unreported differences in breast cancer biology by ethnicity. Maori and Pacific women had reduced breast cancer survival compared with Other NZ women, after adjusting for socio-demographic and cancer characteristics. The potential contributions to survival differences of variations in service access, timeliness and quality of care, need to be examined, along with effects of co- morbidity and biological factors. PMID- 25824783 TI - Dendrosomal curcumin inhibits metastatic potential of human SW480 colon cancer cells through Down-regulation of Claudin1, Zeb1 and Hef1-1 gene expression. AB - Colon cancer is one of the leading causes of cancer-associated death worldwide. The prognosis for advanced colorectal cancers remains dismal, mainly due to the propensity for metastatic progression. Accordingly, there is a need for effective anti-metastasis therapeutic agents. Since a great body of research has indicated anticancer effects for curcumin, we investigated the effects of dendrosomal curcumin (DNC) on cellular migration and adhesion of human SW480 cells and possible molecular mechanisms involved. Different methods were applied in this study including MTT, Scratch and adhesion assays as well as real-time PCR and transwell chamber assays. Based on the results obtained, DNC inhibits metastasis by decreasing Hef 1, Zeb 1 and Claudin 1 mRNA levels and can reduce SW480 cell proliferation with IC50values of 15.9, 11.6 and 7.64 MUM at 24, 48 and 72 h post treatment. Thus it might be considered as a safe formulation for therapeutic purpose in colorectal cancer cases. PMID- 25824784 TI - Gemcitabine plus nedaplatin as salvage therapy is a favorable option for patients with progressive metastatic urothelial carcinoma after two lines of chemotherapy. AB - This study was conducted to evaluate the effectiveness of a combination of gemcitabine and nedaplatin therapy among patients with metastatic urothelial carcinoma previously treated with two lines of chemotherapy. Between February 2009 and August 2013, 30 patients were treated with gemcitabine and paclitaxel as a second-line chemotherapy. All had received a first-line chemotherapy consisting of methotrexate, vinblastine, doxorubicin and cisplatin. Ten patients who had measurable histologically proven advanced or metastatic urothelial carcinoma of the urinary bladder and upper urinary tract received gemcitabine 1,000 mg/m2 on days 1, 8 and 15 and nedaplatin 70 mg/m2 on day 2 as a third-line chemotherapy. Tumors were assessed by imaging every two cycles. The median number of treatment cycles was 3.5. One patient had partial response and three had stable disease. The disease-control rate was 40%, the median overall survival was 8.8 months and the median progression-free survival was 5.0 months. The median overall survival times for the first-line and second-line therapies were 29.1 and 13.9 months, respectively. Among disease-controlled patients (n=4), median overall survival was 14.2 months. Myelosuppression was the most common toxicity. There were no therapy-related deaths. Gemcitabine and nedaplatin chemotherapy is a favorable third-line chemotherapeutic option for patients with metastatic urothelial carcinoma. Given the safety and benefit profile seen in this study, further prospective trials are warranted given the implications of our results with regard to strategic chemotherapy for patients with advanced or metastatic urothelial carcinoma. PMID- 25824785 TI - Loss of heterozygosity at the calcium regulation gene locus on chromosome 10q in human pancreatic cancer. AB - BACKGROUND: Loss of heterozygosity (LOH) on chromosomal regions is crucial in tumor progression and this study aimed to identify genome-wide LOH in pancreatic cancer. MATERIALS AND METHODS: Single-nucleotide polymorphism (SNP) profiling data GSE32682 of human pancreatic samples snap-frozen during surgery were downloaded from Gene Expression Omnibus database. Genotype console software was used to perform data processing. Candidate genes with LOH were screened based on the genotype calls, SNP loci of LOH and dbSNP database. Gene annotation was performed to identify the functions of candidate genes using NCBI (the National Center for Biotechnology Information) database, followed by Gene Ontology, INTERPRO, PFAM and SMART annotation and UCSC Genome Browser track to the unannotated genes using DAVID (the Database for Annotation, Visualization and Integration Discovery). RESULTS: The candidate genes with LOH identified in this study were MCU, MICU1 and OIT3 on chromosome 10. MCU was found to encode a calcium transporter and MICU1 could encode an essential regulator of mitochondrial Ca2+ uptake. OIT3 possibly correlated with calcium binding revealed by the annotation analyses and was regulated by a large number of transcription factors including STAT, SOX9, CREB, NF-kB, PPARG and p53. CONCLUSIONS: Global genomic analysis of SNPs identified MICU1, MCU and OIT3 with LOH on chromosome 10, implying involvement of these genes in progression of pancreatic cancer. PMID- 25824786 TI - Expression and prognostic role of MEKK3 and pERK in patients with renal clear cell carcinoma. AB - Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is an important serine/threonine protein kinase and a member of the MAPK family. MEKK3 can effectively activate the MEK/ERK signaling pathway and promote an autocrine growth loop critical for tumor genesis, cell proliferation, terminal differentiation, apoptosis and survival. To explore the relationship between MEKK3 and cell apoptosis, clinicopathology and prognosis, we characterize the expression of MEKK3, pERK and FoxP3 in the renal clear cell carcinoma (RCCC). Protein expression was detected by tissue microarray and immunochemistry in 46 cases of RCCC and 28 control cases. Expression levels of CD3+ ,CD3+CD4+,CD3+CD8+,CD4+CD25+, CD4+CD25+ FoxP3+ were assessed by flow cytometry and analyzed for their association with pathological factors, correlation and prognosis in RCCC. Expression of MEKK3, pERK and FoxP3 was significantly up regulated in RCCC as compared to control levels (p<0.01), associated with pathological grade (p<0.05)and clinical stage (p<0.05). CD4+CD25+ Foxp3+ Treg cells were also significantly increased in RCCC patients (p<0.05). Cox multivariate regression analysis showed that MEKK3, pERK expression and patholigical stage were independent prognostic factors in patients with RCCC (p<0.05). MEKK3 can be used as an important marker of early diagnosis and prognostic evaluation in RCCC. It may be associated with imbalance of anti-tumor immunity and overexpression of pERK. Expression of MEKK3 and pERK are significantly increased in RCCC, with protein expression and clinical stage acting as independent prognostic factors. PMID- 25824787 TI - Level of knowledge and behavior of family health personnel workers in Izmir about early diagnosis for breast and cervix cancer. AB - PURPOSE: The present study was carried out to measure knowledge level and behavior of family health personnel (FHP) in Izmir on early diagnosis of breast and cervical cancers. MATERIALS AND METHODS: The study population of this cross sectional study was not selected. A questionnaire was applied to all FHP to measure knowledge level and behavior about cancer. The participation rate was 88%. Breast examination, mammography analysis, Papanicolaou smear applications were determined as dependent variables, and knowledge level about breast and cervical cancer, age, professional time as FHP as independent variables. Data were evaluated using definitive statistics, chi-square and logistic regression tests in SPSS software package for Windows 15.0. RESULTS: A total of 970 family health personnel participated in the research. The age range was 20-45 years (82.4%). Mean age was 37.9+/-7.4. Response rate was 87.3%. Of the participants, 88.4% performed breast self-examination. Rate of performing mammography at least once was 24.1%. Rate of performing Pap-smear examination at least once was 61.0%. In logistic regression analyses, it was determined that people with knowledge on breast and cervical cancer were those performing breast self-examination, mammography and Pap-smear examinations (p<0.05. CONCLUSIONS: It is essential that the knowledge, behavior and manners of health providers on early diagnosis for cancer increases awareness in the general population and provides information on execution ofthe most effective methods for generating a healthy society. PMID- 25824788 TI - Association between alterations in the serum 25-hydroxyvitamin d status during follow-up and breast cancer patient prognosis. AB - BACKGROUND: Serum vitamin D status can affect the prognosis of breast cancer patients. Our aim was to determine the association between alterations in the 25 hydroxyvitamin D [25(OH)D] status during follow-up and the prognosis of breast cancer patients. Additionally, we evaluated the association between the 25(OH)D status at the time of diagnosis and the prognosis using a detailed age and stage categorization. MATERIALS AND METHODS: Four hundred and sixty-nine Korean breast cancer patients were included. We collected patient clinicopathological data, including their serum 25(OH)D concentration at diagnosis and at the annual follow up until 4 years after diagnosis. The patients were divided according to their 25(OH)D status at diagnosis into a deficient (<20 ng/ml) and a non-deficient (>=20 ng/ml) group. At follow-up, patients were categorized into the four following groups according to 25(OH)D status alterations: persistently deficient, improved, deteriorated and persistently non-deficient. RESULTS: At diagnosis, 118 patients were classified into the deficient group and 351 into the non-deficient group. After a median follow-up period of 85.8+/-31.0 months, the patients with advanced- stage disease or an older age in the non-deficient group showed a significantly better survival compared with the deficient group. Furthermore, at the 1-year follow-up of 25(OH)D status, the persistently non-deficient group and the improved group had better survival compared with the other two groups. CONCLUSIONS: Our results suggest that maintaining an optimal 25(OH)D status at diagnosis and during the 1-year follow-up period is important for improving breast cancer patient survival. PMID- 25824789 TI - Knowledge level of working and student nurses on cervical cancer and human papilloma virus vaccines. AB - PURPOSE: To determine knowledge levels of working and student nurses about cervical cancer and prophylactic cancer vaccines. MATERIALS AND METHODS: This study was performed on 259 nursing students in the Department of Nursing and 137 nurses working in Health Research and Practice Center, approved to participate in the study between April-June 2012. The study was performed universally without selecting a sample. A questionnaire that was prepared for evaluating participants' knowledge and attitudes about human papilloma virus (HPV) vaccine was distributed to the nurses and data obtained from the forms were transferred to SPSS 15.00 program and statistically analyzed. RESULTS: It was found that 54.8% of the student nurses were between 21-24 years old and 13.1% of working students were between 25-28 years old. When student nurses and working nurses were compared in terms of their knowledge about the causes of cervical cancer, their ideas about prevention from cervical cancer with HPV vaccine, their ideas about possible risks of HPV vaccine and conservation ratios of HPV vaccine, it was observed that there were no statistically significant differences (p>0.05). When student nurses and working nurses were compared in terms of the information source about HPV, ways of HPV contamination, awareness about people who are susceptible to HPV contamination and age of HPV vaccination, it was determined that there was a statistically significant difference (p<0.05). CONCLUSIONS: It was found that all nurses had some knowledge about cervical cancer and HPV vaccine, but this was not sufficient. Therefore; it is recommended to use verbal, written and visual communication tools intensively in order to have topics on cervical cancer, early diagnosis and prevention in bachelor and master programs for nurses, to inform society about cervical cancer and HPV vaccine for public health and to teach precautions for its prevention. PMID- 25824790 TI - Virtual non-contrast computer tomography (CT) with spectral CT as an alternative to conventional unenhanced CT in the assessment of gastric cancer. AB - OBJECTIVE: The purpose of this study was to evaluate computed tomography (CT) virtual non-contrast (VNC) spectral imaging for gastric carcinoma. MATERIALS AND METHODS: Fifty-two patients with histologically proven gastric carcinomas underwent gemstone spectral imaging (GSI) including non-contrast and contrast enhanced hepatic arterial, portal venous, and equilibrium phase acquisitions prior to surgery. VNC arterial phase (VNCa), VNC venous phase (VNCv), and VNC equilibrium phase (VNCe) images were obtained by subtracting iodine from iodine/water images. Images were analyzed with respect to image quality, gastric carcinoma-intragastric water contrast-to-noise ratio (CNR), gastric carcinoma perigastric fat CNR, serosal invasion, and enlarged lymph nodes around the lesions. RESULTS: Carcinoma-water CNR values were significantly higher in VNCa, VNCv, and VNCe images than in normal CT images (2.72, 2.60, 2.61, respectively, vs 2.35, p<=0.008). Carcinoma- perigastric fat CNR values were significantly lower in VNCa, VNCv, and VNCe images than in normal CT images (7.63, 7.49, 7.32, respectively, vs 8.48, p<0.001). There were no significant differences of carcinoma-water CNR and carcinoma-perigastric fat CNR among VNCa, VNCv, and VNCe images. There was no difference in the determination of invasion or enlarged lymph nodes between normal CT and VNCa images. CONCLUSIONS: VNC arterial phase images may be a surrogate for conventional non-contrast CT images in gastric carcinoma evaluation. PMID- 25824791 TI - Evaluation of biochemical recurrence-free survival after radical prostatectomy by cancer of the prostate risk assessment post-surgical (CAPRA-S) score. AB - BACKGROUND: The cancer of the prostate risk assessment (CAPRA) score has been defined to predict prostate cancer recurrence based on the pre-clinical data, then pathological data have also been incorporated. Thus, CAPRA post-surgical (CAPRA-S) score has been developed based on six criteria (prostate specific antigen (PSA) at diagnosis, pathological Gleason score, and information on surgical margin, seminal vesicle invasion, extracapsular extension and lymph node involvement) for the prediction of post-surgical recurrences. In the present study, biochemical recurrence (BCR)-free probabilities after open retropubic radical prostatectomy (RP) were evaluated by the CAPRA-S scoring system and its three-risk level model. MATERIALS AND METHODS: CAPRA-S scores (0-12) of our 240 radical prostatectomies performed between January 2000-May 2011 were calculated. Patients were distributed into CAPRA-S score groups and also into three-risk groups as low, intermediate and high. BCR-free probabilities were assessed and compared using Kaplan-Meier analysis and Cox proportional hazards regression. Ability of CAPRA-S in BCR detection was evaluated by concordance index (c-index). RESULTS: BCR was present in 41 of total 240 patients (17.1%) and the mean follow up time was 51.7+/-33.0 months. Mean BCR-free survival time was 98.3 months (95% CI: 92.3-104.2). Of the patients in low, intermediate and high risk groups, 5.4%, 22.0% and 58.8% had BCR, respectively and the difference among the three groups was significant (P=0.0001). C-indices of CAPRA-S score and three-risk groups for detecting BCR-free probabilities in 5-yr were 0.87 and 0.81, respectively. CONCLUSIONS: Both CAPRA-S score and its three-risk level model well predicted BCR after RP with high c-index levels in our center. Therefore, it is a clinically reliable post-operative risk stratifier and disease recurrence predictor for prostate cancer. PMID- 25824792 TI - Young women with breast cancer in the United States and South Korea: comparison of demographics, pathology and management. AB - BACKGROUND: Breast cancer diagnosed in young women may be more aggressive, with higher rates of local and distant recurrence compared to the disease in older women. Epidemiologic evidence suggests that Korean women have a lower incidence of breast cancer than women in the United States, but that they present at a younger age than their American counterparts. We sought to compare risk factors and management of young women with breast cancer in Boston, Massachusetts (US) with those in Seoul, South Korea (KR). MATERIALS AND METHODS: A retrospective review was performed of consecutive patients less than 35 years old with a diagnosis of breast cancer at academic cancer centers in the US and KR from 2000 2005. Patient data were obtained by chart review. Demographic, tumor and treatment characteristics were compared utilizing Pearson's chi- square or Wilcoxon rank-sum tests where appropriate. All differences were assessed as significant at the 0.05 level. RESULTS: 205 patients from the US and 309 from KR were analyzed. Patients in US were more likely to have hormone receptor positive breast cancer, while patients in KR had a higher rate of triple negative lesions. Patients in US had a higher mean body mass index and more often reported use of birth control pills, while those in the KR were less likely to have a sentinel node procedure performed or to receive post mastectomy radiation. CONCLUSIONS: Patients under 35 diagnosed with breast cancer in the US and KR differ with respect to demographics, tumor characteristics and management. Although rates of breast conservation and mastectomy were similar, US patients were more likely to receive post mastectomy radiation. The lower use of sentinel node biopsy is explained by the later adoption of the technique in KR. Further evaluation is necessary to evaluate recurrence rates and survival in the setting of differing disease subtypes in these patients. PMID- 25824793 TI - Temporal variations of dietary habits in a high-risk area for upper gastrointestinal cancers: a population-based study from northern Iran. AB - BACKGROUND: Nutrition transition is a global health problem, especially in developing countries. It is known as an important factor for development of different types of health conditions including cancers. OBJECTIVES: We aimed to assess the pattern of nutrition transition in a high-risk area for upper gastrointestinal cancers in Northern Iran during the last decade. MATERIALS AND METHODS: This cross-sectional study was conducted on households of Golestan province, Iran. Data on household food consumption between 2001 and 2010 were obtained from the Statistical Center of Iran. The proportions of households with medium/high consumption of main foods were calculated for each year. Joint point software was used for assessing trends. Annual percent changes (APCs) and 95%CIs were calculated. RESULTS: In total, 12,060 households were recruited. The APCs (95%CI) of the proportion of households medium/high consumption of cereals, vegetables, legumes, fish, dairy products and meats were -3.1 (-4.1 to -2.2), 2.9 (-3.8 to -2.1), -2.3 (-3.2 to -1.4), -2.8 (-3.3 to -2.4), -1.9 (-3.0 to -0.9) and 2.7 (1.2 to 4.3), respectively. CONCLUSIONS: We found significant increase in meat consumption among our population between 2001 and 2010. Our results also suggested significant decreasing trend in consumption of so-called healthy foods including, plant foods, fish, and dairy products. Regarding its correlation with health conditions including cancers, nutrition transition should be considered as a priority in health policy making in our region as well as other high-risk populations. It is recommended to conduct community level interventions to increase consumption of plant foods, fish, and dairy products. PMID- 25824794 TI - Comparison of infection between internal-external and external percutaneous transhepatic biliary drainage in treating patients with malignant obstructive jaundice. AB - PURPOSE: Percutaneous transhepatic biliary drainage (PTBD) is a form of palliative care for patients with malignant obstructive jaundice. We here compared the infection incidence between internal-external and external drainage for patients with malignant obstructive jaundice. METHODS: Patients with malignant obstructive jaundice without infection before surgery receiving internal-external or external drainage from January 2008 to July 2014 were recruited. According to percutaneous transhepatic cholangiography (PTC), if the guide wire could pass through the occlusion and enter the duodenum, we recommended internal-external drainage, and external drainage biliary drainage was set up if the occlusion was not crossed. All patients with infection after procedure received a cultivation of blood and a bile bacteriological test. RESULTS: Among 110 patients with malignant obstructive jaundice, 22 (52.4%) were diagnosed with infection after the procedure in the internal-external drainage group, whereas 19 (27.9%) patients were so affected in the external drainage group, the difference being significant (p<0.05). In 8 patients (36.3%) in the internal-external group infection was controlled, as compared to 12 (63.1%) in the external group (p<0.05). The mortality rate for patients with infection not controlled in internal-external group in one month was 42.8%, while this rate in external group was 28.6% (p<0.05). CONCLUSION: External drainage is a good choice, which could significantly reduce the chance of biliary infection caused by bacteria, and decrease the mortality rate at one month and improve the long term prognosis. PMID- 25824795 TI - Educational intervention on breast cancer early detection: effectiveness among target group women in the district of Gampaha, Sri Lanka. AB - PURPOSE: The present study concerns the effectiveness of an educational intervention for improving knowledge, attitudes and practices (KAP) of breast cancer early detection among target group women (TGW) in the district of Gampaha, Sri Lanka. MATERIALS AND METHODS: The study was a community-based intervention. Two medical officer of health areas in Gampaha district were selected using random sampling as intervention (IA) and control (CA). Public health midwives (PHMs) in the IA were exposed to the educational intervention first, conducted the same among the TGW through PHMs. KAP was assessed using an interviewer- administrated questionnaire among 260 TGW from each area selected using cluster sampling before and six months after the intervention. RESULTS: The overall median scores for KAP among TGW in IG increased significantly from pre intervention level of 54% (IQR: 46-59%), 50% (IQR: 41-59%), and 0% (IQR: 0-20%) to post intervention level of 77% (IQR: 72-82%), 68% (IQR: 59- 76 %) and 40% (IQR: 20-60%) respectively. In CG, overall median scores for KAP remained almost the same at pre intervention 54% (IQR:44-59%), 50% (IQR:36-59%) and 0% (IQR: 0 20%) and post intervention 54% (IQR:46-59%), 50% (IQR:36-64%) and 0% (IQR: 0-20%) respectively. CONCLUSIONS: The educational intervention was found to be effective. PMID- 25824796 TI - Effects of TESTIN gene expression on proliferation and migration of the 5-8F nasopharyngeal carcinoma cell line. AB - PURPOSE: To investigate effects of the TESTIN (TES) gene on proliferation and migration of highly metastatic nasopharyngeal carcinoma cell line 5-8F and the related mechanisms. MATERIALS AND METHODS: The target gene of human nasopharyngeal carcinoma cell line 5-8F was amplified by PCR and cloned into the empty plasmid pEGFP-N1 to construct a eukaryotic expression vector pEGFP-N1-TES. This was then transfected into 5-8F cells. MTT assays, flow cytometry and scratch wound tests were used to detect the proliferation and migration of transfected 5 8F cells. RESULTS: A cell model with stable and high expression of TES gene was successfully established. MTT assays showed that the OD value of 5-8F/TES cells was markedly lower than that of 5-8F/GFP cells and 5-8F cells (p<0.05). Flow cytometry showed that the apoptosis rate of 5-8F/TES cells was prominently increased compared with 5-8F/GFP cells and 5-8F cells (p<0.05). In vitro scratch wound assays showed that, the width of the wound area of 5-8F/TES cells narrowed slightly, while the width of the wound area of 5-8F/ GFP cells and 5-8F cells narrowed sharply, suggesting that the TES overexpression could inhibit the migration ability. CONCLUSIONS: TES gene expression remarkably inhibits the proliferation of human nasopharyngeal carcinoma cell line 5-8F and reduces its migration in vitro. Thus, it may be a potential tumor suppressor gene for nasopharyngeal carcinoma. PMID- 25824797 TI - Analysis of molecular pathways in pancreatic ductal adenocarcinomas with a bioinformatics approach. AB - Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death worldwide. Our study aimed to reveal molecular mechanisms. Microarray data of GSE15471 (including 39 matching pairs of pancreatic tumor tissues and patient matched normal tissues) was downloaded from Gene Expression Omnibus (GEO) database. We identified differentially expressed genes (DEGs) in PDAC tissues compared with normal tissues by limma package in R language. Then GO and KEGG pathway enrichment analyses were conducted with online DAVID. In addition, principal component analysis was performed and a protein-protein interaction network was constructed to study relationships between the DEGs through database STRING. A total of 532 DEGs were identified in the 38 PDAC tissues compared with 33 normal tissues. The results of principal component analysis of the top 20 DEGs could differentiate the PDAC tissues from normal tissues directly. In the PPI network, 8 of the 20 DEGs were all key genes of the collagen family. Additionally, FN1 (fibronectin 1) was also a hub node in the network. The genes of the collagen family as well as FN1 were significantly enriched in complement and coagulation cascades, ECM-receptor interaction and focal adhesion pathways. Our results suggest that genes of collagen family and FN1 may play an important role in PDAC progression. Meanwhile, these DEGs and enriched pathways, such as complement and coagulation cascades, ECM-receptor interaction and focal adhesion may be important molecular mechanisms involved in the development and progression of PDAC. PMID- 25824798 TI - Cobalt chloride induces necroptosis in human colon cancer HT-29 cells. AB - Necroptosis, also known as "programmed necrosis", has emerged as a critical factor in a variety of pathological and physiological processes and is considered a cell type-specific tightly regulated process with mechanisms that may vary rather greatly due to the change of cell line. Here we used HT-29, a human colon cancer cell line, to establish a necroptosis model and elucidate associated mechanisms. We discovered that cobalt chloride, a reagent that could induce hypoxia-inducible factor-1alpha(HIF1alpha) expression and therefore mimic the hypoxic microenvironment of tumor tissue in some aspects induces necroptosis in HT-29 cells when caspase activity is compromised. On the other hand, apoptosis appears to be the predominant death form when caspases are functioning normally. HT-29 cells demonstrated significantly increased RIPK1, RIPK3 and MLKL expression in response to cobalt chloride plus z-VAD treatment, which was accompanied by drastically increased IL1alpha and IL6 expression, substantiating the notion that necrosis can induce profound immune reactions. The RIPK1 kinase inhibitor necrostatin-1 and the ROS scavenger NAC each could prevent necrosis in HT-29 cells and the efficiency was enhanced by combined treatment. Thus by building up a necroptosis model in human colon cancer cells, we uncovered that mechanically RIP kinases collaborate with ROS during necrosis promoted by cobalt chloride plus z-VAD, which leads to inflammation. Necroptosis may present a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death. PMID- 25824799 TI - Citrus fruits and their bioactive ingredients: leading four horsemen from front. AB - Cancer is a multifaceted and genomically complex disease and rapidly accumulating high impact research is deepening our understanding related to the mechanisms underlying cancer development, progression and resistance to therapeutics. Increasingly it is being realized that genetic/epigenetic mutations, inactivation of tumor suppressor genes, overexpression of oncogenes, deregulation of intracellular signaling cascades and loss of apoptosis are some of the extensively studied aspects. Confluence of information suggested that rapidly developing resistance to therapeutics is adding another layer of complexity and overwhelmingly increasing preclinical studies are identifying different natural agents with efficacy and minimal off-target effects. We partition this multi component review into citrus fruits and their bioactive ingredients mediating rebalancing of pro- and anti-apoptotic proteins to induce apoptosis in resistant cancer cells. We also discuss how oncogenic protein networks are targeted in cancer cells and how these findings may be verified in preclinical studies. PMID- 25824800 TI - Salvage chemotherapy with weekly paclitaxel for metastatic melanoma. PMID- 25824801 TI - Regarding 'HPV vaccination for cervical cancer prevention is not cost-effective in Japan'. PMID- 25824802 TI - Hepatitis C virus associated hepatocellular carcinoma risk. PMID- 25824803 TI - Retraction notice to: Epression of MRTF-A and AQP1 plays important roles in pathological vascular remodeling. PMID- 25824804 TI - Direct effect of streptozotocin on periodontal ligament cells through myeloid cell leukemia-1. AB - OBJECTIVE: We hypothesized that streptozotocin (STZ) has a direct impact on periodontal ligament cell (PDL) damage as a potential direct inducer of periodontitis. BACKGROUND: Since diabetes was accepted as one of the risk factors for the development of periodontal disease, various scientific studies have been undertaken in the STZ-induced periodontal disease models. STZ induces beta-cell damage and subsequent diabetes development in vivo. Until now, assessment of the impacts of STZ-induced experimental diabetes on periodontitis has generally been conducted on the fundamental assumption that STZ have no direct action on PDL and its function. However, several recent studies suggest that STZ also directly affect many different biological functions in various tissues or organs. MATERIAL AND METHODS: To assess the apoptotic effects of STZ on PDLs, they were treated with or without STZ at different concentrations. Qualitative estimation of apoptotic cell death was obtained by live/dead assay. The expression levels of apoptosis-related proteins were evaluated by western blot analysis. RESULTS: STZ inhibits growth and induces apoptosis in PDLs in a dose-dependent manner. Furthermore, STZ dramatically induced Mcl-1 downregulation in a proteasome dependent manner and thereby induced apoptosis of PDLs through the Bak/Bax apoptotic signaling pathway. CONCLUSION: Our results support the hypothesis that suppression of the cellular Mcl-1 levels by STZ may be at least partly attributed to the development of periodontitis in STZ-induced diabetic animal models. PMID- 25824805 TI - Meter-long multiblock copolymer microfibers via interfacial bioorthogonal polymerization. AB - High-molecular-weight multiblock copolymers are synthesized as robust polymer fibers via interfacial bioorthogonal polymerization employing the rapid cycloaddition of s-tetrazines with strained trans-cyclooctenes. When cell adhesive peptide is incorporated in the tetrazine monomer, the resulting protein mimetic polymer fibers provide guidance cues for cell attachment and elongation. PMID- 25824806 TI - Clinical and laboratory characterization of 114 cases of Castleman disease patients from a single centre: paraneoplastic pemphigus is an unfavourable prognostic factor. AB - This study retrospectively collected the clinical and laboratory data of 114 patients with Castleman disease (CD) from a single medical centre. Clinical classification identified 62 patients (54.4%) with unicentric Castleman disease and 52 (45.6%) with multi-centric Castleman disease. Pathological classification revealed 68 cases (59.6%) of hyaline vascular variant, 16 (14.1%) mixed cellular variant (Mix) and 30 (26.3%) plasmacytic variant. Clinical complications occurred in 69 CD patients, including 37 cases of paraneoplastic pemphigus (PNP) and 25 cases with renal complications. Haematological involvement, pleural effusion and/or ascites and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) were also found. Univariate analysis showed that presence of clinical complications and PNP were both risk factors relating to CD patient survival. Prognostic factors showing P < 0.15 in univariate analysis and those with clinical significance were subjected to multivariate analysis using a Cox regression model. PNP presence and age over 40 years both significantly adversely affected survival. Thus, only presence of PNP was identified as an independent unfavourable survival risk factor in both univariate and multivariate analyses. Overall, the present data provide a panoramic description of CD cases and emphasize that the presence of PNP is an adverse prognostic factor. PMID- 25824807 TI - Sildenafil for the Treatment of Pulmonary Arterial Hypertension in Infants with Bronchopulmonary Dysplasia. AB - Sildenafil, a phosphodiesterase-5 inhibitor, is a controversial treatment option for pulmonary arterial hypertension (PAH), a significant complication of bronchopulmonary dysplasia (BPD). The objective of this study was to evaluate the use of sildenafil in infants with PAH secondary to BPD. This was a retrospective review of medical records of all premature infants with PAH associated with BPD treated with sildenafil between January 2009 and May 2013 in a level 3 neonatal intensive care unit. The primary outcomes were clinical response (20 % decreases in respiratory support score or oxygen requirements) and echocardiographic response (20 % decrease in tricuspid regurgitation gradient or change of at least 1 degrees of septal flattening). Twenty-three infants were included in the study. Significant echocardiographic and clinical responses were, respectively, observed in 71 and 35 % of cases. Most clinical responses were observed in the first 48 h of treatment, and the median time to an echocardiographic response was of 19 days. The median dose of sildenafil used was 4.4 mg/kg/day, with a median time to reach the maximum dose of 9 days. Transient hypotension was the primary reported side effect, and it was observed in 44 % of our study population. Sildenafil treatment in patients with PAH secondary to BPD was associated with an echocardiographic improvement in the majority of patients, whereas clinical improvement was observed in a minority of patients. Many infants presented with transient hypotension during the course of the treatment. Further prospective studies are required to better assess safety and efficacy of this treatment in this population. PMID- 25824809 TI - Frequency-dependent fitness in gynodioecious Lobelia siphilitica. AB - Selection is frequency dependent when an individual's fitness depends on the frequency of its phenotype. Frequency-dependent selection should be common in gynodioecious plants, where individuals are female or hermaphroditic; if the fitness of females is limited by the availability of pollen to fertilize their ovules, then they should have higher fitness when rare than when common. To test whether the fitness of females is frequency dependent, we manipulated the sex ratio in arrays of gynodioecious Lobelia siphilitica. To test whether fitness was frequency dependent because of variation in pollen availability, we compared open pollinated and supplemental hand-pollinated plants. Open-pollinated females produced more seeds when they were rare than when they were common, as expected if fitness is negatively frequency dependent. However, hand-pollinated females also produced more seeds when they were rare, indicating that variation in pollen availability was not the cause of frequency-dependent fitness. Instead, fitness was frequency dependent because both hand- and open-pollinated females opened more flowers when they were rare than when they were common. This plasticity in the rate of anthesis could cause fitness to be frequency dependent even when reproduction is not pollen limited, and thus expand the conditions under which frequency-dependent selection operates in gynodioecious species. PMID- 25824810 TI - Outpatient Hysteroscopic Polypectomy: Bipolar Energy System (Versapoint(r)) versus Mechanical Energy System (TRUCLEAR System(r)) - Preliminary Results. AB - HYPOTHESIS: The new hysteroscopic system with mechanical energy is an effective outpatient technique for diagnosis and treatment that has certain advantages over conventional hysteroscopy in the management of endometrial polyps. OBJECTIVES: Our primary objective was to assess the total duration of hysteroscopy and polypectomy performed in an outpatient setting comparing the new mechanical energy hysteroscopy to the bipolar energy system. Our secondary objective was to compare the level of safety of both hysteroscopic techniques using the procedure success rate, the need for subsequent referral to surgery, existing complications, and comfort experienced by the patient during the procedure. PATIENTS AND METHODS: This randomized controlled trial included the first 90 patients with an ultrasound diagnosis of endometrial polyp (>1 cm) who underwent an outpatient diagnostic and operative hysteroscopy at the Igualada Hospital (Barcelona) and agreed to be included in the study by signing an informed consent. RESULTS: We obtained a 91% success rate with the TRUCLEAR System(r) compared to a 69% success rate with the Versapoint(r) system. Total operating time was 6.36 min in the TRUCLEAR System group versus 10.82 min in the Versapoint system group (p < 0.05), with a polypectomy time of 3.06 and 7.91 min, respectively (p < 0.05). There were no significant differences between the two techniques when analyzing pain using the visual analogue scale. No complications were recorded for either technique. CONCLUSION: The mechanical energy system presents a significant decrease in the total duration of polypectomy and hysteroscopy when performed both by experienced staff and by staff in training, resulting in higher success rates without complications with respect to conventional hysteroscopy with bipolar energy. PMID- 25824812 TI - Valence properties of Cu and Ru in titanium-substituted LnCu3Ru4O12+delta (Ln = La, Pr, Nd) investigated by XANES and TGA. AB - In the solid-solution series La(y)Cu(3)RuxTi(4-x)O(12+delta) (0 <=x<= 4) the Cu and Ru electronic states are highly correlated. With increasing Ru content x the system properties change from a paramagnetic insulator with colossal dielectric constant to a heavy-fermion metal. To further elucidate the occurring phase transitions, the valences of Cu and Ru have been investigated utilizing XANES measurements at the Cu-K and the Ru-K absorption edges. It was found that the Ru oxidation number is close to +4 in all samples, while the Cu valence linearly decreases from +2 for the titanate (x = 0) to +1.6 for the ruthenate (x = 4). Additional thermogravimetric measurements have been used to determine the oxygen content and rather high oxygen excesses up to delta~ 0.7 (for x = 0.5) were obtained. The additional oxygen for x < 2 is required to compensate the constant Ru +4 valence. Our findings are in accordance with the reported phase transitions of the magnetic and transport properties. Both the valence shift and the shapes of the absorption edges suggest a change from localized to itinerant character of the Cu electronic states with increasing x, while the Ru electrons remain localized. Analogous results concerning the valences were found for the Pr(y)Cu(3)RuxTi(4-x)O(12+delta) and Nd(y)Cu(3)RuxTi(4-x)O(12+delta) solid solution series. PMID- 25824811 TI - Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: the fetus at risk for anemia--diagnosis and management. AB - OBJECTIVE: We sought to provide evidence-based guidelines for the diagnosis and management of fetal anemia. METHODS: A systematic literature review was performed using MEDLINE, PubMed, EMBASE, and the Cochrane Library. The search was restricted to English-language articles published from 1966 through May 2014. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion. Evidence reports and published guidelines were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology was used for defining the strength of recommendations and rating the quality of evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence. RESULTS AND RECOMMENDATIONS: We recommend the following: (1) middle cerebral artery peak systolic velocity (MCA-PSV) measured by ultrasound Doppler interrogation be used as the primary technique to detect fetal anemia; (2) amniotic fluid delta OD450 not be used to diagnosis fetal anemia; (3) MCA-PSV assessment be reserved for those patients who are at risk of having an anemic fetus (proper technique for MCA-PSV evaluation includes assessment of the middle cerebral artery close to its origin, ideally at a zero degree angle without angle correction); (4) if a fetus is deemed at significant risk for severe fetal anemia (MCA greater than 1.5 multiples of the median or hydropic), fetal blood sampling be performed with preparation for an intrauterine transfusion, unless the pregnancy is at a gestational age when the risks associated with delivery are considered to be less than those associated with the procedure; (5) if a fetus is deemed at significant risk for severe fetal anemia, the patient be referred to a center with expertise in invasive fetal therapy; (6) MCA-PSV be considered to determine the timing of a second transfusion in fetuses with anemia, and, alternatively, a predicted decline in fetal hemoglobin may be used for timing the second procedure; and (7) pregnancies with a fetus at significant risk for fetal anemia be delivered at 37-38 weeks of gestation unless indications develop prior to this time. PMID- 25824813 TI - Benefits and risks of immediately sequential bilateral cataract surgery: a literature review. AB - Immediately sequential bilateral cataract surgery (ISBCS) is a highly contended issue in ophthalmology, mainly due to the risk of bilateral endophthalmitis and financial penalties that many ophthalmologists face when performing simultaneous cataract surgeries. The purpose of this review is to understand the current status of the knowledge of ISBCS, mainly its benefits and risks and how they compare with the standard of care, delayed sequential bilateral cataract surgery. Evidence, although limited, increasingly supports ISBCS for providing faster rehabilitation, improved visual outcomes, and cost and time savings. Evidence does not support the fear of bilateral endophthalmitis resulting from the simultaneous procedure. However, stronger and greater evidence is needed before ISBCSs can be considered the standard of care. Where ISBCS can potentially create the most beneficial impact is in public eye health programmes in developing countries, but this has not yet been explored. PMID- 25824814 TI - The food industry's current and future role in preventing microbial foodborne illness within the United States. AB - During the past century, the microbiological safety of the US food supply has improved; however, many foodborne illnesses and outbreaks occur annually. Hence, opportunities for the food industry to improve the safety of both domestic and imported food exist through the adoption of risk-based preventive measures. Challenging food safety issues that are on the horizon include demographic changes to a population whose immune system is more susceptible to foodborne and opportunistic pathogens, climate changes that will shift where food is produced, and consumers' preferences for raw and minimally processed foods. Increased environmental and product testing and anonymous data sharing by the food industry with the public health community would aid in identifying system weaknesses and enabling more targeted corrective and preventive actions. Clinicians will continue to play a major role in reducing foodborne illnesses by diagnosing and reporting cases and in helping to educate the consumer about food safety practices. PMID- 25824815 TI - Fatal outbreak of an emerging clone of extensively drug-resistant Acinetobacter baumannii with enhanced virulence. AB - BACKGROUND: Severe Acinetobacter baumannii infections in immunocompetent patients are uncommon, and the virulence mechanisms of this organism are not fully understood. METHODS: Following an outbreak of fatal A. baumannii infections in a cohort of relatively immunocompetent patients (low comorbidity and illness severity scores), isolates were investigated with comparative genomics and in animal models. RESULTS: Two unrelated A. baumannii clades were associated with the outbreak. The clone associated with the majority of patient deaths, clade B, is evolutionarily distinct from the 3 international clonal complexes, belongs to multilocus sequence type (MLST) 10, and is most closely related to strains isolated from the Czech Republic, California, and Germany in 1994, 1997, and 2003, respectively. In 2 different murine models, clade B isolates were more virulent than comparator strains, including the highly virulent reference strain AB5075. The most virulent clade B derivative, MRSN 16897, was isolated from the patient with the lowest combined comorbidity/illness severity score. Clade B isolates possess a unique combination of putative virulence genes involved in iron metabolism, protein secretion, and glycosylation, which was leveraged to develop a rapid and specific clinical assay to detect this clade that cannot be distinguished by MLST. CONCLUSIONS: Clade B warrants continued surveillance and investigation. PMID- 25824808 TI - Nephrectomy for benign disease in the UK: results from the British Association of Urological Surgeons nephrectomy database. AB - OBJECTIVE: To summarize the practice of UK urologists with regard to nephrectomy for benign disease, documenting the indications, procedural techniques and outcomes. METHODS: All patients undergoing nephrectomy for a benign condition in 2012 were identified from the British Association of Urological Surgeons (BAUS) nephrectomy database. Recorded variables included the technique of surgery, the type of minimally invasive procedure, operating time, blood loss, transfusion rate, conversion rate, intra- and postoperative complications and mortality rate. Cases were also sub-analysed according to their pathologies to determine the differences in complication rate between stone disease, pyelonephritis, non functioning kidney and other benign lesions. To contextualize procedural complexity, the simple nephrectomy data were compared with those obtained from the BAUS stage T1 radical nephrectomy audit. RESULTS: A total of 1 093 nephrectomies were performed (537 non-functioning kidneys, 142 stone disease, 129 nephrectomies secondary to pyelonephritis and 285 cases with other benign conditions). Of these, 76% were performed laparoscopically. Blood loss >500 mL was noted in 74 cases with a 4.8% blood transfusion rate. The intra- and postoperative complication rates were 5.2 and 11.9%, respectively. Of the 847 minimally invasive procedures, the conversion rate was 5.9%. Patients with stone disease have the highest intra- and postoperative complications (9.9 and 23.9%, respectively) compared with other benign pathologies. The total number of T1 radical nephrectomies performed was 1 095. In comparison with T1 radical nephrectomy, simple nephrectomy carries an increased risk of conversion to an open procedure (1.8 times), a higher rate of blood transfusion (4.8 vs 2.8%), and a higher risk of intra- and postoperative complications (5.2 vs 3.7% and 11.9 vs 10%, respectively). CONCLUSION: The present study reports the largest series of nephrectomies performed for benign disease and the resultant data now support the bespoke preoperative counselling of patients. Furthermore, it confirms the commonly held view that simple nephrectomy can be more difficult than its radical counterpart. The authors suggest that the term 'simple nephrectomy' is changed to 'benign nephrectomy'. PMID- 25824816 TI - Editorial commentary: the new Acinetobacter equation: hypervirulence plus antibiotic resistance equals big trouble. PMID- 25824817 TI - Hypoxic preconditioning can reduce injury-induced inflammatory processes in the neonatal rat brain. AB - Inflammation plays an important role in the pathophysiology of neonatal hypoxic ischemic (HI) brain injury. Studies have shown that hypoxic preconditioning (HP) can ameliorate brain damage, but its effects on inflammation remain unknown. Postnatal day 6 (P6), Sprague-Dawley rats were divided into normoxia and hypoxia (8% oxygen, 3h) groups. On P7, some pups underwent a right carotid artery occlusion followed by hypoxia (8% oxygen, 3h) while under 1.5% isofluorane anesthesia and the remaining pups underwent sham surgery without occlusion. Animals were sacrificed 5 days later and fixed tissue was used to examine changes in neurons, astrocytes, and microglia in the cortex. Fresh tissue was collected to determine cortical levels of proinflammatory cytokines using ELISA. There was a significant loss in the number of NeuN positive cells in the cortex following HI injury, which was improved when HP was given prior to HI. There was an increase in cortical area of astrocyte staining after HI injury compared to control. HP before HI was able to reduce area of GFAP staining back to control levels. HI caused a large increase in the number of activated microglia compared to control and HP was able to significantly reduce this, although not back to control levels. HP alone increased microglial activation. Interleukin-1beta levels were increased in the cortex 5 days after HI, but HP was not able to significantly reduce this change. The neuroprotective effects of HP appear to be mediated by affecting cellular inflammatory processes in the brain following HI injury. PMID- 25824818 TI - The effects of PBDE-209 exposure during pregnancy on placental ET-1 and eNOS expression and the birth weight of offspring. AB - Decabrominated diphenyl ether (PBDE-209) is a persistent organic pollutant. Gestational exposure to PBDE-209 can accumulate in pregnant women and fetuses via the placenta and umbilical cord, affecting perinatal outcome. In this study, pregnant Sprague-Dawley (SD) rats were randomly divided into five groups and intragastrically administered peanut oil (vehicle) 1, 5 and 10mg/kg by body weight (b.w.) of PBDE-209, or nothing (control) from day 0 (G0) to day 21 (G21) gestation, respectively. Placental samples were collected on G21 by cesarean section. The mRNA and protein expressions of ET-1, eNOS and iNOS in the placenta were examined using qRT-PCR and Western blot, respectively. Total nitric oxide (NO) in the placenta was measured using a specific ELISA kit. Compared with the control and vehicle groups, the mRNA expression of ET-1 and iNOS in the placenta was gradually and significantly increased after exposure to increasing concentrations of PBDE-209 (P<0.05), while the mRNA level of eNOS in the placenta was gradually and significantly reduced after exposure to increasing concentrations of PBDE-209 (P<0.05). The expression trends of ET-1, eNOS and iNOS proteins were consistent with those of mRNA expression. Interestingly, the production of total NO was significantly increased after exposure to 5 and 10mg/kg b.w. PBDE-209 (P<0.05). Finally, the birth weight of the offspring rats was significantly reduced after maternal exposure to 5 and 10 mg/kg b.w. PBDE-209 compared with the control and vehicle groups (P<0.05). These results suggest that PBDE-209 exposure during pregnancy upregulates ET-1 and iNOS expression, but decreases eNOS expression in the placenta, as well as reduces the birth weight of offspring. PMID- 25824819 TI - BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. AB - Follicular helper T cells (Tfh cells) are required for T cell help to B cells, and BCL6 is the defining transcription factor of Tfh cells. However, the functions of BCL6 in Tfh cells have largely remained unclear. Here we defined the BCL6 cistrome in primary human germinal center Tfh cells to assess mechanisms of BCL6 regulation of CD4 T cells, comparing and contrasting BCL6 function in T and B cells. BCL6 primarily acts as a repressor in Tfh cells, and BCL6 binding was associated with control of Tfh cell migration and repression of alternative cell fates. Interestingly, although some BCL6-bound genes possessed BCL6 DNA-binding motifs, many BCL6-bound loci were instead characterized by the presence of DNA motifs for AP1 or STAT. AP1 complexes are key positive downstream mediators of TCR signaling and external stimuli. We show that BCL6 can directly bind AP1, and BCL6 depends on AP1 for recruitment to BCL6-binding sites with AP1 motifs, suggesting that BCL6 subverts AP1 activity. These findings reveal that BCL6 has broad and multifaceted effects on Tfh biology and provide insight into how this master regulator mediates distinct cell context-dependent phenotypes. PMID- 25824820 TI - Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2 p38MAPK pathway. AB - The status of long-term quiescence and dormancy guarantees the integrity of hematopoietic stem cells (HSCs) during adult homeostasis. However the molecular mechanisms regulating HSC dormancy remain poorly understood. Here we show that cylindromatosis (CYLD), a tumor suppressor gene and negative regulator of NF kappaB signaling with deubiquitinase activity, is highly expressed in label retaining dormant HSCs (dHSCs). Moreover, Cre-mediated conditional elimination of the catalytic domain of CYLD induced dHSCs to exit quiescence and abrogated their repopulation and self-renewal potential. This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor associated factor 2). HSCs expressing a mutant CYLD with an intact catalytic domain, but unable to bind TRAF2, showed the same HSC phenotype. Unexpectedly, the robust cycling of HSCs lacking functional CYLD-TRAF2 interactions was not elicited by increased NF-kappaB signaling, but instead by increased activation of the p38MAPK pathway. Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD-TRAF2-p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy. PMID- 25824821 TI - A single glycan on IgE is indispensable for initiation of anaphylaxis. AB - Immunoglobulin epsilon (IgE) antibodies are the primary mediators of allergic diseases, which affect more than 1 in 10 individuals worldwide. IgE specific for innocuous environmental antigens, or allergens, binds and sensitizes tissue resident mast cells expressing the high-affinity IgE receptor, FcepsilonRI. Subsequent allergen exposure cross-links mast cell-bound IgE, resulting in the release of inflammatory mediators and initiation of the allergic cascade. It is well established that precise glycosylation patterns exert profound effects on the biological activity of IgG. However, the contribution of glycosylation to IgE biology is less clear. Here, we demonstrate an absolute requirement for IgE glycosylation in allergic reactions. The obligatory glycan was mapped to a single N-linked oligomannose structure in the constant domain 3 (Cepsilon3) of IgE, at asparagine-394 (N394) in human IgE and N384 in mouse. Genetic disruption of the site or enzymatic removal of the oligomannose glycan altered IgE secondary structure and abrogated IgE binding to FcepsilonRI, rendering IgE incapable of eliciting mast cell degranulation, thereby preventing anaphylaxis. These results underscore an unappreciated and essential requirement of glycosylation in IgE biology. PMID- 25824822 TI - Consecutive interactions with HSP90 and eEF1A underlie a functional maturation and storage pathway of AID in the cytoplasm. AB - Activation-induced deaminase (AID) initiates mutagenic pathways to diversify the antibody genes during immune responses. The access of AID to the nucleus is limited by CRM1-mediated nuclear export and by an uncharacterized mechanism of cytoplasmic retention. Here, we define a conformational motif in AID that dictates its cytoplasmic retention and demonstrate that the translation elongation factor eukaryotic elongation factor 1 alpha (eEF1A) is necessary for AID cytoplasmic sequestering. The mechanism is independent of protein synthesis but dependent on a tRNA-free form of eEF1A. Inhibiting eEF1A prevents the interaction with AID, which accumulates in the nucleus and increases class switch recombination as well as chromosomal translocation byproducts. Most AID is associated to unspecified cytoplasmic complexes. We find that the interactions of AID with eEF1A and heat-shock protein 90 kD (HSP90) are inversely correlated. Despite both interactions stabilizing AID, the nature of the AID fractions associated with HSP90 or eEF1A are different, defining two complexes that sequentially produce and store functional AID in the cytoplasm. In addition, nuclear export and cytoplasmic retention cooperate to exclude AID from the nucleus but might not be functionally equivalent. Our results elucidate the molecular basis of AID cytoplasmic retention, define its functional relevance and distinguish it from other mechanisms regulating AID. PMID- 25824825 TI - Abdominal wall reconstruction using a combination of free tensor fasciae lata and anterolateral thigh myocutaneous flap: a prospective study in 16 patients. AB - BACKGROUND: Reconstruction of the abdominal wall continues to be a challenging problem for plastic surgeons. Transposition of well-vascularized flap tissue is the most effective way to repair composite abdominal wall defects. We retrospectively reviewed the treatment of such patients and assessed the reconstructive technique using combination of an inlay of bioprosthetic materials and a united thigh flap. METHODS: A retrospective review of patients' records in the department was carried out. In total, 16 patients who underwent immediate abdominal wall reconstruction between 2000 and 2013 were identified. Patients' health status, defect sizes, and surgical technique were obtained from medical charts. RESULTS: The immediate reconstruction surgery of the abdominal wall was successful in all patients. One patient with dermatofibrosarcoma protuberans experienced recurrences at the former site. One patient died because of liver metastases at 21 months after surgery. No incisional hernia or infection in this series of patients was observed. CONCLUSION: Full-thickness, giant defects of the complicated abdominal wall can be repaired successfully with relatively minor complications using this reconstructive technique. PMID- 25824824 TI - The long-acting beta2 -adrenoceptor agonist olodaterol attenuates pulmonary inflammation. AB - BACKGROUND AND PURPOSE: beta2 -adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long-acting beta2 adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti-inflammatory actions. EXPERIMENTAL APPROACH: Olodaterol was tested in murine and guinea pig models of cigarette smoke- and LPS-induced lung inflammation. Furthermore, effects of olodaterol on the LPS-induced pro-inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF-alpha release from human whole blood and on the IL-8-induced migration of human peripheral blood neutrophils were investigated. KEY RESULTS: Olodaterol dose dependently attenuated cell influx and pro-inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti-inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro-inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL-8-induced neutrophil transwell migration. CONCLUSIONS AND IMPLICATIONS: This is the first evidence for the anti-inflammatory efficacy of a beta2 -adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long-acting beta2 adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti-inflammatory properties of olodaterol are maintained after repeated dosing for 4 days. PMID- 25824823 TI - T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. AB - The selenoenzyme glutathione peroxidase 4 (Gpx4) is a major scavenger of phospholipid hydroperoxides. Although Gpx4 represents a key component of the reactive oxygen species-scavenging network, its relevance in the immune system is yet to be defined. Here, we investigated the importance of Gpx4 for physiological T cell responses by using T cell-specific Gpx4-deficient mice. Our results revealed that, despite normal thymic T cell development, CD8(+) T cells from T(DeltaGpx4/DeltaGpx4) mice had an intrinsic defect in maintaining homeostatic balance in the periphery. Moreover, both antigen-specific CD8(+) and CD4(+) T cells lacking Gpx4 failed to expand and to protect from acute lymphocytic choriomeningitis virus and Leishmania major parasite infections, which were rescued with diet supplementation of high dosage of vitamin E. Notably, depletion of the Gpx4 gene in the memory phase of viral infection did not affect T cell recall responses upon secondary infection. Ex vivo, Gpx4-deficient T cells rapidly accumulated membrane lipid peroxides and concomitantly underwent cell death driven by ferroptosis but not necroptosis. These studies unveil an essential role of Gpx4 for T cell immunity. PMID- 25824826 TI - Big bubble deep anterior lamellar keratoplasty: the collagen layer in the wall of the big bubble is unique. AB - PURPOSE: In big bubble (BB), deep anterior lamellar keratoplasty intracorneal injection of air separates Descemet's membrane (DM) and the pre-Descemet's layer (Dua's layer [DL]) to create a type 1 BB. We tested the hypothesis that air injection after excision or ablation of DL will fail to produce a BB. METHODS: Nine human sclero-corneal discs were used. Three served as controls. In three, a type 1 BB was created, the bubble wall was excised and more air injected in an attempt to create another BB. In three samples, the DM was removed and 22MU of posterior cornea were ablated by phototherapeutic keratectomy (PTK). Air was injected to induce formation of a BB. Tissue from these experiments was subjected to light and electron microscopy. RESULTS: In all three control eyes, a type 1 BB (DL + DM) was obtained. Air injection after excision of the type 1 BB wall in three samples failed to produce another BB. Following PTK of DL, injection of air failed to create a BB in all three samples. Multiple points of air leak from the deep stroma were observed in all six samples. Light and electron microscopy showed a clear distinction between the ablated and non-ablated areas of cornea. CONCLUSIONS: This study supports the hypothesis that a BB cannot be created once the DL is excised or ablated. This adds to evidence that DL is unique. It also demonstrates that DL is not a random separation of deep stroma of the cornea. PMID- 25824827 TI - Recent developments in the sensorial assessment of cosmetic products: a review. AB - Cosmetic development is not exclusively guided by notions of rational effectiveness but also by notions of sensoriality. Thus, the sensorial properties of a cosmetic product are studied using internationally recognized discriminating or descriptive methods. Descriptive sensory profiling is an essential tool in this process as it allows an experienced panel to assess the qualitative and quantitative characteristics of a product. The results obtained with this method enable to get a more accurate image of the product. However, given the new demands of the industrial world and the new innovation paths (shorter development times, complex products or willingness to include the consumers in the process) a need to access new methods has arisen. These 'alternative' methods that offer product positioning, ratings and attribute citation frequency, can be implemented with either a panel of experts or with consumers. The flash profile, the pivot(r) profile or the check all that apply (CATA) are just a few of the methods that the cosmetic professionals have started to test. This article reviews the methods used in the sensory assessment of cosmetic products. The analysis carried out shows that the complementarity application of sensory assessment is essential in the upstream innovation phase of a product. PMID- 25824828 TI - Characterization of Clostridium perfringens TpeL toxin gene carriage, production, cytotoxic contributions, and trypsin sensitivity. AB - Large clostridial toxins (LCTs) are produced by at least four pathogenic clostridial species, and several LCTs are proven pivotal virulence factors for both human and veterinary diseases. TpeL is a recently identified LCT produced by Clostridium perfringens that has received relatively limited study. In response, the current study surveyed carriage of the tpeL gene among different C. perfringens strains, detecting this toxin gene in some type A, B, and C strains but not in any type D or E strains. This study also determined that all tested strains maximally produce, and extracellularly release, TpeL at the late-log or early-stationary growth stage during in vitro culture, which is different from the maximal late-stationary-phase production reported previously for other LCTs and for TpeL production by C. perfringens strain JIR12688. In addition, the present study found that TpeL levels in culture supernatants can be repressed by either glucose or sucrose. It was also shown that, at natural production levels, TpeL is a significant contributor to the cytotoxic activity of supernatants from cultures of tpeL-positive strain CN3685. Lastly, this study identified TpeL, which presumably is produced in the intestines during diseases caused by TpeL positive type B and C strains, as a toxin whose cytotoxicity decreases after treatment with trypsin; this finding may have pathophysiologic relevance by suggesting that, like beta toxin, TpeL contributes to type B and C infections in hosts with decreased trypsin levels due to disease, diet, or age. PMID- 25824829 TI - Chlamydia muridarum induction of glandular duct dilation in mice. AB - Although Chlamydia-induced hydrosalpinx in women and mice has been used as a surrogate marker for tubal infertility, the medical relevance of nontubal pathologies, such as uterine horn dilation, developed in mice following chlamydial infection remains unclear. We now report that the uterine horn dilation correlates with glandular duct dilation detected microscopically following Chlamydia muridarum infection. The dilated glandular ducts pushed the uterine horn lumen to closure or dilation and even broke through the myometrium to develop extrusion outside the uterine horn. The severity scores of uterine horn dilation observed macroscopically correlated well with the number of cross sections of the dilated glandular ducts counted under microscopy. Chlamydial infection was detected in the glandular epithelial cells, potentially leading to inflammation and dilation of the glandular ducts. Direct delivery of C. muridarum into the mouse uterus increased both uterine horn/glandular duct dilation and hydrosalpinx. However, the chlamydial plasmid, which is essential for the induction of hydrosalpinx, was not required for the induction of uterine horn/glandular duct dilation. Screening 12 strains of mice for uterine horn dilation following C. muridarum infection revealed that B10.D2, C57BL/10J, and C57BL/6J mice were most susceptible, followed by BALB/cJ and A/J mice. Deficiency in host genes involved in immune responses failed to significantly alter the C. muridarum induction of uterine horn dilation. Nevertheless, the chlamydial induction of uterine horn/glandular duct dilation may be used to evaluate plasmid independent pathogenicity of Chlamydia in susceptible mice. PMID- 25824830 TI - The human P-glycoprotein transporter enhances the type I interferon response to Listeria monocytogenes infection. AB - Human multidrug efflux transporters are known for their ability to extrude antibiotics and toxic compounds out of cells, yet accumulating data indicate they have additional functions in diverse physiological processes not related to drug efflux. Here, we show that the human multidrug transporter P-glycoprotein (P-gp) (also named MDR1 and ABCB1) is transcriptionally induced in the monocytic cell line THP-1 upon infection with the human intracellular bacterial pathogen Listeria monocytogenes. Notably, we found that P-gp is important for full activation of the type I interferon response elicited against L. monocytogenes bacteria. Both inhibition of P-gp function by verapamil and inhibition of its transcription using mRNA silencing led to a reduction in the magnitude of the type I response in infected cells. This function of P-gp was specific to type I interferon cytokines elicited against cytosolic replicating bacteria and was not observed in response to cyclic di-AMP (c-di-AMP), a molecule that was shown to be secreted by L. monocytogenes during infection and to trigger type I interferons. Moreover, P-gp was not involved in activation of other proinflammatory cytokines, such as those triggered by vacuolar-restricted L. monocytogenes or lipopolysaccharide (LPS). Taken together, these findings demonstrate a role for P gp in proper development of an innate immune response against intracellular pathogens, highlighting the complexity in employing therapeutic strategies that involve inhibition of multidrug resistance (MDR) efflux pumps. PMID- 25824831 TI - Increased ferroportin-1 expression and rapid splenic iron loss occur with anemia caused by Salmonella enterica Serovar Typhimurium infection in mice. AB - The Gram-negative intracellular bacterium Salmonella enterica serovar Typhimurium causes persistent systemic inflammatory disease in immunocompetent mice. Following oral inoculation with S. Typhimurium, mice develop a hematopathological syndrome akin to typhoid fever with splenomegaly, microcytic anemia, extramedullary erythropoiesis, and increased hemophagocytic macrophages in the bone marrow, liver, and spleen. Additionally, there is marked loss of iron from the spleen, an unanticipated result, given the iron sequestration reported in anemia of inflammatory disease. To establish why tissue iron does not accumulate, we evaluated multiple measures of pathology for 4 weeks following oral infection in mice. We demonstrate a quantitative decrease in splenic iron following infection despite increased numbers of splenic phagocytes. Infected mice have increased duodenal expression of the iron exporter ferroportin-1, consistent with increased uptake of dietary iron. Liver and splenic macrophages also express high levels of ferroportin-1. These observations indicate that splenic and hepatic macrophages export iron during S. Typhimurium infection, in contrast to macrophage iron sequestration observed in anemia of inflammatory disease. Tissue macrophage export of iron occurs concurrent with high serum concentrations of interferon gamma (IFN-gamma) and interleukin 12 (IL-12). In individual mice, high concentrations of both proinflammatory (tumor necrosis factor alpha [TNF-alpha]) and anti-inflammatory (IL-10) cytokines in serum correlate with increased tissue bacterial loads throughout 4 weeks of infection. These in vivo observations are consistent with previous cell culture studies and suggest that the relocation of iron from tissue macrophages during infection may contribute to anemia and also to host survival of acute S. Typhimurium infection. PMID- 25824832 TI - Bistable expression of CsgD in Salmonella enterica serovar Typhimurium connects virulence to persistence. AB - Pathogenic bacteria often need to survive in the host and the environment, and it is not well understood how cells transition between these equally challenging situations. For the human and animal pathogen Salmonella enterica serovar Typhimurium, biofilm formation is correlated with persistence outside a host, but the connection to virulence is unknown. In this study, we analyzed multicellular aggregate and planktonic-cell subpopulations that coexist when S. Typhimurium is grown under biofilm-inducing conditions. These cell types arise due to bistable expression of CsgD, the central biofilm regulator. Despite being exposed to the same stresses, the two cell subpopulations had 1,856 genes that were differentially expressed, as determined by transcriptome sequencing (RNA-seq). Aggregated cells displayed the characteristic gene expression of biofilms, whereas planktonic cells had enhanced expression of numerous virulence genes. Increased type three secretion synthesis in planktonic cells correlated with enhanced invasion of a human intestinal cell line and significantly increased virulence in mice compared to the aggregates. However, when the same groups of cells were exposed to desiccation, the aggregates survived better, and the competitive advantage of planktonic cells was lost. We hypothesize that CsgD based differentiation is a form of bet hedging, with single cells primed for host cell invasion and aggregated cells adapted for persistence in the environment. This allows S. Typhimurium to spread the risks of transmission and ensures a smooth transition between the host and the environment. PMID- 25824833 TI - Listeria monocytogenes spreads within the brain by actin-based intra-axonal migration. AB - Listeria monocytogenes rhombencephalitis is a severe progressive disease despite a swift intrathecal immune response. Based on previous observations, we hypothesized that the disease progresses by intra-axonal spread within the central nervous system. To test this hypothesis, neuroanatomical mapping of lesions, immunofluorescence analysis, and electron microscopy were performed on brains of ruminants with naturally occurring rhombencephalitis. In addition, infection assays were performed in bovine brain cell cultures. Mapping of lesions revealed a consistent pattern with a preferential affection of certain nuclear areas and white matter tracts, indicating that Listeria monocytogenes spreads intra-axonally within the brain along interneuronal connections. These results were supported by immunofluorescence and ultrastructural data localizing Listeria monocytogenes inside axons and dendrites associated with networks of fibrillary structures consistent with actin tails. In vitro infection assays confirmed that bacteria were moving within axon-like processes by employing their actin tail machinery. Remarkably, in vivo, neutrophils invaded the axonal space and the axon itself, apparently by moving between split myelin lamellae of intact myelin sheaths. This intra-axonal invasion of neutrophils was associated with various stages of axonal degeneration and bacterial phagocytosis. Paradoxically, the ensuing adaxonal microabscesses appeared to provide new bacterial replication sites, thus supporting further bacterial spread. In conclusion, intra-axonal bacterial migration and possibly also the innate immune response play an important role in the intracerebral spread of the agent and hence the progression of listeric rhombencephalitis. PMID- 25824834 TI - Staphylococcus aureus MnhF mediates cholate efflux and facilitates survival under human colonic conditions. AB - Resistance to the innate defenses of the intestine is crucial for the survival and carriage of Staphylococcus aureus, a common colonizer of the human gut. Bile salts produced by the liver and secreted into the intestines are one such group of molecules with potent antimicrobial activity. The mechanisms by which S. aureus is able to resist such defenses in order to colonize and survive in the human gut are unknown. Here we show that mnhF confers resistance to bile salts, which can be abrogated by efflux pump inhibitors. MnhF mediates the efflux of radiolabeled cholic acid both in S. aureus and when heterologously expressed in Escherichia coli, rendering them resistant. Deletion of mnhF attenuated the survival of S. aureus in an anaerobic three-stage continuous-culture model of the human colon (gut model), which represents different anatomical areas of the large intestine. PMID- 25824835 TI - Cytotoxic and apoptotic effects of recombinant subtilase cytotoxin variants of shiga toxin-producing Escherichia coli. AB - In this study, the cytotoxicity of the recently described subtilase variant SubAB2-2 of Shiga toxin-producing Escherichia coli was determined and compared to the plasmid-encoded SubAB1 and the chromosome-encoded SubAB2-1 variant. The genes for the respective enzymatic active (A) subunits and binding (B) subunits of the subtilase toxins were amplified and cloned. The recombinant toxin subunits were expressed and purified. Their cytotoxicity on Vero cells was measured for the single A and B subunits, as well as for mixtures of both, to analyze whether hybrids with toxic activity can be identified. The results demonstrated that all three SubAB variants are toxic for Vero cells. However, the values for the 50% cytotoxic dose (CD50) differ for the individual variants. Highest cytotoxicity was shown for SubAB1. Moreover, hybrids of subunits from different subtilase toxins can be obtained which cause substantial cytotoxicity to Vero cells after mixing the A and B subunits prior to application to the cells, which is characteristic for binary toxins. Furthermore, higher concentrations of the enzymatic subunit SubA1 exhibited cytotoxic effects in the absence of the respective B1 subunit. A more detailed investigation in the human HeLa cell line revealed that SubA1 alone induced apoptosis, while the B1 subunit alone did not induce cell death. PMID- 25824836 TI - Inhibition of outer membrane proteases of the omptin family by aprotinin. AB - Bacterial proteases are important virulence factors that inactivate host defense proteins and contribute to tissue destruction and bacterial dissemination. Outer membrane proteases of the omptin family, exemplified by Escherichia coli OmpT, are found in some Gram-negative bacteria. Omptins cleave a variety of substrates at the host-pathogen interface, including plasminogen and antimicrobial peptides. Multiple omptin substrates relevant to infection have been identified; nonetheless, an effective omptin inhibitor remains to be found. Here, we purified native CroP, the OmpT ortholog in the murine pathogen Citrobacter rodentium. Purified CroP was found to readily cleave both a synthetic fluorescence resonance energy transfer substrate and the murine cathelicidin-related antimicrobial peptide. In contrast, CroP was found to poorly activate plasminogen into active plasmin. Although classical protease inhibitors were ineffective against CroP activity, we found that the serine protease inhibitor aprotinin displays inhibitory potency in the micromolar range. Aprotinin was shown to act as a competitive inhibitor of CroP activity and to interfere with the cleavage of the murine cathelicidin-related antimicrobial peptide. Importantly, aprotinin was able to inhibit not only CroP but also Yersinia pestis Pla and, to a lesser extent, E. coli OmpT. We propose a structural model of the aprotinin-omptin complex in which Lys15 of aprotinin forms salt bridges with conserved negatively charged residues of the omptin active site. PMID- 25824837 TI - The Cpx system regulates virulence gene expression in Vibrio cholerae. AB - Bacteria possess signal transduction pathways capable of sensing and responding to a wide variety of signals. The Cpx envelope stress response, composed of the sensor histidine kinase CpxA and the response regulator CpxR, senses and mediates adaptation to insults to the bacterial envelope. The Cpx response has been implicated in the regulation of a number of envelope-localized virulence determinants across bacterial species. Here, we show that activation of the Cpx pathway in Vibrio cholerae El Tor strain C6706 leads to a decrease in expression of the major virulence factors in this organism, cholera toxin (CT) and the toxin coregulated pilus (TCP). Our results indicate that this occurs through the repression of production of the ToxT regulator and an additional upstream transcription factor, TcpP. The effect of the Cpx response on CT and TCP expression is mostly abrogated in a cyclic AMP receptor protein (CRP) mutant, although expression of the crp gene is unaltered. Since TcpP production is controlled by CRP, our data suggest a model whereby the Cpx response affects CRP function, which leads to diminished TcpP, ToxT, CT, and TCP production. PMID- 25824838 TI - The CpAL quorum sensing system regulates production of hemolysins CPA and PFO to build Clostridium perfringens biofilms. AB - Clostridium perfringens strains produce severe diseases, including myonecrosis and enteritis necroticans, in humans and animals. Diseases are mediated by the production of potent toxins that often damage the site of infection, e.g., skin epithelium during myonecrosis. In planktonic cultures, the regulation of important toxins, such as CPA, CPB, and PFO, is controlled by the C. perfringens Agr-like (CpAL) quorum sensing (QS) system. Strains also encode a functional LuxS/AI-2 system. Although C. perfringens strains form biofilm-like structures, the regulation of biofilm formation is poorly understood. Therefore, our studies investigated the role of CpAL and LuxS/AI-2 QS systems and of QS-regulated factors in controlling the formation of biofilms. We first demonstrate that biofilm production by reference strains differs depending on the culture medium. Increased biomass correlated with the presence of extracellular DNA in the supernatant, which was released by lysis of a fraction of the biofilm population and planktonic cells. Whereas DeltaagrB mutant strains were not able to produce biofilms, a DeltaluxS mutant produced wild-type levels. The transcript levels of CpAL-regulated cpa and pfoA genes, but not cpb, were upregulated in biofilms compared to planktonic cultures. Accordingly, Deltacpa and DeltapfoA mutants, in type A (S13) or type C (CN3685) backgrounds, were unable to produce biofilms, whereas CN3685Deltacpb made wild-type levels. Biofilm formation was restored in complemented Deltacpa/cpa and DeltapfoA/pfoA strains. Confocal microscopy studies further detected CPA partially colocalizing with eDNA on the biofilm structure. Thus, CpAL regulates biofilm formation in C. perfringens by increasing levels of certain toxins required to build biofilms. PMID- 25824839 TI - Oral tolerance failure upon neonatal gut colonization with Escherichia coli producing the genotoxin colibactin. AB - The intestinal barrier controls the balance between tolerance and immunity to luminal antigens. When this finely tuned equilibrium is deregulated, inflammatory disorders can occur. There is a concomitant increase, in urban populations of developed countries, of immune-mediated diseases along with a shift in Escherichia coli population from the declining phylogenetic group A to the newly dominant group B2, including commensal strains producing a genotoxin called colibactin that massively colonized the gut of neonates. Here, we showed that mother-to-offspring early gut colonization by colibactin-producing E. coli impairs intestinal permeability and enhances the transepithelial passage of luminal antigen, leading to an increased immune activation. Functionally, this was accompanied by a dramatic increase in local and systemic immune responses against a fed antigen, decreased regulatory T cell population, tolerogenic dendritic cells, and enhanced mucosal delayed-type hypersensitivity response. Conversely, the abolition of colibactin expression by mutagenesis abrogates the alteration of oral tolerance induced by neonatal colonization by E. coli. In conclusion, the vertical colonization by E. coli producing the genotoxin colibactin enhances intestinal translocation and subsequently alters oral tolerance. Thus, early colonization by E. coli from the newly dominant phylogenetic group B2, which produces colibactin, may represent a risk factor for the development of immune-mediated diseases. PMID- 25824840 TI - Phosphorylation events in the multiple gene regulator of group A Streptococcus significantly influence global gene expression and virulence. AB - Whole-genome sequencing analysis of ~800 strains of group A Streptococcus (GAS) found that the gene encoding the multiple virulence gene regulator of GAS (mga) is highly polymorphic in serotype M59 strains but not in strains of other serotypes. To help understand the molecular mechanism of gene regulation by Mga and its contribution to GAS pathogenesis in serotype M59 GAS, we constructed an isogenic mga mutant strain. Transcriptome studies indicated a significant regulatory influence of Mga and altered metabolic capabilities conferred by Mga regulated genes. We assessed the phosphorylation status of Mga in GAS cell lysates with Phos-tag gels. The results revealed that Mga is phosphorylated at histidines in vivo. Using phosphomimetic and nonphosphomimetic substitutions at conserved phosphoenolpyruvate:carbohydrate phosphotransferase regulation domain (PRD) histidines of Mga, we demonstrated that phosphorylation-mimicking aspartate replacements at H207 and H273 of PRD-1 and at H327 of PRD-2 are inhibitory to Mga dependent gene expression. Conversely, non-phosphorylation-mimicking alanine substitutions at H273 and H327 relieved inhibition, and the mutant strains exhibited a wild-type phenotype. The opposing regulatory profiles observed for phosphorylation- and non-phosphorylation-mimicking substitutions at H273 extended to global gene regulation by Mga. Consistent with these observations, the H273D mutant strain attenuated GAS virulence, whereas the H273A strain exhibited a wild type virulence phenotype in a mouse model of necrotizing fasciitis. Together, our results demonstrate phosphoregulation of Mga and its direct link to virulence in M59 GAS strains. These data also lay a foundation toward understanding how naturally occurring gain-of-function variations in mga, such as H201R, may confer an advantage to the pathogen and contribute to M59 GAS pathogenesis. PMID- 25824842 TI - Parity-dependent recognition of DBL1X-3X suggests an important role of the VAR2CSA high-affinity CSA-binding region in the development of the humoral response against placental malaria. AB - Plasmodium falciparum multidomain protein VAR2CSA stands today as the leading vaccine candidate against pregnancy-associated malaria (PAM). Most of the studies aiming to decrypt how naturally acquired immunity develops have assessed the immune recognition of individual VAR2CSA Duffy-binding-like (DBL) domains, thus overlooking the presence of conformational epitopes resulting from the overall folding of the full-length protein. In order to characterize the development of humoral immunity toward VAR2CSA, we made use of a large cohort of 293 Senegalese pregnant women to assess the level of recognition by plasma IgG of the full length VAR2CSA protein of the 3D7 parasite strain (3D7-VAR2CSA), the CSA-binding multidomains 3D7-DBL1X to -DBL3X (3D7-DBL1X-3X), and the CSA nonbinding multidomains 3D7-DBL4epsilon to -DBL6epsilon (3D7-DBL4epsilon-6epsilon), as well as individual 3D7-DBL domains. Our results revealed a parity-dependent recognition of the full-length 3D7-VAR2CSA and of the CSA-binding region, 3D7 DBL1X-3X. Indeed, multigravid women possess significantly higher levels of antibodies directed against these constructs than primigravidae. Our results suggest an important role of antibodies targeting the CSA-binding region in the development of immunity against PAM, therefore providing new insights on how natural protection might be acquired and further information for the design of VAR2CSA-based vaccines. PMID- 25824841 TI - Analysis of the effects of cigarette smoke on staphylococcal virulence phenotypes. AB - Cigarette smoking is the leading preventable cause of death, disease, and disability worldwide. It is well established that cigarette smoke provokes inflammatory activation and impairs antimicrobial functions of human immune cells. Here we explore whether cigarette smoke likewise affects the virulence properties of an important human pathogen, Staphylococcus aureus, and in particular methicillin-resistant S. aureus (MRSA), one of the leading causes of invasive bacterial infections. MRSA colonizes the nasopharynx and is thus exposed to inhalants, including cigarette smoke. MRSA exposed to cigarette smoke extract (CSE-MRSA) was more resistant to macrophage killing (4-fold higher survival; P < 0.0001). CSE-MRSA demonstrated reduced susceptibility to cell lysis (1.78-fold; P = 0.032) and antimicrobial peptide (AMP) (LL-37) killing (MIC, 8 MUM versus 4 MUM). CSE modified the surface charge of MRSA in a dose-dependent fashion, impairing the binding of particles with charge similar to that of AMPs by 90% (P < 0.0001). These changes persisted for 24 h postexposure, suggesting heritable modifications. CSE exposure increased hydrophobicity by 55% (P < 0.0001), which complemented findings of increased MRSA adherence and invasion of epithelial cells. CSE induced upregulation of mprF, consistent with increased MRSA AMP resistance. S. aureus without mprF had no change in surface charge upon exposure to CSE. In vivo, CSE-MRSA pneumonia induced higher mouse mortality (40% versus 10%) and increased bacterial burden at 8 and 20 h postinfection compared to control MRSA-infected mice (P < 0.01). We conclude that cigarette smoke-induced immune resistance phenotypes in MRSA may be an additional factor contributing to susceptibility to infectious disease in cigarette smokers. PMID- 25824844 TI - Evaluation of combinations of in vitro sensitization test descriptors for the artificial neural network-based risk assessment model of skin sensitization. AB - The skin sensitization potential of chemicals has been determined with the use of the murine local lymph node assay (LLNA). However, in recent years public concern about animal welfare has led to a requirement for non-animal risk assessment systems for the prediction of skin sensitization potential, to replace LLNA. Selection of an appropriate in vitro test or in silico model descriptors is critical to obtain good predictive performance. Here, we investigated the utility of artificial neural network (ANN) prediction models using various combinations of descriptors from several in vitro sensitization tests. The dataset, collected from published data and from experiments carried out in collaboration with the Japan Cosmetic Industry Association (JCIA), consisted of values from the human cell line activation test (h-CLAT), direct peptide reactivity assay (DPRA), SH test and antioxidant response element (ARE) assay for chemicals whose LLNA thresholds have been reported. After confirming the relationship between individual in vitro test descriptors and the LLNA threshold (e.g. EC3 value), we used the subsets of chemicals for which the requisite test values were available to evaluate the predictive performance of ANN models using combinations of h CLAT/DPRA (N = 139 chemicals), the DPRA/ARE assay (N = 69), the SH test/ARE assay (N = 73), the h-CLAT/DPRA/ARE assay (N = 69) and the h-CLAT/SH test/ARE assay (N = 73). The h-CLAT/DPRA, h-CLAT/DPRA/ARE assay and h-CLAT/SH test/ARE assay combinations showed a better predictive performance than the DPRA/ARE assay and the SH test/ARE assay. Our data indicates that the descriptors evaluated in this study were all useful for predicting human skin sensitization potential, although combinations containing h-CLAT (reflecting dendritic cell-activating ability) were most effective for ANN-based prediction. PMID- 25824845 TI - Polio vaccination: past, present and future. AB - Live attenuated oral polio vaccine (OPV) and inactivated polio vaccine (IPV) are the tools being used to achieve eradication of wild polio virus. Because OPV can rarely cause paralysis and generate revertant polio strains, IPV will have to replace OPV after eradication of wild polio virus is certified to sustain eradication of all polioviruses. However, uncertainties remain related to IPV's ability to induce intestinal immunity in populations where fecal-oral transmission is predominant. Although substantial effectiveness and safety data exist on the use and delivery of OPV and IPV, several new research initiatives are currently underway to fill specific knowledge gaps to inform future vaccination policies that would assure polio is eradicated and eradication is maintained. PMID- 25824846 TI - Case report: clues to the diagnosis of an unsuspected massive levothyroxine overdose. AB - There is currently little literature pertaining to levothyroxine overdose apart from minor or accidental overdoses in the pediatric population. In particular, there is little information available on how to confidently differentiate levothyroxine overdose from endogenous causes of thyrotoxicosis when there is no history available at the time of assessment. We report a levothyroxine (15,800 mcg) and citalopram (2,460 mg) overdose in a 55-year-old woman presenting with seizure and tachycardia in which the diagnosis was not initially suspected. Clinical data, including a long history of treated hypothyroidism and lack of a goiter; and biochemical findings, such as an incompletely suppressed thyroid stimulating hormone (TSH) level, despite a markedly elevated free thyroxine level (FT4), a normal sex hormone-binding globulin level at baseline, and an undetectable thyroglobulin, supported the diagnosis of thyrotoxicosis due to a massive exogenous thyroid hormone overdose. Treatment was given to decrease free triiodothyronine (FT3) conversion and increase thyroid hormone clearance with dexamethasone and cholestyramine. The patient made a full recovery. Levothyroxine overdose can result in subtle symptoms and signs clinically, even when in massive quantities. This can make diagnosis challenging. Biochemical features, such as the pattern of thyroid hormone elevation and thyroglobulin levels, help differentiate exogenous thyroid hormone overdose from endogenous causes of thyrotoxicosis. PMID- 25824843 TI - In vitro anti-Plasmodium falciparum properties of the full set of human secreted phospholipases A2. AB - We have previously shown that secreted phospholipases A2 (sPLA2s) from animal venoms inhibit the in vitro development of Plasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA2 circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA2s in host defense against P. falciparum has not been investigated. We show here that 4 out of 10 human sPLA2s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potent in vitro anti-Plasmodium properties with half maximal inhibitory concentrations (IC50s) of 2.9 +/- 2.4, 10.7 +/- 2.1, 16.5 +/- 9.7, and 94.2 +/- 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA2 catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic to P. falciparum than native lipoproteins. However, the total enzymatic activities of human sPLA2s on purified lipoproteins or plasma did not reflect their inhibitory activities on P. falciparum. For instance, hGIIF is 9 fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA2s with anti-Plasmodium properties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibiting P. falciparum than those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA2s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA2s toward low- and high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodium activity. Together, our findings indicate that 4 human sPLA2s are active against P. falciparum in vitro and pave the way to future investigations on their in vivo contribution in malaria pathophysiology. PMID- 25824847 TI - Social support moderates the effects of stress on sleep in adolescents. AB - Academic expectations and demands become primary sources of stress during adolescence, negatively affecting sleep. To cope with stress, adolescents may turn to social support figures. The present study tested the extent of main and moderating effects of various sources of social support on the association between stress and sleep. Adolescents (n = 202, meanage 14.6 years, standard deviation = 0.71) reported on academic stress, sleep, and support using questionnaires during a low- and high-stress period, defined by the absence or presence of examinations, respectively. Inquiries were made regarding social support from parents, friends, and class supervisor. During both stress periods, academic stress was associated negatively with sleep quality and positively with sleep reduction. Social support increased sleep quality and lowered sleep reduction. In addition, social support moderated the effects of academic stress on sleep, thus improving sleep quality and lowering sleep reduction. Moderating effects were stronger during a period of high stress. The present study showed that adolescents can benefit from stress moderation through social support by improvements of sleep quality and sleep reduction. Such moderating effects should be taken into account when studying stress and sleep. Implications and recommendations based on these findings are discussed. PMID- 25824848 TI - "Non-classical" paraneoplastic neurological syndromes associated with well characterized antineuronal antibodies as compared to "classical" syndromes - More frequent than expected. AB - OBJECTIVES: Paraneoplastic neurological syndromes (PNSs) are rare disorders in association with cancer and sub-divided into "classical" and "non-classical" syndromes according to a 2004 consensus paper proposed by a panel of PNS experts. "Classical" PNSs are regarded to account for the vast majority of cases. However, systematic reports on clinical PNS manifestations are rare. Therefore, we analyzed the spectrum of PNS in our clinic. METHODS: We retrospectively investigated medical records from consecutive patients diagnosed with definite PNS and serological evidence of well-characterized onconeural antibodies (anti Hu, Yo, Ri, CV2/CRMP5, Ma1, Ma2, and amphiphysin) analyzed between 1991 and 2014 in our clinic. RESULTS: Of the 50 patients identified with onconeural antibody positive PNS, 28 patients (56.0%) had "classical" PNS, and 22 (44.0%) "non classical" PNS. Subacute cerebellar degeneration was the most frequent "classical" syndrome, brainstem encephalitis and subacute sensorimotor neuronopathy the most frequent "non-classical" syndromes. Anti-Hu antibodies were most frequent in both groups. 86.1% of patients developed neurological symptoms before the cancer was known. No differences between "classical" and "non classical" syndromes were detected with respect to age, tumor entities and median time to diagnosis. However, whereas most patients with "classical" syndromes were females, there was no gender predominance in patients with "non-classical" PNS and the latter had significantly more frequent peripheral neurological syndromes. CONCLUSIONS: The so-called "non-classical" PNSs in association with well characterized onconeural antibodies were more common in our patient population than expected. Therefore, in neurological disorders of unclear etiology with a subacute onset and atypical presentation further diagnostic work-up including investigation of onconeural antibodies is necessary. PMID- 25824849 TI - HLA-DRB1 does not have a role in clinical response to interferon-beta among Iranian multiple sclerosis patients. AB - BACKGROUND & OBJECTIVES: The role of human leukocyte antigen (HLA) in clinical response to immunotherapy is not completely known. In this study we evaluated the relationship between HLA-DRB1 genotype, which has been proved to be more common in Iranian MS patients, and clinical response to interferon-beta (IFNbeta), which is the most common immunotherapy for relapsing-remitting MS. DESIGN AND SETTING: In this study 68 Iranian patients with confirmed diagnosis of RRMS who had been referred to and admitted in Neurology Department of Amiralam and Khatam Hospitals in Tehran were selected. Patients were followed prospectively for 2 years since initiation of therapy and clinical data, including EDSS scores were recorded every 3 months. MRI was performed at the time of diagnosis and each year. METHODS: HLA-DRB1 typing was performed by polymerase chain reaction (PCR) for all patients and data was analyzed by STATA 12th edition. RESULTS: There were 47 (69.1%) responders and 21 (30.9%) non-responders. These two groups were demographically and clinically comparable. Fisher's exact test did not show any difference between HLA-DRB1 allele frequencies in responders and non-responders. CONCLUSIONS: Our findings confirmed the lack of association between HLA-DRB1 and clinical response to IFNbeta among MS patients as previous studies had done. PMID- 25824850 TI - Fluorescent gold nanodots based sensor array for proteins discrimination. AB - A series of dual-ligand cofunctionalized fluorescent gold nanodots with similar fluorescence and diverse surface properties has been designed and synthesized to build a protein sensing array. Using this "chemical nose/tongue" strategy, fluorescence response patterns can be obtained on the array and identified via linear discriminant analysis (LDA). Eight proteins have been well distinguished at low concentration (A280 = 0.005) based on this sensor array. The practicability of this sensor array was further validated by high accuracy (100%) examination of 48 unknown protein samples. PMID- 25824851 TI - Additive, modular functionalization of reactive self-assembled monolayers: toward the fabrication of multilevel optical storage media. AB - We report a novel strategy based on iterative microcontact printing, which provides additive, modular functionalization of reactive SAMs by different functional molecules. We demonstrate that after printing the molecules form an interpenetrating network at the SAM surface preserving their individual properties. We exploited the process by fabricating new optical storage media that consist of a multilevel TAG. PMID- 25824852 TI - Comparing Effectiveness of Treatments for Borderline Personality Disorder in Communal Mental Health Care: The Oulu BPD Study. AB - The implementation of effective psychotherapies in community mental health care is challenging. This study aimed to create a well-structured and easily applicable treatment model for patients with severe borderline personality disorder (BPD). We integrated a schema therapy based psycho-educational group into an available individual therapy. Two groups were formed: (1) community treatment by experts (CTBE) patients (n = 24) receiving new treatment and (2) treatment as usual (TAU) patients (n = 47). Changes in symptoms were measured by Borderline Personality Disorder Severity Index-IV interview and quality of life by the 15D health-related quality of life questionnaire. After 1 year the CTBE patients showed a significant reduction in a wider range of BPD symptoms and better quality of life than TAU patients. The results of this study are encouraging. A well-structured treatment model was successfully implemented into community mental health care with improved patient adherence to treatment and superior treatment outcomes compared to TAU patients. PMID- 25824853 TI - Transplant in haste, repent at your leisure? PMID- 25824854 TI - Using a new otologic operating microscope: unexpected complications. AB - The present work report cases of auricular burns after routine otologic surgery possibly induced by the operating microscope. Single-center retrospective study. April 2013 to January 2014, eight children presented with auricular burns after otologic surgery. Median age was 10.1 years. Cheloid scar occurred in six cases. A small scar was present for the other two patients without any other sequelae. No patient had chondritis nor cartilage loss. There was no possibility of physical or electrical trauma in the pretragal or retroauricular cutaneous area during the operations. Therefore, the only remaining hypothesis to explain these burns was thermal damage induced by the operative microscope. PMID- 25824855 TI - Differences in successful treatment completion among pregnant and non-pregnant American women. AB - The present study explores characteristics of successful substance abuse treatment completion of pregnant women through an analysis of retrospective outcomes data. Women without prior treatment admissions, aged 18-44, and not in methadone maintenance therapy were included (N = 678,782). Chi-square tests analyzed significant differences; logistic regression provided predictive probabilities; odds ratios (OR) and risk differences with 95 % confidence intervals represent the effect sizes and clinically meaningful differences. Pregnant women were less likely to successfully complete treatment than non pregnant women (chi (2) = 321.33, df = 1, p < 0.0001), though the difference was not clinically meaningful (risk difference = 4.75, 95 % confidence interval (CI) = 4.23-5.26). Aside from criminal justice agencies, "other community agencies" refer the greatest percentage of pregnant women to treatment (risk difference = 6.37, 95 % CI = 5.89-6.84). Pregnant women successfully complete treatment more than non-pregnant women in only non-intensive outpatient settings (chi (2) = 10,182.48, df = 7, p < 0.0001). Further attention to referral source and treatment setting for pregnant women may improve successful treatment completion by targeting needs of pregnant women. Referring to non-intensive outpatient and residential hospital treatment settings may help to ameliorate prenatal substance abuse treatment contingent on the primary problem substance. PMID- 25824856 TI - Influence of mouse strain on ovarian tissue recovery after engraftment with angiogenic factor. AB - BACKGROUND: For women facing gonadotoxic treatment, cryopreservation of ovarian tissue with subsequent retransplantation during remission is a promising technique for fertility preservation. However, follicle loss within grafted ovarian tissue can be caused by ischemia and progressive revascularization. Several xenograft models using different immunodeficient rodent lines are suitable for studying ovarian tissue survival and follicular viability after frozen-thawed ovarian cortex transplantation. SCID mice, which are deficient for functional B and T cells, are the most commonly used mice for ovarian xenograft studies. However, due to incomplete immunosuppression, NOD-SCID mice displaying low NK cell function and an absence of circulating complement might be more appropriate. The present study aims to define the most appropriate immunodeficient mouse strain for ovarian tissue xenotransplantation by comparing ovarian graft recovery in SCID and NOD-SCID mice following engraftment in the presence of isoform 111 of vascular endothelial growth factor. METHODS: Sheep ovarian cortex fragments were embedded in a collagen matrix, with or without VEGF111, before being stitched onto the ovaries of SCID and NOD-SCID mice. Transplants were recovered after 3 days to study early revascularization or after 3 weeks to evaluate follicle preservation and tissue fibrosis through histological analyses. RESULTS: At day 3, vessels were largely reorganized in the ovarian grafts of both mouse strains. After 3 weeks, the cortical tissue was clearly identifiable in SCID mice but not in NOD-SCID mice. Upon VEGF111 treatment, vascularization was significantly improved 3 days after transplantation in SCID mice. This increase in vessel density was correlated with better follicular preservation in SCID mice 3 weeks after transplantation. Fibrosis was not decreased by VEGF treatment in either mouse strain. CONCLUSIONS: Tissue architecture and follicular morphology were better preserved in ovarian tissues grafted in SCID mice in comparison with NOD-SCID mice. Moreover, tissue revascularization was improved in SCID mice by VEGF111 graft treatment. Thus, we consider SCID mice to be the best murine model for studying ovarian tissue xenografts. PMID- 25824857 TI - Predictors of postoperative morbidity after cytoreduction for advanced ovarian cancer: Analysis and management of complications in upper abdominal surgery. AB - OBJECTIVE: To evaluate the complication rate and its impact in patients who have undergone upper abdominal surgery for treatment of advanced ovarian cancer. METHODS: Patients who have undergone upper abdominal surgery including diaphragm surgery, splenectomy, distal pancreatectomy, gastric resection, liver resection and biliary surgery were considered for the study. Perioperative complications were evaluated and graded according to Clavien-Dindo. RESULTS: One hundred and twenty one patients were included. Two hundred and twelve surgical procedures were performed. Thirty-six patients reported at least one complication, but 61.1% of these the complication was mild. Median hospital stay for patients with and without complication was 7 vs. 13days respectively (p<0.001). There was a significant correlation between post-operative hospital stay and the total number of surgical procedures (R=0.445, p<0.001). At multivariate analysis, diaphragmatic resection and pancreatic resection were associated with a significant increase of postoperative hospital stay, furthermore diaphragmatic resection (p=0.004), hepatic resection (p=0.004), pancreatectomy (p=0.011) and biliary surgery (p=0.049) were independent predictors of severe (G3-G4) complication. CONCLUSIONS: Rate of complications of patients submitted to upper abdominal surgery for ovarian cancer is acceptable. Prediction of severe complications is the goal for its optimal management. Extensive procedures should be avoided with those patients in which optimal residual tumor could not be reached. PMID- 25824858 TI - Underlying Mechanisms for Coexisting Central and Obstructive Sleep Apnea: Nocturnal PaCO2 and Poor Sleep Quality Are Key Issues. AB - Coexisting central and obstructive sleep apnea is a challenging clinical situation. We report a case exhibiting an overnight shift from obstructive to central events. The central sleep apnea component was related to sleep instability, hyperventilation and low nocturnal PaCO2. Both types of respiratory events were successfully treated with adaptive servoventilation. PMID- 25824859 TI - Self-assembled sorbitol-derived supramolecular hydrogels for the controlled encapsulation and release of active pharmaceutical ingredients. AB - A simple supramolecular hydrogel based on 1,3:2,4-di(4-acylhydrazide)benzylidene sorbitol (DBS-CONHNH2), is able to extract acid-functionalised anti-inflammatory drugs via directed interactions with the self-assembled gel nanofibres. Two component hydrogel-drug hybrid materials can be easily formed by mixing and exhibit pH-controlled drug release. PMID- 25824860 TI - Deciphering allogeneic antibody response against native and denatured HLA epitopes in organ transplantation. AB - Anti-HLA donor-specific antibodies are deleterious for organ transplant survival. Class I HLA donor-specific antibodies are identified by using the Luminex single antigen beads (LSAB) assay, which also detects anti-denatured HLA antibodies (anti-dHLAs). Anti-dHLAs are thought to be unable to recognize native HLA (nHLA) on the cell surface and therefore to be clinically irrelevant. Acid denaturation of nHLA on LSAB allows anti-dHLAs to be discriminated from anti-nHLAs. We previously defined a threshold for the ratio between mean fluorescence intensity against acid-treated (D for denaturation) and nontreated (N) LSAB, D >= 1.2 N identifying the anti-dHLAs. However, some anti-dHLAs remained able to bind nHLA on lymphocytes in flow cytometry crossmatches, and some anti-nHLAs conserved significant reactivity toward acid-treated LSAB. After depleting serum anti-nHLA reactivity with HLA-typed cells, we analyzed the residual LSAB reactivity toward nontreated and acid-treated LSABs, and then evaluated the ability of antibodies to recognize nHLA alleles individually. We observed that sera can contain mixtures of anti-nHLAs and anti-dHLAs, or anti-nHLAs recognizing acid-resistant epitopes, all possibly targeting the same allele(s). Therefore, the anti-HLA antibody response can be highly complex and subtle, as is the accurate identification of pathogenic anti-HLA antibodies in human serum. PMID- 25824861 TI - Evaluating the inverse reasoning account of object discovery. AB - People routinely make inferences about unobserved objects. A hotel guest with welts on his arms, for example, will often worry about bed bugs. The discovery of unobserved objects almost always involves a backward inference from some observed effects (e.g., welts) to unobserved causes (e.g., bed bugs). The inverse reasoning account, which is typically formalized as Bayesian inference, posits that the strength of a backward inference is closely connected to the strength of the corresponding forward inference from the unobserved causes to the observed effects. We evaluated the inverse reasoning account of object discovery in three experiments where participants were asked to discover the unobserved "attractors" and "repellers" that controlled a "particle" moving within an arena. Experiments 1 and 2 showed that participants often failed to provide the best explanations for various particle motions, even when the best explanations were simple and when participants enthusiastically endorsed these explanations when presented with them. This failure demonstrates that object discovery is critically dependent on the processes that support hypothesis generation-processes that the inverse reasoning account does not explain. Experiment 3 demonstrated that people sometimes generate explanations that are invalid even according to their own forward inferences, suggesting that the psychological processes that support forward and backward inference are less intertwined than the inverse reasoning account suggests. The experimental findings support an alternative account of object discovery in which people rely on heuristics to generate possible explanations. PMID- 25824863 TI - Computational analysis identifies invasion-associated genes in pituitary adenomas. AB - Pituitary adenomas are considered to be benign tumours. However, they can infiltrate surrounding tissues, which may cause a failure of complete removal during surgical resection. Thus far, no molecular biomarkers have been identified, which are able to reliably predict the behaviour of this type of tumour. In the present study, a list of differentially expressed genes in invasive pituitary adenomas was obtained using a computational bioinformatics analysis on the DNA microarray expression profiles. The gene expression datasets of a total of 16 samples were retrieved from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene set enrichment analysis was later conducted on the significantly (FDR<0.05) differentially expressed genes. A total of 194 genes were identified as differentially expressed. The pathway impact analysis revealed that cell adhesion molecules may be vital in the progression of pituitary adenoma invasion. A total of six genes, claudin 7, contactin associated protein-like 2, integrin alpha6, junctional adhesion molecule 3, protein tyrosine phosphatase, receptor type C and cadherin-associated protein alpha1 were identified as molecular biomarkers for pituitary adenoma invasion. The present study identified six novel molecular biomarkers, which may be used for diagnostic or therapeutic purposes. However, further experimental investigations are required to validate the present findings. PMID- 25824864 TI - Mechanisms, Clinical Strategies, and Promising Treatments of Neurodegenerative Diseases. 12th International Conference AD/PD Nice, France, March 18-22, 2015: Abstracts. PMID- 25824862 TI - Reward and punishment act as distinct factors in guiding behavior. AB - Behavior rests on the experience of reinforcement and punishment. It has been unclear whether reinforcement and punishment act as oppositely valenced components of a single behavioral factor, or whether these two kinds of outcomes play fundamentally distinct behavioral roles. To this end, we varied the magnitude of a reward or a penalty experienced following a choice using monetary tokens. The outcome of each trial was independent of the outcome of the previous trial, which enabled us to isolate and study the effect on behavior of each outcome magnitude in single trials. We found that a reward led to a repetition of the previous choice, whereas a penalty led to an avoidance of the previous choice. Surprisingly, the effects of the reward magnitude and the penalty magnitude revealed a pronounced asymmetry. The choice repetition effect of a reward scaled with the magnitude of the reward. In a marked contrast, the avoidance effect of a penalty was flat, not influenced by the magnitude of the penalty. These effects were mechanistically described using a reinforcement learning model after the model was updated to account for the penalty-based asymmetry. The asymmetry in the effects of the reward magnitude and the punishment magnitude was so striking that it is difficult to conceive that one factor is just a weighted or transformed form of the other factor. Instead, the data suggest that rewards and penalties are fundamentally distinct factors in governing behavior. PMID- 25824865 TI - Hospitalization rates and utilization among patients with giant cell arteritis: A population-based study from 1987 to 2012. AB - BACKGROUND: Patients with giant cell arteritis (GCA) may experience serious vascular and visual complications. It is unknown, however, to what extent the difficulties of the disease may lead to hospitalization. The goal of this study is to discern whether patients with GCA are at greater risk for all-cause hospitalizations when compared to the general population. METHODS: This retrospective, population-based cohort study utilized patients with large vessel or visual involvement who were diagnosed with GCA (as defined by the 1990 ACR criteria) between 1/1/1950 and 12/31/2009, and a reference cohort of patients without GCA matched on age, sex, and calendar year. Each patients' medical record was examined for hospitalizations from 1987 through 2012. For this analysis, follow-up began with the latter of index date or 1/1/1987 and ended at the earlier of death, emigration from Olmsted County, or 12/31/2012. Discharge diagnoses were grouped together using the Clinical Classifications Software (CCS) for ICD-9-CM from Healthcare Cost and Utilization Project (HCUP). Data were analyzed using person-year methods and rate ratios comparing GCA to non-GCA. RESULTS: The GCA cohort consists of 199 patients with a mean age of 76.2 (79.9% female) and follow-up of 8.2 years. The non-GCA cohort is comprised of 194 patients with a mean age of 75.7 (78.9% female) and follow-up of 8.6 years. The patients with GCA had 816 hospitalizations and the non-GCA patients had 737 hospitalizations. GCA patients proved to be at a marginally greater risk for all causes of hospitalization [rate ratio (RR) = 1.13; 95% confidence interval (CI): 1.02-1.25]; however, the rate of hospitalization for patients with and without GCA decreased significantly from 1987 to 2012. Two specific discharge categories are of interest. First, transient cerebral ischemia is a greater risk of hospitalization for patients with GCA who had 16 hospitalizations compared to patients without GCA who only had 5 hospitalizations (RR = 3.06; 95% CI: 1.27 9.47). Second, patients with GCA (21 hospitalizations) are at greater risk of hospitalization for syncope than patients without GCA (5 hospitalizations) (RR = 3.98; 95% CI: 1.72-12.14). CONCLUSION: In this first ever analysis of all-cause hospitalizations in a population-based cohort, patients with GCA appear to be at a marginally greater risk for hospitalization than patients without GCA, although the rate of hospitalization for GCA patients decreased from 1987 to 2012. Patients with GCA are at increased risk of hospitalization for both transient cerebral ischemia and syncope. PMID- 25824866 TI - Enhanced electrochemical performance and thermal stability of LiNi(0.5)Mn(1.5)O4 using an electrolyte with sulfolane. AB - A sulfide-based SEI layer was formed on the surface of a LiNi0.5Mn1.5O4 cathode by using a sulfolane-carbonate mixed solvent electrolyte, which led to an improvement in the electrochemical performance. Moreover, the thermal stability of the LiNi0.5Mn1.5O4 cathode was also significantly improved in the presence of the SEI layer. ARC (Accelerating Rate Calorimetry) tests showed that the self heating rate of the delithiated LiNi0.5Mn1.5O4 material in the sulfolane carbonate electrolyte was suppressed. PMID- 25824867 TI - Diversity among mandarin varieties and natural sub-groups in aroma volatiles compositions. AB - BACKGROUND: Mandarins constitute a large, diverse and important group within the Citrus family. Here, we analysed the aroma volatiles compositions of 13 mandarin varieties belonging to seven genetically different natural sub-groups that included common mandarin (C. reticulata Blanco), clementine (C. clementina Hort. ex. Tan), satsuma (C. unshiu Marcovitch), Mediterranean mandarin (C. deliciosa Tenore), King mandarin (C. nobilis Loureiro), and mandarin hybrids, such as tangor (C. reticulata * C. sinensis) and tangelo (C. reticulata * C. paradisi). RESULTS: We found that mandarin varieties among tangors ('Temple', 'Ortanique'), tangelos ('Orlando', 'Minneola') and King ('King') had more volatiles, at higher levels, and were richer in sesquiterpene and ester volatiles, than other varieties belonging to the sub-groups common mandarin ('Ora', 'Ponkan'), clementine ('Oroval', 'Caffin'), satsuma ('Okitsu', 'Owari') and Mediterranean mandarin ('Avana', 'Yusuf Efendi'). Hierarchical clustering and principal component analysis accurately differentiated between mandarin varieties and natural sub-groups according to their aroma-volatile profiles. CONCLUSIONS: Although we found wide differences in aroma-volatiles compositions among varieties belonging to different natural sub-groups, we detected only minor differences among varieties within any natural sub-group. These findings suggest that selecting appropriate parents would enable manipulation of aroma-volatile compositions in future mandarin breeding programmes. PMID- 25824868 TI - [Cervical cancer screening: Is active recruitment worth the effort?]. AB - OBJECTIVES: To determine the percentage of women who have had a Pap smear in the last 5 years, and the place where it was carried out. To detect cytological abnormalities and precursors of cervical cancer in un-screened or inadequately screened women and the prevalence of HPV-positive determinations. DESIGN: Cross sectional study. SETTING: Natahoyo Health Centre, Gijon (Spain). PARTICIPANTS: Women aged 40-50 years living in the area and assigned to the Health Centre. METHODS: The information was collected from databases, telephone and home surveys. There was active recruitment of unscreened women or inadequately screened in Primary Care as well as offering to perform cytology and HPV determination. RESULTS: Of the 1420 women aged 40 to 50 years, 1236 (87%) had cytology in the last 5 years, and 184 women (13%) had no screening or it was inadequate. Of these 184 women, 108 (58.7%) agreed to have cytology and HPV test performed. No high-grade cervical dysplasia was diagnosed. The prevalence of HPV positive was 8.3%. CONCLUSIONS: In our population there is a high coverage of opportunistic screening for cervical cancer. The active recruitment of women who were not in the screening program was not useful. PMID- 25824870 TI - Population genetics. The peopling of Britain. PMID- 25824869 TI - Genetic linkage analysis in the age of whole-genome sequencing. AB - For many years, linkage analysis was the primary tool used for the genetic mapping of Mendelian and complex traits with familial aggregation. Linkage analysis was largely supplanted by the wide adoption of genome-wide association studies (GWASs). However, with the recent increased use of whole-genome sequencing (WGS), linkage analysis is again emerging as an important and powerful analysis method for the identification of genes involved in disease aetiology, often in conjunction with WGS filtering approaches. Here, we review the principles of linkage analysis and provide practical guidelines for carrying out linkage studies using WGS data. PMID- 25824871 TI - Direct Catalytic Asymmetric Aldol Reaction of an alpha-Azido Amide. AB - A direct aldol reaction of an alpha-azido 7-azaindolinylamide, promoted by a Cu based cooperative catalyst, is documented. Aromatic aldehydes bearing an ortho substituent exhibited diastereodivergency depending on the nature of the chiral ligands used. Smooth reactions with ynals highlighted the broad substrate scope. A vicinal azido alcohol unit in the product allowed direct access to the corresponding aziridine and facile hydrolysis of the 7-azaindolinylamide moiety furnished enantioenriched beta-hydroxy-alpha-azido carboxylic acid derivatives. PMID- 25824872 TI - Triboelectric sensor as self-powered signal reader for scanning probe surface topography imaging. AB - We report a self-powered signal reading mechanism for imaging surface topography using a triboelectric sensor (TES) without supplying an external power or light source. A membrane-structured triboelectric nanogenerator (TENG) is designed at the root of a whisker (probe); the deflection of the whisker causes the two contacting surfaces of the TENG to give an electric output current/voltage that responds to the bending degree of the whisker when it scans over a rough surface. A series of studies were carried out to characterize the performance of the TES, such as high sensitivity of 0.45 V mm(-1), favorable repeating of standard deviation 8 mV, high Z-direction resolution of 18 MUm, as well as lateral resolution of 250 MUm by using a probe of size 11 mm in the length and 120 MUm in radius. It not only can recognize the surface feature and size but also can perform a surface topography imaging in scanning mode. This work shows the potential of a TES as a self-powered tactile sensor for applications at relatively low spatial resolution. PMID- 25824873 TI - Improved tibial component rotation in TKA using patient-specific instrumentation. AB - INTRODUCTION: Patient-specific instrumentation (PSI) was introduced in an attempt to reduce positional outliers of components in total knee arthroplasty (TKA). It was hypothesized that PSI could help with the positioning of tibial components in optimal rotational alignment. METHODS: A magnetic resonance imaging (MRI) analysis of 58 patients following TKA was conducted. Of these, 30 operations were performed using PSI and 28 using conventional instrumentation. The rotation of the tibial components was determined in MRI using three different reference lines: a tangent to the dorsal tibial condyles, the tibial epicondylar line, and the tibial tubercle. Deviations >9 degrees were considered outliers. Also internal rotation >1 degrees was considered an outlier. Data were analyzed statistically for positional outliers using the Chi-squared test. RESULTS: There was excellent inter- and intraobserver reliability with low standard deviations for the determination of tibial component rotation using the tangent to the dorsal condyles and the tibial epicondylar line as reference. Using the dorsal tangent as reference, there were eight components in excessive external rotation (28.6 %) and one component being in relative internal rotation (5.4 degrees ) in the conventional group, while there were two components in excessive external rotation in the PSI group (6.7 %). Using the tibial epicondyles as reference, there were seven components in excessive external rotation (21.4 %) and one component being in relative internal rotation (4.4 degrees ) in the conventional group; while there were two components in excessive external rotation in the PSI group (6.7 %). These differences were statistically significant (p < 0.05). Measurements based on the tibial tubercle showed poor reproducibility in terms of intra- and interobserver reliability and was of little use in the context of the research question. DISCUSSION AND CONCLUSION: In this setup, PSI was effective in significantly reducing outliers of optimal rotational tibial component alignment during TKA. Anatomy of the proximal tibia does not deliver clear landmarks that are prominent and consistent. This makes both, MRI analysis as well as cutting jig production and intraoperative placement a challenge. PMID- 25824874 TI - MPs call for new national patient safety body to lead clinical accident investigations. PMID- 25824875 TI - How to decide which infant can have robotic surgery? Just do the math. AB - BACKGROUND: In pediatric urology, robot-assisted surgery has overcome several impediments of conventional laparoscopy. However, workspace has a major impact on surgical performance. The limited space in an infant can significantly impede the mobility of robotic instruments. There is currently no consensus on which infant can undergo robotic intervention and no parameters to help make this decision, especially for those surgeons at the start of their learning curve. OBJECTIVE: We sought to evaluate our experience with infants to create an objective standard to determine which patients may be most suitable for robotic surgery. STUDY DESIGN: We prospectively evaluated 45 infants (24 males, 21 females), aged 3-12 months old, who underwent a robotic intervention for either upper or lower urinary tract pathology. At the preoperative office visit the attending surgeon measured the distance between both anterior superior iliac spines (ASIS) as well as the puboxyphoid distance (PXD), regardless of whether the approach was for upper or lower tract disease. Patients' weights were also noted. During surgery, we recorded the number of robotic collisions as well as console time. All surgeries were performed utilizing the da Vinci Si Surgical System by a single surgeon. RESULTS: There were no differences in ASIS, PXD, collisions or console time when stratified by gender, age or weight. When arranging by upper or lower tract approach, there was no difference in the number of collisions. There was a strong inverse relationship between both ASIS distance and PXD and the number of collisions. Additionally, there was a strong correlation between the number of collisions and console time (Fig. 1). Using a cutoff of 13 cm for the ASIS, there were significantly fewer collisions in the >13 cm group as compared to the <=13 cm group. This was also true for the PXD using a cutoff of 15 cm: there were significantly fewer collisions in the >15 cm group as compared to the <=15 cm group. DISCUSSION: Safe proliferation of robotic technology in the infant population is, in part, dependent on careful patient selection. Our data demonstrated a reduction in instrument collisions and console time with increasing anterior superior iliac spine and puboxyphoid distances. Neither age nor weight was correlated with these measurements, the number of instrument collisions or console time. Limitations include that this is a single institution study with all infants being operated on by a single surgeon. Therefore, the findings of this study may not be generalizable to a less experienced surgeon. Yet, we believe that ASIS and PXD measurements can be used as a guide for the novice surgeon who is beginning to perform robotic-assisted surgery in infants. CONCLUSION: We found that surgeon ability to perform robotic surgery in an infant is restricted by collisions when the infant has an ASIS measurement of 13 cm or less or a PXD of 15 cm or less. Objective assessment of anterior superior iliac spine and puboxyphoid distance can aid in selecting which infants can safely and efficiently undergo robotic intervention with a minimum of instrument collision, thereby minimizing operative time. PMID- 25824876 TI - The effectiveness of transcutaneous electrical neural stimulation therapy in patients with urinary incontinence resistant to initial medical treatment or biofeedback. AB - OBJECTIVE: While there are many options for children with treatment refractory urinary incontinence, there is no single accepted method. This study's aim was to prospectively evaluate the effect of transcutaneous electrical nerve stimulation in children with urinary incontinence resistant to standard medical, urological therapy and/or biofeedback. PATIENTS & METHODS: This study was performed at a university hospital. For inclusion, patients >5 years of age first underwent evaluation with urinary ultrasonography, uroflow-electromyogram and voiding diaries. Treatment with biofeedback, alpha adrenergic blockers, anticholinergics and/or urotherapy was commenced according to uroflow-EMG and voiding diary findings. Patients with partial or no response to this standard therapy were then included in this study, performed between April 2012 and February 2014. Patients with anatomical or neurological causes for urinary incontinence were excluded. TENS was performed on S3 dermatome, every day for 3 months. Each session lasted 20 min with a frequency of 10 Hz and generated pulse of 350 MUs. Intensity was determined by the child's sensitivity threshold. Medical treatment and urological therapy was continued during TENS. Uroflow parameters (voiding volume as percentage of expected bladder capacity, Qmax, Qave, flow and voiding time, postvoiding residual urine) and urinary system symptoms (presence of urinary tract infection, frequency, urge incontinence, fractionated voiding and constipation) were compared immediately before commencement and immediately after the completion of 3 months of TENS. RESULTS: Twenty-seven patients were included in this study (4 males, 23 females). Patients' average age was 7.2 years, 11 had overactive bladder and 16 had dysfunctional voiding. Comparison of urinary system symptoms and uroflow parameters before and after TENS are shown in Table. After 3 months of TENS; a statistically significant decrease was observed in the number of patients with frequency, urge incontinence, urinary tract infections and constipation. There was a decrease in the number of patients with fractionated voiding, although this change was not statistically significant. Similarly, for uroflow-EMG parameters; bladder capacity, Qmax, Qave and flow time increased while voiding time and PVR decreased. Changes seen in bladder capacity, Qmax and PVR were statically significant, while other changes were not. Patients' response rates after 3 months of TENS were; complete response in 70.4%, partial response in 22.2% and no response in 7.4%. CONCLUSION: This study has shown that transcutaneous electrical nerve stimulation is a promising treatment option for standard-treatment refractory children with urinary incontinence. PMID- 25824877 TI - Alternative ileal flap for bladder augmentation if mesentery is short. AB - PURPOSE: To date the clam ileocystoplasty is the preferred method of bladder augmentation in children when the urodynamic problem is non-compliance and/or detrusor overactivity. The key to this technique is the incision of the bladder wall deep into the pelvis down to the trigone in order to avoid a diverticulum like neobladder and to provide adequate margin for augmentation. The detubularised ileum flap therefore has to reach to the bottom of the divided bladder on a reliable vascular pedicle without significant tension. A short ileal mesentery caused by previous surgery, peritonitis, peritoneal dialysis or ventriculo-peritoneal shunt may complicate surgery and compromise outcome. We hypothesized we can rely on the communication of the intramural vessels within the intestine and can detubularise the ileum adjacent to the mesentery rather than along the antimesenteric line and this could be combined with ligation of some vasa recta (VR) in order to create alternative ileum flaps, which reach further into the pelvis. Our aim was to assess the viability of the alternative flaps detubularised along the paramesenteric line and measure how many VR could be sacrificed beyond the tertiary arcades. MATERIALS AND METHODS: After ethical approval adjacent ileal segments were detubulirased along the antimesenteric line (Group 1) and along the paramesenteric line (Group 2) in 5 minipigs in general anaesthesia. Ligation of 0,1,2,3 and 4 VR has been performed starting from the free end of the segments. The length of the ileal flaps was recorded. The microcirculation of flap edges was detected by in vivo microscopy using orthogonal polarising spectral imaging (Cytoscan A/R Cytometrics, PA, USA). Clam ileocystoplasty was performed with the ileum detubularised along the paramesenteric line without ligation of VR. Specimens of the augmented bladder were obtained after 4 weeks and stained with Hematoxilin + Eosin. RESULTS: No alteration in capillary red blood cell velocity (RBCV) and perfusion rate (PR) was observed after paramesenteric detubularisation. The flaps in Group 2 reached 20.25 +/- 0.5 mm longer vs. CONTROL: This is 98% of the mean bowel width (20.5 +/ 0.57 mm) measured in the animals. Ligation of each VR further increased the length of both flaps (mean: 10.59 +/- 3.18 mm) however ligation of more than 2 VR gradually decreased the microcirculation in both groups. All animals augmented with alternative flap survived, there was no urine leak or suture break down. Histology confirmed viable bowel flaps. CONCLUSION: Paramesenteric detubularisation of the ileum is fully tolerated and results in longer reaching ileal flap vs. CONTROL: Only limited ligation of VR is tolerated. DISCUSSION: This study showed the first time that clam ileocystoplasty is feasible with ileal flap detubularised along the paramesenteric line. The use of the animal model and the relative short postoperative observation are the main limitations of this study. PMID- 25824878 TI - Response to commentary to 'A comparison of the monti and spiral monti procedures: A survival analysis'. PMID- 25824879 TI - The roles of serum and urinary carbohydrate antigen 19-9 in the management of patients with antenatal hydronephrosis. AB - INTRODUCTION: Serum carbohydrate antigen (CA) 19-9 has been clinically applied as a valuable tumor marker for pancreatic and gastrointestinal carcinoma. CA 19-9 is expressed in normal excretory epithelium tissues. Increased CA 19-9 has also been observed in uroepithelial tumors as well as in nonmalignant conditions including hydronephrosis secondary to ureteral stones. OBJECTIVE: The purpose of this article is to evaluate the role of urinary CA 19-9 as a non-invasive biomarker in the postnatal differentiation of obstructive and non-obstructive hydronephrosis in patients with unilateral antenatal hydronephrosis. STUDY DESIGN: Infants with isolated renal pelvic dilatation, defined as the presence of anteroposterior pelvic diameter (APPD) equal to or greater than 7 mm based on antenatal ultrasound after 28 weeks' gestation, underwent systematic investigation for uropathies and were prospectively followed up. The pyeloplasty group consisted of 17 patients with ureteropelvic junction (UPJ) obstruction who had undergone pyeloplasty. The non-obstructive dilatation (NOD) group consisted of 17 patients with non-obstructive hydronephrosis, and the control group consisted of 21 healthy children. Commercial enzyme-linked immunosorbent assay (ELISA) kits were used to measure the urinary and serum CA 19-9 levels. In both hydronephrosis groups (pyeloplasty and non-obstructive dilatation), the correlations between urinary and serum CA 19-9 levels with the anteroposterior pelvic diameter measured at the third trimester and the postnatal initial evaluation and differential renal function were investigated. RESULTS: The initial median urinary CA 19-9 levels were significantly greater in children who underwent pyeloplasty than in both the non-obstructive hydronephrosis (143 +/- 38 vs. 68 +/ 23, respectively; p = 0.007) and the healthy control groups (143 +/- 38 vs. 13 +/- 3, respectively; p = 0.001) (Figure). Three months after surgery, the urinary CA 19-9 levels had decreased significantly according to the preoperative levels in the pyeloplasty group (143 +/- 38 vs. 55 +/- 16, p = 0.039). In both the pyeloplasty and NOD groups, there was a correlation of urinary CA 19-9 levels with differential renal function and a correlation of serum CA 19-9 levels with the initial anteroposterior pelvic diameter. Receiver operator characteristic (ROC) analysis revealed a better diagnostic profile for the urinary CA 19-9 level than for the serum CA 19-9 level in terms of identifying obstruction in the hydronephrosis groups (areas under the curve = 0.8 and 0.7, respectively). The best cut-off value of for urinary CA 19-9 was 85.5 U/mL with 76% sensitivity, 85% specificity. The negative predictive value was 80%. DISCUSSION: The results suggest that voided urine CA 19-9 levels seems to be a more useful marker than serum CA 19-9 in obstructive dilatation. An appropriate decrease in urinary CA 19 9 levels after pyeloplasty may be used as a predictor of surgical outcome. In addition, the results have a number of important diagnostic implications that should be further validated in a larger study population. CONCLUSIONS: Based on these results, we suggest that a high urinary CA 19-9 level is a non-invasive clinically applicable marker for differentiating between obstruction and non obstructive dilatation. PMID- 25824880 TI - Screening for depression and anxiety in childhood neurogenic bladder dysfunction. AB - INTRODUCTION: Patients with chronic illnesses are known to have anxiety disorders and are likely to be depressed. Anxiety and depression (A/D) has been studied in adults with spina bifida (SB), however, no study has directly screened for A/D in pediatric patients with neurogenic bladder (NB) and their caregivers. OBJECTIVE: The aims of our study were to determine the prevalence of A/D in caregivers of all children with SB and other NB dysfunction and in adolescents with validated screening measures. STUDY DESIGN & PATIENTS: This was a preliminary cross sectional screening investigation for A/D in pediatric patients with NB and their caregivers and adolescents with NB. Pediatric patients were defined as ages birth to 19 years and adolescents as ages 10 years-19 years. A caregiver was self defined as a primary parent/guardian who took care of the pediatric patient for a majority of their time on a daily basis. MATERIALS AND METHODS: We contacted 75 families by mail, of which 15 returned the consent and completed the questionnaires. Subsequently, 25 consecutive families whose children were seen for routine office appointments by the pediatric urology service at the Albany Medical Center in New York participated in person. 22 adolescents completed the Hospital Anxiety and Depression Scale (HADS). 47 caregivers completed both the HADS and the Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Depression among adolescents: Of the 22 adolescents who completed the HADS, the median HADS score was 5.5 (Inter-quartile range (IQR): 1.75-8.75) for anxiety and 1.5 (IQR: 0-4.25) for depression; both scores were within the normal range (<8/21). Individual abnormal HADS scores (>=8/21) were seen in 6/22 (27%) for anxiety and 1/22 (5%) for depression. Anxiety and depression among caregivers: Of the 47 caregivers who completed the HADS and CES-D, the median HADS score was 7 (IQR: 4-11) for anxiety and 4 (IQR: 1-7) for depression; both scores were within the normal range. Individual abnormal HADS scores were seen in 23/47 (49%) for anxiety and 10/47 (21%) for depression. Abnormal CES-D scores (>15) were seen in 15/47 (32%). The median CES-D scores were 8 (IQR: 3-19). DISCUSSION: In this preliminary screening study, we found considerable anxiety in adolescents with NB and both A/D in caregivers. When screening by two validated surveys, adolescents with NB had median scores for A/D that were normal; yet 27% of these patients exhibited scores for anxiety that outwit the normal range. For the caregivers, the median scores were also normal; yet 49% and 32% had scores for A/D, respectively, that were abnormal. SB among pediatric patients has been shown to result in alterations in daily functioning and to increase the dependency on adult care, factors that are associated with altered self-concept, psychological distress, including A/D. Our findings underscore such results from previous studies. In caregivers, we observed a higher prevalence of anxiety than adolescents; similar findings have been reported for caregivers of other chronic conditions. Surprisingly, in caregivers, a lower percentage of scores for depression was observed. Although we have no data on the cause of this finding this may be related to a caregiver's ability to adapt to the demands of the situation in chronic illness or perhaps, lower expectations. The cross-sectional nature of our study limited us to draw any causal relationships for anxiety or depression between neurogenic patients and their caregivers. CONCLUSION: Despite our study limitations, the prevalence of anxiety in adolescents and in the caregivers is striking. Our data highlight that clinicians should screen for A/D more aggressively in pediatric patients with NB dysfunction and in their caregivers. PMID- 25824881 TI - Anogenital distance and penile width measurements in The Infant Development and the Environment Study (TIDES): methods and predictors. AB - BACKGROUND: Anogenital distance (AGD) is an androgen responsive anatomic measurement that may have significant utility in clinical and epidemiological research studies. We describe development of standardized measurement methods and predictors of AGD outcomes. METHODS: We examined infants born to 758 participants in The Infant Development and the Environment Study (TIDES cohort) in four clinical centers in 2011-2013. We developed and implemented a detailed training protocol that incorporated multiple quality control (QC) measures. In males, we measured anoscrotal distance (AGDAS), anopenile distance (AGDAP), and penile width (PW) and in females, anofourchette distance (AGDAF,) and anoclitoral distance (AGDAC). A single examiner obtained three repetitions of all measurements, and a second examiner obtained independent measurements for 14% of infants. We used the intra-rater ICC to assess within-examiner variability and the inter-rater ICC to assess between-examiner variability. We used multivariable linear regression to examine predictors of AGD outcomes including: gestational age at birth, birth weight, gestational age, several measures of body size, race, maternal age, and study center. RESULTS: In the full TIDES cohort, including 758 mothers and children, significant predictors of AGD and PW included: age at exam, gestational age at birth, weight-for-length Z-score, maternal age and study center. In 371 males, the mean (SD) AGDAS, AGDAP, and PW were 24.7 (4.5), 49.6 (5.9), and 10.8 (1.3) mm, respectively. In 387 females, the mean (SD) AGDAF and AGDAC were 16.0 (3.2) mm and 36.7 (3.8) mm, respectively. The intra-examiner ICC and inter-examiner ICC averaged over all subjects and examiners were between 0.89 0.92 and 0.69-0.84 respectively. CONCLUSIONS: Our study confirms that with appropriate training and quality control measures, AGD and PW measurements can be performed reliably and accurately in male and female infants. In order for reliable interpretation, these measurements should be adjusted for appropriate covariates in epidemiologic analysis. PMID- 25824882 TI - Long-term functional outcomes of distal hypospadias repair: a single center retrospective comparative study of TIPs, Mathieu and MAGPI. AB - INTRODUCTION: Tubularized Incised-Plate (TIP) urethroplasty is currently the preferred technique for distal hypospadias repair. Nevertheless, concerns have been raised on the long-term functionality of the reconstructed neourethra. OBJECTIVE: The aim of this study is to evaluate long-term uroflowmetry parameters' evolution after TIP surgery over a long-term follow-up including the adolescent period. TIP patients were compared to normal children using established Miskolc nomograms, as well as to patients who underwent Mathieu and Meatal Advancement and Glanuloplasty (MAGPI) surgery repairs for distal hypospadias. STUDY DESIGN: Files from patients who underwent primary distal hypospadias repair at our institution between January 1, 1997 and January 31, 2001 were reviewed. Only patients with documented serial postoperative uroflowmetry profiles at follow-up visits were included. Comparison between surgeries (TIP vs. Mathieu vs. MAGPI) was performed according to the following postoperative time interval endpoints: 0-6 months, 6-12 months, 12-24 months, 24 48 months, 4-6 years, 6-10 years and >10 years. Maximal urinary flow rate (Qmax) in relation to Voiding Volume (VV) adjusted for Age or Body Surface Area (BSA) were also evaluated in comparison to normal children using established Miskolc nomograms and compared between surgery techniques. RESULTS: 153 patients met the inclusion criteria: 70 (43%) TIP, 24 (17%) Mathieu and 59 (35%) MAGPI. Overall, Qmax increases progressively according to time and age and in particular during the period covering adolescence with a similar trend regardless of the type of surgery. Uroflowmetry profiles in terms of Qmax, VV and PVR were equivalent between surgeries at each examined time point. At 10 years of follow-up postopertively, mean Qmax were 17.2 ml/s, 18.8 ml/s and 21.6 ml/s respectively with no significant difference detected between groups (p = 0.344). Compared to normal children when adjusted for voiding volume and BSA, the proportion of obstructive uroflowmetry patterns defined as Qmax< 5th percentile of nomograms was more prevalent in patients aged 2-7 years old at 60% but decreased to less than 10%in patients aged >13 years for all procedures combined (see abstract figure) but without detected differences between surgery types (p = 0.276). DISCUSSION: After sub-optimal obstructive maximal urinary flows in the early postoperative period, hypospadias patients treated with TIP exhibit favourable long-term evolution with age and during adolescence in particular compared to normal children. In addition, a similar trend was found for patients treated with Mathieu and MAGPI with no significant differences detected between procedures. Nevertheless, because of the relatively small sample size we cannot exclude that a statistical difference between surgeries would have been detected if the study was adequately powered on every endpoint. Nevertheless and also as suggested by the values obtained, this potential difference may be quite small and not clinically relevant. CONCLUSION: These results suggest that the obstructive urinary flow pattern observed in patients early on is possibly an intrinsic feature associated to the malformation itself and may be less of a consequence of the surgical technique. PMID- 25824883 TI - Commentary to 'A comparison of the Monti and spiral Monti procedures: A survival analysis'. PMID- 25824884 TI - Uncovering RNA binding proteins associated with age and gender during liver maturation. AB - In the present study, we perform an association analysis focusing on the expression changes of 1344 RNA Binding proteins (RBPs) as a function of age and gender in human liver. We identify 88 and 45 RBPs to be significantly associated with age and gender respectively. Experimental verification of several of the predicted associations in mice confirmed our findings. Our results suggest that a small fraction of the gender-associated RBPs (~40%) are expressed higher in males than females. Altogether, these observations show that several of these RBPs are important and conserved regulators in maintaining liver function. Further analysis of the protein interaction network of RBPs associated with age and gender based on the centrality measures like degree, betweenness and closeness revealed that several of these RBPs might be prominent players in aging liver and impart gender specific alterations in gene expression via the formation of protein complexes. Indeed, both age and gender-associated RBPs in liver were found to show significantly higher clustering coefficients and network centrality measures compared to non-associated RBPs. The compendium of RBPs and this study will help us gain insight into the role of post-transcriptional regulatory molecules in aging and gender specific expression of genes. PMID- 25824885 TI - Simvastatin combined with aspirin increases the survival time of heart allograft by activating CD4(+)CD25(+) Treg cells and enhancing vascular endothelial cell protection. AB - OBJECTIVE: The objective was to investigate whether the combination of simvastatin and aspirin treatment prolongs the survival time of the heart allograft in rat and its underlying mechanism. METHODS: Heterotopic heart transplantation was performed using Wistar rats as donors and Sprague-Dawley (SD) rats as recipients. The SD rats were randomly divided into five groups (n=20/group): sham, HT (heart transplantation), HT+simvastatin (HT+S), HT+aspirin (HT+A), and HT+aspirin+simvastatin (HT+A+S). After transplantation, at 3, 7, 10, 15, 20, 30, and 40 days, the endothelial nitric oxide synthase (eNOS) expression was assessed by immunohistological staining; nitric oxide (NO) levels were analyzed by Griess assay; the activation of CD4(+)CD25(+) T regulatory lymphocytes (Tregs) was analyzed by flow cytometry; and pathological changes in the graft heart were determined by histology. RESULTS: Combined treatment of hearts with simvastatin and aspirin significantly prolonged the mean survival time of heart allografts [8 +/- 1.2 days (n=18), 20 +/- 3.4 days (n=19), 21 +/- 2.8 days (n=19), and 39 +/- 5.3 days (n=19) for HT, HT+S, HT+A, and HT+A+S group, respectively; HT vs. HT+A+S, P<.001; HT vs. HT+S or HT+A, P<.05]. In addition, CONCLUSIONS: Simvastatin given in combination with aspirin delayed the development of pathological changes in the myocardium, reduced vascular damage and prolonged the survival time of cardiac allograft. The underlying mechanism is linked with CD4(+)CD25(+)-Treg-cell-induced immune tolerance and enhanced vascular endothelial cell protection. PMID- 25824886 TI - Correction: Testing and validating electroanalytical simulations. PMID- 25824887 TI - The effect of memory and context changes on color matches to real objects. AB - Real-world color identification tasks often require matching the color of objects between contexts and after a temporal delay, thus placing demands on both perceptual and memory processes. Although the mechanisms of matching colors between different contexts have been widely studied under the rubric of color constancy, little research has investigated the role of long-term memory in such tasks or how memory interacts with color constancy. To investigate this relationship, observers made color matches to real study objects that spanned color space, and we independently manipulated the illumination impinging on the objects, the surfaces in which objects were embedded, and the delay between seeing the study object and selecting its color match. Adding a 10-min delay increased both the bias and variability of color matches compared to a baseline condition. These memory errors were well accounted for by modeling memory as a noisy but unbiased version of perception constrained by the matching methods. Surprisingly, we did not observe significant increases in errors when illumination and surround changes were added to the 10-minute delay, although the context changes alone did elicit significant errors. PMID- 25824888 TI - Selection of multiple cued items is possible during visual short-term memory maintenance. AB - Recent neuroimaging studies suggest that maintenance of a selected object feature held in visual short-term/working memory (VSTM/VWM) is supported by the same neural mechanisms that encode the sensory information. If VSTM operates by retaining "reasonable copies" of scenes constructed during sensory processing (Serences, Ester, Vogel, & Awh, 2009, p. 207, the sensory recruitment hypothesis), then attention should be able to select multiple items represented in VSTM as long as the number of these attended items does not exceed the typical VSTM capacity. It is well known that attention can select at least two noncontiguous locations at the same time during sensory processing. However, empirical reports from the studies that examined this possibility are inconsistent. In the present study, we demonstrate that (1) attention can indeed select more than a single item during VSTM maintenance when observers are asked to recognize a set of items in the manner that these items were originally attended, and (2) attention can select multiple cued items regardless of whether these items are perceptually organized into a single group (contiguous locations) or not (noncontiguous locations). The results also replicate and extend the recent finding that selective attention that operates during VSTM maintenance is sensitive to the observers' goal and motivation to use the cueing information. PMID- 25824889 TI - Attention modulates specificity effects in spoken word recognition: Challenges to the time-course hypothesis. AB - Findings in the domain of spoken word recognition have indicated that lexical representations contain both abstract and episodic information. It has been proposed that processing time determines when each source of information is recruited, with increased processing time being required to access lower frequency episodic instantiations. The time-course hypothesis of specificity effects has thus identified a strong role for retrieval mechanisms mediating the use of abstract versus episodic information. Here we conducted three recognition memory experiments to examine whether the findings previously attributed to retrieval mechanisms might instead reflect attention during encoding. The results from Experiment 1 showed that talker-specificity effects emerged when subjects attended to the individual speakers, but not when they attended to lexical characteristics, during encoding, even though processing times at retrieval were equivalent. The results from Experiment 2 showed that talker-specificity effects emerged when listeners attended to talker gender but not when they attended to syntactic characteristics, even though the processing times at retrieval were significantly longer in the latter condition. The results from Experiment 3 showed no talker-specificity effects when all listeners attended to lexical characteristics, even when processing at retrieval was slowed by the addition of background noise. Collectively, these results suggest that when processing time during retrieval is decoupled from encoding factors, it fails to predict the emergence of talker-specificity effects. Rather, attention during encoding appears to be the putative variable. PMID- 25824890 TI - Diffuse panbronchiolitis in a 10-year-old boy. AB - Diffuse panbronchiolitis is a progressive fatal respiratory disease of unknown cause seen predominantly in Southeast Asian adults. We report this condition in a 10-year-old child of Korean birth because of the uncommon presentation at this age and the favorable outcome associated with early diagnosis. Our objective was also to demonstrate the gradual but complete resolution of the disease and sustained remission from early institution of azithromycin. PMID- 25824891 TI - Neonatal seizures-part 2: Aetiology of acute symptomatic seizures, treatments and the neonatal epilepsy syndromes. AB - Most neonatal epileptic seizures are provoked by an underlying condition or problem-'acute symptomatic seizures'. However, a few neonatal epilepsy syndromes exist, and these are defined by the constellation of seizure types, EEG findings and family history seen. Making an accurate diagnosis of an epilepsy syndrome can help direct investigations, treatment options and provide prognostic information. This article discusses the investigative approach and treatments for neonatal epileptic seizures, including the neonatal epilepsy syndromes. PMID- 25824892 TI - Child health research and social media. PMID- 25824893 TI - Neonatal seizures-part 1: Not everything that jerks, stiffens and shakes is a fit. AB - The neonatal period is the most frequent time of life to have epileptic seizures. However, neonates can also exhibit unusual movements that are not epileptic seizures. Differentiating between epileptic and non-epileptic movements can be difficult. Many neonatal seizures exhibit few or no clinical features at all. This article is for the benefit of paediatric trainees and reviews the published evidence on which neonatal movements are likely to be epileptic seizures and which are not. We also discuss epileptic seizure classification. PMID- 25824894 TI - Spotlight on Express Lane Eligibility (ELE): A Tool to Improve Enrollment and Renewal. AB - OBJECTIVE: We examine a new simplification policy, Express Lane Eligibility (ELE), introduced by the Children's Health Insurance Program Reauthorization Act of 2009 (CHIPRA), to understand ELE's effects on enrollment, renewal, and administrative costs. METHODS: Beginning in January 2012 and lasting through June 2013, we conducted 2 rounds of phone interviews with 38 state administrators and staff in 8 states that implemented ELE in Medicaid, Children's Health Insurance Program (CHIP), or both; we also conducted case studies in these same states, resulting in 136 in-person interviews. We collected administrative data on enrollments and renewals processed through ELE methods from the 8 states. RESULTS: ELE was adopted in different ways; the method of adoption influenced how many children were served and administrative savings. Automatic ELE processes, which enable states to use eligibility findings from partner agencies to automatically enroll or renew children, serve the most children and generate, on average, $1 million annually in administrative savings. Given the size of renewal caseloads and the recurring nature of renewal, using ELE for renewals holds substantial promise for administrative savings and keeping children covered. CONCLUSIONS: Automatic ELE processes are a best practice for using ELE. However, because Congress has not yet made ELE a permanent policy option, states are discouraged from adopting this more efficient method of eligibility determination and redeterminations. Making ELE permanent would support states that have already adopted the policy; in addition, ELE could support the transition of children to Medicaid or exchanges should CHIP not be funded after September 30, 2015. PMID- 25824895 TI - Access to Private Coverage for Children Enrolled in CHIP. AB - OBJECTIVE: To provide updated information on the potential substitution of public for private coverage among low-income children by examining the type of coverage held by children before they enrolled in Children's Health Insurance Program (CHIP) and exploring the extent to which children covered by CHIP had access to private coverage while they were enrolled. METHODS: We conducted a major household telephone survey in 2012 of enrollees and disenrollees in CHIP in 10 states. We used the survey responses and Medicaid/CHIP administrative data to estimate the coverage distribution of all new enrollees in the 12 months before CHIP enrollment and to identify children who may have had access to employer coverage through one of their parents while enrolled in CHIP. RESULTS: About 13% of new enrollees had any private coverage in the 12 months before enrolling in CHIP, and most were found to have lost that coverage as a result of parental job loss. About 40% of CHIP enrollees had a parent with an employer-sponsored insurance (ESI) policy, but only half reported that the policy could cover the child. Approximately 30% of new enrollees had public coverage during the year before but were uninsured just before enrolling. CONCLUSIONS: Access to private coverage among CHIP enrollees is relatively limited. Furthermore, even when there is potential access to ESI, affordability is a serious concern for parents, making it possible that many children with access to ESI would remain uninsured in the absence of CHIP. PMID- 25824896 TI - Primary care provider training in screening, assessment, and treatment of adolescent depression. AB - OBJECTIVE: Adolescent depression is underrecognized and undertreated. Primary care providers (PCP) require training to successfully identify adolescents with depression. We examined the effects of a PCP training program in the screening, assessment, and treatment of adolescent depression (SAT-D) on adolescents' reports of PCP screening for adolescent depression at annual well visits and PCP SAT-D confidence and knowledge. METHODS: PCP (n = 31) attended one SAT-D training program consisting of a 60-minute SAT-D seminar and a 60-minute standardized patient session where PCP practiced SAT-D skills. A pre-post design evaluated effects of training on PCP depression screening practices as reported by 3 groups of adolescent patients at well visits (n = 582 before, n = 525 at 2 to 8 months after training, n = 208 at 18 to 24 months after training). A generalized linear mixed effects logistic regression controlled for provider and patient demographics that may have influenced depression screening. PCP SAT-D self reported confidence and objectively tested knowledge were assessed at baseline, immediately after training, and at 4 to 6 months after training. RESULTS: On the basis of the regression analysis, PCP screening for adolescent depression increased significantly from pretraining (49%) to 2 to 8 months after training (68%, odds ratio 2.78, 95% confidence interval 2.10-3.68) and 18 to 24 months after training (74%, odds ratio 3.17, 95% confidence interval 2.16-4.67; both P < .0001). PCP SAT-D confidence and knowledge also significantly improved. CONCLUSIONS: PCP SAT-D training resulted in significant increases in primary care screening for adolescent depression that were maintained up to 24 months after training. Future studies should determine if changes in PCP screening improve identification of adolescent depression and patient outcomes for adolescents with depression. PMID- 25824897 TI - How Well Is CHIP Addressing Health Care Access and Affordability for Children? AB - OBJECTIVE: We examine how access to care and care experiences under the Children's Health Insurance Program (CHIP) compared to private coverage and being uninsured in 10 states. METHODS: We report on findings from a 2012 survey of CHIP enrollees in 10 states. We examined a range of health care access and use measures among CHIP enrollees. Comparisons of the experiences of established CHIP enrollees to the experiences of uninsured and privately insured children were used to estimate differences in children's health care. RESULTS: Children with CHIP coverage had substantially better access to care across a range of outcomes, other things being equal, particularly compared to those with no coverage. Compared to being uninsured, CHIP enrollees were more likely to have specialty and mental health visits and to receive prescription drugs; and their parents were much more likely to feel confident in meeting the child's health care needs and were less likely to have trouble finding providers. CHIP enrollees were less likely to have unmet needs, but 1 in 4 had at least 1 unmet need. Compared to being privately insured, CHIP enrollees had generally similar health care use and unmet needs. Additionally, CHIP enrollees had lower financial burden related to their health care needs. The findings were generally robust with respect to alternative specifications and subgroup analyses, and they corroborated findings of previous studies. CONCLUSIONS: Enrolling more of the uninsured children who are eligible for CHIP improved their access to a range of care, including specialty and mental health services, and reduced the financial burden of meeting their health care needs; however, we found room for improvement in CHIP enrollees' access to care. PMID- 25824898 TI - Macroglossia. PMID- 25824899 TI - Integrated analysis of toxicity data of two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties to improve the understanding of side effects-A toxicopathologist's view. AB - Data in a toxicity test are evaluated generally per parameter. Information on the response per animal in addition to per parameter can improve the evaluation of the results. The results from the six studies in rats, described in the paper by Kemmerling, J., Fehlert, E., Ruhl-Fehlert, C., Kuper, C.F., Stropp, G., Vogels, J., Krul, C., Vohr, H.-W., 2015. The transferability from rat subacute 4-week oral toxicity study to translational research exemplified by two pharmaceutical immunosuppressants and two environmental pollutants with immunomodulating properties (In this issue), have been subjected to principal component analysis (PCA) and principal component discriminant analysis (PC-DA). The two pharmaceuticals azathioprine (AZA) and cyclosporine A (CSA) and the two environmental pollutants hexachlorobenzene (HCB) and benzo(a)pyrene (BaP) all modulate the immune system, albeit that their mode of immunomodulation is quite diverse. PCA illustrated the similarities between the two independent studies with AZA (AZA1 and AZA2) and CSA (CSA1 and CSA2). The PC-DA on data of the AZA2 study did not increase substantially the information on dose levels. In general, the no-effect levels were lower upon single parameter analysis than indicated by the distances between the dose groups in the PCA. This was mostly due to the expert judgment in the single parameter evaluation, which took into account outstanding pathology in only one or two animals. The PCA plots did not reveal sex-related differences in sensitivity, but the key pathology for males and females differed. The observed variability in some of the control groups was largely a peripheral blood effect. Most importantly, PCA analysis identified several animals outside the 95% confidence limit indicating high-responders; also low-to-non-responders were identified. The key pathology enhanced the understanding of the response of the animals to the four model compounds. PMID- 25824900 TI - Animal models of rheumatoid arthritis: How informative are they? AB - Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo. PMID- 25824901 TI - Automated calcium burden measurement in internal carotid artery plaque with CT: a hierarchical adaptive approach. AB - AIM: Calcium burden measurement in internal carotid artery (ICA) plaque could play an important role in assessing stroke risk and stenosis quantification in the ICA. We propose an automatic method for labelling calcified plaques in ICA in CT images. METHODS: Our approach builds upon the mean shift paradigm via an adaptive thresholding strategy. The data consists of single CT slices from 75 patients, with variety of plaque sizes and number of calcium regions. The manual measurements were carried out by a neuroradiologist for benchmarking. The calcium burden was measured as the area of the labelled plaque. Various metrics were employed to compare manual and automated measurements including correlation coefficient (CC), dice similarity (DS), Jacard Index (JI), polyline distance metric (PDM) and precision of merit (PoM). RESULTS: We found that our automated method of calcium area characterization performed accurately compared to manual measurements with CC=0.978, and PoM=0.915. The PDM, DS, and JI, also indicate a good performance with a mean DS=0.85 (SD=0.085), a mean JI=0.747 (SD=0.12), and a mean PDM=0.195 (SD=0.177). CONCLUSION: The proposed approach for calcium burden measurement, yields reasonably accurate labelling of calcified plaque when benchmarked against manual measurements. The approach is independent of the number and size of calcium regions, and the prototype design shows encouraging results to be adaptable to clinical practice. PMID- 25824902 TI - A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome. AB - BACKGROUND: To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. METHODS: We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. KEY RESULTS: The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. CONCLUSIONS & INFERENCES: Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective. PMID- 25824903 TI - Functional differences between antiviral activities of sulfonated and intact intravenous immunoglobulin preparations toward varicella-zoster virus and cytomegalovirus. AB - Intravenous immunoglobulin (IVIG) is used to treat severe viral infection, especially varicella-zoster virus (VZV) and cytomegalovirus (CMV) infections. The neutralization antibody titers of eleven IVIG preparations from four companies were examined using VZV and CMV with and without complement. The neutralizing antibody titers of intact IgG preparations were three to six times higher after addition of complement. The effectiveness of the sulfonated IgG preparation was not enhanced by complement, but desulfonated IgG regained enhanced neutralization activity with complement. Antibody-dependent cellular cytotoxicity (ADCC) toward VZV-infected cells was observed with both intact and sulfonated IVIG and guinea pig splenocytes, but ADCC toward CMV-infected cells was not, although NK cell activity toward cells infected with VZV or CMV was detected by splenocytes. Sulfonated IVIG had no complement-activated neutralization of VZV and CMV but retained ADCC toward VZV with less activity after dilution than with intact IVIG. Because sulfonated IVIG is converted to the intact form after intravenous administration, it would show complement-enhanced neutralization and ADCC activity similar to that of intact IVIG in vivo. In this study we showed the effects of intact and sulfonated IgG on the functional activity of IgG against VZV and CMV. PMID- 25824904 TI - Vestibular functions of hereditary hearing loss patients with GJB2 mutations. AB - OBJECTIVES: Mutations in the GJB2 gene have been of particular interest as it is the most common causative gene for congenital deafness in all populations. Detailed audiological features, including genotype-phenotype correlations, have been well documented. However, in spite of abundant gene as well as protein expression in the vestibular end organs, neither vestibular symptoms nor vestibular functions have yet been elucidated. In the present study, vestibular functions were evaluated in patients diagnosed with GJB2-related deafness. SUBJECTS AND METHODS: Vestibular functions were evaluated by caloric test and cervical vestibular evoked myogenic potential (cVEMP) testing in 24 patients with biallelic GJB2 mutations. RESULTS AND DISCUSSION: Twenty-one of 23 patients (91.3%) had normal caloric responses and significantly lower cVEMP amplitudes than the control subjects. In the patients who were able to undergo vestibular testing, the mostly normal reactions to caloric testing indicated that the lateral semicircular canal was intact. However, the majority of GJB2 patients showed low cVEMP reactions, indicating a saccular defect. PMID- 25824905 TI - DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies. AB - Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis. PMID- 25824907 TI - The myth of the miracle baby: how neonatal nurses interpret media accounts of babies of extreme prematurity. AB - Improved life sustaining technology in the neonatal intensive care unit (NICU) has resulted in an increased probability of survival in extremely premature babies. Miracle baby stories in the popular press are a regular occurrence and these reports are often the first source from which the general public learn about extremely premature babies. The research from which this paper is drawn sought to explore the care-giving and ethical dilemmas of neonatal nurses when caring for extremely premature babies 24 weeks gestation and less. This current paper aims to outline the views of neonatal nurses on miracle baby stories in the media. Data were collected via a questionnaire to 760 Australian neonatal nurses with 414 returned, representing a response rate of 54.4%. Narrative was collected from semi-structured interviews with 24 experienced neonatal nurses in NSW, Australia. A qualitative approach utilising thematic analysis was utilised to analyse the data. The theme the myth of the miracle baby is seen as generating myths and unrealistic expectations on the part of vulnerable families and the public. Neonatal nurses, as the primary caregivers for tiny babies and their families, viewed popular media publications with suspicion, believing published reports to be incomplete, inaccurate and biased towards the positive. PMID- 25824908 TI - Vortrage. PMID- 25824906 TI - A plug-and-play approach to antibody-based therapeutics via a chemoselective dual click strategy. AB - Although recent methods for the engineering of antibody-drug conjugates (ADCs) have gone some way to addressing the challenging issues of ADC construction, significant hurdles still remain. There is clear demand for the construction of novel ADC platforms that offer greater stability, homogeneity and flexibility. Here we describe a significant step towards a platform for next-generation antibody-based therapeutics by providing constructs that combine site-specific modification, exceptional versatility and high stability, with retention of antibody binding and structure post-modification. The relevance of the work in a biological context is also demonstrated in a cytotoxicity assay and a cell internalization study with HER2-positive and -negative breast cancer cell lines. PMID- 25824909 TI - Diaklinik (DK) - Interessante Falle aus der Welt der DDG (DK). PMID- 25824910 TI - Freie vortrage. PMID- 25824911 TI - Poster. PMID- 25824912 TI - Autorenindex. PMID- 25824914 TI - Inhalt. PMID- 25824913 TI - Editors and reviewers. PMID- 25824915 TI - Stroke volume adjusted to afterload for assessment of cardiac performance in patients with severe aortic stenosis and preserved left ventricular ejection fraction. AB - OBJECTIVES: The aim of this study was to evaluate the relationship between valvular resistance and stroke volume (SV) and to assess SV adequacy to afterload in patients with severe aortic stenosis (AS) and normal left ventricular ejection fraction (LVEF). METHODS: We assessed clinical characteristics and echocardiographic parameters in 44 patients with isolated severe AS and preserved LVEF. LV end-diastolic pressure (LVEDP) and LV mean diastolic pressure (LVMDP) were measured by cardiac catheterization. SV values were plotted in relation to valvular resistance. Patients were divided into 2 groups, with an SV that was higher (group 1) or lower (group 2) than the SV calculated by a regression equation using valvular resistance as the dependent variable. RESULTS: At the same degree of valvular stenosis, the patients in group 1 exhibited better contractility as assessed by global longitudinal strain (p < 0.05), higher peak (p < 0.01) and mean gradient (p < 0.05), indexed SV (p < 0.001) and transvalvular flow (p = 0.01) than the patients in group 2, who had a higher heart rate (HR, p < 0.05), shorter ejection time (ET, p < 0.05) and more elevated LVEDP (p < 0.05) and LVMDP (p < 0.05). CONCLUSION: The presence of inappropriately decreased SV relative to afterload in patients with severe AS and normal LVEF was associated with lower contractility, higher HR, shorter ET and elevated LV diastolic pressure, which suggest failed hemodynamic adaptation to afterload. PMID- 25824916 TI - Celiac disease, gluten-free diet and health-related quality of life. PMID- 25824917 TI - Benefit on health-related quality of life of adherence to gluten-free diet in adult patients with celiac disease. AB - INTRODUCTION: Celiac disease (CD) affects health-related quality of life (HRQOL) of patients suffering it. The exclusion of gluten from the diet (GFD) improves HRQOL, but involves difficulties in following the diet that could adversely affect HRQOL. OBJECTIVE: To determine the effect of adherence to the diet on HRQOL of adult CD patients. METHODS: A prospective, cross-sectional, multicenter study of CD patients treated with a GFD for longer than 1 year. Adherence to the GFD was measured using the Morisky scale, and health status using the specific CD QOL questionnaire and the generic EuroQol-5D questionnaire. RESULTS: 366 patients from 7 hospitals were included: 71.5% of patients reported a perfect treatment adherence, 23.5% unintentional poor adherence and 5% intentional poor adherence. Good adherence to a GFD was related to a higher mean score onthe CD-QOL (75 vs. 68, respectively, p < 0.05) and EuroQol-5D (0.9 vs. 0.8, respectively, p < 0.05). Ease of adherence to a GFD was also related to a better HRQOL (total CD-QOL score of 82 vs. 67 in patients who consider the GFD difficult to follow, p < 0.05). Good symptom control was also related to a better HRQOL (total CD-QOL score of 78 vs. 67 in asymptomatic vs. symptomatic patients, p < 0.01). The worse scored dimension of CD-QOL was related to "inadequate treatment". CONCLUSIONS: In CD, good adherence to a GFD and adequate symptom control result in improved HRQOL. Many patients consider that the lack of therapeutic alternatives to diet worsens their quality of life. PMID- 25824918 TI - The irritable bowel syndrome care process from the patients' and professionals' views. AB - BACKGROUND AND PURPOSE OF THE STUDY: This study assessed the experiences of irritable bowel syndrome patients with the healthcare system. Specifically, this study focused on the barriers that patients found. METHODS: Three focus groups were conducted with the participation of 19 patients and 10 healthcare professionals. From this information a script of questions was designed and 33 structured interviews were conducted. Finally, a scale for evaluation of the perception of patients was designed for primary care (14 items) and gastroenterology (13 items). Internal consistency and construct validity were calculated. RESULTS: The difficulties of accessibility, to clarify doubts, concerns regarding uncertainty, reduced information about prognosis and its social and labour effects were the most cited by patients. Low adherence and persistence in the treatment plan were the problems cited most often by professionals. The items of the scale for primary care were grouped into 4 factors (explained variance, 73%), while those for gastroenterology were grouped into 3 factors (explained variance, 67%). The internal consistency was 0.84 and 0.82, respectively. A total of 29 (88%) patients were satisfied with the care provided in gastroenterology, while 24 (73%) declared themselves satisfied with the primary care physician (Chi-square 2.4, p = 0.21). This study was carried out from November 2013 to July 2014. CONCLUSIONS: This study describes the most relevant problems in the assistance received by these patients. PMID- 25824919 TI - Fecal calprotectin as a biomarker of inflammatory lesions of the small bowel seen by videocapsule endoscopy. AB - INTRODUCTION: The levels of calprotectin in the stools are proportional to neutrophil activity in the enteric lumen, so fecal calprotectin is a useful intestinal inflammatory biomarker. It is an extended tool as predictor of colonic pathology but there is scare evidence about its utility in the small bowel. OBJECTIVE: To test the yield of fecal calprotectin to detect lesions in the small bowel. MATERIAL AND METHODS: We have retrospectively included 71 patients sent for small bowel capsule endoscopy in study for suspected inflammatory bowel disease. All of them had a determination of fecal calprotectin and had been sent to colonoscopy with no findings. Patients have been divided in groups: A, fecal calprotectin < 50 microg/g; B, fecal calprotectin: 50-100 microg/g; C, fecal calprotectin > 100 microg/g, and we have analyzed which of them presented inflammatory lesions in capsule endoscopy studies. RESULTS: The rate of patients with signi ficative lesions was 1 out of 10 (10%) in group A, 6 out of 24 (25%) in group B, and 21 out of 34 (62%) in group C. If we consider levels over 50 ig/g pathologic, fecal calprotectin presents sensitivity: 96%, specificity: 23%, NPV: 90% and PPV: 56%. If we consider levels over 100 ig/g pathologic these values are sensitivity: 75%, specificity: 67%, NPV: 79% and PPV: 62%. CONCLUSIONS: Fecal calprotectin has high sensitivity but not so good specificity for predicting small bowel lesions after a normal colonoscopy. In daily practice it will be more useful to establish in 100 ig/g the limit to indicate capsule endoscopy studies. PMID- 25824920 TI - Long-term follow-up of chronic anal fissure (CAF) on diltiazem 2% using a telephone questionnaire. Do results change? AB - INTRODUCTION: Calcium channel blockers have an excellent effectiveness in the conservative management of chronic anal fissure (CAF). OBJECTIVES: To assess the long-term results of management with diltiazem 2% ointment using a telephone questionnaire. METHODS: A descriptive, retrospective study from March 2004 to March 2011 in patients with CAF on diltiazem 2%, 3 applications daily for 4-6 weeks. Starting at 12 months a questionnaire was administered over the phone by medical staff outside the surgery department to record socio-demographic data, predominant manifestations, and response to diltiazem on a 5-point scale measuring symptom relief (1 = poorest, 5 = best). Patients with therapy failure were referred to surgery. RESULTS: The study was completed for 166 patients with a mean age of 54.1 years. CAF was posterior in 82.3% of subjects. Diltiazem tolerability was excellent with only 4 adverse event cases (3 skin irritation, 1 hypotension). We obtained symptom relief in 62.1% of patients and CAF healing in 51.2%, and referred 33.7% to surgery. The questionnaire showed that 74.1% of patients had used only 2 applications daily, and that results were better with an increased number of applications, albeit without statistical significance. CONCLUSIONS: The telephone questionnaire showed symptom relief for 62% and healing for 51.2% of patients with CAF on diltiazem 2%, which should be considered first-choice for the conservative management of this condition. PMID- 25824921 TI - Endoscopic ultrasound in the diagnosis of chronic pancreatitis. AB - Diagnosis of chronic pancreatitis (CP) remains a challenge. Endoscopic ultrasound (EUS) can be considered nowadays as the technique of choice for the morphological diagnosis of this disease. More than three or four EUS defined criteria of CP need to be present for the diagnosis of the disease. The development of the more restrictive Rosemont classification aims to standardize the criteria, assigning different values to different features but its impact on the EUS-based diagnosis of CP is debatable. A combined use of endoscopic function test and EUS has even increased the diagnostic yield. Elastography and FNA may be also of help for diagnosing CP. EUS also provides with very valuable information on the severity of the disease, giving key information that may influence in the treatment. Differential diagnosis of solid pancreatic masses in the context of a CP is also challenging, EUS plays a key role in this context. It provides with the possibility of obtaining specimens for histopathological diagnosis. Nowadays, new developed techniques associated to EUS, like elastography and contrast enhancement, are also showing promising results for the differentiating between these pancreatic lesions. PMID- 25824922 TI - Acute abdomen due to torsion of the wandering spleen. PMID- 25824923 TI - Orbital metastasis from hepatocellular carcinoma. PMID- 25824924 TI - An elderly woman with obstructive symptoms: a surprising diagnosis. PMID- 25824925 TI - Hypercontractile "jackhammer esophagus". PMID- 25824926 TI - Is the sinusoidal obstructive syndrome post-liver transplantation a pathologic entity with a multifactorial etiology? AB - The sinusoidal obstructive syndrome is a complication typically associated with hematopoietic stem cell transplantation. This syndrome, more commonly known as veno-occlusive disease, has also been described after liver transplantation. It can have a life-threatening course. Herein, we describe the hepatic graft loss secondary to the development of a sinusoidal obstructive syndrome after a severe acute cellular rejection and toxic levels of once daily modified released tacrolimus (TAC). We discuss the role of the endotheliitis of acute rejection and toxic metabolites of some immunosuppressants such as azathioprine and TAC. Based on the current scientific evidence, we contemplate the possibility that the etiology of sinusoidal obstruction syndrome post-liver transplantation is multifactorial. PMID- 25824927 TI - Direct percutaneous endoscopic jejunostomy in pediatric age with a pexies triangulation system: report of a case and literature review. AB - Direct percutaneous endoscopic jejunostomy (DPEJ) is an infrequent procedure as it is not always easy to obtain transillumination, being this the main reason for failure of this technique. In patients with previous surgery, this procedure is more complex and there are only 6 reported cases in pediatric population. In our case, we provide the use of an endoscopic triangulation system with "T" pexies not used before in these cases. With this technique, we guarantee not to replace the introduction system afterwards, obtaining the placement of a balloon fixation system initially. We also provide several improvements that helped us developing the procedure: Placement of the jejunostomy through a gastrostomy; use of water column to avoid penetration in hollow viscus; use of a guide wire, and a triangulation pexy system. PMID- 25824928 TI - [pH-metry/impedance-24 hours pH-metry]. PMID- 25824929 TI - Herpes zoster following percutaneous liver biopsy. PMID- 25824930 TI - Septic shock secondary to colonic fistula as clinical debut of liver hydatid cyst. PMID- 25824931 TI - Portal vein thrombosis following endoscopic treatment for gastric varices with N butyl-2-cyanoacrylate: Management with TIPS. PMID- 25824932 TI - Acute liver failure in a patient consuming Herbalife products and Noni juice. PMID- 25824933 TI - Hypersensitivity perimyocarditis after the first dose of infliximab. PMID- 25824934 TI - Intrahepatic pancreatic pseudocyst: a case report. PMID- 25824935 TI - Hepatitis C genotype 1b and 4 cured after telaprevir-based therapy. PMID- 25824936 TI - Mesenteric vein thrombosis associated with a cytomegalovirus infection. PMID- 25824937 TI - A single inlet two-stage acoustophoresis chip enabling tumor cell enrichment from white blood cells. AB - Metastatic disease is responsible for most cancer deaths, and hematogenous spread through circulating tumor cells (CTC) is a prerequisite for tumor dissemination. CTCs may undergo epithelial-mesenchymal transition where many epithelial cell characteristics are lost. Therefore, CTC isolation systems relying on epithelial cell markers are at risk of losing important subpopulations of cells. Here, a simple acoustophoresis-based cell separation instrument is presented. Cells are uniquely separated while maintained in their initial suspending medium, thus eliminating the need for a secondary cell-free medium to hydrodynamically pre position them before the separation. When characterizing the system using polystyrene particles, 99.6 +/- 0.2% of 7 MUm diameter particles were collected through one outlet while 98.8 +/- 0.5% of 5 MUm particles were recovered through a second outlet. Prostate cancer cells (DU145) spiked into blood were enriched from white blood cells at a sample flow rate of 100 MUL min(-1) providing 86.5 +/ 6.7% recovery of the cancer cells with 1.1 +/- 0.2% contamination of white blood cells. By increasing the acoustic intensity a recovery of 94.8 +/- 2.8% of cancer cells was achieved with 2.2 +/- 0.6% contamination of white blood cells. The single inlet approach makes this instrument insensitive to acoustic impedance mismatch; a phenomenon reported to importantly affect accuracy in multi-laminar flow stream acoustophoresis. It also offers a possibility of concentrating the recovered cells in the chip, as opposed to systems relying on hydrodynamic pre positioning which commonly dilute the target cells. PMID- 25824938 TI - T-lymphocyte phenotype and function triggered by Aggregatibacter actinomycetemcomitans is serotype-dependent. AB - BACKGROUND AND OBJECTIVE: Based on lipopolysaccharide (LPS) antigenicity, different Aggregatibacter actinomycetemcomitans serotypes have been described. Serotype b strains have demonstrated a stronger capacity to trigger cytokine production on dendritic cells (DCs). As DCs regulate the development of T lymphocyte lineages, the objective of this investigation was to study the response of T lymphocytes after being stimulated with autologous DCs primed with different bacterial strains belonging to the most prevalent serotypes of A. actinomycetemcomitans in humans: a-c. MATERIAL AND METHODS: Human DCs were primed with increasing multiplicity of infection (10(-1) -10(2) ) or the purified LPS (10-50 ng/mL) of A. actinomycetemcomitans serotypes a-c and then used to stimulate autologous naive CD4(+) T lymphocytes. The T-helper (Th) type 1, Th2, Th17 and T-regulatory transcription factors T-bet, GATA-3, RORC2 and Foxp3, which are the master-switch genes implied in their specific differentiation, as well as T-cell phenotype-specific cytokine patterns were quantified by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. In addition, the intracellular expression of T-bet/interferon-gamma, GATA 3/interleukin-4, RORC2/interleukin-17A and Foxp3/transforming growth factor-beta1 was analysed by double staining and flow cytometry. RESULTS: All the A. actinomycetemcomitans serotypes led to T-lymphocyte activation; however, when T lymphocytes were stimulated with DCs primed with the A. actinomycetemcomitans serotype b strain or their purified LPS, higher levels of Th1- and Th17 associated transcription factors and cytokines were detected compared with similar experiments with the other serotypes. CONCLUSION: These results demonstrate that serotype b of A. actinomycetemcomitans has a higher capacity of trigger Th1 and Th17 phenotype and function and it was demonstrated that their LPS is a more potent immunogen compared with the other serotypes. PMID- 25824939 TI - A hyper-stretchable elastic-composite energy harvester. PMID- 25824940 TI - Response to ruxolitinib in patients with intermediate-1-, intermediate-2-, and high-risk myelofibrosis: results of the UK ROBUST Trial. AB - Myelofibrosis is characterized by splenomegaly and debilitating constitutional symptoms that negatively impact patients' quality of life. ROBUST, a UK, open label, phase II study, evaluated the safety and efficacy of ruxolitinib in patients with myelofibrosis (N = 48), including intermediate-1 risk patients. The primary composite endpoint was the proportion of patients achieving treatment success [>= 50% reduction in palpable spleen length and/or a >= 50% decrease in Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF TSS)] at 48 weeks. This was the first time that efficacy of ruxolitinib in myelofibrosis has been evaluated based on these criteria and the first time the MF-SAF was used in a population of patients solely from the United Kingdom. Overall, 50% of patients and 57% of intermediate-1 risk patients, achieved treatment success; reductions in spleen length and symptoms were observed in all risk groups. The majority of patients (66.7%) experienced >= 50% reductions from baseline in spleen length at any time. Improvements in MF-SAF TSS were seen in 80.0%, 72.7%, and 72.2% of intermediate-1, intermediate-2, and high-risk patients, respectively. Consistent with other studies of ruxolitinib, the most common haematological adverse events were anaemia and thrombocytopenia. Results indicate that most patients with myelofibrosis, including intermediate-1 risk patients, may benefit from ruxolitinib treatment. PMID- 25824941 TI - The Effect of Controlled Reperfusion in the Prevention of Infertility Caused by Ischemia Induced in the Contralateral Ovary in Rats with Unilateral Ovariectomy. AB - BACKGROUND/AIMS: To investigate the effectiveness of controlled reperfusion (CR) on ovarian tissue malondialdehyde, total glutathione and 8-hydroxyguanine levels and infertility rates in a rat model of induced ischemia-reperfusion (I/R) injury with unilateral oophorectomy. METHODS: A total of 135 adult female albino Wistar rats were divided into 9 groups (n = 15 for each group): unilateral ovariectomy + ovarian I/R (OIR), unilateral ovariectomy alone (OEG), a sham operation group (SG), and unilateral ovariectomy + CR performed at different intervals (the clips were released 10 times for 10, 8, 6, 4, 2 or 1 s and closed again 10 times for 10, 8, 6, 4, 2 or 1 s; OCR-1-6, respectively). Five rats from each group were sacrificed, and their ovaries were removed. RESULTS: Higher ovarian tissue malondialdehyde and 8-hydroxyguanine levels and lower ovarian tissue total glutathione levels were found in the OIR group compared with the SG, OEG and OCR 4-6 groups. The number of rats giving birth during the study period was found to be similar among the SG (n = 8), OEG (n = 8) and OCR-6 (n = 7) groups. CONCLUSION: These results suggest that sterility and ovarian oxidative stress caused by I/R injury decreases in parallel to the shortening of CR duration. PMID- 25824943 TI - RefSeq microbial genomes database: new representation and annotation strategy. PMID- 25824942 TI - RNA editing by T7 RNA polymerase bypasses InDel mutations causing unexpected phenotypic changes. AB - DNA-dependent T7 RNA polymerase (T7 RNAP) is the most powerful tool for both gene expression and in vitro transcription. By using a Next Generation Sequencing (NGS) approach we have analyzed the polymorphism of a T7 RNAP-generated mRNA pool of the mboIIM2 gene. We find that the enzyme displays a relatively high level of template-dependent transcriptional infidelity. The nucleotide misincorporations and multiple insertions in A/T-rich tracts of homopolymers in mRNA (0.20 and 0.089%, respectively) cause epigenetic effects with significant impact on gene expression that is disproportionally high to their frequency of appearance. The sequence-dependent rescue of single and even double InDel frameshifting mutants and wild-type phenotype recovery is observed as a result. As a consequence, a heterogeneous pool of functional and non-functional proteins of almost the same molecular mass is produced where the proteins are indistinguishable from each other upon ordinary analysis. We suggest that transcriptional infidelity as a general feature of the most effective RNAPs may serve to repair and/or modify a protein function, thus increasing the repertoire of phenotypic variants, which in turn has a high evolutionary potential. PMID- 25824944 TI - Heme activation by DNA: isoguanine pentaplexes, but not quadruplexes, bind heme and enhance its oxidative activity. AB - Guanine-rich, single-stranded, DNAs and RNAs are able to fold to form G quadruplexes that are held together by guanine base quartets. G-quadruplexes are known to bind ferric heme [Fe(III)-protoporphyrin IX] and to strongly activate such bound hemes toward peroxidase (1-electron oxidation) as well as oxygenase/peroxygenase (2-electron oxidation) activities. However, much remains unknown about how such activation is effected. Herein, we investigated whether G quadruplexes were strictly required for heme activation or whether related multi stranded DNA/RNA structures such as isoguanine (iG) quadruplexes and pentaplexes could also bind and activate heme. We found that iG-pentaplexes did indeed bind and activate heme comparably to G-quadruplexes; however, iG-quadruplexes did neither. Earlier structural and computational studies had suggested that while the geometry of backbone-unconstrained iG-quintets templated by cations such as Na(+) or NH4 (+) was planar, that of iG-quartets deviated from planarity. We hypothesize that the binding as well as activation of heme by DNA or RNA is strongly supported by the planarity of the nucleobase quartet or quintet that interacts directly with the heme. PMID- 25824945 TI - Differences in genome-wide repeat sequence instability conferred by proofreading and mismatch repair defects. AB - Mutation rates are used to calibrate molecular clocks and to link genetic variants with human disease. However, mutation rates are not uniform across each eukaryotic genome. Rates for insertion/deletion (indel) mutations have been found to vary widely when examined in vitro and at specific loci in vivo. Here, we report the genome-wide rates of formation and repair of indels made during replication of yeast nuclear DNA. Using over 6000 indels accumulated in four mismatch repair (MMR) defective strains, and statistical corrections for false negatives, we find that indel rates increase by 100 000-fold with increasing homonucleotide run length, representing the greatest effect on replication fidelity of any known genomic parameter. Nonetheless, long genomic homopolymer runs are overrepresented relative to random chance, implying positive selection. Proofreading defects in the replicative polymerases selectively increase indel rates in short repetitive tracts, likely reflecting the distance over which Pols delta and epsilon interact with duplex DNA upstream of the polymerase active site. In contrast, MMR defects hugely increase indel mutagenesis in long repetitive sequences. Because repetitive sequences are not uniformly distributed among genomic functional elements, the quantitatively different consequences on genome-wide repeat sequence instability conferred by defects in proofreading and MMR have important biological implications. PMID- 25824946 TI - The interaction of mycobacterial protein Rv2966c with host chromatin is mediated through non-CpG methylation and histone H3/H4 binding. AB - To effectively modulate the gene expression within an infected mammalian cell, the pathogen Mycobacterium tuberculosis would need to bring about epigenetic modifications at appropriate genomic loci. Working on this hypothesis, we show in this study that the mycobacterial protein Rv2966c is a 5-methylcytosine-specific DNA methyltransferase that is secreted out from the mycobacterium and gets localized to the nucleus in addition to the cytoplasm inside the host cell. Importantly, Rv2966c binds to specific DNA sequences, methylates cytosines predominantly in a non-CpG context and its methylation activity is positively influenced by phosphorylation. Interestingly, like the mammalian DNA methyltransferase, DNMT3L, Rv2966c can also interact with histone proteins. Ours is the first study that identifies a protein from a pathogenic bacteria with potential to influence host DNA methylation in a non-canonical manner providing the pathogen with a novel mechanism to alter the host epigenetic machinery. This contention is supported by repression of host genes upon M. tuberculosis infection correlated with Rv2966c binding and non-CpG methylation. PMID- 25824948 TI - Effects of Hfq on the conformation and compaction of DNA. AB - Hfq is a bacterial pleiotropic regulator that mediates several aspects of nucleic acids metabolism. The protein notably influences translation and turnover of cellular RNAs. Although most previous contributions concentrated on Hfq's interaction with RNA, its association to DNA has also been observed in vitro and in vivo. Here, we focus on DNA-compacting properties of Hfq. Various experimental technologies, including fluorescence microscopy imaging of single DNA molecules confined inside nanofluidic channels, atomic force microscopy and small angle neutron scattering have been used to follow the assembly of Hfq on DNA. Our results show that Hfq forms a nucleoprotein complex, changes the mechanical properties of the double helix and compacts DNA into a condensed form. We propose a compaction mechanism based on protein-mediated bridging of DNA segments. The propensity for bridging is presumably related to multi-arm functionality of the Hfq hexamer, resulting from binding of the C-terminal domains to the duplex. Results are discussed in regard to previous results obtained for H-NS, with important implications for protein binding related gene regulation. PMID- 25824947 TI - Suppression of the E. coli SOS response by dNTP pool changes. AB - The Escherichia coli SOS system is a well-established model for the cellular response to DNA damage. Control of SOS depends largely on the RecA protein. When RecA is activated by single-stranded DNA in the presence of a nucleotide triphosphate cofactor, it mediates cleavage of the LexA repressor, leading to expression of the 30(+)-member SOS regulon. RecA activation generally requires the introduction of DNA damage. However, certain recA mutants, like recA730, bypass this requirement and display constitutive SOS expression as well as a spontaneous (SOS) mutator effect. Presently, we investigated the possible interaction between SOS and the cellular deoxynucleoside triphosphate (dNTP) pools. We found that dNTP pool changes caused by deficiencies in the ndk or dcd genes, encoding nucleoside diphosphate kinase and dCTP deaminase, respectively, had a strongly suppressive effect on constitutive SOS expression in recA730 strains. The suppression of the recA730 mutator effect was alleviated in a lexA deficient background. Overall, the findings suggest a model in which the dNTP alterations in the ndk and dcd strains interfere with the activation of RecA, thereby preventing LexA cleavage and SOS induction. PMID- 25824949 TI - The hexameric structure of the human mitochondrial replicative helicase Twinkle. AB - The mitochondrial replicative helicase Twinkle is involved in strand separation at the replication fork of mitochondrial DNA (mtDNA). Twinkle malfunction is associated with rare diseases that include late onset mitochondrial myopathies, neuromuscular disorders and fatal infantile mtDNA depletion syndrome. We examined its 3D structure by electron microscopy (EM) and small angle X-ray scattering (SAXS) and built the corresponding atomic models, which gave insight into the first molecular architecture of a full-length SF4 helicase that includes an N terminal zinc-binding domain (ZBD), an intermediate RNA polymerase domain (RPD) and a RecA-like hexamerization C-terminal domain (CTD). The EM model of Twinkle reveals a hexameric two-layered ring comprising the ZBDs and RPDs in one layer and the CTDs in another. In the hexamer, contacts in trans with adjacent subunits occur between ZBDs and RPDs, and between RPDs and CTDs. The ZBDs show important structural heterogeneity. In solution, the scattering data are compatible with a mixture of extended hexa- and heptameric models in variable conformations. Overall, our structural data show a complex network of dynamic interactions that reconciles with the structural flexibility required for helicase activity. PMID- 25824950 TI - Nucleosomes undergo slow spontaneous gaping. AB - In eukaryotes, DNA is packaged into a basic unit, the nucleosome which consists of 147 bp of DNA wrapped around a histone octamer composed of two copies each of the histones H2A, H2B, H3 and H4. Nucleosome structures are diverse not only by histone variants, histone modifications, histone composition but also through accommodating different conformational states such as DNA breathing and dimer splitting. Variation in nucleosome structures allows it to perform a variety of cellular functions. Here, we identified a novel spontaneous conformational switching of nucleosomes under physiological conditions using single-molecule FRET. Using FRET probes placed at various positions on the nucleosomal DNA to monitor conformation of the nucleosome over a long period of time (30-60 min) at various ionic conditions, we identified conformational changes we refer to as nucleosome gaping. Gaping transitions are distinct from nucleosome breathing, sliding or tightening. Gaping modes switch along the direction normal to the DNA plane through about 5-10 angstroms and at minutes (1-10 min) time scale. This conformational transition, which has not been observed previously, may be potentially important for enzymatic reactions/transactions on nucleosomal substrate and the formation of multiple compression forms of chromatin fibers. PMID- 25824951 TI - Heterogeneous dynamics in DNA site discrimination by the structurally homologous DNA-binding domains of ETS-family transcription factors. AB - The ETS family of transcription factors exemplifies current uncertainty in how eukaryotic genetic regulators with overlapping DNA sequence preferences achieve target site specificity. PU.1 and Ets-1 represent archetypes for studying site discrimination by ETS proteins because their DNA-binding domains are the most divergent in sequence, yet they share remarkably superimposable DNA-bound structures. To gain insight into the contrasting thermodynamics and kinetics of DNA recognition by these two proteins, we investigated the structure and dynamics of site discrimination by their DNA-binding domains. Electrophoretic mobilities of complexes formed by the two homologs with circularly permuted binding sites showed significant dynamic differences only for DNA complexes of PU.1. Free solution measurements by dynamic light scattering showed PU.1 to be more dynamic than Ets-1; moreover, dynamic changes are strongly coupled to site discrimination by PU.1, but not Ets-1. Interrogation of the protein/DNA interface by DNA footprinting showed similar accessibility to dimethyl sulfate for PU.1/DNA and Ets-1/DNA complexes, indicating that the dynamics of PU.1/DNA complexes reside primarily outside that interface. An information-based analysis of the two homologs' binding motifs suggests a role for dynamic coupling in PU.1's ability to enforce a more stringent sequence preference than Ets-1 and its proximal sequence homologs. PMID- 25824952 TI - Selective inhibition of miR-21 by phage display screened peptide. AB - miRNAs are nodal regulators of gene expression and deregulation of miRNAs is causally associated with different diseases, including cancer. Modulation of miRNA expression is thus of therapeutic importance. Small molecules are currently being explored for their potential to downregulate miRNAs. Peptides have shown to have better potency and selectivity toward their targets but their potential in targeting and modulating miRNAs remain unexplored. Herein, using phage display we found a very selective peptide against pre-miR-21. Interestingly, the peptide has the potential to downregulate miR-21, by binding to pre-miR-21 and hindering Dicer processing. It is selective towards miR-21 inside the cell. By antagonising miR-21 function, the peptide is able to increase the expression of its target proteins and thereby increase apoptosis and suppress cell proliferation, invasion and migration. This peptide can further be explored for its anti-cancer activity in vivo and may be even extended to clinical studies. PMID- 25824954 TI - Boosting riboswitch efficiency by RNA amplification. AB - Riboswitches are RNA sensors that regulate gene expression in response to binding of small molecules. Although they conceptually represent simple on/off switches and, therefore, hold great promise for biotechnology and future synthetic biology applications, the induction of gene expression by natural riboswitches after ligand addition or removal is often only moderate and, consequently, the achievable expression levels are not very high. Here, we have designed an RNA amplification-based system that strongly improves the efficiency of riboswitches. We have successfully implemented the method in a biological system for which currently no efficient endogenous tools for inducible (trans)gene expression are available: the chloroplasts of higher plants. We further show that an HIV antigen whose constitutive expression from the chloroplast genome is deleterious to the plant can be inducibly expressed under the control of the RNA amplification enhanced riboswitch (RAmpER) without causing a mutant phenotype, demonstrating the potential of the method for the production of proteins and metabolites that are toxic to the host cell. PMID- 25824955 TI - The most fulminant course of the Marburg variant of multiple sclerosis-autopsy findings. AB - Multiple sclerosis (MS) is usually a chronic and disabling inflammatory disease. Marburg's type of MS is characterized by rapid progression and severe disease course that leads to death within one year after the onset of clinical signs. We describe a fulminant clinical presentation of this malignant subtype of MS and discuss the neuropathological hallmarks as well as differential diagnoses of other fulminant demyelinating diseases. To the best of our knowledge, this is the most fulminant course of this MS variant reported in the literature. PMID- 25824953 TI - Active displacement of RecA filaments by UvrD translocase activity. AB - The UvrD helicase has been implicated in the disassembly of RecA nucleoprotein filaments in vivo and in vitro. We demonstrate that UvrD utilizes an active mechanism to remove RecA from the DNA. Efficient RecA removal depends on the availability of DNA binding sites for UvrD and/or the accessibility of the RecA filament ends. The removal of RecA from DNA also requires ATP hydrolysis by the UvrD helicase but not by RecA protein. The RecA-removal activity of UvrD is slowed by RecA variants with enhanced DNA-binding properties. The ATPase rate of UvrD during RecA removal is much slower than the ATPase activity of UvrD when it is functioning either as a translocase or a helicase on DNA in the absence of RecA. Thus, in this context UvrD may operate in a specialized disassembly mode. PMID- 25824957 TI - Implementation of intersectoral community approaches targeting childhood obesity: a systematic review. AB - The implementation of intersectoral community approaches targeting childhood obesity (IACO) is considered challenging. To help overcome these challenges, an overview of the evidence to date is needed. We searched four databases to identify papers that reported on the determinants of successful implementation of IACOs, resulting in the inclusion of 25 studies. We appraised study quality with the Crowe Critical Appraisal Tool and the Quality Framework; reported implementation outcome indicators were reviewed via narrative synthesis. Quality of included studies varied. The most frequently reported indicators of implementation success were fidelity and coverage. Determinants related to the social-political context and the organization were most often cited as influencing implementation, in particular, 'collaboration between community partners', 'the availability of (human) resources' and 'time available for implementation'. The association between determinants and implementation variability was never explicated. We conclude that although some insights into the effective implementation of IACOs are present, more research is needed. Emphasis should be placed on elucidating the relationship between determinants and implementation success. Research should further focus on developing a 'golden standard' for evaluating and reporting on implementation research. These actions will improve the comparison of study outcomes and may constitute the cumulative development of knowledge about the conditions for designing evidence-based implementation strategies. PMID- 25824958 TI - Comparison of accelerated 3-D spiral chemical shift imaging and single-voxel spectroscopy at 3T in the pediatric age group. AB - Single-voxel spectroscopy (SVS) is usually used in the pediatric population when a short acquisition time is crucial. To overcome the long acquisition time of 3-D phase-encoded chemical shift imaging (CSI) and lack of spatial coverage of single voxel spectroscopy, efficient encoding schemes using spiral k-space trajectories have been successfully deployed, enabling acquisition of volumetric CSI in <5 min. We assessed feasibility of using 3-D spiral CSI sequence routinely in pediatric clinical settings by comparing its reconstructed spectra against SVS spectra. Volumetric spiral CSI obtained spectra from 2-cc isotropic voxels over a 16*16*10-cm region. SVS acquisition encoded a 3.4-cc (1.5-mm) isotropic voxel. Acquisition time was 3 min for every technique. Data were gathered prospectively from 11 random pediatric patients. Spectra from left basal ganglia were obtained using both techniques and were processed with post-processing software. The following metabolite ratios were calculated: N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), lactate/creatine (Lac/Cr) and N-acetylapartate/choline (NAA/Cho). We collected data on 11 children ages 4 days to 10 years. In 10/11 cases, spectral quality of both methods was acceptable. Considering 10/11 cases, we found a statistically significant difference between SVS and 3-D spiral CSI for all three ratios. However, this difference was fixed and was probably caused by a fixed bias. This means that 3-D spiral CSI can be used instead of SVS by removing the mean difference between the methods for each ratio. Accelerated 3-D CSI is feasible in pediatric patients and can potentially substitute for SVS. PMID- 25824959 TI - Smartphone applications in paediatric radiology: availability and authority. AB - BACKGROUND: With the widespread ownership of smartphones, many health care professionals question the degree to which medically related smartphone applications are reliable. OBJECTIVES: To assess the variety of smartphone applications relating to paediatric radiology and the presence of health care professional involvement in their development. As a secondary objective, we explore whether there are gaps within the paediatric radiology app market. MATERIALS AND METHODS: The most popular smartphone marketplaces (Apple iTunes App Store, Blackberry Mobile Market, Google Play Android Market, Nokia Ovi, Samsung and Microsoft Windows Marketplace) were searched for terms relating to paediatric radiology. Cost, review ratings, number of downloads, health care involvement and target audience were recorded. RESULTS: Nine paediatric radiology applications were found in the Apple iTunes App Store and nine in the Google Play Android Market. The target audiences for all applications were health care professionals. None were available for patients or their caregivers. All applications were reported to have medical expertise in their development. CONCLUSION: All paediatric radiology applications were developed with the aid of a health care professional. Due to the small number available online, there is a potential gap in the marketplace for further applications in this field, possibly aimed at patients and their families. PMID- 25824960 TI - Ecological constraint and the evolution of sexual dichromatism in darters. AB - It is not known how environmental pressures and sexual selection interact to influence the evolution of extravagant male traits. Sexual and natural selection are often viewed as antagonistic forces shaping the evolution of visual signals, where conspicuousness is favored by sexual selection and crypsis is favored by natural selection. Although typically investigated independently, the interaction between natural and sexual selection remains poorly understood. Here, we investigate whether sexual dichromatism evolves stochastically, independent from, or in concert with habitat use in darters, a species-rich lineage of North American freshwater fish. We find the evolution of sexual dichromatism is coupled to habitat use in darter species. Comparative analyses reveal that mid-water darter lineages exhibit a narrow distribution of dichromatism trait space surrounding a low optimum, suggesting a constraint imposed on the evolution of dichromatism, potentially through predator-mediated selection. Alternatively, the transition to benthic habitats coincides with greater variability in the levels of dichromatism that surround a higher optimum, likely due to relaxation of the predator-mediated selection and heterogeneous microhabitat dependent selection regimes. These results suggest a complex interaction of sexual selection with potentially two mechanisms of natural selection, predation and sensory drive, that influence the evolution of diverse male nuptial coloration in darters. PMID- 25824961 TI - Neuronal activity-dependent regulation of retinal blood flow. AB - Blood flow in the retina is intrinsically regulated to meet the metabolic demands of its constituent cells. Flickering light or stationary contrast reversals induce an increase in blood flow within seconds of the stimulus onset. This phenomenon is thought to compensate for an increase in ganglion cell activity and energy consumption. Ganglion cell activity is in turn dependent on signals from photoreceptors, bipolar cells, horizontal cells and amacrine cells. The physiological properties of these neurons determine how each type is affected by a particular light characteristic. Neuronal activity then triggers the release of signalling molecules that dilate local blood vessels and increase blood flow. Nitric oxide has been implicated as an important mediator, but metabolites of arachidonic acid may also be involved. Detailed elucidation of these mechanisms, together with advances in imaging technology, may facilitate the use of neurovascular tests to improve the detection of retinal damage in pathological conditions. PMID- 25824962 TI - Unusual near-white electroluminescence of light emitting diodes based on saddle shaped porphyrins. AB - In contrast to the red electroluminescence emission frequently observed in porphyrins based OLED devices, the present devices exhibit a nearly white emission with greenish yellow, yellowish green and blue green hues in the case of Fe(II)(TCPPBr6) (TCPPBr6 = beta-hexabromo-meso-tetrakis-(4-phenyl carboxyl) porphyrinato), Zn(II)(TPPBr6) and Co(II)(TPPBr6), respectively. PMID- 25824963 TI - The rs6060566 of the reactive oxygen species modulator 1 (Romo-1) gene affects Romo-1 expression and the development of diabetic retinopathy in Caucasians with type 2 diabetes. AB - PURPOSE: The aim of this study was to examine the role of the rs6060566 polymorphism of the reactive oxygen species modulator 1 (Romo-1) gene in the development of diabetic retinopathy (DR) in Caucasians with type 2 diabetes (T2DM). Moreover, another aim was to investigate the effect of Romo-1 genotypes on Romo-1 expression in fibrovascular membranes from patients with proliferative DR. METHODS: A total of 806 subjects with T2DM were enrolled in cross-sectional case-control study: 278 patients with DR and 528 subjects without clinical signs of DR. Genetical analysis was performed in 806 subjects with T2DM. Moreover, immunohistochemical analysis of 40 fibrovascular membranes of patients with proliferative DR was performed. The number of positive (labelled) cells per area numerical areal density of the Romo-1-positive cells (the number of positive cells/mm(2) ) - was calculated. RESULTS: A significantly higher frequency of the CC genotype of the rs6060566 polymorphism of the Romo-1 gene was found in subjects with T2DM with DR compared to those without DR (odds ratio=3.3, 95% confidence interval=1.1-8.8; p = 0.024). Moreover, the Romo-1 C allele was found to effect Romo-1 expression in fibrovascular membranes of patients with proliferative DR. CONCLUSIONS: The rs6060566 polymorphism of the Romo-1 gene was found to be an independent risk factor for DR in Caucasians with T2DM. Moreover, the rs6060566 is most probably functional and its effect might be mediated through the increased expression of Romo-1 in the retina. PMID- 25824964 TI - Aspirin-induced histone acetylation in endothelial cells enhances synthesis of the secreted isoform of netrin-1 thus inhibiting monocyte vascular infiltration. AB - BACKGROUND AND PURPOSE: There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, as it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used in cardiovascular prophylaxis, on the synthesis of different isoforms of netrin-1 by endothelial cells under pro-inflammatory conditions, and defined the net effect of aspirin-dependent systemic modulation of netrin-1 on atherosclerosis progression. EXPERIMENTAL APPROACH: Netrin-1 synthesis was studied in vitro using human endothelial cells stimulated with TNF-alpha, with or without aspirin treatment. In vivo experiments were conducted in ApoE(-/-) mice fed with a high fat diet (HFD), receiving either aspirin or clopidogrel. KEY RESULTS: TNF-alpha induced NF-kappaB activation up-regulated the nuclear isoform of netrin-1, while simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent action of the endothelium against monocyte chemotaxis. Aspirin counteracted TNF-alpha-mediated effects on netrin-1 synthesis by endothelial cells through COX-dependent inhibition of NF-kappaB and concomitant histone hyperacetylation. Administration of aspirin to ApoE(-/-) mice on HFD increased blood and arterial wall levels of netrin-1 independently of its effects on platelets, accompanied by reduced plaque size and content of monocytes/macrophages, compared with untreated or clopidogrel-treated mice. In vivo blockade of netrin-1 enhanced monocyte plaque infiltration in aspirin treated ApoE(-/-) mice. CONCLUSIONS AND IMPLICATIONS: Aspirin counteracts down regulation of secreted netrin-1 induced by pro-inflammatory stimuli in endothelial cells. The aspirin-dependent increase of netrin-1 in ApoE(-/-) mice exerts anti-atherogenic effects by preventing arterial accumulation of monocytes. PMID- 25824965 TI - [Characteristics of the population hospitalized for advanced and terminal heart failure and experiences in palliative caring in the Intensive Care Unit of cardiology]. AB - PURPOSE: Advanced heart failure incidence is in progression. Palliative care access remains difficult due to its unpredictable course. The aim of this study was to describe the characteristics of patients admitted in Cardiology Intensive Care Unit for advanced heart failure who received palliative care and compare them to the whole population of acute heart failure hospitalized in the same period. PATIENTS AND METHODS: The patients hospitalized for acute heart failure were retrospectively included from 2009 to 2013. We identified among them those who received palliative care. Specific caring was decided in pluridisciplinary meeting. RESULTS: On 940 patients included, 42 patients (4.5%) receive palliative care. Ischemic heart disease was the main etiology (n=19; 45.2%). Right ventricular dysfunction (n=34; 80.9%) was associated with supra-ventricular arrhythmia (n=28; 66.7%). Twenty-eight patients (57.1%) have died in hospital, 9 (21.4%) were referred to a palliative care unit and 8 (19.1%) was discharged or referred to a rehabilitation center. Time between inclusion and death was 6 days on average. Intra-hospital mortality in control group was 6.8%. CONCLUSION: Palliative care in cardiology is uncommon and has often been too late because of its poor adaptability to advanced heart failure. It is, as consequence, necessary to identify the prognostic factors of these patients in order to propose a personalized care and to adjust the intensity of care ahead of the terminal evolution of heart failure. PMID- 25824966 TI - Canadian Emergency Medicine Residents' Perspectives on Pediatric Pain Management. AB - BACKGROUND: Under-treatment of children's pain in the emergency department (ED) can have many detrimental effects. Emergency medicine (EM) residents often manage pediatric pain, but their educational needs and perspectives have not been studied. METHODS: A novel online survey was administered from May to June 2013 to 122 EM residents at three Canadian universities using a modified Dillman methodology. The survey instrument captured information on training received in pediatric acute pain management, approach to common painful presentations, level of comfort, perceived facilitators, and barriers and attitudes towards pediatric pain. RESULTS: 56 residents participated (46%), 25 of whom (45%) indicated they had not received any training in pediatric pain assessment. All levels of residents reported they were uncomfortable with pain assessment in 0-2 year olds (p=0.07); level of comfort with assessment increased with years of training for patients aged 2-12 years (p=0.02). When assessing children with disabilities, 83% of respondents (45/54) indicated they were 'extremely' or 'somewhat' uncomfortable. Sixty-nine percent (38/55) had received training on how to treat pediatric pain. All residents reported they were more comfortable using pain medication for a 9 year old, as compared to a 1 year old (oral oxycodone p<0.001, oral morphine p<0.001, IV morphine p=0.004). The preferred methods to learn about children's pain management were role-modeling (61%) and lectures (57%). The top challenges in pain management were with non-verbal, younger, or developmentally delayed patients. CONCLUSION: Canadian EM residents report receiving inadequate training in pediatric pain management, and are particularly uneasy with younger or developmentally disabled children. Post-graduate curricula should be adjusted to correct these self-identified weaknesses in children's pain management. PMID- 25824967 TI - Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics. AB - Basal levels of oxidants are indispensible for redox signaling to produce adaptive cellular responses such as vitagenes linked to cell survival; however, at higher levels, they are detrimental to cells, contributing to aging and to the pathogenesis of numerous age-related diseases. Aging is a complex systemic process and the major gap in aging research reminds the insufficient knowledge about pathways shifting from normal "healthy" aging to disease-associated pathological aging. The major complication of normal "healthy" aging is in fact the increasing risk of age-related diseases such as cardiovascular diseases, diabetes mellitus, and neurodegenerative pathologies that can adversely affect the quality of life in general, with enhanced incidences of comorbidities and mortality. In this context, global "omics" approaches may help to dissect and fully study the cellular and molecular mechanisms of aging and age-associated processes. The proteome, being more close to the phenotype than the transcriptome and more stable than the metabolome, represents the most promising "omics" field in aging research. In the present study, we exploit recent advances in the redox biology of aging and discuss the potential of proteomics approaches as innovative tools for monitoring at the proteome level the extent of protein oxidative insult and related modifications with the identification of targeted proteins. PMID- 25824968 TI - Chemistry and liquid chromatography methods for the analyses of primary oxidation products of triacylglycerols. AB - Triacylglycerols (TAGs) are one of the major components of the cells in higher biological systems, which can act as an energy reservoir in the living cells. The unsaturated fatty acid moiety is the key site of oxidation and formation of oxidation compounds. The TAG free radical generates several primary oxidation compounds. These include hydroperoxides, hydroxides, epidioxides, hydroperoxy epidioxides, hydroxyl epidioxides, and epoxides. The presence of these oxidized TAGs in the cell increases the chances of several detrimental processes. For this purpose, several liquid chromatography (LC) methods were reported in their analyses. This review is therefore focused on the chemistry, oxidation, extraction, and the LC methods reported in the analyses of oxidized TAGs. The studies on thin-layer chromatography were mostly focused on the total oxidized TAGs separation and employ hexane as major solvent. High-performance LC (HPLC) methods were discussed in details along with their merits and demerits. It was found that most of the HPLC methods employed isocratic elution with methanol and acetonitrile as major solvents with an ultraviolet detector. The coupling of HPLC with mass spectrometry (MS) highly increases the efficiency of analysis as well as enables reliable structural elucidation. The use of MS was found to be helpful in studying the oxidation chemistry of TAGs and needs to be extended to the complex biological systems. PMID- 25824969 TI - Investigating the widely held belief that men and women with learning disabilities receive poor quality healthcare when admitted to hospital: a single site study of 30-day readmission rates. AB - BACKGROUND: This study aims to use 30-day readmission rates to investigate the presumption that men and women with learning disabilities (LDs, known internationally as intellectual disabilities) receive poorer quality hospital care than their non-disabled peers. METHOD: A 12-month retrospective audit was conducted using Hospital Episode Statistics (HES) at a single acute hospital in the East of England. This identified all in-patient admissions; admissions where the person concerned was recognised as having a LD; and all emergency readmissions within 30 days of discharge. Additionally, the healthcare records of all patients identified as having a LD and readmitted within 30 days as a medical emergency were examined in order to determine whether or not these readmissions were potentially preventable. RESULTS: Over the study period, a total of 66 870 adults were admitted as in-patients, among whom 7408 were readmitted as medical emergencies within 30 days of discharge: a readmission rate of 11%. Of these 66 870 patients, 256 were identified as having a LD, with 32 of them experiencing at least one emergency readmission within 30 days: a readmission rate of 13%. When examined, the healthcare records pertaining to these 32 patients who had a total of 39 unique 30-day readmissions revealed that 69% (n = 26) of these readmissions were potentially preventable. CONCLUSION: Although overall readmission rates were similar for patients with LDs and those from the general population, patients with LDs had a much higher rate of potentially preventable readmissions when compared to a general population estimate from van Walraven et al. This suggests that there is still work to be done to ensure that this patient population receives hospital care that is both safe and of high quality. PMID- 25824970 TI - Ligand-doped liquid crystal sensor system for detecting mercuric ion in aqueous solutions. AB - We developed a liquid crystal (LC) sensor system for detecting mercuric ion (Hg(2+)) in aqueous solutions. In this system, 4-cyano-4'-pentyl biphenyl (5CB) was doped with a sulfur- and nitrogen-containing ligand 5-(pyridine-4-yl)-2-(5 (pyridin-4-yl)thiophen-2-yl)thiazole (ZT) as the Hg(2+) specific LCs. When the system was immersed in the solution containing Hg(2+), the complex of ZT and Hg(2+) formed, which disrupted the orientation of LC and lead to a dark-to-bright transition of the image of LCs. From mercuric binding titrations monitored by UV vis spectroscopy, it was found that 1:1 Hg(2+)/ZT complexes were formed. The limit of detection (LOD) of the system to Hg(2+) is 10 MUM, and it did not respond to Cd(2+), Zn(2+), Cu(2+), Pb(2+), Fe(+), Mg(2+), Ca(2+), Na(+), and K(+). Besides, we also demonstrated that this system is capable of detecting Hg(2+) in tap water and pond water. Because the signal of this system is colorful under ambient light, which is readily understood by normal users, it can be used as a portable device to monitor the water quality at any location. PMID- 25824971 TI - Emerging properties of adhesion complexes: what are they and what do they do? AB - The regulation of cell adhesion machinery is central to a wide variety of developmental and pathological processes and occurs primarily within integrin associated adhesion complexes. Here, we review recent advances that have furthered our understanding of the composition, organisation, and dynamics of these complexes, and provide an updated view on their emerging functions. Key findings are that adhesion complexes contain both core and non-canonical components. As a result of the dramatic increase in the range of components observed in adhesion complexes by proteomics, we comment on newly emerging functions for adhesion signalling. We conclude that, from a cellular or tissue systems perspective, adhesion signalling should be viewed as an emergent property of both the core and non-canonical adhesion complex components. PMID- 25824972 TI - Expression and characterization of hepatitis E virus-like particles and non-virus like particles from insect cells. AB - The hepatitis E virus (HEV) capsid antigen expressed in insect cell has been proposed as a candidate subunit vaccine for the prevention of hepatitis E. However, the expression and purification of HEV virus-like particles (VLPs) from insect cells have not been explored. We aimed to optimize the procedure to obtain HEV VLPs. In this study, two conformations of the HEV capsid proteins were expressed in insect cells, VLPs and non-VLPs, and they were purified separately. The physicochemical properties and the humoral immune responses induced by the two forms were analyzed and compared. We found that HEV VLPs were more immunogenic in mice than HEV non-VLPs. Therefore, we optimized the conditions that yielded high VLPs expression in insect cell cultures and developed an efficient purification method. The results suggest that the distinction and isolation of VLPs from non-VLPs are essential to generate a more immunogenic vaccine. PMID- 25824973 TI - Retraction note: Gene-gene interaction network analysis of ovarian cancer using TCGA data. AB - The Publisher and Editor regretfully retract this article (Ying H, Lv J, Ying T, Jin S, Shao J, Wang L, et al. Gene-gene interaction network analysis of ovarian cancer using TCGA data. J Ovarian Res. 2013;6:88) because the peer-review process was inappropriately influenced and compromised. As a result, the scientific integrity of the article cannot be guaranteed. A systematic and detailed investigation suggests that a third party was involved in supplying fabricated details of potential peer reviewers for a large number of manuscripts submitted to different journals. In accordance with recommendations from COPE we have retracted all affected published articles, including this one. It was not possible to determine beyond doubt that the authors of this particular article were aware of any third party attempts to manipulate peer review of their manuscript. PMID- 25824974 TI - Exposure-dependent Ag+ release from silver nanoparticles and its complexation in AgS2 sites in primary murine macrophages. AB - Silver nanoparticle (AgNP) toxicity is related to their dissolution in biological environments and to the binding of the released Ag(+) ions in cellulo; the chemical environment of recombined Ag(+) ions is responsible for their toxicological outcome, moreover it is indicative of the cellular response to AgNP exposure, and can therefore shed light on the mechanisms governing AgNP toxicity. This study probes the chemistry of Ag species in primary murine macrophages exposed to AgNPs by making use of X-ray Absorption Fine Structure spectroscopy under cryogenic conditions: the linear combination analysis of the near-edge region of the spectra provides the fraction of Ag(+) ions released from the AgNPs under a given exposure condition and highlights their complexation with thiolate groups; the ab initio modelling of the extended spectra allows measuring the Ag-S bond length in cellulo. Dissolution rates depend on the exposure scenario, chronicity leading to higher Ag(+) release than acute exposure; Ag-S bond lengths are 2.41 +/- 0.03 A and 2.38 +/- 0.01 A in acute and chronic exposure respectively, compatible with digonal AgS2 coordination. Glutathione is identified as the most likely putative ligand for Ag(+). The proposed method offers a scope for the investigation of metallic nanoparticle dissolution and recombination in cellular models. PMID- 25824975 TI - Acute and chronic postsurgical pain after living liver donation: Incidence and predictors. PMID- 25824976 TI - Locally Advanced Intrahepatic Cholangiocarcinoma: Complete Pathologic Response to Neoadjuvant Chemotherapy Followed by Left Hepatic Trisectionectomy and Caudate Lobectomy. PMID- 25824977 TI - Artifacts, Noise and Interference: Much Ado about Ultrasound. PMID- 25824978 TI - Measurement of the acute metabolic response to hypoxia in rat tumours in vivo using magnetic resonance spectroscopy and hyperpolarised pyruvate. AB - PURPOSE: To estimate the rate constant for pyruvate to lactate conversion in tumours in response to a hypoxic challenge, using hyperpolarised (13)C1-pyruvate and magnetic resonance spectroscopy. METHODS AND MATERIALS: Hypoxic inspired gas was used to manipulate rat P22 fibrosarcoma oxygen tension (pO2), confirmed by luminescence decay of oxygen-sensitive probes. Hyperpolarised (13)C1-pyruvate was injected into the femoral vein of anaesthetised rats and slice-localised (13)C magnetic resonance (MR) spectra acquired. Spectral integral versus time curves for pyruvate and lactate were fitted to a precursor-product model to estimate the rate constant for tumour conversion of pyruvate to lactate (kpl). Mean arterial blood pressure (MABP) and oxygen tension (ArtpO2) were monitored. Pyruvate and lactate concentrations were measured in freeze-clamped tumours. RESULTS: MABP, ArtpO2 and tumour pO2 decreased significantly during hypoxia. kpl increased significantly (p<0.01) from 0.029+/-0.002s(-1) to 0.049+/-0.006s(-1) (mean+/-SEM) when animals breathing air were switched to hypoxic conditions, whereas pyruvate and lactate concentrations were minimally affected by hypoxia. Both ArtpO2 and MABP influenced the estimate of kpl, with a strong negative correlation between kpl and the product of ArtpO2 and MABP under hypoxia. CONCLUSION: The rate constant for pyruvate to lactate conversion, kpl, responds significantly to a rapid reduction in tumour oxygenation. PMID- 25824979 TI - Noninvasive pulmonary nodule elastometry by CT and deformable image registration. AB - BACKGROUND AND PURPOSE: To develop a noninvasive method for determining malignant pulmonary nodule (MPN) elasticity, and compare it against expert dual-observer manual contouring. METHODS AND MATERIALS: We analyzed breath-hold images at extreme tidal volumes of 23 patients with 30 MPN treated with stereotactic ablative radiotherapy. Deformable image registration (DIR) was applied to the breath-hold images to determine the volumes of the MPNs and a ring of surrounding lung tissue (ring) in each state. MPNs were also manually delineated on deep inhale and exhale images by two observers. Volumes were compared between observers and DIR by Dice similarity. Elasticity was defined as the absolute value of the volume ratio of the MPN minus one normalized to that of the ring. RESULTS: For all 30 tumors the Dice coefficient was 0.79+/-0.07 and 0.79+/-0.06 between DIR with observers 1 and 2, respectively, close to the inter-observer Dice value, 0.81+/-0.1. The elasticity of MPNs was 1.24+/-0.26, demonstrating that volume change of the MPN was less than that of the surrounding lung. CONCLUSION: We developed a noninvasive CT elastometry method based on DIR that measures the elasticity of biopsy-proven MPN. Our future direction would be to develop this method to distinguish malignant from benign nodules. PMID- 25824980 TI - Processing of bilateral versus unilateral conditions: evidence for the functional contribution of the ventral attention network. AB - Processing of multiple or bilateral conditions presented simultaneously in both hemifields reflects the natural mode of perception in our multi-target environment, but is not yet completely understood. While region-of-interest based studies in healthy subjects reported single cortical areas as the right inferior parietal lobe (IPL) or temporoparietal junction (TPJ) to process bilateral conditions, studies in extinction patients with reduced ability in this regard suggested the right superior temporal cortex to hold a key role. The present fMRI study on healthy subjects aimed at resolving these discrepancies by contrasting bilateral versus unilateral visual conditions in a paradigm similar to the bed side test for patients with visual extinction on a whole brain level. Additionally, reduced attentional capacity in spatial processing was investigated in normal aging. Processing of bilateral conditions compared to unilateral ones showed to require stronger activation of not one single cortical region but the entire right-lateralized ventral attention network, bilateral parietal and visual association areas. These results might suggest a conceptual difference between unilateral and bilateral spatial processing with the latter depending on additional anatomical and functional brain resources. Reduced attentional capacity in elderly subjects was associated with compensatory recruitment of contralateral functional homologues [left IPL, TPJ, frontal eye field (FEF)]. These data reveal the functional anatomy of our ability to visually process and respond to the entity of the environment and improve our understanding of neglect and extinction. Moreover, the data demonstrate that a restriction of the attentional capacity is based on processing limitations in the network of high level cortical areas and not due to restriction in the primary sensory ones. PMID- 25824981 TI - Electrophysiological evidence of a typical cognitive distortion in bipolar disorder. AB - Patients suffering from bipolar disorder often report negative thoughts and a bias towards negative environmental stimuli. Previous studies show that this mood congruent attentional bias could mediated by dysfunctions in anterior limbic regions. The Error-Related Negativity (ERN), which originates in the anterior cingulate cortex (ACC), has been used to research this negativity bias in depressed patients, and could also help to better understand the underlying mechanisms causing the negativity bias in bipolar patients. In this study we investigated error processing in patients with bipolar disorder. Acute depressive bipolar patients (n = 20) and age-matched healthy controls (n = 20) underwent a modified Eriksen Flanker Task to assess test performance and two error-related event-related potentials (ERPs), i.e., the ERN and Error Positivity (Pe) were measured by EEG. Half of the patients were measured again in a euthymic state. We found similar ERN amplitudes in bipolar patients as compared to healthy controls, but significantly reduced Pe amplitudes. Moreover, acutely depressed bipolar patients displayed an ERN and Pe even if they responded accurately or too slow, which indicates that correct responses are processed in a way similar to wrong responses. This can be interpreted as a psychophysiological correlate of typical cognitive distortions in depression, i.e., an erroneous perception of personal failures. This biased error perception partially remained when patients were in a euthymic state. Together, our data indicate that aberrant error processing of bipolar patients may be regarded a trait marker possibly reflecting a risk factor for depressive relapses in bipolar disorder. PMID- 25824982 TI - Protective effects of lithium chloride on seizure susceptibility: Involvement of alpha2-adrenoceptor. AB - For more than 60years, lithium has been the mainstay in the treatment of mental disorders as a mood stabilizer. In addition to the antimanic and antidepressant responses, lithium also shows some anticonvulsant properties. In spite of the ascertained neuroprotective effects of this alkali metal, the underlying mechanisms through which lithium regulates behavior are still poorly understood. Among different targets, some authors suggest neuromodulatory effects of lithium are the consequences of interaction of this agent with the brain neurotransmitters including adrenergic system. In order to study the involvement of alpha2-adrenergic system in anticonvulsant effect of lithium, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice. Injection of a single effective dose of lithium chloride (30mg/kg, i.p.) significantly increased the seizure threshold (p<0.01). The anticonvulsant effect of an effective dose of lithium was prevented by pre-treatment with low and per se non-effective dose of clonidine [alpha2-adrenoceptor agonist] (0.05, 0.1 and 0.25mg/kg). On the other hand, yohimbine [alpha2-adrenoceptor antagonist] augmented the anticonvulsant effect of sub-effective dose of lithium (10mg/kgi.p.) at relatively low doses (0.1, 0.5, 1 and 2.5mg/kg). Moreover, UK14304 [a potent and selective alpha2-adrenoceptor agonist] (0.05 and 0.1mg/kg) and RX821008 [a potent and selective alpha2D-adrenoceptor antagonist] (0.05, 0.1 and 0.25mg/kg) repeated the same results confirming that these modulatory effects are conducted specifically through the alpha2D-adrenoceptors. In summary, our findings demonstrated that alpha2-adrenoceptor pathway could be involved in the anticonvulsant properties of lithium chloride in the model of chemically induced clonic seizure. PMID- 25824983 TI - Hydroxycinnamic acid amide derivatives of polyamines reverse spermine-induced CNS excitation. AB - The aim of this study was to examine the acute effect of a range of novel hydroxycinnamic acid derivatives of spermine on the development of spermine induced CNS excitation and convulsions in female Laca mice, and to assess the chronic adverse behavioural effect profile of these compounds over a 5day period. Four of the six novel polyamine analogues dose-dependently inhibited body tremor and tonic convulsions caused by spermine, when administered centrally (icv) or peripherally (ip). BU43b was the most potent analogue tested, but BU31b, 33b, and 36b were also effective (p<0.01, Mann-Whitney U test). A similar profile of effectiveness was seen with peripheral and central administration, indicating that the analogues may cross the blood brain barrier. More chronic investigation of the adverse effects of the compounds administered alone over 5days of observation indicated that the drugs were well tolerated, only causing reduced locomotor activity on the first day of the study and mild changes in behaviours linked to CNS and ANS function. It is likely that NMDA receptor NR2B subunit inhibition is involved in the anticonvulsant effect of these novel analogues, but other mechanisms may also be involved. These novel polyamine derivatives warrant further investigation of their therapeutic potential in treating epilepsy and CNS disorders where excitotoxicity is implicated. PMID- 25824984 TI - Osteopontin is a useful predictor of bone metastasis and survival in patients with locally advanced nasopharyngeal carcinoma. AB - Bone is the most common metastatic site in nasopharyngeal carcinoma (NPC). Osteopontin (OPN) and bone sialoprotein (BSP) are demonstrated to be involved in multiple steps of distant metastasis and correlate with bone metastasis (BM) in cancers. We aim to explore the impacts of OPN and BSP on the prognosis of the patients with locally advanced NPC. A tissue microarray including 162 locally advanced NPC specimens was generated for immunohistochemical evaluation. All of the patients received curative treatment. Twenty-two patients developed BM during follow-up. The OPN expression level was higher in patients with BM than in those without BM (p = 0.005), whereas no significant difference of the BSP expression level was noted (p = 0.634). Univariate analysis demonstrated that a higher level of OPN expression associated with a poorer 8-year metastasis-free survival (MFS) rate (p < 0.001), 8-year bone metastasis-free survival (BMFS) rate (93.6 vs. 87.5 vs. 64.5% for immunoreactivity score 1, 2 and 3, respectively; p = 0.001) and median overall survival (OS) time (p < 0.001). Multivariate Cox analysis confirmed that high level of OPN expression was independent factor associated with decreased BMFS (p = 0.02), MFS (p < 0.001) and OS (p < 0.001). Our findings indicate that OPN is a prognostic biomarker for BM and survival in patients with locally advanced NPC, and therefore it is useful in identifying the patients with an increased risk of cancer progression and BM to guide tailored therapy. PMID- 25824985 TI - Gallic acid can play a chondroprotective role against AGE-induced osteoarthritis progression. AB - BACKGROUND: Advanced glycation end products (AGEs) are a group of stable covalent compounds generated by proteins, lipids, other macromolecules and sugar through a series of non-enzymatic reactions. As reported, AGEs can cause widespread pathophysiological responses through activation of AGE receptors (RAGEs) on the cell surface, and play an important role in the pathogenesis of osteoarthritis (OA). We hypothesized that the antioxidant and anti-glycan agent gallic acid (GA) can work against the effects of AGEs and can be used as a potential drug for the cure of OA. METHODS: The present study first explored the negative functions of AGEs via AGE-treated chondrocytes isolated form rabbits. Then, we observed the protective role of GA in AGE-treated chondrocytes by measuring the reactive oxygen species (ROS), superoxide dismutase (SOD), collagen II, aggrecan, nitric oxide synthase (iNOs) and cyclooxygenase-2 (COX-2) in vitro. Finally, the changes in a cartilage lesion in a rabbit model of knee osteoarthritis was observed. RESULTS: Exposure of chondrocytes to AGEs resulted in a reduction of ROS, SOD, collagen II and aggrecan, and an increase in iNOs and COX-2, which means exposure promoted OA lesions in a clinical setting. When AGE-treated chondrocytes were pretreated with GA, there were no significant changes in these key components compared to the normal chondrocytes. In vivo study showed cartilage degradation was reduced by GA as compared to the vehicle group. CONCLUSION: The results of this study confirmed the chondroprotective role of GA and provide a potential drug for the relief of OA. PMID- 25824986 TI - Identification of therapeutic targets for breast cancer using biological informatics methods. AB - The present study aimed to investigate the modular mechanisms underlying breast cancer and identify potential targets for breast cancer treatment. The differentially expressed genes (DEGs) between breast cancer and normal cells were assessed using microarray data obtained from the Gene Expression Omnibus database. Gene ontology (GO) and pathway enrichment analyses were performed in order to investigate the functions of these DEGs. Subsequently, the protein protein interaction (PPI) network was constructed using the Cytoscape software. The identified subnetworks were further analyzed using the Molecular Complex Detection plugin. In total, 571 genes (241 upregulated and 330 downregulated genes) were found to be differentially expressed between breast cancer and normal cells. The GO terms significantly enriched by DEGs included cell adhesion, immune response and extracellular region, while the most significant pathways included focal adhesion and complement and coagulation cascade pathways. The PPI network was established with 273 nodes and 718 edges, while fibronectin 1 (FN1, degrees score, 39), interleukin 6 (IL6; degree score, 96) and c-Fos protein (degree score, 32) were identified as the hub proteins in subnetwork 2. These dysregulated genes were found to be involved in the development of breast cancer. The FN1, IL6 and FOS genes may therefore be potential targets in the treatment of breast cancer. PMID- 25824987 TI - Overrepresentation of missense mutations in mild hemophilia A patients from Belgium: founder effect or independent occurrence? AB - Roughly 40% of observed mutations responsible for hemophilia A (HA) are novel and present in either a single family or a limited number of unrelated families. During routine diagnostic analysis of 73 unrelated Belgian patients with mild HA, 4 out of 43 different mutations (p.Ser2030Asn, p.Arg2178Cys, p.Arg2178His, and p.Pro2311His) were detected in more than one family, representing 35% of total identified mutations. To discriminate between an independent recurrence or a founder effect, an analysis of intra- and -extragenic single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs) flanking the F8 gene was conducted. SNP haplotype and microsatellite analysis revealed strong evidence that p.Ser2030Asn and p.Pro2311His mutations were probably associated with a founder effect. The two other mutations localized in an F8 cytosine-phosphate guanine (CpG) site likely resulted from recurrent de novo events. This study suggests that missense mutations producing C-to-T or G-to-A substitutions in CpG dinucleotide can occur de novo with more repetition than other causal substitutions that do not affect the CpG site. Analysis of F8 database implied that CpG sites throughout the F8 gene are not all mutated with the same frequency. Causes are still unknown and remain to be identified. PMID- 25824989 TI - Gold nanoparticle array formation on dimpled Ta templates using pulsed laser induced thin film dewetting. AB - Here we show that pulsed laser-induced dewetting (PLiD) of a thin Au metallic film on a nano-scale ordered dimpled tantalum (DT) surface results in the formation of a high quality Au nanoparticle (NP) array. In contrast to thermal dewetting, PLiD does not result in deformation of the substrate, even when the Au film is heated to above its melting point. PLiD causes local heating of only the metal film and thus thermal oxidation of the Ta substrate can be avoided, also because of the high vacuum (low pO2) environment employed. Therefore, this technique can potentially be used to fabricate NP arrays composed of high melting point metals, such as Pt, not previously possible using conventional thermal annealing methods. We also show that the Au NPs formed by PLiD are more spherical in shape than those formed by thermal dewetting, likely demonstrating a different dewetting mechanism in the two cases. As the metallic NPs formed on DT templates are electrochemically addressable, a longer-term objective of this work is to determine the effect of NP size and shape (formed by laser vs. thermal dewetting) on their electrocatalytic properties. PMID- 25824988 TI - Regulation of EMMPRIN (CD147) on monocyte subsets in patients with symptomatic coronary artery disease. AB - INTRODUCTION: The role of individual monocyte subsets in inflammatory cardiovascular diseases is insufficiently understood. Although the Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) regulates important processes for inflammation such as MMP-release, its expression and regulation on monocyte subsets has not been characterized. MATERIALS AND METHODS: In this clinical study, blood was obtained from 80 patients with stable coronary artery disease (CAD), 49 with acute myocardial infarction (AMI) and 34 healthy controls. Monocytes were divided into 3 subsets: CD14(++)CD16(-) (low), CD14(++)CD16(+) (intermediate), CD14(+)CD16(++) (high) according to phenotypic markers analyzed by flow cytometry. Surface expression of EMMPRIN was evaluated and compared with CD36 and CD47 expression. RESULTS: In all patients, EMMPRIN expression was significantly different among monocyte subsets with the highest expression on "classical" CD14(++)CD16(-) monocytes. EMMPRIN was upregulated on all monocyte subsets in patients with AMI as compared to patients with stable CAD. Notably, neither CD47 nor CD36 revealed a significant difference in patients with AMI compared to patients with stable CAD. CONCLUSION: EMMPRIN could serve as a marker for classical monocytes, which is upregulated in patients with acute myocardial infarction. PMID- 25824990 TI - A comparison of juice extraction methods in the pungency measurement of onion bulbs. AB - BACKGROUND: Onion pungency is estimated by measuring the pyruvic acid content in juice extracted from fresh tissues. We compared pyruvic acid content and its variation in the juices extracted by the pressing, maceration, blending with no water, or blending with water (blend/water) methods. RESULTS: There were considerable differences in the pyruvic acid content and coefficient of variation (CV) among these methods, and there was an interaction between the onion cultivars and the juice extraction methods. The pressing method showed over 30% CV in the quartered or composite samples. The blend/water method showed the greatest pyruvic acid content in the shortday-type ('TG1015Y' and 'Texas Early White') onions, while the pressing method showed the greatest pyruvic acid content in the longday-type onions. The blend/water method, which gave ratios between 1:1 and 1:4 (w/w), showed the same pyruvic acid content. The blending (no water) method had the highest correlation, followed by the maceration method. The lowest correlations were found with the pressing method and the blend/water method. CONCLUSIONS: Complete homogenisation of tissues with 1:1 or greater ratios of water was necessary for the maximum consistency and full development of the pyruvic acid reaction for onion pungency measurement. PMID- 25824991 TI - [An outbreak of Burkholderia cepacia bacteremia in a hemodialysis unit, Cadiz, 2014]. AB - INTRODUCTION: In January 2014 a possible outbreak of Burkholderia cepacia bacteremia occurred in a hemodialysis center situated in La Linea de la Concepcion (Cadiz). An investigation was begun to confirm the outbreak, identify the source, and implement control measures. METHODS: A descriptive analysis was performed to describe the characteristics of the patients affected with Burkholderia cepacia bacteremia from November 2013 to February 2014. Environmental samples were taken. A molecular typing study was performed using pulsed field gel electrophoresis (SpeI PFGE) and MLST analysis in order to determine the genetic similarity between the isolates. RESULTS: The bacterium was isolated from blood cultures of 7 patients during the study period. Three of the samples (2 of which were also cases) were endoluminal fluid from catheter locks, and 4 chlorhexidine bottle samples. The patients were coincident in 2 of the 6 work shifts. The mean age of the cases was 67 years of whom 57% were women. Human samples and an environmental sample was analyzed and found to be genetically identical (ST653 clone). CONCLUSIONS: The analysis confirmed the outbreak of Burkholderia cepacia, with 7 cases among the patients of the hemodialysis center. The outbreak was due to the same strain, probably a common source and secondary transmission from person to person. PMID- 25824992 TI - [Hip prosthesis infection due to Streptococcus gallolyticus subsp. pasteurianus]. PMID- 25824993 TI - [Microbiological diagnosis of medical device-associated infections]. AB - The use of surgically implanted medical devices has increased greatly over the last few years. Despite surgical advances and improvements in the materials and design of devices, infection continues to be a major complication of their use. Device-associated infections are produced mainly during their implantation and, are caused by microorganisms that are part of the skin flora. Biofilm development on device surfaces is the most important factor to explain the pathophysiological aspects of infection. Microbiological diagnosis is difficult and can often only be achieved after removal of the device. Sonication of the removed device may be a useful tool, since this procedure dislodges and disaggregates biofilm bacteria from the device. Molecular techniques, especially PCR, applied to the tissues and material obtained after sonication have shown to have a high sensitivity and specificity for the diagnosis of cardiovascular device infections. PMID- 25824994 TI - Restricting access to HIV-related services: a bad public health and economic policy. PMID- 25824995 TI - Benign outcome among positive cystic fibrosis newborn screen children with non-CF causing variants. AB - BACKGROUND: The Clinical and Functional Translation of CFTR project (CFTR2) classified some cystic fibrosis transmembrane conductance regulator (CFTR) gene variants as non-cystic fibrosis (CF)-causing. To evaluate this, the clinical status of children carrying these mutations was examined. METHODS: We analyzed CF disease-defining variables over 2-6 years in two groups of California CF screen- positive neonates born from 2007 to 2011: (1) children with two CF-causing variants and (2) children with one CF-causing and one non-CF-causing variant, as defined by CFTR2. RESULTS: Children carrying non-CF-causing variants had significantly higher birth weight, lower immunoreactive trypsinogen and sweat chloride values, higher first year growth curves, and a lower rate of persistent Pseudomonas aeruginosa colonization compared to children with two CF-causing variants. CONCLUSIONS: The outcomes in children 2-6 years of age with the L997F, G576A, R1162L, V754M, R668C, R31C, and S1235R variants are consistent with the CFTR2 non-CF-causing classification. PMID- 25824996 TI - Therapeutic options in oesophageal dysphagia. AB - High-resolution manometry enables the categorization of patients with oesophageal dysphagia caused by oesophageal motility disorders into diagnostic categories according to the Chicago Classification. This Review provides an overview of the literature concerning treatment options for patients with dysphagia associated with achalasia, hypercontractile disorders and hypocontractility disorders of the oesophagus. In achalasia, pharmacotherapy and botulinum toxin are less effective than pneumatic dilation or surgical Heller myotomy, which had comparable efficacy in the largest controlled trial to date. Peroral endoscopic myotomy is a novel therapeutic modality that is currently being evaluated in controlled trials versus pneumatic dilation or surgical myotomy. A variety of medical treatments have been evaluated in hypermotility disorders, but only botulinum toxin injection yielded favourable results in a single controlled trial. Few studies have addressed the treatment of dysphagia in patients with oesophageal hypomotility. A variety of prokinetic agents have been studied, but there is no evidence of clinically relevant efficacy from controlled trials. PMID- 25824998 TI - Therapy: Oral SMAD7 antisense oligonucleotide proves effective for Crohn's disease. PMID- 25824999 TI - Liver: Reprogramming a hepatocyte's memory of liver disease. PMID- 25824997 TI - Towards a more comprehensive concept for prebiotics. AB - The essential role of the gut microbiota for health has generated tremendous interest in modulating its composition and metabolic function. One of these strategies is prebiotics, which typically refer to selectively fermented nondigestible food ingredients or substances that specifically support the growth and/or activity of health-promoting bacteria that colonize the gastrointestinal tract. In this Perspective, we argue that advances in our understanding of diet microbiome-host interactions challenge important aspects of the current concept of prebiotics, and especially the requirement for effects to be 'selective' or 'specific'. We propose to revise this concept in an effort to shift the focus towards ecological and functional features of the microbiota more likely to be relevant for host physiology. This revision would provide a more rational basis for the identification of prebiotic compounds, and a framework by which the therapeutic potential of modulating the gut microbiota could be more fully materialized. PMID- 25825000 TI - Cyclic hypervalent iodine reagents and iron catalysts: the winning team for late stage C-H azidation. AB - 1+1=3: By combining the exceptional reactivities of cyclic hypervalent iodine reagents and iron catalysts, Sharma and Hartwig achieved the azidation of C?H bonds with unprecedented efficiency and selectivity. The late-stage introduction of azides into complex bioactive molecules will greatly facilitate the synthesis of analogues and accelerate the discovery of new chemical entities. PMID- 25825001 TI - Optimization of the excitation frequency for high probe sensitivity in single eigenmode and bimodal tapping-mode AFM. AB - The cantilever excitation frequency and tip free oscillation amplitude are two critical imaging parameters in amplitude-modulation atomic force microscopy (AM AFM, often referred to as tapping-mode AFM). In general, the excitation frequency is selected to be 'near' the measured resonance frequency of the probe, but there is no established systematic approach for making that choice. In this work we show that the choice of excitation frequency can play a very significant role in the characterization of viscoelastic materials, even when considering small deviations with respect to the resonance frequency. Additionally, we offer an analytical expression, verified through experiments and numerical simulations, which offers guidance for selecting the drive frequency that maximizes probe sensitivity. Our approach is illustrated experimentally through single-eigenmode and bimodal AFM measurements performed on spin-coated Nafion((r)) proton exchange thin films. We find that very often, the phase contrast channel is optimized by selecting an excitation frequency that is not necessarily at or near the free resonance frequency. PMID- 25825002 TI - Transcranial cortical stimulation in the treatment of obsessive-compulsive disorders: efficacy studies. AB - Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive brain stimulation methods that became widely used as therapeutic tools during the past two decades especially in cases of depression and schizophrenia. Low frequency rTMS and cathodal effect of tDCS inhibits cortical functioning while high frequency and anodal effect of tDCS have the opposite effect. Prolonged and repetitive application of either methods leads to changes in excitability of the human cortex that outlast the period of stimulation. Both rTMS and tDCS induce functional changes in the brain-modulating neural activity at cortical level. This paper reviews rTMS and tDCS effects in clinical trials for obsessive-compulsive disorder (OCD). Low frequency rTMS, particularly targeting the supplementary motor area and the orbital frontal cortex, seems to be the most promising in terms of therapeutic efficacy while older studies targeting the prefrontal dorsal cortex were not as successful. tDCS clearly needs to be investigated in large scale and sufficiently powered randomized control studies. From a general point of view, these non-invasive techniques hold promise as novel therapeutic tools for OCD patients. PMID- 25825003 TI - Unrestricted modification search reveals lysine methylation as major modification induced by tissue formalin fixation and paraffin embedding. AB - Formalin-fixed paraffin-embedded (FFPE) tissue is considered as an appropriate alternative to frozen/fresh tissue for proteomic analysis. Here we study formalin induced alternations on a proteome-wide level. We compared LC-MS/MS data of FFPE and frozen human kidney tissues by two methods. First, clustering analysis revealed that the biological variation is higher than the variation introduced by the two sample processing techniques and clusters formed in accordance with the biological tissue origin and not with the sample preservation method. Second, we combined open modification search and spectral counting to find modifications that are more abundant in FFPE samples compared to frozen samples. This analysis revealed lysine methylation (+14 Da) as the most frequent modification induced by FFPE preservation. We also detected a slight increase in methylene (+12 Da) and methylol (+30 Da) adducts as well as a putative modification of +58 Da, but they contribute less to the overall modification count. Subsequent SEQUEST analysis and X!Tandem searches of different datasets confirmed these trends. However, the modifications due to FFPE sample processing are a minor disturbance affecting 2 6% of all peptide-spectrum matches and the peptides lists identified in FFPE and frozen tissues are still highly similar. PMID- 25825004 TI - The effects of abnormality of cVEMP and oVEMP on rehabilitation outcomes in patients with idiopathic benign paroxysmal positional vertigo. AB - The presence of utricular and saccular dysfunction impairs quality of life (QoL) in patients. The aims of the present study were to examine the effect of repositioning maneuvers on QoL of patients with idiopathic benign paroxysmal positional vertigo (BPPV) and to describe the effect of cervical vestibular evoked myogenic potential (cVEMP) or ocular VEMP (oVEMP) abnormalities on patient recovery after rehabilitation. Thirty idiopathic BPPV patients with/without otolith dysfunctions (n = 15, each group) were included in this clinical trial study. Otolith dysfunction was determined using oVEMP and cVEMP abnormalities. EcochG and caloric tests were performed to rule out other causes of secondary BPPV. The QoL in groups of patients with idiopathic BPPV was assessed using a Persian version of the dizziness handicap inventory (DHI-P) before and after treatment with Epley's maneuver. Pre-treatment results showed significant handicaps in both groups. DHI-P scores were higher in BPPV patients with otolith dysfunction (total, functional, emotional, physical score: 34.13, 11.20, 7.06, 15.86, respectively) than those in patients without otolith dysfunction (total, functional, emotional, physical score: 25.46, 7.86, 6.13, 11.46, respectively, P < 0.05). After treatment, DHI-P scores decreased in both groups. However, in the otolith dysfunction group, DHI-P scores (total, functional, emotional, physical score: 9.20, 3.33, 1.33, 4.53, respectively) were higher than those in patients without otolith dysfunction (total, functional, emotional, physical score: 4.13, 0.93, 1.06, 2.00, respectively). In BPPV patients with cVEMP or oVEMP abnormalities, QoL is more compromised in comparison with that in BPPV patients without these dysfunctions. Otolith dysfunction enhances the negative effects of BPPV on QoL. PMID- 25825005 TI - Lung consequences in adults born prematurely. AB - Although survival has improved significantly in recent years, prematurity remains a major cause of infant and childhood mortality and morbidity. Preterm births (<37 weeks of gestation) account for 8% of live births representing >50 000 live births each year in the UK. Preterm birth, irrespective of whether babies require neonatal intensive care, is associated with increased respiratory symptoms, partially reversible airflow obstruction and abnormal thoracic imaging in childhood and in young adulthood compared with those born at term. Having failed to reach their optimal peak lung function in early adulthood, there are as yet unsubstantiated concerns of accelerated lung function decline especially if exposed to noxious substances leading to chronic respiratory illness; even if the rate of decline in lung function is normal, the threshold for respiratory symptoms will be crossed early. Few adult respiratory physicians enquire about the neonatal period in their clinical practice. The management of these subjects in adulthood is largely evidence free. They are often labelled as asthmatic although the underlying mechanisms are likely to be very different. Smoking cessation, maintaining physical fitness, annual influenza immunisation and a general healthy lifestyle should be endorsed irrespective of any symptoms. There are a number of clinical and research priorities to maximise the quality of life and lung health in the longer term not least understanding the underlying mechanisms and optimising treatment, rather than extrapolating from other airway diseases. PMID- 25825006 TI - Monitoring strategies in children with asthma: a randomised controlled trial. AB - BACKGROUND: Asthma guidelines recommend monitoring of asthma control. However, in a substantial proportion of children, asthma is poorly controlled and the best monitoring strategy is not known. OBJECTIVES: We studied two monitoring strategies for their ability to improve asthma outcomes in comparison with standard care (SC): web-based monthly monitoring with the (Childhood) Asthma Control Test (ACT or C-ACT) and 4-monthly monitoring of FENO. METHODS: In this randomised controlled, partly blinded, parallel group multicentre trial with a 1 year follow-up, children aged 4-18 with a doctor's diagnosis of asthma treated in seven hospitals were randomised to one of the three groups. In the web group, treatment was adapted according to ACT obtained via a website at 1-month intervals; in the FENO group according to ACT and FENO, and in the SC group according to the ACT at 4-monthly visits. The primary endpoint was the change from baseline in the proportion of symptom-free days (SFD). RESULTS: Two-hundred and eighty children (mean age 10.4 years, 66% boys) were included; 268 completed the study. Mean changes from baseline in SFD were similar between the groups: 2.1% (web group, n=90), +8.9% (FENO group, n=91) versus 0.15% (SC, n=87), p=0.15 and p=0.78. Daily dose of inhaled corticosteroids (ICS) decreased more in the web based group compared with both other groups (-200 MUg/day, p<0.01), while ACT and SFD remained similar. CONCLUSIONS: The change from baseline in SFD did not differ between monitoring strategies. With web-based ACT monitoring, ICS could be reduced substantially while control was maintained. TRIAL REGISTRATION NUMBER: NTR 1995. PMID- 25825007 TI - Access and non-access site bleeding after percutaneous coronary intervention and risk of subsequent mortality and major adverse cardiovascular events: systematic review and meta-analysis. AB - BACKGROUND: The prognostic impact of site-specific major bleeding complications after percutaneous coronary intervention (PCI) has yielded conflicting data. The aim of this study is to provide an overview of site-specific major bleeding events in contemporary PCI and study their impact on mortality and major adverse cardiovascular event outcomes. METHODS AND RESULTS: We conducted a meta-analysis of PCI studies that evaluated site-specific periprocedural bleeding complications and their impact on major adverse cardiovascular events and mortality outcomes. A systematic search of MEDLINE and Embase was conducted to identify relevant studies and random effects meta-analysis was used to estimate the risk of adverse outcomes with site-specific bleeding complications. Twenty-five relevant studies including 2,400,645 patients that underwent PCI were identified. Both non-access site (risk ratio [RR], 4.06; 95% confidence interval [CI], 3.21-5.14) and access site (RR, 1.71; 95% CI, 1.37-2.13) related bleeding complications were independently associated with an increased risk of periprocedural mortality. The prognostic impact of non-access site-related bleeding events on mortality related to the source of anatomic bleeding, for example, gastrointestinal RR, 2.78; 95% CI, 1.25 to 6.18; retroperitoneal RR, 5.87; 95% CI, 1.63 to 21.12; and intracranial RR, 22.71; 95% CI, 12.53 to 41.15. CONCLUSIONS: The prognostic impact of bleeding complications after PCI varies according to anatomic source and severity. Non-access site-related bleeding complications have a similar prevalence to those from the access site but are associated with a significantly worse prognosis partly related to the severity of the bleed. Clinicians should minimize the risk of major bleeding complications during PCI through judicious use of bleeding avoidance strategies irrespective of the access site used. PMID- 25825008 TI - Anatomic characteristics and clinical implications of angiographic coronary thrombus: insights from a patient-level pooled analysis of SYNTAX, RESOLUTE, and LEADERS Trials. AB - BACKGROUND: The distribution of thrombus-containing lesions (TCLs) in an all comer population admitted with a heterogeneous clinical presentation (stable, ustable angina, or an acute coronary syndrome) and treated with percutaneous coronary intervention is yet unclear, and the long-term prognostic implications are still disputed. This study sought to assess the distribution and prognostic implications of coronary thrombus, detected by coronary angiography, in a population recruited in all-comer percutaneous coronary intervention trials. METHODS AND RESULTS: Patient-level data from 3 contemporary coronary stent trials were pooled by an independent academic research organization (Cardialysis, Rotterdam, the Netherlands). Clinical outcomes in terms of major adverse cardiac events (major adverse cardiac events, a composite of death, myocardial infarction, and repeat revascularization), death, myocardial infarction, and repeated revascularization were compared between patients with and without angiographic TCL. Preprocedural TCL was present in 257 patients (5.8%) and absent in 4193 (94.2%) patients. At 3-year follow-up, there was no difference for major adverse cardiac events (25.3 versus 25.4%; P=0.683); all-cause death (7.4 versus 6.8%; P=0.683); myocardial infarction (5.8 versus 6.0%; P=0.962), and any revascularizations (17.5 versus 17.7%; P=0.822) between patients with and without TCL. The comparison of outcomes in groups weighing the jeopardized myocardial by TCL also did not show a significant difference. TCL were seen more often in the first 2 segments of the right (43.6%) and left anterior descending (36.8%) coronary arteries. The association of TCL and bifurcation lesions was present in 40.1% of the prespecified segments. CONCLUSIONS: TCL involved mainly the proximal coronary segments and did not have any effect on clinical outcomes. A more detailed thrombus burden quantification is required to investigate its prognostic implications. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00114972, NCT01443104, NCT00617084. PMID- 25825009 TI - Cytochrome c biogenesis in Campylobacter jejuni requires cytochrome c6 (CccA; Cj1153) to maintain apocytochrome cysteine thiols in a reduced state for haem attachment. AB - The microaerophilic food-borne pathogen Campylobacter jejuni uses complex cytochrome-rich respiratory chains for growth and host colonisation. Cytochrome c biogenesis requires haem ligation to reduced apocytochrome cysteines, catalysed by the cytochrome c synthase, CcsBA. While ccsBA could not be deleted, we showed that the thiol reductase DsbD and the CcsX homologue Cj1207 are involved in, but not essential for, cytochromes c biogenesis. Mutant phenotypic analyses and biochemical studies with purified proteins revealed that the mono-haem c-type cytochromes Cj1153 (CccA) and Cj1020 (CccB) and the di-haem Cj0037 (CccC) are electron donors to the cb-oxidase (CcoNOQP), with CccC being more efficient than CccA. Remarkably, cccA deletion or site-directed mutagenesis resulted in an almost complete loss of all other c-type cytochromes. Cytochrome c structural and biogenesis genes were still transcribed in the cccA deletion mutant and the quinol oxidase genes (cioAB) were up-regulated. Cytochrome c production could be rescued in this mutant by growth with exogenous dithiothreitol or L-cysteine, suggesting that in the absence of CccA, apocytochrome c haem binding motifs become oxidised, preventing haem attachment. Our results identify CccA, the most abundant periplasmic c-type cytochrome in C. jejuni, as a novel and unexpected protein required for cytochrome c biogenesis in this pathogen. PMID- 25825010 TI - Subxiphoid single-incision thoracoscopic bilateral ablative sympathectomy for hyperhidrosis. AB - We describe the first case of severe palmar hyperhidrosis treated with single incision subxiphoid thoracoscopic ablative sympathectomy, bilaterally, at T3 level. The single-incision subxiphoid thoracoscopic approach required only a 2-cm incision in the upper abdomen. In addition, the technique does not cause postoperative intercostal neuropathy and postoperative pain is minimal as the intercostal space is bypassed. Total operative time was ~60 min and the volume of blood loss was 10 ml. The patient was discharged from the hospital the next day with complete remission of her symptoms. Excess palmar sweating released after operation and there was no compensatory sweating after a 6-month follow-up. PMID- 25825011 TI - Bridge-to-recovery strategy using extracorporeal membrane oxygenation for critical pulmonary hypertension complicated with cardiogenic shock. AB - OBJECTIVES: Studies on mechanical-medical bridging for decompensated pulmonary hypertension (PH) are limited. We analysed the outcomes for critical PH patients who underwent extracorporeal membrane oxygenation (ECMO) support using a bridge to-recovery (BTR) strategy. This study aimed to identify prognostic factors of BTR and evaluate the outcomes of survivors. METHODS: Between 2009 and 2012, 6 patients who received veno-arterial ECMO due to decompensated PH with cardiogenic shock were retrospectively reviewed. All of the patients were managed with an aggressive titration of PH therapies and the optimization of right ventricular (RV) function to wean them off of ECMO. Three of the patients survived to discharge, and the others suffered in-hospital mortality. The differences between their baseline characteristics, ECMO set-up, haemodynamic change and complications were analysed. RESULTS: The average age was 46.67 +/- 14.07 years, with a male-to-female ratio of 1:2. The non-survival group exhibited a higher baseline systolic pulmonary artery pressure (127.67 +/- 25.81 vs 67.67 +/- 24.83 mmHg, P = 0.044) than the survival group before ECMO. All of the non-survivors underwent cardiopulmonary-cerebral resuscitation prior to ECMO implantation (100 vs 0%, P = 0.100). The survivors tended to have received suboptimal PH therapies before ECMO and had more readily correctable predisposing factors of right ventricular failure. The non-survivors required a longer duration of ECMO and suffered more end-organ failure or sepsis, although those differences were not statistically significant. Pneumonia developed in 3 of the survivors and caused late mortality in 2 after discharge. CONCLUSIONS: ECMO provides a therapeutic window for the medical stabilization of critically decompensated PH patients. Prompt ECMO intervention before haemodynamic collapse and careful patient selection are critical for successful BTR outcomes. PMID- 25825012 TI - Synchronized cell attachment triggered by photo-activatable adhesive ligands allows QCM-based detection of early integrin binding. AB - The Quartz Crystal Microbalance with dissipation (QCM-D) technique was applied to monitor and quantify integrin-RGD recognition during the early stages of cell adhesion. Using QCM-D crystals modified with a photo-activatable RGD peptide, the time point of presentation of adhesive ligand at the surface of the QCM-D crystal could be accurately controlled. This allowed temporal resolution of early integrin-RGD binding and the subsequent cell spreading process, and their separate detection by QCM-D. The specificity of the integrin-RGD binding event was corroborated by performing the experiments in the presence of soluble cyclicRGD as a competitor, and cytochalasin D as inhibitor of cell spreading. Larger frequency change in the QCM-D signal was observed for cells with larger spread area, and for cells overexpressing integrin alphavbeta3 upon stable transfection. This strategy enables quantification of integrin activity which, in turn, may allow discrimination among different cell types displaying distinct integrin subtypes and expression levels thereof. On the basis of these findings, we believe the strategy can be extended to other photoactivatable ligands to characterize cell membrane receptors activity, a relevant issue for cancer diagnosis (and prognosis) as other several pathologies. PMID- 25825013 TI - Evaluation of weight loss and metabolic changes in diabetic patients treated with liraglutide, effect of RS 6923761 gene variant of glucagon-like peptide 1 receptor. AB - BACKGROUND: A polymorphism of GLP-1 R (rs6923761) has potential implications in weight loss and metabolic control. We decide to investigate the role of this polymorphism on metabolic changes and weight loss secondary to treatment with liraglutide. MATERIAL AND METHODS: A population of 90 patients with diabetes mellitus type 2 and overweight, unable to achieve glycemic control (HbA1c>7%) with metformin alone that require initiation of liraglutide treatment in progressive dose to 1.8mg/day subcutaneously, was analyzed. RESULTS: Fifty one patients (56.7%) had the genotype GG and 39 (43.3%) patients; GA (30 patients, 33.3%) or AA (9 patients, 10%) (A allele carriers). In patients with both genotypes, body mass index (BMI), weight and fat decreased. The proportion of the mentioned reductions was higher in the variant allele carriers; BMI (-0.59+/ 2.5kg/m(2) vs. -1.69+/-3.9kg/m(2); P<0.05), weight (-2.78+/-2.8kg vs. -4.52+/ 4.6kg; P<0.05) and fat mass (-0.59+/-2.5kg vs. -1.69+/-3.9kg; P<0.05). Weight reduction after liraglutide treatment was greater in the A-allele carriers by 2.9kg (95% CI: 0.27-5.64). The decrease of basal glucose, HOMA-R and HbA1c was similar in both genotypes. CONCLUSION: Our data showed better anthropometric parameters in overweight diabetic subjects with the variant allele (A) of rs6923761 GLP-1 R polymorphism. A allele carriers had a greater decrease in weight and fat mass after treatment with liraglutide. The present study is a preliminary observation, and its results need to be replicated with a higher number of patients in different populations. PMID- 25825014 TI - Visual Outcomes at 12 Months in Patients Following Implantation of a Diffractive Multifocal Intraocular Lens. AB - INTRODUCTION: The aim of this study was to assess distance, intermediate, and near visual acuity, contrast sensitivity, and patient satisfaction outcomes of a multifocal intraocular lens (IOL). METHODS: This multicenter, prospective clinical study was conducted at seven study sites in Turkey. Patients who underwent bilateral cataract removal and implantation of a diffractive, acrylic, hydrophobic, multifocal IOL (Acriva UD Reviol MFB 625; VSY Biotechnology, Istanbul, Turkey) were included. The uncorrected and best corrected distance visual acuities (UCDVA and BCDVA), uncorrected and best corrected intermediate visual acuities (UCIVA and BCIVA), and uncorrected and best corrected near visual acuities (UCNVA and BCNVA) were measured preoperatively and at postoperative 1, 6, and 12 months. Distance and near visual acuity scores (VAS) contrast sensitivities were measured at these time points. Quality of life was evaluated by visual function-14 (VF-14) questionnaire. RESULTS: Two hundred eyes of 100 patients were included. Monocular and binocular visual acuities at all distances showed improvement at postoperative 12 months compared to preoperative measurements (P < 0.001). Monocular and binocular UCIVA and binocular BCIVA at postoperative 12 months were significantly improved compared to measurements at 1 month (P < 0.001). Binocular contrast sensitivity at distance showed significant improvement from postoperative 1 month to postoperative 12 months, except for 3 cycles per degree (cpd; without glare) and 18 cpd (with glare). VAS improved from 75.96 at postoperative 1 month to 76.85 at postoperative 12 months. VF-14 score was 98.2 +/- 4.6. CONCLUSION: The Acriva UD Reviol MFB 625 appears to provide a good level of distance and near visual acuity, quality of life, and patient satisfaction. Further studies with longer follow-up will provide valuable insight into the long-term stability of these visual outcomes. PMID- 25825015 TI - Mefloquine at the crossroads? Implications for malaria chemoprophylaxis in Europe. AB - Since its introduction to the market in 1985, mefloquine has been used for malaria chemoprophylaxis by more than 35 million travellers. In Europe, in 2014, the European Medicines Agency (EMA) issued recommendations on strengthened warnings, prescribing checklists and updates to the product information of mefloquine. Some malaria prevention advisors question the scientific basis for the restrictions and suggest that this cost-effective, anti-malarial drug will be displaced as a first-line anti-malaria medication with the result that vulnerable groups such as VFR and long-term travellers, pregnant travellers and young children are left without a suitable alternative chemoprophylaxis. This commentary looks at the current position of mefloquine prescribing and the rationale of the new EMA recommendations and restrictions. It also describes the new recommendations for malaria prophylaxis that have been adapted by Switzerland, Germany, Austria and Italy where chemoprophylaxis use is restricted to high-risk malaria-endemic areas. PMID- 25825017 TI - War-related extremity injuries in children: 89 cases managed in a combat support hospital in Afghanistan. AB - BACKGROUND: Meeting paediatric needs is among the priorities of western healthcare providers working in Afghanistan. HYPOTHESIS: Insufficient information is available on paediatric wartime injuries to the extremities. Our objective here was to describe these injuries and their management on the field. MATERIALS AND METHODS: We retrospectively reviewed consecutive cases of injuries to the extremities in children (< 16 years of age) due to weapons and managed at the Kabul International Airport (KaIA) Combat Support Hospital between June 2009 and April 2013. We identified 89 patients with a mean age of 10.2 +/- 3.5 years and a total of 137 elemental lesions. RESULTS: Explosive devices accounted for most injuries (78.6%) and carried a significantly higher risk of multiple lesions. There were 54 bone lesions (traumatic amputations and fractures) and 83 soft tissue lesions. The amputation rate was 18%. Presence of bone lesions was associated with a higher risk of injury to blood vessels and nerves. Of the 89 patients, four (4.5%) died and eight (9%) were transferred elsewhere. Of the 77 remaining patients, at last follow-up (median, one month; range, 0.1-16 months), 73 (95%) had achieved a full recovery (healed wound and/or fracture) or were recovering with no expectation that further surgery would be needed. DISCUSSION: Despite the absence of paediatric surgeons, the combat support hospital provided appropriate care at the limb salvage and reconstruction phases. The highly specialised treatments needed to manage sequelae were very rarely provided. These treatments probably deserve to be developed in combat support hospitals. PMID- 25825018 TI - Judge suggests steps to prevent employers unfairly referring whistleblowers to GMC. PMID- 25825016 TI - Geographic variations in cystic fibrosis: An analysis of the U.S. CF Foundation Registry. AB - BACKGROUND: Emerging evidence suggests that the prevalence of pathogens common in cystic fibrosis (CF) may be unevenly distributed across the United States (U.S.). However, very little is known regarding the U.S. distribution of other CF modifiers such as medication usage and patient demographics. Therefore, we sought to determine if regional differences exist in the distribution of demographic variables and patient disease characteristics in the U.S. that may play a role in differential CF outcomes. METHODS: Data were analyzed from the 30,896 subjects in the U.S. CF Foundation Patient Registry during the years 2007-2012, via geographical grouping of states based upon the Nationwide Inpatient Sample classification. RESULTS: Significant differences in racial distribution were seen, including half of the total U.S. African-American CF population residing in the South. Both African-Americans and Hispanics had increased Medicaid usage (52.2%, 41.8%, respectively). Culture-reported pathogens were markedly different across the U.S., with the highest percentage of patients with Methicillin resistant Staphylococcus aureus (41.9%), Pseudomonas aeruginosa (71.2%), and non tuberculous mycobacterium (10.0%) in the South. The South region also had the lowest mean body mass index and forced expiratory volume in one second. Chronic medication usage such as inhaled tobramycin or macrolides followed P. aeruginosa distribution, while inhaled dornase alfa was most used in the West (84.7%). Co morbid conditions varied, with the highest percentage of depressed subjects in the Midwest (18.3%). Mean regional mortality rates were not statistically different among regions, although highest in each age grouping of the South. CONCLUSIONS: The U.S. has significant regional variations in CF demographics, insurance, pathogens, medication usage, and co-morbidities, without an overall impact on regional mortality. Regional variations in care practices should be studied further based on the findings. PMID- 25825019 TI - Targeting the endoplasmic reticulum mediates radiation sensitivity in colorectal cancer. AB - BACKGROUND: Radiotherapy is an established treatment modality for early and locally advanced rectal cancer as part of short course radiotherapy and long course chemoradiotherapy. The unfolded protein response (UPR) is a cellular stress response pathway often activated in human solid tumours which has been implicated in resistance to both chemotherapy and radiotherapy. This research has investigated whether the UPR pathway is upregulated in ex-vivo samples of human colorectal cancer and characterised the interaction between radiotherapy and UPR activation in two human colorectal cancer cell lines in vitro. METHODS: In vitro UPR expression was determined in response to clinical doses of radiotherapy in both the human colorectal adenocarcinoma (HT-29) cell line and a radio-resistant clone (HT-29R) using western blotting and quantitative polymerase chain reaction. The UPR was induced using a glucose deprivation culture technique before irradiation and radiosensitivity assessed using a clonogenic assay. Ex-vivo human colorectal cancer tissue was immuno-histochemically analysed for expression of the UPR marker glucose regulated protein 78 (GRP-78). RESULTS: The UPR was strongly up regulated in ex-vivo human colorectal tumours with 36 of 50 (72.0%) specimens demonstrating moderate to strong staining for the classic UPR marker GRP-78. In vitro, therapeutic doses of radiotherapy did not induce UPR activation in either radiosensitive or radioresistant cell lines. UPR induction caused significant radiosensitisation of the radioresistant cell line (HT-29R SF2Gy=0.90 S.E.M. +/-0.08; HT-29RLG SF2Gy=0.69 S.E.M. +/-0.050). CONCLUSION: This suggests that UPR induction agents may be potentially useful response modifying agents in patients undergoing therapy for colorectal cancer. PMID- 25825020 TI - Anatomically related gray and white matter alterations in the brains of functional dyspepsia patients. AB - BACKGROUND: Previous studies summarized altered brain functional patterns in functional dyspepsia (FD) patients, but how the brain structural patterns are related to FD remains largely unclear. The objective of this study was to determine the brain structural characteristics in FD patients. METHODS: Optimized voxel-based morphometry and tract-based spatial statistics were employed to investigate the changes in gray matter (GM) and white matter (WM) respectively in 34 FD patients with postprandial distress syndrome and 33 healthy controls based on T1-weighted and diffusion-weighted imaging. The Pearson's correlation evaluated the link among GM alterations, WM abnormalities, and clinical variables in FD patients. The optimal brain structural parameters for identifying FD were explored using the receiver operating characteristic curve. KEY RESULTS: Compared to controls, FD patients exhibited a decrease in GM density (GMD) in the right posterior insula/temporal superior cortex (marked as pINS), right inferior frontal cortex (IFC), and left middle cingulate cortex, and an increase in fractional anisotropy (FA) in the posterior limb of the internal capsule, posterior thalamic radiation, and external capsule (EC). Interestingly, the GMD in the pINS was significantly associated with GMD in the IFC and FA in the EC. Moreover, the EC adjacent to the pINS provided the best performance for distinguishing FD patients from controls. CONCLUSIONS & INFERENCES: Our results showed pINS-related structural abnormalities in FD patients, indicating that GM and WM parameters were not affected independently. These findings would lay the foundation for probing an efficient target in the brain for treating FD. PMID- 25825021 TI - Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy. AB - This study evaluated the influence of concomitant antiepileptic drugs (AEDs) on the plasma concentration of lamotrigine (LTG) in pediatric patients with epilepsy. We retrospectively reviewed 1653 plasma samples from 709 patients (aged 6 months to 16 years) and compared the concentration-to-dose ratio (CD ratio) of LTG among different AED regimens. The median CD ratio of patients receiving LTG monotherapy was 1.25 MUg/mL/mg/kg. In patients receiving LTG plus VPA, the CD ratio was increased by about 140%. The CD ratio was elevated from a low VPA concentration (<40 MUg/mL) and the increase was VPA concentration-dependent. In contrast, the median CD ratio of patients treated with LTG plus the inducers phenytoin, phenobarbital, and carbamazepine was 0.42, 0.63, and 0.66, respectively, and phenytoin significantly reduced the CD ratio in comparison with phenobarbital or carbamazepine (p < 0.001). Pediatric patients of all ages beyond infancy showed similar susceptibility to VPA or inducers, but infants had higher CD ratios compared with the other age groups. Among other AEDs, topiramate, ethosuximide, and rufinamide reduced the CD ratio. These findings should be useful for estimating interactions between LTG and concomitant AEDs. PMID- 25825022 TI - Low abundance of mitochondrial DNA changes mitochondrial status and renders cells resistant to serum starvation and sodium nitroprusside insult. AB - Mutation or depletion of mitochondrial DNA (mtDNA) can cause severe mitochondrial malfunction, originating from the mitochondrion itself, or from the crosstalk between nuclei and mitochondria. However, the changes that would occur if the amount of mtDNA is diminished are less known. Thus, we generated rat myoblast H9c2 cells containing lower amounts of mtDNA via ethidium bromide and uridine supplementation. After confirming the depletion of mtDNA by quantitative PCR and gel electrophoresis analysis, we investigated the changes in mitochondrial physical parameters by using flow cytometry. We also evaluated the resistance of these cells to serum starvation and sodium nitroprusside. H9c2 cells with diminished mtDNA contents showed decreased mitochondrial membrane potential, mass, free calcium, and zinc ion contents as compared to naive H9c2 cells. Furthermore, cytosolic and mitochondrial reactive oxygen species levels were significantly higher in mtDNA-lowered H9c2 cells than in the naive cells. Although the oxygen consumption rate and cell proliferation were decreased, mtDNA lowered H9c2 cells were more resistant to serum deprivation and nitroprusside insults than the naive H9c2 cells. Taken together, we conclude that the low abundance of mtDNA cause changes in cellular status, such as changes in reactive oxygen species, calcium, and zinc ion levels inducing resistance to stress. PMID- 25825023 TI - Docosahexaenoic acid inhibits the invasion of MDA-MB-231 breast cancer cells through upregulation of cytokeratin-1. AB - Docosahexaenoic acid (DHA), the main member of the omega-3 essential fatty acid family, has been shown to reduce the invasion of the triple-negative breast cancer cell line MDA-MB-231, but the mechanism involved remains unclear. In the present study, a proteomic approach was used to define changes in protein expression induced by DHA. Proteins from crude membrane preparations of MDA-MB 231 cells treated with 100 uM DHA were separated by two-dimensional electrophoresis (2-DE) and differentially expressed proteins were identified using MALDI-TOF mass spectrometry. The main changes observed were the upregulation of Keratin, type II cytoskeletal 1 (KRT1), catalase and lamin-A/C. Immunocytochemistry analyses confirmed the increase in KRT1 induced by DHA. Furthermore, in vitro invasion assays showed that siRNA against KRT1 was able to reverse the DHA-induced inhibition of breast cancer cell invasion. In conclusion, KRT1 is involved in the anti-invasive activity of DHA in breast cancer cells. PMID- 25825025 TI - Bullying among nurses and its relationship with burnout and organizational climate. AB - Workplace bullying is one of the most common work-related psychological problems. Bullying costs seem higher for organizations composed of health-care workers who perform direct-contact patients-complex tasks. Only a few studies have been carried out among nurses in Italy and integrated models of bullying antecedents and consequences are particularly missing. The aim of this study was to develop a bullying model focused on the interaction between bullying and burnout in the setting of a climate-health relationship. Research involved 658 nurses who completed a survey on health, burnout, bullying and organizational climate. Structural equation modeling was used to test the hypothesis. Results suggest that workplace bullying partially mediates the relationship between organizational climate and burnout and that bullying does not affect health directly, but only indirectly, via the mediation of burnout. Our study demonstrates the key-role of workplace bullying and burnout in the climate-health relationship in order to understand and to improve nurses' health. PMID- 25825026 TI - An adjustable electron achromat for cathode lens microscopy. AB - Chromatic aberration correction in light optics began with the invention of a two color-corrected achromatic crown/flint lens doublet by Chester Moore Hall in 1730. Such color correction is necessary because any single glass shows dispersion (i.e. its index of refraction changes with wavelength), which can be counteracted by combining different glasses with different dispersions. In cathode lens microscopes (such as Photo Electron Emission Microscopy - PEEM) we encounter a similar situation, where the chromatic aberration coefficient of the cathode lens shows strong dispersion, i.e. depends (non-linearly) on the energy with which the electrons leave the sample. Here I show how a cathode lens in combination with an electron mirror can be configured as an adjustable electron achromat. The lens/mirror combination can be corrected at two electron energies by balancing the settings of the electron mirror against the settings of the cathode lens. The achromat can be adjusted to deliver optimum performance, depending on the requirements of a specific experiment. Going beyond the achromat, an apochromat would improve resolution and transmission by a very significant margin. I discuss the requirements and outlook for such a system, which for now remains a wish waiting for fulfilment. PMID- 25825024 TI - Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. AB - Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcgamma receptors (FcgammaR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss. PMID- 25825027 TI - Field evaporation of insulators and semiconductors: Theoretical insights for ZnO. AB - We look at the new challenges associated with Atom Probe Tomography of insulators and semiconductors with regard to local fields inside and on the surface of such materials. The theoretical discovery that in high fields the band gap in these materials is drastically reduced to the point where at the evaporation field strength it vanishes will be crucial in our discussion. To understand Atom Probe results on the field evaporation of insulators and semiconductors we use density functional theory on ZnO clusters to follow the structural and electronic changes during field evaporation and to obtain potential energy curves, HOMO-LUMO gaps, field distributions, desorption pathways and fragments, dielectric constants, and polarizabilities. We also examine the effects of electric field reversal on the evaporation of ZnO and compare the results with Si. PMID- 25825028 TI - Automated voxelization of 3D atom probe data through kernel density estimation. AB - Identifying nanoscale chemical features from atom probe tomography (APT) data routinely involves adjustment of voxel size as an input parameter, through visual supervision, making the final outcome user dependent, reliant on heuristic knowledge and potentially prone to error. This work utilizes Kernel density estimators to select an optimal voxel size in an unsupervised manner to perform feature selection, in particular targeting resolution of interfacial features and chemistries. The capability of this approach is demonstrated through analysis of the gamma / gamma' interface in a Ni-Al-Cr superalloy. PMID- 25825029 TI - Disintegration and field evaporation of thiolate polymers in high electric fields. AB - High electrostatic fields cause major changes in polymers, structural (e.g. electrostriction) and electronic (e.g. reduction of the "band gap" with final metallization). Using density functional theory we have studied field effects on amino-alkane-thiols and perfluoro-alkane-thiols adsorbed on a metal substrate. Our results agree well with the APT fragmentation spectra obtained by Stoffers, Oberdorfer and Schmitz and shed light on disintegration pathways. We demonstrate that in SAMs the HOMO/LUMO gap is again reduced as a function of the field strength and vanishes at evaporation. We also follow the field dependence of the dielectric constant and polarizability. PMID- 25825030 TI - Fever Pitch: Northeast Ohio ebola exposure effect on ED visits to a Cleveland Hospital. PMID- 25825031 TI - The Authors Reply: further consideration in evaluation of right ventricular infarction. PMID- 25825032 TI - Normal anion gap salicylate poisoning. PMID- 25825033 TI - Right lower quadrant abdominal pain, fever, and hypotension: an atypical presentation of meningococcemia. PMID- 25825034 TI - Withdrawal seizures seen in the setting of synthetic cannabinoid abuse. PMID- 25825035 TI - The three-dimensional structure of VIM-31--a metallo-beta-lactamase from Enterobacter cloacae in its native and oxidized form. AB - The metallo-beta-lactamase VIM-31 differs from VIM-2 by only two Tyr224His and His252Arg substitutions. Located close to the active site, the Tyr224His substitution is also present in VIM-1, VIM-4, VIM-7 and VIM-12. The VIM-31 variant was reported in 2012 from Enterobacter cloacae and kinetically characterized. It exhibits globally lower catalytic efficiencies than VIM-2. In the present study, we report the three-dimensional structures of VIM-31 in its native (reduced) and oxidized forms. The so-called 'flapping-loop' (loop 1) and loop 3 of VIM-31 were not positioned as in VIM-2 but instead were closer to the active site as in VIM-4, resulting in a narrower active site in VIM-31. Also, the presence of His224 in VIM-31 disrupts hydrogen-bonding networks close to the active site. Moreover, a third zinc-binding site, which also exists in VIM-2 structures, could be identified as a structural explanation for the decreased activity of VIM-MBLs at high zinc concentrations. PMID- 25825036 TI - Infection due to travel-related carbapenemase-producing Enterobacteriaceae, a largely underestimated phenomenon in Belgium. AB - BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are emerging worldwide, representing a major threat for public health. Early CPE detection is crucial in order to prevent infections and the development of reservoirs/outbreaks in hospitals. In 2008, most of the CPE strains reported in Belgium were imported from patients repatriated from abroad. Actually, this is no longer the case. OBJECTIVES AND METHODS: A surveillance was set up in Belgian hospitals (2012) in order to explore the epidemiology and determinants of CPE, including the link with international travel/hospitalization. The present article describes travel-related CPE reported in Belgium. Different other potential sources for importation of CPE are discussed. RESULTS: Only 12% of all CPE cases reported in Belgium (2012-2013) were travel related (with/without hospitalization). This is undoubtedly an underestimation (missing travel data: 36%), considering the increasing tourism, the immigration from endemic countries, the growing number of foreign patients using scheduled medical care in Belgium, and the medical repatriations from foreign hospitals. The free movement of persons and services (European Union) contributes to an increase in foreign healthcare workers (HCW) in Belgian hospitals. Residents from nursing homes located at the country borders can be another potential source of dissemination of CPE between countries. Moreover, the high population density in Belgium can increase the risk for CPE-dissemination. Urban areas in Belgium may cumulate these potential risk factors for import/dissemination of CPE. CONCLUSIONS: Ideally, travel history data should be obtained from hospital hygiene teams, not from the microbiological laboratory. Patients who received medical care abroad (whatever the country) should be screened for CPE at admission. PMID- 25825037 TI - Soluble CD40 ligand promotes macrophage foam cell formation in the etiology of atherosclerosis. AB - OBJECTIVE: High levels of soluble CD40 ligand (sCD40L) in the circulation have been suggested as an important indicator of cardiovascular diseases such as atherosclerosis and acute coronary syndromes. In the present study, we explored the role of sCD40L in the formation of foam cells. METHODS: Lipid deposition and foam cell formation was measured by high-performance liquid chromatography and Nile Red staining, respectively. Gene expressions were detected by quantitative real-time PCR and Western blot analysis. The interaction between CD40 and sCD40L were blocked by CD40 small interfering RNA or anti-CD40 antibody. RESULTS: sCD40L significantly increased lipid deposition and foam cell formation associated with upregulation of scavenger receptor type A and CD36. Additionally, sCD40L increased adipocyte enhancer-binding protein 1 and cholesterol efflux, and activated NF-kappaB in macrophages. sCD40L promoted foam cell formation via CD40 ligation and disruption of the ligation between CD40 and CD40L either by small interfering RNA or by a blocking anti-CD40 antibody apparently inhibiting foam cell formation in response to sCD40L. CONCLUSION: Our data suggests a novel insight into the role of sCD40L in foam cell formation during atherosclerosis, which further confirms the importance of sCD40L in atherosclerosis and as a target for the treatment of this disease. PMID- 25825038 TI - Metabolic engineering in methanotrophic bacteria. AB - Methane, as natural gas or biogas, is the least expensive source of carbon for (bio)chemical synthesis. Scalable biological upgrading of this simple alkane to chemicals and fuels can bring new sustainable solutions to a number of industries with large environmental footprints, such as natural gas/petroleum production, landfills, wastewater treatment, and livestock. Microbial biocatalysis with methane as a feedstock has been pursued off and on for almost a half century, with little enduring success. Today, biological engineering and systems biology provide new opportunities for metabolic system modulation and give new optimism to the concept of a methane-based bio-industry. Here we present an overview of the most recent advances pertaining to metabolic engineering of microbial methane utilization. Some ideas concerning metabolic improvements for production of acetyl-CoA and pyruvate, two main precursors for bioconversion, are presented. We also discuss main gaps in the current knowledge of aerobic methane utilization, which must be solved in order to release the full potential of methane-based biosystems. PMID- 25825039 TI - Role of stress-related hormones in plant defence during early infection of the cyst nematode Heterodera schachtii in Arabidopsis. AB - Heterodera schachtii, a plant-parasitic cyst nematode, invades host roots and induces a specific syncytial feeding structure, from which it withdraws all required nutrients, causing severe yield losses. The system H. schachtii Arabidopsis is an excellent research model for investigating plant defence mechanisms. Such responses are suppressed in well-established syncytia, whereas they are induced during early parasitism. However, the mechanisms by which the defence responses are modulated and the role of phytohormones are largely unknown. The aim of this study was to elucidate the role of hormone-based defence responses at the onset of nematode infection. First, concentrations of main phytohormones were quantified and the expression of several hormone-related genes was analysed using quantitative real-time (qRT)-PCR or GeneChip. Further, the effects of individual hormones were evaluated via nematode attraction and infection assays using plants with altered endogenous hormone concentrations. Our results suggest a pivotal and positive role for ethylene during nematode attraction, whereas jasmonic acid triggers early defence responses against H. schachtii. Salicylic acid seems to be a negative regulator during later syncytium and female development. We conclude that nematodes are able to impose specific changes in hormone pools, thus modulating hormone-based defence and signal transduction in strict dependence on their parasitism stage. PMID- 25825040 TI - Surface-tuned electron transfer and electrocatalysis of hexameric tyrosine coordinated heme protein. AB - Molecular modeling, electrochemical methods, and quartz crystal microbalance were used to characterize immobilized hexameric tyrosine-coordinated heme protein (HTHP) on bare carbon or on gold electrodes modified with positively and negatively charged self-assembled monolayers (SAMs), respectively. HTHP binds to the positively charged surface but no direct electron transfer (DET) is found due to the long distance of the active sites from the electrode surfaces. At carboxyl terminated surfaces, the neutrally charged bottom of HTHP can bind to the SAM. For this "disc" orientation all six hemes are close to the electrode and their direct electron transfer should be efficient. HTHP on all negatively charged SAMs showed a quasi-reversible redox behavior with rate constant ks values between 0.93 and 2.86 s(-1) and apparent formal potentials ${E{{0{^{?prime }}?hfill ?atop {?rm app}?hfill}}}$ between -131.1 and -249.1 mV. On the MUA/MU-modified electrode, the maximum surface concentration corresponds to a complete monolayer of the hexameric HTHP in the disc orientation. HTHP electrostatically immobilized on negatively charged SAMs shows electrocatalysis of peroxide reduction and enzymatic oxidation of NADH. PMID- 25825041 TI - Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. AB - There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti-CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24.1 months vs. 6.8 months; time to next therapy was 14.8 months vs. 12.3 months; and progression-free survival was 7.4 months vs. 7.9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1-2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile. PMID- 25825042 TI - Genetic and Phenotypic Characteristics of Staphylococcus aureus Isolates from Cystic Fibrosis Patients in Austria. AB - BACKGROUND: Cystic fibrosis (CF) is the most common life-limiting inherited disease in Caucasian populations. While pathological changes can be seen in various organs, morbidity and mortality are mainly related to the respiratory tract, with patients suffering from chronic bronchopulmonary infections with characteristic pathogens including Staphylococcus aureus. OBJECTIVES: To date, there is only very limited data on the genetic and phenotypic characteristics of S. aureus in CF patients. Therefore, in our study, we characterized 58 S. aureus isolates collected from CF patients in Austria by spa typing, DNA microarray profiling, as well as antimicrobial susceptibility testing in order to determine common genomic and antimicrobial resistance features. The tested strain collection exhibited high genomic diversity. RESULTS: The 58 isolates were assigned to 16 clonal complexes and 48 spa types and differed greatly regarding their virulence and resistance gene profiles. The predominant clonal complexes were MLST CC30 (22%), CC15 (16%), CC45 (14%), and CC5 (12%), complexes that are highly prevalent worldwide among S. aureus strains isolated from humans colonized or infected with S. aureus. DNA microarray profiles showed a wide variety of genes encoding antimicrobial resistance and virulence factors such as various leukocidins, haemolysins, enterotoxins, exfoliative toxins, toxic shock syndrome toxin, as well as genes involved in adhesion and immune evasion. CONCLUSIONS: While a large number of strains exhibited resistance to one or several antimicrobial agents, methicillin-resistant S. aureus was found at a low prevalence of 3% (n = 2) only. The two methicillin-resistant S. aureus isolates were assigned to CC152/t355 (SCCmecV) and CC5/t001 (SCCmecI). This is the first study to genetically characterize S. aureus isolates in CF patients in Austria. PMID- 25825043 TI - Mendelian randomization analysis supports the causal role of dysglycaemia and diabetes in the risk of coronary artery disease. AB - INTRODUCTION: Type 2 diabetes is a strong risk factor for coronary artery disease (CAD). However, the absence of a clear reduction in CAD by intensive glucose lowering in randomized controlled trials has fuelled uncertainty regarding the causal role of dysglycaemia and CAD. OBJECTIVE: To assess whether Mendelian randomization supports a causal role of dysglycaemia and diabetes for risk of CAD. METHODS: Effect size estimates of common genetic variants associated with fasting glucose (FG), glycated haemoglobin (HbA1c), and diabetes were obtained from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium and Diabetes Genetics Replication and Meta-Analysis consortia. The corresponding effect estimates of these single nucleotide polymorphisms (SNPs) on the risk of CAD were then evaluated in CARDIOGRAMplusC4D. RESULTS: SNPs associated with HbA1c and diabetes were associated with an increased risk of CAD. Using information from 59 genetic variants associated with diabetes, the causal effect of diabetes on the risk of CAD was estimated at an odds ratio (OR) of 1.63 (95% Confidence Interval (CI): 1.23-2.07; P = 0.002). On the other hand, nine genetic variants associated with HbA1c were associated with an OR of 1.53 per 1% HbA1c increase (95% CI: 1.14-2.05; P = 0.023) in the risk of CAD while this effect was non significant among 30 genetic variants associated with FG per mmol/L (OR: 1.18, 95% CI: 0.97-1.42; P = 0.102). No significant differences were observed when categorizing genetic loci according to their effect on either beta-cell dysfunction or insulin resistance. CONCLUSIONS: These Mendelian randomization analyses support a causal role for diabetes and its associated high glucose levels on CAD, and suggest that long-term glucose lowering may reduce CAD events. PMID- 25825045 TI - Time to subsequent live birth according to mode of delivery in the first birth. AB - OBJECTIVE: To estimate the rate and time to next live birth by mode of delivery. DESIGN: Hospital-based cohort. SETTING: Aarhus University Hospital (AUH), Denmark. POPULATION: All pregnant women attending AUH were invited to enroll in the Aarhus Birth Cohort (ABC) study between 1989 and 2010 (n = 91,625). METHODS: Women were followed from their first live birth until the subsequent live birth or until censoring due to study end using Cox regression models. MAIN OUTCOME MEASURES: Rate and time to subsequent live birth according to mode of delivery. RESULTS: 46,162 index live births were identified, of which 22,462 (49%) had a subsequent live birth. Women with any type of caesarean had a 6% reduction in the rate of subsequent live birth (HR 0.94, 95% CI 0.89, 0.98), which remained unchanged in the analysis by type (emergency, HR 0.95, 95% CI 0.89, 1.02; elective, HR 0.91, 95% CI 0.85, 0.98) compared with women who had a spontaneous vaginal delivery (SVD). Operative vaginal delivery was associated with an 8% reduction in subsequent live birth rates (HR 0.92, 95% CI 0.86, 0.98) and vaginal delivery complicated by shoulder dystocia with a 19% reduction compared with SVD. Median time to next birth in days was shortest in women with a first caesarean (994 days, 95% CI 973, 1026) and longest in women with a vaginal delivery complicated by shoulder dystocia (1065 days, 95% CI 994, 1191). In women with planned pregnancies, the shortest median time to second birth was in women with breech vaginal deliveries (859 days, 95% CI 737, 1089) and the longest in women with vaginal deliveries complicated by shoulder dystocia (1193 days, 95% CI 1028, 1430). CONCLUSION: The impact of mode of delivery on subsequent rate and time to next birth was minimal in this study. The greatest reduction was among women with assisted vaginal delivery complicated by shoulder dystocia. This study is strengthened by data on pregnancy planning as well as information on complications of pregnancy, delivery and neonatal morbidities, all of which may influence a woman's decision on subsequent birth. PMID- 25825044 TI - Assessment of a standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncopes. AB - AIMS: Opinions differ regarding the effectiveness of cardiac pacing in patients affected by reflex syncope. We assessed a standardized guideline-based algorithm in different forms of reflex syncope. METHODS AND RESULTS: In this prospective, multi-centre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncopes, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. POPULATION: 253 patients, mean age 70 +/- 12 years, median 4 (3-6) syncopes, 89% without or with short prodromes. Of these patients, 120 (47%) received a pacemaker and 106 were followed up for a mean of 13 +/- 7 months: syncope recurred in 10 (9%). The recurrence rate was similar in 61 CSM+ (11%), 30 TT+ (7%), and 15 ILR+ (7%) patients. The actuarial total syncope recurrence rate was 9% (95% confidence interval (CI), 6-12) at 1 year and 15% (95% CI, 10-20) at 2 years and was significantly lower than that observed in the group of 124 patients with non diagnostic tests who had received an ILR: i.e. 22% (95% CI, 18-26) at 1 year and 37% (95% CI, 30-43) at 2 years (P = 0.004). CONCLUSION: About half of older patients with severe recurrent syncopes without prodromes have an asystolic reflex for which cardiac pacing goes along with a low recurrence rate. The study supports the clinical utility of the algorithm for the selection of candidates to cardiac pacing in everyday clinical practice. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01509534. PMID- 25825046 TI - Adult nasolacrimal duct cyst causing epiphora. PMID- 25825047 TI - The evolution of parental care in insects: A test of current hypotheses. AB - Which sex should care for offspring is a fundamental question in evolution. Invertebrates, and insects in particular, show some of the most diverse kinds of parental care of all animals, but to date there has been no broad comparative study of the evolution of parental care in this group. Here, we test existing hypotheses of insect parental care evolution using a literature-compiled phylogeny of over 2000 species. To address substantial uncertainty in the insect phylogeny, we use a brute force approach based on multiple random resolutions of uncertain nodes. The main transitions were between no care (the probable ancestral state) and female care. Male care evolved exclusively from no care, supporting models where mating opportunity costs for caring males are reduced-for example, by caring for multiple broods-but rejecting the "enhanced fecundity" hypothesis that male care is favored because it allows females to avoid care costs. Biparental care largely arose by males joining caring females, and was more labile in Holometabola than in Hemimetabola. Insect care evolution most closely resembled amphibian care in general trajectory. Integrating these findings with the wealth of life history and ecological data in insects will allow testing of a rich vein of existing hypotheses. PMID- 25825048 TI - Antifungal potential of Avicennia schaueriana Stapf & Leech. (Acanthaceae) against Cladosporium and Colletotrichum species. AB - There is significant interest in research to develop plant extracts with fungicidal activities that are less harmful to the environment and human health than synthetic fungicides. This study aimed to evaluate the antifungal activity of the extracts of Avicennia schaueriana against Colletotrichum and Cladosporium species and to identify the compounds responsible for the activity. Leaves and stems of A. schaueriana were extracted with ethanol and partitioned with petroleum ether, chloroform and ethyl acetate. The antifungal activity of such extracts was tested by bioautography against Cladosporium sphaerospermum, Cladosporium cladosporioides and Colletotrichum lagenarium. Ethanolic extracts, petroleum ether and chloroform fractions of stems had the highest antifungal activity with several active bands (Rf = 0.72 and Rf = 0.55). In the agar dilution assay, ethanolic extract, petroleum ether and chloroform fractions of stems were the most efficacious, presenting 85, 62 and 63% growth inhibition of Colletotrichum gloeopsporioides and minimum inhibitory concentration values between 1 and 1.5 mg ml(-1) , respectively. Analysis carried out using gas chromatography coupled to a mass spectrometry of petroleum ether and chloroform fractions allowed the identification of fatty acids methyl esters, lupeol and naphthoquinones such as lapachol, alpha-lapachone, naphtho[2,3-b]furan-4,9-dione, 2-isopropyl- and avicenol-C. We may infer that the antifungal activity of A. schaueriana is due to the abundance of these compounds. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that Avicennia schaueriana extracts have a high potential for the growth inhibition of Colletotrichum and Cladosporium ssp. and will provide a starting point for discovering new natural products with antifungal activity. Their development is of particular interest to organic production systems where synthetic fungicides cannot be used. PMID- 25825049 TI - Evaluation of simultaneous autotrophic and heterotrophic denitrification processes and bacterial community structure analysis. AB - This study demonstrated that a combined heterotrophic and autotrophic denitrification (HAD) process is highly effective for the simultaneous removal of acetate, nitrate, and sulfide at an efficiency of 100, 80, and 100 %, respectively. In the HAD system, simultaneous sulfide, acetate, and nitrate removals were observed, which indicated that heterotrophic and autotrophic denitrification occurred simultaneously. When the sulfide was existed in HAD reactor, the main product of sulfide biooxidation was S(0). Once the sulfide was exhausted, the sulfate concentration in the HAD reactor increased and became the main end product. These results provided an alternative method to control the end sulfide biooxidation product by online monitoring sulfide concentration. Nearly half (43 %) of the total clones in our mix-trophic reactor were amphitrophy denitrifiers. The autotrophic denitrifiers, heterotrophic denitrifiers, and amphitrophy denitrifiers coexisted in the HAD reactor to complete the denitrification process. Retrieved bacterial 16S rRNA gene clones affiliated with uncultured Xanthomonadaceae, Thauera, Thiobacillus, and Chromatiales were dominant. PMID- 25825050 TI - Increased intracellular calcium level and impaired nutrient absorption are important pathogenicity traits in the chicken intestinal epithelium during Campylobacter jejuni colonization. AB - Although a high number of chickens carry Campylobacter jejuni, the mechanistic action of colonization in the intestine is still poorly understood. The current study was therefore designed to investigate the effects of C. jejuni on glucose uptake, amino acids availability in digesta, and intracellular calcium [Ca(2+)]i signaling in the intestines of broiler chickens. For this, we compared: control birds (n = 60) and C. jejuni-infected birds (n = 60; infected orally with 1 * 10(8) CFU of C. jejuni NCTC 12744 at 14 days of age). Our results showed that glucose uptake was reduced due to C. jejuni infection in isolated jejunal, but not in cecal mucosa at 14 days postinfection (dpi). The decrease in intestinal glucose absorption coincided with a decrease in body weight gain during the 2 week post-infectious period. A reduction in the amount of the amino acids (serine, proline, valine, leucine, phenylalanine, arginine, histidine, and lysine) in ileal digesta of the infected birds at 2 and/or 7 dpi was found, indicating that Campylobacter utilizes amino acids as a carbon source for their multiplication. Applying the cell-permeable Ca(2+) indicator Fluo-4 and two photon microscopy, we revealed that [Ca(2+)]i was increased in the jejunal and cecal mucosa of infected birds. The muscarinic agonist carbachol induced an increase in [Ca(2+)]i in jejunum and cecum mucosa of control chickens, a response absent in the mucosa of infected chickens, demonstrating that the modulation of [Ca(2+)]i by Campylobacter might be involved in facilitating the necessary cytoskeletal rearrangements that occur during the bacterial invasion of epithelial cells. In conclusion, this study demonstrates the multifaceted interactions of C. jejuni with the gastrointestinal mucosa of broiler chickens. For the first time, it could be shown that a Campylobacter infection could interfere with intracellular Ca(2+) signaling and nutrient absorption in the small intestine with consequences on intestinal function, performance, and Campylobacter colonization. Altogether, these findings indicate that Campylobacter is not entirely a commensal and can be recognized as an important factor contributing to an impaired chicken gut health. PMID- 25825051 TI - The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells. AB - BACKGROUND: Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma. METHODS: TMZ inducibility of metalloproteases was determined in GBM cell lines, primary GBM cells, and tissues from GBM and recurrent GBM. TMZ sensitivity and invasiveness of GBM cells were assessed in the presence of the metalloprotease inhibitors batimastat (BB-94) and marimastat (BB-2516). Metalloprotease-dependent effects of TMZ on mitochondria and pAkt/phosphatidylinositol-3 kinase (PI3K) and phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) pathways were analyzed by fluorescence activated cell sorting, morphometry, and immunoblotting. Invasiveness of GBM cells was determined by Matrigel invasion assays. Potential metalloprotease substrates were identified by proteomics and tested for invasion using blocking antibodies. RESULTS: TMZ induces expression of MMP-1, -9, -14, and ADAM8 in GBM cells and in recurrent GBM tissues. BB-94, but not BB-2516 (ADAM8-sparing) increased TMZ sensitivity of TMZ-resistant and -nonresistant GBM cells with different O(6) methylguanine-DNA methyltransferase states, suggesting that ADAM8 mediates chemoresistance, which was confirmed by ADAM8 knockdown, ADAM8 overexpression, or pharmacological inhibition of ADAM8. Levels of pAkt and pERK1/2 were increased in GBM cells and correlated with ADAM8 expression, cell survival, and invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells. Blocking of HGF R/c-met prevented TMZ-induced invasiveness. CONCLUSIONS: ADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients. PMID- 25825053 TI - Plaque Thrombosis is Reduced by Attenuating Plaque Inflammation with Pioglitazone and is Evaluated by Fluorodeoxyglucose Positron Emission Tomography. AB - INTRODUCTION: The relationship between the beneficial effects of pioglitazone in reducing clinical events and plaque inflammatory burden remains unknown. This study aimed to determine whether pioglitazone can reduce the number of plaque thrombosis incidences and whether decreasing plaque inflammation is the mechanism by which pioglitazone reduces plaque thromboses. METHODS AND RESULTS: therosclerotic rabbits were divided into two groups: the atherosclerosis group (n = 13) and pioglitazone group (n = 10). The rabbits underwent pharmacological triggering to induce thrombosis. Serum inflammatory markers, FDG uptake, macrophage, and neovessel staining detected arterial inflammation. PET/CT scans were performed twice (baseline and posttreatment scans). Plaque area, macrophages, and neovessels were measured and the histologic sections were matched with the PET/CT scans. Serum MMP-9 and hsCRP were lower in the pioglitazone group compared to the atherosclerosis group. The SUVmean significantly decreased in the pioglitazone group (0.62 +/- 0.21 vs. 0.55 +/- 0.19, P = 0.008), but increased in the atherosclerosis group (0.61 +/- 0.15 vs. 0.91 +/- 0.20, P < 0.000). The incidence rate of plaque rupture, plaque area, macrophage density, and neovessel density was significantly lower in rabbits with pioglitazone than without (15% vs. 38%, P < 0.001; 18.00 +/- 2.30 vs. 27.00 +/- 1.60; P < 0.001; 8.80 +/- 3.94 vs. 28.26 +/- 2.49; P < 0.001; 16.50 +/- 3.09 vs. 29.00 +/- 2.11; P < 0.001, respectively). Moreover, plaque area and macrophage density were positively correlated with SUV values. CONCLUSIONS: Our study suggests that pioglitazone can reduce the number of plaque thrombosis incidences by decreasing plaque inflammation. (18)F-FDG-PET/CT can detect plaque inflammation and assess the effects of antiatherosclerotic drugs. PMID- 25825054 TI - [Fecal microbiota transplantation in recurrent Clostridium difficile infections. Framework and pharmaceutical preparation aspects]. AB - The fecal microbiota transplantation consists in introducing a preparation constituted by a dilution of stools of a healthy donor in the digestive tract of a patient recipient, to restore his intestinal physiological balance. This therapeutic approach was the subject of numerous studies showing its efficiency in the treatment of the recurrent infections with Clostridium difficile. The fecal microbiota transplantation has now a high level of clinical evidence, which explains that it appears in various international recommendations. In France, the fecal microbiota transplantation responds to the definition of a medication and can be executed as a pharmaceutical preparation or as an experimental drug for clinical trials under the responsibility of a hospital pharmacy. The objective of this paper is to propose a definition of a framework and to describe the methods of preparation of the fecal microbiota transplantation in the treatment of the recurrent infections with C. difficile and the interactions to consider for hospital pharmacies that do not have technical means to operate this technique. PMID- 25825055 TI - Identifying important ions and positions in mass spectrometry imaging data using CUR matrix decompositions. AB - Mass spectrometry imaging enables label-free, high-resolution spatial mapping of the chemical composition of complex, biological samples. Typical experiments require selecting ions and/or positions from the images: ions for fragmentation studies to identify keystone compounds and positions for follow up validation measurements using microdissection or other orthogonal techniques. Unfortunately, with modern imaging machines, these must be selected from an overwhelming amount of raw data. Existing techniques to reduce the volume of data, the most popular of which are principle component analysis and non-negative matrix factorization, have the disadvantage that they return difficult-to-interpret linear combinations of actual data elements. In this work, we show that CX and CUR matrix decompositions can be used directly to address this selection need. CX and CUR matrix decompositions use empirical statistical leverage scores of the input data to provide provably good low-rank approximations of the measured data that are expressed in terms of actual ions and actual positions, as opposed to difficult to-interpret eigenions and eigenpositions. We show that this leads to effective prioritization of information for both ions and positions. In particular, important ions can be found either by using the leverage scores as a ranking function and using a deterministic greedy selection algorithm or by using the leverage scores as an importance sampling distribution and using a random sampling algorithm; however, selection of important positions from the original matrix performed significantly better when they were chosen with the random sampling algorithm. Also, we show that 20 ions or 40 locations can be used to reconstruct the original matrix to a tolerance of 17% error for a widely studied image of brain lipids; and we provide a scalable implementation of this method that is applicable for analysis of the raw data where there are often more than a million rows and/or columns, which is larger than SVD-based low-rank approximation methods can handle. These results introduce the concept of CX/CUR matrix factorizations to mass spectrometry imaging, describing their utility and illustrating principled algorithmic approaches to deal with the overwhelming amount of data generated by modern mass spectrometry imaging. PMID- 25825056 TI - Impact of anatase and rutile titanium dioxide nanoparticles on uptake carriers and efflux pumps in Caco-2 gut epithelial cells. AB - TiO2 microparticles are widely used in food products, where they are added as a white food colouring agent. This food additive contains a significant amount of nanoscale particles; still the impact of TiO2 nanoparticles (TiO2-NPs) on gut cells is poorly documented. Our study aimed at evaluating the impact of rutile and anatase TiO2-NPs on the main functions of enterocytes, i.e. nutrient absorption driven by solute-liquid carriers (SLC transporters) and protection against other xenobiotics driven by efflux pumps from the ATP-binding cassette (ABC) family. We show that acute exposure of Caco-2 cells to both anatase (12 nm) and rutile (20 nm) TiO2-NPs induce early upregulation of a battery of efflux pumps and nutrient transporters. In addition they cause overproduction of reactive oxygen species and misbalance redox repair systems, without inducing cell mortality or DNA damage. Taken together, these data suggest that TiO2-NPs may increase the functionality of gut epithelial cells, particularly their property to form a protective barrier against exogenous toxicants and to absorb nutrients. PMID- 25825052 TI - Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. AB - BACKGROUND: Pediatric low-grade gliomas (PLGGs), the most frequent pediatric brain tumor, comprise a heterogeneous group of diseases. Recent genomic analyses suggest that these tumors are mostly driven by mitogene-activated protein kinase (MAPK) pathway alterations. However, little is known about the molecular characteristics inherent to their clinical and histological heterogeneity. METHODS: We performed gene expression profiling on 151 paraffin-embedded PLGGs from different locations, ages, and histologies. Using unsupervised and supervised analyses, we compared molecular features with age, location, histology, and BRAF genomic status. We compared molecular differences with normal pediatric brain expression profiles to observe whether those patterns were mirrored in normal brain. RESULTS: Unsupervised clustering distinguished 3 molecular groups that correlated with location in the brain and histological subtype. "Not otherwise specified" (NOS) tumors did not constitute a unified class. Supratentorial pilocytic astrocytomas (PAs) were significantly enriched with genes involved in pathways related to inflammatory activity compared with infratentorial tumors. Differences based on tumor location were not mirrored in location-dependent differences in expression within normal brain tissue. We identified significant differences between supratentorial PAs and diffuse astrocytomas as well as between supratentorial PAs and dysembryoplastic neuroepithelial tumors but not between supratentorial PAs and gangliogliomas. Similar expression patterns were observed between childhood and adolescent PAs. We identified differences between BRAF-duplicated and V600E-mutated tumors but not between primary and recurrent PLGGs. CONCLUSION: Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAF genomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related. PMID- 25825058 TI - Group training of conservation skills with children from a non-technological culture. AB - Group training of conservation of length was undertaken with primary school children in Botswana. Each group contained 10 subjects of mixed academic ability. Three methods of training were used: (1) teacher demonstration accompanied by responsive group recitation, (2) limited manipulation of training materials by students, (3) full manipulation of training materials by students. The three training methods were effective in producing learning, retention, and generalization of conservation. The results are discussed in terms of Piaget's views on the role of environmental influences and the function of action in the development of cognitive structures. The value of Piagetian concepts for non technological societies also is discussed. PMID- 25825057 TI - Long-lasting partnership between insulin resistance and endothelial dysfunction: role of metabolic memory. AB - BACKGROUND AND PURPOSE: The persistence of deleterious effects of hyperglycaemia even after glucose normalization is referred to as 'metabolic memory'. However, similar persistent effects of the metabolic consequences of a high fat diet (HFD) have not been described. EXPERIMENTAL APPROACH: Rats were given a normal pellet diet (NPD) or a HFD for 3 months. The animals from the HFD group were then returned to the NPD to observe the long-term effects of insulin resistance. Endothelial dysfunction was assessed by carbachol-mediated vasorelaxation and eNOS phosphorylation. KEY RESULTS: As expected, HFD consumption resulted in insulin resistance and endothelial dysfunction. Phosphorylation of eNOS at S1177 was decreased in HFD rats, compared with that in the NPD group. Rats on 3 months of HFD showed glucose intolerance and impaired insulin sensitivity and were then switched back to NPD (REV group) . Levels of cholesterol and triglyceride, and adiposity returned to normal in REV rats. However, endothelium-dependent vascular responses to carbachol which were impaired in HFD rats, continued to be impaired in REV rats. Similarly, decreased eNOS phosphorylation after HFD was not improved after 1 or 6 months of REV. CONCLUSIONS AND IMPLICATIONS: Our data indicate that returning to NPD did not improve the insulin sensitivity or the endothelial dysfunction induced by HFD. Although some biochemical parameters responsible for insulin resistance and endothelial dysfunction were normalized, molecular and vascular abnormalities, involving NO, persisted for several months, highlighting the long-lasting effects of metabolic memory. PMID- 25825059 TI - Personal space amongst arabs and americans. AB - Personal space zones were examined amongst Arab and American university students by jointly varying degree of acquaintanceship and sex of subject. Overall, there were few differences between Arab and American males. Arab females, however, showed dramatic differences in comparison to American males and females and to Arab males. Arab females kept male friends very far away relative to female friends. Indeed, male friends were kept almost as far away as male strangers. PMID- 25825060 TI - Simultaneous-successive syntheses and planning in chinese readers. AB - The present study investigated simultaneous-successive syntheses and planning as cognitive processing constructs in 66 grade 4 and 63 grade 6 Chinese children. Principal factor and promax analyses provided evidence of the realities of these independent factors. Simultaneous and successive components contributed to composite reading with varying degrees of variance for each grade. The Luria paradigm provides a useful framework for research into patterns of readers. PMID- 25825061 TI - Studies of cognitive development in papua new Guinea. AB - This paper reviews research dealing with problem solving abilities amongst Papua New Guineans. Studies concerned with individual intelligence tests, group intelligence tests, achievement tests, conservation measures, classificatory skills, and formal operational thinking are considered. Data are discussed which compared the performance of Papua New Guinean children and adults with people elsewhere, and with foreigners resident in Papua New Guinea. As well, important differences within Papua New Guinea related in particular to schooling and language-culture group are noted. By contrast with some previous conclusions about the cognitive skills of Papua New Guineans, it is concluded that while there are differences between some Papua New Guinean groups and groups from English speaking countries in problem-solving performance, developmental patterns appear to be similar. Thus, educated. Papua New Guineans eventually achieve the highest levels of formal thinking. PMID- 25825062 TI - The influence of ethnocentrism and ethnic label on the appreciation of disparagement jokes. AB - This study examined the relationship of ethnocentrism and the presence of an ethnic label to the humor appreciation of jokes with socially acceptable or unacceptable aggressors and victims. Forty high ethnocentrics and 40 low ethnocentrics, half males and half females, each read 12 jokes which varied in the acceptability of aggressor and victim and in the ethnic combination of the characters (neutral aggressor and victim, neutral aggressor and ethnic victim, ethnic aggressor and neutral victim). They rated these jokes on humor, as well as justifiability, hostility, and acceptability of aggressor and victim. Results indicated that high ethnocentrics, but not the low ones, found jokes with neutral aggressors and ethnic victims funnier. In addition, all subjects gave higher humor ratings to jokes with justified aggression. Thus, both ethnic stereotypes and the particular description of the characters appear to be significant influences on humor ratings in disparagement jokes. PMID- 25825063 TI - Children'S experience of three types of cartoon at two age levels. AB - Three cartoons were shown to 87 children at two age levels: 5-6 years, and 9 years. The children's experience was assessed in interviews. The younger children experienced the cartoons in a fragmentary manner and not as a continuous story, understood less of the cartoons, and tended to base their moral judgements of a character's behaviour on whether or not they identified with that character. Six months later, the younger children remembered best those scenes that had made them the most anxious earlier. A subgroup of children with abundant aggressive fantasies had a lower level of moral reasoning than the other children, preferred violent scenes, became less anxious while watching them and tended to give illogical explanations for the behaviour of the cartoon characters. The degree of anxiety provoked by a cartoon depended not on the amount of explicit violence shown but on the way the violence was presented. One cartoon, which contained no explicit violence, was considered the most frightening one due to its sound effects. PMID- 25825064 TI - Positive prejudice in ethnic attitudes: Australian data. AB - An experiment was conducted to determine whether members of a majority ethnic group would exhibit positive prejudice in their attitudes toward an ethnic minority. Subjects were given written communications which evaluated Aborigines and white Australians either favourably or unfavourably. The occurrence of positive prejudice was assessed by examining subjects' overall agreement with each communication as a whole and their level of agreement with specific descriptions which comprised the communications. Results confirmed the existence of positive prejudice in these responses, but also indicated that subjects' reactions to the communications were influenced by the predispositional variable of ethnocentrism. The study further investigated whether positive prejudice is limited to responses illustrating minimal commitment or whether it forms a central component of inter-ethnic attitudes. Analysis of delayed recall of the specific descriptions from the written communications and of agreement with an independent ethnic attitudes questionnaire suggested that positive prejudice does not generalize beyond short-term, inconsequential reactions. The implications of these findings and the relevance of the positive prejudice concept are discussed. PMID- 25825065 TI - Psychology in the Australian context. AB - Psychology formally entered the Australian arena via university departments of Philosophy, commencing last century and taking its initial direction largely from Britain. The previous pattern of development of Australian psychology was more distinctive than is its present state. Although the influences of Germany and the United States have supplemented that of the parent country, it is difficult to discern any locally blended colouration in the discipline or the profession as they now appear. Somewhat distanced from the universities, applied psychology has flourished especially in the public sector beginning with the initial close liaison formed between psychology and education in a developing colonial society. The public impact of research and practice is by no means as apparent as in the United States or Britain. After a burgeoning in the 'sixties and early 'seventies, the present state is one of limited growth concurrent with the general recession. PMID- 25825066 TI - Pay satisfaction: its multidimensional nature and measurement. AB - The present study was guided by the general hypothesis that pay satisfaction is multidimensional. The Pay Satisfaction Questionnaire (PSQ) was developed to assess five dimensions of satisfaction with pay (level, benefits, raises, structure, and administration). Results on two heterogeneous samples of employees provided support for the multidimensional hypothesis, although a four-dimensional solution (level, benefits, raises, structure/administration) provided better representation of the variance in the items studied. These four scales showed high internal consistency reliabilities. Comparison of the pay scales of the Job Descriptive Index and Minnesota Satisfaction Questionnaire with the PSQ dimensions suggested that these well-known scales primarily measure satisfaction with pay level. Implications of the findings for pay satisfaction research, both substantive and measurement oriented, are discussed. PMID- 25825067 TI - Clerodendrum viscosum: traditional uses, pharmacological activities and phytochemical constituents. AB - Clerodendrum viscosum is widely distributed in tropical and subtropical regions of the world particularly in India. Extracts from different parts of the plant have been used elaborately in Ayurveda and Unani for treating different illness. Many phytochemicals were isolated from various parts of the plant, but their pharmacological potentials have not been largely explored. This review focuses on all these aspects of the plant keeping in view the cultural and traditional acceptability of its medicinal use. Its toxicological data are limited and require investigation to address for safety issues prior to recommendating for pharmaceutical use. PMID- 25825068 TI - A theoretical benchmark study of the spectroscopic constants of the very heavy rare gas dimers. AB - Spectroscopic constants for the homonuclear dimers of the very heavy rare gases radon (Rn) and eka-radon (Uuo) are reported. A computational protocol using the eXact 2-Component molecular-mean field Hamiltonian has been established based on extensive calculations of the xenon dimer. We find that reliable results require CCSD(T) calculations at the extrapolated basis set limit. In this limit counterpoise corrected results are closer to experimentally derived values than uncorrected ones. Furthermore, in an attempt to reduce the computational cost while retaining very high accuracy, we studied the performance of range-separated density functional theory. Although we observe a somewhat more favorable basis set convergence and reduced importance of connected triples by range-separated methods compared to pure wave function theory, in practice we have to employ the same computational protocol for obtaining converged results. At the Dirac-Coulomb level we find an almost fourfold increase of binding energy when going from the radon to the eka-radon dimer, but the inclusion of spin-other orbit interaction reduces the dissociation energy of the heaviest dimer by about 40%. PMID- 25825069 TI - Challenges to measure hydration, redness, elasticity and perfusion in the unloaded sacral region of healthy persons after supine position. AB - AIM OF THE STUDY: To combine measurement methods of biophysical skin properties in a clinical setting and to measure baseline values in the unloaded sacral region of healthy persons after lying 30 min in supine position. METHODS: Hydration (Corneometer(r) CM 825), redness (Mexameter(r) MX 18), elasticity (Cutometer(r) MPA 580) and perfusion (PeriFlux System 5000) of the skin in the sacral region of 10 healthy participants (median age: 26.9 years) were measured consecutively in the laying position by two trained examiners. RESULTS: The assessment duration for all four parameters lasted about 15 min. Intra-class correlation coefficients were overall moderate to strong (hydration r = 0.594, redness r = 0.817, elasticity r = 0.719, perfusion r = 0.591). Hydration (median 27.7 arbitrary units (AU)) mainly indicated dry skin conditions. Redness (median 158.5 AU) was low. Elasticity (median 0.880 AU) showed similar values as in the neck region. Perfusion (median 17.1 AU) showed values in the range of results reported in the literature. CONCLUSION: Biophysical skin properties in the sacral region after supine position can be measured within periods of 15 min. The results provide baseline data for the skin of healthy persons as well as insights into skin-physiological variations. But it remains challenging to optimize measurement procedures and test protocols when transferring preclinical tests in a clinical application. PMID- 25825070 TI - Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients. AB - Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single-center treatment protocol of patients with HCV genotype 1 infection who received a 12-week combination regimen of sofosbuvir and simeprevir. Sixty-one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9-8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%-97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%-100%), whereas SVR12 was 89% (95% CI, 74%-95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3-F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%-86%); P = 0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12-week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse. PMID- 25825071 TI - Whether QOF has reduced premature death rates is still unclear. PMID- 25825072 TI - Development of toxicity values and exposure estimates for tetrabromobisphenol A: application in a margin of exposure assessment. AB - Tetrabromobisphenol A (TBBPA) is used in a diverse array of products to improve fire safety. The National Toxicology Program (NTP) recently completed a 2-year bioassay for TBBPA. The objective of the present study was to develop a cancer based and a non-cancer based toxicity value and to compare such to appropriate estimates of human exposure. Data from the NTP 2-year and 13-week studies were selected to develop candidate toxicity values. Benchmark dose modeling and subsequent evaluation of candidate values resulted in selection of an oral reference dose (RfD) of 0.6 mg kg(-1) day(-1) based on uterine hyperplasia in rats and an oral cancer slope factor (OSF) of 0.00315 per mg kg(-1) day(-1) based on an increased incidence of uterine tumors in rats. Lifetime average daily dose (LADD) estimates ranged from 2.2 E(-7) to 3.9 E(-6) mg kg(-1) day(-1) based on age-adjusted exposures to TBBPA via breast milk consumption, dietary intake, soil/dust ingestion and drinking water ingestion in infants, young children, older children and adults. Average daily dose (ADD) estimates ranged from 3.2 E ( 7) to 8.4 E(-5) mg kg(-1) day(-1). Resulting margin of exposure (MOE) values were > 800 000 for non-cancer endpoints and > 32,000,000 for cancer-based endpoints. These data collectively indicate a low level of health concern associated with exposures to TBBPA based on current data. It is anticipated that the exposure estimates, along with the toxicity values described within, should be informative for understanding human health hazards associated with TBBPA. PMID- 25825073 TI - An Unusual Cause of Neonatal Meningitis. PMID- 25825074 TI - Report by the Spanish Foundation for the Brain on the social impact of amyotrophic lateral sclerosis and other neuromuscular disorders. AB - INTRODUCTION: A thorough knowledge of the socioeconomic scope of neuromuscular disease is essential for managing resources and raising social awareness. DEVELOPMENT: Our group reviewed current data on the epidemiology, mortality and dependence rates, and socioeconomic impact of amyotrophic lateral sclerosis and neuromuscular diseases in Spain. We also recorded how neurological care for these patients is organised. CONCLUSIONS: Neuromuscular disorders are a very heterogeneous group of diseases, and some are very rare. These disorders account for between 2.8% and 18% of the total motives for a neurological consultation. In Spain, prevalence and incidence figures for amyotrophic lateral sclerosis are similar to those in other countries; however, figures for patients with other neuromuscular diseases are not known. Since the diseases are chronic, progressive, and debilitating, they cause considerable disability and dependence, which in turn directly affects healthcare and social costs associated with the disease. The costs generated by one patient with amyotrophic lateral sclerosis or Duchenne disease have been calculated at about 50 000 euros per year. Neuromuscular disease shows aetiological, diagnostic, and prognostic complexity, and it requires multidisciplinary management. Follow-up for these patients should be entrusted to specialised units. PMID- 25825075 TI - Status of management effort in 153 marine protected areas across the English Channel. AB - A conceptual framework was developed for assessing the sub-level of protection in 185 multiple-use marine protected areas (MPAs) in the English Channel through a survey on management effort. Data were retrieved from 153 MPAs: 4.56% were assigned low management effort, 83.70% were assigned medium management effort, and 11.76% were assigned high management effort. Overall, French MPAs performed better in terms of management effort than English MPAs and lack of consistency in ratings by different management bodies in England was found. Lack of correlation between management effort and conservation status within an available subset of 13 MPAs suggests that management may not be as influential a factor for the effective conservation of MPAs, especially in marine environments under heavy human pressure such as the English Channel. It is suggested that MPAs in such areas may therefore require an upgrade of their legal level of protection to be effective. PMID- 25825076 TI - Boswellia gum resin/chitosan polymer composites: Controlled delivery vehicles for aceclofenac. AB - This study was undertaken to evaluate the effect of Boswellia gum resin on the properties of glutaraldehyde (GA) crosslinked chitosan polymer composites and their potential as oral delivery vehicles for a non-steroidal anti-inflammatory drug, aceclofenac. The incorporation of resinous material caused a significant improvement in drug entrapment efficiency (~40%) of the polymer composites. Fourier transform infrared (FTIR) spectroscopic analysis confirmed the formation of chitosan-gum resin composites and did not show any evidence of drug-polymer chemical interaction. Field emission scanning electron microscopy (FE-SEM) suggested the formation of particulate polymer composites up to chitosan:gum resin mass ratio of 1:3. Only 8-17% drug was released into HCl solution (pH 1.2) in 2h. The drug release rate of polymer composites was faster in phosphate buffer solution (pH 6.8). The composites released ~60-68% drug load in 7h. In same duration, the drug release rate suddenly boosted up to 92% as the concentration of gum resin in the composites was raised to 80%. The drug release mechanism deviated from non-Fickian to case-II type with increasing resin concentration in the composites. Hence, GA-treated Boswellia resin-chitosan composites could be considered as alternative vehicles for oral delivery of aceclofenac. PMID- 25825077 TI - A novel laccase from basidiomycete Cerrena sp.: Cloning, heterologous expression, and characterization. AB - A novel laccase gene Lac1 and its cDNA were cloned from a white-rot fungus Cerrena sp. and characterized. The 1554-bp cDNA of Lac1 encoded a mature protein with 497 amino acids, preceded by a signal peptide of 20 amino acids. An unconventional intron splice site and incomplete splicing variants of Lac1 were observed. Lac1 was heterologously expressed in the yeast host Pichia pastoris, and a maximal laccase activity of 6.3UmL(-1) in the fermentation broth was achieved after fermentation for 9 days. The recombinant protein rLac1 was purified, and its enzymatic properties and functional characteristics were investigated. When ABTS was used as the substrate, the enzyme was most active at pH 3.5 and 55 degrees C, and stable at pH 4-10 and 20-60 degrees C. The Km and kcat values of rLac1 toward ABTS were 28.9 MUM and 332.4s(-1), respectively. Furthermore, rLac1 was tolerant to common metal ions up to 100mM concentration and capable of decolorizing structurally different dyes in the absence of a redox mediator. Hence, Lac1 may be useful for industrial applications, such as dye decolorization and bioremediation. PMID- 25825078 TI - Interplay of Halogen and pi-pi Charge-Transfer Bondings in Intermolecular Associates of Bromo- or Iododinitrobenzene with Tetramethyl-p-phenylenediamine. AB - Two modes of intermolecular interactions (halogen and pi-pi charge-transfer bonding) between bromo- or iododinitrobenzene (XDNB) and tetramethyl-p phenylenediamine (TMPD) are compared. X-ray crystallography revealed that TMPD.XDNB cocrystals comprise alternating donors/acceptors stacks formed by pi bonded (cofacial) TMPD and XDNB molecules. These structures also show two-point (C-X...O-N) halogen bonding between XDNB molecules resulting in formation of (XDNB)2 dimers. In solutions, XDNB and TMPD molecules formed 1:1 complexes showing strong absorption bands near 550 nm which followed the same Mulliken correlation as the associates of TMPD with the (halogen-free) nitro- and cyanobenzenes. In accord with the experimental data, density functional theory calculations with the M062X functional showed that TMPD.XDNB associates formed via pi-pi charge-transfer bonding are more stable (by 6-12 kcal/mol) than their halogen-bonded analogues. If XDNB is replaced with iodo- or bromoperfluorinated benzenes, or TMPD is replaced with pyridine, the energy gap between the pi-pi and halogen-bonded associates decreased. The analysis of the molecular-orbital interactions and surface electrostatic potentials of the interacting species indicated that charge-transfer contributions represent a critical component which determines variations of the strength of halogen bonding in these systems. PMID- 25825079 TI - Editorial statement on negative findings. PMID- 25825080 TI - Transplantation: The molecular landscape of ABMR. PMID- 25825087 TI - Acute kidney injury: Proximal tubule cells modulate inflammation after renal injury. PMID- 25825086 TI - The genetics of diabetic complications. AB - The rising global prevalence of diabetes mellitus is accompanied by an increasing burden of morbidity and mortality that is attributable to the complications of chronic hyperglycaemia. These complications include blindness, renal failure and cardiovascular disease. Current therapeutic options for chronic hyperglycaemia reduce, but do not eradicate, the risk of these complications. Success in defining new preventative and therapeutic strategies hinges on an improved understanding of the molecular processes involved in the development of these complications. This Review explores the role of human genetics in delivering such insights, and describes progress in characterizing the sequence variants that influence individual predisposition to diabetic kidney disease, retinopathy, neuropathy and accelerated cardiovascular disease. Numerous risk variants for microvascular complications of diabetes have been reported, but very few have shown robust replication. Furthermore, only limited evidence exists of a difference in the repertoire of risk variants influencing macrovascular disease between those with and those without diabetes. Here, we outline the challenges associated with the genetic analysis of diabetic complications and highlight ongoing efforts to deliver biological insights that can drive translational benefits. PMID- 25825084 TI - Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that has a broad spectrum of effects on the majority of organs, including the kidneys. Approximately 40-70% of patients with SLE will develop lupus nephritis. Renal assault during SLE is initiated by genes that breach immune tolerance and promote autoantibody production. These genes might act in concert with other genetic factors that augment innate immune signalling and IFN-I production, which in turn can generate an influx of effector leucocytes, inflammatory mediators and autoantibodies into end organs, such as the kidneys. The presence of cognate antigens in the glomerular matrix, together with intrinsic molecular abnormalities in resident renal cells, might further accentuate disease progression. This Review discusses the genetic insights and molecular mechanisms for key pathogenic contributors in SLE and lupus nephritis. We have categorized the genes identified in human studies of SLE into one of four pathogenic events that lead to lupus nephritis. We selected these categories on the basis of the cell types in which these genes are expressed, and the emerging paradigms of SLE pathogenesis arising from murine models. Deciphering the molecular basis of SLE and/or lupus nephritis in each patient will help physicians to tailor specific therapies. PMID- 25825088 TI - Autophagy inhibition enhances sensitivity of endometrial carcinoma cells to paclitaxel. AB - Autophagy has been shown to be involved in cancer cell resistance to chemotherapy. Paclitaxel, a widely used chemotherapeutic drug, was demonstrated to induce autophagy in various cancer cells. Therefore, we sought to evaluate the role of autophagy on the paclitaxel-induced cell death in endometrial carcinoma. In this study, we found that paclitaxel induced autophagy in paclitaxel insensitive HEC-1A and JEC cells, exhibiting an increased microtubule associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, a decrease in p62/SQSTM1 abundance, the upregulation of Beclin 1 expression and punctate dots of yellow fluorescent protein (YFP)-LC3 in the cytosol. Paclitaxel-mediated cell death was further potentiated by pretreatment with autophagy inhibitor chloroquine (CQ) or shRNA against the autophagic gene beclin 1. Moreover, paclitaxel stimulated reactive oxygen species (ROS) generation, and inhibition of the ROS by antioxidant N acetyl-cysteine (NAC) blocked paclitaxel-induced autophagy, indicating that paclitaxel-induced autophagy in endometrial carcinoma cells is mediated by ROS. These findings suggest that paclitaxel-elicited autophagic response plays a protective role that impedes the eventual death of endometrial carcinoma cell, and that autophagy-inhibitor therapy could be an effective and potent strategy to improve paclitaxel treatment outcomes in the treatment of endometrial carcinoma. PMID- 25825089 TI - Availability of emergency drugs and equipment in general and specialist dental settings in Babol, Iran. AB - AIM: Medical emergencies can frequently happen in dental settings and it is critical to outfit the clinic by emergency drugs and equipment. The aim of this study was to evaluate the emergency drugs and equipment in general and specialist dental settings in Babol, Iran. MATERIALS AND METHODS: A questionnaire containing closed ended questions about the available emergency drugs and equipment was used in this descriptive-analytical study. Data were subjected to descriptive analysis using SPSS 18.0 to identify the most frequent drugs and equipment. Chi-square and t-test were used to evaluate the correlation between the variables. p < 0.05 was considered statistically significant. RESULTS: One hundred and twelve dentists answered the questionnaire. The most available drug and equipment were epinephrine (67%) and single use syringe (81.3%) respectively. Significant correlation was found between degree of education and availability of first group of emergency drugs and between sex and possession of second group of emergency equipment (p < 0.05). CONCLUSION: Degree of availability of emergency drugs and equipment was moderate to low and training about emergencies should be included in the didactic topics of universities and workshops. CLINICAL SIGNIFICANCE: Information about emergency drug and equipment would help to manage the unwanted emergency situations. PMID- 25825090 TI - Comparison of linear measurements and analyses taken from plaster models and three-dimensional images. AB - Digital models are an alternative for carrying out analyses and devising treatment plans in orthodontics. The objective of this study was to evaluate the accuracy and the reproducibility of measurements of tooth sizes, interdental distances and analyses of occlusion using plaster models and their digital images. Thirty pairs of plaster models were chosen at random, and the digital images of each plaster model were obtained using a laser scanner (3Shape R-700, 3Shape A/S). With the plaster models, the measurements were taken using a caliper (Mitutoyo Digimatic((r)), Mitutoyo (UK) Ltd) and the MicroScribe (MS) 3DX (Immersion, San Jose, Calif). For the digital images, the measurement tools used were those from the O3d software (Widialabs, Brazil). The data obtained were compared statistically using the Dahlberg formula, analysis of variance and the Tukey test (p < 0.05). The majority of the measurements, obtained using the caliper and O3d were identical, and both were significantly different from those obtained using the MS. Intra-examiner agreement was lowest when using the MS. The results demonstrated that the accuracy and reproducibility of the tooth measurements and analyses from the plaster models using the caliper and from the digital models using O3d software were identical. PMID- 25825091 TI - The impact of chlorhexidine mouth rinse on the bond strength of polycarbonate orthodontic brackets. AB - OBJECTIVE: The purpose of the current in-vivo study was to assess the effect of using 0.12% chlorhexidine (CHX) mouth rinse, before bonding, on shear bond strength of polycarbonate brackets bonded with composite adhesive. SUBJECTS AND METHODS: Eighteen orthodontic patients with a mean age 21.41 +/- 1.2 years, who were scheduled to have 2 or more first premolars extracted, were included in this study. Patients were referred for an oral prophylaxis program which included, in part, the use of a mouth rinse. Patients were divided into 2 groups, a test group of 9 patients who used 0.12% CHX gluconate mouth rinse twice daily and a control group of 9 patients who used a mouth rinse without CHX, but with same color. After 1 week, polycarbonate brackets were bonded to first premolars with Transbond XT composite adhesive. Premolars were extracted after 28 days and tested for shear bond strength on a universal testing machine. Student's t-test was used to compare shear bond strengths of both groups. RESULTS: No statistically significant difference was found in bond strengths' values between both groups. The test group (with CHX) has mean shear bond strength of 14.21 +/- 2.42 MPa whereas the control group (without CHX) revealed a mean strength of 14.52 +/- 2.31 MPa. CONCLUSION: The use of 0.12% CHX mouth rinse, for one week before bonding, did not affect the shear bond strength of polycarbonate brackets bonded with Transbond composite. Furthermore, these brackets showed clinically acceptable bond strength. PMID- 25825092 TI - Medical emergency management among Iranian dentists. AB - AIMS: More than 18,000 patients need medical emergencies management in dental offices in Iran annually. The present study investigates medical emergencies management among Iranian dentists. MATERIALS AND METHODS: From the list of the cell phone numbers of the dentists practicing in the city of Tehran, 210 dentists were selected randomly. A self-administered questionnaire was used as the data collection instrument. The questionnaire requested information on personal and professional characteristics of the dentists, as well as their knowledge and self reported practice in the field of medical emergency management, and availability of required drugs and equipments to manage medical emergencies in their offices. RESULTS: Totally, 177 dentists (84%) completed the questionnaire. Less than 60% of the participants were knowledgeable about characteristics of hypoglycemic patient, chest pain with cardiac origin, and true cardiopulmonary resuscitation (CPR) practice. Regarding practice, less than one quarter of the respondents acquired acceptable scores. In regression models, higher practice scores were significantly associated with higher knowledge scores (p < 0.001). CONCLUSION: The results call for a need to further education on the subject for dentists. Continuing education and changing dental curriculum in the various forms seems to be useful in enhancement of the self-reported knowledge and practice of dentists. CLINICAL SIGNIFICANCE: To successful control of medical emergencies in the dental office, dentists must be prepared to recognize and manage a variety of such conditions. In addition to dentist's knowledge and skill, availability of necessary equipments and trained staff is also of critical importance. PMID- 25825093 TI - Influence of occlusal contact area on cusp defection and stress distribution. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of occlusal contact area for loading on the cuspal defection and stress distribution in a first premolar restored with a high elastic modulus restorative material. MATERIALS AND METHODS: The Rhinoceros 4.0 software was used for modeling the three-dimensional geometries of dental and periodontal structures and the inlay restoration. Thus, two different models, intact and restored teeth with three occlusal contact areas, 0.1, 0.5 and 0.75 mm(2), on enamel at the occlusal surface of buccal and lingual cusps. Finite element analysis (FEA) was performed with the program ANSYS (Workbench 13.0), which generated a mesh with tetrahedral elements with greater refinement in the regions of interest, and was constrained at the bases of cortical and trabecular bone in all axis and loaded with 100 N normal to each contact area. RESULTS: To analysis of maximum principal stress, the smaller occlusal contact area showed greater compressive stress in region of load application for both the intact and inlay restored tooth. However, tensile stresses at the occlusal isthmus were similar for all three tested occlusal contact areas (60 MPa). To displacement of the cusps was higher for teeth with inlay (0.46-0.48 mm). For intact teeth, the smaller contact area showed greater displacement (0.10 mm). For teeth with inlays, the displacement of the cusps were similar in all types of occlusal area. CONCLUSION: Cuspal displacement was higher in the restored tooth when compared to the intact tooth, but there were no significant variations even with changes in the occlusal contact area. RELEVANCE CLINICAL: Occlusal contacts have a great influence on the positioning of teeth being able to maintain the position and stability of the mandible. Axial loads would be able to generate more uniform stress at the root presenting a greater concentration of load application in the point and the occlusal surface. Thus, is necessary to analyze the relationship between these occlusal contacts as dental wear and subsequent occlusal interferences. PMID- 25825094 TI - Influence of metalloproteinases on dentin hybridization of one-bottle or self etch dental bonding systems. AB - AIM: To assess the influence of dentin substrate and chlorhexidine on the marginal seal of composite resin restorations. MATERIALS AND METHODS: The sample comprised 20 third molars. Four cavities were drilled in the dentin sur face, followed by sealing and restoration of sound dentin (n = 10) or carious dentin (n = 10). In the control group, cavities were immediately restored as follows: G1: one-bottle bonding agent (OB) + composite resin (CR); G2: chlorhexidine 2.0% (CLX) + OB + CR; G3: self-etch bonding agent (SE) + CR; G4: CLX + SE + CR. In the experimental group (carious dentin), carious lesions were induced with S. mutans and cavities were restored as in the control group. Five specimens from each group (sound and carious) were stored in brain-heart infusion (BHI) medium for 6 months. All specimens were submerged in methylene blue 0.5% to test for microleakage. The Kruskal-Wallis and Student-Newman-Keuls tests were used to assess results. RESULTS: On immediate assessment, there were no significant between-group differences in the sound dentin group, whereas in carious dentin, there was less leakage when OB and CLX were used. At 6 months, there was less leakage in the sound dentin group when OB and CLX were used; there were no between-group differences in carious dentin. Comparison of immediate and 6-month assessments showed a significant increase in leakage at 6 months when sound dentin was treated with SE and CLX and when carious dentin was treated with OB and CLX. CONCLUSION: To ensure better dentin hybridization and preservation of the organic constituents of the dentin matrix, the properties of chlorhexidine digluconate and the components of the resin matrix must be taken into account. CLINICAL SIGNIFICANCE: Metalloproteinases influence degradation of the hybrid layer in composite resin restorations, regardless of whether the bonding system used is one-bottle or self-etching. PMID- 25825095 TI - Isolation of Candida species from the oral cavity and fingertips of complete denture wearers. AB - BACKGROUND: Wearing a dental prosthesis is known to increase oral candidal colonization and predispose the wearer to oral candidosis. Denture wearers frequently use fingers to take the prosthesis out of their mouth. Oral Candida, if present may contaminate wearer's finger. The objective of this study was to investigate the simultaneous candidal colonization of oral cavity and fingertips of complete denture wearers. MATERIALS AND METHODS: A total of 25 apparently healthy male subjects who had worn complete dentures for at least 1 year were selected. Information about each patient's denture age, denture hygiene, handling, and wearing habits, and hand washing habits after denture handling were be obtained. Intraoral examination of all the patients was done. For microbiological examination samples were collected from the fingertip and oral rinse of each patient. Candida species were identified with use of germ tube test and commercially available yeast identification system. Data was statistically analyzed. Significance was set at p < 0.05. RESULTS: It was found that frequency of hand washing, denture handling and denture stomatitis with respect to fingertip candidal isolation was not statistically significant. But poor denture hygiene and denture stomatitis with respect to oral candidal colonization was statistically significant. CONCLUSION: Denture wearers with oral Candida had a higher prevalence of Candida contamination on their fingers. Patients with removable prostheses should be informed about the importance of proper prosthesis and personal hygiene and the possibility of microbial contamination of the hands and other parts of the body. PMID- 25825096 TI - Effectiveness of an infiltrant on sealing of composite restoration margins with/without artificial caries. AB - AIM: The aim of this in vitro study was to evaluate the effectiveness of a resin infiltrant (ICON) on marginal sealing ability of class II resin restorations with/without-caries. MATERIALS AND METHODS: Forty-eight noncarious human pre molar teeth were embedded and MO and DO preparations of standard dimensions were prepared. The left side of dentin margins of the cavities were left nonbonded (UB) while the right side were bonded using total etch-bonding agent and all restored with a Nanohybrid composite. The teeth were thermocycled and half of the specimens in the UB and B groups were subjected to an artificial caries process. ICON was applied to caries and noncaries subgroups following the manufacturer's directions. Impressions were made at each step: after the restorations were completed, thermocycling, artificial caries procedures, and infiltrant application and the silicone tag lengths were measured with a stereomicroscope. The specimens were immersed in 0.5% basic fuchsine at 37 degrees C for 24 hours, sectioned and microleakage was evaluated with a stereomicroscope. Selected samples and their replicas were assessed for marginal quality under a stereomicroscope and SEM. Statistical evaluation of the data were made using Kruskal-Wallis, Mann-Whitney U and Wilcoxon Sign Rank tests. RESULTS: While bonding application did not create a meaningful difference, the thermocycling and artificial caries significantly increased the gap length and microleakage (p < 0.05). ICON application was decreased the microleakage, created gap-free margins and closed the gaps which were previously occurred at the same cavities (p < 0.05). CONCLUSION: A resin infiltrant (ICON) application decreased the microleakage, created gap-free margins and closed the gaps, which previously occurred at the same cavities. CLINICAL SIGNIFICANCE: Approximal application of resin infiltrant may increase the success of the class II composite restorations also reduced the risk of needing more complex restoration therapy. PMID- 25825097 TI - Study of pulp chamber morphology of primary mandibular molars using spiral computed tomography. AB - AIM: The purpose of this study was to evaluate the pulp chamber morphology in primary mandibular molars using spiral computed tomography (SCT). MATERIALS AND METHODS: Sixty extracted primary mandibular molars were scanned using SCT for the (i) distance between the central fissure to furcation, (ii) distance between the central fissure to the floor of the pulp chamber, (iii) height of the pulp chamber (roof-floor), (iv) distance between the floor of the pulp chamber to the furcation. The mean and standard deviation was analyzed using statistical package for the social sciences (SPSS) program. RESULTS: The results of this study show that the average mean distance from the central fissure to the floor of the pulp chamber is 5.07 mm in first mandibular primary molar and 5.54 mm in second mandibular primary molar. CONCLUSION: It can be concluded that the greatest depth to which a bur can go during access opening without perforating the furcation in first primary mandibular molar is 5.07 mm and 5.54 mm in second primary mandibular molar. PMID- 25825098 TI - Evaluation of the effect of diacetyl morphine on salivary factors and their changes after methadone therapy. AB - OBJECTIVES: Psychoactive drugs are responsible for pathological changes in the mouth including dental caries, which most troublesome. The aim of the present study was to evaluate the effect of heroin on several salivary factors which are involved in the oral health and their changes after methadone maintenance therapy (MMT). MATERIALS AND METHODS: Forty patients with heroin abuse history, who referred to Imam Reza Hospital for MMT were included. Saliva sampling was carried out two times; at the first visit (time 1) and repeated 1 month after MMT (time 2). The saliva was analyzed immediately to evaluate the total volume, Ph, CPR, the Uric acid concentration, nitric oxide and antioxidant capacity. RESULTS: The mean values for saliva volume, pH, CRP, Uric acid, antioxidant and nitric oxide were 0.38 +/- 0.14, 7.63 +/- 1.22, 5.2 +/- 2.3, 1.47 +/- 0.8, 0.80 +/- 0.23, and 0.26 +/- 0.03, respectively at first visit and 0.34 +/- 0.22, 7.37 +/- 1.01, 6.1 +/- 2.6, 2.18 +/- 0.9, 0.74 +/- 0.3 and 0.29 +/- 0.08 after 1 month of MMT. These values are below the normal ranges; however, there was no significant difference between two times in term of saliva volume, pH and saliva component (p > 0.05). CONCLUSION: Heroin addiction changed the effective salivary factors and therefore could negatively contribute to oral health. These factors were not return to the normal range after 1 month of MMT. Physicians should be informed about focusing on oral health in patients under MMT. PMID- 25825099 TI - Is it possible to use cross-sectional and vertical facial measurements to establish the shape of the mandibular arch? AB - BACKGROUND: Given the benefits of radiographic cephalometric studies in determining patterns of dental-skeletal-facial normality in orthodontics, the aim of this study was to investigate the association between mandibular dental arch shape and cross-sectional and vertical facial measurements. MATERIALS AND METHODS: It was analyzed plaster casts and teleradiographs in frontal and lateral norm belonging to 50 individuals, aged between 15 and 19 years, with no previous history of orthodontic treatment and falling into four of the six Andrews's occlusion keys. The plaster models were scanned (3D) and the images of the dental arches were classified subjectively as oval, triangular and quadrangular by three calibrated examiners, with moderate inter-examiner agreement (Kappa = 0.50). After evaluation of the method error by paired t test (p > 0.05), it was carried out the analysis of cross-sectional and vertical facial measurements to be compared to the shape of the dental arch. Data were subjected to one-way analysis of variance with a significance level of 5%. RESULTS: When the VERT index was compared with the three arch shapes, no measurement showed statistically significant differences (p > 0.05): triangular (0.54); oval (0.43); and quadrangular (0.73); as well as there were no differences (p > 0.05) in the widths of the face (141.20; 141.26; 143.27); maxilla (77.27; 77.57; 78.59) and mandible (105.13; 103.96; 104.28). CONCLUSION: It can be concluded that there was no correlation between different shapes of the mandibular dental arch and the cross-sectional and vertical facial measurements investigated. PMID- 25825100 TI - Evaluation of the relationship between mandibular third molar and mandibular canal by different algorithms of cone-beam computed tomography. AB - OBJECTIVES: Exact location of the inferior alveolar nerve (IAN) bundle is very important. The aim of this study is to evaluate the relationship between the mandibular third molar and the mandibular canal by cone-beam computed tomography. STUDY DESIGN: This was a cross-sectional study with convenience sampling. 94 mandibular CBCTs performed with CSANEX 3D machine (Soredex, Finland) and 3D system chosen. Vertical and horizontal relationship between the mandibular canal and the third molar depicted by 3D, panoramic reformat view of CBCT and cross sectional view. Cross-sectional view was our gold standard and other view evaluated by it. RESULTS: There were significant differences between the vertical and horizontal relation of nerve and tooth in all views (p < 0.001). CONCLUSION: The results showed differences in the position of the inferior alveolar nerve with different views of CBCT, so CBCT images are not quite reliable and have possibility of error. PMID- 25825101 TI - Evaluation of interleukin-1alpha, interleukin-10, tumor necrosis factor-alpha and transforming growth factor-beta in the serum of patients with pemphigus vulgaris. AB - Pemphigus is an autoimmune blistering disease characterized by a loss of cell adhesion result in acantholysis. Genetic factors and immunologic factors such as cytokines particularly IL-1alpha, IL-10, TNF-alpha, and TGF-beta may counterpart to developing of Pemphigus. The aim of this study was to evaluate. The concentration of IL-1alpha, IL-10, TNF-alpha, TGF-beta in serum of pemphigus vulgaris (PV) patients and normal individuals. MATERIAL AND METHODS: In this analytic and descriptive study 25 patients with pemphigus vulgaris (in active phase) and 25 healthy per sons were examined. Serum samples of two groups were obtained and the level of IL-1alpha, IL-10, TNF-alpha and TGF-beta were measured by ELISA technique. The data were analyzed statistically by independent T test (alpha = 0/05). RESULTS: All cytokines tested, showed higher concentration in patient's sera comparing to healthy control individuals. The level of IL-1alpha (p = 0.004), TNF-alpha (p = 0.008) and TGF-beta (p = 0.009) were statistically different in two experimental groups, There was no significant difference in IL 10 level (p = 0.605). CONCLUSION: Cytokines such as IL-1alpha, IL-10, TNF-alpha and TGF-beta probably have a role in pathogenesis of PV. Further comprehensive studies are suggested to confirm these findings. PMID- 25825102 TI - Efficacy of lignocaine in gel and spray form during buccal infiltration anesthesia in children: a randomized clinical trial. AB - AIM: To compare the efficacy of 15% lignocaine spray and 8% lignocaine gel as a topical anesthetic, in reducing pain, during buccal infiltration in children. MATERIALS AND METHODS: Forty-two patients aged between 7 and 12 years requiring restorative procedures/extraction/pulp therapy of primary/ permanent teeth in the maxillary arch, under buccal infiltration anesthesia were selected for the study. The participants were randomly allocated into 2 groups of 21 each. In group A, 8% lignocaine gel and in group B, 15% lignocaine spray was applied prior to buccal infiltration. Pain was assessed using Wong-Baker faces pain rating scale (WBFPRS) and faces legs activity cry and consolability (FLACC) painscale. RESULTS: Pearson's chi-square test revealed that there was no significant difference in the FLACC scores of the two groups (p = 0.54). Independent t-test demonstrated that there was no significant difference in Wong-Bakers faces pain score between the two agents (p = 0.07). CONCLUSION: There is no significant difference in the efficacy of 15% lignocaine spray and 8% lignocaine gel as a topical anesthetic in controlling pain during buccal infiltration anesthesia, in children. PMID- 25825103 TI - Knowledge, attitude and practice of pediatricians and pharmacists in Riyadh City toward the use of sugar free medications. AB - OBJECTIVE: This study was intended to assess the knowledge, attitude and practice of pediatricians and pharmacists about sugar free medications (SFMs) and their impact on oral health. MATERIALS AND METHODS: Self-administered close ended questionnaire was handed out to all pediatricians and pharmacists in five tertiary hospitals in Riyadh (King Khalid University Hospital, King Saud Medical City, King Fahad Medical City, Prince Sultan Medical Military City, Security Forces Hospital) to investigate the knowledge, attitude and practice concerning SFMs. RESULTS: Eighty-five pediatricians and 77 pharmacists participated in this study. The results showed that pediatricians and pharmacists have a good knowledge, but negative attitude toward SFMs. Only (5.9%) of pediatricians had formal undergraduate training which is significantly lower than pharmacists (15.6%) (p = 0.04). One-third of pediatricans and pharmacists prescribe or dispense SFMs. The most influencing factors toward prescription (pediatrician) of SFMs was the medical status of the patient (70.6%), while the most influencing factor of dispensing (pharmacists) SFMs was the availability in the pharmacy (64.9%). Two-third of pediatricians (67%) guide the parents about the risk associated with sugar-containing medications (SCMs) which is significantly higher than pharmacists (p < 0.0001). Also, 53% of pediatricians recommend oral hygiene instructions when prescribing SCMs which is also significantly higher than pharmacists (p = 0.0 02). CONCLUSION: There is a considerable knowledge about SFMs and its impact on dental caries, among pediatricians and pharmacists participated in this study. However, their attitude toward prescribing or dispensing SFMs was not positive and may be linked to the gap in knowledge. Further training and education of healthcare providers regarding the use of SFMs and its negative impact on dental caries has to be reiterated. PMID- 25825104 TI - Analysis of the proliferative potential of odontogenic epithelial cells of pericoronal follicles. AB - AIM: To evaluate the proliferative potential and the cell proliferation rate of odontogenic epithelial cells. MATERIALS AND METHODS: Forty-two cases of pericoronal follicles of impacted third molars were submitted to silver impregnation technique for quantification of argyrophilic nucleolar organizer regions (AgNOR) and immunohistochemical staining for EGFR and Ki-67. For AgNOR quantification, the mean number of active nucleolar organizer regions per nucleus (mAgNOR) and the percentage of cells with 1, 2, 3 and 4 or more AgNORs per nucleus (pAgNOR) were quantified. Ki-67 immunolabeling was quantified, whereas for EGFR, a descriptive analysis of staining patterns (membrane, cytoplasm or membrane + cytoplasm positivity) was performed. We evaluated the reduced epithelium of the enamel organ and/or islands of odontogenic epithelium present in the entire connective tissue. RESULTS: mAgNOR were 1.43 (1.0-2.42) and were significantly different among pericoronary follicles from upper and lower teeth (p = 0.041). Immunostaining of Ki-67 was negative in all cases. EGFR immunolabeling was found mainly in the cytoplasm and was more intense in islands and cords when compared to reduced epithelium of the enamel organ. CONCLUSION: Odontogenic epithelial cells of some pericoronal follicles have proliferative potential, suggesting their association with the development of odontogenic lesions. CLINICAL SIGNIFICANCE: The authors suggest that nonerupted, especially of the lower teeth, should be monitored and if necessary removed. PMID- 25825105 TI - Radiographic localization of mental foramen in Northeast and South Indian ethnic groups of Indian population. AB - BACKGROUND AND OBJECTIVES: The position of mental foramen varies in different ethnic groups. The position of mental foramen is mainly important for achieving effective mental nerve block to carry out dental surgical procedures in mandible. Deviation in its position can be a cause of complication during local anesthesia or surgical procedures. The position of the mental foramen in South Indian and Northeast Indian population has not been reported. The purpose of the current study was to determine the most common location of the mental foramen (MF) and its bilateral symmetry in selected Indian population. MATERIALS AND METHODS: 380 digital panoramic radiographs (DPR) of a randomly selected 2 Ethnic groups of Indian population were studied. RESULTS: The common position (59.2%) of the mental foramen was located between the 1st and 2nd premolars (P3) in Northeast Indians and in South Indians the common location (62.8%) was in line with the long axis of the 2nd premolar (P4), which was statistically significant in both Populations. CONCLUSION: A bilateral symmetry was observed in the location of mental foramina, either mesial to or in line with the long axis of the 2nd premolar, which is consistent with the observations of similar studies in various ethnic or racial groups. In our study a statistically significant association between the 2 ethnic groups and the position of mental foramen exists. Therefore the position of mental foramen may be specific to racial groups facilitating accurate landmark for mental nerve block depending on the ethnic group. Further, studies are required with larger sample for better understanding of mental foramen location in different ethnic groups. PMID- 25825106 TI - A method for retrieving endodontic or atypical nonendodontic separated instruments from the root canal: a report of two cases. AB - AIM: This clinical report presents a new method for retrieving separated instruments from the root canal with minimally invasive procedures. BACKGROUND: The presence of separated instrument in root canal may interfere in the endodontic treatment prognosis. There are several recommended methods to retrieve separated instruments, but some are difficult in clinically practice. CASE REPORT: This study describes two cases of separated instrument removal from the root canal using a stainless-steel prepared needle associated with a K-file. Case 1 presented a fractured gutta-percha condenser within the mandibular second premolar, it was separated during incorrect intracanal medication calcium hydroxide placement. Case 2 had a fractured sewing needle within the upper central incisor that the patient used to remove food debris from the root canal. After cervical preparation, the fractured instruments were fitted inside a prepared needle and then an endodontic instrument (#25 K-file) was adapted with clockwise turning motion between the needle inner wall and the fragment. CONCLUSION: The endodontic or atypical nonendodontic separated instrument may be easily pull on of the root canal using a single and low cost device. CLINICAL SIGNIFICANCE: The methods for retrieving separated instruments from root canal are difficult and destructive procedures. The present case describes a simple method to solve this problem. PMID- 25825107 TI - An unusual case of ameloblastoma observed in the left anterior mandible. AB - AIM: To report a small intaalveolar ameloblastoma which resembled cystic lesion, and to emphasize the value of Computed tomography (CT) in radiographic examination. BACKGROUND: Ameloblastoma is a slow-growing, locally invasive odontogenic neoplasm that accounts for approximately 10% of all tumors detected in the jaws. Radiographically, those tumors are usually well-defined. Computerized tomography is highly recommended to confirm the diagnosis. CASE DESCRIPTION: A 48-year-old female attended with a chief complaint of painless swelling in the left anterior of mandible, 1 month duration. In intraoral examination, non-fluctuant, immobile, approximately 1 * 1 cm in dimension, painless, swelling which had a bone-like hardness and located in the mandibular canine region was detected. Panoramic radiography revealed a well circumscribed unilocular radiolucent lesion located in the inter-radicular area of left mandibular lateral and canine teeth. In CT examination it was realized that the lesion was multilocular. Histopathological examination of the biopsy specimen was reported as ameloblastoma. CLINICAL SIGNIFICANCE: It is extremely difficult to find such an ameloblastoma in small dimension in alvolar bone. PMID- 25825108 TI - Calcium phosphate barrier for augmentation of bone in noncontained periodontal osseous defects: a novel approach. AB - AIM: The aim of this technique is to augment bone in non-contained osseous deformities using a unique self-sustaining calcium phosphate barrier. INTRODUCTION: Bone has the inherent ability to regenerate completely if it is provided with a fracture space or an undisturbed enclosed scaffold. A secluded environment is essential as it provides a secured, sterile and stable wound system that regenerates lost bone by a process of osteopromotion. Reconstructive techniques using bone grafts and barrier membranes utilize this principle for augmentation of deficient bony sites by providing a closed environment that promotes clot stability, graft retention, and facilitates correct cell repopulation. However, in noncontained bone defects like one walled infrabony periodontal defect or sites with horizontal bone loss, regeneration of bone still remains an unrealistic situation since osseous topography at such sites does not favor membrane stability or bone grafts retention. This case report presents a promising technique to augment bone in areas with horizontal loss. TECHNIQUE: Augmentation of bone in the interdental area with horizontal bone loss was accomplished by building a contained defect using a unique self sustaining calcium phosphate cement formulation. The calcium phosphate barrier stimulates the lost cortical plates and promotes graft retention and clot stability. At 6 months, there was a significant bone fill and trabecular formation in the interdental area and reduction in tooth mobility. CONCLUSION: This promising technique could prove to be a good alternative to the conventional approaches for treating osseous deformities. CLINICAL SIGNIFICANCE: Calcium phosphate is a promising barrier graft for repair of noncontained periodontal osseous defect. This technique cues both the clinicians and manufacturers to develop moldable tissue engineered constructs for osseous repair. PMID- 25825109 TI - Mandibular first molar with Vertucci type I canal confguration diagnosed with the help of cone beam computed tomography: a rare case report. AB - The knowledge of root canal morphology and the existing anatomical variations is essential for successful endodontic therapy. This report presents an extraordinary case of unusual tooth morphology involving the mandibular first molar with a single root and a single canal in a patient. Endodontic treatment of the affected tooth 36 was performed. Cone beam computed tomography (CBCT) images confirmed our diagnostic and therapeutic measures after endodontic management of the teeth. This morphologic variation has been reported once in the literature. The availability of three-dimensional images further provided the opportunity for the precise description of the anatomy of mandibular first molar with single roots and single canals. PMID- 25825110 TI - Hypohidrotic ectodermal dysplasia: a clinical case with a longitudinal approach. AB - AIM: This paper describes a clinical case of a male with hypohidrotic ectodermal dysplasia submitted to rehabilitation and occlusal dental interventions with follow-up from 3 to 14 years of age. BACKGROUND: Due to the severe effects on function and esthetics, the clinical manifestations of ectodermal dysplasia exert a negative impact on quality of life. However, oral rehabilitation in childhood poses a challenge due to growth and development. CASE DESCRIPTION: A male with hypohidrotic ectodermal dysplasia began dental intervention at the age of 3 years. The clinical and radiographic exams revealed the absence of several primary and permanent teeth and abnormal shape of the primary maxillary incisors. The facial characteristics were compatible with hypohidrotic ectodermal dysplasia, such as a prominent brow, everted lips, fattened bridge of the nose and small vertical facial height. The treatment proposed involved rehabilitation through successive temporary partial dentures, functional orthopedics of the jaws, esthetic reconstruction of the anterior teeth, timely occlusal intervention and preventive actions for the control of dental caries and plaque. CONCLUSION: The present case demonstrates that early care plays a fundamental role in minimizing the biopsychosocial consequences of hypohidrotic ectodermal dysplasia and preparing the patient for future oral rehabilitation. CLINICAL SIGNIFICANCE: Although, the literature offers a number of papers describing dental treatment for ectodermal dysplasia, few cases include long-term follow-up and the use of a functional orthopedic appliance in combination with removable dentures in such patients. PMID- 25825111 TI - The complex radicular groove: interdisciplinary management with mineral trioxide aggregate and bone substitute. AB - This article is a case report of the successful interdisciplinary management of a maxillary lateral incisor with a deep palatogingival groove. The tooth presented with severe periodontal destruction owing to the deep extension of the groove up to the root apex. The groove was meticulously diagnosed and treated by endodontic and subsequent periodontal surgery leading to complete resolution of the pathological process. PMID- 25825112 TI - Early and immediate loading protocols for overdentures in completely edentulous maxillas: a comprehensive review of clinical trials. AB - A comprehensive review was conducted to answer the question 'Does the immediate loading of dental implants with an overdenture in the maxilla provide predictable clinical and psychological outcomes?' Detailed search strategies were used to identify pertinent articles in English that were published between 1975 and August 2013 and indexed in PubMed, MEDLINE, Embase, The Cochrane Central Register of Controlled Trials, and a personal library; in addition, relevant journals were manually searched. Only randomized controlled clinical trials (RCTs), controlled clinical trials (CCTs), and prospective studies with a follow-up period of at least one year, all involving 10 or more adult participants, were considered. Six prospective studies reporting on outcomes of up to 2 years were included, five of which employed a bar-retained overdenture, and one of which used a ball attachment as a retention mechanism. Short term reports demonstrate that immediate/early loading of dental implants with a maxillary overdenture is a predictable treatment approach and results in favorable implant/prosthesis survival, soft tissue health, and patient satisfaction outcomes. However, for a definitive conclusion, well-designed long-term trials are required to establish a consensus on treatment planning, longevity, long-term complications and maintenance, cost-effectiveness, and patients-mediated outcomes. PMID- 25825113 TI - Halitosis: a review of the etiologic factors and association with systemic conditions and its management. AB - Halitosis is a general term defined as an unpleasant or offensive odor emanating from the breath, arising from either oral or nonoral sources. Extraoral factors, such as ear-nose-throat conditions or gastrointestinal, respiratory, and systemic diseases, may also contribute to oral malodor. Although, halitosis has a multifactorial etiology, local factors play an important role in the majority of cases. Halitosis may lead to significant personal discomfort and social embarrassment. Assessment of halitosis can be performed using organoleptic measurements, sulfide monitoring, gas chromatography, microbial testing and chemical test strips. Management approaches are based on masking oral malodor, reducing the levels of volatile organic compounds (VOCs) and volatile sulfur compounds (VSCs), and mechanical and/or chemical treatment. This review aims to identify the etiology of oral halitosis, describe the methods available for assessment and differential diagnosis and introduce a variety of management strategies. The importance of a multidisciplinary approach for the improvement of overall health and for the management and prevention of halitosis is highlighted. PMID- 25825114 TI - Evaluation of medicinal interventions for the management of oral submucous fibrosis: a systematic review of the literature. AB - Oral submucous fibrosis is a chronic, progressive scarring disease associated with both significant morbidity including pain and limited mouth opening and an increased risk for malignancy. This systematic review evaluated the different medicinal (i.e. nonsurgical) interventions available for the management of oral submucous fibrosis. An automated literature searches of online databases from January 1960 to December 2013 were performed and only studies with high level of evidence based on the guidelines of the Oxford Centre for evidence-based medicine were selected. Thirteen studies (3 randomized controlled trials and 10 clinical trials/controlled clinical trials) were included and drugs like steroids, hyaluronidase, human placenta extracts, chymotrypsin and collagenase, pentoxifylline, nylidrin hydrochloride, iron and multivitamin supplements including lycopene were used. There is a clear lack of evidence on the available drug treatment for oral submucous fibrosis and further high quality randomized controlled trials are needed to evaluate the different therapeutic agents. PMID- 25825115 TI - Osseointegrated silicone finger prosthesis using dental implants: a renovated technique. AB - AIM AND BACKGROUND: In clinical practice, we come across patients with traumatically amputated or congenitally missing partial or complete fingers that can be restored using microsurgical replantation or transplantation procedures. However, in some cases this might not be possible due to systemic or local factors and the lost or missing part has to be replaced prosthetically to offer psychological and functional wellbeing. These prostheses can be constructed with various materials like acrylics or silicone retained with the help of auxiliary aids. However, these prostheses cause some hindrance in performing functions like writing, typing, etc. The aim of the present trial was to ameliorate the existing design of implant supported finger prosthesis. TECHNIQUE: Distal phalange of middle finger replaced with implant supported silicone finger prosthesis is modified by utilizing a metal framework to support silicone material to improve rigidity while working. CONCLUSION AND CLINICAL SIGNIFICANCE: We could achieve a good function, esthetics and tactile sensibility with this modified design. Whenever, feasible this design can improve the performance and patients feel a deep sense of satisfaction and improved self-esteem with this modified prosthesis. PMID- 25825116 TI - Modifying gummy smile: a minimally invasive approach. AB - AIM: Excessive gingival display is a problem that can be managed by variety of procedures. These procedures include non-surgical and surgical methods. The underlying cause of gummy smile can affect the type of procedure to be selected. Most patients prefer minimally invasive procedures with outstanding results. The authors describe a minimally invasive lip repositioning technique for management of gummy smile. MATERIALS AND METHODS: Twelve patients (10 females, 2 males) with gingival display of 4 mm or more were operated under local anesthesia using a modified lip repositioning technique. Patients were followed up for 1, 3, 6 and 12 months and gingival display was measured at each follow up visit. The gingival mucosa was dissected and levator labii superioris and depressor septi muscles were freed and repositioned in a lower position. The levator labii superioris muscles were pulled in a lower position using circumdental sutures for 10 days. Both surgeon's and patient's satisfaction of surgical outcome was recorded at each follow-up visit. RESULTS: At early stage of follow-up the main complaints of patients were the feeling of tension in the upper lip and circum oral area, mild pain which was managed with analgesics. One month postoperatively, the gingival display in all patients was recorded to be between 2 and 4 mm with a mean of (2.6 mm). Patient satisfaction records after 1 month showed that 10 patients were satisfied with the results. Three months postoperatively, the gingival display in all patients was recorded and found to be between 2 and 5 mm with a mean of 3 mm. Patient satisfaction records showed that 8 patients were satisfied with the results as they gave scores between. Surgeon's satisfaction at three months follow up showed that the surgeons were satisfied in 8 patients. The same results were found in the 6 and 12 months follow-up periods without any changes. Complete relapse was recorded only in one case at the third postoperative month. CONCLUSION: This study showed that the proposed lip repositioning technique is an acceptable minimally invasive procedure in managing gummy smile. CLINICAL SIGNIFICANCE: A non-invasive procedure to avoid other complicated surgical procedures. PMID- 25825117 TI - Micrometastasis in head and neck squamous cell carcinoma. PMID- 25825118 TI - A new heterologous fibrin sealant as scaffold to recombinant human bone morphogenetic protein-2 (rhBMP-2) and natural latex proteins for the repair of tibial bone defects. AB - Tissue engineering has special interest in bone tissue aiming at future medical applications Studies have focused on recombinant human bone morphogenetic protein 2 (rhBMP-2) and natural latex proteins due to the osteogenic properties of rhBMP 2 and the angiogenic characteristic of fraction 1 protein (P-1) extracted from the rubber tree Hevea brasiliensis. Furthermore, heterologous fibrin sealant (FS) has been shown as a promising alternative in regenerative therapies. The aim of this study was to evaluate these substances for the repair of bone defects in rats. A bone defect measuring 3mm in diameter was created in the proximal metaphysis of the left tibia of 60 rats and was implanted with rhBMP-2 or P-1 in combination with a new heterologous FS derived from snake venom. The animals were divided into six groups: control (unfilled bone defect), rhBMP-2 (defect filled with 5MUg rhBMP-2), P-1 (defect filled with 5MUg P-1), FS (defect filled with 8MUg FS), FS/rhBMP-2 (defect filled with 8MUg FS and 5MUg rhBMP-2), FS/P-1 (defect filled with 8MUg FS and 5MUg P-1). The animals were sacrificed 2 and 6 weeks after surgery. The newly formed bone projected from the margins of the original bone and exhibited trabecular morphology and a disorganized arrangement of osteocyte lacunae. Immunohistochemical analysis showed intense expression of osteocalcin in all groups. Histometric analysis revealed a significant difference in all groups after 2 weeks (p<0.05), except for the rhBMP-2 and FS/rhBMP-2 groups (p>0.05). A statistically significant difference (p<0.05) was observed in all groups after 6 weeks in relation to the volume of newly formed bone in the surgical area. In conclusion, the new heterologous fibrin sealant was found to be biocompatible and the combination with rhBMP-2 showed the highest osteogenic and osteoconductive capacity for bone healing. These findings suggest a promising application of this combination in the regeneration surgery. PMID- 25825119 TI - CXCR4 blockade attenuates hyperoxia-induced lung injury in neonatal rats. AB - BACKGROUND: Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal-derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. It is not known if antagonism of CXCR4 alleviates lung inflammation in neonatal hyperoxia-induced lung injury. OBJECTIVE: We aimed to determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. METHODS: Newborn rats exposed to normoxia (room air, RA) or hyperoxia (FiO2 = 0.9) from postnatal day 2 (P2) to P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis and inflammation were evaluated at P16. RESULTS: Compared to the RA pups, hyperoxic PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in the macrophage and neutrophil counts in the bronchoalveolar lavage fluid and reduced lung myeloperoxidase activity. CONCLUSION: CXCR4 antagonism decreases lung inflammation and improves alveolar and vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD. PMID- 25825120 TI - Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms. AB - Breast cancers with BRCA1 germline mutation have a characteristic DNA copy number (CN) pattern. We developed a test that assigns CN profiles to be 'BRCA1-like' or 'non-BRCA1-like', which refers to resembling a BRCA1-mutated tumor or resembling a tumor without a BRCA1 mutation, respectively. Approximately one third of the BRCA1-like breast cancers have a BRCA1 mutation, one third has hypermethylation of the BRCA1 promoter and one third has an unknown reason for being BRCA1-like. This classification is indicative of patients' response to high dose alkylating and platinum containing chemotherapy regimens, which targets the inability of BRCA1 deficient cells to repair DNA double strand breaks. We investigated whether this classification can be reliably obtained with next generation sequencing and copy number platforms other than the bacterial artificial chromosome (BAC) array Comparative Genomic Hybridization (aCGH) on which it was originally developed. We investigated samples from 230 breast cancer patients for which a CN profile had been generated on two to five platforms, comprising low coverage CN sequencing, CN extraction from targeted sequencing panels (CopywriteR), Affymetrix SNP6.0, 135K/720K oligonucleotide aCGH, Affymetrix Oncoscan FFPE (MIP) technology, 3K BAC and 32K BAC aCGH. Pairwise comparison of genomic position-mapped profiles from the original aCGH platform and other platforms revealed concordance. For most cases, biological differences between samples exceeded the differences between platforms within one sample. We observed the same classification across different platforms in over 80% of the patients and kappa values of at least 0.36. Differential classification could be attributed to CN profiles that were not strongly associated to one class. In conclusion, we have shown that the genomic regions that define our BRCA1-like classifier are robustly measured by different CN profiling technologies, providing the possibility to retro- and prospectively investigate BRCA1-like classification across a wide range of CN platforms. PMID- 25825121 TI - Sedative-hypnotic medicines and falls in community-dwelling older adults: a cost effectiveness (decision-tree) analysis from a US Medicare perspective. AB - BACKGROUND: Both the 2012 Beers list and the American Geriatric Society 'Choosing Wisely' campaign suggest restraint in the use of sedative-hypnotics for the treatment of insomnia in older people. Sedative hypnotic agents continue to be widely prescribed even though their use in the elderly is associated with an increased risk of falls, fractures, and emergency hospitalizations. OBJECTIVE: The aim of this study was to estimate the cost effectiveness of cognitive behavioral therapy (CBT) compared with sedative-hypnotics and no treatment for insomnia in the US Medicare population, adjusting for the risk of falls and related consequences. METHODS: A model-based economic evaluation (decision tree) using the US Medicare perspective and a conservative annual temporal framework was conducted. Simulations were performed in a hypothetical cohort of Medicare beneficiaries suffering from insomnia. The main outcome measure was the incremental cost per quality-adjusted life year (QALY) gained. Sensitivity analyses assessed the robustness of the base-case analysis. RESULTS: On an annual basis, CBT showed a dominance (cost: US$19,442; QALYs: 0.594) over sedative hypnotics (cost: US$32,452; QALYs: 0.552) and no treatment (cost: US$33,853; QALYs: 0.517). Assuming a willingness to pay of US$50,000, the net monetary benefit was positive for CBT (US$10,287) and negative for sedative hypnotics ( US$4,851) and no treatment (-US$7,993). CBT had a 95% chance of being the dominant strategy, with results most sensitive to an older adult's baseline risk of falling. CONCLUSION: Failure to consider drug harms such as drug-induced falls and hospitalization represents a growing public health concern, significantly underestimating the cost of sedative-hypnotic therapy and loss in quality of life for the elderly. Public payers should reconsider reimbursement of sedative hypnotic drugs as first-line treatment for insomnia in older adults. PMID- 25825122 TI - Sulfonylurea use and risk of hip fractures among elderly men and women with type 2 diabetes. AB - BACKGROUND: Both increased age and type 2 diabetes mellitus are risk factors for developing bone fractures. While recent data in the elderly suggest a link between hypoglycemia and fall-related fractures, the association between sulfonylureas, commonly used hypoglycemic agents, and fracture risk has not been well investigated. METHODS: We used patient data from a large commercial health insurer from 2002-2005. Individuals aged >=65 years receiving oral sulfonylurea treatment (n=13,195) were matched 1:1 to non-users based on propensity for sulfonylurea use. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CIs). RESULTS: During an average 4 years of follow-up, sulfonylurea users experienced 226 incident hip fractures (1.7%) and non-users experienced 157 (1.2%). Sulfonylurea use was associated with increased risk of developing hip fracture (aOR 1.46, 95% CI 1.17-1.82), and this association was apparent for men (120 cases; aOR 1.83, 95% CI 1.25-2.66) and women (263 cases; aOR 1.32, 95% CI 1.03-1.69). Patients with documented hypoglycemia in the follow-up period had increased odds of hip fracture relative to those without such diagnosis (aOR 2.42, 95% CI 1.35-4.34). CONCLUSION: Sulfonylureas are associated with increased risk of hip fracture in elderly men and women with type 2 diabetes. PMID- 25825123 TI - Optimal differentiated thyroid cancer management in the elderly. AB - The incidence of differentiated thyroid cancer is increasing worldwide across all age groups. While most patients with differentiated thyroid cancer have a good prognosis, aggressive disease is more common in the elderly and disease-specific mortality is higher. Treatment options for differentiated thyroid cancer include surgery, levothyroxine, radioactive iodine, external beam radiotherapy and kinase inhibitors. Rational and evidence-based management is particularly important in older individuals because they may experience greater toxicities from the therapeutic options. We advocate an explicit risk-benefit analytic approach to thyroid cancer care that emphasises individual patient factors, likely disease biology and progression, and age-dependent treatment characteristics to ensure optimal treatment. In particular, this risk-benefit approach should seek to identify patients with aggressive disease, and, within a multidisciplinary setting, balance the likelihood of treatment success with the probability of treatment-related adverse effects. PMID- 25825126 TI - Accumulation of rare variants in the arylsulfatase G (ARSG) gene in task-specific dystonia. AB - Musician's dystonia and writer's cramp are examples of task-specific dystonia. Recently, the arylsulfatase G (ARSG) locus was suggested to be associated with musician's dystonia and writer's cramp by a genome-wide association study. To test for the presence of causal variants, the entire coding region and exon intron boundaries of ARSG were sequenced in DNA samples from 158 musician's dystonia patients which were collected at the University of Music, Drama, and Media (Hanover, Germany), and 72 patients with writer's cramp which were recruited at the Academic Medical Centers in Amsterdam and Groningen, the Netherlands. The frequency of variants within ARSG was compared to publically available data at the exome variant server (EVS) from the NHLBI GO Exome Sequencing Project. We identified 11 single nucleotide variants (SNVs) in the patients including eight non-synonymous substitutions. All variants have previously been reported at EVS including two SNVs with a reported minor allele frequency <1%. One rare missense variant, rs61999318 (p.I493T), was significantly enriched in the group of writer's cramp patients compared to European Americans in EVS database (p = 0.0013). In patients with writer's cramp, there was an overall enrichment for rare, protein-changing variants compared to controls (p < 0.01). In conclusion, we did not detect any conclusive mutation in ARSG. However, we showed an association with rs61999318 in patients with writer's cramp that contributed to an overall enrichment for rare, protein-changing variants in these patients. Thus, our data provide further support for a role of ARSG variants in task-specific dystonia, especially writer's cramp. PMID- 25825125 TI - Isolated, subtle, neurological abnormalities in neurologically and cognitively healthy aging subjects. AB - The aim of this study is to describe the frequency of isolated, subtle, neurological abnormalities (ISNAs) in a large population of neurologically and cognitively healthy subjects and to compare ISNAs to various types of MRI detected cerebrovascular lesions and subcortical brain atrophy in different age classes. 907 subjects were selected from a large, prospective hospital-based study. At baseline neurological examination, 17 ISNAs were selected. Primitive reflexes were the most common ISNAs (35.8%), while dysphagia was the most rarely encountered (0.3%). Measures of small vessel disease, i.e., deep and subcortical white matter hyperintensity and lacunar infarcts as well as subcortical atrophy, were variously associated with ISNAs. In the adult group, the ISNAs were associated with hypertriglyceridemia, TIA, and subcortical lacunar infarcts, while in the elderly-old group they were associated with arterial hypertension, subcortical white matter hyperintensity, and subcortical atrophy. An increased risk of ISNAs was associated with lacunae and white matter hyperintensity in the parietal region. This study shows that white matter hyperintensity, lacunae, and subcortical atrophy are associated with an increased risk of ISNAs in cognitively and neurologically healthy aging subjects. ISNAs are not benign signs. Therefore, adults and elderly people presenting with ISNAs should have access to accurate history and diagnosis to prevent progression of small vessel disease and future neurological and cognitive disabilities. PMID- 25825124 TI - Oral health-related quality of life before hematopoietic stem cell transplantation. AB - OBJECTIVES: This study was planned to evaluate the impact of oral health on the quality of life (QoL) of patients undergoing hematopoietic stem cell transplantation (HSCT). MATERIAL AND METHODS: We assessed 200 patients divided into two paired groups: 100 patients prior to HSCT (SG) and 100 healthy volunteers (CG). We applied the Oral Health Impact Profile instrument, which is based on the biopsychosocial problem gradation of World Health Organization (WHO) and relates oral health problems with QoL according to seven dimensions. RESULTS: Fourteen patients in SG were referred for extraction of one to eight teeth, mostly due to deep caries with risk of pulpal infection and possible spread of infection via blood (r = 0.59, p = 0.000). The presence of severely compromised teeth by extensive decay correlated with Oral Health Impact Profile (OHIP-14). The Mann-Whitney test showed a significant difference between SG and CG in the following dimensions: functional limitation (p < 0.001), physical pain (p = 0.025), physical disability (p = 0.016), and social disability (p = 0.01). CONCLUSIONS: The impact of oral health on QoL of onco-hematologic patients is weak but is greater as compared to healthy ones. Nevertheless, a significant impact is seen in patients with severely compromised teeth. CLINICAL RELEVANCE: The negligence of oral care, proper hygiene, and the search for dental care may increase the risk for local and systemic infections. PMID- 25825127 TI - Bacteriophage predation promotes serovar diversification in Listeria monocytogenes. AB - Listeria monocytogenes is a bacterial pathogen classified into distinct serovars (SVs) based on somatic and flagellar antigens. To correlate phenotype with genetic variation, we analyzed the wall teichoic acid (WTA) glycosylation genes of SV 1/2, 3 and 7 strains, which differ in decoration of the ribitol-phosphate backbone with N-acetylglucosamine (GlcNAc) and/or rhamnose. Inactivation of lmo1080 or the dTDP-l-rhamnose biosynthesis genes rmlACBD (lmo1081-1084) resulted in loss of rhamnose, whereas disruption of lmo1079 led to GlcNAc deficiency. We found that all SV 3 and 7 strains actually originate from a SV 1/2 background, as a result of small mutations in WTA rhamnosylation and/or GlcNAcylation genes. Genetic complementation of different SV 3 and 7 isolates using intact alleles fully restored a characteristic SV 1/2 WTA carbohydrate pattern, including antisera reactions and phage adsorption. Intriguingly, phage-resistant L. monocytogenes EGDe (SV 1/2a) isolates featured the same glycosylation gene mutations and were serotyped as SV 3 or 7 respectively. Again, genetic complementation restored both carbohydrate antigens and phage susceptibility. Taken together, our data demonstrate that L. monocytogenes SV 3 and 7 originate from point mutations in glycosylation genes, and we show that phage predation represents a major driving force for serovar diversification and evolution of L. monocytogenes. PMID- 25825128 TI - The effects of arsenic exposure on blood pressure and early risk markers of cardiovascular disease: Evidence for population differences. AB - BACKGROUND: Exposure to inorganic arsenic has been identified as a risk factor for elevated blood pressure and cardiovascular disease. Our aim with this study was to elucidate effects of arsenic on blood pressure and early risk markers of cardiovascular disease in a population with efficient arsenic metabolism that can modify other arsenic-related health effects. METHODS: The study included 225 women in the northern Argentinean Andes. Exposure to arsenic was assessed by the sum of arsenic metabolite concentrations in urine. Blood pressure was measured in the supine position. Blood samples were collected for measurement of hemoglobin, homocysteine, triglycerides, apolipoproteins A and B, and cytokines in separated plasma. RESULTS: The median arsenic concentration in urine was 200 ug/L (range 22 545 ug/L). Unexpectedly, urinary arsenic concentrations were inversely associated with both systolic (p=0.081), and diastolic (p=0.002) blood pressure, and with the ratio of apolipoproteins B/A (p<0.001). There was no clear sign of increased inflammation, measured as cytokine concentrations, in relation to arsenic. Furthermore, urinary arsenic was associated with low hemoglobin concentrations (p<0.001). CONCLUSIONS: Our results show that arsenic exposure was not associated with elevated levels of early risk markers for cardiovascular disease in this population. This provides evidence that the effects of arsenic on risk of cardiovascular disease differ between populations, which needs to be taken into account in risk assessment. PMID- 25825129 TI - Toxicity evaluation of new agricultural fungicides in primary cultured cortical neurons. AB - Fungicides are crucial for food protection as well as for the production of crops of suitable quality and quantity to provide a viable economic return. Like other pesticides, fungicides are widely sprayed on agricultural land, especially in wine-growing areas, from where they can move-off after application. Furthermore, residues of these agrochemicals can remain on crops after harvest and even after some food processing operations, being a major exposure pathway. Although a relatively low toxicity has been claimed for this kind of compounds, information about their neurotoxicity is still scarce. In the present study, nine fungicides recently approved for agricultural uses in the EU - ametoctradin, boscalid, cyazofamid, dimethomorph, fenhexamid, kresoxim-methyl, mepanipyrim, metrafenone and pyraclostrobin - have been evaluated for their toxicity in primary cultured mouse cortical neurons. Exposure to 0.1-100uM for 7 days in vitro resulted in a dose-dependent toxicity in the MTT cell viability assay. Strobilurin fungicides kresoxim-methyl (KR) and pyraclostrobin (PY) were the most neurotoxic compounds (lethal concentration 50 were in the low micromolar and nanomolar levels, respectively) causing a rapid raise in intracellular calcium [Ca(2+)]i and strong depolarization of mitochondrial membrane potential. KR- and PY-induced cell death was reversed by the calcium channels blockers MK-801 and verapamil, suggesting that calcium entry through NMDA receptors and voltage-operated calcium channels are involved in KR- and PY-induced neurotoxicity. These results highlight the need for further evaluation of their neurotoxic effects in vivo. PMID- 25825130 TI - Physiologically-based pharmacokinetic modelling of immune, reproductive and carcinogenic effects from contaminant exposure in polar bears (Ursus maritimus) across the Arctic. AB - Polar bears (Ursus maritimus) consume large quantities of seal blubber and other high trophic marine mammals and consequently have some of the highest tissue concentrations of organohalogen contaminants (OHCs) among Arctic biota. In the present paper we carried out a risk quotient (RQ) evaluation on OHC-exposed polar bears harvested from 1999 to 2008 and from 11 circumpolar subpopulations spanning from Alaska to Svalbard in order to evaluate the risk of OHC-mediated reproductive effects (embryotoxicity, teratogenicity), immunotoxicity and carcinogenicity (genotoxicity). This RQ evaluation was based on the Critical Body Residue (CBR) concept and a Physiologically-Based Pharmacokinetic Modelling (PBPK) approach using OHC concentrations measured in polar bear adipose or liver tissue. The range of OHC concentrations within polar bear populations were as follows for adipose, sum polychlorinated biphenyls ?PCBs (1797-10,537 ng/g lw), sum methylsulphone-PCB ?MeSO2-PCBs (110-672 ng/g lw), sum chlordanes ?CHLs (765 3477 ng/g lw), alpha-hexachlorocyclohexane alpha-HCH (8.5-91.3 ng/g lw), beta hexachlorocyclohexane beta-HCH (65.5-542 ng/g lw), sum chlorbenzenes ?ClBzs (145 304 ng/g lw), dichlorodiphenyltrichloroethane ?DDTs (31.5-206 ng/g lw), dieldrin (69-249 ng/g lw), polybrominated diphenyl ethers ?PBDEs (4.6-78.4 ng/g lw). For liver, the perfluorooctanesulfonic acid (PFOS) concentrations ranged from 231 2792 ng/g ww. The total additive RQ from all OHCs ranged from 4.3 in Alaska to 28.6 in East Greenland bears for effects on reproduction, immune health and carcinogenicity, highlighting the important result that the toxic effect threshold (i.e. RQ>1) was exceeded for all polar bear populations assessed. PCBs were the main contributors for all three effect categories, contributing from 70.6% to 94.3% of the total risk and a RQ between 3.8-22.5. ?MeSO2-PCBs were the second highest effect contributor for reproductive and immunological effects (0.17=50 years of age. METHODS: We calculated 90th and 95th percentile estimates as well as geometric means of MeHg for predictive variables. We used multivariable linear regression analyses to estimate the proportional change in mean MeHg associated with each category of all predictive variables. We calculated the validity of screening procedures using fish consumption questions and TBHg testing to predict elevated MeHg. RESULTS: The geometric mean MeHg levels were highest among Asian WCBA (1.17 ug/L) and Asians >=50 years old (2.49 ug/L). Over 23% of Asian WCBA had levels >=3.5 ug/L and 25% of Asians >=50 years old had levels >=5.8 ug/L. Frequency of fish consumption explained 21-23% of the variation in MeHg. Twenty-five percent of women eating fish >= twice per week had MeHg >=3.5 ug/L. TBHg showed high validity for MeHg >=5.8 ug/L, and two-step screening using >=2 fish meals/month followed by TBHg also showed high validity. CONCLUSION: Asian WCBA continue to have increased MeHg exposure from fish consumption, putting their offspring at risk. Screening for MeHg among high-risk groups should be considered. PMID- 25825132 TI - Do airborne biogenic chemicals interact with the PI3K/Akt/mTOR cell signalling pathway to benefit human health and wellbeing in rural and coastal environments? AB - Living and taking recreation in rural and coastal environments promote health and wellbeing, although the causal factors involved are unclear. It has been proposed that such environments provide a counter to the stresses of everyday living, leading to enhanced mental and physical health. Living in natural environments will result in airborne exposure to a wide range of biogenic chemicals through inhalation and ingestion of airborne microbiota and particles. The "biogenics" hypothesis formulated here is that regular exposure to low concentrations of mixtures of natural compounds and toxins in natural environments confers pleiotropic health benefits by inhibiting the activities of interconnected cell signalling systems, particularly PI3K/Akt/mTORC1. When overactive, Akt and mTOR (mTORC1) can lead to many pathological processes including cancers, diabetes, inflammation, immunosuppression, and neurodegenerative diseases. There is a substantial body of evidence that many natural products (i.e., from bacteria, algae, fungi and higher plants) inhibit the activities of these protein kinases. Other mTOR-related interconnected metabolic control "switches" (e.g., PTEN & NF kappaB), autophagy and other cytoprotective processes are also affected by natural products. The "biogenics" hypothesis formulated here is that regular intermittent exposure to a mixture of airborne biogenic compounds in natural environments confers pleiotropic health benefits by inhibiting activities of the highly interconnected PI3K/Akt/mTORC1 system. It is proposed that future experimental exposures to biogenic aerosols in animal models coupled with epidemiology, should target the activities of the various kinases in the PI3K/Akt/mTORC1 systems and related physiological processes for selected urban, rural and coastal populations in order to test this hypothesis. PMID- 25825133 TI - Hypoglossal nerve paralysis results in hypermetabolic activity on positron emission tomography/computed tomography in the contralateral tongue. AB - False-positive results on combined positron emission tomography/computed tomography can complicate detection and surveillance of head and neck cancers. We present a rare case of false-positive contralateral [18F]-2-fluoro-2-deoxy-D glucose tongue uptake after hypoglossal nerve paralysis caused by squamous cell carcinoma originating from the base of the tongue. PMID- 25825136 TI - Drop sign of the elbow joint after surgical stabilization of an unstable simple posterolateral dislocation: natural course and contributing factors. AB - BACKGROUND: We performed this study to investigate the natural course and factors affecting the incidence of drop sign immediately after stabilization of an unstable posterolateral (PL) dislocation of the elbow. METHODS: Twenty-three patients who underwent a stabilization procedure for persistent instability after closed reduction of PL dislocation of the elbow were enrolled. The natural course was evaluated with simple radiographs taken at regular intervals after the operation. Primary repair of medial or lateral ligaments and overlying muscles, degree of adjacent muscle injury, and type of anesthesia were analyzed to determine their relationship to postoperative drop sign. Functional outcomes were evaluated by the Disabilities of the Arm, Shoulder, and Hand score and Mayo Elbow Performance Score. RESULTS: A postoperative drop sign was observed in 4 cases (17%) and resolved within 1 week after the operation. There was no significant relationship between preoperative factors and drop sign except method of anesthesia. All drop signs were found in patients who had received a regional block (P = .006). There were no statistically significant differences in functional outcome between the drop sign group and the non-drop sign group. CONCLUSIONS: A postoperative drop sign was observed in 17% of patients who underwent a surgical stabilization procedure for an unstable PL elbow dislocation; this sign spontaneously disappeared in all 4 patients within 1 week of the operation. The drop sign was possibly caused by delayed return of muscle tone. A postoperative drop sign did not indicate the need to perform an additional stabilization procedure, nor did it affect postoperative functional outcome. PMID- 25825135 TI - Treatment of humeral shaft fractures using antegrade nailing: functional outcome in the shoulder. AB - BACKGROUND: The purpose of this study was to evaluate shoulder outcomes and function after humeral shaft fractures treated with antegrade nailing. MATERIALS AND METHODS: Thirty patients with acute humeral shaft fractures who underwent antegrade locked intramedullary nailing were retrospectively studied. Range of motion (ROM) of the affected shoulder was evaluated, comparing it with the nonaffected shoulder, radiologic position of the nails, complications, and need for a second surgery. RESULTS: The study enrolled 20 men and 10 women (average age, 41.9 years). The average follow-up was 35.8 months. The average shoulder elevation averaged 157 degrees , internal rotation was variable (reaching the sacroiliac joint to T7), and external rotation averaged 75 degrees . Elbow flexion-extension ROM averaged 133 degrees (115 degrees -145 degrees ). According to the Rodriguez-Merchan criteria, 12 patients achieved excellent results (40%), 7 good (20%), and 6 fair (23.3%); poor results were found in 5 cases (16.6%). Twelve patients achieved full mobility of the shoulder, whereas 18 had some loss of motion, with significant differences between the affected and nonaffected shoulders (P = .001). CONCLUSION: Decreased shoulder ROM is common after antegrade nailing of humeral shaft fractures. Avoidance of nail impingement can improve final outcomes. PMID- 25825134 TI - Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene. AB - Protein adduction is considered to be critical to the loss of cellular homeostasis associated with environmental chemicals undergoing metabolic activation. Despite considerable effort, our understanding of the key proteins mediating the pathologic consequences from protein modification by electrophiles is incomplete. This work focused on naphthalene (NA) induced acute injury of respiratory epithelial cells and tolerance which arises after multiple toxicant doses to define the initial cellular proteomic response and later protective actions related to tolerance. Airways and nasal olfactory epithelium from mice exposed to 15 ppm NA either for 4 h (acute) or for 4 h/day * 7 days (tolerant) were used for label-free protein quantitation by LC/MS/MS. Cytochrome P450 2F2 and secretoglobin 1A1 are decreased dramatically in airways of mice exposed for 4 h, a finding consistent with the fact that CYPs are localized primarily in Clara cells. A number of heat shock proteins and protein disulfide isomerases, which had previously been identified as adduct targets for reactive metabolites from several lung toxicants, were upregulated in airways but not olfactory epithelium of tolerant mice. Protein targets that are upregulated in tolerance may be key players in the pathophysiology associated with reactive metabolite protein adduction. All MS data have been deposited in the ProteomeXchange with identifier PXD000846 (http://proteomecentral.proteomexchange.org/dataset/PXD000846). PMID- 25825137 TI - The role of an octacalcium phosphate in the re-formation of infraspinatus tendon insertion. AB - BACKGROUND: To improve the success rate of rotator cuff repair, we investigated whether octacalcium phosphate (OCP) with gelatin (Gel) vehicle had a positive effect on tendon-to-bone healing. METHODS: We assessed the histologic characteristics of the tendon-to-bone healing using the rabbit rotator cuff repair model. We divided the shoulders into 3 groups: control (without OCP/Gel composite), OCP/Gel composite (OCP+group), and Gel alone without OCP (Gel group) to evaluate the effectiveness of gelatin. RESULTS: Both the number of newly formed tendon fibers and the Sharpey fibers at the repair site increased in the OCP+group compared with those in the other 2 groups on hematoxylin-eosin staining (P < .05). On immunohistochemical evaluation, both the bone and the fibers in the OCP+group demonstrated that type I collagen was picked up, whereas the newly formed tendon fibers and Sharpey fibers revealed type III collagen. CONCLUSION: Treatment with OCP made collagen fibers and the Sharpey fibers, constituted by type I and type III collagens, increase at the tendon-to-bone insertion. It might be beneficial for the healing of rotator cuff tendon to bone. PMID- 25825138 TI - Compressive cryotherapy versus ice-a prospective, randomized study on postoperative pain in patients undergoing arthroscopic rotator cuff repair or subacromial decompression. AB - BACKGROUND: The purpose of this study was to compare the effect of compressive cryotherapy (CC) vs. ice on postoperative pain in patients undergoing shoulder arthroscopy for rotator cuff repair or subacromial decompression. A commercial device was used for postoperative CC. A standard ice wrap (IW) was used for postoperative cryotherapy alone. METHODS: Patients scheduled for rotator cuff repair or subacromial decompression were consented and randomized to 1 of 2 groups; patients were randomized to use either CC or a standard IW for the first postoperative week. All patients were asked to complete a "diary" each day, which included visual analog scale scores based on average daily pain and worst daily pain as well as total pain medication usage. Pain medications were then converted to a morphine equivalent dosage. RESULTS: Forty-six patients completed the study and were available for analysis; 25 patients were randomized to CC and 21 patients were randomized to standard IW. No significant differences were found in average pain, worst pain, or morphine equivalent dosage on any day. CONCLUSION: There does not appear to be a significant benefit to use of CC over standard IW in patients undergoing shoulder arthroscopy for rotator cuff repair or subacromial decompression. Further study is needed to determine if CC devices are a cost-effective option for postoperative pain management in this population of patients. PMID- 25825139 TI - Three-dimensional analysis versus goniometric measurement of total active elevation in normal subjects. AB - BACKGROUND: Multiple planes of motion have been reported for shoulder elevation performed by visual inspection with a goniometer. It is typically measured by a clinician who is standing or sitting at the side of the patient. Instead, accurate assessment of shoulder elevation must be performed by using a plane of reference that is perpendicular to the plane of motion being measured. METHODS: Three repetitions of humeral elevation in the sagittal, scapular, and coronal planes were performed in a random order and measured by goniometry and three dimensional (3D) electromagnetic sensors. A guide bar was used to control the initial plane of motion for the sagittal and coronal planes. The plane of motion at 90 degrees and at peak elevation was recorded for each of the 3 defined planes. A goniometer was used to measure the range of maximal elevation performed in each plane, for each subject, by visual inspection. RESULTS: The 3D data revealed that subjects consistently moved toward scaption as the extremity moved above 90 degrees of elevation, regardless of the initial plane of motion. Significant differences were seen in the goniometric data for the plane of motion at 90 degrees (P = .00) in flexion, abduction, and scaption. Goniometric measurements revealed greater maximum elevation angles in comparison to the 3D kinematic measurements. CONCLUSIONS: Maximal glenohumeral elevation occurred near the plane of the scapula in all subjects, regardless of the plane in which elevation was initiated. Goniometric measurement of total elevation resulted in greater range of motion measurements than actually occurred because the observer was not routinely positioned in a plane perpendicular to the plane of actual elevation of the upper extremity. PMID- 25825140 TI - Alteration and recovery of arm usage in daily activities after rotator cuff surgery. AB - BACKGROUND: The objective measurement of dominant/nondominant arm use proportion in daily life may provide relevant information on healthy and pathologic arm behavior. This prospective case-control study explored the potential of such measurements as indicators of upper limb functional recovery after rotator cuff surgery. METHODS: Data on dominant/nondominant arm usage were acquired with body worn sensors for 7 hours. The postsurgical arm usage of 21 patients was collected at 3, 6, and 12 months after rotator cuff surgery in the sitting, walking, and standing postures and compared with a reference established with 41 healthy subjects. The results were calculated for the dominant and nondominant surgical side subgroups at all stages. The correlations with clinical scores were calculated. RESULTS: Healthy right-handed and left-handed dominant arm usage was 60.2% (+/-6.3%) and 53.4% (+/-6.6%), respectively. Differences in use of the dominant side were significant between the right- and left-handed subgroups for sitting (P = .014) and standing (P = .009) but not for walking (P = .328). The patient group showed a significant underuse of 10.7% (+/-8.9%) at 3 months after surgery (P < .001). The patients recovered normal arm usage within 12 months, regardless of surgical side. The arm underuse measurement was weakly related to function and pain scores. CONCLUSION: This study provided new information on arm recovery after rotator cuff surgery using an innovative measurement method. It highlighted that objective arm underuse measurement is a valuable indicator of upper limb postsurgical outcome that captures a complementary feature to clinical scores. PMID- 25825142 TI - Retraction note: Investigation of the hub genes and related mechanism in ovarian cancer via bioinformatics analysis. AB - The Publisher and Editor regretfully retract this article (Fu LJ, Wang B. Investigation of the hub genes and related mechanism in ovarian cancer via bioinformatics analysis. J Ovarian Res. 2013;6:92.) because the peer-review process was inappropriately influenced and compromised. As a result, the scientific integrity of the article cannot be guaranteed. A systematic and detailed investigation suggests that a third party was involved in supplying fabricated details of potential peer reviewers for a large number of manuscripts submitted to different journals. In accordance with recommendations from COPE we have retracted all affected published articles, including this one. It was not possible to determine beyond doubt that the authors of this particular article were aware of any third party attempts to manipulate peer review of their manuscript. PMID- 25825141 TI - Anti-proliferative effects of qianliening capsules on prostatic hyperplasia in vitro and in vivo. AB - Previous studies by our group showed that Qianliening capsules (QC), a clinically proven effective traditional Chinese formulation that has long been used in the treatment of benign prostatic hyperplasia (BPH), is capable of inhibiting BPH in vivo and in vitro via the promotion of apoptosis, suppression of the EGFR/STAT3 signaling pathway and regulating the expression of sex hormones as well as their receptors. However, the mechanism of its anti-BPH activity has remained to be fully elucidated. The present study aimed to investigate the mechanism underlying the anti-proliferative effect of QC in vivo and in vitro. Castrated male Sprage Dawley (SD) rats where subcutaneously injected with testosterone propionate and the WPMY-1 cell line was stimulated with basic fibroblast growth factor in order to generate BPH in vivo and in vitro separately, both of which were then subjected to QC treatment. Finasteride was used as a positive control drug for the in vivo study. In the present study, it was found that treatment with QC or finasteride significantly reduced the prostatic index (PI=prostate wet weight/body weight x 100) in a rat model of BPH (P<0.05). In addition, reverse transcription quantitative polymerase chain reaction (RT-PCR) and western blot analyses showed that QC or finasteride treatment significantly inhibited model construction-induced upregulation of expression of proliferating cell nuclear antigen, cyclin D1 and cyclin-dependent kinase 4 in prostatic tissues of rats with BPH (P<0.05). The in vitro study further proved that QC exhibited anti proliferative properties via G1/S cell cycle arrest in the WPMY-1 cell line, as evidenced by colony formation, flow cytometric cell cycle, immunoblot and RT-PCR analyses. In conclusion, the present study demonstrated that inhibition of cell proliferation via G1/S cell cycle arrest may be one of the underlying mechanisms of the effect of QC on BPH. PMID- 25825143 TI - Fucosylated chondroitin sulphate from Cusumaria frondosa mitigates hepatic endoplasmic reticulum stress and inflammation in insulin resistant mice. AB - Endoplasmic reticulum (ER) stress-associated inflammation positively contributes to insulin resistance. It is also known that fucosylated chondroitin sulphate from Cusumaria frondosa (Cf-CHS) can mitigate insulin resistance; however, its effects on ER stress and inflammation are not well understood. Therefore, we investigated whether Cf-CHS-influenced ER stress, inflammatory response and signaling in insulin-resistant mice. Our results showed that Cf-CHS lowered serum and hepatic ROS, NO, and FFA levels. Furthermore, Cf-CHS decreased serum proinflammatory cytokines TNF-alpha, CRP, MIP-1, IL-1beta and IL-6 concentrations as well as their hepatic mRNA expression, and increased the anti-inflammatory cytokine IL-10 levels. Moreover, Cf-CHS reduced the ER stress markers Bip, ATF6, PERK, and XBP1 mRNA or protein expression, and PERK, eIF2alpha, and IRE1alpha phosphorylation. These reductions were accompanied by a reduced activation of JNK1 and IKKbeta, NFkappaB nuclear translocation, and IR/IRS-2 serine phosphorylation in Cf-CHS-treated mice. These findings suggested that the Cf-CHS supplementary-induced alleviation of RE stress-associated inflammation could be the mechanism responsible for its beneficial effects against insulin resistance. PMID- 25825144 TI - A Study of Association Between Oral Lichen Planus and Immune Balance of Th1/Th2 Cells. AB - The aims of this study are to investigate the key role of Th1 and Th2 in the pathogenesis of oral lichen planus (OLP) and to explore the possible association between OLP and immune balance of Th1/Th2 cells. We selected 35 patients diagnosed with OLP and 35 age- and sex-matched controls as subjects. The expressed level of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) and the characteristic cytokines of Th1 and Th2 were assayed in the serum of peripheral blood of the patients. The lesional tissue of the two groups was investigated with the methods of double immunofluorescence. The ratio of Th1/Th2 was evaluated, and the difference of the results between serum and lesional tissue was compared. Both IFN-gamma and IL-4 levels increased in the serum and lesional tissue compared with those of the controls (P < 0.001, P = 0.030, P < 0.001, and P < 0.001) and IFN-gamma/IL-4 ratio of OLP patients, which increased significantly (P = 0.001 and P = 0.003). The difference between serum and lesional tissue was obviously insignificant (P = 0.982). Th1 cytokine predominance was proven in this research on Chinese subjects. Th1 cells may play leading roles on Th1/Th2 immune balance to pathogenesis of OLP. PMID- 25825146 TI - Histopathological findings and detection of Toll-like receptor 2 in cutaneous lesions of canine leishmaniosis. AB - A broad spectrum of clinical manifestations ranging from a chronic subclinical infection to a non-self-limiting illness has been described for canine leishmaniosis (CanL). This clinical variation is determined by a variable immune response, presumably genetically determined, against the infection. Although different types of adaptive immune response in dogs with CanL have been investigated in several studies, the mechanisms that underlie and determine this variability are still poorly understood. It is currently thought that innate immune response, and particularly the role of specific mediators of the innate immune system, such as toll-like receptors (TLRs), plays a central role in this polarization. However, there is limited data available concerning the role that TLRs play in canine Leishmania infantum infection. The objective of this descriptive study was to characterize and compare the inflammatory pattern, the Leishmania burden and expression of TLR2 in skin lesions derived from dogs with different clinical stages of leishmaniosis and cutaneous lesions. Routine histology, Leishmania and TLR2 immunohistochemistry assays were performed in 11 patients with papular dermatitis (stage I - mild disease) and 10 patients with other cutaneous lesions (stage II-III - moderate to severe disease). A significantly higher frequency of granuloma formation was demonstrated in skin samples of dogs with stage I when compared with dogs of stage II-III. Although not statistically significant, a trend for a lower parasite burden was observed for skin lesions of dogs with stage I when compared with dogs of stage II-III. A lower expression of TLR2 in skin biopsies from dogs with stage I was statistically significant compared with stage II-III. The results obtained in this study indicated an association with TLR2 in the pathogenesis of canine cutaneous leishmaniosis. Further studies are required to fully elucidate these findings. PMID- 25825147 TI - Temporal genetic variation of Fasciola hepatica from sheep in Galicia (NW Spain). AB - We found low genetic differentiation between two temporal samples of Fasciola hepatica (2006 and 2008) collected from nine sheep of the same flock that shared the same pasture for at least 2 years. However, each sample, represented by four and five infrapopulations respectively, showed strong heterozygote deficits regarding Hardy-Weinberg expectations and a high degree of genetic structure at infrapopulation level. This is an unexpected result since genetic drift should increase temporal variation among years. Our findings are most likely explained by the fact that the parasite can survive many years in the definitive host. Temporal gene flow favored by high longevity probably increases levels of genetic variability of the population but could also contribute to the observed heterozygote deficits within temporal samples and infrapopulations if it favors the Wahlund effect. Despite the homogenizing effect of gene flow, the high genetic divergence observed between infrapopulations is most likely a consequence of strong genetic drift associated to the complexity of the life cycle. PMID- 25825148 TI - Type 2 diabetes in youth. AB - Since the 1990s, concerns about a global obesity epidemic have flourished. These concerns regarding obesity are expressed in popular culture and scientific literature and emphasize both weight and weight loss when defining health and well-being. As a result scholars are now calling attention to a "shadow epidemic" of weight stigma that is shown to have harmful physiological and psychological impacts in youth. In tandem with "globesity" concerns, there has been a similar concern expressed over the epidemic of type 2 diabetes, which some have termed "diabesity." Although there is less known about diabetes stigma, the topic has much overlap with obesity stigma. In this narrative review we discuss the related problems of obesity and type 2 diabetes stigma, with an emphasis on issues specific to youth, as relevant. Drawing from literature on weight bias, critical weight studies, and Health at Every Size (HAES), we highlight pedagogical approaches to address obesity stigma and their implications to redress the problem of type 2 diabetes-related stigma in health care. PMID- 25825149 TI - Ultrasound assisted synthesis of methyl butyrate using heterogeneous catalyst. AB - Ultrasound assisted esterification of butyric acid with methanol was investigated in an ultrasound irradiated isothermal batch reactor using acid ion-exchange resin (amberlyst-15) as a catalyst. Effect of parameters such as temperature (323 353 K), catalyst loading (0-8.5%w/w), alcohol to acid ratio, M (2-6), ultrasound power (0-145 W), duty cycle (0-85%) and amount of molecular sieves added (0 11%w/w) on the rate of reaction was studied. At optimized parameters, a maximum conversion of 91.64% was obtained in 120 min in presence of ultrasound. Experimental kinetic data were correlated by using Eley-Rideal (ER) and Langmuir Hinshelwood-Hougen-Watson (LHH W) models taking into account reverse reaction. Studies showed that single site LHHW with reactants and products both adsorbing on catalyst surface was most suited for the obtained experimental data. Activation energy determined based on heterogeneous kinetics was in the range 49.31-57.54 kJ/mol while it was 18.29 kJ/mol using homogeneous model. PMID- 25825150 TI - Association of Inadequate Health Literacy with Health Outcomes in Patients with Type 2 Diabetes and Depression: Secondary Analysis of a Controlled Trial. AB - OBJECTIVE: To examine the relationship of inadequate health literacy (HL) with changes in depressive symptoms, health-related quality of life and cardiometabolic outcomes in patients with type 2 diabetes mellitus recently screened positive for depression. METHODS: Secondary analysis of data from a clinical trial (N=154) that compared a collaborative team care model and enhanced usual care for primary care for patients with type 2 diabetes and depression. The exposure of interest was inadequate HL, defined as a total summative score of 9 or more on the 3 brief screening questions. Outcomes of interest were differences in the changes in depressive symptoms (Patient Health Questionnaire-9 (PHQ-9) at 12 months, health-related quality of life (short-form health survey 12 [SF-12]) and European Quality of Life-5 Dimensions questionnaire (EQ-5D), glycemic control (A1C), low-density lipoprotein cholesterol and systolic blood pressure. RESULTS: The average age of patients was 58 years; 56% were women and were predominantly white. Only a small proportion (n=24; 16%) had inadequate HL. In adjusted random effects models, there were no statistically significant or clinically important differences in all outcomes between the HL groups. The between-group differences in change over 1 year were -0.55 points for PHQ-9; 0.76 points for physical and 0.56 points for mental summaries of the SF-12; 0.03 points for EQ-5D; -0.17 for A1C; -0.08 mmol/L for low-density lipoprotein; and -1.94 mm Hg for systolic blood pressure. CONCLUSIONS: Among primary care patients with type 2 diabetes who had been screened recently as being positive for depression, it is unlikely that HL impacts health outcomes over 1 year. PMID- 25825152 TI - STAT3 the oncogene - still eluding therapy? AB - The STAT family of transcription factors (signal transducers and activators of transcription) transduce signals from cytokine receptors to the nucleus, where STAT dimers bind to DNA and regulate transcription. STAT3 is the most ubiquitous of the STATs, being activated by a wide variety of cytokines and growth factors. STAT3 has many roles in physiological processes such as inflammatory signalling, aerobic glycolysis and immune suppression, and was also the first family member shown to be aberrantly activated in a wide range of both solid and liquid tumours. STAT3 promotes tumorigenesis by regulating the expression of various target genes, including cell-cycle regulators, angiogenic factors and anti apoptosis genes. Paradoxically, in some circumstances, STAT3 signalling induces cell death. The best known example is the involuting mammary gland, where STAT3 is essential for induction of a lysosomal pathway of cell death. Nevertheless, direct silencing or inhibition of STAT3 diminishes tumour growth and survival in both animal and human studies. This suggests that abolishing STAT3 activity may be an effective cancer therapeutic strategy. However, despite this potential as a therapeutic target, and the extensive attempts by many laboratories and pharmaceutical companies to develop an effective STAT3 inhibitor for use in the clinic, no direct STAT3 inhibitor has been approved for clinical use. In this review, we focus on the role of STAT3 in tumorigenesis, and discuss its potential as a therapeutic target for cancer treatment. PMID- 25825153 TI - The groningen laryngomalacia classification system--based on systematic review and dynamic airway changes. AB - OBJECTIVE: Laryngomalacia is the most common cause of dyspnea and stridor in newborn infants. Laryngomalacia is a dynamic change of the upper airway based on abnormally pliable supraglottic structures, which causes upper airway obstruction. In the past, different classification systems have been introduced. Until now no classification system is widely accepted and applied. Our goal is to provide a simple and complete classification system based on systematic literature search and our experiences. STUDY DESIGN: Retrospective cohort study with literature review. METHODS: All patients with laryngomalacia under the age of 5 at time of diagnosis were included. Photo and video documentation was used to confirm diagnosis and characteristics of dynamic airway change. Outcome was compared with available classification systems in literature. RESULTS: Eighty five patients were included. In contrast to other classification systems, only three typical different dynamic changes have been identified in our series. Two existing classification systems covered 100% of our findings, but there was an unnecessary overlap between different types in most of the systems. Based on our finding, we propose a new a classification system for laryngomalacia, which is purely based on dynamic airway changes. CONCLUSION: The groningen laryngomalacia classification is a new, simplified classification system with three types, based on purely dynamic laryngeal changes, tested in a tertiary referral center: Type 1: inward collapse of arytenoids cartilages, Type 2: medial displacement of aryepiglottic folds, and Type 3: posterocaudal displacement of epiglottis against the posterior pharyngeal wall. PMID- 25825154 TI - DEAD-box helicase DDX27 regulates 3' end formation of ribosomal 47S RNA and stably associates with the PeBoW-complex. AB - PeBoW, a trimeric complex consisting of pescadillo (Pes1), block of proliferation (Bop1), and the WD repeat protein 12 (WDR12), is essential for processing and maturation of mammalian 5.8S and 28S ribosomal RNAs. Applying a mass spectrometric analysis, we identified the DEAD-box helicase DDX27 as stably associated factor of the PeBoW-complex. DDX27 interacts with the PeBoW-complex via an evolutionary conserved F*F motif in the N-terminal domain and is recruited to the nucleolus via its basic C-terminal domain. This recruitment is RNA dependent and occurs independently of the PeBoW-complex. Interestingly, knockdown of DDX27, but not of Pes1, induces the accumulation of an extended form of the primary 47S rRNA. We conclude that DDX27 can interact specifically with the Pes1 and Bop1 but fulfils critical function(s) for proper 3' end formation of 47S rRNA independently of the PeBoW-complex. PMID- 25825156 TI - Nitrogen deficiency hinders etioplast development in stems of dark-grown pea (Pisum sativum) shoot cultures. AB - The effects of nitrogen (N) deprivation were studied in etiolated pea plants (Pisum sativum cv. Zsuzsi) grown in shoot cultures. The average shoot lengths decreased and the stems significantly altered considering their pigment contents, 77 K fluorescence spectra and ultrastructural properties. The protochlorophyllide (Pchlide) content and the relative contribution of the 654-655 nm emitting flash photoactive Pchlide form significantly decreased. The etioplast inner membrane structure characteristically changed: N deprivation correlated with a decrease in the size and number of prolamellar bodies (PLBs). These results show that N deficiency directly hinders the pigment production, as well as the synthesis of other etioplast inner membrane components in etiolated pea stems. PMID- 25825155 TI - Lysophospholipid mediators in the vasculature. PMID- 25825158 TI - Biochemical markers subtyping major depressive disorder. AB - The pathophysiology of major depressive disorder (MDD) remains elusive, and there is no established biochemical marker used in the daily clinical setting. This situation may result in part from the heterogeneity of MDD, which might include heterogeneous subgroups with different biological mechanisms. In this review, we discuss three promising biological systems/markers to potentially subtype MDD: the dopamine system, the hypothalamic-pituitary-adrenal axis, and chronic inflammatory markers. Several lines of evidence suggest that a facet of MDD is a dopamine agonist-responsive subtype. Focusing on the hypothalamic-pituitary adrenal axis, depressive spectrum disorders show hypercortisolism to hypocortisolism, which could be detected by hormonal challenge tests, such as the dexamethasone/corticotrophin-releasing hormone test. Finally, accumulating evidence suggests that at least some MDD patients show characteristics similar to those of chronic inflammatory diseases, including neuroinflammatory markers and reduced tryptophan due to the increased activation of the tryptophan-kynurenine pathway. Future studies should examine the inter-relations between these systems/markers to subtype and integrate the pathophysiology of MDD. PMID- 25825157 TI - Cathodic Electrical Stimulation Combined With Vancomycin Enhances Treatment of Methicillin-resistant Staphylococcus aureus Implant-associated Infections. AB - BACKGROUND: Effective treatments for implant-associated infections are often lacking. Cathodic voltage-controlled electrical stimulation has shown potential as a treatment of implant-associated infections of methicillin-resistant Staphylococcus aureus (MRSA). QUESTIONS/PURPOSES: The primary purpose of this study was to (1) determine if cathodic voltage-controlled electrical stimulation combined with vancomycin therapy is more effective at reducing the MRSA bacterial burden on the implant, bone, and synovial fluid in comparison to either treatment alone or no treatment controls. We also sought to (2) evaluate the histologic effects of the various treatments on the surrounding bone; and to (3) determine if the cathodic voltage-controlled electrical stimulation treatment had an effect on the mechanical properties of the titanium implant as a result of possible hydrogen embrittlement. METHODS: Thirty-two adult male Long-Evans rats (Harlan Laboratories, Indianapolis, IN, USA) with surgically placed shoulder titanium implants were infected with a clinical strain of MRSA (NRS70). One week after infection, eight animals received a treatment of cathodic voltage-controlled electrical stimulation at -1.8 V versus Ag/AgCl for 1 hour (STIM), eight received vancomycin twice daily for 1 week (VANCO), eight received the cathodic voltage controlled electrical stimulation and vancomycin therapy combined (STIM + VANCO), and eight served as controls with no treatment (CONT). Two weeks after initial infection, the implant, bone, and synovial fluid were collected for colony forming unit (CFU) enumeration, qualitative histological analysis by a pathologist blinded to the treatments each animal received, and implant three point bend testing. RESULTS: The implant-associated CFU enumerated from the STIM + VANCO (mean, 3.7 * 10(3); SD, 6.3 * 10(3)) group were less than those from the CONT (mean, 1.3 * 10(6); SD, 2.8 * 10(6); 95% confidence interval [CI] of difference, -4.3 * 10(5) to -9.9 * 10(3); p < 0.001), STIM (mean, 1.4 * 10(6); SD, 2.0 * 10(6); 95% CI of difference, -2.1 * 10(6) to -1.8 * 10(3); p = 0.002), and VANCO (mean, 5.8 x 10(4); SD, 5.7 * 10(4); 95% CI of difference, -6.4 * 10(4) to -1.7 * 10(4); p < 0.001) group. The bone-associated CFU enumerated from the STIM + VANCO group (6.3 * 10(1); SD, 1.1 * 10(2)) were less than those from the CONT (mean, 2.8 * 10(5); SD, 4.8 * 10(5); 95% CI of difference, -9.4 * 10(4) to 5.0 * 10(3); p < 0.001) and STIM (mean, 2.6 * 10(4); SD, 2.5 * 10(4); 95% CI of difference, -4.1 * 10(4) to -1.6 * 10(3); p < 0.001) groups. The VANCO group (4.3 * 10(5); SD, 6.3 * 10(2)) also had lower bone-associated CFU as compared with the CONT (mean 95% CI of difference, -9.3 * 10(4) to -4.5 * 10(3); p < 0.001) and STIM (95% CI of difference, -4.0 * 10(4) to -1.5 * 10(3); p < 0.001) groups. In comparison to the synovial fluid CFU enumerated from the CONT group (mean, 3.3 * 10(4); SD, 6.0 * 10(4)), lower synovial CFU were reported for both the STIM + VANCO group (mean, 4.6 * 10(1); SD, 1.2 * 10(2); 95% CI of difference, -4.9 * 10(3) to -3.0 * 10(2); p < 0.001) and the VANCO group (mean, 6.8 * 10(1); SD, 9.2 * 10(1); 95% CI of difference, -4.9 * 10(3) to -2.8 * 10(2); p = 0.007). The histological analysis showed no discernable deleterious effects on the surrounding tissue as a result of the treatments. No brittle fracture occurred during mechanical testing and with the numbers available, no differences in implant flexural yield strength were detected between the groups. CONCLUSIONS: In this rodent model, cathodic voltage-controlled electrical stimulation combined with vancomycin is an effective treatment for titanium implant-associated infections showing greater than 99.8% reduction in bacterial burden on the implant, surrounding bone, and synovial fluid as compared with the controls and the stimulation alone groups. CLINICAL RELEVANCE: Cathodic voltage-controlled electrical stimulation combined with vancomycin may enable successful treatment of titanium orthopaedic implant-associated infections with implant retention. Future studies will focus on optimization of the stimulation parameters for complete eradication of infection and the ability to promote beneficial host tissue responses. PMID- 25825159 TI - Association between dairy intake and caries among children and adolescents. results from the Danish EYHS follow-up study. AB - The aim of this paper was to investigate associations between the intake of dairy products and the development in caries (DMFS, decayed, missing and filled surfaces) among children/adolescents over a period of 3 and 6 years, and to investigate whether dairy intake protects against caries incidence. A total of 68.9% of the children were caries free at the age of 9 compared with 34.0% of the adolescents at the age of 15 (measured as DMFS = 0). A larger percentage of children/adolescents with a dairy intake above the mean were caries free compared with the group of children/adolescents with an intake below the mean (72.8 vs. 65.8% at age 9 and 41.1 vs. 30.7% at age 15). The results from the generalized estimation equation showed that dairy and milk intake, as well as intakes of components of dairy such as dairy calcium, whey and casein, was generally inversely associated with childhood/adolescent caries experience (measured as DMFS). With regard to caries incidence, the same inverse association was found for incidence over a period of 3 years and for incidence over 6 years, but the results were only statistically significant for the 3-year incidence and for the unadjusted models of the 6-year incidence. This study found that previous dairy intake, as well as milk intake or intake of dairy components, may be a predictor of future risk of caries measured by the DMFS count level. This relationship was inverse, meaning that a high intake of dairy products was associated with less future caries development. However, more studies on larger cohorts are needed to confirm these findings. PMID- 25825161 TI - Implementing a third-year emergency medicine medical student curriculum. AB - BACKGROUND: Emergency medicine (EM) is commonly introduced in the fourth year of medical school because of a perceived need to have more experienced students in the complex and dynamic environment of the emergency department. However, there is no evidence supporting the optimal time or duration for an EM rotation, and a number of institutions offer third-year rotations. OBJECTIVE: A recently published syllabus provides areas of knowledge, skills, and attitudes that third year EM rotation directors can use to develop curricula. This article expands on that syllabus by providing a comprehensive curricular guide for the third-year medical student rotation with a focus on implementation. DISCUSSION: Included are consensus-derived learning objectives, discussion of educational methods, considerations for implementation, and information on feedback and evaluation as proposed by the Clerkship Directors in Emergency Medicine Third-Year Curriculum Work Group. External validation results, derived from a survey of third-year rotation directors, are provided in the form of a content validity index for each content area. CONCLUSIONS: This consensus-derived curricular guide can be used by faculty who are developing or revising a third-year EM medical student rotation and provide guidance for implementing this curriculum at their institution. PMID- 25825162 TI - Venous malformation associated with type 1 neurofibromatosis: a case report. PMID- 25825160 TI - The iron chelator deferasirox affects redox signalling in haematopoietic stem/progenitor cells. AB - The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The underlying mechanisms responsible for this feature, however, are still poorly understood. In this study, we investigated the effect of DFX treatment in human haematopoietic/progenitor stem cells, focussing on its impact on the redox balance, which proved to control the interplay between stemness maintenance, self-renewal and differentiation priming. Here we show, for the first time, that DFX treatment induces a significant diphenyleneiodonium sensitive reactive oxygen species (ROS) production that leads to the activation of POU5F1 (OCT4), SOX2 and SOX17 gene expression, relevant in reprogramming processes, and the reduction of the haematopoietic regulatory proteins CTNNB1 (beta-Catenin) and BMI1. These DFX-mediated events were accompanied by decreased CD34 expression, increased mitochondrial mass and up-regulation of the erythropoietic marker CD71 (TFRC) and were compound-specific, dissimilar to deferoxamine. Our findings would suggest a novel mechanism by which DFX, probably independently on its iron-chelating property but through ROS signalling activation, may influence key factors involved in self-renewal/differentiation of haematopoietic stem cells. PMID- 25825163 TI - Platelet-derived growth factor receptor beta (PDGFRbeta) immunohistochemistry highlights activated bone marrow stroma and is potentially predictive for fibrosis progression in prefibrotic myeloproliferative neoplasia. AB - AIMS: Myelofibrosis is the result of aberrant stromal activity which is determined routinely by reticulin staining in bone marrow biopsies. As matrix fibres are the product of activated fibroblasts, we analysed fibre accumulation compared to stromal cell activity during myelofibrosis progression using the fibroblast activation marker platelet-derived growth factor receptor beta (PDGFRbeta) by immunohistochemistry. METHODS AND RESULTS: Initial and follow-up bone marrow biopsies from 84 patients with myeloproliferative neoplasia, including 55 cases with primary myelofibrosis, were evaluated from five haematopathology centres. The stromal mass was measured by conventional reticulin staining [myelofibrosis (MF) grade, 0-3] and PDGFRbeta-positive cells using a novel PDGFRbeta scoring system (0-3). Results were correlated for prediction of progression. The MF grade and the PDGFRbeta score showed excellent correlation (Spearman's r = 0.83, P < 0.0001). Elevated PDGFRbeta scores (higher than MF grade) predicted myelofibrosis progression in total with 43% sensitivity and 57% specificity, and short-term (within 1 year) progression with 82% sensitivity and 53% specificity. Progression of prefibrotic disease to manifest myelofibrosis could be forecast with 90% sensitivity and 75% specificity. CONCLUSION: PDGFRbeta highlights stromal cell activation in marrow fibrosis, which is closely related to matrix accumulation, indicating a direct clinical impact especially in prefibrotic myeloproliferative disorders. PMID- 25825164 TI - Darwin on the mic. PMID- 25825165 TI - Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF-1/CXCR4 axis toward enhancing the efficacy of stem cells' homing. AB - Clinical applications of mesenchymal stem cells (MSCs) rely on their capacity to home and engraft in the appropriate target injury tissues for the long term. However, their homing efficiency has been observed to be very poor because of the lack or modifications of homing factors SDF-1alpha and CXCR4 receptors. Hence, this study was designed to investigate the homing and retention of pretreated human adipose tissue-derived MSCs (hASCs) from three different delivery routes in response to SDF-1alpha, released from chitosan-based injectable hydrogels. After stimulation of ASCs with a hypoxia mimicking agent, the expression level and functionality of CXCR4 were analyzed by flowcytometric analysis (FACS), transwell migration assay and qPCR. Then, the homing/retention of pretreated DiI-labeled hASCs were compared through three different in vivo delivery routes, 2 weeks after transplantation in Wistar rats. The cells were tracked histologically by fluorescent microscope and by PCR for human-specific CXCR4 gene. Results showed CXCR4 has dynamic expression pattern and pretreatment of hASCs significantly up regulates CXCR4, leading to an increase in migration capacity toward 100 ng/mL SDF-1alpha in vitro and homing into the subcutaneously implanted hydrogel releasing SDF-1alpha in vivo. Furthermore, it seems that SDF-1alpha is particularly important in the retention of ASCs, in addition to its chemoattraction role. In summary, the delivery route in which the ASCs were mixed with the hydrogel rather than systemic delivery and local injection and preconditioning undertaken to increase CXCR4 expression concomitant with SDF 1alpha delivery by the injectable hydrogel, allowed for further homing/retention of ASCs. This might be a promising way to get better therapeutic outcomes in stem cell therapy. PMID- 25825166 TI - Triggering the directional selectivity of a ring-closure reaction leads to pyridoazacarbazoles with anticancer properties. AB - We herein describe a facile and versatile synthetic route to the tetracyclic system of 6-substituted 5,6-dihydro-11H-pyrido[3,2-i]-1-azacarbazoles with promising anticancer properties. These derivatives are built up by an elegant one step base-catalyzed synthetic procedure from commercially available building blocks. One additional step provides the corresponding skeleton hitherto unknown in the literature. The possibility to synthesize a large library of compounds with various substitution patterns utilizing this method underlines the importance of this synthetic procedure. PMID- 25825167 TI - Of muscle modulation and the CFTR gate. PMID- 25825168 TI - Revisiting the role of raphe and serotonin in neuropsychiatric disorders. PMID- 25825169 TI - Cysteine accessibility probes timing and extent of NBD separation along the dimer interface in gating CFTR channels. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) channel opening and closing are driven by cycles of adenosine triphosphate (ATP) binding-induced formation and hydrolysis-triggered disruption of a heterodimer of its cytoplasmic nucleotide-binding domains (NBDs). Although both composite sites enclosed within the heterodimer interface contain ATP in an open CFTR channel, ATP hydrolysis in the sole catalytically competent site causes channel closure. Opening of the NBD interface at that site then allows ADP-ATP exchange. But how frequently, and how far, the NBD surfaces separate at the other, inactive composite site remains unclear. We assessed separation at each composite site by monitoring access of nucleotide-sized hydrophilic, thiol-specific methanothiosulfonate (MTS) reagents to interfacial target cysteines introduced into either LSGGQ-like ATP-binding cassette signature sequence (replacing equivalent conserved serines: S549 and S1347). Covalent MTS-dependent modification of either cysteine while channels were kept closed by the absence of ATP impaired subsequent opening upon ATP readdition. Modification while channels were opening and closing in the presence of ATP caused macroscopic CFTR current to decline at the same speed as when the unmodified channels shut upon sudden ATP withdrawal. These results suggest that the target cysteines can be modified only in closed channels; that after modification the attached MTS adduct interferes with ATP-mediated opening; and that modification in the presence of ATP occurs rapidly once channels close, before they can reopen. This interpretation was corroborated by the finding that, for either cysteine target, the addition of the hydrolysis-impairing mutation K1250R (catalytic site Walker A Lys) similarly slowed, by an order of magnitude, channel closing on ATP removal and the speed of modification by MTS reagent in ATP. We conclude that, in every CFTR channel gating cycle, the NBD dimer interface separates simultaneously at both composite sites sufficiently to allow MTS reagents to access both signature-sequence serines. Relatively rapid modification of S1347C channels by larger reagents-MTS-glucose, MTS-biotin, and MTS-rhodamine-demonstrates that, at the noncatalytic composite site, this separation must exceed 8 A. PMID- 25825170 TI - Depression of voltage-activated Ca2+ release in skeletal muscle by activation of a voltage-sensing phosphatase. AB - Phosphoinositides act as signaling molecules in numerous cellular transduction processes, and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) regulates the function of several types of plasma membrane ion channels. We investigated the potential role of PtdIns(4,5)P2 in Ca(2+) homeostasis and excitation contraction (E-C) coupling of mouse muscle fibers using in vivo expression of the voltage-sensing phosphatases (VSPs) Ciona intestinalis VSP (Ci-VSP) or Danio rerio VSP (Dr-VSP). Confocal images of enhanced green fluorescent protein-tagged Dr-VSP revealed a banded pattern consistent with VSP localization within the transverse tubule membrane. Rhod-2 Ca(2+) transients generated by 0.5-s-long voltage-clamp depolarizing pulses sufficient to elicit Ca(2+) release from the sarcoplasmic reticulum (SR) but below the range at which VSPs are activated were unaffected by the presence of the VSPs. However, in Ci-VSP-expressing fibers challenged by 5-s-long depolarizing pulses, the Ca(2+) level late in the pulse (3 s after initiation) was significantly lower at 120 mV than at 20 mV. Furthermore, Ci-VSP-expressing fibers showed a reversible depression of Ca(2+) release during trains, with the peak Ca(2+) transient being reduced by ~30% after the application of 10 200-ms-long pulses to 100 mV. A similar depression was observed in Dr-VSP-expressing fibers. Cav1.1 Ca(2+) channel-mediated current was unaffected by Ci-VSP activation. In fibers expressing Ci-VSP and a pleckstrin homology domain fused with monomeric red fluorescent protein (PLCdelta1PH-mRFP), depolarizing pulses elicited transient changes in mRFP fluorescence consistent with release of transverse tubule-bound PLCdelta1PH domain into the cytosol; the voltage sensitivity of these changes was consistent with that of Ci-VSP activation, and recovery occurred with a time constant in the 10-s range. Our results indicate that the PtdIns(4,5)P2 level is tightly maintained in the transverse tubule membrane of the muscle fibers, and that VSP-induced depletion of PtdIns(4,5)P2 impairs voltage-activated Ca(2+) release from the SR. Because Ca(2+) release is thought to be independent from InsP3 signaling, the effect likely results from an interaction between PtdIns(4,5)P2 and a protein partner of the E-C coupling machinery. PMID- 25825172 TI - Histological Bulbar Manifestations in the ALS Rat. AB - BACKGROUND: Almost all patients with amyotrophic lateral sclerosis (ALS) develop bulbar symptoms; therefore, it is important to have valid animal models that accurately reflect these features. While the SOD1-G93A rat is extensively used as an ALS model, bulbar symptoms in this model are not well characterized. OBJECTIVE: In the present study, we aimed to better characterize bulbar dysfunction in terms of histology to determine whether the SOD1-G93A rat is a useful model for bulbar-onset ALS. METHODS: Sixty-day-old SOD1-G93A rats on a Sprague-Dawley background and age-matched wild-type controls were assessed weekly for global motor function, facial nerve function, and vagal nerve function. The study endpoint was determined when an SOD1-G93A rat could not right itself within 30 s of being placed on its side. At that point, neuronal counts were assessed in different brainstem cranial nerve nuclei. In addition, the masseter muscle, posterior belly of the digastric muscle, and tongue muscle were evaluated for intact neuromuscular junctions. RESULTS: Our data demonstrate decreases in the number of motor neurons in the trigeminal, facial, and hypoglossal nuclei, as well as compromised neuromuscular junction integrity in the muscles they innervate. CONCLUSION: These findings suggest that, from a histological standpoint, the SOD1-G93A rat is a valid model of ALS bulbar symptoms. PMID- 25825171 TI - Two distinct effects of PIP2 underlie auxiliary subunit-dependent modulation of Slo1 BK channels. AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca(2+)- and voltage-dependent K(+) (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (alpha) subunits as well as various regulatory auxiliary subunits (beta and gamma) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells. PIP2 inhibited macroscopic currents through Slo1 channels without auxiliary subunits and through Slo1 + gamma1 complexes. In contrast, PIP2 markedly increased macroscopic currents through Slo1 + beta1 and Slo1 + beta4 channel complexes and failed to alter macroscopic currents through Slo1 + beta2 and Slo1 + beta2 Delta2-19 channel complexes. Results obtained at various membrane potentials and divalent cation concentrations suggest that PIP2 promotes opening of the ion conduction gate in all channel types, regardless of the specific subunit composition. However, in the absence of beta subunits positioned near the voltage-sensor domains (VSDs), as in Slo1 and probably Slo1 + gamma1, PIP2 augments the negative surface charge on the cytoplasmic side of the membrane, thereby shifting the voltage dependence of VSD-mediated activation in the positive direction. When beta1 or beta4 subunits occupy the space surrounding the VSDs, only the stimulatory effect of PIP2 is evident. The subunit compositions of native Slo1 BK channels differ in various cell types; thus, PIP2 may exert distinct tissue- and divalent cation-dependent modulatory influences. PMID- 25825173 TI - Isavuconazonium sulfate approved for invasive fungal infections. PMID- 25825174 TI - Biosimilar filgrastim approved, but with "placeholder" generic name. PMID- 25825175 TI - Florida hospital embraces pharmacist-led chronic care in physician offices. PMID- 25825176 TI - FDA revives compounding advisory committee. PMID- 25825178 TI - Research on patient safety for off-label use of recombinant factor VIIa. PMID- 25825179 TI - Unreliability of weighing elastomeric pumps for determining volume of fluid infused. PMID- 25825180 TI - Being an academic part-time pharmacist. PMID- 25825181 TI - Pharmacist-led collaborative practice for older adults. PMID- 25825182 TI - Promoting pharmacy business success through the implementation of a departmental operating review series. PMID- 25825183 TI - A professional imperative: developing pharmacy residents as the next generation of practice-based researchers. PMID- 25825184 TI - Safety perspectives on informatics. PMID- 25825185 TI - Outpatient management of febrile neutropenia associated with cancer chemotherapy: risk stratification and treatment review. AB - PURPOSE: Strategies for the management of chemotherapy-induced febrile neutropenia (FN), including assessment tools for determining which patients are at low risk for FN complications and can be treated in the outpatient setting, are discussed. SUMMARY: Due to the potential for life-threatening complications, the development of FN in patients receiving cancer chemotherapy traditionally prompted hospitalization and i.v. antimicrobial therapy, but there is convincing published evidence that an identifiable subset of patients can be safely treated as outpatients. Two validated assessment tools recommended for identifying patients at low risk for FN complications are the Talcott classification system and the Multinational Association for Supportive Care in Cancer (MASCC) risk index; the MASCC index is superior in terms of sensitivity and negative predictive value but has lower specificity. In low-risk FN cases, outpatient oral antimicrobial therapy has been shown to be a safe and effective alternative to i.v. therapy for both inpatients and outpatients; current practice guidelines recommend an oral fluoroquinolone (e.g., ciprofloxacin) in combination with oral amoxicillin-clavulanate. The guidelines emphasize that in certain cases of FN (e.g., those involving prolonged or pronounced neutropenia or serious comorbidities), inpatient i.v. therapy is required. CONCLUSION: Pharmacists can play an important role in the management of chemotherapy-associated FN through involvement in risk assessment to identify candidates for outpatient oral antimicrobial therapy, selection of appropriate pharmacotherapy, drug therapy monitoring, and development of institutional guidelines or pathways. PMID- 25825187 TI - ASHP national survey on informatics: assessment of the adoption and use of pharmacy informatics in U.S. hospitals-2013. AB - PURPOSE: Results of the 2013 ASHP national survey on informatics are presented. METHODS: Pharmacy directors from all types and sizes of U.S. hospitals were included in the sample of 4893 individuals invited to participate in an online survey. The survey contained over 600 data elements that addressed the adoption and use of a variety of pharmacy informatics and technology. Data were analyzed by hospital type and size, accounting for sampling procedures and differences in response rate. RESULTS: Of the 4893 surveys distributed, 465 usable surveys were returned, yielding a response rate of 9.5%. Nearly 33% of hospitals reported having a complete electronic health record (EHR) (i.e., no paper charts). Adoption rates for computerized prescriber order entry, clinical decision support, electronic prescribing, and bar-code-assisted medication administration indicated that these technologies are clear priorities. Nearly half of respondents indicated using solely paper-based medication reconciliation processes, while almost as many reported using processes that combined electronic and paper methods. Overall, automated dispensing cabinets were more common in U.S. hospitals than were carousels and dispensing robots. The adoption of patient portals and personal health records is becoming common. Technologies identified as enablers of the Pharmacy Practice Model Initiative (PPMI) were found in at least 25% of hospitals. The average total number of pharmacy information technology full-time equivalents was 3.12. CONCLUSION: This survey found widespread use of pharmacy informatics and technology across the entire medication-use process. Considerable progress was demonstrated in meeting meaningful-use measures for EHRs and meeting the recommendations of the ASHP PPMI. PMID- 25825186 TI - Resistance to rocuronium and cisatracurium in a patient with a spinal injury and acute respiratory distress syndrome. AB - PURPOSE: A case of resistance to rocuronium and cisatracurium in a patient with a spinal injury who developed acute respiratory distress syndrome (ARDS) is reported. SUMMARY: A 34-year-old, 88-kg Caucasian man with a history of polysubstance abuse fell from a bridge approximately 30-ft high, landing head first in about 2-3 ft of water. The patient sustained anterior subluxation at cervical spine levels C5-C6 and severe spinal canal compromise with cord compression and edema from C5 to C7, resulting in quadriplegia. The patient developed aspiration pneumonia for which he was given vancomycin and piperacillin tazobactam. His pneumonia progressed to ARDS, and drug-induced paralysis was attempted to reduce barotrauma and improve ventilation. Rocuronium was initiated, but the patient did not adequately respond to this treatment. Cisatracurium was then initiated, but the patient did not respond. The decision was made to discontinue the cisatracurium infusion at that time and manage the patient's ARDS without a neuromuscular blocking agent (NMBA). After several attempts to manage the patient's ARDS by adjusting ventilatory values, the patient required the reinitiation of an NMBA. The decision was made to try cisatracurium again. Cisatracurium was again unsuccessful and therefore discontinued. As a last attempt to improve oxygenation, the patient received nitric oxide and sedation with propofol. The patient died due to his complicated hospital course that included quadriplegia, ARDS, cardiac arrest, and sepsis secondary to a gastric perforation. CONCLUSION: Inadequate paralysis was achieved with rocuronium and cisatracurium in a patient who sustained a significant trauma resulting in quadriplegia. PMID- 25825188 TI - Who will sit in my chair? PMID- 25825189 TI - Effect of pharmacy students as primary pharmacy members on inpatient interdisciplinary mental health teams. AB - PURPOSE: The effect of pharmacy students as primary pharmacy members on inpatient interdisciplinary mental health teams was investigated. METHODS: This retrospective study used Veterans Affairs data from veterans who were admitted to an inpatient mental health unit from January 1, 2010, through December 31, 2012. Eligible veterans had to have been hospitalized for at least five days and treated with at least five scheduled medications during the hospitalization. Information collected by the investigators included patient age, psychiatric diagnoses, accuracy of medication reconciliation on admission and at discharge, and readmission rates within six months and one year. Additional information collected included monitoring parameters for lithium, divalproex, first generation antipsychotics, and second-generation antipsychotics. The primary outcome was the percentage of accurate medication reconciliations for treatment teams with a fourth-year pharmacy student and without a pharmacy student. Clinical monitoring and readmission rates were also compared. RESULTS: A total of 526 patients were eligible for study inclusion. Medication reconciliation was performed on admission for all patients followed by a team involving a pharmacy student (experimental group), but only 51% of patients in the control group had documented medication reconciliations in the medical chart. Of the medication reconciliations completed, 82% were performed correctly in the experimental group, compared with 61% when a pharmacy student was not involved (p = 0.006). There were no significant differences between groups in psychotropic monitoring and readmission rates. CONCLUSION: The presence of fourth-year pharmacy students on inpatient mental health interdisciplinary teams was associated with more frequent interventions, patient counseling, and medication reconciliation, compared with rates for teams without a pharmacy student. Medication reconciliation was performed more consistently and accurately when the teams had a pharmacy student than when they did not. PMID- 25825192 TI - ASHP professional policy recommendations--invitation to comment. PMID- 25825190 TI - Preventing chemotherapy errors: updating guidelines to meet new challenges. PMID- 25825193 TI - ASHP guidelines on preventing medication errors with chemotherapy and biotherapy. PMID- 25825194 TI - Efficacy of tenofovir switch therapy for nucleos(t)ide-experienced patients with chronic hepatitis B. AB - BACKGROUND: Tenofovir disoproxil fumarate has been used in chronic hepatitis B patients with suboptimal virologic response to nucleos(t)ide analogues. The efficacy of tenofovir switch therapy has not been well studied in Asian patients. AIM: To evaluate the efficacy of tenofovir switch therapy in nucleos(t)ide experienced patients, and identify the factors associated with treatment response of tenofovir switch therapy. METHODS: Nucleos(t)ide-experienced hepatitis B e antigen-positive and -negative patients prescribed with tenofovir were retrospectively identified and recruited for prospective analysis. Hepatitis B virus (HBV) DNA and other biochemical parameters were monitored in regular 3-6 monthly follow-up visits. Primary efficacy endpoint was maintained-virologic response with tenofovir switch therapy, defined as undetectable HBV DNA (<20 IU/mL) until the last follow-up visit. RESULTS: An overall of 214/252 (84.9%) patients achieved maintained-virologic response after 22 (7-55) months of tenofovir switch therapy. On multivariate analysis, a lower HBV DNA level at the time of switching to tenofovir was an independent factor associated with treatment efficacy. Maintained-virologic response after switching to tenofovir was achieved in 177/190 (93.2%) patients with HBV DNA <20 000 IU/mL vs. 37/62 (59.7%) patients with HBV DNA >=20 000 IU/mL (P < 0.001). Absence of genotypic resistance to lamivudine or adefovir dipivoxil was not associated with improved treatment outcome. CONCLUSIONS: Tenofovir switch therapy is an effective treatment strategy in nucleos(t)ide-experienced chronic hepatitis B patients. However, in patients with HBV DNA >=20 000 IU/mL at the time of switching to tenofovir, the chance of achieving maintained undetectable HBV DNA is significantly reduced. PMID- 25825195 TI - Steroid-Induced Osteonecrosis in Dermatology: A Review. AB - BACKGROUND: Steroid-induced osteonecrosis is unpredictable and highly morbid. METHODS: MEDLINE (Ovid) and PubMed search for relevant literature. RESULTS: Oral steroid doses typically considered to be associated with the condition are >20 mg of prednisone (or equivalent) per day or >2 g within a period of 2 to 3 months. Symptoms may be vague. CONCLUSIONS: Dermatologists must exercise a high degree of clinical suspicion and warn patients about steroid-related risks and conditions for follow-up. PMID- 25825196 TI - Optimal surgical ablation of atrial tachyarrhythmias during correction of Ebstein anomaly. AB - BACKGROUND: Ebstein anomaly (EA) is commonly associated with atrial flutter or fibrillation (AFl/F), which adversely affects outcome. Surgical ablation of AFl/F during surgery for EA has been shown to be effective, but the optimal lesion set remains unknown. METHODS: Between 1995 and 2010, 86 patients had corrective surgery for EA and concomitant maze procedure for associated AFl/F. Median age at operation was 40 years (range, 1 to 72 years), and 49 patients (60%) were male. Preoperative AFl/F was paroxysmal in 43 patients (50%). All patients who had diagnosis of or treatment for accessory pathways and reentrant tachycardia were excluded from this analysis. RESULTS: All patients underwent tricuspid valve surgery for EA and concomitant maze procedure, including right-sided maze (RSM) in 62 patients (72%) and biatrial maze (BAM) in 24 patients (28%). Early mortality occurred in 3 patients (3.5%). During median follow-up of 52 months (range, 3 months to 17 years), overall freedom from AFl/F without antiarrhythmic medications was 79% (RSM, 80% versus BAM, 76%; p = 0.97). Although there was no difference in rhythm outcome between RSM and BAM for patients with paroxysmal AFl/F (p = 0.08), there was a trend toward higher freedom from AF without antiarrhythmic medications in patients with persistent AFl/F for BAM (86%) versus RSM (71%; p = 0.053). Overall, there were no late strokes, and 84% were free from sodium warfarin anticoagulation. CONCLUSIONS: Overall, surgical ablation of preoperative AFl/F is effective in patients undergoing surgery for EA. Although rhythm outcome of RSM and BAM did not differ in patients with preoperative paroxysmal AFl/F, those with persistent or permanent AFl/F may benefit from a biatrial lesion set. PMID- 25825197 TI - Outcomes of atrioventricular valve operation in patients with Fontan circulation. AB - BACKGROUND: Data on outcomes of atrioventricular (AV) valve surgical procedures in patients with Fontan circulation are limited. METHODS: We conducted a retrospective review of all children with Fontan circulation who underwent AV valve operations. RESULTS: From 1981 to 2014, 581 patients underwent Fontan operations, and 9.3% (54/581) of them required AV valve operations. The first AV valve operation was performed before (n = 32), during (n = 15), or after (n = 7) the Fontan operation. The mean follow-up time was 9.8 +/- 7.1 years (range, 6 months to 32 years). Operative mortality for the initial AV valve operation was 1.9% (1/54) and occurred in a patient who had the initial valve operation concomitantly with the Fontan. Late mortality was 5.7% (3/53). Heart transplantation was performed in 13.0% (7/54) of patients. Freedom from death or transplantation after the first AV valve operation was 89.8 +/- 4.4% at 5 years (95% confidence interval [CI], 77.1 to 95.6) and 81.0 +/- 6.2% at 10 years (95% CI, 65.0 to 90.2). Reoperation on the AV valve was performed in 44.4% (24/54) of patients. The median time to initial valve reoperation was 3.1 years (interquartile range, 0.8 to 7.4 years). Freedom from reoperation or transplantation was 63.4 +/- 7.0% at 5 years (95% CI, 48.2 to 75.3) and 48.9 +/- 7.9% at 10 years (95% CI, 32.8 to 63.2). Freedom from moderate or more regurgitation in patients who had not undergone reoperation or transplantation was 74.0 +/- 6.9% (95% CI, 57.5 to 84.8) at 5 years and 67.5 +/- 7.7% (95% CI:,50.0 to 80.0) at 10 years. After initial valve operation, thromboembolic events occurred in 13.0% (7/54) of patients, stroke occurred in 24.1% (13/54) of patients, pacemaker insertion was required in 16.7% (9/54) of patients, and protein-losing enteropathy was diagnosed in 7.4% (4/54) of patients. Of the 43 surviving transplant-free patients, 62.8% (27/43) were in New York Heart Association (NYHA) class I, 34.9% (15/43) were in NYHA class II, and 1 patient was in NYHA class III. CONCLUSIONS: The AV valve operation done before, during, or after the Fontan operation is associated with low operative mortality but a high reoperation rate with significant risk of late death, transplantation, and persistent AV valve regurgitation. PMID- 25825198 TI - Methylated DLX4 Predicts Response to Pathologic Stage I Non-Small Cell Lung Cancer Resection. AB - BACKGROUND: Surgery with curative intent is the standard treatment for patients with stage I non-small cell lung cancer (NSCLC). Even after curative resection, however, many patients have recurrent disease. Thus, there is a need to identify molecular biomarkers for the biological characteristics and prognosis of tumors. METHODS: Methylation-specific polymerase chain reaction analysis was performed for the distal-less homeobox 4 (DLX4) gene in cancer tissues from 109 patients who underwent curative resection for pathologic stage I NSCLC from June 2005 to November 2011. We investigated possible correlations between DLX4 methylation status and disease outcome. RESULTS: Methylated DLX4 was detected in 54 of 109 patients (49.5%). No significant relationship between DLX4 methylation status and clinicopathologic features was found. Multivariate logistic regression analysis revealed that DLX4 methylation was an independent risk factor for recurrence (p < 0.0001). Patients with DLX4 methylation showed significantly poorer recurrence free, cancer-specific, and overall survival than patients without DLX4 methylation (p < 0.0001, p = 0.0001, p = 0.0004, respectively). Cox's proportional hazard regression analysis revealed that DLX4 methylation was an independent risk factor for poor prognosis regarding recurrence-free, cancer specific, and overall survival (p < 0.0001, p = 0.0005, p = 0.0018, respectively). CONCLUSIONS: Methylated DLX4 is a potential biomarker that predicts poor prognosis after curative resection of pathologic stage I NSCLC. Identification of patients with methylated DLX4 may assist stratification for appropriate adjuvant treatment strategies. PMID- 25825199 TI - Clinicopathologic features of resected subcentimeter lung cancer. AB - BACKGROUND: Subcentimeter lung cancers are still rare, and their pathobiologic behavior and management have not yet been fully clarified. METHODS: From 1993 through 2011, 291 patients with resected lung cancers 1.0 cm or less in diameter were studied regarding their clinicopathologic characteristics. According to appearance on high-resolution computed tomography (HRCT), the tumors were classified into four types: type 1 (n = 50), nonsolid ground-glass opacity (GGO) lesion; type 2 (n = 89), part-solid GGO lesion including 50% or more GGO within the lesion; type 3 (n = 62), part-solid GGO lesion including less than 50% GGO within the lesion, and type 4 (n = 90), solid lesion. RESULTS: Although none of types 1 to 3 tumors had lymph node metastases, these were found in 10% of type 4 tumors. Recurrence was observed in 13 patients, almost all of whom had type 4 tumors. The lone exception was a patient with a type 3 tumor in whom local recurrence developed on a surgical staple line. The 5-year overall survival rates were 100% in type 1 and type 2, 98% in type 3, and 88% in type 4. Type 4 had a significantly worse prognosis than the other types. CONCLUSIONS: Subcentimeter lung cancers with a GGO component on HRCT (types 1 to 3) can be considered "early" lung cancers. In these cases, limited resection may be warranted to achieve a cure because they had no lymph node metastasis. By contrast, lobectomy should still be considered the standard operation of choice for type 4 tumors. PMID- 25825200 TI - Moderate versus deep hypothermic circulatory arrest for elective aortic transverse hemiarch reconstruction. AB - BACKGROUND: Deep hypothermic circulatory arrest (DHCA) with retrograde cerebral perfusion (DHCA group) has traditionally been the cerebral protection strategy during transverse hemiarch aortic reconstruction. Recently, we have adopted moderate hypothermic (>= 25 degrees C) circulatory arrest (MHCA) with antegrade cerebral perfusion (MHCA group). We compared the outcomes for these two circulatory arrest management strategies. METHODS: From 2008 to 2012, in a concurrent series of 376 patients (DHCA, 301; MHCA, 75) undergoing transverse hemiarch for aortic aneurysm disease, incidences of concomitant root replacement (44% vs 47%, p = 0.8), and aortic valve replacement (29% vs 21%, p = 0.3) were similar, although atherosclerotic aneurysm pathology was present in patients in the MHCA group (71% vs 33%, p < 0.01). Antegrade cerebral perfusion was established via axillary artery or direct innominate artery cannulation. A database was prospectively maintained. RESULTS: MHCA group patients were older (66 +/- 11 vs 60 +/- 14 years; p < 0.01). Other demographics were similar. Aortic cross-clamp (128 +/- 46 vs 163 +/- 57 minutes, p < 0.01) and cardiopulmonary bypass (167 +/- 49 vs 222 +/- 61 minutes, p < 0.01) times were lower in the MHCA group. Transfusion requirements were significantly reduced with MHCA (38% vs 61%, p < 0.01), especially use of fresh frozen plasma and cryoprecipitate. Direct innominate artery cannulation did not result in any vascular or neurologic complication. Postoperative outcomes were similar. In-hospital and 30-day mortality was 1% in both groups. Stroke (0% vs 2%) and hemodialysis rates (0% vs 1%) were also similar. CONCLUSIONS: MHCA with antegrade cerebral perfusion yields excellent and equivalent outcomes to DHCA for elective aortic hemiarch reconstruction. MHCA significantly improves intraoperative times and, importantly, reduces transfusion requirements compared with DHCA with a retrograde cerebral perfusion strategy. PMID- 25825201 TI - Modified single patch: are we still worried about subaortic stenosis? AB - BACKGROUND: When the modified single-patch technique for atrioventricular septal defect (AVSD) repair was introduced by Dr Benson Wilcox, there was concern that these patients might be at risk for late subaortic stenosis and left ventricular outflow tract obstruction (LVOTO). This review evaluated our modified single patch population for LVOTO in the postoperative period. METHODS: Between January 2000 and 2013, 77 infants underwent AVSD repair with a modified single-patch technique. Median age was 4.2 months, and median weight was 5 kg. Eight patients had a prior repair of coarctation of the aorta via left thoracotomy in the newborn period. RESULTS: The median hospital stay was 10 days. No patient required a pacemaker. The mean and median follow-up times were 4.6 and 3.7 years, respectively. Only 2 patients (2.5%) required reoperation for LVOTO; both had prior repair of coarctation of the aorta (2 of 8 vs 0 of 69, p = 0.01). A discrete fibrous subaortic membrane developed in the first patient that required resection at 3 and 7 years after repair. The other patient had LVOTO from accessory chordae of the left atrioventricular valve and required mitral valve replacement 5 months after repair. One early death occurred at 4 months postoperatively due to liver failure related to hyperalimentation. CONCLUSIONS: At intermediate term follow-up, LVOTO does not appear to be a significant postoperative issue after modified single-patch repair of AVSD. Coarctation of the aorta was the most significant predictor of late LVOTO after repair of AVSD with the modified single-patch technique. PMID- 25825202 TI - Methadone Therapy in Underserved Urban Community: QTc Prolongation and Life Threatening Ventricular Arrhythmias. AB - AIMS: Methadone has been associated with QTc prolongation and ventricular arrhythmias but the prevalence of QTc prolongation and association with ventricular arrhythmias remains unclear. We investigated this in our inner city urban community (Bronx, New York) that has a large number of patients on methadone. METHODS: Telemetry records, nursing documentation and electronic charts of 291 patients spanning856 encounters were evaluated. QT was manually measured from ECG utilizing standardized QT measurement guidelines and was corrected for heart rate using Hodges formula. QTc >470 ms in males and >480 ms in females was considered to be prolonged. RESULTS: Patients had prolonged QTc, QTc >500 ms and ventricular arrhythmias during 25.6%, 14.1% and 3.4% of encounters, respectively. There was a very weak dose dependent relationship between methadone dose and QTc (Spearman's rho = 0.09).In addition to methadone, patients were on at least one QT prolonging drugs during 39% of the encounters. Patients who were receiving two interacting drugs in addition to methadone had the highest prevalence (29%) of QTc prolongation. CONCLUSION: Although the prevalence of QTc prolongation among patients on methadone therapy is high, the prevalence of ventricular arrhythmia is relatively low. Hospitalized patients on sustained methadone therapy are frequently on multiple additional QTc prolonging drugs. There is no significant dose dependent relationship between methadone dose and QTc. However, the concurrent use of methadone and interacting drugs lead to an increased prevalence of QTc prolongation. PMID- 25825204 TI - Online antioxidant activity and ultra-performance LC-electrospray ionisation quadrupole time-of-fight mass spectrometry for chemical fingerprinting of Indian polyherbal formulations. AB - A HPLC-DAD-DPPH method was developed for evaluating the 1, 1-diphenyl-2-picryl hydrazyl free radical scavenging activity of ethylacetate extracts of different polyherbal formulations (draksarista, draksava, lohasava and arvindasava) by using RP-18e column. The ethylacetate extract from polyherbal, 'draksarista' exhibited maximum free radical scavenging activity (99.9 +/- 0.38%) followed by draksava (99.8 +/- 0.34%), lohasava (98.5 +/- 0.30%) and arvindasava (42.3 +/- 0.34%) at 100 MUg mL(-1). Simultaneously, ultra-performance liquid chromatography coupled with electrospray ionisation-quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) was used to study chemical composition of the ethylacetate extracts of formulations. The characteristic electrospray mass ionisation reveals the dominance of polyphenols and their glycosides in the four polyherbal formulations. PMID- 25825205 TI - Taking a hard line with biotemplating: cobalt-doped magnetite magnetic nanoparticle arrays. AB - Rapid advancements made in technology, and the drive towards miniaturisation, means that we require reliable, sustainable and cost effective methods of manufacturing a wide range of nanomaterials. In this bioinspired study, we take advantage of millions of years of evolution, and adapt a biomineralisation protein for surface patterning of biotemplated magnetic nanoparticles (MNPs). We employ soft-lithographic micro-contact printing to pattern a recombinant version of the biomineralisation protein Mms6 (derived from the magnetotactic bacterium Magnetospirillum magneticum AMB-1). The Mms6 attaches to gold surfaces via a cysteine residue introduced into the N-terminal region. The surface bound protein biotemplates highly uniform MNPs of magnetite onto patterned surfaces during an aqueous mineralisation reaction (with a mean diameter of 90 +/- 15 nm). The simple addition of 6% cobalt to the mineralisation reaction maintains the uniformity in grain size (with a mean diameter of 84 +/- 14 nm), and results in the production of MNPs with a much higher coercivity (increased from ~ 156 Oe to ~ 377 Oe). Biotemplating magnetic nanoparticles on patterned surfaces could form a novel, environmentally friendly route for the production of bit-patterned media, potentially the next generation of ultra-high density magnetic data storage devices. This is a simple method to fine-tune the magnetic hardness of the surface biotemplated MNPs, and could easily be adapted to biotemplate a wide range of different nanomaterials on surfaces to create a range of biologically templated devices. PMID- 25825203 TI - A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia. AB - BACKGROUND AND PURPOSE: Epigallocatechin-3-gallate (EGCG) is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent. EXPERIMENTAL APPROACH: Derivatives of EGCG were evaluated for their stability and anti-tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells. KEY RESULTS: EGCG-mono palmitate (EGCG-MP) showed most prolonged stability compared with other EGCG derivatives. EGCG-MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG-MP induced Src-homology 2 domain containing tyrosine phosphatase 1 (SHP-1) leading decreased oncogenic protein BCR ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG-MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared with EGCG. Conversely, depletion of SHP-1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG-MP to suppress phosphorylation of BCR-ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG-MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP-1 activity and decreased phosphorylation of BCR-ABL in the EGCG-MP-treated group relative to that in the EGCG-treated group. CONCLUSIONS AND IMPLICATIONS: EGCG-MP induced SHP-1-mediated inhibition of BCR-ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment. PMID- 25825206 TI - Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism. AB - We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6 propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects. PMID- 25825207 TI - Margaret McCartney: General practice is still the best job in the world. PMID- 25825208 TI - Superoxide dismutase promotes the epithelial-mesenchymal transition of pancreatic cancer cells via activation of the H2O2/ERK/NF-kappaB axis. AB - Our previous study revealed that superoxide dismutase (SOD)-dependent production of reactive oxygen species (ROS) was able to increase the invasive ability of pancreatic cancer cells. However, the underlying mechanisms by which SOD enhances metastasis are still not fully elucidated. As epithelial-mesenchymal transition (EMT) is a key player in tumor metastasis, the aim of this study was to evaluate whether SOD affects EMT in pancreatic cancer cells and the related mechanism. Human pancreatic cancer cells BxPC-3 and Panc-1 were utilized to examine the level of hydrogen peroxide (H2O) in the absence or presence of SOD and catalase (CAT). The activation of phospho-ERK and phospho-NF-kappaB were measured by western blot analysis. Wound healing assay and transwell invasion assay were used to detect the migratory and invasive potential of cancer cells. The EMT-related factors, E-cadherin, N-cadherin and vimentin were detected by QT-PCR and western blot analysis. The results of present study showed that SOD not only increased cell migration and invasion in pancreatic cancer, but also mediated the expression of EMT-related factors and cell morphology. In addition, the levels of phospho-ERK and phospho-NF-kappaB were induced by SOD which could be counter balanced by both CAT treatment and PD 98059 (an ERK inhibitor). Taken together, these data indicate that SOD promotes the invasive and migratory activity of pancreatic cancer. Blocking the H2O2/ERK/NF-kappaB axis might be a novel strategy for the treatment of this severe malignancy. PMID- 25825209 TI - Order and disorder around Cr(3+) in chromium doped persistent luminescent AB2O4 spinels. AB - The X-ray absorption near edge structure (XANES) spectroscopy technique is used to better understand the charging and decharging processes of the persistent luminescence in the Cr(3+)doped AB2O4 spinels (A = Zn, Mg and B = Ga and Al) with low photon energy excitation by visible light. Cr K edge XANES spectra have been simulated for different near neighbour environments around the Cr(3+) recombination centres and compared with the experimental curve. In the Cr(3+):ZnGa2O4 compound, the Cr(3+) local structure corresponds mostly to that of a normal spinel (~70%), while the rest comprises of a distorted octahedral environment arising from cationic site inversion and a contribution from chromium clustering. This local structure is considerably different in Cr(3+):MgGa2O4 and Cr(3+):ZnAl2O4, where, for both cases, chromium clustering represents the main contribution. The strong correlation between the intensity of persistent luminescence and the percentage of Cr in clusters leads us to infer that the presence of Cr clusters is responsible for the decrease of the intensity of the visible light induced persistent luminescence in the Cr(3+) doped AB2O4 spinels. PMID- 25825211 TI - DNA polymerase-catalyzed incorporation of nucleotides modified with a G quadruplex-derived DNAzyme. AB - We show that nucleotides which are modified with a G-quadruplex-derived DNAzyme are substrates for DNA polymerases. Based on this finding we developed a naked eye detection system that allows the detection of single nucleotide variations in DNA. PMID- 25825210 TI - Impairment of the Vascular KATP Channel Imposes Fatal Susceptibility to Experimental Diabetes Due to Multi-Organ Injuries. AB - The vascular isoform of ATP-sensitive K(+) (KATP ) channels regulates blood flow to all organs. The KATP channel is strongly inhibited by reactive oxygen and carbonyl species produced in diabetic tissue inflammation. To address how such channel inhibition impacts vascular regulation as well as tissue viability, we performed studies in experimental diabetic mice. Strikingly, we found that knockout of the Kcnj8 encoding Kir6.1 subunit (Kcnj8-KO) caused mice to be fatally susceptible to diabetes. Organ perfusion studies suggested that the lack of this vascular K(+) channel handicapped activity-dependent vasodilation, leading to hypoperfusion, tissue hypoxia, and multi-organ failure. Morphologically, Kcnj8-KO mice showed greater inflammatory cell infiltration, higher levels of expression of inflammation indicator proteins, more severe cell apoptosis, and worse tissue disruptions. These were observed in the kidney, liver, and heart under diabetic condition in parallel comparison to tissues from WT mice. Patch clamping and molecular studies showed that the KATP channel was S glutathionylated in experimental diabetes contributing to the inhibition of channel activity as well as the reduced arterial responses to vasodilators. These results suggest that the vascular KATP channel is organ protective in diabetic condition, and since the channel is suppressed by diabetic oxidative stress, therapeutical interventions to the maintenance of functional KATP channels may help to lower or prevent diabetic organ dysfunction. PMID- 25825212 TI - Features extraction in anterior and posterior cruciate ligaments analysis. AB - The main aim of this research is finding the feature vectors of the anterior and posterior cruciate ligaments (ACL and PCL). These feature vectors have to clearly define the ligaments structure and make it easier to diagnose them. Extraction of feature vectors is obtained by analysis of both anterior and posterior cruciate ligaments. This procedure is performed after the extraction process of both ligaments. In the first stage in order to reduce the area of analysis a region of interest including cruciate ligaments (CL) is outlined in order to reduce the area of analysis. In this case, the fuzzy C-means algorithm with median modification helping to reduce blurred edges has been implemented. After finding the region of interest (ROI), the fuzzy connectedness procedure is performed. This procedure permits to extract the anterior and posterior cruciate ligament structures. In the last stage, on the basis of the extracted anterior and posterior cruciate ligament structures, 3-dimensional models of the anterior and posterior cruciate ligament are built and the feature vectors created. This methodology has been implemented in MATLAB and tested on clinical T1-weighted magnetic resonance imaging (MRI) slices of the knee joint. The 3D display is based on the Visualization Toolkit (VTK). PMID- 25825213 TI - A novel, nonanaphylactogenic, bispecific IgE-CD3 antibody eliminates IgE(+) B cells. PMID- 25825214 TI - Effect of CYP3A5*3 on asthma control among children treated with inhaled beclomethasone. PMID- 25825215 TI - Comparison of asthma prevalence among African American teenage youth attending public high schools in rural Georgia and urban Detroit. AB - BACKGROUND: The high prevalence of asthma among urban African American (AA) populations has attracted research attention, whereas the prevalence among rural AA populations is poorly documented. OBJECTIVE: We sought to compare the prevalence of asthma among AA youth in rural Georgia and urban Detroit, Michigan. METHODS: The prevalence of asthma was compared in population-based samples of 7297 youth attending Detroit public high schools and in 2523 youth attending public high schools in rural Georgia. Current asthma was defined as a physician diagnosis and symptoms in the previous 12 months. Undiagnosed asthma was defined as multiple respiratory symptoms in the previous 12 months without a physician diagnosis. RESULTS: In Detroit, 6994 (95.8%) youth were AA compared with 1514 (60.0%) in Georgia. Average population density in high school postal codes was 5628 people/mile(2) in Detroit and 45.1 people/mile(2) in Georgia. The percentages of poverty and of students qualifying for free or reduced lunches were similar in both areas. The prevalence of current diagnosed asthma among AA youth in Detroit and Georgia was similar: 15.0% (95% CI, 14.1-15.8) and 13.7% (95% CI, 12.0-17.1) (P = .22), respectively. The prevalence of undiagnosed asthma in AA youth was 8.0% in Detroit and 7.5% in Georgia (P = .56). Asthma symptoms were reported more frequently among those with diagnosed asthma in Detroit, whereas those with undiagnosed asthma in Georgia reported more symptoms. CONCLUSIONS: Among AA youth living in similar socioeconomic circumstances, asthma prevalence is as high in rural Georgia as it is in urban Detroit, suggesting that urban residence is not an asthma risk factor. PMID- 25825218 TI - Adipose-derived stem cells for nerve repair: hype or reality? AB - Peripheral nerve injury is a relatively commonly occurring trauma which seriously compromises the quality of life for many individuals. There is a major need to devise new treatment strategies, and one possible approach is to develop cellular therapies to bioengineer new nerve tissue and/or modulate the endogenous regenerative mechanisms within the peripheral nervous system. In this short review we describe how stem cells isolated from adipose tissue could be a suitable element of this approach. We describe the possible mechanisms through which the stem cells might exert a positive influence on peripheral nerve regeneration. These include their ability to differentiate into cells resembling Schwann cells and their secretion of a plethora of neurotrophic growth factors. We also review the literature describing the effects of these cells when tested using in vivo peripheral nerve injury models. PMID- 25825219 TI - Strong effect of long-term Sparicotyle chrysophrii infection on the cellular and innate immune responses of gilthead sea bream, Sparus aurata. AB - One thousand healthy recipient gilthead sea bream, Sparus aurata, cohabited with 250 donor fish parasitized by Sparicotyle chrysophrii (Van Beneden and Hesse, 1963) (Monogenea: Polyopisthocotylea), a common parasite of the gills of this fish species. Controls consisted of 1000 healthy fish kept in a separate tank. After 10 weeks, fish were weighed and parasite load, hemoglobin concentration and immunological parameters were assessed. Rather than the absence of parasite, hemoglobin concentration was a better marker of the health status of the fish, because S.chrysophrii had detached from the strongly anemic gills of some animals leaving fish with affected immune system but without parasites. The parasite infection seemed to trigger a cellular response of the fish immune system but to inhibit its humoral components. Thus, parasitized fish may control the parasite infection through the action of reactive oxygen species but they may become more sensitive to potential secondary bacterial or parasitical infections. This phenomenon was demonstrated not only through significant differences between recipient and control fish but also through strong correlations between those parameters and parasite load, fish weight and/or hemoglobin concentration. PMID- 25825216 TI - Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade. AB - BACKGROUND: Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive. OBJECTIVE: We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM. METHODS: We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation. RESULTS: We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM. CONCLUSION: PM activates an AhR Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles. PMID- 25825217 TI - Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure. AB - Animal studies suggest that receptor for advanced glycation end products (RAGE) dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE), high mobility group box 1 (HMGB1), and Nepsilon-(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health-sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN-RAGE, CML, and sRAGE were detected by enzyme linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN-RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN-RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score <= 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3-73; P < 0.001). The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research. PMID- 25825220 TI - [The relationship between physical activity in leasure time and the ankle brachial index in a general Spanish population: The ARTPER study]. AB - BACKGROUND AND OBJECTIVE: High levels of daily physical activity have been shown to be linked to decreased functional impairment in peripheral artery disease (PAD) patients and positively related to the ankle brachial index (ABI) in subjects without PAD. The aim of this study was to examine the relationship between leisure time physical activity (LTPA) and the ABI in a general population. MATERIAL AND METHOD: Baseline data from the ARTPER study cohort corresponding to 2,840 subjects>49 years from Barcelona were analyzed. The LTPA variable was obtained through the validated Spanish short version of the Minnesota Leisure Time Physical Activity Questionnaire. ABI<0.9 was taken to indicate PAD. Multivariate logistic regression analysis was performed to evaluate the independent association between LTPA and PAD. RESULTS: Subjects with more LTPA were younger, female, less smokers, and suffered fewer PAD. Total activity, measured in metabolic energy turnover (MET) and the LTPA hours, was significantly higher in subjects without PAD (P<.001). There was an inverse relationship between LTPA and the risk of suffering PAD (odds ratio 0.56, 95% confidence interval 0.38-0.81 for those who expended 2,700 METs or more in 14 days) adjusting for confounding factors. CONCLUSIONS: In our study, LTPA was positively related to the ABI, with those with PAD being the ones with less LTPA. PMID- 25825221 TI - [Diabetes mellitus and cardiovascular risk: Working group recommendations of Diabetes and Cardiovascular Disease of the Spanish Society of Diabetes (SED, 2015)]. AB - The present paper updates the Clinical Practice Recommendations for the management of cardiovascular risk factors (CVRF) in diabetes mellitus. This is a medical consensus agreed by an independent panel of experts from the Spanish Society of Diabetes (SED). Several consensuses have been proposed by scientific and medical Societies to achieve clinical goals. However, the risk score for general population may lack sensitivity for individual assessment or for particular groups at risk, such as diabetics. Traditional risk factors together with non-traditional factors are reviewed throughout this paper. Intervention strategies for managing CVRF in the diabetic patient are reviewed in detail: balanced food intake, weight reduction, physical exercise, smoking cessation, reduction in HbA1c, therapy for high blood pressure, obesity, lipid disorders, and platelet anti-aggregation. It is hoped that these guidelines can help clinicians in the decisions of their clinical activity. This regular update by the SED Cardiovascular Disease Group of the most relevant concepts, and of greater practical and realistic clinical interest, is presented in order to reduce CVR of diabetics. PMID- 25825222 TI - Alzheimer disease: scanning ultrasound elicits amyloid-beta clearance in mice. PMID- 25825224 TI - Definitive outcomes of self-expandable metal stents in patients with refractory post-transplant biliary anastomotic stenosis. AB - BACKGROUND: Endoscopic retrograde cholangio-pancreatography is the gold standard of treatment in patients with biliary complications after liver transplantation. The benefits of fully covered self-expandable metal stents (FCSEMS) lie in their relative simplicity and the need for only two procedures, one for insertion, and the other for removal. Several case series have been published on such stents with generally good outcomes. Objective is to analyze definitive long-term outcomes of this treatment. METHODS: Prospective, observational study in a single, tertiary-care referral centre. All consecutive patients with post transplant biliary stenosis/leak were treated with FCSEMS after failure of conventional treatment. Recurrence was evaluated after four years. RESULTS: From February 2008 to April 2012, 70 patients were included. In all patients, the metal stent was successfully placed. After a mean of 86.7 +/- 38.4 days, the stent was removed. Forty-six patients (65.7%) showed resolution. After a mean of 4 +/- 1.2 years, 61% of patients maintained the results, but 39% showed recurrence. On the tested variables the diagnosis of stenosis, the number of previous procedures and plastic stents placed correlate with better long-term results. CONCLUSIONS: This series suggests a lack of long-term advantages of FCSEMS over plastic stents in the management of biliary stenosis after liver transplantation. PMID- 25825223 TI - A three-pool model dissecting readily releasable pool replenishment at the calyx of held. AB - Although vesicle replenishment is critical in maintaining exo-endocytosis recycling, the underlying mechanisms are not well understood. Previous studies have shown that both rapid and slow endocytosis recycle into a very large recycling pool instead of within the readily releasable pool (RRP), and the time course of RRP replenishment is slowed down by more intense stimulation. This finding contradicts the calcium/calmodulin-dependence of RRP replenishment. Here we address this issue and report a three-pool model for RRP replenishment at a central synapse. Both rapid and slow endocytosis provide vesicles to a large reserve pool (RP) ~42.3 times the RRP size. When moving from the RP to the RRP, vesicles entered an intermediate pool (IP) ~2.7 times the RRP size with slow RP IP kinetics and fast IP-RRP kinetics, which was responsible for the well established slow and rapid components of RRP replenishment. Depletion of the IP caused the slower RRP replenishment observed after intense stimulation. These results establish, for the first time, a realistic cycling model with all parameters measured, revealing the contribution of each cycling step in synaptic transmission. The results call for modification of the current view of the vesicle recycling steps and their roles. PMID- 25825225 TI - Bully/victims: a longitudinal, population-based cohort study of their mental health. AB - It has been suggested that those who both bully and are victims of bullying (bully/victims) are at the highest risk of adverse mental health outcomes. However, unknown is whether most bully/victims were bullies or victims first and whether being a bully/victim is more detrimental to mental health than being a victim. A total of 4101 children were prospectively studied from birth, and structured interviews and questionnaires were used to assess bullying involvement at 10 years (elementary school) and 13 years of age (secondary school). Mental health (anxiety, depression, psychotic experiences) was assessed at 18 years. Most bully/victims at age 13 (n = 233) had already been victims at primary school (pure victims: n = 97, 41.6 % or bully/victims: n = 47, 20.2 %). Very few of the bully/victims at 13 years had been pure bullies previously (n = 7, 3 %). After adjusting for a wide range of confounders, both bully/victims and pure victims, whether stable or not from primary to secondary school, were at increased risk of mental health problems at 18 years of age. In conclusion, children who are bully/victims at secondary school were most likely to have been already bully/victims or victims at primary school. Children who are involved in bullying behaviour as either bully/victims or victims at either primary or secondary school are at increased risk of mental health problems in late adolescence regardless of the stability of victimization. Clinicians should consider any victimization as a risk factor for mental health problems. PMID- 25825227 TI - Psychosomatic Medicine for Non-Psychiatric Residents: Video Education and Incorporation of Technology. AB - OBJECTIVES: Psychiatric education for non-psychiatric residents varies between training programs, and may affect resident comfort with psychiatric topics. This study's goals were to identify non-psychiatric residents' comfort with psychiatric topics and to test the effectiveness of a video intervention. METHODS: Residents in various departments were given a survey. They were asked to rank their comfort level with multiple psychiatric topics, answer questions about medical decision making capacity (MDMC), watch a 15-min video about MDMC, and answer a post-test section. RESULTS: In total, 91 Internal Medicine, General Surgery, and Obstetrics and Gynecology residents responded to the study. Of the 91 residents, 55 completed the pre- and post-test assessments. There was no significant difference in correct responses. Residents' comfort levels were assessed, and a significant improvement in comfort level with MDMC was found. CONCLUSIONS: This study highlights potential opportunities for psychiatric education, and suggests brief video interventions can increase resident physicians' comfort with a psychiatric topic. PMID- 25825226 TI - The intracellular parasite Toxoplasma gondii depends on the synthesis of long chain and very long-chain unsaturated fatty acids not supplied by the host cell. AB - Apicomplexa are parasitic protozoa that cause important human diseases including malaria, cryptosporidiosis and toxoplasmosis. The replication of these parasites within their target host cell is dependent on both salvage as well as de novo synthesis of fatty acids. In Toxoplasma gondii, fatty acid synthesis via the apicoplast-localized FASII is essential for pathogenesis, while the role of two other fatty acid biosynthetic complexes remains unclear. Here, we demonstrate that the ER-localized fatty acid elongation (ELO) complexes are essential for parasite growth. Conditional knockdown of the nonredundant hydroxyacyl-CoA dehydratase and enoyl-CoA reductase enzymes in the ELO pathway severely repressed intracellular parasite growth. (13) C-glucose and (13) C-acetate labeling and comprehensive lipidomic analyses of these mutants showed a selective defect in synthesis of unsaturated long and very long-chain fatty acids (LCFAs and VLCFAs) and depletion of phosphatidylinositol and phosphatidylethanolamine species containing unsaturated LCFAs and VLCFAs. This requirement for ELO pathway was bypassed by supplementing the media with specific fatty acids, indicating active but inefficient import of host fatty acids. Our experiments highlight a gap between the fatty acid needs of the parasite and availability of specific fatty acids in the host cell that the parasite has to close using a dedicated synthesis and modification pathway. PMID- 25825228 TI - Collaborative Training in Fellowship: Implications for Psychiatric Workforce Development. PMID- 25825229 TI - Risk Indicators for Air Leaks in Preterm Infants Exposed to Restrictive Use of Endotracheal Intubation. AB - OBJECTIVES: To identify perinatal risk indicators for air leaks in preterm infants treated with a policy of restrictive use of endotracheal intubation based on sustained inflations followed by noninvasive ventilation in the delivery room. METHODS: Perinatal variables and variables of respiratory support in the delivery room were analyzed retrospectively in a cohort of 297 inborn preterm infants with a gestational age <29 weeks born in 2005-2009 in a tertiary care center with respect to their associations with air leaks. Multivariate logistic regression analysis was performed to analyze independent risk indicators. RESULTS: Gestational age was 26 weeks + 0 days (22+3 to 28+6), birth weight was 790 g (265 1,660) and 270/297 survived (91.0%). A total of 63 (21.2%) developed air leaks, 32 (10.8%) pneumothorax, 44 (14.8%) pulmonary interstitial emphysema, and 1 (0.3%) pneumopericardium. The infants with air leaks had a higher risk of death (p < 0.01) and of intraventricular hemorrhage grade 3/4 (p < 0.05). Air leaks were associated with less use of prenatal steroids (p < 0.01), more frequent use of cardiac compressions (p < 0.01), use of a pressure of 30 cm H2O for sustained inflations (p < 0.05), and intubation in the delivery room (p < 0.01). After multivariate logistic regression only prenatal steroids (OR 0.41, 0.20-0.85), epinephrine (OR 3.56, 1.55-8.15) and surfactant use (OR 12.03, 3.39-42.72) remained significant. CONCLUSIONS: Our approach resulted in a high survival rate but was associated with a substantial rate of air leaks, which were associated with death and severe intraventricular hemorrhage. Prenatal steroids were protective, and epinephrine and surfactant use were significant risk indicators, whereas the use of sustained inflations was not a risk factor. PMID- 25825230 TI - Choroidal involvement in Rosai-Dorfman syndrome may be depicted and followed using enhanced depth imaging optical coherence tomography (EDI-OCT). PMID- 25825232 TI - Transcartilaginous ear piercing and infectious complications: a systematic review and critical analysis of outcomes. AB - OBJECTIVES/HYPOTHESIS: The purpose of this systematic review was to critically analyze infectious complications and treatment following transcartilaginous ear piercing. DATA SOURCES: MEDLINE Pubmed database. REVIEW METHODS: A MEDLINE PubMed database search using free text, including "ear chondritis," "ear perichondritis," "ear cartilage piercing," and "auricle piercing," yielded 483 titles. Based on set inclusion and exclusion criteria, the titles, abstracts, and full text articles were reviewed for inclusion and underwent data extraction. Pooled outcomes are reported. RESULTS: A total of 29 articles met inclusion criteria, including 66 patients. The mean age of the patients was 18.7 +/- 7.6 years (range: 11-49), 87.5% female. Ear deformity was more likely to occur following postpiercing perichondritis of the scapha 100% versus the helix 43% (P = 0.003). Mean duration of symptoms prior to patients seeking medical attention was 6.1 +/- 4.1 days. Greater than 5 days of symptoms prior to seeking treatment was significantly more likely to result in hospitalization. Pseudomonas aeruginosa accounted for 87.2% infections. Of the patients with Pseudomonas, 92.3% were hospitalized versus 75% of the patients infected with Staphylococcus aureus. Initial oral antibiotics prescribed did not target the cultured bacterium in 53.3% of cases; of these, 87.5% were hospitalized. CONCLUSIONS: Transcartilaginous postpiercing infection may lead to ear deformity and hospitalization. Patients (customers) and practitioners must be aware of optimal treatment strategies to minimize associated morbidity. Scapha piercing and delay in presentation are associated with poorer outcomes. Pseudomonas is the most common bacterial infection. Initial antibiotic selection must be optimized accordingly. PMID- 25825231 TI - Long-term visual outcome and prognostic factors of Intravitreal anti-vascular endothelial growth factor treatment for retinal angiomatous proliferation. AB - PURPOSE: To evaluate the long-term visual outcomes and investigate the prognostic factors of anti-vascular endothelial growth factor (VEGF) therapy for retinal angiomatous proliferation (RAP). METHODS: Thirty-eight treatment-naive RAP eyes (38 patients) that received intravitreal anti-VEGF (ranibizumab and/or bevacizumab) injections were included and analyzed in this retrospective case series. All patients were treated with an initial series of three monthly intravitreal anti-VEGF injections, followed by as-needed injections for a total of 36 months. RESULTS: The mean number of anti-VEGF injections was 9.61 +/- 3.1 during the 36-month follow-up. Mean baseline best-corrected visual acuity (BCVA) was 0.79 +/- 0.56 logarithm of the minimum angle of resolution (logMAR; 20/123 Snellen equivalent), and 0.75 +/- 0.41 logMAR (20/112 Snellen equivalent) at 36 months (P = 0.55). Mean BCVA significantly improved at 3 months (P = 0.001), and the significant improvement persisted until 18 months from baseline (P = 0.02). However, the mean BCVA between 18 and 36 months showed no statistical in comparison with baseline values. Geographic atrophy developed in 14 eyes (36.8 %) during the entire 36-month follow-up period. Among baseline characteristics, baseline BCVA, greatest lesion diameter (GLD), and lesion size were significantly correlated with long-term visual outcome (P = 0.008, 0.02, and 0.002 respectively). CONCLUSIONS: Intravitreal anti-VEGF injections for RAP showed a favorable visual outcome during the first year; however, the visual gains declined after the second year from baseline. Better baseline BCVA, smaller lesion size, and smaller baseline GLD are associated with better long-term visual outcomes in patients with RAP. PMID- 25825234 TI - Bromodomains shake the hegemony of pan-acetyl antibodies. AB - Acetylation signaling pathways are involved in numerous cellular processes and are used as therapeutic targets in several disease contexts. However, acetylated proteins only represent a minor fraction of the full proteome, and the identification and quantification of acetylated sites remain a technological challenge. Currently, pan-acetyl antibodies are used to increase the abundance of acetylated peptides through affinity purification before MS analysis. These antibodies are powerful reagents, but they are hampered by a lack of specificity, affinity, and batch-to-batch reproducibility. In this issue, Bryson et al. (Proteomics 2015 15, 1470-1475) present an interesting alternative to these antibodies, in the form of bromodomains. These domains specifically recognize acetylated lysines, and were successfully used in this study to enrich for acetylated peptides before MS analysis. Future development of this pioneering approach could help overcome this limiting step in the characterization of acetylproteomes. PMID- 25825233 TI - Identification of 24h Ixodes scapularis immunogenic tick saliva proteins. AB - Ixodes scapularis is arguably the most medically important tick species in the United States. This tick transmits 5 of the 14 human tick-borne disease (TBD) agents in the USA: Borrelia burgdorferi, Anaplasma phagocytophilum, B. miyamotoi, Babesia microti, and Powassan virus disease. Except for the Powassan virus disease, I. scapularis-vectored TBD agents require more than 24h post attachment to be transmitted. This study describes identification of 24h immunogenic I. scapularis tick saliva proteins, which could provide opportunities to develop strategies to stop tick feeding before transmission of the majority of pathogens. A 24h fed female I. scapularis phage display cDNA expression library was biopanned using rabbit antibodies to 24h fed I. scapularis female tick saliva proteins, subjected to next generation sequencing, de novo assembly, and bioinformatic analyses. A total of 182 contigs were assembled, of which ~19% (35/182) are novel and did not show identity to any known proteins in GenBank. The remaining ~81% (147/182) of contigs were provisionally identified based on matches in GenBank including ~18% (27/147) that matched protein sequences previously annotated as hypothetical and putative tick saliva proteins. Others include proteases and protease inhibitors (~3%, 5/147), transporters and/or ligand binding proteins (~6%, 9/147), immunogenic tick saliva housekeeping enzyme like (17%, 25/147), ribosomal protein-like (~31%, 46/147), and those classified as miscellaneous (~24%, 35/147). Notable among the miscellaneous class include antimicrobial peptides (microplusin and ricinusin), myosin-like proteins that have been previously found in tick saliva, and heat shock tick saliva protein. Data in this study provides the foundation for in-depth analysis of I. scapularis feeding during the first 24h, before the majority of TBD agents can be transmitted. PMID- 25825236 TI - Trends and timing of cigarette smoking uptake among US young adults: survival analysis using annual national cohorts from 1976 to 2005. AB - AIMS: To measure changes over time in cigarette smoking uptake prevalence and timing during young adulthood (ages 19-26 years), and associations between time invariant/-varying characteristics and uptake prevalence/timing. DESIGN: Discrete time survival modeling of data collected from United States high school seniors (modal age 17/18) enrolled in successive graduating classes from 1976 to 2005 and participating in four follow-up surveys (to modal age 25/26). SETTING: The longitudinal component of the Monitoring the Future study. PARTICIPANTS: A total of 10 758 individuals reporting no life-time smoking when first surveyed as high school seniors. MEASUREMENTS: Smoking uptake (any, experimental, occasional and regular); socio-demographic variables; marital, college and work status; time spent socializing. FINDINGS: The percentage of young adults moving from non smoker to experimental smoking [slope estimate 0.11, standard error (SE) = 0.04, P = 0.005] or occasional smoking (slope estimate 0.17, SE = 0.03, P < 0.001) increased significantly across graduating classes; the percentage moving from non smoker to regular smoker remained stable. All forms of smoking uptake were most likely to occur at age 19/20, but uptake prevalence at older ages increased over time [e.g. cohort year predicting occasional uptake at modal age 25/26 adjusted hazard odds ratio (AHOR) = 1.05, P = 0.002]. Time-invariant/-varying characteristics had unique associations with the timing of various forms of smoking uptake (e.g. at modal age 21/22, currently attending college increased occasional uptake risk (AHOR = 2.11, P < 0.001) but decreased regular uptake risk (AHOR = 0.69, P = 0.026). CONCLUSIONS: Young adult occasional and experimental smoking uptake increased in the United States for non-smoking high school seniors graduating from 1976 to 2005. Smoking uptake for these cohorts remained most likely to occur at age 19/20, but prevalence of uptake at older ages increased. PMID- 25825237 TI - A proteomic analysis on human sperm tail: comparison between normozoospermia and asthenozoospermia. AB - PURPOSE: Asthenozoospermia is a common cause of human male infertility characterized by reduced sperm motility. The molecular mechanism that impairs sperm motility is not fully understood. This study proposed to identify novel biomarkers by focusing on sperm tail proteomic analysis of asthenozoospermic patients. METHODS: Sperm were isolated from normozoospermic and asthenozoospermic semen samples. Tail fractions were obtained by sonication followed by Percoll gradient. The proteins were extracted by solubilization and subjected to two dimensional gel electrophoresis (2-DE); then, the spots were analyzed using Image Master 2D Platinum software. The significantly increased/decreased amounts of proteins in the two groups were exploited by matrix-assisted laser desorption ionization time-of-flight/time-of-flight (MALDI-TOF-TOF) mass spectrometry. RESULTS: Three hundred ninety protein spots were detected in both groups. Twenty one protein spots that had significantly altered amounts (p < 0.05) were excised and exploited using MALDI-TOF-TOF mass spectrometry. They led to the identification of the following 14 unique proteins: Tubulin beta 2B; glutathione S-transferase Mu 3; keratin, type II cytoskeletal 1; outer dense fiber protein 2; voltage-dependent anion-selective channel protein 2; A-kinase anchor protein 4; cytochrome c oxidase subunit 6B; sperm protein associated with the nucleus on the X chromosome B; phospholipid hydroperoxide glutathione peroxidase-mitochondrial; isoaspartyl peptidase/L-asparaginase; heat shock-related 70 kDa protein 2; stress 70 protein, mitochondrial; glyceraldehyde-3-phosphate dehydrogenase, testis specific and clusterin. CONCLUSION: Fourteen proteins present in different amounts in asthenozoospermic sperm tail samples were identified, four of which are reported here for the first time. These proteins might be used as markers for the better diagnosis of sperm dysfunctions, targets for male contraceptive development, and to predict embryo quality. PMID- 25825238 TI - Spry2 regulates signalling dynamics and terminal bud branching behaviour during lung development. AB - Development of mammalian lung involves reiterative outgrowth and branching of an epithelial tube into the surrounding mesenchymal bed. Each coordinated growth and branching cycle is driven by reciprocal signalling between epithelial and adjacent mesenchymal cells. This signalling network includes FGF, SHH, BMP4 and other pathways. We have characterized lung defects in 36Pub mice carrying a deletion that removes an antagonist of FGF signalling, Spry2. Spry2 deficient mice show an enlarged cystic structure located in the terminus of each lobes. Our study shows that Spry2 deficient lungs have reduced lung branching and the cystic structure forms in the early lung development stage. Furthermore, mice carrying a targeted disruption of Spry2 fail to complement the lung phenotype characterized in 36Pub mice. A Spry2-BAC transgene rescues the defect. Interestingly, cystic structure growth is accompanied by the reduced and spatially disorganized expression of Fgf10 and elevated expression of Shh and Bmp4. Altered signalling balance due to the loss of Spry2 causes a delayed branch cycle and cystic growth. Our data underscores the importance of restricting cellular responsiveness to signalling and highlights the interplay between morphogenesis events and spatial localization of gene expression. PMID- 25825240 TI - Brevetoxin, the Dinoflagellate Neurotoxin, Localizes to Thylakoid Membranes and Interacts with the Light-Harvesting Complex II (LHCII) of Photosystem II. AB - The brevetoxins are neurotoxins that are produced by the "Florida red tide" dinoflagellate Karenia brevis. They bind to and activate the voltage-gated sodium channels in higher organisms, specifically the Nav 1.4 and Nav 1.5 channel subtypes. However, the native physiological function that the brevetoxins perform for K. brevis is unknown. By using fluorescent and photoactivatable derivatives, brevetoxin was shown to localize to the chloroplast of K. brevis where it binds to the light-harvesting complex II (LHCII) and thioredoxin. The LHCII is essential to non-photochemical quenching (NPQ), whereas thioredoxins are critical to the maintenance of redox homeostasis within the chloroplast and contribute to the scavenging of reactive oxygen. A culture of K. brevis producing low levels of toxin was shown to be deficient in NPQ and produced reactive oxygen species at twice the rate of the toxic culture, implicating a role in NPQ for the brevetoxins. PMID- 25825239 TI - Downregulation of Sprouty homolog 2 by microRNA-21 inhibits proliferation, metastasis and invasion, however promotes the apoptosis of multiple myeloma cells. AB - The aim of the present study was to assess the effects of sprouty homolog 2 (SPRY2) gene regulation by miR-21 on the occurrence, development and tumor metastasis in multiple myeloma (MM). The miR-21 expression lentiviral vector (LV) anti-miR-21 and a liposome transfection method were used to screen MM cell lines with stable silent SPRY2. Real-time quantitative polymerase chain reaction (PCR) and western blot analyses were used to detect SPRY2 expression and miR-21 protein expression levels. An MTT assay was used to assess cell proliferation. Flow cytometry was used for analysis of cell cycle. A scratch test/wound healing assay was used to detect the cell migration ability. A Transwell assay was used to detect the cell invasion ability. Real-time quantitative PCR and western blot analysis showed that in the MM cell lines with high endogenous miR-21 expression (RPMI8226 and KM3), SPRY2 expression was significantly lower. Conversely, in the U266 cell line with low endogenous miR-21 expression, SPRY2 expression was significantly higher, and the gray values of miR-21 and SPRY2 protein in the respective cell lines showed statistically significant differences (P<0.01). Following transfection of U266 cells, the expression of miR-21 in the U266/LV anti-miR21 lentiviral multiplicity of infection (MOI) 20 group and -MOI 40 group decreased significantly compared with that in the untransfected U266 group (P<0.05). SPRY2 protein expression in U266 cells transfected with miR-21 mimics was significantly reduced compared with that in the non-transfected (untreated) group and the negative control-transfected group (P<0.01). An MTT assay showed that compared with the non-transfected and negative control groups, the cell growth rate as well as the proliferation rate were significantly decreased in the transfection group 48, 72 and 96 h after transfection (P<0.01). Flow cytometric analysis showed that 48 and 72 h after transfection of U266 cells with miR-21 mimics, the apoptotic rates were (24.7 +/- 1.97 and 38.6 +/- 1.56%) in the U266 group, (27.3 +/- 1.72 and 37.3 +/- 1.59%) in the siRNA group and (12.7 +/- 1.27 and 22.1 +/- 1.63%) in the U266/miR-21 group. Compared with the two control groups, the apoptotic rate in the U266/miR-21 group was significantly decreased and the G0/G1 phase cell population was significantly reduced (P<0.05). Scratch experiments showed that the cell migration ability was significantly reduced in the transfection group 24 and 48 h after transfection (P<0.05). A Transwell invasion assay confirmed that the number of U266 cells which migrated through a Matrigel-covered polyphosphate membrane significantly decreased in the transfection group 24 and 48 h after transfection. The cell-penetrating ability was also significantly decreased (P<0.05). In conclusion, the downregulation of SPRY2 gene expression mediated by miR-21 promotes the proliferation and invasion of MM cells in vitro, suggesting that miR-21 may be a novel potential molecular therapeutic target in the treatment of MM. PMID- 25825241 TI - C-peptide and zinc delivery to erythrocytes requires the presence of albumin: implications in diabetes explored with a 3D-printed fluidic device. AB - People with type 1 diabetes (T1D) must administer insulin exogenously due to the destruction of their pancreatic beta-cells. Endogenous insulin is stored in beta cell granules along with C-peptide, a 31 amino acid peptide that is secreted from these granules in amounts equal to insulin. Exogenous co-administration of C peptide with insulin has proven to reduce diabetes-associated complications in animals and humans. The exact mechanism of C-peptide's beneficial effects after secretion from the beta-cell granules is not completely understood, thus hindering its development as an exogenously administered hormone. Monitoring tissue-to-tissue communication using a 3D-printed microfluidic device revealed that zinc and C-peptide are being delivered to erythrocytes by albumin. Upon delivery, erythrocyte-derived ATP increased by >50%, as did endothelium-derived NO, which was measured downstream in the 3D-printed device. Our results suggest that hormone replacement therapy in diabetes may be improved by exogenous administration of a C-peptide ensemble that includes zinc and albumin. PMID- 25825242 TI - MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early onset Parkinson's disease. AB - INTRODUCTION: The motor symptoms and signs of early-onset idiopathic Parkinson's disease (PD) in Hoehn and Yahr (H&Y) stage-1 are generally unilateral. We hypothesized that there would be detectable differences in the quantitative MRI parameters in these PD patients between the hemispheres contralateral to the clinically symptomatic and non-symptomatic body side. METHODS: We tested this hypothesis by comparing transverse relaxation rates and diffusion tensor imaging (DTI) parameters in the substantia nigra and putamen between the two hemispheres contralateral to the symptomatic and non-symptomatic side in H&Y stage-1 PD patients who had onset of symptoms between ages of 40-59 years. RESULTS: There were quantifiable hemispheric asymmetries in transverse relaxation rates in the substantia nigra, as well as fractional anisotropy and mean diffusivity in the putamen in early PD, which correlated with the unilaterality of motor symptoms as evaluated using the motor portion of the Unified Parkinson's Disease Rating Scale. CONCLUSION: Transverse relaxation mapping and DTI demonstrated significant differences between the symptomatic and non-symptomatic hemispheres at the early stage of early-onset PD. These findings support the hypothesis of asymmetric neurodegeneration in the bilateral nigrostriatal pathways in the early stage of the disease. PMID- 25825244 TI - Actinoalloteichus hoggarensis sp. nov., an actinomycete isolated from Saharan soil. AB - A moderately halophilic actinomycete strain, designated AH97T, was isolated from Saharan soil in the Hoggar region (south Algeria) and was subjected to polyphasic taxonomic characterization. The morphological and chemotaxonomic characteristics of the strain were consistent with those of the genus Actinoalloteichus. Results of 16S rRNA gene sequence comparison revealed that strain AH97T shared the highest degree of 16S rRNA gene sequence similarity with Actinoalloteichus hymeniacidonis DSM 45092T (99.3 %) and Actinoalloteichus nanshanensis DSM 45655T (98.7 %). However, DNA-DNA hybridization studies showed only 26.5 % relatedness with A. hymeniacidonis DSM 45092T and 28.0 % with A. nanshanensis DSM 45655T. The genotypic and phenotypic data showed that strain AH97T represents a novel species of the genus Actinoalloteichus, for which the name Actinoalloteichus hoggarensis sp. nov. is proposed, with AH97T ( = DSM 45943T = CECT 8639T) as the type strain. PMID- 25825243 TI - Novel familial dilated cardiomyopathy mutation in MYL2 affects the structure and function of myosin regulatory light chain. AB - Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by left ventricular dilatation and diminished contractile function. Here we describe a novel DCM mutation in the myosin regulatory light chain (RLC), in which aspartic acid at position 94 is replaced by alanine (D94A). The mutation was identified by exome sequencing of three adult first-degree relatives who met formal criteria for idiopathic DCM. To obtain insight into the functional significance of this pathogenic MYL2 variant, we cloned and purified the human ventricular RLC wild type (WT) and D94A mutant proteins, and performed in vitro experiments using RLC mutant or WT-reconstituted porcine cardiac preparations. The mutation induced a reduction in the alpha-helical content of the RLC, and imposed intra-molecular rearrangements. The phosphorylation of RLC by Ca2+/calmodulin-activated myosin light chain kinase was not affected by D94A. The mutation was seen to impair binding of RLC to the myosin heavy chain, and its incorporation into RLC-depleted porcine myosin. The actin-activated ATPase activity of mutant-reconstituted porcine cardiac myosin was significantly higher compared with ATPase of wild type. No changes in the myofibrillar ATPase-pCa relationship were observed in wild-type- or D94A-reconstituted preparations. Measurements of contractile force showed a slightly reduced maximal tension per cross-section of muscle, with no change in the calcium sensitivity of force in D94A-reconstituted skinned porcine papillary muscle strips compared with wild-type. Our data indicate that subtle structural rearrangements in the RLC molecule, followed by its impaired interaction with the myosin heavy chain, may trigger functional abnormalities contributing to the DCM phenotype. PMID- 25825245 TI - Bacillus wuyishanensis sp. nov., isolated from rhizosphere soil of a medical plant, Prunella vulgaris. AB - A Gram-staining-positive, rod-shaped, endospore-forming, aerobic bacterium (FJAT 17212(T)) was isolated from the rhizosphere soil of a medical plant, Prunella vulgaris (common selfheal), on the Wuyishan mountain of China. Isolate FJAT 17212(T) grew at 10-50 degrees C (optimum 30 degrees C), pH 5-11 (optimum pH 7) and with 0-6% (w/v) NaCl (optimum 2%). Phylogenetic analyses based on 16S rRNA gene sequences showed that isolate FJAT-17212(T) was a member of the genus Bacillus and was most closely related to Bacillus galactosidilyticus DSM 15595(T) (97.3%). DNA-DNA relatedness between isolate FJAT-17212(T) and B. galactosidilyticus DSM 15595(T) was low (35.2% +/- 2.3). The diagnostic diamino acid of the peptidoglycan of isolate FJAT-17212(T) was meso-diaminopimelic acid and the predominant isoprenoid quinone was MK-7 (80.8%). The major cellular fatty acids were iso-C15 : 0 (35.7%), anteiso-C15 : 0 (29.8%), iso-C14 : 0 (9.9%) and iso-C16 : 0 (9.9%) and the DNA G+C content was 39.8 mol%. Phenotypic, chemotaxonomic and genotypic properties clearly indicated that isolate FJAT 17212(T) represents a novel species within the genus Bacillus, for which the name Bacillus wuyishanensis sp. nov. is proposed. The type strain is FJAT-17212(T) ( = DSM 27848(T) = CGMCC 1.12709(T)). PMID- 25825246 TI - Mucilaginibacter vulcanisilvae sp. nov., isolated from a volcanic forest. AB - A Gram-stain-negative, strictly aerobic, pale-pink-pigmented bacterium, designated strain G27(T), was isolated from a volcanic forest of Jeju Island, South Korea. Cells were catalase- and oxidase-positive, non-motile rods producing exopolysaccharide and flexirubin-type and pale pink pigments. Growth of strain G27(T) was observed at 4-30 degrees C (optimum, 25 degrees C) and pH 5.0-8.0 (optimum, pH 7.0). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain G27(T) formed a phyletic lineage within the genus Mucilaginibacter of the family Sphingobacteriaceae. Strain G27(T) was related most closely to Mucilaginibacter gossypii Gh-67(T) at 96.5% 16S rRNA gene sequence similarity. Strain G27(T) contained menaquinone 7 (MK-7) as the sole isoprenoid quinone and summed feature 3 (comprising C16:1omega7c/C16:1omega6c), iso-C15:0, C16:0, C16:1omega5c and C16:1omega5c as the major cellular fatty acids. Phosphatidylethanolamine was identified as the major polar lipid. The G+C content of the genomic DNA was 46.5 mol%. On the basis of phenotypic, chemotaxonomic and molecular properties, strain G27(T) represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter vulcanisilvae sp. nov. is proposed. The type strain is G27(T) ( = KACC 18231(T) = JCM 30363(T)). PMID- 25825247 TI - Demequina activiva sp. nov., isolated from a tidal flat. AB - A Gram-stain-positive, facultatively anaerobic, non-spore-forming, non flagellated and rod-shaped or ovoid bacterial strain, designated BS-12M(T), was isolated from a tidal flat sediment on the South Sea, South Korea. Strain BS 12M(T) grew optimally at 35 degrees C, at pH 7.0-8.0 and in the presence of 2.0% (w/v) NaCl. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain BS-12M(T) fell within the cluster comprising the type strains of species of the genus Demequina, joining the type strain of Demequina aestuarii with which it shared the highest sequence similarity (98.6%). It exhibited 16S rRNA gene sequence similarity of 96.1-97.9% to the type strains of other species of the genus Demequina. The peptidoglycan type of strain BS 12M(T) was A4beta based on L-Orn -L-Ser -D-Glu. Strain BS-12M(T) contained demethylmenaquinone-9(H4) as the major menaquinone and anteiso-C15:0 and C16:0 as the major fatty acids. The major polar lipids of strain BS-12M(T) were phosphatidylinositol and phosphatidylinositolmannoside. The DNA G+C content of strain BS-12M(T) was 70.7 mol% and its DNA-DNA relatedness values with the type strains of five phylogenetically related species of the genus Demequina were 15 34%. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, revealed that strain BS-12M(T) is separate from other species of the genus Demequina. On the basis of the data presented, strain BS-12M(T) is considered to represent a novel species of the genus Demequina, for which the name Demequina activiva sp. nov. is proposed. The type strain is BS-12M(T) ( =KCTC 29674(T) = NBRC 110675T). PMID- 25825248 TI - Highly Selective Electrochemical Determination of Taxol Based on ds-DNA-Modified Pencil Electrode. AB - In this research, TiO2/ZrO2 nanocomposite has been prepared using sol-gel method. The TiO2/ZrO2 composite was characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscopy (TEM). A sensitive electrochemical biosensor is also presented for the determination of Taxol based on ds-DNA decorated multiwall carbon nanotubes TiO2/ZrO2-chitosan-modified pencil electrode (ds-DNA-MWNTs-TiO2/ZrO2-CHIT-PGE). The UV spectroscopic data and differential pulse voltammetry revealed that there is a strong interaction between ds-DNA and Taxol. The groove binding of Taxol to ds-DNA helix has been characterized by a red shift (less than 8 nm) in wavelength and the decrease in the differential pulse voltammetry oxidation signal intensity of the Taxol at pencil graphite electrode (PGE) after its interaction with ds DNA. Finally, a pretreated PGE modified with ds-DNA-MWNTs-TiO2/ZrO2-CHIT was tested in order to determine Taxol content in the solution. The dynamic range was from 0.7 to 1874.0 nmol L(-1) with a detection limit of 0.01 nmol L(-1). This sensing platform was successfully applied for the determination of Taxol in pharmaceutical and biological samples. PMID- 25825249 TI - An organophosphorus hydrolase-based biosensor for direct detection of paraoxon using silica-coated magnetic nanoparticles. AB - Rapid detection of organophosphorous (OP) compounds such as paraoxon would allow taking immediate decision on efficient decontamination procedures and could prevent further damage and potential casualties. In the present study, a biosensor based on nanomagnet-silica core-shell conjugated to organophosphorous hydrolase (OPH) enzyme was designed for detection of paraoxon. Coumarin1, a competitive inhibitor of the OPH enzyme, was used as a fluorescence-generating molecule. Upon excitation of cumarin1 located at the active site of the enzyme, i.e., OPH, the emitted radiations were intensified due to the mirroring effect of the nanomagnet-silica core-shell conjugated to the enzyme. In presence of paraoxon and consequent competition with the fluorophore in occupying enzyme's active site, a significant reduction in emitted radiations was observed. This reduction was proportional to paraoxon concentration in the sample. The method worked in the 10- to 250-nM concentration range had a low standard deviation (with a coefficient of variation (CV) of 6-10%), and the detection limit was as low as 5 * 10(-6) MUM. PMID- 25825250 TI - Molecular Cloning, Expression Analysis, and Preliminarily Functional Characterization of the Gene Encoding Protein Disulfide Isomerase from Jatropha curcas. AB - Reactive oxygen species (ROS) in plants, arising from various environmental stresses, impair the thiol-contained proteins that are susceptible to irregular oxidative formation of disulfide bonds, which might be alleviated by a relatively specific modifier called protein disulfide isomerase (PDI). From our previous data of the transcriptome and digital gene expression of cold-hardened Jatropha curcas, a PDI gene was proposed to be cold-relevant. In this study, its full length cDNA (JcPDI) was cloned, with the size of 1649 bp containing the entire open reading frame (ORF) of 1515 bp. This ORF encodes a polypeptide of 504 amino acids with theoretical molecular weight of 56.6 kDa and pI value of 4.85. One N terminal signal peptide (-MASKGSIWSCMFLFSLI VAISAGEG-) and the C-terminal anchoring sequence motif (-KDEL-) specific to the endoplasmic reticulum, as well as two thioredoxin domains (-CGHC-), are also found by predictions. Through semi quantitative RT-PCR, the expression of JcPDI was characterized to be tissue differential strongly in leaves and roots, but weakly in stems, and of cold induced alternations. Furthermore, JcPDI overexpression in yeast could notably enhance the cold resistance of host cells. Conclusively, these results explicitly suggested a considerable association of JcPDI to cold response and a putative application potential for its correlated genetic engineering. PMID- 25825251 TI - Imaging of the subsurface structures of "unroofed" Plasmodium falciparum-infected erythrocytes. AB - Intraerythrocytic stages of Plasmodium falciparum parasites modify the membranes of their host erythrocytes with numerous expressed proteins. They also install new membranous structures in the erythrocyte cytoplasm, including Maurer's clefts (MC) and a tubulovesicular network. These structures support molecular trafficking processes that are necessary for the growth and multiplication of P. falciparum intraerythrocytic stages. To study the morphology and organization of these modifications, we prepared samples of P. falciparum-infected erythrocytes by 'unroofing' techniques and examined them by transmission electron microscopy. Images of the 'unroofed' parasitized erythrocytes feature cytoskeleton alterations and the presence of new membranous structures generated by P. falciparum, including small vesicles and MC connected by extensions to the inner erythrocyte membrane. Non-parasitized erythrocytes showed no evidence of these structures or extensions. In further experiments, we observed a relative absence of MC and extensions after treatment of parasitized erythrocytes with aluminum tetrafluoride (AlF4(-)), an inhibitor of vesicle trafficking. The morphology and physical location of MC, extensions and small vesicles in unroofed specimens are consistent with the role of these structures in the trafficking of P. falciparum proteins to the surface of parasitized erythrocytes. PMID- 25825252 TI - UV irradiation responses in Giardia intestinalis. AB - The response to ultraviolet light (UV) radiation, a natural stressor to the intestinal protozoan parasite Giardia intestinalis, was studied to deepen the understanding of how the surrounding environment affects the parasite during transmission. UV radiation at 10 mJ/cm(2) kills Giardia cysts effectively whereas trophozoites and encysting parasites can recover from UV treatment at 100 mJ/cm(2) and 50 mJ/cm(2) respectively. Staining for phosphorylated histone H2A showed that UV treatment induces double-stranded DNA breaks and flow cytometry analyses revealed that UV treatment of trophozoites induces DNA replication arrest. Active DNA replication coupled to DNA repair could be an explanation to why UV light does not kill trophozoites and encysting cells as efficiently as the non-replicating cysts. We also examined UV-induced gene expression responses in both trophozoites and cysts using RNA sequencing (RNA seq). UV radiation induces small overall changes in gene expression in Giardia but cysts show a stronger response than trophozoites. Heat shock proteins, kinesins and Nek kinases are up regulated, whereas alpha-giardins and histones are down-regulated in UV treated trophozoites. Expression of variable surface proteins (VSPs) is changed in both trophozoites and cysts. Our data show that Giardia cysts have limited ability to repair UV-induced damage and this may have implications for drinking- and waste water treatment when setting criteria for the use of UV disinfection to ensure safe water. PMID- 25825253 TI - Community-Based Groundwater Monitoring Network Using a Citizen-Science Approach. AB - Water level monitoring provides essential information about the condition of aquifers and their responses to water extraction, land-use change, and climatic variability. It is important to have a spatially distributed, long-term monitoring well network for sustainable groundwater resource management. Community-based monitoring involving citizen scientists provides an approach to complement existing government-run monitoring programs. This article demonstrates the feasibility of establishing a large-scale water level monitoring network of private water supply wells using an example from Rocky View County (3900 km(2) ) in Alberta, Canada. In this network, community volunteers measure the water level in their wells, and enter these data through a web-based data portal, which allows the public to view and download these data. The close collaboration among the university researchers, county staff members, and community volunteers enabled the successful implementation and operation of the network for a 5-year pilot period, which generated valuable data sets. The monitoring program was accompanied by education and outreach programs, in which the educational materials on groundwater were developed in collaboration with science teachers from local schools. The methodology used in this study can be easily adopted by other municipalities and watershed stewardship groups interested in groundwater monitoring. As governments are starting to rely increasingly on local municipalities and conservation authorities for watershed management and planning, community-based groundwater monitoring provides an effective and affordable tool for sustainable water resources management. PMID- 25825254 TI - Plasma exchange effectively removes 52- and 60-kDa anti-Ro/SSA and anti-La/SSB antibodies in pregnant women with congenital heart block. AB - BACKGROUND: Pregnant women positive for 52- and 60-kDa anti-Ro/SSA and anti La/SSB antibodies can suffer from congenital heart block (CHB), a passively acquired autoimmune disease. STUDY DESIGN AND METHODS: We evaluated the efficacy of plasma exchange (PE) in removing 52- and 60-kDa anti-Ro/SSA and anti-La/SSB antibodies in pregnant women with CHB treated with a combined therapy including PE, intravenous immunoglobulins, and steroids. Antibody levels were monitored in 10 consecutive pregnant women diagnosed with CHB and prospectively followed between 2009 and 2013. Assaying was performed using a homemade enzyme-linked immunosorbent assay test on blood samples collected immediately before and after PE sessions. RESULTS: A significant decrease in mean post-PE antibody levels was noted in all the cases examined. An analysis of antibody level trends in the samples collected before PE sessions showed that there was a steady, significant decrease in 90% of the patients with 52-kDa anti-Ro/SSA, in 80% of those with 60 kDa anti-Ro/SSA antibodies, and in 100% of those with anti-La/SSB antibodies. CONCLUSION: This study demonstrates that PE is effective in removing antibodies linked to the pathogenesis of CHB. PE treatment was found to have a long-term efficacy in all the women positive for anti-La/SSB antibodies and in most of the women positive for 52- and 60-kDa anti-Ro/SSA antibodies. It is interesting that the significant, immediate, and long-term fall in antibody levels that was observed in these patients took place in all the women whose CHB was reversed. This finding could give PE an important role in the treatment of CHB. PMID- 25825255 TI - Extramedullary disease in multiple myeloma in the era of novel agents. PMID- 25825256 TI - Patient-provider interaction during medication encounters: A study in outpatient pharmacies in the Netherlands. AB - OBJECTIVE: To describe communication between pharmacy staff and patients at the counter in outpatient pharmacies. Both content and communication style were investigated. METHODS: Pharmaceutical encounters in three outpatient pharmacies in the Netherlands were video-recorded. Videos were analyzed based on an observation protocol for the following information: content of encounter, initiator of a theme and pharmacy staff's communication style. RESULTS: In total, 119 encounters were recorded which concerned 42 first prescriptions, 16 first refill prescriptions and 61 follow-up refill prescriptions. During all encounters, discussion was mostly initiated by pharmacy staff (85%). In first prescription encounters topics most frequently discussed included instructions for use (83%) and dosage instructions (95%). In first refill encounters, patient experiences such as adverse effects (44%) and beneficial effects (38%) were regularly discussed in contrast to follow-up refills (7% and 5%). Patients' opinion on medication was hardly discussed. CONCLUSION: Pharmacy staff in outpatient pharmacies generally provide practical information, less frequently they discuss patients' experiences and seldom discuss patients' perceptions and preferences about prescribed medication. PRACTICE IMPLICATIONS: This study shows there is room for improvement, as communication is still not according to professional guidelines. To implement professional guidelines successfully, it is necessary to identify underlying reasons for not following the guidelines. PMID- 25825257 TI - Being reflexive in qualitative grounded theory: discussion and application of a model of reflexivity. AB - AIM: A discussion of the meaning of reflexivity in research with the presentation of examples of how a model of reflexivity was used in a grounded theory research project. BACKGROUND: Reflexivity requires the researcher to make transparent the decisions they make in the research process and is therefore important in developing quality in nursing research. The importance of being reflexive is highlighted in the literature in relation to nursing research, however, practical guidance as to how to go about doing research reflexively is not always clearly articulated. DESIGN: This is a discussion paper. DATA SOURCES: The concept of reflexivity in research is explored using the Alvesson and Skoldberg model of reflexivity and practical examples of how a researcher developed reflexivity in a grounded theory project are presented. IMPLICATIONS FOR NURSING: Nurse researchers are encouraged to explore and apply the concept of reflexivity in their research practices to develop transparency in the research process and to increase robustness in their research. The Alvesson and Skoldberg model is of value in applying reflexivity in qualitative nursing research, particularly in grounded theory research. CONCLUSION: Being reflexive requires the researcher to be completely open about decisions that are made in the research process. The Alvesson and Skolberg model of reflexivity is a useful model that can enhance reflexivity in the research process. It can be a useful practical tool to develop reflexivity in grounded theory research. PMID- 25825258 TI - Comparative Evaluation of Changes in Brain Activity and Cognitive Function of Edentulous Patients, with Dentures and Two-Implant Supported Mandibular Overdenture-Pilot Study. AB - BACKGROUND: The relationship between brain and prosthesis was previously assessed either by improving denture function or in fixed implant retained, wherein brain function was assessed only after crown placement. PURPOSE: To prospectively analyze the changes in brain activity and cognitive function of completely edentulous patients in edentulous state, with dentures and two-implant supported mandibular overdenture before and after loading, along with the effect of mastication in the change - a pilot study. MATERIALS AND METHOD: Ten completely edentulous (CE) non-denture wearers were selected. The mandibular prosthesis was loaded with two 3.3 mm * 13 mm myriad snap fit implants. To assess the brain activity and cognitive function, Electroencephalogram (Neurofax EEG 1000 Ver 05 90, Nihon Kohden corporation, Tokyo, Japan) and Mini-Mental State Examination (MMSE) questionnaire, respectively, were taken during the process of rehabilitation. EEG assessment was analyzed using Matlab 2011A 7.9 signal processing tool box. The results were statistically analyzed with SPSS 17.0 version using Wilcoxon signed rank and Friedman test RESULTS: Amplitude, power of alpha waves and cognitive scores increased gradually with highest mean rank for implant supported overdenture (IOD). The bivariate analysis between two groups showed there was significant difference between all the groups (p < 0.05) except for groups CE-I (completely edentulous - implant placement) and CD- I (complete denture insertion - implant placement) in amplitude of alpha waves while in group CD-I with respect to power of alpha waves. MMSE revealed the mean of cognitive scores in Complete Edentulous was 17.40, Complete Denture was 18.30 and finally with Implant Overdenture was 23.80. CONCLUSION: The present study has enlightened the significance of two implant supported mandibular overdenture in improving the mental state of an individual and that the enhancement was due to functional improvement with prosthesis when loaded with implants and not due to mere existence of implant without any function. PMID- 25825259 TI - Liquid-Crystalline Properties of trans-A2 B2 -Porphyrins with Extended pi Electron Systems. AB - Incorporation of four trialkoxyphenyl substituents combined with extending the pi conjugated system has allowed porphyrins to display liquid-crystalline columnar phases at room temperature. 2D and 3D columnar structures were observed as well as a biaxial smectic phase. PMID- 25825260 TI - Decitabine as a conditioning regimen in haploidentical stem cell transplantation for refractory acute myeloid leukaemia. AB - WHAT IS KNOWN AND OBJECTIVE: Chemotherapy can increase treatment-related mortality associated with future haematopoietic stem cell transplantation (HSCT) for patients with relapsed/refractory acute myeloid leukaemia (AML). There is usually insufficient time to find a suitable unrelated donor for these patients. We report on the use of decitabine, a DNA methyltransferase inhibitor as a conditioning regimen for a patient undergoing HSCT. CASE SUMMARY: Our patient was a 21-year-old male diagnosed with AML-M1 with 84.5% blast cells and a normal karyotype. His risk stratum was intermediate, without specific mutations of FLT3/ITD, NPM1, CEBPA and C-kit. He underwent successful haploidentical HSCT using decitabine, a conditioning regimen. WHAT IS NEW AND CONCLUSION: We present the first report of a patient with refractory AML (with 58% blast cells) treated successfully with decitabine as a conditioning regimen in haploidentical HSCT. PMID- 25825261 TI - Continuous postoperative insulin infusion reduces deep sternal wound infection in patients with diabetes undergoing coronary artery bypass grafting using bilateral internal mammary artery grafts: a propensity-matched analysis. AB - OBJECTIVES: Deep sternal wound infection (DSWI), especially in patients with diabetes mellitus (DM), is a major concern after coronary artery bypass grafting (CABG) with bilateral internal mammary artery (BIMA) grafts. We evaluated the risk of DSWI and other clinical outcomes between continuous insulin infusion therapy (CIT) and insulin sliding scale therapy (IST) in a cohort of DM patients who underwent CABG with BIMA. METHODS: The clinical records of DM patients who underwent isolated CABG with BIMA were retrospectively reviewed. The study population consisted of 95 patients who received CIT and 126 patients who received IST. Furthermore, a one-to-one matched analysis based on estimated propensity scores for patients who received CIT or IST yielded two groups comprising 58 patients each. The proportion of patients with DSWI, overall survival rates and major adverse cardiac events were compared between the two groups in the overall and the propensity-matching cohort. RESULTS: The prevalence of DSWI requiring debridement and closure was significantly reduced in the CIT group compared with that in the IST group [1/95 (1.1%) vs 9/126 (7.1%), P = 0.031]; these results were not attenuated even after propensity-matching analysis [0/58 (0%) vs 6/58 (10.3%), P = 0.031]. The mean preoperative glucose levels were similar between the two groups (157.5 +/- 54.6 vs 176.1 +/- +/-70 mg/dl, P = 0.063), whereas the mean glucose values were significantly lower on the first and second operative days in the CIT group than in the IST group (132.9 +/- 44.1 vs 197.8 +/- 78.6 mg/dl, P < 0.0001; 153.5 +/- 58.8 vs 199.6 +/- 89.1 mg/dl, P < 0.0001, respectively). The glucose variability levels within 24 h postoperatively were significantly higher in the IST group (46.1 +/- 19.4 vs 66.4 +/- 26.8 mg/dl, P < 0.0001). The 30-day and 1-year survival rates were similar between the two groups (100 vs 99.2%, P = 0.384; 96.6 vs 94.4%, P = 0.454). No results were changed in the propensity-matching models. CONCLUSIONS: The CIT approach reduced the variability in glucose concentration and resulted in fewer instances of DSWI after CABG with BIMA grafts. PMID- 25825262 TI - Multislice computed tomography-based prediction of the implantation plane in transcatheter aortic valve implantation: determination of the line of perpendicularity and the implanter's views. AB - OBJECTIVES: We demonstrate a multislice computed tomography (MSCT)-based method to calculate the prediction of the so-called 'line of perpendicularity' (LOP) and the 'implanter's views' (IVs) for transcatheter aortic valve implantation (TAVI) procedures. The LOP represents all possible angiographic angulations that result in an orthogonal view to the aortic annulus plane. The IVs allow visual confirmation of correct implantation planes, and are crucial for the commissural aligned implantation of second-generation TAVI prostheses. METHODS: The LOP and IVs of 335 concomitant patients were prospectively analysed using multiple plane reconstruction (MPR) of the patient's MSCT scans. Exclusion criteria were bicuspid valves (n = 18) and valve-in-valve TAVI (n = 15). In the MPRs, the aortic cusps' lowest points were marked. With the marker's three-dimensional coordinates, the graph of the LOP with the IVs was calculated and plotted using vector mathematics. In the last 244 cases, the IV with the right coronary cusp in front was chosen for the first aortic root angiogram of the TAVI procedure. The finally used angulation was confirmed by aortic angiogram prior to the valve implantation. Solid angle differences that show the combined left anterior oblique/right anterior oblique and cranio/caudal movement of the C-arm allow quantification of corrections as well as demonstrate interindividual variations. RESULTS: There is a broad interindividual variation of the aortic valve's topology with solid angle variations of up to 74 degrees . The shape of the LOPs is extremely varying, especially regarding the slope of the curve that indicates differences in valve orientations. Among the 244 patients for whom we used the prediction for the procedure, the first angiogram was considered perfect for implantation without further corrections in 97% (n = 237) of them. In case of the 7 patients with subsequent corrections, the mean solid angle between the prediction and the final angiogram prior to implantation was 6.2 degrees (+/-5 degrees ); the largest correction was 14 degrees . CONCLUSIONS: Prediction of the implantation plane by analysing the patient's MSCT is highly reliable in achieving an adequate view of the aortic annulus in TAVI. The analysis of LOPs showed the large interindividual differences that permit using a standard implantation plane. Therefore, we strongly recommend determining the LOP and IVs during the patient's screening process in each single TAVI case. PMID- 25825263 TI - Complex posterior thoracic wall reconstruction using a crossover combined latissimus dorsi and serratus anterior free flap. AB - Radical resection of an extended malignant sarcoma of the chest wall requires full-thickness thoracic chest wall reconstruction. Reconstruction is tedious in the case of posteriorly located tumours, because the ipsilateral pedicled myocutaneous latissimus dorsi flap is involved and hence not usable for soft tissue coverage. We report an original case of a left giant dorsal chondrosarcoma originating from the 11th costovertebral joint. After extended resection and skeletal reconstruction, soft tissue coverage was achieved with an original contralateral free flap encompassing both latissimus dorsi and serratus anterior muscles. The flap pedicle was anastomosed to the ipsilateral thoracodorsal vessels. PMID- 25825264 TI - The mortality after surgery in primary lung cancer: results from the Danish Lung Cancer Registry. AB - OBJECTIVES: The study has been performed to investigate the mortality within the first year after resection in patients with primary lung cancer, together with associated prognostic factors including gender, age, tumour stage, comorbidity, alcohol abuse, type of surgery and post-surgical complications. METHODS: All patients (n = 3363) from the nationwide Danish Lung Cancer Registry with first resection performed between 1 January 2007 and 31 December 2011 were analysed by Kaplan-Meier techniques and Cox-regression analysis concerning death within the first year after resection. Covariates included gender, age, comorbidity (Charlson comorbidity index), perioperative stage, type of resection, registered complications to surgery and alcohol abuse. RESULTS: The cumulative deaths after 30 days, 90 days, 180 days and 360 days were 72 (2.1%), 154 (4.6%), 239 (7.1%) and 478 (14.2%), respectively. Low stage, female gender, young age, no comorbidity, no postoperative complications, no alcohol abuse and lobectomy as type of resection were favourable for survival. CONCLUSIONS: Our results demonstrate that resection in primary lung cancer impacts mortality far beyond the initial 30 days after resection, which is conventionally considered a time window of relevance for the adverse outcome of surgery. Increased efforts should be made for optimizing the selection of patients suited for resection and for identifying patients at increased risk of death after resection. Furthermore, patients should be monitored more closely and more frequently, in particular those patients with high risk of death after resection. PMID- 25825266 TI - Self-assembled multifunctional DNA nanospheres for biosensing and drug delivery into specific target cells. AB - Self-assembly of three dimensional nucleic acid nanostructures is of great significance in nanotechnology, biosensing and biomedicine. Herein we present a novel class of multifunctional and programmable DNA nanostructures, termed nanospheres (NSs), with monodispersity, dense compaction and uniform size (~ 200 nm) using only four DNAs based on not only Watson-Crick base pair hybridization between single-stranded DNA but also liquid crystallization and dense packing from periodic DNA duplexes. Due to the diversity of the internal structures, the present NSs can easily evolve into other kinds of DNA assemblies, such as DNA spherical structures with a larger size and a rough surface via rolling circle replication (RCR). Importantly, the functional arms incorporated in building units can be readily designed for biosensing and targeted cancer therapy with high payload capacity and excellent biocompatibility. Therefore, the proposed NSs could lead to novel routes for nucleic acid self-assembly, promising versatile applications in biosensing and biomedicine. PMID- 25825267 TI - Navigating the Alcohol Treatment Pathway: A Qualitative Study from the Service Users' Perspective. AB - AIMS: Provision of effective treatment for dependent drinkers has been identified as a priority in England yet evidence suggests that access is problematic and there are low levels of retention. This qualitative study explores how the alcohol treatment system is experienced by service users, identifying barriers and facilitators that influence treatment outcomes. METHODS: A total of 20 semi structured face-to-face interviews were conducted with patients from community alcohol treatment services in three London boroughs in 2012. Interviews were undertaken one year after initially entering treatment. A thematic analysis was conducted, with the results further abstracted to relate them to specific aspects of the treatment journey. RESULTS: Patients journeys were characterized by a perceived lack of control leading to help-seeking, with treatment outcomes influenced by an individuals' self-efficacy and the capabilities and skills of staff in actively engaging and supporting patients on the journey. A focus of services on the detoxification process and fragmented care pathways impacted negatively on engagement. CONCLUSIONS: Current alcohol care pathways require significant levels of motivation and self-efficacy to navigate that few patients possess. Pathways need to better reflect the capacity and capabilities of patients to be successful in supporting recovery. PMID- 25825268 TI - Augmenting effects of gestational arsenite exposure of C3H mice on the hepatic tumors of the F2 male offspring via the F1 male offspring. AB - Gestational exposure can affect the F2 generation through exposure of F1 germline cells. Previous studies reported that arsenite exposure of only F0 females during their pregnancy increases hepatic tumors in the F1 males in C3H mice, whose males are predisposed spontaneously to develop hepatic tumors later in life. The present study addressed the effects of gestational arsenite exposure on tumorigenesis of the F2 males in C3H mice. Expression analysis of several genes in the normal livers at 53 and 80 weeks of age clearly showed significant changes in the F2 males obtained by crossing gestational arsenite-exposed F1 (arsenite F1) males and females compared to the control F2 males. Some of the changes were shown to occur in a late-onset manner. Then the tumor incidence was assessed at 75-82 weeks of age in the F2 males obtained by reciprocal crossing between the control and arsenite-F1 males and females. The results demonstrated that the F2 males born to arsenite-F1 males developed tumors at a significantly higher rate than the F2 males born to the control F1 males, irrespective of exposure of F1 females. Gene expressions of hepatocellular carcinoma markers beta-catenin (CTNNB1) and interleukin-1 receptor antagonist in the tumors were significantly upregulated in the F2 males born to arsenite-F1 males compared to those born to the control F1 males. These results show that arsenite exposure of only F0 pregnant mice causes late-onset changes and augments tumors in the livers of the F2 males by affecting the F1 male offspring. PMID- 25825265 TI - Effects of chronic treatment with the new ultra-long-acting beta2 -adrenoceptor agonist indacaterol alone or in combination with the beta1 -adrenoceptor blocker metoprolol on cardiac remodelling. AB - BACKGROUND AND PURPOSE: The ability of a chronic treatment with indacaterol, a new ultra-long-acting beta2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective beta1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF). EXPERIMENTAL APPROACH: We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, beta-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg.kg(-1) .day(-1) ; HF + metoprolol 100 mg.kg(-1) .day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks. KEY RESULTS: Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased beta1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group. CONCLUSION AND IMPLICATIONS: The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD. PMID- 25825271 TI - Dissociation of CO2 on rhodium nanoclusters (Rh13) in various structures supported on unzipped graphene oxide--a DFT study. AB - The catalytic activity of rhodium nanoclusters (Rh13) on unzipped graphene oxide (Rh13/UGO) has been investigated for comparison with Rh13 nanoclusters and Rh(111) surfaces. The binding energy of Rh atoms on UGO is less than the cohesive energy (-5.75 eV) of bulk Rh, indicating that the Rh atoms adsorbed on UGO tend to collect into clusters. We systematically calculated the adsorption energies of CO2 on Rh13 nanoclusters in various stable shapes on unzipped graphene oxide; Rh13-Ih/UGO had the highest energy (where the Ih represents icosahedral shape), 1.18 eV, with the C-O bond being elongated from 1.17 to 1.29 A; the barrier to dissociation of CO2 on Rh13-Ih/UGO is, accordingly, the smallest (Ea = 0.45 eV), indicating that Rh13-Ih/UGO might act as an effective material to adsorb and activate the scission of the C-O bond of CO2. The calculated data required to support all evidence of this result, including the electronic distribution and the density of states, are provided. PMID- 25825269 TI - Developmental Changes for the Hemolymph Metabolome of Silkworm (Bombyx mori L.). AB - Silkworm (Bombyx mori) is a lepidopteran-holometabolic model organism. To understand its developmental biochemistry, we characterized the larval hemolymph metabonome from the third instar to prepupa stage using (1)H NMR spectroscopy whilst hemolymph fatty acid composition using GC-FID/MS. We unambiguously assigned more than 60 metabolites, among which tyrosine-o-beta-glucuronide, mesaconate, homocarnosine, and picolinate were reported for the first time from the silkworm hemolymph. Phosphorylcholine was the most abundant metabolite in all developmental stages with exception for the periods before the third and fourth molting. We also found obvious developmental dependence for the hemolymph metabonome involving multiple pathways including protein biosyntheses, glycolysis, TCA cycle, the metabolisms of choline amino acids, fatty acids, purines, and pyrimidines. Most hemolymph amino acids had two elevations during the feeding period of the fourth instar and prepupa stage. Trehalose was the major blood sugar before day 8 of the fifth instar, whereas glucose became the major blood sugar after spinning. C16:0, C18:0 and its unsaturated forms were dominant fatty acids in hemolymph. The developmental changes of hemolymph metabonome were associated with dietary nutrient intakes, biosyntheses of cell membrane, pigments, proteins, and energy metabolism. These findings offered essential biochemistry information in terms of the dynamic metabolic changes during silkworm development. PMID- 25825270 TI - Exploring the nurse practitioner role in managing fractures in long-term care. AB - The purpose of this study was to assess the current level of involvement of nurse practitioners (NPs) in activities related to preventing and managing fractures in long-term care (LTC). This study used a sequential explanatory mixed methods design that included two phases-a cross-sectional survey followed by qualitative interviews. A final sample of 12 NPs completed the online survey for a response rate of 67%. Eleven of the 12 NPs who completed the survey agreed to participate in a follow-up interview. NPs reported that they were quite engaged in managing fractures in LTC; specifically, they were most active in caring for residents post-fracture. NPs described their role as being holistic in nature in their assessment and treatments related to managing fractures. The findings from this mixed method study add to the growing body of knowledge related to how NPs manage fractures in LTC. PMID- 25825272 TI - Hyperosmolarity-Induced Down-Regulation of Claudin-2 Mediated by Decrease in PKCbeta-Dependent GATA-2 in MDCK Cells. AB - Hyperosmolarity decreases claudin-2 expression in renal tubular epithelial cells, but the molecular mechanism remains undefined. Here, we found that the hyperosmolarity-induced decrease in claudin-2 expression is inhibited by Go6983, a non-selective protein kinase C (PKC) inhibitor, and PKCbeta specific inhibitor in Madin-Darby canine kidney II cells. Hyperosmolarity increased intracellular free Ca(2+) concentration and phosphorylated PKCbeta level, which were inhibited by RN-1734, an antagonist of transient receptor potential vanilloid 4 channel. Phorbol 12-myristate 13-acetate, a PKC activator, decreased claudin-2 expression. These results indicate hyperosmolarity decreases claudin-2 expression mediated by the activation of RN-1734-sensitive channel and PKCbeta. Hyperosmolarity decreased promoter activity of claudin-2, which was inhibited by Go6983 and PKCbeta inhibitor similar to those in real-time PCR and Western blotting. The effect of hyperosmolarity on promoter activity was not observed in the construct of -469/-6, a deletion mutant. Claudin-2 has hyperosmolarity-sensitive region in its promoter, which includes GATA binding site. Hyperosmolarity decreased the nuclear level of GATA-2, which was inhibited by Go6983 and PKCbeta inhibitor. Mutation of GATA binding site decreased the basal promoter activity and inhibited the effect of hyperosmolarity. In contrast, the hyperosmolarity-induced decrease in reporter activity and claudin-2 expression were rescued by over-expression of wild type GATA-2. Chromatin immunoprecipitation assay showed that GATA-2 bound to promoter region of claudin-2. These results suggest that hyperosmolarity decreases the expression level of claudin-2 via a decrease in PKCbeta-dependent GATA-2 transcriptional activity in renal tubular epithelial cells. PMID- 25825273 TI - Face it, don't Facebook it: Impacts of Social Media Addiction on Mindfulness, Coping Strategies and the Consequence on Emotional Exhaustion. AB - Addiction to social media has now become a problem that societies are concerned with. The aim of the present study is to investigate the impacts that social media addiction has on mindfulness and choice of coping strategy, as well as to explore the consequences on emotional exhaustion. The survey data were collected from 211 employees in 13 enterprises in Thailand. Results from partial least square structural equation modelling revealed that people who are highly addicted to social media tended to have lower mindfulness and tended to use emotion focused coping to deal with stress. Lack of mindfulness and the decision to use emotion-coping strategy are also subsequently associated with higher emotional exhaustion. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25825274 TI - Thiazolidinediones attenuate lipolysis and ameliorate dexamethasone-induced insulin resistance. AB - BACKGROUND: Elevated levels of circulating free fatty acids induce insulin resistance and often occur in obese and diabetic conditions. One pharmacological basis for the antidiabetic effects of thiazolidinediones (TZDs) is that TZDs reduce levels of circulating FFAs by accelerating their uptake and reesterification from plasma into adipocytes. Here, we investigated whether TZDs affect adipose lipolysis, a process controlling triglyceride hydrolysis and FFA efflux to the bloodstream. METHODS: The effects of TZDs on lipolysis were investigated in primary rat adipocytes in vitro and in rats in vivo. RESULTS: In rat primary adipocytes, the TZDs pioglitazone, rosiglitazone and troglitazone inhibited the lipolytic reaction dose- and time-dependently and in a post receptor pathway by decreasing cAMP level and total lipase activity. TZDs increased the phosphorylation of Akt/protein kinase B, an action required for activating cyclic-nucleotide phosphodiesterase 3B, a major enzyme responsible for cAMP hydrolysis in adipocytes. Furthermore, rosiglitazone inhibited the lipolytic action in dexamethasone-stimulated adipocytes, thereby preventing the increased level of circulating FFAs, and ameliorated insulin resistance in vivo in dexamethasone-treated rats. CONCLUSIONS: TZDs may attenuate lipolysis and FFA efflux by activating Akt signaling to decrease cAMP level and hence reduce lipase activity in adipocytes. Inhibiting lipolysis and FFA efflux with TZDs could be a pharmacological basis by which TZDs antagonize diabetes, particularly in patients with hypercortisolemia or glucocorticoid challenge. PMID- 25825275 TI - A method for measuring instantaneous treadmill speed. AB - This paper presents a new method for measuring instantaneous treadmill speed. The method consists of two parts: (1) a motion-capture system and reflective squares placed directly on the treadmill belt, and (2) an algorithm for estimating belt speed and distance traveled from the measured positions of the reflective squares. The method was tested with a single subject walking on an instrumented treadmill. The method is easy to set up and results in an accurate estimate of treadmill speed that is conveniently synchronized with the output of the motion capture system. PMID- 25825279 TI - Immunology: BiP peptides induce epitope-specific T-cell reactions in RA. PMID- 25825278 TI - Uveitis associated with juvenile idiopathic arthritis. AB - Uveitis is a potentially sight-threatening complication of juvenile idiopathic arthritis (JIA). JIA-associated uveitis is recognized to have an autoimmune aetiology characterized by activation of CD4(+) T cells, but the underlying mechanisms might overlap with those of autoinflammatory conditions involving activation of innate immunity. As no animal model recapitulates all the features of JIA-associated uveitis, questions remain regarding its pathogenesis. The most common form of JIA-associated uveitis is chronic anterior uveitis, which is usually asymptomatic initially. Effective screening is, therefore, essential to detect early disease and commence treatment before the development of visually disabling complications, such as cataracts, glaucoma, band keratopathy and cystoid macular oedema. Complications can result from uncontrolled intraocular inflammation as well as from its treatment, particularly prolonged use of high dose topical corticosteroids. Accumulating evidence supports the early introduction of systemic immunosuppressive drugs, such as methotrexate, as steroid-sparing agents. Prospective randomized controlled trials of TNF inhibitors and other biologic therapies are underway or planned. Future research should aim to identify biomarkers to predict which children are at high risk of developing JIA-associated uveitis or have a poor prognosis. Such biomarkers could help to ensure that patients receive earlier interventions and more-potent therapy, with the ultimate aim of reducing loss of vision and ocular morbidity. PMID- 25825282 TI - Basic research: synovial surfaces use synergy to slide. PMID- 25825283 TI - Recent advances in stem cell-mediated peripheral nerve repair. AB - A major advance in the field of peripheral nerve repair has been the advent of stem and progenitor cell use to supplement the regenerative environment in animal models of nerve injury. As Schwann cell replacements, stem cells may be even better suited to promoting regeneration in these scenarios. We review the recent literature detailing the search for the definitive Schwann cell replacement cell, including a look at genetic modification of transplanted cells for nerve injury repair. PMID- 25825281 TI - Atherosclerosis in rheumatoid arthritis: is it all about inflammation? AB - Rheumatoid arthritis (RA) has long been associated with increased cardiovascular risk, but despite substantial improvements in disease management, mortality remains high. Atherosclerosis is more prevalent in RA than in the general population, and atherosclerotic lesions progress at a faster rate and might be more prone to rupture, causing clinical events. Cells and cytokines implicated in RA pathogenesis are also involved in the development and progression of atherosclerosis, which is generally recognized as an inflammatory condition. The two diseases also share genetic and environmental risk factors, which suggests that patients who develop RA might also be predisposed to developing cardiovascular disease. In RA, inflammation and atherosclerosis are closely linked. Inflammation mediates its effects on atherosclerosis both through modulation of traditional risk factors and by directly affecting the vessel wall. Treatments such as TNF inhibitors might have a beneficial effect on cardiovascular risk. However, whether this benefit is attributable to effective control of inflammation or whether targeting specific cytokines, implicated in atherosclerosis, provides additional risk reduction is unclear. Further knowledge of the predictors of cardiovascular risk, the effects of early control of inflammation and of drug-specific effects are likely to improve the recognition and management of cardiovascular risk in patients with RA. PMID- 25825284 TI - Suberoylanilide hydroxamic acid treatment reveals crosstalks among proteome, ubiquitylome and acetylome in non-small cell lung cancer A549 cell line. AB - Suberoylanilide hydroxamic acid (SAHA) is a well-known histone deacetylase (HDAC) inhibitor and has been used as practical therapy for breast cancer and non-small cell lung cancer (NSCLC). It is previously demonstrated that SAHA treatment could extensively change the profile of acetylome and proteome in cancer cells. However, little is known about the impact of SAHA on other protein modifications and the crosstalks among different modifications and proteome, hindering the deep understanding of SAHA-mediated cancer therapy. In this work, by using SILAC technique, antibody-based affinity enrichment and high-resolution LC-MS/MS analysis, we investigated quantitative proteome, acetylome and ubiquitylome as well as crosstalks among the three datasets in A549 cells toward SAHA treatment. In total, 2968 proteins, 1099 acetylation sites and 1012 ubiquitination sites were quantified in response to SAHA treatment, respectively. With the aid of intensive bioinformatics, we revealed that the proteome and ubiquitylome were negatively related upon SAHA treatment. Moreover, the impact of SAHA on acetylome resulted in 258 up-regulated and 99 down-regulated acetylation sites at the threshold of 1.5 folds. Finally, we identified 55 common sites with both acetylation and ubiquitination, among which ubiquitination level in 43 sites (78.2%) was positive related to acetylation level. PMID- 25825285 TI - Gray matter atrophy in narcolepsy: An activation likelihood estimation meta analysis. AB - The authors reviewed the literature on the use of voxel-based morphometry (VBM) in narcolepsy magnetic resonance imaging (MRI) studies via the use of a meta analysis of neuroimaging to identify concordant and specific structural deficits in patients with narcolepsy as compared with healthy subjects. We used PubMed to retrieve articles published between January 2000 and March 2014. The authors included all VBM research on narcolepsy and compared the findings of the studies by using gray matter volume (GMV) or gray matter concentration (GMC) to index differences in gray matter. Stereotactic data were extracted from 8 VBM studies of 149 narcoleptic patients and 162 control subjects. We applied activation likelihood estimation (ALE) technique and found significant regional gray matter reduction in the bilateral hypothalamus, thalamus, globus pallidus, extending to nucleus accumbens (NAcc) and anterior cingulate cortex (ACC), left mid orbital and rectal gyri (BAs 10 and 11), right inferior frontal gyrus (BA 47), and the right superior temporal gyrus (BA 41) in patients with narcolepsy. The significant gray matter deficits in narcoleptic patients occurred in the bilateral hypothalamus and frontotemporal regions, which may be related to the emotional processing abnormalities and orexin/hypocretin pathway common among populations of patients with narcolepsy. PMID- 25825286 TI - The Genome of Dendrobium officinale Illuminates the Biology of the Important Traditional Chinese Orchid Herb. AB - Dendrobium officinale Kimura et Migo is a traditional Chinese orchid herb that has both ornamental value and a broad range of therapeutic effects. Here, we report the first de novo assembled 1.35 Gb genome sequences for D. officinale by combining the second-generation Illumina Hiseq 2000 and third-generation PacBio sequencing technologies. We found that orchids have a complete inflorescence gene set and have some specific inflorescence genes. We observed gene expansion in gene families related to fungus symbiosis and drought resistance. We analyzed biosynthesis pathways of medicinal components of D. officinale and found extensive duplication of SPS and SuSy genes, which are related to polysaccharide generation, and that the pathway of D. officinale alkaloid synthesis could be extended to generate 16-epivellosimine. The D. officinale genome assembly demonstrates a new approach to deciphering large complex genomes and, as an important orchid species and a traditional Chinese medicine, the D. officinale genome will facilitate future research on the evolution of orchid plants, as well as the study of medicinal components and potential genetic breeding of the dendrobe. PMID- 25825288 TI - Doctors are warned not to prescribe generic pregabalin for pain control. PMID- 25825287 TI - The branched CcsA/CckA-ChpT-CtrA phosphorelay of Sphingomonas melonis controls motility and biofilm formation. AB - The CckA-ChpT-CtrA phosphorelay is central to the regulation of the cell cycle in Caulobacter crescentus. The three proteins are conserved in Alphaproteobacteria, but little is known about their roles in most members of this class. Here, we characterized the system in Sphingomonas melonis. We found that the transcription factor CtrA is the master regulator of flagella synthesis genes, the hierarchical transcriptional organization of which is herein described. CtrA also regulates genes involved in exopolysaccharide synthesis and cyclic-di-GMP signaling, and is important for biofilm formation. In addition, the ctrA mutant exhibits an aberrant morphology, suggesting a role for CtrA in cell division. An analysis of the regulation of CtrA indicates that the phosphorelay composed of CckA and ChpT is conserved and that the absence of the bifunctional kinase/phosphatase CckA apparently results in overactivation of CtrA through ChpT. Suppressors of this phenotype identified the hybrid histidine kinase CcsA. Phosphorelays initiated by CckA or CcsA were reconstituted in vitro, suggesting that in S. melonis, CtrA phosphorylation is controlled by a branched pathway upstream of ChpT. This study thus suggests that signals can directly converge at the level of ChpT phosphorylation through multiple hybrid kinases to coordinate a number of important physiological processes. PMID- 25825290 TI - Micronutrients in the treatment of stunting and moderate malnutrition. AB - Linear growth retardation or stunting may occur with or without low weight-for age, but in both cases stunted or moderately malnourished children are deficient in micronutrients. Pregnancy and the first 2 years are critical periods. Dietary deficiency of zinc, iron, calcium, and vitamin A are especially common and often occur together. Zinc is essential for adequate growth, and supplements have been shown to increase intrauterine femur length and to prevent stunting. However, in general, supplements which provide a mixture of micronutrients have been more successful in preventing stunting and are simpler to take and distribute. Multiple micronutrients together with energy and macronutrients are also needed for the management of moderate malnutrition. Multiple micronutrients may be delivered as medicinal-like supplements, but may also be combined with food, for instance in milk drinks, in fortified dried cereal mixes used to supplement complementary foods or in lipid nutrition supplements. The latter also provide essential fats necessary for growth. Micronutrient powders for home fortification are effective in preventing anemia, but present combinations do not prevent stunting. Improving the diets of infant and young children is also possible, and increased intake of animal source foods can improve growth. PMID- 25825291 TI - Discussion on micronutrient requirements. PMID- 25825289 TI - Global micronutrient deficiencies in childhood and impact on growth and survival: challenges and opportunities. AB - Despite numerous advances and improvements in child health, malnutrition still remains as one of the main public health challenges of the 21st century, particularly in developing countries. It undermines the survival, growth and development of children, and is associated with almost 35% of all deaths in children under the age of 5 years worldwide. An estimated 178 million children are stunted globally, and an additional 19 million children have severe acute malnutrition (wasting). These conditions are very often associated with concomitant micronutrient deficiencies, and among these, vitamin A, iron, zinc and iodine deficiencies are the most prevalent in childhood. Vitamin A and zinc deficiency is associated with an estimated 1 million child deaths and 9% of global childhood disability-adjusted life years. Recent data on the timing of growth retardation and stunting in infants suggest that the onset is commensurate with inappropriate complementary feeding and potentially compounded by maternal undernutrition and intrauterine growth retardation, and that the first 24 months represent a critical window of opportunity for intervention. Given the wide prevalence of multiple micronutrient deficiencies in malnourished children in developing countries, the challenge is to implement intervention strategies that combine appropriate infant and young child feeding with micronutrient interventions at scale. Emerging data from community intervention trials now provide evidence that this is both tangible and can lead to alleviation of childhood undernutrition. Some of these recent findings will be discussed. PMID- 25825292 TI - Zinc requirements: assessment and population needs. AB - Reliable estimates of zinc requirements have assumed greater priority as the global public health importance of preventing zinc deficiency has gained increasing recognition. On a global public health basis, our first most evident goal is reliable estimates of average population requirements. Despite expectations of rapid advances towards simpler and more sophisticated strategies, estimations of zinc requirements continue to depend on a factorial approach. Since the Dietary Reference Intakes (DRIs) were published, there have been important advances in techniques for the factorial approach but also confusion resulting from the subsequent publication of conflicting 'international' estimates. The reasons for these differences have now been fully elucidated, removing an obstruction to continuing progress and refinements of our knowledge base. A key advance has been the development and validation of a model that can be simply applied to determine the inhibitory effects of phytate on zinc absorption. Better understanding of maternal and young child zinc requirements continues to present a challenge of special importance. PMID- 25825295 TI - Global burden and significance of multiple micronutrient deficiencies in pregnancy. AB - Maternal mortality, low birthweight infants and childhood stunting continue to be major global public health problems, part of a recurring cycle of disadvantage. Maternal undernutrition in particular is one of the most neglected aspects of nutrition in public health. One possible low-cost public health intervention that might help address these problems is the antenatal provision of multiple micronutrient supplements. If the evidence base could be established, cost effectiveness found to be acceptable and safety ensured, supplementation could ameliorate the impact of poor nutrition and diets, high disease burdens and the sociocultural factors contributing to these problems. There have been good studies in over a dozen countries addressing some of these issues but with conflicting results. Consequently, at least three meta-analyses have been undertaken to establish significant findings that could help guide policies and programs. They concluded that multimicronutrient supplementation improves birthweight and likely reduces the number of infants born low birthweight. Supplementation with iron-folic acid or multimicronutrients also appears to have positive longer-term impacts on the health and development of the offspring. There remain concerns about possible increased infant mortality in some populations. Given the results of the meta-analyses, cautious scaling-up of country effectiveness trials appears justified with careful monitoring and evaluation. PMID- 25825294 TI - Discussion on zinc in maternal and child health. PMID- 25825293 TI - Role of zinc in child health and survival. AB - Zinc deficiency has been estimated to result in more than 450,000 child deaths annually by increasing the risk of diarrhea and pneumonia mortality. Trials of daily supplemental zinc have shown preventive benefits in childhood diarrhea with a 20% reduction in incidence. Use of zinc in treatment of diarrhea has also been successful in shortening the duration of the episode by 10% and reducing the number of prolonged episodes. The World Health Organization recommends that zinc supplements be used for 10-14 days for every episode of childhood diarrhea along with oral hydration and feeding. Large-scale effectiveness trials of these recommendations in Bangladesh and India have found a reduction in hospitalizations due to diarrhea and pneumonia and in child mortality. Trials have also demonstrated a reduction in the incidence childhood pneumonia with zinc supplements and some, but not all, studies have found a therapeutic benefit of zinc as adjunctive treatment along with antibiotics as well. Preventive zinc also improves the growth of children in developing countries and reduces total deaths in 1-to 4-year-old children by 18%. Zinc supplementation is an intervention with proven effectiveness and broad application to address pneumonia and diarrhea, the two most important childhood infectious diseases globally. PMID- 25825296 TI - Intervention strategies to address multiple micronutrient deficiencies in pregnancy and early childhood. AB - Deficiencies of multiple micronutrients are prevalent among women of reproductive age and young children, and represent a risk factor for increased morbidity and mortality in these women and children. The role of multiple micronutrient supplementation during pregnancy and early childhood has been evaluated in randomized trials. Multiple micronutrient supplementation during pregnancy has a positive effect on birthweight and reduces prevalence of low birthweight and small for gestational age babies. It had comparable effects on prevalence of anemia regarding iron-folate supplementation. Multiple micronutrient supplementations in children have been shown to improve linear growth, weight, hemoglobin, serum zinc, serum retinol levels and motor development. Some of the most commonly used strategies to deliver multiple micronutrients include powders (e.g. Sprinkles((r))), crushable tablets (e.g. Foodlets), etc. Multiple micronutrient supplementation during pregnancy and early childhood seems to be an effective way of prevention of micronutrient deficiencies and has a significant protective effect against adverse outcomes related to their deficiencies. Their use on a larger scale should be considered to improve the survival and decrease morbidity and mortality in children and women. PMID- 25825298 TI - Vitamin A supplementation, infectious disease and child mortality: a summary of the evidence. AB - This manuscript reviews the evidence related to the effects of vitamin A (VA) supplementation of women and children on child health and mortality. VA supplementation of children aged 6-59 months has been well studied, and meta analyses have consistently demonstrated effects on all-cause mortality, yet its mechanisms and the reasons for heterogeneous effects on mortality across trials continue to be debated. Recent meta-analysis of cause-specific mortality suggests beneficial effects on diarrheal mortality, with null but potentially beneficial effects also present for mortality from measles, lower respiratory infection, and meningitis. Some evidence suggests that pneumonia severity may increase with VA supplementation in this age group, particularly among well-nourished children. Maternal supplementation with VA during pregnancy has not shown benefits on neonatal mortality in large trials. A recent meta-analysis suggested that high dose supplementation of lactating women immediately following delivery did not affect child survival. There is still uncertainty around the benefits of neonatal VA supplementation that should be resolved once the findings of ongoing trials are reported. PMID- 25825297 TI - Summary on micronutrient requirements and deficiencies in maternal and child nutrition. PMID- 25825299 TI - Issues and controversies with vitamin A in childhood. AB - Vitamin A deficiency is common in the developing world. Vitamin A supplementation (VAS) has been used to prevent or treat vitamin A deficiency and to decrease mortality and morbidity in children. However, there are still controversial issues in relation to the role of universal VAS in different populations. Thus, studies that look at mortality outcomes reveal that VAS decreases mortality in children >6 months of age; however, there is still controversy on the extent to which reduction in morbidity from diarrhea and respiratory infection, other than measles, decreases mortality. Studies in infants 1-5 months old show no protective effect of VAS on mortality; whether this is secondary to environmental influences (breastfeeding), or interactions with DTP vaccine, needs to be further investigated. Studies with VAS in newborns have resulted in contrasting results in countries in Africa and Asia; trials are underway to better understand this. VAS does not have a universal protective effect on lower respiratory tract infection in children; some studies reveal an increase in respiratory morbidity associated with VAS, especially in well-nourished children; in contrast, VAS may confer some protection to malnourished children. The interaction of VAS with different vaccines is under current debate; some discussions are presented. PMID- 25825300 TI - Discussion on vitamin A supplementation in childhood. PMID- 25825301 TI - Discussion on iron. PMID- 25825302 TI - Summary on vitamin A and iron. PMID- 25825303 TI - Are weaning infants at risk of iodine deficiency even in countries with established iodized salt programs?. AB - Because iodine deficiency (ID) during infancy can irreversibly impair neurodevelopment and increase mortality, it is critical that dietary iodine is adequate in this vulnerable group. Lactating mothers consuming iodized salt can transfer adequate iodine to the infant via breast milk, but during the weaning period, infants are at risk for ID for several reasons: (1) requirements per kg bodyweight for iodine and thyroid hormone during infancy are higher than at any other time in the life cycle; (2) experts recommend no extra salt (iodized or not) be given to infants during the first year; (3) cow's milk (a major source of dietary iodine in many countries) is also not recommended for infants during the first year; and (4) iron deficiency, a common disorder during infancy, can impair iodine metabolism and reduce thyroid hormone production. For many weaning infants in industrialized countries, iodine fortified into commercial infant foods becomes important. This has recently been demonstrated in Switzerland, where a long-standing iodized salt program provides adequate iodine to pregnant women and school-age children, but new national data suggest weaning infants not receiving iodine-containing commercial baby foods have inadequate iodine intakes. Thus, even in countries with effective iodized salt programs, infants may be at risk of ID during weaning and may need additional dietary and/or supplemental sources of iodine. PMID- 25825304 TI - Current challenges in meeting global iodine requirements. AB - Iodine deficiency is a global problem of immense magnitude afflicting 2 billion of the world's population. The adverse effects of iodine deficiency in humans, collectively termed iodine deficiency disorders, result from decreased thyroid hormone production and action, and vary in severity from thyroid enlargement (goiter) to severe, irreversible brain damage, termed endemic cretinism. Thyroid hormone is essential throughout life, but it is critical for normal brain development in the fetus and throughout childhood. During pregnancy, maternal thyroid hormone production must increase by 25-50% to meet maternal-fetal requirements. The principal sources of iodine in the diet include milk and dairy products, seafoods and foods with added iodized salt. Vegetables, fruits and cereals are generally poor sources of iodine because most of our soils and water supplies are deficient in iodine. The accepted solution to the problem is Universal Salt Iodization where all salt for human and animal consumption is iodized at a level of 20-40 ug/g. In principle, mandatory fortification represents the most effective public health strategy where safety and efficacy can be assured and there is a demonstrated need for the nutrient in the population. Voluntary fortification of salt and other foods has many limitations and few benefits. Iodine supplementation is a useful, but expensive, inefficient and unsustainable strategy for preventing iodine deficiency. The current worldwide push to decrease salt intake to prevent cardiovascular disease presents an entirely new challenge in addressing iodine deficiency in both developing and developed countries. PMID- 25825305 TI - Folate and vitamin B12: function and importance in cognitive development. AB - The importance of the B vitamins folate and vitamin B12 for healthy neurological development and function is unquestioned. Folate and vitamin B12 are required for biological methylation and DNA synthesis. Vitamin B12 also participates in the mitochondrial catabolism of odd-chain fatty acids and some amino acids. Inborn errors of their metabolism and severe nutritional deficiencies cause serious neurological and hematological pathology. Poor folate and vitamin B12 status short of clinical deficiency is associated with increased risk of cognitive impairment, depression, Alzheimer's disease and stroke among older adults and increased risk of neural tube defects among children born to mothers with low folate status. Folate supplementation and food fortification are known to reduce incident neural tube defects, and B vitamin supplementation may have cognitive benefit in older adults. Less is known about folate and vitamin B12 requirements for optimal brain development and long-term cognitive health in newborns, children and adolescents. While increasing suboptimal nutritional status has observed benefits, the long-term effects of high folate intake are uncertain. Several observations of unfavorable health indicators in children and adults exposed to high folic acid intake make it imperative to achieve a more precise definition of folate and B12 requirements for brain development and function. PMID- 25825306 TI - Discussion on folate and vitamin B12 importance in cognitive development. PMID- 25825307 TI - Pros and cons of increasing folic acid and vitamin B12 intake by fortification. AB - There is no doubt that folic acid fortification can be effective for reducing the incidence of neural tube defects. The degree of efficacy depends on both the level of folate depletion and other, yet to be fully characterized, genetic and/or environmental factors. This article summarizes briefly data on neural tube defect reduction and other benefits of folic acid fortification as these have been reviewed in more detail elsewhere. More attention is drawn to questions that have been raised about the possible adverse effects of folic acid fortification including the incidence of colorectal cancer and immune function. The main question addressed here is whether folic acid fortification can exacerbate the adverse effects of vitamin B12 deficiency. Most analyses of this question have been conducted in wealthier countries based on data from elderly populations - which have the highest prevalence of vitamin B12 deficiency. However, of potentially greater concern is the increasingly common practice of folic acid fortification in developing countries, where folate status is probably often adequate even prior to fortification, and vitamin B12 depletion or deficiency is common. To add to this information, data from a group of Chilean elderly with a range of vitamin B12 status and exposed to high levels of folic acid fortification will be presented. PMID- 25825308 TI - Discussion on vitamin B12 and folic acid fortification. PMID- 25825309 TI - Summary on iodine folate and vitamin B12. PMID- 25825312 TI - Population Structure and Seasonal Migration of the Spotted Eagle Ray, Aetobatus narinari. AB - Few studies have reported on the fine-scale population genetics of batoid species in the Atlantic basin. Here, we investigate the genetic diversity and population structure of the spotted eagle ray, Aetobatus narinari, sampled in the northeastern and southwestern parts of the Gulf of Mexico and in the northwestern Caribbean Sea. Samples were collected from 286 individuals sampled across 3 geographic localities. Estimates of divergence based on the mitochondrial cytochrome b gene and 10 nuclear microsatellite loci reveal weak but significant genetic structure among A. narinari populations in this region. Analysis of molecular variance estimates based on both marker types indicate significant differentiation between Florida and Mexico populations, while comparisons with Cuba suggest high levels of gene flow with rays from both Mexico and Florida. Conflicting results were found from the different marker types when sexes were analyzed separately underscoring the importance of applying multiple marker types when making inferences about population structure and sex-biased dispersal. Results from Bayesian clustering analyses suggest rays may be migrating south out of the Gulf of Mexico and into the northwestern Caribbean Sea. Given the impacts of fisheries on this species, coupled with the lack of population genetic data available, these findings offer valuable information to aid with conservation management strategies. PMID- 25825313 TI - The Arctic: Glacial Refugium or Area of Secondary Contact? Inference from the Population Genetic Structure of the Thick-Billed Murre (Uria lomvia), with Implications for Management. AB - Quaternary glaciations affected the distribution of many species. Here, we investigate whether the Arctic represented a glacial refugium during the Last Glacial Maximum or an area of secondary contact following the ice retreat, by analyzing the genetic population structure of the thick-billed murre (Uria lomvia), a seabird that breeds throughout the North Atlantic, North Pacific and Arctic Oceans. The thick-billed murre is a species of socio-economic importance and faces numerous threats including hunting, oil pollution, gill netting, and climate change. We compared variation in the mitochondrial DNA (mtDNA) control region (n = 424), supplemented by 4 microsatellite loci (n = 445), among thick billed murres sampled throughout their range. MtDNA data indicated that colonies comprise 4 genetically differentiated groups (Phist = 0.11-0.81): 1) Atlantic Ocean plus New Siberian Islands region, 2) Cape Parry, 3) Chukchi Sea, and 4) Pacific Ocean. Microsatellite variation differed between Atlantic and Pacific populations. Otherwise, little substructure was found within either ocean. Atlantic and Pacific populations appear to have been genetically isolated since the last interglacial period and should be considered separate evolutionary significant units for management. The Chukchi Sea and Cape Parry appear to represent areas of secondary contact, rather than arctic refugial populations. PMID- 25825314 TI - Higher adenoma recurrence rate after left- versus right-sided colectomy for colon cancer. AB - BACKGROUND: Patients with history of colonic resection for cancer have an increased risk of the development of metachronous malignant and premalignant lesions. Scanty data are reported on detection rates of premalignant lesions during colonoscopy surveillance in this setting. OBJECTIVE: To assess the risk of metachronous precancerous lesions developing in patients with previous colonic surgery for cancer according to the resection type. DESIGN: Retrospective study. SETTING: Two academic centers in Italy. PATIENTS: A total of 441 patients; 256 with previous left-sided colectomy (LCR) (LCR group) and 185 with previous right sided colectomy (RCR) (RCR group). INTERVENTIONS: Second surveillance colonoscopy. MAIN OUTCOME MEASUREMENTS: Polyp and adenoma detection rates. RESULTS: At least 1 adenoma was diagnosed in 76 of 256 patients (30% adenoma detection rate) and in 35 of 185 patients (19% adenoma detection rate) in the LCR and RCR groups, respectively (P=.014), yielding an odds ratio of 1.83 (95% confidence interval, 1.16-2.89). Corresponding figures for the polyp detection rate were 39% and 25%, respectively (P=.002; odds ratio 1.97; 95% confidence interval, 1.30-3.00). LIMITATIONS: Retrospective study with colonoscopy baseline information missing. CONCLUSIONS: Patients who have undergone LCR are at higher risk of the development of adenomas than those who have undergone RCR. If this result is confirmed by large prospective studies, surveillance programs could be targeted according to the type of colonic resection, with longer intervals for patients with previous RCR compared with LCR. PMID- 25825315 TI - Intraductal cholangioscopic visualization of moving Fasciola hepatica. PMID- 25825316 TI - Endoscopic features of lymphoproliferative diseases. PMID- 25825317 TI - Splenic trauma: Save patients in shock and save the spleen in stable patients! PMID- 25825319 TI - Analysis Grid for Environments Linked to Obesity (ANGELO) framework to develop community-driven health programmes in an Indigenous community in Canada. AB - Indigenous First Nations people in Canada have high chronic disease morbidity resulting in part from enduring social inequities and colonialism. Obesity prevention strategies developed by and for First Nations people are crucial to improving the health status of this group. The research objective was to develop community-relevant strategies to address childhood obesity in a First Nations community. Strategies were derived from an action-based workshop based on the Analysis Grid for Environments Linked to Obesity (ANGELO) framework. Thirteen community members with wide-ranging community representation took part in the workshop. They combined personal knowledge and experience with community-specific and national research to dissect the broad array of environmental factors that influenced childhood obesity in their community. They then developed community specific action plans focusing on healthy eating and physical activity for children and their families. Actions included increasing awareness of children's health issues among the local population and community leadership, promoting nutrition and physical activity at school, and improving recreation opportunities. Strengthening children's connection to their culture was considered paramount to improving their well-being; thus, workshop participants developed programmes that included elders as teachers and reinforced families' acquaintance with First Nations foods and activities. The research demonstrated that the ANGELO framework is a participatory way to develop community-driven health programmes. It also demonstrated that First Nations people involved in the creation of solutions to health issues in their communities may focus on decolonising approaches such as strengthening their connection to indigenous culture and traditions. External funds were not available to implement programmes and there was no formal follow-up to determine if community members implemented programmes. Future research needs to examine the extent to which community members can implement programmes on their own and whether community action plans, when implemented, lead to short- and long-term benefits in health outcomes. PMID- 25825320 TI - Skin targeted lipid vesicles as novel nano-carrier of ketoconazole: characterization, in vitro and in vivo evaluation. AB - Liposomal carriers for topical drug delivery have been studied since the 1980s and have evoked a considerable interest. However, the conventional liposomes do not deeply penetrate into the skin and remain confined to the outer layer of SC. In order to increase skin targeting of ketoconazole (KCZ), a hydrophobic broad spectrum antifungal agent, this study describes novel lipid vesicles as nano carriers for topical delivery. In this paper, lipid vesicular systems including conventional liposomes (CL), ethosomes, deformable liposomes (DL) and ethanol containing deformable liposomes (DEL) were prepared as nano-carriers for KCZ, respectively. Sodium dodecyl sulfate [SDS, 0.08 % (W/V)] was used as edge activator for DL and DEL preparation. Characterization of the vesicles was based on particle size, zeta potential, entrapment efficiency and transmission electron microscopy (TEM). In addition, in vitro permeation profile was obtained using vertical diffusion Franz cells by porcine skin. The in vivo accumulation of KCZ was also evaluated in rat skin. Confocal microscopy was performed to visualize the penetration of fluorescently labeled vesicles into skin. All of the lipid vesicles showed almost spherical structures with low polydispersity index (PDI < 0.3) and nano-metric size (no more than 160 nm). The results demonstrated that DEL dramatically improved both in vitro and in vivo skin deposition compared to the CLs (P < 0.05), which was further confirmed by confocal laser scanning microscopy study. In vivo pharmacodynamic studies showed DEL improved antifungal activity against Candida albicans in shorter duration of time. Therefore, based on present study, the novel nano-carrier DEL capable of enhancing skin target effect and forming a micro drug-depot could serve as an effective skin targeting delivery for KCZ as an anti-fungal agent in local therapy. PMID- 25825322 TI - A polycrystalline SiO2 colloidal crystal film with ultra-narrow reflections. AB - This work reported a high quality photonic crystal film with an ultra-narrow photonic bandgap obtained via a chemical synthetic route. The bandgap is much narrower than that of traditional colloidal crystals, which makes the film qualified for use in optical devices. The narrow PBG originates from not only the high crystallinity and uniform orientations of microcrystals within the film but also the very close refractive indices between the silica and the polymer matrix. Due to the matching of the refractive index, the amorphous contents of the film are optically transparent and do not interfere with the reflection, so that the photonic crystal film is tolerant of the existence of disordered contents. PMID- 25825321 TI - Whole-exome sequencing and its impact in hereditary hearing loss. AB - Next-generation sequencing (NGS) technologies have played a central role in the genetic revolution. These technologies, especially whole-exome sequencing, have become the primary tool of geneticists to identify the causative DNA variants in Mendelian disorders, including hereditary deafness. Current research estimates that 1% of all human genes have a function in hearing. To date, mutations in over 80 genes have been reported to cause nonsyndromic hearing loss (NSHL). Strikingly, more than a quarter of all known genes related to NSHL were discovered in the past 5 years via NGS technologies. In this article, we review recent developments in the usage of NGS for hereditary deafness, with an emphasis on whole-exome sequencing. PMID- 25825323 TI - NMR crystallography of an oxovanadium(V) complex by an approach combining multinuclear magic angle spinning NMR, DFT, and spin dynamics simulations. AB - Bioinorganic vanadium(V) solids are often challenging for structural analysis. Here, we explore an NMR crystallography approach involving multinuclear (13) C/(51) V solid-state NMR spectroscopy, density functional theory (DFT), and spin dynamics numerical simulations, for the spectral assignment and the 3D structural analysis of an isotopically unmodified oxovanadium(V) complex, containing 17 crystallographically inequivalent (13) C sites. In particular, we report the first NMR determination of C-V distances. So far, the NMR observation of (13) C (51) V proximities has been precluded by the specification of commercial NMR probes, which cannot be tuned simultaneously to the close Larmor frequencies of these isotopes (100.6 and 105.2 MHz for (13) C and (51) V, respectively, at 9.4 T). By combining DFT calculations and (13) C-(51) V NMR experiments, we propose a complete assignment of the (13) C spectrum of this oxovanadium(V) complex. Furthermore, we show how (13) C-(51) V distances can be quantitatively estimated. PMID- 25825324 TI - Molecular histology of lung cancer: from targets to treatments. AB - Lung cancer is the leading cause of cancer-related death worldwide with a 5-year survival rate of less than 15%, despite significant advances in both diagnostic and therapeutic approaches. Combined genomic and transcriptomic sequencing studies have identified numerous genetic driver mutations that are responsible for the development of lung cancer. In addition, molecular profiling studies identify gene products and their mutations which predict tumour responses to targeted therapies such as protein tyrosine kinase inhibitors and also can offer explanation for drug resistance mechanisms. The profiling of circulating micro RNAs has also provided an ability to discriminate patients in terms of prognosis/diagnosis and high-throughput DNA sequencing strategies are beginning to elucidate cell signalling pathway mutations associated with oncogenesis, including potential stem cell associated pathways, offering the promise that future therapies may target this sub-population, preventing disease relapse post treatment and improving patient survival. This review provides an assessment of molecular profiling within lung cancer concerning molecular mechanisms, treatment options and disease-progression. Current areas of development within lung cancer profiling are discussed (i.e. profiling of circulating tumour cells) and future challenges for lung cancer treatment addressed such as detection of micro metastases and cancer stem cells. PMID- 25825326 TI - Migrating intrathecal high-velocity projectile. AB - Bullet injuries to the spine can cause significant damage to surrounding tissues and cause serious neurological sequelae. These cases are often associated with neurological deficits. We present a case of a gunshot injury to the spine with a migrating intrathecal bullet which subsequently developed neurological deficits. Initially, the patient did not exhibit any neurological symptoms when first assessed soon after the injury. Subsequently, the patient developed signs of neurological injury as a result of spinal intrathecal migration of the projectile. PMID- 25825325 TI - Evaluating cerebellar dentatotomy for the treatment of spasticity with or without dystonia. AB - Spasticity represents a common and very often incapacitating neurologic condition, for which a limited number of treatment options are available. Stereotactic ablation of the dentate cerebellar nuclei (dentatotomy) was widely used in the past with variable results. In the present study, we reviewed 12 consecutive cases operated on at the Midland Centre for Neurosurgery and Neurology at Birmingham University (Smetwick, UK) in the 1980s. The following clinical aspects were analyzed: severity of spasticity, occurrence of abnormal movements (dystonia/athetosis), language fluency, gait, and overall clinical condition. Follow-up ranged from 0.5 to 94 (mean: 31.6) months. Immediate improvement was noted in 10 patients, and five of them had sustained this improvement at the time of the last assessment. A more pronounced improvement was observed for gait, relative to speech and abnormal movements. No significant morbidity related to the procedure was observed. We conclude that dentatotomy is a safe procedure that should still be considered in specific cases. Here, we review the cases reported in the literature, and present a mechanistic hypothesis about how dentatotomy influences motor tonus, in light of the current knowledge about cerebellar physiology. We believe that this issue is critical for the development of alternative surgical approaches targeting the cerebellum, such as chronic electric stimulation. PMID- 25825327 TI - Treatment concept of chronic subdural haematoma according to an algorithm using evidence-based medicine-derived key factors: A prospective controlled study. AB - INTRODUCTION: Surgical treatment for chronic subdural haematoma (CSH) has been analysed by applying evidence-based medicine (EBM) criteria earlier. Whether implementation of EBM-derived key factors into an optimised treatment algorithm would improve outcome, however, needs to be clarified. MATERIAL AND METHODS: Symptomatic patients with CSH who fulfilled the inclusion criteria were either assigned to an optimised treatment algorithm (OA-EBM group) or to a control group treated by the standard departmental surgical technique (SDST group) in a prospective design. For the OA-EBM algorithm only one burr hole, extensive intraoperative irrigation and a closed system drainage with meticulous avoidance of entry of air was mandatory. A two-catheter technique was used to reduce intracavital air. Final endpoints were neurological outcome (Markwalder Score), recurrence and the amount of intracranial air. RESULTS: A total of 93 out of 117 patients were evaluated accounting for 113 cases because 20 patients had bilateral haematomas. Demographic data of 68 cases in the SDST group did not differ from 45 cases in the OA-EBM group. The Markwalder Score showed greater improvement in the OA-EBM group (0.5 +/- 0.6 vs. 1.0 +/- 1.0, p = 0.003). The recurrence rate was 18% (12 patients) in the SDST group versus 2% (1 patient) in the OA-EBM group (p < 0.05). The amount of intracranial air was significantly lower in the OA-EBM group (3.3 +/- 5.0 cm(3) vs. 5.2 +/- 7.7 cm(3)) with p = 0.04. In the standard group computerised tomography scanning was performed slightly earlier (3 +/- 1.7 days vs. 3.6 +/- 1.4 days). When comparing only non recurrent cases in both groups no significant difference was apparent. CONCLUSIONS: Implementation of EBM key factors into a treatment algorithm for CSH can improve neurological outcome in a typical neurosurgical department, reduce recurrence and minimise the amount of postoperative air within the haematoma cavity. PMID- 25825328 TI - Effect of repeated passive anterior loading on human knee anterior laxity. AB - BACKGROUND: Increased knee anterior laxity results when the anterior cruciate ligament is injured. This increased laxity can cause knee dysfunction. Until recently this laxity was believed to be only diminished through surgery. But recent findings indicate that knee anterior laxity may be decreased with repeated loading of the knee. OBJECTIVE: The purpose of this study was to test the hypothesis that regular passive anterior loading of the uninjured human knee would enhance its stiffness. STUDY DESIGN: Randomized controlled trial. METHODS: Knee anterior laxity was tested using an arthrometer in 22 young, uninjured females before, during and after a 3 month period during which passive anterior loading was applied by a trained physiotherapist over 5 sessions per week to a randomly assigned knee. RESULTS: Knee anterior laxity was not affected by the passive anterior loading of the knee. CONCLUSIONS: Given that in this study repeated passive loading of the knee did not change knee anterior laxity, it would be easy to conclude that this training is ineffective and no further research is required. We caution against this given the relatively short duration and possibly insufficient intensity of the training and the population studied; individuals with normal joint laxity. We recommend that future research be performed that consists of individuals with lax joints who receive training for prolonged periods. PMID- 25825329 TI - Pregnancy in Chronic Kidney Disease: questions and answers in a changing panorama. AB - Chronic kidney disease (CKD) is increasingly encountered in pregnancy because of greater diagnostic awareness, which is a reflection of the newer, broader definitions (i.e., any changes in blood or urine composition or at imaging, or a glomerular filtration rate (GFR) of <60 mL/min lasting at least 3 months) and of increased incidence (higher maternal age and better outcomes of several kidney diseases). CKD is extremely heterogeneous and may be described by the degree of GFR reduction (CKD stages), the presence of proteinuria and hypertension and the type of kidney disease; the risk of adverse pregnancy-related events increases as GFR decreases and it is affected by proteinuria and hypertension. Specific risks are reported in various diseases such as lupus nephropathy or diabetic nephropathy. While transplantation at least partially restores fertility in end stage kidney disease, pregnancy on dialysis is increasingly reported. This chapter deals with the available evidence on the management of CKD patients in pregnancy. PMID- 25825330 TI - The immunoglobulin M-degrading enzyme of Streptococcus suis, IdeSsuis, is a highly protective antigen against serotype 2. AB - Streptococcus suis (S. suis) is a major porcine pathogen causing meningitis, arthritis and several other pathologies. Recently, we identified a highly specific immunoglobulin M degrading enzyme of S. suis, designated IdeSsuis, which is expressed by various serotypes. The objective of this work was to access the immunogenicity and protective efficacy of a recombinant vaccine including IdeSsuis. Vaccination with rIdeSsuis elicited antibodies efficiently neutralizing the IgM protease activity. Importantly, 18 piglets vaccinated with rIdeSsuis alone or in combination with bacterin priming were completely protected against mortality and severe morbidity after S. suis serotype 2 challenge. In contrast, 12 of the 17 piglets either treated with the placebo or primed with the bacterin only, succumbed to S. suis disease. Immunity against IdeSsuis was associated with increased killing of S. suis wt in porcine blood ex vivo leading to a tenfold difference in the bacterial survival factor in blood of placebo-treated and rIdeSsuis-vaccinated piglets. In conclusion, the results of this study indicate that rIdeSsuis is a highly protective antigen in pigs. PMID- 25825331 TI - Cost-benefit of the introduction of new strategies for vaccination against pertussis in Spain: cocooning and pregnant vaccination strategies. AB - BACKGROUND: Pertussis remains a public health problem in countries with high vaccination coverage. Classic vaccination approaches have failed to effectively control the infection. The incidence of pertussis hospitalizations in infants is high, especially in those younger than 3 months who are in high risk of a severe disease and death. Additional strategies are recommended for short-term protection of this vulnerable population. In this study, we estimated the impact of 2 strategies for pertussis prevention in infants younger than 1 year of age-a cocoon vaccination strategy and the vaccination of pregnant women (VPW)-and the cost-benefit of these approaches relative to the current vaccination policy in Spain. METHODS: A cost-benefit analysis was conducted from the perspective of the publically-funded Spanish healthcare system, based on the yearly number of hospitalizations during the period of 2009 to 2011. We calculated the absolute risk reduction, the number of parents that would need to be vaccinated to prevent 1 hospitalization or death in infants <1 year, and the net benefit-to-cost ratio of each strategy. RESULTS: From 2009 to 2011, the incidence of pertussis in Spain was 153.44 hospitalizations per 100,000 infants <1 year. The absolute risk reduction for hospitalization would be 42.1/100,000 with cocooning and 75.2/100,000 with VPW. The number of parents needed to vaccinate with the cocoon strategy to prevent 1 pertussis hospitalization would be 4752 and to prevent 1 death, more than 900,000. With VPW, 1331 pregnant women would have to be vaccinated to prevent 1 hospitalization and 200,000 to prevent 1 death. The benefit-to-cost ratio was 0.04 for cocooning and 0.15 for VPW. PMID- 25825332 TI - Protective effect of a dewaxed whole-cell vaccine against Mycobacterium ulcerans infection in mice. AB - Mycobacterium ulcerans causes Buruli ulcer, a chronic and destructive necrotizing ulcer in humans. Effective vaccination should be one of the best methods for the prevention of this ulcer. However, no effective vaccines have been developed against M. ulcerans infection. In an effort to develop such a vaccine, we examined protective immunity against M. ulcerans infection in a mouse footpad infection model. Prior infection of mice with a virulent strain of M. ulcerans or a mycolactone-deficient strain of M. ulcerans resulted in limited protection against subsequent challenge by a virulent strain of M. ulcerans. Protection was not induced in mice immunized with a formalin-treated killed whole-cell preparation of M. ulcerans. By contrast, a dewaxed whole-cell vaccine, prepared by dewaxing M. ulcerans with organic solvents that removed mycolactones and waxy cell walls from the cells, induced significant protection in mice. Our observations should facilitate development of effective vaccines against Buruli ulcer for control of this disease. PMID- 25825333 TI - A novel non-integrative single-cycle chimeric HIV lentivector DNA vaccine. AB - Novel HIV vaccine vectors and strategies are needed to control HIV/AIDS epidemic in humans and eradicate the infection. DNA vaccines alone failed to induce immune responses robust enough to control HIV-1. Development of lentivirus-based DNA vaccines deficient for integration and with a limited replication capacity is an innovative and promising approach. This type of vaccine mimics the early stages of virus infection/replication like the live-attenuated viruses but lacks the inconvenient integration and persistence associated with disease. We developed a novel lentivector DNA vaccine "CAL-SHIV-IN(-)" that undergoes a single round of replication in the absence of integration resulting in augmented expression of vaccine antigens in vivo. Vaccine gene expression is under control of the LTRs of a naturally attenuated lentivirus, Caprine arthritis encephalitis virus (CAEV) the natural goat lentivirus. The safety of this vaccine prototype was increased by the removal of the integrase coding sequences from the pol gene. We examined the functional properties of this lentivector DNA in cell culture and the immunogenicity in mouse models. Viral proteins were expressed in transfected cells, assembled into viral particles that were able to transduce once target permissive cells. Unlike the parental replication-competent SHIV-KU2 that was detected in DNA samples from any of the serial passage infected cells, CAL-SHIV IN(-) DNA was detected only in target cells of the first round of infection, hence demonstrating the single cycle replication of the vaccine. A single dose DNA immunization of humanized NOD/SCID/beta2 mice showed a substantial increase of IFN-gamma-ELISPOT in splenocytes compared to the former replication and integration defective Delta4SHIV-KU2 DNA vaccine. PMID- 25825334 TI - Crystal structure of an acetylesterase from Talaromyces cellulolyticus and the importance of a disulfide bond near the active site. AB - Carbohydrate esterase catalyzes the de-O or de-N-acylation of substituted saccharides in plant cell walls and thus has great potential for industrial biomass saccharification. We recently identified the putative carbohydrate esterase family 3 (CE3) from Talaromyces cellulolyticus. Here, we prepared the recombinant catalytic domain of the enzyme and crystallized it. The crystal structure was determined to 1.5 A resolution. From the structural analysis, it was elucidated that a n-octyl-beta-D-glucopyranoside bound to near the catalytic triad (Ser10, Asp179 and His182) and was buried in the active site cavity. Site directed mutagenesis showed that the N-terminal disulfide bond located near the catalytic triad is involved in the activity and structural stability of the enzyme. PMID- 25825335 TI - The prognostic value of histopathological grading systems in oral squamous cell carcinomas. AB - OBJECTIVE: This study evaluated the association of four histopathological grading systems (WHO grading system, malignancy grading of the deep invasive margins (MG), histological risk (HR) model, and tumor budding and depth of invasion (BD) model) with clinicopathological parameters and outcome of 113 oral squamous cell carcinomas to identify their roles in prognosis. METHODS: Demographic and clinical features were obtained from patients' records. Sections from all paraffin-embedded blocks were evaluated according to the four grading systems. Demographic and clinical associations were analyzed using chi-square test, and correlations between the grading systems were established with the Spearman's rank correlation test. Survival curves were performed with Kaplan-Meier method, and multivariate analysis based on Cox proportional hazard model was calculated. RESULTS: Significant associations with survival were observed for WHO grading system and BD model in the univariate analysis, but only the BD model was significantly associated with disease outcome as an independent prognostic marker. Age, tumor size, and presence of regional metastasis were also independent markers of reduced survival. CONCLUSION: A significant association between the BD model and outcome of OSCC patients was observed, indicating this new histopathological grading system as a possible prognostic tool. PMID- 25825336 TI - Effect of Membrane Permeability on Cardiovascular Risk Factors and beta2m Plasma Levels in Patients on Long-Term Haemodialysis: A Randomised Crossover Trial. AB - Survival of haemodialysis (HD) patients is influenced by many factors. Mortality is mainly of cardiovascular (CV) origin and related to both traditional and nontraditional CV risk factors. Low plasma Beta2-microglobulin (beta2m) levels are associated with improved HD patient survival. HD session times that are longer than the conventional 4 h (i.e., extended dialysis) provide better middle molecule clearance and are also associated with a survival advantage. In this crossover randomised trial, we investigated the effect of membrane flux on CV risk factors and on beta2m plasma levels in patients treated with extended dialysis. Dialysis session duration was between 5 and 8 h for all patients. Patients were randomly assigned to the treatment sequences low-flux/high-flux dialysis versus high-flux/low-flux dialysis in a crossover design after a 3-month run-in period, with each phase lasting 9 months. Of the initially enrolled 168 patients, 155 patients started the study after the run-in period, 117 patients completed Phase 1, and 83 patients completed the whole study. Lp(a), homocystein, LDL cholesterol, HDL cholesterol and serum albumin were comparable in the low flux and high-flux treatments. The average beta2m level was 43.3 +/- 11.1 mg/l at the end of the low-flux phase. Independent of sequence assignation, average beta2m was significantly lower at the end of the high-flux phase (27.5 +/- 76.0 mg/l, p < 0.0001 versus end of low-flux phase). Both phosphate and nPNA were significantly lower at the end of the high-flux phase compared to the low-flux phase (p = 0.045 and p = 0.002, respectively). Inclusion of those patients who completed Phase 1 and who dropped out of the study during Phase 2 did not significantly change the results. In conclusion, this study did not find an influence of high-flux filters on several traditional CV risk factors in a population of HD patients treated with extended dialysis. However, high-flux filters are necessary to optimise middle molecule clearance and reduce the beta2m level. PMID- 25825337 TI - Influence of Glycemic Control on Peri-Implant Bone Healing: 12-Month Outcomes of Local Release of Bone-Related Factors and Implant Stabilization in Type 2 Diabetics. AB - BACKGROUND: The poor glycemic status seems to be an important factor affecting implant complication rates, including peri-implant bone loss. PURPOSE: This trial evaluated the influence of glycemic control of type 2 diabetes mellitus (T2DM) patients on implant stabilization and on the levels of bone markers in peri implant fluid during the healing. MATERIALS AND METHODS: Systemically healthy patients (SH,n = 19), better-controlled T2DM (BCDM,n = 16), and poorly controlled T2DM (PCDM,n = 16) indicated for implant therapy were recruited. The implant stability quotient (ISQ) was determined at implant placement, 3, 6, and 12 months. Levels of transforming growth factor- beta (TGF-beta), fibroblast growth factor (FGF), osteopontin (OPN), osteocalcin (OC), and osteoprotegerin (OPG) in the peri-implant fluid were quantified at 15 days, and 3, 6, and 12 months, using the Luminex assay. RESULTS: OPG and OPN levels were higher in SH at 12 months than at15 days (p < .05), whereas OC and TGF-beta were lower in PCDM at 12 months compared with the 15-day and 3-month follow-ups, respectively (p < .05). Inter group analyses showed lower OPN levels in PCDM compared with SH at 12 months (p < .05). The ISQ was higher at 12 months when compared with baseline and 3 months in SH (p < .05), whereas no differences were observed during follow-up in diabetics, regardless of glycemic control (p > .05). No difference in ISQ was observed among groups over time (p > .05). CONCLUSION: Poor glycemic control negatively modulated the bone factors during healing, although T2DM, regardless of glycemic status, had no effect on implant stabilization. PMID- 25825338 TI - Life cycle air emissions impacts and ownership costs of light-duty vehicles using natural gas as a primary energy source. AB - This paper aims to comprehensively distinguish among the merits of different vehicles using a common primary energy source. In this study, we consider compressed natural gas (CNG) use directly in conventional vehicles (CV) and hybrid electric vehicles (HEV), and natural gas-derived electricity (NG-e) use in plug-in battery electric vehicles (BEV). This study evaluates the incremental life cycle air emissions (climate change and human health) impacts and life cycle ownership costs of non-plug-in (CV and HEV) and plug-in light-duty vehicles. Replacing a gasoline CV with a CNG CV, or a CNG CV with a CNG HEV, can provide life cycle air emissions impact benefits without increasing ownership costs; however, the NG-e BEV will likely increase costs (90% confidence interval: $1000 to $31 000 incremental cost per vehicle lifetime). Furthermore, eliminating HEV tailpipe emissions via plug-in vehicles has an insignificant incremental benefit, due to high uncertainties, with emissions cost benefits between -$1000 and $2000. Vehicle criteria air contaminants are a relatively minor contributor to life cycle air emissions impacts because of strict vehicle emissions standards. Therefore, policies should focus on adoption of plug-in vehicles in nonattainment regions, because CNG vehicles are likely more cost-effective at providing overall life cycle air emissions impact benefits. PMID- 25825340 TI - Acute suppurative parotitis in a 33-day-old patient. AB - Acute suppurative parotitis is a rare disease in childhood. Its incidence is higher in premature newborns. Parotid swelling and pus drainage from Stenson's duct is pathognomonic, and Staphylococcus aureus is the causative agent in most cases. Here, a 33-day-old patient with acute suppurative parotitis is presented. PMID- 25825341 TI - Profile of non-accidental childhood injury at a tertiary hospital in south-west Nigeria. AB - BACKGROUND: Injury threatens children lives worldwide. Most studies from Nigeria have been on accidental injuries in children. OBJECTIVES: To study the profile of non-accidental injuries among children receiving care at a tertiary hospital in Nigeria. METHODS: Children with non-accidental injuries were serially recruited and studied. The Paediatrics Trauma Score (PTS) was tested against the outcome. RESULTS: Non-accidental injuries accounted for 0.84% of all 5264 patients and 21.3% of the 207 injured. The case fatality rate was 6.8%. Physical abuse, sexual assault, drowning/near drowning, gunshot, poisoning and human bite caused the injuries in 68.2, 13.6, 6.8, 4.5, 4.5 and 2.3%, respectively. One-way analysis of variance and Tukey post hoc analysis showed that the mean PTS score of patients who died was significantly lower than the scores of those who were either discharged home or who discharged against medical advice (p < 0.001). CONCLUSION: The burden of non-accidental childhood injuries was high in the study area. PMID- 25825339 TI - Synergistic enhancement of parasiticidal activity of amphotericin B using copaiba oil in nanoemulsified carrier for oral delivery: an approach for non-toxic chemotherapy. AB - BACKGROUND AND PURPOSE: The aim of this study was to devise a nanoemulsified carrier system (CopNEC) to improve the oral delivery of amphotericin B (AmB) by increasing its oral bioavailability and synergistically enhance its antileishmanial activity with copaiba oil (Cop). EXPERIMENTAL APPROACH: The AmB encapsulated NEC (CopNEC-AmB) comprised of Cop, d-alpha-tocopheryl polyethylene glycol 1000 succinate and phosphatidylcholine was prepared by high-pressure homogenization method. Stability study of CopNEC-AmB was carried out in simulated gastric fluid and simulated intestinal fluid. The CopNEC-AmB and plain AmB were compared as regards their in vitro antileishmanial activity, pharmacokinetics, organ distribution and toxicity. KEY RESULTS: The optimal CopNEC-AmB had a small globule size, low polydispersity index, high zeta potential and encapsulation efficiency. The high resolution transmission electron microscopy illustrated spherical particle geometry with homogeny in their sizes. The optimal CopNEC-AmB was found to be stable in gastrointestinal fluids showing insignificant changes in globule size and encapsulation efficiency. The AUC0-48 value of CopNEC-AmB in rats was significantly improved showing 7.2-fold higher oral bioavailability than free drug. The in vitro antileishmanial activity of CopNEC-AmB was significantly higher than that of the free drug as Cop synergistically enhanced the antileishmanial effect of AmB by causing drastic changes in the morphology of Leishmania parasite and rupturing its plasma membrane. The CopNEC-AmB showed significantly less haemolytic toxicity and cytotoxicity and did not change the histopathology of kidney tissues as compared with AmB alone. CONCLUSIONS AND IMPLICATIONS: This prototype CopNEC formulation showed improved bioavailability and had a non-toxic synergistic effect on the antileishmanial activity of AmB. PMID- 25825342 TI - Eye trauma in children and adolescents: Perspectives from a developing country and validation of the ocular trauma score. AB - OBJECTIVE: To investigate the current causes of ocular trauma and to assess the prognostic value of the ocular trauma score (OTS) in children. DESIGN: Prospective observational study of children with ocular trauma in Sao Paulo, Brazil, over 1 year. METHODS: Initial OTS categories were calculated for each patient and compared with the final visual result. RESULTS: Ninety-six patients were included; most were male (73%). Mean age was 7.3 years. Closed globe trauma was the most frequent (74%), followed by open-globe trauma (10.4%). Household items were mainly responsible for the trauma. Correlation between the predicted and achieved visual acuity was good (Kendall tau-b = 0.7192). CONCLUSION: Closed globe is the most frequent trauma in children and adolescents, and some injuries could be prevented by safety measures and closer adult supervision. The OTS was shown to have limited value in predicting long-term visual acuity in children and adolescents. PMID- 25825343 TI - Neonatal mortality in India's rural poor: Findings of a household survey and verbal autopsy study in Rajasthan, Bihar and Odisha. AB - In 2011, Save the Children India launched a project for the disadvantaged population of Rajasthan, Bihar and Odisha. As a baseline activity, neonatal deaths during January-December 2012 were investigated using modified verbal autopsy tool in six sub-district-level administrative units (blocks) adopting 30 cluster sample survey approach. Our study reported a total of 189 neonatal deaths of which 50% occurred at home and 39% happened on Day 1. About half of the deaths occurred in blocks from Bihar. High number of neonatal deaths belonged to households that were below poverty line (64%) and other disadvantaged classes (46%); among mothers who were illiterate (65%), <20 years of age (54%) and during their first-order births (36%). Birth asphyxia was a major cause of neonatal deaths across all blocks. These findings indicate need for easy and early access to transport services, specialized neonatal care and advocacy targeted towards increasing community awareness. PMID- 25825344 TI - Single- versus multi-phase acquisition protocol for prospective-triggered sequential dual-source CT coronary angiography: comparison of image quality and radiation dose. AB - OBJECTIVE: To investigate image quality and radiation dose of single- versus multi-phase acquisition protocol for prospective-triggered sequential dual-source computed tomography (CT) coronary angiography. MATERIALS AND METHODS: A total of 140 patients were randomly assigned to single- or multi-phase group. Image quality and radiation dose were compared. RESULTS: No significant difference was found in image quality between the two groups. Effective dose of single-phase group was 21.6% lower than that of multi-phase group (P<.001). CONCLUSIONS: Prospective-triggered sequential dual-source CT coronary angiography using single phase protocol can reduce radiation dose without sacrifice of image quality in diastole compared with multi-phase protocol. PMID- 25825345 TI - New hybrid reformations of peripheral CT angiography: do we still need axial images? AB - PURPOSE: To quantify the detectability of peripheral artery stenosis on hybrid CT angiography (CTA) reformations. METHODS: Hybrid reformations were developed by combining multipath curved planar reformations (mpCPR) and maximum intensity projections (MIP). Fifty peripheral CTAs were evaluated twice: either with MIP, mpCPR and axial images or with hybrid reformations only. Digital subtraction angiography served as gold standard. RESULTS: Using hybrid reformations, two independent readers detected 88.0% and 81.3% of significant stenosis, respectively. However, CTA including axial images detected statistically significant more lesions (98%). CONCLUSION: Peripheral CTA reading including axial images is still recommended. Further improvement of these hybrid reformations is necessary. PMID- 25825346 TI - The association between Baker's cyst and medial meniscal tear in patients with symptomatic knee using ultrasonography. AB - INTRODUCTION: There are nearly no studies about the association between Baker's cyst (BC) and medial meniscal tear (MMT) using ultrasonography. PATIENTS AND METHODS: Nonselected patients who were referred for ultrasonography for the evaluation of knee pain were recruited. Demographic, clinical, and ultrasound parameters were documented. RESULTS: One-hundred and nineteen patients were included and 131 knees were evaluated. There were 59 (~50%) female patients and mean age of 46.4+/-17.7 years. BC was found in 31 knees (23%). BC was significantly associated with MMT (P=.029) and age (P=.002) after adjusting for other covariates. CONCLUSIONS: BC was strongly associated with MMT regardless of other intraarticular abnormalities. PMID- 25825347 TI - Early endocrine alterations reflect prolonged stress and relate to 1-year functional outcome in patients with severe brain injury. AB - OBJECTIVE: Severe brain injury may increase the risk of developing acute and chronic hypopituitarism. Pituitary hormone alterations developed in the early recovery phase after brain injury may have implications for long-term functional recovery. The objective of the present study was to assess the pattern and prevalence of pituitary hormone alterations 3 months after a severe brain injury with relation to functional outcome at a 1-year follow-up. DESIGN: Prospective study at a tertiary university referral centre. METHODS: A total of 163 patients admitted to neurorehabilitation after severe traumatic brain injury (TBI, n=111) or non-TBI (n=52) were included. The main outcome measures were endocrine alterations 3.3 months (median) after the brain injury and their relationship to the functioning and ability of the patients at a 1-year follow-up, as measured by the Functional Independence Measure and the Glasgow Outcome Scale-Extended. RESULTS: Three months after the injury, elevated stress hormones (i.e. 30 min stimulated cortisol, prolactin and/or IGF1) and/or suppressed gonadal or thyroid hormones were recorded in 68 and 32% of the patients respectively. At 1 year after the injury, lower functioning level (Functional Independence Measure) and lower capability of performing normal life activities (Glasgow Outcome Scale Extended) were related to both the elevated stress hormones (P<=0.01) and the reduced gonadal and/or thyroid hormones (P<=0.01) measured at 3 months. CONCLUSION: The present study suggests that brain injury-related endocrine alterations that mimic secondary hypogonadism and hypothyroidism and that occur with elevated stress hormones most probably reflect a prolonged stress response 2 5 months after severe brain injury, rather than pituitary insufficiency per se. These endocrine alterations thus seem to reflect a more severe disease state and relate to 1-year functional outcome. PMID- 25825348 TI - Structural biology of the Gram-negative bacterial conjugation systems. AB - Conjugation, the process by which plasmid DNA is transferred from one bacterium to another, is mediated by type IV secretion systems (T4SSs). T4SSs are versatile systems that can transport not only DNA, but also toxins and effector proteins. Conjugative T4SSs comprise 12 proteins named VirB1-11 and VirD4 that assemble into a large membrane-spanning exporting machine. Before being transported, the DNA substrate is first processed on the cytoplasmic side by a complex called the relaxosome. The substrate is then targeted to the T4SS for export into a recipient cell. In this review, we describe the recent progress made in the structural biology of both the relaxosome and the T4SS. PMID- 25825349 TI - A model clarifying the role of mediators in the variability of mood states over time in people who stutter. AB - PURPOSE: Elevated negative mood states such as social anxiety and depressive mood have been found in adults who stutter. Research is needed to assist in the development of a model that clarifies how factors like self-efficacy and social support contribute to the variability of negative mood states over time. METHOD: Participants included 200 adults who stutter. A longitudinal design was employed to assess change in mood states over a period of five months. Hierarchical directed regression (path analysis) was used to determine contributory relationships between change in mood states and self-efficacy, social support, socio-demographic and stuttering disorder variables. Participants completed a comprehensive assessment regimen, including validated measures of mood states, perceived control (self-efficacy) and social support. RESULTS: Results confirmed that self-efficacy performs a protective role in the change in mood states like anxiety and depressive mood. That is, self-efficacy cushioned the impact of negative mood states. Social support was only found to contribute a limited protective influence. Socio-demographic variables had little direct impact on mood states, while perceived severity of stuttering also failed to contribute directly to mood at any time point. CONCLUSIONS: Mood was found to be influenced by factors that are arguably important for a person to cope and adjust adaptively to the adversity associated with fluency disorder. A model that explains how mood states are influenced over time is described. Implications of these results for managing adults who stutter with elevated negative mood states like social anxiety are discussed. EDUCATIONAL OBJECTIVES: The reader will be able to describe: (a) the method involved in hierarchical (directed) regression used in path analysis; (b) the variability of mood states over a period of five months; (c) the nature of the mediator relationship between factors like self-efficacy and social support and mood states like anxiety, and (d) the contribution to mood states of socio-demographic factors like age and education and stuttering disorder variables like stuttering frequency and perceived severity. PMID- 25825352 TI - Using a virtual environment to study child pedestrian behaviours: a comparison of parents' expectations and children's street crossing behaviour. AB - OBJECTIVE: The aim of this study was to compare parents' expectations for their children crossing streets with children's actual crossing behaviours and determine how accurately parents judge their own children's pedestrian behaviours to be. METHOD: Using a fully immersive virtual reality system interfaced with a 3D movement measurement system, younger (7-9 years) and older (10-12 years) children's crossing behaviours were assessed. The parent viewed the same traffic conditions and indicated if their child would cross and how successful she/he expected the child would be when doing so. RESULTS: Comparing children's performance with what their parents expected they would do revealed that parents significantly overestimated the inter-vehicle gap threshold of their children, erroneously assuming that children would show safer pedestrian behaviours and select larger inter-vehicle gaps to cross into than they actually did; there were no effects of child age or sex. Child and parent scores were not correlated and a logistic regression indicated these were independent of one another. CONCLUSIONS: Parents were not accurate in estimating the traffic conditions under which their children would try and cross the street. If parents are not adequately supervising when children cross streets, they may be placing their children at risk of pedestrian injury because they are assuming their children will select larger (safer) inter-vehicle gaps when crossing than children actually do. PMID- 25825353 TI - An examination of concussion education programmes: a scoping review methodology. AB - OBJECTIVES: The primary purpose was to review the literature on concussion education programmes. The secondary purpose was to inform knowledge translation strategies for concussion researchers and practitioners. DESIGN: Research on concussion education programmes is relatively new. As a result, the current study implemented a scoping review methodology, which is a type of literary search used to provide a preliminary assessment of the size and scope of a body of literature, as well as identify strengths, weaknesses and gaps in the research. METHODS: A five-stage process for conducting a scoping review was followed for this study: (a) identifying the research questions, (b) identifying relevant studies, (c) identifying the study selection criteria, (d) charting the data and (e) reporting the results. RESULTS: Concussion education programmes have been developed and implemented with populations ranging in age from 9 to 49 years and have used interactive oral presentations, educational videos and computer-based learning programmes. Although the content of these programmes varied, the topics generally addressed salient aspects of concussion injury and recovery. Quantitative instruments have been the preferred methods for assessment. CONCLUSIONS: Education programmes aimed at improving participants' long-term concussion knowledge, behaviours and attitudes of concussions are needed. Researchers must consider using a knowledge translation framework to enhance concussion education programmes. The application of such a framework can lead to novel and interesting ways of disseminating information about concussive injury and recovery. PMID- 25825351 TI - Genome-wide circulating microRNA expression profiling indicates biomarkers for epilepsy. AB - MicroRNAs (miRNAs) have been proposed as biomarkers for cancer and other diseases due to their stability in serum. In epilepsy, miRNAs have almost been studied in brain tissues and in animals' circulation, but not in circulation of human. To date, a major challenge is to develop biomarkers to improve the current diagnosis of epilepsy. The aim of this study was to evaluate whether circulating miRNAs can be used as biomarkers for epilepsy. We measured the differences in serum miRNA levels between 30 epilepsy patients and 30 healthy controls in discovery and training phases using Illumina HiSeq2000 sequencing followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. The selected miRNAs were then validated in 117 epilepsy patients and 112 healthy controls by qRT-PCR. Let-7d-5p, miR-106b-5p, -130a-3p and -146a-5p were found up-regulated, whereas miR-15a-5p and -194-5p were down-regulated in epilepsy patients compared to controls (P < 0.0001). Among these miRNAs, miR-106b-5p had the best diagnostic value for epilepsy with 80.3% sensitivity and 81.2% specificity. Circulating miRNAs were differentially regulated in epilepsy patients as compared with controls. MiR-106b-5p may serve as a novel, noninvasive biomarker to improve the current diagnosis of epilepsy. PMID- 25825354 TI - Learning to attain an advanced level of professional responsibility. AB - BACKGROUND: After graduation, nurse practitioner students are expected to be capable of providing complex, evidence-based nursing care independently, combined with standardized medical care. The students who follow work-study programs have to develop their competencies in a healthcare environment dominated by efficiency policies. OBJECTIVE: This study aims to explore nurse practitioner students' perceptions of their professional responsibility for patient care. METHOD: This qualitative interpretative study entails a content analysis of 46 reflective case studies written by nurse practitioner students. FINDINGS: The students felt responsible for the monitoring of patients' health status, attending to psychosocial problems, emphasizing compliance, and optimizing the family's role as informal caregivers. At the same time, students struggled to understand the complexities of their patients' needs, and they had difficulty applying their knowledge and skills to complex medical, psychological, and social problems. CONCLUSION: The students' perceptions of their new responsibility were characterized by a strong focus on curative care, while psychosocial components of health and illness concerns were often overlooked. The students experienced difficulties in meeting the criteria of advanced practice nursing described in the Dutch competency framework. PMID- 25825355 TI - Family nursing hospital training and the outcome on job demands, control and support. AB - The purpose of this study was to evaluate the impact of a family systems nursing hospital training educational program (ETI program) on nurses' and midwives' perception of job demands, control, and/or support. Of the nurses and midwives who were working in the Women's and Children's Services Division at The National University Hospital in Iceland, 479 participated in the study on three time periods from 2009 to 2011. Scores for the characteristics of job demands and job control were created to categorize participants into four job types (Karasek and Theorell, 1990). These four job types are high strain (high demand, low control), passive (low demand, low control), low strain (low demand, high control), and active (high demand, high control). However, when the data were evaluated based on the proportion of job characteristics as reported by the nurses and the midwives, no significant difference was found over time (2009 to 2011) (chi(2)=5.203, p=.518). However, based on the results from the independent t tests at time 1, a significant difference was found amongst the high strain job group regarding perceived support from administrators and colleagues among the nurses and midwives who had taken the ETI program compared to those who had not taken the program (chi(2)=2.218, p=.034). This indicates that the health care professionals who characterized their job to be of high demand but with low control evaluated the support from their administrators and colleagues to be significantly higher if they had taken the ETI program than did the nurses and midwives who did not take the ETI program. These findings are promising because they might, in the long run, increase the nurses' and midwives' autonomy and control over their own work. PMID- 25825356 TI - Toll-like receptor 1 N248S polymorphism affects T helper 1 cytokine production and is associated with serum immunoglobulin E levels in Taiwanese allergic patients. AB - BACKGROUND/PURPOSE: This study was carried out to investigate whether toll-like receptor-1 (TLR1) rs4833095 (N248S) variant, common in the Taiwanese population, contributes to pathogenesis of allergy. METHODS: TLR2/1 ligand Pam3CSK4 stimulated cytokine production in peripheral blood mononuclear cells and monocyte derived dendritic cells of different genotypes were measured via enzyme-linked immunosorbent assay. Ninety-three Taiwanese allergic patients (with asthma, allergic rhinitis, or atopic dermatitis) and 76 controls were recruited for genotyping. Serum immunoglobulin E (IgE) levels were evaluated in 60 allergic patients. RESULTS: The homozygous TLR1 C variant allele carrier had increased Pam3CSK4-induced tumor necrosis factor-alpha and interleukin-12 responses in peripheral blood mononuclear cells and monocyte-derived dendritic cells, respectively. Furthermore, although the C/C genotype was not associated with susceptibility to atopic diseases, it was correlated with lower total IgE levels in sera of allergic patients. CONCLUSION: Our data suggest that the TLR1 N248S polymorphism might play a role in Th1/Th2 differentiation, and the determination of serum IgE levels. However, interactions with other genetic and environmental factors might be required to contribute to risk of allergic diseases in our population. PMID- 25825357 TI - N-acetyl-aspartyl-glutamate and inhibition of glutamate carboxypeptidases protects against soman-induced neuropathology. AB - N-acetyl-aspartyl-glutamate (NAAG) is the most abundant neuropeptide in the mammalian brain. In a variety of animal models of brain injury, the administration of NAAG-related compounds, or inhibitors of glutamate carboxypeptidases (GCPs; the enzymes that hydrolyze NAAG), were shown to be neuroprotective. This study determined the impact of the administration of three NAAG-related compounds, NAAG, beta-NAAG (a NAAG homologue resistant to degradation), and 2-phosphonomethyl pentanedioic acid (2-PMPA; an inhibitor of GCP enzymes), on the neuropathology that develops following exposure to the nerve agent, soman. When given 1 min after soman exposure, NAAG-related drug treatments did not alter the survival rate or body weight loss seen 24 h after rats were exposed to soman. Likewise, brain levels of both NAAG and its metabolite, N acetyl-aspartate (NAA), were substantially decreased 24 h after soman, and in particularly vulnerable brain regions the drug treatments were unable to attenuate the reduction in NAA and NAAG levels. Histochemical study indicated there was a dramatic increase in Fluoro-Jade C (FJC) staining, indicative of neuron cell death, 24 h after soman exposure. However, in the amygdala and in the entorhinal and piriform limbic cortex, which sustained severe neuropathology following soman intoxication, single or combined injections of NAAG compounds and 2-PMPA significantly reduced the number of FJC-positive cells, and effect size estimates suggest that in some brain regions the treatments were effective. The findings suggest that NAAG neurotransmission in the central nervous system is significantly altered by soman exposure, and that the administration of NAAG related compounds and 2-PMPA reduces neuron cell death in brain regions that sustain severe damage. PMID- 25825358 TI - Involvement of oxidative stress in the regulation of NPY/CART-mediated appetite control in amphetamine-treated rats. AB - Amphetamine (AMPH) treatment can suppress appetite and increase oxidative stress in the brain. AMPH-induced appetite suppression is associated with the regulation of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. The present study explored whether antioxidants, including glutathione S-transferase (GST) and glutathione peroxidase (GP), were involved in this NPY/CART-mediated appetite control. Rats were treated daily with AMPH for four days. Changes in food intake and expression levels of hypothalamic NPY, CART, GST, and GP were examined and compared. Results showed that, in AMPH treated rats, (1) food intake and NPY expression decreased, while CART, GST, and GP expression increased; (2) NPY knockdown in the brain enhanced the decrease in NPY and the increases in CART, GST, and GP expression; and (3) central inhibition of reactive oxygen species production decreased GST and GP and modulated AMPH anorexia and the expression levels of NPY and CART. The present results suggest that oxidative stress in the brain participates in regulating NPY/CART-mediated appetite control in AMPH-treated rats. These results may advance the knowledge regarding the molecular mechanism of AMPH-evoked or NPY/CART-mediated appetite suppression. PMID- 25825359 TI - Renoprotective effects of angiotensin receptor blocker and stem cells in acute kidney injury: Involvement of inflammatory and apoptotic markers. AB - Cisplatin, Cis-diamminedichloroplatinum (CDDP), is a platinum-based chemotherapy drug, and its chemotherapeutic use is restricted by nephrotoxicity. Inflammatory and apoptotic mechanisms play a central role in the pathogenesis of CDDP-induced acute kidney injury (AKI). The aim of this study was to compare the therapeutic potential of candesartan, angiotensin II receptor blocker, versus bone marrow derived mesenchymal stem cells (BM-MSCs) in a rat model of CDDP-induced nephrotoxicity. Adult male Wistar rats (n = 40) were divided into four groups; Normal control: received saline injection, CDPP group: received CDDP injection (6 mg/kg single dose), Candesartan group: received candesartan (10 mg/kg/day) for 10 days + CDDP at day 3, and Stem cells group: received CDDP + BM-MSCs intravenously one day after CDDP injection. The rats were sacrificed seven days after CDDP injection. Significant elevation in serum creatinine and urea, renal levels of tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1, renal expressions of nuclear factor kappa B (NF-kappaB), p38-mitogen-activated protein kinase (MAPK), caspase-3 and Bcl-2-associated x protein (Bax) were found in CDDP-injected rats when compared to normal rats. Both candesartan and BM-MSCs ameliorated renal function and reduced significantly the inflammatory markers (TNF-alpha , NF-kappaB, p38-MAPK and MCP-1) and apoptotic markers (caspase-3 and Bax) in renal tissue after CDDP injection. Candesartan as well as BM-MSCs have anti-inflammatory and anti-apoptotic actions and they can be used as nephroprotective agents against CDDP-induced nephrotoxicity. BM-MSCs is more effective than candesartan in amelioration of AKI induced by CDDP. PMID- 25825360 TI - Complicated actinomycosis of the temporal bone: A historical case report. AB - INTRODUCTION: Actinomycosis is a chronic infection caused by anaerobic Gram positive bacteria belonging to the Actinomyces family. The zones of predilection of this infection are mainly the head, neck and abdominal regions. CASE REPORT: We report the case of a 30-year-old man admitted for aggressive right oto mastoiditis complicated by facial nerve palsy and sensorineural hearing loss. CT scan demonstrated extensive destruction of the temporal bone. The patient underwent radical mastoidectomy followed by long-term antibiotic therapy. DISCUSSION: Its non-specific symptoms and atypical course, combined with difficult isolation of the causative agent, make actinomycosis a difficult infection to diagnose. Actinomycosis very rarely involves the temporal region, as fewer than 30 cases have been reported in the literature. Treatment of this form of actinomycosis is based on surgery and prolonged antibiotic therapy. Surgical treatment is designed to reduce the bacterial load by mechanical debridement and create aerobic conditions. CONCLUSION: Compared to other cases reported in the literature, the case of temporal actinomycosis reported here was distinguished by its highly aggressive nature. Temporal actinomycosis should be suspected in the context of chronic otitis media with an atypical course. Treatment is based on a combination of surgery and antibiotics. PMID- 25825361 TI - Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents. AB - AIMS: It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. METHODS: People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow up, data were extracted from clinical records over 4 years. RESULTS: Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. CONCLUSION: Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. PMID- 25825363 TI - Labour will cap private providers' profits on NHS work at 5. PMID- 25825362 TI - Citation analysis of otorhinolaryngology journals: follow-up study. AB - OBJECTIVE: This study aimed to evaluate the changes in impact factors of otorhinolaryngology journals over the past 15 years. METHOD: Using the online edition of Journal Citation Reports, standard (2-year) and 5-year impact factors were calculated for the leading 15 journals. RESULTS: The results were compared with the impact factors for 1998. The average standard impact factor and 5-year impact factor increased by 2.72 and 2.05 fold respectively when compared with 1998. The average 2012 standard impact factor and 5-year impact factor were 1.82 and 1.99 respectively, reflecting a 9.3 per cent difference. The average 1998 standard impact factor and 5-year impact factor were 0.67 and 0.97 respectively, reflecting a 44.8 per cent difference. The Journal of the Association for Research in Otolaryngology had the highest standard and five-year impact factors. CONCLUSION: These data may indicate changing clinical and research interests within our field, as well as increased speed and ease with which the internet has allowed citation. As a result, five-year intervals may no longer be necessary to adequately gauge journal impact. PMID- 25825364 TI - Plant synthetic biology. AB - Plant synthetic biology is an emerging field that combines engineering principles with plant biology toward the design and production of new devices. This emerging field should play an important role in future agriculture for traditional crop improvement, but also in enabling novel bioproduction in plants. In this review we discuss the design cycles of synthetic biology as well as key engineering principles, genetic parts, and computational tools that can be utilized in plant synthetic biology. Some pioneering examples are offered as a demonstration of how synthetic biology can be used to modify plants for specific purposes. These include synthetic sensors, synthetic metabolic pathways, and synthetic genomes. We also speculate about the future of synthetic biology of plants. PMID- 25825365 TI - Efficient visible-light photocatalytic degradation system assisted by conventional Pd catalysis. AB - Different approaches like doping and sensitization have been used to develop photocatalysts that can lead to high reactivity under visible-light illumination, which would allow efficient utilization of solar irradiation and even interior lighting. We demonstrated a conceptually different approach by changing reaction route via introducing the idea of conventional Pd catalysis used in cross coupling reactions into photocatalysis. The -O-Pd-Cl surface species modified on Ni-doped TiO2 can play a role the same as that in chemical catalysis, resulting in remarkably enhanced photocatalytic activity under visible-light irradiation. For instance, Pd/Ni-TiO2 has much higher activity than N-TiO2 (about 3 ~ 9 times for all of the 4-XP systems) upon irradiation with wavelength of 420 nm. The catalytically active Pd(0) is achieved by reduction of photogenerated electrons from Ni-TiO2. Given high efficient, stable Pd catalysts or other suitable chemical catalysts, this concept may enable realization of the practical applications of photocatalysis. PMID- 25825366 TI - Femoral footprint variation of the posterolateral bundle of the anterior cruciate ligament and double-bundle reconstruction. AB - BACKGROUND: The study is aimed to observe the range of variation of the ACL PLB femoral footprint and investigate countermeasures for accurate femoral bone tunnel placement during double-bundle ACL reconstruction. METHODS: The femoral insertions of the anteromedial bundle (AMB) and PLB of the ACL were dissected in 30 male cadaveric knees. The ACL footprint on the lateral intercondylar wall (LIW) was observed, and the shape of the LIW, the resident ridge, the angle between the ACL long axis and femoral axis (AA), and the vertical distance from the center of the PLB to the lowest cartilage border of the LIW (PD) were measured. RESULTS: The area most populated by the ACL fibers was directly under the resident ridge. AA = 18.7 degrees +/-15.25 degrees with variation from -18 degrees to 56 degrees , and PD=7.02+/-1.47 mm with variation from 3.75 to 11.08 mm. Both discrete values were very large in both groups of data. There were two kinds of LIW: trapezoidal (8 knees) and triangular (21 knees). Both AA and PD values exhibited significant differences between the two types of LIWs (P=0.00). CONCLUSION: AA and PD vary among individuals. The insertions and centers of the PLB cannot be exactly anatomically determined with one size. For double-bundle ACL reconstruction, an individualized intraoperative footprint observation for fresh cases with footprint remnants, or resident ridge and anteromedial bundle interval identification for old ACL tears, can be reasonable methods for posterolateral tunnel orientation. CLINICAL RELEVANCE: Clinical relevance is observe the range of variation of the PLB femoral footprint for clinical double bundle ACL reconstruction. PMID- 25825367 TI - Reliability and validity of the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E). AB - OBJECTIVE: The aim of this study was to evaluate the clinical reliability and validity of the Chinese version of the Neurological Disorders Depression Inventory for Epilepsy (C-NDDI-E). METHODS: A total of 248 Chinese patients with epilepsy underwent psychometric tests, including the Chinese version of the Mini International Neuropsychiatric Interview (C-MINI), the Chinese version of the Beck Depression Inventory - II (C-BDI-II), and the C-NDDI-E. RESULTS: None of the patients had difficulties understanding or completing the C-NDDI-E. Cronbach's alpha coefficient was 0.824. At a cutoff score of >=14, the C-NDDI-E had a sensitivity of 0.854, a specificity of 0.899, a positive predictive value of 0.625, and a negative predictive value of 0.969. The scores for the C-NDDI-E were positively correlated with those for the C-BDI-II (P<0.001). CONCLUSION: The C NDDI-E is a reliable and valid screening tool for the detection of major depression in Chinese patients with epilepsy. PMID- 25825368 TI - Suicidal risk, affective dysphoric disorders, and quality-of-life perception in patients with focal refractory epilepsy. AB - OBJECTIVES: We aim to study the frequency of (suicidal ideation) in patients with focal refractory epilepsy and its possible association with factors such as perceived QOL (quality of life) and ASDD (affective somatoform dysphoric disorder) using the 2007 ILAE proposal to classify affective disorders of epilepsy. METHODS: A total sample of 82 patients was divided into two groups depending on the presence of suicidal risk: (A) study group - with suicidal risk and (B) control group - without suicidal risk. Questionnaires, scales, interviews, and clinical charts were evaluated by professionals with expertise in neurology and epileptology (RAM and AGA), psychiatry (AGE), and neuropsychology (FGR). Suicidal risk was evaluated with the M.I.N.I. (Mini-International Neuropsychiatric Interview) suicidal module that specifies the current suicidal risk based on scores. Quality of life was evaluated with the Quality of Life in Epilepsy Inventory - 31 (QOLIE-31) survey. Logistic regression was conducted to ascertain if ASDD and QOL significantly predicted suicidal risk. The results were considered statistically significant when the p-value was <0.05. RESULTS: Suicidal risk was present in 33 (40.3%) patients. It was classified as severe in 31.7% of the patients, and it was only present in cases with temporal lobe epilepsy (p=0.002). More than half (52%) of patients with ASDD had risk of suicide (p=0.006). The presence of ASDD was found to be a risk factor for suicidal risk (OR=3.86; IC=1.3-12.2). Patients with suicidal risk had a lower QOL score compared with patients without suicidal risk (57.8+/-16.9 vs. 46.0+/-18.2; p<0.05), and an affected QOL significantly increased suicidal risk (OR=2.9; CI=1.3-7.8). Multivariate analysis demonstrated that an impaired QOL (OR=2.2) and the presence of ASDD (OR=4.1) significantly increased the probability of having suicidal risk (x(2)=13.6; OR=5.2; p=0.009). SIGNIFICANCE: Affective somatoform dysphoric disorder and low QOL perception increase, independently, the risk of suicide. PMID- 25825369 TI - Old dogs with new tricks: Detecting accelerated long-term forgetting by extending traditional measures. AB - Accelerated long-term forgetting (ALF) is a condition in which normal memory performance is displayed after short delays, but significant memory loss is detected when memory is tested after several days or weeks. This condition has been reported in patients with epilepsy, but there are few normative scores available for its detection in clinical practice. In the present study, we assessed 60 healthy control subjects 18-60years of age on three memory measures [Rey Auditory Verbal Learning (RAVLT), Logical Memory (LM), and Aggie Figures] at delays of 30min and 7days. With these normative values, we determined cutoff scores to look for ALF and then categorized the performance of 15 patients with focal epilepsy on the same tasks. Seven of the patients showed ALF, and, in four of these, no other memory deficits (i.e., deficits at 30min on at least one task) were detected. Of the several demographic and epilepsy factors examined, only higher estimated IQ and older age predicted ALF (and only on one task: RAVLT). The findings provide a useful set of data to be applied in the clinic and some insight into the factors that influence retention within the first week. PMID- 25825370 TI - Altered attention networks in benign childhood epilepsy with centrotemporal spikes (BECTS): A resting-state fMRI study. AB - It is noteworthy that some children with benign childhood epilepsy with centrotemporal spikes (BECTS) show attention problems despite their favorable seizure outcome. Resting-state functional magnetic resonance imaging (fMRI) is a method widely used to detect brain network alterations in neuropsychiatric diseases. We used resting-state functional magnetic resonance imaging (fMRI) to investigate specific brain networks related to attention deficit in children with BECTS. Resting-state fMRI was performed in patients with BECTS with ADHD (n=15) and those with BECTS without ADHD (n=15) and in healthy controls (n=15). Unbiased seed-based whole-brain functional connectivity analysis was used to study the connectivity pattern of three resting-state networks, including the ventral attention network (VAN) and the dorsal attention network (DAN) and the default mode network (DMN). Patients with BECTS with ADHD displayed decreased functional connectivity in the DAN compared with other two groups, while patients with BECTS without ADHD showed increased functional connectivity in the DAN. Moreover, we found increased functional connectivity in the VAN and in the DMN in patients with BECTS with or without ADHD when comparing with controls. These results showed that the newly-diagnosed children with BECTS displayed brain activity alterations in the ventral and dorsal attention networks. The difference in the extent of impairment in the dorsal attention network of patients with BECTS with ADHD and patients with BECTS without ADHD may lead to improved understanding of the underlying neuropathophysiology and treatment of BECTS with ADHD and BECTS without ADHD. PMID- 25825371 TI - National walk for epilepsy. PMID- 25825372 TI - Comparison of common data elements from the Managing Epilepsy Well (MEW) Network integrated database and a well-characterized sample with nonepileptic seizures. AB - INTRODUCTION: Epilepsy and psychogenic nonepileptic seizures (PNES) are both chronic illnesses characterized by similar and overlapping clinical features. A limited number of studies comparing people with epilepsy (PWE) and patients with PNES that address determinants of health outcomes exist. We conducted an analysis using a well-characterized sample of people with PNES and the Managing Epilepsy Well (MEW) Network integrated data, comparing descriptive data on samples with epilepsy and with documented PNES. Based on the pooled data, we hypothesized that people with PNES would have worse QOL and higher depression severity than PWE. MATERIAL AND METHODS: We used data from the MEW Network integrated database involving select epilepsy self-management studies comprising 182 PWE and 305 individuals with documented PNES from the Rhode Island Hospital Neuropsychiatry and Behavioral Neurology Clinic. We conducted a matched, case-control study assessing descriptive comparisons on 16 common data elements that included gender, age, ethnicity, race, education, employment, income, household composition, relationship status, age at seizure onset, frequency of seizures, seizure type, health status, healthy days, quality of life, and depression. Standardized rating scales for depression and quality of life were used. RESULTS: Median seizure frequency in the last 30days for PWE was 1, compared to 15 for patients with PNES (p<0.05). People with epilepsy had a QOLIE-10 mean score of 3.00 (SD: 0.91) compared to 3.54 (0.88) (p<0.01) for patients with PNES. Depression severity was moderate to severe in 7.7% of PWE compared to 34.1% (p<0.05) of patients with PNES. DISCUSSION: People with epilepsy in selected MEW Network programs are fairly well educated, mostly women, with few minorities and low monthly seizure rates. Those with PNES, however, have higher levels of not working/on disability and had more frequent seizures, higher depression severity, and worse QOL. These differences were present despite demographics that are largely similar in both groups, illustrating that other determinants of illness may influence PNES. PMID- 25825373 TI - Effects of two alar base suture techniques suture techniques on nasolabial changes after bimaxillary orthognathic surgery in Taiwanese patients with class III malocclusions. AB - A randomized controlled trial was designed to assess the effectiveness of two alar base cinch techniques on the changes in nasolabial morphology after bimaxillary orthognathic surgery. Sixty patients requiring a Le Fort I osteotomy to correct skeletal discrepancies were selected randomly to receive either conventional or modified alar base cinching during the intraoral wound closure procedure. Conventional cinching passed through nasalis muscle and anterior nasal spine. Modified cinching also passed through dermis tissue to increase the anchorage. Postoperative hard and soft tissue changes were evaluated using cone beam computed tomography and three-dimensional stereophotogrammetry at predefined time points. Forty-eight patients with a skeletal class III malocclusion were included. In the conventional group, there was an increase of 0.31 +/- 1.31 mm in nasal width and an increase of 0.97 +/- 1.60mm in columellar length. In the modified group, there was an increase of 0.81 +/- 1.87 mm in the cutaneous height of the upper lip and a decrease of 0.76 +/- 1.56 mm in lower prolabial width. Patients with an initial narrow nasal width, alar base width, and less vertical nostril show were more susceptible to a greater degree of change after surgery. Both alar base suture techniques are effective at controlling nasolabial form changes resulting from class III dual-jaw orthognathic surgery. PMID- 25825374 TI - Auto-reactive T cells revised. Overestimation based on methodology? AB - Autoreactive T cells have been identified in most autoimmune diseases and recently even in healthy individuals. Similar, T cells that recognize either wild type or tumorspecific tumor antigens have been increasingly reported to develop spontaneously in cancer patients. This insight has become possible mainly due to novel immunoassays which have revolutionized the discovery of rare antigen specific T cells. At present, the major dogma that explains this increasing number of reports of autoreactive T cells is that autoreactive T cells are counteracted by CD4+CD25+ regulatory T (Treg) cells in vivo, in particular in healthy individuals, whereas dysfunction in Tregs or Treg responsiveness may unmask the autoreactive T cell responses in patients with autoimmune diseases. However, studies that identify autoreactive T cells are usually performed by culturing T cells with antigen presenting cells loaded with E. coli produced recombinant protein or unmodified synthetic HLA binding peptides. Our concern is that this approach may ignore the presence of natural genetic variation and post translational modifications such as e.g. the complex nature of N- and O-linked glycosylation of mammalian proteins. Thus, T cell antigen reactivities identified with unmodified antigens in vitro may in part represent in vitro T cell activation against neo-epitopes and not true in vivo autoreactivity as postulated. This methodological problem may have implications for the interpretation of the frequent reporting of autoreactive T cells in autoimmunity, T cell responses to wild-type tumor antigens in cancer patients and most important for the increasing reports on naive T cells with specificity against self-antigens in healthy individuals. Here, we discuss and provide examples for the possibility that the experimental methodology applied to document T cell reactivity against unmodified protein or peptide may lead to overinterpretation of the reported frequencies of autoreactive CD4+ and CD8+ T cells. PMID- 25825375 TI - Discrimination within epitope specific antibody populations against Classical swine fever virus is a new means of differentiating infection from vaccination. AB - Serological differentiation between infection and vaccination depends on the detection of pathogen specific antibodies for an epitope that is modified or lacking in a vaccine. Here we describe a new assay principle that is based on differences in the binding properties of epitope specific antibodies. C-DIVA is a potent Classical swine fever vaccine candidate that differs from the parental C strain life attenuated vaccine in the highly immunogenic TAVSPTTLR epitope by the deletion of two and the mutation of one amino acid (TAGSDeltaDeltaTLR). We show that C-DIVA vaccination elicits antibodies with high affinity for both the TAGSDeltaDeltaTLR and TAVSPTTLR epitope, whereas infection elicits only TAVSPTTLR specific antibodies. Differentiation is achieved with a double competition assay with negative selection for antibodies with affinity for the TAGSDeltaDeltaTLR epitope followed by positive selection for antibodies with affinity for the TAVSPTTLR epitope. Our findings add a new strategy for the development of marker vaccines and their accompanying discrimination assays and offer an alternative to the devastating stamping out policy for Classical swine fever. PMID- 25825376 TI - Examining the Validity and Reliability of Antonovsky's Sense of Coherence Scale in a Population of Pregnant Australian Women. AB - Antonovsky's Orientation to Life questionnaires were developed to measure sense of coherence (SOC). Although the SOC 13 instrument is widely used to measure health in general populations, it has not been assessed in pregnant women. If the SOC 13 is to be used to assess women's childbearing health, it requires further examination. The purpose of the research is to assess the psychometric properties of Antonovsky's SOC 13 questionnaire in pregnant women. When administered to 718 pregnant Australian women, the construct validity of the SOC 13 was difficult to establish. The SOC 9 was created by removing 4 items and provided best data fit. The SOC 13 and SOC 9 were found to have sound criterion validity, internal reliability, and equivalence between versions. It is hoped that the present study will stimulate additional research on SOC scales to examine their ability to assess women's childbearing health. PMID- 25825377 TI - Assessment of changes to screening programmes: why randomisation is important. PMID- 25825378 TI - A Comparative Study on the Biomechanical and Histological Properties of Bone-to Bone, Bone-to-Tendon, and Tendon-to-Tendon Healing: An Achilles Tendon-Calcaneus Model in Goats. AB - BACKGROUND: Surgical repair around the bone-tendon insertion (BTI) may involve bone-to-bone (BB), bone-to-tendon (BT), or tendon-to-tendon (TT) reattachment with varying healing outcome. HYPOTHESIS: The repair of Achilles tendon-calcaneus (ATC) by reattachment of homogeneous tissue (BB or TT) would heal faster, with respect to tensile properties at the healing complex, than those of reattachment of heterogeneous tissues (BT) over time. STUDY DESIGN: Controlled laboratory study. METHODS: Forty-seven adolescent male Chinese goats were divided into BB, BT, and TT groups. Osteotomy of the calcaneus, reattachment of Achilles tendon to the calcaneus after removal of the insertion, and tenotomy of the Achilles tendon were performed to simulate BB, BT, and TT repair, respectively. The ATC healing complexes were harvested at 6, 12, or 24 weeks postoperatively. Mechanical and morphological properties of the healing ATC complexes were assessed by tensile testing and qualitative histology, respectively. The contralateral intact ATC complex was used as the control. RESULTS: Failure load of BT was 33.4% lower than that of TT (P = .0243) at week 12. Ultimate strength of BT was 50.2% and 45.3% lower than that of TT at weeks 12 (P = .0002) and 24 (P = .0001), respectively. Tissue morphological characteristics of the BB and TT groups showed faster remodeling. The BT group showed limited regeneration of fibrocartilage zone and excessive formation of fibrous tissue at the healing interface. CONCLUSION: BTI repair between homogeneous tissues (BB and TT healing) showed better healing quality with respect to mechanical and histological assessments than did healing between heterogeneous tissues (BT healing). CLINICAL RELEVANCE: Anatomic reconstruction of ATC complex injury may be a primary concern when selecting the proper surgical approach. However, it is recommended to select fracture fixation (BB) or tendon repair (TT) instead of bone-tendon reattachment (BT) if possible to ensure better outcome at the healing interface. PMID- 25825379 TI - When Is It Too Early for Single Sport Specialization? AB - Over the past 15 years, there has been an increase in youth sports participation with a concomitant increase in early year-round training in a single sport. Many factors contribute to the desire of parents and coaches to encourage early single sport specialization, including the desire to give the young athlete an edge in competition, pursuit of scholarships, and potential professional status, and the ability to label a young athlete as elite at an early age. Despite these perceived advantages, some data suggest that early sport specialization does not lead to a competitive advantage over athletes who participate in multiple sports. Although the data are limited, there is some evidence that early sport specialization may put the young athlete at risk for overuse injuries. The focus of this review is to highlight the evidence regarding early sport specialization and risk for injury; discuss the risk factors for overuse injury in high-risk sports including ice hockey, swimming, gymnastics, and baseball; and discuss future potential research that would help define the risk of injury for young athletes who participate in early sport specialization. PMID- 25825380 TI - The Rpd3/Hda1 family of histone deacetylases regulates azole resistance in Candida albicans. AB - OBJECTIVES: The histone deacetylase (HDAC) has recently been linked to the morphogenesis and virulence of yeast. However, the effects of HDAC on antifungal susceptibility are not well understood. We sought to characterize the action of histone deacetylation on azole resistance in Candida albicans and its possible mechanism of action. METHODS: A total of 40 C. albicans strains were studied. Azole susceptibility with or without trichostatin A (TSA) was determined according to the CLSI microdilution method. The null mutants of HDA1 and RPD3 (genes targeted by TSA) were also investigated using drop-plate assays and a rapid acquisition of adaptation to the azole test. Transcriptional levels of HDAC genes and efflux genes were quantified using RT-PCR for both the basal and fluconazole-induced conditions. RESULTS: The inhibition of HDACs by TSA (0.25 mg/L) markedly reduced the trailing growth and the growth of most C. albicans strains. Trailing growth for C. albicans strains was decreased from 2-fold to 256 fold at 48 h. The deletion of HDA1 or RPD3 increased the susceptibility to azoles compared with the WT strain. The expression of HDA1 and RPD3 was up-regulated to different levels, and returned to the level of the susceptible parental strain when stable resistance had formed during the course of acquired fluconazole resistance both in vitro and in vivo. Efflux genes were poorly expressed in mutant strains compared with those of the WT strain. CONCLUSIONS: Our results indicate the important role of the Rpd3/Hda1 family in the development of azole resistance in C. albicans. Histone deacetylation may govern the expression of genes related to the early stages of adaptation to azole stress, such as efflux pump genes. PMID- 25825381 TI - Coconut atrium. PMID- 25825382 TI - Contrast echocardiography detecting a rare abnormal venous connection. PMID- 25825383 TI - Anomalous single coronary artery from the pulmonary artery in a neonate. PMID- 25825384 TI - Plasmolipin--a new player in endocytosis and epithelial development. PMID- 25825385 TI - Not all patients with displaced proximal humerus fractures are suitable for sling treatment. PMID- 25825386 TI - Dengue serotype-specific differences in clinical manifestation, laboratory parameters and risk of severe disease in adults, singapore. AB - Studies on serotype-specific features of dengue and disease severity on adults are limited. We prospectively recruited adult febrile patients without alternate diagnosis to dengue from April 2005 to December 2011. Outcomes were defined using both the World Health Organization (WHO) 1997 and 2009 criteria; Dengue hemorrhagic fever (DHF) and severe dengue (SD). Infecting serotype was identified in 469 dengue-confirmed patients comprising 22.0% dengue virus serotype 1 (DENV 1), 57.1% DENV-2, 17.1% DENV-3, and 3.8% DENV-4. Cases infected with DENV-1 were more likely to present with red eyes whereas presence of joint pain and lower platelet count was associated with DENV-2 cases. After adjusting for potential confounders, DENV-1 was associated with both DHF (adjusted Relative Risk [aRR] = 1.74) and SD (aRR = 2.1) whereas DENV-2 had a lower risk of DHF (aRR = 0.5). DENV 1 genotype 1 and DENV-2 cosmopolitan were the predominant genotypes identified. Infecting dengue serotype and possibly genotype may play an important role in disease severity among adult dengue patients in Singapore. PMID- 25825388 TI - Schistosoma mansoni infection along the coast of Lake Victoria in Mwanza region, Tanzania. AB - Prevalence and intensity of Schistosoma mansoni infection according to age, sex, and occupation were investigated in 100 first-year students (aged 7-8 years), 100 schoolchildren (aged 9-12 years), and 50 adults (aged 20-55 years) from 149 villages. The schoolchildren provided three stool specimens while the rest provided only one specimen. A total of 31,865 individuals provided at least one specimen with an overall prevalence of 38.5% and geometric mean intensity of positives of 107.0 eggs per gram of feces. With the exception of first-year students, males had higher prevalence than females (P < 0.0005). Schoolchildren had higher prevalence than first-year students that again had higher prevalence than adults. There was no sex difference in intensities among the children, but adult males had higher intensities than adult females. Intensity among the children was higher than that of the adults (P < 0.0005). Prevalence was significantly higher in those having fishing as their main occupation. Three stools samples were obtained from 13,119 schoolchildren, resulting in a prevalence of 38.1% if only one sample was included, 47.5% including two samples, and 52.6% if all three samples were included. PMID- 25825387 TI - Interactions among urogenital, intestinal, skin, and oral infections in pregnant and lactating Panamanian Ngabe women: a neglected public health challenge. AB - Interrelationships among bacteria, protozoa, helminths, and ectoparasites were explored in a cross-sectional survey of 213 pregnant and 99 lactating indigenous women. Prevalences in pregnancy and lactation, respectively, were: vaginitis (89.2%; 46.8%), vaginal trichomoniasis (75.3%; 91.1%), bacterial vaginosis (BV; 60.6%; 63.3%), hookworm (56.6%; 47.8%), asymptomatic bacteriuria/urinary tract infection (AB/UTI; 56.2%; 36.2%), cervicitis (33.3%; 6.3%), vaginal yeast (24.9%; 11.4%), Ascaris (32.5%; 17.4%), vaginal diplococci (20.4%; 31.6%), caries (19.7%; 18.2%), scabies (17.4%; 8.1%), and Trichuris (12.5%; 8.7%). Multiple regressions revealed positive associations during pregnancy (trichomoniasis and AB/UTI; diplococci and Ascaris) and lactation (yeast and scabies). Negative associations were detected in pregnancy (BV and trichomoniasis; hookworm and diplococci) and lactation (BV and yeast). Vaginal Lactobacillus reduced odds of diplococci in pregnancy and lactation, but increased Ascaris eggs per gram (epg) and odds of trichomoniasis in pregnancy and yeast in lactation. These associations raised a concern that treatment of one condition may increase the risk of another. PMID- 25825389 TI - Differential clinical outcome of dengue infection among patients with and without HIV infection: a matched case-control study. AB - Clinical characteristics and outcome among dengue patients with and without human immunodeficiency virus (HIV) infection remain elusive. A total of 10 dengue virus (DENV)-HIV Chinese patients were compared with 40 Chinese dengue patients without HIV, who were matched for age, gender, type of care received, methods, and year of dengue diagnosis from 2005 to 2008. Univariate and multivariate conditional logistics regression were applied. DENV-HIV patients were significantly associated with the World Health Organization (WHO) 2009 severe dengue (conditional odds ratio [COR] = 5.72; 95% confidence interval [CI] = 1.01-32.64) but not with the WHO 1997 dengue hemorrhagic fever/dengue shock syndrome (COR = 0.40; 95% CI = 0.09-1.71). This is mainly due to severe plasma leakage and the lack of hemorrhagic manifestations. Hospitalization duration was longer for DENV HIV patients (10.5 days; interquartile range [IQR] = 5.5-26.3 days) compared with dengue patients (5 days; IQR = 4-6 days). There were no significant differences in presentation of clinical warning signs and symptoms at admission and during hospitalization, except for rash (adjusted COR [ACOR] = 0.06; 95% CI = 0.03 0.92). DENV-HIV patients were associated with higher pulse rate (ACOR = 1.13; 95% CI = 1.02-1.25), eosinophils proportion (ACOR = 3.07; 95% CI = 1.12-8.41) and lower hematocrit level (ACOR = 0.79; 95% CI = 0.64-0.98) compared with dengue patients. Even though DENV-HIV patients may present similarly to dengue patients, they may be more likely to have severe dengue outcome. Hence, close monitoring of DENV-HIV patients is highly recommended as part of dengue clinical care and management. PMID- 25825392 TI - 99mTc-HDP SPECT-CT Aids Localization of Joint Injections in Degenerative Joint Disease of the Foot and Ankle. AB - BACKGROUND: Pain relating to degenerative joint disease within the foot and ankle can be difficult to localize with clinical examination alone due to the complex anatomy of the joints. The aim of this study was to determine whether single photon emission computed tomography combined with conventional computed tomography (SPECT-CT) could be used to localize the site of degenerative joint disease for intra-articular injection and thereby improve the clinical success of the procedure. METHODS: A prospective study was performed involving 203 patients who had undergone triple-phase (99m)Tc-hydroxymethylene diphosphonate bone scans with SPECT-CT of the foot and ankle for degenerative joint disease. Fifty-two patients went on to have joint injections for degenerative joint disease, with clinical follow-up. Correlation with the clinical diagnosis and the outcome of intra-articular injections with 0.5% bupivacaine and 80 mg of Depo-Medrone was performed. A successful outcome was determined by an improvement in the visual analog pain score of at least 50%. RESULTS: In 19 (37%) patients, the site of degenerative joint disease determined by SPECT-CT differed from the initial clinical assessment and resulted in a change in management. Overall, 46 (88%) patients showed an improvement in symptoms. CONCLUSION: The study demonstrated a high clinical success rate for SPECT-CT-guided joint injections. The technique was useful in localizing degenerative joint disease of the ankle, hindfoot, and midfoot as an adjunct to clinical examination. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25825394 TI - Ban commercial confidentiality clauses from state procurement contracts. PMID- 25825393 TI - Clinical Effects of Platelet-Rich Plasma and Hyaluronic Acid as an Additional Therapy for Talar Osteochondral Lesions Treated with Microfracture Surgery: A Prospective Randomized Clinical Trial. AB - BACKGROUND: Osteochondral ankle injuries commonly affect the dome of the talus, and these injuries are a common cause of athletic disability. Various treatment options are available for these injuries including intra-articular hyaluronic acid (HA) and platelet-rich plasma (PRP) injections. The purpose of this study was to compare the effects of HA and PRP as adjunct therapies after arthroscopic microfracture in osteochondral lesions (OCLs) of the talus. METHODS: In this prospective, randomized blinded study, 40 patients with talar OCLs in their ankle joints were treated with arthroscopic debridement and a microfracture technique. Thirteen randomly selected patients received PRP, 14 patients received HA, and the remaining 13 patients received saline as a control group. The participants were assessed using the American Orthopaedic Foot & Ankle Society (AOFAS) and visual analog pain scale (VAS) scores after a 15.3-month (range, 11-25 months) follow-up. RESULTS: Postoperatively, all the groups exhibited significantly increased AOFAS scores and decreased VAS scores compared with their preoperative results (P < .005). The AOFAS scores were significantly increased in the PRP group versus the HA and control groups (P < .005), although the increased AOFAS scores in the HA group versus the control group were also significant (P < .005). Similar to the AOFAS scores, the decrease in the VAS scores was significantly lower in the PRP group versus the HA and control groups (P < .005). In addition, the HA group had significantly lower VAS scores than the control group (P < .005). CONCLUSION: Both PRP and HA injections improved the clinical outcomes of patients who underwent operation for talar OCLs in the midterm period and can be used as adjunct therapies for these patients. Because a single dose of PRP provided better results, we recommend PRP as the primary adjunct treatment option in the talar OCL postoperative period. LEVEL OF EVIDENCE: Level I, prospective randomized study. PMID- 25825391 TI - Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron sulfur deficiency and pulmonary hypertension. AB - Iron-sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings. PMID- 25825395 TI - Target it all right, but do not forget the torchbearer. PMID- 25825397 TI - Targeting pathogenic postischemic self-recognition by natural IgM to protect against posttransplantation cardiac reperfusion injury. AB - BACKGROUND: Natural IgM antibodies represent a class of innate pattern recognition receptors that recognize danger-associated molecular patterns expressed on stressed or dying cells. They play important roles in tissue homeostasis by disposing of prenecrotic cells and suppressing inflammation. However, ischemic insult leads to a pathogenic level of IgM binding and complement activation, resulting in inflammation and injury. We investigate the role of self-reactive IgM in the unique setting of transplantation where the donor organ undergoes both cold and warm ischemia and global ischemic insult. METHODS AND RESULTS: By transplanting hearts from wild-type donor mice into antibody-deficient mice reconstituted with specific self-reactive IgM monoclonal antibodies, we identified neoepitopes expressed after transplantation and demonstrated a key role for IgM recognition of these epitopes in graft injury. With this information, we developed and characterized a therapeutic strategy that exploited the postischemia recognition system of natural antibodies. On the basis of neoepitope identification, we constructed an anti-annexin IV single-chain antibody (scFv) and an scFv linked to Crry, an inhibitor of C3 activation (scFv Crry). In an allograft transplantation model in which recipients contain a full natural antibody repertoire, both constructs blocked graft IgM binding and complement activation and significantly reduced graft inflammation and injury. Furthermore, scFv-Crry specifically targeted to the transplanted heart and, unlike complement deficiency, did not affect immunity to infection, an important consideration for immunosuppressed transplant recipients. CONCLUSIONS: We identified pathophysiologically important epitopes expressed within the heart after transplantation and described a novel translatable strategy for targeted complement inhibition that has several advantages over currently available approaches. PMID- 25825398 TI - Unique case of ST-segment-elevation myocardial infarction related to paradoxical embolization and simultaneous pulmonary embolization: clinical considerations on indications for patent foramen ovale closure in no-guidelines land. PMID- 25825396 TI - Nucleotide-binding oligomerization domain 2 receptor is expressed in platelets and enhances platelet activation and thrombosis. AB - BACKGROUND: Pattern recognition receptor nucleotide-binding oligomerization domain 2 (NOD2) is well investigated in immunity, but its expression and function in platelets has never been explored. METHOD AND RESULTS: Using reverse transcription polymerase chain reaction and Western blot, we show that both human and mouse platelets express NOD2, and its agonist muramyl dipeptide induced NOD2 activation as evidenced by receptor dimerization. NOD2 activation potentiates platelet aggregation and secretion induced by low concentrations of thrombin or collagen, and clot retraction, as well. These potentiating effects of muramyl dipeptide were not seen in platelets from NOD2-deficient mice. Plasma from septic patients also potentiates platelet aggregation induced by thrombin or collagen NOD2 dependently. Using intravital microscopy, we found that muramyl dipeptide administration accelerated in vivo thrombosis in a FeCl3-injured mesenteric arteriole thrombosis mouse model. Platelet depletion and transfusion experiments confirmed that NOD2 from platelets contributes to the in vivo thrombosis in mice. NOD2 activation also accelerates platelet-dependent hemostasis. We further found that platelets express receptor-interacting protein 2, and provided evidence suggesting that mitogen activated-protein kinase and nitric oxide/soluble guanylyl cyclase/cGMP/protein kinase G pathways downstream of receptor interacting protein mediate the role of NOD2 in platelets. Finally, muramyl dipeptide stimulates proinflammatory cytokine interleukin-1beta maturation and accumulation in human and mouse platelets NOD2 dependently. CONCLUSIONS: NOD2 is expressed in platelets and functions in platelet activation and arterial thrombosis, possibly during infection. To our knowledge, this is the first study on NOD-like receptors in platelets that link thrombotic events to inflammation. PMID- 25825400 TI - Quadricuspid aortic valve and anomalous systemic venous connection in a patient with cat-eye syndrome. PMID- 25825401 TI - Rapid diagnosis of cardiac tamponade using pulsatility index variability in a patient with a HeartWare ventricular assist device. PMID- 25825402 TI - Cardiology patient page. Statin intolerance. PMID- 25825403 TI - Letter by Thoma et al regarding article, "A randomized trial of social media from Circulation". PMID- 25825404 TI - Letter by Dixon et al regarding article, "A randomized trial of social media from Circulation". PMID- 25825405 TI - Letter by Semsarian and Ingles regarding article, "A randomized trial of social media from Circulation". PMID- 25825406 TI - Letter by Djuricich and Madanick regarding article, "A randomized trial of social media from Circulation". PMID- 25825407 TI - Response to letters regarding article, "A randomized trial of social media from Circulation". PMID- 25825408 TI - IAP antagonization promotes inflammatory destruction of vascular endothelium. AB - In this study, we show for the first time that the therapeutic antagonization of inhibitor of apoptosis proteins (IAPs) inhibits B16 melanoma growth by disrupting tumor vasculature. Specifically, the treatment of mice bearing B16 melanoma with an IAP antagonist compound A (Comp A) inhibits tumor growth not by inducing direct cytotoxicity against B16 cells but rather by a hitherto unrecognized antiangiogenic activity against tumor vessels. Our detailed analysis showed that Comp A treatment induces NF-kappaB activity in B16 tumor cells and facilitates the production of TNF. In the presence of Comp A, endothelial cells (ECs) become highly susceptible to TNF and undergo apoptotic cell death. Accordingly, the antiangiogenic and growth-attenuating effects of Comp A treatment were completely abolished in TNF-R knockout mice. This novel targeting approach could be of clinical value in controlling pathological neoangiogenesis under inflammatory condition while sparing blood vessels under normal condition. PMID- 25825409 TI - The BMA should apply itself to solving the NHS's productivity problem. PMID- 25825410 TI - High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy. AB - BACKGROUND: Cardiac troponin and B-type natriuretic peptide (BNP) concentrations are associated with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood. METHODS AND RESULTS: We measured high-sensitivity cardiac troponin I (hsTnI) in 12 956 and BNP in 11 076 participants without cardiovascular disease in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial before randomization to rosuvastatin 20 mg/d or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted hazard ratio [aHR], 2.19; 95% confidence interval, 1.56-3.06; P for trend <0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR, 1.94; 95% confidence interval, 1.41-2.68; P for trend <0.001). The risk of all-cause mortality was elevated for the highest versus the lowest tertiles of hsTnI (aHR, 2.61; 95% confidence interval, 1.81-3.78; P for trend <0.001) and BNP (aHR, 1.45; 95% confidence interval, 1.03-2.04; P for trend 0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range, 0.50-0.60) and BNP (aHR range, 0.42-0.67) with no statistically significant evidence of interaction (P for interaction=0.53 and 0.20, respectively). CONCLUSIONS: In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681. PMID- 25825411 TI - Child development assessment tools in low-income and middle-income countries: how can we use them more appropriately? AB - Global emphasis has shifted beyond reducing child survival rates to improving health and developmental trajectories in childhood. Optimum early childhood experience is believed to allow children to benefit fully from educational opportunities resulting in improved human capital. Investment in early childhood initiatives in low-income and middle-income countries (LMICs) is increasing. These initiatives use early childhood developmental assessment tools (CDATs) as outcome measures. CDATs are also key measures in the evaluation of programmatic health initiatives in LMICs, influencing public health policy. Interpretation of CDAT outcomes requires understanding of their structure and psychometric properties. This article reviews the structure and main methods of CDAT development with specific considerations when applied in LMICs. PMID- 25825412 TI - Review of toxicity and trends in the use of tiagabine as reported to US poison centers from 2000 to 2012. AB - BACKGROUND: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gamma-aminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. METHOD: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. RESULTS: A total of 2147 patients had ingested tiagabine, with a mean of 165 year(-1). This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year(-1)) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). CONCLUSIONS: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning. PMID- 25825413 TI - The impact of high fructose on cardiovascular system: Role of alpha-lipoic acid. AB - The aim of this study was to evaluate the role of alpha-lipoic acid (alpha-LA) on oxidative damage and inflammation that occur in endothelium of aorta and heart while constant consumption of high-fructose corn syrup (HFCS). The rats were randomly divided into three groups with each group containing eight rats. The groups include HFCS, HFCS + alpha-LA treatment, and control. HFCS was given to the rats at a ratio of 30% of F30 corn syrup in drinking water for 10 weeks. alpha-LA treatment was given to the rats at a dose of 100 mg/kg/day orally for the last 6 weeks. At the end of the experiment, the rats were killed by cervical dislocation. The blood samples were collected for biochemical studies, and the aortic and cardiac tissues were collected for evaluation of oxidant-antioxidant system, tissue bath, and pathological examination. HFCS had increased the levels of malondialdehyde, creatine kinase MB, lactate dehydrogenase, and uric acid and showed significant structural changes in the heart of the rats by histopathology. Those changes were improved by alpha-LA treatment as it was found in this treatment group. Immunohistochemical expressions of tumor necrosis factor alpha and inducible nitric oxide synthase were increased in HFCS group, and these receptor levels were decreased by alpha-LA treatment. All the tissue bath studies supported these findings. Chronic consumption of HFCS caused several problems like cardiac and endothelial injury of aorta by hyperuricemia and induced oxidative stress and inflammation. alpha-LA treatment reduced uric acid levels, oxidative stress, and corrected vascular responses. alpha-LA can be added to cardiac drugs due to its cardiovascular protective effects against the cardiovascular diseases. PMID- 25825414 TI - Authors' reply to Honeyford and colleagues and Roland. PMID- 25825415 TI - Chinese nurses' perceived barriers and facilitators of ethical sensitivity. AB - BACKGROUND: An overview of ethical sensitivity among Chinese registered nurses is needed to develop and optimize the education programs and interventions to cultivate and improve ethical sensitivity. AIM: The study was conducted to explore the barriers to and facilitators of ethical sensitivity among Chinese registered nurses working in hospital settings. RESEARCH DESIGN: A convergent parallel mixed-methods research design was adopted. PARTICIPANTS AND RESEARCH CONTEXT: In the cross-sectional quantitative study, the Chinese Moral Sensitivity Questionnaire-revised version was used to assess the levels of ethical sensitivity among registered nurses, and the scores were correlated with key demographics, training experiences in ethics, and workplace cultural environments (n = 306). In the qualitative study, semi-structured interviews were used to elicit the nurses' perceptions of the barriers and facilitators in nurturing ethical sensitivity (n = 15). The data were collected from February to June 2014. ETHICAL CONSIDERATIONS: This study was approved by the Institutional Review Boards of Yale University and Central South University. RESULTS: Despite moderately high overall Chinese Moral Sensitivity Questionnaire-revised version scores, the ethical sensitivity among Chinese nurses lags in practice. Barriers to ethical sensitivity include the lack of knowledge related to ethics, lack of working experience as a nurse, the hierarchical organizational climate, and the conformist working attitude. The positive workplace cultural environments and application of ethical knowledge in practice were considered potential facilitators of ethical sensitivity. DISCUSSION: The findings of this study were compared with studies from other countries to examine the barriers and facilitators of ethical sensitivity in Chinese nurses. CONCLUSION: This mixed methods study showed that even though the Chinese nurses have moderately high sensitivity to the ethical issues encountered in hospitals, there is still room for improvement. The barriers to and facilitators of ethical sensitivity identified here offer new and important strategies to support and enhance the nurses' sensitivity to ethical issues. PMID- 25825416 TI - Need for a comprehensive national survey of cannabis use. PMID- 25825417 TI - Study may not be the best approach to assessing link between QOF and premature death. PMID- 25825418 TI - An Unexpected Foreign Body: A Hypopharyngeal Ant. PMID- 25825419 TI - Friction characteristics of trocars in laparoscopic surgery. AB - This article investigates the friction characteristics of the instrument-trocar interface in laparoscopic surgery for varying linear instrument velocities, trocar seal design and material, and trocar tilt. Furthermore, the effect of applying lubrication at the instrument-trocar seal interface on friction was studied. A friction testing apparatus was designed and built to characterise the resistance force at the instrument-trocar interface as a function of the instrument's linear movement in the 12-mm trocar (at constant velocity) for different design, seal material, and angle of tilt. The resistance force depended on the trocar seal design and material properties, specifically surface roughness, elasticity, hardness, the direction of movement, and the instrument linear velocity, and varied between 0.25 and 8 N. Lubricating the shaft with silicone oil reduced the peak resistance force by 75% for all trocars and eliminated the stick-slip phenomenon evident in non-lubricated cases. The magnitude of fluctuation in resistance force depends on the trocar design and is attributed to stick-slip of the sealing mechanism and is generally higher during retraction in comparison to insertion. Trocars that have an inlet seal made of rubber/polyurethane showed higher resistance forces during retraction. Use of a lubricant significantly reduced frictional effects. Comparisons of the investigated trocars indicate that a low friction port, providing the surgeon with improved haptic feedback, can be designed by improving the tribological properties of the trocar seal interface. PMID- 25825420 TI - Commentary on: Long-term follow-up of cadaveric breast augmentation: what can we learn? PMID- 25825421 TI - The efficacy of botulinum toxin A in post-mastectomy breast reconstruction: a pilot study. AB - BACKGROUND: Botulinum toxin A has been successfully used in a variety of areas to temporarily obliterate muscle mobility for either functional or aesthetic gain. Tissue expander-based breast reconstruction has been plagued with pain and discomfort. OBJECTIVE: The purpose of this pilot study was to evaluate the role of a neurotoxin (Botulinum toxin A) in expander-based breast reconstruction. METHODS: Thirty patients underwent mastectomies with immediate expander or acellular dermal matrix reconstruction. The neurotoxin group (n = 15) received 40 units of neurotoxin (Botulinum toxin A, Allergan, Inc, Irvine, CA) into each pectoralis major muscle through 4 serial injections and the placebo group (n = 15) received 4 serial injections of 0.9% NaCl. All patients were followed over 1 year, and patient demographics, VAS (visual analog score), laterality, office visits, amount of expansion and number of times to full expansion, and amount of narcotics required were recorded. Statistical significance was considered as p < .05. RESULTS: There were no significant differences between the two groups in terms of age, laterality, expander size, or complications (p = .46-.66). There was a significant difference between the two groups in the VAS score, demonstrating decreased pain in the neurotoxin group (p < .05). In addition, there was a significant increase in the volume of expansion per visit in the neurotoxin group as compared to the placebo group (p < .05). There was no significant difference in narcotic use in the first 3 days after surgery; however, there was a significant decrease in use of narcotics from 7 to 45 days in the neurotoxin group (p < .05). There were no complications associated with the use of the neurotoxin. CONCLUSIONS: The infiltration of the pectoralis major muscle with neurotoxin in immediate, expander-based reconstruction may be beneficial in reducing pain and expediting expansions. PMID- 25825422 TI - Sebum Production Alteration after Botulinum Toxin Type A Injections for the Treatment of Forehead Rhytides: A Prospective Randomized Double-Blind Dose Comparative Clinical Investigation. AB - BACKGROUND: Research has investigated the decrease in human skin sebum after the application of botulinum toxin. Few studies of the mechanism and objective assessments of this phenomenon have been conducted and the correlation between the sebum production and injection dosages or techniques remains unclear. OBJECTIVES: We prospectively investigated the sebum regulation and its gradient around the injection site in patients who received intramuscular injections of botulinum toxin A (BTX-A) for forehead rhytides, comparing two injection doses. METHODS: Forty-two female volunteers with rhytides on the forehead region were randomly assigned to receive 10 or 20 units of BTX-A, which was administered in five standard injection sites. The baseline and post-treatment sebum production was measured using a Sebumeter. RESULTS: Treatment with BTX-A exhibited significant sebum alteration at the injection site of both groups, with a sebum gradient surrounding the injection point. The efficacy did not improve at higher injection doses, with the four-unit regimen generally not being more potent than the two-unit regimen. The sebum production recovered to normal levels at the 16 week follow-up for both treatment groups, indicating that a higher dosage (four units) did not result in a longer duration until relapse compared with the two unit dose. CONCLUSIONS: We determined that the sebum production has a positive correlation with the distance away from the injection point. Intramuscular injection of BTX-A significantly reduces sebum production at the injection site but increases the sebum production of the surrounding skin at a radius of 2.5 cm at the 2, 4, and 8 week follow-ups. LEVEL OF EVIDENCE: 2 Therapeutic. PMID- 25825423 TI - Long-term follow-up of cadaveric breast augmentation: what can we learn? AB - Breast augmentation with cadaveric fat graft has long been available to patients in Eastern European countries, primarily in the Soviet Union and Eastern Germany. Most such procedures were performed from the 1970s to the 1990s. Although only a few case reports have been published, all of which involved complications that appeared several years after the procedure, it appears that, surprisingly, this nonvascularized and incompatible immunologic tissue is relatively well tolerated. We present the case of a 45-year-old Russian woman who underwent breast explantation, due to breast hardness and pain, 15 years after breast augmentation with cadaveric fat grafting. Through genetic studies, we confirmed that the host and the graft were HLA incompatible. Moreover, results of analyses excluded the possibility of an acute or chronic immunologic rejection by the host. We suppose that the early complications that often occur in such cases might result from a nonspecific, inflammatory reaction induced by acute tissue ischemia and necrosis, and the late local complications that occur years later may relate more to chronic inflammation, due to nonvascularized tissue, than to immunologic rejection. Therefore, we propose that different mechanisms may explain how this allogenic fat tissue could have been tolerated by the patient's immune system. We particularly underline the immunomodulatory effect of mesenchymal stem cells, which are abundant in adipose tissues. This characteristic of fat tissue should be investigated further to assess its potential in treating autoimmune diseases or reducing the likelihood of allograft rejections. PMID- 25825424 TI - Is ketorolac safe to use in plastic surgery? A critical review. AB - BACKGROUND: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that provides postoperative pain control and reduces narcotic requirements. However, concerns regarding postoperative hematoma have limited its use in plastic surgery. OBJECTIVES: Our goal is to critically review the risk of bleeding with ketorolac in plastic surgery patients, with a focus on aesthetic surgery. METHODS: A PubMed/Medline literature search of clinical trials using the keywords "surgery" and "NSAID" yielded 2574 results. Of these results, 1036 included ketorolac and twelve involved plastic surgery patients. Six studies reported postoperative hematoma rates: three prospective randomized trials, two retrospective reviews, and one case series. These were subjected to statistical analysis to determine if an association existed between ketorolac and postoperative hematomas. RESULTS: Six papers reported 981 cases. Ketorolac use resulted in similar hematoma rates when compared to control groups, 2.5% (12 of 483) versus 2.4% (12 of 498), respectively (P = .79). There were no reported hematomas associated with ketorolac in over 115 patients undergoing aesthetic facial procedures. Hematoma rates of those undergoing aesthetic breast surgery, including reduction and augmentation mammoplasties, were 4.3% (11 of 257) in the ketorolac group versus 2.2% (6 of 277) in controls (P = .59). Reduction in postoperative narcotic use and improved pain scores was also reported. CONCLUSIONS: Our literature review did not find a significant association between hematoma formation and ketorolac use in a variety of plastic surgery procedures. These findings are similar to those in other surgical subspecialties. PMID- 25825425 TI - Plant NB-LRR proteins: tightly regulated sensors in a complex manner. AB - As plants are sessile, they have evolved hundreds of resistance (R) genes to defend themselves against multiple pathogens. Most of plant R genes encode proteins with the nucleotide-binding and leucine-rich repeat (NB-LRR) domains that interact with pathogen effectors to induce defense responses. Recent findings describing R proteins structures, host interactors and transcriptional and posttranscriptional regulators have broadened our understanding of R gene activity regulation. Genome-wide analyses of NB-LRR genes are useful for identifying host and nonhost R genes and elucidating complex resistance mechanisms. This review provides an overview of the functions of identified NB LRRs and intra- and intermolecular R gene regulators. PMID- 25825426 TI - Inhibition of Cell Differentiation in Bacillus subtilis by Pseudomonas protegens. AB - Interspecies interactions have been described for numerous bacterial systems, leading to the identification of chemical compounds that impact bacterial physiology and differentiation for processes such as biofilm formation. Here, we identified soil microbes that inhibit biofilm formation and sporulation in the common soil bacterium Bacillus subtilis. We did so by creating a reporter strain that fluoresces when the transcription of a biofilm-specific gene is repressed. Using this reporter in a coculture screen, we identified Pseudomonas putida and Pseudomonas protegens as bacteria that secrete compounds that inhibit biofilm gene expression in B. subtilis. The active compound produced by P. protegens was identified as the antibiotic and antifungal molecule 2,4-diacetylphloroglucinol (DAPG). Colonies of B. subtilis grown adjacent to a DAPG-producing P. protegens strain had altered colony morphologies relative to B. subtilis colonies grown next to a DAPG-null P. protegens strain (phlD strain). Using a subinhibitory concentration of purified DAPG in a pellicle assay, we saw that biofilm-specific gene transcription was delayed relative to transcription in untreated samples. These transcriptional changes also corresponded to phenotypic alterations: both biofilm biomass and spore formation were reduced in B. subtilis liquid cultures treated with subinhibitory concentrations of DAPG. Our results add DAPG to the growing list of antibiotics that impact bacterial development and physiology at subinhibitory concentrations. These findings also demonstrate the utility of using coculture as a means to uncover chemically mediated interspecies interactions between bacteria. IMPORTANCE: Biofilms are communities of bacteria adhered to surfaces by an extracellular matrix; such biofilms can have important effects in both clinical and agricultural settings. To identify chemical compounds that inhibited biofilm formation, we used a fluorescent reporter to screen for bacteria that inhibited biofilm gene expression in Bacillus subtilis. We identified Pseudomonas protegens as one such bacterium and found that the biofilm-inhibiting compound it produces was the antibiotic 2,4 diacetylphloroglucinol (DAPG). We showed that even at subinhibitory concentrations, DAPG inhibits biofilm formation and sporulation in B. subtilis. These findings have potential implications for understanding the interactions between these two microbes in the natural world and support the idea that many compounds considered antibiotics can impact bacterial development at subinhibitory concentrations. PMID- 25825427 TI - Basal Body Structures Differentially Affect Transcription of RpoN- and FliA Dependent Flagellar Genes in Helicobacter pylori. AB - Flagellar biogenesis in Helicobacter pylori is regulated by a transcriptional hierarchy governed by three sigma factors, RpoD (sigma(80)), RpoN (sigma(54)), and FliA (sigma(28)), that temporally coordinates gene expression with the assembly of the flagellum. Previous studies showed that loss of flagellar protein export apparatus components inhibits transcription of flagellar genes. The FlgS/FlgR two-component system activates transcription of RpoN-dependent genes though an unknown mechanism. To understand better the extent to which flagellar gene regulation is coupled to flagellar assembly, we disrupted flagellar biogenesis at various points and determined how these mutations affected transcription of RpoN-dependent (flaB and flgE) and FliA-dependent (flaA) genes. The MS ring (encoded by fliF) is one of the earliest flagellar structures assembled. Deletion of fliF resulted in the elimination of RpoN-dependent transcripts and an ~4-fold decrease in flaA transcript levels. FliH is a cytoplasmic protein that functions with the C ring protein FliN to shuttle substrates to the export apparatus. Deletions of fliH and genes encoding C ring components (fliM and fliY) decreased transcript levels of flaB and flgE but had little or no effect on transcript levels of flaA. Transcript levels of flaB and flgE were elevated in mutants where genes encoding rod proteins (fliE and flgBC) were deleted, while transcript levels of flaA was reduced ~2-fold in both mutants. We propose that FlgS responds to an assembly checkpoint associated with the export apparatus and that FliH and one or more C ring component assist FlgS in engaging this flagellar structure. IMPORTANCE: The mechanisms used by bacteria to couple transcription of flagellar genes with assembly of the flagellum are poorly understood. The results from this study identified components of the H. pylori flagellar basal body that either positively or negatively affect expression of RpoN-dependent flagellar genes. Some of these basal body proteins may interact directly with regulatory proteins that control transcription of the H. pylori RpoN regulon, a hypothesis that can be tested by examining protein protein interactions in vitro. PMID- 25825428 TI - The Matrix Reloaded: Probing the Extracellular Matrix Synchronizes Bacterial Communities. AB - In response to chemical communication, bacterial cells often organize themselves into complex multicellular communities that carry out specialized tasks. These communities are frequently referred to as biofilms, which involve collective behavior of different cell types. Like cells of multicellular eukaryotes, the biofilm cells are surrounded by self-produced polymers that constitute the extracellular matrix (ECM), which binds them to each other and to the surface. In multicellular eukaryotes, it has been evident for decades that cell-ECM interactions control multiple cellular processes during development. While cells, both in biofilms and in multicellular eukaryotes, are surrounded by ECM and activate various genetic programs, until recently it has been unclear whether cell-ECM interactions are recruited in bacterial communicative behaviors. In this review, we will describe the examples reported thus far for ECM involvement in control of cell behavior throughout the different stages of biofilm formation. The studies presented in this review provide a newly emerging perspective of the bacterial ECM as an active player in regulation of biofilm development. PMID- 25825429 TI - A Homology Model Reveals Novel Structural Features and an Immunodominant Surface Loop/Opsonic Target in the Treponema pallidum BamA Ortholog TP_0326. AB - We recently demonstrated that TP_0326 is a bona fide rare outer membrane protein (OMP) in Treponema pallidum and that it possesses characteristic BamA bipartite topology. Herein, we used immunofluorescence analysis (IFA) to show that only the beta-barrel domain of TP_0326 contains surface-exposed epitopes in intact T. pallidum. Using the solved structure of Neisseria gonorrhoeae BamA, we generated a homology model of full-length TP_0326. Although the model predicts a typical BamA fold, the beta-barrel harbors features not described in other BamAs. Structural modeling predicted that a dome comprised of three large extracellular loops, loop 4 (L4), L6, and L7, covers the barrel's extracellular opening. L4, the dome's major surface-accessible loop, contains mainly charged residues, while L7 is largely neutral and contains a polyserine tract in a two-tiered conformation. L6 projects into the beta-barrel but lacks the VRGF/Y motif that anchors L6 within other BamAs. IFA and opsonophagocytosis assay revealed that L4 is surface exposed and an opsonic target. Consistent with B cell epitope predictions, immunoblotting and enzyme-linked immunosorbent assay (ELISA) confirmed that L4 is an immunodominant loop in T. pallidum-infected rabbits and humans with secondary syphilis. Antibody capture experiments using Escherichia coli expressing OM-localized TP_0326 as a T. pallidum surrogate further established the surface accessibility of L4. Lastly, we found that a naturally occurring substitution (Leu(593) -> Gln(593)) in the L4 sequences of T. pallidum strains affects antibody binding in sera from syphilitic patients. Ours is the first study to employ a "structure-to-pathogenesis" approach to map the surface topology of a T. pallidum OMP within the context of syphilitic infection. IMPORTANCE: Previously, we reported that TP_0326 is a bona fide rare outer membrane protein (OMP) in Treponema pallidum and that it possesses the bipartite topology characteristic of a BamA ortholog. Using a homology model as a guide, we found that TP_0326 displays unique features which presumably relate to its function(s) in the biogenesis of T. pallidum's unorthodox OM. The model also enabled us to identify an immunodominant epitope in a large extracellular loop that is both an opsonic target and subject to immune pressure in a human population. Ours is the first study to follow a structure-to-pathogenesis approach to map the surface topology of a T. pallidum rare OMP within the context of syphilitic infection. PMID- 25825430 TI - Abbreviated Pathway for Biosynthesis of 2-Thiouridine in Bacillus subtilis. AB - The 2-thiouridine (s(2)U) modification of the wobble position in glutamate, glutamine, and lysine tRNA molecules serves to stabilize the anticodon structure, improving ribosomal binding and overall efficiency of the translational process. Biosynthesis of s(2)U in Escherichia coli requires a cysteine desulfurase (IscS), a thiouridylase (MnmA), and five intermediate sulfur-relay enzymes (TusABCDE). The E. coli MnmA adenylates and subsequently thiolates tRNA to form the s(2)U modification. Bacillus subtilis lacks IscS and the intermediate sulfur relay proteins, yet its genome contains a cysteine desulfurase gene, yrvO, directly adjacent to mnmA. The genomic synteny of yrvO and mnmA combined with the absence of the Tus proteins indicated a potential functionality of these proteins in s(2)U formation. Here, we provide evidence that the B. subtilis YrvO and MnmA are sufficient for s(2)U biosynthesis. A conditional B. subtilis knockout strain showed that s(2)U abundance correlates with MnmA expression, and in vivo complementation studies in E. coli IscS- or MnmA-deficient strains revealed the competency of these proteins in s(2)U biosynthesis. In vitro experiments demonstrated s(2)U formation by YrvO and MnmA, and kinetic analysis established a partnership between the B. subtilis proteins that is contingent upon the presence of ATP. Furthermore, we observed that the slow-growth phenotype of E. coli DeltaiscS and DeltamnmA strains associated with s(2)U depletion is recovered by B. subtilis yrvO and mnmA. These results support the proposal that the involvement of a devoted cysteine desulfurase, YrvO, in s(2)U synthesis bypasses the need for a complex biosynthetic pathway by direct sulfur transfer to MnmA. IMPORTANCE: The 2-thiouridine (s(2)U) modification of the wobble position in glutamate, glutamine, and lysine tRNA is conserved in all three domains of life and stabilizes the anticodon structure, thus guaranteeing fidelity in translation. The biosynthesis of s(2)U in Escherichia coli requires seven proteins: the cysteine desulfurase IscS, the thiouridylase MnmA, and five intermediate sulfur-relay enzymes (TusABCDE). Bacillus subtilis and most Gram positive bacteria lack a complete set of biosynthetic components. Interestingly, the mnmA coding sequence is located adjacent to yrvO, encoding a cysteine desulfurase. In this work, we provide evidence that the B. subtilis YrvO is able to transfer sulfur directly to MnmA. Both proteins are sufficient for s(2)U biosynthesis in a pathway independent of the one used in E. coli. PMID- 25825431 TI - Oxygen-Dependent Cell-to-Cell Variability in the Output of the Escherichia coli Tor Phosphorelay. AB - Escherichia coli senses and responds to trimethylamine-N-oxide (TMAO) in the environment through the TorT-TorS-TorR signal transduction system. The periplasmic protein TorT binds TMAO and stimulates the hybrid kinase TorS to phosphorylate the response regulator TorR through a phosphorelay. Phosphorylated TorR, in turn, activates transcription of the torCAD operon, which encodes the proteins required for anaerobic respiration via reduction of TMAO to trimethylamine. Interestingly, E. coli respires TMAO in both the presence and absence of oxygen, a behavior that is markedly different from the utilization of other alternative electron acceptors by this bacterium. Here we describe an unusual form of regulation by oxygen for this system. While the average level of torCAD transcription is the same for aerobic and anaerobic cultures containing TMAO, the behavior across the population of cells is strikingly different under the two growth conditions. Cellular levels of torCAD transcription in aerobic cultures are highly heterogeneous, in contrast to the relatively homogeneous distribution in anaerobic cultures. Thus, oxygen regulates the variance of the output but not the mean for the Tor system. We further show that this oxygen dependent variability stems from the phosphorelay. IMPORTANCE: Trimethylamine-N oxide (TMAO) is utilized by numerous bacteria as an electron acceptor for anaerobic respiration. In E. coli, expression of the proteins required for TMAO respiration is tightly regulated by a signal transduction system that is activated by TMAO. Curiously, although oxygen is the energetically preferred electron acceptor, TMAO is respired even in the presence of oxygen. Here we describe an interesting and unexpected form of regulation for this system in which oxygen produces highly variable expression of the TMAO utilization proteins across a population of cells without affecting the mean expression of these proteins. To our knowledge, this is the first reported example of a stimulus regulating the variance but not the mean output of a signaling system. PMID- 25825432 TI - RNase III-Independent Autogenous Regulation of Escherichia coli Polynucleotide Phosphorylase via Translational Repression. AB - The complex posttranscriptional regulation mechanism of the Escherichia coli pnp gene, which encodes the phosphorolytic exoribonuclease polynucleotide phosphorylase (PNPase), involves two endoribonucleases, namely, RNase III and RNase E, and PNPase itself, which thus autoregulates its own expression. The models proposed for pnp autoregulation posit that the target of PNPase is a mature pnp mRNA previously processed at its 5' end by RNase III, rather than the primary pnp transcript (RNase III-dependent models), and that PNPase activity eventually leads to pnp mRNA degradation by RNase E. However, some published data suggest that pnp expression may also be regulated through a PNPase-dependent, RNase III-independent mechanism. To address this issue, we constructed isogenic Deltapnp rnc(+) and Deltapnp Deltarnc strains with a chromosomal pnp-lacZ translational fusion and measured beta-galactosidase activity in the absence and presence of PNPase expressed by a plasmid. Our results show that PNPase also regulates its own expression via a reversible RNase III-independent pathway acting upstream from the RNase III-dependent branch. This pathway requires the PNPase RNA binding domains KH and S1 but not its phosphorolytic activity. We suggest that the RNase III-independent autoregulation of PNPase occurs at the level of translational repression, possibly by competition for pnp primary transcript between PNPase and the ribosomal protein S1. IMPORTANCE: In Escherichia coli, polynucleotide phosphorylase (PNPase, encoded by pnp) posttranscriptionally regulates its own expression. The two models proposed so far posit a two-step mechanism in which RNase III, by cutting the leader region of the pnp primary transcript, creates the substrate for PNPase regulatory activity, eventually leading to pnp mRNA degradation by RNase E. In this work, we provide evidence supporting an additional pathway for PNPase autogenous regulation in which PNPase acts as a translational repressor independently of RNase III cleavage. Our data make a new contribution to the understanding of the regulatory mechanism of pnp mRNA, a process long since considered a paradigmatic example of posttranscriptional regulation at the level of mRNA stability. PMID- 25825433 TI - Genome Modification in Enterococcus faecalis OG1RF Assessed by Bisulfite Sequencing and Single-Molecule Real-Time Sequencing. AB - Enterococcus faecalis is a Gram-positive bacterium that natively colonizes the human gastrointestinal tract and opportunistically causes life-threatening infections. Multidrug-resistant (MDR) E. faecalis strains have emerged, reducing treatment options for these infections. MDR E. faecalis strains have large genomes containing mobile genetic elements (MGEs) that harbor genes for antibiotic resistance and virulence determinants. Bacteria commonly possess genome defense mechanisms to block MGE acquisition, and we hypothesize that these mechanisms have been compromised in MDR E. faecalis. In restriction-modification (R-M) defense, the bacterial genome is methylated at cytosine (C) or adenine (A) residues by a methyltransferase (MTase), such that nonself DNA can be distinguished from self DNA. A cognate restriction endonuclease digests improperly modified nonself DNA. Little is known about R-M in E. faecalis. Here, we use genome resequencing to identify DNA modifications occurring in the oral isolate OG1RF. OG1RF has one of the smallest E. faecalis genomes sequenced to date and possesses few MGEs. Single-molecule real-time (SMRT) and bisulfite sequencing revealed that OG1RF has global 5-methylcytosine (m5C) methylation at 5'-GCWGC-3' motifs. A type II R-M system confers the m5C modification, and disruption of this system impacts OG1RF electrotransformability and conjugative transfer of an antibiotic resistance plasmid. A second DNA MTase was poorly expressed under laboratory conditions but conferred global N(4)-methylcytosine (m4C) methylation at 5'-CCGG-3' motifs when expressed in Escherichia coli. Based on our results, we conclude that R-M can act as a barrier to MGE acquisition and likely influences antibiotic resistance gene dissemination in the E. faecalis species. IMPORTANCE: The horizontal transfer of antibiotic resistance genes among bacteria is a critical public health concern. Enterococcus faecalis is an opportunistic pathogen that causes life-threatening infections in humans. Multidrug resistance acquired by horizontal gene transfer limits treatment options for these infections. In this study, we used innovative DNA sequencing methodologies to investigate how a model strain of E. faecalis discriminates its own DNA from foreign DNA, i.e., self versus nonself discrimination. We also assess the role of an E. faecalis genome modification system in modulating conjugative transfer of an antibiotic resistance plasmid. These results are significant because they demonstrate that differential genome modification impacts horizontal gene transfer frequencies in E. faecalis. PMID- 25825435 TI - Regulation by the modulation of gene expression variability. AB - Classically, transcription is regulated so that the average expression per cell changes, often with a distribution that extends across the population. Roggiani and Goulian (M. Roggiani and M. Goulian, J. Bacteriol. 197:1976-1987, 2015, doi:http://dx.doi.org/10.1128/JB.00074-15) have shown that this is what happens when the torCAD operon of Escherichia coli is induced anaerobically by the addition of trimethylamine-N-oxide (TMAO). However, when the same inducer is added to aerobically growing cells, only a subset of the cells respond, although the mean expression per cell is similar to that obtained anaerobically. Thus, in the presence of oxygen, the variance but not the expression mean is altered. The regulation of gene expression variance appears to be due to noise in the phosphorelay that governs torCAD transcription. PMID- 25825434 TI - Role of Bacillus subtilis DNA Glycosylase MutM in Counteracting Oxidatively Induced DNA Damage and in Stationary-Phase-Associated Mutagenesis. AB - Reactive oxygen species (ROS) promote the synthesis of the DNA lesion 8-oxo-G, whose mutagenic effects are counteracted in distinct organisms by the DNA glycosylase MutM. We report here that in Bacillus subtilis, mutM is expressed during the exponential and stationary phases of growth. In agreement with this expression pattern, results of a Western blot analysis confirmed the presence of MutM in both stages of growth. In comparison with cells of a wild-type strain, cells of B. subtilis lacking MutM increased their spontaneous mutation frequency to Rif(r) and were more sensitive to the ROS promoter agents hydrogen peroxide and 1,1'-dimethyl-4,4'-bipyridinium dichloride (Paraquat). However, despite MutM's proven participation in preventing ROS-induced-DNA damage, the expression of mutM was not induced by hydrogen peroxide, mitomycin C, or NaCl, suggesting that transcription of this gene is not under the control of the RecA, PerR, or sigma(B) regulons. Finally, the role of MutM in stationary-phase-associated mutagenesis (SPM) was investigated in the strain B. subtilis YB955 (hisC952 metB5 leuC427). Results revealed that under limiting growth conditions, a mutM knockout strain significantly increased the amount of stationary-phase-associated his, met, and leu revertants produced. In summary, our results support the notion that the absence of MutM promotes mutagenesis that allows nutritionally stressed B. subtilis cells to escape from growth-limiting conditions. IMPORTANCE: The present study describes the role played by a DNA repair protein (MutM) in protecting the soil bacterium Bacillus subtilis from the genotoxic effects induced by reactive oxygen species (ROS) promoter agents. Moreover, it reveals that the genetic inactivation of mutM allows nutritionally stressed bacteria to escape from growth limiting conditions, putatively by a mechanism that involves the accumulation and error-prone processing of oxidized DNA bases. PMID- 25825436 TI - Sca-1+Lin-CD117- mesenchymal stem/stromal cells induce the generation of novel IRF8-controlled regulatory dendritic cells through Notch-RBP-J signaling. AB - Mesenchymal stem/stromal cells (MSCs) can influence the destiny of hematopoietic stem/progenitor cells (HSCs) and exert broadly immunomodulatory effects on immune cells. However, how MSCs regulate the differentiation of regulatory dendritic cells (regDCs) from HSCs remains incompletely understood. In this study, we show that mouse bone marrow-derived Sca-1(+)Lin(-)CD117(-) MSCs can drive HSCs to differentiate into a novel IFN regulatory factor (IRF)8-controlled regDC population (Sca(+) BM-MSC-driven DC [sBM-DCs]) when cocultured without exogenous cytokines. The Notch pathway plays a critical role in the generation of the sBM DCs by controlling IRF8 expression in an RBP-J-dependent way. We observed a high level of H3K27me3 methylation and a low level of H3K4me3 methylation at the Irf8 promoter during sBM-DC induction. Importantly, infusion of sBM-DCs could alleviate colitis in mice with inflammatory bowel disease by inhibiting lymphocyte proliferation and increasing the numbers of CD4(+)CD25(+) regulatory T cells. Thus, these data infer a possible mechanism for the development of regDCs and further support the role of MSCs in treating immune disorders. PMID- 25825437 TI - Impaired dendritic cell function in a spontaneous autoimmune polyneuropathy. AB - Spontaneous autoimmune polyneuropathy (SAP) in B7-2 knockout NOD mice mimics the progressive form of chronic inflammatory demyelinating polyradiculoneuropathy, and is mediated by myelin protein zero (P0)-reactive Th1 cells. In this study, we focused on the effect of B7-2 deletion on the function of dendritic cells (DCs) within the context of SAP. We found that development of SAP was associated with a preponderance or increase of CD11b(+) DCs in peripheral lymph nodes and sciatic nerves. B7-2 deletion led to altered immunophenotypic properties that differ between CD11b(+) DCs and CD8alpha(+) DCs. Both DC subsets from B7-2 knockout NOD mice exhibited impaired capacity to capture fluorophore-labeled myelin P0, but diminished Ag-presenting function was observed only in CD11b(+) DCs. Clinical assessment, electrophysiologic studies, and splenocyte proliferation studies revealed that absence of B7-2 on DCs was sufficient to cause impaired ability to induce tolerance to P0, which could be overcome by preconditioning with IL-10. Tolerance induction by Ag-pulsed wild-type NOD DCs was dependent on IL-10 and was associated with increased CD4(+) regulatory T cells, whereas tolerance induction by IL-10-conditioned B7-2-deficient DCs was associated with increased percentages of both regulatory T cells and B10 cells in the spleen. We conclude that B7-2 deletion has an impact on the distribution of DC subsets in lymphoid organs and alters the expression of costimulatory molecules, but functional consequences are not uniform across DC subsets. Defective tolerance induction in the absence of B7 2 can be restored by preconditioning of DCs with IL-10. PMID- 25825438 TI - Epitope-specific CD8+ T cell kinetics rather than viral variability determine the timing of immune escape in simian immunodeficiency virus infection. AB - CD8(+) T cells are important for the control of chronic HIV infection. However, the virus rapidly acquires "escape mutations" that reduce CD8(+) T cell recognition and viral control. The timing of when immune escape occurs at a given epitope varies widely among patients and also among different epitopes within a patient. The strength of the CD8(+) T cell response, as well as mutation rates, patterns of particular amino acids undergoing escape, and growth rates of escape mutants, may affect when escape occurs. In this study, we analyze the epitope specific CD8(+) T cells in 25 SIV-infected pigtail macaques responding to three SIV epitopes. Two epitopes showed a variable escape pattern and one had a highly monomorphic escape pattern. Despite very different patterns, immune escape occurs with a similar delay of on average 18 d after the epitope-specific CD8(+) T cells reach 0.5% of total CD8(+) T cells. We find that the most delayed escape occurs in one of the highly variable epitopes, and that this is associated with a delay in the epitope-specific CD8(+) T cells responding to this epitope. When we analyzed the kinetics of immune escape, we found that multiple escape mutants emerge simultaneously during the escape, implying that a diverse population of potential escape mutants is present during immune selection. Our results suggest that the conservation or variability of an epitope does not appear to affect the timing of immune escape in SIV. Instead, timing of escape is largely determined by the kinetics of epitope-specific CD8(+) T cells. PMID- 25825439 TI - SNX17 affects T cell activation by regulating TCR and integrin recycling. AB - A key component in T cell activation is the endosomal recycling of receptors to the cell surface, thereby allowing continual integration of signaling and Ag recognition. One protein potentially involved in TCR transport is sorting nexin 17 (SNX17). SNX proteins have been found to bind proteins involved in T cell activation, but specifically the role of SNX17 in receptor recycling and T cell activation is unknown. Using immunofluorescence, we find that SNX17 colocalizes with TCR and localizes to the immune synapse in T- conjugates. Significantly, knockdown of the SNX17 resulted in fewer T-APC conjugates, lower CD69, TCR, and LFA-1 surface expression, as well as lower overall TCR recycling compared with control T cells. Lastly, we identified the 4.1/ezrin/radixin/moesin domain of SNX17 as being responsible in the binding and trafficking of TCR and LFA-1 to the cell surface. These data suggest that SNX17 plays a role in the maintenance of normal surface levels of activating receptors and integrins to permit optimum T cell activation at the immune synapse. PMID- 25825440 TI - IL-18 triggered by the Nlrp3 inflammasome induces host innate resistance in a pulmonary model of fungal infection. AB - Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain-like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1beta). In this study, we showed that NLR family pyrin domain-containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1beta and IL-18 by P. brasiliensis-infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18-dependent proinflammatory response. PMID- 25825441 TI - Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM. AB - TLR4 recruits TRIF-related adaptor molecule (TRAM, also known as TICAM2) as a sorting adaptor to facilitate the interaction between TLR4 and TRIF and then initiate TRIF-dependent IRF3 activation. However, the mechanisms by which TRAM links downstream molecules are not fully elucidated. In this study, we show that TRAM undergoes tyrosine phosphorylation upon TLR4 activation and that is required for TLR4-induced IRF3 activation. Protein tyrosine phosphatase nonreceptor type 4 (PTPN4), a protein tyrosine phosphatase, inhibits tyrosine phosphorylation and subsequent cytoplasm translocation of TRAM, resulting in the disturbance of TRAM TRIF interaction. Consequently, PTPN4 specifically inhibits TRIF-dependent IRF3 activation and IFN-beta production in TLR4 pathway. Therefore, our results provide new insight into the TLR4 pathway and identify PTPN4 as a specific inhibitor of TRIF-dependent TLR4 pathway. Targeting PTPN4 would be beneficial for the development of new strategy to control TLR4-associated diseases without unwanted side effects. PMID- 25825442 TI - A unique mouse strain that develops spontaneous, iodine-accelerated, pathogenic antibodies to the human thyrotrophin receptor. AB - Abs that stimulate the thyrotropin receptor (TSHR), the cause of Graves' hyperthyroidism, only develop in humans. TSHR Abs can be induced in mice by immunization, but studying pathogenesis and therapeutic intervention requires a model without immunization. Spontaneous, iodine-accelerated, thyroid autoimmunity develops in NOD.H2(h4) mice associated with thyroglobulin and thyroid-peroxidase, but not TSHR, Abs. We hypothesized that transferring the human TSHR A-subunit to NOD.H2(h4) mice would result in loss of tolerance to this protein. BALB/c human TSHR A-subunit mice were bred to NOD.H2(h4) mice, and transgenic offspring were repeatedly backcrossed to NOD.H2(h4) mice. All offspring developed Abs to thyroglobulin and thyroid-peroxidase. However, only TSHR-transgenic NOD.H2(h4) mice (TSHR/NOD.H2(h4)) developed pathogenic TSHR Abs as detected using clinical Graves' disease assays. As in humans, TSHR/NOD.H2(h4) female mice were more prone than male mice to developing pathogenic TSHR Abs. Fortunately, in view of the confounding effect of excess thyroid hormone on immune responses, spontaneously arising pathogenic human TSHR Abs cross-react poorly with the mouse TSHR and do not cause thyrotoxicosis. In summary, the TSHR/NOD.H2(h4) mouse strain develops spontaneous, iodine-accelerated, pathogenic TSHR Abs in female mice, providing a unique model to investigate disease pathogenesis and test novel TSHR Ag-specific immunotherapies aimed at curing Graves' disease in humans. PMID- 25825443 TI - Newly recruited CD11b+, GR-1+, Ly6C(high) myeloid cells augment tumor-associated immunosuppression immediately following the therapeutic administration of oncolytic reovirus. AB - Tumor-associated immunosuppression aids cancer cells to escape immune-mediated attack and subsequent elimination. Recently, however, many oncolytic viruses, including reovirus, have been reported to overturn such immunosuppression and promote the development of a clinically desired antitumor immunity, which is known to promote favorable patient outcomes. Contrary to this existing paradigm, in this article we demonstrate that reovirus augments tumor-associated immunosuppression immediately following its therapeutic administration. Our data show that reovirus induces preferential differentiation of highly suppressive CD11b(+), Gr-1(+), Ly6C(high) myeloid cells from bone marrow hematopoietic progenitor cells. Furthermore, reovirus administration in tumor-bearing hosts drives time-dependent recruitment of CD11b(+), Gr-1(+), Ly6C(high) myeloid cells in the tumor milieu, which is further supported by virus-induced increased expression of numerous immune factors involved in myeloid-derived suppressor cell survival and trafficking. Most importantly, CD11b(+), Gr-1(+), Ly6C(high) myeloid cells specifically potentiate the suppression of T cell proliferation and are associated with the absence of IFN-gamma response in the tumor microenvironment early during oncotherapy. Considering that the qualitative traits of a specific antitumor immunity are largely dictated by the immunological events that precede its development, our findings are of critical importance and must be considered while devising complementary interventions aimed at promoting the optimum efficacy of oncolytic virus-based anticancer immunotherapies. PMID- 25825444 TI - Coordinated expression of DNAM-1 and LFA-1 in educated NK cells. AB - The functional capacity of NK cells is dynamically tuned by integrated signals from inhibitory and activating cell surface receptors in a process termed NK cell education. However, the understanding of the cellular and molecular mechanisms behind this functional tuning is limited. In this study, we show that the expression of the adhesion molecule and activation receptor DNAX accessory molecule 1 (DNAM-1) correlates with the quantity and quality of the inhibitory input by HLA class I-specific killer cell Ig-like receptors and CD94/NKG2A as well as with the magnitude of functional responses. Upon target cell recognition, the conformational state of LFA-1 changed in educated NK cells, associated with rapid colocalization of both active LFA-1 and DNAM-1 at the immune synapse. Thus, the coordinated expression of LFA-1 and DNAM-1 is a central component of NK cell education and provides a potential mechanism for controlling cytotoxicity by functionally mature NK cells. PMID- 25825445 TI - Suppressor of cytokine signaling 1 is a positive regulator of TGF-beta-induced prostaglandin production in human follicular dendritic cell-like cells. AB - PGs are emerging as important immune modulators. Since our report on the expression of PG synthases in human follicular dendritic cells, we investigated the potential immunoregulatory function of PGs and their production mechanisms. In this study, we explored the intracellular signaling molecules mediating TGF beta-induced cyclooxygenase (COX)-2 augmentation in follicular dendritic cell like cells. TGF-beta triggered phosphorylation of Smad3 and ERK, which were essential for the increase in COX-2 protein. Interestingly, depletion of suppressor of cytokine signaling 1 (SOCS1) resulted in an almost complete inhibition of Smad3 phosphorylation and COX-2 induction. Nuclear translocation of Smad3 was inhibited in SOCS1-depleted cells. SOCS1 knockdown also downregulated TGF-beta-stimulated Snail expression and its binding to the Cox-2 promoter. In contrast, overexpression of SOCS1 gave rise to a significant increase in Snail and COX-2 proteins. SOCS1 was reported to be a negative regulator of cytokine signaling by various investigators. However, our current data suggest that SOCS1 promotes TGF-beta-induced COX-2 expression and PG production by facilitating Smad3 phosphorylation and Snail binding to the Cox-2 promoter. The complete understanding of the biological function of SOCS1 might be obtained via extensive studies with diverse cell types. PMID- 25825446 TI - IL-10 critically modulates B cell responsiveness in Rankl-/- mice. AB - The immune and the skeletal system are tightly interconnected, and B lymphocytes are uniquely endowed with osteo-interactive properties. In this context, receptor activator of NF-kappaB (RANK) ligand (RANKL) plays a pivotal role in lymphoid tissue formation and bone homeostasis. Although murine models lacking RANK or RANKL show defects in B cell number, the role of the RANKL-RANK axis on B physiology is still a matter of debate. In this study, we have characterized in detail B cell compartment in Rankl(-/-) mice, finding a relative expansion of marginal zone B cells, B1 cells, and plasma cells associated with increased Ig serum levels, spontaneous germinal center formation, and hyperresponse to CD40 triggering. Such abnormalities were associated with an increased frequency of regulatory B cells and augmented B cell-derived IL-10 production. Remarkably, in vivo IL-10-R blockade reduced T cell-triggered plasma cell differentiation and restrained the expansion of regulatory B cells. These data point to a novel role of the RANKL-RANK axis in the regulation of B cell homeostasis and highlight an unexpected link between IL-10 CD40 signaling and the RANKL pathway. PMID- 25825447 TI - Defects in regulatory T cells due to CD28 deficiency induce a qualitative change of allogeneic immune response in chronic graft-versus-host disease. AB - In patients receiving allogeneic hematopoietic cell transplantation, chronic graft-versus-host disease (cGVHD) remains a frequent complication and resembles autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis. Our previous work demonstrated the critical role of CD28 costimulation of donor T cells for GVHD induction. In this study, we investigate the role of CD28 costimulation of host T cells in cGVHD. CD28-intact mice as hosts showed systemic lupus erythematosus-type cGVHD, whereas CD28-deficient mice developed a distinct phenotype of cGVHD, with fibrotic damage in skin and internal organs, resembling systemic sclerosis. This phenotype was due to a lack of signaling through the C terminal proline-rich motif within host CD28's cytoplasmic tail, a motif previously shown to be required for development of regulatory T cells (Tregs) and function of conventional T cells. Adoptive transfer experiments demonstrated that a defect in host CD4(+)CD25(+) Tregs, but not in conventional T cells, was responsible for disease phenotype. Host Treg deficiency altered the cytokine pattern of donor CD4(+) T cells and the Ag specificity of autoantibodies, and these might lead to phenotypic change. Thus, host CD28 signaling controlled the pathogenesis of cGVHD through effects on host Tregs, whose status impacts qualitatively on the allogeneic immune responses. PMID- 25825448 TI - Effect of TLR agonists on the differentiation and function of human monocytic myeloid-derived suppressor cells. AB - Tumors persist by occupying immunosuppressive microenvironments that inhibit the activity of tumoricidal T and NK cells. Monocytic myeloid-derived suppressor cells (mMDSC) are an important component of this immunosuppressive milieu. We find that the suppressive activity of mMDSC isolated from cancer patients can be reversed by treatment with TLR7/8 agonists, which induce human mMDSC to differentiate into tumoricidal M1-like macrophages. In contrast, agonists targeting TLR1/2 cause mMDSC to mature into immunosuppressive M2-like macrophages. These two populations of macrophage are phenotypically and functionally discrete and differ in gene expression profile. The ability of TLR7/8 agonists to reverse mMDSC-mediated immune suppression suggests that they might be useful adjuncts for tumor immunotherapy. PMID- 25825449 TI - SAMHD1 degradation enhances active suppression of dendritic cell maturation by HIV-1. AB - A hallmark of HIV-1 infection is the lack of sterilizing immunity. Dendritic cells (DCs) are crucial in the induction of immunity, and lack of DC activation might underlie the absence of an effective anti-HIV-1 response. We have investigated how HIV-1 infection affects maturation of DCs. Our data show that even though DCs are productively infected by HIV-1, infection does not induce DC maturation. HIV-1 infection actively suppresses DC maturation, as HIV-1 infection inhibited TLR-induced maturation of DCs and thereby decreased the immune stimulatory capacity of DCs. Interfering with SAMHD1 restriction further increased infection of DCs, but did not lead to DC maturation. Notably, higher infection observed with SAMHD1 depletion correlated with a stronger suppression of maturation. Furthermore, blocking reverse transcription rescued TLR-induced maturation. These data strongly indicate that HIV-1 replication does not trigger immune activation in DCs, but that HIV-1 escapes immune surveillance by actively suppressing DC maturation independent of SAMHD1. Elucidation of the mechanism of suppression can lead to promising targets for therapy or vaccine design. PMID- 25825450 TI - Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire. AB - The human Ig repertoire is vast, producing billions of unique Abs from a limited number of germline Ig genes. The IgH V region (IGHV) is central to Ag binding and consists of 48 functional genes. In this study, we analyzed whether HIV-1 infected individuals who develop broadly neutralizing Abs show a distinctive germline IGHV profile. Using both 454 and Illumina technologies, we sequenced the IGHV repertoire of 28 HIV-infected South African women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 002 and 004 cohorts, 13 of whom developed broadly neutralizing Abs. Of the 259 IGHV alleles identified in this study, approximately half were not found in the International Immunogenetics Database (IMGT). This included 85 entirely novel alleles and 38 alleles that matched rearranged sequences in non-IMGT databases. Analysis of the rearranged H chain V region genes of mAbs isolated from seven of these women, as well as previously isolated broadly neutralizing Abs from other donors, provided evidence that at least eight novel or non-IMGT alleles contributed to functional Abs. Importantly, we found that, despite a wide range in the number of IGHV alleles in each individual, including alleles used by known broadly neutralizing Abs, there were no significant differences in germline IGHV repertoires between individuals who do and do not develop broadly neutralizing Abs. This study reports novel IGHV repertoires and highlights the importance of a fully comprehensive Ig database for germline gene usage prediction. Furthermore, these data suggest a lack of genetic bias in broadly neutralizing Ab development in HIV-1 infection, with positive implications for HIV vaccine design. PMID- 25825451 TI - Programmed cell death 1 and Helios distinguish TCR-alphabeta+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells. AB - TCR-alphabeta(+) double-negative (DN; CD4(-)CD8(-)) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8(+) cells. However, the conditions that govern the loss of CD8 expression after Ag encounter are unknown. In this study, we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate Ags as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate Ag is sensed as self. This process is restricted to tissues where the Ag is present. We also show that DN T cells derived from self reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated with self-Ag encounter. PMID- 25825452 TI - Epigenetic downregulation of SFRP4 contributes to epidermal hyperplasia in psoriasis. AB - Psoriasis is a chronic recurrent inflammatory skin disorder characterized by the dysregulated cross-talk between epidermal keratinocytes and immune cells, leading to keratinocyte hyperproliferation. Several studies demonstrated that Wnt pathway genes were differentially expressed in psoriatic plaques and likely were involved in the pathophysiology of disease. However, the molecular mechanisms underlying Wnt signaling regulation in epidermal hyperplasia in psoriasis remain largely unknown. We report that the expression of secreted frizzled-related protein (SFRP) 4, a negative regulator of the Wnt signaling pathway, was diminished in lesional skin of mouse models and patients with psoriasis. SFRP4 directly inhibited excessive keratinocyte proliferation evoked by proinflammatory cytokines in vitro. Pharmacological inhibition of Wnt signaling or intradermal injection of SFRP4 decreased the severity of the psoriasiform skin phenotype in vivo, including decreased acanthosis and reduced leukocyte infiltration. Mechanistically, we identified that aberrant promoter methylation resulted in epigenetic downregulation of SFRP4 in inflamed skin of patients with psoriasis and in the IL-23-induced mouse model. Our findings suggest that this epigenetic event is critically involved in the pathogenesis of psoriasis, and the downregulation of SFRP4 by CpG island methylation is one possible mechanism contributing to the hyperplasia of epidermis in the disease. PMID- 25825453 TI - A survey of tools for analysing DNA fingerprints. AB - DNA fingerprinting is a genetic typing technique that allows the analysis of the genomic relatedness between samples, and the comparison of DNA patterns. This technique has multiple applications in different fields (medical diagnosis, forensic science, parentage testing, food industry, agriculture and many others). An important task in molecular epidemiology of infectious diseases is the analysis and comparison of pulsed-field gel electrophoresis (PFGE) patterns. This is applied to determine the clonal diversity of bacteria in the follow-up of outbreaks or for tracking specific clones of special relevance. The resulting images produced by DNA fingerprinting are sometimes difficult to interpret, and multiple tools have been developed to simplify this task. In this article, we present a survey of tools for analysing DNA fingerprints. In particular, we compare 33 tools using a set of predefined criteria. The comparison was carried out by hands-on experiences-whenever possible-and inspecting the documentation of the tools. As no system is preferred in all the possible scenarios, we have created a spreadsheet that can be customized by researchers to determine the best system for their needs. PMID- 25825454 TI - Depressed mood amplifies heart-related symptoms in persistent and paroxysmal atrial fibrillation patients: a longitudinal analysis--data from the German Competence Network on Atrial Fibrillation. AB - AIMS: There is limited evidence of an association between the burden of atrial fibrillation (AF)-related symptoms and depressed mood (DM). We used follow-up data from two randomized trials to relate AF symptoms, perceived AF burden, and DM. METHODS AND RESULTS: Baseline data on 319 persistent AF patients from the Flec-SL trial and 244 paroxysmal AF patients from the ANTIPAF trial were available. Data on 400 patients were available at 6-month follow-up. Depressed mood was measured using the major depression inventory, AF symptoms using the AF Symptom Checklist. Generalized estimating equation models were used to assess the association between symptom burden and DM. At baseline, 194 patients (35.2%) reported DM, 294 (52.2%) reported severe AF symptom burden. Burden from all symptoms except fainting was significantly elevated in patients with DM. An improvement in DM from baseline to follow-up was associated with reduced symptom burden [odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.22-3.51]. Patients with DM had three-fold increased odds of severe symptom burden after adjustment for perceived AF-frequency and -duration, sex, and chronic obstructive pulmonary disorder (COPD) (OR = 3.19; 95% CI: 2.65-8.45). Women reported significantly more severe symptom burden than men (OR = 1.44; 95% CI: 1.36-1.95). Uneasiness, nausea, and shortness of breath were most strongly associated with DM. The effect of DM on nausea was more pronounced for men (P(interaction) = 0.041). Perceived AF-frequency and -duration were not associated with DM (P = 0.717 and 0.236, respectively). CONCLUSION: Depressed mood is associated with AF symptom burden over 6 months after adjustment for perceived frequency and duration of AF episodes, COPD, and sex. PMID- 25825455 TI - Various mechanisms and clinical phenotypes in electrical short circuits of high voltage devices: report of four cases and review of the literature. AB - AIMS: An electrical short circuit is a rare complication in a high-voltage implantable cardioverter-defibrillator (ICD). However, the inability of an ICD to deliver appropriate shock therapy can be life-threatening. METHODS AND RESULTS: During the last 2 years, four cases of serious complications related to an electrical short circuit have been reported in Japan. A spark due to an electrical short circuit resulted in the failure of an ICD shock to terminate ventricular tachycardia and total damage to the ICD generator in three of four cases. Two of the four patients died from an electrical short circuit between the right ventricle and superior vena cava (SVC) leads. The others had audible sounds from the ICD generator site and were diagnosed with a lead-to-can abrasion, which was manifested by the arc mark on the surface of the can. CONCLUSION: It is still difficult to predict the occurrence of an electrical short circuit in current ICD systems. To reduce the probability of an electrical short circuit, we suggest the following: (i) avoid lead stress at ICD implantation, (ii) select a single-coil lead instead of a dual-coil lead, or (iii) use a unique algorithm which automatically disconnect can or SVC lead from shock deliver circuit when excessive current was detected. PMID- 25825456 TI - Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family. AB - AIMS: Hypertrophic cardiomyopathy (HCM) mainly results from autosomal-dominant inherited single heterozygous mutations in cardiac sarcomere genes. Contributions of multiple gene mutations to disease heterogeneity in a three-generation family were investigated. METHODS: Clinical, electrocardiographic (ECG), and echocardiographic examination in members of a three-generation Chinese family was followed by exon and boarding intron analysis of 96 genes in the proband using second-generation sequencing. The identified mutations were confirmed by bi directional Sanger sequencing in all family members and 300 healthy controls. RESULTS: Four missense mutations were detected in the family. These were two novel MYH7-H1717Q and MYLK2-K324E mutations accompanied by the KCNQ1-R190W and TMEM70-I147T mutations. The proband carried all four mutations and showed overlapping HCM and LQT1 phenotypes. Five family members each carried two mutations. Subject II-2 only carried TMEM70-I147T. MYH7-H1717Q and TMEM70-I147T came from the paternal side, whereas KCNQ1-R190W and MYLK2-K324E came from the maternal side. Left ventricle mass indices in MYH7-H1717Q carriers were significantly higher than in non-H1717Q carriers (90.05 +/- 7.33 g/m(2), 63.20 +/ 4.53 g/m(2), respectively, P < 0.01). Four KCNQ1-R190W carriers showed QTc intervals that were significantly more prolonged than those in non-R190W carriers (472.25 +/- 16.18 and 408.50 +/- 7.66 ms, respectively, P < 0.05). All MYLK2 K324E carriers showed inverted ECG T waves. The subject with only a TMEM70-I147T mutation showed normal ECG and echocardiographs, suggesting that this had less pathological effects at least in this family. CONCLUSIONS: We demonstrate dual LQT1 and HCM phenotypes in this multiple LQT1- and HCM-related gene mutation carrier family for the first time and suggest that LQT-related gene mutations associate with QT interval prolongation and/or arrhythmia in HCM patients. PMID- 25825457 TI - Electrical superior vena cava isolation using photodynamic therapy in a canine model. AB - AIMS: With the new era of multi-tip radiofrequency or balloon ablation catheters replacing the point-to-point ablation strategy, we aimed to determine the feasibility of a ring-laser catheter ablation technology to electrically isolate the superior vena cava (SVC) by exploring the advantages of the limitless catheter tip size possibly with the photodynamic therapy (PDT)-mediated ablation. METHODS AND RESULTS: We developed a first-generation prototype of a circular laser-mapping catheter by fitting a 7 cm plastic optical fibre onto a circular variable-loop LassoTM mapping catheter. Following SVC venography, both the laser catheter and another ring catheter for monitoring the SVC potentials were placed at the SVC. After the systemic infusion of a photosensitizer (talaporfin sodium), we initiated the irradiation with an output of 1 W in three canines and 0.3 W in four. The creation of electrical isolation as well as occurrence of phrenic nerve injury, sinus node injury, and SVC stenosis were evaluated before, immediately after, and 1 month after the procedure. A PDT-mediated SVC isolation was successfully performed in all seven canines. The isolation was completed with a laser irradiation of 70.4 +/- 71.4 J/cm under 30.9 +/- 5.0 ug/mL of a photosensitizer without any sinus node injury, phrenic nerve palsy, or SVC stenosis in both the acute and chronic evaluations. The minimum isolation time of 270 s was not correlated with the laser input power or the photosensitizer concentration. CONCLUSION: The electrical SVC isolation was successfully and instantly achieved using the PDT laser-ring catheter without any complications. PMID- 25825458 TI - An unusual case of oleandrin poisoning suggesting its possible antiarrhythmic activity. PMID- 25825459 TI - Changes in left ventricular synchrony and systolic function in dilated cardiomyopathy patients with fragmented QRS complexes. AB - AIMS: Fragmented QRS (f-QRS) complexes are associated with adverse cardiovascular events in patients with coronary heart disease; however, the effects on patients with dilated cardiomyopathy (DCM) remain elusive. This study is to investigate the changes of left ventricular (LV) synchrony and systolic function in DCM patients with f-QRS complexes. METHODS AND RESULTS: Twenty DCM patients with f QRS complexes and 29 DCM patients without f-QRS (n-QRS) complexes were enrolled. The LV segmental longitudinal, radial and circumferential time to peak strain and general longitudinal systolic strain, radial strain, circumferential strain were measured, respectively, by speckle tracking imaging. The LV segmental standard deviations and maximal differences were also calculated. The LV dyssynchrony was defined as the time in peak anteroseptal wall to posterior wall strain >130 ms or longitudinal strain delay index >25%. The mean QRS durations in f-QRS and n-QRS groups were not different (P = ns). The incidence of LV dyssynchrony was 15/20 (75%) vs. 5/29 (17%) in two groups (P < 0.01). Two patients died of sudden death in f-QRS group during 2 years follow-up; however, no death in n-QRS group (P < 0.05). Patients in f-QRS group showed worsening LV dyssynchrony in f-QRS group after 2 years follow-up (P < 0.05). Overall, LV function was comparable at baseline (P = ns), but had significantly worsened only in the f-QRS group (P < 0.05). CONCLUSION: The f-QRS complex is significantly associated with LV dyssynchrony in DCM patients and can be used as a reliable index to evaluate ventricular synchrony and predict the prognosis in DCM patients with narrow QRS complexes. PMID- 25825461 TI - Left ventricular wall motion analysis to guide management of CRT non-responders. AB - AIMS: A discordant left ventricular (LV) lead position can be responsible for cardiac resynchronization therapy (CRT) non-response. In this study, tailored optimization of the individual LV wall motion was evaluated for the outcome in these patients. METHODS AND RESULTS: Two hundred and forty-six CRT outpatients were screened for non-response due to a discordant LV lead. In 17 patients, three dimensional data of fluoroscopic rotation scan and echocardiography were integrated to analyse the individual LV wall motion with respect to the LV lead position. Optimization was guided by the systolic dyssynchrony index (SDI) and LV ejection fraction (LVEF) during different interventricular (VV)-delay programming. If re-programming failed, implantation of a second LV lead was performed. A discordant or partly concordant LV lead position was found in nearly all patients (16/17, 94%), which contributed to an unchanged baseline amount of LV dyssynchrony with either CRT on or off (SDI 11.3 vs. 11.0%; P = 0.744). In the majority of patients, VV-delay re-programming achieved better resynchronization, 4/17 patients needed implantation of a second LV lead. After 3 months, significant improvement of NYHA functional class (1 class; P = 0.004), peak oxygen consumption (10 vs. 13 mL/min/kg; P = 0.008), LVEF (27 vs. 39%; P = 0.003), and SDI (11.0 vs. 5.8; P = 0.02) was observed. Clinical and echocardiographic responses were found in 77 and 59%, respectively, with even good results on long-term follow-up. CONCLUSION: Tailored optimization of the individual LV wall motion can lead to significant clinical and echocardiographic improvements in previous CRT non-responders with a discordant LV lead position. PMID- 25825460 TI - Arrhythmic risk assessment in genotyped families with arrhythmogenic right ventricular cardiomyopathy. AB - AIMS: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a genetically determined disorder, mostly caused by mutations in genes encoding desmosomal proteins. We evaluated phenotype/genotype characteristics to predict the risk for the first major arrhythmic event in desmosomal-mutation-associated ARVC families. METHODS AND RESULTS: A cohort of 105 desmosomal-mutation carriers belonging to 39 consecutive ARVC families was evaluated. Serial clinical work-up consisting of history, physical examination, 12-lead/signal-averaged/24 h ambulatory ECG, and two-dimensional echocardiography was performed every 6-12 months. The predictive value of gender and genotype for the first major arrhythmic event was investigated within the cohort using time-to-event analysis. ECG/echocardiographic features were evaluated at the time of event and associated with the outcome using an age-matched nested case-control study within the cohort. Forty-three (41%) participants experienced the primary arrhythmic outcome at median age of 29 (21-46) years. The first event was sustained ventricular tachycardia in 31 and sudden cardiac death in 12. Definite diagnosis according to the 2010 Task Force criteria, showed 57% positive and 100% negative predictive value for the occurrence of arrhythmic outcome. Male gender (hazard ratio = 3.26, 95%CI, 1.63-6.51), predicted the first major arrhythmic event, independently of genotype, on multivariable analysis. Repolarization abnormalities and left ventricular dysfunction independently associated with clinical disease profile at the time of event. CONCLUSION: Male gender, independently of genotype is an arrhythmic risk predictor in ARVC-associated desmosomal-mutation carriers. Repolarization abnormalities and left-ventricular dysfunction are important components of the first event-associated clinical disease profile. PMID- 25825462 TI - Men and women differ in their diurnal expression of monocyte peroxisome proliferator-activated receptor-alpha in the fed but not in the fasted state. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a pivotal role in regulating metabolic response to fasting and is an inhibitor of inflammatory pathways in immune cells. It represents a therapeutic target for treatment of several diseases, mainly hyperlipidemia. To shed light on PPARalpha expression changes in response to fasting, young healthy male and female volunteers were fed or fasted for 24 hours. Monocytes were analyzed every 2 hours to compile both profiles of mRNA and protein expression of PPARalpha and its interactive partner, the circadian pacemaker brain and muscle aryl hydrocarbon receptor nuclear translocator like-1 (BMAL1). We found that women change their diurnal expression profiles of PPARalpha and BMAL1 when switching from the fed to the fasted state, whereas men do not. Interestingly, the PPARalpha and BMAL1 profiles of men and women in the fed state are different, whereas the profiles in the fasted state are virtually identical. The finding of diametrically opposite responses of male and female PPARalpha expression in the fed state might have practical implication in human medicine as PPARalpha activators like fibrates are used for the therapy of chronic lymphocytic leukemia, microvascular complications in diabetes, and kidney diseases. PMID- 25825464 TI - Disseminated cystic lesions: a case of disseminated oligodendroglial-like leptomeningeal tumor. PMID- 25825463 TI - Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. AB - OBJECTIVE: To delineate optimal diagnostic and therapeutic approaches to congenital muscular dystrophy (CMD) through a systematic review and analysis of the currently available literature. METHODS: Relevant, peer-reviewed research articles were identified using a literature search of the MEDLINE, EMBASE, and Scopus databases. Diagnostic and therapeutic data from these articles were extracted and analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and therapeutic studies. Recommendations were linked to the strength of the evidence, other related literature, and general principles of care. RESULTS: The geographic and ethnic backgrounds, clinical features, brain imaging studies, muscle imaging studies, and muscle biopsies of children with suspected CMD help predict subtype specific diagnoses. Genetic testing can confirm some subtype-specific diagnoses, but not all causative genes for CMD have been described. Seizures and respiratory complications occur in specific subtypes. There is insufficient evidence to determine the efficacy of various treatment interventions to optimize respiratory, orthopedic, and nutritional outcomes, and more data are needed regarding complications. RECOMMENDATIONS: Multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD. Accurate assessment of clinical presentations and genetic data will help in identifying the correct subtype-specific diagnosis in many cases. Multiorgan system complications occur frequently; surveillance and prompt interventions are likely to be beneficial for affected children. More research is needed to fill gaps in knowledge regarding this category of muscular dystrophies. PMID- 25825465 TI - Characteristic imaging findings in encephalocraniocutaneous lipomatosis. PMID- 25825466 TI - Naltrexone for impulse control disorders in Parkinson disease: a placebo controlled study. PMID- 25825467 TI - Right brain: the e-lephant in the room: one resident's challenge in transitioning to modern electronic medicine. PMID- 25825468 TI - About deep brain stimulation. PMID- 25825469 TI - Education research: a case-based bioethics curriculum for neurology residents. AB - BACKGROUND: In 2012, the American Academy of Neurology (AAN) updated and expanded its ethics curriculum into Practical Ethics in Clinical Neurology, a case-based ethics curriculum for neurologists. METHODS: We piloted a case-based bioethics curriculum for neurology residents using the framework and topics recommended by the AAN, matched to clinical cases drawn from Columbia's neurologic services. Our primary outcome was residents' ability to analyze and manage ethically complex cases as measured on precurriculum and postcurriculum multiple-choice quizzes. Secondary outcomes included precurriculum and postcurriculum self-assessed comfort in discussing and managing ethically complex cases, as well as attendance at ethics discussion sessions as compared to attendance at other didactic sessions. RESULTS: Resident performance on quizzes improved from 75.8% to 86.7% (p = 0.02). Comfort in discussing ethically complex cases improved from 6.4 to 7.4 on a 10-point scale (p = 0.03). Comfort in managing such cases trended toward improvement but did not reach statistical significance. Attendance was significantly better at ethics discussions (73.5%) than at other didactic sessions (61.7%, p = 0.04). CONCLUSION: Our formal case-based ethics curriculum for neurology residents, based on core topics drawn from the AAN's published curricula, was successfully piloted. Our study showed a statistically significant improvement in residents' ability to analyze and manage ethically complex cases as measured by multiple-choice tests and self-assessments. PMID- 25825470 TI - Pearls & oy-sters: cerebral venous air embolism after central catheter removal: too much air can kill. PMID- 25825471 TI - Teaching neuroimages: optic nerve glioma with perineural arachnoid gliomatosis in a patient with neurofibromatosis-1. PMID- 25825472 TI - Changes in cognitive abilities after deep brain stimulation for Parkinson disease. PMID- 25825473 TI - Change in cell surface properties of Lactobacillus casei under heat shock treatment. AB - We undertake this study in the aim to give new insight about the change in cellular physiological state under heat shock treatment and probiotic strain screening procedure. Different cell properties have been studied like adhesive ability to biotic and abiotic surfaces, the cell surface hydrophobicity and the fatty acids profiles. Compared to the normal cells, the heated cells increased their adhesive ability to biotic surface. However, the adhesion to abiotic surface was decreased. The cell surface hydrophobicity of the heated strains showed a significant decrease (P < 0.05). Our data revealed that high temperature change the fatty acids profiles of the treated cells, especially the proportions of unsaturated and saturated fatty acid. In fact, the ratio of saturated to unsaturated fatty acids of the heated Lactobacillus casei cells was significantly higher than that of the control cells (P < 0.05). The present finding could firstly add new insight about the response of probiotic to stressful conditions, such us the important role of cell membrane, considered as the first main structure to be damaged by physicochemical stress, in stress resistance because of their composition that can change in adaptation to harsh conditions. Secondly, there is no relationship between changes in membrane composition and fluidity induced by heat shock treatment and adhesion to biotic and abiotic surface. PMID- 25825474 TI - The unique characteristics of HOG pathway MAPKs in the extremely halotolerant Hortaea werneckii. AB - HwHog1A/B, Hortaea werneckii homologues of the MAP kinase Hog1 from Saccharomyces cerevisiae, are vital for the extreme halotolerance of H. werneckii. In mesophilic S. cerevisiae, Hog1 is phosphorylated already at low osmolyte concentrations, and regulates expression of a similar set of genes independent of osmolyte type. To understand how HwHog1 kinases activity is regulated in H. werneckii, we studied HwHog1A/B activation in vivo, by following phosphorylation of HwHog1A/B in H. werneckii exposed to various osmolytes, and in vitro, by measuring kinase activities of recombinant HwHog1A, HwHog1B and Hog1DeltaC. To this end, highly pure and soluble recombinant Hog1 homologues were isolated from insect cells. Our results demonstrate that HwHog1A/B are, in general, transiently phosphorylated in cells shocked with >=3 M osmolyte, yet constitutive phosphorylation is observed at extreme NaCl and KCl concentrations. Importantly, phosphorylation profiles differ depending on the osmolyte type. Additionally, phosphorylated recombinant HwHog1A/B show lower specific kinase activities compared to Hog1DeltaC. In summary, HOG pathway MAPKs in the extremely halotolerant H. werneckii show unique characteristics compared to S. cerevisiae homologues. The reported findings contribute to defining the key determinants of H. werneckii osmotolerance, which is important for its potential transfer to economically relevant microorganisms and crops. PMID- 25825475 TI - Complete nucleotide sequence of phiCHU: a Luz24likevirus infecting Pseudomonas aeruginosa and displaying a unique host range. AB - A complete nucleotide sequence of the new Pseudomonas aeruginosa Luz24likevirus phiCHU was obtained. This virus was shown to have a unique host range whereby it grew poorly on the standard laboratory strain PAO1, but infected 26 of 46 clinical isolates screened, and strains harbouring IncP2 plasmid pMG53. It was demonstrated that phiCHU has single-strand interruptions in its genome. Analysis of the phiCHU genome also suggested that recombination event(s) participated in the evolution of the leftmost portion of the genome, presumably encoding early genes. PMID- 25825476 TI - Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane-Anthracycline Containing Chemotherapy-DAFNE (GBG-70). AB - PURPOSE: Dual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane-based chemotherapy can reach pathologic complete response (pCR) rates of up to 60% in HER2-positive breast cancer. The DAFNE (Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment) phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting. EXPERIMENTAL DESIGN: Participants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20 mg/d) and trastuzumab [(8) 6 mg/kg/3 weeks] alone; followed by 12-week treatment with paclitaxel (80 mg/m(2)/1 week), trastuzumab, and afatinib; followed by 12 weeks with epirubicin (90 mg/m(2)/3 weeks), cyclophosphamide (600 mg/m(2)/3 weeks), and trastuzumab before surgery. Primary objective was pCR rate, defined as ypT0/is ypN0. We expected a pCR rate of 70%; 65 patients were needed to exclude a rate of <=55%. RESULTS: pCR rate was 49.2% [90% confidence interval (CI), 38.5-60.1] in 65 treated patients. Patients with hormone receptor-negative (N = 19) or hormone receptor-positive (N = 46) tumors showed pCR rates of 63.2% and 43.5%, respectively (P = 0.153). Patients with (N = 9) or without (N = 56) lymphocyte predominant breast cancer (LPBC) showed pCR rates of 100% and 41.1%, respectively (P < 0.001). PCR rate was not different in patients with or without PIK3CA tumor mutations (P = 0.363). Clinical responses were seen in 96.3% of 54 evaluable patients, and breast conserving surgery was possible in 59.4% of 62 assessable patients. Most frequent nonhematologic grade 3-4 toxicities were diarrhea (7.7%), increased creatinine (4.6%), and infection (4.6%). One patient developed symptomatic congestive heart failure. CONCLUSIONS: Neoadjuvant treatment with afatinib, trastuzumab, and chemotherapy showed acceptable tolerability, and a pCR rate comparable with that of other anti-HER2 doublets but below challenging expectations. PMID- 25825477 TI - DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers. AB - PURPOSE: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. EXPERIMENTAL DESIGN: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). RESULTS: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Deltabetametastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity. CONCLUSIONS: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. PMID- 25825478 TI - Multimerin-1 (MMRN1) as Novel Adverse Marker in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group. AB - PURPOSE: Exploratory gene expression array analyses suggested multimerin-1 (MMRN1) to be a predictive biomarker in acute myelogenous leukemia (AML). Following up on these studies, we evaluated the role of MMRN1 expression as outcome predictor in two recent Children's Oncology Group trials. EXPERIMENTAL DESIGN: We retrospectively quantified MMRN1 expression in 183 participants of AAML03P1 and 750 participants of AAML0531 by reverse-transcriptase PCR and correlated expression levels with disease characteristics and clinical outcome. RESULTS: In AAML03P1, the highest quartile of MMRN1 expression (expression >=0.5 relative to beta-glucuronidase; n = 45) was associated with inferior event-free survival (EFS; P < 0.002) and higher relapse risk (P < 0.004). In AAML0531, in which we quantified MMRN1 mRNA for validation, patients with relative MMRN1 expression >=0.5 (n = 160) less likely achieved remission (67% vs. 77%, P = 0.006), and more frequently had minimal residual disease (43% vs. 24%, P = 0.001) after one induction course. They had inferior overall survival (OS; 44% +/- 9% vs. 69% +/- 4% at 5 years; P < 0.001) and EFS (32% +/- 8% vs. 54% +/- 4% at 5 years; P < 0.001) and higher relapse risk (57% +/- 10% vs. 35% +/- 5% at 5 years; P < 0.001). These differences were partly attributable to the fact that patients with high MMRN1 expression less likely had cytogenetic/molecular low-risk disease (P < 0.001) than those with low MMRN1 expression. Nevertheless, after multivariable adjustment, high MMRN1 expression remained statistically significantly associated with shorter OS (HR, 1.57; 95% confidence interval, 1.17 2.12; P = 0.003) and EFS (HR, 1.34; 1.04-1.73; P = 0.025), and higher relapse risk (HR, 1.40; 1.01-1.94; P = 0.044). CONCLUSIONS: Together, our studies identify MMRN1 expression as a novel biomarker that may refine AML risk stratification. PMID- 25825479 TI - Role of uropathogenic Escherichia coli outer membrane protein T in pathogenesis of urinary tract infection. AB - OmpT is one of the members of the outer membrane protein family that has been identified as a virulence factor in most of the uropathogenic Escherichia coli (UPEC). However, the exact role of OmpT in the urinary tract infections (UTIs) remains unclear. To determine the role of OmpT in the pathogenesis of UPEC, an isogenic deletion mutant of ompT (COTD) was constructed by the lambda Red recombination. Human bladder epithelial cell line 5637(HBEC 5637) was used to evaluate the ability of bacterial adhesion/invasion. A murine model of UTI was established to study the formation of intracellular bacterial communities (IBCs) in the process of UTIs. The cytokines were also examined during the pathogenesis. The results showed that the COTD strain was deficient in bacterial adhesion and invasion as well as in IBC formation compare to the parent strain. ELISA quantification analysis of cytokines showed that the levels of TNF-alpha, IL-6 and IL-8 in the serum, bladder and kidney tissues of the mice infected with COTD were lower than that of the CFT073 group. In summary, these results suggest that OmpT plays a multifaceted role in pathogenesis of UTI, including increased bacterial adhesiveness/invasiveness, formation of IBCs and upregulated proinflammatory cytokines. PMID- 25825480 TI - Should early cranial MRI of preterm infants become routine? PMID- 25825481 TI - Change in Multiple Filtration Markers and Subsequent Risk of Cardiovascular Disease and Mortality. AB - BACKGROUND AND OBJECTIVES: Kidney disease progression, assessed by change in eGFR on the basis of creatinine, is an independent risk factor for cardiovascular disease and death. This study aimed to evaluate whether changes in multiple filtration markers, individually and combined, were associated with cardiovascular disease and death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Creatinine, cystatin C, and beta2-microglobulin were measured among 9716 Atherosclerosis Risk in Communities Study participants in 1990-1992 and 1996 1998. Percentage change in three filtration markers (eGFR on the basis of creatinine, eGFR on the basis of cystatin C, and 1/beta2-microglobulin) individually and the average of percentage change across all three filtration markers were calculated. Cardiovascular events and deaths were ascertained from 1996 to 2011. Cox regression models were adjusted for established risk factors for cardiovascular disease and mortality and first measurement of eGFR on the basis of creatinine. RESULTS: During a median follow-up of 14 years, there were 1922 cardiovascular events and 2285 deaths from any cause. Decline of >30% in each filtration marker was significantly associated with higher risk of mortality compared with stable kidney function (-9.9% to +9.9% change in the filtration marker) with hazard ratios (95% confidence intervals) of 1.91 (1.67 to 2.18) for eGFR on the basis of creatinine, 2.29 (1.99 to 2.63) for eGFR on the basis of cystatin C, and 2.48 (2.15 to 2.86) for 1/beta2-microglobulin, with similar associations for cardiovascular disease. An average decline of >30% across the three markers was strongly associated with higher risk of all-cause mortality (hazard ratio, 2.82; 95% confidence interval, 2.42 to 3.29). CONCLUSIONS: Kidney disease progression was assessed using >30% decline in eGFR on the basis of creatinine, eGFR on the basis of cystatin C, and 1/beta2-microglobulin and average decline of >30% across the three filtration markers is strongly associated with risk of cardiovascular disease and death. PMID- 25825482 TI - Comparison of Subdural Hematoma Risk between Hemodialysis and Peritoneal Dialysis Patients with ESRD. AB - BACKGROUND AND OBJECTIVES: This study compared the risk of subdural hematoma (SDH) and subsequent mortality in hemodialysis (HD) and peritoneal dialysis (PD) patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Claims data were obtained from the National Health Insurance Administration Research Database in Taiwan. This retrospective cohort study comprised 10,136 PD patients and 10,136 HD patients with newly diagnosed ESRD from 1998 to 2010. Patients were matched by propensity score and year of dialysis initiation. Incidence rates and hazard ratios of SDH as well as odds ratios of subsequent 30-day deaths from SDH were evaluated from the date of the first dialysis session to the date when SDH was diagnosed, or the date of renal transplantation, death, withdraw from insurance, or the end of the follow-up period (December 31, 2011). RESULTS: Median (25th percentile, 75th percentile) follow-up times for SDH events were 3.61 years (1.91, 6.33) and 3.33 years (1.83, 5.66) in the HD and PD cohorts, respectively. The overall SDH incidence rate (95% confidence interval [95% CI]) was 61.4% higher in the HD cohort than in the PD cohort (34.7 [95% CI, 31.4 to 35.4] versus 21.5 [95% CI, 20.2 to 22.9] per 10,000 person-years, with an adjusted hazard ratio of 1.62 [95% CI, 1.17 to 2.33]). Approximately 152 of 253 (60%) of SDH events were associated with trauma. Subsequent 30-day SDH-related mortality was not statistically higher in HD patients than in PD patients (29.1% versus 25.3%; adjusted odds ratio, 1.30; 95% CI, 0.70 to 2.41). CONCLUSIONS: HD patients have a higher risk of developing SDH than PD patients. Both patient groups have a high risk of mortality. Routine education on fall prevention is needed for dialysis patients. PMID- 25825483 TI - Association of Serum Ig Free Light Chains with Mortality and ESRD among Patients with Nondialysis-Dependent CKD. AB - BACKGROUND AND OBJECTIVES: High levels of serum polyclonal combined Ig free light chains are associated with inflammation and decreased excretory kidney function, and they are an independent risk factor for mortality. Whether combined Ig free light chain predicted mortality and progression to ESRD in a stages 3-5 CKD cohort was assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective cohort study of 872 patients with stages 3-5 CKD (nondialysis) recruited into the Chronic Renal Insufficiency Standards Implementation Study. Patients were recruited to the Chronic Renal Insufficiency Standards Implementation Study in an unselected manner from secondary care nephrology clinics between 2004 and 2010. Combined Ig free light chain was measured at recruitment and analyzed by quartiles. The cohort was followed up for a median of 41.4 months (interquartile range =28.3-68.0 months). Cox regression analysis was undertaken to determine the variables associated with mortality and progression to ESRD. RESULTS: Combined Ig free light chain quartiles were <49.4, 49.4-68.8, 68.9-100.7, and >100.7 mg/L. An independent association with death and progression to ESRD was associated with the third and fourth combined Ig free light chain quartiles (quartile 3: death: hazard ratio, 1.49; 95% confidence interval, 1.02 to 2.18; P=0.04; ESRD: hazard ratio, 1.72; 95% confidence interval, 1.0 to 2.97; P=0.05; quartile 4: death: hazard ratio, 1.99; 95% confidence interval, 1.34 to 2.93; P<0.001; ESRD: hazard ratio, 3.73; 95% confidence interval, 2.1 to 6.3; P<0.001). The other independent risk factors were (1) preexisting cardiovascular disease, age >65 years old, and eGFR=15-30 ml/min per 1.73 m(2) for death and (2) age <=65 years old, eGFR<30 ml/min per 1.73 m(2), urinary protein-to-creatinine ratio >30 mg/mmol, and serum phosphate level >4.65 mg/dl for progression to ESRD. CONCLUSIONS: An elevated serum combined Ig free light chain level is an independent risk factor for mortality and progression to ESRD in patients with stages 3-5 CKD managed in secondary care. PMID- 25825484 TI - Association of Height with Mortality in Patients Undergoing Maintenance Hemodialysis. AB - BACKGROUND AND OBJECTIVES: Body mass index (BMI), determined as kilograms in body weight divided by the square of the height in meters (m(2)), is inversely associated with mortality in patients undergoing maintenance hemodialysis (MHD). It is commonly inferred that differences in the weight component of the BMI equation are responsible for this negative correlation. However, there are almost no data on the relationship between height and mortality in these patients. This study was conducted to examine the association between height and mortality in MHD patients and to evaluate the contribution of height to the BMI-mortality relationship. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective study conducted from July 1, 2001, through June 30, 2006, enrolled a nationally representative cohort of 117,644 MHD patients receiving treatment in DaVita, Inc. outpatient dialysis facilities with (1) known height and weight, (2) age >=18 years, (3) dialysis vintage >=90 days, and (4) nonoutlying BMI values (>=12 to <=60 kg/m(2)). The end date of follow-up was June 30, 2007, and median follow-up was 852 days (interquartile range, 504-1367 days). Mortality hazard ratios were computed within sex-standardized deciles of height and weight, and outcomes included all-cause mortality and cardiovascular, gastrointestinal, cancer, and infection mortality. Hazard models were unadjusted, adjusted for case-mix variables, or adjusted for case-mix variables plus laboratory variables. RESULTS: Mean age was 61+/-15 years; 45% of patients were women and 57% had diabetes. In adjusted models, height, also adjusted for weight, was directly associated with all-cause mortality and cardiovascular, infection, and cancer mortality. Compared with the median height decile, mortality risk in the highest height decile was 1.18 (95% confidence interval, 1.14 to 1.23) in fully adjusted analyses (P<0.001). Receiver-operating characteristic curves indicated that in adjusted analyses the contribution of height to the relationship between BMI and mortality was almost identical to that of weight. CONCLUSIONS: In MHD patients, height is positively associated with mortality risk and contributes similarly to weight with regard to the negative BMI-mortality relationship. PMID- 25825485 TI - Sleep-Disordered Breathing in Patients with Polycystic Liver and Kidney Disease Referred for Transcatheter Arterial Embolization. AB - BACKGROUND AND OBJECTIVES: Sleep-disordered breathing (SDB) is prevalent among patients with CKD, but its prevalence among patients with symptomatic autosomal dominant polycystic kidney disease (ADPKD) and its association with total liver and kidney volume remain unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the association between height-adjusted total liver and kidney volume (htTLKV) and SDB in a cross-sectional study of 304 adult patients with symptomatic ADPKD who were hospitalized at Toranomon Hospital for transcatheter arterial embolization and who underwent pulse oximetry between April 2008 and November 2013. SDB was defined as having a 3% oxygen desaturation index of >=15 events per hour of sleep. Logistic regression was performed with sex-specific quartiles of htTLKV as the main predictor, using patient data and comorbidities as covariates. RESULTS: Overall (54.6% women, mean age 56.2+/-9.4 years, 83.5% on hemodialysis), 177 of 304 patients (58.2%) had SDB. SDB was strongly associated with htTLKV quartiles, demonstrating that odds ratios (ORs) and 95% confidence intervals (95% CIs) for SDB were 1.63 (0.76 to 3.48), 2.35 (1.09 to 5.06), and 4.61 (1.98 to 10.7) for htTLKV quartiles 2-4 (P for trend, P=0.003), respectively. Older age (OR, 1.81 per 10 years; 95% CI, 1.29 to 2.55), male sex (OR, 3.87; 95% CI, 1.96 to 7.66), receiving hemodialysis (OR, 3.46; 95% CI, 1.62 to 12.1), and higher body mass index (>=25 kg/m(2)) (OR, 3.03; 95% CI, 1.08 to 8.52) were also associated with SDB. CONCLUSIONS: In this highly selected population of patients with symptomatic ADPKD referred for transcatheter arterial embolization, SDB was highly prevalent and independently associated with higher htTLKV. PMID- 25825486 TI - Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria. AB - Proper trafficking of membrane-bound ion channels and transporters is requisite for normal cardiac function. Endosome-based protein trafficking of membrane-bound ion channels and transporters in the heart is poorly understood, particularly in vivo. In fact, for select cardiac cell types such as atrial myocytes, virtually nothing is known regarding endosomal transport. We previously linked the C terminal Eps15 homology domain-containing protein 3 (EHD3) with endosome-based protein trafficking in ventricular cardiomyocytes. Here we sought to define the roles and membrane protein targets for EHD3 in atria. We identify the voltage gated T-type Ca(2+) channels (CaV3.1, CaV3.2) as substrates for EHD3-dependent trafficking in atria. Mice selectively lacking EHD3 in heart display reduced expression and targeting of both Cav3.1 and CaV3.2 in the atria. Furthermore, functional experiments identify a significant loss of T-type-mediated Ca(2+) current in EHD3-deficient atrial myocytes. Moreover, EHD3 associates with both CaV3.1 and CaV3.2 in co-immunoprecipitation experiments. T-type Ca(2+) channel function is critical for proper electrical conduction through the atria. Consistent with these roles, EHD3-deficient mice demonstrate heart rate variability, sinus pause, and atrioventricular conduction block. In summary, our findings identify CaV3.1 and CaV3.2 as substrates for EHD3-dependent protein trafficking in heart, provide in vivo data on endosome-based trafficking pathways in atria, and implicate EHD3 as a key player in the regulation of atrial myocyte excitability and cardiac conduction. PMID- 25825487 TI - Combined rational design and a high throughput screening platform for identifying chemical inhibitors of a Ras-activating enzyme. AB - The Ras family small GTPases regulate multiple cellular processes, including cell growth, survival, movement, and gene expression, and are intimately involved in cancer pathogenesis. Activation of these small GTPases is catalyzed by a special class of enzymes, termed guanine nucleotide exchange factors (GEFs). Herein, we developed a small molecule screening platform for identifying lead hits targeting a Ras GEF enzyme, SOS1. We employed an ensemble structure-based virtual screening approach in combination with a multiple tier high throughput experimental screen utilizing two complementary fluorescent guanine nucleotide exchange assays to identify small molecule inhibitors of GEF catalytic activity toward Ras. From a library of 350,000 compounds, we selected a set of 418 candidate compounds predicted to disrupt the GEF-Ras interaction, of which dual wavelength GDP dissociation and GTP-loading experimental screening identified two chemically distinct small molecule inhibitors. Subsequent biochemical validations indicate that they are capable of dose-dependently inhibiting GEF catalytic activity, binding to SOS1 with micromolar affinity, and disrupting GEF-Ras interaction. Mutagenesis studies in conjunction with structure-activity relationship studies mapped both compounds to different sites in the catalytic pocket, and both inhibited Ras signaling in cells. The unique screening platform established here for targeting Ras GEF enzymes could be broadly useful for identifying lead inhibitors for a variety of small GTPase-activating GEF reactions. PMID- 25825488 TI - Two Putative Polysaccharide Deacetylases Are Required for Osmotic Stability and Cell Shape Maintenance in Bacillus anthracis. AB - Membrane-anchored lipoproteins have a broad range of functions and play key roles in several cellular processes in Gram-positive bacteria. BA0330 and BA0331 are the only lipoproteins among the 11 known or putative polysaccharide deacetylases of Bacillus anthracis. We found that both lipoproteins exhibit unique characteristics. BA0330 and BA0331 interact with peptidoglycan, and BA0330 is important for the adaptation of the bacterium to grow in the presence of a high concentration of salt, whereas BA0331 contributes to the maintenance of a uniform cell shape. They appear not to alter the peptidoglycan structure and do not contribute to lysozyme resistance. The high resolution x-ray structure of BA0330 revealed a C-terminal domain with the typical fold of a carbohydrate esterase 4 and an N-terminal domain unique for this family, composed of a two-layered (4 + 3) beta-sandwich with structural similarity to fibronectin type 3 domains. Our data suggest that BA0330 and BA0331 have a structural role in stabilizing the cell wall of B. anthracis. PMID- 25825490 TI - Regulation of oligomeric organization of the serotonin 5-hydroxytryptamine 2C (5 HT2C) receptor observed by spatial intensity distribution analysis. AB - The questions of whether G protein-coupled receptors exist as monomers, dimers, and/or oligomers and if these species interconvert in a ligand-dependent manner are among the most contentious current issues in biology. When employing spatial intensity distribution analysis to laser scanning confocal microscope images of cells stably expressing either a plasma membrane-associated form of monomeric enhanced green fluorescent protein (eGFP) or a tandem version of this fluorophore, the eGFP tandem was identified as a dimer. Similar studies on cells stably expressing an eGFP-tagged form of the epidermal growth factor receptor demonstrated that, although largely a monomer in the basal state, this receptor rapidly became predominantly dimeric upon the addition of its ligand epidermal growth factor. In cells induced to express an eGFP-tagged form of the serotonin 5 hydroxytryptamine 2C (5-HT2C) receptor, global analysis of construct quantal brightness was consistent with the predominant form of the receptor being dimeric. However, detailed spatial intensity distribution analysis demonstrated the presence of multiple forms ranging from monomers to higher-order oligomers. Furthermore, treatment with chemically distinct 5-HT2C receptor antagonists resulted in a time-dependent change in the quaternary organization to one in which there was a preponderance of receptor monomers. This antagonist-mediated effect was reversible, because washout of the ligand resulted in the regeneration of many of the oligomeric forms of the receptor. PMID- 25825489 TI - Nox2 mediates skeletal muscle insulin resistance induced by a high fat diet. AB - Inflammation and oxidative stress through the production of reactive oxygen species (ROS) are consistently associated with metabolic syndrome/type 2 diabetes. Although the role of Nox2, a major ROS-generating enzyme, is well described in host defense and inflammation, little is known about its potential role in insulin resistance in skeletal muscle. Insulin resistance induced by a high fat diet was mitigated in Nox2-null mice compared with wild-type mice after 3 or 9 months on the diet. High fat feeding increased Nox2 expression, superoxide production, and impaired insulin signaling in skeletal muscle tissue of wild-type mice but not in Nox2-null mice. Exposure of C2C12 cultured myotubes to either high glucose concentration, palmitate, or H2O2 decreases insulin-induced Akt phosphorylation and glucose uptake. Pretreatment with catalase abrogated these effects, indicating a key role for H2O2 in mediating insulin resistance. Down regulation of Nox2 in C2C12 cells by shRNA prevented insulin resistance induced by high glucose or palmitate but not H2O2. These data indicate that increased production of ROS in insulin resistance induced by high glucose in skeletal muscle cells is a consequence of Nox2 activation. This is the first report to show that Nox2 is a key mediator of insulin resistance in skeletal muscle. PMID- 25825491 TI - Reduced Ssy1-Ptr3-Ssy5 (SPS) signaling extends replicative life span by enhancing NAD+ homeostasis in Saccharomyces cerevisiae. AB - Attenuated nutrient signaling extends the life span in yeast and higher eukaryotes; however, the mechanisms are not completely understood. Here we identify the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway as a novel longevity factor. A null mutation of SSY5 (ssy5Delta) increases replicative life span (RLS) by ~50%. Our results demonstrate that several NAD(+) homeostasis factors play key roles in this life span extension. First, expression of the putative malate pyruvate NADH shuttle increases in ssy5Delta cells, and deleting components of this shuttle, MAE1 and OAC1, largely abolishes RLS extension. Next, we show that Stp1, a transcription factor of the SPS pathway, directly binds to the promoter of MAE1 and OAC1 to regulate their expression. Additionally, deletion of SSY5 increases nicotinamide riboside (NR) levels and phosphate-responsive (PHO) signaling activity, suggesting that ssy5Delta increases NR salvaging. This increase contributes to NAD(+) homeostasis, partially ameliorating the NAD(+) deficiency and rescuing the short life span of the npt1Delta mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5Delta mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD(+) homeostasis factor and ssy5Delta mediated life span extension is likely due to concomitantly increased mitochondrial and vacuolar function. Our findings may contribute to understanding the molecular basis of NAD(+) metabolism, cellular life span, and diseases associated with NAD(+) deficiency and aging. PMID- 25825492 TI - Solid-state NMR Reveals the Carbon-based Molecular Architecture of Cryptococcus neoformans Fungal Eumelanins in the Cell Wall. AB - Melanin pigments protect against both ionizing radiation and free radicals and have potential soil remediation capabilities. Eumelanins produced by pathogenic Cryptococcus neoformans fungi are virulence factors that render the fungal cells resistant to host defenses and certain antifungal drugs. Because of their insoluble and amorphous characteristics, neither the pigment bonding framework nor the cellular interactions underlying melanization of C. neoformans have yielded to comprehensive molecular-scale investigation. This study used the C. neoformans requirement of exogenous obligatory catecholamine precursors for melanization to produce isotopically enriched pigment "ghosts" and applied 2D (13)C-(13)C correlation solid-state NMR to reveal the carbon-based architecture of intact natural eumelanin assemblies in fungal cells. We demonstrated that the aliphatic moieties of solid C. neoformans melanin ghosts include cell-wall components derived from polysaccharides and/or chitin that are associated proximally with lipid membrane constituents. Prior to development of the mature aromatic fungal pigment, these aliphatic moieties form a chemically resistant framework that could serve as the scaffold for melanin synthesis. The indole based core aromatic moieties show interconnections that are consistent with proposed melanin structures consisting of stacked planar assemblies, which are associated spatially with the aliphatic scaffold. The pyrrole aromatic carbons of the pigments bind covalently to the aliphatic framework via glycoside or glyceride functional groups. These findings establish that the structure of the pigment assembly changes with time and provide the first biophysical information on the mechanism by which melanin is assembled in the fungal cell wall, offering vital insights that can advance the design of bioinspired conductive nanomaterials and novel therapeutics. PMID- 25825493 TI - Action at a distance: mutations of peripheral residues transform rapid reversible inhibitors to slow, tight binders of cyclooxygenase-2. AB - Cyclooxygenase enzymes (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandin G2. The inhibitory activity of rapid, reversible COX inhibitors (ibuprofen, naproxen, mefenamic acid, and lumiracoxib) demonstrated a significant increase in potency and time dependence of inhibition against double tryptophan murine COX-2 mutants at the 89/90 and 89/119 positions. In contrast, the slow, time-dependent COX inhibitors (diclofenac, indomethacin, and flurbiprofen) were unaffected by those mutations. Further mutagenesis studies suggested that mutation at position 89 was principally responsible for the changes in inhibitory potency of rapid, reversible inhibitors, whereas mutation at position 90 may exert some effect on the potency of COX-2-selective diarylheterocycle inhibitors; no effect was observed with mutation at position 119. Several crystal structures with or without NSAIDs indicated that placement of a bulky residue at position 89 caused a closure of a gap at the lobby, and alteration of histidine to tryptophan at position 90 changed the electrostatic profile of the side pocket of COX-2. Thus, these two residues, especially Val-89 at the lobby region, are crucial for the entrance and exit of some NSAIDs from the COX active site. PMID- 25825494 TI - Heterotrimeric kinesin-2 (KIF3) mediates transition zone and axoneme formation of mouse photoreceptors. AB - Anterograde intraflagellar transport (IFT) employing kinesin-2 molecular motors has been implicated in trafficking of photoreceptor outer segment proteins. We generated embryonic retina-specific (prefix "emb") and adult tamoxifen-induced (prefix "tam") deletions of KIF3a and IFT88 in adult mice to study photoreceptor ciliogenesis and protein trafficking. In (emb)Kif3a(-/-) and in (emb)Ift88(-/-) mice, basal bodies failed to extend transition zones (connecting cilia) with outer segments, and visual pigments mistrafficked. In contrast, (tam)Kif3a(-/-) and (tam)Ift88(-/-) photoreceptor axonemes disintegrated slowly post-induction, starting distally, but rhodopsin and cone pigments trafficked normally for more than 2 weeks, a time interval during which the outer segment is completely renewed. The results demonstrate that visual pigments transport to the retinal outer segment despite removal of KIF3 and IFT88, and KIF3-mediated anterograde IFT is responsible for photoreceptor transition zone and axoneme formation. PMID- 25825495 TI - Recruitment of Matrix Metalloproteinase-9 (MMP-9) to the Fibroblast Cell Surface by Lysyl Hydroxylase 3 (LH3) Triggers Transforming Growth Factor-beta (TGF-beta) Activation and Fibroblast Differentiation. AB - Solid tumor growth triggers a wound healing response. Similar to wound healing, fibroblasts in the tumor stroma differentiate into myofibroblasts (also referred to as cancer-associated fibroblasts) primarily, but not exclusively, in response to transforming growth factor-beta (TGF-beta). Myofibroblasts in turn enhance tumor progression by remodeling the stroma. Among proteases implicated in stroma remodeling, matrix metalloproteinases (MMPs), including MMP-9, play a prominent role. Recent evidence indicates that MMP-9 recruitment to the tumor cell surface enhances tumor growth and invasion. In the present work, we addressed the potential relevance of MMP-9 recruitment to and activity at the surface of fibroblasts. We show that recruitment of MMP-9 to the fibroblast cell surface occurs through its fibronectin-like (FN) domain and that the molecule responsible for the recruitment is lysyl hydroxylase 3 (LH3). Functional assays suggest that both pro- and active MMP-9 trigger alpha-smooth muscle actin expression in cultured fibroblasts, reflecting myofibroblast differentiation, possibly as a result of TGF-beta activation. Moreover, the recombinant FN domain inhibited both MMP-9-induced TGF-beta activation and alpha-smooth muscle actin expression by displacing MMP-9 from the fibroblast cell surface. Together our results uncover LH3 as a new docking receptor of MMP-9 on the fibroblast cell surface and demonstrate that the MMP-9 FN domain is essential for the interaction. They also show that the recombinant FN domain inhibits MMP-9-induced TGF-beta activation and fibroblast differentiation, providing a potentially attractive therapeutic reagent toward attenuating tumor progression where MMP-9 activity is strongly implicated. PMID- 25825496 TI - The Wnt Signaling Antagonist Dapper1 Accelerates Dishevelled2 Degradation via Promoting Its Ubiquitination and Aggregate-induced Autophagy. AB - Autophagy is a regulated process that sequesters and transports cytoplasmic materials such as protein aggregates via autophagosomes to lysosomes for degradation. Dapper1 (Dpr1), an interacting protein of Dishevelled (Dvl), antagonizes Wnt signaling by promoting Dishevelled degradation via lysosomes. However, the mechanism is unclear. Here, we show that Dpr1 promotes the von Hippel-Lindau tumor suppressor (VHL)-mediated ubiquitination of Dvl2 and its autophagic degradation. Knockdown of Dpr1 decreases the interaction between Dvl2 and pVHL, resulting in reduced ubiquitination of Dvl2. Dpr1-mediated autophagic degradation of Dvl2 depends on Dvl2 aggregation. Moreover, the aggregate-prone proteins Dvl2, p62, and the huntingtin mutant Htt103Q promote autophagy in a Dpr1 dependent manner. These protein aggregates enhance the Beclin1-Vps34 interaction and Atg14L puncta formation, indicating that aggregated proteins stimulate autophagy initiation. Ubiquitination is not essential for the aggregate-induced autophagy initiation as inhibition of the ubiquitin-activation E1 enzyme activity did not block the aggregate-induced Atg14L puncta formation. Our findings suggest that Dpr1 promotes the ubiquitination of Dvl2 by pVHL and mediates the protein aggregate-elicited autophagy initiation. PMID- 25825497 TI - LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2. AB - SMYD2 is a lysine methyltransferase that catalyzes the monomethylation of several protein substrates including p53. SMYD2 is overexpressed in a significant percentage of esophageal squamous primary carcinomas, and that overexpression correlates with poor patient survival. However, the mechanism(s) by which SMYD2 promotes oncogenesis is not understood. A small molecule probe for SMYD2 would allow for the pharmacological dissection of this biology. In this report, we disclose LLY-507, a cell-active, potent small molecule inhibitor of SMYD2. LLY 507 is >100-fold selective for SMYD2 over a broad range of methyltransferase and non-methyltransferase targets. A 1.63-A resolution crystal structure of SMYD2 in complex with LLY-507 shows the inhibitor binding in the substrate peptide binding pocket. LLY-507 is active in cells as measured by reduction of SMYD2-induced monomethylation of p53 Lys(370) at submicromolar concentrations. We used LLY-507 to further test other potential roles of SMYD2. Mass spectrometry-based proteomics showed that cellular global histone methylation levels were not significantly affected by SMYD2 inhibition with LLY-507, and subcellular fractionation studies indicate that SMYD2 is primarily cytoplasmic, suggesting that SMYD2 targets a very small subset of histones at specific chromatin loci and/or non-histone substrates. Breast and liver cancers were identified through in silico data mining as tumor types that display amplification and/or overexpression of SMYD2. LLY-507 inhibited the proliferation of several esophageal, liver, and breast cancer cell lines in a dose-dependent manner. These findings suggest that LLY-507 serves as a valuable chemical probe to aid in the dissection of SMYD2 function in cancer and other biological processes. PMID- 25825500 TI - In this issue of Occupational Medicine. PMID- 25825501 TI - The health and safety at work act turned 40. PMID- 25825498 TI - A mycobacterial phosphoribosyltransferase promotes bacillary survival by inhibiting oxidative stress and autophagy pathways in macrophages and zebrafish. AB - Mycobacterium tuberculosis employs various strategies to modulate host immune responses to facilitate its persistence in macrophages. The M. tuberculosis cell wall contains numerous glycoproteins with unknown roles in pathogenesis. Here, by using Concanavalin A and LC-MS analysis, we identified a novel mannosylated glycoprotein phosphoribosyltransferase, encoded by Rv3242c from M. tuberculosis cell walls. Homology modeling, bioinformatic analyses, and an assay of phosphoribosyltransferase activity in Mycobacterium smegmatis expressing recombinant Rv3242c (MsmRv3242c) confirmed the mass spectrometry data. Using Mycobacterium marinum-zebrafish and the surrogate MsmRv3242c infection models, we proved that phosphoribosyltransferase is involved in mycobacterial virulence. Histological and infection assays showed that the M. marinum mimG mutant, an Rv3242c orthologue in a pathogenic M. marinum strain, was strongly attenuated in adult zebrafish and also survived less in macrophages. In contrast, infection with wild type and the complemented DeltamimG:Rv3242c M. marinum strains showed prominent pathological features, such as severe emaciation, skin lesions, hemorrhaging, and more zebrafish death. Similarly, recombinant MsmRv3242c bacteria showed increased invasion in non-phagocytic epithelial cells and longer intracellular survival in macrophages as compared with wild type and vector control M. smegmatis strains. Further mechanistic studies revealed that the Rv3242c- and mimG-mediated enhancement of intramacrophagic survival was due to inhibition of autophagy, reactive oxygen species, and reduced activities of superoxide dismutase and catalase enzymes. Infection with MsmRv3242c also activated the MAPK pathway, NF-kappaB, and inflammatory cytokines. In summary, we show that a novel mycobacterial mannosylated phosphoribosyltransferase acts as a virulence and immunomodulatory factor, suggesting that it may constitute a novel target for antimycobacterial drugs. PMID- 25825502 TI - Working for a healthier future. PMID- 25825503 TI - Dame Barbara Hepworth, Prelude II 1948. PMID- 25825499 TI - Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress. AB - The importance of brown adipose tissue as a site of nonshivering thermogenesis has been well documented. Emerging studies suggest that skeletal muscle is also an important site of thermogenesis especially when brown adipose tissue function is lacking. We recently showed that sarcolipin (SLN), an uncoupler of the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) pump, could contribute to heat production in skeletal muscle. In this study, we sought to understand how loss of UCP1 or SLN is compensated during cold exposure and whether they are both necessary for thermogenesis. Toward this goal, we generated a UCP1;SLN double knock-out (DKO) mouse model and challenged the single and DKO mice to acute and long-term cold exposures. Results from this study show that there is up regulation of SLN expression in UCP1-KO mice, and loss of SLN is compensated by increased expression of UCP1 and browning of white adipose tissue. We found that the DKO mice were viable when reared at thermoneutrality. When challenged to acute cold, the DKO were extremely cold-sensitive and became hypothermic. Paradoxically, the DKO mice were able to survive gradual cold challenge, but these mice lost significant weight and depleted their fat stores, despite having higher caloric intake. These studies suggest that UCP1 and SLN are required to maintain optimal thermogenesis and that loss of both systems compromises survival of mice under cold stress. PMID- 25825504 TI - Early thoughts on g. PMID- 25825505 TI - Slum clinics. PMID- 25825506 TI - Jelly beans and jumbo jets. PMID- 25825507 TI - Responsible corporate change: detecting and managing employee stress. AB - BACKGROUND: All 120 health and safety inspectors employed by the New Zealand regulatory agency had their jobs disestablished during a restructuring process and were required to undergo an assessment process with tight time frames. AIMS: To report on psychological morbidity during the transition to change. METHODS: The Hospital Anxiety and Depression Scale (HADS) questionnaire was emailed to all 120 current inspectors to measure levels of anxiety (HAD-A) and depression (HAD D). A score of <7 is in the normal range, scores of between 8 and 10 are suggestive of an anxiety (HADS-A) or mood (HADS-D) disorder and a score of >11 is indicative of a clinical disorder. RESULTS: Replies were received from 36% (43) of the inspectors. Of the 40 usable responses, 47% (19) and 55% (22), respectively, had HAD-A and HAD-D scores greater than the case cut-off. Only 28% (11) and 15% (6), respectively, had scores that would be considered normal. CONCLUSIONS: The high scores evident in this sample are comparable to those found in patients with serious psychopathology. Change managers should recognize that the onus for primary prevention lies with the organization, in this case designing an assessment process that takes place over a reasonable time frame. They should also realize the requirement for the active monitoring of stress. PMID- 25825508 TI - Can serial PEF measurements separate occupational asthma from allergic alveolitis? AB - BACKGROUND: Occupational asthma commonly results in work-related changes in serial peak expiratory flow (PEF) measurements. Whether alveolitis can result in similar changes is unknown. AIMS: To identify differences and similarities of serial PEF between workers with occupational alveolitis and asthma seen during an outbreak investigation in a factory with metal-working fluid exposure. METHODS: Workers with respiratory symptoms and rest-day improvement were identified by questionnaire. Each was asked to measure PEF 8 times daily for 4 weeks at home and work. Alveolitis was subsequently diagnosed from a validated scoring system including radiological changes, carbon monoxide diffusing capacity, bronchoalveolar lavage and biopsy results. Occupational asthma was confirmed with a positive Oasys score >2.5 and a mean rest-work PEF >16 l/min from serial 2 hourly PEF measurements. The Oasys PEF plotter calculated differences between rest and workdays for mean PEF, diurnal variation and the scores were used to confirm an occupational effect (Oasys, area between curve and time point). Records were compared between the alveolitis group and the group with occupational asthma without alveolitis. RESULTS: Forty workers with occupational asthma and 16 with alveolitis had indistinguishable PEF changes on workdays in terms of magnitude (median reduction 18.5 and 16.1 l/min, respectively) and diurnal variation. Immediate reactions were more common with occupational asthma and late reactions more common with alveolitis. CONCLUSIONS: PEF responses to metal-working fluid aerosols do not distinguish occupational asthma from alveolitis except in timing. They can be used to identify the workplace as the cause of asthma and also alveolitis. PMID- 25825509 TI - Resolving 45-pm-separated Si-Si atomic columns with an aberration-corrected STEM. AB - Si-Si atomic columns separated by 45 pm were successfully resolved with a 300-kV aberration-corrected scanning transmission electron microscope (STEM) equipped with a cold-field emission gun. Using a sufficiently small Gaussian effective source size and a 0.4-eV energy spread at 300 kV, the focused electron probe on the specimen was simulated to be sub-50 pm. Image simulation showed that the present probe condition was sufficient to resolve 45 pm Si-Si dumbbells. A silicon crystalline specimen was observed from the [114] direction with a high angle annular dark field STEM and the intensity profile showed 45 pm separation. A spot corresponding to (45 pm)(-1) was confirmed in the power spectrum of the Fourier transform. PMID- 25825510 TI - One-step nanopatterning of conjugated polymers by electron-beam-assisted electropolymerization. AB - We propose a one-step nanopatterning method where liquid monomers are polymerized directly with an electron beam under an atmospheric pressure. The method allows precise positional control of an electron beam that induces electropolymerization based on an anodic oxidation only in the irradiated areas. Various versatile conjugated polymers, including polypyrrole, polyaniline and poly(3 hexylthiophene), have been directly polymerized from monomers without solvents and patterned by our one-step nanopatterning method. Vertically oriented arrays of nanorods several hundred nanometers in diameter with an aspect ratio (height to diameter) of around two were fabricated. PMID- 25825512 TI - Chiara Zurzolo: GPI knows the way to go. PMID- 25825511 TI - Annual Report to the Nation on the Status of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, Poverty, and State. AB - BACKGROUND: The American Cancer Society (ACS), Centers for Disease Control and Prevention (CDC), National Cancer Institute (NCI), and North American Association of Central Cancer Registries (NAACCR) collaborate annually to produce updated, national cancer statistics. This Annual Report includes a focus on breast cancer incidence by subtype using new, national-level data. METHODS: Population-based cancer trends and breast cancer incidence by molecular subtype were calculated. Breast cancer subtypes were classified using tumor biomarkers for hormone receptor (HR) and human growth factor-neu receptor (HER2) expression. RESULTS: Overall cancer incidence decreased for men by 1.8% annually from 2007 to 2011 [corrected]. Rates for women were stable from 1998 to 2011. Within these trends there was racial/ethnic variation, and some sites have increasing rates. Among children, incidence rates continued to increase by 0.8% per year over the past decade while, like adults, mortality declined. HR+/HER2- breast cancers, the subtype with the best prognosis, were the most common for all races/ethnicities with highest rates among non-Hispanic white women, local stage cases, and low poverty areas (92.7, 63.51, and 98.69 per 100000 non-Hispanic white women, respectively). HR+/HER2- breast cancer incidence rates were strongly, positively correlated with mammography use, particularly for non-Hispanic white women (Pearson 0.57, two-sided P < .001). Triple-negative breast cancers, the subtype with the worst prognosis, were highest among non-Hispanic black women (27.2 per 100000 non-Hispanic black women), which is reflected in high rates in southeastern states. CONCLUSIONS: Progress continues in reducing the burden of cancer in the United States. There are unique racial/ethnic-specific incidence patterns for breast cancer subtypes; likely because of both biologic and social risk factors, including variation in mammography use. Breast cancer subtype analysis confirms the capacity of cancer registries to adjust national collection standards to produce clinically relevant data based on evolving medical knowledge. PMID- 25825513 TI - Damaged mitochondria get a Parkin ticket. PMID- 25825514 TI - To avoid a mating mishap, yeast focus and communicate. AB - During mating, yeast cells must perforate their rigid cell walls at the right place to allow cell-cell fusion. In this issue, Dudin et al. (2015; J. Cell Biol. http://dx.doi.org/jcb.201411124) image mating fission yeast cells with unprecedented spatiotemporal resolution. The authors find that when mating cells come into contact, they form aster-like actin structures that direct cell wall remodeling precisely to the point of contact. PMID- 25825515 TI - A little sugar goes a long way: the cell biology of O-GlcNAc. AB - Unlike the complex glycans decorating the cell surface, the O-linked beta-N acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate-GlcNAc, a precursor responsive to nutrient status and other environmental cues. Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria. OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications. The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport. PMID- 25825516 TI - A novel role of farnesylation in targeting a mitotic checkpoint protein, human Spindly, to kinetochores. AB - Kinetochore (KT) localization of mitotic checkpoint proteins is essential for their function during mitosis. hSpindly KT localization is dependent on the RZZ complex and hSpindly recruits the dynein-dynactin complex to KTs during mitosis, but the mechanism of hSpindly KT recruitment is unknown. Through domain-mapping studies we characterized the KT localization domain of hSpindly and discovered it undergoes farnesylation at the C-terminal cysteine residue. The N-terminal 293 residues of hSpindly are dispensable for its KT localization. Inhibition of farnesylation using a farnesyl transferase inhibitor (FTI) abrogated hSpindly KT localization without affecting RZZ complex, CENP-E, and CENP-F KT localization. We showed that hSpindly is farnesylated in vivo and farnesylation is essential for its interaction with the RZZ complex and hence KT localization. FTI treatment and hSpindly knockdown displayed the same mitotic phenotypes, indicating that hSpindly is a key FTI target in mitosis. Our data show a novel role of lipidation in targeting a checkpoint protein to KTs through protein-protein interaction. PMID- 25825517 TI - A formin-nucleated actin aster concentrates cell wall hydrolases for cell fusion in fission yeast. AB - Cell-cell fusion is essential for fertilization. For fusion of walled cells, the cell wall must be degraded at a precise location but maintained in surrounding regions to protect against lysis. In fission yeast cells, the formin Fus1, which nucleates linear actin filaments, is essential for this process. In this paper, we show that this formin organizes a specific actin structure-the actin fusion focus. Structured illumination microscopy and live-cell imaging of Fus1, actin, and type V myosins revealed an aster of actin filaments whose barbed ends are focalized near the plasma membrane. Focalization requires Fus1 and type V myosins and happens asynchronously always in the M cell first. Type V myosins are essential for fusion and concentrate cell wall hydrolases, but not cell wall synthases, at the fusion focus. Thus, the fusion focus focalizes cell wall dissolution within a broader cell wall synthesis zone to shift from cell growth to cell fusion. PMID- 25825518 TI - CCM2-CCM3 interaction stabilizes their protein expression and permits endothelial network formation. AB - Mutations in the essential adaptor proteins CCM2 or CCM3 lead to cerebral cavernous malformations (CCM), vascular lesions that most frequently occur in the brain and are strongly associated with hemorrhagic stroke, seizures, and other neurological disorders. CCM2 binds CCM3, but the molecular basis of this interaction, and its functional significance, have not been elucidated. Here, we used x-ray crystallography and structure-guided mutagenesis to show that an alpha helical LD-like motif within CCM2 binds the highly conserved "HP1" pocket of the CCM3 focal adhesion targeting (FAT) homology domain. By knocking down CCM2 or CCM3 and rescuing with binding-deficient mutants, we establish that CCM2-CCM3 interactions protect CCM2 and CCM3 proteins from proteasomal degradation and show that both CCM2 and CCM3 are required for normal endothelial cell network formation. However, CCM3 expression in the absence of CCM2 is sufficient to support normal cell growth, revealing complex-independent roles for CCM3. PMID- 25825519 TI - L1CAM/Neuroglian controls the axon-axon interactions establishing layered and lobular mushroom body architecture. AB - The establishment of neuronal circuits depends on the guidance of axons both along and in between axonal populations of different identity; however, the molecular principles controlling axon-axon interactions in vivo remain largely elusive. We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory. We addressed the regulatory mechanisms controlling homophilic Neuroglian-mediated cell adhesion by analyzing targeted mutations of extra- and intracellular Neuroglian domains in combination with cell type-specific rescue assays in vivo. We demonstrate independent and cooperative domain requirements: intercalating growth depends on homophilic adhesion mediated by extracellular Ig domains. For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations. Together, our results provide novel mechanistic insights into cell adhesion molecule-mediated axon-axon interactions that enable precise assembly of complex neuronal circuits. PMID- 25825520 TI - Topical Review: The Emerging Field of Epigenetics: Informing Models of Pediatric Trauma and Physical Health. AB - OBJECTIVE: Trauma experienced during childhood and adolescence has been linked to a number of chronic medical concerns. We highlight major findings from the pediatric trauma literature to provide a model for understanding this association. METHODS: Studies examining the effects of trauma were systematically reviewed and synthesized into a model proposing a central role for epigenetics in the ways that childhood experiences can affect health. RESULTS: Early hypothalamic pituitary adrenal (HPA) axis response may impact initial trauma experience, with downstream effects on posttrauma adjustment reflected in posttrauma neurobiology, psychological health, and physical health. CONCLUSIONS: Prospective research with children and adolescents exposed to trauma is needed to better characterize the genetic and epigenetic influences on the course of HPA and immune processes as related to posttrauma psychological and physical health outcomes. PMID- 25825521 TI - Acute Pain and Posttraumatic Stress After Pediatric Injury. AB - OBJECTIVE: Using a prospective, longitudinal design, we examined the relationship between acute pain and posttraumatic stress symptoms (PTSS) in youth following injury. METHODS: Children aged 8-17 years who sustained an injury (N = 243) and their parents participated in baseline interviews to assess children's worst pain since injury. 6 months later, participants completed follow-up interviews to assess child PTSS. RESULTS: Pain as assessed by the Color Analogue Pain Scale (CAS) predicted PTSS 6 months after injury, even when controlling for demographic and empirically based risk factors. On the other hand, pain as assessed by the Faces Pain Rating Scale was not a significant independent predictor of PTSS. CONCLUSIONS: The CAS may be a useful addition to existing screening tools for PTSS among children. Additional research is warranted to understand underlying mechanisms linking acute pain and PTSS to improve assessment, prevention, and treatment approaches and promote optimal recovery after pediatric injury. PMID- 25825522 TI - Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway. AB - Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3beta (GSK3beta) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3beta pathways. PMID- 25825523 TI - Molecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling. AB - Wnt signaling pathways are tightly regulated by ubiquitination, and dysregulation of these pathways promotes tumorigenesis. It has been reported that the ubiquitin ligase RNF43 plays an important role in frizzled-dependent regulation of the Wnt/beta-catenin pathway. Here, we show that RNF43 suppresses both Wnt/beta catenin signaling and noncanonical Wnt signaling by distinct mechanisms. The suppression of Wnt/beta-catenin signaling requires interaction between the extracellular protease-associated (PA) domain and the cysteine-rich domain (CRD) of frizzled and the intracellular RING finger domain of RNF43. In contrast, these N-terminal domains of RNF43 are not required for inhibition of noncanonical Wnt signaling, but interaction between the C-terminal cytoplasmic region of RNF43 and the PDZ domain of dishevelled is essential for this suppression. We further show the mechanism by which missense mutations in the extracellular portion of RNF43 identified in patients with tumors activate Wnt/beta-catenin signaling. Missense mutations of RNF43 change their localization from the endosome to the endoplasmic reticulum (ER), resulting in the failure of frizzled-dependent suppression of Wnt/beta-catenin signaling. However, these mutants retain the ability to suppress noncanonical Wnt signaling, probably due to interaction with dishevelled. RNF43 is also one of the potential target genes of Wnt/beta-catenin signaling. Our results reveal the molecular role of RNF43 and provide an insight into tumorigenesis. PMID- 25825524 TI - Growth Cone Localization of the mRNA Encoding the Chromatin Regulator HMGN5 Modulates Neurite Outgrowth. AB - Neurons exploit local mRNA translation and retrograde transport of transcription factors to regulate gene expression in response to signaling events at distal neuronal ends. Whether epigenetic factors could also be involved in such regulation is not known. We report that the mRNA encoding the high-mobility group N5 (HMGN5) chromatin binding protein localizes to growth cones of both neuron like cells and of hippocampal neurons, where it has the potential to be translated, and that HMGN5 can be retrogradely transported into the nucleus along neurites. Loss of HMGN5 function induces transcriptional changes and impairs neurite outgrowth, while HMGN5 overexpression induces neurite outgrowth and chromatin decompaction; these effects are dependent on growth cone localization of Hmgn5 mRNA. We suggest that the localization and local translation of transcripts coding for epigenetic factors couple the dynamic neuronal outgrowth process with chromatin regulation in the nucleus. PMID- 25825525 TI - Modulation of Macrophage Gene Expression via Liver X Receptor alpha Serine 198 Phosphorylation. AB - In mouse models of atherosclerosis, normalization of hyperlipidemia promotes macrophage emigration and regression of atherosclerotic plaques in part by liver X receptor (LXR)-mediated induction of the chemokine receptor CCR7. Here we report that LXRalpha serine 198 (S198) phosphorylation modulates CCR7 expression. Low levels of S198 phosphorylation are observed in plaque macrophages in the regression environment where high levels of CCR7 expression are observed. Consistent with these findings, CCR7 gene expression in human and mouse macrophages cell lines is induced when LXRalpha at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXRalpha S198, and this was lost in LXR deficient BMDMs. LXRalpha occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXRalpha (RAW-LXRalpha S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXRalpha (RAW-LXRalpha WT). Expression profiling of ligand-treated RAW-LXRalpha S198A cells compared to RAW LXRalpha WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXRalpha S198 in the nonphosphorylated and phosphorylated states identified phosphorylation-dependent conformational changes in the hinge region commensurate with the presence of sites for protein interaction. Therefore, gene transcription is regulated by LXRalpha S198 phosphorylation, including that of antiatherogenic genes such as CCR7. PMID- 25825527 TI - Research led by participants: a new social contract for a new kind of research. AB - In recent years, there have been prominent calls for a new social contract that accords a more central role to citizens in health research. Typically, this has been understood as citizens and patients having a greater voice and role within the standard research enterprise. Beyond this, however, it is important that the renegotiated contract specifically addresses the oversight of a new, path breaking approach to health research: participant-led research. In light of the momentum behind participant-led research and its potential to advance health knowledge by challenging and complementing traditional research, it is vital for all stakeholders to work together in securing the conditions that will enable it to flourish. PMID- 25825526 TI - RNA Interference Screen to Identify Kinases That Suppress Rescue of DeltaF508 CFTR. AB - Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). DeltaF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in DeltaF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ~750 different kinases and associated signaling proteins. We identified 20 novel suppressors of DeltaF508-CFTR maturation, including the FGFR1. These were subsequently validated by measuring channel activity by the YFP halide-sensitive assay following shRNA-mediated knockdown, immunoblotting for the mature (band C) DeltaF508-CFTR and measuring the amount of surface DeltaF508-CFTR by ELISA. The role of FGFR signaling on DeltaF508-CFTR trafficking was further elucidated by knocking down FGFRs and their downstream signaling proteins: Erk1/2, Akt, PLCgamma-1, and FRS2. Interestingly, inhibition of FGFR1 with SU5402 administered to intestinal organoids (mini-guts) generated from the ileum of DeltaF508-CFTR homozygous mice resulted in a robust DeltaF508-CFTR rescue. Moreover, combination of SU5402 and VX-809 treatments in cells led to an additive enhancement of DeltaF508-CFTR rescue, suggesting these compounds operate by different mechanisms. Chaperone array analysis on human bronchial epithelial cells harvested from DeltaF508/DeltaF508-CFTR transplant patients treated with SU5402 identified altered expression of several chaperones, an effect validated by their overexpression or knockdown experiments. We propose that FGFR signaling regulates specific chaperones that control DeltaF508-CFTR maturation, and suggest that FGFRs may serve as important targets for therapeutic intervention for the treatment of CF. PMID- 25825529 TI - Iodine and the "near" eradication of cretinism. PMID- 25825532 TI - Point-of-care ultrasonography by pediatric emergency medicine physicians. AB - Emergency physicians have used point-of-care ultrasonography since the 1990 s. Pediatric emergency medicine physicians have more recently adopted this technology. Point-of-care ultrasonography is used for various scenarios, particularly the evaluation of soft tissue infections or blunt abdominal trauma and procedural guidance. To date, there are no published statements from national organizations specifically for pediatric emergency physicians describing the incorporation of point-of-care ultrasonography into their practice. This document outlines how pediatric emergency departments may establish a formal point-of-care ultrasonography program. This task includes appointing leaders with expertise in point-of-care ultrasonography, effectively training and credentialing physicians in the department, and providing ongoing quality assurance reviews. PMID- 25825533 TI - Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. AB - OBJECTIVE: Antibiotics have direct effects on the human intestinal microbiota, particularly in infancy. Antibacterial agents promote growth in farm animals by unknown mechanisms, but little is known about their effects on human weight gain. Our aim was to evaluate the impact of antibiotic exposure during infancy on weight and height in healthy Finnish children. METHODS: The population-based cohort comprised 6114 healthy boys and 5948 healthy girls having primary care weight and height measurements and drug purchase data from birth to 24 months. BMI and height, expressed as z-scores at the median age of 24 months (interquartile range 24 to 26 months), were compared between children exposed and unexposed to antibiotics using analysis of covariance with perinatal factors as covariates. RESULTS: Exposed children were on average heavier than unexposed children (adjusted BMI-for-age z-score difference in boys 0.13 SD [95% confidence interval 0.07 to 0.19, P < .001] and in girls 0.07 SD [0.01 to 0.13, P < .05]). The effect was most pronounced after exposure to macrolides before 6 months of age (boys 0.28 [0.11 to 0.46]; girls 0.23 [0.04 to 0.42]) or >1 exposure (boys 0.20 [0.10 to 0.30]; girls 0.13 [0.03 to 0.22]). CONCLUSIONS: Antibiotic exposure before 6 months of age, or repeatedly during infancy, was associated with increased body mass in healthy children. Such effects may play a role in the worldwide childhood obesity epidemic and highlight the importance of judicious use of antibiotics during infancy, favoring narrow-spectrum antibiotics. PMID- 25825535 TI - Incidental findings on brain and spine imaging in children. AB - In recent years, the utilization of diagnostic imaging of the brain and spine in children has increased dramatically, leading to a corresponding increase in the detection of incidental findings of the central nervous system. Patients with unexpected findings on imaging are often referred for subspecialty evaluation. Even with rational use of diagnostic imaging and subspecialty consultation, the diagnostic process will always generate unexpected findings that must be explained and managed. Familiarity with the most common findings that are discovered incidentally on diagnostic imaging of the brain and spine will assist the pediatrician in providing counseling to families and in making recommendations in conjunction with a neurosurgeon, when needed, regarding additional treatments and prognosis. PMID- 25825534 TI - Screening and routine supplementation for iron deficiency anemia: a systematic review. AB - BACKGROUND AND OBJECTIVES: Supplementation and screening for iron-deficiency anemia (IDA) in young children may improve growth and development outcomes. The goal of this study was to review the evidence regarding the benefits and harms of screening and routine supplementation for IDA for the US Preventive Services Task Force. METHODS: We searched Medline and Cochrane databases (1996-August 2014), as well as reference lists of relevant systematic reviews. We included trials and controlled observational studies regarding the effectiveness and harms of routine iron supplementation and screening in children ages 6 to 24 months conducted in developed countries. One author extracted data, which were checked for accuracy by a second author. Dual quality assessment was performed. RESULTS: No studies of iron supplementation in young children reported on the diagnosis of neurodevelopmental delay. Five of 6 trials sparsely reporting various growth outcomes found no clear benefit of supplementation. After 3 to 12 months, Bayley Scales of Infant Development scores were not significantly different in 2 trials. Ten trials assessing iron supplementation in children reported inconsistent findings for hematologic measures. Evidence regarding the harms of supplementation was limited but did not indicate significant differences. No studies assessed the benefits or harms of screening or the association between improvement in impaired iron status and clinical outcomes. Studies may have been underpowered, and control factors varied and could have confounded results. CONCLUSIONS: Although some evidence on supplementation for IDA in young children indicates improvements in hematologic values, evidence on clinical outcomes is lacking. No randomized controlled screening studies are available. PMID- 25825536 TI - Adolescent drug testing policies in schools. AB - More than a decade after the US Supreme Court established the legality of school based drug testing, these programs remain controversial, and the evidence evaluating efficacy and risks is inconclusive. The objective of this technical report is to review the relevant literature that explores the benefits, risks, and costs of these programs. PMID- 25825540 TI - Executive functioning of 4 children with hyperphenylalaninemia from childhood to adolescence. AB - Hyperphenylalaninemia is a variant of phenylketonuria, and debate remains as to what, if any, active management of this condition is required to preserve cognitive function and psychological well-being. This study is the first to examine longitudinally the executive function (EF) in adolescents with hyperphenylalaninemia. Two sibling pairs with mild hyperphenylalaninemia underwent neuropsychological examination in early childhood and again in adolescence using EF tests that were highly sensitive to phenylalanine exposure. By early adolescence, none of the 4 children demonstrated EF impairment. The children demonstrated a typical developmental trajectory of EF from childhood to adolescence, given phenylalanine exposure consistent with their condition. PMID- 25825541 TI - Primary care interventions for pediatric obesity: need for an integrated approach. PMID- 25825539 TI - Motivational interviewing and dietary counseling for obesity in primary care: an RCT. AB - BACKGROUND AND OBJECTIVE: Few studies have tested the impact of motivational interviewing (MI) delivered by primary care providers on pediatric obesity. This study tested the efficacy of MI delivered by providers and registered dietitians (RDs) to parents of overweight children aged 2 through 8. METHODS: Forty-two practices from the Pediatric Research in Office Settings Network of the American Academy of Pediatrics were randomly assigned to 1 of 3 groups. Group 1 (usual care) measured BMI percentile at baseline and 1- and 2-year follow-up. Group 2 (provider only) delivered 4 MI counseling sessions to parents of the index child over 2 years. Group 3 (provider + RD) delivered 4 provider MI sessions plus 6 MI sessions from a RD. The primary outcome was child BMI percentile at 2-year follow up. RESULTS: At 2-year follow-up, the adjusted BMI percentile was 90.3, 88.1, and 87.1 for groups 1, 2, and 3, respectively. The group 3 mean was significantly (P = .02) lower than group 1. Mean changes from baseline in BMI percentile were 1.8, 3.8, and 4.9 across groups 1, 2, and 3. CONCLUSIONS: MI delivered by providers and RDs (group 3) resulted in statistically significant reductions in BMI percentile. Research is needed to determine the clinical significance and persistence of the BMI effects observed. How the intervention can be brought to scale (in particular, how to train physicians to use MI effectively and how best to train RDs and integrate them into primary care settings) also merits future research. PMID- 25825542 TI - Iron depletion results in Src kinase inhibition with associated cell cycle arrest in neuroblastoma cells. AB - Iron is required for cellular proliferation. Recently, using systematic time studies of neuroblastoma cell growth, we better defined the G1 arrest caused by iron chelation to a point in mid-G1, where cyclin E protein is present, but the cyclin E/CDK2 complex kinase activity is inhibited. In this study, we again used the neuroblastoma SKNSH cells lines to pinpoint the mechanism responsible for this G1 block. Initial studies showed in the presence of DFO, these cells have high levels of p27 and after reversal of iron chelation p27 is degraded allowing for CDK2 kinase activity. The initial activation of CDK2 kinase allows cells to exit G1 and enter S phase. Furthermore, we found that inhibition of p27 degradation by DFO is directly associated with inhibition of Src kinase activity measured by lack of phosphorylation of Src at the 416 residue. Activation of Src kinase occurs very early after reversal from the DFO G1 block and is temporally associated with initiation of cellular proliferation associated with entry into S phase. For the first time therefore we show that iron chelation inhibits Src kinase activity and this activity is a requirement for cellular proliferation. PMID- 25825543 TI - A novel cardiac muscle-derived biomaterial reduces dyskinesia and postinfarct left ventricular remodeling in a mouse model of myocardial infarction. AB - Extracellular matrix (ECM) degradation after myocardial infarction (MI) leaves the myocardium structurally weakened and, as a result, susceptible to early infarct zone dyskinesia and left ventricular (LV) remodeling. While various cellular and biomaterial preparations have been transplanted into the infarct zone in hopes of improving post-MI LV remodeling, an allogeneic cardiac muscle derived ECM extract has yet to be developed and tested in the setting of reperfused MI. We sought to determine the effects of injecting a novel cardiac muscle-derived ECM into the infarct zone on early dyskinesia and LV remodeling in a mouse model of MI. Cardiac muscle ECM was extracted from frozen mouse heart tissue by a protocol that enriches for basement membrane constituents. The extract was injected into the infarct zone immediately after ischemia/reperfusion injury (n = 6). Echocardiography was performed at baseline and at days 2, 7, 14, and 28 post-MI to assess 3D LV volumes and cardiac function, as compared to infarcted controls (n = 9). Early infarct zone dyskinesia was measured on day 2 post-MI using a novel metric, the dyskinesia index. End-systolic volume was significantly reduced in the ECM-treated group compared to controls by day 14. Ejection fraction and stroke volume were also significantly improved in the ECM treated group. ECM-treated hearts showed a significant (P < 0.005) reduction in dyskinetic motion on day 2. Thus, using high-frequency ultrasound, it was shown that treatment with a cardiac-derived ECM preparation reduced early infarct zone dyskinesia and post-MI LV remodeling in a mouse model of reperfused MI. PMID- 25825544 TI - Impaired smooth-pursuit in Parkinson's disease: normal cue-information memory, but dysfunction of extra-retinal mechanisms for pursuit preparation and execution. AB - While retinal image motion is the primary input for smooth-pursuit, its efficiency depends on cognitive processes including prediction. Reports are conflicting on impaired prediction during pursuit in Parkinson's disease. By separating two major components of prediction (image motion direction memory and movement preparation) using a memory-based pursuit task, and by comparing tracking eye movements with those during a simple ramp-pursuit task that did not require visual memory, we examined smooth-pursuit in 25 patients with Parkinson's disease and compared the results with 14 age-matched controls. In the memory based pursuit task, cue 1 indicated visual motion direction, whereas cue 2 instructed the subjects to prepare to pursue or not to pursue. Based on the cue information memory, subjects were asked to pursue the correct spot from two oppositely moving spots or not to pursue. In 24/25 patients, the cue-information memory was normal, but movement preparation and execution were impaired. Specifically, unlike controls, most of the patients (18/24 = 75%) lacked initial pursuit during the memory task and started tracking the correct spot by saccades. Conversely, during simple ramp-pursuit, most patients (83%) exhibited initial pursuit. Popping-out of the correct spot motion during memory-based pursuit was ineffective for enhancing initial pursuit. The results were similar irrespective of levodopa/dopamine agonist medication. Our results indicate that the extra retinal mechanisms of most patients are dysfunctional in initiating memory-based (not simple ramp) pursuit. A dysfunctional pursuit loop between frontal eye fields (FEF) and basal ganglia may contribute to the impairment of extra-retinal mechanisms, resulting in deficient pursuit commands from the FEF to brainstem. PMID- 25825546 TI - Assessing biochemical changes during standardization of fermentation time and temperature for manufacturing quality black tea. AB - In black tea manufacturing, one of the most important steps is fermentation which influences the quality of tea. The macerated tea leaves were fermented at various temperatures (20, 25, 30, 35 degrees C) for different duration. Changes in polyphenoloxidase and peroxidase activities, depletion patterns of individual catechins, differences in individual theaflavin levels and formation of thearubigins were measured in leaves during fermentation. Higher stability of polyphenoloxidase and peroxidase enzymes was observed at lower temperature (20 degrees C), and increase in temperature, led to enzyme instability. The rate of degradation of all the catechins was found to be fastest at 35 degrees C and slowest at 20 degrees C. The formation and depletion of individual theaflavins varied with temperature and fermentation duration. The time required for the formation of maximum total theaflavins (TF) was highest at lower temperature and this time duration also varied for different theaflavins formation. Maximum amount of thearubigins (TR) content and liquor colour development was observed at 35 degrees C, and decrease in temperature reduced thearubigins accumulation. However, maximum brightness as well as TF/TR ratio was obtained at 20 degrees C, which suggests that fermentation at lower temperature is suitable for manufacturing quality black tea. PMID- 25825545 TI - Magnetic nanoparticles with high specific absorption rate of electromagnetic energy at low field strength for hyperthermia therapy. AB - Magnetic nanoparticles (MNPs), referred to as the Dartmouth MNPs, which exhibit high specific absorption rate at low applied field strength have been developed for hyperthermia therapy applications. The MNPs consist of small (2-5 nm) single crystals of gamma-Fe2O3 with saccharide chains implanted in their crystalline structure, forming 20-40 nm flower-like aggregates with a hydrodynamic diameter of 110-120 nm. The MNPs form stable (>12 months) colloidal solutions in water and exhibit no hysteresis under an applied quasistatic magnetic field, and produce a significant amount of heat at field strengths as low as 100 Oe at 99-164 kHz. The MNP heating mechanisms under an alternating magnetic field (AMF) are discussed and analyzed quantitatively based on (a) the calculated multi-scale MNP interactions obtained using a three dimensional numerical model called the method of auxiliary sources, (b) measured MNP frequency spectra, and (c) quantified MNP friction losses based on magneto-viscous theory. The frequency responses and hysteresis curves of the Dartmouth MNPs are measured and compared to the modeled data. The specific absorption rate of the particles is measured at various AMF strengths and frequencies, and compared to commercially available MNPs. The comparisons demonstrate the superior heating properties of the Dartmouth MNPs at low field strengths (<250 Oe). This may extend MNP hyperthermia therapy to deeper tumors that were previously non-viable targets, potentially enabling the treatment of some of the most difficult cancers, such as pancreatic and rectal cancers, without damaging normal tissue. PMID- 25825547 TI - A rapid reversed-phase thin layer chromatographic protocol for detection of adulteration in ghee (clarified milk fat) with vegetable oils. AB - Detection of milk fat adulteration with foreign fats/oils continues to be a challenge for the dairy industry as well as food testing laboratories, especially in the present scenario of rampant adulteration using the scientific knowledge by unscrupulous persons involved in the trade. In the present investigation a rapid reversed-phase thin layer chromatographic (RP-TLC) protocol was standardized to ascertain the purity of milk fat. RP-TLC protocol did not show any false positive results in the genuine ghee (clarified butter fat) samples of known origin. Adulteration of ghee with coconut oil up to 7. 5 %, soybean oil, sunflower oil and groundnut oil up to 1 %, while, designer oil up to 2 % level could be detected using the standardized RP-TLC protocol. The protocol standardized is rapid and convenient to use. PMID- 25825548 TI - Geospatial Ecology of Adolescent Problem Behavior: Contributions of Community Factors and Parental Monitoring. AB - Addressed the ecology of deviant peer involvement, antisocial behavior and alcohol use, utilizing publically available information for indices of community risk/protective factors. A geospatial model was developed, combining geographic data (census, crime proximity, race/ethnicity, transportation accessibility) with information gathered for individual adolescents/household, geo-coded by home address. Adolescent-report of delinquency, association with deviant peers, substance use, and parental monitoring was obtained, along with parent-report of demographic characteristics. Deviant peer involvement was predicted by the Crime Proximity Index, with closeness of crime being associated with more deviant peer affiliation, as well as the Transportation Index, with greater accessibility leading to more involvement with troubled peers. Antisocial behaviors also increased with greater access to transportation. Adolescent alcohol use was lower in communities with a higher proportion of a non-Caucasian population, and increased with greater transportation access. Adolescent outcomes were associated with different prediction models, yet parental monitoring emerged as a consistent contributing factor. PMID- 25825549 TI - Exfoliation and intercalation of montmorillonite by small peptides. AB - Understanding structural changes in clay minerals induced by complexation with organic matter is relevant to soil science and agricultural applications. In this study, the effect of peptide storage in montmorillonite and the thermal stability of peptide-clay complexes was examined through characterization by X-ray diffraction (XRD), electron microscopy, UV absorption, and thermogravimetric analysis (TGA). XRD analysis of small peptide-montmorillonite clay complexes produced profiles consisting of reflections associated with the smectite 001 reflection and related peaks similar to that produced by a mixed layer clay mineral structure. Shifts in higher order diffraction maxima were attributed to disorder caused by the intercalation with the peptides. Increasing peptide concentrations resulted in greater shifts towards smaller 2theta from 6.37 degrees (1.39 nm) to 5.45 degrees (1.62 nm) as the interlayer space expanded. The expansion was accompanied by broadening of the 001 reflection (FWHM increases from 0.51 to 1.22 degrees 2theta). The XRD line broadening was interpreted as caused by poorer crystallinity resulting from intercalation and tactoid exfoliation. SEM images revealed montmorillonite platelets with upwardly rolled edges that tend toward cylindrical structures with the production of tubules. High-resolution TEM images revealed bending of montmorillonite platelets, confirming exfoliation. The distribution of basal spacings in the micrographs was determined from the spatial frequencies obtained by Fourier analysis of density profiles. The distribution indicated the presence of discrete coherent crystallite domains. XRD and TGA results indicated that higher peptide concentrations resulted in a greater fraction of intercalated peptides and that surface adsorption of peptides mediated intercalation. Therefore, higher peptide concentration led to more stable organoclay complexes. However, UV absorption and TGA found that peptide adsorption onto montmorillonite had a finite limit at approximately 16% by weight. PMID- 25825550 TI - Risky Sexual Behavior and Substance Use among Adolescents: A Meta-analysis. AB - This study presents the results of a meta-analysis of the association between substance use and risky sexual behavior among adolescents. 87 studies fit the inclusion criteria, containing a total of 104 independent effect sizes that incorporated more than 120,000 participants. The overall effect size for the relationship between substance use and risky sexual behavior was in the small to moderate range (r = .22, CI = .18, .26). Further analyses indicated that the effect sizes did not substantially vary across the type of substance use, but did substantially vary across the type of risky sexual behavior being assessed. Specifically, mean effect sizes were smallest for studies examining unprotected sex (r = .15, CI = .10, .20), followed by studies examining number of sexual partners (r = .25, CI = .21, .30), those examining composite measures of risky sexual behavior (r = .38, CI = .27, .48), and those examining sex with an intravenous drug user (r = .53, CI = .45, .60). Furthermore, our results revealed that the relationship between drug use and risky sexual behavior is moderated by several variables, including sex, ethnicity, sexuality, age, sample type, and level of measurement. Implications and future directions are discussed. PMID- 25825552 TI - Editorial. PMID- 25825551 TI - The sanitation environment in urban slums: implications for child health. AB - I examine the effect of improved sanitation on child health in urban Bangladesh to assess the relative importance of household versus neighborhood characteristics and of adult latrine usage versus safe disposal of children's feces. Using fixed-effects regression, I calculate the change in weight-for height in 153 children as a function of changes in latrine usage in the surrounding community. The use of longitudinal data allows children to act as their own controls, a stumbling point of many other sanitation evaluation studies using cross-sectional or case-control methods. Results provide strong evidence that children's toileting matters more than adult toileting behavior in creating a safe, hygienic environment and reducing diarrheal disease. I conclude that investments in sanitation improvements offer important externalities, and that sanitation programs must encourage the safe disposal of children's feces in order to produce maximum health gains. PMID- 25825553 TI - Violating the theory of single gene-single disorder: inhibitor development in hemophilia. AB - Hemophilia is clinically and genetically heterogeneous blood disorder with several known gene defects accounting for the diversity of disease phenotype and inhibitor production. Although increasing number of causative mutations have been reported, not much is known regarding the root cause of inhibitor development against infused blood clotting factors, which represents a major challenge in the treatment of disease. The variations in the severity and frequency of bleeding in hemophiliacs with same molecular defect, indicates the role of modifier genes in the pathogenesis of disease. Herein, we aim to review and summarise the literature over the past decade, to gain insight into what is critical for the development of inhibitors in hemophilia. Aside from potential mutations in factor VIII and IX, polymorphisms in various genes such as human leukocyte antigen-I (HLA-I), HLA-II, tumor necrosis factor-alpha, interleukin-10 and cytotoxic T lymphocyte associated antigen-4, also tends to contribute to the development of inhibitors. Violating the theory of single gene-single disorder, new research indicates that inhibitor arise from a complex interplay of multiple genetic, immunological and environmental factors. With the revolutionary advances in whole genome sequencing, we propose a detailed genome wide study to identify the spectrum of genetic markers involved in the development of inhibitors for better diagnostics and therapeutics. PMID- 25825554 TI - Clinical and hematological profile of acute megakaryoblastic leukemia: a 2 year study. AB - Acute megakaryoblastic leukemia is a rare subtype of acute myeloid leukemia with a characteristic morphologic and immunophenotypic profile. It has to be distinguished from other subtypes of acute myeloid leukemia as well as acute myeloid leukemia with t (1; 22) (p13;q13) and acute megakaryoblastic leukemia in Down Syndrome because of its poor prognosis. We studied ten cases diagnosed over a period of 2 years (from July 2011 to June 2013). All the ten cases were in the pediatric age group ranging from 4 months to 2 years. On morphology, pointers to the diagnosis were clustering of blasts, presence of cytoplasmic blebs and platelet budding. An additional interesting morphological feature observed in our study was nuclear blebs which were seen in nine cases. Diagnosis was confirmed in all cases by positive immunostaining for CD61. Two of the cases had an extremely rare clinical presentation as granulocytic sarcoma. Although rare, acute megakaryoblastic leukemia should be kept in mind especially in leukemia in infants. PMID- 25825555 TI - Safety and efficacy of indigenous equine antithymocyte globulin along with cyclosporine in subjects with acquired aplastic anemia. AB - To confirm the safety and efficacy of an indigenous equine antithymocyte globulin (eATG) along with cyclosporine in Indian subjects with acquired aplastic anaemia. Subjects >2 years old with acquired aplastic anaemia were enrolled at six hospitals between April 2011 and February 2013, after approval from respective Ethics Committees. Equine ATG at a dose of 40 mg/kg/day was infused for 4 days. Efficacy analysis defined a priori, was in subjects, who had completed eATG treatment and followed-up on day 90 and/or 180. Complete response (CR) was defined as-transfusion independent, haemoglobin >=11 g/dL, absolute neutrophil count (ANC) >1.5 10(9)/L and platelet >=150 10(9)/L; partial response (PR) was transfusion independent, haemoglobin >=8 g/dL, ANC >0.5 10(9)/L and platelet >=20 10(9)/L; non responders were transfusion dependent. Lymphocyte subsets (CD 2, 3, 4 and 8) in the blood were tested on days 0 (pre eATG infusion), 3, 5, 7, 14 and 21 after eATG. Of the 30 subjects (two children <12 years old) enrolled, 19 completed day 90 and 18 completed day 180 visit. Of the remaining 11 subjects, two died on days 12 and 45 due to septicaemia and pneumonia, one was withdrawn after the first dose of eATG due to jaundice and eight were lost to follow-up. The median age was 30 (9-58) years and weight was 57 (26-84) kg. On day 90, 12 of 30 subjects responded (CR 1, PR 11) and 15 of 30 (CR 2, PR 13) on day 180. The most common adverse event was fever related to eATG infusion. There were two serious adverse events (acute renal failure, febrile neutropenia) and both recovered with treatment. There were no unusual adverse events noted during the study period. Blood T lymphocytes showed a mean decrease of 91 % from baseline that recovered by day 21. We conclude that eATG is safe and in combination with cyclosporine showed overall response in 50 % of enrolled subjects. The trial was registered with the clinical trial registry-india (Registration no. CTRI/2012/03/002498). PMID- 25825556 TI - Response of first-line antibiotic therapy in patients with febrile neutropenia during treatment of hematological disorders. AB - Patients with hematological disorders develop febrile neutropenia (FN); most of these events remain undetermined in origin. We performed a prospective study to determine the microbiological characteristics of infections and their response to the first-line antibiotic therapy in FN. The study was conducted at National Institute of Blood Disease and Bone Marrow Transplant. Two-hundred episodes of FN were assessed for the bacterial growth, antimicrobial susceptibility pattern and response to the first-line treatment of FN. All patients were given Ceftazidime and Amikacin Bosch Pharmaceutical (Pvt. Ltd), as first-line antibiotic in FN. Out of 200 episodes we had 108 clinically and microbiologically documented infections. The isolated frequencies for gram negative and gram positive organisms were n = 52 and 49 (48 and 45 %) respectively. Among gram negative micro-organisms, Escherichia coli (E. coli) was isolated in 15 (28.8 %), Klebsiella pneumonae in 4 (7.6 %) and Pseudomonas aeruginosa in 10 (19.2 %) were in highest frequencies. Methicillin sensitive staphylococci emerged as the frequently isolated gram-positive bacteria. Eight-one episodes (45.3 %) responded to the first-line treatment and death reported in 20 cases (10 %). Our study showed almost equal trend of gram positive and gram negative bacteria isolated from patients suffering from neutropenic fever. Empirical use of Ceftazidime and Amikacin as first-line antibiotics was able to cover the infection only in 45.3 % of episodes suffering from FN. PMID- 25825557 TI - Probability of Finding Marrow Unrelated Donor (MUD) for an Indian patient in a Multi-national Human Leukocyte Antigen (HLA) Registry. AB - With an increase in the number of transplants happening globally, hematopoietic stem cells (HSC) transplantation from matched unrelated donor (MUD) has begun. The increasing trend of MUD transplants across countries has been largely facilitated with the conspicuous growth of volunteer HSC donor noted in the last decade i.e. 8 million HSC donors in 2002 to more than 22 million in 2013 registered in 71 member registries of the Bone Marrow Donor Worldwide (BMDW). Some populations of the world are still very poorly represented in these registries. Since, the chances of successful engraftment and disease free survival are directly proportional to the HLA compatibility between the recipient and the prospective donor, the diversity of the HLA system at the antigenic and allelic level and the heterogeneity of HLA data of the registered donors has a bearing on the probability of finding a volunteer unrelated HSC donor for patients from such populations. In the present study 126 patients were identified suffering from hematological diseases requiring MUD transplant. Their HLA typing was performed and search was done using BMDW database. The search results for these Indian patients in the multinational registry as well as in the Indian Registries were analyzed using mean, range, standard deviation and finally evaluated in terms of probability for finding matched donor (MUD). Total Asian population is only 11 % in the BMDW making it difficult to find a MUD for an Asian patient. The current study supports this, experimentally; revealing that the probability of finding an allele match for an Indian patient in the multinational Human Leukocyte Antigen (HLA) registries is 16 % and a dismal 0.008 % in the Indian registries (donors in Indian registries is just 33,678 as compared to 22.5 million in BMDW). This greatly, emphasizes on enhancing the number of Indian donors in Indian and multi-national registries. PMID- 25825558 TI - Novel antifungal drugs against fungal pathogens: do they provide promising results for treatment? AB - The febrile neutropenia episodes of hematological patients and their outcomes were evaluated with respect to fungal pathogens and antifungal therapy in this retrospective study. All patients, who were older than 14 years of age and developed at least one neutropenic episode after chemotherapy due to hematological cancer from November 2010 to November 2012, were included into the study. We retrospectively collected demographic, treatment, and survival data of 126 patients with neutropenia and their 282 febrile episodes. The mean Multinational Association for Supportive Care in Cancer score was 17.18 +/- 8.27. Systemic antifungal drugs were initiated in 22 patients with 30 culture-proven invasive fungal infections (IFIs), 25 attacks of 19 patients with probable invasive pulmonary aspergillosis (IPA), 42 attacks of 38 patients with possible IPA, and 31 attacks of 30 patients with suspected IFI. Voriconazole (VOR), caspofungin and liposomal amphotericin B were used to treat 72 episodes of 65 patients, 45 episodes of 37 patients and 34 episodes of 32 patients as a first line therapy, respectively. Unfavorable conditions of our hematology ward are thought to increase the number of cases with invasive pulmonary aspergillosis and VOR use. It should be taken into consideration that increased systemic and per oral VOR usage predisposes patients to colonization and infection with azole resistant fungal strains. Catheters should be removed in cases where patients' conditions are convenient to remove it. Acute myeloblastic leukemia cases that are more likely to develop invasive fungal infections should be monitored closely for early diagnosis and timely initiation of antifungal drugs which directly correlates with survival rates. PMID- 25825559 TI - Cryoprotective Effect of Disaccharides on Cord Blood Stem Cells with Minimal Use of DMSO. AB - Umbilical cord blood (UCB) is an extremely attractive source of stem cells for the treatment of various benign and malignant hematological and non-hematological disorders. To facilitate the preservation of these stem cells, 10 % dimethylsulfoxide (DMSO) is widely used as cryoprotectant in cord blood banks. But it is found to be toxic at this concentration with the result of serious side effects in recipients after infusion of DMSO-cryopreserved cells. Evaluation of viability and functionality of cryopreserved hematopoietic stem cells is needed with either inclusion of nontoxic additives alone or with reduced DMSO concentration. We assessed the post thawing viability of UCB stem cells in the freezing medium containing disaccharides (sucrose or trehalose) alone and in combination with reduced amount i.e. 2 % DMSO by trypan blue staining. The functionally active progenitor cells content of the optimized media was then evaluated and compared with 5% DMSO by a colony forming unit assay using methylcellulose based media. The freezing solution containing 0.2 M trehalose with 2 % DMSO came out to be superior in the evaluation of viability and generation of hematopoietic colonies of erythroid and myeloid lineage than 5 % DMSO alone. While the percentage of viability was lower than 2 % DMSO, as observed in the medium containing 0.2 M trehalose or sucrose alone, with poor outcome of generation of myeloid lineage based colonies. Our study results suggest that trehalose (0.2M) with the inclusion of reduced concentration of DMSO(2%) can better replace 5%DMSO rather than complete removal of DMSO from the freezing medium. PMID- 25825560 TI - Molecular Characterization of beta-Thalassemia in Nineveh Province Illustrates the Relative Heterogeneity of Mutation Distributions in Northern Iraq. AB - Beta thalassemia is an important health problem in Nineveh province, a large province in Northwestern Iraq. No previous study of significance had focused on the spectrum of beta-thalassemia mutations in this part of the country. A total of 94 unrelated beta-thalassemia minor subjects from the latter province were recruited. Their carrier status was confirmed by full blood count, Hb A2 and F estimation. Thereafter their DNA was subjected to multiplex polymerase chain reaction and reverse hybridization to detect 20 beta-thalassemia mutations. A total of eleven different beta-thalassemia mutations were documented. The most frequent mutation was IVS-I-110 (G>A) documented in 34 %, followed by IVS-I-6 (T>C) in 9.6 %, IVS-I-5(G>C) in 8.5 %, codon 39 (C>T) and codon 44 (-C) in 7.4 % each, while IVS-I-1(G>A) and IVS-II-1(G>A) were encountered in 6.4 % each. Other mutations were less frequent including codon 8 (-AA), IVS-I-130 (G>C), codon 5 ( CT) and IVS-II-745(C>G). The current study revealed notable differences in the relative frequencies of several beta-thalassemia mutations in Nineveh province as compared to other parts of Northern Iraq. Such an observation may be reflective of different ethnic backgrounds and varying historical population interactions. It is believed that these findings complement those of earlier studies on beta thalassemia mutations from the country, and are quite essential in the setting of a proposed national preventive program. PMID- 25825561 TI - Novel Betaeta (beta)-Thalassemia Mutation in Turkish Children. AB - Beta (beta)-thalassemia is the most frequently observed hereditary blood disorder in the world. It is characterized by deficiency of hemoglobin beta-globin gene and is also a profoundly heterogeneous both at the molecular and clinical level. In the case of beta-thalassemia, there is reduced (beta(+) type) or absent (beta(o) type) synthesis of the beta chains of hemoglobin. beta-Thalassemia clinically occurs in three main forms: major, intermedia and minor according to requirement of transfusion. The objective of this study was to evaluate beta thalassemia mutations in 89 patients ranging from 2 months to 16 years of age, who enrolled to Medical School Research and Training Hospital, Gaziantep University. The direct DNA sequence analysis was performed for mutation scanning of beta-globin gene. 89 children with beta-Thalassemia including all types were analyzed, 16 different beta-thalassemia mutations were detected. We have also identified a novel mutation (HBB.c.-80delT, rs397509430) in the promoter region ( 30 TATA box) of beta-globin gene, and clinical data of patient having novel mutation was given. The beta-Thalassemia mutations were determined as beta Thalassemia major type in 42 patients (47.19 %), beta-Thalassemia intermedia in 4 (4.49 %), beta-Thalassemia minor in 43, (48.31 %) patients. The most frequent mutation was IVS I-110 G>A, followed by IVS I-1 G>A, IVS I-6 T>C, IVS II-1 G>A, respectively. PMID- 25825562 TI - Alpha-thalassemia mutations in adana province, southern Turkey: genotype phenotype correlation. AB - To look over the distribution of the mutations in a large series from Adana province, Southern Turkey, and determine the genotype-phenotype correlation of the frequent mutations. Among the 2500 individuals with mild or moderate anemia, microcytosis, and normal iron levels that were referred to our Genetic Diagnosis Center, a population consisting of 539 individuals were included in the study and tested for alpha-thalassemia mutations by using reverse dot blot hybridization technique. Twelve different mutations were detected in 539 patients. Among the 12 different mutations found, the most frequent mutations were the -alpha(3.7) (63.3 %), --(MED) (11.7 %), --(20.5) (10.7 %), alpha2(IVS1(-5nt)) (3.9 %), and alpha2(polyA-2) (3.5 %). The most frequent genotypes were -alpha(3.7)/alphaalpha (35.8 %), -alpha(3.7)/-alpha(3.7)(18.9 %), -(20.5)/alphaalpha (11.5 %), and - (MED)/alphaalpha (10.4 %), respectively. There were statistically significant differences in hematological findings between -alpha(3.7)/-alpha(3.7) and - (MED)/alphaalpha, even though both have two mutated genes in the genotype. Our results show that alpha-thalassemia mutations are highly heterogeneous as well as deletional and -alpha(3.7) single gene deletion is particularly prevalent at Adana province in agreement to other studies from Turkey. PMID- 25825563 TI - Detection of compound heterozygous of hb constant spring and hb q-Thailand by capillary electrophoresis and high performance liquid chromatography. AB - A capillary electrophoresis (CE) has proven to be superior to a high performance liquid chromatography (HPLC) in the detection of hemoglobin Constant Spring (Hb CS). Thus the aim of this study was to analyze the efficacy of CE and HPLC for the detection of Hb CS in samples with compound heterozygous of Hb CS and Hb Q Thailand. Hemoglobin analysis was performed in blood samples of 2 patients with compound heterozygous of Hb CS and Hb Q-Thailand by using HPLC and CE. The HPLC chromatogram and CE electrophoregram of the two techniques were compared. Hb CS was not found on HPLC chromatogram while Hb QA2 (alpha2 (QT)delta2), a derivative of Hb Q-Thailand, was presented at the retention time of 4.70-4.80 min and it was close to the retention time of Hb CS. On CE electrophoregram, Hb CS was presented at zone 2 (Z2) and it was distinctly separated from Hb QA2 which was presented at Z1. Therefore, CE was more efficient to the HPLC for diagnosis of compound heterozygous of Hb CS and Hb Q-Thailand. PMID- 25825564 TI - Prenatal diagnosis of sickle cell disease by the technique of PCR. AB - Sickle cell disease (SCD) is prevalent in Central India and causes major morbidity and mortality. There is a lack of prenatal diagnostic facility near population affected with SCD. This is the pilot study in our region with the aim to establish prenatal diagnostic facility for the couples carrying sickle cell gene in Central India, in order to help them take an informed decision regarding fetus affected with SCD and also to calculate sensitivity of polymerase chain reaction (PCR) technique in our set up with follow up high performance liquid chromatography (HPLC) of baby's blood sample. Fetal sampling was done by chorionic villous biopsy. Extracted DNA was subjected to amplification refractory mutation system (ARMS-PCR) to detect sickle cell mutation (GAG -> GTG) in the sixth codon of beta globin gene. Follow-up HPLC was done to detect baby's Hb pattern. Prenatal diagnosis of sickle cell anemia was offered in total 37 cases out of which one (2.7 %) fetal sample was inadequate. Total 26 (70.27 %) fetuses had AS Hb genotype, 3 (8.11 %) had AA Hb genotype and 3 (8.11 %) had SS Hb genotype while remaining 4 (10.81 %) were given AA/AS Hb genotype. All couples with SS fetuses opted for MTP. Follow up HPLC was performed in 24 cases, out of which 18 (75 %) were correlated and 6 (25 %) were mismatched. In present study sensitivity of ARMS-PCR was 75 %. ARMS-PCR is a simple technique to be established initially for providing rapid prenatal diagnosis to the couples with known sickle cell mutation. The sensitivity of ARMS-PCR can be increased by using suitable techniques to detect maternal cell DNA contamination. PMID- 25825566 TI - High Incidence of Zidovudine Induced Anaemia in HIV Infected Patients in Southern Odisha. AB - Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor was the first breakthrough in AIDS therapy in 1990.This study was conducted with an aim to determine prevalence of AZT induced anaemia in HIV infected patients initiated on AZT containing anti retroviral therapy(ART) regimen and also to find out any risk factor for causing AZT induced anaemia. Study was carried out in ART centre, M.K.C.G, MCH, Berhampur between Jan 2009 and Dec 2011. HIV infected patients registered at ART centre were treated according to National AIDS Control Organisation (NACO) guidelines. Patients (n = 1221) with Hb >8 gm/dl were prescribed AZT based ART regimen. Patients having anaemia (<8 gm/dl) were excluded from the study. Correlation of baseline characteristics (age, sex, weight, Hb level, CD4 count, World Health Organization (WHO) clinical stage) with risk of developing anaemia was also calculated. 178 (14.6 %) patients on AZT regimen developed anaemia. Patients with low CD4 count were more prone to develop severe anaemia. Age, sex, weight, WHO clinical stage had no relation with development of anaemia. Incidence of AZT induced anaemia was very high and patients having low CD4 count were more susceptible to develop anaemia. PMID- 25825565 TI - Implementation of newborn screening for hemoglobin h disease in mainland china. AB - Hemoglobin H disease is the most severe non-fatal form of alpha-thalassemia syndrome characterized by pronounced microcytic hypochromic hemolytic anemia. It is predominantly seen in Southeast Asia, the Middle East and the Mediterranean. Studies suggest that hemoglobin H disease is not as benign a disorder as previously thought. Newborn screening for hemoglobin H disease is especially appealing because the screening test is based on the detection of hemoglobin Bart's (gamma4) that is only possible within the newborn period. In this study, we reported on a 4-year period of newborn screening program at a mainland Chinese hospital, which detected 35 babies with hemoglobin H disease in a total of 26 152 newborns. The overall prevalence for hemoglobin H disease among all newborns in southern China is ~1 in 1,000. These children need appropriate follow-up and potential comprehensive care during their growth and development. PMID- 25825567 TI - Role of intravenous iron sucrose in correction of anemia in antenatal women with advanced pregnancy. AB - The aim of this study is to observe rise in haematological parameters after treatment with iron sucrose in antenatal patients with moderate anemia with period of gestation 32 to 35 weeks. The study included 45 antenatal patients with period of gestation from 32 to 35 weeks having iron deficiency anemia with haemoglobin levels 7-9 g% and serum ferritin levels less than 12 ng/mL. Intravenous iron sucrose was given in the dose of 200 mg on alternate days, according to the calculated dose. The mean haemoglobin and red blood cell indices were compared on days 7, 14, 21, 28 and at the time of delivery from the baseline value. There was a statistically significant rise in haemoglobin value from baseline on days 14, 21, 28 as well as at the time of delivery (p value <0.0001). The mean rise in haemoglobin values was 0.56 g% on day 14, 1.44 g% on day 21 and 2.0 g% on day 28. At the time of delivery, mean haemoglobin was 11.24 g%. After 28 days of treatment, there was a statistically significant rise in the levels of serum ferritin from 10.33 +/- 3.8 ng/mL to 36.89 +/- 5.7 ng/mL. Thus, earlier response achieved by iron sucrose can be utilised in the patients presenting at an advanced period of gestation with iron deficiency anemia. PMID- 25825568 TI - Cobalamin deficiency can mask depleted body iron reserves. AB - Vitamin B12 deficiency impairs DNA synthesis and causes erythroblast apoptosis, resulting in anaemia from ineffective erythropoiesis. Iron and cobalamin deficiency are found together in patients for various reasons. We have observed that cobalamin deficiency masks iron deficiency in some patients. We hypothesised that iron is not used by erythroblasts because of ineffective erythropoiesis due to cobalamin deficiency. Therefore, we aimed to demonstrate that depleted iron body reserves are masked by cobalamin deficiency. Seventy-five patients who were diagnosed with cobalamin deficiency were enrolled in this study. Complete blood counts and serum levels of iron, unsaturated iron binding capacity (UIBC), ferritin, vitamin B12, and thyroid stimulant hormone were determined at diagnosis and after cobalamin therapy. Patients who had a combined deficiency at diagnosis and after cobalamin therapy were recorded. Before cobalamin therapy, we found increased serum iron levels (126.4 +/- 63.4 ug/dL), decreased serum UIBC levels (143.7 +/- 70.8 ug/dL), increased serum ferritin levels (192.5 +/- 116.4 ng/mL), and increased transferrin saturation values (47.2 +/- 23.5 %). After cobalamin therapy, serum iron levels (59.1 +/- 30 ug/dL), serum ferritin levels (44.9 +/- 38.9 ng/mL) and transferrin saturation values (17.5 +/- 9.6 %) decreased, and serum UIBC levels (295.9 +/- 80.6 ug/dL) increased. Significant differences were observed in all values (p < 0.0001). Seven patients (9.3 %) had iron deficiency before cobalamin therapy, 37 (49.3 %) had iron deficiency after cobalamin therapy, and a significant difference was detected between the proportions of patients who had iron deficiency (p < 0.0001). This study is important because insufficient data are available on this condition. Our results indicate that iron deficiency is common in patients with cobalamin deficiency, and that cobalamin deficiency can mask iron deficiency. Therefore, we suggest that all patients diagnosed with cobalamin deficiency should be screened for iron deficiency, particularly after cobalamin therapy. PMID- 25825569 TI - Time Dependent Release of Interleukin-8 and Tumor Necrosis Factor-alpha in Platelet Concentrate. AB - Contaminating white blood cells in stored platelet concentrate (PC) are the source of many pro-inflammatory cytokines. These are implicated in transfusion reactions. To study the release of interleukin (IL)-8 and tumor necrosis factor alpha (TNF-alpha) at different time interval in PC prepared by-platelet rich plasma (PRP) and buffy coat (BC) using different principles. Fifteen PCs were prepared by both the methods. The supernatants of PCs prepared by PRP and BC methods were collected aseptically after 1, 18, 65 and 112 h of preparation. pH, platelet and WBC counts were done. The supernatants were frozen in aliquots at 56 degrees C for measurement of IL-8 and TNF-alpha concentration using ELISA. The Mean +/- SD value of WBC in PRP-PC was 7.4 +/- 3.75 * 10(7) and in BC-PC 3.9 +/- 2.2 * 10(7). The mean platelet counts were 6.05 +/- 1.94 * 10(10) and 6.54 +/ 2.18 * 10(10) respectively. The highest level of IL-8 in one hour was up to 30 pg/ml in both the type of PC. It increased up to 986 pg/ml in PRP-PC and 481 pg/ml in BC-PC at 112 h. IL-8 increased significantly during storage period of 5 days in both types of PCs (P0.000 and P0.01). TNF-alpha level remained low up to 18 h. The highest level was 72 pg/ml in PRP-PC and 57 pg/ml in BC-PC at 65 h. IL 8 levels significantly increased after one hour of storage and TNF-alpha. levels were low up to 18 h and then showed increase. The BC-PC had significantly low levels of IL-8 compared to PRP-PC (P0.0001). PMID- 25825570 TI - Evaluation of Random Donor Platelets Produced from Buffy Coat Stored for 24 h at Ambient Temperature: Should This be Implemented in India? AB - Whole blood derived platelets are made from platelet rich plasma (PRP) method or buffy coat (BC) method. In India majority of random donor platelets (RDPs) are prepared by PRP method. However, BC method offers the advantage of less platelet activation and fewer WBC contamination. Presently in India RDPs are prepared within 8 h of whole blood collection, whereas, in Europe this time limit is up to 24 h. Our aim was to evaluate the platelet count, WBC contamination, platelet CD62P expression, and biochemical parameters of RDPs prepared from BC within 8 h and within 24 h of collection. We prepared 40 units of RDP by the BC method from whole blood stored at room temperature within 8 h of collection (fresh BC), and another 40 units from BC stored at 22 degrees C for <24 h (stored BC). We analyzed the platelet counts, CD62P expression, WBC counts, glucose levels, pH, PO2, PCO2 in both the groups of RDPs, 24 h after respective preparation. The platelet counts from stored BC was higher in fresh BC. CD62P expression was low in stored BC compared to fresh BC. There were no differences of pH, pO2, pCO2 and glucose levels in fresh BC and stored BC. WBC contamination was more in fresh BC. Our study stored BC contained higher platelet counts, less WBC contamination and less platelet activation. We conclude that RDP prepared from stored BC is the better method for RDP production. PMID- 25825571 TI - The role of comprehensive check at the blood bank reception on blood requisitions in detecting potential transfusion errors. AB - Pre-transfusion testing includes proper requisitions, compatibility testing and pre-release checks. Proper labelling of samples and blood units and accurate patient details check helps to minimize the risk of errors in transfusion. This study was aimed to identify requisition errors before compatibility testing. The study was conducted in the blood bank of a tertiary care hospital in north India over a period of 3 months. The requisitions were screened at the reception counter and inside the pre-transfusion testing laboratory for errors. This included checking the Central Registration number (C.R. No.) and name of patient on the requisition form and the sample label; appropriateness of sample container and sample label; incomplete requisitions; blood group discrepancy. Out of the 17,148 blood requisitions, 474 (2.76 %) requisition errors were detected before the compatibility testing. There were 192 (1.11 %) requisitions where the C.R. No. on the form and the sample were not tallying and in 70 (0.40 %) requisitions patient's name on the requisition form and the sample were different. Highest number of requisitions errors were observed in those received from the Emergency and Trauma services (27.38 %) followed by Medical wards (15.82 %) and the lowest number (3.16 %) of requisition errors were observed from Hematology and Oncology wards. C.R. No. error was the most common error observed in our study. Thus a careful check of the blood requisitions at the blood bank reception counter helps in identifying the potential transfusion errors. PMID- 25825572 TI - Lacunae in patient knowledge about oral anticoagulant treatment: results of a questionnaire survey. AB - Oral anticoagulation therapy is affected by the drug used, intensity of anticoagulation, physician's experience, patient compliance, laboratory testing and patient education. Patient education is a key factor in optimal anticoagulation and safety in patients on oral anticoagulant therapy. This study was done to assess the knowledge of patients regarding oral anticoagulant therapy in the outpatient setting. This prospective study was done over 2 months in 101 patients on outpatient oral anticoagulant therapy. A 20-point questionnaire on various aspects of oral anticoagulation therapy was administered to assess their knowledge. The answers were graded on a scale of 0-1. Scores were then added up to quantify the knowledge status in each patient. Descriptive statistics and Student's t test was used to analyse the data. The mean knowledge score among patients was 9.4/18 (52.2 %). More than half (52.8 %) of the patients had a score of <9. More than half (54.4 %) of the patients had adequate knowledge-(>80 % score-5.5/7) about the critical (must know) questions regarding OAT. Patients with age >=60 years had lower mean scores compared to those <60 years of age (p = 0.028). Illiteracy was also associated (p < 0.0001) with poor scores. There are significant lacunae in the knowledge about oral anticoagulation among patients on outpatient treatment. Older age and illiteracy were associated with poor knowledge among patients. More emphasis needs to be given to the vital aspect of patient education to make this therapy safer for patients. PMID- 25825574 TI - Free protein s reference ranges in gravidas without hereditary and acquired thrombophilia. AB - We carried out a retrospective cohort study to construct reference ranges for free protein S (FPS) levels during pregnancy and identify any conditions or factors that may affect FPS levels. Patients that were ordered thrombophilia screening tests during gestational period were identified. Patients demonstrated to have hereditary or acquired thrombophilia were excluded. Reference ranges were constructed using regression analysis. Outcome of the index pregnancy and pregnancy complications was used to identify any confounding factors. A total of 455 pregnant women were included. The quadratic equation for FPS according to gestational age (GA) was [75.497 + (-1.516*GA) + 0.018*GA*GA]. FPS level and GA were negatively correlated (Spearmans rho statistic [rs] = -0.436, p = 0.001). FPS level and fetal growth restriction (FGR) were negatively correlated ([rs] = 0.093, p = 0.049). FPS level and placental abruption were positively correlated ([rs] = 0.098, p = 0.039). Stepwise linear regression model constructed to predict FPS level with gestational age, placental abruption and FGR as the predictor variables. Gestational age was the only variable retaining statistically significant relation with FPS level (chi(2) = 0.216, df = 3, p = 0.001). FPS levels decrease significantly throughout gestation in gravidas without hereditary and/or acquired thrombophilias. In patients without thrombophilia FPS levels are not associated with pregnancy complications. The obtained reference intervals may be useful for the clinicians ordering FPS during pregnancy. PMID- 25825573 TI - Lupus anticoagulants and anticardiolipin antibodies in Indian women with spontaneous, recurrent fetal loss. AB - Spontaneous and recurrent pregnancy loss are common complications of pregnancy resulting from varied causes including antiphospholipid syndrome (APS). Treatment of women with APS increases the chance of a subsequent successful pregnancy. The study aimed to find the prevalence of lupus anticoagulants (LA) and anticardiolipin antibodies (ACAs) in women with spontaneous/recurrent fetal loss and compare with women with normal obstetric history. Hundred women with spontaneous/recurrent fetal loss and 50 healthy pregnant controls were tested for LA by complete blood counts, Prothrombin time, Activated partial thromboplastin time (APTT), LA sensitive APTT and dilute Russell viper venom time (dRVVT) (screening and confirmatory) and ACAs (ELISA). LA was detected in 15 % patients using dRVVT confirmatory test and ACA in 5 %, all controls being negative. Twenty one % patients were detected by LA sensitive APTT (sensitivity 92.9 %, specificity 100 %) and 100 % with dRVVT screening test (sensitivity 98.8 %, specificity 100 %). We recommend that screening for antiphospholipid antibodies must be done in women with spontaneous/recurrent foetal loss even in the absence of other clinical manifestations using a combination of tests. PMID- 25825575 TI - Immunophenotypic aberrancy of a case of hairy cell leukemia. PMID- 25825576 TI - An Adolescent Case of Osteopetrosis with Portal Hypertension as well as Mandibula Osteomyelitis. AB - Osteopetrosis is a clinical syndrome characterized by the failure of osteoclasts to resorb bone. Excessive bone density can interfere with vital tissues and structures, causing serious problems of the body. Hematopoietic insufficiency, disturbed tooth eruption, nerve entrapment syndromes, and growth impairment may develop in a patient with osteopetrosis. Herein, we present an adolescent girl diagnosed with non-infantile type of osteopetrosis with rare complications of the disease like mandibular osteomyelitis and portal hypertension (PHT) without liver cirrhosis. To our knowledge, this is the first pediatric case with osteopetrosis related PHT. PMID- 25825577 TI - Megaloblastic anemia presenting with massive reversible splenomegaly. AB - Megaloblastic anemia (MA) is a common disorder with varied manifestations. It generally results in mild to moderate splenomegaly which is due to sequestration of macrocytic erythrocytes in spleen. Massive splenomegaly is generally seen in infections, myeloproliferative diseases, neoplasms, storage disorders or hematological conditions; but is not heard of and has rarely been reported in MA. We discuss a case of massive splenomegaly who presented with symptomatic anemia and was found to have MA. He was extensive evaluated for all other causes of massive splenomegaly which was normal. Further, after a therapeutic trial of MA he showed a regression in spleen size confirming that the massive splenomegaly was attributable to MA. PMID- 25825578 TI - Primary follicular lymphoma of the breast: a rare clinical entity diagnosed using tissue flow cytometry. PMID- 25825579 TI - Blastic plasmacytoid dendritic cell neoplasm: skin and bone marrow infiltration of three cases and the review of the literature. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a distinct and rare neoplastic entity and was classified as a subgroup of acute myeloblastic leukemia by the WHO in 2008. The median survival of patients was 15.2 months in a large case series. Allogeneic or autologous bone marrow transplantation has been recommended by some reports because of the disease's poor prognosis. We present three patients who presented with both skin and bone marrow infiltration. A 57 year-old man, a 62-year-old woman, a 64-year-old man were admitted to our outpatient clinic because of skin lesions. All of the patient's had bone marrow infiltration with positivity of the CD4, CD56, and CD123 staining. Survival of the patient's were 42, 6 and 12 months, respectively. Two of the patients who presented as blastic form didn't respond to any chemotherapy. BPDCN is a difficult disease to diagnosis and manage. CD4, CD56, CD123, CD303, and T cell leukemia/lymphoma 1. Cutaneous lesions can present as isolated nodules, macules, and disseminated macules and nodules. Positivities are crucial to the diagnosis of the disease in histological examination. Bone marrow infiltration or disease relapse at presentation were related to poor prognosis. Complete immunocytochemical staining must be performed for all patients who have cutaneous lesions with or without blood count abnormalities. Bone marrow (allogeneic or autologous) transplantation should be considered at the first remission. PMID- 25825580 TI - A rare case of follicular dendritic cell sarcoma with pseudochylous effusion and review of literature from India. PMID- 25825581 TI - Acute eosinophilic pneumonia with eosinophilic leukemoid reaction: a rare hematologic presentation. PMID- 25825582 TI - Morphological Spectrum of Paroxysmal Nocturnal Hemoglobinuria (PNH). PMID- 25825583 TI - Oral High Dose Dexamethasone for Pure Red Cell Aplasia Following ABO-Mismatched Allogeneic Peripheral Blood Stem Cell Transplantation: A Case Report. AB - Management of pure red cell aplasia following major ABO-mismatched hematopoietic stem cell transplantation is a therapeutic challenge. Various therapeutic modalities have been tried with variable responses, and patient remains transfusion dependent for a long time. We report here the use of pulsed oral high dose dexamethasone for pure red cell aplasia following ABO-mismatched allogeneic transplant with complete recovery. PMID- 25825584 TI - Emerging influenza: consideration in transfusion medicine. PMID- 25825585 TI - Anemia and H7N9 Bird Flu: A Forgotten Problem. PMID- 25825586 TI - Populations, pools, and peccaries: simulating the impact of ecosystem engineers on rainforest frogs. AB - "Ecosystem engineering" describes habitat alteration by an organism that affects another organism; such nontrophic interactions between organisms are a current focus in ecological research. Our study quantifies the actual impact an ecosystem engineer can have on another species by using a previously identified model system-peccaries and rainforest frogs. In a 4-year experiment, we simulated the impact of peccaries on a population of Allobates femoralis (Dendrobatidae) by installing an array of artificial pools to mimic a forest patch modified by peccaries. The data were analyzed using a gradual before-after control-impact (gBACI) model. Following the supplementation, population size almost doubled as a result of increased autochthonous recruitment driven by a higher per-capita reproduction of males and a higher proportion of reproducing females. The effect was evenly distributed across the population. The differential response of males and females reflects the reproductive behavior of A. femoralis, as only the males use the aquatic sites for tadpole deposition. Our study shows that management and conservation must consider nontrophic relationships and that human "ecosystem engineering" can play a vital role in efforts against the "global amphibian decline." PMID- 25825587 TI - A larger brain confers a benefit in a spatial mate search learning task in male guppies. AB - Brain size varies dramatically among vertebrates, and selection for increased cognitive abilities is thought to be the key force underlying the evolution of a large brain. Indeed, numerous comparative studies suggest positive relationships between cognitively demanding aspects of behavior and brain size controlled for body size. However, experimental evidence for the link between relative brain size and cognitive ability is surprisingly scarce and to date stems from a single study on brain size selected guppies (Poecilia reticulata), where large-brained females were shown to outperform small-brained females in a numerical learning assay. Because the results were inconclusive for males in that study, we here use a more ecologically relevant test of male cognitive ability to investigate whether or not a relatively larger brain increases cognitive ability also in males. We compared mate search ability of these artificially selected large- and small-brained males in a maze and found that large-brained males were faster at learning to find a female in a maze. Large-brained males decreased the time spent navigating the maze faster than small-brained males and were nearly twice as fast through the maze after 2 weeks of training. Our results support that relatively larger brains are better also for males in some contexts, which further substantiates that variation in vertebrate brain size is generated through the balance between energetic costs and cognitive benefits. PMID- 25825589 TI - A Framework for Evaluating and Enhancing Alignment in Self-Regulated Learning Research. AB - We discuss the articles of this special issue with reference to an important yet previously only implicit dimension of study quality: alignment across the theoretical and methodological decisions that collectively define an approach to self-regulated learning. Integrating and extending work by leaders in the field, we propose a framework for evaluating alignment in the way self-regulated learning research is both conducted and reported. Within this framework, the special issue articles provide a springboard for discussing methodological promises and pitfalls of increasingly sophisticated research on the dynamic, contingent, and contextualized features of self-regulated learning. PMID- 25825588 TI - The hippocampo-prefrontal pathway: a possible therapeutic target for negative and cognitive symptoms of schizophrenia. AB - The hippocampo-prefrontal (H-PFC) pathway has been linked to cognitive and emotional disturbances in several psychiatric disorders including schizophrenia. Preclinical evidence from the NMDA receptor antagonism rodent model of schizophrenia shows severe pathology selective to the H-PFC pathway. It is speculated that there is an increased excitatory drive from the hippocampus to the prefrontal cortex due to dysfunctions in the H-PFC plasticity, which may serve as the basis for the behavioral consequences observed in this rodent model. Thus, the H-PFC pathway is currently emerging as a promising therapeutic target for the negative and cognitive symptom clusters of schizophrenia. Here, we have reviewed the physiological, pharmacological and functional characteristics of the H-PFC pathway and we propose that allosteric activation of glutamatergic and cholinergic neurotransmission can serve as a plausible therapeutic approach. PMID- 25825591 TI - Association of Tumor Necrosis Factor-alpha Polymorphisms and Risk of Coronary Artery Disease in Patients With Non-alcoholic Fatty Liver Disease. AB - BACKGROUND: Cardiovascular events account for the main cause of death in patients with non-alcoholic fatty liver disease (NAFLD), and are largely influenced by genetic factors. Although multiple studies showed that tumor necrosis factor alpha (TNF-alpha) polymorphisms are risk factors in the progression of NAFLD, few papers on the association of the polymorphisms and the developing coronary artery disease (CAD) in NAFLD patients have been reported. OBJECTIVES: The present study was designed to evaluate the association of TNF-alpha polymorphisms at residues 238 and -308, with the risk of developing CAD in Chinese patients with NAFLD. PATIENTS AND METHODS: The TNF-alpha polymorphisms at residues 238 and 308 were genotyped in B-type ultrasonography proven NAFLD patients with (n = 246), without (n = 247) CAD and healthy controls (n = 304), using polymerase chain reaction (PCR). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS statistical software, version 20.0 for Mac. RESULTS: We found a significant association between TNF-alpha-238 guanine to alanine (GA) polymorphism and carriers of variant allele A between NAFLD patients with and without CAD (P < 0.05). Carriers of the A allele of TNF alpha-238 had higher serum triglycerides (TG) and low density lipoprotein (LDL) levels in NAFLD patients with CAD (P = 0.025 and 0.001, respectively) and a higher TG level in NAFLD patients without CAD (P = 0.017), than their non-carrier counterparts. CONCLUSIONS: In the Chinese Han population that we studied, NAFLD patients who carry the TNF-alpha-238 GA polymorphism have an increased risk of developing CAD. Mechanisms underlying this potentially important association require further investigation. PMID- 25825590 TI - HAV Immunity in Iranian Medical Students. AB - BACKGROUND: Hepatitis A, a fecal-oral transmitted disease, which has been considered endemic in developing countries, seems to change its pattern in developing countries because of their improved socioeconomic status. OBJECTIVES: In the present study, we aimed to determine the need of vaccination in 270 students at AJA University of Medical Sciences. MATERIALS AND METHODS: The serum level of anti-HAV antibody was checked in 270 students of AJA University of medical students, and effect of different factors, including age, gender, pre university entrance exam region, familial education, familial income, clean water availability, and previous history of jaundice were tested. RESULTS: Of total 270 students, 30 were female. Their age ranged between 18 and 30 years old with the mean age of 20.58 years and just 34% of students had positive level of anti-HAV antibody. Age and sex had no role in positive serum level of anti-HAV antibody. According to analyzed data, lack of clean water availability, pre-university entrance exam region, lower family education, and poor health status estimation increased statistically the risk of HAV infection. CONCLUSIONS: Because 66% of students were anti-HAV antibody negative and they will work as health care workers in future, our study suggest vaccinating all students accepted at AJA University of Medical Sciences. PMID- 25825592 TI - Availability and distribution of human resources for provision of comprehensive emergency obstetric and newborn care in Afghanistan: a cross-sectional study. AB - BACKGROUND: For over a decade, Afghanistan's Ministry of Public Health and its international development partners have invested in strengthening the national health workforce and establishing a system of primary health care facilities and hospitals to reduce the high levels of maternal and child mortality that were documented shortly after the fall of the Taliban in 2001. Significant progress has been made, but many challenges remain. The objective of this study is to assess the availability and distribution of human resources for round-the-clock comprehensive emergency obstetric and newborn care service provision in secure areas of Afghanistan in order to inform policy and program planning. METHODS: A cross-sectional assessment was conducted from December 2009 to February 2010 at the 78 accessible facilities designated to provide emergency obstetric and newborn care in Afghanistan. The availability of staff on call 24 hours a day, seven days a week; involvement of staff in essential clinical functions; turnover rates; and vacancies were documented at each facility. Descriptive statistics were used to summarize results. RESULTS: All facilities assessed had at least one midwife on staff, but most did not meet the minimum staffing requirements set in national guidelines. Given that all facilities assessed are considered referral centers for lower-level clinics, the lack of doctors at 5% of facilities, lack of anesthetists at 10% of facilities and lack of obstetrician/gynecologists at 51% of facilities raises serious concerns about the capacity of the health system to respond with lifesaving care for women with obstetric complications. CONCLUSIONS: While the government continues its efforts to increase the number of qualified female health professionals in Afghanistan after decades with little female education, innovative strategies are needed to facilitate deployment, skill development and retention of female healthcare providers in underserved areas. PMID- 25825593 TI - Organoid modeling for cancer precision medicine. AB - Three-dimensional organotypic culture models show great promise as a tool for cancer precision medicine, with potential applications for oncogene modeling, gene discovery and chemosensitivity studies. PMID- 25825595 TI - Synthesis and Immunogenicity Assessment of Elastin-Like Polypeptide-M2e Construct as an Influenza Antigen. AB - The 23 amino acid-long extracellular domain of the influenza virus transmembrane protein M2 (M2e) has remained highly conserved since the 1918 pandemic, and is thus considered a good candidate for development of a universal influenza A vaccine. However, M2e is poorly immunogenic. In this study we assessed the potential of increasing immunogenicity of M2e by constructing a nanoscale designed protein polymer containing the M2e sequence and an elastin-like polypeptide (ELP) nanodomain consisting of alanine and tyrosine guest residues (ELP(A2YA2)24). The ELP nanodomain was included to increase antigen size, and to exploit the inherent thermal inverse phase transition behavior of ELPs to purify the protein polymer. The ELP(A2YA2)24 + M2e nanodomained molecule was recombinantly synthesized. Characterization of its inverse phase transition behavior demonstrated that attachment of M2e to ELP(A2YA2)24 increased its transition temperature compared to ELP(A2YA2)24. Using a dot blot test we determined that M2e conjugated to ELP is recognizable by M2e-specific antibodies, suggesting that the conjugation process does not adversely affect the immunogenic property of M2e. Further, upon vaccinating mice with ELP(A2YA2)24 + M2e it was found that indeed the nanodomained protein enhanced M2e-specific antibodies in mouse serum compared to free M2e peptide and ELP(A2YA2)24. The immune serum could also recognize M2 expressed on influenza virions. Overall, this data suggests the potential of using molecules containing M2e-ELP nano-domains to develop a universal influenza vaccine. PMID- 25825594 TI - The gut microbiome in cardio-metabolic health. AB - With the prevalence of cardio-metabolic disorders reaching pandemic proportions, the search for modifiable causative factors has intensified. One such potential factor is the vast microbial community inhabiting the human gastrointestinal tract, the gut microbiota. For the past decade evidence has accumulated showing the association of distinct changes in gut microbiota composition and function with obesity, type 2 diabetes and cardiovascular disease. Although causality in humans and the pathophysiological mechanisms involved have yet to be decisively established, several studies have demonstrated that the gut microbiota, as an environmental factor influencing the metabolic state of the host, is readily modifiable through a variety of interventions. In this review we provide an overview of the development of the gut microbiome and its compositional and functional changes in relation to cardio-metabolic disorders, and give an update on recent progress in how this could be exploited in microbiota-based therapeutics. PMID- 25825596 TI - Radionuclide imaging of neurohormonal system of the heart. AB - Heart failure is one of the growing causes of death especially in developed countries due to longer life expectancy. Although many pharmacological and instrumental therapeutic approaches have been introduced for prevention and treatment of heart failure, there are still limitations and challenges. Nuclear cardiology has experienced rapid growth in the last few decades, in particular the application of single photon emission computed tomography (SPECT) and positron emission tomography (PET), which allow non-invasive functional assessment of cardiac condition including neurohormonal systems involved in heart failure; its application has dramatically improved the capacity for fundamental research and clinical diagnosis. In this article, we review the current status of applying radionuclide technology in non-invasive imaging of neurohormonal system in the heart, especially focusing on the tracers that are currently available. A short discussion about disadvantages and perspectives is also included. PMID- 25825598 TI - Zwitterionic poly(carboxybetaine)-based cationic liposomes for effective delivery of small interfering RNA therapeutics without accelerated blood clearance phenomenon. AB - For efficient delivery of small interfering RNA (siRNA) to the target diseased site in vivo, it is important to design suitable vehicles to control the blood circulation of siRNA. It has been shown that surface modification of cationic liposome/siRNA complexes (lipoplexes) with polyethylene glycol (PEG) could enhance the circulation time of lipoplexes. However, the first injection of PEGylated lipoplexes in vivo induces accelerated blood clearance and enhances hepatic accumulation of the following injected PEGylated lipoplexes, which is known as the accelerated blood clearance (ABC) phenomenon. Herein, we developed zwitterionic poly(carboxybetaine) (PCB) modified lipoplexes for the delivery of siRNA therapeutics, which could avoid protein adsorption and enhance the stability of lipoplexes as that for PEG. Quite different from the PEGylation, the PCBylated lipoplexes could avoid ABC phenomenon, which extended the blood circulation time and enhanced the tumor accumulation of lipoplexes in vivo. After accumulation in tumor site, the PCBylation could promote the cellular uptake and endosomal/lysosomal escape of lipoplexes due to its unique chemical structure and pH-sensitive ability. With excellent tumor accumulation, cellular uptake and endosomal/lysosomal escape abilities, the PCBylated lipoplexes significantly inhibited tumor growth and induced tumor cell apoptosis. PMID- 25825597 TI - Molecular imaging of apoptosis: from micro to macro. AB - Apoptosis, or programmed cell death, is involved in numerous human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer, and is often confused with other types of cell death. Therefore strategies that enable visualized detection of apoptosis would be of enormous benefit in the clinic for diagnosis, patient management, and development of new therapies. In recent years, improved understanding of the apoptotic machinery and progress in imaging modalities have provided opportunities for researchers to formulate microscopic and macroscopic imaging strategies based on well-defined molecular markers and/or physiological features. Correspondingly, a large collection of apoptosis imaging probes and approaches have been documented in preclinical and clinical studies. In this review, we mainly discuss microscopic imaging assays and macroscopic imaging probes, ranging in complexity from simple attachments of reporter moieties to proteins that interact with apoptotic biomarkers, to rationally designed probes that target biochemical changes. Their clinical translation will also be our focus. PMID- 25825599 TI - Molecular imaging of tumor-infiltrating macrophages in a preclinical mouse model of breast cancer. AB - Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206) targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors. PMID- 25825600 TI - Charge and hydrophobicity effects of NIR fluorophores on bone-specific imaging. AB - Recent advances in near-infrared (NIR) fluorescence imaging enabled real-time intraoperative detection of bone metastases, bone growth, and tissue microcalcification. Pamidronate (PAM) has been widely used for this purpose because of its high binding affinity toward bone and remarkable therapeutic effects. Herein we describe the development of a series of PAM-conjugated NIR fluorophores that varied in net charges and hydrophobicity, and compared their bone targeting efficiency, biodistribution, and blood clearance. Since the targeting moiety, PAM, is highly negatively charged but small, the overall in vivo bone targeting and biodistribution were mediated by the physicochemical properties of conjugated fluorophores. PMID- 25825601 TI - Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging. AB - Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [(68)Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [(68)Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [(68)Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [(68)Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders. PMID- 25825602 TI - Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells. AB - Increasing cell survival in stem cell therapy is an important challenge for the field of regenerative medicine. Here, we report theranostic mesoporous silica nanoparticles that can increase cell survival through both diagnostic and therapeutic approaches. First, the nanoparticle offers ultrasound and MRI signal to guide implantation into the peri-infarct zone and away from the most necrotic tissue. Second, the nanoparticle serves as a slow release reservoir of insulin like growth factor (IGF)-a protein shown to increase cell survival. Mesenchymal stem cells labeled with these nanoparticles had detection limits near 9000 cells with no cytotoxicity at the 250 ug/mL concentration required for labeling. We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks. The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions. PMID- 25825603 TI - 3D porous calcium-alginate scaffolds cell culture system improved human osteoblast cell clusters for cell therapy. AB - Age-related orthopedic disorders and bone defects have become a critical public health issue, and cell-based therapy is potentially a novel solution for issues surrounding bone tissue engineering and regenerative medicine. Long-term cultures of primary bone cells exhibit phenotypic and functional degeneration; therefore, culturing cells or tissues suitable for clinical use remain a challenge. A platform consisting of human osteoblasts (hOBs), calcium-alginate (Ca-Alginate) scaffolds, and a self-made bioreactor system was established for autologous transplantation of human osteoblast cell clusters. The Ca-Alginate scaffold facilitated the growth and differentiation of human bone cell clusters, and the functionally-closed process bioreactor system supplied the soluble nutrients and osteogenic signals required to maintain the cell viability. This system preserved the proliferative ability of cells and cell viability and up-regulated bone related gene expression and biological apatite crystals formation. The bone-like tissue generated could be extracted by removal of calcium ions via ethylenediaminetetraacetic acid (EDTA) chelation, and exhibited a size suitable for injection. The described strategy could be used in therapeutic application and opens new avenues for surgical interventions to correct skeletal defects. PMID- 25825605 TI - Capacity assessment, successful aging and geriatric humanities. PMID- 25825606 TI - A Long-Term Care-Comprehensive Geriatric Assessment (LTC-CGA) Tool: Improving Care for Frail Older Adults? AB - BACKGROUND: Most older adults living in long-term care facilities (LTCF) are frail and have complex care needs. Holistic understanding of residents' health status is key to providing good care. Comprehensive Geriatric Assessment (CGA) is a valid assessment method which aims to embrace complexity. Here we aimed to study a CGA that has been modified for use in long-term care (the LTC-CGA) and to investigate its acceptability and usefulness to stakeholders and users. METHODS: This mixed methods study, conducted in 10 LTCFs in Halifax, Nova Scotia, reviewed 598 resident charts from pre- and post-implementation of the LTC-CGA. Qualitative methods explored stakeholder perspectives (physicians, nurses, paramedics, administrators, residents and families) though focus groups. RESULTS: The LTC-CGA was present in 78% of LTCF charts in the post -implementation, period though it did not appear in acute care charts of transferred residents, despite the intention that it accompany residents between care sites. Some items had suboptimal completion rates (e.g., Advance Directives at 56.4%), though these were located in other sections of the LTCF chart (98.2%). Nevertheless, qualitative findings suggest the LTC-CGA describes a clinical baseline health status which enabled timely and informed clinical decision-making. CONCLUSIONS: The LTC-CGA is a useful resource whose full capacity may not yet have been realized. PMID- 25825604 TI - Update on intravitreal anti-tumor necrosis factor alpha therapies for ocular disorders. AB - Tumor necrosis factor alpha (TNF-?) is an important pro-inflammatory cytokine associated with a variety of ocular diseases. The currently available TNF-? inhibitors are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Experimental and clinical studies on the intravitreal use of these agents have been reported with etanercept, infliximab, and adalimumab: etanercept has shown limited efficacy in scarce reports; infliximab has been associated with local safety concerns but appears to benefit certain cases; adalimumab has shown no efficacy in cases of age-related macular degeneration (AMD) or diabetic macular edema (DME), but the combination with bevacizumab may be effective in refractory cases of macular diseases. Further preclinical and clinical studies are warranted in order to be able to obtain a more robust conclusion on the use of intravitreal TNF-? inhibitors. PMID- 25825607 TI - Prevalence and distribution of oral mucosal lesions in a geriatric Indian population. AB - BACKGROUND: Oral health is important to individuals of all age groups. Previous epidemiologic studies of the oral health status of the general population in India provided very little information about oral mucosal lesions in the elderly. Hence, the purpose of the present study was to determine the prevalence of the oral lesions in a geriatric Indian population. METHODS: 5,100 patients were clinically evaluated, with age ranging from 60 to 98 years. There were 3,100 males and 2,000 females, with a mean age of 69 +/- 6.3 yrs. The statistical analysis was done using the SPSS software, where p < .05 was considered to be significant. RESULTS: 64% of the patients presented with one or more oral lesions, associated to tobacco, betel nut consumption, and lesions secondary to trauma and prosthesis. Males were more affected than females and this difference was clinically not significant (p > .05). The lesions were more frequently observed between 65 to 70 yrs. The most common alterations observed were smoker's palate (43%), denture stomatitis (34%), oral submucous fibrosis (30%), frictional keratosis (23%), leukoplakia (22%), and pyogenic granuloma (22%). Hard palate was the most commonly affected site (23.1%). CONCLUSIONS: The findings of the present study provide important information when clinically evaluating oral cavity in elderly. Close follow-up and systematic evaluation is required in the elderly population to plan future treatment needs. PMID- 25825608 TI - The development and implementation of a decision-making capacity assessment model. AB - BACKGROUND: Decision-making capacity assessment (DMCA) is an issue of increasing importance for older adults. Current challenges need to be explored, and potential processes and strategies considered in order to address issues of DMCA in a more coordinated manner. METHODS: An iterative process was used to address issues related to DMCA. This began with recognition of challenges associated with capacity assessments (CAs) by staff at Covenant Health (CH). Review of the literature, as well as discussions with and a survey of staff at three CH sites, resulted in determination of issues related to DMCA. Development of a DMCA Model and demonstration of its feasibility followed. RESULTS: A process was proposed with front-end screening/problem- solving, a well-defined standard assessment, and definition of team member roles. A Capacity Assessment Care Map was formulated based on the process. Documentation was developed consisting of a Capacity Assessment Process Worksheet, Capacity Interview Worksheet, and a brochure. Interactive workshops were delivered to familiarize staff with the DMCA Model. A successful demonstration project led to implementation across all sites in the Capital Health region, and eventual provincial endorsement. CONCLUSIONS: Concerns identified in the survey and in the literature regarding CA were addressed through the holistic interdisciplinary approach offered by the DMCA Model. PMID- 25825609 TI - A practical approach to osteoporosis management in the geriatric population. AB - Osteoporosis is a medical condition that is seen commonly in elderly patients, and it is associated with a large burden of morbidity and mortality. This article provides a practical approach to the workup and management of osteoporosis in patients 65 years or older. PMID- 25825610 TI - Successful aging and frailty: mutually exclusive paradigms or two ends of a shared continuum? AB - The conceptualization of positive and negative states of aging is contentious at the inter- and intraparadigm level; lack of consensus exists within and between states. Working within their respective paradigms, successful aging and frailty researchers may have lost sight of the larger picture. Are successful aging researchers describing nonfrail individuals? Are frailty researchers describing unsuccessful aging? It is imperative that researchers are cognizant of the ways in which their perspectives are contextualized within the literature and within related paradigms, so as to be able to clearly communicate their research and to ensure they are working within the appropriate paradigm to facilitate desired outcomes. Here we discuss the similarities and differences between successful aging and frailty in terms of the scope and emphasis of their constituent components and functioning: both SA and frailty include biomedical components; SA examines the high end, whilst frailty predominately examines the low end of the functioning spectrum. Frailty models emphasize the biomedical realm, whilst SA models emphasize both the biomedical and the psychosocial. PMID- 25825611 TI - Humanities and geriatric education: a strategy for recruitment? AB - Ageing is a common subject in arts and literature as it is a universal experience. The use of the humanities in medical education may have a positive effect on trainees' attitude to caring for seniors and on geriatrics as a career choice. This paper summarizes the role of humanities in medical education and provides some examples and thoughts on how humanities curriculum can be used in geriatric teaching. PMID- 25825612 TI - Programmable and on-demand drug release using electrical stimulation. AB - Recent advancement in microfabrication has enabled the implementation of implantable drug delivery devices with precise drug administration and fast release rates at specific locations. This article presents a membrane-based drug delivery device, which can be electrically stimulated to release drugs on demand with a fast release rate. Hydrogels with ionic model drugs are sealed in a cylindrical reservoir with a separation membrane. Electrokinetic forces are then utilized to drive ionic drug molecules from the hydrogels into surrounding bulk solutions. The drug release profiles of a model drug show that release rates from the device can be electrically controlled by adjusting the stimulated voltage. When a square voltage wave is applied, the device can be quickly switched between on and off to achieve pulsatile release. The drug dose released is then determined by the duration and amplitude of the applied voltages. In addition, successive on/off cycles can be programmed in the voltage waveforms to generate consistent and repeatable drug release pulses for on-demand drug delivery. PMID- 25825613 TI - Multiple enzyme-doped thread-based microfluidic system for blood urea nitrogen and glucose detection in human whole blood. AB - This research presents a multiple enzyme-doped thread-based microfluidic system for blood urea nitrogen (BUN) and glucose detection in human whole blood. A novel enzyme-doped thread coated with a thin polyvinylchloride (PVC) membrane is produced for on-site electrochemical detection of urea and glucose in whole blood. Multiple enzymes can be directly applied to the thread without delicate pretreatment or a surface modification process prior to sealing the thread with PVC membrane. Results indicate that the developed device exhibits a good linear dynamic range for detecting urea and glucose in concentrations from 0.1 mM-10.0 mM (R(2 )= 0.9850) and 0.1 mM-13.0 mM (R(2 )= 0.9668), which is suitable for adoption in detecting the concentrations of blood urea nitrogen (BUN, 1.78-7.12 mM) and glucose (3.89-6.11 mM) in serum. The detection result also shows that the developed thread-based microfluidic system can successfully separate and detect the ions, BUN, and glucose in blood. The calculated concentrations of BUN and glucose ante cibum (glucose before meal) in the whole blood sample are 3.98 mM and 4.94 mM, respectively. The developed thread-based microfluidic system provides a simple yet high performance for clinical diagnostics. PMID- 25825614 TI - Improving the dielectric properties of an electrowetting-on-dielectric microfluidic device with a low-pressure chemical vapor deposited Si3N4 dielectric layer. AB - Dielectric breakdown is a common problem in a digital microfluidic system, which limits its application in chemical or biomedical applications. We propose a new fabrication of an electrowetting-on-dielectric (EWOD) device using Si3N4 deposited by low-pressure chemical vapor deposition (LPCVD) as a dielectric layer. This material exhibits a greater relative permittivity, purity, uniformity, and biocompatibility than polymeric films. These properties also increase the breakdown voltage of a dielectric layer and increase the stability of an EWOD system when applied in biomedical research. Medium droplets with mouse embryos were manipulated in this manner. The electrical properties of the Si3N4 dielectric layer-breakdown voltage, refractive index, relative permittivity, and variation of contact angle with input voltage-were investigated and compared with a traditional Si3N4 dielectric layer deposited as a plasma-enhanced chemical vapor deposition to confirm the potential of LPCVD Si3N4 applied as the dielectric layer of an EWOD digital microfluidic system. PMID- 25825615 TI - Embryo formation from low sperm concentration by using dielectrophoretic force. AB - A biochip system imitates the oviduct of mammals with a microfluidic channel to achieve fertilization in vitro of imprinting-control-region (ICR) mice. We apply a method to manipulate and to position the oocyte and the sperm of ICR mice at the same time in our microfluidic channel with a positive dielectrophoretic (DEP) force. The positive dielectrophoretic response of the oocyte and sperm was exhibited under applied bias conditions AC 10 Vpp waveform, 1 MHz, 10 min. With this method, the concentration of sperm in the vicinity of the oocyte was increased and enhanced the probability of natural fertilization. We used commercial numerical software (CFDRC-ACE+) to simulate the square of the electric field and analyzed the location at which the oocyte and sperm are trapped. The microfluidic devices were designed and fabricated with poly(dimethylsiloxane). The results of our experiments indicate that a positive DEP served to drive the position of the oocyte and the sperm to natural fertilization (average rate of fertilization 51.58%) in our microchannel structures at insemination concentration 1.5 * 10(6) sperm ml(-1). Embryos were cultured to two cells after 24 h and four cells after 48 h. PMID- 25825616 TI - Microfluidic generation of PEG-b-PLA polymersomes containing alginate-based core hydrogel. AB - Herein, we demonstrate a novel method for the generation of monodisperse cell like structures containing a biocompatible hydrogel matrix surrounded by a membrane responsive to chemical cues. Specifically, we employ droplet-based microfluidics to generate PEG-PLA polymersomes encapsulating alginate in liquid form. We investigate alginate core gelation by creating an osmotic pressure gradient across the polymeric membrane that, through expansion, allows the passage of calcium ions. The effects of calcium concentration on the core gelation are explored. PMID- 25825617 TI - An automated microfluidic system for single-stranded DNA preparation and magnetic bead-based microarray analysis. AB - We present an integrated microfluidic device capable of performing single stranded DNA (ssDNA) preparation and magnetic bead-based microarray analysis with a white-light detection for detecting mutations that account for hereditary hearing loss. The entire operation process, which includes loading of streptavidin-coated magnetic beads (MBs) and biotin-labeled polymerase chain reaction products, active dispersion of the MBs with DNA for binding, alkaline denaturation of DNA, dynamic hybridization of the bead-labeled ssDNA to a tag array, and white-light detection, can all be automatically accomplished in a single chamber of the microchip, which was operated on a self-contained instrument with all the necessary components for thermal control, fluidic control, and detection. Two novel mixing valves with embedded polydimethylsiloxane membranes, which can alternately generate a 3-MUl pulse flow at a peak rate of around 160 mm/s, were integrated into the chip for thoroughly dispersing magnetic beads in 2 min. The binding efficiency of biotinylated oligonucleotides to beads was measured to be 80.6% of that obtained in a tube with the conventional method. To critically test the performance of this automated microsystem, we employed a commercial microarray-based detection kit for detecting nine mutation loci that account for hereditary hearing loss. The limit of detection of the microsystem was determined as 2.5 ng of input K562 standard genomic DNA using this kit. In addition, four blood samples obtained from persons with mutations were all correctly typed by our system in less than 45 min per run. The fully automated, "amplicon-in-answer-out" operation, together with the white-light detection, makes our system an excellent platform for low cost, rapid genotyping in clinical diagnosis. PMID- 25825618 TI - Streamline based design guideline for deterministic microfluidic hydrodynamic single cell traps. AB - A prerequisite for single cell study is the capture and isolation of individual cells. In microfluidic devices, cell capture is often achieved by means of trapping. While many microfluidic trapping techniques exist, hydrodynamic methods are particularly attractive due to their simplicity and scalability. However, current design guidelines for single cell hydrodynamic traps predominantly rely on flow resistance manipulation or qualitative streamline analysis without considering the target particle size. This lack of quantitative design criteria from first principles often leads to non-optimal probabilistic trapping. In this work, we describe an analytical design guideline for deterministic single cell hydrodynamic trapping through the optimization of streamline distributions under laminar flow with cell size as a key parameter. Using this guideline, we demonstrate an example design which can achieve 100% capture efficiency for a given particle size. Finite element modelling was used to determine the design parameters necessary for optimal trapping. The simulation results were subsequently confirmed with on-chip microbead and white blood cell trapping experiments. PMID- 25825619 TI - Structural design of a double-layered porous hydrogel for effective mass transport. AB - Mass transport in porous materials is universal in nature, and its worth attracts great attention in many engineering applications. Plant leaves, which work as natural hydraulic pumps for water uptake, have evolved to have the morphological structure for fast water transport to compensate large water loss by leaf transpiration. In this study, we tried to deduce the advantageous structural features of plant leaves for practical applications. Inspired by the tissue organization of the hydraulic pathways in plant leaves, analogous double-layered porous models were fabricated using agarose hydrogel. Solute transport through the hydrogel models with different thickness ratios of the two layers was experimentally observed. In addition, numerical simulation and theoretical analysis were carried out with varying porosity and thickness ratio to investigate the effect of structural factors on mass transport ability. A simple parametric study was also conducted to examine unveiled relations between structural factors. As a result, the porosity and thickness ratio of the two layers are found to govern the mass transport ability in double-layered porous materials. The hydrogel models with widely dispersed pores at a fixed porosity, i.e., close to a homogeneously porous structure, are mostly turned out to exhibit fast mass transport. The present results would provide a new framework for fundamental design of various porous structures for effective mass transport. PMID- 25825620 TI - Comparative toxicity of lead (Pb(2+)), copper (Cu(2+)), and mixtures of lead and copper to zebrafish embryos on a microfluidic chip. AB - Investigations were conducted to determine acute effects of Pb(2+) and Cu(2+) presented individually and collectively on zebrafish embryos. Aquatic safety testing requires a cheap, fast, and highly efficient platform for real-time evaluation of single and mixture of metal toxicity. In this study, we have developed a microfluidic system for phenotype-based evaluation of toxic effects of Pb(2+) and Cu(2+) using zebrafish (Danio rerio) embryos. The microfluidic chip is composed of a disc-shaped concentration gradient generator and 24 culture chambers, which can generate one blank solution, seven mixture concentrations, and eight single concentrations for each metal solution, thus enabling the assessment of zebrafish embryos. To test the accuracy of this new chip platform, we have examined the toxicity and teratogenicity of Pb(2+) and Cu(2+) on embryos. The individual and combined impact of Pb(2+) and Cu(2+) on zebrafish embryonic development was quantitatively assessed by recording a series of physiological indicators, such as spontaneous motion at 22 hours post fertilization (hpf), mortality at 24 hpf, heartbeat and body length at 96 hpf, etc. It was found that Pb(2+) or Cu(2+) could induce deformity and cardiovascular toxicity in zebrafish embryos and the mixture could induce more severe toxicity. This chip is a multiplexed testing apparatus that allows for the examination of toxicity and teratogenicity for substances and it also can be used as a potentially cost effective and rapid aquatic safety assessment tool. PMID- 25825621 TI - Dynamic radial positioning of a hydrodynamically focused particle stream enabled by a three-dimensional microfluidic nozzle. AB - The ability to confine flows and focus particle streams has become an integral component of the design of microfluidic systems for the analysis of a wide range of samples. Presented here is the implementation of a 3D microfluidic nozzle capable of both focusing particles as well as dynamically positioning those particles in selected flow lamina within the downstream analysis channel. Through the independent adjustment of the three sheath inlet flows, the nozzle controlled the size of a focused stream for 6, 10, and 15 MUm polystyrene microparticles. Additional flow adjustment allowed the nozzle to dynamically position the focused particle stream to a specific area within the downstream channel. This unique ability provides additional capability and sample flexibility to the system. In order to gain insight into the fluidic behavior of the system, experimental conditions and results were duplicated within 4.75 MUm using a COMSOL Multiphysics((r)) model to elucidate the structure, direction, proportion, and fate of fluid lamina throughout the nozzle region. The COMSOL Multiphysics model showed that the position and distribution of particles upon entering the nozzle have negligible influence over its focusing ability, extending the experimental results into a wider range of particle sizes and system flow rates. These results are promising for the application of this design to allow for a relatively simple, fast, fully fluidically controlled nozzle for selective particle focusing and positioning for further particle analysis and sorting. PMID- 25825622 TI - A numerical study on the dynamics of droplet formation in a microfluidic double T junction. AB - In this study, droplet formations in microfluidic double T-junctions (MFDTD) are investigated based on a two-dimensional numerical model with volume of fluid method. Parametric ranges for generating alternating droplet formation (ADF) are identified. A physical background responsible for the ADF is suggested by analyzing the dynamical stability of flow system. Since the phase discrepancy between dispersed flows is mainly caused by non-symmetrical breaking of merging droplet, merging regime becomes the alternating regime at appropriate conditions. In addition, the effects of channel geometries on droplet formation are studied in terms of relative channel width. The predicted results show that the ADF region is shifted toward lower capillary numbers when channel width ratio is less than unity. The alternating droplet size increases with the increase of channel width ratio. When this ratio reaches unity, alternating droplets can be formed at very high water fraction (wf = 0.8). The droplet formation in MFDTD depends significantly on the viscosity ratio, and the droplet size in ADF decreases with the increase of the viscosity ratio. The understanding of underlying physics of the ADF phenomenon is useful for many applications, including nanoparticle synthesis with different concentrations, hydrogel bead generation, and cell transplantation in biomedical therapy. PMID- 25825623 TI - Sustained release of hydrophobic drugs by the microfluidic assembly of multistage microgel/poly (lactic-co-glycolic acid) nanoparticle composites. AB - The poor solubility of many newly discovered drugs has resulted in numerous challenges for the time-controlled release of therapeutics. In this study, an advanced drug delivery platform to encapsulate and deliver hydrophobic drugs, consisting of poly (lactic-co-glycolic acid) (PLGA) nanoparticles incorporated within poly (ethylene glycol) (PEG) microgels, was developed. PLGA nanoparticles were used as the hydrophobic drug carrier, while the PEG matrix functioned to slow down the drug release. Encapsulation of the hydrophobic agents was characterized by fluorescence detection of the hydrophobic dye Nile Red within the microgels. In addition, the microcomposites prepared via the droplet-based microfluidic technology showed size tunability and a monodisperse size distribution, along with improved release kinetics of the loaded cargo compared with bare PLGA nanoparticles. This composite system has potential as a universal delivery platform for a variety of hydrophobic molecules. PMID- 25825624 TI - Evaporation-based microfluidic production of oil-free cell-containing hydrogel particles. AB - We demonstrate an evaporation-based microfluidic strategy to produce oil-free cell containing hydrogel particles. Perfluoro-n-pentane, which is used as the continuous oil phase to generate cell-containing hydrogel (Extracel) particles, is removed at an elevated temperature. Human colon cancer cells (HCT116) encapsulated in the hydrogel particles show higher viability than cells encapsulated in particles that are produced via a non-evaporative oil phase. In addition, single HCT116 cells can be cultured for a week in such particles and respond to inflammatory stimuli, highlighting the potential applications of the developed strategy for 3D cell culture, drug testing, and cell-based drug delivery. PMID- 25825625 TI - Study Protocol: Validation and Adaptation of community-worker-administered stroke symptom questionnaire in a periurban Pakistani community to determine disease burden. AB - BACKGROUND: Stroke is the second leading cause of mortality and the leading cause of disability in the world today. The disease burden is on the rise in developing nations, but there is scarcity of data from these regions to inform policy decisions. Stroke burden can be determined by clinical diagnosis alone in the public health context and is a far more feasible way to assess disease status in low- to middle-income countries like Pakistan. We aim to translate and adapt a validated stroke symptom questionnaire, train community health workers in its administration, and verify it against assessment by two trained neurologists. METHODS/DESIGN: This is a prospective study, which we aim to carry out in Ibrahim Hyderi, a periurban slum of Karachi. We translated into Urdu the questionnaire for verifying stroke free status (QVSFS), which is an internationally validated tool to assess the same. Two community health workers (CHW) will be identified and will receive training by neurologists, which will include teaching regarding stroke pathophysiology, symptomatology, and detection. They will be familiarized with the QVSFS, and their questionnaire administration will be assessed through roleplay. We intend to recruit 322 subjects from the same community and the CHWs will gather data on them. The same subjects will later be assessed by two trained neurologists, and the findings collaborated to validate those obtained by the CHWs. Sensitivity, specificity, positive and negative predictive values, and Cohen's kappa will be determined for the CHW-administered questionnaire tested against assessment by two neurologists together and separately for the two CHWs. Data analysis will be done using SPSS version 19.0. DISCUSSION: The results of this study will determine if and how well CHW-administered questionnaires are at assessing stroke status in a community. This will facilitate use of the same as a practical alternative for stroke surveillance in the country. TRIAL REGISTRATION: NCT02073955. PMID- 25825626 TI - Large-vessel stenosis in the patients with ischemic stroke in Iran: Prevalence, pattern, and risk factors. AB - BACKGROUND: Large artery disease (LAD) is a common cause of stroke, but a little is known regarding its role in Iranian stroke patients. The current study investigates the prevalence and risk factors for cervicocephalic arterial stenosis in the patients with ischemic stroke using digital subtraction angiography (DSA). METHODS: This was a prospective cross-sectional study performed in hospitals affiliated to Shiraz University of Medical Sciences from March 2011 to March 2013. Patients with ischemic stroke underwent noninvasive vascular and cardiac investigations to find the etiology of the stroke. Patients suspected of having large artery stenosis underwent DSA. The severity of the stenosis was calculated according to the North American Symptomatic Carotid Endarterectomy (NASCET) and Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Trial criteria. The presence of cigarette smoking, hyperlipidemia, hypertension, and diabetes mellitus were documented for all subjects. RESULTS: A total of 3703 stroke patients were identified. Of them, 342 patients (62.3%, male) underwent DSA for LAD. The mean age at the time of angiography was 66.7+/ 10.3 years. Extracranial and intracranial arteries were involved in 305 (89.2%) and 162 (47.4%), respectively. And 301 patients (88%) had anterior circulation and 128 patients (37.4%) had posterior circulation involvement. Diabetes mellitus but not age, sex, hypertension, hyperlipidemia, or smoking was significantly associated with intracranial involvement. (P = 0.002). CONCLUSION: It can be concluded that the distribution of the large arterial atherosclerotic disease in Iran is similar to that seen in North America and Europe. Intracranial stenosis was more prevalent in diabetic patients. PMID- 25825627 TI - Stroke Mimic Secondary to IV Fentanyl Administration. AB - Fentanyl is a potent opioid used commonly in acute care because of its rapid onset and short duration of action. It has fewer side effects when compared with commonly available opioids, such as morphine and hydromorphine. We report an unusual side effect of transient aphasia following fentanyl administration. A 61 year-old female presented for an elective embolization of a periophthalmic artery aneurysm. She developed immediate episodes of aphasia on two separate occasions following administration of intravenous (IV) fentanyl. The high lipid solubility explains the rapid onset of action of fentanyl as it rapidly passes through the blood-brain barrier and through cell membranes. Immediately following the administration of fentanyl, the patient developed aphasia. There were no other clinical or neurological imaging findings that could account for these symptoms. We believe that aphasia may be an unusual side effect of fentanyl, and it is something clinicians should be aware of. PMID- 25825628 TI - Antithrombotic Utilization Trends after Noncardioembolic Ischemic Stroke or TIA in the Setting of Large Antithrombotic Trials (2002-2009). AB - BACKGROUND AND PURPOSE: Several large trials published over the last decade have significantly altered recommended guidelines for therapy following a noncardioembolic ischemic stroke or transient ischemic attack (TIA). The impact of these studies on patient usage of alternative antithrombotic agents has hitherto not been evaluated. We examined the usage of these agents in the United States over the last decade, with regard to the publication of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH), European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT), and Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) clinical trials, in order to test the hypothesis that resulting recommendations are reflected in usage trends. METHODS: Antithrombotic utilization was prospectively collected as part of the National Ambulatory Medical Care Survey (NAMCS) on a total of 53,608,351 patients in the United States between 2002 and 2009. Patients with a history of ischemic stroke or TIA were included. Patients were excluded if there was a prior history of subarachnoid or intracerebral hemorrhage, or if other indications for antithrombotic treatment were present, including deep venous thrombosis, pulmonary embolism, atrial fibrillation or flutter, mechanical cardiac valve replacement, congestive heart failure, coronary artery disease, peripheral arterial disease, and rheumatoid arthritis. Annual utilization of the following antithrombotic strategies was compared in 53,608,351 patients: 1) aspirin monotherapy, 2) clopidogrel monotherapy, 3) combined clopidogrel and aspirin, 4) combined extended-release dipyridamole (ERDP) and aspirin, and 5) warfarin. Annual utilization was compared before and after publication of MATCH, ESPRIT, and PRoFESS in 2004, 2006, and 2008, respectively. Trend analysis was performed with the Mantel-Haenszel test for trends. Sensitivity analysis of demographic and clinical characteristics stratified by antithrombotic-usage group was performed using the Wald Chi-square test. RESULTS: Utilization of combined clopidogrel and aspirin increased from 3.3% to 6.7% after the MATCH trial (p<0.0001). Following the results of the ESPRIT trial, utilization of combination ERDP and aspirin decreased from 4% to 3% (p<0.0001), utilization of clopidogrel declined from 6.8% to 6% (p<0.0001), and utilization of aspirin remained essentially unchanged. After the PRoFESS trial, utilization of clopidogrel increased from 5% to 9% (p<0.0001), utilization of ERDP-aspirin increased from 3 % to 4.6% (p<0.0001), and utilization of aspirin increased from 15.6% to 17.8% (p<0.0001). The proportion of patients on none of the five antithrombotic secondary prevention strategies steadily declined from a peak of 74% in 2003 to 57% by 2009. CONCLUSIONS: The impact of the MATCH, ESPRIT, and PRoFESS trials on antithrombotic utilization has been variable. These findings highlight the importance of addressing factors that affect the implementation of findings from major clinical trials. PMID- 25825630 TI - Marijuana induced Reversible Cerebral Vasoconstriction Syndrome. PMID- 25825629 TI - Study protocol: asymptomatic intracranial atherosclerotic disease in pakistanis. AB - BACKGROUND: Intracranial atherosclerotic disease (ICAD) is the most frequent subtype of ischemic stroke globally. It is important to describe the determinants of early ICAD as a strategy to prevent strokes from clinically evident and progressive ICAD. Our objective is to report the determinants of asymptomatic ICAD by linking the presence or absence of ICAD on magnetic resonance angiogram (MRA) with detailed risk assessment in asymptomatic adults. METHODS: This is an observational cross-sectional analytical study. We plan to recruit 200 adult participants from the radiology departments of two tertiary care centers of Karachi, Pakistan. The participants will first be screened for the absence of stroke symptoms via the Questionnaire for Verifying Stroke Free Status (QVSFS). QVSFS negative will be participants will be eligible. After written informed consent, participants will undergo detailed medical, sociodemographic, lifestyle, and anthropometric evaluation by a detailed interview. They will, in addition, undergo MRA to study the presence, degree, and distribution of asymptomatic ICAD. All MRA scans will be reviewed centrally by vascular neurologists blinded to clinical information. These images would be reviewed on DICOM Viewer 3.0 used for calculating the degree of stenosis using Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study defined criteria employing electronic calipers. A sample size of 200 will achieve 80% power for detecting a minimum difference of 20% in the prevalence of exposure factors (medical and lifestyle) between asymptomatic ICAD positive and ICAD negative persons. This study will generate regional data on risks for ICAD development and prevention in a high risk susceptible population. Study ID: NCT02072876. PMID- 25825631 TI - Endovascular stroke therapy at nighttime and on weekends-as fast and effective as during normal business hours? AB - INTRODUCTION: There is only limited data on the influence of the admission time (normal business hours versus nighttime and weekends) on procedural timings, revascularization efficacy, and outcome after mechanical thrombectomy. We investigated whether the admission time has an impact on the above-mentioned factors. METHODS: Our neurointerventional database was screened for all mechanical thrombectomies in anterior circulation acute ischemic stroke between 07/13 and 06/14. Outcome measures were procedural timings and clinical and demographic data; we compared patients who were admitted at normal business hours (Monday to Friday 8:00-18:00) to those admitted at night or at the weekend. RESULTS: 98 patients were identified. Of them, 52 (53%) were admitted during normal business hours, the remainder at night or at weekend. There was no statistically significant difference between the groups regarding the time from symptom-onset to admission, baseline National Institutes of Health Stroke Scale (NIHSS) or IVT-rate. There was a significant difference between groups for door to-reperfusion timing, favoring patients admitted during normal business hours (146 versus 165 min, p = 0.02). Door-to-groin-puncture and groin-puncture-to reperfusion time did not differ significantly. The rate of successful revascularizations (mTICI >= 2b) and the rate of favorable clinical outcome at discharge (mRS <= 2) did not differ between groups (77% versus 78% and 37% versus 35%, respectively). CONCLUSIONS: There was a statistically significant prolongation of door-to-reperfusion timings for patients admitted during nighttime and weekends; it went along neither with a lower rate of successful revascularizations nor with a lower rate of favorable outcome in our series. ABBREVIATIONS: AFatrial fibrillationAISacute ischemic strokeCTAcomputed tomography angiographyDMdiabetes mellitusENTembolization to new territoryEVTendovascular therapyHLPhyperlipoproteinemiaHTNhypertensionIQRinter quartile rangeIVTintravenous thrombolysismRSmodified Rankin ScaleMTmechanical thrombectomyNIHSSNational Institutes of Health Stroke Scalen.s.not significantsICHsymptomatic intracranial hemorrhage. PMID- 25825632 TI - Multiple hereditary exostoses and stroke due to vertebral artery dissection. AB - Vascular complications related to multiple hereditary exostoses are uncommon. We present a 39-year-old male patient with multiple exostoses in the upper and lower limbs with an associated positive familial history of such lesions. He experienced a sudden onset of left-side ataxia and hypoesthesia secondary to a left lateral medullary infarction, which was due to a stenotic-pattern vertebral artery dissection (V1-V4). This complication is very rare as a differential diagnosis in the vertebro-basilar dissection spectrum, and a nonspecific relation has been found. ABBREVIATIONS: MHEMultiple hereditary exostosesATangiotomographyVADvertebral artery dissectionCADcervical artery dissectionOIosteogenesis imperfecta. PMID- 25825633 TI - Venous Congestive Myelopathy due to Chronic Inferior Vena Cava Thrombosis Treated with Endovascular Stenting: Case Report and Review of the Literature. AB - OBJECTIVE: Impaired inferior vena cava (IVC) outflow can lead to collateralization of blood to the valveless epidural venous plexus, causing epidural venous engorgement and venous congestion. Herein we describe a case of chronic IVC thrombosis presenting as venous congestive myelopathy treated with angioplasty and endovascular stenting. The pathophysiological mechanisms of cord injury are hypothesized, and IVC stenting application is evaluated. METHODS: Case report and review of the literature. RESULTS: IVC outflow obstruction has only rarely been associated with neurologic dysfunction, with reports of lumbosacral nerve root compression in the cases of IVC agenesis, compression, or occlusion. Although endovascular angioplasty with stenting is emerging as a leading treatment option for chronic IVC thrombosis, its use to treat neurologic complications is limited to one case report for intractable sciatica. Our case is the first description of IVC thrombosis presenting with venous congestive myelopathy, and treated successfully with IVC stenting. CONCLUSION: Venous congestive myelopathy should be seen as a broader clinical condition, including not only typical dural arteriovenous fistulas, but also disorders of venous outflow. Therefore, identifying a rare, but potentially treatable, etiology is important to avoid permanent neurologic deficits. IVC stenting is proposed as a novel and effective treatment approach. PMID- 25825634 TI - Metformin and cancer: Technical and clinical implications for FDG-PET imaging. AB - Metformin is the most widely used hypoglycemic agent. Besides its conventional indications, increasing evidence demonstrate a potential efficacy of this biguanide as an anticancer drug. Possible mechanisms of actions seem to be independent from its hypoglycemic effect and seem to involve the interference with key pathways in cellular proliferation and glycolysis. To date, many clinical trials implying the use of metformin in cancer treatment are on-going. The increasing use of (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in cancer evaluation raises a number of questions about the possible interference of the biguanide on FDG distribution. In particular, the interferences exerted by metformin on AMP-activated protein kinase pathway (the cellular energy sensor), on insulin levels and on Hexokinase could potentially have repercussion on glucose handling and thus on FDG distribution. A better comprehension of the impact of metformin on FDG uptake is needed in order to optimize the use of PET in this setting. This evaluation would be useful to ameliorate scans interpretation in diabetic patients under chronic metformin treatment and to critically interpret images in the context of clinical trials. Furthermore, collecting prospective data in this setting would help to verify whether FDG-PET could be a valid tool to appreciate the anticancer effect of this new therapeutic approach. PMID- 25825635 TI - Transarterial chemoembolization for liver metastases from solid pseudopapillary epithelial neoplasm of pancreas: A case report. AB - Solid pseudo-papillary epithelial neoplasm (SPEN) is a rare epithelial tumor of pancreas with a low malignant potential occurs most commonly in young females. We report a case of 40 years old woman presented with extensive liver metastasis from SPEN of pancreatic body for which she was operated four years ago. Due to the extensive nature of metastatic disease she was offered Transarterial chemoembolisation (TACE) using gemcitabine as chemotherapeutic agent. Short term follow up after a month of TACE with multiphase computed tomography showed > 90% resolution in the viable tumor with significant clinical improvement. TACE ensures targeted delivery of chemotherapeutic drugs in higher doses with least systemic toxicity and is more effective and safe than systemic chemotherapy. TACE with gemcitabine was found to be very effective in our patient with numerous liver metastasis. PMID- 25825636 TI - Gastrointestinal manifestations of Henoch-Schonlein purpura: A report of two cases. AB - Henoch-Schonlein purpura (HSP) is a small vessel vasculitis mediated by type III hypersensitivity with deposition of IgA immune complex in the walls of vessels. It is a multi-system disorder characterized by palpable purpura, arthritis, glomerulonephritis and gastrointestinal manifestations and commonly occurs in children and young adults. The patients with gastrointestinal involvement usually present with colicky abdominal pain, vomiting and melena. The imaging findings include multifocal bowel thickening with mucosal hyperenhancement, presence of skip areas, mesenteric vascular engorgement, with involvement of unusual sites like stomach, duodenum and rectum. These imaging findings in a child or young adult with appropriate clinical findings could suggest HSP. PMID- 25825637 TI - Expression of melanocortin-4 receptor and agouti-related peptide mRNAs in arcuate nucleus during long term malnutrition of female ovariectomized rats. AB - OBJECTIVE: Melanocortin-4 receptor (MC4R) and agouti-related peptide (AgRP) are involved in energy homeostasis in the rat. The aim of the present study was to evaluate the expression of MC4R and AgRP mRNAs in arcuate nucleus (ARC) during long term malnutrition of female ovariectomized rats. MATERIALS AND METHODS: Ten female ovariectomized rats were divided into two equal groups (n=6) of normal and restricted diet groups. Using real-time PCR, the relative expressions (compared to controls) of MC4R and AgRP mRNAs were compared between both diet groups. RESULTS: The relative expression of MC4R and AgRP mRNA in the ARC of female ovariectomized rats during long term malnutrition was higher than those with normal diet (P<0.05). CONCLUSION: Changes in the relative expression level of MC4R and AgRP mRNAs during long term malnutrition of rat indicated a stimulatory role of MC4R and AgRP in regulating energy balance in ARC of rat hypothalamus. PMID- 25825638 TI - Effect of Cyperus rotundus on ischemia-induced brain damage and memory dysfunction in rats. AB - OBJECTIVES: Global cerebral ischemia-reperfusion injury causes loss of pyramidal cells in CA1 region of hippocampus. In this study, we investigated the possible neuroprotective effects of the ethanol extract of Cyperus rotundus (EECR) on a model of global transient ischemia in rat, by evaluating the pathophysiology of the hippocampal tissue and spatial memory. MATERIALS AND METHODS: Treatment group (EECR, 100 mg/kg/day) was gavaged from 4 days before, to 3 days after ischemia. Morris water maze test was performed 1 week after ischemia for 4 days. Brain tissue was prepared for Nissl staining. RESULTS: Our data showed no statistical difference between the treatment and ischemia groups in water maze task. So, treatment of ischemia with EECR cannot improve spatial learning and memory. On the contrary EECR ameliorated the CA1 pyramidal cell loss due to transient global ischemia/reperfusion injury. CONCLUSION: These results suggest that EECR cannot reduce the ischemia-induced, cognitive impairments seen after transient, global cerebral ischemia but can prevent pyramidal cell loss in CA1 region of hippocampus. PMID- 25825639 TI - An in vivo and in vitro investigation on hepatoprotective effects of Pimpinella anisum seed essential oil and extracts against carbon tetrachloride-induced toxicity. AB - OBJECTIVES: Protective effects of different extracts and essential oil from Pimpinella anisum L. seeds were examined against carbon tetrachloride (CCl4) induced toxicity. The parameters such as serum transaminases, lactate dehydrogenase activity, hepatic glutathione content, liver lipid peroxidation and histopathological changes of liver were assessed as toxicity markers. In the in vitro model of this study, markers such as cell viability, cellular reduced and oxidized glutathione and lipid peroxidation in HepG2 cells were evaluated. MATERIALS AND METHODS: Human liver cancer cell line HepG2 and male Sprague-Dawley rats were treated with extracts and essential oil, and markers of hepatotoxicity were investigated. RESULTS: The data revealed that the n-hexane extract, effectively attenuated CCl4-induced toxicity in both in vitro and in vivo models in current investigation. CONCLUSION: As the oxidative stress markers were ameliorated, it might be concluded that anise seed possesses protective effects probably due to its antioxidant constituents. PMID- 25825640 TI - Isolation, Identification and Evaluation of Antimicrobial Activity of Streptomyces flavogriseus, strain ACTK2 from Soil Sample of Kodagu, Karnataka State (India). AB - BACKGROUND: The search for novel antibiotics continues to be of immense importance in research programs around the world for pharmaceutical, industrial and agricultural applications. Filamentous soil bacteria, belonging to the Streptomyces genus, are widely used as an important biological tool for their ability to produce a wide range of novel secondary metabolites, such as "antibiotics". OBJECTIVES: The aim of the present study was to isolate and identify a strain of Streptomyces with high antibiotic production capability. MATERIALS AND METHODS: The soil sample was collected randomly from the agricultural land of Kushalnagar Taluk of Kodagu district, Karnataka, India. The ACTK2 strain was isolated by serial dilution method and identified based on cultural, morphological, microscopic, biochemical and sequence analysis of 16S rRNA gene parameters. The isolated ACTK2 was analyzed for antimicrobial activities by perpendicular streak and disc diffusion methods, against the Gram positive bacteria Staphylococcus aureus (MTCC 96), Bacillus subtilis (MTCC 121), Gram-negative Escherichia. coli (MTCC 729), Enterococcus aerogenes (MTCC 2829) and filamentous fungi (Trichoderma harizianum (MTCC6046), Fusarium proliferatum (MTCC 9375). Further, an antimicrobial metabolite from the ACTK2 strain was extracted by solvent extraction method, using n-butanol. The production of the antimicrobial compound by the ACTK2 strain was optimized by using different nutritional media and cultural conditions. RESULTS: The strain Streptomyces flavogriseus designated as ACTK2 (Accession number KC990785) isolated from the soil sample of Kushalnagar Taluk, Kodagu, Karnataka, India, exhibited a broad spectrum of antimicrobial activity against test microorganisms. The optimum growth and antimicrobial compound production by strain ACTK2 was found to be a maximal pH 8, in the shaker incubator at 28oC, for a period of 10 days. CONCLUSIONS: The crude n-butanol extract of the ACTK2 strain of S. flavogriseus showed a broad spectrum of antimicrobial activities against the test organisms and this opened further research investigations on purification and structural characterization of the active compounds from the crude extract. PMID- 25825641 TI - Antimicrobial Susceptibility and Clonal Relation Between Acinetobacter baumannii Strains at a Tertiary Care Center in Turkey. AB - BACKGROUND: Acinetobacter baumannii is an opportunistic pathogen, related with nosocomial infections such as bacteremia, urinary tract infections, and ventilator-associated pneumonia. Multidrug resistant (MDR) A. baumannii strains are first line causes of infection, especially in patients hospitalized at intensive care units (ICUs). Infection with MDR A. baumannii strains has a longer duration at ICUs and hospitals. There are studies using molecular methods which can differentiate MDR A. baumannii strains at the clonal level. This helps controlling these resistant strains and prevents their epidemy. OBJECTIVES: The aim of our study was to investigate the antimicrobial susceptibility and clonal relationship between the A. baumannii strains isolated from our ICU. MATERIALS AND METHODS: The identification and antimicrobial susceptibility of 33 A. baumannii strains were performed by automatized Vitek version 2.0. The clonal relationship among A. baumannii strains was analyzed using enterobacterial repetitive intergenic consensus (ERIC) polymerase chain reaction (PCR). RESULTS: A total of 33 A. baumannii strains were included in this study. A. baumannii complex strains were classified into seven clusters based on the fingerprint results. Our results revealed that two main clusters were responsible for the prevalence of A. baumannii complex strains at the ICU. CONCLUSIONS: MDR A. baumannii strains cause an increment in morbidity and mortality, particularly in ICUs. The use of molecular epidemiological methods can help us with the detection of the pathogen and preventing from spreading of these resistant strains. PMID- 25825642 TI - Comparison of fecal antigen detection using enzyme linked immunosorbent assay with the auramine phenol staining method for diagnosis of human cryptosporidiosis. AB - BACKGROUND: Fecal antigen detection using the enzyme linked immunosorbent assay (ELISA) and oocyst detection using auramine phenol (AP) staining methods, are told to be more sensitive compared to other conventional methods, for diagnosis of cryptosporidiosis. OBJECTIVES: The aim of the present study was to evaluate the antigen-detection capacity in the stool specimens using ELISA and oocyst detection by AP staining methods, for the diagnosis of human cryptosporidiosis. MATERIALS AND METHODS: A total of 228 fecal samples were collected from residents of rural areas of Hamadan, West of Iran. Each fecal sample was divided into two parts, one kept frozen at -20C for Ag-capture ELISA and the other in 10% formalin for the AP staining method. Cryptosporidium Ag-detection ELISA procedure was performed according to the manual of the manufacturer. The preserved samples concentrated using the formalin-ether concentration technique were stained with AP and then investigated under florescent microscopy. RESULTS: Eight (3.5%) and three (1.3%) out of 228 fecal samples were positive for Cryptosporidium infection by ELISA and AP staining methods, respectively. Cryptosporidium Ag-detection using ELISA showed an increased frequency of the infection, compared to the AP staining method (P = 0.062). CONCLUSIONS: For epidemiological studies and diagnostic purposes of the Cryptosporidium infection, especially in asymptomatic individuals, Ag-detection ELISA is an easy to perform and accurate method, compared to other conventional microscopic methods. PMID- 25825643 TI - Effects of pH and Temperature on Antibacterial Activity of Zinc Oxide Nanofluid Against Escherichia coli O157: H7 and Staphylococcus aureus. AB - BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are known as one of the important inorganic materials used in research and health-related applications with effective antibacterial activities. Although the toxic effects of ZnO NPs have already been evaluated, more information is required to understand the possible mechanisms. OBJECTIVES: The aim of the present study was to determine the influences of pH and temperature on antibacterial activity of ZnO NPs against some strains of pathogenic bacteria. Identifying the interrelationship between toxicity and cultural conditions helps us to have a better understanding of the optimum reaction conditions for maximum antimicrobial activity. MATERIALS AND METHODS: ZnO NPs were prepared and characterized and then dispersed in glycerol with the help of ammonium citrate as the dispersant. The antibacterial tests were performed by measuring the growth of Escherichia coli O157:H7 and Staphylococcus aureus with different concentrations of ZnO NPs in glycerol. All the experiments were conducted at different incubation temperatures (25-42( degrees )C) and pH levels (4-10 for E. coli O157:H7 and 5-10 for S. aureus). RESULTS: The results showed that ZnO nanofluid have antibacterial activity against E. coli O157:H7 and S. aureus and the inhibitory effect increases with increasing the nanofluid concentration. The experiments showed that the antibacterial activity of ZnO NPs was influenced by temperature and pH. Higher antibacterial activity was observed at acidic pH levels with the maximum toxicity at pH = 4 and pH = 5 for E. coli O157: H7 and S. aureus, respectively. By raising the temperature, the toxicity of ZnO nanofluid increased, with the highest antibacterial activity at 42 degrees C for both bacterial types in comparison with positive controls under the same conditions. CONCLUSIONS: Analysis of the results demonstrated that exposure media of ZnO NPs and cultural factors play a role in their cytotoxic effects. It could be attributed to the principal mechanism at different reaction conditions. PMID- 25825644 TI - Correlation Between Hepatitis B G1896A Precore Mutations and HBeAg in Chronic HBV Patients. AB - BACKGROUND: Hepatitis B virus (HBV) infection is an important health concern worldwide, with critical outcomes. Hepatitis B e antigen (HBeAg) negative chronic hepatitis B is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame, which creates a stop codon, causing premature termination of the HBe protein. OBJECTIVES: This study aimed to investigate the G1896A PC mutation and its effect on HBeAg detection in chronic HBV patients. PATIENTS AND METHODS: In this study, 120 chronic HBV patients neither vaccinated or who had benefited from immunoglobulin therapy, were recruited. The HBV-DNA was extracted from plasma and polymerase chain reaction (PCR) was performed. Positive PCR products were subjected to automated sequencing. The HBV serological markers [hepatitis B s antigen (HBsAg), HBeAg] were tested. RESULTS: One hundred out of 120 (83.3%) patients were HBeAg negative and 100% were HBsAg positive. The comparison of nucleotide sequences with the reference sequence (Accession number: AB033559) in HBeAg negative patients showed that there was a high rate of mutations in G1896A (93.18%). CONCLUSIONS: This study indicates that the rate of G1896A mutation at the PC region among HBeAg negative patients, in the Golestan province of Iran, was similar to the average rate encountered in other parts of Iran. The PC stop codon mutation was detected in 93.18% of HBeAg negative patients. Further studies with larger sample sizes are required to elucidate the exact role of these mutations in the clinical course of chronic HBV infection. PMID- 25825645 TI - Co-infection of Mycobacterium tuberculosis and Pneumocystis jirovecii in the Iranian Patients With Human Immunodeficiency Virus. AB - BACKGROUND: Based on the authors' knowledge, there is no study on the co infection of opportunistic agents such as Mycobacterium tuberculosis and Pneumocystis jirovecii in the lungs of Iranian patients with immunosuppression. OBJECTIVES: The current study aimed to show the rate of co-infection of M. tuberculosis and P. jirovecii in patients with Human Immunodeficiency Virus (HIV). PATIENTS AND METHODS: Forty-five pulmonary samples were collected from 30 patients with HIV who also infected with Tuberculosis and Pneumonia. All of the patients were admitted to two university hospitals of Mycobacteriology and the Iranian HIV/AIDS research centers. DNA of P. jirovecii was detected using nested Polymerase Chain Reaction (nested-PCR) assay. RESULTS: All of the patients were male with the mean age of 32.95 +/- 7.15 years. The mean of CD4 cell count was 109.25 cell/mm(3). Of 30 patients with HIV, three (10%) were co-infected with M. tuberculosis and P. jirovecii. No other causes of pneumonia were found in those three patients and CD4 cell counts less than 50 cell/mm(3) was reported. CONCLUSIONS: The results of the current study showed a high rate of co-infection of M. tuberculosis and P. jirovecii in the Iranian patients with HIV. As the immune system condition worsened, the probability of occurrence of Pneumocystis Pneumonia (PCP) increased. Therefore, more specific, most rapid and sensitive tests should be utilized for diagnosis of PCP in this group of patients. PMID- 25825646 TI - Comparison of the Antibacterial Properties of Three Mouthwashes Containing Chlorhexidine Against Oral Microbial Plaques: An in vitro Study. AB - BACKGROUND: The mouth provides an environment that allows the colonization and growth of a wide variety of microorganisms, especially bacteria. One of the most effective ways to reduce oral microorganisms is using mouthwashes. OBJECTIVES: The aim of this study was to investigate the antibacterial effects of chlorhexidine mouthwashes (manufacture by Livar, Behsa, Boht) on common oral microorganisms. MATERIALS AND METHODS: In this in vitro study, isolated colonies of four bacteria, including Streptococcus mutans, S. sanguinis, S. salivarius and Lactobacillus casei, were prepared for an antimicrobial mouth rinse test. The tube dilution method was used for determining the minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC). RESULTS: The MICs for Kin gingival, Behsa and Boht mouthwashes were 0.14, 0.48 and 1000 micrograms/mL using the tube method for S. mutans, respectively. The MBCs for the mentioned mouthwashes were 0.23, 1.9 and 2000 micrograms/mL for S. mutans, respectively. The MICs for Kin gingival, Behsa and Boht mouthwashes were 0.073, 0.48 and 250 micrograms/mL using the tube method for S. sanguinis, respectively. The MBCs for the mentioned mouthwashes were 0.14, 1.9 and 1000 micrograms/mL for S. sanguinis, respectively. CONCLUSIONS: The Kin Gingival chlorhexidine mouthwash has a greater effect than Behsa and Boht mouthwashes on oral microorganisms and is recommended to be used for plaque chemical inhibition. PMID- 25825647 TI - Virulence Genes and Antimicrobial Resistance Pattern in Uropathogenic Escherichia coli Isolated From Hospitalized Patients in Kashan, Iran. AB - BACKGROUND: Urinary tract infection (UTI) is one of the most prevalent infectious diseases. Uropathogenic Escherichia coli (UPEC), as the most important cause of UTI, are associated with a number of virulence factors. OBJECTIVES: The current study aimed to investigate the virulence associated determinants as well as their patterns of antibiotic resistance in UPEC isolated from hospitalized patients with UTI. MATERIALS AND METHODS: A total of 150 E. coli isolates were collected from patients with UTI from December 2012 to June 2013 in Kashan, Iran. Antimicrobial susceptibility screening of 12 antibiotics was determined using disk diffusion method. Polymerase Chain Reaction (PCR) assay was used to detect virulence-related genes in UPEC strains. The purified PCR products were sequenced. RESULTS: Of the total 150 UPEC isolates, 111 (74%) were multidrug resistant. High resistance was observed against ampicillin (81.3%), nalidixic acid (71.3%), cotrimoxazole (64.7%) and ciprofloxacin (61.3%), respectively. Eighty-four out of the 150 isolates showed resistance against the extended spectrum cephalosporins. Totally, virulence genes were detected in 126 (84%) UPEC isolates .The PCR results identified the traT gene in (74%), PAIs markers in (61.3%) and the pap gene in (16.6%) of the isolates. CONCLUSIONS: The traT gene and PAI markers were highly prevalent among UPEC strains isolated from patients in Kashan, Iran; therefore these determinants could be used as targets for prophylactic interventions. Also there was a high level of resistance against the antibiotics commonly used for urinary tract infection treatment. To reach better therapeutic outcomes, treatment regimens have to be modified. PMID- 25825648 TI - The FimH Gene in Uropathogenic Escherichia coli Strains Isolated From Patients With Urinary Tract Infection. AB - BACKGROUND: Urinary tract infections (UTIs) are one of main health problems caused by many microorganisms, including uropathogenic Escherichia coli (UPEC). UPEC strains are the most frequent pathogens responsible for 85% and 50% of community and hospital acquired UTIs, respectively. UPEC strains have special virulence factors, including type 1 fimbriae, which can result in worsening of UTIs. OBJECTIVES: This study was performed to detect type 1 fimbriae (the FimH gene) among UPEC strains by molecular method. MATERIALS AND METHODS: A total of 140 isolated E. coli strains from patients with UTI were identified using biochemical tests and then evaluated for the FimH gene by polymerase chain reaction (PCR) analysis. RESULTS: The UPEC isolates were identified using biochemical tests and were screened by PCR. The fimH gene was amplified using specific primers and showed a band about 164 bp. The FimH gene was found in 130 isolates (92.8%) of the UPEC strains. Of 130 isolates positive for the FimH gene, 62 (47.7%) and 68 (52.3%) belonged to hospitalized patients and outpatients, respectively. CONCLUSIONS: The results of this study indicated that more than 90% of E. coli isolates harbored the FimH gene. The high binding ability of FimH could result in the increased pathogenicity of E. coli; thus, FimH could be used as a possible diagnostic marker and/or vaccine candidate. PMID- 25825649 TI - Effect of Carbon, Nitrogen Sources and Water Activity on Growth and Ochratoxin Production of Aspergillus carbonarius (Bainier) Thom. AB - BACKGROUND: Ochratoxin A (OTA) is a toxic secondary metabolite produced by fungi belonging to Aspergillus and Penicillium genera. The production of OTA is influenced by environmental conditions and nutritional requirements. The postharvest application of bunches of table grape fruit (TGF), with water activity of 0.8 aw, was highly effective for controlling OTA contamination in vitro and in vivo (table grape). OBJECTIVES: The aim of this study was to determine the influence of environmental conditions and nutritional requirements on growth and OTA production by Aspergillus carbonarius, as well as, the impact of water activity on OTA production and growth characters of A. carbonarius. Furthermore, we also examined the influence of the application of different levels of water activity (aw 0.8) on the preservation of the general appearance of TGF and control of their contamination with OTA. MATERIALS AND METHODS: The growth and OTA production by A. carbonarius were studied using glucose-ammonium nitrate salt broth medium. Effect of water activity was studied using glycerol (0.80, 0.85, 0.90, and 0.98 aw). The bunches of table grape fruits were immersed in glycerol solution (equivalent to 0.80 aw) and placed as a double layer in cardboard boxes (25 * 35 * 10 cm). The boxes were stored at 20 degrees C for 15 days to simulate local market conditions. RESULTS: The maximum OTA production by A. carbonarius was observed on broth medium after eight days of incubation at 20 degrees C, with pH 4, and fructose and ammonium nitrate supplementation as carbon and nitrogen sources, respectively. The water activity (0.9, 0.85 aw) caused significant decrease in OTA production by A. carbonarius. The postharvest application of water activity (0.8 aw) was highly effective for maintenance of the table grape quality, which was expressed as weight loss, firmness and decay, while it also controlled OTA contamination of fruits under concept of local market conditions. CONCLUSIONS: Our results reported that deterioration of TGF by A. carbonarius could be minimized by application of aw. Our experiments were performed under conditions of local markets, which support the economy of many thousands of families in Egypt, especially in the poor rural areas. In future adequate research is required to use these technologies commercially. PMID- 25825650 TI - The impact of acute brucellosis on mean platelet volume and red blood cell distribution. AB - BACKGROUND: Brucellosis is an inflammatory disease which may infect any organs or systems in the body. Mean Platelet Volume (MPV) is one of the most frequently used surrogate markers of platelet function. It reveals the presence of disease activity in many inflammatory diseases. Red blood cell distribution width (RDW) is a parameter that measures variation in red blood cell size or red blood cell volume. Its predictive value approves inflammatory and infectious diseases. OBJECTIVES: The current study aimed to determine the assessment levels of red blood cell distribution in cases with acute brucellosis. PATIENTS AND METHODS: The current study investigated whether MPV and RDW played any roles in acute brucellosis diagnosis. The study was conducted from 2008 to 2014 through prospective examination of the inflammatory markers found in adult patients with acute brucellosis. RESULTS: The follow-up within the year after treatment was examined. The values of age, gender, leukocyte count, C-reactive protein, RDW and MPV were recorded. The study included 351 subjects, 250 of them in the acute brucellosis group and 101 in the control group. The mean MPV levels were 7.64 +/- 1.30 fL, and 7.67 +/- 1.29 fL in the acute brucellosis and control groups, respectively (P > 0.05). The mean CRP levels were 32.57 +/- 53.20 mg/dL, and 4.81 +/- 4.89 mg/dL in the acute brucellosis and control groups, respectively (P < 0.05). There was no statistically significant difference between the two groups regarding the RDW level and the mean leukocyte count (P > 0.05). CONCLUSIONS: While the CRP value was in patients with acute brucellosis in the current study, the MPV, RDW and leukocyte counts were within the normal range. CRP value remains the most valuable inflammatory marker in cases of acute brucellosis. PMID- 25825651 TI - Expanding the mammalian phenotype ontology to support automated exchange of high throughput mouse phenotyping data generated by large-scale mouse knockout screens. AB - BACKGROUND: A vast array of data is about to emerge from the large scale high throughput mouse knockout phenotyping projects worldwide. It is critical that this information is captured in a standardized manner, made accessible, and is fully integrated with other phenotype data sets for comprehensive querying and analysis across all phenotype data types. The volume of data generated by the high-throughput phenotyping screens is expected to grow exponentially, thus, automated methods and standards to exchange phenotype data are required. RESULTS: The IMPC (International Mouse Phenotyping Consortium) is using the Mammalian Phenotype (MP) ontology in the automated annotation of phenodeviant data from high throughput phenotyping screens. 287 new term additions with additional hierarchy revisions were made in multiple branches of the MP ontology to accurately describe the results generated by these high throughput screens. CONCLUSIONS: Because these large scale phenotyping data sets will be reported using the MP as the common data standard for annotation and data exchange, automated importation of these data to MGI (Mouse Genome Informatics) and other resources is possible without curatorial effort. Maximum biomedical value of these mutant mice will come from integrating primary high-throughput phenotyping data with secondary, comprehensive phenotypic analyses combined with published phenotype details on these and related mutants at MGI and other resources. PMID- 25825652 TI - Growth hormone secretagogue receptor is important in the development of experimental colitis. AB - BACKGROUND: Growth hormone secretagogue receptor (GHSR) and its ligand, ghrelin, are important modulators in weight control and energy homeostasis. Recently, ghrelin is also involved in experimental colitis, but the role of GHSR in the development of colitis is unclear. The aim was to examine the underlying mechanism of GHSR in IBD development. METHODS: The temporal expression of GHSR/ghrelin was determined in dextran sulphate sodium (DSS) induced colitis in Wt mice. The severity of DSS induced colitis from GHSR(-/-) and WT mice was compared at clinical/pathological levels. Furthermore, the function of macrophages was evaluated in vivo and in vitro. RESULTS: Lack of GHSR attenuated colitis significantly at the clinical and pathological levels with reduced colonic pro-inflammatory cytokines (P < 0.05). This is consistent with the observation of less colonic macrophage infiltration and TLRs expression from DSS treated GHSR(-/-) mice compared to WT mice (P < 0.05). Furthermore, there was significantly reduced pro-inflammatory cytokines in LPS-stimulated macrophages in vitro from GHSR(-/-) mice than WT mice (P < 0.05). Moreover, D-lys(3)-GHRP6 (a GHSR antagonist) reduced LPS-induced macrophage pro-inflammatory cytokines from WT mice in vitro. CONCLUSIONS: GHSR contributes to development of acute DSS induced colitis, likely via elevated pro-inflammatory cytokines and activation of macrophages. These data suggest GHSR as a potential therapeutic target for IBD. PMID- 25825653 TI - Welcome to health information science and systems. AB - Health Information Science and Systems is an exciting, new, multidisciplinary journal that aims to use technologies in computer science to assist in disease diagnoses, treatment, prediction and monitoring through the modeling, design, development, visualization, integration and management of health related information. These computer-science technologies include such as information systems, web technologies, data mining, image processing, user interaction and interface, sensors and wireless networking and are applicable to a wide range of health related information including medical data, biomedical data, bioinformatics data, public health data. PMID- 25825655 TI - A patient-centric distribution architecture for medical image sharing. AB - Over the past decade, rapid development of imaging technologies has resulted in the introduction of improved imaging devices, such as multi-modality scanners that produce combined positron emission tomography-computed tomography (PET-CT) images. The adoption of picture archiving and communication systems (PACS) in hospitals have dramatically improved the ability to digitally share medical image studies via portable storage, mobile devices and the Internet. This has in turn led to increased productivity, greater flexibility, and improved communication between hospital staff, referring physicians, and outpatients. However, many of these sharing and viewing capabilities are limited to proprietary vendor-specific applications. Furthermore, there are still interoperability and deployment issues which reduce the rate of adoption of such technologies, thus leaving many stakeholders, particularly outpatients and referring physicians, with access to only traditional still images with no ability to view or interpret the data in full. In this paper, we present a distribution architecture for medical image display across numerous devices and media, which uses a preprocessor and an in built networking framework to improve compatibility and promote greater accessibility of medical data. Our INVOLVE2 system consists of three main software modules: 1) a preprocessor, which collates and converts imaging studies into a compressed and distributable format; 2) a PACS-compatible workflow for self-managing distribution of medical data, e.g. via CD USB, network etc; 3) support for potential mobile and web-based data access. The focus of this study was on cultivating patient-centric care, by allowing outpatient users to comfortably access and interpret their own data. As such, the image viewing software included on our cross-platform CDs was designed with a simple and intuitive user-interface (UI) for use by outpatients and referring physicians. Furthermore, digital image access via mobile devices or web-based access enables users to engage with their data in a convenient and user-friendly way. We evaluated the INVOLVE2 system using a pilot deployment in a hospital environment. PMID- 25825657 TI - Segmentation of ultrasound images of thyroid nodule for assisting fine needle aspiration cytology. AB - The incidence of thyroid nodule is very high and generally increases with the age. Thyroid nodule may presage the emergence of thyroid cancer. Most thyroid nodules are asymptomatic which makes thyroid cancer different from other cancers. The thyroid nodule can be completely cured if detected early. Therefore, it is necessary to correctly classify the thyroid nodule to be benign or malignant. Fine needle aspiration cytology is a recognized early diagnosis method of thyroid nodule. There are still some limitations in the fine needle aspiration cytology, such as the difficulty in location and the insufficient cytology specimen. The accuracy of ultrasound diagnosis of thyroid nodule improves constantly, and it has become the first choice for auxiliary examination of thyroid nodular disease. If we could combine medical imaging technology and fine needle aspiration cytology, the diagnostic rate of thyroid nodule would be improved significantly. The properties of ultrasound, such as echo, shadow, and reflection, will degrade the image quality, which makes it difficult to recognize the edges for physicians. Image segmentation technique based on graph theory has become a research hotspot at present. Normalized cut (Ncut) is a representative one, whose biggest advantage is not prone to small region segmentation but suitable for segmentation of feature parts of medical image. However, how to solve the normalized cut has become a problem, which needs large memory capacity and heavy calculation of weight matrix. It always generates over segmentation or less segmentation which leads to inaccurate in the segmentation. The speckle noise produced in the formation process of B ultrasound image of thyroid tumor makes the quality of the image deteriorate. In the light of this characteristic, we combine the anisotropic diffusion model with the normalized cut in this paper. After the enhancement of anisotropic diffusion model, it removes the noise in the B ultrasound image while preserves the important edges and local details. This reduces the amount of computation in constructing the weight matrix of the improved normalized cut and improves the accuracy of the final segmentation results. The feasibility of the method is proved by the experimental results. PMID- 25825656 TI - iPathCase(KEGG): An iPad interface for KEGG metabolic pathways. AB - BACKGROUND: Kyoto Encyclopedia of Genes and Genomes (KEGG) is an online and integrated molecular database for several organisms. KEGG has been a highly useful site, helping domain scientists understand, research, study, and teach metabolisms by linking sequenced genomes to higher level systematic functions. KEGG databases are accessible through the web pages of the system, but the capabilities of the web interface are limited. Third party systems have been built over the KEGG data to provide extensive functionalities. However, there have been no attempts towards providing a tablet interface for KEGG data. Recognizing the rise of mobile technologies and the importance of tablets in education, this paper presents the design and implementation of iPathCase(KEGG), an iPad interface for KEGG data, which is empowered with multiple browsing and visualization capabilities. RESULTS: iPathCase(KEGG) has been implemented and is available, free of charge, in the Apple App Store (locatable by searching for "Pathcase" in the app store). The application provides browsing and interactive visualization functionalities on the KEGG data. Users can pick pathways, visualize them, and see detail pages of reactions and molecules using the multi touch interface of iPad. CONCLUSIONS: iPathCase(KEGG) provides a mobile interface to access KEGG data. Interactive visualization and browsing functionalities let users to interact with the data in multiple ways. As the importance of tablets and their usage in research education continue to rise, we think iPathCase(KEGG) will be a useful tool for life science instructors and researchers. PMID- 25825654 TI - How bioinformatics influences health informatics: usage of biomolecular sequences, expression profiles and automated microscopic image analyses for clinical needs and public health. AB - ABSTRACT: The currently hyped expectation of personalized medicine is often associated with just achieving the information technology led integration of biomolecular sequencing, expression and histopathological bioimaging data with clinical records at the individual patients' level as if the significant biomedical conclusions would be its more or less mandatory result. It remains a sad fact that many, if not most biomolecular mechanisms that translate the human genomic information into phenotypes are not known and, thus, most of the molecular and cellular data cannot be interpreted in terms of biomedically relevant conclusions. Whereas the historical trend will certainly be into the general direction of personalized diagnostics and cures, the temperate view suggests that biomedical applications that rely either on the comparison of biomolecular sequences and/or on the already known biomolecular mechanisms have much greater chances to enter clinical practice soon. In addition to considering the general trends, we exemplarily review advances in the area of cancer biomarker discovery, in the clinically relevant characterization of patient specific viral and bacterial pathogens (with emphasis on drug selection for influenza and enterohemorrhagic E. coli) as well as progress in the automated assessment of histopathological images. As molecular and cellular data analysis will become instrumental for achieving desirable clinical outcomes, the role of bioinformatics and computational biology approaches will dramatically grow. AUTHOR SUMMARY: With DNA sequencing and computers becoming increasingly cheap and accessible to the layman, the idea of integrating biomolecular and clinical patient data seems to become a realistic, short-term option that will lead to patient-specific diagnostics and treatment design for many diseases such as cancer, metabolic disorders, inherited conditions, etc. These hyped expectations will fail since many, if not most biomolecular mechanisms that translate the human genomic information into phenotypes are not known yet and, thus, most of the molecular and cellular data collected will not lead to biomedically relevant conclusions. At the same time, less spectacular biomedical applications based on biomolecular sequence comparison and/or known biomolecular mechanisms have the potential to unfold enormous potential for healthcare and public health. Since the analysis of heterogeneous biomolecular data in context with clinical data will be increasingly critical, the role of bioinformatics and computational biology will grow correspondingly in this process. PMID- 25825658 TI - Bio and health informatics meets cloud : BioVLab as an example. AB - The exponential increase of genomic data brought by the advent of the next or the third generation sequencing (NGS) technologies and the dramatic drop in sequencing cost have driven biological and medical sciences to data-driven sciences. This revolutionary paradigm shift comes with challenges in terms of data transfer, storage, computation, and analysis of big bio/medical data. Cloud computing is a service model sharing a pool of configurable resources, which is a suitable workbench to address these challenges. From the medical or biological perspective, providing computing power and storage is the most attractive feature of cloud computing in handling the ever increasing biological data. As data increases in size, many research organizations start to experience the lack of computing power, which becomes a major hurdle in achieving research goals. In this paper, we review the features of publically available bio and health cloud systems in terms of graphical user interface, external data integration, security and extensibility of features. We then discuss about issues and limitations of current cloud systems and conclude with suggestion of a biological cloud environment concept, which can be defined as a total workbench environment assembling computational tools and databases for analyzing bio/medical big data in particular application domains. PMID- 25825659 TI - Dynamic integration of biological data sources using the data concierge. AB - BACKGROUND: The ever-changing landscape of large-scale network environments and innovative biology technologies require dynamic mechanisms to rapidly integrate previously unknown bioinformatics sources at runtime. However, existing integration technologies lack sufficient flexibility to adapt to these changes, because the techniques used for integration are static, and sensitive to new or changing bioinformatics source implementations and evolutionary biologist requirements. METHODS: To address this challenge, in this paper we propose a new semantics-based adaptive middleware, the Data Concierge, which is able to dynamically integrate heterogeneous biological data sources without the need for wrappers. Along with the architecture necessary to facilitate dynamic integration, API description mechanism is proposed to dynamically classify, recognize, locate, and invoke newly added biological data source functionalities. Based on the unified semantic metadata, XML-based state machines are able to provide flexible configurations to execute biologist's abstract and complex operations. RESULTS AND DISCUSSION: Experimental results demonstrate that for obtaining dynamic features, the Data Concierge sacrifices reasonable performance on reasoning knowledge models and dynamically doing data source API invocations. The overall costs to integrate new biological data sources are significantly lower when using the Data Concierge. CONCLUSIONS: The Data Concierge facilitates the rapid integration of new biological data sources in existing applications with no repetitive software development required, and hence, this mechanism would provide a cost-effective solution to the labor-intensive software engineering tasks. PMID- 25825660 TI - Improving information retrieval with multiple health terminologies in a quality controlled gateway. AB - BACKGROUND: The Catalog and Index of French-language Health Internet resources (CISMeF) is a quality-controlled health gateway, primarily for Web resources in French (n=89,751). Recently, we achieved a major improvement in the structure of the catalogue by setting-up multiple terminologies, based on twelve health terminologies available in French, to overcome the potential weakness of the MeSH thesaurus, which is the main and pivotal terminology we use for indexing and retrieval since 1995. The main aim of this study was to estimate the added-value of exploiting several terminologies and their semantic relationships to improve Web resource indexing and retrieval in CISMeF, in order to provide additional health resources which meet the users' expectations. METHODS: Twelve terminologies were integrated into the CISMeF information system to set up multiple-terminologies indexing and retrieval. The same sets of thirty queries were run: (i) by exploiting the hierarchical structure of the MeSH, and (ii) by exploiting the additional twelve terminologies and their semantic links. The two search modes were evaluated and compared. RESULTS: The overall coverage of the multiple-terminologies search mode was improved by comparison to the coverage of using the MeSH (16,283 vs. 14,159) (+15%). These additional findings were estimated at 56.6% relevant results, 24.7% intermediate results and 18.7% irrelevant. CONCLUSION: The multiple-terminologies approach improved information retrieval. These results suggest that integrating additional health terminologies was able to improve recall. Since performing the study, 21 other terminologies have been added which should enable us to make broader studies in multiple terminologies information retrieval. PMID- 25825661 TI - Enabling flexible integration of healthcare information using the entity attribute-value storage model. AB - BACKGROUND: For an optimal care of patients in home healthcare, it is essential to exchange healthcare-related information with other stakeholders. Unfortunately, paper-based documentation procedures as well as the heterogeneity between information systems inhibit a well-regulated communication. Therefore, a digital patient care record is introduced to establish the foundation for integrating healthcare-related information. METHODS: For the digital patient care record, suitable integration techniques are required that store data in a compact way and offer flexibility as well as robustness. For this purpose, a generic storage structure based on the entity-attribute-value (EAV) model is introduced. This storage structure fulfills the stated requirements and incoming information can be stored directly without any loss of data. EVALUATION RESULTS AND DISCUSSIONS: First performance tests regarding the query response time are given in this paper. The tests measured the connection time, the query execution time, and the time for traversing the result set. The time for executing the query is lowest. The time for traversing the results strongly depends on the number of documents. A concept comparison to other integration techniques is also presented. CONCLUSIONS: This approach offers flexibility concerning different standard types and the evolution in healthcare knowledge and processes. It also allows for highly sparse data to be stored in a compact way. The underlying database structure is presented, the import process for extracting incoming reports is described and the export process for generating new outgoing standardized reports is briefly illustrated. PMID- 25825662 TI - Analysis of contingency tables based on generalised median polish with power transformations and non-additive models. AB - Contingency tables are a very common basis for the investigation of effects of different treatments or influences on a disease or the health state of patients. Many journals put a strong emphasis on p-values to support the validity of results. Therefore, even small contingency tables are analysed by techniques like t-test or ANOVA. Both these concepts are based on normality assumptions for the underlying data. For larger data sets, this assumption is not so critical, since the underlying statistics are based on sums of (independent) random variables which can be assumed to follow approximately a normal distribution, at least for a larger number of summands. But for smaller data sets, the normality assumption can often not be justified. Robust methods like the Wilcoxon-Mann-Whitney-U test or the Kruskal-Wallis test do not lead to statistically significant p-values for small samples. Median polish is a robust alternative to analyse contingency tables providing much more insight than just a p-value. Median polish is a technique that provides more information than just a p-value. It explains the contingency table in terms of an overall effect, row and columns effects and residuals. The underlying model for median polish is an additive model which is sometimes too restrictive. In this paper, we propose two related approach to generalise median polish. A power transformation can be applied to the values in the table, so that better results for median polish can be achieved. We propose a graphical method how to find a suitable power transformation. If the original data should be preserved, one can apply other transformations - based on so called additive generators - that have an inverse transformation. In this way, median polish can be applied to the original data, but based on a non-additive model. The non-linearity of such a model can also be visualised to better understand the joint effects of rows and columns in a contingency table. PMID- 25825663 TI - Extracting and transforming clinical guidelines into pathway models for different hospital information systems. AB - BACKGROUND: Healthcare providers are facing an enormous cost pressure and a scarcity of resources. They need to realign in the tension between economic efficiency and demand-oriented healthcare. Clinical guidelines and clinical pathways are used in German hospitals to improve the quality of care and to reduce costs at the same time. Clinical guidelines provide evident medical knowledge for diagnostic and therapeutic issues, while clinical pathways are a road map of patient management. The consideration of clinical guidelines during pathway development is highly recommended. But the transfer of evident knowledge (clinical guidelines) to care processes (clinical pathways) is not straightforward due to different information contents and structures. METHODS: We propose a model-based approach to support the development of guideline-compliant pathways and the generation of ready-to-use pathway models for different hospital information systems. A meta-model merges the structures of clinical guidelines and clinical pathways into one generic model. It is encoded through artefacts of Health Level 7 (HL7) in version 3. The deployment process to integrate the defined guideline-compliant pathways into different target systems is supported by an ontology management approach. RESULTS: We defined a step-by-step instruction for translating the narrative guideline content into formalized care processes. The meta-model provides all necessary structures to capture the pertinent knowledge. The entire process of defining and deploying guideline compliant pathways is supported by one consistent IT system. The deployment process is designed detached from specific systems so that the defined pathways can be enacted within different hospital information systems (HIS). CONCLUSIONS: The approach enables hospitals to develop guideline-compliant pathways and to integrate them into their HIS without time-consuming manual transformations. That way, best practice advices based on clinical guidelines can be provided at the point of care and therefore improve patient treatment. PMID- 25825664 TI - Graphical modeling and query language for hospitals. AB - BACKGROUND: So far there has been little evidence that implementation of the health information technologies (HIT) is leading to health care cost savings. One of the reasons for this lack of impact by the HIT likely lies in the complexity of the business process ownership in the hospitals. The goal of our research is to develop a business model-based method for hospital use which would allow doctors to retrieve directly the ad-hoc information from various hospital databases. METHODS: We have developed a special domain-specific process modelling language called the MedMod. Formally, we define the MedMod language as a profile on UML Class diagrams, but we also demonstrate it on examples, where we explain the semantics of all its elements informally. Moreover, we have developed the Process Query Language (PQL) that is based on MedMod process definition language. The purpose of PQL is to allow a doctor querying (filtering) runtime data of hospital's processes described using MedMod. RESULTS: The MedMod language tries to overcome deficiencies in existing process modeling languages, allowing to specify the loosely-defined sequence of the steps to be performed in the clinical process. The main advantages of PQL are in two main areas - usability and efficiency. They are: 1) the view on data through "glasses" of familiar process, 2) the simple and easy-to-perceive means of setting filtering conditions require no more expertise than using spreadsheet applications, 3) the dynamic response to each step in construction of the complete query that shortens the learning curve greatly and reduces the error rate, and 4) the selected means of filtering and data retrieving allows to execute queries in O(n) time regarding the size of the dataset. CONCLUSIONS: We are about to continue developing this project with three further steps. First, we are planning to develop user-friendly graphical editors for the MedMod process modeling and query languages. The second step is to do evaluation of usability the proposed language and tool involving the physicians from several hospitals in Latvia and working with real data from these hospitals. Our third step is to develop an efficient implementation of the query language. PMID- 25825665 TI - Design and implementation of Metta, a metasearch engine for biomedical literature retrieval intended for systematic reviewers. AB - BACKGROUND: Individuals and groups who write systematic reviews and meta-analyses in evidence-based medicine regularly carry out literature searches across multiple search engines linked to different bibliographic databases, and thus have an urgent need for a suitable metasearch engine to save time spent on repeated searches and to remove duplicate publications from initial consideration. Unlike general users who generally carry out searches to find a few highly relevant (or highly recent) articles, systematic reviewers seek to obtain a comprehensive set of articles on a given topic, satisfying specific criteria. This creates special requirements and challenges for metasearch engine design and implementation. METHODS: We created a federated search tool that is connected to five databases: PubMed, EMBASE, CINAHL, PsycINFO, and the Cochrane Central Register of Controlled Trials. Retrieved bibliographic records were shown online; optionally, results could be de-duplicated and exported in both BibTex and XML format. RESULTS: The query interface was extensively modified in response to feedback from users within our team. Besides a general search track and one focused on human-related articles, we also added search tracks optimized to identify case reports and systematic reviews. Although users could modify preset search options, they were rarely if ever altered in practice. Up to several thousand retrieved records could be exported within a few minutes. De-duplication of records returned from multiple databases was carried out in a prioritized fashion that favored retaining citations returned from PubMed. CONCLUSIONS: Systematic reviewers are used to formulating complex queries using strategies and search tags that are specific for individual databases. Metta offers a different approach that may save substantial time but which requires modification of current search strategies and better indexing of randomized controlled trial articles. We envision Metta as one piece of a multi-tool pipeline that will assist systematic reviewers in retrieving, filtering and assessing publications. As such, Metta may find wide utility for anyone who is carrying out a comprehensive search of the biomedical literature. PMID- 25825666 TI - Retinal blood vessels extraction using probabilistic modelling. AB - The analysis of retinal blood vessels plays an important role in detecting and treating retinal diseases. In this review, we present an automated method to segment blood vessels of fundus retinal image. The proposed method could be used to support a non-intrusive diagnosis in modern ophthalmology for early detection of retinal diseases, treatment evaluation or clinical study. This study combines the bias correction and an adaptive histogram equalisation to enhance the appearance of the blood vessels. Then the blood vessels are extracted using probabilistic modelling that is optimised by the expectation maximisation algorithm. The method is evaluated on fundus retinal images of STARE and DRIVE datasets. The experimental results are compared with some recently published methods of retinal blood vessels segmentation. The experimental results show that our method achieved the best overall performance and it is comparable to the performance of human experts. PMID- 25825667 TI - Big data analytics in healthcare: promise and potential. AB - OBJECTIVE: To describe the promise and potential of big data analytics in healthcare. METHODS: The paper describes the nascent field of big data analytics in healthcare, discusses the benefits, outlines an architectural framework and methodology, describes examples reported in the literature, briefly discusses the challenges, and offers conclusions. RESULTS: The paper provides a broad overview of big data analytics for healthcare researchers and practitioners. CONCLUSIONS: Big data analytics in healthcare is evolving into a promising field for providing insight from very large data sets and improving outcomes while reducing costs. Its potential is great; however there remain challenges to overcome. PMID- 25825668 TI - Traits and types of health data repositories. AB - We review traits of reusable clinical data and offer a typology of clinical repositories with a range of known examples. Sources of clinical data suitable for research can be classified into types reflecting the data's institutional origin, original purpose, level of integration and governance. Primary data nearly always come from research studies and electronic medical records. Registries collect data on focused populations primarily to track outcomes, often using observational research methods. Warehouses are institutional information utilities repackaging clinical care data. Collections organize data from more organizations than a data warehouse, and more original data sources than a registry. Therefore even if they are heavily curated, their level of internal integration, and thus ease of use, can be less than other types. Federations are like collections except that physical control over data is distributed among donor organizations. Federations sometimes federate, giving a second level of organization. While the size, in number of patients, varies widely within each type of data source, populations over 10 K are relatively numerous, and much larger populations can be seen in warehouses and federations. One imagined ideal structure for research progress has been called an "Information Commons". It would have longitudinal, multi-leveled (environmental through molecular) data on a large population of identified, consenting individuals. These are qualities whose achievement would require long term commitment on the part of many data donors, including a willingness to make their data public. PMID- 25825669 TI - Risk adjustment and observation time: comparison between cross-sectional and 2 year panel data from the Medical Expenditure Panel Survey (MEPS). AB - BACKGROUND: Risk adjustment models were used to estimate health care consumption after adjusting for individual characteristics or other factors. The results of this technique were not satisfying. One reason could be that the length of time to document consumption might be associated with the mean and variance of observed health care consumption. This study aims to use a simplified mathematical model and real-world data to explore the relationship of observation time (one or two years) and predictability. METHODS: This study used cross sectional (one-year) and 2-year panel data sets of the Medical Expenditure Panel Survey (MEPS) from 1996 to 2008. Comparisons of the health care consumption (total health expenditure, emergency room (ER) and office-based visits) included ratios of means and standard errors (SEs). Risk adjustment models for one- and two-year data used generalized linear model. RESULTS: The ratios of mean health care consumption (two-year to one-year total expenditure, ER and office-based visits) seemed to be two in most age groups and the ratios of SEs varied around or above two. The R-squared of two-year models seemed to be slightly better than that of one-year models. CONCLUSIONS: We find health expenditure and ER or office based visits observed in two consecutive years were about twice those observed in a single year for most age, similar to the ratios predicted in mathematical examples. The ratios of mean spending and visits varied across age groups. The other finding is that the predictability of two-year consumption seems better than that of one-year slightly. The reason is not clear and we will continue studying this phenomenon. PMID- 25825670 TI - The custodian administered research extract server: "improving the pipeline" in linked data delivery systems. AB - BACKGROUND: At Western Australia's Data Linkage Branch (DLB) the extraction of linked data has become increasingly complex over the past decade and classical methods of data delivery are unsuited to the larger extractions which have become the norm. The Custodian Administered Research Extract Server (CARES) is a fast, accurate and predictable approach to linked data extraction. METHODS: The Data Linkage Branch (DLB) creates linkage keys within and between datasets. To comply with the separation principal, these keys are sent to applicable data collection agencies for extraction. Routing requests through multiple channels is inefficient and makes it hard to monitor work and predict delivery times. CARES was developed to address these shortcomings and involved ongoing consultation with the Custodians and staff of collections, plus challenges of hardware, programming, governance and security. RESULTS: The introduction of CARES has reduced the workload burden of linked data extractions, while improving the efficiency, stability and predictability of turnaround times. CONCLUSIONS: As the scope of a linkage system broadens, challenges in data delivery are inevitable. CARES overcomes multiple obstacles with no sacrifice to the integrity, confidentiality or security of data. CARES is a valuable component of linkage infrastructure that is operable at any scale and adaptable to many data environments. PMID- 25825671 TI - A comparative study of improvements Pre-filter methods bring on feature selection using microarray data. AB - BACKGROUND: Feature selection techniques have become an apparent need in biomarker discoveries with the development of microarray. However, the high dimensional nature of microarray made feature selection become time-consuming. To overcome such difficulties, filter data according to the background knowledge before applying feature selection techniques has become a hot topic in microarray analysis. Different methods may affect final results greatly, thus it is important to evaluate these pre-filter methods in a system way. METHODS: In this paper, we compared the performance of statistical-based, biological-based pre filter methods and the combination of them on microRNA-mRNA parallel expression profiles using L1 logistic regression as feature selection techniques. Four types of data were built for both microRNA and mRNA expression profiles. RESULTS: Results showed that pre-filter methods could reduce the number of features greatly for both mRNA and microRNA expression datasets. The features selected after pre-filter procedures were shown to be significant in biological levels such as biology process and microRNA functions. Analyses of classification performance based on precision showed the pre-filter methods were necessary when the number of raw features was much bigger than that of samples. All the computing time was greatly shortened after pre-filter procedures. CONCLUSIONS: With similar or better classification improvements, less but biological significant features, pre-filter-based feature selection should be taken into consideration if researchers need fast results when facing complex computing problems in bioinformatics. PMID- 25825672 TI - Inferring disease transmission networks at a metapopulation level. AB - BACKGROUND: To investigate transmission patterns of an infectious disease, e.g., malaria, it is desirable to use the observed surveillance data to discover the underlying (often hidden) disease transmission networks. Previous studies have provided methods for inferring information diffusion networks in which each node corresponds to an individual person. However, in the case of disease transmission, to effectively propose and implement intervention strategies, it is more realistic and reasonable for policy makers to study the diffusion patterns at a metapopulation level when the disease transmission is affected by mobile population, that is, to consider disease transmission networks in which nodes represent subpopulations, and links indicate their interrelationships. RESULTS: A network inference method called NetEpi (Network Epidemic) is developed and evaluated using both synthetic and real-world datasets. The experimental results show that NetEpi can not only recover most of the ground-truth disease transmission networks using only surveillance data, but also find a malaria transmission network based on a real-world dataset. The inferred malaria network can characterize the real-world observations to a certain extent. In addition, it also discloses some hidden phenomenon. CONCLUSIONS: This research addresses the problem of inferring disease transmission networks at a metapopulation level. Such networks can be useful in several ways: (i) to investigate hidden impact factors that influence epidemic dynamics, (ii) to reveal possible sources of epidemic outbreaks, and (iii) to practically develop and/or improve strategies for controlling the spread of infectious diseases. PMID- 25825673 TI - Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection. AB - BACKGROUND: Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI) that often fails standard antibiotic therapy. Despite its widespread recent use, however, little is known about the stability of the fecal microbiota following FMT. RESULTS: Here we report on short- and long-term changes and provide kinetic visualization of fecal microbiota composition in patients with multiply recurrent CDI that were refractory to antibiotic therapy and treated using FMT. Fecal samples were collected from four patients before and up to 151 days after FMT, with daily collections until 28 days and weekly collections until 84 days post-FMT. The composition of fecal bacteria was characterized using high throughput 16S rRNA gene sequence analysis, compared to microbiota across body sites in the Human Microbiome Project (HMP) database, and visualized in a movie-like, kinetic format. FMT resulted in rapid normalization of bacterial fecal sample composition from a markedly dysbiotic state to one representative of normal fecal microbiota. While the microbiome appeared most similar to the donor implant material 1 day post-FMT, the composition diverged variably at later time points. The donor microbiota composition also varied over time. However, both post-FMT and donor samples remained within the larger cloud of fecal microbiota characterized as healthy by the HMP. CONCLUSIONS: Dynamic behavior is an intrinsic property of normal fecal microbiota and should be accounted for in comparing microbial communities among normal individuals and those with disease states. This also suggests that more frequent sample analyses are needed in order to properly assess success of FMT procedures. PMID- 25825674 TI - A qualitative investigation of non-response in NHS health checks. AB - BACKGROUND: Improving uptake of NHS Health Checks has become a priority in England, but there is a lack of data on the perceptions of programme non attenders. This study aimed to explore how non-attenders of NHS Health Checks perceive the programme, identify reasons for non-attendance and inform strategies to improve uptake. METHOD: This qualitative study involved individuals registered at four general practices in Stoke-on-Trent, UK, who had not taken up their invitation to a NHS Health Check. Semi-structured face-to-face and telephone interviews were audio-recorded and transcribed verbatim for Thematic Analysis. RESULTS: Interviews were completed with 19 males and 22 females (mean age 52.9 +/ 8.5 years), who were socio-demographically representative of the non-attender population. Four main themes identified related to: the positive perception of the Health Check concept among non-attenders; the perceived lack of personal relevance; ineffective invitation method and appointment inconvenience were common barriers; previous experience of primary care can influence uptake. CONCLUSIONS: Fundamental requirements for improving uptake are that individuals recognise the personal relevance of Health Checks and that attendance is convenient. Incorporating more sophisticated and personalised risk communication as part of the invitation could increase impact and promote candidacy. Flexibility and convenience of appointments should be considered by participating general practices. PMID- 25825675 TI - Medicines and universal health coverage: challenges and opportunities. PMID- 25825676 TI - Preliminary observations on the mandibles of palaemonoid shrimp (Crustacea: Decapoda: Caridea: Palaemonoidea). AB - The mandibles of caridean shrimps have been widely studied in the taxonomy and functional biology of the group. Within the Palaemonoidea the mandibles reach a high level of structural diversity reflecting the diverse lifestyles within the superfamily. However, the majority of studies have been restricted to light microscopy, with the ultrastructure at finer levels poorly known. This study investigates the mandible of nine species belonging to six of the recognised families of the Palaemonoidea using SEM and analyses the results in a phylogenetic and dietary framework. The results of the study indicate that little phylogenetic information is conveyed by the structure of the mandible, but that its form is influenced by primary food sources of each species. With the exception of Anchistioides antiguensis, all species examined possessed cuticular structures at the distal end of the pars molaris (molar process). Five types of cuticular structures are recognised herein, each with a unique form, but variable in number, placement and arrangement. Each type is presumed to have a different function which is likewise related to diet. PMID- 25825677 TI - Long live the wasp: adult longevity in captive colonies of the eusocial paper wasp Polistes canadensis (L.). AB - Insects have been used as an exemplary model in studying longevity, from extrinsic mortality pressures to intrinsic senescence. In the highly eusocial insects, great degrees of variation in lifespan exist between morphological castes in relation to extreme divisions of labour, but of particular interest are the primitively eusocial insects. These species represent the ancestral beginnings of eusociality, in which castes are flexible and based on behaviour rather than morphology. Here we present data on the longevity of the primitively eusocial Neotropical paper wasp P. canadensis, in a captive setting removed of environmental hazards. Captive Polistes canadensis had an average lifespan of 193 +/- 10.5 days; although this average is shorter than most bee and ant queens, one individual lived for 506 days in the lab-longer than most recorded wasps and bees. Natal colony variation in longevity does exist between P. canadensis colonies, possibly due to nutritional and genetic factors. This study provides a foundation for future investigations on the effects of intrinsic and extrinsic factors on longevity in primitively eusocial insects, as well as the relationship with natal group and cohort size. PMID- 25825678 TI - Perception of global facial geometry is modulated through experience. AB - Identification of personally familiar faces is highly efficient across various viewing conditions. While the presence of robust facial representations stored in memory is considered to aid this process, the mechanisms underlying invariant identification remain unclear. Two experiments tested the hypothesis that facial representations stored in memory are associated with differential perceptual processing of the overall facial geometry. Subjects who were personally familiar or unfamiliar with the identities presented discriminated between stimuli whose overall facial geometry had been manipulated to maintain or alter the original facial configuration (see Barton, Zhao & Keenan, 2003). The results demonstrate that familiarity gives rise to more efficient processing of global facial geometry, and are interpreted in terms of increased holistic processing of facial information that is maintained across viewing distances. PMID- 25825679 TI - Neonicotinoids impact bumblebee colony fitness in the field; a reanalysis of the UK's Food & Environment Research Agency 2012 experiment. AB - The causes of bee declines remain hotly debated, particularly the contribution of neonicotinoid insecticides. In 2013 the UK's Food & Environment Research Agency made public a study of the impacts of exposure of bumblebee colonies to neonicotinoids. The study concluded that there was no clear relationship between colony performance and pesticide exposure, and the study was subsequently cited by the UK government in a policy paper in support of their vote against a proposed moratorium on some uses of neonicotinoids. Here I present a simple re analysis of this data set. It demonstrates that these data in fact do show a negative relationship between both colony growth and queen production and the levels of neonicotinoids in the food stores collected by the bees. Indeed, this is the first study describing substantial negative impacts of neonicotinoids on colony performance of any bee species with free-flying bees in a field realistic situation where pesticide exposure is provided only as part of normal farming practices. It strongly suggests that wild bumblebee colonies in farmland can be expected to be adversely affected by exposure to neonicotinoids. PMID- 25825680 TI - Selection of reference genes for quantitative RT-PCR (RT-qPCR) analysis of rat tissues under physiological and toxicological conditions. AB - In biological research the analysis of gene expression levels in cells and tissues can be a powerful tool to gain insights into biological processes. For this, quantitative RT-PCR (RT-qPCR) is a popular method that often involve the use of constitutively expressed endogenous reference (or 'housekeeping') gene for normalization of data. Thus, it is essential to use reference genes that have been verified to be stably expressed within the specific experimental setting. Here, we have analysed the expression stability of 12 commonly used reference genes (Actb, B2m, Gapdh, Hprt, Pgk1, Rn18s, Rpl13a, Rps18, Rps29, Sdha, Tbp and Ubc) across several juvenile and adult rat tissues (liver, adrenal, prostate, fat pad, testis and ovaries), both under normal conditions and following exposure to various chemicals during development. Employing NormFinder and BestKeeper softwares, we found Hprt and Sdha to be amongst the most stable genes across normal and manipulated tissues, with several others also being suitable for most tissues. Tbp and B2m displayed highest variability in transcript levels between tissues and developmental stages. It was also observed that the reference genes were most unstable in liver and testis following toxicological exposure. For future studies, we propose the use of more than one verified reference gene and the continuous monitoring of their suitability under various experimental conditions, including toxicological studies, based on changes in threshold (Ct) values from cDNA samples having been reverse-transcribed from a constant input concentration of RNA. PMID- 25825682 TI - Spatiotemporal diversity, structure and trophic guilds of insect assemblages in a semi-arid Sabkha ecosystem. AB - The current study highlights some knowledge on the diversity and structure of insect communities and trophic groups living in Sabkha Djendli (semi-arid area of Northeastern Algeria). The entomofauna was monthly sampled from March to November 2006 using pitfall traps at eight sites located at the vicinity of the Sabkha. Structural and diversity parameters (species richness, Shannon index, evenness) were measured for both insect orders and trophic guilds. The canonical correspondence analysis (CCA) was applied to determine how vegetation parameters (species richness and cover) influence spatial and seasonal fluctuations of insect assemblages. The catches totalled 434 insect individuals classified into 75 species, 62 genera, 31 families and 7 orders, of which Coleoptera and Hymenoptera were the most abundant and constant over seasons and study stations. Spring and autumn presented the highest values of diversity parameters. Individual-based Chao-1 species richness estimator indicated 126 species for the total individuals captured in the Sabkha. Based on catch abundances, the structure of functional trophic groups was predators (37.3%), saprophages (26.7%), phytophages (20.5%), polyphages (10.8%), coprophages (4.6%); whereas in terms of numbers of species, they can be classified as phytophages (40%), predators (25.3%), polyphages (13.3%), saprophages (12%), coprophages (9.3%). The CCA demonstrated that phytophages and saprophages as well as Coleoptera and Orthoptera were positively correlated with the two parameters of vegetation, especially in spring and summer. While the abundance of coprophages was positively correlated with species richness of plants, polyphage density was positively associated with vegetation cover. The insect community showed high taxonomic and functional diversity that is closely related to diversity and vegetation cover in different stations of the wetland and seasons. PMID- 25825683 TI - Bayesian inference of protein structure from chemical shift data. AB - Protein chemical shifts are routinely used to augment molecular mechanics force fields in protein structure simulations, with weights of the chemical shift restraints determined empirically. These weights, however, might not be an optimal descriptor of a given protein structure and predictive model, and a bias is introduced which might result in incorrect structures. In the inferential structure determination framework, both the unknown structure and the disagreement between experimental and back-calculated data are formulated as a joint probability distribution, thus utilizing the full information content of the data. Here, we present the formulation of such a probability distribution where the error in chemical shift prediction is described by either a Gaussian or Cauchy distribution. The methodology is demonstrated and compared to a set of empirically weighted potentials through Markov chain Monte Carlo simulations of three small proteins (ENHD, Protein G and the SMN Tudor Domain) using the PROFASI force field and the chemical shift predictor CamShift. Using a clustering criterion for identifying the best structure, together with the addition of a solvent exposure scoring term, the simulations suggests that sampling both the structure and the uncertainties in chemical shift prediction leads more accurate structures compared to conventional methods using empirical determined weights. The Cauchy distribution, using either sampled uncertainties or predetermined weights, did, however, result in overall better convergence to the native fold, suggesting that both types of distribution might be useful in different aspects of the protein structure prediction. PMID- 25825684 TI - Comparative study of the methane production based on the chemical compositions of Mangifera Indica and Manihot Utilissima leaves. AB - Leaves of Mangifera Indica (MI, mango leaves) and Manihot Utilissima (MU, cassava leaves) are available in tropical regions and are the most accessible vegetal wastes of Kinshasa, capital of Democratic Republic of Congo. These wastes are not suitably managed and are not rationally valorized. They are abandoned in full air, on the soil and in the rivers. They thus pollute environment. By contrast, they can be recuperated and treated in order to produce methane (energy source), organic fertilizer and clean up the environment simultaneously. The main objective of this study was to investigate methane production from MI and MU leaves by BMP tests at 30 degrees C. The yields achieved from the anaerobic digestion of up to 61.3 g raw matter in 1 l medium were 0.001 l/g and 0.100 l CH4/g volatile solids of MI and MU leaves, respectively. The yield of MU leaves was in the range mentioned in the literature for other leaves because of a poor presence of bioactive substrates, and low C/N ratio. This methane yield corresponded to 7% of calorific power of wood. By contrast, the methane yield from MI leaves was almost nil suggesting some metabolism inhibition because of their rich composition in carbon and bioactive substrates. Whereas classical acidogenesis and acetogenesis were recorded. Therefore, methane production from the sole MI leaves seems unfavorable by comparison to MU leaves at the ambient temperature in tropical regions. Their solid and liquid residues obtained after anaerobic digestion would be efficient fertilizers. However, the methane productivity of both leaves could be improved by anaerobic co-digestion. PMID- 25825685 TI - Anticancer effect of black tea extract in human cancer cell lines. AB - In this study we investigated effects of natural extract from the black tea Camellia sinensis (BTE) against human colon carcinoma cell line HT-29, human breast carcinoma cell line MCF-7, human alveolar carcinoma cell line A549 and healthy cell line NIH-3T3. We identified concentration range for cytotoxic/antiproliferative effects using MTT assay and the trypan blue assay, gel electrophoresis we employed to determine the type of cell death induced by BTE and DNA damage we determined by comet assay. Different concentrations of the extract (0.00078 - 5 MUg/mL) we added to the cultured cells and incubated for 216 h. BTE showed cytotoxic effects against all carcinoma cell lines, however HT-29 and MCF-7 cells were more sensitive than A549. BTE showed no antiproliferative effect against healthy cells NIH-3T3 at tested concentrations. We found no apoptotic cell death in HT-29 and MCF-7 cells after 72 h of incubation in case of single administration of BTE but in case of repetitive administration of BTE (BTE was added to the cells each day) we found apoptotic cell death in HT-29 after 72 h incubation. BTE induced also DNA strand breaks and oxidative damage to DNA in carcinoma cells HT-29 and MCF-7. PMID- 25825681 TI - Obesity genetics in mouse and human: back and forth, and back again. AB - Obesity is a major public health concern. This condition results from a constant and complex interplay between predisposing genes and environmental stimuli. Current attempts to manage obesity have been moderately effective and a better understanding of the etiology of obesity is required for the development of more successful and personalized prevention and treatment options. To that effect, mouse models have been an essential tool in expanding our understanding of obesity, due to the availability of their complete genome sequence, genetically identified and defined strains, various tools for genetic manipulation and the accessibility of target tissues for obesity that are not easily attainable from humans. Our knowledge of monogenic obesity in humans greatly benefited from the mouse obesity genetics field. Genes underlying highly penetrant forms of monogenic obesity are part of the leptin-melanocortin pathway in the hypothalamus. Recently, hypothesis-generating genome-wide association studies for polygenic obesity traits in humans have led to the identification of 119 common gene variants with modest effect, most of them having an unknown function. These discoveries have led to novel animal models and have illuminated new biologic pathways. Integrated mouse-human genetic approaches have firmly established new obesity candidate genes. Innovative strategies recently developed by scientists are described in this review to accelerate the identification of causal genes and deepen our understanding of obesity etiology. An exhaustive dissection of the molecular roots of obesity may ultimately help to tackle the growing obesity epidemic worldwide. PMID- 25825686 TI - Predictors and risks of body fat profiles in young New Zealand European, Maori and Pacific women: study protocol for the women's EXPLORE study. AB - BACKGROUND: Body mass index (BMI) (kg/m(2)) is used internationally to assess body mass or adiposity. However, BMI does not discriminate body fat content or distribution and may vary among ethnicities. Many women with normal BMI are considered healthy, but may have an unidentified "hidden fat" profile associated with higher metabolic disease risk. If only BMI is used to indicate healthy body size, it may fail to predict underlying risks of diseases of lifestyle among population subgroups with normal BMI and different adiposity levels or distributions. Higher body fat levels are often attributed to excessive dietary intake and/or inadequate physical activity. These environmental influences regulate genes and proteins that alter energy expenditure/storage. Micro ribonucleic acid (miRNAs) can influence these genes and proteins, are sensitive to diet and exercise and may influence the varied metabolic responses observed between individuals. The study aims are to investigate associations between different body fat profiles and metabolic disease risk; dietary and physical activity patterns as predictors of body fat profiles; and whether these risk factors are associated with the expression of microRNAs related to energy expenditure or fat storage in young New Zealand women. Given the rising prevalence of obesity globally, this research will address a unique gap of knowledge in obesity research. METHODS/DESIGN: A cross-sectional design to investigate 675 NZ European, Maori, and Pacific women aged 16-45 years. Women are classified into three main body fat profiles (n = 225 per ethnicity; n = 75 per body fat profile): 1) normal BMI, normal body fat percentage (BF%); 2) normal BMI, high BF%; 3) high BMI, high BF%. Regional body composition, biomarkers of metabolic disease risk (i.e. fasting insulin, glucose, HbA1c, lipids), inflammation (i.e. IL-6, TNF-alpha, hs-CRP), associations between lifestyle factors (i.e. dietary intake, physical activity, taste perceptions) and microRNA expression will be investigated. DISCUSSION: This research targets post menarcheal, premenopausal women, potentially exhibiting lifestyle behaviours resulting in excess body fat affecting metabolic health. These behaviours may be characterised by specific patterns of microRNA expression that will be explored in terms of tailored solutions specific to body fat profile groups and ethnicities. TRIAL REGISTRATION: ACTRN12613000714785. PMID- 25825687 TI - Overrepresentation of unaccompanied refugee minors in inpatient psychiatric care. AB - BACKGROUND: Unaccompanied refugee minors (URMs) have high levels of psychiatric symptoms, and concerns for their access to mental health services have been raised. From the mid-2000s, an increasing number of asylum-seeking URMs, mainly adolescent boys from Afghanistan, have been referred to the Child & Adolescent Psychiatry emergency unit in Malmo, Sweden. The aim of the study was to compare inpatient psychiatric care between URMs and non-URMs. FINDINGS: All admissions in 2011 at the emergency unit were identified and divided into URMs (n = 56) and non URMs (n = 205). On the basis of unique patients' first treatment occasion, a group level analysis was performed on gender, age, treatment duration, additional treatment occasions/patient, involuntary care, involuntary care by gender, and ICD-10 principal diagnosis. To retrieve further sample characteristics, a questionnaire was administered to the physicians responsible for admitting patients in 2011. More URMs than non-URMs exhibited self-harm or suicidal behaviour in conjunction with referral. 86% of URMs were admitted with symptoms relating to stress in the asylum process. In the catchment area, 3.40% of the URM population received inpatient care and 0.67% inpatient involuntary care, compared to 0.26% and 0.02% respectively of the non-URM population, both comparisons p < 0.001. There were more boys in the URM group (95%) compared to the non-URM group (29%). A difference in use of involuntary care disappeared after adjusting for gender. No differences were found in diagnoses except for neurotic disorders (F40 48), which were more common in the URM group. CONCLUSION: From an epidemiological perspective, URMs were overrepresented in inpatient psychiatric care. PMID- 25825688 TI - Clinical and molecular characteristics of triple-negative breast cancer patients in Northern Israel: single center experience. AB - INTRODUCTION: Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and does not overexpress HER2. It displays a distinct clinical behavior. This study aims to assess the clinical, molecular and prognostic characteristics of TNBC patients. PATIENTS/METHODS: TNBC patients, referred to a tertiary medical center, 1/1/2000 - 31/12/2005, were included. Clinical, molecular and prognostic characteristics were retrospectively collected from patients' records. RESULTS: Overall, 122 consecutive TNBC patients were included with a median age of 54 years. Among the TNBC patients, 101 (82.8%) were Jews and 21 (17.2%) were Arabs. Family history for breast cancer was reported in 30 patients (24.6%). Genetic counseling was conducted in 30 patients (24.6%); 22/30 (73.3%) had BRCA1/2 mutations. Median tumor size was 2 cm and positive lymph nodes were detected in pathological examination in 40 patients (34%). At the time of data analysis, 21/118 patients (17.8%), who initially presented with early disease, had developed metastasis. Local recurrence was detected in four patients (3.4%). The overall survival (OS) was significantly longer for patients younger than 60 years compared to those >= 60 years, (Hazard ratio (HR) =2.1, p=0.046). Nulliparous patients had significantly higher OS than patients with a reproductive history of >= 4 children. (HR=0.31, p= 0.041). Mortality rate was higher for Arabs versus Jews but did not reach significance, (HR=1.33; P=0.64). CONCLUSIONS: TNBC represents an exclusive clinical behavior. Older age and parity were found to be poor prognostic factors. Further larger studies are needed to reaffirm our findings and explore the genetics among non-BRCA1/2 TNBC patients. PMID- 25825689 TI - Metabolic control in type 1 diabetes patients practicing combat sports: at least two-year follow-up study. AB - BACKGROUND: It is well recognized that physical activity should be an integral part of the management of diabetes. It remains controversial, however, whether combat sports, often preferred by young individuals type 1 diabetes mellitus (T1DM), may be performed without high risk of metabolic decompensation. The aim of this observational study was to summarize a two-year follow-up period of five young male patients with T1DM practicing combat sports under the care of a physical-activity oriented specialist diabetes outpatient clinic. Of the five patients, three mixed martial arts and two kick-boxing competitors were included in the study. To control glucose in each patient, an individual approach was used that took into consideration the type of training, the sequence of the exercises, and the relative proportion of different forms of exercise. FINDINGS: During the follow-up, glycemic control was improved and maintained in all individuals. Neither an episode of hospitalization-requiring diabetic ketoacidosis nor severe hypoglycemia occurred in these patients during the follow-up. CONCLUSIONS: In conclusion, an individual approach for T1DM patients practicing combat sports may result in achieving and maintaining satisfactory glycemic control without increased risk of metabolic decompensation. PMID- 25825690 TI - Sami reindeer herders' perspective on herbivory of subarctic mountain birch forests by geometrid moths and reindeer: a case study from northernmost Finland. AB - INTRODUCTION: Geometrid moths and semi-domesticated reindeer are both herbivores which feed on birch leaves in the subarctic mountain birch forests in northern Fennoscandia. The caterpillars of autumnal and winter moths have episodic outbreaks, which can occasionally lead to extensive defoliation of birch forests. Earlier studies have shown that reindeer have a negative effect on the regeneration of defoliated birches by grazing and browsing their seedlings and sprouts. CASE DESCRIPTION: We interviewed 15 reindeer herders in the Kaldoaivi and Paistunturi herding co-operative in northernmost Finland in order to analyse their past, present and future views on the behaviour of moths and the growth of mountain birches. We investigate the behaviour of the two herbivores by combining the indigenous knowledge (IK) of Sami herders with the results of relevant studies in biology and anthropology, applying niche construction theory (NCT) in doing so. DISCUSSION AND EVALUATION: In the first stage, the niche constructors (moths, reindeer, herders, mountain birch and other organisms) are looked upon as "equal constructors" of a shared niche. As changes unfold in their niche, their role changes from that of constructor to key constructor. The role and importance of niche constructors were different when nomadic pasture rotation was used than they are today under the herding co-operative system. Niche construction faced its most radical and permanent negative changes during the border closures that took place over the latter half of the 19(th) century. The large-scale nomadic life among the Sami herders, who migrated between Finland and Norway, came to an end. This phase was followed by stationary herding, which diminished the possibilities of reindeer to look for various environmental affordances. Difficult snow conditions or birch defoliation caused by moth outbreaks made the situation worse than before. Eventually reindeer became key constructors, together with moth larvae, leading to negative ecological inheritance that forced herders to use new, adaptive herding practices. CONCLUSIONS: Both the scientific data and the IK of herders highlight the roles of reindeer and herders as continuous key constructors of the focal niche, one which stands to be modified in more heterogenic ways than earlier due to global warming and hence will result in new ecological inheritance. PMID- 25825691 TI - Erosion in the occipital bone caused by the fixation instrument used for posterior atlantoaxial fusion -report of 4 cases. AB - INTRODUCTION: Conventionally, posterior C1-C2 fusion has been performed using a sublaminar wiring technique with a structural bone graft. Subsequent advent of newer fixation devices, such as the C1 lateral mass screw and C1 hook, has achieved more solid fixation with improved surgical outcome; however, in these fixation systems, the protruding end of the metal implant above the level of the atlas may result in a complication due to contact with the surrounding structures. CASE DESCRIPTION: Two men and two women whose ages at the time of surgery ranged from 14 to 72 years. A supralaminar hook was used as a fixation device for C1 in two cases, whereas a lateral mass screw (Tan's method) and an atlas claw hook were employed for one each of the remaining 2 cases. We retrospectively reviewed the clinical features and postoperative course of these patients using the clinical records. Moreover, we measured the protruding height of the instrument above the atlas as well as the Redlund-Johnell (R-J) value on postoperative radiographs. All patients complained of crepitus and/or pain on neck extension. Erosion in the occipital bone was detected on multiplanar reconstruction computed tomography (MPR-CT), whereas plain radiographs failed to reveal the bony change. In those cases, protruding instruments used for C1 fixation contacted the occipital bone resulting in an erosive change at the impingement point. We removed the implant in all four cases after confirmation of solid bony union. DISCUSSION AND EVALUATION: Two of the four patients complained of occipital crepitus alone without pain. The management options for this condition may be controversial; however, progression of bony erosion may result in perforation of the occipital bone. This may possibly be associated with the serious complication of cerebrospinal fluid leakage. Considering this potential sequela, we removed the implants from all our reported cases after confirmation of solid bony union. CONCLUSIONS: We treated four cases that developed erosion in the occipital bone after posterior spinal instrumentation was performed for upper cervical lesions including C1. MPR-CT was useful in detecting the erosive changes in the occipital bone. PMID- 25825692 TI - Lipoprotein particles and size, total and high molecular weight adiponectin, and leptin in relation to incident coronary heart disease among severely obese postmenopausal women: The Women's Health Initiative Observational Study. AB - BACKGROUND: We hypothesized that higher concentrations of LDL particles (LDL-P) and leptin, and lower concentrations of HDL particles (HDL-P), and total and high molecular weight (HMW) adiponectin, would predict incident coronary heart disease (CHD) among severely obese postmenopausal women. METHODS: In a case-cohort study nested in the Women's Health Initiative Observational Study, we sampled 677 of the 1852 white or black women with body mass index (BMI) >=40 kg/m2 and no prevalent cardiovascular disease (CVD), including all 124 cases of incident CHD over mean 5.0 year follow-up. Biomarkers were assayed on stored blood samples. RESULTS: In multivariable-adjusted weighted Cox models, higher baseline levels of total and small LDL-P, and lower levels of total and medium HDL-P, and smaller mean HDL-P size were significantly associated with incident CHD. In contrast, large HDL-P levels were inversely associated with CHD only for women without diabetes, and higher total and HMW adiponectin levels and lower leptin levels were associated with CHD only for women with diabetes. Higher total LDL-P and lower HDL-P were associated with CHD risk independently of confounders including CV risk factors and other lipoprotein measures, with adjusted HR (95%CIs) of 1.55(1.28, 1.88) and (0.70 (0.57, 0.85), respectively, and similar results for medium HDL-P. CONCLUSIONS: Higher CHD risk among severely obese postmenopausal women is strongly associated with modifiable concentrations of LDL-P and HDL-P, independent of diabetes, smoking, hypertension, physical activity, BMI and waist circumference. GENERAL SIGNIFICANCE: Severely obese postmenopausal women should be considered high risk candidates for lipid lowering therapy. PMID- 25825694 TI - The effect of ferric chloride on superficial bleeding. AB - BACKGROUND: Controlling superficial bleeding, despite all the progress in surgical science, is still a challenge in some settings. OBJECTIVES: This study assesses the hemostatic effects of ferric chloride and compares it with the standard method (suturing technique) to control superficial bleeding. MATERIALS AND METHODS: In this animal model study, 60 male Wistar rats were used. An incision, 2 cm long and 0.5 cm deep was made on rat skin and the hemostasis time was recorded using ferric chloride at different concentrations (5%, 10%, 15%, 25%, and 50%) and then using a control (i.e. control of bleeding by suturing). The skin tissue was examined for pathological changes. Finally, the obtained data were entered into SPSS (ver. 16) and analyzed using Kruskal-Wallis test, Mann Whitney, Kolmogorov-Smirnov, and Wilcoxon signed ranks test. RESULTS: The hemostasis time for the ferric chloride concentration group was significantly less than for the control group (P < 0.001). CONCLUSIONS: Ferric chloride may be an effective hemostatic agent to control superficial bleeding in rats. PMID- 25825693 TI - Measurement of body composition as a surrogate evaluation of energy balance in obese patients. AB - In clinical practice obesity is primarily diagnosed through the body mass index. In order to characterize patients affected by obesity the use of traditional anthropometric measures appears misleading. Beyond the body mass index, there are overwhelming evidences towards the relevance of a more detailed description of the individual phenotype by characterizing the main body components as free-fat mass, muscle mass, and fat mass. Among the numerous techniques actually available, bioelectrical impedance analysis seems to be the most suitable in a clinical setting because it is simple, inexpensive, noninvasive, and highly reproducible. To date, there is no consensus concerning the use of one preferred equation for the resting energy expenditure in overweight and/or obese population. Energy restriction alone is an effective strategy to achieve an early and significant weight loss, however it results in a reduction of both fat and lean mass therefore promoting or aggravating an unfavourable body composition (as sarcobesity) in terms of mortality and comorbidities. Therefore the implementation of daily levels of physical activity should be simultaneously promoted. The major role of muscle mass in the energy balance has been recently established by the rising prevalence of the combination of two condition as sarcopenia and obesity. Physical exercise stimulates energy expenditure, thereby directly improving energy balance, and also promotes adaptations such as fiber type, mitochondrial biogenesis, improvement of insulin resistance, and release of myokines, which may influence different tissues, including muscle. PMID- 25825695 TI - Correlation between magnetic resonance imaging and arthroscopic findings in the knee joint. AB - BACKGROUND: The knee joint is the largest and the most complex joint of the human body. It is not covered by any thick muscular covering anteriorly. OBJECTIVES: The purpose of this study was to explore the diagnostic capabilities of clinical examination, magnetic resonance imaging (MRI), and arthroscopy in traumatic disorders of the knee joint, to seek correlation between clinical findings, MRI findings and arthroscopic. PATIENTS AND METHODS: A total of 26 patients with a presentation suggestive of traumatic knee pathology were studied prospectively. A detailed history was taken and relevant clinical examination was done, which was followed by MRI of the knee. The patients were scheduled for arthroscopy under general/spinal anesthesia, whenever indicated. RESULTS: Keeping arthroscopic examination as standard, the correlation between clinical and arthroscopy showed a sensitivity of 80%, specificity of 86%, accuracy of 63.16%, negative predictive value of 93.48%; whereas MRI vs. arthroscopy showed a sensitivity of 74.42%, specificity of 93.10%, accuracy of 84.21%, and negative predictive value of 88.04%. CONCLUSIONS: The clinical examination is an important and accurate diagnostic modality for evaluation of traumatic derangement of the knee joint. It is noninvasive, easy, available, and valuable diagnostic modality. The MRI is an accurate diagnostic modality. It can be used whenever there is an uncertain indication for arthroscopy. However, costs have to be kept in mind, especially in patients with low socio-economic status. PMID- 25825696 TI - Accuracy of Rapid Ultrasound in Shock (RUSH) Exam for Diagnosis of Shock in Critically Ill Patients. AB - BACKGROUND: Rapid ultrasound in shock (RUSH) is the most recent emergency ultrasound protocol, designed to help clinicians better recognize distinctive shock etiologies in a shorter time frame. OBJECTIVES: In this study, we evaluated the accuracy of the RUSH protocol, performed by an emergency physician or radiologist, in predicting the type of shock in critical patients. PATIENTS AND METHODS: An emergency physician or radiologist performed the RUSH protocol for all patients with shock status at the emergency department. All patients were closely followed to determine their final clinical diagnosis. The agreement between the initial impression provided by RUSH and the final diagnosis was investigated by calculating the Kappa index. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of RUSH for diagnosis of each case. RESULTS: We performed RUSH on 77 patients. Kappa index was 0.71 (P Value = 0.000), reflecting acceptable general agreement between initial impression and final diagnosis. For hypovolemic, cardiogenic and obstructive shock, the protocol had an NPV above 97% yet it had a lower PPV. For shock with distributive or mixed etiology, RUSH showed a PPV of 100% but it had low sensitivity. Subgroup analysis showed a similar Kappa index for the emergency physician and radiologist (0.70 and 0.73, respectively) in performing rush. CONCLUSIONS: This study highlights the role of the RUSH exam performed by an emergency physician, to make a rapid and reliable diagnosis of shock etiology, especially in order to rule out obstructive, cardiogenic and hypovolemic shock types in initial exam of shock patients. PMID- 25825697 TI - Clinical instability of the knee and functional differences following tibial plateau fractures versus distal femoral fractures. AB - BACKGROUND: Fractures of the knee account for about 6% of all trauma admissions. While its management is mostly focused on fracture treatment, it is not the only factor that defines the final outcome. OBJECTIVES: This study aimed to study objective and subjective outcomes after proximal tibial versus distal femoral fractures in terms of knee instability and health-related quality of life. PATIENTS AND METHODS: This retrospective, cross-sectional, cohort study was carried out on 80 patients with either isolated proximal tibial (n = 42) or distal femoral (n = 38) fractures, who underwent open reduction and internal fixation. All the fractures were classified based on the Schatzker and AO classification for tibial plateau and distal femoral fractures, respectively. The patients were followed and examined by an orthopedic knee surgeon for clinical assessment of knee instability. In their last follow-up visit, these patients completed a Lysholm knee score and the short-form (SF) 36 health survey. RESULTS: Among the 42 tibial plateau fractures, 25% were classified as Schatzker type 2. Of the 38 distal femoral fractures, we did not find any type B1 or B3 fractures. The overall prevalence of anterior and posterior instability was 42% and 20%, respectively. Medial Collateral Ligament (MCL) and Lateral Collateral Ligament (LCL) injuries were detected clinically in 50% and 28%, respectively. The incidence rates of ligament injuries in tibial plateau fractures were as follows: Anterior Collateral Ligament (ACL) 26%, Posterior Collateral Ligament (PCL) 7%, MCL 24%, and LCL 14%. Medial collateral ligament injury was the most common in the Schatzker type 2 (50% of the injuries). Distal femoral fractures were associated with ACL injury in 16%, PCL in 13%, MCL in 26% and LCL in 14%. However, final knee range of motion (ROM) and function (Lysholm score) were not associated with fracture location. No statistically significant difference was observed between the two groups, except for the valgus stress test at 30 degrees knee flexion, which was more positive in tibial fractures. All eight domains of SF-36 score in the distal femoral and proximal tibial fractures were significantly different from the normal values; however, there were no statistically significant differences between femoral and tibial fracture scores. CONCLUSIONS: Although ROM is acceptable in knee joint fractures, instability is common. However, it seems that knee function and quality of life are not associated with the location of the fracture. PMID- 25825698 TI - Quality of life of caregiver spouses of veterans with bilateral lower extremity amputations. AB - BACKGROUND: Providing care for patients with chronic disability affects caregivers' social lives and relationships and can lead to poor health and lower quality of life. OBJECTIVES: In this study, our goal was to assess the quality of life in spouses of war veterans with bilateral lower limb amputations to find factors affecting caregivers' quality of life. PATIENTS AND METHODS: In a cross sectional study, spouses of 244 veterans with war-related bilateral lower limb amputations for at least one year were invited to participate in this study; 189 couples accepted to participate. Information about age, gender, education level, duration of time since amputation, duration of care provided by the spouses and SF-36 questionnaire for both veterans and their spouses were collected. RESULTS: The average age of spouses was 47 years and duration of care provided by spouses was 25 years. We found lower scores for general health domains in amputees' spouses compared to the general population. Factors correlated with both Physical Component Summary (PCS) and Mental Component Summary (MCS) included the duration of care, duration of marriage, spouses' education level and the veterans' PCS and MCS scores. Veterans' age, spouses' age and the number of children only correlated with PCS. Veterans' education level only correlated with MCS. In multivariable analysis, only spouses' education level correlated with MCS and the veterans' PCS only correlated with that of spouses. CONCLUSIONS: The quality of life of amputees and their spouses were closely correlated; therefore, any improvement in one is likely to improve the other. In addition, lower education level should be considered as a risk factor for poorer quality of life in amputees' spouses. PMID- 25825699 TI - Bone marrow mesenchymal stem cell and vein conduit on sciatic nerve repair in rats. AB - BACKGROUND: Peripheral nerve repair with sufficient functional recovery is an important issue in reconstructive surgery. Stem cells have attracted extensive research interest in recent years. OBJECTIVES: The purpose of this study was to compare the vein conduit technique, with and without the addition of mesenchymal stem cells in gap-less nerve injury repair in rats. MATERIALS AND METHODS: In this study, 36 Wistar rats were randomly allocated to three groups: In the first group, nerve repair was performed with simple neurorrhaphy (control group), in the second group, nerve repair was done with vein conduit over site (vein conduit group) and in the third group, bone marrow stem cells were instilled into the vein conduit (stem cell group) after nerve repair with vein conduit over site. Six weeks after the intervention, the sciatic function index, electrophysiological study and histological examination were performed. RESULTS: All animals tolerated the surgical procedures and survived well. The sciatic function index and latency were significantly improved in the vein conduit (P = 0.04 and 0.03, respectively) and stem cell group (P = 0.02 and 0.03, respectively) compared with the control group. No significant difference was observed in sciatic function and latency between the vein conduit and stem-cell groups. Moreover, histological analysis showed no significant difference in regenerative density between these two groups. CONCLUSIONS: The results of this study showed that the meticulous microsurgical nerve repair, which was performed using the vein tubulization induced significantly better sciatic nerve regeneration. However, the addition of bone marrow mesenchymal stem cell to vein conduit failed to promote any significant changes in regeneration outcome. PMID- 25825700 TI - First Aid and Transportation Course Contents Based on Experience gained in the Iran-Iraq War: a Qualitative Study. AB - BACKGROUND: Effective first aid and transportation influences injury-induced mortality. But few qualitative studies have been conducted so far in this area. OBJECTIVES: The aim of this study was to identify the content of the first aid and patient transportation course based on experience gained from the Iran-Iraq war. PATIENTS AND METHODS: This was a conventional qualitative content analysis study; a purposeful sample of 14 first aid and transportation experts who had worked during the Iran-Iraq war was recruited. We collected and analyzed the study data by using the semi-structured interview method and the conventional content analysis approach respectively. Each interview transcript was reviewed several times. Words, sentences, and paragraphs were labeled with codes. Codes were compared with each other and categorized according to their similarities. Similar sub-categories and categories were also grouped together and formed themes. RESULTS: Study participants' experiences of wartime first aid and transportation (FAT) education fell into two main themes including 'the congruence of education and educational needs' and 'managers' engagement in FAT education. The four main categories of these two themes were use of appropriate educational facilities, adopting effective teaching strategies, universal FAT education and specialized training skills. CONCLUSIONS: The two key requirements of the first aid and transportation courses are practicality and managerial engagement. We developed and provided specific guidance of FAT curriculum by using the study findings. This curriculum is recommended for educating FAT staffs, paramedics, emergency technicians, and military nurses. PMID- 25825701 TI - Celox-coated gauze for the treatment of civilian penetrating trauma: a randomized clinical trial. AB - BACKGROUND: Uncontrolled hemorrhage is a well-recognized cause of mortality in trauma victims and the control of active hemorrhage is among the initial steps in resuscitation. OBJECTIVES: The purpose of this study was to assess the role of a hemostatic agent "celox" in the management of civilian stab-wound trauma. PATIENTS AND METHODS: In this clinical trial study, 160 patients with penetrating limb trauma were randomly allocated to either the control or intervention group (n = 80, each group). Controls were treated with the simple pressure dressing, while the celox-coated gauze was used in the intervention group. The time for achievement of hemostasis and the amount of bleeding were recorded. Data were analyzed using SPSS Version 21 and Stata 13. A P value of less than 0.05 was considered statistically significant. RESULTS: The mean age of participants was 30.5 and the majority of patients were male (90.6%). The forearm and distal leg were the most sites of injury. Hemostasis was achieved within 5 minutes in 32.5% of the control group and 51.3% of the intervention group. Using the celox-coated gauze significantly reduced the time to hemostasis (P = 0.01). Moreover, the blood loss was significantly lower in the celox group compared to the controls (P < 0.05). CONCLUSIONS: Using the celox-coated gauze is able to achieve hemostasis in penetrating limb trauma faster than the conventional pressure bandage. Further research is required to clarify the subset of patients who will benefit the most from this effect in the emergency department. PMID- 25825702 TI - Use of ferric sulfate to control hepatic bleeding. AB - BACKGROUND: Controlling parenchymal hemorrhage, especially in liver parenchyma, despite all the progress in surgical science, is still one of the challenges surgeons face. Therefore, search for an effective method to control hepatic bleeding is an important research priority. OBJECTIVES: This study attempted to determine the haemostatic effect of ferric sulfate and compare it with the standard method (suturing technique). MATERIALS AND METHODS: In this animal model study, 60 male Wistar rats were used. An incision (2 cm in length and 1/2 cm in depth) was made on each rat's liver and the hemostasis time was measured using ferric sulfate with different concentrations (5%, 10%, 15%, 25%, and 50%) and then using simple suturing. The liver tissue was assessed for pathological changes. RESULTS: In all the groups, complete hemostasis occurred. Hemostasis times of different concentrations of ferric sulfate were significantly less than those of the control group (P < 0.001). CONCLUSIONS: Ferric sulfate was effective in controlling hepatic bleeding in rats. PMID- 25825703 TI - National getaways for the weary trauma surgeon; part 2: the northern provinces. PMID- 25825705 TI - The Community College Effect Revisited: The Importance of Attending to Heterogeneity and Complex Counterfactuals. AB - Community colleges are controversial educational institutions, often said to simultaneously expand college opportunities and diminish baccalaureate attainment. We assess the seemingly contradictory functions of community colleges by attending to effect heterogeneity and to alternative counterfactual conditions. Using data on postsecondary outcomes of high school graduates of Chicago Public Schools, we find that enrolling at a community college penalizes more advantaged students who otherwise would have attended four-year colleges, particularly highly selective schools; however, these students represent a relatively small portion of the community college population, and these estimates are almost certainly biased. On the other hand, enrolling at a community college has a modest positive effect on bachelor's degree completion for disadvantaged students who otherwise would not have attended college; these students represent the majority of community college goers. We conclude that discussions among scholars, policymakers, and practitioners should move beyond considering the pros and cons of community college attendance for students in general to attending to the implications of community college attendance for targeted groups of students. PMID- 25825704 TI - CD8+ TIL recruitment may revert the association of MAGE A3 with aggressive features in thyroid tumors. AB - BACKGROUND: We aimed to investigate a possible role of MAGE A3 and its associations with infiltrated immune cells in thyroid malignancy, analyzing their utility as a diagnostic and prognostic marker. MATERIALS AND METHODS: We studied 195 malignant tissues: 154 PTCs and 41 FTCs; 102 benign tissues: 51 follicular adenomas and 51 goiter and 17 normal thyroid tissues. MAGE A3 and immune cell markers (CD4 and CD8) were evaluated using immunohistochemistry and compared with clinical pathological features. RESULTS: The semiquantitative analysis and ACIS III analysis showed similar results. MAGE A3 was expressed in more malignant than in benign lesions (P < 0.0001), also helping to discriminate follicular-patterned lesions. It was also higher in tumors in which there was extrathyroidal invasion (P = 0.0206) and in patients with stage II disease (P = 0.0107). MAGE A3+ tumors were more likely to present CD8+ TIL (P = 0.0346), and these tumors were associated with less aggressive features, that is, extrathyroidal invasion and small size. There was a trend of MAGE A3+ CD8+ tumors to evolve free of disease. CONCLUSION: We demonstrated that MAGE A3 and CD8+ TIL infiltration may play an important role in malignant thyroid nodules, presenting an interesting perspective for new researches on DTC immunotherapy. PMID- 25825706 TI - Social Baseline Theory: The Social Regulation of Risk and Effort. AB - We describe Social Baseline Theory (SBT), a perspective that integrates the study of social relationships with principles of attachment, behavioral ecology, cognitive neuroscience, and perception science. SBT suggests the human brain expects access to social relationships that mitigate risk and diminish the level of effort needed to meet a variety of goals. This is accomplished in part by incorporating relational partners into neural representations of the self. By contrast, decreased access to relational partners increases cognitive and physiological effort. Relationship disruptions entail re-defining the self as independent, which implies greater risk, increased effort, and diminished well being. The ungrafting of the self and other may mediate recovery from relationship loss. PMID- 25825707 TI - Decreased BECN1 mRNA Expression in Human Breast Cancer is Associated with Estrogen Receptor-Negative Subtypes and Poor Prognosis. AB - Both BRCA1 and Beclin 1 (BECN1) are tumor suppressor genes, which are in close proximity on the human chromosome 17q21 breast cancer tumor susceptibility locus and are often concurrently deleted. However, their importance in sporadic human breast cancer is not known. To interrogate the effects of BECN1 and BRCA1 in breast cancer, we studied their mRNA expression patterns in breast cancer patients from two large datasets: The Cancer Genome Atlas (TCGA) (n=1067) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n=1992). In both datasets, low expression of BECN1 was more common in HER2-enriched and basal-like (mostly triple-negative) breast cancers compared to luminal A/B intrinsic tumor subtypes, and was also strongly associated with TP53 mutations and advanced tumor grade. In contrast, there was no significant association between low BRCA1 expression and HER2-enriched or basal-like subtypes, TP53 mutations or tumor grade. In addition, low expression of BECN1 (but not low BRCA1) was associated with poor prognosis, and BECN1 (but not BRCA1) expression was an independent predictor of survival. These findings suggest that decreased mRNA expression of the autophagy gene BECN1 may contribute to the pathogenesis and progression of HER2-enriched, basal-like, and TP53 mutant breast cancers. PMID- 25825708 TI - SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. AB - Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue. PMID- 25825709 TI - alpha-Synuclein, a chemoattractant, directs microglial migration via H2O2 dependent Lyn phosphorylation. AB - Malformed alpha-Synuclein (alpha-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in alpha-synucleinopathies, such as Parkinson's disease. The mechanisms by which alpha-syn aggregates activate and recruit microglia remain unclear, however. Here we show that alpha-syn aggregates act as chemoattractants to direct microglia toward damaged neurons. In addition, we describe a mechanism underlying this directional migration of microglia. Specifically, chemotaxis occurs when alpha-syn binds to integrin CD11b, leading to H2O2 production by NADPH oxidase. H2O2 directly attracts microglia via a process in which extracellularly generated H2O2 diffuses into the cytoplasm and tyrosine protein kinase Lyn, phosphorylates the F-actin-associated protein cortactin after sensing changes in the microglial intracellular concentration of H2O2. Finally, phosphorylated cortactin mediates actin cytoskeleton rearrangement and facilitates directional cell migration. These findings have significant implications, given that alpha-syn-mediated microglial migration reaches beyond Parkinson's disease. PMID- 25825710 TI - The circadian oscillator in Synechococcus elongatus controls metabolite partitioning during diurnal growth. AB - Synechococcus elongatus PCC 7942 is a genetically tractable model cyanobacterium that has been engineered to produce industrially relevant biomolecules and is the best-studied model for a prokaryotic circadian clock. However, the organism is commonly grown in continuous light in the laboratory, and data on metabolic processes under diurnal conditions are lacking. Moreover, the influence of the circadian clock on diurnal metabolism has been investigated only briefly. Here, we demonstrate that the circadian oscillator influences rhythms of metabolism during diurnal growth, even though light-dark cycles can drive metabolic rhythms independently. Moreover, the phenotype associated with loss of the core oscillator protein, KaiC, is distinct from that caused by absence of the circadian output transcriptional regulator, RpaA (regulator of phycobilisome associated A). Although RpaA activity is important for carbon degradation at night, KaiC is dispensable for those processes. Untargeted metabolomics analysis and glycogen kinetics suggest that functional KaiC is important for metabolite partitioning in the morning. Additionally, output from the oscillator functions to inhibit RpaA activity in the morning, and kaiC-null strains expressing a mutant KaiC phosphomimetic, KaiC-pST, in which the oscillator is locked in the most active output state, phenocopies a DeltarpaA strain. Inhibition of RpaA by the oscillator in the morning suppresses metabolic processes that normally are active at night, and kaiC-null strains show indications of oxidative pentose phosphate pathway activation as well as increased abundance of primary metabolites. Inhibitory clock output may serve to allow secondary metabolite biosynthesis in the morning, and some metabolites resulting from these processes may feed back to reinforce clock timing. PMID- 25825711 TI - Decoding stimulus features in primate somatosensory cortex during perceptual categorization. AB - Neurons of the primary somatosensory cortex (S1) respond as functions of frequency or amplitude of a vibrotactile stimulus. However, whether S1 neurons encode both frequency and amplitude of the vibrotactile stimulus or whether each sensory feature is encoded by separate populations of S1 neurons is not known, To further address these questions, we recorded S1 neurons while trained monkeys categorized only one sensory feature of the vibrotactile stimulus: frequency, amplitude, or duration. The results suggest a hierarchical encoding scheme in S1: from neurons that encode all sensory features of the vibrotactile stimulus to neurons that encode only one sensory feature. We hypothesize that the dynamic representation of each sensory feature in S1 might serve for further downstream processing that leads to the monkey's psychophysical behavior observed in these tasks. PMID- 25825712 TI - Memory, scene construction, and the human hippocampus. AB - We evaluated two different perspectives about the function of the human hippocampus--one that emphasizes the importance of memory and another that emphasizes the importance of spatial processing and scene construction. We gave tests of boundary extension, scene construction, and memory to patients with lesions limited to the hippocampus or large lesions of the medial temporal lobe. The patients were intact on all of the spatial tasks and impaired on all of the memory tasks. We discuss earlier studies that associated performance on these spatial tasks to hippocampal function. Our results demonstrate the importance of medial temporal lobe structures for memory and raise doubts about the idea that these structures have a prominent role in spatial cognition. PMID- 25825713 TI - Molecular mechanism underlying beta1 regulation in voltage- and calcium-activated potassium (BK) channels. AB - Being activated by depolarizing voltages and increases in cytoplasmic Ca(2+), voltage- and calcium-activated potassium (BK) channels and their modulatory beta subunits are able to dampen or stop excitatory stimuli in a wide range of cellular types, including both neuronal and nonneuronal tissues. Minimal alterations in BK channel function may contribute to the pathophysiology of several diseases, including hypertension, asthma, cancer, epilepsy, and diabetes. Several gating processes, allosterically coupled to each other, control BK channel activity and are potential targets for regulation by auxiliary beta subunits that are expressed together with the alpha (BK)-subunit in almost every tissue type where they are found. By measuring gating currents in BK channels coexpressed with chimeras between beta1 and beta3 or beta2 auxiliary subunits, we were able to identify that the cytoplasmic regions of beta1 are responsible for the modulation of the voltage sensors. In addition, we narrowed down the structural determinants to the N terminus of beta1, which contains two lysine residues (i.e., K3 and K4), which upon substitution virtually abolished the effects of beta1 on charge movement. The mechanism by which K3 and K4 stabilize the voltage sensor is not electrostatic but specific, and the alpha (BK)-residues involved remain to be identified. This is the first report, to our knowledge, where the regulatory effects of the beta1-subunit have been clearly assigned to a particular segment, with two pivotal amino acids being responsible for this modulation. PMID- 25825715 TI - Unraveling the association between mRNA expressions and mutant phenotypes in a genome-wide assessment of mice. AB - High-throughput gene expression profiling has revealed substantial leaky and extraneous transcription of eukaryotic genes, challenging the perceptions that transcription is strictly regulated and that changes in transcription have phenotypic consequences. To assess the functional implications of mRNA transcription directly, we analyzed mRNA expression data derived from microarrays, RNA-sequencing, and in situ hybridization, together with phenotype data of mouse mutants as a proxy of gene function at the tissue level. The results indicated that despite the presence of widespread ectopic transcription, mRNA expression and mutant phenotypes of mammalian genes or tissues remain associated. The expression-phenotype association at the gene level was particularly strong for tissue-specific genes, and the association could be underestimated due to data insufficiency and incomprehensive phenotyping of mouse mutants; the strength of expression-phenotype association at the tissue level depended on tissue functions. Mutations on genes expressed at higher levels or expressed at earlier embryonic stages more often result in abnormal phenotypes in the tissues where they are expressed. The mRNA expression profiles that have stronger associations with their phenotype profiles tend to be more evolutionarily conserved, indicating that the evolution of transcriptome and the evolution of phenome are coupled. Therefore, mutations resulting in phenotypic aberrations in expressed tissues are more likely to occur in highly transcribed genes, tissue-specific genes, genes expressed during early embryonic stages, or genes with evolutionarily conserved mRNA expression profiles. PMID- 25825714 TI - Estrogen receptor alpha inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression. AB - Recurrent estrogen receptor alpha (ERalpha)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERalpha biomodulator that selectively blocks proliferation of drug-resistant ERalpha-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERalpha-regulated gene expression, BHPI is effective because it elicits sustained ERalpha-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERalpha: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERalpha(+) cancer cells, BHPI rapidly hyperactivates plasma membrane PLCgamma, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca(2+) stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca(2+) levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration. PMID- 25825716 TI - Alternative splicing of the androgen receptor in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders and a leading cause of female subfertility. The mechanism underlying the pathophysiology of PCOS remains to be illustrated. Here, we identify two alternative splice variants (ASVs) of the androgen receptor (AR), insertion and deletion isoforms, in granulosa cells (GCs) in ~62% of patients with PCOS. AR ASVs are strongly associated with remarkable hyperandrogenism and abnormalities in folliculogenesis, and are absent from all control subjects without PCOS. Alternative splicing dramatically alters genome-wide AR recruitment and androgen induced expression of genes related to androgen metabolism and folliculogenesis in human GCs. These findings establish alternative splicing of AR in GCs as the major pathogenic mechanism for hyperandrogenism and abnormal folliculogenesis in PCOS. PMID- 25825717 TI - Coding of envelopes by correlated but not single-neuron activity requires neural variability. AB - Understanding how the brain processes sensory information is often complicated by the fact that neurons exhibit trial-to-trial variability in their responses to stimuli. Indeed, the role of variability in sensory coding is still highly debated. Here, we examined how variability influences neural responses to naturalistic stimuli consisting of a fast time-varying waveform (i.e., carrier or first order) whose amplitude (i.e., envelope or second order) varies more slowly. Recordings were made from fish electrosensory and monkey vestibular sensory neurons. In both systems, we show that correlated but not single-neuron activity can provide detailed information about second-order stimulus features. Using a simple mathematical model, we made the strong prediction that such correlation based coding of envelopes requires neural variability. Strikingly, the performance of correlated activity at predicting the envelope was similarly optimally tuned to a nonzero level of variability in both systems, thereby confirming this prediction. Finally, we show that second-order sensory information can only be decoded if one takes into account joint statistics when combining neural activities. Our results thus show that correlated but not single neural activity can transmit information about the envelope, that such transmission requires neural variability, and that this information can be decoded. We suggest that envelope coding by correlated activity is a general feature of sensory processing that will be found across species and systems. PMID- 25825718 TI - Reconstitution of a prokaryotic minus end-tracking system using TubRC centromeric complexes and tubulin-like protein TubZ filaments. AB - Segregation of DNA is a fundamental process during cell division. The mechanism of prokaryotic DNA segregation is largely unknown, but several low-copy-number plasmids encode cytomotive filament systems of the actin type and tubulin type important for plasmid inheritance. Of these cytomotive filaments, only actin-like systems are mechanistically well characterized. In contrast, the mechanism by which filaments of tubulin-like TubZ protein mediate DNA motility is unknown. To understand polymer-driven DNA transport, we reconstituted the filaments of TubZ protein (TubZ filaments) from Bacillus thuringiensis pBtoxis plasmid with their centromeric TubRC complexes containing adaptor protein TubR and tubC DNA. TubZ alone assembled into polar filaments, which annealed laterally and treadmilled. Using single-molecule imaging, we show that TubRC complexes were not pushed by filament polymerization; instead, they processively tracked shrinking, depolymerizing minus ends. Additionally, the TubRC complex nucleated TubZ filaments and allowed for treadmilling. Overall, our results indicate a pulling mechanism for DNA transport by the TubZRC system. The discovered minus end tracking property of the TubRC complex expands the mechanistic diversity of the prokaryotic cytoskeleton. PMID- 25825719 TI - Environmental tipping points significantly affect the cost-benefit assessment of climate policies. AB - Most current cost-benefit analyses of climate change policies suggest an optimal global climate policy that is significantly less stringent than the level required to meet the internationally agreed 2 degrees C target. This is partly because the sum of estimated economic damage of climate change across various sectors, such as energy use and changes in agricultural production, results in only a small economic loss or even a small economic gain in the gross world product under predicted levels of climate change. However, those cost-benefit analyses rarely take account of environmental tipping points leading to abrupt and irreversible impacts on market and nonmarket goods and services, including those provided by the climate and by ecosystems. Here we show that including environmental tipping point impacts in a stochastic dynamic integrated assessment model profoundly alters cost-benefit assessment of global climate policy. The risk of a tipping point, even if it only has nonmarket impacts, could substantially increase the present optimal carbon tax. For example, a risk of only 5% loss in nonmarket goods that occurs with a 5% annual probability at 4 degrees C increase of the global surface temperature causes an immediate two thirds increase in optimal carbon tax. If the tipping point also has a 5% impact on market goods, the optimal carbon tax increases by more than a factor of 3. Hence existing cost-benefit assessments of global climate policy may be significantly underestimating the needs for controlling climate change. PMID- 25825720 TI - Lag threads organize the brain's intrinsic activity. AB - It has been widely reported that intrinsic brain activity, in a variety of animals including humans, is spatiotemporally structured. Specifically, propagated slow activity has been repeatedly demonstrated in animals. In human resting-state fMRI, spontaneous activity has been understood predominantly in terms of zero-lag temporal synchrony within widely distributed functional systems (resting-state networks). Here, we use resting-state fMRI from 1,376 normal, young adults to demonstrate that multiple, highly reproducible, temporal sequences of propagated activity, which we term "lag threads," are present in the brain. Moreover, this propagated activity is largely unidirectional within conventionally understood resting-state networks. Modeling experiments show that resting-state networks naturally emerge as a consequence of shared patterns of propagation. An implication of these results is that common physiologic mechanisms may underlie spontaneous activity as imaged with fMRI in humans and slowly propagated activity as studied in animals. PMID- 25825721 TI - Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference. AB - The protein synthesis machineries of two distinct phyla of the Animal kingdom, insects of Arthropoda and mammals of Chordata, have different preferences for how to best encode proteins. Nevertheless, arboviruses (arthropod-borne viruses) are capable of infecting both mammals and insects just like arboviruses that use insect vectors to infect plants. These organisms have evolved carefully balanced genomes that can efficiently use the translational machineries of different phyla, even if the phyla belong to different kingdoms. Using dengue virus as an example, we have undone the genome encoding balance and specifically shifted the encoding preference away from mammals. These mammalian-attenuated viruses grow to high titers in insect cells but low titers in mammalian cells, have dramatically increased LD50s in newborn mice, and induce high levels of protective antibodies. Recoded arboviruses with a bias toward phylum-specific expression could form the basis of a new generation of live attenuated vaccine candidates. PMID- 25825722 TI - Analysis of cell division patterns in the Arabidopsis shoot apical meristem. AB - The stereotypic pattern of cell shapes in the Arabidopsis shoot apical meristem (SAM) suggests that strict rules govern the placement of new walls during cell division. When a cell in the SAM divides, a new wall is built that connects existing walls and divides the cytoplasm of the daughter cells. Because features that are determined by the placement of new walls such as cell size, shape, and number of neighbors are highly regular, rules must exist for maintaining such order. Here we present a quantitative model of these rules that incorporates different observed features of cell division. Each feature is incorporated into a "potential function" that contributes a single term to a total analog of potential energy. New cell walls are predicted to occur at locations where the potential function is minimized. Quantitative terms that represent the well-known historical rules of plant cell division, such as those given by Hofmeister, Errera, and Sachs are developed and evaluated against observed cell divisions in the epidermal layer (L1) of Arabidopsis thaliana SAM. The method is general enough to allow additional terms for nongeometric properties such as internal concentration gradients and mechanical tensile forces. PMID- 25825723 TI - Zinc as chaperone-mimicking agent for retardation of amyloid beta peptide fibril formation. AB - Metal ions have emerged to play a key role in the aggregation process of amyloid beta (Abeta) peptide that is closely related to the pathogenesis of Alzheimer's disease. A detailed understanding of the underlying mechanistic process of peptide-metal interactions, however, has been challenging to obtain. By applying a combination of NMR relaxation dispersion and fluorescence kinetics methods we have investigated quantitatively the thermodynamic Abeta-Zn(2+) binding features as well as how Zn(2+) modulates the nucleation mechanism of the aggregation process. Our results show that, under near-physiological conditions, substoichiometric amounts of Zn(2+) effectively retard the generation of amyloid fibrils. A global kinetic profile analysis reveals that in the absence of zinc Abeta40 aggregation is driven by a monomer-dependent secondary nucleation process in addition to fibril-end elongation. In the presence of Zn(2+), the elongation rate is reduced, resulting in reduction of the aggregation rate, but not a complete inhibition of amyloid formation. We show that Zn(2+) transiently binds to residues in the N terminus of the monomeric peptide. A thermodynamic analysis supports a model where the N terminus is folded around the Zn(2+) ion, forming a marginally stable, short-lived folded Abeta40 species. This conformation is highly dynamic and only a few percent of the peptide molecules adopt this structure at any given time point. Our findings suggest that the folded Abeta40 Zn(2+) complex modulates the fibril ends, where elongation takes place, which efficiently retards fibril formation. In this conceptual framework we propose that zinc adopts the role of a minimal antiaggregation chaperone for Abeta40. PMID- 25825724 TI - ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. AB - Pseudokinases lack conserved motifs typically required for kinase activity. Nearly half of pseudokinases bind ATP, but only few retain phosphotransfer activity, leaving the functional role of nucleotide binding in most cases unknown. Janus kinases (JAKs) are nonreceptor tyrosine kinases with a tandem pseudokinase-kinase domain configuration, where the pseudokinase domain (JAK homology 2, JH2) has important regulatory functions and harbors mutations underlying hematological and immunological diseases. JH2 of JAK1, JAK2, and TYK2 all bind ATP, but the significance of this is unclear. We characterize the role of nucleotide binding in normal and pathogenic JAK signaling using comprehensive structure-based mutagenesis. Disruption of JH2 ATP binding in wild-type JAK2 has only minor effects, and in the presence of type I cytokine receptors, the mutations do not affect JAK2 activation. However, JH2 mutants devoid of ATP binding ameliorate the hyperactivation of JAK2 V617F. Disrupting ATP binding in JH2 also inhibits the hyperactivity of other pathogenic JAK2 mutants, as well as of JAK1 V658F, and prevents induction of erythrocytosis in a JAK2 V617F myeloproliferative neoplasm mouse model. Molecular dynamic simulations and thermal-shift analysis indicate that ATP binding stabilizes JH2, with a pronounced effect on the C helix region, which plays a critical role in pathogenic activation of JAK2. Taken together, our results suggest that ATP binding to JH2 serves a structural role in JAKs, which is required for aberrant activity of pathogenic JAK mutants. The inhibitory effect of abrogating JH2 ATP binding in pathogenic JAK mutants may warrant novel therapeutic approaches. PMID- 25825725 TI - Quantitative analysis of vesicle recycling at the calyx of Held synapse. AB - Vesicle recycling is pivotal for maintaining reliable synaptic signaling, but its basic properties remain poorly understood. Here, we developed an approach to quantitatively analyze the kinetics of vesicle recycling with exquisite signal and temporal resolution at the calyx of Held synapse. The combination of this electrophysiological approach with electron microscopy revealed that ~80% of vesicles (~270,000 out of ~330,000) in the nerve terminal are involved in recycling. Under sustained stimulation, recycled vesicles start to be reused in tens of seconds when ~47% of the preserved vesicles in the recycling pool (RP) are depleted. The heterogeneity of vesicle recycling as well as two kinetic components of RP depletion revealed the existence of a replenishable pool of vesicles before the priming stage and led to a realistic kinetic model that assesses the size of the subpools of the RP. Thus, our study quantified the kinetics of vesicle recycling and kinetically dissected the whole vesicle pool in the calyceal terminal into the readily releasable pool (~0.6%), the readily priming pool (~46%), the premature pool (~33%), and the resting pool (~20%). PMID- 25825726 TI - Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction. AB - Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day ~105 Bos taurus indicus * Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS. PMID- 25825727 TI - Response of seafloor ecosystems to abrupt global climate change. AB - Anthropogenic climate change is predicted to decrease oceanic oxygen (O2) concentrations, with potentially significant effects on marine ecosystems. Geologically recent episodes of abrupt climatic warming provide opportunities to assess the effects of changing oxygenation on marine communities. Thus far, this knowledge has been largely restricted to investigations using Foraminifera, with little being known about ecosystem-scale responses to abrupt, climate-forced deoxygenation. We here present high-resolution records based on the first comprehensive quantitative analysis, to our knowledge, of changes in marine metazoans (Mollusca, Echinodermata, Arthropoda, and Annelida; >5,400 fossils and trace fossils) in response to the global warming associated with the last glacial to interglacial episode. The molluscan archive is dominated by extremophile taxa, including those containing endosymbiotic sulfur-oxidizing bacteria (Lucinoma aequizonatum) and those that graze on filamentous sulfur-oxidizing benthic bacterial mats (Alia permodesta). This record, from 16,100 to 3,400 y ago, demonstrates that seafloor invertebrate communities are subject to major turnover in response to relatively minor inferred changes in oxygenation (>1.5 to <0.5 mL?L(-1) [O2]) associated with abrupt (<100 y) warming of the eastern Pacific. The biotic turnover and recovery events within the record expand known rates of marine biological recovery by an order of magnitude, from <100 to >1,000 y, and illustrate the crucial role of climate and oceanographic change in driving long term successional changes in ocean ecosystems. PMID- 25825728 TI - Phosphatidylinositol 4-phosphate and phosphatidylinositol 3-phosphate regulate phagolysosome biogenesis. AB - Professional phagocytic cells ingest microbial intruders by engulfing them into phagosomes, which subsequently mature into microbicidal phagolysosomes. Phagosome maturation requires sequential fusion of the phagosome with early endosomes, late endosomes, and lysosomes. Although various phosphoinositides (PIPs) have been detected on phagosomes, it remained unclear which PIPs actually govern phagosome maturation. Here, we analyzed the involvement of PIPs in fusion of phagosomes with various endocytic compartments and identified phosphatidylinositol 4 phosphate [PI(4)P], phosphatidylinositol 3-phosphate [PI(3)P], and the lipid kinases that generate these PIPs, as mediators of phagosome-lysosome fusion. Phagosome-early endosome fusion required PI(3)P, yet did not depend on PI(4)P. Thus, PI(3)P regulates phagosome maturation at early and late stages, whereas PI(4)P is selectively required late in the pathway. PMID- 25825729 TI - Four hundred million years of silica biomineralization in land plants. AB - Biomineralization plays a fundamental role in the global silicon cycle. Grasses are known to mobilize significant quantities of Si in the form of silica biominerals and dominate the terrestrial realm today, but they have relatively recent origins and only rose to taxonomic and ecological prominence within the Cenozoic Era. This raises questions regarding when and how the biological silica cycle evolved. To address these questions, we examined silica abundances of extant members of early-diverging land plant clades, which show that silica biomineralization is widespread across terrestrial plant linages. Particularly high silica abundances are observed in lycophytes and early-diverging ferns. However, silica biomineralization is rare within later-evolving gymnosperms, implying a complex evolutionary history within the seed plants. Electron microscopy and X-ray spectroscopy show that the most common silica-mineralized tissues include the vascular system, epidermal cells, and stomata, which is consistent with the hypothesis that biomineralization in plants is frequently coupled to transpiration. Furthermore, sequence, phylogenetic, and structural analysis of nodulin 26-like intrinsic proteins from diverse plant genomes points to a plastic and ancient capacity for silica accumulation within terrestrial plants. The integration of these two comparative biology approaches demonstrates that silica biomineralization has been an important process for land plants over the course of their >400 My evolutionary history. PMID- 25825730 TI - Loose coupling in the bacterial flagellar motor. AB - Physiological properties of the flagellar rotary motor have been taken to indicate a tightly coupled mechanism in which each revolution is driven by a fixed number of energizing ions. Measurements that would directly test the tight coupling hypothesis have not been made. Energizing ions flow through membrane bound complexes formed from the proteins MotA and MotB, which are anchored to the cell wall and constitute the stator. Genetic and biochemical evidence points to a "power stroke" mechanism in which the ions interact with an aspartate residue of MotB to drive conformational changes in MotA that are transmitted to the rotor protein FliG. Each stator complex contains two separate ion-binding sites, raising the question of whether the power stroke is driven by one, two, or either number of ions. Here, we describe simulations of a model in which the conformational change can be driven by either one or two ions. This loosely coupled model can account for the observed physiological properties of the motor, including those that have been taken to indicate tight coupling; it also accords with recent measurements of motor torque at high load that are harder to explain in tight-coupling models. Under loads relevant to a swimming cell, the loosely coupled motor would perform about as well as a two-proton motor and significantly better than a one-proton motor. The loosely coupled motor is predicted to be especially advantageous under conditions of diminished energy supply, or of reduced temperature, turning faster than an obligatorily two-proton motor while using fewer ions. PMID- 25825731 TI - Task-driven intra- and interarea communications in primate cerebral cortex. AB - Neural correlations during a cognitive task are central to study brain information processing and computation. However, they have been poorly analyzed due to the difficulty of recording simultaneous single neurons during task performance. In the present work, we quantified neural directional correlations using spike trains that were simultaneously recorded in sensory, premotor, and motor cortical areas of two monkeys during a somatosensory discrimination task. Upon modeling spike trains as binary time series, we used a nonparametric Bayesian method to estimate pairwise directional correlations between many pairs of neurons throughout different stages of the task, namely, perception, working memory, decision making, and motor report. We find that solving the task involves feedforward and feedback correlation paths linking sensory and motor areas during certain task intervals. Specifically, information is communicated by task-driven neural correlations that are significantly delayed across secondary somatosensory cortex, premotor, and motor areas when decision making takes place. Crucially, when sensory comparison is no longer requested for task performance, a major proportion of directional correlations consistently vanish across all cortical areas. PMID- 25825732 TI - Amygdala lesions do not compromise the cortical network for false-belief reasoning. AB - The amygdala plays an integral role in human social cognition and behavior, with clear links to emotion recognition, trust judgments, anthropomorphization, and psychiatric disorders ranging from social phobia to autism. A central feature of human social cognition is a theory-of-mind (ToM) that enables the representation other people's mental states as distinct from one's own. Numerous neuroimaging studies of the best studied use of ToM--false-belief reasoning--suggest that it relies on a specific cortical network; moreover, the amygdala is structurally and functionally connected with many components of this cortical network. It remains unknown whether the cortical implementation of any form of ToM depends on amygdala function. Here we investigated this question directly by conducting functional MRI on two patients with rare bilateral amygdala lesions while they performed a neuroimaging protocol standardized for measuring cortical activity associated with false-belief reasoning. We compared patient responses with those of two healthy comparison groups that included 480 adults. Based on both univariate and multivariate comparisons, neither patient showed any evidence of atypical cortical activity or any evidence of atypical behavioral performance; moreover, this pattern of typical cortical and behavioral response was replicated for both patients in a follow-up session. These findings argue that the amygdala is not necessary for the cortical implementation of ToM in adulthood and suggest a reevaluation of the role of the amygdala and its cortical interactions in human social cognition. PMID- 25825733 TI - Chiral structures from achiral liquid crystals in cylindrical capillaries. AB - We study chiral symmetry-broken configurations of nematic liquid crystals (LCs) confined to cylindrical capillaries with homeotropic anchoring on the cylinder walls (i.e., perpendicular surface alignment). Interestingly, achiral nematic LCs with comparatively small twist elastic moduli relieve bend and splay deformations by introducing twist deformations. In the resulting twisted and escaped radial (TER) configuration, LC directors are parallel to the cylindrical axis near the center, but to attain radial orientation near the capillary wall, they escape along the radius through bend and twist distortions. Chiral symmetry-breaking experiments in polymer-coated capillaries are carried out using Sunset Yellow FCF, a lyotropic chromonic LC with a small twist elastic constant. Its director configurations are investigated by polarized optical microscopy and explained theoretically with numerical calculations. A rich phenomenology of defects also arises from the degenerate bend/twist deformations of the TER configuration, including a nonsingular domain wall separating domains of opposite twist handedness but the same escape direction and singular point defects (hedgehogs) separating domains of opposite escape direction. We show the energetic preference for singular defects separating domains of opposite twist handedness compared with those of the same handedness, and we report remarkable chiral configurations with a double helix of disclination lines along the cylindrical axis. These findings show archetypally how simple boundary conditions and elastic anisotropy of confined materials lead to multiple symmetry breaking and how these broken symmetries combine to create a variety of defects. PMID- 25825734 TI - Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation. AB - Hedgehog (Hh) signaling is essential for osteoblast differentiation in the endochondral skeleton during embryogenesis. However, the molecular mechanism underlying the osteoblastogenic role of Hh is not completely understood. Here, we report that Hh markedly induces the expression of insulin-like growth factor 2 (Igf2) that activates the mTORC2-Akt signaling cascade during osteoblast differentiation. Igf2-Akt signaling, in turn, stabilizes full-length Gli2 through Serine 230, thus enhancing the output of transcriptional activation by Hh. Importantly, genetic deletion of the Igf signaling receptor Igf1r specifically in Hh-responding cells diminishes bone formation in the mouse embryo. Thus, Hh engages Igf signaling in a positive feedback mechanism to activate the osteogenic program. PMID- 25825735 TI - Islet 1 specifies the identity of hypothalamic melanocortin neurons and is critical for normal food intake and adiposity in adulthood. AB - Food intake and body weight regulation depend on proper expression of the proopiomelanocortin gene (Pomc) in a group of neurons located in the mediobasal hypothalamus of all vertebrates. These neurons release POMC-encoded melanocortins, which are potent anorexigenic neuropeptides, and their absence from mice or humans leads to hyperphagia and severe obesity. Although the pathophysiology of hypothalamic POMC neurons is well understood, the genetic program that establishes the neuronal melanocortinergic phenotype and maintains a fully functional neuronal POMC phenotype throughout adulthood remains unknown. Here, we report that the early expression of the LIM-homeodomain transcription factor Islet 1 (ISL1) in the developing hypothalamus promotes the terminal differentiation of melanocortinergic neurons and is essential for hypothalamic Pomc expression since its initial onset and throughout the entire lifetime. We detected ISL1 in the prospective hypothalamus just before the onset of Pomc expression and, from then on, Pomc and Isl1 coexpress. ISL1 binds in vitro and in vivo to critical homeodomain binding DNA motifs present in the neuronal Pomc enhancers nPE1 and nPE2, and mutations of these sites completely disrupt the ability of these enhancers to drive reporter gene expression to hypothalamic POMC neurons in transgenic mice and zebrafish. ISL1 is necessary for hypothalamic Pomc expression during mouse and zebrafish embryogenesis. Furthermore, conditional Isl1 inactivation from POMC neurons impairs Pomc expression, leading to hyperphagia and obesity. Our results demonstrate that ISL1 specifies the identity of hypothalamic melanocortin neurons and is required for melanocortin-induced satiety and normal adiposity throughout the entire lifespan. PMID- 25825737 TI - Sponge symbionts and the marine P cycle. PMID- 25825736 TI - Sphingomyelin distribution in lipid rafts of artificial monolayer membranes visualized by Raman microscopy. AB - Sphingomyelin (SM) and cholesterol (chol)-rich domains in cell membranes, called lipid rafts, are thought to have important biological functions related to membrane signaling and protein trafficking. To visualize the distribution of SM in lipid rafts by means of Raman microscopy, we designed and synthesized an SM analog tagged with a Raman-active diyne moiety (diyne-SM). Diyne-SM showed a strong peak in a Raman silent region that is free of interference from intrinsic vibrational modes of lipids and did not appear to alter the properties of SM containing monolayers. Therefore, we used Raman microscopy to directly visualize the distribution of diyne-SM in raft-mimicking domains formed in SM/dioleoylphosphatidylcholine/chol ternary monolayers. Raman images visualized a heterogeneous distribution of diyne-SM, which showed marked variation, even within a single ordered domain. Specifically, diyne-SM was enriched in the central area of raft domains compared with the peripheral area. These results seem incompatible with the generally accepted raft model, in which the raft and nonraft phases show a clear biphasic separation. One of the possible reasons is that gradual changes of SM concentration occur between SM-rich and -poor regions to minimize hydrophobic mismatch. We believe that our technique of hyperspectral Raman imaging of a single lipid monolayer opens the door to quantitative analysis of lipid membranes by providing both chemical information and spatial distribution with high (diffraction-limited) spatial resolution. PMID- 25825738 TI - Autoinhibition of MDMX by intramolecular p53 mimicry. AB - The p53 inhibitor MDMX is controlled by multiple stress signaling pathways. Using a proteolytic fragment release (PFR) assay, we detected an intramolecular interaction in MDMX that mechanistically mimics the interaction with p53, resulting in autoinhibition of MDMX. This mimicry is mediated by a hydrophobic peptide located in a long disordered central segment of MDMX that has sequence similarity to the p53 transactivation domain. NMR spectroscopy was used to show this hydrophobic peptide interacts with the N-terminal domain of MDMX in a structurally analogous manner to p53. Mutation of two critical tryptophan residues in the hydrophobic peptide disrupted the intramolecular interaction and increased p53 binding, providing further evidence for mechanistic mimicry. The PFR assay also revealed a second intramolecular interaction between the RING domain and central region that regulates MDMX nuclear import. These results establish the importance of intramolecular interactions in MDMX regulation, and validate a new assay for the study of intramolecular interactions in multidomain proteins with intrinsically disordered regions. PMID- 25825739 TI - Ideal probe single-molecule experiments reveal the intrinsic dynamic heterogeneity of a supercooled liquid. AB - The concept of dynamic heterogeneity and the picture of the supercooled liquid as a mosaic of environments with distinct dynamics that interchange in time have been invoked to explain the nonexponential relaxations measured in these systems. The spatial extent and temporal persistence of these regions of distinct dynamics have remained challenging to identify. Here, single-molecule fluorescence measurements using a probe similar in size and mobility to the host o-terphenyl unambiguously reveal exponential relaxations distributed in time and space and directly demonstrate ergodicity of the system down to the glass transition temperature. In the temperature range probed, at least 200 times the structural relaxation time of the host is required to recover ensemble-averaged relaxation at every spatial region in the system. PMID- 25825740 TI - Extreme rainfall activity in the Australian tropics reflects changes in the El Nino/Southern Oscillation over the last two millennia. AB - Assessing temporal variability in extreme rainfall events before the historical era is complicated by the sparsity of long-term "direct" storm proxies. Here we present a 2,200-y-long, accurate, and precisely dated record of cave flooding events from the northwest Australian tropics that we interpret, based on an integrated analysis of meteorological data and sediment layers within stalagmites, as representing a proxy for extreme rainfall events derived primarily from tropical cyclones (TCs) and secondarily from the regional summer monsoon. This time series reveals substantial multicentennial variability in extreme rainfall, with elevated occurrence rates characterizing the twentieth century, 850-1450 CE (Common Era), and 50-400 CE; reduced activity marks 1450 1650 CE and 500-850 CE. These trends are similar to reconstructed numbers of TCs in the North Atlantic and Caribbean basins, and they form temporal and spatial patterns best explained by secular changes in the dominant mode of the El Nino/Southern Oscillation (ENSO), the primary driver of modern TC variability. We thus attribute long-term shifts in cyclogenesis in both the central Australian and North Atlantic sectors over the past two millennia to entrenched El Nino or La Nina states of the tropical Pacific. The influence of ENSO on monsoon precipitation in this region of northwest Australia is muted, but ENSO-driven changes to the monsoon may have complemented changes to TC activity. PMID- 25825741 TI - Galphai1 and Galphai3 regulate macrophage polarization by forming a complex containing CD14 and Gab1. AB - Heterotrimeric G proteins have been implicated in Toll-like receptor 4 (TLR4) signaling in macrophages and endothelial cells. However, whether guanine nucleotide-binding protein G(i) subunit alpha-1 and alpha-3 (Galphai1/3) are required for LPS responses remains unclear, and if so, the underlying mechanisms need to be studied. In this study, we demonstrated that, in response to LPS, Galphai1/3 form complexes containing the pattern recognition receptor (PRR) CD14 and growth factor receptor binding 2 (Grb2)-associated binding protein (Gab1), which are required for activation of PI3K-Akt signaling. Galphai1/3 deficiency decreased LPS-induced TLR4 endocytosis, which was associated with decreased phosphorylation of IFN regulatory factor 3 (IRF3). Galphai1/3 knockdown in bone marrow-derived macrophage cells (Galphai1/3 KD BMDMs) exhibited an M2-like phenotype with significantly suppressed production of TNF-alpha, IL-6, IL-12, and NO in response to LPS. The altered polarization coincided with decreased Akt activation. Further, Galphai1/3 deficiency caused LPS tolerance in mice. In vitro studies revealed that, in LPS-tolerant macrophages, Galphai1/3 were down regulated partially by the proteasome pathway. Collectively, the present findings demonstrated that Galphai1/3 can interact with CD14/Gab1, which modulates macrophage polarization in vitro and in vivo. PMID- 25825742 TI - RNA-binding protein hnRNPLL regulates mRNA splicing and stability during B-cell to plasma-cell differentiation. AB - Posttranscriptional regulation is a major mechanism to rewire transcriptomes during differentiation. Heterogeneous nuclear RNA-binding protein LL (hnRNPLL) is specifically induced in terminally differentiated lymphocytes, including effector T cells and plasma cells. To study the molecular functions of hnRNPLL at a genome wide level, we identified hnRNPLL RNA targets and binding sites in plasma cells through integrated Photoactivatable-Ribonucleoside-Enhanced Cross-Linking and Immunoprecipitation (PAR-CLIP) and RNA sequencing. hnRNPLL preferentially recognizes CA dinucleotide-containing sequences in introns and 3' untranslated regions (UTRs), promotes exon inclusion or exclusion in a context-dependent manner, and stabilizes mRNA when associated with 3' UTRs. During differentiation of primary B cells to plasma cells, hnRNPLL mediates a genome-wide switch of RNA processing, resulting in loss of B-cell lymphoma 6 (Bcl6) expression and increased Ig production--both hallmarks of plasma-cell maturation. Our data identify previously unknown functions of hnRNPLL in B-cell to plasma-cell differentiation and demonstrate that the RNA-binding protein hnRNPLL has a critical role in tuning transcriptomes of terminally differentiating B lymphocytes. PMID- 25825744 TI - Plant nanobionic materials with a giant temperature response mediated by pectin Ca2+. AB - Conventional approaches to create biomaterials rely on reverse engineering of biological structures, on biomimicking, and on bioinspiration. Plant nanobionics is a recent approach to engineer new materials combining plant organelles with synthetic nanoparticles to enhance, for example, photosynthesis. Biological structures often outperform man-made materials. For example, higher plants sense temperature changes with high responsivity. However, these properties do not persist after cell death. Here, we permanently stabilize the temperature response of isolated plant cells adding carbon nanotubes (CNTs). Interconnecting cells, we create materials with an effective temperature coefficient of electrical resistance (TCR) of -1,730% K(-1), ~2 orders of magnitude higher than the best available sensors. This extreme temperature response is due to metal ions contained in the egg-box structure of the pectin backbone, lodged between cellulose microfibrils. The presence of a network of CNTs stabilizes the response of cells at high temperatures without decreasing the activation energy of the material. CNTs also increase the background conductivity, making these materials suitable elements for thermal and distance sensors. PMID- 25825743 TI - Tectal microcircuit generating visual selection commands on gaze-controlling neurons. AB - The optic tectum (called superior colliculus in mammals) is critical for eye-head gaze shifts as we navigate in the terrain and need to adapt our movements to the visual scene. The neuronal mechanisms underlying the tectal contribution to stimulus selection and gaze reorientation remains, however, unclear at the microcircuit level. To analyze this complex--yet phylogenetically conserved- sensorimotor system, we developed a novel in vitro preparation in the lamprey that maintains the eye and midbrain intact and allows for whole-cell recordings from prelabeled tectal gaze-controlling cells in the deep layer, while visual stimuli are delivered. We found that receptive field activation of these cells provide monosynaptic retinal excitation followed by local GABAergic inhibition (feedforward). The entire remaining retina, on the other hand, elicits only inhibition (surround inhibition). If two stimuli are delivered simultaneously, one inside and one outside the receptive field, the former excitatory response is suppressed. When local inhibition is pharmacologically blocked, the suppression induced by competing stimuli is canceled. We suggest that this rivalry between visual areas across the tectal map is triggered through long-range inhibitory tectal connections. Selection commands conveyed via gaze-controlling neurons in the optic tectum are, thus, formed through synaptic integration of local retinotopic excitation and global tectal inhibition. We anticipate that this mechanism not only exists in lamprey but is also conserved throughout vertebrate evolution. PMID- 25825745 TI - Multiple mechanisms limit meiotic crossovers: TOP3alpha and two BLM homologs antagonize crossovers in parallel to FANCM. AB - Meiotic crossovers (COs) have two important roles, shuffling genetic information and ensuring proper chromosome segregation. Despite their importance and a large excess of precursors (i.e., DNA double-strand breaks, DSBs), the number of COs is tightly regulated, typically one to three per chromosome pair. The mechanisms ensuring that most DSBs are repaired as non-COs and the evolutionary forces imposing this constraint are poorly understood. Here we identified Topoisomerase3alpha (TOP3alpha) and the RECQ4 helicases--the Arabidopsis slow growth suppressor 1 (Sgs1)/Bloom syndrome protein (BLM) homologs--as major barriers to meiotic CO formation. First, the characterization of a specific TOP3alpha mutant allele revealed that, in addition to its role in DNA repair, this topoisomerase antagonizes CO formation. Further, we found that RECQ4A and RECQ4B constitute the strongest meiotic anti-CO activity identified to date, their concomitant depletion leading to a sixfold increase in CO frequency. In both top3alpha and recq4ab mutants, DSB number is unaffected, and extra COs arise from a normally minor pathway. Finally, both TOP3alpha and RECQ4A/B act independently of the previously identified anti-CO Fanconi anemia of complementation group M (FANCM) helicase. This finding shows that several parallel pathways actively limit CO formation and suggests that the RECQA/B and FANCM helicases prevent COs by processing different substrates. Despite a ninefold increase in CO frequency, chromosome segregation was unaffected. This finding supports the idea that CO number is restricted not because of mechanical constraints but likely because of the long-term costs of recombination. Furthermore, this work demonstrates how manipulating a few genes holds great promise for increasing recombination frequency in plant-breeding programs. PMID- 25825746 TI - Systems approach to metal-based pharmacology. PMID- 25825747 TI - Structural basis for the geometry-driven localization of a small protein. AB - In bacteria, certain shape-sensing proteins localize to differently curved membranes. During sporulation in Bacillus subtilis, the only convex (positively curved) surface in the cell is the forespore, an approximately spherical internal organelle. Previously, we demonstrated that SpoVM localizes to the forespore by preferentially adsorbing onto slightly convex membranes. Here, we used NMR and molecular dynamics simulations of SpoVM and a localization mutant (SpoVM(P9A)) to reveal that SpoVM's atypical amphipathic alpha-helix inserts deeply into the membrane and interacts extensively with acyl chains to sense packing differences in differently curved membranes. Based on binding to spherical supported lipid bilayers and Monte Carlo simulations, we hypothesize that SpoVM's membrane insertion, along with potential cooperative interactions with other SpoVM molecules in the lipid bilayer, drives its preferential localization onto slightly convex membranes. Such a mechanism, which is distinct from that used by high curvature-sensing proteins, may be widely conserved for the localization of proteins onto the surface of cellular organelles. PMID- 25825748 TI - Balancing water resource conservation and food security in China. AB - China's economic growth is expected to continue into the next decades, accompanied by sustained urbanization and industrialization. The associated increase in demand for land, water resources, and rich foods will deepen the challenge of sustainably feeding the population and balancing agricultural and environmental policies. We combine a hydrologic model with an economic model to project China's future food trade patterns and embedded water resources by 2030 and to analyze the effects of targeted irrigation reductions on this system, notably on national agricultural water consumption and food self-sufficiency. We simulate interprovincial and international food trade with a general equilibrium welfare model and a linear programming optimization, and we obtain province-level estimates of commodities' virtual water content with a hydrologic model. We find that reducing irrigated land in regions highly dependent on scarce river flow and nonrenewable groundwater resources, such as Inner Mongolia and the greater Beijing area, can improve the efficiency of agriculture and trade regarding water resources. It can also avoid significant consumption of irrigation water across China (up to 14.8 km(3)/y, reduction by 14%), while incurring relatively small decreases in national food self-sufficiency (e.g., by 3% for wheat). Other researchers found that a national, rather than local, water policy would have similar effects on food production but would only reduce irrigation water consumption by 5%. PMID- 25825749 TI - RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission. AB - Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development. PMID- 25825750 TI - CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer. AB - Nonresolving chronic inflammation at the neoplastic site is consistently associated with promoting tumor progression and poor patient outcomes. However, many aspects behind the mechanisms that establish this tumor-promoting inflammatory microenvironment remain undefined. Using bladder cancer (BC) as a model, we found that CD14-high cancer cells express higher levels of numerous inflammation mediators and form larger tumors compared with CD14-low cells. CD14 antigen is a glycosyl-phosphatidylinositol (GPI)-linked glycoprotein and has been shown to be critically important in the signaling pathways of Toll-like receptor (TLR). CD14 expression in this BC subpopulation of cancer cells is required for increased cytokine production and increased tumor growth. Furthermore, tumors formed by CD14-high cells are more highly vascularized with higher myeloid cell infiltration. Inflammatory factors produced by CD14-high BC cells recruit and polarize monocytes and macrophages to acquire immune-suppressive characteristics. In contrast, CD14-low BC cells have a higher baseline cell division rate than CD14-high cells. Importantly, CD14-high cells produce factors that further increase the proliferation of CD14-low cells. Collectively, we demonstrate that CD14-high BC cells may orchestrate tumor-promoting inflammation and drive tumor cell proliferation to promote tumor growth. PMID- 25825751 TI - Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice. AB - Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sanchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia. PMID- 25825752 TI - Revealing the hidden networks of interaction in mobile animal groups allows prediction of complex behavioral contagion. AB - Coordination among social animals requires rapid and efficient transfer of information among individuals, which may depend crucially on the underlying structure of the communication network. Establishing the decision-making circuits and networks that give rise to individual behavior has been a central goal of neuroscience. However, the analogous problem of determining the structure of the communication network among organisms that gives rise to coordinated collective behavior, such as is exhibited by schooling fish and flocking birds, has remained almost entirely neglected. Here, we study collective evasion maneuvers, manifested through rapid waves, or cascades, of behavioral change (a ubiquitous behavior among taxa) in schooling fish (Notemigonus crysoleucas). We automatically track the positions and body postures, calculate visual fields of all individuals in schools of ~150 fish, and determine the functional mapping between socially generated sensory input and motor response during collective evasion. We find that individuals use simple, robust measures to assess behavioral changes in neighbors, and that the resulting networks by which behavior propagates throughout groups are complex, being weighted, directed, and heterogeneous. By studying these interaction networks, we reveal the (complex, fractional) nature of social contagion and establish that individuals with relatively few, but strongly connected, neighbors are both most socially influential and most susceptible to social influence. Furthermore, we demonstrate that we can predict complex cascades of behavioral change at their moment of initiation, before they actually occur. Consequently, despite the intrinsic stochasticity of individual behavior, establishing the hidden communication networks in large self-organized groups facilitates a quantitative understanding of behavioral contagion. PMID- 25825753 TI - Cis and trans interactions between atlastin molecules during membrane fusion. AB - Atlastin (ATL), a membrane-anchored GTPase that mediates homotypic fusion of endoplasmic reticulum (ER) membranes, is required for formation of the tubular network of the peripheral ER. How exactly ATL mediates membrane fusion is only poorly understood. Here we show that fusion is preceded by the transient tethering of ATL-containing vesicles caused by the dimerization of ATL molecules in opposing membranes. Tethering requires GTP hydrolysis, not just GTP binding, because the two ATL molecules are pulled together most strongly in the transition state of GTP hydrolysis. Most tethering events are futile, so that multiple rounds of GTP hydrolysis are required for successful fusion. Supported lipid bilayer experiments show that ATL molecules sitting on the same (cis) membrane can also undergo nucleotide-dependent dimerization. These results suggest that GTP hydrolysis is required to dissociate cis dimers, generating a pool of ATL monomers that can dimerize with molecules on a different (trans) membrane. In addition, tethering and fusion require the cooperation of multiple ATL molecules in each membrane. We propose a comprehensive model for ATL-mediated fusion that takes into account futile tethering and competition between cis and trans interactions. PMID- 25825754 TI - Juvenile hormone-activated phospholipase C pathway enhances transcriptional activation by the methoprene-tolerant protein. AB - Juvenile hormone (JH) is a key regulator of a wide diversity of developmental and physiological events in insects. Although the intracellular JH receptor methoprene-tolerant protein (MET) functions in the nucleus as a transcriptional activator for specific JH-regulated genes, some JH responses are mediated by signaling pathways that are initiated by proteins associated with plasma membrane. It is unknown whether the JH-regulated gene expression depends on the membrane-mediated signal transduction. In Aedes aegypti mosquitoes, we found that JH activated the phospholipase C (PLC) pathway and quickly increased the levels of inositol 1,4,5-trisphosphate, diacylglycerol, and intracellular calcium, leading to activation and autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). When abdomens from newly emerged mosquitoes were cultured in vitro, the JH-activated gene expression was repressed substantially if specific inhibitors of PLC or CaMKII were added to the medium together with JH. In newly emerged female mosquitoes, RNAi-mediated depletion of PLC or CaMKII considerably reduced the expression of JH-responsive genes, including the Kruppel homolog 1 gene (AaKr-h1) and the early trypsin gene (AaET). JH-induced loading of MET to the promoters of AaKr-h1 and AaET was weakened drastically when either PLC or CaMKII was inactivated in the cultured tissues. Therefore, the results suggest that the membrane-initiated signaling pathway modifies the DNA-binding activity of MET via phosphorylation and thus facilitates the genomic responses to JH. In summary, this study reveals an interplay of genomic and nongenomic signaling mechanisms of JH. PMID- 25825755 TI - Diversity partitioning during the Cambrian radiation. AB - The fossil record offers unique insights into the environmental and geographic partitioning of biodiversity during global diversifications. We explored biodiversity patterns during the Cambrian radiation, the most dramatic radiation in Earth history. We assessed how the overall increase in global diversity was partitioned between within-community (alpha) and between-community (beta) components and how beta diversity was partitioned among environments and geographic regions. Changes in gamma diversity in the Cambrian were chiefly driven by changes in beta diversity. The combined trajectories of alpha and beta diversity during the initial diversification suggest low competition and high predation within communities. Beta diversity has similar trajectories both among environments and geographic regions, but turnover between adjacent paleocontinents was probably the main driver of diversification. Our study elucidates that global biodiversity during the Cambrian radiation was driven by niche contraction at local scales and vicariance at continental scales. The latter supports previous arguments for the importance of plate tectonics in the Cambrian radiation, namely the breakup of Pannotia. PMID- 25825756 TI - Sleep- and wake-dependent changes in neuronal activity and reactivity demonstrated in fly neurons using in vivo calcium imaging. AB - Sleep in Drosophila shares many features with mammalian sleep, but it remains unknown whether spontaneous and evoked activity of individual neurons change with the sleep/wake cycle in flies as they do in mammals. Here we used calcium imaging to assess how the Kenyon cells in the fly mushroom bodies change their activity and reactivity to stimuli during sleep, wake, and after short or long sleep deprivation. As before, sleep was defined as a period of immobility of >5 min associated with a reduced behavioral response to a stimulus. We found that calcium levels in Kenyon cells decline when flies fall asleep and increase when they wake up. Moreover, calcium transients in response to two different stimuli are larger in awake flies than in sleeping flies. The activity of Kenyon cells is also affected by sleep/wake history: in awake flies, more cells are spontaneously active and responding to stimuli if the last several hours (5-8 h) before imaging were spent awake rather than asleep. By contrast, long wake (>=29 h) reduces both baseline and evoked neural activity and decreases the ability of neurons to respond consistently to the same repeated stimulus. The latter finding may underlie some of the negative effects of sleep deprivation on cognitive performance and is consistent with the occurrence of local sleep during wake as described in behaving rats. Thus, calcium imaging uncovers new similarities between fly and mammalian sleep: fly neurons are more active and reactive in wake than in sleep, and their activity tracks sleep/wake history. PMID- 25825757 TI - Rate and mechanism of the photoreduction of birnessite (MnO2) nanosheets. AB - The photoreductive dissolution of Mn(IV) oxide minerals in sunlit aquatic environments couples the Mn cycle to the oxidation of organic matter and fate of trace elements associated with Mn oxides, but the intrinsic rate and mechanism of mineral dissolution in the absence of organic electron donors is unknown. We investigated the photoreduction of delta-MnO2 nanosheets at pH 6.5 with Na or Ca as the interlayer cation under 400-nm light irradiation and quantified the yield and timescales of Mn(III) production. Our study of transient intermediate states using time-resolved optical and X-ray absorption spectroscopy showed key roles for chemically distinct Mn(III) species. The reaction pathway involves (i) formation of Jahn-Teller distorted Mn(III) sites in the octahedral sheet within 0.6 ps of photoexcitation; (ii) Mn(III) migration into the interlayer within 600 ps; and (iii) increased nanosheet stacking. We propose that irreversible Mn reduction is coupled to hole-scavenging by surface water molecules or hydroxyl groups, with associated radical formation. This work demonstrates the importance of direct MnO2 photoreduction in environmental processes and provides a framework to test new hypotheses regarding the role of organic molecules and metal species in photochemical reactions with Mn oxide phases. The timescales for the production and evolution of Mn(III) species and a catalytic role for interlayer Ca(2+) identified here from spectroscopic measurements can also guide the design of efficient Mn-based catalysts for water oxidation. PMID- 25825758 TI - Mechanisms for low-frequency variability of summer Arctic sea ice extent. AB - Satellite observations reveal a substantial decline in September Arctic sea ice extent since 1979, which has played a leading role in the observed recent Arctic surface warming and has often been attributed, in large part, to the increase in greenhouse gases. However, the most rapid decline occurred during the recent global warming hiatus period. Previous studies are often focused on a single mechanism for changes and variations of summer Arctic sea ice extent, and many are based on short observational records. The key players for summer Arctic sea ice extent variability at multidecadal/centennial time scales and their contributions to the observed summer Arctic sea ice decline are not well understood. Here a multiple regression model is developed for the first time, to the author's knowledge, to provide a framework to quantify the contributions of three key predictors (Atlantic/Pacific heat transport into the Arctic, and Arctic Dipole) to the internal low-frequency variability of Summer Arctic sea ice extent, using a 3,600-y-long control climate model simulation. The results suggest that changes in these key predictors could have contributed substantially to the observed summer Arctic sea ice decline. If the ocean heat transport into the Arctic were to weaken in the near future due to internal variability, there might be a hiatus in the decline of September Arctic sea ice. The modeling results also suggest that at multidecadal/centennial time scales, variations in the atmosphere heat transport across the Arctic Circle are forced by anticorrelated variations in the Atlantic heat transport into the Arctic. PMID- 25825759 TI - Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus. AB - The discovery of African henipaviruses (HNVs) related to pathogenic Hendra virus (HeV) and Nipah virus (NiV) from Southeast Asia and Australia presents an open ended health risk. Cell receptor use by emerging African HNVs at the stage of host-cell entry is a key parameter when considering the potential for spillover and infection of human populations. The attachment glycoprotein from a Ghanaian bat isolate (GhV-G) exhibits <30% sequence identity with Asiatic NiV-G/HeV-G. Here, through functional and structural analysis of GhV-G, we show how this African HNV targets the same human cell-surface receptor (ephrinB2) as the Asiatic HNVs. We first characterized this virus-receptor interaction crystallographically. Compared with extant HNV-G-ephrinB2 structures, there was significant structural variation in the six-bladed beta-propeller scaffold of the GhV-G receptor-binding domain, but not the Greek key fold of the bound ephrinB2. Analysis revealed a surprisingly conserved mode of ephrinB2 interaction that reflects an ongoing evolutionary constraint among geographically distal and phylogenetically divergent HNVs to maintain the functionality of ephrinB2 recognition during virus-host entry. Interestingly, unlike NiV-G/HeV-G, we could not detect binding of GhV-G to ephrinB3. Comparative structure-function analysis further revealed several distinguishing features of HNV-G function: a secondary ephrinB2 interaction site that contributes to more efficient ephrinB2-mediated entry in NiV-G relative to GhV-G and cognate residues at the very C terminus of GhV-G (absent in Asiatic HNV-Gs) that are vital for efficient receptor-induced fusion, but not receptor binding per se. These data provide molecular-level details for evaluating the likelihood of African HNVs to spill over into human populations. PMID- 25825760 TI - Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain. AB - Embryogenesis requires the precise activation and repression of many transcriptional regulators. The Polycomb group proteins and the associated H3K27me3 histone mark are essential to maintain the inactive state of many of these genes. Mammalian Hox genes are targets of Polycomb proteins and form local 3D clusters centered on the H3K27me3 mark. More distal contacts have also been described, yet their selectivity, dynamics, and relation to other layers of chromatin organization remained elusive. We report that repressed Hox genes form mutual intra- and interchromosomal interactions with other genes located in strong domains labeled by H3K27me3. These interactions occur in a central and active nuclear environment that consists of the HiC compartment A, away from peripheral lamina-associated domains. Interactions are independent of nearby H3K27me3-marked loci and determined by chromosomal distance and cell-type specific scaling factors, thus inducing a moderate reorganization during embryogenesis. These results provide a simplified view of nuclear organization whereby Polycomb proteins may have evolved to repress genes located in gene-dense regions whose position is restricted to central, active, nuclear environments. PMID- 25825761 TI - Plethora of transitions during breakup of liquid filaments. AB - Thinning and breakup of liquid filaments are central to dripping of leaky faucets, inkjet drop formation, and raindrop fragmentation. As the filament radius decreases, curvature and capillary pressure, both inversely proportional to radius, increase and fluid is expelled with increasing velocity from the neck. As the neck radius vanishes, the governing equations become singular and the filament breaks. In slightly viscous liquids, thinning initially occurs in an inertial regime where inertial and capillary forces balance. By contrast, in highly viscous liquids, initial thinning occurs in a viscous regime where viscous and capillary forces balance. As the filament thins, viscous forces in the former case and inertial forces in the latter become important, and theory shows that the filament approaches breakup in the final inertial-viscous regime where all three forces balance. However, previous simulations and experiments reveal that transition from an initial to the final regime either occurs at a value of filament radius well below that predicted by theory or is not observed. Here, we perform new simulations and experiments, and show that a thinning filament unexpectedly passes through a number of intermediate transient regimes, thereby delaying onset of the inertial-viscous regime. The new findings have practical implications regarding formation of undesirable satellite droplets and also raise the question as to whether similar dynamical transitions arise in other free surface flows such as coalescence that also exhibit singularities. PMID- 25825762 TI - Jupiter's role in sculpting the early Solar System. PMID- 25825763 TI - Experimental ocean acidification alters the allocation of metabolic energy. AB - Energy is required to maintain physiological homeostasis in response to environmental change. Although responses to environmental stressors frequently are assumed to involve high metabolic costs, the biochemical bases of actual energy demands are rarely quantified. We studied the impact of a near-future scenario of ocean acidification [800 uatm partial pressure of CO2 (pCO2)] during the development and growth of an important model organism in developmental and environmental biology, the sea urchin Strongylocentrotus purpuratus. Size, metabolic rate, biochemical content, and gene expression were not different in larvae growing under control and seawater acidification treatments. Measurements limited to those levels of biological analysis did not reveal the biochemical mechanisms of response to ocean acidification that occurred at the cellular level. In vivo rates of protein synthesis and ion transport increased ~50% under acidification. Importantly, the in vivo physiological increases in ion transport were not predicted from total enzyme activity or gene expression. Under acidification, the increased rates of protein synthesis and ion transport that were sustained in growing larvae collectively accounted for the majority of available ATP (84%). In contrast, embryos and prefeeding and unfed larvae in control treatments allocated on average only 40% of ATP to these same two processes. Understanding the biochemical strategies for accommodating increases in metabolic energy demand and their biological limitations can serve as a quantitative basis for assessing sublethal effects of global change. Variation in the ability to allocate ATP differentially among essential functions may be a key basis of resilience to ocean acidification and other compounding environmental stressors. PMID- 25825764 TI - Phosphorylation of PCNA by EGFR inhibits mismatch repair and promotes misincorporation during DNA synthesis. AB - Proliferating cell nuclear antigen (PCNA) plays essential roles in eukaryotic cells during DNA replication, DNA mismatch repair (MMR), and other events at the replication fork. Earlier studies show that PCNA is regulated by posttranslational modifications, including phosphorylation of tyrosine 211 (Y211) by the epidermal growth factor receptor (EGFR). However, the functional significance of Y211-phosphorylated PCNA remains unknown. Here, we show that PCNA phosphorylation by EGFR alters its interaction with mismatch-recognition proteins MutSalpha and MutSbeta and interferes with PCNA-dependent activation of MutLalpha endonuclease, thereby inhibiting MMR at the initiation step. Evidence is also provided that Y211-phosphorylated PCNA induces nucleotide misincorporation during DNA synthesis. These findings reveal a novel mechanism by which Y211 phosphorylated PCNA promotes cancer development and progression via facilitating error-prone DNA replication and suppressing the MMR function. PMID- 25825765 TI - Linked topological colloids in a nematic host. AB - Geometric shape and topology of constituent particles can alter many colloidal properties such as Brownian motion, self-assembly, and phase behavior. Thus far, only single-component building blocks of colloids with connected surfaces have been studied, although topological colloids, with constituent particles shaped as freestanding knots and handlebodies of different genus, have been recently introduced. Here we develop a topological class of colloids shaped as multicomponent links. Using two-photon photopolymerization, we fabricate colloidal microparticle analogs of the classic examples of links studied in the field of topology, the Hopf and Solomon links, which we disperse in nematic fluids that possess orientational ordering of anisotropic rod-like molecules. The surfaces of these particles are treated to impose tangential or perpendicular boundary conditions for the alignment of liquid crystal molecules, so that they generate a host of topologically nontrivial field and defect structures in the dispersing nematic medium, resulting in an elastic coupling between the linked constituents. The interplay between the topologies of surfaces of linked colloids and the molecular alignment field of the nematic host reveals that linking of particle rings with perpendicular boundary conditions is commonly accompanied by linking of closed singular defect loops, laying the foundations for fabricating complex composite materials with interlinking-based structural organization. PMID- 25825766 TI - The human sex ratio from conception to birth. AB - We describe the trajectory of the human sex ratio from conception to birth by analyzing data from (i) 3- to 6-d-old embryos, (ii) induced abortions, (iii) chorionic villus sampling, (iv) amniocentesis, and (v) fetal deaths and live births. Our dataset is the most comprehensive and largest ever assembled to estimate the sex ratio at conception and the sex ratio trajectory and is the first, to our knowledge, to include all of these types of data. Our estimate of the sex ratio at conception is 0.5 (proportion male), which contradicts the common claim that the sex ratio at conception is male-biased. The sex ratio among abnormal embryos is male-biased, and the sex ratio among normal embryos is female biased. These biases are associated with the abnormal/normal state of the sex chromosomes and of chromosomes 15 and 17. The sex ratio may decrease in the first week or so after conception (due to excess male mortality); it then increases for at least 10-15 wk (due to excess female mortality), levels off after ~20 wk, and declines slowly from 28 to 35 wk (due to excess male mortality). Total female mortality during pregnancy exceeds total male mortality. The unbiased sex ratio at conception, the increase in the sex ratio during the first trimester, and total mortality during pregnancy being greater for females are fundamental insights into early human development. PMID- 25825767 TI - Metabolic connectivity as a driver of host and endosymbiont integration. AB - The origin of oxygenic photosynthesis in the Archaeplastida common ancestor was foundational for the evolution of multicellular life. It is very likely that the primary endosymbiosis that explains plastid origin relied initially on the establishment of a metabolic connection between the host cell and captured cyanobacterium. We posit that these connections were derived primarily from existing host-derived components. To test this idea, we used phylogenomic and network analysis to infer the phylogenetic origin and evolutionary history of 37 validated plastid innermost membrane (permeome) metabolite transporters from the model plant Arabidopsis thaliana. Our results show that 57% of these transporter genes are of eukaryotic origin and that the captured cyanobacterium made a relatively minor (albeit important) contribution to the process. We also tested the hypothesis that the bacterium-derived hexose-phosphate transporter UhpC might have been the primordial sugar transporter in the Archaeplastida ancestor. Bioinformatic and protein localization studies demonstrate that this protein in the extremophilic red algae Galdieria sulphuraria and Cyanidioschyzon merolae are plastid targeted. Given this protein is also localized in plastids in the glaucophyte alga Cyanophora paradoxa, we suggest it played a crucial role in early plastid endosymbiosis by connecting the endosymbiont and host carbon storage networks. In summary, our work significantly advances understanding of plastid integration and favors a host-centric view of endosymbiosis. Under this view, nuclear genes of either eukaryotic or bacterial (noncyanobacterial) origin provided key elements of the toolkit needed for establishing metabolic connections in the primordial Archaeplastida lineage. PMID- 25825768 TI - Structure-based discovery of NANOG variant with enhanced properties to promote self-renewal and reprogramming of pluripotent stem cells. AB - NANOG (from Irish mythology Tir na nOg) transcription factor plays a central role in maintaining pluripotency, cooperating with OCT4 (also known as POU5F1 or OCT3/4), SOX2, and other pluripotency factors. Although the physiological roles of the NANOG protein have been extensively explored, biochemical and biophysical properties in relation to its structural analysis are poorly understood. Here we determined the crystal structure of the human NANOG homeodomain (hNANOG HD) bound to an OCT4 promoter DNA, which revealed amino acid residues involved in DNA recognition that are likely to be functionally important. We generated a series of hNANOG HD alanine substitution mutants based on the protein-DNA interaction and evolutionary conservation and determined their biological activities. Some mutant proteins were less stable, resulting in loss or decreased affinity for DNA binding. Overexpression of the orthologous mouse NANOG (mNANOG) mutants failed to maintain self-renewal of mouse embryonic stem cells without leukemia inhibitory factor. These results suggest that these residues are critical for NANOG transcriptional activity. Interestingly, one mutant, hNANOG L122A, conversely enhanced protein stability and DNA-binding affinity. The mNANOG L122A, when overexpressed in mouse embryonic stem cells, maintained their expression of self renewal markers even when retinoic acid was added to forcibly drive differentiation. When overexpressed in epiblast stem cells or human induced pluripotent stem cells, the L122A mutants enhanced reprogramming into ground state pluripotency. These findings demonstrate that structural and biophysical information on key transcriptional factors provides insights into the manipulation of stem cell behaviors and a framework for rational protein engineering. PMID- 25825770 TI - Correction for Gonsamo et al., Underestimated role of East Atlantic-West Russia pattern on Amazon vegetation productivity. PMID- 25825769 TI - Continental crust beneath southeast Iceland. AB - The magmatic activity (0-16 Ma) in Iceland is linked to a deep mantle plume that has been active for the past 62 My. Icelandic and northeast Atlantic basalts contain variable proportions of two enriched components, interpreted as recycled oceanic crust supplied by the plume, and subcontinental lithospheric mantle derived from the nearby continental margins. A restricted area in southeast Iceland--and especially the Oraefajokull volcano--is characterized by a unique enriched-mantle component (EM2-like) with elevated (87)Sr/(86)Sr and (207)Pb/(204)Pb. Here, we demonstrate through modeling of Sr-Nd-Pb abundances and isotope ratios that the primitive Oraefajokull melts could have assimilated 2-6% of underlying continental crust before differentiating to more evolved melts. From inversion of gravity anomaly data (crustal thickness), analysis of regional magnetic data, and plate reconstructions, we propose that continental crust beneath southeast Iceland is part of ~350-km-long and 70-km-wide extension of the Jan Mayen Microcontinent (JMM). The extended JMM was marginal to East Greenland but detached in the Early Eocene (between 52 and 47 Mya); by the Oligocene (27 Mya), all parts of the JMM permanently became part of the Eurasian plate following a westward ridge jump in the direction of the Iceland plume. PMID- 25825771 TI - Using bimodal MRI/fluorescence imaging to identify host angiogenic response to implants. AB - Therapies that promote angiogenesis have been successfully applied using various combinations of proangiogenic factors together with a biodegradable delivery vehicle. In this study we used bimodal noninvasive monitoring to show that the host response to a proangiogenic biomaterial can be drastically affected by the mode of implantation and the surface area-to-volume ratio of the implant material. Fluorescence/MRI probes were covalently conjugated to VEGF-bearing biodegradable PEG-fibrinogen hydrogel implants and used to document the in vivo degradation and liberation of bioactive constituents in an s.c. rat implantation model. The hydrogel biodegradation and angiogenic host response with three types of VEGF-bearing implant configurations were compared: preformed cylindrical plugs, preformed injectable microbeads, and hydrogel precursor, injected and polymerized in situ. Although all three were made with identical amounts of precursor constituents, the MRI data revealed that in situ polymerized hydrogels were fully degraded within 2 wk; microbead degradation was more moderate, and plugs degraded significantly more slowly than the other configurations. The presence of hydrogel degradation products containing the fluorescent label in the surrounding tissues revealed a distinct biphasic release profile for each type of implant configuration. The purported in vivo VEGF release profile from the microbeads resulted in highly vascularized s.c. tissue containing up to 16-fold more capillaries in comparison with controls. These findings demonstrate that the configuration of an implant can play an important role not only in the degradation and resorption properties of the materials, but also in consequent host angiogenic response. PMID- 25825772 TI - Eluding catastrophic shifts. AB - Transitions between regimes with radically different properties are ubiquitous in nature. Such transitions can occur either smoothly or in an abrupt and catastrophic fashion. Important examples of the latter can be found in ecology, climate sciences, and economics, to name a few, where regime shifts have catastrophic consequences that are mostly irreversible (e.g., desertification, coral reef collapses, and market crashes). Predicting and preventing these abrupt transitions remains a challenging and important task. Usually, simple deterministic equations are used to model and rationalize these complex situations. However, stochastic effects might have a profound effect. Here we use 1D and 2D spatially explicit models to show that intrinsic (demographic) stochasticity can alter deterministic predictions dramatically, especially in the presence of other realistic features such as limited mobility or spatial heterogeneity. In particular, these ingredients can alter the possibility of catastrophic shifts by giving rise to much smoother and easily reversible continuous ones. The ideas presented here can help further understand catastrophic shifts and contribute to the discussion about the possibility of preventing such shifts to minimize their disruptive ecological, economic, and societal consequences. PMID- 25825774 TI - Retraction. PMID- 25825773 TI - Amplitude of the actomyosin power stroke depends strongly on the isoform of the myosin essential light chain. AB - We have used time-resolved fluorescence resonance energy transfer (TR-FRET) to determine the role of myosin essential light chains (ELCs) in structural transitions within the actomyosin complex. Skeletal muscle myosins have two ELC isoforms, A1 and A2, which differ by an additional 40-45 residues at the N terminus of A1, and subfragment 1 (S1) containing A1 (S1A1) has higher catalytic efficiency and higher affinity for actin than S1A2. ELC's location at the junction between the catalytic and light-chain domains gives it the potential to play a central role in the force-generating power stroke. Therefore, we measured site-directed TR-FRET between a donor on actin and an acceptor near the C terminus of ELC, detecting directly the rotation of the light-chain domain (lever arm) relative to actin (power stroke), induced by the interaction of ATP-bound myosin with actin. TR-FRET resolved the weakly bound (W) and strongly bound (S) states of actomyosin during the W-to-S transition (power stroke). We found that the W states are essentially the same for the two isoenzymes, but the S states are quite different, indicating a much larger movement of S1A1. FRET from actin to a probe on the N-terminal extension of A1 showed close proximity to actin. We conclude that the N-terminal extension of A1-ELC modulates the W-to-S structural transition of acto-S1, so that the light-chain domain undergoes a much larger power stroke in S1A1 than in S1A2. These results have profound implications for understanding the contractile function of actomyosin, as needed in therapeutic design for muscle disorders. PMID- 25825776 TI - Correction for Merz, What are the roles of V-ATPases in membrane fusion? PMID- 25825775 TI - Targeting diverse protein-protein interaction interfaces with alpha/beta-peptides derived from the Z-domain scaffold. AB - Peptide-based agents derived from well-defined scaffolds offer an alternative to antibodies for selective and high-affinity recognition of large and topologically complex protein surfaces. Here, we describe a strategy for designing oligomers containing both alpha- and beta-amino acid residues ("alpha/beta-peptides") that mimic several peptides derived from the three-helix bundle "Z-domain" scaffold. We show that alpha/beta-peptides derived from a Z-domain peptide targeting vascular endothelial growth factor (VEGF) can structurally and functionally mimic the binding surface of the parent peptide while exhibiting significantly decreased susceptibility to proteolysis. The tightest VEGF-binding alpha/beta peptide inhibits the VEGF165-induced proliferation of human umbilical vein endothelial cells. We demonstrate the versatility of this strategy by showing how principles underlying VEGF signaling inhibitors can be rapidly extended to produce Z-domain-mimetic alpha/beta-peptides that bind to two other protein partners, IgG and tumor necrosis factor-alpha. Because well-established selection techniques can identify high-affinity Z-domain derivatives from large DNA-encoded libraries, our findings should enable the design of biostable alpha/beta-peptides that bind tightly and specifically to diverse targets of biomedical interest. Such reagents would be useful for diagnostic and therapeutic applications. PMID- 25825777 TI - Candidate ionotropic taste receptors in the Drosophila larva. AB - We examine in Drosophila a group of ~35 ionotropic receptors (IRs), the IR20a clade, about which remarkably little is known. Of 28 genes analyzed, GAL4 drivers representing 11 showed expression in the larva. Eight drivers labeled neurons of the pharynx, a taste organ, and three labeled neurons of the body wall that may be chemosensory. Expression was not observed in neurons of one taste organ, the terminal organ, although these neurons express many drivers of the Gr (Gustatory receptor) family. For most drivers of the IR20a clade, we observed expression in a single pair of cells in the animal, with limited coexpression, and only a fraction of pharyngeal neurons are labeled. The organization of IR20a clade expression thus appears different from the organization of the Gr family or the Odor receptor (Or) family in the larva. A remarkable feature of the larval pharynx is that some of its organs are incorporated into the adult pharynx, and several drivers of this clade are expressed in the pharynx of both larvae and adults. Different IR drivers show different developmental dynamics across the larval stages, either increasing or decreasing. Among neurons expressing drivers in the pharynx, two projection patterns can be distinguished in the CNS. Neurons exhibiting these two kinds of projection patterns may activate different circuits, possibly signaling the presence of cues with different valence. Taken together, the simplest interpretation of our results is that the IR20a clade encodes a class of larval taste receptors. PMID- 25825778 TI - Molecular cartography of the human skin surface in 3D. AB - The human skin is an organ with a surface area of 1.5-2 m(2) that provides our interface with the environment. The molecular composition of this organ is derived from host cells, microbiota, and external molecules. The chemical makeup of the skin surface is largely undefined. Here we advance the technologies needed to explore the topographical distribution of skin molecules, using 3D mapping of mass spectrometry data and microbial 16S rRNA amplicon sequences. Our 3D maps reveal that the molecular composition of skin has diverse distributions and that the composition is defined not only by skin cells and microbes but also by our daily routines, including the application of hygiene products. The technological development of these maps lays a foundation for studying the spatial relationships of human skin with hygiene, the microbiota, and environment, with potential for developing predictive models of skin phenotypes tailored to individual health. PMID- 25825780 TI - Reply to Tzoulis et al.: Genetic and clinical heterogeneity of essential tremor. PMID- 25825781 TI - HTRA2 p.G399S in Parkinson disease, essential tremor, and tremulous cervical dystonia. PMID- 25825782 TI - Metabolizable energy content of wheat distillers' dried grains with solubles supplemented with or without a mixture of carbohydrases and protease for broilers and turkeys. AB - In this study, 2 experiments were conducted to determine the AME and AMEn of wheat distillers' dried grains with solubles (DDGS) without or with supplementation of an enzyme mixture containing xylanase, amylase, and protease (XAP) in broilers and turkeys. One hundred twenty-six male Ross 308 broilers (Experiment 1) or 126 male BUT 10 turkeys (Experiment 2) were offered a nutrient adequate diet from d 1 to 14. On d 14, birds in each experiment were allocated to 6 treatments consisting of 3 levels of wheat-DDGS (0, 300, or 600 g/kg) and 2 levels of XAP (0 or 250 mg/kg diet) in a randomized complete block design. The AME or AMEn content of wheat-DDGS was determined from the slope of regression of wheat-DDGS-associated energy intake (kilocalories) against wheat-DDGS intake (kilograms). In Experiment 1, wheat-DDGS inclusion in the diets linearly decreased (P<0.05) DM retention, AME, and AMEn, irrespective of XAP supplementation. The AME of wheat-DDGS without or with XAP for broilers was 3,587 or 3,700 kcal/kg DM, respectively, and AMEn was 3,356 and 3,459 kcal/kg DM for wheat-DDGS without and with XAP, respectively. In Experiment 2, wheat-DDGS inclusion in the diet linearly decreased (P<0.05) DM retention irrespective of XAP supplementation. Diet AME and AMEn linearly decreased (P<0.05) as the level of wheat-DDGS increased in the diets without added XAP, whereas there was no effect of increasing wheat-DDGS level on dietary AME or AMEn in the XAP supplemented diets. The AME of wheat-DDGS without and with supplemental XAP for turkeys were 3,355 and 3,558 kcal/kg DM, respectively, and AMEn was 3,109 and 3,294 kcal/kg DM, respectively, for wheat-DDGS without and with XAP. Supplemental XAP increased (P>0.05) the AME and AMEn of wheat-DDGS for broilers and turkeys by up to 6%. It was concluded that wheat-DDGS is a valuable source of AME for broilers and turkeys. PMID- 25825783 TI - Effect of yellow lupine (L. luteus) on the egg yolk fatty acid profile, the physicochemical and sensory properties of eggs, and laying hen performance. AB - The aim of this study was to evaluate the effects of different dietary inclusion of raw yellow lupine seed meal (YLM) on laying hen performance, the fatty acid (FA) profile, physicochemical, and sensory properties of eggs. A total of 224 Lohmann Brown laying hens at 32 wk age were fed isonitrogenous and isocaloric diets for 16 wk. The control diet contained soybean meal (SBM), and in study diets SBM was replaced with YLM at 100, 200, or 300 g/kg. In comparison with soybean, lupine seeds had a higher content of nonstarch polysaccharides (NSP) and raffinose family oligosaccharides (RFO) (29.5 vs. 14.0 and 8.56 vs. 5.91% DM). The dietary 300 g/kg lupine seeds increased the content of NSP and RFO in the ration, from 9.34 to 13.39 and 1.36 to 2.54%, respectively. The YLM inclusion level had no adverse effect on laying performance, including feed intake, FCR, egg production, and egg weight. The final BW of hens fed lupine-based diets were significantly higher compared with the control (P=0.039). Throughout the study, dietary treatments had no effect on eggshell and albumen quality. An increase in the inclusion rate of YLM was followed by a linear increase (P<0.001) in yolk color intensity. Dietary treatments had no influence on the aroma, taste, and texture of eggs evaluated in laying hens at 46 wk age. The inclusion of lupine seeds in experimental diets caused a linear increase in n-6 polyunsaturated FA (PUFA) content and the n-6/n-3 ratio (all P<0.001), but it had no influence on the atherogenic and the thrombogenic indices of egg yolk lipids. The results of this study indicate that YLM can be included at 300 g/kg in layer diets as a partial substitute for soybean meal without compromising laying performance, the physicochemical, and sensory properties of eggs. PMID- 25825779 TI - RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex. AB - For many E3 ligases, a mobile RING (Really Interesting New Gene) domain stimulates ubiquitin (Ub) transfer from a thioester-linked E2~Ub intermediate to a lysine on a remotely bound disordered substrate. One such E3 is the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), which controls cell division by ubiquitinating cell cycle regulators to drive their timely degradation. Intrinsically disordered substrates are typically recruited via their KEN-box, D-box, and/or other motifs binding to APC and a coactivator such as CDH1. On the opposite side of the APC, the dynamic catalytic core contains the cullin-like subunit APC2 and its RING partner APC11, which collaborates with the E2 UBCH10 (UBE2C) to ubiquitinate substrates. However, how dynamic RING-E2~Ub catalytic modules such as APC11-UBCH10~Ub collide with distally tethered disordered substrates remains poorly understood. We report structural mechanisms of UBCH10 recruitment to APC(CDH1) and substrate ubiquitination. Unexpectedly, in addition to binding APC11's RING, UBCH10 is corecruited via interactions with APC2, which we visualized in a trapped complex representing an APC(CDH1) UBCH10~Ub-substrate intermediate by cryo-electron microscopy, and in isolation by X-ray crystallography. To our knowledge, this is the first structural view of APC, or any cullin-RING E3, with E2 and substrate juxtaposed, and it reveals how tripartite cullin-RING-E2 interactions establish APC's specificity for UBCH10 and harness a flexible catalytic module to drive ubiquitination of lysines within an accessible zone. We propose that multisite interactions reduce the degrees of freedom available to dynamic RING E3-E2~Ub catalytic modules, condense the search radius for target lysines, increase the chance of active-site collision with conformationally fluctuating substrates, and enable regulation. PMID- 25825784 TI - Oral peptide specific egg antibody to intestinal sodium-dependent phosphate co transporter-2b is effective at altering phosphate transport in vitro and in vivo. AB - Hyperimmunized hens are an effective means of generating large quantities of antigen specific egg antibodies that have use as oral supplements. In this study, we attempted to create a peptide specific antibody that produced outcomes similar to those of the human pharmaceutical, sevelamer HCl, used in the treatment of hyperphosphatemia (a sequela of chronic renal disease). Egg antibodies were generated against 8 different human intestinal sodium-dependent phosphate cotransporter 2b (NaPi2b) peptides, and hNaPi2b peptide egg antibodies were screened for their ability to inhibit phosphate transport in human intestinal Caco-2 cell line. Antibody produced against human peptide sequence TSPSLCWT (anti h16) was specific for its peptide sequence, and significantly reduced phosphate transport in human Caco-2 cells to 25.3+/-11.5% of control nonspecific antibody, when compared to nicotinamide, a known inhibitor of phosphate transport (P<=0.05). Antibody was then produced against the mouse-specific peptide h16 counterpart (mouse sequence TSPSYCWT, anti-m16) for further analysis in a murine model. When anti-m16 was fed to mice (1% of diet as dried egg yolk powder), egg yolk immunoglobulin (IgY) was detected using immunohistochemical staining in mouse ileum, and egg anti-m16 IgY colocalized with a commercial goat anti-NaPi2b antibody. The effectiveness of anti-m16 egg antibody in reducing serum phosphate, when compared to sevelamer HCl, was determined in a mouse feeding study. Serum phosphate was reduced 18% (P<0.02) in mice fed anti-m16 (1% as dried egg yolk powder) and 30% (P<0.0001) in mice fed sevelamer HCl (1% of diet) when compared to mice fed nonspecific egg immunoglobulin. The methods described and the findings reported show that oral egg antibodies are useful and easy to prepare reagents for the study and possible treatment of select diseases. PMID- 25825785 TI - Oral administration of the Salmonella Typhimurium vaccine strain Nal2/Rif9/Rtt to laying hens at day of hatch reduces shedding and caecal colonization of Salmonella 4,12:i:-, the monophasic variant of Salmonella Typhimurium. AB - A new monophasic variant of Salmonella Typhimurium, Salmonella enterica serotype 4,12:i:-, is rapidly emerging. This serotype is now considered to be among the 10 most common serovars isolated from humans in many countries in Europe and in the United States. The public health risk posed by these emerging monophasic Salmonella Typhimurium strains is considered comparable to that of classical Salmonella Typhimurium strains. The serotype 4,12:i:- is frequently isolated from pigs but also poultry are carrying strains from this serotype. In the current study, we evaluated the efficacy of the Salmonella Typhimurium strain Nal2/Rif9/Rtt, a strain contained in the commercially available live vaccines AviPro Salmonella Duo and AviPro Salmonella VacT, against infection with the emerging monophasic variant in poultry. Three independent trials were conducted. In all trials, laying type chicks were orally vaccinated with the Salmonella Typhimurium strain Nal2/Rif9/Rtt at d hatch, while the birds were challenged the next d with a different infection dose in each trial (low, high, and intermediate). For the intermediate-dose study, a seeder bird model was used in which one out of 3 animals were infected while all individual birds were infected in the other trials. Data obtained from each independent trial show that oral administration of the Salmonella Typhimurium strain Nal2/Rif9/Rtt at d hatch reduced shedding, caecal, and internal organ colonization of Salmonella Typhimurium 4,12:i:-, administered at d 2 life. This indicates that Salmonella Typhimurium strain Nal2/Rif9/Rtt can help to control Salmonella 4,12:i:- infections in poultry. PMID- 25825786 TI - Oxidative damage to poultry: from farm to fork. AB - Poultry and poultry meat are particularly susceptible to oxidative reactions. Oxidation processes have been for decades the focus of animal and meat scientists owing to the negative impact of these reactions on animal growth, performance, and food quality. Lipid oxidation has been recognized a major threat to the quality of processed poultry products. The recent discoveries on the occurrence of protein oxidation in muscle foods have increased the scientific and technological interest in a topic that broadens the horizons of food biochemistry into innovative fields. Furthermore, in recent years we have witnessed a growing interest in consumers on the impact of diet and oxidation on health and aging. Hence, the general description of oxidative reactions as harmful phenomena goes beyond the actual impact on animal production and food quality and reaches the potential influence of oxidized foods on consumer health. Likewise, the current antioxidant strategies aim for the protection of the living tissues, the food systems, and a potential health benefit in the consumer upon ingestion. Along these lines, the application of phytochemicals and other microelements (Se, Cu) with antioxidant potential in the feeds or directly in the meat product are strategies of substantial significance. The present paper reviews in a concise manner the most relevant and novel aspects of the mechanisms and consequences of oxidative reactions in poultry and poultry meat, and describes current antioxidant strategies against these undesirable reactions. PMID- 25825787 TI - Effects of broiler breeder management on pullet body weight and carcass uniformity. AB - An experiment was conducted to study the effect of broiler breeder feeding management practices on pullet performance, BW uniformity, and carcass traits during rearing (to 22 wk of age). At 3 wk of age, 1,200 Ross 308 breeder pullets were assigned to one of 5 treatments: 1) control: standard mash diet, fed daily; 2) high fiber: mash diet containing 25% lower nutrient density, fed daily; 3) scatter: standard diet in pellet form scattered on litter, fed daily; 4) skip-a day: standard mash diet, fed on alternate days; or 5) grading: standard mash diet, fed daily (birds sorted into low, average, and high BW groups every 4 wk). Birds on the high fiber treatment consumed more feed (P<0.0001) and had the highest feed conversion ratio (FCR; P<0.004) but the lowest ME to gain and CP to gain ratios (P<=0.002). Skip-a-day treatment pullets consumed more ME and CP than birds in any other treatment (P<0.001). Grading yielded the highest BW uniformity at 22 wk of age (CV=6.2%), while control and high fiber treatment groups were least uniform (CV>15%; P<0.0001). Skip-a-day feed restriction produced birds with the significantly lowest breast muscle and highest liver weight compared to all other treatments (P<0.05). Variation in shank length, chest width, and breast muscle was lowest in the grading treatment, whereas the CV for fat pad and liver was lowest in the skip-a-day treatment. In this trial, broiler breeder target BW profiles were achieved using combinations of quantitative and qualitative feed restriction, or preemptive management practices. Qualitative diet dilution and skip-a-day management did little to increase flock uniformity relative to the control during the most intense period of feed restriction (7 to 19 wk). Scatter feeding increased flock uniformity to a small degree, whereas grading yielded the highest increase in BW and carcass trait uniformity. PMID- 25825788 TI - mRNA expression of amino acid transporters, aminopeptidase, and the di- and tri peptide transporter PepT1 in the intestine and liver of posthatch broiler chicks. AB - Amino acid (AA) transporter proteins are responsible for the movement of amino acids in and out of cells. Aminopeptidase cleaves AAs from the N-terminus of polypeptides making them available for transport, while PepT1 is a di- and tripeptide transporter. In the intestine, these proteins are present on the brush border and basolateral membranes of enterocytes, and are essential for the uptake of AAs into enterocytes and their release into circulation. The purpose of this study was to determine the level of transcription of these genes after hatch in 3 regions of the small intestine, the ceca, and liver. Heritage broiler chicks (n=5) were sampled at day after hatch and days 3, 5, 7, 10, 12, 14, 17, and 21 posthatch, and mRNA expression level was measured using absolute quantitation. The small intestine (duodenum, jejunum, and ileum) expressed the largest quantities of each gene tested. The expression in the ceca and liver was 1 to 3 orders of magnitude less than that of the small intestine. The expression of basolateral transporters in the small intestine was more constant over days posthatch than the expression of brush border transporters. In the ceca the expression of the brush border transporters decreased over the sampling period, while expression of basolateral genes was relatively constant. In the liver the expression of Na+ independent cationic and zwitterionic amino acid transporter (bo,+AT), Na+ independent cationic amino acid transporter 2 (CAT2), excitatory amino acid transporter 3 (EAAT3), and the heavy chain corresponding to the bo,+) system (rBAT) significantly decreased at 12 days posthatch; however, the expression of Na+ independent cationic and Na+ dependent neutral amino acid transporter 1 (y+LAT1), Na+ coupled neutral amino acid transporter 1; (SNAT1), and Na+ coupled neutral amino acid transporter 2 (SNAT2) significantly increased at day 5 posthatch compared to day 1 and these levels remained throughout the rest of the sampling period. The current results suggest that at 1 day posthatch chicks are capable of AA processing and transport in the intestine as well as the liver. Additionally the ability of the ceca in transporting AA from the lumen may decrease with age. The liver should be capable of amino acid transport, but its capabilities may be more specific since the expression of several transporters in this organ is either absent or very low. PMID- 25825789 TI - Camelina sativa cake for broilers: Effects of increasing dietary inclusion from 0 to 24% on tissue fatty acid proportions at 14, 28, and 42 d of age. AB - The benefits to human from the consumption of omega-3 polyunsaturated fatty acids (N-3 PUFAS) have been recognized. Camelina sativa is an oilseed crop grown for biofuel production. Feeding its cake with 10 to 20% remaining oil (28 to 30% alpha-linolenic acid [ALA]) has the potential to enrich poultry products with n-3 PUFA. An experiment was conducted to assess lipid deposition in brain, liver, breast, and thigh tissue by increasing inclusions of camelina cake (CC) fed to broiler chickens. Male chicks (744, Ross 308) housed in 24 cages were fed 0, 8, 16, or 24% CC for 42 d, 6 replicates per CC level. At the end of the starter (14 d), grower (28 d), and finisher (42 d) phase, brain, liver, breast, and thigh samples were collected from 3 birds/cage and diets were analyzed for fatty acid content. Feeding increasing CC inclusions from 0 to 8, 16, and 24% increased dietary ALA (5.3, 11.1, 15.2, 17.8, respectively) as a proportion of the total fatty acid content. All diets provided a similar level of long-chain n-3 PUFA (about 0.9%). Irrespective of growth phase, increases in dietary CC inclusion led to a linear increase (P<0.001) in the proportion of ALA in breast, thigh, and liver (76, 128, 288%, respectively), but not in brain tissue. An increase in dietary CC inclusion led to a linear increase (P<0.001) in the proportion of long chain n-3 PUFAs, including docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in liver (109 and 80%, respectively) and brain (24 and 6%, respectively) tissue. However, in breast and thigh tissue, increases in dietary CC inclusion led to an increase in only (P<0.005) DPA (24 and 27%, respectively). The predominant n-3 PUFA in liver and brain tissue feeding 24% CC was DHA (48% and 88%, respectively), unlike in breast and thigh meat, where ALA increased (65 and 86%, respectively). The labeling claim requirement for n-3 PUFA enrichment (300 mg/100 g meat) was exceeded in breast and thigh by feeding a 24% CC diet for 28 d or 16% CC diet for 42 d, respectively. PMID- 25825790 TI - Effect of micellized natural (D-alpha-tocopherol) vs. synthetic (DL-alpha tocopheryl acetate) vitamin E supplementation given to turkeys on oxidative status and breast meat quality characteristics. AB - This study evaluates the effect of vitamin E supplementation source (micellized natural vs. the synthetic form) and dosage (40, 80, or 120 mg/kg) on alpha tocopherol concentration in plasma and muscle, antioxidant capacity, and breast meat quality in turkeys. Three hundred female turkeys were randomly selected at an average live weight 63.2 g+/-0.5 and distributed into 7 groups. One group (control) was fed a standard diet without vitamin E supplementation and the other 6 were given mixed diets supplemented with the natural (d-alpha-tocopherol) or synthetic (dl-alpha-tocopheryl acetate) form of vitamin E in 3 dosages (40, 80, or 120 mg/kg). Following 11 wk feeding, results showed that performance parameters were not modified either by source or dosage of vitamin E supplementation to the turkeys. Plasma and muscle alpha-tocopherol at d 9 of refrigerated storage were higher when turkeys were supplemented with the natural form at higher doses. Losses in the concentration of alpha-tocopherol in meat between the beginning and the end of the 9 d refrigerated storage were greater in the groups supplemented with the synthetic form of vitamin E compared to those receiving the natural supplementation. The relationship between plasma alpha tocopherol and the Trolox equivalent antioxidant capacity followed a different trend depending on the vitamin E source. Intramuscular fat was not significantly affected by the vitamin E source supplementation; however the slope of the linear regression equation was lower for the natural form than for the synthetic form. Turkeys given the natural form had higher C18:1n-9 but lower C15:1, C17:1, C20:5n 3, and C22:6n-3 in breast muscle. Meat samples from turkeys supplemented with natural vitamin E had higher deoxymyoglobin at d 3, 6, and 9 and lower metmyoglobin at d 9 of refrigerated storage than those receiving the synthetic form. Dietary supplementation with medium doses (80 mg/kg) micellized d-alpha tocopherol is an interesting feeding strategy for ensuring antioxidant status and improving meat quality. PMID- 25825791 TI - Developing person-centred analysis of harm in a paediatric hospital: a quality improvement report. AB - The provision of safe care is complex and difficult to achieve. Awareness of what happens in real time is one of the ways to develop a safe system within a culture of safety. At Great Ormond Street Hospital, we developed and tested a tool specifically designed for patients and families to report harm, with the aim of raising awareness and opportunities for staff to continually improve and provide safe care. Over a 10-month period, we developed processes to report harm. We used the Model for Improvement and multiple Plan, Do, Study, Act cycles for testing. We measured changes using culture surveys as well as analysis of the reports. The tool was tested in different formats and moved from a provider centric to a person-centred tool analysed in real time. An independent person working with the families was best placed to support reporting. Immediate feedback to families was managed by senior staff, and provided the opportunity for clarification, transparency and apologies. Feedback to staff provided learning opportunities. Improvements in culture climate and staff reporting were noted in the short term. The integration of patient involvement in safety monitoring systems is essential to achieve safety. The high number of newly identified 'near-misses' and 'critical incidents' by families demonstrated an underestimation of potentially harmful events. This testing and introduction of a self-reporting, real-time bedside tool has led to active engagement with families and patients and raised situation awareness. We believe that this will lead to improved and safer care in the longer term. PMID- 25825792 TI - Reconsidering the dynamics in mixtures of methyltetrahydrofuran with tristyrene and polystyrene. AB - Mixtures of methyltetrahydrofuran (MTHF) with tristyrene and high molecular weight polystyrene involve an exceptionally large difference in the glass transition temperatures of the two components not realized in other binary mixtures studied before. The extensive study of the molecular dynamics of these mixtures by various experimental techniques by Blochowicz et al. has revealed the presence of a new alpha'-relaxation not found before in other mixtures and also the more familiar alpha- and beta-relaxations, but their properties are more extreme. Attention was focused on the new alpha'-relaxation by Blochowicz et al. in interpreting it to originate from MTHF in confinement and explaining its properties by the Mode Coupling Theory. In a different direction, we concentrate on the highly unusual properties of the alpha- and beta-relaxations. Earlier, we had success in explaining the properties of these two relaxations and their connection in other mixtures by the coupling model. In this paper, we apply the same model to explain the highly unusual dynamics of the alpha- and beta relaxations found in the mixtures of MTHF with tristyrene and polystyrene. Possible relation between the alpha'- and the beta-relaxations also is explored. PMID- 25825793 TI - Inhibition of Non-ATG Translational Events in Cells via Covalent Small Molecules Targeting RNA. AB - One major class of disease-causing RNAs is expanded repeating transcripts. These RNAs cause diseases via multiple mechanisms, including: (i) gain-of-function, in which repeating RNAs bind and sequester proteins involved in RNA biogenesis and (ii) repeat associated non-ATG (RAN) translation, in which repeating transcripts are translated into toxic proteins without use of a canonical, AUG, start codon. Herein, we develop and study chemical probes that bind and react with an expanded r(CGG) repeat (r(CGG)(exp)) present in a 5' untranslated region that causes fragile X-associated tremor/ataxia syndrome (FXTAS). Reactive compounds bind to r(CGG)(exp) in cellulo as shown with Chem-CLIP-Map, an approach to map small molecule binding sites within RNAs in cells. Compounds also potently improve FXTAS-associated pre-mRNA splicing and RAN translational defects, while not affecting translation of the downstream open reading frame. In contrast, oligonucleotides affect both RAN and canonical translation when they bind to r(CGG)(exp), which is mechanistically traced to a decrease in polysome loading. Thus, designer small molecules that react with RNA targets can be used to profile the RNAs to which they bind in cells, including identification of binding sites, and can modulate several aspects of RNA-mediated disease pathology in a manner that may be more beneficial than oligonucleotides. PMID- 25825794 TI - Chemical characterization of exhaust emissions from selected canadian marine vessels: the case of trace metals and lanthanoids. AB - This paper reports the chemical composition of exhaust emissions from the main engines of five ocean going cargo vessels, as they traveled in Canadian waters. The emission factors (EFs) of PM2.5 and SO2 for vessels tested on various intermediate fuel oils (IFO), ranged from 0.4 to 2.2 g kW(-1) hr(-1) and 4.7 to 10.3 g kW(-1) hr(-1), respectively, and were mainly dependent on the content of sulfur in the fuel. Average NOx, CO, and CO2 EFs for these tests were 12.7, 0.45, and 618 g kW(-1) hr(-1), respectively and were generally below benchmark values commonly used by regulatory agencies. The composition of PM2.5 was dominated by hydrated sulfates, organic carbon and trace metals which accounted for 80-97% of total PM2.5 mass. A substantial decrease of measured emission factors for PM2.5 and SO2 was observed when the fuel was changed from IFO to marine diesel oil (MDO), in one of the tested vessels. The main component of PM2.5 in this case was organic carbon accounting for 65% of PM2.5 mass. In addition to commonly reported pollutants, this study presents EFs of the lanthanoid elements and showed that their distribution patterns in ship-exhaust PM2.5 were very similar to the PM2.5 emitted by oil refining facilities. Hence, using La:Ce:V tertiary diagrams and La/V ratios is necessary to distinguish ship plumes from primary emissions related to accidental and/or routine operation of oil-refining industry. PMID- 25825795 TI - Effect of multiwalled carbon nanotubes on the kinetics of the aniline polymerization: the semi-quantitative OCP approach. AB - We demonstrate applicability of the open-circuit potential (OCP) method for kinetic analysis of the oxidative chemical polymerization of aniline both in clear solution and in dispersions of multiwalled carbon nanotubes (MWCNT). The characteristic points and the shape of the OCP profile are used to estimate the kinetic parameters of the main stages of the known two-step polymerization mechanism of aniline. We have found that the reciprocal values of the duration of the main polymerization stages namely the induction period, pernigraniline (PN) accumulation and reduction of PN with residual aniline are the linear functions of the weight fraction of MWCNT. To compare the kinetic data of the proposed OCP and known approaches the last two stages have been considered as a single heterogeneous stage of emeraldine (EM) formation. The kEM rate constant calculated by the OCP profiles for this EM stage in the solution and dispersion media is in a very good agreement with the known k2 values. PMID- 25825796 TI - Lycium europaeum fruit extract: antiproliferative activity on A549 human lung carcinoma cells and PC12 rat adrenal medulla cancer cells and assessment of its cytotoxicity on cerebellum granule cells. AB - Cancer is a major worldwide health problem and one of the leading causes of death either in developed or developing countries. Plant extracts and derivatives have always been used for various disease treatments and many anticancer agents issued from plants and vegetables are clinically recognized and used all over the world. Lycium europaeum (Solanaceae) also called "wolfberry" was known since ancient times in the Mediterranean area as a medicinal plant and used in several traditional remedies. The Lycium species capacity of reducing the incidence of cancer and also of halting or reserving the growth of cancer was reported by traditional healers. In this study, the antiproliferative capacity, protective properties, and antioxidant activity of the hydro-alcoholic fruit extract of Lycium europaeum were investigated. Results showed that Lycium extract exhibits the ability to reduce cancer cell viability, inhibits proliferation, and induces apoptosis in A549 human lung cancer cells and PC12 rat adrenal medulla cancer cells, in a concentration- and time-dependent manner. Cytotoxic effect on normal rat cerebellum granule cells was assessed to be nonsignificant. Results also showed that Lycium fruit extract protected lipids, proteins, and DNA against oxidative stress damages induced by H2O2 via scavenging reactive oxygen species. PMID- 25825797 TI - Shear banding in drying films of colloidal nanoparticles. AB - Drying suspensions of colloidal nanoparticles exhibit a variety of interesting strain release mechanisms during film formation. These result in the selection of characteristic length scales during failure processes such as cracking and subsequent delamination. A wide range of materials (e.g., bulk metallic glasses) release strain through plastic deformations which occur in a narrow band of material known as a shear band. Here we show that drying colloidal films also exhibit shear banding. Bands are observed to form a small distance behind the drying front and then to propagate rapidly at ~45 degrees to the direction of drying. It is shown that the spacing of the bands depends on salt concentration and the evaporation rate of the colloidal suspension. These combined observations suggest that there is a critical shear rate (related to the film yield stress) which controls the ratio of bandwidth to band spacing. Local deformations were measured in the early stages of drying using fluorescent tracer particles. The measurements were used to show that the existence of shear bands is linked to the compaction of particles perpendicular to the drying front. The spacing of shear bands was also found to be strongly correlated with the characteristic length scale of the compaction process. These combined studies elucidate the role of plastic deformation during pattern formation in drying films of colloidal nanoparticles. PMID- 25825798 TI - Does Mediterranean Diet Reduce Cardiovascular Events and Oxidative Stress in Atrial Fibrillation? AB - Atrial fibrillation (AF) is characterized by enhanced oxidative stress and is complicated by cardiovascular events (CVEs), which are only partially prevented by anticoagulant treatment. The Mediterranean diet (Med-Diet) has a positive effect on atherosclerotic progression. In a prospective cohort of 709 anticoagulated AF patients, adherence to Med-Diet was assessed to investigate whether Med-Diet may reduce CVEs by lowering oxidative stress. The cohort was divided into three groups according to the Med-Diet score: low (0-3 points), medium (4-6 points), and high (7-9 points) adherence. During a mean follow-up of 39.9 months (2604.8 patients/year), we registered 72 (2.8%/year) CVEs: 23.4% in the low-adherence group, 8.4% in the intermediate-adherence group, and 5.3% in the high-adherence group (p<0.001). There were no differences in time in the therapeutic range among groups. The Med-Diet score was inversely correlated with sNOX2-dp (soluble NOX2-derived peptide; Rs: -0.297, p<0.001) and F2-isoprostanes (F2-IsoP; Rs: -0.411, p<0.001). Median values of sNOX2-dp (p<0.001) and F2-IsoP progressively decreased across groups (p<0.001). A Cox regression analysis showed that the Med-Diet score (HR: 0.771, p=0.001), F2-IsoP (HR: 1.002, p=0.004), and heart failure (HR: 1.876, p=0.024) predicted CVEs. In conclusion, these findings raise the hypothesis that adherence to Med-Diet could be associated with a reduction of CVEs, through an antioxidant effect, as shown by a concomitant downregulation of Nox2 and decreased excretion of F2-IsoP. PMID- 25825799 TI - Intravitreal triamcinolone acetonide in the treatment of ophthalmic inflammatory diseases with macular edema: a meta-analysis study. AB - PURPOSE: To perform a meta-analysis of randomized controlled trials (RCTs) that compared the effects of treatment with intravitreal injections of triamcinolone acetonide (TA) with the standard of care for ocular inflammatory diseases. METHODS: Medline database was searched for causes of macular edema terms in association with intravitreal triamcinolone. The primary outcome of interest included changes in best corrected visual acuity (BCVA) and central macular thickness (CMT). Pooled summary estimates for primary outcomes were calculated as weighted mean differences (WMD) either on a fixed- or random-effect model. RESULTS: A total of 8 studies were included for quantitative analysis. Treatment with intravitreal TA showed improvement in BCVA compared with standard of care at 1 month (WMD, -0.09; 95% confidence interval [CI], -0.17 to -0.02), at 4 months (WMD, -0.09; 95% CI, -0.15 to -0.03), at 6 months (WMD, -0.13; 95% CI, -0.21 to 0.05), and in CMT at 1 month (WMD, -88.14; 95% CI, -105.86 to -70.43). Increased intraocular pressure (IOP) among patients treated with intravitreal TA was found at 4 months (WMD, 2.83; 95% CI, 1.96 to 3.70), persisting also at 12 months (WMD, 3.78; 95% CI, 2.97 to 4.59), compared with those receiving the standard of care. All outcomes are mostly equivalent at further follow-up times. CONCLUSIONS: Intravitreal injections of TA may offer certain advantages over the standard of care for ocular inflammatory diseases, especially in the early stage of follow up. However, it is necessary to take into account risks and benefits of TA treatment for ocular inflammatory diseases due to possible ocular hypertension elicited, in general, by intravitreal injection of corticosteroids. PMID- 25825800 TI - Selective Tumor Cell Inhibition Effect of Ni-Ti Layered Double Hydroxides Thin Films Driven by the Reversed pH Gradients of Tumor Cells. AB - Nitinol is widely fabricated as stents for the palliation treatment of many kinds of cancers. It is of great importance to develop nitinol stents with selective tumor cell inhibition effects. In this work, a series of pH sensitive films composed of Ni(OH)2 and Ni-Ti layered double hydroxide (Ni-Ti LDH) with different Ni/Ti ratios were prepared on the surface of nitinol via hydrothermal treatment. The films with specific Ni/Ti ratios would release a large amount of nickel ions under acidic environments but were relatively stable in neutral or weak alkaline medium. Cell viability tests showed that the films can effectively inhibit the growth of cancer cells but have little adverse effects to normal cells. Besides, extraordinarily high intracellular nickel content and reactive oxygen species (ROS) level were found in cancer cells, indicating the death of cancer cells may be induced by the excessive intake of nickel ions. Such selective cancer cell inhibition effect of the films is supposed to relate with the reversed pH gradients of tumor cells. PMID- 25825801 TI - Potential drug interactions associated with glycyrrhizin and glycyrrhetinic acid. AB - Glycyrrhizin (GZ), the main active component of licorice, is a widely used therapeutic in the clinic. Depending on the disease, the treatment may involve a long course of high dose GZ. Another component of licorice, glycyrrhetinic acid (GA), is the main active metabolite of GZ and is thought to be responsible for the majority of the pharmacological properties of GZ. Therefore, GZ and GA are both used for therapeutic purposes. In addition, GZ and GA are also widely used to sweeten and flavor foods. Due to this widespread, multifaceted use of these substances, potential drug interactions with GZ and GA have recently gained attention. Along these lines, this review covers the known effects of GZ and GA on drug-metabolizing enzymes and efflux transporters. We conclude that both GZ and GA may have an effect on the activity of CYPs. For example, GZ may induce CYP3A activity through activation of PXR. Also, GZ and GA may affect glucuronidation in rats and humans. Furthermore, 18beta-GA is a potent inhibitor of P-gp, while GZ and GA are inhibitors of MRP1, MRP2 and BCRP. The pharmacokinetics and pharmacodynamics of many medications may be altered when used concurrently with GZ or GA, which is also covered in this review. Overall, GZ, GA or related products should be taken with caution when taken with additional medications due to the possible drug interactions. PMID- 25825802 TI - Synthesis of functionalized epoxides by copper-catalyzed alkylative epoxidation of allylic alcohols with alkyl nitriles. AB - A copper-catalyzed oxyalkylation of allylic alcohols using nonactivated alkyl nitriles as reaction partners was developed. A sequence involving generation of an alkyl nitrile radical followed by its addition to a double bond and a copper mediated formation of C(sp(3))-O bond was proposed to account for the reaction outcome. The protocol provided an efficient route to functionalized tri- and tetrasubstituted epoxides via formation of a C(sp(3))-C(sp(3)) and a C(sp(3))-O bond with moderate to excellent diastereoselectivity. PMID- 25825803 TI - Tailoring micrometer-long high-integrity 1D array of superparamagnetic nanoparticles in a nanotubular protein jacket and its lateral magnetic assembling behavior. AB - Tailoring of a micrometer-long one-dimensional (1D) array of superparamagnetic iron oxide nanoparticles (SNPs) was achieved by Mg(2+)-mediated supramolecular polymerization of a SNP-containing chaperonin protein (GroELMC?SNP). The inclusion complex GroELMC?SNP formed when ligand-modified SNPs were mixed with GroELMC, a GroEL mutant having multiple merocyanine (MC) units at its apical domains. Upon mixing with MgCl2 in phosphate buffer, GroELMC?SNP polymerized via the formation of multiple MC-Mg(2+)-MC coordination bonds, yielding thermodynamically stable micrometer-long nanotubes encapsulating 1D-arrayed SNPs (NTGroEL?SNP). When the NTGroEL?SNP nanotubes in phosphate buffer were incubated in a 0.5 T magnetic field, they began to assemble laterally and then organized into thick 1D bundles, where longer nanotubes were more preferentially incorporated. When the applied magnetic field was turned off, such bundles disassembled back to the individual 1D nanotubes. Lateral assembly of 1D SNP arrays in a magnetic field has been theoretically predicted but never been proven experimentally. PMID- 25825804 TI - Exploring suitable participation tools for children who need or use power mobility: A modified Delphi survey. AB - OBJECTIVES: To identify suitable tools for measuring important elements of participation for children, aged 18 months to 12 years, who need or use power mobility, and to indicate which tools should be considered for inclusion in a measurement toolkit. METHODS: Parents, therapists and researchers with expertise in paediatric power mobility and participation (n = 70) completed an online modified Delphi survey, with consensus set a priori >80% agreement. Existing tools were matched against participation elements ranked most important for those in early childhood (18 months-5 years) and of school-age (6-12 years) by the panel. RESULTS: Six out of 13 tools demonstrated potential, meeting at least three elements each, although none addressed all elements deemed important to measure by the panel. Only the Participation and Environment Measure for Children and Youth (PEM-CY) reached consensus for inclusion in a participation measure toolkit. CONCLUSION: Further evaluation of these tools with this population is warranted. PMID- 25825805 TI - Peptide code-on-a-microplate for protease activity analysis via MALDI-TOF mass spectrometric quantitation. AB - A peptide-encoded microplate was proposed for MALDI-TOF mass spectrometric (MS) analysis of protease activity. The peptide codes were designed to contain a coding region and the substrate of protease for enzymatic cleavage, respectively, and an internal standard method was proposed for the MS quantitation of the cleavage products of these peptide codes. Upon the cleavage reaction in the presence of target proteases, the coding regions were released from the microplate, which were directly quantitated by using corresponding peptides with one-amino acid difference as the internal standards. The coding region could be used as the unique "Protease ID" for the identification of corresponding protease, and the amount of the cleavage product was used for protease activity analysis. Using trypsin and chymotrypsin as the model proteases to verify the multiplex protease assay, the designed "Trypsin ID" and "Chymotrypsin ID" occurred at m/z 761.6 and 711.6. The logarithm value of the intensity ratio of "Protease ID" to internal standard was proportional to trypsin and chymotrypsin concentration in a range from 5.0 to 500 and 10 to 500 nM, respectively. The detection limits for trypsin and chymotrypsin were 2.3 and 5.2 nM, respectively. The peptide-encoded microplate showed good selectivity. This proposed method provided a powerful tool for convenient identification and activity analysis of multiplex proteases. PMID- 25825806 TI - Methodologies for determining the sources, characteristics, distribution, and abundance of asbestiform and nonasbestiform amphibole and serpentine in ambient air and water. AB - Anthropogenic and nonanthropogenic (erosion) processes contribute to the continuing presence of asbestos and nonasbestos elongated mineral particles (EMP) of amphibole and serpentine in air and water of urban, rural, and remote environments. The anthropogenic processes include disturbance and deterioration of asbestos-containing materials, mining of amphibole- and serpentine-bearing rock, and disturbance of soils containing amphibole and serpentine. Atmospheric dispersal processes can transport EMP on a global scale. There are many methods of establishing the abundance of EMP in air and water. EMP include cleavage fragments, fibers, asbestos, and other asbestiform minerals, and the methods employed do not critically distinguish among them. The results of most of the protocols are expressed in the common unit of fibers per square centimeter; however, seven different definitions for the term "fiber" are employed and the results are not comparable. The phase-contrast optical method used for occupational monitoring cannot identify particles being measured, and none of the methods distinguish amphibole asbestos from other EMP of amphibole. Measured ambient concentrations of airborne EMP are low, and variance may be high, even for similar environments, yielding data of questionable value for risk assessment. Calculations based on the abundance of amphibole-bearing rock and estimates of asbestos in the conterminous United States suggest that amphibole may be found in 6-10% of the land area; nonanthropogenic erosional processes might produce on the order of 400,000 tons or more of amphibole per year, and approximately 50 g asbestos/km(2)/yr; and the order of magnitude of the likelihood of encountering rock bearing any type of asbestos is approximately 0.0001. PMID- 25825807 TI - Exposures and health outcomes in relation to bioaerosol emissions from composting facilities: a systematic review of occupational and community studies. AB - The number of composting sites in Europe is rapidly increasing, due to efforts to reduce the fraction of waste destined for landfill, but evidence on possible health impacts is limited. This article systematically reviews studies related to bioaerosol exposures within and near composting facilities and associated health effects in both community and occupational health settings. Six electronic databases and bibliographies from January 1960 to July 2014 were searched for studies reporting on health outcomes and/or bioaerosol emissions related to composting sites. Risk of bias was assessed using a customized score. Five hundred and thirty-six papers were identified and reviewed, and 66 articles met the inclusion criteria (48 exposure studies, 9 health studies, 9 health and exposure studies). Exposure information was limited, with most measurements taken in occupational settings and for limited time periods. Bioaerosol concentrations were highest on-site during agitation activities (turning, shredding, and screening). Six studies detected concentrations of either Aspergillus fumigatus or total bacteria above the English Environment Agency's recommended threshold levels beyond 250 m from the site. Occupational studies of compost workers suggested elevated risks of respiratory illnesses with higher bioaerosol exposures. Elevated airway irritation was reported in residents near composting sites, but this may have been affected by reporting bias. The evidence base on health effects of bioaerosol emissions from composting facilities is still limited, although there is sufficient evidence to support a precautionary approach for regulatory purposes. While data to date are suggestive of possible respiratory effects, further study is needed to confirm this and to explore other health outcomes. PMID- 25825808 TI - Laparoscopic and robotic calyceal diverticulectomy: outcomes and modifications of technique. AB - OBJECTIVE: To examine the technique and outcomes of robotic and laparoscopic calyceal diverticulectomy in the management of symptomatic calyceal diverticula at a single center. SUBJECTS AND METHODS: Perioperative outcomes of six minimally invasive calyceal diverticulectomies (four laparoscopic and two robotic) between March 2011 and May 2014 were analyzed. Postoperative complications were categorized by Clavien-Dindo grade. RESULTS: The median age of the cohort was 35 years (range, 24-51 years), and mean body mass index was 24 kg/m(2). All 6 patients were female and presented with ipsilateral flank pain, and 3 of the 6 had coexisting recurrent urinary tract infections attributed to the calyceal diverticulum. Five of the 6 patients had failed prior surgical intervention with either endoscopic intervention or extracorporeal shock wave lithotripsy. Hilar clamping was performed in 2 of the 6 cases, with a mean warm ischemia time of 12 minutes (range, 10-14 minutes). Mean operative time was 162 minutes (range, 121 270 minutes), with no intraoperative complications. Mean blood loss was 150 mL (range, 50-300 mL), with no blood transfusions. There was one Clavien grade 1 complication and no major (Clavien grade 3 or higher) complications. Mean hospital stay was 2 days (range, 1-4 days). Four of the 6 patients were seen in follow-up, and all had complete resolution of flank pain and urinary tract infections, with no residual stones on imaging. CONCLUSIONS: Laparoscopic and robotic calyceal diverticulectomies for symptomatic calyceal diverticulum are safe, effective treatment options for symptomatic calyceal diverticula. PMID- 25825809 TI - Amino- and Carboxyl-Terminal CCR5 Mutations in Brazilian HIV-1-Infected Women and Homology Model of p.L55Q CCR5 Mutant. AB - Genetic factors from an HIV-1 host can affect the rate of progression to AIDS and HIV infection. To investigate the frequency of mutations in the CCR5 gene, HIV-1 samples from infected women and uninfected individuals were selected for sequencing of the CCR5 gene regions encoding the N- and C-terminal protein domains. Physicochemical CCR5 modeling and potential protein domain analysis were performed in order to evaluate the impact of the mutations found in the properties and structure of CCR5. The p.L55Q mutation in the N-terminal protein domain was observed only in uninfected individuals, with an allelic frequency of 1.8%. Physicochemical analysis revealed that the p.L55Q mutation magnified the flexibility and accessibility profiles and the modeling of CCR5 structures showed resulting in a small deviation to the right, as well as a hydrophobic to hydrophilic property alteration. The p.L55Q mutation also resulted in a slight modification of the electrostatic load of this region. Additionally, three novel silent mutations were found at the C-terminal coding region among HIV-1-infected women. The results suggest that the p.L55Q mutation might alter CCR5 conformation. Further studies should be conducted to verify the role of this mutation in HIV-1 susceptibility. PMID- 25825810 TI - Tribute to Ted Martonen. PMID- 25825811 TI - Ab Initio Screening of CO2-philic Groups. AB - Ab initio calculations were used to identify CO2-philic groups. Over 55 neutral molecules were screened for CO2 affinity via binding energetics. It is found that poly(ethylene oxide)s (PEO) oligomers with more than three repeating units are good CO2-binding groups, consistent with the high-performance of PEO-based materials for CO2/N2 separation. More interestingly, two triazole groups linked with a methylene chain are also excellent for CO2 binding with a favorable interaction of more than 28 kJ/mol, indicating that polymers or covalent-organic frameworks (COFs) with triazoles may be utilized for CO2 capture. This work provides a useful guide to introduce promising organic groups into polymeric membranes and COFs for CO2/N2 separation media. PMID- 25825812 TI - DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli. AB - BACKGROUND: The aim of the present study was to investigate the association of fMRI blood oxygen-level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). METHODS: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing. RESULTS: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. LIMITATIONS: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. CONCLUSION: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery. PMID- 25825814 TI - Importance of Self-Motivation and Social Support in Medication Adherence in HIV Infected Adolescents in the United Kingdom and Ireland: A Multicentre HYPNet Study. AB - Adolescents are a vulnerable population, not only to the acquisition of HIV, but also to poor adherence to antiretroviral therapy (ART) associated with disease progression and a increased risk of onward viral transmission. The aim of the study was to examine the factors that aid or act as barriers to adherence in a UK population of adolescents and young adults receiving ART. A cross-sectional survey was completed of 138 adolescents (12-24 years) across 14 clinical and community sites in the UK and Ireland. Analysis of results was undertaken using Chi-square testing in SPSS. Of the 138 patients, 48% were female, and 52% were born outside of the UK. Fifty-two of the 138 (43%) reported being on ART for at least 8 years. More than a third of the patients have ever interrupted treatment since initiating ART. One hundred four of the 138 (75%) patients self-reported being >85% adherent to medication for 7 day recall. Self-motivation (e.g., having a routine, specific goal) was cited as being most helpful in medication compliance (33%), followed by reminders by friends and family (25%), with 20% identifing no specific factor. Only 15% chose interventions such as an adherence diary or mobile phone reminders as helpful factors, and 1% chose healthcare professional input such as home visits. This study highlights the importance of self-motivation and social support in medication adherence in an HIV-infected adolescent population, in preference to healthcare professional input. Education and motivational strategies may confer the biggest impact on sustained ART adherence amongst this vulnerable group. PMID- 25825813 TI - Structural and functional differences in the cingulate cortex relate to disease severity in anorexia nervosa. AB - BACKGROUND: The dysfunction of specific brain areas might account for the distortion of body image in patients with anorexia nervosa. The present study was designed to reveal brain regions that are abnormal in structure and function in patients with this disorder. We hypothesized, based on brain areas of altered activity in patients with anorexia nervosa and regions involved in pain processing, an interrelation of structural aberrations in the frontoparietal cingulate network and aberrant functional activation during thermal pain processing in patients with the disorder. METHODS: We determined pain thresholds outside the MRI scanner in patients with anorexia nervosa and matched healthy controls. Thereafter, thermal pain stimuli were applied during fMRI imaging. Structural analyses with high-resolution structural T1-weighted volumes were performed using voxel-based morphometry and a surface-based approach. RESULTS: Twenty-six patients and 26 controls participated in our study, and owing to technical difficulties, 15 participants in each group were included in our fMRI analysis. Structural analyses revealed significantly decreased grey matter volume and cortical thickness in the frontoparietal-cingulate network in patients with anorexia nervosa. We detected an increased blood oxygen level-dependent signal in patients during the painful 45 degrees C condition in the midcingulate and posterior cingulate cortex, which positively correlated with increased pain thresholds. Decreased grey matter and cortical thickness correlated negatively with pain thresholds, symptom severity and illness duration, but not with body mass index. LIMITATIONS: The lack of a specific quantification of body image distortion is a limitation of our study. CONCLUSION: This study provides further evidence for confined structural and functional brain abnormalities in patients with anorexia nervosa in brain regions that are involved in perception and integration of bodily stimuli. The association of structural and functional deviations with thermal thresholds as well as with clinical characteristics might indicate a common neuronal origin. PMID- 25825815 TI - MiR-22/Sp-1 Links Estrogens With the Up-Regulation of Cystathionine gamma-Lyase in Myocardium, Which Contributes to Estrogenic Cardioprotection Against Oxidative Stress. AB - Hydrogen sulfide, generated in the myocardium predominantly via cystathionine gamma-lyase (CSE), is cardioprotective. Our previous study has shown that estrogens enhance CSE expression in myocardium of female rats. The present study aims to explore the mechanisms by which estrogens regulate CSE expression, in particular to clarify the role of estrogen receptor subtypes and the transcriptional factor responsible for the estrogenic effects. We found that either the CSE inhibitor or the CSE small interfering RNA attenuated the protective effect of 17beta-estradiol (E2) against H2O2- and hypoxia/reoxygenation-induced injury in primary cultured neonatal cardiomyocytes. E2 stimulates CSE expression via estrogen receptor (ER)-alpha both in cultured cardiomyocytes in vitro and in the myocardium of female mice in vivo. A specificity protein-1 (Sp-1) consensus site was identified in the rat CSE promoter and was found to mediate the E2-induced CSE expression. E2 increases ERalpha and Sp-1 and inhibits microRNA (miR)-22 expression in myocardium of ovariectomized rats. In primary cardiomyocytes, E2 stimulates Sp-1 expression through the ERalpha-mediated down-regulation of miR-22. It was confirmed that both ERalpha and Sp-1 were targeted by miR-22. In the myocardium of ovariectomized rats, the level of miR-22 inversely correlated to CSE, ERalpha, Sp 1, and antioxidant biomarkers and positively correlated to oxidative biomarkers. In summary, this study demonstrates that estrogens stimulate Sp-1 through the ERalpha-mediated down-regulation of miR-22 in cardiomyocytes, leading to the up regulation of CSE, which in turn results in an increase of antioxidative defense. Interaction of ERalpha, miR-22, and Sp-1 may play a critical role in the control of oxidative stress status in the myocardium of female rats. PMID- 25825816 TI - Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells. AB - Sorting nexin 5 (SNX5) belongs to the SNX family, which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins, receptors, and transporters. SNX5 is important in the resensitization of the dopamine D1-like receptor (D1R). D1R is uncoupled from its effector proteins in hypertension and diabetes, and treatment of diabetes restores D1R function and insulin receptor (IR) expression. We tested the hypothesis that the D1R and SNX5 regulate IR by studying the expression, distribution, dynamics, and functional consequences of their interaction in human renal proximal tubule cells (hRPTCs). D1R, SNX5, and IR were expressed and colocalized in the brush border of RPTs. Insulin promoted the colocalization of SNX5 and IR at the perinuclear area of hRPTCs. Unlike SNX5, the D1R colocalized and coimmunoprecipitated with IR, and this interaction was enhanced by insulin. To evaluate the role of SNX5 and D1R on IR signaling, we silenced via RNA interference the endogenous expression of SNX5 or the D1R gene DRD1 in hRPTCs. We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B, which are crucial components of the IR signal transduction pathway. Our data indicate that SNX5 and D1R are necessary for normal IR expression and activity. It is conceivable that D1R and SNX5 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling. PMID- 25825817 TI - Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat. AB - KNDy neurons facilitate tail skin vasodilation and modulate the effects of estradiol on thermoregulation. We hypothesize that KNDy neurons influence cutaneous vasodilation via projections to neurons in the median preoptic nucleus (MnPO) that express the neurokinin 3 receptor (NK3R). In support of this hypothesis, focal microinjections of senktide, an NK3R agonist, into the MnPO lowers core temperature (TCORE) in the female rat. To further study the role of MnPO NK3R neurons in thermoregulation, these neurons were specifically ablated using a conjugate of a selective NK3R agonist and saporin (NK3-SAP). NK3-SAP or blank-SAP (control) was injected into the MnPO/medial septum. Tail skin temperature (TSKIN) and TCORE were measured in ovariectomized rats exposed to 3 ambient temperatures (TAMBIENT) before and after estradiol-17beta (E2) treatment. Before killing, we injected senktide (sc), monitored TCORE for 70 minutes, and harvested brains for Fos immunohistochemistry. Ablation of MnPO NK3R neurons lowered TSKIN at neutral and subneutral TAMBIENT regardless of E2 treatment. However, ablation did not prevent the effects of E2 on TCORE and TSKIN. In control rats, senktide injections induced hypothermia with numerous Fos immunoreactive cells in the MnPO. In contrast, in NK3-SAP rats, senktide did not alter TCORE and minimal Fos-immunoreactive neurons were identified in the MnPO. These data show that NK3R neurons in the MnPO are required for the hypothermic effects of senktide but not for the E2 modulation of thermoregulation. The lower TSKIN in NK3-SAP-injected rats suggests that MnPO NK3R neurons, like KNDy neurons, facilitate cutaneous vasodilation, an important heat-dissipation effector. PMID- 25825818 TI - Estrogen Replacement Therapy in Ovariectomized Nonpregnant Ewes Stimulates Uterine Artery Hydrogen Sulfide Biosynthesis by Selectively Up-Regulating Cystathionine beta-Synthase Expression. AB - Estrogens dramatically dilate numerous vascular beds with the greatest response in the uterus. Endogenous hydrogen sulfide (H2S) is a potent vasodilator and proangiogenic second messenger, which is synthesized from L-cysteine by cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). We hypothesized that estrogen replacement therapy (ERT) selectively stimulates H2S biosynthesis in uterine artery (UA) and other systemic arteries. Intact and endothelium-denuded UA, mesenteric artery (MA), and carotid artery (CA) were obtained from ovariectomized nonpregnant ewes (n = 5/group) receiving vehicle or estradiol-17beta replacement therapy (ERT). Total RNA and protein were extracted for measuring CBS and CSE, and H2S production was determined by the methylene blue assay. Paraffin-embedded UA rings were used to localize CBS and CSE proteins by immunofluorescence microscopy. ERT significantly stimulated CBS mRNA and protein without altering CSE mRNA or protein in intact and denuded UA. Quantitative immunofluorescence microscopic analyses showed CBS and CSE protein localization in endothelium and smooth muscle and confirmed that ERT stimulated CBS but not CSE protein expression in UA endothelium and smooth muscle. ERT also stimulated CBS, but not CSE, mRNA and protein expression in intact and denuded MA but not CA in ovariectomized ewes. Concomitantly, ERT stimulated UA and MA but not CA H2S production. ERT-stimulated UA H2S production was completely blocked by a specific CBS but not CSE inhibitor. Thus, ERT selectively stimulates UA and MA but not CA H2S biosynthesis by specifically up-regulating CBS expression, implicating a role of H2S in estrogen-induced vasodilation and postmenopausal women's health. PMID- 25825820 TI - Discrete polynuclear manganese(ii) complexes with thiacalixarene ligands: synthesis, structures and photophysical properties. AB - The synthesis, crystal structure and photophysical properties of the new compound [Mn4(ThiaSO2)2F][K(18-crown-6)], ThiaSO2 = p-tert-butylsulphonylcalix[4]arene, are presented and compared to the ones of [Mn4(ThiaSO2)2F]K. The strong orange luminescence is attributed to the Mn(2+) centred (4)T1->(6)A1 transition. Its temperature and pressure dependence and quenching by molecular dioxygen are reported. The latter is attributed to energy transfer from the (4)T1 state exciting dioxygen to its (1)?(+)g state. In the solid state, the quenching is much more efficient in [Mn4(ThiaSO2)2F][K(18-crown-6)] than in [Mn4(ThiaSO2)2F]K. This is attributed to the open pore structure of the former allowing fast diffusion of dioxygen into the crystal lattice. PMID- 25825819 TI - Demographic differences in willingness to provide broad and narrow consent for biobank research. AB - PURPOSE: This study examined acceptability of two biobank consent models and evaluated the impact of beliefs about privacy and genetic safeguards on acceptance. METHODS: U.S. adults surveyed online in English and Spanish were randomly assigned to one of two scenarios examining acceptance of broad consent (n=1528), or narrow consent (n=1533). RESULTS: Overall, willingness to provide broad (76%) and narrow (74%) consents were similar. African Americans were as likely as white non-Hispanics to accept narrow consent (72% vs. 77%, p=0.35) but significantly less likely to accept broad consent (69% vs. 81%, p=0.004). Education, insurance, and blood donation history were also related to acceptance. Adjusting for beliefs about privacy and policy protections (Genetic Information Nondiscrimination Act, GINA), the effects of the variables were reduced. Respondents who drew comfort from GINA were more likely to support both consent (both p<0.001); those who believed it is impossible to maintain privacy were less likely to find both broad (p=0.04) and narrow models acceptable (p=0.02). CONCLUSIONS: Choice of consent model matters when engaging diverse populations in biobank research. Beliefs underlying concerns about privacy and genetic protections should be considered when constructing biobank protocols. PMID- 25825821 TI - [2]Pseudorotaxane composed of heteroditopic macrobicycle and pyridine N-oxide based axle: recognition site dependent axle orientation. AB - A strategy for threading an axle having a hydrogen bond acceptor unit in the cavity of a C3v symmetric amido-amine macrobicycle is investigated. The macrobicycle acts as a wheel in its neutral as well as triprotonated states to form threaded architectures with a pyridine N-oxide derivative. The negative oxygen dipole of the axle is capable of [2]pseudorotaxane formation in two different orientations with the wheel in its neutral and triprotonated states. PMID- 25825822 TI - Simultaneous Detection of 3-Nitrotyrosine and 3-Nitro-4-hydroxyphenylacetic Acid in Human Urine by Online SPE LC-MS/MS and Their Association with Oxidative and Methylated DNA Lesions. AB - Reactive nitrogen species (RNS) can modify proteins at tyrosine and tryptophan residues, and they are involved in the pathogenesis of various human diseases. In this study, we present the first liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method that enables the simultaneous measurement of urinary 3 nitrotyrosine (3-NTYR) and its metabolite 3-nitro-4-hydroxyphenylacetic acid (NHPA). After the addition of stable isotope-labeled internal standards, urine samples were purified and enriched using manual solid-phase extraction (SPE) and HPLC fractionation followed by online SPE LC-MS/MS analysis. The limits of quantification in urine were 3.1 and 2.5 pg/mL for 3-NTYR and NHPA, respectively. Inter- and intraday imprecision was <15%. The mean relative recoveries of 3-NTYR and NHPA in urine were 89-98% and 90-98%, respectively. We further applied this method to 65 urinary samples from healthy subjects. Urinary samples were also analyzed for N-nitrosodimethylamine (NDMA) as well as oxidative and methylated DNA lesions, namely, 8-oxo-7,8-dihydroguanine (8-oxoGua), 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxodGuo), N7-methylguanine (N7-MeG), and N3-methyladenine (N3 MeA), using reported LC-MS/MS methods. Urinary 3-NTYR and NHPA levels were measured at concentrations of 63.2 +/- 51.5 and 77.4 +/- 60.8 pg/mL, respectively. Urinary 3-NTYR and NHPA levels were highly correlated with each other and with 8-oxoGua and 8-oxodGuo. Our findings demonstrated that a relationship exists between oxidative and nitrative stress. However, 3-NTYR and NHPA were correlated with N7-MeG and N3-MeA but not with NDMA, suggesting that NDMA may not be a representative biomarker of N-nitroso compounds that are induced by RNS. PMID- 25825823 TI - Surface engineering of graphene quantum dots and their applications as efficient surfactants. AB - The surface properties of graphene quantum dots (GQDs) control their dispersion and location within the matrices of organic molecules and polymers, thereby determining various properties of the hybrid materials. Herein, we developed a facile, one-step method for achieving systematic control of the surface properties of highly fluorescent GQDs. The surfaces of the as-synthesized hydrophilic GQDs were modified precisely depending on the number of grafted hydrophobic hexylamine. The geometry of the modified GQDs was envisioned by conducting simulations using density functional theory. In stark contrast to the pristine GQDs, the surface-modified GQDs can effectively stabilize oil-in-water Pickering emulsions and submicron-sized colloidal particles in mini-emulsion polymerization. These versatile GQD surfactants were also employed in liquid solid systems; we demonstrated their use for tailoring the dispersion of graphite in methanol. Finally, the particles produced by the GQD surfactants were fluorescent due to luminescence of the GQDs, which offers great potential for various applications, including fluorescent sensors and imaging. PMID- 25825824 TI - In memoriam: A. I. Sabra (June 8, 1924 - December 18, 2013). PMID- 25825825 TI - Response to Foley's review of Swanson's Neuroanatomical Terminology (2014). PMID- 25825826 TI - Bio-inspired multinuclear copper complexes covalently immobilized on reduced graphene oxide as efficient electrocatalysts for the oxygen reduction reaction. AB - Inspired by the multicopper active site of laccase, which efficiently catalyzes the oxygen reduction reaction (ORR), herein we report a novel bio-inspired ORR catalyst composed of a multinuclear copper complex that was immobilized on the surface of reduced graphene oxide (rGO) via the covalently grafted triazole dipyridine (TADPy) dinucleating ligand. This rGO-TADPyCu catalyst exhibited high ORR activity and superior long-term stability compared to Pt/C in alkaline media. PMID- 25825827 TI - Comparative study of dose distributions and cell survival fractions for 1H, 4He, 12C and 16O beams using Geant4 and Microdosimetric Kinetic model. AB - Depth and radial dose profiles for therapeutic (1)H, (4)He, (12)C and (16)O beams are calculated using the Geant4-based Monte Carlo model for Heavy-Ion Therapy (MCHIT). (4)He and (16)O ions are presented as alternative options to (1)H and (12)C broadly used for ion-beam cancer therapy. Biological dose profiles and survival fractions of cells are estimated using the modified Microdosimetric Kinetic model. Depth distributions of cell survival of healthy tissues, assuming 10% and 50% survival of tumor cells, are calculated for 6 cm SOBPs at two tumor depths and for different tissues radiosensitivities. It is found that the optimal ion choice depends on (i) depth of the tumor, (ii) dose levels and (iii) the contrast of radiosensitivities of tumor and surrounding healthy tissues. Our results indicate that (12)C and (16)O ions are more appropriate to spare healthy tissues in the case of a more radioresistant tumor at moderate depths. On the other hand, a sensitive tumor surrounded by more resistant tissues can be better treated with (1)H and (4)He ions. In general, (4)He beam is found to be a good candidate for therapy. It better spares healthy tissues in all considered cases compared to (1)H. Besides, the dose conformation is improved for deep-seated tumors compared to (1)H, and the damage to surrounding healthy tissues is reduced compared to heavier ions due to the lower impact of nuclear fragmentation. No definite advantages of (16)O with respect to (12)C ions are found in this study. PMID- 25825830 TI - Plotting intersections. PMID- 25825829 TI - Use of food practices by childcare staff and the association with dietary intake of children at childcare. AB - The study explored the associations between various childcare staff food practices and children's dietary intake at childcare. A total of 398 one- to four year-old children and 24 childcare staff members from 24 Dutch childcare centers participated in the study. Children's dietary intake (fruit, vegetable, sweet snack, savory snack, water, and sweet drink intake) at childcare was registered on two weekdays, using observations by dieticians and childcare staff. Thirteen childcare staff practices were assessed using questionnaires administered by dieticians. Data were analyzed using multilevel regression analyses. Children consumed relatively much fruit and many sweet snacks at childcare, and they mainly drank sweet drinks. Various staff practices were associated with children's dietary intake. When staff explained what they were doing to the children during food preparation, children ate significantly more fruit. Children ate less sweet snacks when they were allowed to help prepare the meals. When staff encouraged children to continue eating, they ate more vegetables. In conclusion, the study showed the importance of childcare staff food practices for children's food intake at childcare. More research is needed to examine the specific conditions under which food practices can have a positive impact on children's dietary intake. PMID- 25825828 TI - Oral cancer malnutrition impacts weight and quality of life. AB - Diet is important for both quality of life (QoL) and survival of patients with oral cancer. Their intake of food is impeded by functional restrictions in chewing and swallowing. In the DOSAK REHAB STUDY 1652 patients from 38 hospitals within the German-language area of Germany; Austria and Switzerland were examined with regard to functional and psychological variables having an impact on diet. Chewing and swallowing are correlated with mobility of the tongue and the mandible as well as opening of the mouth. Thirty five percent of the patients lost weight; 41% maintained their weight and 24% gained weight. The QoL of patients who were able to maintain their weight and of those who gained weight was significantly better than that of patients who lost weight. A normal diet was important for maintaining weight. Mashed food; liquid food and loss of appetite were closely associated with loss of weight; although it was possible for nutritional counseling and dietary support to be implemented particularly favorably in this respect. Due to problems with eating patients' strength deteriorated; thus restricting activity. Radiotherapy had a negative impact on diet and weight. It influenced sense of taste; dryness of the mouth; swelling and discomfort when ingesting food. Pain and scars in the region of the operation also cause patients to dislike hard; spicy and sour food. Support from a nutritional counselor in implementing a calorie-rich diet remedied this and such support needs to be integrated into patient management. The fact that a poor nutritional status is of such great importance is well-known; but what is often lacking is the systematic implementation of continued professional nutritional counseling over a long period of time; weight control and psycho-social support of the operated patients; particularly those who also have had radiotherapy. PMID- 25825831 TI - Response to "Plotting intersections" by Lentini. PMID- 25825832 TI - Transparency in film: increasing credibility of scientific animation using citation. PMID- 25825833 TI - Cancer: smoother journeys for molecular data. PMID- 25825834 TI - Successful test launch for nanopore sequencing. PMID- 25825835 TI - Better together: multiplexing samples to improve the preparation and reliability of gene expression studies. PMID- 25825838 TI - Comparing techniques to achieve high accuracy and low cost: how should we first diagnose Crohn's disease? PMID- 25825836 TI - Integrative, dynamic structural biology at atomic resolution--it's about time. AB - Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and other techniques are helping us realize the dream of seeing--in atomic detail--how different parts of biomolecules shift between functional substates using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution. PMID- 25825837 TI - Mutagenicity of drinking water sampled from the Yangtze River and Hanshui River (Wuhan section) and correlations with water quality parameters. AB - A total of 54 water samples were collected during three different hydrologic periods (level period, wet period, and dry period) from Plant A and Plant B (a source for Yangtze River and Hanshui River water, respectively), and several water parameters, such as chemical oxygen demand (COD), turbidity, and total organic carbon (TOC), were simultaneously analyzed. The mutagenicity of the water samples was evaluated using the Ames test with Salmonella typhimurium strains TA98 and TA100. According to the results, the organic compounds in the water were largely frame-shift mutagens, as positive results were found for most of the tests using TA98. All of the finished water samples exhibited stronger mutagenicity than the relative raw and distribution water samples, with water samples collected from Plant B presenting stronger mutagenic strength than those from Plant A. The finished water samples from Plant A displayed a seasonal dependent variation. Water parameters including COD (r = 0.599, P = 0.009), TOC (r = 0.681, P = 0.02), UV254 (r = 0.711, P = 0.001), and total nitrogen (r = 0.570, P = 0.014) exhibited good correlations with mutagenicity (TA98), at 2.0 L/plate, which bolsters the argument of the importance of using mutagenicity as a new parameter to assess the quality of drinking water. PMID- 25825839 TI - Translating comparative effectiveness research into Medicaid payment policy: views from medical and pharmacy directors. AB - BACKGROUND: As the USA seeks to expand the conduct and dissemination of comparative effectiveness research (CER), views of key stakeholders will help guide the way. METHODS: We surveyed 60 medical and pharmacy directors from 46 state Medicaid programs. RESULTS: Over 90% felt that CER would lead to better clinical decision-making and overall value within 5 years and were willing to consider cost-effectiveness in setting medical policy. However, perceived poor quality, inconclusive research, restrictive legislative mandates, lack of budget impact and coverage recommendations, and lack of an independent body to interpret study results were major barriers cited to using CER evidence. CONCLUSION: Given the significant resources being invested in CER, it is critical that these barriers are overcome to maximize its usefulness for stakeholders. PMID- 25825840 TI - A meta-analysis platform methodology for determining the comparative effectiveness of antihepatitis C virus regimens. AB - AIM: Many hepatitis C virus regimens are unlikely to be compared head to head. In more difficult to treat populations where there is no standard of care, trials are single arm. We describe a flexible meta-analysis platform in this setting. METHODS: Our meta-analysis is literature based. We illustrate our methodology and show how inference can be extended to single-arm trials. RESULTS: As an example, in the single arm setting, a regimen with response rates of 84, 72 and 54% in genotype 1a across treatment naive, previous partial responders and previous null responders, respectively, would have 95% probability of superiority to IFN-alpha + RBV + TPV. CONCLUSION: This is a rigorous approach to comparative effectiveness that accounts for varying patient populations and plans for the incorporation of emerging treatments. PMID- 25825841 TI - Initiatives in South Africa to enhance the prescribing of generic proton pump inhibitors: findings and implications. AB - BACKGROUND: There have been multiple reforms in South Africa to conserve resources including policies to enhance generic use, such as compulsory generic substitution and copayments. However, there are concerns with the limited knowledge of their impact. OBJECTIVE: The objective was to determine utilization and expenditure of different proton pump inhibitors (PPIs). METHODOLOGY: A retrospective drug utilization study was conducted on a prescription database of a medical aid administrator in 2010. RESULTS: The limited prescribing of single sourced PPIs accounted for 21.5% of total prescriptions. The limited use of originators omeprazole and lansoprazole accounted for 1.8 and 1.4% of total prescriptions for the molecule, respectively. Generic prices accounted for 36-68% of the originator in 2010. Patients received on average 2.91 PPI prescriptions during the year. CONCLUSION: Policies to enhance prescribing of generics appear working. Opportunities exist to further lower generic prices given low prices in some European countries. PMID- 25825842 TI - Evaluating patient and stakeholder engagement in research: moving from theory to practice. AB - Despite the growing demand for research that engages stakeholders, there is limited evidence in the literature to demonstrate its value - or return on investment. This gap indicates a general lack of evaluation of engagement activities. To adequately inform engagement activities, we need to further investigate the dividends of engaged research, and how to evaluate these effects. This paper synthesizes the literature on hypothesized impacts of engagement, shares what has been evaluated and identifies steps needed to reduce the gap between engagement's promises and the underlying evidence supporting its practice. This assessment provides explicit guidance for better alignment of engagement's promised benefits with evaluation efforts and identifies specific areas for development of evaluative measures and better reporting processes. PMID- 25825843 TI - Once-weekly hypofractionated breast irradiation: fool's gold or diamond in the rough? AB - Daily conventionally fractionated breast irradiation over 5-7 weeks is costly and inconvenient. Its use is associated with disparities in both the delivery of quality care and outcomes for vulnerable populations. Alternatively, daily hypofractionated breast irradiation delivered over 3 weeks exhibits equal efficacy and toxicity profiles. Today, a new generation of accelerated radiotherapy for breast cancer has emerged. Once-weekly hypofractionated breast irradiation has been tested in pilot and large randomized studies and the initial data appear promising. As the data mature, this new approach has implications for cost-efficacy and provision of radiotherapy services. The purpose of this review is to explore the evolution of once-weekly hypofractionated breast irradiation including our ongoing institutional clinical trial at the University of Louisville. PMID- 25825844 TI - EORTC QLQ-BR23 and FACT-B for the assessment of quality of life in patients with breast cancer: a literature review. AB - BACKGROUND: This study aims to compare the development, characteristics and validity of two widely used tools in the breast cancer population, the EORTC QLQ BR23 and the FACT-B. METHODS: A literature search was conducted using Ovid MEDLINE, OLDMEDLINE, Embase, Embase Classic and the Cochrane Central Register of Controlled Trials to identify relevant studies. RESULTS: Both tools were found to be reliable and valid. The QLQ-BR23 focuses on physical function, whereas the FACT-B emphasizes emotional well-being. Scoring, item format, organization and response options differ between questionnaires. CONCLUSION: Overall, both questionnaires are effective in assessing breast cancer-specific quality of life. Clear similarities and differences between the two tools exist. Decision-making between the questionnaires should be based on the purpose and design of the study. PMID- 25825845 TI - Heparin and related drugs for venous thromboembolism prophylaxis: subcutaneous or intravenous continuous infusion? AB - In this article, the most evidenced approaches of unfractionated heparin administration for prevention of venous thromboembolism in medical and surgical hospitalized patients will be reviewed. Present data were collected by searching Scopus, PubMed, MEDLINE, Science direct, Clinical trials and Cochrane database systematic reviews. Subcutaneous low doses of unfractionated heparin (10000-15000 IU) in two or three divided doses per day are commonly administrated for venous thromboembolism prevention in different medical and surgical populations. In some populations such as obese surgical and critically ill patients, due to altered pharmacokinetics behavior of unfractionated heparin, continuous intravenous infusion of the low doses of unfractionated heparin has been proposed. PMID- 25825846 TI - Serum sLOX-1 Levels Are Correlated with the Presence and Severity of Obstructive Sleep Apnea. AB - CONTEXT: Inflammation plays a critical role in the development and progression of obstructive sleep apnea (OSA). Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) activation is involved in the pathophysiology of inflammatory process-related disorders. OBJECTIVE: This study aims to investigate whether serum soluble LOX-1 (sLOX-1) levels are associated with the presence and severity of OSA. MATERIALS AND METHODS: A total of 137 OSA patients and 78 controls were recruited in this study. Serum sLOX-1 levels were measured by enzyme-linked immunosorbent assay. The severity of OSA was assessed by the apnea-hypopnea index (AHI). RESULTS: OSA patients had significantly higher serum sLOX-1 levels compared with controls. Serum sLOX-1 levels elevated with the increment of OSA severity. sLOX-1 was the independent predictor of OSA. Serum sLOX-1 levels were significantly correlated with AHI and high-sensitivity C-reactive protein levels. CONCLUSIONS: Serum sLOX-1 levels were independently correlated with the presence and severity of OSA. These findings revealed that sLOX-1 might function as a potential biomarker for monitoring the development and progression of OSA. PMID- 25825848 TI - Prediction of small-for-gestational-age neonates: screening by placental growth factor and soluble fms-like tyrosine kinase-1 at 35-37 weeks. AB - OBJECTIVE: To investigate the potential value of maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) at 35-37 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in singleton pregnancies at 35-37 weeks, including 158 that delivered SGA neonates with birth weight < 5(th) percentile and 3701 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if measuring serum levels of PlGF and sFlt-1 improved the prediction of delivery of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. RESULTS: Compared to the normal group, the median PlGF multiples of the median (MoM) was significantly lower and the median sFlt-1 MoM was significantly higher in the SGA group. Combined screening by maternal factors and EFW at 35-37 weeks predicted, at 10% false-positive rate (FPR), 90%, 92% and 94% of SGA neonates with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment; the respective values for SGA delivering >= 37 weeks were 66%, 73% and 80%. When PlGF and sFlt-1 were added to a model that combines maternal factors and EFW, sFlt-1 did not remain as a significant independent predictor of SGA < 5(th). Combined screening by maternal factors, EFW and serum PlGF, predicted, at a 10% FPR, 88%, 96% and 94% of SGA neonates with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment and the respective values for SGA delivering >= 37 weeks were 64%, 75% and 80%. CONCLUSION: sFlt-1 does not provide significant independent prediction of SGA, in the absence of PE, in addition to combined testing by maternal factors and fetal biometry at 35-37 weeks; whilst the addition of PlGF alone marginally improves the performance of screening. PMID- 25825849 TI - Reaction time, cerebral blood flow, and heart rate responses in fibromyalgia: Evidence of alterations in attentional control. AB - The study investigated cerebral blood flow (CBF) and heart rate (HR) responses during a cued reaction time (RT) task in patients with fibromyalgia syndrome (FMS). CBF velocities in the middle (MCA) and anterior (ACA) cerebral arteries of both hemispheres were recorded in 46 patients and 32 healthy control participants using functional transcranial Doppler sonography (fTCD). Patients exhibited markedly longer RT than healthy participants. Group differences in CBF responses were mainly observed for both ACAs, with greater right hemispherical increases but lower left hemispherical increases in FMS patients than in healthy participants. HR deceleration around the imperative stimulus was more pronounced in healthy participants. RT was inversely related to increases in CBF in both right arteries and in the left ACA in the FMS group, but was positively associated with CBF responses in all four arteries in healthy participants. The magnitude of task-induced HR deceleration correlated negatively with RT in both groups. Patients' clinical pain severity was positively associated with RT and CBF responses; trait anxiety and insomnia were secondary negative predictors of CBF responses. The study provided evidence of a deficit in the alertness component of attention in FMS at behavioral, CBF, and autonomic levels. These results may be interpreted in terms of the neural efficiency hypothesis of intelligence (i.e., less efficient brain activation during cognition in FMS) and the interfering effect of clinical factors on cognition. Clinical factors such as pain, anxiety, and sleep disturbances can affect cognition in FMS by interfering with CBF adjustment to cognitive demands. PMID- 25825850 TI - Relationship Power, Sexual Decision Making, and HIV Risk Among Midlife and Older Women. AB - The number of midlife and older women with HIV/AIDS is high and increasing, especially among women of color. This article addresses these demographic realities by reporting on findings about self-esteem, relationship power, and HIV risk from a pilot study of midlife and older women. A purposive sample (N = 110) of ethnically, economically, and educationally diverse women 40 years and older from the Greater Los Angeles Area was surveyed to determine their levels of self esteem, general relationship power, sexual decision-making power, safer sex behaviors, and HIV knowledge. Women with higher levels of self-esteem exercised greater power in their relationships with their partner. Women with higher levels of general relationship power and self-esteem tend to exercise greater power in sexual decision making, such as having sex and choosing sexual acts. Income and sexual decision-making power were statistically significant in predicting the use of condoms. Implications and recommendations for future HIV/AIDS research and intervention targeting midlife and older women are presented. PMID- 25825851 TI - Clinical zinc deficiency as early presentation of Wilson disease. AB - Wilson disease is a rare autosomal recessive disorder of the copper metabolism caused by homozygous or compound heterozygous mutations in the ATP-ase Cu(2+) transporting polypeptide (ATP7B) gene. The copper accumulation in different organs leads to the suspicion of Wilson disease. We describe a child with clinical zinc deficiency as presenting symptom of Wilson disease, which was confirmed by 2 mutations within the ATP7B gene and an increased copper excretion. PMID- 25825852 TI - Byler disease: early natural history. AB - OBJECTIVES: Byler disease, originally described in Amish kindred, results from mutations in ATPase Class I Type 8b Member 1 (ATP8b1). Specific clinical reports of Amish Byler disease were last published 40 years ago. These investigations were directed at the present detailed clinical understanding of the early course of hepatic manifestations of Byler disease. METHODS: This study analyzed routine clinical practice and outcomes of children with Byler disease (defined by homozygous c.923G>T mutation in ATP8b1), who initially presented to Children's Hospital of Pittsburgh of UPMC between January 2007 and October 2014. Data were analyzed to the earlier of 24 months of age or partial external biliary diversion. RESULTS: Six children presented between 1 and 135 days of life: 2 presented with newborn direct hyperbilirubinemia, 2 had complications of coagulopathy, 1 had failure to thrive and rickets, and 1 sibling was identified by newborn genetic testing. Intensive fat-soluble vitamin supplementation was required to prevent insufficiencies in vitamins D, E, and K. Hyperbilirubinemia was variable both over time and between children. Serum bile acid levels were elevated, whereas gamma-glutamyltranspeptidase levels were low normal. Scratching behavior (pruritus) was intractable in 4 of 6 children with onset between 6 and 12 months of age. Features of portal hypertension were not observed. Partial external biliary diversion was used during the second year of life in 4 children. CONCLUSIONS: Detailed analysis of Byler disease revealed varied disease presentation and course. Nutritional issues and pruritus dominated the clinical picture in the first 2 years of life. PMID- 25825854 TI - Prokinetics prescribing in paediatrics: evidence on cisapride, domperidone, and metoclopramide. AB - OBJECTIVES: Domperidone and metoclopramide are prokinetics commonly prescribed off-label to infants and younger children in an attempt to treat gastro oesophageal reflux symptoms. Another prokinetic drug, cisapride, was used but withdrawn in 2000 in the United Kingdom because of serious arrhythmic adverse events. Medicines and Healthcare Products Regulatory Agency issued safety warnings for domperidone in May 2012 and restricted its indications. We report here national primary care prescribing trends and safety signals of these drugs in children. METHODS: We used data from the General Practice Research Database between 1990 and 2006 for children <18 years. Descriptive statistics and Poisson regressions were performed to characterise prescribing trends. We examined safety signals in nested case-control studies. RESULTS: The proportion of children <2 years old being prescribed one of the medications doubled during the study period. Prescriptions of domperidone increased 10-fold, mainly following the withdrawal of cisapride in 2000. Prescriptions of metoclopramide did not change significantly. Despite the increase in prescriptions of domperidone, no new safety signals were identified. CONCLUSIONS: These data showed dramatic changes in prescribing of cisapride and domperidone despite the lack of good-quality supporting evidence. It is possible that these prescribing trends were influenced by published guidelines. Even if produced without robust efficacy and safety evidence, published guidelines can influence clinicians and consequently affect prescribing. Therefore, improving the evidence base on prokinetics to inform future guidelines is vital. The lack of new safety signals during this period would support the development of suitable powered clinical studies. PMID- 25825853 TI - Mechanical bowel preparation for children undergoing elective colorectal surgery. AB - OBJECTIVES: Adult literature supports the elimination of mechanical bowel preparation (MBP) for elective colorectal surgical procedures. Prospective data for the pediatric population regarding the utility of MBP are lacking. The primary aim of this study was to compare infectious complications, specifically anastomotic leak, intraabdominal abscess, and wound infection in patients who received MBP with those who did not. METHODS: A randomized pilot study comparing MBP with polyethylene glycol with no MBP was performed. Patients, 0 to 21 years old, undergoing elective colorectal surgery were eligible and randomized within 4 age strata. Statistical analyses were performed using chi or Fisher exact test for categorical data and t test or Wilcoxon 2-sample test for continuous data. RESULTS: Forty-four patients were enrolled in the study from December 2010 to February 2013, of which 24 (55%) received MBP and 20 (45%) did not. Two patients (5%) had anastomotic leak, 4 (9%) had intraabdominal infection, and 7 (16%) had wound infections. The rate of anastomotic leak, intraabdominal abscess, and wound infection did not differ between the 2 groups. CONCLUSIONS: MBP for elective colorectal surgery in children does not affect the incidence of infectious complications. A larger multiinstitutional study is necessary to validate the results of this single-institution pilot study. PMID- 25825855 TI - Clinical tube weaning supported by hunger provocation in fully-tube-fed children. AB - BACKGROUND: Children with congenital malformations, mental retardation, and complex early medical history frequently have feeding problems. Although tube feeding is effective in providing the necessary energy and nutrients, it decreases the child's motivation to eat and may lead to oral aversion. In this study, we sought to confirm our previous results, showing that a multidisciplinary clinical hunger provocation program may lead to quick resumption of oral feeding. METHODS: In a crossover study, 22 children of 9 to 24 months of age who were fully dependent on tube feeding were randomly assigned to one of two groups: group A, intervention group (2-week multidisciplinary clinical hunger provocation program); and group B, control group (4-week outpatient treatment by the same multidisciplinary team). Patients failing one treatment were reassigned to the other treatment group. Primary outcome measures were at least 75% orally fed at the conclusion of the intervention and fully orally fed and gaining weight 6 months after the intervention. RESULTS: In group A, 9/11 patients were successfully weaned from tube feeding (2 failures: 1 developed ulcerative colitis, 1 drop-out). In group B, only 1 patient was weaned successfully; 10/11 were reassigned to the clinical hunger provocation program, all being weaned successfully. Six months after the intervention, 1 patient had to resume tube feeding. In total, in the control group, 1/11 (9%) was weaned successfully as compared with 18/21 (86%) in the hunger provocation group (P < 0.001). CONCLUSIONS: Multidisciplinary clinical hunger provocation is an effective short-term intervention for weaning young children from tube feeding. PMID- 25825856 TI - The benefits of weight loss, even if regained, in reducing cardiovascular disease: welcoming evidence! PMID- 25825857 TI - Non-alcoholic fatty liver disease in obese adults: clinical aspects and current management strategies. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder whose prevalence is strongly linked to the current epidemic of obesity in many western countries. The prevalence of NAFLD is two to four times higher in populations with pre-existing metabolic comorbidities than in the general population. The diagnosis of primary NAFLD involves establishing the presence of hepatic steatosis or steatohepatitis by imaging or histology, along with establishing the non-alcoholic nature of the disease process and excluding competing aetiologies for hepatic steatosis. Among the indirect serum biomarkers, the NAFLD fibrosis score can help to identify patients with NAFLD and with higher likelihood of having fibrosis or cirrhosis. A liver biopsy should be considered in NAFLD patients at increased risk for steatohepatitis/advanced fibrosis and in cases where a liver biopsy is necessary to exclude co-existing chronic liver diseases and other aetiologies for hepatic steatosis. The treatment and management recommendations for obesity-associated NAFLD are aimed towards weight reduction. The currently available interventions employed to promote weight loss and improve the metabolic responses in NAFLD include lifestyle modification, pharmacotherapy and bariatric surgery. PMID- 25825858 TI - Evaluation of a multidisciplinary Tier 3 weight management service for adults with morbid obesity, or obesity and comorbidities, based in primary care. AB - A multidisciplinary Tier 3 weight management service in primary care recruited patients with a body mass index >=40 kg.m(-2) , or 30 kg.m(-2) with obesity related co-morbidity to a 1-year programme. A cohort of 230 participants was recruited and evaluated using the National Obesity Observatory Standard Evaluation Framework. The primary outcome was weight loss of at least 5% of baseline weight at 12 months. Diet was assessed using the two-item food frequency questionnaire, activity using the General Practice Physical Activity questionnaire and quality of life using the EuroQol-5D-5L questionnaire. A focus group explored the participants' experiences. Baseline mean weight was 124.4 kg and mean body mass index was 44.1 kg.m(-2) . A total of 102 participants achieved 5% weight loss at 12 months. The mean weight loss was 10.2 kg among the 117 participants who completed the 12-month programme. Baseline observation carried forward analysis gave a mean weight loss of 5.9 kg at 12 months. Fruit and vegetable intake, activity level and quality of life all improved. The dropout rate was 14.3% at 6 months and 45.1% at 1 year. Focus group participants described high levels of satisfaction. It was possible to deliver a Tier 3 weight management service for obese patients with complex co-morbidity in a primary care setting with a full multidisciplinary team, which obtained good health outcomes compared with existing services. PMID- 25825859 TI - Physical activity and sitting time in bariatric surgery patients 1-16 years post surgery. AB - Physical activity (PA) is an important adjunct to bariatric surgery in the treatment of severe obesity; however, patient PA levels prior to and in the short term following surgery are usually low. Scarce data exist describing PA and sedentary behaviours in the long term following surgery. The objectives were to describe PA and sitting time in bariatric patients 1-16 years post-surgery and assess their associations with patient, surgery and weight-loss characteristics. A total of 398 bariatric patients (73% female; mean age 47 +/- 11 years, mean 6 +/- 4 years since surgery) completed a telephone questionnaire. Patients reported moderate-to-vigorous PA (MVPA: # sessions week(-1) >=30 min), sitting time (h d( 1)) and change in PA and sitting time vs. pre-surgery (more/same/less). Associations with patient, surgery and weight-loss characteristics were assessed. Only 53% of patients reported >=1 session week(-1) MVPA, mean sitting time was 7 +/- 4 h d(-1), 74% of patients reported more PA and 53% reported less sitting, now vs. pre-surgery. Age, sex, smoking status, pre-surgery body mass index, time since-surgery and percent excess weight lost were significantly associated with PA and/or sitting outcomes. Patients currently experiencing >=50% excess weight loss had over three times the odds of reporting >=1 session week(-1) MVPA (odds ratio [95% confidence interval] 3.28 [1.57, 6.89]) and almost four times greater odds of reporting 'more' PA vs. pre-surgery (3.78 [2.15, 6.62]) compared with their less successful counterparts. Results point to low PA and high sedentariness among bariatric patients in the long-term following surgery, associated with several characteristics. Associations with long-term weight management highlight the need for tailored interventions to promote active living in this patient population. PMID- 25825860 TI - A qualitative investigation of obese women's experiences of effective and ineffective social support for weight management. AB - An obese individual's social context influences the extent to which they engage in weight control behaviors. Although the available literature acknowledges the importance of social support for weight management, detailed analyses of obese individuals' experiences of social support for weight loss and/or weight loss maintenance have not been undertaken. Using a qualitative approach, this study presents 22 Australian obese women's perspectives of the availability and effectiveness of social support for weight control. Three superordinate categories, namely, ineffective support, effective support and personal barriers to accessing support, and 12 subcategories were identified. Participants reported minimal access to quality support for weight management, while also suggesting ways in which obese women themselves may hamper significant others' provision of effective support. The results support the investigation of interventions designed to enhance the skills of significant others in assisting obese individuals with weight management. PMID- 25825861 TI - Ligand free copper(I)-catalyzed synthesis of diaryl ether with Cs2CO3 via a free radical path. AB - Complexes [Cu(I)(2,4-dimethylphenoxy)2](-) (A) and [Cu(II)(2,4 dimethylphenoxy)2(p-tolyl)](-) (B) were observed by in situ electrospray ionization mass spectrometry (ESI-MS) analysis of the ligand free copper(I) catalyzed C-O coupling reaction using Cs2CO3 under the catalytic reaction conditions indicating that they could be intermediates in the reaction. The radical scavenger cumene retarded the reaction. Catalytic cycles involving a free radical path are proposed based on these observations. PMID- 25825862 TI - Structural characterization and immunomodulatory activity of a new heteropolysaccharide from Prunella vulgaris. AB - A new heteropolysaccharide, here called P1, was isolated from the fruit clusters of Prunella vulgaris using a hot water extraction method. Chemical and physical analyses indicated that P1 had a spherical conformation with an average molecular weight of 1750 kDa and consisted of arabinose (28.37%), xylose (54.67%), mannose (5.61%), glucose (5.46%), and galactose (5.89%). The main types of P1 linkages were proved to be (1->5)-linked alpha-L-Ara, (1->)-linked alpha-L-Ara, (1->3) linked alpha-D-xyl, (1->3)-linked beta-D-Gal, (1->3,6)-linked beta-D-Gal, (1 >3,6)-linked alpha-D-Man and (1->6)-linked alpha-D-Glc according to the periodate oxidation-Smith degradation and NMR analyses. P1 could significantly enhance the secretion of NO, TNF-alpha, and IL-6 in murine RAW 264.7 cells, involving the toll-like receptor 2 (TLR2), TLR4 and complement receptor 3 (CR3). Further studies showed that P1 exhibited stable immune activities in the pH range of 4.0 10.0 and below 121 degrees C. The results suggested that P1 could be used as a potent immunomodulatory agent in functional foods and pharmacological fields. PMID- 25825863 TI - Interventions for the cessation of non-nutritive sucking habits in children. AB - BACKGROUND: Comforting behaviours, such as the use of pacifiers (dummies, soothers), blankets and finger or thumb sucking, are common in babies and young children. These comforting habits, which can be referred to collectively as 'non nutritive sucking habits' (NNSHs), tend to stop as children get older, under their own impetus or with support from parents and carers. However, if the habit continues whilst the permanent dentition is becoming established, it can contribute to, or cause, development of a malocclusion (abnormal bite). A diverse variety of approaches has been used to help children with stopping a NNSH. These include advice, removal of the comforting object, fitting an orthodontic appliance to interfere with the habit, application of an aversive taste to the digit or behaviour modification techniques. Some of these interventions are easier to apply than others and less disturbing for the child and their parent; some are more applicable to a particular type of habit. OBJECTIVES: The primary objective of the review was to evaluate the effects of different interventions for cessation of NNSHs in children. The secondary objectives were to determine which interventions work most quickly and are the most effective in terms of child and parent- or carer-centred outcomes of least discomfort and psychological distress from the intervention, as well as the dental measures of malocclusion (reduction in anterior open bite, overjet and correction of posterior crossbite) and cost-effectiveness. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 8 October 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 9), MEDLINE via OVID (1946 to 8 October 2014), EMBASE via OVID (1980 to 8 October 2014), PsycINFO via OVID (1980 to 8 October 2014) and CINAHL via EBSCO (1937 to 8 October 2014), the US National Institutes of Health Trials Register (Clinical Trials.gov) (to 8 October 2014) and the WHO International Clinical Trials Registry Platform (to 8 October 2014). There were no restrictions regarding language or date of publication in the searches of the electronic databases. We screened reference lists from relevant articles and contacted authors of eligible studies for further information where necessary. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials in children with a non-nutritive sucking habit that compared one intervention with another intervention or a no-intervention control group. The primary outcome of interest was cessation of the habit. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Three review authors were involved in screening the records identified; two undertook data extraction, two assessed risk of bias and two assessed overall quality of the evidence base. Most of the data could not be combined and only one meta-analysis could be carried out. MAIN RESULTS: We included six trials, which recruited 252 children (aged two and a half to 18 years), but presented follow-up data on only 246 children. Digit sucking was the only NNSH assessed in the studies. Five studies compared single or multiple interventions with a no-intervention or waiting list control group and one study made a head-to-head comparison. All the studies were at high risk of bias due to major limitations in methodology and reporting. There were small numbers of participants in the studies (20 to 38 participants per study) and follow-up times ranged from one to 36 months. Short term outcomes were observed under one year post intervention and long-term outcomes were observed at one year or more post intervention. Orthodontics appliance (with or without psychological intervention) versus no treatmentTwo trials that assessed this comparison evaluated our primary outcome of cessation of habit. One of the trials evaluated palatal crib and one used a mix of palatal cribs and arches. Both trials were at high risk of bias. The orthodontic appliance was more likely to stop digit sucking than no treatment, whether it was used over the short term (risk ratio (RR) 6.53, 95% confidence interval (CI) 1.67 to 25.53; two trials, 70 participants) or long term (RR 5.81, 95% CI 1.49 to 22.66; one trial, 37 participants) or used in combination with a psychological intervention (RR 6.36, 95% CI 0.97 to 41.96; one trial, 32 participants). Psychological intervention versus no treatmentTwo trials (78 participants) at high risk of bias evaluated positive reinforcement (alone or in combination with gaining the child's co-operation) or negative reinforcement compared with no treatment. Pooling of data showed a statistically significant difference in favour of the psychological interventions in the short term (RR 6.16, 95% CI 1.18 to 32.10; I(2) = 0%). One study, with data from 57 participants, reported on the long-term effect of positive and negative reinforcement on sucking cessation and found a statistically significant difference in favour of the psychological interventions (RR 6.25, 95% CI 1.65 to 23.65). Head-to-head comparisonsOnly one trial demonstrated a clear difference in effectiveness between different active interventions. This trial, which had only 22 participants, found a higher likelihood of cessation of habit with palatal crib than palatal arch (RR 0.13, 95% CI 0.03 to 0.59). AUTHORS' CONCLUSIONS: This review found low quality evidence that orthodontic appliances (palatal arch and palatal crib) and psychological interventions (including positive and negative reinforcement) are effective at improving sucking cessation in children. There is very low quality evidence that palatal crib is more effective than palatal arch. This review has highlighted the need for high quality trials evaluating interventions to stop non nutritive sucking habits to be conducted and the need for a consolidated, standardised approach to reporting outcomes in these trials. PMID- 25825864 TI - Novel Pathway for Hypoxia-Induced Proliferation and Migration in Human Mesenchymal Stem Cells: Involvement of HIF-1alpha, FASN, and mTORC1. AB - The control of stem cells by oxygen signaling is an important way to improve various stem cell physiological functions and metabolic nutrient alteration. Lipid metabolism alteration via hypoxia is thought to be a key factor in controlling stem cell fate and function. However, the interaction between hypoxia and the metabolic and functional changes to stem cells is incompletely described. This study aimed to identify hypoxia-inducible lipid metabolic enzymes that can regulate umbilical cord blood (UCB)-derived human mesenchymal stem cell (hMSC) proliferation and migration and to demonstrate the signaling pathway that controls functional change in UCB-hMSCs. Our results indicate that hypoxia treatment stimulates UCB-hMSC proliferation, and expression of two lipogenic enzymes: fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD1). FASN but not SCD1 is a key enzyme for regulation of UCB-hMSC proliferation and migration. Hypoxia-induced FASN expression was controlled by the hypoxia inducible factor-1 alpha (HIF-1alpha)/SCAP/SREBP1 pathway. Mammalian target of rapamycin (mTOR) was phosphorylated by hypoxia, whereas inhibition of FASN by cerulenin suppressed hypoxia-induced mTOR phosphorylation as well as UCB-hMSC proliferation and migration. RAPTOR small interfering RNA transfection significantly inhibited hypoxia-induced proliferation and migration. Hypoxia induced mTOR also regulated CDK2, CDK4, cyclin D1, cyclin E, and F-actin expression as well as that of c-myc, p-cofilin, profilin, and Rho GTPase. Taken together, the results suggest that mTORC1 mainly regulates UCB-hMSC proliferation and migration under hypoxia conditions via control of cell cycle and F-actin organization modulating factors. In conclusion, the HIF-1alpha/FASN/mTORC1 axis is a key pathway linking hypoxia-induced lipid metabolism with proliferation and migration in UCB-hMSCs. Stem Cells 2015;33:2182-2195. PMID- 25825865 TI - Infrequent air contamination with Acinetobacter baumannii of air surrounding known colonized or infected patients. AB - Using a validated air sampling method we found Acinetobacter baumannii in the air surrounding only 1 of 12 patients known to be colonized or infected with A. baumannii. Patients' closed-circuit ventilator status, frequent air exchanges in patient rooms, and short sampling time may have contributed to this low burden. PMID- 25825866 TI - Fast hybrid multi-dimensional NMR methods based on ultrafast 2D NMR. AB - Conventional multi-dimensional (nD) NMR experiments are characterized by inherent long acquisition durations, while ultrafast (UF) NMR makes it possible to reduce to a few hundreds of milliseconds the overall acquisition duration of a complete nD NMR dataset. Although extremely promising for a number of specific applications, the UF strategy suffers from significant limitations compared with its conventional counterpart. The main limitations concern the sensitivity, the resolution, and the accessible spectral width. However, when the targeted applications are compatible with an acquisition duration between a few seconds and a few minutes, hybrid UF techniques can be used to improve the performance of UF nD NMR while remaining faster than conventional acquisitions. Much better results in terms of signal-to-noise ratio can be achieved with the multi-scan single-shot approach or with interleaved acquisitions. Even more, for the same experimental duration, and in the case of homonuclear 2D NMR, the multi-scan single-shot approach has a much higher precision than conventional 2D NMR. Interleaved 2D NMR overcomes the drawbacks of single-scan UF NMR in terms of spectral width and provides spectra for which the quality is not significantly different from that obtained with conventional 2D NMR. Finally, high spectral qualities have been demonstrated from hybrid conventional/UF 3D approaches capable of recording a whole 3D spectrum in the time needed to record a conventional 2D spectrum. This mini-review aims at describing the principles, the recent advances and the latest applications of these hybrid techniques. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25825867 TI - High-risk liver transplant candidates: An ethical proposal on where to draw the line. PMID- 25825868 TI - Generic Raman-based calibration models enabling real-time monitoring of cell culture bioreactors. AB - Raman-based multivariate calibration models have been developed for real-time in situ monitoring of multiple process parameters within cell culture bioreactors. Developed models are generic, in the sense that they are applicable to various products, media, and cell lines based on Chinese Hamster Ovarian (CHO) host cells, and are scalable to large pilot and manufacturing scales. Several batches using different CHO-based cell lines and corresponding proprietary media and process conditions have been used to generate calibration datasets, and models have been validated using independent datasets from separate batch runs. All models have been validated to be generic and capable of predicting process parameters with acceptable accuracy. The developed models allow monitoring multiple key bioprocess metabolic variables, and hence can be utilized as an important enabling tool for Quality by Design approaches which are strongly supported by the U.S. Food and Drug Administration. PMID- 25825869 TI - The tumour suppressor CHD5 forms a NuRD-type chromatin remodelling complex. AB - Eukaryotic gene expression is developmentally regulated, in part by chromatin remodelling, and its dysregulation has been linked to cancer. CHD5 (chromodomain helicase DNA-binding protein 5) is a tumour suppressor gene (TSG) that maps to a region of consistent deletion on 1p36.31 in neuroblastomas (NBs) and other tumour types. CHD5 encodes a protein with chromatin remodelling, helicase and DNA binding motifs that is preferentially expressed in neural and testicular tissues. CHD5 is highly homologous to CHD3 and CHD4, which are the core subunits of nucleosome remodelling and deacetylation (NuRD) complexes. To determine if CHD5 forms a similar complex, we performed studies on nuclear extracts from NBLS, SY5Y (both with endogenous CHD5 expression), NLF (CHD5 null) and NLF cells stably transfected with CHD5 cDNA (wild-type and V5-histidine-tagged). Immunoprecipitation (IP) was performed with either CHD5 antibody or antibody to V5/histidine-tagged protein. We identified NuRD components both by GST-FOG1 (Friend Of GATA1) pull-down and by IP. We also performed MS/MS analysis to confirm the presence of CHD5 or other protein components of the NuRD complex, as well as to identify other novel proteins. CHD5 was clearly associated with all canonical NuRD components, including metastasis-associated protein (MTA)1/2, GATA zinc finger domain containing 2A (GATAD2A), histone deacetylase (HDAC)1/2, retinoblastoma-binding protein (RBBP)4/7 and methyl DNA-binding domain protein (MBD)2/3, as determined by Western blotting and MS/MS. Our data suggest CHD5 forms a NuRD complex similar to CHD4. However, CHD5-NuRD may also have unique protein associations that confer functional specificity and may contribute to normal development and to tumour suppression in NB and other cancers. PMID- 25825870 TI - Inflammatory cytokine kinetics to single bouts of acute moderate and intense aerobic exercise in women with active and inactive systemic lupus erythematosus. AB - The aim of this study was to evaluate changes in the cytokines INF-gamma, IL-10, IL-6, TNF-alpha and soluble TNF receptors (sTNFR1 and sTNFR2) in response to single bouts of acute moderate and intense exercise in systemic lupus erythematosus women with active (SLE(ACTIVE)) and inactive (SLE(INACTIVE)) disease. Twelve SLE(INACTIVE) women (age: 35.3 +/- 5.7 yrs; BMI: 25.6+/-3.4 kg/m2), eleven SLE(ACTIVE) women (age: 30.4 +/- 4.5 yrs; BMI: 26.1+/-4.8 kg/m2), and 10 age- and BMI-matched healthy control women (HC) performed 30 minutes of acute moderate (~50% of VO(2)peak) and intense (~70% of VO(2)peak) exercise bout. Cytokines and soluble TNF receptors were assessed at baseline, immediately after, every 30 minutes up to three hours, and 24 hours after both acute exercise bouts. In response to acute moderate exercise, cytokines and soluble TNF receptors levels remained unchanged in all groups (P>0.05), except for a reduction in IL-6 levels in the SLE(ACTIVE) group at the 60th and 180th minutes of recovery (P<0.05), and a reduction in sTNFR1 levels in the HC group at the 90th, 120th, 150th, 180th minutes of recovery (P<0.05). The SLE(INACTIVE) group showed higher levels of TNF-alpha, sTNFR1, and sTNFR2 at all time points when compared with the HC group (P<0.05). Also, the SLE(ACTIVE) group showed higher levels of IL-6 at the 60th minute of recovery (P<0.05) when compared with the HC group. After intense exercise, sTNFR1 levels were reduced at the 150th (P=0.041) and 180th (P=0.034) minutes of recovery in the SLE(INACTIVE) group, whereas the other cytokines and sTNFR2 levels remained unchanged (P>0.05). In the HC group, IL-10, TNF-alpha, sTNFR1, and sTNFR2 levels did not change, whilst INF-gamma levels decreased (P=0.05) and IL-6 levels increased immediately after the exercise (P=0.028), returning to baseline levels 24 hours later (P > 0.05). When compared with the HC group, the SLE(INACTIVE) group showed higher levels of TNF-alpha and sTNFR2 in all time points, and higher levels of sTNFR1 at the end of exercise and at the 30th minute of recovery (P<0.05). The SLE(ACTIVE) group also showed higher levels of TNF-alpha at all time points when compared with the HC group (P<0.05), (except after 90 min, 120 min and 24 hours of recovery) (P>0.05). Importantly, the levels of all cytokine and soluble TNF receptors returned to baseline 24 hours after the end of acute exercise, irrespective of its intensity, in all three groups (P>0.05). This study demonstrated that both the single bouts of acute moderate and intense exercise induced mild and transient changes in cytokine levels in both SLE(INACTIVE) and SLE(ACTIVE) women, providing novel evidence that acute aerobic exercise does not trigger inflammation in patients with this disease. PMID- 25825871 TI - Genetic interaction mapping reveals a role for the SWI/SNF nucleosome remodeler in spliceosome activation in fission yeast. AB - Although numerous regulatory connections between pre-mRNA splicing and chromatin have been demonstrated, the precise mechanisms by which chromatin factors influence spliceosome assembly and/or catalysis remain unclear. To probe the genetic network of pre-mRNA splicing in the fission yeast Schizosaccharomyces pombe, we constructed an epistatic mini-array profile (E-MAP) and discovered many new connections between chromatin and splicing. Notably, the nucleosome remodeler SWI/SNF had strong genetic interactions with components of the U2 snRNP SF3 complex. Overexpression of SF3 components in DeltaSWI/SNF cells led to inefficient splicing of many fission yeast introns, predominantly those with non consensus splice sites. Deletion of SWI/SNF decreased recruitment of the splicing ATPase Prp2, suggesting that SWI/SNF promotes co-transcriptional spliceosome assembly prior to first step catalysis. Importantly, defects in SWI/SNF as well as SF3 overexpression each altered nucleosome occupancy along intron-containing genes, illustrating that the chromatin landscape both affects--and is affected by -co-transcriptional splicing. PMID- 25825872 TI - Preferred SH3 domain partners of ADAM metalloproteases include shared and ADAM specific SH3 interactions. AB - A disintegrin and metalloproteinases (ADAMs) constitute a protein family essential for extracellular signaling and regulation of cell adhesion. Catalytic activity of ADAMs and their predicted potential for Src-homology 3 (SH3) domain binding show a strong correlation. Here we present a comprehensive characterization of SH3 binding capacity and preferences of the catalytically active ADAMs 8, 9, 10, 12, 15, 17, and 19. Our results revealed several novel interactions, and also confirmed many previously reported ones. Many of the identified SH3 interaction partners were shared by several ADAMs, whereas some were ADAM-specific. Most of the ADAM-interacting SH3 proteins were adapter proteins or kinases, typically associated with sorting and endocytosis. Novel SH3 interactions revealed in this study include TOCA1 and CIP4 as preferred partners of ADAM8, and RIMBP1 as a partner of ADAM19. Our results suggest that common as well as distinct mechanisms are involved in regulation and execution of ADAM signaling, and provide a useful framework for addressing the pathways that connect ADAMs to normal and aberrant cell behavior. PMID- 25825873 TI - Robotic versus open radical cystectomy: an updated systematic review and meta analysis. AB - OBJECTIVE: To critically review the currently available evidence of studies comparing robot-assisted radical cystectomy (RARC) with open radical cystectomy (ORC). METHODS: A comprehensive review of the literature from Pubmed, Web of Science and Scopus was performed in April 2014. All relevant studies comparing RARC with ORC were included for further screening. A pooled meta-analysis of all comparative studies was performed and publication bias was assessed by a funnel plot. RESULTS: Nineteen studies were included for the analysis, including a total of 1779 patients (787 patients in the RARC group and 992 patients in the ORC group). Although RARC was associated with longer operative time (p <0.0001), patients in this group might benefit from significantly lower overall perioperative complication rates within 30 days and 90 days (p = 0.005 and 0.0002, respectively), more lymph node yields (p = 0.009), less estimated blood loss (p <0.00001), lower need for perioperative and intraoperative transfusions (p <0.0001 and <0.0001, respectively), and shorter postoperative length of stay (p = 0.0002). There was no difference between two groups regarding positive surgical margin rates (p = 0.19). CONCLUSIONS: RARC appears to be an efficient alternative to ORC with advantages of less perioperative complications, more lymph node yields, less estimated blood loss, lower need for transfusions, and shorter postoperative length of stay. Further studies should be performed to compare the long-term oncologic outcomes between RARC and ORC. PMID- 25825874 TI - Cytoreductive surgery of colorectal peritoneal metastases: outcomes after complete cytoreductive surgery and systemic chemotherapy only. AB - BACKGROUND: Cytoreductive peritoneal surgery (CRS) associated with hyperthermic peritoneal chemotherapy (HIPEC) has long been considered the standard treatment for colorectal peritoneal metastases (CPM). However, although efficacy of surgery has been demonstrated, evidence supporting HIPEC's role is less certain. METHOD: Overall survival (OS), progression-free survival (PFS) and morbidity were analysed retrospectively for fifty consecutively included patients treated for colorectal CPM with complete CRS and systemic chemotherapy only. RESULTS: Median peritoneal cancer index (PCI) was 8 (range 1-24). 23 patients had liver or lung metastases (LLM). 22 patients had synchronous CPM. 27 complications occurred (12 Grade 1/2, 14 Grade 3, 1 Grade 4a, 0 Grade 5). Median follow-up was 62.5 months (95 %CI 45.4-81.3), median survival 32.4 months (21.5-41.7). Three- and 5-year OS were 45.5% (0.31-0.59) and 29.64% (0.17-0.44) respectively. Presence of LLMs associated with peritoneal carcinomatosis was significantly associated with poorer prognosis, with survival at 5 years of 13.95% (95 %CI 2.9-33.6) vs. 43.87% (22.2-63.7) when no metastases were present (P= 0.018). Median PFS was 9.5 months (95 %CI 6.2-11.1). CONCLUSION: With an equivalent PCI range and despite one of the highest rates of LLM in the literature, our survival data of CRS + systemic chemotherapy only compare well with results reported after additional HIPEC. Tolerance was better with acceptable morbidity without any mortality. Extra hepatic metastasis (LLM) is a strong factor of poor prognosis. Awaiting the results of the randomized PRODIGE trial, these results indicate that CRS + systemic chemotherapy only is a robust hypothesis to treat colorectal CPM. PMID- 25825875 TI - Correction: A meta-analysis of P2X7 gene-762T/C polymorphism and pulmonary tuberculosis susceptibility. PMID- 25825876 TI - Genomic prediction of biological shape: elliptic Fourier analysis and kernel partial least squares (PLS) regression applied to grain shape prediction in rice (Oryza sativa L.). AB - Shape is an important morphological characteristic both in animals and plants. In the present study, we examined a method for predicting biological contour shapes based on genome-wide marker polymorphisms. The method is expected to contribute to the acceleration of genetic improvement of biological shape via genomic selection. Grain shape variation observed in rice (Oryza sativa L.) germplasms was delineated using elliptic Fourier descriptors (EFDs), and was predicted based on genome-wide single nucleotide polymorphism (SNP) genotypes. We applied four methods including kernel PLS (KPLS) regression for building a prediction model of grain shape, and compared the accuracy of the methods via cross-validation. We analyzed multiple datasets that differed in marker density and sample size. Datasets with larger sample size and higher marker density showed higher accuracy. Among the four methods, KPLS showed the highest accuracy. Although KPLS and ridge regression (RR) had equivalent accuracy in a single dataset, the result suggested the potential of KPLS for the prediction of high-dimensional EFDs. Ordinary PLS, however, was less accurate than RR in all datasets, suggesting that the use of a non-linear kernel was necessary for accurate prediction using the PLS method. Rice grain shape can be predicted accurately based on genome-wide SNP genotypes. The proposed method is expected to be useful for genomic selection in biological shape. PMID- 25825878 TI - [Hospitalization for cardiac arrest outside hospitals]. PMID- 25825879 TI - [The follow up of patients and their relatives after cardiac arrest varies greatly]. AB - The return to a good life after successfully resuscitated cardiac arrest may be hindered by cardiovascular morbidity, psychological distress and the consequences of anoxic brain injury. To support the return to everyday life, patients and their relatives are in need of health care follow-up with multiple focuses. Usually, this follow-up consists of at least one of three parallel tracks; cardiology for interventions and secondary prevention, post intensive care follow up to capture and prevent consequences of the traumatic event and the ICU stay, or neurological follow-up for patients with neurological sequels. None of these tracks include all patients. In addition, survivors are usually included and followed with patient related outcome measures (PROM) through the multiple Swedish national quality registers. The different clinical follow-up systems and the registers are not coordinated and assessments and questions may be repeated multiple times. A more integrated follow-up model has the potential to benefit the patient and their relatives and to reduce costs. PMID- 25825877 TI - More than half of high school students report disordered eating: a cross sectional study among Norwegian boys and girls. AB - Disordered eating and eating disorders are of great concern due to their associations with physical and mental health risks. Even if adolescence has been identified as the most vulnerable time for developing disordered eating, few studies have used a broad spectrum of criteria to investigate the prevalence of disordered eating among high school students of both genders, in different programs of study, nor assessed correlates of disordered eating among this important target group. The purposes of this study were therefore to investigate the prevalence and correlates of disordered eating among both male and female high school students in sport-, general and vocational programs. A comprehensive questionnaire was completed by 2,451 students (98.7%), aged 15-17 years. The total prevalence of disordered eating was 54.9%, with 64.3% among girls and 45.0% among boys (p<0.001). The highest prevalence of disordered eating was found among vocational students (60.7%), followed by students in general programs (49.8%) and sport students (38.3%) (p<0.001). Female gender, school program (vocational and general), overweight/obesity and weight regulation were positively associated with disordered eating. The high prevalence indicates the importance of tailored prevention efforts directed at high school students, particularly in vocational programs. Furthermore, a smaller girls-boys ratio than expected indicates that the efforts to identify and manage disordered eating among high school students should include both genders. PMID- 25825880 TI - [Question mark of ventilations and chest compressions]. PMID- 25825881 TI - [Distinguishing cardiac arrest among young athletes]. PMID- 25825882 TI - [More and more defibrillators in the community--but few used]. PMID- 25825884 TI - [Not Available]. PMID- 25825883 TI - [Several factors affect the prognosis]. PMID- 25825885 TI - [Few drugs dominate among clinically important interactions. Swedish register study lists problem drugs]. AB - In a recent Swedish register study, a limited number of specific drugs explained a large part of clinically relevant, potential drug-drug interactions (DDI), as defined and detected by the DDI database SFINX. Regarding interactions that should be avoided according to the definition in the database (class D), 15 drug combinations accounted for as much as 80 % of the prevalence in the Swedish population. Ten specific drugs were involved in 94 % of all detected class D interactions. About half of the clinically relevant interactions detected during the four-month study period were associated with an increased risk of adverse drug reactions, whereas the other half has a potential to cause therapeutic failure. An increased awareness among prescribers of these interacting drugs could contribute to safer and more effective drug use. PMID- 25825886 TI - [The physician must be kept outside the influence of the reimbursement systems]. PMID- 25825887 TI - [Wrong thinking in theory resulted in potent drug in practice]. PMID- 25825888 TI - [In the absence of description of aims in the new internship education: When does the common knowledge base become common?]. PMID- 25825889 TI - [The "harmful" maternity round--mysterious phenomenon with many question marks]. PMID- 25825890 TI - [Ligament injuries in the wrist--do not overtreat]. PMID- 25825891 TI - [Health care as an industrial organization]. PMID- 25825892 TI - [Incident reports--fragile basis for improvement work]. PMID- 25825893 TI - [The Swedish Medical Association must influence the reimbursement systems]. PMID- 25825894 TI - [Not Available]. PMID- 25825895 TI - [The Swedish Medical Association must stand up for medical ethics and the physician's role]. PMID- 25825896 TI - [Expected absence of coffee breaks. The robot does the job without complaining]. PMID- 25825897 TI - [Not Available]. PMID- 25825898 TI - [Our message has been misunderstood]. PMID- 25825899 TI - [Early diagnosis is desirable]. PMID- 25825900 TI - ["The survival chain" must be strong]. PMID- 25825901 TI - [Uncertain if drugs do any good after cardiac arrest]. PMID- 25825902 TI - Correction: cyclic GMP-AMP displays mucosal adjuvant activity in mice. AB - [This corrects the article DOI: 10.1371/journal.pone.0110150.]. PMID- 25825903 TI - An efficient algorithm to perform local concerted movements of a chain molecule. AB - The devising of efficient concerted rotation moves that modify only selected local portions of chain molecules is a long studied problem. Possible applications range from speeding the uncorrelated sampling of polymeric dense systems to loop reconstruction and structure refinement in protein modeling. Here, we propose and validate, on a few pedagogical examples, a novel numerical strategy that generalizes the notion of concerted rotation. The usage of the Denavit-Hartenberg parameters for chain description allows all possible choices for the subset of degrees of freedom to be modified in the move. They can be arbitrarily distributed along the chain and can be distanced between consecutive monomers as well. The efficiency of the methodology capitalizes on the inherent geometrical structure of the manifold defined by all chain configurations compatible with the fixed degrees of freedom. The chain portion to be moved is first opened along a direction chosen in the tangent space to the manifold, and then closed in the orthogonal space. As a consequence, in Monte Carlo simulations detailed balance is easily enforced without the need of using Jacobian reweighting. Moreover, the relative fluctuations of the degrees of freedom involved in the move can be easily tuned. We show different applications: the manifold of possible configurations is explored in a very efficient way for a protein fragment and for a cyclic molecule; the "local backbone volume", related to the volume spanned by the manifold, reproduces the mobility profile of all alpha helical proteins; the refinement of small protein fragments with different secondary structures is addressed. The presented results suggest our methodology as a valuable exploration and sampling tool in the context of bio-molecular simulations. PMID- 25825904 TI - [Academic elitism or the obsession with the impact factor]. PMID- 25825905 TI - Effects of functionalized and raw multi-walled carbon nanotubes on soil bacterial community composition. AB - Carbon nanotubes (CNTs) are widely used in industry, but their environmental impacts on soil microbial communities are poorly known. In this paper, we compare the effect of both raw and acid treated or functionalized (fCNTs) multi-walled carbon nanotubes (MWCNTs) on soil bacterial communities, applying different concentrations of MWCNTs (0 ug/g, 50 ug/g, 500 ug/g and 5000 ug/g) to a soil microcosm system. Soil DNA was extracted at 0, 2 and 8 weeks and the V3 region of the 16S rRNA gene was PCR-amplified and sequenced using paired-end Illumina bar coded sequencing. The results show that bacterial diversity was not affected by either type of MWCNT. However, overall soil bacterial community composition, as illustrated by NMDS, was affected only by fMWCNT at high concentrations. This effect, detectable at 2 weeks, remained equally strong by 8 weeks. In the case of fMWCNTs, overall changes in relative abundance of the dominant phyla were also found. The stronger effect of fMWCNTs could be explained by their intrinsically acidic nature, as the soil pH was lower at higher concentrations of fMWCNTs. Overall, this study suggests that fMWCNTs may at least temporarily alter microbial community composition on the timescale of at least weeks to months. It appears, by contrast, that raw MWCNTs do not affect soil microbial community composition. PMID- 25825906 TI - Reference gene validation for RT-qPCR, a note on different available software packages. AB - BACKGROUND: An appropriate normalization strategy is crucial for data analysis from real time reverse transcription polymerase chain reactions (RT-qPCR). It is widely supported to identify and validate stable reference genes, since no single biological gene is stably expressed between cell types or within cells under different conditions. Different algorithms exist to validate optimal reference genes for normalization. Applying human cells, we here compare the three main methods to the online available RefFinder tool that integrates these algorithms along with R-based software packages which include the NormFinder and GeNorm algorithms. RESULTS: 14 candidate reference genes were assessed by RT-qPCR in two sample sets, i.e. a set of samples of human testicular tissue containing carcinoma in situ (CIS), and a set of samples from the human adult Sertoli cell line (FS1) either cultured alone or in co-culture with the seminoma like cell line (TCam-2) or with equine bone marrow derived mesenchymal stem cells (eBM MSC). Expression stabilities of the reference genes were evaluated using geNorm, NormFinder, and BestKeeper. Similar results were obtained by the three approaches for the most and least stably expressed genes. The R-based packages NormqPCR, SLqPCR and the NormFinder for R script gave identical gene rankings. Interestingly, different outputs were obtained between the original software packages and the RefFinder tool, which is based on raw Cq values for input. When the raw data were reanalysed assuming 100% efficiency for all genes, then the outputs of the original software packages were similar to the RefFinder software, indicating that RefFinder outputs may be biased because PCR efficiencies are not taken into account. CONCLUSIONS: This report shows that assay efficiency is an important parameter for reference gene validation. New software tools that incorporate these algorithms should be carefully validated prior to use. PMID- 25825907 TI - Molecular epidemiology of rabies viruses circulating in two rabies endemic provinces of Laos, 2011-2012: regional diversity in Southeast Asia. AB - BACKGROUND: Although rabies is endemic in Laos, genetic characterization of the viruses in this country is limited. There are growing concerns that development in the region may have increased transport of dog through Laos for regional dog meat consumption, and that this may cause spillover of the viruses from dogs brought here from other countries. This study was therefore undertaken to evaluate the current rabies situation and the genetic characteristics of rabies viruses currently circulating in Laos. METHODS: We determined the rate of rabies positive samples by analyzing data from animal samples submitted to the Lao Ministry of Agriculture and Forestry's National Animal Health Centre rabies laboratory from 2004 through 2011. Twenty-three rabies-positive samples were used for viral genetic characterization. Full genome sequencing was performed on two rabies viruses. RESULTS: Rabies-positive samples increased substantially from 40.5% in 2004 to 60.2% in 2009 and continued at this level during the study period. More than 99% of the samples were from dogs, followed by cats and monkeys. Phylogenetic analyses showed that three rabies virus lineages belonging to the Southeast Asian cluster are currently circulating in Laos; these are closely related to viruses from Thailand, Cambodia and Vietnam. Lineages of the circulating Laos rabies viruses diverged from common ancestors as recently as 44.2 years and as much as 55.3 years ago, indicating periodic virus invasions. CONCLUSION: There is an increasing trend of rabies in Laotian animals. Similar to other rabies-endemic countries, dogs are the main viral reservoir. Three viral lineages closely related to viruses from neighboring countries are currently circulating in Laos. Data provide evidence of periodic historic exchanges of the viruses with neighboring countries, but no recent invasion. PMID- 25825908 TI - The microbiota: an exercise immunology perspective. AB - The gut microbiota consists of a cluster of microorganisms that produces several signaling molecules of a hormonal nature which are released into the blood stream and act at distal sites. There is a growing body of evidence indicating that microbiota may be modulated by several environmental conditions, including different exercise stimulus, as well some pathologies. Enriched bacterial diversity has also been associated with improved health status and alterations in immune system, making multiple connections between host and microbiota. Experimental evidence has shown that reduced levels and variations in the bacterial community are associated with health impairments, while increased microbiota diversity improves metabolic profile and immunological responses. So far, very few controlled studies have focused on the interactions between acute or chronic exercise and the gut microbiota. However, some preliminary experimental data obtained from animal studies or probiotics studies show some interesting results at the immune level, indicating that the microbiota also acts like an endocrine organ and is sensitive to the homeostatic and physiological changes associated with exercise. Thus, our review intends to shed some light on the interaction between gut microbiota, exercise and immunomodulation. PMID- 25825909 TI - Breaking the hydrophobicity of the MscL pore: insights into a charge-induced gating mechanism. AB - The mechanosensitive channel of large conductance (MscL) is a protein that responds to membrane tension by opening a transient pore during osmotic downshock. Due to its large pore size and functional reconstitution into lipid membranes, MscL has been proposed as a promising artificial nanovalve suitable for biotechnological applications. For example, site-specific mutations and tailored chemical modifications have shown how MscL channel gating can be triggered in the absence of tension by introducing charged residues at the hydrophobic pore level. Recently, engineered MscL proteins responsive to stimuli like pH or light have been reported. Inspired by experiments, we present a thorough computational study aiming at describing, with atomistic detail, the artificial gating mechanism and the molecular transport properties of a light actuated bacterial MscL channel, in which a charge-induced gating mechanism has been enabled through the selective cleavage of photo-sensitive alkylating agents. Properties such as structural transitions, pore dimension, ion flux and selectivity have been carefully analyzed. Besides, the effects of charge on alternative sites of the channel with respect to those already reported have been addressed. Overall, our results provide useful molecular insights into the structural events accompanying the engineered MscL channel gating and the interplay of electrostatic effects, channel opening and permeation properties. In addition, we describe how the experimentally observed ionic current in a single subunit charged MscL mutant is obtained through a hydrophobicity breaking mechanism involving an asymmetric inter-subunit motion. PMID- 25825910 TI - Specific medicinal plant polysaccharides effectively enhance the potency of a DC based vaccine against mouse mammary tumor metastasis. AB - Dendritic cell (DC) vaccines are a newly emerging immunotherapeutic approach for the treatment and prevention of cancer, but major challenges still remain particularly with respect to clinical efficacy. Engineering and optimization of adjuvant formulations for DC-based vaccines is one strategy through which more efficacious treatments may be obtained. In this study, we developed a new ex vivo approach for DC vaccine preparation. We evaluated two highly purified mixed polysaccharide fractions from the root of Astragalus membranaceus and Codonopsis pilosulae, named Am and Cp, for their use in enhancing the efficiency of a DC based cancer vaccine against metastasis of 4T1 mammary carcinoma in mice. Mixed lymphocyte reaction showed all Am-, Cp- and [Am+Cp]-treated DCs enhanced mouse CD4+ and CD8+ T-cell proliferation. [Am+Cp]-treated DCs exhibited the strongest anti-4T1 metastasis activity in test mice. Treatments with Am, Cp and [Am+Cp] also resulted in augmented expression of CD40, CD80 and CD86 markers in test DCs. Bioinformatics analysis of the cytokine array data from treated DCs identified that [Am+Cp] is efficacious in activation of specific immune functions via mediating the expression of cytokines/chemokines involved in the recruitment and differentiation of defined immune cells. Biochemical analysis revealed that Am and Cp are composed mainly of polysaccharides containing a high level (70-95%) glucose residues, but few or no (< 1%) mannose residues. In summary, our findings suggest that the specific plant polysaccharides Am and Cp extracted from traditional Chinese medicines can be effectively used instead of bacterial LPS as a potent adjuvant in the formulation of a DC-based vaccine for cancer immunotherapies. PMID- 25825911 TI - Cloning and functional characterization of SAD genes in potato. AB - Stearoyl-acyl carrier protein desaturase (SAD), locating in the plastid stroma, is an important fatty acid biosynthetic enzyme in higher plants. SAD catalyzes desaturation of stearoyl-ACP to oleyl-ACP and plays a key role in determining the homeostasis between saturated fatty acids and unsaturated fatty acids, which is an important player in cold acclimation in plants. Here, four new full-length cDNA of SADs (ScoSAD, SaSAD, ScaSAD and StSAD) were cloned from four Solanum species, Solanum commersonii, S. acaule, S. cardiophyllum and S. tuberosum, respectively. The ORF of the four SADs were 1182 bp in length, encoding 393 amino acids. A sequence alignment indicated 13 amino acids varied among the SADs of three wild species. Further analysis showed that the freezing tolerance and cold acclimation capacity of S. commersonii are similar to S. acaule and their SAD amino acid sequences were identical but differed from that of S. cardiophyllum, which is sensitive to freezing. Furthermore, the sequence alignments between StSAD and ScoSAD indicated that only 7 different amino acids at residues were found in SAD of S. tuberosum (Zhongshu8) against the protein sequence of ScoSAD. A phylogenetic analysis showed the three wild potato species had the closest genetic relationship with the SAD of S. lycopersicum and Nicotiana tomentosiformis but not S. tuberosum. The SAD gene from S. commersonii (ScoSAD) was cloned into multiple sites of the pBI121 plant binary vector and transformed into the cultivated potato variety Zhongshu 8. A freeze tolerance analysis showed overexpression of the ScoSAD gene in transgenic plants significantly enhanced freeze tolerance in cv. Zhongshu 8 and increased their linoleic acid content, suggesting that linoleic acid likely plays a key role in improving freeze tolerance in potato plants. This study provided some new insights into how SAD regulates in the freezing tolerance and cold acclimation in potato. PMID- 25825912 TI - Corticospinal and reciprocal inhibition actions on human soleus motoneuron activity during standing and walking. AB - Reciprocal Ia inhibition constitutes a key segmental neuronal pathway for coordination of antagonist muscles. In this study, we investigated the soleus H reflex and reciprocal inhibition exerted from flexor group Ia afferents on soleus motoneurons during standing and walking in 15 healthy subjects following transcranial magnetic stimulation (TMS). The effects of separate TMS or deep peroneal nerve (DPN) stimulation and the effects of combined (TMS + DPN) stimuli on the soleus H-reflex were assessed during standing and at mid- and late stance phases of walking. Subthreshold TMS induced short-latency facilitation on the soleus H-reflex that was present during standing and at midstance but not at late stance of walking. Reciprocal inhibition was increased during standing and at late stance but not at the midstance phase of walking. The effects of combined TMS and DPN stimuli on the soleus H-reflex significantly changed between tasks, resulting in an extra facilitation of the soleus H-reflex during standing and not during walking. Our findings indicate that corticospinal inputs and Ia inhibitory interneurons interact at the spinal level in a task-dependent manner, and that corticospinal modulation of reciprocal Ia inhibition is stronger during standing than during walking. PMID- 25825913 TI - Effects of Mitragynine and a Crude Alkaloid Extract Derived from Mitragyna speciosa Korth. on Permethrin Elimination in Rats. AB - Detoxification and elimination of permethrin (PM) are mediated by hydrolysis via carboxylesterase (CES). Mitragyna speciosa (kratom) contains mitragynine (MG) and other bioactive alkaloids. Since PM and MG have the same catalytic site and M. speciosa is usually abused by adding other ingredients such as pyrethroid insecticides, the effects of MG and an alkaloid extract (AE) on the elimination of PM were investigated in rats. Rats were subjected to single and multiple pretreatment with MG and AE prior to receiving a single oral dose (460 mg/kg) of PM. Plasma concentrations of trans-PM and its metabolite phenoxybenzylalcohol (PBAlc) were measured. The elimination rate constant (kel) and the elimination half-life (t1/2 el) of PM were determined, as well as the metabolic ratio (PMR). A single and multiple oral pretreatment with MG and AE altered the plasma concentration-time courses of both trans-PM and PBAlc during 8-22 h, decreased the PMRs, delayed elimination of PM, but enhanced elimination of PBAlc. Results indicated that PM-MG or AE toxicokinetic interactions might have resulted from the MG and AE interfering with PM hydrolysis. The results obtained in rats suggest that in humans using kratom cocktails containing PM, there might be an increased risk of PM toxicity due to inhibition of PM metabolism and elimination. PMID- 25825914 TI - Microdosimetry of the Auger electron emitting 123I radionuclide using Geant4-DNA simulations. AB - Microdosimetric calculations of the Auger electron emitter (123)I were done in liquid water spheres using the Geant4 toolkit. The electron emission spectrum of (123)I produced by Geant4 is presented. Energy deposition and corresponding S values were calculated to investigate the influence of the sub-cellular localization of the Auger emitter. It was found that S-values calculated by the Geant4 toolkit are generally lower than the values calculated by other Monte Carlo codes for the (123)I radionuclide. The differences in the compared S-values are mainly due to the different particle emission spectra employed by the respective computational codes and emphasizes the influence of the spectra on dosimetry calculations. PMID- 25825915 TI - Folate status and health: challenges and opportunities. AB - Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 MUg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia. PMID- 25825916 TI - Cell cycle regulation and apoptotic cell death in experimental colon carcinogenesis: intervening with cyclooxygenase-2 inhibitors. AB - Relative imbalance in the pathways regulating cell cycle, cell proliferation, or cell death marks a prerequisite for neoplasm. C-phycocyanin, a biliprotein from Spirulina platensis and a selective COX-2 inhibitor along with piroxicam, a traditional nonsteroidal antiinflammatory drug was used to investigate the role of cell cycle regulatory proteins and proinflammatory transcription factor NFkappaB in 1,2-dimethylhydrazine dihydrochloride (DMH)-induced rat colon carcinogenesis. Cell cycle regulators [cyclin D1, cyclin E, cyclin dependent kinase 2 (CDK2), CDK4, and p53], NFkappaB (p65) pathway, and proliferating cell nuclear antigen (PCNA) were evaluated by gene and protein expression, whereas apoptosis was studied by terminal deoxynucleotidyl transferase dUTP nick end labeling and apoptotic bleb assay. Molecular docking of ligand protein interaction was done to validate the in vivo results. Cyclin D1, cyclin E, CDK2, and CDK4 were overexpressed in DMH, whereas piroxicam and c-phycocyanin promoted the cell cycle arrest by downregulating them. Both drugs mediated apoptosis through p53 activation. Piroxicam and c-phycocyanin also stimulated antiproliferation by restraining PCNA expression and reduced cell survival via inhibiting NFkappaB (p65) pathway. Molecular docking revealed that phycocyanobilin (a chromophore of c-phycocyanin) interact with DNA binding site of NFkappaB. Inhibition of cyclin/CDK complex by piroxicam and c-phycocyanin affects the expression of p53 in colon cancer followed by downregulation of NFkappaB and PCNA levels, thus substantiating the antineoplastic role of these agents. PMID- 25825918 TI - Carboxylate Ion Pairing with Alkali-Metal Ions for beta-Lactoglobulin and Its Role on Aggregation and Interfacial Adsorption. AB - We report a combined experimental and computational study of the whey protein beta-lactoglobulin (BLG) in different electrolyte solutions. Vibrational sum frequency generation (SFG) and ellipsometry were used to investigate the molecular structure of BLG modified air-water interfaces as a function of LiCl, NaCl, and KCl concentrations. Molecular dynamics (MD) simulations and thermodynamic integration provided details of the ion pairing of protein surface residues with alkali-metal cations. Our results at pH 6.2 indicate that BLG at the air-water interface forms mono- and bilayers preferably at low and high ionic strength, respectively. Results from SFG spectroscopy and ellipsometry are consistent with intimate ion pairing of alkali-metal cations with aspartate and glutamate carboxylates, which is shown to be more effective for smaller cations (Li(+) and Na(+)). MD simulations show not only carboxylate-alkali-metal ion pairs but also ion multiplets with the alkali-metal ion in a bridging position between two or more carboxylates. Consequently, alkali-metal cations can bridge carboxylates not only within a monomer but also between monomers, thus providing an important dimerization mechanism between hydrophilic surface patches. PMID- 25825919 TI - "Allow Natural Death" versus "Do Not Resuscitate": What Do Patients with Advanced Cancer Choose? AB - BACKGROUND: Many patients with advanced cancer at our hospital request full resuscitative efforts at the end of life. We assessed the knowledge and attitudes of these patients towards end-of-life (EOL) care, and their preferences about "Do Not Resuscitate" (DNR), "Allow Natural Death" (AND), and "full code" orders. METHODS: The first 100 consenting adult patients with advanced cancer were surveyed regarding their diagnosis, prognosis, and attitudes about critical care and resuscitation. They were then presented with hypothetical scenarios in which a decision on their code status had to be made if they had one year, six months, or one month left to live. Half were given a choice between being "full code" and "DNR," and half could choose between "full code" and "AND." RESULTS: All 93 of the participants who completed the survey were considered by their attending physician to have a terminal illness, but only 42% of these interviewees believed they were terminally ill. In addition, only 25% of participants thought that their primary oncologist knew their EOL wishes. Participants were equally likely to choose either of the "no code" options in all hypothetical scenarios (p>0.54), regardless of age, sex, race, type of cancer, education, or income level. A similar proportion of patients who had a living will chose "AND" and "DNR" orders instead of "full code" in all the scenarios (47%-74% and 63%-71%). In contrast, among patients who did not have a living will, 52% chose "DNR," while 19% opted for "AND." CONCLUSIONS: We hypothesized that "AND" orders may be more acceptable to patients with advanced cancer, but there was no statistically significant difference in acceptability between "AND" and "DNR" orders. PMID- 25825920 TI - Effect of humic acids with different characteristics on fermentative short-chain fatty acids production from waste activated sludge. AB - Recently, the use of waste activated sludge to bioproduce short-chain fatty acids (SCFA) has attracted much attention as the sludge-derived SCFA can be used as a preferred carbon source to drive biological nutrient removal or biopolymer (polyhydroxyalkanoates) synthesis. Although large number of humic acid (HA) has been reported in sludge, the influence of HA on SCFA production has never been documented. This study investigated the effects on sludge-derived SCFA production of two commercially available humic acids (referred to as SHHA and SAHA purchased respectively from Shanghai Reagent Company and Sigma-Aldrich) that differ in chemical structure, hydrophobicity, surfactant properties, and degree of aromaticity. It was found that SHHA remarkably enhanced SCFA production (1.7-3.5 folds), while SAHA had no obvious effect. Mechanisms study revealed that all four steps (solubilization, hydrolysis, acidification, and methanogenesis) involved in sludge fermentation were unaffected by SAHA. However, SHHA remarkably improved the solubilization of sludge protein and carbohydrate and the activity of hydrolysis enzymes (protease and alpha-glucosidase) owing to its greater hydrophobicity and protection of enzyme activity. SHHA also enhanced the acidification step by accelerating the bioreactions of glyceradehyde-3P -> d glycerate 1,3-diphosphate, and pyruvate -> acetyl-CoA due to its abundant quinone groups which served as electron acceptor. Further investigation showed that SHHA negatively influenced the activity of acetoclastic methanogens for its competition for electrons and inhibition on the reaction of acetyl-CoA -> 5 methyl-THMPT, which caused less SCFA being consumed. All these observations were in correspondence with SHHA significantly enhancing the production of sludge derived SCFA. PMID- 25825921 TI - My life as a clinician-scientist: trying to bridge the perceived gap between medicine and science. PMID- 25825922 TI - Explaining variance and identifying predictors of children's communication via a multilevel model of single-case design research. AB - The purpose of this study was to explain the variability in data collected from a single-case design study and to identify predictors of communicative outcomes for children with developmental delays or disabilities (n = 4). Using SAS University Edition, we fit multilevel models with time nested within children. Children's initial levels of communication and teachers' frequency of strategy use when directed at the children predicted children's communicative outcomes. These results indicate that teachers' implementation of evidence-based communication strategies, when directed toward children with disabilities, and the interaction between their use of the strategies and children's initial levels of communication predict children's communicative outcomes. Implications for research and practice are provided. PMID- 25825923 TI - Tunable Rare Earth fcu-MOF Platform: Access to Adsorption Kinetics Driven Gas/Vapor Separations via Pore Size Contraction. AB - Reticular chemistry approach was successfully employed to deliberately construct new rare-earth (RE, i.e., Eu(3+), Tb(3+), and Y(3+)) fcu metal-organic frameworks (MOFs) with restricted window apertures. Controlled and selective access to the resultant contracted fcu-MOF pores permits the achievement of the requisite sorbate cutoff, ideal for selective adsorption kinetics based separation and/or molecular sieving of gases and vapors. Predetermined reaction conditions that permitted the formation in situ of the 12-connected RE hexanuclear molecular building block (MBB) and the establishment of the first RE-fcu-MOF platform, especially in the presence of 2-fluorobenzoic acid (2-FBA) as a modulator and a structure directing agent, were used to synthesize isostructural RE-1,4-NDC-fcu MOFs based on a relatively bulkier 2-connected bridging ligand, namely 1,4 naphthalenedicarboxylate (1,4-NDC). The subsequent RE-1,4-NDC-fcu-MOF structural features, contracted windows/pores and high concentration of open metal sites combined with exceptional hydrothermal and chemical stabilities, yielded notable gas/solvent separation properties, driven mostly by adsorption kinetics as exemplified in this work for n-butane/methane, butanol/methanol, and butanol/water pair systems. PMID- 25825924 TI - Reconstructing multiple free energy pathways of DNA stretching from single molecule experiments. AB - Free energy landscapes provide information on the dynamics of proteins and nucleic acid folding. It has been demonstrated that such landscapes can be reconstructed from single molecule force measurement data using Jarzynski's equality, which requires only stretching data. However, when the process is reversible, the Crooks fluctuation theorem combines both stretch and relaxation force data for the analysis and can offer more rapid convergence of free energy estimates of different states. Here we demonstrate that, similar to Jarzynski's equality, the Crooks fluctuation theorem can be used to reconstruct the full free energy landscapes. In addition, when the free energy landscapes exhibit multiple folding pathways, one can use Jarzynski's equality to reconstruct individual free energy pathways if the experimental data show distinct work distributions. We applied the method to reconstruct the overstretching transition of poly(dA) to demonstrate that the nonequilibrium work theorem combined with single molecule force measurements provides a clear picture of the free energy landscapes. PMID- 25825925 TI - An Examination of Influences on Body Dissatisfaction Among Asian American College Females: Do Family, Media, or Peers Play a Role? AB - OBJECTIVE: The etiology of body dissatisfaction and its correlates (eg, disordered eating) among ethnic minorities is generally unknown. The purpose of this study was to replicate the tripartite model of influence in an Asian American college female sample in order to examine this relationship. PARTICIPANTS: Participants were 80 undergraduate Asian American females between the ages of 18 and 25. METHODS: Participants completed a survey that included the Tripartite Influence Scale, Body Parts Satisfaction Scale, and Sociocultural Attitudes towards Appearance Questionnaire-3. RESULTS: Mediation analyses indicated that thin-ideal internalization fully mediated the relationship between media influence and body dissatisfaction and partially mediated the relationship between peer influence and body dissatisfaction. Family influence did not significantly predict body dissatisfaction. CONCLUSIONS: Asian American college females experience body dissatisfaction through mechanisms that have not been examined in detail. These factors must be considered when creating targeted health promotion strategies and developing best practices for eating disorder assessment and treatment protocols at university health centers. PMID- 25825927 TI - Double balloon enteroscopy is a safe and effective procedure in removing entrapped foreign objects in the small bowel for up to 3 months. AB - Recent case series have shown that enteroscopy is safe and effective to remove entrapped small bowel foreign bodies. However, the optimal timing for the foreign body retrieval in terms of duration of entrapment and when to consider surgical intervention are unknown. In this case series, we report that antegrade and retrograde enteroscopy can be used safely to retrieve foreign bodies entrapped in the small bowel for longer than 70 days. In total, 20 patients (mean age, 48 years; 11 females) with entrapped foreign bodies in the small intestine underwent antegrade, retrograde, or combined double balloon enteroscopy for retrieval of objects. Symptoms prompted removal of entrapped, nonsharp objects in all patients and included abdominal pain, nausea, and vomiting. The mean time of entrapment was 83 days (range, 4-272 days). There were 15 cases of retained video capsule endoscopy (VCE) with a mean entrapment time of 106 days (range, 7-272 days). Two VCEs could not be removed safely with enteroscopy. Other retained small bowel objects included in this study were nails and fish hooks. Their average entrapment time was 13 days (range, 4-43 days). Of the 30 enteroscopies, there was only 1 case (3%) with a complication (perforation). According to this case series, experienced endoscopists can safely and effectively retrieve foreign bodies in the small bowel, particularly VCE, that are retained for extended periods of time. PMID- 25825926 TI - Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats. AB - Sustained and safe delivery of dopamine across the blood brain barrier (BBB) is a major hurdle for successful therapy in Parkinson's disease (PD), a neurodegenerative disorder. Therefore, in the present study we designed neurotransmitter dopamine-loaded PLGA nanoparticles (DA NPs) to deliver dopamine to the brain. These nanoparticles slowly and constantly released dopamine, showed reduced clearance of dopamine in plasma, reduced quinone adduct formation, and decreased dopamine autoxidation. DA NPs were internalized in dopaminergic SH-SY5Y cells and dopaminergic neurons in the substantia nigra and striatum, regions affected in PD. Treatment with DA NPs did not cause reduction in cell viability and morphological deterioration in SH-SY5Y, as compared to bulk dopamine-treated cells, which showed reduced viability. Herein, we report that these NPs were able to cross the BBB and capillary endothelium in the striatum and substantia nigra in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Systemic intravenous administration of DA NPs caused significantly increased levels of dopamine and its metabolites and reduced dopamine-D2 receptor supersensitivity in the striatum of parkinsonian rats. Further, DA NPs significantly recovered neurobehavioral abnormalities in 6-OHDA-induced parkinsonian rats. Dopamine delivered through NPs did not cause additional generation of ROS, dopaminergic neuron degeneration, and ultrastructural changes in the striatum and substantia nigra as compared to 6 OHDA-lesioned rats. Interestingly, dopamine delivery through nanoformulation neither caused alterations in the heart rate and blood pressure nor showed any abrupt pathological change in the brain and other peripheral organs. These results suggest that NPs delivered dopamine into the brain, reduced dopamine autoxidation-mediated toxicity, and ultimately reversed neurochemical and neurobehavioral deficits in parkinsonian rats. PMID- 25825928 TI - Characterizing the relationship between tick bites and Lyme disease in active component U.S. Armed Forces in the eastern United States. AB - Lyme disease (LD) is the most commonly diagnosed vector-borne illness in the U.S. Analysis of ticks that are removed from patients (rather than collected from the environment) may inform LD surveillance. In this ecological study, LD rates among active component U.S. Armed Forces in the eastern U.S. were compared with tick data from the U.S. Army Public Health Command Human Tick Test Kit Program (HTTKP) covering the same geographic region. In the population of service members in the study sample, mean annual LD incidence was 52.2 per 100,000 person-years (95% CI+/-; 7.6 per 100,000) between 1 January 2006 and 31 December 2012. A 10% increase in the rate of ticks submitted to the HTTKP corresponded to an increase in LD incidence of 5.7% (p<0.01). Where Borrelia burgdorferi infection of Ixodes scapularis ticks was high (20% or greater tick infection prevalence), tick removal rates explained 53.7% of the annual variation in LD incidence (p=0.01). These data support using location-specific rates of ticks removed while feeding on active component service members to complement LD surveillance. PMID- 25825929 TI - Incidence and prevalence of diagnoses of eye disorders of refraction and accommodation, active component service members, U.S. Armed Forces, 2000-2014. AB - More than half of service members on duty in the active component of the U.S. Armed Forces in July 2014 had been previously diagnosed with at least one of the eye disorders of refraction and accommodation examined in this report. During 2000-2014, the most common diagnoses among service members, in descending order of frequency, were myopia, astigmatism, hyperopia, and presbyopia. The incidence rates for myopia were highest among those younger than 30 years and the rates for hyperopia and presbyopia were highest among those older than 39 years. Incidence rates and prevalence for all the disorders examined were higher among females than males. The methodological limitations of the analysis are discussed with respect to the generalizability of the results to the U.S population. PMID- 25825930 TI - Update: Heat injuries, active component, U.S. Armed Forces, 2014. AB - The incidence rate of heat stroke among active component service members in 2014 was slightly higher than in 2013 but similar to the rates in 2011 and 2012. Incidence rates of heat stroke were higher among males, those younger than 20 years of age, Asian/Pacific Islanders, Marine Corps and Army members, and service members in combat-specific occupations, compared to their respective counterparts. Fewer service members were treated for "other heat injuries" in 2014 (n=1,683) than in any other year of the 5-year surveillance period. In addition, there were fewer reportable medical events for "other heat injuries" in 2014 than in any of the prior 4 years. The incidence rate of "other heat injuries" was higher among females than males and was more than 6-fold higher among recruit trainees than among other enlisted members or officers. During 2010 2014, 851 diagnoses of heat injuries were documented as having occurred among service members serving in Iraq/Afghanistan; 7.1% (n=60) of those diagnoses were for heat stroke. PMID- 25825931 TI - Surveillance snapshot: The geographic distribution of heat injuries among active component service members, U.S. Armed Forces, 2010-2014. PMID- 25825932 TI - Update: Exertional rhabdomyolysis, active component, U.S. Armed Forces, 2010 2014. AB - Among active component U.S. service members in 2014, there were 403 incident episodes of rhabdomyolysis likely due to physical exertion or heat stress ("exertional rhabdomyolysis"). Th e annual incidence rates of exertional rhabdomyolysis increased nearly 50% during 2010-2014. In 2014, the highest incidence rates occurred in service members who were male; younger than 20 years of age; black, non-Hispanic; members of the Marine Corps and Army; recruit trainees; and in combat-specific occupations. Incidence rates were higher among service members with homes of record from the Northeast compared to other U.S. regions. Most cases of exertional rhabdomyolysis were diagnosed at installations that support basic combat/recruit training or major ground combat units of the Army or Marine Corps. Medical care providers should consider exertional rhabdomyolysis in the differential diagnosis when service members (particularly recruits) present with muscular pain and swelling,limited range of motion, or the excretion of dark urine (e.g., myoglobinuria)aft er strenuous physical activity, particularly in hot, humid weather. PMID- 25825933 TI - Update: Exertional hyponatremia, active component, U.S. Armed Forces, 1999-2014. AB - From 1999 through 2014, there were 1,506 incident diagnoses of exertional hyponatremia among active component members of the U.S. Armed Forces. Annual incidence rates rose sharply from 2008 through 2010 then decreased by more than 50% from 2010 through 2013. In 2014, the number of cases (n=98) increased by approximately 30% from the previous year. The recent increase in rates overall reflects increased rates in all Services except the Navy. Relative to their respective counterparts, crude incidence rates of exertional hyponatremia for the entire 16-year surveillance period were higher among females, those in the youngest age group, Marines, and recruit trainees. Service members (particularly recruit trainees) and their supervisors must be vigilant for early signs of heat related illnesses and must be knowledgeable of the dangers of excessive water consumption and the prescribed limits for water intake during prolonged physical activity (e.g., field training exercises, personal fitness training, recreational activities) in hot, humid weather. PMID- 25825934 TI - Design and Synthesis of Antitumor Heck-Coupled Sclareol Analogues: Modulation of BH3 Family Members by SS-12 in Autophagy and Apoptotic Cell Death. AB - Sclareol, a promising anticancer labdane diterpene, was isolated from Salvia sclarea. Keeping the basic stereochemistry-rich framework of the molecule intact, a method for the synthesis of novel sclareol analogues was designed using palladium(II)-catalyzed oxidative Heck coupling reaction in order to study their structure-activity relationship. Both sclareol and its derivatives showed an interesting cytotoxicity profile, with 15-(4-fluorophenyl)sclareol (SS-12) as the most potent analogue, having IC50 = 0.082 MUM against PC-3 cells. It was found that SS-12 commonly interacts with Bcl-2 and Beclin 1 BH3 domain proteins and enhances autophagic flux by modulating autophagy-related proteins. Moreover, inhibition of autophagy by autophagy inhibitors protected against SS-12-induced apoptosis. Finally, SS-12 effectively suppressed tumor growth in vivo in Ehrlich's ascitic and solid Sarcoma-180 mouse models. PMID- 25825935 TI - Enhanced Electrochemical Performance of Fe0.74Sn5@Reduced Graphene Oxide Nanocomposite Anodes for Both Li-Ion and Na-Ion Batteries. AB - The recently found intermetallic FeSn5 phase with defect structure Fe0.74Sn5 has shown promise as a high capacity anode for lithium-ion batteries (LIBs). The theoretical capacity is as high as 929 mAh g(-1) thanks to the high Sn/Fe ratio. However, despite being an alloy, the cycle life remains a great challenge. Here, by combining Fe0.74Sn5 nanospheres with reduced graphene oxide (RGO) nanosheets, the Fe0.74Sn5@RGO nanocomposite can achieve capacity retention 3 times that of the nanospheres alone, after 100 charge/discharge cycles. Moreover, the nanocomposite also displays its versatility as a high-capacity anode in sodium ion batteries (SIBs). The enhanced cell performance in both battery systems indicates that the Fe0.74Sn5@RGO nanocomposite can be a potential anode candidate for the application of Li-ion and Na-ion battery. PMID- 25825936 TI - Identification of Novel Recombinant Forms of Hepatitis B Virus Generated from Genotypes Ae and G in HIV-1-Positive Japanese Men Who Have Sex with Men. AB - The rare hepatitis B virus (HBV) genotype G (HBV/G) coinfects HIV-1-positive individuals along with HBV/A and generates recombinants. However, the circulation of HBV A/G recombinants remains poorly understood. This molecular epidemiologic study examined HBV A/G recombinants in Japanese HIV-1-positive men who have sex with men (MSM). Initially, blood specimens submitted for confirmatory tests of HIV infection in Osaka and Tokyo, Japan, from 2006 to 2013 were examined for HIV 1, and HIV-1-positive specimens were screened for HBV. Among 817 specimens from HIV-1-positive individuals, HBsAg was detected in 59 specimens; of these, HBV/Ae (alternatively A2), a subgenotype of HBV/A prevalent in Europe and North America, was identified in 70.2%, HBV/C in 17.5%, and HBV/G in 10.5%, and HBV/E in 1.8% according to the core gene sequence. The full-length genome analysis of HBV was performed on HBV/G-positive specimens because some HBV A/G recombinants were historically overlooked by genotyping based on a partial genome analysis. It revealed that five of the specimens contained novel Ae/G recombinants, the core gene of which had a high sequence similarity to HBV/G. Detailed analyses showed that novel recombinants were coinfected with HBV/Ae in a recombinant-dominant fashion. No major drug-resistant mutations were found in the newly identified HBV Ae/G recombinants. Some of the individuals asymptomatically coinfected with HIV/HBV suffered mild liver injury. This study demonstrated that novel Ae/G HBV recombinants were identified in Japanese HIV-1-positive MSM. The pathogenicity of novel HBV Ae/G recombinants should be examined in a future longitudinal study. Surveillance of such viruses in HIV-1-positive individuals should be emphasized. PMID- 25825937 TI - Loss of conserved Gsdma3 self-regulation causes autophagy and cell death. AB - Gasdermin A3 (Gsdma3) was originally identified in association with hair-loss phenotype in mouse mutants. Our previous study found that AE mutant mice, with a Y344H substitution at the C-terminal domain of Gsdma3, display inflammation dependent alopecia and excoriation [Zhou et al. (2012) Am. J. Pathol. 180, 763 774]. Interestingly, we found that the newly-generated null mutant of Gsdma3 mice did not display the skin dysmorphology, indicating that Gsdma3 is not essential for differentiation of epidermal cells and maintenance of the hair cycle in normal physiological conditions. Consistently, human embryonic kidney (HEK)293 and HaCaT cells transfected with wild-type (WT) Gsdma3 did not show abnormal morphology. However, Gsdma3 Y344H mutation induced autophagy. Gsdma3 N-terminal domain, but not the C-terminal domain, also displayed the similar pro-autophagic activity. The Gsdma3 Y344H mutant protein and N-terminal domain-induced autophagy was associated with mitochondria and ROS generation. Co-expression of C-terminal domain reversed the cell autophagy induced by N-terminal domain. Moreover, C terminal domain could be co-precipitated with N-terminal domain. These data indicated that the potential pro-autophagic activity of WT Gsdma3 protein is suppressed through an intramolecular inhibition mechanism. Studies on other members of the GSDM family suggested this mechanism is conserved in several sub families. PMID- 25825938 TI - Interventions for Enhancing Adherence to Antiretroviral Therapy (ART): A Systematic Review of High Quality Studies. AB - We sought to review the effectiveness of interventions designed to improve adherence to antiretroviral therapy (ART) from studies included in a recent Cochrane review that reported a clinical and an adherence outcome, with at least 80% follow-up for 6 months or more. Data were extracted independently and in duplicate, with an adjudicator for disagreements. Risk of bias was assessed using the Cochrane Risk of Bias tool. Of 182 relevant studies in the Cochrane review, 49 were related to ART. Statistical pooling was not warranted due to heterogeneity in interventions, participants, treatments, adherence measures and outcomes. Many studies had high risk of bias in elements of design and outcome ascertainment. Only 10 studies improved both adherence and clinical outcomes. These used the following interventions: adherence counselling (two studies); a once-daily regimen (compared to twice daily); text messaging; web-based cognitive behavioral intervention; face-to-face multi-session intensive behavioral interventions (two studies); contingency management; modified directly observed therapy; and nurse-delivered home visits combined with telephone calls. Patient related adherence interventions were the most frequently tested. Uniform adherence measures and higher quality studies of younger populations are encouraged. PMID- 25825939 TI - The nature of singlet exciton fission in carotenoid aggregates. AB - Singlet exciton fission allows the fast and efficient generation of two spin triplet states from one photoexcited singlet. It has the potential to improve organic photovoltaics, enabling efficient coupling to the blue to ultraviolet region of the solar spectrum to capture the energy generally lost as waste heat. However, many questions remain about the underlying fission mechanism. The relation between intermolecular geometry and singlet fission rate and yield is poorly understood and remains one of the most significant barriers to the design of new singlet fission sensitizers. Here we explore the structure-property relationship and examine the mechanism of singlet fission in aggregates of astaxanthin, a small polyene. We isolate five distinct supramolecular structures of astaxanthin generated through self-assembly in solution. Each is capable of undergoing intermolecular singlet fission, with rates of triplet generation and annihilation that can be correlated with intermolecular coupling strength. In contrast with the conventional model of singlet fission in linear molecules, we demonstrate that no intermediate states are involved in the triplet formation: instead, singlet fission occurs directly from the initial 1B(u) photoexcited state on ultrafast time scales. This result demands a re-evaluation of current theories of polyene photophysics and highlights the robustness of carotenoid singlet fission. PMID- 25825940 TI - Correction to Single Particle Nanomechanics in Operando Batteries via Lensless Strain Mapping. PMID- 25825941 TI - Development of a simple droplet-based microfluidic capillary viscometer for low viscosity Newtonian fluids. AB - Viscosity is an easily measured macroscopic property that provides molecular information and is widely used across the sciences and engineering. Here we report a microfluidic capillary viscometer that forms droplets from aqueous samples in an immiscible carrier phase and encodes information about sample viscosity in the droplet spacing. The device shows exceptional calibration stability, with only a 0.6% drift in calibration factor from run to run, the ability to handle aqueous and nonaqueous samples, and the ability to operate with sample volumes as low as 38 nL. Operating range for aqueous sample viscosity was characterized, and was found to be 0.96-52 cP. Operating range for aqueous shear rate was found to depend on aqueous viscosity and varied from 1.9 * 10(1)-4.4 * 10(2) s(-1) for high viscosity samples to 4.1 * 10(2)-6.0 * 10(3) s(-1) for low viscosity samples. Accuracy was tested by comparing measured viscosities of several samples including creme de menthe peppermint liquor, human urine, and baby oil to viscosities of the same samples obtained with a U-tube viscometer. The device was found to be very accurate, with differences between methods as low as 0.1%. The viscometer presented requires only a basic T junction and can utilize off-chip fluorescence to measure viscosity, which could allow for easy addition of viscometric measurement capabilities to existing droplet platforms. Furthermore, the device is capable of performing measurements on Newtonian fluids without precise control over pressures or flow rates, which significantly simplifies device operation. PMID- 25825942 TI - RNA extraction from healthy and failing human myocardium: a comparative evaluation. AB - BACKGROUND: Isolation of high-quality RNA from tissue is mandatory for producing reliable data for downstream applications. In heart tissue, the relative strengths and weaknesses of different approaches to isolate total RNA are unknown. The objective of this study was to compare different RNA isolation methods in healthy and diseased human myocardium. METHODS: Frozen left ventricular myocardium was obtained from individuals with heart failure and individuals who died from non-cardiac causes with normal heart function (control). Three extraction methods, including guanidine isothiocyanate (TRIzol), silica-gel column (RNeasy), and the combination method (TRIzol/RNeasy), were assessed for their effect on the yield, integrity, and gene expression levels of RNA using quantitative real-time PCR. RESULTS: In the control group (n=5), the highest RNA yield per tissue mass was obtained with TRIzol, and a significantly higher RNA integrity was obtained from the RNeasy method. The quantification cycle (Cq) values for both the reference gene GAPDH and two target genes were lower with TRIzol. Normalization by GAPDH showed the highest gene expression levels with RNeasy. Similar patterns were observed in the heart failure group (n=5), suggesting assays were not negatively impacted by myocardial disease processes. CONCLUSION: In both healthy and diseased heart tissue, the TRIzol method provides the highest RNA yield, while the RNeasy method shows superior RNA integrity, demonstrating comparable RNA quality in studies examining myocardial disease. A balanced approach to RNA quality is necessary for the successful downstream applications of RNA. PMID- 25825943 TI - Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat. AB - CONTEXT: Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain. OBJECTIVES: We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose. DESIGN, SETTING, AND PARTICIPANTS: Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy. RESULTS: Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 +/- 1.4% vs 11.0 +/- 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 +/- 0.07 vs 0.46 +/- 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP. CONCLUSION: Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets. PMID- 25825944 TI - Sequential Versus Continual Purified Urinary FSH/hCG in Men With Idiopathic Hypogonadotropic Hypogonadism. AB - CONTEXT: Gonadotropin therapy using a human chorionic gonadotropin (hCG) and FSH preparation is an effective regimen in inducing masculinization and spermatogenesis in men with idiopathic hypogonadotropic hypogonadism (IHH). However, the high cost of medication and frequent injections affect compliance. OBJECTIVE: The aim of this study was to determine the efficacy of sequential use of highly purified urinary FSH (uFSH)/hCG in men with IHH. DESIGN AND SETTING: A randomized, open-label, prospective, controlled noninferiority trial with an 18 month follow-up was conducted in 9 tertiary hospitals. PATIENTS AND INTERVENTION: A total of 67 Chinese men with IHH were randomly allocated into group A receiving continual uFSH (75 U, 3 times a week) and hCG (2000 U, twice a week) injection and group B receiving sequential uFSH (75 U, 3 times a week every other 3 months) and hCG (2000 U, twice a week) injection. MAIN OUTCOME MEASURE: The primary outcome was the proportion of subjects with a sperm concentration of >= 1.0 * 10(6)/mL during the 18 months. The efficacy between groups A and B was compared for noninferiority. RESULTS: Of the patients, 17/33 (51.5%) receiving continual uFSH/hCG and 19/34 (55.9%) receiving sequential uFSH/hCG achieved sperm concentrations of >= 1.0 * 10(6)/mL. The efficacy in the sequential uFSH/hCG group was not inferior to that in the continual uFSH/hCG group (noninferiority, P = .008) by intention-to-treat analysis. CONCLUSIONS: The efficacy of the sequential uFSH/hCG regimen is not inferior to that of the continual uFSH/hCG regimen in inducing spermatogenesis and masculinization of patients with IHH. PMID- 25825945 TI - beta-Cell Sensitivity to GLP-1 in Healthy Humans Is Variable and Proportional to Insulin Sensitivity. AB - CONTEXT: Glucagon-like peptide-1 (GLP-1) is an insulinotropic factor made in the gastrointestinal tract that is essential for normal glucose tolerance. Infusion of GLP-1 increases insulin secretion in both diabetic and nondiabetic humans. However, the degree to which people vary in their beta-cell sensitivity to GLP-1 and the factors contributing to this variability have not been reported. OBJECTIVE: The objective was to measure the sensitivity of insulin secretion to GLP-1 in cohorts of lean and obese subjects across a broad range of insulin sensitivity. METHODS: Insulin secretion was measured during clamped hyperglycemia (7.2 mmol/L) and graded GLP-1 infusion in young, healthy subjects, and GLP-1 sensitivity was computed from the insulin secretion rate (ISR) during progressive increases in plasma GLP-1. RESULTS: All subjects had fasting glucose values <5.2 mm. The obese subjects were insulin resistant compared to the lean group (homeostasis model of assessment 2 for insulin resistance: obese, 2.6 +/- 0.5; lean, 0.8 +/- 0.1; P < .001). ISR increased linearly in both cohorts with escalating doses of GLP-1, but the slope of ISR in response to GLP-1 was greater in the obese than in the lean subjects (obese, 0.17 +/- 0.03 nmol/min/pm; lean, 0.05 +/- 0.01 nmol/min/pm; P < .001). There was a significant association of beta cell GLP-1 sensitivity and insulin resistance (r = 0.83; P < .001), and after correction for homeostasis model of assessment 2 for insulin resistance, the slopes of ISR vs GLP-1 concentration did not differ in the two cohorts (obese, 0.08 +/- 0.01; lean, 0.08 +/- 0.01; P = .98). However, within the entire study group, beta-cell GLP-1 sensitivity corrected for insulin resistance varied nearly 10-fold. CONCLUSIONS: Insulin secretion in response to GLP-1 is proportional to insulin resistance in healthy subjects. However, there is considerable variability in the sensitivity of the beta-cell to GLP-1 that is independent of insulin sensitivity. PMID- 25825946 TI - Maternal Diabetes, Large-for-Gestational-Age Births, and First Trimester Pregnancy-Associated Plasma Protein-A. AB - CONTEXT: Maternal pregnancy-associated plasma protein-A (PAPP-A) is measured at nuchal translucency scanning to assess the risk of fetal chromosomal disorders. OBJECTIVE: The aim of this study was to examine whether PAPP-A might also be a predictor of gestational diabetes (GDM), type 2 diabetes (T2D), or large-for gestational-age (LGA) births. DESIGN: PAPP-A levels were measured in serum from 1664 women at their 10-14-week nuchal translucency scan at a tertiary referral hospital. Maternal diabetes was categorized as T2D, "early GDM" (GDM diagnosed < 22 wk), and "late GDM" (GDM diagnosed >= 22 wk). The relationship between PAPP-A multiples of the median (MoM), maternal diabetes, and LGA was examined with multivariate regression models. RESULTS: PAPP-A MoM was significantly lower in women with T2D and women who developed GDM than in nondiabetic women. PAPP-A MoM was 41.3% lower in T2D, 22.6% lower in early GDM, and 8.6% lower in late GDM. Women in the lowest quartile of PAPP-A MoM were 2.7 times more likely to have early GDM (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.2-6.1) compared with the highest quartile. Birth weight had a positive linear association with PAPP-A MoM. Women in the highest PAPP-A MoM quartile were twice as likely to have an LGA baby (OR, 2.2; 95% CI, 1.39-3.46; P = .0007). CONCLUSIONS: Routinely tested first-trimester PAPP-A is a novel biomarker for maternal diabetes and LGA. PAPP-A decreased with increasing severity of maternal diabetes. Although this cannot infer causality, low PAPP-A may help identify women at risk of GDM, and high PAPP-A may help identify pregnancies at risk of LGA. PMID- 25825947 TI - Autonomic Imbalance as a Predictor of Metabolic Risks, Cardiovascular Disease, Diabetes, and Mortality Autonomic Imbalance Predicts CVD, DM, Mortality. AB - This article was published in its final form as 10.1210/jc.2015-1748 . PMID- 25825948 TI - Sex Differences in the Effects of Weight Loss Diets on Bone Mineral Density and Body Composition: POUNDS LOST Trial. AB - CONTEXT: Weight loss is associated with reduction in bone mineral density (BMD). OBJECTIVE: The objective was to address the role of changes in fat mass (FM) and lean mass (LM) in BMD decline in both sexes. DESIGN: A 2-year randomized controlled trial, the Preventing Overweight Using Novel Dietary Strategies (POUNDS-LOST). SETTING: The setting was the general community. PATIENTS OR OTHER PARTICIPANTS: Enrolled were 424 overweight and obese participants (mean age, 52 +/- 9 y; 57% females). INTERVENTION: Intervention included weight loss diets differing in fat, protein, and carbohydrates. MAIN OUTCOME MEASURES: Main outcome measures were change in spine, total hip (TH), and femoral neck (FN) BMD and sex differences after dietary intervention. RESULTS: At baseline, a stronger correlation between BMD and body composition measurements was observed in women, primarily with LM (r = 0.419, 0.507, and 0.523 for spine, FN, and TH, respectively; all P < .001). In men, only LM correlated with hip BMD (r = 0.298; P < .001). Mean weight loss at 2 years was -6.9%, without differences among diets. Two-year changes in BMD were 0.005 (P = .04), -0.014 (P < .001), and 0.014 g/cm(2) (P < .001), at the spine, TH, and FN, respectively. These changes directly correlated with changes in LM in women (r = 0.200, 0.324, and 0.260 for spine, FN, and TH, respectively), whereas FM loss correlated only with changes in TH BMD (0.274; P < .001). In men, changes in LM (-0.323; P < .001) and FM ( 0.213; P = .027) negatively correlated with changes in spine BMD. CONCLUSIONS: Weight loss diets result in sex-specific effects on BMD. Although men exhibited a paradoxical increase in spine BMD, women tended to decrease in BMD at all sites. PMID- 25825949 TI - Early Surge in Circulatory Adiponectin Is Associated With Improved Growth at Near Term in Very Preterm Infants. AB - CONTEXT: Adiponectin enhances insulin sensitivity and may play a role in fetal and postnatal growth. OBJECTIVE: This study aimed to determine whether early postnatal adiponectin concentration change is related to postnatal growth in very preterm infants. SETTING, DESIGN, AND PATIENTS: This was an in-hospital, prospective, longitudinal cohort study of 52 preterm infants with a gestational age (GA) of 26.0 +/- 1.9 (SD) weeks and birth weight (BW) of 889 +/- 284 g. INTERVENTIONS: An analysis of adiponectin was performed on cord blood at birth and peripheral blood at 72 hours, day 7, and then weekly until postmenstrual age (PMA) 40 weeks. Weight, length, and head circumference (HC) measurement was performed weekly and SD scores (SDS) calculated. Energy and protein intake was calculated daily from birth until PMA 35 weeks. RESULTS: Mean adiponectin concentration increased from 6.8 +/- 4.4 MUg/mL at 72 hours to 37.4 +/- 22.2 MUg/mL at 3 weeks; during days 3-21, it was 21.4 +/- 12 MUg/mL and correlated with GA at birth (r = 0.46, P = .001; BW: r = 0.71, P < .001; BW(SDS): r = 0.42, P = .003). Furthermore, mean adiponectin during days 3-21 correlated with weight(SDS), length(SDS), and HC(SDS) (r = 0.62, 0.65, and 0.62, respectively; all P < .001) at PMA 35 wk). Energy intake (kcal/kg/d) correlated with mean adiponectin during days 3-21 (r = 0.35, P < .013). CONCLUSIONS: In very preterm infants, adiponectin concentrations increased markedly in the first 3 weeks, and a greater increase was associated with improved postnatal growth. PMID- 25825950 TI - Fetal Environment Is a Major Determinant of the Neonatal Blood Thyroxine Level: Results of a Large Dutch Twin Study. AB - CONTEXT: The interindividual variability in thyroid hormone function parameters is much larger than the intraindividual variability, suggesting an individual set point for these parameters. There is evidence to suggest that environmental factors are more important than genetic factors in the determination of this individual set point. OBJECTIVE: This study aimed to quantify the effect of genetic factors and (fetal) environment on the early postnatal blood T4 concentration. METHODS: This was a classical twin study comparing the resemblance of neonatal screening blood T4 concentrations in 1264 mono- and 2566 dizygotic twin pairs retrieved from the population-based Netherlands Twin Register. Maximum likelihood estimates of variance explained by genetic and environmental influences were obtained by structural equation modeling in data from full-term and preterm twin pairs. RESULTS: In full-term infants, genetic factors explained 40%/31% of the variance in standardized T4 scores in boys/girls, and shared environment, 27%/22%. The remaining variance of 33%/47% was due to environmental factors not shared by twins. For preterm infants, genetic factors explained 34%/0% of the variance in boys/girls, shared environment 31%/57%, and unique environment 35%/43%. In very preterm twins, no significant contribution of genetic factors was observed. CONCLUSION: Environment explains a large proportion of the resemblance of the postnatal blood T4 concentration in twin pairs. Because we analyzed neonatal screening results, the fetal environment is the most likely candidate for these environmental influences. Genetic influences on the T4 set point diminished with declining gestational age, especially in girls. This may be due to major environmental influences such as immaturity and nonthyroidal illness in very preterm infants. PMID- 25825951 TI - Photodetachment spectroscopy of fluorenone radical anions microsolvated with methanol: rationalizing the anomalous solvatochromic behavior due to hydrogen bonding. AB - The attribution of the extraordinary blue shift for the intramolecular charge transfer absorption band of fluorenone radical anion solvated in protic media was investigated by means of photodetachment spectroscopy of the gas-phase anions microsolvated with methanol, in conjunction with quantum chemical calculations based on density functional theory. Sequential shifts of the vertical detachment energy as a function of the cluster size are consistent with theoretical predictions, where up to two methanol molecules can directly attach to the carbonyl group. In the photodetachment excitation spectra as alternatives to the photoabsorption spectra, with increasing cluster size, a new absorption band grows in the higher-energy region, which coincides with the blue-shifted band in protic media. Spectral simulations using time-dependent density functional theory with the CAM-B3LYP functional reproduced the feature of the phenomenon. Analyses on the electronic configuration elucidated that the extraordinarily blue shifts originate from energy-level repulsion due to solvation-induced resonant coupling with another electronic state. The orbital transition for the counterpart state corresponds to the first absorption band of the neutral fluorenone molecule, which has small oscillator strength from the ground state. It was found that correction of long-range electron exchange correlation is important for the spectral simulation involving the electronic-state coupling. PMID- 25825952 TI - 1,4-Hydroiodination of dienyl alcohols with TMSI to form homoallylic alcohols containing a multisubstituted Z-alkene and application to Prins cyclization. AB - A regioselective 1,4-hydroiodination of dienyl alcohols has been developed using trimethylsilyl iodide as Lewis acid and iodide source. A range of homoallylic alcohols containing a multisubstituted Z-alkene was synthesized with good to excellent configurational control. The approach was applied in sequential hydroiodination/Prins cyclization to afford multisubstituted tetrahydropyrans diastereoselectively. PMID- 25825953 TI - FeCl3-Mediated Synthesis of beta-Alkynyl Ketones via Domino Nucleophilic Substitution/Intramolecular-Cyclization/Reverse Claisen Condensation of N Cyclohexyl Propargylamines and 1,3-Diketones. AB - The synthesis of beta-alkynyl ketones was achieved in good to excellent yields by an iron-catalyzed domino reaction of N-cyclohexyl propargylamines and 1,3 diketones. A plausible mechanism involving nucleophilic substitution, intramolecular cyclization, and reverse Claisen condensation for this process is proposed. PMID- 25825954 TI - Phenolphthalein-based Poly(arylene ether sulfone nitrile)s Multiblock Copolymers As Anion Exchange Membranes for Alkaline Fuel Cells. AB - A series of phenolphthalein-based poly(arylene ether sulfone nitrile)s (PESN) multiblock copolymers containing 1-methylimidazole groups (ImPESN) were synthesized to prepare anion exchange membranes (AEMs) for alkaline fuel cells. The ion groups were introduced selectively and densely on the unit of phenolphthalein as the hydrophilic segments, allowing for the formation of ion clusters. Strong polar nitrile groups were introduced into the hydrophobic segments with the intention of improving the dimensional stability of the AEMs. A well-controlled multiblock structure was responsible for the well-defined hydrophobic/hydrophilic phase separation and interconnected ion-transport channels, as confirmed by atomic force microscopy and small angle X-ray scattering. The ImPESN membranes with low swelling showed a relatively high water uptake, high hydroxide ion conductivity together with good mechanical, thermal and alkaline stability. The ionic conductivity of the membranes was in the range of 3.85-14.67*10(-2) S.cm(-1) from 30 to 80 degrees C. Moreover, a single H2/O2 fuel cell with the ImPESN membrane showed an open circuit voltage of 0.92 V and a maximum power density of 66.4 mW cm(-2) at 60 degrees C. PMID- 25825955 TI - Effects of Diisodecyl Phthalate on PPAR:RXR-Dependent Gene Expression Pathways in Sea Bream Hepatocytes. AB - Evidence that endocrine-disrupting chemicals (EDCs) may target metabolic disturbances, beyond interference with the functions of the endocrine systems has recently accumulated. Among EDCs, phthalate plasticizers like the diisodecyl phthalate (DiDP) are commonly found contaminants of aquatic environments and have been suggested to function as obesogens by activating peroxisome proliferator activated receptors (PPARs), a subset of nuclear receptors (NRs) that act as metabolic sensors, playing pivotal roles in lipid homeostasis. However, little is known about the modulation of PPAR signaling pathways by DiDP in fish. In this study, we have first investigated the ligand binding efficiency of DiDP to the ligand binding domains of PPARs and retinoid-X-receptor-alpha (RXRalpha) proteins in fish using a molecular docking approach. Furthermore, in silico predictions were integrated by in vitro experiments to show possible dose-relationship effects of DiDP on PPAR:RXR-dependent gene expression pathways using sea bream hepatocytes. We observed that DiDP shows high binding efficiency with piscine PPARs demonstrating a greater preference for RXRalpha. Our studies also demonstrated the coordinate increased expression of PPARs and RXRalpha, as well as their downstream target genes in vitro. Principal component analysis (PCA) showed the strength of relationship between transcription of most genes involved in fatty acid metabolism and PPAR mRNA levels. In particular, fatty acid binding protein (FABP) was highly correlated to all PPARs. The results of this study suggest that DiDP can be considered an environmental stressor that activates PPAR:RXR signaling to promote long-term changes in lipid homeostasis leading to potential deleterious physiological consequences in teleost fish. PMID- 25825956 TI - Metabolic signals and innate immune activation in obesity and exercise. AB - The combination of a sedentary lifestyle and excess energy intake has led to an increased prevalence of obesity which constitutes a major risk factor for several co-morbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system. Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IkappaBalpha kinase/nuclear factor-kappaB (IKK/NF- kappaB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling. Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing obesity- induced chronic inflammation. This review summarizes current knowledge of the cellular recognition mechanisms for FFAs, the inflammatory signaling pathways triggered by excess FFAs in obesity and the counteractive effects of both acute and chronic exercise on obesity-induced activation of inflammatory signaling pathways. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its comorbidities. PMID- 25825957 TI - Identification and survival outcomes of a cohort of patients with cancer of unknown primary in Ontario, Canada. AB - BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS). MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. We cross-validated CUP diagnosis and obtained additional information about metastasis through data linkage with the SDS/DAD database. OS was assessed using Cox regression models adjusting for histology and sites of metastases. RESULTS: We identified 3564 patients diagnosed with CUP. Patients without histologically confirmed disease (n = 1821) had a one year OS of 10.9%, whereas patients with confirmed histology (n = 1743) had a one year OS of 15.6%. The most common metastatic sites were in the respiratory or digestive systems (n = 1603), and the most common histology was adenocarcinoma (n = 939). Three-year survival rates were 3.5%, 5.3%, 41.6% and 3.6% among adenocarcinoma, unspecified carcinoma, squamous cell carcinoma and undifferentiated histology, respectively. Three-year survival rates were 40%, 2.4%, 8.0% and 4.6% among patients with metastases localised to lymph nodes, the respiratory or digestive systems, other specified sites, and unspecified sites, respectively. CONCLUSION: CUP patients in Ontario have a poor prognosis. Some subgroups may have better survival rates, such as patients with metastases localised to lymph nodes and patients with squamous cell histology. PMID- 25825958 TI - Impact of CYP2D6 Polymorphisms on Postoperative Fentanyl Analgesia in Gastric Cancer Patients. AB - BACKGROUND: This study investigated the influence of human cytochrome P450 2D6 (CYP2D6) gene polymorphism in gastric cancer (GC) patients to understand the pharmacogenomic basis for patient response to postoperative fentanyl analgesia. METHODS: The prospective study design contained 212 patients recovering from radical gastrectomy. Peripheral blood samples were collected after general anesthesia, and CYP2D6 genotypes were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. After providing adequate instructions to operate the analgesia pump, patients self-administered fentanyl via patient controlled intravenous analgesia. The cumulative amount of fentanyl self-administered and the associated adverse effects were recorded at 6, 12, 24, and 48 h postoperatively. RESULTS: Five patients, out of the 212 patients recruited to this study, failed to complete the study. The remaining 207 patients were classified into three groups based on their genotypes: W/W group (n=44), M/W group (n=112), and M/M group (n=51). Our results demonstrated that the cumulative amount of fentanyl consumption significantly increased in the M/M group at 6, 12, and 24 h postoperatively, compared with the W/W group (p<0.05). In addition, visual analogue scale (VAS) score in the M/M group was significantly higher than the W/W group in the analepsia period after general anesthesia and at 6 h postoperatively (p<0.05). No significant adverse effects were observed in all the groups (p>0.05). CONCLUSION: CYP2D6 polymorphism influenced patient response to postoperative fentanyl analgesia in GC patients. PMID- 25825959 TI - Effect of motivation on academic fluency performance in survivors of pediatric medulloblastoma. AB - It has been proposed previously that extrinsic motivation may enable survivors of childhood medulloblastoma to significantly improve aspects of neurocognitive performance. In healthy populations, enhanced motivation has been shown to promote academic fluency, a domain likely more relevant to the educational outcomes of pediatric medulloblastoma survivors than academic skill development. The present study investigates the effect of enhanced extrinsic motivation on fluent (i.e., accurate and efficient) academic performance in pediatric medulloblastoma survivors. Participants were 36 children, ages 7-18, who had completed treatment for medulloblastoma. Participants completed a neuropsychological battery that included administration of equivalent tasks on Forms A and B of the Woodcock-Johnson III Tests of Achievement. Half were randomly assigned to an incentive condition prior to the administration of Form B. Provision of a performance-based incentive resulted in statistically significant improvement, but not normalization of function, in performance on measures of academic fluency. No demographic, treatment-related, academic, neuropsychological, or self-perception variables predicted response to incentive. Findings suggest that academic performance of survivors may significantly improve under highly motivating conditions. In addition to implications for educational services, this finding raises the novel possibility that decreased motivation represents an inherent neuropsychological deficit in this population and provides a rationale for further investigation of factors affecting individual differences in motivational processes. Further, by examining effort in a context where effort is not inherently suspect, present findings also significantly contribute to the debate regarding the effects of effort and motivation on neuropsychological performance. PMID- 25825960 TI - Efficacy of antenatal corticosteroids according to maternal and perinatal factors: a retrospective cohort study. AB - OBJECTIVE: The aim of this study is to evaluate the impact of multiple pregnancies, maternal obesity, and preeclampsia on the effect of antenatal steroids on neonatal respiratory distress syndrome (RDS). STUDY DESIGN: The retrospective cohort study was performed in a level III maternity ward. Population was composed of mother-infant pairs. We included inborn infants < 34 weeks gestation, hospitalized in our neonatal intensive care unit, and mothers delivering before 34 weeks gestation and hospitalized before delivery. Primary measurement outcome was RDS. RESULTS: A total of 1,173 subjects were included: 535 mothers and 638 preterm infants. Antenatal corticosteroid (ACS) doses and pulmonary surfactant doses were negatively correlated (r = -0.15, p = 0.0002). Multiple logistic regression: lower gestational age and cesarean section were significantly associated with RDS in single pregnancies (odds ratio [OR], 95% confidence interval [CI]): 2.0 (1.7-2.4) and 3.6 (1.8-7.1), respectively; only gestational age was associated with RDS in twin or higher-order pregnancies: 2.7 (1.9-4.1) and 1.8 (0.6-5.4), respectively. Preterm infants of obese women did not receive more pulmonary surfactant than other preterm infants: OR = 0.67 (0.13 1.40), neither did those born to women with hypertension or preeclampsia. CONCLUSION: More ACS doses were associated with less pulmonary surfactant doses. Cesarean section and low gestational age increased the risk of RDS, independently from ACS administration, but maternal obesity and multiple pregnancies did not. PMID- 25825961 TI - Circulating serum-derived microparticles provide novel proteomic biomarkers of spontaneous preterm birth. AB - OBJECTIVE: The purpose of this study was to determine whether the proteomic biosignature of circulating microparticles in maternal serum obtained in the second trimester could identify pregnancies that result in spontaneous preterm birth (SPTB). STUDY DESIGN: Microparticles were isolated from blinded biorepository-sourced serum samples from 48 pregnant women at 15 to 17 weeks of gestation. Microparticle proteins were extracted and analyzed using label-free liquid chromatography/mass spectrometry. Peptide features were analyzed to assess the association of specific protein patterns with subjects delivering at term (>= 37 weeks gestation; n = 24) and those experiencing SPTB (<= 34 weeks gestation; n = 24). RESULTS: We found 99 proteins that had statistically significant differences in signal intensity between term and SPTB women in both first (n = 26) and second (n = 22) singleton gestation pregnancy cohorts. Additional evaluation identified 18 biomarkers that met criteria for further priority evaluation (12 preterm, 6 term). Pathway analysis showed that differentiating SPTB biomarker proteins were predominantly associated with inflammation and cell injury, while differentiating term biomarkers were associated with cell growth and hematological parameters. CONCLUSION: This study shows for the first time that the proteomic content of serum microparticles isolated in the second trimester can identify with a high degree of accuracy pregnancies that result in SPTB. PMID- 25825963 TI - Short-term outcomes and medical and surgical interventions in infants with congenital diaphragmatic hernia. AB - OBJECTIVE: The aim of this study is to characterize medical and surgical therapies and short-term outcomes in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Retrospective analysis of CDH infants admitted to 27 children's hospitals submitting data to Children's Hospital Neonatal Database (CHND) from 2010 to 2013, stratified by gestational age, birth weight, and survival. RESULTS: A total of 572 infants were identified, 508 (89%) born >= 34 weeks' gestation and >= 2 kg. More mature infants had higher APGAR scores, shorter duration of mechanical ventilation, and were more likely to receive extracorporeal membrane oxygenation (ECMO). Overall, mortality for the cohort was 29%, with mortality lower in infants born >= 34 weeks' gestation and >= 2 kg (26 vs. 50%, p < 0.01). Nonsurvivors were more likely to receive treatment with high frequency oscillatory ventilation (HFOV), vasopressors, pulmonary vasodilators, and ECMO, and to have associated major congenital anomalies than survivors. In hospital morbidity and complications were relatively uncommon among survivors. CONCLUSION: Infants with CDH have a high risk of morbidity and mortality, and for preterm infants with CDH those risks are amplified. Patterns of respiratory and circulatory support appeared to be different for survivors. In addition to established data registries, this consortium of regional neonatal intensive care units provides a new collaborative effort to describe short-term outcomes for infants referred with CDH. PMID- 25825962 TI - Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants. AB - BACKGROUND: We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. OBJECTIVE: This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. STUDY DESIGN: The previously reported study was a multicenter, prospective cohort study of 647 infants >= 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. RESULTS: All the four definitions were associated with greater number of days on MV and days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. CONCLUSIONS: The definition using a threshold BP alone was not consistently associated with adverse short term outcomes. Using only a threshold BP to determine therapy may not improve outcomes. PMID- 25825964 TI - Effects of antenatal magnesium exposure on intestinal blood flow and outcome in preterm neonates. AB - OBJECTIVE: This study aims to investigate the effects of antenatal magnesium sulfate on intestinal blood flow in preterm neonates. STUDY DESIGN: In this prospective case-match study, 25 preterm neonates exposed to magnesium sulfate antenatally were included (study group). Overall, 25 gestational age-matched neonates who had no exposure to magnesium constituted the control group. Serial daily Doppler flow measurements of superior mesenteric artery (SMA) were performed. The time to reach full feeds, first meconium passage were assessed. Presence of feeding intolerance or necrotizing enterocolitis was recorded. RESULTS: Blood flow velocities of SMA were not different between the groups during the first five postnatal days. However, SMA blood flow showed an increasing trend in the control group unlike the study group (control group, p < 0.001; study group, p = 0.29). There was no significant difference between the two groups regarding the time to reach full feeds or first meconium passage and presence of feeding intolerance. No case of necrotizing enterocolitis was seen. CONCLUSION: Antenatal magnesium does not significantly affect intestinal blood flow, but it seems to attenuate the increasing trend of the intestinal blood flow in the early postnatal days. However, this study failed to show any impact of this finding on clinical outcomes. PMID- 25825965 TI - Patent ductus arteriosus management and outcomes in Japan and Canada: comparison of proactive and selective approaches. AB - OBJECTIVE: The aim of this study is to compare patent ductus arteriosus (PDA) management strategies and outcomes between the Neonatal Research Network of Japan (NRNJ) with proactive functional echocardiography and the Canadian Neonatal Network (CNN) with selective conventional echocardiography practice. STUDY DESIGN: Retrospective analyses examined very low-birth-weight infants admitted to the NRNJ or CNN in 2006 to 2008. Multivariable logistic regression analyses compared a composite outcome indicating a mortality or major morbidity (severe intraventricular hemorrhage, periventricular leukomalacia, severe retinopathy of prematurity, bronchopulmonary dysplasia, or necrotizing enterocolitis) between networks, according to PDA diagnosis and treatment, and tested the association between PDA treatment and the composite outcome within networks. RESULTS: PDA treatment (NRNJ:CNN) with conservative management (8%:16%), indomethacin only (77%:59%), ligation only (1%:13%), or indomethacin and ligation (14%:13%) varied significantly between networks. The composite outcome was lower in NRNJ versus CNN only among infants with PDA (odds ratio: 0.70; 95% confidence interval: 0.62 0.80). Surgical ligation was associated with higher composite outcome only in CNN (odds ratio: 1.79; 95% confidence interval: 1.40-2.28). CONCLUSION: Lower composite mortality/morbidity outcome in Japan versus Canada only among infants with PDA, and association of surgical ligation with higher mortality/morbidity only in Canada, suggest differential PDA management and ligation processes contribute to outcome variation. PMID- 25825966 TI - Adverse Impact of Maternal Cigarette Smoking on Preterm Infants: A Population Based Cohort Study. AB - OBJECTIVE: The aim of the study is to examine the impact of exposure to maternal cigarette smoking on neonatal outcomes of very preterm infants. STUDY DESIGN: A retrospective cohort study examined preterm infants (<33 weeks gestational age) admitted to the Canadian Neonatal Network centers between 2003 and 2011. Mortality and major morbidities (bronchopulmonary dysplasia, severe intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy) were compared between infants exposed and unexposed to maternal smoking during pregnancy after adjusting for confounders. RESULTS: Among 29,051 study infants, 4,053 (14%) were exposed to maternal smoking during pregnancy. Multivariable analysis revealed higher odds of grade 3 or 4 intraventricular hemorrhage or periventricular leukomalacia (adjusted odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.04-1.41) and bronchopulmonary dysplasia (adjusted OR: 1.16, 95% CI: 1.02-1.33) in the smoking group, while mortality, severe retinopathy, and necrotizing enterocolitis were not significantly different. CONCLUSION: Maternal smoking during pregnancy is associated with severe neurological injury and bronchopulmonary dysplasia in preterm infants. PMID- 25825967 TI - Hospital of Delivery and the Racial Differences in Late Preterm and Early-Term Labor Induction. AB - OBJECTIVES: To estimate the interhospital differences in induction of labor (IOL) from 34(0/7) to 38(6/7) weeks' gestation by race/ethnicity. METHODS: Women between 34 and 42 weeks' gestation during 1995 and 2009 in three states were identified using linked maternal and infant records. Women with prior cesarean delivery, premature rupture of membranes, gestational hypertension, who delivered at hospitals with < 100 annual births, or who had missing data were excluded. The outcomes were inductions at early-term (ETI: between 37(0/7) and 38(6/7) weeks') and late preterm (LPI: from 34(0/7)-36(6/7) weeks') gestations. Cox proportional hazard ratios (HR) were used to estimate the independent associations between race/ethnicity and hospital of delivery on ETI and LPI. RESULTS: A total of 6.98 million eligible women delivered at 469 hospitals. ETI and LPI occurred in 3.20 and 0.40% of women, respectively. Non-Hispanic white women (3.99%) received ETI most commonly; conversely, LPI was highest among non-Hispanic black women (0.50%). In multivariable analyses, non-Hispanic black race was protective for ETI (HR = 0.89; p < 0.01) and was a risk factor for LPI (HR = 1.26; p < 0.01) after adjusting for patient factors and the delivery hospital. CONCLUSION: Racial differences in ETI and LPI appear to be pervasive. Much of the unaccounted racial/ethnic variation remains seems secondary to within-hospital differences in selecting women for IOL. PMID- 25825968 TI - Predictive Ability of Direct Antibody Testing in Infants Born to Mothers with Rh(D) and Other Minor Red Blood Cell Antibodies. AB - OBJECTIVE: Hemolytic disease of the newborn (HDN) most commonly occurs in neonates whose mothers carry nonpassively acquired antibodies directed against red blood cell (RBC) antigens. Because affected neonates may develop severe hyperbilirubinemia, early identification of at-risk neonates is critically important. We hypothesized that use of the direct antibody test (DAT) would be of high predictive value in identifying those neonates most likely to meet treatment criteria for hyperbilirubinemia. STUDY DESIGN: We performed a retrospective chart review of all mother-infant pairs in which RBC antibodies were detected on routine prenatal screening during the current pregnancy (2011-2013). We then compared DAT results of neonates who eventually met the treatment criteria for hyperbilirubinemia with those who did not. MAIN RESULTS: Fifty-sixty neonates were born to mothers with clinically significant antibodies. The sensitivity and specificity of a positive DAT result for meeting the treatment criteria were 87.5 and 93.3%, respectively. The positive and negative predictive values were 77.8 and 96.6%, respectively. CONCLUSION: The result of a DAT, obtained in neonates of mothers with clinically relevant alloantibodies, is a specific marker with good positive predictive value for identifying those who are most likely to meet the treatment criteria for hyperbilirubinemia. PMID- 25825969 TI - Advances in connective tissue imaging: From basic discovery to translational impact. PMID- 25825970 TI - Registering 2D and 3D imaging data of bone during healing. AB - PURPOSE/AIMS OF THE STUDY: Bone's hierarchical structure can be visualized using a variety of methods. Many techniques, such as light and electron microscopy generate two-dimensional (2D) images, while micro-computed tomography (uCT) allows a direct representation of the three-dimensional (3D) structure. In addition, different methods provide complementary structural information, such as the arrangement of organic or inorganic compounds. The overall aim of the present study is to answer bone research questions by linking information of different 2D and 3D imaging techniques. A great challenge in combining different methods arises from the fact that they usually reflect different characteristics of the real structure. MATERIALS AND METHODS: We investigated bone during healing by means of uCT and a couple of 2D methods. Backscattered electron images were used to qualitatively evaluate the tissue's calcium content and served as a position map for other experimental data. Nanoindentation and X-ray scattering experiments were performed to visualize mechanical and structural properties. RESULTS: We present an approach for the registration of 2D data in a 3D uCT reference frame, where scanning electron microscopies serve as a methodic link. Backscattered electron images are perfectly suited for registration into uCT reference frames, since both show structures based on the same physical principles. We introduce specific registration tools that have been developed to perform the registration process in a semi-automatic way. CONCLUSIONS: By applying this routine, we were able to exactly locate structural information (e.g. mineral particle properties) in the 3D bone volume. In bone healing studies this will help to better understand basic formation, remodeling and mineralization processes. PMID- 25825971 TI - The roles of peroxide protective regulons in protecting Xanthomonas campestris pv. campestris from sodium hypochlorite stress. AB - The exposure of Xanthomonas campestris pv. campestris to sublethal concentrations of a sodium hypochlorite (NaOCl) solution induced the expression of genes that encode peroxide scavenging enzymes within the OxyR and OhrR regulons. Sensitivity testing in various X. campestris mutants indicated that oxyR, katA, katG, ahpC, and ohr contributed to protection against NaOCl killing. The pretreatment of X. campestris cultures with oxidants, such as hydrogen peroxide (H2O2), t-butyl hydroperoxide, and the superoxide generator menadione, protected the bacteria from lethal concentrations of NaOCl in an OxyR-dependent manner. Treating the bacteria with a low concentration of NaOCl resulted in the adaptive protection from NaOCl killing and also provided cross-protection from H2O2 killing. Taken together, the results suggest that the toxicity of NaOCl is partially mediated by the generation of peroxides and other reactive oxygen species that are removed by primary peroxide scavenging enzymes, such as catalases and AhpC, as a part of an overall strategy that protects the bacteria from the lethal effects of NaOCl. PMID- 25825972 TI - Worry and bother: factors in rural women's health decision making. AB - This exploratory study examined older rural women's health decision making. Thirty-three rural women were recruited to participate in semistructured qualitative interviews. Major themes emerged that focused on rural women's comments regarding their concerns about not worrying or bothering their children with personal health matters. Themes were discussed in the context of an ethic of care. Results suggest that it is important for mental health professionals, family physicians, social workers, and other practitioners to be aware of the sense of worry and concern for others that older rural women bring to bear in decision making about personal health issues. PMID- 25825973 TI - Embedding piezoresistive pressure sensors to obtain online pressure profiles inside fiber composite laminates. AB - The production of large and complex parts using fiber composite materials is costly due to the frequent formation of voids, porosity and waste products. By embedding different types of sensors and monitoring the process in real time, the amount of wastage can be significantly reduced. This work focuses on developing a knowledge-based method to improve and ensure complete impregnation of the fibers before initiation of the resin cure. Piezoresistive and capacitive pressure sensors were embedded in fiber composite laminates to measure the real-time the pressure values inside the laminate. A change of pressure indicates resin infusion. The sensors were placed in the laminate and the resin was infused by vacuum. The embedded piezoresistive pressure sensors were able to track the vacuum pressure in the fiber composite laminate setup, as well as the arrival of the resin at the sensor. The pressure increase due to closing the resin inlet was also measured. In contrast, the capacitive type of sensor was found to be inappropriate for measuring these quantities. The following study demonstrates real-time monitoring of pressure changes inside the fiber composite laminate, which validate the use of Darcy's law in porous media to control the resin flow during infusion. PMID- 25825974 TI - Learning to rapidly re-contact the lost plume in chemical plume tracing. AB - Maintaining contact between the robot and plume is significant in chemical plume tracing (CPT). In the time immediately following the loss of chemical detection during the process of CPT, Track-Out activities bias the robot heading relative to the upwind direction, expecting to rapidly re-contact the plume. To determine the bias angle used in the Track-Out activity, we propose an online instance based reinforcement learning method, namely virtual trail following (VTF). In VTF, action-value is generalized from recently stored instances of successful Track-Out activities. We also propose a collaborative VTF (cVTF) method, in which multiple robots store their own instances, and learn from the stored instances, in the same database. The proposed VTF and cVTF methods are compared with biased upwind surge (BUS) method, in which all Track-Out activities utilize an offline optimized universal bias angle, in an indoor environment with three different airflow fields. With respect to our experimental conditions, VTF and cVTF show stronger adaptability to different airflow environments than BUS, and furthermore, cVTF yields higher success rates and time-efficiencies than VTF. PMID- 25825975 TI - Determination of optimum viewing angles for the angular normalization of land surface temperature over vegetated surface. AB - Multi-angular observation of land surface thermal radiation is considered to be a promising method of performing the angular normalization of land surface temperature (LST) retrieved from remote sensing data. This paper focuses on an investigation of the minimum requirements of viewing angles to perform such normalizations on LST. The normally kernel-driven bi-directional reflectance distribution function (BRDF) is first extended to the thermal infrared (TIR) domain as TIR-BRDF model, and its uncertainty is shown to be less than 0.3 K when used to fit the hemispheric directional thermal radiation. A local optimum three angle combination is found and verified using the TIR-BRDF model based on two patterns: the single-point pattern and the linear-array pattern. The TIR-BRDF is applied to an airborne multi-angular dataset to retrieve LST at nadir (Te-nadir) from different viewing directions, and the results show that this model can obtain reliable Te-nadir from 3 to 4 directional observations with large angle intervals, thus corresponding to large temperature angular variations. The Te nadir is generally larger than temperature of the slant direction, with a difference of approximately 0.5~2.0 K for vegetated pixels and up to several Kelvins for non-vegetated pixels. The findings of this paper will facilitate the future development of multi-angular thermal infrared sensors. PMID- 25825976 TI - NFC internal: an indoor navigation system. AB - Indoor navigation systems have recently become a popular research field due to the lack of GPS signals indoors. Several indoors navigation systems have already been proposed in order to eliminate deficiencies; however each of them has several technical and usability limitations. In this study, we propose NFC Internal, a Near Field Communication (NFC)-based indoor navigation system, which enables users to navigate through a building or a complex by enabling a simple location update, simply by touching NFC tags those are spread around and orient users to the destination. In this paper, we initially present the system requirements, give the design details and study the viability of NFC Internal with a prototype application and a case study. Moreover, we evaluate the performance of the system and compare it with existing indoor navigation systems. It is seen that NFC Internal has considerable advantages and significant contributions to existing indoor navigation systems in terms of security and privacy, cost, performance, robustness, complexity, user preference and commercial availability. PMID- 25825977 TI - Quartz enhanced photoacoustic spectroscopy based trace gas sensors using different quartz tuning forks. AB - A sensitive trace gas sensor platform based on quartz-enhanced photoacoustic spectroscopy (QEPAS) is reported. A 1.395 MUm continuous wave (CW), distributed feedback pigtailed diode laser was used as the excitation source and H2O was selected as the target analyte. Two kinds of quartz tuning forks (QTFs) with a resonant frequency (f0) of 30.72 kHz and 38 kHz were employed for the first time as an acoustic wave transducer, respectively for QEPAS instead of a standard QTF with a f0 of 32.768 kHz. The QEPAS sensor performance using the three different QTFs was experimentally investigated and theoretically analyzed. A minimum detection limit of 5.9 ppmv and 4.3 ppmv was achieved for f0 of 32.768 kHz and 30.72 kHz, respectively. PMID- 25825978 TI - An improved electrochemical aptasensor for chloramphenicol detection based on aptamer incorporated gelatine. AB - Because of the biocompatible properties of gelatine and the good affinity of aptamers for their targets, the combination of aptamer and gelatine type B is reported as promising for the development of biosensing devices. Here, an aptamer for chloramphenicol (CAP) is mixed with different types of gelatine and dropped on the surface of disposable gold screen printed electrodes. The signal of the CAP reduction is investigated using differential pulse voltammetry. The diagnostic performance of the sensor is described and a detection limit of 1.83 * 10(-10) M is found. The selectivity and the stability of the aptasensor are studied and compared to those of other CAP sensors described in literature. PMID- 25825979 TI - On the routing protocol influence on the resilience of wireless sensor networks to jamming attacks. AB - In this work, we compare a recently proposed routing protocol, the multi-parent hierarchical (MPH) protocol, with two well-known protocols, the ad hoc on-demand distance vector (AODV) and dynamic source routing (DSR). For this purpose, we have developed a simulator, which faithfully reifies the workings of a given protocol, considering a fixed, reconfigurable ad hoc network given by the number and location of participants, and general network conditions. We consider a scenario that can be found in a large number of wireless sensor network applications, a single sink node that collects all of the information generated by the sensors. The metrics used to compare the protocols were the number of packet retransmissions, carrier sense multiple access (CSMA) inner loop retries, the number of nodes answering the queries from the coordinator (sink) node and the energy consumption. We tested the network under ordinary (without attacks) conditions (and combinations thereof) and when it is subject to different types of jamming attacks (in particular, random and reactive jamming attacks), considering several positions for the jammer. Our results report that MPH has a greater ability to tolerate such attacks than DSR and AODV, since it minimizes and encapsulates the network segment under attack. The self-configuring capabilities of MPH derived from a combination of a proactive routes update, on a periodic-time basis, and a reactive behavior provide higher resilience while offering a better performance (overhead and energy consumption) than AODV and DSR, as shown in our simulation results. PMID- 25825980 TI - Simulated lesion, human observer performance comparison between thin-section dedicated breast CT images versus computed thick-section simulated projection images of the breast. AB - The objective of this study was to compare the lesion detection performance of human observers between thin-section computed tomography images of the breast, with thick-section (>40 mm) simulated projection images of the breast. Three radiologists and six physicists each executed a two alterative force choice (2AFC) study involving simulated spherical lesions placed mathematically into breast images produced on a prototype dedicated breast CT scanner. The breast image data sets from 88 patients were used to create 352 pairs of image data. Spherical lesions with diameters of 1, 2, 3, 5, and 11 mm were simulated and adaptively positioned into 3D breast CT image data sets; the native thin section (0.33 mm) images were averaged to produce images with different slice thicknesses; average section thicknesses of 0.33, 0.71, 1.5 and 2.9 mm were representative of breast CT; the average 43 mm slice thickness served to simulate simulated projection images of the breast.The percent correct of the human observer's responses were evaluated in the 2AFC experiments. Radiologists lesion detection performance was significantly (p < 0.05) better in the case of thin section images, compared to thick section images similar to mammography, for all but the 1 mm lesion diameter lesions. For example, the average of three radiologist's performance for 3 mm diameter lesions was 92% correct for thin section breast CT images while it was 67% for the simulated projection images. A gradual reduction in observer performance was observed as the section thickness increased beyond about 1 mm. While a performance difference based on breast density was seen in both breast CT and the projection image results, the average radiologist performance using breast CT images in dense breasts outperformed the performance using simulated projection images in fatty breasts for all lesion diameters except 11 mm. The average radiologist performance outperformed that of the average physicist observer, however trends in performance were similar. Human observers demonstrate significantly better mass-lesion detection performance on thin-section CT images of the breast, compared to thick-section simulated projection images of the breast. PMID- 25825981 TI - EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF. AB - EMMPRIN/CD147 is mainly known for its protease inducing function but a role in promoting tumor angiogenesis has also been demonstrated. This study provides evidence that EMMPRIN is a new coreceptor for the VEGFR-2 tyrosine kinase receptor in both endothelial and tumor cells, as it directly interacts with it and regulates its activation by its VEGF ligand, signalling and functional consequences both in vitro and in vivo. Computational docking analyses and mutagenesis studies identified a molecular binding site in the extracellular domain of EMMPRIN located close to the cell membrane and containing the amino acids 195/199. EMMPRIN is overexpressed in cancer and hence is able to further potentiate VEGFR-2 activation, suggesting that a combinatory therapy of an antiangiogenic drug together with an inhibitor of EMMPRIN/VEGFR-2 interaction may have a greater impact on inhibiting angiogenesis and malignancy. PMID- 25825982 TI - D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. AB - Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing alpha-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting alpha-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2 hydroxyglutarate dehydrogenase (D2HGDH) increases alpha-KG and related metabolites, restores the activity of some alpha-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis. PMID- 25825983 TI - High expression of cAMP-responsive element-binding protein 1 (CREB1) is associated with metastasis, tumor stage and poor outcome in gastric cancer. AB - cAMP responsive element binding protein 1 (CREB1) has been reported to be implicated in tumor development and progression of human cancers. However, the clinical significance and regulatory mechanisms of CREB1 expression in gastric cancer remain largely unknown. In the present study, immunohistochemistry was performed to detect the expression of CREB1 protein in 185 primary gastric cancer tissues, 50 secondary lymph node metastatic foci and 50 nontumorous gastric tissues. A prognostic model combining CREB1 expression with TNM tumor stage was constructed by logistic regression analysis. Regulation of CREB1 by miRNAs was investigated by luciferase reporter assay and Western blot. It was shown that CREB1 was highly expressed and correlated with lymph node metastasis, distant metastasis and tumor stage and poor outcome in gastric cancer. The prognostic model was proven to be an independent prognosis predictor and performed better than CREB1 or tumor stage alone. CREB1 was identified as a direct target of miR 27b and miR-200b, and down-regulated by miR-27b/miR-200b. We conclude that CREB1 is a promising biomarker to predict tumor metastasis and patient outcome in gastric cancer, and the miR-27b/miR-200b-CREB1 pathway may serve as a potential molecular target for the treatment of gastric cancer. PMID- 25825984 TI - Amphiregulin enhances alpha6beta1 integrin expression and cell motility in human chondrosarcoma cells through Ras/Raf/MEK/ERK/AP-1 pathway. AB - Chondrosarcoma is a malignant tumor that produces cartilage matrix. The most lethal aspect is its metastatic property. We demonstrated that amphiregulin (AR) is significantly upregulated in highly aggressive cells. AR silencing markedly suppressed cell migration. Exogenous AR markedly increased cell migration by transactivation of alpha6beta1 integrin expression. A neutralizing alpha6beta1 integrin antibody can abolish AR-induced cell motility. Knockdown of AR inhibits metastasis of cells to the lung in vivo. Furthermore, elevated AR expression is positively correlated with alpha6beta1 integrin levels and higher grades in patients. These findings can potentially serve as biomarker and therapeutic approach for controlling chondrosarcoma metastasis. PMID- 25825985 TI - HOXB13 overexpression is an independent predictor of early PSA recurrence in prostate cancer treated by radical prostatectomy. AB - HOXB13 is a prostate cancer susceptibility gene which shows a cancer predisposing (G84E) mutation in 0.1-0.6% of males. We analyzed the prognostic impact of HOXB13 expression by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancers. Results were compared to tumor phenotype, biochemical recurrence, androgen receptor (AR) and prostate specific antigen (PSA) as well as molecular subtypes defined by ERG status and genomic deletions of 3p, 5q, 6q, and PTEN. HOXB13 immunostaining was detectable in 51.7% of 10,216 interpretable cancers and considered strong in 9.6%, moderate in 19.7% and weak in 22.3% of cases. HOXB13 expression was linked to advanced pT stage, high Gleason grade, positive lymph node status (p < 0.0001 each), high pre-operative PSA levels (p = 0.01), TMPRSS2:ERG fusion, PTEN deletions, AR expression, cell proliferation, reduced PSA expression and early PSA recurrence (p < 0.0001 each). The prognostic value of HOXB13 was independent from established parameters including Gleason, stage, nodal stage and PSA. Co-expression analysis identified a subset of tumors with high HOXB13 and AR but low PSA expression that had a particularly poor prognosis. HOXB13 appears to be a promising candidate for clinical routine tests either alone or in combination with other markers, including AR and PSA. PMID- 25825986 TI - Preventing Unintended Pregnancy: The Contraceptive CHOICE Project in Review. AB - The Contraceptive CHOICE Project (CHOICE) sought to reduce unintended pregnancies in the St. Louis Region by removing cost, education, and access barriers to highly effective contraception. CHOICE was a prospective cohort study of over 9,000 women 14-45 years of age who received tiered contraceptive counseling to increase awareness of all reversible methods available, particularly long-acting reversible contraceptive (LARC) methods. Participants were provided with contraception of their choice at no cost for 2-3 years. We studied contraceptive method choice, continuation, and population outcomes of repeat abortion and teen pregnancy. Seventy-five percent of study participants chose one of the three LARC methods (46% levonorgestrel intrauterine system, 12% copper intrauterine device, and 17% subdermal implant). LARC users reported greater continuation than non LARC users at 12 months (87% versus 57%) and 24 months (77% versus 41%). In our cohort, LARC methods were 20 times more effective than non-LARC methods. As a result, we observed a reduction in the percent of repeat abortions from 2006 to 2010 in St. Louis compared with Kansas City and nonmetropolitan Missouri and found substantial reductions in teen pregnancy, birth, and abortion (34.0, 19.4, and 9.7 per 1000 teens, respectively) compared with national rates among sexually experienced teens (158.5, 94.0, and 41.5 per 1000, respectively). Improved access to LARC methods can result in fewer unintended pregnancies and abortions and considerable cost savings to the health care system. PMID- 25825987 TI - Focused ultrasound for treatment of bone tumours. AB - PURPOSE: Focused ultrasound (FUS) is a modality with rapidly expanding applications across the field of medicine. Treatment of bone lesions with FUS including both benign and malignant tumours has been an active area of investigation. Recently, as a result of a successful phase III trial, magnetic resonance-guided FUS is now a standardised option for treatment of painful bone metastases. This report reviews the clinical applications amenable to treatment with FUS and provides background on FUS and image guidance techniques, results of clinical studies, and future directions. METHODS: A comprehensive literature search and review of abstracts presented at the recently completed fourth International Focused Ultrasound Symposium was performed. Case reports and older publications revisited in more recent studies were excluded. For clinical studies that extend beyond bone tumours, only the data regarding bone tumours are presented. RESULTS: Fifteen studies assessing the use of focused ultrasound in treatment of primary benign bone tumours, primary malignant tumours, and metastatic tumours meeting the search criteria were identified. For these clinical studies the responders group varied within 91-100%, 85-87% and 64-94%, respectively. Major complications were reported in the ranges 0%, 0-28% and 0-4% for primary benign, malignant and metastatic tumours, respectively. CONCLUSIONS: Image-guided FUS is both safe and effective in the treatment of primary and secondary tumours. Additional phase III trials are warranted to more fully define the role of FUS in treatment of both benign and malignant bone tumours. PMID- 25825988 TI - Impact of the use of an alcohol-based hand sanitizer in the home on reduction in probability of infection by respiratory and enteric viruses. AB - The goal of this study was to determine the reduction in risk of infection by viruses with the use of an alcohol-based hand sanitizer, used in addition to routine hand washing, in family members in households. A quantitative microbial risk model was used to determine the probability of infection from the concentration of virus on the hands. The model incorporated variation in hand size, frequency of touching orifices (nose, mouth, eyes), and percent transfer to the site of infection, as well as, dose-response for each virus. Data on the occurrence of virus on household members' hands from an intervention study using MS-2 coliphage was used to determine the reduction of viruses on the hands pre- and post-intervention. It was found that the risk of rhinovirus, rotavirus or norovirus infection after the intervention was reduced by 47-98% depending upon the initial concentration of virus on the hands. PMID- 25825989 TI - Efficacy of exercises to rehabilitate dysphagia: A critique of the literature. AB - PURPOSE: This review critiques the benefit of commonly used rehabilitative exercises for dysphagia. METHOD: Common goals of rehabilitation for dysphagia and principles of neuroplasticity are introduced as they apply to swallowing and non swallowing exercises. A critique of published studies is offered regarding their evidence for showing benefit from the exercise. RESULT: One of five swallow exercises had preliminary evidence for long-term benefit and two of four non swallow exercises have strong evidence for long-term benefit. CONCLUSION: Only a minority of exercises prescribed for patients with dysphagia have sufficient evidence for long-term improvement in swallowing. PMID- 25825990 TI - Pb7O(OH)3(CO3)3(BO3): first mixed borate and carbonate nonlinear optical material exhibiting large second-harmonic generation response. AB - The first borate carbonate UV nonlinear optical material Pb7O(OH)3(CO3)3(BO3) was hydrothermally synthesized, which features a (3,9)-connected IrSi3-like structure constructed by Pb7O(OH)3(BO3) units and carbonates. This compound exhibits a large second-harmonic generation (SHG) response about 4.5 times that of KH2PO4 (KDP), attributed to synergistic interactions between the stereoeffect of the Pb(II) cations and coparallel BO3 and CO3 triangles groups. PMID- 25825991 TI - Transition Flux Formula for the Electronic Coupling Matrix Element. AB - The transition flux formula for the coupling matrix element of long-distance electron transfer reactions is discussed. Here we present a new derivation which is based on the Golden Rule approach. The electronic Franck-Condon factor that appears in the multielectronic formulation of the coupling element is discussed using the concept of tunneling time. An application of the tunneling flux theory to electron transfer reactions in a model system based on the low-potential heme and high-potential heme (heme bL)/(heme bH) redox pair of ubiquinol:cytochrome c oxidoreductase complex is described; the results are compared to those obtained by measuring energy splitting of the donor/acceptor multielectronic states and the direct calculation method. PMID- 25825992 TI - Global analysis of protein folding thermodynamics for disease state characterization. AB - Current methods for the large-scale characterization of disease states generally rely on the analysis of gene and/or protein expression levels. These existing methods fail to detect proteins with disease-related functions and unaltered expression levels. Here we describe the large-scale use of thermodynamic measurements of protein folding and stability for the characterization of disease states. Using the Stable Isotope Labeling with Amino Acids in Cell Culture and Stability of Proteins from Rates of Oxidation (SILAC-SPROX) technique, we assayed ~800 proteins for protein folding and stability changes in three different cell culture models of breast cancer including the MCF-10A, MCF-7, and MDA-MB-231 cell lines. The thermodynamic stability profiles generated here created distinct molecular markers to differentiate the three cell lines, and a significant fraction (~45%) of the differentially stabilized proteins did not have altered expression levels. Thus, the differential thermodynamic profiling strategy reported here created novel molecular signatures of breast cancer and provided additional insight into the molecular basis of the disease. Our results establish the utility of protein folding and stability measurements for the study of disease processes, and they suggest that such measurements may be useful for biomarker discovery in disease. PMID- 25825994 TI - Use of video modelling to teach complex and meaningful job skills to an adult with autism spectrum disorder. AB - OBJECTIVE: To examine the effectiveness of a video modelling (VM) intervention to teach job-related telephone skills to an adult with Autism Spectrum Disorder (ASD). METHODS: A multiple baseline design across four telephone-relevant behaviours was used to assess the effects of the intervention on the participant's ability to respond to telephone calls. RESULTS: Use of the VM intervention led to immediate improvements in listening and responding to both orders and complaints; more gradual improvements were also observed in the participant's professional speech. All skill increases were maintained at follow up. CONCLUSION: VM may be an effective method of teaching complex vocational skills to adults with ASD, although a stronger focus on social skills may be warranted in the future. PMID- 25825993 TI - Expression profile of C19MC microRNAs in placental tissue in pregnancy-related complications. AB - To demonstrate that pregnancy-related complications are associated with alterations in placental microRNA expression. Gene expression of 15 C19MC microRNAs (miR-512-5p, miR-515-5p, miR-516-5p, miR-517-5p, miR-518b, miR-518f-5p, miR-519a, miR-519d, miR-519e-5p, miR-520a-5p, miR-520h, miR-524-5p, miR-525, miR 526a, and miR-526b) was assessed in placental tissues, compared between groups (21 gestational hypertension [GH], 63 preeclampsia, 36 fetal growth restriction [FGR], and 42 normal pregnancies), and correlated with the severity of the disease with respect to clinical signs, delivery date, and Doppler ultrasound parameters. The expression profile of microRNAs was different between pregnancy related complications and controls. The downregulation of 4 of 15 (miR-517-5p, miR-519d, miR-520a-5p, and miR-525), 6 of 15 (miR-517-5p, miR-518f-5p, miR-519a, miR-519d, miR-520a-5p, and miR-525), and 11 of 15 (miR-515-5p, miR-517-5p, miR 518b, miR-518f-5p, miR-519a, miR-519d, miR-520a-5p, miR-520h, miR-524-5p, miR 525, and miR-526a) microRNAs was associated with GH, FGR, and preeclampsia, respectively. Sudden onset of severe preeclampsia requiring immediate termination of gestation and mild forms of preeclampsia (persisting for several weeks) were associated with similar microRNA expression profile (downregulation of miR-517 5p, miR-520a-5p, miR-524-5p, and miR-525). In addition, miR-519a was found to be associated with severe preeclampsia. The longer the pregnancy-related disorder lasted, the more extensive was the downregulation of microRNAs (miR-515-5p, miR 518b, miR-518f-5p, miR-519d, and miR-520h). The downregulation of some C19MC microRNAs is a common phenomenon shared between GH, preeclampsia, and FGR. On the other hand, some of the C19MC microRNAs are only downregulated just in preeclampsia. PMID- 25825996 TI - Prospective associations between prosocial behavior and social dominance in early childhood: are sharers the best leaders? AB - A short-term longitudinal study during early childhood (N = 96; M = 42.80; SD = 7.57) investigated the concurrent and prospective association between prosocial behavior and social dominance. Time-intensive school-based focal child sampling with continuous recording observations of prosocial behavior to peers were conducted and teacher-reports of social dominance were collected. The study documents significant prospective links between prosocial behavior to peers and increases in social dominance over time. Social dominance was not associated with changes in prosocial behavior. The findings extend past empirical work in early childhood and future directions are discussed. PMID- 25825995 TI - Viewing Human DNA Polymerase beta Faithfully and Unfaithfully Bypass an Oxidative Lesion by Time-Dependent Crystallography. AB - One common oxidative DNA lesion, 8-oxo-7,8-dihydro-2'-deoxyguanine (8-oxoG), is highly mutagenic in vivo due to its anti-conformation forming a Watson-Crick base pair with correct deoxycytidine 5'-triphosphate (dCTP) and its syn-conformation forming a Hoogsteen base pair with incorrect deoxyadenosine 5'-triphosphate (dATP). Here, we utilized time-resolved X-ray crystallography to follow 8-oxoG bypass by human DNA polymerase beta (hPolbeta). In the 12 solved structures, both Watson-Crick (anti-8-oxoG:anti-dCTP) and Hoogsteen (syn-8-oxoG:anti-dATP) base pairing were clearly visible and were maintained throughout the chemical reaction. Additionally, a third Mg(2+) appeared during the process of phosphodiester bond formation and was located between the reacting alpha- and beta-phosphates of the dNTP, suggesting its role in stabilizing reaction intermediates. After phosphodiester bond formation, hPolbeta reopened its conformation, pyrophosphate was released, and the newly incorporated primer 3' terminal nucleotide stacked, rather than base paired, with 8-oxoG. These structures provide the first real-time pictures, to our knowledge, of how a polymerase correctly and incorrectly bypasses a DNA lesion. PMID- 25825997 TI - Laparoscopic intersphincteric resection and hand-sewn coloanal anastomosis: a natural orifice specimen extraction technique. AB - The incidence of rectal cancer in India is on the rise, and unlike in the West, predominantly younger individuals are affected. Surgery for rectal cancer has evolved over the years with the ultimate goals of sphincter preservation and better quality of life, besides oncological safety. With the routine use of magnetic resonance imaging for local staging, intersphincteric resection has become a viable alternative to abdominoperineal resection. Similarly, there is enough evidence to consider laparoscopic surgery as feasible and oncologically safe for rectal cancer. Thus laparoscopic intersphincteric resection fulfills all the objectives of modern-day rectal cancer surgery. Here we describe the technical points while performing the surgery as well as short-term results of our own series. PMID- 25825998 TI - A two-year follow-up case of chronic fatigue syndrome: substantial improvement in personality following a yoga-based lifestyle intervention. AB - BACKGROUND AND OBJECTIVE: Chronic Fatigue Syndrome (CFS) is characterized by excessive fatigue after minimal physical or mental exertion, muscle and joint pain, poor concentration, dizziness, and sleep disturbances. We report here the effect of a yoga-based lifestyle intervention in a 30-year old male patient with a documented diagnosis of CFS with compromised quality of life (QoL) and altered personality. METHODS: The patient initially attended a short-term yoga-based lifestyle intervention program that consisted of yoga-postures, breathing exercises (pranayama), meditation, group discussions, and individualized advice on stress management, diet and physical activity besides group support. Thereafter, patient attended 5 more such programs. RESULTS: There was a notable and consistent improvement in his clinical profile, positive aspects of personality and subjective well-being, and reduction in anxiety following this yoga-based lifestyle intervention. CONCLUSION: Overall, the results suggest that lifestyle intervention may improve clinical condition and personality in patients with CFS. PMID- 25825999 TI - Evaluation of 3-Ethyl-3-(phenylpiperazinylbutyl)oxindoles as PET Ligands for the Serotonin 5-HT7 Receptor: Synthesis, Pharmacology, Radiolabeling, and in Vivo Brain Imaging in Pigs. AB - We have investigated several oxindole derivatives in the pursuit of a 5-HT7 receptor PET ligand. Herein the synthesis, chiral separation, and pharmacological profiling of two possible PET candidates toward a wide selection of CNS-targets are detailed. Subsequent (11)C-labeling and in vivo evaluation in Danish landrace pigs showed that both ligands displayed high brain uptake. However, neither of the radioligands could be displaced by the 5-HT7 receptor selective inverse agonist SB-269970. PMID- 25826001 TI - Flexible one diode-one phase change memory array enabled by block copolymer self assembly. AB - Flexible memory is the fundamental component for data processing, storage, and radio frequency communication in flexible electronic systems. Among several emerging memory technologies, phase-change random-access memory (PRAM) is one of the strongest candidate for next-generation nonvolatile memories due to its remarkable merits of large cycling endurance, high speed, and excellent scalability. Although there are a few approaches for flexible phase-change memory (PCM), high reset current is the biggest obstacle for the practical operation of flexible PCM devices. In this paper, we report a flexible PCM realized by incorporating nanoinsulators derived from a Si-containing block copolymer (BCP) to significantly lower the operating current of the flexible memory formed on plastic substrate. The reduction of thermal stress by BCP nanostructures enables the reliable operation of flexible PCM devices integrated with ultrathin flexible diodes during more than 100 switching cycles and 1000 bending cycles. PMID- 25826000 TI - Genetic Analyses of HIV-1 Strains Transmitted from Mother to Child in Northern Vietnam. AB - We previously reported mother-to-child transmission of HIV-1 in nine (6.7%) of 135 children on nevirapine prophylaxis in Vietnam. In the current study, we investigated the appearance and profile of antiretroviral drug (ARV) resistance mutations, the predicted coreceptor usage, and the genetic diversity of HIV-1 strains isolated from the eight pairs of HIV-1-infected mothers and their children, who were followed up to 12 months after birth. Portions of the pol and env C2V3 regions of the HIV-1 strains were analyzed genetically. HIV-1 CRF01_AE RNA was detected in four (50%) children at delivery. Y181C, a nevirapine resistance mutation, appeared in two (25%) children 1 and 3 months after birth, respectively. No ARV resistance mutation was detected in the mothers, though three mothers were on ARV prophylaxis. Five mothers and their children harbored CCR5-tropic (R5) viruses. Two mothers harbored both R5 and CXCR4-tropic (X4) viruses, but their children harbored only R5 viruses even though the X4 viruses were dominant in the mothers. In the remaining one mother, HIV-1 RNA was not amplified and her child harbored both R5 and X4 viruses at birth, but only X4 virus 12 months after delivery. The infants' viruses were more homogeneous than their mothers' viruses (mean distance: 0.5% vs. 1.1%, respectively). This is the first molecular epidemiological study of vertical HIV-1 infections in Vietnam. These findings may provide useful knowledge for the prevention of mother-to-child transmission of HIV-1 and the antiretroviral treatment of children in Vietnam. PMID- 25826002 TI - Exercise-induced increases in cell free DNA in human plasma originate predominantly from cells of the haematopoietic lineage. AB - The role of cell free DNA (cfDNA) has been intensively discussed under various pathological conditions and after acute bouts of exercise. To date, there is still no conclusive evidence concerning the cellular origin of cfDNA and the entire mechanism leading to elevated cfDNA concentrations in human plasma and serum. Here, we investigated the cellular origin of cfDNA in sex-mismatched haematopoietic stem cell transplantation (HSCT) and liver transplantation (LT) patients by determining the relative proportion of Y-chromosomal to total nuclear cfDNA. Total nuclear cfDNA and Y-chromosomal cfDNA concentrations were determined in blood plasma before and after an incremental exercise test via quantitative real-time PCR (qPCR). Female HSCT patients showed high proportions of Y chromosomal cfDNA. Both total nuclear and Y-chromosomal cfDNA increased significantly and in a highly correlated fashion due to exercise. In male HSCT patients with female donors less than 10% of the cfDNA was of Y-chromosomal origin at any point in time and even though the total amount of cfDNA increased during exercise, no increases in Y-chromosomal DNA could be detected. The percentage of Y-chromosomal cfDNA in female LT patients with male donors was very low and levels remained unchanged during exercise. This indicates that cells not derived from the bone marrow, in this case transplanted liver cells, represented only a minor fraction of cfDNA in blood plasma and were not released during acute physical exercise. Even though many physiological conditions may be altered in transplant patients versus healthy people, our results strongly suggest that cells from the haematopoietic lineage are the main source of cfDNA released during acute bouts of exercise. PMID- 25826003 TI - Programmed DNAzyme-Triggered Dissolution of DNA-Based Hydrogels: Means for Controlled Release of Biocatalysts and for the Activation of Enzyme Cascades. AB - Acrylamide/acrylamide-modified nucleic acid copolymer chains provide building units for the construction of acrylamide-DNA hydrogels. Three different hydrogels are prepared by the cross-linking of the acrylamide-DNA chains with metal ion dependent DNAzyme sequences and their substrates. The metal ion-dependent DNAzyme sequences used in the study include the Cu(2+)-, Mg(2+)-, and Zn(2+)-dependent DNAzymes. In the presence of the respective metal ions, the substrates of the respective DNAzymes are cleaved, leading to the separation of the cross-linking units and to the dissolution of the hydrogel. The different hydrogels were loaded with a fluorophore-modified dextran or with a fluorophore-functionalized glucose oxidase. Treatment of the different hydrogels with the respective ions led to the release of the loaded dextran or the enzyme, and the rates of releasing of the loaded macromolecules followed the order of Cu(2+) > Mg(2+) > Zn(2+). Also, the different hydrogels were loaded with the enzymes beta-galactosidase (beta-Gal), glucose oxidase (GOx), or horseradish peroxidase (HRP). In the presence of the appropriate metal ions, the respective hydrogels were dissolved, resulting in the activation of the beta-Gal/GOx or GOx/HRP bienzyme cascades and of the beta Gal/GOx/HRP trienzyme cascade. PMID- 25826004 TI - Highly diastereo- and enantioselective CuH-catalyzed synthesis of 2,3 disubstituted indolines. AB - A diastereo- and enantioselective CuH-catalyzed method for the preparation of highly functionalized indolines is reported. The mild reaction conditions and high degree of functional group compatibility as demonstrated with substrates bearing heterocycles, olefins, and substituted aromatic groups, renders this technique highly valuable for the synthesis of a variety of cis-2,3-disubstituted indolines in high yield and enantioeselectivity. PMID- 25826006 TI - Automated measurement of multiple cancer biomarkers using quantum-dot-based microfluidic immunohistochemistry. AB - We report an automated multiple biomarker measurement method for tissue from cancer patients using quantum dot (QD)-based protein detection combined with reference-based protein quantification and autofluorescence (AF) removal. For multiplexed detection of biomarkers in tissue samples, visualization of QDs on cytokeratin was performed to create a multichannel microfluidic device on sites with dense populations of tumor cells. Three major breast cancer biomarkers (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) were labeled using QDs successively on cancer cells in tissue sections. For the automated measurement of biomarkers, a cytokeratin-based biomarker normalization method was used to measure the averaged expression of proteins. A novel AF-removal algorithm was developed, which normalizes the reference AF spectra reconstructed from unknown AF spectra based on random sampling. For accurate quantification of QDs, we automatically and accurately removed the AF signal from 344 spots of QD-labeled tissue samples using 240 reference AF spectra. Using analytical data with 10 tissue samples from breast cancer patients, the measured biomarker intensities were in good agreement with the results of conventional analyses. PMID- 25826007 TI - Barriers to HIV Care and Treatment Among Participants in a Public Health HIV Care Relinkage Program. AB - Improving patient retention in HIV care and use of antiretroviral therapy (ART) are key steps to improving the HIV care continuum in the US. However, contemporary quantitative data on barriers to care and treatment from population based samples of persons poorly engaged in care are sparse. We analyzed the prevalence of barriers to clinic visits, ART initiation, and ART continuation reported by 247 participants in a public health HIV care relinkage program in King County, WA. We identified participants using HIV surveillance data (N=188) and referrals from HIV/STD clinics and partner services (N=59). Participants most commonly reported insurance (50%), practical (26-34%), and financial (30%) barriers to care, despite residing in a state with essentially universal access to HIV care. Perceived lack of need for medical care was uncommon (<20%), but many participants (58%) endorsed a perceived lack of need for medication as a reason for not initiating ART. Depression and substance abuse were both highly prevalent (69% and 54%, respectively), and methamphetamine was the most commonly abused substance. Barriers to HIV care and treatment may be amenable to intervention by health department outreach in coordination with existing HIV medical and support services. PMID- 25826008 TI - Long-term stability of total RNA in RNAstable(r) as evaluated by expression microarray. AB - Storage of labile RNA in laboratories is accomplished through ultra-low freezing of the nucleic acids. This however requires expensive freezers, convenient storage, reliable electrical power, and increased shipping costs, thereby making it a less viable option. Biomatrica (San Diego, CA) has created RNAstable((r)), a stabilization reagent that is used to store RNA in a dehydrated state at room temperature (RT) and protects the RNA from degradation. Our objective was to investigate the sequence integrity and suitability of RNA when stored in RNAstable at extended time periods and at varying temperatures through use of Illumina and Agilent RNA expression microarrays. We observed in Bioanalyzer electropherograms that total RNA extracted from 293 cells stored at RT in RNAstable for 4.5 and 11.5 months is similar in quality to RNA stored at -80 degrees C. Illumina mRNA expression array QC metrics and gene expression patterns from RNAstable-protected RNA, in contrast to RNA stored without RNAstable, correlated well with those of freezer controls. Significantly, when RNA was stored in RNAstable at 45 degrees C for 4.5 months, equivalent to 22 months RT storage, RNA quality, microarray probe signal intensities, probe detection rates, and expression profiles remained similar between RNAstable-protected RNA at RT and the -80 degrees C controls. At 10.5 months, miRNA levels were compared among the storage conditions using miRNA expression arrays. Here too we found strong concordance between miRNA expression patterns when total RNA was stored in RNAstable or at -80 degrees C. Further, Bioanalyzer electrophoresis of RNAstable protected samples stored at RT for a relative total of 33 months or 50.5 months showed comparable integrity scores to those of -80 degrees C controls. We conclude that use of RNAstable holds promise as an effective stabilization reagent for total RNA and should be useful in situations where shipping and storage options are limited resources. PMID- 25826009 TI - Double Hole-Lump Interaction between Halogen Atoms. AB - In this paper a theoretical study has been carried out to investigate the nature of the unusual halogen-halogen contacts in the complexes R-X...X-R (with R = -H, Cl, -F and X = Cl, Br, I). AIM, NBO, and MEP analyses have been used to characterize X...X interactions. Formation of the unusual X...X interactions leads to a significant increase of electron charge density in the bonding region between the two halogen atoms. The geometry and stability of these complexes is mainly due to electrostatic interactions lump(X1) -> hole(X2) and lump(X2) -> hole(X1) [or equivalently [VS,min(X1) -> VS,max(X2) and VS,min(X2) -> VS,max(X1)] and the charge transfers LP(X1) -> sigma*(R-X2) and LP(X2) -> sigma*(R-X1). In other words, these findings suggest that the electrostatic interactions and the charge transfer play a substantial role in determining the optimal geometry of these complexes, as in conventional halogen bonds, even though the dispersion term is the most important attractive term for all the complexes studied here, save one. PMID- 25826010 TI - Spatial resolution in Raman spectroscopy. AB - This article is intended to set the scope of the meeting, in particular, the high spatial resolution section. PMID- 25826011 TI - A formal anti-Markovnikov hydroamination of allylic alcohols via tandem oxidation/1,4-conjugate addition/1,2-reduction using a Ru catalyst. AB - A formal anti-Markovnikov hydroamination of allylic alcohols using a Ru catalyst via tandem oxidation/1,4-conjugate addition/1,2-reduction was developed. Thus, the reaction of allylic alcohols with amines was performed in the presence of the catalyst generated from RuClH(CO)(PPh3)3 and 2,6-bis(n-butyliminomethyl)pyridine in situ to afford the corresponding gamma-amino alcohols efficiently. PMID- 25826013 TI - Synergistic effect of hybrid carbon nanotube-graphene oxide as nanoadditive enhancing the frictional properties of ionic liquids in high vacuum. AB - A remarkable synergetic effect between the graphene oxide (GO) layers and multiwalled carbon nanotubes (MWCNTs) in improving friction and wear on sliding diamond-like carbon (DLC) surfaces under high vacuum condition (10(-5) Pa) and low or high applied load is demonstrated. In tests with sliding DLC surfaces, ionic liquid solution that contains small amounts of GO and MWCNTs exhibited the lowest specific friction coefficient and wear rate under all of the sliding conditions. Optical microscope images of the wear scar of a steel ball showed that GO/MWCNT composites exhibited higher antiwear capability than individual MWCNTs and GO did. Transmission electron microscopy images of nanoadditives after friction testing showed that MWCNTs support the GO layers like pillars and prevent assembly between the GO layers. Their synergistic effect considerably enhances IL-GO/MWCNT composites. PMID- 25826012 TI - Structure-activity relationships for antibacterial to antifungal conversion of kanamycin to amphiphilic analogues. AB - Novel fungicides are urgently needed. It was recently reported that the attachment of an octyl group at the O-4" position of kanamycin B converts this antibacterial aminoglycoside into a novel antifungal agent. To elucidate the structure-activity relationship (SAR) for this phenomenon, a lead compound FG03 with a hydroxyl group replacing the 3"-NH2 group of kanamycin B was synthesized. FG03's antifungal activity and synthetic scheme inspired the synthesis of a library of kanamycin B analogues alkylated at various hydroxyl groups. SAR studies of the library revealed that for antifungal activity the O-4" position is the optimal site for attaching a linear alkyl chain and that the 3"-NH2 and 6"-OH groups of the kanamycin B parent molecule are not essential for antifungal activity. The discovery of lead compound, FG03, is an example of reviving clinically obsolete drugs like kanamycin by simple chemical modification and an alternative strategy for discovering novel antimicrobials. PMID- 25826014 TI - Palladium catalyzed vinyltrifluoromethylation of aryl halides through decarboxylative cross-coupling with 2-(trifluoromethyl)acrylic acid. AB - An efficient Pd-catalyzed stereoselective vinyltrifluoromethylation of aryl halides, through decarboxylative cross-coupling with 2-(trifluoromethyl)acrylic acid is described. The ready availability of the starting materials, the high level of functional group tolerance, and excellent E/Z selectivity make this protocol a safe and operationally convenient strategy for efficient synthesis of vinyltrifluoromethyl derivatives. PMID- 25826015 TI - Bioavailability and bioavailable forms of collagen after oral administration to rats. AB - The bioavailability and bioavailable forms of collagen after oral administration to rats were investigated in this study. The relative and absolute bioavailability of collagen were 57.8% and 49.6%, respectively, which was indirectly evaluated by the bioavailability of Hyp in collagen using a pharmacokinetic method. The amino acid profile of plasma showed that more than 63.4% of the collagen was absorbed from the intestine in the form of peptide, and there was a good linear correlation between the absorbed amount of an amino acid and its content in collagen (R(2) = 0.9225). The collagen peptides in plasma were purified by Sephadex G10 and Eclipse XDB C18 chromatography and further indentified (Ala-Asn, Ala-Hyp-Gly, Asp-Glu, Glu-Asn, Glu-Asp, Glu-Met, Gly-Pro Hyp, Leu-Hyp, Leu-Met, Phe-Gly-Asn, Pro-Gly-Leu, Pro-Leu, Ser-Gly-Met, Ser-Hyp, Ser-Pro-Gly, Tyr-Met) with UPLC-ESI-MS. These results may help to speculate about the molecular mechanism behind the physiological effects of collagen after oral administration. PMID- 25826017 TI - The Effect of Temperature on Synchronization of Brood Development of the Bopyrid Isopod Parasite Probopyrus pandalicola with Molting of Its Host, the Daggerblade Grass Shrimp Palaemonetes pugio. AB - The bopyrid isopod Probopyrus pandalicola is a hematophagous ectoparasite that sexually sterilizes some palaemonid shrimps, including female daggerblade grass shrimp Palaemonetes pugio. The reproduction of parasitic isopods is thought to occur synchronously with host molting because the brood would be unsuccessful if molting occurred before the larvae were free swimming. Temperature affects the length of the molting cycle of shrimp, and therefore may also affect the incubation time of isopod broods. The purpose of the present study was to determine the effect of temperature on brood development of the parasite and on the degree of synchronization with the molting of its host. Parasitized P. pugio were monitored daily at 2 experimental temperatures, 23 and 15 C, in temperature controlled chambers for the duration of a full parasite reproductive cycle. Developmental stage was determined by the visible coloration of the brood through the exoskeleton of the host, and was designated as egg, embryo I, embryo II, or epicaridium larvae. Temperature significantly affected median brood incubation time, which was only 11 days at 23 C, as compared to 35 days at 15 C. The final developmental stage (epicaridium larvae) was 3 times shorter at 23 C (median 3 days; n = 45) than at 15 C (median 9 days; n = 15). Temperature significantly affected the intermolt period of parasitized shrimp, which was shorter at 23 C (median 12 days) than at 15 C (median 37 days). A smaller percentage of the intermolt period elapsed between larval release and shrimp molting at 23 C (0.0%) than at 15 C (3.1%), indicating closer synchronization between host molting and parasite reproduction at the warmer temperature. At 15 C, the isopods utilized a smaller proportion of the time that was available for brood incubation during the intermolt period of their host. Brood size ranged from 391 to 4,596 young and was positively correlated with parasite and host size. Because development progressed more rapidly at 23 C, warmer temperatures could increase the prevalence of P. pandalicola. The corresponding reduction in the abundance of ovigerous grass shrimp as a result of sexual sterilization by bopyrids could adversely impact estuarine ecosystems, as grass shrimp are a crucial link in transferring energy from detritus to secondary consumers. PMID- 25826018 TI - De novo produced anti-human leukocyte antigen antibodies relation to alloimmunity in patients with chronic renal failure. AB - AIMS: Chronic renal failure causes patients to become dialysis dependent, which is exhausting for them both financially and psychologically. However, the definitive treatment of chronic renal failure is transplantation. One of the crucial factors affecting success in transplantation is the presence of anti human leukocyte antigen (HLA) antibodies in patients. HLA alloimmunization is caused by various sensitization events such as blood transfusion, pregnancy, and transplantation. In this study, different sensitization events were compared to determine the effectiveness on the panel-reactive antibody status in female solid organ transplantation candidates based upon pregnancy. RESULTS: When results were evaluated in terms of alloimmunization rates, 62.8%, 73.4%, and 14.9% of the patients were found to have blood transfusion, pregnancy, and rejection history, respectively. Three hundred twenty-six of the 444 women had had at least one pregnancy. Panel-reactive antibody (PRA) (class I and/or II)-positive rates were significantly higher among patients with pregnancy and blood transfusion history (43.7%) than patients with only pregnancy history (27.5%) and pregnancy and transplantation history (40%). While transplantation history significantly affects class II anti-HLA levels, blood transfusion raises class I levels. CONCLUSIONS: Solid organ transplantation appears to have the strongest HLA alloimmunization effect followed by pregnancy and blood transfusion, especially for class II HLA antigens. Patients who were sensitized by more than one sensitization event have a lower chance to have a solid organ transplantation. In this case, identification of donor-specific antibodies and the results of the cross-match tests play an important role both before and postrenal transplantation. PMID- 25826019 TI - Timescale separation in recurrent neural networks. AB - Supervised learning in recurrent neural networks involves two processes: the neuron activity from which gradients are estimated and the process on connection parameters induced by these measurements. A problem such algorithms must address is how to balance the relative rates of these activities so that accurate sensitivity estimates are obtained while still allowing synaptic modification to take place at a rate sufficient for learning. We show how to calculate a sufficient timescale separation between these two processes for a class of contracting neural networks. PMID- 25826020 TI - Cortical spatiotemporal dimensionality reduction for visual grouping. AB - The visual systems of many mammals, including humans, are able to integrate the geometric information of visual stimuli and perform cognitive tasks at the first stages of the cortical processing. This is thought to be the result of a combination of mechanisms, which include feature extraction at the single cell level and geometric processing by means of cell connectivity. We present a geometric model of such connectivities in the space of detected features associated with spatiotemporal visual stimuli and show how they can be used to obtain low-level object segmentation. The main idea is to define a spectral clustering procedure with anisotropic affinities over data sets consisting of embeddings of the visual stimuli into higher-dimensional spaces. Neural plausibility of the proposed arguments will be discussed. PMID- 25826021 TI - Refined Generalization Bounds of Gradient Learning over Reproducing Kernel Hilbert Spaces. AB - Gradient learning (GL), initially proposed by Mukherjee and Zhou (2006) has been proved to be a powerful tool for conducting variable selection and dimensional reduction simultaneously. This approach presents a nonparametric version of a gradient estimator with positive definite kernels without estimating the true function itself, so that the proposed version has wide applicability and allows for complex effects between predictors. In terms of theory, however, existing generalization bounds for GL depend on capacity-independent techniques, and the capacity of kernel classes cannot be characterized completely. Thus, this letter considers GL estimators that minimize the empirical convex risk. We prove generalization bounds for such estimators with rates that are faster than previous results. Moreover, we provide a novel upper bound for Rademacher chaos complexity of order two, which also plays an important role in general pairwise type estimations, including ranking and score problems. PMID- 25826022 TI - Homeostatic plasticity for single node delay-coupled reservoir computing. AB - Supplementing a differential equation with delays results in an infinite dimensional dynamical system. This property provides the basis for a reservoir computing architecture, where the recurrent neural network is replaced by a single nonlinear node, delay-coupled to itself. Instead of the spatial topology of a network, subunits in the delay-coupled reservoir are multiplexed in time along one delay span of the system. The computational power of the reservoir is contingent on this temporal multiplexing. Here, we learn optimal temporal multiplexing by means of a biologically inspired homeostatic plasticity mechanism. Plasticity acts locally and changes the distances between the subunits along the delay, depending on how responsive these subunits are to the input. After analytically deriving the learning mechanism, we illustrate its role in improving the reservoir's computational power. To this end, we investigate, first, the increase of the reservoir's memory capacity. Second, we predict a NARMA-10 time series, showing that plasticity reduces the normalized root-mean square error by more than 20%. Third, we discuss plasticity's influence on the reservoir's input-information capacity, the coupling strength between subunits, and the distribution of the readout coefficients. PMID- 25826023 TI - Charge transfer vs. dimensionality: what affects the transport properties of ferecrystals? AB - A series of ([SnSe]1+delta)m(NbSe2)2 compounds with two layers of NbSe2 separated by m bilayers of SnSe, where 1 <= m <= 20, were prepared from modulated precursors by systematically changing the number of SnSe layers in the repeating unit. A change in the c-lattice parameter of 0.579(3) nm per SnSe bilayer was observed. The thickness of the NbSe2 layer was determined to be 1.281(4) nm: twice the value of a single NbSe2 layer. HAADF-STEM images revealed the presence of extensive rotational disorder and the lack of any epitaxial relationship among the constituent layers. Two different coordination environments for the Nb in NbSe2 (trigonal prismatic and octahedral) were observed. The electrical resistivity increases and the carrier concentration decreases in the ([SnSe]1+delta)m(NbSe2)2 compounds with increasing number of SnSe bilayers. The temperature dependence of the resistivity suggests localization of carriers for higher m values. The decline in carrier concentration as a function of m implies the presence of charge transfer from SnSe to NbSe2. The transport properties of the ([SnSe]1+delta)m(NbSe2)2 compounds and the previously reported ([SnSe]1+delta)m(NbSe2)1 compounds both have unusually temperature independent resistivity compared to bulk NbSe2. Compounds with similar m/n ratios exhibit similar transport properties. Consequently, the dominant effect on the transport properties of ([SnSe]1+delta)m(NbSe2)2 is charge transfer, and there are only subtle differences between a monolayer and a bilayer of NbSe2. PMID- 25826024 TI - Titanocene(III) complexes with 2-phosphinoaryloxide ligands for the catalytic dehydrogenation of dimethylamine borane. AB - A study of the dehydrogenation of dimethylamine borane using different titanocene(III) complexes with 2-phosphinoaryloxide ligands is presented. Complexes Cp2Ti(kappa(2)-O, P-O-C6H4-PR2) (3a: R = i-Pr, 3b: R = Ph) (Cp = eta(5) cyclopentadienyl) and Cp*2Ti(kappa(1)-O-O-C6H4-PR2) (5a: R = i-Pr, 5b: R = Ph) (Cp* = eta(5)-pentamethylcyclopentadienyl) were prepared by reactions of the 2 phosphinophenol ligand with different titanocene sources and fully characterised. Their catalytic activity depends on the steric influence of the cyclopentadienyl ligand, the coordination mode of the 2-phosphinoaryloxide ligand and on the used solvent. Complex 3a showed a turnover number of 43.2 in the neat substrate after 24 hours. EPR investigations were used to elucidate the fate of the Ti(III) catalyst. PMID- 25826025 TI - [Clinical trials in Germany: the time to reduce bureaucracy has come!]. PMID- 25826026 TI - [Tumor-caused venous thromboembolism]. PMID- 25826027 TI - [Rare, but often overlooked endocrine syndromes]. PMID- 25826028 TI - [Osteoporosis in elderly]. PMID- 25826029 TI - [Chronic lymphatic leukemia]. AB - Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. Median age at diagnosis is around 70 years. To confirm the diagnosis more than 5000 B-lymphocytes/ul need to be present. The expression of the typical surface markers CD5, CD19, CD20 and CD23 has to be confirmed by flow cytometry. A bone marrow biopsy is not mandatory for the diagnosis. Before start of treatment the assessment of 17 p deletion and/or TP53-mutational status is recommended. Treatment indications include stage Binet C or signs of an active disease as rapidly progressive lymphadenopathy or organomegaly together with physical limitation, B symptoms that cannot be tolerated, rapidly deteriorating blood values, or rapidly increasing leukocyte counts (Lymphocyte doubling time less than 6 months). The patient's physical condition has major impact on the treatment decision. Currently immunochemotherapy with fludarabine, cyclophosphamide and the CD20-antibody rituximab (FCR) is the standard of care in previously untreated and physically fit patients. An alternative regimen is the combination of bendamustine and rituximab (BR) or ofatumumab. Physically compromised patients can be treated with the oral drug chlorambucil in combination with an anti-CD20 antibody. Due to high morbidity and mortality, allogeneic stem cell transplantation is limited to a small group of patients and should be discussed in a high-risk situation, such as 17 p deletion and/or TP53 mutation, lack of response to standard therapy or early relapse. Recently several new chemo-free treatment options have been introduced within clinical trials. Among them are monoclonal antibodies, most of them targeting the CD20 molecule: besides the licensed drugs rituximab and ofatumumab, obinutuzumab, in combination with chemotherapy, has recently shown high clinical efficacy in front-line treatment of elderly patients with CLL. Novel agents have been designed to block aberrant signaling from the B-cell receptor. Ibrutinib acts by inhibiting the Bruton's tyrosine kinase (BTK) while idelalisib represents a first-in-class specific inhibitor of the phosphoinositol-3 kinase (PI3K) delta isoform. Another class of drugs with potential impact for chemo-free treatment strategies in CLL is the BH3-mimetic inhibitor of the Bcl-2 family of pro-survival proteins, ABT 199. Given all these novel agents and targets, chemo-free or at least chemo reduced concepts may become reality in the near future for our patients suffering from CLL. PMID- 25826030 TI - [Postexposure prophylaxis in daily clinical practice]. AB - Postexposure prophylaxis with antiinfective medication or immunizations are common problems in daily care of out- and inpatients in Germany. We discuss the most relevant situations in adult patients, other populations (neonates, children) are not considered. PMID- 25826031 TI - [Limitations of intensive care therapy - is it always appropriate?]. PMID- 25826032 TI - [Myocardial revascularization: the new European guidelines]. AB - The updated 2014 ESC guidelines on myocardial revascularization did indeed impact on current practice. Some of the most important changes are summarized in this review. Importantly, the recommendation for dual antiplatelet therapy after stenting in stable patients was reduced to 6 months. Also, a more liberal use of PCI in left main stem disease was proposed by the ESC guideline committee. PMID- 25826033 TI - [Primary arterial hypertension - update 2015]. AB - The rate of treatment and control increased significantly in Germany during the last years. Severeal studies could demonstrate an association of sodium consumption with blood pressure. The status of renal denervation in the treatment of high blood pressure remains unclear. PMID- 25826034 TI - [Systemic sclerosis - an update]. PMID- 25826035 TI - [Therapy in pancreatic cancer - and still it moves along!]. AB - According to predictions pancreatic ductal adenocarcinoma will be the third most common cancer-related cause of death in 2030 due to its growing incidence and advances in prevention and treatment of other tumor entities. Pancreatic cancer is usually a (too) late diagnosed disease. Already at time of primary diagnosis nearly 80 % of patients have palliative disease due to local irresectability or distant metastases. Even after R0 resection of the primary tumor followed by adjuvant chemotherapy the 5-year overall survival rate does not exceed 20 %. Recently the treatment landscape has significanty changed in metastatic pancreatic cancer. For the first time, we have the opportunity to personalize our therapies in the field of pancreatic cancer. In addition, the range of therapeutic options after failure of first-line treatment expands more and more. After years of stagnation and negative results in clinical trials these advances inspire and dynamize the landscape of new clinical trials in this entity. PMID- 25826036 TI - [Unclear dermatological finding in a 35-year-old patient]. PMID- 25826037 TI - [Exfoliative esophagitis while taking dabigatran]. AB - History | A 77-year-old woman was admitted with severe chest pain, heartburn, dysphagia and odynophagia. She had been on dabigatran for 13 months due to atrial fibrillation and arterial hypertension. Investigations and findings | Endoscopy of the esophagus revealed sloughing of mucosal casts, predominantly in the upper half of the organ. Treatment and course | The patient was placed on pantoprazol, local anaesthetic antacid and i. v. fluids. Dabigatran was discontinued. The symptoms disappeared within 3 days. Control endoscopy after 12 days showed complete healing of the esophageal mucosa. Conclusion | The intake of dabigatran was associated with exfoliative esophagitis, possibly due to caustic tissue damage by prolonged drug contact. PMID- 25826038 TI - [Health care of geriatric patients with urinary incontinence]. AB - Urinary incontinence occurs frequently in geriatric patients. In the doctor's practice, the symptoms are often not mentioned by the patients; this may lead to loss of autonomy and social isolation. A screening for urinary incontinence should therefore be part of each geriatric assessment. In the presence of urinary incontinence, several treatment options are available, which need to be tailored according to the individual capabilities (mobility, motivation and cognitive performance) of the patient. Non-pharmacological treatment options, such as behavior modification, toilet training and pelvic floor training, should be exploited before any pharmacotherapy commences. If the pharmacological treatment involves the use of anticholinergic agents, the cognitive performance should be monitored. An interdisciplinary collaboration is a prerequisite for the optimized treatment and adequate health care of geriatric patients with urinary incontinence. PMID- 25826039 TI - [Developing internal medicine into systems medicine: opportunities and challenges]. PMID- 25826040 TI - [Smoking cessation - what's new?]. PMID- 25826041 TI - [Smoking cessation - what's new?--reply]. PMID- 25826042 TI - An effective and biocompatible antibiofilm coating for central venous catheter. AB - The aim of this study was to investigate the in vitro and in vivo efficacy and the tissue reaction of an antibiofilm coating composed of xylitol, triclosan, and polyhexamethylene biguanide. The antimicrobial activity was analyzed by a turbidimetric method. Scanning electron microscopy was used to evaluate the antiadherent property of central venous catheter (CVC) fragments impregnated with an antibiofilm coating (I-CVC) in comparison with noncoated CVC (NC-CVC) fragments. Two in vivo assays using subcutaneous implantation of NC-CVC and I-CVC fragments in the dorsal area of rats were performed. The first assay comprised hematological and microbiological analysis. The second assay evaluated tissue response by examining the inflammatory reactions after 7 and 21 days. The formulation displayed antimicrobial activity against all tested strains. A biofilm disaggregation with significant reduction of microorganism's adherence in I-CVC fragments was observed. In vivo antiadherence results demonstrated a reduction of early biofilm formation of Staphylococcus aureus ATCC 25923, mainly in an external surface of the I-CVC, in comparison with the NC-CVC. All animals displayed negative hemoculture. No significant tissue reaction was observed, indicating that the antibiofilm formulation could be considered biocompatible. The use of I-CVC could decrease the probability of development of localized or systemic infections. PMID- 25826043 TI - Core and peripheral criteria of video game addiction in the game addiction scale for adolescents. AB - Assessment of video game addiction often involves measurement of peripheral criteria that indicate high engagement with games, and core criteria that indicate problematic use of games. A survey of the Norwegian population aged 16 74 years (N=10,081, response rate 43.6%) was carried out in 2013, which included the Gaming Addiction Scale for Adolescents (GAS). Confirmatory factor analysis showed that a two-factor structure, which separated peripheral criteria from core criteria, fitted the data better (CFI=0.963; RMSEA=0.058) compared to the original one-factor solution where all items are determined to load only on one factor (CFI=0.905, RMSEA=0.089). This was also found when we analyzed men aged <=33 years, men aged >33 years, women aged <=33 years, and women aged >33 years separately. This indicates that the GAS measures both engagement and problems related to video games. Multi-group measurement invariance testing showed that the factor structure was valid in all four groups (configural invariance) for the two-factor structure but not for the one-factor structure. A novel approach to categorization of problem gamers and addicted gamers where only the core criteria items are used (the CORE 4 approach) was compared to the approach where all items are included (the GAS 7 approach). The current results suggest that the CORE 4 approach might be more appropriate for classification of problem gamers and addicted gamers compared to the GAS 7 approach. PMID- 25826044 TI - The Time Is Now: The Role of Pharmacotherapies in Expanding Treatment for Opioid Use Disorder. PMID- 25826045 TI - Routine EPID in-vivo dosimetry in a reference point for conformal radiotherapy treatments. AB - In-vivo dosimetry (IVD) in external beam radiotherapy is used to detect major clinically relevant differences between planned and delivered dose. Moreover, a detailed analysis of its results, when routinely reported and discussed by the radiotherapy staff, can limit the likelihood of error transmission to many treatments. A first experience of routine EPID-based IVD in a reference point has been performed in our department for 3D-CRT treatments over a three-year period. More than 14,000 images were acquired and 1287 treatment plans were verified. The IVD checks were obtained three times in the first week and then weekly. Tolerance levels of +/- 5% for pelvic-abdomen, head-neck and breast irradiations and +/- 6% for lung treatments were adopted for the in-vivo measured dose per fraction. A statistical analysis of the IVD results was performed grouping the data by: anatomical regions, treatment units, open and wedged fields and gantry angles. About 10% of the checked doses per fraction showed dosimetric discrepancies out of the tolerance levels. The causes of the discrepancies were 70% delivery or planning errors, 20% morphological changes and 10% procedural limitations. 41 cases (3.2%) have required special investigations because their in-vivo doses per fraction, averaged over the first three sessions, were out of the tolerance levels and in 19 cases (1.5%) the deviations gave rise to an intervention. Statistically significant differences of average variations between planned and delivered doses were observed for: (i) 30 degrees wedged 10 MV fields with respect to those of other wedged or open 10 MV fields delivered by two linacs, due to the incorrect TPS implementation of that wedge transmission factor; (ii) anterior-posterior and posterior-anterior beams with respect to the other gantry orientations for one linac, due to the beam attenuation introduced by the treatment couch; (iii) lateral fields with respect to medial fields of breast irradiations for all linacs, due to small systematic set-up variations. The analysis of our data shows a substantial homogeneity of the IVD results for all the considered body regions and treatment units. However, the observed discrepancies have supplied indications for taking further steps in the optimization process and in some cases to adopt an adaptive approach. PMID- 25826046 TI - Role of ankle foot orthoses in functional stability of individuals with stroke. AB - PURPOSE: Ankle foot orthoses (AFOs) are frequently prescribed to improve ambulation in individuals with stroke. However, the role of AFOs in balance control is not completely understood. The aim of the study was to evaluate the contribution of the AFOs in functional stability of individuals with stroke. METHODS: Twenty three individuals with unilateral hemiparesis due to stroke were assessed using the Functional Reach Test. The subjects performed reaches forward, left and right while standing with or without an AFO. RESULTS: When provided with AFO, individuals with stroke improved the maximal reaching distance in all the directions (p < 0.05). CONCLUSIONS: The study found that individuals with unilateral stroke clearly demonstrated improvements in functional stability when they were provided with AFOs. This outcome could be used in the optimization of balance rehabilitation of individuals with stroke. Implications for Rehabilitation Functional stability is impaired in individuals with stroke. Functional Reach Test (FRT) was used to assess the role of ankle foot orthoses (AFOs) in balance control. Individuals with stroke improved their functional stability while they were provided with AFOs. Functional Reach Test could assist clinicians in the evaluation of postural stability associated with the use of AFOs. PMID- 25826047 TI - The impact of walking speed on the effects of functional electrical stimulation for foot drop in people with multiple sclerosis. AB - PURPOSE: Functional electrical stimulation (FES) is effective in assisting people with multiple sclerosis (pwMS) with gait. Previous studies have investigated the effects of FES in pwMS with slow self-selected walking speeds (SSWS). This study reports on the effect of the Odstock Dropped Foot Stimulator (ODFS) on the speed and oxygen (O2) cost of gait in pwMS walking at a range of SSWS. METHODS: Twenty pwMS (mean age 50.4 +/- 7.3 years) currently using FES walked at their SSWS for 5 min with and without FES. O2 cost of gait was measured using a gas analysis system, and gait speed was calculated. Data were analysed for all participants, and comparisons were made between those with a SSWS < and >0.8 m/s (walking speed required for community ambulation). RESULTS: Significant improvements in the speed and O2 cost of gait were seen using FES in the group with SSWS <0.8 m/s (n = 11, p = 0.005). When participants' SSWS >0.8 m/s, no difference in gait speed was noted, and a significant increase in O2 cost of gait using FES (n = 9, p = 0.004) was noted. CONCLUSION: FES has a different effect on the speed and O2 cost of gait dependent on the SSWS of pwMS. This requires further investigation. Implications for Rehabilitation Functional electrical stimulation (FES) used for foot drop is effective in improving the speed and oxygen cost of walking in pwMS walking at SSWS <0.8 m/s. FES does not seem to have a beneficial effect on the speed and oxygen cost of walking in pwMS walking at SSWS >0.8 m/s. Further research is needed to understand the possible mechanisms involved so that FES for foot drop can be efficiently prescribed. PMID- 25826048 TI - Identifying participation needs of people with acquired brain injury in the development of a collective community smart home. AB - PURPOSE: This study explored the personalized and collective participation needs of people with acquired brain injury (ABI) living in a future shared community smart home. METHODS: An action research study was conducted with 16 persons, seven with ABI, four caregivers and five rehabilitation or smart home healthcare providers. Twelve interviews and two focus groups were conducted, audiotaped, transcribed and analyzed for content. RESULTS: Seventy personalized and 18 collective participation needs were reported related to daily and social activities. Personalized needs concerned interpersonal relationships, general organization of activities, leisure, housing, fitness and nutrition. Collective needs related mainly to housing, general organization of activities and nutrition. CONCLUSIONS: Personalized and collective participation needs of people with ABI planning to live in a community smart home are diverse and concern daily as well as social activities. Implications for Rehabilitation To meet participation needs of people with ABI, the design of smart homes must consider all categories of daily and social activities. Considering personalized and collective needs allowed identifying exclusive examples of each. As some persons with ABI had difficulty identifying their needs as well as accepting their limitations and the assistance required, rehabilitation professionals must be involved in needs identification. PMID- 25826049 TI - Early signs that predict later haemodynamically significant patent ductus arteriosus. AB - OBJECTIVE: Our aim was to determine the optimal cut-off values, sensitivity, specificity, and diagnostic power of 12 echocardiographic parameters on the second day of life to predict subsequent ductal patency. METHODS: We evaluated preterm infants, born at ?32 weeks of gestation, starting on their second day of life, and they were evaluated every other day until ductal closure or until there were clinical signs of re-opening. We measured transductal diameter; pulmonary arterial diastolic flow; retrograde aortic diastolic flow; pulsatility index of the left pulmonary artery and descending aorta; left atrium and ventricle/aortic root ratio; left ventricular output; left ventricular flow velocity time integral; mitral early/late diastolic flow; and superior caval vein diameter and flow as well as performed receiver operating curve analysis. RESULTS: Transductal diameter (>1.5 mm); pulmonary arterial diastolic flow (>25.6 cm/second); presence of retrograde aortic diastolic flow; ductal diameter by body weight (>1.07 mm/kg); left pulmonary arterial pulsatility index (?0.71); and left ventricle to aortic root ratio (>2.2) displayed high sensitivity and specificity (p0.9). Parameters with moderate sensitivity and specificity were as follows: left atrial to aortic root ratio; left ventricular output; left ventricular flow velocity time integral; and mitral early/late diastolic flow ratio (p0.05) had low diagnostic value. CONCLUSION: Left pulmonary arterial pulsatility index, left ventricle/aortic root ratio, and ductal diameter by body weight are useful adjuncts offering a broader outlook for predicting ductal patency. PMID- 25826050 TI - Structural basis for the inhibition of truncated islet amyloid polypeptide aggregation by Cu(II): insights into the bioinorganic chemistry of type II diabetes. AB - Type 2 diabetes (T2D) is one of the most common chronic diseases, affecting over 300 million people worldwide. One of the hallmarks of T2D is the presence of amyloid deposits of human islet amyloid polypeptide (IAPP) in the islets of Langerhans of pancreatic beta-cells. Recent reports indicate that Cu(II) can inhibit the aggregation of human IAPP, although the mechanism for this inhibitory effect is not clear. In this study, different spectroscopic techniques and model fragments of IAPP were employed to shed light on the structural basis for the interaction of Cu(II) with human IAPP. Our results show that Cu(II) anchors to His18 and the subsequent amide groups toward the C-terminal, forming a complex with an equatorial coordination mode 3N1O at physiological pH. Cu(II) binding to truncated IAPP at the His18 region is the key event for its inhibitory effect in amyloid aggregation. Electron paramagnetic resonance studies indicate that the monomeric Cu(II)-IAPP(15-22) complex differs significantly from Cu(II) bound to mature IAPP(15-22) fibers, suggesting that copper binding to monomeric IAPP(15 22) competes with the conformation changes needed to form beta-sheet structures, thus delaying fibril formation. A general mechanism is proposed for the inhibitory effect of copper and other imidazole-binding metal ions in IAPP amyloid formation, providing further insights into the bioinorganic chemistry of T2D. PMID- 25826051 TI - Changes of thioredoxin, oxidative stress markers, inflammation and muscle/renal damage following intensive endurance exercise. AB - Thioredoxin (TRX) is a 12 kDa protein that is induced by oxidative stress, scavenges reactive oxygen species (ROS) and modulates chemotaxis. Furthermore it is thought to play a protective role in renal ischemia/reperfusion injury. Complement 5a (C5a) is a chemotactic factor of neutrophils and is produced after ischemia/reperfusion injury in the kidney. Both TRX and C5a increase after endurance exercise. Therefore, it may be possible that TRX has an association with C5a in renal disorders and/or renal protection caused by endurance exercise. Accordingly, the aim of this study was to investigate relationships among the changes of urine levels of TRX, C5a and acute kidney injury (AKI) caused by ischemia/reperfusion, inflammatory responses, and oxidative stress following intensive endurance exercise. Also, we applied a newly-developed measurement system of neutrophil migratory activity and ROS-production by use of ex vivo hydrogel methodology with an extracellular matrix to investigate the mechanisms of muscle damage. Fourteen male triathletes participated in a duathlon race consisting of 5 km of running, 40 km of cycling and 5 km of running were recruited to the study. Venous blood and urine samples were collected before, immediately following, 1.5 h and 3 h after the race. Plasma, serum and urine were analyzed using enzyme-linked immunosorbent assays, a free radical analytical system, and the ex vivo neutrophil functional measurement system. These data were analyzed by assigning participants to damaged and minor-damage groups by the presence and absence of renal tubular epithelial cells in the urinary sediments. We found strong associations among urinary TRX, C5a, interleukin (IL)-2, IL-4, IL 8, IL-10, interferon (IFN)-gamma and monocyte chemotactic protein (MCP)-1. From the data it might be inferred that urinary TRX, MCP-1 and beta-N-acetyl-D glucosaminidase (NAG) were associated with renal tubular injury. Furthermore, TRX may be influenced by levels of IL-10, regulate chemotactic activity of C5a and IL 8, and control inflammatory progress by C5a and IL-8. In the longer duration group (minor-damage group), circulating neutrophil count, plasma concentration of myeloperoxidase (MPO) and serum concentration of myoglobin were markedly increased. In the higher intensity group (damaged group), neutrophil activation and degranulation of MPO might be inhibited, because not only was ROS production observed to be higher, but also antioxidant capacity and antiinflammatory cytokines were increased. Critically, the newlydeveloped ex vivo methodology corroborated the neutrophil activation levels in the two groups of participants. PMID- 25826052 TI - Research on acute toxicity and the behavioral effects of methanolic extract from psilocybin mushrooms and psilocin in mice. AB - The pharmacological activities and acute toxicity of the psilocin (PC) and dried residues of the crude extracts of psychotropic mushrooms were investigated in mice. The hallucinogenic substances were effectively isolated, by using methanol, from the species of Psilocybe semilanceata and Pholiotina cyanopus, that were collected in the north-east region of Poland. The chemical analysis of these extracts, which was performed by liquid chromatography with mass spectrometry detection (LC-MS), indicated the presence of psilocin and other hallucinogenic substances, including indolealkylamines and their phosphorylated analogues. When the pure psilocin or fungal extracts were used, slight differences in determined LD50 values were observed. However, the application of PC evoked the highest level of toxicity (293.07 mg/kg) compared to the activity of extracts from Ph. cyanopus and P. semilanceata, where the level of LD50 was 316.87 mg/kg and 324.37 mg/kg, respectively. Furthermore, the behavioral test, which considered the head twitching response (HTR), was used to assess the effects of the studied psychotropic factors on the serotonergic system. Both, the fungal extracts and psilocin evoked characteristic serotoninergic effects depending on the dose administered to mice, acting as an agonist/partial agonist on the serotonergic system. A dose of 200 mg/kg 5-hydroxytryptophan (5-HTP) induced spontaneous head twitching in mice (100% effect), as a result of the formation of 5 hydroxytryptamine (5-HT) in the brain. Compared to the activity of 5-HTP, the intraperitoneal administration of 1mg/kg of psilocin or hallucinogenic extracts of studied mushrooms (Ph. cyanopus and P. semilanceata) reduced the number of head-twitch responses of about 46% and 30%, respectively. In contrast, the administration of PC exhibited a reduction of about 60% in HTR numbers. PMID- 25826054 TI - Cyanobacteria and algae blooms: Review of health and environmental data from the Harmful Algal Bloom-Related Illness Surveillance System (HABISS) 2007-2011. AB - Algae and cyanobacteria are present in all aquatic environments. We do not have a good sense of the extent of human and animal exposures to cyanobacteria or their toxins, nor do we understand the public health impacts from acute exposures associated with recreational activities or chronic exposures associated with drinking water. We describe the Harmful Algal Bloom-related Illness Surveillance System (HABISS) and summarize the collected reports describing bloom events and associated adverse human and animal health events. For the period of 2007-2011, Departments of Health and/or Environment from 11 states funded by the National Center for Environmental Health (NCEH), Centers for Disease Control and Prevention contributed reports for 4534 events. For 2007, states contributed 173 reports from historical data. The states participating in the HABISS program built response capacity through targeted public outreach and prevention activities, including supporting routine cyanobacteria monitoring for public recreation waters. During 2007-2010, states used monitoring data to support196 public health advisories or beach closures. The information recorded in HABISS and the application of these data to develop a wide range of public health prevention and response activities indicate that cyanobacteria and algae blooms are an environmental public health issue that needs continuing attention. PMID- 25826053 TI - Acute cardiotoxicity evaluation of the marine biotoxins OA, DTX-1 and YTX. AB - Phycotoxins are marine toxins produced by phytoplankton that can get accumulated in filter feeding shellfish. Human intoxication episodes occur due to contaminated seafood consumption. Okadaic acid (OA) and dynophysistoxins (DTXs) are phycotoxins responsible for a severe gastrointestinal syndrome called diarrheic shellfish poisoning (DSP). Yessotoxins (YTXs) are marine toxins initially included in the DSP class but currently classified as a separated group. Food safety authorities from several countries have regulated the content of DSPs and YTXs in shellfish to protect human health. In mice, OA and YTX have been associated with ultrastructural heart damage in vivo. Therefore, this study explored the potential of OA, DTX-1 and YTX to cause acute heart toxicity. Cardiotoxicity was evaluated in vitro by measuring hERG (human eter-a-go-go gene) channel activity and in vivo using electrocardiogram (ECG) recordings and cardiac damage biomarkers. The results demonstrated that these toxins do not exert acute effects on hERG channel activity. Additionally, in vivo experiments showed that these compounds do not alter cardiac biomarkers and ECG in rats acutely. Despite the ultrastructural damage to the heart reported for these toxins, no acute alterations of heart function have been detected in vivo, suggesting a functional compensation in the short term. PMID- 25826055 TI - Harmful algal bloom characterization at ultra-high spatial and temporal resolution using small unmanned aircraft systems. AB - Harmful algal blooms (HABs) degrade water quality and produce toxins. The spatial distribution of HAbs may change rapidly due to variations wind, water currents, and population dynamics. Risk assessments, based on traditional sampling methods, are hampered by the sparseness of water sample data points, and delays between sampling and the availability of results. There is a need for local risk assessment and risk management at the spatial and temporal resolution relevant to local human and animal interactions at specific sites and times. Small, unmanned aircraft systems can gather color-infrared reflectance data at appropriate spatial and temporal resolutions, with full control over data collection timing, and short intervals between data gathering and result availability. Data can be interpreted qualitatively, or by generating a blue normalized difference vegetation index (BNDVI) that is correlated with cyanobacterial biomass densities at the water surface, as estimated using a buoyant packed cell volume (BPCV). Correlations between BNDVI and BPCV follow a logarithmic model, with r(2)-values under field conditions from 0.77 to 0.87. These methods provide valuable information that is complimentary to risk assessment data derived from traditional risk assessment methods, and could help to improve risk management at the local level. PMID- 25826057 TI - Enhanced charge-transfer emission in polyimides by cyano-groups doping. AB - Conjugated polyimides (PI) are successfully synthesized by chemical imidization through in situ silylation of diamines by the alteration of different donor acceptor monomers. A detailed photophysical characterization is performed in the monomers and different polymers in tetrahydrofuran solutions. The emission spectra of the related donor-acceptor polymers with electron withdrawing cyano groups showed broader and more intense fluorescence bands in comparison to the polymer without -CN groups. The new emission band results from the contribution of two different charge-transfer (CT) pathways: (i) An intramolecular CT (ICT) state in the donor monomers due to the presence of strong electron withdrawing CN groups, and (ii) a intramolecular CT complex (CTC) in the PI polymer between the donor-acceptor monomers, which is red-shifted and shows longer lifetime respect to the ICT of the diamine monomers. The very wide emission band is a very interesting feature for obtaining white light from UV light. PMID- 25826058 TI - Sensitive Period for the Recovery of the Response Rate of the Wind-Evoked Escape Behavior of Unilaterally Cercus-Ablated Crickets (Gryllus bimaculatus). AB - We examined the compensational recovery of the response rate (relative occurrence) of the wind-evoked escape behavior in unilaterally cercus-ablated crickets (Gryllus bimaculatus) and elucidated the existence of a sensitive period for such recovery by rearing the crickets under different conditions. In one experiment, each cricket was reared in an apparatus called a walking inducer (WI) to increase the sensory input to the remaining cercus, i.e., the self-generated wind caused by walking. In another experiment, each cricket was reared in a small plastic case separate from the outside atmosphere (wind-free: WF). In this rearing condition, the cricket did not experience self-generated wind as walking was prohibited. During the recovery period after the unilateral cercus ablation, the crickets were reared under either the WI or WF condition to investigate the role of the sensory inputs on the compensational recovery of the response rate. The compensational recovery of the response rate occurred only in the crickets reared under the WI condition during the early period after the ablation. In particular, WI rearing during the first three days after the ablation resulted in the largest compensational recovery in the response rate. In contrast, no compensational recovery was observed in the crickets reared under the WF condition during the first three days. These results suggest that a sensitive period exists in which sensory inputs from the remaining cercus affect the compensational recovery of the response rate more effectively than during other periods. PMID- 25826059 TI - HCl Treatment for Preventing Diapause Causes Ca2+ Efflux in Bombyx mori Eggs. AB - To elucidate the mechanism for preventing entry into embryonic diapause or breakdown of diapause in Bombyx mori by HCl and dimethyl sulfoxide (DMSO) treatment or a combination of cold and HCl treatment, we performed quantitative analysis of Ca2+ and Mg2+ in the chorion and egg content using inductively coupled plasma atomic emission spectrometry (ICP-AES). When diapause eggs that had been incubated at 25 degrees C for 2 days from oviposition and at 4 degrees C for an additional six days were treated with HCl solution, the amount of Ca2+ in the chorion and egg content after HCl treatment was reduced to one-seventh, as compared with the amount before treatment. In contrast, there was no change in the amount of Mg2+ with HCl treatment. The amount of Ca2+ in the HCl solution after the diapause eggs were treated increased 7.5-fold, as compared with that of eggs treated with water. Even when 17-day-old diapausing eggs were treated with HCl, which did not break diapause, the amount of Ca2+ in the chorion and egg content was reduced to one-fifth, as compared with the control. Meanwhile, changes in Ca2+ and Mg2+ contents were not observed in 12-hr-old diapause destined eggs before or after treatment with DMSO, which effectively prevents diapause. These data may suggest that Ca2+ efflux from diapause eggs by HCl is not directly associated with preventing entry into diapause or breaking of diapause. In addition, we discovered that the amount of Ca2+ in diapause-destined eggs was more than 2.4-fold larger than in non-diapause-destined eggs. PMID- 25826060 TI - Low culture temperature inhibits myogenic differentiation through mitochondrial activity. AB - A previous study by our group reported that mouse and human myoblasts fail to express myogenin and to fuse into multi-nucleate myotubes when cultured at low temperature, such as 30 degrees C, but that this activity is rescued by adding IGF-I and vitamin C to the culture medium. In the present study, we examined mitochondrial activity as a target of the inhibitory effects of the low culture temperature. It has been suggested that mitochondria regulate myogenesis. By using a mouse myoblast cell line C2C12, we demonstrate that the expression of cytochrome c oxidase subunit I (COX I), which is encoded in mitochondrial genome, increases during myogenic differentiation at the normal culture temperature (38 degrees C), but that this up-regulation is inhibited at 30 degrees C. The mitochondrial membrane potential also decreased at 30 degrees C compared to the culture at 38 degrees C. However, IGF-I and vitamin C rescued both COX I expression and mitochondrial membrane potential at 30 degrees C as promoting muscle differentiation. We also find that the rescue of mitochondrial activity by IGF-I and vitamin C at 30 degrees C occurred after the myogenin expression, which suggests that myogenin regulates mitochondrial function during myogenesis. We suggest that our low temperature-culture system may be suitable for use in studying the detailed mechanism of myogenin-related phenomena during myogenesis. PMID- 25826056 TI - Chlorotoxin: a helpful natural scorpion peptide to diagnose glioma and fight tumor invasion. AB - Chlorotoxin is a small 36 amino-acid peptide identified from the venom of the scorpion Leiurus quinquestriatus. Initially, chlorotoxin was used as a pharmacological tool to characterize chloride channels. While studying glioma specific chloride currents, it was soon discovered that chlorotoxin possesses targeting properties towards cancer cells including glioma, melanoma, small cell lung carcinoma, neuroblastoma and medulloblastoma. The investigation of the mechanism of action of chlorotoxin has been challenging because its cell surface receptor target remains under questioning since two other receptors have been claimed besides chloride channels. Efforts on chlorotoxin-based applications focused on producing analogues helpful for glioma diagnosis, imaging and treatment. These efforts are welcome since gliomas are very aggressive brain cancers, close to impossible to cure with the current therapeutic arsenal. Among all the chlorotoxin-based strategies, the most promising one to enhance patient mean survival time appears to be the use of chlorotoxin as a targeting agent for the delivery of anti-tumor agents. Finally, the discovery of chlorotoxin has led to the screening of other scorpion venoms to identify chlorotoxin-like peptides. So far several new candidates have been identified. Only detailed research and clinical investigations will tell us if they share the same anti-tumor potential as chlorotoxin. PMID- 25826061 TI - Effects of Exposure to Methyl Parathion on Egg Hatchability and Eggshell Chemical Composition in Podocnemis expansa (Testudines, Podocnemididae). AB - Eggshell evaluation may serve as an indicator of the effect of substances released in the environment, which may change eggshell shape, size, structure, and/or chemical composition. Additionally, exposure may interfere with hatching rates in contaminated eggs. The objective of this study was to better understand how exposure to the insecticide methyl parathion interferes with chemical changes in eggshells of Podocnemis expansa throughout their artificial incubation, as well as with egg hatchability. A total of 343 P. expansa eggs were collected in a natural reproduction area for the species. These eggs were transferred to and artificially incubated in the Wild Animal Teaching and Research Laboratory at Universidade Federal de Uberlandia. On the first day of artificial incubation, 0, 35, 350, and 3500 ppb of methyl parathion were incorporated to the substrate. Eggs were collected every three days for chemical analysis of eggshells. Hatchability was evaluated as the number of hatchlings in each treatment, for the eggs that were not used in the chemical analysis. Student's T-test was used for data on eggshell chemical composition, and the Binomial Test for Two Proportions was used in the hatchability analysis, at a 5% significance level. It was observed that the incorporation of methyl parathion to the substrate on the first day of artificial incubation of P. expansa eggs reduced the levels of total fat in the shells throughout their incubation, besides reducing egg hatchability. PMID- 25826062 TI - Demographic Structure and Evolutionary History of Drosophila ornatifrons (Diptera, Drosophilidae) from Atlantic Forest of Southern Brazil. AB - Drosoph1la ornatifrons of the guarani group (Diptera: Drosophilidae) is found mainly in humid areas of the Atlantic Forest biome, especially in the southern region of Brazil. Historical and contemporary fragmentation events influenced species diversity and distribution in this biome, although the role of paleoclimatic and paleogeographic events remain to be verified. The objective of the present study was to evaluate the demographic structure of D. ornatifrons from collection sites that are remnants of Atlantic Forest in southern Brazil, in order to contribute to the understanding of the processes that affected the patterns of genetic variability in this species. To achieve this goal, we sequenced 51 individuals from nine localities and 64 individuals from six localities for the mitochondrial genes Cytochrome Oxidase I and II, respectively. Our results indicate that D. ornatifrons may have experienced a demographic expansion event from the southernmost locations of its distribution, most likely from those located next to the coast and in fragments of Atlantic Forest inserted in the Pampa biome (South 2 group), towards the interior (South 1 group). This expansion probably started after the last glacial maximum, between 20,000 and 18,000 years ago, and was intensified near the Pleistocene-Holocene transition, around 12,000 years ago, when temperature started to rise. In this work we discuss how the haplotypes found barriers to gene flow and dispersal, influenced by the biogeographic pattern of Atlantic Forest. PMID- 25826063 TI - Identification of Sex Chromosomes by Means of Comparative Genomic Hybridization in a Lizard, Eremias multiocellata. AB - Eremias multiocellata is a viviparous lizard that is known to exhibit temperature dependent sex determination (TSD). Conventional Giemsa staining under light microscope examination has identified the karyotype of this species to be 2 n=36 I+2 m, with no detectable heteromorphic sex chromosomes. However, a highly differentiated female-specific chromosome, W, which is homomorphic with the Z chromosome, is found in the present study by the high-resolution cytogenetic method of comparative genomic hybridization (CGH). The results show that E. multiocellata is a viviparous lizard with both TSD and ZW heterogametic sex chromosomes. Despite the fact that a different sex ratio of male offspring was found in two populations (separated by an altitude of 1400 m) in previous incubation experiments, we demonstrate, using genomic in situ hybridization (GISH), that there is no significant chromosomal loss or acquisition between the two populations. This suggests that temperature may play a more important role in lowland populations. These results most likely indicate that E. multiocellata is transitioning between the evolutionary processes of TSD and genotypic sex determination (GSD) systems, and also give clues to the effect of TSD versus GSD in this process. PMID- 25826064 TI - Seeds Recovered from the Droppings at Latrines of the Raccoon Dog (Nyctereutes procyonoides viverrinus): The Possibility of Seed Dispersal. AB - Medium-sized carnivorous mammals are important seed dispersers of fleshy fruits. The raccoon dog (Nyctereutes procyonoides viverrinus) often feeds on fleshy fruits and forms latrines. This behavior may potentially lead to seed dispersal. To determine if this is the case, we studied 1) seed recovery in the droppings of raccoon dogs, and 2) the transportation of seeds between habitats using plastic markers in a western suburb of Tokyo, Japan. In total, 32,473 seeds of 50 plant taxa were recovered from 120 raccoon dog droppings during a year, and 95.7% of the seeds were found to be those of fleshy fruits. The species most frequently recovered were the eurya (Eurya japonica, 52.6%), the brambles (Rubus spp., 17.4%), and the black night shade (Solanum nigrum, 16.0%). A total of 7,412 plastic markers were embedded in baits at 14 bait plots and were recovered in the feces of the raccoon dogs at 22 latrines. The "transportation rates" were calculated in 50-m distance classes and found that most seeds (43.5%) were deposited within 50 m from the bait point, suggesting very short seed dispersal distances. Inter-habitat transportation was observed: 64.9% of the retrieved markers deposited in the forest were transported to other places within the forest. In contrast, almost all of the markers (99.4%) deposited in the open site were transported within the same habitat. These findings suggest that the seeds of forest plants bearing berries can be dispersed out of the forest to open areas by raccoon dogs. PMID- 25826065 TI - Histological and Histochemical Study of the Hepatopancreas of Two Estuarine Crab Species, Cyrtograpsus angulatus and Neohelice granulata (Grapsoidea, Varunidae): Influence of Environmental Salinity. AB - The aim of this study was to analyze the histology and the histochemical distribution of glycoproteins (GPs) and lipids of the hepatopancreas of Cyrtograpsus angulatus and Neohelice granulata acclimated to salinities of 10 psu (hyperregulation) and 35 psu (osmoconformation). Sections of the hepatopancreas of adult male crabs were treated with hematoxylin-eosin; Masson trichrome; Alcian Blue (pHs 2.8, 1.0, 0.5); Toluidine Blue (pHs 5.6, 4.2); periodic acid Schiff; Sudan Black and Red. At salinity 35 psu, the hepatopancreas of both species exhibited typical histological features, whereas at salinity 10 psu, detachment of the basal lamina, desquamated epithelium, disrupted brush border, loss of intercellular cohesion, hypertrophied tubular lumen, and hemolymph infiltration between cells were observed in some zones. Resorptive cells (R-cells) and vacuoles of blister-like cells (B-cells) of both species show a higher glycogen content at 35 psu than at 10 psu. At lower salinities, the cytoplasm of the different cell types evidence higher contents of carboxylated GPs in N. granulata and of su If at ed GPs in C. angulatus. At both salinities, and at the two pHs in N. granulata and at pH 5.6 in C. angulatus, the brush border, the vacuoles of B cells and the peritrophic membrane show metachromasia. R-cell vacuoles and the cytoplasm of all cell types--except for the E-cells--at all salinities in both species show abundant lipid droplets. The results of the present study contribute significant data to the histophysiology of crustacean decapods, favoring the comprehension of the complex adjustment mechanisms facing saline stress in euryhaline crabs. PMID- 25826066 TI - Shape similarities and differences in the skulls of scavenging raptors. AB - Feeding adaptations are a conspicuous feature of avian evolution. Bill and cranial shape as well as the jaw muscles are closely related to diet choice and feeding behaviors. Diurnal raptors of Falconiformes exhibit a wide range of foraging behaviors and prey preferences, and are assigned to seven dietary groups in this study. Skulls of 156 species are compared from the dorsal, lateral and ventral views, by using geometric morphometric techniques with those landmarks capturing as much information as possible on the overall shape of cranium, bill, orbits, nostrils and attachment area for different jaw muscles. The morphometric data showed that the skull shape of scavengers differ significantly from other raptors, primarily because of different feeding adaptations. As a result of convergent evolution, different scavengers share generalized common morphology, possessing relatively slender and lower skulls, longer bills, smaller and more sideward orbits, and more caudally positioned quadrates. Significant phylogenetic signals suggested that phylogeny also played important role in shape variation within scavengers. New World vultures can be distinguished by their large nostrils, narrow crania and small orbits; Caracaras typically show large palatines, crania and orbits, as well as short, deep and sharp bill. PMID- 25826067 TI - Preliminary Analysis of Phylogenetic Relationships of the Asian-Pacific Endemial Subterranean Amphipod Genus Pseudocrangonyx Among Families and Genera of Crangonyctoidean Amphipods Inferred by Partial LSU rDNA Gene Sequences. AB - To analyze the phylogenetic relationships of the genus Pseudocrangonyx within the superfamily Crangonyctoidea, we sequenced a partial LSU rDNA gene from four species (six specimens). The monophyly of Pseudocrangonyx and its affinity to Crymostygius were strongly supported by four reconstruction methods: neighbor joining, minimum evolution, maximum-likelihood, and Bayesian inference. Current geographical distributions of the taxa studied and their phylogenetic relationships established in our study suggest that members of Pseudocrangonyctidae and Crymostygius diverged from a common Crangonyx-like ancestor in the Arctic Basin region of the northern hemisphere. PMID- 25826068 TI - Environmental Factors Affecting Pupation Decision in the Horned Flour Beetle Gnatocerus cornutus. AB - Social environments often affect the development of organisms. In Tenebrionidae beetles, larval development can be arrested at the final instar stage in the presence of conspecific larvae. This developmental plasticity is considered to be an anti-cannibalistic strategy but the critical environmental determinants and actual effects remain to be elucidated. In this study, we examined the effects of the heterospecific environment, conspecific sexual environment (i.e., presence of conspecific male or female), and abiotic physical stimulation on the pupation decision of the sexually dimorphic horned-flour beetle Gnatocerus cornutus. Additionally, actual anti-cannibalistic or antipredatory effects of developmental arrest were evaluated by analyzing stage-dependent vulnerabilities. When G. cornutus larvae were maintained with a G. cornutus larva, a G. cornutus adult, or T. castaneum adult, the developmental period up to the prepupal stage was significantly elongated, suggesting that the cue is not species-specific. Sexual environment did not affect the timing of pupation in G. cornutus; however, we found that abiotic tactile stimulations by glass beads could repress pupation. We also discovered that prepupal and pupal stages were more vulnerable to cannibalism and predation than the larval stage. These data suggest that G. cornutus larvae use non-species specific tactile stimulation as a decision cue for pupation and it has broader defensive effects against heterospecific predation as well as conspecific cannibalism. PMID- 25826069 TI - Histological Description of Gonadal Development of Females and Males of Callinectes sapidus Rathbun, 1896 (Decapoda: Portunidae). AB - This paper describes the characteristics of male and female germ cells during gonadal development and the gonadal maturity scale of the blue crab, Callinectes sapidus. A total of 20 specimens were collected monthly from June to November 2012, in two areas off the coast of the Gulf of Mexico: the San Andres Lagoon and Alvarado Lagoon. The gonads were removed and processed following the standard technique of hematoxylin and eosin staining. An important event in oogenesis (pre vitellogenesis) was the appearance of a perinuclear vesicle in the cytoplasm and the accumulation of yolk granules. Later, vitellogenesis began and there was an accumulation of nutritive droplets and fragmentation of the perinuclear vesicle. During spermatogenesis, the accumulation of two fluids was observed that were involved in the formation of the spermatophore and the delay of spermiogenesis. Based on the histological features of gonad maturity, five stages were described (inactive, early gametogenesis, development, maturity, and resorption), in females and males. This proposal can be useful for the study of reproductive seasonality of this species. PMID- 25826070 TI - First record of association of copepods with highly venomous box jellyfish Chironex, with description of new species of Paramacrochiron (Cyclopoida: Macrochironidae). AB - Paramacrochiron chironecicola n. sp. (Copepoda: Cyclopoida: Macrochironidae) is described from the highly venomous box jellyfish Chironex sp. collected from Malampaya Sound, Palawan Island, The Philippines. This is the first record of copepods associated with cubozoan medusae, although other cnidarian groups such scyphozoans, hydrozoans, and anthozoans are common hosts for symbiotic copepods. The infection sites were on the subumbrella, pedalium, and rhopalium, but also rarely on the adradial furrow. The new species is distinguished from other congeners by a combination of the following features: (1) the fifth pedigerous somite dorsally covering the anterior part of the female genital double-somite; (2) the fine structures of the antenna (relative lengths of segments) and maxilliped (positions of terminal elements) of the female; (3) the relatively long outer spines on the exopodal segments of legs 1-4; (4) the relatively long and thick female leg 5 bearing a long protopodal seta which reaches to the distal margin of the exopod; (5) the relatively short caudal ramus in the female; and (6) the plump prosome and short urosome in the male. Since members of the genus typically parasitize scyphozoans, especially rhizostomes, the association of this parasitic copepod on cubozoans may reflect the relatively close phylogenetic relationship between cubozoans and scyphozoans. PMID- 25826071 TI - A new tree frog of the genus Gracixalus from Thailand (Amphibia: Rhacophoridae). AB - We report a new tree frog of the genus Gracixalus from western Thailand and describe it as a new species Gracixalus seesom based on results of morphological and molecular analyses. The new species is a small-sized Gracixalus (male snout vent length ca. 22 mm) and is morphologically similar to G. gracilipes, but is easily distinguished from it by its dorsal tan color in life, absence of white spot on lower lip, and black markings on its foot webbing. The new species also clearly differs from all the other members of the genus by the combination of small body size, triangular snout, and light yellowish brown dorsum without distinct tuberculations. Problems of phylogeny and taxonomy of the genus Gracixalus are briefly discussed. PMID- 25826072 TI - The oldest post-Palaeozoic Crinoid and Permian-Triassic origins of the Articulata (Echinodermata). AB - The Crinoidea are the most primitive class of living echinoderms, and suffered a severe crisis during the Late Permian mass extinction event. All post-Palaeozoic crinoids, including living species, belong to the Articulata, and morphological and recent molecular studies demonstrate that they form a monophyletic clade. The Articulata originated from Palaeozoic cladid crinoids, but the nature and timing of their origination remains obscure. Problems with understanding the origin and early evolution of the Articulata have arisen because the Permian-Triassic crinoid fossil record is particularly poor. We report on a new genus and species from the earliest Triassic, which is the oldest known post-Palaeozoic articulate crinoid and fundamentally alters our understanding of the early evolution of the Articulata. Prior to this study, the most primitive post-Palaeozoic articulate was thought to be Holocrinus of the order Isocrinida. Unexpectedly, the new taxon belongs to the order Encrinida, which reveals a previously hidden diversity of crinoids in the earliest Triassic. Its discovery implies either a dramatic radiation of crinoids in the immediate post-extinction aftermath, when environmental conditions were at their most severe, or a pre-extinction origin of the crown group articulates and survival of multiple lineages. PMID- 25826073 TI - Interfacing living cells and spherically supported bilayer lipid membranes. AB - Spherically supported bilayer lipid membranes (SS-BLMs) exhibiting co-existing membrane microdomains were created on spherical silica substrates. These 5 MUm SiO2-core SS-BLMs are shown to interact dynamically when interfaced with living cells in culture, while keeping the membrane structure and lipid domains on the SS-BLM surface intact. Interactions between the SS-BLMs and cellular components are examined via correlating fluorescently labeled co-existing microdomains on the SS-BLMs, their chemical composition and biophysical properties with the consequent organization of cell membrane lipids, proteins, and other cellular components. This approach is demonstrated in a proof-of-concept experiment involving the dynamic organization of cellular cytoskeleton, monitored as a function of the lipid domains of the SS-BLMs. The compositional versatility of SS BLMs provides a means to address the relationship between the phenomenon of lipid phase separation and the other contributors to cell membrane lateral heterogeneity. PMID- 25826074 TI - Abiotic regioselective phosphorylation of adenosine with borate in formamide. AB - Nearly 40 years ago, Schoffstall and his coworkers used formamide as a solvent to permit the phosphorylation of nucleosides by inorganic phosphate to give nucleoside phosphates, which (due to their thermodynamic instability with respect to hydrolysis) cannot be easily created in water by an analogous phosphorylation (the "water problem" in prebiotic chemistry). More recently, we showed that borate could stabilize certain carbohydrates against degradation (the "asphalt problem"). Here, we combine the two concepts to show that borate can work in formamide to guide the reactivity of nucleosides under conditions where they are phosphorylated. Specifically, reaction of adenosine in formamide with inorganic phosphate and pyrophosphate in the presence of borate gives adenosine-5' phosphate as the only detectable phosphorylated product, with formylation (as opposed to hydrolysis) being the competing reaction. PMID- 25826075 TI - Synchronous occurrence of gastrointestinal stromal tumors and other digestive tract malignancies in the elderly. AB - BACKGROUND/AIMS: Elderly patients with gastrointestinal stromal tumors (GISTs) synchronous with other digestive tract malignancies have been rarely reported. In this study, clinicopathological characteristics were evaluated among elderly patients with GISTs with or without coexisting digestive tract malignancies. METHODS: A total of 161 patients (>=65 years) were retrospectively reviewed at the West China Hospital, Sichuan University from January 2009 to June 2014. RESULTS: Sixty-one patients were diagnosed with synchronous digestive tract malignancies (synchronous group), whereas 100 patients were diagnosed with no synchronous condition (no-synchronous group). The synchronous group exhibited a higher percentage of males (70.49% vs. 53.00%, P = 0.028) and poorer Eastern Cooperative Oncology Group performance status than the no-synchronous group (P = 0.029). The three-year overall survival (OS) rate was significantly lower among patients with synchronous digestive tract malignancies than that among patients without synchronous condition (64.5% vs. 84.0%, P = 0.003). Multivariate analysis showed that the presence of synchronous digestive tract malignancies (P = 0.002), co-morbidity (P = 0.004), and mitotic count >=10 mitoses/50 high power fields (P = 0.012) were associated with poor OS. CONCLUSIONS: A synchronous condition with other digestive tract malignancies is common in elderly patients with GISTs. OS primarily depends on synchronous digestive tract malignancies, mitotic count, and co-morbidity. PMID- 25826076 TI - Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine. AB - Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122 silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset. PMID- 25826077 TI - FLT3-ITD confers resistance to the PI3K/Akt pathway inhibitors by protecting the mTOR/4EBP1/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia. AB - FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former associated with poor prognosis. Here, we show that the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 induced apoptosis through the mitochondria-mediated intrinsic pathway more efficiently in hematopoietic 32D cells driven by FLT3-TKD (32D/TKD) than FLT3-ITD (32D/ITD), which robustly activated STAT5. The resistance to GDC-0941 and MK-2206 was gained by expression of the constitutively activated STAT5 mutant STAT5A1*6 in 32D/TKD cells, while it was abrogated by the STAT5 inhibitor pimozide in 32D/ITD cells or FLT3-ITD-expressing human leukemic MV4-11 cells. GDC-0941 or MK-2206 induced dephosphorylation of 4EBP1 more conspicuously in 32D/TKD than in 32D/ITD, which was prevented or augmented by STAT5A1*6 or pimozide, respectively, and correlated with downregulation of the eIF4E/eIF4G complex formation and Mcl-1 expression. Furthermore, exogenous expression of Mcl-1 endowed resistance to GDC-0941 and MK 2206 on 32D/TKD cells. Finally, it was confirmed in primary AML cells with FLT3 ITD that pimozide enhanced 4EBP1 dephosphorylation and Mcl-1 downregulation to augment cytotoxicity of GDC-0941. These data suggest that the robust STAT5 activation by FLT3-ITD protects cells treated with the PI3K/Akt pathway inhibitors from apoptosis by maintaining Mcl-1 expression through the mTORC1/4EBP1/eIF4E pathway. PMID- 25826078 TI - Mer receptor tyrosine kinase is frequently overexpressed in human non-small cell lung cancer, confirming resistance to erlotinib. AB - Mer is a receptor tyrosine kinase (RTK) with oncogenic properties that is often overexpressed or activated in various malignancies. Using both immunohistochemistry and microarray analyses, we demonstrated that Mer was overexpressed in both tumoral and stromal compartments of about 70% of non-small cell lung cancer (NSCLC) samples relative to surrounding normal lung tissue. This was validated in freshly harvested NSCLC samples; however, no associations were found between Mer expression and patient features. Although Mer overexpression did not render normal lung epithelial cell tumorigenic in vivo, it promoted the in vitro cell proliferation, clonogenic colony formation and migration of normal lung epithelial cells as well as NSCLC cells primarily depending on MAPK and FAK signaling, respectively. Importantly, Mer overexpression induced resistance to erlotinib (EGFR inhibitor) in otherwise erlotinib-sensitive cells. Furthermore, Mer-specific inhibitor rendered erlotinib-resistant cells sensitive to erlotinib. We conclude that Mer enhances malignant phenotype and pharmacological inhibition of Mer overcomes resistance of NSCLC to EGFR-targeted agents. PMID- 25826079 TI - Prognostic value of receptor conversion after neoadjuvant chemotherapy in breast cancer patients: a prospective observational study. AB - The hormone receptor (HR) status and human epidermal growth hormone receptor 2 (HER2) status of patients with breast cancer may change following neoadjuvant chemotherapy (NCT). This prospective observational study aimed to evaluate the prognostic impact of receptor conversion in breast cancer patients treated with NCT.Of the 423 consecutive patients who had residual disease in the breast after NCT, 55 (13.0%) changed from HR (+) to HR (-), 23 (5.4%) changed from HR (-) to HR (+), 27 (6.4%) changed from HER2 (+) to HER2 (-), and 13 (3.1%) changed from HER2 (-) to HER2 (+). A total of 54 (12.8%) changed to the triple-negative (TN) tumor phenotype. The loss of HR positivity was an independent prognostic factor for worse disease-free survival (DFS) and worse overall survival (OS) in multivariate survival analysis. Furthermore, the switch to the TN phenotype after NCT was another independent prognostic factor for worse survival for both DFS and OS. In conclusion, patients with breast cancer may experience changes in HR status, HER2 status and tumor phenotype after NCT. The loss of HR positivity and the switch to the TN phenotype after NCT were associated with a worse patient outcome. PMID- 25826080 TI - Increased liver carcinogenesis and enrichment of stem cell properties in livers of Dickkopf 2 (Dkk2) deleted mice. AB - Dkk2 a antagonist of the Wnt/beta-catenin-signaling pathway was shown to be silenced in diverse cancers. More recent data indicate that Dkk family members may also possess functions independent of Wnt-signaling during carcinogenesis. The detailed biological function of Dkks and its relevance for liver cancer is unknown. We analyzed the effects of a genetic deletion of Dkk2 (Dkk2-/-) in a hepatocarcinogenesis model using DEN/Phenobarbital. Untreated Dkk2-/- animals, showed considerable atypia with variation of hepatocyte size and chromatin density. In livers of Dkk2-/- mice nodule formation was seen at 9 months of age with focal loss of trabecular architecture and atypical hepatocytes and after DEN induction Dkk2-/- mice developed significantly more liver tumors compared to controls. Whole transcriptome analysis of untreated Dkk2-/- liver tissue revealed a Dkk2-dependent genetic network involving Wnt/beta-Catenin but also multiple additional oncogenic factors, such as e.g. Pdgf-b, Gdf-15 and Hnf4a. Dkk2-/- tumor cells showed a significant deregulation of stemness genes associated with enhanced colony forming properties. Integration of the Dkk2-/- signature into human data was strongly associated with patients survival. Dkk2 deletion results in alterations of liver morphology leading to an increased frequency of liver cancer. The associated genetic changes included factors not primarily related to Wnt/beta-Catenin-signaling and correlated with the clinical outcome of HCC patients. PMID- 25826081 TI - Integrated genomic analysis identifies subclasses and prognosis signatures of kidney cancer. AB - PURPOSE: To define robust miRNA-based molecular classifiers for human clear cell renal cell carcinoma (ccRCC) subgrouping and prognostication. EXPERIMENTAL DESIGN: Multidimensional data of over 500 clear cell renal cell carcinoma (ccRCC) patients were retrieved from The Cancer Genome Atlas (TCGA) archive. Data analysis was based on a novel computational approach that selectively considers patients with extreme expression values of miRNAs to detect survival-associated molecular signatures. RESULTS: Our in silico analysis unveiled a novel ccRCC specific 5-miRNA (miR-10b, miR-21, miR-143, miR-183, and miR-192) signature able, when combined with information from conventional TNM staging and the age of the patient, to prognosticate ccRCC outcome more accurately than known ccRCC miRNA signatures or TNM staging alone. Furthermore, our approach revealed the existence of 6 distinct subgroups of ccRCC characterized by discrete differences in overall survival, tumor stage, and mutational spectra in key ccRCC tumor suppressor genes. It also demonstrated that BAP1 mutations correlate with tumor progression rather than overall survival. CONCLUSION: Integrated analysis of multidimensional data from the TCGA archive allowed to draw a portrait of distinct molecular subclasses of human ccRCC and to define signatures for prognosticating disease outcome. Together, these results offer new prospects for more accurate stratification and prognostication of ccRCC. PMID- 25826082 TI - HPV16 E5 deregulates the autophagic process in human keratinocytes. AB - Autophagy plays key roles during host defense against pathogens, but viruses have evolved strategies to block the process or to exploit it for replication and successful infection. The E5 oncoprotein of human papillomavirus type 16 (HPV16 E5) perturbs epithelial homeostasis down-regulating the expression of the keratinocyte growth factor receptor (KGFR/FGFR2b), whose signaling induces autophagy. Here we investigated the possible effects of 16E5 on autophagy in human keratinocytes expressing the viral protein. The 16E5 presence strongly inhibited the autophagic process, while forced expression and activation of KGFR counteracted this effect, demonstrating that the viral protein and the receptor exert opposite and interplaying roles not only on epithelial differentiation, but also in the control of autophagy. In W12 cells, silencing of the 16E5 gene in the context of the viral full length genome confirmed its role on autophagy inhibition. Finally, molecular approaches showed that the viral protein interferes with the transcriptional regulation of autophagy also through the impairment of p53 function, indicating that 16E5 uses parallel mechanisms for autophagy impairment. Overall our results further support the hypothesis that a transcriptional crosstalk among 16E5 and KGFR might be the crucial molecular driver of epithelial deregulation during early steps of HPV infection and transformation. PMID- 25826083 TI - PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis. AB - Autophagy plays a critical role in the progression of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Protein tyrosine phosphatase receptor type O (PTPRO) was recently identified as a tumor suppressor, but little is known about its role in NASH. Here, we investigated the role of PTPRO-dependent autophagy in insulin resistance, lipid metabolism, and hepatocarcinogenesis. Wild-type (WT) and ptpro-/- mice were fed a high-fat diet (HFD) for another 16 weeks after diethylnitrosamine (DEN) injection to induce NASH. Ptpro-/- mice exhibited severe liver injury, insulin resistance, hepatosteatosis and autophagy deficiency compared with WT littermates. PTPRO deletion also promoted the induction of lipogenic target genes and decreases in beta-oxidation-related genes. Increased activation of AKT and accumulation of cytoplasmic p53 was detected in ptpro-/- mice, which in combination repressed autophagy. Intriguingly, hyperinsulinemia involving AKT activation was also exacerbated in HFD-fed mice due to PTPRO deletion. Activation of AKT induced stabilization of the MDMX/MDM2 heterocomplex, thus promoting p53 accumulation in the cytoplasm. Inhibition of AKT restored autophagy and p53 accumulation in hepatocytes, indicating that AKT acts upstream of p53. Due to hyperinsulinemia and autophagy deficiency, a HFD could aggravate steatohepatitis in ptpro-/- mice. Importantly, the expression of PTPRO was much decreased in human steatohepatitis, which was associated with increased p62 accumulation. Together, these data indicate that PTPRO regulates insulin and lipid metabolism via the PI3K/Akt/MDM4/MDM2/P53 axis by affecting autophagy. PMID- 25826084 TI - Expression and clinicopathological significance of FSIP1 in breast cancer. AB - AIM: To investigate the clinicopathological significance of the expression of fibrous sheath interacting protein 1 (FSIP1) in breast cancer, serum samples, and wound fluid from patients with breast cancer. METHODS: Wound fluid and serum samples from female patients with primary breast cancer, recurrent and metastatic breast cancer, and benign tumors were analyzed for FSIP1 expression using ELISA. 286 paraffin-embedded surgical specimens from breast cancer patients with at least 5 years of follow-up were included for FSIP1 expression assay using immunohistochemistry. RESULTS: Expression of FSIP1 protein was significantly higher in breast cancer tissues compared to tumor-adjacent tissues (p = 0.001). Strong correlation was observed between FSIP1 expression and human epidermal growth factor receptor 2 (Her-2) or Ki67 expression in breast cancer (p = 0.027 and 0.002, respectively). Similarly, serum level of FSIP1 was higher in patients with recurrent and metastatic breast cancer compared to that of primary breast cancer (7, 713 +/- 3, 065 vs. 4, 713 +/- 3, 065 pg/ml, p = 0.003). Finally, patients with high FSIP1 expression showed a worse post-operative disease specific survival (p = 0.024). CONCLUSION: FSIP1 may play an important role in the tumorigenesis and invasion of breast cancer and is a potential biomarker for breast cancer diagnosis or prognosis. PMID- 25826085 TI - Dysregulation of the miR-34a-SIRT1 axis inhibits breast cancer stemness. AB - Enforced expression of miR-34a eliminates cancer stem cells in some malignant tumors. Sirtuin-1 (SIRT1) is a direct target of miR-34a. Here we found low levels of miR-34a and high levels of SIRT1 in CD44+/CD24- breast cancer stem cells (BCSCs). MiR-34a overexpression and knockdown of SIRT1 decreased proportion of BSCSs and mammosphere formation. Expression of CSC markers, ALDH1, BMI1 and Nanog was decreased. In nude mice xenografts, stable expression of miR-34a and silencing of SIRT1 reduced tumor burden. Taken together, our results demonstrated that miR-34a inhibits proliferative potential of BCSCs in vitro and in vivo, at least partially by downregulating SIRT1. The miR-34a-SIRT1 axis may play role in self-renewal of BCSCs. PMID- 25826086 TI - The stromal genome heterogeneity between breast and prostate tumors revealed by a comparative transcriptomic analysis. AB - Stromal microenvironment increases tumor cell survival, proliferation and migration, and promotes angiogenesis. In order to provide comprehensive information on the stromal heterogeneity of diverse tumors, here we employed the microarray datasets of human invasive breast and prostate cancer-associated stromals and applied Gene Set Enrichment Analysis (GSEA) to compare the gene expression profiles between them. As a result, 8 up-regulated pathways and 73 down-regulated pathways were identified in the breast tumor stroma, while 32 up regulated pathways and 18 down-regulated pathways were identified in the prostate tumor stroma. Only 9 pathways such as tryptophan metabolism were commonly up or down regulated, but most of them (including ABC transporters) were specific for these two tumors. Several essential tumors stromal marker genes were also significantly identified. For example, CDH3 was significantly up-regulated in the stromals of both breast and prostate tumors, however EGFR was only significantly down-regulated in the stromal of breast tumor. Our study would be helpful for future therapeutic and predictive applications in breast and prostate cancers. PMID- 25826088 TI - Paxillin promotes colorectal tumor invasion and poor patient outcomes via ERK mediated stabilization of Bcl-2 protein by phosphorylation at Serine 87. AB - Stabilization of Bcl-2 protein by paxillin (PXN)-mediated ERK activation was recently reported to cause an unfavorable response to 5-Fluorouracil-based chemotherapy. Here, we present evidence from cell and animal models to demonstrate that stabilization of Bcl-2 protein by phosphorylation at Serine 87 (pBcl-2-S87) via PXN-mediated ERK activation is responsible for cancer cell invasiveness and occurs via upregulation of MMP2 expression. Immunostainings of 190 tumors resected from colorectal cancer patients indicated that PXN expression was positively correlated with Bcl-2, pBcl-2-S87, and MMP2 expression. A positive correlation of pBcl-2-S87 with Bcl-2 and MMP2 was also observed in this study population. Patients with high PXN, Bcl-2, pBcl-2-S87, and MMP2 had poor overall survival (OS) and shorter relapse free survival (RFS). In conclusion, PXN promotes Bcl-2 phosphorylation at Serine 87 via PXN-mediated ERK activation, and its stabilization associated with increased tumor formation efficacy in mice and poor patient outcome in colorectal cancer patients. PMID- 25826087 TI - Antibody and lectin target podoplanin to inhibit oral squamous carcinoma cell migration and viability by distinct mechanisms. AB - Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN. PMID- 25826090 TI - Vasorin is a potential serum biomarker and drug target of hepatocarcinoma screened by subtractive-EMSA-SELEX to clinic patient serum. AB - We report a new biomarker of hepatocarcinoma, vasorin (VASN), screened by a subtractive EMSA-SELEX strategy from AFP negative serum of hepatocellular carcinoma (HCC) patients with extrahepatic metastases. VASN was verified to be highly expressed in sera of 100 cases of HCC patients compared with 97 cases of normal persons and 129 cases of hepatitis patients. Further validation by Q PCR,IFA and Western blot showed higher expression of VASN at mRNA and protein levels in HCC cell lines and HCC tissues than in normal controls. RNA interference and forced overexpression assays verified that VASN promotes cell proliferation and migration and inhibits apoptosis. Down-regulation of microRNA miR145 and miR146a is an important mechanism leading to high expression of VASN. CONCLUSION: As a membrane protein and/or as free protein, VASN may be an effective target for biological treatment of liver cancer and is a potential biomarker for HCC diagnosis. Small molecular nucleotides targeting VASN are promising biological therapies to HCC. PMID- 25826089 TI - PLK1 is a critical determinant of tumor cell sensitivity to CPT11 and its inhibition enhances the drug antitumor efficacy in squamous cell carcinoma models sensitive and resistant to camptothecins. AB - Intrinsic and acquired tumor drug resistance limits the therapeutic efficacy of camptothecins (CPTs). Downregulation of the mitotic kinase PLK1 was found associated with apoptosis induced by SN38 (CPT11 active metabolite). We investigated the role of PLK1 in the cell response to CPTs in squamous cell carcinoma (SCC) and pediatric sarcoma cell lines and explored the therapeutic potential of the combination of CPT11 and the PLK1 inhibitor BI2536 in CPT sensitive and -resistant tumor models. Gain- and loss-of-function experiments established a direct role for PLK1 in counteracting SN38 antiproliferative and pro-apoptotic effects. The ability to activate an efficient G2/M cell cycle checkpoint allowing PLK1 ubiquitination and degradation was found associated with SN38-induced apoptosis in SCC cells. However, the synergistic interaction between SN38 and BI2536 enhanced apoptosis in cell lines both sensitive and resistant to SN38-induced apoptotic cell death. A well-tolerated CPT11/BI2536 cotreatment resulted in improved antitumor effect against SCC xenografts in mice compared to single agent treatments. The increased apoptosis induction was reflected in a high rate of complete responses and cures in mice harboring SCC, including tumors with intrinsic or acquired resistance to CPTs. PLK1 inhibition represents a promising strategy to improve the antitumor efficacy of CPT11-based regimens. PMID- 25826091 TI - Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver. AB - Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy. PMID- 25826092 TI - Leucine-rich alpha-2-glycoprotein promotes TGFbeta1-mediated growth suppression in the Lewis lung carcinoma cell lines. AB - Leucine-rich alpha2-glycoprotein (LRG) is an approximately 50-kDa glycoprotein that has been found to be elevated in the sera of patients with several types of cancer. LRG directly binds to transforming growth factor beta 1 (TGFbeta1) and modulates TGFbeta1 signaling in endothelial cells; however, the precise function of LRG in cancer remains unclear. This study aimed to investigate the role of LRG in cancer. Lewis lung carcinoma (LLC) cells hardly expressed LRG. The growth of LLC tumors allografted in the LRG knockout (KO) mice was significantly increased compared with wild-type (WT) mice. Conversely, overexpression of LRG significantly inhibited the growth of LLC tumors in WT mice. In the presence of LRG, TGFbeta1 significantly inhibited the proliferation of LLC cells and human hepatocellular carcinoma Hep3B cells in vitro by inducing apoptosis via the potent activation of smad2 and its downstream signaling pathway. Furthermore, administration of a TGFbetaR1 inhibitor (SB431542) significantly enhanced the growth of LLC tumors in WT mice compared with LRG KO mice via inhibition of apoptosis. We propose that LRG potentiates the effect of TGFbeta1 in cancer cells whose growth is suppressed in the presence of TGFbeta1. PMID- 25826093 TI - The attenuated hepatocellular carcinoma-specific Listeria vaccine Lmdd-MPFG prevents tumor occurrence through immune regulation of dendritic cells. AB - Immunotherapy is a promising treatment for liver cancer. Here, we tested the ability of the attenuated hepatocellular carcinoma-specific Listeria vaccine (Lmdd-MPFG) to treat hepatocellular carcinoma (HCC) in a mouse model. Immunization with the vaccine caused a strong anti-tumor response, especially in mice reinfused with dendritic cells (DCs). In mice that were also administered DCs, tumor suppression was accompanied by the strongest cytotoxic T lymphocyte response of all treatment groups and by induced differentiation of CD4+ T cells, especially Th17 cells. Additionally, the Lmdd-MPFG vaccine caused maturation of DCs in vitro. We demonstrated the synergistic effect of TLR4 and NLRP3 or NOD1 signaling pathways in LM-induced DC activation. These results suggest that the Lmdd-MPFG vaccine is a feasible strategy for preventing HCC. PMID- 25826094 TI - Constitutive asymmetric dimerization drives oncogenic activation of epidermal growth factor receptor carboxyl-terminal deletion mutants. AB - Genomic alterations targeting the Epidermal Growth Factor Receptor (EGFR) gene have been strongly associated with cancer pathogenesis. The clinical effectiveness of EGFR targeted therapies, including small molecules directed against the kinase domain such as gefitinib, erlotinib and afatinib, have been proven successful in treating non-small cell lung cancer patients with tumors harboring EGFR kinase domain mutations. Recent large-scale genomic studies in glioblastoma and lung cancer have identified an additional class of oncogenic mutations caused by the intragenic deletion of carboxy-terminal coding regions. Here, we report that combinations of exonic deletions of exon 25 to 28 lead to the oncogenic activation of EGF receptor in the absence of ligand and consequent cellular transformation, indicating a significant role of C-terminal domain in modulating EGFR activation. Furthermore, we show that the oncogenic activity of the resulting C-terminal deletion mutants are efficiently inhibited by EGFR targeted drugs including erlotinib, afatinib, dacomitinib as well as cetuximab, expanding the therapeutic rationale of cancer genome-based EGFR targeted approaches. Finally, in vivo and in vitro preclinical studies demonstrate that constitutive asymmetric dimerization in mutant EGFR is a key mechanism for oncogenic activation and tumorigenesis by C-terminal deletion mutants. Therefore, our data provide compelling evidence for oncogenic activation of C-terminal deletion mutants at the molecular level and we propose that C-terminal deletion status of EGFR can be considered as a potential genomic marker for EGFR-targeted therapy. PMID- 25826095 TI - A functional relay from progesterone to vitamin D in the immune system. AB - Progesterone is a steroid hormone that promotes and maintains pregnancy. Vitamin D (vit. D), another steroid hormone, regulates calcium levels and bone health among many of its functions. The two hormones play important roles also in regulating the immune system. Recently, we discovered that the vitamin D receptor (VDR) is induced in T cells by progesterone. This finding connects the function of progesterone to that of vit. D and suggests that the two steroid hormones cooperate with each other for sequential and effective regulation of the immune system. Potential implications of the regulation in health and disease are discussed. PMID- 25826096 TI - Does Visuomotor Adaptation Proceed in Stages? An Examination of the Learning Model by Chein and Schneider (2012). AB - A new 3-stage model based on neuroimaging evidence is proposed by Chein and Schneider (2012). Each stage is associated with different brain regions, and draws on cognitive abilities: the first stage on creativity, the second on selective attention, and the third on automatic processing. The purpose of the present study was to scrutinize the validity of this model for 1 popular learning paradigm, visuomotor adaptation. Participants completed tests for creativity, selective attention and automated processing before attending in a pointing task with adaptation to a 60 degrees rotation of visual feedback. To examine the relationship between cognitive abilities and motor learning at different times of practice, associations between cognitive and adaptation scores were calculated repeatedly throughout adaptation. The authors found no benefit of high creativity for adaptive performance. High levels of selective attention were positively associated with early adaptation, but hardly with late adaptation and de adaptation. High levels of automated execution were beneficial for late adaptation, but hardly for early and de-adaptation. From this we conclude that Chein and Schneider's first learning stage is difficult to confirm by research on visuomotor adaptation, and that the other 2 learning stages rather relate to workaround strategies than to actual adaptive recalibration. PMID- 25826097 TI - Motivated to survive: high cooperativeness in severe anorexia nervosa. AB - This study assessed the personality of severely ill patients with anorexia nervosa, restricting (AN-R) and binge-purge subtypes (AN-BP), during hospitalization for medical stabilization. Participants (N = 37) completed the Temperament and Character Inventory, Revised. Personality domains were similar between AN-R and AN-BP with the exception of cooperativeness. AN-R patients scored higher on this dimension, suggesting that individuals with restricting anorexia may be more tolerant of treatment during early medical stabilization. Future research is needed to further elucidate this novel finding in order to identify the point at which body mass index predicts a decline in cooperativeness and the potential need for new intervention strategies. PMID- 25826098 TI - Review of advances in the thin layer chromatography of pesticides: 2012-2014. AB - Publications reporting techniques and applications of thin layer chromatography (planar chromatography) for the separation, detection, qualitative, and quantitative determination, and preparative isolation of pesticides and their metabolites are reviewed for the period from November 1, 2012 to November 1, 2014. Analyses are described for a variety of sample types and pesticide classes. In addition to references on residue analysis, studies such as pesticide structure - retention relationships, identification and characterization of natural and synthesized pesticides, metabolism, bioactivity, degradation, soil mobility, and lipophilicity are covered. PMID- 25826099 TI - Presence of PAHs in milk of industrial farms from Tizayuca, Hidalgo, Mexico. AB - The objective of this study was to determine the concentrations of polycyclic aromatic hydrocarbons (PAHs) in cow's milk from industrial farms that are located near an industrial park in Hidalgo, Mexico. It was found that the concentrations of PAHs in the raw milk of cattle from industrial farms have increased in recent years. Composite samples were collected between 2008 and 2010 and analysis carried out according to 8100 EPA procedures and analyzed by gas chromatography with FID detection. The results show that combustion PAHs were mostly Ace, Acy, and Fla (0.25, 0.32, and 0.22 ug g(-1), respectively). Diagnostic ratios were used to show that the probable sources were grass and fuel combustion. The sum of concentrations of 16 individual PAHs did not breach permissible levels in milk (25 ug g(-1) according to the United States EPA), indicating a limited health risk to animals and humans in the study area. The industrial park has adequate pollutant emission regulations. PMID- 25826100 TI - Concentrations and distributions of 18 organochlorine pesticides listed in the Stockholm Convention in surface sediments from the Liaohe River basin, China. AB - Organochlorine pesticides (OCPs) were analyzed in 26 surface sediment samples from the Liaohe River basin, and the distributions of and potential environmental risks posed by OCPs in the basin were evaluated. Eighteen OCPs listed in the Stockholm Convention were determined using isotope-dilution gas chromatography high resolution mass spectrometry. This is the first study of hexachlorobenzene (HCB) in the Liaohe River basin sediments. The total OCP concentrations were 0.39 68.06 ng g(-1) dry weight. The total alpha-, beta-, gamma-, and delta hexachlorocyclohexane (HCH), the total dichlorodiphenyltrichloroethane (DDT - p,p'-dichlorodiphenyldichloroethane (DDD), p,p'-dichlorodiphenyldichloroethylene (DDE), o,p(')-DDT, and p,p'-DDT), and the HCB concentrations in the sediment samples were 0.1-28.48 ng g(-1) (mean 4.01 ng g(-1)), 0.08-6.52 ng g(-1) (mean 3.07 ng g(-1)), and 0.18-24.8 ng g(-1) (mean 4.38 ng g(-1)), respectively. The HCB concentrations were higher than the concentrations of the other OCPs, and the HCHs and HCB together were the dominant OCPs. beta-HCH was the most abundant HCH isomer. The concentrations of DDTs and other OCPs were relatively low, and the (DDE+DDD)/DDT ratios (>0.5) and DDD/DDE ratios (<1) indicated that no recent DDT inputs had occurred in the Liaohe River system. The main sources of HCHs were probably the historical production and agricultural use of HCH in the study area. The DDT and HCH concentrations were generally below or similar to the concentrations that have been found in other parts of the world. An ecotoxicological evaluation indicated that HCHs in surface sediments pose slight risks to human and ecological health in the Liaohe River basin. PMID- 25826101 TI - Photocatalytic degradation of acephate in pak choi, Brassica chinensis, with Ce doped TiO2. AB - The photocatalytic degradation of acephate was investigated using Ce-doped TiO2 (TiO2/Ce) hydrosol. In contrast to previous research conducted under artificial light in the laboratory, this study investigated the decomposition of acephate in a field trial. The results show that acephate can be efficiently degraded by the TiO2/Ce system under natural field conditions; the degradation efficiency was affected by the dosage of the photocatalyst and acephate. The optimum dosage of TiO2/Ce was 2400 g a.i.ha(-1), and the photodegradation efficiency of acephate reached 93.5% after 20 h at an acephate dosage of 675 g a.i.ha(-1). Ultra performance liquid chromatography/mass spectrometry (UPLC/MS) analysis detected and identified four degradation products-methamidophos, phosphorothioic acid O,O,S-trimethyl ester, S-methyl methanethiosulfonate and phosphorous acid-that were formed during the TiO2/Ce photodegradation of acephate. Based on the structural identification of the degradation products, a probable photodegradation pathway was proposed, and the first decomposition step may be the cleavage of the C-N bond of acephate. Subsequently, the P-S and P-O bonds may be oxidized gradually or simultaneously to complete the mineralization. PMID- 25826102 TI - Eruca sativa: Benefits as antioxidants source versus risks of already banned pesticides. AB - Eruca sativa (rocket salad) has been intensely consumed all over the world, insomuch as, this work was undertaken to evaluate the antioxidant status and the environmental contamination (positive and negative nutritional contribution) of leaves and stems from this vegetable. Antioxidant capacity of rocket salad was assessed by mean of optical methods, such as the total phenolic content (TPC), reducing power assay and DPPH radical scavenging activity. The extent of the environmental contamination was reached through the quantification of thirteen organochlorine pesticides (OCP) by using gas chromatography coupled with electron capture detector (GC-ECD) and compound confirmations employing gas chromatography tandem mass-spectrometry (GC-MS/MS). The OCP residues were extracted by using Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) methodology.The extent of the environmental contamination was reached through the quantification of thirteen OCP by using gas chromatography coupled with electron-capture detector (GC-ECD) and compound confirmations employing GC-MS/MS. The OCP residues were extracted by using Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) methodology. This demonstrated that leaves presented more antioxidant activity than stems, emphasizing that leaves contained six times more polyphenolic compounds than stems. In what concerns the OCP occurrence, the average recoveries obtained at the three levels tested (40, 60 and 80 ug kg(-1)) ranged from 55% to 149% with a relative standard deviation of 11%, (except hexachrorobenzene). Three vegetables samples were collected from supermarkets and analysed following this study. According to data, only one sample achieved 16.21 of beta hexachlorocyclohexane, confirmed by GC-MS/MS. About OCP quantification, the data indicated that only one sample achieved 16.21 ug kg(-1) of beta hexachlorocyclohexane, confirmed by GC-MS/MS, being the QuEChERS a good choice for the of OCPs extraction. Furthermore, the leaves consumption guaranty higher levels of antioxidants than stems. PMID- 25826103 TI - Repeated batch and continuous degradation of chlorpyrifos by Pseudomonas putida. AB - The present study was undertaken with the objective of studying repeated batch and continuous degradation of chlorpyrifos (O,O-diethyl O-3,5,6-trichloropyridin 2-yl phosphorothioate) using Ca-alginate immobilized cells of Pseudomonas putida isolated from an agricultural soil, and to study the genes and enzymes involved in degradation. The study was carried out to reduce the toxicity of chlorpyrifos by degrading it to less toxic metabolites. Long-term stability of pesticide degradation was studied during repeated batch degradation of chlorpyrifos, which was carried out over a period of 50 days. Immobilized cells were able to show 65% degradation of chlorpyrifos at the end of the 50th cycle with a cell leakage of 112 * 10(3) cfu mL(-1). During continuous treatment, 100% degradation was observed at 100 mL h(-1) flow rate with 2% chlorpyrifos, and with 10% concentration of chlorpyrifos 98% and 80% degradation was recorded at 20 mL h(-1) and 100 mL h(-1) flow rate respectively. The products of degradation detected by liquid chromatography-mass spectrometry analysis were 3,5,6-trichloro-2-pyridinol and chlorpyrifos oxon. Plasmid curing experiments with ethidium bromide indicated that genes responsible for the degradation of chlorpyrifos are present on the chromosome and not on the plasmid. The results of Polymerase chain reaction indicate that a ~890-bp product expected for mpd gene was present in Ps. putida. Enzymatic degradation studies indicated that the enzymes involved in the degradation of chlorpyrifos are membrane-bound. The study indicates that immobilized cells of Ps. putida have the potential to be used in bioremediation of water contaminated with chlorpyrifos. PMID- 25826104 TI - The prevalence of selected genes involved in the biosynthesis of trichothecenes assessed with the specific PCR tests in Fusarium spp. isolated from cereals in southern Poland. AB - The analysis was conducted using 50 isolates of fungi of the genus Fusarium belonging to the species classified as major trichothecene mycotoxin producers: F. graminearum, F. culmorum, F. sporotrichioides, and F. poae. The tested fungi were isolated from ears of cereal crops in southern Poland during the two growing seasons (2011 and 2012). The aim of this study was to evaluate the prevalence of genes involved in the biosynthesis of trichothecene mycotoxins using the specific PCR tests. Molecular analyses indicated that the genes responsible for the production of trichothecenes (Tri3, Tri5, Tri7, Tri13) were abundant in the examined genetic material. The tested fungal isolates were characterized by a large diversity in terms of the number and composition of the possessed Tri genes. On the other hand, 14 of 50 isolates were found not to carry any of Tri genes. PMID- 25826105 TI - Glucosinolates in collard greens grown under three soil management practices. AB - Glucosinolates (GSLs, beta-D-thioglucoside-N-hydroxysulfates) are polar compounds present in varying amounts in members of the Brassicaceae family. They suppress soil-borne pests due to the biofumigant properties of the highly toxic isothiocyanates present in Brassica vegetables. The objectives of this investigation were to: (1) assess variation in GSLs concentrations among collard plants grown under three soil management practices: sewage sludge (SS) mixed with native soil, chicken manure (CM) mixed with native soil, and no-mulch (NM) native soil, (2) quantify GSLs concentrations in collard roots, leaves, and stems at harvest for potential use of their crude extracts in plant protection, and (3) assess myrosinase activity in soil amended with CM and SS mixed with native soil. Separation of GSLs was accomplished by adsorption on a DEAE-Sephadex ion exchange resin using disposable pipette tips filled with DEAE, a weak base, with a net positive charge when ionized and exchange anions such as GSLs (hydrophilic plant secondary metabolites). Quantification of total GSLs was based on inactivation of collard endogenous myrosinase and liberation of the glucose moiety from the GSLs molecule by addition of standardized myrosinase and colorimetric determination of the liberated glucose moiety. Across all treatments, SS and CM increased soil organic matter content from 2.2% in native soil to 4.2 and 6.5%, respectively. GSLs concentrations were significantly greater in collard leaves (30.9 umoles g( 1) fresh weight) compared to roots and stems (7.8 and 1.2 umoles g(-1) fresh weight), respectively. Leaves of collard grown in soil amended with SS contained the greatest concentrations of GSLs compared to leaves of plants grown in CM and NM treatments. Accordingly, leaves of collard plants grown in soil amended with SS could play a significant role in sustainable agriculture as alternative tools for soil-borne disease management in conventional and organic agriculture. PMID- 25826106 TI - Macro and trace elements in Common Chanterelle (Cantharellus cibarius) mushroom from the European background areas in Poland: Composition, accumulation, dietary exposure and data review for species. AB - This paper gives an up-to-date information on accumulation, occurrence, intake and possible health risks associated with noxious metallic elements (Ag, Cd, Hg, Pb) among mineral constituents (Ag, Al, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, P, Pb, Rb, Sr and Zn) contained in Common Chanterelle (Cantharellus cibarius) mushrooms, a species subjected to a broad use within the domestic market of Poland and widely exported abroad, and presents a short review of data from the available literature. The tasty values of C. cibarius seem to be more rated than the essential minerals contained in its flesh and nominally taken with 1,000 g of fresh fruiting bodies eaten per capita annually, while the contents of toxic or potentially toxic metals, such as Cd, Pb, Hg and Ag, are much below the tolerance limits. PMID- 25826107 TI - Poor Socioeconomic and Nutritional Status Are Associated with Osteoporosis in Korean Postmenopausal Women: Data from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES) 2009. AB - OBJECTIVE: As the population ages, osteoporosis is a growing global public health problem. This study examined potential risk factors associated with osteoporosis in a nationally representative sample of Korean postmenopausal women. METHODS: This study used data from a nationally representative sample of Korean menopausal women participating in the Korea National Health and Nutrition Examination Survey KNHANES 2009 (n = 1467; mean age +/- SE = 65.2 +/- 0.3 years). Bone mineral density of total femur, femoral neck, and spine was measured by dual-energy X-ray absorptiometry. Osteoporosis was determined as t-score of -2.5 or below in at least 1 of the 3 sites. Menopausal status was confirmed by self-reports. RESULTS: About 41% of the study sample met the criteria for osteoporosis. Poor socioeconomic status, lower BMI, and shorter estrogen exposure duration were significantly associated with osteoporosis in the study sample. Poor dietary intake was also related to osteoporosis. In the age- and energy-adjusted logistic regression models, participants consuming less protein, vitamin B2, or vitamin C than the estimated average requirement (EAR) showed higher odds of having osteoporosis than their counterparts. Participants consuming no milk or milk products had 45% increased odds of having osteoporosis than those consuming milk or milk products. CONCLUSION: The findings of this study suggest several risk factors associated with osteoporosis, which can be addressed in the development and implementation of tailored nutritional interventions to promote the bone health of Korean postmenopausal women. PMID- 25826108 TI - The effects of two novel gratitude and mindfulness interventions on well-being. AB - OBJECTIVE: To examine the efficacy of two dual-component interventions, one based on mindfulness and one based on gratitude, to reduce depression and stress and increase happiness levels. DESIGN: Randomized, controlled study with data collected at baseline, 3 weeks, and 5 weeks. SETTINGS: Participants completed an online gratitude or mindfulness intervention at home. Self-report questionnaires were completed at home or at work. PARTICIPANTS: Sixty-five women aged 18-46 years (mean age+/-standard deviation, 28.35+/-6.65 years). INTERVENTIONS: Participants were randomly assigned to a wait-list control condition or to either a gratitude or a mindfulness intervention condition. The interventions were used four times a week for 3 weeks. The gratitude intervention involved a gratitude diary and grateful reflection. The mindfulness intervention involved a mindfulness diary and mindfulness meditation, the Body Scan. OUTCOME MEASURES: The outcome variables were depression, stress, and happiness measured by using the Edinburgh Depression Scale, the Perceived Stress Scale, and the Subjective Happiness Scale, respectively. RESULTS: All outcome variables improved over time in both interventions group but not in the wait-list control group. Efficacy of the interventions differed between the interventions. CONCLUSIONS: These short novel interventions seem to provide a useful way to enhance well-being. Further research in the area is warranted. PMID- 25826109 TI - Synthesis and evaluation of fluorinated fingolimod (FTY720) analogues for sphingosine-1-phosphate receptor molecular imaging by positron emission tomography. AB - Sphingosine-1-phosphate (S1P) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G-protein coupled receptors (GPCRs): S1P1-S1P5. S1P and its receptors (S1PRs) play important roles in the immune, cardiovascular, and central nervous systems and have also been implicated in carcinogenesis. Recently, the S1P analogue Fingolimod (FTY720) has been approved for the treatment of patients with relapsing multiple sclerosis. This work presents the synthesis of various fluorinated structural analogues of FTY720, their in vitro and in vivo biological testing, and their development and application as [(18)F]radiotracers for the study of S1PR biodistribution and imaging in mice using small-animal positron emission tomography (PET). PMID- 25826110 TI - Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. AB - Deep brain stimulation (DBS) is a promising therapy for patients with refractory depression. However, key questions remain with regard to which brain target(s) should be used for stimulation, and which mechanisms underlie the therapeutic effects. Here, we investigated the effect of DBS, with low- and high-frequency stimulation (LFS, HFS), in different brain regions (ventromedial prefrontal cortex, vmPFC; cingulate cortex, Cg; nucleus accumbens (NAc) core or shell; lateral habenula, LHb; and ventral tegmental area) on a variety of depressive like behaviors using rat models. In the naive animal study, we found that HFS of the Cg, vmPFC, NAc core and LHb reduced anxiety levels and increased motivation for food. In the chronic unpredictable stress model, there was a robust depressive-like behavioral phenotype. Moreover, vmPFC HFS, in a comparison of all stimulated targets, produced the most profound antidepressant effects with enhanced hedonia, reduced anxiety and decreased forced-swim immobility. In the following set of electrophysiological and histochemical experiments designed to unravel some of the underlying mechanisms, we found that vmPFC HFS evoked a specific modulation of the serotonergic neurons in the dorsal raphe nucleus (DRN), which have long been linked to mood. Finally, using a neuronal mapping approach by means of c-Fos expression, we found that vmPFC HFS modulated a brain circuit linked to the DRN and known to be involved in affect. In conclusion, HFS of the vmPFC produced the most potent antidepressant effects in naive rats and rats subjected to stress by mechanisms also including the DRN. PMID- 25826111 TI - Risk factors for late-onset generalized anxiety disorder: results from a 12-year prospective cohort (the ESPRIT study). AB - Generalized anxiety disorder (GAD) is a chronic and highly prevalent disorder associated with increased disability and mortality in the elderly. Treatment is difficult with low rate of full remission, thus highlighting the need to identify early predictors for prevention in elderly people. The aim of this study is to identify and characterize incident GAD predictors in elderly people. A total of 1711 individuals aged 65 years and above and free of GAD at baseline were randomly recruited from electoral rolls between 1999 and 2001 (the prospective ESPRIT study). The participants were examined at baseline and five times over 12 years. GAD and psychiatric comorbidity were diagnosed with a standardized psychiatric examination, the Mini-International Neuropsychiatry Interview on the basis of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria and validated by a clinical panel. During the follow-up, 8.4% (95% confidence interval=7.1-9.7%) of the participants experienced incident GAD, 80% being first episodes; the incident rate being 10 per 1000 person-years. The principal predictors of late-onset incident GAD over 12 years derived from a multivariate Cox model were being female, recent adverse life events, having chronic physical (respiratory disorders, arrhythmia and heart failure, dyslipidemia, cognitive impairment) and mental (depression, phobia and past GAD) health disorders. Poverty, parental loss or separation and low affective support during childhood, as well as history of mental problems in parents were also significantly and independently associated with incident GAD. GAD appears as a multifactorial stress-related affective disorder resulting from both proximal and distal risk factors, some of them being potentially modifiable by health care intervention. PMID- 25826112 TI - Stress inoculation modeled in mice. AB - Stress inoculation entails intermittent exposure to mildly stressful situations that present opportunities to learn, practice and improve coping in the context of exposure psychotherapies and resiliency training. Here we investigate behavioral and hormonal aspects of stress inoculation modeled in mice. Mice randomized to stress inoculation or a control treatment condition were assessed for corticosterone stress hormone responses and behavior during open-field, object-exploration and tail-suspension tests. Stress inoculation training sessions that acutely increased plasma levels of corticosterone diminished subsequent immobility as a measure of behavioral despair on tail-suspension tests. Stress inoculation also decreased subsequent freezing in the open field despite comparable levels of thigmotaxis in mice from both treatment conditions. Stress inoculation subsequently decreased novel-object exploration latencies and reduced corticosterone responses to repeated restraint. These results demonstrate that stress inoculation acutely stimulates glucocorticoid signaling and then enhances subsequent indications of active coping behavior in mice. Unlike mouse models that screen for the absence of vulnerability to stress or presence of traits that occur in resilient individuals, stress inoculation training reflects an experience-dependent learning-like process that resembles interventions designed to build resilience in humans. Mouse models of stress inoculation may provide novel insights for new preventive strategies or therapeutic treatments of human psychiatric disorders that are triggered and exacerbated by stressful life events. PMID- 25826113 TI - RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response. AB - Response to antidepressant treatment is highly variable with some patients responding within a few weeks, whereas others have to wait for months until the onset of clinical effects. Gene expression profiling may be a tool to identify markers of antidepressant treatment response and new potential drug targets. In a first step, we selected 12 male, age- and severity-matched pairs of remitters and nonresponders, and analyzed expression profiles in peripheral blood at admission and after 2 and 5 weeks of treatment using Illumina expression arrays. We identified 127 transcripts significantly associated with treatment response with a minimal P-value of 9.41 * 10(-)(4) (false discovery rate-corrected). Analysis of selected transcripts in an independent replication sample of 142 depressed inpatients confirmed that lower expression of retinoid-related orphan receptor alpha (RORa, P=6.23 * 10(-4)), germinal center expressed transcript 2 (GCET2, P=2.08 * 10(-2)) and chitinase 3-like protein 2 (CHI3L2, P=4.45 * 10(-2)) on admission were associated with beneficial treatment response. In addition, leukocyte-specific protein 1 (LSP1) significantly decreased after 5 weeks of treatment in responders (P=2.91 * 10(-2)). Additional genetic, in vivo stress responsitivity data and murine gene expression findings corroborate our finding of RORa as a transcriptional marker of antidepressant response. In summary, using a genome-wide transcriptomics approach and subsequent validation studies, we identified several transcripts including the circadian gene transcript RORa that may serve as biomarkers indicating antidepressant treatment response. PMID- 25826114 TI - The role of APOE-E4 and beta amyloid in the differential rate of recovery from ECT: a review. AB - Individual biological differences may contribute to the variability of outcomes, including cognitive effects, observed following electroconvulsive treatment (ECT). A narrative review of the research literature on carriage of the apolipoprotein E E4 allele (APOE-E4) and the protein biomarker beta amyloid (Abeta) with ECT cognitive outcome was undertaken. ECT induces repeated brain seizures and there is debate as to whether this causes brain injury and long-term cognitive disruption. The majority of ECT is administered to the elderly (over age 65 years) with drug-resistant depression. Depression in the elderly may be a symptom of the prodromal stage of Alzheimer's disease (AD). Carriage of the APOE E4 allele and raised cerebral Abeta are consistently implicated in AD, but inconsistently implicated in brain injury (and related syndromes) recovery rates. A paucity of brain-related recovery, genetic and biomarker research in ECT responses in the elderly was found: three studies have examined the effect of APOE-E4 allele carriage on cognition in the depressed elderly receiving ECT, and two have examined Abeta changes after ECT, with contradictory findings. Cognitive changes in all studies of ECT effects were measured by a variety of psychological tests, making comparisons of such changes between studies problematic. Further, psychological test data-validity measures were not routinely administered, counter to current testing recommendations. The methodological issues of the currently available literature as well as the need for well-designed, hypothesis driven, longitudinal studies are discussed. PMID- 25826115 TI - Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission. AB - Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders. PMID- 25826116 TI - Acute hypoglycemia results in reduced cortical neuronal injury in the developing IUGR rat. AB - BACKGROUND: Hypoglycemia (HG) is common in intrauterine growth restricted (IUGR) neonates. In normally grown (NG) neonatal rats, acute HG causes neuronal injury in the brain; the cerebral cortex is more vulnerable than the hippocampus (HPC). We hypothesized that the IUGR brain is less vulnerable to HG-induced injury while preserving regional variation in vulnerability. METHODS: We induced IUGR via bilateral uterine artery ligation on gestational day 19 (term 22 d) rats. On postnatal day 14, insulin-induced HG of equivalent severity and duration (blood glucose < 40 mg/dl for 240 min) was produced in IUGR and NG (IUGR/HG and NG/HG). Neuronal injury in the cortex and HPC was quantified 6-72 h later using Fluoro Jade B (FJB) histochemistry. The mRNA expression of monocarboxylate transporters, MCT1 and MCT2, and glucose transporters, GLUT1 and GLUT3, was determined using quantitative PCR. RESULTS: There were fewer FJB-positive (FJB+) cells in the cortex of IUGR/HG; no difference was observed in FJB+ cells in HPC. Core body temperature was lower in IUGR/HG compared with NG/HG. MCT2 expression was increased in the IUGR cortex. CONCLUSION: HG-induced neuronal injury is decreased in the cortex of the developing IUGR brain. Adaptations including systemic hypothermia and enhanced delivery of alternative substrates via MCT2 might protect against HG-induced neuronal injury in IUGR. PMID- 25826117 TI - IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling. AB - BACKGROUND: Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21). METHODS: IUGR was induced via maternal thromboxane A2 analog infusion in mice. RESULTS: IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3' distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females. CONCLUSION: IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure. PMID- 25826118 TI - Ontogeny of cerebrovascular critical closing pressure. AB - BACKGROUND: Premature infants are at risk of vascular neurologic insults. Hypotension and hypertension are considered injurious, but neither condition is defined with consensus. Cerebrovascular critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow (CBF) ceases. CrCP may serve to define subject-specific low or high ABP. Our objective was to determine the ontogeny of CrCP. METHODS: Premature infants (n = 179) with gestational age (GA) from 23-31 wk had recordings of ABP and middle cerebral artery flow velocity twice daily for 3 d and then daily for the duration of the first week of life. All infants received mechanical ventilation. CrCP was calculated using an impedance-model derivation with Doppler-based estimations of cerebrovascular resistance and compliance. The association between GA and CrCP was determined in a multivariate analysis. RESULTS: The median (interquartile range) CrCP for the cohort was 22 mm Hg (19-25 mm Hg). CrCP increased significantly with GA (r = 0.6; slope = 1.4 mm Hg/wk gestation), an association that persisted with multivariate analysis (P < 0.0001). CONCLUSION: CrCP increased significantly from 23 to 31 wk gestation. The low CrCP observed in very premature infants may explain their ability to tolerate low ABP without global cerebral infarct or hemorrhage. PMID- 25826121 TI - Modulation of the Electrostatic and Quantum Capacitances of Few Layered Graphenes through Plasma Processing. AB - It is shown that charged defect generation, through argon ion-based plasma processing, in few layer graphene, could substantially enhance the electrical capacitance for electrochemical energy storage. Detailed consideration of the constituent space charge and quantum capacitances were used to delineate a new length scale, correlated to electrically active defects contributing to the capacitance, and was found to be smaller than a structural correlation length determined through Raman spectroscopy. The study offers insights into an industrially viable method (i.e., plasma processing) for modifying and enhancing the energy density of graphene-based electrochemical capacitors. PMID- 25826119 TI - Neutrophil and monocyte toll-like receptor 4, CD11b and reactive oxygen intermediates, and neuroimaging outcomes in preterm infants. AB - BACKGROUND: Activated leukocytes and infection are implicated in neonatal brain injury. Leukocyte surface receptors are increased in stroke models and may be targets for future adjunctive therapies. METHODS: Serial blood samples were analyzed from preterm infants (n = 51; <32 wk gestation) on days 0, 1, 2, and 7 of life. Monocyte and neutrophil activation were evaluated via flow cytometry at baseline and following endotoxin stimulation ex vivo by measuring CD11b (activation), toll-like receptor 4 (TLR-4; endotoxin recognition) expression, and intracellular reactive oxygen intermediate (ROI) production (function). RESULTS: Control preterm infants with normal neuroimaging had elevated baseline CD11b and TLR-4 expression and ROI production compared with adults as well as a robust immune response following endotoxin stimulation. Preterm infants with abnormal neuroimaging had increased neutrophil TLR-4 and ROI compared with all controls. CONCLUSION: Preterm infants have a robust immune response compared with adults. Increased TLR-4 expression in preterm infants with abnormal neuroimaging is similar to findings in adult stroke. In addition, ROI production may cause tissue injury. The modulation of these responses may be beneficial in preterm inflammatory disorders. PMID- 25826120 TI - Real-time detection, classification, and quantification of apneic episodes using miniature surface motion sensors in rats. AB - BACKGROUND: Real-time detection and classification of apneic episodes remain significant challenges. This study explores the applicability of a novel method of monitoring the respiratory effort and dynamics for rapid detection and classification of apneic episodes. METHODS: Obstructive apnea (OA) and hypopnea/central apnea (CA) were induced in nine tracheostomized rats, by short lived airway obstruction and administration of succinylcholine, respectively. Esophageal pressure (EP), EtCO2, arterial O2 saturation (SpO2), heart rate, and blood pressure were monitored. Respiratory dynamics were monitored utilizing three miniature motion sensors placed on the chest and epigastrium. Three indices were derived from these sensors: amplitude of the tidal chest wall displacement (TDi), breath time length (BTL), that included inspiration and rapid expiration phases, and amplitude time integral (ATI), the integral of breath amplitude over time. RESULTS: OA induced a progressive 6.42 +/- 3.48-fold increase in EP from baseline, which paralleled a 3.04 +/- 1.19-fold increase in TDi (P < 0.0012), a 1.39 +/- 0.22-fold increase in BTL (P < 0.0002), and a 3.32 +/- 1.40-fold rise in the ATI (P < 0.024). During central hypopneic/apneic episodes, each sensor revealed a gradual decrease in TDi, which culminated in absence of breathing attempts. CONCLUSION: Noninvasive monitoring of chest wall dynamics enables detection and classification of central and obstructive apneic episodes, which tightly correlates with the EP. PMID- 25826124 TI - Heavily n-Dopable pi-Conjugated Redox Polymers with Ultrafast Energy Storage Capability. AB - We report here the first successful demonstration of a "pi-conjugated redox polymer" simultaneously featuring a pi-conjugated backbone and integrated redox sites, which can be stably and reversibly n-doped to a high doping level of 2.0 with significantly enhanced electronic conductivity. The properties of such a heavily n-dopable polymer, poly{[N,N'-bis(2-octyldodecyl)-1,4,5,8 naphthalenedicarboximide-2,6-diyl]-alt-5,5'-(2,2'-bithiophene)} (P(NDI2OD-T2)), were compared vis-a-vis to those of the corresponding backbone-insulated poly{[N,N'-bis(2-octyldodecyl)-1,4,5,8-naphthalenedicarboximide-2,6-diyl]-alt 5,5'-[2,2'-(1,2-ethanediyl)bithiophene]} (P(NDI2OD-TET)). When evaluated as a charge storage material for rechargeable Li batteries, P(NDI2OD-T2) delivers 95% of its theoretical capacity at a high rate of 100C (72 s per charge-discharge cycle) under practical measurement conditions as well as 96% capacity retention after 3000 cycles of deep discharge-charge. Electrochemical, impedance, and charge-transport measurements unambiguously demonstrate that the ultrafast electrode kinetics of P(NDI2OD-T2) are attributed to the high electronic conductivity of the polymer in the heavily n-doped state. PMID- 25826122 TI - Short Communication: Increase of HIV-1 K103N Transmitted Drug Resistance and Its Association with Efavirenz Use in South Korea. AB - Previous studies reported a relatively low prevalence of transmitted drug resistance (TDR) in South Korea (<5%). A genotypic resistance test was performed on 131 treatment-naive HIV-1-infected individuals from February 2013 to February 2014. Eleven individuals (8.4%) presented TDR, of whom eight had K103N, revealing a significant increase in K103N TDR compared to previous studies (p<0.001). Using phylogenetic analysis, we identified three distinct clustering pairs with genetic relativeness and a total of five independent strains among the eight K103N cases. Our findings suggest that multiple sources of K103N occurred, most likely as a consequence of increased efavirenz use in South Korea. PMID- 25826123 TI - From Nanofibrillar to Nanolaminar Poly(butylene succinate): Paving the Way to Robust Barrier and Mechanical Properties for Full-Biodegradable Poly(lactic acid) Films. AB - The traditional approach toward barrier property enhancement of poly(lactic acid) (PLA) is the incorporation of sheet-like fillers such as nanoclay and graphene, unfortunately leading to the sacrificed biocompatibility and degradability. Here we unveil the first application of a confined flaking technique to establish the degradable nanolaminar poly(butylene succinate) (PBS) in PLA films based on PLA/PBS in situ nanofibrillar composites. The combination of high pressure (10 MPa) and appropriate temperature (160 degrees C) during the flaking process desirably enabled sufficient deformation of PBS nanofibrils and retention of ordered PLA channels. Particularly, interlinked and individual nanosheets were created in composite films containing 10 and 20 wt % PBS, respectively, both of which presented desirable alignment and large width/thickness ratio (nanoscale thickness with a width of 428+/-13.1 and 76.9+/-8.2 MUm, respectively). With the creation of compact polymer "nano-barrier walls", a dramatic decrease of 86% and 67% in the oxygen permeability coefficient was observed for the film incorporated with well-organized 20 wt % PBS nanosheets compared to pure PLA and pure PBS (1.4 and 0.6*10(-14) cm3.cm.cm(-2).s(-1).Pa(-1)), respectively. Unexpectedly, prominent increases of 21% and 28% were achieved in the tensile strength and modulus of composite films loaded 20 wt % PBS nanosheets compared to pure PLA films, although PBS intrinsically presents poor strength and stiffness. The unusual combination of barrier and mechanical performances established in the fully degradable system represent specific properties required in packaging beverages, food and medicine. PMID- 25826125 TI - Effects of normoxic and hypoxic exercise regimens on monocyte-mediated thrombin generation in sedentary men. AB - Exercise and hypoxia paradoxically modulate vascular thrombotic risks. The shedding of procoagulant-rich microparticles from monocytes may accelerate the pathogenesis of atherothrombosis. The present study explores the manner in which normoxic and hypoxic exercise regimens affect procoagulant monocyte-derived microparticle (MDMP) formation and monocyte-promoted thrombin generation (TG). Forty sedentary healthy males were randomized to perform either normoxic (NET; 21% O2, n=20) or hypoxic (HET; 15% O2, n=20) exercise training (60% VO(2max)) for 30 min/day, 5 days/week for 5 weeks. At rest and immediately after HET (100 W under 12% O2 for 30 min), the MDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. The results demonstrated that acute 12% O2 exercise (i) increased the release of coagulant factor V (FV)/FVIII rich, phosphatidylserine (PS)-exposed and tissue factor (TF)-expressed microparticles from monocytes, (ii) enhanced the peak height and rate of TG in monocyte-rich plasma (MRP) and (iii) elevated concentrations of norepinephrine/epinephrine, myeloperoxidase (MPO) and interleukin-6 (IL-6) in plasma. Following the 5-week intervention, HET exhibited higher enhancements of peak work-rate and cardiopulmonary fitness than NET did. Moreover, both NET and HET decreased the FV/FVIII-rich, PS-exposed and TF-expressed MDMP counts and the peak height and rate of TG in MRP following the HET. However, HET elicited more suppression for the HE (hypoxic exercise)-enhanced procoagulant MDMP formation and dynamic TG in MPR and catecholamine/peroxide/pro-inflammatory cytokine levels in plasma than NET. Hence, we conclude that HET is superior to NET for enhancing aerobic capacity. Furthermore, HET effectively suppresses procoagulant MDMP formation and monocyte-mediated TG under severe hypoxic stress, compared with NET. PMID- 25826126 TI - Pig Induced Pluripotent Stem Cell-Derived Neural Rosettes Developmentally Mimic Human Pluripotent Stem Cell Neural Differentiation. AB - For diseases of the brain, the pig (Sus scrofa) is increasingly being used as a model organism that shares many anatomical and biological similarities with humans. We report that pig induced pluripotent stem cells (iPSC) can recapitulate events in early mammalian neural development. Pig iPSC line (POU5F1(high)/SSEA4(low)) had a higher potential to form neural rosettes (NR) containing neuroepithelial cells than either POU5F1(low)/SSEA4(low) or POU5F1(low)/SSEA4(high) lines. Thus, POU5F1 and SSEA4 pluripotency marker profiles in starting porcine iPSC populations can predict their propensity to form more robust NR populations in culture. The NR were isolated and expanded in vitro, retaining their NR morphology and neuroepithelial molecular properties. These cells expressed anterior central nervous system fate markers OTX2 and GBX2 through at least seven passages, and responded to retinoic acid, promoting a more posterior fate (HOXB4+, OTX2-, and GBX2-). These findings offer insight into pig iPSC development, which parallels the human iPSC in both anterior and posterior neural cell fates. These in vitro similarities in early neural differentiation processes support the use of pig iPSC and differentiated neural cells as a cell therapy in allogeneic porcine neural injury and degeneration models, providing relevant translational data for eventual human neural cell therapies. PMID- 25826127 TI - Understanding graft-versus-host disease. Preliminary findings regarding the effects of exercise in affected patients. AB - Advances in this century regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) have led to an expanding population of long-term survivors, many of whom suffer severe side effects, particularly those related to graft-versushost disease (GVHD), a potentially multi-systemic disorder caused by immunoeffector donor lymphocytes that destroy host tissues. The GVHD, especially in its chronic form (cGVHD), generates considerable morbidity and compromises the physical capacity of patients. We have reviewed the main pathophysiological aspects of the disease as well as the data available on the effects of exercise in GVHD, based on animal and human patient research. Although exercise training as an adjunct therapy to improve health outcomes after allo-HSCT shows promise (particularly, this lifestyle intervention can improve physical fitness and possibly immune function while attenuating fatigue), there is a need for more randomized control trials that focus specifically on GVHD. PMID- 25826128 TI - Photophysics of Ru(II) Dyads Derived from Pyrenyl-Substitued Imidazo[4,5 f][1,10]phenanthroline Ligands. AB - The photophysics of a series of Ru(II) dyads based on the 2-(1-pyrenyl)-1H imidazo[4,5-f][1,10]-phenanthroline ligand was investigated. The ability of these metal complexes to intercalate DNA and induce cell death upon photoactivation makes them attractive photosensitizers for a range of photobiological applications, including photodynamic therapy. In the present study, time-resolved transient absorption and emission spectroscopy were used to interrogate the photoinduced processes that follow metal-to-ligand charge transfer excitation of the complexes in solution. It was found that energy transfer to pyrene-localized intraligand triplet states, facilitated by torsional motion of the pyrene moiety relative to the imidazo[4,5-f][1,10]phenanthroline ligand, was an important relaxation pathway governing the photophysical dynamics in this class of compounds. Biphasic decay kinetics were assigned to spontaneous (pre-equilibrium) and delayed emission, arising from an equilibrium established between (3)MLCT and (3)IL states. TDDFT calculations supported these interpretations. PMID- 25826130 TI - Themed issue on radioisotopic bioanalysis. PMID- 25826129 TI - The Present and the Future of Degradable Dendrimers and Derivatives in Theranostics. AB - Interest in dendrimer-based nanomedicines has been growing recently, as it is possible to precisely manipulate the molecular weight, chemical composition, and surface functionality of dendrimers, tuning their properties according to the desired biomedical application. However, one important concern about dendrimer based therapeutics remains-the nondegradability under physiological conditions of the most commonly used dendrimers. Therefore, biodegradable dendrimers represent an attractive class of nanomaterials, since they present advantages over conventional nondegradable dendrimers regarding the release of the loaded molecules and the prevention of bioaccumulation of synthetic materials and subsequent cytotoxicity. Here, we present an overview of the state-of-the-art of the design of biodegradable dendritic structures, with particular focus on the hurdles regarding the use of these as vectors of drugs and nucleic acids, as well as macromolecular contrast agents. PMID- 25826131 TI - Liquid scintillation counting: how has it advanced over the years and what does the future hold? PMID- 25826132 TI - Radiolabeled metabolite and disposition studies in support of safety assessment. PMID- 25826133 TI - Application of (14)C-accelerator MS in pharmaceutical development. PMID- 25826134 TI - Improved pharmacodynamic assay for dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. AB - BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) activity determination in peripheral blood mononuclear cells of DPD deficient patients was hitherto inaccurate due to hemoglobin (Hb) contamination. We developed an improved method for accurate measurement of DPD activity in patients. RESULTS: DPD activity was determined by HPLC with online radioisotope detection using liquid scintillation counting. Hb was determined spectrophotometrically. Method accuracy and precision were significantly improved by using cumulative area of all peaks as IS. Peripheral blood mononuclear cell lysates from DPD deficient patients were highly contaminated with on average 23.3% (range 2.7-51%) of Hb resulting in up to twofold underestimated DPD activity. DPD activities were corrected for Hb contamination. The method was validated and showed good long-term sample stability. CONCLUSION: This method has increased specificity allowing accurate identification of DPD deficient patients. PMID- 25826135 TI - A historical perspective on radioisotopic tracers in metabolism and biochemistry. AB - Radioisotopes are used routinely in the modern laboratory to trace and quantify a myriad of biochemical processes. The technique has a captivating history peppered with groundbreaking science and with more than its share of Nobel Prizes. The discovery of radioactivity at the end of the 19th century paved the way to understanding atomic structure and quickly led to the use of radioisotopes to trace the fate of molecules as they flowed through complex organic life. The 1940s saw the first radiotracer studies using homemade instrumentation and analytical techniques such as paper chromatography. This article follows the history of radioisotopic tracers from meager beginnings, through to the most recent applications. The author hopes that those researchers involved in radioisotopic tracer studies today will pause to remember the origins of the technique and those who pioneered this fascinating science. PMID- 25826136 TI - Radisotopic characterization as an analytical tool: current status, limitations and future challenges. AB - In this review, we describe the growth of current state-of-the-art applications that rely on the 'online' analysis of radiolabeled samples, focus on the nature of the most common measurement techniques and provide some insight into the potential future developments of this powerful analytical tool. In particular, this review will concentrate on two common online analysis methods that utilize radioisotope detection and analysis systems coupled to chromatographic separations: radio-GC and radio-HPLC. The different sample conditions call for different approaches to the method of radiodetection in order to optimize the sensitivity and chromatographic resolution in each case. These methods are also compared with alternative analytical techniques, including accelerator MS and 'offline' counting. PMID- 25826137 TI - Quantitative whole-body autoradiography: past, present and future. AB - Traditional bioanalytical measurements determine concentrations of drug and metabolites in plasma; however, most drugs exert their effects in defined target tissues. As there is no clear relation between concentrations in plasma and those in tissue, alternative methods must be employed to study the absorption, distribution, metabolism and excretion properties of new therapeutic agents. Quantitative whole-body autoradiography is used in the drug development process to determine the distribution and concentrations of radiolabeled test compounds in laboratory animals. Quantitative whole-body autoradiography can provide information on tissue PKs, penetration, accumulation and retention. Although the technique is considered the industry standard for performing preclinical tissue distribution studies, it is perhaps timely, 60 years after the first reported use of the method, to re-assess the technique against modern alternatives. PMID- 25826138 TI - The 10th Annual Bioassays and Bioanalytical Method Development Conference. AB - The 10th Annual Bioassays and Bioanalytical Method Development Conference was hosted in Boston, MA, USA on 20-22 October 2014. This meeting brought together scientists from the biopharmaceutical and life sciences industries, the regulatory agency and academia to share and discuss current trends in cell-based assays and bioanalysis, challenges and ideas for the future of the bioassays and bioanalytical method development. The experiences associated with new and innovative technologies were evaluated as well as their impact on the current bioassays methodologies and bioanalysis workflow, including quality, feasibility, outsourcing strategies and challenges, productivity and compliance. Several presentations were also provided by members of the US FDA, sharing both scientific and regulatory paradigms including a most recent update on the position of the FDA with specific aspects of the draft Bioanalytical Method Validation guidance following its review of the industry's responses. The meeting was jointly coincided with the 15th Annual Immunogenicity for Biotherapeutics meeting, allowing for attendees to also familiarize themselves with new and emerging approaches to overcome the effect of immunogenicity, in addition to investigative strategies. PMID- 25826139 TI - A clinical biomarker assay to quantitate thymic stromal lymphopoietin in human plasma at sub-pg/ml level. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an attractive therapeutic target for the treatment of allergic diseases, and plasma TSLP is a potential patient selection marker in the development of therapeutic agents. RESULTS: We developed and validated an ultrasensitive electrochemiluminescence assay for measurement of TSLP in plasma with a lower limit of quantitation of 0.12 pg/ml, which allowed the quantitation of TSLP in approximately 90% of human plasma samples tested. The assay demonstrated excellent performance characteristics, including precision, accuracy, sensitivity and dilution linearity. Stability and biological variability of TSLP in plasma were also assessed for clinical sample analysis and data interpretation. CONCLUSION: The validated TSLP assay enables assessment of circulating TSLP as a patient selection marker in the development of therapeutics to treat atopic diseases. PMID- 25826141 TI - Opiorphin analysis in equine plasma and urine using hydrophilic interaction LC MS. AB - BACKGROUND: Due to opiorphin's analgesic and antidepressant functions, its illicit use is rumored in some racing jurisdictions. Opiorphin is very difficult to detect due to its hydrophilic nature and rapid degradation in plasma and urine samples. METHODOLOGY & RESULTS: We have developed a sensitive, reliable method for opiorphin detection and confirmation in equine samples, using EDTA to inhibit analyte degradation between the time of collection and analysis. Opiorphin was extracted by weak cation exchange followed by analysis using HILIC-MS/MS. The method was validated and the LOD was determined to be 50 pg/ml in equine plasma and urine. CONCLUSION: The method has good selectivity and precision and is the first reported method for the detection of opiorphin in equine plasma and urine. PMID- 25826140 TI - Immunocapture and microplate-based activity and quantity measurement of pyruvate dehydrogenase in human peripheral blood mononuclear cells. AB - BACKGROUND: Pyruvate dehydrogenase (PDH) activity is altered in many human disorders. Current methods require tissue samples and yield inconsistent results. We describe a modified method for measuring PDH activity from isolated human peripheral blood mononuclear cells (PBMCs). RESULTS/METHODOLOGY: We found that PDH activity and quantity can be successfully measured in human PBMCs. Freeze thaw cycles cannot efficiently disrupt the mitochondrial membrane. Processing time of up to 20 h does not affect PDH activity with proteinase inhibitor addition and a detergent concentration of 3.3% showed maximum yield. Sample protein concentration is correlated to PDH activity and quantity in human PBMCs from healthy subjects. CONCLUSION: Measuring PDH activity from PBMCs is a novel, easy and less invasive way to further understand the role of PDH in human disease. PMID- 25826142 TI - An ultrasensitive nano UHPLC-ESI-MS/MS method for the quantification of three neuromedin-like peptides in microdialysates. AB - AIM: An ultrasensitive nano UHPLC-ESI-MS/MS method is developed to simultaneously monitor three low-concentration neuromedin-like peptides in microdialysates. RESULTS: Peptide preconcentration and sample desalting is performed online on a trap column. A shallow gradient slope at 300 nl/min on the analytical column maintained at 35 degrees C, followed by two saw-tooth column wash cycles, results in the highest sensitivity and the lowest carryover. The validated method allows the accurate and precise quantification of 0.5 pM neurotensin and neuromedin N (2.5 amol on column), and of 3.0 pM neuromedin B (15.0 amol on column) in in vivo microdialysates without the use of internal standards. CONCLUSION: The assay is an important tool for elucidating the role of these neuromedin-like peptides in the pathophysiology of neurological disorders. PMID- 25826143 TI - Effects of Pomegranate Extract Supplementation on Cardiovascular Risk Factors and Physical Function in Hemodialysis Patients. AB - The purpose of this study was to evaluate the effects of oral supplementation with pomegranate extract on cardiovascular risk, physical function, oxidative stress, and inflammation in hemodialysis (HD) patients. Thirty-three HD subjects were randomized to the pomegranate (POM) or placebo (CON) group. Patients in POM ingested a 1000 mg capsule of a purified pomegranate polyphenol extract 7 days/week for 6 months. Individuals in CON ingested a noncaloric placebo capsule using the same protocol. Measurements were conducted at baseline and repeated 6 months following the start of the intervention. Brachial blood pressure (BP) was obtained using an automatic digital BP monitor. Cardiovascular risk was assessed using ultrasound and arterial tonometry. Blood samples were collected for the measurements of circulating markers of inflammation, oxidative stress, and antioxidant capacity. Muscle strength and physical function were assessed by isokinetic dynamometry, a validated shuttle walk test, and a battery of tests to assess functional fitness. Systolic blood pressure and diastolic blood pressure were reduced by 24 +/- 13.7 and 10 +/- 5.3 mmHg, respectively, in POM (P < .05). However, the BP differences in POM were no longer significant after controlling for baseline BP. The paraoxonase-1 activity increased by 26.6% (P < .05) in POM, compared to no significant change in CON. However, pomegranate supplementation had no effect on other markers of cardiovascular disease risk, inflammation and oxidative stress, or measures of physical function and muscle strength. While pomegranate extract supplementation may reduce BP and increase the antioxidant activity in HD patients, it does not improve other markers of cardiovascular risk, physical function, or muscle strength. PMID- 25826144 TI - Physicochemical design and analysis of self-propelled objects that are characteristically sensitive to environments. AB - The development of self-propelled motors that mimic biological motors is an important challenge for the transport of either themselves or some material in a small space, since biological systems exhibit high autonomy and various types of responses, such as taxis and swarming. In this perspective, we review non-living systems that behave like living matter. We especially focus on nonlinearity to enhance autonomy and the response of the system, since characteristic nonlinear phenomena, such as oscillation, synchronization, pattern formation, bifurcation, and hysteresis, are coupled to self-motion of which driving force is the difference in the interfacial tension. Mathematical modelling based on reaction diffusion equations and equations of motion as well as physicochemical analysis from the point of view of the molecular structure are also important for the design of non-living motors that mimic living motors. PMID- 25826145 TI - HF-(NH4)2S2O8-HCl Mixtures for HNO3- and NOx-free Etching of Diamond Wire- and SiC-Slurry-Sawn Silicon Wafers: Reactivity Studies, Surface Chemistry, and Unexpected Pyramidal Surface Morphologies. AB - The wet-chemical treatment of silicon wafers is an important production step in photovoltaic and semiconductor industries. Solutions containing hydrofluoric acid, ammonium peroxodisulfate, and hydrochloric acid were investigated as novel acidic, NOx-free etching mixtures for texturization and polishing of monocrystalline silicon wafers. Etching rates as well as generated surface morphologies and properties are discussed in terms of the composition of the etching mixture. The solutions were analyzed with Raman and UV/vis spectroscopy as well as ion chromatography (IC). The silicon surfaces were investigated by scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), diffuse reflection infrared spectroscopy (DRIFT), and X-ray photoelectron spectroscopy (XPS). Surprisingly, pyramidal surface structures were found after etching SiC-slurry as well as diamond wire-sawn monocrystalline Si(100) wafers with hydrochloric acid-rich HF-(NH4)2S2O8-HCl mixtures. Acidic etching solutions are generally not known for anisotropic etching. Thus, the HNO3-free mixtures might allow to replace KOH/i-propanol and similar alkaline solutions for texturization of monosilicon wafers at room temperature with less surface contamination. Besides, common HNO3-based etching mixtures may be replaced by the nitrate-free system, leading to significant economic and ecological advantages. PMID- 25826146 TI - Tackling Critical Catalytic Residues in Helicobacter pylori L-Asparaginase. AB - Bacterial asparaginases (amidohydrolases, EC 3.5.1.1) are important enzymes in cancer therapy, especially for Acute Lymphoblastic Leukemia. They are tetrameric enzymes able to catalyze the deamination of L-ASN and, to a variable extent, of L GLN, on which leukemia cells are dependent for survival. In contrast to other known L-asparaginases, Helicobacter pylori CCUG 17874 type II enzyme (HpASNase) is cooperative and has a low affinity towards L-GLN. In this study, some critical amino acids forming the active site of HpASNase (T16, T95 and E289) have been tackled by rational engineering in the attempt to better define their role in catalysis and to achieve a deeper understanding of the peculiar cooperative behavior of this enzyme. Mutations T16E, T95D and T95H led to a complete loss of enzymatic activity. Mutation E289A dramatically reduced the catalytic activity of the enzyme, but increased its thermostability. Interestingly, E289 belongs to a loop that is very variable in L-asparaginases from the structure, sequence and length point of view, and which could be a main determinant of their different catalytic features. PMID- 25826147 TI - Synthesis of desfluorinated nebivolol isomers. AB - The syntheses of all possible stereoisomers of desfluorinated side products of the potent antihypertensive beta-blocker nebivolol are reported. A straightforward approach using a common racemic precursor was employed to obtain the desired optically active building blocks. For one series of compounds, a Sharpless asymmetric epoxidation (SAE) route yielded in a direct fashion the required compounds whereas a Mitsunobu reaction was selected to obtain the other series of compounds. This offers a flexible approach to all desfluoronebivolol side-products in order to fully characterize them. PMID- 25826148 TI - Searching for indole derivatives as potential mushroom tyrosinase inhibitors. AB - Tyrosinase is a copper-containing enzyme widely distributed in nature, involved in the biosynthesis of melanin whose role is to protect the skin from ultraviolet damage. A great interest has been shown on the melanin involvement in malignant melanoma and other carcinogenetic processes. These phenomena have encouraged the research of tyrosinase inhibitors useful in therapeutic field as well as in foods and cosmetics to prevent browning. The idea was to screen our "in house" database to select suitable lead compounds for the discovery of potential drug-inhibiting enzyme. The obtained biological results demonstrated that compounds containing 4 fluorobenzyl moiety at N - 1 position of indole system showed the best activity. In addition, the role of the portion linked to the carbonyl group at C - 3 was discussed. A Lineweaver-Burk kinetic analysis of the most active indoles, CHI 1043 and derivative 4, showed a mixed-type inhibition in the presence of L-3,4 dihydroxyphenylalanine (L-DOPA) as substrate. PMID- 25826149 TI - Synthesis and evaluation of naphthalene-based thiosemicarbazone derivatives as new anticancer agents against LNCaP prostate cancer cells. AB - Fourteen new naphthalene-based thiosemicarbazone derivatives were designed as anticancer agents against LNCaP human prostate cancer cells and synthesized. MTT assay indicated that compounds 6, 8 and 11 exhibited inhibitory effect on LNCaP cells. Among these compounds, 4-(naphthalen-1-yl)-1-[1-(4 hydroxyphenyl)ethylidene)thiosemicarbazide (6), which caused more than 50% death on LNCaP cells, was chosen for flow cytometric analysis of apoptosis. Flow cytometric analysis pointed out that compound 6 also showed apoptotic effect on LNCaP cells. Compound 6 can be considered as a promising anticancer agent against LNCaP cells owing to its potent cytotoxic activity and apoptotic effect. PMID- 25826150 TI - Qualitative Multiresidue Screening Method for 143 Veterinary Drugs and Pharmaceuticals in Milk and Fish Tissue Using Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. AB - A wide-scope screening methodology has been developed for the identification of veterinary drugs and pharmaceuticals in fish tissue and milk using ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). The method was validated using a qualitative approach at two concentration levels. The detection of the residues was accomplished by retention time, accurate mass, and the isotopic fit using an in-house database. Product-ion spectra were used for unequivocal identification of the compounds. Generic sample treatment was applied. The majority of the compounds were successfully detected and identified at concentration levels of 150 ng mL(-1) in milk and 200 MUg kg( 1) in fish (>80% of the compounds in both matrices), whereas satisfactory results were also obtained at concentration levels of 15 ng mL(-1) in milk and 20 MUg kg( 1) in fish (>60% of the compounds detected and identified). PMID- 25826152 TI - Synthesis of new sulfonyloximes and their use in free-radical olefin carbo oximation. AB - New bifunctional reagents for free-radical carbo-oximation of olefins have been developed. In this process, a single reagent can act both as a trap for nucleophilic radicals as well as a source of electrophilic radical via an alpha scission of an alkylsulfonyl radical. This strategy involving the addition of a C centered electrophilic radical and an oxime across the double bond of an electron rich alkene is initiated with a t-BuO radical following an unusual mechanism, supported by both experiments and density functional theory calculations. PMID- 25826153 TI - The Turner syndrome in patient with 45X/47XXX mosaic karyotype--case report. AB - BACKGROUND: Turner syndrome (TS) is a gonadal dysgenesis related to partial or total lack of one of the X chromosomes. It this report we describe a young patient presenting some somatic features of TS, who underwent spontaneous puberty and was eumenoorheic up to the age of 23. METHODS: Using fluorescent in situ hybridization (FISH) mosaic karyotype (45X[131]/47XXX[9]) of TS and triple X syndrome was found. RESULTS: She presented uncommon for TS somatic hemihypotrophy and underwent growth hormone and surgical therapy. The patient was diagnosed with premature ovarian failure when she was 23, with absent follicular reserve. Clinical features of this case and a few published cases will be reviewed briefly. PMID- 25826154 TI - Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 30-34 weeks. AB - OBJECTIVE: To investigate the potential value of combined screening by maternal characteristics and medical history (maternal factors), estimated fetal weight (EFW), uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in 9472 singleton pregnancies at 30-34 weeks' gestation, comprising 469 that delivered SGA neonates and 9003 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if UtA-PI, MAP and serum PlGF or sFlt-1, individually or in combination, improved the prediction of SGA neonates provided from screening by maternal factors and EFW. RESULTS: Compared to the normal group, mean log10 multiples of the median (MoM) values of UtA-PI, MAP and serum sFlt-1 were significantly higher and log10 MoM PlGF was lower in the SGA group. Multivariable logistic regression analysis demonstrated that in the prediction of SGA neonates with a birth weight < 5(th) percentile, delivering < 5 weeks and >= 5 weeks after assessment, there were significant independent contributions from maternal factors, EFW, UtA-PI, MAP, and serum PlGF and sFlt-1, but the best performance was provided by a combination of maternal factors, EFW, UtA-PI, MAP and serum PlGF, excluding sFlt-1. Combined screening predicted, at a 10% false positive rate, 89%, 94%, 96% of SGA neonates delivering at 32-36 weeks' gestation with birth weight < 10(th) , < 5(th) and < 3(rd) percentiles, respectively; the respective detection rates of combined screening for SGA neonates delivering >= 37 weeks were 57%, 65% and 72%. CONCLUSION: Combined screening by maternal factors and biophysical and biochemical markers at 30-34 weeks' gestation could identify a high proportion of pregnancies that will deliver SGA neonates. PMID- 25826156 TI - New iron tetrazolate frameworks: synthesis, temperature effect, thermal behaviour, Mossbauer and magnetic studies. AB - The exploration of the FeF3/FeF2-Hamtetraz-HF system in dimethylformamide by solvothermal synthesis evidences two isostructural 3D hybrid fluoroferrates. They are prepared from the same starting mixture at two different synthesis temperatures: 120 degrees C for [Hdma].(Fe4(II)Fe(III)F8(H2O)2(amtetraz)4) () and 140 degrees C for [Hdma]1.5.(Fe4.5(II)Fe0.5(III)F7(H2O)(HCOO)(amtetraz)4) (). Both compounds are characterized by single crystal X-ray diffraction, X-ray thermodiffraction, TGA analysis, Mossbauer spectrometry and SQUID magnetometry. They crystallize in the monoclinic system and are built from two distinct chains connected by aminotetrazolate anions. The first chain infinity(Fe(II)FN4) is common to and and can be found in numerous fluorides. In the second chain infinity(Fe3X12) (X = F, N, O), iron cations adopt both valence states Fe(ii)/Fe(iii). The hydrolysis of DMF implies the formation of a [Hdma](+) cation and a (HCOO)(-) anion. The presence of Fe(3+) in both phases is evidenced by (57)Fe Mossbauer spectrometry. The magnetic properties are studied and two transitions from a paramagnetic regime to a long range ordered state below 30 K and 5 K are identified. PMID- 25826157 TI - Antibiotic dosing in obesity: the search for optimum dosing strategies. AB - Global obesity has nearly doubled and is now a common occurrence in high-income and developing countries. The World Health Organization estimates that more than 1.4 billion adults are obese. Although the prevalence of obesity is increasing over the last decades, pharmacokinetic evaluations are still conducted in individuals with a body weight of approximately 70 kg. Morbid obesity is associated with several pathophysiological changes that can profoundly affect drug distribution and clearance. There are currently no specific dosing recommendations for antibiotics in obese patients, making dosing suggestions primarily based on pharmacokinetic characteristics of the medications and dosing recommendations in other disease states. Understanding of the pharmacokinetic alterations and maximum doses of antibiotics safely used is paramount to appropriate treatment in the obese population. PMID- 25826155 TI - Crystal structure of extracellular domain of human lectin-like transcript 1 (LLT1), the ligand for natural killer receptor-P1A. AB - Emerging evidence has revealed the pivotal roles of C-type lectin-like receptors (CTLRs) in the regulation of a wide range of immune responses. Human natural killer cell receptor-P1A (NKRP1A) is one of the CTLRs and recognizes another CTLR, lectin-like transcript 1 (LLT1) on target cells to control NK, NKT and Th17 cells. The structural basis for the NKRP1A-LLT1 interaction was limitedly understood. Here, we report the crystal structure of the ectodomain of LLT1. The plausible receptor-binding face of the C-type lectin-like domain is flat, and forms an extended beta-sheet. The residues of this face are relatively conserved with another CTLR, keratinocyte-associated C-type lectin, which binds to the CTLR member, NKp65. A LLT1-NKRP1A complex model, prepared using the crystal structures of LLT1 and the keratinocyte-associated C-type lectin-NKp65 complex, reasonably satisfies the charge consistency and the conformational complementarity to explain a previous mutagenesis study. Furthermore, crystal packing and analytical ultracentrifugation revealed dimer formation, which supports a complex model. Our results provide structural insights for understanding the binding modes and signal transduction mechanisms, which are likely to be conserved in the CTLR family, and for further rational drug design towards regulating the LLT1 function. PMID- 25826158 TI - Tricyclic and SSRI usage influences the association between BMI and health risk factors. AB - To determine if selective-serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) influence the association between obesity and cardiovascular disease risk, participants from the Third National Health and Nutrition Examination Survey (NHANES III; 1988-1992) and continuous NHANES (1999 2009, n = 18 274) were used. For a given body mass index (BMI), individuals taking SSRIs (n = 219) tended to have significantly better health risk profiles with lower systolic blood pressure (P = 0.002) and higher high-density lipoprotein (P = 0.003) compared with non-users. Conversely, those who used TCAs (n = 116) had significantly worse health risk profiles with higher diastolic blood pressure (P <= 0.0001) and triglycerides (P = 0.023) as compared with non users for a given BMI. Insulin resistance (HOMA-IR) was higher in TCA users and those with larger BMIs, whereby the differences in insulin resistance between TCA users and non-users was greater with higher BMIs (interaction effect: P = 0.013). Furthermore, individuals taking SSRIs were less likely to have cardiovascular disease than non-users (odds ratio, 95% confidence interval = 0.50, 0.33-0.75) for a given BMI, with no differences by TCA use (odds ratio = 0.74, 0.44-1.24). SSRI and TCA use may alter how body weight relates with cardiovascular risk. When prescribing antidepressant medications, it may be necessary to monitor and consider body weight and cardiovascular risk profile of individual patients. PMID- 25826160 TI - Self-reported physical activity is associated with cognitive function in lean, but not obese individuals. AB - Convergent evidence demonstrates that greater physical activity is associated with better cognitive functioning across many patient and healthy samples. However, this relationship has not been well examined among obese individuals and remains unclear. The present study examined the relationship between performance based measures of attention/executive function and self-reported physical activity, as measured by the International Physical Activity Questionnaire, among lean (n = 36) and obese (n = 36) college students. Lean individuals performed better than obese individuals on measures of attention/executive function. No significant differences in self-reported physical activity emerged between weight groups. Higher self-reported physical activity was related to faster reaction time in lean individuals but slower reaction time in obese individuals. Additionally, in lean individuals, higher levels of self-reported physical activity were related to more errors on a task of speeded inhibitory control. The results are consistent with previous research demonstrating that greater physical activity is associated with faster attention and executive function abilities in healthy samples and highlight the importance of examining reaction time and accuracy indices separately on these measures. The lack of association among obese individuals may be due in part to inaccurate self-report in the current study. Additionally, the cognitive consequences of obesity may outweigh the benefits of physical activity in this group. Future work should investigate these associations in obese individuals using physical activity interventions, as well as a combination of self-report and objective measures to investigate discrepancies in reporting. PMID- 25826159 TI - Prevalence of simple and abdominal obesity in Greek adolescents: the ADONUT study. AB - The aim of this study was to assess the prevalence of underweight, normal body weight, overweight, obesity and abdominal obesity in Greek adolescents. A nationally representative sample of 37,344 Greek adolescents, aged 12-19 years old, was recruited from schools throughout the country during 2010-2012. Body weight, stature and waist circumference were measured. The prevalence of each weight status category was defined according to the International Obesity Task Force criteria and abdominal obesity was diagnosed according to the International Diabetes Federation. One-third of the participants were either overweight or obese. Among adolescent boys, the prevalence of underweight was 3.3%, 27.9% were overweight and 8.9% were considered obese. Among the girls, 5.8% of the population were underweight, 19.4% were considered overweight and 6.0% obese. Abdominal obesity was diagnosed in 9.1% of the sample (8.9% of the boys and 9.2% of the girls). In 4.5% of the population, simple and central obesity coincided. The pooled prevalence of overweight and obesity as well as the rate of abdominal obesity appear to level off during the course of adolescence. The results indicate a high prevalence of overweight among Greek adolescents. PMID- 25826161 TI - Food consumption, obesity and abnormal glycaemic control in a Canadian Inuit community. AB - Dietary and lifestyle factors may contribute to diabetes and obesity in the Canadian Inuit. We documented dietary patterns, physical activity level, obesity, blood glucose abnormalities and diabetes prevalence in a Canadian Inuit community. There were 250 Inuit residents of Repulse Bay, Nunavut, who had an interview about diet and physical activity, measurement of weight and height, and laboratory studies (194 subjects). Children, adolescents and younger adults (aged < 48 years) consumed significantly less country food and more processed snack foods and sweet drinks than older adults (aged >= 48 years). Only 88 of 250 subjects (35%) reported that they went out on the land once or more per week. Of the 85 children and adolescent subjects (aged 7-17 years), 11 (13%) were obese. Average body mass index for adults (aged >= 18 years) was 29 +/- 6 kg m(-2) , and 61 adults (37%) were obese (body mass index >=30 kg m(-2) ). In the 140 adults who had laboratory studies, 18 adults (13%) had a blood glucose abnormality, including 10 adults (7%) with impaired fasting glucose, four adults (3%) with impaired glucose tolerance and six adults (4%) with diabetes (five adults previously undiagnosed). Twelve of the 194 subjects tested (6%) had fasting insulin >=140 pmol L(-1) (mean, 196 +/- 87 pmol L(-1) ). In summary, there was a high prevalence of poor dietary choices, limited physical activity, obesity and type 2 diabetes in this Inuit community. Public health programmes are needed to improve the dietary and health status of this community. PMID- 25826162 TI - The cost-effectiveness of primary care referral to a UK commercial weight loss programme. AB - Primary care referral to commercial weight loss programmes that follow best practice is included in current UK guidance on the management of adult obesity. This study investigated whether such a programme was cost-effective compared with usual care. A decision-analytical Markov model was developed to estimate the lifetime costs and benefits of the referral programme compared with usual care and enable a cost-utility analysis. The model cohort transited between body mass index classifications and type 2 diabetes, stroke and myocardial infarction (MI) with risk, cost and effect parameter values taken from published literature. The cost per incremental quality-adjusted life year (QALY) was calculated. Extensive deterministic and scenario sensitivity analyses and probabilistic sensitivity analyses (PSA) were conducted. At 12 months, the incremental cost-effectiveness ratio was L6906, indicating that programme referral was cost-effective. Over a lifetime, referral to the commercial programme was dominant as it led to a cost saving of L924 and conferred incremental benefit (0.22 QALY) over usual care. Model simulations estimated lower lifetime rates of type 2 diabetes, stroke and MI as a result of the weight loss achieved. The results were robust to extensive sensitivity analyses. The PSA indicated that programme referral had a 68% chance of being cost-effective at a willingness to pay per incremental QALY threshold of L20,000. Referral to the programme dominated usual care, being both cheaper and more effective. These results compare favourably with economic evaluations of other obesity interventions and add to a growing evidence base on the cost effectiveness of commercial weight loss providers and practices. PMID- 25826164 TI - Orlistat-induced fulminant hepatic failure. AB - Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction. PMID- 25826163 TI - The population distribution of the sagittal abdominal diameter (SAD) and SAD/height ratio among Finnish adults. AB - Sagittal abdominal diameter (SAD; 'abdominal height' measured in supine position) may improve upon conventional anthropometry for predicting incident cardiometabolic diseases. However, the SAD is used infrequently by practitioners and epidemiologists. A representative survey of Finnish adults in 2000-2001 collected body measurements including SAD (by sliding-beam calliper) using standardized protocols. Sampled non-pregnant adults (ages 30+ years; 79% participation) provided 6123 SAD measurements from 80 health centre districts. Through stratified, complex survey design, these data represented 2.86 million adults at ages 30+ years. SAD ranged from 13.5 to 38.0 cm, with a population mean (standard error) of 21.7 (0.05) cm and median (interquartile range) of 21.0 (19.1 23.4). Median SAD was higher at ages 50+ years compared with ages 30-49 both for men (22.4 [20.5-24.6] vs. 20.8 [19.3-22.7]) and women (21.7 [19.6-23.9] vs. 19.4 [17.8-21.4]). The SAD/height ratio was similar (0.118) for both sexes at 30-39 years, rising more steeply with age for women than men. Attaining only a basic education, compared with a high level, was associated with increased mean (95% confidence interval) SADs for men (22.6 [22.3-22.8] vs. 22.0 [21.7-22.2]) and women (21.8 [21.5-22.0] vs. 20.6 [20.4-20.8]). Finland's early experience with nationally representative SAD measurements provides normative reference values and physiological insights useful for investigations of cardiometabolic risk. PMID- 25826165 TI - Prevention of stricture after large esophageal endoscopic submucosal dissections. PMID- 25826166 TI - Is there a role for endoscopic ultrasound-guided fine-needle biopsy in pancreatic cancer? PMID- 25826167 TI - Comparison of adenoma detection and miss rates between a novel balloon colonoscope and standard colonoscopy: a randomized tandem study. PMID- 25826168 TI - Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. AB - This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). The Guideline was also reviewed and endorsed by the British Society of Gastroenterology (BSG). It addresses the roles of small bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders. Main recommendations 1 ESGE recommends small bowel video capsule endoscopy as the first-line investigation in patients with obscure gastrointestinal bleeding (strong recommendation, moderate quality evidence). 2 In patients with overt obscure gastrointestinal bleeding, ESGE recommends performing small-bowel capsule endoscopy as soon as possible after the bleeding episode, optimally within 14 days, in order to maximize the diagnostic yield (strong recommendation, moderate quality evidence). 3 ESGE does not recommend the routine performance of second-look endoscopy prior to small-bowel capsule endoscopy; however whether to perform second-look endoscopy before capsule endoscopy in patients with obscure gastrointestinal bleeding or iron deficiency anaemia should be decided on a case-by-case basis (strong recommendation, low quality evidence). 4 In patients with positive findings at small-bowel capsule endoscopy, ESGE recommends device-assisted enteroscopy to confirm and possibly treat lesions identified by capsule endoscopy (strong recommendation, high quality evidence). 5 ESGE recommends ileocolonoscopy as the first endoscopic examination for investigating patients with suspected Crohn's disease (strong recommendation, high quality evidence). In patients with suspected Crohn's disease and negative ileocolonoscopy findings, ESGE recommends small-bowel capsule endoscopy as the initial diagnostic modality for investigating the small bowel, in the absence of obstructive symptoms or known stenosis (strong recommendation, moderate quality evidence).ESGE does not recommend routine small-bowel imaging or the use of the PillCam patency capsule prior to capsule endoscopy in these patients (strong recommendation, low quality evidence). In the presence of obstructive symptoms or known stenosis, ESGE recommends that dedicated small bowel cross-sectional imaging modalities such as magnetic resonance enterography/enteroclysis or computed tomography enterography/enteroclysis should be used first (strong recommendation, low quality evidence). 6 In patients with established Crohn's disease, based on ileocolonoscopy findings, ESGE recommends dedicated cross-sectional imaging for small-bowel evaluation since this has the potential to assess extent and location of any Crohn's disease lesions, to identify strictures, and to assess for extraluminal disease (strong recommendation, low quality evidence). In patients with unremarkable or nondiagnostic findings from such cross-sectional imaging of the small bowel, ESGE recommends small-bowel capsule endoscopy as a subsequent investigation, if deemed to influence patient management (strong recommendation, low quality evidence). When capsule endoscopy is indicated, ESGE recommends use of the PillCam patency capsule to confirm functional patency of the small bowel (strong recommendation, low quality evidence). 7 ESGE strongly recommends against the use of small-bowel capsule endoscopy for suspected coeliac disease but suggests that capsule endoscopy could be used in patients unwilling or unable to undergo conventional endoscopy (strong recommendation, low quality evidence). PMID- 25826169 TI - Assessment of competence in ERCP. PMID- 25826170 TI - Reply to Konge et al. PMID- 25826173 TI - Gastrointestinal endoscopy sedation and monitoring practices in Spain: a nationwide survey in the year 2014. AB - BACKGROUND AND STUDY AIMS: The introduction of new sedative agents and a desire for improved patient care have encouraged the use of sedation for gastrointestinal (GI) endoscopy over the last decade. This survey aims to provide, within Spain, national and regional data on gastroenterologists' endoscopic sedation and monitoring practices, and on their attitudes concerning these practices. METHODS: A 19-item survey covering the current practices of sedation and monitoring in GI endoscopy was electronically mailed to all members of the three nationwide scientific societies. RESULTS: Of 2476 e-mailed questionnaires, a total of 569 (23 %) were returned, proportionally representing the structure of the Spanish health care system. Monitoring and resuscitation resources were universally available, as well as post-endoscopy recovery rooms. Endoscopy teams usually included a registered nurse (98.5 %), an auxiliary nurse (80.5 %), and other physicians (25.7 %), generally anesthesiologists. More than half of esophagogastroduodenoscopies (EGDs) are performed with the patient under sedation; in 25 % of centers, more than 95 % colonoscopies are performed with the patient sedated, but a wide variation was observed. Pre-endoscopic risk is assessed in the vast majority of procedures. Propofol is the most commonly used sedative, either alone (in 70 % of EGDs and 80 % of colonoscopies) or in combination with other drugs. Private funding of a clinic was the only predictor of a significant increase in the use of sedation; 57.7 % of the respondents stated having difficulties in implementing sedation, with the limited availability of anesthesiologists and resuscitation training for the auxiliary staff the most common complaints. CONCLUSIONS: The use of sedation during GI endoscopy in Spain varies widely but is on the increase and is more common in private practice. Propofol is the preferred sedative in all procedures. PMID- 25826174 TI - [In Process Citation]. PMID- 25826175 TI - [In Process Citation]. PMID- 25826176 TI - Video comment on Alberto Larghi et al., pages 308-314. PMID- 25826177 TI - Video comment on Shayan Irani et al., pages 315-321. PMID- 25826179 TI - Effects and mechanisms of the secondary structure on the antimicrobial activity and specificity of antimicrobial peptides. AB - A 15-mer cationic alpha-helical antimicrobial peptide HPRP-A1 was used as the parent peptide to study the effects of peptide secondary structure on the biophysical properties and biological activities. Without changing the amino acid composition of HPRP-A1, we designed two alpha-helical peptides with either higher or lower helicity compared with the parent peptide, a beta-sheet peptide and a random coiled peptide using de novo design approach. The secondary structures were confirmed by circular dichroism spectroscopy. The three alpha-helical peptides exhibited comparable antibacterial activities, but their hemolytic activity varied from extreme hemolysis to no hemolysis, which is correlated with their helicity. The beta-sheet peptide shows poor antibacterial and strong hemolytic activities. More interestingly, the random coil peptide shows no antibacterial activity against Gram-negative bacteria, weak antibacterial activity against Gram-positive bacteria, and extremely weak hemolytic activity. Bacterial membrane permeabilization was also testified on peptides with different secondary structures. Tryptophan fluorescence experiment revealed that the peptide binding preference to the lipid vesicles for mimicking the prokaryotic or eukaryotic membranes was consistent with their biological activities. With the de novo design approach, we proved that it is important to maintain certain contents of amphipathic secondary structure for a desirable biological activity. We believe that the de novo design approach of relocation of the amino acids within a template sequence could be an effective approach in optimizing the specificity of an antimicrobial peptide. PMID- 25826180 TI - Antigenotoxic and antioxidant potentials of newly derivatized compound naringenin oxime relative to naringenin on human mononuclear cells. AB - We investigated antigenotoxic and antioxidative effects of newly derivatized compound naringenin-oxime (NG-Ox) compared to its mother compound naringenin (NG) against oxidative damage induced by hydrogen peroxide (HP) in human peripheral blood mononuclear cells (PBMC). Antigenotoxic activity was assessed using alkaline single cell gel electrophoresis assay (comet assay). Oxidative status was evaluated by measurement of total antioxidant status, total oxidant status and lipid hydroperoxide levels in the cells. Oxidative stress index was also calculated. Both NG and NG-Ox show a protective effect against HP-induced oxidative damage on PBMC and are able to reduce oxidative stress. The percentage of antigenotoxic and antioxidant potential progressively increased in a dose dependent manner. However, these activities were found to be more significant in NG-Ox-treated cells than in NG-treated cells. Taken together, these observations provide evidences indicating that both NG and NG-Ox are able to protect cells against oxidative damage and apparently NG-Ox is more effective than NG. PMID- 25826181 TI - Sex-related effects of imidacloprid modulated by piperonyl butoxide and menadione in rats. Part II: genotoxic and cytotoxic potential. AB - Despite its intended use, imidacloprid causes genotoxic and cytotoxic effects in mammals, especially in the presence of metabolic activation systems. The aim of this study was to determine to which extent these effects are sex related and how its metabolism modulators piperonyl butoxide and menadione affect its toxicity. Male and female Sprague-Dawley rats were injected with the intraperitoneal LD50 dose of imidacloprid alone (170 mg/kg) or pretreated with piperonyl butoxide (100 mg/kg) and menadione (25 mg/kg) for 12 and 24 h. Structural chromosome aberrations, abnormal cells and mitotic index were determined microscopically in bone marrow cells. Male rats showed susceptibility to the genotoxic effects of imidacloprid. Piperonyl butoxide was effective in countering this effect only at 24 h, whereas menadione exacerbated imidacloprid-induced genotoxicity. Piperonyl butoxide and menadione pretreatments increased the percentage of structural chromosome aberrations and abnormal cells in females. Imidacloprid decreased the mitotic index, whereas pretreatment with piperonyl butoxide and menadione showed improvement in both sexes. We believe that CYP450-mediated metabolism of imidacloprid is under the hormonal control and therefore that its genotoxicity is sex related. Piperonyl butoxide pretreatment also showed sex-related modulation. The hormonal effects on imidacloprid biotransformation require further investigation. PMID- 25826182 TI - The in vitro exposure to cypermethrin does not inhibit the proliferative response of peripheral blood mononuclear cells. AB - This study evaluated the effect of in vitro exposure to cypermethrin on peripheral blood mononuclear cells proliferative response, considering reduced peripheral blood mononuclear cells proliferative response observed in individuals occupationally exposed to pyrethroids. Peripheral blood mononuclear cells were obtained from 21 healthy subjects (28.0 +/- 9.0 years old). The effect of cypermethrin (at 0.5, 1.0 and 5.0 mg/ml) on cell viability was evaluated by flow cytometry using an apoptosis detection kit. Cell proliferation (PI) was evaluated by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) fluorescence decay using flow cytometry. Cells labeled with CFSE were exposed, in vitro, to cypermethrin (0.5, 1.0, 2.0, 2.5 and 4 MUg/ml) and stimulated with phytohemagglutinin (PHA 1.0 or 5.0 MUg/ml) for 5 d (37 degrees C, 5% CO2). The in vitro treatment of peripheral blood mononuclear cells with cypermethrin did not induce apoptosis or necrosis after 5 d in culture. Stimulation by PHA induced cell proliferation (PI = 1.29 +/- 1.09 and 2.01 +/- 0.62, PHA at 1.0 and 5.0 MUg/ml, respectively, mean +/- SD) and in vitro exposure to cypermethrin did not alter cellular proliferative response to PHA (PI = 1.80 +/- 0.50, 2.60 +/- 0.05 and 2.10 +/- 1.20 for cypermethrin at 1.0, 2.0 and 4.0 MUg/ml, respectively, and PHA at 5.0 MUg/ml). In vitro treatment of peripheral blood mononuclear cells with cypermethrin, at the doses tested, does not affect cell viability or proliferation. These findings suggest that the reduction of proliferation observed on lymphocytes derived from individuals occupationally exposed to pesticides may be related to other mechanisms than direct action of cypermethrin on lymphocytes. PMID- 25826183 TI - Cytogenetic and hematological alterations induced by acute oral exposure of imidacloprid in female mice. AB - Imidacloprid (IMD), 1(6-chloro-3-pyridinyl)methyl)-N-nitro-2-imidazolidinimine, was administered in female mice to study in vivo cytogenetic (chromosomal aberrations (CAs) and micronucleus assay) and hematological effects. The acute oral LD50 was determined to be 150 mg/kg bw in mice following OECD guidelines using AOT StatPgm425 software. The mice were administered orally with distilled water (negative control); mitomycin C (MMC), 1 mg/kg (positive control) and sub lethal doses of 37.5 (low), 75.0 (medium) and 112.5 (high) mg/kg bw (25%, 50% and 75% of LD50) of IMD to analyze CAs and hematological effects after 24 h, whereas micronucleus test (MT) after 48 h. The genotoxicity analysis revealed that selected test doses of IMD--medium and high doses--induced significantly mitotic inhibition (p < 0.01), CAs (p < 0.01) and at high dose micronucleus (MN) formation (p < 0.05). Significant changes in red blood cell (RBC; p < 0.01), hemoglobin (Hb; p < 0.01) and erythrocyte sedimentation rate (ESR; p < 0.001) were observed, except WBC in which significant increase (p < 0.001) was observed. Present observation substantiates overall significant dose dependent genotoxic potential (p < 0.05; r = 0.98) of IMD. Precautions should be taken to minimize possible risk to exposed farmers of the state of Haryana (India)--an agrarian economy. PMID- 25826184 TI - Synthesis and structures of cadmium carboxylate and thiocarboxylate compounds with a sulfur-rich coordination environment: carboxylate exchange kinetics involving tris(2-mercapto-1-t-butylimidazolyl)hydroborato cadmium complexes, [Tm(Bu(t))]Cd(O2CR). AB - A series of cadmium carboxylate compounds in a sulfur-rich environment provided by the tris(2-tert-butylmercaptoimidazolyl)hydroborato ligand, namely, [Tm(Bu(t))]CdO2CR, has been synthesized via the reactions of the cadmium methyl derivative [Tm(Bu(t))]CdMe with RCO2H. Such compounds mimic aspects of cadmium substituted zinc enzymes and also the surface atoms of cadmium chalcogenide crystals, and have therefore been employed to model relevant ligand exchange processes. Significantly, both (1)H and (19)F NMR spectroscopy demonstrate that the exchange of carboxylate groups between [Tm(Bu(t))]Cd(kappa(2)-O2CR) and the carboxylic acid RCO2H is facile on the NMR time scale, even at low temperature. Analysis of the rate of exchange as a function of concentration of RCO2H indicates that reaction occurs via an associative rather than dissociative pathway. In addition to carboxylate compounds, the thiocarboxylate derivative [Tm(Bu(t))]Cd[kappa(1)-SC(O)Ph] has also been synthesized via the reaction of [Tm(Bu(t))]CdMe with thiobenzoic acid. The molecular structure of [Tm(Bu(t))]Cd[kappa(1)-SC(O)Ph] has been determined by X-ray diffraction, and an interesting feature is that, in contrast to the carboxylate derivatives [Tm(Bu(t))]Cd(kappa(2)-O2CR), the thiocarboxylate ligand binds in a kappa(1) manner via only the sulfur atom. PMID- 25826185 TI - An efficient approach to 1,2,3-trisubstituted indole via rhodium catalyzed carbene C(sp(3))-H bond insertion. AB - A method for convenient synthesis of N-alkyl-2-aryl-indole-3-carbaldehyde has been described. A variety of highly valuable indolyl aldehydes have been prepared through this method. Electron donating groups on both aromatic rings (anilinyl and benzyl) facilitate the formation of the desired products. A benzylic C-H insertion by rhodium carbene is the key step for this transformation. PMID- 25826187 TI - Understanding Community-Level Disaster and Emergency Response Preparedness. AB - OBJECTIVE: Community-level disaster readiness is a major component of community health promotion. However, many readiness programs are focused on the response of emergency and health care personnel and not on the preparedness levels of local citizens. This potentially leaves the public unready and unprepared for emergency event response. METHODS: A 20-item survey on general states of disaster preparedness was delivered to the residents of a midsized midwestern county. The residents were asked to share their knowledge of local hazards, emergency systems, and personal preparedness. RESULTS: A convenience sample of 423 residents responded to the survey. Fifty-seven percent (n=241) reported limited personal preparedness. Seventy-six percent (n=321) acknowledged little to no familiarity with residential emergency systems, and 52% (n=220) reported that they did not know how to gain information on public health emergencies, such as pandemic flu and evacuation response. CONCLUSIONS: Local citizens should become educated on the methods to support personal disaster and emergency readiness. Health care and emergency management organizations are encouraged to include these concepts in routine community health promotion activities and to pay special attention to known areas of community vulnerability. Failure to do so creates a population unable to support themselves in the provision of basic health and safety measures. PMID- 25826186 TI - Development of a modular virus clearance package for anion exchange chromatography operated in weak partitioning mode. AB - Anion exchange chromatography (AEX) operated under weak partitioning mode has been proven to be a powerful polishing step as well as a robust viral clearance step in Pfizer's monoclonal antibody (mAb) platform purification process. A multivariate design of experiment (DoE) study was conducted to understand the impact of operating parameters and feedstream impurity levels on viral clearance by weak partitioning mode AEX. Bacteriophage was used initially as a surrogate for neutral and acidic isoelectric point mammalian viruses (e.g., retrovirus and parvovirus). Five different mAbs were used in the evaluation of process parameters such as load challenge (both product and impurities), load pH, load conductivity, and contact time (bed height and flow-rate). The operating ranges obtained from phage clearance studies and Pfizer's historical data were used to define an appropriate operating range for a subsequent clearance study with model retrovirus and parvovirus. Both phage and virus clearance evaluations included feedstreams containing different levels of impurities such as high molecular mass species (HMMS), host cell proteins (HCPs), and host cell DNA. For all the conditions tested, over 5 log10 of clearance for both retrovirus and parvovirus was achieved. The results demonstrated that weak partitioning mode AEX chromatography is a robust step for viral clearance and has the potential to be included as part of the modular viral clearance approach. PMID- 25826188 TI - Identification of a common epitope between enterovirus 71 and human MED25 proteins which may explain virus-associated neurological disease. AB - Enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease with especially severe neurologic complications, which mainly account for fatalities from this disease. To date, the pathogenesis of EV71 in the central neurons system has remained unclear. Cytokine-mediated immunopathogenesis and nervous tissue damage by virus proliferation are two widely speculated causes of the neurological disease. To further study the pathogenesis, we identified a common epitope (co-epitope) between EV71 VP1 and human mediator complex subunit 25 (MED25) highly expressed in brain stem. A monoclonal antibody (2H2) against the co-epitope was prepared, and its interaction with MED25 was examined by ELISA, immunofluorescence assay and Western blot in vitro and by live small animal imaging in vivo. Additionally, 2H2 could bind to both VP1 and MED25 with the affinity constant (Kd) of 10-7 M as determined by the ForteBio Octet System. Intravenously injected 2H2 was distributed in brain stem of mice after seven days of EV71 infection. Interestingly, 2H2-like antibodies were detected in the serum of EV71-infected patients. These findings suggest that EV71 infection induces the production of antibodies that can bind to autoantigens expressed in nervous tissue and maybe further trigger autoimmune reactions resulting in neurological disease. PMID- 25826189 TI - Association between copper levels and myocardial infarction: a meta-analysis. AB - BACKGROUND AND AIMS: There are conflicting reports as to the correlation between copper (Cu) levels and myocardial infarction (MI). The purpose of the present study is to clarify the association between Cu levels and MI. METHODS: We searched articles in Pubmed and the Chinese Journal Full-text Database published as of October 2014. A meta-analysis was used to pool estimates of the standardized mean difference (SMD) with 95% confidence interval (CI). RESULTS: Pooled analysis indicated that subjects with MI had higher serum Cu levels than healthy controls (SMD = 1.629, 95%CI = [1.027, 2.232], Z = 5.30, p < 0.001). Further subgroup analysis stratified by ethnicity indicated that subjects with MI had higher serum Cu levels than healthy controls among members of the Asian race (SMD = 2.191, 95%CI = [1.401, 2.981], Z = 5.43, p < 0.001), but not among members of the Caucasian race (SMD = 0.411, 95%CI = [-0.030, 0.851], Z = 1.83, p = 0.068). The results obtained from hairs showed no association between MI and hair Cu levels (SMD = 0.338, 95% CI = [-0.171, 0.848], Z = 1.30, p = 0.193). But the subgroup analysis stratified by geological location indicated that subjects with MI had higher hair Cu levels than healthy controls in Pakistan (SMD = 0.785, 95% CI = [0.587, 0.983], Z = 10.29, p < 0.001), but not in India (SMD = -9.028, 95% CI = [-10.747, -7.309], Z = 7.77, p < 0.001). CONCLUSION: This meta-analysis indicates a significant association between high serum Cu levels and MI. However, the subgroup analysis found that there was significant effect modification of Cu levels by ethnicity. Thus, we suggest that a trans-regional multicenter study is needed to obtain better understanding of causal relationships between Cu and MI in different human races. PMID- 25826190 TI - Systematic refinement of Canongia Lopes-Padua force field for pyrrolidinium-based ionic liquids. AB - Reliable force field (FF) is a central issue in successful prediction of physical chemical properties via computer simulations. While Canongia Lopes-Padua (CL&P) FF provides good to excellent thermodynamics and structure of pure room temperature ionic liquids (RTILs), it suffers from drastically and systematically underestimated ionic motion. This occurs due to neglected partial electron transfer from the anion to the cation, resulting in unphysically small simulated self-diffusion and conductivity and high shear viscosities. We report a systematic refinement of the CL&P FF for six pyrrolidinium-based RTILs (1-N-butyl 1-methylpyrrolidinium dicyanamide, triflate, bis(fluorosulfonyl)imide, bis(trifluoromethanesulfonyl)imide, tetrafluoroborate, chloride). The elaborated procedure accounts for specific cation-anion interactions in the liquid phase. Once these interactions are described effectively, experimentally determined transport properties can be reproduced with an acceptable accuracy. Together with the original CL&P parameters, our force field fosters computational investigation of ionic liquids. In addition, the reported results shed more light on the chemical nature of cation-anion binding in various families of RTILs. PMID- 25826191 TI - Letter from the editor. PMID- 25826192 TI - Human Vaccines & Immunotherapeutics awards top reviewer of the year. PMID- 25826194 TI - Against vaccine assay secrecy. AB - Increasing the transparency of the evidence base behind health interventions such as pharmaceuticals, biologics, and medical devices, has become a major point of critique, conflict, and policy focus in recent years. Yet the lack of publicly available information regarding the immunogenicity assays upon which many important, widely used vaccines are based has received no attention to date. In this paper we draw attention to this critical public health problem by reporting on our efforts to secure vaccine assay information in respect of 10 vaccines through Canada's access to information law. We argue, under Canadian law, that the public health interest in having access to the methods for these laboratory procedures should override claims by vaccine manufacturers and regulators that this information is proprietary; and, we call upon several actors to take steps to ensure greater transparency with respect to vaccine assays, including regulators, private firms, researchers, research institutions, research funders, and journal editors. PMID- 25826195 TI - Purification, biochemical characterization, and implications of an alkali tolerant catalase from the spacecraft-associated and oxidation-resistant Acinetobacter gyllenbergii 2P01AA. AB - Herein, we report on the purification, characterization, and sequencing of catalase from Acinetobacter gyllenbergii 2P01AA, an extremely oxidation-resistant bacterium that was isolated from the Mars Phoenix spacecraft assembly facility. The Acinetobacter are dominant members of the microbial communities that inhabit spacecraft assembly facilities and consequently may serve as forward contaminants that could impact the integrity of future life-detection missions. Catalase was purified by using a 3-step chromatographic procedure, where mass spectrometry provided respective subunit and intact masses of 57.8 and 234.6 kDa, which were consistent with a small-subunit tetrameric catalase. Kinetics revealed an extreme pH stability with no loss in activity between pH 5 and 11.5 and provided respective kcat/Km and kcat values of ~10(7) s(-1) M(-1) and 10(6) s(-1), which are among the highest reported for bacterial catalases. The amino acid sequence was deduced by in-depth peptide mapping, and structural homology suggested that the catalases from differing strains of A. gyllenbergii differ only at residues near the subunit interfaces, which may impact catalytic stability. Together, the kinetic, alkali-tolerant, and halotolerant properties of the catalase from A. gyllenbergii 2P01AA are significant, as they are consistent with molecular adaptations toward the alkaline, low-humidity, and potentially oxidizing conditions of spacecraft assembly facilities. Therefore, these results support the hypothesis that the selective pressures of the assembly facilities impact the microbial communities at the molecular level, which may have broad implications for future life-detection missions. PMID- 25826197 TI - Assessing vertical jump developmental levels in childhood using a low-cost motion capture approach. AB - Understanding the developmental levels of fundamental movement skills has a critical role in the improvement of motor competence in childhood. In this respect, the use of Microsoft Kinect to assess vertical jumping skill and to predict developmental levels in 9- to 12-yr.-old children was evaluated. 41 boys and girls repeated the countermovement jump test three times. Vertical jumping skill levels were categorized using observational records, while kinematic and temporal parameters were estimated using a biomechanical model based on data acquired by the Kinect. Multivariate analysis of variance (MANOVA) and discriminant analysis verified that the height of the jump and the flight height predict the primary differences in jumping skill developmental levels, and the Kinect-based assessment discriminates these levels. PMID- 25826196 TI - Anisotropic silk biomaterials containing cardiac extracellular matrix for cardiac tissue engineering. AB - Cardiac malformations and disease are the leading causes of death in the United States in live-born infants and adults, respectively. In both of these cases, a decrease in the number of functional cardiomyocytes often results in improper growth of heart tissue, wound healing complications, and poor tissue repair. The field of cardiac tissue engineering seeks to address these concerns by developing cardiac patches created from a variety of biomaterial scaffolds to be used in surgical repair of the heart. These scaffolds should be fully degradable biomaterial systems with tunable properties such that the materials can be altered to meet the needs of both in vitro culture (e.g. disease modeling) and in vivo application (e.g. cardiac patch). Current platforms do not utilize both structural anisotropy and proper cell-matrix contacts to promote functional cardiac phenotypes and thus there is still a need for critically sized scaffolds that mimic both the structural and adhesive properties of native tissue. To address this need, we have developed a silk-based scaffold platform containing cardiac tissue-derived extracellular matrix (cECM). These silk-cECM composite scaffolds have tunable architectures, degradation rates, and mechanical properties. Subcutaneous implantation in rats demonstrated that addition of the cECM to aligned silk scaffold led to 99% endogenous cell infiltration and promoted vascularization of a critically sized scaffold (10 * 5 * 2.5 mm) after 4 weeks in vivo. In vitro, silk-cECM scaffolds maintained the HL-1 atrial cardiomyocytes and human embryonic stem cell-derived cardiomyocytes and promoted a more functional phenotype in both cell types. This class of hybrid silk-cECM anisotropic scaffolds offers new opportunities for developing more physiologically relevant tissues for cardiac repair and disease modeling. PMID- 25826198 TI - Metal ion-assisted photochemical vapor generation for the determination of lead in environmental samples by multicollector-ICPMS. AB - A novel and sensitive approach for the accurate and precise determination of Pb in environmental samples is presented using transition metal ion-assisted photochemical vapor generation (PVG) for sample introduction with multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) detection. A significant improvement in PVG efficiency of lead is achieved in the presence of transition metal ions (Co(2+) and Ni(2+)) in solutions of 5% (v/v) formic acid. The determination of Pb in digests of sediment or soil samples is readily achieved due to coexisting transition metal ions which facilitate the PVG reaction. The method detection limit of 0.005 ng g(-1) (3sigma) using external calibration is comparable to that obtained using hydride generation (HG) ICPMS. However, PVG methodology is simpler, results in lower blanks, and avoids unstable reagents. The accuracy of the proposed method was demonstrated by analysis of several environmental certified reference materials (CRMs; SLRS-5 and SRM1640a river water CRMs and MESS-3, MESS-4, and SRM2702 sediments) with satisfying results. High precision of determination (<0.4% RSD) of Pb in river water and sediments was realized on the basis of isotope dilution calibration. PMID- 25826199 TI - Limb Dominance and Its Effects on the Benefits of Intralimb Transfer of Learning: A Visuomotor Aiming Task. AB - Research has attempted to address what characteristics benefit from transfer of learning; however, it is still unclear which characteristics are effector dependent or independent. Furthermore, it is not clear if intralimb transfer shows, similarly to interlimb transfer, an asymmetry of benefits between the upper limbs. The purpose of the current study is to examine if effector independence effects emerge, as observed in interlimb transfer studies, when transfer to new effector group within the same limb occurs, and whether the pattern of intralimb transfer benefits differ between the limbs. Our results suggest that a visuomotor task transfers within both limbs, even though the transfer benefits within the limbs seem to differ. This was supported by more transfer occurring in the dominant limb than the nondominant limb. Potential control mechanisms used for intralimb transfer are discussed. PMID- 25826200 TI - Non-specific terminology: Moderating shame and guilt in eating disorders. AB - To examine the effects of terminology on affect, 110 women with eating disorders were randomly assigned to read a manufactured discussion thread with uses of the term "acting out," a thread with clinical terms, or were assigned to a no-reading control. An interaction effect was found in which participants who were treated at a day or inpatient level and were in the "acting out" condition experienced reductions in shame and guilt, while those in the clinical term condition experienced increases in shame and guilt, relative to control participants. The ability of terminology to moderate shame and guilt in this population has implications for clinical practice. PMID- 25826201 TI - Coumarin-fused coumarin: antioxidant story from N,N-dimethylamino and hydroxyl groups. AB - Two coumarin skeletons can form chromeno[3,4-c]chromene-6,7-dione by sharing with the C ? C in lactone. The aim of the present work was to explore the antioxidant effectiveness of the coumarin-fused coumarin via six synthetic compounds containing hydroxyl and N,N-dimethylamino as the functional groups. The abilities to quench 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+*)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical revealed that the rate constant for scavenging radicals was related to the amount of hydroxyl group in the scaffold of coumarin-fused coumarin. But coumarin-fused coumarin was able to inhibit DNA oxidations caused by (*)OH, Cu(2+)/glutathione (GSH), and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) even in the absence of hydroxyl group. In particular, a hydroxyl and an N,N-dimethylamino group locating at different benzene rings increased the inhibitory effect of coumarin fused coumarin on AAPH-induced oxidation of DNA about 3 times higher than a single hydroxyl group, whereas N,N-dimethylamino-substituted coumarin-fused coumarin possessed high activity toward (*)OH-induced oxidation of DNA without the hydroxyl group contained. Therefore, the hydroxyl group together with N,N dimethylamino group may be a novel combination for the design of coumarin-fused heterocyclic antioxidants. PMID- 25826202 TI - The influence of bile salts on the response of liposomes to ultrasound. AB - CONTEXT: Triggering drug release from delivery vehicles with ultrasound has potential applications in targeted drug delivery. It was hypothesized that the addition of bile salts would increase the sensitivity of liposomes to ultrasound through creation of defects. OBJECTIVE: The aim of this study was to investigate whether incorporating bile salts into liposomes would lead to differential effects on their response to low and high frequency ultrasound. MATERIALS AND METHODS: Cholate, chenodeoxycholate, ursodeoxycholate, glycocholate and taurocholate were the selected bile salts. Response to ultrasound was characterized by measuring the release of carboxyfluorescein (CF). RESULTS: At 30 kHz ultrasound, taurocholate containing liposomes were most responsive and released 70% (+/- 2) CF after 30 seconds of sonication. Compared to this, liposomes that did not contain bile salts released just 7% (+/- 2). At 1.1 MHz ultrasound, all liposome formulations were unresponsive. To increase the response of liposomes at 1.1 MHz ultrasound, a combination of membrane destabilizers were added to DSPC liposomes. DOPE, a hexagonal phase lipid was used in combination with taurocholate. Surprisingly, liposomes containing DOPE and taurocholate were more resistant to 1.1 MHz ultrasound than ones containing only DOPE. DISCUSSION: This suggests that the sensitivity of liposomes towards ultrasound may not simply be defined by a single membrane component but instead depends on the interaction between constituting lipid components. Furthermore, strategies other than membrane destabilization may be required to sensitize liposomes towards high frequency ultrasound. CONCLUSION: Bile salts may be used to increase or decrease the sensitivity of liposomes to low frequency ultrasound. PMID- 25826203 TI - Filter-extruded liposomes revisited: a study into size distributions and morphologies in relation to lipid-composition and process parameters. AB - Filter-extrusion is a widely used technique for down-sizing of phospholipid vesicles. In order to gain a detailed insight into size and size distributions of filter-extruded vesicles composed of egg phosphatidyl-choline (with varying fractions of cholesterol)--in relation to extrusion-parameters (pore-size, number of filter passages, and flow-rate), flow field-flow fractionation in conjunction with multi-angle laser light scattering (AF4-MALLS, Wyatt Technology Corp., Santa Barbara, CA) was employed. Liposome size-distributions determined by AF4-MALLS were compared with those of dynamic light scattering and correlated with cryo transmission electron microscopy and (31)P-NMR-analysis of lamellarity. Both the mean size of liposome and the width of size distribution were found to decrease with sequential extrusion through smaller pore size filters, starting at a size range of ~70-415 nm upon repeated extrusion through 400 nm pore-filters, eventually ending with a size range from ~30 to 85 nm upon extrusion through 30 nm pore size filters. While for small pores sizes (50 nm), increased flow rates resulted in smaller vesicles, no significant influence of flow rate on mean vesicle size was seen with larger pores. Cholesterol at increasing mol fractions up to 0.45 yielded bigger vesicles (at identical process conditions). For a cholesterol mol fraction of 0.5 in combination with small filter pore size, a bimodal size distribution was seen indicating cholesterol micro-crystallites. Finally, a protocol is suggested to prepare large (~ 300 nm) liposomes with rather narrow size distribution, based on the filter extrusion at defined flow rates in combination with freeze-/thaw-cycling and bench-top centrifugation. PMID- 25826204 TI - The Impact of Disclosure of Nutrition Information on Consumers' Behavioral Intention in Korea. AB - OBJECTIVE: To investigate the effect of nutritional information disclosure on consumers' nutritional perception, attitude, and behavioral intention to purchase the food item. METHODS: Questionnaires were distributed measuring nutritional perception, attitude, and behavioral intention with different nutritional information about the food (no information, calories only, and six nutritional content information items: food weight(g), calories(kcal), protein(g), sugar(g), sodium(g), and saturated fat(g)). Food items shown to the respondents were hamburgers and bibimbap. RESULTS: Descriptive analysis, analysis of variance, and multiple regression were used in order to examine the effects of nutritional information levels and different food items on consumers' behavioral intentions. Nutritional perception, food attitude, and food choice intention were all affected by levels of nutritional information and different food items. Also, food attitude was a predictor of food choice behavioral intention and was affected by different food items as well. However, results of the study found that objective and subjective knowledge of individuals are not related to their nutritional perception, attitude, and behavioral intention. CONCLUSIONS: Results of this study would help restaurant managers to prepare for consumers' demand on disclosure of nutritional information and adjust their menu ingredients for consumers' healthy food inquiries in order to respond to consumers' interests in nutritional information and ensure consumers satisfaction with the perceived nutritional value of food. PMID- 25826205 TI - SAYE: the story of an antimalarial phytomedicine from Burkina Faso. PMID- 25826207 TI - Correction: Epidemiology and molecular characterization of Cryptosporidium spp. in humans, wild primates, and domesticated animals in the Greater Gombe Ecosystem, Tanzania. PMID- 25826206 TI - Host glycan sugar-specific pathways in Streptococcus pneumoniae: galactose as a key sugar in colonisation and infection [corrected]. AB - The human pathogen Streptococcus pneumoniae is a strictly fermentative organism that relies on glycolytic metabolism to obtain energy. In the human nasopharynx S. pneumoniae encounters glycoconjugates composed of a variety of monosaccharides, which can potentially be used as nutrients once depolymerized by glycosidases. Therefore, it is reasonable to hypothesise that the pneumococcus would rely on these glycan-derived sugars to grow. Here, we identified the sugar specific catabolic pathways used by S. pneumoniae during growth on mucin. Transcriptome analysis of cells grown on mucin showed specific upregulation of genes likely to be involved in deglycosylation, transport and catabolism of galactose, mannose and N acetylglucosamine. In contrast to growth on mannose and N-acetylglucosamine, S. pneumoniae grown on galactose re-route their metabolic pathway from homolactic fermentation to a truly mixed acid fermentation regime. By measuring intracellular metabolites, enzymatic activities and mutant analysis, we provide an accurate map of the biochemical pathways for galactose, mannose and N-acetylglucosamine catabolism in S. pneumoniae. Intranasal mouse infection models of pneumococcal colonisation and disease showed that only mutants in galactose catabolic genes were attenuated. Our data pinpoint galactose as a key nutrient for growth in the respiratory tract and highlights the importance of central carbon metabolism for pneumococcal pathogenesis. PMID- 25826208 TI - Selective and genetic constraints on pneumococcal serotype switching. AB - Streptococcus pneumoniae isolates typically express one of over 90 immunologically distinguishable polysaccharide capsules (serotypes), which can be classified into "serogroups" based on cross-reactivity with certain antibodies. Pneumococci can alter their serotype through recombinations affecting the capsule polysaccharide synthesis (cps) locus. Twenty such "serotype switching" events were fully characterised using a collection of 616 whole genome sequences from systematic surveys of pneumococcal carriage. Eleven of these were within serogroup switches, representing a highly significant (p < 0.0001) enrichment based on the observed serotype distribution. Whereas the recombinations resulting in between-serogroup switches all spanned the entire cps locus, some of those that caused within-serogroup switches did not. However, higher rates of within serogroup switching could not be fully explained by either more frequent, shorter recombinations, nor by genetic linkage to genes involved in beta-lactam resistance. This suggested the observed pattern was a consequence of selection for preserving serogroup. Phenotyping of strains constructed to express different serotypes in common genetic backgrounds was used to test whether genotypes were physiologically adapted to particular serogroups. These data were consistent with epistatic interactions between the cps locus and the rest of the genome that were specific to serotype, but not serogroup, meaning they were unlikely to account for the observed distribution of capsule types. Exclusion of these genetic and physiological hypotheses suggested future work should focus on alternative mechanisms, such as host immunity spanning multiple serotypes within the same serogroup, which might explain the observed pattern. PMID- 25826209 TI - Identification and therapeutic potential of a vitronectin binding region of meningococcal msf. AB - The human pathogen Neisseria meningitides (Nm) attains serum resistance via a number of mechanisms, one of which involves binding to the host complement regulator protein vitronectin. We have shown previously that the Meningococcal surface fibril (Msf), a trimeric autotransporter, binds to the activated form of vitronectin (aVn) to increase Nm survival in human serum. In this study, we aimed to identify the aVn-binding region of Msf to assess its potential as an antigen which can elicit antibodies that block aVn binding and/or possess bactericidal properties. Using several recombinant Msf fragments spanning its surface-exposed region, the smallest aVn-binding recombinants were found to span residues 1-86 and 39-124. The use of further deletion constructs and overlapping recombinant Msf fragments suggested that a region of Msf comprising residues 39-82 may be primarily important for aVn binding and that other regions may also be involved but to a lesser extent. Molecular modelling implicated K66 and K68, conserved in all available Msf sequences, to be involved in the interaction. Recombinant fragments which bound to aVn were able to reduce the survival advantage conveyed by aVn-interaction in serum bactericidal assays. Antibodies raised against one such fragment inhibited aVn binding to Msf. In addition, the antibodies enhanced specific killing of Msf-expressing Nm in a dose-dependent manner. Overall, this study identifies an aVn-binding region of Msf, an adhesin known to impart serum resistance properties to the pathogen; and shows that this region of Msf can elicit antibodies with dual properties which reduce pathogen survival within the host and thus has potential as a vaccine antigen. PMID- 25826210 TI - Development of an indicator to monitor mediterranean wetlands. AB - Wetlands are sensitive ecosystems that are increasingly subjected to threats from anthropogenic factors. In the last decades, coastal Mediterranean wetlands have been suffering considerable pressures from land use change, intensification of urban growth, increasing tourism infrastructure and intensification of agricultural practices. Remote sensing (RS) and Geographic Information Systems (GIS) techniques are efficient tools that can support monitoring Mediterranean coastal wetlands on large scales and over long periods of time. The study aims at developing a wetland indicator to support monitoring Mediterranean coastal wetlands using these techniques. The indicator makes use of multi-temporal Landsat images, land use reference layers, a 50m numerical model of the territory (NMT) and Corine Land Cover (CLC) for the identification and mapping of wetlands. The approach combines supervised image classification techniques making use of vegetation indices and decision tree analysis to identify the surface covered by wetlands at a given date. A validation process is put in place to compare outcomes with existing local wetland inventories to check the results reliability. The indicator's results demonstrate an improvement in the level of precision of change detection methods achieved by traditional tools providing reliability up to 95% in main wetland areas. The results confirm that the use of RS techniques improves the precision of wetland detection compared to the use of CLC for wetland monitoring and stress the strong relation between the level of wetland detection and the nature of the wetland areas and the monitoring scale considered. PMID- 25826211 TI - Lichen symbiosis: nature's high yielding machines for induced hydrogen production. AB - Hydrogen is a promising future energy source. Although the ability of green algae to produce hydrogen has long been recognized (since 1939) and several biotechnological applications have been attempted, the greatest obstacle, being the O2-sensitivity of the hydrogenase enzyme, has not yet been overcome. In the present contribution, 75 years after the first report on algal hydrogen production, taking advantage of a natural mechanism of oxygen balance, we demonstrate high hydrogen yields by lichens. Lichens have been selected as the ideal organisms in nature for hydrogen production, since they consist of a mycobiont and a photobiont in symbiosis. It has been hypothesized that the mycobiont's and photobiont's consumption of oxygen (increase of COX and AOX proteins of mitochondrial respiratory pathways and PTOX protein of chrolorespiration) establishes the required anoxic conditions for the activation of the phycobiont's hydrogenase in a closed system. Our results clearly supported the above hypothesis, showing that lichens have the ability to activate appropriate bioenergetic pathways depending on the specific incubation conditions. Under light conditions, they successfully use the PSII-dependent and the PSII-independent pathways (decrease of D1 protein and parallel increase of PSaA protein) to transfer electrons to hydrogenase, while under dark conditions, lichens use the PFOR enzyme and the dark fermentative pathway to supply electrons to hydrogenase. These advantages of lichen symbiosis in combination with their ability to survive in extreme environments (while in a dry state) constitute them as unique and valuable hydrogen producing natural factories and pave the way for future biotechnological applications. PMID- 25826212 TI - MicroRNA signature characterizes primary tumors that metastasize in an esophageal adenocarcinoma rat model. AB - OBJECTIVE: To establish a miRNA signature for metastasis in an animal model of esophageal adenocarcinoma (EAC). BACKGROUND: The incidence of esophageal adenocarcinoma (EAC) has dramatically increased and esophageal cancer is now the sixth leading cause of cancer deaths worldwide. Mortality rates remain high among patients with advanced stage disease and esophagectomy is associated with high complication rates. Hence, early identification of potentially metastatic disease would better guide treatment strategies. METHODS: The modified Levrat's surgery was performed to induce EAC in Sprague-Dawley rats. Primary EAC and distant metastatic sites were confirmed via histology and immunofluorescence. miRNA profiling was performed on primary tumors with or without metastasis. A unique subset of miRNAs expressed in primary tumors and metastases was identified with Ingenuity Pathway Analysis (IPA) along with upstream and downstream targets. miRNA-linked gene expression analysis was performed on a secondary cohort of metastasis positive (n=5) and metastasis negative (n=28) primary tumors. RESULTS: The epithelial origin of distant metastasis was established by IF using villin (VIL1) and mucin 5AC (MUC5AC) antibodies. miRNome analysis identified four down regulated miRNAs in metastasis positive primary tumors compared to metastasis negative tumors: miR-92a-3p (p=0.0001), miR-141-3p (p=0.0022), miR-451-1a (p=0.0181) and miR133a-3p (p=0.0304). Six target genes identified in the top scoring networks by IPA were validated as significantly, differentially expressed in metastasis positive primary tumors: Ago2, Akt1, Kras, Bcl2L11, CDKN1B and Zeb2. CONCLUSION: In vivo metastasis was confirmed in the modified Levrat's model. Analysis of the primary tumor identified a distinctive miRNA signature for primary tumors that metastasized. PMID- 25826213 TI - Comparison of short- and medium-term clinical outcomes between transradial approach and transfemoral approach in a high-volume PCI heart center in China. AB - BACKGROUND: Transradial approach (TRA) outweighed transfemoral approach (TFA) in acute coronary syndrome patients because the former has better short-term outcomes in high-volume percutaneous coronary intervention (PCI) centers. Our study was one of the limited studies specifically in comparing the short- and medium-term effects of TRA and those of TFA in patients undergoing elective PCIs. METHODS: A total of 21,242 patients who underwent elective PCI with stent implantation were included. Using propensity score methodology, 1,634 patient pairs were matched. Major clinical outcomes and PCI-related complications between TRA and TFA were compared. RESULTS: In the propensity score-matched patients, the rates of in-hospital net adverse clinical events, which included death, myocardial infarction (MI), target vessel revascularization (TVR), stroke, and major bleeding, were much lower with TRA than with TFA (1.8% vs. 3.9%, P < 0.001). This difference was mainly due to the lower rate of major bleeding (0.6% vs. 1.8%, P < 0.001) and the decreased rate of MI (1.1% vs. 1.9%, P = 0.060). PCI related dissection and thrombosis were similar between the TRA and TFA groups (both P > 0.05). Meanwhile, one-year incidence rates of major adverse cardiovascular events, which included death, MI, and TVR, were also similar (4.1% vs. 4.9%, P = 0.272) in TRA and TFA. Multivariable regression analyses showed that TRA was an independent predictor of the low rate of in-hospital net adverse clinical events (odds ratio, 0.53; 95% confidence interval, 0.40 to 0.71), but not of major adverse cardiovascular events at one-year follow-up (hazard ratio, 1.01; 95% confidence interval, 0.96 to 1.06). CONCLUSIONS: In patients undergoing elective PCI, TRA patients had lower rates of in-hospital net adverse clinical outcomes compared with TFA patients. TRA might be recommended as a routine approach in high-volume PCI hospitals for elective PCIs. PMID- 25826214 TI - The impact of the Thai motorcycle transition on road traffic injury: Thai Cohort Study results. AB - OBJECTIVES: The aim of this study was to investigate the impact of motorcycle to car transitioning and urbanisation on traffic injury rates in Thailand. DESIGN: Analysis of two consecutive surveys of a large national cohort study. SETTING: Thailand. PARTICIPANTS: The data derived from 57,154 Thai Cohort Study (TCS) participants who provided relevant data on both the 2005 and 2009 surveys. PRIMARY AND SECONDARY OUTCOME MEASURES: Motorcycle and car traffic crash injury self-reported in 2009, with twelve months' recall. RESULTS: In 2009, 5608(10%) participants reported a traffic crash injury. Most crashes involved a motorcycle (74%). Car access increased and motorcycle use decreased between 2005 and 2009. Among those who used a motorcycle at both time points, traffic injury incidence was 2.8 times greater compared to those who did not use a motorcycle at either time point. Multivariable logistic regression models were used to test longitudinal and cross sectional factors associated with traffic crash injury: in the adjusted model, cars were negatively and motorcycles positively associated with injury. Living in an urban area was not injury protective in the adjusted model of traffic crash injury. CONCLUSIONS: Ongoing urbanisation in Thailand can be expected to lead to further reductions in road traffic injuries based on transition from motorcycles to cars in urban areas. Cities, however, do not provide an intrinsically safer traffic environment. To accommodate a safe transition to car use in Thailand, traffic infrastructural changes anticipating the growing car density in urban areas is warranted. PMID- 25826215 TI - Substrate use of Pseudovibrio sp. growing in ultra-oligotrophic seawater. AB - Marine planktonic bacteria often live in habitats with extremely low concentrations of dissolved organic matter (DOM). To study the use of trace amounts of DOM by the facultatively oligotrophic Pseudovibrio sp. FO-BEG1, we investigated the composition of artificial and natural seawater before and after growth. We determined the concentrations of dissolved organic carbon (DOC), total dissolved nitrogen (TDN), free and hydrolysable amino acids, and the molecular composition of DOM by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI FT-ICR-MS). The DOC concentration of the artificial seawater we used for cultivation was 4.4 MUmol C L(-1), which was eight times lower compared to the natural oligotrophic seawater we used for parallel experiments (36 MUmol C L(-1)). During the three-week duration of the experiment, cell numbers increased from 40 cells mL(-1) to 2x10(4) cells mL(-1) in artificial and to 3x10(5) cells mL(-1) in natural seawater. No nitrogen fixation and minor CO2 fixation (< 1% of cellular carbon) was observed. Our data show that in both media, amino acids were not the main substrate for growth. Instead, FT-ICR-MS analysis revealed usage of a variety of different dissolved organic molecules, belonging to a wide range of chemical compound groups, also containing nitrogen. The present study shows that marine heterotrophic bacteria are able to proliferate with even lower DOC concentrations than available in natural ultra-oligotrophic seawater, using unexpected organic compounds to fuel their energy, carbon and nitrogen requirements. PMID- 25826216 TI - Statistical properties of pairwise distances between leaves on a random Yule tree. AB - A Yule tree is the result of a branching process with constant birth and death rates. Such a process serves as an instructive null model of many empirical systems, for instance, the evolution of species leading to a phylogenetic tree. However, often in phylogeny the only available information is the pairwise distances between a small fraction of extant species representing the leaves of the tree. In this article we study statistical properties of the pairwise distances in a Yule tree. Using a method based on a recursion, we derive an exact, analytic and compact formula for the expected number of pairs separated by a certain time distance. This number turns out to follow a increasing exponential function. This property of a Yule tree can serve as a simple test for empirical data to be well described by a Yule process. We further use this recursive method to calculate the expected number of the n-most closely related pairs of leaves and the number of cherries separated by a certain time distance. To make our results more useful for realistic scenarios, we explicitly take into account that the leaves of a tree may be incompletely sampled and derive a criterion for poorly sampled phylogenies. We show that our result can account for empirical data, using two families of birds species. PMID- 25826217 TI - Two DNA aptamers against avian influenza H9N2 virus prevent viral infection in cells. AB - New antiviral therapy for pandemic influenza mediated by the H9N2 avian influenza virus (AIV) is increasingly in demand not only for the poultry industry but also for public health. Aptamers are confirmed to be promising candidates for treatment and prevention of influenza viral infections. Thus, we studied two DNA aptamers, A9 and B4, selected by capillary electrophoresis-based systemic evolution of ligands by exponential enrichment (CE-SELEX) procedure using H9N2 AIV purified haemagglutinin (HA) as target. Both aptamers had whole-virus binding affinity. Also, an enzyme-linked aptamer assay (ELAA) confirmed binding affinity and specificity against other AIV subtypes. Finally, we studied aptamer inhibitory effects on H9N2 AIV infection in Madin-Darby canine kidney (MDCK) cells and quantified viral load in supernatant and in cell with quantitative PCR (qPCR). Our data provide a foundation for future development of innovative anti influenza drugs. PMID- 25826218 TI - The contribution of former work-related activity levels to predict physical activity and sedentary time during early retirement: moderating role of educational level and physical functioning. AB - BACKGROUND: The transition to retirement introduces a decline in total physical activity and an increase in TV viewing time. Nonetheless, as more time becomes available, early retirement is an ideal stage to implement health interventions. Therefore, knowledge on specific determinants of physical activity and sedentary time is needed. Former work-related physical activity has been proposed as a potential determinant, but concrete evidence is lacking. The aim of this study was to examine if former work-related sitting, standing, walking or vigorous activities predict physical activity and sedentary time during early retirement. Additionally, moderating effects of educational level and physical functioning were examined. METHODS: In total, 392 recently retired Belgian adults (>6 months, <5 years) completed the International Physical Activity Questionnaire, the SF-36 Health Survey and a questionnaire on sociodemographics and former work-related activities. Generalized linear regression analyses were conducted in R. Moderating effects were examined by adding cross-products to the models. RESULTS: More former work-related sitting was predictive of more screen time during retirement. Lower levels of former work-related vigorous activities and higher levels of former work-related walking were associated with respectively more cycling for transport and more walking for transport during retirement. None of the predictors significantly explained passive transportation, cycling and walking for recreation, and leisure-time moderate-to-vigorous physical activity during retirement. Several moderating effects were found, but the direction of the interactions was not univocal. CONCLUSIONS: Former-work related behaviors are of limited importance to explain physical activity during early retirement, so future studies should focus on other individual, social and environmental determinants. Nonetheless, adults who previously had a sedentary job had higher levels of screen time during retirement, so this is an important subgroup to focus on during interventions. Because of the inconsistent moderating effects of educational level and physical functioning, no clear recommendations can be formulated. PMID- 25826219 TI - Implications of network topology on stability. AB - In analogy to chemical reaction networks, I demonstrate the utility of expressing the governing equations of an arbitrary dynamical system (interaction network) as sums of real functions (generalized reactions) multiplied by real scalars (generalized stoichiometries) for analysis of its stability. The reaction stoichiometries and first derivatives define the network's "influence topology", a signed directed bipartite graph. Parameter reduction of the influence topology permits simplified expression of the principal minors (sums of products of non overlapping bipartite cycles) and Hurwitz determinants (sums of products of the principal minors or the bipartite cycles directly) for assessing the network's steady state stability. Visualization of the Hurwitz determinants over the reduced parameters defines the network's stability phase space, delimiting the range of its dynamics (specifically, the possible numbers of unstable roots at each steady state solution). Any further explicit algebraic specification of the network will project onto this stability phase space. Stability analysis via this hierarchical approach is demonstrated on classical networks from multiple fields. PMID- 25826220 TI - Deficits in error-monitoring by college students with schizotypal traits: an event-related potential study. AB - The present study used event-related potentials (ERPs) to investigate deficits in error-monitoring by college students with schizotypal traits. Scores on the Schizotypal Personality Questionnaire (SPQ) were used to categorize the participants into schizotypal-trait (n = 17) and normal control (n = 20) groups. The error-monitoring abilities of the participants were evaluated using the Simon task, which consists of congruent (locations of stimulus and response are the same) and incongruent (locations of stimulus and response are different) conditions. The schizotypal-trait group committed more errors on the Simon task and exhibited smaller error-related negativity (ERN) amplitudes than did the control group. Additionally, ERN amplitude measured at FCz was negatively correlated with the error rate on the Simon task in the schizotypal-trait group but not in the control group. The two groups did not differ in terms of correct related potentials (CRN), error positivity (Pe) and correct-related positivity (Pc) amplitudes. The present results indicate that individuals with schizotypal traits have deficits in error-monitoring and that reduced ERN amplitudes may represent a biological marker of schizophrenia. PMID- 25826222 TI - An anisotropically and heterogeneously aligned patterned electrospun scaffold with tailored mechanical property and improved bioactivity for vascular tissue engineering. AB - The development of vascular scaffolds with controlled mechanical properties and stimulatory effects on biological activities of endothelial cells still remains a significant challenge to vascular tissue engineering. In this work, we reported an innovative approach to prepare a new type of vascular scaffolds with anisotropically and heterogeneously aligned patterns using electrospinning technique with unique wire spring templates, and further investigated the structural effects of the patterned electrospun scaffolds on mechanical properties and angiogenic differentiation of human umbilical vein endothelial cells (HUVECs). Results showed that anisotropically aligned patterned nanofibrous structure was obtained by depositing nanofibers on template in a structurally different manner, one part of nanofibers densely deposited on the embossments of wire spring and formed cylindrical-like structures in the transverse direction, while others loosely suspended and aligned along the longitudinal direction, forming a three-dimensional porous microstructure. We further found that such structures could efficiently control the mechanical properties of electrospun vascular scaffolds in both longitudinal and transverse directions by altering the interval distances between the embossments of patterned scaffolds. When HUVECs were cultured on scaffolds with different microstructures, the patterned scaffolds distinctively promoted adhesion of HUVECs at early stage and proliferation during the culture period. Most importantly, cells experienced a large shape change associated with cell cytoskeleton and nuclei remodeling, leading to a stimulatory effect on angiogenesis differentiation of HUVECs by the patterned microstructures of electrospun scaffolds, and the scaffolds with larger distances of intervals showed a higher stimulatory effect. These results suggest that electrospun scaffolds with the anisotropically and heterogeneously aligned patterns, which could efficiently control the mechanical properties and bioactivities of the scaffolds, might have great potential in vascular tissue engineering application. PMID- 25826221 TI - Nicotinic Acid Adenine Dinucleotide Phosphate Analogues Substituted on the Nicotinic Acid and Adenine Ribosides. Effects on ReceptorMediated Ca2+ Release. AB - Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca(2+) releasing intracellular second messenger in both mammals and echinoderms. We report that large functionalized substituents introduced at the nicotinic acid 5-position are recognized by the sea urchin receptor, albeit with a 20-500-fold loss in agonist potency. 5-(3-Azidopropyl)-NAADP was shown to release Ca(2+) with an EC50 of 31 MUM and to compete with NAADP for receptor binding with an IC50 of 56 nM. Attachment of charged groups to the nicotinic acid of NAADP is associated with loss of activity, suggesting that the nicotinate riboside moiety is recognized as a neutral zwitterion. Substituents (Br- and N3-) can be introduced at the 8 adenosyl position of NAADP while preserving high potency and agonist efficacy and an NAADP derivative substituted at both the 5-position of the nicotinic acid and at the 8-adenosyl position was also recognized although the agonist potency was significantly reduced. PMID- 25826223 TI - Scalable graphene coatings for enhanced condensation heat transfer. AB - Water vapor condensation is commonly observed in nature and routinely used as an effective means of transferring heat with dropwise condensation on nonwetting surfaces exhibiting heat transfer improvement compared to filmwise condensation on wetting surfaces. However, state-of-the-art techniques to promote dropwise condensation rely on functional hydrophobic coatings that either have challenges with chemical stability or are so thick that any potential heat transfer improvement is negated due to the added thermal resistance of the coating. In this work, we show the effectiveness of ultrathin scalable chemical vapor deposited (CVD) graphene coatings to promote dropwise condensation while offering robust chemical stability and maintaining low thermal resistance. Heat transfer enhancements of 4* were demonstrated compared to filmwise condensation, and the robustness of these CVD coatings was superior to typical hydrophobic monolayer coatings. Our results indicate that graphene is a promising surface coating to promote dropwise condensation of water in industrial conditions with the potential for scalable application via CVD. PMID- 25826225 TI - A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer. AB - BACKGROUND: Chemotherapy resistance is a major determinant of poor overall survival rates in high-grade serous ovarian cancer (HGSC). We have previously shown that gene expression alterations affecting the NF-kappaB pathway characterise chemotherapy resistance in HGSC, suggesting that the regulation of an immune response may be associated with this phenotype. METHODS: Given that intrinsic drug resistance pre-exists and is governed by both tumour and host factors, the current study was performed to examine the cross-talk between tumour inflammatory microenvironment and cancer cells, and their roles in mediating differential chemotherapy response in HGSC patients. Expression profiling of a panel of 184 inflammation-related genes was performed in 15 chemoresistant and 19 chemosensitive HGSC tumours using the NanoString nCounter platform. RESULTS: A total of 11 significantly differentially expressed genes were found to distinguish the two groups. As STAT1 was the most significantly differentially expressed gene (P=0.003), we validated the expression of STAT1 protein by immunohistochemistry using an independent cohort of 183 (52 resistant and 131 sensitive) HGSC cases on a primary tumour tissue microarray. Relative expression levels were subjected to Kaplan-Meier survival analysis and Cox proportional hazard regression models. CONCLUSIONS: This study confirms that higher STAT1 expression is significantly associated with increased progression-free survival and that this protein together with other mediators of tumour-host microenvironment can be applied as a novel response predictive biomarker in HGSC. Furthermore, an overall underactive immune microenvironment suggests that the pre existing state of the tumour immune microenvironment could determine response to chemotherapy in HGSC. PMID- 25826224 TI - Proteomic and metabonomic biomarkers for hepatocellular carcinoma: a comprehensive review. AB - Hepatocellular carcinoma (HCC) ranks third in overall global cancer-related mortality. Symptomatic presentation often means advanced disease where potentially curative treatment options become very limited. Numerous international guidelines propose the routine monitoring of those with the highest risk factors for the condition in order to diagnose potential tumourigenesis early. To aid this, the fields of metabonomic- and proteomic-based biomarker discovery have applied advanced tools to identify early changes in protein and metabolite expression in HCC patients vs controls. With robust validation, it is anticipated that from these candidates will rise a high-performance non-invasive test able to diagnose early HCC and related conditions. This review gathers the numerous markers proposed by studies using mass spectrometry and proton nuclear magnetic resonance spectroscopy and evaluates areas of consistency as well as discordance. PMID- 25826226 TI - Muscle-building supplement use and increased risk of testicular germ cell cancer in men from Connecticut and Massachusetts. AB - BACKGROUND: No analytic epidemiological study has examined the relationship between use of muscle-building supplements (MBSs) and testicular germ cell cancer (TGCC) risk. METHODS: We conducted a population-based case-control study including 356 TGCC cases and 513 controls from Connecticut and Massachusetts. RESULTS: The odds ratio (OR) for ever use of MBSs in relation to risk of TGCC was significantly elevated (OR=1.65, 95% confidence interval (CI): 1.11-2.46). The associations were significantly stronger among early users, men with more types of MBSs used, and longer periods of use. CONCLUSIONS: MBS use is a potentially modifiable risk factor that may be associated with TGCC. PMID- 25826228 TI - Dibenzothiopheno[6,5-b:6',5'-f]thieno[3,2-b]thiophene (DBTTT): high-performance small-molecule organic semiconductor for field-effect transistors. AB - We present the synthesis, characterization, and structural analysis of a thiophene-rich heteroacene, dibenzothiopheno[6,5-b:6',5'-f]thieno[3,2-b]thiophene (DBTTT) as well as its application in field-effect transistors. The design of DBTTT is based on the enhancement of intermolecular charge transfer through strong S-S interactions. Crystal structure analysis showed that the intermolecular pi-pi distance is shortened and that the packing density is higher than those of the electronically equivalent benzene analogue, dinaphtho-[2,3 b:2',3'-f]thieno[3,2-b]thiophene (DNTT). The highest hole mobility we obtained in polycrystalline DBTTT thin-film transistors was 19.3 cm(2).V(-1).s(-1), six times higher than that of DNTT-based transistors. The observed isotropic angular mobilities and thermal stabilities at temperatures up to 140 degrees C indicate the great potential of DBTTT for attaining device uniformity and processability. PMID- 25826230 TI - Nasal carriage of Staphylococcus aureus among surgeons and surgical residents: a nationwide prevalence study. AB - BACKGROUND: Staphylococcus aureus nasal carriage is an independent risk factor for developing nosocomial infections and for developing surgical site infection (SSI) in particular. The number of post-operative nosocomial S. aureus infections can be reduced by screening patients and decolonizing nasal carriers. In addition to patients, health care workers may also be S. aureus nasal carriers. The aim of this study was to explore S. aureus nasal carriage rates among surgeons. METHODS: Nasal swabs were collected from surgeons and surgical residents during a national surgical congress. The control group consisted of non-hospitalized patients. Staphylococcus aureus carriage was detected using selective chromogenic agars by use of a fully automated inoculator. Suspected colonies were identified further by positive catalase and slide coagulation reactions. RESULTS: Samples were collected from 366 surgeons and surgical residents and 950 control patients. The S. aureus nasal carriage rate among surgeons and residents was significantly greater compared with the control group (45.4% versus 30.8%, odds ratio [OR] 1.86 [1.45-2.38], p<0.001). No significant difference in carriage rate was found between surgeons and residents (46.8% versus 43.3%, p=0.769) and years of experience as a surgeon was not associated with a greater carriage rate. Male gender was an independent risk factor for carriage among physicians odds ratio ([OR] 1.90 [95% confidence interval 1.19-3.01], p=0.007). CONCLUSIONS: The nationwide rate of S. aureus nasal carriage among surgeons and surgical residents proved to be significantly greater compared with a non-hospitalized patient control group. Male gender is an independent risk factor for carriage among physicians. Future studies are needed to investigate the possible relation with nosocomial post-operative S. aureus infections. PMID- 25826231 TI - Theoretical characterization of dimethyl carbonate at low temperatures. AB - Highly correlated ab initio methods (CCSD(T) and RCCSD(T)-F12) are employed for the spectroscopic characterization of the gas phase of dimethyl carbonate (DMC) at low temperatures. DMC, a relevant molecule for atmospheric and astrochemical studies, shows only two conformers, cis-cis and trans-cis, respectively, of C2v and Cs symmetries. cis-cis-DMC represents the most stable form. Using RCCSD(T) F12 theory, the two sets of equilibrium rotational constants have been computed to be Ae = 10 493.15 MHz, Be = 2399.22 MHz, and Ce = 2001.78 MHz (cis-cis) and to be Ae = 6585.16 MHz, Be = 3009.04 MHz, and Ce = 2120.36 MHz (trans-cis). Centrifugal distortions constants and anharmonic frequencies for all of the vibrational modes are provided. Fermi displacements are predicted. The minimum energy pathway for the cis-cis -> trans-cis interconversion process is restricted by a barrier of ~3500 cm(-1). DMC displays internal rotation of two methyl groups. If the nonrigidity is considered, the molecule can be classified in the G36 (cis-cis) and the G18 (trans-cis) symmetry groups. For cis-cis-DMC, both internal tops are equivalent, and the torsional motions are restricted by V3 potential energy barriers of 384.7 cm(-1). trans-cis-DMC shows two different V3 barriers of 631.53 and 382.6 cm(-1). The far-infrared spectra linked to the torsional motion of both conformers are analyzed independently using a variational procedure and a two-dimensional flexible model. In cis-cis-DMC, the ground vibrational state splits into nine components: one nondegenerate, 0.000 cm(-1) (A1), four quadruply degenerate, 0.012 cm(-1) (G), and four doubly degenerate 0.024 cm(-1) (E1 and E3). The methyl torsional fundamentals are obtained to lie at 140.274 cm(-1) (nu15) and 132.564 cm(-1) (nu30). PMID- 25826229 TI - New clinical advances in immunotherapy for the treatment of solid tumours. AB - Advances in understanding the mechanisms of cancer cells for evading the immune system surveillance, including how the immune system modulates the phenotype of tumours, have allowed the development of new therapies that benefit from this complex cellular network to specifically target and destroy cancer cells. Immunotherapy researchers have mainly focused on the discovery of tumour antigens that could confer specificity to immune cells to detect and destroy cancer cells, as well as on the mechanisms leading to an improved activation of effector immune cells. The Food and Drug Administration approval in 2010 of ipilumumab for melanoma treatment and of pembrolizumab in 2014, monoclonal antibodies against T lymphocyte-associated antigen 4 and programmed cell death 1, respectively, are encouraging examples of how research in this area can successfully translate into clinical use with promising results. Currently, several ongoing clinical trials are in progress testing new anti-cancer therapies based on the enhancement of immune cell activity against tumour antigens. Here we discuss the general concepts related to immunotherapy and the recent application to the treatment of cancer with positive results that support their consideration of clinical application to patients. PMID- 25826227 TI - Ancient inland human dispersals from Myanmar into interior East Asia since the Late Pleistocene. AB - Given the existence of plenty of river valleys connecting Southeast and East Asia, it is possible that some inland route(s) might have been adopted by the initial settlers to migrate into the interior of East Asia. Here we analyzed mitochondrial DNA (mtDNA) HVS variants of 845 newly collected individuals from 14 Myanmar populations and 5,907 published individuals from 115 populations from Myanmar and its surroundings. Enrichment of basal lineages with the highest genetic diversity in Myanmar suggests that Myanmar was likely one of the differentiation centers of the early modern humans. Intriguingly, some haplogroups were shared merely between Myanmar and southwestern China, hinting certain genetic connection between both regions. Further analyses revealed that such connection was in fact attributed to both recent gene flow and certain ancient dispersals from Myanmar to southwestern China during 25-10 kya, suggesting that, besides the coastal route, the early modern humans also adopted an inland dispersal route to populate the interior of East Asia. PMID- 25826232 TI - Site-specific in situ synthesis of eumelanin nanoparticles by an enzymatic autodeposition-like process. AB - A method for in situ formation and controlled deposition of eumelanin nanoparticles is presented. The particles are built up by enzymatic reaction of l DOPA with tyrosinase. The enzyme is tethered onto the support surface to get site specific deposition of eumelanin. Due to the immediate deposition, the particles are monodisperse, with diameters of about 30-60 nm. Up to now, eumelanin particles have only been observed with sizes of about 200 nm. Deposition of those particles is site-specific on the areas where enzyme is present and results in different kinds of patterns on the support surface, including versatile monolayer structures. PMID- 25826235 TI - Adsorption of CO2 on amine-functionalised MCM-41: experimental and theoretical studies. AB - Adsorption of CO2 on MCM-41 functionalised with [3-(2 aminoethylamino)propyl]trimethoxysilane (MCM-41-N2), N(1)-(3 trimethoxysilylpropyl)diethylenetriamine (MCM-41-N3), 4-aminopyridine (MCM-41 aminopyridine), 4-(methylamino)pyridine (MCM-41-methylaminopyridine) and 1,5,7 triazabicyclo[4.4.0]dec-5-ene (MCM-41-guanidine) was investigated. The amine functionalised materials were characterised by (29)Si and (13)C solid-state nuclear magnetic resonance, N2 adsorption/desorption isotherms, X-ray diffraction and transmission electron microscopy. CO2 adsorption at 1.0 bar and 30 degrees C showed that the amount of CO2 (nads/mmol g(-1)) adsorbed on MCM-41-N2 and MCM-41 N3 is approximately twice the amount adsorbed on MCM-41. For MCM-41 aminopyridine, MCM-41-methylaminopyridine and MCM-41-guanidine, the CO2 adsorption capacity was smaller than that of MCM-41 at the same conditions. The proton affinity (computed with wB97x-D/6-311++G(d,p)) of the secondary amino groups is higher than that of the primary amino groups; however, the relative stabilities of the primary and secondary carbamates are similar. The differential heat of adsorption decreases as the number of secondary amino groups increases. PMID- 25826234 TI - Effects of Mung Bean (Vigna radiata L.) Ethanol Extracts Decrease Proinflammatory Cytokine-Induced Lipogenesis in the KK-Ay Diabese Mouse Model. AB - Rapid increase in the prevalence of obesity-related metabolic inflammatory diseases has led to research focused on nutraceuticals for their treatment. This study investigated the effects of the ethanol extracts of mung bean testa (MBT) on the metabolic inflammation-induced lipogenesis in gastrocnemius muscle of KK Ay diabese mice. Ethanol extracts of MBT were orally administered to diabese KK Ay mice for 4 weeks after diet-induced obesity model was generated by feeding a 60% high-fat diet for 3 weeks. Although there were no changes in body weight gain, MBT treatments decreased total weight of white adipose tissue. MBT also decreased triacylglycerol and total cholesterol levels in the muscle by 30%, which was correlated with suppression of lipogenic genes such as ACC, C/EBP alpha, PGC-1 alpha, and PPAR gamma. In particular, decreased levels of p-ERK1/2, PPAR gamma, and C/EBP alpha in the MBT-treated groups suggest that MBT might inhibit adipogenesis and decrease differentiation via the MEK/ERK pathway. Furthermore, significantly lower amounts of plasma interleukin (IL)-6 and intramuscular tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein-1 (MCP-1) were detected in MBT groups, confirming the anti-inflammatory effect of mung bean. In addition, our in vitro pilot study with 3T3-L1 cells showed that vitexin, the functional chemical in MBT, inhibited inflammation induced lipogenesis with significantly lower amounts of IL-6 and MCP-1 after 14 days of vitexin treatment. Thus, the functional compounds in the mung bean ethanol extracts such as vitexin and isovitexin may regulate intracellular lipogenesis and adipogenesis via anti-inflammatory mechanisms and MEK/ERK pathway in the KK-Ay mouse model. PMID- 25826236 TI - Cobalt nanoparticles embedded in nitrogen-doped carbon for the hydrogen evolution reaction. AB - There is great interest in renewable and sustainable energy research to develop low-cost, highly efficient, and stable electrocatalysts as alternatives to replace Pt-based catalysts for the hydrogen evolution reaction (HER). Though nanoparticles encapsulated in carbon shells have been widely used to improve the electrode performances in energy storage devices (e.g., lithium ion batteries), they have attracted less attention in energy-related electrocatalysis. Here we report the synthesis of nitrogen-enriched core-shell structured cobalt-carbon nanoparticles dispersed on graphene sheets and we investigate their HER performances in both acidic and basic media. These catalysts exhibit excellent durability and HER activities with onset overpotentials as low as ~70 mV in both acidic (0.5 M H2SO4) and alkaline (0.1 M NaOH) electrolytes, and the overpotentials needed to deliver 10 mA cm(-2) are determined to be 265 mV in acid and 337 mV in base, further demonstrating their potential to replace Pt-based catalysts. Control experiments reveal that the active sites for HER might come from the synergistic effects between the cobalt nanoparticles and nitrogen-doped carbon. PMID- 25826233 TI - Advances in MRI for the evaluation of carotid atherosclerosis. AB - Carotid artery atherosclerosis is an important source of mortality and morbidity in the Western world with significant socioeconomic implications. The quest for the early identification of the vulnerable carotid plaque is already in its third decade and traditional measures, such as the sonographic degree of stenosis, are not selective enough to distinguish those who would really benefit from a carotid endarterectomy. MRI of the carotid plaque enables the visualization of plaque composition and specific plaque components that have been linked to a higher risk of subsequent embolic events. Blood suppressed T1 and T2 weighted and proton density-weighted fast spin echo, gradient echo and time-of-flight sequences are typically used to quantify plaque components such as lipid-rich necrotic core, intraplaque haemorrhage, calcification and surface defects including erosion, disruption and ulceration. The purpose of this article is to review the most important recent advances in MRI technology to enable better diagnostic carotid imaging. PMID- 25826238 TI - Si nanoparticles encapsulated in elastic hollow carbon fibres for Li-ion battery anodes with high structural stability. AB - Silicon has a large specific capacity which is an order of magnitude beyond that of conventional graphite, making it a promising anode material for lithium ion batteries. However, the large volume changes (~ 300%) during cycling caused material pulverization and instability of the solid-electrolyte interphase resulting in poor cyclability which prevented its commercial application. Here, we have prepared a novel one-dimensional core-shell nanostructure in which the Si nanoparticles have been confined within hollow carbon nanofibres. Such a unique nanostructure exhibits high conductivity and facile ion transport, and the uniform pores within the particles which are generated during magnesiothermic reduction can serve as a buffer zone to accommodate the large volume changes of Si during electrochemical lithiation. Owing to these advantages, the composite shows high rate performance and good cycling stability. The optimum design of the core-shell nanostructure shows promise for the synthesis of a variety of high performance electrode materials. PMID- 25826237 TI - Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS): Two Overlapping Disorders Reviewed through Electroencephalography-What Can be Interpreted from the Available Information? AB - Autism Spectrum Disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders with different but potentially related neurobiological underpinnings, which exhibit significant overlap in their behavioural symptoms. FXS is a neurogenetic disorder of known cause whereas ASD is a complex genetic disorder, with both rare and common genetic risk factors and likely genetic and environmental interaction effects. A comparison of the phenotypic presentation of the two disorders may highlight those symptoms that are more likely to be under direct genetic control, for example in FXS as opposed to shared symptoms that are likely to be under the control of multiple mechanisms. This review is focused on the application and analysis of electroencephalography data (EEG) in ASD and FXS. Specifically, Event Related Potentials (ERP) and resting state studies (rEEG) studies investigating ASD and FXS cohorts are compared. This review explores the electrophysiological similarities and differences between the two disorders in addition to the potentially associated neurobiological mechanisms at play. A series of pertinent research questions which are suggested in the literature are also posed within the review. PMID- 25826239 TI - Total Synthesis and Reassignment of the Structures of the Antimicrobial Lipodepsipeptides Circulocin gamma and delta. AB - The structures of the naturally occurring antimicrobial lipodepsipeptides circulocin gamma and circulocin delta have been reported to comprise a common cyclic depsipeptide core attached to 3-hydroxy,omega-guanidino fatty acid chains differing in length by two methylene units, but analysis of the reported data suggested that the originally reported structures had incorrect side chain lengths. The total synthesis of both side chain epimers of the originally reported structure of circulocin gamma bearing a 19-guanidino-3 hydroxynonadecanoyl (GHND) side chain has been accomplished using a modular approach involving synthesis of the cyclic depsipeptide and side chain fragments followed by a late stage coupling reaction. This revealed that the originally reported structure for circulocin gamma bearing the GHND side chain is incorrect and that this structure is actually that of circulocin delta. It has also enabled the absolute configuration of the side chain hydroxy group of the natural product to be assigned as (R). Subsequent synthesis of the analogue bearing a 17 guanidino-3-(R)-hydroxyheptadecanoyl (GHHD) side chain provided confirmation that this revised structure is that of circulocin gamma. PMID- 25826240 TI - Preserving fertility when choosing chemotherapy regimens - the role of gonadotropin-releasing hormone agonists. AB - INTRODUCTION: The late effects of cancer treatment have recently gained a worldwide ubiquitous interest among reproductive endocrinologists, oncologists, and all health care providers. Despite many publications on this subject, there are many equivocal issues necessitating summary. The case for and against using GnRH-agonist for fertility preservation is summarized with the rationale that preventing ovarian failure may be better than treating it. AREAS COVERED: We searched Medline in the last 10 years using terms: 'fertility preservation', 'female chemotherapy', 'Gonadotropin-releasing hormone (GnRH) analogues', 'GnRH agonists' 'gonadotoxicity', and 'cancer treatment'. We included mainly publications from the past 7 years, but did not exclude previous, commonly referenced publications. Here, we summarize the various methods available for fertility preservation and minimizing chemotherapy induced gonadotoxicity. EXPERT OPINION: Until now, 20 studies (15 retrospective and 5 randomized controlled trial) have reported on 2038 patients treated with GnRH-a in parallel to chemotherapy, showing a significant decrease in premature ovarian failure (POF) rate in survivors versus 8 studies reporting on 509 patients, with negative results. Patients treated with GnRH-a in parallel to chemotherapy preserved their cyclic ovarian function in 91% of cases as compared to 41% of controls, with a pregnancy rate of 19 - 71% in the treated patients. Furthermore, over 10 recent meta-analyses have concluded that GnRH-a are beneficial and may decrease the risk of POF in survivors. Because most of the methods involving ovarian or egg cryopreservation are not yet clinically established and unequivocally successful, these young patients deserve to be informed with all the various modalities to minimize gonadal damage and preserve ovarian function and future fertility. Combining the various modalities for a specific patient may increase the odds of preservation of future fertility. PMID- 25826241 TI - Preparation of gelatin films incorporated with tea polyphenol nanoparticles for enhancing controlled-release antioxidant properties. AB - Gelatin films incorporated with chitosan nanoparticles in various free/encapsulated tea polyphenol (TP) ratios were prepared in order to investigate the influence of different ratios on the physicochemical and antioxidant properties of films. The TP-containing nanoparticles were prepared by cross-linking chitosan hydrochloride (CSH) with sulfobutyl ether-beta cyclodextrin sodium (SBE-beta-CD) at three different encapsulation efficiencies (EE; ~50%, ~80%, and ~100%) of TP. The stability of TP-loaded nanoparticles was maintained during the film drying process from the analysis of free TP content in the redissolved film solutions. Composite films showed no significant difference in visual aspects, while the light transmittance (250-550 nm) was decreased with incorporation of TP. Nanoparticles appeared to be homogeneously dispersed within the film matrix by microstructure analysis (SEM and AFM). TP-loaded films had ferric reducing and DPPH radical scavenging power that corresponded to the EEs. Sunflower oil packaged in bags made of gelatin films embedded with nanoparticles of 80% EE showed the best oxidation inhibitory effect, followed by 100% EE, 50% EE, and free TP, over 6 weeks of storage. However, when the gelatin film was placed over the headspace and was not in contact with the oil, the free TP showed the best effect. The results indicate that sustained release of TP in the contacting surface can ensure the protective effects, which vary with free/encapsulated mass ratios, thus improving antioxidant activities instead of increasing the dosage. PMID- 25826244 TI - Large carbon release legacy from bark beetle outbreaks across Western United States. AB - Warmer conditions over the past two decades have contributed to rapid expansion of bark beetle outbreaks killing millions of trees over a large fraction of western United States (US) forests. These outbreaks reduce plant productivity by killing trees and transfer carbon from live to dead pools where carbon is slowly emitted to the atmosphere via heterotrophic respiration which subsequently feeds back to climate change. Recent studies have begun to examine the local impacts of bark beetle outbreaks in individual stands, but the full regional carbon consequences remain undocumented for the western US. In this study, we quantify the regional carbon impacts of the bark beetle outbreaks taking place in western US forests. The work relies on a combination of postdisturbance forest regrowth trajectories derived from forest inventory data and a process-based carbon cycle model tracking decomposition, as well as aerial detection survey (ADS) data documenting the regional extent and severity of recent outbreaks. We find that biomass killed by bark beetle attacks across beetle-affected areas in western US forests from 2000 to 2009 ranges from 5 to 15 Tg C yr(-1) and caused a reduction of net ecosystem productivity (NEP) of about 6.1-9.3 Tg C y(-1) by 2009. Uncertainties result largely from a lack of detailed surveys of the extent and severity of outbreaks, calling out a need for improved characterization across western US forests. The carbon flux legacy of 2000-2009 outbreaks will continue decades into the future (e.g., 2040-2060) as committed emissions from heterotrophic respiration of beetle-killed biomass are balanced by forest regrowth and accumulation. PMID- 25826245 TI - Investigation of Neonatal Encephalopathy: The Oft-Lost Placental "Black Box". PMID- 25826246 TI - Client and provider perspectives on new HIV prevention tools for MSM in the Americas. AB - Men who have sex with men (MSM) in the Americas require targeted, combination HIV prevention approaches. We solicited client and provider perspectives on emerging prevention interventions including HIV pre-exposure prophylaxis (PrEP) and HIV self-tests through focus groups and in-depth interviews with 130 MSM and 41 providers across four sites: New York, San Francisco, Lima, and Rio de Janeiro. Among the MSM participants, we identified three prevention typologies: non-condom users, inconsistent condom users, and consistent condom users. Northern and Southern MSM differed in the variety of harm reduction strategies utilized: where U.S. MSM relied on condom use as well as disclosure and seroadaptive behaviors for prevention, condom use without disclosure or serostatus discussions was the norm in South America. Interest in new prevention technologies was shaped by the social context. U.S. MSM preferences differed by typology, such that non-condom users were interested in taking PrEP and using home HIV tests. MSM in Brazil, regardless of typology, were interested in exploring new prevention options. MSM in Peru demonstrated moderate interest but were less comfortable with adopting new strategies. MSM and providers' opinions differed substantially with respect to new prevention options. Across sites, most providers were reticent to engage with new prevention options, though some NGO-based providers were more supportive of exploring new prevention tools. Both clients and providers will need to be engaged in developing integrated prevention strategies for MSM. PMID- 25826248 TI - Formative Evaluation: A Case Study of the Illinois Birth-to-Three IV-E Waiver. AB - Few interventions addressing early childhood trauma have adequate evidence. The Illinois Birth-to-Three Waiver is a 5-year federal project to reduce trauma and increase permanency for young children. In this article the authors describe the explorative and formative phases, including: (a) developing a well-built research question; (b) working with purveyors of evidence-supported interventions (ESIs); (c) adapting ESIs to a large public child welfare system; (d) developing fidelity measures, assessment data and outcomes; and (e) managing the challenges of implementing a randomized controlled trial. Public and private agency staff work in conjunction with university partners to merge implementation science, program evaluation, and intervention research. The project's theory of change stipulates that working with the triad of birth parent(s), foster parent(s), and focal child is critical to achieving project outcomes. The authors articulate the importance of working closely with an interdisciplinary team to achieve these outcomes, and the challenges associated with the early stages of implementation. PMID- 25826247 TI - A simplified and robust protocol for immunoglobulin expression in Escherichia coli cell-free protein synthesis systems. AB - Cell-free protein synthesis (CFPS) systems allow for robust protein expression with easy manipulation of conditions to improve protein yield and folding. Recent technological developments have significantly increased the productivity and reduced the operating costs of CFPS systems, such that they can compete with conventional in vivo protein production platforms, while also offering new routes for the discovery and production of biotherapeutics. As cell-free systems have evolved, productivity increases have commonly been obtained by addition of components to previously designed reaction mixtures without careful re examination of the essentiality of reagents from previous generations. Here we present a systematic sensitivity analysis of the components in a conventional Escherichia coli CFPS reaction mixture to evaluate their optimal concentrations for production of the immunoglobulin G trastuzumab. We identify eight changes to the system, which result in optimal expression of trastuzumab. We find that doubling the potassium glutamate concentration, while entirely eliminating pyruvate, coenzyme A, NAD, total tRNA, folinic acid, putrescine and ammonium glutamate, results in a highly productive cell-free system with a 95% reduction in reagent costs (excluding cell-extract, plasmid, and T7 RNA polymerase made in house). A larger panel of other proteins was also tested and all show equivalent or improved yields with our simplified system. Furthermore, we demonstrate that all of the reagents for CFPS can be combined in a single freeze-thaw stable master mix to improve reliability and ease of use. These improvements are important for the application of the CFPS system in fields such as protein engineering, high-throughput screening, and biotherapeutics. PMID- 25826249 TI - Conductive and biphasic pulses in tunable resistive pulse sensing. AB - This experimental study concerns the occurrence of biphasic pulses generated during tunable resistive pulse sensing (TRPS) of 200 nm carboxylate polystyrene spheres. In TRPS, a short-lived pulse in ionic current is observed when an individual colloid passes through a pore which separates two fluid reservoirs. The pulse is conventionally resistive, but conductive pulses are observed under certain experimental conditions, as well as biphasic pulses which include both resistive and conductive components. The experimental variables investigated here include the concentration of the phosphate-buffered saline electrolyte, particle charge, pore size, applied voltage, and the direction of particle motion. The onset upper electrolyte concentration for biphasic pulses in TRPS is ~50 mM, and the ordering of biphasic pulse components can be interpreted using ionic concentration polarization if the conductive component is generated when the particle is in the ion depletion region. Besides providing fundamental understanding, the results are important for the TRPS technique, which is becoming widely used for particle-by-particle measurements of submicron colloids. PMID- 25826250 TI - Infrared fluorescent imaging as a potent tool for in vitro, ex vivo and in vivo models of visceral leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis (VL) is hypoendemic in the Mediterranean region, where it is caused by the protozoan Leishmania infantum. An effective vaccine for humans is not yet available and the severe side-effects of the drugs in clinical use, linked to the parenteral administration route of most of them, are significant concerns of the current leishmanicidal medicines. New drugs are desperately needed to treat VL and phenotype-based High Throughput Screenings (HTS) appear to be suitable to achieve this goal in the coming years. METHODOLOGY/PRINCIPAL FINDINGS: We generated two infrared fluorescent L. infantum strains, which stably overexpress the IFP 1.4 and iRFP reporter genes and performed comparative studies of their biophotonic properties at both promastigote and amastigote stages. To improve the fluorescence emission of the selected reporter in intracellular amastigotes, we engineered distinct constructs by introducing regulatory sequences of differentially-expressed genes (A2, AMASTIN and HSP70 II). The final strain that carries the iRFP gene under the control of the L. infantum HSP70 II downstream region (DSR), was employed to perform a phenotypic screening of a collection of small molecules by using ex vivo splenocytes from infrared-infected BALB/c mice. In order to further investigate the usefulness of this infrared strain, we monitored an in vivo infection by imaging BALB/c mice in a time-course study of 20 weeks. CONCLUSIONS/SIGNIFICANCE: The near-infrared fluorescent L. infantum strain represents an important step forward in bioimaging research of VL, providing a robust model of phenotypic screening suitable for HTS of small molecule collections in the mammalian parasite stage. Additionally, HSP70 II+L. infantum strain permitted for the first time to monitor an in vivo infection of VL. This finding accelerates the possibility of testing new drugs in preclinical in vivo studies, thus supporting the urgent and challenging drug discovery program against this parasitic disease. PMID- 25826251 TI - Diagnostic molecular markers for phosphine resistance in U.S. populations of Tribolium castaneum and Rhyzopertha dominica. AB - Stored product beetles that are resistant to the fumigant pesticide phosphine (hydrogen phosphide) gas have been reported for more than 40 years in many places worldwide. Traditionally, determination of phosphine resistance in stored product beetles is based on a discriminating dose bioassay that can take up to two weeks to evaluate. We developed a diagnostic cleaved amplified polymorphic sequence method, CAPS, to detect individuals with alleles for strong resistance to phosphine in populations of the red flour beetle, Tribolium castaneum, and the lesser grain borer, Rhyzopertha dominica, according to a single nucleotide mutation in the dihydrolipoamide dehydrogenase (DLD) gene. We initially isolated and sequenced the DLD genes from susceptible and strongly resistant populations of both species. The corresponding amino acid sequences were then deduced. A single amino acid mutation in DLD in populations of T. castaneum and R. dominica with strong resistance was identified as P45S in T. castaneum and P49S in R. dominica, both collected from northern Oklahoma, USA. PCR products containing these mutations were digested by the restriction enzymes MboI and BstNI, which revealed presence or absence, respectively of the resistant (R) allele and allowed inference of genotypes with that allele. Seven populations of T. castaneum from Kansas were subjected to discriminating dose bioassays for the weak and strong resistance phenotypes. Application of CAPS to these seven populations confirmed the R allele was in high frequency in the strongly resistant populations, and was absent or at a lower frequency in populations with weak resistance, which suggests that these populations with a low frequency of the R allele have the potential for selection of the strong resistance phenotype. CAPS markers for strong phosphine resistance will help to detect and confirm resistant beetles and can facilitate resistance management actions against a given pest population. PMID- 25826252 TI - Parents' perspectives on the dilemmas with intervention for infants with auditory neuropathy spectrum disorder: A qualitative study. AB - OBJECTIVE: This paper explores parental experiences of choices surrounding auditory management and language and communication development for infants and children with auditory neuropathy spectrum disorder (ANSD) in the light of the heterogeneity of condition, a poor evidence base for best outcomes in relation to management options, and the scarcity of data rooted in parent and family experience. DESIGN: Qualitative narrative study. STUDY SAMPLE: Twenty-five parents of 21 children (aged four months to six years) identified with ANSD through the newborn hearing screening programme. RESULTS: Families identify barriers to early management due to conflicting expert opinions and ANSD-specific challenges with diagnosis and prognosis in infants, and share their accounts on their own evaluations of intervention benefit in their children. CONCLUSIONS: The results are of relevance to the clinicians and other professionals involved in early intervention, management, and support of infants with ANSD. PMID- 25826253 TI - Formulation studies on ibuprofen sodium-cationic dextran conjugate: effect on tableting and dissolution characteristics of ibuprofen. AB - The effect of electrostatic interaction between ibuprofen sodium (IbS) and cationic diethylaminoethyl dextran (Ddex), on the tableting properties and ibuprofen release from the conjugate tablet was investigated. Ibuprofen exhibits poor flow, compaction (tableting) and dissolution behavior due to its hydrophobic structure, high cohesive, adhesive and viscoelastic properties therefore it was granulated with cationic Ddex to improve its compression and dissolution characteristics. Electrostatic interaction and hydrogen bonding between IbS and Ddex was confirmed with FT-IR and DSC results showed a stepwise endothermic solid solid structural transformation from racemic to anhydrous forms between 120 and 175 degrees C which melted into liquid form at 208.15 degrees C. The broad and diffused DSC peaks of the conjugate granules as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. It was evident that Ddex improved the flowability and densification of the granules and increased the mechanical and tensile strengths of the resulting tablets as the tensile strength increased from 0.67 +/- 0.0172 to 1.90 +/- 0.0038 MPa with increasing Ddex concentration. Both tapping and compression processes showed that the most prominent mechanism of densification were particle slippage, rearrangement and plastic deformation while fragmentation was minimized. Ddex retarded the extent of dissolution in general, indicating potentials for controlled release formulations. Multiple release mechanisms including diffusion; anomalous transport and super case II transport were noted. It was concluded that interaction between ibuprofen sodium and Ddex produced a novel formulation with improved flowability, tableting and dissolution characteristics with potential controlled drug release characteristics dictated by Ddex concentration. PMID- 25826254 TI - Identification of the sex pheromone of the tree infesting Cossid Moth Coryphodema tristis (Lepidoptera: Cossidae). AB - The cossid moth (Coryphodema tristis) has a broad range of native tree hosts in South Africa. The moth recently moved into non-native Eucalyptus plantations in South Africa, on which it now causes significant damage. Here we investigate the chemicals involved in pheromone communication between the sexes of this moth in order to better understand its ecology, and with a view to potentially develop management tools for it. In particular, we characterize female gland extracts and headspace samples through coupled gas chromatography electro-antennographic detection (GC-EAD) and two dimensional gas chromatography mass spectrometry (GCxGC-MS). Tentative identities of the potential pheromone compounds were confirmed by comparing both retention time and mass spectra with authentic standards. Two electrophysiologically active pheromone compounds, tetradecyl acetate (14:OAc) and Z9-tetradecenyl acetate (Z9-14:OAc) were identified from pheromone gland extracts, and an additional compound (Z9-14:OH) from headspace samples. We further determined dose response curves for the identified compounds and six other structurally similar compounds that are common to the order Cossidae. Male antennae showed superior sensitivity toward Z9-14:OAc, Z7 tetradecenyl acetate (Z7-14:OAc), E9-tetradecenyl acetate (E9-14:OAc), Z9 tetradecenol (Z9-14:OH) and Z9-tetradecenal (Z9-14:Ald) when compared to female antennae. While we could show electrophysiological responses to single pheromone compounds, behavioral attraction of males was dependent on the synergistic effect of at least two of these compounds. Signal specificity is shown to be gained through pheromone blends. A field trial showed that a significant number of males were caught only in traps baited with a combination of Z9-14:OAc (circa 95% of the ratio) and Z9-14:OH. Addition of 14:OAc to this mixture also improved the number of males caught, although not significantly. This study represents a major step towards developing a useful attractant to be used in management tools for C. tristis and contributes to the understanding of chemical communication and biology of this group of insects. PMID- 25826255 TI - Regulation of coronafacoyl phytotoxin production by the PAS-LuxR family regulator CfaR in the common scab pathogen Streptomyces scabies. AB - Potato common scab is an economically important crop disease that is characterized by the formation of superficial, raised or pitted lesions on the potato tuber surface. The most widely distributed causative agent of the disease is Streptomyces scabies, which produces the phytotoxic secondary metabolite thaxtomin A that serves as a key virulence factor for the organism. Recently, it was demonstrated that S. scabies can also produce the phytotoxic secondary metabolite coronafacoyl-L-isoleucine (CFA-L-Ile) as well as other related metabolites in minor amounts. The expression of the biosynthetic genes for CFA-L Ile production is dependent on a PAS-LuxR family transcriptional regulator, CfaR, which is encoded within the phytotoxin biosynthetic gene cluster in S. scabies. In this study, we show that CfaR activates coronafacoyl phytotoxin production by binding to a single site located immediately upstream of the putative -35 hexanucleotide box within the promoter region for the biosynthetic genes. The binding activity of CfaR was shown to require both the LuxR and PAS domains, the latter of which is involved in protein homodimer formation. We also show that CFA L-Ile production is greatly enhanced in S. scabies by overexpression of both cfaR and a downstream co-transcribed gene, orf1. Our results provide important insight into the regulation of coronafacoyl phytotoxin production, which is thought to contribute to the virulence phenotype of S. scabies. Furthermore, we provide evidence that CfaR is a novel member of the PAS-LuxR family of regulators, members of which are widely distributed among actinomycete bacteria. PMID- 25826256 TI - Phosphorus cycling in Montreal's food and urban agriculture systems. AB - Cities are a key system in anthropogenic phosphorus (P) cycling because they concentrate both P demand and waste production. Urban agriculture (UA) has been proposed as a means to improve P management by recycling cities' P-rich waste back into local food production. However, we have a limited understanding of the role UA currently plays in the P cycle of cities or its potential to recycle local P waste. Using existing data combined with surveys of local UA practitioners, we quantified the role of UA in the P cycle of Montreal, Canada to explore the potential for UA to recycle local P waste. We also used existing data to complete a substance flow analysis of P flows in the overall food system of Montreal. In 2012, Montreal imported 3.5 Gg of P in food, of which 2.63 Gg ultimately accumulated in landfills, 0.36 Gg were discharged to local waters, and only 0.09 Gg were recycled through composting. We found that UA is only a small sub-system in the overall P cycle of the city, contributing just 0.44% of the P consumed as food in the city. However, within the UA system, the rate of recycling is high: 73% of inputs applied to soil were from recycled sources. While a Quebec mandate to recycle 100% of all organic waste by 2020 might increase the role of UA in P recycling, the area of land in UA is too small to accommodate all P waste produced on the island. UA may, however, be a valuable pathway to improve urban P sustainability by acting as an activity that changes residents' relationship to, and understanding of, the food system and increases their acceptance of composting. PMID- 25826257 TI - Use of plant woody species electrical potential for irrigation scheduling. AB - The electrical response of plants to environmental stimuli can be measured and quantitatively related to the intensity of several stimulating sources, like temperature, solar radiation, soil water content, evapotranspiration rates, sap flow and dendrometric cycles. These relations can be used to assess the influence of different environmental situations on soil water availability to plants, defined as a steady state condition between leaf transpirative flow and soil water flow to plant roots. A restricted soil water flow due to soil dryness can trigger water stress in plants, if the atmospheric evaporative demand is high, causing partial stomata closure as a physiological response to avoid plant dehydration; water stressed and unstressed plants manifest a differential electrical response. Real time plant electrical response measurements can anticipate actions that prevent the plant reaching actual stress conditions, optimizing stomata gas exchange and photosynthetic rates. An electrophysiological sensor developed in this work, allows remote real-time recording information on plant electrical potential (EP) in the field, which is highly related to EP measurements obtained with a laboratory Keithley voltmeter sensor used in an highly controlled experimental setup. Our electrophysiological sensor is a wireless, autonomous devise, which transmits EP information via Internet to a data server. Using both types of sensors (EP electrodes with a Keithley voltmeter and the electrophysiological sensor), we measured in real time the electrical responses of Persea americana and Prunus domestica plants, to induced water deficits. The differential response for 2 scenarios: irrigation and water restriction is identified by a progressive change in slope on the daily maximal and minimal electric signal values in stressed plants, and a zero-slope for similar signals for well-watered plants. Results show a correspondence between measured signals obtained by our electrophysiological sensor and the EP electrodes connected to the Keithley voltmeter in each irrigation stage. Also, both sensors show a daily cyclical signal (circadian cycle). PMID- 25826258 TI - Arabidopsis PME17 Activity can be Controlled by Pectin Methylesterase Inhibitor4. AB - The degree of methylesterification (DM) of homogalacturonans (HGs), the main constituent of pectins in Arabidopsis thaliana, can be modified by pectin methylesterases (PMEs). Regulation of PME activity occurs through interaction with PME inhibitors (PMEIs) and subtilases (SBTs). Considering the size of the gene families encoding PMEs, PMEIs and SBTs, it is highly likely that specific pairs mediate localized changes in pectin structure with consequences on cell wall rheology and plant development. We previously reported that PME17, a group 2 PME expressed in root, could be processed by SBT3.5, a co-expressed subtilisin like serine protease, to mediate changes in pectin properties and root growth. Here, we further report that a PMEI, PMEI4, is co-expressed with PME17 and is likely to regulate its activity. This sheds new light on the possible interplay of specific PMEs, PMEIs and SBTs in the fine-tuning of pectin structure. PMID- 25826259 TI - Members of a recently discovered subfamily of cytokinin receptors display differences and similarities to their classical counterparts. AB - Cytokinins represent a group of plant hormones that have been shown to be essential for plant growth and development. A recent large-scale phylogenetic analysis of components of the cytokinin signal transduction pathway revealed, among other findings, the existence of a second, previously unknown subfamily of cytokinin receptors. Here we report that the cytokinin binding domains of the members of the 2 subfamilies contain residues that are highly conserved in either or in both subfamilies. Experiments using fluorescence microscopy hint at an ER and a plasma membrane localization for 2 members of the newly identified subfamily. These data provide new insights in the conservation of sequence and localization properties among the 2 subfamilies. PMID- 25826260 TI - Benzoxazolin-2(3H)-one inhibits soybean growth and alters the monomeric composition of lignin. AB - The effects of the allelochemical benzoxazolin-2-(3H)-one (BOA) were evaluated on growth, lignin content and its monomers p-hydroxyphenyl (H), guaiacyl (G) and syringyl (S) in roots, stems and leaves of soybean. BOA decreased the lengths and fresh weights of roots and stems, and the fresh weights and areas of leaves. Reductions in the growth were accompanied by enhanced lignin content in all tissues. In roots, the allelochemical increased the content of H, G and S monomers as well as the overall amount of lignin (referred to as the sum of H+G+S), but did not alter the S/G ratio. In stems and leaves, BOA increased the H, G, S and H+G+S contents while decreasing the S/G ratio. In brief, BOA-induced inhibition of soybean may be due to excessive production of monomers that increase the degree of polymerization of lignin, limit cell expansion, solidify the cell wall and restrict plant growth. PMID- 25826261 TI - FASCICLIN LIKE ARABINOGALACTAN PROTEIN 4 and RESPIRATORY BURST OXIDASE HOMOLOG D and F independently modulate abscisic acid signaling. AB - We previously suggested that At-FLA4 and ABA signaling act in synergy. Reactive oxygen species generated from the NADPH oxidases At-RBOHD and At-RBOHF play an important role in cell wall integrity control and ABA signaling and here we investigate their role for the At-FLA4 pathway. We find that in the At-fla4 At rbohD At-rbohF triple mutant the root phenotype of At-fla4 is enhanced. Moreover, the abnormally high level of reactive oxygen species in At-fla4 mutant does not depend on AtRBOHD and -F. Likewise, suppression of the At-fla4 phenotype by ABA does not depend on the 2 oxidases. Consistent with their lack of effect on ROS level in At-fla4, transcript level of AtRBOHD and -F is reduced in the At-fla4 mutant background. Taken together, our findings suggest that neither At-RBOHD nor At-RBOHF is involved in the synergism between ABA and At-FLA4. Consistently, the oxidases and At-FLA4 act independently of each other in ROS control. PMID- 25826262 TI - Reduced size and macrophage content of advanced atherosclerotic lesions in mice with bone marrow specific deficiency of alpha 7 nicotinic acetylcholine receptor. AB - In macrophages the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) modulates production of inflammatory cytokines, cholesterol accumulation and lipoprotein uptake. Recently, our laboratory showed that selective stimulation of the alpha7nAChR protects macrophages from apoptosis, an effect that is absent in alpha7nAChR-deficient macrophages. All these observations are suggestive of a potential role of macrophage alpha7nAChR in atherosclerosis. Mouse models of the disease with bone marrow deletion of alpha7nAChR represent an attractive approach to address the in vivo relevance of these in vitro findings. However, recent studies that focused on the impact of hematopoietic deficiency of alpha7nAChR on early atherosclerotic lesions of low density lipoprotein receptor knockout (LDLRKO) mice, yielded controversial results. The question also remained whether macrophage alpha7nAChR modulates the characteristics of advanced lesions. Here we used LDLR knockout mice transplanted with bone marrow from wild-type or alpha7nAChR knockout animals to revisit the effect of hematopoietic deficiency of alpha7nAChR on early lesions and to examine, for the first time, its impact on advanced plaques. Aortic sinus atherosclerotic lesions were analyzed following 8 and 14 weeks on a high fat diet. Early lesions in mice with alpha7nAChR deficient bone marrow were not different from those in control animals. However, advanced lesions of mice with bone marrow deletion of alpha7nAChR exhibited reduction in size, macrophage content and cell proliferation. These studies are the first in examining the impact of hematopoietic deficiency of alpha7nAChR on the characteristics of advanced atherosclerotic lesions in a mouse model of the disease and provide novel evidence underscoring a potential pro-atherogenic role of macrophage alpha7nAChR. PMID- 25826263 TI - Effect of regular circus physical exercises on lymphocytes in overweight children. AB - Obesity associated with a sedentary lifestyle can lead to changes in the immune system balance resulting in the development of inflammatory diseases. The aim of this study was to compare lymphocyte activation mechanisms between overweight children practicing regular circus physical exercises with non-exercised children. The study comprised 60 pubescent children randomly divided into 4 groups: Overweight Children (OWC) (10.67 +/- 0.22 years old), Overweight Exercised Children (OWE) (10.00 +/- 0.41 years old), Eutrophic Children (EC) (11.00 +/- 0.29 years old) and Eutrophic Exercised Children (EE) (10.60 +/- 0.29 years old). OWE and EE groups practiced circus activities twice a week, for 4.3 +/- 0.5 and 4.4 +/- 0.5 months, respectively. Percentage of T regulatory cells (Treg) and the expression of CD95 and CD25 in CD4+ lymphocytes were evaluated by flow cytometry. Lymphocyte proliferation capacity was measured by [14C]-thymidine incorporation and mRNA expression of IL-35, TGF-beta, IL-2 and IL-10 by real-time PCR. Lymphocyte proliferation was higher in OWC and OWE groups compared with the EC (3509 +/- 887; 2694 +/- 560, and 1768 +/- 208 cpm, respectively) and EE (2313 +/- 111 cpm) groups. CD95 expression on lymphocytes was augmented in the EC (953.9 +/- 101.2) and EE groups (736.7 +/- 194.6) compared with the OWC (522.1 +/ 125.2) and OWE groups (551.6 +/- 144.5). CTLA-4 expression was also lower in the OWC and OWE groups compared with the EC and EE groups. Percentage of Treg, IL-35, and IL-10 mRNA expression were lower in the OWC and OWE groups compared with the EC and EE groups. In conclusion, overweight children present altered immune system balance characterized by elevated lymphocyte proliferation due to a decrease in T regulatory cell percentage. These effects were partially reverted by moderate physical exercise, as demonstrated by decreased lymphocyte proliferation. PMID- 25826264 TI - The injured liver induces hyperimmunoglobulinemia by failing to dispose of antigens and endotoxins in the portal system. AB - Hyperimmunoglobulinemia is frequently observed in patients with chronic liver diseases. However, the exact mechanism underlying the high level of antibody formation is not fully understood. In our study, we provide evidence for the functional role of the liver and the stimulation of plasma cell proliferation in hyperimmunoglobulinemia. We collected sera from patients with chronic liver diseases, and the level of serum immunoglobulins in patients was examined; this was also investigated in animal models of liver cirrhosis and hepatocellular carcinoma. An end-to-side microsurgical portacaval shunt was used to mimic liver dysfunction in rats. We used portal vein serum and inferior vena cava serum to immunize healthy rats and mice in order to confirm the function of the healthy liver in disposing of antigens and endotoxins from the gut. For the analysis of the state of plasma cell activation, plasma cells from mice were stained with PE conjugated anti-CD138 and FITC-conjugated anti-BrdU for flow cytometry analysis. Hyperimmunoglobulinemia was observed both in patients with chronic liver diseases and in related animal models, and high plasma LPS levels were also observed. There was a significant increase in the activation and proliferation of plasma cell in mice immunized with antigens or LPS-positive serum compared with controls that were immunized with antigens and LPS-negative serum. We confirmed that the healthy liver plays an important role in disposing of antigens and endotoxins derived from the gut. Hyperimmunoglobulinemia in chronic liver diseases mainly arises due to the collateral circulation secondary to portal hypertension, gut antigens and endotoxins that bypass the liver and reach the antibody-producing cells. PMID- 25826265 TI - Selective sweep analysis in the genomes of the 91-R and 91-C Drosophila melanogaster strains reveals few of the 'usual suspects' in dichlorodiphenyltrichloroethane (DDT) resistance. AB - Adaptation of insect phenotypes for survival after exposure to xenobiotics can result from selection at multiple loci with additive genetic effects. To the authors' knowledge, no selective sweep analysis has been performed to identify such loci in highly dichlorodiphenyltrichloroethane (DDT) resistant insects. Here we compared a highly DDT resistant phenotype in the Drosophila melanogaster (Drosophila) 91-R strain to the DDT susceptible 91-C strain, both of common origin. Whole genome re-sequencing data from pools of individuals was generated separately for 91-R and 91-C, and mapped to the reference Drosophila genome assembly (v. 5.72). Thirteen major and three minor effect chromosome intervals with reduced nucleotide diversity (pi) were identified only in the 91-R population. Estimates of Tajima's D (D) showed corresponding evidence of directional selection in these same genome regions of 91-R, however, no similar reductions in pi or D estimates were detected in 91-C. An overabundance of non synonymous proteins coding to synonymous changes were identified in putative open reading frames associated with 91-R. Except for NinaC and Cyp4g1, none of the identified genes were the 'usual suspects' previously observed to be associated with DDT resistance. Additionally, up-regulated ATP-binding cassette transporters have been previously associated with DDT resistance; however, here we identified a structurally altered MDR49 candidate resistance gene. The remaining fourteen genes have not previously been shown to be associated with DDT resistance. These results suggest hitherto unknown mechanisms of DDT resistance, most of which have been overlooked in previous transcriptional studies, with some genes having orthologs in mammals. PMID- 25826267 TI - 5-(Fluorodinitromethyl)-2H-tetrazole and its tetrazolates -- preparation and characterization of new high energy compounds. AB - 5-(Fluorodinitromethyl)-2H-tetrazole (HFDNTz) has been prepared by the cycloaddition reaction of HN3 with F(NO2)2CCN, which in turn was prepared by aqueous fluorination of sodium dinitrocyanomethanide. HFDNTz was converted into the ammonium, silver and tetraphenylphosphonium 5 (fluorodinitromethyl)tetrazolates. While the reaction of trinitroacetonitrile with HBr, followed by the treatment with NaOH, resulted in the formation of sodium dinitrocyanomethanide, the reaction of trinitroacetonitrile with aqueous ammonia produced ammonium dinitrocyanomethanide. Hydrazinium dinitromethanide was obtained from trinitroacetonitrile and hydrazine hydrate. All compounds were fully characterized by multinuclear NMR spectroscopy, IR spectroscopy and X-ray crystal structure determinations. Initial safety testing (impact and friction sensitivity) and thermal stability measurements (DTA) were also carried out. PMID- 25826268 TI - Photobioreactors with internal illumination - A survey and comparison. AB - The idea of internally illuminated photobioreactors has existed since the 1990s and various systems were developed since. Recently, the interest in these systems has been on the rise again, due to the increased production of and research on high-value products and recombinant proteins from microalgae and plant cell cultures. While promising results in lab-scale have been achieved, the potential of photoautotrophic or mixotrophic production of these compounds is limited due to the lack of scalable photobioreactors, which could be overcome by internally illuminated systems. In this article, we review different internally illuminated photobioreactors from the last two decades and classify them into two major groups. The photobioreactors are compared based on the ratio of illuminated surface-to-culture volume and the occupied volume by internal light-emitting elements, and possible obstacles, challenges and future trends are discussed. Looking forward, new technologies and smaller light sources have improved the potential of internally illuminated photobioreactors with internal light sources and will enable these technologies to compete with systems with internal light guides, but only a few of these systems have currently achieved a relevant scale. PMID- 25826266 TI - Network analyses reveal novel aspects of ALS pathogenesis. AB - Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons, muscle atrophy and paralysis. Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors of hVAPB activity in the intact nervous system, however, represent a fundamental approach towards understanding the in vivo function of hVAPB and its role in ALS pathogenesis. Targeted expression of the disease-causing allele leads to neurodegeneration and progressive decline in motor performance when expressed in the adult Drosophila, eye or in its entire nervous system, respectively. By using these two phenotypic readouts, we carried out a systematic survey of the Drosophila genome to identify modifiers of hVAPB induced neurotoxicity. Modifiers cluster in a diverse array of biological functions including processes and genes that have been previously linked to hVAPB function, such as proteolysis and vesicular trafficking. In addition to established mechanisms, the screen identified endocytic trafficking and genes controlling proliferation and apoptosis as potent modifiers of ALS8-mediated defects. Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet biogenesis and dynamics. Computational analysis reveals that most modifiers can be linked into a complex network of interacting genes, and that the human genes homologous to the Drosophila modifiers can be assembled into an interacting network largely overlapping with that in flies. Identity markers of the endocytic process were also found to abnormally accumulate in ALS patients, further supporting the relevance of the fly data for human biology. Collectively, these results not only lead to a better understanding of hVAPB function but also point to potentially relevant targets for therapeutic intervention. PMID- 25826269 TI - Increased cerebral water content in hemodialysis patients. AB - Little information is available on the impact of hemodialysis on cerebral water homeostasis and its distribution in chronic kidney disease. We used a neuropsychological test battery, structural magnetic resonance imaging (MRI) and a novel technique for quantitative measurement of localized water content using 3T MRI to investigate ten hemodialysis patients (HD) on a dialysis-free day and after hemodialysis (2.4+/-2.2 hours), and a matched healthy control group with the same time interval. Neuropsychological testing revealed mainly attentional and executive cognitive dysfunction in HD. Voxel-based-morphometry showed only marginal alterations in the right inferior medial temporal lobe white matter in HD compared to controls. Marked increases in global brain water content were found in the white matter, specifically in parietal areas, in HD patients compared to controls. Although the global water content in the gray matter did not differ between the two groups, regional increases of brain water content in particular in parieto-temporal gray matter areas were observed in HD patients. No relevant brain hydration changes were revealed before and after hemodialysis. Whereas longer duration of dialysis vintage was associated with increased water content in parieto-temporal-occipital regions, lower intradialytic weight changes were negatively correlated with brain water content in these areas in HD patients. Worse cognitive performance on an attention task correlated with increased hydration in frontal white matter. In conclusion, long-term HD is associated with altered brain tissue water homeostasis mainly in parietal white matter regions, whereas the attentional domain in the cognitive dysfunction profile in HD could be linked to increased frontal white matter water content. PMID- 25826270 TI - A mouse model of human primitive neuroectodermal tumors resulting from microenvironmentally-driven malignant transformation of orthotopically transplanted radial glial cells. AB - There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle--but not to other transplantation sites--of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype. PMID- 25826271 TI - Radiological protection evaluation of the Bucharest Tandetron 3 MV accelerator. AB - Low energy heavy charged particle accelerators are generators of ionizing radiation, due to the ion beam interactions into the machine components, targets and surrounding materials. Nowadays there are available computational tools allowing realistic estimates of radiation doses and residual activity of the activated components. These evaluations are further used to design the radiological safety system required by licensing and operation of the equipment.This paper presents results of measurements and numerical simulations of the radiation doses and residual activity, at the recently commissioned Bucharest 3 MV Cockcroft-Walton type Tandetron accelerator presently used mainly for Ion Beam Analysis (IBA) research. PMID- 25826273 TI - Three-dimensional motion tracking correlates with skill level in upper gastrointestinal endoscopy. AB - BACKGROUND AND STUDY AIM: Feedback is an essential part of training in upper gastrointestinal endoscopy. Virtual reality simulators provide limited feedback, focusing only on visual recognition with no feedback on the procedural part of training. Motion tracking identifies patterns of movement, and this study aimed to explore the correlation between skill level and operator movement using an objective automated tool. METHODS: In this medical education study, 37 operators (12 senior doctors who performed endoscopic retrograde cholangiopancreatography, 13 doctors with varying levels of experience, and 12 untrained medical students) were tested using a virtual reality simulator. A motion sensor was used to collect data regarding the distance between the hands, and height and movement of the scope hand. Test characteristics between groups were explored using Kruskal Wallis H and Man-Whitney U exact tests. RESULTS: All motion-tracking metrics showed discriminative ability primarily between experts and novices in specific sequences. CONCLUSION: Motion tracking can discriminate between operators with different experience levels in upper gastrointestinal endoscopy. Motion tracking can be used to provide feedback regarding posture and movement during endoscopy training. PMID- 25826274 TI - Prospective evaluation of the clinical utility of single-operator peroral cholangioscopy in patients with primary sclerosing cholangitis. AB - BACKGROUND AND STUDY AIMS: The role of cholangioscopy in primary sclerosing cholangitis (PSC) using a single-operator peroral cholangioscopy direct visualization system is unknown. This study aimed to prospectively evaluate the clinical utility of the system in PSC patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: Patients with PSC or suspicion of PSC and a clinical indication for ERCP were enrolled between September 2008 and May 2011. Patients underwent cholangioscopy with sampling from biliary strictures. Clinical data, technical information from the ERCP procedure, and results from sampling by brush cytology and mini-forceps biopsy were collected. Long-term follow-up was conducted. Outcomes included technical success, sampling adequacy, and diagnostic accuracy of cholangioscopy-guided sampling for detection of cholangiocarcinoma (CCA). RESULTS: A total of 47 patients with PSC were included in the study. Median follow-up time was 27 months (range 2 - 64 months). Technical success was achieved in 96 % (45/47). In 9 % (4/45), the target lesion could not have been reached without the cholangioscopic visualization of the bile duct, which enabled further advancement of the investigation. A total of 64 biliary strictures were evaluated. Sample quality was adequate in 98 % (62/63) of the cytology brushings and in 95 % (21/22) of the mini-forceps biopsies. Of the three patients with a final diagnosis of CCA, one was diagnosed at the time of the investigation. The sensitivity, specificity, accuracy, and negative predictive value were 33 %, 100 %, 96 %, and 95 %, respectively. CONCLUSION: Cholangioscopy and cholangioscopy-guided sampling can be utilized successfully in patients with PSC. Cholangioscopy enabled targeted biopsies to be taken and was able to pass otherwise inaccessible strictures, making it potentially valuable for the management of biliary strictures in patients with PSC. Trial registered at ClinicalTrials.gov (NCT01556555). PMID- 25826275 TI - Safety and efficacy of carbon dioxide cryotherapy for treatment of neoplastic Barrett's esophagus. AB - BACKGROUND AND STUDY AIMS: Endoscopic cryotherapy has been used successfully for the ablation of Barrett's esophagus but outcome data are limited. The aim of this study was to assess the long-term safety and efficacy of carbon dioxide (CO2) cryotherapy as primary or rescue treatment for Barrett's esophagus with high grade dysplasia (HGD) or neoplasia. PATIENTS AND METHODS: This was a retrospective, single-center, nonrandomized study carried out in an academic, tertiary care center and affiliated community hospital. A total of 78 patients with neoplastic Barrett's esophagus who had not undergone previous ablation (treatment-naive group) or who had persistent or recurrent neoplasia despite previous treatment (rescue treatment group) were enrolled. Visible Barrett's lesions, when present, were removed by endoscopic mucosal resection, which was followed by CO2 cryotherapy until neoplasia had been eradicated, or intervening therapy was necessary, or treatment was considered to have failed. Surveillance biopsies were obtained at standard intervals. Rates of complete response for cancer, HGD, and intestinal metaplasia were calculated. Treatment failure, recurrence, adverse events, progression, and mortality were also recorded. RESULTS: Between 2006 and 2013, 64 evaluable patients (20 treatment naive, 44 rescue treatment) were treated and followed up (median time 4.2 years). At 1 year, the overall complete response rates were 77 % for cancer (10/13), 89 % for dysplasia 57/64), 94 % for HGD (60/64; 100 % for treatment naive, 91 % for rescue treatment), and 55 % for intestinal metaplasia (35/64). Long-term complete response for neoplasia with rescue therapy was 87 % (56/64). Disease-specific mortality was 1/68 (2 %). Treatment failed to eradicate neoplasia in four patients (6 %) (all in the rescue group). Recurrent or new intestinal metaplasia was detected in 20/64 (31 %) after two negative follow-up procedures. Serious adverse events were noted in two patients (3 %). Post-cryotherapy pain occurred in four patients (6 %; only two needed analgesics). No bleeding or new strictures were noted. Buried Barrett's was detected in 5/68 patients (7 %). CONCLUSIONS: CO2 cryotherapy was a safe and effective primary curative or rescue therapy for Barrett's neoplasia. PMID- 25826276 TI - Complete mucosal healing defined by endoscopic Mayo subscore still demonstrates abnormalities by novel high definition colonoscopy and refined histological gradings. AB - BACKGROUND AND STUDY AIMS: A novel high definition colonoscopy imaging technique (i-Scan) can characterize, in detail, colonic mucosa in patients with ulcerative colitis, and may provide additional information about mucosal healing. The aim of this study was to create a more refined histological and endoscopic criteria based on this novel technique in order to redefine inflammatory activity and mucosal healing. PATIENTS AND METHODS: A total of 78 patients with ulcerative colitis were assessed by high definition colonoscopy as well as by white light endoscopy (WLE). Mayo endoscopic subscores were assigned to patients according to WLE findings. Mucosal and vascular patterns on high definition colonoscopy were each graded from 1 - 4. A histological scoring system (ECAP system) was designed to reflect all histological changes in ulcerative colitis. RESULTS: The overall high definition imaging scores (mucosal and vascular patterns) were significantly correlated with Mayo endoscopic subscores (rs = 0.86, 95 % confidence interval [CI] 0.79 - 0.91; P < 0.0001). Of those with Mayo endoscopic subscore of 0, 30.4 % had an abnormal mucosal pattern and 73.9 % of them had an abnormal vascular pattern on high definition colonoscopy; a score of 6 or less had a sensitivity of 95.8 % (95 %CI 85.7 % - 99.3 %) and specificity of 75.9 % (95 %CI 56.5 % - 90.0 %) to detect mucosal healing as defined by Mayo endoscopy subscore of 0 or 1. Furthermore, mucosal and vascular pattern scores were also significantly correlated with most parameters of the proposed ECAP score. CONCLUSION: The subtle histological abnormalities underlying the apparently healed mucosa in ulcerative colitis could be detected using high definition colonoscopy and the refined ECAP histology scoring system. These techniques detect residual abnormalities in the majority of patients with seemingly complete mucosal healing by conventional Mayo criteria. PMID- 25826277 TI - Clinical outcomes of endoscopic submucosal dissection for superficial esophageal neoplasms: a multicenter retrospective cohort study. AB - BACKGROUND AND STUDY AIMS: The safety and efficacy of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms (SENs) have not been evaluated in a multicenter survey. The aim of this study was to investigate the clinical outcomes in a multicenter study that included municipal hospitals. PATIENTS AND METHODS: Of 312 consecutive patients with 373 esophageal lesions treated by ESD at 11 hospitals from May 2005 to December 2012, a total of 368 SENs in 307 patients were retrospectively analyzed. RESULTS: The median tumor size was 18 mm (range 2 - 85 mm). The median procedure time was 90 minutes (range 12 - 450 minutes). The en bloc resection and complete resection rates were 96.7 % (95 % confidence interval [CI] 94.4 % - 98.1 %) and 84.5 % (95 %CI 80.5 % - 87.8 %), respectively. Perforation (including mediastinal emphysema), postoperative pneumonia, bleeding, and esophageal stricture, occurred in 5.2 % (95 %CI 3.3 % - 7.9 %), 1.6 % (95 %CI 0.7 % - 3.5 %), 0 %, and 7.1 % (95 %CI 4.9 % - 10.2 %) of patients, respectively. All of these complications were cured conservatively. No procedure-related mortality occurred. Early treatment periods (odds ratio [OR] = 4.04; P < 0.01) and low volume institutions (OR = 3.03; P = 0.045) were significantly independent risk factors for perforation. The circumference of the lesion was significantly associated with postoperative stricture (OR = 32.3; P < 0.01). The procedure times significantly decreased in the later period of the study (P < 0.01). Follow-up data (median 35 months; range 4 - 98 months) showed significant differences in overall survival (P = 0.03) and recurrence-free survival (P < 0.01) rates between patients with curative and noncurative resections. CONCLUSIONS: Esophageal ESD has become feasible with acceptable complication risks and favorable long term outcomes. PMID- 25826278 TI - Withdrawal of a novel-design duodenoscope ends outbreak of a VIM-2-producing Pseudomonas aeruginosa. AB - BACKGROUND AND STUDY AIMS: Infections are a recognized risk of endoscopic retrograde cholangiopancreatography (ERCP). This paper reports on a large outbreak of VIM-2-producing Pseudomonas aeruginosa that was linked to the use of a recently introduced duodenoscope with a specific modified design (Olympus TJF Q180V). METHODS: Epidemiological investigations and molecular typing were executed in order to identify the source of the outbreak. Audits on implementation of infection control measures were performed. Additional infection control strategies were implemented to prevent further transmission. The design and the ability to clean and disinfect the duodenoscope were evaluated, and the distal tip was dismantled. RESULTS: From January to April 2012, 30 patients with a VIM-2-positive P. aeruginosa were identified, of whom 22 had undergone an ERCP using a specific duodenoscope, the TJF-Q180V. This was a significant increase compared with the hospital-wide baseline level of 2 - 3 cases per month. Clonal relatedness of the VIM-2 P. aeruginosa was confirmed for all 22 cases and for the VIM-2 strain isolated from the recess under the forceps elevator of the duodenoscope. An investigational study of the new modified design, including the dismantling of the duodenoscope tip, revealed that the fixed distal cap hampered cleaning and disinfection, and that the O-ring might not seal the forceps elevator axis sufficiently. The high monthly number of cases decreased below the pre-existing baseline level following withdrawal of the TJF-Q180V device from clinical use. CONCLUSIONS: Duodenoscope design modifications may compromise microbiological safety as illustrated by this outbreak. Extensive pre-marketing validation of the reprocessability of any new endoscope design and stringent post marketing surveillance are therefore mandatory. PMID- 25826280 TI - Biological therapies for inherited diseases: social and bioethical considerations. Hemophilia as an example. AB - INTRODUCTION: In hemophilia, advanced therapies are warranted from a conceptual and methodological standpoint. Current advanced therapy strategies are centered on the use of adeno-associated viral vectors, although problems related to immunogenicity and hepatotoxicity still remain. AREAS COVERED: Future clinical trials will have to scrupulously observe international bioethical standards in terms of patient selection, particularly children. Patient recruitment rates are likely to remain low due to the stringent exclusion criteria usually imposed on the trial population regarding their hepatic and immunological markers and the presence of viral coinfection; and to the existence of an optimal palliative treatment. EXPERT OPINION: Accordingly, the results obtained are likely to be of low statistical significance, which could hinder their application to clinical practice. Another important issue is the degree to which society embraces these new emerging therapies. The unfamiliarity of society with these new methods, together with the many unresolved questions about them that remain, may threaten their acceptance not only by society at large but also by health-care professionals, which would limit their translational application to clinical practice. PMID- 25826279 TI - Brain isoform glycogen phosphorylase as a novel hepatic progenitor cell marker. AB - An appropriate liver-specific progenitor cell marker is a stepping stone in liver regenerative medicine. Here, we report brain isoform glycogen phosphorylase (GPBB) as a novel liver progenitor cell marker. GPBB was identified in a protein complex precipitated by a monoclonal antibody Ligab generated from a rat liver progenitor cell line Lig-8. Immunoblotting results show that GPBB was expressed in two liver progenitor cell lines Lig-8 and WB-F344. The levels of GPBB expression decreased in the WB-F344 cells under sodium butyrate (SB)-induced cell differentiation, consistent with roles of GPBB as a liver progenitor cell marker. Short hairpin RNA (shRNA)-mediated GPBB knockdown followed by glucose deprivation test shows that GPBB aids in liver progenitor cell survival under low glucose conditions. Furthermore, shRNA-mediated GPBB knockdown followed by SB-induced cell differentiation shows that reducing GPBB expression delayed liver progenitor cell differentiation. We conclude that GPBB is a novel liver progenitor cell marker, which facilitates liver progenitor cell survival under low glucose conditions and cell differentiation. PMID- 25826281 TI - The Lignan Pinoresinol Induces Nuclear Translocation of DAF-16 in Caenorhabditis elegans but has No Effect on Life Span. AB - The lignan pinoresinol is a constituent of flaxseed, sesame seeds and olive oil. Because of different molecular effects reported for this compound, e.g. antioxidative activity, pinoresinol is suggested to cause positive effects on humans. Because experimental data are limited, we have analysed the effects of the lignan on the nematode Caenorhabditis elegans: in spite of a strong antioxidative capacity detected in an in vitro assay, no antioxidative effects were detectable in vivo. In analogy to this result, no modulation of the sensitivity against thermal stress was detectable. However, incubation with pinoresinol caused an enhanced nuclear accumulation of the transcription factor DAF-16 (insulin/IGF-like signalling pathway). Using a strain with an enhanced oxidative stress level (mev-1 mutant), we clearly see an increase in stress resistance caused by this lignan, but no change in reactive oxygen species. Furthermore, we investigated the effects of pinoresinol on the life span of the nematode, but no modulation was found, neither in wild-type nor in mev-1 mutant nematodes. These results suggest that pinoresinol may exert pharmacologically interesting effects via modulation of the insulin-like signalling pathway in C. elegans as well as in other species like mammals due to the evolutionary conservation of this signalling pathway. PMID- 25826282 TI - Adverse childhood event experiences, fertility difficulties and menstrual cycle characteristics. AB - INTRODUCTION: Increased childhood adversity may be affect adult fertility, however, the mechanism through which this occurs is unclear. Menstrual cycle abnormalities are predictive of fertility difficulties, and stress influences menstrual cycle characteristics. Here, we assess whether adverse childhood experiences (ACEs) are associated with fertility difficulties and menstrual cycle dysregulation, offering a plausible mechanism for the link between lifetime stress and fertility. METHODS: From April 2012 to February 2014, 742 pregnant and non-pregnant women aged 18-45 years residing in southeastern Louisiana provided information on childhood adversity and reproductive history. Associations between ACEs and fertility difficulties and menstrual cycle patterns were evaluated. RESULTS: As the number of ACEs increased, risk of fertility difficulties and amenorrhea increased (RR = 1.09, 95% CI 1.05-1.13 and RR = 1.07, 95% CI 1.04 1.10, respectively), while fecundability decreased [fecundability ratio (FR) = 0.97, 95% CI 0.95-1.00]. Compared to women with no adversity, women in the high adversity group were more likely to experience both infertility and amenorrhea (RR = 2.75, 95% CI 1.45-5.21 and RR = 2.54, 95% CI 1.52-4.25, respectively), and reduced fecundability (FR = 0.75, 95% CI 0.56-1.00). Although similar patterns were seen for menstrual cycle irregularity, associations were diminished. Associations did not materially change following adjustment for age, body mass index, race, education, smoking and income. Results are constrained by the self report nature of the study and the limited generalizability of the study population. DISCUSSION: To our knowledge, this is the first study to present evidence of a link between childhood stressors, menstrual cycle disruption and fertility difficulties. The effect of childhood stress on fertility may be mediated through altered functioning of the HPA axis, acting to suppress fertility in response to less than optimal reproductive circumstances. PMID- 25826283 TI - Characterization of Staphylococcus aureus Strains Isolated from Czech Cystic Fibrosis Patients: High Rate of Ribosomal Mutation Conferring Resistance to MLS(B) Antibiotics as a Result of Long-Term and Low-Dose Azithromycin Treatment. AB - Staphylococcus aureus is one of the most frequent pathogens infecting the respiratory tract of patients with cystic fibrosis (CF). This study was the first to examine S. aureus isolates from CF patients in the Czech Republic. Among 100 S. aureus isolates from 92 of 107 observed patients, we found a high prevalence of resistance to macrolide-lincosamide-streptogramin B (MLS(B)) antibiotics (56%). More than half of the resistant strains (29 of 56) carried a mutation in the MLS(B) target site. The emergence of MLS(B) resistance and mutations conferring resistance to MLS(B) antibiotics was associated with azithromycin treatment (p=0.000000184 and p=0.000681, respectively). Methicillin resistance was only detected in 3% of isolates and the rate of resistance to other antibiotics did not exceed 12%. The prevalence of small-colony variant (SCV) strains was relatively low (9%) and eight of nine isolates with the SCV phenotype were thymidine dependent. The study population of S. aureus was heterogeneous in structure and both the most prevalent community-associated and hospital-acquired clonal lineages were represented. Of the virulence genes, enterotoxin genes seg (n=52), sei (n=49), and sec (n=16) were the most frequently detected among the isolates. The PVL genes (lukS-PV and lukF-PV) have not been revealed in any of the isolates. PMID- 25826284 TI - A synchrony-dependent influence of sounds on activity in visual cortex measured using functional near-infrared spectroscopy (fNIRS). AB - Evidence from human neuroimaging and animal electrophysiological studies suggests that signals from different sensory modalities interact early in cortical processing, including in primary sensory cortices. The present study aimed to test whether functional near-infrared spectroscopy (fNIRS), an emerging, non invasive neuroimaging technique, is capable of measuring such multisensory interactions. Specifically, we tested for a modulatory influence of sounds on activity in visual cortex, while varying the temporal synchrony between trains of transient auditory and visual events. Related fMRI studies have consistently reported enhanced activation in response to synchronous compared to asynchronous audiovisual stimulation. Unexpectedly, we found that synchronous sounds significantly reduced the fNIRS response from visual cortex, compared both to asynchronous sounds and to a visual-only baseline. It is possible that this suppressive effect of synchronous sounds reflects the use of an efficacious visual stimulus, chosen for consistency with previous fNIRS studies. Discrepant results may also be explained by differences between studies in how attention was deployed to the auditory and visual modalities. The presence and relative timing of sounds did not significantly affect performance in a simultaneously conducted behavioral task, although the data were suggestive of a positive relationship between the strength of the fNIRS response from visual cortex and the accuracy of visual target detection. Overall, the present findings indicate that fNIRS is capable of measuring multisensory cortical interactions. In multisensory research, fNIRS can offer complementary information to the more established neuroimaging modalities, and may prove advantageous for testing in naturalistic environments and with infant and clinical populations. PMID- 25826286 TI - Promotion of experimental autoimmune encephalomyelitis upon neutrophil granulocytes' stimulation with formyl-methionyl-leucyl-phenylalanine (fMLP) peptide. AB - It has been acknowledged that neutrophil granulocytes, the common mediators of immune responses against extracellular bacteria, can also intercede autoimmune reactions such as experimental autoimmune encephalomyelitis (EAE). Formyl methionyl-leucyl-phenylalanine (fMLP) is a microbial peptide that can be well tolerated when intravenously administered and can directly lead to activation and accumulation of neutrophils into the blood circulation. Here, this antigenic peptide was injected to the mice at the induction of EAE, and the immunological and pathological outcomes were assessed. As a peripheral immune organ, spleen of the animals that received fMLP contained considerably high percentages of Gr 1(hi)Ly7/4(hi) mature neutrophils. In the sera samples, only a slight difference was determined in Th1/Th2/Th17-related cytokine levels. Expression of CXCR1 or CXCR2 chemokine receptors was not significantly modulated in EAE with or without fMLP which might indicate a direct role for this antigenic peptide on neutrophil accumulation. Even though fMLP administration did not propone the clinical (symptomatic) onset of the disease, the animals showed severe body conditions with higher EAE scores. Accordingly, the expression of TNF-alpha and CXCL1 inflammatory mediators in the brain was increased in fMLP-EAE group. In conclusion, with its potent capacity to mobilize neutrophils and to stimulate innate immune cells, fMLP peptide can be used to aggravate immune reactions in EAE. This observation may indicate that the strength of innate immune responses particularly at the induction phase of EAE might influence the clinical course of the disease. PMID- 25826287 TI - Enhancement of the thermoelectric figure of merit in DNA-like systems induced by Fano and Dicke effects. AB - We report a theoretical study highlighting the thermoelectric properties of biological and synthetic DNA molecules. Based on an effective tight-binding model of duplex DNA and by using the nonequilibrium Green's function technique, the thermal conductance, electrical conductance, Seebeck coefficient and thermoelectric figure of merit in the system are numerically calculated by varying the asymmetries of energies and electronic hoppings in the backbone sites to simulate the environmental complications and fluctuations. We find that due to the multiple transport paths in the DNA molecule, the Fano antiresonance occurs, and enhances the Seebeck coefficient and the figure of merit. When the energy difference is produced in every opposite backbone site, the Dicke effect appears. This effect gives rise to a semiconducting-metallic transition, and enhances the thermoelectric efficiency of the DNA molecule remarkably. Moreover, as the Fano antiresonance point is close to the Dicke resonance one, a giant enhancement in the thermoelectric figure of merit in the DNA molecule has been found. These results provide a scenario to obtain effective routes to enhance the thermoelectric efficiency in the DNA molecules, and suggest perspectives for future experiments intending to control the thermoelectric transport in DNA-like nanodevices. PMID- 25826288 TI - Novel "hot exciton" blue fluorophores for high performance fluorescent/phosphorescent hybrid white organic light-emitting diodes with superhigh phosphorescent dopant concentration and improved efficiency roll-off. AB - Two blue fluorophores with excellent hybridized local and charge-transfer (HLCT) and "hot exciton" properties were developed as the blue emitter and the host for orange-red phosphor to achieve highly efficient fluorescent/phosphorescent (F/P) hybrid white organic light-emitting diodes (WOLEDs) in a single-emissive-layer single-dopant (SEML-SD) architecture even at a high concentration of phosphorescent dopant. In the devices, part of the triplet excitons of the blue fluorophores can be utilized to realize reverse intersystem crossing from the triplet excited states to the singlet excited states for blue emission, and the diffusion volume range of the triplet excitons is reduced significantly. When the phosphorescent dopant concentration is up to 1.0 wt %, which is ten times higher than the traditional single-EML-SD F/P hybrid WOLEDs, highly efficient white emission was still achieved with maximum total external quantum efficiency (EQE) of 23.8%, current efficiency (CE) of 56.1 cd A(-1), and power efficiency (PE) of 62.9 lm W(1-). The results will supply a novel method for obtaining high efficiency F/P hybrid WOLEDs in a SEML-SD architecture with easily controllable doping concentration. PMID- 25826285 TI - Temporal phenotypic features distinguish polarized macrophages in vitro. AB - Macrophages are important in vascular inflammation and environmental factors influence macrophage plasticity. Macrophage transitions into pro-inflammatory (M1) or anti-inflammatory (M2) states have been defined predominately by measuring cytokines in culture media (CM). However, temporal relationships between cellular and secreted cytokines have not been established. We measured phenotypic markers and cytokines in cellular and CM of murine bone marrow-derived macrophages at multiple time points following stimulation with IFN-gamma + LPS (M1), IL-4 (M2a) or IL-10 (M2c). Cytokines/proteins in M1-polarized macrophages exhibited two distinct temporal patterns; an early (0.5-3 h), transient increase in cellular cytokines (GM-CSF, KC-GRO, MIP-2, IP-10 and MIP-1beta) and a delayed (3-6 h) response that was more sustained [IL-3, regulated on activation normal T cell expressed and secreted (RANTES), and tissue inhibitor of metalloproteinases 1 (TIMP-1)]. M2a-related cytokine/cell markers (IGF-1, Fizz1 and Ym1) were progressively (3-24 h) increased post-stimulation. In addition, novel patterns were observed. First, and unexpectedly, cellular pro-inflammatory chemokines, MCP 1 and MCP-3 but not MCP-5, were comparably increased in M1 and M2a macrophages. Second, Vegfr1 mRNA was decreased in M1 and increased in M2a macrophages. Finally, VEGF-A was increased in the CM of M1 cultures and strikingly reduced in M2a coinciding with increased Vegfr1 expression, suggesting decreased VEGF-A in M2a CM was secondary to increased soluble VEGFR1. In conclusion, macrophage cytokine production and marker expression were temporally regulated and relative levels compared across polarizing conditions were highly dependent upon the timing and location (cellular versus CM) of the sample collection. For most cytokines, cellular production preceded increases in the CM suggesting that cellular regulatory pathways should be studied within 6 h of stimulation. The divergent polarization-dependent expression of Vegfr1 may be essential to controlling VEGF potentially regulating angiogenesis and inflammatory cell infiltration in the vascular niche. The current study expands the repertoire of cytokines produced by polarized macrophages and provides insights into the dynamic regulation of macrophage polarization and resulting cytokines, proteins and gene expression that influence vascular inflammation. PMID- 25826289 TI - Lack of efficacy of prophylactic application of antibiotic-loaded bone cement for prevention of infection in primary total knee arthroplasty: results of a meta analysis. AB - BACKGROUND: Deep incisional surgical site infection (SSI) is a devastating and costly complication of primary total knee arthroplasty (TKA). The effectiveness of antibiotic-loaded bone cement (ALBC) in preventing these infections remains controversial. METHODS: A meta-analysis was conducted to assess the efficacy of ALBC in preventing deep infection in primary TKA after a detailed and systematic search of the PubMed, Embase, CNKI, and Cochrane databases had been performed to identify appropriate comparative trials on the prophylactic use of ALBC in primary TKA. RESULTS: Five comparative trials were included. In total, 3,461 patients (ALBC group) received ALBC, whereas 3,176 patients (non-antibiotic loaded cement; NALBC group) did not. The incidence of deep incisional SSI in the ALBC group was 1.32% (n=46) whereas the incidence in the NALBC group was 1.89% (n=60), figures which are not significantly different. No adverse events associated with ALBC were reported in any studies. CONCLUSION: Statistical analysis did not reveal a significantly different incidence of deep or superficial SSI in patients receiving and not receiving antibiotic-loaded cement. The prophylactic application of ALBC thus did not show efficacy in primary TKA. More large-sample studies are required to confirm this finding. PMID- 25826290 TI - Male youth with eating disorders: clinical and medical characteristics of a sample of inpatients. AB - A retrospective chart review was conducted to elucidate the clinical and medical characteristics of male youth admitted to a tertiary inpatient treatment center for eating disorders. A total of 23 male youth were identified who had received treatment between January 2003 and February 2014, and for whom charts were available. The majority of the sample (n = 19; 82.6%) received a diagnosis of anorexia nervosa, and the data suggest that these male youth were significantly medically compromised. The patterns in this data will be discussed in the context of previous published research on male youth with eating disorders. PMID- 25826291 TI - The Impact of Gender and Protein Intake on the Success of Weight Maintenance and Associated Cardiovascular Risk Benefits, Independent of the Mode of Food Provision: The DiOGenes Randomized Trial. AB - OBJECTIVE: Maintenance of weight loss and associated cardiovascular benefits after following energy-restricted diets is still a challenging field, and thorough investigation is needed. The present research aimed to determine the role of protein and gender in relation to two different intervention models related to food supply, in a weight maintenance trial. SUBJECTS AND METHODS: The DiOGenes trial was a long-term, multicenter, randomized, dietary intervention study, conducted in eight European countries (Clinical Trials.gov, NCT00390637), focusing on assessing the effectiveness of weight maintenance over 6 months. This secondary analysis intended to evaluate the different benefits for weight maintenance and cardiometabolic markers of two dietary advice delivery models: "shop + instruction intervention" vs "instruction-alone intervention," which were further categorized for gender and macronutrient intake. RESULTS: The weight maintenance intervention based on different macronutrient intake showed, independently of the advice delivery model, in both sexes that higher protein consumption was more effective for weight stability, showing better results in obese women (low protein: 1.65 kg in males and 0.73 Kg in females vs high protein: 1.45 kg in males and -0.93 Kg in females) . Measurements concerning cardiovascular risk markers from subjects on both structured models produced similar trends in the subsequent follow-up period, with a lower rebound in women for most of the markers analyzed. CONCLUSION: The reported dietary benefits for weight sustainability should be ascribed to the macronutrient distribution (higher protein diets) rather than to the structured mode of delivery. Higher weight regain in males was noted, as well as a metabolic divergence attributable to the sex, with a better biochemical outcome in women. PMID- 25826292 TI - Influence of age and physical fitness on miRNA-21, TGF-beta and its receptors in leukocytes of healthy women. AB - The TGF-beta superfamily has been shown to play an important role in a wide range of physiological as well as pathological processes including ageing, immune modulation, atherosclerosis and cancer development. The aim of the current study was to investigate (i) whether TGF-beta signalling in peripheral blood mononuclear cells (PBMCs) would differ between young and old females and (ii) whether physical performance parameters of elderly women would be related to the expression of TGF-beta or its receptors. Sixteen healthy young (22-28 years; YF) and 90 healthy older (65-92 years; OF) females participated in the study. In addition to several components of health-related physical fitness, circulating CRP and TGF-beta levels were determined together with the mRNA expression of TGF beta, TGF-betaRI, TGF-betaRII, and miRNA-21 (known to interfere with TGF-beta signalling) in PBMCs. Physical fitness as determined by 6-minutes walking test (YF:median 932 (range 573-1254) m; OF:360 (114-558) m), handgrip strength (YF: 32 (24-39) kg; OF:18(10-30) kg), relative isokinetic peak torque of knee extensors (YF:1.9 (1.2- 2.3) Nm/kg; OF:1.0 (0.2-1.9) Nm/kg and flexors (YF: 1.1 (0.7- 1.5) Nm/kg; OF: 0.5 (0.2-1.0) Nm/kg was substantially lower in older women (p<0.001 for all comparisons). These changes were paralleled by an increase in hs-CRP (YF: 0.9 (0.1-4.3)mg/L; OF: 2.3 (0.3-56.7)mg/L,p<0.001). Serum levels of TGF-beta and TGF-beta mRNA levels from PBMCs did not differ between young and old women whereas, both TGF- betaRI/GAPDH (YF: 4.07 (1.38-14.60); OF: 2.08 (0.14-28.81); p=0.020) and TGF-betaRII/GAPDH levels (YF: 3.16 (1.14- 10.25); OF: 1.71 (0.51 14.86); p=0.020) were lower with respect to old age. In elderly women, only TGF betaRIota expression correlated negatively with miRNA-21 expression in PBMCs (rho=-0.315; p=0.004). Interestingly, hs-CRP and miRNA correlated positively with handgrip strength (rho=0.237 and rho=243, p<0.05), while none of the TGF-beta related parameters were related to physical performance. The results suggest that age affects TGF-beta signalling in leukocytes by altering the expression levels of its receptors. These changes seem to occur independently of physical fitness of old women. PMID- 25826293 TI - [Effect of high-intensity interval training on the reduction of glycosylated hemoglobin in type-2 diabetic adult patients]. AB - INTRODUCTION: Type 2 diabetes mellitus is one of the major non-communicable chronic diseases in the world. Its prevalence in Chile is significant, and complications associated with this disease involve great costs, which is why prevention and treatment of this condition are essential. Physical exercise is an effective means for prevention and treatment of type 2 diabetes mellitus. The emergence of new forms of physical training, such as "high intensity interval training", presents novel therapeutic alternatives for patients and health care professionals. OBJECTIVE: To assess the validity and applicability of the results regarding the effectiveness of high intensity interval training in reducing glycosylated hemoglobin in adult patients with type 2 diabetes mellitus and answer the following question: In subjects with type 2 diabetes, can the method of high intensity interval training compared to moderate intensity exercise decrease glycosylated hemoglobin? METHODS: We performed a critical analysis of the article "Feasibility and preliminary effectiveness of high intensity interval training in type 2 diabetes". RESULTS: We found no significant differences in the amount of glycosylated hemoglobin between groups of high intensity interval training and moderate-intensity exercise upon completion of the study (p>0.05). CONCLUSION: In adult patients with type 2 diabetes mellitus, high intensity interval training does not significantly improve glycosylated hemoglobin levels. Despite this, the high intensity interval training method shows as much improvement in body composition and physical condition as the moderate intensity exercise program. PMID- 25826295 TI - Associations between stress and quality of life: differences between owners keeping a living dog or losing a dog by euthanasia. AB - OBJECTIVES: The loss of a pet may be stressful to the owner. The main objectives of this study were to compare the levels of stress and to explore the correlates of QOL of healthy adults who currently own or who have just lost their dog. METHODS: The study sample contained 110 current, and 103 bereaved dog owners, all females, who lost their dogs due to euthanasia. QOL was assessed with the WHOQOL BREF questionnaire and divided into four major domains-Physical, Psychological, Relationship, and Environmental. Demographic variables, stress, health behaviors, and social support from family, friends, and significant other were included in multivariate analysis. RESULTS: Stress levels were significantly higher in bereaved owners. QOL in three of the four domains (Physical, Psychological, and Relationship) of current owners were significantly better than among bereaved owners. Stress was significantly associated with these three domains of QOL. Quality of life was found to be positively associated with social support. Age was related directly only to current owners' QOL. CONCLUSIONS: The results suggest that a loss of a dog is associated with stress for the bereaved owner and reduced physical, psychological, and relationship QOL. Lack of social support in the case of death of a companion animal has a strong effect on owners' grief reactions. PMID- 25826296 TI - 5-Alkyl-1,2,3,4-tetrahydroquinolines, new membrane-interacting lipophilic metabolites produced by combined culture of Streptomyces nigrescens and Tsukamurella pulmonis. AB - Eight novel 5-alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs) bearing different side chains have been isolated from a combined culture of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596. The chemical structures including the absolute configuration were elucidated by spectroscopic analysis and total synthesis. 5aTHQs inhibited the growth of wild-type fission yeast while only weakly inhibiting the growth of several mutant strains synthesizing premature ergosterol. These results demonstrate that 5aTHQs are novel antifungals that may target cell membranes. PMID- 25826294 TI - Genetic variants in de novo lipogenic pathway genes predict the prognosis of surgically-treated hepatocellular carcinoma. AB - Over-expression of de novo lipogenesis (DNL) pathway genes is associated with the prognosis of various types of cancers. However, effects of single nucleotide polymorphisms (SNPs) in these genes on recurrence and death of hepatocellular carcinoma (HCC) patients after surgery are still unknown. A total of 492 primary HCC patients treated with surgery were included in this study. Nine SNPs in 3 genes (ACACA, FASN and ACLY) of DNL pathway were genotyped. Multivariate Cox proportional hazard regression model and Kaplan-Meier curve were used to analyze the association of SNPs with clinical outcomes. Two SNPs in ACACA gene were significantly associated with overall survival of HCC patients. Patients carrying homozygous variant genotype (VV) in rs7211875 had significantly increased risk of death, while patients carrying VV genotype in rs11871275 had significant decreased risk of death, when compared with those carrying homozygous wild-type or heterozygous genotypes. Moreover, patients carrying VV genotype in rs11871275 had decreased recurrence risk, while patients carrying variant genotype in rs4485435 of FASN gene had increased recurrence risk. Further cumulative effect analysis showed significant dose-dependent effects of unfavorable SNPs on both death and recurrence. SNPs in DNL genes may serve as independent prognostic markers for HCC patients after surgery. PMID- 25826297 TI - Evaluation of inapparent dengue infections during an outbreak in Southern China. AB - Few studies evaluating inapparent dengue virus (DENV) infections have been conducted in China. In 2013, a large outbreak of DENV occurred in the city of Zhongshan, located in Southern China, which provided an opportunity to assess the clinical spectrum of disease. During the outbreak, an investigation of 887 index case contacts was conducted to evaluate inapparent and symptomatic DENV infections. Post-outbreak, an additional 815 subjects from 4 towns with, and 350 subjects from 2 towns without reported autochthonous DENV transmission, as determined by clinical diagnosis, were evaluated for serological evidence of dengue IgG antibodies. Between July and November 2013, there were 19 imported and 809 autochthonous dengue cases reported in Zhongshan. Of 887 case contacts enrolled during the outbreak, 13 (1.5%) exhibited symptomatic DENV infection, while 28 (3.2%) were inapparent. The overall I:S ratio was 2.2:1 (95% CI: 1.1 4.2:1). Post-outbreak serological data showed that the proportion of DENV IgG antibody detection from the 4 towns with and the 2 towns without reported DENV transmission was 2.7% (95% CI: 1.6%-3.8%) and 0.6% (95% CI: 0-1.4%), respectively. The I:S ratio in the 3 towns where clinical dengue cases were predominately typed as DENV-1 was 11.0:1 (95% CI: 3.7-infinity:1). The ratio in the town where DENV-3 was predominately typed was 1.0:1 (95% CI: 0.5-infinity:1). In this cross-sectional study, data suggests a high I:S ratio during a documented outbreak in Zhongshan, Southern China. These results have important implications for dengue control, implying that inapparent cases might influence DENV transmission more than previously thought. PMID- 25826298 TI - Chlamydia trachomatis load in population-based screening and STI-clinics: implications for screening policy. AB - OBJECTIVES: If the Chlamydia trachomatis (CT) bacterial load is higher in high risk populations than in the general population, this negatively affects the efficacy of CT screening incentives. In the largest retrospective study to date, we investigated the CT load in specimens collected from 2 cohorts: (1) attendants of a sexually transmitted infection (STI)-clinic and (2) participants of the Dutch population-based screening (PBS). METHODS: CT load was determined using quantitative PCR in CT-positive male urine and female cervicovaginal swabs. CT loads were converted into tertiles. Using multinominal logistic regression, independent association of cohort, symptoms, risk behaviour and human cell count on load were assessed. RESULTS: CT loads were determined in 889 CT-positives from PBS (n = 529; 71.8% female) and STI-clinics (n = 360; 61.7% female). In men, STI clinic-cohort, human cell count and urethral discharge were positively associated with CT load. In women, PBS-cohort and cell count were positively associated with CT load. Both cohorts had the same range in CT load. CONCLUSIONS: The general population has a similar range of bacterial CT load as a high-risk population, but a different distribution for cohort and gender, highlighting the relevance of population-based CT-screening. When CT loads are similar, possibly the chances of transmission and sequelae are too. PMID- 25826299 TI - Insight into neutral and disease-associated human genetic variants through interpretable predictors. AB - A variety of methods that predict human nonsynonymous single nucleotide polymorphisms (SNPs) to be neutral or disease-associated have been developed over the last decade. These methods are used for pinpointing disease-associated variants in the many variants obtained with next-generation sequencing technologies. The high performances of current sequence-based predictors indicate that sequence data contains valuable information about a variant being neutral or disease-associated. However, most predictors do not readily disclose this information, and so it remains unclear what sequence properties are most important. Here, we show how we can obtain insight into sequence characteristics of variants and their surroundings by interpreting predictors. We used an extensive range of features derived from the variant itself, its surrounding sequence, sequence conservation, and sequence annotation, and employed linear support vector machine classifiers to enable extracting feature importance from trained predictors. Our approach is useful for providing additional information about what features are most important for the predictions made. Furthermore, for large sets of known variants, it can provide insight into the mechanisms responsible for variants being disease-associated. PMID- 25826300 TI - The neural mechanisms of re-experiencing mental fatigue sensation: a magnetoencephalography study. AB - There have been several studies which have tried to clarify the neural mechanisms of fatigue sensation; however fatigue sensation has multiple aspects. We hypothesized that past experience related to fatigue sensation is an important factor which contributes to future formation of fatigue sensation through the transfer to memories that are located within specific brain structures. Therefore, we aimed to investigate the neural mechanisms of fatigue sensation related to memory. In the present study, we investigated the neural activity caused by re-experiencing the fatigue sensation that had been experienced during a fatigue-inducing session. Thirteen healthy volunteers participated in fatigue and non-fatigue experiments in a crossover fashion. In the fatigue experiment, they performed a 2-back test session for 40 min to induce fatigue sensation, a rest session for 15 min to recover from fatigue, and a magnetoencephalography (MEG) session in which they were asked to re-experience the state of their body with fatigue that they had experienced in the 2-back test session. In the non fatigue experiment, the participants performed a free session for 15 min, a rest session for 15 min, and an MEG session in which they were asked to re-experience the state of their body without fatigue that they had experienced in the free session. Spatial filtering analyses of oscillatory brain activity showed that the delta band power in the left Brodmann's area (BA) 39, alpha band power in the right pulvinar nucleus and the left BA 40, and beta band power in the left BA 40 were lower when they re-experienced the fatigue sensation than when they re experienced the fatigue-free sensation, indicating that these brain regions are related to re-experiencing the fatigue sensation. Our findings may help clarify the neural mechanisms underlying fatigue sensation. PMID- 25826301 TI - Impact of Leishmania infection on host macrophage nuclear physiology and nucleopore complex integrity. AB - The protease GP63 is an important virulence factor of Leishmania parasites. We previously showed that GP63 reaches the perinuclear area of host macrophages and that it directly modifies nuclear translocation of the transcription factors NF kappaB and AP-1. Here we describe for the first time, using molecular biology and in-depth proteomic analyses, that GP63 alters the host macrophage nuclear envelope, and impacts on nuclear processes. Our results suggest that GP63 does not appear to use a classical nuclear localization signal common between Leishmania species for import, but degrades nucleoporins, and is responsible for nuclear transport alterations. In the nucleoplasm, GP63 activity accounts for the degradation and mislocalization of proteins involved amongst others in gene expression and in translation. Collectively, our data indicates that Leishmania infection strongly affects nuclear physiology, suggesting that targeting of nuclear physiology may be a strategy beneficial for virulent Leishmania parasites. PMID- 25826302 TI - The consensus 5' splice site motif inhibits mRNA nuclear export. AB - In eukaryotes, mRNAs are synthesized in the nucleus and then exported to the cytoplasm where they are translated into proteins. We have mapped an element, which when present in the 3'terminal exon or in an unspliced mRNA, inhibits mRNA nuclear export. This element has the same sequence as the consensus 5'splice site motif that is used to define the start of introns. Previously it was shown that when this motif is retained in the mRNA, it causes defects in 3'cleavage and polyadenylation and promotes mRNA decay. Our new data indicates that this motif also inhibits nuclear export and promotes the targeting of transcripts to nuclear speckles, foci within the nucleus which have been linked to splicing. The motif, however, does not disrupt splicing or the recruitment of UAP56 or TAP/Nxf1 to the RNA, which are normally required for nuclear export. Genome wide analysis of human mRNAs, lncRNA and eRNAs indicates that this motif is depleted from naturally intronless mRNAs and eRNAs, but less so in lncRNAs. This motif is also depleted from the beginning and ends of the 3'terminal exons of spliced mRNAs, but less so for lncRNAs. Our data suggests that the presence of the 5'splice site motif in mature RNAs promotes their nuclear retention and may help to distinguish mRNAs from misprocessed transcripts and transcriptional noise. PMID- 25826303 TI - Correction: the five-to-six-coordination transition of ferric human serum heme albumin is allosterically-modulated by ibuprofen and warfarin: a combined XAS and MD study. AB - [This corrects the article DOI: 10.1371/journal.pone.0104231.]. PMID- 25826304 TI - Reward learning in pediatric depression and anxiety: preliminary findings in a high-risk sample. AB - BACKGROUND: Reward learning has been postulated as a critical component of hedonic functioning that predicts depression risk. Reward learning deficits have been established in adults with current depressive disorders, but no prior studies have examined the relationship of reward learning and depression in children. The present study investigated reward learning as a function of familial depression risk and current diagnostic status in a pediatric sample. METHOD: The sample included 204 children of parents with a history of depression (n = 86 high-risk offspring) or parents with no history of major mental disorder (n = 118 low-risk offspring). Semistructured clinical interviews were used to establish current mental diagnoses in the children. A modified signal detection task was used for assessing reward learning. We tested whether reward learning was impaired in high-risk offspring relative to low-risk offspring. We also tested whether reward learning was impaired in children with current disorders known to blunt hedonic function (depression, social phobia, PTSD, GAD, n = 13) compared to children with no disorders and to a psychiatric comparison group with ADHD. RESULTS: High- and low-risk youth did not differ in reward learning. However, youth with current anhedonic disorders (depression, social phobia, PTSD, GAD) exhibited blunted reward learning relative to nondisordered youth and those with ADHD. CONCLUSIONS: Our results are a first demonstration that reward learning deficits are present among youth with disorders known to blunt anhedonic function and that these deficits have some degree of diagnostic specificity. We advocate for future studies to replicate and extend these preliminary findings. PMID- 25826306 TI - Mapping and modelling helminth infections in ruminants in Europe: experience from GLOWORM. AB - Mapping and modelling helminth infections in cattle and sheep in Europe through advanced geospatial research was one of the main task of GLOWORM, a three year project (2012-2014) funded under the European Commission's (EC) seventh framework programme (FP7). Liver flukes as Fasciola hepatica and gastrointestinal nematodes, such as Haemonchus contortus were chosen for the project since these parasites constitute a major cause of lost productivity in small and large ruminants. The output of the GLOWORM project delivered guidelines for standardized and harmonized cross-sectional surveys of helminth parasites in ruminants allowing the development of updated prevalence maps and multi-scale, spatial models for the European area. PMID- 25826305 TI - DNA polymerase zeta-dependent lesion bypass in Saccharomyces cerevisiae is accompanied by error-prone copying of long stretches of adjacent DNA. AB - Translesion synthesis (TLS) helps cells to accomplish chromosomal replication in the presence of unrepaired DNA lesions. In eukaryotes, the bypass of most lesions involves a nucleotide insertion opposite the lesion by either a replicative or a specialized DNA polymerase, followed by extension of the resulting distorted primer terminus by DNA polymerase zeta (Polzeta). The subsequent events leading to disengagement of the error-prone Polzeta from the primer terminus and its replacement with an accurate replicative DNA polymerase remain largely unknown. As a first step toward understanding these events, we aimed to determine the length of DNA stretches synthesized in an error-prone manner during the Polzeta dependent lesion bypass. We developed new in vivo assays to identify the products of mutagenic TLS through a plasmid-borne tetrahydrofuran lesion and a UV-induced chromosomal lesion. We then surveyed the region downstream of the lesion site (in respect to the direction of TLS) for the presence of mutations indicative of an error-prone polymerase activity. The bypass of both lesions was associated with an approximately 300,000-fold increase in the mutation rate in the adjacent DNA segment, in comparison to the mutation rate during normal replication. The hypermutated tract extended 200 bp from the lesion in the plasmid-based assay and as far as 1 kb from the lesion in the chromosome-based assay. The mutation rate in this region was similar to the rate of errors produced by purified Polzeta during copying of undamaged DNA in vitro. Further, no mutations downstream of the lesion were observed in rare TLS products recovered from Polzeta-deficient cells. This led us to conclude that error-prone Polzeta synthesis continues for several hundred nucleotides after the lesion bypass is completed. These results provide insight into the late steps of TLS and show that error-prone TLS tracts span a substantially larger region than previously appreciated. PMID- 25826307 TI - Modelling the spatial distribution of Fasciola hepatica in dairy cattle in Europe. AB - A harmonized sampling approach in combination with spatial modelling is required to update current knowledge of fasciolosis in dairy cattle in Europe. Within the scope of the EU project GLOWORM, samples from 3,359 randomly selected farms in 849 municipalities in Belgium, Germany, Ireland, Poland and Sweden were collected and their infection status assessed using an indirect bulk tank milk (BTM) enzyme linked immunosorbent assay (ELISA). Dairy farms were considered exposed when the optical density ratio (ODR) exceeded the 0.3 cut-off. Two ensemble-modelling techniques, Random Forests (RF) and Boosted Regression Trees (BRT), were used to obtain the spatial distribution of the probability of exposure to Fasciola hepatica using remotely sensed environmental variables (1-km spatial resolution) and interpolated values from meteorological stations as predictors. The median ODRs amounted to 0.31, 0.12, 0.54, 0.25 and 0.44 for Belgium, Germany, Ireland, Poland and southern Sweden, respectively. Using the 0.3 threshold, 571 municipalities were categorized as positive and 429 as negative. RF was seen as capable of predicting the spatial distribution of exposure with an area under the receiver operation characteristic (ROC) curve (AUC) of 0.83 (0.96 for BRT). Both models identified rainfall and temperature as the most important factors for probability of exposure. Areas of high and low exposure were identified by both models, with BRT better at discriminating between low-probability and high probability exposure; this model may therefore be more useful in practise. Given a harmonized sampling strategy, it should be possible to generate robust spatial models for fasciolosis in dairy cattle in Europe to be used as input for temporal models and for the detection of deviations in baseline probability. Further research is required for model output in areas outside the eco-climatic range investigated. PMID- 25826308 TI - Cluster analysis of fasciolosis in dairy cow herds in Munster province of Ireland and detection of major climatic and environmental predictors of the exposure risk. AB - Fasciolosis caused by Fasciola hepatica is a widespread parasitic disease in cattle farms. The aim of this study was to detect clusters of fasciolosis in dairy cow herds in Munster Province, Ireland and to identify significant climatic and environmental predictors of the exposure risk. In total, 1,292 dairy herds across Munster was sampled in September 2012 providing a single bulk tank milk (BTM) sample. The analysis of samples by an in-house antibody-detection enzyme linked immunosorbent assay (ELISA), showed that 65% of the dairy herds (n = 842) had been exposed to F. hepatica. Using the Getis-Ord Gi* statistic, 16 high-risk and 24 low-risk (P <0.01) clusters of fasciolosis were identified. The spatial distribution of high-risk clusters was more dispersed and mainly located in the northern and western regions of Munster compared to the low-risk clusters that were mostly concentrated in the southern and eastern regions. The most significant classes of variables that could reflect the difference between high risk and low-risk clusters were the total number of wet-days and rain-days, rainfall, the normalized difference vegetation index (NDVI), temperature and soil type. There was a bigger proportion of well-drained soils among the low-risk clusters, whereas poorly drained soils were more common among the high-risk clusters. These results stress the role of precipitation, grazing, temperature and drainage on the life cycle of F. hepatica in the temperate Irish climate. The findings of this study highlight the importance of cluster analysis for identifying significant differences in climatic and environmental variables between high-risk and low-risk clusters of fasciolosis in Irish dairy herds. PMID- 25826310 TI - Distribution of Fasciola hepatica in Swedish dairy cattle and associations with pasture management factors. AB - The geographic distribution of Fasciola hepatica infection in relation to management routines was studied in Swedish dairy herds by testing for F. hepatica antibodies with the enzyme-linked immunosorbent assay (ELISA). In addition, all farmers were sent a questionnaire asking for information about type of production, management routines and historical record of F. hepatica at slaughter. A total of 176 farmers (41%) responded to the questionnaire. A total of 426 bulk tank milk (BTM) samples were randomly selected from the period September to October 2012 representing approximately 10% of all herds in Sweden. The overall seroprevalence was 25% (n = 107; 95% confidence interval = 21-29%) with a concentration of herds located in south-western Sweden. Among the seropositive herds, 31 (29%) had antibody levels indicating production loss. There were no significant differences in seropositivity between organic and conventional herds or due to pasture management routines. The length of grazing period, which increased the risk for heifers, was found to be the most influential factor. A discrepancy was noted between reported F. hepatica presence at meat inspection and herds that were seropositive based on BTM-ELISA results. Although the largest proportion of seropositive BTM samples (80%) came from herds where liver fluke presence had been observed at meat inspection after slaughter, seropositive BTM samples were also diagnosed in five herds (17%) with no remarks at slaughter. In conclusion, F. hepatica is a common parasite in Swedish dairy herds and the month of heifer turn-out and the grazing period length were the most influential factors observed. PMID- 25826309 TI - Spatial analysis and risk mapping of Fasciola hepatica infection in dairy herds in Ireland. AB - Fasciolosis is generally a subclinical infection of dairy cows and can cause marked economic losses. This study investigated the prevalence and spatial distribution of fasciolosis in dairy cow herds in Ireland using an in-house antibodydetection enzyme-linked immunosorbent assay applied to bulk tank milk (BTM) samples collected during the autumn of 2012. A total of 5,116 BTM samples were collected from 4,602 different herds, with 514 farmers submitting BTM samples in two consecutive months. Analysis of the BTM samples showed that 82% (n = 3,764) of the dairy herds had been exposed to Fasciola hepatica. A total of 108 variables, including averaged climatic data for the period 1981-2010 and contemporary meteorological data for the year 2012, such as soil, subsoil, land cover and habitat maps, were investigated for a possible role as predictor of fasciolosis. Using mainly climatic variables as the major predictors, a model of the predicted risk of fasciolosis was created by Random Forest modelling that had 95% sensitivity and 100% specificity. The most important predictors in descending order of importance were: average of annual total number of rain-days for the period 1981-2010, total rainfall during September, winter and autumn of 2012, average of annual total number of wet-days for the period 1981- 2010 and annual mean temperature of 2012. The findings of this study confirm the high prevalence of fasciolosis in Irish dairy herds and suggest that specific weather and environmental risk factors support a robust and precise distribution model. PMID- 25826311 TI - Modelling recent and future climatic suitability for fasciolosis in Europe. AB - Fasciola hepatica is a parasitic worm responsible for fasciolosis in grazed ruminants in Europe. The free-living stages of this parasite are sensitive to temperature and soil moisture, as are the intermediate snail hosts the parasite depends on for its life-cycle. We used a climate-driven disease model in order to assess the impact of recent and potential future climate changes on the incidence of fasciolosis and to estimate the related uncertainties at the scale of the European landmass. The current climate appears to be highly suitable for fasciolosis throughout the European Union with the exception of some parts of the Mediterranean region. Simulated climatic suitability for fasciolosis significantly increased during the 2000s in central and northwestern Europe, which is consistent with an observed increased in ruminant infections. The simulation showed that recent trends are likely to continue in the future with the estimated pattern of climate change for northern Europe, possibly extending the season suitable for development of the parasite in the environment by up to four months. For southern Europe, the simulated burden of disease may be lower, but the projected climate change will increase the risk during the winter months, since the simulated changes in temperature and moisture support the development of the free-living and intra-molluscan stages between November and March. In the event of predicted climate change, F. hepatica will present a serious risk to the health, welfare and productivity of all ruminant livestock. Improved, bespoke control programmes, both at farm and region levels, will then become imperative if problems, such as resistance of the parasite associated with increased drug use, are to be mitigated. PMID- 25826312 TI - Sheep and Fasciola hepatica in Europe: the GLOWORM experience. AB - Fasciola hepatica infection challenges health, welfare and productivity of small ruminants throughout the world. The distribution of F. hepatica in sheep in Europe is usually scattered and studies are generally concerned with a single area making it difficult to compare results from different environments, climates and management regimes. In order to elucidate the current scenario in terms of prevalence and intensity of F. hepatica infection in sheep farms across Europe, a standardized cross-sectional survey was conducted in three pilot areas in Ireland, Switzerland and Italy, all part of the EU funded GLOWORM project. Two consecutive field surveys (in 2012 and 2013) were conducted in the three countries in the same period (August-October) in 361 sheep farms in total. Harmonized procedures (from farm to laboratory) based on pooled samples and the highly sensitive and accurate, diagnostic FLOTAC technique were used. The georeferenced parasitological results were modelled (at the pilot area level) following a Bayesian geostatistical approach with correction for preferential sampling and accounting for climatic and environmental covariates. The observed F. hepatica prevalence rates did not differ between the two study years in any of the three pilot areas, but they did vary between the countries showing high values in Ireland (61.6%) compared to Italy (7.9%) and Switzerland (4.0%). Spatial patterns of F. hepatica distribution were detected by the Bayesian geostatistical approach in Ireland with a high risk of infection in the south western part of the pilot area there. The latent factor analysis highlighted the importance of year-to-year variation of mean temperature, rainfall and seasonality within a country, while long-term trends of temperature and rainfall dominated between countries with respect to prevalence of infection. PMID- 25826313 TI - Outbreak of acute fasciolosis in sheep farms in a Mediterranean area arising as a possible consequence of climate change. AB - The objective of the present study was to investigate whether climate change in recent years have influenced the onset of acute outbreaks of Fasciola hepatica in ovine farms in southern Italy. In May-June 2014, a severe outbreak of F. hepatica occurred in three sheep farms in the Campania region. Clinical, coprological and necroscopic examinations were performed. Morbidity and mortality due to F. hepatica were 3-67% and 3-50%, respectively. Coprological examinations showed high values of F. hepatica eggs per gram (EPG) of faeces (860-1,240). Similarly, high adult parasitic burdens were found in animals that had sucombed (124-426 flukes). The study area was georeferenced and climatic data (temperature, humidity, days of rain and total amount of rainfall) were recorded at four georeferenced meterological stations in the study area. Montly data were processed and analyzed for the period 2000-2013 to evaluate the change of the climatic parameters during these years. The results show that there was a significant increase (P<0.001) of temperature, increased rainfall and increase in the number of rainy days compared to previous years. In addition to the outbreak reported here, we discuss the potential effects of climate change on the epidemiology of F. hepatica and the implications for sheep farming in the Mediterranean area. PMID- 25826314 TI - Haemonchus contortus: spatial risk distribution for infection in sheep in Europe. AB - Haemonchus contortus is a species of gastrointestinal strongyles of primary concern for sheep. This highly pathogenic, blood-feeding helminth negatively influences animal health, welfare and productivity. In order to elucidate the current scenario in terms of prevalence and intensity of H. contortus infection in sheep farms across Europe, a standardized crosssectional survey was conducted in three pilot areas in Ireland, Switzerland and Italy, all part of the EU funded GLOWORM project. Two consecutive field surveys (in 2012 and 2013) were conducted in the three countries in the same period (August-October) in 259 sheep farms in total. Harmonized, diagnostic procedures (from farm to laboratory) based on pooled samples, the FLOTAC technique and coproculture were used. The georeferenced parasitological results were modelled (at the pilot area level) following a Bayesian geostatistical approach with correction for preferential sampling and accounting for climatic and environmental covariates. The observed H. contortus prevalence rates did vary between the countries showing high values in Switzerland (77%) and Italy (73%) compared to Ireland (4%). Spatial patterns of H. contortus distribution were detected in Switzerland and Italy with a north south gradient. The latent factor analysis highlighted the importance of seasonality and annual cyclicity within country (particularly in southern Italy), while mean temperature and rainfall dominated between country variations in the prevalence of H. contortus infection. PMID- 25826315 TI - The basic reproduction quotient (Q0) as a potential spatial predictor of the seasonality of ovine haemonchosis. AB - Haemonchus contortus is a gastrointestinal nematode parasite of small ruminants, which feeds on blood and causes significant disease and production loss in sheep and goats, especially in warmer parts of the world. The life cycle includes free living immature stages, which are subject to climatic influences on development, survival and availability, and this species therefore exhibits spatio-temporal heterogeneity in its infection pressure based on the prevailing climate. Models that better explain this heterogeneity could predict future epidemiological changes. The basic reproduction quotient (Q0) was used as a simple process-based model to predict climate-driven changes in the potential transmission of H. contortus across widely different geo-climatic zones, and showed good agreement with the observed frequency of this species in the gastrointestinal nematode fauna of sheep (r = 0.81, P <0.01). Averaged monthly Q0 output was further used within a geographical information system (GIS) to produce preliminary haemonchosis risk maps for the United Kingdom (UK) over a four-year historical span and under future climate change scenarios. Prolonged transmission seasons throughout the UK are predicted, especially in the south although with restricted transmission in peak summer due to rainfall limitation. Additional predictive ability might be achieved if information such as host density and distribution, grazing pattern and edaphic conditions were included as risk layers in the GIS based risk map. However, validation of such risk maps presents a significant challenge, with georeferenced observed data of sufficient spatial and temporal resolution rarely available and difficult to obtain. PMID- 25826316 TI - Molecular insights into frataxin-mediated iron supply for heme biosynthesis in Bacillus subtilis. AB - Iron is required as an element to sustain life in all eukaryotes and most bacteria. Although several bacterial iron acquisition strategies have been well explored, little is known about the intracellular trafficking pathways of iron and its entry into the systems for co-factor biogenesis. In this study, we investigated the iron-dependent process of heme maturation in Bacillus subtilis and present, for the first time, structural evidence for the physical interaction of a frataxin homologue (Fra), which is suggested to act as a regulatory component as well as an iron chaperone in different cellular pathways, and a ferrochelatase (HemH), which catalyses the final step of heme b biogenesis. Specific interaction between Fra and HemH was observed upon co-purification from crude cell lysates and, further, by using the recombinant proteins for analytical size-exclusion chromatography. Hydrogen-deuterium exchange experiments identified the landscape of the Fra/HemH interaction interface and revealed Fra as a specific ferrous iron donor for the ferrochelatase HemH. The functional utilisation of the in vitro-generated heme b co-factor upon Fra-mediated iron transfer was confirmed by using the B. subtilis nitric oxide synthase bsNos as a metabolic target enzyme. Complementary mutational analyses confirmed that Fra acts as an essential component for maturation and subsequent targeting of the heme b co-factor, hence representing a key player in the iron-dependent physiology of B. subtilis. PMID- 25826317 TI - Health gain by salt reduction in europe: a modelling study. AB - Excessive salt intake is associated with hypertension and cardiovascular diseases. Salt intake exceeds the World Health Organization population nutrition goal of 5 grams per day in the European region. We assessed the health impact of salt reduction in nine European countries (Finland, France, Ireland, Italy, Netherlands, Poland, Spain, Sweden and United Kingdom). Through literature research we obtained current salt intake and systolic blood pressure levels of the nine countries. The population health modeling tool DYNAMO-HIA including country-specific disease data was used to predict the changes in prevalence of ischemic heart disease and stroke for each country estimating the effect of salt reduction through its effect on blood pressure levels. A 30% salt reduction would reduce the prevalence of stroke by 6.4% in Finland to 13.5% in Poland. Ischemic heart disease would be decreased by 4.1% in Finland to 8.9% in Poland. When salt intake is reduced to the WHO population nutrient goal, it would reduce the prevalence of stroke from 10.1% in Finland to 23.1% in Poland. Ischemic heart disease would decrease by 6.6% in Finland to 15.5% in Poland. The number of postponed deaths would be 102,100 (0.9%) in France, and 191,300 (2.3%) in Poland. A reduction of salt intake to 5 grams per day is expected to substantially reduce the burden of cardiovascular disease and mortality in several European countries. PMID- 25826318 TI - Genetic characteristics of Japanese clinical Listeria monocytogenes isolates. AB - Listeria monocytogenes causes foodborne illnesses through consumption of ready-to eat foods. Although 135-201annual listeriosis cases have been estimated in Japan, the details regarding the clinical isolates such as infection source, virulence level, and other genetic characteristics, are not known. In order to uncover the trends of listeriosis in Japan and use the knowledge for prevention measures to be taken, the genetic characteristics of the past human clinical isolates needs to be elucidated. For this purpose, multilocus tandem-repeat sequence analysis (MLTSA) and multi-virulence-locus sequence typing (MVLST) were used in this study. The clinical isolates showed a variety of genetically distant genotypes, indicating they were from sporadic cases. However, the MVLST profiles of 7 clinical isolates were identical to those of epidemic clone (EC) I isolates, which have caused several serious outbreaks in other countries, suggesting the possibility that they have strong virulence potential and originated from a single outbreak. Moreover, 6 Japanese food isolates shared their genotypes with ECI isolates, indicating that there may be risks for listeriosis outbreak in Japan. This is the first investigational study on genetic characteristics of Japanese listeriosis isolates. The listeriosis cases happened in the past are presumably sporadic, but it is still possible that some isolates with strong virulence potential have caused listeriosis outbreaks, and future listeriosis risks also exist. PMID- 25826320 TI - Inhibition of monoacylglycerol lipase prevents chronic traumatic encephalopathy like neuropathology in a mouse model of repetitive mild closed head injury. PMID- 25826319 TI - Anti-abeta oligomer IgG and surface sialic acid in intravenous immunoglobulin: measurement and correlation with clinical outcomes in Alzheimer's disease treatment. AB - The fraction of IgG antibodies with anti-oligomeric Abeta affinity and surface sialic acid was compared between Octagam and Gammagard intravenous immunoglobulin (IVIG) using two complementary surface plasmon resonance methods. These comparisons were performed to identify if an elevated fraction existed in Gammagard, which reported small putative benefits in a recent Phase III clinical trial for Alzheimer's Disease. The fraction of anti-oligomeric Abeta IgG was found to be higher in Octagam, for which no cognitive benefits were reported. The fraction and location of surface-accessible sialic acid in the Fab domain was found to be similar between Gammagard and Octagam. These findings indicate that anti-oligomeric Abeta IgG and total surface sialic acid alone cannot account for reported clinical differences in the two IVIG products. A combined analysis of sialic acid in anti-oligomeric Abeta IgG did reveal a notable finding that this subgroup exhibited a high degree of surface sialic acid lacking the conventional alpha2,6 linkage. These results demonstrate that the IVIG antibodies used to engage oligomeric Abeta in both Gammagard and Octagam clinical trials did not possess alpha2,6-linked surface sialic acid at the time of administration. Anti oligomeric Abeta IgG with alpha2,6 linkages remains untested as an AD treatment. PMID- 25826321 TI - Symmetry-breaking charge transfer in a zinc chlorodipyrrin acceptor for high open circuit voltage organic photovoltaics. AB - Low open-circuit voltages significantly limit the power conversion efficiency of organic photovoltaic devices. Typical strategies to enhance the open-circuit voltage involve tuning the HOMO and LUMO positions of the donor (D) and acceptor (A), respectively, to increase the interfacial energy gap or to tailor the donor or acceptor structure at the D/A interface. Here, we present an alternative approach to improve the open-circuit voltage through the use of a zinc chlorodipyrrin, ZCl [bis(dodecachloro-5-mesityldipyrrinato)zinc], as an acceptor, which undergoes symmetry-breaking charge transfer (CT) at the donor/acceptor interface. DBP/ZCl cells exhibit open-circuit voltages of 1.33 V compared to 0.88 V for analogous tetraphenyldibenzoperyflanthrene (DBP)/C60-based devices. Charge transfer state energies measured by Fourier-transform photocurrent spectroscopy and electroluminescence show that C60 forms a CT state of 1.45 +/- 0.05 eV in a DBP/C60-based organic photovoltaic device, while ZCl as acceptor gives a CT state energy of 1.70 +/- 0.05 eV in the corresponding device structure. In the ZCl device this results in an energetic loss between E(CT) and qV(OC) of 0.37 eV, substantially less than the 0.6 eV typically observed for organic systems and equal to the recombination losses seen in high-efficiency Si and GaAs devices. The substantial increase in open-circuit voltage and reduction in recombination losses for devices utilizing ZCl demonstrate the great promise of symmetry breaking charge transfer in organic photovoltaic devices. PMID- 25826322 TI - Thymosin beta4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial. AB - PURPOSE: Standard therapies for severe dry eye are limited and fail to resolve the problem. The purpose of this study was to evaluate the safety and efficacy of Thymosin beta4 eye drops (RGN-259) as a novel therapy for severe dry eye disease (including that associated with graft vs. host disease). METHODS: A small, multicenter, randomized, double-masked, placebo-controlled 56-day phase 2 clinical trial including a 28-day follow-up at 2 US sites. Nine patients with severe dry eye were treated with either RGN-259 (0.1%) or vehicle control 6 times daily over a period of 28 days. Dry eye sign and symptom assessments, such as ocular discomfort (using the OSDI questionnaire) and corneal fluorescein staining (using the NEI workshop grading system), were evaluated at various time points. RESULTS: Statistically significant differences in both symptom and sign assessments, were seen at various time points throughout the study. Of particular note at day 56, the RGN-259-treated group (12 eyes) had 35.1% reduction of ocular discomfort compared with vehicle control (6 eyes) (P = 0.0141), and 59.1% reduction of total corneal fluorescein staining compared with vehicle control (P = 0.0108). Other improvements seen in the RGN-259-treated patients included tear film breakup time and increased tear volume production. CONCLUSIONS: In this small trial, RGN-259 eye drops were safe and well tolerated and met key efficacy objectives with statistically significant symptom and sign improvements, compared with vehicle control, at various time intervals, including 28-days posttreatment. CLINICAL TRIAL REGISTRATION--URL: http://www.clinicaltrials.gov. Unique identifier: NCT01393132. PMID- 25826323 TI - Evaluation of dry eye and meibomian gland dysfunction with meibography in patients with rosacea. AB - PURPOSE: To evaluate the dry eye tests and meibography of patients with ocular rosacea. METHODS: Thirty-six eyes of 18 patients with ocular rosacea (group 1) and 38 eyes of 19 healthy individuals (group 2) were enrolled. Besides full-eye examination, corneal and conjunctival fluorescein staining and Oxford scoring, tear film break-up time, Schirmer 1 test, ocular surface disease index score assessment, and evaluation of upper and lower eyelid meibomian glands using infrared captures of an optical coherence tomography (OCT) (Spectralis HRA+OCT; Heidelberg Engineering) device were performed (grade 0: no loss of meibomian glands, grade 1: gland dropout area <1/3 of the total meibomian glands, grade 2: gland dropout area 1/3 to 2/3 of the total meibomian glands, grade 3: gland dropout >2/3 of the total meibomian glands). RESULTS: The mean ages of group 1 and group 2 were 50.2 +/- 9.5 (range, 32-65), and 46.3 +/- 14.1 years (range, 25 70), respectively (P = 0.225). No significant difference in best-corrected visual acuity and meiboscores of upper eyelids were detected in between groups. Schirmer 1 and tear film break-up time in group 1 were significantly lower than in group 2 (P = 0.005, P < 0.001, respectively). Ocular surface disease index and Oxford scale scores and meiboscores of lower and total (upper + lower) eyelids were significantly higher in group 1 than in group 2 (P = 0.04, P = 0.018, P < 0.001, P = 0.03, respectively). CONCLUSIONS: Ocular rosacea causes dry eye and significant meibomian gland loss that can objectively be demonstrated with meibography. The infrared camera of OCT-that is widely found in many ophthalmology departments-might be used to evaluate meibomian gland dysfunction in these individuals. PMID- 25826324 TI - Outcomes of cataract surgery in graft-versus-host disease. AB - PURPOSE: To study the outcomes of cataract surgery in patients with graft-versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Retrospective review of 72 eyes of 41 patients (age, 17-69 years at the time of surgery) with chronic GVHD after HSCT, who underwent cataract surgery between 2008 and 2012 at the Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan. Ophthalmic data collected included best-corrected visual acuity (BCVA), responses to Ocular Surface Disease Index (OSDI) questionnaire, dry eye severity, and postoperative complications. RESULTS: BCVA improved from 20/49 to 20/25 (P < 0.0001) after surgery. Eight patients (20%) had pretransplantation total body irradiation and 39 patients (95%) received systemic corticosteroids for the treatment of GVHD. Postoperative complications included cystoid macular edema (4 eyes), corneal ulceration with perforation (2 eyes: 1 infected and 1 sterile), and band keratopathy (1 eye). After surgery, subjective OSDI responses and dry eye disease (DED) did not change significantly from before cataract surgery, although OSDI showed a trend toward worsening. CONCLUSIONS: With careful monitoring and management of DED and concurrent ocular surface disease, cataract surgery generally has good visual outcomes in patients with GVHD. However, aggravation of the preexisting ocular surface disease is frequent, and despite meticulous postoperative maintenance therapy, vision-threatening complications may occur. PMID- 25826325 TI - Measuring intraocular pressure after intrastromal corneal ring segment implantation with rebound tonometry and Goldmann applanation tonometry. AB - PURPOSE: The aim of this study was to compare intraocular pressure (IOP) measurements in patients with ectatic corneas after intrastromal corneal ring segment (ICRS) implantation using the Rebound tonometers (RBTs) Icare and Icare Pro, compared with Goldmann applanation tonometry (GAT) and to assess the influence of central corneal thickness (CCT), corneal curvature (CC), and corneal astigmatism (CA) on IOP. METHODS: This prospective cross-sectional study consecutively included 60 eyes of 60 patients with corneal ectasia having ICRS for at least 6 months from January 2011 to December 2013. All subjects underwent GAT, Icare, and Icare Pro IOP measurements in a random order, and CCT, CC, and CA evaluation using a Pentacam. The Bland-Altman method and multivariate regression analysis logistic method were used to assess intertonometer agreement and the influence of corneal variables on IOP measurements. RESULTS: Icare significantly underestimated IOP compared with GAT [GAT - Icare 1.2 +/- 3.0 mm Hg, P = 0.002 (95% confidence interval, 0.5-2.0)], whereas Icare Pro showed no statistical differences compared with GAT [GAT - Icare Pro 0.1 +/- 3.1 mm Hg, P = 0.853 (95% confidence interval, -0.7 to 0.9)]. Both RBTs presented good concordance with GAT (intraclass coefficient correlation > 0.6). All tonometer measurements were influenced by CCT values and age (P < 0.05); the number of ICRS implanted did not influenced IOP measurement with any of the 3 tonometers. CONCLUSIONS: Both RBTs could be an alternative to GAT in patients with corneal ectasia and ICRS; however, Icare Pro shows greater accuracy. PMID- 25826326 TI - Topical NSAIDs effect on corneal sensitivity. AB - PURPOSE: Topical nonsteroidal antiinflammatory drugs (NSAIDs) are administered topically for a variety of ophthalmologic conditions. Brand diclofenac and brand ketorolac were previously shown to have topical anesthetic effects in addition to analgesic effects. Using the same method, we measured similar anesthetic effects of the 4 currently available topical NSAIDs--generic diclofenac, generic ketorolac, brand bromfenac, and brand nepafenac. METHODS: Baseline corneal sensitivity was measured on 10 healthy adult volunteers with a Cochet-Bonnet esthesiometer. One drop of the agent being studied was applied to the right eye every 5 minutes for a total of 4 drops. Corneal sensitivity was measured immediately after the last topical application and every 15 minutes for 60 minutes. After a 1-week washout period, a different agent was studied until all 4 NSAIDs were evaluated. RESULTS: Corneal sensitivity profiles over time were similar for all NSAIDs. Corneal sensitivity decreased significantly from baseline immediately after topical application remaining flat from 0 to 30 minutes and then rising from 45 to 60 minutes back toward baseline in all treatment groups (P < 0.001). The maximal absolute drop in corneal sensitivity as measured by pressure thresholds was greatest for diclofenac [28.6 mm (95% confidence intervals {CI}, 19.8-37.4)], followed by ketorolac [21.1 mm (95% CI, 15.1-27.1)], bromfenac [16.9 mm (10.7-23.1)], and nepafenac [16.4 mm (95% CI, 12.7-20.1)]. Only diclofenac and nepafenac were statistically different in maximal decrease in sensitivity. CONCLUSIONS: All 4 currently available NSAIDs demonstrated anesthetic effects similar to brand diclofenac and brand ketorolac. PMID- 25826327 TI - Comparative antifungal susceptibility analysis of Candida albicans versus non albicans Candida corneal isolates. AB - PURPOSE: To compare the in vitro activity of topical amphotericin B (AMB), natamycin, voriconazole, and fluconazole against human corneal isolates of Candida sp. for guidance in the treatment of Candida keratitis. METHODS: Sixty eight Candida isolates (37 albicans and 31 non-albicans isolates) recovered from corneal scrapings submitted to rule out microbial keratitis, during the years 2005 to 2011, at the Bascom Palmer Eye Institute, were examined in this study. Corneal isolates were cultured on fungal agars for 48 hours. Each yeast isolate was dispensed into 4 microtiter wells, each containing 100 mL of commercial (natamycin 5%) or compounded (AMB 0.15%, voriconazole 1%, and fluconazole 0.2%) antifungal medications. A comparison of growth patterns was conducted. RESULTS: One hundred percent of the samples showed growth inhibition after treatment exposure with AMB or natamycin. The isolates treated with voriconazole demonstrated an 85% inhibition rate overall, with the Candida albicans samples showing a 77% inhibition rate and the non-albicans sp. a 93% inhibition rate. In the fluconazole group, there was only a 19.6% inhibition rate noted, with a 7.7% inhibition rate observed in the C. albicans group versus a 30% inhibition rate in the non-albicans group. CONCLUSIONS: AMB 0.2% and natamycin 5% have equal effectiveness and full inhibition against Candida keratitis isolates. Fluconazole 0.2% is not the drug of choice in both C. albicans and non-albicans keratitis. Voriconazole 1% may need a stronger concentration for higher effectiveness, but potentially may be helpful as a second agent in the treatment of Candida keratitis. PMID- 25826328 TI - Femtosecond laser-assisted anterior lamellar keratoplasty in stromal keratitis caused by an Endoreticulatus-like microsporidia. AB - PURPOSE: To describe a case of stromal keratitis caused by an Endoreticulatus like microsporidia satisfactorily treated with femtosecond-assisted anterior lamellar keratoplasty (femto-ALK). METHODS: Case report. RESULTS: A 65-year-old healthy woman had a 10-month history of foreign body sensation and blurred vision after a flying insect struck her right eye. The patient presented with focal central to paracentral anterior stromal infiltration and edema with keratic precipitates of the right cornea. Confocal microscopy showed enhanced keratocytes with intracellular hyperreflective round and ovoid bodies confined to the anterior two thirds of corneal stroma. Femto-ALK was performed for excisional biopsy and replacement with anterior stromal donor cornea. A modified trichrome stain of corneal tissue showed numerous microsporidial spores whose small subunit rRNA sequence belonged to that of an Endoreticulatus-like microsporidia. CONCLUSIONS: Besides systemic infection, Endoreticulatus-like microsporidia can cause stromal keratitis. With careful patient selection, femto-ALK may be considered a new surgical alternative with satisfactory treatment outcomes. PMID- 25826329 TI - Exercise and inflammation-related epigenetic modifications: focus on DNA methylation. AB - Epigenetics is the study of mitotically or meiotically heritable phenotypes that occur as a result of modifications to DNA, thereby regulating gene expression independently of changes in base sequence due to manipulation of the chromatin structure. These modifications occur through a variety of mechanisms, such as DNA methylation, post-translational histone modifications, and non-coding RNAs, and can cause transcriptional suppression or activation depending on the location within the gene. Environmental stimuli, such as diet and exercise, are thought to be able to regulate these mechanisms, with inflammation as a probable contributory factor. Research into these areas is still in its infancy however. This review will focus on DNA methylation in the context of inflammation (both pro- and anti-inflammatory processes) and exercise. The complexity and relative shortcomings of some existing techniques for studying epigenetics will be highlighted, and recommendations for future study approaches made. PMID- 25826330 TI - Is iloprost effective in secondary Raynaud's phenomenon? AB - Patients with systemic sclerosis frequently have Raynaud's phenomenon and digital ischemic ulcers. Iloprost, a synthetic prostacyclin analogue, may be effective in these cases. Searching in Epistemonikos database, which is maintained by screening 20 databases, we identified three systematic reviews including seven randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded iloprost may lead to little or no difference in the frequency or severity of secondary Raynaud, and it is associated to adverse effects and important costs. PMID- 25826331 TI - Activation of mu or delta opioid receptors in the lumbosacral spinal cord is essential for ejaculatory reflexes in male rats. AB - Ejaculation is controlled by a spinal ejaculation generator located in the lumbosacral spinal cord, consisting in male rats of lumbar spinothalamic (LSt) cells and their inter-spinal projections to autonomic and motor centers. LSt cells co-express several neuropeptides, including gastrin releasing peptide (GRP) and enkephalin. We previously demonstrated in rats that GRP regulates ejaculation by acting within the lumbosacral spinal cord. In the present study, the hypothesis was tested that enkephalin controls ejaculation by acting on mu (MOR) or delta opioid receptors (DOR) in LSt target areas. Adult male rats were anesthetized and spinalized and received intrathecal infusions of vehicle, MOR antagonist CTOP (0.4 or 4 nmol), DOR antagonist (TIPP (0.4, 4 or 40 nmol), MOR agonist DAMGO (0.1 or 10 nmol), or DOR agonist deltorphin II (1.3 or 13 nmol). Ejaculatory reflexes were triggered by stimulation of the dorsal penile nerve (DPN) and seminal vesicle pressure and rhythmic contractions of the bulbocavernosus muscle were analyzed. Intrathecal infusion of MOR or DOR antagonists effectively blocked ejaculatory reflexes induced by DPN stimulation. Intrathecal infusion of DAMGO, but not deltorphin II triggered ejaculation in absence of DPN stimulation. Both MOR and DOR agonists facilitated ejaculatory reflexes induced by subthreshold DPN stimulation in all animals. Overall, these results support the hypothesis that enkephalin plays a critical role in the control of ejaculation in male rats. Activation of either MOR or DOR in LSt target areas is required for ejaculation, while MOR activation is sufficient to trigger ejaculation in the absence of sensory stimulation. PMID- 25826332 TI - Whole genome comparisons suggest random distribution of Mycobacterium ulcerans genotypes in a Buruli ulcer endemic region of Ghana. AB - Efforts to control the spread of Buruli ulcer--an emerging ulcerative skin infection caused by Mycobacterium ulcerans--have been hampered by our poor understanding of reservoirs and transmission. To help address this issue, we compared whole genomes from 18 clinical M. ulcerans isolates from a 30 km2 region within the Asante Akim North District, Ashanti region, Ghana, with 15 other M. ulcerans isolates from elsewhere in Ghana and the surrounding countries of Ivory Coast, Togo, Benin and Nigeria. Contrary to our expectations of finding minor DNA sequence variations among isolates representing a single M. ulcerans circulating genotype, we found instead two distinct genotypes. One genotype was closely related to isolates from neighbouring regions of Amansie West and Densu, consistent with the predicted local endemic clone, but the second genotype (separated by 138 single nucleotide polymorphisms [SNPs] from other Ghanaian strains) most closely matched M. ulcerans from Nigeria, suggesting another introduction of M. ulcerans to Ghana, perhaps from that country. Both the exotic genotype and the local Ghanaian genotype displayed highly restricted intra-strain genetic variation, with less than 50 SNP differences across a 5.2 Mbp core genome within each genotype. Interestingly, there was no discernible spatial clustering of genotypes at the local village scale. Interviews revealed no obvious epidemiological links among BU patients who had been infected with identical M. ulcerans genotypes but lived in geographically separate villages. We conclude that M. ulcerans is spread widely across the region, with multiple genotypes present in any one area. These data give us new perspectives on the behaviour of possible reservoirs and subsequent transmission mechanisms of M. ulcerans. These observations also show for the first time that M. ulcerans can be mobilized, introduced to a new area and then spread within a population. Potential reservoirs of M. ulcerans thus might include humans, or perhaps M. ulcerans infected animals such as livestock that move regularly between countries. PMID- 25826333 TI - Prognostic significance of MYH9 expression in resected non-small cell lung cancer. AB - INTRODUCTION: Myosin-9 (MYH9) belongs to the myosin superfamily of actin-binding motor protein. Recently, MYH9 has been thought to be associated with cancer cell migration, invasion, and metastasis. The aims of this study were to immunohistochemically examine MYH9 expression in surgically resected non-small cell lung cancer (NSCLC), and evaluate its correlations with clinicopathological parameters and the prognosis of patients. METHODS: MYH9 expression was immunohistochemically studied in 266 consecutive resected NSCLCs, and its associations with clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of MYH9 expression on survival. RESULTS: MYH9 expression was detected in 102 of 266 (38.3%) NSCLCs. MYH9 expression was significantly correlated with the adenocarcinoma histology (P = 0.014), poorer differentiation ((P = 0.033), intratumoral vascular invasion and lymphatic invasion ((P = 0.013 and P = 0.045 respectively), and a poorer prognosis ((P = 0.032). In addition, multivariable analysis revealed that MYH9 expression independently predicted a poorer survival (HR, 2.15; 95%CI, 1.17-3.92; (P = 0.01). CONCLUSION: The present study revealed that MYH9 is expressed in a subset of NSCLC with a more malignant nature, and its expression is an indicator of a poorer survival probability. PMID- 25826334 TI - The role of motivation, glucose and self-control in the antisaccade task. AB - Research shows that self-control is resource limited and there is a gradual weakening in consecutive self-control task performance akin to muscle fatigue. A body of evidence suggests that the resource is glucose and consuming glucose reduces this effect. This study examined the effect of glucose on performance in the antisaccade task - which requires self-control through generating a voluntary eye movement away from a target - following self-control exertion in the Stroop task. The effects of motivation and individual differences in self-control were also explored. In a double-blind design, 67 young healthy adults received a 25g glucose or inert placebo drink. Glucose did not enhance antisaccade performance following self-control exertion in the Stroop task. Motivation however, predicted performance on the antisaccade task; more specifically high motivation ameliorated performance decrements observed after initial self-control exertion. In addition, individuals with high levels of self-control performed better on certain aspects of the antisaccade task after administration of a glucose drink. The results of this study suggest that the antisaccade task might be a powerful paradigm, which could be used as a more objective measure of self-control. Moreover, the results indicate that level of motivation and individual differences in self-control should be taken into account when investigating deficiencies in self-control following prior exertion. PMID- 25826335 TI - Hepatic stellate cells express thymosin Beta 4 in chronically damaged liver. AB - Although the various biological roles of thymosin beta4 (Tbeta4) have been studied widely, the effect of Tbeta4 and Tbeta4-expressing cells in the liver remains unclear. Therefore, we investigated the expression and function of Tbeta4 in chronically damaged livers. CCl4 was injected into male mice to induce a model of chronic liver disease. Mice were sacrificed at 6 and 10 weeks after CCl4 treatment, and the livers were collected for biochemical analysis. The activated LX-2, human hepatic stellate cell (HSC) line, were transfected with Tbeta4 specific siRNA and activation markers of HSCs were examined. Compared to HepG2, higher expression of Tbeta4 in RNA and protein levels was detected in the activated LX-2. In addition, Tbeta4 was up-regulated in human liver with advanced liver fibrosis. The expression of Tbeta4 increased during mouse HSC activation. Tbeta4 was also up-regulated and Tbeta4-positive cells were co-localized with alpha-smooth muscle actin (alpha-SMA) in the livers of CCl4-treated mice, whereas such cells were rarely detected in the livers of corn-oil treated mice. The suppression of Tbeta4 in LX-2 cells by siRNA induced the down-regulation of HSC activation-related genes, tgf-beta, alpha-sma, collagen, and vimentin, and up regulation of HSC inactivation markers, ppar-gamma and gfap. Immunofluorescent staining detected rare co-expressing cells with Tbeta4 and alpha-SMA in Tbeta4 siRNA-transfected cells. In addition, cytoplasmic lipid droplets were observed in Tbeta4 siRNA-treated cells. These results demonstrate that activated HSCs expressed Tbeta4 in chronically damaged livers, and this endogenous expression of Tbeta4 influenced HSC activation, indicating that Tbeta4 might contribute to liver fibrosis by regulating HSC activation. PMID- 25826336 TI - Silicon nanowire-induced maturation of cardiomyocytes derived from human induced pluripotent stem cells. AB - The current inability to derive mature cardiomyocytes from human pluripotent stem cells has been the limiting step for transitioning this powerful technology into clinical therapies. To address this, scaffold-based tissue engineering approaches have been utilized to mimic heart development in vitro and promote maturation of cardiomyocytes derived from human pluripotent stem cells. While scaffolds can provide 3D microenvironments, current scaffolds lack the matched physical/chemical/biological properties of native extracellular environments. On the other hand, scaffold-free, 3D cardiac spheroids (i.e., spherical-shaped microtissues) prepared by seeding cardiomyocytes into agarose microwells were shown to improve cardiac functions. However, cardiomyocytes within the spheroids could not assemble in a controlled manner and led to compromised, unsynchronized contractions. Here, we show, for the first time, that incorporation of a trace amount (i.e., ~0.004% w/v) of electrically conductive silicon nanowires (e-SiNWs) in otherwise scaffold-free cardiac spheroids can form an electrically conductive network, leading to synchronized and significantly enhanced contraction (i.e., >55% increase in average contraction amplitude), resulting in significantly more advanced cellular structural and contractile maturation. PMID- 25826337 TI - Analysis of prognostic factors for survival after hepatectomy for hepatocellular carcinoma based on a bayesian network. AB - BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) after hepatectomy involves many factors. Previous studies have evaluated the separate influences of single factors; few have considered the combined influence of various factors. This paper combines the Bayesian network (BN) with importance measures to identify key factors that have significant effects on survival time. METHODS: A dataset of 299 patients with HCC after hepatectomy was studied to establish a BN using a tree-augmented naive Bayes algorithm that could mine relationships between factors. The composite importance measure was applied to rank the impact of factors on survival time. RESULTS: 124 patients (>10 months) and 77 patients (<=10 months) were correctly classified. The accuracy of BN model was 67.2%. For patients with long survival time (>10 months), the true-positive rate of the model was 83.22% and the false-positive rate was 48.67%. According to the model, the preoperative alpha fetoprotein (AFP) level and postoperative performance of transcatheter arterial chemoembolization (TACE) were independent factors for survival of HCC patients. The grade of preoperative liver function reflected the tendency for postoperative complications. Intraoperative blood loss, tumor size, portal vein tumor thrombosis (PVTT), time of clamping the porta hepatis, tumor number, operative method, and metastasis were dependent variables in survival time prediction. PVTT was considered the most significant for the prognosis of survival time. CONCLUSIONS: Using the BN and importance measures, PVTT was identified as the most significant predictor of survival time for patients with HCC after hepatectomy. PMID- 25826339 TI - Dying in America: improving quality and honoring individual preferences near the end of life. PMID- 25826338 TI - Hippocampus is place of interaction between unconscious and conscious memories. AB - Recent evidence suggests that humans can form and later retrieve new semantic relations unconsciously by way of hippocampus-the key structure also recruited for conscious relational (episodic) memory. If the hippocampus subserves both conscious and unconscious relational encoding/retrieval, one would expect the hippocampus to be place of unconscious-conscious interactions during memory retrieval. We tested this hypothesis in an fMRI experiment probing the interaction between the unconscious and conscious retrieval of face-associated information. For the establishment of unconscious relational memories, we presented subliminal (masked) combinations of unfamiliar faces and written occupations ("actor" or "politician"). At test, we presented the former subliminal faces, but now supraliminally, as cues for the reactivation of the unconsciously associated occupations. We hypothesized that unconscious reactivation of the associated occupation-actor or politician-would facilitate or inhibit the subsequent conscious retrieval of a celebrity's occupation, which was also actor or politician. Depending on whether the reactivated unconscious occupation was congruent or incongruent to the celebrity's occupation, we expected either quicker or delayed conscious retrieval process. Conscious retrieval was quicker in the congruent relative to a neutral baseline condition but not delayed in the incongruent condition. fMRI data collected during subliminal face-occupation encoding confirmed previous evidence that the hippocampus was interacting with neocortical storage sites of semantic knowledge to support relational encoding. fMRI data collected at test revealed that the facilitated conscious retrieval was paralleled by deactivations in the hippocampus and neocortical storage sites of semantic knowledge. We assume that the unconscious reactivation has pre-activated overlapping relational representations in the hippocampus reducing the neural effort for conscious retrieval. This finding supports the notion of synergistic interactions between conscious and unconscious relational memories in a common, cohesive hippocampal neocortical memory space. PMID- 25826340 TI - Lessons for conducting health development at the tactical level. PMID- 25826341 TI - Health care utilization behavior of veterans who deployed to Afghanistan and Iraq. AB - BACKGROUND: Previous assessments of Afghanistan/Iraq Veterans have lacked a systematic overview of all injury and illness experiences captured by the Veterans Health Administration (VHA) health care services. In this initial study, we quantify the health care utilization behavior of eligible Veterans and describe the level and type of usage among them. METHODS: A roster of service members who have served in Afghanistan/Iraq and became eligible for VHA care between 2002 and 2010 and their corresponding administrative VA medical encounter data were abstracted from the VHA Office of Public Health Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn Health Surveillance System. RESULTS: Between 2002 and 2010, approximately 55% of eligible Veterans accessed VHA health care. Higher utilization was observed among Veterans 50 years of age and older compared to younger Veterans. Higher utilization was also observed among Veterans with increasing cumulative deployment time. Mental disorder diagnostic codes accounted for the greatest number of visits per Veteran. CONCLUSIONS: Veterans with mental health diagnoses may need a different level of care than other VHA users. Other service factors associated with utilization require further research to better understand the underlying relationship. Current observed results may be reflective of future expected utilization patterns and may assist in resource planning and research. PMID- 25826342 TI - TBI ADAPTER: traumatic brain injury assessment diagnosis advocacy prevention and treatment from the emergency room--a prospective observational study. AB - There is no standard treatment algorithm for patients who present to the emergency department (ED) with acute traumatic brain injury (TBI). This is in part because of the heterogeneity of the injury pattern and the patient profile, and the lack of evidence-based guidelines, especially for mild TBI in adults. As TBI is seen more and more frequently in the ED, a standardized assessment would be beneficial in terms of efficiency. The authors present their ED approach to mild TBI evaluation in the ED, along with results to date. These data represent a prospective observational cohort study, where each patient provided individual, written informed consent. PMID- 25826343 TI - Interest in a digital health tool in veterans with epilepsy: results of a phone survey. AB - OBJECTIVE: Online tools for managing chronic health conditions are becoming increasingly popular. Perceived benefits include ease of use, low costs, and availability but are contingent on patient engagement, Internet access, and digital literacy. This article describes data collected during the recruitment phase of a study evaluating an online self-management platform for epilepsy in a U.S. Veteran population. METHODS: We used administrative data to identify and contact Veterans with a likely diagnosis of epilepsy in the Veterans Health Administration (VHA). Veterans who did not respond directly to a mailed invitation were recruited by phone to determine study interest and evaluate digital access. RESULTS: Of the 2,143 Veterans mailed study invitations, phone calls were made to 1,789 who did not specifically decline participation. Among those reached by phone (n = 1,053): 295 (28%) expressed interest in the study and an online tool, 333 (19%) reported a lack of computer and/or Internet access and 425 (40%) were not interested for other reasons. CONCLUSIONS: This study suggests an interest in online tools for managing health despite the fact that some Veterans lack computer and/or Internet access. As investment in digital health solutions grows, the VHA should prioritize the widespread provision of digital access to more Veterans. PMID- 25826344 TI - Nutritional and sports supplement use among deployed U.S. Army soldiers in a remote, austere combat outpost in eastern Afghanistan. AB - BACKGROUND: Nutritional and sports supplements are commonly used by soldiers, with uncertain implications for health and mission readiness. METHODS: An anonymous survey was conducted of a company of U.S. Army paratroopers deployed to eastern Afghanistan between December 2011 and October 2012. Survey questions covered supplements used, duration of use, adverse effects, and medication interactions. Exercise habits, goals for exercise and supplement use, and information and acquisition sources were also queried. RESULTS: Out of 112 surveys distributed, 100 completed surveys were returned. 77 respondents reported using at least one supplement during deployment. On average, 2.5 supplements were used per individual surveyed. Nine respondents reported adverse effects of supplement use. No respondents reported serious complications of supplement use, drug interactions, or seeking medical care for supplement adverse effects. The Internet was the most frequently reported source of information on supplement use. Most frequently, supplements were acquired by Internet mail order. CONCLUSIONS AND RELEVANCE: Supplement use occurs during deployment among paratroopers at a higher rate than reported in garrison, despite their remote and austere deployed location. These findings have profound implications for military health care providers and policy makers considering the health of deployed combat soldiers. PMID- 25826345 TI - Review of weapon noise measurement and damage risk criteria: considerations for auditory protection and performance. AB - Noise-induced hearing loss resulting from weapon noise exposure has been studied for decades. A summary of recent work in weapon noise signal analysis, current knowledge of hearing damage risk criteria, and auditory performance in impulse noise is presented. Most of the currently used damage risk criteria are based on data that cannot be replicated or verified. There is a need to address the effects of combined noise exposures, from similar or different weapons and continuous background noise, in future noise exposure regulations. Advancements in hearing protection technology have expanded the options available to soldiers. Individual selection of hearing protection devices that are best suited to the type of exposure, the auditory task requirements, and hearing status of the user could help to facilitate their use. However, hearing protection devices affect auditory performance, which in turn affects situational awareness in the field. This includes communication capability and the localization and identification of threats. Laboratory training using high-fidelity weapon noise recordings has the potential to improve the auditory performance of soldiers in the field, providing a low-cost tool to enhance readiness for combat. PMID- 25826346 TI - A qualitative content analysis of global health engagements in Peacekeeping and Stability Operations Institute's stability operations lessons learned and information management system. AB - Many institutions collect reports in databases to make important lessons-learned available to their members. The Uniformed Services University of the Health Sciences collaborated with the Peacekeeping and Stability Operations Institute to conduct a descriptive and qualitative analysis of global health engagements (GHEs) contained in the Stability Operations Lessons Learned and Information Management System (SOLLIMS). This study used a summative qualitative content analysis approach involving six steps: (1) a comprehensive search; (2) two-stage reading and screening process to identify first-hand, health-related records; (3) qualitative and quantitative data analysis using MAXQDA, a software program; (4) a word cloud to illustrate word frequencies and interrelationships; (5) coding of individual themes and validation of the coding scheme; and (6) identification of relationships in the data and overarching lessons-learned. The individual codes with the most number of text segments coded included: planning, personnel, interorganizational coordination, communication/information sharing, and resources/supplies. When compared to the Department of Defense's (DoD's) evolving GHE principles and capabilities, the SOLLIMS coding scheme appeared to align well with the list of GHE capabilities developed by the Department of Defense Global Health Working Group. The results of this study will inform practitioners of global health and encourage additional qualitative analysis of other lessons learned databases. PMID- 25826347 TI - Overview of depression, post-traumatic stress disorder, and alcohol misuse among active duty service members returning from Iraq and Afghanistan, self-report and diagnosis. AB - Previous studies have found deployment to combat areas to be associated with an increased risk of post-traumatic stress disorder (PTSD), depression, and alcohol abuse, but many previous studies were limited by samples that were not representative of the deployed military as a whole. This study presents an overview of these three mental health problems associated with deployment among Air Force, Army, Marine Corp, and Navy service members returning from deployment to Iraq and Afghanistan between January 2007 and March 2008. With postdeployment health data on over 50,000 service men and women, including diagnostic information, we were able to estimate prevalence of those who screened positive for risk of each disorder in self-report data at two time points, as well as prevalence of diagnoses received during health care encounters within the military health care system. The prevalence ranges of the three disorders were consistent with previous studies using similar measures, but service members in the Navy had higher rates of screening positive for all three disorders and higher prevalence of depression and PTSD diagnoses compared to the other branches. Further, PTSD risk was higher for service members returning from Afghanistan compared to Iraq, in contrast to previous findings. PMID- 25826348 TI - A population-based cross-sectional study comparing depression and health service deficits between rural and nonrural U.S. military veterans. AB - With involvement in two wars over the past decade, there has been a documented increase in depression prevalence and suicide incidence among U.S. military veterans. Because higher proportions of veterans come from rural communities, access to care may be an issue when behavioral health care is needed. Although the Veterans Administration has expanded health services in rural areas, this has not always resulted in increased service utilization. This study examined the prevalence of depression and associated health service deficits (HSDs) for rural versus nonrural U.S. military veterans. Using bivariate and multivariate techniques, 2006 Behavioral Risk Factor Surveillance System data were analyzed. Bivariate analysis revealed that rural veterans had greater odds of having at least one HSD, being currently depressed as measured by the Personal Health Questionnaire-8, and having lifetime depression. Logistic regression analysis confirmed that rural veterans had higher odds of both current and lifetime depression than nonrural veterans when controlling for socioeconomic status and race/ethnicity. Additionally, logistic regression analysis also revealed that rural veterans with current depression had higher odds of being Hispanic or Other/Multiracial than Caucasian, not employed for wages than employed for wages, <65 years of age, and reported having at least one HSD. PMID- 25826349 TI - Mental health diagnoses and attrition in Air Force recruits. AB - INTRODUCTION: Mental disorders effect military readiness. Evaluating the frequency and impact of mental health diagnoses (MHD) in recruits, the source of the military workforce, is key to identifying opportunities for screening and prevention. OBJECTIVES: This study assessed the relationship between MHD in the Air Force recruit population and time to discharge. METHODS: A recruit cohort at Lackland Air Force Base was followed through Basic Military Training, technical school, and 14 months of service using data from Trainee Health Online Reporting System. Incidence rate of MHD was calculated. A risk ratio and attributable fraction were calculated for attrition comparing recruits with MHD to recruits receiving other diagnoses (non-MHD). A survival analysis was performed on recruits with MHD compared to those with non-MHD. RESULTS: Incidence of MHD was 7.9%. A recruit with a MHD was 4.28 (95% CI = 4.04-4.54) times more likely to separate in the first 14 months of service as compared to a recruit with a non MHD. CONCLUSIONS: Recruits with MHD were separated faster and more often when compared to non-MHD. This study increases visibility of mental health disorders in recruits as a step toward better identifying those at higher risk of attrition. PMID- 25826350 TI - Translating research into practice: is evidence-based medicine being practiced in military-relevant orthopedic trauma? AB - Orthopedic trauma remains one of the most survivable battlefield injuries seen in modern conflicts. Translating research into practice is a critical bridge that permits surgeons to further optimize medical outcomes. Orthopedic surgeons serving in the military may treat little to no trauma in their stateside practice. In conflict zones, however, the majority of their patients will have traumatic injuries. Determining risk factors for nonevidence-based practice can help identify provider knowledge gaps, which can then be targeted before deployment. Surveys were developed which sought to identify factors contributing to continued medical education and practice, as well as scenario-based questions on military-relevant orthopedic trauma. Analysis of 188 survey respondents revealed that providers with military service and less than 10 years of practice are optimally bridging research into military-relevant orthopedic trauma practice. PMID- 25826351 TI - Examining patient-centered communication and access for veterans with disabilities. AB - OBJECTIVE: To determine if there are significant differences in patient-centered communication and access to care experienced by veterans with disabilities compared to veterans without disabilities and nonveterans with disabilities and what variables contribute to the likelihood of poor patient-centered communication and access to care. METHODS: chi(2) analyses were used to determine differences in patient-centered communication and access to care. Logistic regression analyses were used to identify variables contributing to poor patient centered care. RESULTS: Veterans with disabilities were significantly less likely to say that a physician listened to their concerns, explained care so they understood, treated them with respect, spent enough time with them, and were less likely to get necessary care or experience a delay in getting care than veterans without disabilities. No significant differences were found when comparing patient-centered communication between veterans and nonveterans with disabilities. Veteran status protects against poor patient-centered care, whereas disability status increases the likelihood of poor patient-centered care. CONCLUSIONS: Health care providers should consider the unique strengths and limitations presented by veterans with disabilities in their patient-centered communication. Future research in partnership with veterans with and without disabilities is needed to determine effective strategies to improve patient centered communication and health care access. PMID- 25826352 TI - Obesity and national defense: will America be too heavy to fight? AB - Obesity has been a topic of intense interest in the United States for several years. Rising rates of obesity have led some to question whether or not America will be able to readily sustain a fit fighting force into the future. This study seeks to describe at what point, projecting current trends in obesity and military accession, there would no longer be a sufficient number of qualified applicants to support an effective military fighting force. By analyzing trends in national obesity data and military accession records, the authors were unable to determine a realistic time projection of a year in which the United States would no longer be able to find enough qualified military applicants as a result of increasing obesity rates. PMID- 25826353 TI - Outcomes from two forms of training for first-responder competency in cholinergic crisis management. AB - Military and civilian first responders must be able to recognize and effectively manage mass disaster casualties. Clinical management of injuries resulting from nerve agents provides different challenges for first responders than those of conventional weapons. We evaluated the impact of a mixed-methods training program on competency acquisition in cholinergic crisis clinical management using multimedia with either live animal or patient actor examples, and hands-on practice using SimMan3G mannequin simulators. A purposively selected sample of 204 civilian and military first responders who had not previously completed nerve agent training were assessed pre- and post-training for knowledge, performance, self-efficacy, and affective state. We conducted analysis of variance with repeated measures; statistical significance p < 0.05. Both groups had significant performance improvement across all assessment dimensions: knowledge > 20%, performance > 50%, self-efficacy > 34%, and affective state > 15%. There were no significant differences between the live animal and patient actor groups. These findings could aid in the specification of training for first-responder personnel in military and civilian service. Although less comprehensive than U.S. Army Medical Research Institute of Chemical Defense courses, the training outcomes associated with this easily distributed program demonstrate its value in increasing the competency of first responders in recognizing and managing a mass casualty cholinergic event. PMID- 25826354 TI - Adherence to positive airway pressure therapy in U.S. military personnel with sleep apnea improves sleepiness, sleep quality, and depressive symptoms. AB - OBJECTIVES: Obstructive sleep apnea (OSA) is frequently diagnosed in U.S. military personnel. OSA is associated with sleepiness, poor sleep quality, and service-related illnesses of insomnia, depression, post-traumatic stress disorder, and traumatic brain injury. METHODS: Observational study of active duty military personnel with OSA and adherence to positive airway pressure (PAP) assessed with smart chip technology. RESULTS: 58 men with mean age 36.2 +/- 7.7 years, mean body mass index 31.4 +/- 3.7 with mean apnea-hypopnea index (AHI) 19.1 +/- 19.0 are reported. 23 (39.7%) participants were adherent to PAP, and 35 (60.3%) were nonadherent. No significant differences in baseline demographics, apnea-hypopnea index, service-related illnesses, or clinical instrument scores. Military personnel adherent to PAP had significantly improved sleepiness (p = 0.007), sleep quality (p = 0.013), depressive symptoms (p = 0.01), energy/fatigue (p = 0.027), and emotional well-being (p = 0.024). Participants with moderate severe OSA were more likely to be in the adherent group when compared with participants diagnosed with mild OSA. CONCLUSIONS: Military personnel with OSA have low adherence to PAP. Adherence is associated with improved depressive symptoms, sleepiness, sleep quality, energy/fatigue, emotional well-being, and social functioning. Future research should focus on interventions to improve the management of OSA in military personnel. PMID- 25826355 TI - This dust was once the man: commemorating the 150th anniversary of Lincoln's last hours. PMID- 25826356 TI - Impairment of type I but not type III IFN signaling by hepatitis C virus infection influences antiviral responses in primary human hepatocytes. AB - Peginterferon lambda-1a (Lambda), a type III interferon (IFN), acts through a unique receptor complex with limited cellular expression outside the liver which may result in a differentiated tolerability profile compared to peginterferon alfa (alfa). In Phase 2b clinical studies, Lambda administered in combination with ribavirin (RBV) was efficacious in patients with hepatitis C virus (HCV) infection representing genotypes 1 through 4, and was associated with more rapid declines in HCV RNA compared to alfa plus RBV. To gain insights into potential mechanisms for this finding, we investigated the effects of HCV replication on IFN signaling in primary human hepatocytes (PHH) and in induced hepatocyte-like cells (iHLCs). HCV infection resulted in rapid down-regulation of the type I IFN alpha receptor subunit 1 (IFNAR1) transcript in hepatocytes while the transcriptional level of the unique IFN-lambda receptor subunit IL28RA was transiently increased. In line with this observation, IFN signaling was selectively impaired in infected cells upon stimulation with alfa but not in response to Lambda. Importantly, in contrast to alfa, Lambda was able to induce IFN-stimulated gene (ISG) expression in HCV-infected hepatocytes, reflecting the onset of innate responses. Moreover, global transcriptome analysis in hepatocytes indicated that Lambda stimulation prolonged the expression of various ISGs that are potentially beneficial to antiviral defense mechanisms. Collectively, these observed effects of HCV infection on IFN receptor expression and signaling within infected hepatocytes provide a possible explanation for the more pronounced early virologic responses observed in patients treated with Lambda compared to alfa. PMID- 25826357 TI - What is the potential of epigenetics in drug development? PMID- 25826358 TI - Novel scaffolds for modulation of TRPV1 identified with pharmacophore modeling and virtual screening. AB - AIM: The transient receptor potential vanilloid type 1 (TRPV1) is responsible for pain perception in the peripheral nervous system (PNS). TRPV1 is thus considered a versatile target for development of non-opioid analgesics. RESULTS: Pharmacophore-based clustering of a publicly available data set of TRPV1 antagonists revealed a set of models, which were validated with data sets of inactive compounds, decoys and known drug candidates. The top ranked pharmacophore models were subsequently used for virtual screening. Based on a unique in-house protocol, a set of compounds was selected and biologically tested for modulation of TRPV1 in a voltage-clamp model. CONCLUSION: Pharmacophore models extracted from large public data sets are a valuable source for identification of novel scaffolds for TRPV1 receptor modulation. PMID- 25826359 TI - How to report and discuss ADME data in medicinal chemistry publications: in vitro data or in vivo extrapolations? AB - Early drug discovery projects often utilize data from ADME (absorption, distribution, metabolism, elimination) assays to benchmark data and guide discussion, rather than the predicted in vivo consequences of these data. Here, the two paradigms are compared, using evaluations of metabolic stability based on either microsomal clearance assay data or from the predicted in vivo hepatic clearance and half-life calculated through the combination of the venous well stirred model and Oie-Tozer's model. The need for a shift in paradigm is presented, and its implications discussed. It is suggested that discussions about ADME data should revolve around potential clinical problems that are most likely to surface during the development phase, each benchmarked with a suitable variable derived from the assay data. PMID- 25826360 TI - The RAF-MEK-ERK pathway: targeting ERK to overcome obstacles to effective cancer therapy. AB - AIM: Currently, dozens of BRAF inhibitors and MEK inhibitors targeting RAF-MEK ERK pathway have been introduced into clinical trials for cancer therapy. However, after 6-8 months of initial response, acquired drug resistance among the majority of those treated patients sharply diminished their clinical efficacy. DISCUSSION: Important mechanisms responsible for acquired resistance of BRAF inhibitors and MEK inhibitors have been elucidated. Continually, ERK1/2 locates in the critical position and features unique characteristics, such as activating hundreds of substrates, participating in feedback regulation, being catalyzed by MEK specifically and no acquired resistant mutation. CONCLUSION: Taking in account the inspiring outcomes of ERK inhibitors in preclinical research, ERK1/2 might be the optimal target to overcome acquired drug resistance in RAF-MEK-ERK pathway. PMID- 25826361 TI - Nucleoside analogs and tuberculosis: new weapons against an old enemy. AB - Purine and pyrimidine nucleoside and nucleotide analogs have been extensively studied as anticancer and antiviral agents. In addition to this, they have recently shown great potential against Mycobacterium Tuberculosis, the causative agent of TB. TB ranks as the tenth most common cause of death in the world. The current treatment for TB infection is limited by side effects and cost of the drugs and most importantly by the development of resistance to the therapy. Therefore the development of novel drugs, capable of overcoming the drawbacks of the existing treatments, has become the focus of many research programs. In parallel to that, a tremendous effort has been made to elucidate the unique metabolism of this pathogen with the aim to identify new possible targets. This review presents the state of the art in nucleoside and nucleotide analogs in the treatment of TB. In particular, we report on the inhibitory activity of this class of compounds, both in enzymatic and whole-cell assays, providing a brief insight to which reported target these novel compounds are hitting. PMID- 25826362 TI - New perspectives on the development of antiobesity drugs. AB - After many years of research, obesity is still a disease with an unmet medical need. Very few compounds have been approved, acting mainly on neuromediators; researches, in recent years, pointed toward compounds potentially safer than first-generation antiobesity drugs, able to interact with one or more (multitarget therapy) receptors for substances produced by the gut, adipose tissue and other targets outside CNS. Other holistic approaches, such as those involving gut microbiota and plant extracts, appeared recently in the literature, and undoubtedly will contribute to the discovery of a valuable therapy for this disease. This review deals with the positive results and the pitfalls obtained following these approaches, with a view on their clinical trial studies. PMID- 25826363 TI - Computational solvent mapping in structure-based drug design. AB - Over the past two decades, solvent mapping has emerged as a useful tool for identifying hot spots within binding sites on proteins for drug-like molecules and suggesting properties of potential binders. While the experimental technique requires solving multiple crystal structures of a protein in different solvents, computational solvent mapping allows for fast analysis of a protein for potential binding sites and their druggability. Recent advances in genomics, systems biology and interactomics provide a multitude of potential targets for drug development and solvent mapping can provide useful information to help prioritize targets for drug discovery projects. Here, we review various approaches to computational solvent mapping, highlight some key advances and provide our opinion on future directions in the field. PMID- 25826364 TI - 3-Hydroxypyridinone derivatives as metal-sequestering agents for therapeutic use. AB - Although iron is one of the most important metal ions for living organisms, it becomes toxic when in excess or misplaced. This review presents a glance at representative examples of hydroxypyridinone-based chelators, which have been recently developed as potential clinically useful drugs for metal overload diseases, mostly associated with excess of iron but also other hard metal-ions. It also includes a detailed discussion on the factors assisting chelator design strategy toward fulfillment of the most relevant biochemical properties of hydroxypyridinone chelators, highlighting structure-activity relationships and a variety of potential clinical applications, beyond chelatotherapy. This study appears as a response to the growing interest on metal chelation therapy and opens new perspectives of possible applications in future medicine. PMID- 25826365 TI - Decreased chloride channel expression in the dorsolateral prefrontal cortex in schizophrenia. AB - Alterations in GABAergic neurotransmission are implicated in several psychiatric illnesses, including schizophrenia. The Na-K-Cl and K-Cl cotransporters regulate intracellular chloride levels. Abnormalities in cotransporter expression levels could shift the chloride electrochemical gradient and impair GABAergic transmission. In this study, we performed Western blot analysis to investigate whether the Na-K-Cl and K-Cl cotransporter protein is abnormally expressed in the dorsal lateral prefrontal cortex and the anterior cingulate cortex in patients with schizophrenia versus a control group. We found decreased K-Cl cotransporter protein expression in the dorsal lateral prefrontal cortex, but not the anterior cingulate cortex, in subjects with schizophrenia, supporting the hypothesis of region level abnormal GABAergic function in the pathophysiology of schizophrenia. Subjects with schizophrenia off antipsychotic medication at the time of death had decreased K-Cl cotransporter protein expression compared to both normal controls and subjects with schizophrenia on antipsychotics. Our results provide evidence for KCC2 protein abnormalities in schizophrenia and suggest that antipsychotic medications might reverse deficits of this protein in the illness. PMID- 25826366 TI - Methylation-sensitive expression of a DNA demethylase gene serves as an epigenetic rheostat. AB - Genomes must balance active suppression of transposable elements (TEs) with the need to maintain gene expression. In Arabidopsis, euchromatic TEs are targeted by RNA-directed DNA methylation (RdDM). Conversely, active DNA demethylation prevents accumulation of methylation at genes proximal to these TEs. It is unknown how a cellular balance between methylation and demethylation activities is achieved. Here we show that both RdDM and DNA demethylation are highly active at a TE proximal to the major DNA demethylase gene ROS1. Unexpectedly, and in contrast to most other genomic targets, expression of ROS1 is promoted by DNA methylation and antagonized by DNA demethylation. We demonstrate that inducing methylation in the ROS1 proximal region is sufficient to restore ROS1 expression in an RdDM mutant. Additionally, methylation-sensitive expression of ROS1 is conserved in other species, suggesting it is adaptive. We propose that the ROS1 locus functions as an epigenetic rheostat, tuning the level of demethylase activity in response to methylation alterations, thus ensuring epigenomic stability. PMID- 25826367 TI - Retinoic acid can exacerbate T cell intrinsic TLR2 activation to promote tolerance. AB - The contribution of vitamin A to immune health has been well established. However, recent evidence indicates that its active metabolite, retinoic acid (RA), has the ability to promote both tolerogenic and inflammatory responses. While the outcome of RA-mediated immunity is dependent upon the immunological status of the tissue, the contribution of specific innate signals influencing this response have yet to be delineated. Here, we found that treatment with RA can dampen inflammation during intestinal injury. Importantly, we report a novel and unexpected requirement for TLR2 in RA-mediated suppression. Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells. These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease. PMID- 25826368 TI - Assessment of the chemosensitizing activity of TAT-RasGAP317-326 in childhood cancers. AB - Although current anti-cancer protocols are reasonably effective, treatment associated long-term side effects, induced by lack of specificity of the anti cancer procedures, remain a challenging problem in pediatric oncology. TAT RasGAP317-326 is a RasGAP-derived cell-permeable peptide that acts as a sensitizer to various anti-cancer treatments in adult tumor cells. In the present study, we assessed the effect of TAT-RasGAP317-326 in several childhood cancer cell lines. The RasGAP-derived peptide-induced cell death was analyzed in several neuroblastoma, Ewing sarcoma and leukemia cell lines (as well as in normal lymphocytes). Cell death was evaluated using flow cytometry methods in the absence or in the presence of the peptide in combination with various genotoxins used in the clinics (4-hydroperoxycyclophosphamide, etoposide, vincristine and doxorubicin). All tested pediatric tumors, in response to at least one genotoxin, were sensitized by TAT-RasGAP317-326. The RasGAP-derived peptide did not increase cell death of normal lymphocytes, alone or in combination with the majority of the tested chemotherapies. Consequently, TAT-RasGAP317-326 may benefit children with tumors by increasing the efficacy of anti-cancer therapies notably by allowing reductions in anti-cancer drug dosage and the associated drug-induced side effects. PMID- 25826369 TI - Hyperspectral and thermal imaging of oilseed rape (Brassica napus) response to fungal species of the genus Alternaria. AB - In this paper, thermal (8-13 um) and hyperspectral imaging in visible and near infrared (VNIR) and short wavelength infrared (SWIR) ranges were used to elaborate a method of early detection of biotic stresses caused by fungal species belonging to the genus Alternaria that were host (Alternaria alternata, Alternaria brassicae, and Alternaria brassicicola) and non-host (Alternaria dauci) pathogens to oilseed rape (Brassica napus L.). The measurements of disease severity for chosen dates after inoculation were compared to temperature distributions on infected leaves and to averaged reflectance characteristics. Statistical analysis revealed that leaf temperature distributions on particular days after inoculation and respective spectral characteristics, especially in the SWIR range (1000-2500 nm), significantly differed for the leaves inoculated with A. dauci from the other species of Alternaria as well as from leaves of non treated plants. The significant differences in leaf temperature of the studied Alternaria species were observed in various stages of infection development. The classification experiments were performed on the hyperspectral data of the leaf surfaces to distinguish days after inoculation and Alternaria species. The second derivative transformation of the spectral data together with back-propagation neural networks (BNNs) appeared to be the best combination for classification of days after inoculation (prediction accuracy 90.5%) and Alternaria species (prediction accuracy 80.5%). PMID- 25826370 TI - A single bout of dynamic exercise enhances the expansion of MAGE-A4 and PRAME specific cytotoxic T-cells from healthy adults. AB - The ex vivo expansion of tumor-associated-antigen (TAA)- specific cytotoxic T cells (CTLs) from healthy donors for adoptive transfer to cancer patients is now providing additional treatment options for patients. Many studies have shown that adoptive transfer of expanded CTLs can reduce the risk of relapse in cancer patients following hematopoietic stem cell transplantation (HSCT). However, the procedure can be limited by difficulties in priming and expanding sufficient numbers of TAA-specific-CTLs. Because acute dynamic exercise mobilizes large numbers of T-cells to peripheral blood, we hypothesized that a single bout of exercise would augment the ex vivo expansion of TAA-specific-CTLs.We therefore collected lymphocytes from blood donated by healthy adults at rest and after brief maximal dynamic exercise. TAA-specific CTLs were expanded using autologous monocyte-derived-dendritic cells pulsed with melanoma-associated antigen 4 (MAGE A4), with preferentially expressed antigen in melanoma (PRAME), and with Wilms' tumor protein (WT-1). Post exercise, 84% of the participants had a greater number of CTLs specific for at least one of the three TAA.Cells expanded from post exercise blood yielded a greater number of MAGE-A4 and PRAME-specific-cells in 70% and 61% of participants, respectively. In the 'exercise-responsive' participants (defined as participants with at least a 10% increase in TAA specific-CTLs post-exercise), MAGEA4- and PRAME-specific-CTLs increased 3.4-fold and 6.2- fold respectively. Moreover, expanded TAA-specific CTLs retained their antigen-specific cytotoxic activity. No phenotype differences were observed between expanded cells donated at rest and postexercise. We conclude that exercise can enhance the ex vivo expansion of TAA-specific-CTLs from healthy adults without compromising cytotoxic function. Hence, this study has implications for immunotherapy using adoptive T-cell transfer of donor-derived T cells after allogeneic HSCT. PMID- 25826371 TI - [A general practitioners' program for primary care in Chile]. AB - The public health system in Chile does not have a comprehensive development policy for physician resources in primary care, so there is currently a significant deficit of hours for medical care. The article contains a proposal for a "General Program for Primary Care Physicians", which aims to reduce the gap of general practitioners and specialists in primary care. The program proposes to integrate newly graduated physicians to work in the public medical offices with the subsequent possibility of applying for a scholarship specialty, and consecutively a return period as a specialist in the public health network. The immediate implementation of this program is perfectly feasible given the current availability of doctors, over 1400 medical graduates from universities. PMID- 25826372 TI - MicroRNA-22 impairs anti-tumor ability of dendritic cells by targeting p38. AB - Dendritic cells (DCs) play a critical role in triggering anti-tumor immune responses. Their intracellular p38 signaling is of great importance in controlling DC activity. In this study, we identified microRNA-22 (miR-22) as a microRNA inhibiting p38 protein expression by directly binding to the 3' untranslated region (3'UTR) of its mRNA. The p38 down-regulation further interfered with the synthesis of DC-derived IL-6 and the differentiation of DC driven Th17 cells. Moreover, overexpression of miR-22 in DCs impaired their tumor suppressing ability while miR-22 inhibitor could reverse this phenomenon and improve the curative effect of DC-based immunotherapy. Thus, our results highlight a suppressive role for miR-22 in the process of DC-invoked anti-tumor immunity and that blocking this microRNA provides a new strategy for generating potent DC vaccines for patients with cancer. PMID- 25826373 TI - Effects of unfermented and fermented whole grain rye crisp breads served as part of a standardized breakfast, on appetite and postprandial glucose and insulin responses: a randomized cross-over trial. AB - BACKGROUND: Whole grain rye products have been shown to increase satiety and elicit lower postprandial insulin response without a corresponding change in glucose response compared with soft refined wheat bread. The underlying mechanisms for these effects have not been fully determined The primary aim of the study was to investigate if whole grain rye crisp bread compared to refined wheat crisp bread, elected beneficial effects on appetite and postprandial insulin response, similarly as for other rye products. METHODS: In a randomized cross-over trial, 23 healthy volunteers, aged 27-70 years, BMI 18-31.4 kg/m2, were served a standardized breakfast with unfermented whole grain rye crisp bread (uRCB), fermented whole grain rye crisp bread (RCB) or refined wheat crisp bread (WCB), Appetite was measured using a visual analogue scale (VAS) until 4 h after breakfast. Postprandial glucose and insulin were measured at 0-230 min. Breads were chemically characterized including macronutrients, energy, dietary fiber components, and amino acid composition, and microstructure was characterized with light microscopy. RESULTS: Reported fullness was 16% higher (P<0.001), and hunger 11% and 12% lower (P<0.05) after ingestion of uRCB and RCB, respectively, compared with WCB. Postprandial glucose response did not differ significantly between treatments. Postprandial insulin was 10% lower (P<0.007) between 0-120 min but not significantly lower between 0-230 min for RCB compared with WCB. uRCB induced 13% (P<0.002) and 17% (P<0.001) lower postprandial insulin response between 0-230 min compared with RCB and WCB respectively. CONCLUSION: Whole grain rye crisp bread induces higher satiety and lower insulin response compared with refined wheat crisp bread. Microstructural characteristics, dietary fiber content and composition are probable contributors to the increased satiety after ingestion of rye crisp breads. Higher insulin secretion after ingestion of RCB and WCB compared with uRCB may be due to differences in fiber content and composition, and higher availability of insulinogenic branched chain amino acids. TRIAL REGISTRATION: ClinicalTrials.gov NCT02011217. PMID- 25826374 TI - Loss of Pol32 in Drosophila melanogaster causes chromosome instability and suppresses variegation. AB - Pol32 is an accessory subunit of the replicative DNA Polymerase delta and of the translesion Polymerase zeta. Pol32 is involved in DNA replication, recombination and repair. Pol32's participation in high- and low-fidelity processes, together with the phenotypes arising from its disruption, imply multiple roles for this subunit within eukaryotic cells, not all of which have been fully elucidated. Using pol32 null mutants and two partial loss-of-function alleles pol32rd1 and pol32rds in Drosophila melanogaster, we show that Pol32 plays an essential role in promoting genome stability. Pol32 is essential to ensure DNA replication in early embryogenesis and it participates in the repair of mitotic chromosome breakage. In addition we found that pol32 mutants suppress position effect variegation, suggesting a role for Pol32 in chromatin architecture. PMID- 25826375 TI - The role of macrophage migration inhibitory factor in mast cell-stimulated fibroblast proliferation and collagen production. AB - Current clinical and translational studies have shown that mast cell plays a pivotal role in multiple fibrotic diseases including scleroderma. However, the lack of mature human mast cell culture model exhibits a major obstacle for further dissection of cytokines and signaling molecules required for mast cell mediated fibrosis in various diseases. Macrophage Migration Inhibitory Factor is a mast cell released pro-inflammatory cytokine which is deregulated in scleroderma patients and is also involved in non-scleroderma related fibrosis. In the current study, we successfully generated a practical and reliable human mast cell culture system with bone marrow CD34+ hematopietic precursors. The derivative mast cell is normal in terms of both morphology and function as manifested by normal degranulation. More importantly, we were able to show mast cell conditioned medium as well as MIF supplementation augments fibroblast proliferation and collagen synthesis. This positive regulatory effect of mast cell conditioned medium can be dampened by MIF antibody. In addition, MIF knockdown significantly inhibits pro-fibrotic activities of CD34+ hematopietic precursor derived mast cells. These data strongly suggest that mast cell released MIF is required for mast cell mediated fibrogenic activities. The current manuscript seems to be the first mechanistic report showing the significance of MIF in mast cell mediated fibrosis, which may pave the way for the development of potential MIF-targeted therapy for fibrotic diseases to a further extent. Moreover, we strongly believe mast cell culture and differentiation model as well as corresponding genetic manipulation methodology will be helpful in characterizing novel mast cell based therapeutic targets. PMID- 25826376 TI - Diarrhea, stimulation and growth predict neurodevelopment in young North Indian children. AB - BACKGROUND AND OBJECTIVE: Infants and young children in low to middle-income countries are at risk for adverse neurodevelopment due to multiple risk factors. In this study, we sought to identify stimulation and learning opportunities, growth, and burden of respiratory infections and diarrhea as predictors for neurodevelopment. METHODS: We visited 422 North Indian children 6 to 30 months old weekly for six months. Childhood illnesses were assessed biweekly. At end study, we assessed neurodevelopment using the Ages and Stages Questionnaire 3rd ed. (ASQ-3) and gathered information on stimulation and learning opportunities. We identified predictors for ASQ-3 scores in multiple linear and logistic regression models. RESULTS: We were able to explain 30.5% of the variation in the total ASQ-3 score by the identified predictors. When adjusting for child characteristics and annual family income, stimulation and learning opportunities explained most of the variation by 25.1%. Height for age (standardized beta: 0.12, p<.05) and weight for height z-scores (std. beta: 0.09, p<.05) were positively associated with the total ASQ-3 score, while number of days with diarrhea was negatively associated with these scores (std. beta: -0.13, p<0.01). CONCLUSION: Our results support the importance of early child stimulation and general nutrition for child development. Our study also suggests that diarrhea is an additional risk factor for adverse neurodevelopment in vulnerable children. PMID- 25826377 TI - G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10. AB - Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERalphabeta), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1 treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response. PMID- 25826378 TI - MixtureTree annotator: a program for automatic colorization and visual annotation of MixtureTree. AB - The MixtureTree Annotator, written in JAVA, allows the user to automatically color any phylogenetic tree in Newick format generated from any phylogeny reconstruction program and output the Nexus file. By providing the ability to automatically color the tree by sequence name, the MixtureTree Annotator provides a unique advantage over any other programs which perform a similar function. In addition, the MixtureTree Annotator is the only package that can efficiently annotate the output produced by MixtureTree with mutation information and coalescent time information. In order to visualize the resulting output file, a modified version of FigTree is used. Certain popular methods, which lack good built-in visualization tools, for example, MEGA, Mesquite, PHY-FI, TreeView, treeGraph and Geneious, may give results with human errors due to either manually adding colors to each node or with other limitations, for example only using color based on a number, such as branch length, or by taxonomy. In addition to allowing the user to automatically color any given Newick tree by sequence name, the MixtureTree Annotator is the only method that allows the user to automatically annotate the resulting tree created by the MixtureTree program. The MixtureTree Annotator is fast and easy-to-use, while still allowing the user full control over the coloring and annotating process. PMID- 25826379 TI - UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. AB - Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non genetic determinants of the diseases of middle and old age. PMID- 25826380 TI - Molecular characterization of barley 3H semi-dwarf genes. AB - The barley chromosome 3H accommodates many semi-dwarfing genes. To characterize these genes, the two-rowed semi-dwarf Chinese barley landrace 'TX9425' was crossed with the Australian barley variety 'Franklin' to generate a doubled haploid (DH) population, and major QTLs controlling plant height have been identified in our previous study. The major QTL derived from 'TX9425' was targeted to investigate the allelism of the semi-dwarf gene uzu in barley. Twelve sets of near-isogenic lines and a large NILF2 fine mapping population segregating only for the dwarfing gene from 'TX9425' were developed. The semi-dwarfing gene in 'TX9425' was located within a 2.8 cM region close to the centromere on chromosome 3H by fine mapping. Molecular cloning and sequence analyses showed that the 'TX9425'-derived allele contained a single nucleotide substitution from A to G at position 2612 of the HvBRI1 gene. This was apparently the same mutation as that reported in six-rowed uzu barley. Markers co-segregating with the QTL were developed from the sequence of the HvBRI1 gene and were validated in the 'TX9425'/'Franklin' DH population. The other major dwarfing QTL derived from the Franklin variety was distally located on chromosome 3HL and co-segregated with the sdw1 diagnostic marker hv20ox2. A third dwarfing gene, expressed only in winter-sown trials, was identified and located on chromosome 3HS. The effects and interactions of these dwarfing genes under different growing conditions are discussed. These results improve our understanding of the genetic mechanisms controlling semi-dwarf stature in barley and provide diagnostic markers for the selection of semi-dwarfness in barley breeding programs. PMID- 25826381 TI - Correction: the inhibition of N-glycosylation of glycoprotein 130 molecule abolishes STAT3 activation by IL-6 family cytokines in cultured cardiac myocytes. AB - [This corrects the article DOI: 10.1371/journal.pone.0111097.]. PMID- 25826382 TI - Stereoselectivity in the Lewis acid mediated reduction of ketofuranoses. AB - The Lewis acid mediated reduction of ribose-, arabinose-, xylose-, and lyxose derived methyl and phenyl ketofuranoses with triethylsilane as nucleophile was found to proceed with good to excellent stereoselectivity to provide the 1,2-cis addition products. The methyl ketoses reacted in a more stereoselective manner than their phenyl counterparts. The stereochemical outcome of the reactions parallels the relative stability of the oxocarbenium ion conformers involved, as assessed by calculating the free energy surface maps of their complete conformational space. The Lewis acid mediated reduction allows for a direct synthesis of C-glycosides with predictable stereochemistry. PMID- 25826383 TI - Performance of a Novel Algorithm Using Automated Digital Microscopy for Diagnosing Tuberculosis. AB - RATIONALE: TBDx automated microscopy is a novel technology that processes digital microscopic images to identify acid-fast bacilli (AFB). Use of TBDx as part of a diagnostic algorithm could improve the diagnosis of tuberculosis (TB), but its performance characteristics have not yet been formally tested. OBJECTIVES: To evaluate the performance of the TBDx automated microscopy system in algorithms for diagnosis of TB. METHODS: Prospective samples from patients with presumed TB were processed in parallel with conventional smear microscopy, TBDx microscopy, and liquid culture. All TBDx-positive specimens were also tested with the Xpert MTB/RIF (GXP) assay. We evaluated the sensitivity and specificity of two algorithms-(1) TBDx-GXP (TBDx with positive specimens tested by Xpert MTB/RIF) and (2) TBDx alone-against the gold standard liquid media culture. MEASUREMENTS AND MAIN RESULTS: Of 1,210 samples, 1,009 were eligible for evaluation, of which 109 were culture positive for Mycobacterium tuberculosis. The TBDx system identified 70 specimens (68 culture positive) as having 10 or more putative AFB (high positive) and 207 (19 culture positive) as having 1-9 putative AFB (low positive). An algorithm in which "low-positive" results on TBDx were confirmed by GXP had 78% sensitivity (85 of 109) and 99.8% specificity (889 of 900), requiring 21% (207 of 1,009) specimens to be processed by GXP. As a stand-alone test, a "high-positive" result on TBDx had 62% sensitivity and 99.7% specificity. CONCLUSIONS: TBDx used in diagnostic algorithms with GXP provided reasonable sensitivity and high specificity for active TB while dramatically reducing the number GXP tests performed. As a stand-alone microscopy system, its performance was equivalent to that of a highly experienced TB microscopist. PMID- 25826384 TI - Water deficit during pit hardening enhances phytoprostanes content, a plant biomarker of oxidative stress, in extra virgin olive oil. AB - No previous information exists on the effects of water deficit on the phytoprostanes (PhytoPs) content in extra virgin olive oil from fruits of mature olive (Olea europaea L. cv. Cornicabra) trees during pit hardening. PhytoPs profile in extra virgin olive oil was characterized by the presence of 9-F1t PhytoP, 9-epi-9-F1t-PhytoP, 9-epi-9-D1t-PhytoP, 9-D1t-PhytoP, 16-B1-PhytoP + ent 16-B1-PhytoP, and 9-L1-PhytoP + ent-9-L1-PhytoP. The qualitative and quantitative differences in PhytoPs content with respect to those reported by other authors indicate a decisive effect of cultivar, oil extraction technology, and/or storage conditions prone to autoxidation. The pit hardening period was critical for extra virgin olive oil composition because water deficit enhanced the PhytoPs content, with the concomitant potential beneficial aspects on human health. From a physiological and agronomical point of view, 9-F1t-PhytoP, 9-epi-9-F1t-PhytoP, and 16-B1-PhytoP + ent-16-B1-PhytoP could be considered as early candidate biomarkers of water stress in olive tree. PMID- 25826385 TI - Hb Lansing (HBA2: c.264C > G) and a new beta promoter transversion [-52 (G > T)]: an attempt to define the phenotype of two mutations found in the Omani population. AB - We report two examples showing how problematic it can be to define the phenotype of new or rare globin genes mutations. We describe two mutations observed for the first time in the Omani population: the first was found in the consanguineous parents of a deceased newborn with hepatomegaly, cardiomegaly and severe hemolytic anemia, putatively homozygous for the rare Hb Lansing (HBA2: c.264C > G) variant. The second is a novel beta-globin gene promoter mutation [-52 (G > T)] observed in four independent patients. Two with borderline/elevated Hb A2, alpha-thalassemia (alpha-thal) and hypochromic red cell indices, and two heterozygotes for Hb S (HBB: c.20A > T), alpha-thal and with Hb A/Hb S ratios possibly indicating a very mild beta(+)-thalassemia (beta(+)-thal) mutation. PMID- 25826387 TI - Identification of reference genes for relative quantification of circulating microRNAs in bovine serum. AB - Circulating microRNAs in body fluids have been implicated as promising biomarkers for physiopathology disorders. Currently, the expression levels of circulating microRNAs are estimated by reverse transcription quantitative real-time polymerase chain reaction. Use of appropriate reference microRNAs for normalization is critical for accurate microRNA expression analysis. However, no study has systematically investigated reference genes for evaluating circulating microRNA expression in cattle. In this study, we describe the identification and characterization of appropriate reference microRNAs for use in the normalization of circulating microRNA levels in bovine serum. We evaluated the expression stability of ten candidate reference genes in bovine serum by using reverse transcription quantitative real-time polymerase chain reaction. Data were analyzed using geNorm, NormFinder, and BestKeeper statistical algorithms. The results consistently showed that a combination of miR-93 and miR-127 provided the most stably expressed reference. The suitability of these microRNAs was validated, and even when compared among different genders or breeds, the combination of miR-93 and miR-127 was ranked as the most stable microRNA reference. Therefore, we conclude that this combination is the optimal endogenous reference for reverse transcription quantitative real-time polymerase chain reaction-based detection of microRNAs in bovine serum. The data presented in this study are crucial to successful biomarker discovery and validation for the diagnosis of physiopathological conditions in cattle. PMID- 25826389 TI - Systematic Reviews of the Health or Health care of People with Intellectual Disabilities: A Systematic Review to Identify Gaps in the Evidence Base. AB - BACKGROUND: Systematic reviews are important in evaluating evidence concerning the health of people with intellectual disabilities. This study conducts a systematic review to identify strengths and gaps in this evidence. METHOD: Electronic literature searches and email requests identified systematic reviews published in English from 2008 to 2013 on the health or health care of people with intellectual disabilities. Reviews were categorized using ICD-10 chapter headings and information extracted regarding methods, number of studies reviewed and findings. RESULTS: Ninety-four reviews were identified: 52 related to ICD-10 Chapter V: Mental or behavioural disorders, 28 to Chapter XXI: Factors influencing health status and contact with services, and 14 related to other chapters or encompassed multiple chapters. Nine reviews were 'empty'. No reviews were found for many ICD-10 chapter headings. CONCLUSIONS: Systematic reviews are heavily weighted towards mental health, with little coverage of several areas important to the health and mortality of people with intellectual disabilities. PMID- 25826388 TI - Exercise, skeletal muscle and inflammation: ARE-binding proteins as key regulators in inflammatory and adaptive networks. AB - The role of inflammation in skeletal muscle adaptation to exercise is complex and has hardly been elucidated so far. While the acute inflammatory response to exercise seems to promote skeletal muscle training adaptation and regeneration, persistent, low-grade inflammation, as seen in a multitude of chronic diseases, is obviously detrimental. The regulation of cytokine production in skeletal muscle cells has been relatively well studied, yet little is known about the compensatory and anti-inflammatory mechanisms that resolve inflammation and restore tissue homeostasis. One important strategy to ensure sequential, timely and controlled resolution of inflammation relies on the regulated stability of mRNAs encoding pro-inflammatory mediators. Many key transcripts in early immune responses are characterized by the presence of AU-rich elements (AREs) in the 3' untranslated regions of their mRNAs, allowing efficient fine-tuning of gene expression patterns at the post-transcriptional level. AREs exert their function by recruiting particular RNA-binding proteins, resulting, in most cases, in de stabilization of the target transcripts. The best-characterized ARE-binding proteins are HuR, CUGBP1, KSRP, AUF1, and the three ZFP36 proteins, especially TTP/ZFP36. Here, we give a general introduction into the role of inflammation in the adaptation of skeletal muscle to exercise. Subsequently, we focus on potential roles of ARE-binding proteins in skeletal muscle tissue in general and specifically exercise-induced skeletal muscle remodeling. Finally, we present novel data suggesting a specific function of TTP/ZFP36 in exercise-induced skeletal muscle plasticity. PMID- 25826386 TI - The impact of host diet on Wolbachia titer in Drosophila. AB - While a number of studies have identified host factors that influence endosymbiont titer, little is known concerning environmental influences on titer. Here we examined nutrient impact on maternally transmitted Wolbachia endosymbionts in Drosophila. We demonstrate that Drosophila reared on sucrose- and yeast-enriched diets exhibit increased and reduced Wolbachia titers in oogenesis, respectively. The yeast-induced Wolbachia depletion is mediated in large part by the somatic TOR and insulin signaling pathways. Disrupting TORC1 with the small molecule rapamycin dramatically increases oocyte Wolbachia titer, whereas hyper-activating somatic TORC1 suppresses oocyte titer. Furthermore, genetic ablation of insulin-producing cells located in the Drosophila brain abolished the yeast impact on oocyte titer. Exposure to yeast-enriched diets altered Wolbachia nucleoid morphology in oogenesis. Furthermore, dietary yeast increased somatic Wolbachia titer overall, though not in the central nervous system. These findings highlight the interactions between Wolbachia and germline cells as strongly nutrient-sensitive, and implicate conserved host signaling pathways by which nutrients influence Wolbachia titer. PMID- 25826390 TI - A quantum Monte Carlo study of the reactions of CH with acrolein. AB - To assist understanding of combustion processes, we have investigated reactions of methylidyne (CH) with acrolein (CH2CHCHO) using the quantum Monte Carlo (QMC) and other computational methods. We present a theoretical study of the major reactions reported in a recent experiment on the subject system. Both DFT and MP2 computations are carried out, and the former approach is used to form the independent-particle part of the QMC trial wave function used in the diffusion Monte Carlo (DMC) variant of the QMC method. In agreement with experiment, we find that the dominant product channel leads to formation of C4H4O systems + H with leading products of furan + H and 1,3-butadienal + H. Equilibrium geometries, atomization energies, reaction barriers, transition states, and heats of reaction are computed using the DFT, MP2, and DMC approaches and compared to experiment. We find that DMC results are in close agreement with experiment. The kinetics of the subject reactions are determined by solving master equations with the MultiWell software suite. PMID- 25826391 TI - Need for ethnic-specific guidelines for prevention, diagnosis, and management of type 2 diabetes in South asians. AB - Noncommunicable diseases, including type 2 diabetes mellitus and cardiovascular diseases (CVDs), cause 7.9 million deaths every year in South Asia. India has nearly 65.1 million cases of diabetes, and Pakistan and Bangladesh are at the 12(th) and 13(th) positions in the global list of high prevalence countries, respectively. The prevalence in India is continuously increasing and is recently reported to be nearly 14% and 8% in urban areas and rural areas, respectively. Diabetes in South Asians is, in some manner, different from that in other races; it occurs nearly a decade earlier, at lower body mass index and waist circumference levels, and with more postprandial hyperglycemia, dyslipidemia, nephropathy, and CVD than in whites. Decision regarding prevention and management of diabetes should be taken in the background of heterogeneity of diet, attitudes, and cultural milieu in South Asia. A need for a low-cost, integrated, yet individualized approach specific for South Asian countries has been increasingly felt since escalating research has uncovered characteristic phenotype, dietary and socioeconomic patterns. Although most such guidelines formulated in developed countries such as the United States or the United Kingdom could be generally applied to developing South Asian countries, there are fundamental differences in applicability of lifestyle and diets (heterogeneous, different from western diets), availability and cost of drugs and insulins, monitoring methods and devices, and insulin pump. Moreover, the monitoring, education, care, and rehabilitation will differ according to different socioeconomic strata and levels of health care (primary, secondary, or tertiary). Some of the potential ethnic-specific modifications have been suggested in this review. PMID- 25826392 TI - Ion density deviations in semipermeable ionic microcapsules. AB - By implementing the nonlinear Poisson-Boltzmann theory in a cell model, we theoretically investigate the influence of polyelectrolye gel permeability on ion densities and pH deviations inside the cavities of ionic microcapsules. Our calculations show that variations in permeability of a charged capsule shell cause a redistribution of ion densities within the capsule, which ultimately affects the pH deviation and Donnan potential induced by the electric field of the shell. We find that semipermeable capsules can induce larger pH deviations inside their cavities that can permeable capsules. Furthermore, with increasing capsule charge, the influence of permeability on pH deviations progressively increases. Our theory, while providing a self-consistent method for modeling the influence of permeability on fundamental properties of ionic microgels, makes predictions of practical significance for the design of microcapsules loaded with fluorescent dyes, which can serve as biosensors for diagnostic purposes. PMID- 25826393 TI - Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway. AB - Cardiac hypertrophy is an adaptive response to various physiological and pathological stimuli. Phosphoinositide-3 kinase (PI3K) is a highly conserved lipid kinase involved in physiological cardiac hypertrophy (PHH). PI3K interacting protein1 (Pik3ip1) shares homology with the p85 regulatory subunit of PI3K and is known to interact with the p110 catalytic subunit of PI3K, leading to attenuation of PI3K activity in liver and immune cells. However, the role of Pik3ip1 in the heart remains unknown. In the present study, the effects of Pik3ip1 on cardiac hypertrophy were examined. We found that the expression level of Pik3ip1 was markedly higher in cardiomyocytes than in fibroblasts. The interaction of Pik3ip1 with the p110a subunit of PI3K in the heart was identified by immunoprecipitation using neonatal rat cardiomyocytes (NRCM). Approximately 35% knockdown of Pik3ip1 was sufficient to induce myocardial hypertrophy. Pik3ip1 deficiency was shown to lead to activation of PI3K/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling pathway, increasing protein synthesis and cell size. However, adenovirus-mediated overexpression of Pik3ip1 attenuated PI3K-mediated cardiac hypertrophy. Pik3ip1 was upregulated by PHH due to swimming training, but not by pathological cardiac hypertrophy (PAH) due to pressure-overload, suggesting that Pik3ip1 plays a compensatory negative role for PHH. Collectively, our results elucidate the mechanisms for the roles of Pik3ip1 in PI3K/AKT signaling pathway. PMID- 25826394 TI - Promote health or prevent disease? The effects of health-related advertising on eating behavior intention. AB - The health medical costs of colorectal cancer are increasingly higher in Taiwan. The National Health Insurance Administration (NHI) and The Health Promotion Administration of the Ministry of Health and Welfare (MOHW) in Taiwan encourage individuals to adopt an earnest approach to healthy behavior through advocacy advertising. However, the number of colorectal cancer patients continues to increase annually. Our study explored the effects of health-related advertisements (ads) on healthy behavior intentions as influenced by regulatory focus theory (RFT) and construal level theory (CLT). We conducted an experiment with different public health advocacy ads. A 2 (regulatory focus: promotion vs. prevention) * 2 (temporal distance: one month vs. one year) * 2 (graphics-text ratio: more pictures and less text vs. fewer pictures and more text) three-factor experiment was adopted. The multiple analysis of variance (MANOVA) results revealed that ads with higher construal levels (i.e., more text) had greater effects with a promotion-oriented regulatory focus. However, no significant differences were found in either attitude toward the ads or behavior intention when the regulatory focus was prevention. In addition, according to the young testers and those who were psychologically distant from colorectal cancer, different temporal distances and different construal levels had no statistically significantly effects on attitudes toward advertising or on behavior intentions. The results revealed that viewers found the information easier to understand when the ads triggered the regulatory focuses of the viewers and applied an appropriate graphics-text ratio, which resulted in favorable health-related advertising effectiveness. Thus, we provide two suggestions regarding the use of health-related advertising for MOHW in the future. PMID- 25826397 TI - Exciton dynamics and annihilation in WS2 2D semiconductors. AB - We systematically investigate the exciton dynamics in monolayered, bilayered, and trilayered WS2 two-dimensional (2D) crystals by time-resolved photoluminescence (TRPL) spectroscopy. The exciton lifetime when free of exciton annihilation was determined to be 806 +/- 37 ps, 401 +/- 25 ps, and 332 +/- 19 ps for WS2 monolayer, bilayer, and trilayer, respectively. By measuring the fluorescence quantum yields, we also establish the radiative and nonradiative lifetimes of the direct and indirect excitons. The exciton decay in monolayered WS2 exhibits a strong excitation density-dependence, which can be described using an exciton exciton annihilation (two-particle Auger recombination) model. The exciton exciton annihilation rate for monolayered, bilayered, and trilayered WS2 was determined to be 0.41 +/- 0.02, (6.00 +/- 1.09) * 10(-3) and (1.88 +/- 0.47) * 10(-3) cm(2) s(-1), respectively. Notably, the exciton-exciton annihilation rate is two orders of magnitude faster in the monolayer than in the bilayer and trilayer. We attribute the much slower exciton-exciton annihilation rate in the bilayer and trilayer to reduced many-body interaction and phonon-assisted exciton exciton annihilation of indirect excitons. PMID- 25826395 TI - Drinking water from dug wells in rural ghana--salmonella contamination, environmental factors, and genotypes. AB - Salmonellosis is an important but neglected disease in sub-Saharan Africa. Food or fecal-oral associated transmissions are the primary cause of infections, while the role of waterborne transmission is unclear. Samples were collected from different dug wells in a rural area of Ghana and analyzed for contamination with bacteria, and with Salmonella in particular. In addition, temporal dynamics and riks factors for contamination were investigated in 16 wells. For all Salmonella isolates antibiotic susceptibility testing was performed, serovars were determined and strains from the same well with the same serovar were genotyped. The frequency of well water contamination with Gram-negative rod-shaped bacteria was 99.2% (n = 395). Out of 398 samples, 26 (6.5%) tested positive for Salmonella spp. The serovar distribution was diverse including strains not commonly isolated from clinical samples. Resistance to locally applied antibiotics or resistance to fluoroquinolones was not seen in the Salmonella isolates. The risk of Salmonella contamination was lower in wells surrounded by a frame and higher during the rainy season. The study confirms the overall poor microbiological quality of well water in a resource-poor area of Ghana. Well contamination with Salmonella poses a potential threat of infection, thus highlighting the important role of drinking water safety in infectious disease control. PMID- 25826396 TI - An analysis of the influence of selected genetic and hormonal factors on the occurrence of depressive symptoms in late-reproductive-age women. AB - BACKGROUND: The aim of this study was to analyze the influence of genetic and hormonal factors on incidences of depressive symptoms in late-reproductive-age women. METHODS: The study was performed using the Beck Depression Inventory, the PCR, and genetic tests of 347 healthy late-reproductive-age Polish women. RESULTS: The relationship between the level of anti-Mullerian hormone (AMH) and depressive symptoms was not statistically significant (p > 0.05). Increases in age and FSH levels were accompanied by a decrease in AMH level in a significant way (p < 0.05). There were no statistically significant relationships between the distribution of genotypes and the frequency of alleles of the investigated polymorphisms and depressive symptoms according to the Beck Depression Inventory. CONCLUSIONS: (1) The presence of the s/s genotype of the 5-HTTLPR polymorphism in the serotonin transporter promoter region and the 3/3 genotype of the 30-bp VNTR polymorphism in the monoamine oxidase A promoter region does not contribute to the development of depressive symptoms in late-reproductive-age women. (2) A relationship between the level of anti-Mullerian hormone and depressive symptoms was not confirmed in the group of healthy late-reproductive-age women. (3) AMH level correlates negatively with FSH level and age, which confirms that AMH can be regarded as a factor reflecting the ovarian reserve. PMID- 25826398 TI - Identification of Novel ROS Inducers: Quinone Derivatives Tethered to Long Hydrocarbon Chains. AB - We performed the first synthesis of the 17-carbon chain-tethered quinone moiety 22 (SAN5201) of irisferin A, a natural product exhibiting anticancer activity, and its derivatives. We found that 22 is a potent ROS inducer and cytotoxic agent. Compound 25 (SAN7401), the hydroquinone form of 22, induced a significant release of intracellular ROS and apoptosis (EC50 = 1.3-2.6 MUM) in cancer cell lines, including A549 and HCT-116. Compared with the activity of a well-known ROS inducer, piperlongumine, 22 and 25 showed stronger cytotoxicity and higher selectivity over noncancerous cells. Another hydroquinone tethering 12-carbon chain, 26 (SAN4601), generated reduced levels of ROS but showed more potent cytotoxicity (EC50 = 0.8-1.6 MUM) in cancer cells, although it lacked selectivity over noncancerous cells, implying that the naturally occurring 17-carbon chain is also crucial for ROS production and a selective anticancer effect. Both 25 and 26 displayed strong, equipotent activities against vemurafenib-resistant SK-Mel2 melanoma cells and p53-deficient H1299 lung cancer cells as well, demonstrating their broad therapeutic potential as anticancer agents. PMID- 25826399 TI - Phlebotomus sergenti in a cutaneous leishmaniasis focus in Azilal province (High Atlas, Morocco): molecular detection and genotyping of Leishmania tropica, and feeding behavior. AB - BACKGROUND: Phlebotomus (Paraphlebotomus) sergenti is at least one of the confirmed vectors for the transmission of cutaneous leishmaniasis caused by Leishmania tropica and distributed widely in Morocco. This form of leishmaniasis is considered largely as anthroponotic, although dogs were found infected with Leishmania tropica, suggestive of zoonosis in some rural areas. METHODOLOGY AND FINDINGS: This survey aimed at (i) studying the presence of Leishmania in field caught Phlebotomus sergenti, (ii) investigating genetic diversity within Leishmania tropica and (iii) identifying the host-blood feeding preferences of Phlebotomus sergenti. A total of 4,407 sand flies were collected in three rural areas of Azilal province, using CDC miniature light traps. Samples collected were found to consist of 13 species: Phlebotomus spp. and 3 Sergentomyia spp. The most abundant species was Phlebotomus sergenti, accounting for 45.75 % of the total. 965 female Phlebotomus sergenti were screened for the presence of Leishmania by ITS1-PCR-RFLP, giving a positive rate of 5.7% (55/965), all being identified as Leishmania tropica. Nucleotide heterogeneity of PCR-amplified ITS1-5.8S rRNA gene ITS2 was noted. Analyses of 31 sequences obtained segregated them into 16 haplotypes, of which 7 contain superimposed peaks at certain nucleotide positions, suggestive of heterozygosity. Phlebotomus sergenti collected were found to feed on a large variety of vertebrate hosts, as determined by Cytochrome b sequencing of the DNA from the blood meals of 64 engorged females. CONCLUSION: Our findings supported the notion that Phlebotomus sergenti is the primary vector of Leishmania tropica in this focus, and that the latter is genetically very heterogeneous. Furthermore, our results might be suggestive of a certain level of heterozygosity in Leishmania tropica population. This finding, as well as the feeding of the vectors on different animals are of interest for further investigation. PMID- 25826400 TI - Identification of microRNAs and transcript targets in Camelina sativa by deep sequencing and computational methods. AB - Camelina sativa is an annual oilseed crop that is under intensive development for renewable resources of biofuels and industrial oils. MicroRNAs, or miRNAs, are endogenously encoded small RNAs that play key roles in diverse plant biological processes. Here, we conducted deep sequencing on small RNA libraries prepared from camelina leaves, flower buds and two stages of developing seeds corresponding to initial and peak storage products accumulation. Computational analyses identified 207 known miRNAs belonging to 63 families, as well as 5 novel miRNAs. These miRNAs, especially members of the miRNA families, varied greatly in different tissues and developmental stages. The predicted miRNA target genes are involved in a broad range of physiological functions including lipid metabolism. This report is the first step toward elucidating roles of miRNAs in C. sativa and will provide additional tools to improve this oilseed crop for biofuels and biomaterials. PMID- 25826401 TI - Prediction of overall in vitro microsomal stability of drug candidates based on molecular modeling and support vector machines. Case study of novel arylpiperazines derivatives. AB - Other than efficacy of interaction with the molecular target, metabolic stability is the primary factor responsible for the failure or success of a compound in the drug development pipeline. The ideal drug candidate should be stable enough to reach its therapeutic site of action. Despite many recent excellent achievements in the field of computational methods supporting drug metabolism studies, a well recognized procedure to model and predict metabolic stability quantitatively is still lacking. This study proposes a workflow for developing quantitative metabolic stability-structure relationships, taking a set of 30 arylpiperazine derivatives as an example. The metabolic stability of the compounds was assessed in in vitro incubations in the presence of human liver microsomes and NADPH and subsequently quantified by liquid chromatography-mass spectrometry (LC-MS). Density functional theory (DFT) calculations were used to obtain 30 models of the molecules, and Dragon software served as a source of structure-based molecular descriptors. For modeling structure-metabolic stability relationships, Support Vector Machines (SVM), a non-linear machine learning technique, were found to be more effective than a regression technique, based on the validation parameters obtained. Moreover, for the first time, general sites of metabolism for arylpiperazines bearing the 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione system were defined by analysis of Q-TOF-MS/MS spectra. The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values. Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data. The approach presented provides a novel, comprehensive and reliable tool for investigating metabolic stability, factors that affect it, and the proposed structures of metabolites at the same time. The performance of the DFT-SVM-based approach provides an opportunity to implement it in a standard drug development pipeline. PMID- 25826402 TI - Bees for development: Brazilian survey reveals how to optimize stingless beekeeping. AB - Stingless bees are an important asset to assure plant biodiversity in many natural ecosystems, and fulfill the growing agricultural demand for pollination. However, across developing countries stingless beekeeping remains an essentially informal activity, technical knowledge is scarce, and management practices lack standardization. Here we profited from the large diversity of stingless beekeepers found in Brazil to assess the impact of particular management practices on productivity and economic revenues from the commercialization of stingless bee products. Our study represents the first large-scale effort aiming at optimizing stingless beekeeping for honey/colony production based on quantitative data. Survey data from 251 beekeepers scattered across 20 Brazilian States revealed the influence of specific management practices and other confounding factors over productivity and income indicators. Specifically, our results highlight the importance of teaching beekeepers how to inspect and feed their colonies, how to multiply them and keep track of genetic lineages, how to harvest and preserve the honey, how to use vinegar traps to control infestation by parasitic flies, and how to add value by labeling honey containers. Furthermore, beekeeping experience and the network of known beekeepers were found to be key factors influencing productivity and income. Our work provides clear guidelines to optimize stingless beekeeping and help transform the activity into a powerful tool for sustainable development. PMID- 25826403 TI - A generic model of dyadic social relationships. AB - We introduce a model of dyadic social interactions and establish its correspondence with relational models theory (RMT), a theory of human social relationships. RMT posits four elementary models of relationships governing human interactions, singly or in combination: Communal Sharing, Authority Ranking, Equality Matching, and Market Pricing. To these are added the limiting cases of asocial and null interactions, whereby people do not coordinate with reference to any shared principle. Our model is rooted in the observation that each individual in a dyadic interaction can do either the same thing as the other individual, a different thing or nothing at all. To represent these three possibilities, we consider two individuals that can each act in one out of three ways toward the other: perform a social action X or Y, or alternatively do nothing. We demonstrate that the relationships generated by this model aggregate into six exhaustive and disjoint categories. We propose that four of these categories match the four relational models, while the remaining two correspond to the asocial and null interactions defined in RMT. We generalize our results to the presence of N social actions. We infer that the four relational models form an exhaustive set of all possible dyadic relationships based on social coordination. Hence, we contribute to RMT by offering an answer to the question of why there could exist just four relational models. In addition, we discuss how to use our representation to analyze data sets of dyadic social interactions, and how social actions may be valued and matched by the agents. PMID- 25826405 TI - Collimator based tracking with an add-on multileaf collimator: Moduleaf. AB - Radiotherapy is one of the most important methods used for the treatment of cancer. Irradiating a moving target is also one of the most challenging tasks to accomplish in modern radiotherapy. We have developed a tracking system by modifying an add-on collimator, the Siemens Moduleaf, for realtime applications in radiotherapy. As the add-on collimator works nearly completely independently of the linear accelerator (LinAc), no modifications to the latter were necessary. The adaptations to the Moduleaf were mainly software-based. In order to reduce the complexity of the system, outdated electronic parts were replaced with newer components where practical.Verification was performed by measuring the latency of the system as well as the impact on applied dose to a predefined target volume, moving in the leaf's travel direction. Latency measurements in the software were accomplished by comparing the target and current positions of the leaves. For dose measurements, a Gafchromic EBT2 film was placed beneath the target 4D phantom, in between solid water plates and moved alongside with it. Comparing the dose distribution on the film with a moving target between 'tracking disabled' towards 'tracking enabled' functions resulted in penumbra widths of 23 mm to 4 mm for 0.1 Hz sinusoidal movements with an amplitude of 32 mm, respectively. The maximum speed was therefore 20 mm s(-1). Latency was measured to be less than 50 ms for the signal runtimes. Based on the results, a tracking-capable add-on collimator seems to be a useful tool for reducing the margins for the treatment of small, slow-moving targets. PMID- 25826404 TI - Mapping molecular differences and extracellular matrix gene expression in segmental outflow pathways of the human ocular trabecular meshwork. AB - Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, and lowering IOP remains the only effective treatment for glaucoma. The trabecular meshwork (TM) in the anterior chamber of the eye regulates IOP by generating resistance to aqueous humor outflow. Aqueous humor outflow is segmental, but molecular differences between high and low outflow regions of the TM are poorly understood. In this study, flow regions of the TM were characterized using fluorescent tracers and PCR arrays. Anterior segments from human donor eyes were perfused at physiological pressure in an ex vivo organ culture system. Fluorescently-labeled microspheres of various sizes were perfused into anterior segments to label flow regions. Actively perfused microspheres were segmentally distributed, whereas microspheres soaked passively into anterior segments uniformly labeled the TM and surrounding tissues with no apparent segmentation. Cell-tracker quantum dots (20 nm) were localized to the outer uveal and corneoscleral TM, whereas larger, modified microspheres (200 nm) localized throughout the TM layers and Schlemm's canal. Distribution of fluorescent tracers demonstrated a variable labeling pattern on both a macro- and micro-scale. Quantitative PCR arrays allowed identification of a variety of extracellular matrix genes differentially expressed in high and low flow regions of the TM. Several collagen genes (COL16A1, COL4A2, COL6A1 and 2) and MMPs (1, 2, 3) were enriched in high, whereas COL15A1, and MMP16 were enriched in low flow regions. Matrix metalloproteinase activity was similar in high and low regions using a quantitative FRET peptide assay, whereas protein levels in tissues showed modest regional differences. These gene and protein differences across regions of the TM provide further evidence for a molecular basis of segmental flow routes within the aqueous outflow pathway. New insight into the molecular mechanisms of segmental aqueous outflow may aid in the design and delivery of improved treatments for glaucoma patients. PMID- 25826406 TI - Substituted quinoline quinones as surrogates for the PQQ cofactor: an electrochemical and computational study. AB - Pyrroloquinoline quinones (PQQ) are important cofactors that shuttle redox equivalents in diverse metalloproteins. Quinoline 7,8-quinones have been synthesized and characterized as surrogates for PQQ to elucidate redox energetics within metalloenzyme active sites. The quinoline 7,8-quinones were accessed using polymer-supported iodoxybenzoic acid and the compounds evaluated using solution electrochemistry. Together with a family of quinones, the products were evaluated computationally and used to generate a predictive correlation between a computed DeltaG and the experimental reduction potentials. PMID- 25826407 TI - Correction: medication reconciliation in patients hospitalized in a cardiology unit. AB - [This corrects the article DOI: 10.1371/journal.pone.0115491.]. PMID- 25826408 TI - Anti-Obesity Effects of Soy Leaf via Regulation of Adipogenic Transcription Factors and Fat Oxidation in Diet-Induced Obese Mice and 3T3-L1 Adipocytes. AB - The anti-obesity effects of extracts from soy leaves (SLE) cultivated for 8 weeks (8W) or 16 weeks (16W) were investigated in diet-induced obese mice. The effects of kaempferol, an aglycone of the kaempferol glycosides that are the major component of 8W-SLE, and coumestrol, the major component of 16W-SLE, were also investigated in 3T3-L1 adipocytes. Eight-week-old male C57BL/6J mice were randomly divided into normal diet, high-fat diet (HFD), 8W-SLE (HFD+8W-SLE 50 mg kg(-1) day(-1)), 16W-SLE (HFD+16W-SLE 50 mg kg(-1) day(-1)), and Garcinia cambogia extracts (GE) (HFD+GE 50 mg kg(-1) day(-1)) groups. Body weight gain and fat accumulation of white adipose tissue (WAT) were highly suppressed by daily oral administration of 8W-SLE and 16W-SLE for 10 weeks. Supplementing a HFD with 8W-SLE and 16W-SLE regulated the mRNA expression of peroxisome proliferator activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha (c/EBPalpha), sterol regulatory element-binding protein-1 (SREBP-1), adipocyte protein 2, and fatty acid synthase (FAS), which are related to adipogenesis, in addition to hormone-sensitive lipase (HSL), carnitine palmitoyl transferase 1 (CPT-1), and uncoupling protein 2 (UCP2), which are related to fat oxidation in WAT. In 3T3-L1 adipocytes, kaempferol and coumestrol exhibited anti-adipogenic effects via downregulation of PPARgamma, c/EBPalpha, SREBP-1, and FAS. Kaempferol and coumestrol increased the expression of HSL, CPT-1, and UCP2. PMID- 25826409 TI - The in vitro and in vivo anti-cancer activities of a standardized quassinoids composition from Eurycoma longifolia on LNCaP human prostate cancer cells. AB - Quassinoids are a group of diterpenoids found in plants from the Simaroubaceae family. They are also the major bioactive compounds found in Eurycoma longifolia which is commonly used as traditional medicine in South East Asia to treat various ailments including sexual dysfunction and infertility. These uses are attributed to its ability to improve testosterone level in men. Chronic consumption of E. longifolia extracts has been reported to increase testosterone level in men and animal model but its effect on prostate growth remains unknown. Therefore, the present study investigates the effects of a standardized total quassinoids composition (SQ40) containing 40% of the total quassinoids found in E. longifolia on LNCaP human prostate cancer cell line. SQ40 inhibited LNCaP cell growth at IC50 value of 5.97 MUg/mL while the IC50 on RWPE-1 human prostate normal cells was 59.26 MUg/mL. SQ40 also inhibited 5alpha-dihydrotestosterone stimulated growth in LNCaP cells dose-dependently. The inhibitory effect of SQ40 in anchorage-independent growth of LNCaP cells was also demonstrated using soft agar assay. SQ40 suppressed LNCaP cell growth via G0/G1 phase arrest which was accompanied by the down-regulation of CDK4, CDK2, Cyclin D1 and Cyclin D3 and up regulation of p21Waf1/Cip1 protein levels. SQ40 at higher concentrations or longer treatment duration can cause G2M growth arrest leading to apoptotic cell death as demonstrated by the detection of poly(ADP-ribose) polymerase cleavage in LNCaP cells. Moreover, SQ40 also inhibited androgen receptor translocation to nucleus which is important for the transactivation of its target gene, prostate specific antigen (PSA) and resulted in a significant reduction of PSA secretion after the treatment. In addition, intraperitoneal injection of 5 and 10 mg/kg of SQ40 also significantly suppressed the LNCaP tumor growth on mouse xenograft model. Results from the present study suggest that the standardized total quassinoids composition from E. longifolia promotes anti-prostate cancer activities in LNCaP human prostate cancer cells. PMID- 25826410 TI - Targeted gene editing by transfection of in vitro reconstituted Streptococcus thermophilus Cas9 nuclease complex. PMID- 25826411 TI - Mutual interaction between BCL6 and microRNAs in T cell differentiation. AB - The transcription factor B-cell CLL/lymphoma 6 (BCL6) and the regulatory factor microRNAs (miRNAs) are of great importance in the differentiation of T cell subsets. An increasing body of evidence has demonstrated that BCL6 and miRNAs can target one another and mutually adjust their expression in T cell subsets, such as T helper (Th)-2, Th17, CD8+ regulatory T (CD8+Treg) and T follicular helper (Tfh) cells. Here, we discuss the most recent advances and emerging concepts in how BCL6 and miRNAs regulate one another, and the effects of such mutual regulations on T cell subset differentiation. PMID- 25826412 TI - Deciphering the RNA landscape by RNAome sequencing. AB - Current RNA expression profiling methods rely on enrichment steps for specific RNA classes, thereby not detecting all RNA species in an unperturbed manner. We report strand-specific RNAome sequencing that determines expression of small and large RNAs from rRNA-depleted total RNA in a single sequence run. Since current analysis pipelines cannot reliably analyze small and large RNAs simultaneously, we developed TRAP, Total Rna Analysis Pipeline, a robust interface that is also compatible with existing RNA sequencing protocols. RNAome sequencing quantitatively preserved all RNA classes, allowing cross-class comparisons that facilitates the identification of relationships between different RNA classes. We demonstrate the strength of RNAome sequencing in mouse embryonic stem cells treated with cisplatin. MicroRNA and mRNA expression in RNAome sequencing significantly correlated between replicates and was in concordance with both existing RNA sequencing methods and gene expression arrays generated from the same samples. Moreover, RNAome sequencing also detected additional RNA classes such as enhancer RNAs, anti-sense RNAs, novel RNA species and numerous differentially expressed RNAs undetectable by other methods. At the level of complete RNA classes, RNAome sequencing also identified a specific global repression of the microRNA and microRNA isoform classes after cisplatin treatment whereas all other classes such as mRNAs were unchanged. These characteristics of RNAome sequencing will significantly improve expression analysis as well as studies on RNA biology not covered by existing methods. PMID- 25826413 TI - The role of short RNA loops in recognition of a single-hairpin exon derived from a mammalian-wide interspersed repeat. AB - Splice-site selection is controlled by secondary structure through sequestration or approximation of splicing signals in primary transcripts but the exact role of even the simplest and most prevalent structural motifs in exon recognition remains poorly understood. Here we took advantage of a single-hairpin exon that was activated in a mammalian-wide interspersed repeat (MIR) by a mutation stabilizing a terminal triloop, with splice sites positioned close to each other in a lower stem of the hairpin. We first show that the MIR exon inclusion in mRNA correlated inversely with hairpin stabilities. Employing a systematic manipulation of unpaired regions without altering splice-site configuration, we demonstrate a high correlation between exon inclusion of terminal tri- and tetraloop mutants and matching tri-/tetramers in splicing silencers/enhancers. Loop-specific exon inclusion levels and enhancer/silencer associations were preserved across primate cell lines, in 4 hybrid transcripts and also in the context of a distinct stem, but only if its loop-closing base pairs were shared with the MIR hairpin. Unlike terminal loops, splicing activities of internal loop mutants were predicted by their intramolecular Watson-Crick interactions with the antiparallel strand of the MIR hairpin rather than by frequencies of corresponding trinucleotides in splicing silencers/enhancers. We also show that splicing outcome of oligonucleotides targeting the MIR exon depend on the identity of the triloop adjacent to their antisense target. Finally, we identify proteins regulating MIR exon recognition and reveal a distinct requirement of adjacent exons for C-terminal extensions of Tra2alpha and Tra2beta RNA recognition motifs. PMID- 25826414 TI - The integrity of the G2421-C2395 base pair in the ribosomal E-site is crucial for protein synthesis. AB - During the elongation cycle of protein biosynthesis, tRNAs traverse through the ribosome by consecutive binding to the 3 ribosomal binding sites (A-, P-, and E- sites). While the ribosomal A- and P-sites have been functionally well characterized in the past, the contribution of the E-site to protein biosynthesis is still poorly understood in molecular terms. Previous studies suggested an important functional interaction of the terminal residue A76 of E-tRNA with the nucleobase of the universally conserved 23S rRNA residue C2394. Using an atomic mutagenesis approach to introduce non-natural nucleoside analogs into the 23S rRNA, we could show that removal of the nucleobase or the ribose 2'-OH at C2394 had no effect on protein synthesis. On the other hand, our data disclose the importance of the highly conserved E-site base pair G2421-C2395 for effective translation. Ribosomes with a disrupted G2421-C2395 base pair are defective in tRNA binding to the E-site. This results in an impaired translation of genuine mRNAs, while homo-polymeric templates are not affected. Cumulatively our data emphasize the importance of E-site tRNA occupancy and in particular the intactness of the 23S rRNA base pair G2421-C2395 for productive protein biosynthesis. PMID- 25826415 TI - Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a ~ 125b cluster function by seed-targeting inhibitors in multiple myeloma cells. AB - BACKGROUND: Berberine (BBR) is a natural alkaloid derived from a traditional Chinese herbal medicine. However, the exact mechanisms underlying the different effects of berberine on MM cells have not been fully elucidated. METHODS: A systematic analysis assay integrated common signaling pathways modulated by the 3 miRNA clusters and mRNAs in MM cells after BBR treatment. The role of the mir-99a ~ 125b cluster, an important oncomir in MM, was identified by comparing the effects of t-anti-mirs with complete complementary antisense locked nucleic acids (LNAs) against mature mir-125b (anti-mir-125b). RESULTS: Three miRNAs clusters (miR-99a ~ 125b, miR-17 ~ 92 and miR-106 ~ 25) were significantly down-regulated in BBR-treated MM cells and are involved in multiple cancer-related signaling pathways. Furthermore, the top 5 differentially regulated genes, RAC1, NFkappaB1, MYC, JUN and CCND1 might play key roles in the progression of MM. Systematic integration revealed that 3 common signaling pathways (TP53, Erb and MAPK) link the 3 miRNA clusters and the 5 key mRNAs. Meanwhile, both BBR and seed-targeting t-anti-mir-99a ~ 125b cluster LNAs significantly induced apoptosis, G2-phase cell cycle arrest and colony inhibition. CONCLUSIONS: our results suggest that BBR suppresses multiple myeloma cells, partly by down-regulating the 3 miRNA clusters and many mRNAs, possibly through TP53, Erb and MAPK signaling pathways. The mir 99a ~ 125b cluster might be a novel target for MM treatment. These findings provide new mechanistic insight into the anticancer effects of certain traditional Chinese herbal medicine compounds. PMID- 25826417 TI - Non-coding RNAs' partitioning in the evolution of photosynthetic organisms via energy transduction and redox signaling. AB - Ars longa, vita brevis -Hippocrates Chloroplasts and mitochondria are genetically semi-autonomous organelles inside the plant cell. These constructions formed after endosymbiosis and keep evolving throughout the history of life. Experimental evidence is provided for active non-coding RNAs (ncRNAs) in these prokaryote-like structures, and a possible functional imprinting on cellular electrophysiology by those RNA entities is described. Furthermore, updated knowledge on RNA metabolism of organellar genomes uncovers novel inter communication bridges with the nucleus. This class of RNA molecules is considered as a unique ontogeny which transforms their biological role as a genetic rheostat into a synchronous biochemical one that can affect the energetic charge and redox homeostasis inside cells. A hypothesis is proposed where such modulation by non coding RNAs is integrated with genetic signals regulating gene transfer. The implications of this working hypothesis are discussed, with particular reference to ncRNAs involvement in the organellar and nuclear genomes evolution since their integrity is functionally coupled with redox signals in photosynthetic organisms. PMID- 25826416 TI - Mechanistic insights on the Dicer-independent AGO2-mediated processing of AgoshRNAs. AB - Short hairpin RNAs (shRNAs) are widely used for gene knockdown by inducing the RNA interference (RNAi) mechanism, both for research and therapeutic purposes. The shRNA precursor is processed by the RNase III-like enzyme Dicer into biologically active small interfering RNA (siRNA). This effector molecule subsequently targets a complementary mRNA for destruction via the Argonaute 2 (AGO2) complex. The cellular role of Dicer concerns the processing of pre-miRNAs into mature microRNA (miRNA). Recently, a non-canonical pathway was reported for the biogenesis of miR-451, which bypasses Dicer and is processed instead by the slicer activity of AGO2, followed by the regular AGO2-mediated mRNA targeting step. Interestingly, shRNA designs that are characterized by a relatively short basepaired stem also bypass Dicer to be processed by AGO2. We named this design AgoshRNA as these molecules depend on AGO2 both for processing and silencing activity. In this study, we investigated diverse mechanistic aspects of this new class of AgoshRNA molecules. We probed the requirements for AGO2-mediated processing of AgoshRNAs by modification of the proposed cleavage site in the hairpin. We demonstrate by deep sequencing that AGO2-processed AgoshRNAs produce RNA effector molecules with more discrete ends than the products of the regular shRNA design. Furthermore, we tested whether trimming and tailing occurs upon AGO2-mediated processing of AgoshRNAs, similar to what has been described for miR 451. Finally, we tested the prediction that AgoshRNA activity, unlike that of regular shRNAs, is maintained in Dicer-deficient cell types. These mechanistic insights could aid in the design of optimised AgoshRNA tools and therapeutics. PMID- 25826418 TI - Inuit Elderly: A Systematic Review of Peer Reviewed Journal Articles. AB - Over the last century, Inuit have experienced rapid social changes that have greatly impacted their way of life, health, and intergenerational traditions. Although there is a growing body of research concerning Inuit youth, relatively little is known about elderly Inuit. In an effort to bridge this knowledge gap, a systematic review of peer-reviewed journal articles was conducted. This review identified a dearth of research on older Inuit, and highlighted limitations in service provision to this primarily rural and isolated population. Implications for policy and practice and recommendations for future research are also discussed. PMID- 25826419 TI - Using molecular rotors to probe gelation. AB - A series of fluorescent probes, including a number of molecular rotors, have been used to follow the self-assembly of dipeptide-based low molecular weight gelators. We show that these probes can be used to gain an insight into the assembly process. Thioflavin T, a commonly used stain for beta-sheets, appears to act as a molecular rotor in these gelling systems, with the fluorescence data closely matching that of other rotors. The molecular rotor was incorporated into an assay system with glucose oxidase to enable glucose-concentration specific gelation and hence generating a fluorescent output. Applying this system to urine from patients with various levels of glycosuria (a symptom of diabetes), it was found to provide excellent correlation with different clinical assessments of diabetes. This demonstrates a new concept in gelation-linked biosensing for a real clinical problem. PMID- 25826423 TI - Re-Evaluating Cyclosporine A as a Hair Growth-Promoting Agent in Human Scalp Hair Follicles. PMID- 25826421 TI - The effects of antidepressants "fluoxetine and imipramine" on vascular abnormalities and Toll like receptor-4 expression in diabetic and non-diabetic rats exposed to chronic stress. AB - Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes. METHOD: We investigated the effect of chronic administration of fluoxetine "FLU" and imipramine "IMIP" on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). RESULTS: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-alpha and IL 1beta). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters. CONCLUSION: FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects. PMID- 25826424 TI - Retinoids Bias Integrin Expression and Function in Cutaneous T-Cell Lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of malignancies characterized by accumulation of malignant T-cells within the skin. Retinoids, metabolic derivatives, and synthetic analogs of vitamin A embody an effective CTCL therapy with over three decades of clinical use. The established mechanism of action is induction of growth arrest and apoptosis. However, the natural role of retinoids in T-cell biology is imprinting gut-homing properties by inducing integrin alpha4beta7 expression. How the natural role of retinoids relates to therapeutic effectiveness in CTCL has not been addressed and merits investigation. Here we provide evidence that retinoids, including Bexarotene, selectively induce CTCL lineages to increase integrin beta7 expression and function prior to growth arrest and apoptosis. Interestingly, augmented CTCL cell adhesion obtained with retinoid exposure was potently attenuated by 1,25 dihydroxyvitamin D3, a metabolic vitamin derivative involved in prompting immune cell skin homing. The integrin-dependent adhesion changes in CTCL cells occurred through synergistic activation of RAR and RXR nuclear receptors. These data explore the early cellular changes induced by retinoids that may be pivotal to sensitizing CTCL cells to growth arrest and apoptosis. PMID- 25826422 TI - The Immune Response to Skin Trauma Is Dependent on the Etiology of Injury in a Mouse Model of Burn and Excision. AB - Skin trauma has many different causes including incision, blunt force, and burn. All of these traumas trigger an immune response. However, it is currently unclear whether the immune response is specific to the etiology of the injury. This study was established to determine whether the immune response to excision and burn injury of equivalent extent was the same. Using a mouse model of a full-thickness 19 mm diameter excision or 19 mm diameter full-thickness burn injury, we examined the innate immune response at the level of serum cytokine induction, whole-blood lymphocyte populations, dendritic cell function/phenotype, and the ensuing adaptive immune responses of CD4 and CD8 T-cell populations. Strikingly, both the innate and adaptive immune system responses differed between the burn and excision injuries. Acute cytokine induction was faster and different in profile to that of excision injury, leading to changes in systemic monocyte and neutrophil levels. Differences in the immune profile between burn and excision were also noted up to day 84 post injury, suggesting that the etiology of injury leads to sustained changes in the response. This may in part underlie clinical observations of differences in patient morbidity and mortality in response to different skin injury types. PMID- 25826426 TI - Selective Synthesis of cis-trans-cis Cyclic Tetrasiloxanes and the Formation of Their Two-Dimensional Layered Aggregates. AB - In this study, a single cyclic tetrasiloxane containing propylammonium trifluoromethanesulfonate and methyl side-chain groups (Am-CyTS) was selectively prepared by the hydrolytic condensation of 3-aminopropyldiethoxymethylsilane using aqueous superacid trifluoromethanesulfonic acid. The (1)H NMR spectrum of Am-CyTS in D2O exhibited a single signal assigned to a methyl group, and the (29)Si NMR spectrum of Am-CyTS in DMSO-d6 also exhibited only one signal. In the matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and the electrospray ionization mass spectrometry (ESI MS) analyses, the peaks corresponding to the masses of the cyclic tetrasiloxane were observed. These results indicate that Am-CyTS is a single cyclic tetrasiloxane without isomers. In addition, the result of a single-crystal X-ray structural analysis of its tert-butoxycarbonyl (Boc)-protected compound (Boc-CyTS) indicated the formation of a cis-trans-cis cyclic tetrasiloxane forming two-dimensional layered aggregates. Moreover, it was found that two-dimensional layered aggregates could be formed by drop-casting an aqueous solution of Am-CyTS and chloroform solution of Boc-CyTS onto glass substrates, as shown by powder X-ray diffraction measurements. PMID- 25826425 TI - TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus. AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-kappaB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention. PMID- 25826428 TI - Atomic layer deposition of quaternary oxide (La,Sr)CoO3-delta thin films. AB - A novel atomic layer deposition (ALD) process was developed for fabricating quaternary cobalt oxide (La1-xSrx)CoO3-delta thin films having the eye on future applications of such films in e.g. solid oxide fuel cell cathodes, oxygen separation membranes or thermocouples. The deposition parameters and the conditions of a subsequent annealing step were systematically investigated, and using the thus optimized parameters the cation stoichiometry in the films could be accurately tuned. The most detailed study was conducted for x = 0.7, i.e. the composition with the highest application potential within the (La1-xSrx)CoO3 delta system. PMID- 25826429 TI - Enhancing separation in short-capillary electrophoresis via pressure-driven backflow. AB - We present a novel easy-to-operate and efficient method to improve the separation efficiency in short-capillary electrophoresis by introducing steady backflow to counterbalance electro-osmotic flow without the use of any external pressure. The backflow was easily generated by tapering the capillary end, which was achieved by heating a straight capillary and stretching it with a constant force. We investigated the net fluidic transport rate under different tip lengths and separation voltages. Good run-to-run repeatability and capillary-to-capillary reproducibility of the present method were obtained with RSD less than 1.5%, indicating the stability of the fluid transport rate in the tapered capillary, which ensures the quantification and repeatability of capillary zone electrophoresis (CZE) analysis. Enhanced separation of the tapered short capillary electrophoresis was demonstrated by CZE analyzing amino acids and positional isomers. Baseline separations were achieved in less than 60 s using a tapered capillary with the effective length of 5 cm, while no separation was achieved using a normal capillary without a tapered tip. The present study provides a promising method to use pressure-driven backflow to enhance separation efficiency in short-capillary electrophoresis, which would be of potential value in a wide application for fast analysis of complex samples. PMID- 25826427 TI - Development of circadian oscillators in neurosphere cultures during adult neurogenesis. AB - Circadian rhythms are common in many cell types but are reported to be lacking in embryonic stem cells. Recent studies have described possible interactions between the molecular mechanism of circadian clocks and the signaling pathways that regulate stem cell differentiation. Circadian rhythms have not been examined well in neural stem cells and progenitor cells that produce new neurons and glial cells during adult neurogenesis. To evaluate circadian timing abilities of cells undergoing neural differentiation, neurospheres were prepared from the mouse subventricular zone (SVZ), a rich source of adult neural stem cells. Circadian rhythms in mPer1 gene expression were recorded in individual spheres, and cell types were characterized by confocal immunofluorescence microscopy at early and late developmental stages in vitro. Circadian rhythms were observed in neurospheres induced to differentiate into neurons or glia, and rhythms emerged within 3-4 days as differentiation proceeded, suggesting that the neural stem cell state suppresses the functioning of the circadian clock. Evidence was also provided that neural stem progenitor cells derived from the SVZ of adult mice are self-sufficient clock cells capable of producing a circadian rhythm without input from known circadian pacemakers of the organism. Expression of mPer1 occurred in high frequency oscillations before circadian rhythms were detected, which may represent a role for this circadian clock gene in the fast cycling of gene expression responsible for early cell differentiation. PMID- 25826430 TI - Coxsackie Virus A16 Infection of Placenta with Massive Perivillous Fibrin Deposition Leading to Intrauterine Fetal Demise at 36 Weeks Gestation. AB - Massive perivillous fibrin deposition (MPFD) is an uncommon placental disorder, associated with significant fetal morbidity, mortality, and recurrence; its etiology is unknown. We describe a 31-year-old mother, diagnosed with Coxsackievirus infection and hand-foot-and-mouth disease at 35 weeks gestation. Ultrasound at 35 weeks revealed a normal fetus and placenta. One week later, the mother experienced decreased fetal movement and ultrasound demonstrated intrauterine demise. The autopsy showed mild, acute pericarditis and hypoxic ischemic encephalopathy. Placenta examination showed MPFD involving 80% of the parenchyma. Molecular viral analysis and serotyping showed Coxsackie A16 virus. The mother had an uneventful pregnancy 15 months later. Coxsackievirus infections in pregnant mothers are often asymptomatic. Transplacental Coxsackievirus infection is very rare but is associated with spontaneous abortion, intrauterine demise, or serious neonatal morbidity. Mild, nonspecific histologic changes have been reported in the placenta. To our knowledge, this is the first report of MPFD associated with Coxsackievirus infection. PMID- 25826431 TI - Generation of peanut drought tolerant plants by pingyangmycin-mediated in vitro mutagenesis and hydroxyproline-resistance screening. AB - In order to enlarge the potential resources of drought-tolerant peanuts, we conducted in vitro mutagenesis with Pingyangmycin (PYM) as the mutagen as well as directed screening on a medium supplemented with Hydroxyproline (HYP). After being extracted from mature seeds (cv. Huayu 20), the embryonic leaflets were cultured on somatic embryogenesis-induction medium with 4 mg/L PYM and the generated embryos were successively transferred to a germination medium with 4 and then 8 mmol/L HYP to screen HYP-tolerant plantlets. After that, these plantlets were grafted and transplanted to the experimental field. In the next generation, all seeds were sown in the field, and phenotype variation and trait segregation can be observed in most of the offspring (M2 generation). The M3 generation individuals were subjected to drought stress at the seedling stages. The activities of SOD and POD were substantially increased in eight offspring of 11 HYP-tolerant, regenerated plants than in their mutagenic parents. To determine the correlation between mutant phenotypes and genomic modification, we carried out a comparison of the DNA polymorphisms between the mutagenic parents and 13 M3 generation individuals from different HYP-tolerant, regenerated plants with SSR primers. Results showed that most mutants and parent plants had signs of polymorphisms. Under drought stress, some M3 generation individuals of 10 original HYP-tolerant, regenerated plants produced more pods than the mutagenic parent; twenty individuals among them produced >60 g pods/plant. M4-generation seeds were tested for quality characteristics by Near Infrared Spectroscopy (NIS) and nine individuals with higher protein content (>30%) and 21 individuals with higher oil content (>58%) were screened. We concluded that the use of PYM-based in vitro mutagenesis in combination with directed screening with HYP is effective for the creation of potential drought-tolerant mutants of peanut. PMID- 25826432 TI - Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects. AB - Cytokines are important mediators of various aspects of health and disease, including appetite, glucose and lipid metabolism, insulin sensitivity, skeletal muscle hypertrophy and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in the circulating concentrations of interleukin (IL)-6, IL-8, IL- 10, IL-1 receptor antagonist, granulocyte-colony stimulating factor, and smaller increases in tumor necrosis factor-alpha, monocyte chemotactic protein-1, IL-1beta, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many of these cytokines are also expressed in skeletal muscle, not all are released from skeletal muscle into the circulation during exercise. Conversely, some cytokines that are present in the circulation are not expressed in skeletal muscle after exercise. The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources of circulating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate cytokine synthesis (e.g., RNA-binding proteins, microRNAs, suppressor of cytokine signaling proteins, soluble receptors). PMID- 25826433 TI - The relationship between core self-evaluations, views of god, and intrinsic/extrinsic religious motivation. AB - Core self-evaluations refer to a higher-order construct that subsumes four well established traits in the personality literature: self-esteem, generalized self efficacy, (low) neuroticism, and (internal) locus of control. Studies that have examined the relationship between various measures of religiosity and individual components of core self-evaluations show no clear pattern of relationships. The absence of a clear pattern may be due to the failure of most previous studies in this area to use theory to guide research. Therefore, theories related to core self-evaluations, religious motivation, and views of God were used to develop and test four hypotheses. 220 adults completed measures of four religious attitudes (intrinsic religious motivation, extrinsic religious motivation, viewing God as loving, and viewing God as punitive), general religiosity, and core self evaluations, separated by 6 weeks (with the order of measures counterbalanced). Multivariate multiple regression, controlling for general religiosity, showed that core self-evaluations were positively related to viewing God as loving, negatively related to viewing God as punitive, and negatively related to extrinsic religious motivation. The hypothesis that core self-evaluations would be positively related to intrinsic religious motivation was not supported. PMID- 25826434 TI - Validation of an Arabic version of the GHQ-28 against the Beck depression inventory for screening for depression in war-exposed civilians. AB - This study estimates the psychometric properties of the Arabic GHQ-28 against the BDI-II for screening for depression in war-exposed civilians. Two data sets collected in a civilian sample from South Lebanon were analyzed. Internal consistency in the two samples was high for the GHQ-28 (0.91 and 0.80) and the BDI-II (0.88 and 0.84). The BDI-II was significantly correlated with the GHQ-28 total score and the Depression subscale. The GHQ-28 yielded similar findings for depression cut-off scores compared to the BDI-II: for the GHQ-28 total score, a cut-off at 5/6 is recommended for detecting "severe/moderate" depression, and 8/9 for "severe" only, while from the Depression subscale analysis the recommendation was to use 8/9 as a cutoff for "severe/moderate" and 9/10 for "severe" depression. The Arabic GHQ-28 was found to be a valid instrument for screening for depression in the studied population. PMID- 25826435 TI - Reliability and validity of the Japanese version of the coping inventory for adults for stressful situations in healthy people. AB - The present study examined the validity and reliability of the Japanese version of the Coping Inventory for Stressful Situations-2nd EditionTM (CISS; hereafter the CISS-J). The participants were 1,268 healthy Japanese individuals. The factor analyses yielded three major scales (task-, emotion-, and avoidance-oriented coping) corresponding to the original version. In addition, the avoidance oriented scale of the CISS-J contained two subscales (Distraction and Social diversion), as in the original version. Cronbach's alpha coefficient was found to be .75-.89 for the three scales and two subscales. Results show that the CISS-J is useful for assessing the coping strategies among this sample of Japanese individuals. PMID- 25826436 TI - Turkish version of the Academic Motivation Scale. AB - The purpose of this study was to adapt the college version of the Academic Motivation Scale (AMS) into Turkish. The participants were 797 college students (437 men, 360 women) with a mean age of 20.1 yr. A seven-factor model of the scale, as well as alternative models (five-, three-, two-, and one-factor models) were investigated and compared through confirmatory factor analysis. The seven factor model demonstrated adequate fit to the data. The fit indices obtained from the five-factor model were acceptable also. Hancock's coefficient H values and test-retest correlation coefficients of the subscales indicated that reliability of the scale was adequate except for the identified regulation subscale. The CFA conducted for the groups of men and women produced more acceptable fit indices values for men than women, but women obtained significantly higher scores from the AMS subscales. Correlations among the seven subscales partially supported the simplex pattern which claims that the neighboring subscales should have stronger positive correlations than the non-neighboring subscales and that the subscales which are the farthest apart should have the strongest negative relationships. PMID- 25826437 TI - Inhibitory Effects of (2'R)-2',3'-dihydro-2'-(1-hydroxy-1-methylethyl)-2,6' bibenzofuran-6,4'-diol on Mushroom Tyrosinase and Melanogenesis in B16-F10 Melanoma Cells. AB - (2'R)-2',3'-Dihydro-2'-(1-hydroxy-1-methylethyl)-2,6'-bibenzofuran-6,4'-diol (DHMB) is a natural compound extracted from Morus notabilis. It was found that DHMB acts as a competitive inhibitor against mushroom tyrosinase with a Ki value of 14.77 MUM. Docking results further indicated that it could form strong interactions with one copper ion with a distance of 2.7 A, suggesting the mechanism of inhibition might be due to chelating copper ions in the active site. Furthermore, melanin production in B16-F10 murine melanoma cells was significantly inhibited by DHMB in a concentration-dependent manner without cytotoxicity. The results of western blotting also showed that DHMB decreased 3 isobuty-1-methxlzanthine-induced mature tyrosinase expression. Taken together, these findings indicated that DHMB may be a new promising pigmentation-altering agent for agriculture, cosmetic, and therapeutic applications. PMID- 25826438 TI - 28th Congress of the Italian Society of Neonatology - Lombardy section | Bergamo, 30-31 January 2015. AB - This abstract book contains the abstracts presented at the 28th Congress of the Italian Society of Neonatology - Lombardy section | Bergamo, 30-31 January 2015. PMID- 25826439 TI - Noncontrast Magnetic Resonance Lymphography. AB - BACKGROUND: Different imaging techniques have been used for the investigation of the lymphatic channels and lymph glands. Noncontrast magnetic resonance (MR) lymphography has significant advantages in comparison with other imaging modalities. METHODS: Noncontrast MR lymphography uses very heavily T2-weighted fast spin echo sequences which obtain a nearly complete signal loss in tissue background and specific display of lymphatic vessels with a long T2 relaxation time. The raw data can be processed with different algorithms such as maximum intensity projection algorithm to obtain an anatomic representation. RESULTS: Standard T2-weighted MR images easily demonstrate the location of edema. It appears as subcutaneous infiltration of soft tissue with a classical honeycomb pattern. True collection around the muscular area may be demonstrated in case of severe lymphedema. Lymph nodes may be normal in size, number, and signal intensity; in other cases, lymph nodes may be smaller in size or number of lymph nodes may be restricted. MR lymphography allows a classification of lymphedema in aplasia (no collecting vessels demonstrated); hypoplasia (a small number of lymphatic vessels), and numerical hyperplasia or hyperplasia (with an increased number of lymphatic vessels of greater and abnormal diameter). CONCLUSION: Noncontrast MR lymphography is a unique noninvasive imaging modality for the diagnosis of lymphedema. It can be used for positive diagnosis, differential diagnosis, and specific evaluation of lymphedema severity. It may also be used for follow-up evaluation after treatment. PMID- 25826440 TI - Vasopressor-Dependent Recipient Vessel Blood Flow in Head and Neck Free Tissue Transfer: A Report of Two Cases. PMID- 25826441 TI - Late-Start Days Increase Total Operative Time in Microvascular Breast Reconstruction. AB - BACKGROUND: Prolonged operative time has been associated with increased postoperative complications and higher costs. Many academic centers have a designated day for didactics that cause cases to start 1 hour later. The purpose of this study is to analyze the late-start effect of microvascular breast reconstructions on operative duration. METHODS: A retrospective review was performed on all patients who underwent abdomina-based free flap breast reconstruction from 2007 to 2011 and analyzed by those who had surgery on late start versus normal-start days. Patient demographics, average operative time, postoperative complications, and individual surgeon effects were analyzed. A Student t-test was used to compare operative times with statistical significance set at p < 0.05. A multivariate regression analysis was performed to control for potential confounders. RESULTS: A total of 272 patients underwent 461 free flap breast reconstructions. Twenty-one cases were performed on late-start days and 251 cases were performed on normal-start days. Patient demographics and complications were not statistically different between the groups. The average operative time for all reconstructions was 434.3 minutes. The average operative times were significantly longer for late-start days, 517.6 versus 427.3 minutes (p = 0.002). This was true for both unilateral and bilateral reconstructions (432.8 vs. 350.9 minutes, p = 0.05; 551.5 vs. 461.2 minutes, p = 0.007). There were no differences in perioperative complications and multivariate regression showed no statistically significant relationship of confounders to duration of surgery. CONCLUSION: Starting cases 1 hour later can increase operative times. Although outcomes were not affected, we recommend avoiding lengthy procedures on late-start days. PMID- 25826442 TI - Overcoming the Obstacles of the Ilizarov Device in Extremity Reconstruction: Usefulness of the Perforator as the Recipient Vessel. AB - BACKGROUND: When patients using the Ilizarov device need a free-flap procedure for their thigh and leg, it is difficult to isolate the major vessels as the recipient vessel due to the limited working space around the Ilizarov rings and pins. The usefulness of a perforator as the recipient vessel to allow minimally invasive surgery was investigated in this study. METHODS: Between October 2011 and December 2013, 77 patients using the Ilizarov device needed free flap reconstruction using an anterolateral thigh perforator flap or superficial circumflex iliac artery perforator flap. The perforator was used as a recipient vessel in 50 cases, with which end-to-end anastomosis was performed using a perforator-to-perforator approach, and major vessels were used as a recipient vessel in 27 cases (n = 20, anterior tibial vessel; n = 7, posterior vessel). RESULTS: When the perforator was used as the recipient vessel, total loss developed in one case and marginal necrosis in four cases. When the major vessel was used as the recipient vessel, whole necrosis developed in one case and marginal necrosis in two cases. The procedure increased the freedom of hand movement, decreased the recipient vessel dissection time, and reduced the recipient dissection scar. CONCLUSIONS: The use of perforators as recipients overcomes the obstacles associated with the Ilizarov device and allows convenient and rapid reconstruction, with similar success as microsurgery using major vessels. Further studies are needed to address the limitations of this approach, which include perfusion physiology and the viable limit of the flap dimension. PMID- 25826443 TI - A multi-responsive water-driven actuator with instant and powerful performance for versatile applications. AB - Mechanical actuators driven by water that respond to multiple stimuli, exhibit fast responses and large deformations, and generate high stress have potential in artificial muscles, motors, and generators. Meeting all these requirements in a single device remains a challenge. We report a graphene monolayer paper that undergoes reversible deformation. Its graphene oxide cells wrinkle and extend in response to water desorption and absorption, respectively. Its fast (~0.3 s), powerful (>100 MPa output stress, 7.5 * 10(5) N kg(-1) unit mass force), and controllable actuation can be triggered by moisture, heat, and light. The graphene monolayer paper has potential in artificial muscles, robotic hands, and electromagnetic-free generators. PMID- 25826444 TI - Direct measurements show decreasing methane emissions from natural gas local distribution systems in the United States. AB - Fugitive losses from natural gas distribution systems are a significant source of anthropogenic methane. Here, we report on a national sampling program to measure methane emissions from 13 urban distribution systems across the U.S. Emission factors were derived from direct measurements at 230 underground pipeline leaks and 229 metering and regulating facilities using stratified random sampling. When these new emission factors are combined with estimates for customer meters, maintenance, and upsets, and current pipeline miles and numbers of facilities, the total estimate is 393 Gg/yr with a 95% upper confidence limit of 854 Gg/yr (0.10% to 0.22% of the methane delivered nationwide). This fraction includes emissions from city gates to the customer meter, but does not include other urban sources or those downstream of customer meters. The upper confidence limit accounts for the skewed distribution of measurements, where a few large emitters accounted for most of the emissions. This emission estimate is 36% to 70% less than the 2011 EPA inventory, (based largely on 1990s emission data), and reflects significant upgrades at metering and regulating stations, improvements in leak detection and maintenance activities, as well as potential effects from differences in methodologies between the two studies. PMID- 25826445 TI - Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK. AB - Irisin is a novel myokine produced by skeletal muscle. However, its metabolic role is poorly understood. In the present study, irisin induced glucose uptake in differentiated skeletal muscle cells. It increased AMP-activated protein kinase (AMPK) phosphorylation and the inhibition of AMPK blocked glucose uptake. It also increased reactive oxygen species (ROS) generation. N-acetyl cysteine, a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 MAPK in an AMPK-dependent manner. The inhibition and knockdown of p38 MAPK blocked irisin-induced glucose uptake. A colorimetric absorbance assay showed that irisin stimulated the translocation of glucose transporter type 4 to the plasma membrane and that this effect was suppressed in cells pretreated with a p38 MAPK inhibitor or p38 MAPK small interfering RNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO 609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, blocked irisin-induced AMPK phosphorylation, implying that calcium is involved in irisin mediated signaling. Our results suggest that irisin plays an important role in glucose metabolism via the ROS-mediated AMPK pathway in skeletal muscle cells. PMID- 25826446 TI - Stand competition determines how different tree species will cope with a warming climate. AB - Plant-plant interactions influence how forests cope with climate and contribute to modulate species response to future climate scenarios. We analysed the functional relationships between growth, climate and competition for Pinus sylvestris, Quercus pyrenaica and Quercus faginea to investigate how stand competition modifies forest sensitivity to climate and simulated how annual growth rates of these species with different drought tolerance would change throughout the 21st century. Dendroecological data from stands subjected to thinning were modelled using a novel multiplicative nonlinear approach to overcome biases related to the general assumption of a linear relationship between covariates and to better mimic the biological relationships involved. Growth always decreased exponentially with increasing competition, which explained more growth variability than climate in Q. faginea and P. sylvestris. The effect of precipitation was asymptotic in all cases, while the relationship between growth and temperature reached an optimum after which growth declined with warmer temperatures. Our growth projections indicate that the less drought tolerant P. sylvestris would be more negatively affected by climate change than the studied sub-Mediterranean oaks. Q. faginea and P. sylvestris mean growth would decrease under all the climate change scenarios assessed. However, P. sylvestris growth would decline regardless of the competition level, whereas this decrease would be offset by reduced competition in Q. faginea. Conversely, Q. pyrenaica growth would remain similar to current rates, except for the warmest scenario. Our models shed light on the nature of the species-specific interaction between climate and competition and yield important implications for management. Assuming that individual growth is directly related to tree performance, trees under low competition would better withstand the warmer conditions predicted under climate change scenarios but in a variable manner depending on the species. Thinning following an exponential rule may be desirable to ensure long-term conservation of high-density Mediterranean woodlands, particularly in drought limited sites. PMID- 25826447 TI - Electron microscopy of solid catalysts--transforming from a challenge to a toolbox. PMID- 25826448 TI - Associations between health literacy and health outcomes in a predominantly low income african american population with type 2 diabetes. AB - Inadequate health literacy has been associated with poorer health behaviors and outcomes in individuals with diabetes or depression. This study was conducted to examine the associations between inadequate health literacy and behavioral and cardiometabolic parameters in individuals with type 2 diabetes and to explore whether these associations are affected by concurrent depression. The authors used cross-sectional data from a study of 343 predominantly African Americans with type 2 diabetes. Inadequate health literacy was significantly and modestly associated with diabetes knowledge (r = -0.34) but weakly associated with self efficacy (r = 0.16) and depressive symptoms (r = 0.24). In multivariate regression models, there were no associations between health literacy and A1c, blood pressure, or body mass index or control of any of these parameters. There was no evidence that depression was an effect-modifier of the associations between health literacy and outcomes. Although inadequate health literacy was modestly associated with worse knowledge and weakly associated with self efficacy, it was not associated with any of the cardiometabolic parameters the authors studied. Because this study showed no association between health literacy and behavioral and cardiometabolic outcomes, it is unseemly and premature to embark on trials or controlled interventions to improve health literacy for the purposes of improving patient-related outcomes in diabetes. PMID- 25826449 TI - Young's Modulus, Residual Stress, and Crystal Orientation of Doubly Clamped Silicon Nanowire Beams. AB - Initial or residual stress plays an important role in nanoelectronics. Valley degeneracy in silicon nanowires (SiNWs) is partially lifted due to built-in stresses, and consequently, electron-phonon scattering rate is reduced and device mobility and performance are improved. In this study we use a nonlinear model describing the force-deflection relationship to extract the Young's modulus, the residual stress, and the crystallographic growth orientation of SiNW beams. Measurements were performed on suspended doubly clamped SiNWs subjected to atomic force microscopy (AFM) three-point bending constraints. The nanowires comprised different growth directions and two SiO2 sheath thicknesses, and underwent different rapid thermal annealing processes. Analysis showed that rapid thermal annealing introduces compressive strains into the SiNWs and may result in buckling of the SiNWs. Furthermore, the core-shell model together with the residual stress analysis accurately describe the Young's modulus of oxide covered SiNWs and the crystal orientation of the measured nanowires. PMID- 25826450 TI - Systematic review of expert elicitation methods as a tool for source attribution of enteric illness. AB - Expert elicitation is a useful tool to explore sources of uncertainty and to answer questions where data are expensive or difficult to collect. It has been used across a variety of disciplines and represents an important method for estimating source attribution for enteric illness. A systematic review was undertaken to explore published expert elicitation studies, identify key considerations, and to make recommendations for designing an expert elicitation in the context of enteric illness source attribution. Fifty-nine studies were reviewed. Five key themes were identified: the expert panel including composition and recruitment; the pre-elicitation material, which clarifies the research question and provides training in uncertainty and probability; the choice of elicitation tool and method (e.g., questionnaires, surveys, and interviews); research design; and analysis of elicited data. Careful consideration of these themes is critical in designing and implementing an expert elicitation in order to reduce bias and produce the best possible results. While there are various epidemiological and microbiological methods available to explore source attribution of enteric illness, expert elicitation provides an opportunity to identify gaps in our understanding and where such studies are not feasible or available, represents the only possible method for synthesizing knowledge about transmission. PMID- 25826451 TI - Social behavior and the microbiome. PMID- 25826452 TI - Giving rituximab in patients with occult or resolved hepatitis B virus infection: are the current guidelines good enough? AB - INTRODUCTION: Hepatitis B virus (HBV) reactivation after 'resolved' infection can occur in the setting of immunosuppression, including iatrogenically induced by anti-CD20 antibodies. The presence of antibodies against the HBV core antigen (anti-HBc) is a marker of risk for this phenomenon. The risk of this occurring in patients with circulating HBV surface antigen (HBsAg) is well characterized, but is less well characterized in patients who are HBsAg negative. AREAS COVERED: This article reviews the literature regarding HBV reactivation in the context of rituximab therapy. We have limited our review to HBsAg-negative patients, and clinical outcomes following HBV reactivation. EXPERT OPINION: We have recommended prophylactic anti-viral therapy for all HBsAg-negative/anti-HBc-positive patients undergoing rituximab therapy in combination with other immunosuppressive therapy. PMID- 25826453 TI - Endoscopic enucleation versus open prostatectomy for treating large benign prostatic hyperplasia: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: To evaluate the overall efficacy and safety of endoscopic enucleation of the prostate (EP) vs open prostatectomy (OP) for large benign prostatic hyperplasia (BPH). METHODS: We conducted an electronic search of PubMed/Medline, EMBASE, The Cochrane Library, and Web of Science to detect all relevant randomized controlled trials (RCTs) comparing EP with OP. A meta-analysis was performed using Review Manager 5.3. RESULTS: Seven RCTs (735 patients) were included. At the 3-, 6- and 12-month follow-up, there were no significant differences in the International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), quality of life (QoL) score and post-void residual urine volume (PVR) between EP and OP. The International Index of Erectile Function (IIEF-5) was higher with EP (weighted mean difference [WMD]: 1.00, 95% confidence interval [CI]: 0.21 to 1.78, p=0.01) at the 12-month follow-up. The catheterization time (WMD: 3.80 d, 95%CI: -5.11 to -2.48, P<0.00001) and hospital stay (WMD: 4.93 d, 95%CI: -5.96 to -3.89, P<0.00001) were shorter with EP. The duration of operation was longer for EP compared with OP (WMD: 16.21 min, 95%CI: 3.72 to 28.70, P=0.01). The resected tissue weight (WMD: -9.63 g, 95%CI: -14.46 to -4.81, P<0.0001) and decrease in hemoglobin (WMD: -1.14 g/dL, 95%CI: -1.81 to -0.47, P=0.0008) were less with EP. EP was associated with fewer blood transfusions (risk ratio: 0.22, 95%CI: 0.10 to 0.47, P=0.0001). There were no significant differences between EP and OP when comparing other complications. CONCLUSIONS: Although only a limited number of RCTs with relatively limited follow-up are available, EP is shown to have a similar postoperative profile and comparable safety to OP. By contrast, EP may have a more desirable perioperative profile. EP appears to be an effective and safe minimally invasive option for treating large prostates that requires only brief convalescence. PMID- 25826454 TI - Expression of the immunoglobulin superfamily cell adhesion molecules in the developing spinal cord and dorsal root ganglion. AB - Cell adhesion molecules belonging to the immunoglobulin superfamily (IgSF) control synaptic specificity through hetero- or homophilic interactions in different regions of the nervous system. In the developing spinal cord, monosynaptic connections of exquisite specificity form between proprioceptive sensory neurons and motor neurons, however, it is not known whether IgSF molecules participate in regulating this process. To determine whether IgSF molecules influence the establishment of synaptic specificity in sensory-motor circuits, we examined the expression of 157 IgSF genes in the developing dorsal root ganglion (DRG) and spinal cord by in situ hybridization assays. We find that many IgSF genes are expressed by sensory and motor neurons in the mouse developing DRG and spinal cord. For instance, Alcam, Mcam, and Ocam are expressed by a subset of motor neurons in the ventral spinal cord. Further analyses show that Ocam is expressed by obturator but not quadriceps motor neurons, suggesting that Ocam may regulate sensory-motor specificity in these sensory-motor reflex arcs. Electrophysiological analysis shows no obvious defects in synaptic specificity of monosynaptic sensory-motor connections involving obturator and quadriceps motor neurons in Ocam mutant mice. Since a subset of Ocam+ motor neurons also express Alcam, Alcam or other functionally redundant IgSF molecules may compensate for Ocam in controlling sensory-motor specificity. Taken together, these results reveal that IgSF molecules are broadly expressed by sensory and motor neurons during development, and that Ocam and other IgSF molecules may have redundant functions in controlling the specificity of sensory-motor circuits. PMID- 25826457 TI - High-resolution and large-area nanoparticle arrays using EUV interference lithography. AB - Well-defined model systems are needed for better understanding of the relationship between optical, electronic, magnetic, and catalytic properties of nanoparticles and their structure. Chemical synthesis of metal nanoparticles results in large size and shape dispersion and lack of lateral order. In contrast, conventional top-down lithography techniques provide control over the lateral order and dimensions. However, they are either limited in resolution or have low throughput and therefore do not enable the large patterning area needed to obtain good signal-to-noise ratio in common analytical and characterization techniques. Extreme ultraviolet (EUV) lithography has the throughput and simplicity advantages of photolithography as well as high resolution due to its wavelength. Using EUV achromatic Talbot lithography, we have obtained 15 nm particle arrays with a periodicity of about 100 nm over an area of several square centimeters with high-throughput enabling the use of nanotechnology for fabrication of model systems to study large ensembles of well-defined identical nanoparticles with a density of 10(10) particles cm(-2). PMID- 25826456 TI - Comparative phylogeography of Mississippi embayment fishes. AB - The Mississippi Embayment is a prominent physiographic feature of eastern North America consisting of primarily lowland aquatic habitats and a fish fauna that is largely distinct from nearby highland regions. Numerous studies have demonstrated that both pre-Pleistocene and Pleistocene events have had a strong influence on the distributions and relationships of highland fishes in eastern North America. However, the extent to which these same events affected Embayment distributed taxa remains largely unexplored. The purpose of this study was to investigate the relative roles of pre-Pleistocene and Pleistocene events in shaping phylogeographic relationships of four stream dwelling fishes in the Mississippi Embayment. Molecular genetic analyses of the mitochondrial gene cytochrome b were performed for three ictalurid catfish species (Noturus miurus, n = 67; Noturus hildebrandi, n = 93, and Noturus phaeus, n = 44) and one minnow species (Cyprinella camura, n = 78), all distributed in tributary streams of the Mississippi Embayment. Phylogenetic relationships and divergence times among haplotypes for each species were estimated using maximum likelihood and Bayesian methods. Phylogenetic analyses recovered 6 major haplotype clades within N. miurus, 5 within N. hildbrandi, 8 within N. phaeus, and 8 within C. camura. All three Noturus species show a high degree of isolation by drainage, which is less evident in C. camura. A clade of haplotypes from tributaries in the southern portion of the Mississippi Embayment was consistently recovered in all four species. Divergence times among clades spanned the Pleistocene, Pliocene, and Miocene. Novel relationships presented here for C. camura and N. phaeus suggest the potential for cryptic species. Pre-Pleistocene and Pleistocene era sea level fluctuations coincide with some divergence events, but no single event explains any common divergence across all taxa. Like their highland relatives, a combination of both pre-Pleistocene and Pleistocene era events have driven divergences among Embayment lineages. PMID- 25826455 TI - Pre-exposure to ionizing radiation stimulates DNA double strand break end resection, promoting the use of homologous recombination repair. AB - The choice of DNA double strand break (DSB) repair pathway is determined at the stage of DSB end resection. Resection was proposed to control the balance between the two major DSB repair pathways, homologous recombination (HR) and non homologous end joining (NHEJ). Here, we examined the regulation of DSB repair pathway choice at two-ended DSBs following ionizing radiation (IR) in G2 phase of the cell cycle. We found that cells pre-exposed to low-dose IR preferred to undergo HR following challenge IR in G2, whereas NHEJ repair kinetics in G1 were not affected by pre-IR treatment. Consistent with the increase in HR usage, the challenge IR induced Replication protein A (RPA) foci formation and RPA phosphorylation, a marker of resection, were enhanced by pre-IR. However, neither major DNA damage signals nor the status of core NHEJ proteins, which influence the choice of repair pathway, was significantly altered in pre-IR treated cells. Moreover, the increase in usage of HR due to pre-IR exposure was prevented by treatment with ATM inhibitor during the incubation period between pre-IR and challenge IR. Taken together, the results of our study suggest that the ATM dependent damage response after pre-IR changes the cellular environment, possibly by regulating gene expression or post-transcriptional modifications in a manner that promotes resection. PMID- 25826458 TI - Electrosynthesis of highly transparent cobalt oxide water oxidation catalyst films from cobalt aminopolycarboxylate complexes. AB - Efficient catalysis of water oxidation represents one of the major challenges en route to efficient sunlight-driven water splitting. Cobalt oxides (CoOx ) have been widely investigated as water oxidation catalysts, although the incorporation of these materials into photoelectrochemical devices has been hindered by a lack of transparency. Herein, the electrosynthesis of transparent CoOx catalyst films is described by utilizing cobalt(II) aminopolycarboxylate complexes as precursors to the oxide. These complexes allow control over the deposition rate and morphology to enable the production of thin, catalytic CoOx films on a conductive substrate, which can be exploited in integrated photoelectrochemical devices. Notably, under a bias of 1.0 V (vs. Ag/AgCl), the film deposited from [Co(NTA)(OH2 )2 ](-) (NTA=nitrilotriacetate) decreased the transmission by only 10 % at lambda=500 nm, but still generated >80 % of the water oxidation current produced by a [Co(OH2 )6 ](2+) -derived oxide film whose transmission was only 40 % at lambda=500 nm. PMID- 25826459 TI - Quantitative DNA methylation analysis of candidate genes in cervical cancer. AB - Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID- 25826460 TI - Racial/Ethnic Differences in Cardiovascular Symptoms in Four Major Racial/Ethnic Groups of Midlife Women: A Secondary Analysis. AB - Ethnic minority midlife women frequently do not recognize cardiovascular symptoms that they experience during the menopausal transition. Racial/ethnic differences in cardiovascular symptoms are postulated as a plausible reason for their lack of knowledge and recognition of the symptoms. The purpose of this study was to explore racial/ethnic differences in midlife women's cardiovascular symptoms and to determine the factors related to these symptoms in each racial/ethnic group. This was a secondary analysis of the data from a larger study among 466 participants, collected from 2006 to 2011. The instruments included questions on background characteristics, health and menopausal status, and the Cardiovascular Symptom Index for Midlife Women. The data were analyzed using inferential statistics, including Poisson regression and logistic regression analyses. Significant racial/ethnic differences were observed in the total numbers and total severity scores of cardiovascular symptoms (p < .01). Non-Hispanic Asians had significantly lower total numbers and total severity scores compared to other racial/ethnic groups (p < .05). The demographic and health factors associated with cardiovascular symptoms were somewhat different in each racial/ethnic group. Further studies are needed about possible reasons for the racial/ethnic differences and the factors associated with cardiovascular symptoms in each racial/ethnic group. PMID- 25826461 TI - Accuracy of the Common Predictive Equations for Estimating Resting Energy Expenditure among Normal and Overweight Girl University Students. AB - OBJECTIVE: The aim of the present study was to determine the accuracy of commonly used predictive formulas of resting metabolic rate (RMR) compared to measured RMR in normal and overweight young females. METHODS: In this cross-sectional study, 98 female university students aged 18-30 years with body mass index 18 to 30 kg/m(2) were recruited. Anthropometric indices and body compositions were measured. RMR was measured by indirect calorimetry (FitMate, Cosmed, Rome, Italy) and estimated by 11 predictive formulas. The accuracy of the RMR formulas and mean percentage differences between estimated and measured values were calculated. Paired t test was used to compare estimated and measured RMRs. RESULT: There were no significant differences between measured and estimated RMR by the 4 commonly used formulas (Mifflin, Cunningham, and World Health Organization [WHO]/Food and Agriculture Organization [FAO]). Among all of the equations, the Mifflin formula showed the lowest bias (-2.97 +/- 116.43 kcal/day) at the group level and was the most accurate formula (80.23%) in normal and overweight participants. The over- and underestimated values were about 14% and 5.5%, respectively. In normal and overweight females, Mifflin was the most accurate formula, with 75.51% and 84.61% accuracy, respectively. CONCLUSION: Given the current lack of a standardized formula that consistently delivers accurate results, the Mifflin formula can be recommended for estimating energy requirements in normal and overweight females in clinical practice. PMID- 25826462 TI - CO2 conversion to methanol on Cu(I) oxide nanolayers and clusters: an electronic structure insight into the reaction mechanism. AB - The mechanism of carbon dioxide reduction to methanol on Cu(I) oxide nanolayers and clusters using water as the source of hydrogen was traced using density functional theory. The nature of the active sites is revealed, namely the role of surface copper dimers, which are present on the Cu2O(001) surface and in the nanoclusters of size Cu32O16 and Cu14O7. The major difference between metal catalysts and Cu2O is outlined: the CO2 molecule interacts strongly with the oxide and undergoes bending prior to hydrogenation. The first step of CO2 hydrogenation results in the formation of a stable carboxyl intermediate, CO(OH), which in the following steps is converted to methanol via formic acid and formaldehyde intermediates. The consumption of hydrogen from water leaves surface peroxo- and hydroperoxo-species. The peroxides easily desorb molecular oxygen, while for hydroperoxides the reaction of oxygen evolution requires an activation energy of 130 kJ mol(-1). The maxima in the absorption spectra correspond well with the required activation energies in the elementary steps. PMID- 25826463 TI - A pharmacokinetic/pharmacodynamic analysis of ceftaroline prophylaxis in patients with external ventricular drains. AB - BACKGROUND: Ceftaroline is a broad-spectrum cephalosporin antibiotic with activity against drug-resistant bacteria, including strains of methicillin resistant Staphylococcus aureus (MRSA), and may be useful to prevent and treat ventriculostomy-related infections (VRIs). The purpose of this study was to analyze the pharmacokinetics and pharmacodynamics of prophylactic ceftaroline in neurosurgical patients with an external ventricular drain (EVD). METHODS: Adult patients in the neurosurgical intensive care unit with an EVD were given prolonged prophylaxis with ceftaroline. Serum and cerebral spinal fluid (CSF) were obtained simultaneously at 2, 6, and 12 h after initiation of the fourth dose of ceftaroline and concentrations were measured by a liquid chromatography tandem mass spectrometry assay. Time-kill curves against isolates of coagulase negative S. aureus, methicillin-sensitive S. aureus, MRSA, and Streptococcus pneumoniae were determined in serum and CSF at each collection time point. RESULTS: A total of five patients with a mean age of 63 y and mean weight of 83 kg were enrolled. The mean CSF:serum penetration ratios of ceftaroline were 0.005 (0.5%), 0.021 (2.1%), and 0.043 (4.3%) at 2, 6, and 12 h, respectively. The mean ceftaroline exposure ratio area under the curve (AUC)csf/AUCserum) was 0.011 (1.1%). Bactericidal activity at each collection time point was observed against each strain of staphylococci from serum samples and a penicillin-sensitive strain of S. pneumoniae from CSF samples. CONCLUSION: This investigation suggests that ceftaroline could have clinical utility for the prevention of VRIs in patients with EVDs. PMID- 25826464 TI - Ion hydration and association in aqueous potassium phosphate solutions. AB - Ionic hydration and ion association in aqueous solutions of KH2PO4, K2HPO4, and K3PO4 at 25 degrees C up to high concentrations have been investigated using dielectric relaxation spectroscopy (DRS). The three phosphate anions were found to be extensively hydrated, with total hydration numbers at infinite dilution of ~11 (for H2PO4(-)), ~20 (HPO4(2-)), and ~39 (PO4(3-)). These values are indicative of the existence of a second hydration shell around HPO4(2-) and especially PO4(3-). Two types of hydrating water molecules could be quantified: irrotationally bound (ib, H2O molecules essentially "frozen" on the DRS time scale) and "slow" (loosely bound water molecules with identifiably slower dynamics than bulk water). For H2PO4(-) over the entire concentration range and for HPO4(2-) and PO4(3-) at concentrations c ? 1 mol L(-1), only "slow" H2O was detected; however, at higher concentrations of the latter two anions, an increasing fraction of ib water appears, making up ~50% of the total hydration number close to the saturation limit of K2HPO4. Contrary to common belief, all three salts showed significant ion pair formation, with standard association constants of the 1:1 species increasing in the order: KH2PO4(0)(aq) < KHPO4( )(aq) < KPO4(2-)(aq). The main type of ion pair in solution shifted from solvent shared ion pairs (SIPs) to double-solvent-separated ion pairs (2SIPs) in the same sequence. PMID- 25826465 TI - Cloning and expression analysis of four heat shock protein genes in Ericerus pela (Homoptera: Coccidae). AB - To explore the function of small heat shock protein genes (shsps) and hsp70 in Ericerus pela, we cloned the full-length cDNA sequences of hsp21.5, hsp21.7, hsp70, and hsc70 and the genomic sequence of hsc70. Open reading frames of the four hsps were 570, 564, 1,908, and 1,962 base pairs (bp), respectively, which encode proteins with calculated molecular mass of 21.5, 21.7, 69.8, and 71.6 kDa. Amino acid sequence analysis revealed the presence of the conserved Hsp motifs in all four proteins. The genomic DNA of hsc70 had four introns. ep-hsp21.5 was orthologous and ep-hsp21.7 was species specific. Expression of all four transcripts during heat or cold stress and development was examined by quantitative real-time polymerase chain reaction. All four hsps were upregulated during heat or cold stress in female adults, indicating a correlation between the four hsps and heat or cold-stress tolerance in female adults. ep-hsp21.7 and ep hsp70 were upregulated during heat stress in male larvae, implying a correlation between the two hsps and heat-stress tolerance in male larvae. The four ep-hsps were also upregulated during the developmental process in males, and ep-hsp21.5, ep-hsp70, and ep-hsc70 were upregulated in females, which indicates their possible role in the developmental regulation of E. pela. PMID- 25826466 TI - Performance of an Electronic Diary System for Intensive Insulin Management in Global Diabetes Clinical Trials. AB - BACKGROUND: This report describes the performance of a wireless electronic diary (e-diary) system for data collection and enhanced patient-investigator interactions during intensive insulin management in diabetes clinical trials. MATERIALS AND METHODS: We implemented a customized electronic communication system featuring an e-diary and a Web portal in three global, randomized, controlled Phase 3 clinical trials testing basal insulin peglispro compared with insulin glargine, both combined with prandial insulin lispro, in patients with type 1 or type 2 diabetes mellitus (T1DM and T2DM, respectively). We collected data during 28 weeks of study e-diary use for the report. RESULTS: Patients (n=2,938) in 31 countries used e-diaries to transmit 2,439,087 blood glucose (BG) values, 96% of which were associated by the patient with a protocol time point during the 72-h response window. Of 208,192 hypoglycemia events captured, 96% had a BG value, and 95% had treatments and outcomes entered by patients within the 72 h window. Patients recorded administration of 1,964,477 insulin doses; 93% of basal insulin doses were adherent with the investigator prescription. Investigators adjusted 13 basal and 92 bolus insulin prescriptions per patient year using the e-diary system. After 26 weeks of treatment and e-diary use in the combined study arms, hemoglobin A1c values decreased by 0.6% or 1.6% and fasting BG decreased by 7.8 or 28 mg/dL in patients with T1DM or T2DM, respectively. CONCLUSIONS: The e-diary system enabled comprehensive data collection and facilitated communication between investigators and patients for intensive insulin management in three global clinical trials testing basal insulins. PMID- 25826467 TI - Dual-Enzyme Characteristics of Polyvinylpyrrolidone-Capped Iridium Nanoparticles and Their Cellular Protective Effect against H2O2-Induced Oxidative Damage. AB - Polyvinylpyrrolidone-stabilized iridium nanoparticles (PVP-IrNPs), synthesized by the facile alcoholic reduction method using abundantly available PVP as protecting agents, were first reported as enzyme mimics showing intrinsic catalase- and peroxidase-like activities. The preparation procedure was much easier and more importantly, kinetic studies found that the catalytic activity of PVP-IrNPs was comparable to previously reported platinum nanoparticles. Transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) characterization indicated that PVP-IrNPs had the average size of approximately 1.5 nm and mainly consisted of Ir(0) chemical state. The mechanism of PVP-IrNPs' dual-enzyme activities was investigated using XPS, Electron spin resonance (ESR) and cytochrome C-based electron transfer methods. The catalase-like activity was related to the formation of oxidized species Ir(0)@IrO2 upon reaction with H2O2. The peroxidase-like activity originated from their ability acting as electron transfer mediators during the catalysis cycle, without the production of hydroxyl radicals. Interestingly, the protective effect of PVP-IrNPs against H2O2-induced cellular oxidative damage was investigated in an A549 lung cancer cell model and PVP-IrNPs displayed excellent biocompatibility and antioxidant activity. Upon pretreatment of cells with PVP-IrNPs, the intracellular reactive oxygen species (ROS) level in response to H2O2 was decreased and the cell viability increased. This work will facilitate studies on the mechanism and biomedical application of nanomaterials-based enzyme mimic. PMID- 25826468 TI - Synthesis of carbodiimides by I2/CHP-mediated cross-coupling reaction of isocyanides with amines under metal-free conditions. AB - An I2/CHP-mediated cross-coupling reaction of isocyanides with readily accessible amines via C-N formation is described for carbodiimide synthesis in moderate to excellent yields. This represents a metal-free strategy for a coupling reaction of isocyanides with amines, and it provides an efficient approach for symmetric and unsymmetric functionalized carbodiimide derivative synthesis under mild conditions. PMID- 25826469 TI - Self-assembly molecular dynamics simulations shed light into the interaction of the influenza fusion Peptide with a membrane bilayer. AB - Influenza virus is one of the most devastating human pathogens. In order to infect host cells, this virus fuses its membrane with the host membrane in a process mediated by the glycoprotein hemagglutinin. During fusion, the N-terminal region of hemagglutinin, which is known as the fusion peptide (FP), inserts into the host membrane, promoting lipid mixing between the viral and host membranes. Therefore, this peptide plays a key role in the fusion process, but the exact mechanism by which it promotes lipid mixing is still unclear. To shed light into this matter, we performed molecular dynamics (MD) simulations of the influenza FP in different environments (water, dodecylphosphocholine (DPC) micelles, and a dimyristoylphosphatidylcholine (DMPC) membrane). While in pure water the peptide lost its initial secondary structure, in simulations performed in the presence of DPC micelles it remained stable, in agreement with previous experimental observations. In simulations performed in the presence of a preassembled DMPC bilayer, the peptide became unstructured and was unable to insert into the membrane as a result of technical limitations of the method used. To overcome this problem, we used a self-assembly strategy, assembling the membrane together with the peptide. These simulations revealed that the peptide can adopt a membrane-spanning conformation, which had not been predicted by previous MD simulation studies. The peptide insertion had a strong effect on the membrane, lowering the bilayer thickness, disordering nearby lipids, and promoting lipid tail protrusion. These results contribute to a better understanding of the role of the FP in the fusion process. PMID- 25826470 TI - Dietary components and uterine leiomyomas: a review of published data. AB - Some studies have considered the association between diet and uterine fibroid risk, but the issue is largely unsettled. To identify potential modifiable risk factors for fibroid development, we have herein systematically reviewed prior publications dealing with this aspect. Comprehensive searches in electronic databases were conducted to collect studies published on association between uterine leiomyomas and both nutrients and food groups. We identified 13 publications deriving from 4 case-control, 3 cross-sectional, and 4 cohort studies. A protective effect has been demonstrated for consumption of fruits and green vegetables in both case-control and cohort studies. Moreover, very recent cross-sectional and case-control studies evaluating serum levels of 25 hydroxyvitamin-D3 tend to indicate that vitamin D insufficiency, which may in part be due to the diet intake, may play an important role in the development of uterine fibroids. No association was found with the intake of fibers, vitamin C and E, phytoestrogens and carotenoids, whereas association was controversial for the consumption of meat, fish, dairy products, and vitamin A. Most data have also been discussed herein in light of the available experimental and animal model results. These findings may be useful in devising nutritional strategies to reduce leiomyoma risk in humans. PMID- 25826471 TI - Olfactory and executive dysfunctions following orbito-basal lesions in traumatic brain injury. AB - OBJECTIVE: To study the acute relationship between olfactory function and traumatic brain injury (TBI), cognitive functions and outcome. METHODS: Sixty-two patients with TBI were evaluated within the first 2 weeks following TBI. The Sniffin'Sticks identification test was used to assess olfaction. A neuropsychological evaluation was carried out to assess attention, verbal fluency, naming, memory, problem-solving and mental flexibility. The extended Glasgow Outcome Scale (GOSE) and the Disability Rating Scale (DRS) were rated at discharge from acute care. RESULTS: Traumatic lesions located in the basal frontal area resulted in odour identification scores that were significantly lower than when lesions were elsewhere (p < 0.001). A significant positive correlation was shown between odour identification scores and mental flexibility scores (p = 0.004) and patients with hyposmia had worse performances on executive tests measuring problem-solving, verbal fluency and mental flexibility (p < 0.01). Moreover, the odour identification score and the DRS total score were related (p = 0.019). CONCLUSIONS: These findings add information regarding acute olfactory status following TBI and provide evidence on the importance of assessing olfaction very early post-TBI in order to plan intervention and determine what accident prevention advice will be required for home or work re integration. PMID- 25826472 TI - Correction: the circadian regulation of sleep: impact of a functional ADA polymorphism and its association to working memory improvements. AB - [This corrects the article DOI: 10.1371/journal.pone.0113734.]. PMID- 25826473 TI - NMR spectroscopic method for the assignment of 3,5-dioxygenated aromatic rings in natural products. AB - In recent years, certain "new" naturally occurring compounds (1-28) with 3,5 dioxygenated aromatic rings have been reported. A comparison of the NMR data of these compounds with the data of four model compounds (A-D) indicated that the structures of these "new" compounds were erroneous. The reason for the incorrect elucidation of the structures of 1-28 was attributed to "deceptively simple" (1)H NMR spectra, which displayed two broad singlets with integrations of 1:2 for H-2 and H-5, H-6, respectively. To expose the misleading results from the spectra, serial (1)H NMR experiments on compounds A-D were performed using various deuterated solvents and temperatures. The results revealed separated proton signals for the ABX system in certain deuterated solvents. Additionally, the characteristic differences between 3,4- and 3,5-dioxygenated aromatic rings in their (13)C NMR spectra are summarized based on our experiment and data reported. This approach is useful for analyzing the patterns of dioxygenated aromatic rings in natural products, especially when "deceptively simple" (1)H NMR spectra are displayed. PMID- 25826474 TI - Pilates for Better Sex: Changes in Sexual Functioning in Healthy Turkish Women After Pilates Exercise. AB - Although a large number of studies report the impact of daily exercise on many aspects of women's health, none of them address the relationship between Pilates exercise and sexual function prospectively. The aim of this study was to assess the effect of Pilates exercise on sexual function in healthy young women using a validated questionnaire. In total, 34 premenopausal healthy Turkish women aged between 20 and 50 years who had regular menstrual cycles and sexual relationships were included in the study. Women were asked to complete Beck Depression Inventory (BDI) and Female Sexual Function Index (FSFI) questionnaires. Questionnaires were completed before and after 12 weeks of Pilates exercise. Primary endpoints were changes in total and individual domain scores on the FSFI and BDI. After the 12-week Pilates intervention, BDI scores were decreased and all domains of the FSFI were significantly improved with mean +/- SD total FSFI scores increasing from 25.9 +/- 7.4 to 32.2 +/- 3.6 (p <.0001). This is the first prospective study that quantifies the improvement in sexual function of healthy women after a 12-week Pilates program. Our findings suggest that Pilates may improve sexual function in healthy women. However, further studies with a larger sample size are needed in this field. PMID- 25826475 TI - The invadopodia scaffold protein Tks5 is required for the growth of human breast cancer cells in vitro and in vivo. AB - The ability of cancer cells to invade underlies metastatic progression. One mechanism by which cancer cells can become invasive is through the formation of structures called invadopodia, which are dynamic, actin-rich membrane protrusions that are sites of focal extracellular matrix degradation. While there is a growing consensus that invadopodia are instrumental in tumor metastasis, less is known about whether they are involved in tumor growth, particularly in vivo. The adaptor protein Tks5 is an obligate component of invadopodia, and is linked molecularly to both actin-remodeling proteins and pericellular proteases. Tks5 appears to localize exclusively to invadopodia in cancer cells, and in vitro studies have demonstrated its critical requirement for the invasive nature of these cells, making it an ideal surrogate to investigate the role of invadopodia in vivo. In this study, we examined how Tks5 contributes to human breast cancer progression. We used immunohistochemistry and RNA sequencing data to evaluate Tks5 expression in clinical samples, and we characterized the role of Tks5 in breast cancer progression using RNA interference and orthotopic implantation in SCID-Beige mice. We found that Tks5 is expressed to high levels in approximately 50% of primary invasive breast cancers. Furthermore, high expression was correlated with poor outcome, particularly in those patients with late relapse of stage I/II disease. Knockdown of Tks5 expression in breast cancer cells resulted in decreased growth, both in 3D in vitro cultures and in vivo. Moreover, our data also suggest that Tks5 is important for the integrity and permeability of the tumor vasculature. Together, this work establishes an important role for Tks5 in tumor growth in vivo, and suggests that invadopodia may play broad roles in tumor progression. PMID- 25826476 TI - Does the Well-Being of Individuals with Down Syndrome and Dementia Improve When Using Life Story Books and Rummage Boxes? A Randomized Single Case Series Experiment. AB - BACKGROUND: This study investigated whether a personalized life story book and rummage box enhanced well-being and led to changes in behaviour for people with Down syndrome (DS) who have dementia. MATERIALS AND METHODS: A randomized single case series design was used with five participants who had DS and a diagnosis of dementia. Participants were invited to take part in three conditions at random (i) life story book, (ii) rummage box and (iii) no-intervention condition. RESULTS: The two reminiscence conditions were significantly associated with enhanced well-being as compared to the no-intervention condition. However, for one participant, the life story book was associated with significantly higher well-being, while for another participant, the rummage box was associated with significantly higher well-being, suggesting some participants may prefer one method over another. CONCLUSIONS: Personalized life story books and rummage boxes are associated with higher levels of well-being for people with DS and dementia. PMID- 25826477 TI - Gender disparities in acute coronary syndrome: a closing gap in the short-term outcome. AB - AIMS: The aim of the present study was to analyze gender disparities in a large cohort of acute coronary syndrome (ACS) patients from the Zurich Acute Coronary Syndrome (Z-ACS) Registry. METHODS: Gender disparities in ACS were examined. The primary endpoint included in-hospital death rate, and the secondary endpoint major adverse cardiac and cerebrovascular events (MACCEs) at 30-day follow-up. Furthermore, independent predictors for MACCEs and death were identified. RESULTS: In total, 2612 patients with ACS were identified. Out of these, 23% were women. The mean age was higher in women (68.6 +/- 12.2; P < 0.001). Troponin-T on admission (1.33 +/- 4.64 vs. 1.19 +/- 3.04 MUg/l; P = 0.002) and N-terminal of the prohormone brain natriuretic peptide on admission (3456.2 +/- 7286.7 vs. 1665.6 +/- 4800.6 ng/l; P < 0.001) were higher in women compared with men. Single vessel disease was more common in women (44.9 vs. 39.7%; P = 0.023) and, conversely, multivessel disease was more prevalent in male patients as compared with their female counterparts (59.4 vs. 54.4%; P = 0.029). At discharge, men were more likely prescribed statins (89.4 vs. 85.2%; P = 0.004). Overall mortality and MACCEs were similar for both genders. In women, peak creatine kinase and peak C-reactive protein emerged as independent predictors for MACCEs and SBP on admission, and maximal C-reactive protein and use of glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa) as strong independent predictors for in-hospital death. CONCLUSION: The present results suggest a closing gap in short-term outcome and improvement in cardiac care between women and men. Nonetheless, differences in treatment strategies continue to exist, particularly pertaining to statin regimens at discharge, which might potentially have a powerful impact on long-term outcomes and gender disparities. PMID- 25826478 TI - Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance. AB - RATIONALE: Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide ([Formula: see text]e/[Formula: see text]co2) during exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high [Formula: see text]e/[Formula: see text]co2 in mild COPD and its impact on dyspnea and exercise intolerance. METHODS: Twenty-two subjects (11 patients with GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection. MEASUREMENTS AND MAIN RESULTS: Patients (post-bronchodilator FEV1: 94 +/- 10% predicted; mean +/- SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 +/- 18 vs. 113 +/- 24% predicted; P<0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar-arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P<0.05). [Formula: see text]e/[Formula: see text]co2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P<0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P<0.05). Standardized dyspnea intensity ratings were also higher (P<0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the [Formula: see text]e/[Formula: see text]co2 ratio during submaximal exercise (r=0.780, P<0.001). CONCLUSIONS: High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD. PMID- 25826480 TI - Effect of Posture on Regional Deposition of Coarse Particles in the Healthy Human Lung. AB - BACKGROUND: Understanding the regional partition of deposition of inhaled particles within the lung is important for improving targeted delivery of inhaled aerosolized drugs. One factor affecting regional deposition is gravity. As the lung deforms under its own weight, changes in lung volume, in airway geometries, and in spatial patterns of ventilation distribution between postures have the potential to alter the regional distribution of deposited particles. METHODS: Using gamma-scintigraphy, we measured regional deposition and clearance of (99m)Tc labeled particles (5 MUm) in 6 healthy subjects, with aerosol inhalation occurring both in the supine and seated postures at constant flow (0.5 L/sec) and breathing rate (15 breaths/min). After aerosol deposition, mucociliary clearance data were collected in the seated posture, immediately post-particle administration, 1 h 30 min, 4 h, and 22 h post-inhalation. Relative regional deposition was computed using retention (R) at the different time points, with (1 R(1h30min)), (R(1h30min)- R(4h)), and (R(4h)- R(22h)) corresponding to deposition in the large, intermediate, and small airways, respectively. Alveolar deposition was estimated as the relative retention at 22 h (R(22h)). RESULTS: Relative deposition of coarse particles in the alveolar region decreased from 60+/-8% seated to 34+/-16% supine (p=0.04). This change was accompanied by an increase in relative deposition in the intermediate (7+/-3% seated to 16+/-17% supine, P=0.09) and small airways (19+/-6% seated to 34+/-13% supine, p=0.06) when inhalation occurred in the supine posture. No change was observed in central to peripheral deposition (C/P ratio), the skew of the deposition distribution, or the apex-to-base ratio of deposition between seated and supine postures. CONCLUSIONS: Inhalation of coarse particles in the supine posture shifts relative deposition from the alveolar to the bronchial airways, when compared to the seated posture, likely driven by changes in functional residual capacity, and airway size, as well as changes in the regional distribution of ventilation between postures. PMID- 25826481 TI - Dermatology facing autoinflammatory syndrome. AB - Cutaneous symptoms are characteristic for the autoinflammatory disorders (AIDs), both in the classical autoinflammatory phenotype and in most disorders included in this syndrome, but they are not specific and inconstant. Several skin disorders (pyoderma gangrenosum and pustular acne) may be encountered either isolate or associated with autoinflammatory symptoms, forming well-defined clinical entities within the autoinflammatory syndrome. The high prevalence of cutaneous manifestations is an important characteristic of AIDs. The presence of cutaneous symptoms in AIDs opens the perspective of understanding the contribution of innate immunity mechanisms involved in skin pathology. It is possible that many diseases present the alteration, in various degrees, of the innate immune mechanisms. Recently, dermatology faced two challenges connected to AIDs. The first involves the diagnosis of skin symptoms in a clinical autoinflammatory setting and the investigative approach to identify a disorder classified as AID. The second is to identify the altered mechanisms of inborn immunity among the pathogenetic mechanisms of known dermatological diseases (e.g., neutrophilic dermatoses). On the other hand, cutaneous symptoms are in certain cases regarded as a criterion to asses the efficacy of specific or non specific therapies with monoclonal antibodies in disorders included in AIDs. Dermatology mostly benefits from the identification and knowledge of AIDs due to the role of innate immunity in skin pathogeny and also due to the large extent of clinical forms resulting from the association of skin symptoms with other disorders included in this group. PMID- 25826479 TI - Remote ischemic preconditioning (RIPC) modifies the plasma proteome in children undergoing repair of tetralogy of fallot: a randomized controlled trial. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) has been applied in paediatric cardiac surgery. We have demonstrated that RIPC induces a proteomic response in plasma of healthy volunteers. We tested the hypothesis that RIPC modifies the proteomic response in children undergoing Tetralogy of Fallot (TOF) repair. METHODS AND RESULTS: Children (n=40) were randomized to RIPC and control groups. Blood was sampled at baseline, after cardiopulmonary bypass (CPB) and 6, 12 and 24h post-CPB. Plasma was analysed by liquid chromatography mass spectrometry (LC MS) in an untargeted approach. Peptides demonstrating differential expression (p<0.01) were subjected to tandem LC-MS/MS and protein identification. Corresponding proteins were identified using the NCBI protein database. There was no difference in age (7.3+/-3.5vs6.8+/-3.6 months)(p=0.89), weight (7.7+/ 1.8vs7.5+/-1.9 kg)(p=0.71), CPB time (104+/-7vs94+/-7 min)(p=0.98) or aortic cross-clamp time (83+/-22vs75+/-20 min)(p=0.36). No peptides were differentially expressed at baseline or immediately after CPB. There were 48 peptides with higher expression in the RIPC group 6h post-CPB. This was no longer evident at 12 or 24h, with one peptide down-regulated in the RIPC group. The proteins identified were: inter-alpha globulin inhibitor (42.0+/-11.8 vs 820.8+/-181.1, p=0.006), fibrinogen preproprotein (59.3+/-11.2 vs 1192.6+/-278.3, p=0.007), complement-C3 precursor (391.2+/-160.9 vs 5385.1+/-689.4, p=0.0005), complement C4B (151.5+/-17.8 vs 4587.8+/-799.2, p=0.003), apolipoprotein B100 (53.4+/-8.3 vs 1364.5+/-278.2, p=0.005) and urinary proteinase inhibitor (358.6+/-74.9 vs 5758.1+/-1343.1, p=0.009). These proteins are involved in metabolism, haemostasis, immunity and inflammation. CONCLUSIONS: We provided the first comprehensive analysis of RIPC-induced proteomic changes in children undergoing surgery. The proteomic changes peak 6h post-CPB and return to baseline within 24h of surgery. TRIAL REGISTRATION: ACTR.org.au ACTRN12610000496011. PMID- 25826482 TI - Renal carcinogenesis--insights into signaling pathways. AB - Renal cancer represents about 3% of all human malignancies, 96% of cases being sporadic forms and only 4% hereditary. Research in renal tumor pathogenesis is currently oriented on the genetic and proteins framework of the renal cell carcinoma, with the aim to translate the level of knowledge on tumor subtypes from histological to molecular issues, simultaneously with the deciphering of the manner in which the signaling pathways intervene in the pathogenic mechanism. Alterations identified in proto-oncogenes and tumor suppressor genes lead to abnormal and deficient transmission of signal in the signaling pathways, and initiate the carcinogenesis mechanism by increased proliferation of tumor cells. Although it seems obvious that the classic sequence of carcinogenesis is respected at the renal site, unfortunately, the manner in which signaling pathways are involved, in the specific context of renal tumors, is not extensively investigated. This paper assembles recent data in the mainstream regarding the dialogue opened between the molecules in Wnt/beta-catenin, PI3K/AKT/mTOR, and HGF/cMET signaling pathways. The review is also justified by the fact that these molecules may represent potential prognosis markers and/or therapeutic targets. PMID- 25826483 TI - Microglial voltage-gated sodium channels modulate cellular response in Alzheimer's disease--a new perspective on an old problem. AB - Alzheimer's disease (AD) determines gradual loss of cognition and memory function, eventually leading to clinical manifest dementia. The pathogenic mechanisms of AD remain elusive and treatment options unsatisfactory, targeting only symptoms like memory loss, behavior changes, sleep disorders and seizures. These therapies are not stopping the disease's progression, at their best they can only delay it. Accumulating evidence suggests that AD is associated with a microglial dysfunction. Microglia are resident immune cells that provide continuous surveillance within the brain. When excessively activated, microglial response can also have detrimental effects via the exacerbation of inflammatory processes and release of neurotoxic substances. Recently, it was recognized that microglia express voltage-gated ion channels, in particularly voltage-gated sodium channels (VGSC). Pharmacological block of VGSC has been attempted symptomatically in AD to control the epileptic features often associated with AD, as well as to relieve detrimental behavioral and psychological symptoms of dementia. The success of VGSC treatment in AD was unexpectedly variable, ranging from very beneficial to plain detrimental. This variability could not be satisfactorily explained solely by the neuronal effects. This article will try to discuss possible implication of microglial VGSC dysfunction in AD according to available data, own personal experience of the authors and propose a new way to investigate its possible implications. PMID- 25826484 TI - An overview of permanent vascular access in hemodialyzed patients. AB - In the last decade, because of significant number of end-stage renal disease individuals in need of renal therapy replacement and permanent quest of nephrologist to optimize kidney disease patients' quality of life, there is an increased interest in achieving a suitable permanent vascular access, essential for an efficient dialysis. Furthermore, it is of high importance to preserve arteriovenous fistula in optimal condition and therefore, it is vital to correctly understand the histopathology and pathophysiological mechanisms implicated in maturation and well function of dialysis vascular access. PMID- 25826485 TI - Morphological and quantitative study of collagen fibers in healthy and diseased human gingival tissues. AB - OBJECTIVES: This study aimed to evaluate types I, III and IV collagen in healthy gingival tissue and to compare them to gingival tissues suffering from chronic gingivitis and chronic periodontitis. MATERIALS AND METHODS: Thirty-two man patients were selected. The patients belonged to three diagnostic categories: healthy gingiva (HG), chronic gingivitis (CG) and chronic periodontitis (CP), based on clinical and radiographical criteria. Gingival tissue samples were obtained from patients who underwent periodontal surgery procedures. Hematoxylin and Eosin (HE), Picrosirius red, indirect immunofluorescence by confocal microscopy and quantitative analyses were performed to identify the presence and location of types I, III and IV collagen. Statistical significance was verified using the Kruskal-Wallis test. RESULTS: Samples from HG group showed thick collagen fibers arranged in a parallel pattern. Samples from CG group showed dilated blood vessels; collagen fibers and inflammatory cells were found dispersed throughout the tissue. Samples from CP group showed the extracellular matrix severely damaged, disorganized collagen fibers and large amount of inflammatory cells. The HG group showed an apparent higher expression of type I collagen, when compared to tissues with CG and CP, however no statistical differences were detected (p=0.064). The types III and IV collagen fibers showed no difference in expression in tissues with gingivitis and periodontitis. CONCLUSIONS: Following the periodontal disease there was a morphological destruction of the extracellular matrix with lower expression of collagen, which led to a change in tissue architecture that might compromise its functional capacity. There were differences in type I collagen expression among healthy, chronic gingivitis and chronic periodontitis tissue samples. PMID- 25826486 TI - Combined enriched environment/atipamezole treatment transiently improves sensory functions in stroke rats independent from neurogenesis and angiogenesis. AB - Functional recovery after cerebral ischemia may be enhanced by activation of the noradrenergic system and by environmental enrichment. The underlying mechanisms have remained elusive, but endogenous neurogenesis and perilesional angiogenesis have been speculated to contribute to the behavioral improvement. To address this question, neurogenesis in the subventricular zone (SVZ) and perilesional angiogenesis (RECA-1) were correlated with behavioral performance in forty Wistar rats subjected to transient middle cerebral artery occlusion (MCAO) or sham operation. Atipamezole, an alpha2-adrenoreceptor antagonist (1 mg/kg, i.p.), was administered for 10 days together with housing of rats in an enriched environment. MCAO rats and sham-operated rats housed in single non-enriched cages were used as controls. Histological analysis after 28-day behavioral follow-up showed a massive increase in doublecortin (DCX)-positive cells in the SVZ both in MCAO rats housed in single cages and in the enriched environment together with atipamezole treatment whereas perilesional RECA-1 staining for new blood vessels was not altered. Time to the first contact and time to remove sticky stimuli from the forelimbs indicated improved sensory processing, which disappeared after cessation of atipamezole administration. Skilled forelimb use as measured by performance in Montoya's staircase test was not affected by the treatment. There were no correlations between behavioral measures and histology. Thus, sensory facilitation or reversal of hypometabolism by the combined therapy may be the mechanism accounting for the improved behavior after stroke independent from neurogenesis and angiogenesis. PMID- 25826487 TI - Heterogeneity of collagen secreting cells in gingival fibrosis--an immunohistochemical assessment and a review of the literature. AB - AIM: In this work, we compared the histological features of the gingival lesions clinically diagnosed as fibrotic overgrowths due to various etiologic factors as well as an immunohistochemical assessment of fibroblasts phenotypic heterogeneity using the specific labeling for vimentin, alpha-smooth muscle actin (alpha-SMA) and fibroblast specific protein-1 (FSP1). MATERIALS AND METHODS: Tissue samples were obtained from 12 patients clinically diagnosed with fibrotic gingival overgrowth, divided in four groups. Fragments of gingiva were processed for paraffin embedding. Serial sections were used for routine staining Hematoxylin Eosin, trichromic Masson and Goldner-Szekely, and for immunohistochemical reactions to label vimentin, alpha-SMA and FSP1 using for signal amplification several techniques (EnVision, LSAB, ABC). RESULTS: Storage of collagen fibers, increase of fibroblast number and frequent presence of inflammatory infiltrate are histological issues of all fibrotic gingival overgrowth. The incidence of granulation tissue varies but the frequency of its presence point the attention to the involvement in collagen metabolism imbalance. Immunostaining for vimentin showed a difference between its expression in samples from different groups. Except the cases of fibrosis induced by orthodontic devices, cells positive for alpha-SMA were rare. FSP1-positive fibroblasts were the most frequent in all cases from all the groups selected for this study. CONCLUSIONS: The phenotype of fibroblasts is different in gingival fibrosis in relation to the risk factor, at present the most common being vimentin-positive and FSP1-positive fibroblasts. Myofibroblasts are rare in gingival fibrosis, the most numerous being in local lesions caused by wearing orthodontic devices and in syndromic fibromatosis. Further studies are required to elucidate the manner in which the active fibroblasts are recruited in relation to the etiologic factor of gingival overgrowth. PMID- 25826488 TI - Study regarding the microscopic aspects of pilo-sebaceous units after antiandrogen treatment in hirsute women. AB - AIM: To analyze the morphological data of pilo-sebaceous units in hirsute women before and 12 months after the antiandrogen treatment with Cyproterone acetate (CPA) 100 mg/day. MATERIALS AND METHODS: Fourteen female patients with idiopathic hirsutism that followed an antiandrogen treatment with CPA were biopsied from the androgen-dependent area of the chin before and 12 months after the treatment. Routine sections were stained with Hematoxylin-Eosin, Masson, Van Gieson, Sirius red and picric-indigocarmine, while additional sections were immunostained for S100 protein and vimentin. Electron microscopy was performed in two cases with Langerhans cell hyperplasia. RESULTS: On biopsies-stained sections, an increased number of hair follicles, the deeper part of the epithelial sheath of the hair follicle with epithelial buds, hyperplasia of sebaceous glands, and no inflammatory infiltrate were noticed. Langerhans cells identified with S100 protein and vimentin were normal in terms of numbers and distribution. After the administration of the treatment, atrophy of the pilo-sebaceous units was visible in nine (64.2%) cases, while inflammatory infiltrate and cells included in the vacuoles of the basal layer of the epidermis became apparent. In six of the cases treated with antiandrogens, a marked hyperplasia of Langerhans cells was noticed. In conclusion, the benefit of antiandrogen treatments is supported by atrophy of the hair follicle and the sebaceous glands. The activation of Langerhans cells associated with inflammatory infiltrate in the dermis and hair follicles could be considered as a local consequence of the involution process of hair follicles after the administration of the treatment. PMID- 25826489 TI - In vitro evaluation of curcumin effects on breast adenocarcinoma 2D and 3D cell cultures. AB - Breast adenocarcinoma cell line MDA-MB-231, even if it expresses low levels of E cadherin, still readily form multicellular aggregates of cells, namely spheroids. Curcumin is a diarylheptanoid antitumoral drug while it significantly inhibits cell migration, invasion, and colony formation in vitro and reduces tumor growth and liver metastasis in vivo. Curcumin photoactivation may enhance antiapoptotic role against cancer cells. AIM: To evaluate the effect of low curcumin concentrations, ranged from 1.9 to 15 MUM, with and without photoactivation, using a manufactured 670 nm LED-matrix. A secondary aim was to evaluate the ideal method to produce easy-to-use tumor cell spheroids, comparing two low adherence plate supports. MATERIALS AND METHODS: Breast adenocarcinoma cell line MDA-MB-231 were cultured according to 2D monolayer and 3D spheroid models then submitted to normal and photoactivated curcumin in micromolar concentrations. MTT assay was used to evaluate cell viability following curcumin application on cells. On 2D cell cultures, curcumin inhibits cell tumor development and proliferation at concentrations of 15 MUM, with a viability of 65.7% at 48 hours incubation time. A decreased viability up to 25% for a concentration of 15 MUM was recorded following photoactivation and cytotoxic action on breast cancer tumor cell line continued at concentrations of 7.5 and 3.75 MUM. Curcumin photoactivation increases pro-apoptotic effects in both 2D and 3D tumor cell culture models and also responsiveness to curcumin is slightly reduced in spheroid-like structures. Thus, 3D tumor cell culture systems appear to be the ideal environment for in vitro assays regarding anticancer drug effects on cell viability. PMID- 25826490 TI - Effects of therapy with two combinations of antibiotics on the imbalance of MMP 2/TIMP-2 in chronic periodontitis. AB - Periodontitis represents a chronic bacterial infection that induces immuno inflammatory conditions affecting gingiva and tooth-supporting tissues. The role of some biological mediators in periodontal disease was widely investigated, especially that of MMP-8 and MMP-9. Recently, MMP-2 was also considered to be an appropriate therapeutic target for prevention of periodontal disease progression. However, effects of the combination of metronidazole with amoxicillin or spiramycin on the release and activation of MMP-2 and the balance MMP-2/TIMP-2 were rarely studied. This study was designed to assess the influence of two combinations of antibiotics used for treatment of periodontitis on the balance MMP-2/TIMP-2. Gingival samples obtained from patients with no pharmacological treated chronic periodontitis and those receiving either the association between amoxicillin-metronidazole and spyramicin-metronidazole were processed for paraffin embedding and then used to perform immunohistochemical reactions in order to detect MMP-2 and TIMP-2. All subjects were evaluated clinically and radiographic at the first visit and after treatment completed, the Loe & Silnees gingival index at six sites per tooth for the whole mouth being recorded. Statistical analysis was performed using non-parametrical techniques. Gingiva samples from untreated chronic periodontitis patients revealed a diffuse positive reaction for MMP-2 in the epithelium and also in fibroblasts and macrophages from the lamina propria. For gingiva samples from patients treated with antibiotics, MMP-2 positive reaction was restricted to deep epithelial layers and few cells of the connective tissue. No significant difference was observed for TIMP-2 expression. The clinical indexes were in accordance with immunohistochemical results. After treatment, gingival index values were significantly lower then before (p<0.001) in both groups treated with antibiotics. CONCLUSIONS: The two combinations of antibiotics tested in our study seem to have a dual ability to reduce inflammation as well as to inhibit MMP-2 activity. PMID- 25826491 TI - E-cadherin/CD44 immunophenotype in the epithelial-mesenchymal transition of bladder urothelial carcinomas. AB - The alteration of epithelial stability, which includes changes in the expression of E-cadherin and CD44, is one of the complex biomolecular mechanisms involved in the tumoral epithelial-mesenchymal transition (EMT) process. We followed the E cadherin/CD44 immunophenotype by single and double detections in 25 cases of bladder urothelial carcinomas. Our study investigated simultaneously the differences in expression of the two markers, in different tumoral compartments, according to the prognostic parameters of the lesions. The study indicated significant differences in the expression of E-cadherin in relation to tumor grade, depth of invasion, tumor stage and Ki-67 proliferation index (PI), both intratumoral and at the advancing edge. For CD44, expression differences were found between the tumor grades in intratumoral sites, while for both intratumoral and advancing edge compartments the differences occurred for the depth of tumor invasion, tumor stage and Ki-67 PI. The only differences in the expression of the two markers in relation with the presence of lymph node metastasis were for E cadherin at the advancing edge. In this study, the intratumoral E-caderin-/CD44- immunophenotype, respectively E-caderin-/CD44+ at the advancing edge were associated with the tumor aggressiveness analyzed parameters. The maintenance of CD44 expression at the advancing edge represents a negative prognostic factor for bladder urothelial carcinoma and supports the implication of EMT process, through the existence at this level of a cell population with particular properties. PMID- 25826492 TI - Expression of TLR4 protein is reduced in chronic renal failure: evidence from an experimental model of nephron reduction. AB - Toll-like receptor 4 (TLR4) signaling is involved in various acute and chronic renal lesions and contributes to inflammation and fibrosis in several organs; the latter are important determinants to the progression of chronic kidney disease (CKD). We aimed to assess TLR4 expression in progressive CKD and relate it to severity of kidney damage, using an experimental nephron reduction model. Male Wistar rats were subjected to subtotal nephrectomy using the ligation technique, after 12 weeks of observation, serum creatinine and proteinuria were determined, animals were sacrificed, glomerulosclerosis and interstitial scarring were quantified histologically, and TLR4 expression was assessed by immunohistochemistry. Sham-operated rats served as controls. Case animals had significantly higher creatinine, proteinuria, glomerulosclerosis and tubulointerstitial involvement. TLR4 expression was prominent in proximal tubes, less staining was observed on infiltrating inflammatory cells. Percentage of TLR4 positive tubes was reduced in the subtotal nephrectomy animals, when compared to controls (0.67+/-0.09 versus 0.79+/-0.07, p=0.003). Percentage of TLR4-positive tubes correlated inversely to markers of kidney damage: to proteinuria (r=-0.55, p=0.02), serum creatinine (r=-0.53, p=0.01); percentage of glomeruli with glomerulosclerosis (r=-0.54, p=0.01) and tubulointerstitial score (r=-0.36, p=0.01). As TLR4 staining appears in tubular casts only in nephrectomy animals, shedding from damaged tubular cells is a very likely explanation for the reduced TLR4 expression in the kidneys of subjects with experimental nephron reduction. PMID- 25826493 TI - TNF-alpha evaluation in tonsil cancer. AB - Squamous cell tonsil carcinoma is the most frequent form of oropharyngeal cancer, representing 70-80% of the total of head and neck malignant tumors. Poor clinical symptoms make that 60-80% of patients with squamous cell tonsil carcinoma have a late diagnosis, in the third and fourth stages, when the tumor exceeds the organ limits, invading the pharyngeal wall or the tongue base, being associated with metastases in the laterocervical lymphatic ganglions. The tumor necrosis factor alpha (TNF-alpha) represents an important inflammation mediator associated to carcinogenesis and even to tumor progression. We evaluated the seric values of TNF-alpha in a group of patients with tonsil cancer in comparison to a group of patients with chronic tonsillitis, as well as the reaction of mastocytes and macrophages in the two types of tonsil lesions. Seric levels of TNF-alpha in squamous cell tonsil carcinoma were quite high, varying from 1000 to 2000 pg/mL, and in four patients, with poorly differentiated tonsil carcinoma in the fourth stage, the TNF-alpha values varied from 2000 to 4000 pg/mL. In the patients undergoing radiotherapy, the TNF-alpha seric levels were within normal limits. In chronic tonsillitis, the TNF-alpha seric level varied from 10 to 200 pg/mL. There were not observed any significant differences between the two types of tonsil lesions, regarding the macrophages and mast cells density on the surface unit. PMID- 25826494 TI - Histone acetylation regulates the expression of HoxD9 transcription factor in endothelial progenitor cells. AB - The homeobox (Hox) genes encode transcription factors that are involved in the morphogenesis of body. Recent data showed that the HoxD transcription factors control the cardiovascular system development, by modulation of endothelial cell proliferation and differentiation. For our knowledge, the role of histone acetylation in expression of HoxD9 has not been studied to date; therefore, the aim of this study was to investigate the expression of HoxD9 in endothelial progenitor cells after treatment with valproic acid (VPA), a histone deacetylase inhibitor. Our results showed that VPA inhibits the histone deacetylases leaving chromatin in an acetylated state corresponding to a decondensate conformation. qRT-PCR and Western blot assays showed that the expression of HoxD9 in endothelial progenitor cells treated with VPA was increased at both gene and protein level, suggesting that acetylation regulates HoxD9 expression. Furthermore, flow cytometry analysis revealed that the expression of endothelial specific markers such as CD31, CD105, CD117 and VEGFR2 was decreased in the presence of acetylating agent, VPA. The capacity of endothelial progenitor cells to form vascular networks on Matrigel was also reduced in the presence of VPA. In conclusion, investigating the role of histone acetylation in the regulation of accessibility of transcription factors to genes involved in differentiation can contribute to understanding epigenetic mechanisms underlying the commitment of stem cells. PMID- 25826495 TI - Study of restorative processes in brain laceration in the first seven days after traumatic brain injury. AB - Traumatic brain injuries represent the main cause of death and invalidity all over the world. Persons surviving a severe traumatic brain injury often present long-term disabilities, sensitive and motor deficits, cognitive, vegetative or mental disorders. Brain injuries are directly caused by the traumatic agent, and indirectly caused by the action of cells involved in the restorative process. The main cells involved in the restorative process are microglias and astrocytes. By using an experimental model, we investigated the reaction of these cells in the first week after a severe brain injury, followed by brain laceration. Of the two cell types, the most rapid and intense reaction was held by the macroglias, also known as resident macrophages of the central nervous system. Alongside the activation of local microglias, in the restorative process there were also involved blood monocytes that turned into macrophages. 24 hours after the injury, the number of macrophage cells/mm2 at brain wound level increased 2-4 times, after three days - 10-12 times, and after seven days - over 20 times. The astrocyte reaction was slower, their activation being signaled no sooner than three days from injury, when their number in the perilesional brain parenchyma increased approximately two times, while after seven days - approximately 4-5 times. Both astrocytes and macrophages (microglias), besides their beneficial effects in restoring traumatic brain injuries, may have unfavorable effects upon the nervous cells in the immediate proximity of the injury. Destruction of vascular network by the traumatic agent, and the extremely slow restore of vascularization, partially explain brain neurons death on extend areas. PMID- 25826496 TI - Evaluation of the implantation site morphology in spontaneous abortion. AB - The aim of this study was the characterization of the implantation site through histological and immunohistochemical exams and the evaluation of the changes that appear in the pregnancies ended by spontaneous abortion compared to normal pregnancies ended by requested abortion. One hundred eight patients were divided in two groups: the study group that included 58 patients with spontaneous abortion and the control group that included 50 patients with requested abortion. There has been made uterine curettage in all the cases after a complete preoperative evaluation and the obtained product was sent for histopathological evaluation and immunohistochemical study using a VEGF antibody. Studying the histological sections, we noticed the vasculogenesis stages chronology and then according to the histological aspects of normal pregnancy we noticed the histological changes that occurred at the site of implantation in the cases with pathological pregnancies ended by miscarriage. Our results from this study seem to indicate a correlation between decidual vascular changes and the appearance of miscarriage. In pregnancies ended by miscarriage, we found delays in the trophoblast development according to the gestational age at which the event abortifacient happened. The study emphases the temporal differentiation of utero placental angiogenesis comparing to villous vasculogenesis and angiogenesis in the first trimester miscarriage and normal pregnancy. At the control group, VEGF expression was positive in 88% of cases, while in the study group, pregnancies ended by spontaneous abortion, positive expression of VEGF was present in only 31% of cases. Our data suggest vascular disorders and are in concordance with other histological and ultrasound studies postulating the idea of a link between miscarriage and placental vascular bed pattern changes. PMID- 25826497 TI - The immunoprofile of interstitial Cajal cells within adenomyosis/endometriosis lesions. AB - Adenomyosis and endometriosis are lesions which have aroused the interest for the investigation of antibodies specific to the structures from the composition, but also for the cause behind the appearance of these lesions in completely different structures. The impact they have on fertility is not known entirely, for they are difficult to diagnose. Endometriosis causes infertility and it is a hard to treat lesion. The research performed in the last years has been focused on the so called linkage analysis, or reverse genetics. It refers to identifying the genes which are prone to developing this affection. We investigated clinically 40 female inpatients (n=40) who had underwent genital surgery and received a variegate diagnosis in the "Sf. Ioan" Emergency Hospital, Bucharest, Romania, between January-September 2014 and also their histopathology and immunohistochemistry. We proceeded with the histopathology examination in order to establish a diagnosis in respect to the admission diagnosis and then, using the ABC (Avidin-Biotin complex) method, we analyzed the immunohistochemistry of the following markers: S100 protein (for detection of ganglia and nerve cells), CD117/c-kit (selective detection of interstitial Cajal cells - ICC), desmin and vimentin (intermediary filaments for detecting ICC-like cells, which cohabit with uterine myocytes and are not contractile cells) and CD10 (a sensitive and useful immunomarker in the diagnosis of endometrial stroma and, in some cases, of neoplasia). Our study, regarding the immunoprofile of some markers of adenomyosis/endometriosis lesions, supports the hypothesis that the interstitial Cajal cells are non-reactive, they are not in relationship with investigated lesions, but CD10 is a very useful marker to highlight the endometrial stroma in query cases. PMID- 25826498 TI - Cell populations involved in the processes of local mucosal defense in extended partially edentulous and completely edentulous patients. Clinical and immunohistochemical study. AB - Considering the fact that extended partial edentation and complete edentation have high incidence rates worldwide, the necessity for correct prosthetic treatment is very important. We performed a clinical study on 37 extended partially edentulous patients and completely edentulous patients, who were divided into three groups. We also performed a morphological study using classic techniques of histology and immunohistochemistry methods on sections obtained from oral mucosa fragments collected from these patients and processed by paraffin embedding technique. To identify the cell populations present in the inflammatory processes, we used the CD20, CD8, CD3 and CD68 markers. In the studied cases, we found the presence of changes that have interested both the epithelium and lamina propria. Epithelium showed in particular epithelial hyperplasia aspects, with orthokeratinization and parakeratinization areas and, in some sections, areas of ulceration. We found the inflammatory process present in the lamina propria to be chronic and it consists in particular of lymphocytes, plasma cells and macrophages. This process was differentiated in intensity from one case to another, but varied even within the same case, from one area to another. Inflammation was determined by the local microbial flora enhanced by the action of prosthetic appliances or by the prolonged edentulous state. We observed more intense changes in denture wearers patients. The inflammatory response indicates the reactivity of the edentulous mucosa in response to local aggression, the specific defense mechanism coexisting with the nonspecific defense mechanism, with predominance of cellular immune defense. PMID- 25826499 TI - Identification of the anatomical elements used in periodontal diagnosis on 40 MHz periodontal ultrasonography. AB - Gingival inflammation is highly prevalent among adult populations in all regions of the world. High rates of chronic periodontitis have been reported worldwide. The methods for assessing the gingival inflammation and periodontal disease would need more precision and less user-dependence. The aim of this study consists in identifying the information for diagnosis and staging of periodontal disease using 40 MHz periodontal ultrasonography. Our in vivo study has been made on 49 teeth of 10 patients with marginal periodontal disease. Standard clinical and radiological periodontal examinations were performed. Afterwards the results were compared with the information obtained from images recorded with Ultrasonix SonoTouch used at 40 MHz. On the ultrasound images, were performed very accurate measurements between the cortical bone and the cement-enamel junction or the root wall compared with the measurements made on intraoral digital radiographs. Those measurements could be used to diagnose the bone resorption. In order to monitor the gingival inflammation could be recorded the width of the attached gingival mucosa and the height of the gingival margin on ultrasound images. 40 MHz periodontal ultrasonography is a reliable imagistic method for identifying the necessary anatomical elements in order to make an accurate periodontal diagnosis for the examined area. PMID- 25826500 TI - The loss of Ivy cells and the hippocampal input modulatory O-LM cells contribute to the emergence of hyperexcitability in the hippocampus. AB - Epilepsy is a frequent neurological disorder that affects directly 0.5-1.5% of the world's population. Despite advances regarding therapy, about 30% of patients cannot be relieved of seizures, mainly because the pathophysiological mechanisms are still not elucidated completely. Basket, axo-axonic, bistratified, oriens lacunosum moleculare (O-LM) and Ivy cells exert spatially and temporary different inhibition on principal neurons. Our aim was to evaluate the alterations of these interneuron populations during epileptogenesis. We induced status epilepticus in male Wistar rats using intraperitoneal pilocarpine injection, which was followed, after a latency period, by spontaneous recurrent seizures (SRS). Nissl staining was used for the analysis of gross morphological changes, whereas triple immunofluorescent-labeled sections (parvalbumin, somatostatin, neuropeptide-Y) were used for differentiation of the selected interneuron types. Putative interneurons identified by their neurochemical contents were quantified, and the cell density was calculated. Although animals developing SRS showed similar behavior, the degree of hippocampal sclerosis was different. In animals with hippocampal sclerotic cell death pattern the density of perisomatic inhibitory neurons was higher, but not significantly. The dendritic inhibitory bistratified cells were preserved, whereas the number of O-LM cells showed a significant decrease. A substantial loss was observed in the number and density of Ivy cells. We suggest that the loss of hippocampal input modulatory O-LM cells, and overall excitation controlling Ivy cells, has a role in the emergence of hyperexcitability. In the same time, alterations of output controlling interneurons might contribute to the propagation of the pathological synchronization to the cortex. PMID- 25826501 TI - Macrophage response in patients diagnosed with aseptic necrosis of the femoral head presenting different risk factors. AB - Aseptic necrosis of the femoral head is a condition caused by partial or total interruption of blood supply to the femoral head. The diminished blood supply causes necrosis of the cellular elements and of the bone marrow, followed by the collapse of the bone structure, events that ultimately lead to the destruction of the bone tissue, the appearance of local pain and loss of function in the affected coxofemoral joint. The importance of this condition is that it mainly affects young adults aged 30-50 years, active from a socio-professional standpoint, and increased life expectancy. The material studied to achieve CD68 immunostaining was represented by bone fragments from the area of necrosis and from the adjacent areas of the femoral heads, harvested from 39 patients when performing hip arthroplasty surgery. The patients were diagnosed with aseptic necrosis of the femoral head and hospitalized in the Clinic of Orthopedics and Traumatology, Emergency County Hospital of Craiova, Romania, from June 2014 to January 2015. The 39 patients included in the study were divided into four categories according to presented risk factors (alcohol, alcohol and smoking, trauma, corticosteroids). All the 39 cases had positive immunostaining for CD68, macrophage being highlighted both in the area of necrosis and in the adjacent areas. We noted significant differences in the number and arrangement of macrophages in patients presenting different risk factors. The highest number of macrophages was present in patients presenting a risk factor corticosteroids, and the lowest number of macrophages was found in patients who had trauma as the main risk factor. PMID- 25826502 TI - Synovial inflammation in patients with different stages of knee osteoarthritis. AB - The synovium is an intra-articular mesenchymal tissue and essential for the normal joint function. It is involved in many pathological characteristic processes and sometimes specific for this distinctive tissue. In this study, we refer to synovial proliferative disorders according to the stage of osteoarthritis (OA) disease. Forty-three patients with knee OA were treated in the Department of Orthopedics and Traumatology, Emergency University Hospital of Bucharest, Romania, in the last two years. In all cases, we used at least five criteria for the knee OA: knee pain, knee joint tenderness, no palpable warmth over the knee, stiffness, erythrocyte sedimentation rate and C-reactive protein levels. In all the cases the synovial tissue was selected by the orthopedic surgeon. X-ray examination was taken in every case of the affected joint. Patients who were considered to have early OA underwent arthroscopic synovial biopsy of the symptomatic joint. Synovial tissue samples from patients with late OA were obtained at the time of knee joint arthroplasty. Microscopic examination in early osteoarthritis revealed for more than half of patients with synovial biopsy through arthroscopic technique having synovitis lesions with mononuclear infiltrates, diffuse fibrosis, thickening of the lining layer, macrophages appearance and neoformation vessels also. The synovitis seen in advanced OA knees tends to be diffuse and is not mandatory localized to areas of chondral defects, although an association has been reported between chondral defects and associated synovitis in the knee medial tibio-femoral compartment. The overexpression of mediators of inflammation and the increased mononuclear cell infiltration were seen in early OA, compared with late OA. PMID- 25826503 TI - Histochemical and immunohistochemical evidence of tumor heterogeneity in colorectal cancer. AB - INTRODUCTION: Intratumoral heterogeneity implies the existence of differences between tumor cells, which can best be shown by histochemical and immunohistochemical techniques. The histological study is a mandatory step in any research aimed at characterizing tumor heterogeneity. Immunohistochemistry (IHC) also plays an important role in the differentiation of tumor types, assessing aggressiveness. MATERIALS AND METHODS: Investigated group consisted of 50 patients with colorectal adenocarcinoma, for each were recorded clinicopathological data and harvested samples intraoperatively, which were included in paraffin blocks. We perform Hematoxylin-Eosin staining for histological grade and other indices. IHC study used Avidin-Biotin-Peroxidase (ABC), with the markers: CK7, CK20, MUC1, MUC2, Ki-67, PCNA, p53, KRAS, BCL2, PTEN, EGFR. The resulting data were analyzed by statistical methods. RESULTS: Most of colorectal adenocarcinoma studied had no special histological features and had G2 grade. IHC detected in most cases the CK20+/CK7- phenotype (78%) and MUC1 (74%) protein expression. The proliferation markers (Ki-67 and PCNA) were present in all tumor mass with a variable index, which shows high intratumoral heterogeneity, but p53 and KRAS were distributed more uniformly, showing low intratumoral heterogeneity. PTEN was expressed nuclearly in 86% of the cases and EGFR in 42%. CONCLUSIONS: The expression profiles of cytokeratins and mucins in the colorectal adenocarcinomas are useful in defining tumor phenotypes with different prognosis and therapy. We found a significant positive correlation between KRAS protein expression and BCL2 and TP53 expression. The study demonstrated the intratumoral and intertumoral heterogeneity, expressed at phenotypic level. PMID- 25826504 TI - The prevalence of the red cell morphology changes in patients with type 2 diabetes mellitus. AB - Previous studies have shown that hematological alterations are a common finding in patients with diabetes. The aim of our study was to estimate the prevalence of the red cell morphology changes in diabetic patients and their correlation with markers of glycemic control. Thirty patients with type 2 diabetes mellitus were recruited for this study. Patient demographics, relevant concomitant illnesses and medical history were recorded. Anthropometric, biochemical parameters (fasting plasma glucose - FPG, glycated hemoglobin - HbA1c, glomerular filtration rate - GFR) and morphology of blood smear were assessed. Results were compared with the same measurements in 30 subjects without diabetes mellitus. The groups were similar in terms of age and gender but there were statistically significant differences for the recorded parameters in patients of study group and control subjects. Regarding the assessment of FPG, in the study group were recorded averages of 217.70+/-73.20 mg/dL compared with controls that compared with controls that had a blood glucose value of 90.03+/-6.59 mg/dL. In the study group, mean HbA1c was 7.95+/-1.99%. For the control group, the mean value of HbA1c was 5.65+/-0.32%. In the study group, GFR ranged between 47.70 and 118.90 mL/min./1.73 m2. For the control group, GFR values were between 88.00 and 130.00 mL/min./1.73 m2. In the analysis of blood cytology for the study group, there were changes in the smear type hypochromia, anisocytosis and poikilocyosis (20 patients - 66.66%). In terms of red cell morphology, changes were recorded anulocytes type, red cells in "mark to the target fired" (codocytes), bream (leptocytes), schizocytes, and red cells in "drop" (dacryocytes). We observed a high prevalence of the red cell morphology changes in diabetic patients compared with non-diabetic subjects. Our findings suggest the need of screening for routine hematological tests in type 2 diabetes mellitus. PMID- 25826505 TI - A pilot study on the role of fractal analysis in the microscopic evaluation of colorectal cancers. AB - INTRODUCTION: Colorectal cancer (CRC) represents one of the most common cancers worldwide; its growing incidence and prevalence quickly transforming it into a major health burden. Globally, survival varies from one country to another and constantly remains significantly low, despite increasing diagnostic efforts and tools. Fractal geometry and, specifically, fractal dimension (FD) are interesting tools to quantify cellular elements. In this paper, we aimed to identify and quantify by fractal analysis the elements obtained from medical images from pathological and immunohistochemical investigations of colonic biopsy fragments. MATERIALS AND METHODS: We prospectively selected the study group between September 2014 and January 2015, from patients who underwent surgery for previously diagnosed CRC at the Emergency County Hospital, Craiova, Romania. We performed the histological and immunohistochemical studies by following standardized protocols. Anti-Ki67, anti-p53 and anti-VEGF-C antibodies were used for immunostaining. We performed the fractal analysis with an in-house tool and we performed statistical tests on the results. RESULTS: We have included 41 (29 males) consecutive patients with different characteristics; after analyzing the FDs we found significant differences between adenocarcinomas and the other types of colonic cancers (p<0.001). However, we found no significant differences between most types of CRCs. We found significant statistical differences when compared well-differentiated tumors with all other stages (p<0.001). CONCLUSIONS: Fractal analysis with the calculation of FDs is a novel, interesting tool, for determining the pathologic diagnosis of CRCs and may further improve diagnostic and prognostic rates, thus improving patient care. PMID- 25826506 TI - CT characters versus morphopathological characters in pharyngeal squamous cell carcinoma. AB - Pharyngeal squamous cell carcinoma is a rare neoplasm, whose incidence increases with age. Computed tomography (CT) imaging is an easy way to explore the pharyngeal region, having the advantage of being able to highlight and characterize the existence of a tumor in this region, and to determine its local extension and lymphatic metastasis. In this group were included a total of 27 patients, who, following the histopathological findings were diagnosed with pharyngeal squamous cell carcinoma and who have previously received a CT scan. CT examination protocol included a native scan and post-intravenous administration of contrast medium, in both the arterial phase and in parenchymal and venous phase. The scan was made with 2 mm thin sections, subsequently were performed coronal and sagittal reconstructions. The examination plan included the thoracic region down to the aperture. The paper tries to establish correlations between the morphological appearance and semiological computed tomography characters of the lesions. PMID- 25826507 TI - Relevant infrastructural alterations in invasive pancreatic ductal adenocarcinoma. AB - In this study, we focus our interest on some peculiar infrastructural abnormalities detected in a pancreatic cancer case. Our electron microscopic observations underline the high plasticity of the pancreatic parenchyma cells. Tumor pancreatic exocrine lesions are represented by putative ductal and acinar cells, which proliferate and grow in a haphazard pattern, detrimental to endocrine counterpart. The tumor cells do not exhibit neither a pure ductular or ductal nor a pure acinar phenotype, but tumor lesions represented by neoplastic ductal cells with invasive growth are by far prevalently. In our pancreatic cancer case, electron microscopic investigation clearly shows that a plethora of the epithelial cells from the tumor lesions contain large areas of autophagy leading to the pleomorphic inclusions represented by fibrillary/filamentous inclusions frequently associated with hyaline-amorphous material, and secondary lysosomes. One of the mostly striking and important finding in this report for a case of pancreatic cancer is the high fragility (extensive dissolutions) of plasma membrane of tumor cells leading to pseudo-syncytia formation. Desmosomal junctions are severely altered, almost missing. Plasma membranes showed shedding membrane vesicles. Extravasated inflammatory cells contribute to the dramatic and extensive destructive areas of epithelial cells as well as tumor-stroma counterpart, including the basement membrane. All above severe infrastructural abnormalities, especially down regulation of cell-cell and cell-extracellular matrix adhesions might result in aberrant cell behavior and, consequently, much care should be taken for the postoperatory patient evolution. PMID- 25826508 TI - The use of cone beam computed tomography in the diagnosis and management of internal root resorption associated with chronic apical periodontitis: a case report. AB - Internal root resorption is a consequence of chronic pulp inflammation. Later on, the pulp necrosis followed by a chronic apical periodontitis is installed. Hence, usually, in clinical practice, both lesions have to be simultaneously managed. Conventional periapical radiograph is mandatory in diagnosis. Improving the diagnosis and management of both lesions, cone beam computed tomography proves to be more reliable than conventional radiography. PMID- 25826509 TI - Silent sinus syndrome--report of a case. AB - INTRODUCTION: The "silent sinus syndrome" is a rare entity that was first described in 1964 and given this name 30 years later. Although it is well described both from clinically and radiologically point of view we consider that its rarity still makes it a subject for report. CASE PRESENTATION: A 46-year-old patient was admitted for facial asymmetry, diplopia, unilateral left enophthalmos, and inferior displacement of the eye globe, and decreased occlusal pressure in left dentate region. CT scan revealed interior bulging of all left maxillary sinus walls with osteolysis and intense opacification, enlargement of the left middle meatus especially in the posterior part and lateralization of the uncinate process. Nasal endoscopy with 00 rigid scope visualized mild deviation to the right of the nasal septum, enlargement of the left middle meatus by the lateral deviation of the left intersinusal septum and uncinate process. Surgery was scheduled and performed a left maxillary sinus antrostomy. Histopathological examination on the biopsies revealed inflammation. A complete study was performed to assess the elements of inflammation. Postoperative course was simple. Follow up visit at three and six months, showed significant regression of diplopia and improved facial aspect. CONCLUSIONS: Silent sinus syndrome is a well-defined clinical entity with characteristic imagistic findings. Surgical intervention that restores sinus drainage will interrupt the pathogenesis of the disease and lead to its progressive regression. Topographic associations and density of inflammatory elements analyzed in relation with neoforming vessels suggest their implication in reparatory angiogenesis characteristic to chronic inflammation. Modulating activity in the frame of inflammatory process, of the T-lymphocytes and especially of T-lymphocytes may represent a target for the therapeutic management. Surgery can and should be performed by an endoscopic approach. PMID- 25826510 TI - Giant gastrointestinal stromal tumor of the stomach. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies of the digestive tract. Gastric localization is the most frequent. The aim of this study is to evaluate the importance of immunohistochemical factors (CD117, CD34, alpha-SMA, vimentin, p53, Ki67) in diagnostic and size tumor and mitotic activity as prognostic factors for these tumors. We present the case of a 66-year-old male patient with a giant gastric GIST. Like in the vast majority, the symptomatology in this patient has long been faint, despite the large tumor size, and when it became manifest, it was nonspecific. Imagery wise, the computer tomography (CT) scan was the most efficient, showing the origin of the tumor from the greater curvature of the stomach, its dimensions, as well as the relations with the other abdominal viscera. Surgery in this patient was en bloc, according to the principles of GIST. The histological aspect is characterized by a proliferation of spindle cells positive for CD117 and CD34. Despite complete microscopic resection, the size of the tumor (25*20*27 cm) and the mitotic activity (21/5 mm2) remains important relapse factor. PMID- 25826511 TI - A case with tumor of left parotid gland and denture stomatitis. AB - The article discuss the case of an edentulous patient presented to the dental clinic for pain and burning sensation of oral mucosa and diagnosed subsequently with oxyphilic adenoma. A 58-year-old patient, with maxillary edentulism, treated with complete denture, presented to the Clinic of Prosthetic Dentistry of the Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Romania, for pain of oral mucosa and bad stability of denture. The diagnosis of erythematous denture stomatitis as consequence of salivary flow reduction was establish after patient's clinical examination, and by unstimulated sialometry. Clinical exam suggested hyposalivation could be a consequence of a tumor situated at the level of the left parotid gland. The echography confirmed the diagnosis of left parotid gland tumor. The tumor was surgical removed and histopathological exam confirmed oxyphilic adenoma. Education of patient for wearing new denture while maintaining a strict oral hygiene and dealing with low salivary flow was the treatment for denture stomatitis. General dentist has an important role in finding and diagnosing patients with systemic diseases, especially salivary tumors. PMID- 25826512 TI - Pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia- report of three cases. AB - Pancreatogenous hyperinsulinemic hypoglycemia (PHH) is a rare disorder determined by an abnormally high secretion of insulin in the pancreas, in the absence of other medical or pharmacological factors. Either beta-cell tumors (insulinomas) or beta-cell hyperplasia (nesidioblastosis) can determine this pathology. Most publications on insulinomas or nesidioblastosis approached these subjects from a clinical point of view. This paper aims to analyze pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia. We present two cases of insulinomas with unusual pancreatic localization and size, one of them showing amyloid deposits in the stroma. In both cases, immunohistochemistry confirmed the clinical and imagistic supposition. The third reported case refers to a 57-year old patient with nesidioblastosis with isolated disposition of endocrine cells and areas of focal organization, both morphological aspects being extremely rare in adults. Although clinical and laboratory data are usually identical in the two forms of PHH, histopathological and immunohistochemical diagnosis is essential in differentiating insulinomas from nesidioblastosis, as the surgical management is different: enucleation for insulinomas and total or subtotal pancreatectomy for nesidioblastosis. PMID- 25826513 TI - Microscopic morphological changes of the tooth surface in relation to fixed orthodontic treatment. AB - Orthodontic treatment has, as any other medical intervention, in addition to its benefits, side effects, some of them being perceived as unavoidable. The aim of this case series was to microscopically evaluate the changes of the tooth surface in relation to fixed orthodontic treatment. A case series study was implemented by the usage of four extracted first maxillary premolars, from patients with previous orthodontic treatment, of 12 and 23 months. Analysis was performed using the high precision stereomicroscope (Axiovert, Carl Zeiss, Germany), at magnifications from 10* to 50*. The tooth surface corresponding to the bracket bonding area registered numerous disorderly grooves and cracks, with various directions and depths, and was flattened, having lower convexity compared to teeth surfaces where brackets were not bonded. Root resorption lacunae were more frequently observed in teeth under orthodontic treatment, these having various depths, and sizes considerably larger than those observed in teeth without orthodontic treatment. Following orthodontic treatment, teeth exhibit changes that can be perceived as being directly linked to this medical intervention. These teeth changes usually have low or moderate severity, which can be influenced at some degree by the clinical conduct of the orthodontic treatment. The stereomicroscope proved to be a high sensitivity tool for the analysis of morphological changes of teeth in relation to the fixed orthodontic treatment. PMID- 25826514 TI - Extrarenal retroperitoneal angiomyolipoma with unusual evolution. AB - The aim of this paper is to present the case of an extrarenal retroperitoneal angiomyolipoma with unusual evolution, due to the herniation through the inguinal canal, determining an extraperitoneal hernia. A ureteral duplicity and associated hydronephrosis contributed to the peculiarity of the case. The case was operated (en block tumor and right kidney removal), the postoperative evolution being favorable at seven years after the surgery. PMID- 25826516 TI - Vagus nerve schwannoma in the parapharyngeal space: surgical, histological and immunohistochemical aspects. A case report. AB - Tumors of the parapharyngeal space are rare accounting approximately for 0.5% of all head and neck tumors. In the retrostyloid space, schwannomas are a more common finding, in contrast to other tumors. Usually, they present with a variety of slight symptoms until they grow in size and compress surrounding organs. Surgical treatment of parapharyngeal space tumors is difficult; due to the anatomical complex area, they develop in, and include several approaches, according to its size and relations. In this paper, we present a case of a 63 year-old female with a vagus nerve schwannoma in the parapharyngeal space. Beside the surgical difficulties, the resected tumor had a peculiar histopathological aspect (large areas of degeneration and atypia and little typical palisading) that compelled a thorough histological and immunohistochemical evaluation for positive and differential diagnosis. PMID- 25826515 TI - Gestational choriocarcinoma after term pregnancy: a case report. AB - Choriocarcinoma coexisting with or after a "normal" pregnancy has an incidence of one per 160 000 pregnancies. In case of choriocarcinoma after term pregnancy, early diagnosis by histopathological examination of the placenta is very important, the precocity of the diagnosis influencing the prognosis and tumor response to chemotherapy. In this paper, we report the case of a 29-year-old woman gravidity 2, parity 2, with metastatic choriocarcinoma after term pregnancy, diagnosed at four months after the delivery of a healthy baby. An episode of abundant vaginal bleeding occurred after four months from delivery. The local exam revealed a vaginal tumor whose pathological examination on biopsy samples was inconclusive. Subsequently, she was admitted in our clinic with abundant vaginal bleeding, severe anemia and fever. Abdominal ultrasonography revealed an intracavitary uterine tumoral mass with signs of myometrial invasion to the uterine serosa, strong Doppler signal and moderate ascites. Pulmonary X ray and computed tomography scan excluded extrapelvic tumoral masses. The pretreatment human chorionic gonadotropin (HCG) level was 31 030 IU/mL and her FIGO risk factor score was 8 (high-risk group). Total hysterectomy with bilateral salpingo-oophorectomy and omentectomy was performed as an optimal cytoreduction. Postoperative remaining lesions were represented by the metastasis located in the lower two-thirds of the vagina. Histopathological examination revealed uterine choriocarcinoma with ovarian metastasis. Postoperative was initiated four courses of polychemotherapy. Case evolution was favorable, with the normalization of the betaHCG value in two months postoperative and complete remission of the vaginal metastasis in six weeks postoperative. PMID- 25826517 TI - Analyzing the morphology and intensity of occlusal contacts in implant-prosthetic restorations using T-Scan system. AB - The dentists must have solid knowledge in occlusology in order to obtain predictable long-term results for the implant-prosthetic treatment. The aim of our study was to verify if, with methods and materials currently used in any dental office for occlusal equilibration, the dentist can successfully integrate the implant-prosthetic restoration in the habitual occlusion of the patient. Using the T-Scan II system, we analyzed occlusion of three mandibular class III Kennedy edentulous male patients, from a private practice in Bucharest (Romania), all missing the first mandibular molar and all wearing a metal-ceramic crown on implant. In all these cases, the occlusion of the crowns was adjusted using articulating paper and vinyl polysiloxane biting material. The analysis of occlusion with the T-Scan II system in those three cases showed that the crowns were successfully integrated in the habitual occlusion. This study proves that those traditional methods, which are most frequently used in practice, are good enough to adjust the morphology and intensity of the occlusal contacts, if they are correctly and conscientiously used. PMID- 25826518 TI - Anatomopathological findings in scars: comparative study between different specimens. AB - In spite of the remarkable progress science and medicine have experienced, many facts concerning healing processes and pathological scars are still unknown or incompletely explained. This paper is part of a larger study (research for a PhD thesis) concerning new approaches in the prevention and treatment of pathological post-burn scars. We present and analyze the cases of some patients who developed abnormal scars in order to understand and point out the characteristics, that different types of pathological scars have in common and how we can differentiate them. Knowing what issue to address is the key to any successful therapy. Thus, the information we obtained will help us in applying more appropriate and efficient methods of treatment and in our further research: comparing the efficiency of newer therapies to that of older ones. PMID- 25826519 TI - Biphasic synovial sarcoma in a 19-year-old pregnant woman: a case report. AB - Synovial sarcoma is a rare malignant tumor of mesenchymal multipotent cells. We hereby present a case of synovial sarcoma of the upper left thigh. A 19-year-old patient was referred to our clinic by another hospital in Bucharest, Romania, for a soft tissue mass in the left upper thigh. Local examination of the left thigh revealed a 15/13 cm, ovoid, painful upon touch, soft tissue mass occupying the proximal-medial aspect of the thigh. Bilateral inguinal nodes' enlargement was noticed. Upon suspecting regional node involvement, the surgical team decided to perform left limb amputation due to tumor size and the proximity to major arterial and nervous trunks as well as the femoral shaft, making curative surgery and 'free of disease' resection margins improbable. The patient refused the operation. The surgical team (plastic surgeon, orthopedic surgeon) decided to attempt limb-sparing surgery. After tumor resection, free-of-disease surgical margins were achieved. The pathological examination as well as the immunohistochemistry (IHC) diagnosed a large biphasic synovial sarcoma warranting oncologic treatment. The association between tumor growth and pregnancy poses important therapeutic problems, such as the use of preoperative chemotherapy, potential pregnancy termination, limb amputation versus limb salvage intervention and types of protocols of chemotherapy or radiotherapy indicated. PMID- 25826520 TI - Thoracic endometriosis with a long delay in diagnosis. AB - This paper describes a case of thoracic endometriosis in 36-year-old woman with a long delay in diagnosis. At the admission in the hospital, the patient had a medical history of persistent dysmenorrhea since the age of 13, infertility and an episode of total right pneumothorax two months ago successfully resolved by minimum pleurotomy of the right hemitorax. She came with moderate pain on right hemithorax and dyspnea, which occurred on the first day of menstruation but she did not have any other respiratory symptoms such as hemoptysis, cough. Radiological imaging (chest radiography and computer tomography) at the time of admission confirmed recurrence of the right pneumothorax. She underwent surgical treatment of the right pneumothorax using a single-port video-assisted approach. Intraoperative macroscopic lesions were found catamenial pneumothorax characteristic diagnosis and biopsy material taken (parietal pleura) for histopathology. Immuno-histochemical tests confirmed the diagnosis of thoracic endometriosis. The gonadotropin-releasing hormone analogue was received by the patient early after surgery and there was no clinical or radiological recurrence at a four months follow-up. PMID- 25826521 TI - Velamentous insertion of the umbilical cord vessels with vasa praevia--a case report. AB - Among the abnormal cord insertion pathology, velamentous cord insertion associated with rupture of vasa praevia is the most severe condition related to the outcome of the newborn. In velamentous cord insertion, the fetal vessels run freely through the fetal membranes without protection from Wharton's jelly, umbilical vessels diverging as they traverse the membranes. When the membranes are ruptured, complete tearing of fetal vessels through the torn membranes or partial rupture near the site of membrane rupture may occur. Velamentous insertion occurs in approximately 1% of singleton gestations, but is observed in as many as 15% of monochorionic twin gestations. The risk of perinatal death was doubled in pregnancies with velamentous cord insertion relative to normal cord insertion. This condition can be diagnosed by ultrasonography with a sensitivity of 67% and specificity of 100% in the second trimester. We report a case of a newborn who came from a velamentous cord insertion condition associated with rupture of vasa praevia after the spontaneously membranes rupture. After a difficult resuscitation and stabilization, the newborn survived with a good outcome after the follow-up. PMID- 25826523 TI - Pages from the history of the "Anatomical Meeting" from Cluj. AB - The "Anatomical Meeting" from Cluj was one of the most significant morpho clinical societies from Romania during the interwar period. It was created in 1920 by Professor Titu Vasiliu (1885-1961). The purpose of our paper is to present the most important landmarks of this Society and to put into evidence its place in the Romanian series of morpho-clinical societies. Documentary Material: The activity reports of "Anatomical Meeting" from Cluj, summaries published in "Medical Cluj" journal referring to the presentations and discussions of the cases, which were held at different meetings of this Society. The activity of the "Anatomical Meeting" from Cluj increased, in a significantly and consistently way, the level of morphological and clinical training of physicians from Cluj. There are mentioned some of the most important presentations and the personalities which had special contributions in the evolution of this Society. CONCLUSIONS: The "Anatomical Meeting" was a scientific forum that propagated morpho-clinical concept in Romanian medicine, initially in Cluj, and then on a national level. It contributed to the collaboration between pathologists, clinicians and laboratory physicians from Cluj and favored scientific emulation between them. It also was a tribune from which were discussed a few new medical achievements. PMID- 25826522 TI - Squamous cell carcinoma developed on chronic venous leg ulcer. AB - Chronic venous leg ulcers (VLU), especially long-lasting non-healing ulcers, are among the risk factors for squamous cell carcinoma (SCC). Malignant transformation of a VLU is a rare finding and the relative risk of carcinomatous transformation is quite low (about 5.8). SCC arising in the context of a VLU has a particularly aggressive behavior. A 76-year-old male patient with no relevant medical familial history, with chronic venous insufficiency CEAP C6 for 10 years [recurrent leg ulcers with favorable outcome (healing) after specific local and systemic treatment], showing for about three years one ulcerated lesion located on the anterior upper third of the right calf non-responsive to specific treatment, which subsequently increased their size and merged. Biopsy sample was taken. Histopathology showed epidermal acanthosis, papillomatosis, intense parakeratosis, pseudoepitheliomatous hyperplasia, dysplasia and moderately differentiated squamous cell carcinoma with areas of acantholysis. Immunohistochemistry (Ki67, EMA, cytokeratin 34betaE12 and p63) was performed and all types of immunostaining were moderately to intense positive. Above-knee leg amputation and specific oncologic treatment were proposed as possible curative solutions but the patient refused. Ten months after diagnosis and discharge form the Department of Dermatology, the patient died. Patients with chronic venous leg ulcers and clinically suspicious lesions should be evaluated for malignant transformation of the venous lesion. When diagnosed, malignancy complicating a chronic venous leg ulcer requires a resolute treatment as it may be fatal. PMID- 25826524 TI - First year medical students' attitude toward anatomical corpse dissection and its relationship with their personality. AB - INTRODUCTION: Anatomy is an important and intense mandatory course offered during the first year of medical school. Corpse dissection is very important in Anatomy teaching, and first year students will encounter, most likely for the first time, a dead human body during Anatomy labs. OBJECTIVES: The purpose of this study was to evaluate the anxiety experienced by medical students with no previous corpse dissection background just before, after a week, and then after a month of dissection labs, and to investigate the relationship between students' personality and their attitude towards dissection. SUBJECTS AND METHODS: 138 first year English Section medical students from the "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania, completed a personality inventory, an anxiety scale and a questionnaire to assess their attitudes and reactions to anatomical dissection. RESULTS: The level of anxiety reported by students increased from before the first dissection encounter to after one month of dissection labs. CONCLUSIONS: There is a relationship between the Five Factor model of personality and students' attitudes towards dissection. Medical students could be better prepared for their first corpse dissection experience if the preparation before dissection would take in consideration their psychological traits. PMID- 25826525 TI - .Letter to the editor: Dante and human reproduction: concept of embryogenesis in the Middle Ages. PMID- 25826526 TI - DETECTION OF ANXIETY DISORDERS IN PRIMARY CARE: A META-ANALYSIS OF ASSISTED AND UNASSISTED DIAGNOSES. AB - BACKGROUND: Evidence suggests that general practitioners (GPs) fail to diagnose up to half of common mental disorder cases. Yet no previous research has systematically summarized the evidence in the case of anxiety disorders. The aim of this review was to systematically assess and meta-analyze the diagnostic accuracy of GPs' assisted (i.e., using severity scales/diagnostic instruments) and unassisted (without such tools) diagnoses of anxiety disorders. METHODS: Systematic review (PROSPERO registry CRD42013006736) was conducted. Embase, Ovid Journals--Ovid SP Medline, Pubmed, PsycINFO, Scopus, Web of Science, and Science Direct were searched from January 1980 through June 2014. Seven investigators, working in pairs, evaluated studies for eligibility. The quality of included studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies tool version 2 (QUADAS-2). The main outcome measures were sensitivity and specificity of clinical diagnoses of any anxiety disorder. We pooled sensitivity and specificity levels from included studies using bivariate meta-analyses. RESULTS: Twenty-four studies were included in the meta-analysis with a total sample of 34,902 patients. Pooled sensitivity and specificity were estimated at 44.5% (95% CI 33.7-55.9%) and 90.8% (95% CI 87-93.5%). GPs' sensitivity was higher when diagnoses were assisted (63.6%, 95% CI 50.3-75.1%) than when unassisted (30.5%, 95% CI 20.7-42.5%) to the expense of some specificity loss (87.9%, 95% CI 81.3-92.4% vs. 91.4%, 95% CI 86.6-94.6%, respectively). Identification rates remained constant over time (P-value = .998). CONCLUSIONS: The use of diagnostic tools might improve detection of anxiety disorders in "primary care." PMID- 25826527 TI - Effects of aflatoxin b1 on T-cell subsets and mRNA expression of cytokines in the intestine of broilers. AB - This study was conducted to investigate the effects of aflatoxin B1 (AFB1) on T cell subsets and mRNA expression of cytokines in the small intestine of broilers. One hundred and fifty-six one-day-old healthy Cobb broilers were randomly divided into control group (0 mg/kg AFB1) and AFB1 group (0.6 mg/kg AFB1) with three replicates per group and 26 birds per replicate for 21 days, respectively. At 7, 14, and 21 days of age, the duodenum, jejunum and ileum were sampled for analyzing T cell subsets (CD3+, CD3+CD4+ and CD3+CD8+) by flow cytometry as well as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-gamma and TNF-alpha mRNA expression by qRT PCR. The percentages of T-cells in the intra-epithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) of duodenum, jejunum and ileum in the AFB1 group showed a decreased tendency in comparison to the control group. The mRNA expression of cytokines in the three intestinal segments in the AFB1 group presented a general decline compared with the control groups. Our data demonstrated that 0.6 mg/kg AFB1 in the broilers diet could reduce the percentages of T-cell subsets and the expression level of cytokine mRNA in the small intestine, implying that the immune function of the intestinal mucosa might be affected. The reduction of cytokines mRNA expression may be closely associated with the decreased proportions of T cells subsets induced by AFB1. PMID- 25826528 TI - Application of single molecule fluorescence microscopy to characterize the penetration of a large amphiphilic molecule in the stratum corneum of human skin. AB - We report here on the application of laser-based single molecule total internal reflection fluorescence microscopy (TIRFM) to study the penetration of molecules through the skin. Penetration of topically applied drug molecules is often observed to be limited by the size of the respective drug. However, the molecular mechanisms which govern the penetration of molecules through the outermost layer of the skin are still largely unknown. As a model compound we have chosen a larger amphiphilic molecule (fluorescent dye ATTO-Oxa12) with a molecular weight >700 Da that was applied to excised human skin. ATTO-Oxa12 penetrated through the stratum corneum (SC) into the viable epidermis as revealed by TIRFM of cryosections. Single particle tracking of ATTO-Oxa12 within SC sheets obtained by tape stripping allowed us to gain information on the localization as well as the lateral diffusion dynamics of these molecules. ATTO-Oxa12 appeared to be highly confined in the SC lipid region between (intercellular space) or close to the envelope of the corneocytes. Three main distinct confinement sizes of 52 +/- 6, 118 +/- 4, and 205 +/- 5 nm were determined. We conclude that for this amphiphilic model compound several pathways through the skin exist. PMID- 25826420 TI - Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study. AB - BACKGROUND: Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. METHODS AND FINDINGS: A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >=3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR <= 60 ml/min/1.73 m2. Poisson regression was used to develop a risk score, externally validated on two independent cohorts. In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1:393 chance of developing CKD in the next 5 y in the low risk group (risk score < 0, 33 events), rising to 1:47 and 1:6 in the medium (risk score 0-4, 103 events) and high risk groups (risk score >= 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166 3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. CONCLUSIONS: Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD. PMID- 25826530 TI - Identification of an AMPK phosphorylation site in Drosophila TSC2 (gigas) that regulate cell growth. AB - AMP-activated protein kinase (AMPK) is an important metabolic regulator that mediates cellular adaptation to diverse stresses. One of the AMPK substrates, tuberous sclerosis complex 2 (TSC2), was suggested to mediate AMPK-induced silencing of mTOR complex 1 (mTORC1) signaling that is critical for cell growth. However, it is not known whether the AMPK-dependent TSC2 phosphorylation, originally observed in mammalian cells, is conserved in invertebrates. Here we show that energy depletion inhibits mTORC1 signaling through the AMPK-TSC2 axis in Drosophila S2 cells. We have discovered an AMPK phosphorylation site in TSC2 like genes from many different invertebrate species including Drosophila. The site (Ser1338 in Drosophila TSC2) is specifically and efficiently phosphorylated by AMPK in vitro. To evaluate the functional role of this phosphorylation site in vivo, we generated transgenic flies that can express identical amount of either wild-type or phosphorylation-resistant mutant Drosophila TSC2 in a tissue specific manner. In response to transgenic Sestrin induction, which causes ectopic AMPK activation and subsequent mTORC1 inhibition, wild-type Drosophila TSC2 synergistically reduced tissue growth in the dorsal epithelium of Drosophila wings. However, phosphorylation-resistant mutant Drosophila TSC2 was unable to show such a growth-inhibiting effect, suggesting that this phosphorylation is important for AMPK-dependent regulation of cell growth. PMID- 25826531 TI - Antiangiogenesis, loss of cell adhesion and apoptosis are involved in the antitumoral activity of Proteases from V. cundinamarcensis (C. candamarcensis) in murine melanoma B16F1. AB - The proteolytic enzymes from V. cundinamarcensis latex, (P1G10), display healing activity in animal models following various types of lesions. P1G10 or the purified isoforms act as mitogens on fibroblast and epithelial cells by stimulating angiogenesis and wound healing in gastric and cutaneous ulcers models. Based on evidence that plant proteinases act as antitumorals, we verified this effect on a murine melanoma model. The antitumoral effect analyzed mice survival and tumor development after subcutaneous administration of P1G10 into C57BL/6J mice bearing B16F1 low metastatic melanoma. Possible factors involved in the antitumoral action were assessed, i.e., cytotoxicity, cell adhesion and apoptosis in vitro, haemoglobin (Hb), vascular endothelial growth factor (VEGF), tumor growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) content and N-acetyl-glucosaminidase (NAG) activity. We observed that P1G10 inhibited angiogenesis measured by the decline of Hb and VEGF within the tumor, and TGF-beta displayed a non-significant increase and TNF-alpha showed a minor non-significant reduction. On the other hand, there was an increase in NAG activity. In treated B16F1 cells, apoptosis was induced along with decreased cell binding to extracellular matrix components (ECM) and anchorage, without impairing viability. PMID- 25826529 TI - A review of polyphenolics in oak woods. AB - Polyphenolics, which are ubiquitous in plants, currently are among the most studied phytochemicals because of their perceptible chemical properties and antioxidant activity. Oak barrels and their alternatives, which are widely used in winemaking nowadays, contribute polyphenolics to wines and are thought to play crucial roles in the development of wines during aging. This study summarizes the detailed information of polyphenolics in oak woods and their products by examining their structures and discussing their chemical reactions during wine aging. This paper evaluates the most recent developments in polyphenolic chemistry by summarizing their extraction, separation, and their identification by the use of chromatographic and spectral techniques. In addition, this paper also introduces polyphenol bioactive ingredients in other plant foods. PMID- 25826532 TI - Rapid Characterization of Fatty Acids in Oleaginous Microalgae by Near-Infrared Spectroscopy. AB - The key properties of microalgal biodiesel are largely determined by the composition of its fatty acid methyl esters (FAMEs). The gas chromatography (GC) based techniques for fatty acid analysis involve energy-intensive and time consuming procedures and thus are less suitable for high-throughput screening applications. In the present study, a novel quantification method for microalgal fatty acids was established based on the near-infrared spectroscopy (NIRS) technique. The lyophilized cells of oleaginous Chlorella containing different contents of lipids were scanned by NIRS and their fatty acid profiles were determined by GC-MS. NIRS models were developed based on the chemometric correlation of the near-infrared spectra with fatty acid profiles in algal biomass. The optimized NIRS models showed excellent performances for predicting the contents of total fatty acids, C16:0, C18:0, C18:1 and C18:3, with the coefficient of determination (R2) being 0.998, 0.997, 0.989, 0.991 and 0.997, respectively. Taken together, the NIRS method established here bypasses the procedures of cell disruption, oil extraction and transesterification, is rapid, reliable, and of great potential for high-throughput applications, and will facilitate the screening of microalgal mutants and optimization of their growth conditions for biodiesel production. PMID- 25826534 TI - Reformulation of a clinical-dose system for carbon-ion radiotherapy treatment planning at the National Institute of Radiological Sciences, Japan. AB - At the National Institute of Radiological Sciences (NIRS), more than 8,000 patients have been treated for various tumors with carbon-ion (C-ion) radiotherapy in the past 20 years based on a radiobiologically defined clinical dose system. Through clinical experience, including extensive dose escalation studies, optimum dose-fractionation protocols have been established for respective tumors, which may be considered as the standards in C-ion radiotherapy. Although the therapeutic appropriateness of the clinical-dose system has been widely demonstrated by clinical results, the system incorporates several oversimplifications such as dose-independent relative biological effectiveness (RBE), empirical nuclear fragmentation model, and use of dose averaged linear energy transfer to represent the spectrum of particles. We took the opportunity to update the clinical-dose system at the time we started clinical treatment with pencil beam scanning, a new beam delivery method, in 2011. The requirements for the updated system were to correct the oversimplifications made in the original system, while harmonizing with the original system to maintain the established dose-fractionation protocols. In the updated system, the radiation quality of the therapeutic C-ion beam was derived with Monte Carlo simulations, and its biological effectiveness was predicted with a theoretical model. We selected the most used C-ion beam with alphar = 0.764 Gy( 1) and beta = 0.0615 Gy(-2) as reference radiation for RBE. The C-equivalent biological dose distribution is designed to allow the prescribed survival of tumor cells of the human salivary gland (HSG) in entire spread-out Bragg peak (SOBP) region, with consideration to the dose dependence of the RBE. This C equivalent biological dose distribution is scaled to a clinical dose distribution to harmonize with our clinical experiences with C-ion radiotherapy. Treatment plans were made with the original and the updated clinical-dose systems, and both physical and clinical dose distributions were compared with regard to the prescribed dose level, beam energy, and SOBP width. Both systems provided uniform clinical dose distributions within the targets consistent with the prescriptions. The mean physical doses delivered to targets by the updated system agreed with the doses by the original system within +/- 1.5% for all tested conditions. The updated system reflects the physical and biological characteristics of the therapeutic C-ion beam more accurately than the original system, while at the same time allowing the continued use of the dose-fractionation protocols established with the original system at NIRS. PMID- 25826538 TI - Should kidney donors be genotyped for APOL1 risk alleles? PMID- 25826535 TI - Systematic review of whole body vibration exercises in the treatment of cerebral palsy: Brief report. AB - OBJECTIVE: Whole body vibration (WBV) is increasingly being used to improve balance and motor function and reduce the secondary complications associated with cerebral palsy (CP). The purpose of this study was to systematically appraise published research regarding the effects of static and/or dynamic exercise performed on a vibrating platform on gait, strength, spasticity and bone mineral density (BMD) within this population. METHODS: Systematic searches of six electronic databases identified five studies that met our inclusion criteria (2 at Level II and 3 at Level III-2). Studies were analysed to determine: (a) participant characteristics; (b) optimal exercise and WBV treatment protocol; (c) effect on gait, strength, spasticity and BMD; and (d) the outcome measures used to evaluate effect. As data was not homogenous a meta-analysis was not possible. RESULTS: Several design limitations were identified and intervention protocols are poorly described. The effects on strength, gait, spasticity and BMD in persons with CP remain inconclusive with weak evidence that WBV may improve selected muscle strength and gait parameters and that prolonged exposure may improve BMD; there is currently no evidence that WBV can reduce spasticity. CONCLUSIONS: The evidence for exercise performed on a vibrating platform on mobility, strength, spasticity and BMD in CP remains scant and further larger scale investigations with controlled parameters to better understand the effects of WBV exercises in this population is recommended. PMID- 25826540 TI - Coronary artery stenosis: a new risk factor for chronic kidney injury? AB - Coronary artery stenosis induces renal inflammation and kidney injury in pigs even in the absence of myocardial infarction or clinically significant heart failure. This effect is aggravated by experimentally induced renovascular hypertension. Interestingly, oxidative stress originating from the ischemic myocardium was identified as a possible mediator of this new pathophysiological link between heart and kidney. Renin-angiotensin or sympathetic nervous system activation did not appear to play a role in the observed cardio-renal link. PMID- 25826541 TI - JAK3 talks down to renal 25-hydroxyvitamin D 1alpha-hydroxylase. AB - 25-Hydroxyvitamin D 1alpha-hydroxylase CYP27B1 is expressed in several extrarenal tissues. In the immune system, and likely elsewhere, its expression is not regulated by calcium and phosphate homeostatic inputs. Umbach et al. provide evidence that inflammatory cytokine signaling may also control CYP27B1 expression in renal epithelia. Mice lacking JAK3, a kinase essential for immune homeostasis, displayed mild renal inflammation, elevated renal CYP27B1 expression, and altered phosphate metabolism, linking immune signaling to vitamin D metabolism in the kidney. PMID- 25826542 TI - Take my breath away: necrosis in kidney transplants kills the lungs! AB - Necrosis is not only a regulated process, it is an interconnected molecular network allowing different genetically encoded forms that are more or less immunogenic. Zhao et al. elegantly illustrate this concept, underscore the need for combination therapy to successfully interfere with regulated necrosis, and identify the role of regulated necrosis in the pathophysiology of remote lung injury. PMID- 25826533 TI - Elevated levels of endocannabinoids in chronic hepatitis C may modulate cellular immune response and hepatic stellate cell activation. AB - The endocannabinoid (EC) system is implicated in many chronic liver diseases, including hepatitis C viral (HCV) infection. Cannabis consumption is associated with fibrosis progression in patients with chronic hepatitis C (CHC), however, the role of ECs in the development of CHC has never been explored. To study this question, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) were quantified in samples of HCV patients and healthy controls by gas and liquid chromatography mass spectrometry. Fatty acid amide hydrolase (FAAH) and monoaclyglycerol lipase (MAGL) activity was assessed by [3H]AEA and [3H]2-AG hydrolysis, respectively. Gene expression and cytokine release were assayed by TaqMan PCR and ELISpot, respectively. AEA and 2-AG levels were increased in plasma of HCV patients, but not in liver tissues. Hepatic FAAH and MAGL activity was not changed. In peripheral blood mononuclear cells (PBMC), ECs inhibited IFN-gamma, TNF-alpha, and IL-2 secretion. Inhibition of IL-2 by endogenous AEA was stronger in PBMC from HCV patients. In hepatocytes, 2-AG induced the expression of IL-6, -17A, -32 and COX-2, and enhanced activation of hepatic stellate cells (HSC) co-cultivated with PBMC from subjects with CHC. In conclusion, ECs are increased in plasma of patients with CHC and might reveal immunosuppressive and profibrogenic effects. PMID- 25826543 TI - Friends, social networks, and progressive chronic kidney disease. AB - A report by Dunkler et al. reminds us that social factors are relevant for today's clinical scientist and practitioner. They report that an increasing number of friends reduces the incidence and progression of chronic kidney disease in type 2 diabetes. The observation that 'friends don't let friends' develop kidney disease suggests that social factors, as well as biomarkers, may be relevant in developing 'personalized renal medicine' and may identify areas for future nephrology research and education. PMID- 25826544 TI - Induction of nitric oxide release with nebivolol may improve endothelial dysfunction in polycystic kidney disease. PMID- 25826545 TI - The authors reply. PMID- 25826546 TI - The authors reply. PMID- 25826547 TI - Race, ethnicity, and pediatric transplantation: unanswered question. PMID- 25826548 TI - COL4A3/COL4A4 heterozygous mutations with TBMN presenting as focal segmental glomerulosclerosis. PMID- 25826549 TI - The author replies. PMID- 25826550 TI - Pitfalls with nitric oxide synthase activity assays and their avoidance by gas chromatography-mass spectrometry. PMID- 25826551 TI - The authors reply. PMID- 25826553 TI - The authors reply. PMID- 25826552 TI - Statins in the prevention of lithium-associated diabetes insipidus: preliminary findings. PMID- 25826554 TI - The authors reply. PMID- 25826555 TI - Cardiovascular evaluation of potential transplant recipient: from non-US perspective. PMID- 25826556 TI - The metabolomics grail: promising although not yet holy. PMID- 25826557 TI - Shocking urine. PMID- 25826558 TI - SPECT/CT to diagnose pleuroperitoneal communication-associated hydrothorax in peritoneal dialysis. PMID- 25826560 TI - Examining the effects of accommodation and caregiver burden on relationship satisfaction in caregivers of individuals with OCD. AB - Obsessive-compulsive disorder (OCD) is a debilitating condition that does not always respond well to treatment. People with OCD often require a great deal of assistance from caregivers or family members, which is referred to as family accommodations. Caregivers may experience a great deal of stress, depression, and other problems as a result of caring for their loved one with OCD. They may have decreased relationship satisfaction due to the accommodations required by their family member. The present study examines the experience family members have of caring for someone with OCD and how it relates to caregiver burden, relationship satisfaction, and level of family accommodations. Participants for this study included 50 caregivers of individuals with OCD. Analyses were primarily correlational in nature. Results found that high relationship satisfaction was correlated with caregiver burden and OCD severity. PMID- 25826561 TI - Personality styles and defense mechanisms in a community sample of adolescents: an exploratory study. AB - This study aimed to test if the preference for using certain types of defense mechanisms, according to Ihilevich and Gleser's (1969, 1986) perspective, is associated with personality styles, proposed by Millon (1993), and also, aimed to test if both constructs give a contribution to the identification of global types of psychological functioning in adolescents. Eight hundred and thirty adolescents, ranging in age from 14 to 19 years (M = 16.64, SD = 1.9) participated in the study. The Portuguese versions of the Defense Mechanisms Inventory for Adolescents and the Millon Adolescents Clinical Inventory were administered. Multiple linear regression analysis and principal component analysis were computed. Results demonstrate an association between defense mechanisms and personality styles and both constructs contribute to the identification of two types of psychological functioning in adolescents: an internalizing type and an externalizing type. PMID- 25826562 TI - An evaluation of the construct of earned security in adolescents: evidence from an inpatient sample. AB - In adult attachment research, a group of individuals who convey secure attachments despite recalling difficult early caregiver relationships has been identified. The term earned security refers to individuals in this group, whereas continuous security refers to individuals who convey secure attachments and describe caring early relationships. Evidence on the validity of earned security in adults is mixed--with one longitudinal study showing that earned secure adults, despite contrary recollections, are actually more likely to have experienced positive caregiving than continuous secure adults. There is currently no evidence of earned security in adolescence, and exploring it in this age group may help shed light on the overall problem of the validity of this construct. Therefore, the broad aim of this study was to examine the construct of earned security in a group of inpatient adolescents. First, the authors aimed to identify a group of adolescents with secure attachments and memories of difficult caregiver relationships (i.e., proposed earned secure group) in a sample of 240 inpatient adolescents. Next, to explore external validity, the authors examined whether this group differed from others with regard to internalizing distress and emotion regulation. Findings indicated that a subset of secure adolescents recall difficult caregiving, as has been noted in adults, and that they differ from others with regard to emotion regulation. Despite this preliminary evidence that earned security can be identified in adolescents, the authors conclude with a discussion of the caveats of applying this construct in adolescents as well as adults. PMID- 25826563 TI - Recovery from first-episode psychosis: a dialogical perspective. AB - This study aims to understand the process of change in self and its relationship to recovery in the first 3 months following first-episode psychosis (FEP). Because psychosis is understood as a disorder of self, theories of self are needed to consider how sense of self is affected and restored. The authors used semistructured interviews to explore the experiences of 12 young people who had been diagnosed with FEP. The interviews were conducted at two time points: during the first month following the onset of psychosis and 3 months later. The authors employed Interpretive Phenomenological Analysis to explicate interview data and explore the experience of change following FEP. Themes that emerged in the data came under two superordinate themes: loss of self and strengthening of self. Dialogical theory of self was used to interpret the findings and explore the relationship between sense of self and recovery for young people during this critical phase following FEP. PMID- 25826565 TI - It's a bit over, is that ok? The subtle surplus from tandem alternative splicing. AB - Tandem alternative splice sites (TASS) form a defined class of alternative splicing and give rise to mRNA insertion/deletion variants with only small size differences. Previous work has confirmed evolutionary conservation of TASS elements while many cases show only low tissue specificity of isoform ratios. We pinpoint stochasticity and noise as important methodological issues for the dissection of TASS isoform patterns. Resolving such uncertainties, a recent report showed regulation in a cell culture system, with shifts of alternative splicing isoform ratios dependent on cell density. This novel type of regulation affects not only multiple TASS isoforms, but also other alternative splicing classes, in a concerted manner. Here, we discuss how specific regulatory network architectures may be realized through the novel regulation type and highlight the role of differential isoform functions as a key step in order to better understand the functional role of TASS. PMID- 25826566 TI - A cis-regulatory antisense RNA represses translation in Vibrio cholerae through extensive complementarity and proximity to the target locus. AB - As with all facultative pathogens, Vibrio cholerae must optimize its cellular processes to adapt to different environments with varying carbon sources and to environmental stresses. More specifically, in order to metabolize mannitol, V. cholerae must regulate the synthesis of MtlA, a mannitol transporter protein produced exclusively in the presence of mannitol. We previously showed that a cis acting small RNA (sRNA) expressed by V. cholerae, MtlS, appears to post transcriptionally downregulate the expression of mtlA and is produced in the absence of mannitol. We hypothesized that since it is complementary to the 5' untranslated region (UTR) of mtlA mRNA, MtlS may affect synthesis of MtlA by forming an mtlA-MtlS complex that blocks translation of the mRNA through occlusion of its ribosome binding site. To test this hypothesis, we used in vitro translation assays in order to examine the role MtlS plays in mtlA regulation and found that MtlS is sufficient to suppress translation of transcripts harboring the 5' UTR of mtlA. However, in a cellular context, the 5' UTR of mtlA is not sufficient for targeted repression by endogenous MtlS; additional segments from the coding region of mtlA play a role in the ability of the sRNA to regulate translation of mtlA mRNA. Additionally, proximity of transcription sites between the sRNA and mRNA significantly affects the efficacy of MtlS. PMID- 25826567 TI - Diverse selective regimes shape genetic diversity at ADAR genes and at their coding targets. AB - A-to-I RNA editing operated by ADAR enzymes is extremely common in mammals. Several editing events in coding regions have pivotal physiological roles and affect protein sequence (recoding events) or function. We analyzed the evolutionary history of the 3 ADAR family genes and of their coding targets. Evolutionary analysis indicated that ADAR evolved adaptively in primates, with the strongest selection in the unique N-terminal domain of the interferon inducible isoform. Positively selected residues in the human lineage were also detected in the ADAR deaminase domain and in the RNA binding domains of ADARB1 and ADARB2. During the recent history of human populations distinct variants in the 3 genes increased in frequency as a result of local selective pressures. Most selected variants are located within regulatory regions and some are in linkage disequilibrium with eQTLs in monocytes. Finally, analysis of conservation scores of coding editing sites indicated that editing events are counter-selected within regions that are poorly tolerant to change. Nevertheless, a minority of recoding events occurs at highly conserved positions and possibly represents the functional fraction. These events are enriched in pathways related to HIV-1 infection and to epidermis/hair development. Thus, both ADAR genes and their targets evolved under variable selective regimes, including purifying and positive selection. Pressures related to immune response likely represented major drivers of evolution for ADAR genes. As for their coding targets, we suggest that most editing events are slightly deleterious, although a minority may be beneficial and contribute to antiviral response and skin homeostasis. PMID- 25826568 TI - Noncoding regions of C. elegans mRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript. AB - ADARs (Adenosine deaminases that act on RNA) "edit" RNA by converting adenosines to inosines within double-stranded regions. The primary targets of ADARs are long duplexes present within noncoding regions of mRNAs, such as introns and 3' untranslated regions (UTRs). Because adenosine and inosine have different base pairing properties, editing within these regions can alter splicing and recognition by small RNAs. However, despite numerous studies identifying multiple editing sites in these genomic regions, little is known about the extent to which editing sites co-occur on individual transcripts or the functional output of these combinatorial editing events. To begin to address these questions, we performed an ultra-deep sequencing analysis of 4 Caenorhabditis elegans 3' UTRs that are known ADAR targets. Synchronous editing events were determined for the long duplexes in vivo. Furthermore, the validity of each editing event was confirmed by sequencing the same regions of mRNA from worms that lack A-to-I editing. This analysis identified a large number of editing sites that can occur within each 3' UTR, but interestingly, each individual transcript contained only a small fraction of these A-to-I editing events. In addition, editing patterns were not random, indicating that an editing event can affect the efficiency of editing at subsequent adenosines. Furthermore, we identified specific sites that can be both positively and negatively correlated with additional sites leading to mutually exclusive editing patterns. These results suggest that editing in noncoding regions is selective and hyper-editing of cellular RNAs is rare. PMID- 25826569 TI - The VrrA sRNA controls a stationary phase survival factor Vrp of Vibrio cholerae. AB - Small non-coding RNAs (sRNAs) are emerging regulatory elements in bacteria. The Vibrio cholerae sRNA VrrA has previously been shown to down-regulate outer membrane proteins (OmpA and OmpT) and biofilm matrix protein (RbmC) by base pairing with the 5' region of the corresponding mRNAs. In this study, we present an additional target of VrrA in V. cholerae, the mRNA coding for the ribosome binding protein Vrp. Vrp is homologous to ribosome-associated inhibitor A (RaiA) of Escherichia coli which facilitates stationary phase survival through ribosome hibernation. We show that VrrA down-regulates Vrp protein synthesis by base pairing to the 5' region of vrp mRNA and that the regulation requires the RNA chaperone protein, Hfq. We further demonstrate that Vrp is highly expressed during stationary phase growth and associates with the ribosome of V. cholerae. The effect of the Vrp protein in starvation survival is synergistic with that of the VC2530 protein, a homolog of the E. coli hibernation promoting factor HPF, suggesting a combined role for these proteins in ribosome hibernation in V. cholerae. Vrp and VC2530 are important for V. cholerae starvation survival under nutrient deficient conditions. While VC2530 is down-regulated in cells lacking vrrA, mutation of vrp results in VC2530 activation. This is the first report indicating a regulatory role for an sRNA, modulating stationary factors involved in bacterial ribosome hibernation. PMID- 25826570 TI - RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes. AB - Myocyte enhancer factor 2c (MEF2C) is the MADS-box type transcription factor involved in the differentiation of cardiac and skeletal muscle and synaptic formation. Alternatively spliced transcripts of the MEF2C gene were proven to encode isoforms which exert distinct functions in transcriptional regulation. During the differentiation of brown adipocytes, upregulated RBM4 enhanced skipping of the MEF2Cgamma region which functions as a transcriptional repressor. The presence of an overexpressed MEF2Cgamma- isoform in turn induced transcriptional activity of the RBM4 promoter, constituting a positive feedback circuit in differentiating brown adipocytes. The RBM4-MEF2Cgamma- network induced the expression of "myogenic" miR-1 to a greater extent than did PRDM17, BMP7 C/EBPbeta, or UCP1 transcripts in C3H10T1/2 cells. Overexpression of miR-1 independently exerted the same activity as RBM4 and the MEF2Cgamma- isoform of upregulating brown adipocyte-specific factors in C3H10T1/2 cells, which suggests a potential effect of miR-1 on brown adipocytes. These results indicated that the RBM4-MEF2C-miR-1 network constitutes a novel mechanism which programs the gene expression profile toward the development of brown adipocytes. PMID- 25826571 TI - Design criteria for synthetic riboswitches acting on transcription. AB - Riboswitches are RNA-based regulators of gene expression composed of a ligand sensing aptamer domain followed by an overlapping expression platform. The regulation occurs at either the level of transcription (by formation of terminator or antiterminator structures) or translation (by presentation or sequestering of the ribosomal binding site). Due to a modular composition, these elements can be manipulated by combining different aptamers and expression platforms and therefore represent useful tools to regulate gene expression in synthetic biology. Using computationally designed theophylline-dependent riboswitches we show that 2 parameters, terminator hairpin stability and folding traps, have a major impact on the functionality of the designed constructs. These have to be considered very carefully during design phase. Furthermore, a combination of several copies of individual riboswitches leads to a much improved activation ratio between induced and uninduced gene activity and to a linear dose dependent increase in reporter gene expression. Such serial arrangements of synthetic riboswitches closely resemble their natural counterparts and may form the basis for simple quantitative read out systems for the detection of specific target molecules in the cell. PMID- 25826572 TI - Surface immobilization and bioactivity of TGF-beta1 inhibitor peptides for bone implant applications. AB - TGF-beta1 is the most related cytokine with the production of fibrotic tissue. It plays an important role on the production of collagen by fibroblasts and other types of cells. The inhibition of this cytokine reduces fibrosis in various types of tissue. Biofunctionalization of dental and orthopedic implants with biomolecules enables modification of the physical, chemical and biochemical properties of their surfaces to improve its biological and clinical performance. Our objective was to develop a reliable method to immobilize oligopeptides on Ti surfaces to obtain a surface with TGF-beta1 inhibitory activity that will potentially minimize fibrotic encapsulation of implants during the process of osseointegration. We covalently immobilized TGF-beta1 inhibitor P17-peptides on Ti surfaces and assessed by characterizing each step of the process that we successfully biofunctionalized the implant surfaces. High amounts of peptides were anchored and homogeneously distributed on the surfaces with mechanical and thermochemical stability after in vitro simulated challenges. Notably, the immobilized peptides retained their TGF-beta1 inhibitory activity in vitro. Thus, these biofunctional coatings are potential candidates for inducing a fast and reliable osseointegration in vivo. PMID- 25826573 TI - Computational study of peptide plane stacking with polar and ionizable amino acid side chains. AB - Parallel and T-shaped stacking interactions of the peptide plane with polar and ionizable amino acid side chains (including aspartic/glutamic acid, asparagine/glutamine, and arginine) are investigated using the quantum mechanical MP2 and CCSD computational methods. It is found that the electrostatic interaction plays an essential role in determining the optimal stacking configurations for all investigated stacking models. For certain complexes, the dispersion interaction also contributes considerably to stacking. In the gas phase, the stacking interaction of the charged system is stronger than that of the neutral system, and T-shaped stacking is generally more preferred than parallel stacking, with the stacking energy in the range of -4 to -18 kcal/mol. The solvation effect overall weakens stacking, especially for the charged system and the T-shaped stacking configurations. In water, the interaction energies of different stacking models are comparable. PMID- 25826574 TI - A Qualitative Investigation of Gerontological Practice: The Views of Social Work and Psychology Students, Faculty, and Practitioners. AB - Recently there has been an increase in the population of older adults; however, this increase has not been reflected in the helping professions. The aim of this study was to qualitatively investigate barriers to working with older adults within the human service professions. An online survey was sent to students, academic faculty, and practitioners from the disciplines of social work and psychology throughout Australia, addressing issues related to work with older adults. Thematic analysis was used to extract themes and subthemes from the responses (N = 252). The most important finding was that a barrier to working with older adults appears to be a consequence of a perpetuating cycle among students, academic faculty, and professionals collectively. Faculty members did not feel knowledgeable in the area of gerontology and were therefore not able to educate students in this area appropriately, leading to students to enter the workforce as either faculty members and/or practitioners without expertise to work with older adults. This study highlighted the importance of including more comprehensive gerontological information within social sciences' curriculum, which may promote more realistic images of older adults and help alleviate barriers to working with this population. PMID- 25826576 TI - Heteroleptic naphthalo-phthalocyaninates of lutetium: synthesis and spectral and conductivity properties. AB - Novel heteroleptic naphthalo-phthalocyaninates of lutetium possessing a symmetrical substituted naphthalocyanine deck were synthesized on the basis of two preformed synthetic blocks: naphthalocyanine ligand and lutetium phthalocyaninates. The compounds obtained were characterized by (1)H NMR and high resolution MALDI-TOF/TOF mass spectrometry. The correlation between the nature of the substituents and the spectral properties of the target complexes was determined by the introduction of electron-donating (aryl-, aryloxy-) or electron withdrawing (chloro-) substituents into the phthalocyanine deck. In addition, the nature of peripheral substituents was shown not to affect drastically the phthalocyanine conductivity and activation energy. Conductivity properties depend on thin film morphology which, in turn, relies on intermolecular pi-pi interactions. PMID- 25826575 TI - Mechanistic Investigation of the Radical S-Adenosyl-L-methionine Enzyme DesII Using Fluorinated Analogues. AB - DesII is a radical S-adenosyl-l-methionine (SAM) enzyme that can act as a deaminase or a dehydrogenase depending on the nature of its TDP-sugar substrate. Previous work has implicated a substrate-derived, C3-centered alpha-hydroxyalkyl radical as a key intermediate during catalysis. Although deprotonation of the alpha-hydroxyalkyl radical has been shown to be important for dehydrogenation, much less is known regarding the course of the deamination reaction. To investigate the role played by the C3 hydroxyl during deamination, 3-deutero-3 fluoro analogues of both substrates were prepared and characterized with DesII. In neither case was deamination or oxidation observed; however, in both cases deuterium was efficiently exchanged between the substrate analogues and SAM. These results imply that the C3 hydroxyl plays a key role in both reactions thereby arguing against a 1,2-migration mechanism of deamination-and that homolysis of SAM concomitant with H atom abstraction from the substrate is readily reversible when forward partitioning is inhibited. PMID- 25826577 TI - Surface Analytical Methods Applied to Magnesium Corrosion. AB - Understanding magnesium alloy corrosion is of primary concern, and scanning probe techniques are becoming key analytical characterization methods for that purpose. This Feature presents recent trends in this field as the progressive substitution of steel and aluminum car components by magnesium alloys to reduce the overall weight of vehicles is an irreversible trend. PMID- 25826578 TI - Robustness in the fitting of molecular mechanics parameters. AB - Automated methods for force field parametrization have attracted renewed interest of the community, but the robustness issues associated with the often ill conditioned nature of parameter optimization have been vastly underappreciated in the recent literature. For this reason, this article offers a detailed description of the origin and nature of these issues. This includes a discussion of the restrained electrostatic potential fit (RESP) charge model, which does contain explicit robustness-enhancing measures albeit not in the context of bonded parameters, and which forms an inspiration for the present work. It is also discussed how all the bonded parameters in a Class I force field can be simultaneously fit using the linear least squares (LLS) procedure, and a novel restraining strategy is presented that overcomes robustness issues in the LLS fitting of bonded parameters while minimally impacting the fitted values of well behaved parameters. Two variants of this methodology are then validated through a number of case studies, including the fitting of bond-charge increments, which illustrates the method's potential for robustly solving general LLS problems beyond force field parametrization. PMID- 25826579 TI - Enhanced Estrogenic Activity of Soybean Isoflavones by Coadministration of Liuwei Dihuang Pills in Ovariectomized Rats. AB - Soybean isoflavones are beneficial for treating hormone-related diseases. Simultaneous consumption of soybean isoflavones and Liuwei Dihuang pills (LWPs) is effective for treating perimenopausal period syndrome. However, why the combination of isoflavones and LWPs is more effective than ingestion of each component alone remains unknown. Here, we show that enhanced estrogenic activities would appear when the ovariectomized rats were fed with a soybean diet in combination of LWPs treatment. Our further studies explored enhancements of Lactobacillus (19-fold) and Bifidobacterium (12-fold) contents in the intestine of rat and 1.84-fold higher intestinal beta-glucosidase activity in LWPs treatment group compared with the control group. As a result, steady-state concentrations of genistein (1.20-fold), daidzein (1.36-fold), and equol (1.43 fold) in serum were significantly elevated in the combination group compared with the soybean alone group. The results present the first evidence of the mechanism of enhanced estrogenic activity of dietary soybean isoflavones in combination with LWPs. Our study indicates that alterations of gut bacteria after LWPs treatment play a key role in the enhanced estrogenic effect of dietary soybean, suggesting a direct relationship between dietary soybean, LWPs, and gut flora. PMID- 25826580 TI - Correction: Organization of astaxanthin within oil bodies of Haematococcus pluvialis studied with polarization-dependent harmonic generation microscopy. PMID- 25826581 TI - Correction: enabling dynamic partnerships through joint degrees between low- and high-income countries for capacity development in global health research: experience from the Karolinska Institutet/Makerere University Partnership. AB - [This corrects the article DOI: 10.1371/journal.pmed.1001784.]. PMID- 25826582 TI - Sukhareva--Prior to Asperger and Kanner. AB - As early as 1926, the Kiev-based child psychiatrist Grunya Efimovna Sukhareva (Grunya Efimovna Suxareva) (1891-1981) published a detailed description of autistic traits in a number of children in a scientific German psychiatry and neurology journal. She initially used the term "schizoid (eccentric) psychopathy" but later replaced it with "autistic (pathological avoidant) psychopathy" to describe the clinical picture of autism. Her original article was available almost two decades before the case reports of Asperger and Kanner; nevertheless, Sukhareva's pioneer work has been greatly overlooked. Here we present her description of autistic psychopathy in relation to the DSM-5 criteria of today. PMID- 25826584 TI - Cystic fibrosis and non-cystic fibrosis bronchiectasis. PMID- 25826583 TI - Identification of the sAPRIL binding peptide and its growth inhibition effects in the colorectal cancer cells. AB - BACKGROUND: A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) super family. It binds to its specific receptors and is involved in multiple processes during tumorigenesis and tumor cells proliferation. High levels of APRIL expression are closely correlated to the growth, metastasis, and 5-FU drug resistance of colorectal cancer. The aim of this study was to identify a specific APRIL binding peptide (BP) able to block APRIL activity that could be used as a potential treatment for colorectal cancer. METHODS: A phage display library was used to identify peptides that bound selectively to soluble recombinant human APRIL (sAPRIL). The peptides with the highest binding affinity for sAPRIL were identified using ELISA. The effects of sAPRIL-BP on cell proliferation and cell cycle/apoptosis in vitro were evaluated using the CCK-8 assay and flow cytometry, respectively. An in vivo mouse model of colorectal cancer was used to determine the anti-tumor efficacy of the sAPRIL-BP. RESULTS: Three candidate peptides were characterized from eight phage clones with high binding affinity for sAPRIL. The peptide with the highest affinity was selected for further characterization. The identified sAPRIL-BP suppressed tumor cell proliferation and cell cycle progression in LOVO cells in a dose-dependent manner. In vivo in a mouse colorectal challenge model, the sAPRIL-BP reduced the growth of tumor xenografts in nude mice by inhibiting proliferation and inducing apoptosis intratumorally. Moreover, in an in vivo metastasis model, sAPRIL-BP reduced liver metastasis of colorectal cancer cells. CONCLUSIONS: sAPRIL-BP significantly suppressed tumor growth in vitro and in vivo and might be a candidate for treating colorectal cancers that express high levels of APRIL. PMID- 25826586 TI - Genotypes and phenotypes in cystic fibrosis and cystic fibrosis transmembrane regulator-related disorders. AB - Cystic fibrosis (CF) is characterized by remarkable variability in severity, rate of disease progression, and organ involvement. In spite of the considerable amount of data collected on the relationship between genotype and phenotype in CF, this is still a challenging matter of debate. Barriers to the interpretation of this connection are the large number of mutations in the CF transmembrane regulator (CFTR) gene, the difficulties in attributing several of them to a specific mode of dysfunction, and a limited number of the almost 2,000 mutations so far detected, which have been clinically annotated. In addition to that, the heterogeneity of clinical manifestations in individuals with the same CFTR genotypes indicates that disease severity is modulated by other genes and by environmental factors, of which the most relevant is possibly treatment in its aspects of appropriateness, early start in life, and adherence. The phenotype variability extends to conditions, named CFTR-related disorders, which are connected with CFTR dysfunction, but do not satisfy diagnostic criteria for CF. The current level of knowledge does not allow use of the CFTR genotype to predict individual outcome and cannot be used as an indicator of CF prognosis. This might change with the development of treatments targeting specific mutations and possibly capable of changing the natural history of the disease. PMID- 25826585 TI - Primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder of cilia structure, function, and biogenesis leading to chronic infections of the respiratory tract, fertility problems, and disorders of organ laterality. The diagnosis can be challenging, using traditional tools such as characteristic clinical features, ciliary function, and ultrastructural defects and newer screening tools such as nasal nitric oxide levels and genetic testing add to the diagnostic algorithm. There are 32 known PCD-causing genes, and in the future, comprehensive genetic testing may screen young infants before developing symptoms, thus improving survival. Therapies include surveillance of pulmonary function and microbiology, in addition to airway clearance, antibiotics, and early referral to bronchiectasis centers. As with cystic fibrosis (CF), standardized care at specialized centers using a multidisciplinary approach likely improves outcomes. In conjunction with the CF foundation, the PCD foundation, with experienced investigators and clinicians, is developing a network of PCD clinical centers to coordinate the effort in North America and Europe. As the network grows, clinical care and knowledge will improve. PMID- 25826587 TI - Imaging in cystic fibrosis and non-cystic fibrosis bronchiectasis. AB - Bronchiectasis is defined as a permanent and progressive dilation of the airways, typically as a result of inflammation, infection, and subsequent repair. It typically presents with chronic cough, suppurative sputum production, and airway dilation. High-resolution computed tomography (HRCT) is now well established as the primary imaging tool for its investigation. Cystic fibrosis (CF) remains the most common autosomal recessive inherited disorder worldwide and its pulmonary hallmark is bronchiectasis. Although CF and non-CF bronchiectasis are different clinical entities, they are typically imaged using HRCT and share many imaging aspects, and also some differences. Several important recent CT technology developments have improved the detection and characterization of bronchiectasis and its complications. Many CT aspects of radiation exposure have also undergone important enhancements in recent years resulting in significant dose reductions. This is particularly relevant in a pulmonary disease such as bronchiectasis, which often undergoes serial HRCT surveillance in contemporary practice. Several new CT clinical applications in bronchiectasis have been recently advanced, and CT is now being increasingly incorporated into investigative algorithms to assess bronchiectasis treatment effects. In this review, we assess the latest imaging features of CF and non-CF bronchiectasis, discuss radiation dose reducing methods and technology of the latest scanners, describe recent CT clinical applications, and explore the use of CT as a treatment surrogate in CF and non-CF bronchiectasis. PMID- 25826588 TI - Fungi in cystic fibrosis and non-cystic fibrosis bronchiectasis. AB - Bronchiectasis is a pathologic bronchial dilatation with loss of function that can result from multiple inflammatory and infectious injuries to the conducting airways of the lung. Molds, particularly the filamentous fungus Aspergillus fumigatus, have been implicated as a common cause of both cystic fibrosis (CF) and non-CF bronchiectasis, the latter primarily in patients with severe asthma. The pathogenesis of mold-associated bronchiectasis is usually due to atopic sensitization to mold allergens in the presence of active chronic endobronchial fungal infection with host innate and adaptive immune deviation to a Th2 dominated inflammation, a condition known as allergic bronchopulmonary aspergillosis (ABPA) (or allergic bronchopulmonary mycosis if a non-Aspergillus mold is implicated). Diagnostic criteria of ABPA continue to evolve, while treatment relies upon downregulation of the allergic inflammatory response with immunomodulatory agents and antifungal pharmacotherapy. PMID- 25826589 TI - Nontuberculous mycobacteria in cystic fibrosis and non-cystic fibrosis bronchiectasis. AB - Increasing numbers of cystic fibrosis (CF) and non-CF bronchiectasis patients are affected by pulmonary nontuberculous mycobacteria (NTM) infection worldwide. Two species of NTM account for up to 95% of the pulmonary NTM infections: Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC). Diagnosis of pulmonary NTM infection is based on criteria specified in the 2007 American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) guidelines. While many initial positive cultures do not progress to active NTM disease, even a single positive NTM sputum culture obtained from higher risk groups such as classic CF or older women with bronchiectasis and very low body mass index should be closely monitored for progressive disease. Macrolides remain the most effective agents available against MAC and MABSC. Infection with MABSC may be associated with worse clinical outcomes, as more than half of MABSC isolates have inducible macrolide resistance conferred by an active erm(41) gene. Of growing concern in CF is that MABSC is becoming more common than MAC, seems to target younger patients with classic CF, and is more difficult to manage, often requiring prolonged courses of intravenous antibiotics. Recurrence rates of NTM after initial successful treatment remain high, likely due to nonmodifiable risk factors raising the question of whether secondary prophylaxis is feasible. More rapid and readily available methods for detecting inducible macrolide resistance and better in vitro susceptibility testing methods for other drugs that correlate with clinical responses are needed. This is crucial to identify more effective regimens of existing drugs and for development of novel drugs for NTM infection. PMID- 25826590 TI - The microbiome and emerging pathogens in cystic fibrosis and non-cystic fibrosis bronchiectasis. AB - Chronic pulmonary sepsis is the predominant cause of morbidity for patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously it was thought that respiratory infection in these patients was mostly limited to a very small number of typical pathogens; however, in recent years there have been increasing reports of infection with other emerging potential pathogens including Burkholderia, Stenotrophomonas, Achromobacter, Ralstonia, Pandoraea, nontuberculous mycobacteria, and fungal species. Furthermore, culture-independent methodologies have established that the lungs of patients with CF and non-CF bronchiectasis comprise mixed microbiological communities of aerobic and anaerobic bacteria, fungal and viral species, collectively referred to as the lung microbiome. This article addresses the clinical relevance of emerging pathogens and the lung microbiome in CF and non-CF bronchiectasis. PMID- 25826591 TI - Clinical updates in cystic fibrosis-related diabetes. AB - Improved clinical care has led to a dramatic increase in life expectancy for people with cystic fibrosis (CF). As they live longer, people with CF are therefore developing secondary complications. Cystic fibrosis-related diabetes (CFRD) is the commonest extrapulmonary complication of CF. Insulin deficiency is the primary defect in CFRD, but insulin resistance and impairment of the enteroinsular axis play contributory roles. CFRD affects 9% of people with CF aged 5 to 9 years, 26% aged 10 to 20 years, and up to 50% by the age of 30. The presence of CFRD is associated with accelerated decline in pulmonary function, poorer growth and nutritional status, and increased mortality. The need for early detection of abnormal glucose handling in CF is clear since it is linked with clinical decline. Patients with CFRD may be asymptomatic for many years, so it is recommended that screening be commenced at 10 years of age. Although oral glucose tolerance test is recommended, it is well recognized that early glucose handling abnormalities will not be detected and the chance to intervene early may be missed. Many centers are therefore using continuous glucose monitoring to refine the diagnosis and investigate real-life glycemic control. Future research will hopefully widen our understanding of the pathophysiology of CFRD and therefore the treatment options available. There are clearly some promising results suggesting the use of oral agents may prove beneficial in treating CFRD but insulin should remain the mainstay of treatment until these are further evaluated. PMID- 25826592 TI - Airway clearance strategies in cystic fibrosis and non-cystic fibrosis bronchiectasis. AB - Many patients with cystic fibrosis (CF) and non-CF bronchiectasis present with common symptoms in clinical domains that appear to benefit from airway clearance strategies. These symptoms include chronic productive cough, retention of excessive, purulent mucus in dilated airways, impairment of normal mucociliary clearance (MCC), atelectasis, breathlessness, fatigue, respiratory inflammation, fever, infection, and airflow obstruction. Airway clearance strategies may involve singular and focused interventions for the purpose of removing secretions and improving lung recruitment and gas exchange in patients with atelectasis. Strategies may also involve indirect or adjunctive interventions that facilitate or enhance effective airway clearance at different ages or stages of the disease process, for example, inhalation therapy, exercise, oxygen therapy, or noninvasive ventilation. The aim is to optimize care by selecting any one or combination of these in responding intelligently and sensitively to individual and changing patient requirements during their lifetime. Currently, a solid evidence base does not exist for airway clearance strategies in CF and non-CF bronchiectasis, and much of airway clearance clinical practice remains in the domain of clinical expertise. The paucity of evidence is partly explained by the relatively immature research machinery in allied health care internationally but is also partly to do with inadequate or inappropriate research designs. This article aims to provide an overview of the nature of, and physiological basis for, the direct and indirect airway clearance strategies in CF and non-CF bronchiectasis with reference to the best available evidence. PMID- 25826593 TI - Inhaled antibiotics in Cystic Fibrosis (CF) and non-CF bronchiectasis. AB - Bronchiectasis is a pathological diagnosis describing dilatation of the airways and is characterized by chronic lung sepsis. Bronchiectasis has multiple etiologies, but is usually considered in terms of whether it is due to the genetic disorder cystic fibrosis (CF) or secondary to other causes (non-CF bronchiectasis, NCFB). Inhaled antibiotics are used in bronchiectasis to suppress bacterial pathogens and reduce long-term lung function decline. The majority of the literature on inhaled antibiotics comes from studies on CF where the dominant bacterial pathogen in the airway is usually Pseudomonas aeruginosa. Thus, most aerosolized antibiotic regimens target this bacterium, but the emergence of molecular diagnostic methods has questioned this approach and more tailored strategies may need to be considered in CF based on the community composition of the lung microbiome. Similarly, the lung microbiome in NCFB has been found to be a complex polymicrobial one and the current practice of employing the same inhaled antibiotic regimes as are used in CF may no longer be appropriate in many patients. In this article, the use of inhaled antibiotics in CF and NCFB is considered in the light of improved understanding of the lung microbiome and why more tailored therapy may be needed based on molecular identification of the microbial pathogens present. The evidence for the use of currently available inhaled antibiotics and advances in inhaled drug packaging and delivery devices are discussed. Finally, the urgent need for prospective randomized clinical trials in CF and NCFB is highlighted and areas for future research identified. PMID- 25826594 TI - Cystic fibrosis transmembrane conductance regulator modulators: the end of the beginning. AB - Cystic fibrosis (CF) represents one of the success stories of modern medicine with sustained incremental increases in the survival from one of childhood death to one of adult survival into the middle decades over the past 30 years. Improving survival has focused on multidisciplinary management centered on treating the consequences of this genetic disease. It has been firmly established for more than 20 years that mutations in the CF transmembrane conductance regulator (CFTR) gene result in a defective protein that normally functions as a chloride channel on epithelial cell surfaces. Until recently, modulating CFTR dysfunction was only a research aspiration, however, greater focus placed upon addressing the primary defect of CF has developed several clinical therapeutic strategies in this area. This review highlights the evidence to date on efforts to modulate CFTR and restore robust functional protein to the cell surface. This approach has now led to the licensing of one CFTR potentiator, which has been shown to have significant clinical improvements in a subset of CF patients. This success represents the beginning for CFTR modulation and further research is ongoing which aims to broaden the applicability of these techniques. PMID- 25826596 TI - Association of thyroid diseases with primary extra-thyroidal malignancies in women: results of a cross-sectional study of 6,386 patients. AB - We here analyzed the prevalence of extra-thyroidal malignancies (EM) in 6,386 female patients affected by different thyroid disease (TD). At first, an age matched analysis of EM in all patients was performed. We then evaluated EM prevalence in four TD diagnostic categories: non-nodular TD (n = 2,159); solitary nodule (n = 905); multinodular TD (n = 2,871); differentiated thyroid cancers (n = 451). Finally, patients were grouped based on the absence (n = 3,820) or presence of anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (TPOAb) (n = 2,369), or anti-Thyroid Stmulating Hormone (TSH) receptor autoantibodies (n = 197). A total of 673 EM were recorded. EM prevalence in TD patients was higher compared to the general population (Odds Ratio, OR 3.21) and the most frequent EM was breast cancer (OR 3.94), followed by colorectal (OR 2.18), melanoma (OR 6.71), hematological (OR 8.57), uterus (OR 2.52), kidney (OR 3.40) and ovary (OR 2.62) neoplasms. Age-matched analysis demonstrated that the risk of EM was maximal at age 0-44 yr (OR 11.28), remaining lower, but significantly higher that in the general population, in the 45-59 and 60-74 year age range. Breast and hematological malignancies showed an increased OR in all TD, while other cancers associated with specific TD. An increased OR for melanoma, breast and hematological malignancies was observed in both TPOAb and/or TgAb autoantibody negative and positive patients, while colorectal, uterus, kidney and ovary cancers showed an increased OR only in thyroid autoantibody negative patients. In conclusions, women affected by both benign and malignant TD, especially at a younger age and in absence of thyroid autoimmunity, have an increased risk of developing primary EM, thus requiring a careful follow-up and surveillance. PMID- 25826597 TI - Machine-based method for multiplex in situ molecular characterization of tissues by immunofluorescence detection. AB - Immunofluorescent staining is an informative tool that is widely used in basic research. Automation of immunostaining improves reproducibility and quality of the results. Up to now, use of automation in immunofluorescent staining was mostly limited to one marker. Here we present tyramide signal amplification based method of multiple marker immunofluorescent detection, including detection of antibodies, raised in the same species, in tissue sections and cultured cells. This method can be beneficial for both basic and clinical research. PMID- 25826601 TI - Bioconcentration and transfer of the organophorous flame retardant 1,3-dichloro-2 propyl phosphate causes thyroid endocrine disruption and developmental neurotoxicity in zebrafish larvae. AB - Organophosphate flame retardants are emerging environmental contaminants, although knowledge of their health risks is limited. Here, thyroid hormone homeostasis and neuronal development was studied in the progeny of adult zebrafish exposed to tris(1,3-dichloro-2-propyl) phosphate (TDCPP). Adult zebrafish were exposed to TDCPP (0, 4, 20, and 100 MUg/L) for 3 months. Increased generation of reactive oxygen species and reduced survival rates was observed in exposed F1 larvae. We also observed a significant decrease in plasma thyroxine and 3,5,3'-triiodothyronine levels in F0 females and F1 eggs/larvae. The mRNA and protein expression of factors associated with neuronal development (e.g., alpha1 tubulin, myelin basic protein, and synapsin IIa) were significantly downregulated in exposed F1 larvae, as was the level of the neurotransmitters dopamine, serotonin, gamma amino butyric acid, and histamine. Larval locomotion was significantly decreased in exposed fish, but there was no effect on acetylcholinesterase activity. Bioconcentration of TDCPP was observed in F0 fish. TDCPP was also detected in F1 eggs following parental exposure, indicating maternal transfer of this compound. This study uniquely shows that TDCPP can be transferred to the offspring of exposed adults, causing thyroid endocrine disruption and developmental neurotoxicity. PMID- 25826598 TI - Dietary supplement use among cancer survivors of the NutriNet-Sante cohort study. AB - Dietary supplements (DS) may influence cancer prognosis. Their use in cancer patients has been described in the United States, but data are largely lacking in Europe and notably in France. The present study's objectives were (1) to assess DS use and its sociodemographic, lifestyle, and dietary correlates in a large sample of French cancer survivors; (2) to evaluate the involvement of physicians in such DS use; and (3) to assess the extent of potentially harmful practices. Data were collected by self-administered web-based questionnaires among participants of the NutriNet-Sante cohort. Data on DS use was available for 1081 cancer survivors. DS users were compared to non-users with unconditional logistic regressions. DS use was reported by 62% of women and 29% of men. Vitamins D, B6, C and Mg were the most frequently consumed nutrients. 14% of cancer survivors initiated DS use after diagnosis. For 35% of the DS consumed, subjects did not inform their attending physician. DS use was associated with a healthier lifestyle (normal weight, never smoking and better diet) and substantially contributed to nutrient intake. 18% of DS users had potentially harmful DS use practices, such as the simultaneous use of vitamin E and anticoagulant/antiplatelet agents, the use of beta-carotene and smoking or the use of phyto-oestrogens in hormone-dependent cancer patients. The present study suggests that DS use is widespread among cancer survivors, a large amount of that use is performed without any medical supervision and a substantial proportion of that use involves potentially harmful practices. Physicians should be encouraged to more routinely discuss DS use with their cancer patients. PMID- 25826602 TI - A new color image encryption scheme using CML and a fractional-order chaotic system. AB - The chaos-based image cryptosystems have been widely investigated in recent years to provide real-time encryption and transmission. In this paper, a novel color image encryption algorithm by using coupled-map lattices (CML) and a fractional order chaotic system is proposed to enhance the security and robustness of the encryption algorithms with a permutation-diffusion structure. To make the encryption procedure more confusing and complex, an image division-shuffling process is put forward, where the plain-image is first divided into four sub images, and then the position of the pixels in the whole image is shuffled. In order to generate initial conditions and parameters of two chaotic systems, a 280 bit long external secret key is employed. The key space analysis, various statistical analysis, information entropy analysis, differential analysis and key sensitivity analysis are introduced to test the security of the new image encryption algorithm. The cryptosystem speed is analyzed and tested as well. Experimental results confirm that, in comparison to other image encryption schemes, the new algorithm has higher security and is fast for practical image encryption. Moreover, an extensive tolerance analysis of some common image processing operations such as noise adding, cropping, JPEG compression, rotation, brightening and darkening, has been performed on the proposed image encryption technique. Corresponding results reveal that the proposed image encryption method has good robustness against some image processing operations and geometric attacks. PMID- 25826603 TI - Detection of aortic wall instability with the new dissectometer: Correlation with histological findings. AB - OBJECTIVES: Although risk stratification for aortic dissection or rupture based on aortic diameter is quite suboptimal, alternative methods for the assessment of the aortic wall stability are rare. We assessed the mechanical properties of the aortic wall by a new custom-made device mimicking transversal aortic wall shear stress during open heart surgery in comparison with histological examination. MATERIAL AND METHODS: One-hundred and five aortic walls were tested by the 'dissectometer' (seven different measured and two calculated values) as well as histological examination was performed. RESULTS: Histological examination classified the aortic wall as normal in 54 (51.4%) patients and pathologic in 51 (48.6%) patients. Six out of nine parameters assessed by the dissectometer showed a significant correlation to histological findings. Using ROC-analysis, the most reliable parameter (P9) showed a sensitivity of 93.3% and a specificity of 80.4% with an area under the curve of 0.89 when using a cut-off value of 3.4. In the logistic regression analysis, P9 was an independent predictor for aortic wall instability (OR 28.983, 95% CI 11.507-72.993, p < 0.0001). CONCLUSION: The dissectometer is suitable for discriminating between stable and unstable aortic walls with a good correlation to histological examination holding promise for direct and quick intraoperative identification of aortic walls at risk for dissection. PMID- 25826605 TI - Meniscus-mask lithography for fabrication of narrow nanowires. AB - We demonstrate the efficiency of meniscus-mask lithography (MML) for fabrication of precisely positioned nanowires in a variety of materials. Si, SiO2, Au, Cr, W, Ti, TiO2, and Al nanowires are fabricated and characterized. The average widths, depending on the materials, range from 6 to 16 nm. A broad range of materials and etching processes are used and the generality of approach suggests the applicability of MML to a majority of materials used in modern planar technology. High reproducibility of the MML method is shown and some fabrication issues specific to MML are addressed. Crossbar structures produced by MML demonstrate that junctions of nanowires could be fabricated as well, providing the building blocks required for fabrication of nanowire structures of varied planar geometry. PMID- 25826604 TI - Integration of shallow gradients of Shh and Netrin-1 guides commissural axons. AB - During nervous system development, gradients of Sonic Hedgehog (Shh) and Netrin-1 attract growth cones of commissural axons toward the floor plate of the embryonic spinal cord. Mice defective for either Shh or Netrin-1 signaling have commissural axon guidance defects, suggesting that both Shh and Netrin-1 are required for correct axon guidance. However, how Shh and Netrin-1 collaborate to guide axons is not known. We first quantified the steepness of the Shh gradient in the spinal cord and found that it is mostly very shallow. We then developed an in vitro microfluidic guidance assay to simulate these shallow gradients. We found that axons of dissociated commissural neurons respond to steep but not shallow gradients of Shh or Netrin-1. However, when we presented axons with combined Shh and Netrin-1 gradients, they had heightened sensitivity to the guidance cues, turning in response to shallower gradients that were unable to guide axons when only one cue was present. Furthermore, these shallow gradients polarized growth cone Src-family kinase (SFK) activity only when Shh and Netrin-1 were combined, indicating that SFKs can integrate the two guidance cues. Together, our results indicate that Shh and Netrin-1 synergize to enable growth cones to sense shallow gradients in regions of the spinal cord where the steepness of a single guidance cue is insufficient to guide axons, and we identify a novel type of synergy that occurs when the steepness (and not the concentration) of a guidance cue is limiting. PMID- 25826606 TI - Targeting smokers with empathy appeal antismoking public service announcements: a field experiment. AB - A field experiment study (N = 189) was conducted to investigate the effectiveness of empathy appeal antismoking messages and their potential advantage over fear appeal messages. Data from 12 antismoking public service announcements showed that (a) smokers resist antismoking messages and (b) overall empathy appeal was equally effective as fear appeal messages. There was also evidence for moderators. First, empathy messages were more effective to women than to men. Second, fear appeal messages were more effective to occasional smokers than were empathy messages. Third, empathy messages were more effective to regular smokers than were fear appeal messages. Implications for audience segmentation and message targeting in public health antismoking efforts are discussed. PMID- 25826595 TI - Lung transplantation for cystic fibrosis: results, indications, complications, and controversies. AB - Survival in patients with cystic fibrosis (CF) has improved dramatically over the past 30 to 40 years, with mean survival now approximately 40 years. Nonetheless, progressive respiratory insufficiency remains the major cause of mortality in CF patients, and lung transplantation (LT) is eventually required. Timing of listing for LT is critical, because up to 25 to 41% of CF patients have died while awaiting LT. Globally, approximately 16.4% of lung transplants are performed in adults with CF. Survival rates for LT recipients with CF are superior to other indications, yet LT is associated with substantial morbidity and mortality (~50% at 5-year survival rates). Myriad complications of LT include allograft failure (acute or chronic), opportunistic infections, and complications of chronic immunosuppressive medications (including malignancy). Determining which patients are candidates for LT is difficult, and survival benefit remains uncertain. In this review, we discuss when LT should be considered, criteria for identifying candidates, contraindications to LT, results post-LT, and specific complications that may be associated with LT. Infectious complications that may complicate CF (particularly Burkholderia cepacia spp., opportunistic fungi, and nontuberculous mycobacteria) are discussed. PMID- 25826607 TI - Distribution of virulence-associated genes in a selection of Campylobacter isolates. AB - This study tested 24 Campylobacter isolates for the presence of 35 virulence genes using the polymerase chain reaction. The target genes included those involved in motility (flaA, flaB, flhA, flhB, flgB, flgE2, fliM, fliY), chemotaxis (cheA, cheB, cheR, cheW, cheY, cheZ), cell adhesion (cadF, dnaJ, jlpA, pldA, racR, virB11), invasion (iamA, ciaB, ceuE), cytotoxin production (cdtA, cdtB, cdtC, wlaN), capsule (kpsM), multidrug and bile resistance (cmeA, cmeB, cmeC), stress response/survival (katA, sodB), and the iron uptake system (cfrA, fur). The motility genes (with the exception of flaB), the CmeABC efflux system, cdtABC genes, and the sodB gene were commonly distributed among Campylobacter strains while the virB11 and wlaN genes were rarely detected. Interestingly, the findings suggest that flaB is not essential for full motility and C. coli lacking the flhA gene may be highly invasive. This study provides additional information on the distribution of Campylobacter virulence factors and the effect of their presence/absence on adhesion and invasion. It will inform future studies designed to elucidate the exact mechanisms of pathogenesis in Campylobacter. PMID- 25826609 TI - A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis. AB - INTRODUCTION: Daclizumab (DAC) is a mAb that binds to CD25, a receptor on the surface of lymphocytes for IL-2, a chemical messenger in the immune system. This prevents activation and proliferation of lymphocytes, which are involved in the immune attack in multiple sclerosis (MS). AREAS COVERED: In this review, we will focus on newly emerging DAC-high-yield process (HYP) therapy for MS. Based on published original articles and citable meeting abstracts, we will discuss its mode of action as well as data on efficacy and safety. EXPERT OPINION: DAC has been observed to have multiple (biological) effects, which may contribute to beneficial effects in immune-related disease and particularly in relapsing remitting MS. The positive results in the clinical studies represent achievement of an important milestone in the development of DAC-HYP as a potential new treatment option for MS patients. The benefit/risk ratios of this new biological agent in MS therapy are still being evaluated. Soon, DAC-HYP might qualify as MS therapy. A safety monitoring program is recommended in the clinical practice. PMID- 25826610 TI - Nanoscale metallogel via self-assembly of self-assembled trinuclear coordination rings: multi-stimuli-responsive soft materials. AB - A rare variety of coordination rings having the M3L6 composition are prepared by the combination of Pd(NO3)2 with an imidazolyl or benzimidazolyl appended bidentate non-chelating ligand (i.e.L1 or L2). The variable concentration 1H NMR spectra of the trinuclear complexes [Pd3(L1)6](NO3)6, 1a and [Pd3(L2)6](NO3)6, 2a in DMSO-d6 provided valuable information on the self-assembly phenomenon of the already self-assembled complexes. Interestingly, the signals of 2a are broadened upon increasing the concentration. The solution of 2a in DMSO formed a supramolecular metallogel above a certain concentration (i.e. 2% w/v), however, complex 1a could not form any gel. This phenomenon is attributed to the presence of an auxiliary pi-surface in the benzimidazole moiety in L2, in contrast to the imidazole moiety of L1. The influence of anions in gel formation was studied by preparing several samples using a variety of palladium(II) salts and L2 in DMSO. It was found that oxoanions like nitrate, perchlorate, triflate and tosylate are amicable for gel formation, probably due to their capabilities of forming H bonds. The counter anions like tetrafluoroborate, hexafluorophosphate, or hexafluoroantimonate could not assist in the formation of gel. The stimuli responsive nature of the gel and the reversible gel-sol conversion were demonstrated by dis-assembly and re-assembly processes of 2a as controlled by a pair of stimuli such as halide-nitrate, DMAP-HNO3, and ethylenediamine-Pd(NO3)2. No gel could be prepared by the combination of Ni(NO3)2 or Pt(NO3)2 with ligand L2. Thus, a subtle change in the ligand design, metal ion and counter anion is demonstrated as the responsible parameter for the construction of the three component multi-stimuli-responsive supramolecular gel. PMID- 25826608 TI - Spectrin regulates Hippo signaling by modulating cortical actomyosin activity. AB - The Hippo pathway controls tissue growth through a core kinase cascade that impinges on the transcription of growth-regulatory genes. Understanding how this pathway is regulated in development remains a major challenge. Recent studies suggested that Hippo signaling can be modulated by cytoskeletal tension through a Rok-myosin II pathway. How cytoskeletal tension is regulated or its relationship to the other known upstream regulators of the Hippo pathway remains poorly defined. In this study, we identify spectrin, a contractile protein at the cytoskeleton-membrane interface, as an upstream regulator of the Hippo signaling pathway. We show that, in contrast to canonical upstream regulators such as Crumbs, Kibra, Expanded, and Merlin, spectrin regulates Hippo signaling in a distinct way by modulating cortical actomyosin activity through non-muscle myosin II. These results uncover an essential mediator of Hippo signaling by cytoskeleton tension, providing a new entry point to dissecting how mechanical signals regulate Hippo signaling in living tissues. PMID- 25826612 TI - Facile and eco-friendly synthesis of green fluorescent carbon nanodots for applications in bioimaging, patterning and staining. AB - We report a facile and eco-friendly strategy for the fabrication of green fluorescent carbon nanodots (CDs), and demonstrate their applications for bio imaging, patterning, and staining. A one-pot hydrothermal method using various plant petals yields bright green-emitting CDs, providing an easy way for the production of green fluorescent CDs without the need for a tedious synthetic methodology or the use of toxic/expensive solvents and starting materials. The as prepared CDs show small size distribution and excellent dispersibility. Their strong green fluorescence is observed when the excitation wavelength is between 430 nm and 490 nm. Moreover, they exhibit high tolerance to various external conditions, such as pH values, external cations, and continuous excitation. Due to minimum toxicity as well as good photoluminescence properties, these CDs can be applied to in vitro and in vivo imaging, patterning, and staining. According to confocal fluorescence imaging of human uterine cervical squamous cell carcinoma cells, CDs penetrate into the cell and enter the cytoplasm and the nucleus. More strikingly, carp is directly fed with CDs for in vivo imaging and shows bright green fluorescence at an excitation wavelength of 470 nm. In addition, the obtained CDs are used as fluorescent inks for drawing luminescence patterns. Finally, we also apply the CDs as a fluorescent dye. Interestingly, the absorbent filter paper with staining emits dramatic fluorescence under 470 nm excitation. PMID- 25826611 TI - Personality, perceived environment, and behavior systems related to future smoking intentions among youths: an application of problem-behavior theory in Shanghai, China. AB - BACKGROUND: Smoking among youths is a worldwide problem, particularly in China. Many endogenous and environmental factors influence smokers' intentions to smoke; therefore, a comprehensive model is needed to understand the significance and relationship of predictors. This study aimed to develop a prediction model based on problem-behavior theory (PBT) to interpret intentions to smoke among Chinese youths. METHODS: We conducted a cross-sectional study of 26,675 adolescents from junior, senior, and vocational high schools in Shanghai, China. Data on smoking status, smoking knowledge, attitude toward smoking, parents' and peers' smoking, and media exposure to smoking were collected from students. A structural equation model was used to assess the developed prediction model. RESULTS: The experimental smoking rate and current smoking rate among the students were 11.0% and 3%, respectively. Our constructed model showed an acceptable fit to the data (comparative fit index = 0.987, root-mean-square error of approximation = 0.034). Intention to smoke was predicted by perceived environment (beta = 0.455, P < 0.001) system consisting of peer smoking (beta = 0.599, P < 0.001), parent smoking (beta = 0.152, P < 0.001), and media exposure to smoking (beta = 0.226, P < 0.001), and behavior system (beta = 0.487, P < 0.001) consisting of tobacco experimentation (beta = 0.663, P < 0.001) and current smoking (beta = 0.755, P < 0.001). Smoking intention was irrelevant for personality system in students (beta = -0.113, P>0.05) which consisted of acceptance of tobacco use (beta = 0.668, P < 0.001) and academic performance (beta = 0.171, P < 0.001). CONCLUSION: The PBT based model we developed provides a good understanding of the predictors of intentions to smoke and it suggests future interventions among youths should focus on components in perceived environment and behavior systems, and take into account the moderating effects of personality system. PMID- 25826613 TI - Short-term prognostic factors for primary sclerosing cholangitis. AB - BACKGROUND: It was recently reported that alkaline phosphatase (ALP) levels below 1.5 upper limit of normal (ULN) predicted better prognosis in primary sclerosing cholangitis (PSC). We evaluated whether ALP as well as other laboratory values were useful for the short-term prognosis of PSC in a Japanese cohort. METHODS: In 78 patients with PSC (41 males and 37 females, mean onset age 41.9 years), the relationship between nine parameters (albumin, bilirubin, international normalized ratio of prothrombin time [PT-INR], ALP, aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transpeptidase [gamma-GTP], platelet, and calculated Model for End-Stage Liver Disease [MELD] score), and liver related clinical endpoints (death due to liver failure, variceal bleeding, liver transplantation, and biliary carcinoma) were retrospectively examined. Using receiver operating characteristic (ROC) analysis, we investigated which parameter was useful for predicting the short-term prognosis. RESULTS: Average follow-up period was 8.6 years. The endpoints were evaluated in 40 patients. Seven patients died of liver failure, three patients developed variceal bleeding, nine patients received liver transplantation from a living donor, 13 patients received certified brain-dead liver transplantation, and eight patients developed biliary carcinoma. The parameters with an area under the curve (AUC) of more than 0.8 were albumin, bilirubin, PT-INR, ALP, and MELD score. AUC for ALP was 0.85. The optimal cutoff value was 2.3 ULN. Despite the use or non-use of ursodeoxycholic acid, short-term prognosis of patients with an ALP level below 2.3 ULN was good. CONCLUSIONS: We confirmed that keeping ALP low is associated with better short-term prognosis in a Japanese cohort. In addition, Alb, Bil, PT INR, and MELD score were good predictors. PMID- 25826614 TI - Biochemical and functional characterization of a periplasmic disulfide oxidoreductase from Neisseria meningitidis essential for meningococcal viability. AB - TlpAs (thioredoxin-like proteins) are bacterial thioredoxin-like periplasmic disulfide oxidoreductases generally involved in cytochrome c maturation (Ccm) process. They contain a characteristic CXXC active site motif involved in disulfide exchange reaction. In the human pathogenic Neisseria meningitidis species, no TlpA has been characterized so far. In the present study, using an in silico analysis, we identified a putative periplasmic TlpA, called TlpA2. Biochemical and kinetic characterizations of the soluble form of TlpA2, tTlpA2 (truncated TlpA2), were performed. A reduction potential of -0.230 V at pH 7 was calculated, suggesting that TlpA2 acts as a reductant in the oxidative environment of the periplasm. Using a second-order reactive probe, high pKapp (apparent pKa) values were determined for the two cysteines of the SCXXC motif. The tTlpA2 was shown to be efficiently reduced by the N-terminal domain of the DsbD, whereas tTlpA2 reduced a mimetic peptide of cytochrome c' with a catalytic efficiency similar to that observed with other disulfide oxidoreductase like ResA. Moreover, the corresponding gene tlpA2 was shown to be essential for the pathogen viability and able to partially complement a Bordetella pertussis CcsX mutant. Together, these data support an essential role of TlpA2 in the Ccm process in N. meningitidis. PMID- 25826615 TI - Adherence to a DASH-Style Diet in Relation to Stroke: A Case-Control Study. AB - BACKGROUND: Despite the growing body of evidence from Western societies on the association between dietary patterns and stroke, limited data are available in this regard from developing countries. OBJECTIVE: This study was conducted to examine the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and risk of stroke among the Iranian population. METHODS: This hospital-based case-control study included 194 stroke patients and 194 controls and was conducted at the Alzahra University Hospital, Isfahan, Iran. The cases were stroke patients who were hospitalized in the neurology ward of the Alzahra University Hospital. Controls were randomly selected from among hospitalized patients in the orthopedic or surgical wards of this center. A validated food frequency questionnaire (FFQ) was used to assess the patients' usual dietary intake. We constructed the DASH diet score based on food and nutrients emphasized or minimized in the DASH diet. RESULTS: The prevalence of stroke among those in the top quartile of the DASH diet score was 40%, which was 15% lower than among those in the bottom quartile; this difference was marginally significant (p = 0.10). After controlling for age, sex, and total energy intake, adherence to the DASH diet was inversely associated with the risk of stroke (OR: 0.52; 95% CI: 0.28; 0.98). These associations remained significant even after additionally controlling for physical activity, smoking, hypertension, and diabetes, such that individuals in the highest quartile of the DASH diet score had a 58% lower risk of stroke than those in the lowest category (OR: 0.48; 95% CI: 0.24, 0.96). However, after further adjustment for body mass index (BMI), the association disappeared (OR: 0.62; 95% CI: 0.29, 1.31), indicating an obesity dependent association. CONCLUSION: We found an inverse relationship between the DASH-style diet and prevalence of stroke. Prospective studies are needed to confirm this association. PMID- 25826618 TI - Theoretical chemistry developments: from electronic structure to simulations. PMID- 25826617 TI - Long non-coding RNA expression profile in the kidneys of male, low birth weight rats exposed to maternal protein restriction at postnatal day 1 and day 10. AB - BACKGROUND: Long non-coding RNAs (lncRNAs), which are involved in a variety of biological functions and aberrantly expressed in many types of diseases, are required for postnatal development. In this study, we aimed to investigate the lncRNA profiles in low birth weight (LBW) rats with reduced nephron endowment induced by the restriction of maternal protein intake. LBW by reduced nephron endowment is a risk factor for hypertension and end-stage renal disease in adulthood. METHODS: Kidneys were obtained from LBW rats fed a low-protein diet throughout gestation and lactation as well as from normal control rats born from dams fed normal protein diets at postnatal day 1 (p1) and 10 (p10). The total number of glomeruli in the kidneys was counted at p10. LncRNA expression profiles were analyzed by sequencing and screening using the Agilent Rat lncRNA Array. Quantitative real-time PCR (qRT-PCR) analysis of these lncRNAs confirmed the identity of some genes. RESULTS: The total number of glomeruli per kidney at p10 was significantly lower in LBW rats than in controls. A total of 42 lncRNAs were identified to be significantly differentially expressed, with fold-changes >=2.0, between the two groups. According to correlation analysis between the differentially expressed lncRNAs and mRNAs involved in kidney development, we randomly selected a number of lncRNAs for comparison analysis between LBW and control kidneys at the two time-points, p1 and p10, using qRT-PCR. Three lncRNAs (TCONS_00014139, TCONS_00014138, and TCONS_00017119), which were significantly correlated with the mRNA expression of mitogen-activated protein kinase 4, were aberrantly expressed in LBW rats, compared with controls, at both p1 and p10. CONCLUSIONS: LncRNAs are aberrantly expressed in the kidneys of LBW rats, compared with controls, during nephron development, which indicates that lncRNAs might be involved in impaired nephron endowment. PMID- 25826616 TI - Comparing quality of public primary care between Hong Kong and Shanghai using validated patient assessment tools. AB - OBJECTIVES: Primary care is the key element of health reform in China. The objective of this study was to compare patient assessed quality of public primary care between Hong Kong, a city with established primary care environment influenced by its colonial history, and Shanghai, a city leading primary care reform in Mainland China; and to measure the equity of care in the two cities. METHODS: Cross sectional stratified random sampling surveys were conducted in 2011. Data were collected from 1,994 respondents in Hong Kong and 811 respondents in Shanghai. A validated Chinese version of the primary care assessment tool was employed to assess perceived quality of primary care with respect to socioeconomic characteristics and health status. RESULTS: We analyzed 391 and 725 respondents in Hong Kong and Shanghai, respectively, who were regular public primary care users. Respondents in Hong Kong reported significant lower scores in first contact accessibility (1.59 vs. 2.15), continuity of care (2.33 vs. 3.10), coordination of information (2.84 vs. 3.64), comprehensiveness service availability (2.43 vs. 3.31), comprehensiveness service provided (2.11 vs. 2.40), and the total score (23.40 vs. 27.40), but higher scores in first contact utilization (3.15 vs. 2.54) and coordination of services (2.67 vs. 2.40) when compared with those in Shanghai. Respondents with higher income reported a significantly higher total primary care score in Hong Kong, but not in Shanghai. CONCLUSIONS: Respondents in Shanghai reported better quality of public primary care than those in Hong Kong, while quality of public primary care tended to be more equitable in Shanghai. PMID- 25826619 TI - Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer. AB - So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation. PMID- 25826621 TI - Dopant-controlled selenization in Pd nanocrystals: the triggered Kirkendall effect. AB - Doping foreign impurities in host nanomaterials can induce new materials properties. In addition, doping can also influence the crystallization process and change the shape and/or phase of the host material. While dopant-induced changes in the properties of materials have been well studied, the concept of doping and its chemistry in the design of different nanostructures has rarely been investigated. In order to further understand the doping chemistry, this study investigated the dopant-controlled enhancement of the rate of the chemical reaction during the transformation from one doped material to another and the consequent effect on the shape evolution of the nanostructures. These are performed during the selenization of metal Pd(0), using Ag dopant. While the controlled process produced cuboidal Pd17Se15 from the quasi-spherical nanocrystals of Pd(0), on doping, the shape of Pd17Se15 transformed into hollow cubes. The rate was also enhanced by more than 30 times for the doped case in comparison to undoped Pd(0). Importantly, while for the undoped nanocrystals, the selenization approached in one direction, where for the doped particles, it occurred all around the nanocrystals and triggered the Kirkendall effect. Detailed investigations were conducted to elucidate the influence of the dopant on both the rate and directional approach of selenization in Pd(0), initiation of the fast diffusion of Pd, change in shape, and formation of the hollow structures. To our understanding, the role of dopants in controlling chemical processes is of fundamental importance, and this will undoubtedly broaden the scope of research on the chemistry of doping and crystal growth in solution. PMID- 25826620 TI - Would older adults with mild cognitive impairment adhere to and benefit from a structured lifestyle activity intervention to enhance cognition?: a cluster randomized controlled trial. AB - BACKGROUND: Epidemiologic evidence suggests that cognitive and physical activities are associated with better cognition in late life. The present study was conducted to examine the possible benefits of four structured lifestyle activity interventions and compare their effectiveness in optimizing cognition for older adults with mild cognitive impairment (MCI). METHOD AND FINDINGS: This was a 12-month cluster randomized controlled trial. 555 community-dwelling Chinese older adults with MCI (295 with multiple-domain deficits (mdMCI), 260 with single-domain deficit (sdMCI)) were recruited. Participants were randomized into physical exercise (P), cognitive activity (C), integrated cognitive and physical exercise (CP), and social activity (S, active control) groups. Interventions comprised of one-hour structured activities three times per week. Primary outcome was Clinical Dementia Rating sum of boxes (CDR-SOB) scores. Secondary outcomes included Chinese versions of Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), delayed recall, Mini-Mental State Examination, Category Verbal Fluency Test (CVFT) and Disability Assessment for Dementia - Instrumental Activities of Daily Living (DAD-IADL). Percentage adherence to programs and factors affecting adherence were also examined. At 12th month, 423 (76.2%) completed final assessment. There was no change in CDR-SOB and DAD-IADL scores across time and intervention groups. Multilevel normal model and linear link function showed improvement in ADAS-Cog, delayed recall and CVFT with time (p<0.05). Post-hoc subgroup analyses showed that the CP group, compared with other intervention groups, had more significant improvements of ADAS-Cog, delayed recall and CVFT performance with sdMCI participants (p<0.05). Overall adherence rate was 73.3%. Improvements in ADAS-Cog and delayed recall scores were associated with adherence after controlling for age, education, and intervention groups (univariate analyses). CONCLUSIONS: Structured lifestyle activity interventions were not associated with changes in everyday functioning, albeit with some improvements in cognitive scores across time. Higher adherence was associated with greater improvement in cognitive scores. Factors to enhance adherence should be specially considered in the design of psychosocial interventions for older adults with cognitive decline. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR-TRC-11001359. PMID- 25826622 TI - A journey to zero: reduction of post-operative cesarean surgical site infections over a five-year period. AB - BACKGROUND: Surgical site infections (SSI) are a substantial concern for cesarean deliveries in which a surgical site complication is most unwelcome for a mother with a new infant. Steps taken pre- and post-operatively to reduce the number of complications may be of substantial benefit clinically, economically, and psychologically. METHODS: A risk-based approach to incision management was developed and implemented for all cesarean deliveries at our institution. A number of incremental interventions for low-risk and high-risk patients including pre-operative skin preparations, standardized pre- and post-operative protocols, post-operative nanocrystalline silver anti-microbial barrier dressings, and incisional negative pressure wound therapy (NPWT) were implemented sequentially over a 5-y period. A systematic clinical chart review of 4,942 patients spanning all cesarean deliveries between 2007-2012 was performed to determine what effects the interventions had on the rate of SSI for cesarean deliveries. RESULTS: The percentage of SSI was reduced from 2.13% (2007) to 0.10% (2012) (p<0.0001). There were no substantial changes in the patient population risk factors over this time. As a result of the changes in incision management practice, a total of 92 cesarean post-operative SSIs were avoided: A total cost saving of nearly $5,000,000. CONCLUSION: Applying a clinical algorithm for assessing the risk of surgical site complication and making recommendations on pre-operative and post operative incision management can result in a substantial and sustainable reduction in cesarean SSI. PMID- 25826623 TI - Atomistic Insight into Tetraalkylphosphonium-Bis(oxalato)borate Ionic Liquid/Water Mixtures. I. Local Microscopic Structure. AB - Atomistic simulations have been performed to investigate the microscopic structural organization of aqueous solutions of trihexyltetradecylphosphonium bis(oxalato)borate ([P6,6,6,14][BOB]) ionic liquid (IL). The evolution of the microscopic liquid structure and the local ionic organization of IL/water mixtures as a function of the water concentration is visualized and systematically analyzed via radial and spatial distribution functions, coordination numbers, hydrogen bond network, and water clustering analysis. The microscopic liquid structure in neat IL is characterized by a connected apolar network composed of the alkyl chains of [P6,6,6,14] cations and isolated polar domains consisting of the central segments of [P6,6,6,14] cations and [BOB] anions, and the corresponding local ionic environment is described by direct contact ion pairs. In IL/water mixtures with lower water mole fractions, the added water molecules are dispersed and embedded in cavities between neighboring ionic species and the local ionic structure is characterized by solvent-shared ion pairs through cation-water-anion triple complexes. With a gradual increase in the water concentration in IL/water mixtures, the added water molecules tend to aggregate and form small clusters, intermediate chain-like structures, large aggregates, and eventually a water network in water concentrated simulation systems. A further progressive dilution of IL/water mixtures leads to the formation of self-organized micelle-like aggregates characterized by a hydrophobic core and hydrophilic shell consisting of the central polar segments in [P6,6,6,14] cations and [BOB] anions in a highly branched water network. The striking structural evolution of the [P6,6,6,14][BOB] IL/water mixtures is rationalized by the competition between favorable hydrogen bonded interactions and strong electrostatic interactions between the polar segments in ionic species and the dispersion interactions between the hydrophobic alkyl chains in [P6,6,6,14] cations. PMID- 25826624 TI - Thermosensitive, near-infrared-labeled nanoparticles for topotecan delivery to tumors. AB - Liposomal nanoparticles have proven to be versatile systems for drug delivery. However, the progress in clinic has been slower and less efficient than expected. This suggests a need for further development using carefully designed chemical components to improve usefulness under clinical conditions and maximize therapeutic effect. For cancer chemotherapy, PEGylated liposomes were the first nanomedicine to reach the market and have been used clinically for several years. Approaches toward targeted drug delivery using next generation "thermally triggered" nanoparticles are now in clinical trials. However, clinically tested thermosensitive liposomes (TSLs) lack the markers that allow tumor labeling and improved imaging for tissue specific applied hyperthermia. Here we describe the development of optically labeled TSLs for image guidance drug delivery and proof of-concept results for their application in the treatment of murine xenograft tumors using the anticancer drug topotecan. These labeled TSLs also allow the simultaneous, real-time diagnostic imaging of nanoparticle biodistribution using a near-infrared (NIR; 750-950 nm) fluorophore coupled to a lipidic component of the lipid bilayer. When combined with multispectral fluorescence analysis, this allows for specific and high sensitivity tracking of the nanoparticles in vivo. The application of NIR fluorescence-labeled TSLs could have a transformative effect on future cancer chemotherapy. PMID- 25826625 TI - Contributions of Basal Glucose and Postprandial Glucose Concentrations to Hemoglobin A1c in the Newly Diagnosed Patients with Type 2 Diabetes--the Preliminary Study. AB - OBJECTIVE: The aim of this preliminary study is to investigate contributions of basal glucose (BG) and postprandial glucose (PPG) increments to overall hyperglycemia in newly diagnosed patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We evaluated the relative contributions of BG and PPG to overall hyperglycemia in 59 newly diagnosed T2DM patients according to BG baseline value of 6.1 mmol/L and 24-h glucose profiles of normal glucose tolerance (NGT) subjects obtained by continuous glucose monitoring as baseline, respectively. RESULTS: When the baseline was 24-h glucose profiles of the NGT subjects, the relative contributions of PPG in the T2DM patients with hemoglobin A1c (HbA1c) levels of <= 7.0%, 7.0-9.0%, and >9.0% were 57.58%, 44.69%, and 21.56%, respectively. When the baseline value was equal to 6.1 mmol/L, the relative contributions of PPG in the T2DM patients with HbA1c levels of <= 7.0%, 7.0-9.0%, and >9.0% were 77.23%, 53.43%, and 22.78%, respectively. Compared with the 24-h glucose profiles of the NGT subjects as the baseline, the relative contribution of PPG was overestimated by about 10-20% in the T2DM patients with HbA1c levels of <= 9.0% when 6.1 mmol/L was chosen as the baseline. CONCLUSIONS: In the newly diagnosed T2DM patients with mild hyperglycemia, PPG is a predominant contributor, whereas the relative contributions of BG gradually increase from mild to severe hyperglycemia and obviously exceed PPG in the T2DM patients with HbA1c levels of >9.0%. This finding implies that the initial pharmacotherapy may target PPG in those patients with mild hyperglycemia and target BG in those patients with severe hyperglycemia. PMID- 25826627 TI - Soft-tissue balance in short and straight stem total hip arthroplasty. AB - The growing numbers of short stem hip implants have redefined total hip arthroplasty with new stem geometries and possible functional differences. Several systematic reviews have reported good clinical results with this new class of stems, although kinematic alterations are still unclear in many aspects. The good clinical results obtained at the authors' institution led to the current study. The authors hypothesized that the geometric alignment of the prosthetic components may be closer to the anatomy of the healthy hip joint, thus leading to better function and clinical satisfaction. An examination via finite element analysis was chosen to model the hip joint and virtually implant a short and a standard straight stem. Findings indicated that anchoring of the short stem allowed favorable positioning in the proximal femur, with the femoral head already in the center of the cup. This positioning was not possible for the straight stem, which required further reduction of the femur by a significant translation into the cup, leading to abnormal soft-tissue balancing. The results from the simulation showed an absolute average deviation of ligamentous fiber strains of 6% for the short stem in 30 degrees of flexion and extension versus 29% and 36% for the standard straight stem in 30 degrees of flexion and extension, respectively. A femoral neck guided orientation of the short stem implant seems to allow a more anatomical reconstruction and thus a more balanced hip in terms of the modeled soft tissues. In contrast, the straight stem alters the head position and induces nonphysiological capsular strains. PMID- 25826628 TI - Reproducing the hip center with a femoral neck-retaining implant. AB - Because of the recent trend for total hip arthroplasty in younger patients, more bone-preserving implants have been designed, based partly on the premise that maintenance of more bone stock would allow revision with standard primary implants. Another possible advantage of an implant that retains the femoral neck is that it may allow anatomical recreation of the center of the femoral head, femoral neck anteversion, anterior tilt, and caput-collum-diaphysis (CCD) angle, as well as femoral offset and leg length, without the use of modular implants. To determine whether the proximal femoral anatomy could be recreated, this study used computed tomography data and 3-dimensional modeling from 10 cadaver hips in 6 whole body specimens. Three femoral neck resection levels were investigated: 2 mm, 5 mm (recommended resection), and 10 mm from the base of the femoral neck. Results showed that the center of the femoral head, femoral neck anteversion, and CCD angle could all be recreated with available implant sizes, without modularity, within 2 degrees and 1 mm on average. The addition of a modular neck provided no advantage in recreation of the hip center or other anatomical parameters. Use of a short metaphyseal femoral neck retaining-type of stem should allow restoration of anatomical parameters without the use of an exchangeable modular femoral neck. PMID- 25826626 TI - Crystal structure of a two-subunit TrkA octameric gating ring assembly. AB - The TM1088 locus of T. maritima codes for two proteins designated TM1088A and TM1088B, which combine to form the cytosolic portion of a putative Trk K+ transporter. We report the crystal structure of this assembly to a resolution of 3.45 A. The high resolution crystal structures of the components of the assembly, TM1088A and TM1088B, were also determined independently to 1.50 A and 1.55 A, respectively. The TM1088 proteins are structurally homologous to each other and to other K+ transporter proteins, such as TrkA. These proteins form a cytosolic gating ring assembly that controls the flow of K+ ions across the membrane. TM1088 represents the first structure of a two-subunit Trk assembly. Despite the atypical genetics and chain organization of the TM1088 assembly, it shares significant structural homology and an overall quaternary organization with other single-subunit K+ gating ring assemblies. This structure provides the first structural insights into what may be an evolutionary ancestor of more modern single-subunit K+ gating ring assemblies. PMID- 25826629 TI - Patient selection for shorter femoral stems. AB - The right patient selection with the correct surgical treatment are prerequisite for a positive result in total hip arthroplasty (THA). Short stem implants demand a shorter anchoring length in accordance with the proper indication. Although appropriate indications for short stems have been discussed in the literature, there currently is no clear definition. The lack of an accepted categorization of short hip stems complicates the situation further. This article briefly reviews the literature and highlights the authors' results and experiences in short stem THA in an effort to establish a proper discrimination between indications and contraindications for the Metha short stem. Results presented include a retrospective data collection and follow-up examination of 126 patients who underwent short stem THA with 2- and 4-year results. Anchoring principles of the short stem are reviewed, and a complication and failure analysis based on 7 femoral revisions in 1092 short stem THAs is presented. Selection criteria for short stem THA are patients younger than 70 years with primary osteoarthritis and dysplastic femoral deformities, and indications of avascular head necrosis. Adequate bone quality must be confirmed intraoperatively, assessing whether the bone structure in the area of the femoral neck is strong enough to support the short stem load transmission. Coxa vara and high dysplastic femoral neck antetorsion are contraindications for short stems. Wide and short femoral necks, implant undersizing, and a deep stem position below the femoral osteotomy compromise stability and must be avoided with an appropriate surgical technique. Long-term data are not yet available. PMID- 25826630 TI - Comparative 5-year results of short hip total hip arthroplasty with Ti- or CoCr neck adapters. AB - This prospective study investigated revision after modular short stem implantation. Results are presented for 2 different types of neck adapters (titanium and cobalt-chromium [CoCr]). Eighty-five patients with titanium adapters and 87 patients with CoCr adapters underwent follow-up examination after an average of 5.7 and 5.2 years, respectively. Mean patient age was 57 years in both groups. Indications were primary osteoarthritis (80%), cup dysplasia (14%), and other (6%). Mean Harris Hip Scores were 98 and 99 points (titanium and CoCr groups, respectively). Ninety percent and 96% of patients were very satisfied or satisfied (titanium and CoCr groups, respectively); 3% of patients in both groups were dissatisfied. Pain decreased from visual analog scale score 7 and 6 preoperatively to 0.37 and 0.15 postoperatively for the titanium and CoCr groups, respectively. No joint dislocation occurred. Six patients needed revision within the first year (2 for infection, 1 for via falsa position, and 2 for aseptic loosening in the titanium group, and 1 for aseptic loosening in the CoCr group). Nine revisions occurred due to neck adapter failure (titanium group). Primary standard stems were used in all revisions. Excluding material-related adapter failures in the titanium group, the 5-year survival rate was 94.8% (95% confidence interval [CI], 88.9-97.6 for titanium) and 99% (95% CI, 93.7-99.8 for CoCr). No radiographic signs of loosening were seen at last follow-up. Fine sclerotic lines were detected in Gruen zones 1 (17.2%) and 2 (14%), hypertrophies in zone 3 (4.3%), and periprosthetic cancellous bone compressions in zone 6 (75.8%). No adapter fractures occurred for CoCr components. The treatment and anchoring system of the short stem studied yielded good results and allowed revision using standard stems in all patients. PMID- 25826631 TI - Periprosthetic bone remodeling around short stem. AB - Total hip arthroplasty (THA) has become standard treatment for advanced degenerative changes of the hip. A few studies have reported promising clinical outcomes with the Metha stem fixated by metaphyseal anchoring. This study evaluated early bone remodeling around the Metha stem during 12 months of follow up. The study population included 36 patients (18 women and 18 men) with a mean age of 50.4 years who underwent THA between 2009 and 2011 for advanced degenerative changes of the hip with the Metha stem. Patients were evaluated on the day of surgery, 10 days postoperatively, and then at 3, 6, and 12 months postoperatively. Evaluation included Harris Hip Score and dual-energy x-ray absorptiometry (DEXA) scanning in 7 Gruen zones. At 12 months postoperatively, Harris Hip Score increased significantly by 38 points. A significant change in bone mineral density (BMD) was found immediately after surgery; this change was most pronounced in Gruen zone 3 (+36%), followed by Gruen zones 2 and 5. The smallest postoperative BMD increase was observed in Gruen zone 7 (+3.66%). In contrast, at 3 months postoperatively, a trend toward decreased BMD was observed in all Gruen zones. At 6 months postoperatively, mean BMD decreased in all Gruen zones except for Gruen zone 6. At 12 months postoperatively, mean BMD increased in Gruen zones 2 through 6, with the highest value (30%) observed in Gruen zone 3; in Gruen zones 1 and 2, mean BMD decreased. Short-term assessment of periprosthetic bone remodeling after uncemented Metha stem implantation revealed different host-bone responses. Apparently, the Metha stem can reduce BMD loss in the proximal femur. DEXA is a precise method for assessing BMD changes around implanted Metha stem. PMID- 25826632 TI - Short stem total hip arthroplasty in patients with rheumatoid arthritis. AB - Total hip arthroplasty (THA) has proven successful in patients with rheumatoid arthritis (RA). Patients with RA often require multiple revisions, and bone conservation is mandatory. A variety of short stems is currently available with mid-term results for osteoarthritis. This retrospective study evaluated mid-term clinical results of short stem THA in a series of patients with RA. Between 2005 and 2009, a total of 105 cementless short stems were implanted in patients with RA. Average patient age at the time of the index THA was 44.2 years, and average length of follow-up was 5 years. Clinical evaluation included physical examination and documentation of potential adverse events during the postoperative period. No radiographic failures occurred. Femoral and cup components showed some minor radiolucencies with sclerotic lines, but none involved 100% of the bone-prosthesis interface. Complications included femoral component subsidence in 2 hips after initial full weight bearing; 1 case resolved after 3 months, and the other case was revised to a standard shaft. One intraoperative dorsolateral stem tip perforation occurred with revision to a conventional length stem. Migration in 1 cup led to revision without removal of the short stem implant. No infections or joint dislocations were observed. The transfer of the short stem concept to an additional treatment option for patients with RA proved successful in the early to mid-term postoperative period. Complications and revisions were limited to early migration and early loosening of the implants in line with the results reported in the literature of cementless conventional THA in patients with RA. PMID- 25826633 TI - Expertise in short hip arthroplasty. PMID- 25826634 TI - 10-year experience with short stem total hip arthroplasty. AB - Since 1998, short stem total hip arthroplasty (THA) has been performed at the authors' institution. Currently, 30% of THAs are performed with short stems. This article reports on complications that required revision of a short stem THA. Between September 2005 and February 2012, a total of 1953 Metha short stem THAs were performed; of these, 38 required revision due to mechanical complications. In 12 cases, the modular titanium neck adapter failed. In 19 cases, aseptic implant loosening occurred; of these, 11 cases were due to major stem subsidence. In 2 cases, via falsa (cortical penetration) implantation occurred. In 5 cases, periprosthetic fractures led to revision. This corresponds to an aseptic total revision rate of 1.3% for 26 short stems and 1.9% including the cases of all 38 documented revision cases. Thirty-four cases were revised with cementless standard hip stems, 2 cases were revised with short stems, and 2 cases were revised with long revision stems. Undersizing was analyzed in 58% of aseptic revisions. Fifty-four percent of revisions were performed in male patients - 23% with osteonecrosis of the femoral head, and 7% with short hip stems positioned in varus in coxa vara deformities. Seventy-two percent of revisions after marked early stem subsidence and position change into valgus were performed in female patients. Dysplastic hips with coxa valga did not show elevated revision rates. No revisions were performed for dislocation or femoral thigh pain. Short stem THA with the Metha implant is a bone-preserving option for various indications in select patient groups. PMID- 25826635 TI - Current concepts, classification, and results in short stem hip arthroplasty. AB - Various short hip stems have been introduced with differing implant concepts of femoral fixation and implant length. There is a lack of proper classification for short hip stems, with a clear and accepted definition for implant length and extent of bone preservation in the metaphyseal and diaphyseal femur. This study analyzed the length of short hip stems. Stems were divided into collum, partial collum, and trochanter-sparing implants. An additional category was added, trochanter harming, which was defined as interruption of the circumferential integrity of the femoral neck. For all of the femoral components described, the designs were compared, excluding stems with insufficient clinical data. The 15 finally selected stems were classified as collum (1 stem), partial collum (7 stems), trochanter sparing (4 stems), and trochanter harming (3 stems). Mid-term results (>5 years of follow-up) were available for only 3 designs in the partial collum group. Taking into account the results of short-term studies (<5 years of follow-up), the femoral revision rate per 100 observed component years was <1 for most total hip arthroplasties. However, the studies varied greatly regarding level of significance, and short hip stems without published results are available commercially. Short hip stems cannot be circumscribed by a simple length limit. For some designs, clinical data collected from large patient cohorts showed a survivorship comparable to traditional stems. In cases that must be revised, this often can be performed with a conventional primary stem, fulfilling the promise to preserve bone for potential future revisions in younger patients. PMID- 25826636 TI - A multilayered silicon-reduced graphene oxide electrode for high performance lithium-ion batteries. AB - A multilayered structural silicon-reduced graphene oxide electrode with superior electrochemical performance was synthesized from bulk Si particles through inexpensive electroless etching and graphene self-encapsulating approach. The prepared composite electrode presents a stable charge-discharge performance with high rate, showing a reversible capacity of 2787 mAh g(-1) at a charging rate of 100 mA g(-1), and a stable capacity over 1000 mAh g(-1) was retained at 1 A g(-1) after 50 cycles with a high columbic efficiency of 99% during the whole cycling process. This superior performance can be attributed to its novel multilayered structure with porous Si particles encapsulated, which can effectively accommodate the large volume change during the lithiation process and provide increased electrical conductivity. This facile low-cost approach offers a promising route to develop an optimized carbon encapsulated Si electrode for future industrial applications. PMID- 25826637 TI - Silyloxide-promoted diastereoselective addition of aryl and heterocyclic trimethylsilanes to N-tert-butanesulfinylimines. AB - The addition of a broad variety of substituted aromatic and heterocyclic silanes to chiral N-tert-butanesulfinylimines has been achieved providing 1,1-diaryl and diheterocyclic substituted sulfinamides with excellent diastereoselectivity in all cases. Employing Me3SiO(-)/Bu4N(+) as the Lewis base activator for silicon allowed a general procedure for all silane reagents, including the less reactive aromatic derivatives. Evidence that the diastereoselective additions occur via an open transition state is presented. PMID- 25826638 TI - Biotransformed soybean extract induces cell death of estrogen-dependent breast cancer cells by modulation of apoptotic proteins. AB - The process of soybean biotransformation increases the quantity of isoflavones (daidzein and genistein), which besides being considered an alternative to estroprogestive hormone replacement therapy (HRT), are able of hindering the growth and development of tumor cells. We investigated the effects of soybean extract biotransformed by fungus on estrogen-dependent (MCF-7) and nondependent (SK-BR-3) breast cell lines. Cells were treated with different concentrations of biotransformed (BSE) and nonbiotransformed soybean extract (SE), or daidzein (D) and genistein (G) patterns isolated and in combination (D + G). Afterwards, we analyzed cell viability by MTT assay, phosphatidylserine exposure and cell permeability by flow cytometry; expression of apoptotic proteins by Western blotting. BSE promoted reduction in cell viability and increase in DNA degradation in both cell lines. In addition, we verified increase in cell permeability and in the expression of phosphatidylserine, as well as modulation in the expression of apoptotic proteins in MCF-7 cells. The cells did not show any signs of cell death when incubated with the controls (D, G, and D + G). Unknown components found in the BSE induce cell death by apoptosis and necrosis, mainly in MCF-7 cells. These processes depend on the activation of caspase-3 and involve an increase in the expression of proapoptotic molecules. PMID- 25826639 TI - The effectiveness of therapy on outcome following (BoNT-A) injection for focal spasticity in adults with neurological conditions: A systematic review. AB - OBJECTIVE: To determine the independent effectiveness of adjunctive therapies when provided in conjunction with botulinum neurotoxin (BoNT-A) injection for focal spasticity in adults with neurological conditions. DATA SOURCES: Nine electronic databases. STUDY SELECTION: A systematic search was performed to identify randomized, controlled trials (RCTs) evaluating the benefit of adjunctive therapies following BoNT-A injection. DATA EXTRACTION/SYNTHESIS: Two authors extracted the data independently. Each trial was assessed for internal validity and rated for quality using the PEDro scale. Articles were further appraised using the American Academy of Neurology (AAN) evidence classification to construct concise clinical recommendations. RESULTS: The search identified 12 studies that reported on the effects of eight different adjunctive therapies following BoNT-A injection in adults with focal spasticity. No high level evidence was identified. The mean PEDro score for the 12 studies was 5.6 (SD = 1.6) and the clinical recommendations provided were Grade U, indicating the effectiveness of the adjunctive therapies was unknown or unproven. CONCLUSION: There was insufficient evidence to support or refute the effectiveness of any of the commonly prescribed adjunctive therapies following BoNT-A injection for focal spasticity in adults. PMID- 25826640 TI - Transmitted Drug Resistance Among Recently Diagnosed Adults and Children in Sao Paulo, Brazil. AB - Transmitted drug resistance mutations (TDRM) have been a constant threat to treatment efficacy. We evaluated TDRM in plasma RNA of 217 antiretroviral therapy naive patients from sites in the Sao Paulo metropolitan area, collected from 2012 to 2014. The partial HIV-1 polymerase region was sequenced using Big Dye terminators at an ABI 3130 Genetic Analyzer. TDRM was defined according to the Stanford database calibrated population resistance (CPR v.6.0), but other drug resistance mutations (DRM) considered at the IAS list (IAS, 2014) and at the Stanford HIV Database Genotyping Resistance Interpretation (GRI-HIVdb) were also described. Out of 78% (170/217) of patients with information on the time of diagnosis, most (83%, 141/170) had been recently diagnosed, with the first positive HIV serology at a median of 58 days (IQR 18-184). Subtype B predominated (70%), followed by subtype F (10%), BF (7.5%), C (7.5%), and BC (5%). TDRMs were observed in 9.2% (20/217, CI 95% 5.9% to 13.6%), mostly (5.2%) to nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral class. Among children and adolescents, only a single patient showed TDRMs. Additional non-CPR mutations were observed: 11.5% (25/217) according to IAS or 4.6% (10/217) according to GRI HIVdb. Overall, 23.5% (51/217) of the cases had one or more DRM identified. TDRM prevalence differed significantly among some sites. These trends deserve continuous and systematic surveillance, especially with the new policies of treatment as prevention being implemented in the country. PMID- 25826641 TI - Relational Intimacy and Sexual Frequency: A Correlation or a Cause? A Clinical Study of Heterosexual Married Women. AB - Researchers and practitioners have noted the importance of using clinical samples in sex therapy research. This study investigated the relationship between perceived levels of marital intimacy, sexual frequency, and sexual functioning among heterosexual married women. A clinical sample of 67 women completed the Couples Satisfaction Index (CSI), the Miller Social Intimacy Test (MSI), the Sexual Satisfaction Scale for Women (SSS-W), the Inclusion of the Other in the Self Scale (IOS), and the Female Sexual Functioning Index (FSFI-6). Data analyses revealed that marital intimacy acted as a predictor in univariate relationships on sexual frequency and sexual functioning but did not act as a mediator on sexual frequency and sexual functioning. Overall, these findings may further the discussion in the treatment of relational intimacy, sexual desire discrepancy, and female sexual dysfunction. PMID- 25826642 TI - Distance Measurement on an Endogenous Membrane Transporter in E. coli Cells and Native Membranes Using EPR Spectroscopy. AB - Membrane proteins may be influenced by the environment, and they may be unstable in detergents or fail to crystallize. As a result, approaches to characterize structures in a native environment are highly desirable. Here, we report a novel general strategy for precise distance measurements on outer membrane proteins in whole Escherichia coli cells and isolated outer membranes. The cobalamin transporter BtuB was overexpressed and spin-labeled in whole cells and outer membranes and interspin distances were measured to a spin-labeled cobalamin using pulse EPR spectroscopy. A comparative analysis of the data reveals a similar interspin distance between whole cells, outer membranes, and synthetic vesicles. This approach provides an elegant way to study conformational changes or protein protein/ligand interactions at surface-exposed sites of membrane protein complexes in whole cells and native membranes, and provides a method to validate outer membrane protein structures in their native environment. PMID- 25826643 TI - Genotype-phenotype correlation in Moroccan patients with primary congenital glaucoma. AB - PURPOSE: To investigate the genotype-phenotype correlation in a large cohort of Moroccan primary congenital glaucoma (PCG) in which CYP1B1 mutation spectrum was recently reported by our group. METHODS: This study included 94 patients from 84 unrelated Moroccan PCG families with or without CYP1B1 mutations. Clinical features, severity of the phenotype, and prognosis were mainly compared in patients with no CYP1B1 mutations, double CYP1B1 null alleles or nondouble null but other CYP1B1 mutations; most of them were hypomorphic mutations. Statistical analyses were performed using SAS and SPSS softwares. Significance was set at P<0.05. RESULTS: Mean of intraocular pressure, corneal diameter and number of surgery values and cup-to-disc ratios, and percentages of patients with bilateral PCG, eyes with severe opacities and severe phenotype, and those that needed >1 trabeculectomy were significantly higher in the CYP1B1 mutation carriers (n=51) than in the no CYP1B1 mutation group (n=43). The same results were observed when patients with double CYP1B1 null alleles (n=34) were compared with those with no CYP1B1 mutation. The comparison between the no CYP1B1 mutation patients and those with nondouble null but other CYP1B1 mutations (n=17) showed significant differences in the percentage of bilateral PCG and percentages of eyes with severe opacities and severe phenotype. When the double CYP1B1 null allele carriers were compared with the nondouble null but other CYP1B1 mutation group, only significant differences were observed in the mean number of surgery values. Multivariate analysis revealed that, after adjustment of the parameters that showed significant differences in univariate analyses, corneal diameter was the main factor explaining the severity of PCG only in the double CYP1B1 null allele carriers. CONCLUSIONS: This is the first report of genotype-phenotype correlation in a large cohort of Moroccan PCG. Our results revealed that the worst phenotype and prognosis were observed in the double null CYP1B1 allele carriers followed by the nondouble null but other CYP1B1 mutations. This will contribute to the prediction of the prognosis of the disease. PMID- 25826645 TI - Nocardia exalbida blebitis: a case report. AB - PURPOSE: To report the first documented case of Nocardia exalbida blebitis. METHODS: A 57-year-old immunocompetent African American man with a long-standing history of open-angle glaucoma in both eyes treated with trabeculectomy presented with a diffusely hyperemic, thin, cystic, leaky bleb with no discharge in his left eye. The patient underwent bleb revision using an amniotic membrane patch graft followed by 1 month of antibiotics. He presented second time with an inflamed eye and brisk leakage and underwent a second bleb revision. His cultures remained negative. Two months after this second surgery, an anterior staphyloma had formed within the bleb area, and visible leakage of purulent material and a dense hypopyon was noted. Gram stain of the material showed rare long-branching rods. The material was sent to an outside laboratory for culture and identification. RESULTS: All 6 cultures were positive for N. abscessus complex and N. exalbida. The patient underwent 6 months of Bactrim therapy with topical sulfonamide and amikacin, leading to the disappearance of the hypopyon and an inflammation-free eye. CONCLUSIONS: N. exalbida is a newly identified Nocardia species that must be considered as a possible infectious agent in immunocompetent patients with blebitis refractive to initial topical antibiotic therapy. Delay in diagnosis and initiation of appropriate antibiotic regimen can result in an aggressive inflammatory process and vision loss. PMID- 25826646 TI - Diacerein-Loaded novel gastroretentive nanofiber system using PLLA: Development and in vitro characterization. AB - The purpose of this research is to describe the utility of nanofibers as a gastroretentive dosage form and improve the solubility of diacerein (DIA) by using the above approach. Poly L-(lactic acid) (PLLA) nanofibers loaded with DIA were prepared using the electrospinning technique. The nanofibers developed were characterized for morphology, tensile strength, floating behavior, drug entrapment, drug solubility, mucoadhesive detachment force, and drug release profile. The results demonstrated that the drug-loaded nanofibers were smooth, discrete, & non-woven. Analysis by X-ray crystallography (XRD) revealed that the drug in the nanofiber was present in the amorphous state, which largely contributes to higher drug solubility in the nanofibers developed. The buoyancy study demonstrated that the nanofibers developed exhibited zero lag time. Approximately 61.3% of drug was released in 30 h, thus facilitating the slow release of the drug from the nanofiber system. Finally, we concluded that the electrospun nanofibers developed offer a promising gastroretentive drug delivery system to deliver DIA with improved solubility. PMID- 25826644 TI - Needle bleb revision with bevacizumab and mitomycin C compared with mitomycin C alone for failing filtration blebs. AB - PURPOSE: To report the 6-month comparative outcomes and bleb morphology for needle revision with bevacizumab and mitomycin C (MMC) versus MMC alone of failed trabeculectomy and ExPRESS shunt blebs. METHODS: Patients undergoing bleb needle revision procedures were enrolled in this study. All patients received a subconjunctival injection of 0.1 mL MMC (0.4 mg/mL) mixed with 0.1 mL preservative-free lidocaine (1%) at the beginning of the procedure. The patients were randomized into 2 cohorts assigned to receive either 1.0 mg (0.04 mL of 25 mg/mL) subconjunctival bevacizumab (treatment group) or 0.04 mL of balanced salt solution (control group) injected in an identical manner posterior to the bleb after the bleb needling. Success was defined as >=20% reduction in intraocular pressure (IOP) without any IOP-lowering medications. Qualified success was defined as >=20% reduction of IOP with IOP-lowering medications. Failure was defined as IOP>21 mm Hg, IOP reduction <20%, or need for additional surgery. Bleb morphology was classified using the Indiana Bleb Appearance Grading Scale. RESULTS: Six months postoperatively, in treatment group (n=29), 57% of patients achieved complete success, and 43% failed. In control group (n=29), 41% of patients achieved complete success, 7% achieved qualified success, and 52% failed. The difference in success rates between the 2 groups was not statistically significant (P=0.35). At 6 months, the mean IOP was 11.52 in treatment group and 12.83 in control group (P=0.45); patients in treatment group were on a mean of 0.16 medications as compared with 0.58 medications in control group (P=0.058). For bleb morphology of treatment group compared with control group, the blebs had less vascularity (0.76 vs. 1.20, respectively, on a scale of 0 to 4, P<0.05) and greater extent (2.68 vs. 2.36, on a scale of 0 to 3, P=0.022) in treatment group. CONCLUSIONS: There was no significant difference between the success rates and IOPs at postoperative month 6 between treatment and control groups. Postoperative blebs in the treatment group were less vascular and had greater extent. PMID- 25826647 TI - Optimizing an Internal Airway Percussion Device for Facilitating Exhalate Diagnostics of the Human Respiratory System. AB - PURPOSE: There is an urgent need for simple, inexpensive, noninvasive, and repeatable technique for the diagnosis of pulmonary diseases. Bronchoalveolar lavage, which is the gold standard diagnostic method for pulmonary diseases, does not meet any of these criteria. This study seeks to develop and optimize a novel technique of Internal Airway Percussion (IAP) to facilitate the collection and characterization of human respiratory system exhalates. METHODS: The IAP device transmits sound waves into the respiratory tract, thereby increasing the release of aerosolized particles within exhaled breath by vibrating both lungs. Nine combinations of sound wave frequencies and amplitudes were studied to determine optimal frequency and amplitude combination for maximum aerosol particle gain in healthy human subjects. RESULTS: Square-shaped sound waves generated at 15 Hz and 3 cm H2O resulted in 15 times greater total mass of collected particles in the first 2 min of sampling, and 1.2 to 1.5 times increase in count median diameter of the particles. CONCLUSIONS: IAP, optimized at the frequency of 15 Hz and the pressure amplitude of 3 cm H2O, increased the total mass of particles exhaled from the human respiratory system. IAP has a broad range of potential clinical applications for noninvasive diagnosis of lung diseases including asthma, cystic fibrosis, pneumonia, and lung cancer, along with improvement of mucus clearance. PMID- 25826648 TI - The first mitochondrial genome of the sepsid fly Nemopoda mamaevi Ozerov, 1997 (Diptera: Sciomyzoidea: Sepsidae), with mitochondrial genome phylogeny of cyclorrhapha. AB - Sepsid flies (Diptera: Sepsidae) are important model insects for sexual selection research. In order to develop mitochondrial (mt) genome data for this significant group, we sequenced the first complete mt genome of the sepsid fly Nemopoda mamaevi Ozerov, 1997. The circular 15,878 bp mt genome is typical of Diptera, containing all 37 genes usually present in bilaterian animals. We discovered inaccurate annotations of fly mt genomes previously deposited on GenBank and thus re-annotated all published mt genomes of Cyclorrhapha. These re-annotations were based on comparative analysis of homologous genes, and provide a statistical analysis of start and stop codon positions. We further detected two 18 bp of conserved intergenic sequences from tRNAGlu-tRNAPhe and ND1-tRNASer(UCN) across Cyclorrhapha, which are the mtTERM binding site motifs. Additionally, we compared automated annotation software MITOS with hand annotation method. Phylogenetic trees based on the mt genome data from Cyclorrhapha were inferred by Maximum likelihood and Bayesian methods, strongly supported a close relationship between Sepsidae and the Tephritoidea. PMID- 25826649 TI - Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response. AB - BACKGROUND: Recent years have seen the emergence of a new paradigm for treatment of anxiety disorders focusing on development of drugs that facilitate psychotherapies via targeted effects on neuroplasticity. One compound that has generated interest in this regard is oxytocin (OT), a mammalian neuropeptide that modulates activity of the neurocircuit mediating fear extinction and memory processes. Recent research in healthy humans has suggested that intranasal OT administered prior to fear extinction training enhances fear extinction performance, supporting its potential to augment exposure-based psychotherapy. Here, we tested the hypothesis that OT treatment would facilitate response to exposure therapy in patients with specific phobia. METHODS: We conducted a small proof-of-concept trial investigating the effect of pretreatment intranasal OT administration on a brief, single-session exposure treatment for arachnophobia (fear of spiders). The study was randomized, double-blind, and placebo controlled (n = 13 placebo, 11 females; n = 10 OT, 8 females) with 1-week and 1-month follow up assessments. Dependent measures attended to arachnophobia symptoms (self report), phobic behavior (behavioral avoidance of spider task), and treatment credibility/therapeutic alliance. RESULTS: Administration of OT prior to exposure therapy tended to impede treatment response as measured by self-report of symptoms at both follow-up periods. OT treatment did not significantly affect behavioral measures of fear. Immediately after OT administration but before therapy, the OT group trended toward less confidence in the treatment. The OT group also trended toward lower ratings of therapeutic alliance than placebo. CONCLUSIONS: These results suggest that OT administration effects on extinction may vary depending on conditions and population. PMID- 25826650 TI - Integrated in silico Analyses of Regulatory and Metabolic Networks of Synechococcus sp. PCC 7002 Reveal Relationships between Gene Centrality and Essentiality. AB - Cyanobacteria dynamically relay environmental inputs to intracellular adaptations through a coordinated adjustment of photosynthetic efficiency and carbon processing rates. The output of such adaptations is reflected through changes in transcriptional patterns and metabolic flux distributions that ultimately define growth strategy. To address interrelationships between metabolism and regulation, we performed integrative analyses of metabolic and gene co-expression networks in a model cyanobacterium, Synechococcus sp. PCC 7002. Centrality analyses using the gene co-expression network identified a set of key genes, which were defined here as "topologically important." Parallel in silico gene knock-out simulations, using the genome-scale metabolic network, classified what we termed as "functionally important" genes, deletion of which affected growth or metabolism. A strong positive correlation was observed between topologically and functionally important genes. Functionally important genes exhibited variable levels of topological centrality; however, the majority of topologically central genes were found to be functionally essential for growth. Subsequent functional enrichment analysis revealed that both functionally and topologically important genes in Synechococcus sp. PCC 7002 are predominantly associated with translation and energy metabolism, two cellular processes critical for growth. This research demonstrates how synergistic network-level analyses can be used for reconciliation of metabolic and gene expression data to uncover fundamental biological principles. PMID- 25826652 TI - Numerical models to evaluate the temperature increase induced by ex vivo microwave thermal ablation. AB - Microwave thermal ablation (MTA) therapies exploit the local absorption of an electromagnetic field at microwave (MW) frequencies to destroy unhealthy tissue, by way of a very high temperature increase (about 60 degrees C or higher). To develop reliable interventional protocols, numerical tools able to correctly foresee the temperature increase obtained in the tissue would be very useful. In this work, different numerical models of the dielectric and thermal property changes with temperature were investigated, looking at the simulated temperature increments and at the size of the achievable zone of ablation. To assess the numerical data, measurement of the temperature increases close to a MTA antenna were performed in correspondence with the antenna feed-point and the antenna cooling system, for increasing values of the radiated power. Results show that models not including the changes of the dielectric and thermal properties can be used only for very low values of the power radiated by the antenna, whereas a good agreement with the experimental values can be obtained up to 20 W if water vaporization is included in the numerical model. Finally, for higher power values, a simulation that dynamically includes the tissue's dielectric and thermal property changes with the temperature should be performed. PMID- 25826651 TI - Advances in Understanding Carboxysome Assembly in Prochlorococcus and Synechococcus Implicate CsoS2 as a Critical Component. AB - The marine Synechococcus and Prochlorococcus are the numerically dominant cyanobacteria in the ocean and important in global carbon fixation. They have evolved a CO2-concentrating-mechanism, of which the central component is the carboxysome, a self-assembling proteinaceous organelle. Two types of carboxysome, alpha and beta, encapsulating form IA and form IB d-ribulose-1,5-bisphosphate carboxylase/oxygenase, respectively, differ in gene organization and associated proteins. In contrast to the beta-carboxysome, the assembly process of the alpha carboxysome is enigmatic. Moreover, an absolutely conserved alpha-carboxysome protein, CsoS2, is of unknown function and has proven recalcitrant to crystallization. Here, we present studies on the CsoS2 protein in three model organisms and show that CsoS2 is vital for alpha-carboxysome biogenesis. The primary structure of CsoS2 appears tripartite, composed of an N-terminal, middle (M)-, and C-terminal region. Repetitive motifs can be identified in the N- and M regions. Multiple lines of evidence suggest CsoS2 is highly flexible, possibly an intrinsically disordered protein. Based on our results from bioinformatic, biophysical, genetic and biochemical approaches, including peptide array scanning for protein-protein interactions, we propose a model for CsoS2 function and its spatial location in the alpha-carboxysome. Analogies between the pathway for beta carboxysome biogenesis and our model for alpha-carboxysome assembly are discussed. PMID- 25826653 TI - Using senses to encourage head and upper limb voluntary movement in young infants: Implications for early intervention. AB - PRIMARY OBJECTIVE: It has long been suggested that a neonate's movement and responses to external stimuli are the product of reflexive reactions rather than purposeful movements. However, several studies have demonstrated that this is not the case. Rationale of literature included: This study seeks to review reports showing that sensory stimuli resulted in newborns recognising and responding to different stimuli with active head or upper limb movements. We also discuss this in the context of current literature about early training on the advancement of movement and brain development. Results and outcomes: Taken together, it is clear that early active experience shapes learning in newborns. CONCLUSIONS: The impact of this research is most exciting for applications that would induce infants to make purposeful movements, especially as a means for early intervention and rehabilitation for the treatment of infants with or at high risk for developmental delay. PMID- 25826654 TI - A novel model to predict esophageal varices in patients with compensated cirrhosis using acoustic radiation force impulse elastography. AB - BACKGROUND & AIMS: Few noninvasive methods can accurately identify esophageal varices (EVs) in patients with compensated cirrhosis. We developed and validated a novel, acoustic radiation force impulse (ARFI) elastography-based prediction model for high-risk EVs (HEVs) in patients with compensated cirrhosis. METHODS: A total of 143 patients with compensated cirrhosis between February, 2010 and February, 2013 (training set) and 148 between June, 2010 and May, 2013 (validation set) who underwent ARFI elastography and endoscopy were prospectively recruited. Independent predictors of HEVs were used to construct a prediction model. RESULTS: Based on multivariate analysis, we developed two new statistical models, a varices risk score and ARFI-spleen diameter-to-platelet ratio score (ASPS), the latter of which was calculated as ARFI velocity * spleen diameter/platelet count. The area under receiver operating characteristic curve (AUROC) of the varices risk score and ASPS to predict HEVs were 0.935 (95% confidence interval [CI] 0.882-0.970) and 0.946 (95% CI 0.895-0.977), respectively. When ASPS, a simpler model with a higher AUROC, was applied in the validation set, acceptable diagnostic accuracy for HEVs was observed (AUROC = 0.814 [95% CI 0.743-0.885]). To detect HEVs, a negative predictive value of 98.3% was achieved at ASPS <2.83, whereas a positive predictive value of 100% was achieved at ASPS >5.28. CONCLUSIONS: ASPS, a novel noninvasive ARFI-based prediction model, can accurately identify HEVs in patients with compensated cirrhosis. ASPS <2.83 may safely rule out the presence of HEVs, whereas patients with ASPS >5.28 should be considered for endoscopic examinations or appropriate prophylactic treatment. PMID- 25826655 TI - HIV self-testing could "revolutionize testing in South Africa, but it has got to be done properly": perceptions of key stakeholders. AB - South Africa bears the world's largest burden of HIV with over 6.4 million people living with the virus. The South African government's response to HIV has yielded remarkable results in recent years; over 13 million South Africans tested in a 2012 campaign and over 2 million people are on antiretroviral treatment. However, with an HIV & AIDS and STI National Strategic Plan aiming to get 80 percent of the population to know their HIV status by 2016, activists and public health policy makers argue that non-invasive HIV self-testing should be incorporated into the country HIV Counseling and Testing [HCT] portfolios. In-depth qualitative interviews (N = 12) with key stakeholders were conducted from June to July 2013 in South Africa. These included two government officials, four non governmental stakeholders, two donors, three academic researchers, and one international stakeholder. All stakeholders were involved in HIV prevention and treatment and influenced HCT policy and research in South Africa and beyond. The interviews explored: interest in HIV self-testing; potential distribution channels for HIV self-tests to target groups; perception of requirements for diagnostic technologies that would be most amenable to HIV self-testing and opinions on barriers and opportunities for HIV-linkage to care after receiving positive test results. While there is currently no HIV self-testing policy in South Africa, and several barriers exist, participants in the study expressed enthusiasm and willingness for scale-up and urgent need for further research, planning, establishment of HIV Self-testing policy and programming to complement existing facility-based and community-based HIV testing systems. Introduction of HIV self-testing could have far-reaching positive effects on holistic HIV testing uptake, giving people autonomy to decide which approach they want to use for HIV testing, early diagnosis, treatment and care for HIV particularly among hard-to reach groups, including men. PMID- 25826656 TI - ASH1 mRNP-core factors form stable complexes in absence of cargo RNA at physiological conditions. AB - Asymmetric ASH1 mRNA transport during mitosis of budding yeast constitutes one of the best-studied examples of mRNA localization. Recently, 2 studies used in vitro motility assays to prove that motile ASH1 mRNA-transport complexes can be reconstituted entirely from recombinant factors. Both studies, however, differed in their conclusions on whether cargo RNA itself is required for particle assembly and thus activation of directional transport. Here we provide direct evidence that stable complexes do assemble in absence of RNA at physiologic conditions and even at ionic strengths above cellular levels. These results directly confirm the previous notion that the ASH1 transport machinery is not activated by the cargo RNA itself, but rather through protein-protein interactions. PMID- 25826657 TI - Unveiling the principle of microRNA-mediated redundancy in cellular pathway regulation. AB - Understanding the multifaceted nature of microRNA (miRNA) function in mammalian cells is still a challenge. Commonly accepted principles of cooperativity and multiplicity of miRNA function imply that individual mRNAs can be targeted by several miRNAs whereas a single miRNA may concomitantly regulate a subset of different genes. However, there is a paucity of information whether multiple miRNAs regulate critical cellular events and thereby acting redundantly. To gain insight into this notion, we conducted an unbiased high-content miRNA screen by individually introducing 1139 miRNA mimics into Chinese hamster ovary (CHO) cells. We discovered that 66% of all miRNAs significantly impacted on proliferation, protein expression, apoptosis and necrosis. In summary, we provide evidence for a substantial degree of redundancy among miRNAs to maintain cellular homeostasis. PMID- 25826658 TI - Probing the closed-loop model of mRNA translation in living cells. AB - The mRNA closed-loop, formed through interactions between the cap structure, poly(A) tail, eIF4E, eIF4G and PAB, features centrally in models of eukaryotic translation initiation, although direct support for its existence in vivo is not well established. Here, we investigated the closed-loop using a combination of mRNP isolation from rapidly cross-linked cells and high-throughput qPCR. Using the interaction between these factors and the opposing ends of mRNAs as a proxy for the closed-loop, we provide evidence that it is prevalent for eIF4E/4G-bound but unexpectedly sparse for PAB1-bound mRNAs, suggesting it primarily occurs during a distinct phase of polysome assembly. We observed mRNA-specific variation in the extent of closed-loop formation, consistent with a role for polysome topology in the control of gene expression. PMID- 25826659 TI - The RNA recognition motif of NIFK is required for rRNA maturation during cell cycle progression. AB - Ribosome biogenesis governs protein synthesis. NIFK is transactivated by c-Myc, the key regulator of ribosome biogenesis. The biological function of human NIFK is not well established, except that it has been shown to interact with Ki67 and NPM1. Here we report that NIFK is required for cell cycle progression and participates in the ribosome biogenesis via its RNA recognition motif (RRM). We show that silencing of NIFK inhibits cell proliferation through a reversible p53 dependent G1 arrest, possibly by induction of the RPL5/RPL11-mediated nucleolar stress. Mechanistically it is the consequence of impaired maturation of 28S and 5.8S rRNA resulting from inefficient cleavage of internal transcribed spacer (ITS) 1, a critical step in the separation of pre-ribosome to small and large subunits. Complementation of NIFK silencing by mutants shows that RNA-binding ability of RRM is essential for the pre-rRNA processing and G1 progression. More specifically, we validate that the RRM of NIFK preferentially binds to the 5' region of ITS2 rRNA likely in both sequence specific and secondary structure dependent manners. Our results show how NIFK is involved in cell cycle progression through RRM-dependent pre-rRNA maturation, which could enhance our understanding of the function of NIFK in cell proliferation, and potentially also cancer and ribosomopathies. PMID- 25826660 TI - Replicating Potato spindle tuber viroid mediates de novo methylation of an intronic viroid sequence but no cleavage of the corresponding pre-mRNA. AB - In plants, Potato spindle tuber viroid (PSTVd) replication triggers post transcriptional gene silencing (PTGS) and RNA-directed DNA methylation (RdDM) of homologous RNA and DNA sequences, respectively. PTGS predominantly occurs in the cytoplasm, but nuclear PTGS has been also reported. In this study, we investigated whether the nuclear replicating PSTVd is able to trigger nuclear PTGS. Transgenic tobacco plants carrying cytoplasmic and nuclear PTGS sensor constructs were PSTVd-infected resulting in the generation of abundant PSTVd derived small interfering RNAs (vd-siRNAs). Northern blot analysis revealed that, in contrast to the cytoplasmic sensor, the nuclear sensor transcript was not targeted for RNA degradation. Bisulfite sequencing analysis showed that the nuclear PTGS sensor transgene was efficiently targeted for RdDM. Our data suggest that PSTVd fails to trigger nuclear PTGS, and that RdDM and nuclear PTGS are not necessarily coupled. PMID- 25826661 TI - microRNA-200b and microRNA-200c promote colorectal cancer cell proliferation via targeting the reversion-inducing cysteine-rich protein with Kazal motifs. AB - MicroRNA-200b and microRNA-200c (miR-200b/c) are 2 of the most frequently upregulated oncomiRs in colorectal cancer cells. The role of miR-200b/c during colorectal tumorigenesis, however, remains unclear. In the present study, we report that miR-200b/c can promote colorectal cancer cell proliferation via targeting the reversion-inducing cysteine-rich protein with Kazal motifs (RECK). Firstly, bioinformatics analysis predicted RECK as a conserved target of miR 200b/c. By overexpressing or knocking down miR-200b/c in colorectal cancer cells, we experimentally validated that miR-200b/c are direct regulators of RECK. Secondly, an inverse correlation between the levels of miR-200b/c and RECK protein was found in human colorectal cancer tissues and cell lines. Thirdly, we demonstrated that repression of RECK by miR-200b/c consequently triggered SKP2 (S phase kinase-associated protein 2) elevation and p27(Kip1) (also known as cyclin dependent kinase inhibitor 1B) degradation in colorectal cancer cells, which eventually promotes cancer cell proliferation. Finally, promoting tumor cell growth by miR-200b/c-targeting RECK was also observed in the xenograft mouse model. Taken together, our results demonstrate that miR-200b/c play a critical role in promoting colorectal tumorigenesis through inhibiting RECK expression and subsequently triggering SKP2 elevation and p27(Kip1) degradation. PMID- 25826662 TI - Regulation of human PTCH1b expression by different 5' untranslated region cis regulatory elements. AB - PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG)n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway. PMID- 25826663 TI - Two related trypanosomatid eIF4G homologues have functional differences compatible with distinct roles during translation initiation. AB - In higher eukaryotes, eIF4A, eIF4E and eIF4G homologues interact to enable mRNA recruitment to the ribosome. eIF4G acts as a scaffold for these interactions and also interacts with other proteins of the translational machinery. Trypanosomatid protozoa have multiple homologues of eIF4E and eIF4G and the precise function of each remains unclear. Here, 2 previously described eIF4G homologues, EIF4G3 and EIF4G4, were further investigated. In vitro, both homologues bound EIF4AI, but with different interaction properties. Binding to distinct eIF4Es was also confirmed; EIF4G3 bound EIF4E4 while EIF4G4 bound EIF4E3, both these interactions required similar binding motifs. EIF4G3, but not EIF4G4, interacted with PABP1, a poly-A binding protein homolog. Work in vivo with Trypanosoma brucei showed that both EIF4G3 and EIF4G4 are cytoplasmic and essential for viability. Depletion of EIF4G3 caused a rapid reduction in total translation while EIF4G4 depletion led to changes in morphology but no substantial inhibition of translation. Site directed mutagenesis was used to disrupt interactions of the eIF4Gs with either eIF4E or eIF4A, causing different levels of growth inhibition. Overall the results show that only EIF4G3, with its cap binding partner EIF4E4, plays a major role in translational initiation. PMID- 25826664 TI - Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation. AB - The activation of translation contributes to malignant transformation and is an emerging target for cancer therapies. RNA G-quadruplex structures are general inhibitors of cap-dependent mRNA translation and were recently shown to be targeted for oncoprotein translational activation. In contrast however, the G quadruplex within the 5'UTR of the human vascular endothelial growth factor A (VEGF) has been shown to be essential for IRES-mediated translation. Since VEGF has a pivotal role in tumor angiogenesis and is a major target of anti-tumoral therapies, we investigated the structure/function relationship of the VEGF G quadruplex and defined whether it could have a therapeutic potential. We found that the G-quadruplex within the VEGF IRES is dispensable for cap-independent function and activation in stress conditions. However, stabilization of the VEGF G-quadruplex by increasing the G-stretches length or by replacing it with the one of NRAS results in strong inhibition of IRES-mediated translation of VEGF. We also demonstrate that G-quadruplex ligands stabilize the VEGF G-quadruplex and inhibit cap-independent translation in vitro. Importantly, the amount of human VEGF mRNA associated with polysomes decreases in the presence of a highly selective stabilizing G-quadruplex ligand, resulting in reduced VEGF protein expression. Together, our results uncover the existence of functionally silent G quadruplex structures that are susceptible to conversion into efficient repressors of cap-independent mRNA translation. These findings have implications for the in vivo applications of G-quadruplex-targeting compounds and for anti angiogenic therapies. PMID- 25826665 TI - Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. AB - Alternative splicing at the MAPT gene exon 10 yields similar levels of the 3R and 4R tau protein isoforms. (1) The presence of mutations, particularly in exon 10 and intron 10-11, changes the quantity of tau isoforms. Domination each of the isoform yields tau protein aggregation and frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Here, we report for the first time the secondary structure of the 194/195 nucleotide region for the wild type (WT) and 10 mutants of the MAPT gene pre-mRNA determined using both chemical and microarray mapping. Thermodynamic analyses indicate that single nucleotide mutations in the splicing regulatory element (SRE) that form a hairpin affect its stability by up to 4 and 7 kcal/mol. Moreover, binding the regulatory hairpin of small molecule ligands (neomycin, kanamycin, tobramycin and mitoxantrone) enhance its stability depending on the nature of the ligands and the RNA mutations. Experiments using the cos-7 cell line indicate that the presence of ligands and modified antisense oligonucleotides affect the quantity of 3R and 4R isoforms. This finding correlates with the thermodynamic stability of the regulatory hairpin. An alternative splicing regulation mechanism for exon 10 is postulated based on our experimental data and on published data. PMID- 25826666 TI - miR-214 promotes osteoclastogenesis by targeting Pten/PI3k/Akt pathway. AB - microRNA is necessary for osteoclast differentiation, function and survival. It has been reported that miR-199/214 cluster plays important roles in vertebrate skeletal development and miR-214 inhibits osteoblast function by targeting ATF4. Here, we show that miR-214 is up-regulated during osteoclastogenesis from bone marrow monocytes (BMMs) with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) induction, which indicates that miR-214 plays a critical role in osteoclast differentiation. Overexpression of miR-214 in BMMs promotes osteoclastogenesis, whereas inhibition of miR-214 attenuates it. We further find that miR-214 functions through PI3K/Akt pathway by targeting phosphatase and tensin homolog (Pten). In vivo, osteoclast specific miR-214 transgenic mice (OC-TG214) exhibit down-regulated Pten levels, increased osteoclast activity, and reduced bone mineral density. These results reveal a crucial role of miR-214 in the differentiation of osteoclasts, which will provide a potential therapeutic target for osteoporosis. PMID- 25826668 TI - Determination of chlorophenols in red wine using ionic liquid countercurrent chromatography as a new pretreatment method followed by high-performance liquid chromatography. AB - A countercurrent chromatography method for the enrichment and cleanup of chlorophenols from food samples was successfully established by using an ionic liquid-modified two-phase solvent system composed of dichloromethane containing 2% 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide and water. The column was firstly filled with the organic stationary phase, and then a large volume of sample was pumped into the column after it was equilibrated with pure water at the rotation speed. Finally, the trace amounts of chlorophenols extracted and enriched in the stationary phase were eluted out by an alkaline mobile phase and determined by high-performance liquid chromatography. Under optimized conditions, the enrichment and cleanup of the chlorophenols can be fulfilled online with enrichment factors (34-65) and high recoveries (84.69 95.23%). The method has been applied to the determination of chlorophenols in real red wine samples with the limits of detection in the range of 1.89-4.21 MUg/L. The present method is highly suitable for the pretreatment of large volume of aqueous sample for the determination of trace amounts of contaminants in food and environmental samples. PMID- 25826667 TI - Translation attenuation via 3' terminal codon usage in bovine csn1s2 is responsible for the difference in alphas2- and beta-casein profile in milk. AB - The rate of secretion of alphas2-casein into bovine milk is approximately 25% of that of beta-casein, yet mammary expression of their respective mRNA transcripts (csn1s2 and csn2) is not different. Our objective was to identify molecular mechanisms that explain the difference in translation efficiency between csn1s2 and csn2. Cell-free translational efficiency of csn2 was 5 times that of csn1s2. Transcripts of csn1s2 distributed into heavier polysomes than csn2 transcripts, indicating an attenuation of elongation and/or termination. Stimulatory and inhibitory effects of the 5' and 3' UTRs on translational efficiency were different with luciferase and casein sequences in the coding regions. Substituting the 5' and 3' UTRs from csn2 into csn1s2 did not improve csn1s2 translation, implicating the coding region itself in the translation difference. Deletion of a 28-codon fragment from the 3' terminus of the csn1s2 coding region, which displays codons with low correlations to cell fitness, increased translation to a par with csn2. We conclude that the usage of the last 28 codons of csn1s2 is the main regulatory element that attenuates its expression and is responsible for the differential translational expression of csn1s2 and csn2. PMID- 25826670 TI - Synthesis and characterization of mixed-valence manganese fluorophosphate and analogues with clathrate-like structures: Mn(III)6F12(PO3(OH))8[Na8(Kx(H3O)4 x(H2O)2)M(IV)(OH)6] (M(IV) = Mn, Ti, Ge). AB - A novel, mixed- and high-valence manganese (Mn(3+)/Mn(4+)) fluorophosphate, Mn(III)6F12(PO3(OH))8[Na8(Kx(H3O)4-x(H2O)2)Mn(IV)(OH)6] (denoted as MN), has been prepared via a water-deficient hydrothermal route with phosphoric acid as the sole solvent. This compound features a cubic three-dimensional open-framework structure built from corner-sharing [Mn(III)O4F2] octahedra and [HPO4] groups, which encapsulates a clathrate-like "guest cluster" of Na8(Kx(H3O)4 x(H2O)2)Mn(IV)(OH)6. The guest cluster is architecturally composed of a [Mn(IV)(OH)6] octahedron in a cubic cage of Na(+) cations, which in turn is surrounded by an octahedral arrangement of K(+)/H2O ions, resulting in an unprecedented octahedral @ cubic @ octahedral @ cubic arrangement (OCOC). The +4 oxidation state of Mn in the guest cluster has been confirmed by the synthesis of isotypic Ti- and Ge- analogues (denoted as TI and GE) using TiO2 and GeO2 as the replacement for MnO2 in the starting materials. The compounds MN, TI and GE are not stable in aqueous solution and are peeled off layer-by-layer after the absorption of water. This report provides a new route for the synthesis of mixed- and high-valence manganese phosphates that cannot be produced by conventional hydrothermal methods. PMID- 25826669 TI - An anti-B cell maturation antigen bispecific antibody for multiple myeloma. AB - The development of immunotherapies for multiple myeloma is critical to provide new treatment strategies to combat drug resistance. We report a bispecific antibody against B cell maturation antigen (BiFab-BCMA), which potently and specifically redirects T cells to lyse malignant multiple myeloma cells. BiFab BCMA lysed target BCMA-positive cell lines up to 20-fold more potently than a CS1 targeting bispecific antibody (BiFab-CS1) developed in an analogous fashion. Further, BiFab-BCMA robustly activated T cells in vitro and mediated rapid tumor regression in an orthotopic xenograft model of multiple myeloma. The in vitro and in vivo activities of BiFab-BCMA are comparable to those of anti-BCMA chimeric antigen receptor T cell therapy (CAR-T-BCMA), for which two clinical trials have recently been initiated. A BCMA-targeted bispecific antibody presents a promising treatment option for multiple myeloma. PMID- 25826671 TI - Monosaccharide identification as a first step toward de novo carbohydrate sequencing: mass spectrometry strategy for the identification and differentiation of diastereomeric and enantiomeric pentose isomers. AB - De novo carbohydrate sequencing, including monosaccharide identification, largely remains a tremendous analytical challenge. A first step in the complete structural determination of any large polysaccharide is an accurate and robust method for analysis of the constituent monosaccharides. Herein, the first mass spectrometry-based method for the complete identification and absolute configuration determination of all 12 pentose isomers, including the d and l enantiomers for arabinose, lyxose, ribose, xylose, ribulose, and xylulose, is reported. As compared to earlier work to distinguish hexose isomers, the chiral separation of the pentose isomers was significantly more challenging. Specifically, the 12 pentoses are much more structurally similar to one another, with only the axial or equatorial orientation of two hydroxyl groups differentiating among these isomers in their five-membered ring furanose structure and smaller energetic differences between pentose conformations than between hexose conformations. Despite such inherently minimal energetic differences between the 12 pentoses, two unique fixed ligand kinetic method combinations were discovered to achieve chiral discrimination for this set of isomers. This assay can be readily applied to the identification of any isolated pentose monosaccharide using only microgram quantities and a commercial instrument and complements the method to distinguish hexose isomers. A workflow that incorporates this mass spectrometry-based method and thereby could achieve complete de novo identification of all monosaccharide building blocks in an oligo or polysaccharide is proposed. PMID- 25826673 TI - A total population-based cohort study of female psychiatric inpatients who have served a prison sentence. AB - BACKGROUND: Studies of the overlap between severe mental disorder and criminality tend to focus on prison populations rather than psychiatric populations. AIMS: Our aims were to establish the prevalence of previous imprisonment among female psychiatric inpatients and test relationships between diagnoses, mortality and imprisonment. METHODS: A nationwide cohort of 18-65-year-old women who had been hospitalised for psychiatric disorder between January 1983 and March 2008 was identified from a hospital records database and linked to the database of the Prison and Probation Administration of Iceland as well as the National Register of causes of death at Statistics Iceland from January 1985. RESULTS: Six thousand and ninety-four women had had at least one psychiatric hospitalisation, 102 of them had been imprisoned on 172 occasions between them, giving an imprisonment rate of 118 per 100,000 over the 24 year period of study. The crude imprisonment proportion was 1.7% during a 20-year follow-up period; it was at its peak (5%) among 18-30 year-olds at index admission. Substance use and personality disorders were the most common diagnoses associated with imprisonment. Mortality rates were not statistically different between those imprisoned and not (hazard ratio = 1.3, 95% confidence interval 0.5-3.5). CONCLUSION AND IMPLICATIONS FOR PRACTICE: Women admitted to a psychiatric hospital have higher rates of imprisonment than the general population. Because admission predated imprisonment in most cases, this may be seen as an opportunity for early intervention to reduce later criminality. PMID- 25826674 TI - Reg3alpha Overexpression Protects Pancreatic beta Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome. AB - The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure. This may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3alpha (Reg3alpha) is a pancreatic secretory protein which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3alpha could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3alpha or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3alpha production exhibited significantly lower blood glucose levels (9.057 +/ 0.59 mmol/L versus 13.48 +/- 0.35 mmol/L, P < 0.05) and improved glucose stimulated insulin secretion (1.80 +/- 0.17 ng/mL versus 1.16 +/- 0.16 ng/mL, P < 0.05) compared with the control group. The decline of apoptotic events (0.57% +/- 0.15% versus 1.06% +/- 0.07%, P < 0.05) and increased beta-cell proliferation (0.70% +/- 0.10% versus 0.36% +/- 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3alpha by morphometric analysis. Further experiments showed that Reg3alpha production dramatically protected cultured islets and pancreatic beta cells from cytokine-induced apoptosis and the impairment of glucose stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic beta cells, which was reversed by Reg3alpha overexpression in contrast to control group. These results strongly suggest that Reg3alpha could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation. PMID- 25826672 TI - Mitochondrial Redox Dysfunction and Environmental Exposures. AB - SIGNIFICANCE: Mitochondria are structurally and biochemically diverse, even within a single type of cell. Protein complexes localized to the inner mitochondrial membrane synthesize ATP by coupling electron transport and oxidative phosphorylation. The organelles produce reactive oxygen species (ROS) from mitochondrial oxygen and ROS can, in turn, alter the function and expression of proteins used for aerobic respiration by post-translational and transcriptional regulation. RECENT ADVANCES: New interest is emerging not only into the roles of mitochondria in disease development and progression but also as a target for environmental toxicants. CRITICAL ISSUES: Dysregulation of respiration has been linked to cell death and is a major contributor to acute neuronal trauma, peripheral diseases, as well as chronic neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. FUTURE DIRECTIONS: Here, we discuss the mechanisms underlying the sensitivity of the mitochondrial respiratory complexes to redox modulation, as well as examine the effects of environmental contaminants that have well-characterized mitochondrial toxicity. The contaminants discussed in this review are some of the most prevalent and potent environmental contaminants that have been linked to neurological dysfunction, altered cellular respiration, and oxidation. PMID- 25826675 TI - Macrophage migration inhibitory factor (MIF) enzymatic activity and lung cancer. AB - The cytokine macrophage migration inhibitory factor (MIF) possesses unique tautomerase enzymatic activity, which contributes to the biological functional activity of MIF. In this study, we investigated the effects of blocking the hydrophobic active site of the tautomerase activity of MIF in the pathogenesis of lung cancer. To address this, we initially established a Lewis lung carcinoma (LLC) murine model in Mif-KO and wild-type (WT) mice and compared tumor growth in a knock-in mouse model expressing a mutant MIF lacking enzymatic activity (Mif (P1G)). Primary tumor growth was significantly attenuated in both Mif-KO and Mif (P1G) mice compared with WT mice. We subsequently undertook a structure-based, virtual screen to identify putative small molecular weight inhibitors specific for the tautomerase enzymatic active site of MIF. From primary and secondary screens, the inhibitor SCD-19 was identified, which significantly attenuated the tautomerase enzymatic activity of MIF in vitro and in biological functional screens. In the LLC murine model, SCD-19, given intraperitoneally at the time of tumor inoculation, was found to significantly reduce primary tumor volume by 90% (p < 0.001) compared with the control treatment. To better replicate the human disease scenario, SCD-19 was given when the tumor was palpable (at d 7 after tumor inoculation) and, again, treatment was found to significantly reduce tumor volume by 81% (p < 0.001) compared with the control treatment. In this report, we identify a novel inhibitor that blocks the hydrophobic pocket of MIF, which houses its specific tautomerase enzymatic activity, and demonstrate that targeting this unique active site significantly attenuates lung cancer growth in in vitro and in vivo systems. PMID- 25826678 TI - Restrictive versus Standard Fluid Regimen in Elective Minilaparotomy Abdominal Aortic Repair-Prospective Randomized Controlled Trial. AB - Objective Elective minilaparotomy abdominal aortic aneurysm (AAA) repair is associated with a significant number of complications involving respiratory, cardiovascular, gastrointestinal, and central nervous systems, with mortality ranging up to 5%. In our study, we tested the hypothesis that intra- and postoperative intravenous restrictive fluid regimen reduces postoperative morbidity and mortality, and improves the outcome of minilaparotomy AAA repair. Methods From March 2009 to July 2013, 60 patients operated due to AAA were included in a prospective randomized controlled trial (RCT). About the administration of fluid during the operation and in the early postoperative period, all the patients were randomized into two groups: the group of standard fluid administration (S-group, 30 patients) and the group of reduced fluid administration (R-group, 30 patients). The verification of the treatment success was measured by the length of intensive care unit (ICU) stay, duration of hospitalization after the procedure, as well as the number and type of postoperative complications and mortality. This prospective RCT was registered in a publicly accessible database ClinicalTrials.gov with unique Identifier ID: NTC01939652. Results Total fluid administration and administration of blood products were significantly lower in R-group as compared with S-group (2,445.5 mL vs. 3308.7 mL, p = 0.004). Though the number of nonlethal complications was significantly lower in R-group (2 vs. 9 patients, p = 0.042), the difference in lethal complications remained nonsignificant (0 vs. 1 patient, p = ns). The average ICU stay (1.2 vs. 1.97 days, p = 0.003) and duration of postoperative hospital stay (4.33 vs. 6.20 days, p = 0.035 for R-group and S-group, respectively) were found to be significantly shorter in R-group. Conclusion Intra and postoperative restrictive intravenous fluid regimen in patients undergoing minilaparotomy AAA repair significantly reduces postoperative morbidity, and shortens ICU and overall hospital stay. Even though incidence of lethal complication was lower in R-group, the difference did not reach statistical significance. Therefore, we may assume that this study was probably underpowered to estimate the differences in mortality between R- and S-groups. Further multicentric, sufficiently powered RCTs are needed to confirm these findings and to clarify effect of restrictive fluid management on mortality. PMID- 25826676 TI - Expression of Blimp-1 in dendritic cells modulates the innate inflammatory response in dextran sodium sulfate-induced colitis. AB - A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp 1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1beta- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1beta and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease. PMID- 25826679 TI - Time-Trend Analysis of Pulmonary and Diaphragmatic Functionality in Patients with Diaphragmatic Palsy or with Chronic Diaphragmatic Hernia after Surgical Treatment. AB - Background The aim of this study was to assess long-term pulmonary and diaphragmatic function in two cohorts of patients: the first one affected by diaphragmatic palsy (DP) who underwent plication reinforced by rib-fixed mesh and the second one affected by chronic diaphragmatic hernia (TDH) who underwent surgical reduction and direct suture. Materials and Methods From 1996 to 2011, 10 patients with unilateral DP and 6 patients with TDH underwent elective surgery. Preoperative and long-term (12 months) follow-up assessments were completed in all patients, including pulmonary function tests (PFTs) with diffusion of the lung for carbon monoxide (DLCO), measure of maximum inspiratory pressure (MIP) assessed both in standing and in supine positions, blood gas analysis, chest computed tomographic (CT) scan, and dyspnea score. The Pearson chi-square test, Fisher exact test, and Student t-test were applied when indicated. Results At long-term (12 months) postoperative follow-up, patients operated for DP showed a significant improvement in terms of forced expiratory volume in 1 second (FEV1%) (+ 18.2%, p < 0.001), forced vital capacity (FVC%) (+ 12.8%, p < 0.001), DLCO% (+ 8.3%, p = 0.04), and Po 2 (+ 9.86 mm Hg, p < 0.001) when compared with baseline values. Conversely, when considering the TDH group, only the levels of Po 2 were found to be significantly higher in the postoperative assessment (+ 8.3 mm Hg, p = 0.04). Although MIP increased in both the groups after surgery, a persistent and significant decrease of MIP was detected in TDH group when comparing the levels assessed in supine position with those measured in the standing position (p < 0.001). Medical Research Council dyspnea scale improved in the DP group by a factor of 0.80 (p < 0.001) and in the TDH group by a factor of 0.33 (p = 0.175). Conclusion In patients who underwent surgery for DP, good long-term results may be predicted in terms of pulmonary flows, volumes, and DLCO. Conversely, in patients who underwent elective surgery for chronic TDH, a persistent overall restrictive pattern, lower MIP values in supine position, and paradoxical motion could be expected. PMID- 25826677 TI - Cryoprotectant Toxicity: Facts, Issues, and Questions. AB - High levels of penetrating cryoprotectants (CPAs) can eliminate ice formation during cryopreservation of cells, tissues, and organs to cryogenic temperatures. But CPAs become increasingly toxic as concentration increases. Many strategies have been attempted to overcome the problem of eliminating ice while minimizing toxicity, such as attempting to optimize cooling and warming rates, or attempting to optimize time of adding individual CPAs during cooling. Because strategies currently used are not adequate, CPA toxicity remains the greatest obstacle to cryopreservation. CPA toxicity stands in the way of cryogenic cryopreservation of human organs, a procedure that has the potential to save many lives. This review attempts to describe what is known about CPA toxicity, theories of CPA toxicity, and strategies to reduce CPA toxicity. Critical analysis and suggestions are also included. PMID- 25826680 TI - Genetic risks to nicotine dependence predict negative mood and affect in current non-smokers. AB - Nicotine is the psychoactive agent involved in nicotine dependence. However, nicotine as a drug, and its effects on human psychology are largely under investigated in genetic studies. In this study, we recruited 208 current non smokers to evaluate the effect of nicotine and its relationship to genetic risks to nicotine dependence. Exploratory and confirmatory factor analyses, as well as measurement invariance testing, were conducted to evaluate the latent factor structures of the POMS, PANAS and DEN questionnaires across 3 nicotine doses. Structural models were used to examine the effects of nicotine and their relationship to genetic risks of nicotine dependence. We found that nicotine administration led to the change of both measurement construct and factor means, indicating the causal effect of nicotine on the psychological responses. The genotypes of rs588765 predicted the scores of the DEN Confused and Dizzy factors (p = 0.0003 and 0.001 respectively), and rs16969968 and rs588765 were associated with the PANAS Nervous factor (p = 0.006 and 0.007 respectively). Our study suggested that genetic risk of nicotine dependence is associated with acute psychological responses. The integration of psychometric analyses and dose effects could be a powerful approach for genetic study of nicotine dependence. PMID- 25826682 TI - Correction: intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the Cancer Genome Atlas. AB - [This corrects the article DOI: 10.1371/journal.pmed.1001786.]. PMID- 25826681 TI - Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers. AB - The high morbidity and mortality of patients with esophageal (E) and gastro esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers. PMID- 25826683 TI - Muscle protein turnover in the elderly and its potential contribution to the development of sarcopenia. AB - The underlying aetiology of sarcopenia appears multifaceted and not yet fully defined, but ultimately involves the gradual loss of muscle protein content over time. The present evidence suggests that the loss of lean tissue in the elderly is exacerbated by low dietary protein intake. Moreover, acute stable-isotope based methodologies have demonstrated that the muscle anabolic response to a given amount of protein may decline with age, a phenomenon that has been termed anabolic resistance. Although the mechanism responsible for the inability of muscle to mount a satisfactory anabolic response to protein provision with increasing age is presently unknown, it does not appear due to impaired digestion or absorption of dietary protein. Rather, the issue could reside with any combination of: a diminished delivery of amino acids to peripheral tissues, impaired uptake of amino acids into muscle cells, or an inability of amino acids to elicit intracellular events pivotal for anabolism to occur. Despite the presence of anabolic resistance to dietary protein, present evidence suggests that protein supplementation may be able to overcome these issues, particularly when combined with resistance exercise programmes. As such, protein supplementation may prove to be an effective approach to delay the loss of muscle mass with age and has led to calls for the recommended daily intake of protein to be increased for the elderly population. PMID- 25826684 TI - Sentinel trees as a tool to forecast invasions of alien plant pathogens. AB - Recent disease outbreaks caused by alien invasive pathogens into European forests posed a serious threat to forest sustainability with relevant environmental and economic effects. Many of the alien tree pathogens recently introduced into Europe were not previously included on any quarantine lists, thus they were not subject to phytosanitary inspections. The identification and description of alien fungi potentially pathogenic to native European flora before their introduction in Europe, is a paramount need in order to limit the risk of invasion and the impact to forest ecosystems. To determine the potential invasive fungi, a sentinel trees plot was established in Fuyang, China, using healthy seedlings of European tree species including Quercus petreae, Q. suber, and Q. ilex. The fungal assemblage associated with symptomatic specimens was studied using the tag encoded 454 pyrosequencing of the nuclear ribosomal internal transcribed spacer-1 (ITS 1). Taxa with probable Asiatic origin were identified and included plant pathogenic genera. These results indicate that sentinel plants may be a strategic tool to improve the prevention of bioinvasions. PMID- 25826685 TI - Isomer-Specific Binding Affinity of Perfluorooctanesulfonate (PFOS) and Perfluorooctanoate (PFOA) to Serum Proteins. AB - Perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) are among the most prominent contaminants in human serum, and these were historically manufactured as technical mixtures of linear and branched isomers. The isomers display unique pharmacokinetics in humans and in animal models, but molecular mechanisms underlying isomer-specific PFOS and PFOA disposition have not previously been studied. Here, ultrafiltration devices were used to examine (i) the dissociation constants (Kd) of individual PFOS and PFOA isomers with human serum albumin (HSA) and (ii) relative binding affinity of isomers in technical mixtures spiked to whole calf serum and human serum. Measurement of HSA Kd's demonstrated that linear PFOS (Kd=8(+/-4)*10(-8) M) was much more tightly bound than branched PFOS isomers (Kd range from 8(+/-1)*10(-5) M to 4(+/-2)*10(-4) M). Similarly, linear PFOA (Kd=1(+/-0.9)*10(-4) M) was more strongly bound to HSA compared to branched PFOA isomers (Kd range from 4(+/-2)*10(-4) M to 3(+/-2)*10(-4) M). The higher binding affinities of linear PFOS and PFOA to total serum protein were confirmed when both calf serum and human serum were spiked with technical mixtures. Overall, these data provide a mechanistic explanation for the longer biological half-life of PFOS in humans, compared to PFOA, and for the higher transplacental transfer efficiencies and renal clearance of branched PFOS and PFOA isomers, compared to the respective linear isomer. PMID- 25826686 TI - Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703. AB - Single-stranded oligodeoxynucleotides (ODN), containing nonmethylated cytosine guanine motifs (CpG ODN), are recognized by the innate immune system as "danger signals." CpG ODN are efficacious immunomodulators but require phosphorothioate (PT) or other backbone modifications for metabolic stability, which cause toxicities in mice and primates. We therefore designed a covalently closed DNA molecule (dSLIM((r))) where two single-stranded loops containing CG motifs are connected through a double-stranded stem in the absence of any nonnatural DNA component. The most promising immunomodulator, MGN1703, comprises two loops of 30 nucleotides containing three CG motifs each, and a connecting stem stem of 28 base pairs. MGN1703 stimulates cytokine secretion [interferon (IFN)-alpha, IFN gamma, interleukin (IL)-12, IL-6, and IL-2] and activates immune cells by increased expression of CD80, CD40, human leukocyte antigen (HLA)-DR and ICAM-1. Efficacy of immunomodulation strictly depends on the descriptive dumbbell shape and size of the molecule. Variations in stem length and loop size lead to reduced potency of the respective members of the dSLIM((r)) class. In a representative mouse model, toxicities from injections of high amounts of a CpG ODN-PT and of MGN1703 were evaluated. The CpG ODN-PT group showed severe organ damage, whereas no such or other pathologies were found in the MGN1703 group. Oncological clinical trials of MGN1703 already confirmed our design. PMID- 25826687 TI - Omeprazole Inhibits Pancreatic Cancer Cell Invasion through a Nongenomic Aryl Hydrocarbon Receptor Pathway. AB - Omeprazole and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are aryl hydrocarbon receptor (AhR) agonists that inhibit the invasion of breast cancer cells through inhibition of CXCR4 transcription. Treatment of highly invasive Panc1 pancreatic cancer cells with TCDD, omeprazole, and seven other AhR-active pharmaceuticals showed that only omeprazole and tranilast, but not TCDD, inhibited invasion in a Boyden chamber assay. Similar results were observed in MiaPaCa2 cells, another quasimensenchymal pancreatic ductal adenocarcinoma (QM-PDA) pancreatic cancer cell line, whereas invasion was not observed with BxPC3 or L3.6pL cells, which are classified as classical (less invasive) pancreatic cancer cells. It was also observed in QM-PDA cells that TCDD, omeprazole, and tranilast did not induce CYP1A1 or CXCR4 and that treatment with these compounds did not result in nuclear uptake of AhR. In contrast, treatment of BxPC3 and L3.6pL cells with these AhR ligands resulted in induction of CYP1A1 (by TCDD) and nuclear uptake of AhR, which was similar to that observed for Ah-responsive MDA-MB-468 breast and HepG2 liver cancer cell lines. Results of AhR and AhR nuclear translocator (Arnt) knockdown experiments in Panc1 and MiaPaCa2 cells demonstrated that omeprazole- and tranilast-mediated inhibition of invasion was AhR-dependent but Arnt independent. These results demonstrate that in the most highly invasive subtype of pancreatic cancer cells (QM-PDA) the selective AhR modulators omeprazole and tranilast inhibit invasion through a nongenomic AhR pathway. PMID- 25826690 TI - Single-atom based coherent quantum interference device structure. AB - We describe the fabrication, operation principles, and simulation of a coherent single-atom quantum interference device (QID) structure on Si(100) controlled by the properties of single atoms. The energy and spatial distribution of the wave functions associated with the device are visualized by scanning tunneling spectroscopy and the amplitude and phase of the evanescent wave functions that couple into the quantum well states are directly measured, including the action of an electrostatic gate. Density functional theory simulations were employed to simulate the electronic structure of the device structure, which is in excellent agreement with the measurements. Simulations of device transmission demonstrate that our coherent single-atom QID can have ON-OFF ratios in excess of 10(3) with potentially minimal power dissipation. PMID- 25826688 TI - Facile supermolecular aptamer inhibitors of L-selectin. AB - Multivalent interactions occur frequently in nature, where they mediate high affinity interactions between cells, proteins, or molecules. Here, we report on a method to generate multivalent aptamers (Multi-Aptamers) that target L-selectin function using rolling circle amplification (RCA). We find that the L-selectin Multi-Aptamers have increased affinity compared to the monovalent aptamer, are specific to L-selectin, and are capable of inhibiting interactions with endogenous ligands. In addition, the Multi-Aptamers efficiently inhibit L selectin mediated dynamic adhesion in vitro and homing to secondary lymphoid tissues in vivo. Importantly, our method of generating multivalent materials using RCA avoids many of the challenges associated with current multivalent materials in that the Multi-Aptamers are high affinity, easily produced and modified, and biocompatible. We anticipate that the Multi-Aptamers can serve as a platform technology to modulate diverse cellular processes. PMID- 25826691 TI - Phenotypic and Genotypic Characterization of Salmonella enterica Serovar Enteritidis Isolates Associated with a Mousse Cake-Related Outbreak of Gastroenteritis in Ningbo, China. AB - Salmonella enterica subsp. enterica serovar Enteritidis (Salmonella Enteritidis) is a major pathogen responsible for causing the largest number of sporadic cases and outbreaks of human salmonellosis worldwide. In this study, an outbreak of Salmonella Enteritidis involving 112 cases in Ningbo, China was investigated with a combination of genotypic subtyping methods and phenotypic analysis. The pulsed field gel electrophoresis and multilocus variable-number tandem-repeat analysis profiles showed that most of the outbreak clinical isolates (22/23) were indistinguishable from each other and were identical to the isolates obtained from implicated mousse cakes, demonstrating that this outbreak of gastroenteritis was caused by Salmonella Enteritidis-contaminated mousse cakes. Moreover, all isolates, irrespective of source, had an identical antibiotic susceptibility pattern. Five virulence-associated genes in Salmonella pathogenicity islands and the plasmid-associated virulence genes spvB/C were present in both the food and clinical isolates. Importantly, all of these isolates can survive well under low temperature treatment, indicating that manufacturers of foodstuffs with raw ingredients (not subjected to thermal processing) should use an effective approach to prevent or eliminate the microbial hazards to public health. PMID- 25826692 TI - Computational models of consumer confidence from large-scale online attention data: crowd-sourcing econometrics. AB - Economies are instances of complex socio-technical systems that are shaped by the interactions of large numbers of individuals. The individual behavior and decision-making of consumer agents is determined by complex psychological dynamics that include their own assessment of present and future economic conditions as well as those of others, potentially leading to feedback loops that affect the macroscopic state of the economic system. We propose that the large scale interactions of a nation's citizens with its online resources can reveal the complex dynamics of their collective psychology, including their assessment of future system states. Here we introduce a behavioral index of Chinese Consumer Confidence (C3I) that computationally relates large-scale online search behavior recorded by Google Trends data to the macroscopic variable of consumer confidence. Our results indicate that such computational indices may reveal the components and complex dynamics of consumer psychology as a collective socio economic phenomenon, potentially leading to improved and more refined economic forecasting. PMID- 25826693 TI - Continuous expansion of the interplanar spacing of octacalcium phosphate by incorporation of dicarboxylate ions with a side chain. AB - Octacalcium phosphate (OCP) is composed of apatitic and hydrated layers, and can incorporate dicarboxylate ions in its hydrated layers by substitution of HPO4(2 ). The (100) interplanar spacing of OCP is increased by incorporation of dicarboxylate ions. Herein, we report continuous expansion of the interplanar spacing of OCP by incorporation of dicarboxylate ions with a side chain. We synthesized OCP with incorporated succinic acid (Suc) and mercaptosuccinic acid (Msuc) by a wet chemical process. The (100) interplanar spacing of OCP synthesized with Suc increased non-continuously as the amount of Suc used in the synthesis increased. In contrast, the (100) interplanar spacing of OCP synthesized with Msuc increased continuously with the amount of Msuc used during synthesis, and thus in the OCP. The values of the (100) interplanar spacing of OCP synthesized with Msuc first increased and then became constant as the amount of Msuc increased. OCP with incorporated Msuc formed a continuous solid solution. The expansion of the (100) interplanar spacing of OCP with incorporated Suc and Msuc depended on the chemical structure of the incorporated dicarboxylate ions. The only structural difference between Suc and Msuc is a mercapto (R-SH) side chain. Therefore, continuous solid solution formation was most likely induced by the R-SH side chain of Msuc. These results suggest that incorporation of dicarboxylic acids with a side chain is one approach to obtain OCP with arbitrary interlayer distance. PMID- 25826694 TI - RV mass measurement at end-systole: Improved accuracy, Reproducibility, and reduced segmentation time. AB - PURPOSE: To evaluate the accuracy, reproducibility, and contouring time of RV mass in end-systole (ES) and end-diastole (ED). Magnetic resonance imaging (MRI) has been shown to be accurate and reproducible for the evaluation of right ventricular (RV) volume and function. RV mass, assessed in end-diastolic (ED) phase, is one of the least reproducible variables. The choice of end-systolic (ES) phase could offer an alternative to improve reproducibility, since the selection of the basal slice and the visualization of the usually thin RV wall are easier in this phase. MATERIALS AND METHODS: To evaluate accuracy, 11 sheep were imaged in vivo and their RV free walls were weighed after removing epicardial fat. To evaluate reproducibility, 30 normal subjects and 30 subjects with pulmonary arterial hypertension (PAH) were imaged and interobserver and intraobserver variabilities were assessed in the ES and the ED. Segmentation time was recorded after visual selection of ES and ED phases. RESULTS: ES RV mass measurement has less absolute variability (5.2% +/- 3.2) compared to ED (10.6% +/ 6.3) using weighed RV mass in sheep as the gold standard (P < 0.001). ES segmentation yielded higher intraobserver (intraclass correlation coefficients [ICC] = 0.94-0.99; coefficient of variability [CoV] = 6-7.3%) and interobserver (ICC = 0.85-0.98; CoV = 10.9-11.7%) reproducibility than ED segmentation. Segmentation time in humans was 25-28% faster in ES (P < 0.001). CONCLUSION: The MRI assessment of RV mass is more accurate, reproducible, and faster in the ES phase. PMID- 25826695 TI - Update on emerging treatments for chronic myeloid leukemia. AB - INTRODUCTION: As survival of patients with chronic myeloid leukemia (CML) is dramatically improved over time, the prevalence of the disease is steadily increasing. At this moment, five different tyrosine kinase inhibitors (TKIs) (imatinib, nilotinib, dasatinib, bosutinib and ponatinib) are approved for the treatment of CML. Medical and patients needs nowadays are attention to quality of life (QoL) and drug side effects; overcoming suboptimal responses; preventing progression and possibly discontinuing the drugs. Monitoring is essential to improve on treatment and on the possibility of cure, because it allows patient adapted therapies, according to patients morbidities and early responses. AREAS COVERED: This review focuses on clinical results of imatinib and second- and third-generation TKIs that have been tested in the setting of second-line and front-line treatments. The most promising new drugs in course of clinical investigations are also reported. EXPERT OPINION: The scientific community is focusing on the optimization of the use of the drugs already available, to be also used in association with other experimental drugs directed to several signaling transduction pathways of BCR-ABL, in order to improve the efficacy on resistant cases, and on leukemic stem cells, keeping in mind the issues of long term safety, QoL and the need for treatment - free remission. PMID- 25826697 TI - Discovery of a new caerulescent Psilocybe mushroom in Germany: Psilocybe germanica sp.nov. PMID- 25826698 TI - Novel reactivity of Fhit proteins: catalysts for fluorolysis of nucleoside 5' phosphoramidates and nucleoside 5'-phosphosulfates to generate nucleoside 5' phosphorofluoridates. AB - Fragile histidine triad (HIT) proteins (Fhits) occur in all eukaryotes but their function is largely unknown. Human Fhit is presumed to function as a tumour suppressor. Previously, we demonstrated that Fhits catalyse hydrolysis of not only dinucleoside triphosphates but also natural adenosine 5'-phosphoramidate (NH2-pA) and adenosine 5'-phosphosulfate (SO4-pA) as well as synthetic adenosine 5'-phosphorofluoridate (F-pA). In the present study, we describe an Fhit catalysed displacement of the amino group of nucleoside 5'-phosphoramidates (NH2 pNs) or the sulfate moiety of nucleoside 5'-phosphosulfates (SO4-pNs) by fluoride anion. This results in transient accumulation of the corresponding nucleoside 5' phosphorofluoridates (F-pNs). Substrate specificity and kinetic characterization of the fluorolytic reactions catalysed by the human Fhit and other examples of involvement of fluoride in the biochemistry of nucleotides are described. Among other HIT proteins, human histidine triad nucleotide-binding protein (Hint1) catalysed fluorolysis of NH2-pA 20 times and human Hint2 40 times more slowly than human Fhit. PMID- 25826696 TI - Improved estimation and interpretation of correlations in neural circuits. AB - Ambitious projects aim to record the activity of ever larger and denser neuronal populations in vivo. Correlations in neural activity measured in such recordings can reveal important aspects of neural circuit organization. However, estimating and interpreting large correlation matrices is statistically challenging. Estimation can be improved by regularization, i.e. by imposing a structure on the estimate. The amount of improvement depends on how closely the assumed structure represents dependencies in the data. Therefore, the selection of the most efficient correlation matrix estimator for a given neural circuit must be determined empirically. Importantly, the identity and structure of the most efficient estimator informs about the types of dominant dependencies governing the system. We sought statistically efficient estimators of neural correlation matrices in recordings from large, dense groups of cortical neurons. Using fast 3D random-access laser scanning microscopy of calcium signals, we recorded the activity of nearly every neuron in volumes 200 MUm wide and 100 MUm deep (150-350 cells) in mouse visual cortex. We hypothesized that in these densely sampled recordings, the correlation matrix should be best modeled as the combination of a sparse graph of pairwise partial correlations representing local interactions and a low-rank component representing common fluctuations and external inputs. Indeed, in cross-validation tests, the covariance matrix estimator with this structure consistently outperformed other regularized estimators. The sparse component of the estimate defined a graph of interactions. These interactions reflected the physical distances and orientation tuning properties of cells: The density of positive 'excitatory' interactions decreased rapidly with geometric distances and with differences in orientation preference whereas negative 'inhibitory' interactions were less selective. Because of its superior performance, this 'sparse+latent' estimator likely provides a more physiologically relevant representation of the functional connectivity in densely sampled recordings than the sample correlation matrix. PMID- 25826699 TI - Public Daycare Noncompliance with Prescribed Lunch Menus and Dietary Guidelines. AB - OBJECTIVE: In Brazil, menus for public child daycare centers (PDC) must be planned by a nutritionist in order to meet the infants' nutritional needs and to conform to dietary recommendations. Failure to follow them may jeopardize the infants' health and growth. Therefore, the objectives of this study were to investigate the compliance of actually served lunch menus with the prescribed menus, according to age (7- to 12-month-olds and 13- to 24-month-olds) and whether prescribed and served menus followed the recommended dietary guidelines. METHODS: Five PDCs were randomly selected for observation, out of 14 existing in the city of Concordia, Brazil. Data collection was carried out during 6 consecutive weeks in September (fall/winter menus) and October (spring/summer menus) in order to cover the menus representative of the entire year. RESULTS: Of 60 lunches recorded, only 20% of them matched the prescribed ones entirely; none of the lunches served to infants aged 7-12 months did so. Fourteen food items were prescribed 157 times throughout the year. Omission (number of times on menu but not served) was the most frequent form of noncompliance in the younger group: 62.4% (98/157). Foods more frequently omitted by the cooks were beef, pork, chicken, and lentils. Compliance with dietary guidelines was higher in the prescribed menus and in those actually served to the 13- to 24-month-old age group. CONCLUSIONS: Infants in the 7- to 12-month-old group may be more vulnerable to nutritional inadequacies because menus served to them were less compliant with the prescribed menus. Dietetics professionals should improve the variety of foods on the menus as well as supervise their execution. PMID- 25826700 TI - Correction: Scaling properties of information-theoretic quantities in density functional reactivity theory. PMID- 25826701 TI - Age-dependent sex difference of the incidence and mortality of status epilepticus: a twelve year nationwide population-based cohort study in Taiwan. AB - Status epilepticus (SE) is a serious neurologic emergency associated with a significant mortality. The objective of this study is to investigate its epidemiology in terms of age- and sex-specific incidences and mortality. By using the Taiwan National Health Insurance Research Database during 2000 to 2011, we identified hospitalized patients with a discharged diagnosis of SE and calculated the incidence and in-hospital mortality of SE with respect to age and sex. The overall incidence of SE was 4.61 per 100,000 person-years, which displayed a "J shaped" distribution by age with a little higher under the age of 5 and highest over 60 years. The male-to-female rate ratio was 1.57 and it demonstrated a "mountain-shape" across ages with the peak at 45 to 49 years old. The in-hospital mortality was significantly lower in males (7.38%) than in females (11.12%) with an odds ratio of 0.64 (95% CI 0.56-0.72). Notably, the in-hospital mortality for females increased rapidly after the age of 40 to 45 years. The multivariate analysis found males had a significantly lower risk of mortality than females after, but not before, 45 years of age with an odds ratio of 0.56 (95% CI 0.49 0.65). Sex and age are crucial factors associated with the incidence and in hospital mortality of SE. The females over 45 years of age have a higher risk of occurrence and mortality from SE. The underlying mechanism deserves further study. PMID- 25826702 TI - Tropical forest fragmentation affects floral visitors but not the structure of individual-based palm-pollinator networks. AB - Despite increasing knowledge about the effects of habitat loss on pollinators in natural landscapes, information is very limited regarding the underlying mechanisms of forest fragmentation affecting plant-pollinator interactions in such landscapes. Here, we used a network approach to describe the effects of forest fragmentation on the patterns of interactions involving the understory dominant palm Astrocaryum mexicanum (Arecaceae) and its floral visitors (including both effective and non-effective pollinators) at the individual level in a Mexican tropical rainforest landscape. Specifically, we asked: (i) Does fragment size affect the structure of individual-based plant-pollinator networks? (ii) Does the core of highly interacting visitor species change along the fragmentation size gradient? (iii) Does forest fragment size influence the abundance of effective pollinators of A. mexicanum? We found that fragment size did not affect the topological structure of the individual-based palm-pollinator network. Furthermore, while the composition of peripheral non-effective pollinators changed depending on fragment size, effective core generalist species of pollinators remained stable. We also observed that both abundance and variance of effective pollinators of male and female flowers of A. mexicanum increased with forest fragment size. These findings indicate that the presence of effective pollinators in the core of all forest fragments could keep the network structure stable along the gradient of forest fragmentation. In addition, pollination of A. mexicanum could be more effective in larger fragments, since the greater abundance of pollinators in these fragments may increase the amount of pollen and diversity of pollen donors between flowers of individual plants. Given the prevalence of fragmentation in tropical ecosystems, our results indicate that the current patterns of land use will have consequences on the underlying mechanisms of pollination in remnant forests. PMID- 25826703 TI - Dynamic mechanical properties of a polyelectrolyte adsorbed insoluble lipid monolayer at the air-water interface. AB - Polymers have been used to stabilize interfaces or to tune the mechanical properties of interfaces in various contexts, such as in oil emulsions or biological membranes. Although the structural properties of these systems are relatively well-studied, instrumental limitations continue to make it difficult to understand how the addition of polymer affects the dynamic mechanical properties of thin and soft films. We have solved this challenge by developing a new instrument, an optical-tweezer-based interface shear microrheometer (ISMR). With this technique, we observed that the interface shear modulus, G*, of a dioctadecyldimethylammonium chloride (DODAC) monolayer at the air-water interface significantly increased with adsorption of polystyrenesulfonate (PSS). In addition, the viscous film (DODAC monolayer) became a viscoelastic film with PSS adsorption. At a low salt concentration, 10 mM of NaCl in the subphase, the viscoelasticity of the DODAC/PSS composite was predominantly determined by a particular property of PSS, that is, it behaves as a Gaussian chain in a theta solvent. At a high salt concentration, 316 mM of NaCl, the thin film behaved as a polymer melt excluding water molecules. PMID- 25826704 TI - Evaluation of the UP4FUN intervention: a cluster randomized trial to reduce and break up sitting time in European 10-12-year-old children. AB - BACKGROUND: The UP4FUN intervention is a family-involved school-based intervention aiming at reducing and breaking up sitting time at home (with special emphasis on screen time), and breaking up sitting time in school among 10 12 year olds in Europe. The purpose of the present paper was to evaluate its short term effects. METHODOLOGY/PRINCIPAL FINDINGS: A total of 3147 pupils from Belgium, Germany, Greece, Hungary and Norway participated in a school-randomized controlled trial. The intervention included 1-2 school lessons per week for a period of six weeks, along with assignments for the children and their parents. Screen time and breaking up sitting time were registered by self-report and total sedentary time and breaking up sitting time by accelerometry. The effect of the intervention on these behaviors was evaluated by multilevel regression analyses. All analyses were adjusted for baseline values and gender. Significance level was p<=0.01. No significant intervention effects were observed, neither for self reported TV/DVD or computer/game console time, nor for accelerometer-assessed total sedentary time and number of breaks in sitting time. The intervention group, however, reported more positive attitudes towards (beta = 0.25 (95% CI 0.11, 0.38)) and preferences/liking for (beta = 0.20 (95% CI 0.08, 0.32)) breaking up sitting time than the control group. CONCLUSIONS/SIGNIFICANCE: No significant intervention effect on self-reported screen time or accelerometer assessed sedentary time or breaks in sitting time was observed, but positive effects on beliefs regarding breaking up sitting time were found in favor of the intervention group. Overall, these results do not warrant wider dissemination of the present UP4FUN intervention. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Registry ISRCTN34562078. PMID- 25826705 TI - Metabolites of antibody-maytansinoid conjugates: characteristics and in vitro potencies. AB - Several antibody-maytansinoid conjugates (AMCs) are in clinical trials for the treatment of various cancers. Each of these conjugates can be metabolized by tumor cells to give cytotoxic maytansinoid metabolites that can kill targeted cells. In preclinical studies in mice, the cytotoxic metabolites initially formed in vivo are further processed in the mouse liver to give several oxidized metabolic species. In this work, the primary AMC metabolites were synthesized and incubated with human liver microsomes (HLMs) to determine if human liver would likely give the same metabolites as those formed in mouse liver. The results of these HLM metabolism studies as well as the subsequent syntheses of the resulting HLM oxidation products are presented. Syntheses of the minor impurities formed during the conjugation of AMCs were also conducted to determine their cytotoxicities and to establish how these impurities would be metabolized by HLM. PMID- 25826706 TI - Technology Use for Diabetes Problem Solving in Adolescents with Type 1 Diabetes: Relationship to Glycemic Control. AB - BACKGROUND: This study examines technology use for problem solving in diabetes and its relationship to hemoglobin A1C (A1C). SUBJECTS AND METHODS: A sample of 112 adolescents with type 1 diabetes completed measures assessing use of technologies for diabetes problem solving, including mobile applications, social technologies, and glucose software. Hierarchical regression was performed to identify the contribution of a new nine-item Technology Use for Problem Solving in Type 1 Diabetes (TUPS) scale to A1C, considering known clinical contributors to A1C. RESULTS: Mean age for the sample was 14.5 (SD 1.7) years, mean A1C was 8.9% (SD 1.8%), 50% were female, and diabetes duration was 5.5 (SD 3.5) years. Cronbach's alpha reliability for TUPS was 0.78. In regression analyses, variables significantly associated with A1C were the socioeconomic status (beta = -0.26, P < 0.01), Diabetes Adolescent Problem Solving Questionnaire (beta = -0.26, P = 0.01), and TUPS (beta = 0.26, P = 0.01). Aside from the Diabetes Self-Care Inventory--Revised, each block added significantly to the model R(2). The final model R(2) was 0.22 for modeling A1C (P < 0.001). CONCLUSIONS: Results indicate a counterintuitive relationship between higher use of technologies for problem solving and higher A1C. Adolescents with poorer glycemic control may use technology in a reactive, as opposed to preventive, manner. Better understanding of the nature of technology use for self-management over time is needed to guide the development of technology-mediated problem solving tools for youth with type 1 diabetes. PMID- 25826707 TI - Mg(OH)2 Supported Nanoscale Zero Valent Iron Enhancing the Removal of Pb(II) from Aqueous Solution. AB - In this article, a novel composite (Mg(OH)2 supported nanoscale zerovalent iron (denoted as nZVI@Mg(OH)2) was prepared and characterized by X-ray diffraction, scanning electron microscopy, and transmission electron microscopy method. The morphology analysis revealed that Mg(OH)2 appeared as self-supported flower-like spheres, and nano Fe0 particles were uniformly immobilized on the surface of their "flower petals", thus aggregation of Fe0 particles was minimized. Then the Pb(II) removal performance was tested by batch experiments. The composite presented exceptional removal capacity (1986.6 mg/g) compared with Mg(OH)2 and nanoscale zerovalent iron due to the synergistic effect. Mechanisms were also explored by a comparative study of the phase, morphology, and surface valence state of composite before and after reaction, indicating that at least three paths are involved in the synergistic removal process: (1) Pb(II) adsorption by Mg(OH)2 (companied with ion exchange reaction); (2) Pb(II) reduction to Pb0 by nanoscale zerovalent iron; and (3) Pb(II) precipitation as Pb(OH)2. The hydroxies provided by Mg(OH)2 can dramatically promote the role of nanoscale zerovalent iron as reducer, thus greatly enhancing the whole Pb(II) sequestration process. The excellent performance shown in our research potentially provides an alternative technique for Pb(II) pollution treatment. PMID- 25826709 TI - Convenient access to polyfunctional pyrazoles via a highly efficient and regioselective multicomponent reaction. AB - A multicomponent reaction has been developed for the synthesis of polyfunctional pyrazole derivatives from readily available arylglyoxal monohydrates, tosylhydrazine, and aldehydes or ketones. This synthetic method has significant advantages in broad substrate scope, excellent regioselectivity, and simple operation. PMID- 25826708 TI - The rotary zone thermal cycler: a low-power system enabling automated rapid PCR. AB - Advances in molecular biology, microfluidics, and laboratory automation continue to expand the accessibility and applicability of these methods beyond the confines of conventional, centralized laboratory facilities and into point of use roles in clinical, military, forensic, and field-deployed applications. As a result, there is a growing need to adapt the unit operations of molecular biology (e.g., aliquoting, centrifuging, mixing, and thermal cycling) to compact, portable, low-power, and automation-ready formats. Here we present one such adaptation, the rotary zone thermal cycler (RZTC), a novel wheel-based device capable of cycling up to four different fixed-temperature blocks into contact with a stationary 4-microliter capillary-bound sample to realize 1-3 second transitions with steady state heater power of less than 10 W. We demonstrate the utility of the RZTC for DNA amplification as part of a highly integrated rotary zone PCR (rzPCR) system that uses low-volume valves and syringe-based fluid handling to automate sample loading and unloading, thermal cycling, and between run cleaning functionalities in a compact, modular form factor. In addition to characterizing the performance of the RZTC and the efficacy of different online cleaning protocols, we present preliminary results for rapid single-plex PCR, multiplex short tandem repeat (STR) amplification, and second strand cDNA synthesis. PMID- 25826712 TI - Family involvement in behaviour management following acquired brain injury (ABI) in community settings: A systematic review. AB - OBJECTIVES: To examine family involvement in the management of behavioural problems following ABI in the community. RESEARCH DESIGN: Systematic literature review. METHODS: Six electronic databases relevant to the field of brain injury were searched between 1980-2013. Citation indexes were used and references from articles hand searched for further literature. Studies that met the broad inclusion criteria were screened for relevance and articles selected for full text review independently considered by two reviewers. Those found to be relevant were analysed using PEDro and McMasters critical appraisal tools. RESULTS: Three hundred and three studies were identified after duplicates were removed and 56 were assessed for relevance, yielding 10 studies for review. Although the majority of studies were weak in design, five revealed significant findings supportive of family involvement in the management of behavioural problems following ABI, especially where interventions consisted of both educational components and individualized behavioural plans. Findings revealed no significant changes in family burden following behavioural interventions. CONCLUSIONS: There is limited research and lack of high evidence studies evaluating family involvement in behaviour management following ABI; therefore, no conclusions can be drawn regarding its efficacy. More research is needed, with larger sample sizes and more rigorous design, including proper comparison groups. PMID- 25826713 TI - Isotropic-nematic phase transition in hard platelets as described by a third virial theory. AB - This work discusses a few second- and third-virial (density functional) theory approaches aimed at describing the isotropic-nematic phase transition in three dimensional freely rotating infinitesimally thin hard discs, the basic model for (colloidal) discotic liquid crystals. Both plain and resummed versions are considered, those resummed being based on a simple yet rather accurate analytic equation of state for the isotropic phase. Extensive Monte Carlo simulations, carried out to locate accurately the phase transition, are used to test the performance of these approaches and guide toward an improved ansatz. PMID- 25826711 TI - Meta-Analysis of Long-Chain Omega-3 Polyunsaturated Fatty Acids (LComega-3PUFA) and Prostate Cancer. AB - We conducted a systematic review and meta-analysis to estimate the potential association between LComega-3PUFAs and prostate cancer (PC). A comprehensive literature search was performed through 2013 to identify prospective studies that examined dietary intakes of long-chain omega-3 polyunsaturated fatty acids (LComega-3PUFA) or blood biomarkers of LComega-3PUFA status and risk of PC. Random-effects meta-analyses were conducted to generate summary relative risk estimates (SRREs) for LComega-3PUFAs and total PC, and by stage and grade. Subgroup analyses were also conducted for specific fatty acids and other study characteristics. Twelve self-reported dietary intake and 9 biomarker studies from independent study populations were included in the analysis, with 446,243 and 14,897 total participants, respectively. No association between LComega-3PUFAs and total PC was observed (SRRE = 1.00, 95% CI: 0.93-1.09) for the dietary intake studies (high vs. low LComega-3PUFAs category comparison) or for the biomarker studies (SRRE of 1.07, 95% CI: 0.94-1.20). In general, most summary associations for the dietary intake studies were in the inverse direction, whereas the majority of summary associations for the biomarker studies were in the positive direction, but all were weak in magnitude. The results from this meta-analysis do not support an association between LComega-3PUFAs and PC. PMID- 25826710 TI - Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis. AB - The dopamine D3 receptor (D3R) is a target for developing medications to treat substance use disorders. D3R-selective compounds with high affinity and varying efficacies have been discovered, providing critical research tools for cell-based studies that have been translated to in vivo models of drug abuse. D3R antagonists and partial agonists have shown especially promising results in rodent models of relapse-like behavior, including stress-, drug-, and cue-induced reinstatement of drug seeking. However, to date, translation to human studies has been limited. Herein, we present an overview and illustrate some of the pitfalls and challenges of developing novel D3R-selective compounds toward clinical utility, especially for treatment of cocaine abuse. Future research and development of D3R-selective antagonists and partial agonists for substance abuse remains critically important but will also require further evaluation and development of translational animal models to determine the best time in the addiction cycle to target D3Rs for optimal therapeutic efficacy. PMID- 25826714 TI - An S(N)Ar approach to sterically hindered ortho-alkoxybenzaldehydes for the synthesis of olefin metathesis catalysts. AB - A three-step procedure has been developed for preparing ortho-alkoxybenzaldehydes from ortho-fluorobenzaldehydes that tolerates the use of sterically hindered sodium alkoxide nucleophiles. The protocol is modular and operationally convenient. The ortho-alkoxybenzaldehyde products can be converted in one additional step to ortho-alkoxystyrenes by a Wittig reaction. These styrenes are precursors to the chelating benzylidene moiety in a proposed series of novel ruthenium complexes for use in olefin metathesis. Chelation with three representative styrenes has been demonstrated. PMID- 25826715 TI - The patient safety screener: validation of a brief suicide risk screener for emergency department settings. AB - This study evaluated the concurrent validity of a brief suicide risk screener for adults in the emergency department (ED). Two versions of the verbally administered Patient Safety Screener (2-item, 3-item) were compared to a reference standard, the Beck Scale for Suicide Ideation (BSSI). Analyses included measures of agreement (Kappa). Agreement between the Patient Safety Screener-2 and -3 and the BSSI (n = 951) was almost perfect for overall positive screening (K = 0.94-0.95) and past suicide attempts (K = 0.97-0.98). Agreement on ideation ranged from fair (K = 0.34) for the 2-item version to good (K = 0.61) for the 3 item version. The Patient Safety Screener's concurrent validity with the BSSI ranged from fair to almost perfect and warrants additional study. PMID- 25826716 TI - Highly ordered mesoporous few-layer graphene frameworks enabled by fe3 o4 nanocrystal superlattices. AB - While great progress has been achieved in the synthesis of ordered mesoporous carbons in the past decade, it still remains a challenge to prepare highly graphitic frameworks with ordered mesoporosity and high surface area. Reported herein is a simple synthetic methodology, based on the conversion of self assembled superlattices of Fe3 O4 nanocrystals, to fabricate highly ordered mesoporous graphene frameworks (MGFs) with ultrathin pore walls consisting of three to six stacking graphene layers. The MGFs possess face-centered-cubic symmetry with interconnected mesoporosity, tunable pore width, and high surface area. Because of their unique architectures and superior structural durability, the MGFs exhibit excellent cycling stability and rate performance when used as anode materials for lithium-ion batteries, thus retaining a specific capacity of 520 mAh g(-1) at a current density of 300 mA g(-1) after 400 cycles. PMID- 25826717 TI - The efficacy of deep repetitive transcranial magnetic stimulation over the medial prefrontal cortex in obsessive compulsive disorder: results from an open-label study. AB - BACKGROUND: Significant numbers of patients with obsessive compulsive disorder (OCD) respond minimally to currently available treatments. Furthermore, the application of both high- and low-frequency repetitive transcranial magnetic stimulation (rTMS) to dorsolateral prefrontal cortex has shown to be ineffective in the reduction of OCD symptoms. In this study, we instead targeted the medial prefrontal cortex (mPFC) and applied low-frequency rTMS to patients with OCD and assessed their clinical response. METHODS: In an open-label design, 10 OCD patients with no other current axis I psychiatric disorders were recruited. Twelve hundred pulses of 1-Hz frequency were applied over the mPFC (Brodmann areas 24 and 32) using a double-cone coil for 10 days. Regions of interest were located on participants' MRIs using neuronavigation software. Patients' symptoms were rated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). RESULTS: All patients demonstrated improvement in their OCD symptoms after 10 sessions of rTMS as shown by a mean improvement in Y-BOCS score of 39% (SD = 15%; P < .001, F = 62.95). This improvement persisted 1 month following the last session of rTMS. CONCLUSIONS: Our results suggest the use of low frequency deep rTMS as a promising and robust intervention in OCD symptom reduction. However, this study is limited by its open-label nature and its lack of a control group, so further randomized clinical trials are needed to confirm these results. PMID- 25826718 TI - Influence of molecular weight and degree of deacetylation of low molecular weight chitosan on the bioactivity of oral insulin preparations. AB - The objective of the present study was to prepare and characterize low molecular weight chitosan (LMWC) with different molecular weight and degrees of deacetylation (DDA) and to optimize their use in oral insulin nano delivery systems. Water in oil nanosized systems containing LMWC-insulin polyelectrolyte complexes were constructed and their ability to reduce blood glucose was assessed in vivo on diabetic rats. Upon acid depolymerization and testing by viscosity method, three molecular weights of LMWC namely, 1.3, 13 and 18 kDa were obtained. As for the DDA, three LMWCs of 55%, 80% and 100% DDA were prepared and characterized by spectroscopic methods for each molecular weight. The obtained LMWCs showed different morphological and in silico patterns. Following complexation of LMWCs with insulin, different aggregation sizes were obtained. Moreover, the in vivo tested formulations showed different activities of blood glucose reduction. The highest glucose reduction was achieved with 1.3 kDa LMWC of 55% DDA. The current study emphasizes the importance of optimizing the molecular weight along with the DDA of the incorporated LMWC in oral insulin delivery preparations in order to ensure the highest performance of such delivery systems. PMID- 25826719 TI - Technology-aided leisure and communication: Opportunities for persons with advanced Parkinson's disease. AB - OBJECTIVE: This study investigated whether simple technology-aided programs could be used to promote leisure and communication engagement in three persons with advanced Parkinson's disease. METHOD: The programs included music and video options, which were combined with (a) text messaging and telephone calls for the first participant, (b) verbal statements/requests, text messaging, and reading for the second participant, and (c) verbal statements/requests and prayers for the third participant. The participants could activate those options via hand movement or vocal emission and specific microswitches. RESULTS: All three participants were successful in activating the options available. The mean cumulative frequencies of option activations were about five per 15-min session for the first two participants and about four per 10-min session for the third participant. CONCLUSION: The results were considered encouraging and relevant given the limited amount of evidence available on helping persons with advanced Parkinson's disease with leisure and communication. PMID- 25826720 TI - Marine sequestration of carbon in bacterial metabolites. AB - Linking microbial metabolomics and carbon sequestration in the ocean via refractory organic molecules has been hampered by the chemical complexity of dissolved organic matter (DOM). Here, using bioassay experiments and ultra-high resolution metabolic profiling, we demonstrate that marine bacteria rapidly utilize simple organic molecules and produce exometabolites of remarkable molecular and structural diversity. Bacterial DOM is similar in chemical composition and structural complexity to naturally occurring DOM in sea water. An appreciable fraction of bacterial DOM has molecular and structural properties that are consistent with those of refractory molecules in the ocean, indicating a dominant role for bacteria in shaping the refractory nature of marine DOM. The rapid production of chemically complex and persistent molecules from simple biochemicals demonstrates a positive feedback between primary production and refractory DOM formation. It appears that carbon sequestration in diverse and structurally complex dissolved molecules that persist in the environment is largely driven by bacteria. PMID- 25826721 TI - Downregulation of DNA methyltransferase 1 in zona-free cloned buffalo (Bubalus bubalis) embryos by small interefering RNA improves in vitro development but does not alter DNA methylation level. AB - Aberrant epigenetic reprogramming, especially genomic hypermethylation, is implicated as the primary reason behind the failure of the cloning process during somatic cell nuclear transfer (SCNT). We transfected one-cell-stage zona-free buffalo embryos produced by handmade cloning with 50 nM DNMT1 small interfering RNA (siRNA), using lipofectamine, to knockdown the DNA methyltransferase 1 (DNMT1) gene. siRNA treatment decreased (p<0.001) the expression level of DNMT1 mRNA and DNMT1 protein in the one-cell-stage embryos and increased (p<0.05) the blastocyst rate (52.3 +/- 1.3% vs. 45.3 +/- 2.5%) compared to that in the controls, but did not reduce the DNA methylation level similar to the in vitro fertilized (IVF) embryos. It also increased (p<0.05) the relative mRNA abundance of P53 and CASPASE 3, but not that of HDAC1, DNMT1, and DNMT3a, in the blastocysts of the siRNA group compared to the controls. The global level of H3K18ac was higher (p<0.05) in the blastocysts of the siRNA group than in the controls, whereas that of H3K9ac and H3K27me3 was not significantly different between the two groups. In conclusion, lipofection can be successfully used for transfection of DNMT1 siRNA into one-cell-stage zona-free cloned buffalo embryos. It results in a concomitant decrease in the DNMT1 mRNA and protein levels in the one-cell-stage embryos. siRNA-mediated knockdown increases the blastocyst rate but does not alter the DNA methylation level. PMID- 25826723 TI - Early development of cloned bovine embryos produced from oocytes enucleated by fluorescence metaphase II imaging using a conventional halogen-lamp microscope. AB - Enucleation of a recipient oocyte is one of the key processes in the procedure of somatic cell nuclear transfer (SCNT). However, especially in bovine species, lipid droplets spreading in the ooplasm hamper identification and enucleation of metaphase II (MII) chromosomes, and thereby the success rate of the cloning remains low. In this study we used a new experimental system that enables fluorescent observation of chromosomes in living oocytes without any damage. We succeeded in visualizing and removing the MII chromosome in matured bovine oocytes. This experimental system consists of injecting fluorescence-labeled antibody conjugates that bind to chromosomes and fluorescent observation using a conventional halogen-lamp microscope. The cleavage rates and blastocyst rates of bovine embryos following in vitro fertilization (IVF) decreased as the concentration of the antibody increased (p<0.05). The enucleation rate of the conventional method (blind enucleation) was 86%, whereas all oocytes injected with the antibody conjugates were enucleated successfully. Fusion rates and developmental rates of SCNT embryos produced with the enucleated oocytes were the same as those of the blind enucleation group (p>0.05). For the production of SCNT embryos, the new system can be used as a reliable predictor of the location of metaphase plates in opaque oocytes, such as those in ruminant animals. PMID- 25826722 TI - Prolonged proteasome inhibition cyclically upregulates Oct3/4 and Nanog gene expression, but reduces induced pluripotent stem cell colony formation. AB - There is ample evidence that the ubiquitin-proteasome system is an important regulator of transcription and its activity is necessary for maintaining pluripotency and promoting cellular reprogramming. Moreover, proteasome activity contributes to maintaining the open chromatin structure found in pluripotent stem cells, acting as a transcriptional inhibitor at specific gene loci generally associated with differentiation. The current study was designed to understand further the role of proteasome inhibition in reprogramming and its ability to modulate endogenous expression of pluripotency-related genes and induced pluripotent stem cells (iPSCs) colony formation. Herein, we demonstrate that acute combinatorial treatment with the proteasome inhibitors MG101 or MG132 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) increases gene expression of the pluripotency marker Oct3/4, and that MG101 alone is as effective as VPA in the induction of Oct3/4 mRNA expression in fibroblasts. Prolonged proteasome inhibition cyclically upregulates gene expression of Oct3/4 and Nanog, but reduces colony formation in the presence of the iPSC induction cocktail. In conclusion, our results demonstrate that the 26S proteasome is an essential modulator in the reprogramming process. Its inhibition enhances expression of pluripotency-related genes; however, efficient colony formation requires proteasome activity. Therefore, discovery of small molecules that increase proteasome activity might lead to more efficient cell reprogramming and generation of pluripotent cells. PMID- 25826725 TI - Timing factors affecting blastocyst development in equine somatic cell nuclear transfer. AB - In nuclear transfer (NT), exposure of donor cell chromatin to the ooplast cytoplasm may aid reprogramming; however, the length of exposure feasible is limited by the developmental life span of the oocyte. We examined the effect of duration of nucleus-cytoplasmic exposure before activation and of in vitro maturation (IVM) in equine NT. In experiment 1, 24 h IVM and a delay of 2, 5, or 8 h between reconstruction and activation yielded 4%, 15%, and 11% blastocysts, respectively. In experiment 2, a 5-h activation delay yielded 17% and 22% blastocysts with two donor cell lines. In experiment 3, using a 5-h activation delay, the blastocyst rate was significantly higher using oocytes after 20 h IVM than after 24 h IVM; however, only 28% of oocytes were in metaphase II (MII) at 20 h. In experiment 4, oocytes were denuded of cumulus at 20 h, and those in metaphase I (MI) were returned to culture for 3 h (20+3H treatment); blastocyst rates were 30% and 27%, respectively (8-h and 5-h delay to activation, respectively). Four live foals resulted from the transfer of 17 blastocysts (24%) produced using MII oocytes and a 5- or 8-h activation delay. Use of equine oocytes immediately after reaching MII, combined with a longer delay from reconstruction to activation, increased developmental competence after equine NT. PMID- 25826724 TI - Deficiency of genomic reprogramming in trophoblast stem cells following nuclear transfer. AB - To examine the genomic reprogrammability of trophoblast stem (TS) cells using a nuclear transfer technique, we produced TS cloned embryos using five TS cell lines from three strains of mice (ICR, B6D2F1, and B6CBF1) as donors and observed developmental ability during preimplantation development. The developmental rates of the TS cloned embryos that developed to the two-cell, four- to eight-cell, morula, and blastocyst stages were 58-83%, 0-38.6%, 0-21.3%, and 0-15.9%, respectively, indicating that more than 50% of TS cloned embryos arrested at the two-cell stage. These TS cloned two-cell embryos were expressed low level of Dappa3 (also known as PGC7/Stella), indicating that zygotic gene activation (ZGA) was disrupted in these embryos. However, a small portion of the TS cloned embryos (0-15.9%) reached the blastocyst stage. In these TS cloned blastocysts, the numbers of trophectoderm (TE) and inner cell mass (ICM) cells were 31.9 +/- 4.6 and 12.1 +/- 3.0, respectively, which were not significantly different from those in the fertilized embryos. In addition, the gene expression analysis showed that Oct3/4, and Cdx2, which are ICM- and TE-specific marker genes, respectively, and Dppa3, and Hdac1, which are zygotic gene activation-related genes, were expressed in TS cloned blastocysts at the same levels as in the fertilized blastocysts. These results indicate that although TS cloned embryos are able to differentiate into ICM cells, the genomic reprogrammability of TS cells is very low following nuclear transfer. PMID- 25826726 TI - Derivation and characterization of bovine induced pluripotent stem cells by transposon-mediated reprogramming. AB - Induced pluripotent stem cells (iPSCs) are a seminal breakthrough in stem cell research and are promising tools for advanced regenerative therapies in humans and reproductive biotechnology in farm animals. iPSCs are particularly valuable in species in which authentic embryonic stem cell (ESC) lines are yet not available. Here, we describe a nonviral method for the derivation of bovine iPSCs employing Sleeping Beauty (SB) and piggyBac (PB) transposon systems encoding different combinations of reprogramming factors, each separated by self-cleaving peptide sequences and driven by the chimeric CAGGS promoter. One bovine iPSC line (biPS-1) generated by a PB vector containing six reprogramming genes was analyzed in detail, including morphology, alkaline phosphatase expression, and typical hallmarks of pluripotency, such as expression of pluripotency markers and formation of mature teratomas in immunodeficient mice. Moreover, the biPS-1 line allowed a second round of SB transposon-mediated gene transfer. These results are promising for derivation of germ line-competent bovine iPSCs and will facilitate genetic modification of the bovine genome. PMID- 25826727 TI - Buffalo embryos produced by handmade cloning from oocytes selected using brilliant cresyl blue staining have better developmental competence and quality and are closer to embryos produced by in vitro fertilization in terms of their epigenetic status and gene expression pattern. AB - We compared handmade cloned (HMC) buffalo blastocysts produced from oocytes stained with Brilliant Cresyl Blue (BCB) and classified into those with blue (BCB+) or colorless cytoplasm (BCB-). The blastocyst rate was higher (p<0.001) for BCB+ than for BCB- oocytes (43.41 +/- 2.54 vs. 22.74 +/- 1.76%). BCB+ blastocysts had inner cell mass (ICM) cell number, ICM-to-trophectoderm ratio, global level of H3K18ac, apoptotic index, and expression level of BCL-XL, but not that of CASPASE-3, similar to that of blastocysts produced through in vitro fertilization (IVF), which was higher (p<0.05) than that of BCB- blastocysts. The global level of H3K9me2, which was similar in BCB+ and BCB- blastocysts, was higher (p<0.01) than that in IVF blastocysts. The expression level of OCT4 and SOX2 was higher (p<0.05) and that of GATA2 was lower (p<0.05) in BCB+ than that in BCB- blastocysts, whereas that of DNMT1, DNMT3a, NANOG, and CDX2 was not significantly different between the two groups. The expression level of DNMT1, OCT4, NANOG, and SOX2 was lower (p<0.05) and that of CDX2 was higher (p<0.05) in BCB+ than in IVF blastocysts. In conclusion, because BCB+ blastocysts have better developmental competence and are closer to IVF blastocysts in terms of quality, epigenetic status, and gene expression than BCB- blastocysts, BCB staining can be used effectively for selection of developmentally competent oocytes for HMC. PMID- 25826728 TI - Obesity and difficult-to-treat arterial hypertension. PMID- 25826729 TI - Weight loss improves reproductive outcomes in obese women undergoing fertility treatment: a randomized controlled trial. AB - For women attempting pregnancy, obesity reduces fertility and is an independent risk factor for obstetric and neonatal complications. The aim of this evaluator blinded, randomized controlled trial was to evaluate a weight loss intervention on pregnancy rates in obese women undertaking fertility treatment. Forty-nine obese women, aged <= 37 years, presenting for fertility treatment were randomized to either a 12-week intervention (n = 27) consisting of a very-low-energy diet for the initial 6 weeks followed by a hypocaloric diet, combined with a weekly group multidisciplinary programme; or a control group (n = 22) who received recommendations for weight loss and the same printed material as the intervention. Anthropometric and reproductive parameters were measured at baseline and at 12 weeks. The 22 women who completed the intervention had greater anthropometric changes (-6.6 +/- 4.6 kg and -8.7 +/- 5.6 cm vs. -1.6 +/- 3.6 kg and -0.6 +/- 6.3 cm) compared with the control group (n = 17; P < 0.001). The intervention group achieved a pregnancy rate of 48% compared with 14% (P = 0.007), took a mean two fertility treatment cycles to achieve each pregnancy compared with four in the control group (P = 0.002), and had a marked increase in the number of live births (44% vs. 14%; P = 0.02). A group weight loss programme, incorporating dietary, exercise and behavioural components, is associated with a significant improvement in pregnancy rates and live births in a group of obese women undergoing fertility treatment. PMID- 25826731 TI - The effectiveness of including support people in a cognitive behavioural weight loss maintenance programme for obese adults: study rationale and design. AB - The well-documented finding that obese adults have a high likelihood of weight regain following participation in behavioural weight loss programmes highlights the importance of developing more effective approaches for weight loss maintenance. One promising approach is to improve the quality of social support for effective weight control available to an obese individual by including support people in behavioural weight loss programmes. This paper describes the rationale and design of a randomized controlled trial that evaluates the effectiveness of training support people to assist obese adults in their weight management. The study entails a two-arm randomized controlled trial in which obese participants take part in a 1-year (26-session) cognitive behaviour therapy group weight management programme, including motivational interviewing strategies (CBT-MI). In one arm, participants receive CBT-MI alone, while in the second arm (CBT-MI-SP), participants also have a support person who attends 10 group sessions designed to teach effective skills for supporting an individual in healthy weight control. More specifically, support people will be trained in skills that aim to promote self-motivation for weight management. Assessments of anthropometric, medical, behavioural, motivational, psychological and social functioning take place at pre-treatment, post-treatment and a 1-year follow-up. By helping obese participants to increase and sustain their motivation and skills for weight control both during treatment and in the crucial period after treatment cessation through the ongoing input of support people, the CBT-MI-SP approach of the current study has the potential to effectively help patients to achieve sustained weight loss while minimizing the patient's need for ongoing, intensive weight control treatment with its attendant costs. PMID- 25826730 TI - Direct observation of weight counselling in primary care: alignment with clinical guidelines. AB - Primary care physicians provide care to a disproportionate number of overweight and obese patients and are uniquely positioned to help patients manage their weight in the context of a continuity relationship. The US National Heart, Lung and Blood Institute (NHLBI) developed evidence-based guidelines for the effective and efficient care of overweight/obese patients, but little is known about the use of these guidelines in practice. To determine the content of weight discussions and assess the elements of the NHLBI guidelines that were accomplished, office visits of 544 adult, overweight/obese patients to 28 primary care physicians were observed and audio recorded. Associations between type of weight management discussion and patient, physician and visit characteristics were examined. Fifty per cent (n = 270) of visits included weight discussions; 47% and 38% included use of at least one NHLBI assessment or treatment element during discussions about weight, respectively. Only 35% (n = 193) of discussions included an assessment and treatment strategy; none included all NHLBI recommended elements. Overall, adherence to guidelines was poor, particularly with regard to reporting body mass index to the patient, measuring waist circumference and setting realistic weight loss goals. Weight discussions did not clearly vary by the patient, physician or visit characteristics examined. These findings suggest opportunities to develop and further tailor resources for improved physician training in patient weight management communication and treatment techniques that are both consistent with current standards for effective, evidence-based care and efficient enough for routine use during busy primary care visits. PMID- 25826732 TI - A comparison of the provision of the My Choice Weight Management Programme via general practitioner practices and community pharmacies in the United Kingdom. AB - This study aimed to assess the effectiveness of a novel, community-based weight management programme delivered through general practitioner (GP) practices and community pharmacies in one city in the United Kingdom. This study used a non randomized, retrospective, observational comparison of clinical data collected by participating GP practices and community pharmacies. Subjects were 451 overweight or obese men and women resident in areas of high socioeconomic deprivation (82% from black and minority ethnic groups, 86% women, mean age: 41.1 years, mean body mass index [BMI]: 34.5 kg m(-2)). Weight, waist circumference and BMI at baseline, after 12 weeks and after 9 months were measured. Costs of delivery were also analysed. Sixty-four per cent of participants lost weight after the first 12 weeks of the My Choice Weight Management Programme. There was considerable dropout. Mean percentage weight loss (last observation carried forward) was 1.9% at 12 weeks and 1.9% at final follow-up (9 months). There was no significant difference in weight loss between participants attending GP practices and those attending pharmacies at both 12 weeks and at final follow-up. Costs per participant were higher via community pharmacy which was attributable to better attendance at sessions among community pharmacy participants than among GP participants. The My Choice Weight Management Programme produced modest reductions in weight at 12 weeks and 9 months. Such programmes may not be sufficient to tackle the obesity epidemic. PMID- 25826733 TI - Warfarin dosing after bariatric surgery: a retrospective study of 10 patients previously stable on chronic warfarin therapy. AB - Many changes associated with bariatric surgery have the potential to affect warfarin dosing; yet current literature includes little data describing this phenomenon. Investigating this relationship may allow for determination of post bariatric surgery warfarin dosing using stable pre-operative dosing levels. A retrospective chart review was completed for 10 patients stabilized on chronic warfarin therapy who underwent bariatric surgery. Data collection consisted of the following: warfarin requirement in mg/week, time in target range (TTR), creatinine, liver function, diarrhoea, medication changes, diet, and signs of bleeding and/or thrombosis. Three study patients underwent laparoscopic adjustable gastric banding procedures and seven patients underwent Roux-en-Y gastric bypass. The average (standard deviation) weekly warfarin dose required in the immediate post-operative interval was 64% (25%) of baseline dosing, corresponding to a TTR of 48%. At 6 months, patients required 85% (19%) of baseline weekly dosing, with TTR of 53.4%. At 1 year, dosing was 90% (16%) of baseline with TTR of 63.5%. Patients underwent medication changes as well as transient bouts of diarrhoea. Two patients suffered unspecified haemorrhages of the gastrointestinal tract (international normalized ratio [INR] = 2.3 and 9.8). This patient set demonstrated an initial drop in warfarin requirement, followed by escalating dosing trends that became more predictable as patients were farther out from procedure. PMID- 25826735 TI - Five-year outcome of bariatric surgery in a patient with melanocortin-4 receptor mutation. AB - Monogenic obesity is characterized by mutations in genes involved in the central regulation of food intake. Melanocortin-4 receptor (MC4R) mutations are the most frequent monogenic cause of severe early onset human obesity. Although bariatric surgery is the most effective therapy for idiopathic morbid obesity in adults, little is known about its effectiveness in patients with monogenic obesity syndromes. We report 5-year outcome of gastric bypass surgery in a young man with severe super-obesity associated with MC4R mutation. A 22-year-old man with a weight of 221.6 kg and body mass index of 76.7 kg m(-2) associated with a heterozygous MC4R mutation was referred to our centre for bariatric surgery. He underwent Roux-en-Y gastric bypass (RYGB) surgery and achieved weight loss of 76% of excess weight over a follow-up period of 58 months. Heterozygous MC4R mutations have been associated with dominantly inherited obesity in various ethnic groups, and non-surgical interventions are rarely effective in the long term. One previous report of bariatric surgery in a patient with complete MC4R deficiency reported poor weight loss after gastric banding. We speculate that patients with MC4R mutations achieve superior weight loss outcomes from procedures such as RYGB that produce neurohormonal changes rather than gastric restriction alone due to beneficial effects on appetite and satiety regulation. PMID- 25826734 TI - Diffuse large B-cell lymphoma (DLBCL) in the bypassed stomach after obesity surgery. AB - Laparoscopic Roux-en-Y gastric bypass is the most commonly performed surgical procedure for obesity and, consequently, post-operative patients are increasingly encountered by all specialties. This is a case of a patient presenting with abdominal pain, nausea and fever 9 months following gastric bypass surgery caused by diffuse large B-cell lymphoma (DLBCL) in the bypassed stomach. It demonstrates well that symptoms that may normally be considered 'red-flags' may not be as obvious or specific following an operation. The case also indicates the importance of considering diagnoses unrelated to surgery presenting in the post operative period (especially when conventional investigation methods are not feasible), and the potential danger of assuming they are due to the operation alone; had this occurred in this patient then a malignancy may have been missed. This is only the second reported case of DLBCL in the bypassed stomach, and the third for lymphoma of any type. PMID- 25826736 TI - Clinical pictures. PMID- 25826737 TI - Impact of the Topological Surface State on the Thermoelectric Transport in Sb2Te3 Thin Films. AB - Ab initio electronic structure calculations based on density functional theory and tight-binding methods for the thermoelectric properties of p-type Sb2Te3 films are presented. The thickness-dependent electrical conductivity and the thermopower are computed in the diffusive limit of transport based on the Boltzmann equation. Contributions of the bulk and the surface to the transport coefficients are separated, which enables to identify a clear impact of the topological surface state on the thermoelectric properties. When the charge carrier concentration is tuned, a crossover between a surface-state-dominant and a Fuchs-Sondheimer transport regime is achieved. The calculations are corroborated by thermoelectric transport measurements on Sb2Te3 films grown by atomic layer deposition. PMID- 25826738 TI - Experimental validation of the new modular application of the upper bound theorem in indentation. AB - Nowadays, thanks to the new manufacturing processes, indentation is becoming an essential part of the new arising processes such as the Incremental Forming Processes. This work presents the experimental validation of the analytical model developed for an indentation-based process. The analytical model is originated from the Upper Bound Theorem application by means of its new modular distribution. The modules considered are composed of two Triangular Rigid Zones each. The experimental validation is performed through a series of indentation tests with work-pieces of annealed aluminium EN AW-2030 and punches of steel AISI 304, under plane strain conditions. The results are compared with the ones obtained from the application of this new modular distribution of the Upper Bound Theorem, showing a good approximation and suitability of the model developed for an indentation-based process. PMID- 25826739 TI - Hierarchical LiZnVO4@C nanostructures with enhanced cycling stability for lithium ion batteries. AB - Hierarchical LiZnVO4@C nanostructures composed of thin nanobelt aggregates were synthesized for the first time through an ethanol thermal and subsequent annealing route, and were investigated by X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Furthermore, the synthesized hierarchical nanostructures were used as anode materials for Li-ion intercalation and exhibited a large reversible capacity, high rate performance, and excellent cycling stability. For instance, a high reversible capacity of 675 mA h g(-1) was maintained after 60 cycles at a current density of 50 mA g(-1). These results might be attributed to the following facts: (i) the hierarchical nanostructures could buffer the strain and volume changes during the cycling process; (ii) the thin nanobelts provide a shortened distance for Li-ion intercalation; (iii) the thin carbon layer on the surface of the nanobelts could provide a fast route for electron transportation, leading to an improved capacity and high rate performance. PMID- 25826740 TI - Titanium dioxide nanoparticles increase plasma glucose via reactive oxygen species-induced insulin resistance in mice. AB - There have been few reports about the possible toxic effects of titanium dioxide (TiO2 ) nanoparticles on the endocrine system. We explored the endocrine effects of oral administration to mice of anatase TiO2 nanoparticles (0, 64 and 320 mg kg(-1) body weight per day to control, low-dose and high-dose groups, respectively, 7 days per week for 14 weeks). TiO2 nanoparticles were characterized by scanning and transmission electron microscopy (TEM) and dynamic light scattering (DLS), and their physiological distribution was investigated by inductively coupled plasma. Biochemical analyzes included plasma glucose, insulin, heart blood triglycerides (TG), free fatty acid (FFA), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) 6 and reactive oxygen species (ROS)-related markers (total SOD, GSH and MDA). Phosphorylation of IRS1, Akt, JNK1, and p38 MAPK were analyzed by western blotting. Increased titanium levels were found in the liver, spleen, small intestine, kidney and pancreas. Biochemical analyzes showed that plasma glucose significantly increased whereas there was no difference in plasma insulin secretion. Increased ROS levels were found in serum and the liver, as evidenced by reduced total SOD activity and GSH level and increased MDA content. Western blotting showed that oral administration of TiO2 nanoparticles induced insulin resistance (IR) in mouse liver, shown by increased phosphorylation of IRS1 (Ser307) and reduced phosphorylation of Akt (Ser473). The pathway by which TiO2 nanoparticles increase ROS-induced IR were included in the inflammatory response and phosphokinase, as shown by increased serum levels of TNF-alpha and IL-6 and increased phosphorylation of JNK1 and p38 MAPK in liver. These results show that oral administration of TiO2 nanoparticles increases ROS, resulting in IR and increasing plasma glucose in mice. PMID- 25826741 TI - Augmented reflex cutaneous vasodilatation following short-term dietary nitrate supplementation in humans. AB - NEW FINDINGS: What is the central question of this study? Nitrate supplementation via beetroot juice has been shown to have several benefits in healthy humans, including reduced blood pressure and increased blood flow to exercising muscle. Whether nitrate supplementation can improve blood flow to the skin in heat stressed humans has not been investigated. What is the main finding and its importance? Similar to previous studies, we found that nitrate supplementation reduces blood pressure. Nitrate supplementation increased vasodilatation in the skin of heat-stressed humans but did not directly increase skin blood flow. Nitrate supplementation has been shown to increase NO-dependent vasodilatation through both NO synthase (NOS)-dependent and NOS-independent pathways. We hypothesized that nitrate supplementation would augment reflex cutaneous active vasodilatation. Subjects were equipped with two microdialysis fibres on the forearm randomly assigned as control (Ringer solution) or NOS inhibition (20 mm l NAME). Whole-body heating was performed to raise core temperature by 0.8 degrees C above baseline core temperature. Maximal cutaneous vasodilatation was achieved via 54 mm sodium nitroprusside and local heating to 43 degrees C. Skin blood flow (measured by laser-Doppler flowmetry) and blood pressure were measured. Cutaneous vascular conductance (CVC) was calculated as skin blood flow divided by mean arterial pressure (MAP) and expressed as a percentage of maximal CVC (%CVCmax ). Subjects underwent heat stress before and after nitrate supplementation (3 days of beetroot juice; 5 mm, 0.45 g nitrates per day). During heat stress, MAP was reduced following nitrate supplementation compared with the control conditions (before 88 +/- 3 mmHg versus after 78 +/- 2 mmHg; P < 0.05); however, resting MAP was not different between conditions (before 88 +/- 3 mmHg versus after 83 +/- 2 mmHg; P = 0.117). Nitrate supplementation increased plateau CVC at control sites (before 67 +/- 2%CVCmax versus after 80 +/- 5%CVCmax ; P = 0.01) but not at l NAME-treated sites (before 45 +/- 4%CVCmax versus after 40 +/- 5%CVCmax ; P = 0.617). There was no change in the calculated percentage of NOS-dependent vasodilatation before and after supplementation (before 59 +/- 4% versus after 64 +/- 6%; P = 0.577). These data suggest that nitrate supplementation augments CVC and reduces MAP during heat stress. PMID- 25826742 TI - Identification of multi-target effects of Huaier aqueous extract via microarray profiling in triple-negative breast cancer cells. AB - Breast cancer is one of the most common malignant tumors in the world. Long-term maintenance treatment is important for breast cancer. However, effective maintenance treatment is lacking for triple-negative breast cancer (TNBC). Traditional Chinese medicine (TCM) has shown its potential anticancer roles as an effective maintenance treatment for TNBC. However its mechanisms remained unclear. In this study, we detected the differentially expressed genes (DEGs) after treatment with Huaier aqueous extract by using microarray profiling in MDA MB-231 cells. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene-gene interaction network were conducted to confirm the altered biological functions induced by Huaier extract. Screening of DEGs gave 387 genes (226 upregulated and 161 downregulated) in MDA-MB-231 cells which were regulated significantly by Huaier extract. GO and KEGG pathway analysis suggested that a number of functions were affected by Huaier, including proliferation, apoptosis, migration, and angiogenesis. Gene-gene interaction network showed the detailed molecular signal-net. Based on microarray data, we studied several functions of Huaier extract and in return verified the results of microarray profiling. This study had important guidance roles and indicated new research directions. PMID- 25826743 TI - Buprenorphine for treating cancer pain. AB - BACKGROUND: Many patients with cancer experience moderate to severe pain that requires treatment with strong analgesics. Buprenorphine, fentanyl and morphine are examples of strong opioids used for cancer pain relief. However, strong opioids are ineffective as pain treatment in all patients and are not well tolerated by all patients. The aim of this Cochrane review is to assess whether buprenorphine is associated with superior, inferior or equal pain relief and tolerability compared to other analgesic options for patients with cancer pain. OBJECTIVES: To assess the effectiveness and tolerability of buprenorphine for pain in adults and children with cancer. SEARCH METHODS: We searched CENTRAL (the Cochrane Library) issue 12 or 12 2014, MEDLINE (via OVID) 1948 to 20 January 2015, EMBASE (via OVID) 1980 to 20 January 2015, ISI Web of Science (SCI-EXPANDED & CPCI-S) to 20 January 2015, ISI BIOSIS 1969 to 20 January 2015. We also searched ClinicalTrials.gov (http://clinicaltrials.gov/; metaRegister of Controlled Trials (mRCT) (http://www.controlled-trials.com/mrct/), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/) and the Proceedings of the Congress of the European Federation of International Association for the Study of Pain (IASP; via European Journal of Pain Supplements) on 16 February 2015. We checked the bibliographic references of identified studies as well as relevant studies and systematic reviews to find additional trials not identified by the electronic searches. We contacted authors of included studies for other relevant studies. SELECTION CRITERIA: We included randomised controlled trials, with parallel-group or crossover design, comparing buprenorphine (any formulation and any route of administration) with placebo or an active drug (including buprenorphine) for cancer background pain in adults and children. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data pertaining to study design, participant details (including age, cancer characteristics, previous analgesic medication and setting), interventions (including details about titration) and outcomes, and independently assessed the quality of the included studies according to standard Cochrane methodology. As it was not feasible to meta-analyse the data, we summarised the results narratively. We assessed the overall quality of the evidence for each outcome using the GRADE approach. MAIN RESULTS: In this Cochrane review we identified 19 relevant studies including a total of 1421 patients that examined 16 different intervention comparisons.Of the studies that compared buprenorphine to another drug, 11 studies performed comparative analyses between the randomised groups, and five studies found that buprenorphine was superior to the comparison treatment. Three studies found no differences between buprenorphine and the comparison drug, while another three studies found treatment with buprenorphine to be inferior to the alternative treatment in terms of the side effects profile or patients preference/acceptability.Of the studies that compared different doses or formulations/routes of administration of buprenorphine, pain intensity ratings did not differ significantly between intramuscular buprenorphine and buprenorphine suppository. However, the average severity of dizziness, nausea, vomiting and adverse events as a total were all significantly higher in the intramuscular group relatively to the suppository group (one study).Sublingual buprenorphine was associated with faster onset of pain relief compared to subdermal buprenorphine, with similar duration analgesia and no significant differences in adverse event rates reported between the treatments (one study).In terms of transdermal buprenorphine, two studies found it superior to placebo, whereas a third study found no difference between placebo and different doses of transdermal buprenorphine.The studies that examined different doses of transdermal buprenorphine did not report a clear dose-response relationship.The quality of this evidence base was limited by under-reporting of most bias assessment items (e.g., the patient selection items), by small sample sizes in several included studies, by attrition (with data missing from 8.2% of the enrolled/randomised patients for efficacy and from 14.6% for safety) and by limited or no reporting of the expected outcomes in a number of cases. The evidence for all the outcomes was very low quality. AUTHORS' CONCLUSIONS: Based on the available evidence, it is difficult to say where buprenorphine fits in the treatment of cancer pain with strong opioids. However, it might be considered to rank as a fourth-line option compared to the more standard therapies of morphine, oxycodone and fentanyl, and even there it would only be suitable for some patients. However, palliative care patients are often heterogeneous and complex, so having a number of analgesics available that can be given differently increases patient and prescriber choice. In particular, the sublingual and injectable routes seemed to have a more definable analgesic effect, whereas the transdermal route studies left more questions. PMID- 25826744 TI - Synthesis of high density aviation fuel with cyclopentanol derived from lignocellulose. AB - For the first time, renewable high density aviation fuels were synthesized at high overall yield (95.6%) by the Guerbet reaction of cyclopentanol which can be derived from lignocellulose, followed by the hydrodeoxygenation (HDO). The solvent-free Guerbet reaction of cyclopentanol was carried out under the co catalysis of solid bases and Raney metals. Among the investigated catalyst systems, the combinations of magnesium-aluminium hydrotalcite (MgAl-HT) and Raney Ni (or Raney Co) exhibited the best performances. Over them, high carbon yield (96.7%) of C10 and C15 oxygenates was achieved. The Guerbet reaction products were further hydrodeoxygenated to bi(cyclopentane) and tri(cyclopentane) over a series of Ni catalysts. These alkanes have high densities (0.86 g mL(-1) and 0.91 g mL(-1)) and can be used as high density aviation fuels or additives to bio-jet fuel. Among the investigated HDO catalysts, the 35 wt.% Ni-SiO2-DP prepared by deposition-precipitation method exhibited the highest activity. PMID- 25826745 TI - Emission rates of regulated pollutants from current technology heavy-duty diesel and natural gas goods movement vehicles. AB - Chassis dynamometer emissions testing of 11 heavy-duty goods movement vehicles, including diesel, natural gas, and dual-fuel technology, compliant with US-EPA 2010 emissions standard were conducted. Results of the study show that three-way catalyst (TWC) equipped stoichiometric natural gas vehicles emit 96% lower NOx emissions as compared to selective catalytic reduction (SCR) equipped diesel vehicles. Characteristics of drayage truck vocation, represented by the near-dock and local drayage driving cycles, were linked to high NOx emissions from diesel vehicles equipped with a SCR. Exhaust gas temperatures below 250 degrees C, for more than 95% duration of the local and near-dock driving cycles, resulted in minimal SCR activity. The low percentage of activity SCR over the local and near dock cycles contributed to a brake-specific NOx emissions that were 5-7 times higher than in-use certification limit. The study also illustrated the differences between emissions rate measured from chassis dynamometer testing and prediction from the EMFAC model. The results of the study emphasize the need for model inputs relative to SCR performance as a function of driving cycle and engine operation characteristics. PMID- 25826746 TI - Steroidomic Footprinting Based on Ultra-High Performance Liquid Chromatography Coupled with Qualitative and Quantitative High-Resolution Mass Spectrometry for the Evaluation of Endocrine Disrupting Chemicals in H295R Cells. AB - The screening of endocrine disrupting chemicals (EDCs) that may alter steroidogenesis represents a highly important field mainly due to the numerous pathologies, such as cancer, diabetes, obesity, osteoporosis, and infertility that have been related to impaired steroid-mediated regulation. The adrenal H295R cell model has been validated to study steroidogenesis by the Organization for Economic Co-operation and Development (OECD) guideline. However, this guideline focuses solely on testosterone and estradiol monitoring, hormones not typically produced by the adrenals, hence limiting possible in-depth mechanistic investigations. The present work proposes an untargeted steroidomic footprinting workflow based on ultra-high pressure liquid chromatography (UHPLC) coupled to high-resolution MS for the screening and mechanistic investigations of EDCs in H295R cell supernatants. A suspected EDC, triclocarban (TCC), used in detergents, cosmetics, and personal care products, was selected to demonstrate the efficiency of the reported methodology, allowing the simultaneous assessment of a steroidomic footprint and quantification of a selected subset of steroids in a single analysis. The effects of exposure to increasing TCC concentrations were assessed, and the selection of features with database matching followed by multivariate analysis has led to the selection of the most salient affected steroids. Using correlation analysis, 11 steroids were associated with a high, 18 with a medium, and 8 with a relatively low sensitivity behavior to TCC. Among the candidates, 13 identified steroids were simultaneously quantified, leading to the evaluation and localization of the disruption of steroidogenesis caused by TCC upstream of the formation of pregnenolone. The remaining candidates could be associated with a specific steroid class (progestogens and corticosteroids, or androgens) and represent a specific footprint of steroidogenesis disruption by TCC. This strategy was devised to be compatible with medium/high-throughput screening and could be useful for the mechanistic elucidation of EDCs. PMID- 25826747 TI - Alterations in oral [1-(14)C] 18:1n-9 distribution in lean wild-type and genetically obese (ob/ob) mice. AB - Obesity may result from altered fatty acid (FA) disposal. Altered FA distribution in obese individuals is poorly understood. Lean wild-type C57BL/6J and obese C57BL/6Job/ob mice received an oral dose of [1-(14)C]18:1n-9 (oleic acid), and the radioactivity in tissues was evaluated at various time points. The (14)C concentration decreased rapidly in gastrointestinal tract but gradually increased and peaked at 96 h in adipose tissue, muscle and skin in lean mice. The (14)C concentration was constant in adipose tissue and muscle of obese mice from 4 h to 168 h. (14)C-label content in adipose tissue was significantly affected by genotype, whereas muscle (14)C-label content was affected by genotype, time and the interaction between genotype and time. There was higher total (14)C retention (47.7%) in obese mice than in lean mice (9.0%) at 168 h (P<0.05). The (14)C concentrations in the soleus and gastrocnemius muscle were higher in obese mice than in lean mice (P<0.05). Perirenal adipose tissue contained the highest (14)C content in lean mice, whereas subcutaneous adipose tissue (SAT) had the highest (14)C content and accounted for the largest proportion of total radioactivity among fat depots in obese mice. More lipid radioactivity was recovered as TAG in SAT from obese mice than from lean mice (P<0.05). Gene expression suggested acyl CoA binding protein and fatty acid binding protein are important for FA distribution in adipose tissue and muscle. The FA distribution in major tissues was altered in ob/ob mice, perhaps contributing to obesity. Understanding the disparity in FA disposal between lean and obese mice may reveal novel targets for the treatment and prevention of obesity. PMID- 25826748 TI - Sexuality and romantic relationships in young adult cancer survivors: satisfaction and supportive care needs. AB - OBJECTIVE: In recent years, psycho-oncology has focused more and more on adolescents and young adults with cancer (AYA). Many studies have concentrated on fertility issues in AYAs, but romantic relationships and sexuality have only been researched to a limited extent. This cross-sectional study examined AYAs' quality of relationships and sexuality satisfaction thereby identifying sex differences. METHODS: Ninety-nine cancer patients (N = 33 males) diagnosed between 15 and 39 years who were in a romantic relationship at the time of the survey completed questionnaires on their relationship (Partnership Questionnaire), sexuality (Life Satisfaction Questionnaire), and sexuality needs (Supportive Care Needs Survey). Test for mean differences and regression analyses to determine associated variables were performed. RESULTS: Seventy-six percent of AYAs (N = 75) rated their relationship quality as high. About 64% of patients reported having less sexual intercourse since diagnosis, more women than men (72% vs. 45%; p = .011). The need for support was strongest for changes in sexual feelings (N = 38; 38.3%). Duration of relationship (beta = -0.224), being on sick leave (beta = 0.325), and satisfaction with sexuality (beta = 0.409) were associated with satisfaction with relationship (R(2) = 0.256). Satisfaction with sexuality (R(2) = 0.344) was regressed on physical function (beta = 0.419), satisfaction with relationship (beta = 0.428), and male gender (beta = -0.175). Sexuality need (R(2) = 0.436) was associated with fatigue (beta = 0.232) and satisfaction with sexuality (beta = -0.522). CONCLUSION: Although they reported high satisfaction with their relationships, AYA patients experienced sexual problems and need support with sexual issues. As a substantial proportion of patients felt stressed because of sexual changes, communication and interventions addressing post-cancer sexuality, particularly in women, are indicated. PMID- 25826751 TI - Correction: One-step fabrication of robust fabrics with both-faced superhydrophobicity for the separation and capture of oil from water. PMID- 25826750 TI - A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer. AB - Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid-derived suppressor cells, as well as trigger antitumor effects by inducing an antibody-dependent cellular cytotoxicity on tumor associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2-negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m(2) for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression-free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion-related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS-expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion related reactions with no evidence for increased thrombogenicity. Recent preclinical data suggest that bavituximab can also promote antitumor immune activity that should be explored in future clinical trials. PMID- 25826749 TI - Emerging drugs for head and neck cancer. AB - INTRODUCTION: Despite improvements in treatment, survival rates of head and neck squamous cell carcinoma (HNSCC) are stagnant. The existing chemotherapeutic agents are non-selective and associated with toxicities. Combinations of the only the US FDA-approved epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, with chemotherapy or radiation improves overall survival. However, the response rates to cetuximab are modest. Thus, there is an urgent need for new agents that can be safely integrated into current treatment regimens to improve outcome. AREAS COVERED: Current EGFR-targeted drugs under clinical development include mAbs and tyrosine kinase inhibitors. The modest efficacy of these drugs implicates intrinsic or acquired resistance. Novel molecular agents inhibiting alternative targets to overcome anti-EGFR resistance in HNSCC are under investigation. Gene therapy and immunotherapy are also promising strategies to improve efficacy and reduce toxicity. EXPERT OPINION: To date, only six drugs have been FDA-approved for the treatment of head and neck cancer. Cetuximab is the only approved molecular targeting agent for HNSCC and despite ubiquitous expression of EGFR in HNSCC tumors, clinical responses are limited. Genetic and epigenetic characterization of HNSCC tumors, coupled with improved preclinical models, should facilitate the development of more effective drugs. PMID- 25826752 TI - Metal-free oxysulfenylation of alkenes with 1-(arylthio)pyrrolidine-2,5-diones and alcohols. AB - beta-Alkoxy sulfides are widely used as versatile building blocks in organic synthesis. Therefore, it is highly desirable to develop a convenient and efficient method for oxysulfenylation of alkenes. In this communication, an easy and efficient metal-free approach to beta-alkoxy sulfides has been developed. The protocol uses readily available 1-(arylthio)pyrrolidine-2,5-diones and alcohols as the oxysulfenylating agents, chloroform as the solvent, and no ligand, additive and exclusion of air were required. Therefore, the present method provides a useful strategy for synthesis of beta-alkoxy sulfides. PMID- 25826753 TI - The neuroglial potassium cycle during neurotransmission: role of Kir4.1 channels. AB - Neuronal excitability relies on inward sodium and outward potassium fluxes during action potentials. To prevent neuronal hyperexcitability, potassium ions have to be taken up quickly. However, the dynamics of the activity-dependent potassium fluxes and the molecular pathways underlying extracellular potassium homeostasis remain elusive. To decipher the specific and acute contribution of astroglial Kir4.1 channels in controlling potassium homeostasis and the moment to moment neurotransmission, we built a tri-compartment model accounting for potassium dynamics between neurons, astrocytes and the extracellular space. We here demonstrate that astroglial Kir4.1 channels are sufficient to account for the slow membrane depolarization of hippocampal astrocytes and crucially contribute to extracellular potassium clearance during basal and high activity. By quantifying the dynamics of potassium levels in neuron-glia-extracellular space compartments, we show that astrocytes buffer within 6 to 9 seconds more than 80% of the potassium released by neurons in response to basal, repetitive and tetanic stimulations. Astroglial Kir4.1 channels directly lead to recovery of basal extracellular potassium levels and neuronal excitability, especially during repetitive stimulation, thereby preventing the generation of epileptiform activity. Remarkably, we also show that Kir4.1 channels strongly regulate neuronal excitability for slow 3 to 10 Hz rhythmic activity resulting from probabilistic firing activity induced by sub-firing stimulation coupled to Brownian noise. Altogether, these data suggest that astroglial Kir4.1 channels are crucially involved in extracellular potassium homeostasis regulating theta rhythmic activity. PMID- 25826754 TI - Next-generation sequencing as input for chemometrics in differential sensing routines. AB - Differential sensing (DS) methods traditionally use spatially arrayed receptors and optical signals to create score plots from multivariate data which classify individual analytes or complex mixtures. Herein, a new approach is described, in which nucleic acid sequences and sequence counts are used as the multivariate data without the necessity of a spatial array. To demonstrate this approach to DS, previously selected aptamers, identified from the literature, were used as semi-specific receptors, Next-Gen DNA sequencing was used to generate data, and cell line differentiation was the test-bed application. The study of a principal component analysis loading plot revealed cross-reactivity between the aptamers. The technique generates high-dimensionality score plots, and should be applicable to any mixture of complex and subtly different analytes for which nucleic acid based receptors exist. PMID- 25826756 TI - Arsenic removal by liquid membranes. AB - Water contamination with harmful arsenic compounds represents one of the most serious calamities of the last two centuries. Natural occurrence of the toxic metal has been revealed recently for 21 countries worldwide; the risk of arsenic intoxication is particularly high in Bangladesh and India but recently also Europe is facing similar problem. Liquid membranes (LMs) look like a promising alternative to the existing removal processes, showing numerous advantages in terms of energy consumption, efficiency, selectivity, and operational costs. The development of different LM configurations has been a matter of investigation by several researching groups, especially for the removal of As(III) and As(V) from aqueous solutions. Most of these LM systems are based on the use of phosphine oxides as carriers, when the metal removal is from sulfuric acid media. Particularly promising for water treatment is the hollow fiber supported liquid membrane (HFSLM) configuration, which offers high selectivity, easy transport of the targeted metal ions, large surface area, and non-stop flow process. The choice of organic extractant(s) plays an essential role in the efficiency of the arsenic removal. Emulsion liquid membrane (ELM) systems have not been extensively investigated so far, although encouraging results have started to appear in the literature. For such LM configuration, the most relevant step toward efficiency is the choice of the surfactant type and its concentration. PMID- 25826755 TI - Prediction of week 4 virological response in hepatitis C for making decision on triple therapy: the Optim study. AB - BACKGROUND: Virological response to peginterferon + ribavirin (P+R) at week 4 can predict sustained virological response (SVR). While patients with rapid virological response (RVR) do not require triple therapy, patients with a decline <1 log10 IU/ml HCVRNA (D1L) should have treatment discontinued due to low SVR rate. AIM: To develop a tool to predict first 4 weeks' viral response in patients with hepatitis C genotype 1&4 treated with P+R. METHODS: In this prospective and multicenter study, HCV mono-infected (n=538) and HCV/HIV co-infected (n=186) patients were included. To develop and validate a prognostic tool to detect RVR and D1L, we segregated the patients as an estimation cohort (to construct the model) and a validation cohort (to validate the model). RESULTS: D1L was reached in 509 (80.2%) and RVR in 148 (22.5%) patients. Multivariate analyses demonstrated that HIV co-infection, Forns' index, LVL, IL28B-CC and Genotype-1 were independently related to RVR as well as D1L. Diagnostic accuracy (AUROC) for D1L was: 0.81 (95%CI: 0.76 0.86) in the estimation cohort and 0.71 (95%CI: 0.62 0.79) in the validation cohort; RVR prediction: AUROC 0.83 (95%CI: 0.78 0.88) in the estimation cohort and 0.82 (95%CI: 0.76 0.88) in the validation cohort. Cost analysis of standard 48-week treatment indicated a saving of 30.3% if the prognostic tool is implemented. CONCLUSIONS: The combination of genetic (IL28B polymorphism) and viral genotype together with viral load, HIV co-infection and fibrosis stage defined a tool able to predict RVR and D1L at week 4. Using this tool would be a cost-saving strategy compared to universal triple therapy for hepatitis C. PMID- 25826757 TI - Rethinking prerequisites. PMID- 25826758 TI - Expert modeling, expert/self-modeling versus lecture: a comparison of learning, retention, and transfer of rescue skills in health professions students. AB - BACKGROUND: It is unclear whether traditional lecture followed by simulation leads to the best learning and knowledge and skill retention over time. METHOD: A 3*4 mixed design study used three modes of education-traditional lecture with self-guided learning, expert modeling/dual viewing with brief questioning, and expert plus self-modeling-at four time points to compare knowledge, time to treat, and correct steps over time. RESULTS: No significant differences were found in knowledge or time to treat between training methods. An expert modeling/ dual viewing group with brief questioning performed more steps correctly (p = 0.05) than did the other two groups. CONCLUSION: Expert modeling may help students remember and perform a complex series of tasks in a scenario. Further research is needed to explore expert modeling for novice learners. PMID- 25826759 TI - Student learning outcomes in response to concept-based teaching. AB - BACKGROUND: Concept-based teaching (CBT) has been found to better facilitate students' meaningful learning than traditional pedagogy, but little research has been conducted in nursing education. METHOD: This mixed-methods study investigated meaningful learning in nursing students. Quantitative data were extracted from archived records and analyzed through multiple regression to compare two groups: students who received CBT and students who received traditional teaching. RESULTS: Students' pretest scores were the best predictor of meaningful learning gain (i.e., difference between pre- and post-test higher order thinking [HOT] scores). No significant between-group differences were noted. Qualitative data were collected from 22 CBT students, purposefully selected for their HOT scores, and analyzed through flow mapping. Integrative analysis found that students who verbalized a greater number of knowledge connections had higher HOT scores and a deeper understanding of nursing principles than did students with lower HOT scores. CONCLUSION: CBT students' gain in HOT scores may become more apparent over several semesters. PMID- 25826760 TI - Interprofessional problem-based learning project outcomes between prelicensure baccalaureate of science in nursing and doctor of pharmacy programs. AB - BACKGROUND: Persistently high medical error rates, caregiver dissatisfaction, and compromised patient safety often result from poorly coordinated, increasingly complex health care. Barriers to interprofessional health professions education persist despite the urgent calls for improved quality and safety. Investigators explored the effects of a problem-based learning (PBL) strategy between prelicensure doctorate of pharmacy (PharmD) and baccalaureate nursing (BSN) students. METHOD: A descriptive design was used to compare the learning gains and satisfaction with a PBL hybrid approach for BSN and PharmD prelicensure student groups over three academic terms. RESULTS: Consistent with earlier works, content based learning gains and student satisfaction were not significantly different between groups. Narrative data provide insight into perceived benefits, barriers, and perspectives of participating students and facilitators. CONCLUSION: Attributes of this pedagogical approach provide opportunity for prelicensure students to explore professional interdependence while adequately mastering fact based content. PMID- 25826762 TI - Using a simulated mass casualty incident to teach response readiness: a case study. AB - BACKGROUND: Recent occurrences of disaster events highlight the need for increased attention to improving students' knowledge of disaster readiness. Nursing education continues to struggle with the delivery of consistent, effective, and impactful teaching methods for disaster response. This study aimed to explore the effectiveness of using a simulated mass casualty incident (MCI) and Web-based resources to teach the application of disaster nursing concepts. METHOD: Baccalaureate nursing students (n = 63) were evaluated on their ability and perceived readiness to respond after participation in a disaster educational session and simulated MCI. RESULTS: Quantitative and qualitative data revealed that students developed an increased ability in critical thinking, functionality within the health care team, and learning from their mistakes when responding to a simulated MCI. CONCLUSION: A varied approach of didactic, Web-based, and simulation education is effective in improving student's perceived readiness for disaster response. Continued efforts are recommended to support student development in disaster response. PMID- 25826761 TI - A correlation study of social network usage among health care students. AB - BACKGROUND: Due to anecdotal concerns about adequacy of health professions students' communication skills, health professions faculty at a private university formed an interprofessional research team. The study was designed to explore whether the use of social networking services (SNS) influenced health care students' written and oral communication skills. METHOD: One hundred thirty two students participated in the study. Communication skills were assessed by using assignments from a health care ethics course required of all students. Use of SNS was measured with an information technology questionnaire. RESULTS: Contrary to expected findings, this exploratory correlation study found no meaningful relationship between the frequency of SNS usage and oral and written communication skills in health professions students. CONCLUSIONS: Future studies of SNS would benefit from a younger and more homogeneous study population to assess the use of SNS for learning versus leisure. PMID- 25826763 TI - One thousand words: evaluating an interdisciplinary art education program. AB - BACKGROUND: Art Rounds, an innovative interdisciplinary program, began as a pilot project to determine if use of fine arts instructional strategies would be of benefit in health professional education. Specifically, students were exposed to fine art and taught to use visual thinking strategies (VTS). The initial evaluation of the pilot program revealed improved physical observation skills, increased tolerance for ambiguity, and increased interest in communication skills. More recently, the Art Rounds program has been expanded to an interdisciplinary elective course open to both nursing student and medical students at all levels. METHOD: An evaluation of Art Rounds as a semester- long course was conducted by course faculty and compared to the original pilot program for differences and similarities. RESULTS/CONCLUSION: Outcomes have demonstrated that the use of visual arts and humanities continues to be highly effective in improving students' physical observation skills and a powerful tool for teaching nursing students how to be skilled clinicians. PMID- 25826764 TI - Use of quick response coding to create interactive patient and provider resources. AB - BACKGROUND: Since their creation more than 20 years ago, the proliferation of Quick Response (QR) codes has expanded tremendously. Little was found in the literature to support the innovative use of QR coding in the classroom or in health care provision. Thus, the authors created a doctoral-level practicum experience using QR coding to create interactive, individualized patient or provider resource guides. METHOD: Short, descriptive surveys were used before and after implementation of the practicum experience to determine students' comfort level using QR technology, their knowledge base, ease of use, and overall satisfaction with the practicum. RESULTS: Students reported high levels of satisfaction with this exercise, and all agreed that use of QR coding could have important implications in the clinical environment. CONCLUSION: This practicum experience was a creative, practical, and valuable example of integrating emerging technology into individualized patient care. PMID- 25826765 TI - Incorporating the QSEN competency in evidence-based practice in a mental health clinical rotation. AB - BACKGROUND: Nurse educators continually search for alternative methods of instruction that provide a meaningful experience while meeting clinical objectives. One approach incorporated the Quality Safety Education for Nurses (QSEN) competencies' evidence-based practice (EBP) into the clinical setting. METHOD: The Paint a Picture of Mental Illness assignment is a creative teaching approach in the Psychiatric Mental Health Nursing course. Students prepare a poster presentation using pictures, drawings, and illustrations demonstrating the mental, emotional, physical, financial, and spiritual impact of the mental illness. Students must perform a library search, locate an evidence-based research article related to best practices in patient care, and summarize pertinent information for presentation to the peer group. RESULTS: Nursing students developed an understanding of mental health concepts, addressed real life issues, researched EBP, and effectively communicated their findings to the peer group. CONCLUSION: This assignment helped students to develop empathy for patients with mental health issues and promoted understanding of patients' inner experiences. PMID- 25826766 TI - Giving back: using alumni for a nursing skills day. PMID- 25826768 TI - Quasi-prospective, real-life monitoring of food craving post-bariatric surgery: comparison with overweight and normal weight women. AB - Food cravings are common post-bariatric surgery, suggested as predictors of relapse and weight regain, but relatively unstudied, especially in the longer term. The present study investigated the frequency and nature of food craving experiences after gastric surgery in comparison with non-surgical control participants. Participants were 21 women, 4-38 months post-surgery (mean age = 44 years, 9 following gastric banding, 12 after Roux-en-Y gastric bypass), and two comparison samples of 39 overweight dieters and 33 normal weight non-dieters. They completed a food craving record after every food craving, a daily mood assessment and a food diary over a 7-day period. Over the 299 craving episodes, savoury foods were the most commonly craved (40% of craving events), followed by chocolate (31%). Post-bariatric patients reported more and stronger cravings than normal weight non-dieters but at a similar frequency and strength to overweight dieters. Neither hunger nor negative mood distinguished the food cravings of post bariatric patients from those of comparison participants, nor did the proportion that led to eating (58%). Food cravings should be anticipated post-bariatric surgery but no more so at 12 months post-surgery than by other overweight or obese individuals. Food cravings are not the product of extreme hunger nor do they have the connection with negative mood seen in disordered eating. In addition, the ability to fulfil cravings by eating the craved food is reduced by the surgery itself, although the duration of surgical restraint is uncertain. PMID- 25826767 TI - Changes in physical activity during a weight loss intervention and follow-up: a randomized controlled trial. AB - Physical activity is an important component in weight loss treatment and weight maintenance. We evaluated the physical activity component of two weight loss programmes, either standard care (SC) as defined by national guidelines, or a commercial programme (CP; Weight Watchers) over the period of weight loss and follow-up. 772 adults (mean body mass index: 31.4 +/- 2.6 kg m(-2)) were recruited by primary care practices in Australia, the United Kingdom, and Germany, and randomly assigned to 12 months SC, or the CP. They were then followed up at 24 months. Change in physical activity levels were assessed by the International Physical Activity Questionnaire (IPAQ)-short form, and pedometer recordings. Both groups reported increases in physical activity using the IPAQ from baseline to 12 months and 24 months (within groups P < 0.0001) and in pedometer steps from baseline to 12 months only (within groups P < 0.0001). Differences between groups with both methods of assessment were not significant. There was a significant difference in weight loss between the groups at 12 months favouring the CP group; however, this statistical difference was not maintained at 24 months. In conclusion, despite similar increases in reported activity, there were significant differences in weight loss and regain between groups. Therefore, greater weight loss seen with the CP is unlikely to be due to increases in physical activity. Trends in pedometer steps mirrored changes in weight over time more closely than the IPAQ; however, both assessment tools have limitations. Better activity assessment measures are needed to more accurately gauge changes in physical activity during weight loss interventions. PMID- 25826769 TI - Obese sedentary patients with dyspnoea on exertion who are at low risk for coronary artery disease by clinical criteria have a very low prevalence of coronary artery disease. AB - Dyspnoea, a much less specific symptom of ischaemia than chest discomfort, is common among obese patients. Patients with dyspnoea often undergo stress testing as part of their evaluation. We sought to examine the yield of stress testing in non-elderly, obese, sedentary patients with dyspnoea on exertion (DOE) as a chief complaint.We reviewed stress echocardiograms carried out on 203 patients in a stress testing laboratory at a major tertiary care centre. Of these, 81 (40%) fell into a group that was at low risk for coronary artery disease (CAD) by clinical criteria. Ischaemia was detected in two patients in the low-risk group (2.5%), and these results were likely false positives. In the higher risk group, 9.0% of functional tests showed ischaemia; after further testing, 2.5% of the higher risk patients were found to have obstructive coronary lesions. Clinical follow-up was performed for a mean of 815 days. New obstructive coronary disease was detected in 1.6% of all patients, and these patients were from the higher risk group. In obese sedentary patients with DOE but otherwise at low risk of coronary disease stress testing is of very low yield. DOE is generally not an anginal equivalent in this patient population. PMID- 25826770 TI - Effects of intermittent compared to continuous energy restriction on short-term weight loss and long-term weight loss maintenance. AB - Effective strategies are needed to help individuals lose weight and maintain weight loss. The primary aim of this study was to investigate the effect of intermittent energy restriction (IER) compared to continuous energy restriction (CER) on weight loss after 8 weeks and weight loss maintenance after 12 months. Secondary aims were to determine changes in waist and hip measurements and diet quality. In a randomized parallel study, overweight and obese (body mass index [BMI] >= 27 kg m(-2)) women were stratified by age and BMI before randomization. Participants undertook an 8-week intensive period with weight, waist and hip circumference measured every 2 weeks, followed by 44 weeks of independent dieting. A food frequency questionnaire was completed at baseline and 12 months, from which diet quality was determined. Weight loss was not significantly different between the two groups at 8 weeks (-3.2 +/- 2.1 kg CER, n = 20, -2.0 +/ 1.9 kg IER, n = 25; P = 0.06) or at 12 months (-4.2 +/- 5.6 kg CER, n = 17 -2.1 +/- 3.8 kg IER, n = 19; P = 0.19). Weight loss between 8 and 52 weeks was -0.7 +/ 49 kg CER vs. -1 +/- 1.1 kg IER; P = 0.6. Waist and hip circumference decreased significantly with time (P < 0.01), with no difference between groups. There was an increase in the Healthy Eating Index at 12 months in the CER compared with the IER group (CER 8.4 +/- 9.1 vs. IER -0.3 +/- 8.4, P = 0.006). This study indicates that intermittent dieting was as effective as continuous dieting over 8 weeks and for weight loss maintenance at 12 months. This may be useful for individuals who find CER too difficult to maintain. PMID- 25826771 TI - Food groups and weight gain in Japanese men. AB - Identifying subjects at high risk of weight gain according to consumption of food groups is important for individualizing nutritional education, but prospective studies of this issue have been few. We determined whether intake of specific food groups could predict future weight gain. We evaluated data from health checkups on 1236 Japanese men aged 28 to 87 years in 2005 and 2006. Dietary intake was assessed by a 24-h dietary recall at baseline. Weight change was measured after 1 year. Weight increased in 44.7% (n = 553) of participants. Multivariate regression analysis involving many food groups showed a significant association between sugar intake and weight gain after adjustment for age, body mass index (BMI), total energy intake, alcohol, smoking and regular physical exercise (beta = 0.22, P = 0.04). The effect of intake of 'fats and oils' was significant when adjusted for age and BMI, however, it became insignificant after adjustment for age, BMI and total energy intake. Intake of sugar, which was evaluated as a food group, was predictive of subsequent weight gain among Japanese men, even after adjustment for many confounders. This corroborates the evidence so far concerning the links between sugar intake and weight gain. Further long-term research is required to give robust recommendation to the public. PMID- 25826772 TI - Functional communication as a predictor of depression and anxiety symptoms among adolescents seeking bariatric surgery. AB - The purpose of the present study was to determine whether functional communication and parent-adolescent relations prospectively predict anxiety and depression symptoms among severely obese adolescents seeking bariatric surgery. Participants included 30 adolescents and their primary caregivers, who presented for enrolment in a study assessing the safety and efficacy of the laparoscopic adjustable gastric band. Adolescents and their caregivers completed questionnaires assessing anxiety and depression symptoms, functional communication, and parent-adolescent relations at baseline and immediately prior to having bariatric surgery. Regression analyses revealed that poorer parent reported functional communication at baseline predicted increases in adolescent reported anxiety and depression symptoms immediately prior to surgery (on average 8.8 months later), above and beyond baseline symptoms. Anxiety and depression symptoms did not predict functional communication over time. Parent-adolescent relations, as reported by the adolescent, were concurrently associated with adolescent reported depression symptoms at baseline, and were concurrently associated with adolescent reported anxiety and depression symptoms, as well as parent reported depression symptoms, immediately prior to surgery. Functional communication may be an important prospective risk factor for the development of anxiety and depression symptoms among severely obese adolescents seeking bariatric surgery, whereas adolescent report of the parent-adolescent relationship appears to be concurrently related to anxiety and depression symptoms. Future research should examine whether specifically targeting communication skills and family relationships within psychological treatment would improve psychosocial functioning among severely obese adolescents. PMID- 25826773 TI - Uncontrolled eating is associated with reduced executive functioning. AB - Accumulating evidence indicates obesity is associated with reduced cognitive functioning, particularly attention and executive function, as well as maladaptive eating behaviour such as uncontrolled eating. The current study examined relationships between eating patterns and attention/executive function test performance in lean and obese individuals. Sixty-two (32 lean, 30 obese) healthy young adults (21.13 +/- 2.31 years; 56.5% female) completed the abbreviated Three-Factor Eating Questionnaire (TFEQ-R18) to assess eating patterns, including uncontrolled eating, cognitive restraint, and emotional eating. The Go/No-Go (GNG), Running Memory Continuous Performance Test (RCMPT) and Standard Continuous Performance Test from the Automated Neuropsychological Assessment Metrics-4 were administered as measures of executive functioning and attention. An independent samples t-test revealed greater report of uncontrolled eating in obese compared with lean participants (t[60] = -2.174, P < 0.05; d = 0.55) but no differences in cognitive restraint or emotional eating. Multivariate analysis of variance revealed cognitive differences between lean and obese groups (F[6, 54] = 3.86, P < 0.005; lambda = 0.70; etap(2) = 0.30), which were driven by GNG reaction time (F[1, 59] = 8.36, P < 0.01, d = 0.74). Pearson bivariate correlations revealed a positive correlation between uncontrolled eating and reaction time on GNG (r = 0.343, P < 0.05) and RMCPT (r = 0.267, P < 0.05) in all participants. Relative to lean participants, obese individuals reported higher levels of uncontrolled eating and exhibited slower performance on a task of inhibitory control. In the full sample, greater self-reported dyscontrol in eating behaviour was related to slower inhibitory control and working memory. Results support a link between executive function and control of eating behaviour. Obese individuals may be more vulnerable to difficulties in these domains relative to those who are lean. PMID- 25826774 TI - The cost-effectiveness of the LighterLife weight management programme as an intervention for obesity in England. AB - LighterLife Total is a very low calorie diet total dietary replacement weight reduction programme that provides Foodpacks, behavioural change therapy and group support appropriate for people with a body mass index of 30 kg m(-2) or above. A model was built to assess the cost-effectiveness of LighterLife Total, compared with (i) no treatment, Counterweight, Weight Watchers and Slimming World, as a treatment for obesity in those with a body mass index of 30 kg m(-2) or above, and (ii) no treatment, gastric banding and gastric bypass in those with a body mass index of 40 kg m(-2) or above. Change in body mass index over time was modelled, and prevalence of comorbidities (diabetes, coronary heart disease and colorectal cancer) was calculated. Costs (of intervention and treatment for comorbidities) and quality-adjusted life years were calculated. LighterLife Total was cost-effective against no treatment, Counterweight, Weight Watchers and Slimming World in the 30+ kg m(-2) group (incremental cost-effectiveness ratios: L11 895, L12 453, L12 585 and L12 233, respectively). In the 40+ kg m(-2) group, LighterLife Total was cost-effective against no treatment (incremental cost effectiveness ratio: L4356), but less effective than gastric banding and bypass. PMID- 25826775 TI - Diffusing obesity myths. AB - Misinformation or myths about obesity can lead to weight bias and obesity stigma. Counteracting myths with facts and evidence has been shown to be effective educational tools to increase an individuals' knowledge about a certain condition and to reduce stigma.The purpose of this study was to identify common obesity myths within the healthcare and public domains and to develop evidence-based counterarguments to diffuse them. An online search of grey literature, media and public health information sources was conducted to identify common obesity myths. A list of 10 obesity myths was developed and reviewed by obesity experts and key opinion leaders. Counterarguments were developed using current research evidence and validated by obesity experts. A survey of obesity experts and health professionals was conducted to determine the usability and potential effectiveness of the myth-fact messages to reduce weight bias. A total of 754 individuals responded to the request to complete the survey. Of those who responded, 464 (61.5%) completed the survey. All 10 obesity myths were identified to be deeply pervasive within Canadian healthcare and public domains. Although the myth-fact messages were endorsed, respondents also indicated that they would likely not be sufficient to reduce weight bias. Diffusing deeply pervasive obesity myths will require multilevel approaches. PMID- 25826776 TI - Synthesis and characterization of bis (acetylacetonato kappa-O, O') [zinc(ii)/copper(ii)] hybrid organic-inorganic complexes as solid metal organic precursors. AB - We have synthesized novel metal organic hybrid mixed compounds of bis (acetylacetonato kappa-O, O') [zinc(ii)/copper(ii)]. Taking C10H14O4Zn0.7Cu0.3 (Z0.7C0.3AA) as an example, the crystals are composed of Z0.7C0.3AA units and uncoordinated water molecules. Single-crystal X-ray diffraction results show that the complex Z0.7C0.3AA crystallizes in the monoclinic system, space group P21/n. The unit cell dimensions are a = 10.329(4) A, b = 4.6947(18) A, and c = 11.369(4) A; the angles are alpha = 90 degrees , beta = 91.881(6) degrees , and gamma = 90 degrees , the volume is 551.0(4) A(3), and Z = 2. In this process, the M(ii) ions of Zn and Cu mix and occupy the centers of symmetrical structural units, which are coordinated to two ligands. The measured bond lengths and angles of O-M-O vary with the ratio of metal species over the entire series of the complexes synthesized. The chemistry of the as-synthesized compounds has been characterized using infrared spectroscopy, mass spectroscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy analysis, and the morphology of the products has been characterized using scanning electron microscopy. The thermal decomposition of the Z0.7C0.3AA composites measured by thermogravimetric analysis suggests that these complexes are volatile. The thermal characteristics of these complexes make them attractive precursors for metal organic chemical vapor deposition. PMID- 25826777 TI - New Insights In Intestinal Sar1B GTPase Regulation and Role in Cholesterol Homeostasis. AB - Sar1B GTPase is a key component of Coat protein complex II (COPII)-coated vesicles that bud from the endoplasmic reticulum to export newly synthesized proteins. The aims of this study were to determine whether Sar1B responds to lipid regulation and to evaluate its role in cholesterol (CHOL) homeostasis. The influence of lipids on Sar1B protein expression was analyzed in Caco-2/15 cells by Western blot. Our results showed that the presence of CHOL (200 MUM) and oleic acid (0.5 mM), bound to albumin, increases Sar1B protein expression. Similarly, supplementation of the medium with micelles composed of taurocholate with monooleylglycerol or oleic acid also stimulated Sar1B expression, but the addition of CHOL (200 MUM) to micelle content did not modify its regulation. On the other hand, overexpression of Sar1B impacted on CHOL transport and metabolism in view of the reduced cellular CHOL content along with elevated secretion when incubated with oleic acid-containing micelles for 24 h, thereby disclosing induced CHOL transport. This was accompanied with higher secretion of free- and esterified-CHOL within chylomicrons, which was not the case when oleic acid was replaced with monooleylglycerol or when albumin-bound CHOL was given alone. The aforementioned cellular CHOL depletion was accompanied with a low phosphorylated/non phosphorylated HMG-CoA reductase ratio, indicating elevated enzymatic activity. Combination of Sar1B overexpression with micelle incubation led to reduction in intestinal CHOL transporters (NPC1L1, SR-BI) and metabolic regulators (PCSK9 and LDLR). The present work showed that Sar1B is regulated in a time- and concentration-dependent manner by dietary lipids, suggesting an adaptation to alimentary lipid flux. Our data also suggest that Sar1B overexpression contributes to regulation of CHOL transport and metabolism by facilitating rapid uptake and transport of CHOL. PMID- 25826779 TI - CecropinXJ inhibits the proliferation of human gastric cancer BGC823 cells and induces cell death in vitro and in vivo. AB - We have shown that an antimicrobial peptide (AMP) cecropinXJ isolated from the larvae of Bombyx mori selectively inhibits the proliferation of cancer cells. However, the mechanism remains to be determined. In the present study, we examined the antitumor activity of cecropinXJ against human gastric cancer BGC823 cells and explored the mechanism. The results showed that cecropinXJ inhibited the growth of gastric cancer BGC823 cells in vitro and in vivo. MTT and colony formation assays indicated that cecropinXJ suppressed cell proliferation and reduced colony formation of BGC823 cells in a dose- and time-dependent manner, but without inhibitory effect on normal gastric epithelia GES-1 cells. S-phase arrest in BGC823 cells was observed after treatment with cecropinXJ. Annexin V/PI staining suggested that cecropinXJ induced both early and late phases of apoptosis through activation of mitochondrial-mediated caspase pathway, upregulation of Bax expression and downregulation of Bcl-2 expression. Additionally, cecropinXJ treatment increased reactive oxygen species (ROS) production, disrupted the mitochondrial membrane potential (Deltapsim) and led to release of cytochrome c. Importantly, in vivo study showed that cecropinXJ significantly prevented the growth of xenograft tumor in the BGC823-bearing mice, possibly mediated by the induction of apoptosis and inhibition of angiogenesis. These results suggest that cecropinXJ may be a promising therapeutic candidate for the treatment of gastric cancer. PMID- 25826778 TI - Diagnostic accuracy of placental growth factor and ultrasound parameters to predict the small-for-gestational-age infant in women presenting with reduced symphysis-fundus height. AB - OBJECTIVES: To assess the diagnostic accuracy of placental growth factor (PlGF) and ultrasound parameters to predict delivery of a small-for-gestational-age (SGA) infant in women presenting with reduced symphysis-fundus height (SFH). METHODS: This was a multicenter prospective observational study recruiting 601 women with a singleton pregnancy and reduced SFH between 24 and 37 weeks' gestation across 11 sites in the UK and Canada. Plasma PlGF concentration < 5(th) centile, estimated fetal weight (EFW) < 10(th) centile, umbilical artery Doppler pulsatility index > 95(th) centile and oligohydramnios (amniotic fluid index < 5 cm) were compared as predictors for a SGA infant < 3(rd) customized birth-weight centile and adverse perinatal outcome. Test performance statistics were calculated for all parameters in isolation and in combination. RESULTS: Of the 601 women recruited, 592 were analyzed. For predicting delivery of SGA < 3(rd) centile (n = 78), EFW < 10(th) centile had 58% sensitivity (95% CI, 46-69%) and 93% negative predictive value (NPV) (95% CI, 90-95%), PlGF had 37% sensitivity (95% CI, 27-49%) and 90% NPV (95% CI, 87-93%); in combination, PlGF and EFW < 10(th) centile had 69% sensitivity (95% CI, 55-81%) and 93% NPV (95% CI, 89-96%). The equivalent receiver-operating characteristics (ROC) curve areas were 0.79 (95% CI, 0.74-0.84) for EFW < 10(th) centile, 0.70 (95% CI, 0.63-0.77) for low PlGF and 0.82 (95% CI, 0.77-0.86) in combination. CONCLUSIONS: For women presenting with reduced SFH, ultrasound parameters had modest test performance for predicting delivery of SGA < 3(rd) centile. PlGF performed no better than EFW < 10(th) centile in determining delivery of a SGA infant. PMID- 25826780 TI - MicroRNA profiling of CD3+ CD56+ cytokine-induced killer cells. AB - Studies have proven that IL-2 and IL-15 showed contrasting roles during CIK cells preparation. By employing microarray, we analyzed miRNA expression profiles of PBMC, CIKIL-2 and CIKIL-15. Advanced bioinformatic analyses were performed to explore the key miRNAs which may regulate cell proliferation and anti-tumor activity of CIK. We identified 261 differentially expressed miRNAs (DEMs) between PBMC and CIKIL-2, and 249 DEMs between PBMC and CIKIL-15. MiR-143-3p/miR-145-5p was miRNA cluster which may positively regulate cell proliferation. In contrast, miR-340-5p/miR-340-3p cluster may negatively regulate cell proliferation via induction apoptosis, which may cause decreased cell proliferation capacity of CIKIL-2. MiRNA-target interaction analysis indicated that 10 co-downregulated miRNAs may synergistically turn on the expression of a pool of tumor cytotoxic genes in CIK cells. The DEMs between CIKIL-2 and CIKIL-15 may contribute to enhanced tumor cytotoxic capacity of CIKIL-2. Importantly, we found that repressed miR-193a-5p may regulate the expressions of inhibitory receptor KLRD1. The results of the validation assay have shown that KLRD1 were upregulated in CIK cells. Our findings have provided new insights into mechanisms of CIK cells production and tumor cytotoxic function, and shed light on their safety for clinical trial. PMID- 25826781 TI - Magnetic multiwall carbon nanotubes modified with dual hydroxy functional ionic liquid for the solid-phase extraction of protein. AB - A novel adsorbent based on silica-coated magnetic multiwall carbon nanotubes (MWCNTs) surface modified by dual hydroxy functional ionic liquid (FIL) ([OH]-FIL m-MWCNTs@SiO2) has been designed and used for the purification of lysozyme (Lys) by magnetic solid-phase extraction (MSPE). Fourier transform infrared spectroscopy (FTIR), a vibrating sample magnetometer (VSM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and thermogravimetric analysis (TGA) were employed to characterize [OH]-FIL-m-MWCNTs@SiO2. After extraction, the concentration of Lys was determined by a UV-Vis spectrophotometer at 278 nm. A series of single-factor experiments were carried out to identify the optimal conditions of the extraction and the extraction amount could reach up to 94.6 mg g(-1). The RSD of the precision, the repeatability and the stability experiments were 0.37% (n = 3), 0.47% (n = 3) and 0.52% (n = 3), respectively. Comparison of [OH]-FIL-m-MWCNTs@SiO2 with silica-coated magnetic Fe3O4 (Fe3O4@SiO2), silica coated magnetic multiwall carbon nanotubes (m-MWCNTs@SiO2) and alkyl quaternary ammonium ionic liquid-modified on m-MWCNTs@SiO2 was carried out by extracting Lys. The extraction of bovine serum albumin (BSA), trypsin (Try) and ovalbumin (OVA) was also done by the proposed method. Desorption of Lys was carried out by 0.005 mol L(-1) Na2HPO4-1 mol L(-1) NaCl as the eluent solution and the desorption ratio reached 91.6%. Nearly 97.8% of the [OH]-FIL-m-MWCNTs@SiO2 could be recovered from each run, and the extraction amount decreased less after five runs. The circular dichroism spectral experiment analysis indicated that the secondary structure of Lys was unchanged after extraction. PMID- 25826782 TI - Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure. AB - Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal-associated membrane protein type 2 (LAMP-2). Emerging evidence has highlighted the importance of autophagy in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. To investigate the molecular mechanisms responsible for Danon disease, we created induced pluripotent stem cells (iPSCs) from two patients with different LAMP-2 mutations. Danon iPSC-derived cardiomyocytes (iPSC-CMs) exhibited impaired autophagic flux and key features of heart failure such as increased cell size, increased expression of natriuretic peptides, and abnormal calcium handling compared to control iPSC-CMs. Additionally, Danon iPSC-CMs demonstrated excessive amounts of mitochondrial oxidative stress and apoptosis. Using the sulfhydryl antioxidant N-acetylcysteine to scavenge free radicals resulted in a significant reduction in apoptotic cell death in Danon iPSC-CMs. In summary, we have modeled Danon disease using human iPSC-CMs from patients with mutations in LAMP-2, allowing us to gain mechanistic insight into the pathogenesis of this disease. We demonstrate that LAMP-2 deficiency leads to an impairment in autophagic flux, which results in excessive oxidative stress, and subsequent cardiomyocyte apoptosis. Scavenging excessive free radicals with antioxidants may be beneficial for patients with Danon disease. In vivo studies will be necessary to validate this new treatment strategy. PMID- 25826783 TI - Nisin production of Lactococcus lactis N8 with hemin-stimulated cell respiration in fed-batch fermentation system. AB - In this study, nisin production of Lactococcus lactis N8 was optimized by independent variables of glucose, hemin and oxygen concentrations in fed-batch fermentation in which respiration of cells was stimulated with hemin. Response surface model was able to explain the changes of the nisin production of L. lactis N8 in fed-batch fermentation system with high fidelity (R(2) 98%) and insignificant lack of fit. Accordingly, the equation developed indicated the optimum parameters for glucose, hemin, and dissolved oxygen were 8 g L(-1) h(-1) , 3 MUg mL(-1) and 40%, respectively. While 1711 IU mL(-1) nisin was produced by L. lactis N8 in control fed-batch fermentation, 5410 IU mL(-1) nisin production was achieved within the relevant optimum parameters where the respiration of cell was stimulated with hemin. Accordingly, nisin production was enhanced 3.1 fold in fed-batch fermentation using hemin. In conclusion the nisin production of L. lactis N8 was enhanced extensively as a result of increasing the biomass by stimulating the cell respiration with adding the hemin in the fed-batch fermentation. PMID- 25826784 TI - Simple "on-demand" production of bioactive natural products. AB - Exchange of the native promoter to the arabinose-inducible promoter PBAD was established in entomopathogenic bacteria to silence and/or activate gene clusters involved in natural product biosynthesis. This allowed the "on-demand" production of GameXPeptides, xenoamicins, and the blue pigment indigoidine. The gene clusters for the novel "mevalagmapeptides" and the highly toxic xenorhabdins were identified by this approach. PMID- 25826785 TI - Synthesis of photochromic oligophenylenimines: optical and computational studies. AB - Phenyleneimine oligomers 4,4'-(((1E,1'E)-(((1E,1'E)-(1,4-phenylenebis (azanylylidene))bis(methanylylidene))bis(2,5-bis(octyloxy)-4,1 phenylene))bis(methanylyl-idene))-bis(azanylylidene))dianiline (OIC1MS) and 7,7' (((1E,1'E)-(((1E,1'E)-((9H-fluorene-2,7 diyl)bis(azanylylidene))bis(methanylylidene))bis(2,5-bis(octyloxy) 4,1phenylene))bis- (methanylylidene))bis(azanylylidene))bis(9H-fluoren-2-amine) (OIC2MS) were prepared by means of conventional and mechanochemical synthesis and characterized by FT-IR, 1H- and 13C-NMR techniques. The optical properties of the compounds were studied in solution by using UV-visible spectroscopy, and the optical effects were analyzed as a function of solvent. The results show that OIC2MS exhibits interesting photochromic properties. Furthermore, the structural and electronic properties of the compounds were analyzed by TD-DFT. It was found that the mechanosynthesis is an efficient method for the synthesis of both tetraimines. PMID- 25826786 TI - Cytoprotective effect of hispidin against palmitate-induced lipotoxicity in C2C12 myotubes. AB - It is well known that Phellinus linteus, which produces hispidin and its derivatives, possesses antioxidant activities. In this study, we investigated whether hispidin has protective effects on palmitate-induced oxidative stress in C2C12 skeletal muscle cells. Our results showed that palmitate treatment in C2C12 myotubes increased ROS generation and cell death as compared with the control. However, pretreatment of hispidin for 8 h improved the survival of C2C12 myotubes against palmitate-induced oxidative stress via inhibition of intracellular ROS production. Hispidin also inhibited palmitate-induced apoptotic nuclear condensation in C2C12 myotubes. In addition, we found that hispidin can suppress cleavage of caspase-3, expression of Bax, and NF-kappaB translocation. Therefore, these results suggest that hispidin is capable of protecting C2C12 myotubes against palmitate-induced oxidative stress. PMID- 25826787 TI - Stevia rebaudiana Bert. leaf extracts as a multifunctional source of natural antioxidants. AB - The aim of the presented study was to characterize the content and biological activity of extracts prepared from dried Stevia rebaudiana leaves with potential application in the food or cosmetic industry. Aqueous (A), ethanolic (E) and glycol-aqueous (GA) extracts were analyzed for the content of polyphenols and proteins, showing that the highest amount of phenols (15.50 mg/g) and flavonoids (3.85 mg/g) contained GA. All extracts contained significant amount of protein (69.40-374.67 mg/g). Between analyzed stevia extracts (HPLC) GA contained the highest amount of polyphenols, especially ferulic (5.50 mg/g) and rozmaric (4.95 mg/g) acids derivates. The highest antiradical activity against DPPH* and ABTS*+ was noted for GA and E (IC50 = 0.38 and 0.71 ug flavonoids/mL). The highest ability to chelate Fe2+ was observed for E (IC50 = 2.08 ug flavonoids/mL). Stevia extracts were also analyzed for their cytotoxicity and fibroblast irritation potential in vitro. E and GA were the most cytotoxic and irritating, probably due to the high content of biologically active phytochemicals. On the other hand, a extract was the most tolerable by the cells. To summarize, the presented study evaluated the potential application of A, E and GA stevia extracts as natural source of antioxidants in the food and cosmetic industry. PMID- 25826788 TI - Functional thermoplastic materials from derivatives of cellulose and related structural polysaccharides. AB - This review surveys advances in the development of various material functionalities based on thermoplastic cellulose and related structural polysaccharide derivatives. First, the dependence of thermal (phase) transition behavior on the molecular composition of simple derivatives is rationalized. Next, approaches enabling effective thermoplasticization and further incorporation of material functionalities into structural polysaccharides are discussed. These approaches include: (a) single-substituent derivatization, (b) derivatization with multi-substituents, (c) blending of simple derivatives with synthetic polymers, and (d) graft copolymerization. Some examples addressing the control of supramolecular structures and the regulation of molecular and segmental orientations for functional materials fabrication, which have especially progressed over the past decade, are also addressed. Attractive material functions include improved mechanical performance, controlled biodegradability, cytocompatiblity, and optical functions. PMID- 25826789 TI - Tetrazolium compounds: synthesis and applications in medicine. AB - Tetrazoles represent a class of five-membered heterocyclic compounds with polynitrogen electron-rich planar structural features. This special structure makes tetrazole derivatives useful drugs, explosives, and other functional materials with a wide range of applications in many fields of medicine, agriculture, material science, etc. Based on our research works on azoles and other references in recent years, this review covers reported work on the synthesis and biological activities of tetrazole derivatives. PMID- 25826790 TI - Nonlinear optical properties tuning in meso-tetraphenylporphyrin derivatives substituted with donor/acceptor groups in picosecond and nanosecond regimes. AB - meso-Tetraphenylporphyrin (TPP) and its two substituted derivatives (meso tetrakis(4-cyanophenyl)porphyrin [TPP(CN)4] and meso-tetrakis(4 methoxyphenyl)porphyrin [TPP(OMe)4]) were synthesized. Their nonlinear absorption and refraction properties were studied using the Z-scan technique in the picosecond (ps) and nanosecond (ns) regimes. The open aperture Z-scan results reveal that TPP and TPP(CN)4 display an identical reverse saturable absorption (RSA) character in the ps and ns regimes. While TPP(OMe)4 exhibits a transition from saturable absorption (SA) to RSA in the ps regime and a typical RSA character in the ns regime. The closed aperture Z-scan results show that TPP(CN)4 and TPP(OMe)4 have regular enhancement of the magnitude of nonlinear refraction as compared to their parent TPP in both the ps and ns regimes. In addition, the second-order molecular hyperpolarizabilities (gamma) of these three porphyrins are calculated, and the gamma values of TPP(CN)4 and TPP(OMe)4 are remarkable larger than that of TPP. The introduction of the electron-withdrawing group CN and the electron-donating group OMe into TPP has enhanced its nonlinear refraction and gamma value, and tuned its nonlinear absorption (TPP(OMe)4), which could be useful for porphyrin-related applications based on the desired NLO properties. PMID- 25826791 TI - A review of national health policies and professional guidelines on maternal obesity and weight gain in pregnancy. AB - Maternal obesity creates an additional demand for health-care services, as the routine obstetric care pathway requires alterations to ensure the most optimal care for obese women of childbearing age. This review examines the extent to which relevant national health documents reflect and respond to the health implications of maternal obesity and excessive gestational weight gain. A targeted search of peer-reviewed publications and grey literature was conducted for each country to identify national health documents, which were subsequently content analyzed according to an adapted framework. A total of 37 documents were identified, including one policy, 10 strategies and 26 guidelines, published within the last 10 years. Out of the 31 countries investigated, only 13 countries address maternal obesity while none address excessive gestational weight gain. We found inconsistencies and gaps in the recommendations to health-care service providers for the management of maternal obesity and weight gain in pregnancy. The findings show that only limited guidance on maternal obesity and gestational weight gain exists. The authors recommend that international, evidence-based guidelines on the management of maternal obesity and excessive gestational weight gain should be developed to reduce the associated health-care and economic costs. PMID- 25826792 TI - New molecular targets in the pathophysiology of obesity and available treatment options under investigation. AB - The pharmacotherapy of obesity has historically recorded an overall poor safety and efficacy profile largely because of the complex mechanisms involved in the pathophysiology of obesity. It is hoped that a better understanding of the regulation of body weight will lead us to the development of effective and safer drugs. Recent advances in our understanding of the regulation of energy homeostasis has allowed the design of novel anti-obesity drugs targeting specific molecules crucial for the modulation of energy balance, including drugs that induce satiety, modulate nutrient absorption or influence metabolism or lipogenesis. Almost a decade after the Food and Drug Administration approved the first weight loss medication, it recently approved two novel anti-obesity drugs Belviq (lorcaserin) and Qsymia (topiramate and phentermine), thus signalling the beginning of a new era in the pharmacotherapy of obesity. It is believed that the next generation of weight-loss drugs will be based on combination treatments with gut hormones in a manner that mimics the changes underlying surgically induced weight loss thus introducing the so called 'bariatric pharmacotherapy'. An in depth understanding of the interrelated physiological and behavioural effects of these new molecules together with the development of new treatment paradigms is needed so that future disappointments in the field of obesity pharmacotherapy may be avoided. PMID- 25826793 TI - The efficacy of 12 weeks supervised exercise in obesity management. AB - The objective of this randomized controlled trial was to investigate the effect of adding either aerobic training (AT) or resistance training (RT) to a multidisciplinary teamed (MDT) educational weight management programme on the health-related fitness of morbidly obese individuals. Males (n = 9) and females (n = 24) aged between 24 and 68 years with a body mass index (BMI) of >=40 kg m(2) (>=35 kg m(2) with comorbidities) undertaking a weight management programme were recruited (Completion: M = 8, F = 19). Participants were randomly allocated to either AT (n = 12), RT (n = 11) or CON (n = 10). AT and RT undertook three structured ~60 min moderate intensity sessions weekly, two supervised gym-based and one structured home-based session for 12 weeks; CON undertook usual care alone. Anthropometric, psychological and functional capacity measures were obtained pre- and post-intervention. Both exercise interventions elicited improvements compared with CON in the: shuttle walk test (AT [Delta 207.0 +/- 123.0 metres, 68.0%, P = 0.04], RT [Delta 165.0 +/- 183.3 m, 48.8%, P = 0.06], CON [Delta -14.3 +/- 38.7 m, -6.2%]), triceps skin-fold (P <= 0.001), self efficacy (P = 0.005) and interest/enjoyment (P = 0.006). RT displayed additional improvements compared with CON in BMI (RT [Delta -1.02 +/- 0.91 kg.m(2) , -2.5%, P = 0.033], AT [Delta -1.84 +/- 2.70 kg.m(2) , -4.3%, P = 0.142], CON [Delta 0.31 +/- 1.47 kg.m(2) , -0.6%]), waist circumference (P = 0.022), competence (P = 0.019), biceps skin-fold (P = 0.012) and medial calf skin-fold (P = 0.013). No significant differences were observed between exercise modalities. Regardless of exercise mode, the addition of supervised and structured exercise to a MDT weight management programme significantly improved anthropometric, functional and psychological measures in obese participants with a BMI of >=35 kg.m(2) . PMID- 25826794 TI - Correlates of food addiction in obese individuals seeking bariatric surgery. AB - Recent evidence suggests that palatable, high-calorie foods may have an addictive potential. Accordingly, obesity and overconsumption of such foods have been associated with addiction-like eating behaviour. The present study investigated whether individuals with obesity can be classified as food-addicted and which factors would differentiate between food-addicted and non-addicted individuals. We administered the German version of the Yale Food Addiction Scale and other questionnaires to obese individuals seeking bariatric surgery (N = 96). Results showed that 40% of the sample could be diagnosed as food-addicted. Food-addicted individuals reported more frequent food cravings, higher eating disorder psychopathology and more depressive symptoms than the non-addicted group. Age, body mass and gender distribution did not differ between groups. The food addiction group had higher attentional but similar motor and non-planning impulsivity, and had lower scores on the Alcohol Use Disorders Identification Test (AUDIT) compared with the non-addicted group. Scores on the AUDIT were associated with impulsivity in the non-addicted group only. We conclude that the prevalence of food addiction is higher in candidates for bariatric surgery compared with the general population and obese individuals not seeking bariatric surgery. A diagnosis of food addiction is associated with higher eating pathology and depression. Moreover, only attentional impulsivity, but not other dimensions of impulsivity, is associated with addictive eating. Finally, food addiction and impulsivity interactively predicted alcohol use, suggesting a crucial role of psychological variables and eating style in determining alcohol consumption in pre-bariatric patients, independent of body mass. PMID- 25826795 TI - A middle-aged man with increasing body fat. AB - A 51-year-old man was referred for evaluation of gradual increase in body fat over bilateral arms, chest and abdomen for 6 months. He was a non-smoker and he drank at least four bottles of beer daily since the age of 18. There was no significant past medical history or any family history of obesity or endocrine diseases. Physical examination showed localized large bulk of fat over the neck, both arms and mammary regions, abdomen, and back (Figs and ). The lower limbs and buttock were relatively spared. There was telangiectasia over the face and chest wall, but no palmar erythema nor finger clubbing. The liver span was normal, and the spleen tip was palpated 2 cm below the costal margin. Examination of the cardiovascular, respiratory and neurological system was normal. [Figure: see text] [Figure: see text] Blood tests showed thrombocytopenia (platelet 140 * 10(9) L(-1) [normal: 170-380 * 10(9) L(-1) ]) and liver function derangement (bilirubin 27 MUmol L(-1) , ALP 298 U L(-1) , ALT 127 U L(-1) , AST 165 U L(-1) , GGT 1353 U L(-1) , albumin 33 g L(-1) and globulin 42 g L(-1) ). His clotting profile and renal functions were normal. His hepatitis B surface antigen was positive, but his HBV DNA was <60 copies per mL. Fasting glucose was 5.0 mmol L( 1) . HbA1c was 5.6%. His lipid profile was satisfactory with total cholesterol of 2.9 mmol L(-1) , triglycerides 1.0 mmol L(-1) , HDL-C 1.37 mmol L(-1) and LDL-C 1.1 mmol L(-1) . Ultrasound of the abdomen showed normal-sized liver with coarsened liver parenchymal echogenicity. The spleen was enlarged to 14 cm. This middle-aged man suffered from multiple symmetric lipomatosis and alcoholic liver disease. Dual-energy X-ray showed 1746 gm (40.1%), 1498 gm (32.8%) and 8322 gm (26.8%) fat over the left arm, right arm and trunk, respectively. The legs were unaffected with 1703 gm (19.4%) and 1627 gm (17.7%) fat over the left and right sides, respectively. The patient was advised to stop drinking and he declined surgical treatment. PMID- 25826796 TI - Assessing toxicity of copper nanoparticles across five cladoceran species. AB - As a result of ever increasing applications, nanoparticles will eventually end up in the environment. However, currently no common principle has been established to help understand the toxicity of nanoparticles (NPs) across species. Therefore, it is difficult to estimate the potential risks of nanoparticles to untested species in the environment. The authors exposed 4 different sizes of copper nanoparticles (CuNPs) and 1 submicron-sized copper particle to 5 cladoceran species (Daphnia magna, Daphnia pulex, Daphnia galeata, Ceriodaphnia dubia, and Chydorus sphaericus) to investigate whether morphological attributes of species can help to assess the acute toxicity of CuNPs across species. The results showed that rod-shaped CuNPs caused much lower toxicity to all species than spherical CuNPs. Both the particles and ions contributed to the total toxicity of the CuNP suspensions. Moreover, the toxicity caused by particles in 5 different copper suspensions increases with decreasing body length, surface area, and body volume of neonates of 5 cladoceran species. Especially the correlations between body volume of the 5 cladoceran species tested and the corresponding toxicity caused by 5 different CuNPs were statistically significant, and in all cases radj (2) was higher than 0.51 (p < 0.001). The highest correlation was found between body volume and the toxicity of the 78-nm CuNPs (radj (2) = 0.95, p < 0.001). To conclude, the correlations between attributes of cladoceran species and the toxicity of CuNPs reported in the present study evoke the possibility to assess and extrapolate the toxicity of nanoparticles across species with similar attributes. PMID- 25826797 TI - Prediction of small-for-gestational-age neonates: screening by maternal biochemical markers at 30-34 weeks. AB - OBJECTIVE: To investigate the potential value of serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (beta-hCG) and alpha fetoprotein (AFP) at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in singleton pregnancies at 30-34 weeks' gestation, including 490 that delivered SGA neonates and 9360 cases that were unaffected by SGA, PE or gestational hypertension (normal outcome). Multivariable logistic regression analysis was used to determine if screening by serum PlGF, sFlt-1, PAPP-A, free beta-hCG and AFP, individually or in combination, improved the prediction of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. RESULTS: Compared to the normal group, the mean log10 multiples of the median (MoM) values of PlGF and AFP were significantly lower and the mean log10 MoM values of sFlt-1 and free beta-hCG were significantly higher in the SGA group with a birth weight < 5(th) percentile (SGA < 5(th)) delivering < 5 weeks following assessment. The best model for prediction of SGA was provided by a combination of maternal factors, EFW and serum PlGF. Such combined screening, predicted, at a 10% false-positive rate, 85%, 93% and 92% of SGA neonates delivering < 5 weeks following assessment with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively; the respective detection rates of combined screening for SGA neonates delivering >= 5 weeks following assessment were 57%, 64% and 71%. CONCLUSION: Combined screening by maternal factors, EFW and serum PlGF at 30-34 weeks' gestation can identify a high proportion of pregnancies that subsequently deliver SGA neonates. PMID- 25826798 TI - Large-scale chemical similarity networks for target profiling of compounds identified in cell-based chemical screens. AB - Target identification is one of the most critical steps following cell-based phenotypic chemical screens aimed at identifying compounds with potential uses in cell biology and for developing novel disease therapies. Current in silico target identification methods, including chemical similarity database searches, are limited to single or sequential ligand analysis that have limited capabilities for accurate deconvolution of a large number of compounds with diverse chemical structures. Here, we present CSNAP (Chemical Similarity Network Analysis Pulldown), a new computational target identification method that utilizes chemical similarity networks for large-scale chemotype (consensus chemical pattern) recognition and drug target profiling. Our benchmark study showed that CSNAP can achieve an overall higher accuracy (>80%) of target prediction with respect to representative chemotypes in large (>200) compound sets, in comparison to the SEA approach (60-70%). Additionally, CSNAP is capable of integrating with biological knowledge-based databases (Uniprot, GO) and high-throughput biology platforms (proteomic, genetic, etc) for system-wise drug target validation. To demonstrate the utility of the CSNAP approach, we combined CSNAP's target prediction with experimental ligand evaluation to identify the major mitotic targets of hit compounds from a cell-based chemical screen and we highlight novel compounds targeting microtubules, an important cancer therapeutic target. The CSNAP method is freely available and can be accessed from the CSNAP web server (http://services.mbi.ucla.edu/CSNAP/). PMID- 25826799 TI - Biocatalytic synthesis of C3 chiral building blocks by chloroperoxidase-catalyzed enantioselective halo-hydroxylation and epoxidation in the presence of ionic liquids. AB - The optically active C3 synthetic blocks are remarkably versatile intermediates for the synthesis of numerous pharmaceuticals and agrochemicals. This work provides a simple and efficient enzymatic synthetic route for the environment friendly synthesis of C3 chiral building blocks. Chloroperoxidase (CPO)-catalyzed enantioselective halo-hydroxylation and epoxidation of chloropropene and allyl alcohol was employed to prepare C3 chiral building blocks in this work, including (R)-2,3-dichloro-1-propanol (DCP*), (R)-2,3-epoxy-1-propanol (GLD*), and (R)-3 chloro-1-2-propanediol (CPD*). The ee values of the formed C3 chiral building blocks DCP*, CPD*, and glycidol were 98.1, 97.5, and 96.7%, respectively. Moreover, the use of small amount of imidazolium ionic liquid enhanced the yield efficiently due to the increase of solubility of hydrophobic organic substrates in aqueous reaction media, as well as the improvement of affinity and selectivity of CPO to substrate. PMID- 25826800 TI - Hashing on nonlinear manifolds. AB - Learning-based hashing methods have attracted considerable attention due to their ability to greatly increase the scale at which existing algorithms may operate. Most of these methods are designed to generate binary codes preserving the Euclidean similarity in the original space. Manifold learning techniques, in contrast, are better able to model the intrinsic structure embedded in the original high-dimensional data. The complexities of these models, and the problems with out-of-sample data, have previously rendered them unsuitable for application to large-scale embedding, however. In this paper, how to learn compact binary embeddings on their intrinsic manifolds is considered. In order to address the above-mentioned difficulties, an efficient, inductive solution to the out-of-sample data problem, and a process by which nonparametric manifold learning may be used as the basis of a hashing method are proposed. The proposed approach thus allows the development of a range of new hashing techniques exploiting the flexibility of the wide variety of manifold learning approaches available. It is particularly shown that hashing on the basis of t-distributed stochastic neighbor embedding outperforms state-of-the-art hashing methods on large-scale benchmark data sets, and is very effective for image classification with very short code lengths. It is shown that the proposed framework can be further improved, for example, by minimizing the quantization error with learned orthogonal rotations without much computation overhead. In addition, a supervised inductive manifold hashing framework is developed by incorporating the label information, which is shown to greatly advance the semantic retrieval performance. PMID- 25826801 TI - Estimation of illuminants from projections on the Planckian locus. AB - This paper introduces a new approach for the automatic estimation of illuminants in a digital color image. The method relies on two assumptions. First, the image is supposed to contain at least a small set of achromatic pixels. The second assumption is physical and concerns the set of possible illuminants, assumed to be well approximated by black body radiators. The proposed scheme is based on a projection of selected pixels on the Planckian locus in a well chosen chromaticity space, followed by a voting procedure yielding the estimation of the illuminant. This approach is very simple and learning-free. The voting procedure can be extended for the detection of multiple illuminants when necessary. Experiments on various databases show that the performances of this approach are similar to those of the best learning-based state-of-the-art algorithms. PMID- 25826803 TI - A No-Reference Texture Regularity Metric Based on Visual Saliency. AB - This paper presents a no-reference perceptual metric that quantifies the degree of perceived regularity in textures. The metric is based on the similarity of visual attention (VA) of the textural primitives and the periodic spatial distribution of foveated fixation regions throughout the image. A ground-truth eye-tracking database for textures is also generated as part of this paper and is used to evaluate the performance of the most popular VA models. Using the saliency map generated by the best VA model, the proposed texture regularity metric is computed. It is shown through subjective testing that the proposed metric has a strong correlation with the mean opinion score for the perceived regularity of textures. The proposed texture regularity metric can be used to improve the quality and performance of many image processing applications like texture synthesis, texture compression, and content-based image retrieval. PMID- 25826802 TI - Patient Registration Using Intraoperative Stereovision in Image-guided Open Spinal Surgery. AB - Despite its widespread availability and success in open cranial neurosurgery, image-guidance technology remains more limited in use in open spinal procedures, in large part, because of patient registration challenges. In this study, we evaluated the feasibility of using intraoperative stereovision (iSV) for accurate, efficient, and robust patient registration in an open spinal fusion surgery. Geometrical surfaces of exposed vertebrae were first reconstructed from iSV. A classical multistart registration was then executed between point clouds generated from iSV and preoperative computed tomography images of the spine. With two pairs of feature points manually identified to facilitate the registration, an average registration accuracy of 1.43 mm in terms of surface-to-surface distance error was achieved in eight patient cases using a single iSV image pair sampling 2-3 vertebral segments. The iSV registration error was consistently smaller than the conventional landmark approach for every case (average of 2.02 mm with the same error metric). The large capture ranges (average of 23.8 mm in translation and 46.0 degrees in rotation) found in the iSV patient registration suggest the technique may offer sufficient robustness for practical application in the operating room. Although some manual effort was still necessary, the manually-derived inputs for iSV registration only needed to be approximate as opposed to be precise and accurate for the manual efforts required in landmark registration. The total computational cost of the iSV registration was 1.5 min on average, significantly less than the typical ~30 min required for the landmark approach. These findings support the clinical feasibility of iSV to offer accurate, efficient, and robust patient registration in open spinal surgery, and therefore, its potential to further increase the adoption of image guidance in this surgical specialty. PMID- 25826804 TI - Machine learning-based coding unit depth decisions for flexible complexity allocation in high efficiency video coding. AB - In this paper, we propose a machine learning-based fast coding unit (CU) depth decision method for High Efficiency Video Coding (HEVC), which optimizes the complexity allocation at CU level with given rate-distortion (RD) cost constraints. First, we analyze quad-tree CU depth decision process in HEVC and model it as a three-level of hierarchical binary decision problem. Second, a flexible CU depth decision structure is presented, which allows the performances of each CU depth decision be smoothly transferred between the coding complexity and RD performance. Then, a three-output joint classifier consists of multiple binary classifiers with different parameters is designed to control the risk of false prediction. Finally, a sophisticated RD-complexity model is derived to determine the optimal parameters for the joint classifier, which is capable of minimizing the complexity in each CU depth at given RD degradation constraints. Comparative experiments over various sequences show that the proposed CU depth decision algorithm can reduce the computational complexity from 28.82% to 70.93%, and 51.45% on average when compared with the original HEVC test model. The Bjontegaard delta peak signal-to-noise ratio and Bjontegaard delta bit rate are 0.061 dB and 1.98% on average, which is negligible. The overall performance of the proposed algorithm outperforms those of the state-of-the-art schemes. PMID- 25826805 TI - Modeling neuron selectivity over simple midlevel features for image classification. AB - We now know that good mid-level features can greatly enhance the performance of image classification, but how to efficiently learn the image features is still an open question. In this paper, we present an efficient unsupervised midlevel feature learning approach (MidFea), which only involves simple operations, such as k-means clustering, convolution, pooling, vector quantization, and random projection. We show this simple feature can also achieve good performance in traditional classification task. To further boost the performance, we model the neuron selectivity (NS) principle by building an additional layer over the midlevel features prior to the classifier. The NS-layer learns category-specific neurons in a supervised manner with both bottom-up inference and top-down analysis, and thus supports fast inference for a query image. Through extensive experiments, we demonstrate that this higher level NS-layer notably improves the classification accuracy with our simple MidFea, achieving comparable performances for face recognition, gender classification, age estimation, and object categorization. In particular, our approach runs faster in inference by an order of magnitude than sparse coding-based feature learning methods. As a conclusion, we argue that not only do carefully learned features (MidFea) bring improved performance, but also a sophisticated mechanism (NS-layer) at higher level boosts the performance further. PMID- 25826806 TI - Blind inpainting using l0 and total variation regularization. AB - In this paper, we address the problem of image reconstruction with missing pixels or corrupted with impulse noise, when the locations of the corrupted pixels are not known. A logarithmic transformation is applied to convert the multiplication between the image and binary mask into an additive problem. The image and mask terms are then estimated iteratively with total variation regularization applied on the image, and l0 regularization on the mask term which imposes sparseness on the support set of the missing pixels. The resulting alternating minimization scheme simultaneously estimates the image and mask, in the same iterative process. The logarithmic transformation also allows the method to be extended to the Rayleigh multiplicative and Poisson observation models. The method can also be extended to impulse noise removal by relaxing the regularizer from the l0 norm to the l1 norm. Experimental results show that the proposed method can deal with a larger fraction of missing pixels than two phase methods, which first estimate the mask and then reconstruct the image. PMID- 25826807 TI - Detection of and Compensation for EMG Disturbances for Powered Lower Limb Prosthesis Control. AB - Myoelectric pattern recognition algorithms have been proposed for the control of powered lower limb prostheses, but electromyography (EMG) signal disturbances remain an obstacle to clinical implementation. To address this problem, we used a log-likelihood metric to detect simulated EMG disturbances and real disturbances acquired from EMG containing electrode shift. We found that features extracted from disturbed EMG have much lower log likelihoods than those from undisturbed signals and can be detected using a single threshold acquired from the training data. We designed a linear discriminant analysis (LDA) classifier that uses the log likelihood to decide between using a combination of EMG and mechanical sensors and using mechanical sensors only, to predict locomotion modes. When EMG contained disturbances, our classifier detected those disturbances and disregarded EMG data. Our classifier had significantly lower errors than a standard LDA classifier in the presence of EMG disturbances. The log-likelihood classifier had a low false positive threshold, and thus did not perform significantly differently from the standard LDA classifier when EMG did not contain disturbances. The log-likelihood threshold could also be applied to individual EMG channels, enabling specific channels containing EMG disturbances to be appropriately ignored when making locomotion mode predictions. PMID- 25826808 TI - A Power-Efficient Capacitive Read-Out Circuit With Parasitic-Cancellation for MEMS Cochlea Sensors. AB - This paper proposes a solution for signal read-out in the MEMS cochlea sensors that have very small sensing capacitance and do not have differential sensing structures. The key challenge in such sensors is the significant signal degradation caused by the parasitic capacitance at the MEMS-CMOS interface. Therefore, a novel capacitive read-out circuit with parasitic-cancellation mechanism is developed; the equivalent input capacitance of the circuit is negative and can be adjusted to cancel the parasitic capacitance. Chip results prove that the use of parasitic-cancellation is able to increase the sensor sensitivity by 35 dB without consuming any extra power. In general, the circuit follows a low-degradation low-amplification approach which is more power efficient than the traditional high-degradation high-amplification approach; it employs parasitic-cancellation to reduce the signal degradation and therefore a lower gain is required in the amplification stage. Besides, the chopper stabilization technique is employed to effectively reduce the low-frequency circuit noise and DC offsets. As a result of these design considerations, the prototype chip demonstrates the capability of converting a 7.5 fF capacitance change of a 1-Volt-biased 0.5 pF capacitive sensor pair into a 0.745 V signal conditioned output at the cost of only 165.2 MUW power consumption. PMID- 25826809 TI - Learning a Tracking and Estimation Integrated Graphical Model for Human Pose Tracking. AB - We investigate the tracking of 2-D human poses in a video stream to determine the spatial configuration of body parts in each frame, but this is not a trivial task because people may wear different kinds of clothing and may move very quickly and unpredictably. The technology of pose estimation is typically applied, but it ignores the temporal context and cannot provide smooth, reliable tracking results. Therefore, we develop a tracking and estimation integrated model (TEIM) to fully exploit temporal information by integrating pose estimation with visual tracking. However, joint parsing of multiple articulated parts over time is difficult, because a full model with edges capturing all pairwise relationships within and between frames is loopy and intractable. In previous models, approximate inference was usually resorted to, but it cannot promise good results and the computational cost is large. We overcome these problems by exploring the idea of divide and conquer, which decomposes the full model into two much simpler tractable submodels. In addition, a novel two-step iteration strategy is proposed to efficiently conquer the joint parsing problem. Algorithmically, we design TEIM very carefully so that: 1) it enables pose estimation and visual tracking to compensate for each other to achieve desirable tracking results; 2) it is able to deal with the problem of tracking loss; and 3) it only needs past information and is capable of tracking online. Experiments are conducted on two public data sets in the wild with ground truth layout annotations, and the experimental results indicate the effectiveness of the proposed TEIM framework. PMID- 25826810 TI - Shape-Constrained Sparse and Low-Rank Decomposition for Auroral Substorm Detection. AB - An auroral substorm is an important geophysical phenomenon that reflects the interaction between the solar wind and the Earth's magnetosphere. Detecting substorms is of practical significance in order to prevent disruption to communication and global positioning systems. However, existing detection methods can be inaccurate or require time-consuming manual analysis and are therefore impractical for large-scale data sets. In this paper, we propose an automatic auroral substorm detection method based on a shape-constrained sparse and low rank decomposition (SCSLD) framework. Our method automatically detects real substorm onsets in large-scale aurora sequences, which overcomes the limitations of manual detection. To reduce noise interference inherent in current SLD methods, we introduce a shape constraint to force the noise to be assigned to the low-rank part (stationary background), thus ensuring the accuracy of the sparse part (moving object) and improving the performance. Experiments conducted on aurora sequences in solar cycle 23 (1996-2008) show that the proposed SCSLD method achieves good performance for motion analysis of aurora sequences. Moreover, the obtained results are highly consistent with manual analysis, suggesting that the proposed automatic method is useful and effective in practice. PMID- 25826811 TI - A passive biodegradable implant for subcutaneous soft-tissue trauma monitoring. AB - In-body medical devices can play an important role in clinical monitoring and diagnosis of diseases. Wireless devices implanted within a patient have to be physically small, and must overcome the challenges of having a little or no onboard electrical power and the highly attenuating electromagnetic propagation environment which is the human body. In this paper, we investigate the use of biodegradable implant to monitor the healing of soft-tissue trauma and to allow early stage diagnosis of infection. The implantable tag is designed to degrade in a predetermined and controlled method, the stage of which can be measured from outside the body without the need for further surgical intervention. The speed of degradation of the tag depends on the temperature and acidity of the subcutaneous tissue in which the tag is implanted. We show that as the electrical length of the tag pattern increases due to degradation, the resonant frequency changes significantly, and this change in resonant frequency can be detected from outside the patient. Results are presented showing the tag's performance at normal and oblique incidence, and techniques for miniaturizing and enhancing the tag's response sensitivity are given. As the entire tag is biodegradable, there is no need for further postoperative surgery to remove it from the patient at the end of its useful life. PMID- 25826812 TI - A bendable and wearable cardiorespiratory monitoring device fusing two noncontact sensor principles. AB - A mobile device is presented for monitoring both respiration and pulse. The device is developed as a bendable/flexible inlay that can be placed in a shirt pocket or the inside pocket of a jacket. To achieve optimum monitoring performance, the device combines two sensor principles, which work in a safe noncontact way through several layers of cotton or other textiles. One sensor, based on magnetic induction, is intended for respiratory monitoring, and the other is a reflective photoplethysmography sensor intended for pulse detection. Because each sensor signal has some dependence on both physiological parameters, fusing the sensor signals allows enhanced signal coverage. PMID- 25826813 TI - Adaptive Replacement Strategies for MOEA/D. AB - Multiobjective evolutionary algorithms based on decomposition (MOEA/D) decompose a multiobjective optimization problem into a set of simple optimization subproblems and solve them in a collaborative manner. A replacement scheme, which assigns a new solution to a subproblem, plays a key role in balancing diversity and convergence in MOEA/D. This paper proposes a global replacement scheme which assigns a new solution to its most suitable subproblems. We demonstrate that the replacement neighborhood size is critical for population diversity and convergence, and develop an approach for adjusting this size dynamically. A steady-state algorithm and a generational one with this approach have been designed and experimentally studied. The experimental results on a number of test problems have shown that the proposed algorithms have some advantages. PMID- 25826814 TI - Dynamical Behaviors of Multiple Equilibria in Competitive Neural Networks With Discontinuous Nonmonotonic Piecewise Linear Activation Functions. AB - This paper addresses the problem of coexistence and dynamical behaviors of multiple equilibria for competitive neural networks. First, a general class of discontinuous nonmonotonic piecewise linear activation functions is introduced for competitive neural networks. Then based on the fixed point theorem and theory of strict diagonal dominance matrix, it is shown that under some conditions, such n -neuron competitive neural networks can have 5(n) equilibria, among which 3(n) equilibria are locally stable and the others are unstable. More importantly, it is revealed that the neural networks with the discontinuous activation functions introduced in this paper can have both more total equilibria and locally stable equilibria than the ones with other activation functions, such as the continuous Mexican-hat-type activation function and discontinuous two-level activation function. Furthermore, the 3(n) locally stable equilibria given in this paper are located in not only saturated regions, but also unsaturated regions, which is different from the existing results on multistability of neural networks with multiple level activation functions. A simulation example is provided to illustrate and validate the theoretical findings. PMID- 25826815 TI - Learning Trajectories for Robot Programing by Demonstration Using a Coordinated Mixture of Factor Analyzers. AB - This paper presents an approach for learning robust models of humanoid robot trajectories from demonstration. In this formulation, a model of the joint space trajectory is represented as a sequence of motion primitives where a nonlinear dynamical system is learned by constructing a hidden Markov model (HMM) predicting the probability of residing in each motion primitive. With a coordinated mixture of factor analyzers as the emission probability density of the HMM, we are able to synthesize motion from a dynamic system acting along a manifold shared by both demonstrator and robot. This provides significant advantages in model complexity for kinematically redundant robots and can reduce the number of corresponding observations required for further learning. A stability analysis shows that the system is robust to deviations from the expected trajectory as well as transitional motion between manifolds. This approach is demonstrated experimentally by recording human motion with inertial sensors, learning a motion primitive model and correspondence map between the human and robot, and synthesizing motion from the manifold to control a 19 degree of-freedom humanoid robot. PMID- 25826816 TI - Perinatal Exposure to Traffic-Related Air Pollution and Atopy at 1 Year of Age in a Multi-Center Canadian Birth Cohort Study. AB - BACKGROUND: The role of traffic-related air pollution (TRAP) exposure in the development of allergic sensitization in children is unclear, and few birth cohort studies have incorporated spatiotemporal exposure assessment. OBJECTIVES: We aimed to examine the association between TRAP and atopy in 1-year-old children from an ongoing national birth cohort study in four Canadian cities. METHODS: We identified 2,477 children of approximately 1 year of age with assessment of atopy for inhalant (Alternaria, Der p, Der f, cat, dog, cockroach) and food-related (milk, eggs, peanuts, soy) allergens. Exposure to nitrogen dioxide (NO2) was estimated from city-specific land use regression models accounting for residential mobility and temporal variability in ambient concentrations. We used mixed models to examine associations between atopy and exposure during pregnancy and the first year of life, including adjustment for covariates (maternal atopy, socioeconomic status, pets, mold, nutrition). We also conducted analyses stratified by time-location patterns, daycare attendance, and modeled home ventilation. RESULTS: Following spatiotemporal adjustment, TRAP exposure after birth increased the risk for development of atopy to any allergens [adjusted odds ratio (aOR) per 10 MUg/m3 NO2 = 1.16; 95% CI: 1.00, 1.41], but not during pregnancy (aOR = 1.02; 95% CI: 0.86, 1.22). This association was stronger among children not attending daycare (aOR = 1.61; 95% CI: 1.28, 2.01) compared with daycare attendees (aOR = 1.05; 95% CI: 0.81, 1.28). Trends to increased risk were also found for food (aOR = 1.17; 95% CI: 0.95, 1.47) and inhalant allergens (aOR = 1.28; 95% CI: 0.93, 1.76). CONCLUSION: Using refined exposure estimates that incorporated temporal variability and residential mobility, we found that traffic related air pollution during the first year of life was associated with atopy. CITATION: Sbihi H, Allen RW, Becker A, Brook JR, Mandhane P, Scott JA, Sears MR, Subbarao P, Takaro TK, Turvey SE, Brauer M. 2015. Perinatal exposure to traffic related air pollution and atopy at 1 year of age in a multi-center Canadian birth cohort study. Environ Health Perspect 123:902-908; http://dx.doi.org/10.1289/ehp.1408700. PMID- 25826817 TI - [Why publish technical guidelines for the prevention and treatment of chikungunya fever?]. PMID- 25826818 TI - Why I decided to #TakeAIM. PMID- 25826819 TI - Why I decided to #TakeAIM. PMID- 25826820 TI - A recent article regarding the investigation of a patient with polyarthritis. PMID- 25826821 TI - The importance of awareness of best practice when performing a lumbar puncture. PMID- 25826822 TI - Management of pressures associated with surges of respiratory and diarrhoeal illness. PMID- 25826823 TI - [In Process Citation]. PMID- 25826824 TI - [In Process Citation]. PMID- 25826825 TI - [In Process Citation]. PMID- 25826826 TI - [Comments on the article "Systemic loxoscelism presented in a pregnant patient"]. PMID- 25826827 TI - [In Process Citation]. PMID- 25826828 TI - Increased serum asymmetric dimethylarginine level is an independent predictor of contrast-induced nephropathy. PMID- 25826829 TI - Authors reply. PMID- 25826830 TI - The main argument about the etiology of coronary artery ectasia: is it inflammation or not? PMID- 25826831 TI - Startup Iowa plan's collapse raises fears about co-op finances. PMID- 25826832 TI - Medicare penalties begin taking toll. PMID- 25826833 TI - Hospitals buying doc practices may reap tax savings under IRS ruling. PMID- 25826834 TI - Lung CT scan use expected to swell. PMID- 25826835 TI - 2015 brings financial pressures, reform uncertainties. PMID- 25826836 TI - Downward rate pressure...uncertain reform environment...easy lending...more consolidation. PMID- 25826837 TI - ACA coverage expansion at risk...battle against high drug prices...growing government business. PMID- 25826838 TI - Measurement of clinical value...new partnerships with manufacturers...investment in cost-cutting IT tools. PMID- 25826839 TI - Another doc-fix drama...Medicaid pay cuts...new chronic-care management fee. PMID- 25826840 TI - Measuring beyond the hospital...focus on diagnostic errors...improving transparency. PMID- 25826841 TI - Improving interoperability...balancing privacy protections with treatment...scheduled ICD-10 launch...meeting meaningful-use requirements. PMID- 25826842 TI - Few hospital projects...more smaller renovation projects...stand-alone EDs...more value, less luxury. PMID- 25826843 TI - Self-service insurance. Insurers forced to compete harder for self-insured customers. PMID- 25826844 TI - Lessons from Vermont. PMID- 25826845 TI - Medicaid managed-care patients face hurdles in getting care. PMID- 25826847 TI - 'We would argue strongly against anything that rolls back' ACA coverage. PMID- 25826846 TI - Hospital revamp cuts ED wait times. PMID- 25826848 TI - Rewarding quality--the highest- and lowest-scored hospitals. PMID- 25826850 TI - [Current status of dementia in admitions to national leprosariums nationwide]. AB - The purpose of this study was to get an overview of the following aspects of people admitted to 13 national leprosariums in Japan: the prevalence of dementia, medical and nursing systems, and facilities and equipment. Subjects included 1733 people admitted to wards for patients or disabled people in these leprosariums. Subjects were examined for cognitive function using Nishimura's behavioral rating scale for the mental states of the elderly (NMS), and for the prevalence of behavioral and psychological symptoms of dementia (BPSD). We also investigated medical and nursing systems, facilities and equipment, and status of nursing education. The results showed that, 288 subjects (16.6%) had a diagnosis of dementia. According to the NMS, 47.5% of the subjects were categorized as mild to severe dementia, while cognitive dysfunction was observed in 63.5% if borderline cases were included. Non-specialist physicians managed 30.8% of the subjects in 4 institutions, and there were no certified nurses specialized in dementia management. Results from this study suggest that there is need for the placement of dementia specialists', improvement of specialized medical services, and human resource development of specialized nurses in leprosariums where many elderly people live. PMID- 25826849 TI - [Effectiveness of thalidomide for erythema nodosum leprosum (ENL): retrospective study of 20 Japanese cases in National Sanatrium Oku-Komyoen]. AB - Thalidomide is a TNF-alpha inhibitor and has been administrated for erythema nodosum leprosum (ENL, Type II leprosy reaction) which is one of leprosy reactions and can cause serious illness to patients oflepromatous pole among the immune spectrum. Twenty live cases (at May, 2011) were identified to whom thalidomide had been administrated since 1978 for their ENL reactions. Data were collected from their clinical records in order to evaluate the usage and effectiveness of thalidomide in National Sanatorium Oku-Komyoen, Okayama, Setouchi-city, Japan. Individual data includes bacillary index (BI), total dose, average daily dose, maximum daily dose, minimum daily dose, methods of thalidomide administration and change of symptoms of ENL. Results: No adverse effect was found among 20 cases. Average daily dose of 20 cases was 19 mg. Regarding to the maximum daily dose, in 3 cases (15%) more than 100 mg, in 3 cases (15%) 50 mg, and in 14 cases (70%) less than 40 mg was administrated. Dose was gradually tapered in most cases. From clinical records, thalidomide was found effective for ENL in 19 cases and clinicians concerned were trying to adjust the proper dose of the drug carefully depending on the current symptoms, because there was no guideline of thalidomide administration for ENL. This data suggests that even less than 50-100 mg as the initial daily dose was still effective, though 50-100 mg daily dose is recommended in the current guideline of Japan (2011) and more dose had been administrated in USA and India. PMID- 25826851 TI - [Leprosy and human rights: trends in Japan and in the world]. AB - Leprosy, or Hansen's disease, has long been regarded as an incurable and dreadful contagious disease. The patients have been forcefully hospitalized and deprived of many basic human rights. Their family members have often been discriminated against due to stigma associated with this disease. Soon after the Second World War, a specific remedy called "multi-drug therapy" (MDT) was discovered and leprosy became a relatively easily curable disease. Despite this medical development, it took time to change the policy and legislation of forceful hospitalization of leprosy patients. The stigma surrounding leprosy and consequent discrimination have continued. In Japan, it was only in 1996 that the legislation requiring forceful hospitalization of leprosy patients was repealed. The Government decided to provide remedies to the former patients who had suffered from this policy. At the United Nations, the General Assembly adopted a resolution to eradicate discrimination against persons affected by leprosy and their family members. It is hoped that discrimination associated with Hansen's disease will soon be overcome by the efforts of all concerned, particularly doctors and nurses who are specialists of this disease. PMID- 25826852 TI - [What Hansen's disease research learned from tuberculosis research: from molecular biological aspect]. AB - As for the Mycobacterium leprae which is a causative agent of Hansen's disease, many studies had been done since it was identified in 1873. However, those studies, at the same time, experienced many struggles because of the difficulty of culture of M. leprae on the artificial growth media. Hence, the study of Hansen's disease progressed by taking the knowledge from the study of tuberculosis caused by the bacteria belonging to the same genus, genus Mycobacterium. For instance, the knowledge of mutations in specific genes responsible for rifampicin- and quinolone-resistance in M. tuberculosis led the elucidation of drug-resistant acquisition mechanism of M. leprae. Similarly, it is necessary for the researcher of Hansen's disease to get important information from the latest topic of the tuberculosis study and utilize them to the study of the disease. PMID- 25826853 TI - Huge data hack not expected to hurt Anthem's bottom line. PMID- 25826854 TI - Experts doubt Anthem breach will boost security spending. PMID- 25826855 TI - Obama budget offers 'pay for' blueprint. PMID- 25826856 TI - More transparency needed to combat public distrust on vaccines. PMID- 25826857 TI - His 'resolve, fortitude' helped push hospital industry to back ACA. PMID- 25826858 TI - Leading amid turmoil, keeping focus on the mission. ACHE Gold Metal winner. PMID- 25826859 TI - Leader's goal is employee, patient satisfaction. ACHE Young Healthcare Executive of the Year. PMID- 25826860 TI - Lay health workers promote stronger provider-patient ties. PMID- 25826861 TI - What would Cotton Mather say about the measles vaccine? PMID- 25826862 TI - Improving patient experience requires more data, wiser use of it. PMID- 25826863 TI - Contact-free sensor cuts alarm fatigue. PMID- 25826864 TI - 'If the ACA blows up, it puts a lot of pressure on Republicans'. PMID- 25826865 TI - Largest U.S. travel nurse staffing firms ranked by estimated 2013 U.S. temporary staffing revenue ($ in millions). PMID- 25826866 TI - [Study of neuroprotective, antihypoxic and antiamnesic effects of new mixture of tripeptides]. AB - A new mixture of tripeptides (NMT: H-Lys-Asp-Glu-OH, H-Asp-Glu-Pro-OH, H-Asp-Glu Arg-OH) in doses of 150 and 300 mg/kg per day produces clearly pronounced neuroprotective effect in rats with brain ischemia and decreases neurologic deficiency 1.1 times more effectively than reference drug semax. NMT (10, 50 and 150 mg/kg) had marked antihypoxic effect on mice in hermetic and altitude chamber. NMT in doses of 10 and 50 mg/kg was more effective than semax in hermetic chamber (1.3 and 1.5 times, respectively) and in a dose of 150 mg/kg in altitude chamber (1.9 times). NMT (50 and 150 mg/kg) had also marked antiamnesic effect on model amnesia caused by scopolamine in rats and was more effective (1.5 and 1.4 times, respectively) than semax in equal doses. NMT (50 and 150 mg/kg) also had marked antiamnesic effect on model amnesia caused by maximal electroshock and complex extreme factors in mice and in both doses was 4 times more effective than semax on the first model and in a dose of 150 mg/kg was 2.9 times more effective on the second model. NMT (50 mg/kg) increased the amplitude of transcallosal evoked potential in rat brain by 69% and was more effective than semax in equal dose. Thus, NMT is a promising neurotropic drug with neuroprotective, antihypoxic and antiamnesic activity. PMID- 25826867 TI - [Participation of pineal gland in antistressor activity of adaptogenic drugs]. AB - Chronic stress produces some morphological changes in rats, including thymus weight reduction, adrenal hypertrophy, and peptic ulcers in stomach. Repeated administration of phytoadaptogenic drugs (ginseng and bilobil) decreased these stress-induced disorders. The antistressor activity of drugs was attenuated upon by removal of the pineal gland. Histochemical and morphometric investigation of pineal tissues in stressed animals showed that that the pharmacological effect was accompanied by increasing functional activity of the pineal gland. It is suggested that pineal mobilization may participate in antistressor activity of phytoadaptogenic drugs. PMID- 25826868 TI - [Effect of Gly-His-Lys peptide and its analogs on pain sensitivity in mice]. AB - The intraperitoneal administration of Gly-His-Lys tripeptide to male BALB/c mice 12 min before the beginning of the study at doses 0.5, 1.5, 5, 15, and 50 mg/kg produced analgesic effect in the hot-plate test, which was manifested by an increase in the duration of the latent period of the paw-licking reaction. The replacement of L-lysine by D-lysine in the tripeptide molecule was accompanied by significant weakening of the analgesic effect after administration in the same doses. The attachment of D-alanine to N- or C-end of Gly-His-Lys peptide led to leveling of the analgesic effect. On the contrary, after the administration of these analogs, the duration of the latent period of the paw-licking reaction was increased in almost all experimental groups of animals and reached in some cases significant differences that were indicative of the manifestation of algic effects of the modified peptides. PMID- 25826869 TI - [GABA-ergic mechanism of cerebrovascular and antiischemic effects of docosahexaenoic acid]. AB - In experiments on rats, measurements of the local blood flow in the cortex of cerebrum with the aid of a laser Doppler flow meter showed that docosahexaenoic acid (DHA) enhanced the local cerebral circulation in animals with global transient cerebral ischemia, while not influencing that in intact animals. This vasodilatory effect of DHA in ischemized rats is blocked by bicuculline (specific GABA(A) receptor blocker), which is indicative of a GABA-ergic mechanisms of the vascular tone regulation. The results of radioligand binding assay in vitro showed the possibility of direct DHA interaction with cerebrovascular GABA(A) receptors. PMID- 25826870 TI - [Performance evaluation of integrated cytoprotective therapy of different duration in patients with cerebral infarction]. AB - The paper reviews the preliminary results of a multicenter randomized clinical research. The aim of the study was to determine the optimal duration of different types of energy-correction therapy. 99 case report forms of patients with cerebral infarction were reviewed with their prior envelope randomization into three groups. Patients in the first group (experimental group), consisting of 32 patients, as part of combined therapy received ascorbic acid (5% solution twice a day in a recommended dosage of 20 ml/day for 20 days); the second group (37 patients) received 10 ml of cytoflavin intravenously by drop infusion twice a day for 10 days; the third group received cytoflavin for 20 days (from day 1 to day 10 - 20 ml a day, from day 11 to day 20 - 10 ml a day). The average NIH scale score on admission was 14.9 +/- 2.6. Prescription of cytoflavin came with average 1.7 - 1.8 time regression (p < 0.05) of the volumes of cerebral ischemia in the of cases of the 10- and 20-day courses of treatment, while there were no significant morphologic changes in the ascorbic acid group. These results correlated with the best dynamics and outcomes of the neurological and performance status of patients receiving cytoflavin. Despite the lack of significant general differences in the clinical and morphological data of the second and third groups, the patients with underlying grave medical condition in the 20-day cytoflavin group (with NIH score of 14-20 points on admission) tended to have improved neurologic status parameters in comparison with the experimental group and the 10-day cytoflavin group. These results attest to the advantages of personalized antioxidant energy-correction therapy. PMID- 25826871 TI - [Effect of dopamine D1 and D2 receptor blockade on the immunostimulating effect of delta1 opioid receptor agonist DPDPE in mice with different psychoemotional states]. AB - It is established that activation of delta1 opioid receptors with their selective agonist DPDPE(100 MUg/kg) significantly increases IgM immune response not only in C57BL/6J mice with unchanged psychoemotional state, but also in mice displaying aggressive or depressive-like behavior in the social stress model (10 days of agonistic confrontations). SCH-23390 (1.0 mg/kg), selective antagonist of dopamine D1 receptors, and selective D2 receptor blocker haloperidol (1 mg/kg) prevented the immunostimulating effect of DPDPE in animals not subjected to social stress. At the same time, both SCH-23390 and haloperidol did not affect DPDPE-induced immunostimulation in mice engaged in aggressive or depressive-like behaviors. PMID- 25826872 TI - [Immune homeostasis impairment in acute carbon tetrachloride intoxicated rats corrected by administration of tocopherol acetate and unithiol]. AB - The results of experiments on noninbred albino rats showed that the acute intoxication with carbon tetrachloride (CT) at a dose of 1 LD50 reduced the parameters of cellular immune response and function of Th1 cells more significantly than the levels of humoral immune response and Th2-lymphocyte function, decreases the blood content of immunoregulatory cytokines IFN-g, IL-2, IL-4 and anti-inflammatory cytokine IL-13, while not changing the concentration of anti-inflammatory cytokine IL-10 and increasing the concentration of pro inflammatory cytokine IL-6. The application of unithiol, tocopherol acetate, and combinations partially restores the parameters examined. The combined effects of drugs during intoxication with CT does not exceed their separate action. PMID- 25826873 TI - [AntI-inflammatory, antipyretic and antimicrobial activity of flavonoid containing extract of Gratiola officinalis L]. AB - The extract of Gratiola officinalis L. has been obtained by an original method ensuring the maximum yield of flavonoids. The extract simultaneously exhibits high anti-inflammatory activity, selective antimicrobial properties (with respect to Staphylococcus aureus and Pseudomonas aeruginosa, but not to conditionally pathogenic E. coli) and antipyretic effect (observed for the first time in Gratiola officinalis L. preparations). Advantages of the proposed preparation are low toxicity, availability of the raw material, and broad spectrum of therapeutic effects. PMID- 25826874 TI - [Reparative regeneration of connective tissue structures of mammals under antioxidant therapy conditions]. AB - The influence of administration of the antioxidant complexes consisting of nonenzymatic antioxidants (alpha-tocopherol acetate preparation) and enzymatic antioxidants (ceruloplasmin) has been studied in rabbits with experimental arthritis. The introduction of alpha-tocopherol acetate (at a daily dose of 4 mg) improved metabolic processes in the organism (decreased in the rate of erythrocyte precipitation, total leukocytes and their stub and segmental forms; increased in erythrocyte count; reduced the glycosaminoglycan content as determined from uronic acid and hexose level; decreased ceruloplasmin activity and malonic dialdehyde level ion blood serum, all at p < 0.05), thus favoring reduction in the total activity of the inflammatory process as judged from hematological and biochemical data. Intra-articular introduction of ceruloplasmin (1.5 mg/kg, once per week) positively influenced the state of joint structures in damaged knee joints of the animals: decreased the activity of ceruloplasmin (from 5.28 +/- 0.06 to 3.94 +/- 0.01 AU), and malonic dialdehyde level (0.18 +/- 0.02 to 0.08 +/- 0.01 MUM) in the articular fluid (all at p < 0.05). These effects are probably related to the elimination of inefficiency of the antioxidant system in the synovial medium, thus preventing inflammatory destruction of articular tissues, hindering the development of pannus, and assisting the activation of reparative regeneration of connective tissue structures. PMID- 25826875 TI - [Occupational morbidity of railway transport workers]. AB - The authors present results of medical social monitoring of occupationalhazards that are the most prevalent in railway occupations workers, statistic data on occupational morbidity of railway transport workers over last 10 years. The article covers major causes of unfavorable effects resulting from occupational hazards in various workers categories. Dynamics of occupational morbidity parameters and its structure concerning separate nosologic entities are analyzed. PMID- 25826876 TI - [Occupational fitness examination of individuals directly connected with train operation]. AB - The article covers psychophysiologic aspects of work conditions and work safety in train operator occupations of railway transport. The authors consider problems of medical examination, occupational fitness analysis in these individuals if in various diseases or functional disorders. PMID- 25826877 TI - [On hi-tech cardiologic care model in medical support of train operation safety]. AB - The article covers hi-tech cardiologic care model in system of medical support of train operation safety, with definition of structure blocks in this model. Discussion covers peculiarities of the model functioning in comparison with the governmental system of hi-tech medical care, including its closed cycle principle characteristics, wide patients selection among railway workers, continuous and close cooperation between various medical speicalities, with active involvement of occupational fitness specialists (medical examination committees of various levels, including Central Medical Examination Committee), major extent of interventional rentgenosurgical technologies applied in diseases without significant functional failure. PMID- 25826878 TI - [On evaluation of diuranal profile of blood pressure and its possible variants frequency]. AB - The authors studied frequency of various variants of diurnal blood pressure profile, including discordant ones in systolic and diastolic pressure. The article also covers comparative evaluation of diurnal blood pressure profile results, assessed in amulatory and stationery conditions. When analyzing frequency of various types of diurnal blood pressure profile, it's expedient to outline concordant and discordant variants. Optimal concordant variant--dipper- appears in a group of normal blood pressure and early hypertension individuals in less than 50%. Ambulatory diurnal monitoring of blood pressure presents more favorable parameters, vs. that performed in stationery conditions. PMID- 25826879 TI - [On psychologic profile of locomotive crew workers in Russian Railways JSC and its role in accidents prevention]. AB - The article covers personality characters of locomotive crew workers of Russian Railways JSC, and specifying a block of methods for psychologic support of these workers' occupational activities. According to the results obtained, the authors presented a thorough description of characterologic, motivational personality traits characterizing a select of locomotive crew workers, and analyzed a relationship between the traits and levels of accidents in the workers' occupational activity. PMID- 25826880 TI - [Testing results of telemechanic system controlling train operators wakefulness]. AB - Expert and instrumental assessment covered efficiency of telemechanic system controlling train operators wakefulness in simulation of real night travel, through special simulator complex "Locomotive operator cabin". The telemechanic system controlling train operators wakefulness, if exploited correctly, provides wakefulness of the train operators at the level sufficient for the effective work. That is supported by distribution of falling asleep cases in experiments with activated or deactivated telemechanic system controlling train operators wakefulness. The study proved efficiency of telemechanic system controlling train operators wakefulness. PMID- 25826881 TI - [Influence of Melaxene on brain functional state]. AB - The study covered influence of Melaxene on human brain functional state. Complex dynamic (12-hour) neurophysiologic study revealed that single dose of Melaxene (3 mg) influences brain functional state--reliably increases cross-correlation parameters of global spatial synchronization of cortex biopotentials in various ranges of EEG rhythms. Analysis of functional asymmetry of spatial synchronization of cortex biopotentials in various brain areas proved that Melaxene acitvates important cross-correlation links in spatial synchronization of cortex biopotentials in left and right brain hemispheres, with dominated activity of left hemisphere. PMID- 25826882 TI - [Contemporary reforms and optimization of medical examination committees in Russian Railways JSC]. AB - The authors considered problems of restructurization and organization of medical examination committees in Russian Railways JSC, and their interlevel interactions. Detailed specification included documents circulation, order and terms of medical examination. Principles of conclusion on occupational fitness examination are specified. The article covers tasks of further development of occupational medical examination work in trade occupational medicine. PMID- 25826883 TI - [Information digital technologies and medical psychologic prevention of stress state in railway transport workers]. AB - The authors determined criteria of medical and psychologic training of railway transport workers, with applied information digital technologies. The results obtained prove that application of software "Railway worker" ("Zheleznodorozhnik") reduces frequency and duration of "emotional stress states". PMID- 25826884 TI - [Interdisciplinary approach to evaluation of metabolic syndrome in locomotive crew workers]. AB - The authors revealed features of metabolic syndrome diagnosis by means of various intradisciplinary criteria in locomotive crew workers. The locomotive crew workers, if compared to mounters, demonstrate 1.4 times more frequent excessive body weight, 1.6 times more frequent obesity, 1.4 times more frequent dyslipidemia, 2 times more common arterial hypertension. According to RSCS, metabolic syndrome in locomotive operators appeared more frequent--1.6 times than in IDF, 1.5 times than in ATP, ESN. Frequency of metabolic syndrome in males of stress occupations varies from 30% according to ATP, IDF, ESN to 49% according to RSCS--that is 2.5 times more frequent than in individuals with low occupational stress. Bioimpedometry revealed fluidsretention in 13% of train operators, water deficit in 24%, muscular mass deficiency in 55%. RSCS criteria are priority in interdisciplinary approach to metabolic syndrome evaluation in males under occupational stress. Assessment of visceral fat in locomotive crew workers helps to formulate purposeful prophylactic recommendations. PMID- 25826885 TI - [Determination of tibial bone resection thickness by lateral tibiofemoral joint 90 degrees flexional gap in total knee arthroplasty for varus osteoarthritic knees]. AB - OBJECTIVE: To investigate the efficiency of total knee arthroplasty (TKA) for varus osteoarthritic knees with tibial bone resection determined by lateral tibiofemoral joint 90 degrees flexional gap measurement. METHODS: Between March and June 2013, 60 patients (60 knees) with varus osteoarthritic knees underwent TKA. All patients were randomly divided into traditional osteotomy group (control group, 30 cases) and lateral tibiofemoral joint 90 degrees flexional gap measurement resection group (trial group, 30 cases). There was no significant difference in gender, age, affected side, body mass index and preoperative knee society score (KSS), range of motion (ROM) of the knee, anatomic tibiofemoral angle (ATFA), patellar tilt angle, posterior condylar offset (PCO), and joint line height between 2 groups (P > 0.05). The bone resection thickness of the distal femoral lateral condyle, femoral posterior lateral condyle, and lateral tibial plateau were measured; and the X-ray films were taken to measure and compare ATFA, patellar tilt angle, PCO, and joint line height after TKA. The knee function recovery was evaluated with KSS score and ROM of the knee. RESULTS: The bone resection thickness of the lateral tibial plateau and distal femoral lateral condyle in trial group was significantly smaller than that in control group (P < 0.05); while the bone resection thickness of the femoral posterior lateral condyle was significantly bigger than that in control group (P < 0.05). The 10 mm polyethylene insert was used in 19 cases of the trial group and in 8 cases of the control group, showing significant difference (Z= -4.040, P=0.003). All the patients were followed up 13-16 months (mean, 14.5 months). Radiography at 6 weeks after TKA indicated that the ATFA, patellar tilt angle, and joint line height had no significant difference between 2 groups (P > 0.05); the PCO of trial group was significantly lower than that of control group (P < 0.05). The KSS score and ROM of the knee at 12 months after operation were significantly improved when compared with preoperative ones in 2 groups (P < 0.05), and trial group was significantly better than control group (P < 0.05). CONCLUSION: It was an effective method to determine bone resection thickness using lateral tibiofemoral joint 90 degrees flexional gap measurement in TKA for varus osteoarthritic knees, which can reduce the bone resection thickness of the tibial plateau and distal femoral lateral condyle and restore the joint line and PCO with better early recovery of the knee function. PMID- 25826886 TI - [Clinical studies on effect of bone cement filling on articular cartilage of the knee after curettage of giant cell tumor]. AB - OBJECTIVE: To evaluate the effect of bone cement filling on articular cartilage injury after curettage of giant cell tumor around the knee. METHODS: Fifty-three patients with giant cell tumor who accorded with the inclusion criteria were treated between January 2000 and December 2011, and the clinical data were retrospectively analyzed. There were 30 males and 23 females, aged 16-69 years (mean, 34.2 years). The lesion located at the distal femur in 28 cases and at the proximal tibia in 25 cases. According to Campanacci grade, there were 6 patients at grade I, 38 at grade II, and 9 at grade III. Of 53 patients, 42 underwent curettage followed by bone cement filling, and 11 received curettage followed by bone grafts in the subchondral bony area and bone cement filling. Two groups were divided according to whether secondary osteoarthritis occurred or not during postoperative follow-up. The gender, age, lesion site, the subchondral residual bone thickness, tumor cross section, preoperative Campanacci grade, subchondral bone graft, and Enneking function score were compared between 2 groups, and multivariate logistic regression analysis was done. RESULTS: All incisions healed by first intention. The average follow-up time was 65 months (range, 23-158 months). Of 53 cases, 37 (69.8%) had no osteoarthritis, and 16 (30.2%) had secondary osteoarthritis. Three cases (5.7%) recurred during the follow-up period. Univariate logistic regression analysis showed no significant difference in gender, age, lesion site, and Campanacci grade between 2 groups (P > 0.1); difference was significant in the subchondral residual bone thickness, tumor cross section, Enneking function score, and subchondral bone graft (P < 0.1). The multivariate logistic regression analysis showed that the decreased subchondral residual bone thickness, the increased tumor cross section, and no subchondral bone graft are the risk factors of postoperative secondary osteoarthritis (P < 0.05). CONCLUSION: Curettage of giant cell tumor around the knee followed by bone cement filling can increase the damage of cartilage, and subchondral bone graft can delay or reduce cartilage injury. PMID- 25826887 TI - [effectiveness of open reduction and internal fixation without opening joint capsule on tibial plateau fracture]. AB - OBJECTIVE: To introduce the surgery method to reset and fix tibial plateau fracture without opening joint capsule, and evaluate the safety and effectiveness of this method. METHODS: Between July 2011 and July 2013, 51 patients with tibial plateau fracture accorded with the inclusion criteria were included. All of 51 patients, 17 cases underwent open reduction and internal fixation without opening joint capsule in trial group, and 34 cases underwent traditional surgery method in control group. There was no significant difference in gender, age, cause of injury, time from injury to admission, side of injury, and types of fracture between 2 groups (P > 0.05). The operation time, intraoperative blood loss, incision length, incision healing, and fracture healing were compared between 2 groups. The tibial-femoral angle and collapse of joint surface were measured on X ray film. At last follow-up, joint function was evaluated with Hospital for Special Surgery (HSS) knee function scale. RESULTS: The intraoperative blood loss in trial group was significantly less than that in control group (P < 0.05). The incision length in trial group was significantly shorter than that in control group (P < 0.05). Difference was not significant in operation time and the rate of incision healing between 2 groups (P > 0.05). The patients were followed up 12 30 months (mean, 20.4 months) in trial group and 12-31 months (mean, 18.2 months) in control group. X-ray films indicated that all cases in 2 groups obtained fracture healing; there was no significant difference in the fracture healing time between 2 groups (t=1.382, P=0.173). On X-ray films, difference was not significant in tibial-femoral angle and collapse of joint surface between 2 groups (P > 0.05). HSS score of the knee in trial group was significantly higher than that of control group (t=3.161, P=0.003). CONCLUSION: It can reduce the intraoperative blood loss and shorten the incision length to use open reduction and internal fixation without opening joint capsule for tibial plateau fracture. Traction of joint capsule is helpful in the reduction and good recovery of joint surface collapse. In addition, the surgery without opening joint capsule can avoid joint stiffness and obtain better joint function. PMID- 25826888 TI - [Clinical characteristics and surgical management of Eyres type V coracoid fracture combined with superior shoulder suspensory complex injury]. AB - OBJECTIVE: To investigate the clinical characteristics of Eyres type V coracoid fracture combined with superior shoulder suspensory complex (SSSC) injuries, and the effectiveness of open reduction and fixation. METHODS: Between March 2004 and July 2012, 13 patients with Eyres type V coracoid fracture and SSSC injuries were treated. There were 10 males and 3 females with an average age of 41 years (range, 23-59 years). Injury was caused by falling from height in 4 cases, by traffic accident in 6 cases, and by impact of the heavy weight in 3 cases. The interval from injury to operation was 3-10 days (mean, 5.2 days). SSSC injuries included 9 cases of acromioclavicular joint dislocation, 5 cases of clavicular fractures, and 4 cases of acromion fractures. The coracoid fractures were fixed with cannulated screws; the acromioclavicular joint dislocations were fixed with hook plate (6 cases) or Kirschner wires (2 case) except 1 untreated case; the clavicular fractures were fixed with anatomical locking plate (3 cases) and hook plate (2 cases); the acromion fractures were fixed with cannulated screws (1 case), Kirschner wires (2 cases), or both of them (1 case). RESULTS: The mean operation time was 158.0 minutes (range, 100-270 minutes), and the mean intraoperative blood loss was 207.7 mL (range, 150-300 mL). The other patients obtained primary healing of incision except 1 patient who had inflammation around incision, which was cured after change dressing. All patients were followed up for 22.6 months on average (range, 17-35 months). All fractures achieved union at a mean time of 3.6 months (range, 2-6 months). No nerve injury and implant fixation failure complications were observed. At last follow-up, the Constant score and the disability of the arm, shoulder, and hand (DASH) score had a significant improvement when compared with scores at pre-operation (P < 0.05). The shoulder range of motion in flexion, abduction, and external rotation at last follow-up were significantly higher than those at pre-operation (P < 0.05). CONCLUSION: Eyres type V coracoid fracture associated with SSSC injuries usually results in the instability of the shoulder. With individual surgical treatment, the satisfactory function and good effectiveness can be obtained. PMID- 25826889 TI - [Application of modified traction arch of skull in skull traction]. AB - OBJECTIVE: To investigate the feasibility and effectiveness of the modified traction arch of skull (crossbar traction arch) for skull traction in treating cervical spine injury by comparing with traditional traction arch of skull. METHODS: Between June 2009 and June 2013, 90 patients with cervical vertebrae fractures or dislocation were treated with modified skull traction surgery (trial group, n=45) and traditional skull traction surgery (control group, n=45). There was no significant difference in gender, age, injury types, injury level, the interval between injury and admission, and Frankel grading of spinal injury between 2 groups (P > 0.05). The clinical efficacy was evaluated after operation by the indexes such as traction arch slippage times, operation time, the infection incidence of the pin hole, incidence of skull perforation, visual analogue scale (VAS), and reduction status of cervical dislocation. RESULTS: The traction arch slippage times, the infection incidence of the pin hole, operation time, blood loss, and postoperative VAS score in trial group were significantly lower than those in control group (P < 0.05). There was no significant difference in the incidence of skull perforation caused by clamp crooks of traction arch between 2 groups (P=1.000). At 2 weeks after operation, the patients had no headaches, infections, or other complications in 2 groups. In patients with cervical dislocation, 4 of the trial group and 6 of the control group failed to be reset, the reduction rate was 83.33% (20/24) and 68.42% (13/19) respectively, showing no significant difference (chi2=0.618, P=0.432). CONCLUSION: The operation with modified traction arch of skull has significant advantages to reduce postoperative complication compared with tradition traction arch of skull. PMID- 25826890 TI - [Research progress of effects of strontium ranelate on osteoarthritis]. AB - OBJECTIVE: To review the research progress focused on the effects of strontium ranelate (SR) on osteoarthritis. METHODS: The relevant literature about the effects and mechanism of SR intervening osteoarthritis in recent years was extensively reviewed and comprehensively analyzed. RESULTS: SR not only could improve the microenvironment of bone metabolism in articular cartilage with osteoarthritis, promote activity of osteoblasts, and inhibit activity of osteoclasts, but also could adjust the expression of key proteases which affect cartilage formation, and therefore it has a potential protective effect on subchondral bone during the progression of osteoarthritis cartilage. CONCLUSION: SR is expected to become a drug of osteoarthritis disease remission, but further studies are needed to clarify the mechanism of SR in osteoarthritis, and finally confirm the best application dosage of SR in osteoarthritis treatment. PMID- 25826891 TI - [Research progress of key signaling pathways in osteoblast differentiation and bone formation regulation]. AB - OBJECTIVE: To review the mechanism and research progress of signaling pathways which play key roles in the regulation of osteoblast differentiation and bone formation. METHODS: Recent articles about signaling pathways of osteoblast differentiation and bone formation were reviewed and comprehensively analyzed. RESULTS: At present, multiple signaling pathways have been found to be involved in the regulation of osteoblast differentiation and bone formation, among which bone morphogenetic protein-Smads, Wnt/beta-catenin, Notch, Hedgehog, and fibroblast growth factor signaling pathways may play the most important roles. Not only each pathway has a complex regulatory mechanism itself, but also contacts and impacts with each other, thus they formed a more complicated and sophisticated regulatory network, and regulate together osteoblast differentiation and bone formation. However, the mechanisms in detail of those pathways are still not very clear, because the animal experiment techniques are not yet mature as well as the relevant clinical trials were carried out not too much. CONCLUSION: The complete molecular mechanism of osteoblast differentiation and bone formation should be further investigated, so as to lay a theory foundation for preventing and treating the common bone diseases in clinical which are involve in osteoblast differentiation and bone formation. PMID- 25826892 TI - [Characteristics and treatment of grade III spoke heel injuries in children]. AB - OBJECTIVE: To evaluate the characteristics, treatment, and effectiveness of grade III spoke heel injury in children. METHODS: Between January 2007 and June 2013, 31 children with grade III spoke heel injuries were treated. There were 19 boys and 12 girls, aged from 3 to 12 years (mean, 5.2 years). The time from trauma to operation was 2 hours to 26 days (mean, 4.4 days). The soft tissue defects of the heels ranged from 3.5 cm x 2.5 cm to 8.0 cm x 4.5 cm, which all complicated with Achilles tendon and calcaneus tuberosity defects. In 16 cases of large Achilles tendon defects which can not be stretched straightly to calcaneus tuberosities, repair with sliding gastrocnemius musculocutaneous flaps (16 cm x 5 cm to 21 cm x 10 cm) and insertion reconstruction of the tendon were performed. In 15 cases of Achilles tendon defects which can be stretched straightly to calcaneus tuberosities, repair with reversed pedicled flap (4.0 cm x 2.5 cm to 8.0 cm x 4.5 cm) and insertion reconstruction of the tendon were given. Nerve anastomosis was not performed. The donor site was covered with split-thickness skin graft. RESULTS: All children were followed up 6 months to 4 years (mean, 13 months). The other flaps survived except 3 cases having partial necrosis. The color and appearance of the flaps were satisfactory, with no impact on wearing shoes and walking. The flaps recovered sensory function. As more follow-up time, the angle of dorsal flexion was gradually improved. Heel raising on one leg was restored. The bone amount of calcaneus tuberosity increased slowly based on X-ray films. CONCLUSION: Grade III spoke heel injury in children possesses peculiar features, surgical methods should be based on defects of Achilles tendon and soft tissue. Dorsal flexion of the ankle is obviously limited; as follow-up time goes on, the ankle function is progressively improved. However, long-term follow-up is needed. PMID- 25826893 TI - [Clinical application of sural fasciomyocutaneous perforator flap in repair of soft tissue defect in weight-bearing area of foot]. AB - OBJECTIVE: To assess the effectiveness of the sural fasciomyocutaneous perforator flap in repair of soft tissue defect in weight-bearing area of the foot. METHODS: Between January 2007 and September 2010, 19 patients with soft tissue defects in the weight-bearing area of the foot were treated with sural fasciomyocutaneous perforator flaps. The etiology was traffic accident in 16 patients and crush injury in 3 patients. The interval of injury and admission was 2 hours to 14 days. The size of defect ranged from 8 cm x 6 cm to 26 cm x 16 cm; the size of flap ranged from 7 cm x 7 cm to 25 cm x 12 cm. The donor sites were repaired by free skin graft. The flap survival was observed after operation, and the pain score and sensory recovery at the recipient site were used to assess the effectiveness. RESULTS: The flaps survived with satisfactory aesthetic and functional results in 18 cases. Partial flap necrosis was noted and second healing was achieved after split thickness skingrafting in 1 case. One case of delayed ulceration was also noted after 5 weeks, ulceration was successfully cured after wound care and avoidance of weight-bearing for 2 weeks. All patients were followed up 9-25 months (mean, 14.1 months). The flaps had good appearance, without bulky pedicle. Superficial sensation and deep sensation were restored in 17 cases (89.4%) and 18 cases (94.7%) respectively at last follow-up. CONCLUSION: Sural fasciomyocutaneous perforator flap is a reliable modality in heel reconstruction, having the advantages of low ulceration rate, good wear resistance, and good sensation recovery. PMID- 25826894 TI - [Effectiveness of retrograde island neurocutaneous flap pedicled with lateral antebrachial cutaneous nerve in treatment of hand defect]. AB - OBJECTIVE: To explore the effectiveness of retrograde island neurocutaneous flap pedicled with lateral antebrachial cutaneous nerve in the treatment of soft tissue defect of the hand. METHODS: Between October 2011 and December 2013, 17 cases of skin and soft tissue defects of the hands were treated. There were 8 males and 9 females, aged 23-62 years (mean, 44 years). Of them, defect was caused by trauma in 13 cases, by postoperative wound after degloving injury in 2 cases, and by resection of contracture of the first web in 2 cases; 13 cases of traumas had a disease duration of 2-6 hours (mean, 3.5 hours). The defect sites located at the back of the hand in 5 cases, at the radial side of the palm in 4 cases, at the first web in 2 cases, at the palmar side of the thumb in 4 cases, and at the radial dorsal side of the thumb in 2 cases. The bone, tendons, and other deep tissue were exposed in 15 cases. The defect size varied from 3 cm x 3 cm to 12 cm x 8 cm. The size of the flaps ranged from 3.6 cm x 3.6 cm to 13.2 cm x 8.8 cm. The lateral cutaneous nerve of the forearm was anastomosed with the cutaneous nerve of the recipient sites in 9 cases. The donor sites were repaired by free skin graft or were sutured directly. RESULTS: The other flaps survived, and obtained healing by first intention except 2 flaps which had partial necrosis with healing by second intention at 1 month after dressing change. The skin graft at donor site survived, and incisions healed by first intention. All patients were followed up 5-30 months (mean, 12 months). The flaps had good color and texture. Flap sensory recovery, of S2-S3+ was obtained; in 9 cases undergoing cutaneous nerve flap anastomosis, the sensation of the flaps recovered to S3-S3+ and was better than that of 8 cases that the nerves were disconnected (S2-S3). The patients achieved satisfactory recovery of hand function. Only 2 cases had extended limitation of the proximal interphalangeal joint. At last follow-up, according to the Chinese Medical Society of Hand Surgery function evaluation standards, the results were excellent in 15 cases and good in 2 cases. CONCLUSION: Retrograde island neurocutaneous flap pedicled with lateral antebrachial cutaneous nerve is an effective way to repair skin defects of the hand, with the advantages of reliable blood supply and simple surgical procedure. PMID- 25826895 TI - [Effectiveness of scar split thickness skin graft combined with acellular allogeneic dermis in treatment of large deep II degree burn scar]. AB - OBJECTIVE: To investigate the feasibility and effectiveness of using scar split thickness skin grafts combined with acellular allogeneic dermis in the treatment of large deep II degree burn scar. METHODS: Between January 2013 and December 2013, 20 cases of large deep II degree burn scar undergoing plastic operation were enrolled. There were 14 males and 6 females, aged 4 to 60 years (mean, 40 years). Burn reasons included hydrothermal burns in 10 cases, flame burns in 9 cases, and lime burns in 1 case. The burn area accounted for 70% to 96% total body surface area (TBSA) with an average of 79% TBSA. The time from wound healing to scar repair was 3 months to 2 years (mean, 7 months). Based on self-control, 0.7 mm scar split thickness skin graft was used to repair the wound at the right side of joints after scar resection (control group, n=35), 0.5 mm scar split thickness skin graft combined with acellular allogeneic dermis at the left side of joints (trial group, n=30). Difference was not statistically significant in the scar sites between 2 groups (Z=-1.152, P=0.249). After grafting, negative pressure drainage was given for 10 days; plaster was used for immobilization till wound healing; and all patients underwent regular rehabilitation exercises. RESULTS: No significant difference was found in wound healing, infection, and healing time between 2 groups (P > 0.05). All patients were followed up for 6 months. According to the Vancouver Scar Scale (VSS), the score was 5.23 +/- 1.41 in trial group and was 10.17 +/- 2.26 in control group, showing significant difference (t=8.925, P=0.000). Referring to Activities of Daily Living (ADL) grading standards to assess joint function, the results were excellent in 8 cases, good in 20 cases, fair in 1 case, and poor in 1 case in trial group; the results were excellent in 3 cases, good in 5 cases, fair in 22 cases, and poor in 5 cases in control group; and difference was statistically significant (Z=-4.894, P=0.000). CONCLUSION: A combination of scar split thickness skin graft and acellular allogeneic dermis in the treatment of large deep II degree burn scar is feasible and can become one of solution to the problem of skin source tension. PMID- 25826896 TI - [One-stage nonstented tubularized incised plate urethroplasty for pain and complication after hypospadias repair]. AB - OBJECTIVE: To comparatively analyze the effect of one-stage nonstented tubularized incised plate urethroplasty (TIP) on operative pain and complication by comparing with urethral catheter and urethral stent drainages. METHODS: Between March 2010 and June 2013, 214 cases of distal and mid-shaft hypospadias underwent TIP, and the clinical data were analyzed retrospectively. The patients were divided into 3 groups based on different urinary drainage techniques: indwelling urethral catheter was used in 68 cases (group A), indwelling urethral stent in 70 cases (group B), and nonstented drainage in 76 cases (group C). There was no significant difference in age, hypospadias type, and accompany malformation among 3 groups (P > 0.05). At 2 days after operation, Wong-Banker facial scale (WBS) and Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) were used for pain and praxiology assessment. The complications after operation also were observed and compared among 3 groups. RESULTS: All patients were followed up 6-25 months (median, 11.8 months). At 2 days after operation, the median WBS scores were 4.0 (0-10), 3.5 (0-10), and 3.0 (0-10) in groups A, B, and C, respectively; median CHEOPS pain scores were 6.0 (1-13), 6.0 (1-13), and 4.0 (1-11), respectively. The WBS pain score and CHEOPS pain score in group C were significantly lower than those in groups A and B (P < 0.05), but there was no significant difference between group A and group B (P > 0.05). The postoperative complication occurred in 27 cases (39.7%) of group A, 29 cases (41.4%) of group B, and 13 cases (17.1%) of group C; two or more than two complications occurred in 14, 15, and 9 cases, respectively. There was significant difference in total incidence of postoperative complication among 3 groups (P < 0.05). The incidences of postoperative overactive bladder, bladder spasms, urinary tract infection, and fistula in group C were significantly lower than those in groups A and B (P < 0.05). There was no significant difference in incision infection, acute urinary retention, urinary extravasation, meatal stenosis, and urethral stricture among 3 groups (P > 0.05). CONCLUSION: One-stage nonstented TIP is suitable for distal and mid-shaft hypospadias and could reduce postoperative pain and complications compared with the traditional postoperative indwelling urethral catheter and indwelling urethral stent. PMID- 25826897 TI - [Effectiveness of transforaminal lumbar interbody fusion via Luxor retractor associated with Mantis pedicle screw in treatment of moderate and severe lumbar spondylolisthesis]. AB - OBJECTIVE: To evaluate the effectiveness of transforaminal lumbar interbody fusion (TLIF) via Luxor retractor associated with Mantis pedicle screw for the treatment of moderate or severe lumbar spondylolisthesis (LSL). METHODS: A retrospective analysis was made on the clinical data of 32 patients with LSL treated with TLIF via Luxor retractor associated with Mantis pedicle screw between June 2010 and June 2012. There were 20 males and 12 females, with the mean age of 48 years (range, 36-69 years). LSL occurred at the L4,5 in 17 patients and at the L5, S1 in 15 patients. Of them, 18 cases were rated as Meyerding grade II, and 14 cases as grade III. The disease duration was 8 months to 6 years (mean, 3.5 years). The operation time, intraoperative blood loss, and preoperative and postoperative (1 week and 1 year) intervertebral height and slipping angle were recorded, and the slipping rate was calculated; Japanese Orthopaedic Association (JOA) score was used for clinical efficacy assessment. RESULTS: The operation time was 90-130 minutes (mean, 110 minutes); intraoperative blood loss was 120-300 mL (mean, 210 mL). Incisions healed by first intention. All patients were followed up 24-36 months (mean, 28 months), and no complications of leakage of cerebrospinal fluid and nerve root injury occurred; X-ray films showed satisfactory reduction of spondylolisthesis and good position of pedicle screw and interbody fusion cage. The mean bone fusion time was 4.0 months (range, 3.8-6.0 months). The JOA score, slipping rate, slipping angle, and intervertebral height at 1 week and 1 year after operation were significantly improved when compared with preoperative ones (P < 0.05), but no significant difference was found between at 1 week and at 1 year after operation (P > 0.05). CONCLUSION: TLIF via Luxor retractor associated with Mantis pedicle screw fixation is a safe and effective minimally invasive technique in treating moderate or severe LSL. PMID- 25826898 TI - [Expression of p16INK4a in nucleus pulposus and its effect on degenerated intervertebral discs]. AB - OBJECTIVE: To investigate the expression of p16INK4a in nucleus pulposus (NP) and to clarify its relationship with intervertebral disc degeneration so as to provide evidence for biological repair of intervertebral disc. METHODS: The NP specimens were obtained from 17 patients with intervertebral disc degeneration undergoing discectomy, who aged 40-50 years (mean, 45.4 years). Based on the preoperative MRI, there were 10 cases of grade III degeneration, and 7 cases of grade IV degeneration. Cell senescence was evaluated by detecting senescence associated beta-galactosidase (SA-beta-gal) activity. Senescence marker (p16INK4a) and disc degeneration markers [A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS 5), Aggrecan, and Sry-related HMG box transcription factor 9 (Sox-9)] were determined in the NP specimens with immunohistochemistry and Western blot. The correlation between ADAMTS 5 and p16INK4a was analyzed. RESULTS: Clustered distribution of green SA-beta-gal positive cells was seen in the NP with grade III and IV degeneration. A few single round SA-beta-gal-positive NP cells (NPCs) wrapped by the layered extracellular matrix were also seen in the NP with grade III degeneration. It was difficult to see single distribution of NPCs in the NP with grade IV degeneration. The percentage of SA-beta-gal-positive cells was 22.7% +/- 5.4% and 37.1% +/- 7.6% in the NP with grade III and IV degeneration respectively, showing significant difference (t=-9.666, P=0.000). The percentages of p16INK4a-positive and ADAMTS 5-positive NPCs in the NP with grade IV degeneration were significantly higher than those with grade III degeneration (P < 0.05). The percentages of Aggrecan-positive and Sox-9-positive NPCs in the NP with grade IV degeneration were significantly lower than those in the NP with grade III degeneration (P < 0.05). The protein expressions of Aggrecan and Sox-9 in the NP with grade IV degeneration were significantly lower than those in the NP with grade III degeneration (P < 0.05). The NP with grade IV degeneration showed significantly higher protein expressions of p16INK4a and ADAMTS 5 (P < 0.05). Importantly, there was a good correlation between p16INK4a and ADAMTS 5 protein expressions (r=0.908, P=0.000). CONCLUSION: Premature senescent NPCs increase in the NP with the advancing disc degeneration. The expression of p16INK4a and its association with degeneration grades suggest that the p16INK4a may play a significant role in the pathogenesis of intervertebral disc degeneration. PMID- 25826899 TI - [Experimental study on effect of power-assisted intravascular shunt in replantation of amputated limbs in rabbits]. AB - OBJECTIVE: To investigate the effect of power-assisted intravascular shunt in replantation of amputated limbs of rabbits. METHODS: Eighty rabbits weighing 1.8 2.5 kg (male or female) were selected to establish the model of circular amputation at the hind groin, only femoral arteries and veins were completely preserved. After the femoral artery was clamped in 60 rabbits, the rabbits underwent power-assisted intravascular shunt with high-flow rate (group A, n=20), power-assisted intravascular shunt with low-flow rate (group B, n=20), and no power-assisted intravascular shunt (group C, n=20) to reconstruct blood supply; the femoral artery was not clamped in another 20 rabbits of sham group (group D). Before and after intravascular shunt (1, 3, 6, and 12 hours), the malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine kinase (CK) of the serum were determined. The myeloperoxidase (MPO), MDA, and wet to dry weight ratio (W/D ratio) of the gastrocnemius muscle were measured, and the thrombogenesis and survival rate of limb were observed. RESULTS: Before intravascular shunt, MDA, LDH, and CK of the serum and MPO, MDA, and W/D ratio of the muscle showed no significant difference among 4 groups (P > 0.05). At each time point after intravascular shunt, no significant difference was found in all indexes between groups A and D (P > 0.05); the indexes of groups B and C were significantly higher than those of groups A and D (P < 0.05); the values were the highest in group C (P < 0.05), and reached the peak at 12 hours. All limbs of group A survived with low thrombosis rate, and less limbs could survive with high thrombosis rate in group C. CONCLUSION: The power-assisted intravascular shunt with high-flow rate can effective ensure the blood supply of the amputated limbs of rabbits with lower limb injury and higher survival rate of amputated limbs after replantation. PMID- 25826900 TI - [In vitro experimental study on influences of final degradation products of polyactic acid on proliferation and osteoblastic phenotype of osteoblast-like cells]. AB - OBJECTIVE: To investigate the influences of lactic acid (LA), the final degradation product of polylactic acid (PLA) on the proliferation and osteoblastic phenotype of osteoblast-like cells so as to provide theoretical basis for bone tissue engineering. METHODS: Ros17/2.8 osteoblast-like cells were harvested and divided into 3 groups. In groups A and B, the cells were cultured with the medium containing 4, 8, 16, 22, and 27 mmol/L L-LA and D, L-LA, respectively. In group C, the cells were cultured with normal medium (pH7.4). The cell proliferation was determined with MTT method after 1, 3, and 5 days. The relative growth ratio (RGR) was calculated, and the cytotoxicity was evaluated according to national standard of China. In addition, the alkaline phosphatase (ALP) activity of cells cultured with medium containing 4 mmol/L L-LA (group A), 4 mmol/L D, L-LA (group B), and normal medium (group C) after 1 and 5 days were detected with ALP kits, and the relative ALP ratio (RAR) was calculated; after 21 days, the calcium nodules were tested with von Kossa staining method, and were quantitatively analyzed. RESULTS: When LA concentration was 4 mmol/L, the mean RGR of both groups A and B were all above 80%, and the cytotoxic grades were grade 0 or 1, which meant non-cytotoxicity. When LA concentration was 8 mmol/L and 16 mmol/L, groups A and B showed cytotoxicity after 5 days and 3 days, respectively. When LA concentration was above 22 mmol/L, cell proliferations of groups A and B were inhibited evidently after 1-day culture. At each LA concentration, RGR of group A was significantly higher than that of group B at the same culture time (P < 0.05) except those at 4 mmol/L after 1-day and 3-day culture. After 1 day, the RAR of group A was significantly higher than that of group B on 1 day (144.1% +/- 3.2% vs. 115.2% +/- 9.8%, P < 0.05) and on 5 days (129.6% +/- 9.8% vs. 78.2% +/- 6.9%, P < 0.05). The results of von Kossa staining showed that the black gobbets in group A were obviously more than those of groups B and C. The staining area of group A (91.2% +/- 8.2%) was significantly higher than that of groups B (50.3% +/- 7.9%) and C (54.2% +/- 8.6%) (P < 0.05). CONCLUSION: The concentration and composition of LA have significant effects on the cell proliferation and osteoblastic phenotype of osteoblast-like cells. PMID- 25826901 TI - [Effect of carboxymethylated chitosan on apoptosis and expression of brain derived neurotrophic factor and glial cell line derived neurotrophic factor in oxidative stress induced Schwann cells in vitro]. AB - OBJECTIVE: To investigate the protective effects of carboxymethylated chitosan (CMCS) on oxidative stress induced apoptosis of Schwann cells (SCs), and the expressions of brain derived neurotrophic factor (BDNF) and glial cell line derived neurotrophic factor (GDNF) in oxidative stress induced SCs. METHODS: Twenty-four 3-5 days old Sprague Dawley rats (weighing 25-30 g, male or female) were involved in this study. The bilateral sciatic nerves of rats were harvested and SCs were isolated and cultured in vitro. The purity of SCs was identified by immunofluorescence staining of S-100. SCs were treated with different concentrations of hydrogen peroxide (H2O2, 0.01, 0.10, and 1.00 mmol/L) for 3, 6, 12, and 24 hours to establish the apoptotic model. The cell counting kit 8 (CCK 8) and flow cytometry analysis were used to detect the cell viability and apoptosis induced by H2O2, and the optimal concentration and time for the apoptotic model of SCs were determined. The 2nd passage SCs were divided into 5 groups and were treated with PBS (control), with 1.00 mmol/L H2O2, with 1.00 mmol/L H2O2 + 50 MUg/mL CMCS, with 1.00 mmol/L H2O2 + 100 MUg/mL CMCS, and with 1.00 mmol/L H2O2 + 200 MUg/mL CMCS, respectively. After cultured for 24 hours, the cell viability was assessed by CCK-8, cell apoptosis was detected by flow cytometry analysis, the expressions of mRNA and protein of BDNF and GDNF were detected by real-time quantitative PCR and Western blot. RESULTS: The immunofluorescence staining of S-100 indicated the positive rate was more than 95%. CCK-8 and flow cytometry results showed that H2O2 can inhibit the proliferation of SCs and induce the SCs apoptosis with dose dependent manner, the effect was the most significant at 1.00 mmol/L H2O2 for 24 hours; after addition of CMCS, SCs exhibited the increased proliferation and decreased apoptosis in a dose dependent manner. Real-time quantitative PCR and Western blot analysis showed that 1.00 mmol/L H2O2 can significantly inhibit BDNF and GDNF expression in SCs when compared with control group (P < 0.05), 50-200 MUg/mL CMCS can reverse the oxidative stress-induced BDNF and GDNF expression in SCs in a dose dependent manner, showing significant difference compared with control group and 1.00 mmol/L H2O2 induced group (P < 0.05). There were significant differences among different CMCS treated groups (P < 0.05). CONCLUSION: CMCS has the protective stress on oxidative stress induced apoptosis of SCs, and may promote the BDNF and GDNF expressions of neurotrophic factors in oxidative stress induced SCs. PMID- 25826902 TI - [Advances of preclinical research in xenogeneic (porcine) cell transplantation]. AB - OBJECTIVE: To summarize the advances of preclinical research in xenogeneic (porcine) cell transplantation in recent years. METHODS: The literature about the preclinical research in xenogeneic (porcine) cell transplantation was analyzed and summarized. RESULTS: With the application of new immunosuppressive agents and the generation of transgenic pigs, great progress has been achieved in xenogeneic transplantation of pig-derived nerve cells, islet cells, liver cells, and various types of stem cells. The survival time of xenogeneic cell (porcine) significantly prolonged, but there is still a long way to go before clinical application. CONCLUSION: The source ofxenogeneic (porcine) cells is abundant and the experiments are reproducible. However, how to effectively prevent rejection and prolong the survival time in the host, and avoid the spread of virus between species are still need to be solved in the future research. PMID- 25826903 TI - [Progress of induced osteogenesis of bone marrow mesenchymal stem cells transfected by double-gene]. AB - OBJECTIVE: To review the research progress of induced osteogenesis of bone marrow mesenchymal stem cells (BMSCs) transfected by double-gene. METHODS: The recent literature concerning the comparative research of induced osteogenesis of BMSCs transfected by double-gene was extensively reviewed. The characteristics of BMSCs, the advantage and effect of synergistic inductive osteogenesis, the application prospect and problems of BMSCs transfected by double-gene were summarized. RESULTS: The effect of induced osteogenesis concerning BMSCs transfected by double-gene is far superior to single gene transfection and the activity of osteoblast is also significantly increased. The research used in bone tissue engineering experiment also obtain good effect. CONCLUSION: Induced osteogenesis of BMSCs transfected by double-gene is able to make up for the lack of a single gene transfection and has great development prospects in the orthopaedic field. PMID- 25826904 TI - [Research progress of in vivo nucleic acid delivery with poly (ethylenimine)]. AB - OBJECTIVE: To review the current status and advances of in vivo nucleic acid delivery mediated by poly(ethylenimine) (PEI). METHODS: The related home and abroad literature about nucleic acid delivery with applications in cancer treatments and tissue engineering was extensively reviewed and analyzed. RESULTS: A variety of in vivo study on the potential of PEI-mediated nucleic acid delivery has been carried out and made certain effects in the animal model, ranging from cancer treatments to rectification of physiological defects (eg. cranial defect and corneal epithelium defect). Tail vein injection is the most commonly adopted route of administration in vivo, followed by pulmonary administration and intralesional injection. However, transfection and expression in vivo have some shortcomings, such as low transfection efficiency and short expression time, so there are some limitation in the clinical application. CONCLUSION: PEI mediated nucleic acid delivery provides a good method for cancer treatments and rectification of physiological defects. For future research, not only should more in vivo animal testing be done, but the procedures of experimentation also need to be standardized. PMID- 25826905 TI - [research status and application of magnetic compression anastomosis in surgery]. AB - OBJECTIVE: To summarize the recent development of the magnetic compression anastomosis in surgery. METHODS: The abroad and domestic relevant literature about magnetic compression anastomosis was extensively reviewed, and comprehensive analyzed. RESULTS: Magnetic compression anastomosis in the reconstruction of the body lumen is a simple and effective way; laparoscopy combined with magnetic compression anastomosis has the advantages of small wound and quick recovery. Magnetic compression anastomosis has been increasingly used in clinical practice. But its mechanism has not been fully revealed, and it is difficulty in expelling out of the magnet for the gastrointestinal and certain large-size lumen, so further research and optimization are still needed. CONCLUSION: Relative to the traditional manual suture, magnetic anastomosis has great advantage, especially a combination of magnetic compression anastomosis and minimally invasive surgery has bright prospects for development. PMID- 25826906 TI - [Development research of in vivo kinematics in lumbar degenerative spondylolisthesis]. AB - OBJECTIVE: To review the researches of in vivo kinematics in lumbar degenerative spondylolisthesis (DS). METHODS: Related literature concerning the in vivo kinematics in patients with lumbar DS was extensively reviewed and comprehensively analyzed in 4 terms of the instability of lumbar DS, vertebral motion pattern, the morphological changes of spinal canal, and intraoperative biomechanical measurement. RESULTS: Whether there is lumbar segmental instability in lumbar DS patients is still controversial, which should be based on degenerative stage of lumbar spine and grade of slip. The hypomobility of the lumbar spinous processes and the facet joint is seen in DS. The diameter, cross sectional area, and volume of spinal canal in lumbar DS patients are significantly smaller than those of the normal control. Because of its invasive procedure and medical ethics, the use of the intraoperative measurement device is limited. These reported researches of in vivo kinematics in DS are almost on the sagittal plane. However, few data have been reported on the 6-degree-of-freedom (6DOF) kinematics of the diseased levels under physiological loading conditions. CONCLUSION: The 6DOF kinematics data can accurately reflect the segmental motion characteristics in lumbar DS patients, recent studies have been reported, further studies are still needed. PMID- 25826907 TI - [Research progress of preparation and components of platelet rich plasma]. AB - OBJECTIVE: To review the research progress of the preparation and components of the platelet rich plasma (PRP). METHODS: The recent literature concerning the biological mechanism, preparation, and components of PRP was analyzed and summarized. RESULTS: The biological function of PRP depends on a series of intricate cascade of cellular and molecular events. PRP contains different concentrations of platelets, which would release a large number of the activated molecules, and also contains a small amount of white blood cells and red blood cells. The preparation of PRP is based on platelet concentration. Different preparation techniques would lead to different platelet concentrations, recovery ratios, and components. CONCLUSION: There is no uniform standard for the preparation of PRP. Different preparation methods and technical parameters of PRP will get different components and different concentrations of PRP, which also provide a reference for clinicians to select the most appropriate PRP for individual patient. PMID- 25826908 TI - [Concentration and size distribution of bioaerosols at non-haze and haze days in Beijing]. AB - In recent years, haze has been observed frequently in Beijing. Haze was one of the atmospheric phenomena caused by the accumulation of particulate matter. As an important fraction of particular matter, bioaerosol could potentially cause significantly negative health effects. In this study, we detected the concentration and size distribution of viable bioaerosol during non-haze and haze days, analyzed correlation of viable bioaerosol with the ambient temperature and relative humidity using Spearman's correlation coefficient and finally detected the changing of size distribution of viable bioaerosol in summer and winter. Results indicated that concentrations of viable bioaerosol exhibited a negative correlation with Air Quality Index (AQI) of PM2.5 and positive correlation with temperature. Relative humidity had a negative correlation with airborne bacteria while positive correlation with airborne fungi. The highest concentration of airborne bacteria and fungi were detected at size arrange of 4.5-7.0 MUm and 2. 1 3.3 MUm in the winter, respectively. In the summer, both the highest concentration of airborne bacteria and fungi were observed at size arrange of 3.3 4.5 MUm. The results of this study will provide the basis data for hazard evaluation of bioaerosol on human health at non-haze and haze days. PMID- 25826909 TI - [Light scattering extinction properties of atmospheric particle and pollution characteristics in hazy weather in Hangzhou]. AB - In order to evaluate the influence of particle scattering on visibility, light scattering coefficient, particle concentrations and meteorological factor were simultaneously monitored from July 2011 to June 2012 in Hangzhou. Daily scattering coefficients ranged from 108.4 to 1 098.1 Mm(-1), with an annual average concentration of 428.6 Mm(-1) +/- 200.2 Mm(-1). Seasonal variation of scattering coefficients was significant, with the highest concentrations observed in autumn and winter and the lowest in summer. It was found there were two peaks for the average diurnal variations of the scattering coefficient, which could be observed at 08:00 and 21:00. The scattering efficiencies of PM2.5 and PM10 were 7.6 m2 x g(-1) and 4.4 m2 x g(-1), respectively. The particle scattering was about 90.2 percent of the total light extinction. The scattering coefficients were 684.4 Mm(-1) +/- 218.1 Mm(-1) and 1 095.4 Mm(-1) +/- 397.7 Mm(-1) in hazy and heavy hazy days, respectively, which were 2.6 and 4.2 times as high as in non hazy weather, indicating that particle scattering is the main factor for visibility degradation and the occurrence of hazy weather in Hangzhou. PMID- 25826910 TI - [Characteristic of elements in PM2.5 and health risk assessment of heavy metals during heating season in Taiyuan]. AB - The fine particulate matter (PM2.5) sampled during heating season in Taiyuan city and nineteen samples were used to investigate elemental concentrations and its source potential ecological risks of heavy metals, and to assess human exposure and health risk. The result indicated that main elements were Si, Ca, Al, Na, Mg, K, Fe in PM2.5. The main sources of elements in PM2.5 were divided into five categories including soil dust (43.46%), coal burning (15.69%), vehicle emission (13.41%), industrial dust (9.89%) and the construction cement dust (9.03%). Moreover, the order of potential ecological risk index of heavy metals in PM2.5 was Cd > Ni > Hg > Pb > Cu > Zn > As > Co > Cr > Mn, and the ecological hazards were high. The main exposure of heavy metals in atmosphere was respiratory inhalation . The exposure quantity for children was significantly higher than that for adult. The hazard index values suggested a potential non-carcinogenic risk in PM2.5. PMID- 25826911 TI - [Pollution characteristics of secondary water-soluble inorganic ions of PM2.5 in urban Chengdu, China]. AB - A total of 131 samples of PM2.5 were collected at urban area of Chengdu from April, 2009 to January, 2010. The secondary water-soluble inorganic ions (NH4(+), NO3(-) and SO4(2-)) in PM2.5 were determined to study the pollution characteristics by Ion Chromatography method. The results showed the NH4(+), NO3( ) and SO4(2-) concentrations were (10.4 +/- 8.6), (19.7 +/- 14.6) and (32.8 +/- 21.8) MUg x m(-3), accounting for (5.5 +/- 2.8)%, (11.1 +/- 3.5)% and (19.3 +/- 6.4)% of PM2.5, respectively, and the sum of these three ions accounted for (35.9 +/- 12.7)%. Meanwhile, the seasonal characteristics of secondary inorganic ions were obvious. The seasonal concentrations order of secondary inorganic components was SO4(2-) > NO3(-) > NH4(+) in summer and winter, and the proportion of secondary inorganic ions of PM2.5 was 39.4% in summer and 44.3% in winter. The results of Correlation Analysis showed that most of NH4(+), NO3(-) and SO4(2-) existed as NH4HSO4, (NH4 )2SO4 and NH4NO5 in Chengdu. And the average ratio of NO3(-)/SO4(2-) indicated that the main source of sulfur and nitrogen in the atmosphere was given priority to a fixed source. In addition, the sulfate oxidizing rate (SOR) and nitrate oxidizing rate (NOR) were 0.33 +/- 0.12 and 0.19 +/- 0.09, respectively. It showed that SO4(2-) and NO3(-) in PM2.5 were due to the secondary transformation. PMID- 25826912 TI - [Temporal and spatial distribution characteristics of ozone in Beijing]. AB - Ozone concentrations obtained from 35 automatic air monitoring stations in Beijing were analyzed to investigate their temporal and spatial distribution characteristics. A process with high ozone concentration in summer was analyzed. The results showed that ozone maintained relatively high concentration from May to August while in other months, the ozone concentration was at a low level. Overall, the average concentrations of ozone in different stations in a descending order were comparison and regional station, suburban environment evaluation station, urban environmental assessment station and traffic pollution monitoring station. Ozone diurnal variation showed a single peak distribution, the peak of which appeared at 15:00 or 16:00. Ozone concentration showed obvious weekend effect, which meant ozone concentration in daytime of weekend was higher than that in weekday. Ozone concentration was lower in urban Beijing, higher in surrounding counties and the highest in northeast area with more vegetation. A high ozone concentration process occurred in Beijing on June 3, 2013. Under the effect of southwest wind in the afternoon, the concentration peaks of ozone in Yufa, Fengtaihuayuan, Olympic center and Huairou station occurred in order from south to north. Concentration peak of ozone in Huairou station occurred at 20:00 in the night. It could be concluded that significant ozone transmission characteristic was reflected in this process. PMID- 25826913 TI - [Characteristics and source apportionment of volatile organic compounds (VOCs) in the northern suburb of Nanjing]. AB - Based on the data of volatile organic compounds (VOCs) collected continuously from 1st Mar, 2011 to 29th Feb, 2012 in the northern suburb of Nanjing, characteristics of their variability, differences of ratios of tracers and source apportionment by principal component analysis/absolute principal component scores (PCA/APCS) were analyzed. The results showed that the total VOCs mixing ratios were 43.52 x 10(-9), which accounted for 45.1% of alkanes, alkenes for 25.3%, alkyne for 7.3%, and aromatics for 22.3%. There was an obviously seasonal variation of VOCs, with the maximum in summer and the minimum in winter. There was an obvious seasonal variation of VOCs component, with highest alkanes in winter, highest alkenes in summer, highest aromatic in spring, and highest alkyne in winter. By using the specific pollutant ratios ( hydrocarbons/acetylene and toluene/benzene) method, it indicated that the observation site was greatly affected by the surrounding industrial areas. Source analysis of VOCs by PCA/APCS mode showed that the sources consisted of industrial production sources, automobile emission sources, combustion sources, industrial production volatilization sources, solvent use sources and biogenic emission sources. In addition, there were seasonal variations. Overall, the sources related to industrial production activities represented 45% - 63% of VOCs, and they were followed by automobile emission sources, which represented 34% - 50%. PMID- 25826914 TI - [Environmental significance of wet deposition composition in the central Qilian Mountains, China]. AB - A total of 90 precipitation samples were collected from individual precipitation events at the Qilian Alpine Ecology & Hydrology Research Station (Hulugou Station, 30 degrees 47'N, 90 degrees 58'E; 3 260 m a. s. l) located in the central Qilian Mountains from August 2012 to November 2013. All samples were analyzed for major cations (Na, K+, Ca2+ and Mg2+), anions (Cl- , NO3- and SO4(2 )) and conductivity. Precipitation EC values ranged from 2.26 to 482 MUS x cm(-1) with an average value of 41.9 MUS x cm(-1). The precipitation was of SO4(2-) Mg(2+) -Ca2+ type, which contributed > 70% to the total ionic concentration. The same as the precipitation alkalinity, precipitation events occurred around summer showed lower concentrations, while it had higher concentrations in winter and spring with little precipitation and larger wind speed. Enrichment factor (EF), correlation and factor analysis indicated that regional crustal aerosols and species from central Asian and northwestern China arid regions brought by the westerly circulation were the major sources for these ions, some dust from human pollution were the secondary sources, and the contribution of sea salt was the least due to the long distance transport. These characteristics could be also confirmed by the correlation between ionic concentrations and metrological data in the study region. It is also interesting that the precipitation chemistry was different under the different atmospheric circulation: the monsoon precipitation, the interaction precipitation events ( influenced both by monsoon and westerly) and the westerly precipitation. PMID- 25826915 TI - [Dynamics of nitrogen and sulfur wet deposition in typical forest stand at different spatial levels in Simian Mountain, mid-subtropical region]. AB - In order to investigate the dynamics of nitrogen and sulfur wet deposition in subtropical forest ecosystem, one typical forest stand, evergreen broad-leaved forest, at Simian Mountain located in Chongqing was selected in this research. Based on field monitoring, effects of precipitation, throughfall, litterfall, and groundwater runoff of the typical forest stand on the quality of water of Simian Mountain were investigated from September 2012 to August 2013. Results showed that the rainfall of Simian Mountain was apparently acidic, with average pH of 4.89 and maximum pH of 5.14. The soil, canopies and trunks could increase pH of precipitation, with soils having the maximum increment, followed by the forest canopy. Forest canopy had the function of adsorption and purification of NO3-, NO2- and SO4(2-), and the average entrapment rate was 56.68%, 45.84% and 35.51%, respectively. Moreover, the degradation of litter was probably the main reason for the increase of ion concentrations in the surface litter water. Forest soils could absorb and neutralize NO3-, SO2- and NH4+, and release NO2-. The evergreen broad-leaf forest of mid-subtropical region had the function of interception on NO3-, NO2-, NH4+ and SO4(2-), and the total entrapment rate was 92.86%, 57.86%, 87.24% and 87.25%, respectively, and it had a certain buffering function for the acid rain. PMID- 25826916 TI - [Establishment and assessment of QA/QC method for sampling and analysis of atmosphere background CO2]. AB - To strengthen scientific management and sharing of greenhouse gas data obtained from atmospheric background stations in China, it is important to ensure the standardization of quality assurance and quality control method for background CO2 sampling and analysis. Based on the greenhouse gas sampling and observation experience of CMA, using portable sampling observation and WS-CRDS analysis technique as an example, the quality assurance measures for atmospheric CO,sampling and observation in the Waliguan station (Qinghai), the glass bottle quality assurance measures and the systematic quality control method during sample analysis, the correction method during data processing, as well as the data grading quality markers and data fitting interpolation method were systematically introduced. Finally, using this research method, the CO2 sampling and observation data at the atmospheric background stations in 3 typical regions were processed and the concentration variation characteristics were analyzed, indicating that this research method could well catch the influences of the regional and local environmental factors on the observation results, and reflect the characteristics of natural and human activities in an objective and accurate way. PMID- 25826917 TI - [An investigation of the CH4 and N2O emission factors of light-duty gasoline vehicles]. AB - In China, most of the studies of vehicular greenhouse gas (GHG) emissions have been focused on CO2 emissions. The investigation of non-CO2 GHGs, e.g. CH4 and N2O, are mainly carried out based on models developed in Europe and the US, and there are few vehicle emission tests for CH4 and N2O. In this study, 22 light duty gasoline vehicles (LDGVs) were selected for tailpipe CH4 and N2O tests using chassis dynamometer, and their emission factors were obtained based on the NEDC driving cycle. The results showed that the CH4 emission factors of China I to China IV LDGVs were 0.048 g x km(-1), 0.048 g x km(-1), 0.038 g x km(-1) and 0.028 g x km(-1), respectively. For N2O, the emission factors of China I to China IV were 0.045 g x km(-1), 0.039 g x km(-1), 0.026 g x km(-1) and 0.021 g x km( 1), respectively. In the GHGs emissions (in terms of CO2 Eq.) per LDGV, the percentage of CH4 and N2O emissions decreased gradually with tightening of emission standards. The contribution of CH4 emissions was lower than 0.5% in the total emissions, and N2O share rate was between 3.03% and 6.35%. Therefore, tightening emission standards can effectively reduce the CH4 and N2O emissions, to mitigate the greenhouse effects caused by vehicle emissions. PMID- 25826918 TI - [Experimental study on the size spectra and emission factor of ultrafine particle from coal combustion]. AB - The emission characteristics of ultrafine particles released from pulverized coal combustion were studied, the size spectra of ultrafine particles (5.6-560 nm) were measured with FMPS (fast mobility particle sizer) on a self-built aerosol experiment platform. Meanwhile, a particle dynamic evolution model was established to obtain the particle deposition rate and the emission rate through the optimized algorithm. Finally, the emission factor was calculated. The results showed that at the beginning of particle generation, the size spectra were polydisperse and complex, the initial size spectra was mainly composed of three modes including 10 nm, 30-40 nm and 100-200 nm. Among them, the number concentration of mode around 10 nm was higher than those of other modes, the size spectrum of around 100-200 nm was lognormal distributed, with a CMD (count median diameter) of around 16 nm. Then, as time went on, the total number concentration was decayed by exponential law, the CMD first increased and then tended to be stable gradually. The calculation results showed that the emission factor of particles from coal combustion under laboratory condition was (5.54 x 10(12) +/- 2.18 x 10(12)) unit x g(-1). PMID- 25826919 TI - [Distributions and air-sea fluxes of dissolved nitrous oxide in the Yangtze River estuary and its adjacent marine area in spring and summer]. AB - Distributions and air-sea fluxes of nitrous oxide (N2O) in the seawaters of the Yangtze River estuary and its adjacent marine area were investigated during two cruises in March and July 2012. Dissolved N2O concentrations in surface waters ranged from 9.34 to 49.08 nmol x L(-1) with an average of (13.27 +/- 6.40) nmol x L(-1) in spring and ranged from 7.27 to 27.81 nmol x L(-1) with an average of (10.62 +/- 5.03) nmol x L(-1) in summer. There was no obvious difference between surface and bottom N2O concentrations. N2O concentrations in both surface and bottom waters decreased along the freshwater plume from the river mouth to the open sea. High values of dissolved N2O were found in turbidity maximum zone, which suggests that maximal turbidity enhances nitrification. Temperature had dual effects on dissolved N2O concentrations. N2O saturations in surface waters ranged from 86.9% to 351.3% with an average of (111.5 +/- 41.4)% in spring and ranged from 111.7% to 396.0% with an average of (155.9 +/- 68.4)% in summer. N2O were over-saturated at most stations. The sea-to-air fluxes of N2O were estimated to be (3.2 +/- 10.9), (5.5 +/- 19.3) and (12.2 +/-52.3) MUmol x (m2 x d)(-1) in spring and (7.3 +/- 12.4), (12.7 +/- 20.4) and (20.4 +/- 35.9) MUmol x (m2 x d)( 1) in summer using the LM86, W92 and RC01 relationships, respectively. The annual emissions of N2O from the Yangtze River estuary and its adjacent marine area were estimated to be 0.6 x 10(-2) Tg x a(-1) (LM86), 1.1 x 10(-2) Tg x a(-1) (W92) and 2.0 x 10(-2) Tg x a(-1) (RC01). Although the area of the Yangtze River estuary and its adjacent marine area only accounts for 0.02% of the total area of the world's oceans, their emission of N2O accounts for 0.06% of global oceanic N2O emission, indicating that the Yangtze River estuary and its adjacent marine area is an active area to produce and emit N2O. PMID- 25826920 TI - [Spectral absorption properties of the water constituents in the estuary of Zhujiang River]. AB - Spectral absorption properties of the water constituents is the main factor affecting the light field under the surface of the water and the spectrum above the surface of the water. Thus, the study is useful for understanding of the water spectral property and the remote reversing of water quality parameters. Absorption properties of total suspended particles, non-algal particles, phytoplankton and CDOM were analyzed using the 30 samples collected in July 2013 in the estuary of Zhujiang River. The results indicated that: (1) the non-algal particles absorption dominated the absorption of the total suspended particles; (2) the absorption coefficient of the non-algal particles, which mainly came from the terrigenous deposits, decreased exponentially from short to long wavelength. In addition, the average value and spatial variation of the slope S(d) were higher than those in inland case- II waters; (3) the absorption coefficient of phytoplankton in 440 nm showed a better polynomial relationship with chlorophyll a concentration, while the absorption coefficient of phytoplankton in 675 nm linearly related with the chlorophyll a concentration. Moreover, the influence of accessory pigments on phytoplankton absorption coefficient mainly existed in the range of short wavelength, and Chlorophyll a was the main influencing factor for phytoplankton absorption in long wavelength. The specific absorption coefficient of phytoplankton decreased the power exponentially with the increase of the chlorophyll a concentration; (4) CDOM mainly came from the terrigenous sources and its spectral curve had an absorption shoulder between 250-290 nm. Thus, a piecewise S(g) fitting function could effectively express CDOM absorption properties, i.e., M value and S(g) value in period A (240-260 nm) showed a strong positive correlation. The M value was low, and the humic acid had a high proportion in CDOM; (5) the non-algal particles absorption dominated the total absorption in the estuary of Zhujiang River, and the contribution of the phytoplankton absorption to the total absorption was far lower than that of the non-algal particles. While the contribution of the CDOM was the lowest. The contribution of the CDOM absorption to the total absorption was relatively larger when the content of humic acid was higher. PMID- 25826921 TI - [Characteristics of phosphorus forms and the effects of UV light in the confluences water of Qujiang-Jialing River and Fujiang-Jialing River]. AB - The confluences water of Qujiang-Jialing River and Fujiang-Jialing River was investigated in this paper for understanding the characteristics of phosphorus (P) forms and the effects of ultraviolet (UV) irradiation. Through analysis of P speciation, the results showed that the concentration of total P was above the Eutrophication threshold (0.2 mmol x m(-3)) in this study. Meanwhile, total dissolved P (TDP) and dissolved inorganic P (DIP) were the predominant forms of total P (TP) and TDP respectively at all sampling sites, which was independent of confluences. After confluences of Fujiang-Jialing River and Qujiang-Jialing River, the concentration of all forms of P in main stream increased, among which particulate P (PP) showed the greatest increase of up to 129%. Furthermore, water was fractionated by relative molecular weight (M(r)) of composition, and the results showed the predominant forms of dissolved P (DP, < 0.22 MUm) was in the soluble high M(r) fraction (0.5 x 10(3)-10 x 10(3)), which was ranged from 47% 61% of DP. After confluences, no significant changes of P contents in different M(r) fraction of water were observed in the main stream (Jialing River). Moreover, UV irradiation experiment was conducted, and it suggested that P in free forms of water (< 0.5 x 10(3)) increased by 10% - 29%, as compared with the decreasing P in the other two M(r) fractions of M(r) 10 x 10(3)-0.22 MUm and 0.5 x 10(3)-10 x 10(3). Additionally, in comparison with confluence site samples of Fujiang-Jialing River, the decreasing trend of P in colloid fraction (10 x 10(3) 0.22 MUm) was higher in Qujiang-Jialing River. Thus, it confirmatively indicated that UV was an important environmental factor influencing the geochemical fate of P in aquatic system. PMID- 25826922 TI - [Research on the threshold of Chl-a in Lake Taihu based on microcystins]. AB - Water samples were collected in Lake Taihu from June to October in 2013 in order to investigate the threshold of chlorophyll a (Chl-a). The concentrations of three microcystins isomers (MC-LR, MC-RR, MC-YR) were detected by means of solid phase extraction and high performance liquid chromatography-tandem mass spectrometry. The correlations between various MCs and eutrophication factors, for instance of total nitrogen (TN), total phosphorus (TP), chlorophyll a, permanganate index etc were analyzed. The threshold of Chl-a was studied based on the relationships between MC-LR, MCs and Chl-a. The results showed that Lake Taihu was severely polluted by MCs and its spatial distribution could be described as follows: the concentration in Meiliang Bay was the highest, followed by Gonghu Bay and Western Lake, and Lake Center; the least polluted areas were in Lake Xuhu and Southern Lake. The concentration of MC-LR was the highest among the 3 MCs. The correlation analysis indicated that MC-LR, MC-RR, MC-YR and MCs had very positive correlation with permanganate index, TN, TP and Chl-a (P < 0.01). The threshold value of Chl-a was 12.26 mg x m(-3) according to the standard thresholds of MC-LR and MCs in drinking water. The threshold value of Chl-a in Lake Taihu was very close to the standard in the State of North Carolina, which demonstrated that the threshold value provided in this study was reasonable. PMID- 25826923 TI - [Temporal and spatial characteristic of nitrogen and phosphorus output in the suburb watershed around the Baihua Lake]. AB - Identification of the main pollutants and sources has important practical significance for the control and management of water quality in Guiyang's surrounding river areas. Based on the continuous field observation of the experiment from July, 2010 to April, 2011, this paper studies the concentration of nitrogen and phosphorus loss characteristics of Maixi river watershed, which is near to Guiyang's important water source-Baihua Lake reservoir, so as to provide a reference for Guiyang suburban small watershed source pollution control. The existence of various sources and sinks in this river basin makes great changes of nitrogen output in each sample point at different times, from upstream to downstream. Although different forms of nitrogen content and phosphorus content in water at each sampling point changes with time, it still presents a certain regularity on the whole. The total nitrogen and nitrate nitrogen in July 2010 are above normal level, and the ammonia nitrogen, nitrate nitrogen and total phosphorus are at high levels in October 2010 and December. The differences of various forms of nitrogen and phosphorus content in water at each sampling point decrease from upstream to downstream. The content of TN decreases from 3.297 mg x L(-1) to 2.793 mg x L(-1), and the content of TP decreases from 0.136 mg x L(-1) to 0.098 mg x L(-1). Contrast to the upstream, the nitrogen and phosphorus content in the downstream estuary decreases significantly. But the change is not obvious and the content of ammonia nitrogen rises slightly compared with the middle reaches. From the perspective temporal and spatial variation characteristics of nitrogen and phosphorus output in the basin, the nitrogen, especially ammonia nitrogen and nitrate, has a higher risk of getting into the Baihua Lake by river runoff. The results of the study can provide a reference for the governance of nitrogen and phosphorus loss in the watershed around the Baihua Lake. PMID- 25826924 TI - [Effects of light irradiation on phosphorous releases from typical submerged soils of water-level fluctuation zones of Three Gorges Reservoirs areas]. AB - For understanding the impact of light irradiation on the phosphorus (P) releases from soil-water interface, two types of typical soils sampled from water-level fluctuation zones of Three Gorges Reservoir areas were selected as research objectives, and simulated light irradiation experiment in lab was conducted for unveiling the underlying mechanisms of P releases from submerged soils in the presence of light irradiation. The results showed that light irradiation could inhibit P releases from submerged soils by a certain degree. Under light condition, total P (TP) concentrations in underlying water of submerged purple soil ranged from 0.018 to 0.033 mg x L(-1), as compared to the range of 0.02 0.057 mg x L(-1) in darkness treatment. Additionally, for gray-brown purple soil, TP was in a range of 0.028-0.045 mg x L(-1) when light irradiated, but in the range of 0.04-0. 084 mg x L(-1) under darkness condition. Meanwhile, changes of iron oxides in soils due to light irradiation were possibly to be the important reason to explain the inhabitation of light irradiation on P releases. Moreover, light irradiation resulted in decreasing saturation degree of iron oxides in soils, which further inhibited the iron reduction and production of amorphous iron, further enhanced the underlying mechanisms of decreasing P releases in presence of light irradiation. Further, CO2 and CH4 could reflect decomposition of soil organic carbon (SOC) in submerged condition. Light irradiation significantly decreased SOC transformation into carbon gases. Stimulating consumption of inorganic electron acceptors in submerged soils could also be used to explain the changes of iron oxides under light irradiation condition. Thus, inhabitation of light irradiation on P releases from submerged soils obviously related with iron minerals reduction and decomposition of organic matter in soils. PMID- 25826925 TI - [Mercury dynamics of several plants collected from the water-level fluctuation zone of the Three Gorges Reservoir area during flooding and its impact on water body]. AB - Submerged plants are a major source for the abnormal elevation of methylmercury in reservoir. Several specific plants (Echinochloa crusgalli, Cynodondactylon and Corn stover) were collected and inundated in a simulated aquatic environment in the laboratory for investigating the mercury (Hg) dynamics in plants and the release process into water, aiming to find out the properties of Hg dynamics of plants under inundation conditions and its impact on water body in the Water Level Fluctuation Zone of the Three Gorges Reservoir Area. The results showed that the contents of total mercury in several plants were in the range of 9. 21 12.07 ng x g(-1), and the percentage content of methylmercury (MeHg) was about 1% 2%. The content of total mercury (THg) in plants gradually decreased, by 35.81% 55.96%, whereas that of the dissolved mercury (DHg) increased sharply, by 103.23% -232.15%, which indicated an emission of Hg from plants to water in the process of decomposition. Furthermore, the state of inundation provided sufficient conditions for the methylation process in plants and therefore caused an increase of the content of methylmercury in the plant residues, which was 3.04-6.63 times as much as the initial content. The concentration of dissolved methylmercury (DMeHg) in the overlying water also increased significantly by 14.84- 16.05 times compared with the initial concentration. Meanwhile, the concentration of dissolved oxygen (DO) in the overlying water was significantly and negatively correlated with DMeHg. On the other hand, the concentration of dissolved organic carbon (DOC) in the overlying water was significantly and positively correlated with DMeHg. During the whole inundation period, the increase of DHg in the overlying water accounted for 41.74% -47.01% of the total amount of THg emission, and there was a negative correlation between the content of THg in plant residues and that of DHg in the overlying water. PMID- 25826926 TI - [Effect of nano-TiO2 on the release and activation of mercury in sediment]. AB - To investigate the effects of nano-TiO2 on mercury release and activation in sediment, flooding simulation experiments were conducted. The impacts of nano TiO2 on total mercury and methylmercury concentrations in overlying water were analyzed. And the influences of nano-TiO2 on the migration and transformation of mercury were discussed based on changes of mercury speciation in sediment. The results indicated that nano-TiO2 promoted the release of mercury in sediment, leading to more mercury released into the water. Compared with the control, 4 g x kg(-1) TiO2 nanoparticles increased the total mercury by 91.32%, when the concentration of total mercury in overlying water was the highest. Release of mercury in soil was increased by approximately 10% finally. The main reason may be that the dissolution of oxidation state mercury was improved by nano-TiO2. It indicated that the risk of mercury contamination in water may increase. Moreover, under the experimental conditions, nano-TiO2 may reduce the formation of methylmercury in sediment in the short-term, but no significant effects in the long-term. Generally, the effects of nano-TiO2 on the release and transformation of mercury in sediment showed concentration dependence. Thus, with increasing nano-TiO2 content in sediment or soil, its impact on the geochemical cycle of mercury may increase. PMID- 25826927 TI - [Estimation inventory of polycyclic aromatic hydrocarbons (PAHs) from anthropogenic sources and its impacts within the Yanghe Watershed, an important water-source site of Beijing, China]. AB - The Yanghe Watershed, situated at the upwind of Beijing, is an important water source site and ecologic protection barrier for Beijing and Zhangjiakou cities. The Yanghe Watershed is also a farming-pastoral transitional area and an ecologically vulnerable and sensitive region, as well as the place applying for Winter Olympic Game in 2022. Establishment of atmospheric emissions inventory of polycyclic aromatic hydrocarbons (PAHs) and identification of its sources within the Yanghe Watershed and its possible transportation paths to Beijing can help us get a better understanding of regional environmental pollution (especially air environmental pollution) in Beijing-Zhangjiakou area. In the present study, PAHs emission from different counties and cities within the Yanghe Watershed in 2012 was calculated based on the statistical data of local industries, agriculture and resident living while PAHs emission factors were estimated. According to the cluster analysis for air transport trajectories, main categories of air masses were obtained. Results indicated that total emission of PAHs in 2012 was 4.4 x 10(2) t. Coal combustion and crop-straw burning were the most important emission sources of PAHs, accounting for 76% and 16% of total emission of PAHs, respectively. Xuanhua county had the greatest emission of PAHs (49 t), followed by Xinghe (36 t), Tianzhen (32 t), Huailai (24 t) and Wanquan (15 t). In emission of 16 isomers of PAHs, the emission of high molecular weight isomers containing 4 6 rings was approximate to that of low molecular weight isomers containing 2-3 rings, accounting for approximately 50% of total emission of PAHs. Emission of PAHs had positive correlations with gross industrial production (GIP) (r = 0.96, P < 0.05) and resident income (RI) (r = 0.94, P < 0.05) and population density (PD) (r = 0.92, P < 0.05), but negatively correlated with land area (LA) (r = - 0.9, P < 0.05) and no significant correlationship with gross output value of agriculture (GOA) (r = 0.026, P > 0.01). The high emission of PAHs within the Yanghe Watershed was associated with local energy structure and residents' consumption level. Combined the back trajectory analysis with PAHs emission, high amount of PAHs could be transported to Beijing by northwest airflow, suggesting its potential ecological risk and human health effect in Beijing. PMID- 25826928 TI - [Source identification of toxic wastewaters in a petrochemical industrial park]. AB - Petrochemical wastewaters have toxic impacts on the microorganisms in biotreatment processes, which are prone to cause deterioration of effluent quality of the wastewater treatment plants. In this study, the inhibition effects of activated sludge's oxygen consumption were tested to evaluate the toxicity of production wastewaters in a petrochemical industrial park. The evaluation covered the wastewaters from not only different production units in the park, but also different production nodes in each unit. No direct correlation was observed between the toxicity effects and the organic contents, suggesting that the toxic properties of the effluents could not be predicted by the organic contents. In view of the variation of activated sludge sensitivity among different tests, the toxicity data were standardized according to the concentration-effect relationships of the standard toxic substance 3, 5-dichlorophenol on each day, in order to improve the comparability among the toxicity data. Furthermore, the Quality Emission Load (QEL) of corresponding standard toxic substance was calculated by multiplying the corresponding 3, 5-dichlorophenol concentration and the wastewater flow quantity, to indicate the toxicity emission contribution of each wastewater to the wastewater treatment plant. According to the rank list of the toxicity contribution of wastewater from different units and nodes, the sources of toxic wastewater in the petrochemical industrial park were clearly identified. This study provides effective guidance for source control of wastewater toxicity in the large industrial park. PMID- 25826929 TI - [Investigation of pollution characteristics of erythromycin resistance genes in a sewage treatment plant and the relevant selective factors]. AB - Occurrence and distribution of twelve pharmaceutical and personal care products (PPCPs) were investigated in a sewage treatment plant in Shanghai using solid phase extraction combined with high-performance liquid chromatography-tandem mass spectrometry (SPE-HPLC-MS/MS). Quantitative PCR (qPCR) was used to determine the distribution and removal of seven erythromycin resistance genes (ERY-ARGs). The results showed that five PPCPs including sulfamethoxazole, erythromycin, tetracycline, carbamazepine and triclosan were detected in the collected wastewater samples with concentrations in the ranges of 24.5- 38.7, 47.5-49.2, 43.1-85.4, 2.5-3.9 and 423.2-8 973.3 ng x L(-1), respectively. During the wastewater treatment process, a significant reduction of triclosan was observed, but the removal efficiencies for the other detected PPCPs were relatively low. Additionally, all target ERY-ARGs were detected in the wastewater samples ranging from 9.28 x 10(3) (ermA) to 1.83 x 10(8) (ereA) copies x L(-1) in raw influent. Though significant reductions (1.19 log-3.97 log) of ERY-ARGs were obtained, their concentrations found in the final effluent were still high. Moreover, the concentration of ERY-ARGs exhibited significant positive correlation with the concentration of erythromycin and triclosan (P < 0.05), respectively, elucidating that erythromycin played an important role in the occurrence and spread of ERY ARGs, while triclosan may confer cross-selection for ERY-ARGs. PMID- 25826930 TI - [Variation of pollutants along the height of two media BAF during advanced treatment of dyeing wastewater]. AB - A pilot-scale process with the capacity of 15 t x d(-1) was applied for treatment of the secondary biological effluent from a dyeing industrial park wastewater treatment plant. We studied the variation of pollutants along the height of two media biological aerated filter (BAF), investigated the feasibility of the cheaper and lighter suspended media to substitute activated carbon. The results showed that while the influent average COD and color were 50.2 mg x L(-1) and 58 times, the effluent average COD and color of activated carbon and suspended media BAF were 35.0 mg x L(-1), 18 times and 44.3 mg x L(-1), 26 times, and both of the effluent met the first level A criteria specified in the Discharge Standard of Pollutants for Municipal Wastewater Treatment Plant (GB 18918-2002), while it met the first level A criteria at the height of 2 400 mm in suspended media BAF, higher than the height of 1 800 mm in activated carbon BAF. The removal variation of color, TN and ammonia along the height of suspended media BAF is similar to the activated carbon BAF, but with a low removal efficiency of COD, mainly related to its less biomass. Therefore, suspended media to substitute activated carbon is feasible to the wastewater treatment plant, but the size and material of the media still need to be optimized, and to enhance the biomass, the hybrid process of suspended media with activated carbon BAF may be used to reduce the cost if it is necessary. PMID- 25826931 TI - [Acclimatization and characteristics of microbial community in sulphate-dependent anaerobic methane oxidation]. AB - The greenhouse effect of methane is 26 times worse than that of carbon dioxide, and wastewater containing high concentrations of sulfate is harmful to water, soil and plants. Therefore, anaerobic oxidation of methane driven by sulfate is one of the effective ways for methane reduction. In this paper, with sulfate as the electron accepter, a microbial consortium capable of oxidating methane under anaerobic condition was cultured. The diversity and characteristics of bacterial and archaeal community were investigated by PCR-DGGE, and phylogenetic analysis of the dominant microorganisms was also carried out. The DGGE fingerprints showed that microbial community structure changed distinctly, and the abundance of methane-oxidizing archea and sulfate-reducing bacteria increased in the acclimatization system added sulfate. After acclimatization, the bacterial diversity increased, while archaea diversity decreased slightly. The representative bands in the DGGE profiles were excised and sequenced. Results indicated that the dominant species in the acclimatization system were Spirochaetes, Desulfuromonadales, Methanosarcinales, Methanosaeta. Methane converted into carbon dioxide while sulfate transformed into hydrogen sulfide and sulfur in the process of anaerobic methane oxidation accompanied by sulphate reduction. PMID- 25826932 TI - [Capability and microbial community analysis of a membrane bioreactor for acrylic fiber wastewater treatment]. AB - Sequencing batch membrane bioreactor (SBMBR) was used for the treatment of acrylic fiber polymerization wastewater and acrylonitrile wastewater. The operation efficiencies of SBMBR under different wastewater ratios and operation conditions were investigated, and the microbial community structure of the SBMBR system was analyzed by using PCR-DGGE technology. The results showed that SBMBR had a high removal efficiency on pollutants in acrylic fiber wastewater, and the lacking of carbon source and alkalinity were the main limiting factors for nitrogen removal. Under the designed operation conditions of 90 min anoxic/150 min aerobic cyclic operation and HRT of 24 h, the average COD, NH4(+) -N and TN removal efficiencies were 82.5%, 98.7% and 74.6%, respectively. The effluent of the SBMBR could steadily meet the Grade I standards of the Wastewater Comprehensive Discharge Standard of China (GB 8978-1996). The PCR-DGGE analyses showed that the microbial communities in SBMBR had a significant shift with the changes of influent characteristics and operation conditions. By cloning and sequencing analyses of selected dominant bacteria, 22 16S rDNA sequence were successfully identified from 9 sludge samples, from which 7 dominant functional microorganisms for the degradation of organic pollutants in acrylic fiber wastewater were screened out. PMID- 25826933 TI - [Nitrogen removal performance of ANAMMOX ABR process in tannery wastewater treatment]. AB - Anaerobic ammonium-N removal from tannery wastewater was investigated using a lab scale anaerobic baffled reactor (ABR). The results indicated that ABR could be used as a good anaerobic ammonium oxidation reactor, the stable and effective performance of ammonium-N and COD removal from tannery wastewater was demonstrated in the ANAMMOX ABR. When the NH4(+) -N concentration of the influents were in the range of 25.0 mg x L(-1) to 76.2 mg x L(-1) and COD ranged from 131 mg x L(-1) to 237 mg x L(-1), under the volumetric loading of 0.05 kg x (m3 x d)(-1) to 0.15 kg x (m3 x d)(-1), the NH4(+)-N and COD of the effluents were from 0.20 mg x L(-1) to 7.12 mg x L(-1) and from 35.1 mg x L(-1) to 69.2 mg x L(-1), respectively, and the removal efficiency of NH4(+) -N and COD were 90.8% to 99.6% and 66.9% to 74.7%, respectively. In addition, the brown-red, brown yellow, red granular sludges were developed in ABR. SEM observation confirmed the presence of ANAMMOX bacteria in granular sludge of all four compartments of ANAMMOX ABR. According to FISH results, ANAMMOX bacteria had grown in all four compartments to various degrees during the acclimatization and running process, the percentage of ANAMMOX bacteria in sludge increased from 4% to 9%, 8%, 12% and 30% in compartment 1, compartment 2, compartment 3 and compartment 4, respectively, and a higher population percentage of ANAMMOX bacteria existed in the rear than in the front compartments. PMID- 25826934 TI - [Numerical simulation and operation optimization of biological filter]. AB - BioWin software and two sensitivity analysis methods were used to simulate the Denitrification Biological Filter (DNBF) + Biological Aerated Filter (BAF) process in Yuandang Wastewater Treatment Plant. Based on the BioWin model of DNBF + BAF process, the operation data of September 2013 were used for sensitivity analysis and model calibration, and the operation data of October 2013 were used for model validation. The results indicated that the calibrated model could accurately simulate practical DNBF + BAF processes, and the most sensitive parameters were the parameters related to biofilm, OHOs and aeration. After the validation and calibration of model, it was used for process optimization with simulating operation results under different conditions. The results showed that, the best operation condition for discharge standard B was: reflux ratio = 50%, ceasing methanol addition, influent C/N = 4.43; while the best operation condition for discharge standard A was: reflux ratio = 50%, influent COD = 155 mg x L(-1) after methanol addition, influent C/N = 5.10. PMID- 25826935 TI - [Effect of gas-lift device on the morphology and performance of ANAMMOX sludge]. AB - The upflow reactor with gas-lift device was started up by inoculating ANAMMOX sludge granules of less than 0.9 mm. The effects of gas lift device system on the morphology and performance of ANAMMOX sludge were studied by using the nitrogen gas produced in ANAMMOX to drive the effluent circulation in the reactor. The results showed that, the airlift circulation function was not clear in the startup stage of the reactor, because the nitrogen gas production was very low. At the same time, the ANAMMOX granular sludge was easy to condensate. When the load rate of nitrogen removal reached 3.4 kg x (m3 x d)(-1), the function of gas lift was significant, resulting in gradually increased effluent self-circulation, and the granules were dispersed and grew gradually. After 183d of operation, the granular sludge was dominated by the granules with sizes of 1.6-2.5 mm, which accounted for 53.2% of the total sludge volume. The MLVSS content increased with the increase of sludge particle size. The gas lift device had the same function as the external reflux pump, and was helpful for sludge granulation in the ANAMMOX reactor, while reducing power consumption and the cost of the equipment. PMID- 25826936 TI - [Water treatment residual as a bioretention media amendment for phosphorus removal]. AB - The characteristics of phosphorus adsorption of both soil and water treatment residual (WTR) were investigated through batch tests. The removal of phosphorus in runoff by bioretention column was evaluated. Furthermore, the feasibility of taking the WTR as a bioretention amendment was discussed. The results indicated that the phosphorus adsorptive capacity of WTR was significantly higher than that of soil. With a high influent phosphorus concentrations (1.0 mg x L(-1)), the columns with amended media showed a better long-term removal efficiency than the columns with traditional media. The concentrations of TP in effluent from columns with amended media were less than 0.050 mg x L(-1) after 7 months' continuous operation. According to batch test results, it was estimated that the phosphorus adsorptive capacity of amended media, which was mixed with 4% of WTR, was 4 times as high as the traditional media under same conditions. Adsorption and precipitation by amorphous iron and aluminum is the main mechanism for phosphorus removal in amended media. It is recommended that the mixture with 4% - 5% of WTR by mass in media would improve the phosphorus removal of bioretention in engineering practice. PMID- 25826937 TI - [Nutrient contents and heavy metal pollutions in composted sewage sludge from different municipal wastewater treatment plants in Beijing region]. AB - Changes of nutrient contents and heavy metal pollutions in composted sewage sludge from different municipal wastewater treatment plants (as represented by CSS-A and CSS-B, respectively) in Beijing region were investigated. The results showed that the pH values, nutrient contents, trace elements and heavy metals in CSS-A and CSS-B depended on the sludge resources and particular years. The average of organic matter content in different years (203 338.0 mg x kg(-1)) from CSS-A met both the requirement of sludge quality standard for agricultural use (CJ/T 309-2009) and land improvement (GB/T 24600-2009) in China except the permitted limit of sludge quality standards for garden or park use (GB/T 23486 2009) in China. Moreover, the average of organic matter in different years (298531.5 mg x kg(-1)) from CSS-B and the averages of pH values (7.1 and 7.2, respectively) and NPK concentrations (41 111.7 mg x kg(-1) and 65 901.5 mg x kg( 1), respectively) in different years from CSS-A and CSS-B all met the requirements of sludge quality standards for the above-mentioned disposal types of sewage sludge from municipal wastewater treatment plants. The contents of heavy metals in CSS-A and CSS-B except Hg and Ni were below the permitted limits of the A-class sludge quality standard for agricultural use (CJ/T 309-2009) , being the most stringent standards in China. It was suggested that composted sewage sludge from different municipal wastewater treatment plants in Beijing region use as a fertilizer in agriculture, land improvement, and garden or park, but the top concern about potential environmental pollution of Hg and Ni should be considered. PMID- 25826938 TI - [Polychlorinated biphenyls and their methylsulfonyl metabolites in fish from an electronic waste recycling site in south China: tissue distribution and human dietary exposure]. AB - In the present study, we determined polychlorinated biphenyls and their methylsulfonyl metabolites (MeSO2-PCBs) in the tissues of two fish species-mud carp and northern snakehead-from a natural pond in an electronic waste recycling site in the Pearl River Delta, Southern China. The mean concentrations of PCBs (Sigma PCBs )varied from 560 to 10 462 ng x g(-1) wet weight, and from 580 to 50 492 ng x g(-1) wet weight in the tissues of mud carp and northern snakehead, respectively, with the highest levels found in the liver. Lipid contents played an important role in the determination of tissue distribution of PCBs. The mean concentrations of Sigma MeSO2-PCBs varied between 0.44 and 53 ng x g(-1) wet weight in tissues of mud carp, while varied between 1.86 and 132 ng x g(-1) wet weight in northern snakehead. These levels were one order of magnitude greater than the highest levels of MeSO2-PCBs previously reported in fish. The EF values of chiral PCBs in mud carp were lower than those in the sediments, with an exception of PCB149. However, the declined EFs in mud carp were rebounded in northern snakehead, and some values were even higher than those in the sediment. This result may suggest that the mud carp and the northern snakehead preferred to biotransform different enantiomers of PCB congeners. The elevated levels of Sigma PCBs and Sigma MeSO2-PCBs detected in the present study indicated a high exposure risk to the local residents. Restricting the consumption of these fish in the local markets is important and essential for reducing the health risks to local residents. PMID- 25826939 TI - [Residues and health risk assessment of HCHs, DDTs and heavy metals in water and Tilapias from fish ponds of Guangdong]. AB - Concentrations of copper, lead, cadmium, arsenic, hexachlorcyclohexane (HCHs) and dichlorodiphenyltrichloroethane (DDTs) in the water and the fish samples collected separately from fish pond, markets and supermarkets in four cities of Guangdong Province were measured by using GC-ECD, flame atomic absorption spectrometry and atomic fluorescence spectrometry. Health risk assessments associated with Cu, Pd, Cd, As, HCHs and DDTs were conducted based on the model of health risk assessment recommended by the US EPA. The results showed that the concentration ranges of Cu, Pd, Cd, As, HCHs and DDTs in water samples were nd 0.101 mg x L(-1), nd-0.097 mg x L(-1), nd-0.003 27 mg x L(-1), 0.0121-0.08127 mg x L(-1), 2.63-37.18 ng x L(-1) and 2.05-12.21 ng x L(-1), respectively. The health risk assessment indicates that the carcinogenic and non-carcinogenic risks of Cu, Pd, Cd, HCHs and DDTs in Tilapias both lower than the highest acceptable level of risk set by ICRP, but As cancer risk value slightly exceeded the upper limit of the acceptable risk levels in city population. PMID- 25826940 TI - [Concentration and distribution characteristics of estrogen in aquatic organism from Chongming Island]. AB - Five typical estrogens, including estrone (E1), 17beta-estradiol (E2), estriol (E3), 17alpha-ethynyl estradiol (EE2) and bisphenol A (BPA), were simultaneously determined in typical aquatic organisms from Chongming Island by ultrahigh performance liquid chromatography equipped with tandem mass spectrometry (UHPLC MS2). The distribution pattern of estrogens was studied and preliminary heath risk assessment was discussed. The results showed that the total dry weight concentrations of estrogens were from 1.1 ng x g(-1) to 7.38 ng x g(-1) with a mean of 4.25 ng x g(-1). The lipid content-standardized estrogens concentrations were in the range of 5.01- 83.41 ng x g(-1) with a mean of 40.75 ng x g(-1), showing a descending order of fish > shrimp > crab. Fish and crab, fish and shrimp showed a significant difference in lipid content-standardized estrogen concentrations, whereas no significant difference was found between crab and shrimp. Compared to BPA, the dry weight concentrations of steroids (E1, E2, E3 and EE2) were found at lower levels (0.17-0.69 ng x g(-1)) with lower detection frequency (< 66.67%) in aquatic organisms from Chongming Island. In contrast, the detection rate of BPA reached 100%, and the average dry weight concentration detected was 2.60 ng x g(-1). The results of health risk assessment showed the concentration of estrogens in aquatic products from Chongming Island could not cause any adverse population-level effects. PMID- 25826941 TI - [Photocatalytic degradation of acetamiprid by TiO2 and Xe lamp: kinetics and degradation intermediates]. AB - Photocatalytic degradation kinetics of acetamiprid was studied by both of single variable-at-a-time (SVAT) and central composite design (CCD) experiments based on four factors, such as catalyst dosages, substrate concentration, temperature and pH values. The results indicated that degradation of acetamiprid followed pseudo first-order kinetics by Langmuir-Hinshelwood model, increased with the increasing of temperature and the decreasing of substrate concentration. The photocatalytic degradation kinetic rate of acetamiprid was low in acid solutions, while high in weak acidic and alkaline solutions. After studying the synergistic effects of these four classic parameters, the optimal experiment conditions for photocatalytic degradation of acetamiprid were obtained as follows: TiO2 at 2.30 g x L(-1), initial acetamiprid concentration of 90.0 MUmol x L(-1), temperature of 37.5 degrees C and pH value at 5.0. Lastly, 7 degradation intermediates of acetamiprid were detected during photocatalytic process by HPLC, and 6 of them exhibited more polar than the parent molecule. PMID- 25826942 TI - [Effects of nitrogen addition on available nitrogen content and acidification in cold-temperate coniferous forest soil in the growing season]. AB - Based on a low-level and multi-form N addition control experiment, this study took cold-temperate coniferous forest in Daxing'an Ling as the research object. After long-term and continuous nitrogen addition in situ, the available nitrogen (NH4(+) -N & NO3(-) -N) contents and pH values of the soil (0-10 cm) were measured in the early growing season (May) and the peak growing season (August) in 2010, 2012 and 2013. The results showed that, the available nitrogen in the early and peak growing seasons was mainly NH4(+) -N which accounted for over 96% of the inorganic nitrogen content, while the content of NO3(-) -N was very low. With the time extension of nitrogen addition, the effects of nitrogen addition on the NH4(+) -N content in 0-10 cm soil were more obvious in the early growing season than that in the peak growing season, and the NH4(+) -N content was mainly affected by the type of nitrogen addition. On the contrary, the NO3(-) -N content in 0-10 cm soil was higher in the peak growing season than that in the early growing season. The effect of N input was obvious on NO3(-) -N content in both early and peak growing seasons, and low nitrogen treatment tended to promote the enrichment of NO3(-) -N. As time went on, the response of NH4(+) -N and NO3(-) -N content to N addition was changed from insignificant in the early stage to significant in the late stage. N addition had a significant impact on the pH value of the 0-10 cm soil in the early and peak growing seasons. The pH values of the soil with low nitrogen treatment and the soil in the peak growing season were relatively lower. With the extension of the nitrogen addition time, the response of pH value also turned from insignificant in the early stage to significant in the late stage. Because of the long-term and continuous nitrogen addition, the 0 10 cm soil in this cold-temperate coniferous forest was obviously acidified. PMID- 25826943 TI - [Impact of land use type on stability and organic carbon of soil aggregates in Jinyun Mountain]. AB - Soil aggregates have the important effect on soil fertility, soil quality and the sustainable utilization of soil, and they are the mass bases of water and fertilizer retention ability of soil and the supply or release of soil nutrients. In this paper, in order to study the impact of land use type on stability and organic carbon of soil aggregates in Jinyun Mountain, we separated four land use types of soil, which are woodland, abandoned land, orchard and sloping farmland by wet sieving method, then we got the proportion of large macroaggregates (> 2 mm), small macroaggregates (0.25-2 mm), microaggregates (53 MUm-0.25 mm) and silt + clay (< 53 MUm) and measured the content of organic carbon in each aggregate fraction in soil depth of 0-60 cm and calculated the total content of organic carbon of all aggregates fraction in each soil. The results showed that reclamation of woodland will lead to fragmentation of macroaggregates and deterioration of soil structure, and the proportion of macroaggrgates (> 0.25 mm) were 44.62% and 32.28% respectively in the soils of orchard and sloping farmland, which reduced 38.58% (P < 0.05) and 91.52% (P < 0.05) compared with woodland. While after changing the sloping farmland to abandoned land, which lead to the conversion of soil fraction from silt + clay to large macroaggregates and small macroaggregates, so it will improve the soil structure. MWD (mean weight diameter) and GMD (geometric mean diameter) are important indicators of evaluating the stability of soil aggregates. We found the MWD and GWD in soil depth of 0-60 cm in orchards and sloping farmland were significantly lower than those in woodland (P < 0.05), while after changing the sloping farmland to abandoned land, the MWD and GWD increased significantly (P < 0.05), which indicated that reclamation of woodland will lead to the decrease of stability of soil aggregates, and they will be separated more easily by water. However, after changing the sloping farmland to abandoned land will enhance the stability of soil aggregates, and improve the ability of soil to resist external damage. The organic carbon content in each soil aggregate of four land use types decreased with the increase of soil depth. In soil depth of 0-60 cm, the storage of organic carbon of large macroaggregates in each soil are in orders of woodland (14.98 Mg x hm(-2)) > abandoned land (8.71 Mg x hm(-2)) > orchard (5.82 Mg x hm(-2)) > sloping farmland (2.13 Mg x hm(-2)), and abandoned land (35.61 Mg x hm(-2)) > woodland (20.38 Mg x hm-(-2)) > orchard (13.83 Mg x hm(-2)) > sloping farmland (6.77 Mg x hm(-2)) in small macroaggregates, and abandoned land (22.44 Mg x hm( 2)) > woodland (10.20 Mg x hm(-2)) > orchard (6.80 Mg x hm(-2)) > sloping farmland (5. 60 Mg x hm(-2)) in microaggregates, and abandoned land (22.21 Mg x hm(-2)) > woodland (17.01 Mg x hm(-2)) > orchard (16.70 Mg x hm(-2)) > sloping farmland (9.85 Mg x hm(-2)) in silt and clay fraction. Storage of organic carbon in each aggregate in the soils of woodland and abandoned land were higher than those in the soils of orchard and sloping farmland, which indicated that reclamation of woodland will lead to a loss of organic carbon in each soil aggregate fraction, while after changing the sloping farmland to abandoned land will contribute to restore and sequestrate the soil organic carbon. In addition, it showed that most organic carbon accumulated in small macroaggregate in soils of woodland and abandoned land, while they are in silt and clay in soils of orchard and sloping farmland, indicating that organic carbon in larger aggregates is unstable and is easier to convert during the land use change. PMID- 25826944 TI - [Investigation and canonical correspondence analysis of salinity contents in secondary salinization greenhouse soils in Shanghai suburb]. AB - The salinity characteristics of greenhouse soils with cropping obstacles in Shanghai suburb were investigated and analyzed. The salinity contents of the salinization greenhouse soils showed a trend of first increasing and then decreasing with the increasing cropping duration. The salinized soils mainly included slightly salted, mildly salted and salted soils, which accounted for 17.39%, 56.52% and 13.04%, respectively. Among them, the degree of salinity in greenhouse soil planted with asparagus in Chongming County was the highest. Among the salt ions in greenhouse soils, the cations were mainly Ca2+ and Na+, while the anions were mainly NO3- and SO4(2-). The degree of salinity was mainly influenced by fertilization mode, cropping duration, crop type and management level, which led to the great variation in the salinity contents and salt ions. Canonical correspondence analysis found that the contents of Ca2+, Mg2+ and NO3- in greenhouse soils were greatly affected by cropping duration, and the degree of salinity would be enhanced and attenuated with long-term application of single fertilizer and mixed application of chemical fertilizer and organic manure, respectively. The greenhouse soils in Shanghai suburb could be classified as four patterns influenced by the relationship between salinity ions and samples, and the most soils were influenced by Ca2+, Mg2+, NO3- and Cl-, which required to be primarily controlled. PMID- 25826945 TI - [Spatial distribution prediction of surface soil Pb in a battery contaminated site]. AB - In order to enhance the reliability of risk estimation and to improve the accuracy of pollution scope determination in a battery contaminated site with the soil characteristic pollutant Pb, four spatial interpolation models, including Combination Prediction Model (OK(LG) + TIN), kriging model (OK(BC)), Inverse Distance Weighting model (IDW), and Spline model were employed to compare their effects on the spatial distribution and pollution assessment of soil Pb. The results showed that Pb concentration varied significantly and the data was severely skewed. The variation coefficient of the site was higher in the local region. OK(LG) + TIN was found to be more accurate than the other three models in predicting the actual pollution situations of the contaminated site. The prediction accuracy of other models was lower, due to the effect of the principle of different models and datum feature. The interpolation results of OK(BC), IDW and Spline could not reflect the detailed characteristics of seriously contaminated areas, and were not suitable for mapping and spatial distribution prediction of soil Pb in this site. This study gives great contributions and provides useful references for defining the remediation boundary and making remediation decision of contaminated sites. PMID- 25826946 TI - [Immobilization remediation of Cd and Pb contaminated soil: remediation potential and soil environmental quality]. AB - A pot experiment was conducted to investigate the immobilization remediation effects of sepiolite on soils artificially combined contamination by Cd and Pb using a set of various pH and speciation of Cd and Pb in soil, heavy metal concentration in Oryza sativa L., and soil enzyme activity and microbial quantity. Results showed that the addition of sepiolite increased the soil pH, and the exchangeable fraction of heavy metals was converted into Fe-Mn oxide, organic and residual forms, the concentration of exchangeable form of Cd and Pb reduced by 1.4% - 72.9% and 11.8% - 51.4%, respectively, when compared with the control. The contents of heavy metals decreased with increasing sepiolite, with the maximal Cd reduction of 39.8%, 36.4%, 55.2% and 32.4%, respectively, and 22.1%, 54.6%, 43.5% and 17.8% for Pb, respectively, in the stems, leaves, brown rice and husk in contrast to CK. The addition of sepiolite could improve the soil environmental quality, the catalase and urease activities and the amount of bacteria and actinomycete were increased to some extents. Although the fungi number and invertase activity were inhibited compared with the control group, it was not significantly different (P > 0.05). The significant correlation between pH, available heavy metal content, urease and invertase activities and heavy metal concentration in the plants indicated that these parameters could be used to evaluate the effectiveness of stabilization remediation of heavy metal contaminated soil. PMID- 25826947 TI - [Rules and impact factors of greenhouse gases emission in the saline-alkali paddy fields in different years]. AB - With the method of combining field sampling and plot test, we took saline-alkali paddy field of Qianguo county, Jilin province as an investigation object. According to the nature of soil in the area, we monitored CH4 and N2O which released from soil during rice growth period and tested the soil pH and soil organic carbon to analyze the law and reasons of greenhouse gas emission in the paddy fields. The results showed that N2O emission from paddy fields presented three peaks with distinct seasonal patterns. Application of fertilizer provided additional reactive substrate, which affected N2O emission significantly. Under flooding conditions, the main source of N2O is a denitrification process, while after drainage, nitrification was the predominance. CH4 emission showed a single peak at rice tillering stage when rice grew vigorously. That deoxidation condition dominated in the deep water layer in the paddy fields provided suitable conditions for CH4 producing microorganisms, which result in the emergence of CH4 emission peak. The pH doesn't have an obvious influence on CH4 and N2O, while SOC content in soil and pattern of CH4 emission showed a significantly positive correlation. PMID- 25826949 TI - [Poisoning effect of Ca depositing over Mn-Ce/TiO2 catalyst for low-temperature selective catalytic reduction of NO by NH3]. AB - Calcium carbonate (CaCO3), calcium sulfate (CaSO4), and calcium chloride (CaCl2) were chosen as the precursors to prepare the Ca salts deposited Mn-Ce/TiO2 catalysts through an impregnation method. The influence of Ca on the performance of the Mn-Ce/TiO2 catalyst for low-temperature selective catalytic reduction of NO by NH3 was investigated. Experimental results showed that Ca salts had negative effects on the activity of Mn-Ce/TiO2 and the precursors of Ca salts also affected the catalytic activity. The precursor CaCl2 had a greater impact on the catalytic activity, while CaCO3 had minimal effect. The samples were characterized by Brunner-Emmet-Teller measurements (BET), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and NH3temperature programmed desorption (NH3 -TPD). The characterization results indicated that the significant changes in physical and chemical properties of Mn-Ce/TiO2 were observed after Ca was deposited on the catalysts. The significant decreases in surface areas and NH,3adsorption amounts were observed after Ca was deposited on the catalysts, which could be considered as the main reasons for the deactivation of Ca deposited Mn-Ce/TiO,2 PMID- 25826948 TI - [Adsorption of Cd(II) varies with biochars derived at different pyrolysis temperatures]. AB - Ten biochars were prepared at different pyrolysis temperatures (300- 600 degrees C) using peanut shells and Chinese medicine material residue as raw materials, and were characterized. Adsorption behavior of Cd(II) on these biochars at different solution pHs, sorption times, and Cd(II) concentrations was investigated. The C content, surface area, and aromaticity of the biochars increased with increasing pyrolysis temperature, while the amount of oxygen containing functional groups decreased. In addition, the content of inorganic minerals (e. g., Ca/Mg carbonate or phosphate) was enriched, but their solubility was reduced with increasing pyrolysis temperature. As the solution pHs increased from 2.0 to 6.0, the amount of Cd(II) adsorbed on the biochars gradually increased, and achieved the maximum at pH 6.0. Adsorption processes could be divided into two stages: fast and slow sorption. The rate of Cd(II) adsorption on these biochars was regulated by film and intraparticle diffusion, precipitation and ion exchange. With increasing temperature, the percentage of fast sorption to overall sorption of Cd(II) gradually decreased. Sharp decrease of oxygen containing functional groups and formation of insoluble crystalline minerals reduced the rate of fast sorption on the high-temperature biochars (> 500 degrees C). For low-temperature biochars (<= 400 degrees C), precipitation and ion exchange were the dominant sorption mechanisms. For high-temperature biochars (>= 500 degrees C), more integrated pi-conjugated aromatic structures enhanced the contribution of Cd-pi interaction to the overall sorption, but the formation of phosphate and carbonate minerals probably weakened the sorption. These results will provide important information on screening biochars as engineered adsorbents to remove or immobilize Cd(II) in contaminated water and soil. PMID- 25826950 TI - [A comparative study on domestic and foreign emission standards of air pollutants for cement industry]. AB - The new National Emission Standard of Air Pollutants for Cement Industry (GB 4915 2013) becomes effective on Mar. 1st, 2014. It will play an important role in pollution prevention, total emission reduction, structure adjustment, and layout optimization for cement industry. Based on the research of emission standard in China, U. S., EU and Japan, the similarities and differences in the pollutant projects, control indicators, limits and means of implementation were discussed and advice was proposed, with the purpose to provide a reference for revision of emission standard, and to improve the level of environmental management and pollution control. PMID- 25826951 TI - [Revision process and thinking of emission standard of air pollutants for cement industry]. AB - The new National Emission Standard of Air Pollutants for Cement Industry (GB 4915 2013) was released recently, which is the third revision since the first release in 1985. This paper reviewed the revision process for the emission standard of air pollutants in cement industry, analyzed the impact of environmental protection situation and management policies changes on the content and form of the standard. The standard formulating principles and several key issues together constitute the base of emission standard, which are not only important to complete the theories and methods of emission standard development, but also important to improve the environmental management and pollution control level. PMID- 25826952 TI - [The beginning of a new cycle]. PMID- 25826953 TI - [Prevalence of clinical and subclinical hypothyroidism during pregnancy in a pregnant women population]. AB - OBJECTIVES: To determine the prevalence of hypothyroidism during pregnancy in a group of pregnant patients attending antenatal care at the National Institute of Perinatology and to meet cases not detected by universal screening. MATERIALS AND METHODS: Was conducted from October 2012 to March 2013, in a group of pregnant patients attending to National Institute of Perinatology, thyroid profile was performed according to the recom- mendations of the American Thyroid Association. Patients were referred to endocrinology consultation and treatment was started in case of abnormal thyroid profile. We used central tendency and non-parametric measures for description of the sample. RESULTS: The prevalence of thyroid disease in pregnancy was 33.9% (n = 37), 12.8% (n = 14) with clinical hypothyroidism and 21.1% (n = 23) subclinical hypothyroidism. The 87.1% (n = 95) of patients reported at least one symptom or risk factor history for thyroid disease, only 12.8% (n = 14), had no history or symptoms related to thyroid disease. There is no relationship between a history or symptoms reported and the presence of thyroid disease. CONCLUSIONS: The prevalence of thyroid clinical and subclinical disease is greater than that reported in the literature. There is not relationship with each risk factor for thyroid disease. Perform universal screening detects almost twice thyroid disease during pregnancy. PMID- 25826954 TI - [Intrauterine growth retardation in Peru: stressors and perinatal outcomes Hospital Ministry of Health]. AB - OBJECTIVE: To determine the incidence, stressors and perinatal outcomes of intrauterine growth retardation in the hospitals of the Ministry of Health of Peru. MATERIAL AND METHODS: Cross-sectional, analytical, case-control study of 9777 infants with intrauterine growth retardation (IUGR) in 29 hospitals of the Ministry of Health of Peru in 2010. The Peruvian intrauterine growth curve was used for the diagnosis of IUGR. IUGR newborns (cases) and newborns appropriate for gestational age (controls) were compared using the odds ratio (OR) with a confidence interval of 95%. RESULTS: The incidence of IUGR was 10.1%. The incidence by region was: 8.1% Coast, 11.8% Selva and Sierra 14.6%. The frequency of stress factors of IUGR were: nutrition (92%), psychological (84.8%), social (53%), anatomical (63.6%), toxic/environmental (52.9%), vascular (29,8%), infection (14.1%) and metabolic (0.3%). The newborn with IUGR had higher perinatal morbidity (OR=2,1) and mortality (OR=3.5). CONCLUSION: The healthy fetus is the result of a balance between stress factors and the adaptive response of the mother and fetus. When the response of physiological adaptation is overcome by stress factors, IUGR occurs.The political, psychological, nutritional and medical intervention before 12 weeks of gestation has the potential to change the harmful effects of all human stress factors that affect fetal growth. PMID- 25826955 TI - [Prevalence of urinary tract infection in hospitalized patients with preterm labor]. AB - OBJECTIVE: To determine the prevalence of urinary tract infection (UTI) in patients with preterm labor. METHODS: A prospective, observational, descriptive study, with a sample of 272 patients who were hospitalized in the Hospital de la Mujer at Culiacan, Sinaloa that presented symptoms of preterm labor. Age body mass index (BMI), parity, education, weeks of gestation, mode of delivery, history of preterm delivery and UTI were assessed. RESULTS: Of the 272 patients with threatened preterm delivery, 97 (35.6%) had positive urine culture and of these patients, 32 (32.9%) had preterm labor. Association between urinary tract infection and patients with a hemoglobin (Hb) less than 11 g/dL OR: 2.66 95% CI (1.55-4.55), p 0.0003. Was isolated E. coli in 72 (74.4%) patients, Proteus in 9 (9.2%) patients. It was found that 42% of E. coli strains were resistant to ampicillin and 38.4% to ciprofloxacin. CONCLUSION: The prevalence of UTI is higher than the national prevalence. PMID- 25826956 TI - [Rh alloimmunization in pregnant women, a look to diagnosis and therapeutic approach]. AB - Prior to the onset of immunoglobulin antiD, many of the fetuses of mothers negative for the antigen "D" developing severe disease, history of prenatal diagnosis of alloimmunization is the perfect example of constructive effort by a diagnosis in order to identify cases in need of therapy to decrease morbidity and increase survival with the least number of invasive procedures and reducing the risks associated with them. Today it is difficult to determine the true prevalence of the disease in our environment, but the understanding of the pathophysiology has helped the evolution of diagnostic tests and better treatment approach to positively impact the evolution of the disease. PMID- 25826957 TI - [Endometriosis. Why is not removed by the immune system?]. AB - Endometriosis is a gynecological inflammatory and estrogen dependent pathology, defined as the presence of endometrial tissue outside the uterine cavity. The two most common symptoms of endometriosis are pelvic pain and infertility. This pain can be so intense that it affects the quality of life of women, from their relationships to their daily activities. Approximately 10% of women of reproductive age suffer from this disease. The main objective of this work was to investigate which immune system abnormalities present in patients with endometriosis that prevents ectopic endometrial tissue removal. Here we describe a series of changes in the different types of leukocytes, cytokines and factors that regulate the immune response seen in patients with endometriosis and the mechanisms by which these changes, not only favor "immunological tolerance" to the endometrial implants but at the same time stimulate the development of the disease by increasing cell proliferation and angiogenesis and inhibition of apoptosis ectopic endometrial tissue. PMID- 25826958 TI - [Transabdominal oocyte retrieval: case report on an IVF cycle]. AB - BACKGROUND: Ultrasound-guided transvaginal follicular aspiration is the standard of care in women undergoing oocyte retrieval during vitro fertilization (IVF). When this approach is inaccessible, there are alternative methods to extract the oocytes at the exact moment. One of these alternative options is the transabdominal ultrasound-guided follicular aspiration. We present a case report of a mixed follicular aspiration in a patient with ovaries of difficult access. CASE REPORT: A 36-year-old patient with primary infertility came for medical advice. Because of bilateral tubal occlusion, an in vitro fertilization cycle was started. Transvaginal sonograms revealed a normal left ovary, but the right one was completely attached to the anterior face of the uterus. After ovarian stimulation, transvaginal follicular aspiration was done on the left ovary, meanwhile, on the right ovary; transabdominal follicular aspiration was performed, retrieving 3 oocytes on metaphase II by this technique. Finally, there were no complications during the procedure and the patient got pregnant at the end of the treatment. CONCLUSIONS: Ultrasound-guided transabdominal follicular aspiration, is the safest and most effective technique when transvaginal access to the ovaries is compromised. PMID- 25826959 TI - [Prenatal diagnosis of fetal heterotaxy syndromes: report of two cases and review of the literature]. AB - We describe the prenatal sonographic findings in two cases of fetal heterotaxy syndrome evaluated at the Maternal Fetal Medicine Unit of a tertiary hospital over a period of one year and present a review of the literature on the subject. PMID- 25826960 TI - [Hematocervix, a new variety of hematometra. A case report]. AB - The hematometra should be suspected in a patient with amenorrhea and recurrent pain in low stomach. It is conditioned by anatomical obstruction of the exit way from menstrual bled, that can release the presentation forms described as hematocolpos, hematometra and hematosalpinx. Report does not exist where alone the cervix is affected, for what the case is described with connotation of hematocervix. Patient of 32 years, regular menstruation, begins symptoms 25 days later to the menstruation, characterized by intense abdominal pain, for what goes to the service of gineco-obstetrics urgencies, where it is hospitalized under diagnose of abdominal painful syndrome. The transvaginal sonographic reports long cervix and with distention for a collection liquidates, the intern cervical hole open, the external minimally dehiscent, scarce flow of the contained endocervical toward the vaginal way through the external hole, for its ecographic aspect compatible with hematic material. The diameters anteroposterior and transverse of the cervix of 2.50 and 4.57 cm respectively. Was passed to surgical room, CEH with fibrosis that hindered the open dilation, for what were take both lips of the cervix and proceeded to dilation with Hegar until number 6, begin glide of dark and dense blood approximately in 60 mi. The evolution was good, since later to the anesthetic event, she referred remission of the pain and the sonographic control demonstrated cervix of normal anatomical characteristic, inclusive until year of follow. A wide diversity of symptoms and clinical data have been demonstrated that should have present for the hematometra diagnosis, among those that are the urinary retention, tennesmus and presence of painful pelvic mass, but the recurrent abdominal pain is the constant in all the cases. PMID- 25826961 TI - [Analyze the semantic topics that have given height to this concept and its practical use]. PMID- 25826962 TI - [Insulin resistance frecuency in women's with polycystic ovary syndrome using hyperinsulinemic-euglycemic clamp]. AB - OBJECTIVE: To assess IR in PCOS patients, using the HE-clamp as the IR gold standard. MATERIAL AND METHODS: A transversal design was done. All patients who accepted to participate provided written informed consent. PCOS was diagnosed according to the 2003 Rotterdam criteria. IR was assessed using the H-clamp, and other IR surrogates such as; fasting plasma insulin (FPI), homeostasis model assessment (HOMA) index and insulin/ glucose rate (I/G rate). Statistical analysis was performed using measures of location and spread was used according to data distribution. RESULTS: 21 patients were included. The mean age of the total group studied was 29.5 +/- 4.8 years, and the body mass index (BMI) was 27.2 +/- 3.08 kg/m2. The 85.7% of the patients met the three Rotterdam criteria for the diagnosis of PCOS. According to the HE clamp 95.2% were IR (M/I value < 6 mg/Kg/min), in contrast the prevalence of IR using sur- rogates was 47.6%, 33.3%, and 66.6% for FPI, G/I rate, and HOMA index respectively. CONCLUSIONS: Our findings show that IR is highly prevalent in patients with PCOS, and that this prevalence is even higher when insulin sensitivity is assessed using the glucose clamp technique. This evidence suggests that IR could be considered diagnostic criteria for PCOS. PMID- 25826963 TI - [Histologic chorioamnionitis prevalence in patients with premature rupture membranes]. AB - OBJECTIVE: Search Histologic Chorioamnionitis frequency in patients in week 28 (+/-) and pregnancy with premature rupture of membranes. PATIENTS AND METHOD: Retrospective and observational study in which we studied all patients who came between June 28, 2011 and November 15, 2011 to receive obstetric care in the service of Tocochirurgical of the University Hospital of Saltillo, with greater than or equal 28 weeks of pregnancy. RESULTS: 598 patients were studied, and the frequency of premature rupture of membranes with histologic chorioamnionitis at term patients was, respectively, 1.7 and 5.3% in preterm labor. In the total sample frequency of histologic chorioamnionitis was 0.6% (4 patients) and, of these, 25% were term and 75% with preterm rupture. In patients with premature rupture of membranes the clinical chorioamnionitis was 0% valued by the criteria of Gibbs. CONCLUSIONS: The premature rupture of membranes is a risk factor important for histological chorioamnionitis. To decrease risk factors and possible complications, an established protocol must be taken. PMID- 25826964 TI - [Postmenopausal symptoms severity enhancement oxidative stress in women with metabolic syndrome]. AB - BACKGROUND: Oxidative stress is a serious imbalance between the reactive oxygen species (ROS) produced and the antioxidant systems, and has been identified to cause metabolic syndrome. Postmenopausal women (POS) with severe symptoms have higher oxidative stress; therefore it is possible to observe higher oxidative stress in postmenopausal women with metabolic syndrome and severe menopause related symptoms. OBJECTIVE: To determinate if the severe postmenopausal symptoms increased oxidative stress in women with metabolic syndrome. METHODS: We carry out a cross-sectional study with POS, 48 with metabolic syndrome and 52 healthy. Control group was defined as women heealthy and without severe symptoms (H-SS). Metabolic syndrome was defined according to criteria established by NCEP-ATPIII. We measured lipoperoxides by the TBARS assay as oxidative stress marker. All women answered the Menopause Rating Scale (MRS) that evaluates the severity of global symptoms in three dimensions: psychological, somatic and urogenital; and the Athens Insomnia Scale (AIS). In each questionnaire was used a cutoff value to determine the severity of symptoms and alternative cut-off value for lipoperoxides > or =0.320 mol/L. RESULTS: The prevalence of high plasma lipoperoxides levels was higher in women with metabolic syndrome (WMS), 39 [81%] vs. 33 [64%], p < 0.05. The WMS, independent of severe symptoms (SS), had high lipoperoxides levels, similar to H+SS, except in urogenital MRS dimen- sion and AIS. The risk of higher lipoperoxides increased with MS and severe symptoms RM=6.32, 95% CI: 1.32-30.20, p < 0.05, adjusted by others pro-oxidants factors. CONCLUSION: Our findings suggest that the severity of menopausal related symptoms increased oxidative stress in women with metabolic syndrome. PMID- 25826965 TI - [Body composition and lipidic profile in women's during the third trimester of pregnancy]. AB - OBJECTIVE: To demonstrate the behavior of body composition and lipid profile in pregnant women during the third trimester and who attended a Regional hospital Tepatitlan, Jalisco, Mexico. METHODS: In an observational study, transversal, analytic 36 apparently healthy pregnant women were included with gestational age between 33 to <42 weeks. Anthropometric measurements, body composition and lipid profile were obtained. Student t test, Mann Whitney, chi square, Pearson and Spearman correlation for data analysis were used. RESULTS: 11 participants were overweight and 8 obese. Significant association between higher concentrations of triglycerides and TG / HDL-c index and pre-gestational BMI (p = 0.039 and p = 0.032 respectively) were found. Concentration greater than 200 mg / dL triglycerides are associated with an increased interpregnancy period of 3 years (p = 0.012). There was a significant correlation between abdominal deliveries with anthropometric indicators, pre-gestational weight, pre-gestational BMI and current BMI. CONCLUSION: There is a direct correlation between body composition and lipid profile with age and the incidence of cesarean section. It is necessary to establish a more precise reference criterion for both the longitudinal track for every pregnant woman and for purposes of parametric comparison. PMID- 25826966 TI - [Non evidence of the "evidence". Twenty years from starting its use]. AB - In view of the widespread wrong use in spanish of the erroneous translation of evidence-based Medicine as "medicina basada en la evidencia", comments are made from the general concepts of phylosophy, particularly from the chapter of "semiotics", which demonstrate the falacious use of such a wrong translation and the dangers of its indiscriminate use of this procedure, that may be very valuable in its methodology as proposed by its founders and understood by english speaking physicians, making emphasis in the fact that it is just a method to obtain a better level of certainty and not a system that should replace the criteria employed in traditional medicine. Examples are offered of several serious mistakes that have been made by the erroneous application of results offered even in articles published in english. Finally, a review is made of articles published in five prestigious journals and the difficulty of interpreting their contents as a source of clinically useful information. A novel procedure is proposed as a possible alternative for assessing medical literature. PMID- 25826967 TI - [Decriminalize medical procedures? A first approach from a dual perspective: medicine and law]. AB - The great number of circumstances that Medical doctors face in the "modern" practice of medicine has generated a series of remarks that lead us to meditate the repercussions of the legal approach towards MDs involved in unexpected events and undesirable health outcomes, that generate a denunciation, suit or complaint to the law enforcement agencies. These unexpected events and undesirable health outcomes have a multifactorial origin, but each one of the variables involved rests upon the generic basis of the global impoverishment of our society, which lead us to recall the biblical verse "He that is without sin among you, let him first cast a stone at her". Today we listen, read, believe, and some of us pretend to teach the guidelines that we are supposed to follow to avoid serious consequences of the so-called "judicialization of medicine". Therefore, today more than ever, we are required to express ideas that seek an integration of the experiences in the clinical setting and the experiences in the legal framework, from a dual perspective. PMID- 25826968 TI - [Ductus arteriosus aneurysm. Case report and review of the literature]. AB - The saccular or fusiform dilatation of the ductus arteriosus is called aneurysm (DAA). It is diagnosed in the second trimester during a structural ultrasound. Even though the reported incidence is 2.2%, it remains infrequent, because it is not searched routinely. The pathogenesis is uncertain, resulting from an increase on the circulating blood volume thus in the cardiac afterload, associated to a thinning of the vessel wall, for an inadequate intima development. Ductus arteriosus aneurysm can be classified according by their diameter as small (<7 mm.) and large (> or =8 mm). The smaller commonly closes spontaneously in 70% of the cases, unlike the larger one, they are associate in a greater number of complications, such as thrombosis, embolism, infection, compression effects of adjacent structures and spontaneous rupture. The absence of spontaneous closure, according to the symptoms and possible complications, a neonatal surgical closure should be considered. We report a case of a 35-year-old patient, diagnose on the 35 week pregnancy, a ductus arteriosus aneurysm by ultrasound with an image of the three vessels performed communicating, saccular dilatation of 7-8 mm. and a turbulent Doppler flow. PMID- 25826969 TI - [Giant sacrococcygeal teratoma in twin pregnancy]. AB - Sacrococcygeal teratoma tumors are more frequent in infants alive. It is characterized by its benign histology in the majority of the cases diagnosed prenatally; it is necessary to follow narrow to prevent neonatal complications that can lead to urinary tract complications and fecal, high-output heart failure, hydrops and, in extreme cases, the death of the fetus. CASE REPORT: Primigravidae 30 years old, with gestation twins, bicorial, biamniotic in the first trimester of pregnancy to one of the twins is diagnosed sacrococcygeus teratoma giant, with favorable monitoring in the maternal-fetal Medicine Unit of the University Hospital of La Paz in Madrid, and with postnatal resection surgery successful. We review the diagnostic procedures and treatment of this tumor in unique and twin gestations. PMID- 25826970 TI - Influence of diet on oral health in young adults--pilot study. AB - INTRODUCTION: Diet is a factor that can modify, among others, the course of caries, dental erosive lesions and periodontal disease. It is important to know the influence of diet on the clinical oral condition in young adults. MATERIAL AND METHODS: 20 women and 20 men aged 19-21 participated in the study. During a clinical examination of the patients the following clinical indices were estimated: Ap- proximal Plaque Index (API), Bleeding on Probing (BOP) and DMFT indices. The frequency and quality of food products consumed were noted in a special questionnaire. Results with p <= 0.05 were considered statistically significant. RESULTS: The average API value for the female participants was 77.37%, BOP--23.84% and DMFT--9.9. The t-test results for independent samples showed that women who consumed meat and meat products two times a week or more, had statistically higher API (p = 0.01) and BOP (p = 0.05) values, than the mean value for these indexes. Women who consumed grain products and grain-based products two times a week or more, had higher API values compared to the mean value for this index (p = 0.02). The average API value for the male participants was 34.25%, BOP--10.15% and DMFT--9.05, respectively. Men who consumed milk and dairy products three times a week or less had statistically lower API (p = 0.05) and BOP values (p = 0.02), relative to the mean index values. CONCLUSIONS: The chemical composition and texture of the food intake can affect oral health. Besides instruction in oral hygiene, doctors and dentists should also assess the eating habits of their patients. PMID- 25826971 TI - Cardiac status of persons qualified for living kidney donation--single-center experience. AB - Some of living kidney donors have medical conditions associated with future risk of cardiovascular diseases. It seems justified to identify risk factors and cardiological disorders prior to the donation. AIM: To determine the cardiological status of persons qualified as a living kidney donor. MATERIAL AND METHODS: We analyzed the data of 109 potential living kidney donors, aged 25-70 (mean 45.7 +/- 10.9) years. They underwent clinical and biochemical examination. In some of them extended diagnostics was performed. The presence of risk factors of coronary artery disease were registered. RESULTS: Only 46 (42%) persons were qualified for kidney donation. As many as 40 of them had 21 risk factor. In 75 (68.8%) patients without hypertension, 24-hours ambulatory blood pressure monitoring was done. The masked hypertension was found in 6 persons. In 22 candidates aged > 50 years the exercise test was performed (positive or inconclusive in 3 persons). Coronarography was done in 5 individuals (in no any significant atherosclerotic lesions were found). 63 (58%) person were disqualified. In 15 (23.8%) person the reasons were cardiological. In 2 patient the abdominal aneurysms were found. Both men smoked and had severe dyslipidaemias. In 3rd patient we observed persistent atrial fibrillation. The next 2 men had the peripheral occlusive arterial disease. In 9 patients >= 2 risk factors and in the last one morbid obesity were present. CONCLUSION: In Poland candidates for living kidney donation have very often risk factors of cardiovascular disease. Among the persons proceeded for kidney donation cardiovascular problems are an important cause of disqualification. PMID- 25826972 TI - [The causes of falls and injuries after falls in women over the age of 50 living alone in Krakow]. AB - INTRODUCTION: Falls are one of the most devastating health problems of elderly people. The identification of causes of falls helps to establish proper prevention strategies. MATERIAL AND METHOD: The study was based on a group of community-dwelling, independent women aged over 50 years. The frequency of falls was calculated on the basis of a retrospective analysis of 1326 cases. 100 women were chosen for a telephone questionnaire to identify causes and consequences of falls. The average age was 63.9 (SD 8.6) and the average BMI was 27.6 (SD 5.4). RESULTS: Approximately 31% of 1326 women reported at least one fall a year. In the year preceding the questionnaire 62% of the participants reported one fall, 26%--two falls, 8%--three falls and 5%--four and more falls. In the surveyed group of 100 women 72% of falls occurred outdoors, which is 2.5 times more often than at home (28%). 68% of falls occurred between 12 pm and 6 pm. Summer is the season of the highest occurrence of falls (37%). In winter, the frequency of outdoor falls increases, whereas during summer the frequency of falls happening in and outdoors does not differ. The most frequent cause of falls, both in and outdoors, was slipping. Other important risk factors include: hypnotic drugs, walking impairments, balance deficit, vertigo, analgesics. Most of the falls had various intrinsic and extrinsic causes. KEY POINTS: We found that 30% of women aged over 50 years falls at least once a year. Both at home and outside falls resulted from slipping. For almost 80% of falls as a consequence of an injury. The majority of falls had intrinsic and extrinsic origins. PMID- 25826973 TI - [Nitrates and nitrites content in the samples taken from the dug and drilled wells from the area of Podkarpacie region as a methemoglobinemia risk factors]. AB - The aim of the study was to determine the nitrates and nitrites content in water samples taken from fourteen dug and drilled wells from the area of Podkarpacie, as well as a summary of the previously performed analysis. Private water intakes are not under the supervision of the State Sanitary Inspection. So in the case of exceeding the standards provided by the Regulation of the Minister of Health, regulating the requirements for drinking water, private water intakes can be a serious threat to the health of consumers. Particularly at risk are infants, in whom nitrates and especially nitrites can cause, among others, methemoglobinemia. The analysis was performed by ion chromatography method, making it possible to simultaneously determining the concentrations of nitrates and nitrites. As it turned out there was no presence of nitrites in the water of the tested wells. In five samples taken from the dug wells nitrates concentration exceeding the norm of 50 mg/L have been reported. In two cases, exceeding the nitrate concentrations were significant: 96.53 mg L and 204.65 mg/L. PMID- 25826974 TI - [Changes in the peripheral blood cells count in the early phase of acute pancreatitis]. AB - Peripheral blood count belongs to the most frequently ordered laboratory tests performed in the assessment of the current patients condition. In addition to basic information, including analysis of individual cell populations, additional parameters are given that can be helpful in predicting the course of disease, including acute pancreatitis (AP). The aim of the study was to compare the parameters of blood counts in patients with mild and moderate to severe AP in the early stage of the disease. We confirmed a significant predictive value of monitoring the total white blood cell counts, direct neutrophil counts, platelet counts, and the value of RDW in the first week of AP. Also, the relationship was observed between increased hematocrit value and mortality in patients with severe acute pancreatitis. PMID- 25826975 TI - [Coagulation profile in patients undergoing elective laparoscopic surgery]. AB - INTRODUCTION: Insuflation abdominal cavity with carbon dioxide during laparoscopic surgery increases abdominal pressure, which may cause stasis of the blood flow in inferior vena cava and common iliac veins. Moreover, reverse Trendelenburg position, in which laparoscopic cholecystectomy is performed, decreases venous return. All of this factors makes episode of venous thromboembilism (VTE), an asymptomatic state that could cause serious complications, more probable. AIM: The aim of the study was to asses influence of pneumoperitoneum during laparoscopic procedures on coagulation state and to asses relation between body mass index (BMI), age of patients undergoing laparoscopic procedures and coagulation profile in the postoperative period. MATERIAL AND METHODS: The study enrolled 35 patients (F:M = 28:7, mean age 48.3 +/- 14.6, mean BMI 26 +/- 4.5 kg/m2), without VTE risk factors, not undergoing anticoagulant therapy and without abnormal platelet count. Subjects underwent laparoscopic cholecystectomy. Alteration in coagulation profile was assesed on the basis of aPTT, PT and TT results. Blood samples were taken twice: in the day of admission (samle A) and 5 hours after surgery (sample B). Statistical analysys was performed using Wilcoxon signed rank test and Spearman correlation. RESULTS: Mean aPTT, PT and TT value of the A sample was 34.54 +/- 6.32s, 1.11+/- 0.14 INR; 16.35 +/- 1.93s respectively. Mean aPPT, PT and TT value of the B sample was 34.4 +/- 7.13s; 1.17 +/- 0.11 INR; 16.41 +/- 1.88s, respectively. Change of PT value pre- and postoperatively was statistical significant (p = 0.0009). There was statistical significant correlation between duration of the surgery and sample B PT and TT values (p = 0.0115 and 0.0218 respectively). No other correlation between BMI, age and sample B values was observed. CONCLUSIONS: Creation of pneumoperitoneum has no influence on shortening of clotting times. Because of early mobilisation, fast discharge and recovery that makes natural anticoaculant prevention available short after surgery, clinical risk of DVT is not high. PMID- 25826976 TI - [Evaluation of implementation phase of intraoperative neural monitoring of the recurrent laryngeal nerves in thyroid surgery in a district hospital]. AB - BACKGROUND AND AIMS: Intraoperative neuromonitoring of the recurrent laryngeal nerves (RLN) has gained an increasing acceptance in thyroid surgery in nerve identification and prognostication of nerve function. However, outcomes of monitored thyroid surgery depend on surgical experience and skills in technical application of this adjunct. The aim of this paper was to evaluate the implementation stage of intraoperative neuromonitoring of the RLNs in a district unit of general surgery. METHODS: This prospective study comprised of 50 patients undergoing consecutive thyroid operations during the implementation phase of intraoperative neuromonitoring of the RLNs in 08/2012--07/2013 at a district unit of general surgery in Staszow. Neuromonitoring of the RLNs was conducted in concordance with the International Neural Monitoring Study Group guideline statement, using C2 NerveMonitor (Inomed, Germany). The following parameters were analyzed: patients demographic data, mean operating time, number of identified RLNs, prevalence of loss of signal, predictive value of the method, and prevalence of temporary and permanent RLN injury assessed by videolaryngoscopy in a 6-month postoperative follow-up. RESULTS: The study group comprised of 93 RLNs at risk during 50 thyroid operations (43 total thyroidectomies, and 7 lobectomies), including 46 women and 4 men, at mean age of 56.0 +/- 11.1 years. Mean operating time was 109.9 +/- 19.0 min. Eighty-three of 93 (89.2%) RLNs were identified intraoperatively. Technical setup problems necessitating corrections were encountered in 12 (24.0%) operations. Negative predictive value of neuromonitoring was 89.3%, while positive predictive value was 55.6%. Temporary versus permanent RLN injury was diagnosed in 7 (7.5%) vs. 6 (6.5%) nerves at risk, respectively. CONCLUSIONS: Technical setup problems necessitating corrections are common during the implementation phase of the intraoperative RLNs neuromonitoring leading to a prolonged duration of surgery and limited predictive value of the method. PMID- 25826977 TI - [Falls during hospitalization--prevalence and consequences]. AB - A systematic growth in the number of the elderly among hospitalized patients, including the number of patients in the oldest age group, is being observed over the last few years. A stay in hospital conditions is connected with deterioration of their fitness, reduction of their independence. It also entails the risk of hallucination, falls and hospital-acquired infections. The present analysis concerns 60 patients who fell during their hospitalization in the Internal Diseases and Geriatrics Unit of University Hospital in Krakow in 2012 and 2013 (in the total of 6,061 patients admitted to the Unit in this period), which was recorded in the registry of adverse events. An attempt at characterization of this group was made on the basis of medical record, assessment of fall circumstances and its consequences. This was followed by an attempt at tracing the later outcomes of these patients both during their stay in the unit as well as after the discharge from hospital (telephone contact with patient or with person indicated as contact). Analysis of the data (probably underevaluated due to the lack of unambiguous definition of a fall as well as a retrospective character of study) reveals a relation between falls in hospital and various degrees of body injuries, extended hospitalization time, increasing disability and, in some cases, even death. In the face of the observed growth in the number of hospitalized patients in advanced age, a clear definition and careful monitoring of falls as well as an attempt at an early identification of people at risk of falls may prove to be an effective means of their prevention. PMID- 25826978 TI - Oncological emergencies: syndrome of inappropriate antidiuretic hormone secretion (SIADH). AB - Excessive secretion of vasopressin in the course of Syndrome of Inappropriate Antidiuretic Hormone Secretion is a common cause of hyponatremia in cancer patients. Clinical symptoms depend on the cause, rate of change of sodium level and their absolute values. Treatment options include fluid restrictions, intravenous administration of hypertonic sodium chloride solutions, loop diuretics and vaptans. The sodium level should not be adjusted too fast, because it may lead to irreversible brain damage. The article presents pathophysiology, diagnostics and recommendations of management of this oncological emergency. PMID- 25826979 TI - [Epilepsy, antiepileptic drugs and disorders of reproductive functions of women]. AB - Epilepsy is one of the commonest chronic neurological disorders in developing countries. The disease itself and applied antiepileptic drugs cause fertility problems. As a result of seizures changes in hypothalamic and pituitary hormone secretion occur, resulting in hyperprolactinemia, menstrual disorders, premature ovarian failure as well as occurrence of polycystic ovary syndrome (PCOS). PCOS is the main problem in women with epilepsy caused by both the disease itself as well as treatment, mainly with valproic acid. Antiepileptic drugs exert an effect mainly on the level of active hormones, their synthesis in the ovaries and binding with sex hormone binding globulin. Due to impaired reproductive function, the probability of pregnancy in women with epilepsy is up to 2-fold lower than in healthy ones. It should be, however, consider that antiepileptic drugs cross the placenta, therefore it is very important to choose the appropriate treatment, not only to prevent epileptic seizures during pregnancy, but also not harmful to the developing fetus. PMID- 25826980 TI - [Precocious puberty in boys]. AB - Precocious puberty in boys is defined as the onset of puberty before the age of 9 years. It is divided into two categories: central precocious puberty, characterized by the premature activation of the hypothalamic-pituitary-gonadal axis, and peripheral precocious puberty presents when premature sexual development is dependent on steroid production regardless of gonadotropin secretion. Although precocious puberty occurs more frequently in girls, in the case of boys it is more often associated with identifiable organic disorders of the central nervous system, adrenal glands or testes. The diagnosis should include detailed anamnesis and clinical examination, measurement of pituitary and sex hormones, assessment of bone age, and imaging of the hypothalamus, pituitary gland, adrenal glands and testes. Indications for treatment are based on the type of precocious puberty and its progression rate, advancement of bone age, predicted adult height and psychological evaluation. The purpose of this article was to discuss the etiopathogenesis of precocious puberty in boys and to provide the approach to its diagnosis, differentiation and treatment. PMID- 25826981 TI - [The use of motivational interviewing (MI) in patients with chronic renal failure]. AB - Patients suffering from chronic kidney disease must submit to numerous medical procedures and burdensome changes in lifestyle that make it difficult to adapt to the disease. Therefore, an important issue is to stimulate the patients motivation to comply with medical recommendations. This article describes a therapy tool for developing patient's motivation to change, called therapy or motivational interview (MI), the type of approach that is increasingly being used inhealth care, as an aid to chronically ill patients. Characteristics of this approach generally relies on the assumption that the Motivation for a change should come from a patient, not the provider, and a patient should articulate arnd resolve ambivalence provider persuassion is not effective and enhance resistance from a change. Persuasion by a person healing can only strengthen and enhance the patient's resistance to unwanted habits. PMID- 25826982 TI - [Stanislaw Laskownicki, Member of the Founding Committee of the Polish Urological Society. Biographical note]. PMID- 25826983 TI - [Peptides and CCL11 and HMGB1 as molecular markers of aging: literature review and own data]. AB - Cytokines CCL11 (eotaxin) and HMGB1 (alarmin1) are molecular markers of ageing and neurological, cardiovascular and immune diseases. Created in St. Petersburg Institute of Bioregulation and Gerontology short peptides are known to regulate gene expression and protein synthesis. They promote the mortality decrease and slowdown the development of pathology in the elderly. The article presents the proposed role of dipeptide vilon (Lys-Glu) and tetrapeptide epitalon (Ala-Glu-Asp Gly) in CCL11 and HMGB1 genes regulation as activators of their expression. Geroprotective action of vilon and epitalon probably realizes in suppression of these genes. PMID- 25826984 TI - [The role of genetic polymorphisms of interleukins in chronic lymphocytic leukemia in patients of different ages]. AB - Chronic lymphocytic leukemia (CLL) is a multifactorial disease, in which development the important role played the cytokine genes, in particular interleukins. This type of leukemia is more common in the elderly. The purpose of the study was to evaluate the association of genetic polymorphisms of interleukin with the development of chronic lymphocytic leukemia among residents of the Central Chernozem region of Russia. Genotyping of the -889C/T IL-1A, -590C/T IL-4 and VNTR IL-1 Ra was conducted in 206 patients with CLL and 307 individuals of the control group. The study found that the genetic risk factor for the development of CLL is allele -590T IL-4 (OR=-1,45). The development of thrombocytopenia in patients with CLL is associated with genetic variants -889T IL-1A (OR=1,95), -889TT IL-1A (OR=6,2) and IL-1Ra*1 (OR=-2,32). PMID- 25826985 TI - [Age-dependent CYP1A2 gene polymorphism -163C>A in three ethnic groups of Bashkortostan Republic residents]. AB - On a sample of 1240 persons from Bashkortostan, including Russian, Bashkirs and Tatars, the analysis of allele and genotype frequencies distribution of CYP1A2 gene polymorphism -163C>A was performed by PCR-RFLP in view of belonging to a particular age cohort. In Russian and Bashkirs ethnic groups we observed age dependent decrease of CYP1A2*C allele and CYP1A2*CI*C genotype frequencies (in Russian statistically significant for allele and genotype, the Bashkirs--only for allele) and a statistically significant increase of CYP1A2*A allele and CYP1A2*A/*A genotype frequencies. The set reduction in the frequency of the wild allele CYP1A2*C and increasing the frequency of the mutant allele CYP1A2*A with age may be due to greater survival of persons who are carriers of that allelic variants of CYP1A2 gene, providing a more efficient metabolism of xenobiotics. PMID- 25826986 TI - [Genotype and allele frequencies of UCP and PPAR gene families in residents of besieged Leningrad and in the control group]. AB - Genotype and allele frequencies of uncoupling proteins 2 and 3 genes (UCP2 and UCP3) and peroxisome proliferator-activated receptors genes (PPARA, PPARD and PPARG) were studied in 206 residents of the siege and in 139 individuals of more than 69 years old (control group). Studied polymorphisms included UCP2 (Ala55Val), UCP3 (C-55T), PPARA (G/C), PPARD (+294T/C), and PPARG (Pro12Ala). The G allele and the G/G genotype (PPARA) were overrepresented in the group of survivors and C/C (UCP3) genotype prevailed in the women of besieged Leningrad compared to relevant control groups of the persons of the same age who did not suffered hungry disaster. Feasible protective effects of PPARA gene allele G and C allele of UCP2 genes are briefly discussed. PMID- 25826987 TI - [Aging and respiratory infections in laboratory animals]. AB - Respiratory infections are known as one of significant causes of death in old human as well as aged laboratory animals. However, there is not strong evidence of increase of spontaneous pneumonias incidence in aged rats and mice. Moreover, numerous experimental investigations with different respiratory pathogens did not elucidate clear age-related changes of infection susceptibility even for one and same disease agent yet. It is paradoxical that decline of lung infection mortality of aged animals in compare to young animals was found in some observations. Respectively, investigations of innate and adoptive immunity role in pathogenesis of respiratory infections in old laboratory animals also produced undetermined results. It is probable that such situation is not only related to complex character of age-associated changes in respiratory system, but also to absence of conventional and adequate models for research of the problem. PMID- 25826988 TI - [Special mechanisms for reducing life span of cells and organisms, initiated by some weak external signals]. AB - The study presents the results of many-years research conducted using biological objects of different organization level. It demonstrates special species nonspecific form of weak external signals negative effect to cells life expectancy reduction caused by program damage of cells populations. This effect is detected after weak radiation, radio-chemical and thermal influences. It leads to faster extinction of postmitotic populations which can be a reason for life expectancy reduction of multicellular organisms. A possibility of such effect inheritance in the asexual and sexual reproduction is shown. Epigenetic mechanisms of this phenomenon are assumed. PMID- 25826989 TI - [Mesenchymal stem sell donor age effect on the cerebral cortex microvascular net density in old age rats-recipients of transplant]. AB - Male Wistar-Kyoto rats aged 22-24 months were intracerebrally transplanted with syngenic bone marrow mesenchymal stem cells (BM MSC) established from the donor aged 3-4 months and 20-22 months, respectively. Using a TV device to study microcirculation in vivo, we have established that transplantation of BM MSC from young donors increased a density of the microvascular network in the pia mater of the sensorimotor cortex in old rats approximately 1.9-fold, comparing to age matched controls, while a density of the arteriolar compartment increased approximately 2.1-fold. Transplantation of BM MSC from old donors did not lead to the significant increase in the density of the microvascular network in the pia mater, while a density of the arteriolar compartment increased approximately 1.5 fold. PMID- 25826990 TI - [The characteristic of immunity in long-lived persons and selection of the immunosenescence markers]. AB - Purpose of the work is to select the indices of immunograms, associated with immunosenescence. The lymphocyte subpopulations were defined by the method of polychrome flowing cytometry in 276 patients of 90+ year with the identical spectrum of chronic unspecific inflammatory diseases. The cluster was revealed consisting of subpopulation of T-lymphocytes (T-lymph) with the high frequency of deviations from standard--helper CD4+, cytotoxic CD8+--T-lymph. The activation of immunity was confirmed by the expression of HLA-DR molecule in 100% of persons with an increase of the absolute number CD4+ and/or CD8+. Reduction in the CD8+ and/or CD4+ was associated with the immune deficient state and the frequency of the increased actTcontent within limits of 63-83%. In 36 long-livers a quantity CD4+ and CD8+ corresponded to standard, 33 of them demonstrated actT exceeded standard. These patients were carried to the group of activation also. Basic group had the quantity CD8+ deficit (73%). In this group, frequency of the development of neuro-degenerate distributions and pathologic changes in the osteomuscular tissue were reliably higher in the persons at the age of 92 years and older than in persons younger 92 years. We consider that CD8+ deficit at the age older 90 year is biomarker of immunosenescence and the risk of an increase in the frequency of development of chronic unspecific inflammatory diseases. PMID- 25826991 TI - [Microviscosity of erythrocyte membranes in chronic coronary insufficiency in patients of middle and older age groups]. AB - We examined the ratios microviscosity in the area of integral and annularly lipid membranes of erythrocytes of peripheral blood in patients of 35-50 and 60-75 years with chronic ischemic heart disease, as well as age-matched healthy controls. In healthy donors coefficients microviscosity in the area of integral and annularly lipids proved to be significantly higher in the older age group (60 75 years). In CHD, regardless of the age of the patients, erythrocyte membranes can be characterized as raising and lowering the parameters microviscosity of lipid-lipid interactions. In the protein-lipid contacts for patients aged 35-50 years an increase is typical, while for patients of 60-75 years, on the contrary, a decrease of the coefficient of microviscosity. It is concluded that the values of the microviscosity of erythrocyte membranes in patients of different age groups in the development of chronic ischemic heart disease, reflect both the implementation of the general mechanisms of adaptive changes of cell membranes, and the specifics of an individual, determined by their lipid and protein composition. PMID- 25826992 TI - [Metabolism of nucleotides and its inter-relation with pro-oxidant and antioxidant systems in people of different age ranges]. AB - The interrelation of purine nucleotides with antioxidant system in blood plasma and erythrocytes depending on age, as well as the contribution of the key enzymes of purine decomposition to the formation of reactive oxygen metabolites were studied. 50 conditionally healthy people aged 40-79 years were examined. Increase in all indicators of pro-oxidant system of blood plasma with age was determined. Statistically significant interrelations between the studied parameters and age of the examined persons were determined in the blood plasma. The relationship between the glutathione peroxidase and adenosine deaminase/xanthine oxidase, adenosine deaminase and xanthine oxidase was also determined. A significant increase of products of oxidative proteins modification in plasma and erythrocytes with aging was discovered. Reduction with age of key enzymes of antioxidant protection--superoxide dismutase and glutathione peroxidase in blood plasma and erythrocytes was determined. The data obtained indicate that with age there is an imbalance in the antioxidant system in blood plasma and erythrocytes contributing to the development of pathological conditions by increasing oxidative stress, which is greatly manifested while aging. PMID- 25826993 TI - [The influence of risk factors for malignant tumors of maxillo-facial area on the expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in patients of elderly and senile age period]. AB - Morbidity and mortality from malignant neoplasms increases each year, and the average age of patients with first diagnosed decreases. The peak of incidence of malignant tumors of maxillofacial region falls on the elderly life. Not only age related changes of the organism contribute in the development of this pathology, but also harmful habits. A comprehensive approach to solving the problem requires monitoring of this group of patients to identify risk factors for the development of pathologies in the oral and maxillofacial region. PMID- 25826994 TI - [Age-related features of peripheral blood cell adaptive reaction in women with chronic obstructive pyelonephritis]. AB - The aim of the study was to evaluate the adaptive changes of peripheral blood cells of recurrence inflammation in aged women with chronic obstructive pyelonephritis (COPN). An analysis of clinical and laboratory data was carried out on 50 women who were distributed into two age periods: under 55 years (the comparison group) and over 65 years. In women of 65+, during recurrence of COPN, the degree of leukocyte increase, neutrophils, monocytes and erythrocyte sedimentation rate (ESR) reached 90,1, 20,8, 71,4 and 31,6%, whereas lymphocyte count was less by 2,8 times in comparison with remission. In women under 55 years (in recurrence of COPN), degree of leukocyte increase was 87% (p<0,001), neutrophils--4, 8% (p<0,05), monocytes--in 2,04 times (p<0,001), ESR was less in 3,1 times (p<0,001) and lymphocyte count was less than 19,5% (p>0,05). The manifestation of neutrophilocytosis and lymphocytopenia might be due to age related features of adaptive reaction in peripheral blood cells during the COPN recurrence. PMID- 25826995 TI - [Comparative analysis of gerontologic prophylaxis efficiency and membranotropic action of various gas therapy]. AB - The research was executed on 320 male patients aged 35-92 years with various polyorgan pathology in a compensation stage. The treatment by gases was used: hyperbaric oxygenation, dry carbonic acid baths, ozon therapy, hypo oxygen therapy and their combinations. On indicators of biological age various age dependent geroprophylactics effect of gas therapy was established. On indicators of resistance of erythrocytes various safety of used modes was found. PMID- 25826996 TI - [The effect of leucine and lysine dipeptides on the proliferation of the myocardium and spleen from young and old rats in organotypic culture]. AB - The effect of new dipeptides consisting from leucine and lysine was investigated in organotypic tissue culture on the cell proliferation development in spleen and myocardium explants in 3- and 24-months old rats. Dipeptide L-Leu-Lys stimulated the cell proliferation in the young and old rats at concentrations 0,001-10 ng/ml and 0,01-1 ng/ml accordingly. Dipeptide L-Lys-Leu stimulated as well the cell proliferation in the young and old rats at some deviation of diapason of stimulating concentrations. The data obtained aboutthe new dipeptides with high biological activity create a basis for future research at the organism level for their application in geriatrics to enhance regenerative processes in lymphoid and myocard tissue. PMID- 25826997 TI - [Influence of delta-sleep inducing peptide on the state of lysosomal membranes and intensity of lysosomal proteolysis in different rat tissues during physiological aging of the organism]. AB - It is shown that subcutaneous injection of exogenous delta-sleep inducing peptide (DSIP) to rats aged 2-24 months in a dose of 100 MUg/kg animal body weight by courses of 5 consecutive days per month has a stabilizing effect on the state of lysosomal membranes in rat tissues (brain, heart muscle and liver) at different ontogenetic stages, and this effect is accompanied by increasing intensity of lysosomal proteolysis in these tissues. PMID- 25826998 TI - [Influence of delta-sleep peptide on the enzymes activity of mitochondrial electron transport chain in various rat tissues during aging of the organism]. AB - It is shown that subcutaneous injection of exogenous delta-sleep inducing peptide (DSIP) to rats aged 2-24 months in a dose of 100 MUg/kg animal body weight by courses of 5 consecutive days per month has a stabilizing effect on the NADH dehydrogenase activity in the mitochondrial fractions of various tissues, which together with increasing capacity of the antioxidant system should reduce the production of free radicals and their adverse action on cells macromolecule, herewith the activity of succinate dehydrogenase did not change. PMID- 25826999 TI - [Endovascular revascularization of the carotid area in elderly patients in acute ishemic stroke: the current view of the problem (review of literature)]. AB - This article presents the review of literature devoted to studying of safety and efficacy of early carotid angioplasty and stenting (CAS) in older patients in acute stroke. CAS has been shown to be a non-inferior treatment to carotid endarterectomy for the prevention of recurrent strokes with equivalent rates of major complications (stroke, myocardial infarction and death). Early revascularization is desirable in patients presenting with stroke or transient ischemic attack (TIA) referable to carotid artery stenosis because of the high incidence of recurrent ischemic events. In fact CAS, in the acute stage, remains challenging because of risk perioperative complications and hyperperfusion syndrome or cerebral hemorrhagic infarction after revascularization. In the past years, few researches (Setacci C., 2008; Battocchio C., 2012; Wach M., 2013, et al.) indicate that this procedure can be relatively safe, including elderly patients, even when performed early after a TIA or stroke. However, additional studies of safety and efficacy of early CAS must be undertaken to define the role of endovascular revascularization of the extracranial carotid arteries in the early management of acute stroke. PMID- 25827000 TI - [Endovascular treatment of bifurcation lesions of the coronary arteries in patients of elderly age: a review of the literature No 1]. AB - Stenting of coronary artery bifurcation lesions is one of the most difficult types of interventional procedures for coronary heart disease. The frequency of coronary artery bifurcation lesion occurs up to 20%. The article reflects a wide variety of types of classifications of coronary bifurcations compared with the basic classification for A. Medina. Having considered the arts of bifurcations stenting, from a provisional Tstenting to complex procedures culote and crush stenting, we advocate the use of bifurcation structures, especially in elderly and senile. PMID- 25827001 TI - How to approach to the therapy of diabetes in the elderly. AB - In gerontology diabetes mellitus (DM) is clinically the most frequent and extremely serious metabolic disorder. DM is an important health issue across the globe. With increasing life expectancy physicians are called upon to manage diabetes in the elderly more often. Senior patients suffer predominantly from the type 2 DM--T2DM (70+ up to 90-95%). Apart from genetic predisposition and an environmental influence, nutritional habits, modern lifestyle, stress and minor physical activity are of particular importance. Treatment options for T2DM in the elderly are diet, physical activity, various oral anti-diabetic drugs and insulin. At the start of treatment should primarily take into account: patient's age; self-sufficiency; late micro- and macro-vascular complications; social status; nutritional assessment (incl. dental status); other handicaps--psychic, motoric, visual and aural. Especially in frail, elderly patients, there should be less emphasis on strict glycaemic control than on avoiding malnutrition and hypoglycemia and achieving the best possible quality of life. Therapy of DM in this population is tightly connected with significant risks of micro- and macrovascular complications on one hand, and possible problems of the treatment (e.g. hypoglycemia) with intensive control on the other hand. To realize a comprehensive approach to therapy of diabetes in the old age a holistic approach with main aim improving quality of life is necessary. PMID- 25827002 TI - [The pathogenetic substantiation of new therapeutic approach to the treatment of secondary osteoarthritis in patients with rheumatoid arthritis with basis therapy]. AB - The article concerns the efficacy of the use of new therapeutic approach in the therapy of secondary osteoarthritis in patients with rheumatoid arthritis. The dynamic of Cartilage Oligomeric Matrix Protein, activity of the disease on DAS28, cytokine profile was estimated. The analysis of the results showed the advantages of the use of inhibitor of IL-1 combined with laser therapy in the treatment of secondary osteoarthritis in patients with rheumatoid arthritis. PMID- 25827004 TI - [Personality characteristics in elderly men and women with initiatory stages of brain ischemia]. AB - 52 elderly women and 36 matched by age and education men with initiatory stages of chronic brain ischemia (CBI) have been studied using comparative analysis of personality characteristics. Women with CBI had higher level of psychosocial stress than men. The results demonstrate the predomination of extrapunitive frustration reactions among women. Intropunitive ones prevailed in men. Women patients had higher levels of excitement, stress and anxiety than men that surpassed women by the indicators of emotional security. The received data may be important for individualization of therapeutic intervention. PMID- 25827003 TI - [Peculiarities of clinical course, diagnostics and treatment of overactive bladder in men older than 60 years]. AB - The article presents the issues of the characteristics of the course, diagnostics and treatment of hyperactive urinary bubble in older men. Conservative treatment of urinary incontinence includes changes in lifestyle, behavioural and medical therapy with m-anticholinergic drugs. The combination solifenacini in a dose of 5 mg/day and alpha1-adrenoceptor blocking agent terasolini in a dose of 2 mg/day significantly improves the results of treatment and well tolerated. PMID- 25827005 TI - [Assessment of effectiveness of ischemic heart disease rehabilitation of elderly patients using six-minutes walking test]. AB - The possibility to use the test with a six-minute walk to assess the effectiveness of long-term programs of rehabilitation, definite disability and severity of heart failure in middle-aged and elderly patients with coronary heart disease is discussed. PMID- 25827006 TI - [Gerontological trends of contemporary forms of alcohol dependence. Approaches to full compensation and rehabilitation]. AB - Quality of life has already been investigated in elderly patients with alcohol dependence. Indicators were deteriorated with long-term experience of alcohol and somatic diseases. Practice of Reamberin, Cytoflavin, Cycloferon has improved quality of life and physical status of elderly patients. PMID- 25827007 TI - [Pathogenetic associations of periodontal diseases with somatic therapeutic pathology, comorbid conditions in patients of advanced and senile age: state-of the-art review. Part 1. Associations of periodontal diseases with somatic therapeutic pathology in patients of advanced and senile age]. AB - The state-of-the-art review of literature on existing views on the association of periodontal diseases with somatic therapeutic pathology (first part of the review) and comorbid conditions (second part of the review) is submitted. The conclusion about need of carrying out the further multicenter researches which purpose is development of new integrated indicators, in a complex and comprehensively characterizing not only the periodontal status, but also set of available somatic therapeutic pathology, especially at pa- tients of advanced and senile age is drawn. PMID- 25827008 TI - [Associations of periodontal diseases with somatic therapeutic pathology, comorbid conditions in patients of advanced and senile age: state-of-the-art review. Part 2. Associations of periodontal diseases with comorbid conditions in patients of advanced and senile age]. AB - The state-of-the-art review of literature on existing views on the association of periodontal diseases with somatic therapeutic pathology (part 1 of the review) and comorbid conditions (part 2 of the review) is submitted. The conclusion about need of carrying out the further multicenter researches which purpose is development of new integrated indicators, in a complex and comprehensively characterizing not only the periodontal status, but also set of available somatic therapeutic pathology, especially at patients of advanced and senile age is drawn. PMID- 25827009 TI - [Morphological structure, chemical and mineral composition of hard tooth tissues in age-related aspect]. AB - The article presents the results of research on the structure, chemical and mineral composition of hard tooth tissues of persons of different age groups. The obtained data enable to estimate the resistance of tooth tissues to unfavorable factors of the oral cavity, which should be considered when planning treatment and prevention in patients with diseases of hard tissues of teeth caries and non carious origin depending on their age. PMID- 25827010 TI - [Explanation of some physiological characteristics of homeostasis in elderly patients with temporomandibular joint dysfunction]. AB - Most number of patients, particularly adult and older women with temporomandibular disfunction suffers from pain reaction in maxillofacial area. Pain symptom associated with temporomandibular disfunction is followed by some changes of physiological statistics (high sympathetic level). Temporomandibular disfunction in adult and older women is most pronounced and can serve as an indicator of concomitant chronic diseases among patients with endocrine disorder (hypothyroidism), cardiological pathology (arterial hypertension). PMID- 25827011 TI - [Efficiency of intensive care with cytoflavin in patients of advanced age in combined traumatic brain injury]. AB - Research objective--determination of efficiency of intensive care with inclusion Cytoflavin in patients of old age in combined traumatic brain injury. A prospective controlled blind randomized study was conducted. In 1st group (21 people) the patients received a standard intensive care, in 2nd group (18 persons) Cytoflavin was included in complex intensive care. Using Cytoflavin starting from 2 days post-traumatic period (with the correction of blood circulation and respiration) had antioxidant and detoxification effects, contributed to the recovery rate of free radical and metabolic processes, reduced the degree of impairment in the structural-functional state of membranes and restored the conformational structure of membrane proteins in the earlier periods. Reduction in reactions of disadaptation led to regression of multiple organ dysfunctions, restoration the level of consciousness at an earlier date. The number of cases of severe respiratory distress syndrome decreased. PMID- 25827012 TI - [Optimization of nursing care in emergency cases in elderly patients residing in nursing homes]. AB - The study analyzes data on the frequency of emergencies in elderly patients residing in nursing homes. We propose to introduce into the nursing care the screening phase of emergency conditions in elderly patients residing in nursing homes based on the selection of the leading symptom. This improves the quality of the nursing process in pre-hospital geriatric care in emergencies. PMID- 25827013 TI - [Analysis of condition and prospects in geriatric care of population of Kazakhstan]. AB - Demographic aging of the population determines the need for the development of geriatric component in the work of medical services. In this regard, we have proved promising development of Gerontology and Geriatrics in Kazakhstan, the results of analysis of the existing system of care for the elderly persons and identify ways to improve towards rehabilitation help, long-term care for people over 80 years old, geriatric medical training and the creation of a scientific school of Gerontology and geriatrics. PMID- 25827014 TI - Role of imaging in COPD phenotyping. PMID- 25827015 TI - Rapid ventricular pacing-induced postconditioning attenuates reperfusion injury: effects on peroxynitrite, RISK and SAFE pathways. AB - BACKGROUND AND PURPOSE: Rapid ventricular pacing (RVP) applied before an index ischaemia has anti-ischaemic effects. Here, we investigated whether RVP applied after index ischaemia attenuates reperfusion injury and whether peroxynitrite, reperfusion injury salvage kinase (RISK) and survival activating factor enhancement (SAFE) pathways as well as haem oxygenase 1 (HO1) are involved in the mechanism of RVP-induced postconditioning. EXPERIMENTAL APPROACH: Langendorff perfused rat hearts were subjected to 30 min regional ischaemia and 120 min reperfusion with or without ischaemic postconditioning (6 * 10/10 s reperfusion/ischaemia; IPost) or RVP (6 * 10/10 s non-pacing/rapid pacing at 600 bpm) applied at the onset of reperfusion. KEY RESULTS: Meta-analysis of our previous studies revealed an association between longer reperfusion-induced ventricular tachycardia/fibrillation with decreased infarct size. In the present experiments, we tested whether RVP is cardioprotective and found that both IPost and RVP significantly decreased infarct size; however, only RVP attenuated the incidence of reperfusion-induced ventricular tachycardia. Both postconditioning methods increased the formation of cardiac 3-nitrotyrosine and superoxide, and non-significantly enhanced Akt phosphorylation at the beginning of reperfusion without affecting ERK1/2 and STAT3, while IPost alone induced HO1. Application of brief ischaemia/reperfusion cycles or RVP without preceding index ischaemia also facilitated peroxynitrite formation; nevertheless, only brief RVP increased STAT3 phosphorylation. CONCLUSIONS AND IMPLICATIONS: Short periods of RVP at the onset of reperfusion are cardioprotective and increase peroxynitrite formation similarly to IPost and thus may serve as an alternative postconditioning method. However, downstream mechanisms of the protection elicited by IPost and RVP seem to be partially different. LINKED ARTICLES: This article is part of a themed section on Conditioning the Heart - Pathways to Translation. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-8. PMID- 25827016 TI - Arabidopsis AtbHLH112 regulates the expression of genes involved in abiotic stress tolerance by binding to their E-box and GCG-box motifs. AB - Plant basic helix-loop-helix (bHLH) transcription factors play essential roles in abiotic stress tolerance. However, most bHLHs have not been functionally characterized. Here, we characterized the functional role of a bHLH transcription factor from Arabidopsis, AtbHLH112, in response to abiotic stress. AtbHLH112 is a nuclear-localized protein, and its nuclear localization is induced by salt, drought and abscisic acid (ABA). In addition, AtbHLH112 serves as a transcriptional activator, with the activation domain located at its N-terminus. In addition to binding to the E-box motifs of stress-responsive genes, AtbHLH112 binds to a novel motif with the sequence 'GG[GT]CC[GT][GA][TA]C' (GCG-box). Gain- and loss-of-function analyses showed that the transcript level of AtbHLH112 is positively correlated with salt and drought tolerance. AtbHLH112 mediates stress tolerance by increasing the expression of P5CS genes and reducing the expression of P5CDH and ProDH genes to increase proline levels. AtbHLH112 also increases the expression of POD and SOD genes to improve reactive oxygen species (ROS) scavenging ability. We present a model suggesting that AtbHLH112 is a transcriptional activator that regulates the expression of genes via binding to their GCG- or E-boxes to mediate physiological responses, including proline biosynthesis and ROS scavenging pathways, to enhance stress tolerance. PMID- 25827017 TI - Vitamin D status in pre-school children in rural Nepal. AB - OBJECTIVE: Vitamin D plays a major role in Ca and bone metabolism, and its extraskeletal functions are being appraised. Although inadequate vitamin D concentrations have been reported in populations worldwide, too little is known about vitamin D status and its determinants among children in developing countries. We aimed to determine vitamin D status and its determinants in Nepalese children of pre-school age. DESIGN: A community-based, cross-sectional study. SETTING: Rural Nepal at latitude 27.39 degrees N. SUBJECTS: Healthy children (n 280) aged 12-60 months, selected randomly from the records of a vitamin A supplementation programme. Blood samples were collected using the dried blood spot technique and analysed for serum 25-hydroxyvitamin D (s-25(OH)D) concentration using liquid chromatography-tandem mass spectrometry. Ca intake and background variables were assessed with a structured questionnaire. RESULTS: Hypovitaminosis D, defined as s-25(OH)D concentration less than 50 nmol/l, was found in 91.1% of the children. S-25(OH)D concentration was not related to gender, socio-economic indicators, sun exposure or nutritional status. Currently breast-fed children had higher s-25(OH)D concentrations (36.4 (sd 13.2) nmol/l) than those who were not (28.6 (sd 9.8) nmol/l, P<0.001). Adjustment for sociodemographic factors did not alter the results. CONCLUSION: There is widespread vitamin D deficiency among pre-school children in a rural area of Nepal. In our sample, sociodemographic factors did not affect the vitamin D status of children, but prolonged breast-feeding was associated with higher s 25(OH)D concentrations. Further research is required to investigate the health consequences of poor vitamin D status for this population. PMID- 25827018 TI - From spouse to caregiver and back: a grounded theory study of post-intensive care unit spousal caregiving. AB - AIM: To explore the challenges and caring activities of spouses of intensive care unit survivors during the first year of patient recovery. BACKGROUND: Every year, millions of people globally are discharged from an intensive care unit after critical illness to continue treatment, care and rehabilitation in general hospital wards, rehabilitation facilities and at home. Consequently, millions of spouses become informal caregivers. Little is known, however, about the concrete challenges spouses face in post-intensive care unit everyday life. DESIGN: Explorative, qualitative grounded theory study. METHODS: Participants were spouses of intensive care unit survivors. The study was undertaken in Denmark in 2009-2010. Data consisted of 35 semi-structured dyad interviews at 3 and 12 months post-intensive care unit discharge, two group interviews with patients and two with spouses. FINDINGS: 'Shifting their role from spouse to caregiver and back' was identified as the core category of the study. The role shifts progressed in a dynamic process involving four elements: (1) committing to caregiving; (2) acquiring caregiving skills; (3) negotiating level of caregiving and (4) gradually leaving the caregiver role. Post-ICU caregiving comprised five patient dimensions: observing, assisting, coaching, advocating and managing activities. CONCLUSIONS: Spouses play a vital and multifaceted role in post intensive care unit recovery. The findings can inform healthcare professionals in their efforts to prepare intensive care unit patients' families for the time following intensive care unit and hospital discharge. Hospital staff, rehabilitation experts and primary care professionals must acknowledge spouses' important contribution from intensive care unit admission throughout recovery. PMID- 25827020 TI - Urinary metal concentrations in relation to semen quality: a cross-sectional study in China. AB - Exposure to metals, including essential and nonessential elements, is widespread and may be associated with altered semen quality. This study aimed to examine the association between urinary metal concentrations and semen quality in a Chinese population. We measured semen quality parameters (sperm concentration, count, motility, normal morphology, and abnormal head) and 13 metals [arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), molybdenum (Mo), mercury (Hg), nickel (Ni), selenium (Se), and zinc (Zn)] in the urine of 394 men from an infertility clinic. Multivariable logistic and linear regressions were used to assess the relationship between the creatinine-adjusted urinary metal concentrations and semen quality parameters. We found a significant trend for decreased odds ratios (ORs) for below-reference sperm count with increasing Se quartiles (p for trend = 0.04) and a significant trend for increased sperm percent abnormal head with increasing Ni quartiles (p for trend = 0.03). These associations persisted, even when considering multiple metals. Our results suggest that Ni exposure may be associated with deteriorated sperm morphology and that Se exposure may be associated with better semen quality. However, our findings warrant further studies in a larger and general population. PMID- 25827019 TI - Human spleen microanatomy: why mice do not suffice. AB - The microanatomical structure of the spleen has been primarily described in mice and rats. This leads to terminological problems with respect to humans and their species-specific splenic microstructure. In mice, rats and humans the spleen consists of the white pulp embedded in the red pulp. In the white pulp, T and B lymphocytes form accumulations, the periarteriolar lymphatic sheaths and the follicles, located around intermediate-sized arterial vessels, the central arteries. The red pulp is a reticular connective tissue containing all types of blood cells. The spleen of mice and rats exhibits an additional well-delineated B cell compartment, the marginal zone, between white and red pulp. This area is, however, absent in human spleen. Human splenic secondary follicles comprise three zones: a germinal centre, a mantle zone and a superficial zone. In humans, arterioles and sheathed capillaries in the red pulp are surrounded by lymphocytes, especially by B cells. Human sheathed capillaries are related to the splenic ellipsoids of most other vertebrates. Such vessels are lacking in rats or mice, which form an evolutionary exception. Capillary sheaths are composed of endothelial cells, pericytes, special stromal sheath cells, macrophages and B lymphocytes. Human spleens most probably host a totally open circulation system, as connections from capillaries to sinuses were not found in the red pulp. Three stromal cell types of different phenotype and location occur in the human white pulp. Splenic white and red pulp structure is reviewed in rats, mice and humans to encourage further investigations on lymphocyte recirculation through the spleen. PMID- 25827021 TI - Catheter-directed Thrombolysis in Acute Superior Vena Cava Syndrome Caused by Central Venous Catheters. AB - Indwelling central venous catheters have been reported to increase the risk of superior venous cava (SVC) syndrome. This case report describes the development of acute SVC syndrome in a 28-year-old woman with end-stage renal disease implanted with a left-side hemodialysis reliable outflow graft and a right-side double lumen hemodialysis catheter via internal jugular veins. Her symptoms were not alleviated after catheter removal and systemic anticoagulation therapy. She was eventually treated with catheter-directed thrombolysis and a predischarge computer tomographic venogram on postthrombolytic procedure day 7 showed patent central veins and patient remained asymptomatic. This case demonstrates that catheter-directed thrombolysis can be safely employed to treat refractory catheter-induced acute SVC syndrome in end-stage renal disease patients. PMID- 25827023 TI - Hypertension in Older Persons: A Systematic Review of National and International Treatment Guidelines. AB - Despite good evidence regarding the benefits of managing hypertension in elderly populations, the extent to which this evidence has been incorporated into national and international clinical hypertension treatment guidelines is unknown. A systematic review was conducted to identify recommendations in current national and international hypertension treatment guidelines with a focus on specific targets and treatment recommendations for older persons with uncomplicated hypertension. Guidelines for the management of hypertension published or updated over a 5-year period (2009-2014) were identified by searching Medline, Google, and Google Scholar. Thirteen guidelines that met the predefined inclusion criteria were included in the review. Among these guidelines was considerable variation regarding who is considered an older person. However, there was general consensus regarding blood pressure targets. While current hypertension guidelines do include recommendations regarding management of uncomplicated hypertension in older populations, the depth and breadth of these recommendations vary considerably between guidelines and may limit the usefulness of such treatment guidelines to clinicians. PMID- 25827022 TI - Genomic analysis of host - Peste des petits ruminants vaccine viral transcriptome uncovers transcription factors modulating immune regulatory pathways. AB - Peste des petits ruminants (PPR), is an acute transboundary viral disease of economic importance, affecting goats and sheep. Mass vaccination programs around the world resulted in the decline of PPR outbreaks. Sungri 96 is a live attenuated vaccine, widely used in Northern India against PPR. This vaccine virus, isolated from goat works efficiently both in sheep and goat. Global gene expression changes under PPR vaccine virus infection are not yet well defined. Therefore, in this study we investigated the host-vaccine virus interactions by infecting the peripheral blood mononuclear cells isolated from goat with PPRV (Sungri 96 vaccine virus), to quantify the global changes in the transcriptomic signature by RNA-sequencing. Viral genome of Sungri 96 vaccine virus was assembled from the PPRV infected transcriptome confirming the infection and demonstrating the feasibility of building a complete non-host genome from the blood transcriptome. Comparison of infected transcriptome with control transcriptome revealed 985 differentially expressed genes. Functional analysis showed enrichment of immune regulatory pathways under PPRV infection. Key genes involved in immune system regulation, spliceosomal and apoptotic pathways were identified to be dysregulated. Network analysis revealed that the protein - protein interaction network among differentially expressed genes is significantly disrupted in infected state. Several genes encoding TFs that govern immune regulatory pathways were identified to co-regulate the differentially expressed genes. These data provide insights into the host - PPRV vaccine virus interactome for the first time. Our findings suggested dysregulation of immune regulatory pathways and genes encoding Transcription Factors (TFs) that govern these pathways in response to viral infection. PMID- 25827025 TI - In treating alcohol use disorders, why not use evidence-based treatment? PMID- 25827024 TI - Radial head replacement or repair for the terrible triad of the elbow: which procedure is better? AB - BACKGROUND: The terrible triad of the elbow comprises an ulnar coronoid process fracture, a radial head (RH) fracture and posterior dislocation of the elbow. It is considered severe by many clinicians because it is difficult to repair and has a poor prognosis; therefore, it deserves more attention. METHODS: Thirty-nine patients with terrible triad of the elbow characterized by a Mason type-III RH fracture were randomly divided into either an RH repair group (n = 19) or an RH replacement group (n = 20). The complication rates, radiological outcomes, Mayo Elbow Performance Score and range of motion of the elbow were analysed. RESULTS: Follow-up demonstrated no subluxation or recurrent dislocation of the elbow. Differences in surgery duration between the groups were significant (P < 0.001). The outcomes in terms of Mayo Elbow Performance Score (P = 0.009), flexion extension arc (P = 0.01) and pronation-supination arc (P = 0.04) were significantly better in the RH replacement group. In addition, patients in the RH replacement group displayed significantly fewer post-surgery complications than those in the RH repair group (P = 0.04). CONCLUSION: Treating Mason type-III RH fracture in a terrible triad of the elbow with a metal RH prosthesis resulted in better clinical outcomes and fewer post-surgery complications than treating a terrible triad of the elbow by repairing it with screws or plates. RH replacement might be a more effective approach to better managing a terrible triad of the elbow. PMID- 25827026 TI - C-reactive protein: A stress diathesis marker at the crossroads of maladaptive behavioral and cardiometabolic sequelae. PMID- 25827027 TI - Electronic medical records: fast track to big data in bipolar disorder. PMID- 25827028 TI - Evidence for schizophrenia as a disorder of neuroplasticity. PMID- 25827029 TI - Reporting on China's mental health surveillance. PMID- 25827030 TI - A clinical perspective on the relevance of research domain criteria in electronic health records. AB - OBJECTIVE: The limitations of the DSM nosology for capturing dimensionality and overlap in psychiatric syndromes, and its poor correspondence to underlying neurobiology, have been well established. The Research Domain Criteria (RDoC), a proposed dimensional model of psychopathology, may offer new insights into psychiatric illness. For psychiatric clinicians, however, because tools for capturing these domains in clinical practice have not yet been established, the relevance and means of transition from the categorical system of DSM-5 to the dimensional models of RDoC remains unclear. The authors explored a method of extracting these dimensions from existing electronic health record (EHR) notes. METHOD: The authors used information retrieval and natural language processing methods to extract estimates of the RDoC dimensions in the EHRs of a large health system. They parsed and scored EHR documentation for 2,484 admissions covering 2,010 patients admitted to a psychiatric inpatient unit between 2011 and 2013. These domain scores were compared with DSM-IV-based ICD-9 codes to assess face validity. As a measure of predictive validity, these scores were examined for association with two outcomes: length of hospital stay and time to all-cause hospital readmission. Together, these analyses were intended to address the extent to which RDoC symptom domains might capture clinical features already available in narrative notes but not reflected in DSM diagnoses. RESULTS: In mixed-effects models, loadings for the RDoC cognitive and arousal domains were associated with length of hospital stay, while the negative valence and social domains were associated with hazard of all-cause hospital readmission. CONCLUSIONS: These findings show that a computationally derived tool based on RDoC workgroup reports identifies symptom distributions in clinician notes beyond those captured by ICD-9 codes, and these domains have significant predictive validity. More generally, they point to the possibility that clinicians already document RDoC-relevant symptoms, albeit not in a quantified form. PMID- 25827031 TI - Charles Darwin and the asylum letters. PMID- 25827032 TI - Pragmatic replication trial of health promotion coaching for obesity in serious mental illness and maintenance of outcomes. AB - OBJECTIVE: Few studies targeting obesity in serious mental illness have reported clinically significant risk reduction, and none have been replicated in community settings or demonstrated sustained outcomes after intervention withdrawal. The authors sought to replicate positive health outcomes demonstrated in a previous randomized effectiveness study of the In SHAPE program across urban community mental health organizations serving an ethnically diverse population. METHOD: Persons with serious mental illness and a body mass index (BMI) >25 receiving services in three community mental health organizations were recruited and randomly assigned either to the 12-month In SHAPE program, which included membership in a public fitness club and weekly meetings with a health promotion coach, or to fitness club membership alone. The primary outcome measures were weight and cardiorespiratory fitness (as measured with the 6-minute walk test), assessed at baseline and at 3, 6, 9, 12, and 18 months. RESULTS: Participants (N=210) were ethnically diverse (46% were nonwhite), with a mean baseline BMI of 36.8 (SD=8.2). At 12 months, the In SHAPE group (N=104) had greater reduction in weight and improved fitness compared with the fitness club membership only group (N=106). Primary outcomes were maintained at 18 months. Approximately half of the In SHAPE group (51% at 12 months and 46% at 18 months) achieved clinically significant cardiovascular risk reduction (a weight loss >=5% or an increase of >50 meters on the 6-minute walk test). CONCLUSIONS: This is the first replication study confirming the effectiveness of a health coaching intervention in achieving and sustaining clinically significant reductions in cardiovascular risk for overweight and obese persons with serious mental illness. PMID- 25827033 TI - Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. AB - OBJECTIVE: Increased systemic inflammation is associated with stress-related psychopathology. Specifically, levels of the proinflammatory marker C-reactive protein (CRP) are elevated in individuals with posttraumatic stress disorder (PTSD). Furthermore, single-nucleotide polymorphisms (SNPs) in the CRP gene are associated with CRP level, risk for cardiovascular disease, and obesity. The authors examined whether polymorphisms within the CRP gene and increased CRP levels are associated with PTSD symptoms and fear physiology in a civilian population with high levels of trauma. METHOD: Cross-sectional data and DNA samples were collected from 2,698 individuals recruited from an inner-city public hospital that serves a primarily African American, low-socioeconomic-status population. A subgroup of 187 participants participated in further interviews, testing, and physiological measures; of these, 135 were assessed using the fear potentiated startle paradigm to assess fear-related phenotypes of PTSD. RESULTS: One SNP within the CRP gene, rs1130864, was significantly associated with increased PTSD symptoms (N=2,692), including "being overly alert" as the most significant individual symptom (N=2,698). Additionally, CRP genotype was associated with the odds of PTSD diagnosis (N=2,692). This SNP was also associated with increased CRP level (N=137), and high CRP levels (>3 mg/L) were positively associated with PTSD symptoms (N=187) and fear-potentiated startle to a safety signal (N=135). CONCLUSIONS: Together, these data indicate that genetic variability in the CRP gene is associated with serum CRP level and PTSD symptom severity, including that of hyperarousal symptoms. Elevated CRP levels were also associated with exacerbated fear-related psychophysiology and PTSD symptom ratings and diagnosis. These findings suggest a potential mechanism by which an increased proinflammatory state may lead to heightened PTSD symptoms. PMID- 25827035 TI - Treatments for social anxiety disorder: considerations regarding psychodynamic therapy findings. PMID- 25827036 TI - Response to Hofmann et al. PMID- 25827037 TI - Sex difference in response to varenicline for smoking cessation. PMID- 25827034 TI - Validation of electronic health record phenotyping of bipolar disorder cases and controls. AB - OBJECTIVE: The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects. METHOD: EHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis. RESULTS: The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses. CONCLUSIONS: Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research. PMID- 25827038 TI - Response to Gorelick. PMID- 25827039 TI - Association of a brain methylation site with clinical outcomes in depression does not replicate across populations. PMID- 25827040 TI - Response to Uher et al. PMID- 25827041 TI - Motion Sensors to Assess and Monitor Medical and Surgical Management of Parkinson Disease. AB - Patients with Parkinson disease (PD) often suffer from a resting tremor, bradykinesia, rigidity, postural instability, and gait difficulty. Determining a patient's candidacy for deep-brain stimulation (DBS) surgery and tracking their clinical response postoperatively requires that the frequency, duration, and severity of these symptoms be characterized in detail. Conventional means of assessing these symptoms, however, rely heavily on patient self-reporting, which often fails to provide the necessary level of detail. Wearable accelerometers are a novel tool that can detect and objectively characterize these movement abnormalities in both the clinical setting and the patient's home environment. In this article, we review the role of accelerometers in surgical candidate selection, recording and predicting falls, recording and predicting freezing of gait, evaluating surgical outcomes, and evaluating postoperative recovery and in altering DBS settings. Although accelerometry has yet to make it into the mainstream clinic, there is great promise for this technology in monitoring Parkinson patients. PMID- 25827042 TI - Minimally Invasive Endoscopic Supracerebellar-Infratentorial Surgery of the Pineal Region: Anatomical Comparison of Four Variant Approaches. AB - OBJECTIVE: The endoscopic supracerebellar-infratentorial (SCIT) approach is a viable method to access pathology of the posterior incisura, but a narrow working space and frequent instrument conflict can potentially limit its surgical efficacy. Until now, no rigorous studies were available comparing surgical freedom and angle of attack for four previously well-described approaches to pineal region targets. METHODS: Four formalin-fixed cadaver heads were dissected bilaterally (eight sides). A midline approach and three progressively lateral approaches to the pineal region were performed (paramedian, lateral, extreme lateral), and anatomical targets were identified. Utilizing frameless stereotaxy, we calculated surgical freedom using the vector cross-product method for all approaches for the exposed area and for three anatomical targets (pineal gland, ipsilateral superior colliculus, splenium). The mean and maximum possible angles of attack were calculated in the axial and sagittal planes. RESULTS: Point target surgical freedom, exposed area surgical freedom, and angle of attack for each individual pineal region target can be maximized depending on the medial-to lateral location of the craniotomy. For endoscopic-controlled approaches, the extreme lateral approach provides the largest surgical freedom when accessing the ipsilateral superior colliculus (P < 0.0001), the lateral approach provides the largest surgical freedom to the pineal gland (P < 0.0001), and the paramedian craniotomy provides the largest surgical freedom when accessing the splenium (P < 0.0001). The extreme lateral approach to the pineal gland provided the largest horizontal angle of attack (P < 0.0001), and the extreme lateral approach to the ipsilateral superior colliculus provided the largest vertical angle of attack (P < 0.001). The microscope provides marginally increased surgical freedom and a better angle of attack to specific anatomical targets in the paramedian and extreme lateral approach compared with those provided by the endoscope, but these differences are negligible during intraoperative application. CONCLUSIONS: Presurgical planning and a detailed understanding of the important neurovascular structures in the pineal region are paramount to safe and successful surgical execution. Our current cadaveric study indicates that the medial-to-lateral location of craniotomy can maximize access to pineal region targets. Furthermore, the endoscope is a viable alternative to the microscope for identifying pathology of the posterior incisura. These differences in surgical freedom and angle of attack to the pineal region may be useful to consider when planning minimal access approaches. PMID- 25827043 TI - Extended Endoscopic Endonasal Approach to the Third Ventricle: Multimodal Anatomical Study with Surgical Implications. AB - INTRODUCTION: A certain interest for the extended endoscopic endonasal approach for the management of sellar-suprasellar lesions extending inside the third ventricle has been growing in recent years. The aim of this anatomical study was to evaluate the possibilities in terms of exposure and access to the different areas of the third ventricle, with the endoscopic endonasal technique, as compared with the microscopic or endoscopic view provided via different transcranial approaches. The advantages and limitations of both surgical pathways were analyzed. MATERIALS AND METHODS: Ten human cadaver heads were dissected. In order to standardize the comparison between the endonasal and the transcranial routes, the third ventricle cavity has been divided into four areas by means of two ideal planes, one passing through the optic chiasm and the interthalamic commissure and one passing through the posterior edge of the foramen of Monro and the interthalamic commissure. Accordingly, two anterior (infundibular and foraminal) and two posterior (mesencephalic and tectal) areas have been defined. RESULTS: The endoscopic endonasal approach allows for exploration and surgical maneuverability, especially in the anterior areas of the third ventricle. In the infundibular and foraminal areas the surgical maneuverability seems to be better as compared with that obtained inside the mesencephalic region, while via the endonasal route the tectal area could not be reached. In particular, the infundibular area can be explored either passing through the lamina terminalis or via the tuber cinereum; this latter trajectory enables visualization of the foramina of Monro and the floor of the third ventricle up to the pineal recess. CONCLUSION: This anatomical study shows that the lamina terminalis and, above all, the tuber cinereum represent two safe entry points defining possible surgical corridors to be considered for the extended endoscopic endonasal approach to the third ventricle. PMID- 25827044 TI - History of Neurosurgery in Democratic People's Republic of Korea. AB - Neurosurgery in Democratic People's Republic of Korea (DPRK) has undergone remarkable progress since its beginning in the 1950s. With the initial support from socialist countries of the Soviet bloc, especially Professor Constantin Arseni of Romania, the nation has consistently produced a number of its own neurosurgeons each year and fostered further advancement by establishing the Korean Neurosurgery Association (DPRK). Despite the recent international collaborative activity for North Korean neurosurgery-namely with Foundation for International Education in Neurological Surgery, World Federation of Neurological Surgeons, and Korean American Medical Association-the sparse exchange of information, knowledge, and surgical skills still remains largely inadequate. PMID- 25827045 TI - Flow Diversion Technologies in Evolution: A Review of the First Two Generations of Flow Diversion Devices. AB - Flow diversion technologies have gained popularity as a novel endovascular approach to treating cerebral aneurysms. Thus far, the results of treatment with flow diverters has been excellent, with comparable morbidity and mortality to stent-assisted coiling but higher complete occlusion. Currently, published data exists for four different flow diversion technologies. We review and summarize the most recent results for these technologies and review differences in flow diverter designs. PMID- 25827046 TI - Endoscopic Surgery in Nonhydrocephalous Third Ventricular Colloid Cysts: A Feasibility Study. AB - BACKGROUND: The aim of this study was to investigate the feasibility and effectiveness of endoscopic neurosurgery for patients with third ventricular colloid cysts but without ventriculomegaly. METHODS: Seventy-one patients with third ventricular colloid cysts were identified and recruited to this study. Eighteen of these patients did not have concomitant hydrocephalus and underwent primary endoscopic surgery for cyst resection. The surgical technique, the success rate, and patients' outcome were assessed and compared with another 53 patients with hydrocephalus who underwent similar procedures. Our study was performed in a retrospective basis, although in middle of our work we decided to study and follow nonhydrocephalus cases prospectively. RESULTS: The ventricular compartments were successfully cannulated and gross total resection and near total resection of the colloid cysts was achieved in all patients. There were no persistent operative complications related to the endoscopic procedure. The success rate for endoscopic surgery in patients without hydrocephalus was similar to its value in patients with hydrocephalus. CONCLUSIONS: Endoscopic resection of third ventricular colloid cyst in patients without hydrocephalus seems to be feasible, effective, and not contraindicated. PMID- 25827047 TI - The impact of depression on fatigue in patients with haemodialysis: a correlational study. AB - AIMS AND OBJECTIVES: To investigate the fatigue levels and important fatigue predictors for patients undergoing haemodialysis. BACKGROUND: Fatigue is a common symptom for haemodialysis patients. With its debilitating and distressing effects, it impacts patients in terms of their quality of life while also increasing their mortality rate. DESIGN: A descriptive correlational study. METHODS: Convenience sampling was conducted at six chosen haemodialysis centres in Southern Taiwan. Data were collected via a structured questionnaire from 193 haemodialysis patients. The scales involved in this study were socio-demographic details, the Center for Epidemiologic Studies Depression Scale, and the Fatigue Scale for haemodialysis patients. Data analysis included percentages, means, standard deviations and hierarchical multiple regression analysis. RESULTS: The fatigue level for haemodialysis patients was in the moderate range. Results from the hierarchical multiple regression analysis indicated that age, employment status, types of medications, physical activity and depression were significant. Of those variables, depression had the greatest impact on the patients' fatigue level, accounting for up to 30.6% of the explanatory power. The total explanatory power of the regression model was 64.2%. CONCLUSION: This study determined that for haemodialysis patients, unemployment, increased age, taking more medications or lower exercise frequencies resulted in more severe depression, which translated in turn to higher levels of fatigue. Among all these factors, depression had the greatest impact on the patients' fatigue levels. RELEVANCE TO CLINICAL PRACTICE: Not only is this finding beneficial to future studies on fatigue as a source of reference, it is also helpful in our understanding of important predictors relating to fatigue in the everyday lives of haemodialysis patients. It is recommended that when caring for fatigued patients, more care should be dedicated to their psychological states, and assistance should be provided in a timely way so as to reduce the amount of fatigue suffered. PMID- 25827049 TI - Comprehensive assessment for novel prostate cancer markers in the prostate specific antigen era: focusing on Asians and Asian countries. AB - We reviewed the current evidence for three novel prostate tumor markers (PCA3, TMPRSS2:ERG and proPSA) that have been recently reported predominantly in Western countries. We focus our attention on Asian men in both clinical and basic research studies. There have been no reports on the clinical usefulness of these three markers for Asians living in Western countries. In Asian countries, evidence for the clinical usefulness of PCA3 and proPSA-related indices including Prostate Health Index is being accumulated, mainly in Japan. The process for how a novel marker is approved in the clinical setting is also discussed. PMID- 25827050 TI - Editorial comment to Prostate-specific antigen level, stage or Gleason score: which is best for predicting outcomes after radical prostatectomy and does it vary by the outcome being measured? Results from Shared Equal Access Regional Cancer Hospital database. PMID- 25827051 TI - Editorial comment from Dr Isotani to Three-dimensional printing in urological surgery: what are the possibilities? PMID- 25827052 TI - Adverse Remodeling of the Left Atrium in Patients with Atrial Fibrillation: When Is the Tipping Point in Which Structural Changes Become Permanent? PMID- 25827053 TI - [Combined paralateronasal and cervical approaches for malignant maxillo mandibular tumors extending to the infratemporal fossa]. AB - INTRODUCTION: The common anterior paralateronasal approach for malignant maxillo mandibular tumors extending to the infratemporal fossa is usually difficult, insufficient, or even dangerous. TECHNICAL NOTE: We report a new approach for tumors extending to the infratemporal fossa. It combines a paralateronasal and a cervical approach indicated for tumors extending to the infratemporal fossa, requiring a total monoblock excision of the tumor with as little esthetic sequel as possible. DISCUSSION: The main interest of this technique is to offer a large exposure of the facial skeleton and the tumor, and to spare cervical vascular structures. PMID- 25827054 TI - [Split temporalis muscle flap vascularized by the superficial temporal pedicle]. AB - INTRODUCTION: The temporalis muscle has been used for more than a century for facial reconstruction. But this flap cannot fill defects beyond the midline. Splitting the temporalis muscle in the plane of the tendon insertion allows lengthening the flap and crossing the midline. TECHNICAL NOTE: The scalp incision is followed by a subcutaneous dissection, taking care to spare hair follicles and superficial temporal vessels. Then the temporalis muscle is detached by a strictly subperiosteal dissection and deep temporal pedicles are dissected and ligated. The flap is split in the plane of the insertion tendon up to its distal end. DISCUSSION: This technique allows reconstructing cranio-facial defect beyond the midline with well-vascularized tissue. PMID- 25827055 TI - Evaluation of a clinical tool to test and adjust the programmed overnight basal profiles for insulin pump therapy: a pilot study. AB - OBJECTIVE: Clinical protocols for basal rate testing and adjustment are needed for effective insulin pump therapy. We evaluated the effects of a continuous glucose monitoring (CGM)-based semiautomated basal algorithm on glycemia. METHODS: We developed and piloted a basal rate analyzer that interpreted CGM data from overnight fasts and recommended dose changes for subsequent nights. Subjects uploaded data online using sensor-augmented pumps for evaluation by the analyzer after each of 5 overnight fasts conducted over 2 to 8 weeks. It was designed to be conservative and iterative, making changes that did not exceed 10% at each iteration. The standard deviation and interquartile range of CGM values from midnight to 7 am (SD12-7am and IQR12-7am) over 3 baseline and 3 postintervention nights, hypoglycemia incidence (CGM values <4.0 mmol/L), and glycated hemoglobin (A1C) were compared. RESULTS: Twenty subjects with mean ages of 38+/-13 years and A1C 7.6%+/-0.8% (60+/-8.7 mmol/mol) underwent the 5 iterations of basal assessments over 5+/-3 weeks. SD12-7am and IQR12-7am did not change from baseline to postintervention (1.57+/-0.8 to 1.63+/-0.8 mmol/L; p=0.35; 3.66+/-2.07 to 3.47+/-2.26 mmol/L; p=0.90). However, mean glucose values were lower between 2 to 3 am at baseline compared to postintervention; 3-night hypoglycemia incidence declined from 1.6+/-1.8 to 0.5+/-0.7 episodes (p=0.01), and A1C improved from 7.6%+/-0.8% to 7.4%+/-0.9% (60%+/-8.7% to 57%+/-9.8% mmol/mol; p=0.03). CONCLUSIONS: The use of a basal rate analyzer was associated with reduced hypoglycemia and improved A1C. However, overnight glycemic stability was not improved. Further research into the efficacy of the CGM-based semiautomated algorithm is warranted. PMID- 25827056 TI - An exploratory study of image and performance enhancement drug use in a male British South Asian community. AB - BACKGROUND: Consumerism of image and performance enhancement drugs (IPEDs) is a world-wide public health concern. Given anecdotal reporting of increased normalisation of IPED use and uptake of British South Asian male IPED users at UK needle and syringe exchange services, the study aimed to explore use of IPEDs among this under-researched ethnic group. METHODS: 20 in depth interviews were conducted with a purposive sample of British South Asian males attending harm reduction outreach in the North East of England. The interviews explored motives for use of IPEDs, sourcing routes, information seeking, injecting behaviours and cultural and community sensitivities around IPED use among this group. The data was collected and analysed using the Interpretative Phenomenological Analysis approach (IPA). RESULTS: Motives for use centred on the achievement of enhanced definition and density of muscle, and improved recovery from training and injuries. All participants reported initial stimulation of interest and triggers to seek information on IPEDs due to social media, community and peer messages. Diverse forms of IPED use were described, with rational and moderated use common among older participants. In contrast younger participants adopted more excessive use in seeking short cuts to attaining muscle size. Sourcing of androgenic anabolic steroids (AAS) and growth hormones from originating countries (Pakistan, India) was reported, along with diversification of entrepreneurial activity into IPED dealing networks. Sellers were generally reported to provide effective and reliable products and mentoring to inexperienced users. Group injecting practices were common. IPED use was observed by some as health promotion medium within religious contexts. Crime deterrence and drug abstinence occurred for some while involved in AAS cycles. CONCLUSIONS: The study is intended to contribute to health policy and practice debate around the targeting of dedicated education, outreach and harm reduction for ethnic groups engaged in IPED use. PMID- 25827057 TI - Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice. AB - Liver fibrosis is a pathological condition in which chronic inflammation and changes to the extracellular matrix lead to alterations in hepatic tissue architecture and functional degradation of the liver. Inhibitors of the enzyme soluble epoxide hydrolase (sEH) reduce fibrosis in the heart, pancreas and kidney in several disease models. In this study, we assess the effect of sEH inhibition on the development of fibrosis in a carbon tetrachloride (CCl4)-induced mouse model by monitoring changes in the inflammatory response, matrix remolding and endoplasmic reticulum stress. The sEH inhibitor 1-trifluoromethoxyphenyl-3-(1 propionylpiperidin-4-yl) urea (TPPU) was administered in drinking water. Collagen deposition in the liver was increased five-fold in the CCl4-treated group, and this was returned to control levels by TPPU treatment. Hepatic expression of Col1a2 and 3a1 mRNA was increased over fifteen-fold in the CCl4-treated group relative to the Control group, and this increase was reduced by 50% by TPPU treatment. Endoplasmic reticulum (ER) stress observed in the livers of CCl4 treated animals was attenuated by TPPU treatment. In order to support the hypothesis that TPPU is acting to reduce the hepatic fibrosis and ER stress through its action as a sEH inhibitor we used a second sEH inhibitor, trans-4-{4 [3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (t-TUCB), and sEH null mice. Taken together, these data indicate that the sEH may play an important role in the development of hepatic fibrosis induced by CCl4, presumably by reducing endogenous fatty acid epoxide chemical mediators acting to reduce ER stress. PMID- 25827059 TI - Effects of sodium phosphate and caffeine loading on repeated-sprint ability. AB - The effects of sodium phosphate and caffeine supplementation were assessed on repeated-sprint ability. Using a randomised, double-blind, Latin-square design, 12 female, team-sport players participated in four trials: (1) sodium phosphate and caffeine, (2) sodium phosphate and placebo (for caffeine), (3) caffeine and placebo (for sodium phosphate) and (4) placebo (for sodium phosphate and caffeine), with ~21 days separating each trial. After each trial, participants performed a simulated team-game circuit (4 * 15 min quarters) with 6 * 20-m repeated-sprints performed once before (Set 1), at half-time (Set 2), and after end (Set 3). Total sprint times were faster after sodium phosphate and caffeine supplementation compared with placebo (Set 1: P = 0.003; Set 2: d = -0.51; Set 3: P < 0.001; overall: P = 0.020), caffeine (Set 3: P = 0.004; overall: P = 0.033) and sodium phosphate (Set 3: d = -0.67). Furthermore, total sprint times were faster after sodium phosphate supplementation compared with placebo (Set 1: d = 0.52; Set 3: d = -0.58). Best sprint results were faster after sodium phosphate and caffeine supplementation compared with placebo (Set 3: P = 0.007, d = -0.90) and caffeine (Set 3: P = 0.024, d = -0.73). Best sprint times were also faster after sodium phosphate supplementation compared with placebo (d = -0.54 to -0.61 for all sets). Sodium phosphate and combined sodium phosphate and caffeine loading improved repeated-sprint ability. PMID- 25827058 TI - Pioglitazone treatment enhances the sympathetic nervous system response to oral carbohydrate load in obese individuals with metabolic syndrome. AB - CONTEXT: Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis. OBJECTIVE: This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome. METHODS: Un-medicated individuals (n=42, mean age 56+/-0.8 yrs, body mass index 34+/-0.6 kg/m(2)) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index. RESULTS: PIO increased clamp derived glucose utilisation by 35% (P<0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P<0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all <0.05). The overall norepinephrine spillover response (AUC(0-120)) increased significantly in the PIO group (group * time interaction, P=0.04), with greatest increment at 30 minutes post-glucose (101+/-38 ng/min at baseline versus 241+/-48 ng/min post treatment, P=0.04) and correlated with percent improvement in M. CONCLUSIONS: PIO enhances the early postprandial SNS response to carbohydrate ingestion. PMID- 25827060 TI - Molecular mechanism of ER stress-induced gene expression of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) in macrophages. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, whose members are capable of inducing apoptosis and inflammation. Endoplasmic reticulum stress (ERS) plays a key role in immune surveillance in macrophages. TRAIL mRNA and protein expression have previously been detected in macrophages; however, whether ERS has any effects on TRAIL expression in macrophages has not yet been determined. Here, we demonstrate that thapsigargin (TG) and tunicamycin (TM), two ERS inducers activated macrophages were able to increase TRAIL mRNA and protein expression in RAW264.7 macrophages, the culture supernatant of THP-1 cells, and mouse peritoneal macrophages, indicating that ERS as a potent inducer of TRAIL transcription and expression in macrophages. This effect was blocked by the specific JNK inhibitor SP600125 and transcription factor AP-1 inhibitor SR 1130. Interestingly, at the molecular level, regulation of TRAIL expression by ERS was accompanied by a significant decrease in cytokine signaling suppressor 3 (SOCS3). SOCS3 siRNA clearly increased the expression of TRAIL mRNA and protein under ERS by activating the AP-1 components phosphorylated c-Jun and phosphorylated c-Fos in RAW264.7 cells. In contrast, over-expression of SOCS3 reversed ERS-induced TRAIL expression. These findings provide in vitro evidence that SOCS3 plays a critical negative role in the regulation of ERS-induced TRAIL expression via the Jun N terminal kinase/AP-1 signaling pathway in macrophages. PMID- 25827061 TI - Spray distribution evaluation of different settings of a hand-held-trolley sprayer used in greenhouse tomato crops. AB - BACKGROUND: Hand-held-trolley sprayers have recently been promoted to improve spray application techniques in greenhouses in south-eastern Spain. However, certain aspects remain to be improved. A modified hand-held-trolley sprayer was evaluated under two different canopy conditions (high and low canopy density) and with several sprayer settings (nozzle type, air assistance and spray volume). In this study, the deposition, coverage and uniformity of distribution of the spray on the canopy have been assessed. RESULTS: The deposition on leaves was significantly higher when flat-fan nozzles and air assistance were used at both high and low spray volumes. No differences were detected between the reference system at a high spray volume and the modified trolley at a low spray volume. Flat-fan nozzles with air assistance increased penetrability into the canopy. CONCLUSIONS: Air assistance and flat-fan nozzles allow volume rates to be reduced while maintaining or improving spray quality distribution. The working parameters of hand-held sprayers must be considered to reduce environmental risk and increase the efficacy of the spraying process. (c) 2015 Society of Chemical Industry. PMID- 25827062 TI - The utility of three-dimensional optical projection tomography in nerve injection injury imaging. AB - The examination of nerve microarchitecture has hitherto been limited solely to two-dimensional imaging techniques. The objective of this study was to evaluate the ability of optical projection tomography to discern the nerve microarchitecture and injection injury in three dimensions. Five piglets were studied, whose median and lingual nerves were unilaterally injected post mortem with preset volumes of local anaesthetic, excised and subsequently made transparent with benzyl alcohol benzyl benzoate. Images were captured in three dimensions. The same contralateral nerves were used as controls. Using optical projection tomography, we observed differences between the internal organisation of the median and the lingual nerves, which potentially explain the variations in their susceptibility to injury. This was demonstrated in three dimensions as a disruption to the fascicles in the lingual nerve, and their displacement in the median nerve. This new technology offers potential for studying nerve microarchitecture topography and its tolerance to injection injury. PMID- 25827063 TI - Partner behavioral responses to pain mediate the relationship between partner pain cognitions and pain outcomes in women with provoked vestibulodynia. AB - Partner behavioral responses to pain can have a significant impact on patient pain and depression, but little is known about why partners respond in specific ways. Using a cognitive-behavioral model, the present study examined whether partner cognitions were associated with partner behavioral responses, which prior work has found to predict patient pain and depressive symptoms. Participants were 354 women with provoked vestibulodynia and their partners. Partner pain-related cognitions were assessed using the partner versions of the Pain Catastrophizing Scale and Extended Attributional Style Questionnaire, whereas their behavioral responses to pain were assessed with the Multidimensional Pain Inventory. Patient pain was measured using a numeric rating scale, and depressive symptoms were assessed using the Beck Depression Inventory-II. Path analysis was used to examine the proposed model. Partner catastrophizing and negative attributions were associated with negative partner responses, which were associated with higher patient pain. It was also found that partner pain catastrophizing was associated with solicitous partner responses, which in turn were associated with higher patient pain and depressive symptoms. The effect of partner cognitions on patient outcomes was partially mediated by partner behavioral responses. Findings highlight the importance of assessing partner cognitions, both in research and as a target for intervention. PERSPECTIVE: The present study presents a cognitive behavioral model to partially explain how significant others' thoughts about pain have an effect on patient pain and depressive symptoms. Findings may inform cognitive-behavioral therapy for couples coping with PVD. PMID- 25827064 TI - A retrospective cohort study of long-term immediate-release hydrocodone/acetaminophen use and acetaminophen dosing above the Food and Drug Administration recommended maximum daily limit among commercially insured individuals in the United States (2008-2013). AB - Immediate-release (IR) hydrocodone/acetaminophen is the most prescribed opioid in the United States; however, patterns of use, including long-term treatment and dose, are not well described. Duration of use, including the percentage of patients on long-term treatment (>90 days of continuous use), was assessed for patients newly prescribed IR hydrocodone/acetaminophen compared to other opioid analgesics in a national commercial insurance database (January 2008-September 2013). Though only a small percentage of IR hydrocodone/acetaminophen patients continued treatment long-term (1.7%), the number was large (104,839) and was nearly 5 times the number receiving extended-release (ER) morphine (n = 22,338) and nearly 4 times the number receiving ER oxycodone (n = 26,946) long-term. Using a less conservative allowable gap in treatment increased the number of patients meeting the criteria for long-term use (approximately 160,000 for IR hydrocodone/acetaminophen vs <30,000 for ER morphine and ER oxycodone). Most patients meeting these criteria received IR hydrocodone doses between >20 and <=60 mg/d (n = 56,220, 53.6%) in month 4; 5.5% (n = 5,743) received doses >60 mg/d. Moreover, approximately 15% of IR hydrocodone/acetaminophen patients (n > 900,000) were prescribed total daily acetaminophen doses exceeding 4 g (the limit recommended by the U.S. Food and Drug Administration) at their initial IR hydrocodone/acetaminophen prescription or any time during therapy. PERSPECTIVE: Although most patients were prescribed IR hydrocodone/acetaminophen for acute pain, the number of patients prescribed long-term therapy exceeds the number of patients prescribed ER opioids. It is important to consider the benefits and risks inherent with long-term opioid therapy, whether with IR or ER opioids, to ensure safe use of these products. PMID- 25827066 TI - Oxidative deamination of azafulleroids into C60 by peracids. AB - Oxidation of azafulleroids with peracids regenerated C60 depending on the N substituents. Alkyl-substituted azafulleroids preferred the oxidation of nitrogen to afford N-oxides as possible intermediates for C60 in moderate yields. Phenyl- and tosyl-substituted azafulleroids rather allowed the oxidation at the carbon cage. Theoretical calculations predicted the order of reactivity of azafulleroids as well as the relative N/C nucleophilicity. PMID- 25827065 TI - The role of the commensal microbiota in the regulation of tolerance to dietary allergens. AB - PURPOSE OF REVIEW: We review the evidence that environmental stimuli that perturb naturally selected host-microbe interactions are driving the increasing prevalence of food allergy and examine the mechanisms by which commensal bacteria regulate tolerance to dietary allergens. RECENT FINDINGS: Antibiotic use and the consumption of a high-fat/low-fiber diet have a major and rapid impact on gut bacterial populations, with long-term consequences for both overall microbial community structure and the regulation of host immunity. Recent work emphasizes the role of mucosa-associated commensal bacteria in eliciting a barrier protective response critical to preventing allergic sensitization to food. Murine model studies are informing the development of novel live biotherapeutic approaches as an adjunctive therapy to enhance antigen-specific oral desensitization and to promote lasting tolerance in patients with food allergy. SUMMARY: Strategies based on modulating the composition and/or functionality of the gut microbiome hold promise for the treatment of food allergy. PMID- 25827067 TI - Role of tissue characterization by Cardiac Magnetic Resonance in the diagnosis of constrictive pericarditis. AB - Cardiac Magnetic Resonance (CMR) allows evaluation of the functional and flow changes in pericardial constriction as well as detection of acute pericardial inflammation, fusion and thickening of pericardial layers and pericardial effusion. We sought to evaluate the diagnostic role of tissue characterization by CMR in constrictive pericarditis (CP). We performed a CMR exam in 70 patients (mean age 58 +/- 16) with clinical suspicion of constrictive pericarditis and constrictive pattern at echocardiography and/or catheterization. A multiparametric CMR approach was used to evaluate the initial diagnostic suspicion. A clinical follow-up was performed in all patients for a median of 551 days. The diagnosis of CP was confirmed in 53 patients while 12 patients presented signs of predominant pericardial active inflammation suggesting a diagnosis of transient constrictive pericarditis and five presented effusive constrictive pericarditis. Patients with a final diagnosis of CP had worse prognosis than those with transient constrictive or effusive constrictive pericarditis. The presence of myocardial late gadolinium enhancement was associated to adverse events. Results of the current study confirmed the value of CMR in the differential diagnosis of pericardial disease. A multiparametric CMR approach allowed to distinguish between active inflammation, chronic pericarditis with constriction and effusion without inflammation. PMID- 25827068 TI - Detection of coronary artery disease in diabetic hypertensive patients using conventional transthoratic echocardiography at rest. AB - To investigate the usefulness of conventional transthoratic echocardiography in identifying coronary artery disease (CAD) in diabetic hypertensive patients, transthoratic echocardiography and coronary angiography were performed in 122 diabetic hypertensive patients with suspected CAD. Correlation analysis, multivariate analysis and receiver operating characteristic curve (ROC) analysis were done. Diabetic hypertensive patients with CAD had significantly smaller coronary sinus diameter (Dcs), less velocity time integral (VTI), less coronary sinus flow (Flow) and less Flow divided by left ventricular mass (Flow/LVM) at rest versus normal participants (P < 0.01) and diabetic hypertensive patients without CAD (P < 0.05). The VTI, Dcs, Flow, LVM and Flow/LVM all showed significant correlations with the maximal percent stenosis of the coronary artery lesions (P < 0.05). However, only Flow showed statistically significant correlations with the maximal percent stenosis of the coronary artery lesions (P < 0.01) when multiple stepwise regression analysis was performed. For predicting CAD (angiographically proven, >50%) in diabetic hypertensive patients, the area under the ROC (AUC) was 0.92 for Flow, and a cut-off of <220 ml/min had a 93.2% sensitivity, 87.9% specificity and 91.3% accuracy. For predicting a >70% coronary artery stenosis, the AUC was 0.88 for Flow, and a cut-off of <147 ml/min had an 89.5% sensitivity, 87.4% specificity and 88.5% accuracy. Conventional transthoratic echocardiography can effectively and sensitively detect the CAD in diabetic hypertensive patients at rest. The reduced coronary sinus flow is a sensitive and specific predictor of CAD in diabetic hypertensive patients. PMID- 25827069 TI - Reduced expression and growth inhibitory activity of the aging suppressor klotho in epithelial ovarian cancer. AB - Klotho is an anti-aging transmembrane protein, which can be shed and function as a hormone. Accumulating data indicate klotho as a tumor suppressor in a wide array of malignancies, and we identified klotho as an inhibitor of the insulin like growth factor (IGF-1) pathway in cancer cells. As this pathway is significant in the development of epithelial ovarian cancer (EOC) we studied klotho expression and activity in this tumor. Klotho mRNA levels were reduced in 16 of 19 EOC cell lines and immunohistochemistry analysis revealed high expression in normal ovaries, and reduced expression in 100 of 241 high grade papillary-serous adenocarcinoma of the ovaries, fallopian tubes and peritoneum. Reduced expression was associated with wild-type BRCA status. Klotho reduced EOC cell viability, enhanced cisplatin sensitivity, and reduced expression of mesenchymal markers. Finally, klotho inhibited IGF-1 pathway activation and inhibited transcriptional activity of the estrogen receptor. In conclusion, klotho is silenced in a substantial subset of the tumors and restoring its expression slows growth of EOC cells and inhibits major signaling pathways. As klotho is a hormone, treatment with klotho may serve as a novel treatment for EOC. PMID- 25827071 TI - All-trans retinoic acid induces p53-depenent apoptosis in human hepatocytes by activating p14 expression via promoter hypomethylation. AB - All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, has been extensively studied for the prevention and treatment of cancer; however, the underlying mechanism of its anti-cancer potential is still unclear. Here we found that ATRA induces apoptosis in p53-positive HepG2 cells, but not in p53-negative Hep3B cells. For this effect, ATRA activated p14 expression via promoter hypomethylation, resulting in ubiquitin-dependent degradation of mouse double minute 2 (MDM2) and subsequent stabilization of p53. The potential of ATRA to stabilize p53 was almost completely abolished by knock down of p14 in HepG2 cells and was not observed in p14-negative A549 cells. Upregulation of p14 also abolished the self-regulatory potential of p53 to repress p14 expression via DNA methylation and transcriptionally activate MDM2 expression. The accumulated p53 then activated several apoptosis-related molecules, including Bax, PUMA, caspase-9, Bid, caspase-8, caspase-3, and PARP. Ectopic expression of DNA methyltransferase 1 almost completely abolished the potential of ATRA to activate the p14-MDM2-p53 pathway and induce p53-dependent apoptosis. Therefore, we conclude that ATRA induces p14 promoter hypomethylation to trigger apoptosis. PMID- 25827070 TI - Isorhamnetin augments the anti-tumor effect of capeciatbine through the negative regulation of NF-kappaB signaling cascade in gastric cancer. AB - Development of drug resistance to standard chemotherapy is a common phenomenon that leads to poor prognosis in patients. Thus, novel agents that can attenuate chemoresistance are urgently needed. Therefore, we analyzed whether isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin, can enhance the potential efficacy of capecitabine in gastric cancer. The potential effect of IH on viability was analyzed by MTT assay, apoptosis by flow cytometric analysis, and NF-kappaB activation by DNA binding as well as Western blot assays. The in vivo effect of IH was also examined on the growth of subcutaneously implanted tumors in nude mice. IH inhibited the viability, potentiated the apoptotic effects of capecitabine, abrogated NF-kappaB activation, and suppressed the expression of various NF-kappaB regulated gene products in tumor cells. In a gastric cancer xenograft model, administration of IH alone (1 mg/kg body weight, i.p.) significantly suppressed the tumor growth alone as well as in combination with capecitabine. IH further reduced NF-kappaB activation and the expression of various proliferative and oncogenic biomarkers in tumor tissues. Overall, our results demonstrate that IH can significantly enhance the anti-tumor effects of capecitabine through the negative regulation of NF-kappaB regulated oncogenic genes. PMID- 25827074 TI - WITHDRAWN: Combination of serum miRNAs with Cyfra21-1 for the diagnosis of non small cell lung cancer. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25827073 TI - AC1MMYR2 impairs high dose paclitaxel-induced tumor metastasis by targeting miR 21/CDK5 axis. AB - Paclitaxel (taxol) is a widely used chemo-drug for many solid tumors, while continual taxol treatment is revealed to stimulate tumor dissemination. We previously found that a small molecule inhibitor of miR-21, termed AC1MMYR2, had the potential to impair tumorigenesis and metastasis. The aim of this study was to investigate whether combining AC1MMYR2 with taxol could be explored as a means to limit tumor metastasis. Here we showed that abnormal activation of miR-21/CDK5 axis was associated with breast cancer lymph node metastasis, which was also contribute to high dose taxol-induced invasion and epithelial mesenchymal transition (EMT) in both breast cancer cell line MDA-MB-231 and glioblastoma cell line U87VIII. AC1MMYR2 attenuated CDK5 activity by functional targeting CDK5RAP1, CDK5 activator p39 and target p-FAK(ser732). A series of in vitro assays indicated that treatment of AC1MMYR2 combined with taxol suppressed tumor migration and invasion ability in both MDA-MB-231 and U87VIII cell. More importantly, combination therapy impaired high-dose taxol induced invadopodia, and EMT markers including beta-catenin, E-cadherin and vimentin. Strikingly, a significant reduction of lung metastasis in mice was observed in the AC1MMYR2 plus taxol treatment. Taken together, our work demonstrated that AC1MMYR2 appeared to be a promising strategy in combating taxol induced cancer metastasis by targeting miR-21/CDK5 axis, which highlighted the potential for development of therapeutic modalities for better clinic taxol application. PMID- 25827078 TI - Skin closure methods after single port laparoscopic surgery: a randomized clinical trial. AB - OBJECTIVE: To compare postoperative cosmetic outcomes according to different umbilical closure methods after single port laparoscopic surgery (SP-LS). STUDY DESIGN: A total of 138 women who were scheduled to receive elective SP-LS were randomized to undergo closure of the umbilical incision with either a subcutaneous suture only without subcuticular skin suture (case group, n=68) or both a subcutaneous suture and subcuticular skin suture (control group, n=70) after fascial closure. At postoperative months 1 and 3, the umbilical scar was evaluated using the Vancouver scar scale (VSS), the patient and observer scar assessment scale, and a visual analog scale (VAS). Overall satisfaction with scar cosmesis and surgery was assessed with the VAS. RESULTS: There was no significant difference in the clinical characteristics and operative data between the groups. The objective and subjective scar assessments and the overall satisfaction with scar cosmesis were not different between the groups. In the control group, four (5.7%) women experienced wound discharge and were treated with conservative treatments and delayed closure. In women who completed the first and second assessments, the changes in the scar assessment and overall satisfaction with the scar according to time after surgery were not different in either group, but the patient scar assessment scale in both groups and the VSS in the case group improved. CONCLUSIONS: After SP-LS, the approximation of the fascia and subcutaneous layer seems to be enough for the closure of an umbilical incision. Skin closure with subcuticular sutures did not improve the postoperative cosmetic outcomes and might lead to impaired wound healing. However, large randomized trials with various closure techniques and materials are needed to confirm this finding. PMID- 25827072 TI - FBXO11 promotes ubiquitination of the Snail family of transcription factors in cancer progression and epidermal development. AB - The Snail family of transcription factors are core inducers of epithelial-to mesenchymal transition (EMT). Here we show that the F-box protein FBXO11 recognizes and promotes ubiquitin-mediated degradation of multiple Snail family members including Scratch. The association between FBXO11 and Snai1 in vitro is independent of Snai1 phosphorylation. Overexpression of FBXO11 in mesenchymal cells reduces Snail protein abundance and cellular invasiveness. Conversely, depletion of endogenous FBXO11 in epithelial cancer cells causes Snail protein accumulation, EMT, and tumor invasion, as well as loss of estrogen receptor expression in breast cancer cells. Expression of FBXO11 is downregulated by EMT inducing signals TGFbeta and nickel. In human cancer, high FBXO11 levels correlate with expression of epithelial markers and favorable prognosis. The results suggest that FBXO11 sustains the epithelial state and inhibits cancer progression. Inactivation of FBXO11 in mice leads to neonatal lethality, epidermal thickening, and increased Snail protein levels in epidermis, validating that FBXO11 is a physiological ubiquitin ligase of Snail. Moreover, in C. elegans, the FBXO11 mutant phenotype is attributed to the Snail factors as it is suppressed by inactivation/depletion of Snail homologs. Collectively, these findings suggest that the FBXO11-Snail regulatory axis is evolutionarily conserved and critically governs carcinoma progression and mammalian epidermal development. PMID- 25827079 TI - Comparing outcomes and costs between contingent and combined first-trimester screening strategies for Down's syndrome. AB - OBJECTIVE: To compare a contingent strategy with a combined strategy for prenatal detection of Down's syndrome (DS) in terms of cost, outcomes and safety. STUDY DESIGN: The contingent strategy was based on a simulation, removing measurement of the free beta subunit of human chorionic gonadotropin (free betahCG) and calculating the DS risk retrospectively in 32,371 pregnant women who had been screened with the combined strategy in the first trimester. In the contingent strategy, a risk between 1:31 and 1:1000 in the first trimester indicated further testing in the second trimester (alpha-fetoprotein, inhibin A, unconjugated oestriol and free betahCG). The cut-off risk values for the contingent and combined strategies in the first trimester were 1:30 and 1:250, respectively, and the cut-off risk value for integrated screening in the second trimester was 1:250. Costs were compared in terms of avoided DS births, and the ratio of loss of healthy fetuses following invasive procedures per avoided DS birth was calculated. RESULTS: The combined strategy had sensitivity of 40/44 (90.9%) and a false-positive rate of 2.8%. Corresponding values for the contingent strategy were 39/44 (88.6%) and 1.3%, respectively. Only 11% of pregnant women required tests in the second trimester, and the approximate cost reduction for each avoided DS birth was 5000?. The ratio of lost healthy fetuses following invasive procedures per avoided DS birth improved by up to 0.65. CONCLUSION: The contingent strategy has similar effectiveness to the combined strategy, but has lower costs and fewer invasive procedures. PMID- 25827081 TI - meso-Pyrrole-Substituted 22-Oxacorroles: Building Blocks for the Synthesis of BODIPY-Bridged 22-Oxacorrole Dyads. AB - Novel boron-dipyrromethene (BODIPY)-bridged 22-oxacorrole dyads, using meso pyrrolyl 22-oxacorrole as a key synthon, have been synthesized. The reactivity of the meso-pyrrolyl group of 22-oxacorrole was exploited to synthesize the first examples of BODIPY-bridged 22-oxacorrole dyads in ~40 % yield. The dyads are stable and exhibited interesting spectral and electrochemical properties. PMID- 25827080 TI - Quantification of myocardial perfusion with self-gated cardiovascular magnetic resonance. AB - BACKGROUND: Current myocardial perfusion measurements make use of an ECG-gated pulse sequence to track the uptake and washout of a gadolinium-based contrast agent. The use of a gated acquisition is a problem in situations with a poor ECG signal. Recently, an ungated perfusion acquisition was proposed but it is not known how accurately quantitative perfusion estimates can be made from such datasets that are acquired without any triggering signal. METHODS: An undersampled saturation recovery radial turboFLASH pulse sequence was used in 7 subjects to acquire dynamic contrast-enhanced images during free-breathing. A single saturation pulse was followed by acquisition of 4-5 slices after a delay of ~40 msec. This was repeated without pause and without any type of gating. The same pulse sequence, with ECG-gating, was used to acquire gated data as a ground truth. An iterative spatio-temporal constrained reconstruction was used to reconstruct the undersampled images. After reconstruction, the ungated images were retrospectively binned ("self-gated") into two cardiac phases using a region of interest based technique and deformably registered into near-systole and near diastole. The gated and the self-gated datasets were then quantified with standard methods. RESULTS: Regional myocardial blood flow estimates (MBFs) obtained using self-gated systole (0.64 +/- 0.26 ml/min/g), self-gated diastole (0.64 +/- 0.26 ml/min/g), and ECG-gated scans (0.65 +/- 0.28 ml/min/g) were similar. Based on the criteria for interchangeable methods listed in the statistical analysis section, the MBF values estimated from self-gated and gated methods were not significantly different. CONCLUSION: The self-gated technique for quantification of regional myocardial perfusion matched ECG-gated perfusion measurements well in normal subjects at rest. Self-gated systolic perfusion values matched ECG-gated perfusion values better than did diastolic values. PMID- 25827082 TI - IER3 Promotes Expansion of Adipose Progenitor Cells in Response to Changes in Distinct Microenvironmental Effectors. AB - Adipose tissue expansion is well-orchestrated to fulfill the energy demand. It results from adipocyte hypertrophy and hyperplasia due to adipose progenitor cell (APC) expansion and differentiation. Chronic low grade inflammation and hypoxia take place in obese adipose tissue microenvironment. Both of these events were shown to impact the APC pool by promoting increased self-renewal along with a decrease in the APC differentiation potential. However, no common target has been identified so far. Here we show that the immediate early response 3 gene (IER3) is preferentially expressed in APCs and is essential for APC proliferation and self-renewal. Experiments based on RNA interference revealed that impairing IER3 expression altered cell proliferation through ERK1/2 phosphorylation and clonogenicity. IER3 expression was induced by Activin A, which plays a crucial role in adipocyte differentiation as well as by a decrease in oxygen tension through HIF1-induced transcriptional activation. Interestingly, high levels of IER3 were detected in native APCs (CD34+/CD31- cells) isolated from obese patients and conditioned media from obese adipose tissue-macrophages stimulated its expression. Overall, these results indicate that IER3 is a key player in expanding the pool of APC while highlighting the role of distinct effectors found in an obese microenvironment in this process. PMID- 25827083 TI - Syndromic surveillance system based on near real-time cattle mortality monitoring. AB - Early detection of an infectious disease incursion will minimize the impact of outbreaks in livestock. Syndromic surveillance based on the analysis of readily available data can enhance traditional surveillance systems and allow veterinary authorities to react in a timely manner. This study was based on monitoring the number of cattle carcasses sent for rendering in the veterinary unit of Talavera de la Reina (Spain). The aim was to develop a system to detect deviations from expected values which would signal unexpected health events. Historical weekly collected dead cattle (WCDC) time series stabilized by the Box-Cox transformation and adjusted by the minimum least squares method were used to build the univariate cycling regression model based on a Fourier transformation. Three different models, according to type of production system, were built to estimate the baseline expected number of WCDC. Two types of risk signals were generated: point risk signals when the observed value was greater than the upper 95% confidence interval of the expected baseline, and cumulative risk signals, generated by a modified cumulative sum algorithm, when the cumulative sums of reported deaths were above the cumulative sum of expected deaths. Data from 2011 were used to prospectively validate the model generating seven risk signals. None of them were correlated to infectious disease events but some coincided, in time, with very high climatic temperatures recorded in the region. The harvest effect was also observed during the first week of the study year. Establishing appropriate risk signal thresholds is a limiting factor of predictive models; it needs to be adjusted based on experience gained during the use of the models. To increase the sensitivity and specificity of the predictions epidemiological interpretation of non-specific risk signals should be complemented by other sources of information. The methodology developed in this study can enhance other existing early detection surveillance systems. Syndromic surveillance based on mortality monitoring can reduce the detection time for certain disease outbreaks associated with mild mortality only detected at regional level. The methodology can be adapted to monitor other parameters routinely collected at farm level which can be influenced by communicable diseases. PMID- 25827085 TI - Purification of Recombinant Proteins from Cultured Mammalian Cells by HaloTag Technology. AB - Cultured mammalian cells provide an environment ideal for producing functional recombinant mammalian proteins. However, low expression levels of recombinant proteins present a challenge for their detection and purification. This unit will focus on HaloTag, a protein fusion tag designed to bind selectively and covalently to a chloroalkane ligand that may be attached to a variety of functional groups, allowing both protein detection and immobilization. Detection of HaloTag-fusion protein is achieved through binding to a fluorescent chloroalkane ligand, enabling rapid optimization of expression levels. HaloTag based purification uses covalent capture of the HaloTag fusion onto HaloLink resin coupled with proteolytic cleavage to release the protein of interest from the resin. Covalent binding provides efficient protein capture regardless of expression level and eliminates protein loss during washes of the resin and as a result, offers significant improvements in protein recovery and purity over traditional non-covalent approaches. PMID- 25827084 TI - Age and time trends in the diet of young children: results of the DONALD study. AB - PURPOSE: To describe age and time trends of energy and macronutrient intake during infancy and toddlerhood and to set a special focus on dietary practices with respect to milk, complementary food, and family food intake. METHODS: Three day dietary records (n = 2241) collected at 3, 6, 9, 12, 18, 24, and 36 months (480 subjects) between 2004 and 2013 from the ongoing open cohort DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) study were evaluated using repeated-measures regression analyses for trend analysis. RESULTS: Significant age trends were found for macronutrients with a decrease in fat intake (% of energy intake, %E) and an increase in carbohydrates (%E) and protein (%E). Exclusive and partial breastfeeding rates at 3 and 6 months did not differ between 2004 and 2008 and 2009 and 2013 (p > 0.05). Macronutrient pattern was virtually stable over time, whereas food group intake (% of total food intake excluding beverages, % TFI) changed significantly during the study period. Breast/bottle milk (% TFI) intake increased over time in the toddler subgroup, whereas family food (% TFI) decreased. CONCLUSIONS: Our data demonstrate a period of stagnation in the last 10 years with respect to breastfeeding duration in infancy. Further breastfeeding promotion in Germany is needed to continue the favourable progress of the previous decades. In toddlerhood, breast/bottle milk remains a substantial part of the diet and has increased during the last 10 years. Parents should be encouraged to implement healthy eating habits during early toddlerhood and to facilitate their child's participation in appropriate family meals. PMID- 25827086 TI - Tools and procedures for visualization of proteins and other biomolecules. AB - Protein, peptides, and nucleic acids are biomolecules that drive biological processes in living organisms. An enormous amount of structural data for a large number of these biomolecules has been described with atomic precision in the form of structural "snapshots" that are freely available in public repositories. These snapshots can help explain how the biomolecules function, the nature of interactions between multi-molecular complexes, and even how small-molecule drugs can modulate the biomolecules for clinical benefits. Furthermore, these structural snapshots serve as inputs for sophisticated computer simulations to turn the biomolecules into moving, "breathing" molecular machines for understanding their dynamic properties in real-time computer simulations. In order for the researcher to take advantage of such a wealth of structural data, it is necessary to gain competency in the use of computer molecular visualization tools for exploring the structures and visualizing three-dimensional spatial representations. Here, we present protocols for using two common visualization tools--the Web-based Jmol and the stand-alone PyMOL package--as well as a few examples of other popular tools. PMID- 25827087 TI - Mapping regulatory factors by immunoprecipitation from native chromatin. AB - Occupied Regions of Genomes from Affinity-purified Naturally Isolated Chromatin (ORGANIC) is a high-resolution method that can be used to quantitatively map protein-DNA interactions with high specificity and sensitivity. This method uses micrococcal nuclease (MNase) digestion of chromatin and low-salt solubilization to preserve protein-DNA complexes, followed by immunoprecipitation and paired-end sequencing for genome-wide mapping of binding sites. In this unit, we describe methods for isolation of nuclei and MNase digestion of unfixed chromatin, immunoprecipitation of protein-DNA complexes, and high-throughput sequencing to map sites of bound factors. PMID- 25827088 TI - Site-specific recombinational cloning using gateway and in-fusion cloning schemes. AB - The comprehensive study of protein structure and function, or proteomics, depends on the obtainability of full-length cDNAs in species-specific expression vectors and subsequent functional analysis of the expressed protein. Recombinational cloning is a universal cloning technique based on site-specific recombination that is independent of the insert DNA sequence of interest, which differentiates it from classical restriction enzyme-based cloning methods. Recombinational cloning enables rapid and efficient parallel transfer of DNA inserts into multiple expression systems. This unit summarizes strategies for generating expression-ready clones using the most popular commercial recombinational cloning technologies, Gateway (Life Technologies) and In-Fusion (Clontech). PMID- 25827089 TI - Mapping 3' mRNA isoforms on a genomic scale. AB - Most eukaryotic genes are transcribed into mRNAs with alternative poly(A) sites. Emerging evidence suggests that mRNA isoforms with alternative poly(A) sites can perform critical regulatory functions in numerous biological processes. In recent years, a number of strategies utilizing high-throughput sequencing technologies have been developed to aid in the identification of genome-wide poly(A) sites. This unit describes a modified protocol for a recently published 3'READS (3' region extraction and deep sequencing) method that accurately identifies genome wide poly(A) sites and that can be used to quantify the relative abundance of the resulting 3' mRNA isoforms. This approach minimizes nonspecific sequence reads due to internal priming and typically yields a high percentage of sequence reads that are ideally suited for accurate poly(A) identification. PMID- 25827091 TI - Predatory publishing companies: ethical considerations in the open-access era. PMID- 25827090 TI - Evaluation of Cell-Free Urine microRNAs Expression for the Use in Diagnosis of Ovarian and Endometrial Cancers. A Pilot Study. AB - Among gynaecological cancers, epithelial ovarian cancers are the most deadly cancers while endometrial cancers are the most common diseases. Efforts to establish relevant novel diagnostic, screening and prognostic markers are aimed to help reduce the high level of mortality, chemoresistance and recurrence, particularly in ovarian cancer. MicroRNAs, the class of post-transcriptional regulators, have emerged as the promising diagnostic and prognostic markers associated with various diseased states recently. Urine has been shown as the source of microRNAs several years ago; however, there has been lack of information on urine microRNA expression in ovarian and endometrial cancers till now. In this pilot study, we examined the expression of candidate cell-free urine microRNAs in ovarian cancer and endometrial cancer patients using quantitative real-time PCR. We compared the expression between pre- and post-surgery ovarian cancer samples, and between patients with ovarian and endometrial cancers and healthy controls, within three types of experiments. These experiments evaluated three different isolation methods of urine RNA, representing two supernatant and one exosome fractions of extracellular microRNA. In ovarian cancer, we found miR 92a significantly up-regulated, and miR-106b significantly down-regulated in comparison with control samples. In endometrial cancer, only miR-106b was found down-regulated significantly compared to control samples. Using exosome RNA, no significant de-regulations in microRNAs expression could be found in either of the cancers investigated. We propose that more research should now focus on confirming the diagnostic potential of urine microRNAs in gynaecological cancers using more clinical samples and large-scale expression profiling methods. PMID- 25827092 TI - Authors' response. PMID- 25827093 TI - Discriminating military and civilian traumatic brain injuries. AB - Traumatic brain injury (TBI) occurs at higher rates among service members than civilians. Explosions from improvised explosive devices and mines are the leading cause of TBI in the military. As such, TBI is frequently accompanied by other injuries, which makes its diagnosis and treatment difficult. In addition to postconcussion symptoms, those who sustain a TBI commonly report chronic pain and posttraumatic stress symptoms. This combination of symptoms is so typical they have been referred to as the "polytrauma clinical triad" among injured service members. We explore whether these symptoms discriminate civilian occurrences of TBI from those of service members, as well as the possibility that repeated blast exposure contributes to the development of chronic traumatic encephalopathy (CTE). This article is part of a Special Issue entitled 'Traumatic Brain Injury'. PMID- 25827094 TI - Neuroimaging and traumatic brain injury: State of the field and voids in translational knowledge. AB - Traumatic brain injury (TBI) is a leading cause of death and disability in every developed country in the world and is believed to be a risk factor in the later development of depression, anxiety disorders and neurodegenerative diseases including chronic traumatic encephalopathy (CTE), Alzheimer's Disease (AD), Parkinson's Disease (PD), and amyotrophic lateral sclerosis (ALS). One challenge faced by those who conduct research into TBI is the lack of a verified and validated biomarker that can be used to diagnose TBI or for use as a prognostic variable which can identify those at risk for poor recovery following injury or at risk for neurodegeneration later in life. Neuroimaging continues to hold promise as a TBI biomarker but is limited by a lack of clear relationship between the neuropathology of injury/recovery and the quantitative and image based data that is obtained. Specifically lacking is the data on biochemical and biologic changes that lead to alterations in neuroimaging markers. There are multiple routes towards developing the knowledge required to more definitively link pathology to imaging but the most efficient approach is expanded leveraging of in vivo human blood, serum, and imaging biomarkers with both in vivo and ex vivo animal findings. This review describes the current use and limitations of imaging in TBI including a discussion of currently used animal injury models and the available animal imaging data and extracted markers that hold the greatest promise for helping translate alterations in imaging back to injury pathology. Further, it reviews both the human and animal TBI literature supporting current standards, identifies the remaining voids in the literature, and briefly highlights recent advances in molecular imaging. This article is part of a Special Issue entitled 'Traumatic Brain Injury'. PMID- 25827096 TI - Matrix metalloproteinase-2 and -9 in the cerebellum of teleost fish: Functional implications for adult neurogenesis. AB - Matrix metalloproteinases (MMPs) are a family of highly conserved zinc-dependent proteases involved in both development and pathogenesis. The present study examines the role of MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in adult neurogenesis, using the corpus cerebelli, a subdivision of the cerebellum, of knifefish (Apteronotus leptorhynchus) as a model system. Transcripts of five isoforms of these gelatinases were identified in the central nervous system of this species. Sequence similarity analysis and homology modeling indicated that functionally and structurally critical elements were highly conserved in knifefish gelatinases. Immunohistochemical staining revealed a differential distribution of MMP-2 and MMP-9 at both the cellular and subcellular level. MMP-2 expression was found mainly in Sox2-immunopositive stem/progenitor cells, both quiescent and mitotically active; and was localized in both the cytoplasmic compartment and the nucleus. By contrast, MMP-9 immunoreactivity was absent in neurogenic niches and displayed a more homogenous distribution, with low to moderate intensity levels, in the molecular and granular layers. MMP-9 expression appeared to be restricted to the extracellular space. In situ zymography indicated that gelatinase activity matched the cellular and subcellular distributions of the two MMPs. The observed patterns of gelatinase activity and expression support the hypothesis that MMP-2 is primarily involved in regulation of the activity of stem/progenitor cells that give rise to new granule neurons, whereas MMP-9 facilitates migration of the progeny of these cells by proteolysis of extracellular matrix proteins. PMID- 25827095 TI - Differential targeting of dynamin-1 and dynamin-3 to nerve terminals during chronic suppression of neuronal activity. AB - Neurons express three closely related dynamin genes. Dynamin 1 has long been implicated in the regulation of synaptic vesicle recycling in nerve terminals, and dynamins 2 and 3 were more recently shown also to contribute to synaptic vesicle recycling in specific and distinguishable ways. In cultured hippocampal neurons we found that chronic suppression of spontaneous network activity differentially regulated the targeting of endogenous dynamins 1 and 3 to nerve terminals, while dynamin 2 was unaffected. Specifically, when neural activity was chronically silenced for 1-2weeks by tetrodotoxin (TTX), the clustering of dynamin 1 at nerve terminals was reduced, while the clustering of dynamin 3 significantly increased. Moreover, dynamin 3 clustering was induced within hours by the sustained blockade of AMPA receptors, suggesting that AMPA receptors may function to prevent Dyn3 accumulation within nerve terminals. Clustering of dynamin 3 was induced by an antagonist of the calcium-dependent protein phosphatase calcineurin, but was not dependent upon intact actin filaments. TTX induced clustering of Dyn3 occurred with a markedly slower time-course than the previously described clustering of synapsin 1. Potassium-induced depolarization rapidly de-clustered dynamin 3 from nerve terminals within minutes. These results, which have implications for homeostatic synapse restructuring, indicate that the three dynamins have evolved different regulatory mechanisms for trafficking to and from nerve terminals in response to changes in neural activity. PMID- 25827097 TI - Prevalence of bovine theileriosis in North Central region of Algeria by real-time polymerase chain reaction with a note on its distribution. AB - To determine the presence and distribution of bovine theileriosis in the North Central region of Algeria, 358 DNA samples and 359 blood smears were analyzed from nine provinces. Theileria DNA extracted from cattle blood was amplified by fluorescence resonance energy transfer polymerase chain reaction (FRET-PCR). Blood smears were examined for Theileria piroplasms by microscopical examination (ME) of Giemsa-stained slides. While microscopical identification revealed only 42 animals being infected with Theileria piroplasms, PCR-positive amplification using Theileria genus-specific primers was obtained from 132 Theileria spp. (P < 0.0001). Among the 132 positives, 108 animals (81.8 %) were found positive of Theileria annulata, while 24 (18.2 %) were found positive for Theileria sp. (P < 0.0001). However, melting curve analysis of these latter samples revealed the presence of two different peaks, 51.5 +/- 0.5 degrees C corresponding to Theileria sp1 and 52.5 +/- 0.5 degrees C for Theileria sp2. Cloning and sequencing of Theileria sp1 and Theileria sp2 using the Cox primers indicated that these species are very closely related to Theileria buffeli. There is a highly significant difference in the distribution of theileriosis between different provinces (P < 0.0001). This disparity between provinces is probably due to differences in tick contact, influenced by the subhumid bioclimatic gradient and differences in agricultural land use. PMID- 25827098 TI - Non-inferiority margins employed in clinical trials in Japan. AB - WHAT IS KNOWN AND OBJECTIVE: Determination of the non-inferiority margin is one of the major and most difficult considerations when planning a non-inferiority clinical trial. This article aims to list the non-inferiority margins employed in recent clinical drug-development trials in Japan. METHODS: We investigated non inferiority margins by reviewing new drug-development dossiers for drugs approved between January 2010 and December 2012 in Japan. RESULTS AND DISCUSSION: We identified 174 non-inferiority trials, where the efficacy of the test drug was compared to that of a control drug. We have described 70 clinical endpoints and the corresponding non-inferiority margins. In antidiabetes drug trials, a margin of 0.4% mean difference in haemoglobin A1c level was used most frequently. In trials for glaucoma and ocular hypertension, 1.5 mmHg mean difference in intra ocular pressure value was the commonest margin. A 10% margin of proportion difference was the most frequently chosen in trials of anti-infection drugs. We have provided a short description of the methods used to determine the non inferiority margin. WHAT IS NEW AND CONCLUSION: We report on the non-inferiority margins used for a range of endpoints in recent drug-development trials for a number of different diseases. We hope that the details would be helpful to those appraising, reporting or designing non-inferiority trials. PMID- 25827099 TI - Development and Use of Disease-Specific (Reference) Models for Economic Evaluations of Health Technologies: An Overview of Key Issues and Potential Solutions. PMID- 25827100 TI - Determination of rate constants and branching ratios for TCE degradation by zero valent iron using a chain decay multispecies model. AB - The applicability of a newly-developed chain-decay multispecies model (CMM) was validated by obtaining kinetic rate constants and branching ratios along the reaction pathways of trichloroethene (TCE) reduction by zero-valent iron (ZVI) from column experiments. Changes in rate constants and branching ratios for individual reactions for degradation products over time for two columns under different geochemical conditions were examined to provide ranges of those parameters expected over the long-term. As compared to the column receiving deionized water, the column receiving dissolved CaCO3 showed higher mean degradation rates for TCE and all of its degradation products. However, the column experienced faster reactivity loss toward TCE degradation due to precipitation of secondary carbonate minerals, as indicated by a higher value for the ratio of maximum to minimum TCE degradation rate observed over time. From the calculated branching ratios, it was found that TCE and cis-dichloroethene (cis DCE) were dominantly dechlorinated to chloroacetylene and acetylene, respectively, through reductive elimination for both columns. The CMM model, validated by the column test data in this study, provides a convenient tool to determine simultaneously the critical design parameters for permeable reactive barriers and natural attenuation such as rate constants and branching ratios. PMID- 25827102 TI - Sulfhydryl-mediated redox signaling in inflammation: role in neurodegenerative diseases. AB - Posttranslational modifications of cysteine sulfhydryl (-SH) moieties, e.g., S nitrosylation, S-glutathionylation, or S-sulfuration, play an important role in cellular response to oxidative stress. Reversible cysteine modifications alter protein function and can play a critical role in redox signal transduction. Perturbation of sulfhydryl homeostasis is a hallmark of many diseases, including neurodegenerative disorders. Besides direct oxidative stress within the neurons, inflammation of the central nervous system as well as the periphery is implicated also in the development and progression of neurodegeneration. Therefore, perturbation of redox regulation of key inflammatory mediators is an important component of neurodegenerative diseases. Many proteins involved in inflammation have been shown to undergo S-nitrosylation (-SNO) and/or S-glutathionylation ( SSG) with functional consequences. The mechanistic and functional relationships between these two modifications have yet to be thoroughly investigated. While protein-SNO intermediates in some cases may signal independently of protein-SSG intermediates, the relatively unstable nature of protein-SNO derivatives in the presence of GSH suggests that protein-SNO formation in many cases may serve as a precursor for protein-SSG modifications. In this review, we describe the cysteine modifications of specific inflammation-mediating proteins and their relationship to inflammatory responses such as cytokine and chemokine production. In particular, we consider evidence for sequential protein-SNO -> protein-SSG modifications of these proteins. We conclude that cysteine modifications of critical regulatory proteins are likely to play a central role in the onset and progression of neuroinflammatory diseases and thus should be studied thoroughly in this context. PMID- 25827101 TI - Programming of metabolic effects in C57BL/6JxFVB mice by in utero and lactational exposure to perfluorooctanoic acid. AB - Perfluorooctanoic acid (PFOA) is known to cause developmental toxicity and is a suggested endocrine disrupting compound (EDC). Early life exposure to EDCs has been implicated in programming of the developing organism for chronic diseases later in life. Here we study perinatal metabolic programming by PFOA using an experimental design relevant for human exposure. C57BL/6JxFVB hybrid mice were exposed during gestation and lactation via maternal feed to seven low doses of PFOA at and below the NOAEL used for current risk assessment (3-3000 ug/kg body weight/day). After weaning, offspring were followed for 23-25 weeks without further exposure. Offspring showed a dose-dependent decrease in body weight from postnatal day 4 to adulthood. Growth under high fat diet in the last 4-6 weeks of follow-up was increased in male and decreased in female offspring. Both sexes showed increased liver weights, hepatic foci of cellular alterations and nuclear dysmorphology. In females, reductions in perigonadal and perirenal fat pad weights, serum triglycerides and cholesterol were also observed. Endocrine parameters, such as glucose tolerance, serum insulin and leptin, were not affected. In conclusion, our study with perinatal exposure to PFOA in mice produced metabolic effects in adult offspring. This is most likely due to disrupted programming of metabolic homeostasis, but the assayed endpoints did not provide a mechanistic explanation. The BMDL of the programming effects in our study is below the current point of departure used for calculation of the tolerable daily intake. PMID- 25827103 TI - Application of CRISPR/Cas9 genome editing to the study and treatment of disease. AB - CRISPR/Cas is a microbial adaptive immune system that uses RNA-guided nucleases to cleave foreign genetic elements. The CRISPR/Cas9 method has been engineered from the type II prokaryotic CRISPR system and uses a single-guide RNA to target the Cas9 nuclease to a specific genomic sequence. Cas9 induces double-stranded DNA breaks which are repaired either by imperfect non-homologous end joining to generate insertions or deletions (indels) or, if a repair template is provided, by homology-directed repair. Due to its specificity, simplicity and versatility, the CRISPR/Cas9 system has recently emerged as a powerful tool for genome engineering in various species. This technology can be used to investigate the function of a gene of interest or to correct gene mutations in cells via genome editing, paving the way for future gene therapy approaches. Improvements to the efficiency of CRISPR repair, in particular to increase the rate of gene correction and to reduce undesired off-target effects, and the development of more effective delivery methods will be required for its broad therapeutic application. PMID- 25827104 TI - Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients. AB - Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. PMID- 25827105 TI - Glutamate affects dendritic morphology of neurons grown on compliant substrates. AB - Brain stiffness changes in response to injury or disease. As a secondary consequence, glutamate is released from neurons and astroglia. Two types of glutamate receptors, N-methyl-d-aspartate (NMDA) and alpha-Amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptors, sense mechanotransduction, leading to downstream signaling in neurons. Recently, our group reported that these two receptors affect dendrite morphology in hippocampal neurons grown on compliant substrates. Blocking receptor activity has distinct effects on dendrites, depending on whether neurons are grown on soft or stiff gels. In the current study, we examine whether exposure to glutamate itself alters stiffness mediated changes to dendrites in hippocampal neurons. We find that glutamate augments changes seen when neurons are grown on soft gels of 300 or 600 Pa, but in contrast, glutamate attenuates changes seen when neurons are grown on stiff gels of 3,000 Pa. These results suggest that there is interplay between mechanosensing and glutamate receptor activation in determining dendrite morphology in neurons. PMID- 25827106 TI - Ultrathin MgO diffusion barriers for ferromagnetic electrodes on GaAs(001). AB - Ultrathin MgO(100) films serving as a diffusion barrier between ferromagnetic electrodes and GaAs(001) semiconductor templates have been investigated. Using Fe as an exemplary ferromagnetic material, heterostructures of Fe/MgO/GaAs(001) were prepared at 200 degrees C with the MgO thickness ranging from 1.5 to 3 nm. Structural characterization reveals very good crystalline ordering in all layers of the heterostructure. Auger electron spectroscopy depth-profiling and cross sectional high-resolution transmission electron microscopy evidence diffusion of Fe into MgO and-for too thin MgO barriers-further into GaAs(001). Our results recommend a MgO barrier thickness larger than or equal to 2.6 nm for its application as a reliable diffusion barrier on GaAs(001) in spintronics devices. PMID- 25827109 TI - Laparoscopic common bile duct exploration in cirrhotic patients with choledocholithiasis: Retraction. PMID- 25827110 TI - Modified Pringle maneuver applicable for laparoscopic hepatectomy: Retraction. PMID- 25827111 TI - Effects of the surface stoichiometry of seeds on GaN layer growth by hydride vapour phase epitaxy. AB - The effect of the atmosphere in a reactor prior to hydride vapour phase epitaxy on the surface stoichiometry of both the GaN template and layer growth was studied. The surface stoichiometry of metallic Ga layers was clarified by X-ray photoelectron spectroscopy using templates without NH3 protection. The metallic Ga layer acted as a mask and exerted a significant effect on the subsequent epitaxial layer growth mode. GaN grown on the template without protection followed island growth in the initial growth stage. In contrast, GaN epitaxy on the template with NH3 protection quickly converts to pseudo-2D growth. The images of CL illustrate that the GaN epilayer on the template without protection has a lower dislocation density than the GaN epilayer grown on the template with NH3 protection. Reasons behind this effect have been discussed. PMID- 25827113 TI - Contributions from different model organisms to brain research: Introduction. PMID- 25827112 TI - Differential gene expression profiles of two excitable rat cell lines after over expression of WT- and C121W-beta1 sodium channel subunits. AB - Voltage-dependent sodium channels are membrane proteins essential for cell excitability. They are composed by a pore-forming alpha-subunit, encoded in mammals by up to nine different genes, and four different ancillary beta subunits. The expression pattern of the alpha subunit isoforms confers the distinctive functional and pharmacological properties to different excitable tissues. beta-Subunits are important modulators of channel function and expression. Mutation C121W of the beta1-subunit causes an autosomal dominant epileptic syndrome without cardiac symptoms. In neuroectoderm GH3 and cardiac H9C2 cells, the over-expression of beta1 subunit augments alpha subunit mRNA and protein levels as well as sodium current density. Interestingly, the introduction of the epileptogenic C121W-beta1 subunit produces additional changes in the alpha subunit expression pattern of H9C2 cells, leaving unaltered the sodium channel isoform composition of GH3 cells. The challenge of the present work was to identify those genes that were differentially expressed in response to WT- or C121W-beta1 subunit over-expression in the two rat cell lines under analysis. Hence, we analyzed the total mRNA extracted from control-untransfected and from WT- and C121W-beta1-transfected GH3 and H9C2 cells by DNA-microarray. We found that, in agreement with their different embryonal origin, the over-expression of WT- and C121W-beta1 subunits modifies the expression of different gene sets in GH3 and H9C2 cells. Focusing on the effects of the C121W mutation, we found that it causes the modification of 214 genes, most of them were down-regulated (202) in GH3 cells; on the contrary, it determined the up-regulation of only five genes in H9C2 cells. Interestingly, most genes modified by the C121W beta1 subunit are involved in pivotal processes of the cell such as cellular communication and protein expression. Our results confirm the important role of the sodium channel beta1 subunit in the control of NaCh gene expression, and highlight once more the tissue-specific effect of the C121W mutation. PMID- 25827114 TI - Corrosion and odor management in sewer systems. AB - Sewers emit hydrogen sulfide and various volatile organic sulfur and carbon compounds, which require control and mitigation. In the last 5-10 years, extensive research was conducted to optimize existing sulfide abatement technologies based on newly developed in-depth understanding of the in-sewer processes. Recent advances have also led to low-cost novel solutions targeting sewer biofilms. Online control has been demonstrated to greatly reduce the chemical usage. Dynamic models for both the water, air and solid (concrete) phases have been developed and used for the planning and maintenance of sewer systems. Existing technologies primarily focused on 'hotspots' in sewers. Future research should aim to achieve network-wide corrosion and emission control and management of sewers as an integrated component of an urban water system. PMID- 25827115 TI - Mathematical modeling of unicellular microalgae and cyanobacteria metabolism for biofuel production. AB - The conversion of microalgae lipids and cyanobacteria carbohydrates into biofuels appears to be a promising source of renewable energy. This requires a thorough understanding of their carbon metabolism, supported by mathematical models, in order to optimize biofuel production. However, unlike heterotrophic microorganisms that utilize the same substrate as sources of energy and carbon, photoautotrophic microorganisms require light for energy and CO2 as carbon source. Furthermore, they are submitted to permanent fluctuating light environments due to outdoor cultivation or mixing inducing a flashing effect. Although, modeling these nonstandard organisms is a major challenge for which classical tools are often inadequate, this step remains a prerequisite towards efficient optimization of outdoor biofuel production at an industrial scale. PMID- 25827116 TI - Gene expression changes in plants and microorganisms exposed to nanomaterials. AB - Unique properties of nanomaterials allow them to interact unexpectedly with biological systems. Analysis of the transcriptional response (change in gene expression) in exposed organisms constitutes a powerful approach for understanding the mechanisms of toxicity and molecular responses in cells exposed to nanomaterials. Transcriptional analyses have been conducted to study the effects of nanomaterials on humans, mammalian models, and other organisms important for the ecosystem. The present article reviews recent gene expression studies conducted to understand the effects of nanomaterials on plants and bacteria. As plants and bacteria are essential components of the food chain and/or play a central role in nutrient cycling and biodegradation, their interactions with nanomaterials have important implications for the environment and public health. PMID- 25827117 TI - Ipso-substitution--the hidden gate to xenobiotic degradation pathways. AB - Screening for metabolites of environmental pollutants, the focus is often on transformation products based on well-known pathways. Hydroxylation at unsubstituted positions of the aromatic ring or side chain modifications, followed by meta ring-cleavage pathways are usually considered, whereas less obvious mechanisms are often ignored. Here, a glimpse of the multitude of transformations involving ipso-substitution events, which are often overlooked as such, is presented. These reactions can be catalyzed by a variety of enzymes, proceed via several mechanisms and will often result in metabolites that are not expected to arise from generally known pathways. Hence, there is a future need when looking into transformations of emerging pollutants, to stray from the 'beaten pathways' and explore the possibilities of less obvious mechanisms. PMID- 25827118 TI - Resource recovery from wastewater: application of meta-omics to phosphorus and carbon management. AB - A growing trend at wastewater treatment plants is the recovery of resources and energy from wastewater. Enhanced biological phosphorus removal and anaerobic digestion are two established biotechnology approaches for the recovery of phosphorus and carbon, respectively. Meta-omics approaches (meta-genomics, transcriptomics, proteomics, and metabolomics) are providing novel biological insights into these complex biological systems. In particular, genome-centric metagenomics analyses are revealing the function and physiology of individual community members. Querying transcripts, proteins and metabolites are emerging techniques that can inform the cellular responses under different conditions. Overall, meta-omics approaches are shedding light into complex microbial communities once regarded as 'blackboxes', but challenges remain to integrate information from meta-omics into engineering design and operation guidelines. PMID- 25827119 TI - The Many Faces of FOX-7: A Precursor to High-Performance Energetic Materials. AB - New derivatives of 1,1-diamino-2, 2-dinitroethene (FOX-7) are reported. These highly oxygen- and nitrogen-rich compounds were fully characterized using IR and multinuclear NMR spectroscopy, elemental analysis (EA), and differential scanning calorimetry (DSC). X-ray structure determination of (E)-1,2-bis{(E)-2-chloro-1 (chloroimino)-2,2-dinitroethyl}diazene) (10), N1, N2-dichloro-1, 2 diazenedicarboximidamide (11), and (E,E)-N,N'-1,2-ethanediylidenebis(2, 2-dinitro 2-chloro-ethanamine) (12) was helpful in their characterization. Heats of formation (HOF) were calculated (Gaussian 03) and combined with experimental densities to estimate the detonation velocities (D) and pressures (P) of the high energy-density materials (HEDMs) (EXPLO5, v6.01). The compounds exhibit good thermal stability, high density, positive HOF, acceptable oxygen balances, and excellent detonation properties, which often are superior to that of 1,3,5 trinitroperhydro-1,3,5-triazine (RDX). PMID- 25827120 TI - Improving long-term outcomes for chronic low back pain: time for a new paradigm? AB - These are exciting times for physical therapists who treat people with chronic low back pain (CLBP). Many of the mysteries of this condition are starting to be revealed, and it appears that major breakthroughs are on the way. Advances in neuroimaging, coupled with increased understanding of the molecular and submolecular events associated with the symptoms of back pain, are helping us reconceptualize the etiologies and mechanisms of this condition. The result of these advances is that physical therapists now have a wide range of potential "treatment packages" that can include patient education, manual therapy, and a wide variety of exercise options for people with CLBP. The question is, "How can long-term, self-management programs become more effective?" PMID- 25827121 TI - JOSPT's Board names Dr Haxby Abbott editor-in-chief elect. AB - On behalf of JOSPT's Board of Directors, President John A. Nyland is pleased to announce that J. Haxby Abbott, DPT, PhD, FNZCP, has accepted the position of editor-in-chief for JOSPT. He succeeds Guy G. Simoneau, PT, PhD, ATC, who has served in this role since the January 2002 issue. PMID- 25827122 TI - External validation of a clinical prediction rule to predict full recovery and ongoing moderate/severe disability following acute whiplash injury. AB - STUDY DESIGN: Retrospective secondary analysis of data. OBJECTIVES: To investigate the external validity of the whiplash clinical prediction rule (CPR). BACKGROUND: We recently derived a whiplash CPR to consolidate previously established prognostic factors for poor recovery from a whiplash injury and predicted 2 recovery pathways. Prognostic factors for full recovery were being less than 35 years of age and having an initial Neck Disability Index (NDI) score of 32% or less. Prognostic factors for ongoing moderate/severe pain and disability were being 35 years of age or older, having an initial NDI score of 40% or more, and the presence of hyperarousal symptoms. Validation is required to confirm the reproducibility and accuracy of this CPR. Clinician feedback on the usefulness of the CPR is also important to gauge acceptability. METHODS: A secondary analysis of data from 101 individuals with acute whiplash-associated disorder who had previously participated in either a randomized controlled clinical trial or prospective cohort study was performed using accuracy statistics. Full recovery was defined as NDI score at 6 months of 10% or less, and ongoing moderate/severe pain and disability were defined as an NDI score at 6 months of 30% or greater. In addition, a small sample of physical therapists completed an anonymous survey on the clinical acceptability and usability of the tool. Results The positive predictive value of ongoing moderate/severe pain and disability was 90.9% in the validation cohort, and the positive predictive value of full recovery was 80.0%. Surveyed physical therapists reported that the whiplash CPR was simple, understandable, would be easy to use, and was an acceptable prognostic tool. CONCLUSION: External validation of the whiplash CPR confirmed the reproducibility and accuracy of this dual-pathway tool for individuals with acute whiplash-associated disorder. Further research is needed to assess prospective validation, the impact of inclusion on practice, and to examine the efficacy of linking treatment strategies with predicted prognosis. LEVEL OF EVIDENCE: Prognosis, level 1b. PMID- 25827123 TI - Whiplash: are you at risk for ongoing pain or disability? AB - Have you recently sustained an injury and been diagnosed with whiplash or a whiplash-associated disorder? If so, you may be wondering what your recovery will be like. If health care providers could identify, soon after the initial injury, which patients would probably improve naturally over time and which ones would not, they could better manage the patient's treatment in the early stages of recovery. A study published in the April 2015 issue of JOSPT provides new insights into this challenge, which may help improve decision making for providers and outcomes for patients. PMID- 25827124 TI - A systematic review of the measurement properties of the patient-rated wrist evaluation. AB - STUDY DESIGN: Systematic review of measurement properties. OBJECTIVES: To summarize the measurement properties of the Patient-Rated Wrist Evaluation (PRWE) questionnaire. BACKGROUND: The PRWE is a region-specific outcome measure initially developed for assessing pain and function in individuals with distal radius fracture. However, subsequent research has expanded its use to other wrist/hand conditions. A systematic review of the measurement properties of the PRWE can enhance the understanding of its clinical applicability across different wrist/hand pathologies. METHODS: The MEDLINE, Embase, and CINAHL databases were searched using predefined search terms. A hand search of the bibliography of the primary studies was performed. Studies assessing at least 1 measurement property of the PRWE, either in the English version or versions in other languages, were included in this review. Two raters performed data extraction and critical appraisal of the primary studies using standardized instruments. RESULTS: A total of 22 primary studies met the inclusion criteria. The overall quality of the 22 studies ranged from 38% to 88%, with 9 scoring greater than 70%. Agreement between the raters who determined the quality of the studies was 0.75 (unweighted kappa). The measurement properties of the PRWE were summarized for different wrist/hand conditions. CONCLUSION: The PRWE is reliable, valid, and responsive across many wrist/hand conditions. Future studies should focus on determining values for the minimal detectable change and clinically important differences for the PRWE across different patient populations. PMID- 25827127 TI - April 2015 erratum. PMID- 25827125 TI - Osseous fragment in a patient with knee pain. AB - The patient was a 31-year-old man who was currently serving in the military. He was referred to a physical therapist by his primary care physician for a chief complaint of left anterior knee pain. Due to concern over a loose body, the physical therapist ordered radiographs of the left knee, which revealed an osseous fragment. PMID- 25827128 TI - Pro-inflammatory adipocytokines, oxidative stress, insulin, Zn and Cu: Interrelations with obesity in Egyptian non-diabetic obese children and adolescents. AB - PURPOSE: To investigate the inter-relationships between adipocytokines, oxidative stress, insulin, Zn and Cu and obesity among Egyptian obese non-diabetic children and adolescents. PATIENTS AND METHODS: 72 obese children and adolescents of both sexes (5-17 years) were recruited for the study. 40 healthy normal non-obese persons of matched ages and sexes were used as control group. Lipid profile, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and leptin levels were measured. Malondialdehyde (MDA) and reduced glutathione (GSH) concentrations and superoxide dismutase (SOD) activity were estimated. Micronutrients (Zn and Cu) concentrations in addition to insulin and fasting blood sugar (FBS) levels were also evaluated. Estimation of insulin resistance (homeostatic model assessment (HOMA-IR)) was derived from FBS measurements. RESULTS: Significant elevations (P<0.001) in TNF-alpha, IL-6, leptin, MDA, Cu and FBS levels and significant decreases (P<0.001) in GSH, Zn levels and SOD activity were detected among obese individuals as compared with control group. Insulin and triglyceride levels were significantly increased in obese male children and HDL-cholesterol level was increased significantly in obese adolescent females compared to controls. However, total cholesterol and LDL-cholesterol levels were significantly high in all obese cases as compared with controls. Insulin resistance was detected in 100% of the patients. CONCLUSIONS: We concluded that obesity with pro-inflammatory adipocytokines and hypozincemia together by many mechanisms participate in excessive oxidative stress and are highly associated with inflammation and the development of obesity-related complications. Obesity represents a critical risk factor for development of insulin resistance status. PMID- 25827129 TI - A pilot evaluation of the 3gLM-R - A new supraglottic airway device. AB - INTRODUCTION: Supraglottic airway devices are designed for airway management during anaesthesia. The 3gLM is a novel device with a non-inflatable soft cuff and separate channels for gas delivery and drainage of gastric content. MATERIAL AND METHODS: This prospective observational study of the 3gLM, version R, size 4 in 40 adult patients scheduled for elective surgery, evaluated the insertion success rate at the 1st attempt as the primary outcome. Secondary aims included insertion parameters, such as total success rate, insertion time, oropharyngeal seal pressures, postoperative complications and a comparison between males and females. RESULTS: First attempt insertion success rate was 80% (70% in males, 90% in female patients, p=0.24), while total insertion success rate was 92.5% (85% in males, 100% in females, p=0.23). The oropharyngeal seal pressures were 27cmH2O, higher in females (29.4cmH2O) than in males (24.2cmH2O) - p=0.002. Postoperative complications were only temporary and included sore throat (24.3%), hoarseness (10.8%), pain on swallowing (10.8%) and minor tongue haematoma (2.5%). There was no difference in the incidence of postoperative complications between the genders apart from hoarseness. No aspiration of gastric contents or other long-term complications occurred in this cohort. CONCLUSIONS: The 3gLM exhibited oropharyngeal seal pressures adequate for the controlled ventilation in most patients. Size 4 of the device showed higher pressures in females than in men. PMID- 25827130 TI - FUCCI sensors: powerful new tools for analysis of cell proliferation. AB - Visualizing the cell cycle behavior of individual cells within living organisms can facilitate the understanding of developmental processes such as pattern formation, morphogenesis, cell differentiation, growth, cell migration, and cell death. Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology offers an accurate, versatile, and universally applicable means of achieving this end. In recent years, the FUCCI system has been adapted to several model systems including flies, fish, mice, and plants, making this technology available to a wide range of researchers for studies of diverse biological problems. Moreover, a broad range of FUCCI-expressing cell lines originating from diverse cell types have been generated, hence enabling the design of advanced studies that combine in vivo experiments and cell-based methods such as high-content screening. Although only a short time has passed since its introduction, the FUCCI technology has already provided fundamental insight into how cells establish quiescence and how G1 phase length impacts the balance between pluripotency and stem cell differentiation. Further discoveries using the FUCCI technology are sure to come. PMID- 25827131 TI - Potential clinical use of differentiated cells from embryonic or Mesenchymal stem cells in orthopeadic problems. AB - Stem cells are classified by their tissue source. Embryonic stem cells that derived from inner cell mass of blastocyst stage embryos are highly proliferative in their undifferentiated state. A multipotent type of mesenchymal stem cells isolated from different type of tissues such as bone marrow, fat tissue etc. The dynamics of embryonic and adult stem cell cycles are profoundly dissimilar than the culture of stem cells. After improving the culture conditions and differentiation potentials, differentiated stem cells are the first cells to be preferred in modern regenerative medicine and tissue engineering. This review article focuses on the cell-based therapy on orthopedic problems. We explore the challenges associated with bone repair and regeneration using embryonic or mesenchymal stem cells that use undifferentiated or/and differentiated condition. This paper also discusses optimizing the best cell type, differentiation condition and using them on bone tissue engineering in future investigation. PMID- 25827132 TI - Targeting the immune system to treat lung cancer: rationale and clinical experience. AB - The use of immunotherapy that harnesses and enhances the innate powers of the immune system to fight cancer cells represents the most promising new cancer treatment approach since the development of the first chemotherapies and, more recently, targeted therapies. Unexpectedly, lung cancer has recently emerged as an exciting new target for immune-based therapies. Several approaches to immunotherapy for lung cancer have shown promise in early clinical trials and in late-phase development. The most advanced strategies can be split into two main categories: therapeutic vaccines and checkpoint inhibitors. At this time of great expectations, this review provides the reader with an update on the immunotherapies used to treat lung cancer with a focus on the rationale of targeting the immune system. It reports the results from recent major clinical trials, describes new toxicity profiles associated with such drugs, and particularly the role of the pulmonologists in their management. This review provides an overview of the main perspectives within this field. PMID- 25827133 TI - Radiofrequency Coblation Versus Intramural Bipolar Cautery for the Treatment of Inferior Turbinate Hypertrophy. AB - OBJECTIVE: Compare intramural bipolar electrocautery and radiofrequency coblation in the treatment of inferior turbinate hypertrophy with regards to objective and subjective improvement in nasal obstruction, rate and type of complications, experience during the procedure, and rate of recovery. STUDY DESIGN: Prospective, single-blinded study. SETTING: Single tertiary medical center from 2008 to 2010. SUBJECTS AND METHODS: Forty-one adult patients with inferior turbinate hypertrophy refractory to medical management were treated with radiofrequency coblation in one nostril and intramural bipolar cautery in the other. Subjective and objective data, including use of a Visual Analog Scale (VAS) for subjective outcomes, acoustic rhinometry, and nasal endoscopy, were then obtained from each patient comparing the 2 techniques. RESULTS: Radiofrequency coblation was significantly less painful than intramural bipolar cautery during the procedure (P = .03) and during the early postoperative period (P < .02) and produced less crusting at 3 weeks (P = .009). Both interventions were similar in subjective and objective improvements in nasal obstruction as measured by acoustic rhinometry and subjective VAS outcomes. CONCLUSION: Radiofrequency coblation seems to offer an equivalent alternative to bipolar electrocautery for the treatment of inferior turbinate hypertrophy with less discomfort during the procedure and early post operative period. PMID- 25827134 TI - Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy. AB - BACKGROUND: Growth hormone-releasing hormone agonists (GHRH-As) stimulate cardiac repair following myocardial infarction (MI) in rats through the activation of the GHRH signaling pathway within the heart. We tested the hypothesis that the administration of GHRH-As prevents ventricular remodeling in a swine subacute MI model. METHODS AND RESULTS: Twelve female Yorkshire swine (25 to 30 kg) underwent transient occlusion of the left anterior descending coronary artery (MI). Two weeks post MI, swine were randomized to receive injections of either 30 MUg/kg GHRH-A (MR-409) (GHRH-A group; n=6) or vehicle (placebo group; n=6). Cardiac magnetic resonance imaging and pressure-volume loops were obtained at multiple time points. Infarct, border, and remote (noninfarcted) zones were assessed for GHRH receptor by immunohistochemistry. Four weeks of GHRH-A treatment resulted in reduced scar mass (GHRH-A: -21.9 +/- 6.42%; P=0.02; placebo: 10.9 +/- 5.88%; P=0.25; 2-way ANOVA; P=0.003), and scar size (percentage of left ventricular mass) (GHRH-A: -38.38 +/- 4.63; P=0.0002; placebo: -14.56 +/- 6.92; P=0.16; 2-way ANOVA; P=0.02). This was accompanied by improved diastolic strain. Unlike in rats, this reduced infarct size in swine was not accompanied by improved cardiac function as measured by serial hemodynamic pressure-volume analysis. GHRH receptors were abundant in cardiac tissue, with a greater density in the border zone of the GHRH-A group compared with the placebo group. CONCLUSIONS: Daily subcutaneous administration of GHRH-A is feasible and safe in a large animal model of subacute ischemic cardiomyopathy. Furthermore, GHRH-A therapy significantly reduced infarct size and improved diastolic strain, suggesting a local activation of the GHRH pathway leading to the reparative process. PMID- 25827135 TI - Differentiating primary and extragenital metastatic mucinous ovarian tumours: an algorithm combining PAX8 with tumour size and laterality. AB - AIMS: Our aim was to analyse the utility of the algorithm combining PAX8 with clinicopathological characteristics (tumour size, laterality and patient age) in differentiating primary ovarian mucinous tumours (POMTs) from extragenital metastatic mucinous carcinomas involving the ovary (eMOMCs). METHODS AND RESULTS: Immunohistochemical staining for PAX8 was performed on formalin fixed, paraffin embedded tissues from 47 POMTs, 18 eMOMCs and 70 extragenital primary mucinous carcinomas (ePMCs) using anti-PAX8 rabbit polyclonal antibody (pAb) and anti-PAX8 rabbit monoclonal antibody (mAb). PAX8 (pAb) positive signals were found in 3/18 eMOMCs and in 32/70 ePMCs. PAX8 (mAb) demonstrated superior specificity, with 0% positivity in both eMOMCs and ePMCs, but unfavourable sensitivity, with 60.9% in ovarian mucinous borderline tumours and 45.8% in POMCs. Although PAX8 (mAb) immunostaining status (66.2%), tumour size (75.4%) and laterality (84.6%) demonstrated unsatisfactory accuracy when they were evaluated individually in differentiating POMTs from eMOMCs, a combination of PAX8 (mAb) immunostaining status, tumour size and laterality markedly increased accuracy (86.2%), with a satisfactory Youden Index (63.7%). CONCLUSIONS: PAX8 (mAb) was a specific marker in differentiating POMTs from eMOMCs. As a simple, convenient and high performance to price ratio algorithm, a combination of PAX8 (mAb) immunostaining with tumour size and laterality will improve the diagnostic criteria of ovarian mucinous metastasis. PMID- 25827137 TI - Invasive revascularisation in patients with moderate intermittent claudication provides a significant improvement in quality of life compared with conservative treatment. PMID- 25827136 TI - Families First: the development of a new mentalization-based group intervention for first-time parents to promote child development and family health. AB - AIM: The aim of the present study was to describe the development of Families First, a new mentalization-based group intervention model for supporting early parenthood. The general aim of the intervention was to support well-functioning models of parenting and prevent transmission of negative parenting models over generations, and thus promote child development and overall family health. BACKGROUND: In the Finnish society, great concern has aroused during the last decade regarding the well-being and mental health of children and adolescents. Increased number of divorces, poverty, substance abuse, and mental health problems among parents enhance the risk for child neglect and abuse. New effective, preventive, and health-promoting intervention tools are greatly needed to support families with young children. At present, the Families First intervention is being implemented in primary social and healthcare units all over Finland. METHODS AND FINDINGS: This article will provide a theoretical understanding of the importance of parental mentalization for the development of the parent-child relationship and the development of the child as well as proposed mechanisms of actions in order to enhance mentalizing capacity. The cultural context will be described. The article will also provide a description of the scientific evaluation protocol of the intervention model. Finally, possible limitations and challenges of the intervention model are discussed. PMID- 25827138 TI - Violent reinjury and mortality highlights the need for a comprehensive care approach to youth presenting for assault-related injury. PMID- 25827139 TI - Metformin should not be contraindicated in patients with type 2 diabetes and mild to moderate renal impairment. PMID- 25827140 TI - Air-Seawater Exchange of Organochlorine Pesticides along the Sediment Plume of a Large Contaminated River. AB - Gaseous exchange fluxes of organochlorine pesticides (OCPs) across the air-water interface of the coastal East China Sea were determined in order to assess whether the contaminated plume of the Yangtze River could be an important regional source of OCPs to the atmosphere. Hexachlorocyclohexanes (HCHs), chlordane compounds (CHLs), and dichlorodiphenyltrichloroethanes (DDTs) were the most frequently detected OCPs in air and water. Air-water exchange was mainly characterized by net volatilization for all measured OCPs. The net gaseous exchange flux ranged 10-240 ng/(m2.day) for gamma-HCH, 60-370 ng/(m2.day) for trans-CHL, 97-410 ng/(m2.day) for cis-CHL, and ~0 (e.g., equilibrium) to 490 ng/(m2.day) for p,p'-DDE. We found that the plume of the large contaminated river can serve as a significant regional secondary atmospheric source of legacy contaminants released in the catchment. In particular, the sediment plume represented the relevant source of DDT compounds (especially p,p'-DDE) sustaining net degassing when clean air masses from the open ocean reached the plume area. In contrast, a mass balance showed that, for HCHs, contaminated river discharge (water and sediment) plumes were capable of sustaining volatilization throughout the year. These results demonstrate the inconsistencies in the fate of HCHs and DDTs in this large estuarine system with declining primary sources. PMID- 25827141 TI - A simple technique for reducing phalangeal displaced unicondylar fractures in the hand. PMID- 25827142 TI - One-stage rotational osteotomy for congenital radioulnar synostosis. AB - We report the results of a one-stage rotational osteotomy of the proximal third of the ulna and distal third of the radius with segmental bone resection for treating congenital radioulnar synostosis. We retrospectively reviewed 25 patients (28 forearms) treated by operation. Patients were divided into two groups according to the method of internal fixation at the osteotomy sites. In Group 1 the ulnar osteotomy was stabilized with an intramedullary pin and in Group 2 no fixation was used. The average forearm position improved from 47 degrees pronation before surgery, to 27 degrees supination after surgery. There were no statistically significant differences between the two groups in surgical outcomes. One-stage rotational osteotomy of the proximal third of the ulna and distal third of the radius with segmental bone resection is a simple and safe treatment for patients with congenital radioulnar synostosis. Internal fixation at the osteotomy site seems to be unnecessary. Level of evidence: Level 4. PMID- 25827143 TI - Long-term clinical outcome after epineural coaptation of digital nerves. AB - This study evaluates the long-term clinical outcome and complication rate after digital nerve repair in adults and aims to identify possible prognostic factors of sensory recovery. End-to-end epineural coaptation was performed under magnification. A total of 93 coapted digital nerves were clinically evaluated with a mean follow-up of 3.5 years (range 1-6 years). The mean two-point discrimination was 10.6 mm (versus 4.4 mm for the contralateral side). Cutaneous pressure threshold tested with Semmes-Weinstein monofilaments showed a mean value of 2.7 (versus 2.2 for the contralateral side). Only 2% of our patients developed painful neuromas. None of our patients recovered normal functional sensibility, however, recovery of protective sensation contributed to a high reported level of satisfaction. No correlation was observed between the sensory outcome and age, smoking, mechanism of injury, lesion to or anastomosis of a digital artery, or time of immobilization. The only identified predictor of the result was the surgeon's level of experience. This highlights the importance of adequate training and practice in the surgical repair of smaller peripheral nerves. LEVEL OF EVIDENCE: IV. PMID- 25827144 TI - Outcome of arthroscopic reduction association of the scapholunate joint. AB - This study evaluates the arthroscopic reduction association scapholunate technique and outcomes. A total of 18 patients with chronic scapholunate instability with mean follow-up of 36 months were reviewed. Postoperatively, the mean visual analogue score was 2.5 and the mean DASH score was 8. The grip strength was 27 kg on the operative side compared with 32 kg on the uninjured side. The mean wrist flexion was 46 degrees and extension was 56 degrees . Seven patients had complications. Six patients had scapholunate joint widening, one had windshield-wipering of the screws with loss of reduction, and two demonstrated progression of scapholunate advanced collapse deformity. Four patients underwent revision surgeries: two revision arthroscopic reduction association scapholunates and two proximal row carpectomies. A preoperative scapholunate gap of greater than 5 mm and the presence of scapholunate advanced collapse Grade I were both predictive of a complication or revision surgery. Patients with a scapholunate gap of greater than 5 mm or scapholunate advanced collapse had statistically higher complications rates.Level of Evidence IV. PMID- 25827145 TI - [Functional decline in older persons after acute hospitalization]. AB - Many persons aged 65 years and older encounter new disabilities in activities of daily living after a period of acute hospitalization; this is defined as functional decline. A consequence of functional decline is they are not able to perform essential daily activities, such as bathing, dressing, and walking independently. Recovery from these new disabilities is difficult. Older persons who encounter functional decline report a lower health-related quality of life and are often in need of permanent home care. The systematic in-hospital recording of a patient's functional status prior to hospital stay, early ambulation, and adequate and effective rehabilitation or transitional care can contribute to the prevention of functional decline. However, these interventions are often not applied in clinical practice. Until now, the prevention of functional decline has only been possible in a limited number of older persons. Major research questions include: can all older persons recover from functional decline, which mechanisms contribute most to functional decline and how can these mechanisms be influenced? PMID- 25827146 TI - [A child with primary sclerosing cholangitis]. AB - BACKGROUND: Primary sclerosing cholangitis is a rare liver disease which is mainly diagnosed in adults. This chronic progressive disease, characterised by inflammation, fibrosis and strictures of the intra- and extrahepatic bile ducts, leads to cirrhosis. There is a strong association between primary sclerosing cholangitis and inflammatory bowel disease (IBD). CASE DESCRIPTION: A 10-year-old boy presented at the accident and emergency department with fever, episodes of abdominal pain, nausea, vomiting, fatigue and hepatomegaly. Blood tests, pathology investigations, liver biopsy and magnetic resonance cholangiopancreatography (MRCP) led to the diagnosis of primary sclerosing cholangitis. The patient was treated with ursodeoxycholic acid and later, because of unbearable itching, sequentially with lidocaine 3% ointment, rifampicin, an endoprosthesis in the common bile duct and glucocorticoids. One year later he returned to the paediatrician with abdominal pain and bloody diarrhoea. Endoscopy revealed features of indeterminate colitis. Remission of the disease was achieved quickly after treatment with mesalazine. CONCLUSION: Primary sclerosing cholangitis can develop in childhood and is often associated with IBD. PMID- 25827147 TI - [No visible strings during an IUD check-up]. AB - BACKGROUND: When there are no strings visible during an IUD (intrauterine device) check-up and ultrasound does not show an IUD in the uterine cavity, expulsion is commonly assumed. If the patient has abdominal pain further investigation is advised. This case shows that this policy does not cover every eventuality. CASE DESCRIPTION: The patient is a 32-year-old gravida 2, para 2. One month after IUD insertion she developed abdominal pain. The strings of the IUD were not visible with a speculum and ultrasound revealed an empty uterine cavity. Over the next few years the abdominal pain decreased but she developed atypical symptoms that were interpreted as psychosocial in origin. Two years later she presented with new abdominal symptoms and we referred her to a gynaecologist. An abdominal overview X-ray image revealed the IUD, which was removed laparoscopically. CONCLUSION: If there are no strings visible at an IUD check-up, perforation of the uterus needs to be considered. An abdominal overview X-ray image, which is relatively cheap and non-invasive, can then easily be taken. PMID- 25827148 TI - [The first Dutch debate on anaesthesia in obstetrics]. AB - After the publication of the Dutch medical guideline on pharmacological analgesia during childbirth in 2008, the question of whether pharmacological pain relief should be permissible during labour was hotly debated. This discussion has been going on since the second half of the 19th century when the introduction of ether and chloroform was extensively studied and described in Great Britain. This article looks back on the same debate in the Netherlands when inhalational anaesthetics were introduced into obstetrics. Study of historical journals and textbooks, originating in the Netherlands and elsewhere, and of historical medical literature on anaesthesia and obstetrics shows that the Dutch protagonists adopted more nuanced ideas on this issue than many of their foreign colleagues. This description of the first Dutch debate on anaesthesia in obstetrics shows that in fact the issues and arguments are timeless. PMID- 25827149 TI - [Cryptococcal meningitis]. AB - Immunocompromised patients are at increased risk of disseminated cryptococcal infection, often presenting as a primary respiratory infection with yeast cells originating from bird excreta. Because Cryptococcus neoformans has a tropism for cerebrospinal fluid, most patients suffer from meningitis or meningoencephalitis. Symptoms of cryptococcal meningitis are non-specific: headache, fever, nausea, or altered mental state and behaviour. Case descriptions of a renal transplant recipient and an HIV patient illustrate the non-specific presentation of cryptococcal meningitis. Lumbar puncture seemed to be critical in establishing the diagnosis. Cerebrospinal fluid, blood and other tissues were tested for C. neoformans by microscopy, culture and antigen tests. The patients were successfully treated with amphotericin B or liposomal amphotericin B intravenously and flucytosine intravenously or orally, followed by long-term fluconazole. The mortality rate for cryptococcal meningitis is 41% among renal transplant recipients and 20% in HIV patients. PMID- 25827151 TI - [The refeeding syndrome]. AB - The refeeding syndrome may occur during reintroduction of carbohydrates in malnourished patients. This syndrome is characterized by reduced plasma electrolyte levels, hypophosphataemia being most prevalent. The symptoms can vary from minor symptoms to severe neurological or cardiac symptoms. The pathophysiological mechanism comprises an increase in insulin levels, resulting in shifts of phosphate, potassium and magnesium into the intracellular environment, as well as fluid retention and relative deficiency of vitamin B1. There is growing interest in the screening and treatment of patients with malnutrition, due to which the incidence of refeeding syndrome is probably increasing. Currently, there is no single definition of this syndrome and therefore there is no solid scientific basis for screening and treatment. In this article we describe the rationale for screening and additional laboratory investigations. A prospective, controlled trial is important to define the clinical relevance of the refeeding syndrome and optimize its treatment. PMID- 25827152 TI - [A woman with a rare vascular malformation]. AB - A 30-year-old woman with trisomy 8 syndrome and coagulopathy was diagnosed with a malformation of the vena cava superior. This is a rare anatomical variation, which originates from a non-development of Marshall's ligament during the 8th week of gestation (prevalence: 0.3%). PMID- 25827153 TI - [Hypofractionated adjuvant radiotherapy for breast cancer: no signs of increased risk of cardiotoxicity]. AB - Adjuvant radiotherapy is frequently used in women with breast cancer to improve both local control of the tumour and overall survival. Hypofractionated regimens are increasingly being used as they involve fewer treatment sessions and, in terms of tumour control, the effects of conventionally fractionated and hypofractionated radiotherapy seem to be comparable. However, there is concern regarding increased cardiotoxicity following hypofractionated radiotherapy treatment to the left side. In order to determine if cardiac mortality increases with hypofractionation relative to conventional fractionation, a Canadian research group performed a retrospective analysis in 5334 women with breast cancer treated between 1990-1998 with postoperative radiotherapy to the breast/chest wall only. At 15-year follow-up the authors concluded that cardiac mortality was not statistically different among patients with left-sided breast cancer whether treated with hypofractionated or conventionally fractionated whole breast/chest wall irradiation. This commentary discusses the data presented in the paper, puts them into perspective and describes the clinical implications. PMID- 25827154 TI - [Health care costs in the last years of life: interesting, but for a different reason than is widely believed]. AB - Health care costs have increased due to population ageing. It is often said that the majority of health care spending occurs in the last year of life and that, as a result, the total costs of population ageing are considerably lower than is usually predicted. With the Netherlands facing a rapidly ageing population, such statements are well-received by policy makers. Unfortunately they reflect only part of the truth and are therefore misleading. Nevertheless, health care costs in the last years of life are still interesting, but for a different reason than is widely believed. Taking a lifetime perspective, these costs shed new light on solidarity in health care. PMID- 25827156 TI - Quantitative pixel-wise measurement of myocardial blood flow: the impact of surface coil-related field inhomogeneity and a comparison of methods for its correction. AB - BACKGROUND: Surface coil-related field inhomogeneity potentially confounds pixel wise quantitative analysis of perfusion CMR images. This study assessed the effect of surface coil-related field inhomogeneity on the spatial variation of pixel-wise myocardial blood flow (MBF), and assessed its impact on the ability of MBF quantification to differentiate ischaemic from remote coronary territories. Two surface coil intensity correction (SCIC) techniques were evaluated: 1) a proton density-based technique (PD-SCIC) and; 2) a saturation recovery steady state free precession-based technique (SSFP-SCIC). METHODS: 26 subjects (18 with significant CAD and 8 healthy volunteers) underwent stress perfusion CMR using a motion-corrected, saturation recovery SSFP dual-sequence protocol. A proton density (PD)-weighted image was acquired at the beginning of the sequence. Surface coil-related field inhomogeneity was approximated using a third-order surface fit to the PD image or a pre-contrast saturation prepared SSFP image. The estimated intensity bias field was subsequently applied to the image series. Pixel-wise MBF was measured from mid-ventricular stress images using the two SCIC approaches and compared to measurements made without SCIC. RESULTS: MBF heterogeneity in healthy volunteers was higher using SSFP-SCIC (24.8 +/- 4.1%) compared to PD-SCIC (20.8 +/- 3.0%; p = 0.009), however heterogeneity was significantly lower using either SCIC technique compared to analysis performed without SCIC (36.2 +/- 6.3%). In CAD patients, the difference in MBF between remote and ischaemic territories was minimal when analysis was performed without SCIC (0.06 +/- 0.91 mL/min/kg), and was substantially lower than with either PD SCIC (0.50 +/- 0.63 mL/min/kg; p = 0.013) or with SSFP-SCIC (0.63 +/- 0.89 mL/min/kg; p = 0.005). In 6 patients, MBF quantified without SCIC was artifactually higher in the stenosed coronary territory compared to the remote territory. PD-SCIC and SSFP-SCIC had similar differences in MBF between remote and ischaemic territories (p = 0.145). CONCLUSIONS: This study demonstrates that surface coil-related field inhomogeneity can confound pixel-wise MBF quantification. Whilst a PD-based SCIC led to a more homogenous correction than a saturation recovery SSFP-based technique, this did not result in an appreciable difference in the differentiation of ischaemic from remote coronary territories and thus either method could be applied. PMID- 25827157 TI - Seeing what we hear: an eye to help the ear. PMID- 25827155 TI - Inflammation in acute CNS injury: a focus on the role of substance P. AB - Recently, a number of reports have shown that neurogenic inflammation may play a role in the secondary injury response following acute injury to the CNS, including traumatic brain injury (TBI) and stroke. In particular substance P (SP) release appears to be critically involved. Specifically, the expression of the neuropeptide SP is increased in acute CNS injury, with the magnitude of SP release being related to both the frequency and magnitude of the insult. SP release is associated with an increase in blood-brain barrier permeability and the development of vasogenic oedema as well as neuronal injury and worse functional outcome. Moreover, inhibiting the actions of SP through use of a NK1 receptor antagonist is highly beneficial in both focal and diffuse models of TBI, as well as in ischaemic stroke, with a therapeutic window of up to 12 h. We propose that NK1 receptor antagonists represent a novel therapeutic option for treatment of neurogenic inflammation following acute CNS injury. PMID- 25827158 TI - Diffusion of mepivacaine to adjacent synovial structures after intrasynovial analgesia of the digital flexor tendon sheath. AB - REASONS FOR PERFORMING STUDY: Controversy exists about the specificity of diagnostic analgesia of the digital flexor tendon sheath (DFTS) in horses. OBJECTIVES: To evaluate the degree of diffusion of mepivacaine from the equine DFTS to adjacent synovial structures. STUDY DESIGN: Crossover experiment. METHODS: Under general anaesthesia, the DFTS of one front and one hindlimb of 8 horses were injected simultaneously with mepivacaine. Synovial fluid samples of the injected DFTS, the adjacent metacarpo-/metatarsophalangeal (MCP/MTP) joint, proximal interphalangeal joint, distal interphalangeal joint, navicular bursa and contralateral MCP/MTP joint were collected 15 min post injection (T15) from one of the injected limbs and 60 min post injection (T60) from the other limb. Venous blood samples were obtained at T0, T15 and T60 to evaluate systemic distribution of mepivacaine. After a 2-week washout period, the procedure was repeated using the same limbs but reversing the time of sampling (front vs. hindlimbs). The concentration of mepivacaine in samples was measured with a commercial ELISA kit. RESULTS: Mepivacaine concentrations in the DFTS samples, at both T15 (5077 mg/l) and T60 (3503 mg/l), exceeded those estimated sufficient to produce synovial analgesia (100 mg/l or 300 mg/l). Mepivacaine was found in all synovial structures adjacent to the injected DFTS and in the contralateral MCP/MTP joints, but concentrations were low, with a maximum value of only 3.2 mg/l. With the exception of the navicular bursa samples, the mepivacaine concentrations in the adjacent synovial structures were significantly higher at T60 than at T15 (P<0.03). Significantly higher mepivacaine concentrations were found in the ipsilateral than the contralateral MCP/MTP joints at T60 (P<0.001). Blood samples had significantly higher mepivacaine concentrations at T15 and T60 than at T0 (P<0.001). CONCLUSIONS: Mepivacaine injected into the DFTS of horses diffuses towards adjacent synovial structures without achieving clinically relevant concentrations. PMID- 25827159 TI - Adenocarcinoma of the gastro-oesophageal junction after sleeve gastrectomy: a case report. PMID- 25827160 TI - Pronounced gradients of light, photosynthesis and O2 consumption in the tissue of the brown alga Fucus serratus. AB - Macroalgae live in an ever-changing light environment affected by wave motion, self-shading and light-scattering effects, and on the thallus scale, gradients of light and chemical parameters influence algal photosynthesis. However, the thallus microenvironment and internal gradients remain underexplored. In this study, microsensors were used to quantify gradients of light, O2 concentration, variable chlorophyll fluorescence, photosynthesis and O2 consumption as a function of irradiance in the cortex and medulla layers of Fucus serratus. The two cortex layers showed more efficient light utilization compared to the medulla, calculated both from electron transport rates through photosystem II and from photosynthesis-irradiance curves. At moderate irradiance, the upper cortex exhibited onset of photosynthetic saturation, whereas lower thallus layers exhibited net O2 consumption. O2 consumption rates in light varied with depth and irradiance and were more than two-fold higher than dark respiration. We show that the thallus microenvironment of F. serratus exhibits a highly stratified balance of production and consumption of O2 , and when the frond was held in a fixed position, high incident irradiance levels on the upper cortex did not saturate photosynthesis in the lower thallus layers. We discuss possible photoadaptive responses and consequences for optimizing photosynthetic activity on the basis of vertical differences in light attenuation coefficients. PMID- 25827161 TI - Outcomes of light-chain amyloidosis patients treated with first-line bortezomib: a collaborative retrospective multicenter assessment. AB - Light-chain amyloidosis (AL) is associated with low survival rates, particularly in patients with cardiac involvement. We evaluated the outcome of 73 consecutive, non-selected 'real-world' AL patients, treated with first-line bortezomib-based induction, focusing on the benefit of concurrent administration of alkylating agents. Most patients had renal (77%), cardiac (66%), or multiorgan (74%) involvement. Sixty-eight per cent (n = 50) received alkylating agent (mostly cyclophosphamide). Severe adverse events were seen in 45%, most evident in patients with cardiac involvement, with no increased toxicity in patients receiving an alkylator agent. Hematological response (HemR) was obtained in 77% of patients, including 33% very good partial responses and 19% complete responses. Age <70 yr, lack of cardiac and peripheral neurologic involvement, and co-administration of an alkylating agent were associated with significantly improved HemR. NYHA cardiac failure staging was the only independent factor affecting overall survival. Administration of an alkylating agent and the achievement of both HemR and organ response were associated with a statistically significant improved survival in those surviving the first 6 months of induction. First-line bortezomib-based regimen resulted in favorable response and survival in newly diagnosed patients. Co-administration of an alkylating agent improved outcome without increasing treatment-related toxicity. PMID- 25827162 TI - Morphology of the tympanic-basicranial region in Mirounga leonina (Phocidae, Carnivora), postnatal ontogeny and sexual dimorphism. AB - The auditory region of pinnipeds has seldom been described. Here we describe and analyze the ontogenetic trajectory of the tympanic bulla of the southern elephant seal, Mirounga leonina (Phocidae, Mammalia). This species is extremely sexually dimorphic and highly polygynous (organized in harems). We examined 118 specimens, arranged in three age classes (CI, CII, and CIII), ranging from newborn to adults (males and females). To analyze the overall size and shape of the tympanic bulla we performed a geometric morphometric analysis including 87 skulls. Females reach definitive shape and size of the bulla at earlier ontogenetic stages than males, in agreement with their earlier involvement in reproductive activities. The internal anatomy of the tympanic region (e.g. form and extension of the paries) does not show remarkable differences between sexes or age classes. The greatest differences between age classes are related to bone thickness, resulting from the apposition of new annual layers. An examination of possible sex-related external differences among age classes shows significant shape differences between males and females in CIII. The morphology observed in neonates is conserved across all individuals from CI, which included specimens up to 1 year old. Clear morphological differences were observed between CI individuals, on one hand, and CII individuals plus CIII females on the other. During cranial development of both male and females, the glenoid cavity expands and compresses the bulla; this condition reaches its maximum expression in CIII males. CIII males showed the greatest morphological differences, with respect to both CI and CII individuals, and CIII females. PMID- 25827163 TI - Association of PPAR-gamma2 and beta3-AR Polymorphisms With Postmenopausal Hypertension. AB - The aim of this study was to test the association of peroxisome proliferator activated receptor (PPAR-gamma2) (Pro12Ala, C1431T) and beta3-AR (Trp64Arg) polymorphisms with metabolic, nutritional, and blood pressure parameters in 271 postmenopausal women (151 hypertensive and 120 normotensive controls). The TaqMan genotyping assay and restriction fragment length polymorphism methods were used to determine the distributions of selected alleles and genotype frequencies. Nutritional status was determined by a bioimpedance method and dietary habits were assessed via 7-day dietary recall. The distribution of selected genotypes and allele frequencies did not differ between hypertensive women and normal controls after analysis by chi-square test. The postmenopausal hypertensive women were older and had higher body fat mass, serum glucose, and triglyceride levels. The cluster analysis showed that the hypertensive group with Pro12Pro genotype had highest pulse pressure and mean arterial pressure values when compared with Pro12Ala patients. In the logistic regression analysis, blood glucose (Pro12Ala polymorphism) and energy intake (C1431Tand T1431T polymorphisms) determined hypertension. PMID- 25827164 TI - ANGIOGRAPHIC ANATOMY OF THE MAJOR ABDOMINAL ARTERIAL BLOOD SUPPLY IN THE DOG. AB - Vascular-based interventional radiology (IR) procedures are being more regularly performed in veterinary patients for both diagnostic and therapeutic purposes. A complete description of the fluoroscopic arterial anatomy of the canine abdominal cavity has not been published. This information is essential for performance of IR procedures to allow for improved preparation before and during a particular procedure. The primary purpose of this study was to provide a fluoroscopic description of the vascular branching from the abdominal aorta in a ventro-dorsal projection with a secondary goal of producing pictorial reference images of the major abdominal arterial blood vessels. Five healthy female hound type dogs were enrolled and underwent fluoroscopic arteriography. During fluoroscopy, both nonselective and selective arteriography were performed. The nonselective arteriograms were obtained in the aorta at four locations: cranial to the celiac artery, cranial to the renal arteries, cranial to the caudal mesenteric artery, and cranial to the branching of the external iliac arteries. Selective arteriography was conducted by performing injections into the following arteries: celiac, splenic, common hepatic, cranial mesenteric, left and right renal, and caudal mesenteric. Fluoroscopic arteriography allowed for excellent characterization of the aortic ostia and the location of the lower order vascular branches. Future evaluation of vascular-based treatment options will likely increase as the understanding of the normal and pathologic anatomy improves. PMID- 25827165 TI - Antidiabetic agents and endothelial dysfunction - beyond glucose control. AB - Diabetes is rapidly increasing worldwide, and the number of patients suffering from diabetes is projected to rise by 50% over the next 25 years, then affecting almost 600 million adults. Type 2 diabetes comprises 90-95% of all people with diabetes, and they constitute a patient group that carries a high burden of cardiovascular disease. The relationship between hyperglycaemia and macrovascular complications is still uncertain, at least in terms of the possibility of reducing cardiovascular events solely by improving glycaemic control. This MiniReview has thus focused on the effect of common antidiabetic agents, with emphasis on glucagon-like peptide-1, on the endothelial cells of the vasculature. Patients with type 2 diabetes suffer a two to four times higher risk of myocardial infarction and stroke than healthy persons. In addition to this, patients with diabetes have an increased atherosclerotic burden. Endothelial dysfunction is thought to be an early and important predictor of atherosclerosis and cardiovascular disease, and in people with type 2 diabetes, endothelial dysfunction is a common finding. It is therefore of importance to consider whether drugs used within the clinical management of Type 2 diabetes mellitus (T2DM) exert direct and positive effects on the vasculature independent of their glucose-lowering ability. This might serve to limit the adverse consequences of the macrovascular complications of T2DM, as dysfunction of endothelial cells is believed to contribute to a premature development of atherosclerosis. PMID- 25827166 TI - Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo. AB - OBJECTIVES: To report the secondary analyses of treatment satisfaction and clinically meaningful improvements in a randomized study comparing coadministration of tadalafil 5 mg with finasteride 5 mg versus finasteride alone in men with prostatic enlargement secondary to benign prostatic hyperplasia. METHODS: An international, randomized, double-blind, parallel study was carried out in men aged >=45 years who were 5-alpha reductase inhibitor naive, and had an International Prostate Symptom Score >=13 and prostate volume >=30 mL; 350 men received placebo/finasteride and 345 received tadalafil/finasteride over 26 weeks. Treatment satisfaction was assessed per protocol using the Treatment Satisfaction Scale-Benign Prostatic Hyperplasia. Responder cut-offs, analyzed post-hoc were total International Prostate Symptom Score improvement >=3 points or >=25% from randomization. RESULTS: Baseline patient characteristics were generally comparable between responders and non-responders. The proportion of patients with an International Prostate Symptom Score improvement >=3 points with tadalafil/finasteride and placebo/finasteride, respectively, at week 4 was 57.0% and 47.9% (OR 1.45, 95% confidence interval 1.07-1.97), at week 12 was 68.8% and 60.7% (OR 1.48, 95% confidence interval 1.07-2.05) and at week 26 was 71.4% and 70.2% (OR 1.14, 95% confidence interval 0.81-1.61); for IPSS change >=25%, the corresponding proportions were 44.8% and 32.9% (OR 1.66, 95% confidence interval 1.21-2.28), 55.5% and 51.9% (OR 1.18, 95% confidence interval 0.87-1.62), and 62.0% and 58.3% (OR 1.23, 95% confidence interval 0.89-1.70). Treatment satisfaction at week 26 was significantly greater with tadalafil/finasteride versus placebo/finasteride for total treatment satisfaction scale score (P=0.031) and satisfaction with efficacy subscore (P = 0.025); scores were not significantly different between treatments for satisfaction with dosing or side effects (both P >= 0.371). CONCLUSIONS: Tadalafil/finasteride results in significantly more patients achieving early clinical meaningful improvements in symptoms, and in greater treatment satisfaction versus placebo/finasteride. PMID- 25827167 TI - A TRPA1 channel that senses thermal stimulus and irritating chemicals in Helicoverpa armigera. AB - Sensing and responding to changes in the external environment is important for insect survival. Transient receptor potential (TRP) channels are crucial for various sensory modalities including olfaction, vision, hearing, thermosensation and mechanosensation. Here, we identified and characterized a transient receptor potential gene named as HarmTRPA1 in Helicoverpa armigera antennae. HarmTRPA1 was abundantly expressed in the antennae and labial palps. Transcripts of HarmTRPA1 could also be detected in the head and proboscis. Furthermore, functional analyses of HarmTRPA1 were conducted in the Xenopus Oocyte system. The results showed that the HarmTRPA1 channel could be activated by increasing the temperature from 20 to 45 degrees C. No significant adaptation was observed when the stimulus was repeated. In addition to thermal stimuli, pungent natural compounds including allyl isothiocyanate, cinnamaldehyde and citronellal also activated HarmTRPA1. Taken together, we infer that HarmTRPA1 may function as both a thermal sensor involved in peripheral temperature detection and as a chemical sensor detecting irritating chemicals in vivo. Our data provide valuable insight into the TRPA1 channel in this moth and lay the foundation for developing novel strategies for pest control. PMID- 25827168 TI - Evaluation of a new double-lumen endobronchial tube with an integrated camera (VivaSight-DL(TM) ): a prospective multicentre observational study. AB - The VivaSight-DL(TM) is a new single-use double-lumen endobronchial tube with an integrated camera. We studied this device in 151 consecutive patients scheduled for elective thoracic surgery in four different hospitals. Endobronchial intubation was successful in 148 patients (98%) (95% CI 94-99%). Median (IQR [range]) endobronchial intubation time was 59 (47-82 [17-932]) s and lung isolation was successfully achieved in 147 (99%) patients (95% CI 96-99%). A fibreoptic bronchoscope was required to assist endobronchial tube placement in 19 (13%) patients (95% CI 8-19%). Sore throat was reported by 37 (25%) patients (95% CI 18-33%), but no major complications were observed. We have reported the successful use of the VivaSight double-lumen tube for endobronchial intubation in a multicentre observational trial. PMID- 25827169 TI - Maternal obesity, caesarean delivery and caesarean delivery on maternal request: a cohort analysis from China. AB - BACKGROUND: To quantify the association between maternal obesity and caesarean delivery, particularly caesarean delivery on maternal request (CDMR), a fast growing component of caesarean delivery in many nations. METHODS: We followed 1,019,576 nulliparous women registered in the Perinatal Healthcare Surveillance System during 1993-2010. Maternal body mass index (BMI, kg/m(2) ), before pregnancy or during early pregnancy, was classified as underweight (<18.5), normal (18.5 to <23; reference), overweight (23 to <27.5), or obese (>=27.5), consistent with World Health Organization guidelines for Asian people. The association between maternal obesity and overall caesarean and its subtypes was modelled using log-binomial regression. RESULTS: During the 18-year period, 404,971 (39.7%) caesareans and 93,927 (9.2%) CDMRs were identified. Maternal obesity was positively associated with overall caesarean and CDMR. Adjusted risk ratios for overall caesarean in the four ascending BMI categories were 0.96 [95% confidence interval (CI) 0.94, 0.97], 1.00 (Reference), 1.16 [95% CI 1.14, 1.18], 1.39 [95% CI 1.43, 1.54], and for CDMR were 0.95 [95% CI 0.94, 0.96], 1.00 (Reference), 1.20 [95% CI 1.18, 1.22], 1.48 [95% CI 1.433, 1.54]. Positive associations were consistently found in women residing in southern and northern provinces and in subgroups stratified by year of delivery, urban or rural residence, maternal age, education, level of delivering hospital, and birthweight. CONCLUSIONS: In a large Chinese cohort study, maternal obesity was associated with an increased risk of caesarean delivery and its subtypes, including CDMR. Given the rising global prevalence of obesity, and in view of the growth of CDMR, it seems likely that caesarean births will increase, unless there are changes in obstetrical practice. PMID- 25827170 TI - Directed dewetting of amorphous silicon film by a donut-shaped laser pulse. AB - Irradiation of a thin film with a beam-shaped laser is proposed to achieve site selectively controlled dewetting of the film into nanoscale structures. As a proof of concept, the laser-directed dewetting of an amorphous silicon thin film on a glass substrate is demonstrated using a donut-shaped laser beam. Upon irradiation of a single laser pulse, the silicon film melts and dewets on the substrate surface. The irradiation with the donut beam induces an unconventional lateral temperature profile in the film, leading to thermocapillary-induced transport of the molten silicon to the center of the beam spot. Upon solidification, the ultrathin amorphous silicon film is transformed to a crystalline silicon nanodome of increased height. This morphological change enables further dimensional reduction of the nanodome as well as removal of the surrounding film material by isotropic silicon etching. These results suggest that laser-based dewetting of thin films can be an effective way for scalable manufacturing of patterned nanostructures. PMID- 25827171 TI - Do Beta 2-Glycoprotein I Disulfide Bonds Protect the Human Retina in the Setting of Age-Related Macular Degeneration? AB - Age-related macular degeneration (AMD) affects the region of the retina that is responsible for high-resolution vision. It is a major cause of blindness in the aging population. This is the first study that examines the association of redox modified, cysteine-based, post-translational forms of beta 2-glycoprotein I (beta2GPI) in the plasma of individuals with early and late stages of patients with AMD compared with controls. Exploration is also undertaken to assess whether the free thiol form of beta2GPI versus the oxidized disulfide form have distinct functional properties in the setting of hydrogen peroxide (H(2)O(2))-mediated cell death of an immortalized human retinal pigment epithelium (RPE) cell line. We demonstrate beta2GPI in the retina and choroid of patients with AMD. Free thiol beta2GPI is shown to protect the immortalized human RPE cell line against H(2)O(2)-induced cell death, whereas the oxidized form of beta2GPI and free thiol bovine serum albumin were not protective. Free thiol beta2GPI levels were significantly decreased in patients with late AMD compared with early AMD and healthy controls. Our observations lead to the hypothesis that free thiol beta2GPI may protect against oxidative stress injury to RPE cells in the early stages of AMD. PMID- 25827172 TI - Chronic fatigue is prevalent and associated with hormonal dysfunction in long term non-Hodgkin lymphoma survivors treated with radiotherapy to the head and neck region. AB - The purposes of this study were to assess the prevalence of chronic fatigue (CF) in irradiated survivors of non-Hodgkin lymphoma, analyze for associations between hormonal dysfunction and CF, and to investigate the associations between CF and functioning. Invited survivors were all treated with radiation to the head and neck region, with or without additional chemotherapy. The participants (n=98) responded to questionnaires measuring CF, mental distress (HADS), and functioning (SF-36), and had blood drawn for analyses of four hormonal axes. Hormonal status was categorized as normal, hormone dysfunction in one or more axes, or hormone replacement therapy. A total of 29% of the survivors had CF. In multivariate analyses there was an increased risk of CF among survivors with untreated hormone dysfunction (OR 3.87, 95% CI: 1.20-12.51, p=0.02). Survivors on hormone substitution did not have increased risk for CF compared to survivors with normal hormonal status. CF was significantly associated with reduced functioning. PMID- 25827173 TI - NOD/SCID IL2Rgamma-null mouse xenograft model of human p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma using permanent cell lines. AB - Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53 mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rgamma-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA 519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA 519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively. PMID- 25827174 TI - Magnitude of multiplanar breast kinematics differs depending upon run distance. AB - Recommendations for breast support, dynamic breast pain assessment, and implications for sports performance have been made within breast biomechanics research; however, these studies have been based upon short exercise protocols (2 5 min). The aim of this study was to investigate the effect of breast support on multiplanar breast kinematics over a 5-kilometre run. Ten female participants (34D or 32DD) conducted two 5-kilometre runs, in a low and high breast support. Relative multiplanar breast kinematics were averaged over five gait cycles at six intervals of a 5-kilometre run. Increases in multiplanar breast kinematics were reported from the start to the end of the run, with the greatest rate of increase in breast kinematics reported within the first two kilometres of running. The greatest relative increases in breast range of motion (34%), velocity (33%), and acceleration (41%) were reported in the superioinferior direction at the fifth kilometre (33 min of running) in the high breast support. Key findings suggest that the run distance, and therefore run duration, employed for both fundamental research and product validation protocols should be carefully considered and it is suggested that running protocols for assessing breast biomechanics should exceed 7 min. PMID- 25827175 TI - Repercussions of growth path on carcass characteristics, meat colour and shear force in Alentejana bulls. AB - The aim of this study was to evaluate the carcass and meat characteristics of eight muscles from bulls with distinct growth paths. A total of 40 Alentejana male calves were allocated to two distinct feeding regimes. In the continuous growth (CG) system, the animals were fed concentrates plus hay and were slaughtered at 18 months of age. On the other hand, in the discontinuous growth (DG) system, the animals were fed hay until 15 months of age; the cattle were then fed the same diet provided to the CG group from 15 to 24 months of age. The DG reduced hot carcass weight, fatness and dressing %, but the proportions of fat, bone and muscle tissues in the leg were not affected. In contrast, there was a positive impact of compensatory growth on supraspinatus, triceps brachii, semitendinosus, biceps femoris muscle tenderness, overcoming the negative effects of age at slaughter. The reasons for such improvement in meat tenderness were not related to intra-muscular fat content or myofibrillar protein degradation values. An association between tenderness and muscle collagen properties was not established. The results indicate that the compensatory growth has a muscle dependent effect. PMID- 25827176 TI - Polycyclic Aromatic Acids Are Primary Metabolites of Alkyl-PAHs-A Case Study with Nereis diversicolor. AB - Although concentrations of alkylated polycyclic aromatic hydrocarbons (alkyl PAHs) in oil-contaminated sediments are higher than those of unsubstituted PAHs, only little attention has been given to metabolism and ecotoxicity of alkyl-PAHs. In this study we demonstrated that metabolism of alkyl-PAHs primarily forms polycyclic aromatic acids (PAAs). We generalize this to other alkyl-PAHs, based on literature and the present study of the metabolism of 1-methylphenanthrene, 3,6-dimethylphenanthrene, and 1-, 2-, 3-, and 6-methylchrysene related to their unsubstituted parent PAHs. Also, we observed that body burdens and production of PAAs was related to the position of the methyl group, showing the same isomer specific preferences as for microbial degradation of alkyl-PAHs. We detected a high production of PAAs, and larger metabolism of alkyl-PAHs than their unsubstituted parent PAHs. We therefore propose that carboxylic acid metabolites of alkyl-PAHs have the potential of constituting a new class of contaminants in marine waters that needs attention in relation to ecological risk assessments. PMID- 25827177 TI - Patients undergoing elective coronary artery bypass grafting exhibit poor pre operative intakes of fruit, vegetables, dietary fibre, fish and vitamin D. AB - CHD may ensue from chronic systemic low-grade inflammation. Diet is a modifiable risk factor for both, and its optimisation may reduce post-operative mortality, atrial fibrillation and cognitive decline. In the present study, we investigated the usual dietary intakes of patients undergoing elective coronary artery bypass grafting (CABG), emphasising on food groups and nutrients with putative roles in the inflammatory/anti-inflammatory balance. From November 2012 to April 2013, we approached ninety-three consecutive patients (80% men) undergoing elective CABG. Of these, fifty-five were finally included (84% men, median age 69 years; range 46-84 years). The median BMI was 27 (range 18-36) kg/m(2). The dietary intake items were fruits (median 181 g/d; range 0-433 g/d), vegetables (median 115 g/d; range 0-303 g/d), dietary fibre (median 22 g/d; range 9-45 g/d), EPA+DHA (median 0.14 g/d; range 0.01-1.06 g/d), vitamin D (median 4.9 MUg/d; range 1.9-11.2 MUg/d), saturated fat (median 13.1% of energy (E%); range 9-23 E%) and linoleic acid (LA; median 6.3 E%; range 1.9-11.3 E%). The percentages of patients with dietary intakes below recommendations were 62% (fruits; recommendation 200 g/d), 87 % (vegetables; recommendation 150-200 g/d), 73% (dietary fibre; recommendation 30-45 g/d), 91% (EPA+DHA; recommendation 0.45 g/d), 98% (vitamin D; recommendation 10-20 MUg/d) and 13% (LA; recommendation 5-10 E%). The percentages of patients with dietary intakes above recommendations were 95% (saturated fat; recommendation < 10 E%) and 7% (LA). The dietary intakes of patients proved comparable with the average nutritional intake of the age- and sex-matched healthy Dutch population. These unbalanced pre-operative diets may put them at risk of unfavourable surgical outcomes, since they promote a pro-inflammatory state. We conclude that there is an urgent need for intervention trials aiming at rapid improvement of their diets to reduce peri-operative risks. PMID- 25827178 TI - Late Emergence of the First Possession Heuristic: Evidence From a Small-Scale Culture. AB - Western preschool children often assign ownership based on first possession and some theorists have proposed that this judgment might be an early emerging, innate bias. Five- to 9-year-olds (n = 112) from a small-scale group in Kenya (Kikuyu) watched videotaped interactions of two women passing an object. The object's starting position and the women's gestures were varied. Use of the first possession heuristic increased with age, and 8- to 9-year-olds performed similarly to German 5-year-olds (n = 24). Starting position and gestures had no effect. A control study confirmed that 5-year-old Kikuyus (n = 20) understood the video material. The findings reveal that the first possession heuristic follows different developmental trajectories cross-culturally and stress the role of children's sociocultural environment. PMID- 25827179 TI - Incremental Value of Three-Dimensional Transesophageal Echocardiography over the Two-Dimensional Technique in the Assessment of a Thrombus in Transit through a Patent Foramen Ovale. AB - We report a case of a right atrial thrombus traversing a patent foramen ovale into the left atrium, where three-dimensional transesophageal echocardiography provided considerable incremental value over two-dimensional transesophageal echocardiography in its assessment. As well as allowing us to better spatially characterize the thrombus, three-dimensional transesophageal echocardiography provided a more quantitative assessment through estimation of total thrombus burden. PMID- 25827180 TI - FLASH proton density imaging for improved surface coil intensity correction in quantitative and semi-quantitative SSFP perfusion cardiovascular magnetic resonance. AB - BACKGROUND: A low excitation flip angle (alpha < 10 degrees ) steady-state free precession (SSFP) proton-density (PD) reference scan is often used to estimate the B1-field inhomogeneity for surface coil intensity correction (SCIC) of the saturation-recovery (SR) prepared high flip angle (alpha = 40-50 degrees ) SSFP myocardial perfusion images. The different SSFP off-resonance response for these two flip angles might lead to suboptimal SCIC when there is a spatial variation in the background B0-field. The low flip angle SSFP-PD frames are more prone to parallel imaging banding artifacts in the presence of off-resonance. The use of FLASH-PD frames would eliminate both the banding artifacts and the uneven frequency response in the presence of off-resonance in the surface coil inhomogeneity estimate and improve homogeneity of semi-quantitative and quantitative perfusion measurements. METHODS: B0-field maps, SSFP and FLASH-PD frames were acquired in 10 healthy volunteers to analyze the SSFP off-resonance response. Furthermore, perfusion scans preceded by both FLASH and SSFP-PD frames from 10 patients with no myocardial infarction were analyzed semi-quantitatively and quantitatively (rest n = 10 and stress n = 1). Intra-subject myocardial blood flow (MBF) coefficient of variation (CoV) over the whole left ventricle (LV), as well as intra-subject peak contrast (CE) and upslope (SLP) standard deviation (SD) over 6 LV sectors were investigated. RESULTS: In the 6 out of 10 cases where artifacts were apparent in the LV ROI of the SSFP-PD images, all three variability metrics were statistically significantly lower when using the FLASH PD frames as input for the SCIC (CoVMBF-FLASH = 0.3 +/- 0.1, CoVMBF-SSFP = 0.4 +/ 0.1, p = 0.03; SDCE-FLASH = 10 +/- 2, SDCE-SSFP = 32 +/- 7, p = 0.01; SDSLP FLASH = 0.02 +/- 0.01, SDSLP-SSFP = 0.06 +/- 0.02, p = 0.03). Example rest and stress data sets from the patient pool demonstrate that the low flip angle SSFP protocol can exhibit severe ghosting artifacts originating from off-resonance banding artifacts at the edges of the field of view that parallel imaging is not able to unfold. These artifacts lead to errors in the quantitative perfusion maps and the semi-quantitative perfusion indexes, such as false positives. It is shown that this can be avoided by using FLASH-PD frames as input for the SCIC. CONCLUSIONS: FLASH-PD images are recommended as input for SCIC of SSFP perfusion images instead of low flip angle SSFP-PD images. PMID- 25827181 TI - Literature reviews vs systematic reviews. PMID- 25827182 TI - Quitting activity and tobacco brand switching: findings from the ITC-4 Country Survey. AB - OBJECTIVE: Among Australian smokers, to examine associations between cigarette brand switching, quitting activity and possible causal directions by lagging the relationships in different directions. METHODS: Current smokers from nine waves (2002 to early 2012) of the ITC-4 Country Survey Australian dataset were surveyed. Measures were brand switching, both brand family and product type (roll your-own versus factory-made cigarettes) reported in adjacent waves, interest in quitting, recent quit attempts, and one month sustained abstinence. RESULTS: Switching at one interval was unrelated to concurrent quit interest. Quit interest predicted switching at the following interval, but the effect disappeared once subsequent quit attempts were controlled for. Recent quit attempts more strongly predicted switching at concurrent (OR 1.34, 95%CI=1.18 1.52, p<0.001) and subsequent intervals (OR 1.31, 95%CI=1.12-1.53, p=0.001) than switching predicted quit attempts, with greater asymmetry when both types of switching were combined. One month sustained abstinence and switching were unrelated in the same interval; however, after controlling for concurrent switching and excluding type switchers, sustained abstinence predicted lower chance of switching at the following interval (OR=0.66, 95%CI=0.47-0.93, p=0.016). CONCLUSIONS: The asymmetry suggests brand switching does not affect subsequent quitting. IMPLICATIONS: Brand switching does not appear to interfere with quitting. PMID- 25827183 TI - A commentary re.: Quitting activity and tobacco brand switching: findings from the ITC-4 Country Survey. PMID- 25827184 TI - Unpicking causal possibilities: authors' response to Caldwell. PMID- 25827185 TI - Tobacco tax and the illicit trade in tobacco products in New Zealand. AB - OBJECTIVES: To estimate the size of illegal tobacco trade and consumption and assess the impact of tobacco tax on the illicit tobacco market in New Zealand (NZ). METHODS: Data on the import and seizure of legal and illegal tobacco in NZ was obtained from NZ Customs. Previous literature was used to calculate interception rates of illegal tobacco being smuggled and grown in NZ. Annual tobacco returns figures, obtained via the NZ Ministry of Health, were analysed to assess the market dynamics of legal tobacco products. RESULTS: This study found that illicit tobacco constituted 1.8-3.9% of total national tobacco consumption in NZ in 2013. This represents a minor increase compared to previous estimates from 2007-09, suggesting that tax increases enacted by the NZ Government since 2010 have had a minimal impact on encouraging the use and procurement of illicit tobacco. CONCLUSIONS: The results highlight a slight rise in small-scale tobacco smuggling through ports and mail centres. However, tobacco returns figures show that current tobacco tax policy has forced manufacturers to focus on the production of cheap legal tobacco products, directly competing with and undercutting the demand for illicit tobacco products. At the same time, locally grown illicit tobacco continues to remain a small, isolated problem and, with recent cuts in duty free tobacco allowance, it is expected that overall illicit tobacco will remain a very small proportion of total tobacco consumption in NZ. PMID- 25827186 TI - Sociodemographic differences in the incidence of oropharyngeal and oral cavity squamous cell cancers in New Zealand. AB - OBJECTIVE: To determine whether the incidence of oropharyngeal and oral cavity squamous cell cancers differs by subsite, age, gender, ethnicity and social deprivation. METHODS: Using data from the New Zealand cancer registry, a retrospective review was undertaken of incident cases with a histological diagnosis of invasive squamous cell carcinoma (SCC) in the oral cavity or oropharynx. RESULTS: During the period 1981-2010, rates of oropharyngeal cancers (OPC) and oral cavity cancers (OCC) were higher among males and increased with age. The rapid rise in male OPCs was observed in those aged 40-49, 50-59, 60-69 and >=70 years old. Overall and by gender, Maori had higher OPC rates but lower OCC rates than European/other ethnicities, whereas the inverse was apparent among Pacific Peoples. An upward trend in OPC and OCC rates with increasing deprivation was observed both overall and by gender. CONCLUSIONS: The recent rapid rise in male oropharyngeal SCCs occurred primarily among those aged >=40 years old. IMPLICATIONS: Given oropharyngeal SCCs are more strongly associated with human papillomaviruses (HPV) than OCCs, OPC prevention may be enhanced through HPV vaccination and public health awareness. Clinically, as HPV-related OPCs have a better prognosis and response to radiotherapy, an improvement in survival rates can be predicted. PMID- 25827187 TI - Surveillance of injecting-related injury and diseases in people who inject drugs attending a targeted primary health care facility in Sydney's Kings Cross. AB - OBJECTIVE: This study examined the prevalence of injecting-related injuries and diseases (IRIDs) and associated risk factors among people who inject drugs (PWID) attending a primary health care facility in Sydney's Kings Cross. METHODS: We calculated prevalence of a wide range of IRIDs utilising data reported by 702 PWID who completed a clinician-administered survey at their first visit. Multivariable logistic regressions identified factors independently associated with at least one episode of: i) cutaneous and ii) non-cutaneous IRIDs. RESULTS: Lifetime prevalence of cutaneous IRIDs was 23%. Forty-two per cent of PWID with a history of abscess attended hospital at their most recent episode. Female gender, lifetime receptive syringe sharing (RSS), injecting while in custody, and ever injecting in places other than the arm were independently associated with reporting at least one episode of cutaneous IRIDs. Ever injecting in sites other than the arm, injecting for five or more years and lifetime history of RSS were independently associated with at least one episode of non-cutaneous IRIDs. CONCLUSIONS: IRIDs are a substantial health issue for PWID. Their ongoing surveillance is warranted particularly in primary care settings targeting PWID to inform prevention and early management, thus reducing complications that may require hospital admission. PMID- 25827188 TI - Severe traumatic brain injuries from motor vehicle-related events in New Caledonia: epidemiology, outcome and public health consequences. AB - OBJECTIVE: Traumatic brain injuries (TBI), which are mostly due to road traffic crash (RTC), are a major public health concern. This article describes the incidence, severity and outcome of TBI caused by RTC in New Caledonia over a five year period. METHODS: Data of all individuals admitted in intensive care unit with severe TBI (Glasgow Coma Scale score <=8 at admission) caused by RTC in New Caledonia from 2008 to 2012 were analysed. Causes and severity of trauma, demographic data, and short-term as well as last available long-term outcome of patients were analysed. Five types of road users were compared (car drivers, car passengers, motorcyclists, bicyclists and pedestrians). Outcome was defined according to the Glasgow Outcome Scale classification. RESULTS: A total of 109 patients were included in the study. The median age of patients was 24 [IQR18-33] years with a sex ratio of 2.8 (80 men/29 women). The rate of 44 among Melanesian males was two times higher that among 16 European males (22/100,000 people vs 11/100,000 people). The total survival at the Intensive Care Unit discharge (short-term outcome) was 84%, being the highest among passengers (88%) and the lowest among motorcyclists (69%). Of the patients tested for psychoactive substances, half tested positive. Lost to follow-up rate was 67%. CONCLUSION: Poor outcome occurs in patients with RTC-related TBI, with young Melanesian men being the most affected. Public health action should focus on this group using culturally appropriate messages. PMID- 25827189 TI - Disparities in hepatitis B vaccine funding in Australian jurisdictions: limiting access for priority populations. PMID- 25827192 TI - Retrospective analysis of community hospital red blood cell recovery procedures: improved utilization needed for effectiveness. AB - BACKGROUND: Perioperative blood recovery (PBR) is an important component of patient blood management. We analyzed our experience providing PBR for community hospitals to determine procedure types and clinical variables associated with efficacy and cost-effectiveness. STUDY DESIGN AND METHODS: PBR cases (>25,000) from January 2008 through December 2012 were analyzed. For each procedure type, the median number of returned red blood cell units (rRBCs) and ratio of cases with at least 1 to less than 1 rRBC unit were calculated. Clinical predictors of rRBC were identified by linear and logistic regression. RESULTS: The overall median rRBC was 0.29 units despite median estimated blood loss (EBL) of 350 mL. Only three of 31 common procedure types had >=1:<1 rRBC ratios near to or higher than 1. In nine of 31 common procedure types, at least 50% of cases had no rRBC return. Linear regression demonstrated significant association of rRBCs with increased EBL, longer operative duration, surgeon, PBR device type (autoLog vs. CS5), and decreasing age. EBL, autoLog use, high surgeon case volume, vascular procedures, and emergent versus elective procedures associated with higher odds of at least 1 rRBC. CONCLUSION: Discrepancy between rRBC and EBL and high percentages of cases with no rRBC suggests that PBR technique and case selection need optimization. Identification of procedure types and variables associated with PBR efficacy (>=1 rRBC) should improve utilization of PBR. Association of autoLog use with higher rRBC warrants further investigation. PMID- 25827193 TI - Excision of the seminal vesicles for locally advanced and recurrent rectal and sigmoid cancer. AB - BACKGROUND: This study aims to define the clinical and oncological outcome of 'en bloc' excision of the seminal vesicles for locally advanced and recurrent tumours of the sigmoid and rectum. METHODS: Eight patients were identified from a prospective colorectal cancer database at a tertiary centre as having undergone excision of the seminal vesicles in continuity with a locally advanced or recurrent sigmoid or rectal adenocarcinoma. The presentation, operative details, histopathology, oncological outcome and morbidity of the procedure were assessed. RESULTS: Three patients were referred with recurrent tumours related to an anastomosis and five had a locally advanced sigmoid or rectal cancer. The need for resection of the seminal vesicles was determined from the preoperative pelvic magnetic resonance imaging scan or from an intraoperative finding of loss of the plane of dissection anterior to Denonvilliers' fascia. Restorative resection was achieved in all three patients where the primary tumour was located in the sigmoid or rectosigmoid, while all five patients with a rectal tumour had a permanent stoma. After a median follow-up of 43 months, seven patients are alive and disease-free and one patient has died of distant metastases. No patient has suffered a local recurrence. All five patients who were sexually active before surgery suffered from post-operative impotence. Two patients had temporary urinary retention with overflow. CONCLUSIONS: In carefully selected patients with locally advanced or recurrent rectal and sigmoid cancers that are attached to the seminal vesicles, en-bloc excision confers excellent local control but is associated with a high rate of sexual morbidity. PMID- 25827194 TI - Diabetes Mellitus in Patients Presenting with Cardiovascular Events: Descriptive Analysis from a Tertiary Heart Hospital Over a 22-year Period. AB - BACKGROUND: Diabetes mellitus (DM) remains a health care challenge worldwide. We evaluated the trends and outcome of DM in patients presenting with cardiovascular diseases (CVD) over a 22-year period in Qatar. METHODS AND RESULTS: A retrospective analysis was performed between 1991 and 2012, including 48,803 patients admitted to the tertiary Heart Hospital (HH). The average CVD hospitalization rate was 37 admissions per 10,000 people, of which, 2 out of 5 patients had DM. Diabetic males were 6 years younger than females. DM was more prevalent in Arabs (68 vs. 32%), but its burden showed a decreasing trend over time compared with South Asians. More diabetics presented with ST-elevation myocardial infarction (47.5 vs. 22.7%), which tended to occur 8 years earlier compared with heart failure. Over the study period, beta-blocker use increased substantially (from 10 to 71%). However, angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) were underutilized (from 30 to 56%). There were 4.4 deaths per 100 CVD admissions, which is equivalent to 97 deaths per year. Of this, 52% had DM (2.3 deaths per 100 CVD admissions). The overall case fatality rate (CFR) of DM was 5.6%. Diabetic Asian patients died 9 years earlier than diabetic Arabs at the HH. Multivariate regression analysis revealed that predictors of mortality in DM patients in the HH included lack of beta-blocker use (OR 4.35; 95% CI: 0.20 - 0.27), lack of ACEI/ARBs use (OR 3.58; 95% CI: 0.23 - 0.32), myocardial infarction (OR 3.20; 95% CI: 2.77 - 3.68), lack of aspirin use (OR 2.56; 95% CI: 0.34 - 0.45), congestive heart failure (OR 1.75; 95% CI: 1.50 - 2.04) and age (OR 1.03; 95% CI: 1.02 - 1.04) (P=0.001 for all). CONCLUSION: DM remains a healthcare challenge in Qatar. Although the admission rate of diabetic patients is increasing at the HH, the mortality rate is decreasing. The use of evidence-based medication is still far from the guideline recommendation; however, it has substantially improved. The lack of evidence based CVD medications in diabetic patients was associated with an increased mortality up to 4-fold in the HH. Moreover, there is a need to enhance public awareness regarding CVD risk factors and DM through education programs for the adoption of healthier lifestyles and nutrition. Great efforts are needed for more efficient primary and secondary prevention strategies in diabetic patients. PMID- 25827195 TI - Is Targeting microRNAs the Philosopher's Stone for Vascular Disease? AB - MicroRNAs (miRs) are small non-coding regulatory RNAs that control gene expression. They are involved in the pathogenesis of several diseases, including vascular and cardiac diseases. Their involvement is related to alterations of lipid metabolism, endothelial dysfunction, vascular smooth muscle cell phenotype, atherosclerosis-related low-grade inflammation of the arteries, cardiac hypertrophy or remodelling and heart failure. The manipulation of miRs may eventually be used to prevent or treat vascular or cardiac disease. Available drugs (some statins and renin-angiotensin-system inhibitors, alone or in combination) have beneficial off-target effects mediated through miRs; thus, these drugs may have advantages over other regimens. Inhibition of overexpression of "unfavourable" miRs can be potentially accomplished by silencing them with antisense oligonucleotides, masking, sponges, erasers or decoys. In contrast, down-regulation of "protective" miRs can be tackled by the administration of miR mimics. These approaches may represent a new therapeutic approach to vascular disease; miR manipulation research started recently and is developing rapidly. There is still a long way to go before clinical implementation; at present only one study is in phase II. Thus, the therapeutic manipulation of miRs is not yet the philosopher stone for the prevention or treatment of vascular or cardiac diseases. More research is needed. PMID- 25827196 TI - Genomic Research in Postmenopausal Hypertension. PMID- 25827197 TI - Editorial Comment from Dr Oh-oka to Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo. PMID- 25827198 TI - Intrabronchial Microdialysis: Effects of Probe Localization on Tissue Trauma and Drug Penetration into the Pulmonary Epithelial Lining Fluid. AB - Recent intrabronchial microdialysis data indicate that the respiratory epithelium is highly permeable to drugs. Of concern is whether intrabronchial microdialysis disrupts the integrity of the respiratory epithelium and thereby alters drug penetration into the pulmonary epithelial lining fluid (PELF). The objective of this study was to investigate the effect of intrabronchial microdialysis on the integrity of the bronchial epithelium. Microdialysis sampling in PELF in proximal (n = 4) and distal bronchi (n = 4) was performed after intravenous inulin and florfenicol administration in anaesthetized pigs. Inulin was used as a marker molecule of permeability of the epithelium, and florfenicol was used as test drug. Bronchial tissue was examined by histopathology (distal and proximal bronchi) and gene expression analysis (RT-qPCR, proximal bronchi) at the termination of the experiment (6.5 hr). The microdialysis probe caused overt tissue trauma in distal bronchi, whereas no histopathological lesions were observed in proximal bronchi. A moderate up-regulation of the pro-inflammatory cytokines IL1B, IL6 and acute-phase reactant serum amyloid A was seen in proximal bronchi surrounding the microdialysis probes suggesting initiation of an inflammatory response. The observed up-regulation is considered to have limited impact on drug penetration during short-term studies. Inulin penetrated the respiratory epithelium in both proximal and distal bronchi without any correlation to histopathological lesions. Likewise, florfenicol penetration into PELF was unaffected by bronchial histopathology. However, this independency of pathology on drug penetration may not be valid for other antibiotics. We conclude that short-term microdialysis drug quantification can be performed in proximal bronchi without disruption of tissue integrity. PMID- 25827199 TI - Evaluation of the filling ability of artificial lateral canals using calcium silicate-based and epoxy resin-based endodontic sealers and two gutta-percha filling techniques. AB - AIM: To evaluate the ability of a calcium silicate-based sealer (iRoot SP) and an epoxy resin-based sealer (Topseal) using two gutta-percha filling techniques to fill artificial lateral canals (ALCs). METHODOLOGY: Seventy single-rooted human teeth were selected. Ten of these were used to obtain pilot data. Three ALCs were produced on mesial and distal surfaces of each root, one in each third, using size 10 engine reamers. The roots were randomly assigned to four experimental groups according to the filling technique and sealer used: 1, cold gutta-percha (single-point technique) with iRoot SP (SP-iR); 2, cold gutta-percha (single point technique) with Topseal (SP-T); 3, continuous wave of condensation technique with iRoot SP (CWC-iR); and 4, continuous wave of condensation technique with Topseal (CWC-T). Digital periapical radiographs were taken. After the sealer had set, the roots were demineralized, cleared in methyl-salicylate and examined under a stereomicroscope. The depth of penetration of sealer and/or gutta-percha into the ALC was scored using a 5-point system, conducting an analysis on four surfaces. Filling scores of 0-1 were considered not acceptable, whilst scores of 2-4 were considered acceptable. Pearson's chi-square test was used to compare the experimental groups (P < 0.05). RESULTS: CWC-T was associated with the highest acceptable filling (57.8%), followed by CWC-iR (53.3%), SP-T (48.9%) and SP-iR (36.7%). Only when SP-iR was compared to the other groups, was the difference significant (P < 0.05). The apical third was associated with the lowest acceptable filling (37.5%). It was followed, in ascending order, by the middle (51.6%) and coronal thirds (58.3%). These differences were significant only when the apical thirds were compared to the other root thirds (P < 0.05). CONCLUSION: The calcium silicate-based sealer with continuous wave of condensation was more effective in artificial filling lateral canals than the single-point technique. The epoxy resin-based sealer with both filling techniques was effective in artificial filling lateral canals. PMID- 25827200 TI - Treatment of face and scalp solar (actinic) keratosis with daylight-mediated photodynamic therapy is possible throughout the year in Australia: Evidence from a clinical and meteorological study. AB - BACKGROUND/OBJECTIVES: Solar (actinic) keratosis (AK) is an emergent concern worldwide and is associated with an increased risk of development of non-melanoma skin cancer, especially squamous cell carcinoma. Daylight-mediated photodynamic therapy (DL-PDT) using methyl aminolaevulinate cream has proved to be an effective, nearly painless, and more convenient alternative to conventional PDT for the treatment of AK. In a phase III, randomised, controlled trial performed in Australia, the mean irradiance (light intensity) received by patients during DL-PDT treatment, assessed via a spectroradiometer, was 305 W/m(2) (min. 40 to max. 585 W/m(2) ) with similar efficacy irrespective of intensity or dose. The objective of the present meteorological study was to assess the suitability of natural daylight to perform DL-PDT for the treatment of face and scalp AK during different periods of the year and different geographical locations and latitudes across Australia. METHODS: To determine daylight irradiance during a complete year in eight different geographical locations throughout Australia, we used meteorological software (Meteonorm, Meteotest, Bern, Switzerland), and available solar radiation and weather data from 1986-2005. RESULTS: The average daily irradiance remained within the levels (40-585 W/m(2) ) measured during the clinical DL-PDT study in Australia, throughout the year and in all geographical locations investigated (yearly average from Darwin 548 W/m(2) to Hobart 366 W/m(2) ). CONCLUSIONS: DL-PDT for the treatment of face and scalp AK in Australia can be performed effectively throughout the entire year as long as weather conditions permit daylight exposure and allow participants to remain under direct light for 2 h. PMID- 25827201 TI - Lead-free ZnSnO3/MWCNTs-based self-poled flexible hybrid nanogenerator for piezoelectric power generation. AB - A high-performance flexible piezoelectric hybrid nanogenerator (HNG) based on lead-free perovskite zinc stannate (ZnSnO3) nanocubes and polydimethylsiloxane (PDMS) composite with multiwall carbon nanotubes (MWCNTs) as supplement filling material is demonstrated. Even without any electrical poling treatment, the HNG possesses an open-circuit voltage of 40 V and a short-circuit current of 0.4 MUA, respectively, under repeated human finger impact. It has been demonstrated that the output volume power density of 10.8 MUW cm(-3) from a HNG can drive several colour light emitting diodes (LEDs) and a charge capacitor that powers up a calculator, indicating an effective means of energy harvesting power source with high energy conversion efficiency (~1.17%) for portable electronic devices. PMID- 25827202 TI - Spatial soil heterogeneity has a greater effect on symbiotic arbuscular mycorrhizal fungal communities and plant growth than genetic modification with Bacillus thuringiensis toxin genes. AB - Maize, genetically modified with the insect toxin genes of Bacillus thuringiensis (Bt), is widely cultivated, yet its impacts on soil organisms are poorly understood. Arbuscular mycorrhizal fungi (AMF) form symbiotic associations with plant roots and may be uniquely sensitive to genetic changes within a plant host. In this field study, the effects of nine different lines of Bt maize and their corresponding non-Bt parental isolines were evaluated on AMF colonization and community diversity in plant roots. Plants were harvested 60 days after sowing, and data were collected on plant growth and per cent AMF colonization of roots. AMF community composition in roots was assessed using 454 pyrosequencing of the 28S rRNA genes, and spatial variation in mycorrhizal communities within replicated experimental field plots was examined. Growth responses, per cent AMF colonization of roots and AMF community diversity in roots did not differ between Bt and non-Bt maize, but root and shoot biomass and per cent colonization by arbuscules varied by maize cultivar. Plot identity had the most significant effect on plant growth, AMF colonization and AMF community composition in roots, indicating spatial heterogeneity in the field. Mycorrhizal fungal communities in maize roots were autocorrelated within approximately 1 m, but at greater distances, AMF community composition of roots differed between plants. Our findings indicate that spatial variation and heterogeneity in the field has a greater effect on the structure of AMF communities than host plant cultivar or modification by Bt toxin genes. PMID- 25827203 TI - Value of the "spine sign" on lateral chest views. AB - OBJECTIVE: To determine the performance of the spine sign in detecting lower chest abnormalities in the lateral view. METHODS: This retrospective study included 200 patients who had undergone lateral view and CT scans of the chest within 1 week. Two radiologists independently read the lateral views, and a third radiologist, blinded to the aim of the study, read the scans. The spine sign was considered as positive if the progressive increase in lucency of the vertebral bodies was altered. Interreader agreement was calculated through k-statistics. Sensitivity, specificity, positive- and negative-predictive values, and accuracy were calculated compared with CT. RESULTS: Agreements between readers ranged from 0.12 to 0.68. Positive spine sign could appear in two ways: absent or inversed progressive increase in lucency of the vertebral bodies. Sensitivity, specificity, positive- and negative-predictive values, and accuracy were, respectively, 60% and 70%; 64% and 84%; 91% and 97%; 19% and 29%; and 61% and 72% for each reader (p-value ranging from 0.026 to 0.196). Abnormalities most frequently associated with positive spine sign were plate-like atelectasis, ground-glass opacity, pleural effusion and consolidation. CONCLUSION: The spine sign can present as an absent or inversed progressive increase in lucency of the vertebral bodies. It has a moderate sensitivity but a good positive-predictive value, so it can be useful especially when it appears as inversed progressive increase in lucency of the vertebral bodies to detect various abnormalities usually identifiable on chest radiographs. ADVANCES IN KNOWLEDGE: On lateral chest radiographs, the spine sign is useful to detect lower chest abnormalities and is related to various underlying abnormalities and is, per se, non-specific. PMID- 25827204 TI - Potential of combining iterative reconstruction with noise efficient detector design: aggressive dose reduction in head CT. AB - OBJECTIVE: With further increase of CT numbers and their dominant contribution to medical exposure, there is a recent quest for more effective dose control. While reintroduction of iterative reconstruction (IR) has proved its potential in many applications, a novel focus is placed on more noise efficient detectors. Our purpose was to assess the potential of IR in combination with an integrated circuit detector (ICD) for aggressive dose reduction in head CT. METHODS: Non contrast low-dose head CT [190 mAs; weighted volume CT dose index (CTDIvol), 33.2 mGy] was performed in 50 consecutive patients, using a new noise efficient detector and IR. Images were assessed in terms of quantitative and qualitative image quality and compared with standard dose acquisitions (320 mAs; CTDIvol, 59.7 mGy) using a conventional detector and filtered back projection. RESULTS: By combining ICD and IR in low-dose examinations, the signal to noise was improved by about 13% above the baseline level in the standard-dose control group. Both, contrast-to-noise ratio (2.02 +/- 0.6 vs 1.88 +/- 0.4; p = 0.18) and objective measurements of image sharpness (695 +/- 84 vs 705 +/- 151 change in Hounsfield units per pixel; p = 0.79) were fully preserved in the low-dose group. Likewise, there was no significant difference in the grading of several subjective image quality parameters when both noise-reducing strategies were used in low-dose examinations. CONCLUSION: Combination of noise efficient detector with IR allows for meaningful dose reduction in head CT without compromise of standard image quality. ADVANCES IN KNOWLEDGE: Our study demonstrates the feasibility of almost 50% dose reduction in head CT dose (1.1 mSv per scan) through combination of novel dose-reducing strategies. PMID- 25827205 TI - CT and MRI findings of radiation-induced external auditory canal carcinoma in patients with nasopharyngeal carcinoma after radiotherapy. AB - OBJECTIVE: To summarize the radiological and clinical features of radiation induced external auditory canal carcinomas (RIEACCs) in patients with nasopharyngeal carcinomas (NPCs) after radiation therapy. METHODS: CT, MRI and clinical features in 16 patients with histologically proven RIEACCs were retrospectively reviewed. There were 2 females and 14 males, with a median age of 52.5 years at the time of diagnosis of RIEACC. Imaging parameters including lesion extent, size, margin, shape, bone destruction, adjacent structure invasion, density/signal intensity, and pattern and degree of enhancement were assessed. Clinical features including clinical staging, histological type, treatment and radiation dose (RD) of primary NPC as well as the histological type, staging of radiation-induced tumour and the latent period between NPC and RIT were recorded. RESULTS: All patients had a single RIEACC. The lesions had a size of 3.5 +/- 1.4 cm and were localized (n = 7) or extensive (n = 9). Most of the lesions were partially or ill defined with an irregular shape and had an intermediate density/signal pattern and moderate homogeneous enhancement. The latent period of RIEACCs ranged from 10 to 20 years in nine patients with a RD of 68-70 Gy; from 2 to 10 years in five patients with a RD of 68-74 Gy; and more than 20 years in two patients with a RD of 70 or 72 Gy. CONCLUSION: An external auditory canal (EAC) mass with homogeneous, intermediate CT density or signal intensity in patients with NPC after radiotherapy is highly suggestive of RIEACC, which should be included in the routine surveillance for patients with NPC after radiotherapy. ADVANCES IN KNOWLEDGE: RIEACCs could occur as short as 2 years after radiotherapy in patients with NPC and have distinct features from otitis media and sarcomas. This EAC malignancy should be included in routine surveillance for patients with NPC after radiotherapy. PMID- 25827206 TI - Strain elastography features of epidermoid tumours in superficial soft tissue: differences from other benign soft-tissue tumours and malignant tumours. AB - OBJECTIVE: We evaluated ultrasonographic features of superficial epidermoid tumour with a focus on strain elastography (SE) features that will help in the differential diagnosis of epidermoid tumour from other benign and malignant soft tissue tumours. METHODS: We retrospectively evaluated ultrasonographic and SE data of 103 surgically confirmed superficial soft-tissue tumours and tumour-like lesions: 29 cases of epidermoid tumour, 46 cases of other benign tumours and 28 cases of malignant tumour. SE and B-mode imaging were performed at the same time. SE characteristics were assigned into four grades (1-4) according to their elasticity. Interobserver agreement for the four SE scores between the two radiologists was analysed using kappa statistics. We classified each SE finding as a hard lesion (SE Score 3-4) or soft lesion (SE Score 1-2) and compared these findings using the chi(2) test to identify whether a significant difference in mass hardness existed among epidermoid tumour, other benign tumour and malignant tumour. RESULTS: Overall interobserver agreement according to the four SE scores was moderate (kappa = 0.540), and overall agreement for the hardness [soft (Score 1-2) or hard (Score 3-4)] was almost perfect (kappa = 0.825). Malignant tumours showed higher SE scores (3-4, hard nature) than did epidermoid tumour or other benign soft-tissue tumours. There were no differences in SE score between epidermoid tumour and other benign tumours. CONCLUSION: Superficial epidermoid tumour exhibits a softer nature than does malignant tumour but does not have a different SE pattern from other benign tumours. ADVANCES IN KNOWLEDGE: SE features of epidermoid tumour might be helpful in differentiating from other benign and malignant tumours. PMID- 25827207 TI - Using a commercial software package to support treatment planning peer review activities in small radiotherapy departments. AB - OBJECTIVE: To implement peer review of radiotherapy treatment planning processes between two geographically separated hospitals with different treatment planning systems. METHODS: The feasibility of using Microsoft((r)) Lync 2013TM, available in one of the hospitals, was investigated to determine its utility in sharing radiotherapy treatment planning information between hospitals with small numbers of clinical oncologists available to participate in peer review of treatment plans. RESULTS: Microsoft Lync 2013 has been successfully used to implement remote, real-time review of all aspects of treatment planning, including contours, beam arrangements, isodose distributions and dose-volume histograms. CONCLUSION: A reliable system for remote, real-time peer review of radiotherapy treatment plans has been implemented between two geographically distant hospitals using Microsoft Lync 2013. Interest in use of the system is developing regionally. ADVANCES IN KNOWLEDGE: This work appears to be the first to describe the use of Microsoft Lync 2013 in this area and demonstrates that smaller radiotherapy centres separated by distance can share clinical and scientific resources to participate in improved peer review processes, in line with recent UK national guidance. PMID- 25827208 TI - Chemoradiation for gastric cancer: controversies, updates and novel techniques. AB - The INT0116 trial established the role of adjuvant chemoradiation (CRT) in the multidisciplinary approach to the management of locally advanced gastric cancer. However, whether adjuvant CRT is indispensable for patients undergoing D2 dissection remains undefined. The adjuvant chemoradiation therapy in stomach cancer (ARTIST) trial, which was designed to compare adjuvant chemotherapy to CRT, failed to demonstrate differences in disease-free and overall survival in the whole study group; however, subgroup analysis indicated that patients with lymph node metastasis may benefit from additional radiation. A follow-up ARTIST II trial is currently under way. The efficacy of adjuvant CRT remains controversial because of variation among studies in the inclusion criteria and treatment delivery methods; however, the identification of patients who would benefit from CRT is critical. Advanced radiotherapy techniques such as intensity modulated radiotherapy protect normal tissues via motion management and decreased radiation-induced toxicity and contribute to plan optimization. Further studies integrating clinical and molecular factors as well as neoadjuvant CRT are warranted. PMID- 25827210 TI - Perforation of gastrointestinal tract by poorly conspicuous ingested foreign bodies: radiological diagnosis. AB - Perforation of gastrointestinal (GI) tract by ingested bone fragments, toothpicks and dentures is rare but remains an important life-threatening condition, and the outcomes are poorer when the diagnosis is delayed. Invariably, clinical and radiographic diagnosis is difficult as most patients will have no recollection of ingesting a foreign body, whereas these subtle objects are often not visible on radiographs. In search for the diagnosis, CT is the modality of choice, but ultrasound imaging may be first requested in patients presenting with symptoms of acute appendicitis, cholecystitis, pyelonephritis or pelvic inflammatory disease when an ingested foreign body is not considered. Although ultrasound has limited value in depicting a foreign body, it can frequently uncover secondary signs of perforation. However, the rarity of this condition combined with non-specific clinical presentation and the propensity of these small perforating objects to be subtle makes establishing the correct diagnosis by the radiologist challenging. Therefore, understanding of the appearances of GI perforation seen on CT images or general abdominal ultrasound will aid the radiologist in the diagnosis of this important yet often unsuspected condition. This will lead to earlier diagnosis and surgical management. In this article, we illustrate the spectrum of CT, radiographic and ultrasound imaging features seen in GI perforation caused by swallowed bone fragments, toothpicks, cocktail sticks and dentures. PMID- 25827209 TI - Functional imaging for radiotherapy treatment planning: current status and future directions-a review. AB - In recent years, radiotherapy (RT) has been subject to a number of technological innovations. Today, RT is extremely flexible, allowing irradiation of tumours with high doses, whilst also sparing normal tissues from doses. To make use of these additional degrees of freedom, integration of functional image information may play a key role (i) for better staging and tumour detection, (ii) for more accurate RT target volume delineation, (iii) to assess functional information about biological characteristics and individual radiation resistance and (iv) to apply personalized dose prescriptions. In this article, we discuss the current status and future directions of different clinically available functional imaging modalities; CT, MRI, positron emission tomography (PET) as well as the hybrid imaging techniques PET/CT and PET/MRI and their potential for individualized RT. PMID- 25827211 TI - Isolated MYC cytogenetic abnormalities in diffuse large B-cell lymphoma do not predict an adverse clinical outcome. AB - In this study, we investigated the significance of MYC, BCL2 and BCL6 gene abnormalities in a cohort of 205 diffuse large B-cell lymphoma (DLBCL) patients studied by conventional and/or fluorescence in situ hybridization cytogenetic analysis. Combining these methods, 172 cases (84%) were classified as MYC-, 17 (8%) were MYC+/BCL2-/BCL6-, and 16 (8%) were double/triple-hit lymphomas (i.e. MYC+/BCL2+, MYC+/BCL6+, or MYC+/BCL2+/BCL6+). We found a significant difference in event-free survival (EFS) among the three groups (p = 0.02), with the double/triple-hit group having the worst EFS. Patients who were MYC+, but BCL2- and BCL6-, had the best EFS. We conclude that patients with MYC+ DLBCL, but without BCL2 or BCL6 abnormalities, do not have a worse outcome when compared to those who are MYC-. However, patients with double/triple-hit DLBCL have a very poor outcome and should be treated with aggressive or novel therapies. PMID- 25827212 TI - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) with concurrent high grade component at diagnosis: clinico-pathologic features and treatment strategy. PMID- 25827213 TI - Invasive Saccharomyces cerevisiae in a liver transplant patient: case report and review of infection in transplant recipients. AB - Saccharomyces cerevisiae, an ascosporogenous yeast commonly used in the production of food, is an emerging infection in immunocompromised patients. We report the case of a 60-year-old man whose orthotopic liver transplant was complicated by S. cerevisiae fungemia and peritoneal abscess, successfully treated with caspofungin and drainage. We also review the literature of invasive saccharomycoses in recipients of hematologic and solid organ transplants. PMID- 25827214 TI - Enhanced Indirect Photochemical Transformation of Histidine and Histamine through Association with Chromophoric Dissolved Organic Matter. AB - Photochemical transformations greatly affect the stability and fate of amino acids (AAs) in sunlit aquatic ecosystems. Whereas the direct phototransformation of dissolved AAs is well investigated, their indirect photolysis in the presence of chromophoric dissolved organic matter (CDOM) is poorly understood. In aquatic systems, CDOM may act both as sorbent for AAs and as photosensitizer, creating microenvironments with high concentrations of photochemically produced reactive intermediates, such as singlet oxygen (1O2). This study provides a systematic investigation of the indirect photochemical transformation of histidine (His) and histamine by 1O2 in solutions containing CDOM as a function of solution pH. Both His and histamine showed pH-dependent enhanced phototransformation in the CDOM systems as compared to systems in which model, low-molecular-weight 1O2 sensitizers were used. Enhanced reactivity resulted from sorption of His and histamine to CDOM and thus exposure to elevated 1O2 concentrations in the CDOM microenvironment. The extent of reactivity enhancement depended on solution pH via its effects on the protonation state of His, histamine, and CDOM. Sorption enhanced reactivity was independently supported by depressed rate enhancements in the presence of a cosorbate that competitively displaced His and histamine from CDOM. Incorporating sorption and photochemical transformation processes into a reaction rate prediction model improved the description of the abiotic photochemical transformation rates of His in the presence of CDOM. PMID- 25827215 TI - New insights into hydrosilylation of unsaturated carbon-heteroatom (C?O, C?N) bonds by rhenium(V)-dioxo complexes. AB - The hydrosilylation of unsaturated carbon-heteroatom (C?O, C?N) bonds catalyzed by high-valent rhenium(V)-dioxo complex ReO2I(PPh3)2 (1) were studied computationally to determine the underlying mechanism. Our calculations revealed that the ionic outer-sphere pathway in which the organic substrate attacks the Si center in an eta(1)-silane rhenium adduct to prompt the heterolytic cleavage of the Si-H bond is the most energetically favorable process for rhenium(V)-dioxo complex 1 catalyzed hydrosilylation of imines. The activation energy of the turnover-limiting step was calculated to be 22.8 kcal/mol with phenylmethanimine. This value is energetically more favorable than the [2 + 2] addition pathway by as much as 10.0 kcal/mol. Moreover, the ionic outer-sphere pathway competes with the [2 + 2] addition mechanism for rhenium(V)-dioxo complex 1 catalyzing the hydrosilylation of carbonyl compounds. Furthermore, the electron-donating group on the organic substrates would induce a better activity favoring the ionic outer sphere mechanistic pathway. These findings highlight the unique features of high valent transition-metal complexes as Lewis acids in activating the Si-H bond and catalyzing the reduction reactions. PMID- 25827216 TI - Thoracolumbar injury classification and severity score. PMID- 25827217 TI - Associations between major fatty acids in plant oils fed to dairy goats and C18 isomers in milk fat. AB - Relationships between fatty acids (FAs) in plant oils included in goat diets and milk fat C18 isomers were determined by Principal Factor Analysis (PFA). The three first principal factors (PF1, PF2 and PF3) accounted for 64.5% of the total variation in milk FAs contents. Fatty acids with a double bond at carbons 13, 14, 15 or 16 had high (>0.6) and positive loadings for PF1, trans-4 to trans-8 C18:1 for PF2, whereas trans-10 C18:1, trans-11 C18:1 and cis-9 trans-11 C18:2 showed high and positive loadings for PF3. Pearson's correlations supported that PF1, PF2 and PF3 were related to alpha-linolenic, oleic and linoleic acid intakes, respectively. Our results show that the quantitatively main FAs in plant lipids supplemented to dairy ruminants are often the main cause of the observed changes in milk C18 isomer contents. However, sometimes the observed changes are caused, or at least are influenced, by other FAs present in lower quantities in the plant lipids. Thus, using mixtures of plant oils with differently unsaturated main FAs could be a way of tailoring milk fat composition to a pre-designed pattern. PMID- 25827218 TI - Biodiversity of Lactobacillus helveticus bacteriophages isolated from cheese whey starters. AB - Twenty-one Lactobacillus helveticus bacteriophages, 18 isolated from different cheese whey starters and three from CNRZ collection, were phenotypically and genetically characterised. A biodiversity between phages was evidenced both by host range and molecular (RAPD-PCR) typing. A more detailed characterisation of six phages showed similar structural protein profiles and a relevant genetic biodiversity, as shown by restriction enzyme analysis of total DNA. Latent period, burst time and burst size data evidenced that phages were active and virulent. Overall, data highlighted the biodiversity of Lb. helveticus phages isolated from cheese whey starters, which were confirmed to be one of the most common phage contamination source in dairy factories. More research is required to further unravel the ecological role of Lb. helveticus phages and to evaluate their impact on the dairy fermentation processes where whey starter cultures are used. PMID- 25827219 TI - Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats. AB - Glucagon-like peptide-1 (GLP-1) is secreted by distal enteroendocrine cells in response to luminal nutrients, and exerts insulinotropic and anorexigenic effects. Although GLP-1 secretory responses under established obese or diabetic conditions have been studied, it has not been investigated whether or how postprandial GLP-1 responses were affected during the progression of diet-induced obesity. In the present study, a meal tolerance test was performed every week in rats fed a high-fat and high-sucrose (HF/HS) diet to evaluate postprandial glycaemic, insulin and GLP-1 responses. In addition, gastric emptying was assessed by the acetaminophen method. After 8 weeks of HF/HS treatment, portal vein and intestinal mucosa were collected to examine GLP-1 production. Postprandial glucose in response to normal meal ingestion was increased in the HF/HS group within 2 weeks, and its elevation gradually returned close to that of the control group until day 50. Slower postprandial gastric emptying was observed in the HF/HS group on days 6, 13 and 34. Postprandial GLP-1 and insulin responses were increased in the HF/HS group at 7 weeks. Higher portal GLP-1 and insulin levels were observed in the HF/HS group, but mucosal gut hormone mRNA levels were unchanged. These results revealed that the postprandial GLP-1 response to meal ingestion is enhanced during the progression of diet-induced glucose intolerance and obesity in rats. The boosted postprandial GLP-1 secretion by chronic HF/HS diet treatment suggests increased sensitivity to luminal nutrients in the gut, and this may slow the establishment of glucose intolerance and obesity. PMID- 25827220 TI - The association between cardiovascular risk and cardiovascular magnetic resonance measures of fibrosis: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Risk scores for cardiovascular disease (CVD) are in common use to integrate multiple cardiovascular risk factors in order to identify individuals at greatest risk for disease. The purpose of this study was to determine if individuals at greater cardiovascular risk have T1 mapping indices by cardiovascular magnetic resonance (CMR) indicative of greater myocardial fibrosis. METHODS: CVD risk scores for 1208 subjects (men, 50.8%) ages 55-94 years old were evaluated in the Multiethnic Study of Atherosclerosis (MESA) at six centers. T1 times were determined at 1.5Tesla before and after gadolinium administration (0.15 mmol/kg) using a modified Look-Locker pulse sequence. The relationship between CMR measures (native T1, 12 and 25 minute post-gadolinium T1, partition coefficient and extracellular volume fraction) and 14 established different cardiovascular risk scores were determined using regression analysis. Bootstrapping analysis with analysis of variance was used to compare different CMR measures. CVD risk scores were significantly different for men and women (p < 0.001). RESULTS: 25 minute post gadolinium T1 time showed more statistically significant associations with risk scores (10/14 scores, 71%) compared to other CMR indices (e.g. native T1 (7/14 scores, 50%) and partition coefficient (7/14, 50%) in men. Risk scores, particularly the new 2013 AHA/ASCVD risk score, did not correlate with any CMR fibrosis index. CONCLUSIONS: Men with greater CVD risk had greater CMR indices of myocardial fibrosis. T1 times at greater delay time (25 minutes) showed better agreement with commonly used risk score indices compared to ECV and native T1 time. CLINICAL TRIAL REGISTRATION: http://www.mesa nhlbi.org/, NCT00005487. PMID- 25827221 TI - Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion. AB - In the Netherlands, the majority of hereditary paragangliomas (PGL) is caused by SDHD, SDHB and SDHAF2 mutations. Founder mutations in SDHD are particularly prevalent, but several SDHB founder mutations have also been described. Here, we describe an extended PGL family with a Dutch founder mutation in SDHB, c.201 4429_287-933del. The proband presented with apparently sporadic head and neck paraganglioma at advanced age. Subsequently, evaluation of the family identified several unaffected mutation carriers, asymptomatic and symptomatic PGL patients, and patients presenting with early-onset malignant pheochromocytoma. The calculated penetrance of the SDHB mutation in this kindred is lower than the risk suggested for SDHB mutations in the literature. This may represent a characteristic of this particular SDHB mutation, but may also be a reflection of the inclusion of relatively large numbers of asymptomatic mutation carriers in this family and adequate statistical correction for ascertainment bias. The low penetrance of SDHB mutations may obscure the hereditary nature of SDHB-linked disease and is important in the counseling of SDHB-linked patients. Risk estimates should preferably be based on the specific mutation involved. PMID- 25827222 TI - Urinary screening and urinary abnormalities in 3-year-old children in Japan. AB - In Japan, urinary screening for preschool children has been obligatory since 1961. The system was reconsidered and has been under review since 2012, because many problems in the system had been identified, and its usefulness was uncertain. In the process, the following were analyzed: (i) frequency of urinary abnormalities identified on screening; (ii) diseases identified from urinary abnormalities; (iii) clinical course of children found to have urinary abnormalities; and (iv) screening for asymptomatic urinary tract infection (UTI) as a way of screening for congenital anomalies of the kidney and urinary tract. A computerized literature search was conducted, and study reports issued by the Ministry of Health, Labour and Welfare study group, and data of Akita City and Chiba City were reviewed. The prevalence of abnormal results at the first urinalysis was high, but at the second urinalysis the prevalence decreased in the range 1/6-1/20. The prevalence of tentative diagnosis at the third urinalysis was similar to the school urinary screening results. Serious illness was not found in children who had hematuria alone. In contrast, diseases requiring immediate attention were found in children with proteinuria, although the prevalence of proteinuria was not high. The dipstick method for leukocyturia was inefficient. The importance of two consecutive urinalyses before detailed examination, the lack of usefulness of screening for hematuria in 3-year-old children, and the importance of proteinuria were confirmed. Screening for asymptomatic UTI using urinary leukocytes was very inefficient. PMID- 25827223 TI - Systematic review of electronic remote blood issue. AB - BACKGROUND AND OBJECTIVES: The implementation of electronic remote blood issue (ERBI) may provide safety and efficiency gains for transfusion medicine. This systematic review's objective was to assess whether ERBI affects incidents of adverse events, time taken for blood issue and delivery, and cross-match to transfusion ratios, among other measures of safety and efficiency. The review also sought to uncover barriers and facilitators of ERBI implementation. MATERIALS AND METHODS: We searched four aggregated electronic databases (Medline, EMBASE, CINAHL and BIOSIS) up to 19 July 2012, with an updated search performed on 5 March 2014 for studies on ERBI. No specific study design criteria were used in the initial inclusion due to the low number of studies on ERBI. RESULTS: A total of 4758 citations were initially identified; after 1844 duplicates were removed, 2612 citations were excluded on the basis of the abstract. Two reviewers evaluated a total of 302 full-text articles independently; of these, seven citations were eligible for inclusion. An updated search and the authors' own collections confirmed an additional five citations, totalling 13 citations and six studies within these. CONCLUSION: There is insufficient evidence to demonstrate whether ERBI significantly impacts safety and efficiency of blood transfusion and delivery processes. Rigorously designed studies to assess safety and efficiency outcomes are required using proxy or corollary measures. A number of positive results were reported, however, and most studies included suggestions for facilitating ERBI implementation. PMID- 25827224 TI - Variable presentation of anaplastic large-cell lymphoma in patients with breast implants. AB - BACKGROUND: Anaplastic large-cell lymphoma (ALCL) has recently been reported in women with breast implants. The incidence of breast implant-related ALCL is extremely rare and most surgeons would not expect to see this disease in their career. However, the senior author has had three women present to his practice with ALCL over a 2-year period. METHODS: The three patients and their presentation were reviewed to establish the presenting complaint in each case of subsequently diagnosed ALCL. Literature was reviewed to establish appropriate treatment protocols for any subsequent patients. RESULTS: The average time between first implant placement and presentation with breast implant-associated ALCL was 13.3 years (range: 10-16 years) and age at presentation was 49 years (range: 45-53 years). Each presentation was somewhat different, being a palpable mass, a painless seroma and a painful seroma. Both patients with seroma underwent ultrasound-guided aspiration of fluid which confirmed ALCL. All patients underwent implant removal and complete capsulectomy. The patient with a mass at presentation initially declined adjuvant treatment but subsequently developed an ALCL-associated seroma and was treated with surgery and post-operative chemotherapy. CONCLUSION: Patients with breast implant-associated ALCL can present with different clinical signs and symptoms. Late seroma is a relatively common presentation of breast implant-associated ALCL. While firm guidelines for the management of breast implant-related ALCL are lacking, we suggest that any late seroma in the absence of infection should be managed with aspiration and cytological analysis of the fluid. PMID- 25827225 TI - Time trends in the incidence, prevalence and age at diagnosis of asthma in children. AB - BACKGROUND: Current knowledge on the prevalence of asthma is mainly based on cross-sectional questionnaire data. Current population-based data on the incidence of asthma in children are scarce. OBJECTIVE: To study the incidence, prevalence, and age at diagnosis of asthma in children in the Netherlands over the study period 2000-2012. METHODS: A population-based cohort study was conducted in the Integrated Primary Care Information database. The cohort consisted of 176,516 children (379,536 personyears (PY) of follow-up), aged 5-18 years between 2000 and 2012. All medical records of children with physician diagnosed asthma were validated. Incidence rates, annual percent change (APC), and prevalence for asthma were calculated. Influence of age and gender on incidence rates and change in age at diagnosis were studied. RESULTS: We identified an asthma cohort of 14,303 children with 35,118 PY. The overall incidence rate was 6.7/1000 PY (95% CI, 6.45-6.97). Until 2008, the incidence rate was significantly increasing (APC 5.79 (95% CI 1.43-10.34); from 2008 onwards, a non-significant decrease was observed (APC -12.16 (95% CI -23.07 to 0.28). Incidence for girls was lower than for boys, this difference decreased with increasing age. (p < 0.001) Overall, the age at diagnosis increased over calendar time and was lower for boys. (linear trend p < 0.001). CONCLUSION: Our population-based cohort study observed an incidence rate of 6.7 per 1000 PY of physician-diagnosed asthma in children in the Netherlands over 2000-2012. The asthma incidence rate was increasing until 2008. Further studies are needed to confirm the decrease in asthma incidence rate from 2008 onwards. PMID- 25827226 TI - dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase epsilon variants. AB - Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) epsilon mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol epsilon depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Delta) suppresses the mutator phenotype of pol2-4 (encoding Pol epsilon proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol epsilon base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Delta) and radiation sensitive (Rad) 9 (rad9Delta), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Delta but not rad9Delta; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Delta pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Delta cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol epsilon mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy. PMID- 25827228 TI - Correction for Hoboth et al., Aged insulin granules display reduced microtubule dependent mobility and are disposed within actin-positive multigranular bodies. PMID- 25827227 TI - A comprehensive method for detecting ubiquitinated substrates using TR-TUBE. AB - The identification of substrates for ubiquitin ligases has remained challenging, because most substrates are either immediately degraded by the proteasome or processed by deubiquitinating enzymes (DUBs) to remove polyubiquitin. Although a methodology that enables detection of ubiquitinated proteins using ubiquitin Lys epsilon-Gly-Gly (diGly) remnant antibodies and MS has been developed, it is still insufficient for identification and characterization of the ubiquitin-modified proteome in cells overexpressing a particular ubiquitin ligase. Here, we show that exogenously expressed trypsin-resistant tandem ubiquitin-binding entity(ies) (TR-TUBE) protect polyubiquitin chains on substrates from DUBs and circumvent proteasome-mediated degradation in cells. TR-TUBE effectively associated with substrates ubiquitinated by an exogenously overexpressed ubiquitin ligase, allowing detection of the specific activity of the ubiquitin ligase and isolation of its substrates. Although the diGly antibody enabled effective identification of ubiquitinated proteins in cells, overexpression of an ubiquitin ligase and treatment with a proteasome inhibitor did not increase the level of diGly peptides specific for the ligase relative to the background level of diGly peptides, probably due to deubiquitination. By contrast, in TR-TUBE-expressing cells, the level of substrate-derived diGly peptides produced by the overexpressed ubiquitin ligase was significantly elevated. We developed a method for identifying the substrates of specific ubiquitin ligases using two enrichment strategies, TR-TUBE and diGly remnant antibodies, coupled with MS. Using this method, we identified target substrates of FBXO21, an uncharacterized F-box protein. PMID- 25827229 TI - Correction for Dillin, Profile of Kazutoshi Mori and Peter Walter, 2014 Lasker Basic Medical Research Awardees: The unfolded protein response. PMID- 25827230 TI - Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. AB - We compared whole-exome sequencing (WES) and whole-genome sequencing (WGS) in six unrelated individuals. In the regions targeted by WES capture (81.5% of the consensus coding genome), the mean numbers of single-nucleotide variants (SNVs) and small insertions/deletions (indels) detected per sample were 84,192 and 13,325, respectively, for WES, and 84,968 and 12,702, respectively, for WGS. For both SNVs and indels, the distributions of coverage depth, genotype quality, and minor read ratio were more uniform for WGS than for WES. After filtering, a mean of 74,398 (95.3%) high-quality (HQ) SNVs and 9,033 (70.6%) HQ indels were called by both platforms. A mean of 105 coding HQ SNVs and 32 indels was identified exclusively by WES whereas 692 HQ SNVs and 105 indels were identified exclusively by WGS. We Sanger-sequenced a random selection of these exclusive variants. For SNVs, the proportion of false-positive variants was higher for WES (78%) than for WGS (17%). The estimated mean number of real coding SNVs (656 variants, ~3% of all coding HQ SNVs) identified by WGS and missed by WES was greater than the number of SNVs identified by WES and missed by WGS (26 variants). For indels, the proportions of false-positive variants were similar for WES (44%) and WGS (46%). Finally, WES was not reliable for the detection of copy-number variations, almost all of which extended beyond the targeted regions. Although currently more expensive, WGS is more powerful than WES for detecting potential disease-causing mutations within WES regions, particularly those due to SNVs. PMID- 25827232 TI - Correction for Park et al., RORgammat-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. PMID- 25827231 TI - Colon cancer-associated mutator DNA polymerase delta variant causes expansion of dNTP pools increasing its own infidelity. AB - Defects in DNA polymerases delta (Poldelta) and epsilon (Polepsilon) cause hereditary colorectal cancer and have been implicated in the etiology of some sporadic colorectal and endometrial tumors. We previously reported that the yeast pol3-R696W allele mimicking a human cancer-associated variant, POLD1-R689W, causes a catastrophic increase in spontaneous mutagenesis. Here, we describe the mechanism of this extraordinary mutator effect. We found that the mutation rate increased synergistically when the R696W mutation was combined with defects in Poldelta proofreading or mismatch repair, indicating that pathways correcting DNA replication errors are not compromised in pol3-R696W mutants. DNA synthesis by purified Poldelta-R696W was error-prone, but not to the extent that could account for the unprecedented mutator phenotype of pol3-R696W strains. In a search for cellular factors that augment the mutagenic potential of Poldelta-R696W, we discovered that pol3-R696W causes S-phase checkpoint-dependent elevation of dNTP pools. Abrogating this elevation by strategic mutations in dNTP metabolism genes eliminated the mutator effect of pol3-R696W, whereas restoration of high intracellular dNTP levels restored the mutator phenotype. Further, the use of dNTP concentrations present in pol3-R696W cells for in vitro DNA synthesis greatly decreased the fidelity of Poldelta-R696W and produced a mutation spectrum strikingly similar to the spectrum observed in vivo. The results support a model in which (i) faulty synthesis by Poldelta-R696W leads to a checkpoint-dependent increase in dNTP levels and (ii) this increase mediates the hypermutator effect of Poldelta-R696W by facilitating the extension of mismatched primer termini it creates and by promoting further errors that continue to fuel the mutagenic pathway. PMID- 25827234 TI - Isoflavone profile in soymilk as affected by soybean variety, grinding, and heat processing methods. AB - Isoflavones impart health benefits and their overall content and profile in foods are greatly influenced at each step during processing. In this study, 2 soybean varieties (Prosoy and black soybean) were processed with 3 different grinding (ambient, cold, and hot grinding) and heating methods (traditional stove cooking, 1-phase UHT, and 2-phase UHT) for soymilk making. The results showed after cold, ambient, and hot grinding, the total isoflavones were 3917, 5013, and 5949 nmol/g for Prosoy; the total isoflavones were 4073, 3966, and 4284 nmol/g for black soybean. Grinding could significantly increase isoflavone extraction. The grinding process had a destructive effect on isoflavones and this effect varied with grinding temperature. Different heating methods had different effects on different isoflavone forms. Two soybean varieties showed distinct patterns with respect to the change of isoflavone profile during processing. PMID- 25827235 TI - Editorial Comment from Dr Masumori to Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo. PMID- 25827236 TI - Statistically speaking. PMID- 25827233 TI - alphaIIbbeta3 variants defined by next-generation sequencing: predicting variants likely to cause Glanzmann thrombasthenia. AB - Next-generation sequencing is transforming our understanding of human genetic variation but assessing the functional impact of novel variants presents challenges. We analyzed missense variants in the integrin alphaIIbbeta3 receptor subunit genes ITGA2B and ITGB3 identified by whole-exome or -genome sequencing in the ThromboGenomics project, comprising ~32,000 alleles from 16,108 individuals. We analyzed the results in comparison with 111 missense variants in these genes previously reported as being associated with Glanzmann thrombasthenia (GT), 20 associated with alloimmune thrombocytopenia, and 5 associated with aniso/macrothrombocytopenia. We identified 114 novel missense variants in ITGA2B (affecting ~11% of the amino acids) and 68 novel missense variants in ITGB3 (affecting ~9% of the amino acids). Of the variants, 96% had minor allele frequencies (MAF) < 0.1%, indicating their rarity. Based on sequence conservation, MAF, and location on a complete model of alphaIIbbeta3, we selected three novel variants that affect amino acids previously associated with GT for expression in HEK293 cells. alphaIIb P176H and beta3 C547G severely reduced alphaIIbbeta3 expression, whereas alphaIIb P943A partially reduced alphaIIbbeta3 expression and had no effect on fibrinogen binding. We used receiver operating characteristic curves of combined annotation-dependent depletion, Polyphen 2 HDIV, and sorting intolerant from tolerant to estimate the percentage of novel variants likely to be deleterious. At optimal cut-off values, which had 69-98% sensitivity in detecting GT mutations, between 27% and 71% of the novel alphaIIb or beta3 missense variants were predicted to be deleterious. Our data have implications for understanding the evolutionary pressure on alphaIIbbeta3 and highlight the challenges in predicting the clinical significance of novel missense variants. PMID- 25827238 TI - The rotational spectrum of tyrosine. AB - In this work neutral tyrosine has been generated in the gas phase by laser ablation of solid samples, and its most abundant conformers characterized through their rotational spectra. Their identification has been made by comparison between the experimental and ab initio values of the rotational and quadrupole coupling constants. Both conformers are stabilized by an O-H***N hydrogen bond established within the amino acid skeleton chain and an additional weak N-H***pi hydrogen bond. The observed conformers differ in the orientation of the phenolic OH group. PMID- 25827239 TI - The Effect of Protein Restriction in the In Vitro Metabolism of Albendazole in Rats. AB - This work presents an in vitro investigation of the effect of protein restriction on the metabolism of albendazole (ABZ). This study was conducted using liver microsomal fractions obtained from Wistar rats. For the quantitative analysis, a multidimensional High Performance Liquid Chromatography (2D HPLC) method was fully validated for the determination of the ABZ metabolites: albendazole sulfoxide, albendazole sulfone and albendazole 2-aminesulfone. The target compounds were directly extracted using a C8-RAM-BSA column (5.0x0.46 cm i.d.) and analyzed on a chromatographic chiral column containing amylose tris(3,5 dimethylphenylcarbamate) (150x4.6 mm i.d.). The in vitro biotransformation results showed that the protein restriction influenced the oxidative metabolism of ABZ. The production of R-(+)-ABZ-SO (1309 nmol/L) and S-(-)-ABZ-SO (1456 nmol/L) was higher in the control animals than in the animals fed with a diet containing 6% protein, which produced 778.7 nmol/L and 709.5 nmol/L for R-(+) and S-(-)-ABZ-SO enantiomers, respectively. These results were statistically inspected by Student's t test and the results showed a significant difference between the two means (p<0.05). Moreover, the production of ABZ-SO enantiomers was enantioselective where the S-(-)-ABZ-SO was formed in greater amounts than the R-(+)-ABZ-SO in control animals (p=0.0231). However, the enantioselectivity was not observed when the in vitro biotransformation of ABZ was conducted using the microsomal fractions obtained from protein restriction animals (p>0.05). Furthermore, animal nutritional condition could affect the pattern of ABZ sulphoxidation indicating that the protein nutrition affect primarily the formation of R-(+)-ABZSO and S-(-)-ABZ-SO enantiomers. PMID- 25827240 TI - Push-out bond strength of root fillings made with C-Point and BC sealer versus gutta-percha and AH Plus after the instrumentation of oval canals with the Self Adjusting File versus WaveOne. AB - AIM: To compare the push-out bond strength exhibited by root fillings performed with either C-Point and Endosequence(r) BC sealerTM (BC Sealer) or gutta-percha and AH Plus(r) after the instrumentation of oval canals with either the Self Adjusting File (SAF) System or WaveOne (WO) reciprocating file. METHODOLOGY: Eighty extracted premolars were selected and divided randomly into the following four groups (n = 20): group 1, SAF instrumentation and filling using gutta-percha and AH Plus sealer; group 2, SAF instrumentation and C-Point and BC sealer filling; group 3, WO instrumentation and filling using gutta-percha and AH Plus sealer; and group 4, WO instrumentation and filling with C-Point and BC sealer. Sodium hypochlorite (5.25%) and EDTA (17%) were used as irrigants for all groups. After the sealer was set completely, the teeth were prepared for micro push-out assessment using 1.0-mm-thick root slices. Loading was performed with a universal testing machine at a speed of 0.5 mm min(-1) . Two-way anova and Student's t-test for pairwise comparisons were used to compare groups. RESULTS: All specimens filled with C-Point and BC sealer were associated with significantly higher push out bond strength compared with gutta-percha and AH Plus sealer (P < 0.001). The bond strength was higher for the coronal and apical samples of the C-Point/BC sealer/SAF group (6.6 +/- 0.3 and 3.2 +/- 0.3 MPa) versus those of the gutta percha/AH Plus/WO group (4.8 +/- 0.3 and 1.8 +/- 0.3 MPa), by 38% and by 80% in the coronal and apical parts, respectively (P < 0.001, P < 0.0001). Adhesive bond failure was more common in the WaveOne-instrumented group in general and in the buccal and lingual recesses in this group in particular. CONCLUSIONS: In oval canals, the instrument used and the root filling material significantly affected the push-out values of root fillings. The highest value was recorded in oval root canals instrumented with the SAF System and filled with C-Point and BC sealer, whereas the lowest strength was noted in oval canals instrumented with WaveOne and filled with gutta-percha and AH Plus sealer. PMID- 25827241 TI - Mechanism study on pH-responsive cyclodextrin capped mesoporous silica: effect of different stalk densities and the type of cyclodextrin. AB - Cyclodextrin (CD)-capped mesoporous silica nanoparticles (MSN) with pH-responsive properties were synthesized, but little research has been carried out to evaluate the impact of critical factors such as the stalk density and the type of CD on the pH-responsive release behavior. Here, the effect of different stalk densities on the pH-responsive release behavior was investigated. Either too low or too high density of the grafted p-anisidine stalk could result in poor cargo release, and the optimum stalk density for MSN was measured by thermal analysis, and found to be approximately 8.7 stalks nm(-2). To achieve effective release control, the CD capes, alpha-CD and beta-CD, were also investigated. Isothermal titration calorimetry (ITC) analysis was employed to determine the formation constants (Kf) of the two CD with p-anisidine at different pH values. The results obtained showed that the complex of beta-CD with p-anisidine had excellent pH-responsive behavior as it exhibited the largest changed formation constant (DeltaKf) in different pH media. Furthermore, the pH-responsive mechanism between CD and p anisidine molecules was investigated through ITC and a molecular modeling study. The release of antitumor drug DOX presents a significant prospect toward the development of pH-responsive nanoparticles as a drug delivery vehicle. PMID- 25827242 TI - Functional Connectivity in Multiple Cortical Networks Is Associated with Performance Across Cognitive Domains in Older Adults. AB - Intrinsic functional connectivity MRI has become a widely used tool for measuring integrity in large-scale cortical networks. This study examined multiple cortical networks using Template-Based Rotation (TBR), a method that applies a priori network and nuisance component templates defined from an independent dataset to test datasets of interest. A priori templates were applied to a test dataset of 276 older adults (ages 65-90) from the Harvard Aging Brain Study to examine the relationship between multiple large-scale cortical networks and cognition. Factor scores derived from neuropsychological tests represented processing speed, executive function, and episodic memory. Resting-state BOLD data were acquired in two 6-min acquisitions on a 3-Tesla scanner and processed with TBR to extract individual-level metrics of network connectivity in multiple cortical networks. All results controlled for data quality metrics, including motion. Connectivity in multiple large-scale cortical networks was positively related to all cognitive domains, with a composite measure of general connectivity positively associated with general cognitive performance. Controlling for the correlations between networks, the frontoparietal control network (FPCN) and executive function demonstrated the only significant association, suggesting specificity in this relationship. Further analyses found that the FPCN mediated the relationships of the other networks with cognition, suggesting that this network may play a central role in understanding individual variation in cognition during aging. PMID- 25827243 TI - Genetic consequences of population expansions and contractions in the common hippopotamus (Hippopotamus amphibius) since the Late Pleistocene. AB - Over the past two decades, an increasing amount of phylogeographic work has substantially improved our understanding of African biogeography, in particular the role played by Pleistocene pluvial-drought cycles on terrestrial vertebrates. However, still little is known on the evolutionary history of semi-aquatic animals, which faced tremendous challenges imposed by unpredictable availability of water resources. In this study, we investigate the Late Pleistocene history of the common hippopotamus (Hippopotamus amphibius), using mitochondrial and nuclear DNA sequence variation and range-wide sampling. We documented a global demographic and spatial expansion approximately 0.1-0.3 Myr ago, most likely associated with an episode of massive drainage overflow. These events presumably enabled a historical continent-wide gene flow among hippopotamus populations, and hence, no clear continental-scale genetic structuring remains. Nevertheless, present-day hippopotamus populations are genetically disconnected, probably as a result of the mid-Holocene aridification and contemporary anthropogenic pressures. This unique pattern contrasts with the biogeographic paradigms established for savannah-adapted ungulate mammals and should be further investigated in other water-associated taxa. Our study has important consequences for the conservation of the hippo, an emblematic but threatened species that requires specific protection to curtail its long-term decline. PMID- 25827244 TI - Early Western observations of cutaneous Trichophyton concentricum infection in the Pacific and a history of its vernacular name, tokelau. PMID- 25827245 TI - Managing preterm infants in the first minutes of life. AB - Premature infants often experience difficulties adapting to postnatal life. The most relevant ones are related to establishing an adult type cardiorespiratory circulation and acquiring hemodynamic stability, aerating the lung and attaining a functional residual capacity, performing an adequate gas exchange and switching to an oxygen enriched metabolism, and keeping an adequate body temperature. In recent years a body of evidence supports a trend towards gentle management in the delivery room aiming to reduce damage especially to the lungs in the so-called first golden minutes. Herewith, we describe and update four of the most relevant interventions performed in the delivery room: delayed cord clamping, non-invasive ventilation, individualized oxygen supplementation, and maintaining an adequate body temperature so as to avoid hyperthermia and/or hypothermia. PMID- 25827246 TI - Pyrolysis kinetics and thermal characteristics of microalgae Nannochloropsis oculata and Tetraselmis sp. AB - In this study non-isothermal thermogravimetric analysis were used to investigate pyrolysis behavior and kinetics of microalgae Nannochloropsis oculata (NO) and Tetraselmis sp. (TS). TG/DTG experiments at different heating rates were carried out. Heating rates had slight effect on the decomposition trend, however the maximum temperature and peak of weight loss rate in the DTG curves shifted towards higher temperature with the increase in heating rate. The average activation energy and pre-exponential factor for pyrolysis of NO and TS were estimated by distributed activation energy model. The highest activation energies were observed as 152.20 and 334kJ/mol for NO and TS, respectively, at various conversions. The pre-exponential factors for the corresponding activation energies were observed to be in the order of 10(8)-10(13) and 10(12)-10(25)s(-1) for NO and TS, respectively. Calculated kinetic parameters were used to predict devolatilization curves and results were in well agreement with experimental data. PMID- 25827247 TI - Life cycle cost optimization of biofuel supply chains under uncertainties based on interval linear programming. AB - The aim of this work was to develop a model for optimizing the life cycle cost of biofuel supply chain under uncertainties. Multiple agriculture zones, multiple transportation modes for the transport of grain and biofuel, multiple biofuel plants, and multiple market centers were considered in this model, and the price of the resources, the yield of grain and the market demands were regarded as interval numbers instead of constants. An interval linear programming was developed, and a method for solving interval linear programming was presented. An illustrative case was studied by the proposed model, and the results showed that the proposed model is feasible for designing biofuel supply chain under uncertainties. PMID- 25827248 TI - Soil infiltration bioreactor incorporated with pyrite-based (mixotrophic) denitrification for domestic wastewater treatment. AB - In this study, an integrated two-stage soil infiltration bioreactor incorporated with pyrite-based (mixotrophic) denitrification (SIBPD) was designed for domestic wastewater treatment. Benefited from excellent adsorption ability and water permeability, soil infiltration could avoid clogging, shorten operating time and lower maintenance cost. Respiration and nitrification were mostly engaged in aerobic stage (AES), while nitrate was majorly removed by pyrite-based mixotrophic denitrification mainly occurred in anaerobic stage (ANS). Fed with synthetic and real wastewater for 120days at 1.5h HRT, SIBPD demonstrated good removal performance showing 87.14% for COD, 92.84% for NH4(+)-N and 82.58% for TP along with 80.72% of nitrate removed by ANS. TN removal efficiency was 83.74% when conducting real wastewater. Compared with sulfur-based process, the effluent pH of SIBPD was maintained at 6.99-7.34 and the highest SO4(2-) concentration was only 64.63mgL(-1). This study revealed a promising and feasible application prospect for on-site domestic wastewater treatment. PMID- 25827249 TI - Bio-oil from thermo-chemical hydro-liquefaction of wet sewage sludge. AB - The present work demonstrates the influence of experimental conditions such as weight ratio of sewage sludge to water (1/0-1/15), reaction temperature (200-350 degrees C), initial H2 pressure (2.0-11.0MPa), residence time (10-100min) and type of catalysts (Na2CO3, Raney nickel, FeSO4, MoS2) on hydro-liquefaction process of sewage sludge. High amount of water improves the hydro-liquefaction process of sewage sludge by increasing the yield of bio-oil and the total conversion. The highest yield of bio-oil (47.79 wt.%) from sewage sludge was obtained with initial H2 pressure 5.0MPa, reaction temperature 300 degrees C, and residence time 40min. Under these experimental conditions, using weight ratio of sewage sludge to water 1/5, catalyst (FeSO4) - 5 wt.% of dry SS, mixing speed 350rpm the obtained bio-oil had the highest energy recovery (69.84%), total conversion (70.64%) and its calorific value was 35.22MJ/kg. PMID- 25827250 TI - Activation of accumulated nitrite reduction by immobilized Pseudomonas stutzeri T13 during aerobic denitrification. AB - The excellent removal efficiency of nitrate by the aerobic denitrifier, Pseudomonas stutzeri T13, was achieved in free cells system. However, poor nitrite reduction prevents efficient aerobic denitrification because of the nitrite accumulation. This problem could be conquered by immobilizing the cells on supports. In this study, strain T13 was immobilized by mycelial pellets (MPs), polyurethane foam cubes (PFCs) and sodium alginate beads (SABs). Higher removal percentages of TN in MP (43.78%), PFC (42.31%) and SAB (57.25%) systems were achieved compared with the free cell system (29.7%). Furthermore, the optimal condition for immobilized cell systems was as follows: 30 degrees C, 100rpm shaking speed and pH 7. The shock-resistance of SAB system was relatively poor, which could collapse under either alkaline (pH=9) or high rotating (200rpm) conditions. The recycling experiments demonstrated that the high steady TN removal rate could be maintained for seven cycles in both MP and PFC systems. PMID- 25827253 TI - Self-directed physical activity intervention in older adults undergoing adjuvant chemotherapy for colorectal cancer: Design of a randomized controlled trial. AB - BACKGROUND: Colorectal cancer (CRC) diagnosis and treatment can have substantial detrimental impacts on health related quality of life (HRQOL) and physical function. This is especially true for older CRC patients and is of paramount concern in chemotherapy treatment decision making; yet, few studies to date have focused on understanding and managing fatigue in older CRC patients. We present the design of a study to evaluate the feasibility and impact of a home-based, self-directed physical activity intervention on fatigue in older CRC patients receiving adjuvant chemotherapy treatment. Secondary aims pertain to intervention impact on HRQOL, physical function, and self-efficacy for managing fatigue. METHODS/DESIGN: Multi-site, randomized controlled trial of physical activity intervention compared to usual care in a sample of older adults undergoing adjuvant chemotherapy for CRC. Forty CRC patients will be recruited and study questionnaires/assessments will be performed at baseline, 3 months, and after completion of adjuvant chemotherapy. The primary outcome is a comparison of the change in fatigue from baseline to 3 months between Intervention and Control arms. We will also compare changes in engagement in physical activity, HRQOL, physical function, and self-efficacy. Exploratory analyses will compare Intervention and Control arms with regard to changes in muscle mass and a biomarker aging that is known to increase during chemotherapy (p16(INK4a)). DISCUSSION: If positive, findings from this pilot study would suggest the potential for improving the care of older persons with CRC undergoing adjuvant chemotherapy through a home-based physical activity intervention to manage fatigue, HRQOL, and physical function. TRIAL REGISTRATION: NCT02191969. PMID- 25827255 TI - Effect of intermittent PTH treatment on plasma glucose in osteoporosis: A randomized trial. AB - We investigated the effect of bone turnover on glucose homeostasis, fat distribution and adipokine production during anabolic treatment with PTH. This is a parallel, randomized controlled, open label, trial. The randomization was done by computer generated tables to allocate treatments. Forty-six postmenopausal osteoporotic non-diabetic women were assigned to treatment with calcium and colecalcipherol with (24) or without (22) PTH 1-84. Patients were recalled after 3, 6, 12 and 18 months of treatment and markers of bone turnover, glucose metabolism, adipokine secretion and fat distribution were analyzed. Markers of bone turnover and adipokines were measured by ELISA. Glucose metabolism was evaluated by an oral glucose load test and insulin resistance and secretion were calculated. Fat and lean mass were evaluated by anthropometric measures. The effect of treatment on measured variables was analyzed by repeated measure test, and its effect on glucose was also evaluated by mediation analysis after correction for possible confounders. Twenty patients in the calcium and vitamin D groups and 19 in the group treated with PTH 1-84 completed the study. There were no significance adverse events. Treatment with PTH increases osteocalcin, both total (OC) and undercarboxylated (uOC), and decreases blood glucose, without influence on insulin secretion, resistance and pancreatic beta cell function. Treatment with PTH does not influence fat distribution and adipokine production. The results of the mediation analyses suggest a total effect of PTH on blood glucose, moderately mediated by OC and to a less extent by uOC. Here we suggest that treatment with PTH influences glucose metabolism partially through its effect on bone turnover, without influence on insulin secretion, resistance, pancreatic beta cell function and fat mass. PMID- 25827254 TI - Global transcriptional profiling using RNA sequencing and DNA methylation patterns in highly enriched mesenchymal cells from young versus elderly women. AB - Age-related bone loss in humans is associated with a decrease in bone formation relative to bone resorption, although the mechanisms for this impairment in bone formation with aging are not well understood. It is known that the precursors for the bone-forming osteoblasts reside in the mesenchymal cell population in bone marrow. Thus, in an effort to identify relevant genetic pathways that are altered with aging, we examined the gene expression and DNA methylation patterns from a highly enriched bone marrow mesenchymal cell population from young (mean age, 28.7 years) versus old (mean age, 73.3 years) women. Bone marrow mononuclear cells from these women were depleted of hematopoietic lineage (lin) and endothelial cells using a combination of magnetic- and fluorescence-activated cell sorting, yielding a previously characterized mesenchymal cell population (lin-/CD34-/CD31- cells) that is capable of osteoblast differentiation. Whole transcriptome RNA sequencing (RNAseq) of freshly isolated cells (without in vitro culture) identified 279 differentially expressed genes (p < 0.05, false discovery rate [q]< 0.10) between the young and old subjects. Pathway analysis revealed statistically significant (all p < 0.05) alterations in protein synthesis and degradation pathways, as well as mTOR, gap junction, calcium, melatonin and NFAT signaling pathways. Further, Reduced Representational Bisulphite sequencing (RRBS DNA methylation sequencing) revealed significant differences in methylation between the young and old subjects surrounding the promoters of 1528 target genes that also exhibited significant differences in gene expression by RNAseq. In summary, these studies provide novel insights into potential pathways affected by aging in a highly enriched human mesenchymal cell population analyzed without the confounding effects of in vitro culture. Specifically, our finding of alterations in several genes and pathways leading to impaired protein synthesis and turnover with aging in bone marrow mesenchymal cells points to the need for further studies examining how these changes, as well as the other alterations with aging that we identified, may contribute to the age-related impairment in osteoblast formation and/or function. PMID- 25827256 TI - Characterising the composition of waste-derived fuels using a novel image analysis tool. AB - An experimental study was completed using a previously developed and innovative image analysis approach, which has been applied here to shredded waste materials representative of waste-derived fuels. Waste components were collected from source-segregated recycling containers and shredded to <150 mm. These materials were then used to produce 3* samples of different composition. The samples were spread to represent materials on a conveyor belt, and multiple images of each sample were captured using 10*10 cm and 20*20 cm quadrats. The images were processed using ERDAS Imagine software to determine the area covered by each waste component. This coverage was converted into a mass using density data determined as part of this study, yielding a determined composition which was then compared with the known composition of the samples. The image analysis results indicated a strong correlation with the actual values (mean r=0.89). The area coverage of the sample (10*10 cm or 20*20 cm) contributes to the accuracy as the dot-grid approach used with the particle size within the samples may result in components not being sufficiently monitored. This manuscript presents initial results of the application of an adapted innovative image-based method, and critically assesses how the technique could be improved and developed in the future. PMID- 25827257 TI - Effects of trace element addition on process stability during anaerobic co digestion of OFMSW and slaughterhouse waste. AB - This study used semi-continuous laboratory scale biogas reactors to simulate the effects of trace-element addition in different combinations, while degrading the organic fraction of municipal solid waste and slaughterhouse waste. The results show that the combined addition of Fe, Co and Ni was superior to the addition of only Fe, Fe and Co or Fe and Ni. However, the addition of only Fe resulted in a more stable process than the combined addition of Fe and Co, perhaps indicating a too efficient acidogenesis and/or homoacetogenesis in relation to a Ni-deprived methanogenic population. The results were observed in terms of higher biogas production (+9%), biogas production rates (+35%) and reduced VFA concentration for combined addition compared to only Fe and Ni. The higher stability was supported by observations of differences in viscosity, intraday VFA- and biogas kinetics as well as by the 16S rRNA gene and 16S rRNA of the methanogens. PMID- 25827258 TI - Relationship between recycling rate and air pollution: Waste management in the state of Massachusetts. AB - This study examines the relationship between recycling rate of solid waste and air pollution using data from a waste municipality survey in the state of Massachusetts during the period 2009-2012. Two econometric approaches are applied. The first approach is a fixed effects model, while the second is a Stochastic Frontier Analysis (SFA) with fixed effects model. The advantage of the first approach is the ability of controlling for stable time invariant characteristics of the municipalities, thereby eliminating potentially large sources of bias. The second approach is applied in order to estimate the technical efficiency and rank of each municipality accordingly. The regressions control for various demographic, economic and recycling services, such as income per capita, population density, unemployment, trash services, Pay-as-you-throw (PAYT) program and meteorological data. The findings support that a negative relationship between particulate particles in the air 2.5 MUm or less in size (PM2.5) and recycling rate is presented. In addition, the pollution is increased with increases on income per capita up to $23,000-$26,000, while after this point income contributes positively on air quality. Finally, based on the efficiency derived by the Stochastic Frontier Analysis (SFA) model, the municipalities which provide both drop off and curbside services for trash, food and yard waste and the PAYT program present better performance regarding the air quality. PMID- 25827259 TI - Intersensory redundancy promotes visual rhythm discrimination in visually impaired infants. AB - Infants' attention is captured by the redundancy of amodal stimulation in multimodal objects and events. Evidence from this study demonstrates that intersensory redundancy can facilitate discrimination of rhythm changes presented in the visual modality alone in visually impaired infants, suggesting that multisensory rehabilitation strategies could prove helpful in this population. PMID- 25827260 TI - Caregivers interpret infants' early gestures based on shared knowledge about referents. AB - Gestures are the first forms of conventional communication that young children develop in order to intentionally convey a specific message. However, at first, infants rarely communicate successfully with their gestures, prompting caregivers to interpret them. Although the role of caregivers in early communication development has been examined, little is known about how caregivers attribute a specific communicative function to infants' gestures. In this study, we argue that caregivers rely on the knowledge about the referent that is shared with infants in order to interpret what communicative function infants wish to convey with their gestures. We videotaped interactions from six caregiver-infant dyads playing with toys when infants were 8, 10, 12, 14, and 16 months old. We coded infants' gesture production and we determined whether caregivers interpreted those gestures as conveying a clear communicative function or not; we also coded whether infants used objects according to their conventions of use as a measure of shared knowledge about the referent. Results revealed an association between infants' increasing knowledge of object use and maternal interpretations of infants' gestures as conveying a clear communicative function. Our findings emphasize the importance of shared knowledge in shaping infants' emergent communicative skills. PMID- 25827261 TI - The influence of a hand preference for acquiring objects on the development of a hand preference for unimanual manipulation from 6 to 14 months. AB - Development of hand preferences for unimanual manipulation of objects was explored in 90 infants (57 males) tested monthly from 6 to 14 months. From a larger sample of 380 infants, 30 infants with a consistent left hand preference for acquiring objects were matched for sex and development of locomotion skills with 30 infants with a consistent right hand preference for acquisition and 30 with no preference. Although frequency of unimanual manipulations increased during 6-14 month period, infants with a hand preference for acquisition did more object manipulations than those without a preference for acquisition. Multilevel modeling of unimanual manipulation trajectories for the three hand-preference groups revealed that hand preferences for unimanual manipulation become more distinctive with age, and the preference is predicted by the hand preference for object acquisition. Infants with a right and left hand preference for object acquisition develop a right and left (respectively) hand preference for unimanual manipulation. However, the majority of infants at each month do not exhibit hand preferences for unimanual manipulation that are unlikely to occur by chance, even by 14 months. The results are consistent with a cascading theory of handedness development in which early preferences (i.e., for acquisition) are transferred to later developing preferences (i.e., for unimanual manipulation). PMID- 25827262 TI - Qualitative elements of early motor development that influence reaching of the erect posture. A prospective cohort study. AB - The proposed assessment sheet aims to show in detail, which qualitative elements of motor performance are performed correctly in the 2nd month of life by children who in the 9th month reached the erect posture. Similar analysis was performed for the qualitative assessment in the 6th month. The prospective investigation of motor development involved a group of 109 children (40 girls and 69 boys). The study was based on the previously described quantity and quality assessment sheet of motor performance, validated for the 2nd and 6th month. Final investigation took place in the 9th month of life and was based on a neurological assessment. It could be shown that a completely correct assessment at the age of 2 months precludes future severe motor development disorders, especially cerebral palsy, although it does not rule out a slight delay. Prematurity and the analyzed risk factors, particularly IVH, impair the motor performance. The absence of axial symmetry, the shoulders protraction and improper position of the pelvis are the most important alarming features at the 2nd month. Distal elements observed in the prone position at the 6th month show a good prognosis for the motor performance in the 9th month. Any abnormalities, mainly related to the body axis and symmetry observed at 2 months of age should encourage one to put a child under observation. PMID- 25827263 TI - Finnish mothers' and fathers' reports of their boys and girls by using the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). AB - This study investigated maternal and paternal reports about their very young boys and girls on the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). Two samples were recruited through child health centers in Northern Finland. The infant sample consisted of 227 children (112 boys and 115 girls) (mean age 13.0+/ 1.1 months) and the toddler sample consisted of 208 children (94 boys and 114 girls) (mean age 19.3+/-1.4 months). Among the infants, girls obtained higher paternal competence total scores than boys, whereas among the toddlers, both maternal and paternal competence total scores were higher for girls compared to boys. In the problem total scale, boys were scored higher than girls by mothers, but not by fathers, in both age groups. In the externalizing problem domain, maternal scores were higher for boys compared to girls among both samples, whereas paternal scores were significantly higher for boys than for girls only among the infants. Also maternal internalizing problem scores were higher for boys than for girls among the toddlers. Compared to fathers, mothers perceived more social-emotional competencies in toddler boys and girls, as well as more total, externalizing and dysregulation problems in toddler boys. However, significant differences between the maternal and paternal BITSEA ratings were not found among the infants of either sex. The results suggest that sex differences in the social-emotional/behavior domain may be observed by the parents among children as young as 11 to 24 months of age. Our findings highlight the importance of paying attention to probable sex differences when assessing and treating early social-emotional/behavior problems. PMID- 25827264 TI - Environmental occurrence and risk of organic UV filters and stabilizers in multiple matrices in Norway. AB - Eight organic UV filters and stabilizers were quantitatively determined in wastewater sludge and effluent, landfill leachate, sediments, and marine and freshwater biota. Crab, prawn and cod from Oslofjord, and perch, whitefish and burbot from Lake Mjosa were selected in order to evaluate the potential for trophic accumulation. All of the cod livers analysed were contaminated with at least 1 UV filter, and a maximum concentration of almost 12 MUg/g wet weight for octocrylene (OC) was measured in one individual. 80% of the cod livers contained OC, and approximately 50% of cod liver and prawn samples contained benzophenone (BP3). Lower concentrations and detection frequencies were observed in freshwater species and the data of most interest is the 4 individual whitefish that contained both BP3 and ethylhexylmethoxycinnamate (EHMC) with maximum concentrations of almost 200 ng/g wet weight. The data shows a difference in the loads of UV filters entering receiving water dependent on the extent of wastewater treatment. Primary screening alone is insufficient for the removal of selected UV filters (BP3, Padimate, EHMC, OC, UV-234, UV-327, UV-328, UV-329). Likely due in part to the hydrophobic nature of the majority of the UV filters studied, particulate loading and organic carbon content appear to be related to concentrations of UV filters in landfill leachate and an order of magnitude difference in these parameters correlates with an order of magnitude difference in the effluent concentrations of selected UV filters (Fig. 2). From the data, it is possible that under certain low flow conditions selected organic UV filters may pose a risk to surface waters but under the present conditions the risk is low, but some UV filters will potentially accumulate through the trophic food chain. PMID- 25827265 TI - Beyond QMRA: Modelling microbial health risk as a complex system using Bayesian networks. AB - BACKGROUND: Quantitative microbial risk assessment (QMRA) is the current method of choice for determining the risk to human health from exposure to microorganisms of concern. However, current approaches are often constrained by the availability of required data, and may not be able to incorporate the many varied factors that influence this risk. Systems models, based on Bayesian networks (BNs), are emerging as an effective complementary approach that overcomes these limitations. OBJECTIVES: This article aims to provide a comparative evaluation of the capabilities and challenges of current QMRA methods and BN models, and a scoping review of recent published articles that adopt the latter for microbial risk assessment. Pros and cons of systems approaches in this context are distilled and discussed. METHODS: A search of the peer-reviewed literature revealed 15 articles describing BNs used in the context of QMRAs for foodborne and waterborne pathogens. These studies were analysed in terms of their application, uses and benefits in QMRA. DISCUSSION: The applications were notable in their diversity. BNs were used to make predictions, for scenario assessment, risk minimisation, to reduce uncertainty and to separate uncertainty and variability. Most studies focused on a segment of the exposure pathway, indicating the broad potential for the method in other QMRA steps. BNs offer a number of useful features to enhance QMRA, including transparency, and the ability to deal with poor quality data and support causal reasoning. CONCLUSION: The method has significant untapped potential to describe the complex relationships between microbial environmental exposures and health. PMID- 25827266 TI - Carotid blowout syndrome in pharyngeal cancer patients treated by hypofractionated stereotactic re-irradiation using CyberKnife: A multi institutional matched-cohort analysis. AB - BACKGROUND AND PURPOSE: Although reirradiation has attracted attention as a potential therapy for recurrent head and neck tumors with the advent of modern radiotherapy, severe rate toxicity such as carotid blowout syndrome (CBOS) limits its potential. The aim of this study was to identify the risk factors of CBOS after hypofractionated stereotactic radiotherapy (SBRT). METHODS AND PATIENTS: We conducted a matched-pair design examination of pharyngeal cancer patients treated by CyberKnife reirradiation in four institutes. Twelve cases with CBOS were observed per 60 cases without CBOS cases. Prognostic factors for CBOS were analyzed and a risk classification model was constructed. RESULTS: The median prescribed radiation dose was 30 Gy in 5 fractions with CyberKnife SBRT after 60 Gy/30 fractions of previous radiotherapy. The median duration between reirradiation and CBOS onset was 5 months (range, 0-69 months). CBOS cases showed a median survival time of 5.5 months compared to 22.8 months for non-CBOS cases (1-year survival rate, 36% vs.72%; p=0.003). Univariate analysis identified an angle of carotid invasion of >180 degrees , the presence of ulceration, planning treatment volume, and irradiation to lymph node areas as statistically significant predisposing factors for CBOS. Only patients with carotid invasion of >180 degrees developed CBOS (12/50, 24%), whereas no patient with tumor involvement less than a half semicircle around the carotid artery developed CBOS (0/22, 0%, p=0.03). Multivariate Cox hazard model analysis revealed that the presence of ulceration and irradiation to lymph nodes were statistically significant predisposing factors. Thus, we constructed a CBOS risk classification system: CBOS index=(summation of risk factors; carotid invasion >180 degrees , presence of ulceration, lymph node area irradiation). This system sufficiently separated the risk groups. CONCLUSION: The presence of ulceration and lymph node irradiation are risk factors of CBOS. The CBOS index, including carotid invasion of >180 degrees , is useful in classifying the risk factors and determining the indications for reirradiation. PMID- 25827267 TI - Conductive iron oxide minerals accelerate syntrophic cooperation in methanogenic benzoate degradation. AB - Recent studies have suggested that conductive iron oxide minerals can facilitate syntrophic metabolism of the methanogenic degradation of organic matter, such as ethanol, propionate and butyrate, in natural and engineered microbial ecosystems. This enhanced syntrophy involves direct interspecies electron transfer (DIET) powered by microorganisms exchanging metabolic electrons through electrically conductive minerals. Here, we evaluated the possibility that conductive iron oxides (hematite and magnetite) can stimulate the methanogenic degradation of benzoate, which is a common intermediate in the anaerobic metabolism of aromatic compounds. The results showed that 89-94% of the electrons released from benzoate oxidation were recovered in CH4 production, and acetate was identified as the only carbon-bearing intermediate during benzoate degradation. Compared with the iron-free controls, the rates of methanogenic benzoate degradation were enhanced by 25% and 53% in the presence of hematite and magnetite, respectively. This stimulatory effect probably resulted from DIET-mediated methanogenesis in which electrons transfer between syntrophic partners via conductive iron minerals. Phylogenetic analyses revealed that Bacillaceae, Peptococcaceae, and Methanobacterium are potentially involved in the functioning of syntrophic DIET. Considering the ubiquitous presence of iron minerals within soils and sediments, the findings of this study will increase the current understanding of the natural biological attenuation of aromatic hydrocarbons in anaerobic environments. PMID- 25827268 TI - New treatment method for boron in aqueous solutions using Mg-Al layered double hydroxide: Kinetics and equilibrium studies. AB - Mg-Al layered double hydroxides (LDHs) intercalated with NO3(-) (NO3 . Mg - Al LDHs) and with Cl(-) (Cl . Mg - Al LDHs) were found to take up boron from aqueous solutions. Boron was removed by anion exchange of B(OH)4(-) in solution with NO3( ) and Cl(-) intercalated in the interlayer of the LDH. Using three times the stoichiometric quantity of NO3 . Mg-Al LDH, the residual concentration of B decreased from 100 to 1.9 mg L(-1) in 120 min. Using five times the stoichiometric quantity of Cl . Mg - Al LDH, the residual concentration of B decreased from 100 to 5.6 mg L(-1) in 120 min. It must be emphasized that, in both cases, the residual concentration of B was less than the effluent standards in Japan (10 mg L(-1)). The rate-determining step of B removal by the NO3 . Mg - Al and Cl . Mg - Al LDHs was found to be chemical adsorption involving anion exchange of B(OH)4(-) with intercalated NO3(-) and Cl(-). The removal of B was well described by a pseudo second-order kinetic equation. The adsorption of B by NO3 . Mg - Al LDH and Cl . Mg - Al LDH followed a Langmuir-type adsorption. The values of the maximum adsorption and the equilibrium adsorption constant were 3.6 mmol g(-1) and 1.7, respectively, for NO3 . Mg - Al LDH, and 3.8 mmol g(-1) and 0.7, respectively, for Cl . Mg-Al LDH. The B(OH)4(-) in B(OH)4 . Mg - Al LDH produced by removal of B was found to undergo anion exchange with NO3(-) and Cl( ) in solution. The NO3 . Mg - Al and Cl . Mg - Al LDHs obtained after this regeneration treatment were able to remove B from aqueous solutions, indicating the possibility of recycling NO3 . Mg - Al and Cl . Mg - Al LDHs for B removal. PMID- 25827269 TI - Effects of rice residue incorporation on the speciation, potential bioavailability and risk of mercury in a contaminated paddy soil. AB - To reduce air pollution, straw return instead of burning is being strongly encouraged in China, including some mercury polluted areas. Nevertheless, the possible influences of straw return on methylation, bioavailability and exposure risk of mercury were relatively unknown. In this study, different amounts of rice straw or root were added into a mercury contaminated soil. Potential bioavailability of soil-bound mercury to crops/deposit-feeders was assessed by quantifying extraction rates of mercury (%) by calcium chloride (CaCl2)/bovine serum albumin (BSA). Extraction rates of inorganic mercury (IHg) or methylmercury (MMHg) decreased significantly in rice residue amended soils, possibly due to the strong binding of mercury with organic matter in root/straw. Meanwhile, MMHg concentrations increased by 2-8 times in amended soils. Such increases were attributed to enhanced microbial activities and/or formation of Hg-S-DOM complexes after rice residue incorporation and decomposition. Consequently, potential exposure risk of IHg (quantified as concentration of potentially bioavailable mercury in soil) decreased significantly while that of MMHg increased up to 4 times. To our knowledge, this is the first study demonstrating that rice residue incorporation could significantly affect biogeochemistry of both IHg and MMHg in soils, which should be considered in straw incorporation activities in mercury polluted areas. PMID- 25827270 TI - Co(II)-grafted Ag3PO4 photocatalysts with unexpected photocatalytic ability: Enhanced photogenerated charge separation efficiency, photocatalytic mechanism and activity. AB - Since the photocatalytic capability is determined by the separation and transmission efficiency of photoinduced charges, its improvement remains a challenge for development of efficient photocatalysts. Here, we made large improvement on the surface of Ag3PO4 using Co(II)-grafted Ag3PO4 by a hydrothermal method. During the photocatalytic process, Co(II) was oxidized to Co(III) by the photogenerated holes under visible light radiation, which enhanced the separation efficiency of photogenerated charges. Meanwhile, the Co(III) as formed could oxidize dye molecules, which recovered the Co(II). The synergy of Co(II) and Ag3PO4 greatly promoted the separation and transmission efficiency of the photogenerated charges, and severely improved the photocatalytic activity of Ag3PO4. The surface grafted Co(II) on Ag3PO4 is responsible for the enhancement of photocatalytic activity. PMID- 25827271 TI - Characterization and photocatalytic treatability of red water from Brazilian TNT industry. AB - The current study aims to characterize and evaluate the photocatalytic treatability of the "red water" effluent from a Brazilian TNT production industry. Analyses were performed using physical, chemical, spectroscopic and chromatographic assays, which demonstrated that the effluent presented a significant pollution potential, mainly due to COD, BOD, solids and to the high concentration of nitroaromatic compounds such as 1,3,5-trinitrobenzene, 1-methyl 2,4-dinitrobenzene, 2-methyl-1,3-dinitrobenzene, 2,4,6-trinitrotoluene-3,5 dinitro-p-toluidine and 2-methyl-3,5-dinitro-benzoamine. By a modified sol-gel and a dip-coating technique, it was possible to obtain a TiO2 film on borosilicate glass substrate which functional composition and microstructure were characterized by infrared spectroscopy and scanning electron microscopy. The evaluation of the photocatalytic treatability using borosilicate-glass-TiO2 demonstrated high degradation efficiency. In this context, a reduction of 32 and 100% for COD and nitroaromatic compounds, respectively, was observed. Although the proposed photocatalytic process has found difficulties in reducing the content of organic matter and effluent color in the red water, its potential for degrading refractory chemical compounds such as the nitroaromatic ones enables it to be used as tertiary treatment. PMID- 25827272 TI - Dual-process decomposition in human sensorimotor adaptation. AB - Multiple distinct learning processes are known to contribute to sensorimotor adaptation in humans. It is challenging to identify and characterize these multiple processes, however, because only their summed contribution can typically be observed. A general strategy for decomposing adaptation into its constituent components is to exploit their differential susceptibility to specific experimental manipulations. Several such approaches have recently emerged which, taken together, suggest that two fundamental systems operate together to achieve the adapted state: one system learns slowly, is implicit, is temporally stable over short breaks, is expressible at low reaction times, and its properties do not change based on experience. The second learns rapidly, is explicit, requires a long preparation time to be expressed, and exhibits long-term memory for prior learning. PMID- 25827273 TI - Motor-related signals in the auditory system for listening and learning. AB - In the auditory system, corollary discharge signals are theorized to facilitate normal hearing and the learning of acoustic behaviors, including speech and music. Despite clear evidence of corollary discharge signals in the auditory cortex and their presumed importance for hearing and auditory-guided motor learning, the circuitry and function of corollary discharge signals in the auditory cortex are not well described. In this review, we focus on recent developments in the mouse and songbird that provide insights into the circuitry that transmits corollary discharge signals to the auditory system and the function of these signals in the context of hearing and vocal learning. PMID- 25827274 TI - Feedback control during voluntary motor actions. AB - Humans possess an impressive ability to generate goal-oriented motor actions to move and interact with the environment. The planning and initiation of these body movements is supported by highly distributed cortical and subcortical circuits. Recent studies, inspired by advanced control theory, highlight similar sophistication when we make online corrections to counter small disturbances of the limb or altered visual feedback. Such goal-directed feedback is likely generated by the same neural circuits associated with motor planning and initiation. These common neural substrates afford a highly responsive system to maintain goal-directed control and rapidly select new motor actions as required to deftly move and interact in a complex world. PMID- 25827276 TI - Anesthesiological considerations for children with obstructive sleep apnea. AB - PURPOSE OF REVIEW: To summarize recent evidence-based data regarding outcomes associated with children who have obstructive sleep apnea (OSA). RECENT FINDINGS: Internet surveys conducted by pediatric otolaryngologists and pediatric anesthesiologists have reported a disturbing number of deaths within 24 h of tonsillectomy attributed to postsurgical/anesthesia apnea. Several occurred in the post anesthesia care unit after routine monitors had been removed. In addition, a number of deaths also have been attributed to children who have duplicated cytochromes allowing the rapid conversion of codeine to morphine, thus producing a relative drug overdose. Finally, there is some human and animal evidence suggesting that repeated episodes of hypoxemia result in altered opioid receptors causing relative opioid sensitivity. These factors have important clinical implications. SUMMARY: Perioperative deaths in children with OSA occur at a low frequency. Hypoxia-induced opioid sensitivity combined with an approximate 1-2% incidence of rapid conversion of codeine to morphine suggest the need for new approaches for providing preoperative assessment of risk, extended postoperative observation and the need for alternative opioids to codeine. Additionally, new less painful surgical approaches may help to reduce postoperative opioid requirements and therefore perhaps less risk for opiate induced apnea in this vulnerable population. PMID- 25827275 TI - Brain-controlled neuromuscular stimulation to drive neural plasticity and functional recovery. AB - There is mounting evidence that appropriately timed neuromuscular stimulation can induce neural plasticity and generate functional recovery from motor disorders. This review addresses the idea that coordinating stimulation with a patient's voluntary effort might further enhance neurorehabilitation. Studies in cell cultures and behaving animals have delineated the rules underlying neural plasticity when single neurons are used as triggers. However, the rules governing more complex stimuli and larger networks are less well understood. We argue that functional recovery might be optimized if stimulation were modulated by a brain machine interface, to match the details of the patient's voluntary intent. The potential of this novel approach highlights the need for a better understanding of the complex rules underlying this form of plasticity. PMID- 25827277 TI - Venous access in children: state of the art. AB - PURPOSE OF REVIEW: The aim of this review is to discuss recent developments in vascular access technology and to highlight those that are particularly relevant to the practitioner. RECENT FINDINGS: The need for venous access should always be critically assessed in every child, and it is important to use the limited number of suitable veins wisely and to avoid unnecessary attempts. Near-infrared devices make veins visible, but they do not necessarily increase the success rate of peripheral venous puncture. In contrast, ultrasound is now almost universally used for central venous puncture, and it helped to popularize the supraclavicular puncture of the left anonymous vein. The focus has shifted more toward infectious and especially thrombotic complications. SUMMARY: Despite the development of new technical devices, successful venous puncture remains heavily dependent on the skills of the operator. PMID- 25827278 TI - Modern neuraxial labour analgesia. AB - PURPOSE OF REVIEW: Neuraxial analgesia is considered the gold standard of labour analgesia as it provides the most effective method of pain relief during childbirth. In this article, we explore the recent advances in the initiation and maintenance of epidural analgesia. RECENT FINDINGS: Patient-controlled epidural analgesia, computer-integrated patient-controlled epidural analgesia, intermittent epidural bolus (programmed intermittent bolus, automated mandatory bolus) and variable frequency automated mandatory bolus administration are techniques that allow the individualized titration and optimization of labour analgesia. The debate has moved on to finding the optimal settings for epidural bolus dosing, time intervals and frequency for epidural analgesia with the hope of improving safety and efficacy as well as patient satisfaction. SUMMARY: We examine these recent developments in pump technology and epidural delivery systems and evaluate how these have enhanced the mothers' birthing experiences. PMID- 25827279 TI - What can you do to protect the newborn brain? AB - PURPOSE OF REVIEW: Hypoxic-ischemic brain injury is a leading cause of mortality and morbidity in neonates. Treating such injury by interrupting the excitotoxic oxidative cascade is of immense importance. This review will focus on novel techniques of neuroprotection and describe the latest advances in established therapeutic methods. KEY FINDINGS: Although the primacy of therapeutic hypothermia in treating hypoxic-ischemic encephalopathy is well established, recent research establishes that the arbitrarily chosen regimen of cooling to 33 degrees C for 72 h may indeed be the most appropriate method. The optimal duration of antenatal magnesium therapy for neuroprotection remains unsettled, though it is reassuring that even 12 h or less of magnesium therapy results in comparable neurological outcomes. Combining adjuvant therapies such as melatonin or erythropoietin with therapeutic hypothermia results in favorable neurological outcomes compared with hypothermia alone. Finally, stem cell-based therapies show considerable potential in preclinical studies. SUMMARY: Significant advances have occurred in the management of neonatal brain injury. With establishment of the optimal temperature and duration of hypothermia, combinatory therapies using adjuncts hold the greatest promise. Promising preclinical approaches such as stem cell-based therapy and use of noble gases need to be confirmed with clinical trials. PMID- 25827280 TI - General anesthesia for caesarean section. AB - PURPOSE OF REVIEW: For most anaesthesiologists, the clinical experience with general anaesthesia for caesarean section is very low. General anaesthesia is mostly performed for emergency grade 1 caesarean section and due to a lack of time to apply a neuraxial anaesthesia technique. Unfortunately, the majority of anaesthesiologists rely on historical and partly outdated approaches in this stressful situation. We propose an evidence-based approach to general anaesthesia for caesarean section. RECENT FINDINGS: Rapid sequence induction using propofol and rocuronium should become the standard for general anaesthesia in the obstetric patient. Short-acting opioids are still not given routinely but should never be withheld in case of severe preeclampsia. Cricoid pressure can only be accurately performed by trained caregivers and should be released if intubation appears to be difficult. Supra-glottic airway devices may safely be used in fasted, nonobese elective caesarean section, but endotracheal intubation remains the gold standard, especially in emergency caesarean section in labouring women. Both sevoflurane and propofol are appropriate for the maintenance of general anaesthesia during caesarean section. Awareness remains a major concern in obstetric anaesthesia. SUMMARY: We present a review of recent evidence on general anaesthesia for caesarean section. PMID- 25827281 TI - Blood conservation strategies and the management of perioperative anaemia. AB - PURPOSE OF REVIEW: Anaemia is a global health problem with particularly high prevalence in the perioperative setting and it can significantly affect the patient outcomes. This review addresses new findings on the significance of anaemia and patient blood management (PBM) strategies to prevent and manage anaemia. RECENT FINDINGS: Studies support the independent deleterious effects of anaemia on mortality, morbidity and quality of life as well as its role as a risk factor for transfusion. Although improved understanding of iron regulators such as hepcidin is expected to revolutionize the field, simple algorithms are useful tools for more effective management of anaemia relying on currently available therapies (such as intravenous iron and erythropoiesis-stimulating agents). Other PBM strategies such as optimization of haemostasis and avoidance of blood loss are effective in preventing anaemia or its exacerbation and improving the outcomes of patients. In addition, more attention should be given to hospital acquired anaemia (HAA) and its avoidable causes, such as unnecessary diagnostic phlebotomies. SUMMARY: Despite the high prevalence of anaemia and the significant toll it takes on patients, simple and effective strategies are available to detect, diagnose and treat it. PMID- 25827282 TI - Preoperative oral carbohydrate therapy. AB - PURPOSE OF REVIEW: Management of the postoperative response to surgical stress is an important issue in major surgery. Avoiding preoperative fasting using preoperative oral carbohydrates (POC) has been suggested as a measure to prevent and reduce the extent to which such derangements occur. This review summarizes the current evidence and rationale for this treatment. RECENT FINDINGS: A recent review from the Cochrane Collaboration reports enhanced gastrointestinal recovery and shorter hospital stay with the use of POC with no effect on postoperative complication rates. Multiple randomized controlled trials demonstrate improved postoperative metabolic response after POC administration, including reduced insulin resistance, protein sparing, improved muscle function and preserved immune response. Cohort studies in patients undergoing major abdominal surgery have shown that the use of POC as part of an enhanced recovery after surgery protocol is a significant predictor for improved clinical outcomes. SUMMARY: Avoiding preoperative fasting with POC is associated with attenuated postoperative insulin resistance, improved metabolic response, enhanced perioperative well-being, and better clinical outcomes. The impact is greatest for patients undergoing major surgeries. PMID- 25827283 TI - Improving perioperative outcomes and the giants of evidence-based medicine. PMID- 25827284 TI - Patient-controlled intravenous analgesia remifentanil for labor analgesia: time to stop, think and reconsider. AB - PURPOSE OF REVIEW: Remifentanil is a relatively new but commonly used opioid alternative in the management of labor pain relief. The present article evaluates efficacy and safety of patient-controlled intravenous analgesia (PCIA) with remifentanil in the management of labor pain relief. RECENT FINDINGS: Remifentanil PCIA provides analgesia that is superior to nitrous oxide or other opioids such as meperidine, but is less effective when compared with epidural analgesia. Recent evidence suggests it produces significant respiratory depression making routine use as first line analgesia strategy virtually impossible. SUMMARY: Remifentanil PCIA is a valuable analgesic strategy whenever regional analgesia is contraindicated. Using it as first line strategy seems to be contraindicated because of significant respiratory side-effects to the mother. Whenever used advanced and continuous monitoring using capnography, saturation monitoring and one-to-one midwifery care are mandatory! PMID- 25827285 TI - Identification and characterization of reproductive KRAB-ZF genes in mice. AB - The mammalian genome contains numerous genes encoding transcription factors that contain Kruppel-associated box (KRAB) and C2H2-type zinc finger (ZF) motifs (KRAB ZF). In the present study, we identified KRAB-ZF genes expressed in the mouse testis or ovary, and selected three genes that exhibit gonad-specific or gonad predominant expression. In vitro analyses showed that these gonadal KRAB-ZF proteins are localized in cell nuclei and are able to repress transcriptional activity. We further analyzed one of the gonad-specific reproductive genes, Zfp819, and found that it is expressed exclusively in spermatogenic cells. Overexpression of Zfp819 suppressed cell proliferation and induced apoptosis. Microarray analysis of Zfp819-overexpressing cells allowed us to identify numerous, potential target genes. A number of the down-regulated genes were found to show gene expression levels inversely correlated with Zfp819 during spermatogenesis. Some of the down-regulated genes were previously reported to play significant roles in spermatogenesis and apoptosis. Collectively, our study provides the first comprehensive information regarding the expression of reproductive KRAB-ZF genes in mice and reveals potential functions of Zfp819. PMID- 25827286 TI - Linear mRNA amplification approach for RNAseq from limited amount of RNA. AB - Whole-transcriptome evaluation by next-generation sequencing (NGS) has been widely applied in the investigation of diverse transcriptional scenarios. In many clinical situations, including needle biopsy samples or laser microdissected cells, limited amounts of RNA are usually available for the assessment of the whole transcriptome. Here, we describe an mRNA amplification protocol based on in vitro T7 transcription for transcriptome evaluation by NGS. Initially, we performed RNAseq from two human mammary epithelial cell lines and evaluated several aspects of the transcriptomes generated by linear amplification of Poly (A)(+) mRNA species, including transcript representation, variability and abundance. Our protocol showed to be efficient with respect to full-length transcript coverage and quantitative expression levels. We then evaluated the applicability of using this protocol in a more realistic research scenario, analyzing tumor tissue samples microdissected by laser capture. In order to increase the quantification power of the libraries only the 3' end of transcripts were sequenced. We found highly reproducible RNAseq data among amplified tumor samples, with a median Spearman's correlation of 80%, strongly suggesting that the amplification step and library protocol preparation lead to a consistent transcriptional profile. Altogether, we established a robust protocol for assessing the polyadenylated transcriptome derived from limited amounts of total RNA that is applicable to all NGS platforms. PMID- 25827287 TI - Tuning thermal transport in ultrathin silicon membranes by surface nanoscale engineering. AB - A detailed understanding of the connections of fabrication and processing to structural and thermal properties of low-dimensional nanostructures is essential to design materials and devices for phononics, nanoscale thermal management, and thermoelectric applications. Silicon provides an ideal platform to study the relations between structure and heat transport since its thermal conductivity can be tuned over 2 orders of magnitude by nanostructuring. Combining realistic atomistic modeling and experiments, we unravel the origin of the thermal conductivity reduction in ultrathin suspended silicon membranes, down to a thickness of 4 nm. Heat transport is mostly controlled by surface scattering: rough layers of native oxide at surfaces limit the mean free path of thermal phonons below 100 nm. Removing the oxide layers by chemical processing allows us to tune the thermal conductivity over 1 order of magnitude. Our results guide materials design for future phononic applications, setting the length scale at which nanostructuring affects thermal phonons most effectively. PMID- 25827288 TI - Characterization and quantification of dynamic eccentric regurgitation of the left atrioventricular valve after atrioventricular septal defect correction with 4D Flow cardiovascular magnetic resonance and retrospective valve tracking. AB - BACKGROUND: To characterize and directly quantify regurgitant jets of left atrioventricular valve (LAVV) in patients with corrected atrioventricular septal defect (AVSD) by four-dimensional (4D)Flow Cardiovascular Magnetic Resonance (CMR), streamline visualization and retrospective valve tracking. METHODS: Medical ethical committee approval and informed consent from all patients or their parents were obtained. In 32 corrected AVSD patients (age 26 +/- 12 years), echocardiography and whole-heart 4DFlow CMR were performed. Using streamline visualization on 2- and 4-chamber views, the angle between regurgitation and annulus was followed throughout systole. On through-plane velocity-encoded images reformatted perpendicular to the regurgitation jet the cross-sectional jet circularity index was assessed and regurgitant volume and fraction were calculated. Correlation and agreement between different techniques was performed with Pearson's r and Spearman's rho correlation and Bland-Altman analysis. RESULTS: In 8 patients, multiple regurgitant jets over the LAVV were identified. Median variation in regurgitant jet angle within patients was 36 degrees (IQR 18 64 degrees ) on the 2-chamber and 30 degrees (IQR 20-40 degrees ) on the 4 chamber. Regurgitant jets had a circularity index of 0.61 +/- 0.16. Quantification of the regurgitation volume was feasible with 4DFlow CMR with excellent correlation between LAVV effective forward flow and aortic flow (r = 0.97, p < 0.001) for internal validation and moderate correlation with planimetry derived regurgitant volume (r = 0.65, p < 0.001) and echocardiographic grading (rho = 0.51, p = 0.003). CONCLUSIONS: 4DFlow CMR with streamline visualization revealed multiple, dynamic and eccentric regurgitant jets with non-circular cross sectional shape in patients after AVSD correction. 4DFlow with retrospective valve tracking allows direct and accurate quantification of the regurgitation of these complex jets. PMID- 25827289 TI - Diet quality in older age: the influence of childhood and adult socio-economic circumstances. AB - Socio-economic gradients in diet quality are well established. However, the influence of material socio-economic conditions particularly in childhood, and the use of multiple disaggregated socio-economic measures on diet quality have been little studied in the elderly. In the present study, we examined childhood and adult socio-economic measures, and social relationships, as determinants of diet quality cross-sectionally in 4252 older British men (aged 60-79 years). A FFQ provided data on daily fruit and vegetable consumption and the Elderly Dietary Index (EDI), with higher scores indicating better diet quality. Adult and childhood socio-economic measures included occupation/father's occupation, education and household amenities, which combined to create composite scores. Social relationships included social contact, living arrangements and marital status. Both childhood and adult socio-economic factors were independently associated with diet quality. Compared with non-manual social class, men of childhood manual social class were less likely to consume fruit and vegetables daily (OR 0.80, 95% CI 0.66, 0.97), as were men of adult manual social class (OR 0.65, 95% CI 0.54, 0.79), and less likely to be in the top EDI quartile (OR 0.73, 95% CI 0.61, 0.88), similar to men of adult manual social class (OR 0.66, 95 % CI 0.55, 0.79). Diet quality decreased with increasing adverse adult socio-economic scores; however, the association with adverse childhood socio-economic scores diminished with adult social class adjustment. A combined adverse childhood and adulthood socio-economic score was associated with poor diet quality. Diet quality was most favourable in married men and those not living alone, but was not associated with social contact. Diet quality in older men is influenced by childhood and adulthood socio-economic factors, marital status and living arrangements. PMID- 25827290 TI - Predictors of optimal cytoreduction in patients with newly diagnosed advanced stage epithelial ovarian cancer: Time to incorporate laparoscopic assessment into the standard of care. AB - The standard management of advanced-stage ovarian cancer has been a subject of debate, and much controversy remains as to whether patients should have primary cytoreductive surgery followed by chemotherapy or neoadjuvant chemotherapy followed by interval cytoreductive surgery. In addition, there is increasing evidence that the patients who ultimately gain the most benefit from surgery are those with no residual disease at the completion of surgery (R0 resection). Therefore, to determine the best therapeutic strategy (primary cytoreductive surgery vs. neoadjuvant chemotherapy) for an individual patient, it is critically important to estimate the likelihood that primary cytoreductive surgery will leave no macroscopic residual disease. A number of studies have evaluated the use of serologic markers, such as CA-125, and imaging modalities, such as computed tomography (CT) or positron emission tomography/CT (PET/CT), to determine which patients are ideal candidates for primary cytoreductive surgery. More recently, laparoscopy has been proposed as a reliable predictor of R0 resection. In this report, we provide a review of the existing literature on the proposed criteria to predict the outcome of cytoreductive surgery and the role of laparoscopy-based scores in the management of advanced ovarian cancer. PMID- 25827291 TI - A randomized trial comparing concurrent chemoradiotherapy with single-agent cisplatin versus cisplatin plus gemcitabine in patients with advanced cervical cancer: An Asian Gynecologic Oncology Group study. AB - OBJECTIVE: A recent randomized trial demonstrated that concurrent chemoradiotherapy (CCRT) with weekly cisplatin and gemcitabine, followed by two adjuvant cycles of cisplatin and gemcitabine improved survival for advanced cervical cancer patients. An Asian Gynecologic Oncology Group (AGOG) study was designed to determine whether only adding gemcitabine in the chemoradiation phase without adjuvant chemotherapy could improve survival. METHODS: Between March 2009 and March 2013, 74 eligible patients with International Federation of Obstetrics and Gynecology stage III/IVA cervical cancer or stage I/II with positive pelvic/para-aortic nodal metastasis were enrolled. Thirty-seven patients were randomized to arm C (weekly cisplatin 40mg/m(2)) and 37 patients were randomized to arm CG (weekly cisplatin 40mg/m(2) and gemcitabine 125mg/m(2)), for six cycles. Six eligible patients were excluded before the beginning of treatment. RESULTS: An interim analysis showed superimposable progression-free (PFS) and overall survival (OS), a decision of closing accrual was made. A 3-year PFS was similar in both arms (arm C 65.1% vs. arm CG 71.0%, p=0.71), and a 3-year OS was 74.1% in arm C vs. 85.9% in arm CG (p=0.89), but crossed over at 5years. Grade 2 4 hematological toxicities, including neutropenia (p=0.028) and thrombocytopenia (p=0.001), were more frequent in arm CG than arm C. CONCLUSIONS: Despite limitation in power, it suggests that only adding gemcitabine at the CCRT phase does not provide substantially superior results, but treatment toxicities could increase. Further studies are required to determine the role of post-CCRT adjuvant chemotherapy in advanced cervical cancer. PMID- 25827292 TI - Quality of life after early enteral feeding versus standard care for proven or suspected advanced epithelial ovarian cancer: Results from a randomised trial. AB - BACKGROUND: Malnutrition is common in patients with advanced epithelial ovarian cancer (EOC), and is associated with impaired quality of life (QoL), longer hospital stay and higher risk of treatment-related adverse events. This phase III multi-centre randomised clinical trial tested early enteral feeding versus standard care on postoperative QoL. METHODS: From 2009 to 2013, 109 patients requiring surgery for suspected advanced EOC, moderately to severely malnourished were enrolled at five sites across Queensland and randomised to intervention (n=53) or control (n=56) groups. Intervention involved intraoperative nasojejunal tube placement and enteral feeding until adequate oral intake could be maintained. Despite being randomised to intervention, 20 patients did not receive feeds (13 did not receive the feeding tube; 7 had it removed early). Control involved postoperative diet as tolerated. QoL was measured at baseline, 6weeks postoperatively and 30days after the third cycle of chemotherapy. The primary outcome measure was the difference in QoL between the intervention and the control group. Secondary endpoints included treatment-related adverse event occurrence, length of stay, postoperative services use, and nutritional status. RESULTS: Baseline characteristics were comparable between treatment groups. No significant difference in QoL was found between the groups at any time point. There was a trend towards better nutritional status in patients who received the intervention but the differences did not reach statistical significance except for the intention-to-treat analysis at 7days postoperatively (11.8 intervention vs. 13.8 control, p 0.04). CONCLUSION: Early enteral feeding did not significantly improve patients' QoL compared to standard of care but may improve nutritional status. PMID- 25827293 TI - Immediate radical trachelectomy versus neoadjuvant chemotherapy followed by conservative surgery for patients with stage IB1 cervical cancer with tumors 2cm or larger: A literature review and analysis of oncological and obstetrical outcomes. AB - Radical trachelectomy is the treatment of choice in women with early-stage cervical cancer wishing to preserve fertility. Radical trachelectomy can be performed with a vaginal, abdominal, or laparoscopic/robotic approach. Vaginal radical trachelectomy (VRT) is generally not offered to patients with tumors 2cm or larger because of a high recurrence rate. There are no conclusive recommendations regarding the safety of abdominal radical trachelectomy (ART) or laparoscopic radical trachelectomy (LRT) in such patients. Several investigators have used neoadjuvant chemotherapy in patients with tumors 2 to 4cm to reduce tumor size so that fertility preservation may be offered. However, to our knowledge, no published study has compared outcomes between patients with cervical tumors 2cm or larger who underwent immediate radical trachelectomy and those who underwent neoadjuvant chemotherapy followed by radical trachelectomy. We conducted a literature review to compare outcomes with these 2 approaches. Our main endpoints for evaluation were oncological and obstetrical outcomes. The fertility preservation rate was 82.7%, 85.1%, 89%; and 91.1% for ART (tumors larger than >2cm), ART (all sizes), NACT followed by surgery and VRT (all sizes); respectively. The global pregnancy rate was 16.2%, 24% and 30.7% for ART, VRT, and NACT followed by surgery; respectively. The recurrence rate was 3.8%, 4.2%, 6%, 7.6% and 17% for ART (all sizes), VRT (all sizes), ART (tumors>2cm), NACT followed by surgery, and VRT (tumors>2cm). These outcomes must be considered when offering a fertility sparing technique to patients with a tumor larger than 2cm. PMID- 25827294 TI - Three-dimensional printed calcaneal prosthesis following total calcanectomy. AB - INTRODUCTION: The majority of patients with extremity sarcoma can be surgically treated without amputation. However, limb-salvage surgery for foot sarcomas including the calcaneus remains challenging. PRESENTATION OF CASE: A 71-year-old man presented with a 5-year history of right heel persistent pain. Imaging studies revealed an osteolytic, destructive and highly metabolic lesion in the right calcaneus. Computed tomography guided core needle biopsy confirmed the diagnosis of grade 2 chondrosarcoma. A total calcanectomy was performed, and the defect was reconstructed with a patient matched three-dimensional printed titanium calcaneal prosthesis. Intra-operatively, ligaments including the Achilles tendon, and plantar fascia were reattached. The post-operative course was uneventful, and at the 5-month clinical follow-up, the patient was fully weightbearing, with a mobile ankle without pain. DISCUSSION: This case is the first to use additive manufacturing to create a prosthetic calcaneus. The complex peri-calcaneal articular surfaces and reattachment of tendinous structures facilitate efforts to stabilize the prosthesis in situ. CONCLUSION: Three dimensional-printed prosthesis of the calcaneus is a viable alternative to amputation. PMID- 25827295 TI - Thyroid metastasis as initial presentation of clear cell renal carcinoma. AB - INTRODUCTION: Metastatic tumors account for 1.4-2.5% of thyroid malignancies. About 25-30% of patients with clear cell renal carcinoma (CCRC) have distant metastasis at the time of diagnosis, being the thyroid gland a rare localization [5%]. PRESENTATION OF THE CASE: A 62-year woman who underwent a cervical ultrasonography and a PAAF biopsy reporting atypical follicular proliferation with a few intranuclear vacuoles "suggestive" of thyroid papillary cancer in the context of a multinodular goiter was reported. A total thyroidectomy was performed and the histology of a clear cell renal carcinoma (CCRC) was described in four nodules of the thyroid gland. A CT scan was performed and a renal giant right tumor was found. The patient underwent an eventful radical right nephrectomy and the diagnosis of CCRC was confirmed. DISCUSSION: Thyroid metastasis (TM) from CCRC are usually apparent in a metachronic context during the follow-up of a treated primary (even many years after) but may sometimes be present at the same time than the primary renal tumor. Our case is exceptional because the TM was the first evidence of the CCRC, which was subsequently diagnosed and treated. CONCLUSION: The possibility of finding of an incidental metastatic tumor in the thyroid gland from a previous unknown and non-diganosed primary (as CCRC in our case was) is rare and account only for less than 1% of malignancies. Nonetheless, the thyroid gland is a frequent site of metastasis and the presence of "de novo" thyroid nodules in oncologic patients must be always considered and studied. PMID- 25827296 TI - Abdominal aortitis on PET CT: A case report and review of the literature. AB - INTRODUCTION: Aortitis often occurs in patients with systemic vasculitis. PRESENTATION OF CASE: We reported a 73 year old man with giant cell arteritis who was presented with abdominal pain and weight loss. DISCUSSION: Aortitis was diagnosed on PET-CT scan performed because initial investigations raised the possibility of pancreatic pathology. CONCLUSION: This case highlights the utility of PET-CT in the diagnosis of abdominal aortitis and the need to consider aortitis as a differential in patients with abdominal pain with a history of vasculitis. PMID- 25827297 TI - PAX6 Expression and Retinal Cell Death in a Transgenic Mouse Model for Acute Angle-Closure Glaucoma. AB - PURPOSE: PAX6 is a highly conserved protein essential for the control of eye development both in invertebrates and vertebrates. PAX6 expression persists in the adult inner retina, but little is known about its functions after completion of retinal differentiation. Therefore, we investigated PAX6 expression in wild type and calcitonin receptor-like receptor transgenic (CLR(SMalphaA)) mice with angle-closure glaucoma. METHODS: Intraocular pressure was measured by indentation tonometry in anesthetized mice. Eyes of mice of both genotypes were enucleated at various ages and retinas were processed for morphological analysis and PAX6 immunostaining. The content of PAX6 in retinal extracts was estimated by Western blot analysis. Retinal expression of glaucoma-related genes was analyzed by reverse transcription-polymerase chain reaction. RESULTS: Control mice showed normal retinal morphology between p22 and p428 with steady PAX6 expression in the ganglion cell layer (GCL) and the inner nuclear layer (INL). CLR(SMalphaA) mice examined between p22 and p82 exhibited increased intraocular pressure and a progressive decrease in cell number including PAX6-expressing cells in the GCL. The INL was not affected up to postnatal day 42. Later, a significant increase in PAX6-expressing cells concomitant with an overall loss of cells was observed in the INL of CLR(SMalphaA) as compared with control mice. Retinal up-regulation of glaucoma-related genes was furthermore observed. CONCLUSIONS: Distinctive changes of PAX6 expression in the inner retina of CLR(SMalphaA) mice suggest a role in regulatory mechanisms involved in glaucoma-related retinal cell death. The selective increase of PAX6 expression in the degenerating INL of CLR(SMalphaA) mice may represent an attempt to preserve retinal cytoarchitecture. PMID- 25827298 TI - Characterization of Glaucoma Medication Adherence in Kaiser Permanente Southern California. AB - PURPOSE: To describe adherence to glaucoma medications. PATIENTS AND METHODS: Medication adherence was investigated using the computerized records of Kaiser Permanente Southern California, a group model health maintenance organization that provides care to 3.4 million residents of Southern California. Eligible glaucoma patients were diagnosed between 2005 and 2009 and had medical and prescription drug coverage between 2005 and 2009. Utilization and adherence parameters were calculated for each of the 5 years from the incident date. RESULTS: A total of 17,943 newly diagnosed glaucoma patients were identified between the years 2005 and 2009. Of patients diagnosed with glaucoma in 2005, 71% were continuously eligible for 5 years. Medication adherence was calculated using a medication possession ratio. Adherence was bimodal and not normal in distribution. Overall, the mean age of the entire group was 66 years, with 56% being 65 years of age or older. The high adherence group tended to be older, more likely to be female, and more likely to be white. The low adherent group (younger) tended to have more and worse diabetes, renal disease, myocardial infarction, and stroke. CONCLUSIONS: The shape of the adherence distribution appears bimodal, so analysis based on parametric measures may not be appropriate. Investigations of adherence should probably be performed separately for the low, mid, and high groups. PMID- 25827299 TI - Cup-to-Disc Ratio From Heidelberg Retina Tomograph 3 and High-Definition Optical Coherence Tomography Agrees Poorly With Clinical Assessment. AB - PURPOSE: To investigate the agreement of vertical cup-to-disc ratio (VCDR) measured from Heidelberg Retina Tomograph 3 (HRT-3), high-definition optical coherence tomography (HD-OCT), and clinical grading. METHODS: A total of 933 consecutive subjects underwent optic nerve head imaging with HRT-3 and HD-OCT during a single visit. The vertical dimensions of the disc and cup were measured by slit-lamp examination using an eyepiece graticule. Bland-Altman plots evaluated the agreement in the VCDR obtained by the 2 instruments and clinical grading. RESULTS: We found a significant trend for the difference in VCDR measured clinically and with HRT and HD-OCT (P<0.001 for both). The mean VCDR differed significantly between clinical measurement and that evaluated by HRT and HD-OCT, respectively (0.40 +/- 0.12 vs. 0.37 +/- 0.21 and 0.40 +/- 0.12 vs. 0.50 +/- 0.14, P<0.001 for both), with significantly poor correlation (r(2)=0.35 and 0.34, P<0.001 for both). CONCLUSIONS: In general, there is poor correlation and a lack of agreement of VCDR measured using HRT-3, HD-OCT, and clinical grading. HD OCT has somewhat better agreement with clinical measurements of VCDR. Compared with clinical grading, HD-OCT tended to overestimate VCDR, whereas HRT-3 tended to underestimate it. PMID- 25827300 TI - Evaluation of Quality of Life in Japanese Glaucoma Patients and its Relationship With Visual Function. AB - PURPOSE: We assessed vision-related quality of life (VR-QOL) in glaucoma patients and examined the relationship between VR-QOL and indices of visual function and subjective symptoms. PATIENTS AND METHODS: Four hundred seventy-two glaucoma patients completed a questionnaire concerning VR-QOL and subjective symptoms of glaucoma. VR-QOL was based on 5 subscales selected from the National Eye Institute 25-item Visual Function Questionnaire (NEI VFQ-25), whereas subjective symptoms were examined using original questions that we prepared. The following were selected as visual function indices: corrected visual acuity measured with a distance visual acuity chart, mean deviation scores measured with a static perimeter, and 4 threshold levels in the innermost center of a visual field (4 pericentral test points). Disease staging was conducted according to the Aulhorn classification system. Correlations of visual function with VR-QOL were evaluated using the Spearman test. RESULTS: Correlations were observed in almost all subscales of the NEI VFQ-25, including correlations with corrected vision, disease stage, mean deviation score, and minimum threshold values of the 4-point pericentral test on the temporal side (P<0.0001). Visual function indices affecting driving differed between daytime and night driving (P<0.0001). NEI VFQ 25 subscales were correlated with subjective symptoms felt by the patients while driving (P<0.0001). CONCLUSIONS: Minimum threshold values of the 4 pericentral test points on the temporal side are useful for the assessment of VR-QOL. Minimum threshold values of the 4 pericentral test points on the temporal side are useful for assessing visual field abnormalities that are associated with decreased VR QOL. PMID- 25827301 TI - Evaluating stakeholder's perspective on referred out genetic testing in Canada: a discrete choice experiment. AB - The expanding number and increasing utility of clinical genetic tests is creating a growing burden on the Canadian healthcare system. Administrators are faced with the challenge of determining which genetic tests should be publicly funded. A discrete choice experiment (DCE) was utilized to assess the importance stakeholders place on five attributes of a genetic test. One hundred ninety individuals completed the DCE questions. Analysis of the data revealed that medical benefit of a test had the greatest impact on a respondent's decision to select a test for funding. The detection rate of the test ranked second in importance followed by severity of the condition, aim of the test, and cost. With limited resources available for referred out molecular genetic testing within a public healthcare setting such as Canada's, funding guidelines are critical. Our findings provide further evidence for the value of a decision-making framework and the relative importance of specific test attributes within such a framework. PMID- 25827302 TI - Psychopathology and Related Psychosocial Factors in Children with Office Discipline Referrals at School: Evidence from a Developing Country. AB - Many childhood psychiatric disorders present their first symptoms as challenging behaviors at school. Evidence from cross-national studies enhance the understanding of the biological and cultural variables underlying these behaviours. In this study, we aim to identify the psychopathology among children with office disciplinary referrals and assess psychosocial risk factors related to this situation. Forty-seven students who had received an office discipline referral and eighty-three controls who had never been given an office disciplinary referral participated in this study. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children--Present and Lifetime, socio-demographic data form were administered to children to assess their respective psychopathologies and psychosocial risk factors. Attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, and obsessive compulsive disorder were significantly higher in children with Office discipline referrals. Psychiatric assessment should be one of the first steps in the evaluation processes of assessing challenging behaviors at school. PMID- 25827303 TI - Continuity of Care in Children's Mental Health: Parent, Youth and Provider Perspectives. AB - Continuity of care, how individuals experience care over time as coherent and linked, is considered an ethical principle of care. While continuity has been examined extensively in the adult health literature, there is a paucity of studies examining continuity in children's mental health care. Using qualitative semi-structured interviews with parents, youth, and service providers, the current study found themes and issues unique to this healthcare context, such as coordination across sectors; risks to discontinuity, such as transitions; and consequences of discontinuity, such as parents acting as liaisons. Implications of these findings are discussed. PMID- 25827304 TI - Non-traumatic biliary duct neuroma masquerading as a Klatskin tumour. PMID- 25827305 TI - Prognostic values of 5-hmC, 5-mC and TET2 in epithelial ovarian cancer. AB - PURPOSE: DNA methylation is an important epigenetic modification that is frequently altered in cancer. Recent reports showed that the level of 5 hydroxymethylcytosine (5-hmC) was altered in various types of cancers. The influence of DNA methylation in epithelial ovarian cancer (EOC) is not fully understood. Therefore, the aim of the present study was to investigate factors involved in DNA demethylation in EOC compared with normal ovarian tissues. METHODS: We examined the expression of 5-hmC, 5-mC, and TET2 by immunohistochemistry in 130 cases of EOC and 40 cases of normal ovarian tissues. We assessed the prognostic values of 5-hmC, 5-mC, and TET2 in clinical outcome of EOC. RESULTS: We discovered a significant decrease in 5-hmC and TET2 expression in EOC compared with normal ovarian tissues. In contrast, there was a significant increase in 5-mC expression in EOC compared with normal ovarian tissues. The expression of 5-hmC, 5-mC, and TET2 correlated with pathologic stage, tumor grading, lymph node metastasis, and vascular thrombosis. Furthermore, decreased level of 5-hmC predicts poor prognosis of EOC patients. The expression of 5-hmC was an independent prognostic factor for overall survival of EOC patients. CONCLUSIONS: The data suggest that loss of 5-hmC is an epigenetic event of EOC, and the expression of 5-hmC could serve as a prognostic factor for EOC. PMID- 25827306 TI - Comparison of spray-dried egg and albumen powder with conventional animal protein sources as feed ingredients in diets fed to weaned pigs. AB - We evaluated the apparent (AID) and standardized ileal digestibility (SID) of amino acids (AA) in spray-dried egg (SPE) and albumen powder (AP) compared with spray-dried porcine plasma (SDPP), dried porcine solubles (DPS) and fish meal (FM). Additionally, the effects of these egg byproducts as a replacement for conventional animal proteins on the performance and nutrient digestibility of piglets were studied. In Exp. 1, six barrows fitted with ileal T-cannulas were allotted to a 6 * 6 Latin Square design and fed six diets. The AID and SID of AA were generally higher in AP and FM (P < 0.01) than in the other protein sources. In Exp. 2, 150 piglets weaned at 21 days, were fed diets containing the five protein sources for 3 weeks. Weight gain of piglets fed SDPP was the highest among the treatments. Dry matter and protein digestibility for pigs offered SDPP were higher (P < 0.01) than those offered FM and DPS. AP decreased (P < 0.05) Escherichia coli counts in the cecum. DPS decreased (P < 0.05) serum diamine oxidase compared with SPE. In conclusion, AP and SPE are competitive with traditional animal protein sources and can be successfully fed to piglets without compromising performance. PMID- 25827307 TI - Electrodialytic removal of nitrate from pineapple juice: effect on selected physicochemical properties, amino acids, and aroma components of the juice. AB - This study aimed at investigating the effect of nitrate removal from pineapple juice by electrodialysis (ED) on selected properties of the ED-treated juice. Single-strength pineapple juice with reduced pulp content was treated by ED to reduce the nitrate concentration to 15, 10, or 5 ppm. After ED, the removed pulp was added to the ED-treated juice and its properties, including electrical conductivity, acidity, pH, total soluble solids (TSS), color, amino acids, and selected aroma compounds, were determined and compared with those of the untreated juice. ED could reduce the nitrate content of 1 L of pineapple juice from an initial value of 50 ppm to less than 5 ppm within 30 min. A significant decrease in the electrical conductivity, acidity, pH, TSS, and yellowness, but a significant increase in the lightness, of the juice was observed upon ED. Concentrations of almost all amino acids of the ED-treated juice significantly decreased. The concentrations of 8 major compound contributors to the pineapple aroma also significantly decreased. Adding the pulp back to the ED-treated juice increased the amino acids concentrations; however, it led to a significant decrease in the concentrations of the aroma compounds. PMID- 25827309 TI - Surgical treatment of an atlantoaxial fracture after a delayed diagnosis in a comatose patient. AB - STUDY DESIGN: Case report. OBJECTIVE: To report a case of fractures of the right lateral atlantoaxial joint and C2 body diagnosed more than 5 months after injury. Misdiagnosis of an injury to the cervical spine has been reported frequently. For patients in whom cervical injury is suspected, the primary screening modality is axial CT from the occiput to T1 with sagittal and coronal reconstructions. The inadequacy of this radiological evaluation could delay diagnosis of fractures and lead to unnecessary surgical treatment of the cervical spine. METHODS: We report the case of a 74-year-old woman with an old, displaced combined fracture of the C1 and C2 right facet joint. In this case, CT of the brain was evaluated at the time of injury, but not CT of the cervical spine. As a consequence, diagnosis was delayed and surgical treatment was necessary. RESULTS: We performed posterior fusion surgery for C1 and C2. A pedicle screw was not inserted on both sides of C2, because of destruction of the insertional point on the right side and a high riding VA on the left. Alternatively, a lamina screw and hook were used for C2, fixed with lateral mass screws on C1, with a bone graft harvested from the iliac crest. CONCLUSIONS: To avoid unnecessary surgery, surgeons should recognize the possibility of cervical fractures that cannot be detected without CT, especially in patients who are comatose at injury. Atlantoaxial fixation with a hook and lamina screw in C2 is an option for old upper cervical fractures in cases where a pedicle screw cannot be inserted into C2. PMID- 25827308 TI - Are non-steroidal anti-inflammatory drugs effective for the management of neck pain and associated disorders, whiplash-associated disorders, or non-specific low back pain? A systematic review of systematic reviews by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration. AB - PURPOSE: To evaluate the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) for the management of neck pain and associated disorders (NAD), whiplash associated disorders, and non-specific low back pain (LBP) with or without radiculopathy. METHODS: We systematically searched six databases from 2000 to 2014. Random pairs of independent reviewers critically appraised eligible systematic reviews using the Scottish Intercollegiate Guidelines Network criteria. We included systematic reviews with a low risk of bias in our best evidence synthesis. RESULTS: We screened 706 citations and 14 systematic reviews were eligible for critical appraisal. Eight systematic reviews had a low risk of bias. For recent-onset NAD, evidence suggests that intramuscular NSAIDs lead to similar outcomes as combined manipulation and soft tissue therapy. For NAD (duration not specified), oral NSAIDs may be more effective than placebo. For recent-onset LBP, evidence suggests that: (1) oral NSAIDs lead to similar outcomes to placebo or a muscle relaxant; and (2) oral NSAIDs with bed rest lead to similar outcomes as placebo with bed rest. For persistent LBP, evidence suggests that: (1) oral NSAIDs are more effective than placebo; and (2) oral NSAIDs may be more effective than acetaminophen. For recent-onset LBP with radiculopathy, there is inconsistent evidence on the effectiveness of oral NSAIDs versus placebo. Finally, different oral NSAIDs lead to similar outcomes for neck and LBP with or without radiculopathy. CONCLUSIONS: For NAD, oral NSAIDs may be more effective than placebo. Oral NSAIDs are more effective than placebo for persistent LBP, but not for recent-onset LBP. Different oral NSAIDs lead to similar outcomes for neck pain and LBP. PMID- 25827310 TI - Estimation of exposure to dietary acrylamide based on mercapturic acids level in urine of Polish women post partum and an assessment of health risk. AB - We determined metabolites of acrylamide and glycidamide concentrations (AAMA and GAMA, respectively) in urine of 93 women within the first days after delivery, using LC-MS/MS. The median AAMA and GAMA levels in urine were 20.9 MUg/l (2.3/399.0 MUg/l) and 8.6 MUg/l (1.3/85.0 MUg/l), respectively. In smokers we found significantly (P<0.01) higher levels of metabolites in comparison with the non-smoking women. As demonstrated by the 24-h dietary recall, acrylamide intake was low (median: 7.04 MUg/day). Estimated exposure to acrylamide based on AAMA and GAMA levels in the whole group of women was 0.16 MUg/kg b.w./day (1.15 MUg/kg b.w./day, P95). We found significantly (P<0.05) higher exposure in women who consumed higher amount of acrylamide in the diet (>=10 MUg/day vs <10 MUg/day). A weak but significant positive correlation between acrylamide intake calculated on the basis of urinary levels of AAMA and GAMA and estimated on the basis of 24-h dietary recall (r=0.26, P<0.05) was found. The estimated margin of exposure values were below 10 000 and ranged from 156 for 95th percentile to 1938 for median acrylamide intake. Our results have shown that even a low dietary acrylamide intake may be associated with health risk. PMID- 25827311 TI - Traffic-related air pollution exposure and incidence of stroke in four cohorts from Stockholm. AB - We investigated the risk of stroke related to long-term ambient air pollution exposure, in particular the role of various exposure time windows, using four cohorts from Stockholm County, Sweden. In total, 22,587 individuals were recruited from 1992 to 2004 and followed until 2011. Yearly air pollution levels resulting from local road traffic emissions were assessed at participant residences using dispersion models for particulate matter (PM10) and nitrogen oxides (NOX). Cohort-specific hazard ratios were estimated for time-weighted air pollution exposure during different time windows and the incidence of stroke, adjusted for common risk factors, and then meta-analysed. Overall, 868 subjects suffered a non-fatal or fatal stroke during 238,731 person-years of follow-up. An increment of 20 MUg/m(3) in estimated annual mean of road-traffic related NOX exposure at recruitment was associated with a hazard ratio of 1.16 (95% CI 0.83 1.61), with evidence of heterogeneity between the cohorts. For PM10, an increment of 10 MUg/m(3) corresponded to a hazard ratio of 1.14 (95% CI 0.68-1.90). Time window analyses did not reveal any clear induction-latency pattern. In conclusion, we found suggestive evidence of an association between long-term exposure to NOX and PM10 from local traffic and stroke at comparatively low levels of air pollution. PMID- 25827312 TI - Urinary concentrations of 2,5-dichlorophenol and diabetes in US adults. AB - Para-dichlorobenzene (p-DCB) products are widely used in the home and public buildings, leading to exposure to this chemical in indoor environments. In this study, we explored potential relationships between p-DCB exposure and diabetes in US adults by analyzing a nationally representative subsample of 3063 adult participants aged 20-79 years randomly selected for measurement of urinary concentrations of 2,5-dichlorophenol (2,5-DCP), the major metabolite of p-DCB, in the 2007-2010 National Health and Nutrition Examination Survey. Median urinary 2,5-DCP concentration was 7.0 MUg/l (interquartile range: 2.1-29.9). Of the participants, 560 (13.6%) were diabetic. A dose-dependent increase in the prevalence of diabetes was observed in the study participants across quartiles of urinary 2,5-DCP (P-trend<0.0001). After adjusting for potential confounders, individuals in the highest quartile of urinary 2,5-DCP had an increased odds of diabetes (OR=1.59 (95% CI: 1.06, 2.40)) compared with individuals with the lowest quartile. The highest quartile of urinary 2,5-DCP was also positively associated with insulin resistance (adjusted beta=0.75; 95% CI: 0.27, 1.24). This study demonstrated a potential association between exposure to p-DCB, measured as urinary concentrations of 2,5-DCP, and diabetes in US adults. Additional epidemiologic and mechanistic studies would further explore these interactions. PMID- 25827313 TI - Urinary trace element concentrations in environmental settings: is there a value for systematic creatinine adjustment or do we introduce a bias? AB - Systematic creatinine adjustment of urinary concentrations of biomarkers has been a challenge over the past years because the assumption of a constant creatinine excretion rate appears erroneous and the issue of overadjustment has recently emerged. This study aimed at determining whether systematic creatinine adjustment is to be recommended for urinary concentrations of trace elements (TEs) in environmental settings. Paired 24-h collection and random spot urine samples (spotU) were obtained from 39 volunteers not occupationally exposed to TEs. Four models to express TEs concentration in spotU were tested to predict the 24-h excretion rate of these TEs (TEMUg/24h) considered as the gold standard reference: absolute concentration (TEMUg/l); ratio to creatinine (TEMUg/gcr); TEMUg/gcr adjusted to creatinine (TEMUg/gcr-adj); and concentration adjusted to specific gravity (TEMUg/l-SG). As, Ba, Cd, Co, Cr, Cu, Hg, Li, Mo, Ni, Pb, Sn, Sb, Se, Te, V and Zn were analyzed by inductively coupled argon plasma mass spectrometry. There was no single pattern of relationship between urinary TEs concentrations in spotU and TEMUg/24h. TEMUg/l predicted TEMUg/24h with an explained variance ranging from 0 to 60%. Creatinine adjustment improved the explained variance by an additional 5 to ~60% for many TEs, but with a risk of overadjustment for the most of them. This issue could be addressed by adjusting TE concentrations on the basis of the regression coefficient of the relationship between TEMUg/gcr and creatinine concentration. SG adjustment was as suitable as creatinine adjustment to predict TEMUg/24h with no SG-overadjustment (except V). Regarding Cd, Cr, Cu, Ni and Te, none of the models were found to reflect TEMUg/24h. In the context of environmental exposure, systematic creatinine adjustment is not recommended for urinary concentrations of TEs. SG adjustment appears to be a more reliable alternative. For some TEs, however, neither methods appear suitable. PMID- 25827315 TI - Apolipoprotein E gene polymorphisms associated with processing speed and executive functions in healthy Han Chinese. PMID- 25827314 TI - Effect of time-activity adjustment on exposure assessment for traffic-related ultrafine particles. AB - Exposures to ultrafine particles (<100 nm, estimated as particle number concentration, PNC) differ from ambient concentrations because of the spatial and temporal variability of both PNC and people. Our goal was to evaluate the influence of time-activity adjustment on exposure assignment and associations with blood biomarkers for a near-highway population. A regression model based on mobile monitoring and spatial and temporal variables was used to generate hourly ambient residential PNC for a full year for a subset of participants (n=140) in the Community Assessment of Freeway Exposure and Health study. We modified the ambient estimates for each hour using personal estimates of hourly time spent in five micro-environments (inside home, outside home, at work, commuting, other) as well as particle infiltration. Time-activity adjusted (TAA)-PNC values differed from residential ambient annual average (RAA)-PNC, with lower exposures predicted for participants who spent more time away from home. Employment status and distance to highway had a differential effect on TAA-PNC. We found associations of RAA-PNC with high sensitivity C-reactive protein and Interleukin-6, although exposure-response functions were non-monotonic. TAA-PNC associations had larger effect estimates and linear exposure-response functions. Our findings suggest that time-activity adjustment improves exposure assessment for air pollutants that vary greatly in space and time. PMID- 25827316 TI - Pain following blood donation: a questionnaire study of long-term morbidity (LTM) in blood donors. AB - BACKGROUND: Nerve injury is a main cause of long-term morbidity following blood donation, but little is known about symptoms, impact, prognosis and underlying cause. MATERIALS AND METHODS: A questionnaire, designed to characterize pain and estimate the prevalence of neuropathic pain, was sent to all blood donors registered with a complication related to 3 297 674 blood donations in Denmark from 2000-2009, with a local complication mainly characterized by pain, with severity grade 'long-term morbidity' and imputability grade 'definite' or 'probably'. RESULTS: The questionnaire was sent to 152 donors (4.6 per 100 000 donations). Response rate was 88/152 (57.9%). At the time of the questionnaire, which was between 12 months and 10 years after the blood donation, 69/88, who responded (78.4%) still experienced symptoms. Of the 69 donors with persistent symptom, pain occurred in 51 donors (74%) was moderate to severe in 24/69 donors (35%) and had an impact on daily activity in 17/69 (25%). Neuropathic pain was estimated to be the underlying cause of symptom in 30-52% of the 69 donors with persistent symptoms, using three different systems for estimation, corresponding to 0.6-1.1/100 000 donations. DISCUSSION: Although a rare complication, nerve injury after blood donation may lead to long-term morbidity and may become chronic in a small proportion of donors. The most common symptoms are pain, and we estimate that neuropathic pain can be the underlying cause. PMID- 25827317 TI - Probing Mobility-Selected Saccharide Isomers: Selective Ion-Molecule Reactions and Wavelength-Specific IR Activation. AB - Differential Ion Mobility Spectrometry (DIMS) provides orthogonal separation to mass spectrometry, and DIMS combined with the high sensitivity of a quadrupole ion-trap is shown to be useful for the separation and identification of saccharides. A comprehensive analysis of the separation of anomers (alpha- and beta-methylated glucose) and epimers (alpha-methylated glucose and mannose) ionized with Li(+), Na(+), and K(+) is performed. DIMS separation is found to be better for saccharides cationized with the two latter species. The corresponding resolving power for the two glucose anomers with Na(+) is found to be very close to the corresponding drift-tube IMS value. The lithiated complexes are investigated further using a combination of infrared spectroscopy integrated to ion-trap mass spectrometry and quantum chemical calculations. Together with DIMS, consistent results are obtained. It is found that two competing structural motifs might be at play, depending on the subtle balance between the maximization of the coordination of the metal cation and the intrinsic conformational energetics of the saccharide, which is for a large part driven by hydrogen bonding. The comparison of simulated and observed spectra clearly shows that a band at ~3400 cm(-1) is specific to a structural motif found in the lithiated glucose complexes, which could explain the trends observed in the DIMS spectra of the saccharide complexes. It is shown that DIMS-MS/MS using wavelength specific IR activation would provide a new orthogonal dimension to mass spectrometry. PMID- 25827318 TI - Rational design and application of a redox-active, photoresponsive, discrete metallogelator. AB - A photoresponsive discrete metallogelator was rationally designed by incorporating a photochromic azobenzene subunit in the structure of a redox active ferrocene-peptide conjugate. The target molecule was purposefully equipped with a dipeptide unit capable of self-assembly in response to sonication. The designed molecule was shown to undergo supramolecular self-assembly and achieve organogelation in response to ultrasound, light, heat, and redox signals. The sol gel phase transition of the designed gelator was found to be sensitive to a plethora of input stimuli, allowing the application of the sol-gel transition behavior in basic logic gate operations. A gel-based NOT logic gate operation was realized when the redox-active property of the organogel was examined by using different oxidizing agents. The smart response of the gelator was further exploited in designing XOR operations under oxidizing or non-oxidizing conditions. PMID- 25827319 TI - Transplantation in South Africa. PMID- 25827321 TI - Novel organ preservation methods: not only cool but supercool! PMID- 25827322 TI - Sir Peter J. Morris, AC, FRS: Melbourne and Oxford Universities' transplantation surgeon and retiring editor of Transplantation, 1976-2014. PMID- 25827323 TI - A facilitated method for hepatic vein blood: sampling during liver transplantation. PMID- 25827324 TI - Lupus after kidney donation to an affected male relative. PMID- 25827325 TI - Successful detoxification and liver transplantation in a severe poisoning with a chemical wood preservative containing chromium, copper, and arsenic. PMID- 25827326 TI - Absence of amyloid deposition in human islets transplantation after 13 years insulin independence. PMID- 25827327 TI - Cost-Effectiveness Analysis of Morcellation Hysterectomy for Myomas. AB - STUDY OBJECTIVE: To estimate the cost-effectiveness of eliminating morcellation in the surgical treatment of leiomyomas from a societal perspective. DESIGN: Cost effectiveness analysis. DESIGN CLASSIFICATION: Not applicable. SETTING: A theoretical cohort of women undergoing hysterectomy for myoma disease large enough to require morcellation. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS: A decision analysis model was constructed using probabilities, costs, and utility data from published sources. A cost-effectiveness analysis analyzing both quality-adjusted life years (QALYs) and cases of disseminated cancer was performed to determine the incremental cost-effectiveness ratio (ICER) of eliminating morcellation as a tool in the surgical treatment of leiomyomas. Costs and utilities were discounted using standard methodology. The base case included health care system costs and costs incurred by the patient for surgery related disability. One-way sensitivity analyses were performed to assess the effect of various assumptions. MAIN RESULTS: The cost to prevent 1 case of disseminated cancer was $10 540 832. A strategy of nonmorcellation hysterectomy via laparotomy costed more ($30 359.92 vs $20 853.15) and yielded more QALYs (21.284 vs 21.280) relative to morcellation hysterectomy. The ICER for nonmorcellation hysterectomy compared with morcellation hysterectomy was $2 184 172 per QALY. Health care costs (prolonged hospitalizations) and costs to patients of prolonged time away from work were the primary drivers of cost differential between the 2 strategies. Even when the incidence of occult sarcoma in leiomyoma surgery was ranged to twice that reported in the literature (.98%), the ICER for nonmorcellation hysterectomy was $644 393.30. CONCLUSIONS: Eliminating morcellation hysterectomy as a treatment for myomas is not cost effective under a wide variety of probability and cost assumptions. Performing laparotomy for all patients who might otherwise be candidates for morcellation hysterectomy is a costly policy from a societal perspective. PMID- 25827328 TI - Iatrogenic Uterine Diverticulum in Pregnancy After Robotic-assisted Myomectomy. AB - Uterine diverticula are rare outpouchings of the uterus associated with abnormal uterine bleeding, pelvic pain, dysmenorrhea, and adverse obstetric events. At the time of cesarean delivery at 36 5/7 weeks' gestation during the patient's first pregnancy and 36 6/7 weeks during the second pregnancy, a fundal iatrogenic uterine diverticulum at the site of a prior robotic-assisted myomectomy was noted. The outpouching communicated with the endometrial cavity and was extremely attenuated, palpably 2 to 3 mm thick. Further research is needed to determine the incidence of iatrogenic uterine diverticulum after robotic myomectomy and whether these malformations increase the risk of adverse obstetric outcomes. PMID- 25827329 TI - Immunoglobulin G4-related disease in the urinary bladder. AB - Immunoglobulin G4-related disease is a fibroinflammatory condition of unclear etiology that can present with inflammatory changes and enlargement of a wide variety of organs, most commonly in the gastrointestinal tract. A diagnosis requires an elevated serum immunoglobulin G4 concentration and a tissue biopsy showing a dense plasma cell infiltrate with an increased percentage of immunoglobulin G4+ plasma cells. This disease infrequently presents in the genitourinary tract, and as such might be unfamiliar to and potentially overlooked by urologists. Here we present the third reported case of immunoglobulin G4-related disease manifesting as a mass in the urinary bladder. PMID- 25827330 TI - Convenient synthesis of deazaflavin cofactor FO and its activity in F(420) dependent NADP reductase. AB - F420 and FO are phenolic 5-deazaflavin cofactors that complement nicotinamide and flavin redox coenzymes in biochemical oxidoreductases and photocatalytic systems. Specifically, these 5-deazaflavins lack the single electron reactivity with O2 of riboflavin-derived coenzymes (FMN and FAD), and, in general, have a more negative redox potential than NAD(P)(+). For example, F420-dependent NADP(+) oxidoreductase (Fno) is critical to the conversion of CO2 to CH4 by methanogenic archaea, while FO functions as a light-harvesting agent in DNA repair. The preparation of these cofactors is an obstacle to their use in biochemical studies and biotechnology. Here, a convenient synthesis of FO was achieved by improving the redox stability of synthetic intermediates containing a polar, electron-rich aminophenol fragment. Improved yields and simplified purification techniques for FO are described. Additionally, Fno activity was restored with FO in the absence of F420. Investigating the FO-dependent NADP(+)/NADPH redox process by stopped flow spectrophotometry, steady state kinetics were defined as having a Km of 4.00 +/- 0.39 MUM and a kcat of 5.27 +/- 0.14 s(-1). The preparation of FO should enable future biochemical studies and novel uses of F420 mimics. PMID- 25827331 TI - Evolutionary dynamics of Rh2 opsins in birds demonstrate an episode of accelerated evolution in the New World warblers (Setophaga). AB - Low rates of sequence evolution associated with purifying selection can be interrupted by episodic changes in selective regimes. Visual pigments are a unique system in which we can investigate the functional consequences of genetic changes, therefore connecting genotype to phenotype in the context of natural and sexual selection pressures. We study the RH2 and RH1 visual pigments (opsins) across 22 bird species belonging to two ecologically convergent clades, the New World warblers (Parulidae) and Old World warblers (Phylloscopidae) and evaluate rates of evolution in these clades along with data from 21 additional species. We demonstrate generally slow evolution of these opsins: both Rh1 and Rh2 are highly conserved across Old World and New World warblers. However, Rh2 underwent a burst of evolution within the New World genus Setophaga, where it accumulated substitutions at 6 amino acid sites across the species we studied. Evolutionary analyses revealed a significant increase in dN /dS in Setophaga, implying relatively strong selective pressures to overcome long-standing purifying selection. We studied the effects of each substitution on spectral tuning and found they do not cause large spectral shifts. Thus, substitutions may reflect other aspects of opsin function, such as those affecting photosensitivity and/or dark-light adaptation. Although it is unclear what these alterations mean for colour perception, we suggest that rapid evolution is linked to sexual selection, given the exceptional plumage colour diversification in Setophaga. PMID- 25827332 TI - Preserved otolith organ function in caspase-3-deficient mice with impaired horizontal semicircular canal function. AB - Genetically engineered mice are valuable models for elucidation of auditory and vestibular pathology. Our goal was to establish a comprehensive vestibular function testing system in mice using: (1) horizontal angular vestibulo-ocular reflex (hVOR) to evaluate semicircular canal function and (2) otolith-ocular reflex (OOR) to evaluate otolith organ function and to validate the system by characterizing mice with vestibular dysfunction. We used pseudo off-vertical axis rotation to induce an otolith-only stimulus using a custom-made centrifuge. For the OOR, horizontal slow-phase eye velocity and vertical eye position were evaluated as a function of acceleration. Using this system, we characterized hVOR and OOR in the caspase-3 (Casp3) mutant mice. Casp3 (-/-) mice had severely impaired hVOR gain, while Casp3 (+/-) mice had an intermediate response compared to WT mice. Evaluation of OOR revealed that at low-to-mid frequencies and stimulus intensity, Casp3 mutants and WT mice had similar responses. At higher frequencies and stimulus intensity, the Casp3 mutants displayed mildly reduced otolith organ-related responses. These findings suggest that the Casp3 gene is important for the proper function of the semicircular canals but less important for the otolith organ function. PMID- 25827333 TI - Childhood exposure to a parental suicide attempt and risk for substance use disorders. AB - Childhood exposure to parental suicidal behavior has been linked to a variety of adverse behavioral and health outcomes. However, relatively little is known about the degree to which such exposure may place individuals at risk for a substance use disorder (SUD). Employing data from the National Epidemiologic Survey on Alcohol and Related Conditions, we compared the prevalence of SUDs among those who experienced childhood exposure to parental suicide attempts. Childhood exposure to parental suicide attempts was not associated with increased risk for the development of alcohol, cannabis, or cocaine use disorders. However, individuals who were exposed to a parental suicide attempt as children were significantly more likely to have met criteria for stimulant (AOR=1.40, 95% CI=1.18-1.67), sedative (AOR=1.24, 95% CI=1.04-1.47), tranquilizer (AOR=1.78, 95% CI=1.45-2.20), and opioid (AOR=1.41, 95% CI=1.19-1.67) use disorders in their lifetime. No significant gender differences were identified with respect to the magnitude of the relationship between exposure to parental suicide attempts and SUD risk among men and women. Findings suggest that, controlling for an array of sociodemographic, parental, mental health, and childhood adversity confounds, childhood exposure to parental suicide attempts is a vulnerability factor for low prevalence illicit drugs (i.e. stimulants, sedatives, tranquilizers, opioids), but not for more commonly used substances. PMID- 25827334 TI - The effect of electronic cigarette advertising on intended use among college students. AB - INTRODUCTION: . Aside from prohibiting health claims, there are presently no restrictions on electronic cigarette advertising in the U.S. Studies have shown college students have a positive view of e-cigarettes and use on campuses is increasing. The purpose of this study was to test if the appeal of e-cigarette advertisements and beliefs about the addictiveness of e-cigarettes may affect their uptake among college students. METHODS: The study was framed within the Theory of Reasoned Action, which posits that behavioral intention can be understood in terms of social norms and attitudes toward a behavior. We also included variables capturing appeal of e-cigarette advertisements, belief that e cigarettes are not as addictive as cigarettes, and tobacco use. Attitudes toward e-cigarettes, perceived norms concerning their use, beliefs that e-cigarettes are not as addictive as cigarettes, and positive appraisal of e-cigarette advertising videos were all hypothesized to be independently positively associated with intention to use an e-cigarette. Data were collected through a survey of students at a major U.S. university (participation rate 78%, N=296). Participants were exposed to three e-cigarette video advertisements in random order. RESULTS: In a regression analysis we found positive reaction to the ads and holding the belief that e-cigarettes are not as addictive were both independently associated with intention. Attitudes and norms were also associated but were controlled by inclusion of the other variables. CONCLUSIONS: These findings suggest that advertising may promote the uptake of e-cigarettes and may do so in addition to current smoking and alternate tobacco use status. PMID- 25827335 TI - Specific dimensions of impulsivity are differentially associated with daily and non-daily cigarette smoking in young adults. AB - Young adults are at risk for initiation of tobacco use and progression to tobacco dependence. Not every person who smokes cigarettes becomes tobacco dependent, however, and non-daily smoking is becoming more prevalent among those who use tobacco. It is likely that individual differences in psychosocial and behavioral factors influence risk for engaging in non-daily and daily cigarette smoking. The objective of this study was to investigate the associations between impulsivity and smoking status in young adults who vary in frequency of cigarette smoking. Young adult first-year college students between the ages of 18-24 (512) were classified to one of three groups: non-smokers, non-daily smokers, or daily smokers, and impulsivity was assessed using the UPPS-P (negative and positive urgency, lack of premeditation, lack of perseverance, sensation seeking). When all impulsivity dimensions were used simultaneously to predict smoking status, negative urgency predicted increased risk of membership in the daily smoking group and lack of premeditation predicted increased risk of membership in the non daily smoking group. These results suggest that dimensions of impulsivity may contribute differentially to forms of smoking behavior in young adults. PMID- 25827336 TI - Problem gambling and internalising symptoms: a longitudinal analysis of common and specific social environmental protective factors. AB - INTRODUCTION: Comorbidity between problem gambling and internalising disorders (anxiety and depression) has long been recognised. However, it is not clear how these relationships develop, and what factors can foster resilience to both conditions. The current study draws on longitudinal cohort data to investigate: 1) the cross-sectional and longitudinal relationships between problem gambling and internalising symptoms; 2) whether there are common and/or specific social environmental factors protective against both internalising symptoms and problem gambling in young adulthood; and 3) interactive protective factors (i.e., those that moderate the relationship between problem gambling and internalising symptoms). METHODS: A sample of 2248 young adults (55% female) completed a survey in 2010 (T1) and 2012 (T2) which assessed problem gambling (measured via two items based on established measures), internalising symptoms, and social environmental protective factors. RESULTS: A positive cross-sectional relationship between problem gambling and internalising symptoms was found; however, there was no statistically significant longitudinal relationship between the two conditions. Protective factors for internalising symptoms were observed within the domains of the community, family and peer group; however, there were no statistically significant protective factors identified for problem gambling. CONCLUSIONS: These findings demonstrate that the social environmental protective factors for adult internalising symptoms assessed in the present study are poor longitudinal predictors of young adult problem gambling. Given the lack of common protective factors, it may be necessary to focus on separate factors to protect against each condition, if we are to address the comorbidity between problem gambling and internalising symptoms. PMID- 25827337 TI - The Prevalence of Mixed Helicobacter pylori Infections in Symptomatic and Asymptomatic Subjects in Dhaka, Bangladesh. AB - BACKGROUND: Helicobacter pylori is a highly genetically diverse bacterial species, which can persist in the gastric environment for decades. Recent studies have shown that single infections predominate in developed countries, whereas mixed infections are more prevalent in developing countries. Mixed infections of this bacterium may be important for adaptation to the hostile gastric environment and may facilitate dyspeptic symptoms. MATERIALS AND METHODS: To calculate the prevalence of mixed infections in symptomatic and asymptomatic subjects, 2010 H. pylori isolates collected from 83 symptomatic and 91 asymptomatic subjects from Dhaka, Bangladesh, were analyzed by (i) random amplified polymorphic DNA fingerprinting (RAPD) and (ii) multiplex PCR amplification for cagA and vacA virulence gene alleles. RESULTS: The overall prevalence of mixed H. pylori infection was 60.15% (77/128), indicating substantial co-colonization in this population. We additionally found that symptomatic subjects (53%) had a significantly higher rate of mixed infection than asymptomatic individuals (36.3%) (p = .016) and that the prevalence of the cagA and vacA and vacA m1/s1 and vacA m2/s1 alleles were higher in subjects with mixed infection. CONCLUSION: Our findings suggest that an increased diversity of the H. pylori strains in the gastric environment may contribute to the development of disease symptoms. PMID- 25827338 TI - Synthesis and biological evaluation of dimeric furanoid macroheterocycles: discovery of new anticancer agents. AB - A recently developed dimerization/macrocyclization was employed to synthesize a series of macroheterocycles which were biologically evaluated, leading to the discovery of a number of potent cytotoxic agents (e.g., 27: GI50 = 51 nM against leukemia CCRF-CEM cell line; 29: GI50 = 99 nM against melanoma MDA-MB-435 cell line). Further biological studies support an apoptosis mechanism of action for these compounds involving deregulation of the tricarboxylic acid cycle activity and suppression of mitochondrial function in cancer cells. PMID- 25827339 TI - Development of a gluten-free rice noodle by utilizing protein-polyphenol interaction between soy protein isolate and extract of Acanthopanax sessiliflorus. AB - BACKGROUND: The potential of the protein-polyphenol interaction was applied to crosslinking reinforced protein networks in gluten-free rice noodles. Specifically, inter-component interaction between soy protein isolate and extract of Acanthopanax sessiliflorus fruit (ogaja) was examined with a view to improving its quality. RESULTS: In a components-interacting model system, a mixture of soy protein isolate (SPI) and ogaja extract (OE) induced a drastic increase in absorbance at 660 nm by haze formation, while the major anthocyanin of ogaja, cyanidin-3-O-sambubioside, sparsely interacted with SPI or gelatin. Individual or combined treatment of SPI and OE on rice dough decreased all the viscosity parameters in rapid visco analysis. However, SPI-OE treatment significantly increased all the texture parameters of rice dough derived from Mixolab((r)) analysis (P < 0.05). Incorporation of SPI in rice dough significantly reduced endothermic DeltaH, and SPI-OE treatment further decreased this value. SPI-OE interaction significantly increased the tensile properties of cooked noodle and decreased 53.7% of cooking loss compared to the untreated rice noodle. CONCLUSION: SPI-OE treatment caused a considerable reinforcement of the network as shown by reducing cooking loss and suggested the potential for utilizing protein-polyphenol interaction for gluten-free rice noodle production. PMID- 25827340 TI - Editorial: is it time for an evolutionarily based human endocrinology? PMID- 25827343 TI - Corrigendum: qPMS9: an efficient algorithm for quorum planted motif search. PMID- 25827344 TI - Self-reported risk-taking behavior during matched-frequency sessions of alcohol versus combined alcohol and energy drinks consumption: does co-ingestion increase risk-taking? AB - BACKGROUND: Emerging evidence indicates that consumers of alcohol mixed with energy drink (AmED) self-report lower odds of risk-taking after consuming AmED versus alcohol alone. However, these studies have been criticized for failing to control for relative frequency of AmED versus alcohol-only consumption sessions. These studies also do not account for quantity of consumption and general alcohol related risk-taking propensity. The aims of the present study were to (i) compare rates of risk-taking in AmED versus alcohol sessions among consumers with matched frequency of use and (ii) identify consumption and person characteristics associated with risk-taking behavior in AmED sessions. METHODS: Data were extracted from 2 Australian community samples and 1 New Zealand community sample of AmED consumers (n = 1,291). One-fifth (21%; n = 273) reported matched frequency of AmED and alcohol use. RESULTS: The majority (55%) of matched frequency participants consumed AmED and alcohol monthly or less. The matched frequency sample reported significantly lower odds of engaging in 18 of 25 assessed risk behaviors in AmED versus alcohol sessions. Similar rates of engagement were evident across session type for the remaining behaviors, the majority of which were low prevalence (reported by <15%). Regression modeling indicated that risk-taking in AmED sessions was primarily associated with risk taking in alcohol sessions, with increased average energy drink (ED) intake associated with certain risk behaviors (e.g., being physically hurt, not using contraception, and driving while over the legal alcohol limit). CONCLUSIONS: Bivariate analyses from a matched-frequency sample align with past research showing lower odds of risk-taking behavior after AmED versus alcohol consumption for the same individuals. Multivariate analyses showed that risk-taking in alcohol sessions had the strongest association with risk-taking in AmED sessions. However, hypotheses of increased risk-taking post-AmED consumption were partly supported: Greater ED intake was associated with increased likelihood of specific behaviors, including drink-driving, sexual behavior, and aggressive behaviors in the matched-frequency sample after controlling for alcohol intake and risk-taking in alcohol sessions. These findings highlight the need to consider both personal characteristics and beverage effects in harm reduction strategies for AmED consumers. PMID- 25827345 TI - Transcriptional Hallmarks of Heterogeneous Neural Stem Cell Niches of the Subventricular Zone. AB - Throughout postnatal life in mammals, neural stem cells (NSCs) are located in the subventricular zone (SVZ) of the lateral ventricles. The greatest diversity of neuronal and glial lineages they generate occurs during early postnatal life in a region-specific manner. In order to probe heterogeneity of the postnatal SVZ, we microdissected its dorsal and lateral walls at different postnatal ages and isolated NSCs and their immediate progeny based on their expression of Hes5 EGFP/Prominin1 and Ascl1-EGFP, respectively. Whole genome comparative transcriptome analysis revealed transcriptional regulators as major hallmarks that sustain postnatal SVZ regionalization. Manipulation of single genes encoding for locally enriched transcription factors (loss-of-function or ectopic gain-of function in vivo) influenced NSC specification indicating that the fate of regionalized postnatal SVZ-NSCs can be readily modified. These findings reveal the pronounced transcriptional heterogeneity of the postnatal SVZ and provide targets to recruit region-specific lineages in regenerative contexts. Stem Cells 2015;33:2232-2242. PMID- 25827346 TI - Probe-Directed Degradation (PDD) for Flexible Removal of Unwanted cDNA Sequences from RNA-Seq Libraries. AB - Most applications for RNA-seq require the depletion of abundant transcripts to gain greater coverage of the underlying transcriptome. The sequences to be targeted for depletion depend on application and species and in many cases may not be supported by commercial depletion kits. This unit describes a method for generating RNA-seq libraries that incorporates probe-directed degradation (PDD), which can deplete any unwanted sequence set, with the low-bias split-adapter method of library generation (although many other library generation methods are in principle compatible). The overall strategy is suitable for applications requiring customized sequence depletion or where faithful representation of fragment ends and lack of sequence bias is paramount. We provide guidelines to rapidly design specific probes against the target sequence, and a detailed protocol for library generation using the split-adapter method including several strategies for streamlining the technique and reducing adapter dimer content. PMID- 25827347 TI - Neural stem cell-mediated delivery of oncolytic adenovirus. AB - The use of stem cells (SCs) as carriers for therapeutic agents has now progressed to early clinical trials. These clinical trials exploring SC-mediated delivery of oncolytic adenoviruses will commence in the near future, hopefully yielding meritorious results that can provoke further scientific inquiry. Preclinical animal studies have demonstrated that SCs can be successfully loaded with conditionally-replicative adenoviruses and delivered to the tumor, whereupon they may evoke pronounced therapeutic efficacy. In this protocol, we describe the maintenance of SCs, provide an analysis of optimal adenoviral titers for SC loading, and evaluate the optimized viral loading on SCs. PMID- 25827348 TI - Use of Affymetrix Arrays in the Diagnosis of Gene Copy-Number Variation. AB - Diagnosing constitutional pathogenic copy number variants (CNVs) requires detecting submicroscopic segmental chromosomal imbalances. The Affymetrix GeneChip mapping array was one of the initial microarray platforms used to measure duplication and deletion of genetic material in DNA samples. Unlike oligonucleotide microarrays from NimbleGen and Agilent, developed around the same time to infer copy number status for the DNA sequence covered by the probe, the Affymetrix GeneChip system used 25-mer oligonucleotide probes designed to interrogate SNPs. Thus, it was possible to use the Affymetrix 'SNP chips' to both identify SNPs and to identify copy number status. Affymetrix now offers the CytoScan microarray platforms, which are optimized for copy-number analyses, and provides accompanying software. They also offer several other microarray platforms suitable for copy-number analyses. Here we discuss the application of the CytoScan high-density (HD) platform for the detection of genomic imbalance. We provide an overview of the sequence of computational analyses involved in identifying pathogenic CNVs and highlight important parameters for consideration in assessing the pathogenicity of a detected CNV. PMID- 25827350 TI - Preparation of Amniocytes for Interphase Fluorescence In Situ Hybridization (FISH). AB - FISH has been used to detect and clarify deletions and/or other structural rearrangements, and also has applications in interphase analysis. This unit describes preparation of uncultured amniotic fluid cells for FISH analysis. Cells are swollen, and then slides are prepared by standard methods. The cells are then fixed and permeabilized for subsequent FISH. An alternate protocol describes attachment of amniocytes to a glass or plastic surface followed by hypotonic swelling, fixation, and permeabilization for subsequent FISH. Interphase FISH analysis of amniotic fluid cells is also described. PMID- 25827349 TI - Diagnosis of Fanconi anemia by diepoxybutane analysis. AB - Fanconi anemia (FA) is a genetically and phenotypically heterogeneous disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer, particularly hematological malignancies and solid tumors of the head and neck. The main role of FA proteins is in the repair of DNA interstrand crosslinks (ICLs). FA results from pathogenic variants in at least sixteen distinct genes, causing genomic instability. Although the highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, diagnosis based on a profound sensitivity to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. Diepoxybutane (DEB) analysis is the preferred test for FA because other agents have higher rates of false-positive and false-negative results. PMID- 25827351 TI - Conformation diversity of a fused-ring pyrazine derivative on au(111) and highly ordered pyrolytic graphite. AB - Heterocyclic aromatic compounds have attracted considerable attention because of their high carrier mobility that can be exploited in organic field-effect transistors. This contribution presents a comparative study of the packing structure of 3,6-didodecyl-12-(3,6-didodecylphenanthro[9,10-b]phenazin-13 yl)phenanthro[9,10-b]phenazine (DP), an N-heterocyclic aromatic compound, on Au(111) and highly ordered pyrolytic graphite (HOPG). High-resolution scanning tunneling microscopy (STM) combined with atomistic simulations provide a picture of the interface of this organic semiconductor on an electrode that can have an impact on the field-effect transistor (FET) performance. DP molecules adsorb with different conformational isomers (R/S: trans isomers; C: cis isomer) on HOPG and Au(111) substrates. All three isomers are found in the long-range disordered lamella domains on Au(111). In contrast, only the R/S trans isomers self-assemble into stable chiral domains on the HOPG surface. The substrate-dependent adsorption configuration selectivity is supported by theoretical calculations. The van der Waals interaction between the molecules and the substrate dominates the adsorption binding energy of the DP molecules on the solid surface. The results provide molecular evidence of the interface structures of organic semiconductors on electrode surfaces. PMID- 25827353 TI - Electrochemical reduction of an Ag2VO2PO4 particle: dramatic increase of local electronic conductivity. AB - Previously, we reported that electrodes containing silver vanadium phosphate (Ag2VO2PO4) powder exhibit a 15,000 fold increase in conductivity after discharge, concurrent with the formation of silver metal. In this study, in order to disentangle the complex nature of electrodes composed of electroactive powders, an electrochemical reduction of individual particles of Ag2VO2PO4 was conducted, to more directly probe the intrinsic materials properties of Ag2VO2PO4. Specifically, individual particle conductivity data from a nanoprobe system combined with SEM and optical imaging results revealed that the depth of discharge within an Ag2VO2PO4 particle is closely linked to the conductivity increase. Notably, the formation of silver metal may affect both inter- and intraparticle conductivity of the Ag2VO2PO4 material. PMID- 25827352 TI - Decreased Mechanical Strength and Collagen Content in SPARC-Null Periodontal Ligament Is Reversed by Inhibition of Transglutaminase Activity. AB - The periodontal ligament (PDL) is a critical tissue that provides a physical link between the mineralized outer layer of the tooth and the alveolar bone. The PDL is composed primarily of nonmineralized fibrillar collagens. Expression of secreted protein acidic and rich in cysteine (SPARC/osteonectin), a collagen binding matricellular protein, has been shown to be essential for collagen homeostasis in PDL. In the absence of SPARC, PDL collagen fibers are smaller and less dense than fibers that constitute WT PDL. The aim of this study was to identify cellular mechanisms by which SPARC affected collagen fiber assembly and morphology in PDL. Cross-linking of fibrillar collagens is one parameter that is known to affect insoluble collagen incorporation and fiber morphology. Herein, the reduction in collagen fiber size and quantity in the absence of SPARC expression was shown to result in a PDL with reduced molar extraction force in comparison to that of WT mice (C57Bl/6J). Furthermore, an increase in transglutaminase activity was found in SPARC-null PDL by biochemical analyses that was supported by immunohistochemical results. Specifically, collagen I was identified as a substrate for transglutaminase in PDL and transglutaminase activity on collagen I was found to be greater in SPARC-null tissues in comparison to WT. Strikingly, inhibition of transglutaminase activity in SPARC null PDL resulted in increases in both collagen fiber thickness and in collagen content, whereas transglutaminase inhibitors injected into WT mice resulted in increases in collagen fiber thickness only. Furthermore, PDL treated with transglutaminase inhibitors exhibited increases in molar extraction force in WT and in SPARC-null mice. Thus, SPARC is proposed to act as a critical regulator of transglutaminase activity on collagen I with implications for mechanical strength of tissues. PMID- 25827354 TI - Thermal stability and molecular ordering of organic semiconductor monolayers: effect of an anchor group. AB - The thermal stability and molecular order in monolayers of two organic semiconductors, PBI-PA and PBI-alkyl, based on perylene derivatives with an identical molecular structure except for an anchor group for attachment to the substrate in PBI-PA, are reported. In situ X-ray reflectivity measurements are used to follow the stability of these monolayers in terms of order and thickness as temperature is increased. Films have thicknesses corresponding approximately to the length of one molecule; molecules stand upright on the substrate with a defined structure. PBI-PA monolayers have a high degree of order at room temperature and a stable film exists up to 250 degrees C, but decomposes rapidly above 300 degrees C. In contrast, stable physisorbed PBI-alkyl monolayers only exist up to 100 degrees C. Above the bulk melting point at 200 degrees C no more order exists. The results encourage using anchor groups in monolayers for various applications as it allows enhanced stability at the interface with the substrate. PMID- 25827355 TI - Penile enhancement with rectus muscle fascia and testicular tunica vaginalis grafts: an experimental animal study. AB - PURPOSE: To enhance rat penises experimentally with rectus muscle fascia (RMF) and testicular tunica vaginalis grafts (TVG). METHODS: Twelve Wistar albino rats were distributed into two equal Groups, A and B. There were six rats in each group. RMF and TVG were used to enhance rat penises in Groups A and B, respectively. Circumferences of the penises were measured preoperatively and at three different times after the operation. Two, two and eight rats were killed 10 days, 1 month and 2 months after the operation, respectively, for histopathological examinations. RESULTS: When we compared the measurements of preoperative and immediately postoperative circumferences, the mean increase was 23.4 +/- 2.9 % in Group A and 19.9 +/- 1.7 % in Group B. According to paired t test, the difference was significant (p < 0001), but the comparison between preoperative and postoperative first-month measurements was not found to be significant (p > 0.05). Histological examinations revealed an intensive inflammatory process at 10 days after the operation. Grafts were found to be totally absorbed in the first- and second-month examinations. CONCLUSION: In our study, implanted TVG and RMF could not survive because of insufficient vascularization and failure to maintain satisfactory surgical success. More studies are needed to increase the effectiveness of surgical techniques. PMID- 25827356 TI - Inferring mutational timing and reconstructing tumour evolutionary histories. AB - Cancer evolution can be considered within a Darwinian framework. Both micro and macro-evolutionary theories can be applied to understand tumour progression and treatment failure. Owing to cancers' complexity and heterogeneity the rules of tumour evolution, such as the role of selection, remain incompletely understood. The timing of mutational events during tumour evolution presents diagnostic, prognostic and therapeutic opportunities. Here we review the current sampling and computational approaches for inferring mutational timing and the evidence from next generation sequencing-informed data on mutational timing across all tumour types. We discuss how this knowledge can be used to illuminate the genes and pathways that drive cancer initiation and relapse; and to support drug development and clinical trial design. PMID- 25827357 TI - Dual effects of Metarhizium spp. and Clonostachys rosea against an insect and a seed-borne pathogen in wheat. AB - BACKGROUND: Crops are often prone to both insect herbivory and disease, which necessitate multiple control measures. Ideally, an efficacious biological control agent must adequately control the target organism and not be inhibited by other biological control agents when applied simultaneously. Wheat seeds infected with the plant pathogen Fusarium culmorum were treated with Metarhizium brunneum or M. flavoviride and Clonostachys rosea individually and in combination, with the expectation to control both root-feeding insects and the pathogen. Emerging roots were evaluated for disease and then placed with Tenebrio molitor larvae, which were monitored for infection. RESULTS: Plant disease symptoms were nearly absent for seeds treated with C. rosea, both individually and in combination with Metarhizium spp. Furthermore, roots grown from seeds treated with Metarhizium spp. caused significant levels of fungal infection in larvae when used individually or combined with C. rosea. However, cotreated seeds showed reduced virulence towards T. molitor when compared with treatments using Metarhizium spp. only. CONCLUSIONS: This study clearly shows that seed treatments with both the entomopathogenic fungus M. brunneum and the mycoparasitic fungus C. rosea can protect plant roots from insects and disease. The dual-treatment approach to biological control presented here is consistent with the ideals of IPM strategies. PMID- 25827358 TI - Cryofibrinogenemia: a marker of severity of cryoglobulinemic vasculitis. AB - BACKGROUND: Cryofibrinogenemia is frequently associated with cryoglobulinemia. The aim of this study was to determine the characteristics associated with the presence of cryofibrinogenemia in patients with cryoglobulinemic vasculitis. METHODS: This was a single-center retrospective study that included patients with cryoglobulinemic vasculitis who were tested for cryofibrinogen at a tertiary referral center between January 1, 2011 and December 31, 2012. Twenty-nine patients fulfilled the CryoVas (cryoglobulinemic vasculitis) Survey criteria for cryoglobulinemic vasculitis. Eighteen patients had a detectable cryofibrinogen (CF-positive) and 11 had no detectable cryofibrinogen (CF-negative). Median cryoglobulin levels were 89 +/- 129 mg/L in the CF-positive group and 68 +/- 82 mg/L in the CF-negative group (P = .32). Median cryofibrinogen level was 70 +/- 174 mg/L. Clinical manifestations were similar in both groups. Cancers and hematological disorders were more frequent among CF-positive patients (39% vs 0%, P = .026). Levels of alpha-1 and alpha-2 globulinemia were higher in the CF positive group. Cryofibrinogenemia >= 100 mg/L was associated with cryoglobulinemic vasculitis (odds ratio [OR] 2.86; 95% confidence interval [CI], 1.06-7.73) in cryoglobulinemic patients. Presence of cryofibrinogenemia was associated with use of corticosteroids, immunosuppressants, or plasmapheresis in cryoglobulinemic vasculitis patients (OR 22.7; 95% CI, 2.02-256.44). CONCLUSIONS: Our results strongly suggest that presence of cryofibrinogenemia is associated with a more severe phenotype among patients with cryoglobulinemic vasculitis. PMID- 25827359 TI - Misconceptions and Facts About Atrial Fibrillation. AB - Atrial fibrillation is an increasingly common arrhythmia associated with substantial but largely preventable risk of ischemic stroke. There has been an exponential increase in research related to atrial fibrillation in recent years, resulting in some major advances in the therapeutic management. Novel oral anticoagulant agents have become available and require thorough assessment of risk-to-benefit ratio. While the knowledge is rapidly accumulating, the basic principles of atrial fibrillation management remain proper recognition, risk stratification, and appropriate prevention of thromboembolic complications. This review highlights some common misconceptions about atrial fibrillation. PMID- 25827360 TI - New ways to provide community aged care services. AB - This paper will focus on the provision of community aged care services via 'direct payments' and 'social enterprise'. These are two solutions that were not fully considered by the Productivity Commission as a way to make the provision of community aged care more sustainable in Australia. The empowerment component of social enterprise activities and 'direct payments' have the potential to generate improvements in the community aged care system. PMID- 25827361 TI - Start-up, performance and optimization of a compost biofilter treating gas-phase mixture of benzene and toluene. AB - The performance of a compost biofilter inoculated with mixed microbial consortium was optimized for treating a gas-phase mixture of benzene and toluene. The biofilter was acclimated to these VOCs for a period of ~18d. The effects of concentration and flow rate on the removal efficiency (RE) and elimination capacity (EC) were investigated by varying the inlet concentration of benzene (0.12-0.95g/m(3)), toluene (0.14-1.48g/m(3)) and gas-flow rate (0.024 0.072m(3)/h). At comparable loading rates, benzene removal in the mixture was reduced in the range of 6.6-41% in comparison with the individual benzene degradation. Toluene removal in mixture was even more affected as observed from the reductions in REs, ranging from 18.4% to 76%. The results were statistically interpreted by performing an analysis of variance (ANOVA) to elucidate the main and interaction effects. PMID- 25827362 TI - Development of direct conversion method for microalgal biodiesel production using wet biomass of Nannochloropsis salina. AB - In this work, the effects of several factors, such as temperature, reaction time, and solvent and acid quantity on in situ transesterification yield of wet Nannochloropsis salina were investigated. Under equivalent total solvent volume to biomass ratio, pure alcohol showed higher yield compared to alcohol-chloroform solvent. For esterifying 200 mg of wet cells, 2 ml of methanol and 1 ml of ethanol was sufficient to complete in situ transesterification. Under temperatures of 105 degrees C or higher, 2.5% and 5% concentrations of sulfuric acid was able to successfully convert more than 90% of lipid within 30 min when methanol and ethanol was used as solvents respectively. Also, it was verified that the optimal condition found in small-scale experiments is applicable to larger scale using 2 L scale reactor as well. PMID- 25827363 TI - Flexible razor blade for harvesting tumours in Mohs micrographic surgery. AB - A useful application of the flexible razor blade in Mohs micrographic surgery that can save time and result in a well-presented specimen is described. PMID- 25827364 TI - Omics for aquatic ecotoxicology: control of extraneous variability to enhance the analysis of environmental effects. AB - There are multiple sources of biological and technical variation in a typical ecotoxicology study that may not be revealed by traditional endpoints but that become apparent in an omics dataset. As researchers increasingly apply omics technologies to environmental studies, it will be necessary to understand and control the main source(s) of variability to facilitate meaningful interpretation of such data. For instance, can variability in omics studies be addressed by changing the approach to study design and data analysis? Are there statistical methods that can be employed to correctly interpret omics data and make use of unattributed, inherent variability? The present study presents a review of experimental design and statistical considerations applicable to the use of omics methods in systems toxicology studies. In addition to highlighting potential sources that contribute to experimental variability, this review suggests strategies with which to reduce and/or control such variability so as to improve reliability, reproducibility, and ultimately the application of omics data for systems toxicology. PMID- 25827365 TI - Taking a closer look for a broader view: combining powder diffraction with electron crystallography for a better understanding of modulated structures. AB - Electron crystallography has made enormous progress over the last decade. It can provide the necessary information that complements powder diffraction data and allows for successful structure analysis of (not only) modulated structures. PMID- 25827366 TI - Synergy between transmission electron microscopy and powder diffraction: application to modulated structures. AB - The crystal structure solution of modulated compounds is often very challenging, even using the well established methodology of single-crystal X-ray crystallography. This task becomes even more difficult for materials that cannot be prepared in a single-crystal form, so that only polycrystalline powders are available. This paper illustrates that the combined application of transmission electron microscopy (TEM) and powder diffraction is a possible solution to the problem. Using examples of anion-deficient perovskites modulated by periodic crystallographic shear planes, it is demonstrated what kind of local structural information can be obtained using various TEM techniques and how this information can be implemented in the crystal structure refinement against the powder diffraction data. The following TEM methods are discussed: electron diffraction (selected area electron diffraction, precession electron diffraction), imaging (conventional high-resolution TEM imaging, high-angle annular dark-field and annular bright-field scanning transmission electron microscopy) and state-of-the art spectroscopic techniques (atomic resolution mapping using energy-dispersive X ray analysis and electron energy loss spectroscopy). PMID- 25827367 TI - Hydrogen bonding patterns in salts of derivatives of aminopyrimidine and thiobarbituric acid. AB - Three salts, namely 2-amino-4,6-dimethylpyrimidin-1-ium thiobarbiturate trihydrate (I), 2-amino-4,6-dimethoxypyrimidin-1-ium thiobarbiturate dihydrate (II) and 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidin-1-ium thiobarbiturate (III), were synthesized and characterized by IR and X-ray diffraction techniques. The primary interaction between the acid and base happens via N-H...O hydrogen bonds in (II) and (III), and via water-mediated N-H...OW and OW-HW...S in (I). The water molecules present in compound (I) form a (H2O)12 water cluster via water-water interactions. In all three compounds (I)-(III), thiobarbiturate anions form self-complementary pairs with a robust R2(2)(8) motif via a pair of N H...O/N-H...S hydrogen bonds. They mimic the nucleobase base pairs by utilizing the same groups (thymine/uracil uses N3-H and C4=O8 groups during the formation of Watson-Crick and Hoogsteen base pairs with adenine). Compound (I) forms a water-mediated base pair through N-H...OW hydrogen bonds and forms an R4(2)(12) motif. The formation of N-H...S hydrogen bonds, water-mediated base pairs and water-water interactions in these crystal systems offers scope for these systems to be considered as a model in the study of hydration of nucleobases and water mediated nucleobase base pairs in macromolecules. PMID- 25827368 TI - Structure and stability of BaTiSi2O7. AB - Due to their optical, photo-luminescence (PL), and afterglow properties, barium titanosilicates are compounds of great interest for functional materials and light-emitting devices. Among them, BaTiSi2O7 (BTS2) is certainly one of the most intriguing; it displays peculiar properties (e.g. PL orange emission) whose exhaustive explanation has been hampered to date by the lack of a structure model. In this work, BTS2 and the related compound BaTiSi4O11 (BTS4) were synthesized through conventional solid-state reaction methods. BTS2 invariably shows complex twinning patterns. Thus, its structure solution and Rietveld structure refinement were attempted using synchrotron powder diffraction. BTS2 was found to be an intergrowth of monoclinic and triclinic crystals. The monoclinic phase has the space group P21/n and unit cell a = 7.9836 (3), b = 10.0084 (4), c = 7.4795 (3) A, and beta = 100.321 (3) degrees , whereas the triclinic phase has the space group P?bar 1 and unit cell a = 7.99385 (4), b = 10.01017 (5), c = 7.47514 (3) A, alpha = 90.084 (8), beta = 100.368 (8) and gamma = 89.937 (9) degrees . These lattices can be seen as a distortion of that of tetragonal synthetic beta-BaVSi2O7 with Ti in place of V. The structure models obtained from this study confirm the presence of fivefold coordinated Ti atoms in a distorted pyramidal configuration. The proposed solution supports existing theories for the explanation of the PL orange colour in BTS2. PMID- 25827369 TI - A comprehensive classification and nomenclature of carboxyl-carboxyl(ate) supramolecular motifs and related catemers: implications for biomolecular systems. AB - Carboxyl and carboxylate groups form important supramolecular motifs (synthons). Besides carboxyl cyclic dimers, carboxyl and carboxylate groups can associate through a single hydrogen bond. Carboxylic groups can further form polymeric-like catemer chains within crystals. To date, no exhaustive classification of these motifs has been established. In this work, 17 association types were identified (13 carboxyl-carboxyl and 4 carboxyl-carboxylate motifs) by taking into account the syn and anti carboxyl conformers, as well as the syn and anti lone pairs of the O atoms. From these data, a simple rule was derived stating that only eight distinct catemer motifs involving repetitive combinations of syn and anti carboxyl groups can be formed. Examples extracted from the Cambridge Structural Database (CSD) for all identified dimers and catemers are presented, as well as statistical data related to their occurrence and conformational preferences. The inter-carboxyl(ate) and carboxyl(ate)-water hydrogen-bond properties are described, stressing the occurrence of very short (strong) hydrogen bonds. The precise characterization and classification of these supramolecular motifs should be of interest in crystal engineering, pharmaceutical and also biomolecular sciences, where similar motifs occur in the form of pairs of Asp/Glu amino acids or motifs involving ligands bearing carboxyl(ate) groups. Hence, we present data emphasizing how the analysis of hydrogen-containing small molecules of high resolution can help understand structural aspects of larger and more complex biomolecular systems of lower resolution. PMID- 25827370 TI - Phosphoramides bearing isoxazole derivative: spectroscopic and structural characterization, study of hydrogen-bonding interactions and two lanthanide complexes (LnIII = Ce and Eu). AB - In this study, the synthesis and spectroscopic characterization of new phosphoramides based on 3-amino-5-methylisoxazole with the formula R2P(O)[NH C4H4NO], R = C6H5O (1), C6H5 (2), RP(O)[NH-C4H4NO]2, R = C6H5O (3), CH3-C6H4O (4), C6H5NH (5), (C6H5)ClP(O)[NH-C4H4NO] (6) and two lanthanide complexes [Ln(2)2(NO3)3(EtOH)].EtOH, Ln(III) = Ce (7) and Eu (8), have been reported. The structural study of (3) shows the presence of two conformers (crystallographically independent molecules) in the crystalline lattice, caused by different orientations of the phenyl and isoxazole rings. For (3), the intermolecular interactions have been studied by Hirshfeld surface analysis and fingerprint plots. Furthermore, the electronic and energy aspects of hydrogen bonds between molecules of (3) have been explored by density functional theory (DFT) calculations. X-ray crystallography of complexes (7) and (8) reveals that two phosphoramide ligands take part in coordination to the metal, one as monodentate from O(phosphoryl), and the other one as chelate through O(phosphoryl) and N(ring). The complexes are also composed of two conformers in the solid-state structure. Quantum theory of atoms in molecules (QTAIM) analysis discloses the electrostatic nature of the Ln-ligand interaction. PMID- 25827371 TI - Structure of fluorite-like compound based on Nd5Mo3O16 with lead partly substituting for neodymium. AB - A single crystal of Nd5Mo3O16 with lead partly substituting for neodymium, which has a fluorite-like structure, was studied by precision X-ray diffraction, high resolution transmission microscopy and EDX microanalysis. The crystal structure is determined in the space group Pn3-n. It was found that the Pb atoms substitute in part for Nd atoms in the structure and are located in the vicinity of Nd2 positions. Partial substitutions of Mo cations for Nd positions and of Nd for Mo positions in crystals of the Ln5Mo3O16 oxide family are corroborated by X-ray diffraction for the first time. The first experimental verification of the location of an additional oxygen ion in the voids abutting MoO4 tetrahedra was obtained. PMID- 25827372 TI - Structure of the mixed-metal carbonate KAgCO3 revisited: order-disorder (OD) polytypism and allotwinning. AB - Crystals of KAgCO3 belong to an order-disorder (OD) family of structures composed of layers of two kinds. There are two polytypes with a maximum degree of order [MDO1: Pccb; MDO2: Ibca, doubled a-axis compared with MDO1], which are both realised to a different extent in two crystals under investigation [volume fraction MDO1:MDO2 in crystal (I): 0.0216:0.9784 (3) and in crystal (II): 0.9657:0.0343 (3)]. Sharp diffraction spots and the absence of diffuse scattering indicate highly ordered macroscopic domains. The structure of KAgCO3 was refined concurrently against all reflections using an allotwin model (addition of the intensities of both domains). It is shown that a disorder model refined against reflections of only one domain can lead to a significant overestimation of the volume fraction of this domain. PMID- 25827373 TI - Lack of a threefold rotation axis in alpha-Fe2O3 and alpha-Cr2O3 crystals. AB - The crystal structure of alpha-Fe2O3 and alpha-Cr2O3 is usually described with the corundum-type trigonal crystal structure based on the space group R3-c. There are, however, some observations of the magnetic ordering of both alpha-Fe2O3 and alpha-Cr2O3 that are incompatible with the trigonal symmetry. We show experimental evidence based on X-ray powder diffraction and supported by transmission electron microscopy that the symmetry of the crystal structure of both alpha-Fe2O3 and alpha-Cr2O3 is monoclinic and it is described with the space group C2/c (derived from R3-c by removing the threefold rotation axis). The magnetic orderings of alpha-Fe2O3 and alpha-Cr2O3 are compatible with the magnetic space groups C2/c and C2/c', respectively. These findings are in agreement with the idea from Curie [(1894), J. Phys. 3, 393-415] that the dissymmetry of the magnetic ordering should be associated with a dissymmetry of the crystal structure. PMID- 25827374 TI - Cocrystals of 6-chlorouracil and 6-chloro-3-methyluracil: exploring their hydrogen-bond-based synthon motifs with several triazine and pyrimidine derivatives. AB - In order to obtain complexes held together by hydrogen as well as halogen bonds, 6-chlorouracil [6-chloropyrimidin-2,4(1H,3H)-dione; 6CU] and its 3-methyl derivative [6-chloro-3-methylpyrimidin-2,4(1H,3H)-dione; M6CU] were cocrystallized with 2,4,6-triaminopyrimidine and the three triazine derivatives 2,4,6-triamino-1,3,5-triazine (melamine), 2,4-diamino-6-methyl-1,3,5-triazine and 2-chloro-4,6-diamino-1,3,5-triazine, which all offer complementary hydrogen bonding sites. Three of these compounds form cocrystals with 6CU; however, melamine yielded only a new pseudopolymorph with 6CU, but formed a cocrystal with M6CU. All six cocrystals contain solvent molecules (N,N-dimethylformamide, N,N dimethylacetamide or N-methylpyrrolidin-2-one), whose intermolecular interactions contribute significantly to the stabilization of the crystal packing. Each of these structures comprises chains, which are primarily formed by strong hydrogen bonds with a basic framework built by R2(2)(8) hydrogen bonds of either pure N H...N or mixed patterns. Solvent molecules are aligned to the border of these chains via N-H...O hydrogen bonds. Two of the reported crystal structures containing 6CU show additional Cl...O halogen bonds, which connect the chains to two-dimensional layers, while one weak and one strong Cl...Cl interaction are observed in the two structures in which molecules of M6CU are present. PMID- 25827375 TI - Synthesis and structural elucidation of new complexes of 2,4- and 3,5-dimethyl diphenyldithiophosphates with cobalt(II). AB - A new series of donor-stabilized addition complexes of cobalt(II) with disubstituted diphenyldithiophosphates [{(ArO)2PS2}2CoL2] {Ar = 2,4-(CH3)2C6H3 [(1)-(3)] and 3,5-(CH3)2C6H3 [(4)-(6)]; L = C5H5N [(1), (4)], 3,4-(CH3)2C5H3N [(2), (5)] and 4-(C2H5)C5H4N [(3), (6)]} were successfully isolated and characterized by elemental analyses, magnetic moment measurements, IR and single crystal X-ray analysis. Complexes (3), (4) and (5) crystallize in the monoclinic space groups P2(1)/n, P2(1)/n and P2(1)/c, respectively, whereas complex (6) crystallizes in the triclinic space group P1-. X-ray diffraction analysis of complexes (3)-(6) reveals a six-coordinated distorted octahedral geometry for the CoS4N2 chromophore defined by two chelating diphenyldithiophosphate anions as well as two N-donor ligands. Two diphenyldithiophosphate ligands are coordinated to the cobalt ion as a bidentate ligand chelating via the two thiolate S atoms. Each of them forms a four-membered chelate ring in the equatorial plane. The N atoms from two donor ligands are axially coordinated to the Co atom in a mutually trans position. PMID- 25827376 TI - Resonance-stabilized partial proton transfer in hydrogen bonds of incommensurate phenazine-chloranilic acid. AB - The co-crystal of phenazine (Phz) and chloranilic acid (H2ca) becomes ferroelectric upon cooling through the loss of inversion symmetry. Further cooling results in the development of an incommensurate ferroelectric phase, followed by a lock-in transition towards a twofold superstructure. Here we present the incommensurately modulated crystal structure of Phz-H2ca at T = 139 K with a symmetry given by the superspace group P2(1)(1/2 sigma(2) 1/2)0 and sigma(2) = 0.5139. The modulation mainly affects the positions of the protons within half of the intermolecular hydrogen bonds that are responsible for the spontaneous polarization in all three low-temperature phases. Evidence for proton transfer in part of the hydrogen bonds is obtained from the correlated dependence on the phase of the modulation of the lengths of bonds involved in resonance stabilization of the acidic anion, and much smaller variations of bond lengths of atoms not involved in the resonance mechanism. Incommensurability is explained as competition between proton transfer favored for single hydrogen bonds on the basis of pKa values and avoiding unfavorable Coulomb repulsion within the lattice of the resulting ionic molecules. PMID- 25827377 TI - Predicting the lattice constants of the ternary pyrochlores A2B2O6O'. AB - The pyrochlores A2B2O6O' attract much attention because of their physical properties. Several models which relate chemical compositions of ternary pyrochlores with lattice constants have been proposed. Analysis of these models shows that some of them are statistically inadequate and cannot be used. Statistical models to predict lattice constants of ternary pyrochlores A2B2O6O' have been derived using multiple linear regression analysis. PMID- 25827378 TI - First experimental charge density study using a Bruker CMOS-type PHOTON 100 detector: the case of ammonium tetraoxalate dihydrate. Addendum. PMID- 25827380 TI - Left ventricular dysfunction after mitral valve repair: predetermined or caused? PMID- 25827381 TI - Better to avoid disaster than rescue defeat--ventricular dysfunction after delayed mitral valve repair. PMID- 25827382 TI - Two techniques are better than one. PMID- 25827383 TI - Size matters. PMID- 25827384 TI - High activated clotting time, or venous graft, or off-pump coronary artery bypass grafting? Too early to call off the party! PMID- 25827385 TI - Definition of proximal anastomosis in the doors study. PMID- 25827386 TI - Thoracic aortic surgery in Europe: does volume mean necessarily quality? PMID- 25827387 TI - Improving outcomes in Europe. PMID- 25827388 TI - 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. PMID- 25827389 TI - Identification of a subcentimeter pulmonary adenocarcinoma using intraoperative near-infrared imaging during video-assisted thoracoscopic surgery. PMID- 25827390 TI - Early developmental delay in children with autism: A study from a developing country. AB - Early diagnosis is appropriate and important for developmental disorders such as autism spectrum disorder. In many less developed countries, unfortunately, diagnosis of this disorder is delayed. The aim of the present study is to determine whether this disorder can be screened using simple strategies such as comparison of the age of acquisition of motor skills. For this purpose, 124 children with autism were chosen to enter the study, and their parents were asked to retrospectively specify the age of achieving milestones of sitting without support, standing alone and walking alone. Information obtained from the parents was compared with World Health Organization standards. Results indicate that participants (male and female) have significantly delayed age of acquisition of all three skills. Based on this result, it can be suggested that existing standards, as a simple means with low cost and easy availability, can be used for early screening of the disease at a younger age so that treatment can be provided more quickly. PMID- 25827391 TI - A study of enhanced performance of VUV/UV process for the degradation of micropollutants from contaminated water. AB - VUV/UV is a chemical-free and straightforward solution for the degradation of emerging contaminants from water sources. The objective of this work was to investigate the feasibility of VUV/UV advanced oxidation process for the effective degradation of a target micropollutant, atrazine, under continuous flow operation of 0.5-6.5L/min. To provide an in-depth understanding of process, a comprehensive computational fluid dynamics (CFD) model, incorporating flow hydrodynamics, 185nm VUV and 254nm UV radiation propagation along with a complete kinetic scheme, was developed and validated experimentally. The experimental degradation rates and CFD predicted values showed great consistency with less than 2.9% average absolute relative deviation (AARD). Utilizing the verified model, energy-efficiency of the VUV/UV process under a wide range of reactor configurations was assessed in terms of electrical energy-per-order (EEO), OH concentration as well as delivered UV and VUV dose distributions. Thereby, the extent of mixing and circulation zones was found as key parameter controlling the treatment economy and energy-efficiency of the VUV/UV process. Utilizing a CFD driven baffle design strategy, an improved VUV/UV process with up to 72% reduction in the total electrical energy requirement of atrazine degradation was introduced and verified experimentally. PMID- 25827392 TI - Amino-functionalized adsorbent prepared by means of Cu(II) imprinted method and its selective removal of copper from aqueous solutions. AB - An amino-functionalized modified metal ion imprinting adsorbent was newly synthesized for the selective extraction and the removal of Cu(II) from aqueous solution. The adsorption capacity of the amino-functionalized ion-imprinted adsorbent was found to be significantly more than the several adsorbents reported in the literatures. The carbon based adsorbent was characterized by SEM, TEM, XPS, Elemental analysis and FTIR respectively. The optimum pH for Cu(II) adsorption was found to be 5. The adsorption equilibrium isotherm could be described by Langmuir model, the Langmuir isotherm has shown an agreement with experimental data, and the maximum adsorption capacity of copper ions for Cu(II) imprinted adsorbent was 33.33mg/g. The selectivity coefficients of the imprinted material for Cu(II)/Cd(II), Cu(II)/Co(II), Cu(II)/Ni(II) and Cu(II)/Zn(II) were 31.8, 90.2, 38.6 and 36.1, respectively. Those were 10.6, 6.22, 7.11 and 39.2 times greater than that of non-imprinted material, respectively. The high adsorption capacity and selectivity coefficient indicated that this amino functionalized ion-imprinted adsorbent can be used as the selective adsorbent for the removal of copper ions from wastewater. In this work, glucose, tetraethylene pentamine (TEPA) and copper ions as template are combined together with specific mole radio for preparing carbon-based adsorbent by means of hydrothermal synthesis method. PMID- 25827393 TI - Polyphenolic Composition and Antioxidant Activities of 6 New Turmeric (Curcuma Longa L.) Accessions. AB - The phytochemical composition and antioxidant capacities of 6 new NRCRI turmeric (Curcuma longa L.) accessions (39, 35, 60, 30, 50 and 41) were determined using standard techniques. The moisture contents of the tumeric samples ranged from 15.75 to 47.80% and the curcumin contents of the turmeric samples fell within the range of curcumin obtained from turmeric in other countries of the world. Furthermore, the turmeric accessions contained considerable amounts of antioxidants (measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and reducing power assays), alkaloids, flavonoids, anthocyanins, and phenolics. There was significant correlation between the anthocyanin contents of the tumeric accessions versus their alkaloid (0.744) and flavonoid contents (0.986) suggesting an additive effect between the anthocyanins and alkaloids in turmeric; significant correlation between the inhibition of the turmeric accessions on DPPH radical versus their flavonoid (0.892) and anthocyanin (0.949) contents and significant correlation between the reducing power of the turmeric accessions versus their flavonoid (0.973) and anthocyanin (0.974) contents suggesting that anthocyanins as flavonoids largely contribute to the antioxidant activities of turmeric. The positive regression recorded between inhibition of DPPH radical by the turmeric accessions and quercetin versus reducing power (R2 = 0.852) suggest that any of these methods could be used to assess the antioxidant activities of tumeric. Finally, the study indicated the potentials of the turmeric accessions especially accessions 30 and 50 as promising sources of antioxidants. PMID- 25827394 TI - Stem cell therapy for chronic heart failure. AB - PURPOSE OF REVIEW: The aim of this review was to discuss recent advances in clinical aspects of stem cell therapy in heart failure with emphasis on patient selection, stem cell types and delivery methods. RECENT FINDINGS: Several stem cell types have been considered for the treatment of patients with heart failure. In nonischemic heart failure, transplantation of CD34 cells improved myocardial performance, functional capacity and neurohumoral activation. In ischemic heart failure, cardiosphere-derived cells were shown to reduce myocardial scar burden with concomitant increase in viable tissue and regional systolic wall thickening. Both autologous and allogeneic mesenchymal stem cells were shown to be effective in improving heart function in patients with ischemic heart failure; this may represent an important step toward the development of a standardized stem cell product for widespread clinical use. SUMMARY: Although trials of stem cell therapy in heart failure have shown promising results, the findings are not consistent. Given the wide spectrum of heart failure, it may be difficult to define a uniform stem cell therapy for all subsets of patients; instead, future stem cell therapeutic strategies should aim for a more personalized approach by establishing optimal stem cell type, dose and delivery method for an individual patient and disease state. PMID- 25827395 TI - Spotlight on new therapies in heart failure. PMID- 25827396 TI - Designing ordered nucleic acid self-assembly processes. AB - A major goal of self-assembly research is the synthesis of biomolecular structures with diverse, intricate features across multiple length scales. Designing self-assembly processes becomes more difficult as the number of species or target structure size increases. Just as the ordered assembly of a machine or device makes complex manufacturing possible, ordered (or 'algorithmic') biomolecular self-assembly processes could enable the self-assembly of more complex structures. We discuss the design of ordered assembly processes with particular attention to DNA and RNA. The assembly of complexes can be ordered using selective, multivalent interactions or active components that change shape after assembly. The self-assembly of spatial gradients driven by reaction diffusion can also be ordered. We conclude by considering topics for future research. PMID- 25827397 TI - Activity and in vivo tracking of Amphotericin B loaded PLGA nanoparticles. AB - The development of biocompatible polymeric nanoparticles has become an important strategy for optimizing the therapeutic efficacy of many classical drugs, as it may expand their activities, reduce their toxicity, increase their bioactivity and improve biodistribution. In this study, nanoparticles of Amphotericin B entrapped within poly (lactic-co-glycolic) acid and incorporated with dimercaptosuccinic acid (NANO-D-AMB) as a target molecule were evaluated for their physic-chemical characteristics, pharmacokinetics, biocompatibility and antifungal activity. We found high plasma concentrations of Amphotericin B upon treatment with NANO-D-AMB and a high uptake of nanoparticles in the lungs, liver and spleen. NANO-D-AMB exhibited antifungal efficacy against Paracoccidioides brasiliensis and induced much lower cytotoxicity levels compared to D-AMB formulation in vivo and in vitro. Together, these results confirm that NANO-D-AMB improves Amphotericin B delivery and suggest this delivery system as a potential alternative to the use of Amphotericin B sodium deoxycholate. PMID- 25827398 TI - Structure-activity relationship studies of SEN12333 analogues: determination of the optimal requirements for binding affinities at alpha7 nAChRs through incorporation of known structural motifs. AB - Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimer's disease (AD). Structure affinity relationship studies of the previously described alpha7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the alpha7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8). PMID- 25827399 TI - Enhancing the cellular anti-proliferation activity of pyridazinones as c-met inhibitors using docking analysis. AB - A series of 2, 6-disubstituted pyridazinone derivatives were evaluated and optimized for their c-Met inhibitory activity in enzyme and cellular assay. An analysis of the SAR results arising from computer modeling analysis of members of the library led to the proposal that in order to obtain optimal inhibitory activity in cellular systems the lipophilic/hydrophilic properties of individual structural fragments in the inhibitors need to match those of corresponding binding pockets in the enzyme. Guided by this proposal, the quinoline pyridazinone 8a, containing hydrophobic 6-indolyl pyridazinone and quinoline moieties along with a hydrophilic morpholine terminal group, was designed and synthesized. The results of studies with this substance showed that it is a selective c-Met inhibitor with both a high enzyme inhibition IC50 value of 4.2 nM and a high EBC-1 cell proliferation inhibition IC50 value of 17 nM. PMID- 25827400 TI - Synthetic phenylethanoid glycoside derivatives as potent neuroprotective agents. AB - Several phenylethanoid glycoside derivatives were designed and synthesized. Most of the synthetic compounds showed significant neuroprotective effects, including antioxidative and anti-apoptotic properties. Specifically, target compounds displayed potent effects against various toxicities such as H2O2 and 6 hydroxydopamine (6-OHDA) in PC12 cells. Among the synthetic derivatives, three compounds (5, 6, 8) exhibited much superior activities to the marketed drug Edaravone. The compounds were able to prevent the 6-OHDA-induced damage in PC12 cells in a dose-dependent manner. The anti-apoptotic effects could be observed via cell morphological changes. Moreover, the compounds significantly reduced the intracellular ROS increase resulting from 6-OHDA treatment. The preliminary structure-activity relationships were also explored. Compounds 5, 6, 8 may hold the potential as promising neuroprotective agents and new lead compounds for the treatment of neurodegenerative diseases or cerebral ischemia. PMID- 25827401 TI - New paradigm of an old target: an update on structural biology and current progress in drug design towards plasmepsin II. AB - Malaria is one of the major parasitic disease whose rapid spreading and mortality rate affects all parts of the world especially several parts of Asia as well as Africa. The emergence of multi-drug resistant strains hamper the progress of current antimalarial therapy and displayed an urgent need for new antimalarials by targeting novel drug targets. Until now, several promising targets were explored in order to develop a promising Achilles hill to counter malaria. Plasmepsin, an aspartic protease, which is involved in the hemoglobin breakdown into smaller peptides emerged as a crucial target to develop new chemical entities to counter malaria. Due to early crystallographic evidence, plasmepsin II (Plm II) emerged as well explored target to develop novel antimalarials as well as a starting point to develop inhibitors targeting some other subtypes of plasmepsins i.e. Plm I, II, IV and V. With the advancements in drug discovery, several computational and synthetic approaches were employed in order to develop novel inhibitors targeting Plm II. Strategies such as fragment based drug design, molecular dynamics simulation, double drug approach etc. were employed in order to develop new chemical entities targeting Plm II. But majority of Plm II inhibitors suffered from poor selectivity over cathepsin D as well as other subtypes of plasmepsins. This review highlights an updated account of drug discovery efforts targeting plasmepsin II from a medicinal chemistry perspective. PMID- 25827402 TI - 3,4-Diaza-bicyclo[4.1.0]hept-4-en-2-one phenoxypropylamine analogs of irdabisant (CEP-26401) as potent histamine-3 receptor inverse agonists with robust wake promoting activity. AB - A novel series of 3,4-diaza-bicyclo[4.1.0]hept-4-en-2-ones were designed and synthesized as H3R analogs of irdabisant 6. Separation of the isomers, assignment of the stereochemistry by crystallography, and detailed profiling of diastereomers 25 and 26 led to the identification of (1R,6S)-5-{4-[3-((R)-2 methyl-pyrrolidin-1-yl)propoxy]phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one 25 as a potential second generation H3R candidate. Diastereomer 25 had high H3R binding affinity, excellent selectivity, displayed potent H3R functional antagonism and robust wake-promoting activity in vivo, and showed acceptable pharmacokinetic and pharmaceutical profiles for potential further development. PMID- 25827403 TI - Histone deacetylase inhibitor-polymer conjugate nanoparticles for acid-responsive drug delivery. AB - We report the synthesis of acid-responsive polymeric nanoparticles (NPs) consisting of a polymer-histone deacetylase inhibitor conjugate. An innovative aspect of this drug delivery particle lies in the NP conjugation of a histone deacetylase (HDAC) inhibitor, CI-994 (Tacedinaline), introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. Another novelty lies in the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring Opening Metathesis Polymerization (ROMP) and functionalization through azide alkyne click chemistry. Herein we demonstrate that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity (0.04), high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrug loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Such NPs should minimize drug release in vivo during blood circulation and trigger intracellular delivery after endocytosis, holding promises for improved efficacy of this class of epigenetic inhibitors. This standardized synthesis paves the way for multifunctional nanoparticles synthesis. PMID- 25827404 TI - Dermal uptake of petroleum substances. AB - Petroleum products are complex substances comprising varying amounts of linear and branched alkanes, alkenes, cycloalkanes, and aromatics which may penetrate the skin at different rates. For proper interpretation of toxic hazard data, understanding their percutaneous absorption is of paramount importance. The extent and significance of dermal absorption of eight petroleum substances, representing different classes of hydrocarbons, was evaluated. Literature data on the steady-state flux and permeability coefficient of these substances were evaluated and compared to those predicted by mathematical models. Reported results spanned over 5-6 orders of magnitude and were largely dependent on experimental conditions in particular on the type of the vehicle used. In general, aromatic hydrocarbons showed higher dermal absorption than more lipophilic aliphatics with similar molecular weight. The results showed high variation and were largely influenced by experimental conditions emphasizing the need of performing the experiments under "in use" scenario. The predictive models overestimated experimental absorption. The overall conclusion is that, based on the observed percutaneous penetration data, dermal exposure to petroleum hydrocarbons, even of aromatics with highest dermal absorption is limited and highly unlikely to be associated with health risks under real use scenarios. PMID- 25827405 TI - Oxidative DNA damage and disturbance of antioxidant capacity by alternariol in Caco-2 cells. AB - Oxidative stress occurs as a consequence of an imbalance between the prooxidant/antioxidant systems, causing an increase of intracellular generation of reactive oxygen species. Alternariol (AOH), a mycotoxin produced by Alternaria sp. can alter the action of glutathione (GSH) and the enzymes involved in the redox system, causing damage to cellular macromolecules such as DNA. The aims of this work were to determine the induction of oxidative stress by the antioxidant defenses imbalance in relation to glutathione (GSH), glutathione reductase (GR), glutathione transferase (GST), glutathione peroxidase (GPx) levels and DNA damage in Caco-2 cells derived from adenocarcinoma human colon. Oxidative stress by AOH was confirmed by alteration of GSH levels and the antioxidant defense system after 15, 30 and 60 MUM AOH exposure during 24h. GSH levels significantly decreased by 43% after treatment with 60 MUM AOH compared to the control. The activity of GPx and GR was reduced by 30% and 23%, respectively after 60 MUM AOH. The GST activity was significantly increased (approximately 22%) with 30 MUM AOH, while 60 MUM AOH decreased it by 30% in comparison to the control. Analysis of DNA damage was performed using the Comet assay after 24h, where the % of DNA in tail increased from 70% to 85% compared the control. PMID- 25827406 TI - BK/TD models for analyzing in vitro impedance data on cytotoxicity. AB - The ban of animal testing has enhanced the development of new in vitro technologies for cosmetics safety assessment. Impedance metrics is one such technology which enables monitoring of cell viability in real time. However, analyzing real time data requires moving from static to dynamic toxicity assessment. In the present study, we built mechanistic biokinetic/toxicodynamic (BK/TD) models to analyze the time course of cell viability in cytotoxicity assay using impedance. These models account for the fate of the tested compounds during the assay. BK/TD models were applied to analyze HepaRG cell viability, after single (48 h) and repeated (4 weeks) exposures to three hepatotoxic compounds (coumarin, isoeugenol and benzophenone-2). The BK/TD models properly fit the data used for their calibration that was obtained for single or repeated exposure. Only for one out of the three compounds, the models calibrated with a single exposure were able to predict repeated exposure data. We therefore recommend the use of long-term exposure in vitro data in order to adequately account for chronic hepatotoxic effects. The models we propose here are capable of being coupled with human biokinetic models in order to relate dose exposure and human hepatotoxicity. PMID- 25827407 TI - Percutaneous penetration of silver from a silver containing garment in healthy volunteers and patients with atopic dermatitis. AB - Human data on dermal absorption of silver under "in use" scenario are scarce which hampers health risk assessment. The main objective of the present study was to determine percutaneous penetration of silver after dermal exposure to silver containing garment in healthy individuals and atopic dermatitis (AD) patients. Next to assess pro-inflammatory effect of silver in the skin. Healthy subjects (n=15) and patients with AD (n=15) wore a sleeve containing 3.6% (w/w) silver on their lower arms for 8h during 5 consecutive days. The percutaneous penetration parameters were deduced from the silver concentration-depth profiles in the stratum corneum (SC) collected by adhesive tapes. Furthermore, silver was measured in urine samples collected before and after exposure. Inflammatory response was assessed by measuring IL-1alpha and IL-1RA in the exposed and non exposed skin sites. Dermal flux of silver in healthy subjects and AD patients was respectively 0.23 and 0.20 ng/cm(2)/h. The urine silver concentrations showed no increase after exposure. Furthermore, exposure to silver did not lead to the changes in the profiles of IL-1alpha and IL-1RA. Dermal absorption of silver under "real life scenario" was lower than the current reference dose. Furthermore, dermal exposure did not lead to altered expression of inflammatory IL-1 cytokines in the skin. PMID- 25827408 TI - Gender specific patterns of age-related decline in aortic stiffness: a cardiovascular magnetic resonance study including normal ranges. AB - BACKGROUND: Young females exhibit lower cardiovascular event rates that young men, a pattern which is lost, or even reversed with advancing age. As aortic stiffness is a powerful risk factor for cardiovascular events, a gender difference with advancing age could provide a plausible explanation for this pattern. METHODS: 777 subjects (?n = 408, ?n = 369) across a wide range of age (21-85 years) underwent cardiovascular magnetic resonance to assess aortic pulse wave velocity (PWV) and, in addition, aortic distensibility at three levels; 1) ascending aorta (Ao) and 2) proximal descending aorta (PDA) at the level of the pulmonary artery and 3) the abdominal aorta (DDA). RESULTS: There was a strong negative correlation between increasing age and regional aortic distensibility (Ao?R-0.84, ?R-0.80, PDA?R-0.82, ?R-0.77, DDA?R-0.80, ?R-0.71 all p < 0.001) and a strong positive correlation with PWV, (?R0.53, ?R 0.63 both p < 0.001). Even after adjustment for mean arterial pressure, body mass index, heart rate, smoking and diabetes, females exhibited a steeper decrease in all distensibility measures in response to increasing age (Ao?-1.3 vs ?-1.1 mmHg-1, PDA ?-1.2 vs ?-1.0 mmHg, DDA ?-1.8 vs ?-1.4 mmHg-1 per 10 years increase in age all p < 0.001). No gender difference in PWV increase with age was observed (p = 0.11). CONCLUSION: Although advancing age is accompanied by increased aortic stiffness in both males and females, a significant sex difference in the rate of change exists, with females showing a steeper decline in aortic elasticity. As aortic stiffness is strongly related to cardiovascular events our observations may explain the increase in cardiovascular event rates that accompanies the menopausal age in women. PMID- 25827409 TI - Biofunctionalized ceramic with self-assembled networks of nanochannels. AB - Nature designs circulatory systems with hierarchically organized networks of gradually tapered channels ranging from micrometer to nanometer in diameter. In most hard tissues in biological systems, fluid, gases, nutrients and wastes are constantly exchanged through such networks. Here, we developed a biologically inspired, hierarchically organized structure in ceramic to achieve effective permeation with minimum void region, using fabrication methods that create a long range, highly interconnected nanochannel system in a ceramic biomaterial. This design of a synthetic model-material was implemented through a novel pressurized sintering process formulated to induce a gradual tapering in channel diameter based on pressure-dependent polymer agglomeration. The resulting system allows long-range, efficient transport of fluid and nutrients into sites and interfaces that conventional fluid conduction cannot reach without external force. We demonstrate the ability of mammalian bone-forming cells placed at the distal transport termination of the nanochannel system to proliferate in a manner dependent solely upon the supply of media by the self-powering nanochannels. This approach mimics the significant contribution that nanochannel transport plays in maintaining living hard tissues by providing nutrient supply that facilitates cell growth and differentiation, and thereby makes the ceramic composite "alive". PMID- 25827410 TI - The effect of mealybug Pseudococcus longispinus (Targioni Tozzetti) infestation of different density on physiological responses of Phalaenopsis * hybridum 'Innocence'. AB - Cultivated orchids are the most abundantly attacked by polyphagous mealybugs. This study documented how different density of mealybug Pseudococcus longispinus (Targioni Tozzetti) infestation is associated with a response of antioxidative systems of Phalaenopsis * hybridum 'Innocence'. The degree of cell damage, estimated by electrolyte leakage measurement and the level of thiobarbituric acid reactive substances (TBARS), the content of pigments as well as the activity of antioxidative enzymes and proline level, as measurements of stress and stress compensation in moth orchid were examined. The highest electrolyte leakage (E L) value among samples from colonized plants was found in the orchids from series III (50 individuals/plant), whereas the lowest in the plants from series II (20 individuals/plant). The TBARS content reached the highest level at the lowest number of feeding insects (series I). Peroxidase activity toward guaiacol was significantly increased in series I (5 individuals/plant). The highest catalase activity was recorded in plants colonized by the highest number of scale insects (series III). Whereas, the highest value of proline was in series II. The content of individual photosynthetic pigments (chlorophyll a, chlorophyll b and carotenoids) in plant tissues did not vary significantly between control and colonized orchids. The results have not confirmed hypothesis that the increasing number of mealybugs occurring on plant enhanced plant physiological response. The degree of longtailed mealybug infestation on plants was positively correlated only with electrolyte leakage and catalase activity in leaf tissues. PMID- 25827411 TI - How much of the variation in mortality across Norwegian municipalities is explained by the socio-demographic characteristics of the population? AB - The goal was to find out whether much of the variation in mortality between the 430 Norwegian municipalities could be attributed to socio-demographic characteristics of the population - operating through individual- or aggregate level mechanisms. Two-level discrete-time hazard models were estimated for women and men at age 60-89 in 2000-2008, using registers covering the entire population. Year, age and a municipality-level random term were included in the first step. When socio-demographic characteristics of the individual and others in the municipality were added, the variance of the random term was reduced by 73 80% almost exclusively because of aggregate-level effects. Policy implications of these findings are discussed. PMID- 25827412 TI - Association between arterial stiffness, cerebral small vessel disease and cognitive impairment: A systematic review and meta-analysis. AB - Arterial stiffness may be a cause of cerebral small vessel disease and cognitive impairment. We therefore performed a systematic review and meta-analysis of studies on the association between stiffness, cerebral small vessel disease and cognitive impairment. For the associations between stiffness (i.e. carotid femoral pulse wave velocity (cfPWV), brachial-ankle PWV (baPWV), carotid stiffness and pulse pressure) on the one hand and cerebral small vessel disease and cognitive impairment on the other, we identified 23 (n=15,666/20 cross sectional; 1 longitudinal; 2 combined cross-sectional/longitudinal) and 41 studies (n=57,671/26 cross-sectional; 11 longitudinal; 4 combined cross sectional/longitudinal), respectively. Pooled analyses of cross-sectional studies showed that greater stiffness was associated with markers of cerebral small vessel disease with odds ratios, per +1 SD, of 1.29-1.32 (P<.001). Studies on cognitive impairment could not be pooled due to large heterogeneity. Some (but not all) studies showed an association between greater stiffness and cognitive impairment, and the strength of this association was relatively weak. The present study supports the hypothesis that greater arterial stiffness is a contributor to microvascular brain disease. PMID- 25827413 TI - Recoding of the vesicular stomatitis virus L gene by computer-aided design provides a live, attenuated vaccine candidate. AB - Codon pair bias (CPB), which has been observed in all organisms, is a neglected genomic phenomenon that affects gene expression. CPB results from synonymous codons that are paired more or less frequently in ORFeomes regardless of codon bias. The effect of an individual codon pair change is usually small, but when it is amplified by large-scale genome recoding, strikingly altered biological phenotypes are observed. The utility of codon pair bias in the development of live attenuated vaccines was recently demonstrated by recodings of poliovirus (a positive-strand RNA virus) and influenza virus (a negative-strand segmented RNA virus). Here, the L gene of vesicular stomatitis virus (VSV), a nonsegmented negative-sense RNA virus, was partially recoded based on codon pair bias. Totals of 858 and 623 silent mutations were introduced into a 5'-terminal segment of the viral L gene (designated L1) to create sequences containing either overrepresented or underrepresented codon pairs, designated L1(sdmax) and L1(min), respectively. Analysis revealed that recombinant VSV containing the L1(min) sequence could not be recovered, whereas the virus with the sdmax sequence showed a modest level of attenuation in cell culture. More strikingly, in mice the L1(sdmax) virus was almost as immunogenic as the parental strain but highly attenuated. Taken together, these results open a new road to attain a balance between VSV virulence and immunogenicity, which could serve as an example for the attenuation of other negative-strand, nonsegmented RNA viruses. IMPORTANCE: Vesicular stomatitis virus (VSV) is the prototypic rhabdovirus in the order Mononegavirales. A wide range of human pathogens belong to this family. Using a unique computer algorithm and large-scale genome synthesis, we attempted to develop a live attenuated vaccine strain for VSV, which could be used as an antigen delivery platform for humans. Recombinant VSVs with distinct codon pair biases were rationally designed, constructed, and analyzed in both cell culture and an animal model. One such recombinant virus, L1(sdmax), contained extra overrepresented codon pairs in its L gene open reading frame (ORF) and showed promise as an effective vaccine candidate because of a favorable balance between virulence and immunogenicity. Our study not only contributes to the understanding of the underlying mechanism of codon pair bias but also may facilitate the development of live attenuated vaccines for other viruses in the order Mononegavirales. PMID- 25827414 TI - Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system. AB - Strains of Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever (RMSF), differ dramatically in virulence despite >99% genetic homology. Spotted fever group (SFG) rickettsiae produce two immunodominant outer membrane proteins, rickettsial OmpA (rOmpA) and rOmpB, which are conserved throughout the SFG and thought to be fundamental to pathogenesis. rOmpA is present in all virulent strains of R. rickettsii but is not produced in the only documented avirulent strain, Iowa, due to a premature stop codon. Here we report the creation of an isogenic ompA mutant in the highly virulent strain Sheila Smith by insertion of intronic RNA to create a premature stop codon 312 bp downstream of the 6,747-bp open reading frame initiation site (int312). Targeted insertion was accomplished using an LtrA group II intron retrohoming system. Growth and entry rates of Sheila Smith ompA::int312 in Vero cells remained comparable to those of the wild type. Virulence was assessed in a guinea pig model by challenge with 100 PFU of either ompA::int312 Sheila Smith or the wild type, but no significant difference in either fever peak (40.5 degrees C) or duration (8 days) were shown between the wild type and the knockout. The ability to disrupt genes in a site specific manner using an LtrA group II intron system provides an important new tool for evaluation of potential virulence determinants in rickettsial disease research. IMPORTANCE: R. rickettsii rOmpA is an immunodominant outer membrane autotransporter conserved in the spotted fever group. Previous studies and genomic comparisons suggest that rOmpA is involved in adhesion and may be critical for virulence. Little information is available for rickettsial virulence factors in an isogenic background, as limited systems for targeted gene disruption are currently available. Here we describe the creation of an rOmpA knockout by insertion of a premature stop codon into the 5' end of the open reading frame using a group II intron system. An isogenic rOmpA knockout mutation in the highly virulent Sheila Smith strain did not cause attenuation in a guinea pig model of infection, and no altered phenotype was observed in cell culture. We conclude that rOmpA is not critical for virulence in a guinea pig model but may play a role in survival or transmission from the tick vector. PMID- 25827415 TI - Distinct roles of the repeat-containing regions and effector domains of the Vibrio vulnificus multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin. AB - Vibrio vulnificus is a seafood-borne pathogen that destroys the intestinal epithelium, leading to rapid bacterial dissemination and death. The most important virulence factor is the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin comprised of effector domains in the center region flanked by long repeat-containing regions which are well conserved among MARTX toxins and predicted to translocate effector domains. Here, we examined the role of the repeat-containing regions using a modified V. vulnificus MARTX (MARTX(Vv)) toxin generated by replacing all the internal effector domains with beta-lactamase (Bla). Bla activity was detected in secretions from the bacterium and also in the cytosol of intoxicated epithelial cells. The modified MARTX(Vv) toxin without effector domains retained its necrotic activity but lost its cell-rounding activity. Further, deletion of the carboxyl-terminal repeat-containing region blocked toxin secretion from the bacterium. Deletion of the amino-terminal repeat containing region had no effect on secretion but completely abolished translocation and necrosis. Neither secretion nor translocation was affected by enzymatically inactivating the cysteine protease domain of the toxin. These data demonstrate that the amino-terminal and carboxyl-terminal repeat-containing regions of the MARTXVv toxin are necessary and sufficient for the delivery of effector domains and epithelial cell lysis in vitro but that effector domains are required for other cytopathic functions. Furthermore, Ca(2+)-dependent secretion of the modified MARTX(Vv) toxin suggests that nonclassical RTX-like repeats found in the carboxyl-terminal repeat-containing region are functionally similar to classical RTX repeats found in other RTX proteins. IMPORTANCE: Up to 95% of deaths from seafood-borne infections in the United States are due solely to one pathogen, V. vulnificus. Among its various virulence factors, the MARTX(Vv) toxin has been characterized as a critical exotoxin for successful pathogenesis of V. vulnificus in mouse infection models. Similarly to MARTX toxins of other pathogens, MARTX(Vv) toxin is comprised of repeat-containing regions, central effector domains, and an autoprocessing cysteine protease domain. Yet how each of these regions contributes to essential activities of the toxins has not been fully identified for any of MARTX toxins. Using modified MARTX(Vv) toxin fused with beta-lactamase as a reporter enzyme, the portion(s) responsible for toxin secretion from bacteria, effector domain translocation into host cells, rapid host cell rounding, and necrotic host cell death was identified. The results are relevant for understanding how MARTX(Vv) toxin serves as both a necrotic pore forming toxin and an effector delivery platform. PMID- 25827416 TI - The glycerol-dependent metabolic persistence of Pseudomonas putida KT2440 reflects the regulatory logic of the GlpR repressor. AB - The growth of the soil bacterium Pseudomonas putida KT2440 on glycerol as the sole carbon source is characterized by a prolonged lag phase, not observed with other carbon substrates. We examined the bacterial growth in glycerol cultures while monitoring the metabolic activity of individual cells. Fluorescence microscopy and flow cytometry, as well as the analysis of the temporal start of growth in single-cell cultures, revealed that adoption of a glycerol-metabolizing regime was not the result of a gradual change in the whole population but rather reflected a time-dependent bimodal switch between metabolically inactive (i.e., nongrowing) and fully active (i.e., growing) bacteria. A transcriptional Phi(glpD gfp) fusion (a proxy of the glycerol-3-phosphate [G3P] dehydrogenase activity) linked the macroscopic phenotype to the expression of the glp genes. Either deleting glpR (encoding the G3P-responsive transcriptional repressor that controls the expression of the glpFKRD gene cluster) or altering G3P formation (by overexpressing glpK, encoding glycerol kinase) abolished the bimodal glpD expression. These manipulations eliminated the stochastic growth start by shortening the otherwise long lag phase. Provision of glpR in trans restored the phenotypes lost in the DeltaglpR mutant. The prolonged nongrowth regime of P. putida on glycerol could thus be traced to the regulatory device controlling the transcription of the glp genes. Since the physiological agonist of GlpR is G3P, the arrangement of metabolic and regulatory components at this checkpoint merges a positive feedback loop with a nonlinear transcriptional response, a layout fostering the observed time-dependent shift between two alternative physiological states. IMPORTANCE: Phenotypic variation is a widespread attribute of prokaryotes that leads, inter alia, to the emergence of persistent bacteria, i.e., live but nongrowing members within a genetically clonal population. Persistence allows a fraction of cells to avoid the killing caused by conditions or agents that destroy most growing bacteria (e.g., some antibiotics). Known molecular mechanisms underlying the phenomenon include genetic changes, epigenetic variations, and feedback-based multistability. We show that a prolonged nongrowing state of the bacterial population can be brought about by a distinct regulatory architecture of metabolic genes when cells face specific nutrients (e.g., glycerol). Pseudomonas putida may have adopted the resulting carbon source dependent metabolic bet hedging as an advantageous trait for exploring new chemical and nutritional landscapes. Defeating such naturally occurring adaptive features of environmental bacteria is instrumental in improving the performance of these microorganisms as whole-cell catalysts in a bioreactor setup. PMID- 25827417 TI - Subinhibitory antibiotic therapy alters recurrent urinary tract infection pathogenesis through modulation of bacterial virulence and host immunity. AB - The capacity of subinhibitory levels of antibiotics to modulate bacterial virulence in vitro has recently been brought to light, raising concerns over the appropriateness of low-dose therapies, including antibiotic prophylaxis for recurrent urinary tract infection management. However, the mechanisms involved and their relevance in influencing pathogenesis have not been investigated. We characterized the ability of antibiotics to modulate virulence in the uropathogens Staphylococcus saprophyticus and Escherichia coli. Several antibiotics were able to induce the expression of adhesins critical to urothelial colonization, resulting in increased biofilm formation, colonization of murine bladders and kidneys, and promotion of intracellular niche formation. Mice receiving subinhibitory ciprofloxacin treatment were also more susceptible to severe infections and frequent recurrences. A ciprofloxacin prophylaxis model revealed this strategy to be ineffective in reducing recurrences and worsened infection by creating larger intracellular reservoirs at higher frequencies. Our study indicates that certain agents used for antibiotic prophylaxis have the potential to complicate infections. IMPORTANCE: Antibiotics are the mainstay treatment for bacterial infections; however, evidence is emerging that argues these agents may have off-target effects if sublethal concentrations are present. Most studies have focused on changes occurring in vitro, leaving questions regarding the clinical relevance in vivo. We utilized a murine urinary tract infection model to explore the potential impact of low-dose antibiotics on pathogenesis. Using this model, we showed that subinhibitory antibiotics prime uropathogens for adherence and invasion of murine urothelial tissues. These changes in initial colonization promoted the establishment of chronic infection. Furthermore, treatment of chronically infected mice with subtherapeutic ciprofloxacin served to exacerbate infection. A part of these changes was thought to be due to suppression of mucosal immunity, as demonstrated through reductions in cytokine secretion and migration of leukocytes into the urinary tract. This work identifies novel risk factors associated with antibiotic therapy when dosing strategies fall below subtherapeutic levels. PMID- 25827418 TI - Rapid genome assembly and comparison decode intrastrain variation in human alphaherpesviruses. AB - Herpes simplex virus (HSV) is a widespread pathogen that causes epithelial lesions with recurrent disease that manifests over a lifetime. The lifelong aspect of infection results from latent viral infection of neurons, a reservoir from which the virus reactivates periodically. Recent work has demonstrated the breadth of genetic variation in globally distributed HSV strains. However, the amount of variation or capacity for mutation within one strain has not been well studied. Here we developed and applied a streamlined new approach for assembly and comparison of large DNA viral genomes such as HSV-1. This viral genome assembly (VirGA) workflow incorporates a combination of de novo assembly, alignment, and annotation strategies to automate the generation of draft genomes for large viruses. We applied this approach to quantify the amount of variation between clonal derivatives of a common parental virus stock. In addition, we examined the genetic basis for syncytial plaque phenotypes displayed by a subset of these strains. In each of the syncytial strains, we found an identical DNA change, affecting one residue in the gB (UL27) fusion protein. Since these identical mutations could have appeared after extensive in vitro passaging, we applied the VirGA sequencing and comparison approach to two clinical HSV-1 strains isolated from the same patient. One of these strains was syncytial upon first culturing; its sequence revealed the same gB mutation. These data provide insight into the extent and origin of genome-wide intrastrain HSV-1 variation and present useful methods for expansion to in vivo patient infection studies. IMPORTANCE: Herpes simplex virus (HSV) infects more than 70% of adults worldwide, causing epithelial lesions and recurrent disease that manifests over a lifetime. Prior work has demonstrated that HSV strains vary from country to country and between individuals. However, the amount of variation within one strain has not been well studied. To address this, we developed a new approach for viral genome assembly (VirGA) and analysis. We used this approach to quantify the amount of variation between sister clones of a common parental virus stock and to determine the basis of a unique fusion phenotype displayed by several variants. These data revealed that while sister clones of one HSV stock are more than 98% identical, these variants harbor enough genetic differences to change their observed characteristics. Comparative genomics approaches will allow us to explore the impacts of viral inter- and intrastrain diversity on drug and vaccine efficacy. PMID- 25827419 TI - Essential gene discovery in the basidiomycete Cryptococcus neoformans for antifungal drug target prioritization. AB - Fungal diseases represent a major burden to health care globally. As with other pathogenic microbes, there is a limited number of agents suitable for use in treating fungal diseases, and resistance to these agents can develop rapidly. Cryptococcus neoformans is a basidiomycete fungus that causes cryptococcosis worldwide in both immunocompromised and healthy individuals. As a basidiomycete, it diverged from other common pathogenic or model ascomycete fungi more than 500 million years ago. Here, we report C. neoformans genes that are essential for viability as identified through forward and reverse genetic approaches, using an engineered diploid strain and genetic segregation after meiosis. The forward genetic approach generated random insertional mutants in the diploid strain, the induction of meiosis and sporulation, and selection for haploid cells with counterselection of the insertion event. More than 2,500 mutants were analyzed, and transfer DNA (T-DNA) insertions in several genes required for viability were identified. The genes include those encoding the thioredoxin reductase (Trr1), a ribosome assembly factor (Rsa4), an mRNA-capping component (Cet1), and others. For targeted gene replacement, the C. neoformans homologs of 35 genes required for viability in ascomycete fungi were disrupted, meiosis and sporulation were induced, and haploid progeny were evaluated for their ability to grow on selective media. Twenty-one (60%) were found to be required for viability in C. neoformans. These genes are involved in mitochondrial translation, ergosterol biosynthesis, and RNA-related functions. The heterozygous diploid mutants were evaluated for haploinsufficiency on a number of perturbing agents and drugs, revealing phenotypes due to the loss of one copy of an essential gene in C. neoformans. This study expands the knowledge of the essential genes in fungi using a basidiomycete as a model organism. Genes that have no mammalian homologs and are essential in both Cryptococcus and ascomycete human pathogens would be ideal for the development of antifungal drugs with broad-spectrum activity. IMPORTANCE: Fungal infections are very common in humans but may be neglected due to misdiagnosis and inattention. Cryptococcus neoformans is a yeast that infects mainly immunocompromised people, causing high mortality rates in developing countries. The fungus infects the lungs, crosses the blood-brain barrier, and invades the cerebrospinal fluid, causing fatal meningitis. C. neoformans infections are treated with amphotericin B, flucytosine, and azoles, all developed decades ago. However, problems with antifungal agents highlight the urgent need for more-effective drugs to treat C. neoformans and other invasive fungal infections. These issues include the negative side effects of amphotericin B, the spontaneous resistance of C. neoformans to azoles, and the inefficacy of the echinocandin antifungals. In this study, we report the identification of C. neoformans essential genes as targets for the development of novel antifungals. Because of the level of evolutionary divergence between C. neoformans and the ascomycetes, a subset of these genes is likely essential in all fungi. Genes identified in this study represent an excellent starting point for the future development of new antifungals by pharmaceutical companies. PMID- 25827420 TI - Structural and mechanistic roles of novel chemical ligands on the SdiA quorum sensing transcription regulator. AB - Bacteria engage in chemical signaling, termed quorum sensing (QS), to mediate intercellular communication, mimicking multicellular organisms. The LuxR family of QS transcription factors regulates gene expression, coordinating population behavior by sensing endogenous acyl homoserine lactones (AHLs). However, some bacteria (such as Escherichia coli) do not produce AHLs. These LuxR orphans sense exogenous AHLs but also regulate transcription in the absence of AHLs. Importantly, this AHL-independent regulatory mechanism is still largely unknown. Here we present several structures of one such orphan LuxR-type protein, SdiA, from enterohemorrhagic E. coli (EHEC), in the presence and absence of AHL. SdiA is actually not in an apo state without AHL but is regulated by a previously unknown endogenous ligand, 1-octanoyl-rac-glycerol (OCL), which is ubiquitously found throughout the tree of life and serves as an energy source, signaling molecule, and substrate for membrane biogenesis. While exogenous AHL renders to SdiA higher stability and DNA binding affinity, OCL may function as a chemical chaperone placeholder that stabilizes SdiA, allowing for basal activity. Structural comparison between SdiA-AHL and SdiA-OCL complexes provides crucial mechanistic insights into the ligand regulation of AHL-dependent and -independent function of LuxR-type proteins. Importantly, in addition to its contribution to basic science, this work has implications for public health, inasmuch as the SdiA signaling system aids the deadly human pathogen EHEC to adapt to a commensal lifestyle in the gastrointestinal (GI) tract of cattle, its main reservoir. These studies open exciting and novel avenues to control shedding of this human pathogen in the environment. IMPORTANCE: Quorum sensing refers to bacterial chemical signaling. The QS acyl homoserine lactone (AHL) signals are recognized by LuxR-type receptors that regulate gene transcription. However, some bacteria have orphan LuxR-type receptors and do not produce AHLs, sensing them from other bacteria. We solved three structures of the E. coli SdiA orphan, in the presence and absence of AHL. SdiA with no AHL is not in an apo state but is regulated by a previously unknown endogenous ligand, 1-octanoyl-rac-glycerol (OCL). OCL is ubiquitously found in prokaryotes and eukaryotes and is a phospholipid precursor for membrane biogenesis and a signaling molecule. While AHL renders to SdiA higher stability and DNA-binding affinity, OCL functions as a chemical chaperone placeholder, stabilizing SdiA and allowing for basal activity. Our studies provide crucial mechanistic insights into the ligand regulation of SdiA activity. PMID- 25827421 TI - Genome sequence of the Drosophila melanogaster male-killing Spiroplasma strain MSRO endosymbiont. AB - Spiroplasmas are helical and motile members of a cell wall-less eubacterial group called Mollicutes. Although all spiroplasmas are associated with arthropods, they exhibit great diversity with respect to both their modes of transmission and their effects on their hosts; ranging from horizontally transmitted pathogens and commensals to endosymbionts that are transmitted transovarially (i.e., from mother to offspring). Here we provide the first genome sequence, along with proteomic validation, of an endosymbiotic inherited Spiroplasma bacterium, the Spiroplasma poulsonii MSRO strain harbored by Drosophila melanogaster. Comparison of the genome content of S. poulsonii with that of horizontally transmitted spiroplasmas indicates that S. poulsonii has lost many metabolic pathways and transporters, demonstrating a high level of interdependence with its insect host. Consistent with genome analysis, experimental studies showed that S. poulsonii metabolizes glucose but not trehalose. Notably, trehalose is more abundant than glucose in Drosophila hemolymph, and the inability to metabolize trehalose may prevent S. poulsonii from overproliferating. Our study identifies putative virulence genes, notably, those for a chitinase, the H2O2-producing glycerol-3 phosphate oxidase, and enzymes involved in the synthesis of the eukaryote-toxic lipid cardiolipin. S. poulsonii also expresses on the cell membrane one functional adhesion-related protein and two divergent spiralin proteins that have been implicated in insect cell invasion in other spiroplasmas. These lipoproteins may be involved in the colonization of the Drosophila germ line, ensuring S. poulsonii vertical transmission. The S. poulsonii genome is a valuable resource to explore the mechanisms of male killing and symbiont-mediated protection, two cardinal features of many facultative endosymbionts. IMPORTANCE: Most insect species, including important disease vectors and crop pests, harbor vertically transmitted endosymbiotic bacteria. These endosymbionts play key roles in their hosts' fitness, including protecting them against natural enemies and manipulating their reproduction in ways that increase the frequency of symbiont infection. Little is known about the molecular mechanisms that underlie these processes. Here, we provide the first genome draft of a vertically transmitted male-killing Spiroplasma bacterium, the S. poulsonii MSRO strain harbored by D. melanogaster. Analysis of the S. poulsonii genome was complemented by proteomics and ex vivo metabolic experiments. Our results indicate that S. poulsonii has reduced metabolic capabilities and expresses divergent membrane lipoproteins and potential virulence factors that likely participate in Spiroplasma-host interactions. This work fills a gap in our knowledge of insect endosymbionts and provides tools with which to decipher the interaction between Spiroplasma bacteria and their well-characterized host D. melanogaster, which is emerging as a model of endosymbiosis. PMID- 25827422 TI - Virus-induced dormancy in the archaeon Sulfolobus islandicus. AB - We investigated the interaction between Sulfolobus spindle-shaped virus (SSV9) and its native archaeal host Sulfolobus islandicus. We show that upon exposure to SSV9, S. islandicus strain RJW002 has a significant growth delay where the majority of cells are dormant (viable but not growing) for 24 to 48 hours postinfection (hpi) compared to the growth of controls without virus. We demonstrate that in this system, dormancy (i) is induced by both active and inactive virus particles at a low multiplicity of infection (MOI), (ii) is reversible in strains with active CRISPR-Cas immunity that prevents the establishment of productive infections, and (iii) results in dramatic and rapid host death if virus persists in the culture even at low levels. Our results add a new dimension to evolutionary models of virus-host interactions, showing that the mere presence of a virus induces host cell stasis and death independent of infection. This novel, highly sensitive, and risky bet-hedging antiviral response must be integrated into models of virus-host interactions in this system so that the true ecological impact of viruses can be predicted and understood. IMPORTANCE: Viruses of microbes play key roles in microbial ecology; however, our understanding of viral impact on host physiology is based on a few model bacteria that represent a small fraction of the life history strategies employed by hosts or viruses across the three domains that encompass the microbial world. We have demonstrated that rare and even inactive viruses induce dormancy in the model archaeon S. islandicus. Similar virus-induced dormancy strategies in other microbial systems may help to explain several confounding observations in other systems, including the surprising abundance of dormant cell types found in many microbial environments, the difficulty of culturing microorganisms in the laboratory, and the paradoxical virus-to-host abundances that do not match model predictions. A more accurate grasp of virus-host interactions will expand our understanding of the impact of viruses in microbial ecology. PMID- 25827423 TI - Cryptococcus neoformans host adaptation: toward biological evidence of dormancy. AB - Cryptococcosis is an opportunistic infection due to the ubiquitous yeast Cryptococcus neoformans. This yeast interacts closely with innate immune cells, leading to various fates, including fungal persistence within cells, making possible the dissemination of the yeast cells with monocytes via a Trojan horse strategy. In humans, the natural history of the infection begins with primoinfection during childhood, which is followed by dormancy and, in some individuals, reactivation upon immunosuppression. To address the question of dormancy, we studied C. neoformans infection at the macrophage level (in vitro H99-macrophage interaction) and at the organ level in a murine model of cryptococcosis. We analyzed the diversity of yeast adaptation to the host by characterizing several C. neoformans populations with new assays based on flow cytometry (quantitative flow cytometry, multispectral imaging flow cytometry, sorting), microscopy (dynamic imaging), and gene expression analysis. On the basis of parameters of multiplication and stress response, various populations of yeast cells were observed over time in vivo and in vitro. Cell sorting allowed the identification of a subpopulation that was less prone to grow under standard conditions than the other populations, with growth enhanced by the addition of serum. Gene expression analysis revealed that this population had specific metabolic characteristics that could reflect dormancy. Our data suggest that dormant yeast cells could exist in vitro and in vivo. C. neoformans exhibits a huge plasticity and adaptation to hosts that deserves further study. In vitro generation of dormant cells is now the main challenge to overcome the limited number of yeast cells recovered in our models. IMPORTANCE: Cryptococcus neoformans is a sugar-coated unicellular fungus that interacts closely with various cells and organisms, including amoebas, nematodes, and immune cells of mammals. This yeast is able to proliferate and survive in the intracellular environment. C. neoformans causes cryptococcosis, and yeast dormancy in humans has been suggested on the basis of epidemiological evidence obtained years ago. By studying an in vitro model of yeast-macrophage interaction and murine models of cryptococcosis, we observed that yeast cells evolve in heterogeneous populations during infection on the basis of global metabolic activity. We compared the growth ability and gene expression of yeast cells belonging to various populations in those two models. We eventually found a population of yeast cells with low metabolism that fit some of the criteria for dormant cells. This paves the way for further characterization of dormancy in C. neoformans. PMID- 25827424 TI - Expression of xCT and activity of system xc(-) are regulated by NRF2 in human breast cancer cells in response to oxidative stress. AB - Cancer cells adapt to high levels of oxidative stress in order to survive and proliferate by activating key transcription factors. One such master regulator, the redox sensitive transcription factor NF E2 Related Factor 2 (NRF2), controls the expression of cellular defense genes including those encoding intracellular redox-balancing proteins involved in glutathione (GSH) synthesis. Under basal conditions, Kelch-like ECH-associated protein 1 (KEAP1) targets NRF2 for ubiquitination. In response to oxidative stress, NRF2 dissociates from KEAP1, entering the nucleus and binding to the antioxidant response element (ARE) in the promoter of its target genes. Elevated reactive oxygen species (ROS) production may deplete GSH levels within cancer cells. System xc(-), an antiporter that exports glutamate while importing cystine to be converted into cysteine for GSH synthesis, is upregulated in cancer cells in response to oxidative stress. Here, we provided evidence that the expression of xCT, the light chain subunit of system xc(-), is regulated by NRF2 in representative human breast cancer cells. Hydrogen peroxide (H2O2) treatment increased nuclear translocation of NRF2, also increasing levels of xCT mRNA and protein and extracellular glutamate release. Overexpression of NRF2 up-regulated the activity of the xCT promoter, which contains a proximal ARE. In contrast, overexpression of KEAP1 repressed promoter activity and decreased xCT protein levels, while siRNA knockdown of KEAP1 up regulated xCT protein levels and transporter activity. These results demonstrate the importance of the KEAP1/NRF2 pathway in balancing oxidative stress in breast cancer cells through system xc(-). We have previously shown that xCT is upregulated in various cancer cell lines under oxidative stress. In the current investigation, we focused on MCF-7 cells as a model for mechanistic studies. PMID- 25827425 TI - An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins--From superoxide dismutation to H2O2-driven pathways. AB - Most of the SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2( ) dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also. Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2(-) dismutation process, the most powerful Mn porphyrin-based SOD mimics reduce and oxidize O2(-) with close to identical rate constants. MnPs reduce and oxidize other reactive species also (none of them specific to MnPs), acting as reductants (antioxidant) and pro-oxidants. Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects we observe; the latter may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2(-) dismutation parallels all other reactivities (such as ONOO(-) reduction) and in turn their therapeutic efficacies. Assuming that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the appropriate strategy for the design of potent redox active therapeutics. PMID- 25827426 TI - Association of Job Strain With Cortisol and Alpha-Amylase Among Shift-Working Health Care Professionals in Laboratory and Field. AB - Although the prevalence of work-related stress has increased, knowledge on the contributions of that stress to long-term adverse health effects is still lacking. Stress biomarkers can reveal early signs of negative health effects, but no previous studies have measured both acute stress reactions and long-term exposure to job strain using both salivary cortisol and alpha-amylase (AA). The present study examines the association between job strain and these biomarkers among shift-working female health care professionals in the laboratory and the field. The 95 participants were recruited from hospital wards categorized in either the top (high job strain [HJS] group, n = 42) or the bottom quartile of job strain (low job strain [LJS] group, n = 53), as rated by survey responses. Participants' self-perceived job strain was at least as high or low as the ward's average estimation. Saliva samples were collected during the Trier Social Stress Test (TSST), preselected morning and night shifts, and a day off. There was a larger increase in the cortisol concentration of participants in the HJS than in the LJS group (2.27- vs. 1.48-fold, respectively, nonsignificant) during the TSST. Participants in the HJS group also had higher salivary AA levels 30 min after awakening on the morning-shift day than those in the LJS group (p = .02), whereas the salivary cortisol awakening response on the day off was higher in the LJS group (p = .05, education as a covariate). The remaining stress-biomarker results did not differ significantly between groups. These data suggest that HJS in shift-working health care professionals is weakly associated with changes in stress biomarkers. PMID- 25827427 TI - Effect of angiotensin II on voltage-gated sodium currents in aortic baroreceptor neurons and arterial baroreflex sensitivity in heart failure rats. AB - BACKGROUND: Impairment of arterial baroreflex sensitivity is associated with mortality in patients with chronic heart failure (CHF). Elevation of plasma angiotension II (Ang II) contributes to arterial baroreflex dysfunction in CHF. A reduced number of voltage-gated sodium (Nav) channels in aortic baroreceptor neurons are involved in CHF-blunted arterial baroreflex. METHOD: In this study, we investigated acute effect of Ang II on Nav currents in the aortic baroreceptor neuron and on arterial baroreflex in sham and coronary artery ligation-induced CHF rats. RESULTS: Using Ang II I radioimmunoassay, real-time reverse transcription-PCR and western blot, we found that Ang II levels, and mRNA and protein expression of angiotension II type 1 receptor in nodose ganglia from CHF rats were higher than that from sham rats. Local microinjection of Ang II (0.2 nmol) into the nodose ganglia decreased the arterial baroreflex sensitivity in sham rats, whereas losartan (1 nmol, an angiotension II type 1 receptor antagonist) improved the arterial baroreflex sensitivity in CHF rats. Data from patch-clamp recording showed that Ang II (100 nmol/l) acutely inhibited Nav currents in the aortic baroreceptor neurons from sham and CHF rats. In particular, inhibitory effect of Ang II on Nav currents in the aortic baroreceptor neurons was larger in CHF rats than that in sham rats. Losartan (1 MUmol/l) totally abolished the inhibitory effect of Ang II on Nav currents in sham and CHF aortic baroreceptor neurons. CONCLUSION: These results suggest that elevation of endogenous Ang II in the nodose ganglia contributes to impairment of the arterial baroreflex function in CHF rats through inhibiting Nav channels. PMID- 25827428 TI - Association between N-terminal pro B-type natriuretic peptide and day-to-day blood pressure and heart rate variability in a general population: the Ohasama study. AB - BACKGROUND: In addition to day-to-day variability in blood pressure (BP) or heart rate (HR), N-terminal pro B-type natriuretic peptide (NT-proBNP) has been reported to be a predictor of cardiovascular disease. Here, we tested the hypothesis that day-to-day BP or HR variability calculated as the intraindividual standard deviation (SD) of home BP or HR is associated with elevated NT-proBNP in a cross-sectional study. METHODS: Among 664 participants (mean age, 61.9 years; female, 70.5%) from a general Japanese population without a history of heart disease, 86 (13.0%) had NT-proBNP at least 125 pg/ml. RESULTS: Each 1 SD increase in the SD of home systolic BP (SBP) [odds ratio (OR), 1.82; P < .0001) and in the SD of home HR (OR, 1.44; P = 0.008) were significantly associated with the prevalence of NT-proBNP at least 125 pg/ml after adjustment for possible confounding factors including home SBP and HR. Among the four groups defined by the median SD of home SBP and of home HR, the group with higher SDs in home SBP (>=8.0 mmHg) and HR (>=5.0 bpm) had the greatest OR for the prevalence of NT proBNP at least 125 pg/ml (OR, 4.80; P = 0007 vs. a reference group with lower SDs of home SBP and HR). CONCLUSION: These results suggest that day-to-day variability in BP and HR may be associated with target-organ damage or complications, which can lead to an elevated NT-proBNP level. An elevated NT proBNP level may be involved in the prognostic significance of day-to-day variability in BP or HR. PMID- 25827429 TI - Pulse wave velocity distribution in a cohort study: from arterial stiffness to early vascular aging. AB - BACKGROUND: By contrast with other southern European people, north Portuguese population registers an especially high prevalence of hypertension and stroke incidence. We designed a cohort study to identify individuals presenting accelerated and premature arterial aging in the Portuguese population. METHOD: Pulse wave velocity (PWV) was measured in randomly sampled population dwellers aged 18-96 years from northern Portugal, and used as a marker of early vascular aging (EVA). Of the 3038 individuals enrolled, 2542 completed the evaluation. RESULTS: Mean PWV value for the entire population was 8.4 m/s (men: 8.6 m/s; women: 8.2 m/s; P < 0.02). The individuals were classified with EVA if their PWV was at least 97.5th percentile of z-score for mean PWV values adjusted for age (using normal European reference values as comparators). The overall prevalence of EVA was 12.5%; 26.1% of individuals below 30 years presented this feature and 40.2% of individuals in that same age strata were placed above the 90th percentile of PWV; and 18.7% of the population exhibited PWV values above 10 m/s, with male predominance (17.2% of men aged 40-49 years had PWV > 10 m/s). Logistic regression models indicated gender differences concerning the risk of developing large artery damage, with women having the same odds of PWV above 10 m/s 10 years later than men. CONCLUSION: The population PWV values were higher than expected in a low cardiovascular risk area (Portugal). High prevalence rates of EVA and noteworthy large artery damage in young ages were found. PMID- 25827431 TI - Central pulse pressure is a determinant of heart and brain remodeling in the elderly: a quantitative MRI and PET pilot study. AB - OBJECTIVE: The sustained elevation of blood pressure (BP) and especially of central pulse pressure (cPP) leads to heart and brain damage. This pilot study was aimed to precise the relationships between peripheral and central BP levels, and the remodeling of heart and brain as objectively quantified by cardiac MRI and brain F-fluorodeoxyglucose (FDG)-PET imaging in the elderly. METHODS: Twenty eight apparently healthy elderly individuals (66-85 years old, 14 women) were prospectively recruited and allocated into two half groups, one with and one without hypertension, and all were referred for the quantitative determinations of peripheral and central BP using applanation tonometry, indexed left ventricular mass (per m of body surface area) using cardiac MRI, and brain metabolism with a voxel-based analysis of FDG-PET images adjusted for age and sex. RESULTS: Indexed left ventricular mass, reflecting cardiac remodeling, was correlated with the overall pressure variables involving both peripheral and central levels of systolic and pulse pressure (all P <= 0.001). By contrast, brain metabolism was significantly correlated with only cPP (P < 0.02). A cPP of at least 50 mmHg was associated with both a lower metabolism in frontal areas (P = 0.005) and a higher indexed left ventricular mass (P = 0.03). CONCLUSION: This pilot study suggests that, when quantified by MRI and PET imaging, left ventricular mass and brain metabolism of elderly individuals are related to the cPP and to the 50 mmHg threshold, corresponding to what has previously been documented for the risk of cardiovascular event. PMID- 25827430 TI - Urine angiotensinogen and salt-sensitivity and potassium-sensitivity of blood pressure. AB - OBJECTIVE: Urinary excretion of angiotensinogen [urine angiotensinogen (UAGT)] has been proposed as a biomarker of intrarenal renin-angiotensin system activity. We investigated the association between UAGT and salt-sensitivity and potassium sensitivity of blood pressure (BP) among Genetic Epidemiology Network of Salt Sensitivity study participants. METHODS: The intervention consisted of a 7-day low-sodium diet (51.3 mmol sodium/day), 7-day high-sodium diet (307.8 mmol sodium/day), and 7-day high-sodium diet with potassium supplementation (307.8 mmol sodium/day and 60 mmol potassium/day). Twenty-four-hour UAGT was estimated at baseline and at the end of each intervention for 100 randomly selected participants. RESULTS: Median UAGT (MUg/24 h) and UAGT-to-creatinine ratio (UAGT/Cr, MUg/g) were significantly reduced during the low-sodium and potassium supplementation interventions and increased during the high-sodium intervention (both P = 0.01). Baseline log-transformed UAGT and UAGT/Cr ratio were significantly positively associated with BP at baseline and at the end of each intervention. For example, one standard deviation higher log-UAGT/Cr ratio (1.2 MUg/g) was associated with a 5.0-mmHg (95% confidence interval 2.3-7.8) higher SBP at the end of the high-sodium intervention, after adjusting for multiple covariates (P = 0.003). In addition, one standard deviation higher log-UAGT/Cr ratio was associated with a 1.6-mmHg increase in age-adjusted and sex-adjusted SBP from the low-sodium intervention to the high-sodium intervention (95% confidence interval 0.1-3.1, P = 0.04). This association was no longer statistically significant after multivariable adjustment. CONCLUSION: These data indicate that elevated UAGT are associated with BP sodium sensitivity. Augmentation of intrarenal renin-angiotensin system activity may play an important role in developing salt-sensitive hypertension. PMID- 25827432 TI - Sympathetic nerve traffic and baroreflex function in optimal, normal, and high normal blood pressure states. AB - OBJECTIVE: Adrenergic activation and baroreflex dysfunction are common in established essential hypertension, elderly hypertension, masked and white-coat hypertension, resistant hypertension, and obesity-related hypertension. Whether this autonomic behavior is peculiar to established hypertension or is also detectable in the earlier clinical phases of the disease, that is, the high normal blood pressure (BP) state, is still largely undefined, however. METHODS: In 24 individuals with optimal BP (age: 37.1 +/- 2.1 years, mean +/- SEM) and in 27 with normal BP and 38 with high-normal BP, age matched with optimal BP, we measured clinic, 24-h and beat-to-beat BP, heart rate (HR), and muscle sympathetic nerve activity (MSNA) at rest and during baroreceptor stimulation and deactivation. Measurements also included anthropometric as well as echocardiographic and homeostasis model assessment (HOMA) index. RESULTS: For similar anthropometric values, clinic, 24-h ambulatory, and beat-to-beat BPs were significantly greater in normal BP than in optimal BP. This was the case when the high-normal BP group was compared to the normal and optimal BP groups. MSNA (but not HR) was also significantly greater in high-normal BP than in normal BP and optimal BP (51.3 +/- 2.0 vs. 40.3 +/- 2.3 and 41.1 +/- 2.6 bursts per 100 heartbeats, respectively, P < 0.01). The sympathetic activation seen in high normal BP was coupled with an impairment of baroreflex HR control (but not MSNA) and with a significant increase in HOMA Index, which showed a significant direct relationship with MSNA. CONCLUSION: Thus, independently of which BP the diagnosis is based, high-normal BP is a condition characterized by a sympathetic activation. This neurogenic alteration, which is likely to be triggered by metabolic rather than reflex alterations, might be involved, together with other factors, in the progression of the condition to established hypertension. PMID- 25827433 TI - Fifteen minute consultation on children 'hearing voices': when to worry and when to refer. AB - Auditory hallucinations are uncommon paediatric presentations, but they can be alarming and lead to emergency consultations. This review outlines the phenomenology of auditory hallucinations, their assessment and clinical significance. Auditory hallucinations are seen in the course of acute medical disorders, often together with decreased levels of consciousness, as in febrile illness and in toxic, neurologically compromised states; they can also be a feature of episodic neurological conditions such as migraine and temporal lobe epilepsy. Auditory hallucinations are key symptoms in psychiatric disorders such as schizophrenic and other psychotic states, but they can also present with depressive and anxiety disorders, and in the context of virtually every psychiatric disorder of childhood. In fact hallucinations--usually simple and transient--are common in the general child populations. Auditory hallucinations become clinically significant when they occur as part of a medical disorder or in the context of acute psychotic states and schizophrenia, when they are frequent, complex, distressing and cause impairment. The treatment of clinically relevant hallucinations is that of the primary medical or psychiatric disorder. Occasionally they require treatment in their own right with psychological treatments, and only when these have been tried and fail, a careful trial of antipsychotic medication may be appropriate. PMID- 25827434 TI - Diagnostic pitfall in antenatal manifestations of CPT II deficiency. AB - Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy-Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy-Walker anomaly or another brain dysgenesis. PMID- 25827435 TI - Bcl11b SWI/SNF-complex subunit modulates intestinal adenoma and regeneration after gamma-irradiation through Wnt/beta-catenin pathway. AB - SWI/SNF chromatin remodeling complexes constitute a highly related family of multi-subunit complexes to modulate transcription, and SWI/SNF subunit genes are collectively mutated in 20% of all human cancers. Bcl11b is a SWI/SNF subunit and acts as a haploinsufficient tumor suppressor in leukemia/lymphomas. Here, we show expression of Bcl11b in intestinal crypt cells and promotion of intestinal tumorigenesis by Bcl11b attenuation in Apc (min/+) mice. Of importance, mutations or allelic loss of BCL11B was detected in one-third of human colon cancers. We also show that attenuated Bcl11b activity in the crypt base columnar (CBC) cells expressing the Lgr5 stem cell marker enhanced regeneration of intestinal epithelial cells after the radiation-induced injury. Interestingly, BCL11B introduction in human cell lines downregulated transcription of beta-catenin target genes, whereas Bcl11b attenuation in Lgr5(+) CBCs increased expression of beta-catenin targets including c-Myc and cyclin D1. Together, our results argue that Bcl11b impairment promotes tumor development in mouse and human intestine at least in part through deregulation of beta-catenin pathway. PMID- 25827436 TI - Automated Microfluidic Platform for Serial Polymerase Chain Reaction and High Resolution Melting Analysis. AB - We report the development of an automated genetic analyzer for human sample testing based on microfluidic rapid polymerase chain reaction (PCR) with high resolution melting analysis (HRMA). The integrated DNA microfluidic cartridge was used on a platform designed with a robotic pipettor system that works by sequentially picking up different test solutions from a 384-well plate, mixing them in the tips, and delivering mixed fluids to the DNA cartridge. A novel image feedback flow control system based on a Canon 5D Mark II digital camera was developed for controlling fluid movement through a complex microfluidic branching network without the use of valves. The same camera was used for measuring the high-resolution melt curve of DNA amplicons that were generated in the microfluidic chip. Owing to fast heating and cooling as well as sensitive temperature measurement in the microfluidic channels, the time frame for PCR and HRMA was dramatically reduced from hours to minutes. Preliminary testing results demonstrated that rapid serial PCR and HRMA are possible while still achieving high data quality that is suitable for human sample testing. PMID- 25827437 TI - Microbiota at teeth and implants in partially edentulous patients. A 10-year retrospective study. AB - OBJECTIVE: To determine the microbiota at implants and adjacent teeth 10 years after placement of implants with a sandblasted and acid-etched surface. MATERIAL AND METHODS: Plaque samples obtained from the deepest sites of 504 implants and of 493 adjacent teeth were analyzed for certain bacterial species associated with periodontitis, for staphylococci, for aerobic gram-negative rods, and for yeasts using nucleic acid-based methods. RESULTS: Species known to be associated with periodontitis were detectable at 6.2-78.4% of the implants. Significantly higher counts at implants in comparison with teeth were assessed for Tannerella forsythia, Parvimonas micra, Fusobacterium nucleatum/necrophorum, and Campylobacter rectus. Higher counts of periodontopathogenic species were detectable at implants of current smokers than at those of non-smokers. In addition, those species were found in higher quantities at implants of subjects with periodontitis. The prevalence of Prevotella intermedia, Treponema denticola, C. rectus, and moreover of Staphylococcus warneri might be associated with peri implant inflammation. Selected staphylococcal species (not Staphylococcus aureus), aerobic gram-negative rods, and yeasts were frequently detected, but with the exception of S. warneri, they did not show any association with periodontal or peri-implant diseases. CONCLUSIONS: Smoking and periodontal disease are risk factors for colonization of periodontopathic bacteria at implants. Those bacterial species may play a potential role in peri-implant inflammation. The role of S. warneri needs further validation. PMID- 25827438 TI - Diabetes distress: understanding the hidden struggles of living with diabetes and exploring intervention strategies. AB - Diabetes distress is a rational emotional response to the threat of a life changing illness. Distinct from depression, it is conceptually rooted in the demands of diabetes management and is a product of emotional adjustment. Diabetes distress has been found to be significantly associated with glycated haemoglobin (HbA1c) level and the likelihood of an individual adopting self-care behaviours. The lack of perceived support from family, friends and healthcare professionals significantly contributes to elevated diabetes distress, and this issue tends to be overlooked when designing interventions. Pioneering large-scale research, DAWN2, gives voices to the families of those with diabetes and reaffirms the need to consider psychosocial factors in routine diabetes care. Structured diabetes education programmes are the most widely used in helping individuals cope with diabetes, but they tend not to include the psychological or interpersonal aspects of diabetes management in their curricula. The need for health practitioners, irrespective of background, to demonstrate an understanding of diabetes distress and to actively engage in discussion with individuals struggling to cope with diabetes is emphasised. PMID- 25827439 TI - Reduced rod electroretinograms in carrier parents of two Japanese siblings with autosomal recessive retinitis pigmentosa associated with PDE6B gene mutations. AB - PURPOSE: To present the clinical and genetic findings in two siblings with autosomal recessive retinitis pigmentosa (RP) and their non-symptomatic parents. METHODS: We studied two siblings, a 48-year-old woman and her 44-year-old brother, and their parents. They had general ophthalmic examinations including ophthalmoscopy, perimetry, and electroretinography (ERG). Their whole exomes were analyzed by the next-generation sequence technique. RESULTS: The two siblings had night blindness for a long time, and clinical examinations revealed diffuse retinal degeneration with bone spicule pigmentation, constriction of the visual field, and non-recordable ERGs. Their parents were non-symptomatic and had normal fundi; however, their rod ERGs were reduced. Genetic examination revealed compound heterozygous mutations of I535N and H557Y in the PDE6B gene in the siblings, and the parents were heterozygous carriers of the mutations. CONCLUSIONS: Heterozygous mutation in the PDE6B gene can cause a reduction in the rod function to different degrees. The retinal function of non-symptomatic carriers of autosomal recessive RP should be evaluated with care. PMID- 25827440 TI - Review: Quality of life in lower limb peripheral vascular surgery. AB - PURPOSE: Vascular intervention studies generally consider patency and limb salvage as primary outcomes. However, quality of life is increasingly considered an important patient-oriented outcome measurement of vascular interventions. Existing literature was analyzed to determine the effect of different treatments on quality of life for patients suffering from either claudication or critical limb ischemia. BASIC METHODS: A review of the literature was undertaken in the Medline library. A search was performed on quality of life in peripheral arterial disease. Results were stratified according to treatment groups. PRINCIPAL FINDINGS: Twenty-one articles described quality of life in approximately 4600 patients suffering from peripheral arterial disease. Invasive treatment generally results in better quality of life scores (at a maximum of 2 years of follow-up), compared with non-invasive treatment. In patients with critical limb ischemia, successful revascularization improves quality of life scores. Only one study reported long-term results. CONCLUSIONS: Increase in quality of life scores can be found for any intervention performed for peripheral arterial disease. However, there is scarce information on long-term quality of life after vascular intervention. PMID- 25827441 TI - Efficacy and safety of empagliflozin twice daily versus once daily in patients with type 2 diabetes inadequately controlled on metformin: a 16-week, randomized, placebo-controlled trial. AB - Patients with type 2 diabetes mellitus (T2DM) with a glycated haemoglobin (HbA1c) level >=7 and <=10% were randomized to receive empagliflozin 12.5 mg twice daily (n = 219), 25 mg once daily (n = 218), 5 mg twice daily (n = 219) or 10 mg once daily (n = 220), or placebo (n = 107) as add-on to stable-dose metformin immediate release (IR) twice daily for 16 weeks. The primary endpoint was change from baseline in HbA1c at week 16. At week 16, change from baseline in HbA1c with empagliflozin twice daily was non-inferior to empagliflozin once daily and vice versa. The adjusted mean (95% confidence interval) difference in change from baseline in HbA1c with empagliflozin 12.5 mg twice daily versus 25 mg once daily was -0.11% (-0.26, 0.03), and with empagliflozin 5 mg twice daily versus 10 mg once daily it was -0.02% (-0.16, 0.13). All empagliflozin regimens were well tolerated; thus, when used as add-on to metformin IR in patients with T2DM, the therapeutic effect of empagliflozin twice-daily and once-daily regimens can be considered equivalent. PMID- 25827442 TI - Relationship between nasal septal deformity, symptoms and disease severity in chronic rhinosinusitis. AB - The objective of this study was to evaluate the interaction of nasal septal deformity (NSD), including the contribution of septal spurs, with the severity of subjective symptoms, impairment of health-related quality of life (HRQoL) and sinus mucosal hyperplasia in patients with chronic rhinosinusitis (CRS). One hundred seventeen patients with CRS were assigned to three groups with mild, moderate or severe NSD, according to the measured nasal septal angle, including the presence of contact septal spurs. All CRS patients completed the visual analog scale (VAS) symptom severity score and the Sino-Nasal Outcome Test (SNOT 22) questionnaire. Symptoms scores, SNOT-22 and Lund-Mackay (LM) scores among the three NSD groups were compared. Related anatomy from the study group was compared with 100 control patients. VAS score for postnasal discharge in CRS patients was significantly higher in patients with mild NSD. There was a significantly higher LM score in CRS patients with severe NSD, compared to those with mild (P = 0.001) or moderate NSD (P = 0.005). CRS patients with a contact spur demonstrated a significantly higher LM score (P = 0.006) compared to those without a contact spur, and no differences in VAS symptom scores or HRQoL scores. There was a similar prevalence of septal deformities in CRS patients and in the non-ENT population. Our results support the conclusion that in patients with CRS, associated NSD or contact septal spur do not contribute significantly to CRS symptom severity or HRQoL impairment, but may have an impact on sinus mucosal hyperplasia. PMID- 25827443 TI - Effects of dietary supplementation of fermented Ginkgo biloba L. residues on growth performance, nutrient digestibility, serum biochemical parameters and immune function in weaned piglets. AB - This study evaluated the effects of fermented Ginkgo biloba L. residues (FGBLR) on growth performance, nutrient digestibility, serum biochemical parameters and immune function in weaned piglets. Pigs were allotted to five dietary treatments, including negative control (NC: antibiotic free basal diet), positive control (PC) (NC + 30 mg apramycin/kg) and FGBLR-50, 100, 150 (NC + 50, 100, 150 g FGBLR/kg). Pigs in FGBLR-100 and PC treatments showed increased final body weight, average daily gain, gain:feed and apparent total tract digestibility of dry matter, N and gross energy (P < 0.05) compared with NC, FGBLR-50 and FGBLR 150 treatments, In addition, pigs fed with FGBLR-100 diet showed higher serum total protein, albumin, alkaline phosphatase, glucose, hemoglobin, total iron, total iron binding capacity, superoxide dismutase and glutathione superoxide dismutase levels, and lower serum blood urea nitrogen, malondialdehyde, glutamic pyruvic transaminase, glutamic-oxalacetic transaminase, triglyceride and total cholesterol levels than those fed with PC and NC diets (P < 0.05). Moreover, feeding FGBLR-100 could increase levels of immunoglobulin G (IgG), IgA and IgM, as well as lymphocyte transformation rates, ratio of CD4+ to CD8+ cells and proportions of CD2+, CD4+, B, major histocompatibility complex (MHC)-I and MHC-II cells, and can decrease proportion of CD8+ cells in blood of piglets compared with PC and NC groups (P < 0.05). These results indicate that dietary supplementation with 10% of FGBLR showed greatest beneficial effects on growth performance, nutrient digestibility, serum biochemical parameters and immune function in weaned piglets, which were superior to antibiotic supplemental diets. PMID- 25827444 TI - Effects of shape and size of agar gels on heating uniformity during pulsed microwave treatment. AB - Model gel systems with different shape (sphere, cylinder, and slab) and size (180 and 290 g) were prepared with agar (5%) and sucrose (5%). Dielectric constant (epsilon'), loss factor (epsilon"), thermophysical properties, and temperature distribution of the model system were measured. Each agar model system was immersed and suspended in water, and then, heated in a microwave oven with intermittent heating until the core temperature reached 50 degrees C. The epsilon' and epsilon" of agar gels decreased when frequency increased. The density and thermal conductivity values of the agar gels were 1033 kg/m(3) and 0.55 W/m degrees C, respectively. The temperature distribution of sphere, cylinder, and slab was different when similar power doses were applied. The slab reached 50 degrees C in less time (10 min) and showed a more uniform heating than spheres and cylinders in both sizes. Agar model systems of 180 g heated faster than those of 290 g. The coldest point was the center of the model systems in all studied cases. Shape and size are critical food factors that affect the heating uniformity during microwave heating processes. PMID- 25827445 TI - Erratum to: Can the chemotherapeutic agents perform anticancer activity through miRNA expression regulation? Proposing a new hypothesis. PMID- 25827446 TI - Mojave desert tortoise (Gopherus agassizii) thermal ecology and reproductive success along a rainfall cline. AB - Desert resource environments (e.g. microclimates, food) are tied to limited, highly localized rainfall regimes which generate microgeographic variation in the life histories of inhabitants. Typically, enhanced growth rates, reproduction and survivorship are observed in response to increased resource availability in a variety of desert plants and short-lived animals. We examined the thermal ecology and reproduction of US federally threatened Mojave desert tortoises (Gopherus agassizii), long-lived and large-bodied ectotherms, at opposite ends of a 250-m elevation-related rainfall cline within Ivanpah Valley in the eastern Mojave Desert, California, USA. Biophysical operative environments in both the upper elevation, "Cima," and the lower-elevation, "Pumphouse," plots corresponded with daily and seasonal patterns of incident solar radiation. Cima received 22% more rainfall and contained greater perennial vegetative cover, which conferred 5 degrees C-cooler daytime shaded temperatures. In a monitored average rainfall year, Cima tortoises had longer potential activity periods by up to several hours and greater ephemeral forage. Enhanced resource availability in Cima was associated with larger-bodied females producing larger eggs, while still producing the same number of eggs as Pumphouse females. However, reproductive success was lower in Cima because 90% of eggs were depredated versus 11% in Pumphouse, indicating that predatory interactions produced counter-gradient variation in reproductive success across the rainfall cline. Land-use impacts on deserts (e.g. solar energy generation) are increasing rapidly, and conservation strategies designed to protect and recover threatened desert inhabitants, such as desert tortoises, should incorporate these strong ecosystem-level responses to regional resource variation in assessments of habitat for prospective development and mitigation efforts. PMID- 25827447 TI - Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. AB - Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood. PMID- 25827449 TI - Simultaneous passenger lymphocyte syndrome and multiple alloimmunization against donor's blood group antigens after liver transplantation. AB - BACKGROUND: If 'passenger lymphocyte syndrome' (PLS) is a well-recognized complication in ABO-mismatched solid organ transplantation, the coexistence of this reaction with recipient's alloimmunization against multiple antigens expressed on the residual red blood cells in the graft is less common and unpredictable. METHODS: The receiver of an ABO minor-mismatch liver graft from a cadaveric donor developed haemolytic anaemia within 2 weeks after transplantation. The organ donor was of blood group O D+C+c+E+e+ K+k+ Le(a+b-) and the recipient, A1 D-C-c+E-e+ K-k+ Le(a-b-). The donor and recipient were both tested for irregular antibodies. Elution was performed on the recipient's red blood cells (RBCs). RESULTS: None of the recipient and donor had irregular alloantibodies at the time of transplantation. On day 10, anti-A antibodies were detected in the recipient's serum and eluted from his RBCs. At the same time, the patient developed multiple alloantibodies: anti-D, anti-C, anti-E, anti-K and anti-Le(a) against the donor's erythrocyte antigens. CONCLUSION: Although serological analysis and haemolytic parameters confirmed the diagnosis of PLS which required transfusion support, no sign of graft damage due to recipient's immune reaction was detected. This case illustrates the required follow-up of the recipient after transplantation. PMID- 25827448 TI - Short-Term Adjuvant Therapy with Terminalia arjuna Attenuates Ongoing Inflammation and Immune Imbalance in Patients with Stable Coronary Artery Disease: In Vitro and In Vivo Evidence. AB - The present study evaluated the cardioprotective effects of Terminalia arjuna on classical and immuno-inflammatory markers in coronary artery disease (CAD) as an adjuvant therapy. One hundred sixteen patients with stable CAD were administered placebo/T. arjuna (500 mg twice a day) along with medications in a randomized, double-blind clinical trial. To understand the specificity and efficacy of T. arjuna, we evaluated its effect through microarray and in silico analysis in few representative samples. Data was further validated via real-time PCR (n = 50) each at baseline, 3 months, and 6 months, respectively. rIL-18 cytokine was used to induce inflammation in vitro to compare its effects with atorvastatin. T. arjuna significantly down-regulated TG, VLDL-C, and immuno-inflammatory markers in stable CAD versus placebo-treated subjects. Microarray and pathway analysis of a few samples from T. arjuna/placebo-treated groups and real-time PCR validation further confirmed our observations. Our data demonstrate the anti-inflammatory and immunomodulatory effects of T. arjuna that may attenuate ongoing inflammation and immune imbalance in medicated CAD subjects. PMID- 25827450 TI - Acid/Base-mediated uptake and release of halide anions with a preorganized aryl triazole foldamer. AB - A new approach for the construction of artificial receptors capable of selectively uptake and release of halides to mimic the biological halide ions pumps is developed, in which the preorganized aryl-triazole foldamer was designed to bear a resorcinolic group in the central strand as a switch regulator. By using 1,8-diazabicyclo[5.4.0]undec-7-ene/picric acid as the trigger, the foldamer can be switched between "w"-shape and helical conformation. Due to the large, half-open cavity as well as the additional electrostatic repulsion between oxyanions and guest halide, the foldamer in "w"-shape possesses a much weaker affinity for chloride, bromide, and iodide anions than those in the helical conformation in 6:94 (v/v) [D6 ]DMSO/CDCl3 . When the foldamer and chloride ions have the same initial concentrations of 1 mM, 70 % chloride ions in the solution could be reversibly bound or released upon switching. PMID- 25827451 TI - A closer look at papillary thyroid carcinoma. AB - Recent surge of thyroid cancer, especially papillary thyroid carcinoma (PTC), ignited a debate on over-diagnosis of cancer. Such increase in incidence is a worldwide phenomenon, but it has been the most prominent in Korea. Although increased detection might have played a major role, some evidences suggest that true increase in incidence have also contributed to such phenomenon. PTC is a very common disease being the most common cancer in human. As the mortality due to PTC is relatively low, understanding pathophysiology of the disease and risk prediction in individual patient have particular importance for optimal management, but little has been known. I suggest a reason for such a commonality of PTC, and would like to describe my view on some aspects of PTC including unresolved issue on management based on our recent observations. PMID- 25827452 TI - Clinical Guidelines for the Diagnosis and Treatment of Cushing's Disease in Korea. AB - Cushing's disease (CD) is a rare disorder characterized by the overproduction of adrenocorticotropic hormone due to a pituitary adenoma that ultimately stimulates excessive cortisol secretion from the adrenal glands. Prior to the detection of pituitary adenomas, various clinical signs of CD such as central obesity, moon face, hirsutism, and facial plethora are usually already present. Uncontrolled hypercortisolism is associated with metabolic, cardiovascular, and psychological disorders that result in increased mortality. Hence, the early detection and treatment of CD are not only important but mandatory. Because its clinical manifestations vary from patient to patient and are common in other obesity related conditions, the precise diagnosis of CD can be problematic. Thus, the present set of guidelines was compiled by Korean experts in this field to assist clinicians with the screening, diagnoses, and treatment of patients with CD using currently available tests and treatment modalities. PMID- 25827453 TI - Update on denosumab treatment in postmenopausal women with osteoporosis. AB - Denosumab, a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL), blocks binding of RANKL to the RANK receptor, found on the surface of osteoclasts and osteoclast precursors, resulting in decreased bone resorption. Subcutaneous denosumab administration once every 6 months increases bone mineral density at the lumbar spine, total hip, and/or femoral neck, and reduces markers of bone turnover significantly in postmenopausal women with osteoporosis. Relative to placebo, denosumab treatment reduces the risk of vertebral, nonvertebral, and hip fractures significantly. The benefits of denosumab treatment are generally obvious after the first dose and were continued for up to 8 years of treatment in an extension study. The tolerability profile of denosumab during this extension phase was consistent with that observed during the initial 3-year FREEDOM trial. Postmarketing safety surveillance has not shown any unexpected findings. Ongoing safety surveillance will more fully define the long-term safety of denosumab. The benefits of denosumab would seem to be greater than its risks. Denosumab is an important choice in the treatment of postmenopausal women with osteoporosis at increased risk of fractures, including older patients who have difficulty with oral bisphosphonate intake and patients who are intolerant of, or unresponsive to, other therapies. PMID- 25827454 TI - The risks and benefits of calcium supplementation. AB - The association between calcium supplementation and adverse cardiovascular events has recently become a topic of debate due to the publication of two epidemiological studies and one meta-analysis of randomized controlled clinical trials. The reports indicate that there is a significant increase in adverse cardiovascular events following supplementation with calcium; however, a number of experts have raised several issues with these reports such as inconsistencies in attempts to reproduce the findings in other populations and questions concerning the validity of the data due to low compliance, biases in case ascertainment, and/or a lack of adjustment. Additionally, the Auckland Calcium Study, the Women's Health Initiative, and many other studies included in the meta analysis obtained data from calcium-replete subjects and it is not clear whether the same risk profile would be observed in populations with low calcium intakes. Dietary calcium intake varies widely throughout the world and it is especially low in East Asia, although the risk of cardiovascular events is less prominent in this region. Therefore, clarification is necessary regarding the occurrence of adverse cardiovascular events following calcium supplementation and whether this relationship can be generalized to populations with low calcium intakes. Additionally, the skeletal benefits from calcium supplementation are greater in subjects with low calcium intakes and, therefore, the risk-benefit ratio of calcium supplementation is likely to differ based on the dietary calcium intake and risks of osteoporosis and cardiovascular diseases of various populations. Further studies investigating the risk-benefit profiles of calcium supplementation in various populations are required to develop population specific guidelines for individuals of different genders, ages, ethnicities, and risk profiles around the world. PMID- 25827455 TI - NF-kappaB-Mediated Regulation of Osteoclastogenesis. AB - Osteoclasts are multinucleated cells formed mainly on bone surfaces in response to cytokines by fusion of bone marrow-derived myeloid lineage precursors that circulate in the blood. Major advances in understanding of the molecular mechanisms regulating osteoclast formation and functions have been made in the past 20 years since the discovery that their formation requires nuclear factor kappaB (NF-kappaB) signaling and that this is activated in response to the essential osteoclastogenic cytokine, receptor activator of NF-kappaB ligand (RANKL), which also controls osteoclast activation to resorb (degrade) bone. These studies have revealed that RANKL and some pro-inflammatory cytokines, including tumor necrosis factor, activate NF-kappaB and downstream signaling, including c-Fos and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), and inhibition of repressors of NFATc1 signaling, to positively regulate osteoclast formation and functions. However, these cytokines also activate NF kappaB signaling that can limit osteoclast formation through the NF-kappaB signaling proteins, TRAF3 and p100, and the suppressors of c-Fos/NFATc1 signaling, IRF8, and RBP-J. This paper reviews current understanding of how NF kappaB signaling is involved in the positive and negative regulation of cytokine mediated osteoclast formation and activation. PMID- 25827456 TI - Metformin-associated lactic acidosis. PMID- 25827457 TI - Articles in 'endocrinology and metabolism' in 2014. PMID- 25827458 TI - Determination of Mother Centriole Maturation in CPAP-Depleted Cells Using the Ninein Antibody. AB - BACKGROUND: Mutations in centrosomal protein genes have been identified in a number of genetic diseases in brain development, including microcephaly. Centrosomal P4.1-associated protein (CPAP) is one of the causal genes implicated in primary microcephaly. We previously proposed that CPAP is essential for mother centriole maturation during mitosis. METHODS: We immunostained CPAP-depleted cells using the ninein antibody, which selectively detects subdistal appendages in mature mother centrioles. RESULTS: Ninein signals were significantly impaired in CPAP-depleted cells. CONCLUSION: The results suggest that CPAP is required for mother centriole maturation in mammalian cells. The selective absence of centriolar appendages in young mother centrioles may be responsible for asymmetric spindle pole formation in CPAP-depleted cells. PMID- 25827459 TI - Increased sclerostin levels after further ablation of remnant estrogen by aromatase inhibitors. AB - BACKGROUND: Sclerostin is a secreted Wnt inhibitor produced almost exclusively by osteocytes, which inhibits bone formation. Aromatase inhibitors (AIs), which reduce the conversion of steroids to estrogen, are used to treat endocrine responsive breast cancer. As AIs lower estrogen levels, they increase bone turnover and lower bone mass. We analyzed changes in serum sclerostin levels in Korean women with breast cancer who were treated with an AI. METHODS: We included postmenopausal women with endocrine-responsive breast cancer (n=90; mean age, 57.7 years) treated with an AI, and compared them to healthy premenopausal women (n=36; mean age, 28.0 years). The subjects were randomly assigned to take either 5 mg alendronate with 0.5 MUg calcitriol (n=46), or placebo (n=44) for 6 months. RESULTS: Postmenopausal women with breast cancer had significantly higher sclerostin levels compared to those in premenopausal women (27.8+/-13.6 pmol/L vs. 23.1+/-4.8 pmol/L, P<0.05). Baseline sclerostin levels positively correlated with either lumbar spine or total hip bone mineral density only in postmenopausal women (r=0.218 and r=0.233; P<0.05, respectively). Serum sclerostin levels increased by 39.9%+/-10.2% 6 months after AI use in postmenopausal women; however, no difference was observed between the alendronate and placebo groups (39.9%+/-10.2% vs. 55.9%+/-9.13%, P>0.05). CONCLUSION: Serum sclerostin levels increased with absolute deficiency of residual estrogens in postmenopausal women with endocrine-responsive breast cancer who underwent AI therapy with concurrent bone loss. PMID- 25827460 TI - Metformin-associated lactic acidosis: predisposing factors and outcome. AB - BACKGROUND: Metformin is considered the first choice oral treatment for type 2 diabetes patients in the absence of contraindications. Rarely, life-threatening complications associated with metformin treatment are seen in some patients with underlying diseases. The aim of this study was to further investigate the clinical profiles and risk factors for metformin-associated lactic acidosis (MALA) and the treatment modalities according to survival. METHODS: To identify MALA, we performed a retrospective study in seven diabetic patients who were taking metformin and had been diagnosed with lactic acidosis at Inha University Hospital between 1995 and 2012. For each patient, we recorded the age, sex, daily metformin dosage, laboratory test results, admission diagnosis, and risk factors. Also, concurrent conditions, treatment modalities, and outcomes were evaluated. RESULTS: Six patients had risk factors for lactic acidosis before admission. All patients had renal impairment on admission as a precipitating risk factor. Five patients survived and two patients died despite early renal replacement therapy. Older patients tended to have a poorer prognosis. CONCLUSION: Renal function must be monitored in elderly type 2 diabetes mellitus patients with underlying diseases and conditions causing renal impairment who begin metformin treatment. Accurate recognition of MALA and initiation of renal replacement are essential for treatment. PMID- 25827461 TI - Erratum: Figure Correction: Standardized Thyroid Cancer Mortality in Korea between 1985 and 2010. PMID- 25827462 TI - Ionic strength assay via polyacrylate-ferriferrous oxide magnetic photonic crystals. AB - Convenient reading out and/or determination of ionic strength (IS) is of great significance for both scientific research and real life applications. We presented here a novel method for the rapid and sensitive IS assay based on the electrolyte-induced sensitive wavelength blueshifts of the reflection spectra of polyacrylate capped Fe3O4 magnetic photonic crystals (PA-Fe3O4-MPCs). For HCl, MgSO4 and the common electrolytes corresponding to the salinity of seawater (including NaCl, KCl, MgCl2, CaCl2, Na2SO4 and their mixtures), the PA-Fe3O4-MPCs displayed wavelength blueshifts identical to the total IS of the aqueous solutions, regardless of the kind of above-mentioned electrolytes in the solutions. Besides, the PA-Fe3O4-MPCs exhibited relatively high sensitivity (an average of 294 nm L mmol(-1) in the range of 0.05-0.30 mmol L(-1), and an even higher value of 386 nm L mmol(-1) at 0.05-0.15 mmol L(-1)) and fast response (within 8 s) to the IS of aqueous solutions. The relative standard deviation (RSD) for IS (NaCl, 0.1 mmol L(-1)) was 4.4% (n = 5). The developed method was applied to determine the salinity of seawater samples, and the determined results were validated by the traditional standard chlorinity titration and electric conductimetry method. The recoveries were in the range of 92-104%. The proposed PA-Fe3O4-MPCs based reflectometry method would have great potential for IS and salinity assays. PMID- 25827463 TI - The autoimmune side of hereditary angioedema: insights on the pathogenesis. AB - Hereditary angioedema (HAE) is an autosomal dominant disease resulting from the deficiency of C1 inhibitor (C1-INH), a glycosylated serine protease inhibitor that plays a regulatory role in the complement system (CS), the contact system and the intrinsic coagulation cascade. HAE disease severity is highly variable and may be influenced by genetic polymorphisms as well as by other factors, such as gender hormone-mediated effects. In HAE, the potential inadequate clearance of immune-complexes (IC) in the presence of reduced levels of CS components and in turn an excess of IC in the tissues results in inflammatory damage and release of autoantigens that may trigger an autoimmune response. Occasional reports link HAE with autoimmune conditions and only few studies have been conducted on large patient populations with controversial results. Although several immunoregulatory disorders have been documented, the prevalence of defined autoimmune diseases in patients with HAE remains debated. The occurrence of autoimmune conditions in HAE patients may worsen the disease severity enhancing the complexity of the comprehensive care. PMID- 25827464 TI - Extent of misconceptions, negative prejudices and discriminatory behaviour to psoriasis patients in France. AB - BACKGROUND: The perception of stigmatization of patients with psoriasis is largely due to misconceptions and negative prejudice about this skin disease. 'Uneducated' judgments can give rise to discriminatory behaviours. OBJECTIVE: Evaluate the prevalence, in France, of misconceptions, negative prejudice and discriminatory behaviour towards psoriasis patients. METHODS: Online survey conducted in June 2011, aimed at 1005 persons aged 16-64 years, representative of the French population. The representativeness of the sample was ensured by quota methodology (gender, age, occupation of the interviewed person) after stratification by region and location category. The respondents were asked to respond to a questionnaire on their knowledge of psoriasis, their attitude and main feelings/perceptions towards psoriasis patients. RESULTS: About 62.4% of respondents recognize a lack of information about psoriasis and 19.7% have misconceptions about this disease. About 16.5% believe that psoriasis is contagious, 6.8% believe this skin disease is related to personal hygiene and 3.2% believe that it affects more people with low personal hygiene. About 50.0% of respondents show discriminatory behaviour towards psoriasis patients, reflected by reluctance to maintain friendship ties/a relationship of friendliness (7.6%), to have lunch or dinner with a person with visible manifestations (17.9%), to give a kiss on the cheek in greeting (29.7%), to shake hands (28.8%) and to have sexual relations/intercourse (44.1%). Patients with negative prejudice about the psoriasis frequently have misconceptions towards psoriasis patients. About 52.8% of respondents do not know anyone with psoriasis. Socio-demographic indicators such as gender, education level and rural or urban way of life are not associated with an increased prevalence of misconceptions and/or discriminatory behaviour. CONCLUSION: The lack of knowledge about psoriasis in France is important. There is an urgent need to strengthen information campaigns about psoriasis intended for the General Public. PMID- 25827465 TI - Stereoselective synthesis of the C13-C22 fragment of callystatin A by a non-aldol approach. AB - An efficient synthetic route to the C13-C22 subunit of callystatin A is reported. The key features include diastereoselective alkylation, using Myers auxiliary, for the preparation of the three carbon synthon 7, stereo- and regioselective oxidative vicinal functionalization of an electron deficient trisubstituted (Z) olefin using an intramolecular sulfinyl group as the nucleophile, diastereoselective radical debromination of a bromohydrin derivative using Guindon's protocol to prepare the C16-C18 anti-anti stereotriad, Lewis acid promoted crotylation following Keck's protocol to create C19, C20 stereocenters and the use of the Pummerer reaction to reveal an aldehyde for the extension of two carbons by Wittig olefination. PMID- 25827466 TI - The chimerical genome of Isla del Coco feral pigs (Costa Rica), an isolated population since 1793 but with remarkable levels of diversity. AB - The history of domestic species and of their wild ancestors is not a simple one, and feral processes can clarify key aspects of this history, including the adaptive processes triggered by new environments. Here, we provide a comprehensive genomic study of Isla del Coco (Costa Rica) feral pigs, a unique population that was allegedly founded by two individuals and has remained isolated since 1793. Using SNP arrays and genome sequencing, we show that Cocos pigs are hybrids between Asian and European pigs, as are modern international pig breeds. This conclusively shows that, as early as the 18th century, British vessels were loading crossbred pigs in Great Britain and transporting them overseas. We find that the Y chromosome has Asian origin, which has not been reported in any international pig breed. Chinese haplotypes seem to have been transmitted independently between Cocos and other pig breeds, suggesting independent introgression events and a complex pattern of admixing. Although data are compatible with a founder population of N = 2, variability levels are as high in Cocos pigs as in international pig breeds (~1.9 SNPs/kb) and higher than in European wild boars or local breeds (~1.7 SNPs/kb). Nevertheless, we also report a 10-Mb region with a marked decrease in variability across all samples that contains four genes (CPE, H3F3C, SC4MOL and KHL2) previously identified as highly differentiated between wild and domestic pigs. This work therefore illustrates how feral population genomic studies can help to resolve the history of domestic species and associated admixture events. PMID- 25827467 TI - Influence of alkalinity and VFAs on the performance of an UASB reactor with recirculation for the treatment of Tequila vinasses. AB - The main problem linked to the stability of upflow anaerobic sludge blanket (UASB) reactors during the treatment of Tequila vinasse is the high acidity and the null alkalinity present in this effluent. This research evaluates the effect of alkalinity and volatile fatty acids (VFAs) concentration on the performance of an UASB reactor with recirculation of the effluent for removing organic matter and biogas production from Tequila vinasses. Recirculation of the effluent reduces the impact of VFAs and organic matter concentration present in the influent, inducing the stability of the reactor. The UASB reactor was operated during 235 days at organic loading rates from 2.5 to 20.0 kg m(-3) d(-1), attaining a removal efficiency of COD greater than 75% with a methane yield of 335 ml CH4 g(-1) COD at SPT, maintaining a ratio of VFAs/Alk <= 0.5. Therefore, an optimal ratio of VFAs/Alk was established for the system operating in stable conditions for the treatment of Tequila vinasses. Under these conditions, the alkalinity was recuperated by the system itself, without the addition of external alkalinity. PMID- 25827468 TI - Social inequalities in childcare quality and their effects on children's development at school entry: findings from the Longitudinal Study of Australian Children. AB - BACKGROUND: Higher quality childcare in the years before school may help narrow developmental gaps between the richest and poorest children in our societies, but specific evidence is limited and inconsistent. We address this issue by examining whether higher quality childcare is associated with better developmental outcomes at school entry for children from lower than higher income families. METHODS: The sample from the Longitudinal Study of Australian Children included children attending childcare from 2 to 3 years (n=980-1187, depending on outcome). Childcare quality was measured using carers assessment of their relationship with the child. Children's receptive vocabulary was directly assessed in the child's home, and behavioural difficulties were measured by teachers and parents at 4-5 years. We assessed additive and multiplicative income-related effect measure modification of the quality of carer-child relationship on developmental outcomes. RESULTS: After adjusting for confounding, there was some evidence of effect measure modification on the additive and multiplicative scales of childcare quality by income. Children experiencing higher quality relationships and lower income had almost the same risk of poorer receptive vocabulary as children in higher quality relationships and higher incomes (relative excess risk due to interaction=0.18; 95% CI -0.20 to 0.52), ratio of relative risks=1.11 (1.04 to 1.17)). These patterns were similar for teacher-reported and parent reported behavioural difficulties. CONCLUSIONS: The effects of higher quality childcare, in terms of quality relationships with carers, on children's cognitive and behavioural development at school entry were stronger among children from lower income families. This provides some evidence that higher quality relationships in childcare may be especially important in helping reduce developmental gaps for children from lower income families. PMID- 25827469 TI - Association between maternal health literacy and child vaccination in India: a cross-sectional study. AB - BACKGROUND: Education of mothers may improve child health. We investigated whether maternal health literacy, a rapidly modifiable factor related to mother's education, was associated with children's receipt of vaccines in two underserved Indian communities. METHODS: Cross-sectional surveys in an urban and a rural site. We assessed health literacy using Indian child health promotion materials. The outcome was receipt of three doses of diphtheria-tetanus-pertussis (DTP3) vaccine. We used multivariate logistic regression to investigate the relationship between maternal health literacy and vaccination status independently in each site. For both sites, adjusted models considered maternal age, maternal and paternal education, child sex, birth order, household religion and wealth quintile. Rural analyses used multilevel models adjusted for service delivery characteristics. Urban analyses represented cluster characteristics through fixed effects. RESULTS: The rural analysis included 1170 women from 60 villages. The urban analysis included 670 women from nine slum clusters. In each site, crude and adjusted models revealed a positive association between maternal health literacy and DTP3. In the rural site, the adjusted OR was 1.57 (95% CI 1.11 to 2.21, p=0.010) for those with medium health literacy, and OR=1.30 (95% CI 0.89 to 1.91, p=0.172) for those with high health literacy. In the urban site, the adjusted OR was 1.10 (95% CI 0.65 to 1.88, p=0.705) for those with medium health literacy, and OR=2.06 (95% CI 1.06 to 3.99, p=0.032) for those with high health literacy. CONCLUSIONS: In these study settings, maternal health literacy is independently associated with child vaccination. Initiatives targeting health literacy could improve vaccination coverage. PMID- 25827470 TI - Dynamic interaction between micro- and macro-circulation: a concept with feet of clay. PMID- 25827471 TI - Response to "Mutual micro- and macrovascular impairment in hypertension: shaping clay into a pot". PMID- 25827472 TI - Gynecomastia and drugs: a critical evaluation of the literature. AB - PURPOSE: A large number of medications have been implicated in the genesis of gynecomastia. However, gynecomastia is common in men, asymptomatic, increases with age, and is considered to be due to an increased estradiol/testosterone ratio. This complicates the interpretation of medication-related gynecomastia. Therefore, we have reviewed the literature in order to assess the data relating gynecomastia onset with utilization of specific medications. METHODS: The literature was searched in PubMed and the Ovid/Medline databases from the 1946 to January 2015 with the search terminology of "gynecomastia, drugs/medications." A few other articles were found and included. RESULTS: One hundred ten publications were reviewed. Sixty-three were single case reports. There were 24 population based studies of which 8 were HIV-infected patients treated with antiretroviral agents. Among the case reports, 49 were for individual medications, and 2 were reports of antineoplastic or antiretroviral drug regimens. In the great majority, mastodynia with or without breast enlargement was present and referred to as gynecomastia. Generally, hormonal profiles could not explain the breast enlargement. The pain/tenderness and breast enlargement resolved spontaneously over time. CONCLUSION: Many different medications have been associated with the presence of "gynecomastia." Generally, it presents as a syndrome characterized by a single painful/tender breast (mastodynia) associated with breast enlargement and is transient. We suggest that these cases be referred to as an acute gynecomastia syndrome. This syndrome also occurs independent of medication use. Thus, in an individual patient, whether it is medication induced often remains uncertain. The pathogenesis remains unknown. PMID- 25827473 TI - Ultrasound elastography for evaluation of cervical lymph nodes. AB - Ultrasound (US) elastography has been introduced as a noninvasive imaging technique for evaluating cervical lymph nodes. US elastography techniques include strain elastography and shear wave-based elastography. The application of this technique is based on the fact that stiff tissues tend to deform less and show less strain than compliant tissues when the same force is applied. In general, metastatic lymph nodes demonstrate higher stiffness than benign lymph nodes. Overall, preliminary studies suggest that US elastography may be useful in differentiating benign and malignant cervical lymph nodes, thereby informing decisions to perform a biopsy and facilitating follow-up. For US elastography to be accepted into clinical practice, however, its techniques, associated diagnostic criteria, and reliability need to be further refined. PMID- 25827474 TI - Portal venous perfusion steal causing graft dysfunction after orthotopic liver transplantation: serial imaging findings in a successfully treated patient. AB - A 53-year-old male with hepatocellular carcinoma underwent orthotopic liver transplantation. Preoperative computed tomography revealed main portal vein luminal narrowing by flat thrombi and the development of cavernous transformation. On post-transplantation day 1, thrombotic portal venous occlusion occurred, and emergency thrombectomy was performed. Subsequent Doppler ultrasonography and contrast-enhanced ultrasonography confirmed the restoration of normal portal venous flow. The next day, however, decreased portal venous velocity was observed via Doppler ultrasonography, and serum liver enzymes and bilirubin levels remained persistently elevated. Direct portography identified massive perfusion steal through prominent splenorenal collateral veins. Stent insertion and balloon angioplasty of the portal vein were performed, and subsequent Doppler ultrasonography demonstrated normalized portal flow parameters. Afterwards, the serum liver enzymes and bilirubin levels rapidly normalized. PMID- 25827475 TI - Dengue vaccines for travelers: has the time come? PMID- 25827476 TI - Purification and characterization of a ~43 kDa antioxidant protein with antitumor activity from Pholiota nameko. AB - BACKGROUND: Pholiota nameko water-soluble protein (PNWSP), isolated from the dried fruiting bodies of Pholiota nameko, was purified by a successive chromatographic process using Q anion exchange column, SP cation exchange column and Superdex 200 gel filtration column. PNWSP was assessed for antioxidant activities in different assay systems, and the effect on cell proliferation of human breast cancer MCF7 cells was investigated. RESULTS: Sodium dodecyl sulfate polyacrylamide gel electrophoresis and analytical ultracentrifugation analysis revealed the homogeneity of PNWSP with apparent molecular weight of ~43 kDa, and the identification was confirmed by peptide mass fingerprint analysis. It showed potential antioxidant activities in scavenging free radicals, reducing power and chelating effect on Fe(2+), and had a protective effect against DNA amage. Moreover, it inhibited the proliferation of MCF7 cells by inducing apoptosis, in which the change in cell cycle distribution and the loss of mitochondrial transmembrane potential were observed by flow cytometry. CONCLUSIONS: The results showed that PNWSP could be a natural antioxidant and developed as a potential chemotherapeutic agent candidate against human breast cancer. PMID- 25827477 TI - Indications for transcatheter aortic valve implantation--now and next? AB - Aortic stenosis (AS) is the most common valvular pathology and its prevalence is expected to increase rapidly in coming decades as a consequence of the increasingly elderly population. Without treatment, severe symptomatic AS has a very poor prognosis with a mortality of 50% at two years. Whilst surgical aortic valve replacement is the gold standard treatment, a significant minority of patients are deemed inoperable and declined surgery due to prohibitively high risk. The advent of transcatheter aortic valve implantation (TAVI) has revolutionised their treatment. In this review, we discuss current indications for TAVI, other applications of this technology and future indications. PMID- 25827478 TI - Detection of PHLPP1alpha/beta in human and mouse brain by different anti-PHLPP1 antibodies. AB - Pleckstrin homology domain and leucine rich repeat protein phosphatase 1 (PHLPP1) is a member of the serine/threonine family of phosphatases. It has been studied in organs including brain, heart, pancreas, adipose, breast, and prostate. Human PHLPP1 encodes two splice variants - PHLPP1alpha (~140-150 kDa) and PHLPP1beta (~180-190 kDa). Commercial antibodies are widely used to characterize PHLPP1 proteins in cells/tissues. Here we validate five different antibodies to detect PHLPP1alpha/beta by Western blot using PHLPP1 WT/KO mice. All antibodies recognize PHLPP1beta in brain. Only a single antibody (Cosmo Bio Co) detects PHLPP1alpha (~145-150 kDa). The other four antibodies detect a non-specific signal at ~150 kDa as evidenced by its abundance in PHLPP1 KO tissues. Results suggest Cosmo antibody is a better reagent to detect PHLPP1alpha by Western blot. In contrast, we found it unsuitable for immunofluorescence applications in brain. Our findings caution interpretation of the ~150 kDa band detected by some PHLPP1 antibodies in rodent and human tissues. Results also recapitulate the importance of including molecular weight standards in Western blot data to simplify retrospective analysis. PMID- 25827479 TI - Steady-state metabolism of ethanol in perfused rat livers treated with cyanamide: quantitative analysis of acetaldehyde effects on the metabolic flux rates. AB - BACKGROUND: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol in mammals. The steady state metabolic flux of ethanol has been poorly understood. METHODS: We investigated flux rates of the individual steps of ethanol metabolism in perfused rat livers treated with ALDH inactivator cyanamide as an attempt to mimic human ALDH2 deficiency commonly seen in East Asians. The net rates of ethanol oxidation, acetaldehyde oxidation, and acetate activation were determined with a set of defined equations, based on the set influx rates of ethanol and the measured efflux rates of ethanol, acetaldehyde, and acetate. RESULTS: After intraperitoneal injections of 0.2 and 1.5 mg/kg cyanamide, hepatic activities of mitochondrial ALDH2 and cytoplasmic ALDH1A1 decreased to a similar degree, that is, 51 to 57% and 69 to 74%, compared with the corresponding controls, respectively, whereas cytoplasmic ADH1 activity remained unchanged. At infusing 2 mM ethanol, acetaldehyde oxidation rate well matched (99%) the net ethanol oxidation rate in control liver. Both the ethanol and acetaldehyde oxidation rates were significantly decreased after cyanamide treatments. At 10 mM ethanol, the efflux acetaldehyde was significantly higher than that infusing 2 mM ethanol in both control and cyanamide groups. Seventy-eight percent of the oxidized ethanol released as efflux acetate. At 2 mM ethanol, the apparent flux control coefficients of ADH1 were assessed to be 0.78, 0.54, and 0.39, respectively, in control, low, and high cyanamide-treated livers. Kinetic simulations revealed that inhibition by acetaldehyde may largely account for the observed reduction of ADH1 oxidation rates after cyanamide treatment. CONCLUSIONS: Our results provide the first flux evidence that ADH and ALDH are steps influencing steady-state metabolism of ethanol in rat livers with inactivated ALDHs. PMID- 25827480 TI - Demethylation of IGFBP5 by Histone Demethylase KDM6B Promotes Mesenchymal Stem Cell-Mediated Periodontal Tissue Regeneration by Enhancing Osteogenic Differentiation and Anti-Inflammation Potentials. AB - Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered a promising method for periodontitis treatment. The molecular mechanism underlying directed differentiation and anti-inflammatory actions remains unclear, thus limiting potential MSC application. We previously found that insulin-like growth factor binding protein 5 (IGFBP5) is highly expressed in dental tissue-derived MSCs compared with in non-dental tissue-derived MSCs. IGFBP5 is mainly involved in regulating biological activity of insulin-like growth factors, and its functions in human MSCs and tissue regeneration are unclear. In this study, we performed gain- and loss-of-function assays to test whether IGFBP5 could regulate the osteogenic differentiation and anti inflammatory potential in MSCs. We found that IGFBP5 expression was upregulated upon osteogenic induction, and that IGFBP5 enhanced osteogenic differentiation in MSCs. We further showed that IGFBP5 prompted the anti-inflammation effect of MSCs via negative regulation of NFkappaB signaling. Depletion of the histone demethylase lysine (K)-specific demethylase 6B (KDM6B) downregulated IGFBP5 expression by increasing histone K27 methylation in the IGFBP5 promoter. Moreover, IGFBP5 expression in periodontal tissues was downregulated in individuals with periodontitis compared with in healthy people, and IGFBP5 enhanced MSC-mediated periodontal tissue regeneration and alleviated local inflammation in a swine model of periodontitis. In conclusion, our present results reveal a new function for IGFBP5, provide insight into the mechanism underlying the directed differentiation and anti-inflammation capacities of MSCs, and identify a potential target mediator for improving tissue regeneration. PMID- 25827481 TI - Cell volume measurements by optical transmission microscopy. AB - Cell volume is an important parameter in cell adaptation to anisosmotic stress, in the development of apoptosis and necrosis, and in the pathogenesis of several diseases. This unit describes a method for measuring the volume of adherent cells using a standard light microscope. A coverslip with attached cells is placed in a shallow chamber in a medium containing a strongly absorbing and cell-impermeant dye, Acid Blue 9. When such a sample is imaged in transmitted light at a wavelength of maximum dye absorption (630 nm), the resulting contrast quantitatively reflects cell thickness. Once the thickness is known at every point, the volume can be computed as well. Technical details, interpretation of data, and possible artifacts are discussed. Measurements in absolute units require knowledge of the absorption coefficient, and a similar procedure for the measurement of absorption coefficient is described. PMID- 25827482 TI - High-Sensitivity Detection of PNH Red Blood Cells, Red Cell Precursors, and White Blood Cells. AB - Flow cytometry is the method of choice to 'diagnose' paroxysmal nocturnal hemoglobinuria (PNH) and has led to improved patient management. Most laboratories have limited experience with PNH testing, and many different flow approaches are used. Careful selection and validation of antibody conjugates has allowed the development of reagent cocktails suitable for detection of PNH RBCs, CD71+ reticulocytes, and WBCs in clinical/sub-clinical PNH samples. A CD235a FITC/CD59-PE assay was developed capable of detecting Type III PNH RBCs at 0.01% sensitivity. A protocol targeting immature CD71+ RBCs can detect PNH reticulocytes at similar sensitivity. Four-color FLAER-based neutrophil and monocyte assays were developed to detect PNH phenotypes at a level of 0.01% and 0.04% sensitivity, respectively. For instrumentation with five or more PMTs, a single-tube 5-color FLAER/CD157-based assay to simultaneously detect PNH neutrophils and monocytes is described. Using these standardized approaches, results have demonstrated good intra- and inter-laboratory performance characteristics even in laboratories with little prior experience performing PNH testing. PMID- 25827483 TI - Uncompensated Polychromatic Analysis of Mitochondrial Membrane Potential Using JC 1 and Multilaser Excitation. AB - The lipophilic cation JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl benzimidazolyl carbocyanine iodide) has been used for more than 20 years as a specific dye for measuring mitochondrial membrane potential (DeltaPsi(m)). In this unit, we revise our original protocol (that made use of a single 488 nm laser for the detection of monomers and aggregates, and where compensation was an important step) to use dual-laser excitation. Moreover, thanks to recently developed multilaser instruments and novel probes for surface and intracellular markers, JC-1 can be utilized by polychromatic flow cytometry to simultaneously detect, without any compensation between fluorescences, DeltaPsi(m) along with other biological parameters, such as apoptosis and the production of reactive oxygen species. PMID- 25827484 TI - Cell Proliferation Method: Click Chemistry Based on BrdU Coupling for Multiplex Antibody Staining. AB - Determination of incorporation of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) into DNA is a widely used method to analyze the cell cycle. However, DNA denaturation is required for BrdU detection with the consequence that most protein epitopes are destroyed and their immunocytochemical detection for multiplex analysis is not possible. A novel assay is presented for identifying cells in active S-phase that does not require the DNA denaturation step but nevertheless detects BrdU. For this purpose, cells were pulsed for a short time by 5-ethynyl-2'-deoxyuridine (EdU) which is incorporated into DNA. The nucleotide exposed ethynyl residue was then derivatized by a copper-catalyzed cycloaddition reaction ("click chemistry" coupling) using a BrdU azide probe. The resulting DNA bound bromouracil moieties were then detected by commercial anti-BrdU monoclonal antibodies without the need for a denaturation step. This method has been tested using several cell lines and is more sensitive than traditional BrdU and allows multicolor and multiplex analysis in flow cytometry (FCM) and image-based cytometry. PMID- 25827485 TI - Flow cytometry of murine spermatocytes. AB - Protocols for purification of murine male germ cells by FACS based on Hoechst 33342 (Ho342) dye staining have been reported and optimized. However, the protocols are often challenging to follow, partly due to difficulties related to sample preparation, instrument parameters, data display, and selection strategies. In addition, troubleshooting of flow cytometry experiments usually requires some fluency in technical principles and instrument specifications and settings. This unit describes setup and procedures for analysis and sorting of male meiotic prophase I (MPI) cells and other germ cells. Included are procedures that guide data acquisition, display, gating, and back-gating critical for optimal data visualization and cell sorting. Additionally, a flow cytometry analysis of spermatogenesis-defective testis is provided to illustrate the applicability of the technique to the characterization and purification of cells from mutant testis. PMID- 25827486 TI - Measurement of intracellular ions by flow cytometry. AB - Using flow cytometry, single-cell measurements of calcium can be made on isolated populations identified by one or more phenotypic characteristics. Most earlier techniques for measuring cellular activation parameters determined the mean value for a population of cells, which did not permit optimal resolution of the responses. The flow cytometer is particularly useful for this purpose because it can measure ion concentrations in large numbers of single cells and thereby allows ion concentration to be correlated with other parameters such as immunophenotype and cell cycle stage. A limitation of flow cytometry, however, is that it does not permit resolution of certain complex kinetic responses such as cellular oscillatory responses. This unit describes the preparation of cells, including labeling with antibodies and with calcium probes, and discusses the principles of data analysis and interpretation. PMID- 25827487 TI - Manipulation of shell morphology of silicate spheres from structural evolution in a purely inorganic system. AB - We have investigated the structural transformation of solid silica spheres into various more complex spherical structures including flower-like, thick or thin nanosheet-shelled and porous shelled spheres. In the absence of organic additives, sodium salts contained in this inorganic reaction system apparently direct the silica dissolution and regrowth of dissolved silicate at the nanometer scale, leading to the formation of a nanosheet network rather than solid aggregates. Subsequent removal of the salts by simple water washing results in voids in the siloxane network and a significant availability of surface silanol groups so that the resulting nanosheets and spheres composed of them possess large surface areas, pore volumes, and morphological flexibility, which can be varied by an applied stimulus. The results represent a rare example of the transformation of a simple silicate structure into a much more complex spherical structure involving a purely inorganic reaction system. PMID- 25827488 TI - Monocarboxylate transporter-dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures. AB - Hypoxic and low-glucose stressors contribute to neuronal death in many brain diseases. Astrocytes are anatomically well-positioned to shield neurons from hypoxic injury. During hypoxia/ischemia, lactate released from astrocytes is taken up by neurons and stored for energy. This process is mediated by monocarboxylate transporters (MCTs) in the central nervous system. In the present study, we investigated the ability of astrocytes to protect neurons from oxygen- and glucose-deprivation (OGD) injury via an MCT-dependent mechanism in vitro. Primary cultures of neurons, astrocytes, and astrocytes-neurons derived from rat hippocampus were subjected to OGD, MCT inhibition with small interfering (si)RNA. Cell survival and expression of MCT4, MCT2, glial fibrillary acidic protein, and neuronal nuclear antigen were evaluated. OGD significantly increased cell death in neuronal cultures and up-regulated MCT4 expression in astrocyte cultures, but no increased cell death was observed in neuron-astrocyte co-cultures or astrocyte cultures. However, neuronal cell death in co-cultures was increased by exposure to MCT4- or MCT2-specific siRNA, and this effect was attenuated by the addition of lactate into the extracellular medium of neuronal cultures prior to OGD. These findings demonstrate that resistance to OGD injury in astrocyte-neuron co cultures occurs via an MCT-dependent mechanism. PMID- 25827489 TI - Effect of sex steroid hormones on the number of serotonergic neurons in rat dorsal raphe nucleus. AB - Disorders caused by the malfunction of the serotonergic system in the central nervous system show sex-specific prevalence. Many studies have reported a relationship between sex steroid hormones and the brain serotonergic system; however, the interaction between sex steroid hormones and the number of brain neurons expressing serotonin has not yet been elucidated. In the present study, we determined whether sex steroid hormones altered the number of serotonergic neurons in the dorsal raphe nucleus (DR) of adult rat brains. Animals were divided into five groups: ovariectomized (OVX), OVX+low estradiol (E2), OVX+high E2, castrated males, and intact males. Antibodies against 5-hydroxytryptamine (5 HT, serotonin) and tryptophan hydroxylase (Tph), an enzyme for 5-HT synthesis, were used as markers of 5-HT neurons, and the number of 5-HT-immunoreactive (ir) or Tph-ir cells was counted. We detected no significant differences in the number of 5-HT-ir or Tph-ir cells in the DR among the five groups. By contrast, the intensity of 5-HT-ir showed significant sex differences in specific subregions of the DR independent of sex steroid levels, suggesting that the manipulation of sex steroid hormones after maturation does not affect the number and intensive immunostaining of serotonergic neurons in rat brain. Our results suggest that, the sexual dimorphism observed in the serotonergic system is due to factors such as 5-HT synthesis, transportation, and degradation but not to the number of serotonergic neurons. PMID- 25827490 TI - Intestinal Depletion of NaPi-IIb/Slc34a2 in Mice: Renal and Hormonal Adaptation. AB - The Na(+) -dependent phosphate-cotransporter NaPi-IIb (SLC34A2) is widely expressed, with intestine, lung, and testis among the organs with highest levels of mRNA abundance. In mice, the intestinal expression of NaPi-IIb is restricted to the ileum, where the cotransporter localizes specifically at the brush border membrane (BBM) and mediates the active transport of inorganic phosphate (Pi). Constitutive full ablation of NaPi-IIb is embryonically lethal whereas the global but inducible removal of the transporter in young mice leads to intestinal loss of Pi and lung calcifications. Here we report the generation of a constitutive but intestinal-specific NaPi-IIb/Slc34a2-deficient mouse model. Constitutive intestinal ablation of NaPi-IIb results in viable pups with normal growth. Homozygous mice are characterized by fecal wasting of Pi and complete absence of Na/Pi cotransport activity in BBM vesicles (BBMVs) isolated from ileum. In contrast, the urinary excretion of Pi is reduced in these animals. The plasma levels of Pi are similar in wild-type and NaPi-IIb-deficient mice. In females, the reduced phosphaturia associates with higher expression of NaPi-IIa and higher Na/Pi cotransport activity in renal BBMVs, as well as with reduced plasma levels of intact FGF-23. A similar trend is found in males. Thus, NaPi-IIb is the only luminal Na(+) -dependent Pi transporter in the murine ileum and its absence is fully compensated for in adult females by a mechanism involving the bone-kidney axis. The contribution of this mechanism to the adaptive response is less apparent in adult males. PMID- 25827491 TI - Energetics of sodium-calcium exchanged zeolite A. AB - A series of calcium-exchanged zeolite A samples with different degrees of exchange were prepared. They were characterized by powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). High temperature oxide melt drop solution calorimetry measured the formation enthalpies of hydrated zeolites CaNa A from constituent oxides. The water content is a linear function of the degree of exchange, ranging from 20.54% for Na-A to 23.77% for 97.9% CaNa-A. The enthalpies of formation (from oxides) at 25 degrees C are -74.50 +/- 1.21 kJ mol(-1) TO2 for hydrated zeolite Na-A and -30.79 +/- 1.64 kJ mol(-1) TO2 for hydrated zeolite 97.9% CaNa-A. Dehydration enthalpies obtained from differential scanning calorimetry are 32.0 kJ mol(-1) H2O for hydrated zeolite Na-A and 20.5 kJ mol(-1) H2O for hydrated zeolite 97.9% CaNa-A. Enthalpies of formation of Ca exchanged zeolites A are less exothermic than for zeolite Na-A. A linear relationship between the formation enthalpy and the extent of calcium substitution was observed. The energetic effect of Ca-exchange on zeolite A is discussed with an emphasis on the complex interactions between the zeolite framework, cations, and water. PMID- 25827492 TI - Contrast blush in pediatric blunt splenic trauma does not warrant the routine use of angiography and embolization. AB - BACKGROUND: Splenic artery embolization (SAE) in the presence of contrast blush (CB) has been recommended to reduce the failure rate of nonoperative management. We hypothesized that the presence of CB on computed tomography has minimal impact on patient outcomes. METHODS: A retrospective review was conducted of all children (<18 years) with blunt splenic trauma over a 10-year period at a level 1 pediatric trauma center. Data are presented as mean +/- standard error of mean. RESULTS: Seven hundred forty children sustained blunt abdominal trauma, of which 549 had an identified solid organ injury. Blunt splenic injury was diagnosed in 270 of the 740 patients. All patients were managed nonoperatively without SAE. CB was seen on computed tomography in 47 patients (17.4%). There were no significant differences in the need for blood transfusion (12.5% vs 11.1%) or length of stay (3.1 vs 3.3 days) or need for splenectomy when compared in children with or without CB. CONCLUSION: Pediatric trauma patients with blunt splenic injuries can be safely managed without SAE and physiologic response and hemodynamic stability should be the primary determinants of appropriate management. PMID- 25827493 TI - Stress-related cortisol response and laboratory eating behavior in obese women. AB - Stress-related cortisol secretion has been linked to increased appetite and subsequent food intake in overweight individuals. The present study addresses this relationship in a repeated-measures randomized controlled laboratory experiment. Nineteen obese women were compared to 36 normal weight controls with respect to stress-induced salivary cortisol and laboratory eating behavior, measured by a universal eating monitor. The trier social stress test served as stressor. Stress-induced cortisol levels were significantly higher in the obese compared to the normal weight controls. Unexpectedly, a corresponding increase in laboratory food intake was not detected. The results are interpreted and discussed with regard to restrained eating, which was found to be present to a significant degree in the obese women. PMID- 25827494 TI - Ca2+ signal contributing to the synthesis and emission of monoterpenes regulated by light intensity in Lilium 'siberia'. AB - The floral scent is an important part of plant volatile compounds, and is influenced by environmental factors. The emission of monoterpenes of Lilium 'siberia' is regulated by light intensity, but the mechanism is large unknown. In this study, the expression of Li-mTPS, a monoterpene synthase gene in the tepals of Lilium 'siberia', and net Ca(2+) flux were investigated after exposure to different levels of light intensity (0, 100, 300, 600, 1000, and 1500 MUmol m(-2) s(-1)). Moreover the effect of LaCl3 and ethylene glycol-bis-(2-aminoethylether) N,N,N',N'-tetraacetic acid (EGTA) on the Li-mTPS expression, monoterpene emission, and net Ca(2+) flux were examined at 600 MUmol m(-2) s(-1). The results showed that along with the enhancement of light intensity, the expression level of Li-mTPS increased gradually, and the net Ca(2+) influx was also enhanced showing a similar pattern. It was found that LaCl3 and EGTA effectively inhibited the increase in expression of Li-mTPS and the net Ca(2+) influx induced by light treatment. Moreover, the release amounts of monoterpenes decreased significantly after treatment with LaCl3 and EGTA. So it can be concluded that Ca(2+) signal contributed to the biosynthesis and emission of monoterpenes regulated by light intensity in Lilium 'siberia' tepals. The increased light intensity firstly triggered the Ca(2+) influx to cytoplasm, and then the gene expression of monoterpene synthases downstream was activated to regulate the biosynthesis and emission of monoterpenes. But in the signaling pathway other mechanisms were thought to be involved in the emission of monoterpenes regulated by light intensity, which need to be investigated in future research. PMID- 25827495 TI - The fusion of genomes leads to more options: A comparative investigation on the desulfo-glucosinolate sulfotransferases of Brassica napus and homologous proteins of Arabidopsis thaliana. AB - Sulfotransferases (SOTs) (EC 2.8.2.-) play a crucial role in the glucosinolate (Gl) biosynthesis, by catalyzing the final step of the core glucosinolate formation. In Arabidopsis thaliana the three desulfo (ds)-Gl SOTs AtSOT16, AtSOT17 and AtSOT18 were previously characterized, showing different affinities to ds-Gls. But can the knowledge about these SOTs be generally transferred to other Gl-synthesizing plants? It was investigated how many SOTs are present in the economically relevant crop plant Brassica napus L., and if it is possible to predict their characteristics by sequence analysis. The recently sequenced B. napus is a hybrid of Brassica rapa and Brassica oleracea. By database research, 71 putative functional BnSOT family members were identified and at least eleven of those are putative ds-Gl SOTs. Besides the homologs of AtSOT16 - 18, phylogenetic analyses revealed new subfamilies of ds-Gl SOTs, which are not present in A. thaliana. Three of the B. napus ds-Gl SOT proteins were expressed and purified, and characterized by determining the substrate affinities to different ds-Gls. Two of them, BnSOT16-a and BnSOT16-b, showed a significantly higher affinity to an indolic ds-Gl, similarly to AtSOT16. Additionally, BnSOT17 a was characterized and showed a higher affinity to long chained aliphatic Gls, similarly to AtSOT17. Identification of homologs to AtSOT18 was less reliable, because putative SOT18 sequences are more heterogeneous and confirmation of similar characteristics was not possible. PMID- 25827496 TI - Nuclear-Spin-Induced Circular Dichroism in the Infrared Region for Liquids. AB - Recently, the nuclear-spin-induced optical rotation (NSOR) and circular dichroism (NSCD) for liquids were discovered and extensively studied and developed. However, so far, nuclear-spin-induced magnetic circular dichroism in the IR region (IR-NSCD) has not been explored, even though all polyatomic molecules exhibit extensive IR spectra. Herein, IR-NSCD is proposed and discussed theoretically. The results indicate that in favorable conditions the IR-NSCD angle may be much larger than the NSOR angle in the UV/Vis region due to a vibrational resonance effect and can be measurable by using the NSOR experiment scheme. IR-NSCD can automatically combine and give NMR spectra and IRCD spectra of the nuclear spin prepolarized samples in liquids, which, in principle, could be developed to become a unique, novel analytical tool. PMID- 25827497 TI - Manipulations of extracellular Loop 2 in alpha1 GlyR ultra-sensitive ethanol receptors (USERs) enhance receptor sensitivity to isoflurane, ethanol, and lidocaine, but not propofol. AB - We recently developed ultra-sensitive ethanol receptors (USERs) as a novel tool for investigation of single receptor subunit populations sensitized to extremely low ethanol concentrations that do not affect other receptors in the nervous system. To this end, we found that mutations within the extracellular Loop 2 region of glycine receptors (GlyRs) and gamma-aminobutyric acid type A receptors (GABAARs) can significantly increase receptor sensitivity to micro-molar concentrations of ethanol resulting in up to a 100-fold increase in ethanol sensitivity relative to wild-type (WT) receptors. The current study investigated: (1) Whether structural manipulations of Loop 2 in alpha1 GlyRs could similarly increase receptor sensitivity to other anesthetics; and (2) If mutations exclusive to the C-terminal end of Loop 2 are sufficient to impart these changes. We expressed alpha1 GlyR USERs in Xenopus oocytes and tested the effects of three classes of anesthetics, isoflurane (volatile), propofol (intravenous), and lidocaine (local), known to enhance glycine-induced chloride currents using two electrode voltage clamp electrophysiology. Loop 2 mutations produced a significant 10-fold increase in isoflurane and lidocaine sensitivity, but no increase in propofol sensitivity compared to WT alpha1 GlyRs. Interestingly, we also found that structural manipulations in the C-terminal end of Loop 2 were sufficient and selective for alpha1 GlyR modulation by ethanol, isoflurane, and lidocaine. These studies are the first to report the extracellular region of alpha1 GlyRs as a site of lidocaine action. Overall, the findings suggest that Loop 2 of alpha1 GlyRs is a key region that mediates isoflurane and lidocaine modulation. Moreover, the results identify important amino acids in Loop 2 that regulate isoflurane, lidocaine, and ethanol action. Collectively, these data indicate the commonality of the sites for isoflurane, lidocaine, and ethanol action, and the structural requirements for allosteric modulation on alpha1 GlyRs within the extracellular Loop 2 region. PMID- 25827499 TI - Efficacy and environmental fate of imazapyr from directed helicopter applications targeting Tamarix species infestations in Colorado. AB - BACKGROUND: Aerial imazapyr applications are the most common and cost-effective method for controlling invasive tamarisk, but few studies have investigated whether or how infestation and site characteristics influence control and non target impacts. This study used vertical stands with filter papers, plus soil and tree canopy sampling, to investigate how tamarisk canopies affected retention of applied imazapyr, soil herbicide residues and tree mortality. RESULTS: Tamarisk canopies captured 71% of aerially applied imazapyr, resulting in significantly lower soil residues beneath the tree canopy. Although initial imazapyr soil residue levels outside the tree canopy were 4 times greater than those inside, soil degradation occurred 2.4 times faster outside the tamarisk canopy and resulted in lower herbicide residues. Tamarisk mortality within 3 years was 70%, but variability in control appeared to be affected by non-linear stand boundaries and tall site obstructions. These same factors also increased variability in the actual quantity of herbicide applied, exacerbating collateral impacts on desirable understory species. CONCLUSION: While aerial imazapyr applications are highly effective in controlling tamarisk, our study provides evidence for the importance of evaluating overall site suitability for this management strategy so the probability of unintended ecological effects can be minimized. PMID- 25827498 TI - Rodent auditory perception: Critical band limitations and plasticity. AB - What do animals hear? While it remains challenging to adequately assess sensory perception in animal models, it is important to determine perceptual abilities in model systems to understand how physiological processes and plasticity relate to perception, learning, and cognition. Here we discuss hearing in rodents, reviewing previous and recent behavioral experiments querying acoustic perception in rats and mice, and examining the relation between behavioral data and electrophysiological recordings from the central auditory system. We focus on measurements of critical bands, which are psychoacoustic phenomena that seem to have a neural basis in the functional organization of the cochlea and the inferior colliculus. We then discuss how behavioral training, brain stimulation, and neuropathology impact auditory processing and perception. PMID- 25827500 TI - Intrarenal hemodynamic and oxidative stress in patients with obstructive sleep apnea syndrome. AB - BACKGROUND: Oxygen desaturation and reoxygenation, related to intermittent hypoxia cycles due to upper airway obstruction, are major pathophysiologic features of obstructive sleep apnea syndrome (OSAS) and are thought to be responsible for an increased risk of cardiovascular diseases. Continuous positive airway pressure (CPAP) is therefore considered the gold standard in the management of OSAS. Further data demonstrated a high prevalence of OSAS in patients with altered renal function despite the underlying pathophysiological mechanisms that have not been clarified. This study aims to provide evidence on the reported high prevalence of endothelial dysfunction and alterations of the intrarenal hemodynamic in patients affected by OSAS. Furthermore, we evaluated the effect of a CPAP therapy on these endpoints. METHODS: Twenty patients were enrolled in a prospective study and underwent ultrasound examination to assess endothelial dysfunction, by collecting brachial flow-mediated dilation (FMD) and intrarenal artery stiffness, pre- and post a 30-day treatment with CPAP. RESULTS: Endothelial dysfunction and intrarenal artery stiffness significantly improved in all patients after a month of CPAP. In particular, we observed a significant reduction in the renal resistance index (RI) (p < 0.001) and systolic/diastolic ratio (S/D) ratio (p < 0.001) and a significant increase of FMD (p < 0.001). The apnea-hypopnea index (AHI) showed a negative correlation with Delta FMD (p < 0.05, r = -0.46). Conversely, a positive correlation exists between Delta RI and the oxygen desaturation index (ODI) (specificare la sigla) (p < 0.05, r = 0.46). CONCLUSIONS: Our study firstly showed a significant effect of CPAP on renal perfusion and endothelial function in OSAS patients without concomitant cardiovascular comorbidities. PMID- 25827501 TI - Effect of CPAP therapy on job productivity and psychosocial occupational health in patients with moderate to severe sleep apnea. AB - PURPOSE: The aim of the present study was to assess the effect of continuous positive airflow pressure (CPAP) therapy on burnout symptoms and job productivity, stress, and satisfaction in patients with obstructive sleep apnea syndrome. METHODS: The sample was composed of 55 patients (mean age 48.5 +/- 8.9, BMI 31.1 +/- 5.7, AIH 56.8 +/- 22.1), diagnosed with obstructive sleep apnea syndrome (OSAS) using polysomnography (PSG) with a therapeutic indication of CPAP. Before and after 6 months of receiving CPAP therapy, participants completed the following questionnaires: the index of the impact of the disease on job productivity (IMPALA), the job content questionnaire(JCQ), the Maslach burnout inventory-general survey (MBI-GS), the Shirom-Melamed burnout questionnaire (SMBQ), the index of job satisfaction, the Epworth sleepiness scale (ESS), and the Pittsburgh sleep quality index (PSQI). We explored the efficacy of CPAP therapy at improving the indices of severity of OSAS using therapeutic PSG. RESULTS: CPAP therapy was associated with a beneficial effect on job productivity (IMPALA) (p = 0.000) and decreasing burnout symptoms such as physical fatigue (SMBQ) (p = 0.000), emotional exhaustion (SMBQ) (p = 0.014), cognitive weariness (SMBQ) (p = 0.004), exhaustion (MBI) (p = 0.000), and cynicism (MBI) (p = 0.002). However, CPAP did not decrease job stress or job dissatisfaction. DISCUSSION: In patients with severe OSAS, CPAP therapy has a beneficial effect on patients' occupational well-being and job productivity. PMID- 25827502 TI - The significance of base deficit in acidemic term neonates. AB - OBJECTIVE: Much emphasis is placed on the metabolic component of umbilical cord acidemia at birth, with an importance attached to an arterial level of <7.00 accompanied by a base deficit of 12 mmol/L. We hypothesized that in acidemic neonates, the level of arterial base deficit provides no prognostic information beyond that provided by the level of arterial pH. STUDY DESIGN: This is a cohort study using a database of deliveries from a major teaching hospital, with additional information from neonatal records. A total of 8797 term, singleton, nonanomalous neonates were identified who had paired and validated cord blood gas analysis. Of these, 520 were acidemic (pH <7.1) and 84 were severely acidemic (pH <7.0). Outcomes examined were encephalopathy grade 2/3 and/or death, Apgar <7 at 5 minutes, neonatal unit admission, and composite outcomes of neurological and systemic involvement. Hierarchical logistic regressions were done using IBM SPSS Statistics 20.0 (Armonk, NY) to assess the predictive value of arterial pH and arterial base deficit. RESULTS: For each outcome the median pH and base deficit of those neonates affected by the adverse outcome was significantly lower than for those who were unaffected. Hierarchical logistic regressions showed that pH is a significant predictor of all adverse outcomes studied (P < .001 for all outcomes). When base deficit, and then the cross-product, are added to the model, neither add predictive value. CONCLUSION: In acidemic neonates, the metabolic component does not predict those at risk of adverse outcomes once pH is taken into account. The apparently worse outcomes with greater base deficit simply reflect a greater degree of acidemia. The prognostic significance attached to the base deficit among acidemic neonates is questionable. PMID- 25827503 TI - Women with preterm birth have a distinct cervicovaginal metabolome. AB - OBJECTIVE: Metabolomics has the potential to reveal novel pathways involved in the pathogenesis of preterm birth (PTB). The objective of this study was to investigate whether the cervicovaginal (CV) metabolome was different in asymptomatic women destined to have a PTB compared with term birth. STUDY DESIGN: A nested case-control study was performed using CV fluid collected from a larger prospective cohort. The CV fluid was collected between 20-24 weeks (V1) and 24-28 weeks (V2). The metabolome was compared between women with a spontaneous PTB (n = 10) to women who delivered at term (n = 10). Samples were extracted and prepared for analysis using a standard extraction solvent method. Global biochemical profiles were determined using gas chromatography/mass spectrometry and ultra performance liquid chromatography/tandem mass spectrometry. An ANOVA was used to detect differences in biochemical compounds between the groups. A false discovery rate was estimated to account for multiple comparisons. RESULTS: A total of 313 biochemicals were identified in CV fluid. Eighty-two biochemicals were different in the CV fluid at V1 in those destined to have a PTB compared with term birth, whereas 48 were different at V2. Amino acid, carbohydrate, and peptide metabolites were distinct between women with and without PTB. CONCLUSION: These data suggest that the CV space is metabolically active during pregnancy. Changes in the CV metabolome may be observed weeks, if not months, prior to any clinical symptoms. Understanding the CV metabolome may hold promise for unraveling the pathogenesis of PTB and may provide novel biomarkers to identify women most at risk. PMID- 25827504 TI - Unplanned pregnancies and reproductive health among women with bipolar disorder. AB - BACKGROUND: The aim of this study was to investigate reproductive health and level of planning of pregnancies among women with bipolar disorder (BDW). METHODS: 63 euthymic women, with bipolar disorder type I, II or not otherwise specified diagnosis, were included and were matched with a control group of 63 healthy women. Demographic and clinical data, structured reproductive health measures and planning level of pregnancies were obtained and compared between groups. RESULTS: Lower level of planning of pregnancies and higher frequency of unplanned pregnancies were found among BDW. Women with bipolar disorder reported history of voluntary interruption of pregnancies more frequent than women from control group. Current reproductive health care showed no differences between groups. LIMITATIONS: Data based on self-report of participants and retrospective nature of some collected measures may be affected by information bias. The pregnancy planning measure has not been validated in this population before. Demographic and clinical characteristics of the sample study limit generalization of these findings. CONCLUSIONS: Adverse reproductive events, as unplanned pregnancies and elective interruption of pregnancies, may be more frequent among BDW. Clinician must be aware of the reproductive health during treatment of young BDW and take measures to improve better family planning access. PMID- 25827508 TI - Council of Australian Therapeutic Advisory Groups: supporting the Quality Use of Medicines across the acute-care sector. PMID- 25827505 TI - Characteristics of Bipolar I patients grouped by externalizing disorders. AB - BACKGROUND: Bipolar disorder co-occurs with a number of disorders with externalizing features. The aim of this study is to determine whether Bipolar I (BPI) subjects with comorbid externalizing disorders and a subgroup with externalizing symptoms prior to age 15 have different clinical features than those without externalizing disorders and whether these could be attributed to specific genetic variations. METHODS: A large cohort (N=2505) of Bipolar I subjects was analyzed. Course of illness parameters were compared between an Externalizing Group, an Early-Onset Subgroup and a Non-Externalizing Group in the Discovery sample (N=1268). Findings were validated using an independent set of 1237 BPI subjects (Validation sample). Genetic analyses were carried out. RESULTS: Subjects in the Externalizing Group (and Early-Onset Subgroup) tended to have a more severe clinical course, even in areas specifically related to mood disorder such as cycling frequency and rapid mood switching. Regression analysis showed that the differences are not completely explainable by substance use. Genetic analyses identified nominally associated SNPs; calcium channel genes were not enriched in the gene variants identified. LIMITATIONS: Validation in independent samples is needed to confirm the genetic findings in the present study. CONCLUSIONS: Our findings support the presence of an externalizing disorder subphenotype within BPI with greater severity of mood disorder and possible specific genetic features. PMID- 25827507 TI - An exploratory study of responses to low-dose lithium in African Americans and Hispanics. AB - OBJECTIVES: Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS). METHODS: LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) vs. OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes. RESULTS: African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups. CONCLUSIONS: African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group. PMID- 25827506 TI - Altered insular activation and increased insular functional connectivity during sad and happy face processing in adolescent major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide and occurs commonly first during adolescence. The insular cortex (IC) plays an important role in integrating emotion processing with interoception and has been implicated recently in the pathophysiology of adult and adolescent MDD. However, no studies have yet specifically examined the IC in adolescent MDD during processing of faces in the sad-happy continuum. Thus, the aim of the present study is to investigate the IC during sad and happy face processing in adolescents with MDD compared to healthy controls (HCL). METHODS: Thirty-one adolescents (22 female) with MDD and 36 (23 female) HCL underwent a well validated emotional processing fMRI paradigm that included sad and happy face stimuli. RESULTS: The MDD group showed significantly less differential activation of the anterior/middle insular cortex (AMIC) in response to sad versus happy faces compared to the HCL group. AMIC also showed greater functional connectivity with right fusiform gyrus, left middle frontal gyrus, and right amygdala/parahippocampal gyrus in the MDD compared to HCL group. Moreover, differential activation to sad and happy faces in AMIC correlated negatively with depression severity within the MDD group. LIMITATIONS: Small age-range and cross sectional nature precluded assessment of development of the AMIC in adolescent depression. CONCLUSIONS: Given the role of the IC in integrating bodily stimuli with conscious cognitive and emotional processes, our findings of aberrant AMIC function in adolescent MDD provide a neuroscientific rationale for targeting the AMIC in the development of new treatment modalities. PMID- 25827509 TI - Overview of shorthand medical glossary (OMG) study. AB - BACKGROUND: Shorthand is commonplace in clinical notation. While many abbreviations are standard and widely accepted, an increasing number are non standard and/or unrecognisable. AIM: We sought to describe the frequency of inappropriate and ambiguous shorthand in discharge summaries. METHODS: Eighty electronic discharge summaries from the four General Medical Units at the Royal Melbourne Hospital were randomly extracted from the hospital's electronic records. Extraction was stratified by the four units and by the four quarters between July 2012 and June 2013. All abbreviations were assigned into one of four categories according to appropriateness: 1. 'Universally accepted and understood even without context'; 2. 'Understood when in context'; 3. 'Understood but inappropriate and/or ambiguous'; and 4. 'Unknown'. These categories were determined by the authors, which included junior and senior medical staff. RESULTS: The 80 discharge summaries contained 840 different abbreviations used on 6269 occasions. Of all words, 20.1% were abbreviations. Of the 6269 occasions of shorthand, 6.8% were categorised as 'Understood but inappropriate and/or ambiguous' or 'Unknown' (category 3 or 4), equating to 1.4% of all words, and an average of 5.4 words per discharge summary. CONCLUSION: Abbreviations are common in electronic discharge summaries, occurring at a frequency of one in five words. While the majority of shorthand used seems to be appropriate, the use of inappropriate, ambiguous or unknown shorthand is still frequent. This has implications for safe and effective patient care and highlights the need for better awareness and education regarding use of shorthand in clinical notation. PMID- 25827510 TI - Hypomagnesaemia linked to depression: a systematic review and meta-analysis. AB - BACKGROUND: The reported risk of depression in patients with hypomagnesaemia is controversial. AIM: The objective of this meta-analysis was to assess the association between depression and hypomagnesaemia. METHODS: A literature search was performed using MEDLINE, EMBASE, Cochrane Database and clinicaltrials.gov from inception through October 2014. Studies that reported odds ratios, relative risks or hazard ratios comparing the risk of depression in patients with hypomagnesaemia were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Six observational studies (three cohort studies, two cross sectional studies and a case-control study) with a total of 19,137 patients were identified and included in the data analysis. The pooled RR of depression in patients with hypomagnesaemia was 1.34 (95% CI, 1.01-1.79, I(2) = 33%). The association between depression and hypomagnesaemia was marginally insignificant after the sensitivity analysis including only cohort and case-control studies, with a pooled RR of 1.38 (95% CI, 0.92-2.07, I(2) = 24%). CONCLUSION: Our study demonstrates a potential association between hypomagnesaemia and depression. Further studies assessing the benefits of treatment of hypomagnesaemia in patients with depression are needed. PMID- 25827512 TI - Potential role of coenzyme Q10 in facilitating recovery from statin-induced rhabdomyolysis. AB - Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. Coenzyme Q10 is generally well tolerated, and may potentially benefit patients with statin induced rhabdomyolysis. PMID- 25827511 TI - Appropriate clinical use of human leukocyte antigen typing for coeliac disease: an Australasian perspective. AB - The past decade has seen human leukocyte antigen (HLA) typing emerge as a remarkably popular test for the diagnostic work-up of coeliac disease with high patient acceptance. Although limited in its positive predictive value for coeliac disease, the strong disease association with specific HLA genes imparts exceptional negative predictive value to HLA typing, enabling a negative result to exclude coeliac disease confidently. In response to mounting evidence that the clinical use and interpretation of HLA typing often deviates from best practice, this article outlines an evidence-based approach to guide clinically appropriate use of HLA typing, and establishes a reporting template for pathology providers to improve communication of results. PMID- 25827513 TI - Delusional infestation: an Australian multicentre study of 23 consecutive cases. AB - Delusional infestation remains a debilitating condition that is therapeutically challenging for clinicians. This case series identifies 23 patients with delusional infestation in an Australian setting. The majority of patients are women and unlikely to have a psychiatric comorbid background. The use of unnecessary anti-parasitic medication is prevalent. PMID- 25827514 TI - Macro-creatine kinase: a neglected cause of elevated creatine kinase. AB - Macro-creatine kinase (macro-CK) is a neglected cause of raised CK. Over a 10 year period, we observed five cases. Three patients had macro-CK type 1. One patient with fibromyalgia underwent several explorations to find a muscular pathology; another, who had elevated CK-MB (muscle-brain fraction) activity, was referred to a cardiologist, and statin therapy was erroneously discontinued in two patients. Two patients had macro-CK type 2: a man with a neuroendocrine carcinoma and a woman with rheumatoid arthritis. Diagnosis of type 1 obviates the need to carry out pointless and expensive investigations seeking a neuromuscular or cardiac pathology, and also, the unwarranted discontinuation of statin therapy. Type 2 must prompt investigations for a neoplasm. PMID- 25827515 TI - Isolated iliac vein thrombosis in pregnancy. PMID- 25827516 TI - 'Avoidable' death of a pregnant Jehovah's Witness with acute promyelocytic leukaemia: ethical considerations and the internal conflicts and challenges encountered by practitioners. PMID- 25827517 TI - Adult onset autoimmune lymphoproliferative syndrome due to somatic FAS mutation. PMID- 25827518 TI - Increasing clindamycin resistance among Australian group B streptococcus isolates. PMID- 25827519 TI - Impaired doctors: the Royal Australasian College of Physicians' support for Fellows in difficulty. PMID- 25827520 TI - Author reply: To PMID 25442756. PMID- 25827521 TI - Magnesium deficiency: a possible cause of restless leg syndrome in haemodialysis patients. PMID- 25827522 TI - Synthesis and evaluation of benzosuberone embedded with 1,3,4-oxadiazole, 1,3,4 thiadiazole and 1,2,4-triazole moieties as new potential anti proliferative agents. AB - As an aspect of our ongoing research in search of new anti proliferative agents, a series of novel analogs of benzosuberone embedded with 1,3,4-oxadiazole, 1,3,4 thiadiazole and 1,2,4-triazole moieties were synthesized in excellent yields (82 93%). All the newly synthesized compounds were characterized by (1)H NMR, (13)C NMR, ESI/LC-MS, HRMS and evaluated for their in vitro anti proliferative activity against four human cancer cell lines (cervical, breast, pancreatic and alveolar). Among the synthesized compounds, 4b, 6a, 7d and 7l showed potent anti proliferative activity with GI50 values range of 0.079-0.957MUM against four human cancer cell lines. However, it was revealed that the compound 7d have shown very close GI50 value 0.079MUM as compared with positive control of colchicine against cervical cancer cell line. PMID- 25827523 TI - Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors. AB - VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species. PMID- 25827524 TI - Improving both aqueous solubility and anti-cancer activity by assessing progressive lead optimization libraries. AB - Thiazolidinone compounds 1-3 are lead compounds that have cytoselective toxicity toward non-small cell lung cancer (NSCLC) cells and drug-resistant NSCLC cells while showing low toxicity to normal human fibroblasts (NHFB). However, this class of compounds generally has a very low aqueous solubility (~0.1 MUg/ml). In order to improve both solubility and anti-cancer activity, we designed and synthesized two lead-optimization libraries and investigated these libraries using simultaneous high-throughput solubility and cytotoxicity assays. By all around modifications on R(1), R(2) and R(3) substitutions, consecutive library synthesis, and testing, we improved the aqueous solubility (5-fold improvement in solubility, from 0.1 to 0.5 MUg/ml) and anti-cancer activity (10-fold improvement in EC50 from 0.72-0.98 MUM to 0.08-0.16 MUM) in the new lead thiazolidinone compound 31. PMID- 25827525 TI - Synthesis and biological evaluation of 2-arylbenzimidazoles targeting Leishmania donovani. AB - A set of 56 2-arylbenzimidazoles was designed, synthesized and tested against Leishmania donovani amastigotes. The left- and right-hand side rings of the molecule, as well as the amide linker were modified. Structurally different derivatives were screened on L. donovani axenic amastigotes at concentrations of 5, 15 and 50 MUM, and the ten most active derivatives were selected for further testing. 2-Arylbenzimidazole derivative 24 was active against L. donovani infected THP-1 cells showing 46% parasite inhibition at 5 MUM. PMID- 25827526 TI - Histone H3 peptide based LSD1-selective inhibitors. AB - A series of candidates for the histone H3 peptide based LSD1-selective inhibitor were designed and synthesized. Among peptides 1a-c and 2a-c, peptide 1a, which has a phenylcyclopropylamine (PCPA) moiety at Lys-4 of the 21 amino acid residues of histone H3, was the most potent LSD1-selective inhibitor. Truncation studies of peptide 1a revealed the significance of the peptide sequence length. These findings will be useful for the further development of histone H3 peptide based LSD1-selective inhibitors. PMID- 25827527 TI - Punch biopsy of melanoma causing tumour cell implantation: another peril of utilising partial biopsies for melanocytic tumours. AB - The recommended initial management for suspected melanoma is excisional biopsy. The use of partial biopsies of melanocytic tumours poses potential problems including misdiagnosis due to either unrepresentative sampling or the difficulty in evaluating important diagnostic features; an inaccurate assessment of Breslow thickness and other important prognostic features; and the induction of changes capable of mimicking melanoma (i.e., pseudomelanoma). Misdiagnosis, in turn, may lead to inappropriate management of the patient and an adverse outcome. In this report we document a previously unrecognised pitfall of partial biopsies of melanocytic tumours: implantation of tumour cells at the biopsy site potentially leading to the overestimation of tumour thickness or a misdiagnosis of the presence of microsatellites in the subsequent wide excision specimen. PMID- 25827528 TI - Heat shock protein 70 is associated with CSFV NS5A protein and enhances viral RNA replication. AB - The non-structural 5A (NS5A) protein of classical swine fever virus (CSFV) is proven to be involved in viral replication and can also modulate cellular signaling via to its ability to interact with various cellular proteins. Here, HSP70/NS5A complex formation is confirmed by coimmunoprecipitation and GST pulldown studies. Additionally, the N-terminal amino acids (29-240) of NS5A were identified as the interaction region through in vivo deletion analyses, and confocal microscopy showed that NS5A and HSP70 colocalized in the cytoplasm. Overexpression of HSP70 via the eukaryotic expression plasmid pDsRED N1 or lentivirus significantly promoted viral RNA synthesis. Whereas the knockdown of HSP70 by lentivirus-mediated shRNA or inhibition by quercetin markedly decreased the viral load. These data suggest that HSP70 plays a critical role in the viral life cycle, particularly during the virus RNA replication period. The investigation of HSP70 protein functions may be beneficial for developing new strategies to treat CSFV infection. PMID- 25827529 TI - Mucosal vaccination by adenoviruses displaying reovirus sigma 1. AB - We developed adenovirus serotype 5 (Ad5) vectors displaying the sigma 1 protein from reovirus as mucosal vaccines. Ad5-sigma retargets to JAM-1 and sialic acid, but has 40-fold reduced gene delivery when compared to Ad5. While weaker at transduction, Ad5-sigma generates stronger T cell responses than Ad5 when used for mucosal immunization. In this work, new Ad5-fiber-sigma vectors were generated by varying the number of fiber beta-spiral shaft repeats (R) between the fiber tail and sigma. Increasing chimera length led to decreasing insertion of these proteinsAd5 virions. Ad-R3 and R14 vectors effectively targeted JAM-1 in vitro while R20 did not. When wereused to immunize mice by the intranasal route, Ad5-R3-sigma produced higher serum and vaginal antibody responses than Ad5. These data suggest optimized Ad-sigma vectors may be useful vectors for mucosal vaccination. PMID- 25827530 TI - Limited susceptibility of mice to Usutu virus (USUV) infection and induction of flavivirus cross-protective immunity. AB - Flaviviruses are RNA viruses that constitute a worrisome threat to global human and animal health. In Europe, West Nile virus (WNV) outbreaks have dramatically increased in number and severity in recent years, with dozens of human and horse deaths and a high avian mortality across the continent. Besides WNV, the only clinically relevant mosquito-borne flavivirus detected so far in Europe has been the Usutu virus (USUV), which after being reported for the first time in Austria in 2001, quickly spread across Europe, causing a considerable number of bird deaths and neurological disorders in a few immunocompromised patients. Even though USUV infects multiple avian species that develop antibodies, there is little information about USUV susceptibility, pathogenicity and cross-reactive immunity. Here, the susceptibility of suckling and adult mice to USUV infection and the induction of cross-protective immunity against WNV challenge have been addressed. PMID- 25827531 TI - Immune evasion activities of accessory proteins Vpu, Nef and Vif are conserved in acute and chronic HIV-1 infection. AB - Heterosexual HIV-1 transmission has been identified as a genetic bottleneck and a single transmitted/founder (T/F) variant with reduced sensitivity to type I interferon initiates productive infection in most cases. We hypothesized that particularly active accessory protein(s) may confer T/F viruses with a selective advantage in establishing HIV infection. Thus, we tested vpu, vif and nef alleles from six T/F and six chronic (CC) viruses in assays for 9 immune evasion activities involving the counteraction of interferon-stimulated genes and modulation of ligands known to activate innate immune cells. All functions were highly conserved with no significant differences between T/F and CC viruses, suggesting that these accessory protein functions are important throughout the course of infection. PMID- 25827532 TI - Dispersal of H9N2 influenza A viruses between East Asia and North America by wild birds. AB - Samples were collected from wild birds in western Alaska to assess dispersal of influenza A viruses between East Asia and North America. Two isolates shared nearly identical nucleotide identity at eight genomic segments with H9N2 viruses isolated from China and South Korea providing evidence for intercontinental dispersal by migratory birds. PMID- 25827533 TI - Application of knowledge discovery process on the prediction of stroke. AB - OBJECTIVE: Stroke is a prominent life-threatening disease in the world. The current study was performed to predict the outcome of stroke using knowledge discovery process (KDP) methods, artificial neural networks (ANN) and support vector machine (SVM) models. MATERIALS AND METHODS: The records of 297 (130 sick and 167 healthy) individuals were acquired from the databases of the department of emergency medicine. Nine predictors (coronary artery disease, diabetes mellitus, hypertension, history of cerebrovascular disease, atrial fibrillation, smoking, the findings of carotid Doppler ultrasonography [normal, plaque, plaque+stenosis>=50%], the levels of cholesterol and C-reactive protein) were used for predicting the stroke. Feature selection based on the Cramer's V test was carried out for reducing the predictors. Multilayer perceptron (MLP) ANN and SVM with radial basis function (RBF) kernel were used for the prediction based on the selected predictors. RESULTS: The accuracy values were 81.82% for ANN and 80.38% for SVM in the training dataset (n=209), and 85.9% for ANN and 84.62% for SVM in the testing dataset (n=78), respectively. ANN and SVM models yielded area under curve (AUC) values of 0.905 and 0.899 in the training dataset, and 0.928 and 0.91 in the testing dataset, consecutively. CONCLUSION: The findings of the current study pointed out that ANN had more predictive performance when compared with SVM in predicting stroke. The proposed ANN model would be useful when making clinical decisions regarding stroke. PMID- 25827534 TI - Offense Characteristics of Incompetent to Stand Trial Defendants Charged With Violent Offenses. AB - The current study compared offender and offense characteristics of pretrial defendants found incompetent to stand trial (IST) against those described as general offenders by victims in the 2008 Bureau of Justice Statistics (BJS) survey and evaluated factors that differentiated IST defendants who allegedly used weapons from those who did not during the course of a violent offense. IST defendants were older and used "weapons" more frequently than those reported in the BJS survey; however, other characteristics, including use of firearms, did not differ. No demographic, clinical, or legal factors differentiated pretrial defendants who used weapons from those who did not. Overall, pretrial defendants were frequently diagnosed with a comorbid substance use disorder, and were homeless, unemployed, and had an extensive history of psychiatric hospitalizations and prior arrests at the time of their alleged offenses. Such results indicate that models for comprehensive discharge planning may have utility in addressing the unique needs of this subgroup of mentally disordered offenders. The findings also raise questions about the federal and state prohibition of gun rights to all IST defendants. PMID- 25827535 TI - Succinate dehydrogenase B: a new prognostic biomarker in clear cell renal cell carcinoma. AB - Succinate dehydrogenase B (SDHB) is a mitochondrial enzyme complex subunit. Loss of SDHB protein expression has been found to correlate with SDHx gene mutations. Little is known about its expression in subtypes of renal cell carcinoma (RCC) and whether it is a prognostic indicator. Four hundred fifty renal epithelial neoplasms were analyzed for SDHB, comprising clear cell RCC (CCRCC) (n = 240), papillary RCC (n = 84), chromophobe RCC (n = 49), renal oncocytoma (n = 47), clear cell papillary RCC (CCPRCC) (n = 19), and von Hippel-Lindau (VHL) associated CCPRCC-like tumors (n = 11). Succinate dehydrogenase B expression was graded based upon staining intensity using a 4-tiered system (0-3+), in which 3+ was strongest and complete absence was 0. Neoplasms were further categorized based upon staining extent into SDHB weak (1+-2+) and strong (3+). Succinate dehydrogenase B was strongly preserved in 131 (55%) of 240 CCRCCs, 84 (100%) of 84 papillary RCCs, 49 (100%) of 49 chromophobe RCCs, 1 (5%) of 19 CCPRCC, 5 (45%) of 11 VHL-associated CCPRCC-like tumors, and 47 (100%) of 47 renal oncocytomas. The remaining 109 CCRCCs, 18 CCPRCCs, and 6 VHL-associated CCPRCC-like tumors had weak but preserved SDHB. Succinate dehydrogenase B expression in CCRCCs with high International Society of Urological Pathology nucleolar grade (G3-G4) correlated significantly with survival (log-rank, P = .0004). Succinate dehydrogenase B is variably expressed in RCCs with clear cell morphology and strongly preserved in most other neoplasms. Therefore, weak staining, particularly in clear neoplasms, should not be misinterpreted as negative. Finally, SDHB expression in CCRCCs with high nucleolar grade (G3-G4) is significantly associated with survival, indicating it may be both a diagnostic and prognostic marker in RCC. PMID- 25827536 TI - Ocular oncology--a multidisciplinary specialty. PMID- 25827537 TI - Trends in the management of intraocular tumors over 40 years. PMID- 25827539 TI - Retinoblastoma: achieving new standards with methods of chemotherapy. AB - The management of retinoblastoma (RB) has dramatically changed over the past two decades from previous radiotherapy methods to current chemotherapy strategies. RB is a remarkably chemotherapy-sensitive tumor. Chemotherapy is currently used as a first-line approach for children with this malignancy and can be delivered by intravenous, intra-arterial, periocular, and intravitreal routes. The choice of route for chemotherapy administration depends upon the tumor laterality and tumor staging. Intravenous chemotherapy (IVC) is used most often in bilateral cases, orbital RB, and as an adjuvant treatment in high-risk RB. Intra-arterial chemotherapy (IAC) is used in cases with group C or D RB and selected cases of group E tumor. Periocular chemotherapy is used as an adjunct treatment in eyes with group D and E RB and those with persistent/recurrent vitreous seeds. Intravitreal chemotherapy is reserved for eyes with persistent/recurrent vitreous seeds. In this review, we describe the various forms of chemotherapy used in the management of RB. A database search was performed on PubMed, using the terms "RB," and "treatment," "chemotherapy," "systemic chemotherapy," "IVC," "IAC," "periocular chemotherapy," or "intravitreal chemotherapy." Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID- 25827538 TI - Uveal melanoma: estimating prognosis. AB - Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms "uvea," "iris," "ciliary body," "choroid," "melanoma," "uveal melanoma" and "prognosis," "metastasis," "genetic testing," "gene expression profiling." Relevant English language articles were extracted, reviewed, and referenced appropriately. PMID- 25827540 TI - Using risk factors for detection and prognostication of uveal melanoma. AB - The early detection of malignancy, particularly uveal melanoma, is crucial in protecting visual acuity, salvaging the eye, and preventing metastasis. Risk factors for early detection of uveal melanoma have been clearly delineated in the literature and allow identification of melanoma when it is tiny and simulates a nevus. These factors include thickness >2 mm, presence of subretinal fluid (SRF), symptoms, the orange pigment, margin near optic disc, acoustic hollowness, surrounding halo, and absence of drusen. The importance of early detection is realized when one considers melanoma thickness, as each millimeter increase in melanoma thickness imparts 5% increased risk for metastatic disease. Newer imaging modalities like enhanced depth imaging optical coherence tomography and fundus autoflouroscence facilitate in detection of SRF and orange pigment. Additional molecular biomarkers and cytological features have been identified which can predict the clinical behavior of a small melanocytic lesion. Features that suggest a poor prognosis include higher blood levels of tyrosinase m-RNA, vascular endothelial growth factor, insulin-like growth factor; monosomy 3 and gains in chromosome 8. Management of uveal melanoma includes enucleation (for large), local eye wall resection, brachytherapy, charged particle irradiation, and thermotherapy (for small to medium tumors). Although the role of a good clinical evaluation cannot be underestimated, it is advisable to evaluate the various radiological, molecular, and cytological features, to enhance the accuracy of early diagnosis and improved prognosis. PMID- 25827541 TI - Review of spectral domain enhanced depth imaging optical coherence tomography of tumors of the choroid. AB - BACKGROUND: Spectral domain enhanced depth imaging optical coherence tomography (EDI-OCT) can provide anatomic localization of intraocular tumors. AIMS: The aim was to identify topographical and intrinsic patterns of choroidal tumors on EDI OCT. SETTINGS AND DESIGN: Retrospective review. MATERIALS AND METHODS: Analysis of published reports and personal observations using office based EDI-OCT. RESULTS: Using EDI-OCT, choroidal nevus displayed a smooth, dome-shaped topography with overlying retinal pigment epithelium alterations, drusen, and occasional subretinal cleft demonstrating photoreceptor loss. Small choroidal melanoma showed smooth, moderately dome-shaped topography, commonly with overlying shallow subretinal fluid that often depicted "shaggy" photoreceptors. Choroidal metastasis showed a minimally "lumpy, bumpy" surface topography and with overlying subretinal fluid and shaggy photoreceptors. Choroidal hemangioma showed a smooth, dome-shaped topography, with expansion of the affected small, medium, and large choroidal vessels. Choroidal lymphoma showed varying topography with increasing tumor thickness as "flat, rippled, or undulating (seasick)" surface. Choroidal osteoma displayed a smooth undulating surface with visible intralesional horizontal lines suggestive of bone lamellae and occasional horizontal and vertical tubules with intralesional "spongy" flecks. Choroidal melanocytosis appeared as uniformly thickened choroid with increased stromal density surrounding the normal choroidal vascular structures. CONCLUSIONS: Enhanced depth imaging-OCT can depict characteristic patterns that are suggestive of various choroidal tumors. PMID- 25827542 TI - Choroidal metastases: origin, features, and therapy. AB - The choroid is the most common ocular site for metastatic disease, owing to abundant vascular supply. The primary cancers that most commonly lead to choroidal metastases include breast cancer (40-47%) and lung cancer (21-29%). Bilateral, multifocal metastases are most often secondary to breast cancer, whereas unilateral, unifocal metastasis are more commonly found with lung cancer. The treatment of choroidal metastasis depends on the systemic status of the patient and number, location, and laterality of the choroidal tumors. Treatment options include observation in patients with poor systemic status or those with resolved or asymptomatic disease; systemic chemotherapy, immunotherapy, hormone therapy, or whole eye radiotherapy if the metastases are active, multifocal and bilateral; plaque radiotherapy, transpupillary radiotherapy, or photodynamic therapy for active, solitary metastasis; and enucleation for those with blind painful eye. A database search was performed on PubMed, using the terms "choroidal metastasis," or "choroidal metastases," in combination with terms such as "treatment," "features," or "diagnosis." Relevant articles were extracted and reviewed. PMID- 25827543 TI - Review of spectral domain-enhanced depth imaging optical coherence tomography of tumors of the retina and retinal pigment epithelium in children and adults. AB - BACKGROUND: Spectral domain (SD) enhanced depth imaging optical coherence tomography (EDI-OCT) is a useful tool for anatomic, cross-sectional imaging of retinal conditions. AIMS: The aim was to identify characteristic patterns of retinal and retinal pigment epithelial tumors on EDI-OCT in children and adults. SETTINGS AND DESIGN: Retrospective review. MATERIALS AND METHODS: Analysis of published reports and personal observations using office-based EDI-OCT for adults and portable hand-held SD OCT for infants and children. RESULTS: Using EDI-OCT, retinal tumors such as small retinoblastoma, astrocytic hamartoma, and hemangioblastoma arose abruptly from the retina, immediately adjacent to normal retina. Small exophytic retinoblastoma and retinal hemangioblastoma showed the full-thickness, homogeneous retinal disorganization with surrounding normal retina "draping" over the margins. Retinoblastoma occasionally had intralesional cavities and surrounding subretinal fluid. Hemangioblastoma often had adjacent intraretinal edema and subretinal fluid. Astrocytic hamartoma arose within the nerve fiber layer and sometimes with a "moth-eaten" or cavitary appearance. Retinal pigment epithelial (RPE) lesions such as congenital hypertrophy of RPE appeared flat with shadowing, occasional subretinal cleft, and abrupt photoreceptor loss. Congenital simple hamartoma showed an abrupt elevation from the inner retina with crisp, dark posterior shadowing. Combined hamartoma of the retina/RPE showed vitreoretinal traction causing "sawtooth mini-peak" or gently "maxi-peak" folding of the retina. RPE adenoma often produces remote macular edema or epiretinal membrane and the tumor has an irregular, "rugged" surface with deep shadowing. CONCLUSIONS: Enhanced depth imaging optical coherence tomography shows characteristic patterns that are suggestive of certain retinal and RPE tumors. PMID- 25827544 TI - Vascular tumors of the choroid and retina. AB - Vascular tumors of the retina and choroid can be seen occasionally. In the following article, the key clinical and diagnostic features of the major retinal and choroidal vascular tumors, their systemic associations, and the literature pertaining to the most currently available treatment strategies are reviewed. PMID- 25827545 TI - The role of intravitreal chemotherapy for retinoblastoma. AB - Targeted therapy in retinoblastoma (RB) is widely accepted as the current management tool with an aim of increasing drug availability at the tumor location. Inevitably the effect is several times higher compared to systemic delivery of chemotherapeutic drugs and carries less systemic toxicity. Despite tremendous advancement in saving life, eye salvage in advanced RB especially with active vitreous seeds remains a challenge. The hypoxic environment of the vitreous and reduced vitreous concentration of the drugs delivered makes these tumor seeds resistant to chemotherapy. Direct delivery of chemotherapeutic drugs into the vitreous cavity aids to overcome these challenges and is progressively being accepted worldwide. However, intraocular procedure in RB was abandoned due to high risk of extraocular tumor dissemination. Recently, the forbidden therapeutic technique was re-explored and modified for safe use. Although eye salvage rate has tremendously improved after intravitreal chemotherapy (IVitC), retinal toxicity, and vision salvage are yet to be validated. In our preliminary report of intravitreal melphalan in 11 eyes, we reported 100% eye salvage and 0% recurrence with an extended 15 months mean follow-up. In this review, we analyzed published reports on IVitC in RB via PubMed, Medline, and conference proceedings citation index, electronic database search, without language restriction that included case series and reports of humans and experimental animal eyes with RB receiving IVitC. PMID- 25827546 TI - Chromatic-achromatic perimetry in four clinic cases: Glaucoma and diabetes. AB - BACKGROUND: Some diseases that affect the visual system may show loss of chromatic-achromatic sensitivity before obvious physical signs appear in the usual examination of the eye's posterior segment. A perimetric study has been conducted with four typical patients with glaucoma and diabetes, at different stages of the disease. MATERIALS AND METHODS: In addition to the standard white on-white (standard automated perimetry [SAP]), a test battery has been used to study patient's contrast sensitivity, using stimuli with different chromatic, spatial, and temporal content (multichannel perimetry). The choice of stimuli tries to maximize the response of different visual mechanisms: Achromatic (parvocellular and magnocellular origin); chromatic red-green (parvocellular origin); and chromatic blue-yellow (koniocellular origin). RESULTS: The results seem to indicate losses in the achromatic-parvocellular perimetry and both chromatic perimetry tests, undetected by conventional SAP. CONCLUSIONS: Our results illustrate that our patients without visible retinal alterations show signs of suspicion in multichannel perimetry. PMID- 25827547 TI - Quality of sunglasses available in the Iranian market; a study with emphasis on sellers' license. AB - CONTEXT: Sunglasses should follow minimum requirements to sufficiently protect eyes. It is not known whether all items obtainable from the market are appropriately designed. AIMS: To compare ultraviolet (UV)-protective properties of commercially available sunglasses obtained from authorized and unauthorized Iranian sellers. Settings and Study Design: An analytic-descriptive study performed in a metropolitan area (Tehran). MATERIALS AND METHODS: Using a UV visible standard spectrophotometer, the percentage transmittance was scanned between 280 and 400 nm in 348 pairs of nonprescription sunglasses (price range: 20-80 US$) obtained anonymously and randomly from authorized (permitted by the Ministry of Health, 189 pairs) and unauthorized (159 pairs) sellers in the Iranian capital city, Tehran. The Australian/New Zealand Standard (AS/NZS) and the American National Standards Institute [ANSI] standards were followed. STATISTICAL ANALYSIS: Chi-square test, independent samples t-test or Mann-Whitney U-test. Results UV-protective properties of the sunglasses obtained from authorized sellers complied with AS/NZS and ANSI guidelines in 92.6% and 95.2% of items, respectively. The corresponding rates for sunglasses obtained from unauthorized sellers were 0% and 8.2%, respectively (P < 0.001 for both). The rate of defective polarizing capability of lenses was 27.4% in sunglasses obtained from authorized sellers versus 90.4% in sunglasses obtained from unauthorized sellers (P < 0.001). Neither brand nor price played significant contributions to UV protection/lens polarizing capability of sunglasses obtained from authorized sellers. CONCLUSIONS: Sunglasses provided by unauthorized sellers are alarmingly unreliable and could be potentially hazardous for the eye. Brand and price do not guarantee optimal protection against UV radiation or polarizing performance of the lens. PMID- 25827548 TI - Photorefractive keratectomy in mild to moderate keratoconus: outcomes in over 40 year-old patients. AB - BACKGROUND: Keratoconus is a contraindication for photorefractive keratectomy (PRK). In the recent decade, some efforts have been made to perform PRK in patients with keratoconus whose corneas are stable naturally or by doing corneal collagen crosslinking. These studies have suggested residual central corneal thickness (CCT) >=450 MUm. AIMS: The aim was to evaluate the long-term outcomes of PRK in patients with mild to moderate keratoconus in patients older than 40 with residual CCT >= 400 MUm. SETTINGS AND DESIGN: This prospective study was conducted in our Cornea Research Center, Mashhad, Iran. MATERIALS AND METHODS: Patients over 40 years old, with a grade I/II keratoconus without progression in the last 2 years were recruited. Patients with a predicted postoperative CCT < 400 MUm were excluded. PRK with tissue saving protocol was performed with Tecnolas 217 Z. Mitomycin-C was applied after ablation. The final endpoints were refraction parameters the last follow-up visit (mean: 35 months). Paired t-test and Chi-square were used for analysis. RESULTS: A total of 38 eyes of 21 patients were studied; 20 eyes (52.6%) with a grade I and 18 eyes (47.4%) with grade II keratoconus. The mean uncorrected visual acuity, best corrected visual acuity (BCVA), spherical equivalent, cylindrical power and keratometric readings were significantly improved at the final endpoint compared to preoperation measurements (P < 0.001). Two eyes (5%) lost two lines of BCVA at the final visit. No case of ectasia occurred during the follow-up course. CONCLUSIONS: PRK did not induce keratoconus progression in patients older than 40 with a grade I/II keratoconus. Residual CCT >= 450 MUm seems to be sufficient to prevent the ectasia. PMID- 25827549 TI - Angiographic and spectral domain optical coherence tomography features in case of Vogt-Koyanagi-Harada disease. PMID- 25827550 TI - A case of subretinal tubercular abscess presenting as disc edema. AB - We report a case of ocular tuberculosis (TB) which initially presented with disc edema and was mistaken for optic neuritis. With no definite pathology being identified, the patient was treated on the lines of optic neuritis with intravenous (IV) steroid with beneficial effect. Ocular TB was suspected when he presented later with a subretinal abscess. Based on positive Mantoux, QuantiFERON TB gold results and radiographic findings, a diagnosis of subretinal abscess of presumed tubercular etiology was made. The patient was successfully treated with anti-tubercular therapy. To the best of our knowledge, this is the first case report of ocular TB presenting as disc edema followed by subretinal abscess. PMID- 25827551 TI - Human papillomavirus 52 positive squamous cell carcinoma of the conjunctiva. AB - Human papillomavirus (HPV) infection is strongly associated with several human cancers; the most known genotypes involved being HPV 16 and HPV 18. We report the detection of HPV 52 in a sample taken from a 47-year-old patient with squamous cell carcinoma of the conjunctiva of the left eye. The method used for the detection of HPV was real time polymerase chain reaction. The evolution was favorable after surgical removal of the tumor and the patient was explained that long-term follow-up is essential to avoid recurrence. PMID- 25827552 TI - Regarding fundus imaging with a mobile phone: a review of techniques. PMID- 25827553 TI - Water drinking test and angle closure glaucoma. PMID- 25827554 TI - Comment on: central corneal thickness and intraocular pressure in premature and full-term newborns. PMID- 25827555 TI - Human ocular thelaziasis in Karnataka. PMID- 25827556 TI - Comment on: endoilluminator-assisted scleral buckling: our results. PMID- 25827558 TI - Automated diabetic retinopathy imaging in Indian eyes: a pilot study: erratum. PMID- 25827557 TI - Comment on: refractive outcome analyses in myopes. PMID- 25827559 TI - History of fat grafting: from ram fat to stem cells. AB - Fat injection empirically started 100 years ago to correct contour deformities mainly on the face and breast. The German surgeon Eugene Hollaender (1867-1932) proposed a cocktail of human and ram fat, to avoid reabsorption. Nowadays, fat injection has evolved, and it ranks among the most popular procedures, for it provides the physician with a range of aesthetic and reconstructive clinical applications with regenerative effects on the surrounding tissues. New research from all over the world has demonstrated the role of adipose-derived stem cells, present in the adipose tissue, in the repair of damaged or missing tissues. PMID- 25827560 TI - Adipose tissue and stem/progenitor cells: discovery and development. AB - "Adipose tissue is a valuable, exploitable, appealing source of regenerative cells that can be used for a variety of clinical challenges. This article reviews the history of the development of adipose-derived cell science, particularly in the context of tissue engineering and regenerative medicine. It describes some of the advancements made in the field, as well as highlighting challenges and obstacles." PMID- 25827561 TI - Adipose stem cells: biology, safety, regulation, and regenerative potential. AB - This article discusses adipose-derived stem cell (ASC) biology, describes the current knowledge in the literature for the safety and regulation of ASCs, and provides a brief overview of the regenerative potential of ASCs. It is not an exhaustive listing of all available clinical studies or every study applying ASCs in tissue engineering and regenerative medicine, but is an objective commentary of these topics. PMID- 25827562 TI - How does fat survive and remodel after grafting? AB - Autologous fat grafting has become an important procedure for volumization and revitalization, although clinical outcomes depend greatly on technique. It was revealed recently how grafted fat tissue survives, regenerates, or dies. Experimental results provided the underlying mechanism and clinical implications for therapeutic strategies to maximize the effects of fat grafting, minimize necrosis, and avoid oil cyst formation. PMID- 25827563 TI - Condensation of tissue and stem cells for fat grafting. AB - Aspirated fat contains unnecessary components such as water, oil, and blood cells. For better outcomes, tissue purification and condensation are useful, especially when injection volume to the recipient site is limited. Because aspirated fat is relatively poor in adipose-derived stem/stromal cells (ASCs), ASC condensation seems important for obtaining better regeneration and retention. Reducing tissue volume by removing some adipocytes or supplementation of stromal vascular fraction or ASCs can increase the ASC/adipocyte ratio in the graft. Clinical results of ASC supplementation remain controversial, but ASC condensation seems to lead to expanding applications of fat grafting into revitalization of stem cell-depleted tissue. PMID- 25827564 TI - Can we standardize the techniques for fat grafting? AB - Fat grafting still remains technique dependent with possible less favorable long term results because there are no standardized techniques used by the surgeon to perform the procedure. In this article, the authors have tried to standardize the techniques for fat grafting as first proposed and popularized by Coleman. These techniques, supported by the most recent scientific studies and understandings of clinical course following autologous fat transplantation, emphasize proper fat harvesting, processing, and placement so that a predictable long-lasting result can be achieved. PMID- 25827565 TI - Update on cryopreservation of adipose tissue and adipose-derived stem cells. AB - This article first discusses some fundamentals of cryobiology and challenges for cell and tissue cryopreservation. Then, the results of cryopreservation of adipose cells and tissues, including adipose-derived stem cells, in the last decade are reviewed. In addition, from the viewpoint of cryobiology, some desired future work in fat cryopreservation is proposed that would benefit the optimization, standardization, and better application of such techniques. PMID- 25827566 TI - Fat grafting in facial rejuvenation. AB - Patients with significant facial atrophy and age-related loss of facial fat generally achieve suboptimal improvement from both surface treatments of facial skin and surgical lifts. Restoring lost facial volume by fat grafting is a powerful technique that is now acknowledged by most plastic surgeons and other physicians engaged in treating the aging face as one of the most important advances in aesthetic surgery. Properly performed, the addition of fat to areas of the face that have atrophied because of age or disease can produce a significant and sustained improvement in appearance that is unobtainable by other means. PMID- 25827567 TI - Gluteal augmentation with fat grafting: the Brazilian buttock technique: 30 years' experience. AB - The author started injecting large quantities of fat in the breasts, thighs, and buttocks in 1985. The Brazilian Buttock technique was first presented in 1987; since then, The author has been writing and lecturing about it worldwide. In the past few years, the technique became very popular; it has changed the ideal of beauty in many countries. Recently, The author started using adipose-derived stem cell-based therapies for buttock augmentation to improve the results of fat graft survival. PMID- 25827568 TI - Fat grafting for treatment of burns, burn scars, and other difficult wounds. AB - This article presents the authors' 3-year experience with the use of fat grafting, via the Coleman technique, for the adjuvant treatment of burn wounds, venous ulcers, diabetic ulcers, and burn scars. It demonstrates the regenerative effects of fat injected under the scar, and of fat injected under the wound, in the periphery of the wound, and within a bone fracture line or space, and of fat deposited over the wound. PMID- 25827569 TI - Fat grafting: current concept, clinical application, and regenerative potential, part 1. PMID- 25827570 TI - Genetically Modified Foods and Consumer Perspective. AB - Genetically modified food is able to oppose the world's hunger and preserve the environment, even if the patents in this matter are symptomatic of several doubts. And also, transgenic consumption causes problems and skepticism among consumers in several European countries, but above all in Italy, where there is a strong opposition over recent years. So, the present study conducted a research to study the consumption of genetically modified food products by Italian young generation. This research presented the following purposes: firstly, to analyze genetically modified products' consumption among a particular category of consumers; secondly, to implement a quantitative model to understand behaviour about this particular kind of consumption and identify the factors that determine their purchase. The proposed model shows that transgenic consumption is especially linked to knowledge and impact on environment and mankind's health. PMID- 25827571 TI - Secretome analysis identifies novel signal Peptide peptidase-like 3 (Sppl3) substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways. AB - Signal peptide peptidase-like 3 (Sppl3) is a Golgi-resident intramembrane cleaving protease that is highly conserved among multicellular eukaryotes pointing to pivotal physiological functions in the Golgi network which are only beginning to emerge. Recently, Sppl3 was shown to control protein N glycosylation, when the key branching enzyme N-acetylglucosaminyltransferase V (GnT-V) and other medial/trans Golgi glycosyltransferases were identified as first physiological Sppl3 substrates. Sppl3-mediated endoproteolysis releases the catalytic ectodomains of these enzymes from their type II membrane anchors. Protein glycosylation is a multistep process involving numerous type II membrane bound enzymes, but it remains unclear whether only few of them are Sppl3 substrates or whether Sppl3 cleaves many of them and thereby controls protein glycosylation at multiple levels. Therefore, to systematically identify Sppl3 substrates we used Sppl3-deficient and Sppl3-overexpression cell culture models and analyzed them for changes in secreted membrane protein ectodomains using the proteomics "secretome protein enrichment with click sugars (SPECS)" method. SPECS analysis identified numerous additional new Sppl3 candidate glycoprotein substrates, several of which were biochemically validated as Sppl3 substrates. All novel Sppl3 substrates adopt a type II topology. The majority localizes to the Golgi network and is implicated in Golgi functions. Importantly, most of the novel Sppl3 substrates catalyze the modification of N-linked glycans. Others contribute to O-glycan and in particular glycosaminoglycan biosynthesis, suggesting that Sppl3 function is not restricted to N-glycosylation, but also functions in other forms of protein glycosylation. Hence, Sppl3 emerges as a crucial player of Golgi function and the newly identified Sppl3 substrates will be instrumental to investigate the molecular mechanisms underlying the physiological function of Sppl3 in the Golgi network and in vivo. Data are available via ProteomeXchange with identifier PXD001672. PMID- 25827573 TI - Radon and thoron concentrations in public workplaces in Brisbane, Australia. AB - Radon and thoron are radioactive gases that can emanate from soil and building materials, and it can accumulate in indoor environments. The concentrations of radon and thoron in the air from various workplace categories in Brisbane, Australia were measured using an active method. The average radon and thoron concentrations for all workplace categories were 10.5 +/- 11.3 and 8.2 +/- 1.4 Bq m(-3), respectively. The highest radon concentration was detected in a confined area, 86.6 +/- 6.0 Bq m(-3), while the maximum thoron level was found in a storage room, 78.1 +/- 14.0 Bq m(-3). At each site, the concentrations of radon and thoron were measured at two heights, 5 cm and 120 cm above the floor. The effect of the measurement heights on the concentration level was significant in the case of thoron. The monitoring of radon and thoron concentrations showed a lower radon concentration during work hours than at other times of the day. This can be attributed to the ventilation systems, including the air conditioner and natural ventilation, which normally operate during work hours. The diurnal variation was less observed in the case of thoron, as the change in its concentration during and after the working hours was insignificant. The study also investigated the influence of the floor level and flooring type on indoor radon and thoron concentrations. The elevated levels of radon and thoron were largely found in basements and ground floor levels and in rooms with concrete flooring. PMID- 25827572 TI - "And now for the good news..." the impact of negative and positive messages in self-management education for people with Type 2 diabetes: A qualitative study in an ethnically diverse population. AB - OBJECTIVES: To explore the impact of Diabetes Education and Self Management for Ongoing and Newly Diagnosed (DESMOND) Foundation education, particularly from interviewees' narratives regarding recall of good and bad news messages and behaviour changes. METHODS: In-depth, semi-structured interviews were conducted with a purposive sample (n=19) of people who had attended education sessions as part of a randomised controlled trial in two UK sites with ethnically diverse populations. Data collection and analysis were informed by the constant comparative approach and facilitated through charting. RESULTS: Findings were similar in people from different ethnic backgrounds. Exploration of levels of recall of the sessions suggested that this was variable and sometimes very limited, but that interviewees had all assimilated some relevant learning. Key themes emerged relating to the way in which interviewees recalled and had been influenced by positive (good news) and negative (bad news) messages within the education sessions, including biomedical explanations. Both types of message appeared to have an important role in terms of motivation to change behaviour, but a notable observation was that none of the interviewees recalled receiving bad news messages when diagnosed. DISCUSSION: Our findings have highlighted the importance of providing and combining both negative and positive messages within education designed to promote self-management behaviour change. PMID- 25827574 TI - The effect of bicarbonate on the microbial dissolution of autunite mineral in the presence of gram-positive bacteria. AB - Bacteria are key players in the processes that govern fate and transport of contaminants. The uranium release from Na and Ca-autunite by Arthrobacter oxydans strain G968 was evaluated in the presence of bicarbonate ions. This bacterium was previously isolated from Hanford Site soil and in earlier prescreening tests demonstrated low tolerance to U(VI) toxicity compared to other A. oxydans isolates. Experiments were conducted using glass serum bottles as mixed bioreactors and sterile 6-well cell culture plates with inserts separating bacteria cells from mineral solids. Reactors containing phosphorus-limiting media were amended with bicarbonate ranging between 0 and 10 mM and meta-autunite solids to provide a U(VI) concentration of 4.4 mmol/L. Results showed that in the presence of bicarbonate, A. oxydans G968 was able to enhance the release of U(VI) from Na and Ca autunite at the same capacity as other A. oxydans isolates with relatively high tolerance to U(VI). The effect of bacterial strains on autunite dissolution decreases as the concentration of bicarbonate increases. The results illustrate that direct interaction between the bacteria and the mineral is not necessary to result in U(VI) biorelease from autunite. The formation of secondary calcium-phosphate mineral phases on the surface of the mineral during the dissolution can ultimately reduce the natural autunite mineral contact area, which bacterial cells can access. This thereby reduces the concentration of uranium released into the solution. This study provides a better understanding of the interactions between meta-autunite and microbes in conditions mimicking arid and semiarid subsurface environments of western U.S. PMID- 25827575 TI - Effects of radiocesium inventory on (137)Cs concentrations in river waters of Fukushima, Japan, under base-flow conditions. AB - To investigate the behavior of nuclear accident-derived (137)Cs in river water under base-flow conditions, concentrations of dissolved and particulate (137)Cs were measured at 16 sampling points in seven rivers of Fukushima Prefecture, Japan, in 2012 and 2013. The concentration of dissolved (137)Cs was significantly correlated with the mean (137)Cs inventory in the catchment area above each sampling point in both sampling years. These results suggest that the concentration of dissolved (137)Cs under base-flow conditions is primarily determined by the (137)Cs inventory of the catchment area above the sampling point. However, the concentration of particulate (137)Cs did not show a clear relationship with either the mean (137)Cs inventory or the dissolved (137)Cs concentration, thus indicating that particulate and dissolved forms do not effectively interact in rivers. To evaluate the contribution of the (137)Cs inventory within catchment areas, we analyzed relations between the (137)Cs concentration and the mean (137)Cs inventory over the area within certain flow path lengths that were traced along the river and slope above the sampling point. Coefficients of determination for dissolved (137)Cs concentrations were highest for the longest flow path, i.e., the whole catchment area, and lower for shorter flow paths. Coefficients of determination for particulate (137)Cs concentrations were only moderately high for the shortest flow path in 2012, whereas the values were quite low for all flow paths in 2013. These results suggest that dissolved (137)Cs can originate from a larger area of the catchment even under base-flow conditions; however, particulate (137)Cs did not show such behavior. The results also show that under base-flow conditions, dissolved and particulate (137)Cs behave independently during their transport from river catchments to the ocean. PMID- 25827576 TI - Migration of (137)Cs, (90)Sr, and (239+240)Pu in Mediterranean forests: influence of bioavailability and association with organic acids in soil. AB - The understanding of downward migration of anthropogenic radionuclides in soil is a key factor in the assessment of their environmental behavior. There are several factors that can affect this process, such as the radionuclide source, their chemical form, soil and environmental characteristics, etc. Two Mediterranean pinewood ecosystems in Spain, which were affected mainly by global fallout, were selected to assess the migration of (137)Cs, (90)Sr, and (239+240)Pu. Using auxiliary modeling (diffusion-convection equation and compartmental model), it followed from field observations that the migration velocities of (90)Sr and (239+240)Pu were similar and higher than that of (137)Cs. The downward migration of radionuclides can be considered a consequence of their association with soil particles. A sequential speciation procedure also confirmed that (90)Sr was the most bioavailable radionuclide followed by (239+240)Pu and (137)Cs. Although this can explain the different velocity of (90)Sr and (137)Cs, bioavailability could not explain by itself the similar velocities of (239+240)Pu and (90)Sr. The presence of organic acids in the soil can also influence the migration of radionuclides attached to them, which decreased in the order: (239+240)Pu > (90)Sr > (137)Cs. Thus, the joint consideration of bioavailable and humic + fulvic acid fractions can explain the observed differences in the downward velocities. PMID- 25827577 TI - Returning land contaminated as a result of radiation accidents to farming use. AB - An assessment is given of the possibility of sorbents based on natural aluminosilicates (glauconite and clinoptilolite) being used for remediation of radioactively contaminated land with the aim of returning it to farming use. A comparative study of selectivity and reversibility of radiocaesium and radiostrontium sorption by natural aluminosilicates as well as by modified ferrocyanide sorbents based on these aluminosilicates was made. It was found that surface modification of aluminosilicates by ferrocyanides increases the selectivity of synthesized sorbents to caesium by 100-1000 times, increases sorption capacity and makes caesium sorption almost irreversible, whereas, selectivity of these sorbents to strontium radionuclides remains approximately the same as for natural aluminosilicates. The caesium distribution coefficient for mixed nickel-potassium ferrocyanide on glauconite is 10((5.0+/-0.6)) L kg( 1), the static exchange capacity (SEC) is 63 mg g(-1); for mixed nickel-potassium ferrocyanide based on clinoptilolite caesium distribution coefficients in various concentration ranges are 10((7.0+/-1.0)), 10((5.7+/-0.4)) and 10((3.2+/-0.7)) L kg(-1), total SEC was 500 mg g(-1). Caesium leaching by various leaching solutions from saturated mixed nickel-potassium ferrocyanide based on clinoptilolite was lower than 2%; from saturated mixed nickel-potassium ferrocyanide based on glauconite it was 1.5-14.6%. Ferrocyanide sorbents, based on glauconite and clinoptilolite are recommended for remediation of land, contaminated by caesium as a result of the Fukushima accident in Japan. Use of these sorbents should decrease the transfer of caesium to agricultural vegetation up to a factor of 20. PMID- 25827578 TI - A carbon nanotube/poly [Ni-(Protoporphyrin IX)] composite for amperometric detection of long chain aliphatic amines. AB - Poly [Ni-Protoporphyrin] film (pNiPP), containing multiwall carbon nanotubes (MWCNT) was used to cover a glassy carbon electrode. The hybrid material (pNiPP/MWCNT) successfully combines the permselectivity of pNiPP with the high conductivity of MWCNT. The modified electrode was used to perform amperometric detection of long chain aliphatic amines (LCAA) in order to prevent the passivation effect of the aliphatic chain. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) demonstrated that the pNiPP/MWCNT facilitates the electron transfer reaction. The charge transfer resistance (Rct) values were significantly lower by up to one order of magnitude compared to the bare electrode. Differential pulse polarography (DPP) showed a marked decrease of the overpotential generated by the aliphatic chain. The calibration of the amperometric peak area vs. concentrations of derivatized LCAA exhibits a linear response within the range of 0.018 and 28 MUM and correlation coefficient (R(2)) higher than 0.999 (n=5). The quantitation limit of the pNiPP/MWCNT electrode is about 400 times lower than the UV-visible detection. RSD of 7.2%, 5.8%, 2.5% and 2.3% was obtained for concentrations of 0.028, 0.28, 2.8 and 28 MUM of ferrocenyl octadecylamine. A solution of sphingosine, 0.23 MUM, was exclusively detected with HPLC-ECD with pNiPP/MWCNT electrode. PMID- 25827579 TI - Surviving a flood: effects of inundation period, temperature and embryonic development stage in locust eggs. AB - The Australian plague locust, Chortoicetes terminifera (Walker), is an important agricultural pest and oviposits into compacted soil across vast semi-arid and arid regions prone to irregular heavy summer rainfall. This study aimed to quantify the effects of flooding (control, 7, 14, 21, 28 and 35 days) at different temperatures (15, 20 and 25 degrees C) and embryonic development stages (25 and 75%) on egg viability, hatchling nymph body mass and survival to second instar. Egg viability after flooding was dependent on temperature and flood duration. Eggs inundated at 15 degrees C showed >=53.5% survival regardless of flood duration and development stage compared with <=29.6% for eggs at 25 degrees C for >=21 days early in development and >=14 days late in development. Hatchling nymphs did not differ in body mass relative to temperature or flood duration, but weighed more from eggs inundated early in development rather than late. Survival to second-instar was <=55.1% at 15 and 20 degrees C when eggs were flooded for >=28 days late in development, <=35.6% at 25 degrees C when flooded for >=28 days early in development, and zero when flooded for >=21 days late in development. These results suggest that prolonged flooding in summer and early autumn may cause very high egg mortality and first-instar nymph mortality of any survivors, but is likely to only ever affect a small proportion of the metapopulation. More common flash flooding for <=14 days is unlikely to cause high mortality and have any direct effect on distribution and abundance. PMID- 25827580 TI - Pericytes, mesenchymal stem cells and their contributions to tissue repair. AB - Regenerative medicine using mesenchymal stem cells for the purposes of tissue repair has garnered considerable public attention due to the potential of returning tissues and organs to a normal, healthy state after injury or damage has occurred. To achieve this, progenitor cells such as pericytes and bone marrow derived mesenchymal stem cells can be delivered exogenously, mobilised and recruited from within the body or transplanted in the form organs and tissues grown in the laboratory from stem cells. In this review, we summarise the recent evidence supporting the use of endogenously mobilised stem cell populations to enhance tissue repair along with the use of mesenchymal stem cells and pericytes in the development of engineered tissues. Finally, we conclude with an overview of currently available therapeutic options to manipulate endogenous stem cells to promote tissue repair. PMID- 25827581 TI - Anion-exchange chromatography of phosphopeptides: weak anion exchange versus strong anion exchange and anion-exchange chromatography versus electrostatic repulsion-hydrophilic interaction chromatography. AB - Most phosphoproteomics experiments rely on prefractionation of tryptic digests before online liquid chromatography-mass spectrometry. This study compares the potential and limitations of electrostatic repulsion-hydrophilic interaction chromatography (ERLIC) and anion-exchange chromatography (AEX). At a pH higher than 5, phosphopeptides have two negative charges per residue and are well retained in AEX. However, peptides with one or two phosphate groups are not separated from peptides with multiple Asp or Glu residues, interfering with the identification of phosphopeptides. At a pH of 2, phosphate residues have just a single negative charge but Asp and Glu are uncharged. This facilitates the separation of phosphopeptides from unmodified acidic peptides. Singly phosphorylated peptides are retained weakly under these conditions, due to electrostatic repulsion, unless hydrophilic interaction is superimposed in the ERLIC mode. Weak anion-exchange (WAX) and strong anion-exchange (SAX) columns were compared, with both peptide standards and a HeLa cell tryptic digest. The SAX column exhibited greater retention at pH 6 than did the WAX column. However, only about 60% as many phosphopeptides were identified with SAX at pH 6 than via ERLIC at pH 2. In one ERLIC run, 12 467 phosphopeptides were identified, including 4233 with more than one phosphate. We conclude that chromatography of phosphopeptides is best performed at low pH in the ERLIC mode. Under those conditions, the performances of the SAX and WAX materials were comparable. The data have been deposited with the ProteomeXchange with identifier PXD001333. PMID- 25827583 TI - What is microcirculatory shock? AB - PURPOSE OF REVIEW: Microcirculatory shock is a condition defined by the presence of tissue hypoperfusion despite the normalization of systemic and regional blood flow. In this article, we discuss the characteristics of the microcirculation in septic shock, the main form of microcirculatory shock, along with its interaction with systemic hemodynamics, and the response to different therapies. RECENT FINDINGS: In septic shock, microcirculatory abnormalities are common, and more severe in nonsurvivors. In addition, the microcirculation shows a behavior that is frequently dissociated from that of systemic hemodynamics. Therefore, microcirculatory alterations may persist despite correction of systemic hemodynamic variables. Sublingual and intestinal microcirculation might also display divergent behaviors. Moreover, microvascular alterations may improve in response to hemodynamic resuscitation, but the response might depend on the underlying microcirculatory alterations. Particularly, the response to fluids seems to be related to both its basal state and the magnitude of the increase in cardiac output. SUMMARY: The optimal treatment of microcirculatory shock might require monitoring and therapeutic goals targeted on the microcirculation, more than in systemic variables. The clinical benefits of this approach should be demonstrated in clinical trials. PMID- 25827582 TI - Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel. AB - Paclitaxel is a chemotherapeutic agent widely used for treating carcinomas. Patients receiving paclitaxel often develop neuropathic pain and have a reduced quality of life which hinders the use of this life-saving drug. In this study, we determined the role of GABA transporters in the genesis of paclitaxel-induced neuropathic pain using behavioral tests, electrophysiology, and biochemical techniques. We found that tonic GABA receptor activities in the spinal dorsal horn were reduced in rats with neuropathic pain induced by paclitaxel. In normal controls, tonic GABA receptor activities were mainly controlled by the GABA transporter GAT-1 but not GAT-3. In the spinal dorsal horn, GAT-1 was expressed at presynaptic terminals and astrocytes while GAT-3 was only expressed in astrocytes. In rats with paclitaxel-induced neuropathic pain, the protein expression of GAT-1 was increased while GAT-3 was decreased. This was concurrently associated with an increase in global GABA uptake. The paclitaxel induced attenuation of GABAergic tonic inhibition was ameliorated by blocking GAT 1 but not GAT-3 transporters. Paclitaxel-induced neuropathic pain was significantly attenuated by the intrathecal injection of a GAT-1 inhibitor. These findings suggest that targeting GAT-1 transporters for reversing disinhibition in the spinal dorsal horn may be a useful approach for treating paclitaxel-induced neuropathic pain. Patients receiving paclitaxel for cancer therapy often develop neuropathic pain and have a reduced quality of life. In this study, we demonstrated that animals treated with paclitaxel develop neuropathic pain, have enhancements of GABA transporter-1 protein expression and global GABA uptake, as well as suppression of GABAergic tonic inhibition in the spinal dorsal horn. Pharmacological inhibition of GABA transporter-1 ameliorates the paclitaxel induced suppression of GABAergic tonic inhibition and neuropathic pain. Thus, targeting GAT-1 transporters for reversing GABAergic disinhibition in the spinal dorsal horn could be a useful approach for treating paclitaxel-induced neuropathic pain. PMID- 25827584 TI - Lung volume assessment in acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: Measurements of lung volumes allow evaluating the pathophysiogical severity of acute respiratory distress syndrome (ARDS) in terms of the degree of reduction in aerated lung volume, calculating strain, quantifying recruitment and/or hyperinflation, and gas volume distribution. We summarize the current techniques for lung volume assessment selected according to their possible usage in the ICU and discuss the recent findings obtained with implementation of these techniques in patients with ARDS. RECENT FINDINGS: Computed tomography technique remains irreplaceable in terms of quantitative aeration of different lung regions, but the commonly used cut-offs for classification may be questioned with recent findings on nonpathological lungs. Monitoring end expiratory lung volume using nitrogen washout technique enhanced our understanding on lung volume change during positioning, pleural effusion drainage, intra-abdominal hypertension, and recruitment maneuver. Recent studies supported that tidal volume could not surrogate tidal strain, which needs measurement of functional residual capacity and which is correlated with pro inflammatory lung response. SUMMARY: Although lung volume measurements are still limited to research area of ARDS, recent progress in technology provides clinicians more opportunities to evaluate lung volumes noninvasively at the bedside and may facilitate individualization of ventilator settings based on the specific physiological understandings of a given patient. PMID- 25827585 TI - Clinical assessment of peripheral circulation. AB - PURPOSE OF REVIEW: Monitoring of the peripheral circulation can be done noninvasively in contrast to the more traditional invasive systemic haemodynamic monitoring in the intensive care unit. Physical examination of peripheral circulation based on clinical assessment has been well emphasized for its convenience, accessibility, and relation to the prognosis of patients with circulatory shock. The purpose of this article is to highlight the main findings according to recent literature into the clinical applications of the peripheral perfusion assessment in patient management. RECENT FINDINGS: Clinical assessment of peripheral circulation includes physical examination by inspecting the skin for pallor or mottling, and measuring capillary refill time on finger or knee. Studies have addressed the capillary refill time assessment in adults and its relation to normal range, body site, effect of skin temperature, and its reliability among examiners. These are easily applicable methods in many circumstances, and it has been used for predicting unfavourable outcomes in critically ill adult patients. Current studies are ongoing to determine the effects of different interventions on the clinical parameters of peripheral circulation in critically ill patients during shock resuscitation. SUMMARY: The feasibility and reproducibility of the clinical assessment of peripheral circulation are substantial, and reliance on capillary refill time, skin temperature, and mottling score must be emphasized and exploited. Incorporating therapeutic strategies into resuscitation protocols that aim at normalizing these peripheral circulation parameters are being developed to investigate the impact of peripheral perfusion-targeted resuscitation in the survival of critically ill patients. PMID- 25827586 TI - How to monitor a recruitment maneuver at the bedside. AB - PURPOSE OF REVIEW: To provide an overview on most recent knowledge on methods currently available for monitoring of recruitment maneuvers at the bedside. RECENT FINDINGS: The effects of recruitment maneuvers on clinical outcomes in patients with moderate to severe acute respiratory distress syndrome and in patients with healthy lungs undergoing major surgery were recently assessed. Despite being part of a multifaceted approach of protective ventilation, recruitment maneuvers are supposed to decrease mortality and improve postoperative outcomes. However, the role of recruitment maneuver remains controversial in routine practice owing to concerns regarding complications, especially its effects on hemodynamics. In addition, although recruitment maneuvers are being increasingly used, there remains a great deal of uncertainty regarding the precise way to evaluate the effect of recruitment.An effective recruitment maneuver is expected to reinflate nonaerated lung units. End expiratory lung volume, compliance, dead space, volumetric capnography, and bedside imaging techniques such as lung ultrasound and electrical impedance tomography have all different strengths and weaknesses. A multimodal and multiparametric approach could be a valuable option for bedside monitoring of recruitment maneuvers both in the ICU and in the operative room. SUMMARY: Several methods offer evaluation of lung recruitability and allow the monitoring of positive and negative effects of recruitment maneuvers. More than the type of method used, a multifaceted approach of monitoring of recruitment maneuvers should be regarded. PMID- 25827587 TI - Continuous noninvasive hemoglobin monitoring: ready for prime time? AB - PURPOSE OF REVIEW: Determination of hemoglobin (Hb) concentration is essential for the detection of anemia and hemorrhage and is widely used to evaluate a patient for a possible blood transfusion. Although commonly accepted as intrinsic to the process, traditional laboratory measurements of Hb are invasive, intermittent, and time-consuming. Noninvasive Hb (NIHb)-monitoring devices have recently become available and promise the potential for detecting sudden changes in a patient's Hb level. In addition to reduced delays in clinical intervention, these devices also allow for a reduction in patient discomfort, infection risk, required personnel, and long-term costs. Unfortunately, it has been shown that many clinical factors can influence their accuracy. RECENT FINDINGS: Many studies have been published on the accuracy and precision of NIHb-monitoring devices in various clinical settings. A recent meta-analysis has shown a small mean difference but wide limits of agreement between NIHb and laboratory measurements, indicating that caution should be used by physicians when making clinical decisions based on this device. SUMMARY: NIHb measurements may currently be considered to be a supplemental tool for monitoring trends in Hb concentration, but are not currently developed enough to replace an invasive approach. Moreover, further studies are still required before implementing NIHb in the clinical decision-making process. Specifically, no studies have demonstrated that this technology improves clinical outcomes or patient safety. PMID- 25827589 TI - Controlled drug release from hydrogel-based matrices: Experiments and modeling. AB - Controlled release by oral administration is mainly achieved by pharmaceuticals based on hydrogels. Once swallowed, a matrix made of hydrogels experiences water up-take, swelling, drug dissolution and diffusion, polymer erosion. The detailed understanding and quantification of such a complex behavior is a mandatory prerequisite to the design of novel pharmaceuticals for controlled oral delivery. In this work, the behavior of hydrogel-based matrices has been investigated by means of several experimental techniques previously pointed out (gravimetric, and based on texture analysis); and then all the observed features were mathematically described using a physical model, defined and recently improved by our research group (based on balance equations, rate equations and swelling predictions). The agreement between the huge set of experimental data and the detailed calculations by the model is good, confirming the validity of both the experimental and the theoretical approaches. PMID- 25827590 TI - Does sodium intake affect the relationship between blood pressure and vascular damage? AB - INTRODUCTION: Although the differences between central and peripheral blood pressure (BP) values have been known for decades, the consequences of decision making based on peripheral rather than central BP have only recently been recognized. Recently, a U-shaped relation between sodium intake and cardiovascular risk has been suggested. OBJECTIVES: The aim of the study was to evaluate the relationship between intima-media thickness (IMT) and central and peripheral BP as well as the effect of 24-hour urinary sodium excretion on this relationship. PATIENTS AND METHODS: The study included 182 subjects (mean age, 37.3 +/-14.0 years, 92 men and 90 women) who were members of families randomly selected from one of the gminas (administrative regions) in southern Poland. In all patients, peripheral and central BP (using applanation tonometry), IMT, and 24-hour sodium excretion were measured. RESULTS: Hypertension was observed in 44.5% of the participants. The mean urinary sodium excretion was 243 +/-81 mmol/d. IMT was significantly more correlated with central pulse pressure (PP) compared with peripheral PP (r = 0.54 vs r = 0.27; P <0.01). After multivariate adjustments, IMT remained significantly related to central systolic BP and central and peripheral PP. When the study group was divided according to the tertiles of sodium excretion, central PP was related to IMT only in the second and third tertiles. When the study group was divided according to sex and sex specific median values of sodium excretion, IMT was associated with central PP only in subjects with sodium excretion exceeding the median values (both in men and women). CONCLUSIONS: IMT is more correlated with central than with peripheral BP. The association between IMT and central PP may be modulated by sodium intake. This hypothesis should be tested in larger studies. PMID- 25827591 TI - Localization of annexins A1 and A2 in the respiratory tract of healthy calves and those experimentally infected with Mannheimia haemolytica. AB - Annexins A1 and A2 are proteins known to function in the stress response, dampening inflammatory responses and mediating fibrinolysis. We found, in healthy cattle recently arrived to a feedlot, that lower levels of these proteins correlated with later development of pneumonia. Here we determine the localization of annexin A1 and A2 proteins in the respiratory tract and in leukocytes, in healthy calves and those with Mannheimia haemolytica pneumonia. In healthy calves, immunohistochemistry revealed cytoplasmic expression of annexin A1 in the surface epithelium of large airways, tracheobronchial glands and goblet cells, to a lesser degree in small airways, but not in alveolar epithelium. Immunocytochemistry labeled annexin A1 in the cytoplasm of neutrophils from blood and bronchoalveolar lavage fluid, while minimal surface expression was detected by flow cytometry in monocytes, macrophages and lymphocytes. Annexin A2 expression was detected in surface epithelium of small airways, some mucosal lymphocytes, and endothelium, with weak expression in large airways, tracheobronchial glands and alveolar septa. For both proteins, the level of expression was similar in tissues collected five days after intrabronchial challenge with M. haemolytica compared to that from sham-inoculated calves. Annexins A1 and A2 were both detected in leukocytes around foci of coagulative necrosis, and in necrotic cells in the center of these foci, as well as in areas outlined above. Thus, annexins A1 and A2 are proteins produced by airway epithelial cells that may prevent inflammation in the healthy lung and be relevant to development of pneumonia in stressed cattle. PMID- 25827592 TI - In vitro effects of binuclear (eta (6)-p-cymene)ruthenium(II) complex containing bridging bis(nicotinate)-polyethylene glycol ester ligand on differentiation pathways of murine Th lymphocytes activated by T cell mitogen. AB - T cell differentiation into distinct T helper (Th) subpopulations is crucial in governing acquired immune responses as well as some inflammatory and autoimmune disorders. This study investigated potential of the novel neutral binuclear ruthenium(II) complexes 1-8 with general formula [{RuCl2(eta(6)-p-cym)}2MU (N(?)N)] (N(?)N = bis(nicotinate)- and bis(iso-nicotinate)-polyethylene glycol esters; (3-py)COO(CH2CH2O) n CO(3-py) and (4-py)COO(CH2CH2O) n CO(4-py); n = 1 4), as well as [RuCl2(eta(6)-p-cym)(nic)] (R1, nic = nicotinate) and [RuCl2(eta(6)-p-cym)(inic)] (R2, inic = isonicotinate) as an immunomodulatory agents capable to direct Th cell differentiation. From all investigated complexes, [{RuCl2(eta(6)-p-cym)}2MU-{(3-py)COO(CH2CH2O)4CO(3-py)}] (4) was selected for further study because it did not affect splenocyte viability (in concentration up to 50 MUM), but significantly reduced secretion of representative Th1 cytokine, IFN-gamma induced by T cell mitogen. Besides IFN gamma, 4 inhibited dose dependently expression and production of representative Th17 cytokine, IL-17, in these cells. Otherwise, the production of anti inflammatory cytokines IL-4 and IL-10 was upregulated. Also, 4 significantly increased CD4(+)CD25(+)FoxP3(+) Treg cell frequency in the activated splenocytes. Moreover, ConA-induced expression of Th1 transcription factors, T-bet and STAT1, as well as of Th17-related protein STAT3 was attenuated upon exposure to 4, while the expression of Th2-related transcription factor GATA3 remained stable. In conclusion, ruthenium(II) complex 4 modulates immune system cell functions in vitro by inhibiting T cell differentiation towards pathogenic Th1/Th17 phenotype and inducing a regulatory phenotype characterized by IL-10 and IL-4 production, which may provide novel therapeutic opportunities for immune-inflammatory and/or autoimmune disorders. PMID- 25827593 TI - Conformational dynamics of metallo-beta-lactamase CcrA during catalysis investigated by using DEER spectroscopy. AB - Previous crystallographic and mutagenesis studies have implicated the role of a position-conserved hairpin loop in the metallo-beta-lactamases in substrate binding and catalysis. In an effort to probe the motion of that loop during catalysis, rapid-freeze-quench double electron-electron resonance (RFQ-DEER) spectroscopy was used to interrogate metallo-beta-lactamase CcrA, which had a spin label at position 49 on the loop and spin labels (at positions 82, 126, or 233) 20-35 A away from residue 49, during catalysis. At 10 ms after mixing, the DEER spectra show distance increases of 7, 10, and 13 A between the spin label at position 49 and the spin labels at positions 82, 126, and 233, respectively. In contrast to previous hypotheses, these data suggest that the loop moves nearly 10 A away from the metal center during catalysis and that the loop does not clamp down on the substrate during catalysis. This study demonstrates that loop motion during catalysis can be interrogated on the millisecond time scale. PMID- 25827594 TI - Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise. AB - Dysregulated anabolic responses to nutrition/exercise may contribute to sarcopenia; however, these characteristics are poorly defined in female populations. We determined the effects of two feeding regimes in older women (66 +/- 2.5 yr; n = 8/group): bolus whey protein (WP-20 g) or novel low-dose leucine enriched essential amino acids (EAA) [LEAA; 3 g (40% leucine)]. Using [(13)C6]phenylalanine infusions, we quantified muscle (MPS) and albumin (APS) protein synthesis at baseline and in response to both feeding (FED) and feeding plus exercise (FED-EX; 6 * 8 knee extensions at 75% 1-repetition maximum). We also quantified plasma insulin/AA concentrations, whole leg (LBF)/muscle microvascular blood flow (MBF), and muscle anabolic signaling by phosphoimmunoblotting. Plasma insulinemia and EAA/aemia were markedly greater after WP than LEAA (P < 0.001). Neither LEAA nor WP modified LBF in response to FED or FED-EX, whereas MBF increased to a similar extent in both groups only after FED-EX (P < 0.05). In response to FED, both WP and LEAA equally stimulated MPS 0-2 h (P < 0.05), abating thereafter (0-4 h, P > 0.05). In contrast, after FED-EX, MPS increased at 0-2 h and remained elevated at 0-4 h (P < 0.05) with both WP and LEAA. No anabolic signals quantifiably increased after FED, but p70 S6K1 Thr(389) increased after FED-EX (2 h, P < 0.05). APS increased similarly after WP and LEAA. Older women remain subtly responsive to nutrition +/- exercise. Intriguingly though, bolus WP offers no trophic advantage over LEAA. PMID- 25827596 TI - Further consideration in evaluation of right ventricular infarction. PMID- 25827595 TI - Clinical diagnosis of influenza in the ED. AB - BACKGROUND: Timely and accurate diagnosis of influenza remains a challenge but is critical for patients who may benefit from antiviral therapy. This study determined the test characteristics of provider diagnosis of influenza, final ED electronic medical record (EMR) diagnosis of influenza, and influenza-like illness (ILI) in patients recommended to receive antiviral treatment according to Centers for Disease Control and Prevention (CDC) guidelines. In addition, we evaluated the compliance with CDC antiviral guidelines. METHODS: A prospective cohort of adults presenting to a tertiary care ED with an acute respiratory illness who met CDC criteria for recommended antiviral treatment were enrolled and tested for influenza. A clinical diagnosis of influenza was assessed by asking the clinician: "Do you think this patient has influenza?" Influenza-like illness was defined according to current CDC criteria. RESULTS: In this cohort of 270 subjects, 42 (16%; 95% confidence interval [CI], 11%-20%) had influenza. Clinician diagnosis had a sensitivity of 36% (95% CI, 22%-52%) and specificity of 78% (95% CI, 72%-83%); EMR final ED diagnosis had a sensitivity of 26% (95% CI, 14%-42%) and specificity of 97% (95% CI, 94%-99%); ILI had a sensitivity of 31% (95% CI, 18%-47%) and specificity of 88% (95% CI, 83%-92%). Only 15 influenza positive patients (36%) received antiviral treatment. CONCLUSION: Clinician diagnosis, final ED EMR diagnosis, and ILI have low sensitivity for diagnosing influenza, and there is overall poor compliance with CDC antiviral treatment recommendations. Improved methods of influenza diagnosis are needed to help guide management in the clinical setting. PMID- 25827597 TI - Comparison of the efficacy of diclofenac, acupuncture, and acetaminophen in the treatment of renal colic. AB - OBJECTIVE: The objective is to compare the analgesic effects of diclofenac, acetaminophen, and acupuncture in urolithiasis-driven renal colic pain relief. METHODS: Renal colic patients were divided randomly into 3 groups. Patients in group I (n = 40) were treated with intravenous acetaminophen, those in group II (n = 41) with acupuncture, and those in group III (n = 40) with a 75-mg intramuscular injection diclofenac sodium. Visual analogue scale (VAS) and verbal rating scale (VRS) were used to assess pain intensity after 10, 30, 60, and 120 minutes. RESULTS: No significant differences in baseline VAS or VRS were found with regard to age or sex. After 10 minutes, all 3 groups experienced a significant decrease in VAS and VRS scores, with the most drastic decrease occurring in group II. After 30 minutes, there was a significantly higher decrease in group III than in group I (P = .001). After 60 minutes, mean VAS scores of groups I and III (P = .753) were similar. The mean VAS score of group III was lower than that of group II (P = .013). After 120 minutes, the difference in the VAS scores was (P = .000) between groups I and II and between groups II and III. Yet, the VAS evaluation made after 120 minutes revealed statistically similar outcomes for groups I and III (P = .488). The statistical findings for VRS evaluations made after 10, 30, 60, and 120 were similar to those for VAS. CONCLUSIONS: In renal colic patients with a possible nonsteroidal anti inflammatory drug and acetaminophen side effect risk, acupuncture emerges as an alternative treatment modality. PMID- 25827598 TI - K2 types and their contents: are product disclosures true? PMID- 25827599 TI - Shared rules of development predict patterns of evolution in vertebrate segmentation. AB - Phenotypic diversity is not uniformly distributed, but how biased patterns of evolutionary variation are generated and whether common developmental mechanisms are responsible remains debatable. High-level 'rules' of self-organization and assembly are increasingly used to model organismal development, even when the underlying cellular or molecular players are unknown. One such rule, the inhibitory cascade, predicts that proportions of segmental series derive from the relative strengths of activating and inhibitory interactions acting on both local and global scales. Here we show that this developmental design rule explains population-level variation in segment proportions, their response to artificial selection and experimental blockade of putative signals and macroevolutionary diversity in limbs, digits and somites. Together with evidence from teeth, these results indicate that segmentation across independent developmental modules shares a common regulatory 'logic', which has a predictable impact on both their short and long-term evolvability. PMID- 25827600 TI - A prospective clinical study to evaluate the performance of zirconium dioxide dental implants in single-tooth gaps. AB - INTRODUCTION: Dental implants have traditionally been made from titanium or its alloys, but recently full-ceramic implants have been developed with comparable osseointegration properties and functional strength properties to titanium. These ceramic implants may have advantages in certain patients and situations, for example, where esthetic outcomes are particularly important. OBJECTIVE: The objective of this investigation was to evaluate the performance of a newly developed full-ceramic ZrO2 monotype implant design (PURE Ceramic Implant; Institut Straumann AG, Basel, Switzerland) in single-tooth gaps in the maxilla and mandible. MATERIAL AND METHODS: This was a prospective, open-label, single arm study in patients requiring implant rehabilitation in single-tooth gaps. Full ceramic implants were placed, with provisional and final prostheses inserted after 3 and 6 months, respectively. Crestal bone level was measured at implant placement and after 6 and 12 months. Implant survival and success were evaluated after 6 and 12 months. Further evaluations are planned after 24 and 36 months. RESULTS: Forty-six patients were screened for potential study participation, of whom 44 (17 men and 27 women, mean age 48 +/- 14 years) were recruited into the study. The majority of implants (90.9%) were placed in the maxilla. The implant survival and implant success rate after 12 months were 97.6%. A minor change of the mean bone level occurred between implant loading (final prosthesis insertion after 6 months) and 12 months (-0.14 mm) after initial bone remodeling was observed between implant placement and loading (-0.88 mm). CONCLUSIONS: The results indicated that monotype ceramic implants can achieve clinical outcomes comparable to published outcomes of equivalent titanium implants. PMID- 25827601 TI - Sweetless'n low LDL-C targets for PCSK9 treatment. PMID- 25827603 TI - Yes, hyperglycaemia is indeed a modifiable cardiac risk factor: so says Mendel. PMID- 25827605 TI - Correlations between phytohemagglutinin response and leukocyte profile, and bactericidal capacity in a wild rodent. AB - Phytohemagglutinin (PHA)-induced swelling is widely used to investigate cell mediated and innate immunity across different vertebrate taxa. However, its physiological mechanism is still an open question due to the complexity of the involved immune components. In the present study, we measured the synchronous variations of PHA response, the proportion of different subtypes of leukocytes, as well as serum bactericidal capacity in circulation blood at 6, 12 and 24 h after PHA versus PBS injection in striped hamster, Cricetulus barabensis. First, the results showed that PHA responses reached a peak at 6 h postinjection, then sharply declined at 12 h and 24 h postinjection. Serum bactericidal capacity was higher at 6 h and 12 h than at 24 h. The proportion of different subtypes of leukocytes, as well as the ratio of neutrophils to lymphocytes did not display significant changes across different time points. Second, PHA response was positively correlated with the proportion of neutrophils and serum bactericidal capacity. The proportion of monocytes was negatively correlated with that of eosinophils and neutrophils. The proportion of basophils was negatively correlated with that of lymphocytes. Our results indicate that earlier enhanced PHA response is important for the striped hamster to cope with changing environmental conditions due to its small body mass, and the increased components of innate immunity in circulation blood may contribute to the enhancement of PHA swelling response. PMID- 25827604 TI - Does radiotherapy have an impact on the thickness of the puborectal muscle? PMID- 25827602 TI - Haeme oxygenase signalling pathway: implications for cardiovascular disease. AB - Evidence now points to the haeme oxygenase (HO) pathway as a possible actor in modulating risk for cardiovascular disease (CVD). In particular, the HO pathway may represent a key endogenous modulator of oxidative, inflammatory, and cytotoxic stress while also exhibiting vasoregulatory properties. In this review, we summarize the accumulating experimental and emerging clinical data indicating how activity of the HO pathway and its products may play a role in mechanisms underlying the development of CVD. We also identify gaps in the literature to date and suggest future directions for investigation. Because HO pathway activity can be influenced not only by genetic traits and environmental stimuli but also by a variety of existing pharmacologic interventions, the pathway could serve as a prime target for reducing the overall burden of CVD. Further work is needed to determine the role of HO pathway products as possible prognostic markers of risk for clinical CVD events and the extent to which therapeutic augmentation or inhibition of HO pathway activity could serve to modify CVD risk. PMID- 25827606 TI - Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics. AB - Polyoxin and nikkomycin are naturally occurring peptidyl nucleoside antibiotics with potent antifungal bioactivity. Both exhibit similar structural features, having a nucleoside skeleton and one or two peptidyl moieties. Combining the refactoring of the polyoxin producer Streptomyces aureochromogenes with import of the hydroxypyridylhomothreonine pathway of nikkomycin allows the targeted production of three designer nucleoside antibiotics designated as nikkoxin E, F, and G. These structures were determined by NMR and/or high resolution mass spectrometry. Remarkably, the introduction of an extra copy of the nikS gene encoding an ATP-dependent ligase significantly enhanced the production of the designer antibiotics. Moreover, all three nikkoxins displayed improved bioactivity against several pathogenic fungi as compared with the naturally occurring antibiotics. These data provide a feasible model for high efficiency generation of nucleoside antibiotics related to polyoxins and nikkomycins in a polyoxin cell factory via synthetic biology strategy. PMID- 25827607 TI - A randomized controlled evaluation study of the effects of a one-day advanced rider training course. AB - Motorcyclists have a relative high risk of crash involvement. As a consequence there is an on-going search for safety measures to improve road safety for motorcyclists. One popular measure is motorcycle training. Although intuitively sound, there are only few thorough studies on rider training courses and they do not always show a positive safety effect. The aim of this study was to assess the effects of the advanced rider training course 'Risk'. Through random assignment motorcyclists (N=222) were assigned to an experimental and control condition. At pre- and post-test, participants completed a questionnaire and their riding behaviour was assessed in an on-road ride. Furthermore, a selection of participants took a hazard perception test at post-test. Participants in the experimental condition (n=137) followed the advanced training course 'Risk' between pre- and post-test. RESULT: s indicated that trained participants were rated higher on safe riding than the control group. A positive effect was also found for riding behaviour, i.e., speed and position on the road if it needed to be adapted to increase visibility and in reaction to potential hazard. The training did not affect riders' assessment of their own riding behaviour. Overall the trained riders performed better on the hazard perception test. This study is a step forward to demonstrate that motorcyclists' traffic behaviour can be positively influenced by the right training course. Crucial for this training course is that it did not lead to overconfidence, while it quantifiably improved traffic behaviour. PMID- 25827608 TI - Relationships of diet-related blood parameters and blood lead levels with psychopathology and aggression in forensic psychiatric inpatients. AB - BACKGROUND: Earlier studies have suggested associations between diet-related blood parameters and both aggression and psychopathological symptoms, but little is known about this in forensic psychiatric inpatients. AIM: This article aims to explore the levels of diet-related blood parameters and their relationship to aggressive behaviour and/or psychopathology among Dutch forensic psychiatric inpatients. METHODS: Minerals, vitamins, lead and fatty acid levels were measured in blood samples from 51 inpatients, well enough to consent and participate in the study, from a possible total of 99. Levels of aggression and psychopathology were assessed using questionnaires, observation instruments and clinical data. Associations between blood parameters and behavioural measures were calculated. RESULTS: Low average levels of vitamin D3 and omega (omega)-3 fatty acids were found, with nearly two-thirds of the patients having below recommended levels of D3 , while vitamin B6 levels were high. Magnesium, iron, zinc, copper and lead were overall within reference values, but copper/zinc ratios were high. Several significant associations between levels of fatty acid measures and both aggression and psychopathology were observed. CONCLUSION: In our sample of forensic psychiatric inpatients, fatty acids - but not mineral or vitamin levels were associated with aggression and psychopathology. A potentially causal link between fatty acids and aggression could be tested in a randomised, placebo controlled trial of fish oil supplements. General health of such patients might be improved by better vitamin D status (increased sun exposure and/or supplement use) and better omega-3 fatty acid status (oily fish or fish oil consumption), but discouraging unnecessary self-prescription of B vitamins where necessary. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25827609 TI - Embodied harms: gender, shame, and technology-facilitated sexual violence. AB - Criminality in cyberspace has been the subject of much debate since the 1990s, yet comparatively little attention has been paid to technology-facilitated sexual violence and harassment (TFSV). The aim of this article is to explore the ways in which retraditionalized gender hierarchies and inequalities are manifested in online contexts, and to conceptualize the cause and effects of TFSV as "embodied harms." We argue that problematic mind/body and online/off-line dualisms result in a failure to grasp the unique nature of embodied harms, precluding an adequate understanding and theorization of TFSV. PMID- 25827610 TI - Letter to the Editor. PMID- 25827611 TI - Social and health care professionals' views on responsible agency in the process of ending intimate partner violence. AB - This article examines social and health care professionals' views, based on their encounters with both victims and perpetrators, on the division of responsibility in the process of ending intimate partner violence. Applying discourse analysis to focus group discussions with a total of 45 professionals on solutions to the problem, several positions of responsible agency in which professionals place themselves and their clients are identified. The results suggest that one key to understanding the complexities involved in violence intervention lies in a more adequate theorization of the temporal and intersubjective dimensions of the process of assigning responsibility for the problem. PMID- 25827612 TI - Pain experience of adults with intellectual disabilities--caregiver reports. AB - BACKGROUND: Pain is a problem for individuals with intellectual and developmental disability (IDD), secondary to their impairments, due to invasive medical procedures that these individuals undergo on a regular basis. Current literature indicates pain as a common experience for children with IDD, yet no such reports have been made in regard to adults with IDD. PURPOSES: This study aimed (1) to re establish the reliability of caregivers as proxy observers; (2) to evaluate the pain experience of adults with IDD by caregivers' proxy report; and (3) to assess the sensitivity of the Non-Communicating Adult Pain Checklist (NCAPC) as a pain scale for chronic pain (CP) in individuals with IDD. METHOD: Frothy-three caregivers, working for more than 3 years with adults with IDD, performed pain assessments of 187 individuals living in a residential facility. Two caregivers evaluated whether each resident suffers from pain and assessed the intensity, causes and duration of pain experience. Furthermore, 52/187 residents [26 with CP and 26 pain free (PF) based on medical record and caregiver reports] were evaluated by an additional seven caregivers using the NCAPC in order to establish the reliability of caregivers as proxy observers. RESULTS: According to caregivers' report, 48% of adults with IDD suffer from pain at a mean level of 6/10, with more than 10% suffering from high levels of pain on a constant basis. Inter-rater agreement was found mostly high with intraclass correlation values ranging between 0.73 and 0.93. Using the NCAPC, we were able to identify CP and PF individuals with a significant score difference (P = 0.003). CONCLUSIONS: The results support the use of the NCAPC as a scale to evaluate CP in adults with IDD. The findings reiterate the reliability of caregivers as proxy observers and the importance of involving them in identifying pain behaviours of their protegees. Our findings reiterate the need for an immediate action for appropriate pain management protocols for adult with IDD. PMID- 25827613 TI - DESI MS based screening method for phthalates in consumer goods. AB - Phthalates are used as plasticizes in many everyday items, but some of them are known as hormone disruptors, being especially harmful during childhood. The European Union therefore restricted their application in children's toys and certain food packaging to 0.1%w. Due to the ever increasing number of plastic containing consumer goods, rapid screening methods are needed to ensure and improve consumer safety in the future. In this study we evaluated the performance of desorption electrospray ionization (DESI) mass spectrometry (MS) for rapid quantitative screening of phthalates in toys. DESI allowed for direct surface sampling of the toys under atmospheric conditions with minimal sample preparation, while the high performance mass spectrometer used provided a high sensitivity and reliable identification via accurate mass measurements, high mass resolving power and MS/MS capabilities. External calibration curves for six banned phthalates (DBP, BBP, DEHP, DNOP, DINP and DIDP) were obtained from matrix matched reference materials. Coefficients of determination were greater than 0.985, LOQs ranged from 0.02%w (DIDP) to 2.26%w (DINP) and the relative standard deviation of the calibration curve slope was less than 7.8% for intraday and 11.4% for interday comparison. The phthalate contents of eleven authentic samples were determined in a proof-of-concept approach using DESI MS and results were compared to those from confirmatory methods. The phthalate content was correctly assigned with relative deviations ranging from -20% to +10% for the majority of samples. Given further optimization and automation, DESI MS is likely to become a useful tool for rapid and accurate phthalate screening in the future. PMID- 25827614 TI - Nitric oxide for anammox recovery in a nitrite-inhibited deammonification system. AB - The anaerobic ammonium oxidation (anammox) process is widely used for N-rich wastewater treatment. In the current research the deammonification reactor in a reverse order (first anammox, then the nitrifying biofilm cultivation) was started up with a high maximum N removal rate (1.4 g N m(-2) d(-1)) in a moving bed biofilm reactor. Cultivated biofilm total nitrogen removal rates were accelerated the most by anammox intermediate - nitric oxide (optimum 58 mg NO-N L(-1)) addition. Furthermore, NO was added in order to eliminate inhibition caused by nitrite concentrations (>50 mg [Formula: see text]) increasing [Formula: see text] (2/1, respectively) along with a higher ratio of [Formula: see text] (0.6/1, respectively) than stoichiometrical for this optimal NO amount added during batch tests. Planctomycetales clone P4 sequences, which was the closest (98% and 99% similarity, respectively) relative to Candidatus Brocadia fulgida sequences quantities increase to 1 * 10(6) anammox gene copies g(-1) total suspended solids to till day 650 were determined by quantitative polymerase chain reaction. PMID- 25827615 TI - Dermoscopy of drug-induced aquagenic wrinkling phenomenon. PMID- 25827616 TI - Spectroscopic and electrochemical properties of group 12 acetates of di-2 pyridylketone thiophene-2-carboxylic acid hydrazone (dpktch-H) complexes. The structure of [Cd(eta3-N,N,O-dpktch-H)2]. AB - The reaction between [dpktch] and [M(OAc)2] (M=group 12 metal atom) in refluxing CH3CN gave [M(eta(2)-O,O-OAc)(eta(3)-N,N,O-dpktch-H)].nH2O (n=0 or 1). The infrared and (1)H NMR spectra are consistent with the coordination of [eta(2)-O,O OAc] and [eta(3)-N,N,O-dpktch-H](-) and the proposed formulations. The electronic absorption spectra of [M(eta(2)-O,O-OAc)(eta(3)-N,N,O-dpktch-H)].nH2O measured in non-aqueous solvents revealed a highly intense intra-ligand-charge transfer (ILCT) transition due to pi-pi* of dpk followed by dpk->thiophene charge transfer. The electronic transitions of [M(eta(2)-O,O-OAc)(eta(3)-N,N,O-dpktch H)].nH2O are solvent and concentration dependent. Spectrophotometric titrations of dmso solutions of [M(eta(2)-O,O-OAc)(eta(3)-N,N,O-dpktch-H)].nH2O with benzoic acid revealed irreversible inter-conversion between [M(eta(2)-O,O-OAc)(eta(3) N,N,O-dpktch-H)].nH2O and it conjugate acid [M(eta(2)-O,O-OAc)(eta(3)-N,N,O dpktch)].nH2O pointing to ligand exchange between the acetate and benzoate anions. When CH2Cl2 solutions of [M(eta(2)-O,O-OAc)(eta(3)-N,N,O-dpktch-H)].nH2O were titrated with dmso, changes appeared pointing to solvolysis or ligand exchange reactions. Electrochemical measurements on dmso solutions of [M(eta(2) O,O-OAc)(eta(3)-N,N,O-dpktch-H)].nH2O divulged irreversible redox transformations consistent with electrochemical decomposition of [M(eta(2)-O,O-OAc)(eta(3)-N,N,O dpktch-H)].nH2O. The solid state structure of a single crystal of [Cd(eta(3) N,N,O-dpktch-H)2] obtained from a dmso solution of [Cd(eta(2)-O,O-OAc)(eta(3) N,N,O-dpktch-H)].nH2O confirmed the ligand scrambling of [M(eta(2)-O,O OAc)(eta(3)-N,N,O-dpktch-H)].nH2O. The extended structure of [Cd(eta(3)-N,N,O dpktch-H)2] revealed stacks of [Cd(eta(3)-N,N,O-dpktch-H)2] locked via a network of hydrogen bonds. A significant amount of empty space (35.5%) was observed in the solid state structure of [Cd(eta(3)-N,N,O-dpktch-H)2]. PMID- 25827617 TI - Effect of annealing on the luminescence properties of YVO4:Dy3+ phosphor on co doping Pb2+ ions. AB - Pb(2+) co-doped YVO4:Dy(3+) phosphors have been synthesized at a relatively low temperature of 120 degrees C via ethylene glycol route. The samples are further annealed at 500 and 900 degrees C. The prepared samples were characterized by XRD, SEM, spectra energy dispersive analysis of X-ray (EDAX) and photoluminescence spectroscopy. XRD patterns of all samples are well indexed with single tetragonal phase of YVO4. The emission intensity of Dy(3+) is significantly enhanced on co-doping Pb(2+) ions. The highest emission is obtained at 7 at.% Pb(2+) for 900 degrees C annealed samples. Both emission intensity and decay lifetime increases on annealing the samples from 500 to 900 degrees C. On co-doping Pb(2+) into YVO4:Dy(3+) phosphors, the emission color falls near the white region and then shift towards yellow region on annealing from 500 to 900 degrees C thereby indicating that annealing temperature play a role on tuning the color of the phosphors. As well as the emission color of the phosphors remain the same even on changing the excitation wavelengths from 280 nm, which would serve as potential phosphors for white emission in LED applications. PMID- 25827618 TI - Prognostic significance of ischemia location on stress myocardial perfusion SPECT: Tracing the fingerprints of the widow maker. PMID- 25827619 TI - Assessment of atherosclerosis in large vessel walls: A comprehensive review of FDG-PET/CT image acquisition protocols and methods for uptake quantification. AB - There is growing evidence showing the importance of fluorodeoxyglucose positron emission tomography (FDG-PET) in the evaluation of vessel wall inflammation and atherosclerosis. Although this imaging modality has been increasingly used, there are various methods for image acquisition and evaluating FDG uptake activity in the vessel walls and atherosclerotic lesions, including qualitative visual scaling, semi-quantitative, and quantitative evaluations. Using each of these image acquisition protocols and measurement methods may result in different findings. In this review, we are going to describe the various image acquisition methods and common measurement strategies reflected in the literature and discuss their advantages and flaws. PMID- 25827620 TI - Prognostic impact of location and extent of vessel-related ischemia at myocardial perfusion scintigraphy in patients with or at risk for coronary artery disease. AB - BACKGROUND: Myocardial perfusion scintigraphy (MPS) has an established diagnostic and prognostic role in patients with or at risk for coronary artery disease, with ischemia severity and extent having already been identified as key predictors. Whether this is affected by the location of myocardial ischemia is uncertain. We aimed at comparing the prognostic outlook of patients undergoing MPS according to the site of ischemia. METHODS: Our institutional database was queried for subjects undergoing MPS, without myocardial necrosis or recent revascularization. We focused on the prognostic impact of location of vessel-related ischemia (VRI) at MPS, distinguishing four mutually exclusive groups: single-VRI involving left anterior descending (LAD), single-VRI not involving LAD, multi-VRI involving LAD, and multi-VRI not involving LAD. The primary outcome was the long-term (>1 year) rate of death or myocardial infarction (D/MI). RESULTS: A total of 13,254 patients were included. Moderate or severe VRI occurred in 2,627 (20%) patients. Clinical outcomes were significantly different among the groups of patients with moderate or severe VRI, including death, cardiac death, non-fatal myocardial infarction or their composites (overall P < .001). Specifically, and excluding subjects undergoing revascularization as first follow-up event, D/MI occurred in 8.4% of patients with single-VRI involving LAD, 5.5% of subjects with single-VRI not involving LAD, 16.5% of those with multi-VRI involving LAD, and 7.3% of patients with multi-VRI not involving LAD (overall P < .001). Even at incremental multivariable Cox proportional analysis, hierarchical VRI was independently associated with an increased risk of D/MI [hazard ratio = 1.17 (1.04-1.08) for each class increment, P = .010]. CONCLUSIONS: Location and extent of myocardial ischemia at MPS according to the VRI concept have a hierarchical predictive impact, with multi-VRI involving LAD being significantly and independently more prognostically ominous than other types of VRI. PMID- 25827621 TI - Inflammatory features of pancreatic cancer highlighted by monocytes/macrophages and CD4+ T cells with clinical impact. AB - Pancreatic ductal adenocarcinoma (PDAC) is among the most fatal of malignancies with an extremely poor prognosis. The objectives of this study were to provide a detailed understanding of PDAC pathophysiology in view of the host immune response. We examined the PDAC tissues, sera, and peripheral blood cells of PDAC patients using immunohistochemical staining, the measurement of cytokine/chemokine concentrations, gene expression analysis, and flow cytometry. The PDAC tissues were infiltrated by macrophages, especially CD33+CD163+ M2 macrophages and CD4+ T cells that concomitantly express programmed cell death-1 (PD-1). Concentrations of interleukin (IL)-6, IL-7, IL-15, monocyte chemotactic protein-1, and interferon-gamma-inducible protein-1 in the sera of PDAC patients were significantly elevated. The gene expression profile of CD14+ monocytes and CD4+ T cells was discernible between PDAC patients and healthy volunteers, and the differentially expressed genes were related to activated inflammation. Intriguingly, PD-1 was significantly upregulated in the peripheral blood CD4+ T cells of PDAC patients. Correspondingly, the frequency of CD4+PD-1+ T cells was increased in the peripheral blood cells of PDAC patients, and this increase correlated to chemotherapy resistance. In conclusion, inflammatory conditions in both PDAC tissue and peripheral blood cells in PDAC patients were prominent, highlighting monocytes/macrophages as well as CD4+ T cells with influence of the clinical prognosis. PMID- 25827622 TI - Photodynamic antibacterial enhanced effect of methylene blue-gold nanoparticles conjugate on Staphylococcal aureus isolated from impetigo lesions in vitro study. AB - BACKGROUND: Staphylococcal aureus is the most common organism which has been encountered in impetigo infection. Gold nanoparticles can be used as a tool to deliver antimicrobials or to enhance photodynamic destruction of bacteria. OBJECTIVE: To evaluate the photodynamic effect of methylene blue gold nanoparticles (MB-gold nanoparticles conjugate) on S. aureus which were isolated from impetigo lesions. PATIENT AND METHODS: Twenty children were diagnosed clinically as impetigo, and aged from 3 to 5 years of both sexes were recruited in the study. Two bacteriological samples were collected from each patient, identified and cultured. Samples of S. aureus of a concentration of 10(-1)ml were divided into four groups. S. aureus was treated by MB-gold nanoparticles conjugate, gold nanoparticles, MB, and the fourth group served as a control group. Diode laser (660 nm) was used for photoactivation. The bacterial growth inhibition was determined by two methods: the percentage of reduction of viable bacteria count and the optical density (O.D) of bacterial growth. RESULTS: The highest significant inhibitory effect on S. aureus was obtained with MB-gold nanoparticles conjugate when irradiated by diode laser 660 nm (P < 0.0001). The percentage of viable bacteria was 3%. The photoactivated gold nanoparticles showed a significant inhibitory effect on bacterial growth (P < 0.05). A non significant inhibitory effect was elicited in other groups. CONCLUSION: The photoactivated MB-gold nanoparticles conjugate showed the maximum inhibitory effect on S. aureus activity. The gold nanoparticles proved efficacy as a drug delivery system. It enhanced the photodynamic antibacterial effect of methylene blue. PMID- 25827623 TI - Comparing two basic subtypes in OCD across three large community samples: a pure compulsive versus a mixed obsessive-compulsive subtype. AB - Due to its heterogeneous phenomenology, obsessive-compulsive disorder (OCD) has been subtyped. However, these subtypes are not mutually exclusive. This study presents an alternative subtyping approach by deriving non-overlapping OCD subtypes. A pure compulsive and a mixed obsessive-compulsive subtype (including subjects manifesting obsessions with/without compulsions) were analyzed with respect to a broad pattern of psychosocial risk factors and comorbid syndromes/diagnoses in three representative Swiss community samples: the Zurich Study (n = 591), the ZInEP sample (n = 1500), and the PsyCoLaus sample (n = 3720). A selection of comorbidities was examined in a pooled database. Odds ratios were derived from logistic regressions and, in the analysis of pooled data, multilevel models. The pure compulsive subtype showed a lower age of onset and was characterized by few associations with psychosocial risk factors. The higher social popularity of the pure compulsive subjects and their families was remarkable. Comorbidities within the pure compulsive subtype were mainly restricted to phobias. In contrast, the mixed obsessive-compulsive subtype had a higher prevalence and was associated with various childhood adversities, more familial burden, and numerous comorbid disorders, including disorders characterized by high impulsivity. The current comparison study across three representative community surveys presented two basic, distinct OCD subtypes associated with differing psychosocial impairment. Such highly specific subtypes offer the opportunity to learn about pathophysiological mechanisms specifically involved in OCD. PMID- 25827624 TI - Molecular characterization and biological effects of a CXCL8 homologue in large yellow croaker (Larimichthys crocea). AB - CXCL8 also called interleukin-8, is a CXC-type chemokine that plays a key role in promoting inflammation. Three subgroups of CXCL8 homologues have been reported in teleost fish, including CXCL8_L1, CXCL8_L2 and CXCL8_L3. In the present study, we identified a CXCL8 homologue belonging to CXCL8_L1 subgroup (LycCXCL8_L1) in large yellow croaker (Larimichthys crocea) that shares low identity to the previously reported large yellow croaker CXCL8 (LycCXCL8). The full-length cDNA of LycCXCL8_L1 is 716 nucleotides (nt) long and encodes a protein consisting of 99 amino acids (aa) with a putative molecular weight of 11.2 kDa. The deduced LycCXCL8_L1 protein contains a 22-aa signal peptide and a 77-aa mature polypeptide, which possesses an arrangement of four cysteines typical of other known CXC chemokines (C(34), C(36), C(60), and C(77)). Genomic analysis revealed that the LycCXCL8_L1 gene consisted of four exons and three introns and exhibited a similar exon-intron organization to LycCXCL8 and other species CXCL8 genes except for a different intron length. Phylogenetic analysis showed that both LycCXCL8_L1 and LycCXCL8 belong to CXCL8_L1 subgroup. LycCXCL8_L1 mRNA was constitutively expressed in all tissues examined although at different levels. Upon bacterial vaccine induction, LycCXCL8_L1 mRNA expression was rapidly increased in the spleen and head kidney tissues. Recombinant LycCXCL8_L1 and LycCXCL8 proteins produced in Escherichia coli both induced chemotaxis and superoxide production in peripheral blood leucocytes from large yellow croaker. These results indicate that two CXCL8_L1 molecules exist in large yellow croaker and play roles in inflammatory response. PMID- 25827625 TI - Hsp90, Hsp60 and sHsp families of heat shock protein genes in channel catfish and their expression after bacterial infections. AB - Heat shock proteins (Hsps) are a suite of highly conserved proteins whose expressions are generally induced by elevated temperature. However, many Hsps play important roles in both innate and adaptive immunity. On the basis of our previous work on Hsp40 and Hsp70 gene families in channel catfish (Ictalurus punctatus), the objective of this study was to characterize Hsp90, Hsp60, Hsp10, and small Hsp genes, and to investigate their expression profiles after bacterial infections. A total of 20 Hsp genes were identified and annotated in the channel catfish genome, including five Hsp90 genes, one Hsp60 gene, one Hsp10 gene, and 13 sHsp genes. Six Hsp genes were differentially expressed after Edwardsiella ictaluri infection, and 12 were differentially expressed after Flavobacterium columnare infection. Although expression of these genes exhibited both temporal and spatial regulation, the induction of Hsp genes was observed soon after bacterial infection, while the suppression of Hsp genes was observed at later time-points, suggesting their distinct roles in immune responses and disease defenses. A pathogen-specific expression pattern of Hsp90 was observed. After F. columnare infection, all Hsp90 genes were found up-regulated except Hsp90ab1, which was not significantly regulated. However, after E. ictaluri infection, only one Hsp90 gene was found significantly down-regulated. Both pathogen-specific and tissue-specific pattern of expression were observed with small Hsps after E. ictaluri and F. columnare bacterial infections. These results suggested that most of Hsp genes may play important roles in immune response and/or disease defense in channel catfish. PMID- 25827626 TI - Identification of differentially expressed proteins of brain tissue in response to methamidophos in flounder (Paralichthys olivaceus). AB - Methamidophos (MAP), an organophosphorus pesticide used around the world, has been associated with a wide spectrum of toxic effects on organisms in the environment. In this study, the flounder Paralichthys olivaceus was subjected to 10 mg/L MAP for 72 h and 144 h, and the morphological and proteomic changes in the brain were observed, analyzed and compared with those in the non-exposed control group. Under the light microscope and transmission electron microscope, MAP had evidently induced changes in or damage to the flounder tissues. Gas chromatography analysis demonstrated that the MAP residues were significantly accumulated in the flounder brain tissues. Proteomic changes in the brain tissue were revealed using two-dimensional gel electrophoresis and 27 protein spots were observed to be significantly changed by MAP exposure. The results indicated that the regulated proteins were involved in immune and stress responses, protein biosynthesis and modification, signal transduction, organismal development, and 50% of them are protease. qRT-PCR was used to further detect the corresponding change of transcription. These data may be beneficial to understand the molecular mechanism of MAP toxicity in flounder, be very useful for MAP-resistance screening in flounder culture. According to our results and analyzing, heat shock protein 90 (HSP90) and granzyme K (GzmK) had taken important part in immune response to MAP-stress and could be biomarkers for MAP-stress in flounder. PMID- 25827627 TI - Effects of dietary administration of stinging nettle (Urtica dioica) on the growth performance, biochemical, hematological and immunological parameters in juvenile and adult Victoria Labeo (Labeo victorianus) challenged with Aeromonas hydrophila. AB - We investigated effects of dietary administration of stinging nettle (Urtica dioica) on growth performance, biochemical, hematological and immunological parameters in juvenile and adult Victoria Labeo (Labeo victorianus) against Aeromonas hydrophila. Fish were divided into 4 groups and fed for 4 and 16 weeks with 0%, 1%, 2% and 5% of U. dioica incorporated into the diet. Use of U. dioica in the diet resulted in improved biochemical, hematological and immunological parameters. Among the biochemical parameters; plasma cortisol, glucose, triglyceride and cholesterol decreased while total protein and albumin in fish increased with increasing dietary inclusion of U. dioica. Among the haematology parameters: red blood cell (RBC), white blood cell (WBC) counts, haematocrit (Htc), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC) and netrophiles increased with increasing dietary inclusion levels of U. dioica, some depending on the fish age. Serum immunoglobulins, lysozyme activity and respiratory burst were the main immunological parameters in the adult and juvenile L. victorianus measured and they all increased with increasing herbal inclusion of U. dioica in the diet. Dietary incorporation of U. dioica at 5% showed significantly higher relative percentage survival (up to 95%) against A. hydrophila. The current results demonstrate that using U. dioica can stimulate fish immunity and make L. victorianus more resistant to bacterial infection (A. hydrophila). PMID- 25827628 TI - Modulation of innate immune response, mucosal parameters and disease resistance in rainbow trout (Oncorhynchus mykiss) upon synbiotic feeding. AB - The present study investigates the effects of dietary supplements of galactooligosaccharides (GOS), Pediococcus acidilactici and P. acidilactici + GOS on innate immune response, skin mucus as well as disease resistance of rainbow trout (Oncorhynchus mykiss) fingerlings (15.04 +/- 0.52 g). After 8 weeks of feeding, several innate immune (lysozyme, alternative complement and respiratory burst activities) and skin mucus parameters (bactericidal activity against Streptococcus faecium, Streptococcus iniae, Serratia marcescens, Staphylococcus aureus and Escherichia coli and mucus protein content) were studied. The results indicated that the three supplemented diet significantly increased innate immune response and skin mucus parameters in rainbow trout. The highest innate immune response, skin mucus activity as well as protein level was observed in synbiotic fed fish. Furthermore, at the end of the feeding experiment, some fish were intraperitoneally injected with Streptococcus iniae to determine the disease resistance. The mortality of fingerlings fed supplemented diet was significantly lower than fish from control group being the lowest mortality recorded in synbiotic fed fish group. PMID- 25827629 TI - Establishment of Health Utility Indices for Post-Infectious Functional Gastrointestinal Disorders in Active Duty US Military. AB - INTRODUCTION: Knowledge of disease burden attributable to functional gastrointestinal disorders (FGD) in travelers is lacking, despite the high incidence of travelers' diarrhea (TD) associated with increased FGD risk. One tool for assessing the impact of disease on health-related quality of life is the health utility index (HUI), which values health states based on preferential health outcomes. Health utilities can be used as preference weights in the estimation of quality-adjusted life-years (QALYs). METHODS: Six months following travel to Egypt or Turkey, 120 US military personnel completed a survey on TD during deployment, health-related quality of life (SF-36), and the onset of functional bowel disorders (Rome II). Elements from the SF-36 were used to develop SF-6D values, which were combined with health state valuations to enable calculation of HUI scores for each subject. Mean index scores were compared across functional outcomes, specific symptoms, and demographic profiles. RESULTS: The presence of FGD significantly reduced index scores, with irritable bowel syndrome (IBS) and dyspepsia showing the greatest impact (-0.17 and -0.19, respectively) compared with those with no FGD (p < 0.05). Importantly, however, several individuals met multiple FGD outcome definitions. Additionally, a number of symptoms associated with abnormal bowel habits and abdominal pain were associated with reduced index scores regardless of outcome. CONCLUSION: FGD are associated with significant morbidity as assessed by HUIs. Given the strong link between TD and FGD as well as the large number of travelers from the developed to the developing world, additional study is needed to further understand this association and efforts aimed at primary disease prevention are warranted. PMID- 25827630 TI - Younger and older adults weigh multiple cues in a similar manner to generate judgments of learning. AB - One's memory for past test performance (MPT) is a key piece of information individuals use when deciding how to restudy material. We used a multi-trial recognition memory task to examine adult age differences in the influence of MPT (measured by actual Trial 1 memory accuracy and subjective confidence judgments, CJs) along with Trial 1 judgments of learning (JOLs), objective and participant estimated recognition fluencies, and Trial 2 study time on Trial 2 JOLs. We found evidence of simultaneous and independent influences of multiple objective and subjective (i.e., metacognitive) cues on Trial 2 JOLs, and these relationships were highly similar for younger and older adults. Individual differences in Trial 1 recognition accuracy and CJs on Trial 2 JOLs indicate that individuals may vary in the degree to which they rely on each MPT cue when assessing subsequent memory confidence. Aging appears to spare the ability to access multiple cues when making JOLs. PMID- 25827631 TI - The ambidextrous cyclooxygenase: an enduring target. AB - With the discovery of COX, pain has not been treated in a relentless manner. Numbers of drugs with fewer side effects were discovered and are used successfully for treatment of pain. With new research coming into being since the discovery of COX, it was established that COX can be targeted not only for treatment of pain but for curing various diseases like cancer, Alzheimer's, Parkinson's disease, Glaucoma etc. With the sighting of COX-3, another isoform of COX, new diseases are being targeted for better treatment. PMID- 25827632 TI - Organic memory devices based on a bis-cyclometalated alkynylgold(III) complex. AB - A bis-cyclometalated alkynylgold(III) complex, [Au((t)BuC^N^C(t)Bu)(C=C C6H4N(C6H5)2-p)] ((t)BuHC^N^CH(t)Bu = 2,6-bis(4-tert-butylphenyl)pyridine), has been synthesized and characterized. The complex was found to exhibit rich photophysical and electrochemical properties. More interestingly, the complex has been employed in the fabrication of organic memory devices. The as-fabricated memory devices exhibited good performances with low operating voltage, high ON/OFF ratio, long retention time, and good stability. PMID- 25827634 TI - No evidence of transfusion transmission of Adenovirus and Epstein-Barr virus infections in paediatric recipients post-bone marrow transplant. AB - Adenovirus and Epstein-Barr virus can cause significant morbidity and mortality in paediatric patients post-bone marrow transplant. The source of infection is thought to be either reactivation of latent viruses or primary infection. We have investigated whether transfusion of blood components from viraemic donors could provide a route of primary infection in these patients and sought the prevalence of viraemia in the blood donor population from England. In 32 linked donor/recipient samples and 300 unselected blood donors, we found no evidence to suggest that these infections in paediatric bone marrow transplant recipients had been acquired from transfused blood components. PMID- 25827635 TI - Gas-phase VUV photoionisation and photofragmentation of the silver deuteride nanocluster [Ag10D8L6](2+) (L = bis(diphenylphosphino)methane). A joint experimental and theoretical study. AB - The bis(diphenylphosphino)methane (L = Ph2PCH2PPh2) ligated silver deuteride nanocluster dication, [Ag10D8L6](2+), has been synthesised in the condensed phase via the reaction of bis(diphenylphosphino)methane, silver nitrate and sodium borodeuteride in the methanol : chloroform (1 : 1) mixed solvent system. The photoionisation and photofragmentation of this mass-selected cluster were studied using a linear ion trap coupled to the DESIRS VUV beamline of the SOLEIL Synchrotron. At 15.5 eV the main ionic products observed are [Ag10D8L5](2+), [Ag10D8L4](2+), [Ag10D8L6](3+), [Ag9D8L4](2+), and [AgL2](+). The later two products arise from fragmentation of [Ag10D8L6](3+). An analysis of the yields of these product ions as a function of the photon energy reveals the onset for the formation of [AgL2](+) and [Ag9D8L4](2+) is around 2 eV higher than that for ionisation to produce [Ag10D8L5](3+). The onset of ionisation energy of [Ag10D8L6](2+) was determined to be 9.3 +/- 0.3 eV from a fit of the yield of the product ion, [Ag10D8L6](3+), as a function of the VUV photon energy. DFT calculations at the RI-PBE/RECP-def2-SVP level of theory were carried out to search for a possible structure of the cluster and to estimate its vertical and adiabatic ionisation energies. The calculated lowest energy structure of the [Ag10D8L6](2+) nanocluster contains a symmetrical bicapped square antiprism as a silver core in which hydrides are located as a mix of triangular faces and edges. Four of the bisphosphines bind to the edges of the cluster core as bidentate ligands, the remaining two bisphosphines bind via a single phosphorus donor atom to each of the apical silver atoms. The DFT calculated adiabatic ionisation energy for this structure is 8.54 eV, in satisfactory agreement with experiment. PMID- 25827637 TI - Relevance of tissue Doppler imaging for assessment of right ventricular performance in preterm neonates. PMID- 25827636 TI - Sonographic evidence of abnormal tracheal cartilage ring structure in cystic fibrosis. AB - OBJECTIVES/HYPOTHESIS: Tracheal cartilage ring structural abnormalities have been reported in cystic fibrosis (CF) mice and pigs. Whether similar findings are present in humans with CF is unknown. We hypothesized that tracheal cartilage ring shape and size would be different in people with CF. STUDY DESIGN: Tracheal cartilage ring size and shape were measured in adults with (n = 21) and without CF (n = 18). METHODS: Ultrasonography was used in human subjects to noninvasively assess tracheal cartilage ring structure in both the sagittal and the transverse planes. Tracheal cartilage ring thickness was also determined from histological sections obtained from newborn non-CF and CF pigs. These values were compared with human data. RESULTS: Human CF tracheas had a greater width and were less circular in shape compared to non-CF subjects. CF tracheal cartilage rings had a greater midline cross-sectional area and were thicker compared to non-CF rings. Maximal tracheal cartilage ring thickness was also greater in both newborn CF pigs and human adults with CF, compared to non-CF controls. CONCLUSIONS: Our findings demonstrate that structural differences exist in tracheal cartilage rings in adults with CF. Comparison with newborn CF pig data suggests that some of these changes may be congenital in nature. LEVEL OF EVIDENCE: 3b PMID- 25827638 TI - Theoretical Investigation of the Reaction Mechanism of the Photoisomerization of 1,2-Dihydro-1,2-azaborine. AB - The photoisomerization of 1,2-dihydro-1,2-azaborine was investigated by high level multireference ab initio and density functional theory calculations. The intermediates (IMs) and transition states (TSs) on the S(0) and S(1) states were optimized using the state-averaged complete active space self-consistent field method. The multireference configuration interaction method with the Davidson correction was used to obtain accurate energetics. Moreover, the conical intersections (CIs), which play a crucial role in photoisomerization, were also optimized. On the basis of the calculation results, the most favorable proposed reaction pathway is as follows: reactant->Franck-Condon region->TS(1) ->CI->IM(0) ->TS(0P) ->product. The product was not directly formed through the CI, and the IM(0) existed on the S(0) state. These results show that the isomerization of 1,2 dihydro-1,2-azaborine involves both photoreactions and thermal reactions. The calculated results clarify recent experimental observations. PMID- 25827639 TI - Association between preconceptional treatment with insulin pumps and improved metabolic status in early pregnancy in women with type 1 diabetes. AB - INTRODUCTION: An adverse intrauterine environment in early pregnancy in women with type 1 diabetes is associated with several perinatal complications including spontaneous abortions, fetal congenital defects, and preeclampsia. OBJECTIVES: We compared metabolic parameters in the first trimester of pregnancy between women with type 1 diabetes treated with continuous subcutaneous insulin infusion (CSII) and those treated with multiple daily injections (MDI). PATIENTS AND METHODS: A total of 168 women in the first trimester of pregnancy (33 using CSII and 135 using MDI) were enrolled in this cross-sectional single-center study. Anthropometric parameters, fasting serum levels of hemoglobin A(1c) (HbA(1c)), lipid profile, and estimated glucose disposal rate (eGDR) were determined. RESULTS: Patients did not differ in gestational or maternal age, diabetes duration, and the frequency of planned pregnancies. Women using CSII before pregnancy had lower body mass index and waist-to-hip ratio than those using MDI (22.3 vs 23.3 and 0.77 vs 0.79, respectively, P = 0.01). A similar number of women had hypertension; however, the CSII group had lower diastolic blood pressure (P = 0.02). Moreover, the CSII group had a significantly lower insulin requirement (0.54 vs 0.63 units/kg; P = 0.02), significantly higher eGDR (11.3 vs 10.5 mg/kg/min; P = 0.0007), and significantly lower serum triglyceride levels (53.1 vs 61.8 mg/dl; P = 0.004). In a multiple regression analysis, CSII therapy was associated with higher eGDR, lower HbA(1c), and lower serum triglyceride levels. CONCLUSIONS: The use of CSII before pregnancy in patients with type 1 diabetes is associated with better metabolic profile in the first trimester. PMID- 25827640 TI - Trophic factor-induced activity 'signature' regulates the functional expression of postsynaptic excitatory acetylcholine receptors required for synaptogenesis. AB - Highly coordinated and coincidental patterns of activity-dependent mechanisms ("fire together wire together") are thought to serve as inductive signals during synaptogenesis, enabling neuronal pairing between specific sub-sets of excitatory partners. However, neither the nature of activity triggers, nor the "activity signature" of long-term neuronal firing in developing/regenerating neurons have yet been fully defined. Using a highly tractable model system comprising of identified cholinergic neurons from Lymnaea, we have discovered that intrinsic trophic factors present in the Lymnaea brain-conditioned medium (CM) act as a natural trigger for activity patterns in post- but not the presynaptic neuron. Using microelectrode array recordings, we demonstrate that trophic factors trigger stereotypical activity patterns that include changes in frequency, activity and variance. These parameters were reliable indicators of whether a neuron expressed functional excitatory or inhibitory nAChRs and synapse formation. Surprisingly, we found that the post- but not the presynaptic cell exhibits these changes in activity patterns, and that the functional expression of excitatory nAChRs required neuronal somata, de novo protein synthesis and voltage gated calcium channels. In summary, our data provides novel insights into trophic factor mediated actions on neuronal activity and its specific regulation of nAChR expression. PMID- 25827641 TI - In Situ Formation of Efficient Cobalt-Based Water Oxidation Catalysts from Co(2+) Containing Tungstate and Molybdate Solutions. AB - Replacing rare and expensive noble-metal catalysts with inexpensive and earth abundant ones is of great importance to split water either electrochemically or photoelectrochemically. In this study, two amorphous cobalt oxide catalysts (Co-W film and Co-Mo film) with high activity for electrocatalytic water oxidation were prepared by fast, simple electrodeposition from aqueous solutions of Na2WO4 and Na2MoO4 containing Co(2+). In solutions of Na2WO4 and Na2MoO4, sustained anodic current densities up to 1.45 and 0.95 mA cm(-2) were obtained for Co-W film at 1.87 V versus a reversible hydrogen electrode (RHE) and Co-Mo film on fluorine doped tin oxide (FTO) substrates at 1.85 V versus RHE. For the Co-W film, a much higher current density of 4.5 mA cm(-2) was acquired by using a stainless-steel mesh as the electrode substrate. Significantly, in long-term electrolysis for 13 h, the Co-W film exhibited improved stability in cobalt-free buffer solution in comparison with the previously reported Co-Pi film. PMID- 25827642 TI - A comparison of risperidone and haloperidol for the risk of ischemic stroke in the elderly: a propensity score-matched cohort analysis. AB - OBJECTIVE: With an increase in antipsychotic use in the elderly, the safety profile of antipsychotics has been emphasized. Strong concerns have been raised about whether the risk of ischemic stroke differs between risperidone and haloperidol. This study compared the risk of ischemic stroke between elderly patients taking risperidone and haloperidol. METHOD: We conducted a retrospective cohort study using the Korea Health Insurance Review and Assessment Service database, applying a propensity-matched analysis. The cohort consisted of elderly patients who were newly prescribed haloperidol or risperidone between January 1, 2006 and December 31, 2009. Patients with prior cerebrovascular diseases (ICD-10, I60-I69), transient ischemic attack (ICD-10, G45), or cerebral tumors (ICD-10, C31) during 365 days prior to the initiation date were excluded. The study subjects were selected by propensity score matching. The outcome was defined as the first hospitalization for ischemic stroke (ICD-10, I63). Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) for ischemic stroke with haloperidol compared with risperidone use. RESULTS: A total of 14,103 patients were included in the propensity-matched cohort for each drug. Overall, the incidence rate was higher for haloperidol users compared to the risperidone users (6.43 per 1000 person-years vs. 2.88 per 1000 person-years). A substantially increased risk was observed in haloperidol users (adjusted HR = 2.02, 95% CI, 1.12-3.62). CONCLUSIONS: The evidence showed that haloperidol should be prescribed in the elderly with caution. PMID- 25827643 TI - Plasma BDNFs level initially and post treatment in acute mania: comparison between ECT and atypical antipsychotic treatment and healthy controls. AB - BACKGROUND: Inconsistent findings concerning brain-derived neurotrophic factor (BDNF) levels across different episodes in bipolar disorder have been reported, which is also in line with the treatment effects on BDNF levels in acute mania. We aimed to compare plasma BDNF level alterations after pure antipsychotic drug or ECT plus antipsychotic drug treatment in acute mania. METHODS: Sixty-eight patients with mania were divided into two treatment arms: the antipsychotic treatment arm (AP) and electroconvulsive therapy (ECT)+AP arm. In addition, 30 healthy controls were included in the study. RESULTS: There was no significant statistical difference according to mean age, education level, marital and working status between patients and healthy controls. The initial serum BDNF level in patients with acute mania was significantly lower than healthy controls. The initial BDNF level between the ECT arm and AP arm was not significant. The BDNF level decreased significantly after reaching remission in patients with acute mania. The change in BDNF level in the AP arm was not significant while in the ECT arm it was significant after treatment. CONCLUSIONS: In this study, for the first time we revealed a significant decrease in BDNF levels after ECT sessions in acute manic patients. Besides clinical remission after treatment in acute mania, the decrement in BDNF levels does not seem to be related to clinical response. Thus cumulative effects of mood episodes for the ongoing decrease in BDNF levels might be borne in mind despite the achievement of remission and/or more time being required for an increase in BDNF levels after treatment. PMID- 25827644 TI - Role of the serotonin transporter gene locus in the response to SSRI treatment of major depressive disorder in late life. AB - It has been suggested that the serotonin or 5-hydroxytriptamine (5-HT) transporter (5-HTT) and its gene-linked polymorphic region (5-HTTLPR) are selective serotonin reuptake inhibitor (SSRI) response modulators in late-life depression (LLD), and particularly in late-life major depressive disorder (MDD). Previous studies differed in design and results. Our study aimed to investigate the solute carrier family 6 (neurotransmitter transporter and serotonin) member 4 (SLC6A4) gene locus, encoding 5-HTT and SSRI treatment response in late-life MDD. For a prospective cohort study, we enrolled 234 patients with late-life MDD to be treated with escitalopram, sertraline, paroxetine or citalopram for 6 months. The SLC6A4 polymorphisms rs4795541 (5-HTTLPR), rs140701 and rs3813034 genotypes spanning the SLC6A4 locus were investigated in blinded fashion. No placebo group was included. We assessed responder or non-responder phenotypes according to a reduction in the 21-item version of the Hamilton Depression Rating Scale (HDRS 21) score of ? 50%. At follow-up, 30% of the late-life MDD patients were non responders to SSRI treatment. No time-course of symptoms and responses was made. A poor response was associated with a higher baseline HDRS-21 score. We observed a significant over-representation of the rs4795541-S allele in the responder patients (0.436 versus 0.321; p = 0.023). The single S-allele dose-additive effect had OR = 1.74 (95% CI 1.12-2.69) in the additive regression model. Our findings suggested a possible influence of 5-HTTLPR on the SSRI response in patients with late-life MDD, which is potentially useful in identifying the subgroups of LLD patients whom need a different pharmacological approach. PMID- 25827645 TI - Simvastatin as an adjuvant therapy to fluoxetine in patients with moderate to severe major depression: A double-blind placebo-controlled trial. AB - Statins have been shown to decrease depressive symptoms in certain groups of patients, an effect that is mostly attributed to their anti-inflammatory and neurotransmitter modulatory potentials. We aimed to investigate the antidepressant effects of simvastatin as an adjuvant therapy in patients with moderate to severe depression. In this double-blind placebo-controlled clinical trial, 48 patients were randomly allocated to receive simvastatin or placebo as an adjunct to fluoxetine for six weeks. Patients were evaluated with the Hamilton Depression Rating Scale (HDRS) at baseline and weeks 2, 4 and 6. Probable clinical and laboratory adverse events were also monitored and compared between the two groups. Simvastatin-treated patients experienced significantly more reductions in HDRS scores compared to the placebo group by the end of the trial (p=0.02). Early improvement and response rates were significantly greater in the simvastatin group than the placebo group (p=0.02 and p=0.01, respectively) but remission rate was not significantly different between the two groups (p=0.36). No serious adverse event was reported during this trial. In conclusion, simvastatin seems to be a safe and effective adjuvant therapy for patients suffering from major depressive disorder. However, more confirmatory studies are warranted. PMID- 25827646 TI - Immunology and human reproduction. AB - PURPOSE OF REVIEW: The immune system's role in recurrent reproductive failure is a controversial issue in assisted reproduction. New insight about maternal tolerance in assisted reproduction has been reported and could explain some of the recurrent miscarriage and/or recurrent implantation failure related causes named until now as unknown. RECENT FINDINGS: Most of the previous studies about immune system implication in reproduction were focused on finding markers on peripheral blood. Maternal tolerance begins at the uterine level, so successful adaptation to the fetus happens after a complicated process. Insufficient invasion of the uterine lining by invading extravillous trophoblast is the primary defect in pregnancy disorders such as recurrent miscarriage, and this process is regulated by interaction between maternal killer immunoglobulin-like receptors (KIRs) expressed by the uterine natural killer cells and their ligand human leukocyte antigen (HLA)-C expressed by extravillous trophoblast. Pregnancies are an increased risk of disorders in mothers with KIR AA when the fetus has paternal HLA-C2. Recently, it has been reported that the expression of more than one paternal HLA-C by extravillous trophoblast in assisted reproduction may affect placentation in mothers with KIR AA. SUMMARY: The review provides insight about the immune tolerance process. These insights could have an impact on the selection of single embryo transfer and/or oocyte/sperm donor according to HLA-C in patients with recurrent miscarriage or recurrent implantation failure and a KIR AA haplotype. PMID- 25827647 TI - Understanding and improving endometrial receptivity. AB - PURPOSE OF THE REVIEW: For a successful pregnancy, the synchronic coordination between the embryonic development and the endometrial status is crucial. The endometrium is a hormonally regulated organ that is nonadhesive to embryos throughout most of the menstrual cycle in humans. Endometrial receptivity refers to a hormone-limited period in which the endometrial tissue acquires a functional and transient ovarian steroid-dependent status allowing blastocyst implantation and therefore pregnancy initiation. RECENT FINDINGS: Our group has developed the endometrial receptivity array (ERA), a customized array based on the expression of 238 genes coupled to a computational predictor capable of diagnosing a functionally receptive endometrium regardless of its histological appearance. Clinical results obtained in our laboratory demonstrate the diagnostic and therapeutic efficiency of the ERA test in patients with implantation failure, allowing the personalization of the optimal day for embryo transfer. SUMMARY: To keep improving the global knowledge of endometrial receptivity stage, new high throughput techniques like RNA-seq or genome-wide association studies will be crucial in the near future. Also the identification of new biomarkers of endometrial receptivity that could be assessed by noninvasive methods has become a challenging goal to help diagnose the endometrial status to increase implantation rates and pregnancy outcomes in patients undergoing assisted reproductive treatments. PMID- 25827648 TI - Circumstances and Outcomes of a Firearm Seizure Law: Marion County, Indiana, 2006 2013. AB - Indiana statute allows police to seize firearms without a warrant if the officer believes a person meets the law's definition of "dangerous." Review of the use of this law in Marion County (Indianapolis), Indiana, showed that prosecutors filed petitions in court to retain weapons seized by police under this law 404 times between 2006 and 2013. Police removed weapons from people due to identification of a risk of suicide (68%) or violence (21%), or the presence of psychosis (16%). The firearm seizures occurred in the context of domestic disputes in 28% of cases and intoxication was noted in 26% of cases. There were significant demographic differences in the circumstances of firearm seizures and the firearms seized. The seized firearms were retained by the court at the initial hearing in 63% of cases; this retention was closely linked to the defendant's failure to appear at the hearing. The court dismissed 29% of cases at the initial hearing, closely linked to the defendant's presence at the hearing. In subsequent hearings of cases not dismissed, the court ordered the destruction of the firearms in 72% of cases, all when the individual did not appear in court, and dismissed 24% of the cases, all when the individual was present at the hearing. Overall, the Indiana law removed weapons from a small number of people, most of whom did not seek return of their weapons. The firearm seizure law thus functioned as a months-long cooling-off period for those who did seek the return of their guns. PMID- 25827649 TI - Development and evaluation of information resources for patients, families, and healthcare providers addressing behavioral and cognitive sequelae among adults with a primary brain tumor. AB - Behavioral and cognitive changes in patients with primary brain tumor (PBT) are common and may be distressing to patients and their family members. Healthcare professionals report a strong need for information, practical strategies, and training to assist consumers and better address management issues. A literature review by the current project found that 53% of the information resources currently available to consumers and health professionals contained minimal or no information about cognitive/behavioral changes after PBT, and 71% of the resources contained minimal or no information on associated strategies to manage these changes. This project aimed to develop an information resource for patients, carers, and health professionals addressing the behavioral and cognitive sequelae of PBT, including strategies to minimize the disabling impact of such behaviors. In consultation with staff and patient groups, 16 key information topics were identified covering cognitive and communication changes and challenging behaviors including executive impairment, behavioral disturbance, and social/emotional dysfunction. Sixteen fact sheets and 11 additional resource sheets were developed and evaluated according to established consumer communication guidelines. Preliminary data show that these resources have been positively received and well utilized. These sheets are the first of their kind addressing challenging behaviors in the neuro-oncology patient group and are a practical and useful information resource for health professionals working with these patients and their families. The new resource assists in reinforcing interventions provided to individual patients and their relatives who are experiencing difficulties in managing challenging behaviors after PBT. PMID- 25827650 TI - Biochemical effects of the pharmaceutical drug paracetamol on Anguilla anguilla. AB - The ever-increasing presence of pharmaceutical drugs in the environment is a motif of concern, and human-use drugs are of particular importance. This is the case of paracetamol, a widely employed drug in human therapeutics, as analgesic and antipyretic, whose toxicity on aquatic organisms is still not fully characterized. The present study aimed to assess the toxic deleterious effects of paracetamol on European eel, Anguila anguilla, by using a comprehensive battery of antioxidant biomarkers (activities of enzymes such as catalase (CAT) and glutathione S-transferases (GSTs)), and the quantification of oxidative damage (measurement of levels of lipid peroxidation (thiobarbituric acid reactive substances (TBARS) assay)). Other biochemical effects elicited by this substance were also quantified, in terms of anaerobic respiration (activity of lactate dehydrogenase, LDH) and neurotoxicity (acetylcholinesterase, AChE, activity). The obtained results showed the occurrence of an oxidative base response, and paracetamol also seemed to inhibit AChE, showing that this drug can also elicit neurotoxicity. The lack of response by both CAT and LDH show that, despite the occurrence of toxicity, eels have detoxification mechanisms that are effective to cope with paracetamol, preventing additional deleterious alterations, including in the main pathway by which they obtain energy. PMID- 25827651 TI - Removal of trimethylamine (fishy odor) by C3 and CAM plants. AB - From screening 23 plant species, it was found that Pterocarpus indicus (C3) and Sansevieria trifasciata (crassulacean acid metabolism (CAM)) were the most effective in polar gaseous trimethylamine (TMA) uptake, reaching up to 90% uptake of initial TMA (100 ppm) within 8 h, and could remove TMA at cycles 1-4 without affecting photosystem II (PSII) photochemistry. Up to 55 and 45% of TMA was taken up by S. trifasciata stomata and leaf epicuticular wax, respectively. During cycles 1-4, interestingly, S. trifasciata changed its stomata apertures, which was directly induced by gaseous TMA and light treatments. In contrast, for P. indicus the leaf epicuticular wax and stem were the major pathways of TMA removal, followed by stomata; these pathways accounted for 46, 46, and 8%, respectively, of TMA removal percentages. Fatty acids, particularly tetradecanoic (C14) acid and octadecanoic (C18) acid, were found to be the main cuticular wax components in both plants, and were associated with TMA removal ability. Moreover, the plants could degrade TMA via multiple metabolic pathways associated with carbon/nitrogen interactions. In CAM plants, one of the crucial pathways enabled 78% of TMA to be transformed directly to dimethylamine (DMA) and methylamine (MA), which differed from C3 plant pathways. Various metabolites were also produced for further detoxification and mineralization so that TMA was completely degraded by plants. PMID- 25827653 TI - Lake and watershed influences on the distribution of elemental contaminants in the Rideau Canal System, a UNESCO world heritage site. AB - Watershed-specific variables such as sediment particle size distribution, water depth, sedimentation rate, focusing factors, and catchment area to lake area ratio can affect the distribution of trace element contaminants to lakes. The aim of this study was to investigate sources of metals to three headwater lakes and to quantify effects of watershed-specific variables on spatial and temporal trends of trace elements (As, Cd, Co, Cr, Cu, Hg, K, Ni, Pb, Rb, and Zn) in sediments and mercury (Hg) concentrations in fish. Surface sediment and water samples were used to characterize spatial patterns, while sediment cores were collected to portray temporal trends. Historical trends of Hg in northern pike (Esox lucius) were assessed in relation to paleolimnological trends of sediment Hg concentrations. Similarity in timing of sediment peak trace element concentrations for the lakes suggests large-scale, atmospheric sources. The lake with highest catchment area-to-lake area ratio was consistently associated with highest sediment elemental concentrations and displayed significant correlations between increased sediment Hg concentrations and decreased pike tissue concentrations over time. This suggests that catchment area-to-lake area ratio is an important factor influencing the concentration of atmospherically derived contaminants within lake sediments and their transfer through the food web. PMID- 25827652 TI - Elements and polycyclic aromatic hydrocarbons in exhaust particles emitted by light-duty vehicles. AB - The main purpose of this work was to evaluate the chemical composition of particulate matter (PM) emitted by eight different light-duty vehicles. Exhaust samples from petrol and diesel cars (Euro 3 to Euro 5) were collected in a chassis dynamometer facility. To simulate the real-world driving conditions, three ARTEMIS cycles were followed: road, to simulate a fluid traffic flow and urban with hot and cold starts, to simulate driving conditions in cities. Samples were analysed for the water-soluble ions, for the elemental composition and for polycyclic aromatic hydrocarbons (PAHs), respectively, by ion chromatography, inductively coupled plasma atomic emission spectroscopy (ICP-AES), inductively coupled plasma mass spectrometry (ICP-MS) and gas chromatography-mass spectrometry (GC-MS). Nitrate and phosphate were the major water-soluble ions in the exhaust particles emitted from diesel and petrol vehicles, respectively. The amount of material emitted is affected by the vehicle age. For vehicles >=Euro 4, most elements were below the detection limits. Sodium, with emission factors in the ranges 23.5-62.4 and 78.2-227MUg km(-1), for petrol and diesel Euro 3 vehicles, respectively, was the major element. The emission factors of metallic elements indicated that diesel vehicles release three to five times more than petrol automobiles. Element emissions under urban cycles are higher than those found for on-road driving, being three or four times higher, for petrol vehicles, and two or three times, for diesel vehicles. The difference between cycles is mainly due to the high emissions for the urban cycle with hot start-up. As registered for elements, most of the PAH emissions for vehicles >=Euro 4 were also below the detection limits. Regardless of the vehicle models or driving cycles, the two- to four-ring PAHs were always dominant. Naphthalene, with emission factors up to 925 MUg km(-1), was always the most abundant PAH. The relative cancer risk associated with naphthalene was estimated to be up to several orders of magnitude higher than any of the chemical species found in the PM phase. The highest PAH emission factors were registered for diesel-powered vehicles. The condition of the vehicle can exert a decisive influence on both element and PAH emissions. PMID- 25827654 TI - Resistance training improves hyperglycemia and dyslipidemia, highly prevalent among nonelderly, nondiabetic, chronically disabled stroke patients. AB - OBJECTIVE: To test the effect of 8 weeks of lower body resistance training on hyperglycemia and dyslipidemia, which may be prevalent among nonelderly, nondiabetic, chronically disabled stroke patients. DESIGN: Randomized controlled study. SETTING: Outpatient clinics of rehabilitation centers. PARTICIPANTS: Nonelderly, nondiabetic, chronically disabled stroke subjects (N=56) were enrolled and randomly assigned to an experimental group (n=28) and a control group (n=28). INTERVENTIONS: Lower body resistance training was performed by subjects in the experimental group 3 times a week for 8 weeks. The control group was given duration-matched stretch exercises. MAIN OUTCOME MEASURES: Fasting glucose level, fasting insulin level, 2-hour blood glucose level during oral glucose tolerance test, homeostasis model assessment of insulin resistance (HOMA IR), glycosylated hemoglobin (Hb A1c), total triglyceride level, total cholesterol level, high-density lipoprotein (HDL) cholesterol level, low-density lipoprotein (LDL) cholesterol level, body mass index, lower limb muscle strength, and Fugl-Meyer motor score. RESULTS: Before the intervention, 34 subjects (60.7%) had hyperglycemia and 38 (67.9%) had dyslipidemia. Fifty-one subjects finished the study. Subjects in the experimental group (n=26) showed significant improvements in fasting insulin and 2-hour blood glucose levels; HOMA-IR; total cholesterol, HDL cholesterol, and LDL cholesterol levels; and muscle strength compared with control subjects (n=25) after the intervention (P<.05). CONCLUSIONS: Resistance training may play a significant role in improving hyperglycemia and dyslipidemia, which are frequently present among nonelderly, nondiabetic, chronically disabled stroke patients. PMID- 25827655 TI - Therapeutic effects of whole-body vibration training in knee osteoarthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To examine the current evidence regarding the effects of whole-body vibration (WBV) training in individuals with knee osteoarthritis (OA). DATA SOURCES: We searched PubMed, CINAHL, Embase, Scopus, Physiotherapy Evidence Database (PEDro), and Science Citation Index for research articles published prior to January 2015 using the keywords whole body vibration, vibration training, and vibratory exercise in combination with the Medical Subject Heading osteoarthritis knee. STUDY SELECTION: This meta-analysis was restricted to randomized controlled trials published in the English language. The quality of the selected studies was assessed by the PEDro Scale. The risk of bias was assessed using the Cochrane collaboration's tool in the domain-based evaluation. We also evaluated the quality of each study based on the criteria given by the International Society of Musculoskeletal and Neuronal Interactions for reporting WBV intervention studies, consisting of 13 factors. DATA EXTRACTION: Descriptive data regarding subjects, design, intervention, WBV parameters, outcomes, and conclusions were collected from each study by 2 independent evaluators. The mean and SD of the baseline and final endpoint scores for pain, stiffness, and function were extracted from the included studies. DATA SYNTHESIS: A total of 83 studies were found in the search. Of these, 5 studies met the inclusion criteria and were further analyzed. Four of these 5 studies reached high methodologic quality on the PEDro Scale. Overall, studies demonstrated mixed results in favor of additive effects of WBV for reducing pain and improving function in knee OA. There was considerable variation in the parameters of the WBV included in this systematic review. CONCLUSIONS: WBV training reduces pain and improves function in individuals with knee OA. PMID- 25827656 TI - Health behavior change counseling in surgery for degenerative lumbar spinal stenosis. Part II: patient activation mediates the effects of health behavior change counseling on rehabilitation engagement. AB - OBJECTIVE: To determine the effect of health behavior change counseling (HBCC) on patient activation and the influence of patient activation on rehabilitation engagement, and to identify common barriers to engagement among individuals undergoing surgery for degenerative lumbar spinal stenosis. DESIGN: Prospective clinical trial. SETTING: Academic medical center. PARTICIPANTS: Consecutive lumbar spine surgery patients (N=122) defined in our companion article (Part I) were assigned to a control group (did not receive HBCC, n=59) or HBCC group (received HBCC, n=63). INTERVENTION: Brief motivational interviewing-based HBCC versus control (significance, P<.05). MAIN OUTCOME MEASURES: We assessed patient activation before and after intervention. Rehabilitation engagement was assessed using the physical therapist-reported Hopkins Rehabilitation Engagement Rating Scale and by a ratio of self-reported physical therapy and home exercise completion. Common barriers to rehabilitation engagement were identified through thematic analysis. RESULTS: Patient activation predicted engagement (standardized regression weight, .682; P<.001). Postintervention patient activation was predicted by baseline patient activation (standardized regression weight, .808; P<.001) and receipt of HBCC (standardized regression weight, .444; P<.001). The effect of HBCC on rehabilitation engagement was mediated by patient activation (standardized regression weight, .079; P=.395). One-third of the HBCC group did not show improvement compared with the control group. Thematic analysis identified 3 common barriers to engagement: (1) low self-efficacy because of lack of knowledge and support (62%); (2) anxiety related to fear of movement (57%); and (3) concern about pain management (48%). CONCLUSIONS: The influence of HBCC on rehabilitation engagement was mediated by patient activation. Despite improvements in patient activation, one-third of patients reported low rehabilitation engagement. Addressing these barriers should lead to greater improvements in rehabilitation engagement. PMID- 25827657 TI - Health behavior change counseling in surgery for degenerative lumbar spinal stenosis. Part I: improvement in rehabilitation engagement and functional outcomes. AB - OBJECTIVE: To examine whether a brief motivational interviewing [MI]-based health behavior change counseling (HBCC) intervention increased patient participation in physical therapy and/or home exercise programs (HEPs), reduced disability, and improved health status after surgery for degenerative lumbar spinal stenosis. DESIGN: Prospective clinical trial. SETTING: Academic medical center. PARTICIPANTS: From December 2009 through August 2012, consecutive patients (N=122) underwent surgery for degenerative lumbar spinal stenosis and, based on enrollment date, were prospectively assigned to a control (n=59) or HBCC intervention (n=63) group in a prospective, lagged-control clinical trial. INTERVENTIONS: Brief MI-based HBCC versus attention control. MAIN OUTCOME MEASURES: Rehabilitation participation (primary); disability and health status (secondary). Therapists assessed engagement in, and patients reported attendance at, postoperative rehabilitation (physical therapy and/or HEP). At 3 and 6 months, disability and health status were assessed (Oswestry Disability Index [ODI] and Medical Outcomes Study 12-Item Short-Form Health Survey, version 2 [SF 12v2]) (significance, P<.05). RESULTS: Compared with controls, HBCC patients had significantly higher rehabilitation engagement (21.20+/-4.56 vs 23.57+/-2.71, respectively; P<.001), higher physical therapy (.67+/-.21 vs .82+/-.16, respectively; P<.001) and HEP (.65+/-.23 vs .75+/-.22, respectively; P=.019) attendance, and better functional outcomes at 3 months (difference: ODI, -10.7+/ 4.4, P=.015; SF-12v2, 6.2+/-2.2, P=.004) and 6 months (difference: ODI, -12.7+/ 4.8, P=.008; SF-12v2, 8.9+/-2.4, P<.001). The proportion of the HBCC intervention impact on functional recovery mediated by rehabilitation participation was approximately half at 3 months and one-third at 6 months. CONCLUSIONS: HBCC can improve outcomes after spine surgery through improved rehabilitation participation. PMID- 25827658 TI - Drug safety evaluation of apremilast for treating psoriatic arthritis. AB - INTRODUCTION: Apremilast is an orally available small molecule that targets PDE4. PDE4 modulates intracellular signaling and thereby can impact various proinflammatory and anti-inflammatory mediators. Apremilast has been approved by the USA FDA for the treatment of active psoriatic arthritis (PsA) and moderate-to severe psoriasis (PsO). Although there are several therapies approved and used for the treatment of PsA, there is still an unmet need for additional effective and well-tolerated therapeutic options. In PsA clinical trials, apremilast has been shown to be efficacious and to have an acceptable safety profile. AREAS COVERED: This review article covers the mechanism of action of apremilast, its efficacy in clinical trials and a detailed focus on its safety profile, mainly from Phase III clinical trials. EXPERT OPINION: Based on the available literature, apremilast has proven to be an efficacious therapy for PsA and PsO. It may offer some advantage as compared to other therapeutic options given its favorable safety profile, including a lack of need for routine laboratory monitoring. PMID- 25827659 TI - A pilot trial of prazosin, an alpha-1 adrenergic antagonist, for comorbid alcohol dependence and posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and alcohol dependence (AD) commonly co-occur and are associated with greater symptom severity and costs than either disorder alone. No pharmacologic interventions have been found to decrease both alcohol use and PTSD symptom severity relative to matched placebo. Prazosin, an alpha-1 adrenoreceptor antagonist, has demonstrated the efficacy of reducing PTSD and AD symptoms among individuals with one or the other disorder and may be useful in addressing comorbid PTSD/AD. METHODS: Prazosin and matched placebo were compared in the context of an outpatient 6-week double-blind randomized controlled pilot trial involving 30 individuals with comorbid PTSD/AD. Medication was titrated to 4 mg q am, 4 mg q pm and 8 mg qhs by the end of week 2. Participants in both conditions received 5 medical management sessions. Information regarding alcohol use, craving, and PTSD was gathered daily using a telephone interactive voice response system. RESULTS: Participants randomized to prazosin had a greater reduction in percent days drinking per week and percent days heavy drinking per week between baseline and week 6 than did placebo participants. No significant differences were detected within or between groups in change from weeks 1 to 6 in total PTSD symptoms. Participants in the prazosin condition reported drowsiness on significantly more days than those in the placebo condition. CONCLUSIONS: Consistent with the extant research evaluating medications for comorbid PTSD/AD, the current evaluation of prazosin also found decreased alcohol consumption but no medication effect on PTSD symptomatology. PMID- 25827660 TI - International travel in the immunocompromised patient: a cross-sectional survey of travel advice in 254 consecutive patients. AB - AIMS: Our primary aim was to determine the rate of overseas travel in immunocompromised individuals attending appropriate clinics at an Australian tertiary care hospital. We also aimed to characterise health-seeking behaviour prior to travel and investigated sources of pre-travel advice, compared travel patterns and activities between three specific immunosuppressed groups, and examined pre-immunosuppression patient serology. METHODS: We implemented a cross sectional survey of patients between February and August 2012. This survey was implemented among three outpatient populations at Monash Medical Centre, an Australian tertiary care hospital. RESULTS: We recruited 254 immunosuppressed adults from three patient populations: human immunodeficiency virus-positive individuals, renal transplant patients and rheumatology patients requiring immunosuppressive therapy. No clinical intervention was performed. In the 10 years preceding the survey, 153 (60.2%) participants reported international travel. Of these, 105 (68.6%) were immunosuppressed at the time of travel. These patients were 47.6% male and 60% Australian born. Forty per cent were visiting friends and relatives as part of their travel. Fifty-four per cent of those immunocompromised at the time of travel were going to high-risk destinations. Pathology files indicated that serological screening was frequently not performed prior to immunosuppression in the renal transplant and rheumatology groups. CONCLUSIONS: Immunocompromised patients often travel to high-risk destinations with limited or inadequate pre-travel preparations. Doctors caring for the immunocompromised should be aware of travel risks, suitable vaccination protocols and when to refer to specialist travel clinics. PMID- 25827661 TI - A resected case of neuroendocrine carcinoma of the stomach with unusual lymph node metastasis. AB - Gastric endocrine cell carcinoma is a relatively rare tumor. We experienced a case of early gastric cancer in which an endocrine cell carcinoma was identified within a differentiated adenocarcinoma, and a component of this endocrine cell carcinoma had metastasized to lymph nodes of the stomach. In its 2010 revision regarding digestive system tumors, WHO classified cancer cells with characteristics of both glandular system cells and neuroendocrine cells as mixed adeno neuroendocrine carcinoma (MANEC) under the neuroendocrine carcinoma (NEC) category. In this case, we observed an endocrine cell carcinoma continuous with an intramucosal differentiated adenocarcinoma, and cancer cells with an irregular gland duct structure were observed in the proliferative portion of the submucosal tissue. In addition, there was a 35 mm size lymph node metastasis in the lesser curvature of the stomach consisting entirely of poorly differentiated cancer cells with polymorphic, highly atypical nuclei and scant cytoplasm. Immunohistological analysis showed that the endocrine carcinoma in the gastric mucosa was chromogranin A positive and the infiltrated area of the submucosal tissue was also chromogranin A positive. The lymph node metastasis was positive not only for chromogranin A, but also for Synaptophysin and CD56. Furthermore, the Ki67 labeling index was high at approximately 80 % for the gastric endocrine cell carcinoma and approximately 90 % for the lymph node metastases. Until now, there are no reports related to the patients with early gastric cancer accompanied with lymph node metastasis of MANEC. This case is very interested in considering the mechanism of lymph node metastasis of MANEC. The patient has shown no sign of recurrence for 1 year and 4 months after postoperative chemotherapy. PMID- 25827662 TI - Laparoscopic ultrasound: a surgical "must" for second line intra-operative evaluation of pancreatic cancer resectability. AB - BACKGROUND: Advanced laparoscopy for pancreatic cancer surgery should include laparoscopic ultrasound (LUS), in order to accurately evaluate resectability and rule out the presence of undetected metastases and/or vascular infiltration. LUS should be done as a preliminary step whenever pre-operative imaging casts doubts on resectability. PATIENTS AND METHODS: We hereby report our experience of 18 consecutive patients, aged 43-76, coming to our attention during a six months period (Jan-Jun 2013), with a diagnosis of pancreas head or body cancer. RESULTS: LUS allowed to rule out undetected metastases or mesenteric vessels infiltration in 11 patients (61.1%), who were submitted, as previously scheduled, to radical duodeno-pancreatectomy (9 cases) and spleno-caudal pancreatectomy (2 cases). Among the remaining patients, three had been correctly evaluated as non resectable radically at pre-operative work out, and confirmed at LUS, while LUS detected non resectable disease in further 4 patients (22.2%), who underwent palliative procedures. In 2 patients of this group liver micro-metastases were found, while 2 were excluded because of mesenteric vessels infiltration. CONCLUSIONS: LUS provided a higher level of diagnostic accuracy, allowing in our experience to exclude 4 patients from radical surgery (22.2%). The evaluation of surgical resectability is an issue of crucial importance to decide surgical strategy in pancreas tumor surgery. In our opinion LUS should be considered a mandatory step in laparoscopic approach to pancreatic tumors, to better define disease staging and evaluate resectability. PMID- 25827663 TI - Colorectal cancer in aged patients. Toward the routine treatment through laparoscopic surgical approach. AB - AIM: Colorectal cancer is one of the most common malignancies in general population. The incidence seems to be higher in older age. Surgery remains the treatment of choice and laparoscopic approach offers numerous benefits. We report our personal experience in elderly patients operated on for colorectal cancer with laparoscopic resection. PATIENTS AND METHODS: From January 2003 to September 2013, out of 160 patients aged 65 years or older and operated with minimally invasive techniques, 30 cases affected by colorectal cancer and operated on with laparoscopic approach were analyzed in this study. RESULTS: Male/female ratio was 1.35 and mean age 72 years. Constipation, weight loss, anemia and rectal bleeding were the most commonly reported symptoms. Lesions involved descending-sigmoid colon in 53% of cases, rectum in 37% and ascending colon in 10%. Among laparoscopic colo-rectal operations laparoscopic left colectomy was the most frequently performed, followed by right colectomy, abdominoperineal resection and Hartmann procedure. Operative times ranged from 3 to 5 hours depending on surgical procedure performed. Mean hospital stay was 6 days (range 4-9). Conversion to open approach occurred only in a case of laparoscopic right colectomy (3%) for uncontrolled bleeding. A single case of mortality was reported. In two cases (7%) anastomotic leakage was observed, conservatively treated in one patient and requiring reoperation in the other one. CONCLUSIONS: Laparoscopic colorectal surgery is feasible and effective for malignancies in elderly population offering several advantages including immunologic and oncologic ones. However an experienced surgical team is essential in reducing risks and complications. PMID- 25827664 TI - Acute necrotizing pancreatitis: can tigecycline be included in a therapeutic strategy? AB - INTRODUCTION: Acute necrotizing pancreatitis is a severe and life-threatening disease. Infection, which occurs in about 30% of cases, is the most feared complication. Antibiotic therapy is still discussed and there are no clear recommendation in literature. These clinical series underline the importance of having a clear antibiotic protocol, including tigecycline, in the management of acute necrotizing pancreatitis. Clinical series. Six patients with clinical and radiological diagnosis of necrotizing acute pancreatitis are treated in Emergency Surgery Department, following a conservative management, which includes fluid resuscitation, intensive care unit and radiological monitoring, ultrasound-guided percutaneous drainage and an antibiotic treatment protocol, that includes tigecycline. No one of the six patient undergo surgery (mean hospital stay: 44 days). In a six months follow-up all patients are alive and in good clinical conditions. DISCUSSION: Infection is the most important factor which determinate prognosis and outcome of acute necrotizing pancreatitis. Antibiotic prophylaxis is still discussed and there are no clear antibiotic treatment guidelines in literature. Despite its side effects on pancreatic gland, tigecycline is successful in resolution of sepsis, caused by infected pancreatic necrosis. CONCLUSIONS: Collaboration with infectivologist and a clear antibiotic protocol is fundamental to solve infected necrosis. Antibiotic treatment, set up as soon as possible, is successful in our six patients, as they recover without undergoing surgical procedures. Tigecycline offers broad coverage and efficacy against resistant pathogens for the treatment of documented pancreatic necrosis infection. However, further studies are necessary to fully understand the safety profile and efficacy of tigecycline. PMID- 25827665 TI - How to prevent mesh erosion in transobturator Tension-Free Incontinence Cystocoele Treatment (TICT): a comparative survey. AB - BACKGROUND: Tension-Free Incontinence Cystocoele Treatment (TICT) was introduced by Leanza-Gasbarro-Caschetto in 2001, on the basis of experimental and clinical investigations to obtain a physiologic mechanism of closure and opening of the urethra in the event of genuine stress urinary incontinence (S.U.I.) and cistocoele. TICT took origin from the previous retropubic tension-free vaginal tape (TVT) based on the integral theory according which mid-urethra has a main role for urinary continence but differs in that the former restores the anatomy and physiology of the entire anterior compartment. Simultaneously Delorme in 2001 spread the TOT (Trans-Obturator Tape) technique, emphasizing the needle passage across the obturator foramen which represents a new and less invasive route in comparison with the retropubic one. Trans-obturator TICT exploits the advantages of TOT, adding the anatomical repair of bladder prolapse. Introduction of mesh for treatment of pelvic defects gives a lower rate of recurrence, but introduces new complications due to the extraneous materials, among which the most common is represented by mesh erosion. At present the rate of mesh erosion reported is 4.7% in the TOT. Aim of our survey was to verify a technique allowing post-operative erosion prevention. PATIENTS AND METHODS: 230 women with urodynamic stress incontinence and cystocoele after diagnostic phase were allocated to 2 treatment groups (A end B-group), with open alternative method. Agroup women underwent transobturator TICT procedure after preparation of anterior compartment by means of a transversal incision taking care to preserve the integrity of the vaginal skin in the site where the mesh would be allocated. Conversely, B-group transobturator TICT was carried out in a classical way, through a longitudinal incision of anterior vaginal skin and suturing after placing the mesh. Each of the two groups was initially constituted by 115 subjects. There were 14 preoperative dropouts among which 6 (115-6=109) in A-group and 8 (115-8=107) in B group and, after, 16 postoperative dropouts including 7 (109-7=102) in the former and 9 (107-9=98) in the latter. Other pelvic defects were solved during the same operation for a complete repair of pelvic floor. RESULTS: A-group: subjectively SUI was cured in 87/102 (85.3%) objectively, SUI was cured in 88/102 (86.3%) of patients; cystocoele in 87/102 (85.3%). B-group: subjectively SUI was cured in 86/98 (87.7%) and objectively in 87/98 (88.8%) of patients; cystocoele was solved in 86/98 (87.7%). Between the two groups both anti-incontinence end cystocoele treatment was superimposable (p value > 0.05). Nevertheless regarding mesh erosion, a percentage of 5.1% (5/98) was found among B-group while none among A group patients where integrity of vaginal skin beneath the mesh was preserved. CONCLUSION: Integrity of the vagina beneath the mesh is the right.key to prevent ad externum mesh erosion. PMID- 25827666 TI - Tracheal varices caused by mediastinal compression of a large intrathoracic goiter: report of a case. AB - INTRODUCTION: Tracheal varices are a rare condition but they can be an important source of massive or recurrent haemoptysis. Usually they are related to increased pressure in the pulmonary veins. Mediastinal goiter is often associated to compressive effects on the surrounding structures, including mediastinal vessels with potential superior vena cava syndrome. CASE REPORT: We describe a case, not previously reported in literature, of mediastinal goiter with hemoptysis as first clinical manifestation. Bleeding was attributed to a superior vena cava syndrome associated to a tracheal fragile mucosa with an easily bleeding intramural nodule which was diagnosed as tracheal varices after total thyroidectomy. The nodule in fact disappeared together with the venous hypertensive signs after venous decompression of the mediastinum. CONCLUSIONS: Compressive symptoms including tracheal varices, related to mediastinal goiter, can be treated surgically by total thyroidectomy via cervicotomy and when required with associated median sternotomy. PMID- 25827667 TI - Intramural duodenal hematoma after submucosal injection of epinephrine for a bleeding ulcer: case report and review. AB - We present a case of intramural duodenal hematoma as a complication of endoscopic therapy for a bleeding duodenal ulcer in an adult patient with no evidence of other pathologies. A 18-year-old man was admitted in emergency room with gastrointestinal bleeding manifested by melena. Previous medical history revealed that he had endoscopic sclerotherapy for bleeding duodenal ulcer 5 months before. Endoscopy revealed a Forrest 2a ulcer in the duodenal bulb and sclerotherapy was performed by injecting 10 ml of 0.2% epinephrine and 20 ml of Na- Cl 0.9% solution. Upper occlusion's signs appeared 36 hours after the procedure. The hematoma, that was identified by endoscopy and confirmed by MRI and CT scan of the abdomen, caused transient duodenal obstruction. Combined conservative management with nasogastric tube and total parenteral nutrition resulted in reduction of obstructive symptoms within 4 weeks. PMID- 25827668 TI - Surgical removal of multiple mesenteric fibroids (Kg 4,500) by abdominal spread of previous laparoscopic uterine myomectomy. AB - INTRODUCTION: Huge and multiple mesenteric fibroids (4,500 Kg weight) are very unusual. In many cases they are mistaken for subserosal fibroids of the womb due to the proximity with uterine walls. When they have a rapid growth, the risk of becoming malignant (sarcoma) has not to be underestimated. Surgery is challenging to remove abdominal nodes. CASE REPORT: A case of a 40-year old woman, admitted to the hospital with abdominal masses occupying the entire cavity was reported. Both computerized tomography (CT) and ultrasounds (US) were not diriment for belonging of tumours. Clinical history of patient reports a laparoscopic removal of uterine fibroids, using the morcellator. Laparoscopy was performed four years before. Open surgery by means of a large transversal suprapubic laparotomy according to Pfannestiel was carried out. Multiple and huge mesenteric, peritoneal and intestinal tumours spread in the whole abdominal cavity were found, removed and examined by frozen section histology; in addition a series of small conglomerated myomas in the site of previous laparoscopic transumbilical route was taken away as well (the largest fibroid weighed Kg 3.500 and the all tumors removed 4,500 Kg); the result was benign (fibroids) and genital apparatus was preserved. Operation was challenging. Postoperative course was uneventful; after five days patient was discharged. CONCLUSIONS: This case is very interesting for many factors: A) many extra-uterine fibroids spread throughout abdominal cavity; B) considerable weight of the masses C) intraoperative and postoperative danger. Finally, due to involvement of previous laparoscopic transumbilical incision together with other findings, the hypothesis of post laparoscopic dissemination has to be considered. A case of so large extragenital abdominal fibroids following laparoscopic uterine myomectomy has never been published so far. PMID- 25827669 TI - A monolateral TMJ replacement under intraoral endoscopic assistance for jaw osteomielitis: a modified approach. AB - Alloplastic replacement has become a valid treatment for TMJ endstage disease. The Alkayat and Bramley pre-auricular approach combined with the submandibular incision are the current surgical approaches for TMJ surgery. The present study shows a modified approach using intraoral endoscopic assistance. A female patient affected by jaw osteomielitis with condylar detachment was treated with total left TMJ alloplastic replacement combined with a right TMJ arthroplasty. No subamandibular incision was performed and, subsequently, the risks for permanent or temporary damage to the marginalis mandibulae nerve and surgical submandibular scar were avoided. Postoperative CT-Scan evidenced a good prosthesis position. No complications occurred after two years of follow-up. PMID- 25827670 TI - Effect of vitamin D3 supplementation and influence of BsmI polymorphism of the VDR gene of the inflammatory profile and oxidative stress in elderly women with vitamin D insufficiency: Vitamin D3 megadose reduces inflammatory markers. AB - OBJECTIVE: This study aimed to evaluate the effect of vitamin D3 megadose supplementation and influence of BsmI polymorphism in the VDR gene on the inflammatory profile and oxidative stress in elderly women with vitamin D deficiency. METHODS: A double blind, randomized, placebo-controlled trial was conducted with 40 elderly women (aged 68+/-6 years) diagnosed with vitamin D insufficiency (24.7+/-3.1 ng/mL). Participants were distributed into a supplementation group that received 200,000 IU of vitamin D3 (SG; n=20) and a placebo group (PG; n=20). Blood samples were collected at baseline and after intervention to analyse the 25(OH)D, parathyroid hormone, serum calcium, ultra sensitive C-reactive protein (us-CRP), alpha 1-acid glycoprotein (AGP-A), total antioxidant capacity (TAC), and malondialdehyde (MDA) levels, as well as the renal and hepatic function, and genotyping was performed for BsmI polymorphism. RESULTS: Four weeks after supplementation, elderly women in the SG group showed a significant increase in the serum concentration of 25(OH)D (25.29+/-2.8 to 31.48+/-6.0; p=0.0001), which was followed by increased TAC (65.25+/-15.66 to 71.83+/-10.71; p=0.03) and decreased serum PTH (46.32+/-13.2 to 35.45+/-11.0; p=0.009), us-CRP (0.38+/-0.3 to 0.19+/-0.1; p=0.007) and AGP-A levels (75.3+/ 15.4 to 61.1+/-5.9; p=0.005). Changes in BP, ANAC and MDA were not observed. The 25(OH)D and PTH, us-CRP and AGP-A levels of participants with the BB/Bb genotype were more responsive to supplementation, but their other markers did not change. CONCLUSIONS: Supplementation with a vitamin D3 megadose reduced inflammatory markers and increased the total antioxidant capacity in elderly women with vitamin D insufficiency. The 25(OH)D, PTH, us-CRP and AGP-A levels of elderly patients with the BB/Bb genotype were more responsive to supplementation compared with those with the bb genotype. PMID- 25827671 TI - Novel test procedure to evaluate the treatability of wastewater with ozone. AB - Organic micropollutants such as pharmaceuticals, estrogens or pesticides enter the environment continuously through the effluent of municipal wastewater treatment plants (WWTPs). Enhanced treatment of wastewater (WW) by ozone (O3) is probably one of the simplest measures for abatement of organic micropollutants to avoid their discharge to the aquatic environment. During ozonation most organic micropollutants present in treated WW are oxidized either by a direct reaction with O3 or by secondarily formed hydroxyl radicals (OH). However, undesired oxidation by-products from the oxidative transformation of matrix components can also be formed. A modular laboratory decision tool based on the findings of previous investigations is presented to test the feasibility of ozonation as an option to upgrade specific WWTPs. These modules consist of investigations to assess (i) the matrix effects on ozone stability, (ii) the efficiency of micropollutant removal, (iii) the oxidation by-product formation, as well as (iv) bioassays to measure specific and unspecific toxicity of the treated WWs. Matrix effects on ozone stability (quantified as O3 and OH exposures) can give first indications on the suitability of an ozonation step. Ozonation of WWs yielding O3 and OH exposures and micropollutant abatement similar to reference values evoked a significant improvement of the water quality as indicated by a broad range of bioassays. Irregular behavior of the ozonation points towards unknown compounds, possibly leading to the formation of undesired degradation products. It has been observed that in such WWs ozonation partly enhanced toxicity. In summary, the presented tiered laboratory test procedure represents a relatively cheap and straight-forward methodology to evaluate the feasibility of ozonation to upgrade specific WWTPs for micropollutant removal based on chemical and biological measurements. PMID- 25827672 TI - Neonatal hypoplastic left heart syndrome: effects of bloodstream infections on outcomes and costs. AB - BACKGROUND: Hypoplastic left heart syndrome (HLHS) is not only a devastating disease, but also the most expensive birth defect managed in the US. Nosocomial bloodstream infections (NBIs) are common in neonates with HLHS. We examined the effects of NBIs on in-hospital mortality, length of stay, and costs for late preterm and term infants with HLHS undergoing stage 1 palliation, at both individual patient and hospital levels. METHODS: We conducted a retrospective study of infants 35 weeks or greater gestation with HLHS, admitted to our institution January 1, 2003 to January 1, 2013. Children with other cardiac abnormalities, major comorbid conditions, or perinatal infections were excluded. Univariable and multivariable analyses were performed. To estimate the effects of reduced NBI incidence on resource utilization, predictive models were used. RESULTS: One hundred forty-three children met inclusion criteria. In-hospital mortality was 9.1% (n = 13). Postoperative infection was observed in 12.6% (n = 18). Median length of stay was 23 days for survivors (IQR, 17 to 40; range, 9 to 132). Median costs were $83,000 for survivors, in 2013 dollars (IQR, $62,000 to $123,000; range, $17,000 to $517,000). NBIs were not associated with changes in mortality. In multivariable analyses, at a patient level NBIs were associated with a 74% increase in length of stay (95% confidence interval [CI], 31% to 132%, p < 0.001) and a 65% increase in costs (95% CI, 28% to 114%, p < 0.001). On a hospital level, in this cohort a 50% reduction in the incidence of NBIs would be expected to yield a 4.3% decrease in average length of stay and a 3.8% decrease in average in-patient costs. CONCLUSIONS: Nosocomial bloodstream infections in neonates with HLHS are associated with large increases in lengths of stay and costs on a patient level, but not a hospital level. For hospitals without particularly high incidences, studies are needed to identify additional targets for quality improvement. PMID- 25827673 TI - Safe resection of the aortic wall infiltrated by lung cancer after placement of an endoluminal prosthesis. AB - BACKGROUND: Few investigators have reported the results of combined resection of lung cancer infiltrating the thoracic aorta; only anecdotal accounts of off-label use of thoracic aortic endografts to facilitate resection of such tumors have been published. In this paper, we describe our experience using this innovative approach in terms of technical details and outcomes. METHODS: We retrospectively reviewed data on 9 patients (6 men and 3 women, median age 61 years) with preoperatively suspected thoracic aorta neoplastic invasion, who were operated on after positioning of an endograft and underwent en bloc tumor resection including the aortic wall. RESULTS: All but one cancer were non-small cell lung carcinomas; 4 patients received neoadjuvant chemotherapy, and 7 received adjuvant therapy. Aortic endografting was performed 2 to 17 days before resection of the tumor in 7 patients and as part of a one-stage procedure in 2 patients. The proximal end of the stent graft was deployed in the aortic arch (n = 1) or the descending aorta (n = 8). Lung resections were left pneumonectomies in 4 patients and left lower lobectomies in 5. Five patients underwent additional buttressing of the aortic defect using a synthetic patch (n = 2) or the omentum (n = 3). No cardiopulmonary bypass was required. At the last follow-up, 3 patients had evidence of tumor recurrence (one local and two distant). No endograft-related complications were detected. CONCLUSIONS: Thoracic aortic endografting allowed safe en bloc resection of tumors invading the aortic wall, avoiding the need for extracorporeal circulatory support. Such an extended indication for thoracic aortic endografts seems promising and should be considered for selected oncologic cases. PMID- 25827674 TI - Multiinstitutional analysis of single-port video-assisted thoracoscopic anatomical resection for primary lung cancer. AB - BACKGROUND: Multiinstitutional analysis of single-port video-assisted thoracic surgery (VATS) for anatomic pulmonary resection is rare. This study aimed to address the technical feasibility and applicability of single-port video-assisted anatomical resection for primary lung cancer. METHODS: A total of 121 patients with primary lung cancer undergoing single-port video-assisted anatomical resection between 2011 and 2014 in 4 hospitals were included. The clinicopathologic variables and perioperative outcomes were collected and analyzed retrospectively. RESULTS: Single-port VATS segmentectomies and lobectomies were performed in 24 (19.8%) and 97 (80.2%) patients, respectively. One hundred seven of 121 (88.4%) patients had adenocarcinoma and 93 of 121 (76.9%) had pathologic stage I lung cancer. The average operative time and estimated blood loss was 198.8 +/- 65.4 minutes and 99.1 +/- 147.6 mL, respectively. The conversion and complication rates were 2.5% (3 of 121 cases) and 14.0% (17 of 121 cases), respectively. There was no surgical mortality, and the average length of hospital stay was 6.6 +/- 2.6 days. The mean resected lymph node was 22.6 +/- 12.0. We also identified patient age of 60 years or more, male sex, and tumor size greater than 3 cm as unfavorable perioperative outcome predictors after single-port video-assisted anatomical pulmonary resection. CONCLUSIONS: This first multiinstitutional single-port VATS study demonstrated that anatomical resection for primary lung cancer can be safely and effectively completed through a single-port VATS approach in hospitals experienced in VATS techniques. PMID- 25827675 TI - Effects of extended pleurectomy and decortication on quality of life and pulmonary function in patients with malignant pleural mesothelioma. AB - BACKGROUND: Maximal cytoreductive surgeries--extrapleural pneumonectomy and extended pleurectomy and decortication (EPD)--are effective surgical treatments in selected patients with malignant pleural mesothelioma. Extended pleurectomy and decortication results in equivalent survival yet better health-related quality of life (HRQoL). METHODS: Patients with malignant pleural mesothelioma were studied for the effects of EPD on HRQoL and pulmonary function. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 was used to evaluate HRQoL before operation, and at 4 to 5 and 7 to 8 months postoperatively. Pulmonary function tests were measured immediately before and 5 to 7 months after the operation. Patients were compared according to World Health Organization baseline performance status (PS). RESULTS: Of the 36 patients enrolled, 17 were PS 0 and 19 were PS 1 or PS 2 at baseline. Patients in groups PS 1 and PS 2 had significantly worse global health, functional, and symptoms scores. After EPD, PS 0 patients had no change in global health or function and symptoms scores except for emotional function, whereas PS 1 or PS 2 patients showed improvements at 4 to 5 months with further improvements at 7 to 8 months. The PS 0 patients demonstrated a significant decrease in forced vital capacity (p = 0.001), forced expiratory volume in 1 second (p = 0.002), total lung capacity (p = 0.0006) and diffusing capacity of the lung for carbon monoxide (p = 0.003) after EPD, whereas no change was observed in PS 1 and PS 2 patients. CONCLUSIONS: Extended pleurectomy and decortication did not improve overall HRQoL and had a negative impact in pulmonary function in minimally symptomatic patients. In symptomatic patients, a significant improvement in HRQoL was observed after EPD, which continued at late follow-up, although the pulmonary function was not affected. As changes in HRQoL are multidimensional, the preservation of the pulmonary function may have contributed to the net benefit observed in PS 1 and PS 2 patients. PMID- 25827676 TI - Pulmonary retransplantation in the Nordic countries. AB - BACKGROUND: The increasing demand for pulmonary retransplantation (re-LTx) raises ethical issues on the correct allocation of the scarce donor pool. Thus, we performed a thorough review of the current results for re-LTx in the Nordic countries. METHODS: Seventy-five patients with a median age of 50 years (range, 22 to 64 years) underwent re-LTx from 1992 until June 2013, of which 53 had single re-LTx, 21 had double re-LTx, and 1 patient underwent a heart-lung retransplantation. Primary graft dysfunction (PGD) was the primary indication in 9 cases, bronchiolitis obliterans syndrome (BOS) in 62 cases, and airway complications in 4 cases. RESULTS: Patients who underwent re-LTx in the period 1992 to 1999 (n = 16) had a 1-year survival of 37.5% (95% confidence interval [CI], 19.9 to 70.6), whereas patients who underwent re-LTx in the period 2000 to 2013 (n = 64) had a 1-year survival of 81.0% (95% CI, 71.5 to 91.8). Corresponding 5-year survival was 25.0% (95% CI, 10.7 to 58.4) in the early era group (1992 to 1999) and 57.2% (95% CI, 44.3 to 73.7) in the more recent era group (2000 to 2013; p = 0.0151). Patients with BOS who underwent re-LTx in the period 1992 to 1999 (n = 13) had a 1-year survival of 38.5% (95% CI, 19.3 to 76.5), whereas patients with BOS who underwent re-LTx in the period 2000 to 2013 (n = 49) had a 1-year survival of 85.4% (95% CI, 75.9 to 96.0). Corresponding 5 year survival was 23.1% (95% CI, 8.6 to 62.3) in the early era group (1992 to 1999) and 56.1% (95% CI, 41.9 to 75.2) in the more recent era group (2000 to 2013; p = 0.0199). The cumulative incidence among patients who underwent re-LTx because of BOS and developed BOS again after re-LTX was analyzed. The cumulative incidence curves for time periods 1992 to 1999 and 2000 to 2013 are not statistically different for repeat BOS (p = 0.5087), but they are highly significant for time periods among patients who died (p = 0.02381). CONCLUSIONS: Results for re-LTx have improved over time, especially when BOS is the primary indication. The cumulative incidence among patients who underwent re-LTx because of BOS and developed repeat BOS after re-LTX showed equal risk between 1992 to 1999 and 2000 to 2013 in the aspect of developing repeat BOS, but in the later era the patients had a significantly higher chance of surviving. PMID- 25827677 TI - Transfemoral and perventricular device occlusions and surgical repair for doubly committed subarterial ventricular septal defects. AB - BACKGROUND: Transfemoral and perventricular device occlusions are performed for doubly committed subarterial ventricular septal defect (dcVSD) to reduce the invasiveness of the conventional surgical repair through a median sternotomy. Few comparative studies have been conducted of these three procedures. METHODS: Inpatients with isolated dcVSD who had undergone transfemoral and perventricular device occlusions or conventional surgical repair from January 2009 to June 2013 were reviewed to compare the three procedures. RESULTS: Procedure success was achieved in 33 transfemoral (66%), in 74 perventricular (94.9%), and in 205 repair (97.6%) procedures. The transfemoral group had the lowest success rate (p < 0.001), whereas the perventricular and repair groups had similar success rates (p = 0.418). Transfemoral patients were the oldest (p < 0.001) and had a dcVSD size similar to that of patients in other two groups (p = 0.518). The repair group required the longest hospitalization and longest stays in the intensive care unit (p < 0.001), required the longest operating room and mechanical ventilation times (p < 0.001), and had the highest rate of transfusion (p < 0.001). Major adverse events occurred in one transfemoral (3%), in two perventricular (2.7%), and in three repair (1.4%) procedures. Minor adverse events were absent in transfemoral (0%) and occurred in three perventricular (4%) and 14 repair (6.7%) procedures. No significant difference was noted in the rates of adverse events the three groups (p = 0.569). No grade 3 valvular regurgitation or complete atrioventricular block was observed in the studied patients. CONCLUSIONS: Device occlusion may be an alternative to surgical repair in selected patients with dcVSD. Perventricular occlusion was the preferred approach because it showed a higher success rate than transfemoral occlusion. PMID- 25827678 TI - Prognostic Significance of Aberrant Methylation of Solute Carrier Gene Family 5A8 in Lung Adenocarcinoma. AB - BACKGROUND: Solute carrier family 5 member A8 (SLC5A8) is a sodium-coupled transporter for several chemicals. The SLC5A8 gene has been reported to function as a tumor suppressor gene that contributes to carcinogenesis and tumor progression. The expression of SLC5A8 is silenced in colon neoplasia by hypermethylation of CpG-rich islands located in exon 1. In this study, we assessed the significance of aberrant methylation of the SLC5A8 gene as a prognostic factor for lung adenocarcinoma (AD). METHODS: We analyzed the methylation levels of a consecutive series of 143 node-negative stage I and II lung AD samples using pyrosequencing. RESULTS: The methylation level of exon 1 in the SLC5A8 gene was significantly associated with poor prognosis in cases of node negative stage I and II lung AD. CONCLUSIONS: Gene silencing of SLC5A8 by hypermethylation was associated with poor prognosis in cases of node-negative stage I and II lung AD. PMID- 25827679 TI - Spinal cord ischemia after selective cerebral perfusion in a porcine "frozen elephant trunk" simulation model. AB - BACKGROUND: The "frozen elephant trunk" procedure (FET) represents the therapy of choice for extended aortic diseases. The aim of our study was to analyze whether 90 minutes of selective cerebral perfusion (SCP) at 28 degrees C followed by permanent occlusion of the thoracic segmental arteries (TSA) would cause spinal cord ischemia in a porcine model. METHODS: 14 pigs (41 +/- 3 kg) were cooled on CPB to 28 degrees C. After aortic clamping, SCP was established for 90 minutes. Randomly, in 7 animals the TSA were clipped (T4-T13); the TSA of 7 animals remained untouched. After the animals were weaned from CPB, hemodynamic data were registered for 120 minutes. Regional spinal cord blood flow (SCBF) was calculated, and motor-evoked potentials (MEP) were assessed at 6 time points. After sacrifice of the animals, the spinal cord was analyzed histologically by use of a schematic grading system (0 = normal; 8 = total necrosis). RESULTS: During SCP the SCBF was maintained at baseline (5.9 +/- 2.4 mL/min/100 g) in the T4-T13 region but showed a decrease (from 8.4 +/- 4.3 to 1.3 +/- 1.5 mL/min/100 g) in the L1-L5 region. During reperfusion it increased, with two to three times higher values in the nonclipped animals. After 90 minutes of SCP, the MEP reached lower levels in the L1-L5 region of the TSA-clipped animals: 59% +/- 7% vs 84 +/- 15% (vastus medialis muscle) and 48% +/- 6% vs 82% +/- 26% (tibialis anterior muscle). The MEP recovered only in the nonclipped group. Higher ischemia rates were seen in the L1-L5 region of the TSA-clipped animals (score: 6.0 +/- 0.6 vs 2.5 +/- 2.3). CONCLUSIONS: 90 minutes of SCP provided sufficient spinal cord protection during arch replacement at 28 degrees C. In combination with permanent TSA occlusion, the lumbar spinal cord perfusion may be altered, which causes functional and structural damage. PMID- 25827680 TI - Evaluation of an inertial sensor system for analysis of timed-up-and-go under dual-task demands. AB - Functional tests, such as the timed-up-and-go (TUG), are routinely used to screen for mobility issues and fall risk. While the TUG is easy to administer and evaluate, its single time-to-completion outcome may not discriminate between different mobility challenges. Wearable sensors provide an opportunity to collect a variety of additional variables during clinical tests. The purpose of this study was to assess a new wearable inertial sensor system (iTUG) by investigating the effects of cognitive tasks in a dual-task paradigm on spatiotemporal and kinematic variables during the TUG. No previous studies have looked at both spatiotemporal variables and kinematics during dual-task TUG tests. 20 healthy young participants (10 males) performed a total 15 TUG trials with two different cognitive tasks and a normal control condition. Total time, along with spatiotemporal gait parameters and kinematics for all TUG subtasks (sit-to-stand, walking, turn, turn-to-sit), were measured using the inertial sensors. Time-to completion from iTUG was highly correlated with concurrent manual timing. Spatiotemporal variables during walking showed expected differences between control and cognitive dual-tasks while trunk kinematics appeared to show more sensitivity to dual-tasks than reported previously in straight line walking. Non walking TUG subtasks showed only minor changes during dual-task conditions indicating a possible attentional shift away from the cognitive task. Stride length and some variability measures were significantly different between the two cognitive tasks suggesting an ability to discriminate between tasks. Overall, the use of the iTUG system allows the collection of both traditional and potentially more discriminatory variables with a protocol that is easily used in a clinical setting. PMID- 25827681 TI - Kinematic and kinetic comparison of barefoot and shod running in mid/forefoot and rearfoot strike runners. AB - Barefoot running has been associated with decreased stride length and switching from a rearfoot strike (RFS) pattern to a mid/forefoot strike (M/FFS) pattern. However, some individuals naturally contact the ground on their mid/forefoot, even when wearing cushioned running shoes. The purpose of this study was to determine if the mechanics of barefoot running by natural shod RFS runners differed from natural shod M/FFS runners. Twenty habitually shod runners (ten natural M/FFS and ten natural RFS) participated in this study. Three-dimensional motion analysis and ground reaction force data were captured as subjects ran at their preferred running speed in both barefoot and shod conditions. M/FFS experienced only a decrease in stride length when switching from shod to barefoot running. Whereas, when switching from shod to barefoot running, RFS individuals experienced a decrease in stride length, switched to a plantarflexed position at ground contact and saw reduced impact peak magnitudes. These results suggest that when barefoot, the RFS group ran similar to the M/FFS group running barefoot or shod. PMID- 25827682 TI - TGFbeta1 inhibits IFNgamma-mediated microglia activation and protects mDA neurons from IFNgamma-driven neurotoxicity. AB - Microglia-mediated neuroinflammation has been reported as a common feature of familial and sporadic forms of Parkinson's disease (PD), and a growing body of evidence indicates that onset and progression of PD correlates with the extent of neuroinflammatory responses involving Interferon gamma (IFNgamma). Transforming growth factor beta1 (TGFbeta1) has been shown to be a major player in the regulation of microglia activation states and functions and, thus, might be a potential therapeutic agent by shaping microglial activation phenotypes during the course of neurodegenerative diseases such as PD. In this study, we demonstrate that TGFbeta1 is able to block IFNgamma-induced microglia activation by attenuating STAT1 phosphorylation and IFNgammaRalpha expression. Moreover, we identified a set of genes involved in microglial IFNgamma signaling transduction that were significantly down-regulated upon TGFbeta1 treatment, resulting in decreased sensitivity of microglia toward IFNgamma stimuli. Interestingly, genes mediating negative regulation of IFNgamma signaling, such as SOCS2 and SOCS6, were up-regulated after TGFbeta1 treatment. Finally, we demonstrate that TGFbeta1 is capable of protecting midbrain dopaminergic (mDA) neurons from IFNgamma-driven neurotoxicity in mixed neuron-glia cultures derived from embryonic day 14 (E14) midbrain tissue. Together, these data underline the importance of TGFbeta1 as a key immunoregulatory factor for microglia by silencing IFNgamma-mediated microglia activation and, thereby, rescuing mDA neurons from IFNgamma-induced neurotoxicity. Interferon gamma (IFNgamma) is a potent pro-inflammatory factor that triggers the activation of microglia and the subsequent release of neurotoxic factors. Transforming growth factor beta1 (TGFbeta1) is able to inhibit the IFNgamma-mediated activation of microglia, which is characterized by the release of nitric oxide (NO) and tumor necrosis factor alpha (TNFalpha). By decreasing the expression of IFNgamma-induced genes as well as the signaling receptor IFNgammaR1, TGFbeta1 reduces the responsiveness of microglia towards IFNgamma. In mixed neuron-glia cultures, TGFbeta1 protects midbrain dopaminergic (mDA) neurons from IFNgamma-induced neurotoxicity. PMID- 25827683 TI - Measurement of body composition should become routine in nutritional assessment of children with cerebral palsy. PMID- 25827684 TI - Assessment of toxicity and coagulopathy of brodifacoum in Japanese quail and testing in wild owls. AB - Based on detection of hepatic residues, scavenging and predatory non-target raptors are widely exposed to second generation anticoagulant rodenticides (SGARs). A small proportion, generally <10%, of tested birds are diagnosed as acutely poisoned. Little is known, however, of sub-lethal effects of SGARs, such as interaction of clotting capacity with traumatic injury. Assessment of coagulation function of birds submitted live to wildlife rehabilitators or veterinarians may provide a means of establishing the proportion of animals suffering sub-lethal coagulopathies, as well as identifying individuals requiring treatment. As a first step in exploring the potential of this approach, we dosed Japanese quail (Coturnix japonica) with the SGAR, brodifacoum, at 0, 0.8, 1.4, 1.9, and 2.5 mg/kg and sampled birds at 1, 3, 5 and 7 days post-dosing. Prothrombin time (PT), which measures the extrinsic coagulation pathway, was significantly prolonged in 98% of brodifacoum-exposed quail in a dose- and time dependent manner. 50-fold prolongation of PT occurred at higher brodifacoum dosages and correlated to hemorrhage found at necropsy. Activated clotting time (ACT), a measure of the intrinsic pathway also increased with dose and time. Hemoglobin (Hb) and hematocrit (Hct) decreased dose- and time-dependently at doses >=1.4 mg/kg with no significant change at 0.8 mg/kg. Reference intervals for PT (10.0-16.2 s), ACT (30-180 s), Hb (9.6-18.4 g/dl), and Hct (34-55%) were established in Japanese quail. Species-specific reference intervals are required as barn owl PT (17-29 s) and quail PT were different. The proportion of brodifacoum-exposed quail with hemorrhage was not correlated with liver residues, but was correlated with PT, suggesting that this assay is a useful indicator of avian anticoagulant rodenticide exposure. PTs measured in free-living barn owls sampled between April 2009 and August 2010 in the lower Fraser Valley of BC do not suggest significant exposure to SGARs. PMID- 25827685 TI - Risk of recurrent ischaemic events after myocardial infarction in long-distance ski race participants. AB - AIMS: To study whether a high level of physical activity prior to myocardial infarction (MI) also protects against recurrent MI (re-MI) or death. METHODS AND RESULTS: A longitudinal study of a primary cohort consisting of 204,038 skiers with a proved substantially high level of physical activity in the world's largest long-distance ski race, Vasaloppet, and 499,543 non-skiers selected from the Swedish population. Individuals with severe diseases at baseline were excluded. In the nationwide clinical register, Swedeheart, we identified 7092 individuals with a first MI incident between 1989 and 2010. Of these, 1039 (0.5%) were skiers and 6053 (1.2%) were non-skiers. One hundred and sixty-three (15.7%) skiers and 1352 (22.3%) non-skiers suffered a re-MI or died during follow-up (median 4.44 years), corresponding to an incidence rate of 38.9 (95% confidence interval (CI) 33.2-45.4)/1000 person-years and 55.6 (95% CI 52.7-58.7)/1000 person-years, respectively. Severity of MI in both groups was the same. For skiers compared to non-skiers the unadjusted hazard ratio (HR) for re-MI was 0.66 (95% CI 0.52-0.82). For death or re-MI, HR was 0.70 (95% CI 0.59-0.82) with consistent results in subgroups based on race year, age, gender, education level, marital status. After adjustment for also smoking, diabetes, hypertension and cardiovascular medication, HR was 0.80 (95% CI 0.67-0.97). CONCLUSIONS: This large cohort study supports the hypothesis that patients with MI and with prior physical activity and healthy lifestyle, as evidenced by their participation in a long-distance ski race, have a lower risk of subsequent re-MI or death. PMID- 25827686 TI - Comparison of application of different methods to estimate lifetime cardiovascular risk. AB - BACKGROUND: Recent guidelines recommend assessment of lifetime cardiovascular risk on the basis of traditional risk factors in adults who are not at high short term risk. The aim of this study is to determine the implications of estimating the lifetime cardiovascular risk in individuals in a large occupational cohort in Spain. DESIGN: National cross-sectional study in an occupational cohort with an in-person interview including laboratory tests. METHODS: Volunteer workers who were examined between January 2011 and December 2011 were included. A total of 580,236 workers were eligible during this year and 259,834 were examined (participation rate of 44.7%). Short-term (10-year) and lifetime cardiovascular risk were estimated using the American College of Cardiology (ACC) and the American Heart Association (AHA) tool and the QRISK2 and QRISK. RESULTS: Sixty eight per cent were male, mean age was 39 years, with an age range of 16 to 75 years. Total number of individuals included in this study was 258,676. The percentage of patients at high short-term risk was 6.85% (95% confidence interval (CI) 6.75%-6.95% and 20.83% (95% CI 20.60%-21.07%) with the QRISK2, and the ACC/AHA risk equations, respectively. Of the percentage of patients classified as not at high risk with the different tools 1.61% (95% CI 1.55%-1.66%) were high lifetime risk on QRISK, and 27.41% (95% CI 27.11%-27.70%) on ACC/AHA risk. CONCLUSIONS: Application of lifetime cardiovascular risk engages greater numbers of individuals at high risk with substantial differences between the different methods available. These differences can have important clinical implications specifically in the percentage of candidates for lifestyle changes and eventually lipid lowering drugs. PMID- 25827687 TI - Impact of Transcollation technology in thoracic surgery: a retrospective study. AB - OBJECTIVES: This is a retrospective study to evaluate the effectiveness of Transcollation technology (TT) in reducing blood loss and improving the postoperative outcome in patients with severe pleural-parenchymal adhesions who underwent major lung resection. METHODS: Between November 2010 and February 2012, TT was used to perform lysis of adhesions and dissection in 110 patients (TT Group) who underwent major lung resections via thoracotomy. Conventional electrocoagulation was used in 129 patients (EC Group). Operative time, daily drainage amount at 24, 48 and 72 h, pre- and postoperative haemoglobin levels, need for blood transfusion, intra- and postoperative air leaks and duration of chest tube placement and hospital stay were analysed. RESULTS: No adverse events related to the TT system occurred, including reoperation for bleeding. The mean operating time was 95.2 +/- 35.4 min in the TT Group versus 117.1 +/- 73.4 min in the EC Group (P = 0.017). The mean postoperative haemoglobin level was 12.3 +/- 3.9 g/dl versus the preoperative level of 13.8 +/- 2.2 g/dl in the TT Group (P = 0.154) and 9.6 +/- 2.8 vs 13.2 +/- 2.1 g/dl in the EC Group (P = 0.001). Only 2 patients (1.8%) received postoperative blood transfusion in the TT Group vs 19 patients (14.7%) in the EC Group (P = 0.001). Intraoperative and postoperative (24 h) air leak rates were 4.7% (n = 5) and 2.8% (n = 3) in the TT Group vs 13.9% (n = 18) and 12.4% (n = 16) in the EC Group (P = 0.001), respectively. The mean duration of chest tube placement was shorter in the TT Group (4.7 +/- 0.8 vs 6.8 +/- 1.1 days, P = 0.013), as well as the mean hospital stay (5.3 +/- 1.9 vs 7.5 +/- 0.3 days, P = 0.007). CONCLUSIONS: The use of TT seems to reduce haemorrhage occurrence and postoperative hospital stay after major lung resection in patients with severe pleural-parenchymal adhesions. PMID- 25827688 TI - New parameter of the right gastroepiploic arterial graft using the power spectral analysis device named MemCalc soft. AB - OBJECTIVES: Transit-time flow measurement (TTFM) parameters such as mean graft flow (MGF, ml/min), pulsatility index (PI) and diastolic filling (DF, %) have been extensively researched for internal mammary arterial or saphenous vein grafts. In our experience of using the right gastroepiploic arterial (GEA) graft for right coronary artery (RCA) grafting, we observed unique GEA graft flow waveforms. We analysed the GEA graft flow waveforms for their effectiveness in determining GEA graft patency by power spectral analysis. METHODS: Forty-five patients underwent off-pump coronary artery bypass using the GEA graft for RCA grafting individually. The means of intraoperative MGF, PI and DF were compared between patent and non-patent grafts, postoperatively. Furthermore, the GEA flow data were output and analysed using power spectral analysis. RESULTS: Forty grafts were 'patent' and five were 'non-patent'. There were no significant differences in the mean TTFM parameters between the patent and non-patent grafts (MGF: 22 vs 8 ml/min, respectively, P = 0.068; PI: 3.5 vs 6.5, respectively, P = 0.155; DF: 63 vs 53%, respectively, P = 0.237). Results of the power spectral analysis presented clear differences; the power spectral density (PSD) of patent grafts presented high peaks at frequency levels of 1, 2 and 3 Hz, and the non patent graft PSD presented high peaks that were not limited to these frequencies. The PSD had a sensitivity and specificity of 80 and 87.5%, respectively. CONCLUSIONS: Power spectral analysis of the GEA graft flow is useful to distinguish between non-patent and patent grafts intraoperatively. This should be used as a fourth parameter along with MGF, PI and DF. PMID- 25827689 TI - Urban metabolism: Measuring the city's contribution to sustainable development. AB - Urban metabolism refers to the assessment of the amount of resources produced and consumed by urban ecosystems. It has become an important tool to understand how the development of one city causes impacts to the local and regional environment and to support a more sustainable urban design and planning. Therefore, the purpose of this paper was to measure the changes in material and energy use occurred in the city of Curitiba (Brazil) between the years of 2000 and 2010. Results reveal better living conditions and socioeconomic improvements derived from higher resource throughput but without complete disregard to environmental issues. Food intake, water consumption and air emissions remained at similar levels; energy use, construction materials and recycled waste were increased. The paper helps illustrate why it seems more adequate to assess the contribution a city makes to sustainable development than to evaluate if one single city is sustainable or not. PMID- 25827690 TI - Linking the environmental loads to the fate of PPCPs in Beijing: Considering both the treated and untreated wastewater sources. AB - The environmental loads of pharmaceutical and personal care products (PPCPs) in Beijing were estimated from direct discharge of untreated wastewater and WWTP treated effluent. The annual environmental loads of 15 PPCP components ranged from 16.3 kg (propranolol) to 9.85 tons (caffeine). A fugacity model was developed to successfully estimate the PPCP pollution based on the estimated environmental load. The modeled results approximated the observed PPCP concentrations in Beijing. The untreated wastewater contributed significantly to PPCP pollution in Beijing, ranging from 46% (propranolol) to 99% (caffeine). The total environmental burden of target PPCPs ranged from 0.90 kg (propranolol) to 536 kg (caffeine). Water is the most important media for the fate of PPCPs. Monte Carlo-based concentration distributions of PPCPs are consistent with the observed results. The most important way to reduce the PPCP pollution is to both improve wastewater collection rate and adopt deep treatment technologies. PMID- 25827691 TI - Organochlorine pesticides accumulated by SPMD-based virtual organisms and feral fish in Three Gorges Reservoir, China. AB - Organochlorine pesticides (OCPs) accumulated by semipermeable membrane device (SPMD) -based virtual organisms (VOs) and local feral fish were studied in Three Gorges Reservoir (TGR), China. VOs were deployed at seven sites in TGR for two periods in 2009 and 5 species of fish with different living habitats and feeding habits collected in the same periods from two counties in TGR. 28 OCPs were analyzed and the concentration and profile of OCPs in fish were quite different from those in VOs. The lipid-based concentrations of OCPs in fish ranged from 225.7 ng/g lw to 1996.4 ng/g lw which were much higher than those in VOs which ranged from 17.3 to 112.4 ng/g lw. Dichlorodiphenyltrichloroethanes (DDTs) were the prevalent OCPs in the investigated fish, while hexachlorobenzene (HCB) was the dominant compound in VOs. DDT in the few fish sample analyzed was not of concern based on chemical contaminant limits of non-carcinogenic effect. PMID- 25827692 TI - Adsorption of perfluoroalkyl acids by carbonaceous adsorbents: Effect of carbon surface chemistry. AB - Adsorption by carbonaceous sorbents is among the most feasible processes to remove perfluorooctane sulfonic (PFOS) and carboxylic acids (PFOA) from drinking and ground waters. However, carbon surface chemistry, which has long been recognized essential for dictating performance of such sorbents, has never been considered for PFOS and PFOA adsorption. Thus, the role of surface chemistry was systematically investigated using sorbents with a wide range in precursor material, pore structure, and surface chemistry. Sorbent surface chemistry overwhelmed physical properties in controlling the extent of uptake. The adsorption affinity was positively correlated carbon surface basicity, suggesting that high acid neutralizing or anion exchange capacity was critical for substantial uptake of PFOS and PFOA. Carbon polarity or hydrophobicity had insignificant impact on the extent of adsorption. Synthetic polymer-based Ambersorb and activated carbon fibers were more effective than activated carbon made of natural materials in removing PFOS and PFOA from aqueous solutions. PMID- 25827694 TI - Patients' attitudes toward the attire of male physicians: a single-center study in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: The doctor-patient relationship has been influenced by the appearance of physicians, and there is an association between a physician's physical appearance and the patients' initial perceptions of physician competence. This study aims to explore patients' preferences toward the attire of a male physician, and to examine if a physician's choice of uniform influences the degree of trust, confidence, and follow-up care among respondents. DESIGN AND SETTINGS: A cross-sectional survey conducted among patients of the Alwazarat family medicine center in Riyadh, Saudi Arabia. PATIENTS AND METHODS: A self administered questionnaire was completed by 300 patients (50% were male and 83.6% had received a secondary education; the mean age was 33.4 [10.1] years) in the Alwazarat family medicine center in Riyadh. The questionnaire was also customized for the local setting with the inclusion of photos of a male doctor in Saudi Arabian national costume, and 3 other dress styles (Western dress with white coat, scrubs with white coat, and scrubs only). RESULTS: Overall, across all questions regarding physician dress style preferences, participants significantly preferred Western dress (39.9%, P < .001), followed by Saudi national dress (26.3%), a scrub suit with a white coat (22.3%), and scrubs only (11.5%). Respondents reported that they were more likely to follow medical advice and would return for follow-up care if a physician wore Western dress. They were significantly more willing to share their social, sexual, and psychological problems with a physician wearing Saudi national dress (P < .001). The importance of a physician's appearance was ranked significantly higher by older patients (P=.002). CONCLUSION: Respondents were more likely to favor a physician wearing Western attire with a white coat. However, Saudi national dress, followed by Western dress, is the preferred attire when physicians are dealing with social, sexual, and psychological problems. PMID- 25827693 TI - Myocardial protection and early outcome of different coronary surgical techniques for diabetic patients with triple vessels. AB - BACKGROUND AND OBJECTIVES: For patients with diabetes and triple-vessel disease, coronary artery bypass grafting (CABG) surgery is a well-established procedure, but cardiopulmonary bypass support may also lead to severe complications to these patients. The aim of this study was to compare myocardial protection and early outcomes in patients with diabetes and triple-vessel disease following different coronary surgical techniques. DESIGN AND SETTINGS: Prospective randomized trial of patients treated at the First Affiliated Hospital of China Medical University over a 3-year period (2011- 2013). METHODS: In a single-center randomized trial, 668 patients with diabetes and triple-vessel disease were randomly assigned to off-pump (OPCAB) (number [n]=222), on-pump beating heart (OnP-BH) (n=223), and conventional CABG (OnP) (n=223) between January 2011 and October 2013. Myocardial injury was assessed by measuring the serial release of cardiac troponin I (cTnI) preoperatively, 1 hour, 12 hours, 24 hours, and 72 hours postoperatively. The early outcomes were compared among these 3 groups. RESULTS: Preoperative characteristics of the patients in all 3 groups were similar. No significant difference was found regarding the number of anastomoses, the use of the internal thoracic artery, postoperative new-onset atrial fibrillation, hemodialysis, stroke, reoperation for bleeding, and infective complications in the 3 groups (P > .05). The complete revascularization, postoperative drainage loss, intra-aortic balloon pump support, blood requirements, postoperative myocardial infarction, pulmonary complications, gastrointestinal complications, inotropic requirements > 24 hours, ventilation > 24 hours, intensive care unit stay > 24 hours, and in hospital stay > 7 days were significantly lower in the OPCAB group than in the other 2 groups (P < .05). In-hospital mortality was lower in the OPCAB group than in the other 2 groups, but no statistical difference was observed (P > .05). Preoperative cTnI in the 3 groups was similar (P > .05); however, the lowest cTnI value was noted in the OPCAB group, followed by the OnP group, and it was highest in the OnP-BH group 1 hour, 12 hours, 24 hours, and 72 hours postoperatively (P < .05). CONCLUSION: OPCAB is superior to the OnP-BH and OnP techniques in terms of postoperative complications and myocardial protection in patients with diabetes and triple-vessel disease. Myocardial injury in the OnP-BH group was significantly higher than that in the OnP group. PMID- 25827695 TI - A founder splice site mutation underlies glycogen storage disease type 3 in consanguineous Saudi families. AB - BACKGROUND AND OBJECTIVES: Glycogen storage disease type 3 (GSD III) is an autosomal recessive disorder caused by genetic mutations in the gene AGL. AGL encodes amylo-a-1, 6-glucosidase, 4-a-glucanotransferase, a glycogen debranching enzyme. GSD III is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy, and cardiomyopathy due to storage of abnormally structured glycogen in both skeletal and cardiac muscles and/or liver. The aim of this study is to detect mutations underlying GSD III in Saudi patients. DESIGN AND SETTINGS: A cross-sectional clinical genetic study of 5 Saudi consanguineous families examined at the metabolic clinic of the Madinah Maternity and Children Hospital. PATIENTS AND METHODS: We present a biochemical and molecular analysis of 5 consanguineous Saudi families with GSD III. DNA was isolated from the peripheral blood of 31 individuals, including 12 patients, and the AGL gene was sequenced bidirectionally. DNA sequences were compared with the AGL reference sequence from the ensemble genome browser. RESULTS: Genotyping and sequence analysis identified a homozygous intronic splice acceptor site mutation (IVS32-12A > G) in 4 families perfectly segregating with the phenotype. Complementary (c)DNA sequence analysis of the AGL gene revealed an 11-bp sequence insertion between exon 32 and exon 33 due to the creation of a new 3' splice site. The predicted mutant enzyme was truncated by 112 carboxyl-terminal amino acids as a result of premature termination. CONCLUSION: Haplotype analysis revealed that the mutation arises as a result of founder effect, not an independent event. This is the first report of a genetic mutation in the AGL gene from Saudi Arabia. Screening for this mutation can improve genetic counseling and prenatal diagnosis of GSD III in Saudi Arabia. PMID- 25827696 TI - Middle Eastern Respiratory Syndrome Corona Virus (MERS CoV): case reports from a tertiary care hospital in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Middle Eastern respiratory syndrome caused by novel coronavirus (MERS CoV) has been a major public health challenge since it was first described in 2012 in Saudi Arabia. So far, there is no effective treatment for this serious illness, which features a high mortality rate. We report an initial experience of the use of ribavirin and interferon (IFN)-a2b in the management of MERS CoV at a tertiary care hospital. DESIGN AND SETTINGS: A case series of 6 patients admitted with a confirmed diagnosis of MERS CoV were treated with ribavirin and IFN-a2b in addition to supportive management. The patients' demographics, clinical parameters, and outcomes were recorded. Fifty-four close contacts of these patients were screened for MERS CoV. METHODS: Six patients with MERS CoV infection were included in this study. Four cases featured symptomatic disease, including pneumonia and respiratory failure, while 2 were asymptomatic close contacts of the MERS CoV patients. The MERS CoV infection was confirmed by reverse transcription-polymerase chain reaction detection of the consensus viral RNA targets upstream of the E gene (UPE) and open reading frame (ORF1b) on a sputum sample. The patients' demographics, comorbid conditions, time to diagnosis and initiation of treatment, and clinical outcomes were recorded. RESULTS: Three out of 6 patients who had comorbid conditions died during the study period, while 3 had suc.cessful outcomes. The diagnosis and treatment was delayed by an average of 15 days in those patients who died. Only 2 close contacts out of the 54 screened (3.7%) were positive for MERS CoV. CONCLUSION: Treatment with ribavirin and IFN-a2b may be effective in patients infected with MERS CoV. There appears to be a low infectivity rate among close contacts of MERS CoV patients. PMID- 25827697 TI - Presence of HCV RNA in peripheral blood mononuclear cells may predict patients response to interferon and ribavirin therapy. AB - BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) is considered a hepatotropic virus, but it can repli.cate in peripheral blood mononuclear cells (PBMCs), which influence the sustained virological response (SVR) of the patients, as well as relapse in successfully treated patients. The main objective of this study was to establish the importance of PBMC HCV RNA detection as a primary test to declare the patient as a responder, and the secondary objective was to investigate the risk of non-SVR or relapse in individuals who showed an end-of-treatment (ETR). DESIGN AND SETTINGS: Blood samples were collected after the completion of 6 months of therapy, and they were collected 6 months after the completion of treatment. PATIENTS AND METHODS: A total 103 patients infected with the 3a genotype of HCV and those who were treated with interferon-a-2b and ribavirin for 24 weeks were selected. HCV RNA in plasma of at the end of treatment and 6 months after the completion of treatment was determined with the help of quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Of the 103 patients, 74.8% (number [n]=77) were end-of-treatment responders, while 25.2% (n=26) were nonresponders. Seventy-seven responders were tested for HCV RNA in their PBMCs. The HCV RNA was detected in the PBMCs of 29 patients (37.7%). After 6 months of the end of treatment, 15 (19.5%) of 77 ETR patients showed virological relapse, while 62 (80.5%) patients attained SVR. Relapse appeared significantly more often in patients with HCV RNA in their PBMCs at the ETR stage when compared to the patients who did not have the viral RNA (34.5% versus 10.4%, respectively; R2=6.67, P=.01; odds ratio [OR]: 1.3; 95% confidence interval [CI]=1.032-1.811). CONCLUSION: Patients with HCV RNA in their PBMCs after attaining an ETR are more likely to show relapse as compared to patients who are negative for viral RNA in PBMCs at the ETR stage. PMID- 25827698 TI - Polymorphisms of tumor necrosis factor-alpha and interleukin-6 gene and C reactive protein profiles in patients with idiopathic dilated cardiomyopathy. AB - BACKGROUND AND OBJECTIVES: The tumor necrosis factor-alpha (TNF-a) and interleukin (IL)-6 gene polymorphism has a controversial role in the pathogenesis of cardiovascular disease among different populations. The effect of the cytokine's gene polymorphism on idiopathic dilated cardiomyopathy (IDCM) is still unresolved. The current study aimed to evaluate the association of the TNF-a -308 G/A and IL-6 -174 G/C polymorphism with IDCM in a Pakistani population. DESIGN AND SETTINGS: Blood samples for this case-control study were collected from the cardiology out.patient department of multiple cardiology centers of Rawalpindi/Islamabad, Pakistan, between July 2012 and December 2012. PATIENTS AND METHODS: IDCM cases (number [n]=250) and healthy controls (n=300) were genotyped using polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The TNF-a -308 variant genotypes GA and AA were more prevalent in patients compared with the control group (P < .0001). Similarly, the IL-6 -174 variant genotypes GC and CC showed a high prevalence in patients with IDCM compared with healthy controls (P=.0019). IDCM cases had a higher prevalence of the TNFa-308A (P < .0001) and the IL-6 -174C (P=.0008) mutant alleles than did the control group. The IDCM cases bearing the TNF-a-308 and IL-6 variant genotypes revealed elevated levels of high-sensitivity C-reactive protein (hs CRP) when compared with the corresponding controls (P < .05). CONCLUSION: The TNF a -308 G/A and IL-6 -174 G/C gene polymorphisms and high levels of hs-CRP may be associated with the pathogenesis of IDCM in the study population. PMID- 25827699 TI - Arrhythmogenic right ventricular cardiomyopathy/dysplasia in Saudi Arabia: a single-center experience with long-term follow-up. AB - BACKGROUND AND OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a rare genetic disorder that primarily involves the right ventricle (RV). It is characterized by progressive replacement of RV myocardium by fibrofatty tissues. It commonly presents with ventricular tachycardia (VT) of RV origin and may result in RV failure. The aim of this study is to evaluate the clinical characteristics of adult patients with ARVC/D treated at the Heart Centre, King Faisal Specialist Hospital and Research Centre (KFSH&RC), Riyadh, Saudi Arabia. DESIGN AND SETTINGS: This is a retrospective study of patients with ARVC/D diagnosed and treated at the KFSH&RC Heart Centre in Riyadh. PATIENTS AND METHODS: Twenty-two cases with ARVC/D with regular follow up at our Heart Centre from January 2007 to May 2010 were included in this study. The diagnosis of ARVC/D was made according to the revised International Task Force Criteria. The clinical data were collected from patients' charts and electronic medical records. RESULTS: The majority of patients were males (18; 82%). The diagnosis of ARVC/D was definite in 18 patients (82%), borderline in 2 (9%), and possible in 2 (9%). The mean age at diagnosis was 33.3 years. The follow-up period ranged from 29 to 132 months, with a mean follow-up period of 84 months. Ten patients presented with sustained VT, and 3 were survivors of cardiac arrest. Electrocardiogram abnormalities were present in 16/22 patients (72.7%). Echocardiographic changes meeting major diagnostic criteria were seen in 16 patients (76%). Cardiac magnetic resonance imaging was performed in 11 patients, and showed changes compatible with major diagnostic criteria in 7 patients (64%). Implantable cardioverter defibrillators (ICDs) were implanted in 17 patients; 8 had appropriate ICD shocks and 5 had inappropriate ICD shocks. Antitachycardia pacing was effective in terminating most of the VT/ventricular fibrillation episodes. CONCLUSION: ARVC/D is a rare but increasingly recognized heart muscle disease seen in Saudi Arabia and other parts of the world. It is associated with a highly nonspecific presentation. VT of RV origin is a common presentation for this disease. Antiarrhythmic medications and ICD implantation are the main management options. PMID- 25827700 TI - Designing an autoverification system in Zagazig University Hospitals Laboratories: preliminary evaluation on thyroid function profile. AB - BACKGROUND AND OBJECTIVES: The current practice in Zagazig University Hospitals Laboratories (ZUHL) is manual verification of all results for the later release of reports. These processes are time consuming and tedious, with large inter individual variation that slows the turnaround time (TAT). Autoverification is the process of comparing patient results, generated from interfaced instruments, against laboratory-defined acceptance parameters. This study describes an autoverification engine designed and implemented in ZUHL, Egypt. DESIGN AND SETTINGS: A descriptive study conducted at ZUHL, from January 2012-December 2013. MATERIALS AND METHODS: A rule-based system was used in designing an autoverification engine. The engine was preliminarily evaluated on a thyroid function panel. A total of 563 rules were written and tested on 563 simulated cases and 1673 archived cases. The engine decisions were compared to that of 4 independent expert reviewers. The impact of engine implementation on TAT was evaluated. RESULTS: Agreement was achieved among the 4 reviewers in 55.5% of cases, and with the engine in 51.5% of cases. The autoverification rate for archived cases was 63.8%. Reported lab TAT was reduced by 34.9%, and TAT segment from the completion of analysis to verification was reduced by 61.8%. CONCLUSION: The developed rule-based autoverification system has a verification rate comparable to that of the commercially available software. However, the in-house development of this system had saved the hospital the cost of commercially available ones. The implementation of the system shortened the TAT and minimized the number of samples that needed staff revision, which enabled laboratory staff to devote more time and effort to handle problematic test results and to improve patient care quality. PMID- 25827701 TI - A written consent form dating back to 1524 in Bursa Ser'iye (Sharia Court) records and a proposal of a new start date for consent forms. AB - BACKGROUND AND OBJECTIVES: Qadi registers are important documents for Ottoman medical history re.search. "Sharia Court Records (Ser'iyye Sicilleri)" are notebooks that include the records that qadis kept with regard to their decisions and deeds. These registers are the only authentic sources from which to acquire information on rural life, away from the center of the town, and to understand the daily practices of the Ottoman society. The objective of this study is to provide evidence for the fact that the concept of informed consent on medical interventions, and hence the written consent documents arranged between patients and physicians, dates back to older times in our history when compared to the Western world. DESIGN AND SETTING: A large number of Ser'iyye (Sharia Court) record originals have been surveyed. The consent form registered as A-40. 221a in Ser'iyye (Sharia Court) Records found in Bursa has been presented here as the earliest consent document found by the authors. Transcription of the original document has been performed and analyzed. The aforementioned consent form dates back to 26/Dhu al-Qi'dah/933 (August 24, 1524). METHODS: The original version of the referenced consent document is the earliest consent document presented so far to the best of the authors' knowledge; it was found in Bursa Ser'iyye Records and evaluated accordingly. RESULTS: Based on the document, it is argued that the history of consent forms dates back about 500 years. CONCLUSION: Obtaining consent in scientific research from human beings was considered to have originated from the Nuremberg Code (1949). However, with this study, it has been shown that the concept of informed consent was already present in the Ottoman Period, during the 16th century, and that the original consent document dates back to 1524, pertaining to a surgical intervention. PMID- 25827702 TI - Fatal case of cryptogenic organizing pneumonia associated with everolimus. AB - Noninfectious pneumonitis (NIP) has been reported with everolimus; however, the majority of the reported cases were mild to moderate. We report a fatal case of cryptogenic organizing pneumonia (COP) in a 61-year-old man. About 4 weeks after starting everolimus, the patient was admitted to the hospital with complaints of a 1-week history of progressive dyspnea with exertion and cough. The chest radiograph showed bilateral multifocal dense opacities, and he was started on antibiotics. However, his respiratory status deteriorated, and he was subsequently intubated and transferred to the intensive care unit. Chest computed tomography showed bronchocentric consolidation associated with widespread bilateral fine reticular opacification. Video-assisted thoracoscopic lung biopsy showed noncaseating granulomatous inflammation and features of COP. All cultures were negative for bacterial, viral, and fungal infections. Despite discontinuing everolimus and initiating corticosteroids, the patient died of progressive respiratory failure secondary to COP. PMID- 25827703 TI - A hitherto undescribed case of cerebellar ataxia as the sole presentation of thyrotoxicosis in a young man: a plausible association. AB - A 16-year-old male presented to hospital following an episode of unusual behavior on the football pitch, where he was witnessed as grossly ataxic by his teammates. The assessment demonstrated marked cerebellar signs on examination but no other neurological deficit. The investigation showed the evidence of biochemical thyrotoxicosis with free T4 at 37 pmol/L (normal reference range: 11-27) and thyrotropin (TSH) < 0.003 mU/L. Following admission, full investigations including computed tomographic brain scan with contrast, lumbar puncture with cerebrospinal fluid examination, magnetic resonance imaging, and magnetic resonance angiography did not reveal abnormalities. He was initiated on carbimazole 40 mg every day. Thyroid ultrasonography revealed a goiter with increased blood flow, and his thyroid antibodies showed positive thyroid peroxidase antibodies but negative TSH receptor antibodies. Electroencephalogram did not reveal any abnormalities. His neurological disability resolved completely after his thyroid function normalized. The association of cerebellar syndromes is well described with hypothyroidism; however, it is hitherto undescribed with thyrotoxicosis. The causal relationship is plausible because alternative etiologies were excluded, and the normalization of thyroid function with treatment was coupled with complete resolution of the neurological syndrome. Cerebellar syndromes may well be one of the presenting features of thyrotoxicosis, and this should be in the list of its differential diagnosis. PMID- 25827704 TI - Primary fallopian tube carcinoma diagnosed preoperatively by cervical smear. AB - Primary fallopian tube carcinoma is a rare clinical entity that constitutes a diagnostic challenge in gynecological practice. Patients generally suffer from the three symptoms: vaginal bleeding, pelvic pain, and vaginal discharge; however, this is usually not sufficient for confirming the diagnosis preoperatively in most circumstances. In this case report, we present a 49-year old woman whose cervical smear raised a suspicion for fallopian tube carcinoma. All preoperative examination measures such as ultrasonography, hysteroscopy, and endometrial aspiration were normal. Repeated cervical smears were consistent with adenocarcinoma presumably ensourcing from the fallopian tube. The patient underwent laparatomy,total abdominal hysterectomy, bilateral salpingo oophorectomy, and pelvic para-aortic lymph node dissection. The primary serous papillary adenocarcinoma of the right fallopian tube was detected at the histopathological analysis, and the patient was referred for adjuvant chemotherapy. Cervical smear findings can be the only clue for the diagnosis of fallopian tube carcinoma. PMID- 25827705 TI - Pulmonary epitheloid hemangioendothelioma PET CT findings and review of literature. AB - We describe a case of pulmonary epitheloid hemangioendothelioma (PEH) in a 13 years old girl, the aggressive nature of the tumor in this particular case and the PET CT findings. PEH are rare tumors of vascular origin, first described by Dial and Liebow in 1975. This is an uncommon pulmonary neoplasm, 4 times more common in young women. This tumor can affect multiple organs (lung, liver, bones and soft tissue, skin, heart, central nervous system). However lung and liver represent 2 main locations. Clinical manifestations are variable; typically patients are asymptomatic, and PEH is detected on routine chest radiographs as bilateral small (1 cm or less) nodules in the lungs Diagnosis usually requires a surgical lung biopsy. The prognosis is very unpredictable, with life expectancy ranging from 1 to 15 years. The tumor is usually considered as low to intermediate grade sarcoma. There is no single effective treatment however spontaneous remissions and aggressive behavior has been described. PMID- 25827706 TI - A 72-year-old man presenting with progressive lower limb weakness and unconsciousness. Thrombosis of the vein of Galen. PMID- 25827707 TI - Acute necrotizing encephalopathy secondary to sepsis. PMID- 25827709 TI - Functional analysis of bovine TLR5 and association with IgA responses of cattle following systemic immunisation with H7 flagella. AB - Flagellin subunits are important inducers of host immune responses through activation of TLR5 when extracellular and the inflammasome if cytosolic. Our previous work demonstrated that systemic immunization of cattle with flagella generates systemic and mucosal IgA responses. The IgA response in mice is TLR5 dependent and TLR5 can impact on the general magnitude of the adaptive response. However, due to sequence differences between bovine and human/murine TLR5 sequences, it is not clear whether bovine TLR5 (bTLR5) is able to stimulate an inflammatory response following interaction with flagellin. To address this we have examined the innate responses of both human and bovine cells containing bTLR5 to H7 flagellin from E. coli O157:H7. Both HEK293 (human origin) and embryonic bovine lung (EBL) cells transfected with bTLR5 responded to addition of H7 flagellin compared to non-transfected controls. Responses were significantly reduced when mutations were introduced into the TLR5-binding regions of H7 flagellin, including an R90T substitution. In bovine primary macrophages, flagellin-stimulated CXCL8 mRNA and secreted protein levels were significantly reduced when TLR5 transcript levels were suppressed by specific siRNAs and stimulation was reduced with the R90T-H7 variant. While these results indicate that the bTLR5 sequence produces a functional flagellin-recognition receptor, cattle immunized with R90T-H7 flagella also demonstrated systemic IgA responses to the flagellin in comparison to adjuvant only controls. This presumably either reflects our findings that R90T-H7 still activates bTLR5, albeit with reduced efficiency compared to WT H7 flagellin, or that other flagellin recognition pathways may play a role in this mucosal response. PMID- 25827710 TI - Scatterhoarding rodents favor higher predation risks for cache sites: The potential for predators to influence the seed dispersal process. AB - Scatterhoarding rodents often place caches in the open where pilferage rates are reduced, suggesting that they tradeoff higher risks of predation for more secure cache sites. We tested this hypothesis in two study systems by measuring predation risks inferred from measures of giving-up densities (GUDs) at known cache sites and other sites for comparison. Rodent GUDs were measured with small trays containing 3 L of fine sand mixed with sunflower seeds. In the first experiment, we relied on a 2-year seed dispersal study in a natural forest to identify caches of eastern gray squirrels (Sciurus carolinensis) and then measured GUDs at: (i) these caches; (ii) comparable points along logs and rocks where rodent activity was assumed highest; and (iii) a set of random points. We found that GUDs and, presumably, predation risks, were higher at both cache and random points than those with cover. At the second site, we measured GUDs of eastern gray squirrels in an open park system and found that GUDs were consistently lowest at the base of the tree compared to more open sites, where previous studies show caching by squirrels to be highest and pilferage rates by naive competitors to be lowest. These results confirm that predation risks can influence scatterhoarding decisions but that they are also highly context dependent, and that the landscape of fear, now so well documented in the literature, could potentially shape the temporal and spatial patterns of seedling establishment and forest regeneration in systems where scatterhoarding is common. PMID- 25827711 TI - The prevalence of benign breast diseases in patients with nodular goiter and Hashimoto's thyroiditis. AB - PURPOSE: The evidence regarding association between thyroid disorders and benign and malignant breast diseases is increasing. The studies exploring the relationship between thyroid and breast diseases usually have focused on thyroid autoimmunity and functions in patients with breast pathologies. In this study, we aimed to reveal the frequency of benign breast conditions in patients with nodular thyroid disease (NTD) and Hashimoto's thyroiditis (HT). METHODS: Seventy one women with NTD, ninety-five women with HT and seventy-two healthy people as a control group were included in the study. Serum thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and thyroid peroxidase autoantibody levels were measured, and thyroid and breast ultrasonography were performed by a single operator in order to determine thyroid and breast pathology. RESULTS: Benign breast diseases were detected in 54.9% of patients with NTD, in 47.4% of those with HT, and 29.2% of control group in the study (p < 0.01 for nodular and Hashimoto groups versus control group). Simple cyst was found to be the most frequent pathology among benign breast diseases; fibrocystic changes, mixed lesions, benign solid mass, ductal ectasia, and complex cyst followed it. No significant relation was found regarding thyroid function and autoimmunity in patients diagnosed with benign breast disease (p > 0.05). CONCLUSIONS: The results of our study support the association between benign breast diseases and thyroid diseases. An important implication of this finding may be demonstration of the necessity of scanning for potential breast pathology in women with nodular or autoimmune thyroid disease in clinical practice. PMID- 25827712 TI - Evaluating lifestyle and health-related characteristics of older adults with co occurring depressive symptoms and cardiometabolic abnormalities. AB - OBJECTIVE: Comorbid depression and cardiometabolic abnormalities might represent an important subgroup of depression. The aim of the present study was to evaluate lifestyle and health-related characteristics of individuals with both depressive symptoms and cardiometabolic abnormalities. METHODS: Data were from the English Longitudinal Study of Ageing. The sample was comprised of 5365 adults aged 50-80 years. High depressive symptoms were based on the eight-item Center for Epidemiologic Studies - Depression scale. Cardiometabolic abnormalities were defined as having >=3 cardiometabolic risk factors (hypertension, impaired glycemic control, systemic inflammation, low high-density lipoprotein cholesterol, hypertriglyceridemia, and central obesity). Four groups were created based on Center for Epidemiologic Studies - Depression scores and cardiometabolic abnormalities: those with (i) comorbid depressive symptoms and cardiometabolic abnormalities (DCM); (ii) depressive symptoms only (DnoCM); (iii) cardiometabolic abnormalities only; and (iv) neither depressive symptoms nor cardiometabolic abnormalities. Lifestyle and health-related characteristics of the four groups were compared using chi-square tests. A modified Poisson regression analysis was performed to compare the DCM and the DnoCM groups with respect to lifestyle and health-related characteristics. RESULTS: Those in the DCM group were significantly less physically active (p = 0.003), had poorer self-rated health (p < 0.001), had lower income (p = 0.001), and were more likely to be retired (p < 0.001) than those in the DnoCM group. The pattern of results remained after controlling for other lifestyle and health-related factors. CONCLUSION: These results provide support for a cardiometabolic subgroup of depression that is associated with physical inactivity, poorer self-rated health, lower income, and retirement. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25827714 TI - The expression profiling and ontology analysis of noncoding RNAs in peritoneal fibrosis induced by peritoneal dialysis fluid. AB - Increasing amounts of evidence have indicated that noncoding RNAs (ncRNAs) have important regulatory potential in various biological processes. However, the contributions of ncRNAs, especially long noncoding RNAs (lncRNAs), to peritoneal fibrosis remain largely unknown. The aim of this study was to investigate miRNA, lncRNA and mRNA expression profiles and their potential roles in the process of peritoneal fibrosis. Microarray expression profiles of the miRNAs, lncRNAs and mRNAs were determined in normal control peritoneum and in a mouse model of peritoneal dialysis fluid (PDF)-induced fibrotic peritoneum. Differential expression, pathway and gene network analyses were developed to identify possible functional RNA molecules in peritoneal fibrosis. Compared to the normal control, 232 lncRNAs (127 up-regulated and 105 down-regulated), 154 mRNAs (87 up-regulated and 67 down-regulated) and 15 miRNAs (14 miRNAs up-regulated and 1 down regulated) were differentially expressed in the fibrotic peritoneum. Among the differentially expressed ncRNAs, 9 lncRNAs and 5 miRNAs were validated by real time RT-PCR. Pathway analysis showed that the Jak-STAT, TGF-beta and MAPK signaling pathways had a close relationship with peritoneal fibrosis. Gene co expression network analysis identified many genes, including JunB, HSP72, and Nedd9. It also identified lncRNAs AK089579, AK080622, and ENSMUST00000053838 and miRNAs miR-182 and miR-488. All of these species potentially play a key role in peritoneal fibrosis. Our results provide a foundation and an expansive view of the roles and mechanisms of ncRNAs in PDF-induced peritoneal fibrosis. PMID- 25827715 TI - The identification of novel PMADS3 interacting proteins indicates a role in post transcriptional control. AB - PMADS3, a known MADS-box transcriptional factor and a C-class gene for floral development, plays dual roles in controlling the identity of inner floral organs and the termination of flower meristems in petunia. In this study, it was confirmed by bimolecular fluorescence complementation (BiFC) assays that the PMADS3 protein can interact individually with E-class proteins FBP2, FBP5, FBP9 and PMADS12. A yeast two-hybrid cDNA library was screened using the entire PMADS3 as bait, and this identified further potential interaction candidates. Two novel genes, PheIF3f and PhAGO10, were isolated, and suggested to regulate mRNA and translational processes according to the analysis of protein functional domains and subcellular localization predictions. Notably, the PhAGO10 protein belongs to the Argonaute family, members of which are major players in small-RNA-guided gene silencing processes via mRNA cleavage or translational inhibition. The results of yeast two-hybrid and BiFC assays indicated that PheIF3f and PhAGO10 could interact with PMADS3. Our findings indicate that the C-class gene PMADS3 potentially participates in post-transcriptional control, as well as transcriptional regulation. PMID- 25827713 TI - Development of a Fluorescent Reporter System to Delineate Cancer Stem Cells in Triple-Negative Breast Cancer. AB - Advanced cancers display cellular heterogeneity driven by self-renewing, tumorigenic cancer stem cells (CSCs). The use of cell lines to model CSCs is challenging due to the difficulty of identifying and isolating cell populations that possess differences in self-renewal and tumor initiation. To overcome these barriers in triple-negative breast cancer (TNBC), we developed a CSC system using a green fluorescent protein (GFP) reporter for the promoter of the well established pluripotency gene NANOG. NANOG-GFP+ cells gave rise to both GFP+ and GFP(-) cells, and GFP+ cells possessed increased levels of the embryonic stem cell transcription factors NANOG, SOX2, and OCT4 and elevated self-renewal and tumor initiation capacities. GFP+ cells also expressed mesenchymal markers and demonstrated increased invasion. Compared with the well-established CSC markers CD24(-) /CD44(+) , CD49f, and aldehyde dehydrogenase (ALDH) activity, our NANOG GFP reporter system demonstrated increased enrichment for CSCs. To explore the utility of this system as a screening platform, we performed a flow cytometry screen that confirmed increased CSC marker expression in the GFP+ population and identified new cell surface markers elevated in TNBC CSCs, including junctional adhesion molecule-A (JAM-A). JAM-A was highly expressed in GFP+ cells and patient derived xenograft ALDH+ CSCs compared with the GFP(-) and ALDH(-) cells, respectively. Depletion of JAM-A compromised self-renewal, whereas JAM-A overexpression induced self-renewal in GFP(-) cells. Our data indicate that we have defined and developed a robust system to monitor differences between CSCs and non-CSCs in TNBC that can be used to identify CSC-specific targets for the development of future therapeutic strategies. PMID- 25827717 TI - Identification and expression analysis of a Spsb gene in planarian Dugesia japonica. AB - The SPSB family is comprised of four highly conserved proteins, each containing a C-terminal SOCS box motif and a central SPRY domain. Presently, Spsb genes have been found in mammals and in a few invertebrates, however, the specific functions of these genes are still unknown. In this study, we identified a Spsb gene from the planarian Dugesia japonica and termed it DjSpsb. The temporal and spatial expression patterns of DjSpsb were examined in both intact and regenerative animals, and expression levels were also quantified in response to various stressors. The results show that (1) DjSpsb is highly conserved in evolutionary history in metazoans and is at closer relationship to Spsb1, Spsb2 and Spsb4; (2) DjSpsb mRNA is mainly expressed in the head and also throughout head regeneration processes, particularly, its expression up-regulated observably on day 5 after amputation; (3) DjSpsb is also expressed in the testes and yolk glands; (4) DjSpsb expression is induced by high temperature and ethanol but inhibited by high doses of ionic liquids. The date suggests that the DjSpsb gene might be active in central nervous system (CNS) formation and functional recovery during head regeneration, and it is also involved in the development of germ cells and stress responses in the planarians. PMID- 25827716 TI - ChREBP and LXRalpha mediate synergistically lipogenesis induced by glucose in porcine adipocytes. AB - Glucose is a substrate for fatty acid synthesis, and induces lipogenesis and expressions of lipogenic genes. It was proposed that transcriptional factor ChREBP, LXRalpha and SREBP-1c are key mediators in lipogenesis induced by glucose, however the underlying mechanism remains unclear in porcine adipocytes. In this study, glucose stimulated lipogenesis and expressions of ChREBP, LXRalpha, SREBP-1c and lipogenic genes FAS and ACC1 in primary porcine adipocytes. When ChREBP expression was knocked down by RNAi, lipogenesis and FAS and ACC1 expressions decreased significantly, and lipogenesis induced by glucose decreased by 75.6%, whereas neither the basal expressions under glucose-free nor glucose induced expressions of LXRalpha and SREBP-1c were evidently affected, suggesting that ChREBP was a main mediator of lipogenesis stimulated by glucose. Glucose promoted LXRalpha gene expression, and activation of LXRalpha by T0901317 increased SREBP-1c expression and enhanced the stimulation of glucose on lipogenesis, but this stimulatory effect of LXRalpha depended on glucose. Activated LXRalpha stimulated lipogenesis and ChREBP mRNA expression, which was much lower than that elevated by glucose, and was markedly lower in ChREBP silencing than in unperturbed adipocytes. SREBP-1c activation blocked by fatostatin markedly decreased lipogenesis and expressions of FAS and ACC1 induced by glucose. Lipogenesis and lipogenic gene expression stimulated by LXRalpha activation were attenuated by fatostatin, however there was still a slightly increase in ChREBP-silencing adipocytes. These dates suggested that LXRalpha could directly or through SREBP-1c mediate the lipogenesis induced by glucose. Together, glucose induced lipogenesis and lipogenic gene expressions directly through ChREBP, and directly through LXRalpha or via SREBP-1c. PMID- 25827718 TI - Cyclic stretch and compression forces alter microRNA-29 expression of human periodontal ligament cells. AB - MicroRNAs (miRs) play an important role in the development and remodeling of tissues through the regulation of large cohorts of extracellular matrix (ECM) genes. The purpose of the present study was to determine the response of miR-29 family expression to loading forces and their effects on ECM gene expression in periodontal ligament cells, the key effector cell population during orthodontic tooth movement. In a comparison between miRs from human periodontal ligament cells (PDLCs) and alveolar bone cells (ABCs) from healthy human subjects, the ABC cohort of miRs was substantially greater than the corresponding PDLC cohort. Cyclic mechanical stretch forces at 12% deformation at 0.1Hz for 24h decreased expression of miR-29 family member miRs about 0.5 fold while 2g/cm(2) compression force for 24h increased miR-29 family member expression in PDLCs 1.8-4 folds. Cyclic stretch up-regulated major ECM genes in PDLCs, such as COL1A1, COL3A1 and COL5A1, while the compression force resulted in a down-regulation of these ECM genes. Direct interactions of miR-29 and Col1a1, Col3a1 and Col5a1 were confirmed using a dual luciferase reporter gene assay. In addition, transient transfection of a miR-29b mimic in mouse PDLCs down-regulated Col1a1, Col3a1 and Col5a1 while the transfection of miR-29b inhibitor up-regulated these genes compared to control transfection indicating that these target ECM genes directly responded to the altered level of miR-29b. These results provided a possible explanation for the effects of the miR-29 family on loaded PDLCS and their roles in extracellular matrix gene expression. PMID- 25827719 TI - High-resolution melt and morphological analyses of mealybugs (Hemiptera: Pseudococcidae) from cacao: tools for the control of Cacao swollen shoot virus spread. AB - BACKGROUND: Mealybugs (Hemiptera: Coccoidea: Pseudococcidae) are key vectors of badnaviruses, including Cacao swollen shoot virus (CSSV), the most damaging virus affecting cacao (Theobroma cacao L.). The effectiveness of mealybugs as virus vectors is species dependent, and it is therefore vital that CSSV resistance breeding programmes in cacao incorporate accurate mealybug identification. In this work, the efficacy of a CO1-based DNA barcoding approach to species identification was evaluated by screening a range of mealybugs collected from cacao in seven countries. RESULTS: Morphologically similar adult females were characterised by scanning electron microscopy, and then, following DNA extraction, were screened with CO1 barcoding markers. A high degree of CO1 sequence homology was observed for all 11 individual haplotypes, including those accessions from distinct geographical regions. This has allowed the design of a high-resolution melt (HRM) assay capable of rapid identification of the commonly encountered mealybug pests of cacao. CONCLUSIONS: HRM analysis readily differentiated between mealybug pests of cacao that cannot necessarily be identified by conventional morphological analysis. This new approach, therefore, has potential to facilitate breeding for resistance to CSSV and other mealybug transmitted diseases. PMID- 25827720 TI - Transport of citrate-coated silver nanoparticles in unsaturated sand. AB - Chemical factors and physical constraints lead to coupled effects during particle transport in unsaturated porous media. Studies on unsaturated transport as typical for soils are currently scarce. In unsaturated porous media, particle mobility is determined by the existence of an air-water interface in addition to a solid-water interface. To this end, we measured breakthrough curves and retention profiles of citrate-coated Ag nanoparticles in unsaturated sand at two pH values (5 and 9) and three different flow rates corresponding to different water contents with 1 mM KNO3 as background electrolyte. The classical DLVO theory suggests unfavorable deposition conditions at the air-water and solid water interfaces. The breakthrough curves indicate modification in curve shapes and retardation of nanoparticles compared to inert solute. Retention profiles show sensitivity to flow rate and pH and this ranged from almost no retention for the highest flow rate at pH=9 to almost complete retention for the lowest flow rate at pH=5. Modeling of the breakthrough curves, thus, required coupling two parallel processes: a kinetically controlled attachment process far from equilibrium, responsible for the shape modification, and an equilibrium sorption, responsible for particle retardation. The non-equilibrium process and equilibrium sorption are suggested to relate to the solid-water and air-water interfaces, respectively. This is supported by the DLVO model extended for hydrophobic interactions which suggests reversible attachment, characterized by a secondary minimum (depth 3-5 kT) and a repulsive barrier at the air-water interface. In contrast, the solid-water interface is characterized by a significant repulsive barrier and the absence of a secondary minimum suggesting kinetically controlled and non-equilibrium interaction. This study provides new insights into particle transport in unsaturated porous media and offers a model concept representing the relevant processes. PMID- 25827721 TI - Studies on chemistry, spectroscopy and antioxidant activities of chromium(III) hydrazide complexes. AB - Acid hydrazides are vital chemical entities due to their biological activities. Upon complexation with certain metal ions, their biological activities are known to be positively enhanced. The present work describes the synthesis of Cr(III) hydrazide complexes, and their structural, spectroscopic and antioxidant properties to reveal their chemistry and biochemistry. Physical (magnetic moment, conductivity measurements), analytical (C, H, N and Cr analysis) and spectral (EI Mass, FTIR) techniques are used for the characterization of synthesized compounds. All Cr(III)-hydrazide complexes exhibit octahedral geometry with general formula [Cr(L)2(H2O)2]Cl3. In these complexes, the hydrazide ligands are coordinated via carbonyl oxygen and terminal amino nitrogen in a bidentate fashion. All Cr(III)-hydrazide complexes were screened for in vitro diphenyldipicryl hydrazine (DPPH), superoxide dismutase and nitric oxide radical scavenging activities. Majority of the Cr(III)-hydrazide complexes were found to be more potent scavengers than their uncoordinated hydrazide ligands. This study demonstrates an interesting structure-activity relationship (SAR) which is presented here. PMID- 25827722 TI - Phosphorylation-directed assembly of a single quantum dot based nanosensor for protein kinase assay. AB - Protein kinases play crucial roles in intracellular signal transduction and metabolic pathways, and the monitoring of protein kinase activity is essential to the understanding of fundamental biochemical processes and the clinical diagnosis. Here, we demonstrate the phosphorylation-directed assembly of a single quantum dot (QD)-based nanosensor for sensitive detection of cAMP-dependent protein kinase (PKA). This assay involves (1) the PKA-directed simultaneous phosphorylation and biotinylation of cyanine 5 (Cy5)-labeled substrate peptides, (2) the assembly of phosphorylated and biotinylated peptides onto the surface of the QD, and (3) the illumination of Cy5 by means of fluorescence resonance energy transfer (FRET) between the QD and Cy5. With an adenosine triphosphate (ATP) analogue, gamma-biotin-ATP, as the phosphoryl donor, the PKA-catalyzed phosphorylation reaction incorporates the biotin-conjugated phosphate group into the substrate peptides to form the biotinylated peptides. The biotin entity subsequently drives the assembly of peptides onto the surface of streptavidin functionalized QD to form the sandwiched Cy5-peptide-QD nanostructure, enabling the occurrence of FRET between the QD and Cy5. The FRET signal can be easily recorded by either the conventional fluorescence spectrometer or the total internal reflection fluorescence (TIRF) microscope. In contrast, the absence of PKA cannot lead to the formation of Cy5-peptide-QD complex and no Cy5 signal can be detected. This protein kinase-actuated FRET assay is straightforward, without the involvement of either washing or separation steps, and has a significant advantage of high sensitivity with a detection limit of 9.3 * 10(-6) U/MUL. Moreover, this method can be used to estimate the half-maximal inhibitory concentration (IC50) value of PKA inhibitor H-89 (N-[2-(p bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride) and to monitor forskolin (Fsk)/3-isobutyl-1-methylxanthine (IBMX)-triggered activation of PKA in cell lysates, thus holding great potential for further applications in protein kinase-related biological researches and drug discovery. PMID- 25827723 TI - A shotgun metalloproteomic approach enables identification of proteins involved in the speciation of a ruthenium anticancer drug in the cytosol of cancer cells. AB - The study reported herein focused on the development and optimization of a versatile analytical methodology for characterization of intracellular distribution of protein-bound species of ruthenium originating from an anticancer Ru-based drug, indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]. A direct analysis of the drug-treated cytosol of cancer cells using size-exclusion chromatography (SEC) interfaced with inductively coupled plasma mass spectrometry (ICP-MS) revealed that over 85% of ruthenium is converted into a high molecular mass fraction. To further determine the ruthenium binding pattern, a shotgun approach was used, with the entire proteome being digested and the resulting peptides being analyzed by capillary high-performance liquid chromatography (MUHPLC) combined with electrospray ionization triple quadrupole MS. This allowed for identification of the ruthenated proteins on the basis of characteristic MS/MS spectra of the respective peptides. It was found that both Ru(III)- and Ru(II)-ligated functionalities participate in adduct formation, the hydrolyzed forms of the drug being attached to the majority of the binding proteins. Of an array of proteins responding to drug treatment, the most important - from the viewpoint of unveiling the exact mode of action - are inhibitor, pro-apoptotic, and DNA reparation proteins. PMID- 25827724 TI - Getting under the skin: qualitative methods in dermatology research. PMID- 25827725 TI - Cutaneous leishmaniasis--treatment options in children. PMID- 25827726 TI - Reshaping the treatment of autoimmune blistering diseases: from consensus guidelines to prospective data from 'the crowd'. PMID- 25827727 TI - New insights into the association of socioeconomic status with cutaneous malignant melanoma. PMID- 25827728 TI - Programmed death 1 expressing regulatory T cells in vitiligo. PMID- 25827729 TI - Exploring the biological mechanisms of thymic stromal lymphopoietin. PMID- 25827730 TI - Dermoscopy of naevoid melanoma. PMID- 25827731 TI - Production of numerous autoantibodies in paraneoplastic pemphigus. PMID- 25827732 TI - Revisiting the dogma of acne pathogenesis. PMID- 25827733 TI - The hand eczema proteome: imbalance of epidermal barrier proteins. PMID- 25827734 TI - Fractional epidermal skin grafting. PMID- 25827735 TI - Growth of periocular basal cell carcinoma. PMID- 25827736 TI - Sentinel lymph node biopsy for cutaneous squamous cell carcinoma: valuable or not valuable? PMID- 25827737 TI - No difference in skin condition between workers exposed and not exposed to glove occlusion in a semiconductor company. PMID- 25827738 TI - Mobile teledermatology is here to stay. PMID- 25827739 TI - Association between genetic factors, naevus count and dermoscopic pattern. PMID- 25827740 TI - Human herpesvirus 6 involvement in paediatric drug hypersensitivity syndrome. PMID- 25827741 TI - Importance of genotype-phenotype correlation in xeroderma pigmentosum. PMID- 25827742 TI - Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. AB - Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients, bullae may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. Our consensus for the treatment of bullous pemphigoid has been developed under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations. PMID- 25827747 TI - Comparative proteomic analysis provides insight into cadmium stress responses in brown algae Sargassum fusiforme. AB - Sargassum fusiforme is one of the most widely consumed seaweeds in China, Korea and Japan. In this work, we performed growth analysis and comparative proteomics to investigate the molecular mechanisms of the response to 1 day and 5 days Cd stress in S. fusiforme. Our results showed a significant decrease in growth rate and an increase in Cd ion content in S. fusiforme in response to Cd treatment. Comparative proteomic analysis revealed 25 and 51 differentially expressed protein spots in S. fusiforme under 1 day and 5 days Cd stress, respectively. A great number of these proteins was metabolic enzymes involved in carbohydrate metabolism and energy metabolism. Many proteins involved in the processing of genetic information showed a decrease in abundance under 1 day Cd stress. In contrast, 9 of the identified protein spots primarily involved in genetic information processing and carbohydrate metabolism were greatly enriched under 5 days Cd stress. Overall, our investigation indicated that Cd stress negatively affects the metabolic activity of S. fusiforme through the down-regulation of key metabolic enzymes. In addition, S. fusiforme may adapt to 5 days Cd stress by promoting consumption of photoassimilates through the up-regulation of glycolysis and the citrate cycle to supply energy for survival. PMID- 25827748 TI - Di-(2-ethylhexyl)-phthalate disrupts pituitary and testicular hormonal functions to reduce sperm quality in mature goldfish. AB - Di-(2-ethylhexyl) phthalate (DEHP) interferes with male reproductive endocrine system in mammals, however its effects on fish reproduction are largely unknown. We evaluated sperm quality and investigated reproductive endocrine system in mature goldfish (Carassius auratus) exposed to nominal 1, 10, and 100MUg/L DEHP. To examine DEHP estrogenic activity, one group of goldfish was exposed to 17beta estradiol (5MUg/L E2) for comparison. Following 30d of exposure, sperm production was decreased and suppressed in DEHP and E2 treated goldfish, respectively. Sperm motility and velocity were decreased in goldfish exposed to 100 and 10MUg/L DEHP at 15s post-sperm activation, respectively. Compared to control, 11 ketotestosterone (11-KT) levels were decreased at 10 and 1MUg/L DEHP at day 15 and 30, respectively. In E2 treated goldfish, 11-KT levels were decreased compared to control during the period of exposure. E2 levels were increased in goldfish exposed to E2, but remained unchanged in DEHP treated goldfish during the period of exposure. StAR mRNA levels encoding regulator of cholesterol transfer to steroidogenesis were decreased in DEHP and E2 treated goldfish following 15 and 30d of exposure, respectively. Luteinizing hormone (LH) levels were decreased in DEHP and E2 treated goldfish following 15 and 30d of exposure, respectively. In DEHP treated goldfish, gnrh3, kiss1 and its receptor (gpr54) mRNA levels did not change during the experimental period. In E2 treated goldfish, gnrh3 mRNA levels were decreased at day 7, but kiss1 and gpr54 mRNA levels were increased at day 30 of exposure. The mRNA levels of genes encoding testicular LH and androgen receptors remained unchanged in DEHP and E2 treated goldfish. In contrast to E2 treated goldfish, vitellogenin production was not induced in DEHP treated goldfish and mRNA levels of genes with products mediating estrogenic effects remained unchanged or decreased. In conclusion, DEHP interferes with testis and pituitary hormonal functions to reduce sperm quality in goldfish and does not exhibit estrogenic activity. PMID- 25827750 TI - Ammonium removal at low temperature by a newly isolated heterotrophic nitrifying and aerobic denitrifying bacterium Pseudomonas fluorescens wsw-1001. AB - A heterotrophic nitrifier wsw-1001 was isolated from Songhua River and identified as Pseudomonas fluorescens. Ammonium removal by the strain at low temperature was investigated. The effect of initial ammonium concentration (from 5 to 1000 mg/L) and culture temperature (from 4 degrees C to 30 degrees C) on ammonium removal efficiency was studied. Biodegradation product, [Formula: see text], [Formula: see text], N2, N2O and intercellular N were monitored. The results indicated that the strain had potential for water and wastewater treatment. Ammonium could be removed by the strain at low temperature. Ammonium removal efficiency increased with temperature from 4 degrees C to 20 degrees C and decreased with ammonium concentration from 5 to 1000 mg/L. The strain exhibited a capability of heterotrophic nitrification and aerobic denitrification using [Formula: see text] as the sole nitrogen source at 8 degrees C. [Formula: see text] and [Formula: see text] were reduced by the strain. Nitrogen balance analysis in the presence of 39.7 mg/L [Formula: see text] indicated that 71.2% [Formula: see text] was removed by converting to N2 (46.3%) and assimilating as biomass (42.5%). Substances such as [Formula: see text], [Formula: see text] and N2O were detected at very low concentrations. Ammonium mono-oxygenase, hydroxylamine oxidase, nitrite reductase and nitrate reductase activity were measured. The ammonium removal pathway of the strain was speculated to be [Formula: see text]. PMID- 25827749 TI - A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling. AB - Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity. PMID- 25827751 TI - Novel FAM20A mutation causes autosomal recessive amelogenesis imperfecta. AB - OBJECTIVE: To relate the peculiar phenotype of amelogenesis imperfecta in a large Bedouin family to the genotype determined by whole genome linkage analysis. DESIGN: Amelogenesis imperfecta (AI) is a broad group of inherited pathologies affecting enamel formation, characterized by variability in phenotypes, causing mutations and modes of inheritance. Autosomal recessive or compound heterozygous mutations in FAM20A, encoding sequence similarity 20, member A, have been shown to cause several AI phenotypes. Five members from a large consanguineous Bedouin family presented with hypoplastic amelogenesis imperfecta with unerupted and resorbed permanent molars. Following Soroka Medical Center IRB approval and informed consent, blood samples were obtained from six affected offspring, five obligatory carriers and two unaffected siblings. Whole genome linkage analysis was performed followed by Sanger sequencing of FAM20A. RESULTS: The sequencing unravelled a novel homozygous deletion mutation in exon 11 (c.1523delC), predicted to insert a premature stop codon (p.Thr508Lysfs*6). CONCLUSIONS: We provide an interesting case of novel mutation in this rare disorder, in which the affected kindred is unique in the large number of family members sharing a similar phenotype. PMID- 25827752 TI - Rho is involved in periodontal tissue remodelling with experimental tooth movement in rats. AB - OBJECTIVE: To characterise in vivo the close relationship between the Rho signalling pathway and periodontal tissue remodelling in experimental tooth movement in rats. MATERIALS AND METHODS: In total, 24 male Sprague Dawley rats were divided randomly into four groups. Closed-coil springs were used to create a 40-g mesial force to move the right upper first molars in anaesthetised rats. The untreated contralateral side served as a control. On days 3, 7, 10, and 14 after force application, paraffin wax-embedded sections of the dissected maxilla were prepared for immunohistochemistry to localise Rho kinase (ROCK), LIM kinase (LIMK), and its downstream effector (cofilin). The immunoreactivity of the molecules investigated in the periodontal ligament area was converted into grey scale values. RESULTS: The expression of Rho and its signalling were detected mainly in the disto-coronal areas of the root in the periodontal ligament area of the control and loaded teeth. In contrast, ROCK-, LIMK-, and cofilin-positive cells were rare in the mesio-coronal areas. In the experimental group, the expression of ROCK, LIMK, and cofilin on the tension side (disto-coronal areas) increased significantly on days 7, 10, and 14, compared with those of untreated control teeth. CONCLUSIONS: These data suggest that Rho is involved in periodontal tissue remodelling during orthodontic tooth movement, modulating ROCK, LIMK, and cofilin activity. PMID- 25827754 TI - A single-blind, parallel trial of L-hydroxyproline in healthy adult subjects. PMID- 25827753 TI - Reconstructive challenges in the extended endoscopic transclival approach. AB - OBJECTIVE: We wanted to present our experience with the extended endoscopic approach to clival pathology, focusing on cerebrospinal fluid leak and reconstruction challenges. METHODS: We examined a consecutive series of 37 patients undergoing the extended endoscopic approach for skull base tumours, 9 patients with clival pathology. Patients were examined for the incidence of post operative cerebrospinal fluid leak in relation to tumour pathology, location, size, reconstruction and lumbar drain. RESULTS: The overall incidence of post operative cerebrospinal fluid leak was 10.8 per cent. Seventy-five per cent of patients who had a post-operative cerebrospinal fluid leak underwent a transclival approach (p < 0.05). All patients with clival pathology who underwent an intradural dissection had a post-operative cerebrospinal fluid leak (p < 0.05). CONCLUSION: Post-operative cerebrospinal fluid leak rates after the extended endoscopic approach have improved significantly after advancements including the vascularised nasoseptal flap. Despite this, transclival approaches continue to pose much difficulty. Further investigation is necessary to develop technical improvements that can meet the unique challenges associated with this region. PMID- 25827755 TI - Cryptic 3' mRNA processing signals hinder the expression of Schistosoma mansoni integrins in yeast. AB - The expression of parasite genes has often proven difficult in heterologous systems such as yeast or E. coli. Most often, promoter choice and codon usage were hypothesised to be the main reason for expression failures. The trematode parasite Schistosoma mansoni has five integrin genes named Smalpha-Int1-4 and Smbeta-Int1, which we aimed to express in the yeast Saccharomyces cerevisiae. This has not been achieved, however, as only Smbeta-Int1 integrin could be expressed. When the four alpha integrins were driven by a stronger promoter, this enabled Smalpha-Int1 to be expressed as well, but the remaining integrins, Smalpha-Int2-4, still could not be expressed. Evidence from RT-PCR experiments suggested that this was due to premature transcription termination. Using detailed in silico sequence analyses we identified AT-rich stretches in these integrin genes, which have high similarity to yeast mRNA 3'-end processing signals. We hypothesised that these signals were causing the premature truncation. To test this, we designed an optimised version of Smalpha-Int3, in which the sequence was modified to replace the yeast 3' processing signals. This strategy allowed us to express Smalpha-Int3 integrin successfully in S. cerevisiae. These findings show that the misinterpretation of AT-rich sequences by yeast 3'-mRNA processing machinery can cause problems when attempting to express genes containing such sequences in this host. PMID- 25827757 TI - New insights on the pathophysiology of inspiratory flow limitation during sleep. AB - INTRODUCTION: Inspiratory flow limitation (IFL) is defined as a "flattened shape" of inspiratory airflow contour detected by nasal cannula pressure during sleep and can indicate increased upper airway resistance especially in mild sleep related breathing disorders (SRBD). The objective of this study was to investigate the association between upper airway abnormalities and IFL in patients with mild SRBD. METHODS: This study was derived from a general population study consisting of selected individuals with apnea-hypopnea index (AHI) below 5 events/h of sleep, ("no obstructive sleep apnea" group) and individuals with AHI between 5 and 15 events/h ("mild obstructive sleep apnea" group). A total of 754 individuals were divided into four groups: group 1: AHI <5/h and <30 % of total sleep time (TST) with IFL (515 individuals), group 2: AHI <5/h and >30 % of TST with IFL (46 individuals), group 3: AHI: 5-15/h and <30 % of TST with IFL (168 individuals), and group 4: AHI: 5-15/h and >30 % of TST with IFL (25 individuals). RESULTS: Individuals with complains of oral breathing demonstrated a risk 2.7-fold larger of being group 4 compared with group 3. Abnormal nasal structure increased the chances of being in group 4 3.2-fold in comparison to group 1. Individuals with voluminous lateral wall demonstrated a risk 4.2-fold larger of being group 4 compared with group 3. CONCLUSION: More than 30 % of TST with IFL detected in sleep studies was associated with nasal and palatal anatomical abnormalities in mild SRBD patients. PMID- 25827756 TI - Quantification of female and male Plasmodium falciparum gametocytes by reverse transcriptase quantitative PCR. AB - The transmission of malaria parasites depends on the presence of sexual stages (gametocytes) in the blood, making the ratio and densities of female and male gametocytes important determinants of parasite fitness. This manuscript describes the development of reverse transcriptase quantitative PCR (RT-qPCR) assays to separately quantify mature female and male gametocytes of the human malaria parasite Plasmodium falciparum, and reveals that Pfs25 mRNA is expressed only in female gametocytes. The female (Pfs25) and male (Pfs230p) gametocyte specific RT qPCR assays have lower detection limits of 0.3 female and 1.8 male gametocytes per microlitre of blood, respectively, making them more sensitive than microscopy. Accurate quantification of the ratio and densities of female and male gametocytes will increase understanding of P. falciparum transmission and improve the evaluation of transmission blocking interventions. PMID- 25827758 TI - Genetic analysis of familial spontaneous pneumothorax in an Indian family. AB - Familial spontaneous pneumothorax is one of the phenotypes of Birt-Hogg-Dube syndrome (BHDS), an autosomal dominant condition associated with folliculin (FLCN). We investigated clinical and genetic data of an Indian family having two patients suffering from spontaneous pneumothorax in the absence of skin lesions or renal tumors. HRCT scan of patient's lung revealed paracardiac cysts, and DNA sequencing of all 14 exons of FLCN from patients showed the presence of heterozygous "C allele" deletion in the poly-cytosine (poly-C) tract of exon 11 leading to truncated folliculin. This mutation was also observed in four asymptomatic members of the family. Our results confirmed the presence of deletion mutation in poly-C tract of FLCN in members of BHDS family. This is the first report of genetic insight in a BHDS family from India but in-depth studies with a larger sample set are necessary to understand mechanism of familial pneumothorax. PMID- 25827759 TI - Can inflammatory bowel disease really be solved by the multiple -omics and meta omics analyses? PMID- 25827760 TI - Characterization of prepared In2O3 thin films: The FT-IR, FT-Raman, UV-Visible investigation and optical analysis. AB - In this original work, the Indium oxide (In2O3) thin film is deposited cleanly on microscope glass substrate at different temperatures by spray pyrolysis technique. The physical properties of the films are characterized by XRD, SEM, AFM and AFM measurements. The spectroscopic investigation has been carried out on the results of FT-IR, FT-Raman and UV-Visible. XRD analysis exposed that the structural transformation of films from stoichiometric to non-stoichiometric orientation of the plane vice versa and also found that, the film is polycrystalline in nature having cubic crystal structure with a preferred grain orientation along (222) plane. SEM and AFM studies revealed that, the film with 0.1M at 500 degrees C has spherical grains with uniform dimension. The complete vibrational analysis has been carried out and the optimized parameters are calculated using HF and DFT (CAM-B3LYP, B3LYP and B3PW91) methods with 3-21G(d,p) basis set. Furthermore, NMR chemical shifts are calculated by using the gauge independent atomic orbital (GIAO) technique. The molecular electronic properties; absorption wavelengths, excitation energy, dipole moment and frontier molecular orbital energies, molecular electrostatic potential energy (MEP) analysis and Polarizability first order hyperpolarizability calculations are performed by time dependent DFT (TD-DFT) approach. The energy excitation on electronic structure is investigated and the assignment of the absorption bands in the electronic spectra of steady compound is discussed. The calculated HOMO and LUMO energies showed the enhancement of energy gap by the addition of substitutions with the base molecule. The thermodynamic properties (heat capacity, entropy, and enthalpy) at different temperatures are calculated and interpreted in gas phase. PMID- 25827761 TI - Theoretical investigation on vibrational spectra, first order hyperpolarizability and NBO analysis of 4-Phenylpyridinium hydrogen squarate. AB - The vibrational frequencies of 4-Phenylpyridinium hydrogen squarate (4PHS) in the ground state have been investigated by using B3LYP/6-311++G(d,p) level. The analysis of molecular structure, natural bond orbitals and frontier molecular orbitals was also performed. The IR spectra were obtained and interpreted by means of potential energies distributions (PEDs) using MOLVIB program. NBO analysis proved the presence of C-H?O and N-H?O hydrogen bonding interactions, which is consistent with the analysis of molecular structure. The dipole moments and first-order hyperpolarizability (betatot) are calculated and are 5.856 D and 4.72*10(-30) esu, respectively. The high betatot value and the low HOMO-LUMO energy gap (4.062eV) are responsible for the optical and electron-transfer properties of 4PHS molecule. The photoresponse-related results indicate that 4PHS molecule is an excellent organic candidate of photon-responsive materials. PMID- 25827762 TI - Tuning zinc coordination architectures by benzenedicarboxylate position isomers and bis(triazole). AB - Three position isomers 1,2-, 1,3-, 1,4-benzenedicarboxylate and 1,4-bis(1,2,4 triazol-4-yl)benzene were used to assembly zinc(II) coordination polymers {[Zn2(btx)0.5(1,2-bdc)2(H2O)].H2O}n (1), {[Zn(btx)(1,3-bdc)].2H2O.(DMF)}n (2) and {[Zn(btx)(1,4-bdc)].3H2O}n (3). 1 is a (3,4,4,4)-connected two-dimensional network with point symbol (4(2).6)(4(4).6(2))(4(3).6(2).8)(4(2).6.10(3)). 2 shows a two-dimensional (4,4) network. 3 exhibits a 5-fold interpenetrated three dimensional diamondoid network. The structural versatility shows that the structures of coordination polymers can be tuned by the position isomers ligands. The luminescence and thermal stability were investigated. PMID- 25827763 TI - Solid phase microextraction of diclofenac using molecularly imprinted polymer sorbent in hollow fiber combined with fiber optic-linear array spectrophotometry. AB - A simple solid phase microextraction method based on molecularly imprinted polymer sorbent in the hollow fiber (MIP-HF-SPME) combined with fiber optic linear array spectrophotometer has been applied for the extraction and determination of diclofenac in environmental and biological samples. The effects of different parameters such as pH, times of extraction, type and volume of the organic solvent, stirring rate and donor phase volume on the extraction efficiency of the diclofenac were investigated and optimized. Under the optimal conditions, the calibration graph was linear (r(2)=0.998) in the range of 3.0 85.0 MUg L(-1) with a detection limit of 0.7 MUg L(-1) for preconcentration of 25.0 mL of the sample and the relative standard deviation (n=6) less than 5%. This method was applied successfully for the extraction and determination of diclofenac in different matrices (water, urine and plasma) and accuracy was examined through the recovery experiments. PMID- 25827764 TI - Synthesis, structural characterization and theoretical approach of the tri(2-(2,6 dichlorophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) cobalt(II). AB - The crystal structure of a new coordination compound tri(2-(2,6-dichlorophenyl) 1H-imidazo[4,5-f][1,10]phenanthroline) Co(II) complex ([Co(dcpip)3]Cl2) was measured with X-ray diffraction measurements. The compound is crystallizes triclinic, Pi space group. The ligand, 2-(2,6-dichlorophenyl)-1H-imidazo[4,5 f][1,10]phenanthroline(dcpip), binds to Co(II) ions with a bis-dentate mode, and each Co(II) ion with a distorted octahedral coordination geometry. The calculated interaction energies of Co(II) with coordination atoms N are between 101.7-206.5 kJ/mol and 115.3-230.9 kJ/mol for B3LYP/6-31+G(*) and PBE1PBE/6-31+G(*) theoretical methods, respectively. The experimental Fourier transform infrared spectrum was assigned. The calculated IR based on B3LYP/6-31+G(*) and PBE1PBE/6 31+G(*) methods were performed and compared with experimental results. The UV-Vis experimental spectrum of [Co(dcpip)3]Cl2 was measured in methanol solution. The calculated electronic spectrum was performed with TD/B3LYP and TD/PBE1PBE methods with 6-31+G(*) basis set. The first and second order hyperpolarizability for the compound was calculated. The calculated values of gammatot are -1.5551344 * 10( 33) esu for B3LYP method and -1.3323259 * 10(-33) esu for PBE1PBE method. The nature bond orbital analysis and temperature dependence of the thermodynamic properties were calculated with the same methods. PMID- 25827765 TI - Exploring the process-structure-function relationship of horseradish peroxidase through investigation of pH- and heat induced conformational changes. AB - Given the importance of peroxidase as an indicator for the preservation of vegetables by heat treatment, the present study is focused on enzyme behavior under different pH and temperature conditions, in terms of process-structure function relationships. Thus, the process-structure-function relationship of peroxidase was investigated by combining fluorescence spectroscopy, in silico prediction methods and inactivation kinetic studies. The fluorescence spectra indicated that at optimum pH value, the Trp(117) residue is not located in the hydrophobic core of the protein. Significant blue- and red-shifts were obtained at different pH values, whereas the heat-treatment did not cause significant changes in Trp and Tyr environment. The ANS and quenching experiments demonstrated a more flexible conformation at lower pH and respectively at higher temperature. On the other hand molecular dynamics simulations at different temperatures highlighted that the secondary structure appeared better preserved against temperature, whereas the tertiary structure around the heme was more affected. Temperature dependent changes in the hydrogen bonding and ion paring involving amino acids from the heme-binding region (His(170) and Asp(247)) might trigger miss-coordination of the heme iron atom by His(170) residue and further enzyme activity loss. PMID- 25827766 TI - Vibrational spectra, NBO, HOMO-LUMO and conformational stability studies of 4 hydroxythiobenzamide. AB - In this work, the experimental and theoretical study on molecular structure, vibrational spectral analysis of 4-hydroxythiobenzamide (HTB) have been reported. The solid phase FTIR (4000-400 cm(-1)) and FT-Raman spectra (3500-50 cm(-1)) were recorded. The molecular geometry, harmonic vibrational frequencies and bonding features of HTB in the ground-state have been calculated by the density functional method (B3LYP) with 6-311+G(d,p) and 6-311++G(d,p) as basis sets. Utilizing the observed FTIR and FT-Raman data, a complete vibrational assignment and analysis of the fundamental modes of the compound were carried out. Stability of the molecule arising from hyperconjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The results show that the value of electron density (ED) in the sigma(*) antibonding orbitals and E((2)) energies confirms the occurrence of ICT (intra-molecular charge transfer) within the molecule. The UV spectrum was measured in ethanol solution. The energy and oscillator strength calculated by time-dependent density functional theory (TD-DFT) correlates with the experimental findings. The calculated molecular electrostatic potential (MESP), HOMO and LUMO energies show that charge transfer occurs within the molecule. Besides, the simulated infrared and Raman spectra of the title compound which show good agreement with observed spectra. PMID- 25827767 TI - Electronic absorption spectroscopic behavior and acidity constants of some new dinitrophenylhydrazone derivatives. AB - In the present study, UV-visible electronic spectra of three new 2,4 dinitrophenylhydrazone derivatives (C1, C2 and C3) have been studied. Different bands observed have been assigned to the proper electronic transitions. The solvatochromic behaviors of these compounds were investigated by studying their electronic spectra in several organic solvents with different polarities. The longer wavelength band is assigned to an intermolecular charge transfer transition. The solvated H-bonding complexes formed between dimethylformamide and 2,4-dinitrophenylhydrazone derivatives were also investigated. DeltaG, and the Kf values of the molecular complexes formed in solution have been determined. Effects of temperature increase and concentration changes on the longer spectroscopic wavelength band of the studied compounds were investigated. In this work, the behavior of acidity constants of these compounds in different pH values is studied by a multiwavelength spectrophotometric method too. PMID- 25827768 TI - Design, synthesis, characterization, quantum-chemical calculations and anti inflammatory activity of novel series of thiophene derivatives. AB - Interaction of 1-(4-morpholinophenyl)ethanone 1 with either malononitrile or ethyl cyanoacetate 2 afforded Knoevenagel-Cope product 3. In subsequent treatment of 3 with sulfur, the 2-aminothiophene derivatives (4a, 4b) are formed under basic conditions. The solvent-free reaction of thiophene derivative 4a with ethyl cyanoacetate afforded thieno[2,3-d][1,3]oxazine derivative 6. The base catalyzed condensation of 2-aminothiophene derivative (4a) with ethyl cyanoacetate afforded N-(thieno-2-yl) cyanoacetamide derivative 7. The latter was used to synthesize different heterocyclic derivatives comprising, pyridine and coumarin rings. Also, several substituted thieno[2,3-d]pyrimidines have been prepared from reaction of 2-aminothiophene-3-carbonitrile 4b with some electrophilic reagents. The structure of the newly compounds were confirmed on the basis of elemental analysis and spectral data. The molecular modeling of the synthesized compounds has been drawn and their molecular parameters were calculated. Also, valuable information is obtained from calculation of the molecular parameters including electronegativity, net dipole moment of the compounds, total energy, electronic energy, binding energy, HOMO and LUMO energy. Evaluation of anti-inflammatory activity of the tested compounds was performed in albino rats by producing carrageenan induced paw oedema and measuring the zone of inflammation at different time intervals i.e. 1, 2, 3 and 4h after carrageenan injection. Results indicated that most of the tested compounds showed moderate to good activity comparable to indomethacin. Also, compound 16 with additional morpholine ring beside the thiophene ring inhibits carrageenan induced paw oedema more than the standard indomethacin drug at all the time scales studied. Thus, compound 16 is considered as a promising compound for further modification to obtain clinically useful anti-inflammatory agent. PMID- 25827769 TI - First principal studies of spectroscopic (IR and Raman, UV-visible), molecular structure, linear and nonlinear optical properties of L-arginine p-nitrobenzoate monohydrate (LANB): A new non-centrosymmetric material. AB - In current work, the authors have been applied the density functional theory (DFT) using B3LYP and CAM-B3LYP exchange-correlation functional with 6-31G(*) basis set on l-arginine p-nitrobenzoate monohydrate (LANB) molecule for the first time to optimize its geometry and study the spectroscopic, electronic structure, nonlinear optical properties. Vibrational modes were found in good agreement with experimental reports. The calculated UV spectra by B3LYP/6-31G(*) and CAM-B3LYP/6 31G(*) level of theory shows an electronic transition at ~268 nm (4.63 eV) and 264 nm (4.70 eV) respectively. To explain the charge interaction taking place within the molecule highest occupied molecular orbital and lowest unoccupied molecular orbital were analyzed and their calculated energy gap was found to be 4.3eV with an oscillatory strength 0.3796 at B3LYP/6-31G(*) level of theory. The dipole moment (MUtot), average and anisotropy of polarizability (alphatot, Deltaalpha) and static and total first hyperpolarizability (beta0, betatot) values were calculated. The value of MUtot and betatot are found to be 4.124D and 1.630 * 10(-30) esu and 4.127D and 1.133 * 10(-30) esu using B3LYP/6-31G(*) and CAM-B3LYP/6-31G(*) functional respectively. The value of betatot is >4 and >3 times higher than prototype urea molecule calculated at both level of theory, respectively. The molecular electrostatic potential (MEP), frontier molecular orbital's (FMOs), global reactivity descriptors and thermodynamic properties are also calculated and discussed. The properties of LANB calculated at B3LYP are in good correlation with experimental than the CAM-B3LYP level of theory. The obtained results show that LANB molecule can be treated as a good candidate for nonlinear optical devices. PMID- 25827770 TI - Biophysical insights into the intercalative interaction of surfactant cobalt(III) complexes of certain diimine ligands bound to yeast tRNA: Effects of hydrophobicity. AB - The interaction of two surfactant cobalt(III) complexes, cis [Co(ip)2(DA)2](ClO4)3 1 and cis-[Co(dpq)2(DA)2](ClO4)3 2 where ip=imidazo[4,5 f][1,10]phenanthroline and dpq=dipyrido[3,2-d:2'-3'-f]quinoxaline with yeast tRNA have been explored by using electronic absorption, competitive binding, electrochemical studies and viscosity measurements. The results suggest that these complexes can bind to tRNA by intercalation. The presence of hydrophobic diimine ligand and the long aliphatic double chains of these complexes facilitate its intercalative interaction with the hydrophobic interior of the tRNA. The extent of tRNA binding of complex 2 has greater affinity than that of complex containing imidazo[4,5-f][1,10]phenanthroline ligands. PMID- 25827772 TI - Synthesis, NMR, FT-IR, X-ray structural characterization, DFT analysis and isomerism aspects of 5-(2,6-dichlorobenzylidene)pyrimidine-2,4,6(1H,3H,5H) trione. AB - The synthesis and spectral characterization of the 5-(2,6 dichlorobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione;3 was reported. The solid state molecular structure of 3 was studied using X-ray crystallography. The relative stabilities of the seven possible isomers of 3 were calculated by DFT/B3LYP method using 6-311 G(d,p) basis set. The calculated total energies and thermodynamic parameters were used to predict the relative stabilities of these isomers. The effect of solvent polarity on the relative stability of these isomers was studied at the same level of theory using PCM. It was found that the keto form, (T0), is the most stable isomer both in the gaseous state and solution. In solution, the calculated total energies of all isomers are decreased indicating that all isomers are stabilized by the solvent effect. The vibrational spectra of the most stable isomer, 3(T0) are calculated using the same level of theory and the results are compared with the experimentally measured FTIR spectra. Good correlation was obtained between the experimental and calculated vibrational frequencies (R(2)=0.9992). The electronic spectra of 3(T0) in gas phase as well as in solutions were calculated using the TD-DFT method. All the predicted electronic transitions showed very little spectral shifts and increase in the intensity of absorption due to solvent effect. Also the (1)H- and (13)C NMR chemical shifts of the stable isomer were calculated and the results were correlated with the experimental data. Good correlations between the experimental and calculated chemical shifts were obtained. PMID- 25827771 TI - Synthesis, spectroscopic characterization and structural investigation of a new charge transfer complex of 2,6-diaminopyridine with 4-nitrophenylacetic acid: Antimicrobial, DNA binding/cleavage and antioxidant studies. AB - A new hydrogen-bonded charge-transfer complex (CT) formed by the reaction between donor, 2,6-diaminopyridine and acceptor, 4-nitrophenylacetic acid in methanol at room temperature. The crystal was characterized by elemental analysis, IR, NMR spectroscopic studies and thermal studies. The elemental analysis of CT complex, obtained data revealed that the formation of 1:1 ratio CT complex was proposed. Infrared and NMR studies confirm the chemical constituents and molecular structure of the synthesized complex crystal. The high thermal stability is due to the molecular frame work through H-bonding interactions. Structural investigation indicates that cation and anion are linked through strong N(+)-H?O( ) type of hydrogen bond. The hydrogen bonded charge transfer crystal was screened for its pharmacology, such as antimicrobial, DNA binding/cleavage and antioxidant studies. The CT complex was screened for its antibacterial and antifungal activity against various bacterial and fungal species, which shows good antimicrobial activity. The DNA binding results indicated that the compound could interact with DNA through intercalation. It should have weak to moderate capacity of scavenging with DPPH. PMID- 25827773 TI - Synthesis, spectral, antitumor, antioxidant and antimicrobial studies on Cu(II), Ni(II) and Co(II) complexes of 4-[(1H-Benzoimidazol-2-ylimino)-methyl]-benzene 1,3-diol. AB - A new Schiff base of 2-aminobenzimidazole with 2,4-dihydroybezaldehyde (H3L), and its Cu(II), Ni(II) and Co(II) complexes have been synthesized and characterized by elemental analyses, molar conductance, thermal analysis (TGA), inductive coupled plasma (ICP), magnetic moment measurements, IR, EI-mass, UV-Vis. and ESR spectral studies. On the basis of spectral studies and analytical data, it is evident that the Schiff base acts as dibasic tridentate ligand coordinating via deprotonated OH, NH and azomethine nitrogen atom. The results showed that Co(II) and Ni(II) complexes have tetrahedral structure while Cu(II) complexes has octahedral geometry. The kinetic and thermodynamic parameters of the thermal decomposition stages have been evaluated. The studied complexes were tested for their in vitro antimicrobial activities against some bacterial strains. The anticancer activity of the ligand and its metal complexes is evaluated against human liver Carcinoma (HEPG2) cell. These compounds exhibited a moderate and weak activity against the tested HEPG2 cell lines with IC50 of 9.08, 18.2 and 19.7 MUg/ml for ligand, Cu(II) and Ni(II) complexes, respectively. In vitro antioxidant activity of the newly synthesized compounds has also been evaluated. PMID- 25827774 TI - In vitro metabolism of canagliflozin in human liver, kidney, intestine microsomes, and recombinant uridine diphosphate glucuronosyltransferases (UGT) and the effect of genetic variability of UGT enzymes on the pharmacokinetics of canagliflozin in humans. AB - O-glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of 2 major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently to assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively. Although M7 and M5 were formed in liver microsomes, only M7 was formed in kidney microsomes. Participants from 7 phase 1 studies were pooled for pharmacogenomic analyses. A total of 134 participants (mean age, 41 years; men, 63%; white, 84%) were included in the analysis. In UGT1A9*3 carriers, exposure of plasma canagliflozin (Cmax,ss , 11%; AUCtau,ss , 45%) increased relative to the wild type. An increase in exposure of plasma canagliflozin (Cmax,ss , 21%; AUCt,ss , 18%) was observed in participants with UGT2B4*2 genotype compared with UGT2B4*2 noncarriers. Metabolites further delineate the role of both enzymes. The pharmacokinetic findings in participants carrying the UGT1A9*3 and UGT2B4*2 allele implicate that UGT1A9 and UGT2B4 are involved in the metabolism of canagliflozin to M7 and M5, respectively. PMID- 25827775 TI - Alcohol Consumption, Athlete Identity, and Happiness Among Student Sportspeople as a Function of Sport-Type. AB - AIMS: To examine the differences in alcohol consumption and psychosocial antecedents between team and individual sportspeople via secondary data analysis. METHODS: Questionnaires measured alcohol consumption, athlete identity and subjective happiness from a sample of UK university sportspeople (N = 1785; male = 1048, 58.7%), involved in team (77.9%) and individual sports. RESULTS: Team sports players were more likely to be categorized as hazardous drinkers, and reported significantly greater rates of alcohol consumption, stronger athlete identity and higher levels of happiness than individual sports players. Athlete identity was a significant predictor for alcohol consumption, however there was no significant relationship found between happiness and consumption. Further regression analyses revealed interactions between sport-type and athlete identity on alcohol consumption. For individual sport players, as athlete identity increased alcohol consumption significantly reduced; however, there was a positive association between identity and consumption for team sport players. CONCLUSIONS: Our findings implicate the role of identity as an important factor to consider when addressing the issue of hazardous drinking among sportspeople. PMID- 25827776 TI - Personality and Alcohol Expectancies Discriminate Alcohol Consumption Patterns in Female College Students. AB - AIMS: To characterize patterns of alcohol use in a sample of Argentinean female college students according to personality traits and alcohol expectancies. METHODS: Data from 298 female college students (M age = 18.27 years; SD = 1.37 years) from the city of Cordoba, Argentina were analysed using multinomial regression. RESULTS: Three drinking categories were identified, abstainers, moderate drinkers and regular drinkers with heavy episodic drinking, and these were differentiated by three personality traits [extraversion, disinhibition (DIS) and experience seeking (ES)] and three alcohol expectancies dimensions (sociability, risk/aggression and negative mood). Regular drinkers with heavy episodic drinking and moderate drinkers had, compared to abstainers, higher scores in extroversion and alcohol expectancies for social facilitation, and lower scores in alcohol expectancies for risk and aggression. Regular drinkers with heavy episodic drinking exhibited, compared to moderate drinkers, higher scores in ES, DIS, extroversion, alcohol expectancies for social facilitation and negative mood alcohol expectancies; as well as lower scores in risk and aggression alcohol expectancies. CONCLUSION: College women in Argentina with problematic alcohol drinking can be distinguished from those drinking moderately. PMID- 25827777 TI - Former Heroin-Dependent Alcohol Use Disorder Patients. Prevalence, Addiction History and Clinical Features. AB - AIMS: To examine the prevalence of former heroin dependence (FHA) in Alcohol Use Disorder (AUD) patients; to compare the clinical characteristics of FHA-AUD patients versus AUD patients without any past use of heroin at alcohol treatment entry; to document the heroin dependence history of FHA-AUD patients, and review treatment strategies for this group. METHODS: Retrospective case review of 448 consecutive AUD patients. RESULTS: The annual entry of FHA-AUD showed stability over the study period of 3 years overall 60/448 (13.3%). FHA-AUD patients showed higher concomitant use of cocaine, benzodiazepines, cannabis and hallucinogens than other heroin addicts. They consumed higher amounts of alcohol at the beginning of their alcohol dependence history, and reached a high maximum level of alcohol consumption, than other AUD patients, and tended to have more physical disorders. The most important signals of FHA-AUD were polyabuse and older age at the time of presentation. FHA-AUD patients tended to have had a severe pattern of heroin dependence associated with inadequate agonist opiate treatment. CONCLUSIONS: The prevalence of FHA-AUD patients is not negligible. This may relate to previous inadequate treatment of heroin addiction contributing to the development of severe AUD. For these patients we propose a reconsideration of 'soft' (low dose) agonist opiate treatment. PMID- 25827780 TI - What is known about the subjective needs of people with behavioural variant frontotemporal dementia? A scoping review. AB - Behavioural variant frontotemporal dementia (bvFTD) is an early-onset and progressive neurodegenerative disease associated with strong changes in judgement, behaviour, personality and emotions. These changes can cause significant problems in everyday life for people with bvFTD and their families, and have implications for health and society. Currently, there are no suitable evidence-based specific interventions for people with bvFTD. This scoping review aims to identify the self-expressed needs, demands and coping strategies of people with bvFTD. Identifying these issues is the first step towards the development of need-based psycho-social interventions for people with bvFTD. A comprehensive literature research was conducted of German and English scientific articles published between January 2000 and October 2014 using the databases MEDLINE, CINAHL, PsycINFO, PSYNDEX, SocINDEX, GeroLit, the Cochrane Library, ProQuest, the German National Library and additional search strategies in terms of a scoping review. Articles were identified by combining search terms related to 'frontotemporal dementia' with terms related to 'self-expressions', 'needs/demands' and 'coping'. After excluding duplicates, two independent reviewers screened the titles and abstracts of 2317 records for eligibility. Because eligibility could not be assessed from the titles or abstracts of 28 articles, those articles were assessed using the full text. One poster abstract met our research question and a few articles were related, but no article met all of the inclusion criteria. This lack of scientifically based knowledge concerning the perspective of people with bvFTD is discussed with reference to the search strategy and the research questions, disease-related aspects such as changes in behaviour or language and emotions and the difficulties in researching this topic. Recommendations are formulated for future research considering the perspective of people with bvFTD and that will involve the development of appropriate data collection methods. Subsequently, specialised interventions must be developed. PMID- 25827778 TI - ADIPOQ polymorphism rs182052 is associated with clear cell renal cell carcinoma. AB - Recent studies have indicated that low circulating adiponectin concentrations are associated with a higher risk of several cancers, including renal cell carcinoma. In this case-control study, we examined the frequency of single nucleotide polymorphisms (rs182052G>A, rs266729C>G, and rs3774262G>A) in the adiponectin gene (ADIPOQ) in 1004 patients with clear cell renal cell carcinoma (ccRCC) compared with a group of healthy subjects (n = 1108). Fasting serum adiponectin concentrations were also examined. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). The association of serum adiponectin concentration with genetic variants was calculated using a multivariate linear regression model. A significantly higher ccRCC risk was associated with the rs182052 variant A allele (adjusted OR, 1.36 and 95% CI, 1.07 1.74 for AA vs GG, P = 0.013; adjusted OR, 1.27 and 95% CI, 1.04-1.56 for AA vs GG+AG, P = 0.019), and this positive association was more evident in overweight subjects. Fasting serum adiponectin was lower in subjects carrying A alleles of rs182052 in both ccRCC patients (beta = -0.399, P = 0.018) and healthy controls (beta = -0.371, P = 0.024). These results suggest that ADIPOQ rs182052 is significantly associated with ccRCC risk. PMID- 25827782 TI - A meta-analysis of the reliability of the history in suspected poisoning. AB - BACKGROUND: Management of acute poisoning depends on the reliability of history of the poisoning event. OBJECTIVE: The objective of this study was to perform a meta-analysis from published data to determine summary measures of reliability of history in suspected acute poisoning. METHOD: Relevant studies were selected from a search on the Medline database to perform a meta-analysis to calculate pooled estimates of kappa statistic for agreement between history of poisoning and laboratory diagnosis. RESULTS: A total of seven articles were included in the meta-analysis. The kappa statistic varied from 0.35 (95% confidence interval [CI] 0.135-0.558) for 3,4-methylenedioxy-N-methylamphetamine (MDMA, also known as ecstasy) to 0.69 (95% CI 0.648-0.733) for paracetamol. CONCLUSIONS: A history of paracetamol ingestion is moderately reliable, and further evaluation is required to make a clinical diagnosis of acute poisoning with street drugs. PMID- 25827781 TI - Atorvastatin Prevents Cognitive Deficits Induced by Intracerebroventricular Amyloid-beta1-40 Administration in Mice: Involvement of Glutamatergic and Antioxidant Systems. AB - Deposition of amyloid-beta (Abeta) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Abeta-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Abeta1-40 in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Abeta1-40 administration. Abeta1-40 caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Abeta1-40 decreased hippocampal and cortical Na(+) dependent glutamate uptake. However, Abeta1-40 increased Na(+)-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Abeta1-40 treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Abeta1-40 and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Abeta1-40 demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Abeta in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex. PMID- 25827783 TI - Comment on "Associations between the incidence of antiphosphatidylserine and antiphosphatidylethanolamine antibodies and clinical manifestations of systemic lupus erythematosus". PMID- 25827784 TI - Comment on "Associations between the incidence of antiphosphatidylserine and antiphosphatidylethanolamine antibodies and clinical manifestations of systemic lupus erythematosus". Authors' reply. PMID- 25827785 TI - Comment on "Correlation between the activity of the autonomic nervous system and endothelial function in patients with acute coronary syndrome". Authors' reply. PMID- 25827786 TI - Pay attention to the skeletal muscles in left ventricular hypertrabeculation / noncompaction. PMID- 25827787 TI - Pay attention to the skeletal muscles in left ventricular hypertrabeculation / noncompaction. Authors' reply. PMID- 25827788 TI - Clinical significance of measuring inflammatory markers in patients with pulmonary arterial hypertension. PMID- 25827789 TI - Clinical significance of measuring inflammatory markers in patients with pulmonary arterial hypertension. Authors' reply. PMID- 25827790 TI - Comment on "Correlation between the activity of the autonomic nervous system and endothelial function in patients with acute coronary syndrome". PMID- 25827791 TI - Recent advances in arsenic bioavailability, transport, and speciation in rice. AB - Widespread arsenic (As) contamination in paddy rice (Oryza sativa) from both geologic and anthropogenic origins is an increasing concern globally. Substantial efforts have been made to elucidate As transformation and uptake processes in rhizosphere and metabolism in rice plant, which provides an essential foundation for the development of mitigation strategies. However, a range of crucial mechanisms from As mobilization in rhizosphere to transport to grains remain poorly understood. To provide new insight into the underlying mechanisms of As accumulation in rice, a range of new perspectives on As bioavailability, transport pathways, and in situ speciation are reviewed here. Specifically, the prominent effects of water regime, Fe plaque, and biochar on As mobilization in rice rhizosphere are discussed critically. An updated understanding of arsenite (AsIII) and methylated As transport from root to vascular bundle and grain is integrated and discussed in detail. Special attention is given to As speciation and distribution in rice grain with potential coping strategies being provided and discussed. Future research priorities are also identified. The new insight into As bioavailability, transport and speciation in rice would lead to a better understanding of As contamination in rice. They would also provide useful strategies from agronomic measures to genetic engineering for more effective restriction of As transport and accumulation in food chain. PMID- 25827792 TI - Interacting effects of age and time of day on verbal fluency performance and intraindividual variability. AB - We explored the effects of age and time of day (TOD) on verbal fluency ability with respect to performance level and intraindividual variability (IIV). Verbal fluency, which involves complex cognitive operations, was examined in 20 older (mean age = 72.8 years) and 20 younger (mean age = 24.2 years) adults with test start time alternating between morning and evening across four days. Older adults generated more words in the morning and younger adults more in the evening, corresponding with self-report peak TOD. Age by TOD interactions were also observed across fluency tasks on the number of switches among subcategory exemplars during word generation and on the IIV observed in switching behavior. Older adults exhibited greater variability in switching in the evening than in the morning, whereas younger adults showed the opposite pattern. These findings demonstrate that processes involving energization (initiating and sustaining) and attentional control may be particularly sensitive to age differences in TOD influences on cognition. PMID- 25827793 TI - Follistatin and secreted frizzled-related protein 1, OVO homolog-like 1-regulated genes, are important for hair follicle neogenesis. PMID- 25827794 TI - Apparent IgE negative anaphylactic reaction to banana combined with kiwi allergy complementary diagnostic value of purified single banana allergens. PMID- 25827795 TI - Effects on bleeding complications of pharmacogenetic testing for initial dosing of vitamin K antagonists: a systematic review and meta-analysis: reply. PMID- 25827796 TI - 62 years of gastrointestinal research: 1951-2013. AB - In 1951, I began a 2-year postdoctoral research fellowship under Dr Simon Komarov at Temple University. Later, as a staff gastroenterologist at the Orange County General Hospital in California, I was interested in the possible role of blood flow alterations in peptic ulcer disease. We adapted Silvio Baez's just described in vivo microscopy technique to study blood flow in the gastric microcirculation in the anesthetized cat. In 1969, I joined the Gastroenterology Service at the West Los Angeles Veterans Administration (VA), primarily because of the presence there of Dr Morton Grossman, one of the leading researchers in gastrointestinal physiology. The most important lesson I learned from Dr Grossman was the importance of openness--investigators sharing their ideas, thoughts, and findings. Dr Harold Wayland, Professor, California Institute of Technology, helped me in setting up my laboratory at the VA and arranged with his friend Dr Masaharu Tsuchiya, Chair of Gastroenterology at Keio University, Tokyo, Japan, for a collaborative effort with fellows from Keio coming for 2-year fellowships with us (under my grant). Harold introduced us to the fluorescein-labeled albumen technique for the study of microvascular permeability. Later, Dr Jonathon Kaunitz, a colleague at the VA, and Kotaro Kaneko, my Keio University fellow, succeeded in modifying this technique to measure pHi in surface gastric cells in vivo. When I retired in 1993, Dr Kaunitz took charge of my laboratory. He and his associate Dr Akiba have completed extensive studies comparing and contrasting how stomach and duodenal surface cells defend themselves against acid loads. In the course of this work, they have become deeply involved in cell signaling and intracellular pathways when nutrients enter the duodenum. They have developed a technique for using confocal microscopy in vivo in this work. Dr Grossman was right: when investigators share their ideas, everyone benefits and science advances. PMID- 25827797 TI - Ethical issues in gastroenterology research. AB - Ethical issues have become increasingly important in gastroenterology research. This is for several reasons, including (i) an understanding of how conflicts of interest might affect research, (ii) the influence of the drug and device industries on research, (iii) ghostwriting (taking credit for something you did not write), (iv) the occurrence of ethically inappropriate research and scientific misconduct, and (v) respect for the rights of research subjects. These include the rights (i) to give informed consent to participate after understanding the purposes, risks, and benefits of the research; (ii) to ask questions; and (iii) to withdraw from participation at any time. Notions of doing good (beneficence), avoiding harm (non-maleficence), confidentiality, and, most important, the primacy of the welfare of the patient or research subject can be traced to antiquity. In the modern era, the Nuremburg Code (1947), the Declaration of Helsinki (1964), the Belmont report (1979), and other events and reports have led to the refinement of ethical practices in both clinical and research domains, have reinforced those long observed principles, and have given rise to the newer principles of autonomy and justice. The ethical conduct of research not only promotes good research but also is in the best interests of research subjects, investigators, sponsors, patients, and the public. PMID- 25827798 TI - Inflammatory bowel disease pathogenesis: where are we? AB - Inflammatory bowel disease (IBD) is presently one of the most investigated human disorders. Expansion of knowledge of its pathophysiology has helped in developing novel medications to combat gut inflammation with a considerably degree of success. Despite this progress, much more remains to be done in regard to gaining a more profound understanding of IBD pathogenesis, detecting inflammation before it clinically manifests, implementing lifestyle modifications, and developing agents that can modify the natural course of the disease. One of the limitations to achieve these goals is the lack of integration of the major components of IBD pathogenesis, that is the exposome, the genome, the gut microbiome, and the immunome. An "IBD integrome" approach that takes advantage of all functional information derived from the detailed investigation of each single pathogenic component through the use of systems biology may offer the solution to understand IBD and cure it. PMID- 25827799 TI - Atypical symptoms and health-related quality of life of patients with asymptomatic reflux esophagitis. AB - BACKGROUND AND AIM: Asymptomatic reflux esophagitis (RE) is simply regarded as RE without the typical reflux symptoms, but it is unknown whether patients with asymptomatic RE have atypical symptoms. The aim of this study was to examine the clinical characteristics and health-related quality of life (HRQOL) of patients with asymptomatic RE. PATIENTS AND METHODS: Consecutive patients with RE were enrolled during January 2010 to August 2012, and of them, 41 who had taken acid suppressing drugs were excluded, leaving 280 patients as the study group. The patients' symptoms were evaluated using a self-completed questionnaire (modified Frequency Scale for the Symptoms of gastroesophageal reflux disease [FSSG]), as well as an HRQOL questionnaire (SF-8). We defined the typical symptoms of RE as heartburn and regurgitation. Asymptomatic RE was defined if the total symptom score was 0 or the minimum (1 point) for typical reflux symptoms in the modified FSSG. RESULTS: Of the 280 RE patients, 71.8% (n = 201) were symptomatic and 28.2% (n = 79) were asymptomatic. The atypical symptom scores were significantly lower in asymptomatic RE (2.2 +/- 2.2) than in symptomatic RE patients (6.9 +/- 5.2) (P < 0.0001), and the HRQOL scores were significantly higher in asymptomatic RE than in symptomatic RE (P < 0.0001). Sleep was significantly less disturbed and chronic cough less frequent in asymptomatic RE than in symptomatic RE. CONCLUSION: Frequency and severity of atypical symptoms in patients with asymptomatic RE were significantly less than in patients with symptomatic RE, and the HRQOL score was significantly higher in those patients. These observations suggest a specific patient cohort that is truly unlikely to manifest symptoms. PMID- 25827800 TI - Pretreatment prediction of symptom response to proton pump inhibitor therapy. AB - BACKGROUND AND AIM: This prospective pilot study investigated whether it is possible to predict the therapeutic response in both the early phase (1 week) and sustained phase (4 weeks) before starting proton pump inhibitor (PPI) therapy for functional dyspepsia (FD) or non-erosive reflux disease (NERD). METHODS: We administered rabeprazole 10 mg for 4 weeks to NERD/FD patients, who also answered a modified version of the Frequency Scale for Symptoms of gastroesophageal reflux disease (GERD) (FSSG), which added a pain score to the FSSG. Total score (TS), reflux score (RS), dysmotility score (DS), and pain score (PS) were analyzed. Symptom improvement was defined as >= 50% improvement in each score. RESULTS: We enrolled 83 patients (age [mean +/- SD] 50.8 +/- 15.8 years, 29 males, 54 females), of whom 62 could be classified into four groups: achieved symptom improvement within 1 week and maintained it for 4 weeks (Early-R, 40.3%); achieved symptom improvement within 1 week but lost it after 4 weeks (Temp-R, 9.7%); did not achieve symptom improvement within 1 week but did after 4 weeks (Late-R, 9.7%); and no improvement (Non-R, 40.3%). Mean TS, RS, DS, and PS in the Non-R group were significantly higher than in the Early-R group (23.9, 10.5, 11.0, and 2.4 vs 14.3, 6.8, 6.4, and 1.2). However, the Temp-R, Late-R, and Non-R groups could not be distinguished by TS, RS, or DS. CONCLUSION: The magnitude of the pretreatment modified FSSG score seemed to be associated with the response at 1 week and 4 weeks. PMID- 25827801 TI - Gastroesophageal reflux disease in patients with diabetes: preliminary study. AB - BACKGROUND AND AIM: Some studies report that complications of gastroesophageal reflux disease (GERD) occur more frequently in patients with diabetes mellitus (DM) than in non-diabetic patients. This study used transnasal endoscopy to elucidate the current status of concurrent GERD in patients with type 2 diabetes mellitus, and to examine the associations between intraesophageal pressure and GERD, as well as other neuropathic conditions. METHODS: The study included 57 outpatients with type 2 diabetes mellitus. The mean age was 67 years and the duration of DM was 13 years. The mean hemoglobin A1c was 6.8%. Transnasal endoscopic evaluation items were (i) the presence or absence of esophagitis and its severity; (ii) intraesophageal pressure; and (iii) Helicobacter pylori status, which was evaluated by endoscopic findings, such as the presence or absence of gastritis and peptic ulcer, and by urea breath test. RESULTS: Of 57 patients, 24 (42.1%) were given a diagnosis of GERD based on endoscopy. Patients with concurrent GERD were younger, had shorter duration of DM, and were taller and heavier. Interestingly, no difference in body mass index was observed. There was no significant association between the presence of concurrent GERD and diabetic complications, including peripheral neuropathy, and infection or non infection with H. pylori. Although there was no significant association between the presence of concurrent GERD and intraesophageal pressure values, we found aging, reduced estimated glomerular filtration rate, and the presence of autonomic nerve symptoms to correlate with reduced intraesophageal pressure. CONCLUSION: The results of this study could be used to answer the question of whether or not endoscopic GERD is a diabetic complication; however, further study is required. PMID- 25827802 TI - Usefulness of baseline impedance in patients with proton pump inhibitor refractory nonerosive reflux disease. AB - BACKGROUND AND AIM: Approximately more than half of patients with non-erosive reflux disease (NERD) do not respond to proton pump inhibitor (PPI) therapy. Although NERD is a heterogeneous entity, previous study showed that multichannel intraluminal impedance (MII)-pH monitoring could distinguish reflux-related disease from PPI-refractory NERD. The aim of this study was to examine the usefulness of baseline impedance in PPI-refractory NERD patients. METHODS: We used MII-pH monitoring to analyze reflux parameters, symptom index (SI), and baseline impedance in 37 PPI-refractory NERD patients on PPI. Reflux was divided into acid (nadir pH <= 4) and non-acid (nadir pH > 4). Subjects were classified as having reflux-related disease based on abnormal reflux parameters or positive SI (>= 50%), or non-reflux-related disease, including functional heartburn, based on negative SI with normal reflux parameters. RESULTS: A total of 26 of the 37 subjects were diagnosed with reflux-related disease, including eight with acid reflux type and 18 with non-acid-reflux type, and nine with functional heartburn and two with pseudohypersalivation. There were no significant differences in the clinical characteristics of the acid-reflux type, non-acid-reflux type, and functional heartburn groups. The baseline impedance value in the acid-reflux type (1245 +/- 392 Omega) was significantly lower than that in the non-acid-reflux type (2824 +/- 1160 Omega) and functional heartburn (3546 +/- 1353 Omega) groups. Baseline impedance values inversely correlated with reflux percent time, acid reflux time, and acid exposure time. CONCLUSION: Among patients with PPI refractory NERD, acid-reflux type was associated with lower baseline impedance compared with non-acid-reflux type and functional heartburn. PMID- 25827803 TI - Surveillance of short-segment Barrett's esophagus using ultrathin transnasal endoscopy. AB - BACKGROUND AND AIM: Newly developed ultrathin transnasal endoscope, the GIF XP290N, makes possible a resolving power similar to the GIF-H260 at a distance of 3 mm. We conducted surveillance of subjects with Barrett's esophagus using this ultrathin transnasal endoscopy. In Japan the lower margin of the lower esophageal palisade vessels is defined the gastroesophageal junction in deep inspiration. We diagnose Barrett's esophagus if columnar epithelium is present on the oral side of the gastroesophageal junction. METHODS AND RESULTS: Barrett's esophagus was confirmed in 116 out of 135 subjects (85.9%), with 17 cases of short-segment Barrett's esophagus (SSBE) and 99 of ultra-short-segment Barrett's esophagus. Close observation of the Barrett's esophagus mucosal structural pattern using narrow band imaging revealed 29 cases with an oval or round pattern, 29 with a long straight pattern, 47 with a villous pattern, 8 with a cerebriform pattern, and 6 with an irregular pattern according to Goda classification. Mucosal biopsies from all subjects with SSBE are examined. Histological examination revealed intestinal metaplasia in only eight subjects. We grouped the oval/round and long straight patterns as closed type, and the villous, cerebriform, and irregular patterns as open type. Analysis of the relationship between these mucosal patterns and background factors revealed a significant correlation between intestinal metaplasia and the open-type pattern. CONCLUSION: We consider this new ultrathin transnasal endoscopy to be a useful technique for surveillance of Barrett's esophagus, especially SSBE. PMID- 25827804 TI - Therapeutic roles of carbon monoxide in intestinal ischemia-reperfusion injury. AB - Intestinal ischemia-reperfusion (I-R) injury is a complex, multifactorial, pathophysiological process with high morbidity and mortality, leading to serious difficulty in treatment. The mechanisms involved in the pathogenesis of intestinal I-R injury have been examined in detail and various therapeutic approaches for intestinal I-R injury have been developed; however, existing circumstances have not yet led to a dramatic change of treatment. Carbon monoxide (CO), one of the by-products of heme degradation by heme oxygenase (HO), is considered as a candidate for treatment of intestinal I-R injury and indeed HO-1 derived endogenous CO and exogenous CO play a pivotal role in protecting the gastrointestinal tract from intestinal I-R injury. Interestingly, anti inflammatory effects of CO have been elucidated sufficiently in various cell types including endothelial cells, circulating leukocytes, macrophages, lymphocytes, epithelial cells, fibroblast, organ-specific cells, and immune presenting cells. In this review, we herein focus on the therapeutic roles of CO in intestinal I-R injury and the cell-specific anti-inflammatory effects of CO, clearly demonstrating future therapeutic strategies of CO for treating intestine I-R injury. PMID- 25827805 TI - Study of the mechanisms of a Japanese traditional fermented medicine in the improvement of constipation. AB - BACKGROUND AND AIM: Gut Working Tablet (GWT) is a Japanese traditional fermented medicine based on Aspergillus oryzae NK-fermented grain germ. Although GWT has been used by patients with constipation, the mechanism has not been investigated. The aim of this study was to examine the possible mechanisms of the effect of GWT on constipation. METHODS: The effect of GWT water extracts on gut contractility using ileum strips from guinea pig and on the growth of Bifidobacterium longum were examined in vitro. The 14 Sprague Dawley rats were administered loperamide at 10 mg/day per kg for 3 days. They were fed with and without 5% of GWT before and during administration of loperamide. Number of stools and weight of feces were measured before and during administration of loperamide. The concentrations of short-chain fatty acids (SCFAs) in the feces and cecal contents were measured by gas chromatography. RESULTS: GWT water extracts dose-dependently induced ileal contractile responses, which were inhibited by atropine. The growth of B. longum was increased in the presence of GWT water extracts in a dose-dependent manner (P < 0.01 vs control). The decrease in both the number and weight of feces caused by loperamide was improved by GWT administration (P < 0.05 vs loperamide). The decrease in the butyric acid concentration in feces and cecal contents induced by the administration of loperamide was inhibited by GWT (P = 0.035 and 0.018). CONCLUSION: GWT water extracts may induce cholinergic-like stimulation and promote the growth of probiotics. Furthermore, GWT water extract contributed to normalization of colonic SCFAs. These results may explain, at least in part, the beneficial effects of GWT on constipation. PMID- 25827806 TI - The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice. AB - BACKGROUND AND AIM: Luminal nutrients stimulate enteroendocrine L cells to release gut hormones, including intestinotrophic glucagon-like peptide-2 (GLP-2). Because L cells express the bile acid receptor TGR5 and dipeptidyl peptidase-IV (DPPIV) rapidly degrades GLPs, we hypothesized that luminal TGR5 activation may attenuate intestinal injury via GLP-2 release, which is enhanced by DPPIV inhibition. METHODS: Intestinal injury was induced in mice by administration of dextran sulfate sodium (DSS) in drinking water (free access to water containing 5% DSS for 7 days). The selective TGR5 agonist betulinic acid (BTA) and the DPPIV inhibitor sitagliptin phosphate monohydrate (STG) were administered orally for 7 days. Male C57BL/6 mice (6-7 weeks old) were divided into five groups: normal control group, disease control group, BTA low group (drinking water containing 15 mg/L BTA), BTA high group (50 mg/L BTA), and BTA high + STG (3 mg/kg, i.g.) group. RESULTS: The selective TGR5 agonist BTA dose-dependently suppressed disease activity index and mRNA expression of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in the colon. Nevertheless, STG administration had little additive effect on BTA-induced protection. Fibroblast activation protein mRNA expression, but not expression of other DPP family members, was increased in the colon of DSS-treated mice with increased mucosal DPPIV. Co-administration of the selective GLP-2 antagonist GLP 2 (3-33) reversed the effect of BTA. CONCLUSION: The selective TGR5 agonist BTA ameliorated DSS-induced colitis in mice via the GLP-2 pathway with no effect of DPPIV inhibition, suggesting that other DPP enzymatic activity is involved in GLP 2 degradation. PMID- 25827807 TI - Clinical impact of ultrathin colonoscopy for Crohn's disease patients with strictures. AB - BACKGROUND AND AIM: Mucosal healing is now the ideal treatment goal for patients with Crohn's disease (CD) and endoscopy is suitable for both visualizing the intestinal mucosa and optimizing treatment according to the objective endoscopic findings; however, passing through strictures with a conventional colonoscope is sometimes difficult. An ultrathin colonoscope (outer diameter 9.2 mm) has been developed for superior insertion performance. METHODS: CD patients with strictures that could not be passed with a conventional colonoscope were eligible for entry into the study. We investigated the rate of passage of the ultrathin colonoscope beyond strictures. We also investigated the clinical impact of optimizing the treatment strategy according to the endoscopic findings beyond the stricture. RESULTS: Of 49 patients, the ultrathin colonoscope could pass the stricture in 59.2% (29/49). The main reason for failure compared with the "pass" group was anal stricture (P = 0.005). When including finger bougie for severe anal stricture, passage of the stricture was achieved in 83.7% (41/49) of cases and the oral mucosa beyond the stricture was visualized. In these cases, 56.1% (23/41) had treatment efficacy confirmed and 43.9% (18/41) required a change of treatment. Importantly, half (9/18) of them were in clinical remission. There were no complications of the study. CONCLUSION: The ultrathin colonoscope could provide optimized treatment based on objective findings of the activity of the oral-side mucosa in CD patients complicated with stricture. Selection of the appropriate endoscope to visualize the responsible lesion is essential to optimize the treatment strategy in each case of CD. PMID- 25827808 TI - Clinical features of eosinophilic esophagitis: differences between Asian and Western populations. AB - The prevalence and incidence of eosinophilic esophagitis (EoE) have been rapidly increasing in Western countries. It is thought to be more common among Caucasians than other racial or ethnic groups, but epidemiological studies have not been fully evaluated in Asian populations, and its clinical manifestation is rarely documented. In this review, recent reports regarding EoE in Asian countries have been collected, and differences in the clinical features, including symptoms and endoscopic findings, between Asian and Western populations have been evaluated. In Asia, EoE is still much less prevalent than in Western countries. Baseline values for average age, male/female ratio, and personal history of allergic disease were comparable to those in Western populations. Predominant symptoms were dysphagia, and food impaction was extremely rare among Asian patients. Although the frequency of abnormal endoscopic findings varies among studies, over 90% of patients with EoE have shown abnormal findings such as linear furrow, which is the most common findings, in recent prospective studies in Asia. There are few reports regarding the treatment of EoE and no prospective studies evaluating drugs or elimination diet in patient with EoE have been reported in Asia. Overall, EoE had similar clinical characteristics in Asian populations. Because the incidence of EoE could increase in the future with the increase in allergic disorders in Asian countries, large-scale, nationwide prospective studies should be performed to more fully understand the epidemiology and pathophysiology of EoE in Asian populations. PMID- 25827809 TI - Detailed analysis of epithelial-mesenchymal transition and tumor budding identifies predictors of long-term survival in pancreatic ductal adenocarcinoma. AB - BACKGROUND AND AIM: Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biology and poor prognosis even after resection. Long-term survival is very rare and cannot be reliably predicted. Experimental data suggest an important role of epithelial-mesenchymal transition (EMT) in invasion and metastasis of PDAC. Tumor budding is regarded as the morphological correlate of local invasion and cancer cell dissemination. The aim of this study was to evaluate the biological and prognostic implications of EMT and tumor budding in PDAC of the pancreatic head. METHODS: Patients were identified from a prospectively maintained database, and baseline, operative, histopathological, and follow-up data were extracted. Serial tissue slices stained for Pan Cytokeratin served for analysis of tumor budding, and E-Cadherin, Beta-Catenin, and Vimentin staining for analysis of EMT. Baseline, operative, standard pathology, and immunohistochemical parameters were evaluated for prediction of long-term survival (>= 30 months) in uni- and multivariate analysis. RESULTS: Intra- and intertumoral patterns of EMT marker expression and tumor budding provide evidence of partial EMT induction at the tumor-host interface. Lymph node ratio and E-Cadherin expression in tumor buds were independent predictors of long term survival in multivariate analysis. CONCLUSIONS: Detailed immunohistochemical assessment confirms a relationship between EMT and tumor budding at the tumor host interface. A small group of patients with favorable prognosis can be identified by combined assessment of lymph node ratio and EMT in tumor buds. PMID- 25827810 TI - Confocal laser endomicroscopy: a new gold standard for the assessment of mucosal healing in ulcerative colitis. AB - BACKGROUND AND AIM: Endoscopic assessment of mucosal healing in ulcerative colitis (UC) is increasingly accepted as a measure of disease activity, therapeutic goal, and the key prognostic indicator. While regular endoscopy evaluates appearance of the mucosal surface, confocal laser endomicroscopy (CLE) enables in vivo visualization of subepithelial mucosa at 1000* magnification during ongoing endoscopy. Our aims were to determine using CLE whether endoscopically normal appearing colonic mucosa in patients with UC in remission (UC-IR) has fully regenerated mucosal structures, resolved inflammation, and to identify the mechanisms. METHODS: Twelve patients (six controls and six with UC IR) underwent colonoscopy using CLE and intravenous fluorescein infusion. During colonoscopy, CLE images of colonic mucosa and conventional mucosal biopsies were obtained and evaluated using image-analysis systems. We quantified; (i) regeneration of colonic crypts and blood microvessels; (ii) cyclooxygenase 2 (COX2) expression; (iii) mitochondrial DNA (mtDNA) mutations; (iv) inflammatory infiltration; and (v) vascular permeability (VP). RESULTS: In control subjects, CLE demonstrated normal colonic crypts and microvasculature. COX2 expression was minimal, and < 7% crypts showed mtDNA mutations. Colonic mucosa of UC-IR patients had impaired and distorted crypt regeneration, increased COX2, 69% crypts with mtDNA mutations, persistent inflammation, and abnormal vascular architecture with increased VP (all P < 0.001 vs normal mucosa). CONCLUSIONS: (i) Endoscopically normal appearing colonic mucosa of patients with UC-IR remains abnormal: CLE demonstrates impaired crypt regeneration, persistent inflammation, distinct abnormalities in angioarchitecture and increased vascular permeability; molecular imaging showed increased COX2 and mtDNA mutations; (ii) CLE may serve as a new gold standard for the assessment of mucosal healing in UC. PMID- 25827811 TI - Co-registration and distortion correction of diffusion and anatomical images based on inverse contrast normalization. AB - Diffusion MRI provides quantitative information about microstructural properties which can be useful in neuroimaging studies of the human brain. Echo planar imaging (EPI) sequences, which are frequently used for acquisition of diffusion images, are sensitive to inhomogeneities in the primary magnetic (B0) field that cause localized distortions in the reconstructed images. We describe and evaluate a new method for correction of susceptibility-induced distortion in diffusion images in the absence of an accurate B0 fieldmap. In our method, the distortion field is estimated using a constrained non-rigid registration between an undistorted T1-weighted anatomical image and one of the distorted EPI images from diffusion acquisition. Our registration framework is based on a new approach, INVERSION (Inverse contrast Normalization for VERy Simple registratION), which exploits the inverted contrast relationship between T1- and T2-weighted brain images to define a simple and robust similarity measure. We also describe how INVERSION can be used for rigid alignment of diffusion images and T1-weighted anatomical images. Our approach is evaluated with multiple in vivo datasets acquired with different acquisition parameters. Compared to other methods, INVERSION shows robust and consistent performance in rigid registration and shows improved alignment of diffusion and anatomical images relative to normalized mutual information for non-rigid distortion correction. PMID- 25827812 TI - Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice. AB - Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- * 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the MU-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice. PMID- 25827813 TI - The Risk of Sexual Assault and Rape During International Travel: Implications for the Practice of Travel Medicine. PMID- 25827814 TI - Inclusion excluded: Chiroptical sensing of the external surface of sulfated cyclodextrins. AB - It is shown that the heparin antagonist bis-aminoquinoline derivative surfen interacts with sulfated cyclodextrins in a unique fashion. Analysis of the UV spectroscopic data revealed exceptionally strong association (K(a) ~ 10(7) M(-1)) of several surfen molecules to the external surface of the cyclodextrin hosts. H bonded to the sulfate groups in 1:1 stoichiometry, the drug molecules form a chiral layer around the macrocycles. Due to the steric proximity, dipole-dipole coupling occurs between the adjacent aminoquinoline rings that accounts for the large UV hypochromism and the induced exciton couplet in the circular dichroism spectra. PMID- 25827815 TI - p53 signalling mediates acupuncture-induced neuroprotection in Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of dopamine (DA) neurons in the substantia nigra of the midbrain. Recently, it has been demonstrated that acupuncture treatment has protective effects in PD. However, to date, the molecular mechanisms underlying acupuncture's effect on DA neuronal protection are largely unknown. In this study, we report that p53 signalling mediates the protective effects of acupuncture treatment in a mouse model of PD. We found that the acupuncture treatment in the mouse PD model results in significant recovery to the normal in the context of behaviour and molecular signatures. We found that the gene network associated with p53 signalling is closely involved in the protective effects of acupuncture treatment in PD. Consistent with this idea, we demonstrated that specific knockout of the p53 gene in the midbrain DA neurons abrogates the acupuncture induced protective effects in the mouse model of PD. Thus, these data suggest that p53 signalling mediates the protective effects of acupuncture treatment in PD. PMID- 25827816 TI - Laparoscopic sphincter-saving surgery for low rectal cancer--a video vignette. PMID- 25827817 TI - Clinical follow-up does not improve survival after resection of stage I-III colorectal cancer: A cohort study. AB - INTRODUCTION: The benefit of clinical follow-up alongside CT & CEA in detecting recurrent colorectal cancer (CRC) remains unclear. Despite this, clinical review remains part of most surveillance protocols. This study assessed the efficacy of clinical follow-up in addition to CT/CEA in detecting disease recurrence. METHODS: Patients undergoing surgery for CRC at a single centre between 2009 and 2011 were identified. Follow-up included clinical review, CT and CEA for 5 years. The primary endpoint of the study was method of detection of recurrence. Secondary endpoints included detection of surgically treatable recurrence, compliance with follow-up, disease free survival and overall survival. RESULTS: 118 patients with stage I-III CRC were included. Only 68.9% of scheduled follow up events were performed (76.6% clinical reviews, 76.2% CT scans and 60.4% CEA tests). At median follow-up of 36 months, 26 patients had developed recurrence (median DFS 45.8 months). 17 patients (14.7%) had died (median OS 49.3 months). Sensitivity and specificity of follow up modality in detecting recurrence were; CT (92.3%, 100%), CEA (57.7%, 100%), clinical review (23.0%, 27.2%). Addition of clinical review did not identify any disease recurrence that was not detected by scheduled CT. Eight patients (30.7%) had surgically treatable recurrence - all were identified by scheduled CT. CONCLUSION: The addition of CEA testing and clinical review to scheduled CT scanning offered no benefit in the detection of recurrent disease. Clinical review could be removed from follow-up protocols without any reduction in the detection of recurrent cancer. PMID- 25827818 TI - Preparation of the monolith of hierarchical macro-/mesoporous calcium silicate ultrathin nanosheets with low thermal conductivity by means of ambient-pressure drying. AB - Calcium silicate monolith was prepared by the hydrothermal reaction of a slurry of SiO2 , calcium hydroxide, and surfactant (OP-10) obtained by high-energy ball milling, followed by drying at ambient pressure. By using this strategy, the shrinkage due to the collapse of pores during the drying of porous materials, which is a commonly observed phenomena, was successfully avoided. It has a unique microstructure of hierarchical macro-/mesoporous ultrathin calcium silicate nanosheets with a layered gyrolite crystalline structure. Very interestingly, the calcium silicate nanosheets can be peeled off to give a single-layer nanosheet (1.23 nm) of gyrolite by ultrasonication. The monolith has a low apparent density (0.073 g cm(-3) ) and low thermal conductivity (0.0399 W K(-1) m(-1) ). The reasons behind why the formation of the unique hierarchical macro-/mesoporous ultrathin nanosheets avoids shrinkage during the hydrothermal reaction and drying, and considerably decreases the thermal conductivity, is discussed. PMID- 25827819 TI - O2 activation by metal-ligand cooperation with Ir(I) PNP pincer complexes. AB - A unique mode of molecular oxygen activation, involving metal-ligand cooperation, is described. Ir pincer complexes [((t)BuPNP)Ir(R)] (R = C6H5 (1), CH2COCH3 (2)) react with O2 to form the dearomatized hydroxo complexes [((t)BuPNP*)Ir(R)(OH)] ((t)BuPNP* = deprotonated (t)BuPNP ligand), in a process which utilizes both O atoms. Experimental evidence, including NMR, EPR, and mass analyses, indicates a binuclear mechanism involving an O-atom transfer by a peroxo intermediate. PMID- 25827821 TI - The evolving epidemiology of hepatocellular carcinoma: a global perspective. AB - Primary liver cancer, the majority of which are hepatocellular carcinomas, is now the second leading cause of cancer death worldwide. Hepatocellular carcinoma is a unique cancer that typically arises in the setting of chronic liver disease at a rate dependent upon the complex interplay between the host, disease and environmental factors. Infection with chronic hepatitis B or C virus is currently the dominant risk factor worldwide. However, changing lifestyle and environmental factors in western countries plus rising neonatal hepatitis B vaccination rates and decreasing exposure to dietary aflatoxins in developing countries are driving an evolution of the epidemiology of this cancer. An understanding of this change is crucial in combating the rising incidence currently being seen in western regions and will underpin the efforts to reduce the mortality rates associated with this cancer. PMID- 25827820 TI - Phase 2 study of MK-2206, an allosteric inhibitor of AKT, as second-line therapy for advanced gastric and gastroesophageal junction cancer: A SWOG cooperative group trial (S1005). AB - BACKGROUND: The AKT inhibitor MK-2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers. METHODS: Patients who had progressed after first-line treatment were eligible. Pertinent eligibility criteria included adequate organ function, a fasting serum glucose level <= 150 mg/dL, and less than grade 2 malabsorption or chronic diarrhea. MK-2206 was given orally (60 evaluable patients required). The primary endpoint was overall survival, and a median survival of 6.5 months (power, 89%; significance level, 0.07) was considered encouraging for further investigation. RESULTS: Seventy patients were included in the final analyses. The median age was 59.8 years (range, 30.4-86.7 years); 70% were male, 89% were white, and 7% were Asian. There were 2 deaths possibly related to the study drug (cardiac arrest and respiratory failure). Grade 4 adverse events included hyperglycemia, anemia, and lung infection (1 each). Grade 3 adverse events occurred in < 5% of patients except for fatigue (6%). Other adverse events (all grades) included anemia (17%), anorexia (30%), diarrhea (26%), fatigue (50%), hyperglycemia (30%), nausea (40%), vomiting (22%), dry skin (19%), maculopapular rash (30%), and acneiform rash (13%). The response rate was 1%, the median progression-free survival was 1.8 months (95% confidence interval, 1.7-1.8 months), and the median overall survival was 5.1 months (95% confidence interval, 3.7-9.4 months) CONCLUSIONS: MK-2206 as second-line therapy was well tolerated by an unselected group of patients with gastric/gastroesophageal junction cancers, but it did not have sufficient activity (response rate, 1%; overall survival, 5.1 months) to warrant further testing in this population. PMID- 25827823 TI - Folding-induced modulation of excited-state dynamics in an oligophenylene ethynylene-tethered spiral perylene bisimide aggregate. AB - The excited-state photophysical behavior of a spiral perylene bisimide (PBI) folda-octamer (F8) tethered to an oligophenylene-ethynylene scaffold is comprehensively investigated. Solvent-dependent UV/Vis and fluorescence studies reveal that the degree of folding in this foldamer is extremely sensitive to the solvent, thus giving rise to an extended conformation in CHCl(3) and a folded helical aggregate in methylcyclohexane (MCH). The exciton-deactivation dynamics are largely governed by the supramolecular structure of F8. Femtosecond transient absorption (TA) in the near-infrared region indicates a photoinduced electron transfer process from the backbone to the PBI core in the extended conformation, whereas excitation power- and polarization-dependent TA measurements combined with computational modeling showed that excitation energy transfer between the unit PBI chromophores is the major deactivation pathway in the folded counterpart. PMID- 25827822 TI - Identification of a novel selective agonist of PPARgamma with no promotion of adipogenesis and less inhibition of osteoblastogenesis. AB - Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in the regulation of glucose homeostasis and lipid metabolism. However, current PPARgamma-targeting drugs such as thiazolidinediones (TZDs) are associated with undesirable side effects. We identified a small molecular compound, F12016, as a selective PPARgamma agonist by virtual screening, which showed moderate PPARgamma agonistic activity and binding ability for PPARgamma. F12016 did not activate other PPAR subtypes at 30 MUM and selectively modulated PPARgamma target gene expression. In diabetic KKAy mice, F12016 had insulin-sensitizing and glucose-lowering properties, and suppressed weight gain. In vitro, F12016 effectively increased glucose uptake and blocked cyclin-dependent kinase 5-mediated phosphorylation of PPARgamma at Ser273, but slightly triggered adipogenesis and less inhibited osteoblastogenesis than rosiglitazone. Moreover, compared with the full agonist rosiglitazone, F12016 had a distinct group of coregulators and a different predicted binding mode for the PPARgamma ligand-binding domain. A site mutation assay confirmed the key epitopes, especially Tyr473 in AF-2. In summary, our study shows that F12016 is a non-TZD, novel selective PPARgamma agonist without the classical lipogenic side effects, which may provide a new structural strategy for designing PPARgamma ligands with advantages over TZDs. PMID- 25827824 TI - Beyond the Academic Journal: Unfreezing Misconceptions About Mental Illness and Gun Violence Through Knowledge Translation to Decision-Makers. AB - In a policy arena characterized by polarized debate, such as the consideration of legal interventions to prevent gun violence, research evidence is an important tool to inform decision-making processes. However, unless the evidence is communicated to stakeholders who can influence policy decisions, the research will often remain an academic exercise with little practical impact. The Educational Fund to Stop Violence's process of "unfreezing" individual perceptions and conventional interpretations of the relationship between mental illness and gun violence, forming a consensus, and translating this knowledge to stakeholders through state discussion forums is one way to inform policy change. The recent passage of gun violence prevention legislation in California provides an example of successfully closing the knowledge translation gap between research and decision-making processes. PMID- 25827825 TI - Commentary on Effect of a second injection of botulinum toxin on lower facial contouring, as evaluated using 3-dimensional laser scanning. PMID- 25827826 TI - A lower lip reconstruction. PMID- 25827827 TI - Chronic inflammatory reaction after thread lifting: delayed unusual complication of nonabsorbable thread. PMID- 25827828 TI - Commentary on Malignant hidroacanthoma simplex treated with Mohs surgery. PMID- 25827829 TI - Tris(8-methoxy-2-quinolylmethyl)amine (8-MeOTQA) as a highly fluorescent Zn(2+) probe prepared by convenient C3-symmetric tripodal amine synthesis. AB - A convenient synthesis of C3-symmetric tribenzylamine (TBA) derivatives has been investigated. The reaction of benzyl chlorides with acetaldehyde ammonia trimer () in the presence of base afforded tribenzylamines in high yields. This efficient method allows the diverse synthesis of TPA (tris(2-pyridylmethyl)amine) and TQA (tris(2-quinolylmethyl)amine) derivatives. Among the TQA compounds prepared, tris(8-methoxy-2-quinolylmethyl)amine (8-MeOTQA, ) exhibited superior properties as a fluorescent zinc probe with high quantum yield (phiZn = 0.51) and high sensitivity (limit of detection (LOD) = 3.4 nM). The X-ray crystallographic analysis of [Zn(8-MeOTQA)](2+) revealed that the steric and electronic effect of 8-methoxy substituents kicks out the solvent and counterion molecules from the metal coordination sphere, resulting in short Zn-Nquinoline coordination distances (2.04-2.07 A). The pseudo hexacoordinate complex of 6-methoxy derivative, [Zn(6-MeOTQA)(DMF)(ClO4)](+), exhibited longer Zn-Nquinoline distances (2.07-2.19 A) and much smaller fluorescence intensity (phiZn = 0.027). The replacement of one of the three 8-methoxyquinolines with pyridine also afforded much less fluorescent zinc complex (phiZn = 0.095) due to the solvent coordination (Zn-Nquinoline = 2.05-2.18 A for [Zn(8-MeOBQPA)(CH3OH)](2+)). PMID- 25827830 TI - Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease. AB - Intravascular hemolysis describes the relocalization of heme and hemoglobin (Hb) from erythrocytes to plasma. We investigated the concept that erythrocyte membrane microparticles (MPs) concentrate cell-free heme in human hemolytic diseases, and that heme-laden MPs have a physiopathological impact. Up to one third of cell-free heme in plasma from 47 patients with sickle cell disease (SCD) was sequestered in circulating MPs. Erythrocyte vesiculation in vitro produced MPs loaded with heme. In silico analysis predicted that externalized phosphatidylserine (PS) in MPs may associate with and help retain heme at the cell surface. Immunohistology identified Hb-laden MPs adherent to capillary endothelium in kidney biopsies from hyperalbuminuric SCD patients. In addition, heme-laden erythrocyte MPs adhered and transferred heme to cultured endothelial cells, inducing oxidative stress and apoptosis. In transgenic SAD mice, infusion of heme-laden MPs triggered rapid vasoocclusions in kidneys and compromised microvascular dilation ex vivo. These vascular effects were largely blocked by heme-scavenging hemopexin and by the PS antagonist annexin-a5, in vitro and in vivo. Adversely remodeled MPs carrying heme may thus be a source of oxidant stress for the endothelium, linking hemolysis to vascular injury. This pathway might provide new targets for the therapeutic preservation of vascular function in SCD. PMID- 25827831 TI - How I treat Langerhans cell histiocytosis. AB - "Langerhans cell histiocytosis" (LCH) describes a spectrum of clinical presentations ranging from a single bone lesion or trivial skin rash to an explosive disseminated disease. Regardless of clinical severity, LCH lesions share the common histology of CD1a(+)/CD207(+) dendritic cells with characteristic morphology among an inflammatory infiltrate. Despite historical uncertainty defining LCH as inflammatory vs neoplastic and incomplete understanding of mechanisms of pathogenesis, clinical outcomes have improved markedly over the past decades through cooperative randomized clinical trials based on empiric therapeutic strategies. Significant advances include recognition of high- and low-risk clinical groups defined by hematopoietic and/or hepatic involvement, and of the importance of optimal intensity and of duration of chemotherapy. Nevertheless, mortality of high-risk patients, disease recurrence, lack of robustly tested salvage strategies, and significant disease morbidity of both high- and low-risk patients remain challenges. Recent discovery of recurrent somatic mutations in mitogen-activated protein kinase pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy. PMID- 25827832 TI - The tumor virus landscape of AIDS-related lymphomas. AB - Immunodeficiency dramatically increases susceptibility to cancer as a result of reduced immune surveillance and enhanced opportunities for virus-mediated oncogenesis. Although AIDS-related lymphomas (ARLs) are frequently associated with known oncogenic viruses, many cases contain no known transforming virus. To discover novel transforming viruses, we profiled a set of ARL samples using whole transcriptome sequencing. We determined that Epstein-Barr virus (EBV) was the only virus detected in the tumor samples of this cohort, suggesting that if unidentified pathogens exist in this disease, they are present in <10% of cases or undetectable by our methods. To evaluate the role of EBV in ARL pathogenesis, we analyzed viral gene expression and found highly heterogeneous patterns of viral transcription across samples. We also found significant heterogeneity of viral antigen expression across a large cohort, with many patient samples presenting with restricted type I viral latency, indicating that EBV latency proteins are under increased immunosurveillance in the post-combined antiretroviral therapies era. Furthermore, EBV infection of lymphoma cells in HIV positive individuals was associated with a distinct host gene expression program. These findings provide insight into the joint host-virus regulatory network of primary ARL tumor samples and expand our understanding of virus-associated oncogenesis. Our findings may also have therapeutic implications, as treatment may be personalized to target specific viral and virus-associated host processes that are only present in a subset of patients. PMID- 25827833 TI - The role of rituximab in adults with warm antibody autoimmune hemolytic anemia. AB - Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. When therapy is needed, corticosteroids remain the cornerstone of initial treatment but are able to cure only a minority of patients (<20%). Splenectomy is usually proposed when a second-line therapy is needed. This classical approach is now challenged by the use of rituximab both as second-line and as first-line therapy. Second-line treatment with rituximab leads to response rates similar to splenectomy (~70%), but rituximab-induced responses seem less sustained. However, additional courses of rituximab are most often followed by responses, at the price of reasonable toxicity. In some major European centers, rituximab is now the preferred second-line therapy of warm antibody hemolytic anemia in adults, although no prospective study convincingly supports this attitude. A recent randomized study strongly suggests that in first-line treatment, rituximab combined with steroids is superior to monotherapy with steroids. If this finding is confirmed, rituximab will emerge as a major component of the management of warm antibody hemolytic anemia not only after relapse but as soon as treatment is needed. PMID- 25827834 TI - How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors. AB - Inhibitor development poses a significant challenge in the management of hemophilia because once an inhibitor is present, bleeding episodes can no longer be treated with standard clotting factor replacement therapy. Consequently, patients with inhibitors are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three clinical trials in patients with inhibitors have demonstrated that prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life compared with on-demand bypassing therapy. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or FIX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined. PMID- 25827835 TI - Visual acuity trade-offs and microhabitat-driven adaptation of searching behaviour in psyllids (Hemiptera: Psylloidea: Aphalaridae). AB - Insects have evolved morphological and physiological adaptations in response to selection pressures inherent to their ecology. Consequently, visual performance and acuity often significantly vary between different insect species. Whilst psychophysics has allowed for the accurate determination of visual acuity for some Lepidoptera and Hymenoptera, very little is known about other insect taxa that cannot be trained to positively respond to a given stimulus. In this study, we demonstrate that prior knowledge of insect colour preferences can be used to facilitate acuity testing. We focused on four psyllid species (Hemiptera: Psylloidea: Aphalaridae), namely Ctenarytaina eucalypti, Ctenarytaina bipartita, Anoeconeossa bundoorensis and Glycaspis brimblecombei, that differ in their colour preferences and utilization of different host-plant modules (e.g. apical buds, stems, leaf lamellae) and tested their visual acuity in a modified Y-maze adapted to suit psyllid searching behaviour. Our study revealed that psyllids have visual acuity ranging from 6.3 to 8.7 deg. Morphological measurements for different species showed a close match between inter-ommatidial angles and behaviourally determined visual angles (between 5.5 and 6.6 deg) suggesting detection of colour stimuli at the single ommatidium level. Whilst our data support isometric scaling of psyllids' eyes for C. eucalypti, C. bipartita and G. brimblecombei, a morphological trade-off between light sensitivity and spatial resolution was found in A. bundoorensis. Overall, species whose microhabitat preferences require more movement between modules appear to possess superior visual acuity. The psyllid searching behaviours that we describe with the help of tracking software depict species-specific strategies that presumably evolved to optimize searching for food and oviposition sites. PMID- 25827836 TI - The potential effects of climate-change-associated temperature increases on the metabolic rate of a small Afrotropical bird. AB - Studies have only recently begun to underline the importance of including data on the physiological flexibility of a species when modelling its vulnerability to extinction from climate change. We investigated the effects of a 4 degrees C increase in ambient temperature (Ta), similar to that predicted for southern Africa by the year 2080, on certain physiological variables of a 10-12 g passerine bird endemic to southern Africa, the Cape white-eye Zosterops virens. There was no significant difference in resting metabolism, body mass and intraperitoneal body temperature between birds housed indoors at 4 degrees C above outside ambient temperature and those housed indoors at outside ambient temperature. We conclude that the physiological flexibility of Cape white-eyes will aid them in coping with the 4 degrees C increase predicted for their range by 2080. PMID- 25827837 TI - The lateral line is necessary for blind cavefish rheotaxis in non-uniform flow. AB - When encountering a unidirectional flow, many fish exhibit an unconditioned orienting response known as rheotaxis. This multisensory behavior can reportedly involve visual, vestibular, tactile and lateral line cues. However, the precise circumstances under which different senses contribute are still unclear and there is considerable debate, in particular, about the contributions of the lateral line. In this study, we investigate the rheotactic behavior of blind cavefish under conditions of spatially non-uniform flow (a jet stream), which in theory, should promote reliance on lateral line cues. The behavior of individual lateral line enabled and disabled fish was videorecorded under IR light in a square arena that prevented streamwise biases and that contained a narrow jet stream in the center of the tank. Whereas the stream's peak velocity (8 cm s(-1)) declined very little in the streamwise direction, it declined steeply in the cross-stream direction (~3-4.5 cm s(-1) cm(-1)). Lateral line enabled fish showed higher levels of orientation to the stream and its source (a 1-cm-wide nozzle) when in the central (jet stream) region of the tank compared with surrounding regions, whereas lateral line disabled fish showed random orientations in all regions of the tank. The results of this study indicate that the spatial characteristics of flow play a role in determining the sensory basis of rheotaxis. PMID- 25827838 TI - Spectral sensitivity of cone photoreceptors and opsin expression in two colour divergent lineages of the lizard Ctenophorus decresii. AB - Intraspecific differences in sensory perception are rarely reported but may occur when a species range extends across varying sensory environments, or there is coevolution between the sensory system and a varying signal. Examples in colour vision and colour signals are rare in terrestrial systems. The tawny dragon lizard Ctenophorus decresii is a promising candidate for such intraspecific variation, because the species comprises two geographically and genetically distinct lineages in which throat colour (a social signal used in intra- and inter-specific interactions) is locally adapted to the habitat and differs between lineages. Male lizards from the southern lineage have UV-blue throats, whereas males from the northern lineage are polymorphic with four discrete throat colours that all show minimal UV reflectance. Here, we determine the cone photoreceptor spectral sensitivities and opsin expression of the two lineages, to test whether they differ, particularly in the UV wavelengths. Using microspectrophotometry on retinal cone photoreceptors, we identified a long wavelength-sensitive (LWS) visual pigment, a 'short' and 'long' medium-wavelength sensitive (MWS) pigment and a short-wavelength-sensitive (SWS) pigment, all of which did not differ in lambdamax between lineages. Through transcriptome analysis of opsin genes we found that both lineages express four cone opsin genes, including the SWS1 opsin with peak sensitivity in the UV range, and that amino acid sequences did not differ between lineages with the exception of a single leucine to valine substitution in the RH2 opsin. Counts of yellow and transparent oil droplets associated with LWS+MWS and SWS+UVS cones, respectively, showed no difference in relative cone proportions between lineages. Therefore, contrary to predictions, we find no evidence of differences between lineages in single cone photoreceptor spectral sensitivity or opsin expression. However, we confirm the presence of four single cone classes, suggesting tetrachromacy in C. decresii, and we also provide the first evidence of UV sensitivity in agamid lizards. PMID- 25827839 TI - Ammonia first? The transition from cutaneous to branchial ammonia excretion in developing rainbow trout is not altered by exposure to chronically high NaCl. AB - Larval rainbow trout (Oncorhynchus mykiss) were reared from hatch under control ([Na(+)]=0.60 mmol l(-1)) or high NaCl ([Na(+)]=60 mmol l(-1)) conditions to elucidate the driving force for the ontogeny of branchial Na(+)/NH4 (+) exchange, one of the earliest gill functions. We hypothesized that if Na(+) uptake is the driving force, then in high NaCl there would be a delay in the skin-to-gill shift in ammonia excretion (Jamm) and/or an elevation in whole-body total ammonia (Tamm). In both groups, however, the skin-to-gill shift for Jamm, determined using divided chambers, occurred at the same time (13 days post-hatch; dph) and whole-body Tamm was unchanged. Moreover, high NaCl larvae displayed elevated whole-body [Na(+)] relative to controls by 18 dph, suggesting that maintaining branchial Jamm occurs at the expense of Na(+) balance. Overall, these results support the 'ammonia hypothesis', which posits that ammonia excretion, probably as Na(+)/NH4 (+) exchange, is the primary function of the early fish gill. PMID- 25827840 TI - Warm acclimation and oxygen depletion induce species-specific responses in salmonids. AB - Anthropogenic activities are greatly altering the habitats of animals, whereby fish are already encountering several stressors simultaneously. The purpose of the current study was to investigate the capacity of fish to respond to two different environmental stressors (high temperature and overnight hypoxia) separately and together. We found that acclimation to increased temperature (from 7.7+/-0.02 degrees C to 14.9+/-0.05 degrees C) and overnight hypoxia (daily changes from normoxia to 63-67% oxygen saturation), simulating climate change and eutrophication, had both antagonistic and synergistic effects on the capacity of fish to tolerate these stressors. The thermal tolerance of Arctic char (Salvelinus alpinus) and landlocked salmon (Salmo salar m. sebago) increased with warm acclimation by 1.3 and 2.2 degrees C, respectively, but decreased when warm temperature was combined with overnight hypoxia (by 0.2 and 0.4 degrees C, respectively). In contrast, the combination of the stressors more than doubled hypoxia tolerance in salmon and also increased hypoxia tolerance in char by 22%. Salmon had 1.2 degrees C higher thermal tolerance than char, but char tolerated much lower oxygen levels than salmon at a given temperature. The changes in hypoxia tolerance were connected to the responses of the oxygen supply and delivery system. The relative ventricle mass was higher in cold- than in warm acclimated salmon but the thickness of the compact layer of the ventricle increased with the combination of warm and hypoxia acclimation in both species. Char had also significantly larger hearts and thicker compact layers than salmon. The results illustrate that while fish can have protective responses when encountering a single environmental stressor, the combination of stressors can have unexpected species-specific effects that will influence their survival capacity. PMID- 25827841 TI - Burrowing by small polychaetes - mechanics, behavior and muscle structure of Capitella sp. AB - Worms of different sizes extend burrows through muddy sediments by fracture, applying dorso-ventral forces that are amplified at the crack tip. Smaller worms displace sediments less than larger worms and therefore are limited in how much force they can apply to burrow walls. We hypothesized that small worms would exhibit a transition in burrowing mechanics, specifically a lower limit in body size for the ability to burrow by fracture, corresponding with an ontogenetic transition in muscle morphology. Kinematics of burrowing in a mud analog, external morphology and muscle arrangement were examined in juveniles and adults of the small polychaete Capitella sp. We found that it moves by peristalsis, and no obvious differences were observed among worms of different sizes; even very small juveniles were able to burrow through a clear mud analog by fracture. Interestingly, we found that in addition to longitudinal and circular muscles needed for peristaltic movements, left- and right-handed helical muscles wrap around the thorax of worms of all sizes. We suggest that in small worms helical muscles may function to supplement forces generated by longitudinal muscles and to maintain hydrostatic pressure, enabling higher forces to be exerted on the crack wall. Further research is needed, however, to determine whether surficial sediments inhabited by small worms fail by fracture or plastically deform under forces of the magnitudes applied by Capitella sp. PMID- 25827842 TI - Alcohol-preferring P rats emit spontaneous 22-28 kHz ultrasonic vocalizations that are altered by acute and chronic alcohol experience. AB - BACKGROUND: Emotional states are often thought to drive excessive alcohol intake and influence the development of alcohol use disorders. To gain insight into affective properties associated with excessive alcohol intake, we utilized ultrasonic vocalization (USV) detection and analyses to characterize the emotional phenotype of selectively bred alcohol-preferring (P) rats; an established animal model of excessive alcohol intake. USVs emitted by rodents have been convincingly associated with positive (50-55 kHz frequency-modulated [FM]) and negative (22-28 kHz) affective states. Therefore, we hypothesized that 50-55 and 22-28 kHz USV emission patterns in P rats would reveal a unique emotional phenotype sensitive to alcohol experience. METHODS: 50-55 kHz FM and 22 28 kHz USVs elicited from male P rats were assessed during access to water, 15 and 30% EtOH (v/v). Ethanol (EtOH; n = 12) or water only (Control; n = 4) across 8 weeks of daily drinking-in-the-dark (DID) sessions. RESULTS: Spontaneous 22-28 kHz USVs are emitted by alcohol-naive P rats and are enhanced by alcohol experience. During DID sessions when alcohol was not available (e.g., "EtOH OFF" intervals), significantly more 22-28 kHz than 50-55 kHz USVs were elicited, while significantly more 50-55 kHz FM than 22-28 kHz USVs were emitted when alcohol was available (e.g., "EtOH ON" intervals). In addition, USV acoustic property analyses revealed chronic effects of alcohol experience on 22-28 kHz USV mean frequency, indicative of lasting alcohol-mediated alterations to neural substrates underlying emotional response. CONCLUSIONS: Our findings demonstrate that acute and chronic effects of alcohol exposure are reflected in changes in 22 28 and 50-55 kHz FM USV counts and acoustic patterns. These data support the notion that initiation and maintenance of alcohol intake in P rats may be due to a unique, alcohol-responsive emotional phenotype and further suggest that spontaneous 22-28 kHz USVs serve as behavioral markers for excessive drinking vulnerability. PMID- 25827843 TI - Predictive value of serum markers for the development of interstitial lung disease in patients with polymyositis and dermatomyositis: a comparative and prospective study. AB - BACKGROUND: Interstitial lung disease (ILD) is one of the most common and devastated complication of polymyositis/dermatomyositis (PM/DM). Several studies have focused on serum biomarkers for ILD in PM/DM patients; however, there have been no prospective studies. AIM: To explore and compare the predictive value of four serum markers for the development of ILD in patients with PM/DM. METHODS: One hundred adult PM/DM patients were included in this prospective clinical study at baseline. Forty-four PM/DM patients without ILD were followed up for 1 year. Fifty-six PM/DM patients with ILD were treated and followed up for 2 months. Serum samples were analysed for the levels of Krebs von den Lungen-6 (KL-6), monocyte chemotactic protein-1 (MCP-1), surfactant protein-A and D (SP-A, SP-D). RESULTS: Serum KL-6 (1542.8 +/- 760.8 U/mL) (P < 0.001), MCP-1 (1870 +/- 1590 pg/mL) (P = 0.014), SP-A (56 +/- 28 ng/mL) (P < 0.001) and SP-D (230 +/- 196 ng/mL) (P < 0.001) were significantly elevated in PM/DM patients with ILD compared with those in the patients without ILD (KL-6 429 +/- 105.8 U/mL; MCP-1 1349 +/- 1303 pg/mL; SP-A 34 +/- 26 ng/mL; SP-D 96 +/- 63 ng/mL). In PM/DM patients without ILD who were followed up for 1 year, KL-6 presented the highest predictive value among single markers. In patients who were treated and followed up, KL-6 concentrations increased with the progression of ILD and decreased along with the improvement of ILD. CONCLUSION: Considering the ability of KL-6 for predicting the onset of ILD and monitoring the treatment response of ILD in PM/DM patients, it may be of great significance for clinical practice, and the prognosis of patients may be substantially improved if serum KL-6 was regularly monitored. PMID- 25827844 TI - The assessment of sewage sludge gasification by-products toxicity by ecotoxicologial test. AB - The process of gasification of sewage sludge generates by-products, which may be contaminated with toxic and hazardous substances, both organic and inorganic. It is therefore important to assess the environmental risk associated with this type of waste. The feasibility of using an ecotoxicological tests for this purpose was determined in the presented study. The applied tests contained indicator organisms belonging to various biological groups (bacteria, crustaceans, plants). The subject of the study were solid (ash, char) and liquid (tar) by-products generated during gasification (in a fixed bed reactor) of dried sewage sludge from various wastewater treatment systems. The tested samples were classified based on their toxic effect. The sensitivity of the indicator organisms to the tested material was determined. In-house procedures for the preparation for toxicity analysis of both sewage sludge and by-products generated during the gasification were presented. The scope of work also included the determination of the effect of selected process parameters (temperature, amount of gasifying agent) on the toxicity of gasification by-products depending on the sewage sludge source. It was shown that both the type of sewage sludge and the parameters of the gasification process affects the toxicity of the by-products of gasification. However, the results of toxicity studies also depend on the type of ecotoxicological test used, which is associated with a different sensitivity of the indicator organisms. Nevertheless, it may be concluded that the by-products formed during the gasification of the low toxicity sewage sludge can be regarded as non-toxic or low toxic. However, the results analysis of the gasification of the toxic sludge were not conclusive, which leads to further research needs in this area. PMID- 25827845 TI - The existing situation and challenges regarding the use of plastic carrier bags in Europe. AB - Since day one, retailers and consumers have favoured plastic carrier bags. However, owing to the numerous environmental disadvantages, lightweight plastic carrier bags have been drawing the attention of the European Union competent authorities. Therefore, many European Union member states have taken action so as to reduce the use of plastic carrier bags. Based on the existing legislation and voluntary initiatives for the reduction of lightweight plastic carrier bags, the challenges and achieved outcomes from the implemented policy options in the various European Union member states are discussed and commented regarding the forthcoming transposition of the 'Directive 94/62/EC on packaging and packaging waste to reduce the consumption of lightweight plastic carrier bags' into the European Union member states' national law. PMID- 25827846 TI - Recent developments and perspective of the spent waste printed circuit boards. AB - The amount of spent electronic and electrical solid wastes (i.e. e-wastes) has increased to a new level with the rapid development of electronic and electrical industries. Management of e-wastes challenges the administrators and researchers. As a major component of the e-waste stream, pollution caused by the spent printed circuit boards has captured increasing attention. Various innovative methods have recently been developed to dispose and reuse these municipal spent printed circuit boards. In this mini-review article, the disposal approaches for spent printed circuit boards are highlighted. The present state and future perspective are also discussed. We hope that this mini-review can promote the extensive understanding and effective disposal of the spent printed circuit boards in the field of solid waste treatment and resources. PMID- 25827847 TI - Urban waste management and the mobile challenge. AB - Digital evolution and mobile developments are carving a new era that affects human behaviour and global governance. Interconnectivity and flow of information through various types of modern means create new opportunities for cooperation and ways to work. Waste management could not stay unaffected by these changes. New potentials are arising for the sector, offering a novel field for innovation, changing the way waste practices are applied. In this framework, mobile products and apps can become valuable tools for authorities, companies, civilians and other stakeholders, integrating these technologies in the battle for environmental protection, recycling, etc. This article examines the unexplored challenges of mobile apps to deliver sustainable waste management with emphasis on recycling and waste prevention performance, especially for emerging developing countries. It presents the opportunities that are involved in using mobile apps to improve both the systemic performance of a specific waste management system and the individual behaviour of the users. Furthermore, the article reviews the most important relevant literature and summarises the key findings of the recent research on mobile apps and human behaviour. Useful conclusions are drawn for both the content and the format of the mobile apps required for recycling and waste prevention. Finally, the article presents the most characteristic mobile apps that are already in place in the waste management sector. PMID- 25827848 TI - Antimicrobial properties of Kalanchoe blossfeldiana: a focus on drug resistance with particular reference to quorum sensing-mediated bacterial biofilm formation. AB - OBJECTIVES: This study attempts to investigate the antimicrobial properties of Kalanchoe blossfeldiana with a particular reference to quorum sensing (QS) mediated biofilm formation. METHODS: The methanol extract of K. blossfeldiana leaves (MEKB) was evaluated for antimicrobial properties including QS-controlled production of biofilm (including virulence factor, motility and lactone formation) in Pseudomonas aeruginosa. Methanol extract of K. blossfeldiana was also evaluated for anti-cytokine (tumour necrosis factor-alpha, interleukin-6 and interleukin-1 beta) properties in peripheral blood mononuclear cells (PBMC). KEY FINDINGS: Methanol extract of K. blossfeldiana exhibited antimicrobial effect on clinical isolates, as well as standard reference strains. Pseudomonas aeruginosa exposed to MEKB (subminimum inhibitory concentration (MIC)) displayed reduced biofilm formation, whereas supra-MIC produced destruction of preformed biofilms. Methanol extract of K. blossfeldiana reduced the secretion of virulence factors (protease and pyoverdin) along with generation of acyl homoserine lactone (AHL). Confocal laser scanning microscopy images indicate reduction of biofilm thickness. The extract also reduced cytokine formation in lipopolysaccharide stimulated PBMC. CONCLUSIONS: Kalanchoe blossfeldiana was found to interfere with AHL production, which in turn may be responsible for downregulating QS-mediated production of biofilm and virulence. This first report on the antibiofilm and anticytokine properties of this plant may open up new vistas for future exploration of this plant for combating biofilm-related resistant infections. PMID- 25827849 TI - Multiple acyl-CoA dehydrogenation deficiency as decreased acyl-carnitine profile in serum. AB - We report a case with late onset riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency (MADD) characterized by decreased acyl-carnitine profile in serum which is consistent with primary systemic carnitine deficiency (CDSP) while just the contrary to a typical MADD. This patient complained with muscle weakness, muscle pain and intermittent vomiting, and was diagnosed as polymyositis, received prednisone therapy before consulted with us. Muscle biopsy revealed mild lipid storage. The findings of serum acyl-carnitines were consistent with CDSP manifesting as decreased free and total carnitines in serum. But oral L-carnitine supplementation was not very effective to this patient and mutation analysis of the SLC22A5 gene for CDSP was normal. Later, another acyl carnitine analysis revealed a typical MADD profile in serum, which was characterized by increased multiple acyl-carnitines. Compound heterozygous mutations were identified in electron transferring-flavoprotein dehydrogenase (ETFDH) gene which confirmed the diagnosis of MADD. After administration of riboflavin, he improved dramatically, both clinically and biochemically. Thus, late onset riboflavin-responsive MADD should be included in the differential diagnosis for adult carnitine deficiency. PMID- 25827850 TI - Smoking Cessation Intervention for severe Mental Ill Health Trial (SCIMITAR): a pilot randomised control trial of the clinical effectiveness and cost effectiveness of a bespoke smoking cessation service. AB - BACKGROUND: There is a high prevalence of smoking among people who experience severe mental ill health (SMI). Helping people with disorders such as bipolar illness and schizophrenia to quit smoking would help improve their health, increase longevity and also reduce health inequalities. Around half of people with SMI who smoke express an interest in cutting down or quitting smoking. There is limited evidence that smoking cessation can be achieved for people with SMI. Those with SMI rarely access routine NHS smoking cessation services. This suggests the need to develop and evaluate a behavioural support and medication package tailored to the needs of people with SMI. OBJECTIVE: The objective in this project was to conduct a pilot trial to establish acceptability of the intervention and to ensure the feasibility of recruitment, randomisation and follow-up. We also sought preliminary estimates of effect size in order to design a fully powered trial of clinical effectiveness and cost-effectiveness. The pilot should inform a fully powered trial to compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual general practitioner (GP) care for people with SMI. DESIGN: A pilot pragmatic two arm individually randomised controlled trial (RCT). Simple randomisation was used following a computer-generated random number sequence. Participants and practitioners were not blinded to allocation. SETTING: Primary care and secondary care mental health services in England. PARTICIPANTS: Smokers aged > 18 years with a severe mental illness who would like to cut down or quit smoking. INTERVENTIONS: A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual GP care. MAIN OUTCOME MEASURES: The primary outcome was carbon monoxide-verified smoking cessation at 12 months. Smoking-related secondary outcomes were reduction of number of cigarettes smoked, Fagerstrom test of nicotine dependence and motivation to quit (MTQ). Other secondary outcomes were Patient Health Questionnaire-9 items and Short Form Questionnaire-12 items to assess whether there were improvements or deterioration in mental health and quality of life. We also measured body mass index to assess whether or not smoking cessation was associated with weight gain. These were measured at 1, 6 and 12 months post randomisation. RESULTS: The trial recruited 97 people aged 19-73 years who smoked between 5 and 60 cigarettes per day (mean 25 cigarettes). Participants were recruited from four mental health trusts and 45 GP surgeries. Forty-six people were randomised to the BSC intervention and 51 people were randomised to usual GP care. The odds of quitting at 12 months was higher in the BSC intervention (36% vs. 23%) but did not reach statistical significance (odds ratio 2.9; 95% confidence interval 0.8% to 10.5%). At 3 and 6 months there was no evidence of difference in self-reported smoking cessation. There was a non-significant reduction in the number of cigarettes smoked and nicotine dependence. MTQ and number of quit attempts all increased in the BSC group compared with usual care. There was no difference in terms of quality of life at any time point, but there was evidence of an increase in depression scores at 12 months for the BSC group. There were no serious adverse events thought likely to be related to the trial interventions. The pilot economic analysis demonstrated that it was feasible to carry out a full economic analysis. CONCLUSIONS: It was possible to recruit people with SMI from primary and secondary care to a trial of a smoking cessation intervention based around behavioural support and medication. The overall direction of effect was a positive trend in relation to biochemically verified smoking cessation and it was feasible to obtain follow-up in a substantial proportion of participants. A definitive trial of a bespoke cessation intervention has been prioritised by the National Institute for Health Research (NIHR) and the SCIMITAR pilot trial forms a template for a fully powered RCT to examine clinical effectiveness and cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79497236. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 19, No. 25. See the NIHR Journals Library website for further project information. PMID- 25827852 TI - Signposts along the journey toward high-quality palliative care: the value of measuring what matters. PMID- 25827851 TI - Palliative Care Physicians' Attitudes Toward Patient Autonomy and a Good Death in East Asian Countries. AB - CONTEXT: Clarification of the potential differences in end-of-life care among East Asian countries is necessary to provide palliative care that is individualized for each patient. OBJECTIVES: The aim was to explore the differences in attitude toward patient autonomy and a good death among East Asian palliative care physicians. METHODS: A cross-sectional survey was performed involving palliative care physicians in Japan, Taiwan, and Korea. Physicians' attitudes toward patient autonomy and physician-perceived good death were assessed. RESULTS: A total of 505, 207, and 211 responses were obtained from Japanese, Taiwanese, and Korean physicians, respectively. Japanese (82%) and Taiwanese (93%) physicians were significantly more likely to agree that the patient should be informed first of a serious medical condition than Korean physicians (74%). Moreover, 41% and 49% of Korean and Taiwanese physicians agreed that the family should be told first, respectively; whereas 7.4% of Japanese physicians agreed. Physicians' attitudes with respect to patient autonomy were significantly correlated with the country (Japan), male sex, physician specialties of surgery and oncology, longer clinical experience, and physicians having no religion but a specific philosophy. In all 12 components of a good death, there were significant differences by country. Japanese physicians regarded physical comfort and autonomy as significantly more important and regarded preparation, religion, not being a burden to others, receiving maximum treatment, and dying at home as less important. Taiwanese physicians regarded life completion and being free from tubes and machines as significantly more important. Korean physicians regarded being cognitively intact as significantly more important. CONCLUSION: There are considerable intercountry differences in physicians' attitudes toward autonomy and physician-perceived good death. East Asia is not culturally the same; thus, palliative care should be provided in a culturally acceptable manner for each country. PMID- 25827853 TI - When Physicians Report Having Used Medical Drugs to Deliberately End a Patient's Life: Findings of the "End-of-Life in France" Survey. AB - CONTEXT: The debate on the decriminalization of active assistance in dying is still a topical issue in many countries where it is regarded as homicide. Despite the prohibition, some physicians say they have used drugs to intentionally end a patient's life. OBJECTIVES: To provide some empirical grounding for the ongoing debate. METHODS: Using data from the End-of-Life in France survey (a representative sample of 15,000 deaths that occurred in December 2009, questionnaires completed anonymously by the physicians who had certified the deaths), we selected all the cases where the physician had used one or more drugs to intentionally end a patient's life and compared the decisions and decision making process with the conditions imposed by the French law for decisions to withhold or withdraw life-supporting treatments and by the Belgian law on euthanasia. RESULTS: Of the 36 cases analyzed, four situations seemed to be deliberate acts after explicit requests from the patients, and only two seemed to fulfill the eligibility and due care conditions of the Belgian euthanasia law. Decisions made without any discussion with patients were quite common, and we observed inadequate labeling, frequent signs of ambivalence (artificial feeding and hydration not withdrawn, types of drug used), and little interprofessional consultation. Where the patient had requested euthanasia, the emotional burden on the physician was heavy. CONCLUSION: These findings underscore the pressing need for a clarification of the concepts involved among health professionals, patients, and society at large, and better training and support for physicians. PMID- 25827854 TI - Do-Not-Resuscitate (DNR) Orders and Consultants' Willingness to Perform Invasive Procedures. PMID- 25827855 TI - Single-Dose Subcutaneous Benzodiazepines for Insomnia in Patients With Advanced Cancer. PMID- 25827856 TI - Statins and Nonadherence: Should We RELATE Better? AB - Statin nonadherence is a major challenge to optimal management. Patients nonadherent to statin therapy do not receive the expected benefit relative to the degree of low-density lipoprotein cholesterol (LDL-C) lowering obtained. This is important because new evidence guidelines recommend statins as the first-line therapy for those in high-risk groups (secondary prevention, patients with diabetes 40-75 years of age, and LDL-C >= 190 mg/dL) and in selected primary prevention patients. Statin assignment in the latter group occurs only in those with an estimated >=7.5% 10-year atherosclerotic cardiovascular disease risk after shared decision making in a clinician-patient risk discussion. However, in numerous studies, statin nonadherence shows little or no benefit in reducing cardiovascular events or mortality compared to placebo, effectively negating the risk reduction expected from statin use and concomitantly increasing the total cost of health care. The causes and solutions for nonadherence are multifactorial and include patient, clinician, and health system factors. We believe that a clinician-patient partnership that facilitates patients' understanding of the potential for optimal benefit with the least adverse effects is an important first step toward improving adherence. A transtheoretical model of stages of behavior change helps clinicians address many of the common factors limiting adherence to statins. We conclude with a teaching tool emphasizing a structured approach to statin therapy with patient-centered risk discussions. PMID- 25827857 TI - Periprocedural Management of New Oral Anticoagulants in Atrial Fibrillation Ablation. AB - BACKGROUND: Patients who undergo catheter ablation for atrial fibrillation (AF) are at increased risk of developing thromboembolic and bleeding complications periprocedurally. Many patients are now on newer oral anticoagulants (NOACs), but data regarding their safety and efficacy during AF ablation are limited. METHODS AND RESULTS: This article reviews the literature in PubMed from 1998 to 2014 and includes clinical trials and meta-analysis that analyzed the safety and efficacy of NOACs during AF catheter ablation. Dabigatran seems to be as effective and safe as warfarin, although most data are from single-center studies, with small samples and very low overall bleeding and thromboembolic complications. Periprocedural anticoagulation protocols also vary greatly between studies. Some recent meta-analysis has shown that warfarin could still be a safer and more effective alternative. There are fewer studies with rivaroxaban in AF ablation, and there have been no meta-analysis yet comparing rivaroxaban to warfarin or dabigatran. There seems to be no significant differences in safety or efficacy of rivaroxaban compared to warfarin. Interestingly, there are no available data for apixaban in AF ablation yet. DISCUSSION: There are no consensus guidelines regarding the use of NOACs during AF ablation. Dabigatran and rivaroxaban seem as safe and effective as warfarin, although larger studies with standardized protocols are needed, as available studies may be underpowered to detect small differences in bleeding and thromboembolic rates. PMID- 25827858 TI - High-frequency percussive ventilation: a new strategy for separation from extracorporeal membrane oxygenation. AB - We report the case of a 48-year-old woman who developed severe septic shock and lung injury after community-acquired pneumonia. She was supported on arteriovenous extracorporeal membrane oxygenation (ECMO) for 19 days. To facilitate decannulation and separation from ECMO, we began trials of high frequency percussive ventilation (HFPV) using the volumetric diffusive respiration ventilator VDR-4 (Percussionaire Corp, Sandpoint, Idaho) for 4 consecutive days (1 before and 3 after). Decannulation was achieved successfully, and the patient was transferred to the floor 3 months later. During the 4 days of HFPV, the chest radiograph improved, as did gas exchange and clearance of pulmonary secretions. HFPV may be a promising strategy for improving lung recruitment and airway clearance during separation from ECMO in the critically ill patient. PMID- 25827859 TI - Editorial comment: High frequency ventilation and extracorporeal membrane oxygenation: a winning combination? PMID- 25827860 TI - Paradoxical air embolus during endoscopic retrograde cholangiopancreatography: an uncommon fatal complication. AB - Air embolism during endoscopic retrograde cholangiopancreatography is a rare but potentially fatal complication. A 66-year-old man underwent endoscopic retrograde cholangiopancreatography and remained stable until the end of the procedure, when he was found to have mottling on his right side and became hypoxic and unresponsive. Transesophageal echocardiography showed air within the left ventricle, consistent with systemic air embolism. Mortality resulted from significant cardiac and cerebral ischemia. The literature suggests that capnography is helpful in early diagnosis of air embolus, but it could not be used in this case because the patient's trachea was not intubated. PMID- 25827861 TI - Massive pulmonary embolism in pregnancy treated with catheter-directed tissue plasminogen activator. AB - Pulmonary embolism is a leading cause of maternal death in the United States, contributing to the death of approximately 2 women per 100,000 live births each year. Thrombosis during pregnancy traditionally is treated conservatively with unfractionated heparin or low-molecular-weight heparin; however, cardiovascular collapse associated with a large pulmonary embolus may require immediate aggressive intervention to save the mother and fetus. We report the use of catheter infusion thrombolysis in the successful management of a third-trimester pregnant patient with a hemodynamically significant saddle pulmonary embolus. PMID- 25827862 TI - Anesthesia for a pediatric patient with cardiofaciocutaneous syndrome. AB - Cardiofaciocutaneous syndrome is a rare syndrome that is characterized by distinct craniofacial features, cardiac abnormalities, and multiple organ involvement. Patients may present with pulmonary stenosis, hypertrophic cardiomyopathy, micrognathia, a short neck, laryngomalacia, and tracheomalacia; all of which may significantly impact the perioperative course of these patients. We describe a 6-year-old child with cardiofaciocutaneous syndrome presenting for an orthopedic procedure. He had an uneventful perioperative and postoperative course. PMID- 25827863 TI - Survival rates, prognostic factors and treatment of anaplastic meningiomas. AB - Intracranial anaplastic meningioma is a malignant type of meningioma with a high rate of recurrence and death. Given its rarity, minimal information regarding this tumour is available. Thus, we studied a series of patients with anaplastic meningiomas and analysed the survival rates, prognostic factors and treatment methods associated with these patients. Forty-three anaplastic meningioma cases treated at our hospital between July 2002 and June 2012 were compiled into a single database used to summarise the clinical characteristics from a retrospective review of patient records. Progression free survival (PFS) and overall survival (OS) were analysed as a function of each possible prognostic factor. The 1, 3 and 5 year PFS rates were 90.7%, 51.3%, and 37.0%, respectively, whereas the corresponding values of OS rates were 95.3%, 68.0% and 49.2%, respectively. A number of factors were selected to analyse association with prognosis. Simpson Grade I and II resections exhibited increased PFS rates and radiotherapy improved the OS rate in anaplastic meningiomas. Tumours with homogeneous contrast enhancement on MRI were associated with increased PFS and OS. Sex, age, tumour location, first or transformed anaplastic tumour, pre operative Karnofsky Performance Scores, tumour volumes and bone involvement had no significant effect on either PFS or OS. MRI homogeneous contrast may be a useful prognostic factor and surgery followed by radiotherapy is recommended for the treatment of anaplastic meningiomas. PMID- 25827864 TI - Symptomatic osteolipoma of the tuber cinereum masquerading as calcified retroclival mass. AB - We present a case of symptomatic osteolipoma of the tuber cinereum in a 51 year old male with rapid visual deterioration over several months leading to bilateral visual loss. Preoperatively the lesion masqueraded as a calcified retroclival mass. Intracranial osteolipomas are rare benign lesions that are usually asymptomatic and have an indolent course. Additionally, we discuss our intraoperative findings highlighting the technical challenges encountered along with a review of the English language literature on histologically proven intracranial osteolipomas. PMID- 25827865 TI - Complications of post-craniectomy cranioplasty: risk factor analysis and implications for treatment planning. AB - The aim of this study was to review all post-craniectomy cranioplasties performed in a single institution, with an emphasis on procedure-related complications and risk factor analysis. Post-craniectomy cranioplasty is known to be associated with significant complications. Previous studies on predictors of complications have yielded conflicting results. We conducted a retrospective study on prospectively collected data on all cranioplasties done between 1 January 2003 and 31 December 2012. Multivariate analysis was performed to interrogate potential risk factors predisposing to procedure-related complications. Of the 162 procedures, the overall complication rate was 16.7%. Infection and flap depression occurred in 13 (8%) and five patients (3.1%), respectively. These led to reoperations in 12 patients. The presence of a ventriculoperitoneal shunt during cranioplasty was the only significant factor associated with a higher rate of infection (28.6% versus 9.7%, p=0.001) and flap depression (14.3% versus 3.3%, p=0.03). Indications for the initial craniectomy, choice of graft materials and the time interval between craniectomy and cranioplasty had no significant association with complications. The presence of ventriculoperitoneal shunt at the time of cranioplasty is a significant risk factor for cranioplasty complications. Early cranioplasty is safe. Whether temporizing lumbar or external ventricular drainage is a better alternative to shunting in patients who are drainage dependent at the time of cranioplasty remain to be determined. PMID- 25827867 TI - Hypofractionated stereotactic radiotherapy in medium-sized to large arteriovenous malformations. AB - We have reviewed treatment results in terms of obliteration and complications in 24 patients with medium to large sized cerebral arteriovenous malformations (AVMs) (mean volume 18.5+/-8.9cm(3); range: 10-42) treated with hypofractionated stereotactic radiotherapy (HSRT). AVMs are congenital lesions associated with a high morbidity and mortality. Radiosurgery is one option for treatment. However, in larger AVMs with volumes exceeding 10cm(3) obliteration rates are less favourable and radiation induced complications more frequent. For larger AVMs, volume-staged radiosurgery is one option while another option may be the use of HSRT. Patients were treated with 6-7Gy in five fractions to a total dose of 30 35Gy (mean total dose 32.9+/-1.6Gy [standard error of the mean]). Sixteen patients (69.6%) showed obliteration after a mean time of 35.2+/-14.8 months (range: 24-60). Only one patient (4.2%) experienced symptomatic radionecrosis. Our treatment with HSRT seems safe and efficient for treatment of medium to large sized AVMs. Treatment results seem to be in line with volume-staged radiosurgery and may be an alternative for AVMs not suitable for single fraction radiosurgery. PMID- 25827868 TI - Assessment of body composition in children with cerebral palsy: a cross-sectional study in Norway. AB - AIM: The assessment of growth and body composition is challenging in children with cerebral palsy (CP). The aim of this study was to compare clinical assessments of body composition with measurements obtained using dual-energy X ray absorptiometry (DXA) in this population. METHOD: Knee height, weight, and triceps and subscapular skinfold thickness (SFT) were measured in 47 children with CP (age range 8-18y; 18 females, 29 males). Height was estimated from knee height, and used to calculate body mass index (BMI). Using SFT measurements, body fat percentage was calculated by standard ('Slaughter') and CP-modified ('Gurka') equations and compared with results obtained using DXA. RESULTS: Children with severe gross motor function impairments (Gross Motor Function Classification System [GMFCS] level III or IV) exhibited stunted growth and had higher fat percentages and lower lean body mass than children classified in GMFCS level I or II. In 10 children classified as 'thin' according to their BMI (five of whom were assigned thinness grade of 2 or lower), percentage of body fat, as determined by DXA, was normal or high. The Slaughter equations significantly underestimated body fat percentages, whereas the precision of the CP-modified Gurka equations was excellent. INTERPRETATION: In this study, children with CP and severe motor impairments displayed stunted growth, but were not undernourished. Relying solely upon BMIs may be misleading in children with CP. Therefore, clinicians should be encouraged to measure SFT and to calculate body fat percentages using the CP modified version of the Slaughter equation. PMID- 25827866 TI - Different imaging characteristics of concurrent pituitary adenomas in a patient with Cushing's disease. AB - We report a patient with Cushing's disease (CD) and two pituitary adenomas that demonstrated different imaging characteristics and therefore suggest an alternative imaging strategy for these patients. A 42-year-old woman presented with signs and symptoms of CD. Biochemical evaluation confirmed hypercortisolemia and suggested CD. On pituitary MRI with spoiled gradient recalled acquisition in the steady-state and T1-weighted spin echo protocols, a 5mm hypoenhancing region typical for a pituitary adenoma was identified on the left. However, after surgical resection the patient remained hypercortisolemic and pathology revealed a non-functional adenoma. At early repeat surgical exploration a 10mm adenoma was found in the right side of the gland. Postoperatively the patient became hypocortisolemic and pathology demonstrated an adrenocorticotropic hormone (ACTH) staining adenoma. On review of the initial MRI this tumor corresponded to a region of contrast retention best visualized on delayed fluid attenuated inversion recovery (FLAIR) imaging. While the incidentaloma in this case demonstrated classical imaging characteristics of a pituitary adenoma the larger ACTH-secreting tumor was best appreciated by contrast retention. This suggests a role for delayed postcontrast FLAIR imaging in the preoperative evaluation of CD. ACTH-secreting tumors causing CD cause significant morbidity. Due to their small size, a pituitary adenoma is frequently not identified on imaging despite endocrinologic testing suggesting CD. Regardless of improvements in MRI, many tumors are only identified at surgical exploration. PMID- 25827869 TI - Tacrine derivatives as dual topoisomerase I and II catalytic inhibitors. AB - This study examines the binding properties of a series of newly synthetized tacrine derivatives 1-4 and their anticancer effects. Spectroscopic techniques (UV-Vis, fluorescence spectroscopy, thermal denaturation, and linear spectropolarimetry) and viscometry were used to study DNA binding properties and to determine the types of DNA interaction with the studied derivatives. The binding constants for the complexes with DNA were obtained using UV-Vis spectroscopic titrations (K = 1.6 * 10(4)-4.0 * 10(5) M(-1)) and electrophoretic methods were used to determine the effect of the derivatives on topoisomerase I and II activity. Monotacrine derivative 1 showed evidence of topoisomerase Irelaxation activity at a concentration of 30 * 10(-6) M, while bistacrine derivatives 2-4 produced a complete inhibition of topoisomerase Iat a concentration of 5 * 10(-6) M. The biological activities of the derivatives were studied using MTT-assay and flow cytometric methods (detection of mitochondrial membrane potential and measurement of cell viability) following incubation of 24 and 48 h with human leukemic cancer cell line HL60. The ability of the derivatives to impair cell proliferation was also tested through the analysis of cell cycle distribution. PMID- 25827871 TI - Beads-on-a-string on a bead: reconstitution and analysis of chromatin on a solid support. AB - Complex experimental strategies involving in vitro reconstituted chromatin or simple chromatin interaction studies are much facilitated by immobilizing the nucleosomal arrays to paramagnetic beads. Chromatin-containing beads can be retrieved from a reaction mix solution on a magnet fast and quantitatively, effectively separating bound, loosely attached and unbound components efficiently. This chapter details a convenient strategy for immobilization of linear plasmid DNA on streptavidin-coated beads, the reconstitution of chromatin on such beads, and some fundamental handling procedures. PMID- 25827870 TI - Clinical differences between respiratory viral and bacterial mono- and dual pathogen detected among Singapore military servicemen with febrile respiratory illness. AB - BACKGROUND: Although it is known that febrile respiratory illnesses (FRI) may be caused by multiple respiratory pathogens, there are no population-level studies describing its impact on clinical disease. METHODS: Between May 2009 and October 2012, 7733 FRI patients and controls in the Singapore military had clinical data and nasal wash samples collected prospectively and sent for PCR testing. Patients with one pathogen detected (mono-pathogen) were compared with those with two pathogens (dual pathogen) for differences in basic demographics and clinical presentation. RESULTS: In total, 45.8% had one pathogen detected, 20.2% had two pathogens detected, 30.9% had no pathogens detected, and 3.1% had more than two pathogens. Multiple pathogens were associated with recruits, those with asthma and non-smokers. Influenza A (80.0%), influenza B (73.0%) and mycoplasma (70.6%) were most commonly associated with mono-infections, while adenovirus was most commonly associated with dual infections (62.9%). Influenza A paired with S. pneumoniae had higher proportions of chills and rigors than their respective mono pathogens (P = 0.03, P = 0.009). H. influenzae paired with either enterovirus or parainfluenzae had higher proportions of cough with phlegm than their respective mono-pathogens. Although there were observed differences in mean proportions of body temperature, nasal symptoms, sore throat, body aches and joint pains between viral and bacterial mono-pathogens, there were few differences between distinct dual-pathogen pairs and their respective mono-pathogen counterparts. CONCLUSION: A substantial number of FRI patients have multiple pathogens detected. Observed clinical differences between patients of dual pathogen and mono-pathogen indicate the likely presence of complex microbial interactions between the various pathogens. PMID- 25827872 TI - Preparation and analysis of positioned mononucleosomes. AB - Short DNA fragments containing single nucleosomes have been extensively employed as simple model experimental systems for analysis of many intranuclear processes, including binding of proteins to nucleosomes, covalent histone modifications, transcription, DNA repair, and ATP-dependent chromatin remodeling. Here we describe several recently developed procedures for obtaining and analysis of mononucleosomes assembled on 200-350-bp DNA fragments. PMID- 25827874 TI - Isolation of specific genomic regions and identification of associated molecules by engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) using CRISPR. AB - Isolation of specific genomic regions retaining molecular interactions is necessary for their biochemical analysis. Here, we describe engineered DNA binding molecule-mediated chromatin immunoprecipitation (enChIP) using the CRISPR system, for purification of specific genomic regions retaining molecular interactions. In this form of enChIP, specific genomic regions are immunoprecipitated with antibody against a tag(s), which is fused to a catalytically inactive form of Cas9 (dCas9), which is co-expressed with a guide RNA (gRNA) and recognizes endogenous DNA sequence in the genomic regions of interest. enChIP combined with mass spectrometry (enChIP-MS), next-generation sequencing (enChIP-Seq), and RNA-Seq (enChIP-RNA-Seq) can identify proteins, other genomic regions, and RNA, respectively, that interact with the target genomic region. PMID- 25827873 TI - Chromatin imaging with time-lapse atomic force microscopy. AB - Time-lapse atomic force microscopy (AFM) is widely used for direct visualization of the nanoscale dynamics of various biological systems. The advent of high-speed AFM instrumentation made it possible to image the dynamics of proteins and protein-DNA complexes within millisecond time range. This chapter describes protocols for studies of structure and dynamics of nucleosomes with time-lapse AFM including the high-speed AFM instrument. The necessary specifics for the preparation of chromatin samples for imaging with AFM including the protocols for the surface preparation are provided. PMID- 25827875 TI - Drug-induced premature chromosome condensation (PCC) protocols: cytogenetic approaches in mitotic chromosome and interphase chromatin. AB - Chromosome analysis is a fundamental technique which is used in wide areas of cytogenetic study including karyotyping species, hereditary diseases diagnosis, or chromosome biology study. Chromosomes are usually prepared from mitotic cells arrested by colcemid block protocol. However, obtaining mitotic chromosomes is often hampered under several circumstances. As a result, cytogenetic analysis will be sometimes difficult or even impossible in such cases. Premature chromosome condensation (PCC) (see Note 1) is an alternative method that has proved to be a unique and useful way in chromosome analysis. Former, PCC has been achieved following cell fusion method (cell-fusion PCC) mediated either by fusogenic viruses (e.g., Sendai virus) or cell fusion chemicals (e.g., polyethylene glycol), but the cell fusion PCC has several drawbacks. The novel drug-induced PCC using protein phosphatase inhibitors was introduced about 20 years ago. This method is much simpler and easier even than the conventional mitotic chromosome preparation protocol use with colcemid block and furthermore obtained PCC index (equivalent to mitotic index for metaphase chromosome) is usually much higher than colcemid block method. Moreover, this method allows the interphase chromatin to be condensed to visualize like mitotic chromosomes. Therefore drug-induced PCC has opened the way for chromosome analysis not only in metaphase chromosomes but also in interphase chromatin. The drug-induced PCC has thus proven the usefulness in cytogenetics and other cell biology fields. For this second edition version, updated modifications/changes are supplemented in Subheadings 2, 3, and 4, and a new section describing the application of PCC in chromosome science fields is added with citation of updated references. PMID- 25827876 TI - Analysis of genomic aberrations using comparative genomic hybridization of metaphase chromosomes. AB - Comparative genomic hybridization (CGH) allows the global screening of copy number aberrations within a sample. Specifically, large (>20 mb) deletions and amplifications are detected, based on utilization of test and reference (karyotypically normal) DNA. These samples are whole-genome amplified by DOP-PCR and then differentially labeled with fluorophores via nick translation. Test and reference samples are competitively hybridized to normal metaphase chromosomes. The relative amount of each DNA that binds to a chromosomal locus is indicative of the abundance of that DNA. Thus, if a chromosomal region is amplified, the test DNA will out-compete the reference DNA for binding and fluorescence will indicate amplification. Conversely, if a region is deleted, more reference DNA will bind and fluorescence will indicate a deletion. The following chapter outlines the protocols used for CGH analysis of metaphase chromosomes. These protocols include metaphase chromosome slide preparation, DNA extraction (from blood, cell lines, and microdissected formalin-fixed paraffin-embedded tissue), DOP-PCR, nick translation, in situ hybridization, and fluorescence microscopy and image analysis. PMID- 25827877 TI - Histone deacetylase activity assay. AB - Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from the epsilon-amino groups of conserved lysine residues in the amino terminal tail of histones. Accumulating evidence suggests that many, if not all, HDACs can also deacetylate nonhistone proteins. Through deacetylating histones and nonhistone proteins, HDACs regulate a variety of cellular processes including gene transcription, cell differentiation, DNA damage responses, and apoptosis. Aberrant HDACs are implicated in many human diseases and, therefore, it is important to have a consistent and reliable assay for analyzing HDAC activities. The focus of this chapter is to provide up-to-date, easy-to-follow, approaches and techniques, for the assay of HDAC enzymatic activities. PMID- 25827878 TI - In vitro histone demethylase assays. AB - Histone methylation plays pivotal roles in modulating chromatin structure and dynamics and in turn regulates genomic processes that require access to the DNA template. The methylation status at different sites is dynamically regulated by histone methyltransferases and demethylases. During the past decade, two classes of proteins have been characterized to actively remove methyl groups from lysine residues through different mechanisms. The LSD1/KDM1 family of amine oxidases require flavin adenine dinucleotide (FAD) for reaction, while the larger Jumonji C (JmjC) family of hydroxylases utilize Fe(II) and alpha-ketoglutarate as cofactors to demethylate histones. Since their discoveries, histone demethylases have been implicated in the precise control of gene expression program during development, cell identity, and fate decision. Several demethylases have also been linked to various human diseases such as neurological disorders and cancer. This chapter describes several in vitro assay conditions and detection methods for two classes of histone demethylases. We also discuss the protocols to prepare various substrates for different histone demethylase assays. PMID- 25827879 TI - Integrated DNA methylation and chromatin structural analysis at single-molecule resolution. AB - Chromatin limits the accessibility of DNA to trans-acting factors in transcription, replication, and repair. Although transcriptional variation between cells in a population may contribute to survival and disease, most assays of chromatin structure recover only population averages. We have developed DNA methyltransferases (MTases) as probing agents of DNA accessibility in chromatin, either expressed in vivo in budding yeast or as recombinant enzymatic probes of nuclei isolated from mammalian cells. In this chapter, we focus on the use of recombinant MTase (M) M.CviPI to probe chromatin accessibility in nuclei isolated from mammalian cell lines and animal tissue. This technique, named methylation accessibility protocol for individual templates (MAPit), reports protein-DNA interactions at single-molecule resolution. The single-molecule readout allows identification of chromatin subpopulations and rare epigenetic variants within a cell population. Furthermore, the use of M.CviPI in mammalian systems gives a comprehensive view of both chromatin structure and endogenous DNA methylation in a single assay. PMID- 25827880 TI - Determination of DNA methylation levels using Illumina HumanMethylation450 BeadChips. AB - DNA methylation is a modifiable epigenetic phenomenon that has a strong influence over transcriptional regulation and as such has been consistently implicated in development and disease. Several platforms are targeted toward the identification of DNA methylation changes that might be pertinent to the disease process and include regional analysis (e.g., pyrosequencing) as well as genome-wide analysis (e.g., next-generation sequencing and microarray). The Illumina HumanMethylation450 BeadChip is one of the most comprehensive microarray platforms available, and due to the high costs associated with next-generation sequencing, it is becoming a widely used tool for the analysis of genome-wide DNA methylation levels. Providing quantitative DNA methylation levels at 482,421 CpG sites within CpG islands, shores, and shelves, as well as intergenic regions, the HumanMethylation450 BeadChip can allow accurate assessment of differential methylation across large studies. This chapter outlines the laboratory methodologies associated with performing the Illumina Infinium Methylation Assay, including bisulfite conversion, whole-genome amplification, BeadChip hybridization, XStain procedures, and imaging systems. Furthermore, this chapter provides an outline of data analysis tools, including the GenomeStudio pipeline, quality control measures, and additional statistical considerations. This comprehensive overview can aid not only in performing the Illumina Infinium Methylation Assay but also in the interpretation of data derived from this platform. PMID- 25827881 TI - Investigation of genomic methylation status using methylation-specific and bisulfite sequencing polymerase chain reaction. AB - Epigenetic modification plays a central role in the regulation of gene expression and therefore in the development of disease states. In particular, genomic methylation of cytosines within CpG dinucleotides is crucial to development, gene silencing, and chromosome inactivation. Importantly, aberrant methylation profiles of various genes are associated with cancer as well as autoimmune disease, psychiatric and neurodegenerative disorders, diabetes, and heart disease. Various methods are available for the detection and quantification of methylation in a given sample. Most of these methods rely upon bisulfite conversion of DNA, which converts unmethylated cytosines to uracil, while methylated cytosines remain as cytosines. Methylation-specific amplification of DNA can be used to detect methylation at one or more (typically up to about 4) CpG sites by using primers specific to either methylated or unmethylated DNA. Alternatively, amplification of both methylated and unmethylated DNA followed by sequencing can be used to detect methylation status at multiple CpG sites. The following chapter provides protocols for bisulfite conversion of DNA, methylation specific PCR and bisulfite sequencing PCR. PMID- 25827882 TI - In vitro and in vivo assays for studying histone ubiquitination and deubiquitination. AB - Posttranslational histone modifications play important roles in regulating chromatin structure and function (Rando, Curr Opin Genet Dev 22:148-155, 2012; Zentner and Henikoff, Nat Struct Mol Biol 20:259-266, 2013). One example of such modifications is histone ubiquitination, which occurs predominately on H2A and H2B. Recent studies have highlighted important regulatory roles of H2A ubiquitination in Polycomb group protein-mediated gene silencing and DNA damage repair (de Napoles et al., Dev Cell 7:663-676, 2004; Wang et al., Nature 431:873 878, 2004; Doil et al., Cell 136:435-446, 2009; Gatti et al., Cell Cycle 11:2538 2544, 2012; Mattiroli et al., Cell 150:1182-1195, 2012; Stewart et al., Cell 136:420-434, 2009; Bergink et al., Genes Dev 20:1343-1352, 2006; Facchino et al., J Neurosci 30:10096-10111, 2010; Ginjala et al., Mol Cell Biol 31:1972-1982, 2011; Ismail et al., J Cell Biol 191:45-60, 2010), H2B ubiquitination in transcription initiation and elongation (Xiao et al., Mol Cell Biol 25:637-651, 2005; Kao et al., Genes Dev 18:184-195, 2004; Pavri et al., Cell 125:703-717, 2006; Kim et al., Cell 137:459-471, 2009), pre-mRNA splicing (Jung et al. Genome Res 22:1026-1035, 2012; Shieh et al., BMC Genomics 12:627, 2011; Zhang et al., Genes Dev 27:1581-1595, 2013), nucleosome stabilities (Fleming et al., Mol Cell 31:57-66, 2008; Chandrasekharan et al., Proc Natl Acad Sci U S A 106:16686-16691, 2009), H3 methylation (Sun and Allis, Nature 418:104-108, 2002; Briggs et al., Nature 418:498, 2002; Dover et al., J Biol Chem 277:28368-28371, 2002; Ng et al., J Biol Chem 277:34655-34657, 2002), and DNA methylation (Sridhar et al., Nature 447:735-738, 2007). Here we describe methods for in vitro histone ubiquitination and deubiquitination assays. We also describe approaches to investigate the in vivo function of putative histone ubiquitin ligase(s) and deubiquitinase(s). These experimental procedures are largely based on our studies in mammalian cells. These methods should provide useful tools for studying this bulky histone modification. PMID- 25827883 TI - Immunostaining analysis of tissue cultured cells and tissue sections using phospho-Histone H3 (Serine 10) antibody. AB - Post-translational modifications of histones play an important role in regulation of gene expression through condensation and decondensation of chromatin structure. These modifications include acetylation, methylation, phosphorylation and ubiquitination. Phosphorylation on histones is associated with cellular responses such as DNA damage, transcription, chromatin compaction and mitosis or meiosis. One of the most extensively studied modifications of histones is the Serine 10 phosphorylation on histone H3 N-terminal tail. This specific phosphorylation on Histone H3 has been associated with condensation and transcriptional inactivation of mitotic chromosomes, but recent studies have suggested a role for this specific phosphorylation in chromatin relaxation and activation of transcription in interphase cells. Co-immunostaining analysis of cells using antibodies specific to serine 10P-Histone H3 together with those to cell cycle specific markers will allow us to determine the nature of phosphorylation in a cell cycle-specific manner. In a complex system, such as tissue specimens, analysis using P-Histone H3 and a cell type specific antibody will allow identification of specific cells that are affected by this histone modification. This is of particular interest in the field of cancer biology or neurobiology where identification or quantification of the transcriptionally active or mitotic cells will enable one to evaluate the progression of the disease development. The protocol described here provides details on how co immunostaining and analysis can be performed in tissue cultured cells or tissue sections. PMID- 25827884 TI - Identification and characterization of nonhistone chromatin proteins: human positive coactivator 4 as a candidate. AB - The highly dynamic nucleoprotein structure of eukaryotic genome is organized in an ordered fashion, the unit of which is the nucleosome. The nucleosome is composed of core histones and DNA of variable size wrapped around it. Apart from the histone proteins, several nonhistone proteins also interact with the complex consisting of the DNA, the core and linker histones conferring highly regulated fluidity on the chromatin and permitting fine tuning of its functions. The nonhistone proteins are multifunctional and accentuate diverse cellular outcomes. In spite of the technical challenges, the architectural role of the nonhistone proteins altering the topology of the chromatin has been studied extensively. To appreciate the significance of the chromatin for genome function, it is essential to examine the role of the nonhistone proteins in different physiological conditions. Here, taking the example of a highly abundant chromatin protein, PC4 (Positive coactivator 4), we describe strategies for the identification of the chromatin-associated proteins and their structural and functional characterization. PMID- 25827885 TI - Methods to study transcription-coupled repair in chromatin. AB - The effect of endogenous and exogenous DNA damage on the cellular metabolism can be studied at the genetic and molecular level. A paradigmatic case is the repair of UV-induced pyrimidine dimers (PDs) by nucleotide excision repair (NER) in Saccharomyces cerevisiae. To follow the formation and repair of PDs at specific chromosome loci, cells are irradiated with UV-light and incubated in the dark to allow repair by NER. Upon DNA isolation, cyclobutane pyrimidine dimers, which account for about 90 % of PDs, can be cleaved in vitro by the DNA nicking activity of the T4 endonuclease V repair enzyme. Subsequently, strand-specific repair in a suitable restriction fragment is determined by denaturing gel electrophoresis followed by Southern blot and indirect end-labeling using a single-stranded DNA probe. Noteworthy, this protocol could potentially be adapted to other kind of DNA lesions, as long as a DNA nick is formed or a lesion specific endonuclease is available.Transcription-coupled repair (TC-NER) is a sub pathway of NER that catalyzes the repair of the transcribed strand of active genes. RNA polymerase II is essential for TC-NER, and its occupancy on a damaged template can be analyzed by chromatin immunoprecipitation (ChIP). In this chapter, we provide an up-dated protocol for both the DNA repair analysis and ChIP approaches to study TC-NER in yeast chromatin. PMID- 25827886 TI - Analysis of DNA replication associated chromatin decondensation: in vivo assay for understanding chromatin remodeling mechanisms of selected proteins. AB - Of critical importance to many of the events underlying transcriptional control of gene expression are modifications to core and linker histones that regulate the accessibility of trans-acting factors to the DNA substrate within the context of chromatin. Likewise, control over the initiation of DNA replication, as well as the ability of the replication machinery to proceed during elongation through the multiple levels of chromatin condensation that are likely to be encountered, is known to involve the creation of chromatin accessibility. In the latter case, chromatin access will likely need to be a transient event so as to prevent total genomic unraveling of the chromatin that would be deleterious to cells. While there are many molecular and biochemical approaches in use to study histone changes and their relationship to transcription and chromatin accessibility, few techniques exist that allow a molecular dissection of the events underlying DNA replication control as it pertains to chromatin changes and accessibility. Here, we outline a novel experimental strategy for addressing the ability of specific proteins to induce large-scale chromatin unfolding (decondensation) in vivo upon site-specific targeting to an engineered locus. Our laboratory has used this powerful system in novel ways to directly address the ability of DNA replication proteins to create chromatin accessibility, and have incorporated modifications to the basic approach that allow for a molecular genetic analysis of the mechanisms and associated factors involved in causing chromatin decondensation by a protein of interest. Alternative approaches involving co-expression of other proteins (competitors or stimulators), concurrent drug treatments, and analysis of co-localizing histone modifications are also addressed, all of which are illustrative of the utility of this experimental system for extending basic findings to physiologically relevant mechanisms. Although used by our group to analyze mechanisms underlying DNA replication associated chromatin accessibility, this unique and powerful experimental system has the propensity to be a valuable tool for understanding chromatin remodeling mechanisms orchestrated by other cellular processes such as DNA repair, recombination, mitotic chromosome condensation, or other chromosome dynamics involving chromatin alterations and accessibility. PMID- 25827887 TI - Non-radioactive assay methods for the assessment of telomerase activity and telomere length. AB - The Telomeric repeat amplification protocol (TRAP) is a highly sensitive PCR based assay and prove to be an important tool for understanding the role of telomerase in cancer and various tissues that harbors telomerase positive stem cells. This assay measures telomerase activity where the amount of target is dependent upon the activity of the enzyme. This protocol consists of two steps: first, telomeric repeats are added to the substrate by telomerase present in the cell and second, the extended products are amplified by Taq-DNA polymerase. The amplified TRAP products are separated on 10 % native PAGE and detected by SYBR Green I dye. PMID- 25827889 TI - Imaging local deposition of newly synthesized histones in UVC-damaged chromatin. AB - DNA damage not only jeopardizes genome integrity but also challenges the well organized association of DNA with histone proteins into chromatin, which is key for regulating gene expression and cell functions. The extent to which the original chromatin structure is altered after repair of DNA lesions is thus a critical issue. Dissecting histone dynamics at sites of DNA damage has provided mechanistic insights into chromatin plasticity in response to genotoxic stress. Here, we present an experimental protocol for visualizing the deposition of newly synthesized histone H3 variants at sites of UVC damage in human cells that couples SNAP-tag based labeling of new histones with local UVC irradiation of cells through micropore filters. PMID- 25827888 TI - Detecting ATM-dependent chromatin modification in DNA damage response. AB - Loss of function or mutation of the ataxia-telangiectasia mutated gene product (ATM) results in inherited genetic disorders characterized by neurodegeneration, immunodeficiency, and cancer. Ataxia-telangiectasia mutated (ATM) gene product belongs to the PI3K-like protein kinase (PIKKs) family and is functionally implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, cell-cycle control, and telomere maintenance. The ATM protein kinase is primarily activated in response to DNA double strand breaks (DSBs), the most deleterious form of DNA damage produced by ionizing radiation (IR) or radiomimetic drugs. It is detected at DNA damage sites, where ATM autophosphorylation causes dissociation of the inactive homodimeric form to the activated monomeric form. Interestingly, heat shock can activate ATM independent of the presence of DNA strand breaks. ATM is an integral part of the sensory machinery that detects DSBs during meiosis, mitosis, or DNA breaks mediated by free radicals. These DNA lesions can trigger higher order chromatin reorganization fuelled by posttranslational modifications of histones and histone binding proteins. Our group, and others, have shown that ATM activation is tightly regulated by chromatin modifications. This review summarizes the multiple approaches used to discern the role of ATM and other associated proteins in chromatin modification in response to DNA damage. PMID- 25827890 TI - In vitro replication assay with mammalian cell extracts. AB - Regulatory mechanisms are crucial to control DNA replication during cell cycle in eukaryotic cells. Cell-free in vitro replication assay (IVRA) is one of the widely used assays to understand the complex mammalian replication system. IVRA can provide a snapshot of the regulatory mechanisms controlling replication in higher eukaryotes by using a single plasmid, pEPI-1. This chapter outlines the general strategies and protocols used to perform IVRA to study the differential recruitment of replication factors either independently or in combination, based on the experience in studying the role of prohibitin in replication as well as other published protocols. This method can be employed to identify not only proteins that assist replication but also proteins that inhibit replication of mammalian genome. PMID- 25827891 TI - Fluorescent in situ hybridization on comets: FISH comet. AB - The DNA in eukaryotic cells is organized into loop domains that represent basic structural and functional units of chromatin packaging. The comet assay, a sensitive method for monitoring DNA damage and repair, involves electrophoresis of nucleoids comprising supercoiled DNA attached to the nuclear matrix. Breaks in the DNA relax the supercoiling and allow DNA loops to expand, and on electrophoresis to move towards the anode, giving the appearance of a comet tail. We use fluorescent in situ hybridization (FISH) to investigate the structure of the chromatin within comet preparations and to study specific DNA sequences within comets. In this chapter we describe our FISH comets protocols, deal with some technical questions and outline the theory. FISH with comets should be useful to researchers interested in the structural organization of DNA and chromatin, the localization of DNA damage, and the kinetics of repair of damage. PMID- 25827892 TI - Methods to study histone chaperone function in nucleosome assembly and chromatin transcription. AB - Histone chaperones are histone interacting proteins that are involved in various stages of histone metabolism in the cell such as histone storage, transport, nucleosome assembly and disassembly. Histone assembly and disassembly are essential processes in certain DNA-templated phenomena such as replication, repair and transcription in eukaryotes. Since the first histone chaperone Nucleoplasmin was discovered in Xenopus, a plethora of histone chaperones have been identified, characterized and their functional significance elucidated in the last 35 years or so. Some of the histone chaperone containing complexes such as FACT have been described to play a significant role in nucleosome disassembly during transcription elongation. We have reported earlier that human Nucleophosmin (NPM1), a histone chaperone belonging to the Nucleoplasmin family, is a co-activator of transcription. In this chapter, we describe several methods that are used to study the histone chaperone activity of proteins and their role in transcription. PMID- 25827893 TI - Preparation of mononucleosomal templates for analysis of transcription with RNA polymerase using spFRET. AB - Single positioned nucleosomes have been extensively employed as simple model experimental systems for analysis of various intranuclear processes. Here we describe an experimental system containing positioned mononucleosomes allowing transcription by various RNA polymerases. Each DNA template contains a pair of fluorescent labels (Cy3 and Cy5) allowing measuring relative distances between the neighboring coils of nucleosomal DNA using Forster resonance energy transfer (FRET). The single-particle FRET (spFRET) approach for analysis of DNA uncoiling from the histone octamer during transcription through chromatin is described in detail. PMID- 25827894 TI - Transcriptome-wide identification of in vivo interactions between RNAs and RNA binding proteins by RIP and PAR-CLIP assays. AB - Comprehensive genomic and computational studies in the era of high-throughput sequencing revealed that the major proportion of the human genome is transcribed. This novel insight confronted the scientific community with new questions concerning the expanded role of RNA, especially noncoding RNA (ncRNA), in cellular pathways. In recent years, there has been mounting evidence that ncRNAs and RNA binding proteins (RBPs) are involved in a wide range of biological processes, such as developmental transitions, cell differentiation, stress response, genome organization, and regulation of gene expression. In particular, in the chromatin field long noncoding RNAs (lncRNAs) have drawn increasing attention to their function in epigenetic regulation due to the fact that they were found to interact with multiple chromatin regulators and modifiers. Recently, techniques to study the extent of RNA-protein interactions have been developed in many research laboratories. Here we describe protocols for RNA Immunoprecipitation-Sequencing (RIP-Seq) and Photoactivatable-Ribonucleoside Enhanced Cross-linking and Immunoprecipitation combined with deep sequencing (PAR CLIP-Seq) to identify RNA targets of RNA-binding proteins (RBPs) on a transcriptome-wide level, discussing advantages and drawbacks. PMID- 25827895 TI - Chromatin immunoprecipitation assays: analyzing transcription factor binding and histone modifications in vivo. AB - Studies in the past decade have shown that differential gene expression depends not only on the binding of specific transcription factors to discrete promoter elements but also on the epigenetic modification of the DNA as well as histones associated with the promoter. While techniques like electrophoretic mobility shift assays could detect and characterize the binding of specific transcription factors present in cell lysates to DNA sequences in in vitro binding conditions, they were not effective in assessing the binding in intact cells. Development of chromatin immunoprecipitation technique in the past decade enabled the analysis of the association of regulatory molecules with specific promoters or changes in histone modifications in vivo, without overexpressing any component. ChIP assays can provide a snapshot of how a regulatory transcription factor affects the expression of a single gene, or a variety of genes at the same time. Availability of high quality antibodies that recognizes histones modified in a specific fashion further expanded the use of ChIP assays to analyze even minute changes in histone modification and nucleosomes structure. This chapter outlines the general strategies and protocols used to carry out ChIP assays to study the differential recruitment of transcription factors as well as histone modifications. PMID- 25827896 TI - ChIP on chip and ChIP-Seq assays: genome-wide analysis of transcription factor binding and histone modifications. AB - Deregulation of transcriptional activity of many genes has been causatively linked to human diseases including cancer. Altered patterns of gene expression in normal and cancer cells are the result of inappropriate expression of transcription factors and chromatin modifying proteins. Chromatin immunoprecipitation assay is a well-established tool for investigating the interactions between regulatory proteins and DNA at distinct stages of gene activation. ChIP coupled with DNA microarrays, known as ChIP on chip, or sequencing of DNA associated with the factors (ChIP-Seq) allow us to determine the entire spectrum of in vivo DNA binding sites for a given protein. This has been of immense value because ChIP on chip assays and ChIP-Seq experiments can provide a snapshot of the transcriptional regulatory mechanisms on a genome-wide scale. This chapter outlines the general strategies used to carry out ChIP-chip assays to study the differential recruitment of regulatory molecules based on the studies conducted in our lab as well as other published protocols; these can be easily modified to a ChIP-Seq analysis. PMID- 25827897 TI - ChIP-on-chip analysis methods for Affymetrix tiling arrays. AB - Although the ChIP-sequencing has gained significant attraction recently, ChIP analysis using microarrays is still an attractive option due to the low cost, ease of analysis, and access to legacy and public data sets. The analysis of ChIP Chip data entails a multistep approach that requires several different applications to progress from the initial stages of raw data analysis to the identification and characterization of ChIP binding sites. There are multiple approaches to data analysis and there are several applications available for each stage of the analysis pipeline. Each application must be evaluated for its suitability for the particular experiment as well as the investigator's background with computational tools. This chapter is a review of the commonly available applications for Affymetrix ChIP-Chip data analysis, as well as the general workflow of a ChIP-Chip analysis approach. The purpose of the chapter is to allow the researcher to better select the appropriate applications and provide them with the direction necessary to proceed with a ChIP-Chip analysis. PMID- 25827898 TI - Temporal distribution of air quality related to meteorology and road traffic in Madrid. AB - The impact of climatology--air temperature, precipitation and wind speed--and road traffic--volume, vehicle speed and percentage of heavy-duty vehicles (HDVs)- on air quality in Madrid was studied by estimating the effect for each explanatory variable using generalized linear regression models controlling for monthly variations, days of week and parameter levels. Every 1 m/s increase in wind speed produced a decrease in PM10 concentrations by 10.3% (95% CI 12.6-8.6) for all weekdays and by 12.4% (95% CI 14.9-9.8) for working days (up to the cut off of 2.4 m/s). Increases of PM10 concentrations due to air temperature (7.2% (95% CI 6.2-8.3)) and traffic volume (3.3% (95% CI 2.9-3.8)) were observed at every 10 degrees C and 1 million vehicle-km increases for all weekdays; oppositely, slight decreases of PM10 concentrations due to percentage of HDVs (3.2% (95% CI 2.7-3.7)) and vehicle speed (0.7% (95% CI 0.6-0.8)) were observed at every 1% and 1 km/h increases. Stronger effects of climatology on air quality than traffic parameters were found. PMID- 25827899 TI - Synthesis and application of ion-imprinted polymer nanoparticles for the extraction and preconcentration of copper ions in environmental water samples. AB - Novel Cu(II) ion-imprinted polymers (Cu-IIP) nanoparticles were prepared by using Cu(II) ion-thiosemicarbazide complex as the template molecule and methacrylic acid, ethylene glycol dimethacrylate (EGDMA), and 2,2'azobisisobutyronitrile (AIBN) as the functional monomer, cross-linker, and the radical initiator, respectively. The synthesized polymer nanoparticles were characterized by using infrared spectroscopy (IR), thermo gravimetric analysis (TGA), X-ray diffraction (XRD), and scanning electron microscopic (SEM) techniques. Some parameters such as pH, weight of the polymer, adsorption time, elution time, eluent type, and eluent volume which affect the extraction efficiency of the polymer were studied. In the proposed method, the maximum sorbent capacity of the ion-imprinted polymer was calculated to be 38.8 mg g(-1). The preconcentration factor, relative standard deviation, and limit of detection of the method were found to be 80, 1.7%, and 0.003 MUg mL(-1), respectively. The prepared ion-imprinted polymer nanoparticles have an increased selectivity toward Cu(II) ions over a range of competing metal ions with the same charge and similar ionic radius. The method was applied to the determination of ultra trace levels of Cu2+ in environmental water samples with satisfactory results. PMID- 25827900 TI - Medicinal properties of mangiferin, structural features, derivative synthesis, pharmacokinetics and biological activities. AB - The identification of biologically active and potentially therapeutically useful pharmacophores from natural products has been a long-term focus in the pharmaceutical industry. The recent emergence of a worldwide obesity and Type II diabetes epidemic has increased focus upon small molecules that can modulate energy metabolism, insulin sensitivity and fat biology. Interesting preliminary work done on mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera indica L., portends potential for this pharmacophore as a novel parent compound for treating metabolic disorders. MGF is comprised of a C glucosylated xanthone. Owing to the xanthone chemical structure, MGF has a redox active aromatic system and has antioxidant properties. MGF exerts varied and impressive metabolic effects in animals, improving metabolic disorders. For example we have discovered that MGF is a novel activator of the mammalian pyruvate dehydrogenase complex, leading to enhancement of carbohydrate utilization in oxidative metabolism, and leading to increased insulin sensitivity in animal models of obesity and insulin resistance. In addition, recent unbiased proteomics studies revealed that MGF upregulates proteins pivotal for mitochondrial bioenergetics and downregulates proteins controlling de novo lipogenesis in liver, helping to explain protective effects of MGF in prevention of liver steatosis. Several chemical studies have achieved synthesis of MGF, suggesting possible synthetic strategies to alter its chemical structure for development of structure-activity relationship (SAR) information. Ultimately, chemical derivatization studies could lead to the eventual development of novel therapeutics based upon the parent pharmacophore structure. Here we provide comprehensive review on chemical features of MGF, synthesis of its derivatives, its pharmacokinetics and biological activities. PMID- 25827902 TI - Re: 'Analysis of the increasing prevalence of necrotising fasciitis referrals to a regions plastic surgery unit: A retrospective case series'. PMID- 25827901 TI - Breed differences in humoral and cellular responses of lambs to experimental infection with the gastrointestinal nematode Teladorsagia circumcincta. AB - While Texel lambs have increased resistance to infection with the gastrointestinal nematode Teladorsagia circumcincta compared to Suffolk lambs, the underlying resistance mechanisms are still unknown. The aim of this study was to compare parasitological, humoral and cellular responses of Texel and Suffolk lambs over time following a single experimental infection with T. circumcincta. Gastrointestinal nematode free (but not naive) lambs received a single oral dose of 3 * 104 infective T. circumcincta larvae. The variables examined included worm burden, mucosal and serum IgA, abomasal mast cells and eosinophils, haematological parameters and plasma pepsinogen. Texel lambs had significantly lower worm burden on day 14 and lower plasma pepsinogen concentration from day 14 onwards than Suffolks and their response in mucosal IgA to infection occurred earlier. The results from the study suggest that an earlier local IgA response in the Texel contributes to the resistant characteristics of the breed, while the increased level of plasma pepsinogen in the Suffolk lambs implies greater abomasal tissue damage arising from the nematode infection. PMID- 25827903 TI - Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations. AB - Application of amorphous solid dispersions (ASDs) is considered one of the most promising approaches to increase the dissolution rate and extent of bioavailability of poorly water soluble drugs. Such intervention is often required for new drug candidates in that enablement, bioavailability is not sufficient to generate a useful product. Importantly, tableting of ASDs is often complicated by a number of pharmaceutical and technological challenges including poor flowability and compressibility of the powders, compression-induced phase changes or phase separation and slow disintegration due to the formation of a gelling polymer network (GPN). The design principles of an ASD-based system include its ability to generate supersaturated systems of the drug of interest during dissolution. These metastable solutions can be prone to precipitation and crystallization reducing the biopharmaceutical performance of the dosage form. The main aim of the research in this area is to maintain the supersaturated state and optimally enhance bioavailability, meaning that crystallization should be delayed or inhibited during dissolution, as well as in solid phase (e.g., during manufacturing and storage). Based on the expanding use of ASD technology as well as their downstream processing, there is an acute need to summarize the results achieved to this point to better understand progress and future risks. The aim of this review is to focus on the conversion of ASDs into tablets highlighting results from various viewpoints. PMID- 25827904 TI - After the earthquake, tsunami and nuclear crisis. PMID- 25827905 TI - The limits of research. PMID- 25827906 TI - Should English healthcare providers be penalised for failing to collect patient reported outcome measures? A retrospective analysis. AB - OBJECTIVE: The best practice tariff for hip and knee replacement in the English National Health Service (NHS) rewards providers based on improvements in patient reported outcome measures (PROMs) collected before and after surgery. Providers only receive a bonus if at least 50% of their patients complete the preoperative questionnaire. We determined how many providers failed to meet this threshold prior to the policy introduction and assessed longitudinal stability of participation rates. DESIGN: Retrospective observational study using data from Hospital Episode Statistics and the national PROM programme from April 2009 to March 2012. We calculated participation rates based on either (a) all PROM records or (b) only those that could be linked to inpatient records; constructed confidence intervals around rates to account for sampling variation; applied precision weighting to allow for volume; and applied risk adjustment. SETTING: NHS hospitals and private providers in England. PARTICIPANTS: NHS patients undergoing elective unilateral hip and knee replacement surgery. MAIN OUTCOME MEASURES: Number of providers with participation rates statistically significantly below 50%. RESULTS: Crude rates identified many providers that failed to achieve the 50% threshold but there were substantially fewer after adjusting for uncertainty and precision. While important, risk adjustment required restricting the analysis to linked data. Year-on-year correlation between provider participation rates was moderate. CONCLUSIONS: Participation rates have improved over time and only a small number of providers now fall below the threshold, but administering preoperative questionnaires remains problematic in some providers. We recommend that participation rates are based on linked data and take into account sampling variation. PMID- 25827907 TI - The curious stories of drugs with two lives: a new paradigm in drug development. PMID- 25827908 TI - Putting patient-reported outcomes on the 'Big Data Road Map'. PMID- 25827909 TI - In situ encapsulation of Pd inside the MCM-41 channel. AB - Pd nanoparticles were successfully introduced into the channels of mesoporous silica MCM-41 with their dispersion well-tuned. We identified the dual role played by CTAB, which was critical for both the micelle template and Pd grafting, leading to the formation of a highly active Pd-MCM-41 nanocomposite for catalysing the Suzuki reaction. PMID- 25827911 TI - The 8-silyloxyquinoline scaffold as a versatile platform for the sensitive detection of aqueous fluoride. AB - Utilizing a novel 8-silyloxyquinoline scaffold, we demonstrate the ability to synthesize fluorogenic probes for the sensitive and selective detection of inorganic fluoride (NaF) in aqueous samples. Our initial probe design (2) is capable of detecting inorganic fluoride at levels as low as 3.8 MUM (72 ppb) in aqueous solutions, well below PHS recommended levels for drinking water (0.7-1.2 ppm), placing this probe among the most sensitive fluoride sensors reported to date. Furthermore, our results highlight the utility of the readily modifiable 8 silyloxyquinoline scaffold for the design of tailored fluoride sensing platforms. We demonstrate the ability to rationally tune the fluorescence and physical properties of the 8-silyloxyquinoline scaffold, producing a red-shifted fluoride probe (4) capable of detecting 50 MUM (0.95 ppm) NaF in aqueous samples using a straightforward test-strip-based assay format. Taken together this work provides a template for the design of fluoride sensors capable of reporting on relevant concentrations of fluoride in the laboratory and in the field. PMID- 25827910 TI - IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells. AB - We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells under defined culture conditions. While both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process, and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling. PMID- 25827912 TI - Comparative immunohistochemical evaluation of the zonal distribution of extracellular matrix and inflammation markers in human meniscus in osteoarthritis and rheumatoid arthritis. AB - The purpose of our study was to analyze the distribution of the major extracellular matrix glycosaminoglycan hyaluronan (HA), its receptor CD44 and cells which influence (re)modeling of the extracellular matrix (T- and B-cells, macrophages, endothelial cells) in menisci obtained from patients suffering from rheumatoid arthritis or osteoarthritis in order to analyze whether these markers could be useful to differentiate between both arthropathies. Human menisci were sampled from patients undergoing total knee arthroplasty. Histological staining (H&E, PAS/Alcian Blue for neutral and charged carbohydrate residues) and (immuno)histochemistry were performed for detection of HA, CD44, sphingosine-1 phosphate receptor 1 (EDG-1) as a marker for endothelial cells, CD3 as a marker for T-cells, CD20 as a marker for B-cells and CD68 as a marker for macrophages. The extracellular matrix in the vascularized zone showed higher amounts of HA as well as acid carbohydrate residues in comparison to the poorly vascularized zones of the meniscus in both disease entities. EDG-1 positive endothelial cells were present in all zones, with fewer cells being detected in the inner zones of the rheumatoid menisci than in the osteoarthritic ones. Macrophages, T- and B-cells as well as CD44-positive cells were more prominent in the vascularized zone of the meniscus than in the poorly vascularized central zone. The distribution patterns of the extracellular matrix components as well as the CD44-positive cells and the inflammation markers in the peripheral zone resembled the distribution in synovial tissue, indicating that both synovia and meniscus were involved in pathological changes in osteoarthritis and rheumatoid arthritis. IN CONCLUSION: the distribution of extracellular glycoconjugates and of cells modulating their synthesis showed similar results in both arthropathies, not enabling a differentiation between rheumatoid arthritis and osteoarthritis but underlining the role of these markers in inflammation and degradation in human meniscus. PMID- 25827913 TI - Bilateral cystic encephalomalacia following multiple intrauterine transfusions for anti-Kell isoimmunisation. AB - Fetal and neonatal haemolytic diseases result from maternal allo-immunisation to fetal antigens. Maternal antibodies cross the placenta causing red cell haemolysis, resulting in fetal anaemia and, in severe cases, hydrops and perinatal death. Intravascular intrauterine blood transfusion (IUT) has markedly reduced perinatal mortality and is now a standard procedure. IUT is considered to be a safe procedure with fetal loss rate reported to be less than 5% and no reported increase in the rate of neurodevelopment impairment. In this report, we are presenting a case of bilateral cystic encephalomalacia following fetal anaemia secondary to anti-Kell iso-immunisation treated with multiple IUTs. Such a significant adverse outcome following IUT for anti-Kell iso-immunisation has not been reported in the literature. This case highlights the need for appropriate parental counselling and routine postnatal head ultrasound in all babies delivered following multiple IUTs. PMID- 25827914 TI - Ophthalmic manifestations postlightning strike. AB - Various ophthalmic complications affecting the anterior and posterior segments have been identified due to lightning strike. We report the first case of an indirect lightning-induced full thickness macular hole formation in the UK as evidenced by slit lamp examination and optical coherence tomography (OCT) scan in a 77-year-old woman presenting with sudden visual loss in her right eye and thermal skin injury affecting her scalp. Her best corrected visual acuities were LogMAR 0.46 and 0.12 in the right and left eyes, respectively. There were no other ocular manifestations observed in either eye. She was initially managed conservatively with non-steroidal anti-inflammatory drug eye drops but surgery was later advised due to minimal changes in the visual acuity and macular hole on follow-up. OCT scanning is important in diagnosing macular holes, which usually warrant surgical intervention. PMID- 25827915 TI - A liver lesion in primary sclerosing cholangitis. AB - Primary sclerosing cholangitis is associated with an increased risk of cholangiocarcinoma; appropriate surveillance should be undertaken for this. Our case illustrates an unexpected liver lesion in such a patient, which would not have been detected with imaging alone. In suspected cancer, if a patient is not a candidate for liver resection, liver biopsy should be considered in case there is a treatment option for an alternative cause of the liver lesion. This is a careful decision to be made due to the risk of tumour seeding compromising cure and needs to be discussed via the hepatobiliary multidisciplinary team. PMID- 25827916 TI - Jack in the box: inguinal endometriosis. AB - A 39-year-old woman with a left-sided inguinal swelling was referred to us with a diagnosis of inguinal hernia. On asking leading questions, the patient gave a typical history of cyclical pain and increased swelling during menstruation. Fine needle aspiration biopsy revealed endometrial glands. Preoperatively, the extent of the endometriotic lesion was delineated using MRI. The lesion was approached through the patient's caesarean scar for cosmetic reasons and excised in toto. Final diagnosis was round ligament endometriosis. The patient was asymptomatic at 3, 6 and 12 months' follow-up. This case re-emphasises the fact that endometriosis is an enigmatic disease and can be found anywhere in the body. Thus, a woman of reproductive age presenting with any cyclical symptom should be asked about its relation to her menstrual cycle. PMID- 25827917 TI - Diagnosis and management of isolated pituitary metastasis from adenocarcinoma of unknown origin presenting as loss of libido. AB - Pituitary gland metastasis from primary tumours is uncommon on its own. Rarely, some of these primary tumours may be of unknown origin. This metastasis to the pituitary gland could manifest as diabetes insipidus, cranial nerve palsies, headaches, fatigue and other symptoms. In rare cases, it could present as loss of libido. We describe here this rare presentation, loss of libido, examine the diagnosis and management undertaken, and provide a systematic review of the literature for similar cases. PMID- 25827918 TI - A 54-year-old woman with premature ventricular complexes and a rapidly changing ECG. AB - Premature ventricular complexes (PVCs) are common findings in asymptomatic participants during ECG recordings. While most PVCs are treated conservatively, some patients may develop adverse cardiac events needing further investigations and definitive ablation by radiofrequency. Spectral strain ultrasonography has demonstrated ventricular dysfunction as a sequel to high burden PVCs, but the exact underlying pathophysiology is still uncertain. Cohort studies have associated PVCs with increased risks for overall cardiovascular morbidity and mortality, and yet consensus is still lacking for threshold in treating PVCs. Our case is that of a 54-year-old woman with an unusual bradycardiac presentation of PVCs and an ECG that changed rapidly within minutes. PMID- 25827919 TI - Colovesical fistula presenting as Listeria monocytogenes bacteraemia. AB - We present a case of colovesical fistula presenting with a clinical syndrome of urosepsis subsequently demonstrated to be due to Listeria monocytogenes bacteraemia. The patient had a history of previous rectal cancer with a low anterior resection and a covering ileostomy that had been reversed 6 months prior to this presentation. L. monocytogenes was also isolated among mixed enteric organisms on urine culture. There were no symptoms or signs of acute gastrointestinal listeriosis or meningoencephalitis. This unusual scenario prompted concern regarding the possibility of communication between bowel and bladder, which was subsequently confirmed with CT and a contrast enema. The patient recovered well with intravenous amoxicillin and to date has declined surgical management of his colovesical fistula. This case illustrates the importance of considering bowel pathology when enteric organisms such as Listeria are isolated from unusual sites. PMID- 25827920 TI - Acute upper airway obstruction and emergency front of neck access in an achondroplastic patient. AB - Dwarfism is defined as a failure to attain a height of 148 cm in adulthood. Achondroplasia is the most common form of short-limbed dwarfism. Although this condition is relatively rare, with an incidence of 0.5-1.5 per 10,000 live births, most medical professionals will come across the achondroplastic dwarf (AD) during their career. Faulty endochondral ossification produces the characteristic short stature phenotype, as well as severe craniofacial, central nervous system, spinal, respiratory and cardiac anomalies. These unusual characteristics may present airway management difficulties in elective as well as emergency situations. Within the literature there is very little information regarding the emergency insertion of a surgical airway in an adult AD. We present our experience of this situation in the form of a case report and a review of the relevant literature. PMID- 25827921 TI - Does fertilizer (N15P15K15) amendment enhance phytoremediation of petroleum polluted aquatic ecosystem in the presence of water hyacinth (Eichhornia crassipes [Mart.] Solms)? AB - This study investigated the effects of inorganic fertilizer (N15P15K15) amendments on crude oil uptake by water hyacinth. Experimental units (water hyacinth grown in fresh water) were spiked with 0, 20, 40 and 60 mg/L crude oil. After 24 h, they were randomly assigned fertilizer (N15P15K15) at three different concentrations; 0, 6 and 10 mg/L. Crude oil degradation and absorption were determined by measuring total petroleum hydrocarbon (TPH) in the water column and water hyacinth, respectively. The measurements were taken monthly for six months (February-August 2010). The results showed that TPH concentration in the water column in the treatment amended at 6 mg/L (0.30 +/- 0.01 mg/L) was significantly lower (p < .05) than the treatment amended at 10 mg/L (0.76 +/- 0.15 mg/L) but was similar to the control (0.33 +/- 0.03 mg/L). The water hyacinth in the control (phytoremediation) absorbed significantly higher (p < .05) TPH than the fertilizer-amended treatments. The first-order kinetic model gave a better description of the degradation of petroleum hydrocarbons. The study showed that phytoremediation of crude oil by water hyacinth and biostimulation with fertilizer (N15P15K15) is possible. PMID- 25827922 TI - Summarization vs Peptide-Based Models in Label-Free Quantitative Proteomics: Performance, Pitfalls, and Data Analysis Guidelines. AB - Quantitative label-free mass spectrometry is increasingly used to analyze the proteomes of complex biological samples. However, the choice of appropriate data analysis methods remains a major challenge. We therefore provide a rigorous comparison between peptide-based models and peptide-summarization-based pipelines. We show that peptide-based models outperform summarization-based pipelines in terms of sensitivity, specificity, accuracy, and precision. We also demonstrate that the predefined FDR cutoffs for the detection of differentially regulated proteins can become problematic when differentially expressed (DE) proteins are highly abundant in one or more samples. Care should therefore be taken when data are interpreted from samples with spiked-in internal controls and from samples that contain a few very highly abundant proteins. We do, however, show that specific diagnostic plots can be used for assessing differentially expressed proteins and the overall quality of the obtained fold change estimates. Finally, our study also illustrates that imputation under the "missing by low abundance" assumption is beneficial for the detection of differential expression in proteins with low abundance, but it negatively affects moderately to highly abundant proteins. Hence, imputation strategies that are commonly implemented in standard proteomics software should be used with care. PMID- 25827923 TI - Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption. AB - Genetic and environmental factors contribute nearly in equal power to the development of alcoholism. Environmental factors, such as negative life events or emotionally disruptive conditions, initiate and promote alcohol drinking and relapse. The endocannabinoid system is involved in hedonic control and modulates stress reactivity. Furthermore, chronic alcohol drinking alters endocannabinoid signalling, which in turn influences the stress reactivity. Recently, it has been shown that CB2 receptor activity influences stress sensitivity and alcohol drinking. We hypothesized that CB2 receptors influence the impact of environmental risk factors on alcohol preference and consumption. Therefore, in this study, we investigated the alcohol-drinking pattern of wild-type and CB2 deficient animals under single- and group-housing conditions using different alcohol-drinking models, such as forced drinking, intermittent forced drinking and two-bottle choice paradigms. Our data showed that CB2 receptor modulates alcohol consumption and reward. Interestingly, we detected that lack of CB2 receptors led to increased alcohol drinking in the intermittent forced drinking paradigm under group-housing conditions. Furthermore, we found that CB2 knockout mice consumed more food and that their body weight gain was modulated by social environment. On the basis of these data, we conclude that social environment critically affects the modulatory function of CB2 receptors, especially in alcohol intake. These findings suggest that a treatment strategy targeting CB2 receptors may have a beneficial effect on pathological drinking, particularly in situations of social stress and discomfort. PMID- 25827924 TI - Activation of MU opioid receptors in the LPBN facilitates sodium intake in rats. AB - Important inhibitory mechanisms for the control of water and sodium intake are present in the lateral parabrachial nucleus (LPBN). Opioid receptors are expressed by LPBN neurons and injections of beta-endorphin (nonspecific opioid receptor agonist) in this area induce 0.3M NaCl and water intake in satiated rats. In the present study, we investigated the effects of the injections of endomorphin-1 (MU opioid receptor agonist) alone or combined with the blockade of MU, kappa or delta opioid receptors into the LPBN on 0.3M NaCl and water intake induced by subcutaneous injections of the diuretic furosemide (FURO) combined with low dose of the angiotensin converting enzyme inhibitor captopril (CAP). Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of endomorphin-1 (0.1, 0.25, 0.5, 1.0, 2.0 and 4.0nmol/0.2MUl) into the LPBN increased 0.3M NaCl and water intake induced by FURO+CAP. The previous blockade of MU opioid receptor with CTAP (1.0nmol/0.2MUl) into the LPBN reduced the effect of endomorphin-1 on FURO+CAP-induced 0.3M NaCl. GNTI (kappa opioid receptor antagonist; 2.0nmol/0.2MUl) and naltrindole (delta opioid receptor antagonist; 2.0nmol/0.2MUl) injected into the LPBN did not change the effects of endomorphin-1 on FURO+CAP-induced 0.3M NaCl. The results suggest that MU opioid receptors in the LPBN are involved in the control of sodium intake. PMID- 25827926 TI - An isolated retrieval trial before extinction session does not prevent the return of fear. AB - Several studies have shown that an isolated retrieval trial before the extinction session (retrieval-extinction) prevents the return of fear memory by inhibition of reconsolidation. Other studies have reported that retrieval-extinction did not prevent the return of the fear. To date, it is still unclear whether retrieval extinction prevents the return of the original fear memory. A previous study revealed that reconsolidation of conditioned fear memory was not induced by the brevity of the retrieval session. Thus, we examined whether the number of retrievals in the retrieval-extinction paradigm was involved in the prevention of return of fear (Experiment 1). Furthermore, studies with different-age experimental subjects have shown conflicting results. We investigated the potential impact of age on the inhibitory effect of retrieval-extinction on the return of fear (Experiment 2). Our major findings were as follows: (1) Retrieval extinction procedure did not prevent the return of fear, regardless of the intensity (number of presentations) of the stimulus inducing retrieval of fear memory. (2) The mice in both juvenile and adult age groups (4 and 8 weeks old) retrieved fear memory after retrieval-extinction. These results suggest the possibility that extinction after retrieval does not inhibit reconsolidation of previously consolidated fear memory. PMID- 25827925 TI - Concentration- and age-dependent effects of chronic caffeine on contextual fear conditioning in C57BL/6J mice. AB - Chronic caffeine exerts negligible effects on learning and memory in normal adults, but it is unknown whether this is also true for children and adolescents. The hippocampus, a brain region important for learning and memory, undergoes extensive structural and functional modifications during pre-adolescence and adolescence. As a result, chronic caffeine may have differential effects on hippocampus-dependent learning in pre-adolescents and adolescents compared with adults. Here, we characterized the effects of chronic caffeine and withdrawal from chronic caffeine on hippocampus-dependent (contextual) and hippocampus independent (cued) fear conditioning in pre-adolescent, adolescent, and adult mice. The results indicate that chronic exposure to caffeine during pre adolescence and adolescence enhances or impairs contextual conditioning depending on concentration, yet has no effect on cued conditioning. In contrast, withdrawal from chronic caffeine impairs contextual conditioning in pre-adolescent mice only. No changes in learning were seen for adult mice for either the chronic caffeine or withdrawal conditions. These findings support the hypothesis that chronic exposure to caffeine during pre-adolescence and adolescence can alter learning and memory and as changes were only seen in hippocampus-dependent learning, which suggests that the developing hippocampus may be sensitive to the effects of caffeine. PMID- 25827927 TI - Speech training alters consonant and vowel responses in multiple auditory cortex fields. AB - Speech sounds evoke unique neural activity patterns in primary auditory cortex (A1). Extensive speech sound discrimination training alters A1 responses. While the neighboring auditory cortical fields each contain information about speech sound identity, each field processes speech sounds differently. We hypothesized that while all fields would exhibit training-induced plasticity following speech training, there would be unique differences in how each field changes. In this study, rats were trained to discriminate speech sounds by consonant or vowel in quiet and in varying levels of background speech-shaped noise. Local field potential and multiunit responses were recorded from four auditory cortex fields in rats that had received 10 weeks of speech discrimination training. Our results reveal that training alters speech evoked responses in each of the auditory fields tested. The neural response to consonants was significantly stronger in anterior auditory field (AAF) and A1 following speech training. The neural response to vowels following speech training was significantly weaker in ventral auditory field (VAF) and posterior auditory field (PAF). This differential plasticity of consonant and vowel sound responses may result from the greater paired pulse depression, expanded low frequency tuning, reduced frequency selectivity, and lower tone thresholds, which occurred across the four auditory fields. These findings suggest that alterations in the distributed processing of behaviorally relevant sounds may contribute to robust speech discrimination. PMID- 25827928 TI - Orexin receptor 1 signaling contributes to ethanol binge-like drinking: Pharmacological and molecular evidence. AB - Orexins (OX) have been recently implicated in ethanol seeking and self administration. A few recent studies have provided additional evidence that OX receptor antagonists effectively reduce voluntary ethanol consumption in subjects spontaneously showing high levels of ethanol intake. The present study further evaluates the contribution of OXR1 to excessive binge-like drinking of ethanol in ad libitum-fed C57BL/6J mice from a pharmacological and molecular approach. The main findings in the study are: (1) Icv administration of SB-334867 (3 MUg/MUl) blunted ethanol (20% v/v), but not saccharin (0.15% w/v) binge-like drinking in a drinking in the dark procedure, without any alteration of chow consumption or total calories ingested; (2) Icv administration of SB-334867 (3 MUg/MUl) increased the latency to recover the righting reflex after a sedative dose of ethanol without any significant alteration in ethanol peripheral metabolism; (3) four repetitive, 2-h daily episodes of saccharin, but not ethanol binge-like drinking blunted OXR1 mRNA expression in the lateral hypothalamus. Present findings extend the current knowledge pointing to a role for OX signaling in ethanol sedation, which might partially explain the inhibitory effect of OXR1 antagonists on ethanol consumption. Combined pharmacological and molecular data suggesting the contribution of OXR1 in ethanol binge-drinking leading us to propose the idea that targeting OXR1 could represent a novel pharmacological approach to control binge-consumption episodes of ethanol in vulnerable organisms failing to spontaneously reduce OX activity. PMID- 25827929 TI - Study of antidepressant drugs in GPR39 (zinc receptor-/-) knockout mice, showing no effect of conventional antidepressants, but effectiveness of NMDA antagonists. AB - The monoamine-based antidepressants that are currently used generate many side effects, and more than 30% of depressed patients do not respond to this therapy. Glutamate-based antidepressants seem to play an important role in therapy for depression, but there is still an extensive search for safe drugs. An antagonist of the glutamatergic NMDA receptor - namely, zinc - plays a part in maintaining homeostasis between glutamate and GABA via the GPR39 receptor, which has been found to be involved in the pathophysiology of depression. In this study we investigated the behavioral response resulting from chronic or acute treatment with monoamine-based antidepressants, such as imipramine, escitalopram or reboxetine, and from glutamate-based MK-801 or ketamine, as measured by the forced swim test (FST) in GPR39 knockout (GPR39 KO, -/-) mice versus wild-type (WT, +/+) controls. All the tested agents reduced the immobility time in the FST in the wild-type animals. However, only chronic or acute administration of MK-801 and ketamine (but not monoamine-based antidepressants) were active in the FST in GPR39 KO mice. Our results show for the first time that GPR39 is required for the antidepressant effect of monoamine-based antidepressants. PMID- 25827930 TI - Monitoring dopamine transmission in the rat nucleus accumbens shell and core during acquisition of nose-poking for sucrose. AB - On the basis of between subjects monitoring of in vivo dopamine (DA) transmission in the rat nucleus accumbens (NAc) shell and core during response-contingent and non-contingent sucrose feeding we have hypothesized that long term, daily exposure to sucrose feeding results in the acquisition of conditioned/discriminative stimuli capable of activating accumbens shell DA transmission in a non-habituating fashion. In order to verify this hypothesis we have now monitored within the same subject the changes in accumbens shell and core DA during acquisition of fixed ratio 1 (FR1) nose-poking for sucrose pellets. Once full training was obtained, dialysate DA was monitored in the same rat on three different sessions: responding for sucrose, extinction and non contingent sucrose presentation. Dialysate DA steadily increased in the shell during operant sessions as training progressed but was activated in the core only early and transiently in training (5th session). After full training, reinforced as well as non-reinforced responding for sucrose activated DA selectively in the NAc shell. Non-contingent sucrose feeding activated DA in the shell and in the core. No habituation of shell DA responsiveness was observed under contingent and non-contingent sucrose feeding. These observations are consistent with the hypothesis that learning of FR1 nose-poking for sucrose involves acquisition of conditioned activation of DA transmission in the shell and active suppression in the core and that loss of habituation of shell DA responsiveness is related to change from primary-rewarding to conditioned/discriminative as driving stimuli of DA transmission in this area. PMID- 25827931 TI - Harmonic and frequency modulated ultrasonic vocalizations reveal differences in conditioned and unconditioned reward processing. AB - Novelty and sensation seeking (NSS) and ultrasonic vocalizations (USVs) are both used as measures of individual differences in reward sensitivity in rodent models. High responders in the inescapable novelty screen have a greater response to low doses of amphetamine and acquire self-administration more rapidly, while the novelty place preference screen is positively correlated with compulsive drug seeking. These screens are uncorrelated and implicated in separate drug abuse models. 50 kHz USVs measure affective state in rats and are evoked by positive stimuli. NSS and USVs are each implicated in drug response, self-administration, and reveal differences in individual behavior, yet their relationship with each other is not understood. The present study screened rats for their response to novelty and measured USVs of all call types in response to heterospecific play to determine the relationships between these individual difference traits. Generally, we hypothesized that 50k Hz USVs would be positively correlated with the NPP screen, and that 22 kHz would be positively correlated with the IEN screen. Results indicate none of the screens were correlated indicating they are measuring different individual difference traits. However, examination of the subtypes of USVs indicated harmonic USVs and the novelty place preference were positively correlated. Harmonic 50 kHz USVs increased in response to reward associated context, suggesting animals conditioned to the heterospecific tickle arena and anticipated rewarding stimuli, while FM only increased in response to tickling. USV subtypes can be used to elucidate differences in attribution of incentive value across conditioned stimuli and receipt of rewarding stimuli. These data provide strong support that harmonic and FM USVs can be used to understand reward processing in addition to NSS. PMID- 25827933 TI - Unique distal size selectivity with a digold catalyst during alkyne homocoupling. AB - Metal-catalysed chemical reactions are often controlled by steric hindrance around the metal atom and it is rare that substituents far away of the reaction site could be differentiated during reaction, particularly if they are simple alkyl groups. Here we show that a gold catalyst is able to discriminate between linear carbon alkynes with 10 or 12 atoms in the chain during the oxidative homocoupling of alkynes: the former is fully reactive and the latter is practically unreactive. We present experimental evidences, which support that the distal size selectivity occurs by the impossibility of transmetallating two long alkyl chains in an A-framed, mixed-valence digold (I, III) acetylide complex. We also show that the reductive elimination of two alkyne molecules from a single Au(III) atom occurs extremely fast, in <1 min at -78 degrees C (turnover frequency>0.016 s(-1)). PMID- 25827934 TI - Correlation between the International Neuroblastoma Pathology Classification and genomic signature in neuroblastoma. AB - The International Neuroblastoma Pathology Classification (INPC) has a prognostic impact that distinguishes two categories of neuroblastoma: favorable histology (FH) and unfavorable histology (UH). We analyzed 92 cases of neuroblastoma with the INPC evaluation and genomic grouping to investigate the correlation between the INPC and genomic signature, together with their prognostic significance. The correlation of UH tumor and partial gains and/or losses (GGP), as well as the correlation of FH tumor and whole gains and/or losses (GGW), was statistically significant. Both UH and GGP were late-onset (median age at diagnosis was 36 and 48 months, respectively) and had poor prognosis (overall survival rate [OS], 43.1% and 42.4%, respectively). In contrast, both FH and GGW were early-onset (median age at diagnosis, 4 and 9.5 months, respectively) and had favorable prognosis (OS, 88.6% and 87.1%, respectively). Unfavorable histology and GGP had significantly inferior OS compared to FH and GGW. Overall survival was not significantly different among the genomic groups in FH; however, it was inferior in UH with GGP. In UH with a single copy MYCN, genomic subgroups GGP2s (both 1p and 11q losses) and GGP3s (partial 11q loss but not 1p loss) indicated significantly poor prognosis compared to GGP4s (no partial 1p and 11q loss). As INPC and MYCN amplification were found to be the most powerful prognostic biological factors, they should be included with genomic grouping as treatment stratification for patients with UH and single copy of MYCN. PMID- 25827935 TI - Social determinants of health in the setting of hypertrophic cardiomyopathy. AB - INTRODUCTION: Social determinants of health play an important role in explaining poor health outcomes across many chronic disease states. The impact of the social gradient in the setting of an inherited heart disease, hypertrophic cardiomyopathy (HCM), has not been investigated. This study sought to profile the socioeconomic status of patients attending a specialized multidisciplinary clinic and to determine the impact on clinical factors, psychosocial wellbeing and adherence to medical advice. METHODS: Patients with HCM and at-risk relatives attending a specialized multidisciplinary clinic in Sydney Australia between 2011 and 2013 were included. Clinical, socioeconomic, geographic remoteness and adherence data were available. A broader clinic and registry-based group completed a survey including psychological wellbeing, health-related quality of life, Morisky Medication Adherence Scale and individual-level socioeconomic information. RESULTS: Over a 3-year period, 486 patients were seen in the specialized clinic. There was an over-representation of patients from socioeconomically advantaged and the least geographically remote areas. Socioeconomic disadvantage was associated with comorbidities, poor psychological wellbeing and health-related quality of life, lower understanding of HCM and more complex clinical management issues such as NYHA class, atrial fibrillation and left ventricular outflow tract obstruction. Approximately 10% of patients were non-adherent to medical advice, and poor medication adherence was seen in 30% of HCM patients with associated factors being younger age, minority ethnicity, anxiety and poor mental quality of life. CONCLUSIONS: Of all the patients attending a specialized cardiac genetic clinic, there is an overrepresentation of patients from very advantaged and major metropolitan areas and suggests that those most in need of a multidisciplinary approach to care are not accessing it. PMID- 25827936 TI - The value of transthoracic echocardiography in the diagnosis of anomalous origin of the right pulmonary artery from the ascending aorta: A single center experience from China. AB - BACKGROUND: Anomalous origin of pulmonary artery (AOPA) from the ascending aorta is a rare but serious congenital cardiac malformation, which frequently involves the right pulmonary artery (RPA). METHODS: We retrospectively analyzed the echocardiographic characteristics of 9 cases with anomalous origin of the right pulmonary artery from the ascending aorta (AORPA) studied from 2007 to 2014 in our institution. The results were compared with the findings at surgery. RESULTS: The corrective surgery was performed in all 9 cases with AORPA. The diagnosis by transthoracic echocardiography (TTE) of 8 cases with AORPA was confirmed at surgery. The coincidence rate for TTE and surgical findings was 88.9%. One case was misdiagnosed as anomalous origin of the left pulmonary artery from the ascending aorta. The anomalous RPA in all cases had a proximal origin from the posterior or lateral part of the ascending aorta in our series. The mean distance from the aortic valve to the site of origin of pulmonary artery was 16.1 +/- 6.6 mm (range: 7.0 mm-24.0 mm). The mean diameter of the anomalous pulmonary artery was 9.6 +/- 4.5 mm (range: 4.5 mm-17.0 mm). In 4 of 9 (44.5%) cases there were associated aortopulmonary septal defect, intact ventricular septum, patent ductus arteriosus and interruption of aortic arch (Type A), also known as the Berry's syndrome. Other associated cardiovascular abnormalities included patent ductus arteriosus, ventricular septal defect and atrial septal defect. Severe pulmonary arterial hypertension was noted in all cases. CONCLUSIONS: TTE plays an important role in the non-invasive and accurate diagnosis of AORPA. TTE can clearly display its site of origin and course, as well as other associated malformations and hemodynamic changes. TTE also plays an important role in the preoperative diagnosis of AORPA. PMID- 25827937 TI - Is low VO2max/kg in obese heart failure patients indicative of cardiac dysfunction? AB - PURPOSE: Low peak O2 consumption (VO2max/kg) has been widely used as an indirect indicator of poor cardiac fitness, and often guides management of patients with severe heart failure (HF). We hypothesized that it should be as good an indicator of cardiac dysfunction in obese and non-obese HF patients. METHODS: We compared the cardiopulmonary exercise performance and non-invasive hemodynamics of 152 obese (BMI>34 kg.m(-2)) and 173 non-obese (BMI<=32) male HF patients in NYHA classes II and III, with reference to 101 healthy male controls. Their physical and cardiac functional reserves were measured during treadmill exercise testing with standard respiratory gas analyses and CO2 rebreathing to measure cardiac output non-invasively during peak exercise. Data are given as mean +/- SD. RESULTS: Obese HF patients with BMI 40.9 +/- 7.5 kg.m(-2) (age 56.1 +/- 14.0 years, NYHA 2.5 +/- 0.5) exercised to acceptable cardiopulmonary limits (peak RER=1.07 +/- 0.12), and achieved a mean VO2max/kg of 18.6 +/- 5.2 ml.kg(-1).min( 1), significantly lower than in non-obese HF counterparts (19.9 +/- 5.6 ml.kg( 1).min(-1), P=0.02, age 55.8 +/- 10.6 years, BMI 26.6 +/- 3.1, NYHA 2.4 +/- 0.5, peak RER=1.07 +/- 0.09), with both lower than controls (38.5 +/- 9.7 ml.kg( 1).min(-1), P<10(-6)). In contrast, the uncorrected VO2max was higher in obese (2.31 +/- 0.69 ml.min(-1)) than non-obese HF patients (1.61 +/- 0.49 ml.min(-1), P<10(-6)). When cardiac dysfunction was evaluated directly, peak cardiac power was significantly greater in obese than non-obese HF patients (4.11 +/- 1.21 W vs 2.73 +/- 0.82 W, P<10(-6)), with both lower than controls (5.42 +/- 1.04 W, P<10( 6)). CONCLUSION: These results demonstrate that VO2max/kg is not a generally reliable indicator of cardiac fitness in all patients. Instead, we found that despite having lower VO2max/kg, obese HF patients had stronger hearts capable of generating greater cardiac power than non-obese HF patients of equivalent clinical HF status. PMID- 25827938 TI - Relation between left ventricular ejection time and pulmonary hemodynamics in pulmonary hypertension. PMID- 25827939 TI - Intra-myocardial hemorrhage in STEMI reperfusion: An alternative explanation for failures from "augmented" fibrinolysis regimes and fibrinolysis-facilitated PCI? PMID- 25827940 TI - Gemella morbillorum tricuspid valve endocarditis resulting in septic pulmonary emboli in a patient with intracranial hemorrhage. PMID- 25827941 TI - Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. AB - BACKGROUND: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low molecular-weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE. METHODS: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12. FINDINGS: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. CONCLUSION: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months. PMID- 25827942 TI - The relationship among computer work, environmental design, and musculoskeletal and visual discomfort: examining the moderating role of supervisory relations and co-worker support. AB - PURPOSE: The prevalence of work-related upper extremity musculoskeletal disorders and visual symptoms reported in the USA has increased dramatically during the past two decades. This study examined the factors of computer use, workspace design, psychosocial factors, and organizational ergonomics resources on musculoskeletal and visual discomfort and their impact on the safety and health of computer work employees. METHODS: A large-scale, cross-sectional survey was administered to a US manufacturing company to investigate these relationships (n = 1259). Associations between these study variables were tested along with moderating effects framed within a conceptual model. RESULTS: Significant relationships were found between computer use and psychosocial factors of co worker support and supervisory relations with visual and musculoskeletal discomfort. Co-worker support was found to be significantly related to reports of eyestrain, headaches, and musculoskeletal discomfort. Supervisor relations partially moderated the relationship between workspace design satisfaction and visual and musculoskeletal discomfort. CONCLUSION: This study provides guidance for developing systematic, preventive measures and recommendations in designing office ergonomics interventions with the goal of reducing musculoskeletal and visual discomfort while enhancing office and computer workers' performance and safety. PMID- 25827943 TI - D-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-kappaB. AB - Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA) initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 +/- 0.56, which was significantly reduced to 5.74 +/- 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-kappaB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above mentioned parameters along with NF-kappaB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis. PMID- 25827945 TI - Tissue-specific metabolic responses of Cyprinus flammans to copper. AB - Copper (Cu) contamination is serious in China, with <=2.76 mg/L in some waters. Exposure to Cu causes a high toxicity to the aquatic organisms and subsequent ecological risk. To understand fish responses to Cu exposure, we analyzed the metabonomic changes in multiple tissues (gill, liver, and muscle) of Cyprinus flammans using an nuclear magnetic resonance-based metabonomic technique. Our results showed that metabolic alterations are dose-dependent. No significant metabolic alterations in three tissues of fish are caused by 0.25 mg/L Cu. However, 1.53 mg/L Cu caused changes of energy-related metabolites and amino acids, which we suggest are due to enhanced metabolic acidosis in gill and muscle, decreased tricarboxylic acid cycle activity in muscle, increased gluconeogenesis from amino acids in liver, and improved glycogenesis in liver and muscle. The Cori cycle between liver and muscle is concurrently triggered. Furthermore, high concentration of Cu resulted in the alteration of choline metabolism such that we hypothesize that Cu induces membrane damage and detoxification of CuSO4 in gill as well as altered osmoregulation in all three tissues. Choline-O-sulfate in gill may be used as a biomarker to provide an early warning of Cu exposure in C. flammans. Moreover, Cu exposure caused alterations of nucleoside and nucleotide metabolism in both gill and muscle. These findings provide a new insight into the metabolic effects of Cu exposure on C. flammans and highlight the value of metabonomics in the study of metabolic metal disturbance in fish. PMID- 25827944 TI - Liver delipidating effect of a combination of resveratrol and quercetin in rats fed an obesogenic diet. AB - Liver steatosis is characterized by an abnormal accumulation of triacylglycerols in this organ. This metabolic disorder is closely associated with obesity. In the present study, we aimed to analyse the effect of a combination of resveratrol and quercetin on liver steatosis in an animal model of dietetic obesity, and to compare it with one induced by the administration of each polyphenol separately. Rats were divided into four dietary groups of nine animals each and fed a high fat, high-sucrose diet: an untreated control group and three groups treated either with resveratrol (RSV; 15 mg/kg/day), with quercetin (Q; 30 mg/kg/day), or with both (RSV + Q; 15 mg resveratrol/kg/day and 30 mg quercetin/kg/day) for 6 weeks. Liver weight and triacylglycerol content decreased only in the RSV + Q group. A significant reduction in acetyl-CoA carboxylase activity was observed in RSV and RSV + Q groups, without changes in fatty acid synthase activity. A significant increase in carnitine palmitoyltransferase-1a activity was observed only in rats treated with the combination of resveratrol and quercetin, suggesting increased fatty acid oxidation. Citrate synthase, a marker of mitochondrial density, remained unchanged in all groups. No significant changes were observed in the expression of peroxisome proliferator-activated receptor alpha (PPARalpha), nuclear respiratory factor 1 (NRF-1) and transcription factor A mitochondrial (TFAM). In conclusion, resveratrol and quercetin together, combining two doses which were shown to be ineffective singly, is an interesting tool to prevent liver steatosis associated with high-fat high-sucrose feeding. The delipidating effect seems to be mediated by increased fatty acid oxidation not associated with increased mitochondriogenesis, and by reduced de novo lipogenesis. PMID- 25827946 TI - The importance of the beta spectrum calculation for accurate activity determination of 63Ni by means of liquid scintillation counting. AB - The activity concentration of a (63)Ni solution was determined by means of two liquid scintillation counting techniques: the TDCR method and the CIEMAT/NIST efficiency tracing technique. The results of both methods are in excellent agreement, provided that the (63)Ni beta spectrum calculation accounts for the atomic exchange effect. Thus, new beta spectrum calculations resolve a discrepancy that has been found in previous analyses. The influence of the computed beta spectrum on the final uncertainty of the activity concentration is discussed. PMID- 25827947 TI - Convenient recycling and reuse of bombarded [18O]H2O for the production and the application of [18F]F-. AB - The limited availability and the increasing demands of [(18)O]H2O force the reuse of bombarded [(18)O]H2O for the production of [(18)F]F(-) at least for the purposes of research. Therefore, inorganic and organic contaminants have to be removed from the [(18)O]H2O after bombardment. We present a simple, effective, easy-handling and reliable method of [(18)O]H2O purification including oxidation and distillation. The obtained recycled [(18)O]H2O had comparable quality to commercially distributed [(18)O]water. This was confirmed by a detailed comparison of produced radionuclides and their activities and the application of [(18)F]F(-) for the automated synthesis of [(18)F]fluspidine. PMID- 25827948 TI - Melanin biosynthesis inhibitory activity of a compound isolated from young green barley (Hordeum vulgare L.) in B16 melanoma cells. AB - In the course to find compounds that inhibit melanin biosynthesis (i.e., whitening agents), we evaluated the effects of the methanol-soluble fraction (i.e., the water-soluble portion of methanol extracts-CHP20P-MeOH eluted fraction) from young green barley leaves on melanin production in B16 melanoma cells. Activity-guided fractionation led to an isolate called tricin (compound 1) as an inhibitory compound of melanin production in B16 melanoma cells. Furthermore, tricin analogs such as tricetin, tricetin trimethyl ether, luteolin, and apigenin were used for analyzing the structure-activity relationships (SAR) of 5,7-dihydroxyflavones studies. Tricin demonstrated stronger inhibitory activity compared to three other compounds. The results suggest that a hydroxyl group at the C-4' position and methoxy groups at the C-3',5' positions of the tricin skeleton may have important roles in this inhibitory activity in B16 melanoma cells. Our results suggest that tricin inhibits melanin biosynthesis with higher efficacy than arbutin, and it could be used as a whitening agent. PMID- 25827950 TI - Myiasis in Travelers. AB - BACKGROUND: Cutaneous myiasis is a well-established diagnosis in returning travelers from tropical countries. The most common form of myiasis seen in this population is localized furuncular myiasis caused by Dermatobia hominis and Cordylobia anthropophaga. There are limited data on the disease course and outcome in travelers to tropical countries. METHODS: A retrospective observational study of patients who presented with myiasis was conducted between 1999 and July 2014 in the post-travel clinics in Israel. Data regarding exposure history, travel duration, clinical presentation, treatment, and parasitological identification were collected and analyzed. RESULTS: Among 6,867 ill returning Israeli travelers, 1,419 (21%) had a dermatologic complaint, 90 (6.3%) of them were diagnosed with myiasis. Myiasis was acquired in Latin America by 72 (80%) patients, mainly (54%) in the Madidi National Park, Amazonas Basin, Bolivia; 18 cases (20%) were acquired in Africa. In 76% of cases, manual extraction was sufficient to remove the larva; 24% required surgical intervention. Despite the fact that most patients did not receive antibiotic treatment, only one developed secondary infection, upon partial removal of the larva. CONCLUSIONS: This is the largest myiasis case series in ill returning travelers. Myiasis is not a rare dermatologic complaint with most Israeli cases imported from Latin America and specifically the Madidi National Park in Bolivia. Treatment is based on full extraction of the larva after which no antibiotic treatment is needed. Myiasis is a preventable disease and travelers should be informed of the different preventive measures according to their travel destination. PMID- 25827949 TI - Genome-wide association study identifies new susceptibility loci for cutaneous lupus erythematosus. AB - Cutaneous lupus erythematosus (CLE) is a chronic autoimmune disease of the skin with typical clinical manifestations. Here, we genotyped 906 600 single nucleotide polymorphisms (SNPs) in 183 CLE cases and 1288 controls of Central European ancestry. Replication was performed for 13 SNPs in 219 case subjects and 262 controls from Finland. Association was particularly pronounced at 4 loci, all with genomewide significance (P < 5 * 10(-8) ): rs2187668 (PGWAS = 1.4 * 10(-12) ), rs9267531 (PGWAS = 4.7 * 10(-10) ), rs4410767 (PGWAS = 1.0 * 10(-9) ) and rs3094084 (PGWAS = 1.1 * 10(-9) ). All mentioned SNPs are located within the major histocompatibility complex (MHC) region of chromosome 6 and near genes of known immune functions or associations with other autoimmune diseases such as HLA DQ alpha chain 1 (HLA-DQA1), MICA, MICB, MSH5, TRIM39 and RPP21. For example, TRIM39/RPP21 read through transcript is a known mediator of the interferon response, a central pathway involved in the pathogenesis of CLE and systemic lupus erythematosus (SLE). Taken together, this genomewide analysis of disease association of CLE identified candidate genes and genomic regions that may contribute to pathogenic mechanisms in CLE via dysregulated antigen presentation (HLA-DQA1), apoptosis regulation, RNA processing and interferon response (MICA, MICB, MSH5, TRIM39 and RPP21). PMID- 25827951 TI - Pyoderma gangrenosum of the penis possibly associated with pazopanib treatment. PMID- 25827953 TI - Iron for proliferation of cell lines and hematopoietic progenitors: Nailing down the intracellular functional iron concentration. AB - Iron is an essential nutrient which must be provided in sufficient amounts to support growth of eukaryotic cells. All organisms devote specialized pathways to ensure proper delivery. Yet, a quantitative assessment of the intra-cellular iron concentration needed to allow the cell cycle to proceed in mammalian cells is missing. Starting from iron-depleted cell lines or primary hematopoietic progenitors prepared with clinically implemented iron chelators, replenishment via transferrin and other iron sources has been quantitatively monitored through the main endogenous markers of the cellular iron status, namely proteins involved in the uptake (transferrin receptor), the storage (ferritin), and the sensing (Iron Regulatory Proteins) of iron. When correlated with measurements of iron concentrations and indicators of growth, this minimally intrusive approach provided an unprecedented estimate of the intracellular iron concentration acting upon iron-centered regulatory pathways. The data were analyzed with the help of a previously developed theoretical treatment of cellular iron regulation. The minimal cellular iron concentration required for cell division was named functional iron concentration (FIC) to distinguish it from previous estimates of the cellular labile iron. The FIC falls in the low nanomolar range for all studied cells, including hematopoietic progenitors. These data shed new light on basic aspects of cellular iron homeostasis by demonstrating that sensing and regulation of iron occur well below the concentrations requiring storage or becoming noxious in pathological conditions. The quantitative assessment provided here is relevant for monitoring treatments of conditions in which iron provision must be controlled to avoid unwanted cellular proliferation. PMID- 25827954 TI - PKC theta and p38 MAPK activate the EBV lytic cycle through autophagy induction. AB - PKC activation by combining TPA with sodium butyrate (T/B) represents the most effective and widely used strategy to induce the Epstein-Barr virus (EBV) lytic cycle. The results obtained in this study show that novel PKCtheta is involved in such process and that it acts through the activation of p38 MAPK and autophagy induction. Autophagy, a mechanism of cellular defense in stressful conditions, is manipulated by EBV to enhance viral replication. Besides promoting the EBV lytic cycle, the activation of p38 and autophagy resulted in a pro-survival effect, as indicated by p38 or ATG5 knocking down experiments. However, this pro-survival role was counteracted by a pro-death activity of PKCtheta, due to the dephosphorylation of AKT. In conclusion, this study reports, for the first time, that T/B activates a PKCtheta-p38 MAPK axis in EBV infected B cells, that promotes the viral lytic cycle and cell survival and dephosphorylates AKT, balancing cell life and cell death. PMID- 25827955 TI - Rotenone inhibits primary murine myotube formation via Raf-1 and ROCK2. AB - Rotenone (ROT) is a widely used inhibitor of complex I (CI), the first complex of the mitochondrial oxidative phosphorylation (OXPHOS) system. However, particularly at high concentrations ROT was also described to display off-target effects. Here we studied how ROT affected in vitro primary murine myotube formation. We demonstrate that myotube formation is specifically inhibited by ROT (10-100nM), but not by piericidin A (PA; 100nM), another CI inhibitor. At 100nM, both ROT and PA fully blocked myoblast oxygen consumption. Knock-down of Rho associated, coiled-coil containing protein kinase 2 (ROCK2) and, to a lesser extent ROCK1, prevented the ROT-induced inhibition of myotube formation. Moreover, the latter was reversed by inhibiting Raf-1 activity. In contrast, ROT induced inhibition of myotube formation was not prevented by knock-down of RhoA. Taken together, our results support a model in which ROT reduces primary myotube formation independent of its inhibitory effect on CI-driven mitochondrial ATP production, but via a mechanism primarily involving the Raf-1/ROCK2 pathway. PMID- 25827957 TI - Oxytocin-induced coping with stressful life events in old age depends on attachment: findings from the cross-sectional KORA Age study. AB - BACKGROUND: Whether oxytocin functions as a stress hormone in older age is unknown. We investigated oxytocin levels and the perceived stress of an adverse life event in an older population-representative sample and considered the effect of a secure/insecure attachment style on this association. METHODS: Non-fasting plasma oxytocin was measured from 952 participants (65-90 years) of the cross sectional KORA-Age study. The psychological impact of an adverse life event was assessed based on the Psychosocial Stress Questionnaire. Attachment style was determined by the Relationship-Specific Attachment Scales for Adults. Linear regression models of oxytocin, stratified for attachment style, were controlled for age, sex, and further for alcohol, smoking, and physical activity. Adjusted least squares means of oxytocin were calculated. RESULTS: Oxytocin levels did not differ between men and women (mean, 95% confidence interval (CI), 321 (277-365) and 309 (272-345)pg/ml, respectively). Oxytocin levels were positively associated with the experience of an adverse event (n=273, 29%) versus no event (n=679, 71%), in securely attached (beta estimate=0.17, standard error (SE)=0.08, P value=0.03) but not in insecure participants (-0.10, 0.09), P=0.28). Oxytocin was positively associated with diminished stress among securely attached participant (event with little suffering: beta=0.35. SE=0.12, great suffering: beta=0.15. SE=0.14, severe suffering: beta=0.03. SE=0.12). Among participants who reported minimal suffering, insecure individuals had lower oxytocin (adjusted mean, 95%CI: 172, 127-216 pg/ml) than securely attached individuals (279, 222-352 pg/ml, P=0.006). CONCLUSIONS: These epidemiologic data support the hypothesis that oxytocin may have an attenuating effect on perceived stress due to adverse life events in old age. The conditional role of attachment style in stress-induced endogenous oxytocin production is highlighted. PMID- 25827958 TI - Increase systemic levels of IL-23 as a possible constitutive marker in schizophrenia. AB - Inflammation appears to play significant role in schizophrenia. IL-23 is key molecule in mediating IL-17 dependent inflammatory response. Therefore, we analyzed the serum concentrations of IL-23 levels in patients with first episode psychosis (78 subjects), in patients with acute exacerbation of schizophrenia who were already treated with antipsychotics (47 subjects) and healthy controls (35 subjects). Diagnoses were established using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Psychopathology was evaluated using the Positive and Negative Syndrome Scale (PANSS) and serum levels of IL-23 were measured using sensitive enzyme-linked immunosorbent assay (ELISA). Serum levels of IL-23 were higher in patients with first psychotic episode and in patients with schizophrenia in relapse than in healthy subjects (p=0.000) and no difference was established between these two groups of patients before therapy. Also, after 4 weeks of antipsychotic therapy levels of IL-23 remains elevated in both groups of patients with no differences between two groups. It appears that increased level of IL-23 in psychotic patients independently of antipsychotic therapy can be a constitutive marker in this disorder. PMID- 25827952 TI - Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment. AB - Bcl-2, the founding member of a family of apoptotic regulators, was initially identified as the protein product of a gene that is translocated and overexpressed in greater than 85% of follicular lymphomas (FLs). Thirty years later we now understand that anti-apoptotic Bcl-2 family members modulate the intrinsic apoptotic pathway by binding and neutralizing the mitochondrial permeabilizers Bax and Bak as well as a variety of pro-apoptotic proteins, including the cellular stress sensors Bim, Bid, Puma, Bad, Bmf and Noxa. Despite extensive investigation of all of these proteins, important questions remain. For example, how Bax and Bak breach the outer mitochondrial membrane remains poorly understood. Likewise, how the functions of anti-apoptotic Bcl-2 family members such as eponymous Bcl-2 are affected by phosphorylation or cancer-associated mutations has been incompletely defined. Finally, whether Bcl-2 family members can be successfully targeted for therapeutic advantage is only now being investigated in the clinic. Here we review recent advances in understanding Bcl-2 family biology and biochemistry that begin to address these questions. PMID- 25827959 TI - Anterior cingulate cortex gray matter volume mediates an association between 2D:4D ratio and trait aggression in women but not men. AB - Previous research demonstrates that prenatal testosterone exposure increases aggression, possibly through its effects on the structure and function of neural circuits supporting threat detection and emotion regulation. Here we examined associations between regional gray matter volume, trait aggression, and the ratio of the second and fourth digit of the hand (2D:4D ratio) as a putative index of prenatal testosterone exposure in 464 healthy young adult volunteers. Our analyses revealed a significant positive correlation between 2D:4D ratio and gray matter volume of the dorsal anterior cingulate cortex (dACC), a brain region supporting emotion regulation, conflict monitoring, and behavioral inhibition. Subsequent analyses demonstrated that reduced (i.e., masculinized) gray matter volume in the dACC mediated the relationship between 2D:4D ratio and aggression in women, but not men. Expanding on this gender-specific mediation, additional analyses demonstrated that the shared variance between 2D:4D ratio, dACC gray matter volume, and aggression in women reflected the tendency to engage in cognitive reappraisal of emotionally provocative stimuli. Our results provide novel evidence that 2D:4D ratio is associated with masculinization of dACC gray matter volume, and that this neural phenotype mediates, in part, the expression of trait aggression in women. PMID- 25827960 TI - Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial. AB - Long-term opioid therapy has been associated with low cortisol levels due to central suppression of the hypothalamic-pituitary-adrenal axis. The implications of hypocortisolism on wellbeing have not been established. Our aim was to determine whether intervention with physiologic glucocorticoid replacement therapy improves wellbeing and analgesic responses in patients with chronic non cancer pain on long-term opioid therapy with mild cortisol deficiency. We performed a pilot randomized, double-blind, placebo-controlled crossover study of oral hydrocortisone replacement therapy in 17 patients recruited from a Pain Clinic at a single tertiary center in Adelaide, Australia. Patients were receiving long-term opioid therapy (>= 20 mg morphine equivalents per day for >= 4 weeks) for chronic non-cancer pain with mild hypocortisolism, as defined by a plasma cortisol response <= 350 nmol/L at 60 min following a cold pressor test. The crossover intervention included 28-day treatment with either 10mg/m(2)/day of oral hydrocortisone in three divided doses or placebo. Improvement in wellbeing was assessed using Version 2 of the Short Form-36 (SF-36v2), Brief Pain Inventory Short Form, and Addison's disease quality of life questionnaires; improvement in analgesic response was assessed using cold pressor threshold and tolerance times. Following treatment with hydrocortisone, the bodily pain (P=0.042) and vitality (P=0.013) subscales of the SF-36v2 were significantly better than scores following treatment with placebo. There was also an improvement in pain interference on general activity (P=0.035), mood (P=0.03) and work (P=0.04) following hydrocortisone compared with placebo. This is the first randomized, double-blind placebo-controlled trial of glucocorticoid replacement in opioid users with chronic non-cancer pain and mild hypocortisolism. Our data suggest that physiologic hydrocortisone replacement produces improvements in vitality and pain experiences in this cohort compared with placebo. TRIAL REGISTRATION: Therapeutic Goods Administration Clinical Trials Notification Scheme (Drugs), Trial Number 2012/0476. PMID- 25827961 TI - Sexually dimorphic adaptations in basal maternal stress physiology during pregnancy and implications for fetal development. AB - There is clear evidence of reciprocal exchange of information between the mother and fetus during pregnancy but the majority of research in this area has focussed on the fetus as a recipient of signals from the mother. Specifically, physiological signals produced by the maternal stress systems in response to the environment may carry valuable information about the state of the external world. Prenatal stress produces sex-specific adaptations within fetal physiology that have pervasive and long-lasting effects on development. Little is known, however, about the effects of sex-specific fetal signals on maternal adaptations to pregnancy. The current prospective study examined sexually dimorphic adaptations within maternal stress physiology, including the hypothalamic-adrenal-pituitary (HPA) axis and the autonomic nervous system (ANS) and associations with fetal growth. Using diurnal suites of saliva collected in early and late pregnancy, we demonstrate that basal cortisol and salivary alpha-amylase (sAA) differ by fetal sex. Women carrying female fetuses displayed greater autonomic arousal and flatter (but more elevated) diurnal cortisol patterns compared to women carrying males. Women with flatter daytime cortisol trajectories and more blunted sAA awakening responses also had infants with lower birth weight. These maternal adaptations are consistent with sexually dimorphic fetal developmental/evolutionary adaptation strategies that favor growth for males and conservation of resources for females. The findings provide new evidence to suggest that the fetus contributes to maternal HPA axis and ANS regulation during pregnancy and that these systems also contribute to the regulation of fetal growth. PMID- 25827962 TI - Plasma adiponectin levels in schizophrenia and role of second-generation antipsychotics: a meta-analysis. AB - BACKGROUND: People with schizophrenia are more likely than general population to suffer from metabolic abnormalities, with second-generation antipsychotics (SGAs) increasing the risk. Low plasma adiponectin levels may lead to metabolic dysregulations but evidence in people with schizophrenia, especially for the role of SGAs, is still inconclusive. OBJECTIVE: To compare plasma adiponectin levels between people with schizophrenia and healthy controls, and to estimate the relative effect of schizophrenia and SGAs on adiponectin. METHODS: We performed a systematic review and meta-analysis of observational studies published up to 13 June 2014 in main electronic databases. Pooled standardized mean differences (SMDs) between index and control groups were generated. Appropriate subanalyses and additional subgroup analyses were carried out. RESULTS: Data from 2735 individuals, 1013 with and 1722 without schizophrenia, respectively, were analysed. Schizophrenia was not associated with lower adiponectin levels (SMD of 0.28, 95%CI: -0.59, 0.04; p=0.09). However, individuals with schizophrenia taking SGAs had plasma levels significantly lower than controls (p=0.002), which was not the case of drug free/drug naive subjects (p=0.52). As regards single antipsychotic drugs clozapine (p<0.001) and olanzapine (p=0.04)--but not risperidone (p=0.88)--were associated with adiponectin levels lower than controls. CONCLUSIONS: People with schizophrenia per se may not have levels of adiponectin lower than controls, though treatment with SGAs is associated with this metabolic abnormality. This bears clinical significance because of hypoadiponectinemia involvement in cardiovascular diseases, even if mechanisms whereby SGAs affect adiponectin remain unexplained. Longitudinal studies evaluating long-term effects of SGAs on adiponectin are needed. PMID- 25827963 TI - Integration of neural networks activated by amphetamine in females with different estrogen levels: a functional imaging study in awake rats. AB - Previous studies demonstrate that schizophrenia symptomatology in women is dependent upon estrogen levels. Estrogen has beneficial properties when administered in conjunction with antipsychotics, and estrogen also alters, in rats, dopamine neurotransmission, which is a common target of all antipsychotic medications, suggesting a possible interaction between the two. The aim of the current study was to investigate this possible interaction using functional magnetic resonance imaging in awake, female rats. Amphetamine-sensitized, ovariectomized rats receiving no, chronic low, or phasic high levels of estradiol replacement were used, and changes in blood-oxygen-level-dependent (BOLD) signal were recorded over time in response to an acute amphetamine injection. Increasing levels of estradiol enhanced BOLD activation in pathways previously known to be implicated in schizophrenia symptomatology, such as the mesocorticolimbic, habenular and olfactory pathways, as well as more widespread areas. We propose here the first comprehensive "amphetamine activation map" integrating brain regions where amphetamine-related BOLD activity is influenced by estrogen levels in sensitized female rats. PMID- 25827964 TI - In vivo evaluation of biomimetic fluorosurfactant polymer-coated expanded polytetrafluoroethylene vascular grafts in a porcine carotid artery bypass model. AB - OBJECTIVE: The objective of this study was to evaluate the potential for biomimetic self-assembling fluorosurfactant polymer (FSP) coatings incorporating heptamaltose (M7-FSP) to block nonspecific protein adsorption, the cell adhesive RGD peptide (RGD-FSP), or the endothelial cell-selective CRRETAWAC peptide (cRRE FSP) to improve patency and endothelialization in small-diameter expanded polytetrafluoroethylene (ePTFE) vascular graft implants. METHODS: ePTFE vascular grafts (4 mm in diameter, 5 cm in length) were coated with M7-FSP, RGD-FSP, or cRRE-FSP by dissolving FSPs in distilled water and flowing solution through the graft lumen for 24 hours. Coatings were confirmed by receding water contact angle measurements on the lumen surface. RGD-FSP and cRRE-FSP grafts were presodded in vitro with porcine pulmonary artery endothelial cells (PPAECs) using a custom designed flow system. PPAEC coverage on the lumen surface was visualized with epifluorescent microscopy and quantified. Grafts were implanted as carotid artery interposition bypass grafts in seven pigs for 33 +/- 2 days (ePTFE, n = 3; M7 FSP, n = 4; RGD-FSP, n = 3; cRRE-FSP, n = 4). Patency was confirmed immediately after implantation with duplex color flow ultrasound and at explantation with contrast-enhanced angiography. Grafts were sectioned for histology and stained: Movat pentachrome stain to outline vascular layers, immunofluorescent staining to identify endothelial cells (anti-von Willebrand factor antibody), and immunohistochemical staining to identify smooth muscle cells (anti-smooth muscle alpha-actin antibody). Neointima to lumen area ratio was determined to evaluate neointimal hyperplasia. RESULTS: Receding water contact angle measurements on graft luminal surfaces were significantly lower (P < .05) on FSP-coated ePTFE surfaces (M7-FSP, 40 +/- 16 degrees; RGD-FSP, 25 +/- 10 degrees; cRRE-FSP, 33 +/- 16 degrees) compared with uncoated ePTFE (126 +/- 2 degrees), confirming presence of the FSP layer. In vitro sodding of PPAECs on RGD-FSP and cRRE-FSP grafts resulted in a confluent monolayer of PPAECs on the luminal surface, with a similar cell population on RGD-FSP (1200 +/- 187 cells/mm(2)) and cRRE-FSP (1134 +/- 153 cells/mm(2)) grafts. All grafts were patent immediately after implantation, and one of three uncoated, two of three RGD-FSP, two of four M7 FSP, and two of four cRRE-FSP grafts remained patent after 1 month. PPAEC coverage of the lumen surface was seen in all patent grafts. RGD-FSP grafts had a slightly higher neointima to lumen area ratio (0.53 +/- 0.06) compared with uncoated (0.29 +/- 0.15), M7-FSP (0.20 +/- 0.15), or cRRE-FSP (0.17 +/- 0.09) grafts. CONCLUSIONS: Biomimetic FSP-coated ePTFE grafts can be used successfully in vivo and have potential to support endothelialization. Grafts modified with the M7-FSP and cRRE-FSP showed lower intimal hyperplasia compared with RGD-FSP grafts. PMID- 25827965 TI - Rates and predictors of readmission after minor lower extremity amputations. AB - OBJECTIVE: One goal of the Patient Protection and Affordable Care Act is to reduce hospital readmissions, with financial penalties applied for excessive rates of unplanned readmissions within 30 days among Medicare beneficiaries. Recent data indicate that as many as 24% of Medicare patients require readmission after vascular surgery, although the rate of readmission after limited digital amputations has not been specifically examined. The present study was therefore undertaken to define the rate of unplanned readmission among patients after digital amputations and to identify the factors associated with these readmissions to allow the clinician to implement strategies to reduce readmission rates in the future. METHODS: The electronic medical and billing records of all patients undergoing minor amputations (defined as toe or transmetatarsal amputations using International Classification of Diseases, Ninth Revision, codes) from January 2000 through July 2012 were retrospectively reviewed. Data were collected for procedure- and hospital-related variables, level of amputation, length of stay, time to readmission, and level of reamputation. Patient demographics included hypertension, diabetes, hyperlipidemia, smoking history, and history of myocardial infarction, congestive heart failure, peripheral arterial disease, chronic obstructive pulmonary disease, and cerebrovascular accident. RESULTS: Minor amputations were performed in 717 patients (62.2% male), including toe amputations in 565 (72.8%) and transmetatarsal amputations in 152 (19.5%). Readmission occurred in 100 patients (13.9%), including 28 (3.9%) within 30 days, 28 (3.9%) between 30 and 60 days, and 44 (6.1%) >60 days after the index amputation. Multivariable analysis revealed that elective admission (P < .001), peripheral arterial disease (P < .001), and chronic renal insufficiency (P = .001) were associated with readmission. The reasons for readmission were infection (49%), ischemia (29%), nonhealing wound (19%), and indeterminate (4%). Reamputation occurred in 95 (95%) of the readmitted patients, including limb amputation in 64 (64%) of the patients (below knee in 58, through knee in 2, and above knee in 4). CONCLUSIONS: Readmission after minor amputation was associated with limb amputation in the majority of cases. This study identified a number of nonmodifiable patient factors that are associated with an increased risk of readmission. Whereas efforts to reduce unplanned hospital readmissions are laudable, payers and regulators should consider these observations in defining unacceptable rates of readmission. Further, although beyond the scope of this study, it is not unreasonable to assume that pressure to reduce readmission rates in the population of patients with extensive comorbidity may induce practitioners to undertake amputation at a higher level initially to minimize the risk of readmission for reamputation and associated financial penalties and thus deprive the patient the chance for limb salvage. PMID- 25827967 TI - Risk factors for spinal cord ischemia after endovascular repair of thoracoabdominal aortic aneurysms. AB - OBJECTIVE: The introduction of fenestrated and multibranched endografting transformed the treatment paradigm of patients with thoracoabdominal aortic aneurysms (TAAAs). However, despite the minimally invasive character of the procedure, spinal cord ischemia (SCI) remains a devastating complication. The aim of this study was to address the SCI rates after endovascular TAAA repair and to analyze potential risk factors leading to this complication. METHODS: A consecutive cohort of patients with nonruptured TAAAs treated by means of fenestrated and multibranched endografting between January 2010 and September 2014 was analyzed. Neurologic examination was routinely performed by an independent neurologist before operation and at discharge. The main outcome measure was the onset of SCI (paraplegia or paraparesis). Secondary outcomes were neurologic complications associated with cerebrospinal fluid drainage (CSFD) and 30-day mortality. Finally, a multivariate regression analysis identified risk factors for SCI. RESULTS: A consecutive 142 patients with TAAAs (Crawford type II, n = 54 [38%]; type III, n = 76 [54%]; type IV, n = 12 [8%]) were included in this study. The majority of patients (n = 129 [91%]) were treated for an atherosclerotic aneurysm, whereas 13 patients (9%) were treated for a postdissection aneurysm. The mean maximal aortic diameter was 65 +/- 13 mm. SCI developed in 23 patients (16%; paraplegia in 12 [8%] and paraparesis in 11 [8%]). Of these 23 patients, 10 patients (43%) showed the neurologic deficit directly after the procedure, 11 patients (48%) in the first 24 hours, and 2 patients (9%) after 24 hours. There was an improvement of the neurologic status in the majority of patients, with only three patients (2%) showing irreversible paraplegia at discharge. There was no difference in the 30-day mortality between patients with and without SCI (no SCI, n = 3 [3%] vs SCI, n = 1 [4%]; P = .511). Prophylactic use of CSFD before the procedure was performed in 64 patients (45%), and among them, 4 patients (6%) developed a CSFD-associated complication. No clinical benefit for patients receiving prophylactic placement of CSFD was found (P = .498). The multivariate analysis revealed the percentage of thoracic aortic coverage as the only significant risk factor for SCI (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .001). CONCLUSIONS: The SCI rate after endovascular repair of TAAA was 16%, with 8% of those patients suffering from paraplegia. Prophylactic use of CSFD could not reduce the SCI rate and was associated with 6% adverse events. The percentage of thoracic aortic coverage was the most powerful determinant of SCI in these series. PMID- 25827966 TI - Digital pressure and oxygen saturation measurements in the diagnosis of chronic hemodialysis access-induced distal ischemia. AB - OBJECTIVE: Hemodialysis access-induced distal ischemia (HAIDI) can be classified as acute (on the first postoperative day), subacute (<=1 month), or chronic (>1 month), based on the time of onset after access creation. The diagnosis is mainly clinical. However, performing additional tests is beneficial in further assessment of patients. The purpose of this study was to evaluate the use of finger pressure and oxygen saturation measurements for the diagnosis of chronic HAIDI. METHODS: A total of 20 patients with chronic HAIDI (cases) and 40 asymptomatic hemodialysis patients (controls) were matched for age, sex, etiology of end-stage renal disease, and type of arteriovenous access. Basal digital pressure (BDP), digital pressure during manual compression of access, digital brachial index (DBI), change in digital pressure with access compression (CDP), digital pressure of the contralateral side, and bilateral oxygen saturation (O2 Sat) were measured in all patients. RESULTS: In the case group, compression of the arteriovenous fistula (AVF) increased mean BDP from 61 +/- 26 to 118 +/- 28 mm Hg (P < .001), which failed to reach the non-AVF side mean digital pressure of 151 +/- 25 mm Hg (P < .001). In addition, O2 Sat of the AVF side was significantly lower than the contralateral side (92.9% +/- 2.1% vs 95.6% +/- 1.4%; P = .001). Among the controls, manual AVF compression raised the mean BDP from 114 +/- 36 mm Hg to 133 +/- 29 mm Hg (P < .001), which was still significantly lower than the contralateral side mean digital pressure of 141 +/- 30 mm Hg (P = .002). In addition, O2 Sat values of the two sides were different (96.7% +/- 2.1% vs 97.1% +/- 1.9%; P = .01). Comparing the cases and controls, the mean BDP (61 +/- 26 mm Hg vs 114 +/- 36 mm Hg; P < .001), DBI (0.44 +/- 0.16 vs 0.82 +/- 0.19; P < .001), and O2 Sat (92.9% +/- 2.1% vs 96.7% +/- 2.1%; P < .001) were significantly lower and CDP (57 +/- 24 mm Hg vs 19 +/- 17 mm Hg; P < .001) was significantly higher in the cases than in the controls. The optimal discriminatory thresholds of 80 mm Hg for BDP, 0.7 for DBI, 40 mm Hg for CDP, and 94% for O2 Sat were determined. CONCLUSIONS: Digital pressure and O2 Sat measurements are useful additional methods to assist in the clinical evaluation of hemodialysis patients with access-related hand ischemia. BDP <80 mm Hg, DBI <0.7, CDP >40 mm Hg, and O2 Sat <94% are associated with chronic HAIDI. PMID- 25827968 TI - Cost-effectiveness of endovascular repair, open repair, and conservative management of splenic artery aneurysms. AB - OBJECTIVE: Open repair (OPEN) and conservative management (CONS) have been the treatments of choice for splenic artery aneurysms (SAAs) for many years. Endovascular repair (EV) has been increasingly used with good short-term results. In this study, we evaluated the cost-effectiveness of OPEN, EV, and CONS for the treatment of SAAs. METHODS: A decision analysis model was developed using TreeAge Pro 2013 software (TreeAge Inc, Williamstown, Mass) to evaluate the cost effectiveness of the different treatments for SAAs. A hypothetical cohort of 10,000 55-year-old female patients with SAAs was assessed in the reference-case analysis. Perioperative mortality, disease-specific mortality rates, complications, rupture risks, and reinterventions were retrieved from a recent and extensive meta-analysis. Costs were analyzed with the 2014 Medicare database. The willingness to pay was set to $60,000/quality-adjusted life years (QALYs). Outcomes evaluated were QALYs, costs from the health care perspective, and the incremental cost-effectiveness ratio (ICER). Extensive sensitivity analyses were performed and different clinical scenarios evaluated. Probabilistic sensitivity analysis was performed to include the uncertainty around the variables. A flowchart for clinical decision-making was developed. RESULTS: For a 55-year-old female patient with a SAA, EV has the highest QALYs (11.32; 95% credibility interval [CI], 9.52-13.17), followed by OPEN (10.48; 95% CI, 8.75-12.25) and CONS (10.39; 95% CI, 8.96-11.87). The difference in effect for 55-year-old female patients between EV and OPEN is 0.84 QALY (95% CI, 0.42-1.34), comparable with 10 months in perfect health. EV is more effective and less costly than OPEN and more effective and more expensive compared with CONS, with an ICER of $17,154/QALY. Moreover, OPEN, with an ICER of $223,166/QALY, is not cost-effective compared with CONS. In elderly individuals (age >78 years), the ICER of EV vs CONS is $60,503/QALY and increases further with age, making EV no longer cost-effective. Very elderly patients (age >93 years) have higher QALYs and lower costs when treated with CONS. The EV group has the highest number of expected reinterventions, followed by CONS and OPEN, and the number of expected reinterventions decreases with age. CONCLUSIONS: EV is the most cost-effective treatment for most patient groups with SAAs, independent of the sex and risk profile of the patient. EV is superior to OPEN, being both cost-saving and more effective in all age groups. Elderly patients should be considered for CONS, based on the high costs in relation to the very small gain in health when treated with EV. The very elderly should be treated with CONS. PMID- 25827969 TI - Percutaneous versus femoral cutdown access for endovascular aneurysm repair. AB - OBJECTIVE: Prior studies suggest that percutaneous access for endovascular abdominal aortic aneurysm repair (pEVAR) offers significant operative and postoperative benefits compared with femoral cutdown (cEVAR). National data on this topic, however, are limited. We compared patient selection and outcomes for elective pEVAR and cEVAR. METHODS: We identified all patients undergoing either pEVAR (bilateral percutaneous access, whether successful or not) or cEVAR (at least one planned groin cutdown) for abdominal aortic aneurysms from January 2011 to December 2013 in the Targeted Vascular data set from the American College of Surgeons National Surgical Quality Improvement Program database. Emergent cases, ruptures, cases with an iliac conduit, and cases with a preoperative wound infection were excluded. Groups were compared by chi(2) test or t-test or the Mann-Whitney test where appropriate. RESULTS: We identified 4112 patients undergoing elective EVAR, 3004 cEVAR patients (73%) and 1108 pEVAR patients (27%). Of all EVAR patients, 26% had bilateral percutaneous access; 1.0% had attempted percutaneous access converted to cutdown (4% of pEVARs); and the remainder had a planned cutdown, 63.9% bilateral and 9.1% unilateral. There were no significant differences in age, gender, aneurysm diameter, or prior open abdominal surgery. Patients undergoing cEVAR were less likely to have congestive heart failure (1.5% vs 2.4%; P = .04) but more likely to undergo any concomitant procedure during surgery (32% vs 26%; P < .01) than patients undergoing pEVAR. Postoperatively, pEVAR patients had shorter operative time (mean, 135 vs 152 minutes; P < .01), shorter length of stay (median, 1 day vs 2 days; P < .01), and fewer wound complications (2.1% vs 1.0%; P = .02). On multivariable analysis, the only predictor of percutaneous access failure was performance of any concomitant procedure (odds ratio, 2.0; 95% confidence interval, 1.0-4.0; P = .04). CONCLUSIONS: Currently, one in four patients treated at Targeted Vascular National Surgical Quality Improvement Program centers are getting pEVAR, which is associated with a high success rate, shorter operation time, shorter length of stay, and fewer wound complications compared with cEVAR. PMID- 25827970 TI - Test-retest reliability and responsiveness of centre of pressure measurements in patients with hip osteoarthritis. AB - OBJECTIVE: The aim of this study was to determine a set of measures for the evaluation of balance in patients suffering from hip osteoarthritis (OA) that were both reliable and responsive to change. DESIGN: Three groups of subjects; Healthy, hip OA patients without surgery, and hip OA with surgery (pre and post surgery) were included in this study. Subjects had to perform balance tests in two positions: standard and narrowed stance. CoP-based measures test-retest reliability was assessed in hip OA without surgery group, responsiveness were assessed between all groups and between pre and post-surgery. RESULTS: Intraclass Correlation Coefficient (ICC) values from hip OA without surgery ranged from 0.03 to 0.9 for only five parameters (CoP path length, SD velocity, mean velocity, and antero-posterior Root Mean Square (RMS(AP)) having values over 0.7. SD velocity and RMS(AP) showed significant differences between healthy and surgery group in standard stance whereas narrowed stance revealed most differences between all groups. RMS(AP) showed the best responsiveness (Standardized Response Mean ~0.5) between pre vs post-surgery in both conditions. RMS(AP) was also capable of discriminating between hip OA with surgery vs without surgery groups with good sensitivity and specificity. CONCLUSIONS: Our results showed there to be reliability and responsiveness of five postural parameters in hip OA patients in two conditions of standing balance. More parameters were significantly different in narrowed stance whereas sensitivity was better in standard stance. SD velocity and RMS(AP) discriminate between degrees of OA severity and highlight potential balance deficits even after arthroplasty. Selected parameters during standing balance could be assessed to complete the set of quantitative measures to quantify hip OA patient deficiencies. PMID- 25827971 TI - Mechanics and biology in intervertebral disc degeneration: a vicious circle. AB - Intervertebral disc degeneration is a major cause of low back pain. Despite its long history and large socio-economical impact in western societies, the initiation and progress of disc degeneration is not well understood and a generic disease model is lacking. In literature, mechanics and biology have both been implicated as the predominant inductive cause; here we argue that they are interconnected and amplify each other. This view is supported by the growing awareness that cellular physiology is strongly affected by mechanical loading. We propose a vicious circle of mechanical overloading, catabolic cell response, and degeneration of the water-binding extracellular matrix. Rather than simplifying the disease, the model illustrates the complexity of disc degeneration, because all factors are interrelated. It may however solve some of the controversy in the field, because the vicious circle can be entered at any point, eventually leading to the same pathology. The proposed disease model explains the comparable efficacy of very different animal models of disc degeneration, but also helps to consider the consequences of therapeutic interventions, either at the cellular, material or mechanical level. PMID- 25827972 TI - Osteoarthritis progression: is diabetes a culprit? PMID- 25827973 TI - Third eyelid gland neoplasms of dogs and cats: a retrospective histopathologic study of 145 cases. AB - PURPOSE: To describe the various types of primary neoplasms affecting the third eyelid (TEL) gland of dogs and cats. METHODS: A retrospective search of the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) database was performed. Veterinary ophthalmologists, primary care veterinarians, and, when appropriate, owners were contacted for patient follow-up information. Patient data points collected included species, age, sex, breed, laterality, tumor type, surgical margins, recurrence, metastasis, and length of follow-up. RESULTS: A total of 127 canine and 18 feline cases met the inclusion criteria. The most common canine TEL gland tumor was adenocarcinoma (n = 108; 85.0%) followed by adenoma (n = 18; 14.2%) and squamous cell carcinoma (SCC) (n = 1; 0.8%). For canine cases with follow-up information available (n = 62), 8.1% had confirmed or suspected metastasis and 11.3% had confirmed or suspected local recurrence of disease. The most common feline TEL gland tumor was adenocarcinoma (n = 15; 83.3%) followed by SCC (n = 3; 16.7%). For feline cases with follow-up information available (n = 9), 40.0% had confirmed or suspected metastasis and 30.0% had confirmed or suspected local recurrence of disease. CONCLUSIONS: This study determined that adenocarcinoma was the most common third eyelid gland tumor in both dogs and cats. The overall survival times were less, and metastatic occurrence and recurrence rates appeared to be higher for feline tumors as compared to those diagnosed in dogs. This is the first report of SCC originating from glandular ductular epithelium. PMID- 25827974 TI - An exploration of factors associated with post-traumatic stress in ER nurses. AB - BACKGROUND: Emergency room (ER) nurses are frequently exposed to traumatic events (TE) at work. These events can lead to symptoms of post-traumatic stress disorder (PTSD). AIM: The goal of the present study was to describe the factors associated with PTSD symptoms. METHODS: A cross-sectional descriptive correlational design was used. The sample consisted of 35 nurses from an ER in Quebec (Canada). Data were collected through self-administered questionnaires. RESULTS: TEs presenting a grief component (e.g. intentional injury to a child and patient suicide) are positively associated with peritraumatic distress (PD) in the days after the event. PD is positively associated with PTSD symptoms. Two personality traits (neuroticism and extraversion) should also be considered. Neuroticism is positively associated with PD whereas extraversion is negatively associated with PD and PTSD symptoms. CONCLUSION: The results are consistent with the literature, but some of these results are new to nurses. They suggest that in this population, TEs in the ER represent 'red flags'. Their occurrence should mobilise support structures. PD and its personality traits are also key factors to consider. IMPLICATION FOR NURSING MANAGEMENT: To provide adequate support for nurses, ER managers should be on the alert for these conditions. Interventions should be adapted to these findings. PMID- 25827975 TI - Paclitaxel combined with oxaliplatin as first-line chemotherapy for locally advanced or metastatic gastric cancer. AB - PURPOSE: This retrospective study was designed to evaluate the efficacy and safety of Paclitaxel (PTX) combined with Oxaliplatin (OXA) as first-line chemotherapy for locally advanced or metastatic gastric cancer (AGC). METHODS: Untreated patients with histologically confirmed AGC who received PTX at 135 mg/m(2) and OXA at 85 mg/m(2) every 2 weeks were studied. Antitumor activity was assessed by imaging and toxicities were evaluated. RESULTS: Thirty-nine (39) patients were enrolled. With 9.83 months median time of follow-up, 1 year OS rate was 42.0%. Complete response, partial response, stable disease and progressive disease was 2.6, 66.7, 17.9 and 12.0% respectively, the overall response rate was 69.2%. The mPFS was 8.5 months and the mOS 14.4 months. Grade 3/4 of toxicities included neutropenia (38.5%), febrile neutropenia (20.5%), vomiting (7.7%) and hypertransaminasemia (7.7%). Grade 2 peripheral neuropathy occurred in 33.3% patients. CONCLUSIONS: The combination of PTX combined with OXA is an active and safe regime for AGC and has a high overall response rate. PMID- 25827977 TI - Help determine our Patient's Choice winner. PMID- 25827976 TI - Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood. METHOD: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of the natural history of TSC. One hundred and twenty-five UK children age 0-16 years with TSC and born between January 2001 and December 2006 were studied. Intelligence was assessed using standardized measures at >=2 years of age. The age of onset of epilepsy, the type of seizure disorder, the frequency and duration of seizures, as well as the response to treatment was assessed at interview and by review of medical records. The severity of epilepsy in the early years was estimated using the E Chess score. Genetic studies identified the mutations and the number of cortical tubers was determined from brain scans. RESULTS: TSC2 mutations were associated with significantly higher cortical tuber count than TSC1 mutations. The extent of brain involvement, as indexed by cortical tuber count, was associated with an earlier age of onset and severity of epilepsy. In turn, the severity of epilepsy was strongly associated with the degree of intellectual impairment. Structural equation modelling supported a causal pathway from genetic abnormality to cortical tuber count to epilepsy severity to intellectual outcome. Infantile spasms and status epilepticus were important contributors to seizure severity. CONCLUSIONS: The findings support the proposition that severe, early onset epilepsy may impair intellectual development in TSC and highlight the potential importance of early, prompt and effective treatment or prevention of epilepsy in tuberous sclerosis. PMID- 25827978 TI - Labour's clear majority at health hustings. PMID- 25827979 TI - Registrants given extra time to prepare portfolios for revalidation. PMID- 25827980 TI - Students tested in emergency mock-up. PMID- 25827981 TI - Commission to improve urgent care for older people seeks nursing input. PMID- 25827982 TI - Employers to be rated by adherence to equality standards for BME staff. PMID- 25827984 TI - 'Give people with learning disabilities greater rights'. PMID- 25827983 TI - Student bursary 'forces nurses to work for free'. PMID- 25827985 TI - Trusts asked to act on flexible visiting. PMID- 25827986 TI - RCN fellow to chair review of English maternity services. PMID- 25827988 TI - Surprise at requirement for nursing students to attain Care Certificate. PMID- 25827989 TI - 'Calm down' boxes found to help service users manage agitation. PMID- 25827990 TI - 'Why should we vote for you?' Nurses give candidates a grilling. PMID- 25827996 TI - Maintaining a healthy weight. PMID- 25827997 TI - Workforce equality: raising the standard. AB - The NHS Workforce Race Equality Standard, which comes into effect this month, will require trusts to show progress against a number of indicators that reflect equality for staff. PMID- 25827998 TI - Grateful patients name their fab four. PMID- 25828011 TI - Only legislation and monitoring will improve food standards. PMID- 25828012 TI - Safe staffing levels will be achieved through legal mandate, not tool kits. PMID- 25828013 TI - Saying more nurses lead to safer care is a costly assumption. PMID- 25828014 TI - Nurses should use the election to make their opinions heard. PMID- 25828015 TI - Training and experience will help prevent patient suicide. PMID- 25828017 TI - Correction. PMID- 25828020 TI - Nutrition and fluid management. AB - Management of fluid intake and nutrition is an essential component of nursing care and should be practised skilfully by all nurses and nursing students. This requirement forms the basis of the fourth essential skills cluster, nutrition and fluid management. The essential skills clusters stipulate key skills and behaviours to be demonstrated to meet the standards for registration with the Nursing and Midwifery Council. This article, the fourth in a series on the essential skills clusters, discusses the core aspects of nutrition and fluid management and emphasises their importance in recovery from illness and in maintaining optimal health. PMID- 25828021 TI - Quantitative research. AB - This article describes the basic tenets of quantitative research. The concepts of dependent and independent variables are addressed and the concept of measurement and its associated issues, such as error, reliability and validity, are explored. Experiments and surveys - the principal research designs in quantitative research - are described and key features explained. The importance of the double-blind randomised controlled trial is emphasised, alongside the importance of longitudinal surveys, as opposed to cross-sectional surveys. Essential features of data storage are covered, with an emphasis on safe, anonymous storage. Finally, the article explores the analysis of quantitative data, considering what may be analysed and the main uses of statistics in analysis. PMID- 25828022 TI - Supporting patients in shared decision making in clinical practice. AB - This article defines shared decision making in patient care and describes the background to this philosophy. The shared decision making approach is part of a wider initiative to promote patient-centred care and increase patient involvement in clinical decisions. Shared decision making recognises patients' rights to make decisions about their care and is used to assist them to make informed and individualised decisions about care and treatment. As well as reviewing the principles of shared decision making, the article offers practical guidance on how nurses can implement this initiative, including information on sharing expertise, agenda setting, assessing risks and benefits, setting goals, and support and follow up. PMID- 25828023 TI - COPD. PMID- 25828024 TI - Find your dream job. PMID- 25828026 TI - Fast response, better outcomes. PMID- 25828028 TI - Spiritual connections. PMID- 25828029 TI - Super long viewing distance light homogeneous emitting three-dimensional display. AB - Three-dimensional (3D) display technology has continuously been attracting public attention with the progress in today's 3D television and mature display technologies. The primary characteristics of conventional glasses-free autostereoscopic displays, such as spatial resolution, image depths, and viewing angle, are often limited due to the use of optical lenses or optical gratings. We present a 3D display using MEMS-scanning-mechanism-based light homogeneous emitting (LHE) approach and demonstrate that the display can directly generate an autostereoscopic 3D image without the need for optical lenses or gratings. The generated 3D image has the advantages of non-aberration and a high-definition spatial resolution, making it the first to exhibit animated 3D images with image depth of six meters. Our LHE 3D display approach can be used to generate a natural flat-panel 3D display with super long viewing distance and alternative real-time image update. PMID- 25828030 TI - Top down and bottom up selection drives variations in frequency and form of a visual signal. AB - The frequency and form of visual signals can be shaped by selection from predators, prey or both. When a signal simultaneously attracts predators and prey selection may favour a strategy that minimizes risks while attracting prey. Accordingly, varying the frequency and form of the silken decorations added to their web may be a way that Argiope spiders minimize predation while attracting prey. Nonetheless, the role of extraneous factors renders the influences of top down and bottom up selection on decoration frequency and form variation difficult to discern. Here we used dummy spiders and decorations to simulate four possible strategies that the spider Argiope aemula may choose and measured the prey and predator attraction consequences for each in the field. The strategy of decorating at a high frequency with a variable form attracted the most prey, while that of decorating at a high frequency with a fixed form attracted the most predators. These results suggest that mitigating the cost of attracting predators while maintaining prey attraction drives the use of variation in decoration form by many Argiope spp. when decorating frequently. Our study highlights the importance of considering top-down and bottom up selection pressure when devising evolutionary ecology experiments. PMID- 25828031 TI - Mechanistic studies of copper(I)-catalyzed 1,3-halogen migration. AB - An ongoing challenge in modern catalysis is to identify and understand new modes of reactivity promoted by earth-abundant and inexpensive first-row transition metals. Herein, we report a mechanistic study of an unusual copper(I)-catalyzed 1,3-migration of 2-bromostyrenes that reincorporates the bromine activating group into the final product with concomitant borylation of the aryl halide bond. A combination of experimental and computational studies indicated this reaction does not involve any oxidation state changes at copper; rather, migration occurs through a series of formal sigmatropic shifts. Insight provided from these studies will be used to expand the utility of aryl copper species in synthesis and develop new ligands for enantioselective copper-catalyzed halogenation. PMID- 25828032 TI - Effects of long-term exercise on spatial learning, memory ability, and cortical capillaries in aged rats. AB - BACKGROUND: This study aimed to determine the effects of long-term running exercise on spatial learning, spatial memory, and cortical capillaries in aged rats. MATERIAL AND METHODS: Fourteen-month-old female and male Sprague-Dawley rats were randomly divided into an exercised group (EG) and a non-exercised group (NG). The EG rats were trained on treadmill running for 4 or 14 months. The NG rats were housed under identical conditions without running. Spatial learning and memory were assessed with the Morris water maze. The cortical capillary parameters were quantitatively investigated using immunohistochemical and stereological methods. RESULTS: The escaped latencies of the EG were significantly different from those of the NG in 18-month-old females and 28-month old males (p<0.05). However, 28-month-old females and 18-month-old males showed no differences in escape latency between the EG and NG (p>0.05). In 28-month-old female rats, stereological techniques showed significant differences between the EG and NG in the cortical capillary volume (median, 22.55 vs. 11.42, p<0.05) and the cortical capillary surface area (median, 7474.13 vs. 3935.90, p<0.05). In 28 month-old male rats, the EG had a significantly longer total cortical capillary length (median, 530.35 vs. 156.27, p<0.05), significantly larger cortical capillary volume (median, 16.47 vs. 3.65, p<0.01), and a significantly larger cortical capillary total surface area (median, 7885.79 vs. 1957.16, p<0.01) compared with the NG group. CONCLUSIONS: These data demonstrate that exercise improved spatial learning, memory capacity and cortical capillaries in aged rats. PMID- 25828033 TI - Case report of a rare complication of open-heart surgery masquerading as a gunshot wound: an autopsy diagnosis. AB - INTRODUCTION: Poststernotomy mediastinitis is a rare feared sequelae of open heart surgery with low incidence of 1% to 3% but a high mortality rate (10%-35%). Poststernotomy mediastinitis can in uncommon instances give rise to sternocutaneous fistulas in 0.25% to 10% of cases. Although scant reports have documented prosthetic valve endocarditis occurring in a setting of deep sternal wire infections, it is an infrequent but well-documented fatal complication of valvular replacement surgery. CASE REPORT: A 52-year-old male smoker with aortic valve replacement (2011), on Coumadin and Monocor, was found dead on September 2013 with a hole along a surgical scar over the sternum, masquerading as a gunshot wound. Chest radiograph revealed no foreign body, and no evidence of homicidal/suicidal or accidental cause was found at autopsy. Examination revealed a chronic fistulous tract from a deep sternal wire infection to the skin, in addition to a chronic sinus tract eroding into the root of the aorta with recent prosthetic valve endocarditis. DISCUSSION: To our knowledge, this is the first case report documenting poststernotomy mediastinitis causing a simultaneous occurrence of sternocutaneous fistula and prosthetic valve endocarditis. Either of these 2 exceptional but lethal complications would have sufficed as the cause of death. PMID- 25828034 TI - Hypostasis and time since death: state of the art in Italy and a novel approach for an operative instrumental protocol. AB - Hypostasis is a common postmortem change, whose presence or absence is used by forensic pathologists as a means of determining the approximate time of death. This assessment plays a primary role in Italian forensic practice, but blanching of hypostasis is still estimated only on the basis of subjective impressions. To understand how forensic pathologists test livor mortis on the crime scene and during forensic daily practice in Italy, an inquiry was made into lividity testing. Subsequently, with the aim of proposing a more objective approach, a study on postmortem lividity was performed; 101 cadavers were analyzed, and the color of hypostasis was measured by a colorimeter. Different conditions of time and pressure on hypostasis were tested. Linear regression analysis was performed to determine the relationship between postmortem interval and the color of the skin after a predefined intensity and duration of pressure. Herein we propose a novel operative instrumental protocol using new, more standardized conditions for the analysis of hypostasis, thus providing pathologists with a more rigorous approach to postmortem interval estimation. PMID- 25828035 TI - New concepts in fillers. PMID- 25828036 TI - Basics of dermal filler rheology. AB - BACKGROUND: Hyaluronic acid injectable fillers are the most widely used dermal fillers to treat facial volume deficits, providing long-term facial aesthetic enhancement outcomes for the signs of aging and/or facial contouring. OBJECTIVES: The purpose of this article was to explain how rheology, the study of the flow of matter, can be used to help physicians differentiate between dermal fillers targeted to certain areas of the face. METHODS: This article describes how rheological properties affect performance when filler is used in various parts of the face and exposed to mechanical stress (shear deformation and compression/stretching forces) associated with daily facial animation and other commonly occurring external forces. RESULTS: Improving facial volume deficits with filler is linked mainly to gel viscoelasticity and cohesivity. These 2 properties set the level of resistance to lateral and vertical deformations of the filler and influence filler tissue integration through control of gel spreading. CONCLUSION: Selection of dermal filler with the right rheological properties is a key factor in achieving a natural-looking long-lasting desired aesthetic outcome. PMID- 25828037 TI - A randomized, evaluator-blinded, controlled study of effectiveness and safety of small particle hyaluronic acid plus lidocaine for lip augmentation and perioral rhytides. AB - OBJECTIVE: To compare the safety and effectiveness of small particle hyaluronic acid plus lidocaine (SPHAL) versus no treatment for lip augmentation and perioral rhytides. METHODS AND MATERIALS: Adults scoring 1 (very thin) to 2 (thin) on the Medicis Lip Fullness Scale (MLFS) for upper and lower lips were randomized (3:1) to SPHAL or no treatment. Treatment success was an MLFS increase >=1 point at Week 8. Secondary end points (MLFS score, independent photographic review, Global Aesthetic Improvement Scale, Wrinkle Assessment Scale for Upper Lip Lines) and safety were assessed throughout. RESULTS: Statistically significantly more patients were treatment successes with SPHAL (upper lip [80.2% vs 11.9%], lower lip [84.2% vs 18.4%], and upper and lower lips combined [76.1% vs 11.6%]), compared with no treatment (p <.001, all outcomes). Patients treated for both lip augmentation and perioral rhytides were rated as having an aesthetically meaningful improvement in perioral rhytides (p <.001). Most common treatment emergent adverse events (AEs) included lip bruising, swelling, and pain and were mostly mild and transient in nature, without anticipated device AEs. CONCLUSION: Small particle hyaluronic acid plus lidocaine was effective and well tolerated and significantly more effective when both lips and perioral rhytides were treated, with improvement evident up to 6 months after treatment. PMID- 25828038 TI - Functional safety assessments used in a randomized controlled study of small gel particle hyaluronic acid for lip augmentation. AB - BACKGROUND: Dermal fillers are commonly injected in the lips for aesthetic treatment. Small gel particle hyaluronic acid (SGP-HA) is the only filler approved by the US Food and Drug Administration for this indication, based on a pivotal trial of effectiveness and safety. OBJECTIVE: To assess multiple measures of tolerability and lip function in a randomized controlled trial of SGP-HA (without lidocaine) for lip augmentation. MATERIALS AND METHODS: Patients were randomized to SGP-HA (n = 135) or no treatment (n = 45) at baseline; all could receive SGP-HA after 6 months. Assessments for tolerability and lip function at clinic visits throughout the study included lip texture, firmness, symmetry, movement, function, and sensation; device palpability; mass formation; and ease of repeat injection. RESULTS: Many assessments were normal (lip function, sensation) or unremarkable (movement, mass formation, ease of reinjection) in most patients. Nearly all abnormalities with other assessments (texture, firmness, symmetry, device palpability) were mild and transient (<4 weeks). CONCLUSION: Lip augmentation with SGP-HA showed excellent safety with the assessments used in this study. Further study should be conducted to validate these assessments with the goal of developing a comprehensive scale for measuring potential functional complications and risks. PMID- 25828039 TI - Ultrastructural analysis of 3 hyaluronic acid soft-tissue fillers using scanning electron microscopy. AB - BACKGROUND: Although hyaluronic acid (HA) specifications such as molecular weight and particle size are fairly well characterized, little information about HA ultrastructural and morphologic characteristics has been reported in clinical literature. OBJECTIVE: To examine uniformity of HA structure, the effects of extrusion, and lidocaine dilution of 3 commercially available HA soft-tissue fillers. MATERIALS AND METHODS: Using scanning electron microscopy and energy dispersive x-ray analysis, investigators examined the soft-tissue fillers at various magnifications for ultrastructural detail and elemental distributions. RESULTS: All HAs contained oxygen, carbon, and sodium, but with uneven distributions. Irregular particulate matter was present in RES but BEL and JUV were largely particle free. Spacing was more uniform in BEL than JUV and JUV was more uniform than RES. Lidocaine had no apparent effect on morphology; extrusion through a 30-G needle had no effect on ultrastructure. CONCLUSION: Descriptions of the ultrastructural compositions and nature of BEL, JUV, and RES are helpful for matching the areas to be treated with the HA soft-tissue filler architecture. Lidocaine and extrusion through a 30-G needle exerted no influence on HA structure. Belotero Balance shows consistency throughout the syringe and across manufactured lots. PMID- 25828040 TI - Facial treatment preferences in aesthetically aware women. AB - BACKGROUND: Individuals typically self-identify symptoms of facial aging that lead them to seek facial aesthetic treatments. No systematic data exist to describe preferences for facial areas requiring treatment. OBJECTIVE: To determine (1) the facial areas most likely to be treated first, (2) the relationship between the most bothersome facial area and the area first planned for treatment, and (3) differences between younger and older women. METHODS: A total of 603 women aged 30 to 65 years considering aesthetic treatments participated in an online research survey using Maximum Difference scaling. RESULTS: Maximum Difference analysis revealed that crow's feet lines (CFLs) were most likely to be treated first (82% of the first preferences), followed by oral commissures (74%) and tear troughs (72%). There was a strong correlation between the most bothersome facial area and the area first planned for treatment. In women younger than 45 years, features of the upper face were more likely to be treated first, whereas women aged 50 years or older had an increased preference for treating features of the lower face, with a reduction in preference for upper face treatment. CONCLUSION: This cross-sectional survey suggests that aesthetically oriented women have changing facial treatment preferences with age; however, CFLs are of most concern. PMID- 25828041 TI - Commentary on Facial treatment preferences in aesthetically aware women. PMID- 25828042 TI - The use of nontraditional fillers and neuromodulators to improve patient satisfaction. PMID- 25828043 TI - An interesting reaction to a high- and low-molecular weight combination hyaluronic acid. PMID- 25828044 TI - Arginine, dimethylated arginine and homoarginine in relation to cardiovascular risk in patients with moderate chronic kidney disease. AB - OBJECTIVES: Arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine/ADMA ratio and homoarginine could potentially affect nitric oxide production and have been studied in relation to cardiovascular risk (CVR) in various clinical populations. Prospective studies on the CVR associated with arginine/ADMA ratio and homoarginine in patients with moderate chronic kidney disease (CKD) are still scarce. We have studied how arginine, homoarginine and dimethylated arginine can predict cardiovascular events in such a population. DESIGN AND METHODS: We measured plasma concentrations of arginine (P-arginine), ADMA (P-ADMA), SDMA (P-SDMA), homoarginine (P-homoarginine) and other covariates in 160 patients with predialytic CKD (mean age 57 years and mean eGFR 43 mL/min/1.73 m(2)) and followed them for 58 months in median. The risks of fatal and non-fatal cardiovascular events associated with the predictors were evaluated with multivariable Cox proportional hazard analysis. RESULTS: There were 31 cardiovascular events during the observation period. In a multivariable model adjusted for age, sex, previous cardiovascular disease, P-cystatin C and P homoarginine, the hazard ratio (HR) associated with an increase in arginine/ADMA ratio by 10 was 0.83 (P=0.03). The HR of a 1 MUmol/L increase in P-homoarginine in the same model was 1.78 (P=0.01). A statistically significant interaction between P-homoarginine and P-cystatin C was found in an extended multivariable model. P-SDMA was not associated with increased CVR after adjustment for basic covariates. CONCLUSION: This study demonstrates a negative association between arginine/ADMA ratio and CVR in CKD patients and a positive association between P homoarginine and CVR. The latter is in contrast to what has been demonstrated by others. PMID- 25828045 TI - CT-pro-AVP as a tool for assessment of intravascular volume depletion in severe hyponatremia. AB - BACKGROUND: Assessment of volume status is essential to best manage hyponatremic patients but is not always accurate in clinical practice. The aim of this study was to evaluate the reliability of C-terminal portion of pro-arginine-vasopressin (CT-pro-AVP), a surrogate biomarker of vasopressin release, in assessing intravascular volume (IVV) depletion in hypoosmolar hyponatremic patients. METHODS: Plasma CT-pro-AVP and urea-to-creatinine ratio (Ur/Cr) were performed in 131 hospitalized patients presenting chronic severe hypoosmolar hyponatremia. At hospital discharge, their IVV was evaluated regardless of CT-pro-AVP concentrations. All patients were then classified as decreased or as normal/expanded IVV group. RESULTS: Plasma CT-pro-AVP levels were higher in patients with decreased IVV (34.6 vs. 11.3 pmol/L, p<0.001) and exhibited a reliable performance for assessment of decreased IVV (ROC AUC at 0.717 [95% CI 0.629-0.805]). The combination of CT-pro-AVP and Ur/Cr resulted in an improved ROC AUC up to 0.787 (95% CI 0.709-0.866). CONCLUSIONS: Our findings support the hypothesis that CT-pro-AVP plasma level may reflect IVV and would be a tool for its assessment. This performance has been magnified by its combination with Ur/Cr. A dual-marker strategy may help clinicians to optimize the management of severe hyponatremia especially in case of confusing clinical presentations. PMID- 25828046 TI - Value of reflex testing based on hypogammaglobulinemia as demonstrated in serum protein electrophoresis. AB - OBJECTIVES: Hypo-gammaglobulinemia (hypoGG) in serum protein electrophoresis (SPE) reflects, variably, reduced serum immunoglobulin (Ig) concentrations, which may be caused by hematological neoplasms, among other causes. HypoGG in the absence of a discernible M-spike (MC) has been the basis of reflexive testing e.g., by immunofixation electrophoresis (IFE). However, the utility of this practice has not been fully evaluated. Thus, we aimed to (1) determine the predictive power of hypoGG for reduced Ig levels, (2) compare the IFE positive rates and sensitivity between hypoGG and non-hypoGG patients, and (3) examine the M-protein isotype distributions. METHODS: We retrospectively analyzed 3974 matched SPE and IFE results at the Sunnybrook Health Sciences Centre from January 2010 to June 2013. SPE and IFE were performed on the Sebia CapillarysTM 2 and HydrasysTM systems respectively. RESULTS: 2723/3974 (68.5%) patients were SPE negative, 246/2723 (9%) had hypoGG and 192 (7.1%) were IFE positive. HypoGG predicted 93.1% cases with at least one Ig reduction. Among SPE-negative patients, the IFE positive rate and sensitivity in hypoGG were 12.2% and 15.6% respectively, compared to 6.4% and 77.1% in normo-GG. Proportion of non-IgG isotypes in both groups were comparable but fewer MC were detected in hypoGG. CONCLUSIONS: Both the 7% false negative rate of SPE and the poor sensitivity (16%) of reflex testing based on hypoGG should be taken into consideration when devising a screening strategy based on SPE. PMID- 25828047 TI - Digital PCR analysis of circulating nucleic acids. AB - Detection of plasma circulating nucleic acids (CNAs) requires the use of extremely sensitive and precise methods. The commonly used quantitative real-time polymerase chain reaction (PCR) poses certain technical limitations in relation to the precise measurement of CNAs whereas the costs of massively parallel sequencing are still relatively high. Digital PCR (dPCR) now represents an affordable and powerful single molecule counting strategy to detect minute amounts of genetic material with performance surpassing many quantitative methods. Microfluidic (chip) and emulsion (droplet)-based technologies have already been integrated into platforms offering hundreds to millions of nanoliter or even picoliter-scale reaction partitions. The compelling observations reported in the field of cancer research, prenatal testing, transplantation medicine and virology support translation of this technology into routine use. Extremely sensitive plasma detection of rare mutations originating from tumor or placental cells among a large background of homologous sequences facilitates unraveling of the early stages of cancer or the detection of fetal mutations. Digital measurement of quantitative changes in plasma CNAs associated with cancer or graft rejection provides valuable information on the monitoring of disease burden or the recipient's immune response and subsequent therapy treatment. Furthermore, careful quantitative assessment of the viral load offers great value for effective monitoring of antiviral therapy for immunosuppressed or transplant patients. The present review describes the inherent features of dPCR that make it exceptionally robust in precise and sensitive quantification of CNAs. Moreover, I provide an insight into the types of potential clinical applications that have been developed by researchers to date. PMID- 25828048 TI - Synthesis and characterization of copper(ii) complexes with multidentate ligands as catalysts for the direct hydroxylation of benzene to phenol. AB - Four copper(ii) complexes with multidentate ligands, ([CuL1Cl2]), ([Cu(HL2)Cl2]), ([Cu2(L2)2](ClO4)2) and ([CuL3(HOCH3)ClO4]) {L1 = N,N-bis((pyridin-2-yl)methyl) prop-2-yn-1-amine, HL2 = 2-((((1-methyl-1H-imidazol-2-yl)methyl)(pyridin-2 ylmethyl)amino)methyl)phenol and HL3 = 2-((((1-methyl-1H-imidazol-2 yl)methyl)(pyridin-2-ylmethyl)amino)methyl)-2-t-butyl-phenol} are reported. The complexes were characterized by UV-vis spectroscopy, elemental analysis and electrochemical analysis. Complexes and were further characterized by X-ray single crystal diffraction analysis. The catalytic performances of these complexes were evaluated in the direct hydroxylation of benzene to phenol with hydrogen peroxide as an oxidant in aqueous acetonitrile media. Under optimized reaction conditions, complex with the most negative reduction potential exhibited the highest conversion without considering the dinuclear complex . A correlation between the catalytic efficiency and the reduction potentials of these complexes was observed, that is the more negative the reduction potential, the higher the benzene conversion. A radical mechanism for the catalysis was confirmed by the fact that addition of radical scavengers such as TEMPO into the reaction mixture could severely suppress the catalysis. PMID- 25828049 TI - Porous Co3O4/CuO composite assembled from nanosheets as high-performance anodes for lithium-ion batteries. AB - Upon dealloying a carefully designed CoCuAl ternary alloy in NaOH solution at room temperature, a Co3 O4 /CuO nanocomposite with an interconnected porous microstructure assembled by a secondary structure of nanosheets was successfully fabricated. By using the dealloying strategy, the target metals directly grew to form uniform bimetallic oxide nanocomposites. Owing to the unique hierarchical structure and the synergistic effect of both active electrode materials, the Co3 O4 /CuO nanocomposite exhibits much enhanced electrochemical performance with higher capacities and better cycling stability compared to anodes of pure Co3 O4 . Moreover, it performs excellently in terms of cycle reversibility, Coulombic efficiency, and rate capability, at both low or high current rates. With the advantages of unique performance and ease of preparation, the as-made Co3 O4 /CuO nanocomposite demonstrates promising application potential as an advanced anode material for lithium-ion batteries. PMID- 25828050 TI - Organic electronics: recent developments. PMID- 25828051 TI - Intracranial Vertebral Artery Aneurysms: Clinical Features and Outcome of 190 Patients. AB - BACKGROUND: Vertebral artery (VA) aneurysms comprise approximately one-third of posterior circulation aneurysms. They are morphologically variable, and located critically close to the cranial nerves and the brainstem. We aim to represent the characteristics of these aneurysms and their treatment, and to analyze the outcome. METHODS: We reviewed retrospectively 9709 patients with intracranial aneurysms. Of these, we included 190 with aneurysms at the VA or VA-posterior inferior cerebellar artery junction. These patients were treated in the Department of Neurosurgery, Helsinki, Finland, between 1934 and 2011. RESULTS: The 190 patients had 193 VA aneurysms, among which 131 (68%) were ruptured. The VA aneurysm caused a mass effect in 7 and ischemia in 2 patients. Compared to 4387 patients with a ruptured aneurysm in other locations, those with a VA aneurysm were older, their aneurysms were more often fusiform, and more often caused intraventricular hemorrhages. Among surgically treated aneurysms, clipping was the treatment in 91 (88%) saccular and 11 (50%) fusiform aneurysms. Treatment was endovascular in 13 (9%), and multimodal in 6 (4%) aneurysms. Within a year after aneurysm diagnosis, 53 (28%) patients died. Among the survivors, 104 (93%) returned to an independent or to their previous state of life; only 2 (2%) were unable to return home. CONCLUSIONS: Microsurgery is a feasible treatment for VA aneurysms, although cranial nerve deficits are more common than in endovascular surgery. Despite the challenge of an often severe hemorrhage, of challenging morphology, and risk for laryngeal palsy, most patients surviving the initial stage return to normalcy. PMID- 25828052 TI - Socioeconomic disparities in neurocognitive development in the first two years of life. AB - Socioeconomic status (SES) is strongly associated with cognition and achievement. Socioeconomic disparities in language and memory skills have been reported from elementary school through adolescence. Less is known about the extent to which such disparities emerge in infancy. Here, 179 infants from socioeconomically diverse families were recruited. Using a cohort-sequential design, 90 infants were followed at 9 and 15 months, and 89 were followed at 15 and 21 months. SES disparities in developmental trajectories of language and memory were present such that, at 21 months of age, children of highly educated parents scored approximately .8 standard deviations higher in both language and memory than children of less educated parents. The home language and literacy environment and parental warmth partially accounted for disparities in language, but not memory development. PMID- 25828053 TI - Pasteurellosis in lumpsucker Cyclopterus lumpus, farmed in Norway. PMID- 25828054 TI - Cultural Impact on Medication Instructions: The Case of the Turkish Teaspoon. AB - Medication errors are preventable events related to inappropriate medication use that could potentially result in patient harm. Here we present a patient encounter that has exemplified the importance of appropriate communication and the inevitable role of every individual in ensuring appropriate prescription medication use. Multidisciplinary efforts are required to ensure patient safety in today's systems based practice. This case highlights cultural barriers to the practice of medicine and the growing need to explore and address them appropriately. PMID- 25828056 TI - Structure versus function-The impact of computational methods on the discovery of specific GPCR-ligands. AB - Over the past decades, computational methods have become invaluable for drug design campaigns but also as auxiliary tool for structural biology. The combination of experimental and in silico methods in the field of G protein coupled receptors (GPCRs) is indispensable. Despite recent groundbreaking achievements in GPCR crystallography, structural information for the vast majority of this physiologically important protein class is only accessible through homology models. Since the understanding of the conformational changes resulting in multiple activation pathways is incomplete, the design of specific GPCR modulating drugs remains a major challenge. However, due to the highly interdisciplinary requirements for the investigation of receptor function and the necessity of joining scientist from different fields, computational approaches gain importance in rationalizing and illustrating certain specific effects. In silico methods, such as molecular dynamics (MD) simulations, pharmacophore modeling or docking, proved to be suitable to complement experimental approaches. In this review, we highlight recent examples of in silico studies that were successfully applied in the field of GPCR research. Those approaches follow two main goals: Firstly, structural investigations that help to understand the receptor function and the characterization of ligand binding and secondly the identification of novel GPCR modulators as potential drugs. PMID- 25828055 TI - Rational design of allosteric-inhibition sites in classical protein tyrosine phosphatases. AB - Protein tyrosine phosphatases (PTPs), which catalyze the dephosphorylation of phosphotyrosine in protein substrates, are critical regulators of metazoan cell signaling and have emerged as potential drug targets for a range of human diseases. Strategies for chemically targeting the function of individual PTPs selectively could serve to elucidate the signaling roles of these enzymes and would potentially expedite validation of the therapeutic promise of PTP inhibitors. Here we report a novel strategy for the design of non-natural allosteric-inhibition sites in PTPs; these sites, which can be introduced into target PTPs through protein engineering, serve to sensitize target PTPs to potent and selective inhibition by a biarsenical small molecule. Building on the recent discovery of a naturally occurring cryptic allosteric site in wild-type Src homology-2 domain containing PTP (Shp2) that can be targeted by biarsenical compounds, we hypothesized that Shp2's unusual sensitivity to biarsenicals could be strengthened through rational design and that the Shp2-specific site could serve as a blueprint for the introduction of non-natural inhibitor sensitivity in other PTPs. Indeed, we show here that the strategic introduction of a cysteine residue at a position removed from the Shp2 active site can serve to increase the potency and selectivity of the interaction between Shp2's allosteric site and the biarsenical inhibitor. Moreover, we find that 'Shp2-like' allosteric sites can be installed de novo in PTP enzymes that do not possess naturally occurring sensitivity to biarsenical compounds. Using primary-sequence alignments to guide our enzyme engineering, we have successfully introduced allosteric-inhibition sites in four classical PTPs-PTP1B, PTPH-1, FAP-1, and HePTP-from four different PTP subfamilies, suggesting that our sensitization approach can likely be applied widely across the classical PTP family to generate biarsenical-responsive PTPs. PMID- 25828057 TI - Hip arthroplasty with high chromium and cobalt blood levels--Case report of a patient followed during pregnancy and lactation period. AB - Metal-on-metal arthroplasty may lead to elevated blood chromium (Cr) and cobalt (Co) levels (>7 MUg/l). Since carcinogenic, mutagenic, and teratogenic effects have been suggested, there is concern of pregnancy hazards for women with this condition. The 34-year-old patient has had a unilateral hip replacement for seven years. Before her pregnancy high Cr (47 MUg/l) and Co (103 MUg/l) blood concentrations were measured, but she did not develop any symptoms. A male infant was delivered after 41 weeks with first degree hypospadias. His levels were increased at 3 weeks of age: 14 MUg/l (Cr) and 20 MUg/l (Co), but decreased by 9 weeks to 6.7 MUg/l (Cr) and 10.0 MUg/l (Co). Maternal levels at delivery were 25 MUg/l (Cr) and 51 MUg/l (Co). The child was fully breast-fed and developed normally. An association between hypospadias and Cr/Co has to be considered speculative. The otherwise favorable outcome of this case may be reassuring for pregnant and breast-feeding patients with metal-on-metal hip replacements. PMID- 25828058 TI - Manganese exposure through drinking water during pregnancy and size at birth: A prospective cohort study. AB - The essential element manganese (Mn) might be toxic at excess exposure. We assessed the impact of elevated Mn exposure through drinking water during pregnancy on birth size in a population-based cohort(n = 1695) in rural Bangladesh. Concentrations of water Mn (median = 236 MUg/L, range = 7.1-6336; n = 1177) and erythrocyte Mn (median = 30 MUg/kg, range = 6.3-114; n = 758) were measured using ICP-MS. In regression analyses, newborns of women in the highest tertile of water Mn (median = 1495 MUg/L) were 0.49 cm (0.20 SD) shorter (B = 0.42; 95% CI: -0.77, -0.08) than those in the lowest tertile (56MUg/L). The inverse association was significant in girls and also in boys of mothers with lowest hemoglobin values, likely due to higher absorption of Mn. Manganese concentrations in water and erythrocytes did not correlate, and the associations of the latter with birth size were less obvious. This study suggests that consumption of water with highly elevated Mn levels during pregnancy may impair fetal growth. PMID- 25828059 TI - Impact of kudzu and puerarin on sperm function. AB - The goal of this study was to investigate the impact of kudzu (Pueraria mirifica) and the isoflavone puerarin in functional toxicological tests on spermatozoa and to assess the affinity of extracts and pure isoflavones for estrogen receptor (ER)-alpha and -beta (ERalpha, ERbeta) in receptor binding assays. Capacitation, acrosome reaction and chromatin decondensation in spermatozoa were analyzed using microscopic analysis. Kudzu, but not puerarin, reduced motility of sperm. Puerarin reduced the percent spontaneous acrosome reaction in spermatozoa. The pathways used by kudzu that affect sperm function are not fully mirrored by puerarin. Puerarin, kudzu and its other phytoestrogenic components displayed preferential affinity for ERbeta, however the diverse effects of kudzu and puerarin on sperm function implicate the involvement of multiple signaling systems. PMID- 25828060 TI - Pharmacoepidemiology and thalidomide embryopathy surveillance in Brazil. AB - INTRODUCTION: Thalidomide causes congenital defects in children, such as limb reduction defects. Currently, it is used for a few indications; in Brazil, where leprosy is endemic, thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of thalidomide embryopathy have been reported. METHODS: We analyzed the frequency of births with phenotypes consistent with thalidomide embryopathy (TEP) and correlated this with the distribution of thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil. RESULTS: A total of 5,889,210 thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54-1.66) and TEP was 0.11 (CI95%: 0.10-0.13) per 10,000 births. Poisson regression showed an increase in cases of TEP and limb reduction defects per 100,000 tablets dispensed. Clusters and geographical isolates were identified in several regions. CONCLUSIONS: There is a correlation between thalidomide and TEP showing that thalidomide embryopathy should be monitored in countries where this medication is available. PMID- 25828061 TI - Withania somnifera (Ashwagandha) in neurobehavioural disorders induced by brain oxidative stress in rodents: a systematic review and meta-analysis. AB - OBJECTIVES: Withania somnifera has been in use for several thousand years in Ayurveda to treat various neurological disorders. There is, however, not much scientific data on its protective role in neuronal pathology specifically against brain oxidative stress. Hence, an attempt is made in this work for systematic review and meta-analysis of W. somnifera on neurobehavioural disorders induced by brain oxidative stress in rodents. METHODS: A systematic search of the effect of W. somnifera on brain oxidative stress-induced neuronal pathology was performed using electronic databases. The systematic review was performed on neurobehavioural parameters, whereas meta-analysis of W. somnifera effect was done on oxidative stress markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione and lipid peroxidation), nitrite, protein carbonyl, AchE, ChAT and Ach of rodent brain. Data were analysed using Review Manager Software. KEY FINDINGS: Twenty-eight studies were selected based upon the inclusion and exclusion criteria. W. somnifera appreciably inhibited the neurological abnormalities due to oxidative stress in rodent brain produced by different physical and chemical stimuli. W. somnifera also significantly restored the altered oxidative and other stress markers in different parts of rodent brain. SUMMARY: The systematic review provides scientific evidence for the traditional claim of W. somnifera use in different neurological aliments. However, future clinical trials are mandated to establish the therapeutic efficacy and safety in human beings. PMID- 25828062 TI - Weighing privacy against effective epidemiology. PMID- 25828063 TI - The "first hit" toward alcohol reinforcement: role of ethanol metabolites. AB - This review analyzes literature that describes the behavioral effects of 2 metabolites of ethanol (EtOH): acetaldehyde and salsolinol (a condensation product of acetaldehyde and dopamine) generated in the brain. These metabolites are self-administered into specific brain areas by animals, showing strong reinforcing effects. A wealth of evidence shows that EtOH, a drug consumed to attain millimolar concentrations, generates brain metabolites that are reinforcing at micromolar and nanomolar concentrations. Salsolinol administration leads to marked increases in voluntary EtOH intake, an effect inhibited by mu opioid receptor blockers. In animals that have ingested EtOH chronically, the maintenance of alcohol intake is no longer influenced by EtOH metabolites, as intake is taken over by other brain systems. However, after EtOH withdrawal brain acetaldehyde has a major role in promoting binge-like drinking in the condition known as the "alcohol deprivation effect"; a condition seen in animals that have ingested alcohol chronically, are deprived of EtOH for extended periods, and are allowed EtOH re-access. The review also analyzes the behavioral effects of acetate, a metabolite that enters the brain and is responsible for motor incoordination at low doses of EtOH. Also discussed are the paradoxical effects of systemic acetaldehyde. Overall, evidence strongly suggests that brain generated EtOH metabolites play a major role in the early ("first-hit") development of alcohol reinforcement and in the generation of relapse-like drinking. PMID- 25828065 TI - Coagulase-negative staphylococcal bacteremia: risk factors for mortality and impact of initial appropriate antimicrobial therapy on outcome. AB - It is uncertain whether an initial inappropriate empirical antibiotic treatment of coagulase-negative staphylococci (CoNS) bacteremia adversely affects the outcome. A retrospective cohort study of CoNS bacteremia was performed at the Dongguk University Ilsan Hospital during a 3-year period. During the study period, 109 patients with CoNS bacteremia were enrolled. The median age of the patients was 72 years and most (96%, 105/109) had one or more comorbid diseases. Among the participants, 29% (32/109) received an appropriate empirical antimicrobial therapy. The 30-day mortality was 24% (26/109) and CoNS bacteremia related mortality was 14% (15/109). There was no difference in the CoNS bacteremia-related mortality between the group with an inappropriate empirical treatment (13%, 10/77) and that with an appropriate treatment (16%, 5/32) (p = 0.46). In the multivariate analysis using the Cox regression analysis method, Pitt bacteremia scores [hazard ratio (HR) 1.48; 95% confidence interval (CI) 1.09 2.01; p = 0.01] and retention of eradicable focus (HR 5.0; 95% CI 1.39-17.9; p = 0.01) were found to be associated with CoNS bacteremia-related mortality. The results suggest that inappropriate empirical therapy might not necessarily be associated with the 30-day mortality or CoNS bacteremia-related mortality. Conversely, Pitt bacteremia scores and retention of eradicable focus were associated with poor outcomes. PMID- 25828066 TI - Prevalence of incidental pulmonary nodules on computed tomography of the thorax in trauma patients. AB - BACKGROUND/AIMS: Lung cancer is the third leading cause of death in high-income countries. Early detection leads to improved clinical outcomes, with evidence showing that lung cancer screening reduces lung cancer mortality. Knowledge of the population prevalence of pulmonary nodules affects the efficacy and cost effectiveness of a local screening programme. METHODS: We performed a retrospective review of our trauma database looking for the prevalence of incidental pulmonary nodules on computed tomography of the thorax. Prevalence of nodules and follow up according to Fleischner Guidelines were reviewed. RESULTS: Two hundred and forty-eight patients underwent a computed tomography thorax as part of their trauma assessment. 8.5% (21/248) had incidental pulmonary nodules. Eighty-one per cent of these (17/21) required follow up according to the Fleischner Society Guidelines. One was subsequently diagnosed with primary lung cancer, one with metastatic sigmoid cancer and one with invasive aspergillus. CONCLUSIONS: Incidental pulmonary nodules are common in the general population. This has implications for possible lung cancer screening recommendations in the Australian population. Referral and/or review systems are essential to ensure adequate follow up of incidental findings, as it is likely some patients are not receiving adequate follow up at present. PMID- 25828064 TI - Capnocytophaga canimorsus: an emerging cause of sepsis, meningitis, and post splenectomy infection after dog bites. AB - Newly named in 1989, Capnocytophaga canimorsus is a bacterial pathogen found in the saliva of healthy dogs and cats, and is transmitted to humans principally by dog bites. This review compiled all laboratory-confirmed cases, animal sources, and virulence attributes to describe its epidemiology, clinical features, and pathogenesis. An estimated 484 patients with a median age of 55 years were reported, two-thirds of which were male. The case-fatality rate was about 26%. Its clinical presentations included severe sepsis and fatal septic shock, gangrene of the digits or extremities, high-grade bacteremia, meningitis, endocarditis, and eye infections. Predispositions were prior splenectomy in 59 patients and alcoholism in 58 patients. Dog bites before illness occurred in 60%; additionally, in 27%, there were scratches, licking, or other contact with dogs or cats. Patients with meningitis showed more advanced ages, higher male preponderance, lower mortality, and longer incubation periods after dog bites than patients with sepsis (p < 0.05). Patients with prior splenectomy presented more frequently with high-grade bacteremia than patients with intact spleens (p < 0.05). The organism possesses virulence attributes of catalase and sialidase production, gliding motility, cytotoxin production, and resistance to killing by serum complement due to its unique lipopolysaccharide. Penicillin is the drug of choice, but some practitioners prefer third-generation cephalosporins or beta lactamase inhibitor combinations. C. canimorsus has emerged as a leading cause of sepsis, particularly post-splenectomy sepsis, and meningitis after dog bites. PMID- 25828067 TI - Sorption and biodegradation of selected benzotriazoles and hydroxybenzothiazole in activated sludge and estimation of their fate during wastewater treatment. AB - Biodegradation of benzotriazole (BTR), 5-chlorobenzotriazole (CBTR), xylytriazole (XTR), 4-methyl-1H-benzotriazole (4TTR), 5-methy-1H-lbenzotriazole (5TTR) and 2 hydroxybenzothiazole (OHBTH) was studied in activated sludge batch experiments under aerobic and anoxic conditions, presence of organic substrate and different sludge residence times (SRTs). Their sludge-water distribution coefficients were also calculated in sorption experiments and ranged between 87 and 220 L kg(-1). Significant biodegradation of BTR, CBTR, XTR and OHBTH was observed in all biotic experiments. Half-life values ranged between 23 and 45 h (BTR), 18 and 47 h (CBTR), 14 and 26 h (XTR), 6.5 and 24 h (OHBTH). The addition of substrate did not suppress biodegradation kinetics; whereas in some cases accelerated biodegradation of microcontaminants. Except for CBTR, no effect of SRT on biodegradation constants was observed. Prediction of micropollutants removal in Sewage Treatment Plants (STPs) indicated that they will be partially removed, mainly due to aerobic biodegradation. Higher removal is expected at STPs operating at higher SRT and higher suspended solids concentrations. PMID- 25828068 TI - Longitudinal study of acute haematologic toxicity in cervical cancer patients treated with chemoradiotherapy. AB - INTRODUCTION: Acute hematologic toxicity (HT) limits optimal delivery of concurrent chemoradiotherapy (CRT) for patients with pelvic malignancies. We tested the hypothesis that pelvic bone marrow (PBM) dose-volume metrics were associated with weekly reductions in peripheral blood cell counts in cervical cancer patients undergoing CRT. METHODS: We included 102 cervical cancer patients treated with concurrent cisplatin (40 mg/m(2) /week) and pelvic radiotherapy treated at three US centres. No patient received granulocyte-monocyte colony stimulating factor (GM-CSF) or platelet transfusions. Using linear-mixed effects modelling, we analysed weekly reductions in log-transformed peripheral blood cell counts as a function of time (weeks), mean PBM dose and the PBM volume receiving >=10 Gy (V(10)), 20 Gy (V(20)), 30 Gy (V(30)) and 40 Gy (V(40)). RESULTS: Increases in mean PBM radiation dose, V(20), V(30) and V(40) were all significantly associated with a greater weekly reduction in white blood cell (WBC) and absolute neutrophil counts (ANCs). We estimated that with every 1 Gy increase in mean PBM dose, ln(ANC) was reduced by 9.6/MUL per week (95% confidence interval, 1.9-17.3, P = 0.015). Subregion analysis also identified significant associations between weekly reductions in ln(WBC) and ln(ANC) within lumbosacral spine, ischium and proximal femora, as opposed to ilium. CONCLUSIONS: PBM radiation dose-volume metrics are significantly associated with weekly reductions in peripheral blood cell counts in cervical cancer patients undergoing CRT, particularly within the lower pelvis and lumbosacral spine. PMID- 25828070 TI - Healing the health system after civil unrest. PMID- 25828069 TI - Review of HIV response in Pakistan using a system thinking framework. AB - Pakistan has moved from a 'low prevalence-high risk' to a 'concentrated epidemic' state, yet the forcefulness required for managing this silent escalation of HIV infected numbers is not being highlighted, as it should be. A more comprehensive review of the national strategy for HIV/AIDS would necessitate a system's thinking. For this purpose, the WHO's Health Systems Building Blocks have been discussed to analyse whether this framework can be employed to take some corrective measures. An extensive literature review in this regard helps to understand that the service delivery has to be responsive, but skilled human resources, a robust information system, an uninterrupted supplies and use of latest technology, adequate financing, and above all good governance at operational level are essential ingredients, which call for re-orienting the national programme today. Lack of coordination, capacity, and interventions with questionable sustainability pave a perilous path. Hitherto, the issue can be addressed by involving stakeholders from all levels of the society and managing the void between policy and implementation. Furthermore, interventions that focus on the long-term future are imperative to combat the menace threatening human lives. PMID- 25828071 TI - The importance of considering the evidence in the MTP 2014 Amendment debate in India - unsubstantiated arguments should not impede improved access to safe abortion. AB - With the objective to improve access to safe abortion services in India, the Ministry of Health and Welfare, with approval of the Law Ministry, published draft amendments of the MTP Act on October 29, 2014. Instead of the expected support, the amendments created a heated debate within professional medical associations of India. In this commentary, we review the evidence in response to the current discourse with regard to the amendments. It would be unfortunate if unsubstantiated one-sided arguments would impede the intention of improving access to safe abortion care in India. PMID- 25828072 TI - Use of glyburide to treat gestational diabetes is linked to adverse outcomes in babies, study finds. PMID- 25828074 TI - Interpreter-mediated dentistry. AB - The global movements of healthcare professionals and patient populations have increased the complexities of medical interactions at the point of service. This study examines interpreter mediated talk in cross-cultural general dentistry in Hong Kong where assisting para-professionals, in this case bilingual or multilingual Dental Surgery Assistants (DSAs), perform the dual capabilities of clinical assistant and interpreter. An initial language use survey was conducted with Polyclinic DSAs (n = 41) using a logbook approach to provide self-report data on language use in clinics. Frequencies of mean scores using a 10-point visual analogue scale (VAS) indicated that the majority of DSAs spoke mainly Cantonese in clinics and interpreted for postgraduates and professors. Conversation Analysis (CA) examined recipient design across a corpus (n = 23) of video-recorded review consultations between non-Cantonese speaking expatriate dentists and their Cantonese L1 patients. Three patterns of mediated interpreting indicated were: dentist designated expansions; dentist initiated interpretations; and assistant initiated interpretations to both the dentist and patient. The third, rather than being perceived as negative, was found to be framed either in response to patient difficulties or within the specific task routines of general dentistry. The findings illustrate trends in dentistry towards personalized care and patient empowerment as a reaction to product delivery approaches to patient management. Implications are indicated for both treatment adherence and the education of dental professionals. PMID- 25828073 TI - Identification of systemic immune response markers through metabolomic profiling of plasma from calves given an intra-nasally delivered respiratory vaccine. AB - Vaccination procedures within the cattle industry are important disease control tools to minimize economic and welfare burdens associated with respiratory pathogens. However, new vaccine, antigen and carrier technologies are required to combat emerging viral strains and enhance the efficacy of respiratory vaccines, particularly at the point of pathogen entry. New technologies, specifically metabolomic profiling, could be applied to identify metabolite immune-correlates representative of immune protection following vaccination aiding in the design and screening of vaccine candidates. This study for the first time demonstrates the ability of untargeted UPLC-MS metabolomic profiling to identify metabolite immune correlates characteristic of immune responses following mucosal vaccination in calves. Male Holstein Friesian calves were vaccinated with Pfizer Rispoval(r) PI3 + RSV intranasal vaccine and metabolomic profiling of post vaccination plasma revealed 12 metabolites whose peak intensities differed significantly from controls. Plasma levels of glycocholic acid, N [(3alpha,5beta,12alpha)-3,12-Dihydroxy-7,24-dioxocholan-24-yl]glycine, uric acid and biliverdin were found to be significantly elevated in vaccinated animals following secondary vaccine administration, whereas hippuric acid significantly decreased. In contrast, significant upregulation of taurodeoxycholic acid and propionylcarnitine levels were confined to primary vaccine administration. Assessment of such metabolite markers may provide greater information on the immune pathways stimulated from vaccine formulations and benchmarking early metabolomic responses to highly immunogenic vaccine formulations could provide a means for rapidly assessing new vaccine formulations. Furthermore, the identification of metabolic systemic immune response markers which relate to specific cell signaling pathways of the immune system could allow for targeted vaccine design to stimulate key pathways which can be assessed at the metabolic level. PMID- 25828075 TI - Characteristics of incident female breast cancer in Lebanon, 1990-2013: Descriptive study of 612 cases from a hospital tumor registry. AB - Despite the fact that breast cancer is a major health issue, very few studies describe its characteristics in the Arab world or the Middle East, particularly in Lebanon. We report in this article a retrospective pilot study of the characteristics of breast cancer in Lebanon. The pathological characteristics of 624 patients diagnosed between 1990 and 2013 randomly chosen from the archives of an oncology clinic affiliated to Hotel Dieu de France Hospital are analyzed. The mean age at diagnosis is 54.6+/-13.4 years with 43% diagnosed before the age of 50 years. The infiltrative ductal carcinoma represents the major pathological subtype. One third of the tumors had a size of more than 2 cm at diagnosis. Estrogen-receptors are positive in more than 50% of our patients and Her2-neu is overexpresssed in 30%. Luminal A represents 45.5% and the triple negative subgroup constitutes only 8.3%. Breast cancer in Lebanon is evolving to a more indolent disease. Therefore, public awareness and institution of screening programs are required. These programs should be based on national epidemiological data and necessitate the activation of the national cancer registry. PMID- 25828076 TI - Speech Auditory Brainstem Response through hearing aid stimulation. AB - Millions of people across the world are hearing impaired, and rely on hearing aids to improve their everyday life. Objective audiometry could optimize hearing aid fitting, and is of particular interest for non-communicative patients. Speech Auditory Brainstem Response (speech ABR), a fine electrophysiological marker of speech encoding, is presently seen as a promising candidate for implementing objective audiometry; yet, unlike lower-frequency auditory-evoked potentials (AEPs) such as cortical AEPs or auditory steady-state responses (ASSRs), aided speech ABRs (i.e., speech ABRs through hearing aid stimulation) have almost never been recorded. This may be due to their high-frequency components requesting a high temporal precision of the stimulation. We assess here a new approach to record high-quality and artifact-free speech ABR while stimulating directly through hearing aids. In 4 normal-hearing adults, we recorded speech ABR evoked by a /ba/ syllable binaurally delivered through insert earphones for quality control or through hearing aids. To assess the presence of a potential stimulus artifact, recordings were also done in mute conditions with the exact same potential sources of stimulus artifacts as in the main runs. Hearing aid stimulation led to artifact-free speech ABR in each participant, with the same quality as when using insert earphones, as shown with signal-to-noise (SNR) measurements. Our new approach consisting in directly transmitting speech stimuli through hearing aids allowed for a perfect temporal precision mandatory in speech ABR recordings, and could thus constitute a decisive step in hearing impairment investigation and in hearing aid fitting improvement. PMID- 25828077 TI - Tension Band Plating for Chronic Anterior Tibial Stress Fractures in High Performance Athletes. AB - BACKGROUND: Anterior tibial stress fractures are associated with high rates of delayed union and nonunion, which can be particularly devastating to a professional athlete who requires rapid return to competition. Current surgical treatment strategies include intramedullary nailing, which has satisfactory rates of fracture union but an associated risk of anterior knee pain. Anterior tension band plating is a biomechanically sound alternative treatment for these fractures. HYPOTHESIS: Tension band plating of chronic anterior tibial stress fractures leads to rapid healing and return to physical activity and avoids the anterior knee pain associated with intramedullary nailing. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 2001 and 2013, there were 13 chronic anterior tibial stress fractures in 12 professional or collegiate athletes who underwent tension band plating after failing nonoperative management. Patient charts were retrospectively reviewed for demographics, injury history, and surgical details. Radiographs were used to assess time to osseous union. Follow-up notes and phone interviews were used to determine follow-up time, return to training time, and whether the patient was able to return to competition. RESULTS: Cases included 13 stress fractures in 12 patients (9 females, 3 males). Five patients were track-and-field athletes, 4 patients played basketball, 2 patients played volleyball, and 1 was a ballet dancer. Five patients were Division I collegiate athletes and 7 were professional or Olympic athletes. Average age at time of surgery was 23.6 years (range, 20-32 years). Osseous union occurred on average at 9.6 weeks (range, 5.3-16.9 weeks) after surgery. Patients returned to training on average at 11.1 weeks (range, 5.7-20 weeks). Ninety-two percent (12/13) eventually returned to preinjury competition levels. Thirty-eight percent (5/13) underwent removal of hardware for plate prominence. There was no incidence of infection or nonunion. CONCLUSION: Anterior tension band plating for chronic tibial stress fractures provides a reliable alternative to intramedullary nailing with excellent results. Compression plating avoids the anterior knee pain associated with intramedullary nailing but may result in symptomatic hardware requiring subsequent removal. PMID- 25828078 TI - Changes in involved and uninvolved limb function during rehabilitation after anterior cruciate ligament reconstruction: implications for Limb Symmetry Index measures. AB - BACKGROUND: Functional testing is used to assess anterior cruciate ligament (ACL) reconstruction rehabilitation, with the goal of symmetric ability. The pattern of change in the uninvolved limb's function during rehabilitation is not established. HYPOTHESES: (1) Involved and uninvolved limb ability increases during rehabilitation, but the uninvolved limb ability increases to a lesser degree. (2) Hop tests will show larger initial asymmetry and will improve the most with rehabilitation. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This was a retrospective case series of 122 patients who underwent ACL reconstruction at our ambulatory surgery center and received multiple postoperative Standard Functional Tests (SFTs) between October 2009 and October 2013. Ten of the 12 individual tests within the SFT battery were analyzed. The patients' earliest and latest SFTs were compared for changes in Limb Symmetry Index (LSI) and absolute function in each limb. We also analyzed the subgroup with SFTs (n = 38) at both 4 and 6 months postoperatively. RESULTS: In all patients with multiple SFTs, involved limb performance increased in all tests except eyes-closed stork. Uninvolved limb performance increased in 4 SFT component tests and decreased in none. LSI significantly improved in 6 tests, all of which also showed involved limb improvement that was significant. Of these 6 tests, 5 showed initial LSI below 90%: single-leg squat, retro step-up, single leg hop, crossover triple hop, and timed hop. Retro step-up and single-leg hop showed LSI improvements greater than 10 percentage points. In patients with 4- and 6-month data, involved limb performance increased in all tests except single leg triple hop. Uninvolved limb performance increased in 5 SFT component tests and decreased in none. LSI significantly improved in 4 tests, all of which had initial LSI below 90%, and showed involved limb improvement that was significant. Retro step-up, single-leg hop, and crossover triple hop showed LSI improvements greater than 10 percentage points. CONCLUSION: During ACL reconstruction rehabilitation, LSI improvements indicated absolute increases in involved limb ability and were not attributable to uninvolved limb deterioration. The single leg squat, retro step-up, single-leg hop, crossover triple hop, and timed hop are suggested as highly useful tests, since all showed initial LSI below 90%, with significant LSI improvement after rehabilitation. PMID- 25828079 TI - The prevalence of radiographic findings of structural hip deformities in female collegiate athletes. AB - BACKGROUND: Structural deformities of the hip, including femoroacetabular impingement (FAI) and acetabular dysplasia, often limit athletic activity. Previous studies have reported an increased prevalence of radiographic cam FAI in male athletes, but data on the prevalence of structural hip deformities in female athletes are lacking. PURPOSE: (1) To quantify the prevalence of radiographic FAI deformities and acetabular dysplasia in female collegiate athletes from 3 sports: volleyball, soccer, and track and field. (2) To identify possible relationships between radiographic measures of hip morphologic characteristics and physical examination findings. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Anteroposterior (AP) pelvis and frog-leg lateral radiographs were obtained from 63 female athletes participating in Division I collegiate volleyball, soccer, and track and field. Lateral center edge angle (LCEA) and acetabular index were measured on AP films. Alpha angle and head-neck offset were measured on frog-leg lateral films. Pain during the supine impingement examination and hip rotation at 90 degrees of flexion were recorded. Random effects linear regression was used for group comparisons and correlation analyses to account for the lack of independence of observations made on left and right hips. RESULTS: Radiographic cam deformity (alpha angle >50 degrees and/or head neck offset <8 mm) was found in 48% (61/126) of hips. Radiographic pincer deformity (LCEA >40 degrees ) was noted in only 1% (1/126) of hips. No hips had radiographic mixed FAI (at least 1 of the 2 cam criteria and LCEA >40 degrees ). Twenty-one percent (26/126) of hips had an LCEA <20 degrees , indicative of acetabular dysplasia, and an additional 46% (58/126) of hips had borderline dysplasia (LCEA >=20 degrees and <=25 degrees ). Track and field athletes had significantly increased alpha angles (48.2 degrees +/- 7.1 degrees ) compared with the soccer players (40.0 degrees +/- 6.8 degrees ; P < .001) and volleyball players (39.1 degrees +/- 5.9 degrees ; P < .001). There was no significant difference in the LCEA (all P > .914) or the prevalence of dysplasia (LCEA <20 degrees ) between teams (all P > .551). There were no significant correlations between the radiographic measures and internal rotation (all P > .077). There were no significant differences (all P > .089) in radiographic measures between hips that were painful (n = 26) during the impingement examination and those that were not. CONCLUSION: These female athletes had a lower prevalence of radiographic FAI deformities compared with previously reported values for male athletes and a higher prevalence of acetabular dysplasia than reported for women in previous studies. PMID- 25828080 TI - Alterations in knee kinematics after partial medial meniscectomy are activity dependent. AB - BACKGROUND: Alterations in knee kinematics after partial meniscectomy have been linked to the increased risk of osteoarthritis in this population. Understanding differences in kinematics during static versus dynamic activities of increased demand can provide important information regarding the possible underlying mechanisms of these alterations. HYPOTHESIS: Differences in the following 2 kinematics measures will increase with activity demand: (1) the offset toward external tibial rotation for the meniscectomized limb compared with the contralateral limb during stance and (2) the difference in knee flexion angle at initial foot contact between the meniscectomized and contralateral limbs. STUDY DESIGN: Controlled laboratory study. METHODS: This study compared side-to-side differences in knee flexion and rotation angles during static and dynamic activities. Thirteen patients (2 female) were tested in a motion capture laboratory at 6 +/- 2 months after unilateral, arthroscopic, partial medial meniscectomy during a static reference pose and during 3 dynamic activities: walking, stair ascent, and stair descent. RESULTS: The meniscectomized limb demonstrated more external tibial rotation compared with the contralateral limb during dynamic activities, and there was a trend that this offset increased with activity demand (repeated-measures analysis of variance [ANOVA] for activity, P = .07; mean limb difference: static pose, -0.1 degrees +/- 3.3 degrees , P = .5; walking, 1.2 degrees +/- 3.8 degrees , P = .1; stair ascent, 2.0 degrees +/- 3.2 degrees , P = .02; stair descent, 3.0 degrees +/- 3.5 degrees , P = .005). Similarly, the meniscectomized knee was more flexed at initial contact than the contralateral limb during dynamic activities (repeated-measures ANOVA for activity P = .006; mean limb difference: reference pose, 1.0 degrees +/- 2.5 degrees , P = .09; walking, 2.0 degrees +/- 3.9 degrees , P = .05; stair ascent, 5.9 degrees +/- 5.3 degrees , P = .009; stair descent, 3.5 degrees +/- 4.0 degrees , P = .004). CONCLUSION: These results suggest both a structural element and a potential muscular element for the differences in kinematics after partial medial meniscectomy and highlight the importance of challenging the knee with activities of increased demands to detect differences in kinematics from the contralateral limb. CLINICAL RELEVANCE: With further investigation, these findings could help guide clinical rehabilitation of patients with torn meniscus tissue, especially in the context of the patients' increased risk of joint degeneration. PMID- 25828081 TI - An ultrasensitive impedimetric glycan biosensor with controlled glycan density for detection of lectins and influenza hemagglutinins. AB - An impedimetric glycan biosensor with optimised glycan density was applied for the detection of lectins and influenza hemagglutinins down to attomolar concentrations (aM). PMID- 25828082 TI - Mitochondrial Carnitine/Acylcarnitine Translocase: Insights in Structure/Function Relationship. AB - The mitochondrial carnitine/acylcarnitine translocase has been identified, purified and reconstituted in liposomes in 1990. Since that time it has been object of studies aimed to characterize its function and to define the molecular determinants of the translocation pathway. Thanks to these tenacious studies the molecular map of the amino acids involved in the catalysis has been constructed and the roles of critical residues in the translocation pathway have been elucidated. This has been possible through the combination of transport assay in reconstituted liposomes, site-directed mutagenesis, chemical labeling and bioinformatics. Recently some molecules which modulate CACT activity have been identified, such as glutathione and hydrogen peroxide, constituting some of the few cases of control mechanisms of mitochondrial carriers. The vast knowledge on the carnitine/acylcarnitine translocase is essential both as a progress in basic science and as instrument to foresee therapeutic or toxic effects of xenobiotics and drugs. Such studies have been already started pointing out the inhibitory action of drugs such as KM+/H+-ATPase inhibitors (omeprazole) or antibiotics (β-lactams) on the carnitine/acylcarnitine translocase, which can explain some of their adverse effects. PMID- 25828083 TI - Resistin Promotes Angiogenesis in Endothelial Progenitor Cells Through Inhibition of MicroRNA206: Potential Implications for Rheumatoid Arthritis. AB - Endothelial progenitor cells (EPCs) promote angiogenesis and are therefore key contributors to a wide variety of angiogenesis-related autoimmune diseases such as rheumatoid arthritis (RA). However, the signaling mechanisms through which these progenitor cells influence RA pathogenesis remain unknown. The aim of this study was to examine whether resistin plays a role in the pathogenesis of and angiogenesis associated with RA by circulating EPCs. We found that levels of resistin in synovial fluid and tissue from patients with RA and from mice with collagen-induced arthritis were overexpressed and promoted the homing of EPCs into the synovium, thereby inducing angiogenesis. EPCs isolated from healthy donors were used to investigate the signal transduction pathway underlying EPC migration and tube formation after treatment with resistin. We found that resistin directly induced a significant increase in expression of vascular endothelial growth factor (VEGF) in EPCs. We also found that the expression of microRNA-206 (miR-206) was negatively correlated with the expression of resistin during EPC-mediated angiogenesis. Notably, the increased expression of VEGF was associated with decreased binding of miR-206 to the VEGF-A 3' untranslated region through protein kinase C delta-dependent AMP-activated protein kinase signaling pathway. Moreover, blockade of resistin reduced EPC homing into synovial fluid and angiogenesis in vivo. Taken together, our study is the first to demonstrate that resistin promotes EPCs homing into the synovium during RA angiogenesis via a signal transduction pathway that involves VEGF expression in primary EPCs. These findings provide support for resistin as a therapeutic target for the patients with RA. Stem Cells 2015;33:2243-2255. PMID- 25828084 TI - JAK inhibitors and myelofibrosis, Einstein and ruxolitinib. PMID- 25828085 TI - Ofatumumab and its role as immunotherapy in chronic lymphocytic leukemia. PMID- 25828086 TI - Hematopoietic cell transplantation for acute leukemia: selecting donors. PMID- 25828087 TI - Aging and blood disorders: new perspectives, new challenges. PMID- 25828089 TI - Student nurse perceptions on evidence-based practice and research: an exploratory research study involving students from the University of Greenwich, England and the Faculty of Health Care Jesenice, Slovenia. AB - BACKGROUND: The importance of evidence-based practice (EBP) and research within nursing has been acknowledged since the 1970s. Research proficiencies for nurses include the abilities to search for and evaluate evidence, disseminate findings and apply findings to practice within the context of caring. However, there is a lack of information on how new undergraduate nursing curriculums have impacted on student nurses' perceptions on and importance of EBP and research. OBJECTIVES: The study aimed to explore student nurses' perceptions on and importance of EBP and research. METHODS: Data were collected via focus groups in 2013 with undergraduate student nurses from the University of Greenwich, England (n=7) and the Faculty of Health Care Jesenice, Slovenia (n=3). Cross-sectional sampling included focus groups with 1st year nursing students (4, n=22), 2nd year (4, n=38) and 3rd year (2, n=10). Data were analysed using Interpretative Phenomenological Analysis (IPA). RESULTS: Four emergent themes regarding students' perceptions of EBP and research were 'provided confidence, knowledge and empowerment in clinical practice', 'vital for improvements in patient care and safety', students' 'responsibility to develop nursing as a profession' and 'realities of research in clinical practice'. DISCUSSION: Student nurses found EBP and research daunting and difficult to understand, although perceived EBP and research as necessary for their current and future practice. However, student nurses highlighted the lack of clinical nurses' involvement in research and therefore struggled to conceptualise how they could maintain their EBP and research skills on leaving the academic setting. CONCLUSION: The importance of EBP and research was realised by student nurses across the two institutions. However, further development and involvement of clinical nurses with EBP and research is required to enable students to develop a clear understanding of how to take these skills forward in their future careers. PMID- 25828090 TI - Who wants to work with older people? Swedish student nurses' willingness to work in elderly care--a questionnaire study. AB - BACKGROUND: The aging population is a globally recognized challenge for the health care service. The growing number of older people will probably lead to increased demands for nurses working in elderly care. Clinical practice has been shown to have an impact on how student nurses perceive a particular field of nursing. OBJECTIVES: To compare perceptions of the clinical learning environment in nursing homes among students considering a career in aged care or not, and to examine the difference in age, gender and previous working experience as health care assistants in elderly care between the two groups. DESIGN: This was a cross sectional study using the Swedish version of the Clinical Learning Environment and Nurse Teacher evaluation scale. METHODS: Consecutive sampling was performed over three semesters from September 2011 to December 2012. The survey was conducted with 183 student nurses. Mann-Whitney U-test was used to examine differences in relation to two groups namely student nurses who did or did not consider to work in elderly care. A chi-square test of independence was performed to examine the difference in age, gender and previous working experience between the two groups. RESULTS: The analysis leaned towards an overall positive evaluation of the clinical learning environment with more positive values for students considering a career. There were no significant differences between younger students (18-23) and older students (24-50) regarding willingness to work in elderly care or not. Neither was any significant difference displayed between students, based on gender nor for previous work experience. CONCLUSION: Age, gender and previous work experiences as health care assistants did not impact on students' willingness to work in elderly care. Future studies need to acknowledge the complexity of why student nurses choose a particular pathway in nursing by longitudinal studies following cohorts of students during the course of the nursing programme. PMID- 25828088 TI - beta-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. AB - beta-thalassemias are monogenic disorders characterized by defective synthesis of the beta-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the beta-globin gene or its regulatory elements have been associated with beta-thalassemias. Due to the complexity of the regulation of the beta-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of beta-globin and abnormal erythropoiesis, as well as current and novel therapies. PMID- 25828091 TI - Key influences identified by first year undergraduate nursing students as impacting on the quality of clinical placement: A qualitative study. AB - BACKGROUND: Despite the fact that high quality clinical placement is an integral component of pre-registration nursing education for the development of the future nursing workforce, the literature identifies an ongoing struggle to 'get it right'. OBJECTIVE: To examine qualitative data gathered through the Quality Clinical Placements Evaluation project to identify what pre-registration nursing students deemed helpful and not helpful influences on their first year Professional Experience Placement. DESIGN: A total of 553 first year undergraduate nursing students from 2010 to 2012 were enrolled in the programme and all were invited to complete a validated survey to measure the quality of their first clinical placement. A total of 361 completed surveys were returned. This paper examines the data provided through open-ended questions within the survey related to most helpful and least helpful aspects of their clinical experience. METHODS: An inductive analysis approach using NVIVO allowed inherent areas to emerge from the raw data forming three key themes that influenced the experience of students. RESULTS: Feeling welcomed, individual versus team attitudes, and student expectations of supervising ward nurses were the themes identified that were perceived by the student as important to the success of learning and the quality of the experience overall. CONCLUSION: The findings echo previous research into the student experience of clinical placement; however the focus regarding the need for students to have a quality relationship with the supervising nurse is an area that warrants further exploration. Furthermore, we argue that students should be purposely engaged in the tertiary sector and provided guidance and strategies related to forming and maintaining relationships with those that supervise their clinical placement, in order to ensure consistent positive experiences. The outcomes from this study suggest that a missing component is teaching undergraduates how to manage relationships in clinical settings. PMID- 25828092 TI - An investigation of the validity of the Work Assessment Triage Tool clinical decision support tool for selecting optimal rehabilitation interventions for workers with musculoskeletal injuries. AB - OBJECTIVE: To evaluate the concurrent validity of a clinical decision support tool (Work Assessment Triage Tool (WATT)) developed to select rehabilitation treatments for injured workers with musculoskeletal conditions. DESIGN: Methodological study with cross-sectional and prospective components. SETTING: Data were obtained from the Workers' Compensation Board of Alberta rehabilitation facility in Edmonton, Canada. SUBJECTS: A total of 432 workers' compensation claimants evaluated between November 2011 and June 2012. MAIN MEASURES: Percentage agreement between the Work Assessment Triage Tool and clinician recommendations was used to determine concurrent validity. In claimants returning to work, frequencies of matching were calculated and compared between clinician and Work Assessment Triage Tool recommendations and the actual programs undertaken by claimants. The frequency of each intervention recommended by clinicians, Work Assessment Triage Tool, and case managers were also calculated and compared. RESULTS: Percentage agreement between clinician and Work Assessment Triage Tool recommendations was poor (19%) to moderate (46%) and Kappa = 0.37 (95% CI -0.02, 0.76). The Work Assessment Triage Tool did not improve upon clinician recommendations as only 14 out of 31 claimants returning to work had programs that contradicted clinician recommendations, but were consistent with Work Assessment Triage Tool recommendations. Clinicians and case managers were inclined to recommend functional restoration, physical therapy, or no rehabilitation while the Work Assessment Triage Tool recommended additional evidence-based interventions, such as workplace-based interventions. CONCLUSIONS: Our findings do not provide evidence of concurrent validity for the Work Assessment Triage Tool compared with clinician recommendations. Based on these results, we cannot recommend further implementation of the Work Assessment Triage Tool. However, the Work Assessment Triage Tool appeared more likely than clinicians to recommend interventions supported by evidence; thus warranting further research. PMID- 25828093 TI - Is Stroke Early Supported Discharge still effective in practice? A prospective comparative study. AB - OBJECTIVE: Randomised controlled trials have shown the benefits of Early Supported Discharge (ESD) of stroke survivors. Our aim was to evaluate whether ESD is still beneficial when operating in the complex context of frontline healthcare provision. DESIGN: We conducted a cohort study with quasi experimental design. A total of 293 stroke survivors (transfer independently or with assistance of one, identified rehabilitation goals) within two naturally formed groups were recruited from two acute stroke units: 'ESD' n=135 and 'Non ESD' n=158 and 84 caregivers. The 'ESD' group accessed either of two ESD services operating in Nottinghamshire, UK. The 'Non ESD' group experienced standard practices for discharge and onward referral. Outcome measures (primary: Barthel Index) were administered at baseline, 6 weeks, 6 months and 12 months. RESULTS: The ESD group had a significantly shorter length of hospital stay (P=0.029) and reported significantly higher levels of satisfaction with services received (P<0.001). Following adjustment for age differences at baseline, participants in the ESD group (n=71) had significantly higher odds (compared to the Non ESD group, n=85) of being in the ?90 Barthel Index category at 6 weeks (OR = 1.557, 95% CI 2.579 to 8.733), 6 months (OR = 1.541, 95% CI 2.617 to 8.340) and 12 months (OR 0.837, 95% CI 1.306 to 4.087) respectively in relation to baseline. Carers of patients accessing ESD services showed significant improvement in mental health scores (P<0.01). CONCLUSION: The health benefits of ESD are still evident when evidence based models of these services are implemented in practice. PMID- 25828094 TI - Feasibility of turbidity removal by high-gradient superconducting magnetic separation. AB - Several studies have focused on pollutant removal by magnetic seeding and high gradient superconducting magnetic separation (HGSMS). However, few works reported the application of HGSMS for treating non-magnetic pollutants by an industrial large-scale system. The feasibility of turbidity removal by a 600 mm bore superconducting magnetic separation system was evaluated in this study. The processing parameters were evaluated by using a 102 mm bore superconducting magnetic separation system that was equipped with the same magnetic separation chamber that was used in the 600 mm bore system. The double-canister system was used to process water pollutants. Analytical grade magnetite was used as a magnetic seed and the turbidity of the simulated raw water was approximately 110 NTU, and the effects of polyaluminum chloride (PAC) and magnetic seeds on turbidity removal were evaluated. The use of more PAC and magnetic seeds had few advantages for the HGSMS at doses greater than 8 and 50 mg/l, respectively. A magnetic intensity of 5.0 T was beneficial for HGSMS, and increasing the flow rate through the steel wool matrix decreased the turbidity removal efficiency. In the breakthrough experiments, 90% of the turbidity was removed when 100 column volumes were not reached. The processing capacity of the 600 mm bore industry scale superconducting magnetic separator for turbidity treatment was approximately 78.0 m(3)/h or 65.5 * 10(4) m(3)/a. The processing cost per ton of water for the 600 mm bore system was 0.1 $/t. Thus, the HGSMS separator could be used in the following special circumstances: (1) when adequate space is not available for traditional water treatment equipment, especially the sedimentation tank, and (2) when decentralized sewage treatment HGSMS systems are easier to transport and install. PMID- 25828095 TI - Dehydroepiandrosterone and multiple measures of functional immunity in young adults. AB - OBJECTIVES: Human immune function is strongly influenced by variation in hormone concentrations. The adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEA-S) are thought to be beneficial to immune function and disease resistance, but physiologically interact with testosterone and cortisol. We predict that DHEA and DHEA-S will interact with these other hormones in determining immunological outcomes. Understanding the interactive effects of these hormones will aid in understanding variability in immunocompetence and clarify discrepancies in human studies of androgen-immune interactions. METHODS: Thirty-eight participants collected morning saliva over three days, from which concentrations of DHEA, DHEA-S, testosterone, and cortisol were measured, as well as salivary bacteria killing ability to measure innate immune function. From blood collection, serum was collected to measure innate immune function via a hemolytic complement assay, and whole blood collected and processed to measure proliferative responses of lymphocytes in the presence of mitogens. RESULTS: DHEA was negatively correlated with T cell proliferation, and positively correlated with salivary bacteria killing in male participants. Additionally, using regression models, DHEA-S was negatively associated with hemolytic complement activity, but interaction variables did not yield statistically significant relationships for any other outcome measure. CONCLUSIONS: While interactions with other hormones did not significantly relate with immune function measures in this sample, DHEA and DHEA-S did differentially impact multiple branches of the immune system. Generally characterized as immunosupportive in action, DHEA is shown to inhibit certain facets of innate and cell-mediated immunity, suggesting a more complex role in regulating immunocompetence. PMID- 25828097 TI - Blocking integrin inactivation as an anti-angiogenic therapy. PMID- 25828096 TI - Insm1 cooperates with Neurod1 and Foxa2 to maintain mature pancreatic beta-cell function. AB - Key transcription factors control the gene expression program in mature pancreatic beta-cells, but their integration into regulatory networks is little understood. Here, we show that Insm1, Neurod1 and Foxa2 directly interact and together bind regulatory sequences in the genome of mature pancreatic beta-cells. We used Insm1 ablation in mature beta-cells in mice and found pronounced deficits in insulin secretion and gene expression. Insm1-dependent genes identified previously in developing beta-cells markedly differ from the ones identified in the adult. In particular, adult mutant beta-cells resemble immature beta-cells of newborn mice in gene expression and functional properties. We defined Insm1, Neurod1 and Foxa2 binding sites associated with genes deregulated in Insm1 mutant beta-cells. Remarkably, combinatorial binding of Insm1, Neurod1 and Foxa2 but not binding of Insm1 alone explained a significant fraction of gene expression changes. Human genomic sequences corresponding to the murine sites occupied by Insm1/Neurod1/Foxa2 were enriched in single nucleotide polymorphisms associated with glycolytic traits. Thus, our data explain part of the mechanisms by which beta-cells maintain maturity: Combinatorial Insm1/Neurod1/Foxa2 binding identifies regulatory sequences that maintain the mature gene expression program in beta-cells, and disruption of this network results in functional failure. PMID- 25828098 TI - An upp-based markerless gene replacement method for genome reduction and metabolic pathway engineering in Pseudomonas mendocina NK-01 and Pseudomonas putida KT2440. AB - A markerless gene replacement method was adapted by combining a suicide plasmid, pEX18Tc, with a counterselectable marker, the upp gene encoding uracil phosphoribosyltransferase (UPRTase), for the medium-chain length polyhydroxyalkanoates (PHA(MCL))-producing strain Pseudomonas mendocina NK-01. An NK-01 5-fluorouracil (5-FU) resistant background strain was first constructed by deleting the chromosomal upp gene. The suicide plasmid pEX18Tc, carrying a functional allele of the upp gene of P. mendocina NK-01, was used to construct the vectors to delete the algA (encoding mannose-1-phosphate guanylyltransferase) and phaZ (encoding PHA(MCL) depolymerase) genes, and a 30 kb chromosomal fragment in the 5-FU resistant background host. The genes were removed efficiently from the genome of P. mendocina NK-01 and left a markerless chromosomal mutant. In addition, two exogenous genes were inserted into the phaC1 (PHA(MCL) polymerase) loci of Pseudomonas putida KT-?UPP simultaneously. Thus, we constructed a genetically stable and marker-free P. putida KT2440 mutant with integrated mpd (encoding methyl parathion hydrolase (MPH)) and pytH (encoding a pyrethroid hydrolyzing carboxylesterase (PytH)) gene on the chromosome. The upp-based counterselection system could be further adapted for P. mendocina NK-01 and P. putida KT2440 and used for genome reduction and metabolic pathway engineering. PMID- 25828099 TI - Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. AB - Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through blood brain barrier (BBB). However, the molecular mechanism behind the passage through this natural barrier remains unclear. Here we show that cancer-derived extracellular vesicles (EVs), mediators of cell-cell communication via delivery of proteins and microRNAs (miRNAs), trigger the breakdown of BBB. Importantly, miR-181c promotes the destruction of BBB through the abnormal localization of actin via the downregulation of its target gene, PDPK1. PDPK1 degradation by miR 181c leads to the downregulation of phosphorylated cofilin and the resultant activated cofilin-induced modulation of actin dynamics. Furthermore, we demonstrate that systemic injection of brain metastatic cancer cell-derived EVs promoted brain metastasis of breast cancer cell lines and are preferentially incorporated into the brain in vivo. Taken together, these results indicate a novel mechanism of brain metastasis mediated by EVs that triggers the destruction of BBB. PMID- 25828101 TI - Genomic profiles and predictors of early allograft dysfunction after human liver transplantation. AB - Early hepatic allograft dysfunction (EAD) manifests posttransplantation with high serum transaminases, persistent cholestasis, and coagulopathy. The biological mechanisms are poorly understood. This study investigates the molecular mechanisms involved in EAD and defines a gene expression signature revealing different biological pathways in subjects with EAD from those without EAD, a potential first step in developing a molecular classifier as a potential clinical diagnostic. Global gene expression profiles of 30 liver transplant recipients of deceased donor grafts with EAD and 26 recipients without graft dysfunction were investigated using microarrays of liver biopsies performed at the end of cold storage and after graft reperfusion prior to closure. Results reveal a shift in inflammatory and metabolic responses between the two time points and differences between EAD and non-EAD. We identified relevant pathways (PPARalpha and NF kappaB) and targets (such as CXCL1, IL1, TRAF6, TIPARP, and TNFRSF1B) associated with the phenotype of EAD. Preliminary proof of concept gene expression classifiers that distinguish EAD from non-EAD patients, with Area Under the Curve (AUC) >0.80 were also identified. This data may have mechanistic and diagnostic implications for EAD. PMID- 25828100 TI - ANMS-ESNM position paper and consensus guidelines on biofeedback therapy for anorectal disorders. AB - BACKGROUND: Anorectal disorders such as dyssynergic defecation, fecal incontinence, levator ani syndrome, and solitary rectal ulcer syndrome are common, and affect both the adult and pediatric populations. Although they are treated with several treatment approaches, over the last two decades, biofeedback therapy using visual and verbal feedback techniques has emerged as an useful option. Because it is safe, it is commonly recommended. However, the clinical efficacy of biofeedback therapy in adults and children is not clearly known, and there is a lack of critical appraisal of the techniques used and the outcomes of biofeedback therapy for these disorders. PURPOSE: The American Neurogastroenterology and Motility Society and the European Society of Neurogastroenterology and Motility convened a task force to examine the indications, study performance characteristics, methodologies used, and the efficacy of biofeedback therapy, and to provide evidence-based recommendations. Based on the strength of evidence, biofeedback therapy is recommended for the short-term and long-term treatment of constipation with dyssynergic defecation (Level I, Grade A), and for the treatment of fecal incontinence (Level II, Grade B). Biofeedback therapy may be useful in the short-term treatment of Levator Ani Syndrome with dyssynergic defecation (Level II, Grade B), and solitary rectal ulcer syndrome with dyssynergic defecation (Level III, Grade C), but the evidence is fair. Evidence does not support the use of biofeedback for the treatment of childhood constipation (Level 1, Grade D). PMID- 25828102 TI - The screening value of baPWV and hs-crp to ASCVD in middle and elderly community population in Shanghai. PMID- 25828103 TI - Central venous cannulation and antegrade arterial perfusion for minimally invasive aortic valve surgery: Return to the basics. PMID- 25828104 TI - Combined angiotensin receptor blockade and neprilysin inhibition attenuates angiotensin-II mediated renal cellular collagen synthesis. PMID- 25828105 TI - Response to the letter by Akinori Sairaku et al.: Different mechanisms = synergic effect. PMID- 25828106 TI - Cardiovascular disease is associated with the perception of worsening psychosocial work characteristics. PMID- 25828107 TI - A case of malignant aortic calcification in congenital heart disease and rheumatoid arthritis. PMID- 25828108 TI - Exercise improves cardiac function and attenuates insulin resistance in Dahl salt sensitive rats. AB - BACKGROUND: The development of heart failure (HF) secondary to hypertension is a complex process related to a series of physiological and molecular factors including glucose dysregulation. The overall objective of this study was to investigate whether exercise training could improve cardiac function and insulin resistance in a rat model of hypertensive HF. METHODS: Seven week old Dahl salt sensitive rats received either 8% NaCl (n = 30) or 0.3% NaCl (n = 18) diet. After a 5-week diet, animals were randomly assigned to exercise training (treadmill running at 18 m/min, 5% inclination for 60 min, 5 days/week) or kept sedentary for 6 additional weeks. 2D echocardiography was used to calculate left ventricular (LV) dimensions, volumes and global functional parameters. LV global deformation parameters were measured with speckle tracking echocardiography. Insulin resistance was assessed using 1h oral glucose tolerance testing. RESULTS: High salt diet led to cardiac hypertrophy and HF, characterized by increased wall thicknesses and LV volumes as well as reduced deformation parameters. In addition, high salt diet was associated with the development of insulin resistance. Exercise training improved cardiac function, reduced the extent of interstitial fibrosis and reduced insulin levels 60 min post-glucose administration. CONCLUSIONS: Even if not fully reversed, exercise training in HF animals improved cardiac function and insulin resistance. Adjusted modalities of exercise training might offer new insights not only as a preventive strategy, but also as a treatment for HF patients. PMID- 25828109 TI - Impact of local endothelial shear stress on neointima and plaque following stent implantation in patients with ST-elevation myocardial infarction: A subgroup analysis of the COMFORTABLE AMI-IBIS 4 trial. AB - BACKGROUND: Numerous studies have demonstrated an association between endothelial shear stress (ESS) and neointimal formation after stent implantation. However, the role of ESS on the composition of neointima and underlying plaque remains unclear. METHODS: Patients recruited in the Comfortable AMI-IBIS 4 study implanted with bare metal stents (BMS) or biolimus eluting stents (BES) that had biplane coronary angiography at 13 month follow-up were included in the analysis. The intravascular ultrasound virtual-histology (IVUS-VH) and the angiographic data were used to reconstruct the luminal surface, and the stent in the stented segments. Blood flow simulation was performed in the stent surface, which was assumed to represent the luminal surface at baseline, to assess the association between ESS and neointima thickness. The predominant ESS was estimated in 3-mm segments and was correlated with the amount of neointima, neointimal tissue composition, and with the changes in the underlying plaque burden and composition. RESULTS: Forty three patients (18 implanted with BMS and 25 with BES) were studied. In both stent groups negative correlations were noted between ESS and neointima thickness in BMS (P < 0.001) and BES (P = 0.002). In BMS there was a negative correlation between predominant ESS and the percentage of the neointimal necrotic core component (P = 0.015). In BES group, the limited neointima formation did not allow evaluation of the effect of ESS on its tissue characteristics. ESS did not affect vessel wall remodeling and the plaque burden and composition behind BMS (P > 0.10) and BES (P > 0.45). CONCLUSIONS: ESS determines neointimal formation in both BMS and BES and affects the composition of the neointima in BMS. Conversely, ESS does not impact the plaque behind struts irrespective of stent type throughout 13 months of follow-up. PMID- 25828110 TI - The combined effect of physical activity and sedentary behaviors on a clustered cardio-metabolic risk score: The Helena study. AB - BACKGROUND/OBJECTIVE: Increased physical activity (PA) and decreased sedentary behaviors (SBs) may have beneficial effects on cardio-metabolic risk in adolescents. The aim of this study was to examine the associations between independent/combined effects of PA and SB with individual/clustered cardio metabolic risk factors. METHODS: A sample of 769 adolescents (12.5-17.5 years) from the HELENA cross-sectional study (Healthy Lifestyle in Europe by Nutrition in Adolescence) and with valid data on metabolic risk factors were included. RESULTS: Concerning moderate-to-vigorous-PA (MVPA) and vigorous-PA (VPA), measured with accelerometers, girls tended to do more MVPA (36%) and VPA (114%) than boys. Unadjusted analyses show a positive association between "PA >= 60 min/d; SB >= 2 h" and the ratio TC/HDL-c (beta = 0.27; 95%CI 0.01 to 0.52; p < 0.05), and a negative association between "MVPA >= 60 min/d; SB < 2h" with the ? 4Skinfolds (beta = -0.32; 95%CI -0.61 to -0.02; p<0.05). Moreover, "SB >= 2 h/d" was associated with increased cardio-metabolic risk (PR 1.59; 95%CI 1.05 to 2.39; p < 0.05), while "PA >= 60 min/d; SB < 2h" had a protective effect against cardio metabolic risk (PR 0.48; 95%CI 0.25 to 0.91; p < 0.05). After adjustment for potential confounders, a positive association between SB and ? 4Skinfolds was shown (beta = 0.28; 95%CI 0.04 to 0.53; p < 0.05). Furthermore, VO2max (mL/kg/min) tends to increase in those participants who do higher VPA and less SB (p = 0.042), and there was a protective effect of "VPA >= 30 min/d; SB < 2h" against cardio-metabolic risk (PR 0.24; 95%CI 0.07 to 0.85; p < 0.05). CONCLUSION: The current study suggests that adolescents should be encouraged to decrease sedentary lifestyle and increase physical activity, especially vigorous physical activity, in order to reduce cardio-metabolic risk. PMID- 25828111 TI - Accuracy of 64-slice coronary computed tomography in patients with tako-tsubo cardiomyopathy. PMID- 25828112 TI - Blood borne catecholamines and Takotsubo syndrome: An unsettled relationship. PMID- 25828113 TI - Increasing burden of psychiatric comorbidities amongst patients with Ischaemic Heart Disease. PMID- 25828114 TI - Relation of circumferential and longitudinal strain to other independent prognostic imaging markers in first time ST-elevation myocardial infarction. PMID- 25828115 TI - Impaired pain processing in patients with silent myocardial ischemia. PMID- 25828116 TI - Late presentation and surgical repair of ALCAPA. PMID- 25828117 TI - A case of repetitive and simultaneous stent thromboses. PMID- 25828118 TI - Safety of dabigatran or rivaroxaban for thoracoscopic ablation in patients with atrial fibrillation. PMID- 25828119 TI - Heart rate response to simulated obstructive apnea while awake predicts bradycardia during spontaneous obstructive sleep apnea. PMID- 25828120 TI - Prevalence of M4 macrophages within human coronary atherosclerotic plaques is associated with features of plaque instability. AB - BACKGROUND: The platelet chemokine CXCL4 induces monocyte differentiation resulting in a macrophage phenotype called "M4", which co-expresses CD68, MMP7, and S100A8. We hypothesized that M4 macrophages are associated with plaque destabilization. METHODS: Atherosclerotic arteries were obtained from explanted hearts of patients with severe coronary artery disease (CAD, n = 32) and of patients with dilated cardiomyopathy and no or mild CAD (controls, n = 19). Coronary arteries were stained with H&E, and immuno-fluorescence was performed against CD68, MMP7, and S100A8. RESULTS: Both CD68(+) macrophages representing the entire macrophage population and MMP7(+)S100A8(+)CD68(+) M4 macrophages could be reproducibly identified within all arterial layers. The average proportion of the M4 macrophage phenotype amongst all CD68(+) macrophages was 31.7 +/- 16.2%. The highest number of M4 macrophages was found in the adventitia, followed by the intima. CD68(+) and M4 macrophage numbers were significantly higher in patients with severe CAD. The presence of M4 macrophages within the intima and the media was significantly associated with plaque instability as determined by Stary class. Multivariate analysis showed a highly significant contribution of cardiovascular risk factors (P = 0.008) to plaque instability, while only trends were observed for age (P = 0.060) and intimal prevalence of M4 macrophages (P = 0.098). CONCLUSIONS: We demonstrate for the first time that M4 macrophages can be reproducibly found in coronary artery plaques. The prevalence of M4 macrophages is associated with indexes of plaque instability, most likely representing a surrogate marker of inflammatory activity. These findings suggest a pathogenetic role of M4 macrophages in vulnerable atherosclerotic plaques. PMID- 25828121 TI - Simultaneous computerised activation of the primary percutaneous coronary intervention pathway reduces out-of-hours door-to-balloon time but not mortality. AB - BACKGROUND: In 2009 activation of out of hours (OOH) primary percutaneous coronary intervention (PPCI) in our institution changed from separate telephone calls to a simultaneous computerised alert. We assessed the impact of this protocol change on door-to-balloon (DTB) time, in hospital and 1 year mortality. METHODS: Retrospective survey of our Myocardial Ischaemia National Audit Project (MINAP) database. OOH patients were categorized--pre- (Group 1) and post- (Group 2) introduction of the computerised alert protocol. RESULTS: OOH PPCI was performed for 793 patients (mean age 61, 73.4% male)--295 in Group 1 and 498 in Group 2. Median DTB times were 92 min (interquartile range [IQR] 75-111) for Group 1 and 76 min (IQR 64-97) for Group 2 (p < 0.0001). Forty-eight percent achieved DTB in <= 90 min in Group 1 compared to 70% in Group 2 (p < 0.0001). Computerised alert was associated with a shorter DTB time on multivariate analysis (beta coefficient -0.09, p = 0.03 for linear regression and OR 2.8, 95% CI 1.6-5.0, p < 0.0001 for logistic regression). In hospital mortality was 4.1% in Group 1 and 5% in Group 2 (p = 0.60). All-cause mortality at 1 year was 6.1% in Group 1 and 9.9% in Group 2 (p = 0.09). CONCLUSIONS: Simultaneous computerised activation for OOH PPCI reduced DTB times, increased the number of patients achieving target DTB times but did not affect mortality. PMID- 25828122 TI - Operative finding of aortic cusp prolapse in benfluorex-induced aortic regurgitation. PMID- 25828123 TI - Takotsubo (stress) cardiomyopathy and obstructive renal stones in an infant with norovirus gastroenteritis. PMID- 25828124 TI - Syncope associated with carotid sinus syndrome in an occult nasopharyngeal carcinoma. PMID- 25828125 TI - A honeycomb-like structure in chronic total occlusion demonstrated by frequency domain optical coherence tomography. PMID- 25828126 TI - Duration of daily TV/screen watching with cardiovascular, respiratory, mental and psychiatric health: Scottish Health Survey, 2012-2013. AB - BACKGROUND: The link of duration of TV and/or screen watching and chronic health conditions by subtypes is unclear. Therefore, the relationship between TV and/or screen watching hours and cardiovascular, respiratory, mental and psychiatric health and well-being (happiness) was assessed in an independent population-based survey to identify correlations of various hours with health conditions. METHODS: Data was retrieved from the Scottish Health Survey, 2012-2013. Information on demographics, lifestyle factors, self-reported health conditions and TV and/or screen watching duration in both Scottish adults and children was collected by annual household interviews. Chi-square test and survey weighted logistic and multi-nominal modelling were performed. RESULTS: 5527 (57.0%) Scottish adults aged 16-99 watched TV and/or screen daily for 3 + h on average. There was a trend toward more hypertension, angina, stroke, diabetes, chronic obstructive pulmonary disease and poor self-rated health and mental health. Reporting watching TV and/or screen for 4 + h, for 5 + h and for 8 + h was associated with higher rates of heart attack, heart murmur or other heart troubles and abnormal heart rhythms, respectively. 414 (20.7%) Scottish children aged 4-12 watched TV and/or screen for 3h or more. They tended to have poor self-rated health and life difficulties perceived as emotional and behavioural problems. CONCLUSION: There were associations between various hours of TV and/or screen watching (3+h) and poor health observed both in Scottish adults and children. Future educational and public health programmes minimising TV and/or screen watching in order to protect cardiovascular, respiratory, mental and psychiatric health might be considered. PMID- 25828127 TI - Sudomotor function and obesity-related risk factors in an elderly healthy population: The PROOF-Synapse Study. PMID- 25828129 TI - Transparency in medical research: Time for a paradigm shift. PMID- 25828128 TI - Spectral analysis-based risk score enables early prediction of mortality and cerebral performance in patients undergoing therapeutic hypothermia for ventricular fibrillation and comatose status. AB - BACKGROUND: Early prognosis in comatose survivors after cardiac arrest due to ventricular fibrillation (VF) is unreliable, especially in patients undergoing mild hypothermia. We aimed at developing a reliable risk-score to enable early prediction of cerebral performance and survival. METHODS: Sixty-one out of 239 consecutive patients undergoing mild hypothermia after cardiac arrest, with eventual return of spontaneous circulation (ROSC), and comatose status on admission fulfilled the inclusion criteria. Background clinical variables, VF time and frequency domain fundamental variables were considered. The primary and secondary outcomes were a favorable neurological performance (FNP) during hospitalization and survival to hospital discharge, respectively. The predictive model was developed in a retrospective cohort (n = 32; September 2006-September 2011, 48.5 +/- 10.5 months of follow-up) and further validated in a prospective cohort (n = 29; October 2011-July 2013, 5 +/- 1.8 months of follow-up). RESULTS: FNP was present in 16 (50.0%) and 21 patients (72.4%) in the retrospective and prospective cohorts, respectively. Seventeen (53.1%) and 21 patients (72.4%), respectively, survived to hospital discharge. Both outcomes were significantly associated (p < 0.001). Retrospective multivariate analysis provided a prediction model (sensitivity = 0.94, specificity = 1) that included spectral dominant frequency, derived power density and peak ratios between high and low frequency bands, and the number of shocks delivered before ROSC. Validation on the prospective cohort showed sensitivity = 0.88 and specificity = 0.91. A model derived risk-score properly predicted 93% of FNP. Testing the model on follow-up showed a c-statistic >= 0.89. CONCLUSIONS: A spectral analysis-based model reliably correlates time-dependent VF spectral changes with acute cerebral injury in comatose survivors undergoing mild hypothermia after cardiac arrest. PMID- 25828130 TI - Paclitaxel-eluting vs. bare metal stent implantation in saphenous vein graft lesions: Very long-term follow-up of the SOS (Stenting of Saphenous vein grafts) trial. PMID- 25828131 TI - Post-infarction biventricular free wall rupture with an extracardiac left to right shunt thorough a pseudoaneurysm. PMID- 25828132 TI - Clinical outcomes among patients with extreme obesity undergoing elective coronary revascularization: Evaluation of major complications in contemporary practice. AB - BACKGROUND/OBJECTIVES: Individuals with extreme obesity (EO), defined by a body mass index (BMI) >= 40 kg/m(2), constitute an increasingly prevalent population at higher risk of procedural complications. The implications of increasing weight burdens among this subset of patients in the setting of elective coronary revascularization have yet to be adequately studied. METHODS: We sought to define major complications in this group at one year following contemporary revascularization strategies by retrospectively analysing a cohort of consecutive EO patients undergoing elective percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The primary endpoint was a composite of peri- and post-procedural complications. Secondary endpoints included a cardiovascular composite and target vessel revascularization (TVR). RESULTS: Adjusted event-free survival curves for the primary endpoint among 133 patients differed significantly with higher BMI (>43.2 kg/m(2)) associated with greater risk (p=0.02). The primary endpoint occurred more frequently with CABG compared to PCI (24.2% vs. 5.0%, p < 0.01), which remained significant after adjusting for differences in baseline variables. Rates of the cardiovascular composite and TVR were comparable. CONCLUSIONS: Increasing BMI was associated with greater risk for major complications among EO patients undergoing elective coronary revascularization. PCI was associated with fewer complications; however, both revascularization strategies demonstrated equivalent rates of death, MI, and/or stroke. Larger studies may permit a better understanding of the associations between increasing BMI and specific outcomes and to evaluate the role for pre procedural weight loss in this select population. PMID- 25828133 TI - Low birth weight and large adult waist circumference increase the risk of cardiovascular disease in remote indigenous Australians--An 18 year cohort study. PMID- 25828134 TI - The effects of angiotensin receptor blockers on outcomes of Chinese patients with atrial fibrillation. PMID- 25828135 TI - In vivo characterization of changes in composition of organized thrombus in patient with chronic thromboembolic pulmonary hypertension treated with balloon pulmonary angioplasty. PMID- 25828136 TI - CYP2C19*2 genotype influence in acute coronary syndrome patients undergoing serial clopidogrel dose tailoring based on platelet function testing: Analysis from randomized controlled trial NCT02096419. PMID- 25828137 TI - Clinical and anatomical predictors of MitraClip therapy failure for functional mitral regurgitation: single central clip strategy in asymmetric tethering. PMID- 25828138 TI - Coronary strictures, intraluminal thrombus and aneurysms: Unreported imaging appearance of ALCAPA syndrome post Takeuchi procedure. PMID- 25828139 TI - Ventricular aneurysms in cardiac sarcoidosis: From physiopathology to surgical treatment through a clinical case presenting with ventricular arrhythmias. PMID- 25828140 TI - Is there a "chronic Takotsubo syndrome"? Could "smart-phone"-based technology be of aid? PMID- 25828141 TI - Anxiety and depression scores in patients with coronary artery disease and coronary artery ectasia. PMID- 25828142 TI - Elevated serum soluble ST2 levels may predict the fatal outcomes in patients with chronic heart failure. PMID- 25828143 TI - The repeated bout effect of typical lower body strength training sessions on sub maximal running performance and hormonal response. AB - PURPOSE: This study examined the effects of two typical strength training sessions performed 1 week apart (i.e. repeated bout effect) on sub-maximal running performance and hormonal. METHODS: Fourteen resistance-untrained men (age 24.0 +/- 3.9 years; height 1.83 +/- 0.11 m; body mass 77.4 +/- 14.0 kg; VOpeak 48.1 +/- 6.1 M kg(-1) min(-1)) undertook two bouts of high-intensity strength training sessions (i.e. six-repetition maximum). Creatine kinase (CK), delayed onset muscle soreness (DOMS), counter-movement jump (CMJ) as well as concentrations of serum testosterone, cortisol and testosterone/cortisol ratio (T/C) were examined prior to and immediately post, 24 (T24) and 48 (T48) h post each strength training bout. Sub-maximal running performance was also conducted at T24 and T48 of each bout. RESULTS: When measures were compared between bouts at T48, the degree of elevation in CK (-58.4 +/- 55.6 %) and DOMS (-31.43 +/- 42.9 %) and acute reduction in CMJ measures (4.1 +/- 5.4 %) were attenuated (p < 0.05) following the second bout. Cortisol was increased until T24 (p < 0.05) although there were no differences between bouts and no differences were found for testosterone and T/C ratio (p > 0.05). Sub-maximal running performance was impaired until T24, although changes were not attenuated following the second bout. CONCLUSIONS: The initial bout appeared to provide protection against a number of muscle damage indicators suggesting a greater need for recovery following the initial session of typical lower body resistance exercises in resistance-untrained men although sub-maximal running should be avoided following the first two sessions. PMID- 25828144 TI - Evaluation of force-velocity and power-velocity relationship of arm muscles. AB - PURPOSE: A number of recent studies have revealed an approximately linear force velocity (F-V) and, consequently, a parabolic power-velocity (P-V) relationship of multi-joint tasks. However, the measurement characteristics of their parameters have been neglected, particularly those regarding arm muscles, which could be a problem for using the linear F-V model in both research and routine testing. Therefore, the aims of the present study were to evaluate the strength, shape, reliability, and concurrent validity of the F-V relationship of arm muscles. METHODS: Twelve healthy participants performed maximum bench press throws against loads ranging from 20 to 70 % of their maximum strength, and linear regression model was applied on the obtained range of F and V data. One repetition maximum bench press and medicine ball throw tests were also conducted. RESULTS: The observed individual F-V relationships were exceptionally strong (r = 0.96-0.99; all P < 0.05) and fairly linear, although it remains unresolved whether a polynomial fit could provide even stronger relationships. The reliability of parameters obtained from the linear F-V regressions proved to be mainly high (ICC > 0.80), while their concurrent validity regarding directly measured F, P, and V ranged from high (for maximum F) to medium-to-low (for maximum P and V). CONCLUSIONS: The findings add to the evidence that the linear F V and, consequently, parabolic P-V models could be used to study the mechanical properties of muscular systems, as well as to design a relatively simple, reliable, and ecologically valid routine test of the muscle ability of force, power, and velocity production. PMID- 25828145 TI - Complex ophthalmoplaegia denoting Wernicke encephalopathy in a non-alcoholic individual. PMID- 25828147 TI - Clinical Profile and Quality of Life of Adult Patients After the Fontan Procedure. AB - Increasingly, more patients with univentricular heart reach adulthood. Therefore, long-term psychological features are an important concern. The aim of this study was to evaluate the clinical and psychological profile of post-Fontan adult patients and to identify the most significant determinants of quality of life. In this retrospective cross-sectional study, we reviewed the surgical and medical history of post-Fontan adult patients. Patients underwent a 24-h electrocardiogram, echocardiography and exercise testing. Self-report questionnaires were used to assess the Work Ability Index, quality of life (Satisfaction with Life Scale), perceived health status (SF-36 questionnaire), coping strategies (Brief Cope questionnaire) and presence of mood disorders (Hospital Anxiety and Depression Scale). Thirty-nine patients aged between 18 and 48 years (mean 27.5 years) were enrolled. The mean follow-up was 21.5 years. Most patients were unmarried (82.9 %), had a high school diploma (62.9 %) and were employed (62.9 %). Twenty-nine patients (82.3 %) had at least one long-term complication. The median single ventricle ejection fraction was 57 %, and the median maximal oxygen consumption was 26.8 ml/min/kg. This population tended to be anxious and to use adaptive coping strategies. Quality of life was perceived as excellent or good in 57.2 % of cases and was not related to either cardiac function or exercise capacity. Both quality of life and SF-36 domains were related to the Work Ability Index. This cohort of post-Fontan adult patients enjoyed a good quality of life irrespective of disease severity. PMID- 25828146 TI - Highlights on mechanisms of drugs targeting MDSCs: providing a novel perspective on cancer treatment. AB - The hallmark of tumor microenvironment is that it makes up of numerous immunomodulatory cells and factors which exert essential roles in immunoprotection and immunosuppression in addition to tumor cells. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells reported to promote immunosuppression and angiogenesis and facilitate tumor metastasis and invasion. The wide scope of MDSCs functional activities make these cells promising targets for effective cancer treatments. In this review, we briefly discuss the origin, subpopulation, and functions of MDSCs, as well as the potential to target these cells for therapeutic benefit. We focus on the underlying molecular mechanisms of these drugs targeting MDSCs, mainly from the standpoint of molecules related to drug targets. PMID- 25828148 TI - Standard error or standard deviation? PMID- 25828149 TI - A Budget Impact Analysis of Newly Available Hepatitis C Therapeutics and the Financial Burden on a State Correctional System. AB - Hepatitis C virus (HCV) infection continues to disproportionately affect incarcerated populations. New HCV drugs present opportunities and challenges to address HCV in corrections. The goal of this study was to evaluate the impact of the treatment costs for HCV infection in a state correctional population through a budget impact analysis comparing differing treatment strategies. Electronic and paper medical records were reviewed to estimate the prevalence of hepatitis C within the Rhode Island Department of Corrections. Three treatment strategies were evaluated as follows: (1) treating all chronically infected persons, (2) treating only patients with demonstrated fibrosis, and (3) treating only patients with advanced fibrosis. Budget impact was computed as the percentage of pharmacy and overall healthcare expenditures accrued by total drug costs assuming entirely interferon-free therapy. Sensitivity analyses assessed potential variance in costs related to variability in HCV prevalence, genotype, estimated variation in market pricing, length of stay for the sentenced population, and uptake of newly available regimens. Chronic HCV prevalence was estimated at 17% of the total population. Treating all sentenced inmates with at least 6 months remaining of their sentence would cost about $34 million-13 times the pharmacy budget and almost twice the overall healthcare budget. Treating inmates with advanced fibrosis would cost about $15 million. A hypothetical 50% reduction in total drug costs for future therapies could cost $17 million to treat all eligible inmates. With immense costs projected with new treatment, it is unlikely that correctional facilities will have the capacity to treat all those afflicted with HCV. Alternative payment strategies in collaboration with outside programs may be necessary to curb this epidemic. In order to improve care and treatment delivery, drug costs also need to be seriously reevaluated to be more accessible and equitable now that HCV is more curable. PMID- 25828150 TI - CCL7 contributes to the TNF-alpha-dependent inflammation of lesional psoriatic skin. AB - Chemokines are small chemotactic proteins that have a crucial role in leukocyte recruitment into tissue. Targeting these mediators has been suggested as a potential therapeutic option in inflammatory skin diseases such as psoriasis. Using quantitative RT-PCR, we found CCL7, a chemokine ligand known to interact with multiple C-C chemokine receptors, to be markedly increased in lesional psoriasis as opposed to atopic dermatitis, lichen planus, non-lesional psoriatic and normal control skin. Surprisingly, this increase in CCL7 mRNA expression exceeded that of all other chemokines investigated, and keratinocytes and dermal blood endothelial cells were identified as its likely cellular sources. In an imiquimod-induced psoriasis-like mouse model, CCL7 had a profound impact on myeloid cell inflammation as well as on the upregulation of key pro-psoriatic cytokines such as CCL20, IL-12p40 and IL-17C, while its blockade led to an increase in the antipsoriatic cytokine IL-4. In humans receiving the TNF-alpha blocker infliximab, CCL7 was downregulated in lesional psoriatic skin already within 16 hours after a single intravenous infusion. These data suggest that CCL7 acts as a driver of TNF-alpha-dependent Th1/Th17-mediated inflammation in lesional psoriatic skin. PMID- 25828151 TI - Lymphadenopathy in Patients With Chikungunya Virus Infection Imported From Hispaniola: Case Reports. AB - Chikungunya virus (CHIKV) is currently spreading in the Caribbean and America. Lymphadenopathy, described in infections with other alphaviruses, is not commonly reported in CHIKV infections. Painful lymphadenopathy was found in three of the first six CHIKV infections from the current outbreak diagnosed at a reference center in Madrid, Spain. PMID- 25828152 TI - Not just ordinary hand dermatitis: mechanic's hands revealing dermatomyositis. PMID- 25828153 TI - Expectations of pregnant women of Mexican origin regarding their health care providers. AB - OBJECTIVE: To explore the expectations of pregnant women of Mexican origin regarding trust and communication with their health care providers. DESIGN: Qualitative, descriptive inquiry. SETTING: A large metropolitan area community clinic in Texas that provided services to predominately Hispanic women. PARTICIPANTS: The sample consisted of 13 women between ages 19 and 36 (mean = 29) who received prenatal health care at a community clinic that offers care to Hispanic women. METHODS: Semistructured interviews were conducted with open-ended starter questions and follow-up questions based on the participant responses. Based on the women's language preference nine interviews were conducted in Spanish and four in English. RESULTS: Themes emerged from the beginning interviews, and after five interviews, saturation was reached. Data were arranged by the emerged themes of the model of trust and communication (Figure 1). The themes reflected the perception of trust, communication, patient centeredness, and satisfaction with health care providers. CONCLUSION: These women wanted their providers to provide them with "everything," to be direct, to speak their language, and to present information as friends. Health care providers need to be able to provide communication not only in the participant's preferred language, but also in a way that is culturally sensitive. PMID- 25828154 TI - Blink-related dynamic switching between internal and external orienting networks while viewing videos. AB - Humans spontaneously generate eyeblinks every few seconds. However, because this blink rate is several times more common than is required for ocular lubrication, the function of most spontaneous eyeblinks remains unknown. Because spontaneous eyeblinks tend to occur at implicit breakpoints in video stories, I hypothesized that spontaneous eyeblinks play an active role in attentional disengagement from external stimuli. Consistent with this, we previously found that spontaneous eyeblinks involve the concurrent deactivation of the dorsal attention network and activation of the default mode network when individuals are viewing videos. However, this previous study examined only the upper brain regions to increase the temporal resolution of the data. Therefore, the present study examined whether the temporal and subcortical regions exhibited blink-related activations or deactivations using the same visual stimuli as in the previous study. Data revealed that the bilateral hippocampus and cerebellum showed a prominent but momentary activation after the blink onset. In contrast, a blink-related deactivation was observed in both the right ventral and dorsal attention networks. These results suggest that spontaneous eyeblinks are involved in the attentional disengagement from external visual information via the massive and dynamic alteration of brain activity between the external and internal orienting networks. PMID- 25828155 TI - Reliability of structure tensors in representing soft tissues structure. AB - Structure tensors have been applied as descriptors of tissue morphology for constitutive modeling. Here the reliability of these tensors in representing tissues structure is investigated by model simulations of a few examples of generated and measured planar fiber orientation distributions. Reliability was evaluated by comparing the data with the orientation density distribution recovered from the structure tensor representation, and with a orientation density recovered from an alternative representation by Fourier series of spherical harmonics. The results show that except for the case of uniform or close to uniform orientation distributions, the distributions recovered from the structure tensor fit the data poorly. On the other hand, orientation distributions recovered from Fourier series of spherical harmonics converge to the data distributions provided sufficient terms are included in the truncated series. These results suggest that the structure tensor is a reliable descriptor of tissue structure only under very limited cases. PMID- 25828156 TI - Effects of aneurysm on the directional, regional, and layer distribution of residual strains in ascending thoracic aorta. AB - Stress analyses in ascending thoracic aortic aneurysms require measurement of the stress-free state of tissue, for which there is limited information. The true reference configuration can also be difficult to delineate with opening angle measurements, due to (a) the variability in aneurysmal shape and (b) layered wall structure, suggesting spatial dependency of the residual strain field, and (c) the non-consideration of axial residual strains. The present study was designed to overcome these difficulties, by providing extensive data about the consequences of aneurysm on the directional, regional, and layer distribution of residual strains in the ascending thoracic aorta. We demonstrate that the opening angle of rings cut-open anteriorly correlated positively with age, diameter, degree of atherosclerosis, and circumferential residual strain at the external wall and negatively with that at the internal wall. As anticipated from the highly curved and non-axisymmetric geometry, the opening angle of ascending thoracic aortic aneurysms from tricuspid aortic valve patients declined notably, from ~240 to 190 deg, along a relatively short vessel length and residual strains varied strongly from one layer to another, being compressive in the intima and tensile in the media and adventitia, and depended also on circumferential position and direction. Smaller opening angles were found in aneurysms from bicuspid aortic valve patients and non-aneurysmal aorta, but differences were only significant for the latter that also showed less pronounced axial decline and smaller layer-specific residual strains. Dimensional data of the aortic layers obtained via histology support the association between opening angle change and non-uniform tissue remodeling, with the greater cross-sectional area of the intima and media in the wall of tricuspid aortic valve aneurysms explaining the increase of opening angle in this patient class compared to control. PMID- 25828157 TI - Microstructure and compressive mechanical properties of cortical bone in children with osteogenesis imperfecta treated with bisphosphonates compared with healthy children. AB - Osteogenesis imperfecta (OI) is a genetic disorder characterized by a change in bone tissue quality, but little data are available to describe the factors involved at the macroscopic scale. To better understand the effect of microstructure alterations on the mechanical properties at the sample scale, we studied the structural and mechanical properties of six cortical bone samples from children with OI treated with bisphosphonates and compared them to the properties of three controls. Scanning electron microscopy, high resolution computed tomography and compression testing were used to assess these properties. More resorption cavities and a higher osteocyte lacunar density were observed in OI bone compared with controls. Moreover, a higher porosity was measured for OI bones along with lower macroscopic Young's modulus, yield stress and ultimate stress. The microstructure was impaired in OI bones; the higher porosity and osteocyte lacunar density negatively impacted the mechanical properties and made the bone more prone to fracture. PMID- 25828158 TI - FEM simulation of single beard hair cutting with foil-blade-shaving system. AB - The performance of dry-shavers depends on the interaction of the shaving components, hair and skin. Finite element models on the ABAQUS/Explicit platform are established to simulate the process of beard hair cutting. The skin is modelled as three-layer structure with a single cylindrical hair inserted into the skin. The material properties of skin are considered as Neo-Hookean hyper elastic (epidermis) and Prony visco-elastic (dermis and hypodermis) with finite deformations. The hair is modelled as elastic-plastic material with shear damage. The cutting system is composed of a blade and a foil of shaver. The simulation results of cutting processes are analyzed, including the skin compression, hair bending, hair cutting and hair severance. Calculations of cutting loads, skin stress, and hair damage show the impact of clearance, skin bulge height, blade dimension and shape on cutting results. The details show the build-up of finite element models for hair cutting, and highlight the challenges arising during model construction and numerical simulation. PMID- 25828159 TI - Predicting composition-property relationships for glass ionomer cements: a multifactor central composite approach to material optimization. AB - Adjusting powder-liquid ratio (P/L) and polyacrylic acid concentration (AC) has been documented as a means of tailoring the handling and mechanical properties of glass ionomer cements (GICs). This work implemented a novel approach in which the interactive effects of these two factors on three key GIC properties (working time, setting time, and compressive strength) were investigated using a central composite design of experiments. Using nonlinear regression analysis, formulation property relationships were derived for each property, which enabled prediction of an optimal formulation (P/L and AC) through application of the desirability approach. A novel aluminum free GIC was investigated, as this material may present the first clinically viable GIC for use in injectable spinal applications, such as vertebroplasty. Ultimately, this study presents the first series of predictive regression models that explain the formulation-dependence of a GIC, and the first statistical method for optimizing both P/L and AC depending on user-defined inputs. PMID- 25828160 TI - The effect of meat cuts and thermal processing on selected mineral concentration in beef from Holstein-Friesian bulls. AB - The impact of meat cuts (nine muscles and liver) and thermal processing on selected mineral (potassium, sodium, phosphorus, magnesium, zinc, iron, including heme form) concentration in beef from Holstein-Friesian bulls was evaluated in the present study. The mineral's content widely varied depending on the tissue type (skeletal muscles/liver, except zinc) and between the different bovine muscles. The greatest diversity between the muscles demonstrated was zinc (3.5 6.9 mg 100 g(-1)f/w) and iron (1.7-2.3 mg 100 g(-1)f/w), however, there were no significant differences in heme iron to total iron ratio (average 74%). Thermal processes conducted on longissimus dorsi muscles also significantly affected mineral concentration. Grilled, roasted and fried bovine meat was characterised by a higher content (by 6-26%) of most studied minerals (except sodium) as compared to raw meat. Sodium levels in processed meat were 16-33% lower than in raw samples. PMID- 25828161 TI - Increased work pace is unprofitable: a beef-cutting case study. AB - The beef industry worldwide is showing a trend towards increased cutting pace aimed at higher profits. However, prior research in the duck meat industry suggested that a higher cutting pace reduced quality and yield, leading to losses. This study aimed to test this hypothesis by investigating the effects of varying beef-cutting paces on yield, quality and economy. A field experiment was conducted on six workers cutting beef fillet, sirloin and entrecote. Three types of paces were sequentially tested: Baseline (i.e., status quo), 'Quantity focus' (i.e., pace required to maximise quantity) and 'Quality focus' (i.e., pace required to minimise errors). The results showed a significant drop in yield, increased rate of quality deficiency and economic losses with the change to 'Quantity focus' (from Baseline and 'Quality focus') for all meat types. Workers supported these results and also added health problems to the list. The results confirmed that an increased cutting pace is unprofitable. PMID- 25828162 TI - Reverse electron transport effects on NADH formation and metmyoglobin reduction. AB - The objective was to determine if NADH generated via reverse electron flow in beef mitochondria can be used for electron transport-mediated reduction and metmyoglobin reductase pathways. Beef mitochondria were isolated from bovine hearts (n=5) and reacted with combinations of succinate, NAD, and mitochondrial inhibitors to measure oxygen consumption and NADH formation. Mitochondria and metmyoglobin were reacted with succinate, NAD, and mitochondrial inhibitors to measure electron transport-mediated metmyoglobin reduction and metmyoglobin reductase activity. Addition of succinate and NAD increased oxygen consumption, NADH formation, electron transport-mediated metmyoglobin reduction, and reductase activity (p<0.05). Addition of antimycin A prevented electron flow beyond complex III, therefore, decreasing oxygen consumption and electron transport-mediated metmyoglobin reduction. Addition of rotenone prevented reverse electron flow, increased oxygen consumption, increased electron transport-mediated metmyoglobin reduction, and decreased NADH formation. Succinate and NAD can generate NADH in bovine tissue postmortem via reverse electron flow and this NADH can be used by both electron transport-mediated and metmyoglobin reductase pathways. PMID- 25828163 TI - A comparison of technical replicate (cuts) effect on lamb Warner-Bratzler shear force measurement precision. AB - The Warner-Bratzler shear force (WBSF) of 335 lamb m. longissimus lumborum (LL) caudal and cranial ends was measured to examine and simulate the effect of replicate number (r: 1-8) on the precision of mean WBSF estimates and to compare LL caudal and cranial end WBSF means. All LL were sourced from two experimental flocks as part of the Information Nucleus slaughter programme (CRC for Sheep Industry Innovation) and analysed using a Lloyd Texture analyser with a Warner Bratzler blade attachment. WBSF data were natural logarithm (ln) transformed before statistical analysis. Mean ln(WBSF) precision improved as r increased; however the practical implications support an r equal to 6, as precision improves only marginally with additional replicates. Increasing LL sample replication results in better ln(WBSF) precision compared with increasing r, provided that sample replicates are removed from the same LL end. Cranial end mean WBSF was 11.2 +/- 1.3% higher than the caudal end. PMID- 25828164 TI - Simple and sensitive monitoring of beta2-agonist residues in meat by liquid chromatography-tandem mass spectrometry using a QuEChERS with preconcentration as the sample treatment. AB - A liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) method was established for the simultaneous determination of the levels of 10 beta2-agonists in meat. The samples were extracted using an aqueous acidic solution and cleaned up using a Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) technique utilising a DVB-NVP-SO3Na sorbent synthesised in-house. First, the beta2-agonist residues were extracted in an aqueous acidic solution, followed by matrix solid-phase dispersion for clean-up. The linearities of the method were R(2)=0.9925-0.9998, with RSDs of 2.7-15.3% and 73.7-103.5% recoveries. Very low limits of detection (LOD) and quantitation (LOQ) of 0.2-0.9 MUg/kg and 0.8-3.2 MUg/kg, respectively, were achieved for spiked meat. The values obtained were lower than the maximum residue limits (MRLs) established by the EU and China. These results clearly demonstrate the feasibility of the proposed approach. The evaluated method provided reliable screening, quantification and identification of 10 beta2-agonists in meat. PMID- 25828165 TI - Species-specific effects on non-enzymatic metmyoglobin reduction in vitro. AB - Our objectives were to determine the non-enzymatic metmyoglobin reduction properties of bovine, porcine, and equine myoglobins and to characterize the effects of pre-incubation of 4-hydroxy-2-nonenal (HNE) with myoglobins on non enzymatic metmyoglobin reduction in vitro. Purified bovine, porcine, and equine metmyoglobins (0.05 mM) were reduced at pH 5.6 and 7.4 in the presence or absence of HNE. Rates of metmyoglobin reduction were monitored by spectrophotometry, and myoglobin adducts were characterized by high-resolution mass-spectrometry. Results showed that the species origins of individual myoglobins determined rates of non-enzymatic reduction (beef>equine>pork; P<0.05). Irrespective of species, pre-incubation of HNE myoglobin decreased non-enzymatic metmyoglobin reduction compared with control at both pH 5.6 and 7.4 (P<0.05). Mass spectrometric analysis revealed adducts of HNE with bovine, porcine, and equine myoglobins. The results indicate that the amino acid composition and the covalent binding of HNE with myoglobin can significantly decrease the ability of heme to accept electrons. PMID- 25828166 TI - Does Suture Technique Affect Re-Rupture in Arthroscopic Rotator Cuff Repair? A Meta-analysis. AB - PURPOSE: To evaluate the effects of suture configuration, repair method, and tear size on rotator cuff (RC) repair healing. METHODS: We conducted a literature search of articles that examined surgical treatment of RC tears published between January 2003 and September 2014. For single-row (SR) repairs, we calculated rerupture rates for simple, mattress, and modified Mason-Allen sutures while stratifying by tear size. All double-row repairs-those using 2 rows of suture anchors (DA) and those using a suture bridge (SB)--were performed using mattress sutures, and we compared rerupture rates by repair method while stratifying by tear size. A random-effects model with pooled estimates for between-study variance was used to estimate the overall rerupture proportion and corresponding 95% confidence interval for each group. Statistical significance was defined as P < .05. RESULTS: A total of 682 RC repairs from 13 studies were included. For SR repairs of tears measuring less than 3 cm, there was no significant difference in rerupture rates for modified Mason-Allen sutures versus simple sutures (P = .18). For SR repairs of tears measuring 3 cm or more, there was no significant difference in rerupture rates for mattress sutures versus simple sutures (P = .23). The rates of rerupture did not differ between SB and DA repairs for tears measuring less than 3 cm (P = .29) and 3 cm or more (P = .50). CONCLUSIONS: For SR repairs, there were no significant differences in rerupture rates between suture techniques for any repair method or tear size. All DA and SB repairs were secured with mattress sutures, and there were no differences in the rates of rerupture between these methods for either size category. These findings suggest that suture technique may not affect rerupture rates after RC repair. LEVEL OF EVIDENCE: Level IV, systematic review of Level I through IV studies. PMID- 25828167 TI - Prognostic Factors of Arthroscopic Extensor Carpi Radialis Brevis Release for Lateral Epicondylitis. AB - PURPOSE: The purpose of this study was to analyze factors affecting the treatment outcomes and prognoses of arthroscopic debridement for refractory lateral epicondylitis. METHODS: We included 45 patients who had undergone arthroscopic extensor carpi radialis brevis release for chronic refractory lateral epicondylitis between October 2008 and December 2012. Demographic data, magnetic resonance imaging studies, and arthroscopic findings were examined and analyzed. RESULTS: The mean age of the enrolled patients (23 men and 22 women) was 45.9 +/- 7.8 years, and the mean follow-up duration was 26.9 +/- 9.0 months. All the patients showed significant clinical improvement on all parameters assessed using the visual analog scale (6.9 preoperatively to 0.9 postoperatively), the Upper Extremity Functional Scale (34.8 to 66.7), and the Mayo Elbow Score (63.5 to 92.3) (P < .05). There were no reports of serious surgical complications. At final follow-up, 37 patients (82.2%) were satisfied with their outcomes whereas 8 patients (17.8%) were dissatisfied. In terms of demographic factors, female sex was significantly different between the 2 groups. On preoperative magnetic resonance imaging, 7 patients in the satisfied group (18.9%) had a definite tendon lesion (grade III defect, >=6 mm) whereas 6 patients in the dissatisfied group (75%) had a grade III defect (P = .016). CONCLUSIONS: Overall, clinical outcome scores showed improvement after arthroscopic extensor carpi radialis brevis release for refractory lateral epicondylitis. However, preoperative tendon status and sex were associated with dissatisfaction and poor postoperative outcomes after the arthroscopic release procedure. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25828168 TI - Multicenter Outcomes of Endoscopic Pubic Symphysectomy for Osteitis Pubis Associated With Femoroacetabular Impingement. AB - PURPOSE: To investigate outcomes of athletic patients treated with concurrent femoroacetabular impingement (FAI) and osteitis pubis (OP) surgery including endoscopic pubic symphysectomy. METHODS: We performed a multicenter retrospective case series of 7 consecutive adult patients (4 men) with a mean age of 33 years with symptomatic FAI and OP who underwent arthroscopic surgery for the former and endoscopic pubic symphysectomy for the latter with a mean follow-up period of 2.9 years (range, 2.0 to 5.0 years). The visual analog scale (VAS) score, the Non Arthritic Hip Score (NAHS), and patient satisfaction were measured. Complications and revision surgical procedures were reported, and preoperative and postoperative radiographs were assessed. RESULTS: The mean preoperative VAS score of 6.7 (range, 4 to 8) improved to a mean postoperative VAS score of 1.5 (range, 0 to 7) (P = .03). The mean preoperative NAHS of 50.2 points (range, 21 to 78 points) improved to a mean postoperative NAHS of 84.7 points (range, 41 to 99 points) (P = .03). The mean patient satisfaction rating was 8.3 (range, 3 to 10). Two male patients had postoperative scrotal swelling that resolved spontaneously. There were no other complications. Preoperative and postoperative radiographs showed no anterior or posterior pelvic ring instability. One patient underwent pubic symphyseal arthrodesis because of continued pain. CONCLUSIONS: Endoscopic pubic symphysectomy is a minimally invasive treatment for athletic OP with encouraging early outcomes that may be performed concurrently with surgery for FAI in co-afflicted patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25828170 TI - Imaging in prostate cancer with multiparametric magnetic resonance imaging and gallium positron emission tomography-computed tomography: 'the real deal'? PMID- 25828169 TI - Porphyromonas gingivalis attenuates ATP-mediated inflammasome activation and HMGB1 release through expression of a nucleoside-diphosphate kinase. AB - Many intracellular pathogens evade the innate immune response in order to survive and proliferate within infected cells. We show that Porphyromonas gingivalis, an intracellular opportunistic pathogen, uses a nucleoside-diphosphate kinase (NDK) homolog to inhibit innate immune responses due to stimulation by extracellular ATP, which acts as a danger signal that binds to P2X7 receptors and induces activation of an inflammasome and caspase-1. Thus, infection of gingival epithelial cells (GECs) with wild-type P. gingivalis results in inhibition of ATP induced caspase-1 activation. However, ndk-deficient P. gingivalis is less effective than wild-type P. gingivalis in reducing ATP-mediated caspase-1 activation and secretion of the pro-inflammatory cytokine, IL-1beta, from infected GECs. Furthermore, P. gingivalis NDK modulates release of high-mobility group protein B1 (HMGB1), a pro-inflammatory danger signal, which remains associated with chromatin in healthy cells. Unexpectedly, infection with either wild-type or ndk-deficient P. gingivalis causes release of HMGB1 from the nucleus to the cytosol. But HMGB1 is released to the extracellular space when uninfected GECs are further stimulated with ATP, and there is more HMGB1 released from the cells when ATP-treated cells are infected with ndk-deficient mutant than wild type P. gingivalis. Our results reveal that NDK plays a significant role in inhibiting P2X7-dependent inflammasome activation and HMGB1 release from infected GECs. PMID- 25828171 TI - Survival after the diagnosis of prostate cancer for Australian Aboriginal and Maori men. PMID- 25828172 TI - Cognitive existential couple therapy (CECT) in men and partners facing localised prostate cancer: a randomised controlled trial. AB - OBJECTIVES: To assess the efficacy of cognitive existential couple therapy (CECT) for relationship function, coping, cancer distress and mental health in men with localised prostate cancer and in their partners. PATIENTS SUBJECTS AND METHODS: A randomised controlled trial was conducted with 62 couples randomly assigned to the six-session CECT programme or care as usual. The couple's relationship function (primary outcome), and coping, cancer distress and mental health (secondary outcomes) were evaluated at T0 (baseline), T1 (after treatment) and T2 (9 months from T0). A repeated-measures analysis of covariance model, which incorporated T0 measurements as a covariate, was used to compare treatment groups at T1 and T2. RESULTS: After CECT, patients reported significantly greater use of adaptive coping (P = 0.03) and problem-focused coping (P = 0.01). These gains were maintained at follow-up, while relationship cohesion had improved (P = 0.03), as had relationship function for younger patients (P = 0.01). Younger partners reported less cancer-specific distress (P = 0.008), avoidance (P = 0.04), intrusive thought (P = 0.006), and hyperarousal (P = 0.01). Gains were maintained at follow-up, while relationship cohesion (P = 0.007), conflict resolution (P = 0.01) and relational function (P = 0.009) all improved. CONCLUSION: CECT resulted in improved coping for patients and lower cancer distress for partners. Maintained over time this manifests as improved relationship function. CECT was acceptable to couples, alleviated long-term relationship decline, and is therefore suitable as a preventative mental health intervention for couples facing prostate cancer. Given resourcing demands, we recommend dissemination of CECT be targeted at younger couples, as CECT was more acceptable to the younger group, and they derived greater benefit from it. PMID- 25828173 TI - Evaluation of clinical efficacy, safety and patient satisfaction rate after low intensity extracorporeal shockwave therapy for the treatment of male erectile dysfunction: an Australian first open-label single-arm prospective clinical trial. AB - OBJECTIVE: To evaluate the efficacy, safety and patient satisfaction rate with low-intensity extracorporeal shockwave therapy (LiESWT) in Australian men with erectile dysfunction (ED), as LiESWT induces neovascularisation and potentially enhances penile perfusion and improves erectile function. PATIENTS AND METHODS: Open-label single-arm prospective study of patients with ED with five-item version of the International Index of Erectile Function (IIEF-5) scores of >12 at baseline were enrolled after informed consent. Patient demographics, change in IIEF-5 and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores, and overall satisfaction score (on a 5-point scale) were recorded. Treatment consists of 3000 shockwaves (1000 shockwaves to the distal penis, base of penis and corporal bodies at the perineum) twice weekly for 6 weeks. RESULTS: All patients had tried and failed oral phosphodiesterase type 5 inhibitors and most of the patients hah had ED for >18 months [mean (range) 21.8 (6-60) months]. No side-effects to LiESWT were reported. Most patients reported an improvement in IIEF-5 score by 5 points (60%) and EDITS Index score by >50% (70%). Most patients were satisfied (scoring 4 out of 5; 67%) and would recommend the therapy to their friends (80%). CONCLUSION: LiESWT appears to improve erectile function, is safe and potential plays an important role in penile rehabilitation in men whom failed medical therapy. PMID- 25828174 TI - Nauru and detention of children. PMID- 25828175 TI - Floppy baby. PMID- 25828176 TI - Ethical dilemmas in child protection for paediatricians. PMID- 25828177 TI - Perspective: 'The forgotten children: national inquiry into children in immigration detention (2014)'. PMID- 25828178 TI - Diffuse small glistening papules in a child. Generalised lichen nitidus. PMID- 25828179 TI - Fever, abdominal distension and hepatomegaly. Pentastomiasis. PMID- 25828186 TI - Kawasaki disease in Campbelltown, a suburban hospital. PMID- 25828187 TI - Male circumcision debate has made progress. PMID- 25828189 TI - Small molecule glucagon receptor antagonists: a patent review (2011 - 2014). AB - INTRODUCTION: Glucagon receptor antagonists (GCGRAs) have been an area of ongoing research in the pharmaceutical industry for more than two decades. Blocking the action of the glucagon peptide leads to repression of hepatic glucose production and reduced blood glucose. Small molecule GCGRAs continue to be pursued as a potential new treatment for diabetes. AREAS COVERED: The current review summarizes small molecule GCGRA patents and patent applications that first appeared during 2011 - 2014. The search term 'glucagon receptor' was used to find patents of the desired type. EXPERT OPINION: Several companies have brought forward GCGRAs into human clinical trials with the most advanced to date being in Phase II. This field is mature and the number of patents has been decreasing in the last few years. PMID- 25828190 TI - Berry syndrome: the importance of genetic evaluation before surgical intervention. AB - Berry syndrome is a rare CHD. Approximately 29 cases have been described in the literature. Surgical correction has been successfully performed as well. We report the case of a newborn diagnosed with Berry syndrome who was subsequently diagnosed with trisomy 13. Cytogenetic analysis should be performed before surgical repair for optimal management. PMID- 25828192 TI - Microscopic mechanisms contributing to the synchronous improvement of strength and plasticity (SISP) for TWIP copper alloys. AB - In this study, the concept of "twinning induced plasticity (TWIP) alloys" is broadened, and the underlying intrinsic microscopic mechanisms of the general TWIP effect are intensively explored. For the first aspect, "TWIP copper alloys" was proposed following the concept of "TWIP steels", as they share essentially the same strengthening and toughening mechanisms. For the second aspect, three intrinsic features of twinning: i.e. "dynamic development", "planarity", as well as "orientation selectivity" were derived from the detailed exploration of the deformation behavior in TWIP copper alloys. These features can be considered the microscopic essences of the general "TWIP effect". Moreover, the effective cooperation between deformation twinning and dislocation slipping in TWIP copper alloys leads to a desirable tendency: the synchronous improvement of strength and plasticity (SISP). This breakthrough against the traditional trade-off relationship, achieved by the general "TWIP effect", may provide useful strategies for designing high-performance engineering materials. PMID- 25828193 TI - A 5-week whole body vibration training improves peak torque performance but has no effect on stretch reflex in healthy adults: a randomized controlled trial. AB - AIM: This study aimed to investigate the neuromuscular adaptation following a 5 week high frequency and low amplitude whole body vibration (WBV) exercise training. METHODS: The study is a prospective, double blind, randomized controlled intervention design with a total of 19 subjects volunteered to participate in the study. They were randomly assigned either to WBV exercise training or control group. Both groups participated in a 5-week training program. The intervention group received WBV in semi-squat position on a device with an amplitude of 0.76 mm, frequency of 40Hz, and peak acceleration of 23.9 m/s2. Each vibration training session consisted of 6 series of 60s on with 30s rest period in between. The control group underwent the same statically mini-squatting position without exposure to WBV. The effectiveness of the vibration program was evaluated by vertical jump test and the isokinetic knee extensor peak torque. The possible neural factors that contributed to the improved muscular performance were evaluated by the stretch induced knee jerk reflex. RESULTS: WBV training significantly enhanced the isokinetic knee extensor peak torque performance. Two way mixed repeated measures analysis of variance revealed significant time effect of the changes in the peak torque (P=0.043) and the effect was significantly different between the intervention and control group (P=0.042). WBV did not affect vertical jump height, reflex latency of VL, EMGVL, and knee jerk angle. CONCLUSION: The results of this study do not support the hypothesis that the improvement in the muscular performance when subjects exposed to WBV training is attributed by neuromuscular efficiency via modulation of the muscle spindle sensitivity. PMID- 25828194 TI - A comparison of upper and lower body energetics during high-intensity exercise. AB - AIM: The aim of the present study was to measure and compare the aerobic, anaerobic alactic and anaerobic lactic energy system contribution during the 30 sec Wingate anaerobic test (WAnT) for the upper and lower body within the same individuals. METHODS: Physically active men (N.=14) completed two WAnTs on an electronic arm ergometer and a cycle ergometer separated by three days. A fly wheel braking force corresponding to 5% and 7.5% of the participants body weight was used for the upper and lower body WAnTs respectively. Oxygen uptake and blood lactate were measured before, during and after both WAnTs, and body composition was measured using dual-energy X-ray absorptiometry (DEXA). RESULTS: The anaerobic lactic energy system contribution was significantly (P<0.01) higher during the upper body (60.3+/-5.6%) compared to the lower body (46.9+/-6.9%) WAnT. The contribution of the anaerobic alactic system was significantly higher (P<0.01) during the lower body (36.5+/-6.3%) compared to the upper body (28.3+/ 4.9%) WAnT, with the aerobic system contribution significantly (P<0.05) higher for the lower body (16.8+/-2.5%) compared to the upper body (11.4+/-1.4%) WAnT. CONCLUSION: The anaerobic lactic energy system provides over 60% of the energy requirements during an upper body WAnT but provides less the 50% during the lower body WAnT. In contrast, the aerobic and anaerobic alactic energy system contribution was significantly less for the upper body WAnT compared to the lower body WAnT. PMID- 25828191 TI - A proposed set of metrics for standardized outcome reporting in the management of low back pain. AB - BACKGROUND AND PURPOSE: Outcome measurement has been shown to improve performance in several fields of healthcare. This understanding has driven a growing interest in value-based healthcare, where value is defined as outcomes achieved per money spent. While low back pain (LBP) constitutes an enormous burden of disease, no universal set of metrics has yet been accepted to measure and compare outcomes. Here, we aim to define such a set. PATIENTS AND METHODS: An international group of 22 specialists in several disciplines of spine care was assembled to review literature and select LBP outcome metrics through a 6-round modified Delphi process. The scope of the outcome set was degenerative lumbar conditions. RESULTS: Patient-reported metrics include numerical pain scales, lumbar-related function using the Oswestry disability index, health-related quality of life using the EQ-5D-3L questionnaire, and questions assessing work status and analgesic use. Specific common and serious complications are included. Recommended follow-up intervals include 6, 12, and 24 months after initiating treatment, with optional follow-up at 3 months and 5 years. Metrics for risk stratification are selected based on pre-existing tools. INTERPRETATION: The outcome measures recommended here are structured around specific etiologies of LBP, span a patient's entire cycle of care, and allow for risk adjustment. Thus, when implemented, this set can be expected to facilitate meaningful comparisons and ultimately provide a continuous feedback loop, enabling ongoing improvements in quality of care. Much work lies ahead in implementation, revision, and validation of this set, but it is an essential first step toward establishing a community of LBP providers focused on maximizing the value of the care we deliver. PMID- 25828195 TI - Jumping performance differences among elite professional handball players with or without previous ACL reconstruction. AB - AIM: Handball is one of the most challenging sports for the knee joint. Persistent strength and jumping capacity alterations may be observed among athletes who have suffered anterior cruciate ligament (ACL) injury. The aim of this study was to examine unilateral and bilateral jumping ability differences between previously ACL-reconstructed rehabilitated elite handball athletes and sex, age and uninjured sport activity level-pairs of control players. METHODS: It was a Cross-sectional study with one factor: previous ACL injury. We recruited 22 male (6 ACL-reconstructed and 16 uninjured control players) and 21 female (6 ACL reconstructed and 15 uninjured control players) elite handball players who were evaluated 6.2+/-3.4 years after surgical ACL reconstruction. A battery of jump tests, including both bilateral and unilateral maneuvers, was performed. Two tailed unpaired (intergroup comparison) and paired (intragroup comparison) t tests were performed for mean comparisons. The P-value cut-off for significance was set at <0.05. RESULTS: The previously ACL-reconstructed female athletes showed a lower bilateral drop jump contact time (0.429+/-179.9 vs. 0.349+/-151 s, P<0.05) and less distance reached (3.820+/-0.54 vs. 4.428+/-0.44 m, P<0.05) in the unilateral triple hop for distance (UTHD) on their reconstructed leg compared with the dominant legs of the uninjured control athletes. No significant differences were observed for any other recorded variable. Among the male athletes, no significant differences between groups were found for the studied jumping variables. CONCLUSION: Previously ACL-reconstructed elite female handball athletes demonstrated both lower vertical bilateral drop jump (VBDJ) contact times and lower UTHD scores for the injured leg several years after injury. These deficits could contribute to an increase in ACL re-injury risk. PMID- 25828196 TI - Fitness and bone density in women: the role of age, weight, calcium, vitamin D, and menopause. AB - BACKGROUND: The purpose of the present study was to evaluate the relationship between manifold measures of fitness and bone mineral density (BMD) of the hip and spine in 233 middle-aged women. An additional objective was to determine the effect of several potential confounding variables, including age, body weight, calcium consumption, vitamin D intake, and menopause status on the relationships between fitness and BMD. METHODS: A cross-sectional design was used. Fitness was indexed using multiple variables: bench press, sit-ups, best jump, VO2max, and total fitness. Total fitness was indexed using the mean Z-score of the other fitness tests. Hip and spine BMD were assessed using dual energy X-ray absorptiometry. RESULTS: The associations between hip BMD and bench press (F=5.3, P=0.0219), sit-up (F=7.5, P=0.0065), best jump (F=11.6, P=0.0008), VO2max (F=9.3, P=0.0025), and Total Fitness (F=16.1, P<=0.0001) were statistically significant. Relationships between spine BMD and four of the dimensions of fitness were significant: bench press (F=9.4, P=0.0025), sit-up (F=11.7, P=0.0007), best jump (F=6.9, P=0.0093), and the composite fitness score (F=13.4, P=0.0003). VO2max was not predictive of spine BMD (F=2.0, P=0.1610). Age had the strongest confounding effect on the hip BMD associations, whereas menopause status had the strongest influence on the spine BMD relationships. CONCLUSIONS: In conclusion, findings suggest that objectively measured fitness is a strong predictor of differences in BMD of the hip and spine in middle-aged women, before and after adjusting for differences in several potential confounding variables. PMID- 25828197 TI - Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressive Effects of Mycophenolate Mofetil and Hepatitis B Virus Infection. AB - The purpose of this study is to investigate whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) affect the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBV) infection. Hepatic NK cells were isolated from C57BL/6 and C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice treated with MMF in the presence or absence of IL-15. After incubation of isolated hepatic NK cells in the presence or absence of MPA, reverse transcription polymerase chain reaction and immunolabeling were used to assess the expression of NK receptors Ly49A, NKG2A and NKG2D. In addition, cytokine enzyme-linked immunosorbent assay and [H]-TdR-release assay were carried out to assess NK cell activation and cytotoxic capacity. After treatment with MMF in the presence or absence of IL-15, HBsAg titers were measured in C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice. Treatment with either MPA or MMF resulted in reduced NK cell cytotoxicity, downregulated NKG2D and Ly49A expression and upregulated NKG2A. Interestingly, NKG2D downregulation was ameliorated by IL-15. In HBV-transgenic mice, MMF treatment impaired NK cell activity but did not affect virus replication, whereas IL-15 treatment reduced HBsAg titers. MPA and MMF mediate NKG2D downregulation both in vitro and in vivo, reducing the cytotoxic capacity of NK cells. These findings indicate that NKG2D regulation may be important in the immunosuppressive effect NK cells and involved in HBV infection. PMID- 25828198 TI - Cardiovascular safety profile and clinical experience with high-dose domperidone therapy for nausea and vomiting. AB - INTRODUCTION: Domperidone is a dopamine receptor antagonist with peripheral prokinetic and central antiemetic properties. Prolongation of the QTc interval with chronic use of oral domperidone in standard doses has been reported in the literature. Our goal was to investigate cardiac toxicity in patients receiving 2 fold greater doses than in previous reports. METHODS: A retrospective chart review was conducted of patients with nausea (N) and vomiting (V) receiving domperidone from 2009 to 2013 under an Investigational New Drug (IND) protocol. Patient demographics, indications for therapy, clinical outcomes, cardiac symptoms and electrocardiogram tracings were reviewed. Prolonged QTc was verified if >470 milliseconds in females (F) and >450 milliseconds in males (M). RESULTS: A total of 64 patients, 44 female (37% Hispanic, 60% white, 3% African American), were taking domperidone for diabetic gastroparesis 45%; idiopathic gastroparesis 36%; chronic N&V 8%; dumping syndrome 5%; cyclic vomiting 5% and conditioned vomiting 1%. Mean duration of therapy was 8 months (range, 3 months to 4 years). Doses ranged from 40 to 120 mg/d with 90% receiving 80 to 120 mg compared with the standard dose of 40 mg. Of note, 73% of subjects benefited from treatment with reduced nausea and vomiting. Thirty-seven patients had follow-up electrocardiograms available, and they showed that the mean QTc at baseline was 424 milliseconds +/- 28.4 (SD) compared with 435 milliseconds +/- 27.2 (SD) at follow-up (not significant). Ten of these patients had prolonged QTc at F/U ranging from 453 to 509 milliseconds, without any cardiovascular complaints. There was no relationship between prolonged QTc and daily dose of domperidone, body mass index or age. CONCLUSIONS: Our data indicate that at very high dosing, the prokinetic/antiemetic agent domperidone has a low risk of adverse cardiovascular events while exhibiting good clinical efficacy. PMID- 25828199 TI - The protein tyrosine phosphorylation during in vitro capacitation and cryopreservation of mammalian spermatozoa. AB - Before the process of fertilization, spermatozoa necessitate a period of residence in the female reproductive environment, and undergo a sequence of physiological and biochemical changes collectively referred to as capacitation. Accumulated evidences from several laboratories indicated that the protein tyrosine phosphorylation (PTP) is one of the most important intracellular signaling events regulating sperm function, and is a meaningful indicator of capacitation. Different factors that affect PTP are cholesterol efflux, influx of HCO3(-), increased intracellular Ca(2+), cAMP and reactive oxygen species (ROS). cAMP/PKA and extracellular signal regulated kinases (ERKs) are the known important signaling pathways primarily involved in PTP. Advanced proteomics approaches have revealed several proteins that undergo tyrosine phosphorylation during capacitation. Semen cryopreservation subjects spermatozoa to frequent stressors, which result in capacitation like changes (cryo-capacitation). The cryo-capacitated spermatozoa usually show different patterns of PTP than the normal in vitro capacitated spermatozoa. In the current manuscript, we have summarized some information about the proteins undergoing tyrosine phosphorylation during capacitation and the effect of cryopreservation on PTP as well as the possibilities to reduce the changes associated with cryopreservation process. PMID- 25828200 TI - Two phosphaalkene radical cations with inverse spin density distributions. AB - Two phosphaalkene radical cations 1(*+) and 2(*+) have been reported. 1(*+) is stable in the solid state and has been structurally characterized. 2(*+) only remains persistent in solution. 1(*+) is described as a phosphorus-centered radical, while 2(*+) as a delocalized radical with little contribution from phosphorus. PMID- 25828201 TI - Water-soluble MoS3 nanoparticles for photocatalytic H2 evolution. AB - Polyvinylpyrrolidone (PVP)-modified MoS3 nanoparticles with unusual water solubility up to 1.0 mg mL(-1) were synthesized through a facile hydrothermal method in the presence of thioacetic acid. The amorphous nanoparticles wrapped by PVP have sizes of around 2.5 nm, which represent the smallest MoS3 clusters reported. The photocatalytic performance of the MoS3 nanoparticles was evaluated under visible light for H2 evolution using xanthene dyes as photosensitizers. The quantum efficiency of the optimized system for H2 evolution under green light irradiation (520 nm) is up to 36.2 %, which is comparable with those of other excellent photocatalytic systems involving earth-abundant catalysts. The excellent photocatalytic activity can be attributed to its good dispersion in water, amorphous nature and limited layers with abundant surface active sites, and possibly higher conduction band potential for proton reduction and larger indirect band gap for a longer lifetime of the excited electrons. PMID- 25828202 TI - Schizencephaly: Dramatic Images in a Normally Functioning Adult. PMID- 25828203 TI - Spinal Schwannoma: An Unusual Case of Lumbar Radiculopathy. PMID- 25828204 TI - Clinical Experience With Continuous Intrathecal Baclofen Trials Prior to Pump Implantation. AB - OBJECTIVE: To report our clinical experience using continuous intrathecal baclofen (ITB) trials prior to permanent pump implantation. DESIGN: Retrospective chart review. SETTING: An inpatient neurosurgery unit and outpatient physical medicine and rehabilitation clinics. PARTICIPANTS: Fifty-seven patients with refractory spasticity who underwent a continuous ITB trial during the years 2006 2012. METHODS: Patients underwent placement of a temporary intrathecal catheter that was connected to an external pump. A successful trial was defined as a one level reduction in lower limb modified Ashworth scores in key spastic lower limb muscles identified for each individual patient. Subjective improvement in function or ease of performing functional tasks also were monitored. MAIN OUTCOME MEASURES: Modified Ashworth scores, functional mobility in ambulatory patients only, and the incidence and severity of adverse events during the trial and up to 1 year after implantation. RESULTS: Spasticity significantly decreased during the trial. Average ambulation distance was unchanged, although 34% of ambulatory patients progressed to a less restrictive assistive device by trial completion. Adverse events (AEs) occurred in 26 patients. Minor AEs were seen in 18 patients, with the most common being nausea, transient urinary retention, and headache. Pumps were implanted in 86% of patients; 14% did not receive a pump because of AEs or because goals were not met. Six patients had their pump removed at 12 months for the following reasons: pump malfunctions (3), skin breakdown around the pump (1), infection (1), and expectations not met (1). CONCLUSIONS: Continuous trials via an external catheter could be an option if patients and clinicians desire a comprehensive assessment of systemic and functional effects of ITB before pump implantation. The majority of AEs were minor and resolved spontaneously, and the most effective starting intrathecal dose was determined by pump insertion. PMID- 25828205 TI - Impact of Organized Sports on Activity, Participation, and Quality of Life in People With Neurologic Disabilities. AB - Physical activity and exercise is the mainstay of chronic disease prevention and health maintenance for all people with and without a disability, and clear evidence exists of the benefits among various populations with neurologic disabilities. However, the potential benefits of organized sports for people with neurologic disabilities are not as well explored. In this narrative review, current evidence regarding the impact of organized sports on activity, participation, and quality of life in people with neurologic disabilities of all ages is summarized, and facilitators of and barriers to participation in sports for this population are discussed. The articles reviewed were divided into 2 sets: (1) children and adolescents and (2) adults. The subjects of almost all of the studies were persons with a spinal cord injury. Children and adolescents with a disability who engaged in sports reported self-concept scores close to those of able-bodied athletes, as well as higher levels of physical activity. Adults with a spinal cord injury who engaged in organized sports reported decreased depression and anxiety, increased life satisfaction, and increased opportunity for gainful employment compared with nonathletic persons with disabilities. General facilitators, regardless of age, were fitness, fun, health, competence, and social aspects, whereas overall barriers were lack of or inappropriate medical advice and facilities, decreased self-esteem, poor finances, dependency on others, and views held by others. The importance of this topic for further research is highlighted, and suggestions for future studies are proposed. PMID- 25828206 TI - The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis. AB - The IL-17A producing T-helper-17 (Th17) cell population plays a major role in rheumatoid arthritis (RA) pathogenesis and has gained wide interest as treatment target. IL-17A expressing Th cells are characterized by the expression of the chemokine receptor CCR6 and the transcription factor RORC. In RA, CCR6+ Th cells were identified in peripheral blood, synovial fluid and inflamed synovial tissue. CCR6+ Th cells might drive the progression of an early inflammation towards a persistent arthritis. The CCR6+ Th cell population is heterogeneous and several subpopulations can be distinguished, including Th17, Th22, Th17.1 (also called non-classic Th1 cells), and unclassified or intermediate populations. Interestingly, some of these populations produce low levels of IL-17A but are still very pathogenic. Furthermore, the CCR6+ Th cells phenotype is unstable and plasticity exists between CCR6+ Th cells and T-regulatory (Treg) cells and within the CCR6+ Th cell subpopulations. In this review, characteristics of the different CCR6+ Th cell populations, their plasticity, and their potential impact on rheumatoid arthritis are discussed. Moreover, current approaches to target CCR6+ Th cells and future directions of research to find specific CCR6+ Th cell targets in the treatment of patients with RA and other CCR6+ Th cell mediated autoimmune diseases are highlighted. PMID- 25828207 TI - Effect of diisocyanate linkers on the degradation characteristics of copolyester urethanes as potential drug carrier matrices. AB - In this study, the effect of three aliphatic diisocyanate linkers, L-lysine diisocyanate ethyl ester (LDI), hexamethylene diisocyanate (HDI), and racemic 2,2,4-/2,4,4-trimethyl hexamethylene diisocyanate (TMDI), on the degradation of oligo[(rac-lactide)-co-glycolide] (64:36 mol%) based polyester urethanes (PEU) was examined. Samples were characterized for their molecular weight, mass loss, water uptake, sequence structure, and thermal and mechanical properties. Compared to non-segmented PLGA, the PEU showed higher water uptake and generally degraded faster. Interestingly, the rate of degradation was not directly correlating with the hydrophilicity of the diisocyanate moieties; instead, competing intra /intermolecular hydrogen bonds in between urethane moieties appear to substantially decrease the rate of degradation for LDI-derived PEU. By comparing microparticles (MUm) and films (mm) as matrices of different dimensions, it was shown that autocatalysis remains a contributor to degradation of the larger-sized PEU matrices as it is typical for non-segmented lactide/glycolide copolymers. The shown capacity of lactide/glycolide-based multiblock copolymers to degrade faster than PLGA and exhibit improved elastic properties could be of interest for medical implants and drug release systems. PMID- 25828208 TI - Quantitative detection of caffeine in human skin by confocal Raman spectroscopy- A systematic in vitro validation study. AB - For rational development and evaluation of dermal drug delivery, the knowledge of rate and extent of substance penetration into the human skin is essential. However, current analytical procedures are destructive, labor intense and lack a defined spatial resolution. In this context, confocal Raman microscopy bares the potential to overcome current limitations in drug depth profiling. Confocal Raman microscopy already proved its suitability for the acquisition of qualitative penetration profiles, but a comprehensive investigation regarding its suitability for quantitative measurements inside the human skin is still missing. In this work, we present a systematic validation study to deploy confocal Raman microscopy for quantitative drug depth profiling in human skin. After we validated our Raman microscopic setup, we successfully established an experimental procedure that allows correlating the Raman signal of a model drug with its controlled concentration in human skin. To overcome current drawbacks in drug depth profiling, we evaluated different modes of peak correlation for quantitative Raman measurements and offer a suitable operating procedure for quantitative drug depth profiling in human skin. In conclusion, we successfully demonstrate the potential of confocal Raman microscopy for quantitative drug depth profiling in human skin as valuable alternative to destructive state-of-the art techniques. PMID- 25828209 TI - Effectiveness of eye armor during blast loading. AB - Ocular trauma is one of the most common types of combat injuries resulting from the interaction of military personnel with improvised explosive devices. Ocular blast injury mechanisms are complex, and trauma may occur through various injury mechanisms. However, primary blast injuries (PBI) are an important cause of ocular trauma that may go unnoticed and result in significant damage to internal ocular tissues and visual impairment. Further, the effectiveness of commonly employed eye armor, designed for ballistic and laser protection, in lessening the severity of adverse blast overpressures (BOP) is unknown. In this paper, we employed a three-dimensional (3D) fluid-structure interaction computational model for assessing effectiveness of the eye armor during blast loading on human eyes and validated results against free field blast measurements by Bentz and Grimm (2013). Numerical simulations show that the blast waves focused on the ocular region because of reflections from surrounding facial features and resulted in considerable increase in BOP. We evaluated the effectiveness of spectacles and goggles in mitigating the pressure loading using the computational model. Our results corroborate experimental measurements showing that the goggles were more effective than spectacles in mitigating BOP loading on the eye. Numerical results confirmed that the goggles significantly reduced blast wave penetration in the space between the armor and the eyes and provided larger clearance space for blast wave expansion after penetration than the spectacles. The spectacles as well as the goggles were more effective in reducing reflected BOP at higher charge mass because of the larger decrease in dynamic pressures after the impact. The goggles provided greater benefit of reducing the peak pressure than the spectacles for lower charge mass. However, the goggles resulted in moderate, sustained elevated pressure loading on the eye, that became 50-100% larger than the pressure loading experienced by the unprotected eye after 0.2 ms of impact of blast wave, for lower as well as higher charge mass. The present model provides fundamental insights of flow and pressure fields in the ocular region, which helps to explain the effectiveness of the eye armor. Since the measurements of these fields are not trivial, the computational model aids in better understanding of development of PBI. PMID- 25828210 TI - The Healthy Kids, Healthy Communities national program. AB - In 2007, the Robert Wood Johnson Foundation announced a bold and unprecedented commitment of $500 million to reverse the epidemic of childhood obesity by 2015, especially in communities at greatest risk based on income, race, ethnicity, and geographic location. To support this work, the foundation launched an array of complementary initiatives aimed at building the evidence base, testing advocacy approaches, and supporting on-the-ground action to reverse the childhood obesity epidemic. Healthy Kids, Healthy Communities (HKHC), a 5-year $33.4 million national program, was one of the foundation's earliest such investments. Building on previous successes, HKHC was designed to address the policies, systems, and environments that make it easier for low-income children and their families to engage in physical activity and play and to access healthy food in their communities. As part of its strategy, the Robert Wood Johnson Foundation funded 50 multidisciplinary partnerships across the country, with a special focus on 15 southern states where health disparities were most significant. The selection of Active Living By Design to lead the HKHC National Program Office and Transtria, LLC, to lead the evaluation leveraged these organizations' experience in addressing the systemic issues that contribute to physical inactivity and unhealthy eating, using a broader healthy community lens. Key elements of HKHC included funding, ongoing technical assistance and consultation, a peer learning network, and participatory evaluation. The successes of the HKHC grant program are well documented in this journal as well as through case studies and case reports, spotlights, leadership profiles, and other products available at www.healthykidshealthycommunities.org and http://www.transtria.com/hkhc.php. PMID- 25828211 TI - Redesigning a neighborhood park to increase physical activity: a community-based participatory approach. AB - BACKGROUND: Community collaboration and active engagement of neighborhood residents in park redesign are promising strategies for creating public spaces that support physical activity. OBJECTIVE: This research brief describes the process of community engagement and discusses outcomes of a participatory park redesign project. METHODS: A community design charrette was held in collaboration with community organizations. Environmental audits of park features and amenities were completed before and after implementation of park redesign. A guided discussion with stakeholders following the park redesign was conducted to discuss challenges, successes, and next steps. RESULTS: Although level of activity among youth observed in the post implementation observations did not differ, there were a greater variety of activities observed among both children and adolescents. Furthermore, the goals of the project related to capacity building and meeting residents' needs were accomplished. CONCLUSIONS: Active participation of residents in a neighborhood park redesign requires time, commitment, and communication from a variety of stakeholders. However, the creation of a park that supports a variety of activity types, and builds community capacity, supports the need for involving stakeholders in redesigning neighborhood parks. PMID- 25828212 TI - Enhanced evaluation data initiates a collaborative out-of-school time food sponsors work group. AB - BACKGROUND: Philadelphia's Healthy Kids, Healthy Communities Out-of-School Time (OST) Initiative led by the Health Promotion Council developed 10 Healthy Living Guidelines for Out-of-School Time Programs to support a healthy environment for Philadelphia youth in 200 OST programs. Health Promotion Council participated in an enhanced cross-site evaluation with the national Robert Wood Johnson Foundation evaluator during the final year of funding to learn more about food and nutrition in the OST setting, and to share data and engage the OST food providers. METHODS: A plate waste study measured the quantity and nutrition composition of meals served to youth compared to food not eaten. Staff interviews measured program adherence to the Healthy Living Guidelines, along with other facets of the food environment in 7 Philadelphia OST programs. Online surveys were sent to OST programs. Food providers (sponsors) were interviewed using Appreciative Inquiry methodology to gain insight into systems, goals, and common interests. RESULTS: Aggregated plate waste data from 7 observations showed an average of 42% of the food uneaten after meal/snack consumption, and high sodium content of the meals. Twenty-nine staff at OST programs completed the online survey, and 3 food sponsors were interviewed. Recommendations to improve the food included increasing variety, offering more salads, fruits and vegetables, and culturally appropriate foods. Food sponsor interviews showed a variety of meal production, distribution, service and training systems, and an interest in working together. The food sponsors met to review the data and prioritized common goals. They continue to work together to improve systems and meals for food service. CONCLUSIONS: A food sponsors work group formed and continues as a result of sharing enhanced cross-site data about food in OST settings. Food sponsors continue to work together to improve systems and nutritional offerings for Philadelphia OST programs. PMID- 25828213 TI - Promoting active commuting to school through environmental and policy supports in Buffalo, New York. AB - BACKGROUND: Children in Buffalo, New York, have limited opportunities for safe, enjoyable physical activity. The Healthy Kids, Healthy Communities-Buffalo partnership established in 2009 created environmental and policy supports to facilitate physical activity among youth. METHODS: This article uses a mixed methods approach to document environment and policy changes in support of active commuting to school. Built environment data were collected using a pre-post research design with the Street Design Environmental Audit Tool. Supplementary sources of information include Geographic Information Systems, US Census data, and property parcel data. RESULTS: This exploratory study found modest improvements in the built environment during the period of assessment. Specifically, sidewalk conditions were improved. In addition, assessment of citywide policy indicates that systemic supports for active living have been put into place through the new (proposed) land use plan and the proposed zoning ordinance. CONCLUSIONS: Exploratory evaluation results suggest that Healthy Kids, Healthy Communities-Buffalo partnership was able to make some environmental and policy changes to promote active transportation. A long-term assessment is required to develop a fuller understanding of how environmental and policy changes impact active transportation. PMID- 25828214 TI - Using frameworks to diagram value in complex policy and environmental interventions to prevent childhood obesity. AB - BACKGROUND: To date, few tools assist policy makers and practitioners in understanding and conveying the implementation costs, potential impacts, and value of policy and environmental changes to address healthy eating, active living, and childhood obesity. For the Evaluation of Healthy Kids, Healthy Communities (HKHC), evaluators considered inputs (resources and investments) that generate costs and savings as well as benefits and harms related to social, economic, environmental, and health-related outcomes in their assessment of 49 HKHC community partnerships funded from 2009 to 2014. METHODS: Using data collected through individual and group interviews and an online performance monitoring system, evaluators created a socioecological framework to assess investments, resources, costs, savings, benefits, and harms at the individual, organizational, community, and societal levels. Evaluators customized frameworks for 6 focal strategies: active transportation, parks and play spaces, child care physical activity standards, corner stores, farmers' markets, and child care nutrition standards. RESULTS: To illustrate the Value Frameworks, this brief highlights the 38 HKHC communities implementing at least 1 active transportation strategy. Evaluators populated this conceptual Value Framework with themes from the strategy-specific inputs and outputs. The range of factors corresponding to the implementation and impact of the HKHC community partnerships are highlighted along with the inputs and outputs. CONCLUSIONS: The Value Frameworks helped evaluators identify gaps in current analysis models (ie, benefit-cost analysis, cost-effectiveness analysis) as well as paint a more complete picture of value for potential obesity prevention strategies. These frameworks provide a comprehensive understanding of investments needed, proposed costs and savings, and potential benefits and harms associated with economic, social, environmental, and health outcomes. This framing also allowed evaluators to demonstrate the interdependence of each socioecological level on the others in these multicomponent interventions. This model can be used by practitioners and community leaders to assess realistic and sustainable strategies to combat childhood obesity. PMID- 25828215 TI - Evaluating the implementation and impact of policy, practice, and environmental changes to prevent childhood obesity in 49 diverse communities. AB - BACKGROUND: The purpose of this article is to assess and understand the intervention reach, dose, and impact of policy, practice, and environmental changes implemented by the 49 Healthy Kids, Healthy Communities (HKHC) community partnerships across the United States and in Puerto Rico. These partnerships planned and implemented healthy eating and active living policy, system, and environmental interventions to support healthier communities for children and families, with special emphasis on reaching children at highest risk for obesity. METHODS: Using a mixed-methods, participatory evaluation design, investigators analyzed multiple qualitative and quantitative data sources collected during the HKHC initiative from 2009 to 2014. Evaluators used an inductive approach to develop indicators to assess intervention reach, dose, and impact for 6 cross site strategies, including corner stores, farmers' markets, child care nutrition standards, child care physical activity standards, active transportation, and parks and play spaces. RESULTS: Across HKHC community partnerships, 4261 policy, practice, or environmental changes occurred in 1536 intervention settings. Several trends emerged from the data related to how different levels of intervention (ie, community-level, setting-level, and within-setting), the size and access to intervention settings, the stage of implementation, and the sociodemographic composition of the intervention settings play important roles in the way policy, practice, and environmental changes "count" toward intervention reach, dose, and impact. CONCLUSIONS: This exploratory analysis provided a method and typology for increasing understanding in the field related to the reach, dose, and impact of policy, practice, and environmental changes promoting healthy eating and active living in order to reduce childhood overweight and obesity. PMID- 25828216 TI - Thoughts on supporting sustainable community change. PMID- 25828217 TI - Applying a mixed-methods evaluation to Healthy Kids, Healthy Communities. AB - From 2008 to 2014, the Healthy Kids, Healthy Communities (HKHC) national program funded 49 communities across the United States and Puerto Rico to implement healthy eating and active living policy, system, and environmental changes to support healthier communities for children and families, with special emphasis on reaching children at highest risk for obesity on the basis of race, ethnicity, income, or geographic location. Evaluators designed a mixed-methods evaluation to capture the complexity of the HKHC projects, understand implementation, and document perceived and actual impacts of these efforts. Eight complementary evaluation methods addressed 4 primary aims seeking to (1) coordinate data collection for the evaluation through the web-based project management system (HKHC Community Dashboard) and provide training and technical assistance for use of this system; (2) guide data collection and analysis through use of the Assessment and Evaluation Toolkit; (3) conduct a quantitative cross-site impact evaluation among a subset of community partnership sites; and (4) conduct a qualitative cross-site process and impact evaluation among all 49 community partnership sites. Evaluators identified successes and challenges in relation to the following methods: an online performance-monitoring HKHC Community Dashboard system, environmental audits, direct observations, individual and group interviews, partnership and community capacity surveys, group model building, photographs and videos, and secondary data sources (surveillance data and record review). Several themes emerged, including the value of systems approaches, the need for capacity building for evaluation, the value of focusing on upstream and downstream outcomes, and the importance of practical approaches for dissemination. The mixed-methods evaluation of HKHC advances evaluation science related to community-based efforts for addressing childhood obesity in complex community settings. The findings are likely to provide practice-relevant evidence for public health. PMID- 25828218 TI - Partnership and community capacity characteristics in 49 sites implementing healthy eating and active living interventions. AB - BACKGROUND: One component of the Evaluation of Healthy Kids, Healthy Communities, funded by the Robert Wood Johnson Foundation, was to assess partnership and community capacity characteristics of 49 cross-sector, multidisciplinary community demonstration projects to increase healthy eating and active living as well as to prevent and reduce childhood obesity. METHODS: From December 2012 to December 2013, an 82-item partnership and community capacity survey instrument assessed perspectives of community partnership members and community representatives from 48 of the 49 communities on the structure and function of their partnerships and the capacity of the community to create change. Through factor analysis and descriptive statistics, the evaluators described common characteristics of the partnerships, their leadership, and their relationships to the broader communities. RESULTS: A total of 603 individuals responded from 48 of the 49 partnerships. Evaluators identified 15 components, or factors that were broken into a themes, including leadership, partnership structure, relationship with partners, partnership capacity, political influence of partnership, and perceptions of partnership's involvement with the community and community members. CONCLUSIONS: Survey respondents perceived the Healthy Kids, Healthy Communities partnerships to have the capacity to ensure the partnerships' effectiveness in forming and growing their structures and functions, collaborating to implement policy and environmental change, and planning for sustainability. PMID- 25828219 TI - Paso a paso: the role of civic engagement and community capacity in the mixed methods evaluation of Healthy Kids, Healthy Communities and where to go next. PMID- 25828220 TI - HKHC Community Dashboard: design, development, and function of a Web-based performance monitoring system. AB - BACKGROUND: As part of Robert Wood Johnson Foundation's Healthy Kids, Healthy Communities (HKHC) national grant program, a technical assistance team designed the HKHC Community Dashboard, an online progress documentation and networking system. The Dashboard was central to HKHC's multimethod program evaluation and became a communication interface for grantees and technical assistance providers. METHODS: The Dashboard was designed through an iterative process of identifying needs and priorities; designing the user experience, technical development, and usability testing; and applying visual design. The system was created with an open-source content management system and support for building an online community of users. The site developer trained technical assistance providers at the national program office and evaluators, who subsequently trained all 49 grantees. Evaluators provided support for Dashboard users and populated the site with the bulk of its uploaded tools and resource documents. The system tracked progress through an interactive work plan template, regular documentation by local staff and partners, and data coding and analysis by the evaluation team. Other features included the ability to broadcast information to Dashboard users via e-mail, event calendars, discussion forums, private messaging, a resource clearinghouse, a technical assistance diary, and real-time progress reports. RESULTS: The average number of Dashboard posts was 694 per grantee during the grant period. Technical assistance providers and grantees uploaded a total of 1304 resource documents. The Dashboard functions with the highest grantee satisfaction were its interfaces for sharing and progress documentation. A majority of Dashboard users (69%) indicated a preference for continued access to the Dashboard's uploaded resource documents. CONCLUSIONS: The Dashboard was a useful and innovative tool for participatory evaluation of a large national grant program. While progress documentation added some burden to local project staff, the system proved to be a useful resource-sharing technology. PMID- 25828221 TI - Evaluation of Healthy Kids, Healthy Communities. PMID- 25828222 TI - Behavior-over-time graphs: assessing perceived trends in healthy eating and active living environments and behaviors across 49 communities. AB - CONTEXT: In the evaluation of the Healthy Kids, Healthy Communities initiative, investigators implemented Group Model Building (GMB) to promote systems thinking at the community level. As part of the GMB sessions held in each community partnership, participants created behavior-over-time graphs (BOTGs) to characterize their perceptions of changes over time related to policies, environments, collaborations, and social determinants in their community related to healthy eating, active living, and childhood obesity. OBJECTIVE: To describe the process of coding BOTGs and their trends. DESIGN: Descriptive study of trends among BOTGs from 11 domains (eg, active living environments, social determinants of health, funding) and relevant categories and subcategories based on the graphed variables. In addition, BOTGs were distinguished by whether the variables were positively (eg, access to healthy foods) or negatively (eg, screen time) associated with health. SETTING: The GMB sessions were held in 49 community partnerships across the United States. PARTICIPANTS: Participants in the GMB sessions (n = 590; n = 5-21 per session) included key individuals engaged in or impacted by the policy, system, or environmental changes occurring in the community. MAIN OUTCOME MEASURES: Thirty codes were developed to describe the direction (increasing, decreasing, stable) and shape (linear, reinforcing, balancing, or oscillating) of trends from 1660 graphs. RESULTS: The patterns of trends varied by domain. For example, among variables positively associated with health, the prevalence of reinforcing increasing trends was highest for active living and healthy eating environments (37.4% and 29.3%, respectively), partnership and community capacity (38.8%), and policies (30.2%). Examination of trends of specific variables suggested both convergence (eg, for cost of healthy foods) and divergence (eg, for farmers' markets) of trends across partnerships. CONCLUSIONS: Behavior-over-time graphs provide a unique data source for understanding community-level trends and, when combined with causal maps and computer modeling, can yield insights about prevention strategies to address childhood obesity. PMID- 25828223 TI - Systems thinking in 49 communities related to healthy eating, active living, and childhood obesity. AB - BACKGROUND: Community partnerships to promote healthy eating and active living in order to prevent childhood obesity face a number of challenges. Systems science tools combined with group model-building techniques offer promising methods that use transdisciplinary team-based approaches to improve understanding of the complexity of the obesity epidemic. This article presents evaluation methods and findings from 49 Healthy Kids, Healthy Communities sites funded to implement policy, system, and environmental changes from 2008 to 2014. METHODS: Through half-day group model-building sessions conducted as part of evaluation site visits to each community between 2010 and 2013, a total of 50 causal loop diagrams were produced for 49 communities (1 community had 2 causal loop diagrams representing different geographic regions). The analysis focused on the following evaluation questions: (1) What were the most prominent variables in the causal loop diagrams across communities? (2) What were the major feedback structures across communities? (3) What implications from the synthesized causal loop diagram can be translated to policy makers, practitioners, evaluators, funders, and other community representatives? RESULTS: A total of 590 individuals participated with an average of 12 participants per session. Participants' causal loop diagrams included a total of 227 unique variables in the following major subsystems: healthy eating policies and environments, active living policies and environments, health and health behaviors, partnership and community capacity, and social determinants. In a synthesized causal loop diagram representing variables identified by at least 20% of the communities, many feedback structures emerged and several themes are highlighted with respect to implications for policy and practice as well as assessment and evaluation. CONCLUSIONS: The application of systems thinking tools combined with group model-building techniques creates opportunities to define and characterize complex systems in a manner that draws on the authentic voice of residents and community partners. PMID- 25828224 TI - Healthy Kids, Healthy Cuba: findings from a group model building process in the rural Southwest. AB - BACKGROUND: Healthy Kids, Healthy Cuba (HKHCuba) is 1 of 49 community partnerships that participated in the national Healthy Kids, Healthy Communities program of the Robert Wood Johnson Foundation. One method of evaluation was to introduce systems thinking at the community level by identifying the essential parts of the HKHCuba system and how it influences policy and environmental changes to promote healthy eating and active living as well as to prevent childhood obesity in this unique, triethnic, rural community in New Mexico. METHODS: In this cross-sectional design, 12 HKHCuba partners participated in a group model building (GMB) session to develop behavior over time graphs and a causal loop diagram. RESULTS: Twenty-seven influences identified in the behavior over time graphs emerged as feedback loops and 5 subsystems emerged within the causal loop diagram. In addition to specific strategy-related influences (eg, access to healthy food, participation in community gardens), sense of cultural pride, sense of community, and social engagement, particularly among youth, were highly salient topics. CONCLUSIONS: The GMB process provided participants with the opportunity to explore the connections across their specific areas of work and make connections between policy and environmental influences on healthy eating and active living behaviors. The GMB processes and systems thinking approaches were new to the majority of participants, received positively, and perhaps should have been introduced earlier in the project period. PMID- 25828225 TI - Using group model building to understand factors that influence childhood obesity in an urban environment. AB - BACKGROUND: Despite increased attention, conventional views of obesity are based upon individual behaviors, and children and parents living with obesity are assumed to be the primary problem solvers. Instead of focusing exclusively on individual reduction behaviors for childhood obesity, greater focus should be placed on better understanding existing community systems and their effects on obesity. The Milwaukee Childhood Obesity Prevention Project is a community-based coalition established to develop policy and environmental change strategies to impact childhood obesity in Milwaukee, Wisconsin. The coalition conducted a Group Model Building exercise to better understand root causes of childhood obesity in its community. METHODS: Group Model Building is a process by which a group systematically engages in model construction to better understand the systems that are in place. It helps participants make their mental models explicit through a careful and consistent process to test assumptions. This process has 3 main components: (1) assembling a team of participants; (2) conducting a behavior over-time graphs exercise; and (3) drawing the causal loop diagram exercise. RESULTS: The behavior-over-time graph portion produced 61 graphs in 10 categories. The causal loop diagram yielded 5 major themes and 7 subthemes. CONCLUSIONS: Factors that influence childhood obesity are varied, and it is important to recognize that no single solution exists. The perspectives from this exercise provided a means to create a process for dialogue and commitment by stakeholders and partnerships to build capacity for change within the community. PMID- 25828226 TI - Group model building: a framework for organizing healthy community program and policy initiatives in Columbia, Missouri. AB - BACKGROUND: Between 2008 and 2012, the multidisciplinary Healthy Community Partnership of Columbia, Missouri, participated in a national program to address child obesity. This article describes a systems-level evaluation of their work to implement healthy eating and active living policy, system, and environmental changes to support healthier communities for children. METHODS: In 2011, the partnership participated in a Group Model Building session, consisting of 2 primary activities. First, participants sketched behavior-over-time graphs, illustrating the evolution of community variables related to child obesity, such as prevalence of walking to school or the marketing of high-sugar drinks. Later, the graphs were arranged on a large area of wall space and connections were drawn between those variables that were believed to influence each other--either positively (reinforcing connections) or negatively (opposing connections). The resulting causal loop diagram is a visual representation of the interacting systems, as perceived by the partnership. RESULTS: In reviewing the diagram, the group identified areas where they felt the diagram "made sense" and other areas where there were inconsistencies between the diagram and their own mental model of the processes at work. To address the inconsistencies, participants were surveyed to determine which specific modifications should be made to the diagram so it would become an accurate representation of the group's shared concept of the relevant relationships. DISCUSSION: The group felt that the final Modified causal loop diagram achieved this goal and that it provides useful insight into how their work addresses child obesity. They believe the diagram also has the potential to improve community engagement by serving as a visual model, improve planning through better resource allocation, improve implementation by identifying policy leverage points, and increase resources when used in grant applications. PMID- 25828227 TI - Collaborating to support Healthy Kids, Healthy Communities partnerships. AB - The Robert Wood Johnson Foundation (RWJF) (http://www.rwjf.org/en.html) launched Healthy Kids, Healthy Communities (HKHC) in 2008, with a $33.4 million commitment to help reverse the childhood obesity epidemic by 2015. With grant funding and technical assistance, HKHC supported 50 diverse community partnerships focusing on populations at greatest risk for obesity. Active Living By Design served as the national program office, and St. Louis-based Transtria conducted the evaluation. Collaboration fundamentally shaped HKHC's national program design and strategy, the grantee selection process, technical assistance, the HKHC learning network, and evaluation. This article describes the ways in which the concept of collaboration was defined and practiced among the Robert Wood Johnson Foundation, Active Living By Design, Transtria, and other national partners, and how it shaped the evolving vision for and expectations from HKHC grantees. Collaboration contributed to HKHC grantees' success, helped build the healthy communities movement, and influenced philanthropic practices. PMID- 25828228 TI - Improving park space access for the Healthy Kids, Healthy Communities partnership in Denver, Colorado. AB - BACKGROUND: In 2010, Denver Public Health at Denver Health was awarded a Robert Wood Johnson Foundation Healthy Kids, Healthy Communities (HKHC) grant that supported policy, system, and environmental changes to expand healthy food access through gardens and large-chain grocery stores and expand environments that are safe for all children to play, walk, and bike. Systems-thinking approaches enhanced the Denver partnership's work to identify and address the multiple and complex factors affecting the environment changes implemented to increase active living and healthy eating. Continued application of the systems-thinking approach in Denver will sustain outcomes for obesity prevention efforts beyond the grant project cycle, specifically in park space redevelopment. METHODS: Key members of the Denver HKHC coalition were invited to participate in a half-day group model building workshop to create behavior-over-time graphs and a causal loop diagram. These activities were intended to build on the Denver HKHC partnership's work by identifying factors that affect or are affected by policy, system, and environmental changes that influence active living, healthy eating or childhood obesity. RESULTS: Environments (ie, park space, farms, gardens) developed or renovated should consider identifying and addressing a range of factors that may influence access and utilization of active living and healthy eating. CONCLUSIONS: Denver's partnership found the experience highly valuable for identifying the policy, system, and environment change pathways that lead to increases in active living and healthy food access. In addition, it highlighted the need to identify and address the multiple and complex change pathways to ensure the outcomes of environment change, especially with park space, implemented in Denver achieve increased access to active living and healthy eating. PMID- 25828229 TI - Advancing systems thinking through the Healthy Kids, Healthy Communities evaluation. PMID- 25828230 TI - Increasing community capacity for participatory evaluation of healthy eating and active living strategies through direct observations and environmental audits. AB - BACKGROUND: Local partnerships from the Healthy Kids, Healthy Communities initiative elected to participate in enhanced evaluation trainings to collect data through environmental audits and direct observations as well as to build their evaluation capacity. METHODS: Environmental audit and direct observation tools and protocols were adapted for the relevant healthy eating and active living policy and environmental change approaches being conducted by the Healthy Kids, Healthy Communities partnerships. Customized trainings were conducted by the evaluation team to increase capacity and understanding for evaluation activities. RESULTS: A total of 87 trainings were conducted by the evaluation team in 31 Healthy Kids, Healthy Communities community partnerships. Data were collected for a total of 41 environmental audits and 17 direct observations. Community case examples illustrate how these trainings developed evaluation capacity. For instance, youth from one community presented environmental audit findings to local elected officials. CONCLUSIONS: The 31 partnerships participating in the community-based evaluation efforts resulted in 164 individuals trained in collecting context-specific data to assess the impact of healthy eating and active living policy and environmental strategies designed to create community change. PMID- 25828231 TI - Using an integrated approach to evaluate "Where do Flint's families play". AB - BACKGROUND: Once home to a thriving auto industry, Flint, Michigan, is now an economically distressed city of just over 100 000 people. With more than one third of the population obese and one-third of the population younger than 18 years, it is essential to have safe spaces for children and families to be physically active. To address this, the Healthy Kids, Healthy Communities Flint Community Partnership (Partnership) worked to revitalize local parks and evaluate these efforts to effectively guide future park resource allocation, investments, and approaches to create a more equitable, vibrant parks system. METHODS: After 2 years of initial park investments, 2 intervention parks (Max Brandon Park and Bassett Park) and 2 comparison parks (Brennan Park and Whaley Park) were selected for direct observation to determine whether parks that experienced investment had more use and users participating in higher levels of physical activity than in parks with no investment. In addition, the Partnership implemented community engagement strategies to hear residents' needs and desires for parks, as well as technical assessments such as a park facilities assessment, policy review, and equity analysis. RESULTS: Intervention parks had a higher number of uses and higher physical activity levels than comparison parks. This complemented community engagement results that highlighted people do not use parks that are perceived as unsafe and in poor condition. Even though demand for parks can be met with the current supply of park space, many parks had outdated and hazardous equipment; this, plus inconsistent maintenance, (perceived) lack of safety, and lack of activities were the main deterrents to using city parks for physical activity. CONCLUSIONS: Parks receiving investment had higher use and physical activity levels; thus, investing in park facilities and programming could increase opportunities for Flint residents to lead more active, healthy lifestyles. PMID- 25828232 TI - The parasite Ichthyophonus sp. in Pacific herring from the coastal NE Pacific. AB - The protistan parasite Ichthyophonus occurred in populations of Pacific herring Clupea pallasii Valenciennes throughout coastal areas of the NE Pacific, ranging from Puget Sound, WA north to the Gulf of Alaska, AK. Infection prevalence in local Pacific herring stocks varied seasonally and annually, and a general pattern of increasing prevalence with host size and/or age persisted throughout the NE Pacific. An exception to this zoographic pattern occurred among a group of juvenile, age 1+ year Pacific herring from Cordova Harbor, AK in June 2010, which demonstrated an unusually high infection prevalence of 35%. Reasons for this anomaly were hypothesized to involve anthropogenic influences that resulted in locally elevated infection pressures. Interannual declines in infection prevalence from some populations (e.g. Lower Cook Inlet, AK; from 20-32% in 2007 to 0-3% during 2009-13) or from the largest size cohorts of other populations (e.g. Sitka Sound, AK; from 62.5% in 2007 to 19.6% in 2013) were likely a reflection of selective mortality among the infected cohorts. All available information for Ichthyophonus in the NE Pacific, including broad geographic range, low host specificity and presence in archived Pacific herring tissue samples dating to the 1980s, indicate a long-standing host-pathogen relationship. PMID- 25828233 TI - Comparing and sharing information across health care settings: a difficult but potentially invaluable task. PMID- 25828234 TI - Multivitamin use and risk of stroke mortality: the Japan collaborative cohort study. AB - BACKGROUND AND PURPOSE: An effect of multivitamin supplement on stroke risk is uncertain. We aimed to examine the association between multivitamin use and risk of death from stroke and its subtypes. METHODS: A total of 72 180 Japanese men and women free from cardiovascular diseases and cancers at baseline in 1988 to 1990 were followed up until December 31, 2009. Lifestyles including multivitamin use were collected using self-administered questionnaires. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of total stroke and its subtypes in relation to multivitamin use. RESULTS: During a median follow-up of 19.1 years, we identified 2087 deaths from stroke, including 1148 ischemic strokes and 877 hemorrhagic strokes. After adjustment for potential confounders, multivitamin use was associated with lower but borderline significant risk of death from total stroke (HR, 0.87; 95% confidence interval, 0.76-1.01), primarily ischemic stroke (HR, 0.80; 95% confidence interval, 0.63 1.01), but not hemorrhagic stroke (HR, 0.96; 95% confidence interval, 0.78-1.18). In a subgroup analysis, there was a significant association between multivitamin use and lower risk of mortality from total stroke among people with fruit and vegetable intake <3 times/d (HR, 0.80; 95% confidence interval, 0.65-0.98). That association seemed to be more evident among regular users than casual users. Similar results were found for ischemic stroke. CONCLUSIONS: Multivitamin use, particularly frequent use, was associated with reduced risk of total and ischemic stroke mortality among Japanese people with lower intake of fruits and vegetables. PMID- 25828236 TI - Effect of public awareness campaigns on calls to ambulance across Australia. AB - BACKGROUND AND PURPOSE: The National Stroke Foundation of Australia has run 12 public awareness campaigns since 2004. Campaign exposure and funding has varied annually and regionally during this time. The aim of this study was to measure the effect of campaigns on calls to ambulance for stroke across Australia in exposed regions (paid or pro bono advertising). METHODS: All ambulance services in Australia provided monthly ambulance dispatch data between January 2003 and June 2014. We performed multivariable regression to measure the effect of campaign exposure on the volume of stroke-related emergency calls, after controlling for confounders. RESULTS: The final model indicated that 11 of the 12 National Stroke Foundation campaigns were associated with increases in the volume of stroke-related calls (varying between 1% and 9.9%) in regions with exposure to advertising. This increase lasted ~3 months, with an additional 10.2% relative increase in the volume of the calls in regions with paid advertising. We found no significant additional effect of the campaigns on stroke calls where ambulance services are publicly funded. CONCLUSIONS: The National Stroke Foundation stroke awareness campaigns are associated with increases to calls to ambulance for stroke in regions receiving advertising and promotion. Research is now required to examine whether this increased use in ambulance is for appropriate emergencies. PMID- 25828235 TI - Reperfusion of very low cerebral blood volume lesion predicts parenchymal hematoma after endovascular therapy. AB - BACKGROUND AND PURPOSE: Ischemic stroke patients with regional very low cerebral blood volume (VLCBV) on baseline imaging have increased risk of parenchymal hemorrhage (PH) after intravenous alteplase-induced reperfusion. We developed a method for automated detection of VLCBV and examined whether patients with reperfused-VLCBV are at increased risk of PH after endovascular reperfusion therapy. METHODS: Receiver operating characteristic analysis was performed to optimize a relative CBV threshold associated with PH in patients from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2 (DEFUSE 2) study. Regional reperfused-VLCBV was defined as regions with low relative CBV on baseline imaging that demonstrated normal perfusion (Tmax <6 s) on coregistered early follow-up magnetic resonance imaging. The association between VLCBV, regional reperfused-VLCBV and PH was assessed in univariate and multivariate analyses. RESULTS: In 91 patients, the greatest area under the curve for predicting PH occurred at an relative CBV threshold of <0.42 (area under the curve, 0.77). At this threshold, VLCBV lesion volume >=3.55 mL optimally predicted PH with 94% sensitivity and 63% specificity. Reperfused-VLCBV lesion volume was more specific (0.74) and equally sensitive (0.94). In total, 18 patients developed PH, of whom 17 presented with VLCBV (39% versus 2%; P=0.001), all of them had regional reperfusion (47% versus 0%; P=0.01), and 71% received intravenous alteplase. VLCBV lesion (odds ratio, 33) and bridging with intravenous alteplase (odds ratio, 3.8) were independently associated with PH. In a separate model, reperfused-VLCBV remained the single independent predictor of PH (odds ratio, 53). CONCLUSIONS: These results suggest that VLCBV can be used for risk stratification of patients scheduled to undergo endovascular therapy in trials and routine clinical practice. PMID- 25828237 TI - Acute cerebral infarction presenting with weakness in both legs and one arm. PMID- 25828238 TI - Trends in Door-to-Thrombolysis Time in the Safe Implementation of Stroke Thrombolysis Registry: Effect of Center Volume and Duration of Registry Membership. AB - BACKGROUND AND PURPOSE: Shorter delays between symptom onset and treatment translate into better outcomes after ischemic stroke thrombolysis. There are considerable intercenter variations in treatment delivery. We analyzed the trends of door-to-needle times (DNTs) in the Safe Implementation of Thrombolysis in Stroke registry between 2003 and 2011. METHODS: We extracted from the Safe Implementation of Thrombolysis in Stroke registry (n=45 079) year of treatment, center code, DNT, sex, age, National Institutes of Health Stroke Scale, and comorbidity. For each center, the year they joined the registry and the annual volume of patients were determined (<5, 5-24, 25-49, 50-74, 75-99, and >=100 patients/y). RESULTS: DNT was not available for 720 (1.6%) patients. The overall mean (SD) DNT was 73 (37) minutes with a median (interquartile range) of 67 (47 91) minutes. The DNT was 65 (46-90), 68 (50-92), and 72 (51-98) minutes for centers joined early (2003-2005), later (2006-2009), and recently (2009-2011), respectively. Center volume had more robust effect on DNT than year of treatment, and the shortest DNTs were seen in centers with volumes >=100 patients/y. Earlier enrollment period was also associated with shorter delays. CONCLUSIONS: Centers that joined the registry earlier and those with high annual volume achieved shorter DNT than centers that joined later and low-volume centers. However, in most of the centers, DNT did not change much during the registry period. A multicenter project aiming to reduce DNT is warranted. PMID- 25828239 TI - Door-to-Needle Times: Let's Not Leave Smaller Hospitals Behind. PMID- 25828240 TI - Impulsive choice predicts anxiety-like behavior, but not alcohol or sucrose consumption, in male Long-Evans rats. AB - BACKGROUND: Prior human research indicates robust, positive relations between impulsive choice (i.e., preference for smaller, immediate over larger, delayed rewards) and alcohol use disorders. However, varied findings in the nonhuman literature reveal a relatively ambiguous relation between impulsive choice and alcohol consumption in rodents. In addition, few rodent studies have investigated potential relations between impulsive choice and common covariates of alcohol consumption (e.g., avidity for sweet substances or anxiety-like behavior). METHODS: Ninety-two male Long-Evans rats completed an impulsive-choice task. From this larger sample, extreme high- and low-impulsive groups (n = 30 each) were retained for further testing. In separate tests, subsequent open-field behavior and consumption of oral alcohol (12% w/v) and isocaloric sucrose were examined. Impulsive choice was then retested to examine whether behavior remained stable over the course of the experiment. RESULTS: No significant relations emerged between impulsive choice and either alcohol or sucrose consumption. However, impulsive choice predicted greater anxiety-like behavior (avoidance of the center field, defecation) in the open-field test. In turn, greater anxiety predicted lower alcohol and sucrose consumption. Finally, choice remained generally stable across the experiment, although high-impulsive rats tended toward less impulsive choice in the retest. CONCLUSIONS: Although impulsive choice and alcohol consumption appear to share some variance with anxiety-like behavior, the present data offer no support for a relation between impulsive choice and alcohol consumption in Long-Evans rats. Together with mixed rodent data from prior reports, these findings attenuate cross-species comparisons to human relations between impulsive choice and alcohol use disorders. PMID- 25828241 TI - Macroscopic nuclear spin diffusion constants of rotating polycrystalline solids from first-principles simulation. AB - A method for quantitatively calculating nuclear spin diffusion constants directly from crystal structures is introduced. This approach uses the first-principles low-order correlations in Liouville space (LCL) method to simulate spin diffusion in a box, starting from atomic geometry and including both magic-angle spinning (MAS) and powder averaging. The LCL simulations are fit to the 3D diffusion equation to extract quantitative nuclear spin diffusion constants. We demonstrate this method for the case of (1)H spin diffusion in ice and L-histidine, obtaining diffusion constants that are consistent with literature values for (1)H spin diffusion in polymers and that follow the expected trends with respect to magic angle spinning rate and the density of nuclear spins. In addition, we show that this method can be used to model (13)C spin diffusion in diamond and therefore has the potential to provide insight into applications such as the transport of polarization in non-protonated systems. PMID- 25828242 TI - Comparison of pulse sequences for R1-based electron paramagnetic resonance oxygen imaging. AB - Electron paramagnetic resonance (EPR) spin-lattice relaxation (SLR) oxygen imaging has proven to be an indispensable tool for assessing oxygen partial pressure in live animals. EPR oxygen images show remarkable oxygen accuracy when combined with high precision and spatial resolution. Developing more effective means for obtaining SLR rates is of great practical, biological and medical importance. In this work we compared different pulse EPR imaging protocols and pulse sequences to establish advantages and areas of applicability for each method. Tests were performed using phantoms containing spin probes with oxygen concentrations relevant to in vivo oxymetry. We have found that for small animal size objects the inversion recovery sequence combined with the filtered backprojection reconstruction method delivers the best accuracy and precision. For large animals, in which large radio frequency energy deposition might be critical, free induction decay and three pulse stimulated echo sequences might find better practical usage. PMID- 25828243 TI - Broadband electrically detected magnetic resonance using adiabatic pulses. AB - We present a broadband microwave setup for electrically detected magnetic resonance (EDMR) based on microwave antennae with the ability to apply arbitrarily shaped pulses for the excitation of electron spin resonance (ESR) and nuclear magnetic resonance (NMR) of spin ensembles. This setup uses non-resonant stripline structures for on-chip microwave delivery and is demonstrated to work in the frequency range from 4 MHz to 18 GHz. pi pulse times of 50 ns and 70 MUs for ESR and NMR transitions, respectively, are achieved with as little as 100 mW of microwave or radiofrequency power. The use of adiabatic pulses fully compensates for the microwave magnetic field inhomogeneity of the stripline antennae, as demonstrated with the help of BIR4 unitary rotation pulses driving the ESR transition of neutral phosphorus donors in silicon and the NMR transitions of ionized phosphorus donors as detected by electron nuclear double resonance (ENDOR). PMID- 25828244 TI - NMR spin-lattice relaxation time T(1) of thin films obtained by magnetic resonance force microscopy. AB - We obtained the NMR spectrum and the spin-lattice relaxation time (T1) for thin film samples by magnetic resonance force microscopy (MRFM). The samples were CaF2 thin films which were 50 nm and 150 nm thick. T1 was measured at 18 K using a cyclic adiabatic inversion method at a fixed frequency. A comparison of the bulk and two thin films showed that T1 becomes shorter as the film thickness decreases. To make the comparison as accurate as possible, all three samples were loaded onto different beams of a multi-cantilever array and measured in the same experimental environment. PMID- 25828245 TI - Endoscopic bariatric therapies. PMID- 25828246 TI - CPUY11018, an azimilide derivative, ameliorates isoproterenol-induced cardiac insufficiency through relieving dysfunctional mitochondria and endoplasmic reticulum. AB - OBJECTIVES: Deterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum (ER) that is likely related to an activation of NADPH oxidase (NOX) and an increase in pro inflammatory factors. We investigated if a new compound CPUY11018 (CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance. METHODS: Forty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol (ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin (APO) - an inhibitor of NOX. KEY FINDINGS: In ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22(phox) and p47(phox) were significant, associated with upregulation of Src, IkappaBbeta and NFkappaB, and downregulation of pAMPK/AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO. CONCLUSIONS: CPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart. PMID- 25828247 TI - Telomere Length as an Indicator of the Robustness of B- and T-Cell Response to Influenza in Older Adults. AB - BACKGROUND: Telomeres provide a key mechanism for protecting the integrity of chromosomes and their attrition after cell division and during aging are evident in lymphocytes. However, the significance of telomere shortening in age associated decline of immune function is unknown. METHODS: We selected 22 HLA-A2 positive healthy older adults who have relatively short or long telomere lengths to compare their antibody response against the influenza vaccine, and their CD8(+) T-cell response against an influenza antigen. RESULTS: B cells from individuals with a robust antibody response to the influenza vaccine had significantly longer telomeres than those with a poor antibody response. Monocyte derived antigen-presenting cells of both short and long telomere groups induced similar expansions of influenza M1-specific CD8(+) T cells. Vaccination did not increase M1-specific CD8(+) T cells in blood, but M1-specific CD8(+) T cells from the long telomere group exhibited significantly greater expansion in vitro than those from the short telomere group. Finally, M1-specific CD8(+) T cells that underwent more expansions had significantly longer telomeres than cells with fewer divisions. CONCLUSIONS: Telomere length is positively associated with a robust lymphocyte response, and telomere attrition may contribute to the age associated decline of adaptive immunity. PMID- 25828249 TI - Simple education reduces inappropriate blood glucose self monitoring in type 2 diabetes, study shows. PMID- 25828248 TI - 18F-fluorodeoxyglucose Positron Emission Tomography in Kaposi Sarcoma Herpesvirus Associated Multicentric Castleman Disease: Correlation With Activity, Severity, Inflammatory and Virologic Parameters. AB - BACKGROUND: Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative inflammatory disorder commonly associated with human immunodeficiency virus (HIV). Its presentation may be difficult to distinguish from HIV and its complications, including lymphoma. Novel imaging strategies could address these problems. METHODS: We prospectively characterized (18)F-fluorodeoxyglucose positron emission tomography (PET) findings in 27 patients with KSHV-MCD. Patients were imaged with disease activity and at remission with scans evaluated blind to clinical status. Symptoms, C-reactive protein level, and HIV and KSHV loads were assessed in relation to imaging findings. RESULTS: KSHV-MCD activity was associated with hypermetabolic symmetric lymphadenopathy (median maximal standardized uptake value [SUVmax], 6.0; range, 2.0-8.0) and splenomegaly (3.4; 1.2-11.0), with increased metabolism also noted in the marrow (2.1; range, 1.0-3.5) and salivary glands (3.0; range, 2.0-6.0). The (18)F-fluorodeoxyglucose PET abnormalities improved at remission, with significant SUVmax decreases in the lymph nodes (P = .004), spleen (P = .008), marrow (P = .004), and salivary glands (P = .004). Nodal SUVmax correlated with symptom severity (P = .005), C-reactive protein level (R = 0.62; P = .004), and KSHV load (R = 0.54; P = .02) but not HIV load (P = .52). CONCLUSIONS: KSHV-MCD activity is associated with (18)F-FDG PET abnormalities of the lymph nodes, spleen, marrow, and salivary glands. These findings have clinical implications for the diagnosis and monitoring of KSHV-MCD and shed light on its pathobiologic mechanism. PMID- 25828250 TI - Low concentration toxic metal mixture interactions: Effects on essential and non essential metals in brain, liver, and kidneys of mice on sub-chronic exposure. AB - The deleterious effects of long term exposure to individual toxic metals in low doses are well documented. There is however, a paucity of information on interaction of low dose toxic metal mixtures with toxic and essential metals. This study reports on interactions between low dose mixtures of lead (Pb), mercury (Hg), arsenic (As) and cadmium (Cd) and toxic and essential metals. For 120d, six groups of forty mice each were exposed to metal mixtures, however, the control group was given distilled water. Exposure to Pb+Cd increased brain Pb by 479% in 30d, whiles Pb+Hg+As+Cd reduced liver Hg by 46.5%, but increased kidney As by 130% in 30d. Brain Cu, increased by 221% on Pb+Hg+As+Cd exposure, however, liver Ca reduced by 36.1% on Pb+Hg exposure in 60-d. Interactions within metal mixtures were largely synergistic. Principal component analysis (PCA) showed that low dose metal exposures influenced greatly levels of Hg (in brain and liver) and As (brain). The influence exerted on essential metals was highest in liver (PC1) followed by kidney (PC2) and brain (PC3). Exposure to low dose metal mixtures affected homeostasis of toxic and essential metals in tissues of mice. PMID- 25828251 TI - Toxicity and sublethal effects of six insecticides to last instar larvae and adults of the biocontrol agents Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae) and Adalia bipunctata (L.) (Coleoptera: Coccinellidae). AB - To further develop Integrated Pest Management (IPM) strategies against crop pests, it is important to evaluate the effects of insecticides on biological control agents. Therefore, we tested the toxicity and sublethal effects (fecundity and fertility) of flonicamid, flubendiamide, metaflumizone, spirotetramat, sulfoxaflor and deltamethrin on the natural enemies Chrysoperla carnea and Adalia bipunctata. The side effects of the active ingredients of the insecticides were evaluated with residual contact tests for the larvae and adults of these predators in the laboratory. Flonicamid, flubendiamide, metaflumizone and spirotetramat were innocuous to last instar larvae and adults of C. carnea and A. bipunctata. Sulfoxaflor was slightly toxic to adults of C. carnea and was highly toxic to the L4 larvae of A. bipunctata. For A. bipunctata, sulfoxaflor and deltamethrin were the most damaging compounds with a cumulative larval mortality of 100%. Deltamethrin was also the most toxic compound to larvae and adults of C. carnea. In accordance with the results obtained, the compounds flonicamid, flubendiamide, metaflumizone and spirotetramat might be incorporated into IPM programs in combination with these natural enemies for the control of particular greenhouse pests. Nevertheless, the use of sulfoxaflor and deltamethrin in IPM strategies should be taken into consideration when releasing either of these biological control agents, due to the toxic behavior observed under laboratory conditions. The need for developing sustainable approaches to combine the use of these insecticides and natural enemies within an IPM framework is discussed. PMID- 25828252 TI - The fate and transport of the Cry1Ab protein in an agricultural field and laboratory aquatic microcosms. AB - Genetically engineered crops expressing insecticidal crystalline proteins derived from Bacillus thuringiensis (Bt), were commercialized almost two decades ago as a means to manage agricultural pests. The Bt proteins are highly specific and only lethal upon ingestion, limiting the scope of toxicity to target insects. However, concern of exposure to non-target organisms and negative public perceptions regarding Bt crops has caused controversy surrounding their use. The objective of this research was to monitor the fate and transport of a Bt protein, Cry1Ab, in a large-scale agricultural field containing maize expressing the Cry1Ab protein and a non-Bt near isoline, and in aquatic microcosms. The highest environmental concentrations of the Cry1Ab protein were found in runoff water and sediment, up to 130ngL(-1) and 143ngg(-1) dry weight, respectively, with the Cry1Ab protein detected in both Bt and non-Bt maize fields. As surface runoff and residual crop debris can transport Bt proteins to waterways adjacent to agricultural fields, a series of laboratory experiments were conducted to determine the potential fate of the Cry1Ab protein under different conditions. The results showed that sediment type and temperature can influence the degradation of the Cry1Ab protein in an aquatic system and that the Cry1Ab protein can persist for up to two months. Although Cry1Ab protein concentrations measured in the field soil indicate little exposure to terrestrial organisms, the consistent input of Bt contaminated runoff and crop debris into agricultural waterways is relevant to understanding potential consequences to aquatic species. PMID- 25828253 TI - Is excessive acetaminophen intake associated with transaminitis in adult patients with dengue fever? AB - BACKGROUND: Dengue, an endemic infection causing severe flu-like symptoms and fever, is often treated with high-dose acetaminophen that can exceed recommended daily dosages. This leads to hepatotoxicity, although the underlying mechanism is poorly understood. We hypothesised that excessive acetaminophen causes hepatic toxicity in dengue patients. AIMS: To investigate a correlation between elevated serum transaminases and excessive acetaminophen intake, and other aggravating factors of liver injury in dengue cases. METHODS: This prospective observational study obtained blood samples from 150 participants with acute febrile illness for dengue serological tests, blood counts, and the detection of serum transaminases and acetaminophen levels. Other factors were determined by questionnaire. RESULTS: Of 150 participants enrolled, 77 had dengue fever. Abnormally high serum aspartate transaminase and alanine transaminase levels were present in 97.0% and 75.3% of dengue cases respectively. Multivariate analysis of cases with increased serum transaminases more than threefold normal upper limits indicated that male gender (odds ratio (OR) = 3.62, 95% confidence interval (CI) 1.38-9.42) and consuming >8 g acetaminophen orally (OR = 4.62, 95% CI 1.37-13.18) correlated with transaminitis. No correlation was found for other factors such as age, fever day at presentation, body mass index, alcohol intake or dengue severity classification (all P > 0.05). Chronic alcohol consumption was higher in non dengue (2.6%) versus dengue cases (27.8%) (P < 0.01). CONCLUSIONS: Most dengue patients had mild-to-moderate transaminitis. Male gender and acetaminophen >8 g were associated with increased serum transaminases. Thus, 1000 mg acetaminophen every 8 h or <3000 mg/day is recommended for dengue cases. Chronic alcohol consumption might be protective against dengue infection. PMID- 25828254 TI - Use of traditional Chinese medicine in patients with hyperlipidemia: A population based study in Taiwan. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Chinese herbal products (CHPs) are commonly used in patients with hyperlipidemia in traditional Chinese medicine (TCM). Because hyperlipidemia and related disease are common issues worldwide, this study analyzed the prescription patterns and frequencies of CHPs for treating patients with hyperlipidemia in Taiwan. BACKGROUND: Traditional Chinese medicine (TCM) has become popular as a therapy for controlling symptoms in patients with hyperlipidemia. This study aimed to analyze the prescription patterns of TCM for patients with hyperlipidemia in Taiwan. METHODS: The study population was recruited from a random-sampled cohort of 1,000,000 people from the National Health Insurance Research Database between 2003 and 2009. We identified 30,784 outpatient visits related with hyperlipidemia diagnosis and collected these medical records. Association rules of data mining were conducted to explore the co-prescription patterns for Chinese herbal products (CHPs). RESULTS: The most commonly prescribed herbal formula for hyperlipidemia treatment was Xue-Fu-Zhu-Yu Tang (16.1%), and Shan Zha (Crataegi fructus; 25.0%) was the most commonly prescribed single herb. The most commonly prescribed combination of an herbal formula and a single herb was Xue-Fu-Zhu-Yu-Tang and Dan Shen (Radix Salviae Miltiorrhizae), and the most commonly prescribed combination of couplet herbs was Dan Shen and Shan Zha. CONCLUSION: Xue-Fu-Zhu-Yu-Tang is the most frequently prescribed formula and is typically prescribed with Shan Zha, Dan Shen, and He Shou Wu for patients with hyperlipidemia. Clinical trials are warranted in future research to investigate the effects of the CHPs in terms of safety and efficacy and in particular to evaluate potential interactions with conventional treatments. PMID- 25828255 TI - Evaluation of the effect of zoom function on lesion detection by soft-copy reading of screening mammograms. AB - INTRODUCTION: This study aims to evaluate the effectiveness of zooming in improving screen-reader performance in reporting digital mammograms. METHOD: Two experiments were conducted. In the first experiment, 5 readers were asked to report 59 two-view bilateral mammograms retrospectively with zooming function turned off. The second session was similar to the first one except that zooming was enabled. The task of readers was to assess if the mammograms were normal or abnormal and rate the confidence levels for each of the lesion they detected. The reader performances were evaluated via case sensitivity, lesion sensitivity, specificity, receiver operating characteristics (ROC) area under the curve (AUC) and jackknife free-response receiver operating characteristics (JAFROC) figure of merit (FOM). RESULTS: There was no significant improvement in overall reader performance in detecting abnormalities in zooming condition compared with no zooming in terms of case sensitivity (96% and 87%, P = 0.285) or lesion sensitivity (88% and 81%, P = 0.224). However, differences in ROC AUC and JAFROC FOM (P <= 0.05) were found in two readers when they performed the test set with zooming function. CONCLUSION: The results suggested that the use of the zooming function did improve the performance of some readers in detecting abnormal cases. PMID- 25828256 TI - Dynamic nuclear polarization of membrane proteins: covalently bound spin-labels at protein-protein interfaces. AB - We demonstrate that dynamic nuclear polarization of membrane proteins in lipid bilayers may be achieved using a novel polarizing agent: pairs of spin labels covalently bound to a protein of interest interacting at an intermolecular interaction surface. For gramicidin A, nitroxide tags attached to the N-terminal intermolecular interface region become proximal only when bimolecular channels forms in the membrane. We obtained signal enhancements of sixfold for the dimeric protein. The enhancement effect was comparable to that of a doubly tagged sample of gramicidin C, with intramolecular spin pairs. This approach could be a powerful and selective means for signal enhancement in membrane proteins, and for recognizing intermolecular interfaces. PMID- 25828257 TI - Exploiting image registration for automated resonance assignment in NMR. AB - Analysis of protein NMR data involves the assignment of resonance peaks in a number of multidimensional data sets. To establish resonance assignment a three dimensional search is used to match a pair of common variables, such as chemical shifts of the same spin system, in different NMR spectra. We show that by displaying the variables to be compared in two-dimensional plots the process can be simplified. Moreover, by utilizing a fast Fourier transform cross-correlation algorithm, more common to the field of image registration or pattern matching, we can automate this process. Here, we use sequential NMR backbone assignment as an example to show that the combination of correlation plots and segmented pattern matching establishes fast backbone assignment in fifteen proteins of varying sizes. For example, the 265-residue RalBP1 protein was 95.4% correctly assigned in 10 s. The same concept can be applied to any multidimensional NMR data set where analysis comprises the comparison of two variables. This modular and robust approach offers high efficiency with excellent computational scalability and could be easily incorporated into existing assignment software. PMID- 25828259 TI - Intimate partner violence, modern contraceptive use and conflict in the Democratic Republic of the Congo. AB - Intimate partner violence (IPV) has been found to be negatively associated with contraceptive use in developing countries, but evidence from Africa is mixed. This study examines whether the above association differs in conflict settings, which have the potential for both higher levels of violence and more limited access to family planning. We use nationally representative data from the Democratic Republic of the Congo to examine the relationship between individual- and community-level IPV and modern contraceptive use, and to explore whether conflict modifies the relationship between IPV and contraceptive use. Nationally, only 6% of women reported current modern contraceptive use, while 53% reported experiencing physical IPV and 32% reported experiencing sexual IPV. In multivariate models, we found that individual-level sexual IPV was positively associated with current using modern contraceptive use, but that a combined measure of physical and sexual IPV did not demonstrate a similar association. Community-level IPV was not associated with individual-level contraceptive use. Conflict exposure was neither an independent predictor nor modifier of contraceptive use. Results suggest improved access to family planning should be a priority for programming in DRC, and efforts should ensure that sufficient resources are allocated towards the reproductive health needs of women in both conflict and non-conflict regions. PMID- 25828258 TI - Grazing livestock are exposed to terrestrial cyanobacteria. AB - While toxins from aquatic cyanobacteria are a well-recognised cause of disease in birds and animals, exposure of grazing livestock to terrestrial cyanobacteria has not been described. This study identified terrestrial cyanobacteria, predominantly Phormidium spp., in the biofilm of plants from most livestock fields investigated. Lower numbers of other cyanobacteria, microalgae and fungi were present on many plants. Cyanobacterial 16S rDNA, predominantly from Phormidium spp., was detected in all samples tested, including 6 plant washings, 1 soil sample and ileal contents from 2 grazing horses. Further work was performed to test the hypothesis that ingestion of cyanotoxins contributes to the pathogenesis of some currently unexplained diseases of grazing horses, including equine grass sickness (EGS), equine motor neuron disease (EMND) and hepatopathy. Phormidium population density was significantly higher on EGS fields than on control fields. The cyanobacterial neurotoxic amino acid 2,4-diaminobutyric acid (DAB) was detected in plant washings from EGS fields, but worst case scenario estimations suggested the dose would be insufficient to cause disease. Neither DAB nor the cyanobacterial neurotoxins beta-N-methylamino-L-alanine and N-(2 aminoethyl) glycine were detected in neural tissue from 6 EGS horses, 2 EMND horses and 7 control horses. Phormidium was present in low numbers on plants where horses had unexplained hepatopathy. This study did not yield evidence linking known cyanotoxins with disease in grazing horses. However, further study is warranted to identify and quantify toxins produced by cyanobacteria on livestock fields, and determine whether, under appropriate conditions, known or unknown cyanotoxins contribute to currently unexplained diseases in grazing livestock. PMID- 25828260 TI - Effectiveness of public deliberation methods for gathering input on issues in healthcare: Results from a randomized trial. AB - Public deliberation elicits informed perspectives on complex issues that are values-laden and lack technical solutions. This Deliberative Methods Demonstration examined the effectiveness of public deliberation for obtaining informed public input regarding the role of medical evidence in U.S. healthcare. We conducted a 5-arm randomized controlled trial, assigning participants to one of four deliberative methods or to a reading materials only (RMO) control group. The four deliberative methods reflected important differences in implementation, including length of the deliberative process and mode of interaction. The project convened 76 groups between August and November 2012 in four U.S. LOCATIONS: Chicago, IL; Sacramento, CA; Silver Spring, MD; and Durham, NC, capturing a sociodemographically diverse sample with specific attention to ensuring inclusion of Hispanic, African-American, and elderly participants. Of 1774 people recruited, 75% participated: 961 took part in a deliberative method and 377 participants comprised the RMO control group. To assess effectiveness of the deliberative methods overall and of individual methods, we evaluated whether mean pre-post changes on a knowledge and attitude survey were statistically different from the RMO control using ANCOVA. In addition, we calculated mean scores capturing participant views of the impact and value of deliberation. Participating in deliberation increased participants' knowledge of evidence and comparative effectiveness research and shifted participants' attitudes regarding the role of evidence in decision-making. When comparing each deliberative method to the RMO control group, all four deliberative methods resulted in statistically significant change on at least one knowledge or attitude measure. These findings were underscored by self-reports that the experience affected participants' opinions. Public deliberation offers unique potential for those seeking informed input on complex, values-laden topics affecting broad public constituencies. PMID- 25828261 TI - Eating disorders and their putative risk factors among female German professional athletes. AB - This study examines putative non-sport-specific and sport-specific risk factors for eating disorders (ED) among groups of professional female athletes versus non athletes. In detail, societal pressure to be thin, its internalisation, body dissatisfaction, sports pressure and early specialisation were investigated. The cross-sectional study included 46 aesthetic and 62 ball game sports athletes, and 108 age-matched non-athletes. Study methods comprised a clinical interview to detect ED and questionnaires. More athletes from aesthetic (17%) than from ball game sports (3%) and non-athletes (2%) suffered from ED. Aesthetic sports athletes did not differ from non-athletes in non-sport-specific factors but obtained higher levels than ball game sports athletes in sport-specific variables (p < .01). All factors together accounted for 57.3% of variation in disordered eating, with sports pressure and body dissatisfaction as significant predictors. The results confirm ED risk for German aesthetic athletes and indicate the importance of sports pressure and body dissatisfaction in explaining athletes' vulnerability. PMID- 25828262 TI - Intersectoral collaboration for physical activity in Korean Healthy Cities. AB - Intersectoral collaboration (ISC) is important in the health field because the complexity of determinants of health makes it difficult for one institution to resolve all health issues. Promotion of physical activity can especially benefit from a multi-sectoral approach. Despite so much emphasis on its importance in both primary health and health promotion, ISC has been underachieved in the field. This study aimed to examine the characteristics and level of ISC among physical activity programs in Healthy Cities as compared to non-Healthy Cities. I conducted a postal survey where 24 people from Healthy Cities and 72 people from non-Healthy Cities participated. The survey included questions to measure the level of ISC as well as to determine ISC partners and activities. Among the entire 393 physical activity programs, 336 (85.5%) had some kind of collaboration with one or more partners. The percentage having one or more partners was greater in Healthy Cities than in non-Healthy Cities. However, there were no statistical differences between the two groups in terms of the level of ISC within a municipal organization. Collaboration activities of the other departments were mostly supportive, such as providing a venue, recruiting participants and publicizing, and other kinds of administrative support. To strengthen ISC in Korean Healthy Cities, various actions including providing a legal basis, specific and substantive supports, financial incentives, and organizational recognitions will be helpful as well as the development of partnerships with other departments in urban planning, transport, urban design, and communication. PMID- 25828263 TI - Current laboratory practices in flow cytometry for the enumeration of CD 4(+) T lymphocyte subsets. AB - BACKGROUND: CD4(+) T-lymphocyte subset enumeration is routinely used for monitoring HIV disease progression, with approximately 300,000 tests performed annually in the UK alone. Technical variables can impact upon any laboratory test and therefore the final result obtained. Here, we report the findings of a survey questionnaire issued to 1,587 clinical flow cytometry laboratories to: (a) determine if the UK NEQAS for Leucocyte Immunophenotyping (UK NEQAS LI) lymphocyte subset external quality assessment (EQA) programme was suitable for current laboratory needs and practices; and (b) assess the impact of these responses on clinical practice where CD4(+) T-lymphocyte subsets analysis is undertaken. The survey covered areas not traditionally examined by EQA such as: staffing numbers, flow cytometer age and service intervals, plus six test specific sections covering: leukaemia immunophenotyping, CD4(+) T-lymphocyte subsets analysis (reported here), CD34(+) stem cell testing, low level leucocyte enumeration, minimal residual disease testing and PNH testing. RESULTS: The responses revealed major methodological variations between centres undertaking CD4(+) T-lymphocyte subset analysis. Significant differences existed in basic laboratory practices such as: normal range derivation; pipetting techniques; instrument maintenance and units of reporting, all of which results in non adherence to international guidelines. DISCUSSION: Despite the availability of international guidelines our survey highlighted a lack of concordance amongst laboratory techniques. Such variation could adversely impact on patient care and clinical trial data. Therefore, it is recommended centres undertaking flow cytometric CD4(+) T-lymphocyte subsets analysis urgently review their methodologies and normal ranges to ensure they are fit for purpose and meet current international guidelines. PMID- 25828264 TI - Lactate kinetics and mitochondrial respiration in skeletal muscle of healthy humans under influence of adrenaline. AB - Plasma lactate is widely used as a biomarker in critical illness. The aims of the present study were to elucidate the usefulness of a three-compartment model for muscle lactate kinetics in humans and to characterize the response to an exogenous adrenaline challenge. Repeated blood samples from artery and femoral vein together with blood flow measurements and muscle biopsies were obtained from healthy male volunteers (n=8) at baseline and during an adrenaline infusion. Concentrations of lactate and enrichment of [13C]lactate were measured and kinetics calculated. Mitochondrial activity, glycogen concentration, oxygen uptake and CO2 release were assessed. The adrenaline challenge increased plasma lactate 4-fold as a result of a greater increase in the rate of appearance (R(a)) than the increase in the rate of disappearance (R(d)). Leg muscle net release of lactate increased 3.5-fold, whereas intramuscular production had a high variation but did not change. Mitochondrial state 3 respiration increased by 30%. Glycogen concentration, oxygen uptake and CO2 production remained unchanged. In conclusion a three-compartment model gives additional information to the two-compartment model but, due to its larger variation and invasive muscle biopsy, it is less likely to become a regularly used tool in clinical research. Hyperlactataemia in response to adrenergic stimuli was driven by an elevated lactate release from skeletal muscle most probably due to a redirection of a high intramuscular turnover rather than an increased production. PMID- 25828265 TI - Anomalous small cardiac vein draining into the superior vena cava. AB - Coronary venous anatomy is little studied, and an abnormal coronary vein drainage is a rarely reported entity. Few cases about abnormal drainage of the great cardiac vein into the superior vena cava have been reported in literature. Herein we present a case of anomalous small cardiac vein draining into superior vena cava. PMID- 25828266 TI - Enantioselective photolysis and quantitative chiral analysis of tryptophan complexed with alkali-metalized L-serine in the gas phase. AB - The enantioselective photolysis of a cold gas-phase noncovalent complex of tryptophan with alkali-metalized L-serine, M(+) (L-Ser)(Trp) (M = Na and Li), was examined using a tandem mass spectrometer containing a variable-temperature ion trap. CO2 loss from Trp in the clusters was enantiomerically selective in ultraviolet excitation with linearly polarized light. M(+) (L-Ser) promoted the enantioselective photolysis of Trp as a chiral auxiliary. The enantioselective photolysis of the D-enantiomer was applied to a quantitative chiral analysis, in which the optical purity of tryptophan could be determined by measuring the relative abundance ratio R of the enantioselective CO2 loss to the chiral independent evaporation of L-Ser in a single photodissociation mass spectrum of M(+) (L-Ser)(Trp). PMID- 25828267 TI - Incidence rates of atopic dermatitis, asthma, and allergic rhinoconjunctivitis in Danish and Swedish children. AB - BACKGROUND: Several studies have shown that the prevalence of the frequent chronic conditions of atopic dermatitis, asthma, and allergy has increased substantially for reasons not fully understood. Atopic diseases affect quality of life in both children and their family members. OBJECTIVE: Using national registers, we sought to establish up-to-date incidence rates of atopic dermatitis, asthma, and allergic rhinoconjunctivitis in the Danish and Swedish child populations. METHODS: Children born in Denmark from 1997 to 2011 or born in Sweden from 2006 to 2010 participated in this cross-national, population-based cohort study. Incidence rates of atopic dermatitis, asthma, and allergic rhinoconjunctivitis in the Danish and Swedish child cohorts were ascertained through disease-specific dispensed prescribed medication, specific hospital contacts, or both. RESULTS: In both countries the incidence rate of atopic dermatitis was stable during the study periods. The incidence rate of asthma increased until 2006 and stabilized for the rest of the study period in Denmark and increased in Sweden. The incidence rate of allergic rhinoconjunctivitis decreased in both countries. CONCLUSION: The study revealed similar trends, with stable incidence rates of atopic dermatitis in both Danish and Swedish children, an increase and then stabilization in asthma incidence rates in Denmark and an increase in Sweden, and a decrease in allergic rhinoconjunctivitis incidence rates. At age 5 years, one third of all children were affected with at least one of the conditions of atopic dermatitis, asthma, or allergic rhinoconjunctivitis. PMID- 25828269 TI - Exposing the gaps in awareness, knowledge and estimation of risk for anal cancer in men who have sex with men living with HIV: a cross-sectional survey in Australia. AB - INTRODUCTION: The incidence of anal cancer is significantly higher in men who have sex with men (MSM) living with HIV when compared to the general population. We aimed to assess their awareness, knowledge and perceived level of personal risk for anal cancer to help inform educational strategies targeting this group. METHODS: A cross-sectional study of 327 HIV positive MSM in Melbourne, Australia, attending clinical settings (a sexual health centre, tertiary hospital HIV outpatients and high HIV caseload general practices) completed a written questionnaire in 2013/14. Poor knowledge was defined as those who had never heard of anal cancer, or scored 5 or less out of 10 in knowledge questions amongst those who reported ever hearing about anal cancer. Underestimation of risk was defined as considering themselves as having the same or lower risk for anal cancer compared to the general population. RESULTS: Of 72% (95% confidence interval (CI): 67-77) who had heard of anal cancer, 47% (95% CI: 41-53) could not identify any risk factors for anal cancer. Of total men surveyed, 51% (95% CI: 46 57) underestimated their risk for anal cancer. Multivariate analysis showed that men who underestimated their risk were older (OR 1.04 (per year increase in age), 95% CI: 1.01-1.07), had poor anal cancer knowledge (OR 2.06, 95% CI: 1.21-3.51), and more likely to have ever had an anal examination (OR 2.41, 95% CI: 1.18 4.93). They were less likely to consult a physician if they had an anal abnormality (OR 0.54, 95% CI: 0.31-0.96), to have had receptive anal sex (OR 0.12, 95% CI: 0.02-0.59) or speak English at home (OR 0.28, 95% CI: 0.09-0.90). CONCLUSIONS: This survey of MSM living with HIV demonstrated limited awareness, knowledge level and estimation of risk for anal cancer. Further educational and public health initiatives are urgently needed to improve knowledge and understanding of anal cancer risk in MSM living with HIV. PMID- 25828270 TI - Impact of fibrate therapy on plasma plasminogen activator inhibitor-1: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this systematic review was to perform a meta-analysis of randomized controlled trials (RCTs) examining the efficacy of fibrate therapy in reducing plasma concentration or activity of plasminogen activator inhibitor 1 (PAI-1). METHODS: Scopus and MEDLINE databases were searched (up to October 15, 2014) to identify RCTs investigating whether fibrates lower plasma PAI-1 concentration or activity. A random-effects model and the generic inverse variance method were used for quantitative data synthesis. Sensitivity analyses were conducted using the one-study remove approach. Random-effects meta regression was performed to assess the impact of potential moderators on the estimated effect sizes. RESULTS: A total of 14 RCTs examining the effects of gemfibrozil (6 trials), bezafibrate (4 trials), and fenofibrate (5 trials) were included. Meta-analysis suggested that fibrate therapy did not significantly reduce plasma PAI-1 concentration (weighed mean difference [WMD]: -11.39 ng/mL, 95% CI: -26.64, 3.85, p=0.143) or activity (WMD: 2.02 U/mL, 95% CI: -0.87, 4.90, p=0.170). These results remained unchanged after subgroup analysis according to duration of treatment (<12 and >=12 weeks) and type of fibrate administered (fenofibrate, bezafibrate or gemfibrozil). The estimated effects of fibrate therapy on plasma concentration and activity of PAI-1 were independent of treatment duration and changes in plasma triglyceride levels in the meta regression analysis. CONCLUSION: This meta-analysis of RCTs suggested that fibrate therapy does not reduce plasma concentration or activity of PAI-I. The putative benefits of fibrate therapy in patients with cardiovascular disease appear to be exerted via mechanisms independent of effects on PAI-1. PMID- 25828268 TI - Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology. OBJECTIVE: We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. METHODS: Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. RESULTS: Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (DeltaPsim), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced DeltaPsim, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-beta-induced ASM cell proliferation and CXCL8 release. CONCLUSIONS: Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD. PMID- 25828271 TI - A novel structural Fenton-like nanocatalyst with highly improved catalytic performance for generalized preparation of iron oxide@organic dye polymer core shell nanospheres. AB - FexOy@FexOy/C nanoparticles with a soap-bubble-like shell have been synthesized, and the materials exhibit excellent Fenton catalytic performance. More importantly, FexOy@FexOy/C nanoparticles as catalysts and precursors could catalyze organic dye molecules to form iron oxide@organic dye polymer core-shell nanospheres. PMID- 25828272 TI - Glycine plays a crucial role as a co-agonist of NMDA receptors in the neuronal circuit generating body movements in rat fetuses. AB - Neuronal circuits generating fetal movements in mammals are localized in the brainstem and the spinal cord. It has been shown that glycine plays an important role through the strychnine-sensitive glycine receptors in these circuits. However, the role of glycine as the NMDA receptor co-agonist in fetal period is not fully understood. In this study, we examined the contribution of glycine to the perinatal rat spinal circuit generating forelimb movements utilizing isolated brainstem-cervical-spinal-cord preparations. In late embryonic-days-preparations, spontaneous motor bursts related to forelimb movements (forelimb-movement-related bursts; FMRBs) and respiration-related activity were observed. In neonatal preparations, spontaneous FMRBs were not observed but periodic motor bursts resembling the FMRBs could be induced after bath application of strychnine (strychnine-induced motor bursts; SIMBs). Both FMRBs and SIMBs were blocked by either the NMDA receptor antagonist APV or the antagonists of the glycine binding site of NMDA receptors [5,7-dichlorokynurenic acid (DCKA) or L-689560]. Furthermore, these motor bursts were facilitated by the glycine uptake blocker sarcosine. This effect of sarcosine was blocked by DCKA. The findings indicate that glycine plays a crucial role as a NMDA receptor co-agonist in generating spontaneous fetal motor activity before functioning as a classical inhibitory neurotransmitter in suppressing the fetal neuronal circuits. PMID- 25828273 TI - Atmospheric chemistry of oxygenated volatile organic compounds: impacts on air quality and climate. PMID- 25828274 TI - New global viral threats. AB - Infectious diseases have caused great catastrophes in human history, as in the example of the plague, which wiped out half of the population in Europe in the 14th century. Ebola virus and H7N9 avian influenza virus are 2 lethal pathogens that we have encountered in the second decade of the 21st century. Ebola infection is currently being seen in West Africa, and H7N9 avian flu appears to have settled in Southeast Asia. This article focuses on the current situation and the future prospects of these potential infectious threats to mankind. PMID- 25828275 TI - Gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy. It is associated with maternal and neonatal adverse outcomes. Maintaining adequate blood glucose levels in GDM reduces morbidity for both mother and baby. There is a lack of uniform strategies for screening and diagnosing GDM globally. This review covers the latest update in the diagnosis and management of GDM. The initial treatment of GDM consists of diet and exercise. If these measures fail to achieve glycemic goals, insulin should be initiated. Insulin analogs are more physiological than human insulin, and are associated with less risk of hypoglycemia, and may provide better glycemic control. Insulin lispro, aspart, and detemir are approved to be used in pregnancy. Insulin glargine is not approved in pregnancy, but the existing studies did not show any contraindications. The use of oral hypoglycemic agents; glyburide and metformin seems to be safe and effective in pregnancy. PMID- 25828276 TI - The association of interleukin-10 -1082, -819, -592 polymorphisms and tuberculosis risk. AB - OBJECTIVES: To assess the association between interleukin (IL)-10 -1082, -819, 592 polymorphisms and tuberculosis (TB) risk. METHODS: This study was conducted between July and October 2014 in West China Hospital, Chengdu, Sichuan, China. We searched and collected data from PUBMED, EMBASE, Web of Science, China National Knowledge Infrastructure, VIP, and WANGFANG up to October 2014. RESULTS: A total of 37 studies were enrolled, including 8625 TB cases, and 9928 healthy controls. The IL-10-1082G/A polymorphism was found to be associated with TB susceptibility in Caucasian (GG versus GA+AA, odds ratio [OR] - 1.83, 95% confidence interval [CI] - 1.03-3.24). The IL-10-819C/T polymorphism was related to TB susceptibility among Asians (C versus T, OR - 0.88, 95% CI - 0.81-0.97; CC versus TT: OR - 0.79, 95% CI - 0.64-0.97; CC+CT versus TT: OR - 0.87, 95% CI - 0.77-0.98; CC versus CT+TT: OR - 0.82, 95% CI - 0.68-0.98). The IL-10-592C/A polymorphism was in association with TB susceptibility in Asians (C versus A: OR - 0.74, 95% CI - 0.65-0.85; CC versus AA: OR - 0.55, 95% CI - 0.41-0.75; CA versus AA: OR - 0.73, 95% CI - 0.60-0.89; CC+CA versus AA: OR - 0.69, 95% CI 0.58-0.83; CA versus AA: OR - 0.66, 95% CI 0.51-0.86), Caucasian (C versus A: OR - 1.25, 95% CI - 1.08 1.45; CC versus CA+AA: OR-1.48, 95% CI - 1.16-1.89), and Europeans (C versus A: OR - 1.31, 95% CI - 1.02-1.67; CC versus AA: OR - 1.88, 95% CI - 1.05-3.37). CONCLUSION: This meta-analysis suggests that IL-10-1082G/A, IL-819C/T, and IL 592C/A polymorphisms might be associated with TB susceptibility in certain ethnicities. PMID- 25828277 TI - Road safety and road traffic accidents in Saudi Arabia. A systematic review of existing evidence. AB - OBJECTIVES: To identify the changing trends and crucial preventive approaches to road traffic accidents (RTAs) adopted in the Kingdom of Saudi Arabia (KSA) over the last 2.5 decades, and to analyze aspects previously overlooked. METHODS: This systematic review was based on evidence of RTAs in KSA. All articles published during the last 25 years on road traffic accident in KSA were analyzed. This study was carried out from December 2013 to May 2014 in the Department of Family and Community Medicine, Taibah University, Al-Madinah Al-Munawwarah, KSA. RESULTS: Road traffic accidents accounted for 83.4% of all trauma admissions in 1984-1989, and no such overall trend was studied thereafter. The most frequently injured body regions as reported in the latest studies were head and neck, followed by upper and lower extremities, which was found to be opposite to that of the studies reported earlier. Hospital data showed an 8% non-significant increase in road accident mortalities in contrast to police records of a 27% significant reduction during the years 2005-2010. Excessive speeding was the most common cause reported in all recent and past studies. CONCLUSION: Disparity was common in the type of reporting of RTAs, outcome measures, and possible causes over a period of 2.5 decade. All research exclusively looked into the drivers' faults. A sentinel surveillance of road crashes should be kept in place in the secondary and tertiary care hospitals for all regions of KSA. PMID- 25828278 TI - Culture and language differences as a barrier to provision of quality care by the health workforce in Saudi Arabia. AB - OBJECTIVES: To identify, synthesize, and summarize issues and challenges related to the culture and language differences of the health workforce in Saudi Arabia. METHODS: A comprehensive systematic review was conducted in May 2014 to locate published articles. Two independent researchers in consultation with several experts used 4 electronic databases (ISI Web of Knowledge, Science Direct, PubMed, and Cochrane) to scrutinize articles published from January 2000 - March 2014. Each of the studies was given a quality assessment rating of weak, moderate, or strong, and was evaluated for methodological soundness using Russell and Gregory's criteria. RESULTS: The online literature search identified 12 studies that met the inclusion criteria. Lack of knowledge of non-Muslim nurses or culture in Saudi Arabia, difficulties in achieving cultural competence, and culture shock were documented as cultural difference factors. Issues in language difference include the clarity of language use by health care providers in giving information and providing adequate explanation regarding their activities. CONCLUSION: The available information provided by this review study shows that there is a communication barrier between patients and health care workers such as healthcare workers demonstrate low cultural competency. Despite the fact that the government provides programs for expatriate healthcare workers, there is a need to further improve educational and orientation programs regarding the culture and language in Saudi Arabia. PMID- 25828279 TI - The comparison of ProSeal and I-gel laryngeal mask airways in anesthetized adult patients under controlled ventilation. AB - OBJECTIVES: To compare the insertion time, ease of device insertion, ease of gastric tube insertion, airway leakage pressure, and complications between the laryngeal mask airway (LMA) ProSeal (P-LMA) and I-gel (I-gel) groups. METHODS: Eighty patients with age range 18-65 years who underwent elective surgery were included in the study. The study took place in the operation rooms of Haydarpasa Numune Hospital, Istanbul, Turkey from November 2013 to April 2014. Patients were equally randomized into 2 groups; the I-gel group, and the P-LMA group. In both groups, the same specialist inserted the supraglottic airway devices. The insertion time of the devices, difficulty during insertion, difficulty during gastric tube insertion, coverage of airway pressure, and complications were recorded. RESULTS: The mean insertion time in the I-gel group was significantly lower than that of the P-LMA group (I-gel: 8+/-3; P-LMA: 13+/-5 s). The insertion success rate was higher in the I-gel group (100%, first attempt) than in the P LMA group (82.5%, first attempt). The gastric tube placement success rate was higher in the I-gel group (92.5%, first attempt) than in the P-LMA group (72.5%, first attempt). The airway leakage pressures were similar. CONCLUSION: Insertion was easier, insertion time was lower, and nasogastric tube insertion success was higher with the I-gel application, and is, therefore, the preferred LMA. PMID- 25828280 TI - Effect of preemptive intravenous oxycodone on low-dose bupivacaine spinal anesthesia with intrathecal sufentanil. AB - OBJECTIVES: To evaluate the efficacy of preemptive intravenous oxycodone on low dose bupivacaine spinal anesthesia with intrathecal sufentanil in patients undergoing transurethral resection of the prostate (TURP). METHODS: In this randomized, double-blinded, placebo-controlled trial, 60 patients undergoing TURP were allocated into 2 groups: oxycodone group (group O, n=30) and a normal saline group (group N, n=30). Oxycodone 0.1 mg/kg, or normal saline 0.1 ml/kg was administered intravenously 10 minutes before surgical procedures in group O, or in group N. All patients received sufentanil 5 ug + bupivacaine 0.5% (0.8 ml) + normal saline 0.7 ml - in total, bupivacaine 0.25% (1.6 ml) intrathecally. Spinal block characteristics, hemodynamic values, the perioperative analgesic requirements, visual analogue scale (VAS) scores, Ramsay sedation scale, and side effects were assessed. The study was carried out at the First Hospital of Jilin University, Jilin, China between March and September 2014. RESULTS: The time to 2 segment regression of sensory block, full recovery of sensory block, and first analgesic request was longer in group O. Fewer patients required postoperative analgesics, and the VAS pain scores at 4, 8, 16, and 24 hour after operation were significantly lower in group O. CONCLUSION: Preemptive intravenous oxycodone was an efficient and safe method to decrease postoperative pain and reduce tramadol analgesia in patients under low-dose dilute bupivacaine spinal anesthesia combined with intrathecal sufentanil. PMID- 25828281 TI - Prevalence and treatment outcomes of second primary malignancies in Saudi patients with differentiated thyroid cancers. AB - OBJECTIVES: To evaluate the clinicopathologic features, and explore the treatment outcomes of synchronous, or metachronous second primary malignancies (SPM) in conjunction with differentiated thyroid cancers (DTC). METHODS: This retrospective study was conducted on 823 DTC patients treated between 2000 and 2012 at 2 tertiary care hospitals (King Fahad Medical City and King Khalid University Hospital) in Riyadh, Kingdom of Saudi Arabia. Forty-one (5%) DTC patients were found to have SPM (61% metachronous and 39% synchronous). These patients with SPM were studied for clinicopathological features and treatment outcomes. RESULTS: The patients with DTC and SPM were older (median age: 54.3 years) than those without SPM (median age: 43.2 years); p=0.04. The frequency of SPM was breast (51.2%), colon (12.2%), kidney (7.3%), astrocytoma (7.3%), parotid (7.3%), rectum (4.9%), lymphoma (4.9%), nasopharynx (2.4%), and stomach (2.4%). Median follow-up was 8.05 years. Ten-year disease free survival, and overall survival (OS) rates were lower in DTC patients with SPM (56.1% for 10-year survival, and 71.7% for OS) than without SPM (95.5% for 10-year survival, and 97.8% for OS); p=0.0001. Metachronous SPM had better 10-year disease free survival rates (60.2%) than synchronous SPM (45%). CONCLUSION: The co-occurrence of SPM with DTC affects long-term disease free survival and OS rates. PMID- 25828282 TI - Prevalence and causes of blindness and diabetic retinopathy in Southern Saudi Arabia. AB - OBJECTIVES: To determine the prevalence and causes of blindness and diabetic retinopathy (DR) in Jazan district, Southern Saudi Arabia. METHODS: Using the standardized Rapid Assessment for Avoidable Blindness (RAAB) and DR cross sectional methodology, 3800 subjects were randomly selected from the population of >=50 years of age in Jazan, Saudi Arabia between November 2011 and January 2012. Participants underwent screening comprised of interview, random blood glucose test, and ophthalmic assessment including visual acuity (VA) and fundus examination. Among participants with VA less than 6/18 in either eye, the cause(s) of visual impairment was determined. Participants were classified as diabetic if they had previous diagnoses of diabetes, or random blood glucose more than 200 mg/dl. Diabetic participants were assessed for DR using dilated fundus examination. All data were recorded using the RAAB + DR standardized forms. RESULTS: The prevalence of bilateral blindness less than 3/60 was 3.3% (95% confidence interval [CI]: 2.74 - 3.90). Cataract was the leading cause of blindness (58.6%); followed by posterior segment diseases (20%), which included DR (7; 3.3%). The prevalence of diabetes mellitus (DM) was 22.4%, (95% CI: 21.09 23.79]), among them; 27.8% had DR. The prevalence of sight-threatening DR was 5.7%. CONCLUSION: The prevalence of DM and the corresponding proportion of DR in this region is lower than that reported in other regions of Saudi Arabia. However, the prevalence of blindness not related to DR is relatively higher than the other studies. PMID- 25828283 TI - Evaluation of knowledge and behavior of workers in Prince Mohammed International Airport in Western Saudi Arabia regarding public health emergency measures applied during Hajj season 2014. AB - OBJECTIVES: To evaluate the knowledge and behavior of workers at a Saudi airport regarding public health emergency measures applied during Hajj season. METHODS: This study is a cross-sectional study conducted at the Prince Mohammed International Airport in Al-Madinah Al-Munawwarah, Saudi Arabia between August and September 2014. Data were collected by semi-structured questionnaires during personal interviews. Non-random purposive sampling was conducted to target workers at higher risk of acquiring infection from travellers. RESULTS: One hundred and eighty-six participants were recruited of whom 92.5% were males. The study participants were workers in 8 different sectors. Twenty-six percent of the participants were health workers. Non-health workers were more likely to be concerned on acquiring infection while working at the airport compared with health workers (p=0.023). The most commonly feared disease was Ebola viral disease (EBV) among 30% of health workers, and 47% of non-health workers. Approximately 47% of non-health workers reported no knowledge of the procedures implemented during public health emergencies. The proportion of participants who received public health related training among non-health workers was significantly lower compared with health workers (p less than 0.00001). CONCLUSION: More emphasis should be given to educating airport workers on the potential health threats at the airport. Specific guidelines for public health emergencies at the airport should be established and communicated with airport sectors. PMID- 25828284 TI - Periodontal findings in systemic lupus erythematosus patients and healthy controls. AB - OBJECTIVES: To compare periodontal findings in systemic lupus erythematosus (SLE) patients and healthy controls, and to determine, whether there is a correlation between periodontal parameters and SLE biomarkers. METHODS: This cross-sectional study was conducted in the Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between November 2012 and February 2014. Twenty five participants diagnosed with SLE and 50 healthy controls were selected. Periodontal assessment consisted of clinical attachment level (CAL), probing depth (PD), bleeding on probing, and plaque scores. For the SLE group, several laboratory tests were obtained, such as, white blood cell count, hemoglobin level, platelet count, anti-nuclear antibody, anti-double-stranded DNA antibody, calcium level, and vitamin D. RESULTS: Periodontal findings in SLE patients and controls were not significantly different. The SLE patients who had no flare-ups for more than a year showed significant bleeding on probing and deeper PD compared with those who had flare-ups less than a year before starting the study. The SLE patients with arthritis symptoms showed more CAL than those without arthritis. In the SLE patients, no significant correlation was found between their periodontal findings and SLE biomarkers. CONCLUSION: Periodontal health was not different between SLE patients and healthy controls. In SLE patients however, flare-ups and presence of arthritis had a significant relation with periodontal health. PMID- 25828285 TI - Short term effects of periodontal therapy on inflammatory markers in patients with type-2 diabetes. AB - OBJECTIVES: To evaluate the influence of periodontal therapy on glycosylated hemoglobin and fasting blood glucose and serum levels of interleukin (IL)-4, IL 6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-alpha) in chronic periodontitis (CP) patients with type-2 diabetes mellitus (T2DM) and in controls. METHODS: A total of 30 periodontal patients, 15 of which were systemically healthy (control group), and 15 were T2DM patients (test group) were included in this study. This prospective study was carried out at Istanbul University, Istanbul, Turkey between February 2011 and December 2013. Plaque index, gingival index, bleeding on probing, periodontal probing depth, and clinical attachment level were assessed and recorded at baseline, one, and 3 months after therapy. Serum samples were collected at the same time-points and analyzed using Luminex assay for the levels of IL-4, IL-6, IL-8, IL-10, and TNF-alpha. The change in the metabolic control was also monitored. RESULTS: All clinical parameters were significantly improved after the periodontal therapy in both groups (p less than l0.001). Glycosylated hemoglobin levels were decreased; however, the difference was not significant (p more than 0.05). Fasting blood glucose levels were decreased one month after therapy, and increased at 3 months. Patients with T2DM had significantly higher levels of circulating IL-8 at each time point, and TNF alpha (p less than 0.05) at baseline. The IL-4 and IL-10 levels were decreased at one month after therapy (p more than 0.05). CONCLUSION: Periodontal therapy has limited impact on the serum levels of IL-4, IL-6, IL-8, IL-10, and TNF-alpha. Metabolic control levels were not influenced by periodontal therapy. PMID- 25828286 TI - Comparing dental students' perceptions of their educational environment in Northwestern Saudi Arabia. AB - OBJECTIVES: To compare the perceptions of dental students over a 5-year period. METHODS: This cohort study was carried at Taibah University, College of Dentistry, Al-Madinah Al-Munawwarah, Saudi Arabia between 2009 and 2014. Data was obtained using the Dundee Ready Education Environment Measure (DREEM), which consists of 50 items, 4 of these were irrelevant to this cohort and were excluded. All students registered in 2009 were included and followed up in 2014. Their responses were compared using the paired student's t-test. RESULTS: Thirty four students completed the questionnaire in 2009, and 30 of them participated in 2014 (12% drop out rate). The mean domain and total scores decreased over time. The mean scores for 6 items decreased significantly, while 4 of them had a significant increase. The lowest mean score in 2009 regarding support for stressed students increased (p=0.004) in 2014. However, the highest mean score in 2009 related to having a good social life, reduced (p=0.007) in 2014. This could be an indication of the high workload and its impact on their social lives. CONCLUSION: Student's perceptions were relatively low at the beginning, and remained low throughout the study. There were no significant changes in mean domain, and total scores and although scores of some items improved, most decreased over the study period. PMID- 25828287 TI - Middle East respiratory syndrome coronavirus in children. AB - The Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). The disease is reported mainly in adults. Data in children are scarce. The disease caused by MERS-CoV in children presents with a wide range of clinical manifestations, and it is associated with a lower mortality rate compared with adults. Poor outcome is observed mainly in admitted patients with medical comorbidities. We report a new case of MERS-CoV infection in a 9-month-old child complicated by severe respiratory symptoms, multi-organ dysfunction, and death. We reviewed the literature in an attempt to characterize the mode of presentation, the risk factors, and outcome of MERS-CoV infection in the pediatric population. PMID- 25828288 TI - Large multicystic pulmonary chondroid hamartoma in a child presenting as pneumothorax. AB - We describe a 10-year-old boy with a rare large multicystic pulmonary chondroid hamartoma in the right lower lobe presenting with severe respiratory distress. The radiological evaluation showed a large multicystic lesion in the right lower lobe with pneumothorax. Commonly, pulmonary hamartomas are asymptomatic, small in size, and are diagnosed incidentally in adults. Our case is highly unusual due to its young age, prominent clinical symptoms of severe respiratory distress with pneumothorax at presentation, very large size, and prominent cystic change. The lesion was surgically excised, and histopathological features were compatible with a multicystic chondroid hamartoma. PMID- 25828289 TI - Facial fistula. Long-term sequelae of a complicated exodontia. AB - Facial cutaneous fistula is a complication of odontogenic infection that is often misdiagnosed with dermatological infection, and hence, mistreated. We report a case of facial fistula that developed 8 years following a dental extraction, presenting its clinical appearance, radiographical findings, and treatment approach. PMID- 25828290 TI - Leishmaniasis, malaria, and schistosomiasis concurrently in an 8-year-old boy. AB - An overlap in the distribution of the 2 diseases (leishmaniasis and malaria) was reported in endemic areas, and it can cause significant delay in the diagnosis of leishmaniasis. Here, an 8-year-old Yemeni boy who was initially diagnosed as malaria and schistosomiasis, and later on as leishmaniasis is reported. He presented with prolonged fever, hepatosplenomegaly, and diarrhea. His blood film was positive for Plasmodium falciparum malaria, and his stool was positive for Schistosoma mansoni. Although a full therapeutic course of antimalarial and schistosoma was administered, his fever, weight loss, and increased hepatosplenomegaly continued. Bone marrow aspiration was carried out revealing Leishman-Donovan bodies (amastigote form). He was successfully treated with a full course of sodium stibogluconate. This case stresses the importance of alertness among the treating physicians to this disease occurring in a patient from an endemic area, presenting with prolonged fever, and hepatosplenomegaly. PMID- 25828291 TI - Urinary tract infection in children younger than 5 years. Etiology and associated urological anomalies. AB - OBJECTIVES: To investigate the most common underlying organisms, and associated urological anomalies in children presenting with urinary tract infection (UTI). METHODS: Retrospectively, all children with confirmed UTI between October 2013 and February 2014 were evaluated at King Abdulaziz University Hospital, Riyadh, Kingdom of Saudi Arabia. The electronic files of 279 children presenting with UTI, aged less than 5 years were reviewed. RESULTS: A total of 153 patients (85 males) with a mean (SD) age of 15 (19.86) months were included in the study. Recurrent UTI was present in 45.1%. Urine collection in children less than 2 years of age was through trans-urethral catheterization in 69.4%, while midstream urine was the main method in those above 2 years (78.6%). Escherichia coli (E. coli) was the causative organism in 41.2% of first UTI. The second most common organism was Klebsiella Pneumoniae, seen in 19.6%. Urological anomalies were found in 28.1% of the overall study population. Ninety percent of those with single UTI did not have anomalies. However, urological anomalies were reported in 50.7% of those with recurrent episodes of UTI (p less than 0.005). Non-E. coli cases were associated with a higher percentage of abnormal renal ultrasonography results (p=0.006). CONCLUSION: Escherichia coli was the most common causative organism for UTI, and a single episode of UTI signified normal urological anatomy. PMID- 25828292 TI - Unexpected cause of conjunctival injection. PMID- 25828294 TI - The nature of domain walls in ultrathin ferromagnets revealed by scanning nanomagnetometry. AB - The capacity to propagate magnetic domain walls with spin-polarized currents underpins several schemes for information storage and processing using spintronic devices. A key question involves the internal structure of the domain walls, which governs their response to certain current-driven torques such as the spin Hall effect. Here we show that magnetic microscopy based on a single nitrogen vacancy defect in diamond can provide a direct determination of the internal wall structure in ultrathin ferromagnetic films under ambient conditions. We find pure Bloch walls in Ta/CoFeB(1 nm)/MgO, while left-handed Neel walls are observed in Pt/Co(0.6 nm)/AlOx. The latter indicates the presence of a sizable interfacial Dzyaloshinskii-Moriya interaction, which has strong bearing on the feasibility of exploiting novel chiral states such as skyrmions for information technologies. PMID- 25828295 TI - The TUDCA trial--innovative trial designs for amyotrophic lateral sclerosis drugs? PMID- 25828296 TI - The effect of gum chewing on sensitivity associated with in-office whitening procedures. AB - OBJECTIVES: Tooth sensitivity is the most common side effect of in-office tooth whitening procedures. The purpose of this study was to determine whether chewing gum containing 0.6% casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) before tooth whitening would reduce tooth sensitivity during an in-office whitening procedure. METHODS: Thirty participants were enrolled and randomized into three groups as follows: group 1 was instructed to not chew gum during the study period; group 2 chewed five pieces of gum (with 0.6% CPP-ACP) for 10 min each day 1 week before whitening; and group 3 chewed five pieces of gum (without CPP-ACP) for 10 min each day 1 week before whitening. All participants had their teeth whitened with a 30% hydrogen peroxide in-office whitening procedure. The participants' shades of teeth were evaluated with a spectrophotometer four times during the study: at the initial screening visit, immediately before whitening, immediately after whitening and 1 week after whitening. Participants' sensitivity levels were evaluated each time the shades were evaluated and additionally at 24 h after whitening using a 100-mm visual analogue scale. RESULTS: Thirty participants were enrolled in the study. The average shade change was -2.27 (+/- 2.07). The average sensitivity for all groups at visit 1 was 5.12 (+/- 13.94). The average sensitivity for all groups after whitening was 19.81 (+/- 13.95). There were significant differences in sensitivity between groups 2 and 3 (P = 0.02), but neither group was significantly different from the control group (P = 0.86, P = 0.07). CONCLUSIONS: Chewing gum before whitening, including gum with CPP-ACP, did not reduce sensitivity during in-office whitening procedures. PMID- 25828297 TI - Multiple infective coronary arteritis complicated with bacterial pericarditis. PMID- 25828298 TI - Left main percutaneous coronary intervention improves left ventricular systolic function assessed by tissue Doppler echocardiography. PMID- 25828299 TI - Microvolt T-wave alternans in Chagas disease. PMID- 25828300 TI - Long-term effect of If-channel inhibition on diastolic function and exercise capacity in heart failure patients with preserved ejection fraction. PMID- 25828301 TI - Impact of gender on outcomes after atrial fibrillation ablation. PMID- 25828302 TI - Longitudinal change in maximum phonation time and exercise capacity in chronic heart failure patients. PMID- 25828303 TI - SAP: structure, function, and its roles in immune-related diseases. AB - Serum amyloid P component (SAP), also known as pentraxin-2, is a member of the pentraxin protein family with an established relationship to the immune response. In the last century, SAP has been used as a diagnostic marker in amyloidosis diagnosis and patient follow-up. SAP has been thought to have potential for treating and curing amyloidosis and fibrosis diseases. More recently, it has been shown that SAP may serve as both a diagnostic marker and a therapeutic target for many immune-related diseases, such as cardiovascular, pulmonary, nephritic, neurological and autoimmune diseases. In the cardiovascular system, SAP has been defined as the culprit in amyloidosis in the heart. SAP may also exert a protective role during the early stage of atherosclerosis and myocardial fibrosis. In noncardiovascular system diseases, SAP is being developed for the treatment of pulmonary fibrosis. In this review, we summarize SAP history, structure, and its roles in immune-related diseases in different systems with emphasis on the cardiovascular system. PMID- 25828304 TI - Relationships between nutritional status and markers of congestion in patients with pulmonary arterial hypertension. PMID- 25828305 TI - Is hypothyroidism (on levothyroxine replacement) a precipitant of Takotsubo syndrome? PMID- 25828306 TI - Blockade of mTOR pathway inhibition in the neointimal hyperplasia and promoting macrophage autophagy - Effect of statin-eluting stents to reduce in-stent restenosis. PMID- 25828307 TI - Potential contribution of virtual histology plaque composition to hemodynamic morphologic dissociation in patients with non-ST elevation acute coronary syndrome. AB - OBJECTIVE: Histologic plaque characteristics may influence the hemodynamic effect generated by physiologically significant unstable coronary lesions where plaque content and surface related factors are expected to contribute to the maximum translesional pressure drop. In this study, we aimed to identify local lesion specific virtual histological characteristics that may potentially affect hemodynamic outcome measures. METHODS: Forty-eight consecutive patients with non ST-elevation acute coronary syndrome (NSTEACS) having paired hemodynamic and morphological data were enrolled. A dual sensor guide-wire was used for the assessment of fractional flow reserve (FFR) and stenosis resistance (HSR) in the culprit vessel. Virtual histology intravascular ultrasound imaging was performed after obtaining hemodynamic data. RESULTS: In a hemodynamically significant lesion subset (FFR<0.75 [n=34]), after controlling for lesion length, MLA and coronary artery compliance, FFR correlated with necrotic core (NC) area (r= 0.423, p=0.028) at MLA and NC volume (r=-0.497, p=0.008) and dense calcium (DC) volume (r=-0.332, p=0.03) across the entire lesion segment. Likewise, NC (r= 0.544, p=0.005) and DC (r=0.376, p=0.03) areas at MLA and NC (r=0.545, p=0.005) and DC (r=0.576, p=0.003) volumes across the entire lesion segment were associated with HSR in the hemodynamically significant lesion group (HSR>0.80 [n=33]). However, no correlation has been observed between intracoronary hemodynamic end-points and plaque components in hemodynamically insignificant lesions. CONCLUSIONS: This study demonstrated that for a given coronary stenosis geometry and arterial compliance, plaque composition may influence hemodynamic outcome measures in functionally significant stenoses in patients with NSTEACS. PMID- 25828308 TI - Endothelial cell is critical in HMGB1 mediated cardiac impairment in ischemic heart disease. PMID- 25828309 TI - Consumption of 'gofio', a roasted cereal flour from the Canary Islands, is associated with exercise capacity and risk of coronary heart disease in the elderly. PMID- 25828310 TI - The right side or left side of noninvasive transcutaneous vagus nerve stimulation: Based on conventional wisdom or scientific evidence? PMID- 25828311 TI - Reverse remodelling in systolic heart failure: A puzzle yet to be solved? PMID- 25828312 TI - Coronary bifurcation lesions: Present status and future perspectives. AB - Coronary bifurcation lesions (CBLs) are challenging and associated with a higher rate of adverse events than non-bifurcation lesions. In the era of drug-eluting stents, 2 primary interventional strategies for treating CBL include the complex strategy the main vessel (MV) and side-branch (SB) stenting, and the simple strategy MV stenting combined with provisional SB stenting. The meta-analysis of the simple vs. complex strategies demonstrated an increased incidence of myocardial infarction in the complex strategy. Likewise, the Tryton dedicated bifurcation stents, as compared with the simple strategy, increased the rate of myocardial infarction. In contrast, the Nordic-Baltic Bifurcation Study IV demonstrated that event rates were not significantly different comparing the simple vs. complex strategies in true bifurcation lesions involving a large SB. Fractional flow reserve (FFR) has emerged as a powerful catheter based tool for the functional assessment of a stenosis, but the role of FFR on the long-term outcomes of patients with CBL has not been studied. Given the recent evidence that Tryton stents (a dedicated bifurcation stent) increased event rates, and the lack of benefit from using 2-stent techniques (the Nordic Baltic Bifurcation Study IV) in true CBL, assessing the FFR of the SB seems now of outmost importance, but randomized data are lacking. An intravascular study showed that kissing balloon inflation (KBI) significantly reduced SB stenosis, restored stent lumen at the carina, and expanded stent in the proximal segment. However, a recent randomized study showed no significant benefit of routine KBI. This review highlights current concepts and future perspectives in patients with CBL. PMID- 25828313 TI - The magic and mystery of statins in aging: The potent preventive and therapeutic agent. PMID- 25828314 TI - Genetic testing and antiplatelet treatment: Still way to go? AB - Despite medical and technical advancements stent thrombosis continued to poses a significant risk in patients after drug eluting stent (DES) implantation and clopidogrel resistance has been recognized as an important determinant of this risk. Novel antiplatelets such as prasugrel and ticagrelor can be used in cases of clopidogrel resistance however bleeding complications remain the Achilles' heel of antiplatelet therapy. Several genetic polymorphisms affect the clopidogrel absorption and bio-activation in the active form of the drug. CYP2C19 is responsible for most of the clopidogrel bio-transformation and loss of function as well as, gain of function polymorphisms of this enzyme has been recognized. Early studies have linked CYP2C19 genetic polymorphisms with clinical events, although, these findings were not confirmed by later studies. However, when the estimated thrombotic risk is high a combination of genetic information and functional platelet tests should be essential for clinicians to access clopidogrel effectiveness and to recommend alternative antiplatelet management. PMID- 25828315 TI - Antiarrhythmic properties of ranolazine: A review of the current evidence. AB - Ranolazine was developed as an antianginal agent and was approved by the Food and Drug Administration in 2006 for use in chronic stable angina pectoris. Experimental and clinical studies have shown that it also has antiarrhythmic properties based on the frequency-dependent blockade of peak sodium channel current (peak INa) and rapidly activating delayed rectifier potassium current (IKr) in the atria and blockade of late phase of the inward sodium current (late INa) in the ventricles. Recent clinical studies have revealed the efficacy of ranolazine in prevention of atrial fibrillation in patients with acute coronary syndromes, prevention as well as conversion of postoperative atrial fibrillation after cardiac surgery, conversion of recent-onset atrial fibrillation and maintenance of sinus rhythm in recurrent atrial fibrillation. Ranolazine has also been shown to reduce ventricular tachycardia and drug-refractory implantable cardioverter defibrillator shocks. The antiarrhythmic effect of ranolazine is preserved in the setting of chronic heart failure and clinical studies have demonstrated its safety in patients with heart failure. This review discusses the available preclinical and clinical data on the antiarrhythmic effects of this novel antianginal agent. PMID- 25828316 TI - Statin therapy and bone marrow CD34+ cell frequency in type 2 diabetes mellitus: Dose and form. PMID- 25828317 TI - ECG score correlates with myocardial fibrosis assessed by magnetic resonance: A study in Chagas heart disease. PMID- 25828318 TI - Is the use of risk scores an indicator of guideline adherence for patients with acute coronary syndromes? Insights from the EYESHOT Registry. PMID- 25828319 TI - Maternal and fetal outcomes of pregnancy with Fontan circulation: A multicentric observational study. AB - BACKGROUND: Despite serious long-term sequel, women with Fontan palliation have reached childbearing age. However there is paucity of data on the pregnancy outcomes and management of this condition. We aimed to determine the maternal and fetal outcomes of pregnancy in women with Fontan palliation. METHODS: This multicentric, retrospective study included women with Fontan circulation followed in 13 French specialized centers from January 2000 to June 2014. All pregnancies were reviewed, including miscarriages, abortions, premature and term births. We reviewed maternal and fetal outcomes. RESULTS: Thirty-seven patients had 59 pregnancies. Mean age was 27 +/- 5 years at first pregnancy. There were 16 miscarriages (27%) and 36 live births with 1 twin pregnancy. Cardiac events occurred in 6 (10%) pregnancies, with no maternal death. The most common cardiac complication was atrial arrhythmia, which occurred in 3 patients. Hematological complications including thromboembolic/hemorrhagic events (n=3/7) occurred in 5 women antepartum (n=2/3), and 4 women postpartum (n=1/4). Two of the 3 thromboembolic events occurred in patients without anticoagulation. There was a high incidence of prematurity (n=25/36, 69%). Anticoagulation was associated with adverse neonatal outcome (OR=10.0, 95% CI [1.5-91.4], p<0.01). After a median follow-up of 24 months, there was no significant worsening of clinical status and thromboembolic disease noted. CONCLUSIONS: Pre-selected women can successfully complete pregnancy with Fontan circulation. There is an increase in cardiac and neonatal morbidity during pregnancy. Because thromboembolism could have a severe consequence on Fontan circulation, anticoagulation should be indicated during pregnancy and postpartum period. PMID- 25828320 TI - Meta-analysis on the impact of percutaneous coronary intervention of chronic total occlusions on left ventricular function and clinical outcome. AB - BACKGROUND: Percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) may have a beneficial effect on survival through a better-preserved or improved LVEF. Current literature consists of small observational studies therefore we performed a weighted meta-analysis on the impact of revascularization of CTOs on left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and long-term mortality. METHODS: We conducted a meta-analysis evaluating LVEF before and after CTO PCI and long-term mortality. No language or time restrictions were applied. References from the identified articles and reviews were examined to find additional relevant manuscripts. RESULTS: Of the 812 citations, 34 studies performed between 1987 2014 in 2243 patients were eligible for LVEF and 27 studies performed between 1990-2013 in 11,085 patients with success and 4347 patients that failed CTO PCI were eligible for long-term mortality. After successful CTO PCI, LVEF increased with 4.44% (95% CI: 3.52-5.35, p<0.01) compared to baseline. In a small cohort of ~70 patients, no significant difference in LVEF was observed after non-successful CTO PCI or reocclusion. Additionally, 8 studies reported the change in left ventricular end-diastolic volume (LVEDV) in a total of 412 patients. LVEDV decreased with 6.14 ml/m(2) (95% CI: -9.31 to -2.97, p<0.01). Successful CTO PCI was also associated with reduced mortality in comparison with failed CTO PCI (OR: 0.52, 95% CI: 0.43-0.62, p-value<0.01). CONCLUSIONS: The current meta-analysis revealed that successful recanalization of a CTO resulted in an overall improvement of 4.44% absolute LVEF points, reduced adverse remodeling and an improvement of survival (OR: 0.52). PMID- 25828321 TI - Different optical coherence tomography findings for intracoronary stripe-like filling defects on coronary angiogram in patients with acute coronary syndrome. PMID- 25828322 TI - Regulator of G-protein signaling 6 (RGS6) in cardiology and oncology. PMID- 25828323 TI - Response to letter to the editor: "Exercise oscillatory ventilation - Perfusion abnormality in heart failure". PMID- 25828324 TI - Interval exercise training increases maximal and submaximal exercise performance in heart failure with biventricular assist device therapy. PMID- 25828325 TI - Dynamic drug-induced organic mitral regurgitation during exercise echocardiography following chronic exposure to ergotamine. PMID- 25828326 TI - Doctors should share their uncertainty with patients and make decisions together. PMID- 25828327 TI - Validity of SYNTAX score II for risk stratification of percutaneous coronary interventions: A patient-level pooled analysis of 5,433 patients enrolled in contemporary coronary stent trials. AB - OBJECTIVES: To assess the clinical profile and long-term mortality in SYNTAX score II based strata of patients who received percutaneous coronary interventions (PCI) in contemporary randomized trials. BACKGROUND: The SYNTAX score II was developed in the randomized, all-comers' SYNTAX trial population and is composed by 2 anatomical and 6 clinical variables. The interaction of these variables with the treatment provides individual long-term mortality predictions if a patient undergoes coronary artery bypass grafting (CABG) or PCI. METHODS: Patient-level (n=5433) data from 7 contemporary coronary drug-eluting stent (DES) trials were pooled. The mortality for CABG or PCI was estimated for every patient. The difference in mortality estimates for these two revascularization strategies was used to divide the patients into three groups of theoretical treatment recommendations: PCI, CABG or PCI/CABG (the latter means equipoise between CABG and PCI for long term mortality). RESULTS: The three groups had marked differences in their baseline characteristics. According to the predicted risk differences, 5115 patients could be treated either by PCI or CABG, 271 should be treated only by PCI and, rarely, CABG (n=47) was recommended. At 3-year follow-up, according to the SYNTAX score II recommendations, patients recommended for CABG had higher mortality compared to the PCI and PCI/CABG groups (17.4%; 6.1% and 5.3%, respectively; P<0.01). CONCLUSIONS: The SYNTAX score II demonstrated capability to help in stratifying PCI procedures. PMID- 25828328 TI - Acute coronary syndrome or Takotsubo cardiomyopathy: The suspect may not always be the culprit. PMID- 25828329 TI - Digoxin and risk of acute pancreatitis. PMID- 25828330 TI - Typical Takotsubo syndrome and McConnell's phenomenon: What else lies beneath? PMID- 25828331 TI - Health status, geriatric syndromes and prescription of oral anticoagulant therapy in elderly medical in-patients with atrial fibrillation: a prospective observational study. PMID- 25828332 TI - Waist to sitting height ratio may be a new useful index for screening obesity and related health risk. PMID- 25828333 TI - Reperfusion therapy for ST elevation acute myocardial infarction in Yemen: Description of the current situation: Data from Gulf Registry of Acute Coronary Events (the Gulf RACE-I). PMID- 25828334 TI - Effect of door-to-balloon time on in-hospital mortality in patients with myocardial infarction: A meta-analysis. PMID- 25828335 TI - Vectorcardiography: diagnostic advantage over electrocardiography in arrhythmogenic cardiomyopathy. PMID- 25828336 TI - Myocardial fibrosis in stroke survivors. PMID- 25828337 TI - The butler did it! A very late stent thrombosis of TAXUS evaluated with Optical Coherence Tomography. PMID- 25828338 TI - First description of successful weaning from ECMO in a patient with Eisenmenger syndrome after repair of pulmonary artery dissection. PMID- 25828339 TI - Significance of QRS duration in non-ST elevation myocardial infarction. PMID- 25828340 TI - Atrial sympathetic remodeling in experimental hyperthyroidism and hypothyroidism rats. PMID- 25828341 TI - Letter regarding the article: Changes in BNP and cardiac troponin I after high intensity interval and endurance exercise in heart failure patients and healthy controls. PMID- 25828342 TI - Takotsubo cardiomyopathy and co-existing coronary artery disease. PMID- 25828343 TI - The reproducibility of coronary artery calcium scoring on different software platforms. PMID- 25828344 TI - Intra-atrial reentrant tachycardia in adult patients after Fontan operation. AB - BACKGROUND: Atrial tachyarrhythmia is a major late complication in adult Fontan patients. This study examined the clinical features and risk factors of late intra-atrial reentrant tachyarrhythmia (IART) in adult patients after Fontan surgery and the mid-term outcome of Fontan conversion with or without antiarrhythmic surgery in these patients. METHODS: We conducted a retrospective study on adult patients who were born before 1994 and survived at least 3 months after a Fontan operation at Seoul National University Children's Hospital. RESULTS: We followed 160 patients over 20.9 +/- 4.1 years. Sustained atrial tachycardia was identified in 51 patients, and IART was found in 41, appearing a mean 13.6 years after surgery. By the 25 year follow-up, 40% had developed IART. The incidence of IART significantly increased over time. Patients with an atriopulmonary connection (APC) (n=65) had significantly longer follow-up duration and higher incidence of IART than patients with a lateral tunnel (n=86) or extracardiac conduit Fontan (n=9). On multivariate analysis, APC, sinus node dysfunction, and nonsustained atrial tachycardia were found to be significantly associated with IART. Twenty-four patients with IART underwent Fontan conversion. Over the follow-up period, IART severity scores in the 22 patients who survived after Fontan conversion decreased significantly, and New York Heart Association functional class significantly improved. On multivariate analysis, protein losing enteropathy and ventricular dysfunction were found to be significant risk factors for mortality. CONCLUSIONS: IART was common in adult Fontan patients, and Fontan conversion with or without antiarrhythmic surgery and pacemaker placement helped to control it. PMID- 25828345 TI - Heart against veno-arterial ECMO: Competition visualized. PMID- 25828346 TI - Distribution, genetic and cardiovascular determinants of FVIII:c - Data from the population-based Gutenberg Health Study. AB - BACKGROUND: Elevated levels of FVIII: c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex specific distribution and reference ranges of plasma FVIII: c and its cardiovascular determinants is available. METHODS: FVIII: c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany. Multivariable regression analyses for FVIII: c were performed under adjustment for genetic determinants, cardiovascular risk factors and cardiovascular disease. RESULTS AND CONCLUSIONS: Females (126.6% (95% CI: 125.2/128)) showed higher FVIII: c levels than males (121.2% (119.8/122.7)). FVIII: c levels increased with age in both sexes (beta per decade: 5.67% (4.22/7.13) male, 6.15% (4.72/7.57) female; p<0.001). Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms for FVIII: c were created. FVIII: c was approximately 25% higher in individuals with non-O blood type. Adjusted for sex and age, ABO blood group accounted for 18.3% of FVIII: c variation. In multivariable analysis, FVIII: c was notably positively associated with diabetes mellitus, obesity, hypertension and dyslipidemia and negatively with current smoking. In a fully adjusted multivariable model, the strongest associations observed were of elevated FVIII: c with diabetes and peripheral artery disease in both sexes and with obesity in males. Effects of SNPs in the vWF, STAB2 and SCARA5 gene were stronger in females than in males. The use of nomograms for valuation of FVIII: c might be useful to identify high-risk cohorts for thromboembolism. Additionally, the prospective evaluation of FVIII: c as a risk predictor becomes feasible. PMID- 25828347 TI - Sports participation in adults with congenital heart disease. AB - BACKGROUND: It is unclear whether sports participation in adults with repaired congenital heart disease is safe and has benefits. METHODS: Congenital heart disease (ConHD) patients who underwent corrective surgery for Atrial Septal Defect, Ventricular Septal Defect, Pulmonary Stenosis, Tetralogy of Fallot or Transposition of the Great Arteries in our center between 1968 and 1980 were included, and participated in our longitudinal follow-up study with serial evaluations in 2001 and 2011. At both time points patients filled in questionnaires on sports participation, subjective physical functioning and quality of life. Exercise testing, echocardiogram and 24-hour continuous ambulatory ECG-monitoring were performed in both 2001 and 2011. All clinical events (re-intervention, arrhythmia, heart failure) were prospectively recorded. RESULTS: No relationship was found between practicing sports and the occurrence of sudden death, PVCs or SVTs. Patients with moderate/complex forms of ConHD practiced fewer hours of sports compared with the general Dutch normative population. Patients with both simple and moderate/complex ConHD who practiced sports showed a higher exercise capacity. More favorable subjective physical functioning was found for moderate/complex patients who practiced sports. CONCLUSIONS: Adults with repaired ConHD are less often involved in sports than the Dutch general population. The patients that were engaged in sports show a higher exercise capacity than those who did not. Sports participation in patients with ConHD was not associated with an increased incidence of adverse cardiac events. PMID- 25828348 TI - Increased visit-to-visit blood pressure variability is associated with worse cardiovascular outcomes in low ejection fraction heart failure patients: Insights from the HEAAL study. AB - BACKGROUND: Recent data have highlighted shortcomings of the usual blood pressure (BP) hypothesis in several populations, and emphasized the importance of visit-to visit variability of BP in predicting cardiovascular events. Herein, we aimed at assessing the association between visit-to-visit BP variability and outcomes in chronic heart failure (CHF) patients enrolled in the Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL). METHODS AND RESULTS: The HEAAL study randomized 3834 patients with HF and reduced ejection fraction administered 150 mg or 50mg losartan daily in a double blind, randomized, controlled trial. The patients were followed up for up to 6.8 years after randomization, and BP was measured at 3 time points in the first year and at semi annual visits in the years thereafter. Three measures of visit-to-visit BP variability were computed for each subject: the standard deviation, the coefficient of variation and the average absolute visit-to-visit variation. Cox proportional hazard models were used to investigate the relationship between variations in systolic blood pressure, baseline covariates and the time to death or heart failure hospitalization (i.e. primary outcome). In multivariate analyses stratified on baseline BP, the patients with higher visit-to visit BP variability exhibited poorer outcomes (average absolute difference in SBP in mmHg:hazard ratio: 1.023 [95% CI (1.013, 1.034), P<0.0001]), independent from high dose losartan (still beneficial). CONCLUSIONS: For the first time, visit-to-visit BP variability was found elevated in CHF patients with reduced ejection fraction, and associated with poorer cardiovascular outcomes. Such assessments should be prioritized for testing prevention strategies in CHF. CLINICAL TRIAL REGISTRATION: This study is registered with the ClinicalTrials.gov, number NCT00090259. PMID- 25828349 TI - Length of hospital stay is shorter in South Asian patients with ischaemic stroke. PMID- 25828350 TI - HRA2pl peptide: a fusion inhibitor for human metapneumovirus produced in tobacco plants by transient transformation. AB - MAIN CONCLUSION: The HRA2pl peptide expressed by transient transformation in N. tabacum plants is capable of inhibiting the binding of the human metapneumovirus to HEp-2 cells at the fusion stage. Human metapneumovirus (hMPV) is an agent responsible for acute respiratory infections that mainly affects children under 3 years, the elderly and immunocompromised patients. In children younger than 5 years, respiratory tract infections account for 20 % of deaths worldwide. However, there is currently no treatment or vaccine available against hMPV. The production of a safe, efficient and low cost treatment against this virus is a current challenge. Plants provide a system for recombinant protein production that is cost effective and is easier to scale up to an industrial level than other platforms; in addition, the plant tissue may be used as raw food, dried or, alternatively, proteins may be partially or fully purified and administered in aerosol or capsules as dry powder. In this study, we designed a gene expressing an antiviral peptide against hMPV based on the heptad repeat A domain of the F protein of the virus. We produced the recombinant peptide by a viral transient expression system (Magnifection((r))) in Nicotiana tabacum plants. The efficacy of this antiviral peptide was confirmed by in vitro assays in HEp-2 cell line. This is a promising result that can offer a prophylactic approach against hMPV. PMID- 25828352 TI - Ionization of EPA contaminants in direct and dopant-assisted atmospheric pressure photoionization and atmospheric pressure laser ionization. AB - Seventy-seven EPA priority environmental pollutants were analyzed using gas chromatography-mass spectrometry (GC-MS) equipped with an optimized atmospheric pressure photoionization (APPI) and an atmospheric pressure laser ionization (APLI) interface with and without dopants. The analyzed compounds included e.g., polycyclic aromatic hydrocarbons (PAHs), nitro compounds, halogenated compounds, aromatic compounds with phenolic, acidic, alcohol, and amino groups, phthalate and adipatic esters, and aliphatic ethers. Toluene, anisole, chlorobenzene, and acetone were tested as dopants. The widest range of analytes was ionized using direct APPI (66/77 compounds). The introduction of dopants decreased the amount of compounds ionized in APPI (e.g., 54/77 with toluene), but in many cases the ionization efficiency increased. While in direct APPI the formation of molecular ions via photoionization was the main ionization reaction, dopant-assisted (DA) APPI promoted ionization reactions, such as charge exchange and proton transfer. Direct APLI ionized a much smaller amount of compounds than APPI (41/77 compounds), showing selectivity towards compounds with low ionization energies (IEs) and long-lived resonantly excited intermediate states. DA-APLI, however, was able to ionize a higher amount of compounds (e.g. 51/77 with toluene), as the ionization took place entirely through dopant-assisted ion/molecule reactions similar to those in DA-APPI. Best ionization efficiency in APPI and APLI (both direct and DA) was obtained for PAHs and aromatics with O- and N-functionalities, whereas nitro compounds and aliphatic ethers were the most difficult to ionize. Halogenated aromatics and esters were (mainly) ionized in APPI, but not in APLI. PMID- 25828351 TI - Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1. AB - The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1 deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research. PMID- 25828353 TI - Running a postmortem service--a business case and clinical experience. AB - The purpose of the postmortem examination is to offer answers to explain the cause and manner of death. In the case of perinatal, infant and paediatric postmortem examinations, the goal is to identify unsuspected associated features, to describe pathogenic mechanisms and new conditions, and to evaluate the clinical management and diagnosis. Additionally, the postmortem examination is useful to counsel families regarding the probability of recurrence in future pregnancies and to inform family planning. Worldwide the rate of paediatric autopsy examinations has significantly declined during the last few decades. Religious objections to postmortem dissection and organ retention scandals in the United Kingdom provided some of the impetus for a search for non-invasive alternatives to the traditional autopsy; however, until recently, imaging studies remained an adjunct to, rather than a replacement for, the traditional autopsy. In 2012, Sheffield Children's Hospital National Health Service Foundation Trust set up the service provision of minimally invasive fetal, perinatal and neonatal autopsy, while a postmortem imaging service has been running in Melbourne, Australia, since 2008. Here we summarise the essentials of a business case and practical British and Australian experiences in terms of the pathological and radiologic aspects of setting up a minimally invasive clinical service in the United Kingdom and of developing a clinical postmortem imaging service as a complementary tool to the traditional autopsy in Australia. PMID- 25828354 TI - The future of pediatric and perinatal postmortem imaging. AB - The field and applications of postmortem imaging are exponentially growing. Its potential to identify the cause of death in trauma and ballistic cases is now properly documented, as well as its use in drug mule identification. In pediatric and perinatal practice, large significant series are less available, except for MRI and central nervous system analysis where scientific evidence is now robust. In this review, after a short historical review and analysis of current problems and challenges, we will try to depict the way we see the future of this subspecialty of postmortem cross-sectional imaging, including all specific situations: terminations of pregnancy, intrauterine death, sudden unexpected infant death and identification issues. PMID- 25828355 TI - Normal pediatric postmortem CT appearances. AB - Postmortem radiology is a rapidly developing specialty that is increasingly used as an adjunct to or substitute for conventional autopsy. The goal is to find patterns of disease and possibly the cause of death. Postmortem CT images bring to light processes of decomposition most radiologists are unfamiliar with. These postmortem changes, such as the formation of gas and edema, should not be mistaken for pathological processes that occur in living persons. In this review we discuss the normal postmortem thoraco-abdominal changes and how these appear on CT images, as well as how to differentiate these findings from those of pathological processes. PMID- 25828356 TI - Normal perinatal and paediatric postmortem magnetic resonance imaging appearances. AB - As postmortem imaging becomes more widely used following perinatal and paediatric deaths, the correct interpretation of images becomes imperative, particularly given the increased use of postmortem magnetic resonance imaging. Many pathological processes may have similar appearances in life and following death. A thorough knowledge of normal postmortem changes is therefore required within postmortem magnetic resonance imaging to ensure that these are not mistakenly interpreted as significant pathology. Similarly, some changes that are interpreted as pathological if they occur during life may be artefacts on postmortem magnetic resonance imaging that are of limited significance. This review serves to illustrate briefly those postmortem magnetic resonance imaging changes as part of the normal changes after death in fetuses and children, and highlight imaging findings that may confuse or mislead an observer to identifying pathology where none is present. PMID- 25828357 TI - Postmortem cardiac imaging in fetuses and children. AB - Fetal and pediatric cardiac autopsies have a crucial role in the counseling of parents with regard to both the cause of death of their child and the implications of such findings for future pregnancies, as well as for quality assurance of antenatal screening programs and antemortem diagnostic procedures. Postmortem imaging allows an opportunity to investigate the heart in situ prior to dissection, and both postmortem CT and postmortem MRI have shown excellent accuracy in detecting the majority of clinically significant cardiac lesions in the perinatal and pediatric population. As less-invasive autopsy becomes increasingly popular, clinical guidelines for maximal diagnostic yield in specific circumstances can be developed. PMID- 25828359 TI - Common normal variants of pediatric vertebral development that mimic fractures: a pictorial review from a national longitudinal bone health study. AB - Children with glucocorticoid-treated illnesses are at risk for osteoporotic vertebral fractures, and growing awareness of this has led to increased monitoring for these fractures. However scant literature describes developmental changes in vertebral morphology that can mimic fractures. The goal of this paper is to aid in distinguishing between normal variants and fractures. We illustrate differences using lateral spine radiographs obtained annually from children recruited to the Canada-wide STeroid-Associated Osteoporosis in the Pediatric Population (STOPP) observational study, in which 400 children with glucocorticoid treated leukemia, rheumatic disorders, and nephrotic syndrome were enrolled near glucocorticoid initiation and followed prospectively for 6 years. Normal variants mimicking fractures exist in all regions of the spine and fall into two groups. The first group comprises variants mimicking pathological vertebral height loss, including not-yet-ossified vertebral apophyses superiorly and inferiorly, which can lead to a vertebral shape easily over-interpreted as anterior wedge fracture, physiological beaking, or spondylolisthesis associated with shortened posterior vertebral height. The second group includes variants mimicking other radiologic signs of fractures: anterior vertebral artery groove resembling an anterior buckle fracture, Cupid's bow balloon disk morphology, Schmorl nodes mimicking concave endplate fractures, and parallax artifact resembling endplate interruption or biconcavity. If an unexpected vertebral body contour is detected, careful attention to its location, detailed morphology, and (if available) serial changes over time may clarify whether it is a fracture requiring change in management or simply a normal variant. Awareness of the variants described in this paper can improve accuracy in the diagnosis of pediatric vertebral fractures. PMID- 25828361 TI - Basing RNA-seq explored the regulatory mechanism of the carbohydrate metabolism pathways during chicken male germ cell differentiation. AB - Our study aimed to explore the regulatory mechanism of the carbohydrate metabolism signaling pathways and related genes during the differentiation of chicken embryonic stem cells to male germ cells, providing the basis for improving the efficiency of the in vitro induction system. Cell sorting was used to obtain highly purified embryonic stem cells (ESCs), primitive germ cells (PGCs), and spermatogonial stem cells (SSCs). The total RNA was then extracted from each cell type. The transcriptions of ESCs, PGCs, and SSCs were sequenced by DNA microarray and mRNA sequencing (RNA-seq). The results were analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. The key pathways and genes of carbohydrate metabolism were screened during the differentiation process of chicken male germ cell. We concluded that 419 differentially expressed genes enriched to 26 carbohydrate metabolism pathways during the differentiation process of ESCs to SSCs, all of the chondroitin sulfate (CS) signaling pathway was significant. We screened the key genes CHSY3, B3GAT1, CHPF, and B4GALT7 which was significantly expressed in CS pathway. Quantitative RT-PCR showed that the expression trend of these genes is consistent with DNA Microarray and RNA-seq results. Our study supports the opinion that CS pathway is significantly different during the differentiation of chicken male germ cell (P < 0.05) and that CHSY3, B3GAT1, CHPF, and B4GALT7 are key genes. PMID- 25828362 TI - Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis. AB - The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 * 3 mg/kg or 1 * 10 mg/kg on Day 1, or 3 * 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL 17A-directed therapies such as secukinumab. PMID- 25828363 TI - Comparison of intratumoral heterogeneity of HER2 expression between primary tumor and multiple organ metastases in gastric cancer: Clinicopathological study of three autopsy cases and one resected case. AB - Intratumoral heterogeneity of HER2 expression in the metastatic foci of HER2 positive advanced gastric cancer remains unclear. In this study, we compared HER2 expression between primary and metastatic tumors in HER2-positive three autopsied cases and one resected case with multiple organ metastases by immunohistochemistry (IHC) and dual color in situ hybridization (DISH). All four cases judged positive (IHC3+) at the primary tumor tissues showed varying HER2 gene amplification (GA) status. One homogeneously HER2-positive autopsied case (Case 1) and one intratumorally heterogeneous positive resected case (Case 2) with high GA showed a homogeneous positive staining pattern in all the metastatic foci. One heterogeneously HER2-positive autopsied case (Case 3) with low GA showed a partially heterogeneous HER2 staining pattern in all the metastatic foci. In contrast, one heterogeneously HER2-positive autopsied case (Case 4) with equivocal GA showed a completely heterogeneous HER2 staining pattern in the metastatic foci. These results indicate that HER2-positive gastric cancers with low to high GA at the primary tumor show substantially homogeneous HER2 overexpression in the metastatic foci, whereas HER2-positive gastric cancers with equivocal GA expressed HER2 heterogeneously within the metastatic tumor, suggesting that metastatic foci of the latter HER2-positive cases would be potentially resistant to trastuzumab. PMID- 25828364 TI - Protein costs do not explain evolution of metabolic strategies and regulation of ribosomal content: does protein investment explain an anaerobic bacterial Crabtree effect? AB - Protein investment costs are considered a major driver for the choice of alternative metabolic strategies. We tested this premise in Lactococcus lactis, a bacterium that exhibits a distinct, anaerobic version of the bacterial Crabtree/Warburg effect; with increasing growth rates it shifts from a high yield metabolic mode [mixed-acid fermentation; 3 adenosine triphosphate (ATP) per glucose] to a low yield metabolic mode (homolactic fermentation; 2 ATP per glucose). We studied growth rate-dependent relative transcription and protein ratios, enzyme activities, and fluxes of L. lactis in glucose-limited chemostats, providing a high-quality and comprehensive data set. A three- to fourfold higher growth rate rerouted metabolism from acetate to lactate as the main fermentation product. However, we observed hardly any changes in transcription, protein levels and enzyme activities. Even levels of ribosomal proteins, constituting a major investment in cellular machinery, changed only slightly. Thus, contrary to the original hypothesis, central metabolism in this organism appears to be hardly regulated at the level of gene expression, but rather at the metabolic level. We conclude that L. lactis is either poorly adapted to growth at low and constant glucose concentrations, or that protein costs play a less important role in fitness than hitherto assumed. PMID- 25828365 TI - Perinatal experiences of Somali couples in the United States. AB - OBJECTIVE: To explore the perspectives of Somali couples on care and support received during the perinatal period in the United States. DESIGN: Descriptive phenomenology. SETTING: A private room at the participants' homes or community center. PARTICIPANTS: Forty-eight immigrant women and men from Somalia (26 women and 22 men) who arrived in the United States within the past 5 years and had a child or children born in their homelands or refugee camps and at least one child born in the United States. All of the participants resided in the Pacific Northwest. METHODS: Semistructured individual interviews, interviews with couples, and a follow-up phone interview. Colaizzi's method guided the research process. RESULTS: Data analysis revealed an overarching theme of Navigating through the conflicting values, beliefs, understandings and expectations that infiltrated the experiences captured by the three subthemes: (a) Feeling vulnerable, uninformed, and misunderstood, (b) Longing for unconditional respect and acceptance and (c) Surviving and thriving as the recipients of health care. CONCLUSIONS: Integration of new Somali immigrant couples into the Western health care system can present many challenges. The perinatal experience for new Somali immigrant couples is complicated by cultural and language barriers, limited access to resources, and commonly, an exclusion of husbands from prenatal education and care. Nurses and other health care providers can play an important role in the provision of services that integrate Somali women and men into the plan of care and consider their culture-based expectations to improve childbirth outcomes. PMID- 25828366 TI - Use of hollow microneedles for targeted delivery of phenylephrine to treat fecal incontinence. AB - A hollow microneedle (HM) was prepared to deliver a phenylephrine (PE) solution into the anal sphincter muscle as a method for treating fecal incontinence. The goal of this study was the local targeted delivery of PE into the sphincter muscle through the perianal skin with minimal pain using hollow microneedles, resulting in the increase of resting anal sphincter pressure. PE was administered on the left and the right sides of the anus of a rat through the perianal skin using 1.5mm long HM. An in vivo imaging system study was conducted after injection of Rhodamine B, and a histological study was performed after injection of gentian violet. The resting anal sphincter pressure in response to various drug doses was measured by using an air-charged catheter. Anal pressure change produced by HM administration was compared with change produced by intravenous injection (IV), subcutaneous (SC) injection and intramuscular (IM) injection. The change in mean blood pressure produced by HM administration as a function of PE dose was compared with change produced by PBS injection. A pharmacokinetic study of the new HM administration method was performed. A model drug solution was localized in the muscle layer under the perianal skin at the injection site and then diffused out over time. HM administration of PE induced significant contraction of internal anal sphincter pressure over 12h after injection, and the maximum anal pressure was obtained between 5 and 6h. Compared to IV, SC and IM treatments, HM treatment produced greater anal pressure. There was no increase in blood pressure after HM administration of PE within the range of predetermined concentration. Administration of 800MUg/kg of PE using HM produced 0.81+/-0.38h of tmax. Our study suggests that HM administration enables local delivery of a therapeutic dose of PE to the anal sphincter muscle layer with less pain. This new treatment has great potential as a clinical application because of the ease of the procedure, minimal pain, and dose-dependent response. PMID- 25828367 TI - Systematic study for DNA recovery and profiling from common IED substrates: From laboratory to casework. AB - Improvised explosive devices (IEDs) made from household items are encountered in terrorist attacks worldwide. Assembling an IED leaves trace DNA on its components, but deflagration degrades DNA. To maximize the amount of DNA recovered, a systematic evaluation of DNA collection methods was carried out and the most efficient methods were implemented with IED casework evidence as a validation exercise. Six swab types and six moistening agents were used to collect dried buffy coat stains on four common IED substrates. The most efficient swab/moistening agent combinations were then compared with tape-lifting using three brands of adhesive tape and also with direct DNA extraction from evidence. The most efficient collection methods for different IED substrates (post-study protocol) were then implemented for IED casework and compared with the pre-study protocol using 195 pieces of IED evidence. There was no single best swab type or moistening agent. Swab type had the largest effect on DNA recovery percentages, but moistening agents, substrates, and the interactions between factors all affected DNA recovery. The most efficient swab/moistening agent combinations performed equally well when compared with the best adhesive tape and direct extraction. The post-study protocol significantly improved STR profiles obtained from IED evidence. This paper outlines a comprehensive study of DNA collection methods for trace DNA and the validation of the most efficient collection methods with IED evidence. The findings from both parts of this study emphasize the need to continuously re-evaluate standard operating protocols with empirical studies. PMID- 25828368 TI - Development and validation of a new STR 25-plex typing system. AB - In this study, a new STR 25-plex typing system, including 23 autosomal STRs (D1S1656, D2S1338, D2S441, D3S1358, D5S818, D6S1043, D7S820, D8S1179, D10S1248, D12S391, D13S317, D16S539, D18S51, D19S433, D21S11, D22S1045, CSF1PO, FGA, Penta D, Penta E, TH01, TPOX, vWA) and a Y-STR locus of DYS391 and amelogenin, was developed. The included 24 STRs belonged to the main international DNA databases (CODIS, ISSL, ESS-extended, UCL, GCL and NCIDD) except D6S1043 (specially chosen for Chinese population). Developmental validation indicated that the STR 25-plex typing system was reproducible, accurate, sensitive and robust. The sensitivity testing of the system was such that a full profile was obtainable even with 125pg of human DNA. Specificity testing was demonstrated by the lack of cross reactivity with a variety of commonly encountered animal species and microbial pool. For the stability testing, full profiles can been obtained with humic acid concentration<=60ng/MUL and hematin<500MUM. Also, this multiplex system is suitable for mixture study. All of the minor alleles were called for ratios of 1:1, 1:3 and 3:1 of the mixture with the system. In addition, the whole PCR amplification can finish within 1h, making the system suitable for fast detection. For the forensic evaluation of the multiplex system, 23 autosomal STRs included followed the Hardy-Weinberg equilibrium. A total of 268 alleles were detected for the 23 autosomal STR loci among 200 individuals. Since 23 autosomal STRs were independent from each other, CMECduo was 0.99999916563607 and CMECtri was 0.99999999986525. All the forensic efficiency parameters demonstrated that this multiplex system is highly polymorphic and informative in the Han population of China. PMID- 25828369 TI - An optimized procedure for obtaining DNA from fired and unfired ammunition. AB - Gun crimes are a significant problem facing law enforcement agencies. Traditional forensic examination of firearms involves comparisons of markings imparted to bullets and cartridge casings during the firing process. DNA testing of casings and cartridges may not be routinely done in crime laboratories due a variety of factors including the typically low amounts of DNA recovered. The San Diego Police Department (SDPD) Crime Laboratory conducted a study to optimize the collection and profiling of DNA from fired and unfired ammunition. The method was optimized to where interpretable DNA results were obtained for 26.1% of the total number of forensic casework evidence samples, and provided some insights into the level of secondary transfer that might be expected from this type of evidence. Briefly detailed are the results from the experimental study and the forensic casework analysis using the optimized process. Mixtures (samples having more DNA types than the loader's known genotype detected or visible at any marker) were obtained in 39.8% of research samples and the likely source of DNA mixtures is discussed. PMID- 25828371 TI - Renal Denervation After SYMPLICITY HTN-3: Where Do We Go? AB - Previous preclinical and clinical studies provide insight into the mechanisms that account for the chronic lowering of blood pressure (BP) during suppression of central and peripheral sympathetic outflow. From these mechanisms, novel and alternative approaches to BP control in patients with hypertension resistant to medical therapy have been proposed. Over the past 5 years, data from prospective cohorts and randomized studies showed that renal denervation therapy is a safe procedure associated with a significant reduction of office BP but only a modest reduction in ambulatory BP despite intensive ongoing medical therapy. Recently, the failure of the most rigourously designed randomized study, SYMPLICITY HTN-3, to meet its primary efficacy end point has raised several questions and unresolved methodological issues. Further prospective randomized controlled trials are required to further assess the efficacy, durability, and cost effectiveness of renal denervation therapy and its effects on cardiovascular and renal outcomes in carefully selected patients with true treatment-resistant hypertension. PMID- 25828370 TI - The interaction of patient race, provider bias, and clinical ambiguity on pain management decisions. AB - Although racial disparities in pain care are widely reported, much remains to be known about the role of provider and contextual factors. We used computer simulated patients to examine the influence of patient race, provider racial bias, and clinical ambiguity on pain decisions. One hundred twenty-nine medical residents/fellows made assessment (pain intensity) and treatment (opioid and nonopioid analgesics) decisions for 12 virtual patients with acute pain. Race (black/white) and clinical ambiguity (high/low) were manipulated across vignettes. Participants completed the Implicit Association Test and feeling thermometers, which assess implicit and explicit racial biases, respectively. Individual- and group-level analyses indicated that race and ambiguity had an interactive effect on providers' decisions, such that decisions varied as a function of ambiguity for white but not for black patients. Individual differences across providers were observed for the effect of race and ambiguity on decisions; however, providers' implicit and explicit biases did not account for this variability. These data highlight the complexity of racial disparities and suggest that differences in care between white and black patients are, in part, attributable to the nature (ie, ambiguity) of the clinical scenario. The current study suggests that interventions to reduce disparities should differentially target patient, provider, and contextual factors. PERSPECTIVE: This study examined the unique and collective influence of patient race, provider racial bias, and clinical ambiguity on providers' pain management decisions. These results could inform the development of interventions aimed at reducing disparities and improving pain care. PMID- 25828372 TI - Regular Drug-Eluting Stent vs Dedicated Coronary Bifurcation BiOSS Expert Stent: Multicenter Open-Label Randomized Controlled POLBOS I Trial. AB - BACKGROUND: Results of regular drug-eluting stents (rDESs) in bifurcation treatment are not optimal. The aim of the Polish Bifurcation Optimal Stenting I (POLBOS I) trial was to compare bifurcation treatment with any rDES vs the dedicated bifurcation paclitaxel-eluting stent BiOSS Expert (Balton, Poland). The second aim was to study the effect of final kissing balloon (FKB) inflation on clinical outcomes. METHODS: Between October 2010 and January 2013 patients with stable coronary artery disease or non-ST-elevation acute coronary syndrome were assigned 1:1 to 1 of 2 treatment strategies: BiOSS Expert stent or rDES implantation. Coronary angiography was performed at 12 months. The primary end point was a composite of cardiac-related death, myocardial infarction (MI), and target lesion revascularization (TLR) at 12 months. RESULTS: The BiOSS Expert was implanted in 120 patients (49.4%), and an rDES was implanted in 123 patients. The target vessel was the left anterior descending (LAD) artery (52% vs 70%) followed by the left main stem (LMS) coronary artery (22% vs 15%). In the rDES group, 38.2% received paclitaxel-eluting stents. There were 3 stent implantation failures (2 in the rDES group and 1 in the BiOSS Expert group). Side branch treatment with an rDES was required in 10% of cases in both groups. At 12 months, the incidence of cumulative major adverse cardiovascular events (MACE) was similar in both groups: 13.3% vs 12.2% (P = 0.7). The TLR rate was significantly higher in the BiOSS Expert group compared with the rDES group (11.5% vs 7.3%; P = 0.02). Significantly lower rates of restenosis were observed in FKB subgroups of both the BiOSS Expert (8.1% vs 13.2%; P < 0.05) and rDES groups (4.9% vs 9.5%; P < 0.05). CONCLUSIONS: MACE rates were comparable between the 2 groups; however, the TLR rate was higher in the BiOSS Expert group. A more aggressive protocol yielded better angiographic and clinical outcomes. PMID- 25828373 TI - Targeting MicroRNA-208a to Suppress Adverse Postmyocardial Infarction Remodelling Related to RNA Activation of Endoglin Gene Expression. PMID- 25828375 TI - Morphine and children: An Australian perspective. PMID- 25828374 TI - A New Algorithm for the Diagnosis of Hypertension in Canada. AB - Accurate blood pressure measurement is critical to properly identify and treat individuals with hypertension. In 2005, the Canadian Hypertension Education Program produced a revised algorithm to be used for the diagnosis of hypertension. Subsequent annual reviews of the literature have identified 2 major deficiencies in the current diagnostic process. First, auscultatory measurements performed in routine clinical settings have serious accuracy limitations that have not been overcome despite great efforts to educate health care professionals over several years. Thus, alternatives to auscultatory measurements should be used. Second, recent data indicate that patients with white coat hypertension must be identified earlier in the process and in a systematic manner rather than on an ad hoc or voluntary basis so they are not unnecessarily treated with antihypertensive medications. The economic and health consequences of white coat hypertension are reviewed. In this article evidence for a revised algorithm to diagnose hypertension is presented. Protocols for home blood pressure measurement and ambulatory blood pressure monitoring are reviewed. The role of automated office blood pressure measurement is updated. The revised algorithm strongly encourages the use of validated electronic digital oscillometric devices and recommends that out-of-office blood pressure measurements, ambulatory blood pressure monitoring (preferred), or home blood pressure measurement, should be performed to confirm the diagnosis of hypertension. PMID- 25828376 TI - Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. AB - INTRODUCTION: Radix Glycyrrhiza has been used in China for thousand years to treat cancer. However, focus on its tumor-suppressing mechanism has been concentrated on its effect on tumor cell growth and apoptosis. OBJECTIVES: With the aid of a panel of human breast cancer cell lines, we reveal that glycyrrhetinic acid (GA), a major component of Radix Glycyrrhiza, is actually a significantly more potent agent to suppress invasion than cell survival. RESULTS: GA effectively inhibits breast cancer cell MMP-2/MMP-9 expression; GA-induced reduction in the MMP-2/9 expression is apparently mediated by GA's ability to specifically inhibit the p38 MAPK activity and its downstream AP1 activation. Moreover, we show that GA down regulates the levels of Fra-1 and c-Jun, two main components of AP1 transcription complex in invasive breast cancer cells and that AP1-specific inhibitor abrogates breast cancer cell invasion. These results suggest that GA impairs the p38 MAPK-AP1 signaling axis, leading to the repression of breast cancer cell invasion. Finally, we demonstrate that GA effectively suppresses breast tumor outgrowth and pulmonary metastasis without causing animal weight loss or eliciting liver/kidney toxicity to the recipient animals. CONCLUSION: This study indicates that GA represents a good candidate compound for the potential development of therapeutic drug. PMID- 25828377 TI - Prevalence and diagnostic accuracy of heart disease in children with asymptomatic murmurs. AB - This study was performed to determine the prevalence of CHD among children referred with asymptomatic murmurs and to determine the diagnostic accuracy of the assessment of asymptomatic heart murmurs by general paediatricians. We reviewed the records of children who had been referred by general paediatricians to a cardiology clinic for further evaluation of a heart murmur. The referring paediatricians' clinical assessment of the murmur was compared with the cardiologist's echocardiographic diagnosis. A total of 150 children were referred by paediatricians to a paediatric cardiologist for further assessment of a heart murmur. Out of 150 children, 72 had a paediatrician's diagnosis of innocent murmur; of these 72 patients, two (3%) had heart disease on echocardiography. In all, after echocardiography, a range of congenital heart lesions was found in 28 (19%) of the 150 children. CHD is not rare among children with asymptomatic heart murmurs. In this series of children with asymptomatic murmurs, 19% had heart lesions on echocardiography. Most, but not all, of the children with heart lesions were identified on clinical examination by general paediatricians. PMID- 25828378 TI - Novel experimental rabbit model of anterior glottic web formation. AB - CONCLUSION: The rabbit model of anterior glottic web (AGW) formation using the laryngofissure technique resulted in reproducible and stable AGW formation that may facilitate research into this area. OBJECTIVE: To introduce and validate a novel experimental animal model of AGW formation using the rabbit. METHODS: The inner larynges of eight New Zealand white rabbits were exposed through the laryngofissure technique. The mucosa of the bilateral true vocal fold was stripped off using the bevel of a needle tip. On the basis of the laryngoscopic findings at 8 weeks postoperatively, the extent of AGW was measured, and the success of this procedure was validated. Laryngeal specimens were sampled at 8 weeks for high-speed recording and histological analysis. RESULTS: In seven (87.5%) rabbits, laryngoscopic examination revealed the formation of a scar band involving the anterior commissure. The mean extent of AGW ratio on the left and right sides was 0.58 +/- 0.073 and 0.55 +/- 0.075, respectively. The symmetric formation of AGW (p = 0.655, p = 0.128) and stability of the AGW procedure (p = 0.491, left; p = 0.501, right) were statistically validated. On high-speed recording, the vocal mucosal wave was hindered by AGW formation. Histologically, fibro-connective tissue, especially collagen fiber, was observed in the anterior commissure. PMID- 25828379 TI - Towards source level evaluation of the evidential value of fibre examinations. AB - This paper aims to provide the first steps towards a numerical source level evaluation of fibre evidence. For that purpose, likelihood ratio equations are derived for four generic scenarios, in which the source frequency, the number of references and trace types investigated, and the number of matches vary. Previous experimental studies into the evaluation of fibre evidence are reviewed and we demonstrate how the results of these studies, as well as other data, can be used to evaluate the derived equations for the four scenarios. Evaluation is not straightforward and requires a number of assumptions. This is mainly because the relevant population under consideration in a specific case cannot be sufficiently evaluated. In addition, the subjective match-criterion in current forensic fibre examinations makes it impossible to implement a good evaluation of the within variation of samples. As a result, the discrimination power, currently calculated for discrimination studies, is only valid for samples with negligible heterogeneity. We conclude that reporting a numerical evidential value for forensic fibre examinations is not yet feasible as the data are available for only a few types of fibres and cannot be used without several assumptions. We propose a number of developments that are required to improve the accuracy and numerical analysis. PMID- 25828380 TI - A new method to reduce false positives due to antimony in detection of gunshot residues. AB - False positives due to the presence of antimony in vehicle seat fabrics are a problem in gunshot residue (GSR) analysis, in particular, when graphite furnace atomic absorption spectrometry (GFAAS) is employed. In this study, we sought to determine the reason for the prevalence of false positive results and to propose a new approach for the analysis of GSR on vehicle seats. GFAAS was used to examine adhesive tape swabs collected from 100 seats of 50 different automobiles. Characterization of seat fabrics was carried out by using Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy with energy dispersive X-ray (SEM/EDX) spectroscopy. The results of FTIR analysis indicated that all seat covers containing antimony were composed of polyester. Experimental results obtained by SEM/EDX analysis revealed that the fabrics in these seat covers contained evenly distributed antimony within the structure of polyester fibers. This study shows that the type of seat fabric should be determined by FTIR spectroscopy before elemental GSR analysis. In this way, most of the false positives caused by polyester fibers in GSR analysis can be prevented. PMID- 25828381 TI - A new disaster victim identification management strategy targeting "near identification-threshold" cases: Experiences from the Boxing Day tsunami. AB - The international disaster victim identification (DVI) response to the Boxing Day tsunami, led by the Royal Thai Police in Phuket, Thailand, was one of the largest and most complex in DVI history. Referred to as the Thai Tsunami Victim Identification operation, the group comprised a multi-national, multi-agency, and multi-disciplinary team. The traditional DVI approach proved successful in identifying a large number of victims quickly. However, the team struggled to identify certain victims due to incomplete or poor quality ante-mortem and post mortem data. In response to these challenges, a new 'near-threshold' DVI management strategy was implemented to target presumptive identifications and improve operational efficiency. The strategy was implemented by the DNA Team, therefore DNA kinship matches that just failed to reach the reporting threshold of 99.9% were prioritized, however the same approach could be taken by targeting, for example, cases with partial fingerprint matches. The presumptive DNA identifications were progressively filtered through the Investigation, Dental and Fingerprint Teams to add additional information necessary to either strengthen or conclusively exclude the identification. Over a five-month period 111 victims from ten countries were identified using this targeted approach. The new identifications comprised 87 adults, 24 children and included 97 Thai locals. New data from the Fingerprint Team established nearly 60% of the total near-threshold identifications and the combined DNA/Physical method was responsible for over 30%. Implementing the new strategy, targeting near-threshold cases, had positive management implications. The process initiated additional ante-mortem information collections, and established a much-needed, distinct "end-point" for unresolved cases. PMID- 25828382 TI - Systematic investigation of drip stains on apparel fabrics: The effects of prior laundering, fibre content and fabric structure on final stain appearance. AB - Bloodstain pattern analysis is the investigation of blood deposited at crime scenes and the interpretation of that pattern. The surface that the blood gets deposited onto could distort the appearance of the bloodstain. The interaction of blood and apparel fabrics is in its infancy, but the interaction of liquids and apparel fabrics has been well documented and investigated in the field of textile science (e.g. the processes of wetting and wicking of fluids on fibres, yarns and fabrics). A systematic study on the final appearance of drip stains on torso apparel fabrics (100% cotton plain woven, 100% polyester plain woven, blend of polyester and cotton plain woven and 100% cotton single jersey knit) that had been laundered for six, 26 and 52 cycles prior to testing was investigated in the paper. The relationship between drop velocity (1.66+/-0.50m/s, 4.07+/-0.03m/s, 5.34+/-0.18m/s) and the stain characteristics (parent stain area, axes 1 and 2 and number of satellite stains) for each fabric was examined using analysis of variance. The experimental design and effect of storing blood were investigated on a reference sample, which indicated that the day (up to five days) at which the drops were generated did not affect the bloodstain. The effect of prior laundering (six, 26 and 52 laundering cycles), fibre content (cotton vs. polyester vs. blend) and fabric structure (plain woven vs. single jersey knit) on the final appearance of the bloodstain were investigated. Distortion in the bloodstains produced on non-laundered fabrics indicated the importance of laundering fabrics to remove finishing treatments before conducting bloodstain experiments. For laundered fabrics, both the cotton fabrics and the blend had a circular to oval stain appearance, while the polyester fabric had a circular appearance with evidence of spread along the warp and weft yarns, which resulted in square-like stains at the lowest drop velocity. A significant (p<0.001) increase in the stain size on laundered blend fabric was identified. Bloodstain characteristics varied due to fibre content (p<0.001) and fabric structure (p<0.001). Blood on polyester fabric, after impact, primarily moved due to capillary force and wicking of the blood along the fibres/yarns, while for the cotton fabrics wicking was accompanied by movement of blood into the fibres/yarns. This study highlights the importance for forensic analysts of apparel evidence to consider the age, the fibre type and the fabric structure before interpreting bloodstain patterns. PMID- 25828383 TI - Printing 2-dimentional droplet array for single-cell reverse transcription quantitative PCR assay with a microfluidic robot. AB - This paper describes a nanoliter droplet array-based single-cell reverse transcription quantitative PCR (RT-qPCR) assay method for quantifying gene expression in individual cells. By sequentially printing nanoliter-scale droplets on microchip using a microfluidic robot, all liquid-handling operations including cell encapsulation, lysis, reverse transcription, and quantitative PCR with real time fluorescence detection, can be automatically achieved. The inhibition effect of cell suspension buffer on RT-PCR assay was comprehensively studied to achieve high-sensitivity gene quantification. The present system was applied in the quantitative measurement of expression level of mir-122 in single Huh-7 cells. A wide distribution of mir-122 expression in single cells from 3061 copies/cell to 79998 copies/cell was observed, showing a high level of cell heterogeneity. With the advantages of full-automation in liquid-handling, simple system structure, and flexibility in achieving multi-step operations, the present method provides a novel liquid-handling mode for single cell gene expression analysis, and has significant potentials in transcriptional identification and rare cell analysis. PMID- 25828384 TI - Light-induced lipid oxidation in sheep milk: effects of dietary grape seed and linseed, alone or in combination, on milk oxidative stability. AB - The present work aimed to investigate the milk oxidative stability when the sheep diet includes a source of polyphenols (grape seed, (GS)) and a source of polyunsaturated fatty acids (linseed, (LIN)), alone or in combination (MIX) compared to a control group (CON). For this purpose light-induced oxidation in milk was studied. After 24 h of light exposure the lipid hydroperoxides increased in milk in the LIN and MIX groups. The calculated ratio between the level of lipid hydroperoxides and unsaturated fatty acids (UFAs) in milk was lower in the GS and MIX than in the LIN group. At the same time the level of the ratio between hexanal/linoleic acid in milk was lower in the GS and MIX than in the CON group. Although the dietary inclusion of grape seed did not reduce the level of lipid oxidation products in sheep milk, it effectively reduced the extent of oxidation of UFA. PMID- 25828385 TI - Changes in cerebral oxygen saturation following prone positioning for orthopaedic surgery under general anaesthesia: a prospective observational study. AB - BACKGROUND: Prone positioning is often necessary in orthopaedic surgery. The prone position, however, may result in impaired cerebral venous drainage with a subsequent reduction in cerebral perfusion. As a consequence, cerebral hypoxia may occur with the potential for neurological impairment. OBJECTIVE: We assessed the changes in cerebral oxygen saturation with near-infrared spectroscopy using two different monitors after positioning the patient from supine to prone. DESIGN: Prospective observational study. SETTING: Primary Care University Hospital, from May 2010 to February 2011. PARTICIPANTS: Forty patients undergoing general anaesthetic procedures, of which 35 completed the investigation. Similar measurements were done in 35 volunteers, who were studied while awake. INTERVENTIONS: Near-infrared spectroscopy was measured throughout anaesthesia using INVOS (a trend monitor using two infrared wavelengths) for one hemisphere and FORE-SIGHT (a monitor using four wavelengths of laser light to calculate absolute oxygen saturation) for the other hemisphere in an alternate randomisation pattern. OUTCOME MEASUREMENTS: The primary outcome was a change in cerebral oxygen saturation of more than 5% during prone positioning. A comparison with the changes obtained in awake volunteers following similar positioning was also made. RESULTS: Cerebral oxygen saturation increased during prone positioning with INVOS 0.032% per minute (P < 0.01) and with FORE-SIGHT 0.032% per minute (P < 0.01) in anaesthetised patients. Awake volunteers showed an increase of 0.171% per minute (INVOS) and 0.082% per minute (FORE-SIGHT) during prone positioning. Comparison of INVOS with FORE-SIGHT showed a good association, with a gradient of 0.80% per 1% change (P < 0.01). CONCLUSION: Both monitors detected a small increase in cerebral oxygen saturation of less than 5% in patients undergoing orthopaedic surgery in the prone position and in awake volunteers. This small increase is of limited clinical relevance and prone positioning may be regarded as safe in terms of the maintenance of cerebral oxygen saturation. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01275898. PMID- 25828386 TI - Dedifferentiated liposarcoma of the spermatic cord: a series of 42 cases. AB - Dedifferentiated liposarcoma (DDL) of the spermatic cord is rare, with limited data regarding morphology and prognosis. We analyzed the morphologic spectrum of DDL of the spermatic cord and its clinical significance in 42 patients from 1990 to 2014. The median age of the patients was 70.5 years (range: 43 to 90 y). The median tumor size was 10.9 cm (range: 3 to 30 cm). Six cases were low-grade DDL, 28 were high-grade DDL, and in 8 cases both coexisted. Five cases had osteosarcoma, and 2 had leiomyosarcoma differentiation. Low-grade DDL had a fibrosarcoma-like (n=11), myxofibrosarcoma-like (n=2), and fibrosarcoma and inflammatory-like (n=1) pattern. High-grade DDL had a fibrosarcoma-like (n=22), undifferentiated pleomorphic sarcoma-like (n=7), myxofibrosarcoma and undifferentiated pleomorphic sarcoma-like (n=4), fibrosarcoma and undifferentiated pleomorphic sarcoma-like (n=2), and myxofibrosarcoma-like (n=1) pattern. Resection margins were positive in 22, negative in 13, and unknown in 7 cases. MDM2 was positive in 24/24 cases. Two patients received neoadjuvant radiotherapy (1 with chemotherapy). Patients received postoperative radiation (n=13), reexcision (n=5) with radiation (n=3), chemotherapy (n=2), chemotherapy and radiation (n=1), no therapy (n=11), and unknown (n=6). Follow-up information was available in 31 patients (mean: 54.2 mo; median: 38.5 mo; range: 2 to 180 mo). Seven patients developed local recurrence. Two patients had systemic metastases and succumbed to disease. Recurrence developed at an average of 40.9 months (median: 24 mo; range: 12 to 100 mo) after resection. Average follow-up in patients without recurrence was 45.2 months (median: 25 mo; range: 2 to 180 mo) (P=0.87). Margin status, size, and grade did not correlate with recurrence (P>0.05). Thus, DDL of the spermatic cord includes a spectrum of morphologic patterns. Complete excision is difficult at first attempt. Local recurrence is common, and relatively few patients develop systemic disease. PMID- 25828387 TI - Atypical Polypoid Adenomyoma of the Uterus: An Immunohistochemical and Molecular Study of 21 Cases. AB - Atypical polypoid adenomyoma (APA) is an uncommon uterine lesion that commonly recurs after local excision and is occasionally associated with or precedes the development of atypical hyperplasia or endometrioid adenocarcinoma. Despite the fact that about 230 cases have been reported in the literature, only 2 studies of 6 and of 7 cases have investigated the molecular aspects; as such, molecular alterations that occur in APA remain largely unknown. We undertook a comprehensive immunohistochemical and molecular analysis of 21 cases of APA in 17 patients (including 4 recurrent/persistent lesions). The analyzed genes were PTEN and TP53 (by fluorescence in situ hybridization) and KRAS, BRAF, EGFR, and NRAS (all by polymerase chain reaction). Immunohistochemical staining was performed for PTEN, p53, mTOR, beta-catenin, HNF-1beta, and GLUT1 and for the mismatch repair proteins MLH-1, MSH-2, MSH-6, and PMS-2. In most cases, there was nuclear expression of beta-catenin in squamous morules and expression of HNF-1beta, mTOR, and GLUT1 in the glandular component. All cases exhibited "wild-type" expression of p53. A common finding was loss of PTEN expression (6/19 cases). In 1 of these cases, loss of PTEN expression was accompanied by PTEN deletion. Mutation of the KRAS gene was found in 5/19 cases. Intact mismatch-repair protein expression was present in all cases, and TP53 abnormalities or mutations of EGFR, NRAS, or BRAF genes were not found. Given the association with atypical hyperplasia and endometrioid adenocarcinoma and the shared immunohistochemical and molecular features, we feel that, conceptually, APA is best regarded as analogous to a localized form of atypical hyperplasia. PMID- 25828388 TI - Distinctive Patterns of Transthyretin Amyloid in Salivary Tissue: A Clinicopathologic Study of 92 Patients With Amyloid-containing Minor Salivary Gland Biopsies. AB - Accurate typing of amyloidosis is still a major issue for pathologists and clinicians. Besides clinical data and immunohistochemistry, the histologic distribution of amyloid could represent a useful tool to prevent typing errors, such as the misdiagnosis of hereditary and senile amyloidosis as light chain related amyloidosis (AL). Minor salivary gland biopsy (MSGB) is a widely performed procedure for amyloidosis diagnosis and typing. In the largest clinicopathologic series of amyloid-containing MSGB specimens to date, we investigated for the first time whether amyloidosis subtypes can be distinguished according to their pattern of salivary amyloid deposition. The histologic distribution and semiquantification of amyloid within salivary tissue were thoroughly reassessed for each case using Congo red-fluorescence. Clinical data were retrospectively collected. The cohort included 92 patients with amyloid containing minor salivary gland biopsies. The type of amyloidosis was AL in 51 patients (55.4%), non-V30M mutant ATTR in 10 (10.9%), V30M mutant ATTR in 8 (8.7%), serum amyloid A-derived amyloidosis (AA) in 6 (6.5%), wild-type ATTR in 4 (4.3%), gelsolin in 3 (3.3%), and unclassified in 10 (10.9%). Amyloid was more abundant in AL and AA compared with ATTR amyloidosis, because of more extensive basement membranes and vascular deposits. Conversely, non-V30M mutant ATTR and wt ATTR were strongly associated with peculiar amyloid nodules located in close contact with salivary excretory ducts, with a specificity of 91.7%. In conclusion, our study suggests for the first time that MSGB, in addition to its high sensitivity for amyloidosis diagnosis, is a simple and effective tool for the recognition of ATTR amyloidosis. PMID- 25828389 TI - MYC cytogenetic status correlates with expression and has prognostic significance in patients with MYC/BCL2 protein double-positive diffuse large B-cell lymphoma. AB - MYC/BCL2 double-hit lymphoma (DHL), defined by conventional cytogenetic or fluorescence in situ hybridization (FISH) analysis, and MYC/BCL2 double-positive lymphoma (DPL), defined by immunohistochemistry, are associated with a poor prognosis. However, DHL and DPL are not concordant, and it is unclear whether MYC and BCL2 aberrations have prognostic impact in DPL patients. In a cohort of 135 patients diagnosed with large B-cell lymphoma between 2010 and 2014 in whom MYC/8q24 and BCL2/t(14;18)(q32;q21) statuses were assessed by FISH at diagnosis, we evaluated MYC and BCL2 expression by immunohistochemistry. A total of 54 (40%) cases were positive for MYC and BCL2 supporting DPL. Among them, 19 (35%) had MYC rearrangement including 11 DHLs, 12 (22%) had multiple copies of MYC, 19 had no MYC abnormalities, and in 4 cases FISH analysis failed. BCL2 abnormalities were present in 28/54 (52%) cases (20 rearranged and 8 multiple copies). MYC rearrangement correlated with a significantly worse overall survival in DPL (P<0.05), whereas BCL2 genetic status did not correlate with survival (P>0.05). MYC and BCL2 expression by immunohistochemistry correlates with gene status by FISH; however, immunohistochemistry is neither specific nor adequately sensitive to be used as a surrogate for MYC and BCL2 gene status using any cutoff level. In conclusion, MYC rearrangement identifies a subset of patients with DPL who have a significantly worse prognosis. Although immunohistochemical assessment for MYC and BCL2 may be a helpful initial screen to identify higher-risk patients, FISH analysis for MYC remains important for further risk stratification in patients with DPL. PMID- 25828390 TI - Yolk Sac Tumor of the Testis in Infants and Children: A Clinicopathologic Analysis of 33 Cases. AB - We report 33 pure yolk sac tumors of the testis from boys 5 to 71 months of age (mean 20.7 mo) diagnosed from 1918 to 2014. All except 1 underwent orchiectomy, with lymph node dissections (all negative) performed in 18; 21 also received chemotherapy and 12 radiotherapy. The tumors were 1.6 to 7.0 cm (mean 3.7 cm) and were nonencapsulated, with a gray to yellow, often mucoid, cut surface. The commonest pattern was reticular-microcystic, but macrocystic, papillary, endodermal sinus (Schiller-Duval bodies), labyrinthine, myxomatous, glandular, and solid patterns were also observed. Follow-up was available for 32 patients (mean 100.5 mo; range, 3 to 456 mo). Twenty-four patients (including 4 who did not receive adjuvant therapy) were without evidence of disease, 8 had metastatic disease; 5 of the latter died of tumor and 1 of treatment complications. Two patients with metastasis were cured with radiation with or without chemotherapy. Two or more of the following were associated with a poor outcome in patients presenting with stage I cases: tumor size >4.5 cm (4/6 tumors [67%]), invasion of rete testis and/or epididymis (3/7 tumors [43%]), and necrosis (6/17 tumors [35%]). In the nonmetastasizing group, 2 or more unfavorable features occurred in only 3/24 tumors (13%) (P=0.0001). It is crucial that this tumor be distinguished from the juvenile granulosa cell tumor, which occurs at a slightly younger age and has distinctive features, although there may be some morphologic overlap. The survival of young boys with testicular yolk sac tumor is very good because of both effective chemotherapy and likely, the inherent characteristics of the tumor in this age group. PMID- 25828391 TI - Triple-hit B-cell Lymphoma With MYC, BCL2, and BCL6 Translocations/Rearrangements: Clinicopathologic Features of 11 Cases. AB - Lymphomas with translocations/rearrangements of MYC, BCL2, and BCL6, so-called triple-hit B-cell lymphoma, are rare, and few studies on these tumors are available in the literature. We report 11 cases of triple-hit B-cell lymphoma and characterize their clinicopathologic findings. All patients were men, with a median age of 64 years (range, 45 to 80 y), and 4 patients had antecedent or concurrent follicular lymphoma. Using the 2008 World Health Organization classification, these cases were classified as: 5 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma; 4 DLBCL; 1 DLBCL with concurrent follicular lymphoma; and 1 low-grade follicular lymphoma. All cases were positive for CD10, BCL2, and FOXP1. Ten of 11 cases were positive for CD20. MYC expression was high in 10/11 (91%), BCL6 was positive in 8/11 (73%), and MUM1/IRF4 was positive in 6/11 (55%) cases. T-cell antigens, TdT, and Epstein-Barr virus-encoded RNA were negative in all cases. Ten of 11 cases showed a high proliferation index-70% to 100%, and the follicular lymphoma had a 30% proliferation rate. Using most algorithms, all cases belonged to germinal center B-cell-like group. All patients received standard or more aggressive immunochemotherapy regimens. Three patients had no response to chemotherapy; 4 patients showed a partial response; 2 patients had complete remission after chemotherapy; and 2 patients had just begun chemotherapy. Three patients underwent a stem cell transplant. The median follow up time was 5.3 months. Five patients died, and 6 patients were alive at last follow-up. Two patients who underwent stem cell transplant after complete response to chemotherapy were in remission with 16 to 19 months of clinical follow-up. In summary, triple-hit lymphomas are clinically aggressive tumors associated with a poor prognosis. Patients often respond poorly to chemotherapy, but a subset may completely respond to chemotherapy followed by stem cell transplant. PMID- 25828393 TI - One-pot two-step synthesis of core-shell mesoporous silica-coated gold nanoparticles. AB - Gold nanoparticles coated with mesoporous silica (Au@mSiO2) have been prepared by a facile one-pot two-step method. The resultant Au@mSiO2 exhibit an ideal core shell structure with uniform mSiO2 coverage and without any interfacial adhesive layer on the Au surface. Some new explanations on the role that CTAB plays in the synthesis of Au@mSiO2 are discussed. PMID- 25828392 TI - Intestinal organoids: a model of intestinal fibrosis for evaluating anti-fibrotic drugs. AB - BACKGROUND & AIMS: Intestinal fibrosis is a critical complication of Crohn's disease (CD). Current in vitro models of intestinal fibrosis cannot model the complex intestinal architecture, while in vivo rodent models do not fully recapitulate human disease and have limited utility for large-scale screening. Here, we exploit recent advances in stem cell derived human intestinal organoids (HIOs) as a new human model of fibrosis in CD. METHODS: Human pluripotent stem cells were differentiated into HIOs. We identified myofibroblasts, the key effector cells of fibrosis, by immunofluorescence staining for alpha-smooth muscle actin (alphaSMA), vimentin, and desmin. We examined the fibrogenic response of HIOs by treatment with transforming growth factor beta (TGFbeta) in the presence or absence of the anti-fibrotic drug spironolactone. Fibrotic response was assayed by expression of fibrogenic genes (COL1A1 (collagen, type I, alpha 1), ACTA2 (alpha smooth muscle actin), FN1 (fibronectin 1), MYLK (myosin light chain kinase), and MKL1 (megakaryoblastic leukemia (translocation) 1)) and proteins (alphaSMA). RESULTS: Immunofluorescent staining of organoids identified a population of myofibroblasts within the HIO mesenchyme. TGFbeta stimulation of HIOs produced a dose-dependent pro-fibrotic response. Spironolactone treatment blocked the fibrogenic response of HIOs to TGFbeta. CONCLUSIONS: HIOs contain myofibroblasts and respond to a pro-fibrotic stimulus in a manner that is consistent with isolated human myofibroblasts. HIOs are a promising model system that might bridge the gap between current in vitro and in vivo models of intestinal fibrosis in IBD. PMID- 25828394 TI - Solid tumor metastases to the pancreas diagnosed by FNA: A single-institution experience and review of the literature. AB - BACKGROUND: Pancreatic fine-needle aspiration (FNA) is useful for diagnosing pancreatic masses. This article describes the experience of a single institution with metastases to the pancreas sampled by FNA and provides a review of the literature. METHODS: Medical records were retrospectively searched for pancreatic FNA that showed metastatic disease. Data were gathered for the tumor size, focality, and time period between the primary tumor and the metastasis. A literature search using PubMed was performed. RESULTS: Pancreatic FNA was performed 2327 times in 14 years at the authors' institution. Twenty-two cases showed metastatic disease. The average size of the metastatic lesions in their greatest dimension was 3.7 cm (range, 1.5-6.5 cm). The majority of the tumors were unifocal (16 of 22 or 73%). A rapid onsite adequacy evaluation was performed for 13 patients (4 were diagnostic of metastasis, 3 were positive for malignant cells, 6 were atypical, and none were negative). There were 14 renal cell carcinomas, 2 colonic adenocarcinomas, 1 urothelial carcinoma, 1 non-small cell lung carcinoma, 1 ovarian serous carcinoma, 1 prostatic adenocarcinoma, 1 papillary thyroid carcinoma, and 1 mesenchymal chondrosarcoma. The median time between the diagnosis of the primary tumor and the initial pancreatic metastasis was 9 years (range, concurrent diagnosis to 21 years). A literature review yielded 12 case series with a variety of metastases to the pancreas diagnosed by FNA and surgical pathology specimens. CONCLUSIONS: In agreement with prior series, the most common metastasis to the pancreas was renal cell carcinoma. A variety of other primary malignancies were also documented in this study and in the literature. Also, this article reports the first case of metastatic mesenchymal chondrosarcoma to the pancreas diagnosed by FNA. PMID- 25828395 TI - Use of a blood test incorporating age, sex, and gene expression influences medical decision-making in the evaluation of women presenting with symptoms suggestive of obstructive coronary artery disease: summary results from two ambulatory care studies in primary care. AB - OBJECTIVE: Clinicians need better approaches to evaluating women at midlife and beyond who present to primary care with chest pain and related symptoms. A previously validated blood-based test, which includes age, sex, and gene expression levels, showed a 96% negative predictive value for determining an individual's current likelihood of having obstructive coronary artery disease (CAD) in a combined population of men and women. We hypothesized that age/sex/gene expression score (ASGES) would be incorporated into medical decision making and would influence the rate of further cardiac evaluation. METHODS: An aggregate analysis of female cohorts from the Investigation of a Molecular Personalized Coronary Gene Expression Test on Primary Care Practice Pattern (IMPACT-PCP; NCT01594411) and REGISTRY I (NCT01557855) studies was conducted. Data on 320 women presenting with stable symptoms suggestive of obstructive CAD and undergoing ASGES testing (from 16 primary care providers in geographically diverse sites) were pooled. The primary outcome of this analysis was the association between ASGES and referrals for further cardiac evaluation. RESULTS: The mean participant age was 57.8 years, and the mean ASGES (predefined as low [ASGES <=15] or elevated [ASGES >15]) was 10.3. The referral rate for further cardiac evaluation was 4.0% (10 of 248) for women with low ASGES versus 83.3% (60 of 72) for women with elevated ASGES, with an overall follow-up major adverse cardiac event/revascularization rate of 1.2%. After adjustment for clinical covariates, women with low ASGES were significantly less likely to be referred for further cardiac evaluation (odds ratio, 0.013; P < 0.0001). CONCLUSIONS: ASGES can be incorporated into medical decision-making to help primary care providers rule out obstructive CAD among symptomatic women who are unlikely to benefit from further cardiac testing. PMID- 25828396 TI - Activation of PPARbeta/delta protects cardiac myocytes from oxidative stress induced apoptosis by suppressing generation of reactive oxygen/nitrogen species and expression of matrix metalloproteinases. AB - Heart failure still remains one of the leading causes of morbidity and mortality worldwide. A major contributing factor is reactive oxygen/nitrogen species (RONS) overproduction which is associated with cardiac remodeling partly through cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily and have been implicated in cardioprotection. However, the molecular mechanisms are largely unexplored. In this study we sought to investigate the potential beneficial effects evoked by activation of PPARbeta/delta under the setting of oxidative stress induced by H2O2 in adult rat cardiac myocytes. The selective PPARbeta/delta agonist GW0742 inhibited the H2O2-induced apoptosis and increased cell viability. In addition, generation of RONS was attenuated in cardiac myocytes in the presence of PPARbeta/delta agonist. These effects were abolished in the presence of the PPARbeta/delta antagonist indicating that the effect was through PPARbeta/delta receptor activation. Treatment with PPARbeta/delta agonist was also associated with attenuation of caspase-3 and PARP cleavage, upregulation of anti-apoptotic Bcl-2 and concomitant downregulation of pro-apoptotic Bax. In addition, activation of PPARbeta/delta inhibited the oxidative-stress-induced MMP-2 and MMP-9 mRNA upregulation. It is concluded that PPARbeta/delta activation exerts a cytoprotective effect in adult rat cardiac myocytes subjected to oxidative stress via inhibition of oxidative stress, MMP expression, and apoptosis. Our data suggest that the novel connection between PPAR signaling and MMP down-regulation in cardiac myocytes might represent a new target for the management of oxidative stress-induced cardiac dysfunction. PMID- 25828397 TI - Uniaxial and Multiaxial Fatigue Life Prediction of the Trabecular Bone Based on Physiological Loading: A Comparative Study. AB - Fatigue assessment of the trabecular bone has been developed to give a better understanding of bone properties. While most fatigue studies are relying on uniaxial compressive load as the method of assessment, in various cases details are missing, or the uniaxial results are not very realistic. In this paper, the effect of three different load histories from physiological loading applied on the trabecular bone were studied in order to predict the first failure surface and the fatigue lifetime. The fatigue behaviour of the trabecular bone under uniaxial load was compared to that of multiaxial load using a finite element simulation. The plastic strain was found localized at the trabecular structure under multiaxial load. On average, applying multiaxial loads reduced more than five times the fatigue life of the trabecular bone. The results provide evidence that multiaxial loading is dominated in the low cycle fatigue in contrast to the uniaxial one. Both bone volume fraction and structural model index were best predictors of failure (p < 0.05) in fatigue for both types of loading, whilst uniaxial loading has indicated better values in most cases. PMID- 25828398 TI - Molecular evidence for a bacterium of the family Midichloriaceae (order Rickettsiales) in skin and organs of the rainbow trout Oncorhynchus mykiss (Walbaum) affected by red mark syndrome. PMID- 25828399 TI - Origin, evolution, and population genetics of the selfish Segregation Distorter gene duplication in European and African populations of Drosophila melanogaster. AB - Meiotic drive elements are a special class of evolutionarily "selfish genes" that subvert Mendelian segregation to gain preferential transmission at the expense of homologous loci. Many drive elements appear to be maintained in populations as stable polymorphisms, their equilibrium frequencies determined by the balance between drive (increasing frequency) and selection (decreasing frequency). Here we show that a classic, seemingly balanced, drive system is instead characterized by frequent evolutionary turnover giving rise to dynamic, rather than stable, equilibrium frequencies. The autosomal Segregation Distorter (SD) system of the fruit fly Drosophila melanogaster is a selfish coadapted meiotic drive gene complex in which the major driver corresponds to a partial duplication of the gene Ran-GTPase activating protein (RanGAP). SD chromosomes segregate at similar, low frequencies of 1-5% in natural populations worldwide, consistent with a balanced polymorphism. Surprisingly, our population genetic analyses reveal evidence for parallel, independent selective sweeps of different SD chromosomes in populations on different continents. These findings suggest that, rather than persisting at a single stable equilibrium, SD chromosomes turn over frequently within populations. PMID- 25828400 TI - Theoretical effects of fully ductile versus fully brittle behaviors of bone tissue on the strength of the human proximal femur and vertebral body. AB - The influence of the ductility of bone tissue on whole-bone strength represents a fundamental issue of multi-scale biomechanics. To gain insight, we performed a computational study of 16 human proximal femurs and 12 T9 vertebral bodies, comparing the whole-bone strength for the two hypothetical bounding cases of fully brittle versus fully ductile tissue-level failure behaviors, all other factors, including tissue-level elastic modulus and yield stress, held fixed. For each bone, a finite element model was generated (60-82 MUm element size; up to 120 million elements) and was virtually loaded in habitual (stance for femur, compression for vertebra) and non-habitual (sideways fall, only for femur) loading modes. Using a geometrically and materially non-linear model, the tissue was assumed to be either fully brittle or fully ductile. We found that, under habitual loading, changing the tissue behavior from fully ductile to fully brittle reduced whole-bone strength by 38.3+/-2.4% (mean+/-SD) and 39.4+/-1.9% for the femur and vertebra, respectively (p=0.39 for site difference). These reductions were remarkably uniform across bones, but (for the femur) were greater for non-habitual (57.1+/-4.7%) than habitual loading (p<0.001). At overall structural failure, there was 5-10-fold less failed tissue for the fully brittle than fully ductile cases. These theoretical results suggest that the whole-bone strength of the proximal femur and vertebra can vary substantially between fully brittle and fully ductile tissue-level behaviors, an effect that is relatively insensitive to bone morphology but greater for non-habitual loading. PMID- 25828401 TI - Overcoming the barrier to implementing authentic research experiences through faculty mentorship. PMID- 25828402 TI - The grass isn't always greener: perceptions of and performance on open-note exams. AB - Undergraduate biology education is often viewed as being focused on memorization rather than development of students' critical-thinking abilities. We speculated that open-note testing would be an easily implemented change that would emphasize higher-order thinking. As open-note testing is not commonly used in the biological sciences and the literature on its effects in biology education is sparse, we performed a comprehensive analysis of this intervention on a primary literature-based exam across three large-enrollment laboratory courses. Although students believed open-note testing would impact exam scores, we found no effect on performance, either overall or on questions of nearly all Bloom's levels. Open note testing also produced no advantage when examined under a variety of parameters, including research experience, grade point average, course grade, prior exposure to primary literature-focused laboratory courses, or gender. Interestingly, we did observe small differences in open- and closed-note exam performance and perception for students who experienced open-note exams for an entire quarter. This implies that student preparation or in-test behavior can be altered by exposure to open-note testing conditions in a single course and that increased experience may be necessary to truly understand the impact of this intervention. PMID- 25828403 TI - Increasing persistence in undergraduate science majors: a model for institutional support of underrepresented students. AB - The 6-yr degree-completion rate of undergraduate science, technology, engineering, and mathematics (STEM) majors at U.S. colleges and universities is less than 40%. Persistence among women and underrepresented minorities (URMs), including African-American, Latino/a, Native American, and Pacific Islander students, is even more troubling, as these students leave STEM majors at significantly higher rates than their non-URM peers. This study utilizes a matched comparison group design to examine the academic achievement and persistence of students enrolled in the Program for Excellence in Education and Research in the Sciences (PEERS), an academic support program at the University of California, Los Angeles, for first- and second-year science majors from underrepresented backgrounds. Results indicate that PEERS students, on average, earned higher grades in most "gatekeeper" chemistry and math courses, had a higher cumulative grade point average, completed more science courses, and persisted in a science major at significantly higher rates than the comparison group. With its holistic approach focused on academics, counseling, creating a supportive community, and exposure to research, the PEERS program serves as an excellent model for universities interested in and committed to improving persistence of underrepresented science majors and closing the achievement gap. PMID- 25828404 TI - Beyond the GRE: using a composite score to predict ?the success of Puerto Rican students in a biomedical ?PhD program. AB - The use and validity of the Graduate Record Examination General Test (GRE) to predict the success of graduate school applicants is heavily debated, especially for its possible impact on the selection of underrepresented minorities into science, technology, engineering, and math fields. To better identify candidates who would succeed in our program with less reliance on the GRE and grade point average (GPA), we developed and tested a composite score (CS) that incorporates additional measurable predictors of success to evaluate incoming applicants. Uniform numerical values were assigned to GPA, GRE, research experience, advanced course work or degrees, presentations, and publications. We compared the CS of our students with their achievement of program goals and graduate school outcomes. The average CS was significantly higher in those students completing the graduate program versus dropouts (p < 0.002) and correlated with success in competing for fellowships and a shorter time to thesis defense. In contrast, these outcomes were not predicted by GPA, science GPA, or GRE. Recent implementation of an impromptu writing assessment during the interview suggests the CS can be improved further. We conclude that the CS provides a broader quantitative measure that better predicts success of students in our program and allows improved evaluation and selection of the most promising candidates. PMID- 25828405 TI - In-vitro evaluation of performance of solid immediate release dosage forms of weak bases in upper gastrointestinal lumen: experience with miconazole and clopidogrel salts. AB - OBJECTIVES: Evaluate the impact of salt and counterion identity on performance of solid immediate release dosage forms of miconazole and clopidogrel, respectively, in fasted upper gastrointestinal lumen using in-vitro methodologies. METHODS: Two miconazole chemical forms (free base and nitrate salt) and three clopidogrel chemical forms (bisulfate, besylate and hydrochloride salts) were studied. Solubilities of miconazole forms were measured in simulated gastric fluids. Gastrointestinal transfer of the five chemical forms was evaluated by using a flow-through, three-compartmental set-up. Precipitation in duodenal compartment was evaluated by using solutions in gastric compartment. KEY FINDINGS: Solubilities in simulated gastric fluids, concentrations in duodenal compartment and solubilities in duodenal compartment indicated poorer performance of miconazole nitrate vs. miconazole free base in upper gastrointestinal lumen. In line with the low crystallization tendency of free base, duodenal precipitation of miconazole from a free base solution was limited. Concentrations in duodenal compartment indicated that counterion identity does not affect the performance of clopidogrel; precipitation in duodenal compartment was extensive in all cases. CONCLUSIONS: Miconazole data indicate that salts may adversely affect performance of immediate release dosage forms of weak bases. In line with existing in-vivo data, clopidogrel data indicate that counterion identity is unimportant for the performance of clopidogrel salts in upper intestinal lumen. PMID- 25828406 TI - Impact of hydrocarbons, PCBs and heavy metals on bacterial communities in Lerma River, Salamanca, Mexico: Investigation of hydrocarbon degradation potential. AB - Freshwater contamination usually comes from runoff water or direct wastewater discharges to the environment. This paper presents a case study which reveals the impact of these types of contamination on the sediment bacterial population. A small stretch of Lerma River Basin, heavily impacted by industrial activities and urban wastewater release, was studied. Due to industrial inputs, the sediments are characterized by strong hydrocarbon concentrations, ranging from 2 935 to 28 430MUg.kg(-1) of total polyaromatic hydrocarbons (PAHs). These sediments are also impacted by heavy metals (e.g., 9.6MUg.kg(-1) of Cd and 246MUg.kg(-1) of Cu, about 8 times the maximum recommended values for environmental samples) and polychlorinated biphenyls (ranging from 54 to 123MUg.kg(-1) of total PCBs). The bacterial diversity on 6 sediment samples, taken from upstream to downstream of the main industrial and urban contamination sources, was assessed through TRFLP. Even though the high PAH concentrations are hazardous to aquatic life, they are not the only factor driving bacterial community composition in this ecosystem. Urban discharges, leading to hypoxia and low pH, also strongly influenced bacterial community structure. The bacterial bioprospection of these samples, using PAH as unique carbon source, yielded 8 hydrocarbonoclastic strains. By sequencing the 16S rDNA gene, these were identified as similar to Mycobacterium goodii, Pseudomonas aeruginosa, Pseudomonas lundensis or Aeromonas veronii. These strains showed high capacity to degrade naphthalene (between 92 and 100% at 200mg.L(-1)), pyrene (up to 72% at 100mg.L(-1)) and/or fluoranthene (52% at 50mg.L(-1)) as their only carbon source on in vitro experiments. These hydrocarbonoclastic bacteria were detected even in the samples upstream of the city of Salamanca, suggesting chronical contamination, already in place longer before. Such microorganisms are clearly potential candidates for hydrocarbon degradation in the treatment of oil discharges. PMID- 25828407 TI - Simulating the effect of climate change on stream temperature in the Trout Lake Watershed, Wisconsin. AB - The potential for increases in stream temperature across many spatial and temporal scales as a result of climate change can pose a difficult challenge for environmental managers, especially when addressing thermal requirements for sensitive aquatic species. This study evaluates simulated changes to the thermal regime of three northern Wisconsin streams in response to a projected changing climate using a modeling framework and considers implications of thermal stresses to the fish community. The Stream Network Temperature Model (SNTEMP) was used in combination with a coupled groundwater and surface water flow model to assess forecasts in climate from six global circulation models and three emission scenarios. Model results suggest that annual average stream temperature will steadily increase approximately 1.1 to 3.2 degrees C (varying by stream) by the year 2100 with differences in magnitude between emission scenarios. Daily mean stream temperature during the months of July and August, a period when cold-water fish communities are most sensitive, showed excursions from optimal temperatures with increased frequency compared to current conditions. Projections of daily mean stream temperature, in some cases, were no longer in the range necessary to sustain a cold water fishery. PMID- 25828408 TI - Forecasting of VOC emissions from traffic and industry using classification and regression multivariate methods. AB - In this study, advanced multivariate methods were applied for VOC source apportionment and subsequent short-term forecast of industrial- and vehicle exhaust-related contributions in Belgrade urban area (Serbia). The VOC concentrations were measured using PTR-MS, together with inorganic gaseous pollutants (NOx, NO, NO2, SO2, and CO), PM10, and meteorological parameters. US EPA Positive Matrix Factorization and Unmix receptor models were applied to the obtained dataset both resolving six source profiles. For the purpose of forecasting industrial- and vehicle exhaust-related source contributions, different multivariate methods were employed in two separate cases, relying on meteorological data, and on meteorological data and concentrations of inorganic gaseous pollutants, respectively. The results indicate that Boosted Decision Trees and Multi-Layer Perceptrons were the best performing methods. According to the results, forecasting accuracy was high (lowest relative error of only 6%), in particular when the forecast was based on both meteorological parameters and concentrations of inorganic gaseous pollutants. PMID- 25828409 TI - Effects of rainfall patterns on water quality in a stratified reservoir subject to eutrophication: Implications for management. AB - The seasonal variation of hydrological conditions caused by shifting rainfall patterns observed in recent years has significant effects on water quality. High volume inflows following heavy rainfall events that significantly disturb stratification lead to increased dissolved oxygen (DO) at the bottom of the reservoir, inhibiting the release of nutrients from sediments and causing a rapid reduction of algal biomass in the reservoir. However, the duration and extent of these effects depend not only on the frequency and intensity of heavy rainfall events but also on the period of thermal stratification in the reservoir. The effects of heavy rainfall events on water quality during three typical stratification periods of the reservoir were systematically investigated using extensive field data. The continuous heavy rainfall that occurred in September 2011 (stratification began to diminish) completely mixed the reservoir and produced a high concentration of DO along with a low phytoplankton concentration throughout the reservoir until stratification occurred the following year. Conversely, several days were required for anoxic conditions (in the hypolimnion) and cyanobacterial blooms to reappear after the storm runoff that occurred during the stable period of stratification (August 2012). In addition, the heavy rainfall that occurred in May 2013 accelerated the formation of an anoxic zone at the bottom of the reservoir and promoted cyanobacterial blooms due to the high nutrient input and the increased water temperature after the storm runoff ended. Water-lifting aerators (WLAs) were employed in the Shibianyu Reservoir to inhibit algal growth and to control the release of nutrients. Based on our field observations and theoretical analyses, optimized management strategies are recommended to improve water quality in the reservoir under different rainfall patterns at a reduced cost. PMID- 25828410 TI - Effect of biochar on leaching of organic carbon, nitrogen, and phosphorus from compost in bioretention systems. AB - Compost is used in bioretention systems to improve soil quality, water infiltration, and retention of contaminants. However, compost contains dissolved organic matter, nitrate, and phosphorus, all of which can leach out and potentially contaminate ground and surface waters. To reduce the leaching of nutrients and dissolved organic matter from compost, biochar may be mixed into the bioretention systems. Our objective was to test whether biochar and co composted biochar mixed into mature compost can reduce the leaching of organic carbon, nitrogen, and phosphorus. There was no significant difference between the effects of biochar and co-composted biochar amendments on nutrient leaching. Further, biochar amendments did not significantly reduce the leaching of dissolved organic carbon, nitrate, and phosphorus as compared to the compost only treatment. The compost-sand mix was the most effective in reducing nitrate and phosphorus leaching among the media. PMID- 25828411 TI - Perchlorate in dust fall and indoor dust in Malta: An effect of fireworks. AB - We report on the presence of perchlorate in the settleable dust of Malta, a small central Mediterranean island. Both dust fall collected directly as it precipitated from atmosphere over a period of one month and deposited indoor dust from domestic residences were studied. Perchlorate was determined by ion chromatography of water extracts of the collected dusts. Dust fall was collected from 43 towns during 2011 to 2013 and indoor dust was sampled from homes in the same localities. Perchlorate was detected in 108 of 153 samples of dust fall (71%) and in 28 of 37 indoor dust samples (76%). Detectable perchlorate in dust fall ranged from 0.52MUgg(-1) to 561MUgg(-1) with a median value of 6.2MUgg(-1); in indoor dust, levels were from 0.79MUgg(-1) to 53MUgg(-1) with a median value of 7.8MUgg(-1), the highest recorded anywhere to date. Statistical analysis suggested that there was no significant difference in perchlorate content of indoor dust and dust fall. Perchlorate levels in dust fall escalate during the summer in response to numerous religious feasts celebrated with fireworks and perchlorate persists at low MUgg(-1) concentrations for several months beyond the summer festive period. In Malta, perchlorate derives exclusively from KClO4, imported for fireworks manufacture. Its residue in dust presents an exposure risk to the population, especially via ingestion by hand to mouth transfer. Our results suggest that wherever intensive burning of fireworks takes place, the environmental impact may be much longer lived than realised, mainly due to re suspension and deposition of contaminated settled dust in the urban environment. PMID- 25828412 TI - Factors controlling accumulation of soil organic carbon along vegetation succession in a typical karst region in Southwest China. AB - Vegetation succession enhances the accumulation of carbon in the soil. However, little is known about the mechanisms underlying soil organic carbon (SOC) accumulation in different vegetation types in the karst region of Southwest China. The goal of this study was to identify and prioritize the effects of environmental parameters, including soil physico-chemical properties, microbial biomass, enzyme activities, and litter characteristics, on SOC accumulation along a vegetation succession sere (grassland, shrubland, secondary forest, and primary forest) in the karst landscape of Southwest China. Relationships between these parameters and SOC were evaluated by redundancy analysis. The results showed that SOC accumulation was significantly different among vegetation types (P<0.01) and increased with vegetation succession (from 29.10g.kg(-1) in grassland to 73.92g.kg(-1) in primary forest). Soil biochemistry and physical characteristics significantly affected the accumulation of SOC. Soil microbial biomass showed a predominant effect on SOC in each of the four vegetation types. In addition, the soil physical property (especially the silt content) was another controlling factor in the early stages (grassland), and urease activity and saccharase activity were important controlling factors in the early-middle and middle-late stages, respectively. Litter characteristics only showed mild effects on SOC accumulation. Variation partitioning analysis showed that the contribution of sole main factors to SOC variation decreased, while the interaction effect among parameters increased along the succession gradient. PMID- 25828413 TI - Pseudomonads biodegradation of aromatic compounds in oil sands process-affected water. AB - Aromatic naphthenic acids (NAs) have been shown to be more toxic than the classical NAs found in oil sands process-affected water (OSPW). To reduce this toxicity, Pseudomonas fluorescens and Pseudomonas putida were used to determine their ability to biodegrade aromatic compounds including treatments considering the impacts of external carbon and iron addition. Results showed that with added carbon P. fluorescens and P. putida have the capability of biodegrading these aromatics. In the presence of external carbon, gene expression of a functional PAH-ring hydroxylating dioxygenase (PAH-RHDalpha) was determined through reverse transcription real-time PCR, suggesting active degradation of OSPW aromatic compounds. Although no significant classical NAs removal was observed during this process, toxicity was reduced by 49.3% under optimal conditions. OSPW toxicity was eliminated with the combination of ozonation at a dose of 80 mg/L followed by biodegradation, indicating that it is a promising combined OSPW treatment approach for the safe discharge to the aquatic environment. PMID- 25828414 TI - Prediction, risk and control of anti-influenza drugs in the Yodo River Basin, Japan during seasonal and pandemic influenza using the transmission model for infectious disease. AB - To reduce the risk of producing an anti-influenza drug-resistant virus from wildfowl, it is important to estimate the concentrations of anti-influenza drugs in river water during an influenza pandemic and to evaluate the concentrations that keep river basins safe. We first created a newly designed infectious disease transmission model based on the Susceptible-Infected-Recovered model. This model was then applied to replicate the transitional changes of three representative anti-influenza drugs, oseltamivir (OS), oseltamivir carboxylate (OC), and zanamivir (ZAN), in the urban area of the Yodo River system, which is one of the major basins in Japan with a population of 12 million; this region contains nearly 10% of the country's flu cases during the seasonal influenza outbreaks between 1999 and 2010. The results showed high correlations between the estimated number of influenza cases and the concentrations of the three investigated anti influenza drugs with the reported values. We then extended the application of the model to estimate the concentration level of these anti-influenza drugs during the several influenza pandemics. The maximum estimated concentrations for OS, OC, and ZAN were known to be 260-450ng/L, 1500-2600ng/L and 40-70ng/L, respectively, at the peak of the influenza pandemic. These results suggest that it is possible that a drug-resistant influenza virus can originate from wild mallard when there is a large-scale influenza pandemic. However, ozonation before discharge at sewage treatment plants is known to significantly reduce the release of such drugs into the aquatic environment to reduce the risk of a drug-resistant virus outbreak. It was also suggested that further environmental risk could be reduced by decreasing these concentrations further in river water. PMID- 25828415 TI - Replicon typing of plasmids carrying blaCTX-M-15 among Enterobacteriaceae isolated at the environment, livestock and human interface. AB - One of the currently most important antibiotic resistance mechanisms in Enterobacteriaceae is based on the production of ESBL enzymes that inactivate beta-lactam antibiotics including cephalosporins and monobactams by hydrolyzing their beta-lactam ring. In humans, the most prevalent ESBL enzyme type is encoded by blaCTX-M-15. CTX-M-15 producing enterobacterial strains were also frequently isolated from environmental samples including surface water and freshwater fish. Plasmids, which can be grouped in different plasmid incompatibility types, play a key role in the horizontal spread of these multidrug resistance genes. The purpose of this study was to investigate the diversity of plasmids that carry blaCTX-M-15 genes among Enterobacteriaceae isolated at the environment, livestock and human interface. In total, 81 blaCTX-M-15-harboring isolates collected between 2009 and 2014 were tested for its ability to transfer blaCTX-M-15 by conjugation. These plasmids were further typed. Transfer of a single blaCTX-M-15 harboring plasmid was observed in 32 (39.5%) of the isolates. The most frequent replicon types detected among these plasmids are IncF-type plasmids (n=12) (mostly multi replicon plasmids with a combination of following replicons: IncFII, IncFIA and IncFIB), followed by IncI1 (n=8), IncK (n=3) and IncR (n=1). A noticeable number of plasmids (n=8) could not be assigned to any of the tested replicon types. Knowledge about the plasmid types circulating in bacterial populations is indispensable for understanding epidemiological dynamics and for establishing intervention strategies to stop further dissemination of particular plasmids. PMID- 25828416 TI - Elevated levels of perfluoroalkyl substances in estuarine sediments of Charleston, SC. AB - Urban areas are sources of perfluoroalkyl substances (PFASs) in the environment, although little is known about specific point sources and distribution of PFASs. Sentinel species, like bottlenose dolphins, are important indicators of environmental perturbations. The high PFAS levels found in dolphins inhabiting Charleston, South Carolina prompted investigation of these chemicals in this area. This study provides further evidence on the extent of contamination and potential sources of PFASs. In this study, concentrations of 11 PFASs measured in estuarine sediments collected in 2012 from the Charleston Harbor and the Ashley and Cooper Rivers (n=36) in South Carolina revealed higher levels than those reported in any other U.S. urban areas. Detectable levels were found in all sample locations with mean total PFAS concentrations of 3.79ngg(-1) (range 0.22 to 19.2ngg(-1) d.w.). Dominant compounds were perfluorooctane sulfonate (PFOS) (mean 1.52ngg(-1); range 0.09-7.37ngg(-1) d.w.), followed by perfluorodecanoate (PFDA) (mean 0.83ngg(-1); range 0.06-4.76ngg(-1) d.w.) and perfluorooctanoate (PFOA) (mean 0.42ngg(-1); range 0.02-2.52ngg(-1) d.w.). PFOS levels in sediments at 19 of 36 sites (representing 52% of the study area) exceeded the published global median PFOS sediment concentration of 0.54ngg(-1). PMID- 25828418 TI - Future proofing the NHS: the new care models. PMID- 25828417 TI - Occurrence of antibiotics in soils and manures from greenhouse vegetable production bases of Beijing, China and an associated risk assessment. AB - The occurrence of 15 antibiotics in soil and manure samples from 11 large-scale greenhouse vegetable production (GVP) bases in Beijing, China was investigated. Results showed that the greenhouse soils were ubiquitously contaminated with antibiotics, and that antibiotic concentrations were significantly higher in greenhouses than in open field soils. The mean concentrations of four antibiotic classes decreased in the following order: tetracyclines (102MUg/kg)>quinolones (86MUg/kg)>sulfonamides (1.1MUg/kg)>macrolides (0.62MUg/kg). This investigation also indicated that fertilization with manure and especially animal feces might be the primary source of antibiotics. A risk assessment based on the calculated risk quotients (RQs) demonstrated that oxytetracycline, chlortetracycline, norfloxacin, ciprofloxacin and enrofloxacin could pose a high risk to soil organisms. These results suggested that the ecological effects of antibiotic contamination in GVP bases and their potential adverse risks on human health need to be given special attention. PMID- 25828419 TI - Proton pump inhibitors utilisation in older people in New Zealand from 2005 to 2013. AB - BACKGROUND: The prescriptions for proton pump inhibitors (PPI) to treat acid related disorders continue to rise internationally and in New Zealand. Concerns have been raised regarding its widespread use, costs and potential adverse effects in older people. AIMS: This study aimed to characterise the utilisation of PPI by older people (aged 65 years and older) in New Zealand from 2005 to 2013. METHODS: Repeated cross-sectional analysis of population-level dispensing data was conducted from 1 January 2005 to 31 December 2013. Dispensing data for all PPI prescriptions from 2005 to 2013 were obtained from the Ministry of Health, New Zealand. Utilisation was measured in defined daily doses (DDD) per 1000 older people per day using the World Health Organization Collaborating Centre for Drug Statistics Methodology anatomic, therapeutic and chemical classification system. Utilisation was standardised by sex, age, ethnicity and district health board. RESULTS: Overall PPI utilisation showed a 26.7% increase from 2005 to 2013, from 273.41 to 346.53 DDD/1000/day. The greatest utilisation was observed in individuals aged between 80 and 84 years. Middle Eastern/Latin American/African utilised more PPI compared with other ethnic groups. CONCLUSIONS: Utilisation of PPI among older people in New Zealand increased by a fifth from 2005 to 2013. Given the concerns surrounding the long-term PPI use in older people, the appropriateness of the increased utilisation needs to be continuously re-evaluated by prescribers and health policy makers. PMID- 25828420 TI - Superior target volume and organ stability with the use of endorectal balloons in post-prostatectomy radiotherapy. AB - INTRODUCTION: We investigated the endorectal balloon (ERB) as a method to improve post-prostatectomy clinical target volume (CTV) stability. METHODS: Seventy cone beam CT (CBCT) obtained during radiotherapy treatment from seven patients treated with an ERB and 68 CBCT from seven patients treated without an ERB were contoured according to published guidelines. CTV was subdivided into superior and inferior CTV; whole rectal volume was subdivided into superior and inferior rectum and anal volume. Concordance index (CI) of CBCT treatment volumes compared with planning volumes was calculated and displacements were measured. RESULTS: Whole rectal, superior and inferior rectum and anal CI were significantly improved with the ERB by 21%, 17%, 26% and 17% respectively (P < 0.0001). Overall CTV and inferior CTV CI was improved by 4% with the ERB (overall CTV P = 0.021; Inferior CTV P < 0.0001). In the ERB cohort, average displacement for superior CTV was 0.37 cm anterior-posterior (AP) and 0.10 cm left-right (LR). Average standard deviation was 0.27 cm AP and 0.11 cm LR. Inferior CTV average displacement was 0.11 cm AP and 0.02 cm LR. Average standard deviation was 0.11 cm AP and 0.02 cm LR. In the non-ERB cohort, average displacement for superior CTV was 0.43 cm AP and 0.10 mm left-right (LR). Average standard deviation was 0.45 cm AP and 0.13 cm LR. Inferior CTV average displacement was 0.16 cm AP and 0.01 cm LR. Average standard deviation was 0.17 cm AP and 0.03 cm LR. There was no statistically significant impact of bladder filling on CTV CI in ERB patients (P = 0.551) as opposed to non-ERB patients (P = 0.0421). CONCLUSION: ERBs in the post prostatectomy setting resulted in increased rectal and CTV stability while negating the effects of bladder filling on CTV stability. PMID- 25828421 TI - Support Desired by Women Following Termination of Pregnancy for a Fetal Anomaly. AB - With the rapidly evolving field of prenatal testing, there is a growing need to provide support for women pursuing termination of pregnancy following the discovery of a fetal anomaly. Previous studies have documented that women in this situation often feel unsupported, but the type of resources desired by this population remains undetermined. We studied the awareness and utilization of support resources in 51 women at the time of the procedure, at 6 weeks, and at 3 months following the event. Though largely knowledgeable of existing resources at the time of the procedure, only 50 % admitted contemplating their individualized need for support. Most expected to rely on the support of family and friends. Additionally, 50 % expressed the desire to commemorate the pregnancy, though none wanted direct contact with their healthcare provider(s). Responses from the 6 weeks and 3 months assessments were consistent with previous literature as many women indicated not coping as expected and were unprepared for the psychological consequences following the procedure. Our findings indicate that women in these situations may not realize what their long-term support needs will be. They further indicate that guidelines for routine follow-up care should be established among healthcare providers that respect this population's initial desires to avoid reminders of the pregnancy and promote a flexible timeframe for support uptake. Additional support resources that promote flexible uptake as well as meet the desires of anonymity and ease of access need to be developed for this population. PMID- 25828423 TI - The role of phonology, morphology, and orthography in English and Russian spelling. AB - The purpose of the present study was to explore the role of phonology, morphology and orthography in predicting the spelling performance in English-speaking and Russian-speaking children. Tests that tap phonology, morphology and orthography were administered to students in grades 4 and 6 in the USA and Russia. Multiple regression analyses showed that phonology and morphology contributed more for spelling of English words while orthography and morphology contributed more to the spelling of Russian words. The results are explained in terms of the orthographic nature of English and Russian languages as well as the instructional practices and the importance of morphology in spelling in both the languages. PMID- 25828422 TI - Uptake of Genetic Counseling, Knowledge of Bleeding risks and Psychosocial Impact in a South African Cohort of Female Relatives of People with Hemophilia. AB - In excess of 200 people with hemophilia (PWH) and their families have received genetic counseling (GC) at the Hemophilia Comprehensive Care Centre at Charlotte Maxeke Johannesburg Academic Hospital. However, very few of their at-risk female relatives have attended GC to discuss their reproductive risks and options, or their potential bleeding risks. Limited research has been conducted internationally on factors influencing uptake of GC and testing amongst female relatives of PWH. This prospective study aimed to explore the factors that influence the uptake of GC and testing by female relatives of PWH. An open-ended semi-structured interview schedule was developed. Participants included female relatives of PWH who at least had a family member who had received GC. Seventeen participants were interviewed; 7 who had GC previously and 10 who had not. All participants who had previously received GC found the service helpful and were mothers referred because their sons had hemophilia. Of those who had not had GC, possible deterrents included: being unaware of GC service, focus in clinic on PWH and not potential carriers, misunderstood risks related to hemophilia and carrier status, fear of finding out carrier status, and non-disclosure in families. Most participants were unaware of potential bleeding risks for carriers. The information will be used to provide a better service to female relatives of PWH with a goal being to set up a dedicated hemophilia carrier clinic. PMID- 25828424 TI - Experimentally induced lameness in turkeys inoculated with a newly emergent turkey reovirus. AB - Newly emergent turkey arthritis reoviruses (TARVs) have been isolated from cases of lameness in male turkeys over 10 weeks of age. In a previous study, experimental inoculation of TARV in one-week-old turkey poults produced lymphocytic tenosynovitis at four weeks post inoculation but without causing clinical lameness. This study was undertaken to determine if TARV infection at an early age can lead to clinical lameness in birds as they age. One-week-old male turkeys were inoculated orally with a TARV (strain TARV-O'Neil) and monitored for the development of gait defects until 16 weeks of age. At 4, 8, 12 and 16 weeks of age, a subset of birds was euthanized followed by the collection of gastrocnemius tendon, digital flexor tendon, and intestines for virus detection by rRT-PCR and for histologic inflammation scoring. Clinical lameness was first displayed in TARV-infected turkeys at 8 weeks of age and ruptured gastrocnemius tendons with progressive lameness were also seen at 12-16 weeks of age. The virus was detected in gastrocnemius tendon of 4- 8- and 12-week-old turkeys but not in 16-week-old turkeys. Histologic inflammation scores of tendons at each of the four time points were significantly higher in the virus-inoculated group than in the control group (p < 0.01). Lesions began as lymphocytic tenosynovitis with mild synoviocyte hyperplasia at four weeks of age and progressed to fibrosis as the birds aged. These results demonstrate the potential of TARV to infect young turkeys and to produce subclinical tenosynovitis that becomes clinically demonstrable as the turkeys age. PMID- 25828425 TI - Eyelid myokymia in patients with migraine taking topiramate. AB - OBJECTIVE: Although ocular side effects of topiramate are common, neuroophthalmologic manifestations such as blepharospasm, myokymia and oculogyric crisis are scarcely reported. METHODS: We present a serie of 8 patients with migraine who developed eyelid myokymia after treatment with topiramate. We reviewed all patients with migraine treated with topiramate attending the headache outpatient clinic of our hospital from January 2008 to December 2012. RESULTS: During the study period, a total of 140 patients with migraine were treated with topiramate in our headache clinic. Eight presented eyelid myokymia after beginning treatment with topiramate (5,7%). Topiramate was stopped and myokymia disappeared in all patients, it was prescribed again and eyelid myokymia reappeared with their previous characteristics in all patients. CONCLUSIONS: Eyelid myokymia is an underreported side-effect of topiramate in patients with migraine, of unknown cause, so that in future, further studies are need to examine whether patients with migraine are predisposed or not to this adverse effect. PMID- 25828426 TI - The july effect: an analysis of never events in the nationwide inpatient sample. AB - BACKGROUND: Prior studies examining the impact of the "July effect" on in hospital mortality rates have generated variable results. In 2008, the Centers for Medicare & Medicaid Services published a series of high-cost, high-volume, nonreimbursable hospital-acquired complications (HACs). These events were believed to be preventable and indicate deficiencies in healthcare delivery. OBJECTIVE: The present study aims to investigate the impact of July admissions on patient safety in a national sample using the HACs as a metric. DESIGN/SETTING/PATIENTS: Discharge data were collected from all admissions recorded in the Nationwide Inpatient Sample database from 2008 to 2011. HAC incidence was evaluated as a function of admission month, adjusting for demographic and hospital factors in multivariable analysis. MEASURES: The outcome measures were HAC occurrence, prolonged length of stay (LOS), and higher inpatient costs. RESULTS: A total of 143,019,381 inpatient admissions were recorded, with an overall HAC occurrence of 4.7%. July admissions accounted for 7.6% of the total number of inpatient admissions. July admissions experienced a 6% increase in likelihood of HAC occurrence (odds ratio = 1.06, 95% confidence interval: 1.06-1.07, P < 0.001) when compared to those admitted during all other months. Patients with HAC occurrence had almost 2 times increased likelihood of prolonged LOS (P < 0.001) and higher inpatient costs (P < 0.001). CONCLUSIONS: July admissions are associated with increased likelihood of HAC occurrence. This trend may represent breakdowns in organization structure distinct from traditional quality measures, requiring novel transition protocols dedicated to improving HACs. PMID- 25828427 TI - The Effectiveness of 1 Hz rTMS Over the Primary Motor Area of the Unaffected Hemisphere to Improve Hand Function After Stroke Depends on Hemispheric Dominance. AB - OBJECTIVE: Inhibition of motor cortex excitability of the contralesional hemisphere may improve dexterity of the affected hand after stroke. METHODS: 40 patients (17 dominant hemispheric stroke, 23 non-dominant hemispheric stroke) with a mild to moderate upper limb motor impairment were enrolled in a double blind, randomized, placebo-controlled trial with two parallel-groups. Both groups received 15 daily sessions of motor training preceded by either 1 Hz rTMS or sham rTMS. Behavioral and neurophysiological evaluations were performed at baseline, after the first week and after the third week of treatment, and after a 6 months follow-up. RESULTS: In both groups motor function of the affected hand improved significantly. Patients with stroke of the non-dominant hemisphere made a similar improvement, regardless of whether the motor training was preceded by sham or 1 Hz rTMS. Patients with stroke of the dominant hemisphere had a less favorable improvement than those with stroke of the non-dominant hemisphere after motor training preceded by sham rTMS. However, when 1 Hz rTMS preceded the motor training, patients with stroke of the dominant hemisphere made a similar improvement as those with stroke of the non-dominant hemisphere. INTERPRETATION: Motor recovery of the affected upper limb after stroke is determined by dominance of the affected hemisphere. Stroke of the dominant hemisphere is associated with per se poorer improvement of the affected hand. 1 Hz rTMS over the contralesional M1 significantly improves dexterity of the affected hand in patients with stroke of the dominant hemisphere, but not in those with stroke of the non-dominant hemisphere. PMID- 25828428 TI - Right intralobar sequestration with arterial supply from left gastric artery. PMID- 25828429 TI - Endobronchial lipoma mimicking bronchial carcinoid tumour. PMID- 25828430 TI - Improved embryonic cryosurvival observed after in vitro supplementation with conjugated linoleic acid is related to changes in the membrane lipid profile. AB - The aim of this study was to evaluate the effect of supplementing serum containing media with a mixture of cis- and trans-9,11- and -10,12-conjugated isomers of linoleic acid (CLA) during different steps of the in vitro production (IVM, IVC, or IVM + IVC) of bovine embryos on their embryonic development, cryotolerance, and lipid profile. To evaluate the impact of the CLA on membrane lipids, such as phosphatidylcholine (PC) and sphingomyelin (SM), the embryos' lipid profiles were obtained using matrix-assisted laser desorption ionization mass spectrometry. The cleavage rates (78.6%-84.8%) and blastocyst development (44.8%-51.2%) remained unaltered. The postthawing reexpansion rates were higher (P < 0.05) when the CLA was added to the IVM medium (82.6%) or to the IVM + IVC medium (83.8%) than the control (69.3%) or IVC medium (63.0%). Changes in the blastocysts' lipid profile occurred when supplementation was restricted to the IVM or IVC medium. However, the most prominent effects of the CLA on the embryonic PC and SM profiles were observed when the supplement was added to IVM + IVC media, which was an increase in the level of highly unsaturated PCs containing 36 or 38 carbons, which are likely to contain CLA residues. These results showed that the molecular mechanism resulting in the improved cryosurvival, observed with CLA supplementation during bovine embryonic in vitro production, was related to the composition of structural lipids of cellular membranes and is dependent on the treatment length. Monitoring the lipid profile of embryonic membranes may improve the CLA supplementation strategy and facilitate the development of new IVC systems to improve the cryopreservation of bovine embryos and those of other domestic species. PMID- 25828431 TI - Mesoporous metal-organic frameworks with size-, shape-, and space-distribution controlled pore structure. PMID- 25828432 TI - The structural and mechanical properties of the Achilles tendon 2 years after surgical repair. AB - BACKGROUND: Acute ruptures of the Achilles tendon affect the tendon's structural and mechanical properties. The long-term effects of surgical repair on these properties remain unclear. PURPOSE: To evaluate effects of early mobilization versus traditional immobilization rehabilitation programs 2 years after surgical Achilles tendon repair, by comparing force-elongation and stress-strain relationships of the injured tendon to those of the uninjured tendon. METHODS: A group of males with previous Achilles tendon rupture (n=18) and a group of healthy male controls (n=9) participated. Achilles tendon rupture group consisted of patients that had received early mobilization (n=9) and patients that had received traditional immobilization with a plaster cast (n=9). Comparisons of tendon structural and mechanical properties were made between Achilles tendon rupture and healthy control groups, and between the uninjured and injured sides of the two rehabilitation groups in Achilles tendon rupture group. Ultrasound was used to determine bilaterally tendon cross-sectional area, tendon resting length, and tendon elongation as a function of torque during maximal voluntary plantar flexion. From these data, Achilles tendon force-elongation and stress-strain relationships were determined. FINDINGS: The Achilles tendon rupture group uninjured side was not different from healthy control group. Structural and mechanical parameters of the injured side were not different between the Achilles tendon rupture early mobilization and the immobilization groups. Compared to the uninjured side, the injured side showed a reduction in stress at maximal voluntary force, in Young's modulus and in stiffness. INTERPRETATION: Two years post-surgical repair, the Achilles tendon mechanical properties had not returned to the uninjured contralateral tendon values. PMID- 25828433 TI - Effect of posterior cruciate ligament rupture on the radial displacement of lateral meniscus. AB - BACKGROUND: The relationship between lateral meniscus tear and posterior cruciate ligament injury is not well understood. The present study aims to investigate and assess the effect of posterior cruciate ligament rupture on lateral meniscus radial displacement at different flexion angles under static loading conditions. METHODS: Twelve fresh human cadaveric knee specimens were divided into four groups such as posterior cruciate ligament intact, anterolateral band rupture, posteromedial band rupture and posterior cruciate ligament complete rupture groups, according to the purpose and order of testing. Radial displacement of lateral meniscus was measured under different loads (200-1000N) at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion. FINDINGS: Compared with posterior cruciate ligament intact group, the displacement values of lateral meniscus in anterolateral band rupture group increased at 0 degrees flexion with 600N, 800N, and 1000N and at 30 degrees , 60 degrees and 90 degrees flexion under all loading conditions. Posteromedial band rupture group exhibited higher displacement at 0 degrees flexion under all loading conditions, at 30 degrees and 60 degrees flexion with 600, 800N and 1000N, and at 90 degrees flexion with 400N, 600N, 800N, and 1000N than the posterior cruciate ligament intact group. The posterior cruciate ligament complete rupture group had a higher displacement value of lateral medial meniscus at 0 degrees , 30 degrees , 60 degrees and 90 degrees flexion under all loading conditions, as compared to the posterior cruciate ligament intact group. INTERPRETATION: The study concludes that partial and complete rupture of the posterior cruciate ligament can trigger the increase of radial displacement on lateral meniscus. PMID- 25828434 TI - The effect of water chemistry on homoaggregations of various nanoparticles: specific role of Cl- ions. AB - Colloidal behavior of various nanoparticles (NPs) could be quite different under the influence of complicated water chemistry. Homoaggregations of four types of nanoparticles (NPs) were investigated with a focus on the effects of electrolyte ions, pH, and natural organic matter (NOM). Results show that critical coagulation concentrations (CCCs) of NaCl and CaCl2 for anatase TiO2, rutile TiO2, or CeO2 NPs were all inversely proportional to the valence of cations, following the Schulze-Hardy Rule, and homoaggregations of the three NPs were similarly inhibited by the presence of NOM within pH 3-9. Although the homoaggregation of Ag NPs was also increased as the concentration or valence of cations increased, the relationship between CCC and valence of the cations was far away from the Schulze-Hardy Rule; moreover, NOM only slightly increased CCC of CaCl2 and surprisingly decreased CCC of NaCl for Ag NPs. Excessively-adsorbed Cl(-) on the formed Ag-AgCl colloidal nucleus was detected, which could increase the electronegativity of Ag NPs and thus limit the aggregation effect of chlorides and the dispersion effect of NOM as well. These results are expected to increase our knowledge on the colloidal behavior and fate of NPs in aquatic environments. PMID- 25828435 TI - Dynamics of double emulsion break-up in three phase glass capillary microfluidic devices. AB - Pinch-off of a compound jet in 3D glass capillary microfluidic device, which combines co-flowing and countercurrent flow focusing geometries, was investigated using an incompressible three-phase axisymmetric Volume of Fluid-Continuum Surface Force (VOF-CSF) numerical model. The model showed good agreement with the experimental drop generation and was capable of predicting formation of core/shell droplets in dripping, narrowing jetting and widening jetting regimes. In dripping and widening jetting regimes, the presence of a vortex flow around the upstream end of the necking thread facilitates the jet break-up. No vortex flow was observed in narrowing jetting regime and pinch-off occurred due to higher velocity at the downstream end of the coaxial thread compared to that at the upstream end. In all regimes, the inner jet ruptured before the outer jet, preventing a leakage of the inner drop into the outer fluid. The necking region moves at the maximum speed in the narrowing jetting regime, due to the highest level of shear at the outer surface of the thread. However, in widening jetting regime, the neck travels the longest distance downstream before it breaks. PMID- 25828436 TI - Characterization of gold nanoparticles with different hydrophilic coatings via capillary electrophoresis and Taylor dispersion analysis. Part I: determination of the zeta potential employing a modified analytic approximation. AB - Taking gold nanoparticles with different hydrophilic coatings as an example, it is investigated whether capillary electrophoresis in combination with Taylor dispersion analysis allows for the precise determination of mean electrophoretic mobilities, electrophoretic mobility distributions, and zeta potentials in a matrix of exactly known composition and the calibration-free determination of number-weighted mean hydrodynamic radii. Our experimental data confirm that the calculation of the zeta potential for colloidal nanoparticles with zeta>25 mV requires to take the relaxation effect into account. Because of the requirement to avoid particle-wall interactions, a solution of disodiumtetraborate decahydrate (borax) in deionized water had been selected as suitable electrolyte. Measurements of the electrophoretic mobility at different ionic strength and application of the analytic approximation developed by Ohshima show that in the present case of a buffered solution with a weak electrolyte co-ion and a strong electrolyte counterion, the effective ionic drag coefficient should be approximated with the ionic drag coefficient of the counterion. The obtained results are in good agreement with theoretical expectations regarding the dependence of the zeta potential and the electrokinetic surface charge density on the ionic strength. We also show that Taylor dispersion analysis (besides estimation of the number-weighted mean hydrodynamic radius) provides additional information on the type and width of the number-weighted particle distribution. PMID- 25828438 TI - Thermoresponsive Properties of PNIPAM-Based Hydrogels: Effect of Molecular Architecture and Embedded Gold Nanoparticles. AB - Thermoresponsive hydrogels were successfully prepared from poly(N isopropylacrylamide)-based polymers with different architectures (linear, branched, or hyperbranched). The macromolecular architectures strongly influence the internal structure of the hydrogels, therefore modulating their thermoresponsive and rheological properties. These hydrogels were used for the in situ synthesis of gold nanoparticles. Significant changes in hydrogel microstructures and in average pore size due to the presence of gold nanoparticles were observed. Additionally, their presence significantly increases both the mechanical strength and the toughness of the hydrogel networks. PMID- 25828439 TI - Welcome to the first issue of Public Health Research & Practice. PMID- 25828437 TI - Flaviviral NS4b, chameleon and jack-in-the-box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention. AB - Dengue virus and other flaviviruses such as the yellow fever, West Nile, and Japanese encephalitis viruses are emerging vector-borne human pathogens that affect annually more than 100 million individuals and that may cause debilitating and potentially fatal hemorrhagic and encephalitic diseases. Currently, there are no specific antiviral drugs for the treatment of flavivirus-associated disease. A better understanding of the flavivirus-host interactions during the different events of the flaviviral life cycle may be essential when developing novel antiviral strategies. The flaviviral non-structural protein 4b (NS4b) appears to play an important role in flaviviral replication by facilitating the formation of the viral replication complexes and in counteracting innate immune responses such as the following: (i) type I IFN signaling; (ii) RNA interference; (iii) formation of stress granules; and (iv) the unfolded protein response. Intriguingly, NS4b has recently been shown to constitute an excellent target for the selective inhibition of flavivirus replication. We here review the current knowledge on NS4b. PMID- 25828440 TI - The Australian Prevention Partnership Centre: systems thinking to prevent lifestyle-related chronic illness. AB - Chronic diseases are the major cause of death in Australia and the biggest contributor to premature death and disability. Although prevention of chronic disease can be effective and cost-effective, it has proven difficult to systematically implement interventions that target important lifestyle-related risk factors for chronic disease such as poor nutrition, physical inactivity and harmful alcohol use. Prevention efforts targeting these lifestyle-related risk factors have had mixed success due to issues around designing and implementing effective interventions that address the complexity of risk factors, and incorporating evidence and implementing interventions at a scale, duration, intensity and quality required to achieve population effects. There is increasing recognition that multilevel, multisector approaches are required for the effective and sustained prevention of complex chronic disease. The Australian Prevention Partnership Centre, one of two National Health and Medical Research Council Partnership Centres established in 2013, is researching and developing systems perspectives to prevent lifestyle-related chronic disease in Australia. The Centre's collaborative approach is providing opportunities for researchers to work with policy makers and practitioners to develop research questions, conduct research, and analyse, interpret and disseminate the findings. As such, it is the model of interaction that is being tested as much as the specific projects. With its funding partners, the Centre has developed plans for more than 30 projects. It has also established four capacity units that will improve the gathering, sharing and use of evidence to build a prevention system in Australia. The Centre is exploring new ways to advance prevention by bringing together researchers, policy makers and practitioners to determine the information and actions needed for an effective prevention system for Australia. PMID- 25828441 TI - Planning and evaluating population interventions to reduce noncommunicable disease risk - reconciling complexity and scientific rigour? AB - Noncommunicable diseases (NCDs) are the leading global causes of morbidity and mortality. It is important to develop and deliver effective NCD prevention programs, but these have been difficult to evaluate. Technical approaches differ, with academic researchers, practitioners and policy makers each bringing different perspectives and priorities to the task of NCD program evaluation. Epidemiologically defined hierarchies of research evidence give preference to evaluation methods that are often unsuitable for assessing complex NCD prevention interventions. This may lead to interventions that provide the 'right answer to the wrong question', or to evaluation data that are insufficient to inform NCD prevention efforts. This paper recommends a set of standardised stages in the planning, development and evaluation of NCD prevention programs, including the use of logic models, the expanded use of process evaluation to better understand and record the context for implementation, and the use of appropriate research designs for assessing the impact of both subcomponents and the whole program. NCD prevention agencies and academic stakeholders need to recognise the limitations of established evaluation designs and support greater flexibility in the application of evaluation methods that are fit for purpose in describing the stages in NCD programs. This involves assessing policy development and implementation, measuring intermediate indicators, using mixed methods of evaluation, and employing population surveillance systems to assess long-term outcomes. PMID- 25828442 TI - Putting the genie back in the bottle: protecting children from lead exposure in the 21st century. A report from the field. AB - This paper highlights progress on an important public health issue which, despite significant progress, has now stalled and is in need of renewed investment. The objective is to describe the effectiveness of efforts to reduce childhood lead exposure in Broken Hill - a historic mining town in western NSW - and what is required to further reduce exposure. Lead has no known function in the human body, and emerging evidence suggests that no level of exposure is without health effects. A 1991 blood lead survey of 1-4-year-old children identified lead exposure as a significant public health issue in Broken Hill. A major NSW Government-funded program to reduce lead exposure began in 1994, and, by 2001, blood lead levels had reduced by two-thirds. The program was then integrated into other services and funding significantly reduced; blood lead levels have remained relatively unchanged since 2005. At present, 53% of children in Broken Hill have blood lead levels above the recently released National Health and Medical Research Council draft reference value for lead. Participation in annual blood lead screening declined from 52% to 38% after project funding decreased, but recent changes have doubled participation rates. A comprehensive abatement program is required to further reduce lead exposure in this community, and further research is required into how to maintain low blood lead levels and how best to engage the community about reducing individual lead risks. Findings from such studies would be relevant to the broader Australian community. PMID- 25828443 TI - Group model building: a participatory approach to understanding and acting on systems. AB - With mounting appreciation of the complexity of chronic disease, there is a growing need to understand the systemic causes of current health trends. This will support the development of a prevention system and the use of systems thinking to achieve better, more equitable and more sustainable health outcomes. With new language and a need to change our thinking, the push towards systems practice in preventive health is challenging, and calls for a method to support its application. Group model building (GMB) is a participatory approach that is widely used to build the capacity of practitioners to think in a systems way. However, it is a resource-intensive approach that requires high-level buy-in and the investment of time. We discuss the evidence, including a systematic review of the literature examining the effectiveness of GMB approaches across a wide range of contexts. The results of the review are generally positive and suggest that GMB improves problem understanding, increases engagement in systems thinking, builds confidence in the use of systems ideas and develops consensus for action among diverse stakeholders. PMID- 25828444 TI - Reconnecting urban planning with health: a protocol for the development and validation of national liveability indicators associated with noncommunicable disease risk behaviours and health outcomes. AB - AIM: Liveable communities create the conditions to optimise health and wellbeing outcomes in residents by influencing various social determinants of health - for example, neighbourhood walkability and access to public transport, public open space, local amenities, and social and community facilities. This study will develop national liveability indicators that are (a) aligned with state and federal urban policy, (b) developed using national data (where available), (c) standard and consistent over time, (d) suitable for monitoring progress towards creating more liveable, equitable and sustainable communities, (e) validated against selected noncommunicable disease risk behaviours and/or health outcomes, and (f) practical for measuring local, national and federal built environment interventions. STUDY TYPE: Protocol. METHOD: Over two years, the National Liveability Study, funded through The Australian Prevention Partnership Centre (TAPPC), will develop and validate a national set of spatially derived built environment liveability indicators related to noncommunicable disease risk behaviours and/or health outcomes, informed by a review of relevant policies in selected Australian state and territory governments. To create national indicators, we will compare measures developed using national data with finer grained state-level data, which have been validated against a range of outcomes. Finally, we will explore the creation of a national database of built environment spatial indicators. RESULTS: A national advisory group comprising stakeholders in state and federal government, federal nongovernment organisations and state-based technical working groups located in the ACT, Victoria, NSW, Queensland and WA has been established; a policy analysis is under way and work programs are being prepared. CONCLUSION: This project seeks to build the capacity for built environment and health systems research by developing national indicators to monitor progress towards creating healthy and liveable communities. This ambition requires multisector engagement and an interdisciplinary research team. PMID- 25828445 TI - What are the key organisational capabilities that facilitate research use in public health policy? AB - AIM: Literature about research use suggests that certain characteristics or capabilities may make policy agencies more evidence attuned. This study sought to determine policy makers' perceptions of a suite of organisational capabilities identified from the literature as potentially facilitating research uptake in policy decision making. METHOD: A literature scan identified eight key organisational capabilities that support research use in policy making. To determine whether these capabilities were relevant, practical and applicable in real world policy settings, nine Australian health policy makers were consulted in September 2011. We used an open-ended questionnaire asking what facilitates the use of research in policy and program decision making, followed by specific questions rating the proposed capabilities. Interviews were transcribed and the content analysed. RESULTS: There was general agreement that the capabilities identified from the literature were relevant to real world contexts. However, interviewees varied in whether they could provide examples of experiences with the capabilities, how essential they considered the different capabilities to be and how difficult they considered the capabilities were to achieve. CONCLUSION: Efforts to improve the use of research in policy decision making are likely to benefit from targeting multiple organisational capabilities, including staff skills and competence, tools such as templates and checklists to aid evidence use and leadership support for the use of research in policy development. However, such efforts should be guided by an understanding of how policy agencies use evidence and how they view their roles, and external factors such as resource constraints and availability of appropriate research. PMID- 25828446 TI - Approaches to maximising the accuracy of anthropometric data on children: review and empirical evaluation using the Australian Longitudinal Study of Indigenous Children. AB - AIM: Despite the burgeoning research interest in weight status, in parallel with the increase in obesity worldwide, research describing methods to optimise the validity and accuracy of measured anthropometric data is lacking. Even when 'gold standard' methods are employed, no data are 100% accurate, yet the accuracy of anthropometric data is critical to produce robust and interpretable findings. To date, described methods for identifying data that are likely to be inaccurate seem to be ad hoc or lacking in clear justification. METHODS: This paper reviews approaches to evaluating the accuracy of cross-sectional and longitudinal data on height and weight in children, focusing on recommendations from the World Health Organization (WHO). This review, together with expert consultation, informed the development of a method for processing and verifying longitudinal anthropometric measurements of children. This approach was then applied to data from the Australian Longitudinal Study of Indigenous Children. RESULTS: The review identified the need to assess the likely plausibility of data by (a) examining deviation from the WHO reference population by calculating age- and sex-adjusted height, weight and body mass index z-scores, and (b) examining changes in height and weight in individuals over time. The method developed identified extreme measurements and implausible intraindividual trajectories. It provides evidence based criteria for the exclusion of data points that are most likely to be affected by measurement error. CONCLUSIONS: This paper presents a probabilistic approach to identifying anthropometric measurements that are likely to be implausible. This systematic, practical method is intended to be reproducible in other settings, including for validating large databases. PMID- 25828447 TI - Applying a performance monitoring framework to increase reach and adoption of children's healthy eating and physical activity programs. AB - The allocation of a significant amount of new funding for health promotion in Australia through the National Partnership Agreement on Preventive Health (2009 14) created a unique opportunity to implement a comprehensive approach to the prevention of chronic diseases and demonstrate significant health improvements. Building on existing health promotion infrastructure in Local Health Districts, the NSW Ministry of Health adopted a scaled-up state-wide capacity-building model, designed to alter policies and practices in key children's settings to increase healthy eating and physical activity among children. NSW also introduced a performance monitoring framework to track implementation and impacts. This paper describes the model that NSW developed for monitoring state-wide programs in the Children's Healthy Eating and Physical Activity Program and presents the model's application to early childhood education and care and primary school settings, including current results. This approach to monitoring the scaling up of program implementation at the state-wide level has potential for more widespread application in other policy areas in NSW. PMID- 25828448 TI - An update on the epidemiology and key issues associated with the diagnosis and management of Creutzfeldt-Jakob disease cases in NSW. AB - Creutzfeldt-Jakob disease (CJD) is a fatal disease caused by the accumulation of abnormal prion proteins in neurological tissues. Routine notification data reveal that NSW has similar rates of CJD to other states and territories in Australia; however, it is likely that there is significant under-ascertainment of cases. It is important that clinicians and public health staff remain vigilant for the clinical signs of CJD and understand the limitations of the different diagnostic tests available. This paper provides a brief overview of the epidemiology of CJD in NSW, as well as current issues in the diagnosis and public health investigation of CJD. PMID- 25828449 TI - Alcohol summit calls for urgent action. PMID- 25828450 TI - Employees support incentives to cycle to work. PMID- 25828451 TI - Soda tax win brings hope to diabesity campaigners. PMID- 25828452 TI - Highly selective fluorescence imaging of zinc distribution in HeLa cells and Arabidopsis using a naphthalene-based fluorescent probe. AB - 2-(N,N-Dimethylamino)naphthalene-based probe 1 was found to exhibit a dramatic enhancement in fluorescence upon addition of Zn(2+), but not with any other metal ions. Probe 1 as a chemoprobe enabled high-resolution fluorescence imaging of zinc ions in HeLa cells and Arabidopsis. PMID- 25828453 TI - Folding of influenza virus hemagglutinin in insect cells is fast and efficient. AB - Folding of influenza virus hemagglutinin (HA) in the endoplasmic reticulum has been well defined in mammalian cells. In different mammalian cell lines the protein follows the same folding pathway with identical folding intermediates, but folds with very different kinetics. To examine the effect of cellular context on HA folding and to test to which extent insect cells would support the HA folding process, we expressed HA in Sf9 insect cells. Strikingly, in this invertebrate system HA folded faster and more efficiently, still via the same folding intermediates as in vertebrate cells. Our results suggest that insect cells provide a highly efficient and effective folding environment for influenza virus HA and the ideal production platform for HA (emergency) vaccines. PMID- 25828454 TI - Automated production of functional membrane proteins using eukaryotic cell-free translation systems. AB - Due to their high abundance and pharmacological relevance there is a growing demand for the efficient production of functional membrane proteins. In this context, cell-free protein synthesis represents a valuable alternative that allows for the high-throughput synthesis of functional membrane proteins. Here, we demonstrate the potential of our cell-free protein synthesis system, based on lysates from cultured Spodoptera frugiperda 21 cells, to produce pro- and eukaryotic membrane proteins with individual topological characteristics in an automated fashion. Analytical techniques, including confocal laser scanning microscopy, fluorescence detection of eYFP fusion proteins in a microplate reader and in-gel fluorescence of statistically incorporated fluorescent amino acid derivatives were employed. The reproducibility of our automated synthesis approach is underlined by coefficients of variation below 7.2%. Moreover, the functionality of the cell-free synthesized potassium channel KcsA was analyzed electrophysiologically. Finally, we expanded our cell-free membrane protein synthesis system by an orthogonal tRNA/synthetase pair for the site-directed incorporation of p-Azido-l-phenylalanine based on stop codon suppression. Incorporation was optimized by performance of a two-dimensional screening with different Mg(2+) and lysate concentrations. Subsequently, the selective modification of membrane proteins with incorporated p-Azido-l-phenylalanine was exemplified by Staudinger ligation with a phosphine-based fluorescence dye. PMID- 25828455 TI - Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. AB - Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against colitis. SCFAs binding to the 'metabolite-sensing' receptors GPR43 and GPR109A in non-haematopoietic cells mediate these protective effects. The inflammasome pathway has hitherto been reported as a principal pathway promoting gut epithelial integrity. SCFAs binding to GPR43 on colonic epithelial cells stimulates K(+) efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. Dietary fibre also shapes gut bacterial ecology, resulting in bacterial species that are more effective for inflammasome activation. SCFAs and metabolite receptors thus explain health benefits of dietary fibre, and how metabolite signals feed through to a major pathway for gut homeostasis. PMID- 25828456 TI - Interpreting important health-related quality of life change using the Haem-A QoL. AB - The Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) measures health-related quality of life (HRQoL) in adults with haemophilia; however, change score thresholds for identifying individuals experiencing a HRQoL benefit have not been appropriately investigated. The objective of this analysis was to derive appropriate HRQoL responder definitions (RDs) for two Haem-A-QoL domains that reflect key impairments, 'Physical Health' and 'Sports & Leisure,' and the Haem-A-QoL 'Total Score' using anchor- and distribution-based methods. In this analysis, data from adults in A-LONG and B-LONG, two Phase 3 clinical studies of rFVIIIFc in haemophilia A and rFIXFc in haemophilia B, respectively, were used. The anchor-based approach identified Haem-A-QoL changes corresponding to EQ-5D item improvements between baseline and 6 months; the distribution-based methods examined the magnitude at baseline of one-half standard deviation and the standard error of measurement. Through triangulation, the most appropriate RDs were derived. Of the 133 A-LONG and 73 B-LONG subjects with baseline Haem-A-QoL scores, 67 and 51 subjects, respectively, completed the Haem-A-QoL questionnaire at both baseline and 6 months follow-up. Triangulation of anchor- and distribution-based estimates with the observed Haem-A-QoL change scores identified a 10-point reduction in the 'Physical Health' and 'Sports & Leisure' domains, and a 7-point reduction in 'Total Score' as the RD thresholds most indicative of HRQoL benefit. These empirically derived RDs for two key Haem-A-QoL domains and 'Total Score' are reasonable and practical thresholds for identifying subjects with notable improvements in HRQoL, and provides HRQoL RDs that can be used for further analysis and interpretation of data from haemophilia clinical trials. PMID- 25828457 TI - Toward assessment of density functionals for vibronic coupling in two-photon absorption: A case study of 4-nitroaniline. AB - In this study, we predict vibronic two-photon absorption (TPA) spectra for 4 nitroaniline in vacuo. The simulations are performed using density functional theory and the approximate second-order coupled-cluster singles and doubles model CC2. Thereby we also demonstrate the possibility of simulations of vibronic TPA spectra with ab initio wavefunction methods that include electron correlation for medium-sized systems. A special focus is put on the geometric derivatives of the second-order transition moment and the dipole moment difference between the charge-transfer excited state and the ground state. The results of CC2 calculations bring new insight into the vibronic coupling mechanism in TPA spectra of 4-nitroniline and demonstrate that the mixed term is quite large and that it also exhibits a negative interference with the Franck-Condon contribution. PMID- 25828459 TI - Almanac 2014: aortic valve disease. AB - The past few years have seen major advances in the diagnosis of aortic valve disease and in our understanding of the pathophysiology of disease. In addition, transcatheter aortic valve implantation has transformed our clinical management options. This article summarises new aortic valve disease research published in Heart in 2013 and 2014, within the context of other major studies published in general medical journals, including a discussion of the potential impact of these new research findings on the clinical approach to management of adults with aortic valve disease. PMID- 25828458 TI - Information theory and artificial grammar learning: inferring grammaticality from redundancy. AB - In artificial grammar learning experiments, participants study strings of letters constructed using a grammar and then sort novel grammatical test exemplars from novel ungrammatical ones. The ability to distinguish grammatical from ungrammatical strings is often taken as evidence that the participants have induced the rules of the grammar. We show that judgements of grammaticality are predicted by the local redundancy of the test strings, not by grammaticality itself. The prediction holds in a transfer test in which test strings involve different letters than the training strings. Local redundancy is usually confounded with grammaticality in stimuli widely used in the literature. The confounding explains why the ability to distinguish grammatical from ungrammatical strings has popularized the idea that participants have induced the rules of the grammar, when they have not. We discuss the judgement of grammaticality task in terms of attribute substitution and pattern goodness. When asked to judge grammaticality (an inaccessible attribute), participants answer an easier question about pattern goodness (an accessible attribute). PMID- 25828460 TI - Severe tricuspid regurgitation is predictive for adverse events in tetralogy of Fallot. AB - OBJECTIVE: Patients with surgically repaired tetralogy of Fallot (rTOF) may develop functional tricuspid regurgitation (TR) due to annulus dilation. Guidelines suggest pulmonary valve replacement (PVR) in patients with rTOF with progressive TR, but data on clinical outcomes are lacking. Our objective was to determine whether TR was predictive for adverse events after PVR. METHODS: In this retrospective, multicenter cohort study, patients with rTOF who had undergone PVR after preoperative echocardiographic assessment of TR grade were included. Preoperative and postoperative imaging data and a composite of adverse clinical events (death, sustained ventricular tachycardia, heart failure, or supraventricular tachycardia) were collected. Multivariate Cox hazards regression analysis was used to determine which factors were predictive for adverse events after PVR. RESULTS: A total of 129 patients (61% men, age at PVR 32.9+/-10.4 years) were included. The composite endpoint occurred in 39 patients during 8.4+/ 4.2 years of follow-up. In multivariate analysis, severe preoperative TR (HR 2.49, 95% CI 1.11 to 5.52), right ventricular end-systolic volume (HR 1.02/mL/m(2), 95% CI 1.01 to 1.03) and age at PVR (HR 1.07/year, 95% CI 1.04 to 1.09) were predictive for adverse events. Early postoperative TR was not predictive for adverse events (p=0.96). In patients without any risk factor (age >40 years, right ventricular end-systolic volume >90 mL/m(2) or severe TR), 5 year event-free survival was 100% as compared with 61% in patients with two or three risk factors. CONCLUSIONS: In patients with rTOF, severe preoperative TR was predictive for adverse events after PVR. Close surveillance is warranted in these patients irrespective of postoperative TR. PMID- 25828461 TI - A High Throughput, 384-Well, Semi-Automated, Hepatocyte Intrinsic Clearance Assay for Screening New Molecular Entities in Drug Discovery. AB - A high throughput, semi-automated clearance screening assay in hepatocytes was developed allowing a scientist to generate data for 96 compounds in one week. The 384-well format assay utilizes a Thermo Multidrop Combi and an optimized LC-MS/MS method. The previously reported LCMS/ MS method reduced the analytical run time by 3-fold, down to 1.2 min injection-to-injection. The Multidrop was able to deliver hepatocytes to 384-well plates with minimal viability loss. Comparison of results from the new 384-well and historical 24-well assays yielded a correlation of 0.95. In addition, results obtained for 25 marketed drugs with various metabolism pathways had a correlation of 0.75 when compared with literature values. Precision was maintained in the new format as 8 compounds tested in >=39 independent experiments had coefficients of variation <=21%. The ability to predict in vivo clearances using the new stability assay format was also investigated using 22 marketed drugs and 26 AbbVie compounds. Correction of intrinsic clearance values with binding to hepatocytes (in vitro data) and plasma (in vivo data) resulted in a higher in vitro to in vivo correlation when comparing 22 marketed compounds in human (0.80 vs 0.35) and 26 AbbVie Discovery compounds in rat (0.56 vs 0.17), demonstrating the importance of correcting for binding in clearance studies. This newly developed high throughput, semi automated clearance assay allows for rapid screening of Discovery compounds to enable Structure Activity Relationship (SAR) analysis based on high quality hepatocyte stability data in sufficient quantity and quality to drive the next round of compound synthesis. PMID- 25828462 TI - Sensory uncertainty leads to systematic misperception of the direction of motion in depth. AB - Although we have made major advances in understanding motion perception based on the processing of lateral (2D) motion signals on computer displays, the majority of motion in the real (3D) world occurs outside of the plane of fixation, and motion directly toward or away from observers has particular behavioral relevance. Previous work has reported a systematic lateral bias in the perception of 3D motion, such that an object on a collision course with an observer's head is frequently judged to miss it, with obvious negative consequences. To better understand this bias, we systematically investigated the accuracy of 3D motion perception while manipulating sensory noise by varying the contrast of a moving target and its position in depth relative to fixation. Inconsistent with previous work, we found little bias under low sensory noise conditions. With increased sensory noise, however, we revealed a novel perceptual phenomenon: observers demonstrated a surprising tendency to confuse the direction of motion-in-depth, such that approaching objects were reported to be receding and vice versa. Subsequent analysis revealed that the lateral and motion-in-depth components of observers' reports are similarly affected, but that the effects on the motion-in depth component (i.e., the motion-in-depth confusions) are much more apparent than those on the lateral component. In addition to revealing this novel visual phenomenon, these results shed new light on errors that can occur in motion perception and provide a basis for continued development of motion perception models. Finally, our findings suggest methods to evaluate the effectiveness of 3D visualization environments, such as 3D movies and virtual reality devices. PMID- 25828464 TI - Revisiting the spread of sparing in the attentional blink. AB - The attentional blink (AB) refers to a deficit in reporting the second of two targets (T2) in a rapid serial visual presentation (RSVP) stream when this target is presented less than 500 ms after the onset of the first target (T1). It is under debate whether the AB originates from a limitation of cognitive resources or from an attentional suppression process triggered by a distractor or by target discontinuity. In this study, we placed a distractor (D(inter)) or an extra target (T(inter)) between T1 and T2 while at the same time manipulating the time interval between D(inter) (or T(inter)) and T2 (0, 200, or 500 ms). The level of attentional enhancement induced by the detection of T1 was also manipulated by adding external noise to T1. The results showed that, as compared to the dual target condition, T2 performance was better in the consecutive-target condition, when T2 was close in time to T(inter) (i.e., the spread of sparing), but was worse with a longer interval between T2 and the preceding item. Adding external noise to T1 improved T2 performance when T2 was close in time to the preceding item, irrespective of whether this item was D(inter) or T(inter). These findings present difficulties for the existing models of the AB, although the overall pattern observed is generally more consistent with the episodic simultaneous type, serial-token (eSTST) model than with conventional resource accounts or distractor-based attentional selection accounts of the AB. PMID- 25828465 TI - Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. AB - The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab have been recently licensed by the Food and Drug Administration for the treatment of advanced melanoma. Immune checkpoint inhibitors such as these can induce endocrine adverse events but autoimmune diabetes has not been described to date. However, there is a strong preclinical rationale that supports this autoimmune toxicity. We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab. The presence of high serum titres of anti-glutamic acid decarboxylase antibodies together with a suggestive clinical presentation, age of the patient and preclinical data strongly support an autoimmune aetiology of the diabetes. Moreover, the patient was found to have a well-known high-risk human leucocyte antigen type for the development of type 1 diabetes in children, so the PD-1 inhibition is very likely to have triggered the autoimmune phenomenon. Our case suggests that insulin-dependent diabetes might be a rare but important anti PD-1 immune-related adverse event. PMID- 25828463 TI - The cocktail-party problem revisited: early processing and selection of multi talker speech. AB - How do we recognize what one person is saying when others are speaking at the same time? This review summarizes widespread research in psychoacoustics, auditory scene analysis, and attention, all dealing with early processing and selection of speech, which has been stimulated by this question. Important effects occurring at the peripheral and brainstem levels are mutual masking of sounds and "unmasking" resulting from binaural listening. Psychoacoustic models have been developed that can predict these effects accurately, albeit using computational approaches rather than approximations of neural processing. Grouping-the segregation and streaming of sounds-represents a subsequent processing stage that interacts closely with attention. Sounds can be easily grouped-and subsequently selected-using primitive features such as spatial location and fundamental frequency. More complex processing is required when lexical, syntactic, or semantic information is used. Whereas it is now clear that such processing can take place preattentively, there also is evidence that the processing depth depends on the task-relevancy of the sound. This is consistent with the presence of a feedback loop in attentional control, triggering enhancement of to-be-selected input. Despite recent progress, there are still many unresolved issues: there is a need for integrative models that are neurophysiologically plausible, for research into grouping based on other than spatial or voice-related cues, for studies explicitly addressing endogenous and exogenous attention, for an explanation of the remarkable sluggishness of attention focused on dynamically changing sounds, and for research elucidating the distinction between binaural speech perception and sound localization. PMID- 25828466 TI - Integrative approach in prevention and therapy of basal cellular carcinoma by association of three actives loaded into lipid nanocarriers. AB - Basal cell carcinoma (BCC) is one of the commonest malignancies occurred on sun exposed skin, mainly by UV-B radiation, of lighter-skinned individuals. The aim of the present study was to develop advanced drug delivery formulations used in BCC therapy that overcomes chemotherapy-induced side-effects of skin photosensitivity by an integrative approach of nanoencapsulation in conjunction with combination therapy that uses chemotherapeutic, chemoprotective and sunscreen agents. The combination of anticancer drug together with sunscreen agent is very useful in therapy, especially for individuals who are more exposed to the sun without using a sunscreen. Nanostructured lipid carriers (NLCs) employed as drug delivery systems were co-loaded with 5-fluorouracil (5-FU), a hydrophilic chemotherapeutic drug, and ethylhexyl salicylate (EHS), a lipophilic UV-B sunscreen agent. The NLCs were developed using bioactive squalene (50.8% w/w) from amaranth seed oil as chemoprotective agent. By varying the concentrations of 5-FU and EHS, the co-loaded NLCs presented particle sizes of about 100nm, acceptable physical stability with values smaller than -25mV and appropriate entrapment efficiency that reaches values over 65% for both types of drugs. The UV-B blocking ability of EHS loaded into NLCs were influenced by the concentration of 5-FU. The amaranth oil offered a capacity of 70% in scavenging the free radicals. In vitro drug release showed that NLCs presented sustained release of 5-FU that followed the Fick's law of diffusion. PMID- 25828467 TI - Has evidence-based medicine left quackery behind? AB - Evidence-based medicine (EBM) is generally considered as the most complete paradigm in the practice of clinical medicine. Its application should preclude all kinds of quackery. Therapeutic reformers of the second half of the twentieth century have convinced the medical community that the double-blind randomized controlled trial (RCT) versus placebo is the gold standard in clinical research to establish evidence of treatment usefulness. Nevertheless, this paradigm ignores the importance of non-specific effects in the healing process and can generate misrepresentations. Additionally, because of methodological limitations, RCTs as they are used in practice can give rise to new forms of quackery by promoting drugs that are not useful for the patients who actually receive them, or are so expensive that their value is open to criticism. This is precisely the case when surrogate outcomes, with questionable clinical significance, are used. These can divert attention from clinically relevant outcomes, such as safety issues that are probably the core of treatment evaluation. The boundaries between quackery and EBM that clinicians are faced with are not so clear-cut. There is a need for doctors to acknowledge their share in quackery and to be continually conscious of the possible pitfalls of their therapeutic practice. PMID- 25828468 TI - Ex vivo human skin and SZ95 sebocytes exhibit a homoeostatic interaction in a novel coculture contact model. AB - The sebaceous gland displays key functions of the human skin, such as hormone synthesis in situ, antimicrobial activity and participation to inflammatory responses. Consequently, there is an emerging need of advanced in vitro models to study complex interactions between the sebaceous gland and the other skin compartments. Despite the evolution of both full-skin organ culture and reconstructed three-dimensional skin models, no satisfactory solutions have been provided for the integration of sebaceous glands and/or sebaceous gland cells in those models, probably due to their problematic maintenance both in vitro and ex vivo. We have developed a coculture model of explant skin in direct contact with immortalized SZ95 sebocytes, which resulted in overall improved structural integrity of the epidermis, higher percentage of proliferating basal epidermal cells and reduced apoptosis of differentiating keratinocytes after 6 days, as detected by Ki67 and TUNEL staining, respectively. Furthermore SZ95 sebocytes exhibited morphological and biochemical signs of normal differentiation and lipid accumulation, while interleukin-6 expression in the supernatant of the cocultures was decreased in comparison with the control. The data provide evidence of a beneficial interaction between sebocytes and skin explants and provide the rationale for their integration in future three-dimensional skin models. PMID- 25828469 TI - Jean Delay Prize for Professor Mitsumoto Sato. PMID- 25828470 TI - Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety. AB - Although ASIC4 is a member of the acid-sensing ion channel (ASIC) family, we have limited knowledge of its expression and physiological function in vivo. To trace the expression of this ion channel, we generated the ASIC4-knockout/CreERT(2) knockin (Asic4(Cre) (ERT) (2)) mouse line. After tamoxifen induction in the Asic4(Cre) (ERT)(2)::CAG-STOP(floxed)-Td-tomato double transgenic mice, we mapped the expression of ASIC4 at the cellular level in the central nervous system (CNS). ASIC4 was expressed in many brain regions, including the olfactory bulb, cerebral cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, brain stem, cerebellum, spinal cord and pituitary gland. Colocalisation studies further revealed that ASIC4 was expressed mainly in three types of cells in the CNS: (i) calretinin (CR)-positive and/or vasoactive intestine peptide (VIP)-positive interneurons; (ii) neural/glial antigen 2 (NG2)-positive glia, also known as oligodendrocyte precursor cells; and (iii) cerebellar granule cells. To probe the possible role of ASIC4, we hypothesised that ASIC4 could modulate the membrane expression of ASIC1a and thus ASIC1a signaling in vivo. We conducted behavioral phenotyping of Asic4(Cre) (ERT)(2) mice by screening many of the known behavioral phenotypes found in Asic1a knockouts and found ASIC4 not involved in shock-evoked fear learning and memory, seizure termination or psychostimulant-induced locomotion/rewarding effects. In contrast, ASIC4 might play an important role in modulating the innate fear response to predator odor and anxious state because ASIC4-mutant mice showed increased freezing response to 2,4,5-trimethylthiazoline and elevated anxiety-like behavior in both the open-field and elevated-plus maze. ASIC4 may modulate fear and anxiety by counteracting ASIC1a activity in the brain. PMID- 25828471 TI - Why is it so difficult to recruit patients to research in emergency care? Lessons from the AHEAD study. AB - INTRODUCTION: In February 2014, all 23 National Institute for Health Research medical research specialities were failing to meet recruitment targets, with 'Injuries and Emergencies' research performing particularly poorly. In this paper, the multicentre AHEAD study was used to explore issues surrounding recruitment in UK emergency departments. METHOD: The AHEAD study investigated management and outcomes in over 3000 anticoagulated patients who suffered a head injury. Data from the study were used to compare patient recruitment at 33 Type-1 emergency departments. A questionnaire was sent to a research nurse at each of these sites and 30 replied (91% response rate). The survey investigated the difficulties encountered during patient recruitment and whether these were related to recruitment methods. More detailed interviews were conducted with three research nurses, to gain further insight into the barriers and facilitators involved. RESULTS: Overall recruitment varied widely between sites with an eightfold variation in recruitment rates. Population demographics and other uncontrollable factors will partly contribute to this variation. However, research nurses reported many problems, including site resources, lack of staff engagement and flaws in recruitment strategies, which could be improved. CONCLUSIONS: Many of the barriers to recruiting patients for research studies encountered by research nurses have previously been reported in the literature, but there remain consistent problems. Until solutions are found, researchers will continue to miss recruitment targets and this will have implications for the efficiency and quality of emergency medicine research in the UK. PMID- 25828472 TI - Stimulation of hepatocarcinogenesis by neutrophils upon induction of oncogenic kras expression in transgenic zebrafish. AB - BACKGROUND & AIMS: Chronic inflammation is a major etiological factor for hepatocellular carcinoma (HCC), but how immune cells respond in the initiation of hepatocarcinogenesis remains uncharacterized. This study aims to investigate the response and roles of neutrophils in early hepatocarcinogenesis. METHODS: By inducible expression of oncogenic kras(V12) in hepatocytes in transgenic zebrafish combined with live imaging of neutrophils in transparent larvae, the response of neutrophils to oncogenic liver was characterized and their roles investigated by pharmaceutical and genetic manipulations. RESULTS: We found a rapid recruitment of neutrophils to the liver upon induction of kras(V12) expression. Pharmaceutical stimulation of neutrophils resulted in further increases of neutrophils in oncogenic livers, liver size and tumor severity, while inhibition of neutrophils caused decreases of liver-associated neutrophils and liver size. Time-lapse video indicated that neutrophils had a stagnant migratory pattern meandering along the tumor edge but became relatively stationary upon entering the kras(V12)-expressing liver. Both oncogenic hepatocytes and tumor-associated neutrophils (TANs) were isolated via fluorescence-activated cell sorting. Molecular analyses indicated a pro inflammatory microenvironment, as marked by increased tgfbeta1a expression in kras(V12)-expressing hepatocytes and a loss of anti-tumor activities in TANs. Depletion of Tgf-beta significantly reduced the number of TANs and the size of oncogenic liver. CONCLUSIONS: An inflammatory cue from oncogenic hepatocytes upon induction of kras(V12) expression causes a rapid recruitment of neutrophils to oncogenic liver and the neutrophils play a promoting role in early hepatocarcinogenesis. PMID- 25828473 TI - Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features. AB - BACKGROUND & AIMS: Overexpression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma (HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in HCC through epigenetic silencing of the Ras regulators. We investigated the roles of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features. METHODS: We employed a transgenic mouse model that expresses the oncogenic Ras in the liver. That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were analyzed. Also, FoxM1 siRNA was used in human HCC cell lines to determine its role in the survival of the HCC cells with stem cell features. RESULTS: Ras-driven tumors overexpress FoxM1. Deletion of FoxM1 inhibits HCC progression. There was increased accumulation of reactive oxygen species (ROS) in the FoxM1 deleted HCC cells. Moreover, FoxM1 deletion caused a disproportionate loss of the CD44+ and EpCAM+ HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44 in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted to FoxM1 for ROS regulation and survival. CONCLUSION: Our results provide genetic evidence for an essential role of FoxM1 in the progression of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with stem cell features by regulating ROS. PMID- 25828474 TI - Intussusception of the Meckel's diverticulum within its own lumen: Unknown complication. AB - INTRODUCTION: Intussusception with the Meckel's diverticulum (MD) is a rare cause of chonic abdominal pain in the adults. We wish to present this first case of intussusception of MD within its own lumen without small bowel obstruction. PRESENTATION OF CASE: We report the case of a 27-year-old man who was admitted to the emergency room due to a diffuse abdominal pain. Abdominal CT scan showed invagination of MD. The exploratory laparoscopy revealed the presence of intussusception of MD within its own lumen. Segmental resection of the small intestine was performed. The patient was discharged on the third post-operative day. DISCUSSION: The prevalence of MD is 1 to 4%. Diagnosis is often difficult and delayed because clinical symptoms are not specific and the diagnosis is performed mainly by imaging studies. Factors pre-disposing these patients to intussusception of MD within its own lumen include a narrow diverticulum, large diverticululm, and associated inflammation of the diverticulum. Intestinal obstruction is a more common complication in adults, whereas in children, bleeding is the more common complication. In our case, the patient had a diffuse abdominal pain without small bowel obstruction because the intussusception of MD was within its own lumen. Laparoscopy may be useful for confirming the presence of intussusception, and demonstrating the underlying organic lesion serving as the lead point. CONCLUSION: It is important to differentiate this rare pathological feature of MD from other entities as the treatment is surgical rather than medical. Abdominal surgeons should bear in mind this rare entity. PMID- 25828475 TI - Femoral herniation of transplanted ureter after deceased-donor kidney transplantation. AB - INTRODUCTION: Herniation of the ureter after kidney transplant is a rare and under documented event. Many of these herniations are due to abdominal wall defects or ureteral redundancy. After an extensive review of available literature, there has not been a reported case of a femoral herniation of ureter after kidney transplant. We report a case of late allograft renal transplant failure due to ureteral obstruction secondary to femoral herniation of the ureter. CASE PRESENTATION: We report a case of 64 year old male with a history of kidney transplant, who was found to have an inguinal bulge. He was diagnosed with a femoral hernia containing transplant ureter using transplant kidney ultrasound and CT of the abdomen and pelvis. Subsequently he developed transplant kidney failure due to obstructive uropathy from the femoral hernia. The patient underwent a femoral hernia repair with biologic mesh. Compromised ureter was excised and a neoureterocystostomy was created. Post operatively his creatinine returned to baseline. DISCUSSION: In our literature search there are two types of inguinal ureteral hernias described. Paraperitoneal, which makes up the majority of the cases, and extraperitoneal. There are no classifications for ureteral femoral hernias. We may extract these definitions to femoral hernias, as evidenced by our case where we encountered a paraperitoneal femoral hernia containing transplant kidney ureter. CONCLUSION: To the best of our knowledge this is the first reported case of a femoral ureter hernia. Due to its rarity in the literature, an understanding of management is critical to patient outcome. PMID- 25828476 TI - A pancreatic pseudopapillary tumor enucleated curatively. AB - INTRODUCTION: Pseudopapillary tumors (PPT) of the pancreas are very rare, comprising 0.3-2.7% of all pancreatic tumors, and they occur mostly in young women. Generally, they are benign, but in rare cases they can enlarge, invade adjacent organs, and metastasize distantly. Radiological assessments and biochemical markers are important for diagnosing tumor characteristics. The main treatment is tumor resection. PRESENTATION OF CASE: An 18-year-old female was referred to our department suffering from abdominal discomfort and upper quadrant abdominal pain. Abdominal computed tomography (CT) revealed a 6-*5-cm mass between the pancreatic head and right adrenal gland (Fig. 1). The histological assessment was a solid PPT of the pancreas with intact surgical borders. DISCUSSION: PPT are very rare, comprising approximately 5% of cystic pancreatic tumors and ~1% of exocrine pancreatic neoplasms and present mainly during the second and third decades of life. PPTs are usually indolent tumors. As such, they tend to produce vague nonspecific symptoms or may be detected incidentally on imaging. Complete surgical resection (R0) is the most effective therapy for PPT. CONCLUSION: Although PPT is a very rare, benign tumor, it has the potential to metastasize to adjacent and distant organs. Consequently, they should be detected early, so that they can be treated surgically before malignant conversion. PMID- 25828477 TI - Fat infiltration of paraspinal muscles is associated with low back pain, disability, and structural abnormalities in community-based adults. AB - BACKGROUND CONTEXT: Low back pain and disability are major public health problems and may be related to paraspinal muscle abnormalities, such as a reduction in muscle size and muscle fat content. PURPOSE: The aim of this study was to examine the associations between paraspinal muscle size and fat content with lumbar spine symptoms and structure. STUDY DESIGN/SETTING: This was a community-based magnetic resonance imaging (MRI) cohort study. PATIENT SAMPLE: A total of 72 adults not selected on the basis of low back pain were included in the study. OUTCOME MEASURES: The outcomes measured were lumbar modic change and intervertebral disc height. Pain intensity and disability were measured from the Chronic Pain Grade Questionnaire at the time of MRI. METHODS: The cross-sectional area (CSA) and amount of fat in multifidus and erector spinae (high percentage defined by >50% of muscle) were measured, and their association with outcome was assessed. RESULTS: Muscle CSA was not associated with low back pain/disability or structure. High percentage of fat in multifidus was associated with an increased risk of high-intensity pain/disability (odds ratio [OR], 12.6; 95% confidence interval [CI], 2.0-78.3; p=.007) and modic change (OR, 4.3; 95% CI, 1.1-17.3; p=.04). High fat replacement of erector spinae was associated with reduced intervertebral disc height (beta=-0.9 mm; 95% CI, -1.4 to -0.3; p=.002) and modic change (OR, 4.9; 95% CI, 1.1-21.9; p=.04). CONCLUSIONS: Paraspinal fat infiltration, but not muscle CSA, was associated with high-intensity pain/disability and structural abnormalities in the lumbar spine. Although cause and effect cannot be determined from this cross-sectional study, longitudinal data will help to determine whether disabling low back pain and structural abnormalities of the spine are a cause or result of fat replacement of paraspinal muscles. PMID- 25828478 TI - Short-segment percutaneous pedicle screw fixation with cement augmentation for tumor-induced spinal instability. AB - BACKGROUND CONTEXT: Pathologic vertebral compression fractures (VCFs) represent a major source of morbidity and diminished quality of life in the spinal oncology population. Procedures with low morbidity that effectively treat patients with pathologic fractures are especially important in the cancer population where life expectancy is limited. Vertebroplasty and kyphoplasty are often not effective for mechanically unstable pathologic fractures extending into the pedicle and facet joints. Combination of cement augmentation and percutaneous instrumented stabilization represents a minimally invasive treatment option that does not delay radiation and systemic therapy. PURPOSE: The objective of the study was to evaluate the safety and efficacy of cement-augmented short-segment percutaneous posterolateral instrumentation for tumor-associated VCF with pedicle and joint involvement. METHODS: Forty-four consecutive patients underwent cement-augmented percutaneous spinal fixation for unstable tumors between 2011 and 2014. Retrospective analysis of prospectively collected data, including visual analog pain scale (VAS) response score and procedural complications, was performed. RESULTS: Patients with a median composite Spinal Instability Neoplastic Scale score of 10 (range=8-15) were treated with constructs spanning one to four disk spaces (median of two spaces, constituting 84% of all cases). The proportion of patients with severe pain decreased from 86% preoperatively to 0%; 65% of patients reported no referable instability pain postoperatively. There was one adjacent-level fracture responsive to kyphoplasty, and one case of asymptomatic screw pullout. Two patients subsequently required decompression in the setting of disease progression despite radiation; there was no perioperative morbidity. CONCLUSIONS: Percutaneous cement-augmented posterolateral spinal fixation is a safe and effective option for palliation of appropriately selected mechanically unstable VCF that extends into pedicle and/or joint. PMID- 25828479 TI - Water immersion-induced skin wrinkling test in complex regional pain syndrome. PMID- 25828480 TI - Response. PMID- 25828481 TI - Plant-based oral delivery of beta-glucocerebrosidase as an enzyme replacement therapy for Gaucher's disease. AB - Gaucher's disease (GD), a lysosomal storage disorder caused by mutations in the gene encoding glucocerebrosidase (GCD), is currently treated by enzyme replacement therapy (ERT) using recombinant GCD that is administered intravenously every 2 weeks. However, intravenous administration includes discomfort or pain and might cause local and systemic infections that may lead to low patient compliance. An orally administered drug has the potential to alleviate these problems. In this study, we describe the potential use of plant cells as a vehicle for the oral delivery of recombinant human GCD (prGCD) expressed in carrot cells. The in vitro results demonstrate that the plant cells protect the recombinant protein in the gastric fluids and may enable absorption into the blood. Feeding experiments, with rat and pig as model animals, using carrot cells containing prGCD, show that active recombinant prGCD was found in the digestive tract and blood system and reached both, liver and spleen, the target organs in GD. These results demonstrate that the oral administration of proteins encapsulated in plant cells is feasible. Specifically, carrot cells containing recombinant human prGCD can be used as an oral delivery system and are a feasible alternative to intravenous administration of ERT for GD. PMID- 25828482 TI - Relationships between maternal overweight prior to pregnancy, feeding mode and infant feeding beliefs and practices. AB - AIM: This study aimed to examine whether pre-pregnancy weight status was associated with maternal feeding beliefs and practices in the early post-partum period. METHODS: This study uses secondary analysis of longitudinal data from Australian mothers. Participants (n = 486) were divided into two weight status groups based on self-reported pre-pregnancy weight and measured height: healthy weight (body mass index (BMI) <25 kg/m(2) ; n = 321) and overweight (BMI > 25 kg/m(2) ; n = 165). Feeding beliefs and practices were self-reported via an established questionnaire that assessed concerns about infant overeating and undereating, awareness of infant cues, feeding to a schedule and using food to calm. RESULTS: Infants of overweight mothers were more likely to have been given solid foods in the previous 24 h (29% vs. 20%) and fewer were fully breastfed (50% vs. 64%). Multivariable regression analyses (adjusted for maternal education, parity, average infant weekly weight gain, feeding mode and introduction of solids) revealed that pre-pregnancy weight status was not associated with using food to calm, concern about undereating, awareness of infant cues or feeding to a schedule. However, feeding mode was associated with feeding beliefs and practices. CONCLUSIONS: Although no evidence for a relationship between maternal weight status and early maternal feeding beliefs and practices was observed, differences in feeding mode and early introduction of solids were observed. The emergence of a relationship between feeding practices and maternal weight status may occur when the children are older, solid feeding is established and they become more independent in feeding. PMID- 25828483 TI - Periodic Epileptiform Discharges in Children With Advanced Stages of Progressive Myoclonic Epilepsy. AB - Huntington's disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA) are monogenic forms of neurodegenerative disorders with autosomal dominant inheritance. Compared with adult-onset HD and DRPLA, children with these disorders are more severely affected and are known to manifest the devastating symptoms of progressive myoclonic epilepsy (PME) syndrome. In this report, we present a 6-year-old girl with HD from a family, and 2 siblings with DRPLA from another unrelated family. Serial neuroimaging and electroencephalography (EEG) studies showed that periodic epileptiform discharges and synchronized paroxysmal activity became prominent with their disease progression. Periodic complexes in EEG may emerge at advanced stages of childhood PME as a consequence of rapidly degenerating processes of their brain functions. PMID- 25828484 TI - Clinical, Electroencephalographic, and Neuroradiological Outcome Predictors in Acute Nonhypoxic Encephalopathy: A Nine-Year Cohort Study. AB - Marked impairment of consciousness, brain lesion on neuroimaging, and nonreactive electroencephalographic (EEG) background activity are established outcome predictors in patients with hypoxic encephalopathy. In this observational cohort study, we aimed to assess the predictive value of clinical, neuroimaging and EEG characteristics for outcome in different types of acute nonhypoxic encephalopathic patients. All adult intensive care unit patients from a tertiary academic medical care center with clinical and EEG evidence of acute nonhypoxic encephalopathy were included from 2004 to 2012. Clinical data, neuroimaging studies, EEG characteristics, and outcome were assessed. In-hospital death was the main outcome. Median age of 262 patients was 65 years (range 18-98 years). Mortality was 12.6%. In Poisson regression analyses, older age (P=.02), intracranial hemorrhage (P=.008), coma (P=.012), and nonreactive EEG background activity (P<.0001) were independently associated with death with nonreactive EEG being the strongest predictor (relative risk 3.74; 95% confidence interval 2.02 6.91). Subgroup analysis revealed no significant effect modification for the predictive value of nonreactive EEG by the presence or absence of coma and different types of acute brain lesions. In conclusion, this study identifies and quantifies the independent predictive value of older age, intracranial hemorrhage, coma, and nonreactive EEG for death, in patients with different types of acute nonhypoxic encephalopathy. These results add further credence to the limited body of evidence that EEG provides important prognostic information in different types of acute encephalopathy not related to hypoxic brain injury. Further studies are warranted to analyze the robustness of this predictor in larger subpopulations with specific etiologies of acute nonhypoxic encephalopathies. PMID- 25828485 TI - Introduction: craniocervical junction. PMID- 25828486 TI - Minimally invasive approach for small ventrally located intradural lesions of the craniovertebral junction. AB - OBJECT: The surgical management of lesions ventral to the neuraxis at the level of the craniovertebral junction (CVJ) and upper cervical spine is challenging. Here, the authors describe a minimally invasive dorsal approach for small ventrally located intradural lesions at the CVJ as an alternative for the more extensive classic transoral approach or variants of suboccipital approaches. METHODS: Between 2012 and 2014, 6 symptomatic patients with a small lesion of the ventral aspect at the CVJ level were treated using a minimally invasive dorsal approach at the University Medical Center in Hamburg-Eppendorf, Germany. The anatomical distance between the posterior atlantooccipital membrane and the posterior atlantoaxial ligament, as determined by CT images, was assessed in the treated patients and in 100 untreated persons. RESULTS: The authors treated 6 patients (mean age 54.7 years) who had a clinical presentation of mild neurological symptoms that disappeared after resection. Minimally invasive surgical dorsal access was achieved by using tubular systems and using the natural space between the occiput (C-0) and C-1, and in 1 case between C-1 and C 2, without having to remove bony structures. The postoperative course in each of the 6 patients was uneventful. The neuropatho-logical findings confirmed a meningotheliomatous meningioma (WHO Grade I) in 5 cases and an extramedullary cavernous hemangioma in 1 case. MRI confirmed complete resection of all the lesions. The atlantooccipital distances ranged from 3 to 17 mm (mean 8.98 mm) in the supine neutral position, and the atlantoaxial distances ranged from 5 to 17 mm (mean 10.56 mm). There were no significant differences between women and men (atlantooccipital p = 0.14; atlantoaxial p = 0.72). CONCLUSIONS: The results of this study demonstrate that the minimally invasive dorsal approach using the space between C-0 and C-1 or C-1 and C-2 provides direct and sufficient exposure for the safe surgical resection of small ventrally located intradural lesions at the CVJ level while reducing the necessity for musculoskeletal preparation to a minimum. PMID- 25828487 TI - Surgical treatment of Type II odontoid fractures: anterior odontoid screw fixation or posterior cervical instrumented fusion? AB - Odontoid fractures comprise as many as 20% of all cervical spine fractures. Fractures at the dens base, classified by the Anderson and D'Alonzo system as Type II injuries, are the most common pattern of all odontoid fractures and are also the most common cervical injuries in patients older than 70 years of age. Surgical treatment is recommended for patients older than 50 years with Type II odontoid fractures, as well as in patients at a high risk for nonunion. Anterior odontoid screw fixation (AOSF) and posterior cervical instrumented fusion (PCIF) are both well-accepted techniques for surgical treatment but with unique indications and contraindications as well as varied reported outcomes. In this paper, the authors review the literature about specific patients and fracture characteristics that may guide treatment toward one technique over the other. AOSF can preserve atlantoaxial motion, but requires a reduced odontoid, an intact transverse ligament, and a favorable fracture line to achieve adequate fracture compression. Additionally, older patients may have a higher rate of pseudarthrosis using this technique, as well as postoperative dysphagia. PCIF has a higher rate of fusion and is indicated in patients with severe atlantoaxial misalignment and with poor bone quality. PCIF allows direct open reduction of displaced fragments and can reduce any atlantoaxial subluxation. It is also used as a salvage procedure after failed AOSF. However, this technique results in loss of atlantoaxial motion, requires prone positioning, and demands a longer operative duration than AOSF, factors that can be a challenge in patients with severe medical conditions. Although both anterior and posterior approaches are acceptable, many clinical and radiological factors should be taken into account when choosing the best surgical approach. Surgeons must be prepared to perform both procedures to adequately treat these injuries. PMID- 25828488 TI - Chiari I malformation with and without basilar invagination: a comparative study. AB - OBJECT: Chiari I malformation is the most common craniocervical malformation. Its combination with basilar invagination in a significant proportion of patients is well established. This study presents surgical results for patients with Chiari I malformation with and without additional basilar invagination. METHOD: Three hundred twenty-three patients underwent 350 operations between 1985 and 2013 (mean age 43 +/- 16 years, mean history of symptoms 64 +/- 94 months). The clinical courses were documented with a score system for individual neurological symptoms for short-term results after 3 and 12 months. Long-term outcomes were analyzed with Kaplan-Meier statistics. The mean follow-up was 53 +/- 58 months (the means are expressed +/- SD). RESULTS: Patients with (n = 46) or without (n = 277) basilar invagination in addition to Chiari I malformation were identified. Patients with invagination were separated into groups: those with (n = 31) and without (n = 15) ventral compression by the odontoid in the foramen magnum. Of the 350 operations, 313 dealt with the craniospinal pathology, 28 surgeries were undertaken for degenerative diseases of the cervical spine, 3 were performed for hydrocephalus, and 6 syrinx catheters were removed for cord tethering. All craniospinal operations included a foramen magnum decompression with arachnoid dissection, opening of the fourth ventricle, and a duraplasty. In patients without invagination, craniospinal instability was detected in 4 individuals, who required additional craniospinal fusion. In patients with invagination but without ventral compression, no stabilization was added to the decompression. In all patients with ventral compression, craniospinal stabilization was performed with the foramen magnum decompression, except for 4 patients with mild ventral compression early in the series who underwent posterior decompression only. Among those with ventral compression, 9 patients with caudal cranial nerve dysfunctions underwent a combination of transoral decompression with posterior decompression and fusion. Within the 1st postoperative year, neurological scores improved for all symptoms in each patient group, with the most profound improvement for occipital pain. In the long term, late postoperative deteriorations were related to reobstruction of CSF flow in patients without invagination (18.3% in 10 years), whereas deteriorations in patients with invagination (24.9% in 10 years) were exclusively related either to instabilities becoming manifest after a foramen magnum decompression or to hardware failures. Results for ventral and posterior fusions for degenerative disc diseases in these patients indicated a trend for better long-term results with posterior operations. CONCLUSIONS: The great majority of patients with Chiari I malformations with or without basilar invagination report postoperative improvements with this management algorithm. There were no significant differences in short-term or long-term outcomes between these groups. Chiari I malformations without invagination and those with invaginations but without ventral compression can be managed by foramen magnum decompression alone. The majority of patients with ventral compression can be treated by posterior decompression, realignment, and stabilization, reserving anterior decompressions for patients with profound, symptomatic brainstem compression. PMID- 25828489 TI - Dyspnea and dysphagia from upper airway obstruction after occipitocervical fusion in the pediatric age group. AB - Upper airway obstruction resulting from overflexion of the craniocervical junction after occipitocervical fusion is a rare but potentially life-threatening complication and is associated with morbidity. The authors retrospectively reviewed the medical records and diagnostic images of 2 pediatric patients who underwent occipitocervical fusion by the Neuro-Spine Program at Texas Children's Hospital and experienced dyspnea and/or dysphagia from new upper airway obstruction in the postoperative period. Patient demographics, operative data, and preoperative and postoperative occiput-C2 angles were recorded. A review of the literature for similar complications after occipitocervical fusion was performed. A total of 13 cases of prolonged upper airway obstruction after occipitocervical fusion were analyzed. Most of these cases involved adults with rheumatoid arthritis. To the best of the authors' knowledge, there have been no previous reports of prolonged upper airway obstruction in children after an occipitocervical fusion. Fixation of the neck in increased flexion (-18 degrees to -5 degrees ) was a common finding among these adult and pediatric cases. The authors' cases involved children with micrognathia and comparatively large tongues, which may predispose the oropharynx to obstruction with even the slightest amount of increased flexion. Close attention to a satisfactory fixation angle (occiput-C2 angle) is necessary to avoid airway obstruction after an occipitocervical fusion. Children with micrognathia are particularly sensitive to changes in flexion at the craniocervical junction after occipitocervical fixation. PMID- 25828490 TI - "Lazy" far-lateral approach to the anterior foramen magnum and lower clivus. AB - The far-lateral approach (FLA) has become a mainstay for skull base surgeries involving the anterior foramen magnum and lower clivus. The authors present a surgical technique using the FLA for the management of lesions of the anterior/ anterolateral foramen magnum and lower clivus. The authors consider this modification a "lazy" FLA. The vertebral artery (VA) is both a critical anatomical structure and a barrier that limits access to this region. The most important nuance of this FLA technique is the management of this critical vessel. When the lazy FLA is used, the VA is reflected laterally, encased in its periosteal sheath and wrapped in the dura, greatly minimizing the risk for vertebral injury while preserving a wide working space. To accomplish this step, drilling is performed lateral to the point where the VA pierces the dura. The dura is incised medial to the VA entry point by using a slightly curved longitudinal cut. Drilling of the condyle and the C-1 lateral mass is performed in a manner that preserves craniocervical stability. The lazy FLA is a true FLA that is based on manipulation of the VA and lateral bone removal to obtain excellent exposure ventral to the spinal cord and medulla, yet it is among the most conservative FLA techniques for management of the VA and provides a safer window for bone work and lesion management. Among 44 patients for whom this technique was used to resect 42 neoplasms and clip 2 posterior inferior cerebral artery aneurysms, there was no surgical mortality and no injury to the VA. PMID- 25828491 TI - Endoscopic endonasal approach for craniovertebral junction pathology: a review of the literature. AB - OBJECT: The transoral approach is the gold standard for ventral decompression of the brainstem caused by craniovertebral junction (CVJ) pathology. This approach is often associated with significant morbidity, related to swallowing and respiratory complications. The endoscopic endonasal approach was introduced to reduce the rate of these complications. However, the exact role of this approach in the treatment of CVJ pathology is not well defined. METHODS: A comprehensive literature search was performed to identify series of patients with pathology of the CVJ treated via the endoscopie endonasal approach. Data on patient characteristics, indications for treatment, complications, and outcome were obtained and analyzed. RESULTS: Twelve studies involving 72 patients were included. The most common indications for treatment were rheumatoid pannus (38.9%) and basilar invagination (29.2%). Cerebrospinal fluid leak was found in 18% of cases intraoperatively and 4.2% of cases postoperatively. One case of meningitis complicated by sepsis and death represents the procedure-related mortality of 1.4%. Of the patients without preoperative swallowing impairment, 95% returned to oral feeding on the 3rd postoperative day. Ninety-three percent of patients experienced improvement in neurological symptoms after the procedure. CONCLUSIONS: The endonasal endoscopie approach is effective for the treatment of neural compression caused by CVJ pathology. It offers advantages such as lower rates of postoperative dysphagia and respiratory complications when compared with the more traditional transoral approach. However, these 2 approaches should be seen as complementary rather than alternatives. Patient-related factors as well as the surgeon's expertise must be considered when making treatment decisions. PMID- 25828492 TI - The rhinopalatine line as a reliable predictor of the inferior extent of endonasal odontoidectomies. AB - OBJECT: The endoscopic endonasal approach (EEA) provides a minimally invasive corridor through which the cervicomedullary junction can be decompressed with reduced morbidity rates compared to those with the classic transoral approaches. The limit of the EEA is its inferior extent, and preoperative estimation of its reach is vital for determining its suitability. The aim of this study was to evaluate the actual inferior limit of the EEA in a surgical series of patients and develop an accurate and reliable predictor that can be used in planning endonasal odontoidectomies. METHODS: The actual inferior extent of surgery was determined in a series of 6 patients with adequate preoperative and postoperative imaging who underwent endoscopie endonasal odontoidectomy. The medians of the differences between several previously described predictive lines, namely the nasopalatine line (NPL) and nasoaxial line (NAxL), were compared with the actual surgical limit and the hard-palate line by using nonparametric statistics. A novel line, called the rhinopalatine line (RPL), was established and corresponded best with the actual limit of the surgery. RESULTS: There were 4 adult and 2 pediatric patients included in this study. The NPL overestimated the inferior extent of the surgery by an average (+/- SD) of 21.9 +/- 8.1 mm (range 14.7-32.5 mm). The NAxL and RPL overestimated the inferior limit of surgery by averages of 6.9 +/- 3.8 mm (range 3.7-13.3 mm) and 1.7 +/- 3.7 mm (range -2.8 to 8.3 mm), respectively. The medians of the differences between the NPL and NAxL and the actual surgery were statistically different (both p = 0.0313). In contrast, there was no statistically significant difference between the RPL and the inferior limit of surgery (p = 0.4375). CONCLUSIONS: The RPL predicted the inferior limit of the EEA to the craniovertebral junction more accurately than previously described lines. The use of the RPL may help surgeons in choosing suitable candidates for the EEA and in selecting those for whom surgery through the oropharynx or the facial bones is the better approach. PMID- 25828493 TI - Endoscopic endonasal transclival transodontoid approach for ventral decompression of the craniovertebral junction: operative technique and nuances. AB - The transoral approach is considered the gold-standard surgical route for performing anterior odontoidectomy and ventral decompression of the craniovertebral junction for pathological conditions that result in symptomatic cervicomedullary compression, including basilar invagination, rheumatoid pannus, platybasia with retroflexed odontoid processes, and neoplasms. Extended modifications to increase the operative corridor and exposure include the transmaxillary, extended "open-door" maxillotomy, transpalatal, and transmandibular approaches. With the advent of extended endoscopic endonasal skull base techniques, there has been increased interest in the last decade in the endoscopic endonasal transclival transodontoid approach to the craniovertebral junction. The endonasal route represents an attractive minimally invasive surgical alternative, especially in cases of irreducible basilar invagination in which the pathology is situated well above the palatine line. Angled endoscopes and instrumentation can also be used for lower-lying pathology. By avoiding the oral cavity and subsequently using a transoral retractor, the endonasal route has the advantages of avoiding complications related to tongue swelling, tracheal swelling, prolonged intubation, velopharyngeal insufficiency, dysphagia, and dysphonia. Postoperative recovery is quicker, and hospital stays are shorter. In this report, the authors describe and illustrate their method of purely endoscopic endonasal transclival odonotoidectomy for anterior decompression of the craniovertebral junction and describe various operative pearls and nuances of the technique for avoiding complications. PMID- 25828494 TI - Pooled data analysis on anterior versus posterior approach for rheumatoid arthritis at the craniovertebral junction. AB - OBJECT: Rheumatoid arthritis (RA) is one of the most debilitating autoimmune diseases affecting the craniovertebral junction (CVJ). Patients predominantly present with myelopathic symptoms and intractable neck pain. The surgical approach traditionally has been either a combined anterior and posterior approach or a posterior-only approach. In this article, the authors review pooled data from the literature and discuss the benefits of the two types of approaches. METHODS: A search of the PubMed database was conducted using key words that describe spine deformities in RA and specific spinal interventions. The authors evaluated the neurological outcomes based on the Ranawat scale in both the groups through chi-square analysis. Multiple logistic regression was carried out to further examine for potential confounders. Any adverse sequalae resulting from either approach were also documented. Because all the procedures performed via a transoral approach in the analyzed articles also involved posterior fixation, for convenience of comparison, the combined procedures are referred to as "anterior approach" or "anterior-posterior" in the present study. RESULTS: The search yielded 233 articles, of which 11 described anterior approaches and 14 evaluated posterior approaches. The statistical analysis showed that patients treated with a posterior approach fared better than those treated with an anterior (combined) approach. It was noted that those patients in whom the cervical subluxations were reducible on traction predominantly underwent posterior approaches. CONCLUSIONS: CVJ instability is a serious complication of RA that requires surgical intervention. Although the anterior-posterior combined approach can provide direct decompression, it is associated with morbidity, and the analysis showed no statistically significant benefit to patients. In contrast, the posterior approach has been shown to provide statistically significant superiority with respect to stabilization and subsequent pannus reduction. Surgical approaches are undertaken based on the reducibility of subluxations with traction and the vector of compressive force. However, the choice of surgical approach should be based on the individual patient's pathology. PMID- 25828495 TI - National trends of incidence, treatment, and hospital charges of isolated C-2 fractures in three different age groups. AB - OBJECT: Incidence of C-2 fracture is increasing in elderly patients. Patient age also influences decision making in the management of these fractures. There are very limited data on the national trends of incidence, treatment interventions, and resource utilization in patients in different age groups with isolated C-2 fractures. The aim of this study is to investigate the incidence, treatment, complications, length of stay, and hospital charges of isolated C-2 fracture in patients in 3 different age groups by using the Nationwide Inpatient Sample (NIS) database. METHODS: The data were obtained from NIS from 2002 to 2011. Data on patients with closed fractures of C-2 without spinal cord injury were extracted using ICD-9-CM diagnosis code 805.02. Patients with isolated C-2 fractures were identified by excluding patients with other associated injuries. The cohort was divided into 3 age groups: < 65 years, 65-80 years, and > 80 years. Incidence, treatment characteristics, inpatient/postoperative complications, and hospital charges (mean and total annual charges) were compared between the 3 age groups. RESULTS: A total of 10,336 patients with isolated C-2 fractures were identified. The majority of the patients were in the very elderly age group (> 80 years; 42.3%) followed by 29.7% in the 65- to 80-year age group and 28% in < 65-year age group. From 2002 to 2011, the incidence of hospitalization significantly increased in the 65- to 80-year and > 80-year age groups (p < 0.001). However, the incidence did not change substantially in the < 65-year age group (p = 0.287). Overall, 21% of the patients were treated surgically, and 12.2% of the patients underwent nonoperative interventions (halo and spinal traction). The rate of nonoperative interventions significantly decreased over time in all age groups (p < 0.001). Regardless of treatment given, patients in older age groups had a greater risk of inpatient/postoperative complications, nonroutine discharges, and longer hospitalization. The mean hospital charges were significantly higher in older age groups (p < 0.001). CONCLUSIONS: The incidence of hospitalization for isolated C-2 fractures is progressively increasing in older age groups. Simultaneously, there has been a steadily decreasing trend in the preference for nonoperative interventions. Due to more complicated hospital stay, longer hospitalizations, and higher rates of nonroutine discharges, the patients in older age groups seem to have a higher propensity for greater health care resource utilization. PMID- 25828496 TI - Anatomy and biomechanics of the craniovertebral junction. AB - The craniovertebral junction (CVJ) has unique anatomical structures that separate it from the subaxial cervical spine. In addition to housing vital neural and vascular structures, the majority of cranial flexion, extension, and axial rotation is accomplished at the CVJ. A complex combination of osseous and ligamentous supports allow for stability despite a large degree of motion. An understanding of anatomy and biomechanics is essential to effectively evaluate and address the various pathological processes that may affect this region. Therefore, the authors present an up-to-date narrative review of CVJ anatomy, normal and pathological biomechanics, and fixation techniques. PMID- 25828497 TI - Magnetic resonance imaging of traumatic injury to the craniovertebral junction: a case-based review. AB - OBJECT: The craniovertebral junction (CVJ) is unique in the spinal column regarding the degree of multiplanar mobility allowed by its bony articulations. A network of ligamentous attachments provides stability to this junction. Although ligamentous injury can be inferred on CT scans through the utilization of craniometric measurements, the disruption of these ligaments can only be visualized directly with MRI. Here, the authors review the current literature on MRI evaluation of the CVJ following trauma and present several illustrative cases to highlight the utility and limitations of craniometric measures in the context of ligamentous injury at the CVJ. METHODS: A retrospective case review was conducted to identify patients with cervical spine trauma who underwent cervical MRI and subsequently required occipitocervical or atlantoaxial fusion. Craniometric measurements were performed on the CT images in these cases. An extensive PubMed/MEDLINE literature search was conducted to identify publications regarding the use of MRI in the evaluation of patients with CVJ trauma. RESULTS: The authors identified 8 cases in which cervical MRI was performed prior to operative stabilization of the CVJ. Craniometric measures did not reliably rule out ligamentous injury, and there was significant heterogeneity in the reliability of different craniometric measurements. A review of the literature revealed several case series and descriptive studies addressing MRI in CVJ trauma. Three papers reported the inadequacy of the historical Traynelis system for identifying atlantooccipital dislocation and presented 3 alternative classification schemes with emphasis on MRI findings. CONCLUSIONS: Recognition of ligamentous instability at the CVJ is critical in directing clinical decision making regarding surgical stabilization. Craniometric measures appear unreliable, and CT alone is unable to provide direct visualization of ligamentous injury. Therefore, while the decision to obtain MR images in CVJ trauma is largely based on clinical judgment with craniometric measures used as an adjunct, a high degree of suspicion is warranted in the care of these patients as a missed ligamentous injury can have devastating consequences. PMID- 25828498 TI - Radiological evaluation of cervical spine involvement in rheumatoid arthritis. AB - Cervical spine involvement commonly occurs in patients with rheumatoid arthritis (RA), especially those with inadequate treatment or severe disease forms. The most common site affected by RA is the atlantoaxial joint, potentially resulting in atlantoaxial instability, with cervical pain and neurological deficits. The second most common site of involvement is the subaxial cervical spine, often with subluxation, resulting in nerve root or spinal cord compression. In this paper, the authors review the most commonly used plain radiographic criteria to diagnose cervical instabilities seen with RA. Finally, we discuss the advantages and disadvantages of cervical CT and MRI in the setting of cervical involvement in RA. PMID- 25828499 TI - Computed tomography evaluation of the normal craniocervical junction craniometry in 100 asymptomatic patients. AB - OBJECT: Most of the craniometric relationships of the normal craniocervical junction (CCJ), especially those related to angular craniometry, are still poorly studied and based on measurements taken from simple plain radiographs. In this study, the authors performed a craniometric evaluation of the CCJ in a population without known CCJ anomalies. The purpose of the study was to evaluate the normal CCJ craniometry based on measurements obtained from CT scans. METHOD: The authors analyzed 100 consecutive CCJ CT scans obtained in adult patients who were admitted at their tertiary hospital for treatment of non-CCJ conditions between 2010 and 2012. A total of 17 craniometrical measurements were performed, including the relation of the odontoid with the cranial base, the atlantodental interval (ADI), the clivus length, the clivus-canal angle (CCA)-the angle formed by the clivus and the upper cervical spine, and the basal angle. RESULTS: The mean age of the 100 patients was 50.6 years, and the group included 52 men (52%) and 48 women (48%). In 5 patients (5%), the tip of the odontoid process was more than 2 mm above the Chamberlain line, and in one of these 5 patients (1% of the study group). it was more than 5 mm above it. One patient had a Grabb-Oakes measurement above 9 mm (suggesting ventral cervicomedullary encroachment). The mean ADI value was 1.1 mm. The thickness of the external occipital protuberance ranged from 7.42 to 22.36 mm. The mean clivus length was 44.74 mm, the mean CCA was 153.68 degrees (range 132.32 degrees -173.95 degrees ), and the mean basal angle was 113.73 degrees (ranging from 97.06 degrees -133.26 degrees ). CONCLUSIONS: The data obtained in this study can be useful for evaluating anomalies of the CCJ in comparison with normal parameters, potentially improving the diagnostic criteria of these anomalies. When evaluating CCJ malformations, one should take into account the normal ranges based on CT scans, with more precise bone landmarks, instead of those obtained from simple plain radiographs. PMID- 25828500 TI - Motion-related vascular abnormalities at the craniocervical junction: illustrative case series and literature review. AB - The craniocervical junction (CCJ) functions within a complicated regional anatomy necessary to protect and support vital neurovascular structures. In select instances, vascular pathology can be attributed to this complicated interplay of motion and structure found within this narrow space. The authors report 3 cases of complex vascular pathology related to motion at the CCJ and detail the management of these cases. Two cases involved posterior circulation vascular compression syndromes, and one case involved a vascular anomaly and its relation to aneurysm formation and rupture. The patient in Case 1 was a 66-year-old man with a history of syncopal episodes resulting from the bilateral vertebral artery becoming occluded when he rotated his head. Successful microsurgical decompression at the skull base resulted in patent bilateral vertebral artery V3 segments upon head movement in all directions. The patient in Case 2 was a 53 year-old woman who underwent elective resection of a right temporal meningioma and who experienced postoperative drowsiness, dysphagia, and mild right-arm ataxia. Subsequent MRI demonstrated bilateral posterior inferior cerebel-lar artery (PICA) strokes. Cerebral angiography showed a single PICA, of extradural origin, supplying both cerebellar hemispheres. The PICA exhibited dynamic extradural compression when the patient rotated her head; the bilateral PICA strokes were due to head rotation during surgical positioning. In Case 3, a 37 year-old woman found unconscious in her home had diffuse subarachnoid hemorrhage and evidence of a right PICA aneurysm. A right far-lateral craniectomy was performed for aneurysm clipping, and she was found to have a dissecting aneurysm with an associated PICA originating extradurally. There was a shearing phenomenon of the extradural PICA along the dura of the foramen magnum, and this microtraumatic stress imposed on the vessel resulted in a dissecting aneurysm. This series of complex and unusual cases highlights the authors' understanding of vascular pathology of the CCJ and its management. PMID- 25828501 TI - Bow hunter's syndrome revisited: 2 new cases and literature review of 124 cases. AB - Rotational occlusion of the vertebral artery (VA), or bow hunter's syndrome, is a rare yet surgically treatable cause of vertebrobasilar insufficiency. The underlying pathology is dynamic stenosis of the VA by osteophytes, fibrous bands, or lateral disc herniation with neck rotation or extension. The authors present 2 previously unreported cases of bow hunter's syndrome and summarize 124 cases identified in a literature review. Both patients in the new cases were treated by VA decompression and fusion of the subaxial spine. Each had > 50% occlusion of the left VA at the point of entry into the transverse foramen with a contralateral VA that ended in the posterior inferior cerebellar artery. Analyzing data from 126 cases (the 2 new cases in addition to the previously published 124), the authors report that stenosis was noted within V1 in 4% of cases, in V2 in 58%, in V3 in 36%, and distal to C-1 in 2%. Patients presented in the 5th to 7th decade of life and were more often male than female. The stenotic area was decompressed in 85 (73%) of the 116 patients for whom the type of treatment was reported (V1, 4 [80%] of 5; V2, 52 [83%] of 63; V3/V4, 29 [60%] of 48). Less commonly, fusion or combined decompression and fusion was used (V2, 7 [11%] of 63; V3/V4, 14 [29%] of 48). Most patients reported complete resolution of symptoms. The authors conclude that patients with bow hunter's syndrome classically have an impaired collateral blood flow to the brainstem. This condition carries an excellent prognosis with decompression, fusion, or combined surgery, and individual patient characteristics should guide the choice of therapy. PMID- 25828502 TI - Evolution of transoral approaches, endoscopic endonasal approaches, and reduction strategies for treatment of craniovertebral junction pathology: a treatment algorithm update. AB - The craniovertebral junction (CVJ), or the craniocervical junction (CCJ) as it is otherwise known, houses the crossroads of the CNS and is composed of the occipital bone that surrounds the foramen magnum, the atlas vertebrae, the axis vertebrae, and their associated ligaments and musculature. The musculoskeletal organization of the CVJ is unique and complex, resulting in a wide range of congenital, developmental, and acquired pathology. The refinements of the transoral approach to the CVJ by the senior author (A.H.M.) in the late 1970s revolutionized the treatment of CVJ pathology. At the same time, a physiological approach to CVJ management was adopted at the University of Iowa Hospitals and Clinics in 1977 based on the stability and motion dynamics of the CVJ and the site of encroachment, incorporating the transoral approach for irreducible ventral CVJ pathology. Since then, approaches and techniques to treat ventral CVJ lesions have evolved. In the last 40 years at University of Iowa Hospitals and Clinics, multiple approaches to the CVJ have evolved and a better understanding of CVJ pathology has been established. In addition, new reduction strategies that have diminished the need to perform ventral decompressive approaches have been developed and implemented. In this era of surgical subspecialization, to properly treat complex CVJ pathology, the CVJ specialist must be trained in skull base transoral and endoscopic endonasal approaches, pediatric and adult CVJ spine surgery, and must understand and be able to treat the complex CSF dynamics present in CVJ pathology to provide the appropriate, optimal, and tailored treatment strategy for each individual patient, both child and adult. This is a comprehensive review of the history and evolution of the transoral approaches, extended transoral approaches, endoscopie assisted transoral approaches, endoscopie endonasal approaches, and CVJ reduction strategies. Incorporating these advancements, the authors update the initial algorithm for the treatment of CVJ abnormalities first published in 1980 by the senior author. PMID- 25828503 TI - Unilateral fixation for treatment of occipitocervical instability in children with congenital vertebral anomalies of the craniocervical junction. AB - OBJECT Patients with occipitocervical (OC) instability from congenital vertebral anomalies (CVAs) of the craniocervical junction (CCJ) often have bony abnormalities that make instrumentation placement difficult. Within this patient population, some bilateral instrumentation constructs either fail or are not feasible, and a unilateral construct must be used. The authors describe the surgical management and outcomes of this disorder in patients in whom unilateral fixation constructs were used to treat OC instability. METHODS From a database of OC fusion procedures, the authors identified patients who underwent unilateral fixation for the management of OC instability. Patient characteristics, surgical details, and radiographic outcomes were reviewed. In each patient, CT scans were performed at least 4 months after surgery to evaluate for fusion. RESULTS Eight patients with CVAs of the CCJ underwent unilateral fixation for the treatment of OC instability. For 4 patients, the procedure occurred after a bilateral OC construct failed or infection forced hardware removal. For the remainder, it was the primary procedure. Two patients required reoperation for hardware revision and 1 developed nonunion requiring revision of the bone graft. Ultimately, 7 patients demonstrated osseous fusion on CT scans and 1 had a stable fibrous union. CONCLUSIONS These findings demonstrate that a unilateral OC fixation is effective for the treatment of OC instability in children with CVAs of the CCJ in whom bilateral screw placement fails or is not feasible. PMID- 25828504 TI - Appraisals of Internal States and their Consequences: Relationship to Adolescent Analogue Bipolar Symptoms. AB - BACKGROUND: Extreme appraisals of internal states correlate with and prospectively predict mood symptoms in adults, and discriminate individuals with bipolar disorder from individuals with unipolar depression and non-clinical controls. AIMS: These findings required replication in adolescents. This study sought to investigate the relationships between appraisals of internal states, mood symptoms and risk for bipolar disorder in an adolescent sample. METHOD: A non-clinical sample (n = 98) of adolescents completed measures of mood symptoms, appraisals, and mania risk, alongside covariates. RESULTS: Appraisals of internal states were associated with analogue bipolar symptoms, independently of impulsivity and responses to positive affect. Positive appraisals of activated mood states were uniquely associated with hypomania, whilst negative appraisals were uniquely associated with depression and irritability symptoms. Individuals who appraised activated states as both extremely positive and extremely negative were more likely to score at high or moderate risk for future mania. CONCLUSIONS: This study is the first to demonstrate associations between appraisals of internal states, analogue mood symptoms and mania risk in adolescents. Clinical implications are discussed. PMID- 25828505 TI - Carnitine is associated with fatigue following chemoradiotherapy for head and neck cancer. AB - CONCLUSION: Longitudinal assessments of carnitine and fatigue in patients with head and neck squamous cell carcinoma suggest that cisplatin damages the carnitine system in patients undergoing chemoradiotherapy and that carnitine deficiency increases fatigue. OBJECTIVES: The purpose of this study was to monitor carnitine levels and fatigue in patients who received cisplatin-based CRT and, for comparison, in patients treated by surgery alone. METHODS: To investigate the level of carnitine, mice were administered cisplatin. Next, a prospective analysis was performed to compare plasma carnitine levels before and after cisplatin-based chemoradiotherapy and to assess the relationship between carnitine levels and fatigue. RESULTS: The plasma levels of total carnitine (TC), free carnitine (FC), and fatty acylcarnitine (AC) were significantly lower in mice receiving cisplatin compared with control mice. Mean total carnitine and free carnitine levels were significantly lower 2 weeks after chemoradiotherapy (total carnitine: Mean = 45.6, SD = 16.5, p = 0.01; free carnitine: Mean = 37.8, SD = 12.7, p = 0.02) than before chemoradiotherapy (total carnitine: Mean = 57.7, SD = 12.2; free carnitine: Mean = 48.1, SD = 11.6). There was a significant inverse correlation between carnitine levels and fatigue after chemoradiotherapy. PMID- 25828506 TI - Chemometric analyses for the characterization of raw and processed seeds of Descurainia sophia (L.) based on HPLC fingerprints. AB - The seeds of Descurainia sophia (L.) (short for DSS below), with a long history of medicinal utilization in China, have attracted the attention of many Chinese medicine practitioners for the potent efficacy. In the present study, the raw and processed DSS were differentiated by several chemometrics methods based on HPLC fingerprints. Moreover, peaks which were mainly responsible for the differentiation between raw and roasted DSS were found. Therefore, the method of the chromatographic fingerprints combined with multivariate statistical analysis was effective and reasonable in orientating chemical constituents which were mainly responsible for the differentiation between raw and roasted materials, thus shedding light on illustrating the processing mechanism. What's more, this method can also be applied in the identification of authenticity. PMID- 25828507 TI - Development of liquid chromatographic method for the analysis of dabigatran etexilate mesilate and its ten impurities supported by quality-by-design methodology. AB - In this paper, the development of reversed-phase liquid chromatographic method for the analysis of dabigatran etexilate mesilate and its ten impurities supported by quality by design (QbD) approach is presented. The defined analytical target profile (ATP) was the efficient baseline separation and the accurate determination of the investigated analytes. The selected critical quality attributes (CQAs) were the separation criterions between the critical peak pairs because the mixture complexity imposed a gradient elution mode. The critical process parameters (CPPs) studied in this research were acetonitrile content at the beginning of gradient program, acetonitrile content at the end of gradient program and the gradient time. Plan of experiments was defined by Box Behnken design. The experimental domains of the three selected factors x1- content of the acetonitrile at the start of linear gradient, x2--content of the acetonitrile at the end of linear gradient and x3--gradient time (tG) were [10%, 30%], [48%, 60%] and [8 min, 15 min], respectively. In order to define the design space (DS) as a zone where the desired quality criteria is met providing also the quality assurance, Monte Carlo simulations were performed. The uniform error distribution equal to the calculated standard error was added to the model coefficient estimates. Monte Carlo simulation included 5000 iterations in each of 3969 defined grid points and the region having the probability pi >= 95% to achieve satisfactory values of all defined CQAs was computed. As a working point, following chromatographic conditions suited in the middle of the DS were chosen: 22% acetonitrile at the start of gradient program, 55.5% acetonitrile at the end of gradient program end and the gradient time of 11.5 min. The developed method was validated in order to prove its reliability. PMID- 25828508 TI - Novel strategy for herbal species classification based on UPLC-HRMS oligosaccharide profiling. AB - Oligosaccharides, which exist widely in herbs, present diverse important pharmacological activities. However, the complexity of oligosaccharides seriously challenges their profiling, quality control, and elucidation of activity. In this paper, a novel oligosaccharide analytical method based on a new derivatization pretreatment and ultra-performance liquid chromatography coupled with high resolution tandem mass spectrometry (UPLC-HRMS) procedure was developed to rapidly profile and identify the oligosaccharides of Epimedium. Oligosaccharides are easily derivatized by 2,4-bis(diethylamino)-6-hydrazino-1,3,5-triazine under convenient and mild conditions. Without any further purification steps, oligosaccharides were analyzed by an established UPLC-HRMS/MS method with high sensitivity, good separation efficiency and speed. Benefitting from the derivatization, the oligosaccharides generated a response in the MS two orders of magnitude higher than that of the free oligosaccharide. Oligosaccharides of 52 Epimedium samples were profiled and identified based on the high-resolution mass spectral data. A total of 66 oligosaccharide compounds detected in 52 Epimedium herbs were relatively quantified and statistically processed by principal component analysis (PCA). The 52 Epimedium herbs could be classified into different species based on their oligosaccharide composition and content. Thirteen oligosaccharide compounds demonstrated potential as markers for Epimedium species classification, and their structures were preliminarily identified using MS/MS spectra. PMID- 25828509 TI - Development, validation and comparison of NIR and Raman methods for the identification and assay of poor-quality oral quinine drops. AB - Poor quality antimalarial drugs are one of the public's major health problems in Africa. The depth of this problem may be explained in part by the lack of effective enforcement and the lack of efficient local drug analysis laboratories. To tackle part of this issue, two spectroscopic methods with the ability to detect and to quantify quinine dihydrochloride in children's oral drops formulations were developed and validated. Raman and near infrared (NIR) spectroscopy were selected for the drug analysis due to their low cost, non destructive and rapid characteristics. Both of the methods developed were successfully validated using the total error approach in the range of 50-150% of the target concentration (20%W/V) within the 10% acceptance limits. Samples collected on the Congolese pharmaceutical market were analyzed by both techniques to detect potentially substandard drugs. After a comparison of the analytical performance of both methods, it has been decided to implement the method based on NIR spectroscopy to perform the routine analysis of quinine oral drop samples in the Quality Control Laboratory of Drugs at the University of Kinshasa (DRC). PMID- 25828510 TI - Relating Water Deficiency to Berry Texture, Skin Cell Wall Composition, and Expression of Remodeling Genes in Two Vitis vinifera L. Varieties. AB - The cell wall (CW) is a dynamic structure that responds to stress. Water shortage (WS) impacts grapevine berry composition and its sensorial quality. In the present work, berry texture, skin CW composition, and expression of remodeling genes were investigated in two V. vinifera varieties, Touriga Nacional (TN) and Trincadeira (TR), under two water regimes, Full Irrigation (FI) and No Irrigation (NI). The global results allowed an evident separation between both varieties and the water treatments. WS resulted in increased anthocyanin contents in both varieties, reduced amounts in cellulose and lignin at maturation, but an increase in arabinose-containing polysaccharides more tightly bound to the CW in TR. In response to WS, the majority of the CW related genes were down-regulated in a variety dependent pattern. The results support the assumption that WS affects grape berries by stiffening the CW through alteration in pectin structure, supporting its involvement in responses to environmental conditions. PMID- 25828512 TI - A Meta-analysis of Central Corneal Thickness Changes With Overnight Orthokeratology. AB - OBJECTIVES: To assess the change of central corneal thickness (CCT) in the treatment of orthokeratology in patients with myopia. METHODS: A systematic search of all relevant studies published through April 2014 was conducted, and 95% confidence intervals (CI) of CCT change were calculated. Random or fixed effects models were used according to heterogeneity. Publication bias of the articles was evaluated using funnel plots and Begg test. RESULTS: A total of 10 studies with 239 patients (339 eyes) from clinical studies were included. Central corneal thickness reduced significantly from 1 day to 1 week by 5.73 MUm (95% CI, 1.75-9.70 MUm; P=0.005), and a significant mean reduction of 5.89 MUm also occurred from 1 day to 1 month (95% CI, 3.50-8.29 MUm; P<0.001). No significant reduction was found between 1 week and 1 month (P=0.32). CONCLUSIONS: Our meta analysis demonstrated that most reduction of CCT occurred during the first week and remained thinner for 1 month. Further randomized controlled trials with larger sample sizes, standardized outcome measurements, and different follow-up periods are warranted to find the precise change. PMID- 25828511 TI - ENaC in the Rabbit Lacrimal Gland and its Changes During Sjogren Syndrome and Pregnancy. AB - PURPOSE: Epithelial sodium channel (ENaC) plays a critical role in the control of Na(+) balance and the development and progression of exocrine gland pathologic condition. The aim of the present study was to investigate the presence of ENaC in the rabbit lacrimal gland (LG) and its potential changes during induced autoimmune dacryoadenitis (IAD) and pregnancy. METHODS: Total messenger RNA (mRNA) of alpha, beta, and gamma subunits was extracted from whole LG, acinar cells, and ductal cells by laser capture microdissection (LCM) for real-time reverse-transcriptase polymerase chain reaction. Lacrimal glands were processed for Western blot and immunofluorescence. RESULTS: Messenger RNA for both alpha and gamma was expressed in whole LG lysates, whereas beta was undetectable. In rabbits with IAD, the levels of mRNA for alpha and gamma were 20.9% and 58.9% lower (P<0.05), whereas no significant changes were observed in term-pregnant rabbits (P=0.152). However, we were unable to detect mRNA of any subunit in LCM specimens of ductal cells because of their low levels. Western blot demonstrated bands for both alpha (90 kDa) and gamma (85 kDa) but beta was undetectable. In rabbits with IAD, densitometry analysis showed that expression of alpha decreased 22%, whereas gamma decreased 26% (P<0.05). In pregnant rabbits, however, alpha expression was 31% lower, whereas gamma expression was 34% lower (P<0.05). From immunofluorescence studies, all subunits were present in ductal cells, whereas virtually no immunoreactivity was detected in acini. No noticeable changes of their distribution pattern and intensity were found in rabbits with IAD or during pregnancy. CONCLUSIONS: The present study demonstrated the presence of ENaC in the rabbit LG and its alterations in IAD and pregnancy, suggesting that ENaC may contribute to the pathogenesis of altered LG secretion and ocular surface symptoms in these animals. PMID- 25828513 TI - Etiologies, Quantitative Hypoesthesia, and Clinical Outcomes of Neurotrophic Keratopathy. AB - OBJECTIVES: To report a series of patients with neurotrophic keratopathy and to correlate visual outcomes with the causative condition, grade of ulceration, and degree of cornea hypoesthesia. METHODS: A retrospective review of patients with neurotrophic keratopathy was conducted. The causality, visual acuities, ulcer grade, quantitative corneal sensitivity, treatments, and ocular comorbidities were recorded. RESULTS: Forty-six eyes were identified, and 20 experienced corneal sensation quantified by the Cochet-Bonnet aesthesiometer. Diabetes followed by herpes simplex and neurosurgical sequelae were the most common causes. Grade II ulcers were the most commonly seen ulcers. Twenty-eight percent of eyes failed conservative treatment and required surgical therapy. Overall, the initial (20/289) and final (20/158) acuities were poor, although the improvement was significant (P=0.05). However, there was no difference in visual recovery by disease (P=0.46). There was little correlation between ulcer grade and visual improvement (rs=0.24). Corneal sensation ranged from 0 to 3 cm generally for all causality of disease. There were little correlations between corneal hypoesthesia and ulcer grade (rs=-0.25), between corneal hypoesthesia and visual improvement (r=0.16), or between corneal hypoesthesia and final visual outcome (r=-0.36). A large percentage of eyes had significant ocular comorbidities. CONCLUSIONS: Visual outcomes for neurotrophic keratopathy can be poor because of both the cornea and the underlying disease. We did not find correlations regarding the causality of the disease, severity of ulceration, or degree of hypoesthesia with visual recovery or outcome. We hope future studies will shed further light on the disease to help better predict patient outcomes and thereby improve therapies. PMID- 25828514 TI - Objective Assessment of Eye Dominance Using the VEP: A Pilot Study. AB - OBJECTIVES: To develop a clinical protocol for the determination of eye dominance using an objective method (i.e., the visual evoked potential [VEP]), and furthermore to determine the correlation of these objective findings with clinical subjective tests of eye dominance to provide guidance in clinical monovision refractive correction. METHODS: The Diopsys NOVA-TR system was used to record the VEP amplitude and latency of 10 visually-normal, presbyopic, adult subjects aged 50 to 70 years ((Equation is included in full-text article.)=60, SEM=0.17 years). First, eye dominance was assessed in two ways: a sensory-based "sensitivity to blur task" and a motor-based "sighting task." Next, while monocularly defocused, subjects binocularly viewed a black-and-white checkerboard (20-min arc size), pattern-reversal stimulus under 7 different test conditions: (1) baseline, (2) dominant (DE) eye blurred +1 diopter (D), (3) nondominant (NDE) eye blurred +1 D, (4) DE +2 D, (5) NDE +2 D, (6) DE +3 D, and (7) NDE +3 D. RESULTS: Under nearly all conditions (22/24=92%), the amplitude and latency were significantly different from baseline with any amount of defocus (P<0.05). Monocular defocus decreased, and increased, the mean binocular VEP amplitude and latency, respectively. There were no significant differences in either the binocular VEP amplitude or latency values when comparing defocused dominant vs. nondominant eyes. CONCLUSIONS: Eye dominance type (i.e., sensory or motor) and status (i.e., DE or NDE) did not provide a differential effect with respect to the VEP findings. Thus, the VEP technique does not show promise as an objective adjunct in the fitting of monovision correction. PMID- 25828515 TI - Evaluation of contact lens multipurpose solutions on bacterial biofilm development. AB - OBJECTIVES: No sooner are contact lenses (CLs) inserted into the eyes than lipids, proteins, and glycoproteins rapidly accumulate on their surface, thus favoring the adhesion of commensal bacteria and biofilm formation. Infections may be caused by the proliferation of indigenous flora or other opportunistic pathogens. Our purpose was to evaluate the activity and the capacity of different CL solutions to interfere with the mechanisms of biofilm formation and stability and use of a system to study dynamically biofilm development. METHODS: We evaluated the antibiofilm activity of three different multipurpose solutions (MPSs): Regard, Biotrue, and OPTI-FREE PureMoist on four bacterial species (Serratia marcescens, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus). Static biofilm assay was first performed to analyze the effect of MPSs. Dynamic assays were performed with the BioFlux system to analyze the effect of the OxyChlorite solution Regard on the biofilm formation. RESULTS: Our studies show that MPSs are able to completely inhibit biofilm formation of Staphylococcus species and of S. marcescens after only 4 hr of incubation. Moreover, a reduction of biofilm formation by Pseudomonas was noted. Best results on P. aeruginosa were obtained with Regard. Regard was also used for dynamic assay, revealing its ability to disaggregate the mature biofilm. Regard completely inhibited biofilm formation by S. epidermidis and slowed down biofilm development by P. aeruginosa. CONCLUSIONS: Our findings indicate that the CL solutions tested were all able to reduce biofilm formation. Furthermore, the BioFlux system was proven to be useful for the evaluation of the effectiveness of CL solutions against microbial biofilm formation. PMID- 25828516 TI - Faculty development programs improve the quality of Multiple Choice Questions items' writing. AB - The aim of this study was to assess the utility of long term faculty development programs (FDPs) in order to improve the quality of multiple choice questions (MCQs) items' writing. This was a quasi-experimental study, conducted with newly joined faculty members. The MCQ items were analyzed for difficulty index, discriminating index, reliability, Bloom's cognitive levels, item writing flaws (IWFs) and MCQs' nonfunctioning distractors (NFDs) based test courses of respiratory, cardiovascular and renal blocks. Significant improvement was found in the difficulty index values of pre- to post-training (p = 0.003). MCQs with moderate difficulty and higher discrimination were found to be more in the post training tests in all three courses. Easy questions were decreased from 36.7 to 22.5%. Significant improvement was also reported in the discriminating indices from 92.1 to 95.4% after training (p = 0.132). More number of higher cognitive level of Bloom's taxonomy was reported in the post-training test items (p<0.0001). Also, NFDs and IWFs were reported less in the post-training items (p<0.02). The MCQs written by the faculties without participating in FDPs are usually of low quality. This study suggests that newly joined faculties need active participation in FDPs as these programs are supportive in improving the quality of MCQs' items writing. PMID- 25828517 TI - Eicosapentaenoic Acid Versus Docosahexaenoic Acid as Options for Vascular Risk Prevention: A Fish Story. AB - Vascular inflammation is a key component involved in the process of arthrosclerosis, which in turn increases the risk for cardiovascular injury. In the last 10 years, there have been many trials that looked at omega-3 fatty acids as a way to reduce cardiovascular risk. These trials observed the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the traditional lipid panel and found that both EPA and DHA reduce triglyceride (TG) level and increase high-density lipoprotein cholesterol (HDL-C) levels but also increase the low-density lipoprotein cholesterol (LDL-C) levels. In the 2 more recent trials, the MARINE and ANCHOR, EPA was given as an adjunct therapy to high-risk patients and not only was the traditional lipids measured but also examined the vascular inflammatory biomarkers. The results of these 2 trials not only showed reduction in cardiovascular risk because of reduction in vascular inflammation and reduction in the lipid panel but also showed that one of the MARINE-derived omega-3 fatty acid is superior to the other. Data search for omega-3 fatty acids and cardiovascular risk was performed, and articles were selected for review from 2006 to date. The research studies were all double-blind randomized trials except for one, which was a single-blind and focused on the effects of omega-3 fatty acids on the entire lipid panel. The participants received DHA/EPA and compared with a placebo group on the effect seen in the lipid panel. The first 7 studies looked at the effects of omega-3 fatty acids on TG, LDL-C, and HDL-C; of the 7, 1 directly compared DHA and EPA, 2 focused on EPA, and 4 were directed towards DHA alone. The MARINE and ANCHOR trials were more recent and also looked at the same parameter but also monitored vascular inflammatory biomarkers and how they were affected by omega-3 fatty acids. A second data search was performed for vascular biomarkers and cardiovascular risk, and articles that focused on high-sensitivity C-reactive protein and oxidized low-density lipoprotein were selected for review. Omega-3 fatty acids have shown to decrease TG level in multiple trials, but they have also shown to increase LDL and HDL levels, likely because omega-3 fatty acids promote TG conversion into HDL/LDL. The older data suggested that the benefits of omega-3 fatty acids are nullified by their effects on LDL levels. The data from the MARINE and ANCHOR trials have shown that EPA alone at 4 g per day has shown to decrease TG and total cholesterol without affecting the LDL levels. The earlier data showed that both EPA and DHA decreased TG level and increased levels of HDL-C, but that the DHA alone and direct comparison of DHA/EPA showed that DHA has more undesirable effects on LDL. Furthermore, the MARINE and ANCHOR trials have both shown that not only does EPA improve the lipid panel but also helps to decrease the levels of the vascular inflammatory biomarkers, thus further helping to decrease cardiovascular risk. The use of EPA as an adjunct therapy for high-risk patient has shown to help decrease cardiovascular risk. The reduction in risk is performed not only by decreasing TG but also by reducing vascular inflammation. Although because there are no randomized double-blind study looking at this, the research is inconclusive and requires further investigation. PMID- 25828518 TI - CHFR methylation strongly correlates with methylation of DNA damage repair and apoptotic pathway genes in non-small cell lung cancer. AB - DNA methylation occurs commonly in non-small cell lung cancer (NSCLC). We sought to determine the frequency and relationship of methylation of key genes involved in the pathways of mitotic checkpoint control, DNA damage repair, apoptosis, and growth factor signaling in these patients. We analyzed the DNA methylation status of eight genes (CHFR, FANCF, MGMT, p16, DAPK, ASC or TMS-1, RAR-B, and CRBP1) using nested methylation-specific PCR (MSP) on over 314 paraffin-embedded, human non-small cell lung cancer samples. We determined the methylation frequency of each gene in addition to the association of the methylation of each gene with other members of the panel. Methylation was a common event in these samples. Our methylation analysis showed frequencies of methylation of 10% for CHFR, 14% for FANCF, 30% for MGMT, 29% for p16, 17% for DAPK, 33% for ASC, 38% for RAR-B, and 7% for CRBP1. There was a strong correlation between methylation of the mitotic G2-M checkpoint gene, CHFR, and methylation of other genes in our panel involved in DNA damage repair (FANCF and MGMT) and apoptosis (DAPK and ASC) but not with other genes in our panel, including p16 (the G1-S checkpoint gene), CRBP1, or RAR B. In addition, MGMT methylation strongly correlated with the pro-apoptotic gene, ASC. There are distinct associations of methylated genes in non-small cell lung cancer involving DNA damage repair, apoptosis, and the G2-M mitotic checkpoint control. Further studies are warranted to determine whether these methylation patterns have implications for prognosis in addition to prediction of response to chemotherapeutic agents commonly used in the treatment of non-small cell lung cancer, such as radiotherapy and platinum- or taxane-based chemotherapy. PMID- 25828519 TI - Advances in mechanisms, diagnosis, and treatment of pernicious anemia. AB - Pernicious anemia (PA) is an entity initially described in 1849 as a condition that consisted of pallor, weakness, and progressive health decline. Since then several advances led to the conclusion that PA is an autoimmune disease characterized by the deficient absorption of dietary cobalamin. It is currently recognized as the most common cause of cobalamin deficiency worldwide. We hereby review the current understanding of the disease and its neurological, hematological, and biochemical manifestations with emphasis on the diagnostic approach, treatment, and monitoring strategies. We propose an algorithm for the diagnostic approach considering the current performance and limitations of the available diagnostic tools for evaluation of cobalamin status and the presence of autoimmune chronic atrophic gastritis (CAG). Patients with PA require lifelong treatment with cobalamin replacement therapy. The current widely available treatment can be provided through enteral or parenteral cobalamin supplements, with comparable efficacy and tolerability. PMID- 25828520 TI - Dendritic-tumor fusion cells in cancer immunotherapy. AB - A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines. PMID- 25828521 TI - Genetic causes of pituitary hormone deficiencies. AB - In recent decades, dozens of genes that cause isolated and combined pituitary hormone deficiencies have been discovered. We will review the clinically relevant genes known to cause isolated and combined pituitary hormone deficiencies in humans. This review will address genetic causes of adrenocorticotropic hormone deficiency, thyroid stimulating hormone deficiency, growth hormone deficiency, hypogonadotropic hypogonadism, and diabetes insipidus. Additionally, we will discuss genetic causes of combined pituitary hormone deficiency, septo-optic dysplasia, holoprosencephaly, and multisystemic syndromes in which hypopituitarism is a significant component. With the widespread clinical availability of next generation sequencing and ongoing identification of new disease causing genes, genetic diagnoses are determined for increasing numbers of patients. With new insights into mechanisms of disease resulting from multiple gene interactions, an increasingly nuanced understanding of the underlying genetic etiology of pituitary hormone deficiencies is possible. PMID- 25828522 TI - New concepts on functional chronic pelvic and perineal pain: pathophysiology and multidisciplinary management. AB - The management of chronic pelvic and perineal pain has been improved by a better understanding of the mechanisms of this pain and an optimized integrated multidisciplinary approach to the patient. The concept of organic lesions responsible for a persistent nociceptive factor has gradually been replaced by that of dysregulation of nociceptive messages derived from the pelvis and perineum. In this setting, painful diseases identified by organ specialists are usually also involved and share several common denominators (triggering factors, predisposing clinical context). These diseases include painful bladder syndrome, irritable bowel syndrome, vulvodynia, and chronic pelvic pain syndrome. The painful symptoms vary from one individual to another and according to his or her capacity to activate pain inhibition/control processes. Although the patient often attributes chronic pain to a particular organ (with the corollary that pain will persist until the organ has been treated), this pain is generally no longer derived from the organ but is expressed via this organ. Several types of clinical presentation of complex pelvic pain have therefore been pragmatically identified to facilitate the management of treatment failures resulting from a purely organ based approach, which can also reinforce the patient's impression of incurability. These subtypes correspond to neuropathic pain, central sensitization (fibromyalgia), complex regional pain syndrome, and emotional components similar to those observed in post-traumatic stress disorder. These various components are also often associated and self-perpetuating. Consequently, when pelvic pain cannot be explained by an organ disease, this model, using each of these four components associated with their specific mechanisms, can be used to propose personalized treatment options and also to identify patients at high risk of postoperative pelvic pain (multi-operated patients, central sensitization, post-traumatic stress disorder, etc.), which constitutes a major challenge for prevention of these types of pain that have major implications for patients and society. PMID- 25828523 TI - Safety and efficacy of rivaroxaban versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a meta-analysis of observational studies. AB - The safety and efficacy of rivaroxaban in the periprocedural anticoagulation for patients undergoing catheter ablation of atrial fibrillation is not well established. We sought to systematically review this evidence using data from multiple studies. A thorough literature search was conducted in MEDLINE, EMABSE, Web of knowledge, clinicaltrials.gov, and the Cochrane library up to November 2014. Studies of at least 100 patients in rivaroxaban and warfarin groups were included. Nine observational studies were identified enrolling a total of 4,334 patients (1,210 treated with rivaroxaban and 3,124 with warfarin). The primary outcomes were thromboembolic events and major bleeding. The fixed-effects model meta-analysis was performed and risk ratios (RRs) were calculated. No significant differences were found between patients treated with rivaroxaban and warfarin with regard to thromboembolic events (0.25% rivaroxaban vs. 0.29% warfarin; RR: 0.61; 95%CI: 0.21-1.76; P=0.36) and major bleeding (1.03% rivaroxaban vs. 1.83% warfarin; RR: 0.51; 95%CI: 0.26-1.00; P=0.05). This meta-analysis suggests that patients treated with rivaroxaban have a similar incidence of thromboembolic events and major bleeding compared to warfarin. Signals were seen favoring rivaroxaban; however, considering low events rates, more high-quality studies are necessary to thoroughly compare the two strategies. PMID- 25828524 TI - Current and emerging roles of functional imaging in radiation therapy. AB - The advent of functional imaging facilitates the acquisition of patient-specific tumor characteristics, including its metabolic state and regional oxygen tension. Recent advances promote incorporating this information with data obtained from current imaging techniques, such as MRI and CT, to manage various malignancies. Functional imaging's vital roles progressively evolved to include: aiding in diagnosis, improving radiation treatment planning, differentiating tumor volume from surrounding normal tissues which enables dose escalation to the former while improving sparing of the latter, adapting radiation therapy regimens according to a tumor's response to initial treatment, and assessing radiation therapy response and toxicity. This review explores functional imaging in radiation oncology in the context of these five applications, as well as its comparison to, and integration with, existing imaging modalities. In parallel with advances in functional imaging and understanding of tumor microbiology, the emergence of diverse tracers provides a plethora of options to distinguish and manage malignancies on the basis of specific metabolic processes and changing microenvironmental cues. Current limitations, potential concerns, and future innovations of functional imaging are also discussed. PMID- 25828525 TI - Hematopoietic cell transplantation in chronic myeloid leukemia in the age of tyrosine kinase inhibitors. AB - The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic myeloid leukemia (CML) patients who fail or are intolerant to TKIs. Its long-term cost effectiveness compared to TKIs, however, has maintained its use as front-line treatment in some areas. Advances in HCT, including the development of intravenous busulfan and plasma assays permitting dose adjustment, have improved results of HCT in CML. Improved supportive care has lowered the incidence of non relapse mortality and improved survival. The availability of reduced-intensity preparative regimens, molecular typing of unrelated donors, and the use of cord blood and haploidentical donors has expanded the application of HCT to nearly any patient with an appropriate indication. From 2006 to 2010, approximately one thousand HCTs were performed annually in patients with CML. Better understanding of recent advances will improve the appropriate use and results of HCT in patients with CML. PMID- 25828526 TI - Immune effects of targeted radiation therapy for cancer. AB - Radiation therapy plays an important role in the treatment of the majority of cancers, and is commonly used to treat both localized and metastatic disease. Immunotherapy has recently been firmly integrated into the treatment of metastatic melanoma, and holds significant promise in treating a variety of other cancers. Although large field radiation has historically been appreciated for its immunosuppressive ability, targeted radiation can induce substantial changes in the tumor microenvironment beyond cellular cytotoxicity that evoke innate and adaptive immune responses. Previous studies have highlighted radiation-induced changes in proinflammatory cytokines, chemokines, effector, and immunosuppressive T cell subsets, as well as in immune receptors on tumor cells. Some of these changes in localized and systemic immune mediators have been linked to expansion of tumor-reactive T cells, improved clinical responses, and increased overall survival in preclinical and clinical models. Taken together, this evidence suggests that targeted radiation therapy can impact anti-tumor immune responses, and may potentially be combined with immunotherapy for synergistic effect. PMID- 25828527 TI - An unexpected journey: how cancer immunotherapy has paved the way for an HIV-1 cure. AB - Over 30 million people worldwide are currently infected with human immunodeficiency virus type-1 (HIV-1). While HIV-1 infection was initially thought to be a death sentence, the advent of combination antiretroviral therapy (cART) in the mid-1990's resulted in decreases in viremia and an extended lifespan for infected persons. Despite this, long-term control of the virus in the absence of drug therapy has yet to be achieved, owing to the rebound in viral load and resumption of disease progression that follows removal of the patient from cART. Currently, the most promising candidates for an HIV-1 cure are immunotherapies that harness the patient's own immune system and induce cytotoxic T lymphocyte (CTL)-mediated clearance of infected cells. Most of these approaches were developed and optimized in the cancer setting and have had varying degrees of success, the findings from which have wide applications to various disease models. In this review, we evaluate the past successes and failures of cancer immunotherapy and how the findings have shaped our journey toward an HIV-1 cure. PMID- 25828528 TI - Surgical team member assessment of the safety of surgery practice in 38 South Carolina hospitals. AB - We assessed surgical team member perceptions of multiple dimensions of safe surgical practice in 38 South Carolina hospitals participating in a statewide initiative to implement surgical safety checklists. Primary data were collected using a novel 35-item survey. We calculated the percentage of 1,852 respondents with strongly positive, positive, and neutral/negative responses about the safety of surgical practice, compared results by hospital and professional discipline, and examined how readiness, teamwork, and adherence related to staff perception of care quality. Overall, 78% of responses were positive about surgical safety at respondent's hospitals, but in each survey dimension, from 16% to 40% of responses were neutral/negative, suggesting significant opportunity to improve surgical safety. Respondents not reporting they would feel safe being treated in their operating rooms varied from 0% to 57% among hospitals. Surgeons responded more positively than nonsurgeons. Readiness, teamwork, and practice adherence related directly to staff perceptions of patient safety (p < .001). PMID- 25828529 TI - Nutrient stress revamps cancer cell metabolism. AB - Efforts to identify new therapeutic targets in cancer primarily focused on oncogenes and tumor suppressor genes, and their mechanisms of action. However, there is an emerging alternative strategy that involves identification of target proteins that are not encoded by oncogenes, but are, nonetheless, required to accommodate cancer-specific stresses. PMID- 25828530 TI - Three-dimensional human facial morphologies as robust aging markers. AB - Aging is associated with many complex diseases. Reliable prediction of the aging process is important for assessing the risks of aging-associated diseases. However, despite intense research, so far there is no reliable aging marker. Here we addressed this problem by examining whether human 3D facial imaging features could be used as reliable aging markers. We collected > 300 3D human facial images and blood profiles well-distributed across ages of 17 to 77 years. By analyzing the morphological profiles, we generated the first comprehensive map of the aging human facial phenome. We identified quantitative facial features, such as eye slopes, highly associated with age. We constructed a robust age predictor and found that on average people of the same chronological age differ by +/- 6 years in facial age, with the deviations increasing after age 40. Using this predictor, we identified slow and fast agers that are significantly supported by levels of health indicators. Despite a close relationship between facial morphological features and health indicators in the blood, facial features are more reliable aging biomarkers than blood profiles and can better reflect the general health status than chronological age. PMID- 25828531 TI - Resolving sorting mechanisms into exosomes. AB - The complexity of mechanisms driving protein sorting into exosomes is only beginning to emerge. In a paper recently published in Cell Research, Roucourt et al. report that trimming of heparan sulfate side chains of syndecans by endosomal heparanase facilitates sorting into exosomes by the formation of tight syndecan clusters that are recruited by the multivalent adaptor syntenin to the ALIX-ESCRT sorting machinery at endosomes. PMID- 25828532 TI - TREM2 enables amyloid beta clearance by microglia. AB - In a recent paper published in Cell, Wang et al. report that deficiency of triggering receptor expressed on myeloid cells 2 (TREM2) augments amyloid beta accumulation and neuronal loss in a mouse model of Alzheimer's disease. TREM2 acts as a signaling receptor involved in innate immunity for the natural clearance of this toxic protein by microglia. PMID- 25828535 TI - Induced-charge electroosmotic trapping of particles. AB - Position-controllable trapping of particles on the surface of a bipolar metal strip by induced-charge electroosmotic (ICEO) flow is presented herein. We demonstrate a nonlinear ICEO slip profile on the electrode surface accounting for stable particle trapping behaviors above the double-layer relaxation frequency, while no trapping occurs in the DC limit as a result of a strong upward fluidic drag induced by a linear ICEO slip profile. By extending an AC-flow field effect transistor from the DC limit to the AC field, we reveal that fixed-potential ICEO exceeding RC charging frequency can adjust the particle trapping position flexibly by generating controllable symmetry breaking in a vortex flow pattern. Our results open up new opportunities to manipulate microscopic objects in modern microfluidic systems by using ICEO. PMID- 25828534 TI - Brain mitochondrial ATP-insensitive large conductance Ca+2-activated K+ channel properties are altered in a rat model of amyloid-beta neurotoxicity. AB - Mitochondrial dysfunction is a hallmark of amyloid-beta (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). However, the underlying mechanism of how Abeta affects mitochondrial function remains uncertain. Because mitochondrial potassium channels have been involved in several mitochondrial functions including cytoprotection, apoptosis and calcium homeostasis, a study was undertaken to investigate whether the gating behavior of the mitochondrial ATP- and ChTx-insensitive-IbTx-sensitive Ca(2+)-activated potassium channel (mitoBKCa) is altered in a rat model of Abeta neurotoxicity. Abeta1-42 (4 MUg/MUl) was intracerebroventricularly injected in male Wistar rats (220-250 g). Brain Abeta accumulation was confirmed two weeks later on the basis of an immunohistochemistry staining assay, and physiological impacts measured in passive avoidance task cognitive performance experiments. Brain mitochondrial inner membranes were then extracted and membrane vesicles prepared for channel incorporation into bilayer lipid. Purity of the cell fraction was confirmed by Western blot using specific markers of mitochondria, plasma membrane, endoplasmic reticulum, and Golgi. Our results first provide evidence for differences in mitoBKCa ion permeation properties with channels coming from Abeta vesicle preparations characterized by an inward rectifying I-V curve, in contrast to control mitoBKCa channels which showed a linear I-V relationship under the same ionic conditions (200 mM cis/50mM trans). More importantly the open probability of channels from Abeta vesicles appeared 1.5 to 2.5 smaller compared to controls, the most significant decrease being observed at depolarizing potentials (30 mV to 50 mV). Because BKCa-beta4 subunit has been documented to shift the BKCa channel voltage dependence curve, a Western blot analysis was undertaken where expression of mitoBKCa alpha and beta4 subunits was estimated using anti-alpha and beta4 subunit antibodies. Our results indicated a significant increase in mitoBKCa beta4 subunit expression coupled to a decrease in the expression of alpha subunit. Our results thus demonstrate a modification in the mitoBKCa channel gating properties in membrane preparations coming from a rat model of Abeta neurotoxicity, an effect potentially linked to a change in mitoBKCa-beta4 and alpha subunits expression or increased ROS production due to an enhanced Abeta mitochondrial accumulation. Our results may provide new insights into the cellular mechanisms underlying mitochondrial dysfunctions in Abeta neurotoxicity. PMID- 25828536 TI - Small-scale purification of butyrylcholinesterase from human plasma and implementation of a MULC-UV/ESI MS/MS method to detect its organophosphorus adducts. AB - Human butyrylcholinesterase (hBChE) is a serine hydrolase (EC 3.1.1.8) present in all mammalian tissues and the bloodstream. Similar to acetylcholinesterase, the enzyme reacts with organophosphorus compounds (OP) like nerve agents or pesticides that cause enzyme inhibition (BChE adducts). These adducts represent valuable biomarkers for analytical verification of OP exposure. For establishment of these mass spectrometry based methods sufficient amounts of hBChE in high purity are required. Unfortunately, commercial lots are of inappropriate purity thus favouring in-house isolation. Therefore, we developed a small scale procedure to isolate hBChE from citrate plasma. After precipitation by polyethylene glycol (8% w/v and 20% w/v PEG 6000) hBChE was purified from plasma by four consecutive chromatographic steps including anion exchange, affinity extraction and size exclusion. Protein elution was monitored on-line by UV absorbance (280 nm) followed by continuous fractionation for off-line analysis of (1) hBChE enzyme activity by Ellman assay, (2) protein purity by gel electrophoresis, and (3) protein identity by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Numerous major impurities separated from hBChE were identified. The purified material was used for in vitro incubation with diverse OP to establish a MU-liquid chromatography-ultra violet detection/electrospray ionization tandem-mass spectrometric method (MULC-UV/ESI MS/MS) for detection of hBChE adducts suitable for verification analysis. Analytical data for diverse OP pesticides including deuterated analogues as well as G- and V-type nerve agents and their precursor are summarized. This method was successfully applied to plasma samples provided by the Organisation for the Prohibition of Chemical Weapons (OPCW) for the 4th Biomedical Exercise. PMID- 25828533 TI - Astrocyte roles in traumatic brain injury. AB - Astrocytes sense changes in neural activity and extracellular space composition. In response, they exert homeostatic mechanisms critical for maintaining neural circuit function, such as buffering neurotransmitters, modulating extracellular osmolarity and calibrating neurovascular coupling. In addition to upholding normal brain activities, astrocytes respond to diverse forms of brain injury with heterogeneous and progressive changes of gene expression, morphology, proliferative capacity and function that are collectively referred to as reactive astrogliosis. Traumatic brain injury (TBI) sets in motion complex events in which noxious mechanical forces cause tissue damage and disrupt central nervous system (CNS) homeostasis, which in turn trigger diverse multi-cellular responses that evolve over time and can lead either to neural repair or secondary cellular injury. In response to TBI, astrocytes in different cellular microenvironments tune their reactivity to varying degrees of axonal injury, vascular disruption, ischemia and inflammation. Here we review different forms of TBI-induced astrocyte reactivity and the functional consequences of these responses for TBI pathobiology. Evidence regarding astrocyte contribution to post-traumatic tissue repair and synaptic remodeling is examined, and the potential for targeting specific aspects of astrogliosis to ameliorate TBI sequelae is considered. PMID- 25828537 TI - Spectroscopic and molecular modelling analysis of the interaction between ethane 1,2-diyl bis(N,N-dimethyl-N-hexadecylammoniumacetoxy)dichloride and bovine serum albumin. AB - Several spectroscopic approaches namely fluorescence, time-resolved fluorescence, UV-visible, and Fourier transform infra-red (FT-IR) spectroscopy were employed to examine the interaction between ethane-1,2-diyl bis(N,N-dimethyl-N hexadecylammoniumacetoxy)dichloride (16-E2-16) and bovine serum albumin (BSA). Fluorescence studies revealed that 16-E2-16 quenched the BSA fluorescence through a static quenching mechanism, which was further confirmed by UV-visible and time resolved fluorescence spectroscopy. In addition, the binding constant and the number of binding sites were also calculated. The thermodynamic parameters at different temperatures (298 K, 303 K, 308 K and 313 K) indicated that 16-E2-16 binding to BSA is entropy driven and that the major driving forces are electrostatic interactions. Decrease of the alpha-helix from 53.90 to 46.20% with an increase in random structure from 22.56 to 30.61% were also observed by FT-IR. Furthermore, the molecular docking results revealed that 16-E2-16 binds predominantly by electrostatic and hydrophobic forces to some residues in the BSA sub-domains IIA and IIIA. PMID- 25828538 TI - TGF-beta Suppresses Ift88 Expression in Chondrocytic ATDC5 Cells. AB - Ift88 is an intraflagella transport protein, critical for the cilium, and has been shown to be required for the maintenance of chondrocytes and cartilage. However, how Ift88 is controlled by cytokines that play a role in osteoarthritis is not well understood. Therefore, we examined the effects of TGF-beta on the expression of Ift88. We used ATDC5 cells as chondrocytes and analyzed the effects of TGF-beta on gene expression. TGF-beta treatment suppresses the levels of Ift88 mRNA in a dose-dependent manner starting from as low as 0.5 ng/mL and reaching the nadir at around 2 ng/mL. TGF-beta treatment also suppresses the protein levels of Ift88. TGF-beta suppression of Ift88 is still observed when the cells are cultured in the presence of a transcriptional inhibitor while the TGF-beta suppression is weakened in the presence of a protein synthesis inhibitor, cycloheximide. TGF-beta treatment suppresses the levels of Ift88 mRNA stability suggesting the presence of posttranscriptional regulation. TGF-beta treatment reduces the number of cilia positive cells and suppresses average length of cilia. Knockdown of Ift88 by siRNA enhances TGF-beta-induced increase in type II collagen mRNA expression in ATDC5 cells revealing the suppressive role of Ift88 on TGF-beta-induced regulation of extracellular matrix protein expression. TGF beta also suppresses Ift88 mRNA expression in primary culture of rib chondrocytes. These data indicate that TGF-beta regulates Ift88 gene expression at least in part via posttrascriptional manner. PMID- 25828539 TI - How Blink Anomalies Can Contribute to Post-LASIK Neurotrophic Epitheliopathy. AB - : Post-LASIK (laser in situ keratomileusis) symptoms and signs of dry eye have multiple causes. For example, tear osmolarity and the concentration of inflammatory mediators can increase because of reduced aqueous production and increased evaporative loss as a result of lower blink rates and increased interblink intervals. The tear concentration of inflammatory mediators can also increase because of surgical trauma, wound healing, comorbid systemic and ocular diseases, and the use of punctal plugs. Studies that examine only mechanical sensitivity of the cornea cannot detect changes in chemical sensitivity, which can persist longer. Symptoms may be partly attributed to sensitization of the traumatized corneal or lid wiper sensory nerves by inflammatory mediators. Increased lid wiper sensitivity could increase awareness of blinks, especially if ocular surface lubricity is reduced. Incomplete blinks have been found to represent 10 to 22% of the total number of blinks. Loss of neural stimuli and lower blink rates increase the significance of incomplete blinks that approximately double related interblink intervals and tear evaporation. The most common location of post-LASIK epitheliopathy is the inferior area of the cornea, which is overexposed by incomplete blinks. The relevance of incomplete blinking to post-LASIK epitheliopathy is supported by the relative absence of this complication in the similarly neurotrophically disadvantaged upper corneal areas for which blink rates and other tear functions usually appear to be adequate to prevent epitheliopathy, which stains. Occupational or leisure-time activities such as computer use and reading, which have been found to reduce blink rates and blink completeness, appear to be significant risk factors for symptoms and signs of dry eye. Apart from reducing symptoms and signs of dry eye, prophylactic and post-LASIK blink exercises to reduce incomplete blink rates and associated overexposure of the ocular surface may also contribute to more accurate refractive outcomes through faster wound healing. PMID- 25828540 TI - Delayed post-treatment with bone marrow-derived mesenchymal stem cells is neurorestorative of striatal medium-spiny projection neurons and improves motor function after neonatal rat hypoxia-ischemia. AB - Perinatal hypoxia-ischemia is a major cause of striatal injury and may lead to cerebral palsy. This study investigated whether delayed administration of bone marrow-derived mesenchymal stem cells (MSCs), at one week after neonatal rat hypoxia-ischemia, was neurorestorative of striatal medium-spiny projection neurons and improved motor function. The effect of a subcutaneous injection of a high-dose, or a low-dose, of MSCs was investigated in stereological studies. Postnatal day (PN) 7 pups were subjected to hypoxia-ischemia. At PN14, pups received treatment with either MSCs or diluent. A subset of high-dose pups, and their diluent control pups, were also injected intraperitoneally with bromodeoxyuridine (BrdU), every 24h, on PN15, PN16 and PN17. This permitted tracking of the migration and survival of neuroblasts originating from the subventricular zone into the adjacent injured striatum. Pups were euthanized on PN21 and the absolute number of striatal medium-spiny projection neurons was measured after immunostaining for DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32), double immunostaining for BrdU and DARPP-32, and after cresyl violet staining alone. The absolute number of striatal immunostained calretinin interneurons was also measured. There was a statistically significant increase in the absolute number of DARPP-32-positive, BrdU/DARPP-32-positive, and cresyl violet-stained striatal medium-spiny projection neurons, and fewer striatal calretinin interneurons, in the high-dose mesenchymal stem cell (MSC) group compared to their diluent counterparts. A high-dose of MSCs restored the absolute number of these neurons to normal uninjured levels, when compared with previous stereological data on the absolute number of cresyl violet-stained striatal medium-spiny projection neurons in the normal uninjured brain. For the low-dose experiment, in which cresyl violet-stained striatal medium-spiny neurons alone were measured, there was a lower statistically significant increase in their absolute number in the MSC group compared to their diluent controls. Investigation of behavior in another cohort of animals showed that delayed administration of a high-dose of bone marrow-derived MSCs, at one week after neonatal rat hypoxia-ischemia, improved motor function on the cylinder test. Thus, delayed therapy with a high- or low-dose of adult MSCs, at one week after injury, is effective in restoring the loss of striatal medium-spiny projection neurons after neonatal rat hypoxia-ischemia and a high-dose of MSCs improved motor function. PMID- 25828541 TI - Development of a metacognitive effort construct of empathy during clinical training: a longitudinal study of the factor structure of the Jefferson Scale of Empathy. AB - Empathy is crucial for effective clinical care but appears to decline during undergraduate medical training. Understanding the nature of this decline is necessary for addressing it. The Jefferson Scale of Empathy (JSE) is used to measure medical students' clinical empathy attitudes. One recent study described a 3-factor model of the JSE. This model was found in responses from matriculating medical students, but little is known about how the factor structure of the scale changes during clinical training. The Learning Environment Study is a longitudinal prospective study of two cohorts from 28 medical schools. At matriculation and at the end of each subsequent year, students self-reported clinical empathy attitudes using the JSE. Data from 4,797 students were randomly partitioned for exploratory (EFA) and confirmatory factor analyses using responses from preclinical and clinical years of medical school. Five models were compared for confirmatory factor analysis: two null models for control, the recent 3-factor model, and the two models resulting from the EFAs of preclinical and clinical year responses. Preclinical year responses yielded a 3-factor model similar to the recent 3-factor model. Clinical year responses yielded a 4-factor model ("feelings," "importance," "ease," and "metacognitive effort") suggesting changes in the structure of clinical empathy attitudes over time. Metacognitive effort showed the largest decline over time. The model is a better fit for both preclinical and clinical responses and may provide more insight into medical students' clinical empathy attitudes than other models. The emergence of metacognitive effort in the clinical years suggests empathy may become more nuanced for students after clinical exposure and may account for much of the observed decline in clinical empathy attitudes. PMID- 25828542 TI - Understanding carbon partitioning and its role in determining plant growth. PMID- 25828543 TI - Clomiphene citrate as a preventive treatment for intractable chronic cluster headache: a second reported case with long-term follow-up. AB - OBJECTIVE: To describe a second case of treatment refractory chronic cluster headache responsive to clomiphene citrate and with long-term follow-up. METHODS: Case report with 7-year evaluation. CASE: A 63-year-old man with a 17-year history of chronic cluster headache preceded to have significant adverse events or was nonresponsive to multiple cluster headache preventive medications including verapamil, lithium, valproic acid, topiramate, baclofen as well as greater occipital nerve blocks and inpatient hospitalization. The patient experienced 3-5 headaches per day. On clomiphene citrate 100 mg/day he became 100% pain-free and remained so for 3.5 years with only mild fatigue as a side effect. He then had cluster headache recurrence and did well on gabapentin for another 3 years with repeat headache recurrence. Clomiphene was restarted, and he became pain-free once again. DISCUSSION: This is the second reported case of the effective use of clomiphene citrate for the preventive treatment of medicinal refractory chronic cluster headache. This is the first case to report long-term follow-up of this neurohormonal treatment. Clomiphene citrate appears to be safe for extended use in chronic cluster headache even in an elderly sufferer and has a minimal side effect profile. The mechanism of action of how clomiphene prevents cluster headache may involve both its ability to enhance testosterone production and its ability to bind to hypothalamic estrogen receptors. Clomiphene citrate should join the list of alternative cluster headache prophylactic treatments to be considered by headache specialists when conventional cluster headache preventives are ineffective. PMID- 25828544 TI - Separation of linear synthetic polymers in non-aqueous capillary zone electrophoresis using cationic surfactant. AB - A method for separating water-insoluble and neutral synthetic polymers using non aqueous capillary zone electrophoresis (NACZE) was developed. The non-aqueous solvent system comprising a mixture of tetrahydrofuran, acetonitrile, and ethanol containing cetyltrimethylammonium chloride was used for solubilizing and conferring positive charges to the polymers. A mixture of polystyrene (PS, Mn=6500) and polybutadiene (PBD, Mn=5900) was successfully separated by the NACZE method using cationic surfactants. Evaluation of the effect of the molecular weight of the polymers on the electrophoretic behavior demonstrated that PSs with different molecular weights (Mn=6500, 10,200, 19,600, 200,000) were co-eluted as a single peak. That is, the apparent electrophoretic mobility of the PSs was independent of the molecular weight. In contrast, evaluation of PBD and polycarbonate (PC) demonstrated that the solubility of polymers in the medium affected the apparent electrophoretic mobility of the polymers, where low solubility resulted in reduced apparent electrophoretic mobility. Using the proposed method, poly(styrene-co-methylmethacrylate)s with different compositions were successfully separated. PMID- 25828546 TI - Risk assessment for extending the Biopharmaceutics Classification System-based biowaiver of immediate release dosage forms of fluconazole in adults to the paediatric population. AB - OBJECTIVES: The paediatric population undergoes developmental changes in gastric pH, gastric emptying, intestinal transit time, membrane permeability, protein binding, body water, distribution and metabolism. It is widely recognised that changes in these parameters may result in an alteration of the plasma profile and thus in key bioequivalence parameters such as Cmax (maximum plasma concentration of drug) and area under the plasma concentration vs time profile curve. The aim of this work is to assess the risk of extending the biowaiver for immediate release dosage formulations of fluconazole from the adult to the paediatric population. METHODS AND KEY FINDINGS: Fluconazole exhibits good solubility and very rapid dissolution characteristics in various pH media. The absorption of fluconazole in children is known to be complete (over 90%) and not impaired by elevated pH, which is prevalent during the early days of life. Dose numbers calculated using body surface area are less than 1. Therefore, the risk to drug absorption due to differences in gastric pH, gastric emptying, intestinal transit, membrane permeability and metabolising enzymes between adults and children is considered low. CONCLUSIONS: Thus, it can be safely concluded that fluconazole meets highly soluble and highly permeable criteria in the paediatric population and can be allocated to class 1 of the Biopharmaceutics Classification System (BCS) for this population as well as in adults. Additionally, fluconazole has an excellent safety profile in children, similar to that in adults. The BCS based biowaiver claimed in adults can be safely extended to the paediatric population provided that the requirements in excipient selection and dissolution profile comparison using BCS-based dissolution conditions as stated in the biowaiver monograph for fluconazole immediate release dosage forms in adults are fulfilled. PMID- 25828545 TI - Iron oxide functionalized graphene nano-composite for dispersive solid phase extraction of chemical warfare agents from aqueous samples. AB - Present study deals with the preparation and evaluation of graphene based magnetic nano-composite for dispersive solid phase extraction of Chemical Weapons Convention (CWC) relevant chemicals from aqueous samples. Nano-composite, Fe3O4@SiO2-G was synthesized by covalently bonding silica coated Fe3O4 onto the graphene sheets. Nerve agents (NA), Sulfur mustard (SM) and their non-toxic environmental markers were the target analytes. Extraction parameters like amount of sorbent, extraction time and desorption conditions were optimized. Dispersion of 20 milligram of sorbent in 200mL of water sample for 20min. followed by methanol/chloroform extraction produced average to good recoveries (27-94%) of targeted analytes. Recoveries of real agents exhibited great dependency upon sample pH and ionic strength. Sarin produced maximum recovery under mild acidic conditions (56% at pH 5) while VX demanded alkaline media (83% at pH 9). Salts presence in the aqueous samples was found to be advantageous, raising the recoveries to as high as 94% for SM. Excellent limits of detection (LOD) for sulphur mustard and VX (0.11ngmL(-1) and 0.19ngmL(-1) respectively) proved the utility of the developed method for the off-site analysis of CWC relevant chemicals. PMID- 25828547 TI - International note: The relationship between achievement goals and academic related boredom. AB - In a sample of 520 Chinese high school students, the present study aimed to replicate the prior Western findings about the relationship between achievement goals and academic boredom. Our findings indicated that mastery-approach goals and performance-avoidance goals predicted academic boredom, but mastery-avoidance goals and performance-approach goals did not. PMID- 25828548 TI - Understanding affluent adolescent adjustment: The interplay of parental perfectionism, perceived parental pressure, and organized activity involvement. AB - This cross-sectional study examined relations between affluent adolescent adjustment and culturally salient factors within parent-child relationship and extracurricular domain. Bootstrapping techniques evaluated mediated effects among parental perfectionism, perceived parental pressure, intensity of organized activity (OA) involvement, and adolescent adjustment (i.e., depressive and anxiety symptoms, life satisfaction) within a sample of 10th graders and their parents (n = 88 parent-child pairs) from four high schools in affluent communities. Findings indicated that adolescents with more perfectionistic parents perceived more parental pressure and experienced poorer adjustment. Results also demonstrated that affluent adolescents who perceived more parental pressure were more intensely involved in OAs, but that higher OA intensity was linked to better adjustment. Findings highlight the importance of considering parental perfectionism when understanding adolescent behaviors and psychological outcomes, confirm the negative direct effects of parental pressure on adjustment, and corroborate prior research dispelling that highly intense OA involvement is linked to adolescent maladjustment. PMID- 25828549 TI - Back on the streets: Maturation and risk factors for recidivism among serious juvenile offenders. AB - This study examines how social and cognitive factors shape future criminal activity among serious juvenile offenders and assesses how adolescents' cognitive development affects the relative impact of those factors over time. The sample, from the Pathways to Desistance Study, is comprised of youth (aged 14-18 years) in the United States convicted of serious criminal offenses, and the outcome measure is self-reported crime. We rely on data collected when the youth were first interviewed (n = 1088) and 18-24 months later (n = 904). Logistic regression analyses reveal a strong relationship between impulsiveness and criminal behavior, regardless of age. Susceptibility to peer pressure and perceived risk that friends would be arrested were found to predict future criminal activity among younger adolescents, but have little impact at later ages. External factors such as amount of social support and gang membership have varying effects over time. PMID- 25828550 TI - Non-suicidal self-injury in high school students: Associations with identity processes and statuses. AB - Non-suicidal self-injury (NSSI) refers to the direct, deliberate destruction of one's body tissue without suicidal intent. Research has highlighted the importance of identity synthesis versus confusion for NSSI. However, the association with identity processes and statuses remains unknown. A total of 568 adolescents reported on NSSI, identity, anxiety, and depression. Although identity processes of identification with commitment (negatively) and ruminative exploration (positively) were related to NSSI variables, these relationships were no longer significant when controlling for anxiety and depression. When examining identity statuses (using cluster analysis), individuals who had engaged in NSSI in the past (but not currently) were more likely to be in the moratorium cluster and less likely to be in the achievement cluster. Individuals who were currently engaging in NSSI were more likely to be in the troubled diffusion cluster. Clinicians should be attentive to the complex interplay between identity and NSSI when treating adolescents. PMID- 25828551 TI - Predicting adolescent's cyberbullying behavior: A longitudinal risk analysis. AB - The current study used the risk factor approach to test the unique and combined influence of several possible risk factors for cyberbullying attitudes and behavior using a four-wave longitudinal design with an adolescent US sample. Participants (N = 96; average age = 15.50 years) completed measures of cyberbullying attitudes, perceptions of anonymity, cyberbullying behavior, and demographics four times throughout the academic school year. Several logistic regression equations were used to test the contribution of these possible risk factors. Results showed that (a) cyberbullying attitudes and previous cyberbullying behavior were important unique risk factors for later cyberbullying behavior, (b) anonymity and previous cyberbullying behavior were valid risk factors for later cyberbullying attitudes, and (c) the likelihood of engaging in later cyberbullying behavior increased with the addition of risk factors. Overall, results show the unique and combined influence of such risk factors for predicting later cyberbullying behavior. Results are discussed in terms of theory. PMID- 25828552 TI - Sex, violence, & rock n' roll: Longitudinal effects of music on aggression, sex, and prosocial behavior during adolescence. AB - The current study examined longitudinal associations between listening to aggression, sex, and prosocial behavior in music on a number of behavioral outcomes across a one-year period during adolescence. Adolescents (N = 548, M age = 15.32, 52% female) completed a number of questionnaires on musical preferences, general media use, aggression, sexual outcomes, and prosocial behavior at two different time points separated by about one year. Using structural equation modeling to analyze the data, results revealed that listening to aggression in music was associated with increased aggression and decreased prosocial behavior over time, even when controlling for initial levels of these behaviors. Listening to sexual content in music was associated with earlier initiation of sexual intercourse and a trend for a higher number of sexual partners (reported at Time 2). Prosocial behavior in music was not associated with any behavioral outcome longitudinally. Collectively, these results suggest that listening to certain types of content in music can have a longitudinal effect on behavior during adolescence. PMID- 25828553 TI - Nuclear medicine incident reporting in Australia: control charts and notification rates inform quality improvement. AB - BACKGROUND: Australia has a statutory incident reporting system for radiopharmaceutical maladministrations, but additional research into registry data is required for the purpose of quality improvement in nuclear medicine. AIMS: We (i) used control charts to identify factors contributing to special cause variation (indicating higher than expected rates) in maladministrations and (ii) evaluated the impact of heterogeneous notification criteria and extent of underreporting among jurisdictions and individual facilities, respectively. METHODS: Anonymised summaries of Australian Radiation Incident Register reports permitted calculation of national monthly maladministration notification rates for 2007-2012 and preparation of control charts. Multivariate logistic regression assessed the association of population, insurance and regulatory characteristics with maladministration notifications in each Australian State and Territory. Maladministration notification rates from two facilities with familiarity of notification processes and commitment to radiation protection were compared with those elsewhere. RESULTS: Special cause variation occurred in only 3 months, but contributed to 21% of all incidents (42 of 197 patients), mainly because of 'clusters' of maladministrations (n = 24) arising from errors in bulk radiopharmaceutical dispensing. Maladministration notification rates varied significantly between jurisdictions (0 to 12.2 maladministrations per 100 000 procedures (P < 0.05)) and individual facilities (31.7 vs 5.8 per 100 000; chi(2) = 40; 1 degree of freedom, P < 0.001). CONCLUSIONS: Unexpected increases in maladministration notifications predominantly relate to incident 'clusters' affecting multiple patients. The bulk preparation of radiopharmaceuticals is a vulnerable process and merits additional safeguards. Maladministration notification rates in Australia are heterogeneous. Adopting uniform maladministration notification criteria among States and Territories and methods to overcome underreporting are warranted. PMID- 25828554 TI - Certain performance values arising from mammographic test set readings correlate well with clinical audit. AB - INTRODUCTION: Test sets have been increasingly utilised to augment clinical audit in breast screening programmes; however, their relationship has never been satisfactorily understood. This study examined the relationship between mammographic test set performance and clinical audit data. METHODS: Clinical audit data over a 2-year period was generated for each of 20 radiologists. Sixty mammographic examinations, consisting of 40 normal and 20 cancer cases, formed the test set. Readers located any identifiable cancer, and levels of confidence were scored from 2 to 5, where a score of 3 and above is considered a recall rating. Jackknifing free response operating characteristic (JAFROC) figure-of merit (FOM), location sensitivity and specificity were calculated for individual readers and then compared with clinical audit values using Spearman's rho. RESULTS: JAFROC FOM showed significant correlations to: recall rate at a first round of screening (r = 0.51; P = 0.02); rate of small invasive cancers per 10 000 reads (r = 0.5; P = 0.02); percentage of all cancers read that were not recalled (r = -0.51; P = 0.02); and sensitivity (r = 0.51; P = 0.02). Location sensitivity demonstrated significant correlations with: rate of small invasive cancers per 10 000 reads (r = 0.46; P = 0.04); rate of DCIS (ductal carcinoma in situ) per 10 000 reads (r = 0.44; P = 0.05); detection rate of all invasive cancers and DCIS per 10 000 reads (r = 0.54; P = 0.01); percentage of all cancers read that were not recalled (r = -0.57; P = 0.009); and sensitivity (r = 0.57; P = 0.009). No other significant relationships were noted. CONCLUSION: Performance indicators from test set demonstrate significant correlations with specific aspects of clinical performance, although caution needs to be exercised when generalising test set specificity to the clinical situation. PMID- 25828555 TI - Modelling the spread of bovine viral diarrhea virus (BVDV) in a beef cattle herd and its impact on herd productivity. AB - Bovine viral diarrhea virus (BVDV) is a common pathogen of cattle herds that causes economic losses due to reproductive disorders in breeding cattle and increased morbidity and mortality amongst infected calves. Our objective was to evaluate the impact of BVDV spread on the productivity of a beef cow-calf herd using a stochastic model in discrete time that accounted for (1) the difference in transmission rates when animals are housed indoors versus grazing on pasture, (2) the external risk of disease introductions through fenceline contact with neighboring herds and the purchase of infected cattle, and (3) the risk of individual pregnant cattle generating persistently infected (PI) calves based on their stage in gestation. The model predicted the highest losses from BVDV during the first 3 years after disease was introduced into a naive herd. During the endemic phase, the impact of BVDV on the yearly herd productivity was much lower due to herd immunity. However, cumulative losses over 10 years in an endemic situation greatly surpassed the losses that occurred during the acute phase. A sensitivity analysis of key model parameters revealed that herd size, the duration of breeding, grazing, and selling periods, renewal rate of breeding females, and the level of numerical productivity expected by the farmer had a significant influence on the predicted losses. This model provides a valuable framework for evaluating the impact of BVDV and the efficacy of different control strategies in beef cow-calf herds. PMID- 25828556 TI - Cervical 10 kHz spinal cord stimulation in the management of chronic, medically refractory migraine: A prospective, open-label, exploratory study. AB - BACKGROUND: A significant minority of chronic migraine (CM) subjects fail conventional medical treatment (rCM), becoming highly disabled. Implantation of an occipital nerve stimulator is a therapeutic option for these subjects. Paresthesia-free cervical 10 kHz spinal cord stimulation (HF10 SCS) may provide an alternative. We report the results of a prospective, open-label, exploratory study assessing the long-term safety, tolerability and efficacy of cervical HF10 SCS in cohort of rCM subjects. METHODS: Included subjects were diagnosed with CM by an experienced headache specialist with the aid of an hourly headache diary. They were refractory to conventional medical treatments including onabotulinumtoxin-A injections. Medication overuse headache was not an exclusion criteria. Enrolled subjects underwent a 2- to 4-week tunnelled cervical HF10 SCS trial followed by a permanent system implant if a significant, subjective reduction in headache intensity/episodes was reported during the trial. Subjects were evaluated at baseline and 6 months after implantation with the aid of monthly diaries and headache-specific questionnaires. RESULTS: Seventeen subjects underwent a trial of cervical HF10 SCS; 14 were still implanted at 6 months (one trial failure, one trial infection, one implant site infection). Seven of the 14 subjects had >30% reduction in headache days. The average reduction in headache days was 6.9 for the overall population and 12.9 among the responders. Three subjects reported tenderness over the IPG/connection site, and one had a lead migration that required surgical revision. CONCLUSION: Paresthesia-free cervical HF10 SCS may be a safe and effective therapeutic option for chronic migraineurs refractory to conventional treatments. PMID- 25828557 TI - Better use of public health facilities in India could improve kala-azar diagnosis, say researchers. PMID- 25828558 TI - Different Experiences and Goals in Different Advanced Diseases: Comparing Serial Interviews With Patients With Cancer, Organ Failure, or Frailty and Their Family and Professional Carers. AB - CONTEXT: Quality care for people living with life-limiting illnesses is a global priority. A detailed understanding of the varied experiences of people living and dying with different conditions and their family and professional caregivers should help policymakers and clinicians design and deliver more appropriate and person-centered care. OBJECTIVES: To understand how patients with different advanced conditions and their family and professional caregivers perceive their deteriorating health and the services they need. METHODS: We used a narrative framework to synthesize eight methodologically comparable, longitudinal, and multiperspective interview studies. We compared the end-of-life experiences of people dying from cancer (lung, glioma, and colorectal cancer), organ failure (heart failure, chronic obstructive pulmonary disease, and liver failure), and physical frailty and those of their family and professional caregivers in socioeconomically and ethnically diverse populations in Scotland. RESULTS: The data set comprised 828 in-depth interviews with 156 patients, 114 family caregivers, and 170 health professionals. Narratives about cancer typically had a clear beginning, middle, and an anticipated end. Cancer patients gave a well rehearsed account of their illness, hoping for recovery alongside fear of dying. In contrast, people with organ failure and their family caregivers struggled to pinpoint when their illness began, or to speak openly about death, hoping instead to avoid further deterioration. Frail older people tended to be frustrated by their progressive loss of independence, fearing dementia or nursing home admission more than dying. CONCLUSION: These contrasting illness narratives affect and shape the experiences, thoughts, and fears of patients and their carers in the last months of life. Palliative care offered by generalists or specialists should be provided more flexibly and equitably, responding to the varied concerns and needs of people with different advanced conditions. PMID- 25828561 TI - "We Are Strangers Walking Into Their Life-Changing Event": How Prehospital Providers Manage Emergency Calls at the End of Life. AB - CONTEXT: Emergency 911 calls are often made when the end stage of an advanced illness is accompanied by alarming symptoms and substantial anxiety for family caregivers, particularly when an approaching death is not anticipated. How prehospital providers (paramedics and emergency medical technicians) manage emergency calls near death influences how and where people will die, if their end of-life choices are upheld and how appropriately health care resources are used. OBJECTIVES: The purpose of this study was to explore and describe how prehospital providers assess and manage end-of-life emergency calls. METHODS: In-depth and in person interviews were conducted with 43 prehospital providers. Interviews were audiotaped, transcribed, and entered into ATLAS.ti for data management and coding. Qualitative data analysis involved systematic and axial coding to identify and describe emergent themes. RESULTS: Four themes illustrate the nature and dynamics of emergency end-of-life calls: 1) multifocal assessment (e.g., of the patient, family, and environment), 2) family responses (e.g., emotional, behavioral), 3) conflicts (e.g., missing do-not-resuscitate order, patient-family conflicts), and 4) management of the dying process (e.g., family witnessed resuscitation or asking family to leave, decisions about hospital transport). After a rapid comprehensive multifocal assessment, family responses and the existence of conflicts mediate decision making about possible interventions. CONCLUSION: The importance of managing symptom crises and stress responses that accompany the dying process is particularly germane to quality care at life's end. The results suggest the importance of increasing prehospital providers' abilities to uphold advance directives and patients' end-of-life wishes while managing family emotions near death. PMID- 25828562 TI - Unusually High Optical Transparency in Hexagonal Nanopatterned Graphene with Enhanced Conductivity by Chemical Doping. AB - Graphene has received appreciable attention for its potential applications in flexible conducting film due to its exceptional optical, mechanical, and electrical properties. However increasing transmittance of graphene without sacrificing the electrical conductivity has been difficult. The fabrication of optically highly transparent (~98%) graphene layer with a reasonable electrical conductivity is demonstrated here by nanopatterning and doping. Anodized aluminium oxide nanomask prepared by facile and simple self-assembly technique is utilized to produce an essentially hexagonally nanopatterned graphene. The electrical resistance of the graphene increases significantly by a factor of ~15 by removal of substantial graphene regions via nanopatterning into hexagonal array pores. However, the use of chemical doping on the nanopatterned graphene almost completely recovers the lost electrical conductivity, thus leading to a desirably much more optically transparent conductor having ~6.9 times reduced light blockage by graphene material without much loss of electrical conductivity. It is likely that the availability of large number of edges created in the nanopatterned graphene provides ideal sites for chemical dopant attachment, leading to a significant reduction of the sheet resistance. The results indicate that the nanopatterned graphene approach can be a promising route for simultaneously tuning the optical and electrical properties of graphene to make it more light-transmissible and suitable as a flexible transparent conductor. PMID- 25828559 TI - Predictors and Trajectories of Morning Fatigue Are Distinct From Evening Fatigue. AB - CONTEXT: Fatigue is the most common symptom in oncology patients during chemotherapy. Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients. OBJECTIVES: An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (n = 586) completed demographic and symptom questionnaires a total of six times over two cycles of chemotherapy. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index, who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance, and depressive symptoms reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients' ethnicity and younger age. CONCLUSION: The modifiable risk factors that were associated with only morning fatigue were body mass index, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors. PMID- 25828560 TI - Trajectories of Evening Fatigue in Oncology Outpatients Receiving Chemotherapy. AB - CONTEXT: Fatigue is a distressing persistent sense of physical tiredness that is not proportional to a person's recent activity. Fatigue impacts patients' treatment decisions and can limit their self-care activities. Although significant interindividual variability in fatigue severity has been noted, little is known about predictors of interindividual variability in initial levels and trajectories of evening fatigue severity in oncology patients receiving chemotherapy. OBJECTIVES: To determine whether demographic, clinical, and symptom characteristics were associated with initial levels and the trajectories of evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N = 586) completed demographic and symptom questionnaires a total of six times over two cycles of chemotherapy. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the evening fatigue trajectories. A piecewise model fit the data best. Patients who were white, diagnosed with breast, gynecological, or lung cancer, and who had more years of education, childcare responsibilities, lower functional status, and higher levels of sleep disturbance and depression reported higher levels of evening fatigue at enrollment. CONCLUSION: This study identified both nonmodifiable (e.g., ethnicity) and modifiable (e.g., childcare responsibilities, depressive symptoms, sleep disturbance) risk factors for more severe evening fatigue. Using this information, clinicians can identify patients at higher risk for more severe evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors. PMID- 25828563 TI - Detection of Merkel cell and other human polyomavirus DNA in lesional and nonlesional skin from patients with Kaposi sarcoma. PMID- 25828564 TI - Use of Salad Bars in Schools to Increase Fruit and Vegetable Consumption: Where's the Evidence? PMID- 25828565 TI - Reprint of "The mitochondrial permeability transition pore and its adaptive responses in tumor cells". AB - This review covers recent progress on the nature of the mitochondrial permeability transition pore (PTP) - a key effector in the mitochondrial pathways to cell death - and on the adaptive responses of tumor cells that desensitize the PTP to Ca(2+) and reactive oxygen species (ROS), thereby playing an important role in the resistance of tumors to cell death. The discovery that the PTP forms from dimers of F-ATP synthase; and the definition of the Ca(2+)- and ROS dependent signaling pathways affecting the transition of the F-ATP synthase from an energy-conserving to an energy-dissipating device open new perspectives for therapeutic intervention in cancer cells. PMID- 25828566 TI - An intelligent nano-antenna: Primary cilium harnesses TRP channels to decode polymodal stimuli. AB - The primary cilium is a solitary hair-like organelle on the cell surface that serves as an antenna sensing ever-changing environmental conditions. In this review, we will first recapitulate the molecular basis of the polymodal sensory function of the primary cilia, specifically focusing on transient receptor potential (TRP) channels that accumulate inside the organelle and conduct calcium ions (Ca(2+)). Each subfamily member, namely TRPP2 TRPP3, TRPC1 and TRPV4, is gated by multiple environmental factors, including chemical (receptor ligands, intracellular second messengers such as Ca(2+)), mechanical (fluid shear stress, hypo-osmotic swelling), or physical (temperature, voltage) stimuli. Both activity and heterodimer compositions of the TRP channels may be dynamically regulated for precise tuning to the varying dynamic ranges of the individual input stimuli. We will thus discuss the potential regulation of TRP channels by local second messengers. Despite its reported importance in embryonic patterning and tissue morphogenesis, the precise functional significance of the downstream Ca(2+) signals of the TRP channels remains unknown. We will close our review by featuring recent technological advances in visualizing and analyzing signal transduction inside the primary cilia, together with current perspectives illuminating the functional significance of intraciliary Ca(2+) signals. PMID- 25828568 TI - The Dual-Loop Model and the Human Mirror Neuron System: an Exploratory Combined fMRI and DTI Study of the Inferior Frontal Gyrus. AB - The inferior frontal gyrus (IFG) is active during both goal-directed action and while observing the same motor act, leading to the idea that also the meaning of a motor act (action understanding) is represented in this "mirror neuron system" (MNS). However, in the dual-loop model, based on dorsal and ventral visual streams, the MNS is thought to be a function of the dorsal steam, projecting to pars opercularis (BA44) of IFG, while recent studies suggest that conceptual meaning and semantic analysis are a function of ventral connections, projecting mainly to pars triangularis (BA45) of IFG. To resolve this discrepancy, we investigated action observation (AO) and imitation (IMI) using fMRI in a large group of subjects. A grasping task (GR) assessed the contribution from movement without AO. We analyzed connections of the MNS-related areas within IFG with postrolandic areas with the use of activation-based DTI. We found that action observation with imitation are mainly a function of the dorsal stream centered on dorsal part of BA44, but also involve BA45, which is dorsally and ventrally connected to the same postrolandic regions. The current finding suggests that BA45 is the crucial part where the MNS and the dual-loop system interact. PMID- 25828569 TI - Sensing Solvents with Ultrasensitive Porous Poly(ionic liquid) Actuators. PMID- 25828567 TI - A Major Human White Matter Pathway Between Dorsal and Ventral Visual Cortex. AB - Human visual cortex comprises many visual field maps organized into clusters. A standard organization separates visual maps into 2 distinct clusters within ventral and dorsal cortex. We combined fMRI, diffusion MRI, and fiber tractography to identify a major white matter pathway, the vertical occipital fasciculus (VOF), connecting maps within the dorsal and ventral visual cortex. We use a model-based method to assess the statistical evidence supporting several aspects of the VOF wiring pattern. There is strong evidence supporting the hypothesis that dorsal and ventral visual maps communicate through the VOF. The cortical projection zones of the VOF suggest that human ventral (hV4/VO-1) and dorsal (V3A/B) maps exchange substantial information. The VOF appears to be crucial for transmitting signals between regions that encode object properties including form, identity, and color and regions that map spatial information. PMID- 25828570 TI - Dialysate and serum potassium in hemodialysis. AB - Most patients with end-stage renal disease depend on intermittent hemodialysis to maintain levels of serum potassium and other electrolytes within a normal range. However, one of the challenges has been the safety of using a low-potassium dialysate to achieve that goal, given the concern about the effects that rapid and/or large changes in serum potassium concentrations may have on cardiac electrophysiology and arrhythmia. Additionally, in this patient population, there is a high prevalence of structural cardiac changes and ischemic heart disease, making them even more susceptible to acute arrhythmogenic triggers. This concern is highlighted by the knowledge that about two-thirds of all cardiac deaths in dialysis are due to sudden cardiac death and that sudden cardiac death accounts for 25% of the overall death for end-stage renal disease. Developing new approaches and practice standards for potassium removal during dialysis, as well as understanding other modifiable triggers of sudden cardiac death, such as other electrolyte components of the dialysate (magnesium and calcium), rapid ultrafiltration rates, and safety of a number of medications (ie, drugs that prolong the QT interval or use of digoxin), are critical in order to decrease the unacceptably high cardiac mortality experienced by hemodialysis-dependent patients. PMID- 25828572 TI - Inserting random and site-specific changes into the genome of chickens. AB - During the past decade, modifications to the chicken genome have evolved from random insertions of small transgenes using viral vectors to site-specific deletions using homologous recombination vectors and nontargeted insertions of large transgenes using phi-31 integrase. Primordial germ cells (PGC) and gonocytes are the germline-competent cell lines in which targeted modifications and large transgenes are inserted into the genome. After extended periods of in vitro culture, PGC retain their capacity to form functional gametes when reintroduced in vivo. Rates of stable germline modification vary from 1*10(-5) for nontargeted insertions to 1*10(-8) for targeted insertions. Following transfection, clonally derived cell lines are expanded, injected into Stage 13-15 Hamburger and Hamilton embryos, and putative chimeras are incubated to term in surrogate shells. Green fluorescent protein (GFP) is incorporated into transgenes to reveal the presence of genetically modified PGC in culture and the extent of colonization of the gonad during the first week posthatch. If the extent of colonization is adequate, cohorts of putative chimeras are reared to sexual maturity. Semen is collected and the contribution from donor PGC is estimated by evaluating GFP expression using flow cytometry and PCR. The most promising candidates are selected for breeding to obtain G1 heterozygote offspring. To date, this protocol has been used to (1) knockout the immunoglobulin heavy and light chain genes and produce chickens lacking humoral immunity, (2) insert human V genes and arrays of pseudo V genes into the heavy and light immunoglobulin loci to produce chickens making antibodies with human V regions, (3) insert GFP into nontargeted locations within the genome to produce chickens expressing GFP, and (4) insert Cre recombinase into the genome to produce chickens that excise sequences of DNA flanked by loxP sites. PMID- 25828571 TI - Exploring avian deep-brain photoreceptors and their role in activating the neuroendocrine regulation of gonadal development. AB - In the eyes of mammals, specialized photoreceptors called intrinsically photosensitive retinal ganglion cells (ipRGC) have been identified that sense photoperiodic or daylight exposure, providing them over time with seasonal information. Detectors of photoperiods are critical in vertebrates, particularly for timing the onset of reproduction each year. In birds, the eyes do not appear to monitor photoperiodic information; rather, neurons within at least 4 different brain structures have been proposed to function in this capacity. Specialized neurons, called deep brain photoreceptors (DBP), have been found in the septum and 3 hypothalamic areas. Within each of the 4 brain loci, one or more of 3 unique photopigments, including melanopsin, neuropsin, and vertebrate ancient opsin, have been identified. An experiment was designed to characterize electrophysiological responses of neurons proposed to be avian DBP following light stimulation. A second study used immature chicks raised under short-day photoperiods and transferred to long day lengths. Gene expression of photopigments was then determined in 3 septal-hypothalamic regions. Preliminary electrophysiological data obtained from patch-clamping neurons in brain slices have shown that bipolar neurons in the lateral septal organ responded to photostimulation comparable with mammalian ipRGC, particularly by showing depolarization and a delayed, slow response to directed light stimulation. Utilizing real-time reverse-transcription PCR, it was found that all 3 photopigments showed significantly increased gene expression in the septal hypothalamic regions in chicks on the third day after being transferred to long day photoperiods. Each dissected region contained structures previously proposed to have DBP. The highly significant increased gene expression for all 3 photopigments on the third, long-day photoperiod in brain regions proposed to contain 4 structures with DBP suggests that all 3 types of DBP (melanopsin, neuropsin, and vertebrate ancient opsin) in more than one neural site in the septal-hypothalamic area are involved in reproductive function. The neural response to light of at least 2 of the proposed DBP in the septal/hypothalamic region resembles the primitive, functional, sensory ipRGC well characterized in mammals. PMID- 25828573 TI - Scan-rescan reproducibility of parallel transmission based amide proton transfer imaging of brain tumors. AB - PURPOSE: To evaluate the reproducibility of amide proton transfer (APT) imaging of brain tumors using a parallel transmission-based technique. MATERIALS AND METHODS: Thirteen patients with brain tumors (four low-grade gliomas, three glioblastoma multiforme, five meningiomas, and one malignant lymphoma) were included in the study. APT imaging was conducted at 3T using a 2-channel parallel transmission scheme with a saturation time of 2 seconds and B1 amplitude of 2 MUT. A 2D fast spin-echo sequence with driven-equilibrium refocusing was used for imaging. Z-spectra were obtained at 25 frequency offsets from -6 to +6 ppm (step 0.5 ppm). A point-by-point B0 correction was performed with a B0 map. A scan rescan reproducibility test was performed in two sessions on separate days for each patient. The interval between the two sessions was 4.8 +/- 3.5 days. Regions of-interest (ROIs) were placed to include the whole tumor for each case. A mean and 90-percentile value of APT signal for the whole tumor histogram was calculated for each session. The between-session and within-session reproducibility was evaluated using linear regression analysis, intraclass correlation coefficient (ICC), and a Bland-Altman plot. RESULTS: The mean and 90 percentile values of the APT signal for whole tumor ROI showed excellent agreements between the two sessions, with R(2) of 0.91 and 0.96 in the linear regression analysis and ICC of 0.95 and 0.97, respectively. CONCLUSION: Parallel transmission-based APT imaging of brain tumors showed good reproducibility. PMID- 25828574 TI - Highly Emissive Nanoparticles Based on AIE-Active Molecule and PAMAM Dendritic "Molecular Glue". AB - The highly emissive nanoparticles Gn-TCMPE (n = 0-4) were prepared by using PAMAM dendrimers as "molecular glue" to adhere an AIE-active molecule tetra(4 (carboxymethoxy)phenyl)ethylene (TCMPE). The electrostatic interaction of ammonium-carboxylate ion pairs provides a driving force between TCMPE and PAMAM dendrimers to form the nanoparticles Gn-TCMPE (n = 0-4), which is validated by the FTIR and (1)H NMR spectra. The formation of nanoparticles dramatically blocks the nonradiative pathway and enhances the fluorescence of TCMPE. The quantum yields of Gn-TCMPE gradually boost at first and then reach to a plateau with increasing the generation of PAMAM dendrimers, and the highest absolute quantum yields are obtained to be 0.42 and 0.64 for Gn-TCMPE (n = 2-4) in methanol dispersion and solid phases, respectively. The fluorescence of the nanoparticles can be tuned by addition of trifluoroacetic acid (TFA). Furthermore, the G4-TCMPE has been successfully applied to selectively image cytoplasm of Hela cells with excellent photostability and low cytotoxicity. This study provides a novel noncovalent strategy for developing highly emissive and robust organic materials fitting for cell fluorescence imaging. PMID- 25828576 TI - Characterizing in vivo stability and potential interactions of a UL5 helicase primase mutation previously shown to reduce virulence and in vivo replication of Marek's disease virus. AB - The unpredictable yet recurrent emergence of more virulent field strains of Marek's disease virus (MDV) in Marek's disease (MD) vaccinated flocks of chickens has prompted concerns regarding the sustainability of MD vaccines. A single non synonymous point mutation (I682R) within the UL5 helicase-primase unit was shown to reduce virulence by over 90%. Considering in vitro attenuation is commonly used to generate MD vaccines, this result prompted further characterization of this mutation, particularly to better understand the potential of point mutations for use in vaccine development. Incorporation of a second non-synonymous point mutation (UL46-Q117R; tegument) found at high frequencies in the same attenuated MDV as the UL5 mutation did not further reduce virulence compared to the single UL5 mutation alone. Furthermore, when the UL5-containing MDV was serially passed three times in vivo, the resulting viruses did not show increases in replication or virulence, and no revertant viruses could be detected. This suggests that point mutations that reduce fitness and in vivo replication may be more stable than initially anticipated, which may alleviate some concerns regarding rationally designed MD vaccines based upon point mutations. PMID- 25828575 TI - Intracellular EP2 prostanoid receptor promotes cancer-related phenotypes in PC3 cells. AB - Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1alpha (HIF-1alpha) affect many mechanisms that have been involved in the pathogenesis of prostate cancer (PC). HIF-1alpha, which is up-regulated by PGE2 in LNCaP cells and PC3 cells, has been shown to contribute to metastasis and chemo-resistance of castrate-resistant PC (a lethal form of PC) and to promote in PC cells migration, invasion, angiogenesis and chemoresistance. The selective blockade of PGE2-EP2 signaling pathway in PC3 cells results in inhibition of cancer cell proliferation and invasion. PGE2 affects many mechanisms that have been shown to play a role in carcinogenesis such as proliferation, apoptosis, migration, invasion and angiogenesis. Recently, we have found in PC3 cells that most of these PGE2 induced cancer-related features are due to intracellular PGE2 (iPGE2). Here, we aimed to study in PC3 cells the role of iPGE2-intracellular EP2 (iEP2)-HIF-1alpha signaling in several events linked to PC progression using an experimental approach involving pharmacological inhibition of the prostaglandin uptake transporter and EGFR and pharmacological and genetic modulation of EP2 receptor and HIF-1alpha. We found that iPGE2 increases HIF-1alpha expression through iEP2 dependent EGFR transactivation and that inhibition of any of the axis iEP2-EGFR HIF-1alpha in cells treated with PGE2 or EP2 agonist results in prevention of the increase in PC3 cell proliferation, adhesion, migration, invasion and angiogenesis in vitro. Of note, PGE2 induced EP2 antagonist-sensitive DNA synthesis in nuclei isolated from PC3 cells, which indicates that they have functional EP2 receptors. These results suggest that PGE2-EP2 dependent intracrine mechanisms involving EGFR and HIF-1alpha play a role in PC. PMID- 25828578 TI - Harvesting dissipated energy with a mesoscopic ratchet. AB - The search for new efficient thermoelectric devices converting waste heat into electrical energy is of major importance. The physics of mesoscopic electronic transport offers the possibility to develop a new generation of nanoengines with high efficiency. Here we describe an all-electrical heat engine harvesting and converting dissipated power into an electrical current. Two capacitively coupled mesoscopic conductors realized in a two-dimensional conductor form the hot source and the cold converter of our device. In the former, controlled Joule heating generated by a voltage-biased quantum point contact results in thermal voltage fluctuations. By capacitive coupling the latter creates electric potential fluctuations in a cold chaotic cavity connected to external leads by two quantum point contacts. For unequal quantum point contact transmissions, a net electrical current is observed proportional to the heat produced. PMID- 25828577 TI - Repurposing de novo designed entities reveals phosphodiesterase 3B and cathepsin L modulators. AB - Using computational bioactivity prediction models we identified phosphodiesterase 3B (PDE3B) and cathepsin L as macromolecular targets of de novo designed compounds. By disclosing the most potent cathepsin L activator known to date, small molecule repurposing by target panel prediction represents a feasible route towards innovative leads for chemical biology and molecular medicine. PMID- 25828579 TI - The molecular basis of low activity levels of coagulation factor VII: a Brazilian cohort. AB - Inherited factor VII (FVII) deficiency is the most common among the rare bleeding disorders. It is transmitted as an autosomal recessive inheritance, due to mutations in the FVII gene (F7). Molecular studies of FVII deficiency are rare in non-Caucasian populations. The aim of the study was to evaluate the molecular basis behind low levels of FVII activity (FVII:C) levels in a cohort of Brazilian patients. A total of 34 patients with low FVII levels were clinically evaluated and submitted to laboratory tests, among these, prothrombin time and FVII:C, with different thromboplastins. All exons and intron/exon boundaries of F7 were amplified and sequenced. A total of 14 genetic alterations were identified, of which six were described previously, c.1091G>A, c.1151C>T, c.-323_ 313insCCTATATCCT, c.285G>A, c.525C>T, c.1238G>A and eight (54.0%) and eight were new, c.128G>A, c.252C>T, c.348G>A, c.417G>A, c.426G>A, c.745_747delGTG, c.843G>A and c.805+52C>T. In addition to the mutation c.1091G>A, known as FVII Padua, the mutation c.1151C>T also presented discrepant FVII:C levels when tested with human and rabbit brain thromboplastin. There was no association between phenotype and genotype. Most of the identified genetic alterations found were polymorphisms. Low levels of FVII:C in this population were mostly related to polymorphisms in F7 and associated with a mild clinical phenotype. Mutation c.1151C>T was associated with discrepant levels of FVII:C using different thromboplastins, such as reported with FVII Padua. PMID- 25828580 TI - How do children complete a seated combined cognitive and motor multi-tasking paradigm? AB - Healthy children (n=12, age 7years) and young adults (n=11, age 21years) were asked to perform a bimanual balance and reaching protocol in a seated posture. Subjects balanced a ball on a Frisbee on the non-dominant palm of the hand while reaching with the dominant hand to pick up a toy off the ground. During half of the trials, an auditory Stroop task was administered simultaneous to onset of the participants' reach. All children (CH) and adults (AD) successfully completed both motor and cognitive tasks when combined: the ball and Frisbee were not dropped and cognitive accuracy rate for both groups was 77%. Angular range of motion (ROM) measures indicated that the trunk, upper arm (UA) and forearm (FA) segments were moving as articulated individual segments in both adults and children (ROM for trunk?UA?FA; p<.001). However, differences between CH and AD upper body segmental control were evident: greater variability existed between trials and between subjects for segmental ROM in CH compared to AD (p<.001), suggesting that adult-like control is still developing in this age group. Results indicate children aged 7years can successfully perform a simultaneous upper body motor and cognitive task in a seated posture, however motor performance control is not yet at the same level as adults. PMID- 25828581 TI - Robustness to temporal constraint explains expertise in ball-over-net sports. AB - The present study investigated motor expertise in interpersonal competitive ball over-net sports in terms of a dynamical system with temporal input. In a theoretical framework, the behavior of the system is characterized by a fractal like structure according to switching input, which changes uniquely according to the duration of input and internal parameter of the system. We investigated periodic movements, in which the player executed a forehand or backhand stroke repeatedly, and continuous switching movements, in which the player continuously switched between two movement patterns corresponding to hitting the ball under two ball directions and with six temporal constraint conditions during a table tennis rally. In the periodic movement, we observed two limit-cycle attractors corresponding to each direction in the phase space independent of temporal constraint or skill level. Conversely, in the continuous switching movement, a transition in trajectories between the two limit-cycle attractors was observed in the phase space, and this transition was characterized by a fractal-like structure. The fractal-like structure moved closer to the random structure as temporal constraint increased independent of skill level. However, the temporal constraint condition closest to the random structure was higher for the advanced players than for the novices, indicating that robustness to the temporal constraint was higher for the advanced players than for the novices. Our results suggest that motor expertise in interpersonal competitive ball-over-net sports is more robust to temporal constraints with various inputs. PMID- 25828582 TI - A minimal limit-cycle model to profile movement patterns of individuals during agility drill performance: Effects of skill level. AB - Identification of control strategies during agility performance is significant in understanding movement behavior. This study aimed at providing a fundamental mathematical model for describing the motion of participants during an agility drill and to determine whether skill level constrained model components. Motion patterns of two groups of skilled and unskilled participants (n=8 in each) during performance of a forward/backward agility drill modeled as limit-cycles. Participant movements were recorded by motion capture of a reflective marker attached to the sacrum of each individual. Graphical and regression analyses of movement kinematics in Hooke's plane, phase plane and velocity profile were performed to determine components of the models. Results showed that the models of both skilled and unskilled groups had terms from Duffing stiffness as well as Van der Pol damping oscillators. Data also indicated that the proposed models captured on average 97% of the variance for both skilled and unskilled groups. Findings from this study revealed the movement patterning associated with skilled and unskilled performance in a typical forward/backward agility drill which might be helpful for trainers and physiotherapists in enhancing agility. PMID- 25828584 TI - Active role of small peptides in Arabidopsis reproduction: Expression evidence. PMID- 25828585 TI - Biologic therapy in ANCA-negative vasculitis. AB - Standard therapeutic schemes for vasculitis are usually associated with numerous side effects and uneven clinical response. However, recent advances in understanding of the pathogenesis of these systemic diseases have resulted in the development of a group of biologic agents potentially useful in patients with vasculitis. Thus, anti-tumor necrosis factor-alpha drugs may be effective in patients with refractory Kawasaki disease but have failed to do so in giant cell arteritis, and their role in Takayasu arteritis is yet unclear. Preliminary reports on the use of the anti-IL6-receptor antibody, tocilizumab, in large vessel vasculitis have been encouraging. Interferon alpha has showed positive results in hepatitis B virus-associated polyarteritis nodosa, and hepatitis C virus-induced cryoglobulinemia. Early experience with rituximab in several types of vasculitis has been quite promising, but must be confirmed in ongoing randomized clinical trials. The development of new biologic targeted therapies will probably open a hopeful future for patients with vasculitis. PMID- 25828583 TI - Manipulation of apoptosis and necroptosis signaling by herpesviruses. AB - Like apoptosis, necroptosis is an innate immune mechanism that eliminates pathogen-infected cells. Receptor-interacting protein kinase (RIP)3 (also called RIPK3) mediates necrotic death by phosphorylating an executioner protein, MLKL, leading to plasma membrane leakage. The pathway is triggered against viruses that block caspase 8. In murine CMV, the viral inhibitor of caspase 8 activation prevents extrinsic apoptosis but also has the potential to unleash necroptosis. This virus encodes the viral inhibitor of RIP activation to prevent RIP homotypic interaction motif (RHIM)-dependent signal transduction and necroptosis. Recent investigations reveal a similar mechanism at play in the human alpha herpesviruses, herpes simplex virus (HSV)1 and HSV2, where RHIM competitor function and caspase 8 suppression are carried out by the virus-encoded large subunit of ribonucleotide reductase (R1). In human cells, R1 inhibition of caspase 8 prevents TNF-induced apoptosis, but sensitizes to TNF-induced necroptosis. The RHIM and caspase 8 interaction domains of R1 collaborate to prevent RIP3-dependent steps and enable both herpesviruses to deflect host cell death machinery that would cut short infection. In mouse cells, HSV1 infection by itself triggers necroptosis by driving RIP3 protein kinase activity. HSV1 R1 contributes to the activation of RIP3 adaptor function in mice, a popular host animal for experimental infection. Based on these studies, infection of RIP3 kinase inactive mice should be explored in models of pathogenesis and latency. The necrotic death pathway that is suppressed during infection in the natural host becomes a cross-species barrier to infection in a non-natural host. PMID- 25828586 TI - Temporary blindness after an anterior chamber cosmetic filler injection. AB - Blindness is a rare but devastating complication of cosmetic filler injection. A primary cause of blindness following hyaluronic acid filler injection is retrograde intravascular embolization into the small ocular arteries. We here report a case of temporary blindness associated with the injection of hyaluronic acid filler into the anterior chamber of eye. This is the first report of temporary blindness after cosmetic filler injection into the anterior chamber, and the first described case that recovered completely after the filler was removed. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25828587 TI - A new method for inframammary fold recreation using a barbed suture. AB - BACKGROUND: There are inherent limitations with previously reported inframammary fold (IMF) recreation methods. The IMF is firmly fixed to the chest wall, but not physiologically, and it is difficult to determine the correct IMF position in the supine position and in the absence of an implant. METHODS: With our new IMF reconstruction method (i.e., drawstring method), the IMF is recreated by drawing a barbed suture, penetrating the dermis, along the IMF. The barbed suture is fixed to the costal cartilage at the medial IMF, and the head is drawn and cut externally at the lateral IMF. The IMF level and depth can be finely adjusted by the tension, in a seated position after implant insertion. Furthermore, the approach can be from a small incision, and a smooth IMF curve is reconstructed. RESULTS: Our drawstring method was performed in 102 patients who underwent reconstruction using a breast implant (n = 95) or flap (n = 7). The mean patient age was 52.0 years (range 33-77 years) and the follow-up period was 12 months (range 3-18 months). Suture or implant infection or exposure did not occur. Suture slack occurred in ten patients with implant-based reconstruction; their IMF became shallow. Insufficient skin expansion (P < 0.005) and strong traction of the barbed suture from the caudal side (P < 0.05) were related to IMF slack. The total revision rate was 2.9 %. CONCLUSIONS: With sufficient skin expansion, the drawstring method using a barbed suture enables smooth and symmetrical IMF reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25828588 TI - Expression of TNFalpha membrane-bound receptors in the peripheral blood mononuclear cells (PMBC) in rheumatoid arthritis patients. AB - OBJECTIVE: To investigate the expression of TNFalpha membrane-bound receptors: the percentage of cells expressing these receptors and the number of molecules expressed on different immune cell subsets, and to evaluate serum concentrations of soluble TNFalpha and its receptors (sTNFRI and sTNFRII) in patients with rheumatoid arthritis in acute stage and after response to treatment compared to healthy donors. METHODS: The objects of the study are peripheral blood mononuclear cells (PBMC) of healthy donors (n=150) and RA patients (n=40) subjected to hospital treatment with either biological agents (Rituximab) or glucocorticosteroids (methylprednisolone). To determine PBMC phenotype antibodies anti-hCD3-APC, anti-hCD19 PECy7, anti-hCD14 FITC (eBioscience), as well as anti hTNFRI-PE and anti-hTNFRII-PE (R&D Systems) were used. To determine receptor number on the cells Quantibrite PE Beads (BD) were used. RESULTS: Cells obtained from patients who responded to therapy and achieved disease remission exhibited either an increase in the percentage of TNFRI+ cells or elevated expression density of this receptor type. CONCLUSION: Subsets of immunocompetent cells from RA patients show variation in the percentage of membrane-bound receptor positive cells and receptor expression density, which influences the development and progression of the pathological processes in RA. Response to therapy and achievement of disease remission are associated with an increase of TNFRI expression. PMID- 25828589 TI - In vivo relative quantitative proteomics reveals HMGB1 as a downstream mediator of oestrogen-stimulated keratinocyte migration. AB - It is known that oestrogen influences skin wound healing by modulating the inflammatory response, cytokine expression and extracellular matrix deposition; accelerating re-epithelialization; and stimulating angiogenesis. To identify novel proteins associated with effects of oestrogen on keratinocyte, stable isotope labelling by amino acids in cell culture (SILAC)-based mass spectrometry was performed. Using SILAC, quantification of 1085 proteins was achieved. Among these proteins, 60 proteins were upregulated and 32 proteins were downregulated. Among significantly upregulated proteins, high-mobility group protein B1 (HMGB1) has been further evaluated for its role in the effect of oestrogen on keratinocytes. HMGB1 expression was strongly induced in oestrogen-treated keratinocytes in dose- and time-dependent manner. Further, HMGB1 was able to significantly accelerate the rate of HaCaT cell migration. To determine whether HMGB1 is involved in E2-induced HaCaT cell migration, cells were transfected with HMGB1 siRNA. Knockdown of HMGB1 blocked oestrogen-induced keratinocyte migration. Collectively, these experiments demonstrate that HMGB1 is a novel downstream mediator of oestrogen-stimulated keratinocyte migration. PMID- 25828590 TI - Reply: To PMID 24890124. PMID- 25828591 TI - Interplay of Drug-Metabolizing Enzymes and Transporters in Drug Absorption and Disposition. AB - In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed the "transport-metabolism interplay". The current mechanistic understanding for this interplay is first discussed. In the present article, studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed in vitro, in situ, in silico, in animals and humans, followed by CYPs-uptake transporters, CYPs-uptake transporters-efflux transporters, and phase II metabolic enzymes transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g. nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs and DTs and to delineate the underlying mechanisms. PMID- 25828592 TI - PepT1, ASBT-Linked Prodrug Strategy to Improve Oral Bioavailability and Tissue Targeting Distribution. AB - With the rapid development of molecular biology, various of drug transporters have been discovered in several important organs of the body, which determine intracellular exposure and pharmacokinetic performances of drugs by modulating cellular entry and exit. This article focuses on the design of transporter-linked prodrug to enhance oral bioavailability and to acquire tissue-specific distribution pattern, especially paying attention to peptide transporter 1 (PepT1) and apical sodium dependent bile acid transporter (ASBT). Conjugation of the native promotety to active drug was one of the effective methods to improve membrane permeability and distribution profiles of drugs. In this review, we highlight the transporter-linked prodrug design modality based on PepT1 and ASBT. The biology of transporters, structure-transport relationship, key features of natural substrates and successful examples of transporter-linked prodrugs are overviewed in detail. PMID- 25828593 TI - Recent Advances in the Methodology and Application for the Metabolism of Phytochemical Compounds-An Update Covering the Period of 2009-2014. AB - The research of drug metabolism is essential for successful drug discovery. Phytochemicals, particularly those from herbal medicines, have the potential to affect diseases such as cancer, heart disease, diabetes, and high blood pressure, etc., showing great advantages in disease prevention and personalized treatment. In the past decade, phytochemical metabolism played a major role in the discovery of valuable leading compounds of new drugs. However, the metabolic studies of phytochemical compounds are extremely challenging due to numerous analogs with similar structures, complex endogenous matrices with multi-components in biofluids and cell or tissue extracts. For the feasibility of monitoring phytochemical metabolism, suitable bioanalytical tools and strategies have to be developed and validated. Here we critically review the literature from 2009 to 2014, and present generalized strategy for phytochemical metabolism in biological matrices, including the methodology of metabolism, sample preparation methods and detection techniques. In addition, the present paper covers the diverse aspects of metabolism studies on phenolic acids, flavonoids, anthraquinones, alkaloids, terpenoids, coumarins, lignans and steroids in medicinal plants. Finally, prospects for further research are also considered. PMID- 25828594 TI - Nucleic Acids Delivery Systems: A Challenge for Pharmaceutical Technologists. AB - Nucleic acids (NA) therapies, including therapy with genes, aptamers or antisense oligonucleotides, have been showing promising results, especially in the treatment of severe diseases (e.g. cancer and AIDS). Nevertheless, the full success of medical treatments requires efficient achievement of the therapeutic target and also the safety and effectiveness of the pharmaceutical system. NA are not very efficient when administered alone, which means that the use of appropriate methods for in vivo transfection of these molecules into targeted cells is fundamental. Examples of these techniques are the use of viral and non viral vectors to transfer the NA to the cells nucleus. Despite viral vectors have been demonstrating superior effectiveness for NA transfer, some drawbacks have been pointed out, which focused the research in the non-viral vectors. However, the development of effective NA delivery systems remains a challenge for pharmaceutical technologists, mainly because of their in vivo failure, which hinders their clinical application. In this review article we address the characteristics of NA molecules and their respective limitations for formulation and administration. An update on the state of the art related to the latest and outstanding developments from the in vivo applications of NA viral and non-viral delivery systems is also presented. From this review, we can conclude that there is a lack of research regarding pre-clinical studies in specific animal models of disease, which is required for further human clinical trials and for their use in clinics. PMID- 25828595 TI - Pulmonary acantholytic squamous cell carcinoma with focal signet ring cell morphology mimicking malignant mesothelioma on fine needle aspiration cytology: a case report. PMID- 25828596 TI - Binge eating in bariatric surgery candidates: The role of insecure attachment and emotion regulation. AB - Binge eating has a high prevalence among bariatric patients and is associated with post-surgical weight gain. This study examined the potential mediating role of emotion regulation difficulties in the relation between attachment insecurity and binge eating among this population. Participants were 1388 adult pre bariatric surgery candidates from an accredited bariatric surgery assessment centre in Toronto, Ontario. Participants completed measures of psychological functioning, including attachment style and emotion regulation. Mediation analyses revealed that difficulties with emotion regulation mediated a positive association between insecure-anxious attachment and binge eating. An insecure avoidant attachment was found to have a non-significant association with binge eating when examining the total effect. However, when difficulties with emotion regulation were controlled for in the model to examine its role as a mediator, this association became significant, and emotion regulation difficulties also mediated the relationship between attachment avoidance and binge eating. These findings suggest that difficulties in emotion regulation may be an important clinical issue to address in order to reduce binge eating in adult bariatric surgery candidates. PMID- 25828597 TI - Artificial sweeteners are not the answer to childhood obesity. AB - While no single factor is responsible for the recent, dramatic increases in overweight and obesity, a scientific consensus has emerged suggesting that consumption of sugar-sweetened products, especially beverages, is casually linked to increases in risk of chronic, debilitating diseases including type 2 diabetes, cardiovascular disease, hypertension and stroke. One approach that might be beneficial would be to replace sugar-sweetened items with products manufactured with artificial sweeteners that provide sweet tastes but with fewer calories. Unfortunately, evidence now indicates that artificial sweeteners are also associated with increased risk of the same chronic diseases linked to sugar consumption. Several biologically plausible mechanisms may explain these counterintuitive negative associations. For example, artificial sweeteners can interfere with basic learning processes that serve to anticipate the normal consequences of consuming sugars, leading to overeating, diminished release of hormones such as GLP-1, and impaired blood glucose regulation. In addition, artificial sweeteners can alter gut microbiota in rodent models and humans, which can also contribute to impaired glucose regulation. Use of artificial sweeteners may also be particularly problematic in children since exposure to hyper sweetened foods and beverages at young ages may have effects on sweet preferences that persist into adulthood. Taken as a whole, current evidence suggests that a focus on reducing sweetener intake, whether the sweeteners are caloric or non caloric, remains a better strategy for combating overweight and obesity than use of artificial sweeteners. PMID- 25828598 TI - 50 is the new 70: Short ventriculoatrial times are common in children with atrioventricular reciprocating tachycardia. AB - BACKGROUND: One of the basic electrophysiological principles of atrioventricular reciprocating tachycardia (AVRT) is that ventriculoatrial (VA) times during tachycardia are >70 ms. We hypothesized, however, that children may commonly have VA times <70 ms in AVRT. OBJECTIVE: This study sought to determine the incidence and characteristics associated with short-VA AVRT in children. METHODS: A retrospective single-center review of children with AVRT from 2000 to 2014 was performed. All patients <=18 years of age with AVRT at electrophysiology study were included. Patients with persistent junctional reciprocating tachycardia, atrioventricular nodal reentry tachycardia, and tachycardia not unequivocally proven to be AVRT were excluded. VA time was defined as the time between earliest ventricular activation and earliest atrial activation in any lead and was confirmed by 2 electrophysiologists. Patients with VA times <70 ms (SHORT-VA) and those with standard VA times >=70 ms (STD-VA) were compared. Logistic regression analysis identified characteristics of SHORT-VA patients. RESULTS: A total of 495 patients with AVRT were included (mean age 11.7 +/- 4.1 years). There were 265 patients (54%) with concealed accessory pathways (APs) and 230 (46%) with Wolff Parkinson-White syndrome. AP location was left-sided in 301 patients (61%) and right-sided in 194 (39%). The mean VA time in AVRT was 100 +/- 33 ms. A total of 63 patients (13%) had VA times <70 ms (SHORT-VA). The shortest VA time during AVRT was 50 ms. There was no difference in age, AV nodal block cycle, or body surface area between SHORT-VA and STD-VA patients, but SHORT-VA patients had lower weight (43 +/- 17 vs 51 +/- 23 kg, P = .02), lower AV nodal effective refractory period (AVNERP; 269 +/- 50 vs 245 +/- 52 ms, P < .01), and more left sided APs (50 [79%] vs 251 [58%]; P < .01]. On multivariate logistic regression, factors associated with SHORT-VA included left-sided AP (odds ratio [OR] 5.79, confidence interval [95% CI] 2.21-15.1, P < .01), shorter AVNERP (OR 0.99, CI 0.98-0.99, P < .01), and lower weight (OR 0.97, CI 0.95-0.99, P < .01). CONCLUSIONS: Children with AVRT can frequently have VA times <70 ms, with 50 ms being the shortest VA time. This finding debunks the classic electrophysiology principle that VA times in AVRT must be >70 ms. SHORT-VA AVRT was more common in children with left-sided APs. PMID- 25828599 TI - "Needle-in-needle" epicardial access: Preliminary observations with a modified technique for facilitating epicardial interventional procedures. PMID- 25828600 TI - Differential diagnosis of regular, narrow-QRS tachycardias. AB - We present an update on clinical and electrophysiological criteria used for the differential diagnosis of regular supraventricular tachycardias. Although several electrocardiographic clues may assist in the differential diagnosis, this is usually accomplished at electrophysiology study, and most often, the differential diagnosis is between atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia due to a concealed accessory pathway, and atrial tachycardia. Atrial and ventricular pacing maneuvers during sinus rhythm or tachycardia have been used with various success rates. In clinical practice, these techniques cannot be applied to all cases, and multiple criteria must be used for the differential diagnosis of narrow-complex tachycardias with atypical characteristics. PMID- 25828601 TI - His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) typically is attempted with biventricular pacing (BiVP). One-third of patients are nonresponders. His-bundle pacing (HBP) has been evaluated as an alternative means of effecting CRT because it generates truly physiologic ventricular activation, as evidenced in part by the morphologic identity between normally conducted and paced QRS complexes. OBJECTIVE: The purpose of this study was to assess the feasibility of, and clinical response to, permanent HBP as an alternative to BiVP in CRT-indicated patients. METHODS: Patients were implanted with a right atrial pacing lead, defibrillation lead, left ventricular (LV) lead via the coronary sinus, and HBP lead. His and LV leads were plugged into the LV port via a Y-adapter. After successful implant, patients were randomized in single patient-blinded fashion to either HBP or BiVP. After 6 months, patients were crossed over to the other pacing modality and followed for another 6 months. Quality-of-life assessments, echocardiographic measurements, New York Heart Association classification, and 6 minute hall walk test were obtained at baseline and at each 6-month follow-up. RESULTS: Twenty-nine patients were enrolled; 21 (72%) demonstrated electrical resynchronization (QRS narrowing) at implant. Twelve patients completed the crossover analysis at 1 year. Clinical outcomes (quality of life, New York Heart Association functional class, 6-minute hall walk test, LV ejection fraction) were significantly improved for both pacing modes compared with baseline measures. CONCLUSION: In this crossover comparison between HBP and BiVP, HBP was found to effect an equivalent CRT response. QRS narrowing was observed in 21 of 29 patients, suggesting this approach may be feasible in more patients with left bundle branch block than previously assumed. PMID- 25828602 TI - Long-chain polyunsaturated fatty acid status in obesity: a systematic review and meta-analysis. AB - Long-chain polyunsaturated fatty acid (LCPUFA) status has recently been related to the pathogenesis of obesity. Our aims were to systematically review observational studies investigating LCPUFA status from different blood compartments in overweight or obese subjects and to assess the relationship between LCPUFA profile and obesity. The Ovid MEDLINE, Scopus and Cochrane Library CENTRAL databases were searched from inception to January 2014. The meta-analysis showed significant differences in the LCPUFA composition of total plasma lipids, plasma phospholipids and plasma cholesteryl esters between overweight or obese subjects and controls. Dihomo-gamma-linolenic acid (DGLA) values were significantly higher in overweight or obese subjects compared with controls in all the investigated biomarkers. In addition, the DGLA/linoleic acid ratio (surrogate parameter for Delta6 desaturase activity) in plasma phospholipids was significantly elevated (mean difference [MD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08; n = 280), while the arachidonic acid/DGLA ratio (surrogate parameter for Delta5 desaturase activity) was significantly decreased (MD: -0.55; 95% CI: 0.71, -0.39; n = 347) in overweight or obese subjects compared with controls. The results of the present meta-analysis confirm that LCPUFA profile is altered in obesity and suggest that the differences observed in desaturase activities may be responsible for the disturbed LCPUFA metabolism in obesity. PMID- 25828603 TI - General Movements Assessment of infants in the neonatal intensive care unit following surgery. AB - AIM: There is an identified gap in the literature regarding the use of the General Movements (GMs) Assessment to identify risk in infants post-surgery. This paper aims to examine the GMs for infants who have undergone surgery to identify common risk profiles in the writhing age. METHODS: This was a prospective cohort study of 170 infants (99 male, 58%) admitted to a neonatal surgical unit from 2012 until June 2014. Infants were born at a mean age of 38 weeks (standard deviation (SD) 2.3), and writhing GMs were conducted at term (40 weeks, SD 2.6) following either cardiac (n = 84, 49%) or non-cardiac surgery (n = 86, 51%). GMs were categorised by three trained assessors. RESULTS: Normal writhing was recorded in 64 infants (38%). The most common profile was poor repertoire (n = 80, 47%), with 14 (8%) cramped synchronised. There was no difference in scores between infants who had undergone cardiac versus non-cardiac surgery (P = 0.45). CONCLUSION: This is the first report on the GMs assessment in an infant surgical population. Infants who have undergone surgery most commonly display poor repertoire writhing movements. Research is needed to determine the ability of the GMs to predict neurodevelopmental outcomes in this population. PMID- 25828604 TI - A COMPREHENSIVE STUDY ON APOPTOSIS INDUCTION BY AZADIRACHTIN IN Spodoptera frugiperda CULTURED CELL LINE Sf9. AB - The induction of apoptosis by azadirachtin, a well-known botanical tetranortriterpenoid isolated from the neem tree (Azadirachta indica A. Juss) and other members of the Meliaceae, was investigated in Spodoptera frugiperda cultured cell line (Sf9). Morphological changes in Sf9 cells treated by various concentrations of azadirachtin were observed at different times under light microscopy. Morphological and biochemical analysis indicated that Sf9 cells treated by 1.5 MUg/mL azadirachtin showed typical morphological changes, which were indicative of apoptosis and a clear DNA ladder. The flow cytometry analysis showed the apoptosis rate reached a maximum value of 32.66% at 24 h with 1.5 MUg/mL azadirachtin in Sf9 cells. The inhibition of Sf9 cell proliferation suggested that the effect of azadirachtin was dose dependent and the EC50 at 48 and 72 h was 2.727 * 10(-6) and 6.348 * 10(-9) MUg/mL, respectively. The treatment of azadirachtin in Sf9 cells could significantly increase the activity of Sf caspase-1, but showed no effect on the activity of Topo I, suggesting that the apoptosis induced by azadirachtinin Sf9 cells is through caspase-dependent pathway. These results provided not only a series of morphological, biochemical, and toxicological comprehensive evidences for induction of apoptosis by azadirachtin, but also a reference model for screening insect cell apoptosis inducers from natural compounds. PMID- 25828605 TI - Attenuating effect of bioactive coumarins from Convolvulus pluricaulis on scopolamine-induced amnesia in mice. AB - Convolvulus pluricaulis Chois. (Convolvulaceae) has been used in Ayurveda as Medhya Rasyana (nervine tonic) to treat various mental disorders. This study was designed to isolate the bioactive compound(s) of this plant and to evaluate their effect against scopolamine-induced amnesia. Column chromatography of the chloroform and ethyl-acetate fractions led to the isolation of three coumarins identified as scopoletin, ayapanin and scopolin. All the three compounds at 2.5, 5, 10 and 15 mg/kg, p.o. were evaluated for memory-enhancing activity against scopolamine-induced amnesia using elevated plus maze and step down paradigms. Effect on acetylcholinesterase activity in mice brain was also evaluated. Scopoletin and scopolin, in both the paradigms, significantly and dose dependently attenuated the scopolamine-induced amnesic effect. Furthermore, these compounds at 10 and 15 mg/kg exhibited activity comparable to that of standard drug, donepezil. The compounds also exhibited significant acetylcholinesterase inhibitory activity. PMID- 25828606 TI - Household food insecurity and dietary intake in Korea: results from the 2012 Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: To examine the prevalence of household food insecurity and compare dietary intake by food security status in a representative Korean population. DESIGN: Cross-sectional. Food security status of households was classified using an eighteen-item food security questionnaire. The nutrition survey comprised questions on dietary habits, a 24 h dietary recall and a semi-quantitative FFQ. SETTING: The 2012 Korea National Health and Nutrition Examination Survey. SUBJECTS: A total of 3007 households completed the food security questionnaire. Family members within each household aged >=1 year (n 7118) participated in the nutrition survey. RESULTS: Results from the 2012 survey indicated that 88.7% of Korean households showed food security. The remaining 11.3% (9.3% for food insecurity without hunger and 2.0% for food insecurity with hunger) were in food insecure households. The prevalence of household food insecurity was 13.2% in households with children and 10.3% in households without children. Mean daily intakes of energy, fat and carbohydrates were not significantly different between food-secure and food-insecure adults. In contrast, mean daily intakes of protein, crude fibre, vitamins and minerals as well as weekly consumption frequencies of vegetables, seaweeds, fruits, fruit juice, nuts, and milk and milk products were significantly lower in food-insecure adults compared with food-secure adults. CONCLUSIONS: The study demonstrated that food insecurity is associated with reduced intakes of healthy foods and nutrients essential for health and growth in a representative Korean population. PMID- 25828607 TI - Professionalism. PMID- 25828609 TI - Lightening the load: an overview of caregiver burden in dementia care. AB - Home health clinicians frequently encounter patients with dementia living in the community. The plan of care is usually developed around the needs of the affected person, with focus on safety and quality of life. In caring for these individuals, the clinician is faced with an even greater task of supporting the caregiver and identifying caregiver fatigue and burden. Improving the competence and knowledge of caregivers is valuable in minimizing burden. Home care clinicians have the knowledge, skills, and resources to ease the burden of caregiving and prolong the time that the person with dementia can remain in the home. This article describes current research and approaches to care, specifically with problems involving behavior, functional limitations, and safety. PMID- 25828611 TI - Closing the transition gaps the changing context of home healthcare coordination. AB - Legislative enactment of the Patient Protection and Affordable Care Act in 2010 created an impetus for change within the healthcare industry. As a result, the entire healthcare continuum is under greater scrutiny and incentives for performance levels and subsequent outcomes. Home healthcare clinicians have a vital role in the emerging spotlight of care transitions from hospital to home. Home healthcare clinicians will need to understand the concepts of patient engagement and patient activation, and have tactical plans for success. Understanding best practices and recommendations will be an element of competitive differentiation. This article reviews these concepts, along with interventions to target health literacy, communication with patients and families, and the use of motivational interviewing. PMID- 25828612 TI - Staff perceptions of social work student contributions to home health care services at an independent living facility. AB - This exploratory qualitative study examined staff perceptions of social work student contributions to client services, family and client communication, and staff workload in an independent living setting for older adults. Ten employees who had contact with the students, clients, and family were interviewed using a semistructured interview method. The findings suggest a positive response to the presence of social work students in the enhancement of home healthcare and in this independent living environment. In particular, their contributions were viewed as helpful in client quality of life, quality of care, communication with clients and families, and work performance. PMID- 25828613 TI - Evolving role of the transitional care nurse in a small rural community. AB - The shift in focus from individual episodes of illness to a focus on health and wellness, and population health, has created a need for care coordination to address the complex needs of high-risk patients as they transition through the healthcare continuum. A Vermont medical center identified the Clinical Nurse Specialist as having the requisite skills to fill the role of care coordinator. This article describes the development of the Transitional Care Nurse (TCN) program and includes case studies that exemplify how the TCN can intervene to improve care coordination. PMID- 25828614 TI - Management of the individual in the home suspected of having exposure to the ebola virus. PMID- 25828615 TI - Exercise and diabetes. PMID- 25828616 TI - ISMP Medication Errors. PMID- 25828617 TI - Don't tell momma... PMID- 25828618 TI - Growing our own. PMID- 25828619 TI - Home healthcare nursing: death spiral or ascending the spiral staircase. PMID- 25828620 TI - Emergence of double-dome superconductivity in ammoniated metal-doped FeSe. AB - The pressure dependence of the superconducting transition temperature (Tc) and unit cell metrics of tetragonal (NH3)yCs0.4FeSe were investigated in high pressures up to 41 GPa. The Tc decreases with increasing pressure up to 13 GPa, which can be clearly correlated with the pressure dependence of c (or FeSe layer spacing). The Tc vs. c plot is compared with those of various (NH3)yMxFeSe (M: metal atoms) materials exhibiting different Tc and c, showing that the Tc is universally related to c. This behaviour means that a decrease in two dimensionality lowers the Tc. No superconductivity was observed down to 4.3 K in (NH3)yCs0.4FeSe at 11 and 13 GPa. Surprisingly, superconductivity re-appeared rapidly above 13 GPa, with the Tc reaching 49 K at 21 GPa. The appearance of a new superconducting phase is not accompanied by a structural transition, as evidenced by pressure-dependent XRD. Furthermore, Tc slowly decreased with increasing pressure above 21 GPa, and at 41 GPa superconductivity disappeared entirely at temperatures above 4.9 K. The observation of a double-dome superconducting phase may provide a hint for pursuing the superconducting coupling-mechanism of ammoniated/non-ammoniated metal-doped FeSe. PMID- 25828622 TI - Could the Mediterranean diet be effective in women with polycystic ovary syndrome? A proof of concept. PMID- 25828621 TI - A combination of palm oil tocotrienols and citrus peel polymethoxylated flavones does not influence elevated LDL cholesterol and high-sensitivity C-reactive protein levels. AB - BACKGROUND/OBJECTIVES: Lipid-lowering and anti-inflammatory effects have been individually described for tocotrienols (TTs) and polymethoxylated flavones (PMFs). This study investigated low-density lipoprotein-cholesterol (LDL-C)- and high-sensitivity C-reactive protein (hsCRP)-reducing effects of combined TT-PMF treatment in low doses in hypercholesterolemic individuals with subclinical inflammation. SUBJECTS/METHODS: In the double-blind, placebo-controlled study, 240 Caucasians with LDL-C ?3.36 mmol/l and hsCRP ?1 mg/l were enrolled and randomized into group S1 (12 mg/day TT and 103 mg/day PMF), group S2 (27 mg/day TT and 32 mg/day PMF) or placebo. RESULTS: Twenty-three subjects dropped out of the study, 13 were excluded from the analysis because of lack of compliance. A total of 204 subjects per-protocol analysis were included. After 12 weeks of treatment, no significant differences in LDL-C levels (primary outcome) were observed between groups. LDL-C levels significantly decreased in all intervention groups (S1: -5.2%, S2: -4.8% and P: -4.2%). Total cholesterol and hsCRP (secondary outcome) did not change significantly. CONCLUSIONS: PMF-TT supplements had no effect beyond that of placebo on elevated LDL-C and hsCRP levels. PMID- 25828623 TI - Seasonal variation in food intake and the interaction effects of sex and age among adults in southern Brazil. AB - BACKGROUND/OBJECTIVES: Because studies have evidenced variations in nutrient intake, further investigation of the interaction between demographic characteristics and the seasons is necessary. We aimed to test the differences in food intake throughout the seasons and the interaction between the seasons and sex and age. SUBJECTS/METHODS: This study included 273 individuals. Food intake was evaluated with 24-hour dietary recalls, and the reported food items were sorted into food groups. We performed the test on the differences in intake of food groups throughout the seasons with repeated measures and on the interaction effect by using the Generalized Estimate Equation. RESULTS: Intake of fruits and natural fruit juices and sweetened beverages was lower, whereas that of grains and derivatives was higher in the winter. The intake of leafy vegetables and fish and seafood was lower in the autumn. The consumption of coffee and eggs was higher in the spring. Intake of chocolate powder and sugar, salt and lean poultry was higher in the winter. The variation in consumption of grains and derivatives, eggs, fatty poultry and processed meat over the seasons was more likely to be modified by sex. Age interacted with the seasons for leafy vegetables, beans and lentils, lean beef, lean poultry, low fat milk and light yogurt, vegetable oil and unsalted margarine, chocolate powder and sugar and processed meat. CONCLUSIONS: This study shows that food intake may change seasonally and that seasonal variation depends on sex and age, which might aggregate a specific co variation component. PMID- 25828624 TI - Metabolic and physiologic effects from consuming a hunter-gatherer (Paleolithic) type diet in type 2 diabetes. AB - BACKGROUND/OBJECTIVES: The contemporary American diet figures centrally in the pathogenesis of numerous chronic diseases--'diseases of civilization'--such as obesity and diabetes. We investigated in type 2 diabetes whether a diet similar to that consumed by our pre-agricultural hunter-gatherer ancestors ('Paleolithic' type diet) confers health benefits. SUBJECTS/METHODS: We performed an outpatient, metabolically controlled diet study in type 2 diabetes patients. We compared the findings in 14 participants consuming a Paleo diet comprising lean meat, fruits, vegetables and nuts, and excluding added salt, and non-Paleolithic-type foods comprising cereal grains, dairy or legumes, with 10 participants on a diet based on recommendations by the American Diabetes Association (ADA) containing moderate salt intake, low-fat dairy, whole grains and legumes. There were three ramp-up diets for 7 days, then 14 days of the test diet. Outcomes included the following: mean arterial blood pressure; 24-h urine electrolytes; hemoglobin A1c and fructosamine levels; insulin resistance by euglycemic hyperinsulinemic clamp and lipid levels. RESULTS: Both groups had improvements in metabolic measures, but the Paleo diet group had greater benefits on glucose control and lipid profiles. Also, on the Paleo diet, the most insulin-resistant subjects had a significant improvement in insulin sensitivity (r = 0.40, P = 0.02), but no such effect was seen in the most insulin-resistant subjects on the ADA diet (r = 0.39, P = 0.3). CONCLUSIONS: Even short-term consumption of a Paleolithic-type diet improved glucose control and lipid profiles in people with type 2 diabetes compared with a conventional diet containing moderate salt intake, low-fat dairy, whole grains and legumes. PMID- 25828626 TI - The EU pledge for responsible marketing of food and beverages to children: implementation in food companies. AB - BACKGROUND/OBJECTIVES: Increasing political pressure on the food industry's marketing activities stimulated the formation of the collective EU Pledge for responsible marketing of foods and beverages to children. The objective of the study is to evaluate the commitments made by companies in joining the pledge for the purpose of assessing its effectiveness in regulating signatory companies' marketing activities. SUBJECTS/METHODS: Data on company commitments in relation to the EU Pledge were collected, analyzed and recalculated in order to enable comparison across companies and with general nutritional recommendations. Data on companies' product portfolio and market orientation were collected from their most recent available annual reports. Data on the companies' product profiles were generated via review of the companies' main websites. Similar data were generated for a reference group of companies outside the EU Pledge. RESULTS: Compared with a reference group of large food and beverage companies, EU Pledge signatory companies have a public image strongly based on products with appeal to children. The EU Pledge sets common standards for regulating signatory companies' marketing behaviour towards children. Further scrutiny of the companies' stated commitments revealed considerable variation in their actual content and in their de facto bindingness on the companies' marketing behavior--for example, in the definition of target audience for advertising or in nutritional characteristics making products eligible for advertising to children. CONCLUSIONS: In order for voluntary self-regulation schemes such as the EU Pledge to be a credible alternative to public regulation of marketing behaviour, more transparency and stringency are needed. PMID- 25828625 TI - Do patients with type 2 diabetes still need to eat snacks? PMID- 25828627 TI - Baseline characteristics associated with different BMI trajectories in weight loss trials: a case for better targeting of interventions. AB - BACKGROUND/OBJECTIVES: Dietary weight loss interventions have heterogeneous outcomes in long-term studies, with many participants regaining part or all of the lost weight. Growth mixture modelling is a novel analytic approach that can be used to identify different trajectories of weight change during a trial rather than focussing on the total amount of weight lost. SUBJECTS/METHODS: Data were pooled from two 12-month dietary weight loss studies where no significant difference was detected between the treatment and control arms, thus allowing analysis independent of treatment. The data set included 231 subjects (74.5% female), with a mean weight loss of 6.40 kg (4.96). Growth mixture models were used to identify participants with similar trajectories of change in body mass index (BMI). RESULTS: Three subgroups were identified. A rapid and continuing BMI loss over the study period (rapid, n=53), a rapid initial weight loss in the first 3 months with a slowing rate over the remaining 9 months (maintainers, n=146) and those with an initial loss trajectory, which slowed and began to increase at 9 months (recidivists, n=53). Age (s.d.) and BMI (s.d.) were significantly different between the three groups (rapid 53 years (7), 28.99 kg/m(2) (3.30); maintainers 47 years (9), 30.90 kg/m(2) (2.95); recidivists 44 years (7), 34.84 kg/m(2) (1.92), both P<0.001). CONCLUSIONS: Older subjects with lower BMIs were more likely to have a rapid and continuing weight loss in a 1 year dietary-based weight loss intervention. Different interventional approaches may be necessary for different ages and baseline BMIs and stratification prior to randomisation may be necessary to prevent confounding in weight loss trials. PMID- 25828628 TI - High intra- and inter-individual variability of plasma vitamin K concentrations in patients with atrial fibrillation under warfarin therapy. AB - BACKGROUND/OBJECTIVES: Vitamin K intake is considered as a controllable contributor to warfarin sensitivity. It is restricted in warfarin-treated patients. However, little study has assessed the vitamin K status in warfarin treated patients. We directly measured plasma vitamin K in warfarin-treated patients and evaluated its effect on anticoagulation. SUBJECTS/METHODS: A total of 302 plasma vitamin K concentrations were assessed using high-performance liquid chromatography for 203 outpatients with atrial fibrillation under warfarin treatment. Clinical and laboratory information including warfarin dosage, plasma warfarin concentrations, prothrombin time international normalized ratio (PT INR) and CYP2C9/VKORC1 genotypes was reviewed retrospectively. The anticoagulation stability (intra-individual variability, frequency of PT INR tests and complications) was investigated in 163 patients with long-term warfarin therapy. Plasma vitamin K was measured in 40 healthy subjects and in 40 patients before and after initial warfarin treatment. RESULTS: Vitamin K concentrations were significantly decreased after the initiation of warfarin treatment (before treatment: 1.72 ng/ml; after treatment: 0.59 ng/ml, P<0.05). There was a large inter-individual variability in vitamin K levels (0.2-4.2 ng/ml) in warfarin treated patients. PT INR was more frequently checked in patients with low plasma vitamin K levels than in those with high vitamin K levels (9.5 times/year vs 7.5 times/year, P=0.029). Two patients with gross hematuria showed very low vitamin K levels (<0.4 ng/ml). CONCLUSIONS: We found high inter- and intra-individual variability in vitamin K concentration in warfarin-treated patients. Low vitamin K concentration in warfarin-treated patients suggested excessive dietary restriction. Plasma vitamin K measurement would be helpful for dietary control and anticoagulation stability. PMID- 25828629 TI - Calibration of bioelectrical impedance analysis for body composition assessment in Ethiopian infants using air-displacement plethysmography. AB - BACKGROUND/OBJECTIVES: Assessment of infant body composition (BC) is crucial to understand the consequences of suboptimal nutritional status and postnatal growth, and the effects of public health interventions. Bioelectrical impedance analysis (BIA) is a feasible, relatively inexpensive and noninvasive method for assessing BC. However, very little research has been conducted in low- and middle income populations, where efforts to prevent or treat malnutrition in early life are a public health priority. We aimed to develop equations for predicting fat free mass (FFM) and fat mass (FM) based on BIA in 0- to 6-month-old Ethiopian infants. SUBJECTS/METHODS: The study comprised a total of 186 BC assessments performed in 101 healthy infants, delivered at Jimma University Specialized Hospital. Infant air-displacement plethysmography (IADP) was the criterion method, whereas weight, length, sex, age and an impedance index (L(2)/Z50) were predictors. Prediction equations were developed using stepwise multiple linear regression and the accuracy was evaluated with a 10-fold cross-validation approach. RESULTS: A linear regression model based on body weight, age and sex predicted FFM, estimated by IADP, with an adjusted R(2) and root mean square error (RMSE) of 0.94 and 200 g, respectively. Adding impedance index to the model resulted in a significantly improved model fit (R(2)=0.95; RMSE=181 g). For infants below 3 months of age, inclusion of impedance index did not contribute to an improved model fit for predicting FFM compared with a model already comprising weight, sex and age. CONCLUSIONS: The derived equations predicted FFM with acceptable accuracy and may be used in future field surveys, epidemiological studies and clinical trials conducted in similar sub-Saharan African population groups aged 0-6 months. PMID- 25828631 TI - Microfluidic studies of polymer adsorption in flow. AB - Adsorption of polymers from solutions moving past solid or liquid surfaces controls a broad range of phenomena in science, technology, and medicine. In the present work, a microfluidic methodology was developed to study polymer adsorption in flow under well-defined conditions by integrating an attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectrometer with a microfluidic device. Polymer adsorption in flow using exemplary polyelectrolytes such as polystyrene sulfonate and polyacrylic acid was studied under varying flow rates, polymer concentrations, pH values, and ionic strengths of the solution. Furthermore, the microfluidic platform was utilized to study layer-by-layer adsorption of alternating anionic and cationic polyelectrolytes such as polyacrylic acid and polyallylamine hydrochloride. The proposed methodology paves the way for studies of in-flow adsorption of biologically relevant molecules, which would mimic processes occurring in the cardiovascular microcirculation system. PMID- 25828630 TI - Predictors of body composition changes during tuberculosis treatment in Mwanza, Tanzania. AB - BACKGROUND/OBJECTIVES: Gains in fat mass and lean mass during tuberculosis (TB) treatment may determine functional recovery and survival; yet, data are scarce. We aimed to assess predictors of fat and fat-free mass during 2 months of intensive TB treatment in a cohort in Mwanza, Tanzania. SUBJECTS/METHODS: Fat and fat-free mass were determined at the start of TB treatment and repeated after 2 months using the deuterium dilution technique. Gains in fat and fat-free mass were determined and predictors assessed using regression analysis. RESULTS: Data for 116 patients were available at baseline and during follow-up. Of these, 38.8% were females, mean age was 37.3 (s.d. 13.5) years, 69% (81) had sputum-positive TB, 45.7% (53) were HIV infected and 25% (29) were current smokers. The mean weight gain was 3.3 kg (95% confidence interval: 2.7; 3.8), and it did not differ by sex. However, compared with females, males had 1.0 (0.4; 1.6) kg/m(2) lower fat mass but 0.7 (0.2; 1.3) kg/m(2) higher fat-free mass gain. Current smoking was associated with higher fat mass (0.7 kg/m(2), 0.04; 1.4) but lower fat-free mass (-0.5 kg/m(2), -1.2; 0.07) gain. Among HIV-infected patients, antiretroviral therapy (ART) led to a lower fat gain (-1.2 kg/m(2), -2.2; -0.2) but to a higher fat-free mass among sputum-negative (2.9 kg/m(2), 0.8; 5.1) but not sputum positive patients. CONCLUSIONS: During intensive phase of TB treatment, sex, smoking and ART were predictors of body composition. Larger studies are needed to further understand predictors of body composition during recovery, to help design interventions to improve treatment outcomes. PMID- 25828632 TI - Alternative reproductive tactics in female striped mice: Solitary breeders have lower corticosterone levels than communal breeders. AB - Alternative reproductive tactics (ARTs), where members of the same sex and population show distinct reproductive phenotypes governed by decision-rules, have been well-documented in males of many species, but are less well understood in females. The relative plasticity hypothesis (RPH) predicts that switches between plastic ARTs are mediated by changes in steroid hormones. This has received much support in males, but little is known about the endocrine control of female ARTs. Here, using a free-living population of African striped mice (Rhabdomys pumilio) over five breeding seasons, we tested whether females following different tactics differed in corticosterone and testosterone levels, as reported for male striped mice using ARTs, and in progesterone and oestrogen, which are important in female reproduction. Female striped mice employ three ARTs: communal breeders give birth in a shared nest and provide alloparental care, returners leave the group temporarily to give birth, and solitary breeders leave to give birth and do not return. We expected communal breeders and returners to have higher corticosterone, owing to the social stress of group-living, and lower testosterone than solitary breeders, which must defend territories alone. Solitary breeders had lower corticosterone than returners and communal breeders, as predicted, but testosterone and progesterone did not differ between ARTs. Oestrogen levels were higher in returners (measured before leaving the group) than in communal and solitary breeders, consistent with a modulatory role. Our study demonstrates hormonal differences between females following (or about to follow) different tactics, and provides the first support for the RPH in females. PMID- 25828634 TI - pH-responsive fluorescence chemical sensor constituted by conjugated polymers containing pyridine rings. AB - Poly(p-pyridinium phenylene ethynylene)s (PPyPE) functionalized with alternating donor-acceptor repeat units were synthesized by a Pd-catalyzed Sonogashira coupling reaction between diethynyl monomer and di-iodopyridine for use as a pH responsive fluorescence chemical sensor. The synthesized PPyPE, containing pyridine units, was characterized by FT-IR, (1)H and (13)C NMR, UV-visible and fluorescence spectroscopies. We investigated the relationship between changes of optical properties and protonation/deprotonation of PPyPE containing pyridine units in solution. Addition of HCl decreased and red-shifted the fluorescence intensity of the conjugated polymers that contained pyridine rings; fluorescence intensity of the polymers increased upon addition of NaOH solution. The synthesized PPyPE was found to be an effective and reusable chemical sensor for pH sensing. PMID- 25828633 TI - Optimal treatment scheduling of ionizing radiation and sunitinib improves the antitumor activity and allows dose reduction. AB - The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting. PMID- 25828635 TI - Evaluation of a pharmacokineticpharmacodynamic approach using software to optimize the carbapenem antibiotic regimen. AB - OBJECTIVE: Meropenem (MEPM) and doripenem (DRPM), whose antipseudomonal activity is more potent than that of other carbapenem antimicrobials, were used in the study. Monte Carlo simulation of drug concentrations was performed to develop an administration plan for MEPM and DRPM that takes into account the pharmacokinetics (PK)-pharmacodynamics (PD) of MEPM and DRPM and the renal function of each patient. Drug administration plans were proactively applied to patients with pneumonia to determine the usefulness of the method by assessing treatment efficacy and safety. METHODS: Patients with healthcareassociated pneumonia and an indication for MEPM or DRPM chemotherapy underwent drug administration in accordance with the MEPM and DRPM treatment plan developed by the PK-PD software applications. The primary efficacy endpoints were the clinical and bacteriological efficacy of the drugs agains pneumonia. The safety of the antimicrobials was assessed based on abnormal laboratory findings and the seizure disorders in accordance with the criteria for safety evaluation of antimicrobial agents. RESULTS: This study examined 12 and 11 patients in the MEPM and DRPM group, respectively; however, 3 DRPM patients were excluded due to the administration of anti-methicillin-resistant Staphylococcus aureus drugs after the initiation of DRPM treatment. MEPM and DRPM drug administration was determined to be safe and effective in all patients. CONCLUSIONS: The present results suggest that the Monte Carlo simulation-based PK-PD software is an effective tool for planning individualized antimicrobial chemotherapy with carbapenem in accordance with the PK-PD theory of antimicrobials. It is also possible to propose safe and effective drug administration plans for patients with healthcare-associated pneumonia. PMID- 25828636 TI - Pharmacokinetic properties and bioequivalence of two irbesartan/ hydrochlorothiazide fixed-dose combination tablets in healthy male Chinese volunteers. AB - OBJECTIVES: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and a branded reference formulation of irbesartan/ hydrochlorothiazide FDC tablets, and to assess the bioequivalence of the two products in healthy Chinese male volunteers. MATERIALS AND METHODS: 24 male healthy volunteers participated in the open-label, single-dose, randomized sequence, 2-way crossover study. Eligible subjects were randomly assigned (1:1) to receive a single 300/12.5-mg dose of either the test or reference formulation followed by a 1-week washout. Blood samples were obtained before (0 hours) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours after dosing. Plasma concentrations of irbesartan and hydrochlorothiazide were analyzed by two separate validated liquid chromatography/tandem mass spectrometric (LC-MS/MS) methods. RESULTS: For irbesartan, the 90% confidence intervals (CIs) of AUC0-t, AUC0-infinity, and Cmax were 103.27-116.71%, 105.01-121.47%, and 84.15-96.88%, respectively. For hydrochlorothiazide, the 90% CIs of AUC0-t, AUC0-infinity, and Cmax were 96.11-109.02%, 95.15-107.35%, and 91.66-101.40%, respectively. A total of 3 mild AEs were reported in 3 subjects (12.5%). CONCLUSION: In this study, a single dose (300/12.5-mg) of the test formulation of irbesartan and hydrochlorothiazide FDC tablet in fasting healthy Chinese male volunteers met WHO's and China's FDA regulatory criteria for assumption of bioequivalence to the reference formulation based on AUC and Cmax. Both formulations were well tolerated. PMID- 25828637 TI - Bioequivalence study of two formulations of etoposide in advanced lung cancer patients. AB - INTRODUCTION: The present randomized, two-period, cross-over bioequivalence study compared two soft capsules of etoposide (test and reference formulations), in treating 18 advanced lung cancer patients. MATERIALS AND METHODS: The pharmacokinetic parameters were determined based on the concentrations of etoposide, using HPLC with fluorescence detector. In each of the two study periods, a single dose of test or reference product was administered. The pharmacokinetic parameters assessed included area under the plasma concentration time curve (AUC(0-12h)) from 0 to 12 hours, AUC(0-T) from time zero to infinity, the peak plasma concentration of the drug (C(max)), time to achieve C(max), and the elimination half-life. RESULTS: Comparison of the test and reference products containing etoposide showed that geometric mean ratios (90% confidence interval (CI)) of AUC(0-T), AUC(0-infinity)?, and C(max) were 99.7% (92.1 - 103.7%), 99.4% (92.3 - 105.2%), and 101.5% (94.2 - 109.6%), respectively. Both AUC and C(max) ratio 90% CI of test and reference formulations were within its acceptable range for bioequivalence. The values of tmax and t1/2 were not found to have a statistically significant difference between the test and the reference drug (p > 0.05). No adverse events occurred in this bioequivalence study. CONCLUSION: The two etoposide soft capsules (the test and reference formulations) were bioequivalent. PMID- 25828638 TI - Trends and patterns of five antihypertensive drug classes between 2007 and 2012 in China using hospital prescription data. AB - PURPOSE: To examine prescription trends and patterns in five antihypertensive drug classes during 2007 - 2012 in China. METHODS: A retrospective time series data was investigated from 2007 to 2012. Prescription data of five classes of antihypertensive drugs (calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, and diuretics) were accessed from the Hospital Prescription Analysis Program Database, including 59 hospitals in four cities in China. The drugs were coded using the Anatomic Chemical Therapeutic (ATC) classification. Quantities were standardized using the defined daily dose (DDD) measurement methodology. RESULTS: The total number of DDDs of the five classes of antihypertensive drugs prescribed in the sample hospitals increased by 83.3% and the total cost of antihypertensive drugs increased by 92.4% from 2007 to 2012. During the whole study period, CCBs, ARBs, ACEIs, beta-blockers, and diuretics represented in DDDs 42.8%, 28.3%, 13.3%, 10.8%, and 4.8%, respectively, of the total five classes of anti hypertensive drugs. The average annual increase rate of ARBs, beta-blockers, CCBs, ACEIs, and diuretics, in DDDs, was 23.4%, 13.3%, 13.2%, 1.4%, and -4.2%, respectively CONCLUSIONS: The consumption of the five classes of antihypertensive drugs in China nearly doubled from 2007 to 2012. The top-prescribed antihypertensive drug classes were CCBs and ARBs, and the latter increased most rapidly. PMID- 25828639 TI - Factors on trough teicoplanin levels, associations between levels, efficacy and safety in patients with gram-positive infections. AB - OBJECTIVE: The objective of this study was to identify the factors influencing trough teicoplanin concentrations (C(min)), to investigate the relationship between teicoplanin C(min) with efficacy and safety, and to determine a target therapeutic concentration. METHODS: An analysis was performed on 95 serum concentrations from 50 patients with gram-positive infections who received teicoplanin treatment. Teicoplanin serum concentrations were measured by high performance liquid chromatography. Univariate and multivariable analysis were performed to investigate the effect of independent variables on teicoplanin C(min). A logistic regression analysis was used to determine the relationship between teicoplanin C(min) and efficacy and safety. RESULTS: Teicoplanin therapy was effective in 74.0% (37/50) of patients, and 10.0% (5/50) of patients exhibited signs of adverse events. Using multivariable linear regression, two covariates were found to be a significant effect on teicoplanin C(min): dosage (mg/kg), and creatinine clearance rate (CL(cr). There was no covariate that has a significant impact on the safety of teicoplanin and only teicoplanin C(min) has a significant impact on the efficacy of treatment in the logistics regression. The logistics regression analysis showed that teicoplanin C(min) of 10 mg/L was associated with a 79.4% probability of success response. CONCLUSIONS: This study highlighted that teicoplanin C(min) was strongly influenced by the values of dosage (mg/kg) and CL(cr) and the teicoplanin C(min) range of 10 -?? 20 mg/L was identified as the therapeutic target with optimum clinical efficacy and safety. PMID- 25828640 TI - Modeling the dermatopharmacokinetic profile of two loxoprofen patches for bioequivalence confirmation. PMID- 25828641 TI - The oestrogen-leptin paradox. PMID- 25828642 TI - Computational diversity in the hippocampus: a matter of components. PMID- 25828643 TI - All ON pathways are not alike. PMID- 25828644 TI - Stimulation is never quite as simple as it seems. PMID- 25828646 TI - Reframing coalitions as systems interventions: a network study exploring the contribution of a youth violence prevention coalition to broader system capacity. AB - This longitudinal research conceptualizes community coalitions as events in local intervention systems (Hawe et al. in Am J Commun Psychol 43(3-4):267-276, 2009). It explores the potential contribution coalitions make, through the collaborative activities of their members, to the broader intervention systems in which they are embedded. Using social network analysis, it examines patterns of structural change in a network of 99 organizations focused on youth violence prevention (YVP) over a 5-year period in which 30 of the 99 organizations were involved in a local YVP Coalition. Both longitudinal modeling and cross sectional analyses are used to examine change in system capacity-strong interorganizational networks related to patterns of network density, centralization, and hierarchy. Somewhat surprisingly, the study found that capacity in the broader YVP Intervention System actually diminished during the 5-year period of the coalition's operation, though part of the system-the sub-network that made up the YVP Coalition-was marginally strengthened. In this case, therefore, the evidence suggests that power and relational resources in the broader YVP Intervention System were redistributed. The article explores how the definition of capacity related to density and hierarchy may be contextually dependent. Implications for the role of coalitions in building system capacity are discussed. PMID- 25828645 TI - Engineering physiologically stiff and stratified human cartilage by fusing condensed mesenchymal stem cells. AB - For a long time, clinically sized and mechanically functional cartilage could be engineered from young animal chondrocytes, but not from adult human mesenchymal stem cells that are of primary clinical interest. The approaches developed for primary chondrocytes were not successful when used with human mesenchymal cells. The method discussed here was designed to employ a mechanism similar to pre cartilaginous condensation and fusion of mesenchymal stem cells at a precisely defined time. The formation of cartilage was initiated by press-molding the mesenchymal bodies onto the surface of a bone substrate. By image-guided fabrication of the bone substrate and the molds, the osteochondral constructs were engineered in anatomically precise shapes and sizes. After 5 weeks of cultivation, the cartilage layer assumed physiologically stratified histomorphology, and contained lubricin at the surface, proteoglycans and type II collagen in the bulk phase, collagen type X at the interface with the bone substrate, and collagen type I within the bone phase. For the first time, the Young's modulus and the friction coefficient of human cartilage engineered from mesenchymal stem cells reached physiological levels for adult human cartilage. We propose that this method can be effective for generating human osteochondral tissue constructs. PMID- 25828647 TI - Contributions of photosynthetic and non-photosynthetic cell types to leaf respiration in Vicia faba L. and their responses to growth temperature. AB - In intact leaves, mitochondrial populations are highly heterogeneous among contrasting cell types; how such contrasting populations respond to sustained changes in the environment remains, however, unclear. Here, we examined respiratory rates, mitochondrial protein composition and response to growth temperature in photosynthetic (mesophyll) and non-photosynthetic (epidermal) cells from fully expanded leaves of warm-developed (WD) and cold-developed (CD) broad bean (Vicia faba L.). Rates of respiration were significantly higher in mesophyll cell protoplasts (MCPs) than epidermal cell protoplasts (ECPs), with both protoplast types exhibiting capacity for cytochrome and alternative oxidase activity. Compared with ECPs, MCPs contained greater relative quantities of porin, suggesting higher mitochondrial surface area in mesophyll cells. Nevertheless, the relative quantities of respiratory proteins (normalized to porin) were similar in MCPs and ECPs, suggesting that ECPs have lower numbers of mitochondria yet similar protein complement to MCP mitochondria (albeit with lower abundance serine hydroxymethyltransferase). Several mitochondrial proteins (both non-photorespiratory and photorespiratory) exhibited an increased abundance in response to cold in both protoplast types. Based on estimates of individual protoplast respiration rates, combined with leaf cell abundance data, epidermal cells make a small but significant (2%) contribution to overall leaf respiration which increases twofold in the cold. Taken together, our data highlight the heterogeneous nature of mitochondrial populations in leaves, both among contrasting cell types and in how those populations respond to growth temperature. PMID- 25828648 TI - Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs. saline with the Tx360 device for treatment of chronic migraine. AB - BACKGROUND: This study aims to determine if repetitive sphenopalatine ganglion (SPG) blockades with 0.5% bupivacaine delivered with the Tx360 device results in long-term improvement in chronic migraine (CM). The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. In a previous article, these authors reported repetitive SPG blockades with 0.5% bupivacaine delivered by the Tx360 device, which was an effective and well-tolerated intervention to incrementally decrease baseline headache intensity of subjects with CM. METHODS: This was a double blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. A total of 41 subjects were enrolled at two headache specialty clinics in the USA. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by International Classification of Headache Disorders-II definition. Subjects were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer generated lists 2:1 to receive 0.3 cc of 0.5% bupivacaine or saline, respectively, delivered with the Tx360 twice a week for 6 weeks. Secondary end points reported in this manuscript include post-treatment measures including number of headache days and quality of life measures. RESULTS: The final data set included 38 subjects: 26 in the bupivacaine group and 12 in the saline group. Our primary end-point for the study, difference in numeric pain rating scale scores, was met and reported in a previous article. The supplemental secondary end-points reported in this manuscript did not reach statistical significance. When looking collectively at these end-points, trends were noticed and worthy of reporting. Subjects receiving bupivacaine reported a decrease in the number of headache days 1 month post-treatment (Mdiff = -5.71), whereas those receiving saline only saw a slight improvement (Mdiff = -1.93). Headache Impact Test 6 scores were decreased in the bupivacaine group at 1 month (Mdiff = -5.13) and 6 months (Mdiff = -4.78) post-treatment, but only a modest reduction was seen for those receiving saline at 1 and 6 months, respectively (Mdiff = -2.08, Mdiff = 1.58). Furthermore, subjects receiving bupivacaine reported a reduction in acute medication usage and improved quality of life measures (average pain in the previous 24 hours, mood, normal work, and general activity) up to 6 months post treatment. The changes in these measures for the saline group were minimal. CONCLUSIONS: Data from this exploratory pilot study suggest that there may be long-term clinical benefits with the use of repetitive SPG blockades with bupivacaine delivered with the simple to use Tx360 device. These include a sustained reduction of headache days and improvement in several important quality of life assessments. The SPG blockades were not associated with any significant or lasting adverse events. Further research on SPG blockade is warranted. PMID- 25828649 TI - The Use of Fall Risk Increasing Drugs (FRIDs) in Patients With Dizziness Presenting to a Neurotology Clinic. AB - OBJECTIVE: To characterize the use of fall risk increasing drugs (FRIDs) in patients with dizziness who presented to a Neurotology academic practice and to evaluate for predictors of FRID use in this population. PATIENTS: A total of 292 subjects presented with dizziness between July 1, 2013 and December 31, 2013. INTERVENTION: Demographic information and FRID use were recorded. MAIN OUTCOME MEASURE: The prevalence and type of FRIDs (psychotropics, antihypertensives, and/or narcotics) used among participants. RESULTS: The overall prevalence of any FRID use was 40.8%. Thirty-nine percent of patients were on psychotropic medications, 37% on antihypertensives, and 8.2% on narcotics. The proportion of patients on two or more FRIDs at presentation was 34%. When categorizing by age group, 40% of patients aged 50 years or greater versus 24% of younger patients (p = 0.004) were on two or more FRIDs. With every decade increase in age, the odds of being on two or more FRIDs increased by 7%. CONCLUSIONS: Forty percent of all patients presenting to a Neurotology Clinic for dizziness were on a FRID. Older patients were significantly more likely to be on multiple FRIDs, specifically antihypertensives and narcotic medications. These findings suggest that to fully assess and treat older patients with dizziness, the use of these medications should be evaluated. PMID- 25828651 TI - Hypersensitivity reaction during epirubicin infusion in a cat. PMID- 25828650 TI - 4D hyperspherical harmonic (HyperSPHARM) representation of surface anatomy: a holistic treatment of multiple disconnected anatomical structures. AB - Image-based parcellation of the brain often leads to multiple disconnected anatomical structures, which pose significant challenges for analyses of morphological shapes. Existing shape models, such as the widely used spherical harmonic (SPHARM) representation, assume topological invariance, so are unable to simultaneously parameterize multiple disjoint structures. In such a situation, SPHARM has to be applied separately to each individual structure. We present a novel surface parameterization technique using 4D hyperspherical harmonics in representing multiple disjoint objects as a single analytic function, terming it HyperSPHARM. The underlying idea behind HyperSPHARM is to stereographically project an entire collection of disjoint 3D objects onto the 4D hypersphere and subsequently simultaneously parameterize them with the 4D hyperspherical harmonics. Hence, HyperSPHARM allows for a holistic treatment of multiple disjoint objects, unlike SPHARM. In an imaging dataset of healthy adult human brains, we apply HyperSPHARM to the hippocampi and amygdalae. The HyperSPHARM representations are employed as a data smoothing technique, while the HyperSPHARM coefficients are utilized in a support vector machine setting for object classification. HyperSPHARM yields nearly identical results as SPHARM, as will be shown in the paper. Its key advantage over SPHARM lies computationally; HyperSPHARM possess greater computational efficiency than SPHARM because it can parameterize multiple disjoint structures using much fewer basis functions and stereographic projection obviates SPHARM's burdensome surface flattening. In addition, HyperSPHARM can handle any type of topology, unlike SPHARM, whose analysis is confined to topologically invariant structures. PMID- 25828652 TI - A novel statistical approach to detect differences in fat and protein test values among mid-infrared spectrophotometers. AB - Our objective was to develop a statistical approach that could be used to determine whether a handler's fat, protein, or other solids mid-infrared (MIR) spectrophotometer test values were different, on average, from a milk regulatory laboratory's MIR test values when split-sampling test values are not available. To accomplish this objective, the Proc GLM procedure of SAS (SAS Institute Inc., Cary, NC) was used to develop a multiple linear regression model to evaluate 4 mo of MIR producer payment testing data (112 to 167 producers per month) from 2 different MIR instruments. For each of the 4 mo and each of the 2 components (fat or protein), the GLM model was Response=Instrument+Producer+Date+2-Way Interactions+3-Way Interaction. Instrument was significant in determining fat and protein tests for 3 of the 4 mo, and Producer was significant in determining fat and protein tests for all 4 mo. This model was also used to establish fat and protein least significant differences (LSD) between instruments. Fat LSD between instruments ranged from 0.0108 to 0.0144% (alpha=0.05) for the 4 mo studied, whereas protein LSD between instruments ranged from 0.0046 to 0.0085% (alpha=0.05). In addition, regression analysis was used to determine the effects of component concentration and date of sampling on fat and protein differences between 2 MIR instruments. This statistical approach could be performed monthly to document a regulatory laboratory's verification that a given handler's instrument has obtained a different test result, on average, from that of the regulatory laboratory's and that an adjustment to producer payment may be required. PMID- 25828653 TI - Seasonal trends in milk quality in Ireland between 2007 and 2011. AB - The objectives of this study were to evaluate annual and seasonal trends in bulk tank somatic cell count (SCC), total bacterial count (TBC), and laboratory pasteurization count (LPC) in Ireland between 2007 and 2011 (inclusive), and to compare trends based on herd type and herd size. The unadjusted median SCC and TBC of all records were 266,000 and 17,000 cfu/mL, respectively. Data were transformed to log values and analyzed using a mixed model. Fixed effects included milk processor, year, month, and total monthly milk volume; milk producer was fitted as a random variable. After analysis, means were back transformed for interpretation. Annual SCC increased slightly from 259,000 cells/mL in 2007 to a peak of 272,647 cells/mL in 2009 and then declined slightly thereafter. Although statistically significant changes in annual TBC are probably not biologically relevant, values ranged between 23,922 and 26,290 cfu/mL. Annual LPC peaked in 2008 (265 cfu/mL), declined in 2009, and increased thereafter. Monthly mean SCC of all records increased from April onward, with the greatest increases seen from October to December, when the majority of cows entered late lactation. Monthly mean TBC exhibited a seasonal trend, whereby TBC was greatest at the beginning and end of the year, coinciding with winter housing. Seasonal milk production herds (n=8,002 herds) calve all cows in spring (February to April), whereas split-calving herds (n=1,829 herds) calve cows in the spring and autumn. From February to September, monthly SCC was lower for seasonal herds than for split-calving herds, whereas SCC was lower for split-calving herds for the remaining months. During winter (October to March), split-calving herds had lower monthly TBC than seasonal herds, most likely because of stricter regulations imposed upon them. Herd size was approximated using total annual milk production figures. Across all months, larger herds had lower SCC and TBC compared with smaller herds. No obvious improvements in milk quality were seen between 2007 and 2011. Farmers have the opportunity to improve milk quality by reducing bulk tank SCC in late lactation and by imposing stricter hygiene practices at the beginning and end of the year to overcome the seasonal variation of bulk tank TBC. PMID- 25828654 TI - Technical note: Improving the accuracy of mid-infrared prediction models by selecting the most informative wavelengths. AB - Mid-infrared spectroscopy (MIRS) is widely used to collect milk phenotypes at the population level. The aim of this study was to test the ability of the uninformative variable elimination (UVE) method to select and remove uninformative wavelength variables before partial least squares (PLS) analysis. Milk titratable acidity (TA) and Ca content were used as examples to illustrate the procedure. Reference values and MIRS spectra (n=208) of TA and Ca were retrieved from an existing database. The data set was randomly divided into calibration (70% of data) and validation (30% of data) sets, and PLS analysis was carried out before and after the UVE procedure. The UVE procedure selected 244 and 113 informative wavelengths for TA and Ca, respectively, from a total of 1,060. The elimination of uninformative variables before PLS regression increased the accuracy of MIRS prediction models, and it substantially reduced the computation time. Dealing with fewer variables is expected to enhance the efficiency of MIRS models to predict phenotypes at population level. PMID- 25828655 TI - Colostrum composition of Santa Ines sheep and passive transfer of immunity to lambs. AB - This study aimed to analyze the chemical composition and the IgG concentration of the colostrum, transitional milk, and mature milk of Santa Ines ewes as well as the transfer of passive immunity to lambs. Thirty-two pregnant ewes and 38 lambs were used. Ewes were milked immediately after lambing and at 12, 24, 36 h and 10 d postpartum. Colostrum was provided to the lambs at 40+/-15 min (mean+/-SE) after birth and then at 30-min intervals for obtaining the intake closest to 10% of body weight, and transitional milk was provided ad libitum. Blood from the lambs was collected 36 h after birth for measuring the serum concentrations of IgG, total protein, albumin, and gamma-globulin. The production was lower in primiparous than in multiparous ewes with body condition score (BCS)<2.75, but did not differ between primiparous and multiparous with BCS>=2.75 (interaction parity and BCS). The IgG concentration and fat, protein, lactose, and defatted dry extract percentages were not affected by the BCS of the ewe at lambing or by the parity. The total solids percentage in the colostrum was higher in ewes with BCS<2.75 (interaction BCS and time). The production and the protein, total solid, and defatted dry extract percentages showed quadratic behavior, the fat percentage decreased linearly, and the lactose percentage increased linearly with time postpartum. The IgG concentration in the colostrum was not correlated with the ewe's weight or BCS at the time of lambing. Moreover, the parity, the BCS, the ewe's type of gestation, and the lamb's sex did not influence the serum concentrations of IgG, total protein, albumin, and gamma-globulin in lambs. Adequate passive immune transfer (PIT) was observed in lambs for which the IgG intake was higher than 30 g. Failure in PIT was observed in 39.5% of lambs when considering a serum IgG concentration lower than 15 mg/mL and in 21% when considering a serum total protein concentration lower than 45 mg/mL. The mean apparent efficiency of absorption was 38.10%, with values between 0.02% and 98.80%. The serum IgG concentration was correlated with the total protein concentration (according to the enzymatic colorimetric method), the gamma globulin concentration, and the absorption efficiency. The extreme variation on apparent efficiency of absorption may have an effect on the success of PIT. Lambs should consume at least 30 g of IgG in the first 24 h of life to ensure adequate PIT. PMID- 25828656 TI - Quantification of whey in fluid milk using confocal Raman microscopy and artificial neural network. AB - In this work, we assessed the use of confocal Raman microscopy and artificial neural network as a practical method to assess and quantify adulteration of fluid milk by addition of whey. Milk samples with added whey (from 0 to 100%) were prepared, simulating different levels of fraudulent adulteration. All analyses were carried out by direct inspection at the light microscope after depositing drops from each sample on a microscope slide and drying them at room temperature. No pre- or posttreatment (e.g., sample preparation or spectral correction) was required in the analyses. Quantitative determination of adulteration was performed through a feed-forward artificial neural network (ANN). Different ANN configurations were evaluated based on their coefficient of determination (R2) and root mean square error values, which were criteria for selecting the best predictor model. In the selected model, we observed that data from both training and validation subsets presented R2>99.99%, indicating that the combination of confocal Raman microscopy and ANN is a rapid, simple, and efficient method to quantify milk adulteration by whey. Because sample preparation and postprocessing of spectra were not required, the method has potential applications in health surveillance and food quality monitoring. PMID- 25828657 TI - Manufacture of modified milk protein concentrate utilizing injection of carbon dioxide. AB - Dried milk protein concentrate is produced from skim milk using a combination of processes such as ultrafiltration (UF), evaporation or nanofiltration, and spray drying. It is well established that dried milk protein concentrate (MPC) that contains 80% (MPC80) and greater protein content (relative to dry matter) can lose solubility during storage as a result of protein-protein interactions and formation of insoluble complexes. Previous studies have shown that partial replacement of calcium with sodium improves MPC80 functionality and prevents the loss in solubility during storage. Those studies have used pH adjustment with the addition of acids, addition of monovalent salts, or ion exchange treatment of UF retentate. The objective of this study was to use carbon dioxide to produce MPC80 with improved functionality. In this study, reduced-calcium MPC80 (RCMPC) was produced from skim milk that was subjected to injection of 2,200 ppm of CO2 before UF, along with additional CO2 injection at a flow rate of 1.5 to 2 L/min during UF. A control MPC80 (CtrlMPC) was also produced from the same lot of skim milk without injection of CO2. The above processes were replicated 3 times, using different lots of skim milk for each replication. All the UF retentates were spray dried using a pilot-scale dryer. Skim milk and UF retentates were tested for zeta-potential (net negative charge), particle size, and viscosity. All the MPC were stored at room (22+/-1 degrees C) and elevated (40 degrees C) temperatures for 6 mo. Solubility was measured by dissolving the dried MPC in water at 22 degrees C and at 10 degrees C (cold solubility). Injection of CO2 and the resultant solubilization of calcium phosphate had a significant effect on UF performance, resulting in 10 and 20% loss in initial and average flux, respectively. Processing of skim milk with injection of CO2 also resulted in higher irreversible fouling resistances. Compared with control, the reduced calcium MPC had 28 and 34% less ash and calcium, respectively. Injection of CO2 resulted in a significant decrease in zeta-potential and a significant increase in the size of the casein micelle. Moreover, RCMPC had a significantly higher solubility after storage at room temperature and at elevated temperature. This study demonstrates that MPC80 with a reduced calcium and mineral content can be produced with injection of CO2 before and during UF of skim milk. PMID- 25828658 TI - Effect of maternal dry period length on colostrum immunoglobulin content and on natural and specific antibody titers in calves. AB - The objective was to study the effect of dry period length in dairy cows on immunoglobulin content and natural antibodies (NAb) titers in colostrum, growth, and plasma natural and specific antibody titers in plasma of calves. Holstein Friesian dairy cows (n=167) were randomly assigned to 3 dry period lengths (0, 30, or 60 d). Colostrum production, concentration of colostrum IgG and IgM, and titers of NAb (isotypes IgG and IgM) binding keyhole limpet hemocyanin (KLH) and human serum albumin (HuSA) in colostrum were measured. Female calves were immunized with both KLH and HuSA at wk 6 and 10 of life. Titers of NAb and specific antibody (SpAb) for isotypes IgG, IgM, and total immunoglobulin (IgT) binding KLH or HuSA were determined in plasma of female calves. Primary and secondary antibody responses to KLH or HuSA from wk 6 and 10 were expressed as the increase in antibody titers to wk 10 and 11 of life after primary and secondary challenges, respectively. Pregnancy length for cows with a 0-d dry period was 3d shorter compared with cows with a 30- or 60-d dry period. Birth weight of calves from cows with a 0-d dry period was lower compared with calves from cows with a 30-d dry period. Growth of calves until 12 wk of life was not affected by dry period length. Colostrum production and IgG and IgM concentration in colostrum were lower for cows with a 0-d dry period than a 60-d dry period. Natural IgG and IgM titers binding KLH or HuSA were lower in colostrum from cows with a 0-d dry period compared with cows with a 60-d dry period. Natural antibody titers (IgG, IgM, and IgT) binding KLH or HuSA in plasma were lower during the first 2 wk of life for calves from cows with a 0-d dry period compared with calves from cows with a 30- or 60-d dry period. After primary and secondary immunization of calves with KLH and HuSA, SpAb titers of calves were not affected by dry period length. After secondary immunization, the response of IgG and IgT binding KLH was higher in plasma of calves from cows with a 0-d dry period. The results of this study demonstrate that, although omission of the dry period of dairy cows leads to lower plasma NAb titers in calves during the first 2 wk of life, SpAb titers in calves were not affected and even the secondary antibody responses were enhanced compared with calves from cows with a 30- or 60-d dry period. PMID- 25828659 TI - Casein polymorphism heterogeneity influences casein micelle size in milk of individual cows. AB - Milk samples from individual cows producing small (148-155 nm) or large (177-222 nm) casein micelles were selected to investigate the relationship between the individual casein proteins, specifically kappa- and beta-casein phenotypes, and casein micelle size. Only kappa-casein AA and beta-casein A1A1, A1A2 and A2A2 phenotypes were found in the large casein micelle group. Among the small micelle group, both kappa-casein and beta-casein phenotypes were more diverse. kappa Casein AB was the dominant phenotype, and 3 combinations (AA, AB, and BB) were present in the small casein micelle group. A considerable mix of beta-casein phenotypes was found, including B and I variants, which were only found in the small casein micelle group. The relative amount of kappa-casein to total casein was significantly higher in the small micelle group, and the nonglycosylated and glycosylated kappa-casein contents were higher in the milks with small casein micelles (primarily with kappa-casein AB and BB variants) compared with the large micelle group. The ratio of glycosylated to nonglycosylated kappa-casein was higher in the milks with small casein micelles compared with the milks with large casein micelles. This suggests that although the amount of kappa-casein (both glycosylated and nonglycosylated) is associated with micelle size, an increased proportion of glycosylated kappa-casein could be a more important and favorable factor for small micelle size. This suggests that the increased spatial requirement due to addition of the glycosyl group with increasing extent of glycosylation of kappa-casein is one mechanism that controls casein micelle assembly and growth. In addition, increased electrostatic repulsion due to the sialyl residues on the glycosyl group could be a contributory factor. PMID- 25828660 TI - Short communication: A new minicurd model system for hard cooked cheeses. AB - The aim of this study was to propose and validate a new minicurd model of young hard cheese. Curd particles and whey obtained from conventional cheese making of Reggianito Argentino were separated and frozen. Then, both fractions were thawed and the mixture of whey and curds was reconstituted, from which minicurds were made on the laboratory scale. Repeatability and the effect of freezing on minicurd composition were investigated by assessing pH, protein and moisture contents, sodium chloride content, and total thermophilic lactic flora counts. Good repeatability was achieved, and no significant differences were found between minicurds made from fresh compared with frozen materials. Composition of the minicurd was appropriate for modeling Reggianito Argentino cheese. PMID- 25828661 TI - Total volatile fatty acid concentrations are unreliable estimators of treatment effects on ruminal fermentation in vivo. AB - Volatile fatty acid concentrations ([VFA], mM) have long been used to assess the effect of dietary treatments on ruminal fermentation in vivo. However, discrepancies in statistical results between [VFA] and VFA pool size (VFAmol) possibly related to ruminal digesta liquid amount (LIQ, kg) indicate potential issues with the use of [VFA]. We investigated relationships among [VFA], VFAmol, and LIQ measured 2 h postfeeding using individual lactating cow data (n=175) from 7 separate feeding studies. Regression analyses were performed using mixed models with "study" as a discrete random variable. The mean across studies and average range of values within studies, respectively, were 151 and 75 for [VFA], 11.2 and 9.8 for VFAmol, 73.3 and 41.0 for LIQ, and 289 and 83 mmol/kg for rumen fluid osmolality. Liquid amount changed with VFAmol (3.76 VFAmol+31.2; average within study R2=0.69), but the relationship was weak between [VFA] and LIQ (0.524 LIQ+112.8; average within-study R2=0.12). The relationship between LIQ and VFAmol was likely a function of the osmotic gradient between rumen liquid and blood. The VFA are a major ruminal solute; VFAmol amounts can affect water flux in the rumen as similar tonicities of rumen fluid and blood are maintained. This also has a damping effect on ruminal solute concentration, creating the weak relationship between [VFA] and LIQ. Within studies, similar [VFA] were found in LIQ differing by 30 kg or more. The difference between minimum and maximum LIQ within cow within study was 12.7 kg (standard deviation=7.1), so inclusion of "cow" in analyses did not correct for the variation in LIQ. To allow valid comparisons of experimental treatments, responses must be on an equivalent basis; concentrations in different LIQ are not on an equivalent basis and so are not valid to use for comparing treatment effects. The [VFA] changed with VFAmol (5.80 VFAmol+86.3; average within-study R2=0.56). However, the ratio of [VFA] to VFAmol ranged from 9.0 to 24.1 as a function of 1,000/LIQ; this reflects the inherent calculated relationship among the variables. The varying relationship of [VFA] to VFAmol further indicates that [VFA] is not an appropriate measure to evaluate the progress or effect of treatments on ruminal fermentation. Predictions of LIQ and VFAmol using cow and ruminal measures were insufficiently precise to be used in research. Previously drawn conclusions based on [VFA] need to be reevaluated, and alternate evaluations for in vivo ruminal fermentation are needed. PMID- 25828662 TI - Foot and leg conformation traits have a small effect on genomic predictions of claw disorders in Norwegian Red cows. AB - The aim of this study was to evaluate whether the predictive correlation of genomic breeding values (GEBV) for claw disorders increased by including genetically correlated traits as additional information in the analyses. Predictive correlations of GEBV for claw disorders were calculated based on claw disorders only and by analyzing claw disorders together with genetically correlated foot and leg conformation traits. The claw disorders analyzed were corkscrew claw (CSC); infectious claw disorder, including dermatitis, heel horn erosion, and interdigital phlegmon; and laminitis-related claw disorder, including sole ulcer, white line disorder, and hemorrhage of sole and white line. The foot and leg conformation traits included were hoof quality, foot angle, rear leg rear view new, and rear leg rear view old. The data consisted of 183,728 daughters with claw health records and 421,319 daughters with foot and leg conformation scores. A 25K/54K single nucleotide polymorphism (SNP) data set containing 48,249 SNP was available for the analyses. The number of genotyped sires with daughter information in the analyses was 1,093 including claw disorders and 3,111 including claw disorders and foot and leg conformation traits. Predictive correlations of GEBV for CSC, infectious claw disorder, and laminitis-related claw disorder were calculated from a 10-fold cross-validation and from an additional validation set including the youngest sires. Only sires having daughters with claw health records were in the validation sets, thus increasing the reference population when adding foot and leg conformation traits. The results showed marginal improvement in the predictive correlation of GEBV for CSC when including hoof quality and foot angle, both in 10-fold cross-validation (from 0.35 to 0.37) and in the validation including the youngest sires (from 0.38 to 0.49). For infectious claw disorder and laminitis-related claw disorder, including foot and leg conformation traits had no effect on the predictive correlation of GEBV. Claw disorders are novel traits with a limited amount of historical data and, therefore, a small reference population. Increasing the reference population by including sires with daughter information on foot and leg conformation traits had small effect on the predictive correlation of GEBV. However, the small increase in predictive correlation of GEBV for CSC shows a possible gain when including moderate to high genetically correlated traits. PMID- 25828663 TI - Short communication: Evaluation of the microbiota of kefir samples using metagenetic analysis targeting the 16S and 26S ribosomal DNA fragments. AB - Milk kefir is produced by fermenting milk in the presence of kefir grains. This beverage has several benefits for human health. The aim of this experiment was to analyze 5 kefir grains (and their products) using a targeted metagenetic approach. Of the 5 kefir grains analyzed, 1 was purchased in a supermarket, 2 were provided by the Ministry of Agriculture (Namur, Belgium), and 2 were provided by individuals. The metagenetic approach targeted the V1-V3 fragment of the 16S ribosomal (r)DNA for the grains and the resulting beverages at 2 levels of grain incorporation (5 and 10%) to identify the bacterial species population. In contrast, the 26S rDNA pyrosequencing was performed only on kefir grains with the aim of assessing the yeast populations. In parallel, pH measurements were performed on the kefir obtained from the kefir grains using 2 incorporation rates. Regarding the bacterial population, 16S pyrosequencing revealed the presence of 20 main bacterial species, with a dominance of the following: Lactobacillus kefiranofaciens, Lactococcus lactis ssp. cremoris, Gluconobacter frateurii, Lactobacillus kefiri, Acetobacter orientalis, and Acetobacter lovaniensis. An important difference was noticed between the kefir samples: kefir grain purchased from a supermarket (sample E) harbored a much higher proportion of several operational taxonomic units of Lactococcus lactis and Leuconostoc mesenteroides. This sample of grain was macroscopically different from the others in terms of size, apparent cohesion of the grains, structure, and texture, probably associated with a lower level of Lactobacillus kefiranofaciens. The kefir (at an incorporation rate of 5%) produced from this sample of grain was characterized by a lower pH value (4.5) than the others. The other 4 samples of kefir (5%) had pH values above 5. Comparing the kefir grain and the kefir, an increase in the population of Gluconobacter in grain sample B was observed. This was also the case for Acetobacter orientalis in sample D. In relation to 26S pyrosequencing, our study revealed the presence of 3 main yeast species: Naumovozyma spp., Kluyveromyces marxianus, and Kazachastania khefir. For Naumovozyma, further studies are needed to assess the isolation of new species. In conclusion, this study has proved that it is possible to establish the patterns of bacterial and yeast composition of kefir and kefir grain. This was only achieved with the use of high-throughput sequencing techniques. PMID- 25828664 TI - Patterns of circulating serotonin and related metabolites in multiparous dairy cows in the peripartum period. AB - Dairy cows are challenged to maintain Ca and glucose homeostasis during the transition period. Serotonin (5-HT) is a monoamine that modulates Ca and glucose homeostasis in rodents. Serotonin is positively correlated with Ca and glucose status in dairy cows on d 1 of lactation. However, the pattern of circulating concentrations of 5-HT over the course of a 305-d lactation is unknown. In this observational, longitudinal study, we examined the metabolite patterns of 5-HT, Ca, glucose, parathyroid hormone-related protein, and beta-hydroxybutyrate on 2 commercial dairy farms in south-central Wisconsin. Cows sampled on farm 1 were multiparous Jersey cows (n=30) that calved within a 23-d period; cows on farm 2 were multiparous Holstein cows (n=35) that calved within a 20-d period. Blood samples were collected daily between d -5 and d 10 relative to parturition and on d 30, 60, 90, 150, and 300 of lactation. Farms 1 and 2 were analyzed individually because of the presence of a farm effect in the initial analysis; a time effect was present on both farms. Concentrations of 5-HT decreased near parturition compared with prepartum by 57.9 and 29.5% on farm 1 and 2, respectively. Transition period 5-HT nadirs were observed on d 1 on farm 1, and on d 1 and 9 on farm 2. Serotonin recovered to prepartum concentrations by d 5 on farm 1. On farm 2, 5-HT recovered to prepartum concentrations by d 4, with a subsequent decrease of 34.6% on d 9 to a level similar to that observed on d 1. Furthermore, 5-HT increased markedly in cows on both farms near peak lactation (d 60, 90, and 150) and decreased on d 300. Compared with prepartum concentrations, Ca decreased by 34.2 and 11.2% on farms 1 and 2, respectively. Circulating total Ca nadir was observed on d 1 on both farms. Circulating 5-HT and circulating Ca were positively correlated during the early lactation period (d 1 to 5 and d 6 to 10) on farm 1 (r=0.31 and r=0.22, respectively) and d 6 to 10 on farm 2 (r=0.16). Circulating 5-HT and glucose were negatively correlated during the early lactation period (d 1 to 5) on farm 1 (r=-0.21) and during mid-lactation (d 30 to 150) on farm 2 (r=-0.26). Milk 5-HT and milk total Ca were positively correlated on farm 2 (r=0.34). These results demonstrate that 5-HT concentrations change dynamically throughout the transition period, with a pattern similar to that of total Ca concentrations. Further research using controlled experiments should be aimed at discerning the association between 5-HT and Ca and between 5-HT and glucose in dairy cows. PMID- 25828665 TI - Effect of intrauterine dextrose on reproductive performance of lactating dairy cows diagnosed with purulent vaginal discharge under certified organic management. AB - The objectives of the study were to assess responses to treatments (clinical cure and resumption of estrous cycles) of cows with purulent vaginal discharge (PVD) that received intrauterine infusion of a hypertonic solution of 50% dextrose (DEX) or untreated control (CON) cows and the subsequent pregnancy per artificial insemination (PAI) in cows with and without PVD. Cows (n=2,852) from 2 dairy herds were screened for PVD using the gloved hand technique at exam 1 [26+/-3 d in milk (DIM)]. Cows with vaginal discharge scores of 2 or 3 (0-3 scale) were stratified by parity and randomly allocated into 1 of 2 treatment groups: (1) intrauterine infusion (~200 mL) of 50% DEX solution (n=456), or (2) untreated control animals (CON, n=491). Fourteen days posttherapy (40+/-3 DIM), cows with PVD were re-examined at exam 2 (40+/-3 DIM) to assess the response to treatments. All cows were subjected to the same reproductive program, which consisted of estrus detection twice daily (using tail chalking and visual observation) for the first 5 artificial inseminations; then, open lactating cows were turned out with bulls. Cows displaying signs of standing estrus underwent AI and no reproductive hormones were used. Pregnancy diagnosis (PD) was performed via transrectal palpation at 40+/-3 d post-AI. The risk of culling within 14 d posttherapy was not different among treatment groups. Cows with PVD had greater cervical diameter at exam 1 and decreased PAI compared with cows without PVD. Treatment with DEX increased the proportion of cows with clear vaginal discharge (clinical cure) and cyclicity 14 d posttherapy compared with CON cows. Pregnancy per AI for DEX (29.2+/-2%) cows was significantly greater than that for CON (22.5+/-2%) cows. Cows without PVD had a greater proportion of cycling cows (65.6%) and PAI (37%) with reduced pregnancy losses (5.7%) compared with DEX or CON cows. The use of intrauterine DEX alone improved reproductive performance of cows with PVD. PMID- 25828666 TI - Low body condition predisposes cattle to lameness: An 8-year study of one dairy herd. AB - Lameness in dairy cows is a multifactorial and progressive disease with complex interactions between risk factors contributing to its occurrence. Detailed records were obtained from one United Kingdom dairy herd over an 8-yr period. Weekly locomotion scores were used to classify cows as not lame (score 1 to 2), mildly lame (score 3) and severely lame (score 4 to 5). These outcomes were used to investigate the hypothesis that low body condition score (BCS) is associated with an increased risk of lameness in dairy cows. Mixed effect multinomial logistic regression models were used to investigate the association between prior BCS and repeat lameness events during the longitudinal period of the study. Discrete time survival models were used to explore the relationship between prior BCS and first lifetime lameness events. In total, 79,565 cow weeks at risk were obtained for 724 cows. The number of lameness events was 17,114, of which 8,799 were categorized as mildly lame and 8,315 as severely lame. The median BCS was 2.25 (range, 0.75 to 4.25) and the mean body weight (BW) and age at first calving were 619.5 kg (range, 355.6 to 956.4 kg) and 25.8 mo (range, 20.5 to 37.8 mo), respectively. Subsets of the data were used in the discrete time survival models: 333 mild and 211 severe first lifetime lameness events in heifers (first lactation cows), and 81 mild and 49 severe first lifetime lameness events in cows second lactation or greater. Low BCS 3 wk before a repeated lameness event was associated with a significantly increased risk of lameness. Cows with BCS<2 were at greatest risk of mild or severe lameness, and an increased BCS above 2 was associated with a reduced risk of mild or severe lameness. Low BCS 16 or 8 wk before a first mild or severe lifetime lameness event, respectively, also had a positive association with risk of lameness in cows second lactation or greater. This provides evidence to support targeting management toward maintaining BCS to minimize the risk of lameness. Low BW (independent of BCS) and increased age at first calving above 24 mo were also associated with increased long-term risk of repeated lameness events. Overall, the model explained 62 and 60% of the variability for mild and severe lameness, respectively, highlighting the importance of these variables as risk factors and hence where management could be targeted to significantly affect reducing the risk of lameness. PMID- 25828667 TI - Radiofrequency Probe and Sharp Transection for Tenoscopic-Guided Desmotomy of the Accessory Ligament of the Superficial Digital Flexor Tendon. AB - OBJECTIVE: To compare intra and postoperative clinical features of desmotomy of the accessory ligament of the superficial digital flexor tendon (ALSDFT) using the Saber radiofrequency (SaberRF) electrosurgical probe versus sharp transection with a tenotomy knife. STUDY DESIGN: Randomized, controlled, blocked (horse) design. ANIMALS: Adult horses (n = 6). METHODS: Each horse received bilateral, tenoscopic-guided ALSDFT desmotomy with a SaberRF and tenotomy knife, randomly assigned to left, or right limb. The desmotomy duration and intraoperative hemorrhage grades were recorded. Postoperatively, the grades for surgical incision, carpal sheath effusion, carpal range of motion, flexion pain, and lameness were recorded. Light microscopy using hematoxylin and eosin, and viability staining were performed on the ALSDFT, flexor carpi radialis tendon, radial head of the deep digital flexor tendon, and the deep digital flexor tendon. Variables were compared between desmotomy methods with a paired t-test, Wilcoxon signed rank test, or a repeated measures mixed model. Statistical significance was set at P < .05. RESULTS: Desmotomy of the ALSDFT was completed in all horses. Only mild hemorrhage was observed and not different between methods (SaberRF 2/5 limbs; tenotomy knife 5/6 limbs, P = .078). Carpal sheath effusion was greater for SaberRF at Day 1 (P = .019) but not different from tenotomy knife at any later time. There was no significant difference between methods for viability staining or other measured outcomes. CONCLUSIONS: Tenoscopic-guided ALSDFT desmotomy with the SaberRF probe showed no difference in measured outcomes to sharp transection with a tenotomy knife and minimal collateral tissue damage was observed. PMID- 25828668 TI - LAA CT contrast defects correlate with TEE LAA velocity and CHADS2-score and are a prognostic indicator for embolism in subjects with atrial fibrillation or flutter. PMID- 25828669 TI - Psoriasis and risk of atrial fibrillation. PMID- 25828670 TI - Mitral valve replacement therapy causes higher 30-day postoperative mortality than mitral valvuloplasty in patients with severe ischemic mitral regurgitation: A meta-analysis of 12 studies. PMID- 25828671 TI - Pre-hospital prediction of death or cardiovascular complications during hospitalisation and death within one year in suspected acute coronary syndrome patients. AB - OBJECTIVES: To identify pre-hospital predictors of a) death or the development of cardiovascular complications during hospitalisation (primary objective) and b) all-cause death during one year of follow-up (secondary objective), in chest pain patients with suspected acute coronary syndrome (ACS). METHODS: A prospective study that comprised patients in western Sweden, who were transported to hospital by the emergency medical service (EMS) due to chest pain and suspected ACS. Multiple logistic regression was used to identify independent predictors of adverse outcomes. RESULTS: Among all 1600 eligible patients, 21% died or had a cardiovascular complication during hospitalisation and 10% died during one year of follow-up. Nine factors were identified pre-hospitalisation as independent predictors of death or cardiovascular complications during hospitalisation. They were increasing age, a history of congestive heart failure, nausea and/or vomiting, rapid breathing rate, low oxygen saturation, high heart rate, together with ST-segment elevation, ST-segment depression and right bundle branch block on the pre-hospital electrocardiogram (ECG). For the secondary objective of death during one year of follow-up, the following five factors were identified as independent predictors: increasing age, a history of congestive heart failure, dyspnea, low oxygen saturation and left bundle branch block on the pre-hospital ECG. CONCLUSIONS: In the pre-hospital setting of chest pain and suspected ACS, we identified nine predictors of the primary adverse outcome. They were factors representing previous history, symptoms and ECG findings. This information may contribute to the development of a decision support system for the EMS, which then needs to be clinically tested. PMID- 25828672 TI - A victory for statins or a defeat for diet policies? Cholesterol falls in Poland in the past decade: A modeling study. AB - AIM: The present study is aimed to examine whether recent changes in population total cholesterol (TC) levels in Poland might be attributed to increased use statins. METHODS: Two independent, nationally representative cross-sectional studies were conducted in adults aged 18-79 years in 2002 (n=2993, mean age 46.2 years) and 2011 (n=2413, mean age 45.8 years), including measurements of TC in venous blood samples. The mean change of TC between 2002 and 2011 was assessed. Then the expected therapeutic reduction in TC level in 2011 attributable to statins only was calculated based on already published statin effectiveness data. Uncertainty was quantified using probabilistic sensitivity analysis. RESULTS: Statin uptake in Poland rose to 11.2% in 2011 (95% Confidence Intervals (CI): 10% to 12.5%) and approximately 32% (95% CI: 28.4 to 36.0%) in subjects aged 60-79 years. Mean TC in Poland in 2002 was 5.35 mmol/l, and fell by 0.21 mmol/l (95% CI: 0.14 to 0.28) by 2011. This fall would have been only 0.03 mmol/l (95% CI: 0.04 to 0.10) for the total adult population and 0.06 mmol/l (95% CI: -0.09 to 0.22) in people aged 60-79 years if statins had not been used. Statin use thus apparently explained approximately 85% (95% CI: 49% to 120%) of the observed decrease. CONCLUSION: Between 2002 and 2011, statin medications apparently explained a large part of the observed fall in population cholesterol level, suggesting very little changes in population TC attributed to dietary changes. PMID- 25828673 TI - FGF-21 alleviates diabetes-associated vascular complications: Inhibiting NF kappaB/NLRP3 inflammasome-mediated inflammation? PMID- 25828674 TI - Free Light Chains in patients with acute coronary syndromes: Relationships to inflammation and renal function. AB - AIMS: We assessed changes of serum combined free immunoglobulin light chains (cFLC) levels, which are associated with increased all-cause mortality, in ST elevation myocardial infarction (STEMI) in relation to inflammation and renal function indices. METHODS: cFLC were measured in 48 patients with STEMI on days 1, 3, 7 and 30 with assessment of their relationships with monocyte subsets, high sensitivity C-reactive protein (hsCRP), and cystatin C. Day 1 levels in STEMI patients were compared to 40 patients with stable coronary artery disease, and 37 healthy controls. RESULTS: There were no significant differences in cFLC levels between the study groups. In STEMI patients, cFLC values peaked on day 7 post-MI and remained elevated on day 30 (p<0.001 vs. day 1 for both). hsCRP concentrations peaked on day 3 of STEMI followed by their gradual reduction to the levels seen in the controls (p<0.001). In STEMI cFLC correlated with cystatin C (r=0.55, p<0.001), and negatively correlated with counts of CD14++CD16- monocytes (r=-0.55, p<0.001). On multivariate Cox regression analysis, cFLC concentrations were associated with increased need for future percutaneous coronary intervention (PCI) (p=0.019). CONCLUSION: cFLC levels increase during STEMI with peak values on day 7 after presentation and predict the need for future PCI. PMID- 25828675 TI - Non-surgical repair of ventricular septal rupture after acute myocardial infarction. AB - BACKGROUND: Ventricular septal rupture (VSR) following myocardial infarction is a rare complication with high mortality. Although transcatheter closure has emerged as a less invasive method of VSR closure, the optimal timing and technique remain unclear. METHODS: This is a single-center, retrospective, cohort study. Eleven patients that underwent transcatheter closure of post-AMI VSR from 2006 to 2013 at the Second Xiangya Hospital were included in this study. The clinical, procedural, and outcome data were analyzed. RESULTS: VSR occurred in 4 patients at anterior, 4 at posterior, and 3 at apical ventricular septum. Atrial Septal Defect occluder was used in 2 patients, muscular Ventricular Septal Defect occluder was used in 6 patients, and Patent Ductus Arteriosus occluder was used in 3 patients. The median time between VSR diagnosis and transcatheter closure was 18 days (range, 13-30 days). The median size of the VSR was 12 mm (range, 8 17 mm). The occlusion device was deployed successfully in 10 of 11 patients. Three patients died between zero and seven days after the procedure (30-day mortality, 27.3%). Eight patients survived during a follow-up of 150-1960 days. A follow-up TTE showed no residual shunt in three patients and a trivial or small residual shunt in five patients. CONCLUSION: Transcatheter closure of post-AMI VSR using Atrial Septal Defect, Ventricular Septal Defect, and Patent Ductus Arteriosus occluders is feasible and effective. If the clinical conditions permit, intervention can be delayed to the late phase (>2-3 weeks) after VSR diagnosis. PMID- 25828676 TI - Spreading patterns of the invasive Caulerpa cylindracea Sonder along the west Istrian Coast (northern Adriatic Sea, Croatia). AB - The northern Adriatic Sea represents the northernmost and thus the coldest biogeographic sector of the Mediterranean Sea. In 2004, the invasive green alga Caulerpa cylindracea was recorded for the first time in the northern Adriatic at a site of the west Istrian Coast. Until 2010, additional C. cylindracea mats have only formed up to 7 km northward from the first colonisation site. Subsequently, the alga was also recorded at sites widespread along the entire coast. Both the first 2004 colonisation event and the 2011-2014 colonisation of distant sites occurred during periods of winter seawater temperatures higher than 9 degrees C. In general, algal spreading was markedly slow. Approximately 10 years after the first record, C. cylindracea has affected less than 1% of the entire west Istrian coastline. The colonisation predominantly occurred in ports and urbanised bays (seaside resorts) suggesting that anthropogenic activities might enhance algal diffusion. PMID- 25828677 TI - Medical education and law: withholding/withdrawing treatment from adults without capacity. AB - BACKGROUND: Law is increasingly involved in clinical practice, particularly at the end of life, but undergraduate and postgraduate education in this area remains unsystematic. We hypothesised that attitudes to and knowledge of the law governing withholding/withdrawing life-sustaining treatment from adults without capacity (the WWLST law) would vary and demonstrate deficiencies among medical specialists. AIMS: We investigated perspectives, knowledge and training of medical specialists in the three largest (populations and medical workforces) Australian states, concerning the WWLST law. METHODS: Following expert legal review, specialist focus groups, pre-testing and piloting in each state, seven specialties involved with end-of-life care were surveyed, with a variety of statistical analyses applied to the responses. RESULTS: Respondents supported the need to know and follow the law. There were mixed views about its helpfulness in medical decision-making. Over half the respondents conceded poor knowledge of the law; this was mirrored by critical gaps in knowledge that varied by specialty. There were relatively low but increasing rates of education from the undergraduate to continuing professional development (CPD) stages. Mean knowledge score did not vary significantly according to undergraduate or immediate postgraduate training, but CPD training, particularly if recent, resulted in greater knowledge. Case-based workshops were the preferred CPD instruction method. CONCLUSIONS: Teaching of current and evolving law should be strengthened across all stages of medical education. This should improve understanding of the role of law, ameliorate ambivalence towards the law and contribute to more informed deliberation about end-of-life issues with patients and families. PMID- 25828678 TI - Sleep regulatory factors. AB - The state of sleep consists of different phases that proceed in successive, tightly regulated order through the night forming a physiological program, which for each individual is different but stabile from one night to another. Failure to accomplish this program results in feeling of unrefreshing sleep and tiredness in the morning. The pro- gram core is constructed by genetic factors but regulated by circadian rhythm and duration and intensity of day time brain activity. Many environmental factors modulate sleep, including stress, health status and ingestion of vigilance-affecting nutrients or medicines (e.g. caffeine). Knowledge of the factors that regulate the spontaneous sleep-wake cycle and factors that can affect this regulation forms the basis for diagnosis and treatment of the many common disorders of sleep. PMID- 25828679 TI - Sleep and bodily functions: the physiological interplay between body homeostasis and sleep homeostasis. AB - Body homeostasis and sleep homeostasis may both rely on the complex integrative activity carried out by the hypothalamus. Thus, the three main wake-sleep (WS) states (i.e. wakefulness, NREM sleep, and REM sleep) may be better understood if the different cardio-respiratory and metabolic parameters, which are under the integrated control of the autonomic and the endocrine systems, are studied during sleep monitoring. According to this view, many physiological events can be considered as an expression of the activity that physiological regulations should perform in order to cope with the need to fulfill body and sleep homeostasis. This review is aimed at making an assessment of data showing the existence of a physiological interplay between body homeostasis and sleep homeostasis, starting from the spontaneous changes observed in the somatic and autonomic activity during sleep, through evidence showing the deep changes occurring in the central integration of bodily functions during the different WS states, to the changes in the WS states observed when body homeostasis is challenged by the external environment and when the return to normal ambient conditions allows sleep homeo- stasis to run without apparent physiological restrictions. The data summarized in this review suggest that an approach to the dichotomy between NREM and REM sleep based on physiological regulations may offer a framework within which observations that a traditional behavioral approach may overlook can be interpreted. The study of the interplay between body and sleep homeostasis appears, therefore, to be a way to understand the function of complex organisms beyond that of the specific regulations. PMID- 25828680 TI - Sleep and memory in the making. Are current concepts sufficient in children? AB - Memory consolidation is an active process wired in brain plasticity. How plasticity mechanisms develop and are modulated after learning is at the core of current models of sleep-dependent memory consolidation. Nowadays, two main classes of sleep-related memory consolidation theories are proposed, namely system consolidation and synaptic homeostasis. However, novel models of consolidation emerge, that might better account for the highly dynamic and interactive processes of encoding and memory consolidation. Processing steps can take place at various temporal phases and be modulated by interactions with prior experiences and ongoing events. In this perspective, sleep might support (or not) memory consolidation processes under specific neurophysiological and environmental circumstances leading to enduring representations in long-term memory stores. We outline here a discussion about how current and emergent models account for the complexity and apparent inconsistency of empirical data. Additionally, models aimed at understanding neurophysiological and/or cognitive processes should not only provide a satisfactory explanation for the phenomena at stake, but also account for their ontogeny and the conditions that disrupt their organisation. Looking at the available literature, this developmental condition appears to remain unfulfilled when trying to understand the relationships between sleep, learning and memory consolidation processes, both in healthy children and in children with pathological conditions. PMID- 25828681 TI - The reciprocal link between sleep and immune responses. AB - Good sleep is necessary for both physical and mental health; sleep and immune responses are reciprocally and closely linked. Sleep loss impairs the immune response, while, on the other hand, the immune response, activated for instance by an infection, alters sleep. Sleep alterations induced by immune activation are mediated by cytokines such as interleukin-1. In the past, it was thought that cytokines were produced only by the immune system, and active only there as signaling molecules. Today it is clear that IL-1 and other cytokines are present and active in the healthy brain, where they physiologically interact with the brain circuits and the neurotransmitter systems (for instance the serotonergic, GABAergic, and cholinergic systems) that control sleep. These interactions are altered by immune response, and, as a result, non-rapid eye movement (NREM) sleep is increased and fragmented, whereas rapid eye movements (REM) sleep is inhibited. PMID- 25828682 TI - Effects of acute and chronic sleep deprivation on cardiovascular regulation. AB - Sleep is a fundamental physiological process, characterized by the activation of several cortical and subcortical neural networks. The relation between sleep and cardiovascular system is complex and bidirectional: sleep disorders may alter cardiovascular system, leading to an increased cardiovascular risk, while, on the contrary, cardio- vascular diseases are characterized by an alteration of physiological sleep. Autonomic nervous system (ANS) plays a key role in the regulation of cardiovascular functions during different sleep stages, with sympatho-vagal balance dynamically shifting towards sympathetic or vagal predominance across different sleep stages. Sleep deprivation (SD) has becoming one of the most relevant health problem in modern societies. SD can be related to aging, which is associated with increased sleep fragmentation, and to sleep disorders, such as sleep disordered breathing and neurological disorders. Experimental studies in animals showed that SD significantly affects cardiovascular functions, altering heart rate and blood pressure responses, and increasing sympathetic activity and neuroendocrine response to stressor stimuli. Clinical studies in humans have shown that SD, either due to experimental sleep loss and to sleep disorders, can affect different biological pathways, such as cardiovascular autonomic control, inflammation, immunity responses and metabolism. All these alterations may predispose subjects with SD to an increased cardiovascular risk. Hence, it is fundamental to identify the presence of a sleep disorder, which could be per se responsible for sleep loss, or the presence of sleep deprivation due to other factors, such as social life, habits etc., in order to identify subjects at high risk for cardiovascular events. PMID- 25828683 TI - REM sleep alteration and depression. AB - Alterations in sleep patterns are often recognized as a premorbid symptom accompanied by affective disorders, particularly by major depression. However, the mechanism is rather complex, and differentiating its causalities from those of depression undergoes hardships. Indeed, depression is a complex disease. It has been clearly demonstrated that depressed patients display very characteristic changes in sleep architecture. Previous animal studies also demonstrated that several depression models, which had targeted elevated hypothalamic-pituitary adrenocortical (HPA) axis, showed increased rapid eye movement (REM) sleep while insomniac sleep phenotype did not evidently appear. However, all stress hormones seem to be elevated in those models. Therefore, it has been difficult to determine which particular hormone in the HPA axis is primarily responsible for altered sleep in depression. In recent years, we have widely analyzed sleep characteristics of conditional transgenic mouse lines focusing on corticotropin releasing hormone (CRH), the initial mediator of the HPA system, in which the levels of peripheral stress hormones are normal. Conditional CRH-overexpressing (COE) mice, especially those overexpress CRH limitedly within the forebrain including limbic structures (CRH-COE-Cam), dis- play enhanced REM sleep. Further, the higher occurrence of REM sleep in CRH-COE-Cam mice could be due to their hyper-cholinergic activity. REM sleep disinhibition observed in depressed patients similarly appears in animals which are genetically stress-vulnerable strain or chronically stressed, possibly due to enhanced action of limbic CRH. Indeed, REM sleep is a fragile vigilance state and closely connected with emotional control. Thus, depressive episodes may affect REM sleep earlier than nonREM sleep, and such altered REM sleep can be a state marker of depression. PMID- 25828684 TI - Animal models of REM dysfunctions: what they tell us about the cause of narcolepsy and RBD? AB - Rapid eye movement sleep behavior disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during paradoxical (REM) sleep (PS). Conversely, cataplexy, one of the key symptoms of narcolepsy, is a striking sudden episode of muscle weakness triggered by emotions during wakefulness, and comparable to REM sleep atonia. The neuronal dysfunctions responsible for RBD and cataplexy are not known. In the present review, we present the most recent results on the neuronal network responsible for PS. Based on these results, we propose an updated integrated model of the mechanisms responsible for PS and explore different hypotheses explaining RBD and cataplexy. We propose that RBD is due to a specific degeneration of a subpopulation of PS-on glutamatergic neurons specifically responsible of muscle atonia, localized in the caudal pontine sublaterodorsal tegmental nucleus (SLD). Another possibility is the occurrence in RBD patients of a specific lesion of the glycinergic/GABAergic premotor-neurons localized in the medullary ventral gigantocellular reticular nucleus. Conversely, cataplexy in narcoleptics would be due to the activation during waking of the caudal PS-on SLD neurons responsible for muscle atonia. A direct or indirect pathway activated during positive emotion from the central amygdala to the SLD PS-on neurons would induce such activation. In normal conditions, the activation of SLD neurons would be blocked by the simultaneous excitation by the hypocretins of the PS-off GABAergic neurons localized in the ventrolateral periaqueductal gray and the adjacent deep mesencephalic reticular nucleus gating the activation of the PS-on SLD neurons. PMID- 25828685 TI - REM Sleep Behavior Disorder (RBD) as a marker of neurodegenerative disorders. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) can occur in the absence of any other obvious associated neurologic disorder or in association with a neurodegenerative disease, in which case it is considered as symptomatic RBD. RBD is frequently associated with Parkinson's disease (PD), Lewy body dementia or multiple system atrophy (MSA), and in several cases may even antedate the occurrence of motor symptoms by decades. When no neurologic disorder is obvious, RBD can be considered as idiopathic (iRBD). Several studies have looked at neurophysiologic and neuropsychological functions in iRBD and have found evidence of CNS dysfunction during both wakefulness and sleep in a variable proportion of these patients, challenging the concept of iRBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies. Some prospective results in iRBD showed that potential markers of neurodegeneration are the following: 1) marked EEG slowing on spectral analysis; 2) decreased striatal 123I-FPCIT; 3) impaired color vision. PMID- 25828686 TI - Slow wave activity as the default mode of the cerebral cortex. AB - The function of sleep remained one of largest enigmas of neuroscience for most of the 20th century. However in recent years different evidence has accumulated in support of a critical role of sleep on functions such as replay and memory consolidation. In particular slow wave sleep, and its underlying corticothalamocortical activity, slow oscillations, could be critical not only for memory but also for the maintenance of the brain's structural and func- tional connectivity. In this article we ask: why slow oscillations? To answer this question we put forward the idea that slow oscillations are the default activity of the cortical network based on both experimental and theoretical evidence. We go on to discuss why slow oscillations emerge from the cortical circuits and what are the dynamic advantages of this activity pattern, such as the resilience to perturbances and the facilitation of transitions between a disconnected (e.g. deep sleep) brain and a connected, awake brain. PMID- 25828687 TI - Long-term history and immediate preceding state affect EEG slow wave characteristics at NREM sleep onset in C57BL/6 mice. AB - The dynamics of cortical activity across the 24-h day and at vigilance state transitions is regulated by an interaction between global subcortical neuromodulatory influences and local shifts in network synchrony and excitability. To address the role of long-term and immediate preceding history in local and global cortical dynamics, we investigated cortical EEG recorded from both frontal and occipital regions during an undisturbed 24-h recording in mice. As expected, at the beginning of the light period, under physiologically increased sleep pressure, EEG slow waves were more frequent and had higher amplitude and slopes, compared to the rest of the light period. Within discrete NREM sleep episodes, the incidence, amplitude and slopes of individual slow waves increased progressively after episode onset in both derivations by approximately 10-30%. Interestingly, at the beginning of NREM sleep episodes slow waves in the frontal and occipital derivations frequently occurred in isolation, as quantified by longer latencies between consecutive slow waves in the two regions. Notably, slow waves during the initial period of NREM sleep following REM sleep episodes were significantly less frequent, lower in amplitude and exhibited shallower slopes, compared to those that occurred in NREM episodes after prolonged waking. Moreover, the latencies between consecutive frontal and occipital NREM slow waves were substantially longer when they occurred directly after REM sleep compared to following consolidated wakefulness. Overall these data reveal a complex picture, where both time of day and preceding state contribute to the characteristics and dynamics of slow waves within NREM sleep. These findings suggest that NREM sleep initiates in a more "local" fashion when it occurs following REM sleep episodes as opposed to sustained waking bouts. While the mechanisms and functional significance of such a re-setting of brain state after individual REM sleep episodes remains to be investigated, we suggest that it may be an essential feature of physiological sleep regulation. PMID- 25828688 TI - Fluid boundaries between wake and sleep: experimental evidence from Stereo-EEG recordings. AB - Sleep and waking have been traditionally considered global behavioural states regulated by subcortical neuromodulatory circuits in a top-down fashion. Over the last years, we have been experiencing a paradigm shift towards a view that both wake and sleep are in essence local processes. Here we review recent clinical and basic research works supporting this view by taking advantage of stereotactic electroencephalography (Stereo-EEG, SEEG) recordings performed in epileptic patients. Specifically, we will discuss a growing body of evidence showing how electrophysiological features of sleep and wakefulness are coexisting across diffuse brain areas in pathological and physiological sleep as well as during state transitions (sleep onset and awakenings). Finally, we will discuss their implication for sleep medicine to extent that, reconsidering the classical definition of wakefulness and sleep as separate and mutually exclusive states may offer new insight for the understanding of parasomnias and other dissociated states. PMID- 25828689 TI - PFR2: a curated database of planktonic foraminifera 18S ribosomal DNA as a resource for studies of plankton ecology, biogeography and evolution. AB - Planktonic foraminifera (Rhizaria) are ubiquitous marine pelagic protists producing calcareous shells with conspicuous morphology. They play an important role in the marine carbon cycle, and their exceptional fossil record serves as the basis for biochronostratigraphy and past climate reconstructions. A major worldwide sampling effort over the last two decades has resulted in the establishment of multiple large collections of cryopreserved individual planktonic foraminifera samples. Thousands of 18S rDNA partial sequences have been generated, representing all major known morphological taxa across their worldwide oceanic range. This comprehensive data coverage provides an opportunity to assess patterns of molecular ecology and evolution in a holistic way for an entire group of planktonic protists. We combined all available published and unpublished genetic data to build PFR(2), the Planktonic foraminifera Ribosomal Reference database. The first version of the database includes 3322 reference 18S rDNA sequences belonging to 32 of the 47 known morphospecies of extant planktonic foraminifera, collected from 460 oceanic stations. All sequences have been rigorously taxonomically curated using a six-rank annotation system fully resolved to the morphological species level and linked to a series of metadata. The PFR(2) website, available at http://pfr2.sb-roscoff.fr, allows downloading the entire database or specific sections, as well as the identification of new planktonic foraminiferal sequences. Its novel, fully documented curation process integrates advances in morphological and molecular taxonomy. It allows for an increase in its taxonomic resolution and assures that integrity is maintained by including a complete contingency tracking of annotations and assuring that the annotations remain internally consistent. PMID- 25828690 TI - Fundamental challenges for autism research: the science-practice gap, demarcating autism and the unsuccessful search for the neurobiological basis of autism. AB - One of the central aims of autism research is to identify specific neurodevelopmental mechanisms that cause and explain the visible autistic signs and symptoms. In this short paper, I argue that the persistent search for autism specific pathophysiologies has two fundamental difficulties. The first regards the growing gap between basic autism science and clinical practice. The second regards the difficulties with demarcating autism as a psychiatric condition. Instead of the unremitting search for the neurobiological basis of autism, I suggest that basic autism research should focus on experiences of impairment and distress, and on how these experiences relate to particular (autistic) behaviors in particular circumstances, regardless of whether we are dealing with an autism diagnosis or not. PMID- 25828691 TI - Field and experimental data indicate that the eastern cottontail (Sylvilagus floridanus) is susceptible to infection with European brown hare syndrome (EBHS) virus and not with rabbit haemorrhagic disease (RHD) virus. AB - The eastern cottontail (Sylvilagus floridanus) is an American lagomorph. In 1966, it was introduced to Italy, where it is currently widespread. Its ecological niche is similar to those of native rabbits and hares and increasing overlap in distribution brings these species into ever closer contact. Therefore, cottontails are at risk of infection with the two lagoviruses endemically present in Italy: Rabbit Haemorrhagic Disease virus (RHDV) and European Brown Hare Syndrome Virus (EBHSV). To verify the susceptibility of Sylvilagus to these viruses, we analyzed 471 sera and 108 individuals from cottontail populations in 9 provinces of north-central Italy from 1999 to 2012. In total, 15-20% of the cottontails tested seropositive for EBHSV; most titres were low, but some were as high as 1/1280. All the cottontails virologically tested for RHDV and EBHSV were negative with the exception of one individual found dead with hares during a natural EBHS outbreak in December 2009. The cottontail and the hares showed typical EBHS lesions, and the EBHSV strain identified was the same in both species (99.9% identity). To experimentally confirm the diagnosis, we performed two trials in which we infected cottontails with both EBHSV and RHDV. One out of four cottontails infected with EBHSV died of an EBHS-like disease, and the three surviving animals developed high EBHSV antibody titres. In contrast, neither mortality nor seroconversion was detected after infection with RHDV. Taken together, these results suggest that Sylvilagus is susceptible to EBHSV infection, which occasionally evolves to EBHS-like disease; the eastern cottontail could therefore be considered a "spill over" or "dead end" host for EBHSV unless further evidence is found to confirm that it plays an active role in the epidemiology of EBHSV. PMID- 25828692 TI - No effect of the cyclooxygenase-2 inhibitor etoricoxib on pre-emptive and post operative analgesia in visceral surgery: results of a randomized controlled trial. AB - BACKGROUND: Pre-emptive analgesia in perioperative care has potential benefits for patients. The pre-emptive and postoperative analgesic effects of the cyclooxygenase-2 inhibitor etoricoxib have been investigated using a 2 * 2 factorial trial design. METHODS: According to the 2 * 2 factorial study design, 103 patients scheduled for visceral surgery, were randomly allocated to two groups prior to surgery. Patients could receive either etoricoxib or placebo (to investigate pre-emptive analgesia). Subsequent to surgery, patients randomly received either etoricoxib or placebo, again. It follows, that four treatment modalities (continuous or replaced intervention) result, to investigate postoperative analgesia. Main Outcome Measure was the cumulative morphine use 48 h post-surgery. Other outcomes included pain intensities, pain thresholds and sensory detection. RESULTS: Eighty-six patients (female n = 42; mean age 53.82 +/ 13.61 years) were evaluated on the basis of an intention to treat analysis. Pre emptive administration of 120 mg etoricoxib did not significantly reduce the cumulative morphine dose within the first 48 h after surgery, when compared to the administration of placebo. The analysis of the post-operative treatment groups showed a non-significant 8% reduction in morphine dose during the continuous administration of etoricoxib. There were no changes in sensory perception as detected with QST before and after surgery or between groups. CONCLUSIONS: The effect of administering etoricoxib was not superior to placebo in reducing the morphine dose required for postoperative analgesia. The lack of changes in peripheral nociception suggests that central algetic mechanisms are of higher impact in the development of postoperative pain following abdominal or thoracic surgery. PMID- 25828693 TI - Development and comparative evaluation of loop mediated isothermal amplification (LAMP) assay for simple visual detection of orf virus in sheep and goats. AB - A loop-mediated isothermal amplification (LAMP) assay targeting DNA Pol gene was optimized and evaluated for the rapid detection of orf virus in clinical samples. The LAMP assay was found to be specific and sensitive. The detection rate of LAMP (89.3%) was better than PCR (67.9%) and comparable to real-time PCR (91.1%) in clinical samples by gel electrophoresis and visual detection methods. This LAMP assay is simple and does not rely upon any special equipment and could be employed in clinical diagnosis and epidemiological survey of orf infection. PMID- 25828694 TI - Employing a Flexible and Low-Cost Polypyrrole Nanotube Membrane as an Anode to Enhance Current Generation in Microbial Fuel Cells. AB - The flexible and low-cost polypyrrole nanotube membrane is demonstrated as a promising anode in microbial fuel cells, which significantly enhances the extracellular electron transfer between Shewanella oneidensis MR-1 and the electrode, owing to the large active surface area and high electrical conductivity. PMID- 25828695 TI - Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. AB - We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas (iNHLs). Of 83 evaluable patients, 91.6% attained an overall response and 86.8% a complete or unconfirmed complete response. The 3-year progression-free survival (PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses (P = 0.01): 83% [95% confidence interval (CI): 0.72, 0.96] for follicular lymphomas, 73% (95% CI: 0.54, 1.0) for marginal zone lymphomas and 61% (95% CI: 0.46, 0.81) for small lymphocytic lymphomas. The most common adverse events were haematological. Of 509 cycles of chemotherapy administered, grade 3 or 4 neutropenia was reported in 68 cycles (13% of cycles administered) and most frequently occurred during cycles 4-6. This is the first report demonstrating the effectiveness of pentostatin, cyclophosphamide and rituximab in patients with previously untreated iNHLs, including those over 60 years of age. PMID- 25828696 TI - Quantification of liver fat with respiratory-gated quantitative chemical shift encoded MRI. AB - PURPOSE: To evaluate free-breathing chemical shift-encoded (CSE) magnetic resonance imaging (MRI) for quantification of hepatic proton density fat-fraction (PDFF). A secondary purpose was to evaluate hepatic R2* values measured using free-breathing quantitative CSE-MRI. MATERIALS AND METHODS: Fifty patients (mean age, 56 years) were prospectively recruited and underwent the following four acquisitions to measure PDFF and R2*; 1) conventional breath-hold CSE-MRI (BH CSE); 2) respiratory-gated CSE-MRI using respiratory bellows (BL-CSE); 3) respiratory-gated CSE-MRI using navigator echoes (NV-CSE); and 4) single voxel MR spectroscopy (MRS) as the reference standard for PDFF. Image quality was evaluated by two radiologists. MRI-PDFF measured from the three CSE-MRI methods were compared with MRS-PDFF using linear regression. The PDFF and R2* values were compared using two one-sided t-test to evaluate statistical equivalence. RESULTS: There was no significant difference in the image quality scores among the three CSE-MRI methods for either PDFF (P = 1.000) or R2* maps (P = 0.359-1.000). Correlation coefficients (95% confidence interval [CI]) for the PDFF comparisons were 0.98 (0.96-0.99) for BH-, 0.99 (0.97-0.99) for BL-, and 0.99 (0.98-0.99) for NV-CSE. The statistical equivalence test revealed that the mean difference in PDFF and R2* between any two of the three CSE-MRI methods was less than +/-1 percentage point (pp) and +/-5 s(-1) , respectively (P < 0.046). CONCLUSION: Respiratory-gated CSE-MRI with respiratory bellows or navigator echo are feasible methods to quantify liver PDFF and R2* and are as valid as the standard breath hold technique. PMID- 25828697 TI - Oligonucleotide delivery with cell surface binding and cell penetrating Peptide amphiphile nanospheres. AB - A drug delivery system designed specifically for oligonucleotide therapeutics can ameliorate the problems associated with the in vivo delivery of these molecules. The internalization of free oligonucleotides is challenging, and cytotoxicity is the main obstacle for current transfection vehicles. To develop nontoxic delivery vehicles for efficient transfection of oligonucleotides, we designed a self assembling peptide amphiphile (PA) nanosphere delivery system decorated with cell penetrating peptides (CPPs) containing multiple arginine residues (R4 and R8), and a cell surface binding peptide (KRSR), and report the efficiency of this system in delivering G-3129, a Bcl-2 antisense oligonucleotide (AON). PA/AON (peptide amphiphile/antisense oligonucleotide) complexes were characterized with regards to their size and secondary structure, and their cellular internalization efficiencies were evaluated. The effect of the number of arginine residues on the cellular internalization was investigated by both flow cytometry and confocal imaging, and the results revealed that uptake efficiency improved as the number of arginines in the sequence increased. The combined effect of cell penetration and surface binding property on the cellular internalization and its uptake mechanism was also evaluated by mixing R8-PA and KRSR-PA. R8 and R8/KRSR decorated PAs were found to drastically increase the internalization of AONs compared to nonbioactive PA control. Overall, the KRSR-decorated self-assembled PA nanospheres were demonstrated to be noncytotoxic delivery vectors with high transfection rates and may serve as a promising delivery system for AONs. PMID- 25828698 TI - [Cardiovascular alterations associated with doping]. AB - Doping -the abuse of anabolic-androgenic steroids in particular- is widespread in amateur and recreational sports and does not solely represent a problem of professional sports. Excessive overdose of anabolic steroids is well documented in bodybuilding or powerlifting leading to significant side effects. Cardiovascular damages are most relevant next to adverse endocrine effects.Clinical cases as well as forensic investigations of fatalities or steroid consumption in connection with trafficking of doping agents provide only anecdotal evidence of correlations between side effects and substance abuse. Analytical verification and self-declarations of steroid users have repeatedly confirmed the presumption of weekly dosages between 300 and 2000 mg, extra to the fact that co-administration of therapeutics to treat side-effects represent a routine procedure. Beside the most frequent use of medications used to treat erectile dysfunction or estrogenic side-effects, a substantial number of antihypertensive drugs of various classes, i.e. beta-blockers, diuretics, angiotensin II receptor antagonists, calcium channel blockers, as well as ACE inhibitors were recently confiscated in relevant doping cases. The presumptive correlation between misuse of anabolic steroids and self-treatment of cardiovascular side effects was explicitly confirmed by detailed user statements.Two representative fatalities of bodybuilders were introduced to outline characteristic, often lethal side effects of excessive steroid abuse. Moreover, illustrative autopsy findings of steroid acne, thrombotic occlusion of Ramus interventricularis anterior and signs of cardiac infarctions are presented.A potential steroid abuse should be carefully considered in cases of medical consultations of patients exhibiting apparent constitutional modifications and corresponding adverse effects. Moreover, common self medications -as frequently applied by steroid consumers- should be taken into therapeutic considerations. PMID- 25828699 TI - Zein-based films and their usage for controlled delivery: Origin, classes and current landscape. AB - Zein is a class of alcohol-soluble prolamine proteins present in maize endosperm, which was approved as a generally recognized as safe (GRAS) excipient in 1985 by the United States Food and Drug Administration (US-FDA) for film coating of pharmaceuticals, e.g., tablets. Despite its long-term application in tablet production, effects of zein coating on tablet properties are still not fully understood. Moreover, many studies have also been conducted to illustrate its potential as an active ingredient of direct compressed tablets and film-based delivery carriers. In addition, the use of zein as a functional film coating material for new biomedical applications was also widely investigated in recent reports, which involved medical devices, nanoparticles, quantum dots and nanofibers. In this review, the present status of zein in the form of a thin film and uniform layer for use as a biomedical material is discussed. In addition, studies related to the behaviors and properties of zein films are also summarized and analyzed based on published works to gain mechanistic insights into the relationship between zein film and various improved profiles. This review will benefit future prospects of the use of zein film in drug delivery and biomedical applications. PMID- 25828700 TI - N,N'-Dialkyl-N,N'-diaryl-1,10-phenanthroline-2,9-dicarboxamides as donor ligands for separation of rare earth elements with a high and unusual selectivity. DFT computational and experimental studies. AB - N,N'-Dialkyl-N,N'-diaryl-1,10-phenanthroline-2,9-dicarboxamides (IV) were predicted (DFT simulation) and then were proved experimentally to be efficient donor ligands with high and unusual selectivity for the extraction separation of lanthanides. Distribution coefficients D of lanthanide cations in two-phase aqueous solution-polar organic solvent decrease with increasing Ln(3+) atomic number. The selectivity factors SFLn1/Ln2 for adjacent lanthanide ions were found to be about 3. PMID- 25828702 TI - Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence. AB - In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol dependent patients; (2) PIT was significantly associated with blood oxygen level dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence. PMID- 25828701 TI - Glycogen synthase kinase 3beta ubiquitination by TRAF6 regulates TLR3-mediated pro-inflammatory cytokine production. AB - TRAF6 is critical for the production of inflammatory cytokines in various TLR mediated signalling pathways. However, it is poorly understood how TRAF6 regulates TLR3 responses. Here we demonstrate that GSK3beta interacts with TRAF6 and positively regulates the TLR3-mediated signalling. Suppression of GSK3beta expression or its kinase activity drastically reduces the production of inflammatory cytokines and the induction of c-Fos by decreasing ERK and p38 phosphorylation. GSK3beta physically associates with TRAF6 in a TLR3 ligand poly I:C-dependent manner. TRAF6 is determined to be a direct E3 ligase for GSK3beta, and TRAF6-mediated GSK3beta ubiquitination is essential for poly I:C-dependent cytokine production by promoting the TLR3 adaptor protein TRIF-assembled signalling complex. PMID- 25828703 TI - Abnormal sonographic appearance of posterior brain at 11-14 weeks and fetal outcome. AB - OBJECTIVE: The aim of this retrospective study was to describe the sonographic appearance of the posterior brain anatomy in normal fetuses at 11 to 14 weeks of pregnancy and to determine the fetal outcome when one of the posterior brain anatomical space is not recognized. METHODS: Two groups of patients were included in the study: a control group of consecutive 311 healthy fetuses with a normal sonogram and a study group of 21 fetuses with absence of one of the three posterior brain spaces. In each fetus, images of the mid-sagittal view of the fetal face and brain at 11 to 14 weeks of gestation were obtained. RESULTS: In all fetuses with absence of one of the three posterior brain spaces, a severe anomaly, including open spina bifida, cephalocele, Dandy-Walker complex, and chromosomal aberrations, was associated. CONCLUSION: Our study indicates that the sonographic finding characterized by the absence of one of the three posterior brain spaces seems to facilitate not only the detection of open spina bifida, as previously reported, but also of other neural tube defects, such as cephalocele, and is an important risk factor for cystic posterior brain anomalies, and/or chromosomal abnormalities. Thus it seems a poor prognostic finding for major fetal abnormalities. PMID- 25828704 TI - Prevalence and characterization of ESBL- and AmpC-producing Enterobacteriaceae on retail vegetables. AB - In total 1216 vegetables obtained from Dutch stores during 2012 and 2013 were analysed to determine the prevalence of 3rd-generation cephalosporin (3GC) resistant bacteria on soil-grown fresh produce possibly consumed raw. Vegetables grown conventionally and organically, from Dutch as well as foreign origin were compared. Included were the following vegetable types; blanched celery (n=192), bunched carrots (n=190), butterhead lettuce (n=137), chicory (n=96), endive (n=188), iceberg lettuce (n=193) and radish (n=120). Overall, 3GC-resistant Enterobacteriaceae were detected on 5.2% of vegetables. Based on primary habitat and mechanism of 3GC-resistance, these bacteria could be divided into four groups: ESBL-producing faecal species (Escherichia coli, Enterobacter spp.), AmpC producing faecal species (Citrobacter freundii, Enterobacter spp.), ESBL producing environmental species (Pantoea spp., Rahnella aquatilis, Serratia fonticola), and AmpC-producing environmental species (Cedecca spp., Hafnia alvei, Pantoea spp., Serratia plymuthica), which were detected on 0.8%, 1.2%, 2.6% and 0.4% of the vegetables analysed, respectively. Contamination with faecal 3GC resistant bacteria was most frequently observed in root and bulb vegetables (average prevalence 4.4%), and less frequently in stem vegetables (prevalence 1.6%) and leafy greens (average prevalence 0.6%). In Dutch stores, only four of the included vegetable types (blanched celery, bunched carrots, endive, iceberg lettuce) were available in all four possible variants: Dutch/conventional, Dutch/organic, foreign/conventional, foreign/organic. With respect to these vegetable types, no statistically significant difference was observed in prevalence of 3GC-resistant Enterobacteriaceae between country of origin or cultivation type (5.2%, 5.7%, 5.7% and 3.3%, respectively). Vegetables consumed raw may be a source of dissemination of 3GC-resistant Enterobacteriaceae and their resistance genes to humans. The magnitude of the associated public health risk presumably depends on the types of bacteria that are ingested, i.e., faecal or environmental species, and may therefore be higher for root and bulb vegetables compared to leafy greens. PMID- 25828705 TI - Identification of acetic acid bacteria in traditionally produced vinegar and mother of vinegar by using different molecular techniques. AB - Culture-dependent and culture-independent methods were combined for the investigation of acetic acid bacteria (AAB) populations in traditionally produced vinegars and mother of vinegar samples obtained from apple and grape. The culture independent denaturing gradient gel electrophoresis (DGGE) analysis, which targeted the V7-V8 regions of the 16S rRNA gene, showed that Komagataeibacter hansenii and Komagataeibacter europaeus/Komagataeibacter xylinus were the most dominant species in almost all of the samples analyzed directly. The culture independent GTG5-rep PCR fingerprinting was used in the preliminary characterization of AAB isolates and species-level identification was carried out by sequencing of the 16S rRNA gene, 16S-23S rDNA internally transcribed to the spacer (ITS) region and tuf gene. Acetobacter okinawensis was frequently isolated from samples obtained from apple while K. europaeus was identified as the dominant species, followed by Acetobacter indonesiensis in the samples originating from grape. In addition to common molecular techniques, real-time PCR intercalating dye assays, including DNA melting temperature (Tm) and high resolution melting analysis (HRM), were applied to acetic acid bacterial isolates for the first time. The target sequence of ITS region generated species-specific HRM profiles and Tm values allowed discrimination at species level. PMID- 25828706 TI - Prevalence, molecular characterization, and antibiotic susceptibility of Cronobacter spp. in Chinese ready-to-eat foods. AB - Cronobacter spp. are foodborne pathogens that cause rare but life-threatening diseases in neonates and infants; they can also cause disease in adults. Cronobacter spp. contamination of ready-to-eat (RTE) foods has been reported previously. However, to date, the prevalence and contamination levels of these bacteria in RTE foods in China have not yet been determined. Therefore, the aim of this study was to investigate the prevalence of Cronobacter spp. in RTE foods marketed in China. Two-hundred and eighty RTE food samples were collected from different producers and retailers and analyzed using quantitative methods. The isolates obtained were identified to the species level based on fusA sequences, and were subtyped using a PCR-based serotyping technique. Selected isolates were further characterized by multilocus sequence typing (MLST) and antimicrobial sensitivity determination. Of 280 samples tested, 52 (18.6%) were positive for Cronobacter spp. The contamination levels were less than 110 MPN/g for 78.8% (41/52) of the samples. The results of the O-antigen serotyping for 111 isolates showed that Cronobacter sakazakii serogroup O2 (28 isolates) was the most prevalent serotype. MLST analyses produced 41 sequence types (STs), including 20 novel STs. ST8 was the most prevalent ST (9 isolates) followed by ST4 (5 isolates). Antimicrobial sensitivity testing showed that 84.5% and 46.5% of the isolates were resistant to penicillin G and cephalothin, respectively; in contrast, all of the tested isolates were susceptible to cefotaxime, ciprofloxacin, tetracycline, and nalidixic acid. To the best of our knowledge, this is the first report on Cronobacter spp. prevalence in RTE foods in China, and the findings of our study nonetheless suggested that Cronobacter spp. contamination of Chinese RTE foods poses a potential risk for the consumer. Thus, the study highlights the significance of developing more effective control strategies during the manufacturing process. PMID- 25828707 TI - Contribution of the tricarboxylic acid (TCA) cycle and the glyoxylate shunt in Saccharomyces cerevisiae to succinic acid production during dough fermentation. AB - Succinic acid produced by yeast during bread dough fermentation can significantly affect the rheological properties of the dough. By introducing mutations in the model S288C yeast strain, we show that the oxidative pathway of the TCA cycle and the glyoxylate shunt contribute significantly to succinic acid production during dough fermentation. More specifically, deletion of ACO1 and double deletion of ACO1 and ICL1 resulted in a 36 and 77% decrease in succinic acid levels in fermented dough, respectively. Similarly, double deletion of IDH1 and IDP1 decreased succinic acid production by 85%, while also affecting the fermentation rate. By contrast, double deletion of SDH1 and SDH2 resulted in a two-fold higher succinic acid accumulation compared to the wild-type. Deletion of fumarate reductase activity (FRD1 and OSM1) in the reductive pathway of the TCA cycle did not affect the fermentation rate and succinic acid production. The changes in the levels of succinic acid produced by mutants Deltaidh1Deltaidp1 (low level) and Deltasdh1Deltasdh2 (high level) in fermented dough only resulted in small pH differences, reflecting the buffering capacity of dough at a pH of around 5.1. Moreover, Rheofermentometer analysis using these mutants revealed no difference in maximum dough height and gas retention capacity with the dough prepared with S288C. The impact of the changed succinic acid profile on the organoleptic or antimicrobial properties of bread remains to be demonstrated. PMID- 25828708 TI - Estrogen receptor alpha polymorphisms and the risk of prostate cancer development. AB - PURPOSE: The main purpose of the study was to evaluate the effect of two polymorphisms in the estrogen receptor alpha, rs2077647 and rs3798577, on the development of prostate cancer, their correlation with selected clinical characteristics, as well as consideration of potential interactions between four estrogen receptor alpha polymorphisms (rs2077647, rs3798577, PvuII, XbaI). METHODS: The study was performed using 395 patients with histologically verified prostate cancer and 253 healthy male controls. RESULTS: The CC genotype of rs2077647 was significantly associated with prostate cancer (OR = 1.61). No association was found between rs3798577 polymorphism and prostate cancer. After stratification of patients according to the age at diagnosis and Gleason score, we observed significant correlation between rs2077647 polymorphism and prostate cancer risk in patients diagnosed before the age of 60 as well as patients with Gleason score <7, while rs3798577 was significantly associated with prostate cancer risk development in patients older than 60 and with Gleason score >=7. Double analysis of each combination of four studied polymorphisms showed that presence of at least three variant alleles was associated with prostate cancer risk in all combinations, while each containing rs3798577 was significantly associated with development of high-grade carcinomas. CONCLUSIONS: The present study suggests that rs2077647 polymorphism may be a risk factor for prostate cancer especially in patients diagnosed before the age of 60, while rs3798577 polymorphism could probably serve rather as promoting factor in combination with other polymorphisms in estrogen receptor alpha contributing preferably to development of high-grade carcinomas. PMID- 25828709 TI - Transcriptome shock in an interspecific F1 triploid hybrid of Oryza revealed by RNA sequencing. AB - Interspecific hybridization is a driving force in evolution and speciation of higher plants. Interspecific hybridization often induces immediate and saltational changes in gene expression, a phenomenon collectively termed "transcriptome shock". Although transcriptome shock has been reported in various plant and animal taxa, the extent and pattern of shock-induced expression changes are often highly idiosyncratic, and hence entails additional investigations. Here, we produced a set of interspecific F1 triploid hybrid plants between Oryza sativa, ssp. japonica (2n = 2x = 24, genome AA) and the tetraploid form of O. punctata (2n = 4x = 48, genome, BBCC), and conducted RNA-seq transcriptome profiling of the hybrids and their exact parental plants. We analyzed both homeolog expression bias and overall gene expression level difference in the hybrids relative to the in silico "hybrids" (parental mixtures). We found that approximately 16% (2,541) of the 16,112 expressed genes in leaf tissue of the F1 hybrids showed nonadditive expression, which were specifically enriched in photosynthesis-related pathways. Interestingly, changes in the maternal homeolog expression, including non-stochastic silencing, were the major causes for altered homeolog expression partitioning in the F1 hybrids. Our findings have provided further insights into the transcriptome response to interspecific hybridization and heterosis. PMID- 25828710 TI - Tips to treat the 5 most common nail disorders: brittle nails, onycholysis, paronychia, psoriasis, onychomycosis. AB - Nail disorders are difficult to treat and often frustrating both for patients and clinicians. Because of the slow growth rate of the nail plate and the difficulty of getting the drug actives to penetrate the nail tissues, it is usually necessary to wait several months before seeing the results of treatments. This delay often leads to discontinuation of therapy by the patients. This article therefore helps clinicians to find the right treatment of the 5 most common nail disorders (brittle nails, onycholysis, paronychia, psoriasis, and onychomycosis) and provides practical tips that might improve patients' compliance. PMID- 25828711 TI - Tips for diagnosis and treatment of nail pigmentation with practical algorithm. AB - The observation of a black-brown pigmentation of the nail is often alarming for the patient and for the clinician, as they are aware that it can be a possible clinical manifestation of melanoma of the nail apparatus. Luckily, however, nail melanoma is a much less frequent cause of brown-black nail color than other melanocytic and nonmelanocytic pigmentations, which include subungual hematoma, exogenous pigmentations, and melanonychia due to benign conditions. A correct clinical history and careful examination help the clinician to distinguish the different conditions and to decide the correct management of melanonychia both in children and in adults. PMID- 25828712 TI - Tips to diagnose uncommon nail disorders. AB - This article reviews 6 nail disorders that, although easy to diagnose, are misdiagnosed frequently by dermatologists and general practitioners. Diagnostic clues are emphasized to familiarize readers with features that indicate the correct diagnosis. We focus on two common tumors (onychomatricoma and onychopapilloma), two rare genetic conditions that can be diagnosed owing to nail changes (Darier disease and nail patella syndrome), and two uncommon acquired disorders (the yellow nail syndrome and lichen striatus). PMID- 25828713 TI - Diagnosis using the proximal and lateral nail folds. AB - This article includes the etiology and pathophysiological data of each entity, classifying them as dermatologic, systemic, infectious, neoplastic, traumatic, and other classifications. The entities inherent to the periungual folds are also included, such as acute paronychia, chronic paronychia, retronychia, hangnails, hematomas of the proximal fold caused by oximeter, onychocryptosis, hypertrophy of the lateral folds, and infections caused by Candida albicans, Pseudomonas, and Staphylococcus aureus. Additionally, pathologies caused by diabetes mellitus, sepsis, endocarditis, drug reactions, and finally less frequent diseases that also affect the nail folds are discussed. PMID- 25828714 TI - Diagnosis using nail matrix. AB - Diagnosing nail matrix diseases requires knowledge of the nail matrix function and anatomy. This allows recognition of the clinical manifestations and assessment of potential surgical risk. Nail signs depend on the location within the matrix (proximal or distal) and the intensity, duration, and extent of the insult. Proximal matrix involvement includes nail surface irregularities (longitudinal lines, transverse lines, roughness of the nail surface, pitting, and superficial brittleness), whereas distal matrix insult induces longitudinal or transverse chromonychia. Clinical signs are described and their main causes are listed to enable readers to diagnose matrix disease from the nail's clinical features. PMID- 25828715 TI - Diagnosis using the nail bed and hyponychium. AB - "Nails protect the fingertips and toes. Diseases affecting the nail can cause cosmetic disfigurement and social embarrassment. Physical functioning may be impaired. Disorders of the nail bed may cause pain or create difficulty grasping fine objects. The nail bed is the area beneath the nail plate between the lunula and the hyponychium. Disorders of the nail bed can cause onycholysis, subungual hyperkeratosis, and/or onychogryphosis. Ventral pterygium is less common. Tumors of the nail bed are rare and commonly missed." PMID- 25828716 TI - Nail surgery: best way to obtain effective anesthesia. AB - Nail procedures require an effective and reliable approach to anesthesia of the distal digit. Several techniques have been described in the literature. Herein, the relevant anatomy of the nail unit, pain pathways, anesthetic options, and several injection approaches to achieve complete anesthesia are reviewed. Also considered are the potential pitfalls and complications and their management. Ultimately, the physician's approach must be individualized to the patient, procedure, and setting. PMID- 25828717 TI - Best way to perform a punch biopsy. AB - Nail punch biopsy is used to obtain a tissue sample for the diagnosis and treatment of nail diseases. The best results will be possible if the surgeon is familiar with the anatomy and physiology of the nail apparatus. A punch biopsy can be used in all regions of the nail apparatus in the presence or absence of nail plate. When the procedure is performed with a careful handling of the anatomic site and specimen, in most cases a successful diagnosis can be achieved. PMID- 25828718 TI - Best way to treat an ingrown toenail. AB - Nail phenolization is considered a useful procedure for treating ingrowing toenails. Nail phenolization is indicated when partial and definitive removal of the nail plate is necessary. Nail phenolization is simple and inexpensive, and associated with little postoperative discomfort, a quick return to normal activities, and a low rate of complication and recurrence. The Howard-Dubois and super U techniques are indicated when ingrowing nails are caused by hypertrophy of nail folds, according to the degree of severity. PMID- 25828719 TI - Best way to remove a subungual tumor. AB - "Subungual tumors are relatively rare; yet dermatologists are often called upon to examine, diagnose, and treat these patients. Many dermatologists do not feel comfortable performing surgical procedures of the nail unit. With knowledge of the nail unit anatomy and execution of few simple techniques, dermatologist can safely and effectively remove subungual tumors in the office setting. This article reviews the basic steps for removal of a subungual tumor. It discusses preoperative evaluation, highlights techniques to avoid complete nail plate avulsion, and touches on potential complications and postoperative care." PMID- 25828720 TI - Diagnostic applications of nail clippings. AB - "Nail clipping is a simple technique for diagnosis of several nail unit dermatoses. This article summarizes the practical approach, utility, and histologic findings of a nail clipping in evaluation of onychomycosis, nail unit psoriasis, onychomatricoma, subungual hematoma, melanonychia, and nail cosmetics, and the forensic applications of this easily obtained specimen. It reviews important considerations in optimizing specimen collection, processing methods, and efficacy of special stains in several clinical contexts. Readers will develop a greater understanding and ease of application of this indispensable procedure in assessing nail unit dermatoses." PMID- 25828721 TI - How to submit a nail specimen. AB - The scarcity of specific submission protocols for nail unit biopsies presents many challenges for appropriate specimen processing. Many nail biopsies are received fragmented or without orientation, often resulting in less-than-ideal tissue embedding and poor histologic sections, which are difficult to interpret. Methods are described for proper nail matrix/bed biopsy and plate submission that incorporate aspects of previous submission protocols and include inking the biopsy specimen along with submitting the tissue on a drawing of the nail. Also described is a technique for maintaining adherence of nail plate to glass slides, a chronic challenge in the laboratory. PMID- 25828722 TI - Nail disorders: practical tips for diagnosis and treatment. Preface. PMID- 25828723 TI - Retirement timing of women and the role of care responsibilities for grandchildren. AB - This article considers the potential relationship between providing care for grandchildren and retirement, among women nearing retirement age. Using 47,444 person-wave observations from the Health and Retirement Study (HRS), we find that the arrival of a new grandchild is associated with more than an 8 % increase in the retirement hazard despite little overall evidence of a care/retirement interaction. We document that although family characteristics seem to be the most important factors driving the care decision, they are also important determinants of retirement. In contrast, although financial incentives such as pensions and retiree health insurance have the largest influence on retirement, the opportunity cost associated with outside income seems to have little effect on whether a grandmother provides care. There is little evidence of substitution between caring for grandchildren versus providing care for elderly parents or engaging in volunteer activities; grandchild care is instead taken on as an additional responsibility. Our findings suggest that policies aimed at prolonging work life may need to consider grandchild care responsibilities as a countervailing factor, while those policies focused on grandchild care may also affect elderly labor force participation. PMID- 25828724 TI - How to Prepare a Patient for Transarterial Radioembolization? A Practical Guide. AB - Transarterial radioembolization consist in delivering small particles loaded with Yttrium90, a pure beta emitter, in order to treat primary and secondary liver tumors. This treatment needs precaution since inadequate delivery of these beads can lead to severe complications. Moreover, a precise radiation dosing is crucial to achieve a good clinical success and to avoid complications such as radioembolization-induced liver disease. This review describes all the precautions and highlights clinical and technical considerations that need to be taken to avoid complications. PMID- 25828725 TI - Side-Hole Catheter Placement with Fixation and Embolization in Common Hepatic Artery for Hepatic Arterial Infusion Chemotherapy (Modified CHA-Coil Method) for Patients with Celiac Artery Stenosis or Occlusion. AB - PURPOSE: We retrospectively assessed the feasibility of a side-hole catheter placement with fixation and embolization in the common hepatic artery (CHA) (modified CHA-coil method) for hepatic arterial infusion (HAI) chemotherapy. MATERIALS AND METHODS: HAI catheter placement was attempted with modified CHA coil method in five patients with unresectable hepatic malignancies between 2000 and 2013. The reason for using this method, the mode of catheter placement, and the duration of HAI were investigated. RESULTS: All patients had either occlusion or stenosis of the celiac artery (CA) or CHA, and, as a result, CHA blood flow had either reversed or decreased and hepatopetal GDA flow was observed. In three patients, the proper hepatic artery was extremely short. The side-hole catheter was inserted through the left subclavian artery and was placed from CA to the right gastroepiploic artery in an anterograde manner (n = 4) and from the superior mesenteric artery to the splenic artery in a retrograde manner through GDA (n = 1). The side hole of the catheter was positioned at the proximal portion of GDA. Using a separate catheter inserted from the right femoral artery, coils were placed around the indwelling catheter of CHA to embolize CHA and to fix the catheter. Coil mislocation was not observed, and catheter placement was successful in all patients. HAI chemotherapy was administered for a median of 136 days. The catheter displacement was not observed during HAI. CONCLUSION: The modified CHA-coil method can be used as a stable method for catheter placement when CHA is narrow or there is retrograde CHA blood flow. PMID- 25828726 TI - Comparison of C-arm Computed Tomography and Digital Subtraction Angiography in Patients with Chronic Thromboembolic Pulmonary Hypertension. AB - PURPOSE: To assess the feasibility and diagnostic performance of contrast enhanced, C-arm computed tomography (CACT) of the pulmonary arteries compared to digital subtraction angiography (DSA) in patients suffering from chronic thromboembolic pulmonary hypertension (CTEPH). MATERIALS: Fifty-two patients with CTEPH underwent ECG-gated DSA and contrast-enhanced CACT. Two readers (R1, R2) independently evaluated pulmonary artery segments and their sub-segmental branching using DSA and CACT for optimal image quality. Afterwards, the diagnostic findings, i.e., intraluminal filling defects, stenosis, and occlusion, were compared. Inter-modality and inter-observer agreement was calculated, and subsequently consensus reading was done and correlated to a reference standard representing the overall consensus of both modalities. Fisher's exact test and Cohen's Kappa were applied. RESULTS: A total of 1352 pulmonary segments were evaluated, of which 1255 (92.8 %) on DSA and 1256 (92.9 %) on CACT were rated to be fully diagnostic. The main causes of the non-diagnostic image quality were motion artifacts on CACT (R1:37, R2:78) and insufficient contrast enhancement on DSA (R1:59, R2:38). Inter-observer agreement was good for DSA (kappa = 0.74) and CACT (kappa = 0.75), while inter-modality agreement was moderate (R1: kappa = 0.46, R2: kappa = 0.47). Compared to the reference standard, the inter-modality agreement for CACT was excellent (kappa = 0.96), whereas it was inferior for DSA (kappa = 0.61) due to the higher number of abnormal consensus findings read as normal on DSA. CONCLUSION: CACT of the pulmonary arteries is feasible and provides additional information to DSA. CACT has the potential to improve the diagnostic work-up of patients with CTEPH and may be particularly useful prior to surgical or interventional treatment. PMID- 25828727 TI - Comparison of in-cell lipid removal efficiency of adsorbent mixtures for extraction of polybrominated diphenyl ethers in fish. AB - Polybrominated diphenyl ethers (PBDEs) have become ubiquitous environmental contaminants due to their incorporation into many consumer products. Their ability to bioaccumulate to alarming levels in fat-rich matrices such as fish demands fast and efficient methods to monitor these contaminants. We present an analytical method for selective-pressurised liquid extraction (S-PLE) of PBDEs from fish tissue. Fat removal performance of different mixtures of Florisil, silica gel and sulphuric acid-impregnated silica gel were evaluated using a response surface experimental design approach for determining the optimal fat retaining mixture for S-PLE. Acid-silica gel had the greatest individual effect on fat retention; with a two-thirds acid-silica one-third Florisil mixture found to be the most efficient (>97%). Method validation was performed using recovery experiments at three spiked concentration levels (0.05, 0.5 and 5ngg(-1) ww). Mean recoveries of target analytes in spiked samples ranged from 70 to 124%, with relative standard deviations <27%. The S-PLE lipid removal efficiency combined with the sensitivity of triple quadrupole mass spectrometers provides a fast and comparatively inexpensive analytical method for analysis of PBDEs in fish samples. PMID- 25828728 TI - Purity determination of amphotericin B, colistin sulfate and tobramycin sulfate in a hydrophilic suspension by HPLC. AB - A suspension comprising of the three antibiotic substances amphotericin B, colistin sulfate and tobramycin sulfate is often used in clinical practice for the selective decontamination of the digestive tract of patients in intensive care. Since no detailed procedures, specifications or stability data are available for manufacturing this suspension, there may be discrepancies regarding formulation and stability of suspensions prepared in different pharmacies. The aim of this work is to develop a standardized formulation and to determine its stability under defined storage conditions. This would help guarantee that all patients receive the same preparation, therefore ensuring similar efficacy and improved safety. The first step in this process is to develop the required analytical tools to measure the content and purity of the drug substances in this complex mixture. In this paper, the development and validation of these tools as well as the development of the drug suspension formulation is described. The formulation comprises of Ampho-Moronal((r))-Suspension (Dermapharm) and a buffered, preservated aqueous solution of colistin sulfate and tobramycin sulfate. Two simple, well established high-performance liquid chromatography (HPLC) methods in the European Pharmacopoeia (EP) for impurity profiling of the two active ingredients amphotericin B and colistin sulfate were combined with a newly developed sample extraction procedure for the suspension. Sufficient selectivity and stability-indicating power have been demonstrated. Additionally, a new robust routine method was developed to determine possible degradation products of tobramycin sulfate in the investigated suspension. The specificity, precision, accuracy and linearity of the analytical procedures were demonstrated. The recovery rate was in the range of 90-110%. The precision results for the calculated impurities showed variation coefficients of <10%. The calibration curves were found to be linear with correlation of greater than 0.9994 for all components. The results show the suitability of the methods for the quality control analysis of the suspension. PMID- 25828730 TI - Cryobiopsy and multidisciplinary diagnosis of idiopathic pulmonary fibrosis. PMID- 25828729 TI - Interaction of Mycobacterium leprae with the HaCaT human keratinocyte cell line: new frontiers in the cellular immunology of leprosy. AB - Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae affecting the skin and peripheral nerves. Despite M. leprae invasion of the skin and keratinocytes importance in innate immunity, the interaction of these cells in vitro during M. leprae infection is poorly understood. Conventional and fluorescence optical microscopy, transmission electronic microscopy, flow cytometry and ELISA were used to study the in vitro interaction of M. leprae with the HaCaT human keratinocyte cell line. Keratinocytes uptake of M. leprae is described, and modulation of the surface expression of CD80 and CD209, cathelicidin expression and TNF-alpha and IL-1beta production of human keratinocytes are compared with dendritic cells and macrophages during M. leprae interaction. This study demonstrated that M. leprae interaction with human keratinocytes enhanced expression of cathelicidin and greatly increased TNF-alpha production. The highest spontaneous expression of cathelicidin was by dendritic cells which are less susceptible to M. leprae infection. In contrast, keratinocytes displayed low spontaneous cathelicidin expression and were more susceptible to M. leprae infection than dendritic cells. The results show, for the first time, an active role for keratinocytes during infection by irradiated whole cells of M. leprae and the effect of vitamin D on this process. They also suggest that therapies which target cathelicidin modulation may provide novel approaches for treatment of leprosy. PMID- 25828731 TI - Successful transfusion of antigen positive blood to alloimmunised patients using a monocyte monolayer assay. AB - BACKGROUND: Providing adequate transfusion support for alloimmunised patients for whom antigen negative blood is not readily available is hampered by the risk of a haemolytic reaction. The monocyte monolayer assay (MMA) has shown good correlation between the antibody clinical significance and the fate of antigen positive blood. MATERIALS AND METHODS: From 2006 to 2013, the clinical significance of red cell alloantibodies produced by 61 patients was evaluated using a MMA; and antigen positive blood offering the best survival advantage was selected for transfusion following a secondary MMA crossmatch. Post-transfusion, patients were evaluated for clinical signs of haemolysis. RESULTS: Overall, 19 of 61 (31.1%) of our antibodies were potentially clinically significant, with a monocyte index (MI) > 5%. There was no correlation between the clinical significance as showed by the MMA, and the specificity of the antibody or the strength of reactivity at antihuman globulin (AHG) phase. Using the MMA as a secondary crossmatch method, 31 alloimmunised patients (including: eight anti hr(B), four anti-Yt(a), one each anti-Rg1, -Co(a), Er(a), Le(b), -LW, -Sl1) received 103 antigen positive blood units with no clinical sign of a post transfusion reaction. For three patients (one each anti-Jo(a), -AnWj, unidentified 'HTLA'), initial MMA was performed as part of an investigation of a suspected haemolytic reaction. In each case, the MMA accurately identified the unit responsible for the reaction. CONCLUSION: Used as a crossmatch surrogate, the MMA provided valuable information in the decision of transfusing antigen positive blood to alloimmunised patients, avoiding delay because of the search of rare antigen negative units. PMID- 25828732 TI - Impulse control disorder manifesting as hidden sexual self-injury. PMID- 25828733 TI - Death in pregnancy: a call for neurological action. PMID- 25828734 TI - A novel recombinant chlorophyllase from cyanobacterium Cyanothece sp. ATCC 51142 for the production of bacteriochlorophyllide a. AB - Bacteriopheophorbide a (BPheid a) is used as a precursor for bacteriochlorin a (BCA), which can be used for photodynamic therapy in both in vitro and in vivo biochemical applications. This study successfully isolated and expressed a photosynthetic bacterium (Cyanothece sp. ATCC 51142) chlorophyllase called CyanoCLH, which can be used as a biocatalyst for the production of a BCA precursor by degrading bacteriochlorophyll a (BChl a). Substrate specificity and enzyme kinetic analyses were performed and the results verified that the recombinant CyanoCLH preferred hydrolyzing BChl a to produce bacteriochlorophyllide a (BChlide a), which can be converted to BPheid a by removing magnesium ion. The recombinant CyanoCLH was cloned and expressed in Escherichia coli BL-21 (DE3), and its molecular weight was 54.7 kDa. The deduced amino acid sequence of the recombinant CyanoCLH comprised a unique lipase-motif GHSLG, which differs from the GHSRG sequence of other plants and lacks a histidine of the typical and conserved catalytic triad Ser-Asp-His. The recombinant CyanoCLH was subjected to biochemical analyses, and the results indicated that its optimal pH and temperature were 7.0 and 60 degrees C, respectively. PMID- 25828735 TI - Comparison of the susceptibility of porcine and human dipeptidyl-peptidase IV to inhibition by protein-derived peptides. AB - The enzyme dipeptidyl-peptidase IV (DPP-IV) is recognized to be a promising target for the management of type 2 diabetes. Over the last decade, numerous synthetic molecules and more recently, peptides from dietary proteins, have been reported to be able to inhibit DPP-IV activity. Most studies that have investigated the in vitro effect of these inhibitors have used porcine or human DPP-IV. Although structurally alike, it is unclear whether these two species display similar inhibition patterns. Therefore, the objective of this study was to compare the effects of protein-derived peptides on the activity of porcine and recombinant human DPP-IV. The two species showed different inhibition susceptibility to 43 of the 62 peptide sequences investigated. While 37 protein derived peptides were more effective at inhibiting the porcine DPP-IV, only six caused a stronger inhibition of the activity of the human enzyme. Although the peptides WR, IPIQY and WCKDDQNPHS were found to be among the most potent inhibitors of both species, the inhibitory effect was greater on the porcine enzyme than on human DPP-IV (alphaKi or Ki=11.5, 13.4, 13.3 MUM and 31.4, 28.2, 75.0 MUM for porcine and human DPP-IV, respectively). Investigation into the mode of action of the most effective inhibitory peptides revealed that both species were inhibited in a similar manner by short fragments (<=5 amino acid residues), but that some of the longer peptides acted differently on the enzymes. This study shows that porcine DPP-IV is generally inhibited with greater potency by protein derived peptides than is the human enzyme. PMID- 25828736 TI - Ghrelin suppresses proliferation of fetal neural progenitor cells, and induces their differentiation into neurons. AB - Although considerable progress has been made in understanding how the temporal and regional control of neural progenitor cells (NPCs) dictates their fate, their key regulators during neural development are still unknown. Ghrelin, which is isolated from porcine stomach extract, is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). The widespread expression of ghrelin and GHS-R in the central nervous system during development suggests that ghrelin may be involved in developmental neural growth. However, its role in regulating fetal NPCs is still unclear. In this study, we investigated the effects of ghrelin on primary cultured NPCs derived from fetal mouse telencephalon. The expressions of both ghrelin and its receptor were observed in NPCs using RT-PCR, immunoblotting and immunocytostaining. Interestingly, the exposure of fetal NPCs to ghrelin at concentrations of 10(-7) and 10(-9)M suppressed their proliferation, and caused them to differentiate into neurons and to extend neurites. These results strongly suggest that ghrelin plays an autocrine modulatory role in fetal neural development. PMID- 25828737 TI - Laparoscopic Removal of an Intramyometrial Fetus After Uterine Curettage. AB - STUDY OBJECTIVE: To show the removal of an intramyometrial fetus after uterine curettage using laparoscopy as a safe surgical technique that offers excellent results and fewer complications than laparotomy. DESIGN: Presentation of the clinical case and step-by-step explanation of the technique. SETTINGS: Uterine curettage is a frequently performed gynecologic abortion procedure. Dilatation and curettage is considered to be a safe surgical technique, with a low percentage of complications. The most common is uterine perforation, with higher risks in advanced gestational age, retroflexed uterus, or uterine leiomyomas. INTERVENTIONS: After institutional review board approval, we present the case of a 29-year-old women referred to our hospital from another clinic with a suspected uterine perforation after an elective curettage for a 14-week pregnancy. She presented with moderate abdominal pain. Vaginal ultrasound revealed intramyometrial fetal parts on isthmus and right parametrium and minimal free fluid in the pouch of Douglas. A laparoscopic approach was chosen. After a complete revision of the abdominal cavity, the right paravesical space was dissected, confirming no right uterine artery or ureter injury. One cavity was objectified in the posterior leaf of the broad ligament related to a uterine perforation and containing fetal bone parts, which were removed. The myometrial defect and the peritoneum were closed with intracorporeal sutures. The removal of fetal parts was done with a surgical glove thimble. After the procedure, the patient was treated with clindamycin and gentamycin, with a satisfactory recovery. CONCLUSION: The presence of an intramyometrial fetus is not a common complication of curettage. The use of laparoscopy is feasible and offers excellent results and advantages versus laparotomy regarding its treatment. PMID- 25828738 TI - Facial disfigurement due to osteitis fibrosa cystica or brown tumor from secondary hyperparathyroidism in patients on dialysis: A systematic review and an illustrative case report. AB - Osteitis fibrosa cystica (OFC) is the most frequent type of osseous change in renal osteodystrophy affecting the majority of dialysis patients. Brown tumors are a severe form of OFC. The involvement of the craniofacial skeleton causing facial disfigurement in patients on dialysis appears to be limited to case reports. After searching PubMed, we performed a systematic review of 127 cases with a severe form of OFC resulting in a facial disfigurement to understand possible determinants for this condition. We found that since the first published case in 1974, and after a peak in 1996, there appears to be an increase in published reported cases. Only 27.6% of these cases were published in nephrology journals. The most common region for reported cases was North America. Mean age of these patients was 31.2 years with a mean dialysis duration of 7 years. Almost 67% were women, and almost all were on hemodialysis. The disease tended to most commonly localize to the maxilla (73.2%) and mandible (57.5%). As part of the treatment, 59% of patients had a parathyroidectomy. More than one-third (35.4%) had symptomatic improvement at follow-up. Mean follow-up was 1.6 years. Clinicians should be aware of this clinical presentation of a severe form of OFC and/or brown tumors. Timely diagnosis and intervention may help to prevent or decrease destructive bone changes and reduce negative psychological consequences of facial disfigurement. PMID- 25828739 TI - Culture and the Immune System: Cultural Consonance in Social Support and C reactive Protein in Urban Brazil. AB - In this article, we examine the distribution of a marker of immune system stimulation-C-reactive protein-in urban Brazil. Social relationships are associated with immunostimulation, and we argue that cultural dimensions of social support, assessed by cultural consonance, are important in this process. Cultural consonance is the degree to which individuals, in their own beliefs and behaviors, approximate shared cultural models. A measure of cultural consonance in social support, based on a cultural consensus analysis regarding sources and patterns of social support in Brazil, was developed. In a survey of 258 persons, the association of cultural consonance in social support and C-reactive protein was examined, controlling for age, sex, body mass index, low-density lipoprotein cholesterol, depressive symptoms, and a social network index. Lower cultural consonance in social support was associated with higher C-reactive protein. Implications of these results for future research are discussed. PMID- 25828740 TI - Postconditioning attenuates early ventricular arrhythmias in patients with high risk ST-segment elevation myocardial infarction. AB - BACKGROUND: It has been demonstrated that postconditioning (postcon), brief episodes of ischemia during reperfusion period, in patients with ST-segment elevation myocardial infarction (STEMI) confers protection against ischemia reperfusion injury and as a result, postcon might reduce infarct size. However, whether postcon may exert its beneficial effect on STEMI patients by reducing the occurrence of early malignant ventricular arrhythmias (VA) is still unknown. The aim of the study was to evaluate the influence of postcon on the presence of VA in early presenters with high-risk STEMI treated with primary coronary intervention (PCI). METHODS: Seventy-five STEMI patients treated with primary PCI within 6h from symptoms onset were randomly assigned to postcon group (n=37) or conventional PCI group (n=38) in 1:1 ratio. Postcon was performed immediately after restoration of coronary flow as follows: the angioplasty balloon was inflated 4* 1min with low-pressure inflations, each separated by 1min of deflation. After that the patients were continuously monitored electrographically for 48h. The end-point of the study was the occurrence of VA (ventricular fibrillation-VF, sustained ventricular tachycardia-sVT, non-sustained ventricular tachycardia-nsVT) within 48h after the procedure. RESULTS: In the postcon group, the occurrence of VAs was significantly lower: VF-3, sVT-0, nsVT-15, i.e. (18 patients - 48.6%) in comparison to control group: VF-2, sVT-4, nsVT-23 (29 patients - 76.3%); p=0.013. The occurrence of accelerated idioventricular rhythm varied insignificantly between both groups (postcon - 45.9% vs control - 34.2%; p=NS). CONCLUSIONS: Postcon may reduce the occurrence of malignant VA in patients with STEMI treated with primary PCI. PMID- 25828741 TI - Social media in medicine: The volume that Twitter built. PMID- 25828742 TI - High prevalence of undernutrition and low dietary diversity in institutionalised elderly living in Sri Lanka. AB - OBJECTIVE: The present study aimed to assess nutritional status, dietary diversity and lifestyle risk factors associated with undernutrition in an institutionalised Sri Lankan elderly population. DESIGN: The study was of cross sectional design followed by a stratified sampling method. SETTING: Twelve homes for the elderly recruited from six provinces in Sri Lanka. SUBJECTS: A total of 311 institutionalised elderly aged >=60 years. RESULTS: The mean age of the study population was 75 (sd 8) years. Prevalence of undernutrition was 30 %. Mean food variety score, dietary diversity score and dietary serving score of the study population were 8.7 (sd 1.5), 7.3 (sd 1.2) and 10.9 (sd 2.0), respectively. Mean daily intakes of fruit, vegetables, meat, fish, eggs and pulses and dairy portions were below the national recommendations, whereas the mean consumption of sugar exceeded the national recommendation. Only the mean intake of starch was within the recommendation. Food allergies (OR=8.0; 95 % CI 3.9, 16.2), skipping meals (OR=3.8; 95 % CI 2.0, 7.5) and lack of leisure activities (OR=3.1; 95 % CI 1.5, 6.7) significantly increased the risk of undernutrition, whereas the use of dentures decreased the risk (OR=0.20; 95 % CI 0.06, 0.69). CONCLUSIONS: High prevalence of undernutrition and low dietary diversity were observed in an institutionalised elderly Sri Lankan population. Therefore, there is an urgent need to implement nutrition interventions as part of geriatric care to reduce undernutrition and improve the diets of the institutionalised elderly population in Sri Lanka. PMID- 25828743 TI - Possible underestimation by sports medicine of the effects of early physical exercise practice on the prevention of diseases in adulthood. AB - In modern society, combatting cardiovascular and metabolic diseases has been highlighted as an urgent global challenge. In recent decades, the scientific literature has identified that behavioral variables (e.g. smoking, unhealthy diet and physical inactivity) are related to the development of these outcomes and, therefore, preventive actions should focus on the promotion of physical exercise practice and a healthy diet, as well as combatting the smoking habit from an early age. The promotion of physical exercise in the general population has been suggested as a relevant goal by significant health organizations around the world. On the other hand, recent literature has indicated that physical exercise performed in early life prevents the development of diabetes mellitus, dyslipidemia and arterial hypertension during adulthood, although this protective effect seems to be independent of the physical activity performed during adulthood. Apparently, the interaction between physical exercise and human growth in early life constitutes an issue which is not completely understood by sports medicine. The aim of the present review was therefore to discuss recent evidence on the effects of physical exercise performed during childhood and adolescence on cardiovascular and metabolic outcomes in adulthood. PMID- 25828744 TI - Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway. AB - There are few studies on the correlation between heme oxygenase-1 (HO-1) and acute myeloid leukemia (AML). We found that HO-1 was aberrantly overexpressed in the majority of AML patients, especially in patients with acute monocytic leukemia (M5) and leukocytosis, and inhibited the apoptosis of HL-60 and U937 cells. Moreover, silencing HO-1 prolonged the survival of xenograft mouse models. Further studies demonstrated that HO-1 suppressed the apoptosis of AML cells through activating the JNK/c-JUN signaling pathway. These data indicate a molecular role of HO-1 in inhibiting cell apoptosis, allowing it to be a potential target for treating AML. PMID- 25828745 TI - Discontinuation of hypomethylating agent therapy in patients with myelodysplastic syndromes or acute myelogenous leukemia in complete remission or partial response: retrospective analysis of survival after long-term follow-up. AB - Hypomethylating agents (HMA), such as 5-azacitidine or decitabine, are currently used to treat patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) until treatment failure. However, the outcomes for patients who discontinue therapy after achieving partial response (PR) or complete remission (CR) but before treatment failure have not been reported. We present a series of 16 patients with higher-risk MDS (n=5; 31%) or AML (n=11; 69%) who achieved PR (n=1) or CR (n=15) and stopped HMA therapy while in response in the context of clinical trials. They received a median of 12 courses (range 1-24) and achieved response after a median of 1 course of therapy (1-4). Loss of response after discontinuation of therapy was rapid, with a median progression-free survival of 4 months (95% CI: 2-6). Median overall survival (OS) from the time of therapy discontinuation was 15 months (95% CI: 6-24). Patients who received 12 cycles of therapy or more had significantly better OS (median: 20 months [95% CI: 12-27]) than those who received fewer than 12 cycles (median: 4 months [95% CI: 1-8]) (p=0.043). Poor-risk cytogenetics were also associated with lower 1-year OS (33% versus 69%; p=0.046). According to these results and considering the poor prognosis after HMA failure, HMA interruption should be avoided once a sustained response has been achieved. PMID- 25828750 TI - The Impact of Percent Reduction in CA-125 Levels on Prediction of the Extent of Interval Cytoreduction and Outcome in Patients With Advanced-Stage Cancer of Mullerian Origin Treated With Neoadjuvant Chemotherapy. AB - OBJECTIVE: To investigate the role of CA-125 percent reduction after neoadjuvant chemotherapy in predicting the extent of the interval debulking surgery (IDS) and outcomes in patients with advanced-stage mullerian carcinoma. METHODS: Patients who received neoadjuvant chemotherapy for advanced-stage mullerian carcinoma from 2000 to 2013 were identified. Percent reduction in CA-125 was categorized into 2 groups: >= 90% (CA >= 90%) and <90% (CA < 90%) reduction from prechemotherapy to preoperative CA-125. RESULTS: Of the 115 patients identified, 73% had CA >= 90% and 27% had CA < 90%. Optimal and complete IDS were achieved in 87% and 38%, respectively. Compared with the CA < 90% group, the CA >= 90% group was more likely to have complete IDS (P = 0.035), less likely to have a bowel resection (P < 0.001), and more likely to have no viable tumor/microscopic disease with treatment effect (P < 0.001). No difference in overall survival (OS; P = 0.81) and progression-free survival (PFS; P = 0.60) was noted between the groups. In multivariable analysis, CA >= 90% was not a predictor of PFS (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.65-1.79; P = 0.77) or OS (HR, 1.45; 95% CI, 0.73-2.9; P = 0.29). Patients with preoperative CA-125 < 20 had significantly longer OS (P = 0.05) and PFS (P = 0.005) than did those with preoperative CA-125 >= 20. In multivariable analysis, preoperative CA-125 < 20 was a predictor of PFS (HR, 0.37; 95% CI, 0.20-0.66; P < 0.001) but not OS (HR, 0.64; 95% CI, 0.34-1.21; P = 0.17). CONCLUSIONS: A reduction in CA-125 of at least 90% is associated with complete IDS, favorable pathologic response, and fewer bowel resections. A preoperative CA-125 < 20 suggests improved outcome. These findings are helpful for treatment planning and patient counseling. PMID- 25828751 TI - Outcome of patients with advanced-stage borderline ovarian tumors after a first peritoneal noninvasive recurrence: impact on further management. AB - OBJECTIVES: The aims of this study were to report the outcome of patients with advanced-stage serous borderline ovarian tumors (SBOT) after a first noninvasive recurrence and the impact of conservative treatment in that context and to define the best management for those patients. STUDY DESIGN: From 1973 to 2006, 168 patients were treated at or referred to our institution for an SBOT with peritoneal implants. Their slides were reviewed by the same expert pathologist. Selection criteria were as follows: advanced stage (International Federation of Gynecology and Obstetrics >= II), with at least 1 recurrence (only noninvasive ones) and more than 5 years of follow-up. RESULTS: Twenty patients met the inclusion criteria. The median duration of follow-up was 12 years (range, 6-23 years). Median age was 26 years (14-61 years). Initial surgical management was conservative for 14 patients and radical for 6. In the study population, 4 patients recurred, all with invasive disease. Time to invasive recurrence was at least 3 years for 3 of 4 patients. None of those 4 patients had a second-look surgery initially or after the first recurrence. Two patients had small-sized residual disease after initial management; only 1 of these 4 patients is currently alive and disease-free. There was no significant difference between conservative and radical treatment of the risk of second recurrence. CONCLUSIONS: This study emphasizes the need for a long follow-up after recurrence of advanced stage SBOT and the risk of a new invasive recurrence after a first noninvasive peritoneal recurrence. Conservative treatment does not seem as a risk factor and is still justified after a first noninvasive recurrence for young patients who desire to preserve fertility. PMID- 25828752 TI - A hybrid chimeric system for versatile and ultra-sensitive RNase detection. AB - We developed a new versatile strategy that allows the detection of several classes of RNases (i.e., targeting ss- or ds-RNA, DNA/RNA hetero-hybrid or junctions) with higher sensitivity than existing assays. Our two-step approach consists of a DNA-RNA-DNA chimeric Hairpin Probe (cHP) conjugated to magnetic microparticles and containing a DNAzyme sequence in its terminal region, and molecular beacons for fluorescence signal generation. In the first step, the digestion of the RNA portion of the cHP sequences in presence of RNases leads to the release of multiple copies of the DNAzyme in solution. Then, after magnetic washing, each DNAzyme molecule elicits the catalytic cleavage of numerous molecular beacons, providing a strong amplification of the overall sensitivity of the assay. We successfully applied our approach to detect very low concentrations of RNase A, E. coli RNase I, and RNase H. Furthermore, we analyzed the effect of two antibiotics (penicillin and streptomycin) on RNase H activity, demonstrating the applicability of our strategy for the screening of inhibitors. Finally, we exploited our system to detect RNase activity directly in crude biological samples (i.e., blood and saliva) and in cell culture medium, highlighting its suitability as cheap and sensitive tool for the detection of RNase levels. PMID- 25828753 TI - Letter to the editor: the evidence of exercise-induced bronchoconstriction in endurance runners; genetic basis and gender differences. PMID- 25828754 TI - Relationship between Autophagy and Ventilator-induced Diaphragmatic Dysfunction. AB - BACKGROUND: Mechanical ventilation (MV) is associated with atrophy and weakness of the diaphragm muscle, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Autophagy is a lysosomally mediated proteolytic process that can be activated by oxidative stress, which has the potential to either mitigate or exacerbate VIDD. The primary goals of this study were to (1) determine the effects of MV on autophagy in the diaphragm and (2) evaluate the impact of antioxidant therapy on autophagy induction and MV-induced diaphragmatic weakness. METHODS: Mice were assigned to control (CTRL), MV (for 6 h), MV + N acetylcysteine, MV + rapamycin, and prolonged (48 h) fasting groups. Autophagy was monitored by quantifying (1) autophagic vesicles by transmission electron microscopy, (2) messenger RNA levels of autophagy-related genes, and (3) the autophagosome marker protein LC3B-II, with and without administration of colchicine to calculate the indices of relative autophagosome formation and degradation. Force production by mouse diaphragms was determined ex vivo. RESULTS: Diaphragms exhibited a 2.2-fold (95% CI, 1.8 to 2.5) increase in autophagic vesicles visualized by transmission electron microscopy relative to CTRL after 6 h of MV (n = 5 per group). The autophagosome formation index increased in the diaphragm alone (1.5-fold; 95% CI, 1.3 to 1.8; n = 8 per group) during MV, whereas prolonged fasting induced autophagosome formation in both the diaphragm (2.5-fold; 95% CI, 2.2 to 2.8) and the limb muscle (4.1-fold; 95% CI, 1.8 to 6.5). The antioxidant N-acetylcysteine further augmented the autophagosome formation in the diaphragm during MV (1.4-fold; 95% CI, 1.2 to 1.5; n = 8 per group) and prevented MV-induced diaphragmatic weakness. Treatment with the autophagy-inducing agent rapamycin also largely prevented the diaphragmatic force loss associated with MV (n = 6 per group). CONCLUSIONS: In this model of VIDD, autophagy is induced by MV but is not responsible for diaphragmatic weakness. The authors propose that autophagy may instead be a beneficial adaptive response that can potentially be exploited for therapy of VIDD. PMID- 25828755 TI - Serological evidence of increased susceptibility to varicella-zoster virus reactivation or reinfection in natalizumab-treated patients with multiple sclerosis. AB - BACKGROUND: Serious adverse drug reactions of disease-modifying drugs in multiple sclerosis (MS) therapy may include enhanced susceptibility to reactivation of neurotropic herpes viruses like varicella-zoster virus (VZV) and the John Cunningham (JC) polyomavirus. OBJECTIVE: Because symptomatic reactivation of these viruses are rare events, we determined the incidence of rises in anti-VZV IgG antibody levels as a potential marker for enhanced susceptibility to subclinical and symptomatic reactivation of neurotropic viruses. METHODS: Anti VZV IgG levels were measured in paired serum samples taken 6-8 months apart from natalizumab-treated MS patients, healthy blood donors and human immunodeficiency virus (HIV) infected patients. RESULTS: The incidence of significant rises in anti-VZV IgG levels in natalizumab-treated MS patients was 4.26 per 100 person years, which was significantly higher than in healthy blood donors. Retrospective evaluation of the available medical records of patients with rises of anti-VZV IgG levels did not reveal herpes zoster (i.e. shingles) manifestations. CONCLUSIONS: The increased incidence of significant rises of anti-VZV IgG levels in natalizumab-treated MS patients might indicate an association of natalizumab treatment of MS with an elevated risk of a subclinical VZV reactivation and/or reinfection events. Whether this is predictive of an increased risk of herpes zoster or even symptomatic reactivation of other neurotropic viruses remains to be determined in larger prospective studies. PMID- 25828756 TI - Cognitive impairment in Chinese neuromyelitis optica. AB - BACKGROUND: Cognitive dysfunction is frequently seen in neuromyelitis optica (NMO). However, the features and influencing factors of cognitive impairment of Chinese NMO patients are unclear. OBJECTIVE: To investigate the patterns of cognitive impairment in Chinese NMO patients, and correlate the neuropsychiatric scores with clinical and MRI parameters. METHODS: Thirty-six Chinese NMO patients, and 30 sex and age-matched healthy controls were recruited with extensive neuropsychological assessments, using the modified Minimal Assessment of Cognitive Function in MS (MACFIMS). The demographic and clinical characteristics as well as MRI parameters were compared between cognitively impaired (CI) and cognitively preserved (CP) patients. RESULTS: NMO patients were significantly impaired in the Paced Auditory Serial Addition Task (P<0.05), the Symbol Digit Modalities Test (P<0.001), the California Verbal Learning Test Second Edition (P<0.05), the Brief Visuospatial Memory Test-Revised (P<0.05) and semantic fluency (P<0.001). Only lower education level was associated with cognitive dysfunction in NMO (odds ratio: 0.57, P<0.05). There were no significant differences of MRI parameters regarding white matter (WM) lesions, grey matter and WM brain volume between CI and CP patients. CONCLUSIONS: Chinese NMO patients particularly demonstrated cognitive impairment in information processing speed, executive function and memory. Lower education level was the main factor contributing to cognitive impairment in NMO. PMID- 25828757 TI - The only certain measure of the effectiveness of multiple sclerosis therapy is cerebrospinal neurofilament level - YES. PMID- 25828758 TI - A comparative optical coherence tomography study in neuromyelitis optica spectrum disorder and multiple sclerosis. AB - OBJECTIVES: The aim of this study was to find, using spectral domain-optical coherence tomography (SD-OCT), retinal imaging biomarkers differentiating neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS) and healthy controls (HCs). MATERIALS AND METHODS: The population was composed of patients with NMOSD (n=23) or MS (n=110) and of HCs (n=75). Evaluation criteria were retinal thickness/volume, visual acuity, low contrast vision acuity and Expanded Disability Status Scale score. RESULTS: Considering all eyes and after statistical adjustments including the number of optic neuritis (ON) episodes, we found that NMOSD patients did not have significantly more retinal atrophy than MS patients; whereas MS non-optic neuritis (NON) eyes had thinner temporal (p=0.032) and temporo-superior peripapillary retinal nerve fibre layer (pRNFL; p=0.011) thicknesses than NMOSD NON eyes; in addition, NMOSD NON eyes presented significant naso-inferior pRNFL (p=0.024), temporal pRNFL (p=0.039), macular ganglion cell complex (p=0.004) and ganglion cell layer (p=0.002) atrophy vs HC eyes. We identified significant correlations between visual and clinical disability and retinal thicknesses in both diseases. CONCLUSION: OCT may help to differentiate NMOSD and MS by focusing on the NON eyes (temporal pRNFL atrophy more severe in MS). Moreover, we discuss the possibility of a retinal degenerative process independent of ON in NMOSD. PMID- 25828759 TI - Uhthoff questioned. PMID- 25828760 TI - Production of indole antibiotics induced by exogenous gene derived from sponge metagenomes. AB - Sponge metagenomes are accessible genetic sources containing genes and gene clusters responsible for the biosynthesis of sponge-derived bioactive natural products. In this study, we obtained the clone pDC112, producing turbomycin A and 2,2-di(3-indolyl)-3-indolone, based on the functional screening of the metagenome library derived from the marine sponge Discodermia calyx. The subcloning experiment identified ORF 25, which is homologous to inosine 5'-monophosphate dehydrogenase and required for the production of 2,2-di(3-indolyl)-3-indolone in Escherichia coli. PMID- 25828761 TI - Predictors of change in weight and waist circumference: 15-year longitudinal study in Australian adults. PMID- 25828763 TI - Help-seeking behaviour among Finnish adolescent males. AB - BACKGROUND: Adolescent males have a low rate of seeking help for mental health problems. The onset for many psychiatric disorders occur during the adolescence. Previous studies have identified previous help seeking, parental opinion, parental divorce and suicidal thoughts as factors associated with contacting mental health services. Yet studies on the rate of use of mental health services remain few, as do studies concerning factors associated with use of mental health services. AIMS: To study prevalence and risk factors of use of mental health services among Finnish adolescent males. METHODS: Factors associated with use of mental health services during the preceding 12 months were studied in a general population sample of 4309 men attending military call-up in 2009. The mean age was 18.3 +/- 0.45 years. RESULTS: Within the previous 12 months, 3.2% of men had used mental health services and an additional 2.3% had considered contacting mental health services. Factors associated with service use were living alone, having a poor paternal relationship, having no contact with father, death of father, high internalizing symptoms, suicidal thoughts, regular smoking and use of illicit drugs. Frequent drunkenness was associated with mental health service use, whereas occasional use of alcohol was inversely associated with use of mental health services. CONCLUSIONS: The rate of mental health service use among males in late adolescence is very low. The inability of young people to contact service providers should be addressed more efficiently. CLINICAL IMPLICATIONS: A majority of the troubled men did not contact professionals for help, although approximately a quarter of the men had a self-perceived mental health problem. A major challenge is to find ways for mental health services to be made more accessible to adolescent males. PMID- 25828764 TI - Screening efficiency of the self-report version of the Multidimensional Anxiety Scale for Children in a highly comorbid inpatient sample. AB - BACKGROUND: The Multidimensional Anxiety Scale for Children (MASC) is a widely used self-report questionnaire for the assessment of anxiety symptoms in children and adolescents with well documented predictive validity of the total score and subscales in internalizing and mixed clinical samples. However, no data exist on the screening efficiency in an inpatient sample of adolescents. AIM: To examine the psychometric properties and screening efficiency of the MASC in a high comorbid inpatient sample. METHOD: The current study used receiver operating characteristic (ROC) analyses to investigate the predictive value of the MASC total and subscale scores for the Schedule for Affective Disorders and Schizophrenia for School-age children-Present and Lifetime version (K-SADS-PL), DSM-IV diagnoses of generalized anxiety disorder (GAD), separation anxiety disorder (SAD) and social phobia (SoP) in a highly comorbid inpatient sample of adolescents (11-18 years). RESULTS: The MASC total score predicted any anxiety disorder (AD) and GAD moderately well. Physical symptoms predicted GAD moderately well. Social anxiety and separation anxiety/panic did not predict SoP or SAD, respectively. Physical symptoms and harm avoidance also predicted the presence of major depressive disorder. CONCLUSIONS: The findings support the utility of the MASC total score to predict the presence of any AD and GAD. However, the utility of the social anxiety and separation anxiety/panic subscales showed limited utility to predict the presence of SAD and SoP, respectively. The MASC has probably a more limited function in screening for AD among a highly comorbid inpatient sample of severely affected adolescents. Our results should be interpreted in the light of a small, mixed sample of inpatient adolescents. PMID- 25828762 TI - Cardiac myocyte alternans in intact heart: Influence of cell-cell coupling and beta-adrenergic stimulation. AB - BACKGROUND: Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca(2+) transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca(2+) alternans and sarcoplasmic reticulum (SR) Ca(2+) release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in the intact heart remains unknown. OBJECTIVE: We assessed the effects of cell-to-cell coupling on local alternans in intact Langendorff-perfused mouse hearts, measuring single myocyte [Ca(2+)] alternans synchronization among neighboring cells, and effects of beta-adrenergic receptor (beta-AR) activation and reduced GJ coupling. METHODS AND RESULTS: Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo8-AM to record cardiac myocyte [Ca(2+)] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25 MUM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. beta-AR stimulation only reduced Ca(2+) alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. CONCLUSIONS: Ca(2+) alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca(2+) alternans, and made them more sensitive to reversal by beta-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established. PMID- 25828765 TI - Optimized extraction of a single-chain variable fragment of antibody by using aqueous micellar two-phase systems. AB - In this work, the purification of a single-chain variable fragment (scFv) of an antibody by using liquid-liquid extraction in aqueous micellar two-phase systems was optimized by means of central composite design. Protein partitioning assays were performed by using the selected system composition in previous works: Triton X-114 at 4% wt/wt, yeast fermentation supernatant at 60% wt/wt, McIlvaine buffer pH 7.00. The other system component concentrations, Cibacron Blue F3GA (CB), FabsorbentTM F1P HF (HF) and NaCl, were selected as independent variables. ScFv recovery percentage (%R) and purification factor (PF) were selected as the responses. According to the optimization process both, scFv recovery percentage and purification factor were favored with the addition of HF and NaCl in a range of concentrations around the central point of the second central composite design (HF 0.0120% w/w, CB 0.0200% w/w, NaCl 0.200% w/w). These experimental conditions allowed the concentration and pre-purification of scFv in the micelle-rich bottom phase of the systems with a recovery percentage superior to 88% and a purification factor of approximately 3.5. These results improved the previously presented works and demonstrated the convenience of using aqueous micellar two phase systems as a first step in the purification of scFv molecules. PMID- 25828766 TI - Biofilm formation and fibrinogen and fibronectin binding activities by Corynebacterium pseudodiphtheriticum invasive strains. AB - Biofilm-related infections are considered a major cause of morbidity and mortality in hospital environments. Biofilms allow microorganisms to exchange genetic material and to become persistent colonizers and/or multiresistant to antibiotics. Corynebacterium pseudodiphtheriticum (CPS), a commensal bacterium that colonizes skin and mucosal sites has become progressively multiresistant and responsible for severe nosocomial infections. However, virulence factors of this emergent pathogen remain unclear. Herein, we report the adhesive properties and biofilm formation on hydrophilic (glass) and hydrophobic (plastic) abiotic surfaces by CPS strains isolated from patients with localized (ATCC10700/Pharyngitis) and systemic (HHC1507/Bacteremia) infections. Adherence to polystyrene attributed to hydrophobic interactions between bacterial cells and this negatively charged surface indicated the involvement of cell surface hydrophobicity in the initial stage of biofilm formation. Attached microorganisms multiplied and formed microcolonies that accumulated as multilayered cell clusters, a step that involved intercellular adhesion and synthesis of extracellular matrix molecules. Further growth led to the formation of dense bacterial aggregates embedded in the exopolymeric matrix surrounded by voids, typical of mature biofilms. Data also showed CPS recognizing human fibrinogen (Fbg) and fibronectin (Fn) and involvement of these sera components in formation of "conditioning films". These findings suggested that biofilm formation may be associated with the expression of different adhesins. CPS may form biofilms in vivo possibly by an adherent biofilm mode of growth in vitro currently demonstrated on hydrophilic and hydrophobic abiotic surfaces. The affinity to Fbg and Fn and the biofilm-forming ability may contribute to the establishment and dissemination of infection caused by CPS. PMID- 25828767 TI - Lysobacter fragariae sp. nov. and Lysobacter rhizosphaerae sp. nov. isolated from rhizosphere of strawberry plant. AB - Two bacterial strains, designated THG-DN8.7(T) and THG-DN8.3(T), were isolated from the rhizosphere of a strawberry plant in Gyeryong Mountain, South Korea. Cells of both isolates were observed to be Gram-negative, yellow-coloured and rod shaped. Comparative 16S rRNA gene sequence analysis showed that strain THG DN8.7(T) had highest sequence similarities to Lysobacter yangpyeongensis KACC 11407(T) (97.2 %), Lysobacter niabensis KACC 11587(T) (97.0 %) and Lysobacter oryzae KCTC 22249(T) (96.9 %), while strain THG-DN8.3(T) had closely similarity with L. niabensis KACC 11587(T) (98.1 %), L. oryzae KCTC 22249(T) (97.1 %) and L. yangpyeongensis KACC 11407(T) (96.1 %). DNA-DNA relatedness values between strains THG-DN8.7(T) and THG-DN8.3(T) and their closest phylogenetically neighbours were below 30.0 %, which indicates that strains THG-DN8.7(T) and THG DN8.3(T) represent distinct species within the genus Lysobacter. Both strains were found to contain iso-C15:0, iso-C16:0 and iso-C17:1 omega9c as predominant fatty acids and ubiquinone-8 as major isoprenoid quinone. The major polar lipids were identified as phosphatidylethanolamine, phosphatidyl-N-methylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The DNA G+C content of strains THG-DN8.7(T) and THG-DN8.3(T) were determined to be 66.9 and 67.8 mol%, respectively. These data are consistent with the affiliation of the two new species represented by THG-DN8.7(T) and THG-DN8.3(T) to the genus Lysobacter. The names Lysobacter fragariae sp. nov. and Lysobacter rhizosphaerae sp. nov. are proposed for these species with the type strains THG-DN8.7(T) (=KCTC 42236(T) = JCM 30322(T)) and THG-DN8.3(T) (=KCTC 42237(T) = JCM 30321(T)), respectively. PMID- 25828772 TI - Metabolic and transcriptomic signatures of rice floral organs reveal sugar starvation as a factor in reproductive failure under heat and drought stress. AB - Heat and drought stress are projected to become major challenges to sustain rice (Oryza sativa L.) yields with global climate change. Both stresses lead to yield losses when they coincide with flowering. A significant knowledge gap exists in the mechanistic understanding of the responses of rice floral organs that determine reproductive success under stress. Our work connects the metabolomic and transcriptomic changes in anthers, pistils before pollination and pollinated pistils in a heat-tolerant (N22) and a heat-sensitive (Moroberekan) cultivar. Systematic analysis of the floral organs revealed contrasts in metabolic profiles across anthers and pistils. Constitutive metabolic markers were identified that can define reproductive success in rice under stress. Six out of nine candidate metabolites identified by intersection analysis of stressed anthers were differentially accumulated in N22 compared with Moroberekan under non-stress conditions. Sugar metabolism was identified to be the crucial metabolic and transcriptional component that differentiated floral organ tolerance or susceptibility to stress. While susceptible Moroberekan specifically showed high expression of the Carbon Starved Anthers (CSA) gene under combined heat and drought, tolerant N22 responded with high expression of genes encoding a sugar transporter (MST8) and a cell wall invertase (INV4) as markers of high sink strength. PMID- 25828773 TI - An autopsied case of adult-onset bulbospinalform Alexander disease with a novel S393R mutation in the GFAP gene. AB - A 50-year-old Japanese man with no apparent family history noticed diplopia. He gradually showed gait disturbance and dysuria. Abducens disorder of eye movement with nystagmus, tongue atrophy with fasciculation, spastic tetraparesis, and sensory disturbance were also observed. MRI showed severe atrophy of the medulla oblongata to the cervical cord ("tadpole appearance"). Tracheotomy and gastrostomy were performed 7 years after onset due to the development of bulbar palsy. Death occurred following respiratory failure after 11 years total disease duration. The brain weighed 1,380 g. The cerebrum, cerebellum, midbrain, and upper pons were preserved from atrophy, but the medulla oblongata to the cervical cord showed severe atrophy. A few Rosenthal fibers were observed in the cerebral white matter, basal ganglia, and cerebellum, whereas numerous Rosenthal fibers were observed in the medulla oblongata to the cervical cord. Myelin loss with relatively preserved axons was extensively observed from the middle of the pons to the spinal cord. The clinicopathological diagnosis was adult-onset bulbospinal form Alexander disease. Glial fibrillary acidic protein (GFAP) gene analysis revealed a novel mutation of S393R. Expression patterns of S393R mutant GFAP using adrenal carcinoma-derived cells (SW13 cells) showed a decreased number of filamentous structures and abnormal aggregates. PMID- 25828774 TI - Does aberrant architecture of nuclear LINC complex stop muscle cell development? AB - The linker of nucleoskeleton and cytoskeleton (LINC) complex is a structure that spans the entire nuclear envelope (NE) and integrates the nuclear interior with the cytoskeleton. Lamin A/C together with nesprins that mainly reside along the inner nuclear membrane (INM) and outer nuclear membrane (ONM) are core components of the LINC complex. Integrity of this specific nuclear structure is critical for muscle cell maturation and function. In the present study, we analyzed the ultrastructure of the LINC complex observed in two neonates with severe hypotonia and respiratory distress. Disruption of the LINC complex manifests in a wide separation of the ONM from the INM; the loss of perinuclear space (PNS) and delayed muscle cell maturation were predominating findings. This nuclear phenomenon has never been reported and provides further support for the appearance of a neonatal form of laminopathy. PMID- 25828775 TI - Morphological changes of skeletal muscle in spinal and bulbar muscular atrophy (SBMA), Kennedy's disease: a case report. AB - Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an X-linked recessive disease affecting lower motor neurons. In the present case report, we describe morphological changes in a muscle biopsy obtained from a 62-year-old patient with gynecomastia and with the following neurological symptoms: dysphagia, dysarthria, wasting and fasciculation of the tongue, proximal weakness, fasciculations in the limb muscles, and an absence of all tendon reflexes. Neurogenic alternations were predominantly observed using light and electron microscopy. The angulated atrophic muscle fibers formed bundles. The numerous nuclei were pyknotic or pale, some of them were also ubiquitin positive; they were grouped inside so-called "nuclear sacks". At the ultrastructural level, atrophic muscle fibers revealed disruption and loss of sarcomeres, duplication of Z-line, and rod-like structures. The nuclei, often with irregular shapes, revealed varying degrees of chromatin condensation, from dispersed to highly condensed, like pyknotic nuclei. Occasionally electron-dense inclusions in the nuclei were found. Some myogenic features like hypertrophic muscle fibers and proliferation of connective tissue were also visible. The neurogenic and myogenic pathological changes suggested SBMA, which was confirmed with genetic analysis (trinucleotide CAG (glutamie)-repeat expansion in the androgen-receptor gene). PMID- 25828776 TI - Dementia pugilistica: a severe tribute to a career. AB - A 59-year-old man, ex-professional boxer, met clinical criteria for probable Alzheimer's disease. The patient agreed to be included in a clinico-pathological study with donation to the brain bank, and he died at 71. The brain was grossly atrophic, with a prominent atrophy of the entorhinal cortex and hippocampus, and with pallor of the substantia nigra. Immunohistochemistry with anti-tau A4 revealed abundant and diffuse deposits in the neo-cortex, whereas amyloid angiopathy was absent. Coupled anti-tau AT8 immunohistochemistry and Congo red staining showed no neuritic plaques. tau-AT8-positive glial tangles and neurofibrillary tangles involved preferentially the superficial cortical layers, and were irregularly concentrated in the depth of cortical sulci and near vessels. Neurofibrillary degeneration was marked in amygdala, hippocampus, substantia nigra, and locus ceruleus. Enlarged and/or distorted axons were numerous in hippocampus and mid-brain. TDP 43-positive neuronal inclusions were numerous in amygdala and hippocampus. There was no synucleinopathy. These observations are in accordance with the previously reported data on chronic traumatic encephalopathy. The discussion is focused on professional boxing as it becomes evident that repetitive trauma on the brain provokes the deposition of abnormal proteins involved in neurodegeneration. PMID- 25828777 TI - The prevalence of IgG4-positive plasma cells in hypophysitis: a possible relationship to IgG4-related disease. AB - AIMS: Hypophysitis is a rare chronic inflammation of the pituitary gland corresponding currently to six histopathological subtypes. Among them, immunoglobulin- G4-related hypophysitis was recently added in this classification. The aim of this study was to perform a retrospective histopathological and immunohistochemical analysis to evaluate the prevalence of IgG4-related hypophysitis and review reported cases. METHODS: All samples of hypophysitis from Lariboisiere hospital were reviewed by two pathologists to assess their subtypes. An immunohistochemistry against IgG4 and IgG was performed. Slides were numerized, and IgG4-positive plasma cells and IgG plasma cells were counted in three high-power fields to evaluate the ratio. RESULTS: Eight cases were included: 5 lymphocytic hypophysitis, 1 granulomatous subtype, and 2 IgG4-related hypophysitis, affecting two young women without other coaffected organ. CONCLUSION: Our results show that IgG4-related hypophysitis is not an exceptional entity. Storiform fibrosis and obliterative phlebitis, histopathological characteristics of IgG4-related disease in other organs, are lacking in pituitary lesions. This study proves the interest of immunohistochemistry for diagnosis of IgG4-related hypophysitis. Due to the sensibility of IgG4-disease to steroids in other organs, this finding could be of clinical relevance. PMID- 25828778 TI - Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye. AB - BACKGROUND: We used in vivo corneal confocal microscopy to investigate structural differences in the sub-basal corneal nerve plexus in chronic migraine patients and a normal population. We used a validated questionnaire and tests of lacrimal function to determine the prevalence of dry eye in the same group of chronic migraine patients. Activation of the trigeminal system is involved in migraine. Corneal nociceptive sensation is mediated by trigeminal axons that synapse in the gasserian ganglion and the brainstem, and serve nociceptive, protective, and trophic functions. Noninvasive imaging of the corneal sub-basal nerve plexus is possible with in vivo corneal confocal microscopy. METHODS: For this case-control study, we recruited chronic migraine patients and compared them with a sex- and age-similar group of control subjects. Patients with peripheral neuropathy, a disease known to be associated with a peripheral neuropathy, or prior corneal or intraocular surgery were excluded. Participants underwent in vivo corneal confocal microscopy using a Heidelberg Retinal Tomography III confocal microscope with a Rostock Cornea Module. Nerve fiber length, nerve branch density, nerve fiber density, and tortuosity coefficient were measured using established methodologies. Migraine participants underwent testing of basal tear production with proparacaine, corneal sensitivity assessment with a cotton-tip applicator, measurement of tear break-up time, and completion of a validated dry eye questionnaire. RESULTS: A total of 19 chronic migraine patients and 30 control participants completed the study. There were no significant differences in age or sex. Nerve fiber density was significantly lower in migraine patients compared with controls (48.4 +/- 23.5 vs. 71.0 +/- 15.0 fibers/mm2 , P < .001). Nerve fiber length was decreased in the chronic migraine group compared with the control group, but this difference was not statistically significant (21.5 +/- 11.8 vs. 26.8 +/- 5.9 mm/mm2, P < .084). Nerve branch density was similar in the two groups (114.0 +/- 92.4 vs. 118.1 +/- 55.9 branches/mm2 , P < .864). Tortuosity coefficient and log tortuosity coefficient also were similar in the chronic migraine and control groups. All migraine subjects had symptoms consistent with a diagnosis of dry eye syndrome. CONCLUSIONS: We found that in the sample used in this study, the presence of structural changes in nociceptive corneal axons lends further support to the hypothesis that the trigeminal system plays a critical role in the pathogenesis of migraine. In vivo corneal confocal microscopy holds promise as a biomarker for future migraine research as well as for studies examining alterations of corneal innervation. Dry eye symptoms appear to be extremely prevalent in this population. The interrelationships between migraine, corneal nerve architecture, and dry eye will be the subject of future investigations. PMID- 25828779 TI - Cardiac dysfunction following brain death in children: prevalence, normalization, and transplantation. AB - OBJECTIVES: Cardiac dysfunction has been reported to occur in as much as 42% of adults with brain death, and may limit cardiac donation after brain death. Knowledge of the prevalence and natural course of cardiac dysfunction after brain death may help to improve screening and transplant practices but adequately sized studies in pediatric brain death are lacking. The aims of our study are to describe the prevalence and course of cardiac dysfunction after pediatric brain death. DESIGN: Cross-sectional study. SETTING/SUBJECTS: We examined an organ procurement organization database (Life Center Northwest) of potential pediatric cardiac donors diagnosed with brain death between January 2011 and November 2013. INTERVENTION: Transthoracic echocardiograms were reviewed for cardiac dysfunction (defined as ejection fraction <50% or the presence of regional wall motion abnormalities). Descriptive statistics were used to analyze clinical characteristics and describe longitudinal echocardiogram findings in a subgroup of patients. We examined for heterogeneity between cardiac dysfunction with respect to cause of brain death. MEASUREMENT AND MAIN RESULTS: We identified 60 potential pediatric cardiac donors (age <= 18 yr) with at least one transthoracic echocardiogram following brain death. Cardiac dysfunction was present in 23 patients (38%) with brain death. Mean ejection fraction (37.6% vs 62.2%) and proportion of procured hearts (56.5% vs 83.8%) differed significantly between the groups with and without cardiac dysfunction, respectively. Of the 11 subjects with serial transthoracic echocardiogram data, the majority of patients with cardiac dysfunction (73%) improved over time, leading to organ procurement. No heterogeneity between cardiac dysfunction and particular causes of brain death was observed. CONCLUSION: The frequency of cardiac dysfunction in children with brain death is high. Serial transthoracic echocardiograms in patients with cardiac dysfunction showed improvement of cardiac function in most patients, suggesting that initial decisions to procure should not solely depend on the initial transthoracic echocardiogram examination results. PMID- 25828781 TI - Nutritional status and clinical outcome in postterm neonates undergoing surgery for congenital heart disease. AB - OBJECTIVE: Poor growth is a common complication in infants with congenital heart disease. There has been much focus on low birth weight as having increased risk of adverse outcomes following neonatal heart surgery. In this study, we examined whether preoperative nutritional status, measured by admission weight-for-age z score, was associated with postoperative clinical outcome. DESIGN: Retrospective case series. SETTING: Pediatric Cardiac ICU at the Royal Brompton Hospital. PATIENTS: Neonates undergoing surgery for congenital heart disease. Those undergoing ductus arteriosus ligation alone were excluded. Children with coexisting noncardiac morbidity were excluded. Outcome variables included prevalence of postoperative complications (including sepsis, delayed chest closure, renal impairment, and necrotizing enterocolitis), duration of ventilation, intensive care stay, postoperative mortality, and mortality at 1 year after surgery. INTERVENTIONS: None. Analysis of patient data only. MEASUREMENTS AND MAIN RESULTS: Two hundred forty-eight neonates fulfilled the entry criteria. Median (interquartile range) age was 7 days (2-15 d), median (interquartile range) weight was 3.3 kg (2.91-3.6 kg), and median weight-for-age z score was -0.77 (-1.44 to 0.01). Twenty-eight children (11%) had a weight-for age z score of less than -2. There was no evidence that children with lower weight-for-age z score had less severe surgery as measured by the Risk Adjustment for Congenital Heart Surgery 1 score. In multivariable regression analysis, the weight-for-age z at admission had strong correlation with the number of days free of respiratory support (invasive and noninvasive ventilation) at 28 days (p < 0.0001) and with all-cause mortality at 1 year (p = 0.001). CONCLUSIONS: Poor nutritional status as measured by weight-for-age z is associated with adverse short- and long-term outcomes in neonates undergoing surgery for congenital heart disease. PMID- 25828780 TI - Evolution of Noninvasive Mechanical Ventilation Use: A Cohort Study Among Italian PICUs. AB - OBJECTIVE: To assess how clinical practice of noninvasive ventilation has evolved in the Italian PICUs. DESIGN: National, multicentre, retrospective, observational cohort. SETTING: Thirteen Italian medical/surgical PICUs that participated in the Italian PICU Network. PATIENTS: Seven thousand one-hundred eleven admissions of children with 0-16 years old admitted from January 1, 2011, to December 31, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cause of respiratory failure, length and mode of noninvasive ventilation, type of interfaces, incidence of treatment failure, and outcome were recorded. Data were compared with an historical cohort of children enrolled along 6 months from November 1, 2006, to April 30, 2007, over the viral respiratory season. Seven thousand one-hundred eleven PICU admissions were analyzed, and an overall noninvasive ventilation use of 8.8% (n = 630) was observed. Among children who were admitted in the PICU without mechanical ventilation (n = 3,819), noninvasive ventilation was used in 585 patients (15.3%) with a significant increment among the three study years (from 11.6% in 2006 to 18.2% in 2012). In the endotracheally intubated group, 17.2% children received noninvasive ventilation at the end of the weaning process to avoid reintubation: 11.9% in 2006, 15.3% in 2011, and 21.6% in 2012. Noninvasive ventilation failure rate raised from 10% in 2006 to 16.1% in 2012. CONCLUSIONS: Noninvasive ventilation is increasingly and successfully used as first respiratory approach in several, but not all, Italian PICUs. The current study shows that noninvasive ventilation represents a feasible and safe technique of ventilatory assistance for the treatment of mild acute respiratory failure. Noninvasive ventilation was used as primary mode of ventilation in children with low respiratory tract infection (mainly in bronchiolitis and pneumonia), in acute on chronic respiratory failure or to prevent reintubation. PMID- 25828783 TI - Neuromonitoring During Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature. AB - OBJECTIVE: Neurologic injury remains a significant morbidity and risk factor for mortality in critically ill patients undergoing extracorporeal membrane oxygenation. Our goal was to systematically review the literature on the use of neuromonitoring methods during extracorporeal membrane oxygenation. DATA SOURCES: Electronic searches of PubMed, CINAHL, EMBASE, Web of Science, Cochrane, and Scopus were conducted in March 2014, using a combination of medical subject heading terms and text words to define concepts of extracorporeal life support, neurologic monitoring techniques, evaluation, and outcomes. STUDY SELECTION: Studies were selected based on inclusion and exclusion criteria defined a priori. DATA EXTRACTION: Two authors reviewed all citations independently. A standardized data extraction form was used to construct evidence tables by neuromonitoring method. Evidence was graded using the Oxford Evidence-Based Medicine scoring system. DATA SYNTHESIS: Of 3,459 unique citations, 39 studies met the inclusion criteria. Study designs were retrospective observational cohort studies (n = 20), prospective observational studies (n = 17), case-control studies (n = 2), and no interventional studies. Most studies evaluated newborns (n = 30). Extracorporeal membrane oxygenation neuromonitoring methods included neuroimaging (head ultrasound) (n = 12); intermittent, conventional, multichannel electroencephalography (n = 5); 1- to 2-channel amplitude-integrated electroencephalography (n = 2); Doppler ultrasound (n = 7); cerebral oximetry (n = 6); plasma brain injury biomarkers (n = 4); and other (n = 3). All evidence was graded 2B-4, with the majority of studies graded 3B (20/39 studies) and 4 (10/39 studies). Due to the heterogeneity of the studies included, aggregate analysis was not possible. CONCLUSIONS: Data supporting the use and effectiveness of current neuromonitoring methods are limited. Most studies have modest sample sizes, are observational in nature, and include patient populations that are of different ages and pathologies, with very limited data for pediatric and adult ages. Well-designed studies with adequate power and standardized short- and long term outcomes are needed to develop guidelines for neuromonitoring and ultimately neuroprotection in patients on extracorporeal membrane oxygenation. PMID- 25828782 TI - Impact of Kidney Disease on Survival in Neonatal Extracorporeal Life Support. AB - OBJECTIVE: To investigate the prevalence and survival to discharge of neonates with kidney disease who received extracorporeal life support. DESIGN: We analyzed the Extracorporeal Life Support Organization international registry of neonates (< 30 d old) who received extracorporeal life support from 1989 to 2012. We used International Classification of Diseases and Related Health Problems, 9th Revision, Clinical Modification, codes to identify neonates with kidney disease at time of cannulation for extracorporeal life support. SETTING: Participating Extracorporeal Life Support Organization centers. PATIENTS: All neonates who received extracorporeal life support at an Extracorporeal Life Support Organization center from 1989 to 2012. INTERVENTIONS: We performed bivariate logistic regression to estimate associations between survival and covariates. We used unadjusted and adjusted logistic regression to compare survival to discharge between neonates with and without kidney disease. Odds ratios were estimated separately for three groups based on extracorporeal life support indication: pulmonary indication without congenital diaphragmatic hernia, pulmonary indication with congenital diaphragmatic hernia, and cardiac indication. Adjusted models included covariates identified as significant in bivariate models for each group. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was survival to discharge from hospitalization. Of the 28,755 neonates who received extracorporeal life support, 405 had kidney disease (extracorporeal life support indication: 210 pulmonary indication without congenital diaphragmatic hernia, 65 pulmonary indication with congenital diaphragmatic hernia, and 130 cardiac indication). Survival was lower in neonates with kidney disease than those without (49% vs 82% pulmonary indication without congenital diaphragmatic hernia, 25% vs 51% pulmonary indication with congenital diaphragmatic hernia, 21% vs 41% cardiac indication). Kidney disease was associated with reduced survival in adjusted models (95% CI for odds ratio 0.31-0.59 pulmonary indication without congenital diaphragmatic hernia, 0.27-0.89 pulmonary indication with congenital diaphragmatic hernia, 0.31-0.77 cardiac indication). CONCLUSIONS: Neonates with kidney disease who receive extracorporeal life support have poorer survival to discharge compared with other neonates who receive extracorporeal life support, suggesting that kidney disease should be considered when making extracorporeal life support initiation decisions. PMID- 25828784 TI - Factor VIII May Predict Catheter-Related Thrombosis in Critically Ill Children: A Preliminary Study. AB - OBJECTIVE: If we can identify critically ill children at high risk for central venous catheter-related thrombosis, then we could target them for pharmacologic thromboprophylaxis. We determined whether factor VIII activity or G value was associated with catheter-related thrombosis in critically ill children. DESIGN: Prospective cohort study. SETTING: Two tertiary academic centers. PATIENTS: We enrolled children younger than 18 years who were admitted to the PICU within 24 hours after insertion of a central venous catheter. We excluded children with a recently diagnosed thrombotic event or those anticipated to receive anticoagulation. Children with thrombosis diagnosed with surveillance ultrasonography on the day of enrollment were classified as having prevalent thrombosis. Those who developed catheter-related thrombosis thereafter were classified as having incident thrombosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We enrolled 85 children in the study. Once enrolled, we measured factor VIII activity with one-stage clotting assay and determined G value with thromboelastography. Of those enrolled, 25 had incident and 12 had prevalent thromboses. The odds ratio for incident thrombosis per SD increase in factor VIII activity was 1.98 (95% CI, 1.10-3.55). The area under the receiver operating characteristic curve was 0.66 (95% CI, 0.52-0.79). At factor VIII activity more than 100 IU/dL, which was the optimal threshold identified using Youden index, sensitivity and specificity were 92.0% and 41.3%, respectively. The association between factor VIII activity and incident thrombosis remained significant after adjusting for important clinical predictors of thrombosis (odds ratio, 1.93; 95% CI, 1.10-3.39). G value was associated with prevalent but not with incident thrombosis. CONCLUSION: Factor VIII activity may be used to stratify critically ill children based on their risk for catheter-related thrombosis. PMID- 25828785 TI - Anti-hyperplasia effects of Rosa rugosa polyphenols in rats with hyperplasia of mammary gland. AB - Rosa rugosa (Thunb.) is used in Chinese traditional medicine with the functions of promoting blood circulation, relieving the depressed liver and attenuating breast disorders. This study was to investigate the anti-hyperplasia effects of the polyphenols-rich fraction from R. rugosa (FRR) in rat. Rat model of hyperplasia of mammary gland (HMG) was induced by intramuscularly injected with estrogen (0.5mg/kg/d) for 25 days, and followed with progestogen (5mg/kg/d) for another 5 days. Meanwhile, FRR was orally given for 30 days. Then, the levels of estradiol and oxidative stress were assessed. The mammary expressions of AKT and JNK were evaluated by Western blot analysis. The expressions of NFkappaB-p65, COX 2 and VEGF were measured by immunohistochemical analysis. The whole results indicated that FRR could exert anti-hyperplasia effects in rat via modulating the mammary expression of JNK and AKT, as well as alleviating the NFkappaB related oxidative stress and inflammatory responses. PMID- 25828786 TI - Evaluation of a combination chemotherapy protocol including lomustine and doxorubicin in canine histiocytic sarcoma. AB - OBJECTIVES: To describe a chemotherapy protocol combining lomustine and doxorubicin in canine histiocytic sarcoma, including outcomes and toxicity. MATERIALS AND METHODS: Retrospective review of case records for dogs with histiocytic sarcoma treated with lomustine and doxorubicin (+/- cyclophosphamide) alternating every 2 weeks. Data collected included signalment, clinical signs, clinicopathological abnormalities, extent of disease, response, toxicity, time to tumour progression and survival time. RESULTS: Of 17 dogs, 15 had disseminated or metastatic disease. The median number of chemotherapy cycles (one dose of each drug) received was three; most dogs discontinued therapy due to progressive disease. Dose reductions or delays occurred in 18% of cycles. The overall response rate was 58%, with a median time to tumour progression of 185 (range, 59 to 268) days for responders. The overall median survival time was 185 (18 to 402) days. No significant prognostic factors were identified. CLINICAL SIGNIFICANCE: The protocol appeared well-tolerated, had some efficacy against canine histiocytic sarcoma in the study population and could be considered as an alternative to single-agent protocols; prospective comparison may be warranted. PMID- 25828787 TI - An in vitro bioassay for the quantitative evaluation of mosquito repellents against Stegomyia aegypti (=Aedes aegypti) mosquitoes using a novel cocktail meal. AB - To assess the efficacy of new insect repellents, an efficient and safe in vitro bioassay system using a multiple-membrane blood-feeding device and a cocktail meal was developed. The multiple-membrane blood-feeding device facilitates the identification of new insect repellents by the high-throughput screening of candidate chemicals. A cocktail meal was developed as a replacement for blood for feeding females of Stegomyia aegypti (=Aedes aegypti) (L.) (Diptera: Culicidae). The cocktail meal consisted of a mixture of salt, albumin and dextrose, to which adenosine triphosphate was added to induce engorging. Feeding rates of St. aegypti on the cocktail meal and pig blood, respectively, did not differ significantly, but were significantly higher than the feeding rate on citrate phosphate dextrose-adenine 1 (CPDA-1) solutions, which had been used to replace bloodmeals in previous repellent assays. Dose-dependent biting inhibition rates were analysed using probit analysis. The RD(50) (the dose producing 50% repellence of mosquito feeding) values of DEET, citronella, carvacrol, geraniol, eugenol and thymol were 1.62, 14.40, 22.51, 23.29, 23.83 and 68.05 ug/cm(2), respectively. PMID- 25828788 TI - Mammary analogue secretory carcinoma of the sinus ethmoidalis. PMID- 25828789 TI - Case report of chronic cough and legs edema of an 84-year-old man: when the solution is found in the nails. PMID- 25828790 TI - Undetected vitamin D deficiency in a Chinese nursing home older adult. PMID- 25828791 TI - English translation of the Kihon Checklist. PMID- 25828792 TI - Operationalization of a frailty index using routine data from the Toulouse Frailty Clinic. PMID- 25828793 TI - A new treatment algorithm for the management of myopic choroidal neovascularization using intravitreal ranibizumab. PMID- 25828794 TI - Leaf-trait plasticity and species vulnerability to climate change in a Mongolian steppe. AB - Climate change is expected to modify plant assemblages in ways that will have major consequences for ecosystem functions. How climate change will affect community composition will depend on how individual species respond, which is likely related to interspecific differences in functional traits. The extraordinary plasticity of some plant traits is typically neglected in assessing how climate change will affect different species. In the Mongolian steppe, we examined whether leaf functional traits under ambient conditions and whether plasticity in these traits under altered climate could explain climate-induced biomass responses in 12 co-occurring plant species. We experimentally created three probable climate change scenarios and used a model selection procedure to determine the set of baseline traits or plasticity values that best explained biomass response. Under all climate change scenarios, plasticity for at least one leaf trait correlated with change in species performance, while functional leaf trait values in ambient conditions did not. We demonstrate that trait plasticity could play a critical role in vulnerability of species to a rapidly changing environment. Plasticity should be considered when examining how climate change will affect plant performance, species' niche spaces, and ecological processes that depend on plant community composition. PMID- 25828796 TI - Introducing a new senior editor. PMID- 25828795 TI - The potential spread of severe footrot in Norway if no elimination programme had been initiated: a simulation model. AB - When severe footrot was detected in Norway in 2008, a surveillance programme was initiated and followed by an elimination programme. By 2013 the disease had spread to two of 19 counties and a total of 119 (1%) sheep flocks had been diagnosed with severe footrot. A simulation model was developed to estimate the potential spread of severe footrot in Norway and to estimate the relative importance of the different spreading routes. The model parameters were based on the rate of spread of the first 38 diagnosed cases and the management and climatic factors particular for Norway. The model showed that by 2013, severe footrot would have spread to six counties and infected 16% of the sheep flocks if no elimination programme had been initiated. If this is compared with the 1% of flocks that were diagnosed in Norway by 2013, there seems to be a large effect of the implemented footrot elimination programme. By 2035, it was estimated that severe footrot would have spread to 16 counties and 64% of the sheep flocks. Such an extensive spread would probably impose a large negative impact on the sheep industry and welfare of the sheep. The most effective way to curb the spread of severe footrot was by decreasing the within county infection rate. This could be achieved by decreasing the contact between flocks or by decreasing the environmental load of D. nodosus, for example by footbathing sheep, culling diseased sheep or eliminating severe footrot in the flock. PMID- 25828799 TI - ProSight Lite: graphical software to analyze top-down mass spectrometry data. AB - Many top-down proteomics experiments focus on identifying and localizing PTMs and other potential sources of "mass shift" on a known protein sequence. A simple application to match ion masses and facilitate the iterative hypothesis testing of PTM presence and location would assist with the data analysis in these experiments. ProSight Lite is a free software tool for matching a single candidate sequence against a set of mass spectrometric observations. Fixed or variable modifications, including both PTMs and a select number of glycosylations, can be applied to the amino acid sequence. The application reports multiple scores and a matching fragment list. Fragmentation maps can be exported for publication in either portable network graphic (PNG) or scalable vector graphic (SVG) format. ProSight Lite can be freely downloaded from http://prosightlite.northwestern.edu, installs and updates from the web, and requires Windows 7 or a higher version. PMID- 25828801 TI - Biosensor-based real-time monitoring of paracetamol photocatalytic degradation. AB - This paper presents for the first time the integration of a biosensor for the on line, real-time monitoring of a photocatalytic degradation process. Paracetamol was used as a model molecule due to its wide use and occurrence in environmental waters. The biosensor was developed based on tyrosinase immobilization in a polyvinylalcohol photocrosslinkable polymer. It was inserted in a computer controlled flow system installed besides a photocatalytic reactor including titanium dioxide (TiO2) as photocatalyst. It was shown that the biosensor was able to accurately monitor the paracetamol degradation with time. Compared with conventional HPLC analysis, the described device provides a real-time information on the reaction advancement, allowing a better control of the photodegradation process. PMID- 25828800 TI - Spinal antinociceptive effects of the novel NOP receptor agonist PWT2 nociceptin/orphanin FQ in mice and monkeys. AB - BACKGROUND AND PURPOSE: Using an innovative chemical approach, peptide welding technology (PWT), a tetrabranched derivative of nociceptin/orphanin FQ (N/OFQ) has been generated and pharmacologically characterized. Both in vitro and in vivo PWT2-N/OFQ displayed the same pharmacological profile to the natural ligand. It was more potent and produced longer-lasting effects. The aim of the present study was to investigate the spinal effects of PWT2-N/OFQ in nociceptive and neuropathic pain models in mice and non-human primates. EXPERIMENTAL APPROACH: Tail withdrawal assay in mice and monkeys was used as a nociceptive pain model and mechanical threshold in mice subjected to chronic constriction injury was used as a neuropathic pain model. The antinociceptive effects of spinally administered N/OFQ and PWT2-N/OFQ were assessed in these models. KEY RESULTS: PWT2-N/OFQ mimicked the spinal antinociceptive effects of N/OFQ both in nociceptive and neuropathic pain models in mice as well as in non-human primates displaying 40-fold higher potency and a markedly prolonged duration of action. The effects of N/OFQ and PWT2-N/OFQ were sensitive to the N/OFQ receptor (NOP) antagonist SB-612111, but not to opioid receptor antagonists. CONCLUSIONS AND IMPLICATIONS: The present study has demonstrated that PWT2-N/OFQ mimicked the antinociceptive effects of the natural peptide in rodents and non-human primates acting as a potent and longer-lasting NOP-selective agonist. More generally, PWT derivatives of biologically active peptides can be viewed as innovative pharmacological tools for investigating those conditions and states in which selective and prolonged receptor stimulation promotes beneficial effects. PMID- 25828802 TI - Integrated environmental quality monitoring around an underground methane storage station. AB - The study reports an integrated environmental quality monitoring of a 100 km2 area in central Italy mostly occupied by an underground station of methane storage, working since 1982. The nitrogen oxides, ozone and isoprene concentration detached with a network monitoring of passive filters were compared with the results of lichens biomonitoring. Data from the two monitorings were in accordance: there was an inversely correlation between lichen biodiversity index (IBL) and NOx (-0.96) and ozone (-0.80), and a positive correlation between IBL and isoprene (0.67). IBL indicated that the area ranged between medium naturalness and medium alteration status, values fully compatible with the medium high level of eutrophication, caused by intensive agriculture. Only two areas were in high alteration status, due to their proximity to glass factories and to a quarries area. Despite almost thirty years of activity, the environment quality of the area around the station did not show signs of declining. PMID- 25828803 TI - Hand amyotrophy and ventral intraspinal fluid collection. PMID- 25828804 TI - [Primary tumor resection of neuroendocrine pancreatic tumors with liver metastases]. PMID- 25828805 TI - Human RAD50 makes a functional DNA-binding complex. AB - The MRE11-RAD50-NBS1 (MRN) complex has several distinct functions in DNA repair including important roles in both non-homologous end-joining (NHEJ) and homologous recombination (HR). The biochemical activities of MR(N) have been well characterized implying specific functional roles for the components. The arrangement of proteins in the complex implies interdependence of their biochemical activities making it difficult to separate specific functions. We obtained purified human RAD50 and observed that it binds ATP, undergoes ATP dependent conformational changes as well as having ATPase activity. Scanning force microscopy analysis clearly showed that RAD50 binds DNA although not as oligomers. RAD50 alone was not functional in tethering DNA molecules. ATP increased formation of RAD50 multimers which were however globular lacking extended coiled coils, in contrast to the MR complex where ATP induced oligomers have obvious coiled coils protruding from a central domain. These results suggest that MRE11 is important in maintaining the structural arrangement of RAD50 in the protein complex and perhaps has a role in reinforcing proper alignment of the coiled coils in the ATP-bound state. PMID- 25828806 TI - Mechanistic overview of ADP-ribosylation reactions. AB - ADP-ribosylation reactions consist of mono-ADP-ribosylation, poly-ADP ribosylation and cyclic ADP-ribosylation. These reactions play essential roles in many important physiological and pathophysiological events. The types of chemical linkages, the evolutionarily conserved motif within the enzymes to determine the target specificity, stereochemistry of the ADP-ribosylated products, and the chemical reactions taking place among the enzymes and substrates are discussed. PMID- 25828807 TI - A new protocol for nickel-catalysed regio- and stereoselective hydrocyanation of allenes. AB - Regio- and stereoselective hydrocyanation under nickel catalysis is described. This report shows that allenyl C-C double bonds are discriminated and converted to the corresponding carbonitriles as a single product. The key functionalities for achieving high regio- and stereocontrol are aryl and cyclopropyl groups in the substrates. PMID- 25828808 TI - Corrigendum: Interferon regulatory factor 9 is critical for neointima formation following vascular injury. PMID- 25828810 TI - UHPLC-MS method for determination of gambogic acid and application to bioavailability, pharmacokinetics, excretion and tissue distribution in rats. AB - A sensitive ultrahigh performance liquid chromatography tandem mass spectrometry (UHPLC-MS) method was developed for determination of gambogic acid (GA) in rat plasma, urine, bile and main tissues. GA was separated on an Agilent Zorbax XDB C18 column (50 * 2.1 mm, 1.8 um) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by negative electrospray ionization with multiple reaction monitoring mode. The calibration curves of GA were linear between 1.0 and 1000 ng/mL in rat plasma and bile and between 1.0 and 500 ng/mL in urine and tissues. The lowest limit of quantification for all matrices was 1.0 ng/mL. Both accuracy and precision of the assay were satisfactory. This validated method was firstly applied to bioavailability (BA), pharmacokinetics, excretion and tissue distribution in rats. The BAs of GA (40 and 80 mg/kg) in rats were 0.25 and 0.32%, respectively. GA was distributed extensively in rats after oral administration and exhibited the highest level in liver. GA reached the cumulative excretion amount of 25.3 +/- 1.7 ug in bile and 0.275 +/- 0.08 ug in urine after i.g. 80 mg/kg to rats at 24 h. The present results would be helpful for further clinical use of GA as a potential anticancer drug. PMID- 25828809 TI - Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence? AB - Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding. PMID- 25828811 TI - Supportive care for men with prostate cancer: why are the trials not working? A systematic review and recommendations for future trials. AB - Men with prostate cancer are likely to have a long illness and experience psychological distress for which supportive care may be helpful. This systematic review describes the evidence for effectiveness and cost-effectiveness of supportive care for men with prostate cancer, taking into account treatment pathway and components of interventions. MEDLINE, EMBASE, CINAHL, CENTRAL, and Psychinfo were searched from inception--July 2013 for randomized controlled trials and controlled trials. Two authors independently assessed risk of bias and extracted data. Twenty-six studies were included (2740 participants). Interventions were delivered pre and during (n = 12), short-term (n = 8), and longer term (18 months) (n = 5) after primary treatment. No interventions were delivered beyond this time. Few trials recruited ethnic minorities and none recruited men in same sex relationships. Intervention components included information, education, health professional discussion, homework, peer discussion, buddy support, cognitive behavioral therapy, cognitive restructuring, psychoeducation, Reiki and relaxation. Most interventions were delivered for 5-10 weeks. Risk of bias of trials was assessed as unclear for most domains due to lack of information. The majority of trials measuring quality of life and depression found no effect. Relatively few trials measured anxiety, coping skills and self-efficacy, and the majority found no effect. No cost data were available. Trials of supportive care for men with prostate cancer cover a range of interventions but are limited by population diversity, inconsistent measurement and reporting of outcomes, and inability to assess risk of bias. Recommendations on design and conduct of future trials are presented. PMID- 25828812 TI - CsRNASET2 is an important component of Clonorchis sinensis responsible for eliciting Th2 immune response. AB - Many parasites can trigger the host immune response by releasing excretory/secretory proteins (ESPs). CsRNASET2, a glycosylated T2 ribonuclease present in ESPs of Clonorchis sinensis (C. sinensis, Cs), has recently been reported to possess potent effects in regulating mouse dendritic cells (DCs). However, it is unclear whether CsRNASET2 can induce adaptive immune response. In this study, we carried out further investigations on biochemical features of CsRNASET2. Besides, we immunized Balb/c mice with CsRNASET2 and orally infected Balb/c mice with C. sinensis, respectively. Sera of immunized mice were collected and evaluated for specific antibody titers by ELISA. Splenocytes of experimental mice were isolated and stimulated in vitro. The expression levels of IL-4 and IFN gamma in splenocytes of immunized mice and infected mice were detected by ELISA and flow cytometry. Our results showed that the sequence of CsRNASET2 had close relationship with the homologue from Echinococcus multilocularis. The conserved active site (CAS) motifs, active histidine residues, and N-linked glycosylation region of CsRNASET2 were close to each other in the three-dimensional structure. In addition, sera of CsRNASET2 immunized mice had obviously higher levels of specific antibody titers. Splenocytes from both CsRNASET2 immunized mice and C. sinensis infected mice expressed increased levels of IL-4, while the production of IFN-gamma exhibited no significant difference. Immunization with CsRNASET2 elicited Th2 immune response by promoting the synthesis of IL-4, consistent with the immune response initiated by infection of C. sinensis. Taken together, these data suggested that CsRNASET2 was important for C. sinensis to trigger Th2 immune response. PMID- 25828813 TI - Analysis of the effect of soil saprophytic fungi on the eggs of Baylisascaris procyonis. AB - Baylisascaris procyonis is a soil-transmitted helminth mainly found in raccoons (Procyon lotor) which can also affect other domestic and sylvatic animals, as well as humans, when the eggs released in the feces of parasitized raccoons are accidentally ingested. Three assays have been conducted to assess the effect of three saprophytic fungi, Mucor circinelloides, Paecilomyces lilacinus, and Verticillium sp., on the eggs of B. procyonis. Firstly, their ovicidal effect was in vitro ascertained by placing 1 mL with 2 * 10(6) spores of each fungus in Petri plates with water-agar (2 %) and simultaneously adding 200 eggs of Baylisascaris/plate. Two in vivo probes were carried out, by spraying the fungal spores (3 mL containing about 2 * 10(6) spores/mL) on the feces of raccoons and coatis (Nasua narica) passing eggs of B. procyonis in a zoological park; the other assay consisted of evaluating the activity of the fungi after adding sand to fecal samples from raccoons. An ovicidal type 3 activity characterized by morphological damage of the eggshell with hyphal penetration, internal egg colonization, and embryo alteration was observed for all the tested fungi. In the plate assays, viability of Baylisascaris eggs reduced significantly by 53-69 % with Mucor, 45-62 % with Paecilomyces, and 52-67 % with Verticillium. A similar ovicidal effect was detected in the feces with sand. These results demonstrate the usefulness of spraying spores of M. circinelloides, Pa. lilacinus, or Verticillium sp. on the feces of animals infected by Baylisascaris to decrease the numbers of viable eggs and, thus, the risk of infection. PMID- 25828814 TI - A scanning electron microscope technique for studying the sclerites of Cichlidogyrus. AB - The genus Cichlidogyrus (Monogenea: Ancyrocephalidae) includes more than 90 species, most of which are gill parasites of African cichlid fishes. Cichlidogyrus has been studied extensively in recent years, but scanning electron microscope (SEM) investigations of the isolated hard parts have not yet been undertaken. In this paper, we describe a method for isolating and scanning the sclerites of individual Cichlidogyrus worms. Twenty-year-old, formol-fixed specimens of Cichlidogyrus casuarinus were subjected to proteinase K digestion in order to release the sclerites from the surrounding soft tissues. SEM micrographs of the haptoral sclerites and the male copulatory organ are presented. The ability to digest formol-fixed specimens makes this method a useful tool for the study of historical museum collections. PMID- 25828815 TI - Erratum to: Pediculicidal treatment using ethanol and Melia azedarach L. PMID- 25828816 TI - The intraocular pressure and central corneal thickness in healthy premature infants. AB - PURPOSE: To describe the normal values of intraocular pressure (IOP) and central corneal thickness (CCT) in healthy premature infants. METHODS: Infants of <32 weeks' gestational age who underwent screened for retinopathy of prematurity were prospectively enrolled. The same ophthalmologist measured IOP by applanation tonometry and CCT using ultrasonic pachymetry. Infants were divided into four groups according to postconceptional ages (PCA). The mean values of the IOP and CCT were compared by nonparametric statistical tests, and the relationship of the PCA with IOP and CCT were analyzed with correlation tests. Only right eye measurements were analyzed. RESULTS: A total of 470 infants (mean PCA, 35.94 +/- 4.00 weeks) were enrolled. The mean IOP with standard deviation was 16.86 +/- 2.93 mm Hg; the mean CCT, 590 +/- 58.26 MUm. Both IOP and CCT values were found to be significantly higher in infants with lower versus higher PCA (P < 0.001). There was a statistically significant negative linear relationship between the PCA and the values of IOP and CCT, separately. CONCLUSIONS: IOP and CCT values may be higher in infants with lower PCA. Higher IOP values in these infants may be associated with higher CCT values. PMID- 25828817 TI - Outcomes of three different vertical rectus muscle transposition procedures for complete abducens nerve palsy. AB - PURPOSE: To compare the efficacy of three different vertical rectus muscle transposition (VRT) techniques performed as a sole procedure to correct ocular alignment and improve abduction in cases of complete abducens nerve palsy. METHODS: The medical records of patients with complete abducens nerve palsy who underwent one of three different VRT procedures without simultaneous medial rectus weakening over a period of 20 years were retrospectively reviewed. The following procedures were used: full-tendon transposition (FTT), FTT with 4 mm resections before reinsertion (FTTR), and FTT with myopexy sutures (FTTM). We recorded the pre- and postoperative alignments, limitations of adduction and abduction, and complications. Follow-up was at least 6 months. RESULTS: A total of 26 patients (age range, 8-74 years) were included: 25 unilateral and 1 bilateral. Follow-up ranged from 6 to 21 months. Among 25 patients having unilateral surgery, the mean changes in esotropia were: 36.0(Delta) for FTT (n = 9), 46.4(Delta) for FTTR (n = 7), and 41.3(Delta) for FTTM (n = 9). Mean improvements in abduction grading were 0.94 for FTT (9 eyes), 1.64 for FTTR (7 eyes), and 1.41 for FTTM (11 eyes). For both measures the means were not significantly different. Three patients (2 FTT and 1 FTTM) had new postoperative vertical tropias >3(Delta). Only 1 patient (with FTTR) had an overcorrection. CONCLUSIONS: FTTR corrected the most esotropia and improved abduction to the greatest degree, with the advantages of a low risk of creating a new vertical deviation and avoiding the risks of extra scleral sutures. PMID- 25828818 TI - Photodynamic therapy for diffuse choroidal hemangioma in a child with Sturge Weber syndrome. AB - Sturge-Weber syndrome is a rare neurocutaneous disorder involving the leptomeninges, skin of the face, and, in 40% of cases, diffuse choroidal hemangioma. We report the case of a 6-year-old girl with Sturge-Weber syndrome and a large diffuse choroidal hemangioma with retinal detachment involving the majority of the retina. The patient underwent photodynamic therapy. The retinal detachment resolved completely within 3 months of treatment. This case represents the youngest patient in the literature to undergo successful treatment with photodynamic therapy for Sturge-Weber syndrome-associated diffuse choroidal hemangioma. PMID- 25828819 TI - Nonsurgical treatment of cyclic esotropia. AB - Cyclic esotropia is characterized by a 24-hour period of straight eye position followed by 24 hours of large-angle esotropia. Possible mechanisms include notably progressive loss of compensation of a latent strabismus. The classic treatment is surgical correction of the angle measured on the days with manifest deviation. We report the first case of cyclic esotropia successfully treated by prismatic correction of the latent strabismus present on "straight" days. PMID- 25828820 TI - Low cerebrospinal fluid protein in prepubertal children with idiopathic intracranial hypertension. AB - PURPOSE: To evaluate a clinical observation that prepubertal children with idiopathic intracranial hypertension (IIH) have low cerebrospinal fluid (CSF) protein levels compared to healthy children and pubertal patients with IIH. METHODS: The medical records of prepubertal and pubertal IIH patients and controls seen in the pediatric neuro-ophthalmology clinic at Duke between 2003 and 2013 were retrospectively reviewed. The control group consisted of children who had normal intracranial pressure on lumbar puncture performed to evaluate for headaches or anomalous-looking optic nerves. The records were analyzed with attention to demographic characteristics, clinical presentation, course, and lumbar puncture results. RESULTS: A total of 23 prepubertal children with IIH (age range, 0.75-13 years), 16 pubertal patients with IIH (age range, 13-21 years), and 12 controls (age range 3-14 years) were included. CSF analysis revealed that prepubertal children with IIH had significantly lower CSF protein levels (17.3 +/- 5.7 mg/dL) compared to pubertal subjects with IIH (23.4 +/- 8.4 mg/dL; P = 0.019) or healthy controls (23.5 +/- 6.4 mg/dL; P = 0.011). Furthermore, 9 of 23 prepubertal IIH patients (39%) had abnormally low CSF protein level (<15 mg/dL), compared to zero pubertal IIH patients (P = 0.005) and zero controls (P = 0.015). Acetazolamide increased CSF protein level in 100% of patients who underwent repeat lumbar puncture after starting the medication (average increase, 10.3 +/- 6.6 mg/dL). CONCLUSIONS: Low CSF protein level may have diagnostic utility as a biomarker for prepubertal IIH. Furthermore, this finding suggests that some cases of prepubertal IIH may be caused by CSF overproduction rather than decreased CSF resorption. PMID- 25828821 TI - The incidence and visual acuity outcomes of children identified with ametropic amblyopia by vision screening. AB - PURPOSE: To determine the incidence of ametropic amblyopia within a vision screening program's population and report the visual acuity outcomes of children identified with the condition. METHOD: The medical records of children who underwent vision screening as their first assessment at 4-5 years of age between September 1, 2005 and August 31, 2006, were retrospectively reviewed. Children referred with <=0.30 logMAR in each eye with at least 1 year of follow-up had their hospital notes reviewed and data on final visual acuity, refractive error, and follow-up period collected. RESULTS: A total of 33 children identified as having ametropic amblyopia with a follow-up of at least 1 year. The incidence of ametropic amblyopia was 2%-3.2%, depending on the definition used. The mean visual acuity achieved after treatment was 0.12 logMAR, which is significantly less than the age-appropriate mean of 0.00 logMAR (P < 0.01). CONCLUSIONS: Ametropic amblyopia responds to treatment, but most children demonstrate persistent reduced visual acuity at age 7 years. The incidence of ametropic amblyopia within a routine vision screening population shows that significant numbers fail to self-present. PMID- 25828822 TI - Risk factors associated with retinal hemorrhage in suspected abusive head trauma. AB - PURPOSE: To determine risk factors associated with retinal hemorrhage (RH) in pediatric abusive head trauma (AHT) suspects. METHODS: Records of children aged 0 3 years hospitalized for suspected AHT from January 2007 to November 2011 were retrospectively reviewed in this case-control study. Children were classified into case and control groups based on RH presence. Medical history, presenting symptoms, reasons, and characteristics of injury were recorded. Logistic regression analysis was performed to identify risk factors. RESULTS: A total of 168 children (104 males) were included. Of these, 103 were classified as cases and 65 as controls. The mean age (with standard deviation) was 9.3 +/- 8.3 months (range, 1 day-36 months). Of the 103 cases, 22 (21%) had subretinal hemorrhage, 9 (9%) had retinoschisis, and 1 (1%) had vitreous hemorrhage. Children presenting with lethargy or altered mental status (P < 0.0001), subdural hemorrhage (P < 0.0001), and other radiologic findings (eg, cerebral ischemia, diffuse axonal injury, hydrocephalus, or solid organ injury; P = 0.01546) were likely to have RH. All 23 children with skull or nonskull fracture without intracranial hemorrhage did not have RH (P < 0.0001 both categories). CONCLUSIONS: Retinal hemorrhages were almost never found in the absence of intracranial hemorrhage and not found in the setting of fracture without intracranial hemorrhage. PMID- 25828823 TI - Anomalous optical coherence tomography findings in Wyburn-Mason syndrome and isolated retinal arteriovenous malformation. AB - We report 2 cases of unilateral retinal arteriovenous malformation (AVM) with previously unreported anomalies of the inner retinal layers detected on spectral domain optical coherence tomography (SD-OCT): a 5-year-old girl with a large unilateral retinal AVM, ipsilateral visual acuity of 20/200, and ipsilateral intracranial AVM; and a 10-year-old boy with a large unilateral retinal AVM, ipsilateral visual acuity of 20/20, ipsilateral temporal visual field defects, and no intracranial AVM. Both macular SD-OCT findings showed multiple large inner retinal vessels that created a prominent shadowing artifact, retinal thickening, and speckling and heterogeneity of inner retinal layers. PMID- 25828824 TI - A case of familial exudative vitreoretinopathy identified after genetic testing. AB - We report the case of a 21-month-old girl who was found to have familial exudative vitreoretinopathy after genetic testing revealed a genetic deletion at 7q22. She had previously been followed for exotropia; however, fundus examinations in the office were thought to be normal. After the pediatric geneticist identified the link between 7q22 deletions and vitreoretinopathies an examination under anesthesia was performed. Fluorescein angiography during this examination confirmed the presence of avascular areas of the retina. PMID- 25828825 TI - Sagging eye syndrome presenting as a form of strabismus fixus. AB - Lateral rectus-superior rectus band degeneration with aging is the major cause of sagging eye syndrome, which usually presents with small-angle esotropia or hypotropia. In contrast, heavy eye syndrome, also called myopic strabismus fixus, is characterized by profound esotropia and hypotropia with the eyeball fixed nasally. We report the case of a 71-year-old man with sagging eye syndrome presenting with strabismus fixus and no myopia. PMID- 25828826 TI - Design, synthesis and biological activity of novel asymmetric C66 analogs as anti inflammatory agents for the treatment of acute lung injury. AB - Acute lung injury (ALI) is a leading cause of morbidity and mortality in critically-ill patients. Previously, we reported that a symmetric mono-carbonyl analog of curcumin, (C66), exhibits enhanced stability and was found to have efficacy and be involved in potential cytokines inhibition. In the present study, a series of novel asymmetric C66 analogs were designed and synthesized. A majority of them effectively inhibited the LPS-induced expression of TNF-alpha and IL-6. Significantly, compound 4b2 was found to effectively reduce LPS-induced pulmonary inflammation, as reflected by reductions in concentration of total protein, inflammatory cell count as well as the lung W/D ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, in vivo administration of 4b2 resulted in remarkable improvement in histopathological changes of lung in rats. PMID- 25828827 TI - Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives as potential tubulin assembling inhibitors. AB - A series of novel pyrazoline-containing derivatives (15-47) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC50 = 0.07 MUM, 0.05 MUM, 0.03 MUM, respectively) and the tubulin polymerization inhibitory activity (IC50 = 1.88 MUM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin. PMID- 25828828 TI - Thermoluminescence properties of lithium magnesium borate glasses system doped with dysprosium oxide. AB - We report the impact of dysprosium (Dy(3+)) dopant and magnesium oxide (MgO) modifier on the thermoluminescent properties of lithium borate (LB) glass via two procedures. The thermoluminescence (TL) glow curves reveal a single prominent peak at 190 degrees C for 0.5 mol% of Dy(3+). An increase in MgO contents by 10 mol% enhances the TL intensity by a factor of 1.5 times without causing any shift in the maximum temperature. This enhancement is attributed to the occurrence of extra electron traps created via magnesium and the energy transfer to trivalent Dy(3+) ions. Good linearity in the range of 0.01-4 Gy with a linear correlation coefficient of 0.998, fading as low as 21% over a period of 3 months, excellent reproducibility without oven annealing and tissue equivalent effective atomic numbers ~8.71 are achieved. The trap parameters, including geometric factor (MUg), activation energy (E) and frequency factor (s) associated with LMB:Dy are also determined. These favorable TL characteristics of prepared glasses may contribute towards the development of Li2O-MgO-B2O3 radiation dosimeters. PMID- 25828829 TI - Ethionamide-induced Pellagra. AB - Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antituberculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and treatment with nicotinamide can prevent life-threatening complications. To date, only three cases have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that resolved after the administration of niacin. PMID- 25828830 TI - Prevalence of Dicrocoelium dendriticum ova in Ghanaian school children. PMID- 25828831 TI - Anemia among school children in eastern Nepal. AB - Anemia is one of the most common public health problems in developing countries like Nepal. This study was done to find the prevalence of anemia among the children aged 4-13 years in eastern Nepal. A cross-sectional study was conducted in 2012 in four districts (Morang, Udayapur, Bhojpur and Ilam) of eastern Nepal to find the prevalence of anemia among the school children of eastern Nepal. Children aged 4-13 years were selected randomly from different schools of above districts and 618 venous blood samples were collected. Hemoglobin level was estimated by using cyanmethemoglobin method. The mean hemoglobin level was 12.2 +/- 1.82 gm/dl. About 37.9% (n = 234) children were found anemic. Anemia prevalence was 42.4% (n = 78), 31.6% (n = 60), 45.3% (n = 48) and 34.8% (n = 48) among school children of Morang, Udayapur, Bhojpur and Ilam district, respectively. The study finds anemia as a significant health problem among the school children of eastern Nepal. PMID- 25828832 TI - Human milk banking and milk kinship: Perspectives of mothers in a Muslim country. AB - AIM: The present study aims to determine the knowledge, attitudes and views of mothers regarding infant feeding, breast milk, wet-nursing, milk kinship and human milk banks. METHODS: This descriptive cross-sectional study was composed of 1042 mothers who delivered at two different hospitals in Turkey. RESULTS: Almost half of the participating mothers, 49.9%, agreed with the establishment of alternative HMBs in Turkey. Only 7.7% of the mothers in this study expressed views in favour of the establishment of Western-style HMBs. Approximately half of the mothers (42.4%) indicated that they were against the establishment of any kind of HMBs in Turkey. Only 9.2% of the mothers in this study stated that they would volunteer to donate their breast milk to the Western-style HMBs, and only 6.9% of the mothers approved obtaining milk from this type of HMB. Finally, 44.2% of the mothers stated that they would donate their breast milk to the alternative HMBs, and 31.9% of the mothers approved obtaining milk from this type of HMB. CONCLUSION: This is the first study conducted among mothers in a Muslim community about issues such as infant feeding, breast milk, wet-nursing, milk kinship and HMBs. The majority of the mothers in this study are against the establishment of Western-style HMBs, whereas they have a more positive response to an alternative HMB when their religious concerns are relieved. PMID- 25828833 TI - Out-of-pocket nonmedical expenses associated with out-patient treatment of common childhood illnesses. AB - BACKGROUND: Out-of-pocket expenses, medical and non-medical, have an impoverishing effect on the family. OBJECTIVE: Determine non-medical out-of pocket expenses incurred during out-patient attendance for primary care services. METHODS: A descriptive survey was undertaken at a rural medical college using interviewer-administered questionnaire to parents of children <6 years over a period of 6 weeks. Seventy-six participants were interviewed for collecting demographic data and actual cost on travel and meals. RESULTS: Median expenditure for travel was Indian rupees (INR) 20 with inter-quartile range (IQR) 14-48 and on food it was INR 110 with IQR 40-155. Median total expenditure on the visit was INR 122 with IQR 61-220. Among those who travelled >5 km, 36% attendance was for respiratory complaints, 27% with fever and as many as 86% for vaccination. CONCLUSION: Families in rural India have substantial costs incurred in OPD attendance, most of which is for preventive health care such as immunization. PMID- 25828834 TI - Influenza virus infections in the tropics during the first year of life. AB - Pediatric influenza virus infections in the tropics, particularly during infancy, are not well described. We identified influenza virus infections among infants with non-dengue acute undifferentiated febrile illnesses in San Pablo, Laguna, Philippines, as part of an ongoing clinical study of dengue virus infections during infancy. We found that 31% of infants with non-dengue acute undifferentiated febrile illnesses in San Pablo, Laguna, Philippines, had influenza virus infections. The majority were influenza A virus infections and outpatient cases. The infant ages were 11.1 [9.8-13.0] months (median [95% confidence interval]), and the cases clustered between June and December. Influenza episodes are a common cause of non-dengue acute undifferentiated febrile illnesses in the tropics during the first year of life. PMID- 25828835 TI - Editorial: Faux amis: Langerin-expressing DC in humans and mice. PMID- 25828836 TI - Editorial: Crossing the divide: a novel Cd8 enhancer with activity in CTLs and CD8alphaalpha+ dendritic cells. PMID- 25828837 TI - Traumatic atrial myxoma rupture mimicking post-concussive symptoms. PMID- 25828838 TI - Isolated blepharoptosis may point to HIV-associated Burkitt's lymphoma. PMID- 25828839 TI - Osteotomy of the greater trochanter: effect on gluteus medius function. AB - PURPOSE: Advancement of the greater trochanter alters the function of the gluteus medius muscle. However, with the exception of clinical studies and biomechanical lever arm studies, no publications that analyze the consequences of advancement of the greater trochanter on the muscle function exist. The aim of the study was to analyze the mechanical changes of gluteus medius after osteotomy of the greater trochanter in a lab setting. METHODS: An anatomical study of origin and insertion of the gluteus medius was carried out on four hips. Based on the dissections, a string model was developed dividing the muscle into five sectors. Changes in muscle fiber length were measured for every 10 degrees of flexion, internal and external rotation and abduction with the trochanter in anatomic, proximalized and distalized positions. RESULTS: Distalization of the trochanter leads to an imbalance of muscle action, moving the isometric sector of the muscle anteriorly with more muscle sectors being active during flexion and less during extension. Stretching of the muscle increases passive forces but decreases the force generation capacity of the muscle and at the same time increased muscle fiber excursion may require more energy consumption, which may explain earlier fatigue of the abductor musculature after distalization of the trochanter. For abduction, distalization of the muscle attachment leads to a change in contraction pattern from isometric to isotonic. Optimal balancing and excursion of the muscle is when the tip of the greater trochanter is at level with the hip rotation center. CONCLUSIONS: In hips with high riding trochanter, the optimal position is at the level of the center of hip rotation. Excessive distalization should be avoided. As the conclusions and considerations are based on a lab setting, transfer to clinical practice may not necessarily apply. PMID- 25828840 TI - Not hating what you see: Self-compassion may protect against negative mental health variables connected to self-objectification in college women. AB - Self-objectification is related to maladaptive mental health variables, but little is known about what could ameliorate these associations. Self-compassion, a construct associated with mindfulness, involves taking a non-judgmental attitude toward the self. In this study, 306 college-aged women were recruited; those who were highest (n=106) and lowest (n=104) in self-compassion were retained for analyses. Levels of body surveillance, body shame, depression, and negative eating attitudes were lower in the high self-compassion group. Furthermore, the fit of a path model wherein body surveillance related to body shame, which, in turn, related to negative eating attitudes and depressive symptomatology was compared for each group, controlling for body mass index. The model fit significantly differently such that the connections between self objectification and negative body and eating attitudes were weaker in the high self-compassion group. Treatment implications of self-compassion as a potential means to interrupt the self-objectification process are discussed. PMID- 25828841 TI - Confirmatory factor analysis of the Drive for Muscularity Scale-S (DMS-S) and Male Body Attitudes Scale-S (MBAS-S) among male university students in Buenos Aires. AB - Several studies have demonstrated that men express body dissatisfaction differently than women. Although specific instruments that address body dissatisfaction in men have been developed, only a few have been validated in Latin-American male populations. The aim of this study was to reassess the factor structure of the Spanish versions of the Drive for Muscularity Scale (DMS-S) and the Male Body Attitudes Scale (MBAS-S) in an Argentinian sample. A cross sectional study was conducted among 423 male students to examine: the factorial structure (confirmatory factor analysis), the internal consistency reliability, and the concurrent, convergent and discriminant validity of both scales. Results replicated the two factor structures for the DMS-S and MBAS-S. Both scales showed excellent levels of internal consistency, and various measures of construct validity indicated that the DMS-S and MBAS-S were acceptable and valid instruments to assess body dissatisfaction in Argentinian males. PMID- 25828842 TI - The Breast Size Rating Scale: Development and psychometric evaluation. AB - Existing measures of breast size dissatisfaction have poor ecological validity or have not been fully evaluated in terms of psychometric properties. Here, we report on the development of the Breast Size Rating Scale (BSRS), a novel measure of breast size dissatisfaction consisting of 14 computer-generated images varying in breast size alone. Study 1 (N=107) supported the scale's construct validity, insofar as participants were able to correctly order the images in terms of breast size. Study 2 (N=234) provided evidence of the test-retest reliability of BSRS-derived scores after 3 months. Studies 3 (N=730) and 4 (N=234) provided evidence of the convergent validity of BSRS-derived breast size dissatisfaction scores, which were significantly associated with a range of measures of body image. The BSRS provides a useful tool for researchers examining women's breast size dissatisfaction. PMID- 25828843 TI - Do fluoroscopy systems influence the level of scatter radiation exposure during endoscopic procedures? PMID- 25828844 TI - Multi-institutional retrospective cohort study of patients with severe pulmonary hypertension associated with respiratory diseases. AB - BACKGROUND AND OBJECTIVE: Pulmonary hypertension (PH) is often associated with respiratory diseases, but only a small number of patients present with severe PH defined as mean pulmonary arterial pressure >= 35 mm Hg. We here conducted a multicenter, retrospective study of patients with severe PH associated with respiratory diseases (R-PH) to reveal their demographics, treatment, prognosis and determinants of prognosis. METHODS: From 101 patients with severe R-PH collected by postal survey at the first stage, 70 patients with four major diseases (chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis with emphysema (CPFE), interstitial pneumonia associated with connective tissue disease (CTD-IP), interstitial pneumonia (IP)) and normal pulmonary arterial wedge pressure were studied for clinical characteristics, treatment and prognosis. RESULTS: Three-year survival rates were 50% for COPD (n = 18), 35.7% for IP (n = 19) and 68.1% for CTD-IP (n = 20), and the 2-year survival rate for CPFE (n = 13) was only 22.6%. Eighty-one per cent of patients had been treated with pharmacotherapy specific for pulmonary arterial hypertension. Those patients who had received phosphodiesterase-5 inhibitors (PDE-5I) displayed significantly better survival from the date of diagnosis than those who had not (3-year survival: 61.8% vs 20.0% P < 0.0001), especially in the IP, CTD-IP and CPFE groups. Multivariate analysis also revealed that treatment with PDE-5I was a positive prognostic factor. CONCLUSIONS: We here demonstrated the dismal prognosis of patients with severe R-PH. The remarkably better survival in those patients who had received PDE-5I warrants and facilitates future prospective randomized studies in this particular population. PMID- 25828846 TI - Characterisation of an unusual telomere motif (TTTTTTAGGG)n in the plant Cestrum elegans (Solanaceae), a species with a large genome. AB - The characterization of unusual telomere sequence sheds light on patterns of telomere evolution, maintenance and function. Plant species from the closely related genera Cestrum, Vestia and Sessea (family Solanaceae) lack known plant telomeric sequences. Here we characterize the telomere of Cestrum elegans, work that was a challenge because of its large genome size and few chromosomes (1C 9.76 pg; n = 8). We developed an approach that combines BAL31 digestion, which digests DNA from the ends and chromosome breaks, with next-generation sequencing (NGS), to generate data analysed in RepeatExplorer, designed for de novo repeats identification and quantification. We identify an unique repeat motif (TTTTTTAGGG)n in C. elegans, occurring in ca. 30 400 copies per haploid genome, averaging ca. 1900 copies per telomere, and synthesized by telomerase. We demonstrate that the motif is synthesized by telomerase. The occurrence of an unusual eukaryote (TTTTTTAGGG)n telomeric motif in C. elegans represents a switch in motif from the 'typical' angiosperm telomere (TTTAGGG)n . That switch may have happened with the divergence of Cestrum, Sessea and Vestia. The shift in motif when it arose would have had profound effects on telomere activity. Thus our finding provides a unique handle to study how telomerase and telomeres responded to genetic change, studies that will shed more light on telomere function. PMID- 25828845 TI - Physicochemical and biomechanical stimuli in cell-based articular cartilage repair. AB - Articular cartilage is a unique load-bearing connective tissue with a low intrinsic capacity for repair and regeneration. Its avascularity makes it relatively hypoxic and its unique extracellular matrix is enriched with cations, which increases the interstitial fluid osmolarity. Several physicochemical and biomechanical stimuli are reported to influence chondrocyte metabolism and may be utilized for regenerative medical approaches. In this review article, we summarize the most relevant stimuli and describe how ion channels may contribute to cartilage homeostasis, with special emphasis on intracellular signaling pathways. We specifically focus on the role of calcium signaling as an essential mechanotransduction component and highlight the role of phosphatase signaling in this context. PMID- 25828847 TI - Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. PMID- 25828848 TI - An organic solvent-stable lipase from a newly isolated Staphylococcus aureus ALA1 strain with potential for use as an industrial biocatalyst. AB - In this study, a new strain, ALA1, was identified as Staphylococcus aureus by biochemical tests, and its 16S ribosomal DNA sequence was isolated from dromedary milk. ALA1 lipase production was optimized in shake flask experiments and measured with varying pH (3-11), temperature (20-55 degrees C) and substrate concentrations. The maximum lipase production was recorded at pH 8 and 30 degrees C for up to 30 H of culture period for the S. aureus ALA1 strain. Among the substrates tested, selected carbon sources, xylose, nitrogen source, yeast extract, and olive oil (1%) were suitable for maximizing lipase production. The effects of surfactants were investigated and showed that Tween 20, Tween 80, and Triton X-100 prevented lipase production. Interestingly, isolate ALA1 was able to grow in high concentrations of benzene or toluene (up to 50% (v/v)). Moreover, the lipolytic activity of the S. aureus ALA1 lipase was stimulated by diethyl ether, whereas almost 100% of S. aureus ALA1 lipase activity was retained in 25% acetone, acetonitrile, benzene, 2-propanol, ethanol, methanol, or toluene. Because of its stability in organic solvent, the S. aureus ALA1 lipase was used as a biocatalyst to synthesize high levels of added value molecules. S. aureus ALA1 lipase could be considered as an ideal choice for applications in detergent formulations because of its high stability and compatibility with various surfactants, oxidizing agents, and commercial detergents. PMID- 25828849 TI - Imaging genetics studies on monoaminergic genes in major depressive disorder. AB - Although depression is the leading cause of disability worldwide, current understanding of the neurobiology of depression has failed to be translated into clinical practice. Major depressive disorder (MDD) pathogenesis is considered to be significantly influenced by multiple risk genes, however genetic effects are not simply expressed at a behavioral level. Therefore the concept of endophenotype has been applied in psychiatric genetics. Imaging genetics applies anatomical or functional imaging technologies as phenotypic assays to evaluate genetic variation and their impact on behavior. This paper attempts to provide a comprehensive review of available imaging genetics studies, including reports on genetic variants that have most frequently been linked to MDD, such as the monoaminergic genes (serotonin transporter gene, monoamine oxidase A gene, tryptophan hydroxylase-2 gene, serotonin receptor 1A gene and catechol-O-methyl transferase gene), with regard to key structures involved in emotion processing, such as the hippocampus, amygdala, anterior cingulate cortex and orbitofrontal cortex. PMID- 25828850 TI - Extended full-genome phylogenetic analysis of the first human A/H5N1 avian influenza case in North America. PMID- 25828851 TI - Accuracy Comparison of Implant Impression Techniques: A Systematic Review. AB - BACKGROUND: Several studies link the seamless fit of implant-supported prosthesis with the accuracy of the dental impression technique obtained during acquisition. In addition, factors such as implant angulation and coping shape contribute to implant misfit. PURPOSE: The aim of this study was to identify the most accurate impression technique and factors affecting the impression accuracy. MATERIAL AND METHODS: A systematic review of peer-reviewed literature was conducted analyzing articles published between 2009 and 2013. The following search terms were used: implant impression, impression accuracy, and implant misfit. A total of 417 articles were identified; 32 were selected for review. RESULTS: All 32 selected studies refer to in vitro studies. Fourteen articles compare open and closed impression technique, 8 advocate the open technique, and 6 report similar results. Other 14 articles evaluate splinted and non-splinted techniques; all advocating the splinted technique. Polyether material usage was reported in nine; six studies tested vinyl polysiloxane and one study used irreversible hydrocolloid. Eight studies evaluated different copings designs. Intraoral optical devices were compared in four studies. CONCLUSIONS: The most accurate results were achieved with two configurations: (1) the optical intraoral system with powder and (2) the open technique with splinted squared transfer copings, using polyether as impression material. PMID- 25828852 TI - Higher Dietary Calcium Intakes Are Associated With Reduced Risks of Fractures, Cardiovascular Events, and Mortality: A Prospective Cohort Study of Older Men and Women. AB - The aim of this population-based, prospective cohort study was to investigate long-term associations between dietary calcium intake and fractures, non-fatal cardiovascular disease (CVD), and death from all causes. Participants were from the Melbourne Collaborative Cohort Study, which was established in 1990 to 1994. A total of 41,514 men and women (~99% aged 40 to 69 years at baseline) were followed up for a mean (SD) of 12 (1.5) years. Primary outcome measures were time to death from all causes (n = 2855), CVD-related deaths (n = 557), cerebrovascular disease-related deaths (n = 139), incident non-fatal CVD (n = 1827), incident stroke events (n = 537), and incident fractures (n = 788). A total of 12,097 participants (aged >=50 years) were eligible for fracture analysis and 34,468 for non-fatal CVD and mortality analyses. Mortality was ascertained by record linkage to registries. Fractures and CVD were ascertained from interview ~13 years after baseline. Quartiles of baseline energy-adjusted calcium intake from food were estimated using a food-frequency questionnaire. Hazard ratios (HR) and odds ratios (OR) were calculated for quartiles of dietary calcium intake. Highest and lowest quartiles of energy-adjusted dietary calcium intakes represented unadjusted means (SD) of 1348 (316) mg/d and 473 (91) mg/d, respectively. Overall, there were 788 (10.3%) incident fractures, 1827 (9.0%) incident CVD, and 2855 people (8.6%) died. Comparing the highest with the lowest quartile of calcium intake, for all-cause mortality, the HR was 0.86 (95% confidence interval [CI] 0.76-0.98, p(trend) = 0.01); for non-fatal CVD and stroke, the OR was 0.84 (95% CI 0.70-0.99, p(trend) = 0.04) and 0.69 (95% CI 0.51-0.93, p(trend) = 0.02), respectively; and the OR for fracture was 0.70 (95% CI 0.54-0.92, p(trend) = 0.004). In summary, for older men and women, calcium intakes of up to 1348 (316) mg/d from food were associated with decreased risks for fracture, non-fatal CVD, stroke, and all-cause mortality. PMID- 25828853 TI - Catheter Ablation of Arrhythmia During Pregnancy. AB - Cardiac arrhythmia as a complication of pregnancy can be problematic to maternal health and fetal life and development. Catheter ablation of tachyarrhythmias during pregnancy has been successfully performed in selected patients with limited experience. Techniques to limit maternal and fetal radiation exposure, including intracardiac echo and electroanatomic mapping systems, are particularly important in this setting. Specific accommodations are necessary in the care of the gravid patient during catheter ablation. PMID- 25828854 TI - Analysis of unique mutations in the LPAR6 gene identified in a Japanese family with autosomal recessive woolly hair/hypotrichosis: Establishment of a useful assay system for LPA6. AB - BACKGROUND: Woolly hair (WH) is a hair shaft anomaly characterized by tightly curled hair and is frequently associated with hypotrichosis. Non-syndromic forms of WH can show either autosomal dominant or recessive inheritance. The autosomal recessive form of WH (ARWH) is caused by mutations in either lipase H (LIPH) or lysophosphatidic acid receptor 6 (LPAR6) gene, encoding an LPA-producing enzyme PA-PLA1alpha and an LPA receptor LPA6, respectively. OBJECTIVE: To define the molecular basis of ARWH/hypotrichosis in a Japanese family. METHODS: We performed mutational analysis of candidate genes and a series of expression and in vitro functional analyses, which we improved in this study, to determine the consequences resulting from the mutations identified in the family. RESULTS: Novel compound heterozygous LPAR6 mutations were identified in the patient. One was a nonsense mutation c.756T>A (p.Tyr252*); the other was a large insertion mutation within the promoter region of LPAR6. Expression studies detected LPAR6 mRNA only from the c.756T>A allele in the patient's hair follicles, suggesting that the insertion in the other allele disrupted the LPAR6 promoter and thus led to a failure of transcription. Furthermore, an improved LPA6 functional assay developed in this study demonstrated aberrant expression and a subsequent loss of function of the p.Tyr252*-mutant protein. CONCLUSION: Through establishing a useful assay system for LPA6, our results further underscore the crucial roles of LPAR6 in hair follicle development and hair growth in humans at molecular levels. PMID- 25828855 TI - NF-kappaB-regulated transcriptional control of CLCA in a differentiated mouse keratinocyte line. AB - BACKGROUND: CLCA was postulated to be a calcium-activated chloride channel accessory protein. Recent reports indicate that CLCA isoforms are likely to be expressed in different layers of the stratified epithelium of the skin. OBJECTIVE: The present study investigated the transcriptional mechanism by which murine CLCA2 (mCLCA2) is expressed in the transformed keratinocyte line Pam212 that can differentiate. METHODS: A luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, reverse transcription-PCR, and immunocytochemistry were performed using Pam212 cells. RESULTS: Promoter activity of mCLCA2 was inhibited profoundly by site-directed mutagenesis of a putative nuclear factor-kappaB (NF-kappaB) binding site and by treatment with siRNA against p65. ChIP and transcription factor assays showed the specific association of endogenously activated p65 protein with the NF-kappaB binding domain. As confirmed by the nuclear translocation of p65, tumor necrosis factor alpha and caffeic acid phenethyl ester (CAPE) increased and decreased mCLCA2 promoter activity, respectively, but exhibited modest effects on endogenous mCLCA2 expression in cells in culture medium containing 0.05 mM Ca(2+). When the Ca(2+) concentration was raised to 1.0mM, the mRNA and protein levels of mCLCA2 increased as well as those of the differentiation markers keratin 1 (K1) and K10. CAPE profoundly suppressed only the Ca(2+)-triggered expression of mCLCA2, not K1 or K10. Immunohistochemistry of native skin and organotypic 3D cultures confirmed the distribution of the CLCA2 homolog in differentiated cells. CONCLUSION: The present study revealed for the first time that basal NF-kappaB activity is involved in the Ca(2+)-dependent regulation of mCLCA2 expression in a mouse keratinocyte line. PMID- 25828856 TI - Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. AB - OBJECTIVE: To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee. DATA EXTRACTION: Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration's tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions. RESULTS: 12 reports (13 randomised trials) were included. There was "high quality" evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference -0.5, 95% confidence interval 2.9 to 1.9) and disability (0.4, -1.7 to 2.5) or improving quality of life (0.4, 0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was "high quality" evidence that paracetamol provides a significant, although not clinically important, effect on pain (-3.7, -5.5 to 1.9) and disability (-2.9, -4.9 to -0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. "High quality" evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain. CONCLUSIONS: Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42013006367. PMID- 25828857 TI - Managing back pain and osteoarthritis without paracetamol. PMID- 25828858 TI - Evidence and rhetoric about access to UK primary care. PMID- 25828859 TI - Experiences of overweight/obese adolescents in navigating their home food environment. AB - OBJECTIVE: To explore perceived factors that impede or facilitate healthful eating within the home environment among overweight/obese adolescents. DESIGN: In the present qualitative photovoice study, participants were instructed to take photographs of things that made it easier or harder to make healthful food choices at home. Digital photographs were reviewed and semi-structured interviews were conducted to promote discussion of the photographs. Data were analysed using constant comparative analysis. SETTING: Vancouver, Canada, in 2012-2013. SUBJECTS: Twenty-two overweight/obese adolescents who completed a family-based lifestyle modification intervention. RESULTS: The mean age of participants was 14 (sd 1.9) years, 77% were female and their mean BMI Z-score was 2.4 (sd 0.6). Adolescents talked about six aspects of the home environment that influenced their eating habits (in order of frequency): home cooking, availability and accessibility of foods/beverages, parenting practices, family modelling, celebrations and screen use/studying. In general, homes with availability of less healthful foods, where family members also liked to eat less healthful foods and where healthier foods were less abundant or inaccessible were described as barriers to healthful eating. Special occasions and time spent studying or in front of the screen were also conducive to less healthful food choices. Home cooked meals supported adolescents in making healthier food choices, while specific parenting strategies such as encouragement and restriction were helpful for some adolescents. CONCLUSIONS: Adolescents struggled to make healthful choices in their home environment, but highlighted parenting strategies that were supportive. Targeting the home food environment is important to enable healthier food choices among overweight/obese adolescents. PMID- 25828860 TI - Prevalence and predictors of self-reported student maltreatment by teachers in South Korea. AB - This study first investigated the prevalence of emotional and physical maltreatment by teachers in South Korea and then identified factors that predict student maltreatment by teachers. Specific areas of interest were the associations between student demographic characteristics (gender and grade level), family (economic status), and school experience (academic performance and student-teacher relationships) and how these characteristics were related to student maltreatment. Data were obtained by questionnaire from a random sample of 1,777 students in middle schools in Seoul, the largest metropolitan area, and its surrounding province, Gyeonggi-Do. Questionnaires were completed during school time. All information was collected anonymously. Of those surveyed, 18.2% reported emotional maltreatment by teachers and 24.3% physical maltreatment. Overall, 30.7% reported being either emotionally or physically mistreated by teachers at least once in the previous year. Hierarchical regression analysis showed that gender, family economic status, academic performance, and student teacher relationships were predictors of student maltreatment by teachers. The results have practical and policy implications for the design of programs that will results in altering abusive teacher classroom behavior. PMID- 25828861 TI - Posttraumatic stress avoidance symptoms as mediators in the development of alcohol use disorders after exposure to childhood sexual abuse in a Swiss community sample. AB - This study examined the role of posttraumatic stress disorder (PTSD) symptoms of re-experience, avoidance, and hyperarousal in the relationship between different types of trauma and alcohol use disorders (AUD). We used data from 731 trauma exposed individuals who participated in the first wave of the PsyCoLaus-study. Trauma characteristics were assessed relatively to the occurrence of lifetime PTSD symptoms and AUD. The results suggest that lifetime and childhood sexual abuse as well as overall childhood trauma were directly linked to AUD and PTSD symptoms, in particular to avoidance symptoms. From single symptom clusters PTSD avoidance was found to specifically mediate the trauma-AUD pathway. Both childhood and sexual trauma strongly contribute to the comorbidity of PTSD and AUD and avoidance-type symptoms appear to play a central role in maintaining this association. Hence, the alleviation of avoidance symptoms might be an important target for therapeutic intervention among victims of sexual abuse before specific addiction treatment is initiated. PMID- 25828862 TI - Multifold fluorescence enhancement in nanoscopic fluorophore-clay hybrids in transparent aqueous media. AB - Valuable emissive properties of organic fluorophores have become indispensable analytical tools in biophotonics, but frequently suffer from low solubilities and radiationless deactivation in aqueous media, that is, in biological ambience as well. In this report, nanoscaled dye-clay hybrids based on laponite, Na0.7 {(Li0.3 Mg5.5 )[Si8 O20 (OH)4 ]}, are taken advantage of to solubilize neutral dyes, which are natively not encountered in water. Previously reported efficiency and solubility bottlenecks of such hybrids can to a large extent be overcome by comparably simple chemical measures, as demonstrated here for two prominent examples, the fluorescent dyes Nile Red and Coumarin 153. On controlled co adsorption of small bifunctional quaternary ammonium ions (Me3 N(+) C2 H5 OH and Me3 N(+) C2 H5 NH2 ) we observed an outright efficiency boost by an order of magnitude, and a 30-fold brightness gain. Even at higher concentrations, transparency and stability of the hybrid dispersions are retained, rendering them useful for employment as optically functional nanoparticles in bioassays and beyond. PMID- 25828863 TI - Discovery, Synthesis, and Biological Evaluation of Thiazoloquin(az)olin(on)es as Potent CD38 Inhibitors. AB - A series of thiazoloquin(az)olinones were synthesized and found to have potent inhibitory activity against CD38. Several of these compounds were also shown to have good pharmacokinetic properties and demonstrated the ability to elevate NAD levels in plasma, liver, and muscle tissue. In particular, compound 78c was given to diet induced obese (DIO) C57Bl6 mice, elevating NAD > 5-fold in liver and >1.2 fold in muscle versus control animals at a 2 h time point. The compounds described herein possess the most potent CD38 inhibitory activity of any small molecules described in the literature to date. The inhibitors should allow for a more detailed assessment of how NAD elevation via CD38 inhibition affects physiology in NAD deficient states. PMID- 25828864 TI - Functional impairment in patients with major depression in clinical remission: results from the VIVAL-D-Rem, a nationwide, naturalistic, cross-sectional survey. AB - In recent years, the standard for successful treatment of major depression has switched from response to remission; however, little is known about patients who have achieved remission, but still have some residual symptoms and whether they regain previous levels of functioning. In a large, nationwide, cross-sectional, naturalistic survey (VIVAL-D) of 907 patients with major depression treated with a new course of an antidepressant in 41 Italian community psychiatric centers, patients with a Hamilton Rating Scale for Depression, 17-item version (HAM-D17) score up to 14 were selected (n=499). Of these, 169 were considered to be in remission (HAM-D17 <= 7) and the other 330 to be mildly depressed. Their level of functioning was evaluated using the SF-12. Only a few (3%) patients in remission were completely symptom free; most were affected by residual symptoms. Patients in remission had better SF-12 scores than those with mild depression, but their functioning was significantly worse than general population norms. In the logistic regression analysis, the HAM-D17 total score and individual items were predictive of poor functioning. Analysis of sensitivity and specificity values showed that a lower cut-off score (4/5) of the HAM-D17 scale was best for predicting poor performance so that a reconsideration of the usual cut-off for remission of 7/8 for HAM-D17 seems overdue. PMID- 25828865 TI - High sensitivity flexible Lamb-wave humidity sensors with a graphene oxide sensing layer. AB - This paper reports high performance flexible Lamb wave humidity sensors with a graphene oxide sensing layer. The devices were fabricated on piezoelectric ZnO thin films deposited on flexible polyimide substrates. Two resonant peaks, namely the zero order antisymmetric (A0) and symmetric (S0) mode Lamb waves, were observed and fitted well with the theoretical analysis and modelling. With graphene oxide microflakes as the sensing layer, the sensing performance of both wave modes was investigated. The humidity sensitivity of the A0 mode is 145.83 ppm per %RH (at humidity 85%RH), higher than that of S0 mode of 89.35 ppm per %RH. For the first time, we have demonstrated that the flexible humidity sensors work as usual without noticeable deterioration in performance even under severe bending conditions up to 1500 MUepsilon. Also the sensors showed an excellent stability upon repeated bending for thousand times. All the results demonstrated that the Lamb wave flexible humidity sensors have a great potential for application in flexible electronics. PMID- 25828866 TI - Preoperative Aspirin-dosing Strategy and Mortality After Coronary Artery Bypass Graft Surgery. PMID- 25828867 TI - Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Summary and recommendations. PMID- 25828868 TI - Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy. AB - Abeta-related cerebral amyloid angiopathy (CAA) is a major cause of primary non traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a ~1.5-fold increased APP expression, resulting in Abeta overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3'untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3'UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3'UTR sequence variants as genetic determinants of Abeta-CAA. PMID- 25828870 TI - Functional characterization of a conserved archaeal viral operon revealing single stranded DNA binding, annealing and nuclease activities. AB - The majority of archaeal viral genes are of unknown function hindering our understanding of the virus life cycle and viral interactions with their host. Here, we first describe functional characterization of ORF131b (gp17) and ORF436 (gp18) of Sulfolobus islandicus rod-shaped virus 2 (SIRV2), both encoding proteins of unknown function and forming an operon with ORF207 (gp19). SIRV2 gp17 was found to be a single-stranded DNA (ssDNA) binding protein different in structure from all previously characterized ssDNA binding proteins. Mutagenesis of a few conserved basic residues suggested a U-shaped binding path for ssDNA. The recombinant gp18 showed an ssDNA annealing activity often associated with helicases and recombinases. To gain insight into the biological role of the entire operon, we characterized SIRV2 gp19 and showed it to possess a 5' -> 3' ssDNA exonuclease activity, in addition to the previously demonstrated ssDNA endonuclease activity. Further, in vitro pull-down assay demonstrated interactions between gp17 and gp18 and between gp18 and gp19 with the former being mediated by the intrinsically disordered C-terminus of gp17. The strand displacement replication mode proposed previously for rudiviruses and the close interaction among the ssDNA binding, annealing and nuclease proteins strongly point to a role of the gene operon in genome maturation and/or DNA recombination that may function in viral DNA replication/repair. PMID- 25828871 TI - Engaging Immigrants in Early Psychosis Treatment: A Clinical Challenge. AB - OBJECTIVE: The study compared engagement in treatment and medication adherence of immigrants and nonimmigrants in early intervention services for persons with first-episode psychosis. METHODS: This two-year longitudinal prospective cohort study recruited patients with first-episode psychosis who were entering early intervention services in Montreal, Canada (N=223). Data on sociodemographic characteristics, symptoms, and social functioning were collected annually. RESULTS: At two years, immigrants had more than three times the odds of attrition than nonimmigrants after the analysis controlled for potential confounding factors (first-generation immigrants: odds ratio [OR]=3.11, 95% confidence interval [CI]=1.01-9.57, p=.049); second-generation immigrants: OR=3.65, CI=1.07 12.50, p=.039). Medication adherence was similar among those who remained in the programs. CONCLUSIONS: During the two years after entering a program for first episode psychosis, immigrants were more likely than nonimmigrants to disengage from treatment. Further research is warranted to understand this phenomenon and to improve the ability of services to engage immigrants with first-episode psychosis. PMID- 25828869 TI - Non-coding RNAs and hypertension-unveiling unexpected mechanisms of hypertension by the dark matter of the genome. AB - Hypertension is a major risk factor of cardiovascular diseases and a most important health problem in developed countries. Investigations on pathophysiology of hypertension have been based on gene products from coding region that occupies only about 1% of total genome region. On the other hand, non coding region that occupies almost 99% of human genome has been regarded as "junk" for a long time and went unnoticed until these days. But recently, it turned out that noncoding region is extensively transcribed to non-coding RNAs and has various functions. This review highlights recent updates on the significance of non-coding RNAs such as micro RNAs and long non-coding RNAs (lncRNAs) on the pathogenesis of hypertension, also providing an introduction to basic biology of noncoding RNAs. For example, microRNAs are associated with hypertension via neuro-fumoral factor, sympathetic nerve activity, ion transporters in kidneys, endothelial function, vascular smooth muscle phenotype transformation, or communication between cells. Although reports of lncRNAs on pathogenesis of hypertension are scarce at the moment, new lncRNAs in relation to hypertension are being discovered at a rapid pace owing to novel techniques such as microarray or next-generation sequencing. In the clinical settings, clinical use of non-coding RNAs in identifying cardiovascular risks or developing novel tools for treating hypertension such as molecular decoy or mimicks is promising, although improvement in chemical modification or drug delivery system is necessary. PMID- 25828872 TI - Surveys of Police Chiefs and Sheriffs and of Police Officers About CIT Programs. AB - OBJECTIVE: Two surveys were conducted on the crisis intervention team (CIT) model, a police-based program designed to improve responses to individuals with mental illnesses. METHODS: Data were collected between July and September 2013 from 171 police chiefs and sheriffs (42 had implemented CIT in their agency), and 353 law enforcement officers (273 had CIT training) in Georgia. RESULTS: Police chiefs and sheriffs reported barriers to implementing CIT, such as not having enough officers and insufficient access to mental health services. CIT-trained officers differed from non-CIT-trained officers only with regard to being less likely to use force in response to a man with psychotic agitation described in a vignette, when the analysis controlled for whether the officer carried an electronic control device. CONCLUSIONS: Some hypothesized differences, such as in job satisfaction and work burnout, were not observed. However, CIT-trained officers appeared to be less likely to revert to force in a situation involving psychotic agitation. PMID- 25828873 TI - Predicting Participation in Psychiatric Randomized Controlled Trials: Insights From the STEP-BD. AB - OBJECTIVE: Differences between patients who do and do not participate in randomized controlled trials (RCTs) could diminish the generalizability of results. This study examined whether RCT participants differ from non-RCT participants who are recruited from the same patient and provider population. METHODS: The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP BD) was an observational study in which participants also could enroll in an RCT during exacerbations of acute depression. The odds that a patient was enrolled in the STEP-BD acute depression RCTs (pharmacotherapy or psychotherapy) were estimated by fitting logistic regression models to STEP-BD participants with acute bipolar depression (total N=2,222; RCT, N=413; observational arm, N=1,809). Predictor variables included demographic characteristics, clinical information (including severity scales and comorbidities), and study site. The extent to which site determined RCT participation was estimated by using the area under the receiver operating characteristic curve (AUC). RESULTS: RCT participation was associated with having no insurance (odds ratio [OR]=1.58, 95% confidence interval [CI]=1.16-2.15), a Clinical Global Impression score indicating greater severity (severe versus mild: OR=1.52, CI=1.08-2.15), and site (predicted probability range 8%-31%). Site was the most significant predictor of RCT enrollment (model excluding site, AUC=.61, CI=.58-.64; full model, AUC=.70, CI=.67-.73). CONCLUSIONS: STEP-BD RCT participants differed from those in the observational arm in few clinical or demographic characteristics. Site was the strongest predictor of RCT participation. Future study is needed to understand site characteristics associated with RCT participation and whether these characteristics are associated with patient outcomes and to test these findings in usual-care settings. PMID- 25828874 TI - A potential role for family members in mental health care delivery: the family community navigation specialist. AB - OBJECTIVE: Opening Doors to Recovery (ODR) in southeast Georgia included a family community navigation specialist (F-CNS) in addition to a peer specialist and a mental health professional. This qualitative study assessed the usefulness of the F-CNS role. METHODS: Semistructured interviews were conducted with 30 respondents (ten ODR participants with serious mental illnesses; ten family members; and ten ODR leaders and team members, including two F-CNSs). Interviews were recorded and transcribed for qualitative analysis. RESULTS: Many respondents found the F-CNS to be helpful, providing psychosocial support, serving as a communication liaison, and being a team member dedicated to the family. Aspects that might require improvement include insufficient description of the F-CNS role to participants and the limited experience and training of the F-CNSs. CONCLUSIONS: The F-CNS represents an unexplored role for family members of persons with serious mental illnesses that may complement the roles of other service providers and strengthen recovery-oriented teams. PMID- 25828876 TI - Psychiatric readmissions in a community-based sample of patients with mental disorders. AB - OBJECTIVE: This study examined whether receipt of outpatient psychiatric services after hospital discharge was associated with reduced risk of readmission. METHODS: Treatment records from patients admitted to San Diego County psychiatric hospitals over a one-year period were obtained from the San Diego County Behavioral Health Services electronic health record system. A discrete-time proportional hazards model was used to examine the association of receipt of outpatient psychiatric services with readmission within 30 days of discharge from the index hospitalization. RESULTS: Of the 4,663 patients, 16% were readmitted within 30 days. In an adjusted model, receipt of outpatient therapy after discharge was associated with a greater likelihood of being readmitted (hazard ratio=1.36, 95% confidence interval=1.14-1.67), whereas receipt of case management or medication management was not associated with readmission. CONCLUSIONS: The differential risk of readmission by service type suggests a need for studies that explore reasons for an increased risk of readmission with certain types of services. PMID- 25828875 TI - Forecasting Medicaid Expenditures for Antipsychotic Medications. AB - OBJECTIVE: The ongoing transition from use of mostly branded to mostly generic second-generation antipsychotic medications could bring about a substantial reduction in Medicaid expenditures for antipsychotic medications, a change with critical implications for formulary restrictions on second-generation antipsychotics in Medicaid. This study provided a forecast of the impact of generics on Medicaid expenditures for antipsychotic medications. METHODS: Quarterly (N=816) state-level aggregate data on outpatient antipsychotic prescriptions in Medicaid between 2008 and 2011 were drawn from the Medicaid state drug utilization database. Annual numbers of prescriptions, expenditures, and cost per prescription were constructed for each antipsychotic medication. Forecasts of antipsychotic expenditures in calendar years 2016 and 2019 were developed on the basis of the estimated percentage reduction in Medicaid expenditures for risperidone, the only second-generation antipsychotic available generically throughout the study period. Two models of savings from generic risperidone use were estimated, one based on constant risperidone prices and the other based on variable risperidone prices. The sensitivity of the expenditure forecast to expected changes in Medicaid enrollment was also examined. RESULTS: In the main model, annual Medicaid expenditures for antipsychotics were forecasted to decrease by $1,794 million (48.8%) by 2016 and by $2,814 million (76.5%) by 2019. Adjustment for variable prices of branded medications and changes in Medicaid enrollment only moderately affected the magnitude of these reductions. CONCLUSIONS: Within five years, antipsychotic expenditures in Medicaid may decline to less than half their current levels. Such a spending reduction warrants a reassessment of the continued necessity of formulary restrictions for second-generation antipsychotics in Medicaid. PMID- 25828877 TI - The many faces of risk: a qualitative study of risk in outpatient involuntary treatment. AB - OBJECTIVE: This study aimed to derive a conceptualized model of risk in outpatient involuntary psychiatric treatment that has utility and meaning for stakeholders. METHODS: Thirty-eight participants-patients, caregivers, clinicians, and legal decision makers-participated in qualitative interviews about their experiences of outpatient involuntary psychiatric treatment. Interview data were analyzed by using a general inductive method. RESULTS: Six types of risk were identified: actual harm, social adversity, therapeutic outcome or compromised treatment, the system, interpersonal distress, and epistemic issues. There were overlaps between discourses on risk but variation in how different aspects of risk were emphasized by participant groups. CONCLUSIONS: A comprehensive model of risk contextualized to outpatient involuntary treatment is proposed. It incorporates domains of risk of harm to self or others, risk of social adversity, risk of excess distress, and risk of compromised treatment. This model may have instrumental value in the implementation and the scrutiny of risk-based mental health laws. PMID- 25828878 TI - System-Level Influences on the Sustainability of a Cognitive Therapy Program in a Community Behavioral Health Network. AB - OBJECTIVE: The purpose of this study was to examine influences on the sustainability of a program to implement an evidence-based psychotherapy in a mental health system. METHODS: Interviews with program administrators, training consultants, agency administrators, and supervisors (N=24), along with summaries of program evaluation data and program documentation, were analyzed with a directed content-analytic approach. RESULTS: Findings suggested a number of interconnected and interacting influences on sustainability, including alignment with emerging sociopolitical influences and system and organizational priorities; program-level adaptation and evolution; intervention flexibility; strong communication, collaboration, planning, and support; and perceived benefit. These individual factors appeared to mutually influence one another and contribute to the degree of program sustainability achieved at the system level. Although most influences were positive, financial planning and support emerged as potentially both facilitator and barrier, and evaluation of benefits at the patient level remained a challenge. CONCLUSIONS: Several factors appeared to contribute to the sustainability of a psychosocial intervention in a large urban mental health system and warrant further investigation. Understanding interconnections between multiple individual facilitators and barriers appears critical to advancing understanding of sustainability in dynamic systems and adds to emerging recommendations for other implementation efforts. In particular, implications of the findings include the importance of implementation strategies, such as long term planning, coalition building, clarifying roles and expectations, planned adaptation, evaluation, diversification of financing strategies, and incentivizing implementation. PMID- 25828879 TI - Using distance technologies to facilitate a learning collaborative to implement stagewise treatment. AB - OBJECTIVE: This report describes experiences and outcomes of an online learning collaborative focused on implementation of stagewise treatment. METHODS: Eleven participating programs convened online monthly for a year. Between meetings, program staff created an implementation plan and programs collected performance indicator data, including assessment of staff knowledge of integrated treatment for people with co-occurring disorders, whether a person's current stage of treatment was documented in his or her chart, and whether the treatments were appropriate for the stage of treatment. Descriptive statistics were used to characterize performance indicators and feedback. Wilcoxon matched-pairs signed rank tests examined changes in performance indicators over time. RESULTS: Program staff generally demonstrated significant improvements in performance indicators over time and rated the distance learning collaborative favorably. CONCLUSIONS: Distance learning collaboratives can be structured to provide opportunities for program staff to interact and learn from one another and to implement and sustain changes. PMID- 25828880 TI - Testing Alternative Definitions of Chronic Homelessness. AB - OBJECTIVE: This study examined the potential impact of a proposed change to the official federal definition of chronic homelessness. METHODS: Using administrative data from the emergency shelters in a large U.S. city, this study estimated the number of persons identified as chronically homeless under the current definition of chronic homelessness, a proposed new federal definition, and two alternative definitions and examined shelter utilization for each group. RESULTS: Fewer than half as many people were considered chronically homeless under the proposed new federal definition compared with the current definition. Persons considered chronically homeless by the proposed new definition and, to a lesser extent, by the two alternative definitions, made heavier use of shelter compared with persons who met the current definition. CONCLUSIONS: A proposed new and two alternative definitions of chronic homelessness are better suited than the existing federal definition for identifying persons with the most protracted experiences of homelessness. PMID- 25828881 TI - How Can the Use of Evidence in Mental Health Policy Be Increased? A Systematic Review. AB - OBJECTIVE: The aim of this review was to explore what is known about the effectiveness of strategies to increase the use of research in mental health policies. METHODS: PsycINFO, MEDLINE, PubMed and EMBASE were searched for peer reviewed journal articles by using the terms information dissemination OR knowledge OR diffusion of innovation OR knowledge transfer OR knowledge exchange OR evidence based OR evidence informed AND mental health policy OR decision makers. Searches were limited to articles pertaining to humans, written in English, and published from 1995 to 2013. Studies were excluded if they did not include a component related either to mental health policy or to mental health policy and decision makers or did not describe the development, implementation, or evaluation of an intervention that included a component aimed at increasing use of evidence. Reference lists were scanned to identify additional papers. RESULTS: The search returned 2,677 citations. Fifty additional papers were identified via reference lists of relevant articles. Nine separate intervention studies were identified that included a component aimed at increasing use of evidence in mental health policy. All employed at least three strategies to increase evidence use, mostly in regard to implementation of a particular evidence-based policy. Methodologies of the identified studies did not enable estimation of the effectiveness of individual strategies to increase evidence use. CONCLUSIONS: Little research has examined how to increase the use of evidence in mental health policy. Available research suggests a number of potentially effective strategies for increasing the use of evidence that warrant further examination. PMID- 25828882 TI - Apoptin interacts with and regulates the activity of protein kinase C beta in cancer cells. AB - Apoptin, the VP3 protein from chicken anaemia virus (CAV), induces tumour cell specific cell death and represents a potential future anti-cancer therapeutic. In tumour but not in normal cells, Apoptin is phosphorylated and translocates to the nucleus, enabling its cytotoxic activity. Recently, the beta isozyme of protein kinase C (PKCbeta) was shown to phosphorylate Apoptin in multiple myeloma cell lines. However, the exact mechanism and nature of interaction between PKCbeta and Apoptin remain unclear. Here we investigated the physical and functional link between PKCbeta and CAV-Apoptin as well as with the recently identified Apoptin homologue derived from human Gyrovirus (HGyV). In contrast to HCT116 colorectal cancer cells the normal colon mucosa cell lines expressed low levels of PKCbetaI and showed reduced Apoptin activation, as evident by cytoplasmic localisation, decreased phosphorylation and lack of cytotoxic activity. Co-immunoprecipitation and proximity ligation assay studies identified binding of both CAV- and HGyV Apoptin to PKCbetaI in HCT116 cells. Using Apoptin deletion constructs the N terminal domain of Apoptin was found to be required for interacting with PKCbetaI. FRET-based PKC activity reporter assays by fluorescence lifetime imaging microscopy showed that expression of Apoptin in cancer cells but not in normal cells triggers a significant increase in PKC activity. Collectively, the results demonstrate a novel cancer specific interplay between Apoptin and PKCbetaI. Direct interaction between the two proteins leads to Apoptin-induced activation of PKC and consequently activated PKCbetaI mediates phosphorylation of Apoptin to promote its tumour-specific nuclear translocation and cytotoxic function. PMID- 25828883 TI - Antineoplastic impact of leishmanial sphingolipid in tumour growth with regulation of angiogenic event and inflammatory response. AB - Very often conventional therapy, i.e. chemotherapeutic treatment, develops resistance in cancer cells and fails to be effective against disease states. An alternative strategy or a new entity may resolve the problem. Interestingly, the microbial world has begun to be explored in medicinal research as a potential new source to deliver bio-active molecules such as sphingolipids for efficacious cancer treatment. A sphingolipid of microbial origin, especially from Leishmania donovani (LSPL), is a novel entity which may exert anti-cancer activity by regulating cellular growth. The present study reveals that among a range of cancer cells evaluated, LSPL-1 (a component of LSPL) reduces cell viability, annexin exposures and arrests cell cycle in B16F10 cells in a concentration and time dependent manner. Flowcytometric analysis showed that it alters mitochondrial membrane potential and generates a number of ROS positive melanoma cells. It activates p53 at serine anchor region via up-regulation of p21 subunit along with PUMA and NOXA. It also exerts activity in vivo by reducing tumor micro vessel and mitotic index while simultaneously improving the survival rate. The inflammatory responses including elevated level of cytokine-chemokine and increased expression of PCNA and F480 are subdued by LSPL-1 treatment in tumour bearing mice. Besides, it reduces the metastatic outburst of angiogenic factors like VEGF, Ang-2, and CD34 through the involvement of several growth promoting factors. These findings indicate that LSPL-1 may be explored as a potent entity against melanoma growth and the associated angiogenic promotion. PMID- 25828884 TI - Dynamic reorganization of brain functional networks during cognition. AB - How does cognition emerge from neural dynamics? The dominant hypothesis states that interactions among distributed brain regions through phase synchronization give basis for cognitive processing. Such phase-synchronized networks are transient and dynamic, established on the timescale of milliseconds in order to perform specific cognitive operations. But unlike resting-state networks, the complex organization of transient cognitive networks is typically not characterized within the graph theory framework. Thus, it is not known whether cognitive processing merely changes the strength of functional connections or, conversely, requires qualitatively new topological arrangements of functional networks. To address this question, we recorded high-density EEG while subjects performed a visual discrimination task. We conducted an event-related network analysis (ERNA) where source-space weighted functional networks were characterized with graph measures. ERNA revealed rapid, transient, and frequency specific reorganization of the network's topology during cognition. Specifically, cognitive networks were characterized by strong clustering, low modularity, and strong interactions between hub-nodes. Our findings suggest that dense and clustered connectivity between the hub nodes belonging to different modules is the "network fingerprint" of cognition. Such reorganization patterns might facilitate global integration of information and provide a substrate for a "global workspace" necessary for cognition and consciousness to occur. Thus, characterizing topology of the event-related networks opens new vistas to interpret cognitive dynamics in the broader conceptual framework of graph theory. PMID- 25828885 TI - New insights into an RNAi approach for plant defence against piercing-sucking and stem-borer insect pests. AB - Insect double-stranded (ds)RNA expression in transgenic crops can increase plant resistance to biotic stress; however, creating transgenic crops to defend against every insect pest is impractical. Arabidopsis Mob1A is required for organ growth and reproduction. When Arabidopsis roots were soaked in dsMob1A, the root lengths and numbers were significantly suppressed and plants could not bolt or flower. Twenty-four hours after rice roots were immersed in fluorescent-labelled dsEYFP (enhanced yellow fluorescent protein), fluorescence was observed in the rice sheath and stem and in planthoppers feeding on the rice. The expression levels of Ago and Dicer in rice and planthoppers were induced by dsEYFP. When rice roots were soaked in dsActin, their growth was also significantly suppressed. When planthoppers or Asian corn borers fed on rice or maize that had been irrigated with a solution containing the dsRNA of an insect target gene, the insect's mortality rate increased significantly. Our results demonstrate that dsRNAs can be absorbed by crop roots, trigger plant and insect RNAi and enhance piercing sucking and stem-borer insect mortality rates. We also confirmed that dsRNA was stable under outdoor conditions. These results indicate that the root dsRNA soaking can be used as a bioinsecticide strategy during crop irrigation. PMID- 25828886 TI - The specific relationship between vitamin D deficiency and diabetic nephropathy among patients with advanced chronic kidney disease: a cross-sectional study in Gran Canaria, Spain. AB - AIMS: Vitamin D deficiency is highly prevalent in subjects with advanced chronic kidney disease (CKD), but diabetes, the most common cause of CKD, has also been linked to low levels of serum 25-hydroxyvitamin D [25(OH)D]. We compare vitamin D status between subjects with type 2 diabetes-related advanced CKD and subjects with either advanced CKD without diabetes or type 2 diabetes without advanced CKD. METHODS: Subjects were patients with advanced CKD (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2) from February 2011 to November 2013 (113 with diabetes-related CKD and 80 without diabetes) and 61 patients with long lasting type 2 diabetes without advanced CKD, simultaneously enrolled from our center. Participants fulfilled a survey questionnaire and underwent physical examination, blood samples, and 24-h urine collection. Kidney disease was assessed using eGFR and 24-h urinary protein excretion. Serum 25(OH)D was measured by chemiluminescence immunoassay. RESULTS: The prevalence of vitamin D deficiency (25(OH)D < 20 ng/mL) was 70.8% in subjects with diabetes-related CKD, 38.8% in subjects with non-diabetic CKD and 41% in subjects with diabetes without advanced CKD. Adjusted means (95% confidence interval (CI)) of 25(OH)D in participants with diabetes-related CKD, in nondiabetic participants with CKD, and in participants with diabetes without advanced CKD were, respectively, 17.5 (14.2 - 20.7), 23.6 (19.4 - 27.8), and 23.5 (16.8 - 30.3) ng/mL (p = 0.023). CONCLUSIONS: Low vitamin D status is characteristically associated with advanced diabetic nephropathy. This relationship is not entirely attributable to the individual effects of CKD or long-lasting diabetes. PMID- 25828887 TI - The molecular structure of chloritoid: a mid-infrared and near-infrared spectroscopic study. AB - The mineral chloritoid collected from the argillite in the bottom of Yaopo Formation of Western Beijing was characterized by mid-infrared (MIR) and near infrared (NIR) spectroscopy. The MIR spectra showed all fundamental vibrations including the hydroxyl units, basic aluminosilicate framework and the influence of iron on the chloritoid structure. The NIR spectrum of the chloritoid showed combination (nu+delta)OH bands with the fundamental stretching (nu) and bending (delta) vibrations. Based on the chemical component data and the analysis result from the MIR and NIR spectra, the crystal structure of chloritoid from western hills of Beijing, China, can be illustrated. Therefore, the application of the technique across the entire infrared region is expected to become more routine and extend its usefulness, and the reproducibility of measurement and richness of qualitative information should be simultaneously considered for proper selection of a spectroscopic method for the unit cell structural analysis. PMID- 25828888 TI - Managing hypophosphatemia in critically ill patients: a report on an under diagnosed electrolyte anomaly. AB - WHAT IS KNOWN AND OBJECTIVE: Correction of acute hypophosphatemia leaves no long term complications, but failure to recognize and treat an acute situation can be fatal. CASE SUMMARY: A 65-year-old female presented to the Emergency department with complaints of abdominal pain, multiple episodes of watery stools and vomiting for 3 days. On the 3rd day, she developed abdominal distension and breathlessness and was referred to this hospital for further management and finally diagnosed with hypophosphatemia. WHAT IS NEW AND CONCLUSION: As hypophosphatemia is often underestimated, this case report emphasizes the importance of correcting hypophosphatemia in all critically ill patients. PMID- 25828889 TI - Lead accumulation, oxidative damage and histopathological alteration in testes and accessory glands of freshwater crab, Sinopotamon henanense, induced by acute lead exposure. AB - Lead (Pb) is one of the most toxic environmental pollutants and known to exert multiple toxic effects including gonadotoxic and spermiotoxic effects. In order to understand toxic mechanisms of lead (Pb) on the testes and the accessory glands of crabs, we investigated Pb accumulation in testes and accessory glands and the survival rate of sperms of freshwater crab, Sinopotamon henanense. The tissue damaging effects of Pb was also investigated by histopathological examination and analyses of antioxidant enzymes as well as lipid peroxidation. Crabs were exposed to different Pb concentrations (0, 3.675, 7.35, 14.7, 29.4 and 58.8 mg/L) for 3, 5 and 7 days. The results showed that Pb levels in testes and accessory glands increased significantly following Pb exposure for 5 and 7 days in almost all treated groups, and survival rate of sperm decreased with increasing Pb concentrations at 5 and 7 days. Morphological changes identified histologically were discovered in testes, including a disordered arrangement of germ cells, a decreased number of sperm in the lumina of the seminiferous tubules, extensive necrosis in the germinal layer of the seminiferous tubules, etc. At the same time, histological abnormalities were discovered in accessory glands, the wall cells were separated from the basement membrane, and wall cells were missing partly. The activities of SOD, GPx and CAT in testes showed no statistically significant changes compared to the control for 3 days, and initially increased and subsequently decreased with increasing Pb concentrations at 5 and 7 days. The antioxidant enzyme activities in accessory glands initially increased and subsequently decreased with increasing Pb concentrations and Pb exposure. This was accompanied with an increase in malondialdehyde (MDA) content in a concentration-dependent manner. These results showed that acute Pb exposure led to a reduction of survival rate of sperm and harmful effects at the cellular level of crab testes and accessory glands, which are most likely linked to Pb induced oxidative stress. PMID- 25828890 TI - Seahorse (Hippocampus reidi) as a bioindicator of crude oil exposure. AB - This study explored the suitability of the seahorse Hippocampus reidi (Ginsburg, 1933) for assessing biomarkers of genotoxic effects and its use as a sentinel organism to detect the effects of acute exposure to petroleum hydrocarbons. Fish were exposed to three concentrations of crude oil (10, 20 and 30 g/kg) for 96 h, and the activity of phase II biotransformation enzyme glutathione S-transferase (GST) was measured. In addition, we performed genotoxicity assays, such as comet assay, micronucleus (MN) test and nuclear abnormalities (NA) induction, on the erythrocytes of the fish species. Our results revealed that the inhibition of hepatic GST activity in H. reidi was dependent on increasing crude oil concentrations. In contrast, an increase in the damage index (DI) and MN frequency were observed with increased crude oil concentrations. These results indicate that the alkaline comet assay and micronucleus test were suitable and useful in the evaluation of the genotoxicity of crude oil, which could improve determinations of the impact of oil spills on fish populations. In addition, H. reidi is a promising "sentinel organism" to detect the genotoxic impact of petroleum hydrocarbons. PMID- 25828891 TI - Effects of chlorpyrifos ethyl on acetylcholinesterase activity in climbing perch cultured in rice fields in the Mekong Delta, Vietnam. AB - Climbing perch is commonly harvested in rice fields and associated wetlands in the Mekong Delta. Despite its importance in providing food and income to local households, there is little information how this fish species is affected by the high use of pesticides in rice farming. Organophosphate insecticides, such as chlorpyrifos ethyl, which are highly toxic to aquatic organisms, are commonly used in the Mekong Delta. This study shows that the brain acetylcholinesterase (AChE) activity in climbing perch fingerlings cultured in rice fields, was significantly inhibited by a single application of chlorpyrifos ethyl, at doses commonly applied by rice farmers (0.32-0.64 kg/ha). The water concentration of chlorpyrifos ethyl decreased below the detection level within 3 days, but the inhibition of brain AChE activity remained for more than 12 days. In addition, the chlorpyrifos ethyl treatments had a significant impact on the survival and growth rates of climbing perch fingerlings, which were proportional to the exposure levels. The results indicate that the high use of pesticides among rice farmers in the Mekong Delta could have a negative impact on aquatic organisms and fish yields, with implications for the aquatic biodiversity, local people's livelihoods and the aquaculture industry in the Mekong Delta. PMID- 25828892 TI - Little field evidence of direct acute and short-term effects of current pesticides on the grey partridge. AB - Direct lethal and sublethal effects of pesticides on farmland birds' populations are recurring questions and largely debated. In this context, we conducted an innovative study combining radiotelemetry, farmer surveys, residue analyses on carcasses and modelling to assess the unintentional effects of pesticides on terrestrial birds. We chose the grey partridge Perdix perdix as a case study because this typical bird of European cereal ecosystems is highly exposed to pesticides. In this paper we focused on acute and short-term impacts of pesticides on adult mortality during spring and summer in a one-substance approach (multiple exposure were not studied here) but for a large variety of active substances (a.s.) actually used in cultivated farmland of Northern France. The fate and the location of 529 partridges were monitored twice a day from early March to late August 2010 and 2011 on 12 sites (14,500 ha). Their daily potential exposure to 183 a.s. was determined by overlapping birds' habitat use and daily pesticide application data. Based on this procedure, we calculated mortality rates within 10 days following a potential exposure for 157 different a.s.. 5 a.s. were associated with a "10-day mortality rate" higher than 10% but a single one (thiacloprid) is reported to be highly toxic to birds. We recorded 261 mortalities among which 94 carcasses were in suitable condition for residue analyses. We detected at least one a.s in 39.4% of carcasses. However, only 2 mortality cases were attributed to poisoning (carbofuran). Furthermore, modelling results showed that these lethal pesticide-related poisonings decreased the population growth rate by less than 1%. In conclusion, we did not point out important direct acute and short-term effects of pesticides currently used by farmers during the breeding season on the grey partridge. This is discussed with regards to the complexity of potential effects in operational conditions. PMID- 25828895 TI - Comments on the current status and future development of natural orifice transluminal endoscopic surgery. PMID- 25828894 TI - Distinct expression patterns of Toll-like receptor 7 in tumour cells and fibroblast-like cells in oral squamous cell carcinoma. AB - AIMS: Toll-like receptor (TLR)-7 agonists have been used in cancer immunotherapy, but tumour heterogeneity means that TLR-7 activity is variable in different components of the tumour microenvironment and the characteristics of TLR-7 in oral squamous cell carcinoma (OSCC) are unclear. METHODS AND RESULTS: Twenty healthy oral tissues, 50 oral leukoplakia tissues and 166 retrospective primary OSCC samples were collected for immunohistochemical staining of TLR-7 and showed up-regulated expression during carcinogenesis. Moreover, patients with high expression of TLR-7 in tumour cells (TCs) had poor differentiation and prognosis. Interestingly, patients with high expression of TLR-7 in stroma fibroblast-like cells (FLCs) had low tumour stage, no lymph node metastasis (LNM) and better prognosis. Furthermore, Ki-67, CD3, CD4, CD8 and forkhead box protein 3 (FoxP3)(+) tumour-infiltrated lymphocytes were assessed and we found that TLR 7(high) TCs were infiltrated by fewer CD3(+) CD4(+) but more FoxP3(+) lymphocytes. Importantly, patients with TLR-7(low) TCs and TLR-7(high) FLCs had less FoxP3(+) lymphocyte infiltration and longer survival time than those with TLR-7(high) TCs/TLR-7(low) FLCs, although TLR-7 was not an independent prognostic factor for OSCC. CONCLUSIONS: The low expression of TLR-7 in tumour and high expression of TLR-7 in stroma predict a good clinical outcome for OSCC patients, and stroma FLCs might be amenable to immunotherapy by a TLR-7 agonist. PMID- 25828893 TI - c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias. AB - Leukemias expressing the constitutively activated tyrosine kinases (TK) BCR-ABL1 and FLT3/ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSB), and error-prone repair. The nonhomologous end-joining (NHEJ) pathway is a major pathway for DSB repair and is highly aberrant in TK-activated leukemias; an alternative form of NHEJ (ALT-NHEJ) predominates, evidenced by increased expression of DNA ligase IIIalpha (LIG3) and PARP1, increased frequency of large genomic deletions, and repair using DNA sequence microhomologies. This study, for the first time, demonstrates that the TK target c-MYC plays a role in transcriptional activation and subsequent expression of LIG3 and PARP1 and contributes to the increased error-prone repair observed in TK-activated leukemias. c-MYC negatively regulates microRNAs miR-150 and miR-22, which demonstrate an inverse correlation with LIG3 and PARP1 expression in primary and cultured leukemia cells and chronic myelogenous leukemia human patient samples. Notably, inhibition of c-MYC and overexpression of miR-150 and -22 decreases ALT NHEJ activity. Thus, BCR-ABL1 or FLT3/ITD induces c-MYC expression, leading to genomic instability via augmented expression of ALT-NHEJ repair factors that generate repair errors. IMPLICATIONS: In the context of TK-activated leukemias, c MYC contributes to aberrant DNA repair through downstream targets LIG3 and PARP1, which represent viable and attractive therapeutic targets. PMID- 25828896 TI - Low-energy falls. PMID- 25828897 TI - Emerging role of the robot in rectal cancer surgery. PMID- 25828898 TI - Re: Consensus statements in surgery: intra-operative neural monitoring for thyroid surgery. PMID- 25828899 TI - Re: Ward safety checklist in the acute surgical unit. PMID- 25828900 TI - Metastatic colorectal cancer presenting with haematochezia and disseminated intravascular coagulation. PMID- 25828901 TI - Increasing roles for surgical outpatients. PMID- 25828902 TI - Dr. Leon S. Dure, III (1931-2014). PMID- 25828903 TI - External cephalic version for breech presentation at term. AB - BACKGROUND: Management of breech presentation is controversial, particularly in regard to manipulation of the position of the fetus by external cephalic version (ECV). ECV may reduce the number of breech presentations and caesarean sections, but there also have been reports of complications with the procedure. OBJECTIVES: The objective of this review was to assess the effects of ECV at or near term on measures of pregnancy outcome. Methods of facilitating ECV, and ECV before term are reviewed separately. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Register (28 February 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of ECV at or near term (with or without tocolysis) compared with no attempt at ECV in women with breech presentation. DATA COLLECTION AND ANALYSIS: Two review authors assessed eligibility and trial quality, and extracted the data. MAIN RESULTS: We included eight studies, with a total of 1308 women randomised. The pooled data from these studies show a statistically significant and clinically meaningful reduction in non-cephalic presentation at birth (average risk ratio (RR) 0.42, 95% confidence interval (CI) 0.29 to 0.61, eight trials, 1305 women); vaginal cephalic birth not achieved (average RR 0.46, 95% CI 0.33 to 0.62, seven trials, 1253 women, evidence graded very low); and caesarean section (average RR 0.57, 95% CI 0.40 to 0.82, eight trials, 1305 women, evidence graded very low) when ECV was attempted in comparison to no ECV attempted. There were no significant differences in the incidence of Apgar score ratings below seven at one minute (average RR 0.67, 95% CI 0.32 to 1.37, three trials, 168 infants) or five minutes (RR 0.63, 95% CI 0.29 to 1.36, five trials, 428 infants, evidence graded very low), low umbilical vein pH levels (RR 0.65, 95% CI 0.17 to 2.44, one trial, 52 infants, evidence graded very low), neonatal admission (RR 0.80, 95% CI 0.48 to 1.34, four trials, 368 infants, evidence graded very low), perinatal death (RR 0.39, 95% CI 0.09 to 1.64, eight trials, 1305 infants, evidence graded low), nor time from enrolment to delivery (mean difference -0.25 days, 95% CI -2.81 to 2.31, two trials, 256 women).All of the trials included in this review had design limitations, and the level of evidence was graded low or very low. No studies attempted to blind the intervention, and the process of random allocation was suboptimal in several studies. Three of the eight trials had serious design limitations, however excluding these studies in a sensitivity analysis for outcomes with substantial heterogeneity did not alter the results. AUTHORS' CONCLUSIONS: Attempting cephalic version at term reduces the chance of non-cephalic presentation at birth, vaginal cephalic birth not achieved and caesarean section. There is not enough evidence from randomised trials to assess complications of ECV at term. Large observational studies suggest that complications are rare. PMID- 25828904 TI - April 2015 at a glance. PMID- 25828905 TI - HFpEF vs. HFrEF: can microRNAs advance the diagnosis? PMID- 25828906 TI - Chagas, a cardiomyopathy emerging from obscurity. PMID- 25828907 TI - Structural insight in the inhibition of adherence of F4 fimbriae producing enterotoxigenic Escherichia coli by llama single domain antibodies. AB - Enterotoxigenic Escherichia coli that cause neonatal and post-weaning diarrhea in piglets express F4 fimbriae to mediate attachment towards host receptors. Recently we described how llama single domain antibodies (VHHs) fused to IgA, produced in Arabidopsis thaliana seeds and fed to piglets resulted in a progressive decline in shedding of F4 positive ETEC bacteria. Here we present the structures of these inhibiting VHHs in complex with the major adhesive subunit FaeG. A conserved surface, distant from the lactose binding pocket, is targeted by these VHHs, highlighting the possibility of targeting epitopes on single domain adhesins that are non-involved in receptor binding. PMID- 25828909 TI - Investigation of the electrical impedance of acupuncture points and non acupuncture points before and after acupuncture, using a four-electrode device. AB - AIM: To evaluate the effect of acupuncture on skin electrical impedance of selected points, before and after acupuncture on one acupuncture point (PC6), using a four-electrode device. METHODS: Six acupuncture and non-acupuncture points on both sides of the body were selected to evaluate the effects of acupuncture on electrical properties of these points. RESULTS: There were no results significant differences of electrical impedance before and after acupuncture in the selected points. CONCLUSIONS: According to our experimental set-up, acupuncture at one point without stimulation does not alter skin electrical impedance in healthy volunteers and there is no difference between acupuncture points and non-acupuncture points. PMID- 25828908 TI - Effectiveness of acupuncture combined with rehabilitation for treatment of acute or subacute stroke: a systematic review. AB - OBJECTIVES: To determine whether the combination of acupuncture and rehabilitation produces better results in the treatment of acute or subacute stroke sequelae than rehabilitation alone. METHODS: A systematic review was carried out. A search was conducted in March 2014 using PubMed, Medline, the Cochrane Library, Chinese National Knowledge Infrastructure database (CNKI) and Wanfang databases. English and Chinese language articles published within 10 years of the search were reviewed for inclusion. Randomised control trials comparing combined treatment with acupuncture and rehabilitation and rehabilitation alone in patients with acute or subacute stroke (onset until 3 months after stroke) were included in this review. Three review authors independently checked the titles and abstracts of trials for inclusion based on selection criteria. Studies measuring changes of motor function, activities of daily living, neurological deficit or spasticity/range of motion during the treatment period and at the end of follow-up were included. RESULTS: 17 trials met the inclusion criteria, of which five were of good quality. 14 trials had results favourable to acupuncture combined with rehabilitation, compared with conventional rehabilitation treatment alone. CONCLUSIONS: Acupuncture in combination with rehabilitation may have benefits for the treatment of acute and subacute stroke sequelae in comparison with rehabilitation alone. However, many of the studies were at risk of bias. Future studies should focus on reaching a consensus about the most appropriate modality of acupuncture intervention, and the appropriate length of treatment for both interventions, to maximise the potential synergistic outcomes. PMID- 25828910 TI - RcsAB is a major repressor of Yersinia biofilm development through directly acting on hmsCDE, hmsT, and hmsHFRS. AB - Biofilm formation in flea gut is important for flea-borne transmission of Yersinia pestis. There are enhancing factors (HmsHFRS, HmsCDE, and HmsT) and inhibiting one (HmsP) for Yersinia pestis biofilm formation. The RcsAB regulatory complex acts as a repressor of Yesinia biofilm formation, and adaptive pseudogenization of rcsA promotes Y. pestis to evolve the ability of biofilm formation in fleas. In this study, we constructed a set of isogenic strains of Y. pestis biovar Microtus, namely WT (RscB+ and RcsA-), c-rcsA (RscB+ and RcsA+), DeltarcsB (RscB- and RcsA-), and DeltarcsB/c-rcsA (RscB- and RcsA+). The phenotypic assays confirmed that RcsB alone (but not RcsA alone) had an inhibiting effect on biofilm/c-di-GMP production whereas assistance of RcsA to RcsB greatly enhanced this inhibiting effect. Further gene regulation experiments showed that RcsB in assistance of RcsA tightly bound to corresponding promoter proximal regions to achieve transcriptional repression of hmsCDE, hmsT and hmsHFRS and, meanwhile, RcsAB positively regulated hmsP most likely in an indirect manner. Data presented here disclose that pseudogenization of rcsA leads to dramatic remodeling of RcsAB-dependent hms gene expression between Y. pestis and its progenitor Y. pseudotuberculosis, enabling potent production of Y. pestis biofilms in fleas. PMID- 25828911 TI - The Nordic Obstetric Surveillance Study: a study of complete uterine rupture, abnormally invasive placenta, peripartum hysterectomy, and severe blood loss at delivery. AB - OBJECTIVE: To assess the rates and characteristics of women with complete uterine rupture, abnormally invasive placenta, peripartum hysterectomy, and severe blood loss at delivery in the Nordic countries. DESIGN: Prospective, Nordic collaboration. SETTING: The Nordic Obstetric Surveillance Study (NOSS) collected cases of severe obstetric complications in the Nordic countries from April 2009 to August 2012. SAMPLE AND METHODS: Cases were reported by clinicians at the Nordic maternity units and retrieved from medical birth registers, hospital discharge registers, and transfusion databases by using International Classification of Diseases, 10th revision codes on diagnoses and the Nordic Medico-Statistical Committee Classification of Surgical Procedure codes. MAIN OUTCOME MEASURES: Rates of the studied complications and possible risk factors among parturients in the Nordic countries. RESULTS: The studied complications were reported in 1019 instances among 605 362 deliveries during the study period. The reported rate of severe blood loss at delivery was 11.6/10 000 deliveries, complete uterine rupture was 5.6/10 000 deliveries, abnormally invasive placenta was 4.6/10 000 deliveries, and peripartum hysterectomy was 3.5/10 000 deliveries. Of the women, 25% had two or more complications. Women with complications were more often >35 years old, overweight, with a higher parity, and a history of cesarean delivery compared with the total population. CONCLUSION: The studied obstetric complications are rare. Uniform definitions and valid reporting are essential for international comparisons. The main risk factors include previous cesarean section. The detailed information collected in the NOSS database provides a basis for epidemiologic studies, audits, and educational activities. PMID- 25828912 TI - Functional analysis of sex-determination genes by gene silencing with LNA-DNA gapmers in the silkworm, Bombyx mori. AB - The sexual fate of B. mori is determined genetically; ZW, female and ZZ, male. Recently, we successfully identified a strong candidate gene at the top of the sex determination cascade in B. mori. This gene was termed Feminizer (Fem) and revealed to be a source of Fem-piRNA. Further, we found that B. mori doublesex (Bmdsx) splicing was markedly altered to produce the male-type isoform when a Fem piRNA inhibitor was injected into ZW embryos. Moreover, knockdown of Masculinizer (Masc), a Fem-piRNA target gene, altered to produce the female-type isoform of Bmdsx in male embryos. However, it remains unclear as to whether Masc directly regulates the sex-specific expression of Bmdsx. In previous studies, we determined that the male-specific isoform of the Bombyx homolog of IGF-II mRNA binding protein (Imp(M)) was involved in the male-specific splicing of Bmdsx. In an attempt to clarify the genetic relationship between Fem, Masc, Imp(M), and Bmdsx, knockdown experiments were performed. Knockdown of Fem shifted into male type Bmdsx, Imp(M) and Masc in female embryos. Knockdown of Masc led to the production of the female-type Bmdsx and a dramatic reduction in Imp(M) expression in male embryos. Knockdown of Imp(M) shifted Bmdsx splice mode from the male-type into the female-type. Our results suggest that: (1) Fem reduces Masc expression, (2) Masc dramatically induces Imp(M) expression, and (3) Imp(M) shifting Bmdsx splice mode from the female-type into the male-type. Based on these findings, we propose a possible genetic cascade regulating sex determination in B. mori. PMID- 25828913 TI - Chemo-Enzymatic Synthesis of Linear and Branched Cationic Peptides: Evaluation as Gene Carriers. AB - Cationic peptides such as poly(l-lysine) and poly(l-arginine) are important tools for gene delivery since they can efficiently condense DNA. It is difficult to produce cationic peptides by recombinant bacterial expression, and its chemical synthesis requires several steps of protection/deprotection and toxic agents. Chemo-enzymatic synthesis of peptides is a clean chemistry technique that allows fast production under mild conditions. With the aim to simplify the production of cationic peptides, the present work develops an enzymatic reaction which enables the synthesis of linear cationic peptides and, through terminal functionalization with tris(2-aminoethyl)amine, of branched cationic peptide conjugates, which show improved DNA complex formation. Cytotoxicity and transfection efficiency of all the chemo-enzymatically synthesized cationic peptides are evaluated for their novel use as gene delivery agents. Synthesized peptides exhibit transfection efficiencies comparable to previously reported monodisperse peptides. Chemo enzymatic synthesis opens the door for efficient production of cationic peptides for their use as gene delivery carriers. PMID- 25828915 TI - Association of trace elements with lipid profiles and glycaemic control in patients with type 1 diabetes mellitus in northern Sardinia, Italy: An observational study. AB - Sardinia is an Italian region with a high incidence of type 1 diabetes mellitus. This study aimed to determine the associations of trace elements with lipid profiles and glycaemic control in patients with T1DM. A total of 192 patients with T1DM who attended the Unit of Diabetology and Metabolic Diseases in Sassari, Italy, were enrolled. Trace elements zinc, copper, selenium, chromium, and iron were measured in whole blood by sector field inductively coupled plasma mass spectrometry. The correlations between metabolic variables and the levels of trace elements were determined. Zinc was positively correlated with total cholesterol (P=0.023), low-density lipoprotein (P=0.0015), and triglycerides (P=0.027). Iron as significantly correlated with TC (P=0.0189), LDL (P=0.0121), and high-density lipoprotein (HDL) (P=0.0466). In males, Cr was positively correlated with HDL (P=0.0079) and Se, in females was correlated with TG (P=0.0113). The mean fasting plasma glucose was166.2mgdL(-1). Chromium was correlated with fasting plasma glucose (P=0.0149), particularly in males (P=0.0038). Overall, 63.5% of the patients had moderate HbA1c (7-9%). Copper was significantly correlated with HbA1c% in males (P=0.0155). In conclusion, the results of this study indicate that trace elements show different associations with lipid levels and glycaemic control in T1DM. Zinc, Fe, and Se were associated with lipid levels whereas Cu and Cr were associated with HbA1c%. PMID- 25828914 TI - Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3beta kinases and Per1 expression in the rat suprachiasmatic nucleus. AB - BACKGROUND AND PURPOSE: Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling. EXPERIMENTAL APPROACH: A time-dependent effect of morphine (1 mg.kg( 1) , i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3beta, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [(35) S]-GTPgammaS binding assay. KEY RESULTS: Morphine stimulated a rise in pERK1/2 and pGSK3beta levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the delta receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3beta levels in the rat ventrolateral and dorsomedial SCN. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the phase shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3beta. PMID- 25828916 TI - Toxicity of leachate from weathering plastics: An exploratory screening study with Nitocra spinipes. AB - Between 60% and 80% of all marine litter is plastic. Leachate from plastics has previously been shown to cause acute toxicity in the freshwater species Daphnia magna. Here, we present an initial screening of the marine environmental hazard properties of leachates from weathering plastics to the marine harpacticoid copepod [Crustacea] Nitocra spinipes. Twenty-one plastic products made of different polymeric materials were leached and irradiated with artificial sunlight. Eight of the twenty-one plastics (38%) produced leachates that caused acute toxicity. Differences in toxicity were seen for different plastic products, and depending on the duration of irradiation. There was no consistent trend in how toxicity of leachate from plastics changed as a function of irradiation time. Leachate from four plastics became significantly more toxic after irradiation, two became significantly less toxic and two did not change significantly. Analysis of leachates from polyvinyl chloride (PVC) by liquid chromatography coupled to a full-scan high-resolution mass spectrometer showed that the leachates were a mixture of substances, but did not show evidence of degradation of the polymer backbone. This screening study demonstrates that leachates from different plastics differ in toxicity to N. spinipes and that the toxicity varies under simulated weathering. PMID- 25828917 TI - Biological response of earthworm, Eisenia fetida, to five neonicotinoid insecticides. AB - Earthworms (Eisenia fetida) are one of the most abundant terrestrial species, and play an important role in maintaining the ecological function of soil. Neonicotinoids are some of the most widely used insecticides applied to crops. Studies on the effect of neonicotinoids on E. fetida are limited. In the present work, we evaluated the effects of five neonicotinoid insecticides on reproduction, cellulase activity and the tissues of E. fetida. The results showed that, the LC50 of imidacloprid, acetamiprid, nitenpyram, clothianidin and thiacloprid was 3.05, 2.69, 4.34, 0.93 and 2.68mgkg(-1), respectively. They also could seriously affect the reproduction of E. fetida, reducing the fecundity by 84.0%, 39.5%, 54.3%, 45.7% and 39.5% at the sub-lethal concentrations of 2.0, 1.5, 0.80, 2.0 and 1.5mgkg(-1), respectively. The cellulase activity of E. fetida was most sensitive to clothianidin. Significant disruption of the epidermal and midgut tissue was observed after 14d exposure. In summary, we demonstrate that imidacloprid, acetamiprid, nitenpyram, clothianidin and thiacloprid have high toxic to earthworm, and can significantly inhibited fecundity and cellulase activity of E. fetida, and they also damage the epidermal and midgut cells of earthworm. PMID- 25828918 TI - Volcanogenic pollution and testicular damage in wild mice. AB - Many evidences have surfaced the adverse effects of environmental pollutants on male reproduction. Volcanogenic pollution is understudied, although it is a well known source of hazardous contaminants. This study aims to assess the effects of chronic exposure to volcanogenic pollution on wild mice testes by studying: (i) diameter of seminiferous tubules; (ii) relative volumetric density of different spermatogenic cells and interstitial space; (iii) damage in the seminiferous tubules and (iv) apoptotic level in the germinal epithelium. The mice from the polluted site showed higher levels of the selected heavy metals than those from the reference site. The mean diameter of seminiferous tubules and the relative volume occupied by spermatozoa and lumen in exposed mice were significantly lower than in the unexposed group. Contrarily, exposed mice showed a significantly higher relative volume occupied by interstitium, as well as, a higher degree of damage and a significantly higher number of apoptotic cells in the germinal epithelium. Results show that secondary manifestations of volcanic activity can pose a serious risk of testicular injury and therefore for male reproduction. PMID- 25828919 TI - In situ measurements of organic carbon in soil profiles using vis-NIR spectroscopy on the Qinghai-Tibet plateau. AB - We wish to estimate the amount of carbon (C) stored in the soil at high altitudes, for which there is little information. Collecting and transporting large numbers of soil samples from such terrain are difficult, and we have therefore evaluated the feasibility of scanning with visible near-infrared (vis NIR) spectroscopy in situ for the rapid measurement of the soil in the field. We took 28 cores (~1 m depth and 5 cm diameter) of soil at altitudes from 2900 to 4500 m in the Sygera Mountains on the Qinghai-Tibet Plateau, China. Spectra were acquired from fresh, vertical faces 5 * 5 cm in area from the centers of the cores to give 413 spectra in all. The raw spectra were pretreated by several methods to remove noise, and statistical models were built to predict of the organic C in the samples from the spectra by partial least-squares regression (PLSR) and least-squares support vector machine (LS-SVM). The bootstrap was used to assess the uncertainty of the predictions by the several combinations of pretreatment and models. The predictions by LS-SVM from the field spectra, for which R(2) = 0.81, the root-mean-square error RMSE = 8.40, and the ratio of the interquartile distance RPIQ = 2.66, were comparable to the PLSR predictions from the laboratory spectra (R(2) = 0.85, RMSE = 7.28, RPIQ = 3.09). We conclude that vis-NIR scanning in situ in the field is a sufficiently accurate rapid means of estimating the concentration of organic C in soil profiles in this high region and perhaps elsewhere. PMID- 25828920 TI - Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents. AB - AIMS/HYPOTHESIS: Type 2 diabetes is characterised by progressive loss of pancreatic beta cell mass and function. Therefore, it is of therapeutic interest to identify factors with the potential to improve beta cell proliferation and insulin secretion. Bone morphogenetic protein 4 (BMP4) expression is increased in diabetic animals and BMP4 reduces glucose-stimulated insulin secretion (GSIS). Here, we investigate the molecular mechanism behind this inhibition. METHODS: BMP4-mediated inhibition of GSIS was investigated in detail using single cell electrophysiological measurements and live cell Ca(2+) imaging. BMP4-mediated gene expression changes were investigated by microarray profiling, quantitative PCR and western blotting. RESULTS: Prolonged exposure to BMP4 reduced GSIS from rodent pancreatic islets. This inhibition was associated with decreased exocytosis due to a reduced Ca(2+) current through voltage-dependent Ca(2+) channels. To identify proteins involved in the inhibition of GSIS, we investigated global gene expression changes induced by BMP4 in neonatal rat pancreatic islets. Expression of the Ca(2+)-binding protein calbindin1 was significantly induced by BMP4. Overexpression of calbindin1 in primary islet cells reduced GSIS, and the effect of BMP4 on GSIS was lost in islets from calbindin1 (Calb1) knockout mice. CONCLUSIONS/INTERPRETATION: We found BMP4 treatment to markedly inhibit GSIS from rodent pancreatic islets in a calbindin1 dependent manner. Calbindin1 is suggested to mediate the effect of BMP4 by buffering Ca(2+) and decreasing Ca(2+) channel activity, resulting in diminished insulin exocytosis. Both BMP4 and calbindin1 are potential pharmacological targets for the treatment of beta cell dysfunction. PMID- 25828921 TI - Hemodynamic targets during therapeutic hypothermia after cardiac arrest: A prospective observational study. AB - AIM: In analogy with sepsis, current post-cardiac arrest (CA) guidelines recommend to target mean arterial pressure (MAP) above 65 mmHg and SVO2 above 70%. This is unsupported by mortality or cerebral perfusion data. The aim of this study was to explore the associations between MAP, SVO2, cerebral oxygenation and survival. METHODS: Prospective, observational study during therapeutic hypothermia (24h - 33 degrees C) in 82 post-CA patients monitored with near infrared spectroscopy. RESULTS: Forty-three patients (52%) survived in CPC 1-2 until 180 days post-CA. The mean MAP range associated with maximal survival was 76-86 mmHg (OR 2.63, 95%CI [1.01; 6.88], p = 0.04). The mean SVO2 range associated with maximal survival was 67-72% (OR 8.23, 95%CI [2.07; 32.68], p = 0.001). In two separate multivariate models, a mean MAP (OR 3.72, 95% CI [1.11; 12.50], p=0.03) and a mean SVO2 (OR 10.32, 95% CI [2.03; 52.60], p = 0.001) in the optimal range persisted as independently associated with increased survival. Based on more than 1625000 data points, we found a strong linear relation between SVO2 (range 40-90%) and average cerebral saturation (R(2) 0.86) and between MAP and average cerebral saturation for MAP's between 45 and 101 mmHg (R(2) 0.83). Based on our hemodynamic model, the MAP and SVO2 ranges associated with optimal cerebral oxygenation were determined to be 87-101 mmHg and 70-75%. CONCLUSION: we showed that a MAP range between 76-86 mmHg and SVO2 range between 67% and 72% were associated with maximal survival. Optimal cerebral saturation was achieved with a MAP between 87-101 mmHg and a SVO2 between 70% and 75%. Prospective interventional studies are needed to investigate whether forcing MAP and SVO2 in the suggested range with additional pharmacological support would improve outcome. PMID- 25828922 TI - Cost-effectiveness of a national public access defibrillation programme. AB - AIM: Proposed Irish legislation aimed at increasing survival from out-of-hospital cardiac-arrest (OHCA) mandates the provision of automated external defibrillators (AEDs) in a comprehensive range of publicly accessible premises in urban and rural areas. This study estimated the clinical and cost effectiveness of the legislation, compared with alternative programme configurations involving more targeted AED placement. METHODS: We used a cost-utility analysis to estimate the costs and consequences of public access defibrillation (PAD) programmes from a societal perspective, based on AED deployment by building type. Comparator programmes ranged from those that only included building types with the highest incidence of OHCA, to the comprehensive programme outline in the proposed legislation. Data on OHCA incidence and outcomes were obtained from the Irish Out of-Hospital-Cardiac-Arrest Register (OHCAR). Costs were obtained from the Irish health service, device suppliers and training providers. RESULTS: The incremental cost effectiveness ratio (ICER) for the most comprehensive PAD scheme was ?928,450/QALY. The ICER for the most scaled-back programme involving AED placement in transport stations, medical practices, entertainment venues, schools (excluding primary) and fitness facilities was ?95,640/QALY. A 40% increase in AED utilisation when OHCAs occur in a public area could potentially render this programme cost effective. CONCLUSION: National PAD programmes involving widespread deployment of static AEDs are unlikely to be cost-effective. To improve cost-effectiveness any prospective programmes should target locations with the highest incidence of OHCA and be supported by efforts to increase AED utilisation, such as improving public awareness, increasing CPR and AED training, and establishing an EMS-linked AED register. PMID- 25828923 TI - Piezochromic luminescence behaviors of two new benzothiazole-enamido boron difluoride complexes: intra- and inter-molecular effects induced by hydrostatic compression. AB - Two new propeller-shaped benzothiazole-enamide boron difluoride complexes exhibiting piezochromic luminescence upon mechanical grinding or hydrostatic compression were prepared. The two analogues displayed the red shift in luminescence under high pressure, while compound 2 with ICT effects showed a more sensitive piezochromic response at low pressure (<1.5 GPa). The different piezochromic luminescence behaviors of these compounds were investigated. PMID- 25828924 TI - Epistemic injustice in assessment of delusions. AB - Delusions are one of the most elusive concepts in psychiatry. There have been several theories on the nature and definition of delusions. Jaspers described them as entailing a total transformation of reality and considered primary delusions as un-understandable. When it comes to clinical practice, psychiatrists resort to criteria of falsity, incorrigibility, conviction and being out of keeping with the person's culture. All these criteria have been subject to various criticisms, some of which will be discussed in the paper. We will use the concept of epistemic injustice to explore the role of stereotypes and prejudice in the identification of delusions. We will discuss cases where patients are suffering from testimonial injustice by virtue of having a mental disorder that is so often associated with attributions of irrationality, bizarreness and incomprehensibility. Two vignettes will be presented to show that this is often the case in clinical practice. We will discuss relevant issues around the epistemology of the delusions. We think that in order to challenge the testimonial injustice, there needs to be an awareness of its possibility and thus recognition of the role of certain stereotypes in assessing these mental states. Challenging the stigma against mentally ill and adopting a holistic view of delusions can help tackle the prejudice that pre-empt the testimonial injustice. PMID- 25828925 TI - HPLC with fluorescence detection assay of perampanel, a novel AMPA receptor antagonist, in human plasma for clinical pharmacokinetic studies. AB - Perampanel (Fycompa(r)), a novel alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor antagonist, is registered for the adjunctive treatment of patients (aged >=12 years) with refractory partial-onset seizures. To support therapeutic drug monitoring, a simple high-performance liquid chromatography (HPLC) assay with fluorescence detection was developed to determine perampanel concentrations in human plasma and validated to support clinical trials. Human plasma samples (1.0 mL) were processed by liquid extraction using diethyl ether, followed by chromatographic separation on a YMC Pack Pro C18 column (150 * 4.6 mm i.d., 5 um) with isocratic elution of acetonitrile-water-acetic acid-sodium acetate (840:560:3:1.8, v/v/v/w) at a flow rate of 1.0 mL/min. Column eluent was monitored at excitation and emission wavelengths of 290 and 430 nm, respectively. The assay was linear (range 1.0-500 ng/mL) and this could be extended to 25 ug/mL by 50-fold dilution integrity. No endogenous peaks were detected in the elution of analytes in drug-free blank human plasma from six individuals and no interference was observed with co medications tested. Intra- and inter-batch reproducibility studies demonstrated accuracy and precision within the acceptance criteria of bioanalytical guidelines. Validation data demonstrated that our assay is simple, selective, reproducible and suitable for therapeutic drug monitoring of perampanel. PMID- 25828926 TI - Simultaneous treatment of food-waste recycling wastewater and cultivation of Tetraselmis suecica for biodiesel production. AB - There is an increasing interest in the use of cultivated microalgae to simultaneously produce biodiesel and remove nutrients from various wastewaters. For this purpose, Tetraselmis suecica was cultivated in flasks and fermenters using diluted food-waste recycling wastewater (FRW). The effect of FRW dilution on T. suecica growth and nutrient removal was initially tested in flasks. The maximal microalgal concentration after 14 days was in medium with a twofold dilution (28.3 * 10(6) cells/mL) and a fivefold dilution (25.5 * 10(6) cells/mL). When fivefold diluted medium was used in fermenters, the final dry cell weight of T. suecica was 2.0 g/L. The removal efficiencies of ammonium and phosphate in the fermenters were 99.0 and 52.3%, respectively. In comparison with the results of previous studies, the growth data of T. suecica in the FRW medium indicate that microalgal cultivation system incorporating removal of nutrients in FRW is feasible at the field level. PMID- 25828927 TI - Invasive pulmonary aspergillosis due to Aspergillus lentulus: Successful treatment of a liver transplant patient. AB - We report a patient with severe invasive pulmonary fungal infection caused by Aspergilllus lentulus, which was identified by genetic analysis, following liver transplantation. The patient was initially suspected to have Aspergilllus fumigatus infection, but worsened clinically despite antifungal therapy appropriate for that species. The patient survived after accurate diagnosis, and detailed drug susceptibility testing led to adequate therapy, demonstrating the importance of performing these investigations for severely immunocompromised patients, including organ transplant recipients. PMID- 25828928 TI - Thiophene containing trisubstituted methanes [TRSMs] as identified lead against Mycobacterium tuberculosis. AB - Triarylmethanes (TRAMs) and thiophene containing trisubstituted methanes (TRSMs) have been reported by us, having potential against Mycobacterium tuberculosis and Mycobacterium fortuitum strains, respectively. Further, extension through synthesis and biological evaluation of novel TRSMs resulted into an identified lead 36 (S006-830) [(diisopropyl-(2-{4-[(4-methoxy-phenyl)- thiophen-2-yl-methyl] phenoxy}-ethyl)-amine)] with MIC: 1.33 mg/L, non-toxic against Vero C-1008 cell line with selectivity index >10, ex vivo efficacy equivalent to first line TB drugs-isoniazid (INH), rifampicin (RFM) and pyrazinamide (PZA) in the mouse and human macrophages, and lung CFU count of 2.2 * 10(7) (approximately 15 fold lesser than untreated mice, 31 * 10(7)) with efficacies comparable to ethambutol (EMB) (1.27 * 10(7)) and PZA (1.9 * 10(7)). Further, S006-830 also showed potent bactericidal activity against multi-drug resistant and single-drug resistant clinical isolates of M. tuberculosis. PMID- 25828929 TI - Distinct novel quinazolinone exhibits selective inhibition in MGC-803 cancer cells by dictating mutant p53 function. AB - The mutant p53 proteins and their corresponding cellular response can be manipulated by novel quinazolinone derivatives 4-8 (a-i) in p53 mutant cancer cells. Of the two most potent compounds, 4a exhibited promising broad-spectrum anti-cancer effects, whereas 6c showed selective and exclusive inhibition activity in p53 mutant cancer cell lines but low toxicity to wild-type p53 cancer cell A375 and normal lung fibroblast WI-38 cells. Furthermore, 6c exhibited a more sophisticated mechanism for cell-destructive response by causing S/G2 phase arrest effect and cell size reduction. Compared with the cellular response of 6b and genetic background of cell lines studied, p53 mutation was found to be the key factor and main target for 6c evoked cell-destructive response. Molecular mechanism studies indicated that p53 phosphorylation and acetylation dual targeting inhibitor 6c exerted anti-cancer activities with a special mechanism in evoking cell apoptosis by arresting mutant p53 function to trigger the deregulation of Cdk2 caused Bim-mediated apoptosis. To the best of our knowledge, 6c is the first quinazolinone derivative to dictate mutant p53 function for apoptotic cell death. PMID- 25828930 TI - Structural, morphological and steady state photoluminescence spectroscopy studies of red Eu(3+)-doped Y2O3 nanophosphors prepared by the sol-gel method. AB - Europium trivalent (Eu(3+))-doped Y2O3 nanopowders of different concentrations (0.5, 2.5, 5 or 7 at.%) were synthesized by the sol-gel method, at different pH values (pH 2, 5 or 8) and annealing temperatures (600 degrees C, 800 degrees C or 1000 degrees C). The nanopowders samples were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FT-IR) and steady state photoluminescence spectroscopy. The effect of pH of solution and annealing temperatures on structural, morphological and photoluminescence properties of Eu(3+)-doped Y2O3 were studied and are discussed. It was found that the average crystallite size of the nanopowders increased with increasing pH and annealing temperature values. The Y2O3:Eu(3+) material presented different morphology and its evolution depended on the pH value and the annealing temperature. Activation energies at different pH values were determined and are discussed. Under ultraviolet (UV) light excitation, Y2O3:Eu(3+) showed narrow emission peaks corresponding to the (5)D0- (7) FJ (J = 0, 1, 2 and 3) transitions of the Eu(3+) ion, with the most intense red emission at 611 assigned to forced electric dipole (5)D0 -> (7)F2. The emission intensity became more intense with increasing annealing temperature and pH values, related to the improvement of crystalline quality. For the 1000 degrees C annealing temperature, the emission intensity presented a maximum at pH 5 related to the uniform cubic-shaped particles. It was found that for lower annealing temperatures (small crystallite size) the CTB (charge transfer band) position presented a red shift. PMID- 25828931 TI - Intraoral diode laser epiglottectomy for treatment of epiglottis chondrosarcoma in a dog. AB - Laryngeal tumours are rare in dogs. Surgery is the treatment of choice, but it is usually palliative in malignant conditions, due to advanced stage of the tumour at the time of diagnosis. In veterinary medicine, little information is available about the use of diode laser in laryngeal oncological surgery. In the case reported here, a dog with an epiglottic chondrosarcoma was successfully treated with diode laser epiglottectomy. The surgical technique and follow up are described. PMID- 25828932 TI - Special issue: epigenetics: introduction. AB - Epigenetic studies focus on changes in genetic information that rely on histone modification, which complements information encoded by the DNA sequence. Research in this rapidly expanding field has greatly contributed to a better understanding of processes such as gene regulation, chromatin structure, and cell differentiation and disease. The most recent advances in this area are reviewed in the collection of papers included in this Special Issue. PMID- 25828933 TI - Developing an educational video on lung lobectomy for the general surgery resident. AB - BACKGROUND: The educational resources available to general surgery residents preparing for complex thoracic surgeries vary greatly in content and target audience. We hypothesized that the preparatory resources could be improved in both efficiency of use and targeting. METHODS: A formal needs analysis was performed to determine residents' knowledge gaps and desired format and/or content of an educational tool while preparing for their first lung resections. The results of the needs assessment then guided the creation of a 20-min video tool. The video was evaluated by a focus group of experts for appropriateness to the target audience, ease of use, and relevance. RESULTS: The needs assessment illustrated that residents feel there is a paucity of appropriate resources available to them while preparing for the lung resection procedure; 82% of respondents felt that easy-to-use and concise resources on the lobectomy procedure were either "not at all" or "somewhat" accessible. Residents reported that video was their preferred format for a learning tool overall and identified a broad spectrum of most challenging procedural aspects. These results were used to guide the creation of a 20-min video tool. A focus group validated the efficacy and appropriateness of the video. CONCLUSIONS: Targeted and efficient tools for residents preparing for complex subspecialty procedures are needed and valued. These results clearly encourage further work in the creation of focused educational tools for surgical residents, especially in the format of short video overviews. PMID- 25828934 TI - Alternative treatment of symptomatic pancreatic fistula. AB - BACKGROUND: The management of symptomatic pancreatic fistula after pancreaticoduodenectomy is complex and associated with increased morbidity and mortality. We here report continuous irrigation and drainage of the pancreatic remnant to be a feasible and safe alternative to total pancreatectomy. MATERIALS AND METHODS: Between 2005 and 2011, patients were analyzed, in which pancreaticojejunal anastomosis was disconnected because of grade C fistula, and catheters for continuous irrigation and drainage were placed close to the pancreatic remnant. Clinical data were monitored and quality of life was evaluated. RESULTS: A total of 13 of 202 patients undergoing pancreaticoduodenectomy required reoperation due to symptomatic pancreatic fistula. Ninety-day mortality of these patients was 15.3%. Median length of stay on the intensive care unit and total length of stay was 18 d (range 3-45) and 46 d (range 33-96), respectively. Patients with early reoperation (<10 d) had significantly decreased length of stay on the intensive care unit and operation time (P < 0.05). Global health status after a median time of 22 mo (range 6-66) was nearly identical, when compared with that of a healthy control group. Mean follow-up was 44.4 mo (+/-27.2). Four patients (36.6 %) died during the follow-up period; two patients from tumor recurrence, one patient from pneumonia, and one patient for unknown reasons. CONCLUSIONS: Treatment of pancreatic fistula by continuous irrigation and drainage of the preserved pancreatic remnant is a simple and feasible alternative to total pancreatectomy. This technique maintains a sufficient endocrine function and is associated with low mortality and reasonable quality of life. PMID- 25828935 TI - Erratum to: Adrenal hypofunction from histoplasmosis: a literature review from 1971 to 2012. PMID- 25828936 TI - Antibiotic use varies substantially among adults: a cross-national study from five European Countries in the ARITMO project. AB - PURPOSE: To examine patterns of outpatient and community antibiotic use among adults in five European countries. METHODS: We used healthcare data of 28.8 million adults from six population-based ARITMO project databases to ascertain information on systemic antibiotic use in Denmark (2000-2008), the Netherlands (1999-2010), Italy (2000-2010), the UK (1996-2009), and Germany (2004-2008). We estimated overall, and age-group and sex specific antibiotic use as defined daily doses (DDD) per 1000 inhabitants per day. We computed annual age- and sex standardized population prevalence of antibiotic use per 1000 persons-years (p-y) and the mean duration (in days) of antibiotic use. RESULTS: The overall antibiotic use varied from 8.7 DDD per 1000 inhabitants per day in the UK to 18.1 DDD in Denmark, representing a 2.1-fold geographical variation. In all countries, prescribing was relatively high among individuals aged 15-19 years; lower in those aged 20-50 years; and then increased steadily reaching 41.8 DDD per 1000 inhabitants per day in individuals >= 85 years in Denmark. After age- and sex standardization, prevalence of antibiotic use varied threefold from 160.2/1000 p y in the UK to 421.1/1000 p-y in Italy. The ratio of broad- to narrow-spectrum penicillin, cephalosporin, and macrolide use varied from 0.6 in Denmark to 120.2 in Italy. Women used more antibiotics than men did in all countries. Across countries, the mean duration of antibiotic use varied 1.3 to 21.1-fold for different antibiotics. CONCLUSIONS: Antibiotic use is high in women and the elderly. Prescribing patterns vary substantially across European countries, both according to overall consumption, user prevalence, duration, and narrow- versus broad-spectrum antibiotics. PMID- 25828937 TI - Recipient-born bloodstream infection due to extensively drug-resistant Acinetobacter baumannii after emergency heart transplant: report of a case and review of the literature. AB - Infections due to drug-resistant Gram-negative rods are an emerging risk factor for increased mortality after solid organ transplant. Extensively drug-resistant (XDR) Acinetobacter baumannii (Acb) is a major threat in several critical care settings. The limited available data on the outcome of XDR Acb infections in organ transplant recipients mostly comes from cases of donor-derived infections. However, recipients of life-saving organs are often critically ill patients, staying long term in intensive care units, and therefore at high risk for nosocomial infections. In this report, we describe our experience with the exceedingly complex management of a recipient-born XDR Acb bloodstream infection clinically ensued shortly after heart transplant. We also review the current literature on this mounting issue relevant for intensive care, transplant medicine and infectious diseases. PMID- 25828938 TI - Retinal and central nervous system involvement in T cell large granular lymphocyte leukaemia. PMID- 25828939 TI - Primary intracranial low-grade fibromyxoid sarcoma with FUS gene rearrangement. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare sarcoma typically presenting as a deep soft tissue mass in the lower extremities or trunk. Only four cases of primary intracranial LGFMS have been reported in the literature, but none with molecular/cytogenetic data. We report here a new bona fide case confirmed by the characteristic FUS gene rearrangement, as shown by fluorescence in situ hybridization analysis, in addition to typical histopathological findings. This would be the first genetically confirmed report of the extremely rare occurrence of intracranial LGFMS. PMID- 25828940 TI - ASIA: asbestos stop in Asia. PMID- 25828942 TI - What is the Utility Of a Limb Lengthening and Reconstruction Service in an Academic Department of Orthopaedic Surgery? AB - BACKGROUND: Limb lengthening and reconstruction surgery is a relatively new subspecialty of orthopaedic surgery in the United States. Despite increased awareness and practice of the specialty, it is rarely vested as a separate clinical service in an academic department of orthopaedic surgery. We have had experience growing such a dedicated service within an academic department of orthopaedic surgery over the past 9 years. QUESTIONS/PURPOSES: We explored (1) the use of a limb deformity service (LDS) in an academic department of orthopaedic surgery by examining data on referral patterns, our clinical volume, and academic productivity; and (2) the surgical breadth of cases comprising the patients of the LDS in an academic department of orthopaedic surgery by examining data on caseload by anatomic sites, category, and surgical techniques/tools. METHODS: We (SRR, ATF, EWB) retrospectively examined data on numbers of surgical cases and outpatient visits from the limb lengthening and complex reconstruction service at the Hospital for Special Surgery from 2005 to 2013 to evaluate growth. We studied 672 consecutive surgical cases performed by our service for a sample period of 1 year, assessing referral patterns within and outside our medical center, anatomic region, surgical category, and surgical technique/tool. Academic productivity was measured by review of our service's publications. RESULTS: During the time period studied (2005-2013), outpatient and surgical volume significantly increased by 120% (1530 to 3372) and 105% (346 to 708), respectively, on our LDS. Surgical volume growth was similar to the overall growth of the department of orthopaedic surgery. Referrals were primarily from orthopaedic surgeons (56%) and self/Internet research (25%). Physician referrals were predominantly from our own medical center (83%). Referrals from within our institution came from a variety of clinical services. Forty-nine peer-reviewed articles and 23 book chapters were published by staff members of our service. Anatomic surgical sites, surgical categories, and technique/tools used on our LDS were diverse, yet procedures were specialized to the discipline of limb deformity. CONCLUSIONS: There is a substantial role for an LDS within an academic department of orthopaedic surgery. With establishment of a dedicated service comes focus and resources that establish an environment for growth in volume, intramural and extramural referral, and purposeful research and education. The majority of referrals were from orthopaedic surgeons from our own medical center, suggesting needfulness. The LDS provides patients access to specialized surgery. The number of intramural referrals suggests that the specialty service helps retain patients within our academic orthopaedic department. Future research will try to determine if such a dedicated service leads to improved outcomes, efficiency, and value. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 25828944 TI - CORR Insights((r)): The Chitranjan Ranawat Award: Running Subcuticular Closure Enables the Most Robust Perfusion After TKA: A Randomized Clinical Trial. PMID- 25828943 TI - Clinical Implications of Psychosocial Factors on Pediatric External Fixation Treatment and Recommendations. AB - BACKGROUND: Pediatric limb reconstruction using circular external fixation is a prolonged treatment that interrupts patients' daily function. Patient personality characteristics and expectations may interfere with planned treatment, making complicated medical procedures more challenging. The aims of this study are to identify factors impacting treatment outcome and recommendations for preoperative evaluation and planning. QUESTIONS/PURPOSES: (1) Are there group differences between patients with and without a preexisting mental health condition(s) in terms of unplanned reoperations? (2) Does the number of surgical procedures before current external fixator placement correlate with the number of unplanned readmissions, unplanned reoperations, and days spent in circular external fixation? (3) Are there group differences between single- compared with two parent households in terms of inpatient narcotic doses, length of inpatient stay, number of unplanned readmissions, length of readmission(s), and/or unplanned outpatient clinic visits? (4) Does patient age at the time of surgery have an impact on treatment duration, postoperative complications, and treatment outcome? METHODS: This is a retrospective chart review of pediatric patients who underwent limb reconstruction between 2008 and 2012. Patients with limb length discrepancy > 4 cm or severe angular deformity and who agreed to intervention were treated with circular external fixation. Sixty-seven patients were included; 16 patients were excluded. Statistical analyses included Pearson r correlation and t-test. RESULTS: Patients who reported preexisting mental health diagnosis (13%) had more unplanned reoperations than patients who did not (no mental health diagnosis; 87%) (mental health diagnosis 3.4 +/- 10.3 versus no mental health diagnosis 0.2 +/- 0.5 reoperation[s], p = 0.022). Number of previous surgical procedures correlated with number of unplanned reoperations (r = 0.448, p < 0.001), number of unplanned readmissions (r = 0.375, p < 0.001), and number of days in an apparatus (r = 0.275, p = 0.018). Compared with patients from two-parent households, patients from single-parent households received a greater number of inpatient narcotic doses (single-parent 129 +/- 118 versus two-parent 73 +/- 109 doses, p = 0.039), longer length of inpatient stay (single-parent 73 +/- 63 versus two-parent 40 +/- 65 days, p = 0.036), more unplanned readmissions (single parent 0.4 +/- 0.1 versus two-parent 0.2 +/- 0.2 readmission, p = 0.024), longer hospitalization when readmitted (single-parent 5 +/- 11 versus two-parent 1 +/- 3 day(s), p = 0.025), and fewer unplanned outpatient visits (single-parent 0.2 +/- 0.8 versus two-parent 0.9 +/- 1.1 visit, p = 0.005). Apparatus applications with successful outcome had higher average age than those with poor outcome (successful outcome 16 +/- 3 versus poor outcome 13 +/- 4 years old, p = 0.011). Age at time of apparatus application correlated with number of prescribed antibiotics (r = 0.245, p = 0.036) and number of days in an apparatus (r = 0.233, p = 0.047). CONCLUSIONS: As a result of the inherent challenges of limb reconstruction, surgical candidates should be preoperatively assessed and mitigating psychosocial factors managed to maximize successful treatment outcome. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25828941 TI - Developmental Dislocation of the Hip Successfully Treated by Preoperative Traction and Medial Open Reduction: A 22-year Mean Followup. AB - BACKGROUND: During the last 35 years, the medial approach has been reported more frequently than the anterior approach for open reduction of developmental dislocation of the hip (DDH), however, few studies have followed children treated by medial open reduction to adulthood. QUESTIONS/PURPOSES: The purposes of our study were: (1) to assess the development of 71 completely dislocated hips after medial open reduction, the incidence of additional surgery and avascular necrosis during the followup period, and the long-term radiographic and functional results; and (2) to compare our results with those obtained by others who performed open reduction either by the medial or anterior approach. PATIENTS AND METHODS: We retrospectively evaluated, after the end of growth, 71 hips in 52 patients who underwent open reduction by the medial approach. The mean age of the patients was 16 months (range, 3-36 months). After surgery, the hips were immobilized in 100 degrees flexion, 60 degrees abduction, and neutral rotation for an average of 6 months. All patients had staged clinical and radiographic followups until skeletal maturity. The length of followup averaged 22 years (range, 13-32 years). RESULTS: In all the surgically treated hips, the acetabular index normalized by the end of growth, the incidence of avascular necrosis was 18%, and additional surgery was required in 15% of our cases. At the last followup, 93% of the hips were classified as Severin Classes I or II and 7% as Class III; 76% of the hips had an excellent result, 17% had a good result, and 7% had a fair result according to the McKay scale as modified by Barrett and colleagues. CONCLUSIONS: Open reduction of DDH through a medial approach provided good long-term radiographic and functional results in patients 3 to 36 months old and it was the only surgery performed in 85% of our cases. Future comparative studies are needed to confirm our results, especially in older children. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25828945 TI - Blast Injury in the Spine: Dynamic Response Index Is Not an Appropriate Model for Predicting Injury. AB - BACKGROUND: Improvised explosive devices are a common feature of recent asymmetric conflicts and there is a persistent landmine threat to military and humanitarian personnel. Assessment of injury risk to the spine in vehicles subjected to explosions was conducted using a standardized model, the Dynamic Response Index (DRI). However, the DRI was intended for evaluating aircraft ejection seats and has not been validated in blast conditions. QUESTIONS/PURPOSES: We asked whether the injury patterns seen in blast are similar to those in aircraft ejection and therefore whether a single injury prediction model can be used for both situations. METHODS: UK military victims of mounted blast (seated in a vehicle) were identified from the Joint Theatre Trauma Registry. Each had their initial CT scans reviewed to identify spinal fractures. A literature search identified a comparison population of ejected aircrew with spinal fractures. Seventy-eight blast victims were identified with 294 fractures. One hundred eighty-nine patients who had sustained aircraft ejection were identified with 258 fractures. The Kruskal-Wallis test was used to compare the population injury distributions and Fisher's exact test was used to assess differences at each spinal level. RESULTS: The distribution of injuries between blast and ejection was not similar. In the cervical spine, the relative risk of injury was 11.5 times higher in blast; in the lumbar spine the relative risk was 2.9 times higher in blast. In the thoracic spine, the relative risk was identical in blast and ejection. At most individual vertebral levels including the upper thoracic spine, there was a higher risk of injury in the blast population, but the opposite was true between T7 and T12, where the risk was higher in aircraft ejection. CONCLUSIONS: The patterns of injury in blast and aircraft are different, suggesting that the two are mechanistically dissimilar. At most vertebral levels there is a higher relative risk of fracture in the blast population, but at the apex of the thoracic spine and in the lower thoracic spine, there is a higher risk in ejection victims. The differences in relative risk at different levels, and the resulting overall different injury patterns, suggest that a single model cannot be used to predict the risk of injury in ejection and blast. CLINICAL RELEVANCE: A new model needs to be developed to aid in the design of mine-protected vehicles for future conflicts. PMID- 25828946 TI - Comparison of macular thickness and inflammatory cytokine levels after microincision versus small incision coaxial cataract surgery. AB - PURPOSE: To compare the macular thickness and volume change, and inflammatory cytokine levels after cataract surgery performed using two different sizes of incision (microincision versus small incision). METHODS: In this randomized, comparative clinical trial, 84 eyes with nuclear density from Grade 3-4 were randomly divided into two groups (microincision, 2.2 mm; and small incision, 2.75 mm). Forty-two patients underwent phacoemulsification with microincision coaxial cataract surgery and 42 patients underwent phacoemulsification with small incision coaxial cataract surgery. Clinical measurements included preoperative, 1 week, 1-month and 2-month postoperative best corrected visual acuity, central corneal thickness (CCT) and endothelial cell count. ELISA and RT-PCR were performed for IL-1beta, IL-6, VEGF and PGE2 preoperatively and at 1 week postoperatively. RESULTS: The percentage increase in CCT in the microincision group was significantly higher than that in the small incision group at 1 week after cataract surgery (p = 0.01). The increase in macular thickness in the microincision group was significantly higher than that in small incision group at 1 month after cataract operation (p = 0.04). Also, IL-1beta, IL-6, VEGF and PGE2 concentrations and their expression ratio in the microincision group were significantly higher than those in the small incision group at 1 week after cataract surgery compared to the preoperative period (p < 0.05). CONCLUSIONS: Phacoemulsification with microincision coaxial cataract surgery may increase the macular thickness compared to phacoemulsification with small incision coaxial cataract surgery. Blood-aqueous barrier breakdown may occur more frequently after microincision cataract surgery than after small incision cataract surgery. PMID- 25828947 TI - Upregulation of endoplasmic reticulum stress and reactive oxygen species by naturally occurring mutations in hepatitis B virus core antigen. AB - Hepatitis B virus (HBV) infection is associated with a broad spectrum of clinical manifestations, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress and subsequent oxidative stress have been implicated in liver carcinogenesis and disease progression with chronic inflammation. In our previous study, several mutations in the precore/core region of HBV genotype C were identified from 70 Korean chronic patients, and the mutations were associated with HCC and/or HBV e antigen serostatus. Here, we found that the naturally occurring mutations P5T/H/L of the HBV core antigen induced ER stress. The upregulation of ER stress resulted in higher reactive oxygen species production, intracellular calcium concentration, inflammatory cytokines as well as surface antigen production and apoptosis of cells. This study suggested that these mutations may contribute to the progression of liver disease in chronic patients. PMID- 25828948 TI - MCF-7 cells--changing the course of breast cancer research and care for 45 years. AB - It is 45 years since a pleural effusion from a patient with metastatic breast cancer led to the generation of the MCF-7 breast cancer cell line. MCF-7 is the most studied human breast cancer cell line in the world, and results from this cell line have had a fundamental impact upon breast cancer research and patient outcomes. But of the authors for the nearly 25000 scientific publications that used this cell line, how many know the unique story of its isolation and development? In this commentary we will review the past, present, and future of research using MCF-7 breast cancer cells. PMID- 25828949 TI - Depression and socio-economical burden are more common in primary caregivers of patients who are not aware of their cancer: TURQUOISE Study by the Palliative Care Working Committee of the Turkish Oncology Group (TOG). AB - In this study, we aimed to determine the personal, social and economic burden and the frequency of depression, as well as in caregivers of cancer patients who are being treated with chemotherapy in Turkey. The study is designed as a cross sectional survey study using a 5-point Likert-type response scale, and the last part of the questionnaire includes the Beck Depression Inventory. The depression rate was found to be 64% (n = 476) among all subjects (n = 968), with 91% of those with depression demonstrating signs of mild depression. In this study, a significant difference was found between the presence of depression and age (young), sex (female), educational level (high), economic status (low), financial loss during treatment, patient's lack of knowledge about his/her diagnosis, metastatic disease and short survival time. In addition, 64% of all subjects had concerns of getting cancer, and 44% of all subjects had feelings of anger/rage against other people. In a multivariate regression analysis, the patient's lack of knowledge of the diagnosis was the independent risk factor. In conclusion, depression incidence and burden rate increased among cancer caregivers, and care burden was highly associated with depression. Accordingly, approaches to reducing the psycho-social effects of cancer should focus intensively on both the patients and their caregivers in Turkey. PMID- 25828950 TI - Effects of PaCO2 derangements on clinical outcomes after cerebral injury: A systematic review. AB - OBJECTIVE: Partial pressure of arterial carbon dioxide (PaCO2) is a major regulator of cerebral blood flow (CBF). Derangements in PaCO2 have been thought to worsen clinical outcomes after many forms of cerebral injury by altering CBF. Our aim was to systematically analyze the biomedical literature to determine the effects of PaCO2 derangements on clinical outcomes after cerebral injury. METHODS: We performed a search of Cochrane Library, PUBMED, CINHAL, conference proceedings, and other sources using a comprehensive strategy. Study inclusion criteria were (1) human subjects; (2) cerebral injury; (3) mechanical ventilation post-injury; (4) measurement of PaCO2; and (5) comparison of a clinical outcome measure (e.g. mortality) between different PaCO2 exposures. We performed a qualitative analysis to collate and summarize effects of PaCO2 derangements according to the recommended methodology from the Cochrane Handbook. RESULTS: Seventeen studies involving different etiologies of cerebral injury (six traumatic brain injury, six post-cardiac arrest syndrome, two cerebral vascular accident, three neonatal ischemic encephalopathy) met all inclusion and no exclusion criteria. Three randomized control trials were identified and only one was considered a high quality study as per the Cochrane criteria for assessing risk of bias. In 13/17 (76%) studies examining hypocapnia, and 7/10 (70%) studies examining hypercapnia, the exposed group (hypercapnia or hypocapnia) was associated with poor clinical outcome. CONCLUSION: The majority of studies in this report found exposure to hypocapnia and hypercapnia after cerebral injury to be associated with poor clinical outcome. However, the optimal PaCO2 range associated with good clinical outcome remains unclear. PMID- 25828951 TI - Maxillary Three-Implant Overdentures Opposing Mandibular Two-Implant Overdentures: 10-Year Surgical Outcomes of a Randomized Controlled Trial. AB - BACKGROUND: The surgical placement of four maxillary implants for overdentures may not be obligatory when opposing mandibular two-implant overdentures. PURPOSE: To determine 10-year surgical outcomes and implant success of three narrow diameter implants in edentulous maxillae with conventional loading. MATERIALS AND METHODS: Forty participants with mandibular two-implant overdentures were randomly allocated for surgery for maxillary overdentures. Using osteotomes, three implants of similar systems were placed with a one-stage procedure and 12 week loading with splinted and unsplinted prosthodontic designs. Marginal bone and stability measurements were done at surgery, 12 weeks, 1-, 2-, 5-, 7-, 10 years. RESULTS: One hundred seventeen implants were placed in 39 participants, with 35 being seen at 1 year; 29 at 2 years; 28 at 5 years; 26 at 7 years; and 23 (59%) at 10 years. Marginal bone loss was 1.35 mm between surgery and 12 weeks; 0.36 mm between 12 weeks and 1 year; 0.48 mm between 1 and 5 years; and 0.22 mm between 5 and 10 years. Implant stability quotients were 56.05, 57.54, 60.88, 58.80, 61.17 at surgery, 12 weeks, 1 year, 5 years, and 10 years. Four-field tables by implant showed success rates of 82% at 1 year; 69.2% at 2 years; 66.7% at 5 years; 61.5% at 7 years; 51.3% at 10 years. Data showed no differences between surgical technique, systems, or prosthodontic designs. CONCLUSIONS: Surgical placement with osteotomes of three narrow diameter implants for maxillary overdentures, opposing mandibular two-implant overdentures, is an acceptable approach, subject to strict patient selection. Implant success is independent of prosthodontic design. PMID- 25828952 TI - Heavy atom labeled nucleotides for measurement of kinetic isotope effects. AB - Experimental analysis of kinetic isotope effects represents an extremely powerful approach for gaining information about the transition state structure of complex reactions not available through other methodologies. The implementation of this approach to the study of nucleic acid chemistry requires the synthesis of nucleobases and nucleotides enriched for heavy isotopes at specific positions. In this review, we highlight current approaches to the synthesis of nucleic acids enriched site specifically for heavy oxygen and nitrogen and their application in heavy atom isotope effect studies. This article is part of a special issue titled: Enzyme Transition States from Theory and Experiment. PMID- 25828953 TI - When gas analysis assists with postmortem imaging to diagnose causes of death. AB - Postmortem imaging consists in the non-invasive examination of bodies using medical imaging techniques. However, gas volume quantification and the interpretation of the gas collection results from cadavers remain difficult. We used whole-body postmortem multi-detector computed tomography (MDCT) followed by a full autopsy or external examination to detect the gaseous volumes in bodies. Gases were sampled from cardiac cavities, and the sample compositions were analyzed by headspace gas chromatography-mass spectrometry/thermal conductivity detection (HS-GC-MS/TCD). Three categories were defined according to the presumed origin of the gas: alteration/putrefaction, high-magnitude vital gas embolism (e.g., from scuba diving accident) and gas embolism of lower magnitude (e.g., following a traumatic injury). Cadaveric alteration gas was diagnosed even if only one gas from among hydrogen, hydrogen sulfide or methane was detected. In alteration cases, the carbon dioxide/nitrogen ratio was often >0.2, except in the case of advanced alteration, when methane presence was the best indicator. In the gas embolism cases (vital or not), hydrogen, hydrogen sulfide and methane were absent. Moreover, with high-magnitude vital gas embolisms, carbon dioxide content was >20%, and the carbon dioxide/nitrogen ratio was >0.2. With gas embolisms of lower magnitude (gas presence consecutive to a traumatic injury), carbon dioxide content was <20% and the carbon dioxide/nitrogen ratio was often <0.2. We found that gas analysis provided useful assistance to the postmortem imaging diagnosis of causes of death. Based on the quantifications of gaseous cardiac samples, reliable indicators were determined to document causes of death. MDCT examination of the body must be performed as quickly as possible, as does gas sampling, to avoid generating any artifactual alteration gases. Because of cardiac gas composition analysis, it is possible to distinguish alteration gases and gas embolisms of different magnitudes. PMID- 25828954 TI - Polyclonality of Parathyroid Tumors in Neonatal Severe Hyperparathyroidism. AB - Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder characterized by major hypercalcemia, elevated parathyroid hormone levels, and marked enlargement of multiple parathyroid glands, usually associated with germline mutations in the calcium receptor gene CASR. However, little is known about the outgrowth of parathyroid tumors in NSHPT, including whether they represent monoclonal or polyclonal expansions. We sought to examine the clonality of parathyroid tissues resected from a patient with NSHPT and biallelic CASR mutations. DNA from two distinct parathyroid tumors resected from a girl with NSHPT, plus polyclonal/monoclonal control samples, were subjected to analyses of clonality by two independent methods, X-chromosome inactivation analysis at the androgen receptor locus (HUMARA) and BAC array comparative genomic hybridization (CGH). Both parathyroid tumor samples revealed polyclonal patterns by X-inactivation analysis, with polyclonal and monoclonal controls yielding the expected patterns. Similarly, by BAC array CGH, neither parathyroid sample contained monoclonal copy number changes and both appeared identical to the patient-matched polyclonal controls. Our observations provide direct experimental evidence that the markedly enlarged parathyroid tumors in the setting of NSHPT constitute polyclonal, generalized hyperplastic growths rather than monoclonal neoplasms. PMID- 25828955 TI - Violation of Lower Rate Limit: What Is the Mechanism? PMID- 25828956 TI - Letter to the editor: re: Saliva and serum levels of pentraxin-3 and interleukin 1beta in generalized aggressive or chronic periodontitis. Gumus P, Nizam N, Nalbantsoy A, Ozcaka O, Buduneli N. (J Periodontol 2014;85:e40-e46.). PMID- 25828957 TI - Letter to the editor: Authors' response. PMID- 25828958 TI - Letter to the editor: re: Coffee consumption and periodontal disease in males. Ng N, Kaye EK, Garcia RI. (J Periodontol 2014;85:1042-1049.). PMID- 25828959 TI - Letter to the editor: Authors' response. PMID- 25828960 TI - Asynchronous event-based corner detection and matching. AB - This paper introduces an event-based luminance-free method to detect and match corner events from the output of asynchronous event-based neuromorphic retinas. The method relies on the use of space-time properties of moving edges. Asynchronous event-based neuromorphic retinas are composed of autonomous pixels, each of them asynchronously generating "spiking" events that encode relative changes in pixels' illumination at high temporal resolutions. Corner events are defined as the spatiotemporal locations where the aperture problem can be solved using the intersection of several geometric constraints in events' spatiotemporal spaces. A regularization process provides the required constraints, i.e. the motion attributes of the edges with respect to their spatiotemporal locations using local geometric properties of visual events. Experimental results are presented on several real scenes showing the stability and robustness of the detection and matching. PMID- 25828961 TI - Phase synchronization of coupled bursting neurons and the generalized Kuramoto model. AB - Bursting neurons fire rapid sequences of action potential spikes followed by a quiescent period. The basic dynamical mechanism of bursting is the slow currents that modulate a fast spiking activity caused by rapid ionic currents. Minimal models of bursting neurons must include both effects. We considered one of these models and its relation with a generalized Kuramoto model, thanks to the definition of a geometrical phase for bursting and a corresponding frequency. We considered neuronal networks with different connection topologies and investigated the transition from a non-synchronized to a partially phase synchronized state as the coupling strength is varied. The numerically determined critical coupling strength value for this transition to occur is compared with theoretical results valid for the generalized Kuramoto model. PMID- 25828962 TI - Molecular biology and targeted therapies for urothelial carcinoma. AB - Metastatic urothelial cancer (UC) is associated with poor prognosis. In the first line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. With no validated treatment proven to increase survival after platinum failure, there is an urgent unmet medical need to develop new and efficacious cytotoxic agents. A better understanding of the molecular signaling pathways regulating UC has led to the development of new and innovative therapeutic strategies. Despite this, many recent drugs show only modest activity as single agents, and combining them with standard chemotherapy does not seem to enhance efficacy. Ongoing research is producing, however, a generation of new drugs that are showing promising results in clinical trials. This paper aims to review the most important mechanisms in bladder cancer tumorigenesis and describe the new therapeutic options currently undergoing evaluation in clinical trials. PMID- 25828963 TI - Pincer-Type Platinum(II) Complexes Containing N-Heterocyclic Carbene (NHC) Ligand: Structures, Photophysical and Anion-Binding Properties, and Anticancer Activities. AB - Two classes of pincer-type Pt(II) complexes containing tridentate N-donor ligands (1-8) or C-deprotonated N^C^N ligands derived from 1,3-di(2-pyridyl)benzene (10 13) and auxiliary N-heterocyclic carbene (NHC) ligand were synthesized. [Pt(trpy)(NHC)](2+) complexes 1-5 display green phosphorescence in CH2 Cl2 (Phi: 1.1-5.3 %; tau: 0.3-1.0 MUs) at room temperature. Moderate-to-intense emissions are observed for 1-7 in glassy solutions at 77 K and for 1-6 in the solid state. The [Pt(N^C^N)(NHC)](+) complexes 10-13 display strong green phosphorescence with quantum yields up to 65 % in CHCl3 . The reactions of 1 with a wide variety of anions were examined in various solvents. The tridentate N-donor ligand of 1 undergoes displacement reaction with CN(-) in protic solvents. Similar displacement of the N^C^N ligand by CN(-) has been observed for 10, leading to a luminescence "switch-off" response. The water-soluble 7 containing anthracenyl functionalized NHC ligand acts as a light "switch-on" sensor for the detection of CN(-) ion with high selectivity. The in vitro cytotoxicity of the Pt(II) complexes towards HeLa cells has been evaluated. Complex 12 showed high cytotoxicity with IC50 value of 0.46 MUM, whereas 1-4 and 6-8 are less cytotoxic. The cellular localization of the strongly luminescent complex 12 traced by using emission microscopy revealed that it mainly localizes in the cytoplasmic structures rather than in the nucleus. This complex can induce mitochondria dysfunction and subsequent cell death. PMID- 25828965 TI - Does a nitrogen matter? Synthesis and photoinduced electron transfer of perylenediimide donors covalently linked to C59N and C60 acceptors. AB - The first perylenediimide (PDI) covalently linked to an azafullerene (C59N) is described. PDI-C59N and PDI-C60 dyads where PDI acts as an electron-donor moiety have been synthesized by connection of the balls to the PDI 1-bay position. Photoexcitation of the PDI unit in both systems results in formation of the charge-separated state by photoinduced electron transfer from the singlet excited state of the PDI moiety to the C59N or to the C60 moiety. The charge-separated state has a lifetime of 400 ps in the case of PDI-C59N and 120 ps for the PDI-C60 dyad in benzonitrile at 298 K. This result has significant implications for the design of organic solar cells based on covalent donor-acceptor systems using C59N as an electron acceptor, indicating that longer-lived charge-separated states can be attained using C59N systems instead of C60 systems. PMID- 25828966 TI - Major incidents in England. PMID- 25828964 TI - Monoclonal and Single Domain Antibodies Targeting beta-Integrin Subunits Block Sexual Transmission of HIV-1 in In Vitro and In Vivo Model Systems. AB - BACKGROUND: Poor adherence to prevention regimens for gel-based anti-HIV-1 microbicides has been a major obstacle to more effective pre-exposure prophylaxis. Concern persists that the antiretroviral drug containing microbicides might promote development of antiretroviral resistance. METHODS: Using in vitro transwell systems and a humanized mouse model of HIV-1 sexual transmission, we examined, as candidate microbicides, antibodies targeting the heterodimeric leukocyte function-associated antigen 1 (LFA-1), a non-virally encoded protein acquired by the virus that also plays a critical role cell movement across endothelial and epithelial barriers. LFA-1-specific single domain variable regions from alpaca heavy-chain only antibodies (VHH) were identified and evaluated for their ability to inhibit HIV-1 transmission in the in vitro transwell system. RESULTS: Monoclonal antibodies targeting the CD11a and CD18 components of LFA-1 significantly reduced cell-free and cell-associated HIV-1 transmission in the in vitro transwell culture system and prevented virus transmission in the humanized mouse model of vaginal transmission. The broadly neutralizing monoclonal antibody b12 was unable to block transmission of cell free virus. CD11a-specific VHH were isolated and expressed and the purified variable region protein domains reduced in vitro transepithelial transmission with an efficacy comparable with that of the CD11a monoclonal antibody. CONCLUSIONS: Targeting integrins acquired by HIV-1 during budding and which are critical to interactions between epithelial cells and lymphocytes can reduce viral movement across epithelial barriers and prevent transmission in a humanized mouse model of sexual transmission. VHH capable of being produced by transformed bacteria can significantly reduce transepithelial virus transmission in in vitro model systems. PMID- 25828967 TI - Increasing procoagulant activity of circulating microparticles in patients with Philadelphia-negative myeloproliferative neoplasms: a single-centre experience. AB - Microparticles are small membrane fragments with dimension between 0.1 and 1 MUm, which are released during cell activation or apoptosis, exposing the phospholipid phosphatidylserine and membrane antigens typical for cellular origin. Philadelphia-negative myeloproliferative neoplasms (MPNs) are characterized by an increased risk of thrombosis. Data from literature suggest an association between thrombosis and the procoagulant activity of microparticles. Association between the procoagulant activity of microparticles and the incidence of thrombosis was assesed in a group of 126 patients with Philadelphia-negative MPNs. Measurement of microparticles procoagulant activity was performed using a functional assay, namely the Zymuphen MP-activity (Hyphen Biomed, Neuville-sur-oise, France). A total of 539 samples were analysed within this group of patients, regardless of patients' state of health. A significantly higher circulating microparticles procoagulant activity was found in MPN patients as compared with the control group (P < 0.001). A pathological level of procoagulant activity was observed more frequently in patients with polycythaemia vera (88%, P = 0.002) than groups of patients with essential thrombocythaemia (73.2%) and primary myelofibrosis (68.3%); the same result was confirmed in patients with a history of venous thrombosis in comparison with patients without thrombosis (84.7 vs. 73.2%, P = 0.029). Patients without cytoreductive treatment had a higher activity of microparticles (P = 0.010). Furthermore, presence of JAK2 V617F mutation was associated with an increased procoagulant activity (P = 0.007), as well as the higher JAK2 V617F allele burden (P = 0.001). Further prospective clinical studies will be necessary to evaluate the clinical relevance of microparticles in the prediction hypercoagulable state in these patients. PMID- 25828968 TI - Insights into direct anticoagulants. AB - For the past five decades, vitamin K antagonists (VKA) have been the only class of oral anticoagulants available for treating or preventing venous and arterial thromboembolism. Recently, new oral anticoagulants were developed to address significant restrictions regarding the use of VKAs. These drugs act by direct blockade of activated coagulation factor X (FXa) or thrombin. This present mini review highlights the pharmacological properties of these new anticoagulants, and discusses the supporting evidence for their usage as well as points to potential advantages and disadvantages of using these novel drugs in clinical practice. PMID- 25828969 TI - Factor XIII deficiency revealed by spontaneous intramedullary hemorrhage: confirmation of a severe mutation. AB - The factor XIII deficiency is a very rare disorder. We report here two cases of congenital deficiency of factor XIII, revealed by spontaneous intra-axial hemorrhage, one of them manifested with an intramedullary hemorrhage never described in the literature before. Our two patients were cousins from two consanguineous parents. We discuss in this study the clinical presentation, the diagnosis, the treatment, and the prevention of factor XIII deficiency coagulopathy. A mutation described only once before was confirmed and correlated again with a severe clinical presentation. PMID- 25828970 TI - Two symptomatic cases of dysfibrinogenemia in China: one with gamma-chain Arg275Cys mutation and another without detectable mutation in fibrinogen genes. AB - The aim of this study was to investigate causative mutations of two unrelated symptomatic Chinese children with dysfibrinogenemia and their family members.Fibrinogen genes, including FGA, FGB and FGG of all participants were PCR amplified, followed by direct sequencing. Precipitated plasma fibrinogen of some family members was analyzed by western blotting, fibrin polymerization and scanning electron microscopy (SEM).Proband 1 associated with frequent epistaxis was identified to harbor a heterozygous Arg275Cys mutation in FGG, along with a polymorphism Arg448Lys in FGB. Proband 2 with apparently prolonged thrombin time and very low functional fibrinogen had undergone both spontaneous intracranial hemorrhages and deep venous thrombosis. Sequencing of all proximal promoters, coding regions, introns and 3'-untranslated region using genomic DNA of Proband 2 yielded no mutation in three fibrinogen genes. Western blotting of this patient's precipitated plasma fibrinogen detected no truncated protein. Fibrinogen polymerization curve showed prolonged lag phase and severely decreased final turbidity, and SEM observations of fibrin clots made from Proband 2 revealed an abnormal sponge-like mass with large pores. We speculate that other underlying mechanisms responsible for dysfibrinogenemia such as abnormal posttranscriptional processing or posttranslational modification, which are independent of detectable mutations in the genomic DNA sequence, may exist. PMID- 25828971 TI - Acute renal infarction associated with homozygous methylenetetrahydrofolate reductase mutation C677T and IgA beta-2-glycoprotein antibodies. AB - Arterial thrombosis of the kidney(s) is a rare clinical entity usually presenting as a result of cardioembolic disease, though rare inherited hypercoagulable states have also been implicated. Within this context, both hyperhomocysteinemia triggered by a mutated methylenetetrahydrofolate reductase (MTHFR) gene product and the presence of antiphospholipid antibodies have been separately associated with arterial thrombotic events, including renal artery embolism. We present a case of combined homozygous MTHFR C677T mutation and IgA beta-2-glycoprotein antibody positivity resulting in acute renal infarction and previous silent myocardial infarction. An acute and otherwise unexplained thrombotic event of unusual location always warrants further investigation, which should include testing for hereditary thrombophilic disorders. PMID- 25828972 TI - Effect of serum monoclonal protein concentration on haemostasis in patients with multiple myeloma. AB - Abnormalities in haemostasis are often detected in patients with multiple myeloma and the fundamental factors that lead to these abnormities are worthy of exploration. The objective of this study was to investigate bleeding diathesis and coagulopathy in different multiple myeloma types or stages and assess how paraprotein concentration contributes to differences in these conditions. Haemostasis screening tests and serum monoclonal protein (M protein) concentration were retrospectively analysed in 101 patients newly diagnosed with multiple myeloma from January 2012 to April 2014. No significant differences were found between bleeding diathesis and types or International Staging System (ISS) stages of multiple myeloma; however, prolonged thrombin time (TT) was found in most of patients (77.7%) and was positively related to light-chain concentration (P <= 0.01). Prolonged prothrombin time (PT) was more obvious in IgA and IgG-type multiple myeloma than in the light-chain type (P <= 0.01). With increased clinical staging, PT remarkably increased (P <= 0.01). M protein concentration was significantly higher in patients with prolonged PT than in those with normal PT (P <= 0.01). The D-dimer mean was significantly higher than normal (>0.5 MUg/ml) (P <= 0.01). Fibrinogen was negatively related to M protein levels (P <= 0.01); however, there was no correlation between activated partial thromboplastin time (APTT) and multiple myeloma stages or types, M protein levels and serum light-chain concentration (P >= 0.05). Patients with light-chain type multiple myeloma were more likely to have prolonged TT than patients with other types. M protein levels had an obvious effect on PT. Prolonged PT was more common in IgA and IgG-type multiple myeloma. Abnormal haemostasis test results are not always accompanied by clinically apparent haemostatic complications. PMID- 25828973 TI - Brain Mechanisms Underlying Urge Incontinence and its Response to Pelvic Floor Muscle Training. AB - PURPOSE: Urge urinary incontinence is a major problem, especially in the elderly, and to our knowledge the underlying mechanisms of disease and therapy are unknown. We used biofeedback assisted pelvic floor muscle training and functional brain imaging (functional magnetic resonance imaging) to investigate cerebral mechanisms, aiming to improve the understanding of brain-bladder control and therapy. MATERIALS AND METHODS: Before receiving biofeedback assisted pelvic floor muscle training functionally intact, older community dwelling women with urge urinary incontinence as well as normal controls underwent comprehensive clinical and bladder diary evaluation, urodynamic testing and brain functional magnetic resonance imaging. Evaluation was repeated after pelvic floor muscle training in those with urge urinary incontinence. Functional magnetic resonance imaging was done to determine the brain reaction to rapid bladder filling with urgency. RESULTS: Of 65 subjects with urge urinary incontinence 28 responded to biofeedback assisted pelvic floor muscle training with 50% or greater improvement of urge urinary incontinence frequency on diary. However, responders and nonresponders displayed 2 patterns of brain reaction. In pattern 1 in responders before pelvic floor muscle training the dorsal anterior cingulate cortex and the adjacent supplementary motor area were activated as well as the insula. After the training dorsal anterior cingulate cortex/supplementary motor area activation diminished and there was a trend toward medial prefrontal cortex deactivation. In pattern 2 in nonresponders before pelvic floor muscle training the medial prefrontal cortex was deactivated, which changed little after the training. CONCLUSIONS: In older women with urge urinary incontinence there appears to be 2 patterns of brain reaction to bladder filling and they seem to predict the response and nonresponse to biofeedback assisted pelvic floor muscle training. Moreover, decreased cingulate activation appears to be a consequence of the improvement in urge urinary incontinence induced by training while prefrontal deactivation may be a mechanism contributing to the success of training. In nonresponders the latter mechanism is unavailable, which may explain why another form of therapy is required. PMID- 25828974 TI - Prostate Biopsy Markers of Inflammation are Associated with Risk of Clinical Progression of Benign Prostatic Hyperplasia: Findings from the MTOPS Study. AB - PURPOSE: Factors associated with worsening of benign prostatic hyperplasia are not well understood. We measured inflammatory markers from prostate biopsies to study if inflammation is related to clinical progression of benign prostatic hyperplasia. MATERIALS AND METHODS: We measured inflammatory cell markers CD45, CD4, CD8 and CD68 in transition zone biopsies from 859 men in the MTOPS biopsy substudy. Using novel imaging techniques we quantified amounts of moderate/severe inflammation. Benign prostatic hyperplasia clinical progression was defined as a confirmed 4-point or greater increase in the AUA symptom score from baseline, or the occurrence of urinary incontinence or acute urinary retention. Baseline clinical parameters including concomitant medication use were determined. Kaplan Meier curves and multivariate Cox proportional hazard models were used to determine the risk of progression. RESULTS: Inflammation as measured by CD45, CD4 and CD68 increased the risk of clinical progression of benign prostatic hyperplasia. CD4 showed the highest risk where men in the highest tertile of moderate/severe inflammation were at twice the risk of progression compared to men in the lower 2 tertiles combined (HR 2.03, p=0.001). Inflammation was more strongly associated with progression defined by acute urinary retention or incontinence (HR ranging from 2.39 [CD8, p=0.03] to 3.08 [CD4, p=0.01]) than an AUA symptom score increase (CD4, HR 1.86, p=0.01). Men who reported use of nonsteroidal anti-inflammatory drugs or steroids at baseline tended to be at higher risk for progression. CONCLUSIONS: Although our data show that inflammation increases the risk of progression, our findings suggest that inflammation has a greater role in men who have conditions requiring anti inflammatory medications. PMID- 25828975 TI - Alternative modes of biofilm formation by plant-associated Bacillus cereus. AB - The ability to form multicellular communities known as biofilms is a widespread adaptive behavior of bacteria. Members of the Bacillus group of bacteria have been found to form biofilms on plant roots, where they protect against pathogens and promote growth. In the case of the model bacterium Bacillus subtilis the genetic pathway controlling biofilm formation and the production of an extracellular matrix is relatively well understood. However, it is unclear whether other members of this genus utilize similar mechanisms. We determined that a plant-associated strain of Bacillus cereus (905) can form biofilms by two seemingly independent pathways. In one mode involving the formation of floating biofilms (pellicles) B. cereus 905 appears to rely on orthologs of many of the genes known to be important for B. subtilis biofilm formation. We report that B. cereus 905 also forms submerged, surface-associated biofilms and in a manner that resembles biofilm formation by the pathogen Staphylococcus aureus. This alternative mode, which does not rely on B. subtilis-like genes for pellicle formation, takes place under conditions of glucose fermentation and depends on a drop in the pH of the medium. PMID- 25828976 TI - Hiring peers as vocational specialists. PMID- 25828978 TI - Step up to the bar: avoiding discrimination in professional licensure. AB - In their efforts to protect the public from impaired professionals, licensure boards often have created special rules for applicants with mental disorders. The authorities in charge of admission to the Louisiana bar required extensive disclosure of mental health status, even if an applicant's professional functioning was not impaired. After the U.S. Department of Justice found that Louisiana's practices violated applicants' rights under the Americans with Disabilities Act, the state agreed to focus on applicants' functional impairment rather than on mental disorders. This settlement may provide a model for licensure boards in other states and for other professions, including the health professions. PMID- 25828979 TI - Finding Hannah. PMID- 25828980 TI - Associations between continuity of care and patient outcomes in mental health care: a systematic review. AB - OBJECTIVE: Research investigating the association between continuity of care (CoC) and patient outcomes in mental health care is limited. A previous review (1970-2002) concluded that evidence for an association between CoC and outcomes was inconsistent and limited. This systematic review, conducted a decade later, provides an update. METHODS: Searches (1950-2014) were conducted on MEDLINE and PsycINFO. Included studies used a clearly identified measure of CoC and examined its relation to an outcome among adults (ages 18-65). Only English-language publications were included. RESULTS: A total of 984 studies were identified that measured CoC. Eighteen met inclusion criteria, and 13 found an association between CoC and an outcome. As found in the previous review, studies reported conflicting results for the most frequently examined outcomes (hospitalization, symptom severity, social functioning, and service satisfaction). Little consistency was found between studies in choice of CoC measures and outcomes. Studies varied markedly in quality. Two of the three studies rated as good quality reported significant associations between CoC and social functioning. Compared with older studies, studies published since the previous systematic review (2002-2014) found a larger proportion of significant associations. CONCLUSIONS: Little consistency was found in the way CoC was measured, which made it difficult to compare studies. Therefore, clear evidence about the association between CoC and outcomes remains limited. Results in regard to social functioning are encouraging. However, in order for conclusions to be made, researchers need to be more consistent with the measures they choose to allow comparison of studies. PMID- 25828981 TI - First outpatient follow-up after psychiatric hospitalization: does one size fit all? AB - OBJECTIVE: Claims-based indicators of follow-up within seven and 30 days after psychiatric discharge have face validity as quality measures: early follow-up may improve disease management and guide appropriate service use. Yet these indicators are rarely examined empirically. This study assessed their association with subsequent health care utilization for adults with comorbid conditions. METHODS: Postdischarge follow-up and subsequent utilization were examined among adults enrolled in North Carolina Medicaid who were discharged with claims-based diagnoses of depression or schizophrenia and not readmitted within 30 days. A total of 24,934 discharges (18,341 individuals) in fiscal years 2008-2010 were analyzed. Follow-up was categorized as occurring within 0-7 days, 8-30 days, or none in 30 days. Outcomes in the subsequent six months included psychotropic medication claims, adherence (proportion of days covered), number of hospital admissions, emergency department visits, and outpatient visits. RESULTS: Follow up within seven days was associated with greater medication adherence and outpatient utilization, compared with no follow-up in 30 days. This was observed for both follow-up with a mental health provider and with any provider. Adults receiving mental health follow-up within seven days had equivalent, or lower, subsequent inpatient and emergency department utilization as those without follow up within 30 days. However, adults receiving follow-up with any provider within seven days were more likely than those with no follow-up to have an inpatient admission or emergency department visit in the subsequent six months. Few differences in subsequent utilization were observed between mental health follow up within seven days versus eight to 30 days. CONCLUSIONS: For patients not readmitted within 30 days, follow-up within 30 days appeared to be beneficial on the basis of subsequent service utilization. PMID- 25828982 TI - Efficacy of aftercare services for people with severe mental disorders in Iran: a randomized controlled trial. AB - OBJECTIVES: This study aimed to determine whether aftercare services reduced the number of rehospitalizations and length of hospital stay among patients with severe mental disorders. METHODS: A total of 120 patients with schizophrenia and schizoaffective or bipolar disorder between the ages of 15 and 65 were recruited from 2010 to 2012 for a randomized controlled trial. The participants were followed up for 20 months after discharge from a university-affiliated hospital in Tehran, Iran. The selection procedure was random sampling. Sixty patients received aftercare services, which included treatment follow-up, family psychoeducation, and patient social skills training, and 60 patients received treatment as usual. Number of hospitalizations and length of hospital stay were primary outcome measures, and severity of psychopathology and severity of illness were secondary outcome measures. The quantitative primary and secondary outcomes measures were compared by using repeated-measures analysis. RESULTS: Three members of the control group did not complete the study. The cumulative number of hospitalizations during the follow-up period was 55 for the control group and 26 for the intervention group. Length of stay was significantly greater in the control group compared with the intervention group (rate ratio=2.38, 95% confidence interval=2.17-2.62). Psychopathology was less severe in the intervention group compared with the control group (p<.001). CONCLUSIONS: Aftercare services are efficacious for reducing both the need for rehospitalization and the severity of psychopathology. PMID- 25828983 TI - Concurrent use of stimulants and second-generation antipsychotics among children with ADHD enrolled in Medicaid. AB - OBJECTIVE: This study examined the prevalence of and factors associated with concurrent use of long-acting stimulants (LAS) and second-generation antipsychotic agents among children and adolescents with attention-deficit hyperactivity disorder (ADHD). METHODS: The study involved retrospective longitudinal analysis of 2003-2007 Medicaid data from four states for children and adolescents between the ages of six and 17 years who were diagnosed as having ADHD and initiated LAS treatment. Concurrent use of LAS and second-generation antipsychotic medications was defined as simultaneous receipt of both medications for at least 14 days. On the basis of the conceptual framework of the Andersen behavioral model, multivariable logistic regression analysis was used to examine predisposing, enabling, and need factors associated with concurrent use. RESULTS: Among the 61,793 children who initiated LAS treatment for ADHD, 11,866 (19.2%) received LAS and second-generation antipsychotics concurrently for at least 14 days. Overall, the average length of concurrent use was 130+/-98 days. Multivariable logistic regression revealed that concurrent use was higher among boys, blacks, and foster care children compared with their respective counterparts. Comorbid psychiatric conditions, including disorders that are not approved indications for second-generation antipsychotic use, were associated with concurrent use of LAS and second-generation antipsychotics. CONCLUSIONS: Almost one in five children and adolescents who initiated LAS also received second-generation antipsychotics concurrently for at least 14 days. Approved and nonapproved indications of second-generation antipsychotics influenced concurrent use in pediatric ADHD. PMID- 25828984 TI - Detection and treatment of mental health issues by pediatric PCPs in New York State: an evaluation of Project TEACH. AB - OBJECTIVE: The authors evaluated Project TEACH (PT), a statewide training and consultation program for pediatric primary care providers (PCPs) on identification and treatment of mental health conditions. METHODS: An intervention group of 176 PCPs who volunteered for PT training was compared with a stratified random sample of 200 PCPs who did not receive PT training. Data on prescription practices, diagnoses, and follow-up care were from New York State Medicaid files (2009-2013) for youths seen by the trained (N=21,784) and untrained (N=46,607) PCPs. RESULTS: The percentage of children prescribed psychotropic medication increased after PT training (9% to 12%, p<.001), a larger increase than in the untrained group (4% to 5%, p<.001) (comparison, p<.001). Fewer differences were noted in diagnoses and in medication use and follow-up care among children with depression. CONCLUSIONS: This intervention may have an impact on providers' behaviors, but further research is needed to clarify its effectiveness. PMID- 25828985 TI - Smoking and smoking cessation treatment among hospitalized psychiatric patients. PMID- 25828986 TI - Grief, bereavement and depression: a clarification. PMID- 25828987 TI - Grief, bereavement and depression: a clarification: in reply. PMID- 25828988 TI - Symptom severity and readiness to quit among hospitalized smokers with mental illness. PMID- 25828990 TI - The Role of Breast Size and Areolar Pigmentation in Perceptions of Women's Sexual Attractiveness, Reproductive Health, Sexual Maturity, Maternal Nurturing Abilities, and Age. AB - Women's breast morphology is thought to have evolved via sexual selection as a signal of maturity, health, and fecundity. While research demonstrates that breast morphology is important in men's judgments of women's attractiveness, it remains to be determined how perceptions might differ when considering a larger suite of mate relevant attributes. Here, we tested how variation in breast size and areolar pigmentation affected perceptions of women's sexual attractiveness, reproductive health, sexual maturity, maternal nurturing abilities, and age. Participants (100 men; 100 women) rated images of female torsos modeled to vary in breast size (very small, small, medium, and large) and areolar pigmentation (light, medium, and dark) for each of the five attributes listed above. Sexual attractiveness ratings increased linearly with breast size, but large breasts were not judged to be significantly more attractive than medium-sized breasts. Small and medium-sized breasts were rated as most attractive if they included light or medium colored areolae, whereas large breasts were more attractive if they had medium or dark areolae. Ratings for perceived age, sexual maturity, and nurturing ability also increased with breast size. Darkening the areolae reduced ratings of the reproductive health of medium and small breasts, whereas it increased ratings for large breasts. There were no significant sex differences in ratings of any of the perceptual measures. These results demonstrate that breast size and areolar pigmentation interact to determine ratings for a suite of sociosexual attributes, each of which may be relevant to mate choice in men and intra-sexual competition in women. PMID- 25828991 TI - Gender Differences and Similarities in Receptivity to Sexual Invitations: Effects of Location and Risk Perception. AB - Since the publication of the seminal paper by Clark and Hatfield (1989), there has been an ongoing discussion about their finding that men accept sexual invitations from females more willingly than vice versa. We focused on two questions that have not yet been answered: First, what happens when the same request for casual sex is made in a different setting where social pressure is lower and such a request more common? To address this issue, 6 male and 8 female average looking confederates approached 162 men and 119 women either at a university campus or in a nightclub and asked for a date or for casual sex. The gender difference remained, with significantly more men than women consenting to a sexual invitation. The second issue concerned the perceived risk for women of accepting such an offer. We made up an elaborate cover story and invited 60 male and female participants into our laboratory. They were shown 10 pictures of persons of the opposite sex and led to believe that these people either consented to date or to have sex with them. The participants then could choose from the pictures who they wanted to meet to engage in a date or sex. In this subjectively safer environment, the gender difference disappeared, with the same proportion of men and women consenting to a date or sex. However, men were more liberal in their choice in either condition, compared to the female subjects. We conclude that while gender differences remained in both experiments, women were more liberal in a subjectively safer situation. PMID- 25828992 TI - Drug-induced cholestasis detection in cryopreserved rat hepatocytes in sandwich culture. AB - INTRODUCTION: In vitro identification of compounds that cause cholestasis in vivo still remains a problem in pharmaceutical R&D. Currently existing in vitro systems show poor predictivity towards the clinical situation. Recently, our research group developed a model, based on sandwich-cultured (rat) hepatocytes (SC(R)H), to detect compounds causing cholestasis via altered bile acid (BA) homeostasis (Chatterjee et al., 2014). In the present study, we assessed whether this model performs equally well with freshly-isolated and cryopreserved hepatocytes. METHODS: We exposed sandwich cultures from rat hepatocytes before and after cryopreservation to the cholestatic compounds, cyclosporin A (CsA) and troglitazone (Tro), in the presence and in the absence of a BA mixture. At the end of the incubations, the capability of the hepatocytes to produce urea was measured to determine changes in the drug-induced cholestasis index (DICI). RESULTS: The mean (+/- SEM) urea production was significantly higher in sandwich cultures from freshly-isolated hepatocytes (27.88 (+/- 0.96) nmol/cm(2)), compared to cultures from cryopreserved hepatocytes (22.86 (+/- 1.91) nmol urea/cm(2)). However, after normalization for confluence rate (based on light microscopic image analysis), it appeared that the urea production was similar for all the batches of SCRH. The mean (+/- SEM) DICI values for CsA 10 MUM and Tro 75 MUM were 0.89 (+/- 0.03) and 0.93 (+/- 0.03), respectively. Higher concentrations, CsA (>= 15 MUM) and Tro (>= 100 MUM), elicited a significant decrease in urea production when incubated in the presence of a BA mixture compared to the compound alone. This was the case for all the batches of SCRH, irrespective of cryopreservation history. DISCUSSION: In conclusion, no significant differences were seen when the previously described in vitro cholestasis model was applied in SCRH before or after cryopreservation. This study demonstrates the robustness of the model, which implies that it can be used with SCRH obtained from both freshly-isolated and cryopreserved hepatocytes. PMID- 25828993 TI - Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality. AB - BACKGROUND: Clostridium difficile infection (CDI) can cause severe disease and death, especially in older adults. A better understanding of risk factors for adverse outcomes is needed. This study tests the hypotheses that infection with specific ribotypes and presence of stool toxins independently associate with severity and constructs predictive models of adverse outcomes. METHODS: Cases of non-recurrent CDI were prospectively included after positive stool tests for toxins A and/or B by enzyme immunoassay (EIA) or tcdB by polymerase chain reaction. Outcomes included severe CDI (intensive care unit admission, colectomy, or death attributable to CDI within 30 days of diagnosis) and 30-day all-cause mortality. Adjusted models were developed to test hypotheses and predict outcomes. RESULTS: In total, 1144 cases were included. The toxin EIA was positive in 37.2% and 35.6% of patients were of age >65 years. One of the 137 unique ribotypes was ribotype 027 (16.2%). Detectable stool toxin did not associate with outcomes. Adjusting for covariates, including age, Ribotype 027 was a significant predictor of severe CDI (90 cases; odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.89; P = .037) and mortality (89 cases; OR, 2.02; 95% CI, 1.19-3.43; P = .009). Concurrent antibiotic use associated with both outcomes. Both multivariable predictive models had excellent performance (area under the curve >0.8). CONCLUSIONS: Detection of stool toxin A and/or B by EIA does not predict severe CDI or mortality. Infection with ribotype 027 independently predicts severe CDI and mortality. Use of concurrent antibiotics is a potentially modifiable risk factor for severe CDI. PMID- 25828996 TI - Editorial commentary: Clostridium difficile ribotype 027: an intrinsically virulent strain, but clinical virulence remains to be determined at the bedside. PMID- 25828994 TI - Concurrent Anemia and Elevated C-Reactive Protein Predicts HIV Clinical Treatment Failure, Including Tuberculosis, After Antiretroviral Therapy Initiation. AB - BACKGROUND: Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART. METHODS: A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP >= 10 mg/L) with clinical failure were assessed using multivariable Cox models. RESULTS: Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation. CONCLUSIONS: ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening. PMID- 25828997 TI - Assessing the Likely Impact of a Rotavirus Vaccination Program in England: The Contribution of Syndromic Surveillance. AB - BACKGROUND: In July 2013, a rotavirus vaccination program for 2- to 3-month-olds was introduced in the United Kingdom. We present an initial impact analysis of this new vaccine program using national syndromic surveillance systems. METHODS: General practitioner (GP) in-hours, GP out-of-hours, and emergency department (ED) syndromic surveillance systems were used to monitor GP consultations and ED visits for gastroenteritis, diarrhea, and vomiting. Data were stratified by age group and compared between pre- and postvaccine-year rotavirus seasons. Incidence rate ratios (IRRs) and percentage ratios were calculated for GP in-hours consultations and GP out-of-hours and ED data, respectively. RESULTS: There was a significant reduction in gastroenteritis, diarrhea, and vomiting GP in-hours consultations in children aged 0-4 years when comparing the rotavirus season in the pre- and postvaccine years (P < .001 for all indicators). IRRs illustrated a 26%-33% and 23%-31% decrease in gastroenteritis incidence in the <1 and 1-4 years age groups, respectively, across the syndromic surveillance systems. There was also an 8% decrease recorded in the 5-14 years age group in the GP in-hours and ED systems. CONCLUSIONS: Syndromic surveillance revealed a marked decline in gastroenteritis, coinciding with the introduction of the new rotavirus vaccine program in England. The largest reduction in disease was observed in infants, although some impact was also demonstrated in children aged 1-4 and 5-14 years, suggesting possible herd protection in older age groups. This study was limited to the first postvaccine year, and further analysis is required to assess the longer-term impact of the vaccine. PMID- 25828998 TI - Extensive Household Outbreak of Urinary Tract Infection and Intestinal Colonization due to Extended-Spectrum beta-Lactamase-Producing Escherichia coli Sequence Type 131. AB - BACKGROUND: Reasons for the successful global dissemination of multidrug resistant Escherichia coli sequence type 131 (ST131) are undefined, but may include enhanced transmissibility or ability to colonize the intestine compared with other strains. METHODS: We identified a household in which 2 young children had urinary tract infection (UTI) caused by an extended-spectrum beta-lactamase (ESBL)-producing, multidrug-resistant ST131 E. coli strain. We assessed the prevalence of ST131 intestinal colonization among the 7 household members (6 humans, 1 dog). Fecal samples, collected 3 times over a 19-week period, were cultured selectively for E. coli. Isolates were characterized using clone specific polymerase chain reaction to detect ST131 and its ESBL-associated H30Rx subclone, pulsed-field gel electrophoresis, extended virulence genotyping, and antimicrobial susceptibility testing. RESULTS: In total, 8 different E. coli pulsotypes (strains) were identified. The index patient's urine isolate represented ST131-H30Rx strain 903. This was the most widely shared and persistent strain in the household, colonizing 5 individuals at each sampling. In contrast, the 7 non-ST131 strains were each found in only 1 or 2 household members at a time, with variable persistence. The ST131 strain was the only strain with both extensive virulence and antimicrobial resistance profiles. CONCLUSIONS: An ESBL-producing ST131-H30Rx strain caused UTI in 2 siblings, plus asymptomatic intestinal colonization in multiple other household members, and was the household's most extensively detected and persistent fecal E. coli strain. Efficient transmission and intestinal colonization may contribute to the epidemiologic success of the H30Rx subclone of E. coli ST131. PMID- 25828999 TI - Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications. AB - BACKGROUND: Good syndrome (GS) is a rare condition in which thymoma is associated with hypogammaglobulinemia. It is characterized by increased susceptibility to bacterial, viral, and fungal infections, as well as autoimmunity. Most patients have no circulating B cells. METHODS: The French DEFicit Immunitaire de l'adulte cohort provides detailed clinical and immunological descriptions of 690 adults with primary hypogammaglobulinemia. Comparisons between patients with GS, those with common variable immunodeficiency (CVID), and those with B(-) CVID (circulating B cells <1%) were performed. RESULTS: Twenty-one patients had GS and 440 had CVID, including 39 B(-) CVID, with a median age at diagnosis of 60, 35, and 34 years, respectively. Invasive bacterial infections were observed in 90.5% of GS, 54% of CVID, and 72% of B(-) CVID patients. Eight patients with GS had opportunistic infections, despite normal peripheral CD4(+) T-cell numbers. Autoimmune complications were demonstrated in 76% of GS, 29% of CVID, and 26% of B(-) CVID patients. The spectrum of autoimmunity in GS was uncommon, consisting of oral lichen planus, graft-vs-host disease-like colitis, and pure red cell aplasia, different from the pattern observed in CVID patients. GS patients did not display lymphoid hyperplasia nor lymphoma, unlike those with CVID or B(-) CVID. CONCLUSIONS: GS differs notably from CVID and B(-) CVID: very late onset, no familial cases, and absence of lymphoid hyperplasia. The key observation is the very high frequency of invasive bacterial infections in GS, an issue that physicians should be aware of. PMID- 25829001 TI - Comparative effectiveness of high-dose versus standard-dose influenza vaccination in community-dwelling veterans. AB - BACKGROUND: Influenza is a significant cause of morbidity and mortality in older adults. High-dose (HD) trivalent inactivated vaccine has increased immunogenicity in older adults compared with standard-dose (SD) vaccine. We assessed the relative effectiveness of HD influenza vaccination (vs SD influenza vaccination). METHODS: We conducted a retrospective cohort study among patients who receive primary care at Veteran Health Administration (VHA) medical centers, and who received influenza vaccine in the 2010-2011 influenza season. The primary outcome was hospitalization for influenza or pneumonia. We also conducted an analysis in subgroups defined by age. RESULTS: We evaluated 25 714 patients who received HD vaccine and 139 511 who received SD vaccine in 23 VHA medical centers. The rate of hospitalization for influenza or pneumonia was 0.3% in both groups in the influenza season. After accounting for patient characteristics in propensity adjusted analyses, the risk of hospitalization for influenza or pneumonia was not significantly lower among patients receiving HD vaccine vs those receiving SD vaccine (risk ratio, 0.98; 95% confidence interval, .68-1.40). In the subgroup of patients >=85 years of age, receiving HD (compared with SD) vaccine was associated with lower rates of hospitalization for influenza or pneumonia. CONCLUSIONS: HD vaccine was not found to be more effective than SD vaccine in protecting against hospitalization for influenza or pneumonia; however, we found a protective effect in the oldest subgroup of patients. Additional studies are needed to evaluate the effectiveness of HD vaccine. PMID- 25829002 TI - Editorial commentary: genotyping of Mycobacterium tuberculosis in China and missing links in the chain of ongoing transmission of tuberculosis. PMID- 25829000 TI - Transmission of Mycobacterium tuberculosis in China: a population-based molecular epidemiologic study. AB - BACKGROUND: Understanding the transmission of Mycobacterium tuberculosis is essential for the development of efficient tuberculosis control strategies. China has the second-largest tuberculosis burden in the world. Recent transmission and infection with M. tuberculosis, particularly drug-resistant strains, may account for many new tuberculosis cases. METHODS: We performed a population-based molecular epidemiologic study of pulmonary tuberculosis in China during 1 July 2009 to 30 June 2012. We defined clusters as cases with identical variable number tandem repeat genotype patterns and identified the risk factors associated with clustering, by logistic regression. Relative transmission rates were estimated by the sputum smear status and drug susceptibility status of tuberculosis patients. RESULTS: Among 2274 culture-positive tuberculosis patients with genotyped isolates, there were 705 (31.0%) tuberculosis patients in 287 clusters. Multidrug resistant (MDR) tuberculosis (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.25-2.63) and infection with a Beijing family strain (aOR, 1.56; 95% CI, 1.23-2.96) were associated with clustering. Eighty-four of 280 (30.0%) clusters had a putative source case that was sputum smear negative, and 30.6% of their secondary cases were attributed to transmission by sputum smear-negative patients. The relative transmission rate for sputum smear negative compared with sputum smear-positive patients was 0.89 (95% CI, .68-1.10), and was 1.51 (95% CI, 1.00-2.24) for MDR tuberculosis vs drug-susceptible tuberculosis. CONCLUSIONS: Recent transmission of M. tuberculosis, including MDR strains, contributes substantially to tuberculosis disease in China. Sputum smear-negative cases were responsible for at least 30% of the secondary cases. Interventions to reduce the transmission of M. tuberculosis should be implemented in China. PMID- 25829004 TI - High-dose oral amoxicillin plus probenecid is highly effective for syphilis in patients with HIV infection. AB - BACKGROUND: Intramuscular benzathine penicillin G (BPG) is widely used for the treatment of syphilis. However, BPG is not available in some countries. This study examined the effectiveness and safety of high-dose oral amoxicillin plus probenecid for the treatment of syphilis in patients with human immunodeficiency virus type 1 (HIV-1). METHODS: This retrospective observational study included 286 HIV-infected male patients with syphilis (median age, 36 years; median CD4 count, 389 cells/uL) who were treated with oral amoxicillin 3 g plus probenecid. Syphilis was diagnosed by both serum rapid plasma reagin (RPR) titers >=8 and positive Treponema pallidum hemagglutination test. Patients with neurosyphilis diagnosed by cerebrospinal fluid examination were excluded. Successful treatment was defined as a at least 4-fold decrement in RPR titer. RESULTS: The overall treatment efficacy was 95.5% (95% confidence interval [CI], 92.4%-97.7%; 273/286 patients), and efficacy for primary, secondary, early latent, late latent, and unknown duration syphilis was 93.8% (95% CI, 68.1%-99.8%; 15/16), 97.3% (95% CI, 92.9%-99.2%; 142/146), 100% (95% CI, 90.5%-100%; 37/37), 85.7% (95% CI, 58.6% 96.4%; 18/21), and 92.4% (95% CI, 81.9%-97.3%; 61/66), respectively. Treatment duration was mostly 14-16 days (49.7%) or 28-30 days (34.3%), with efficacy of 94.4% (134/142) and 95.9% (94/98), respectively; 96.3% of successfully treated patients achieved a >=4-fold decrement in RPR titer within 12 months. Adverse events were noted in 28 (9.8%) patients, and 25 of these (89.3%) were successfully treated. Only 6% of patients underwent lumbar puncture. CONCLUSIONS: The combination of oral amoxicillin 3 g plus probenecid was highly effective and tolerable for the treatment of syphilis in patients with HIV-1 infection. PMID- 25829005 TI - Type VI secretion system. AB - Bacteria employ a variety of tools to survive in a competitive environment. Salomon and Orth describe one such tool-the Type 6 Secretion Systems used by bacteria to deliver a variety of toxins into competing cells. PMID- 25829006 TI - Symmetry is less than meets the eye. AB - Symmetry is a ubiquitous feature in the visual environment and can be detected by a variety of species, ranging from insects through to humans [1,2]. Here we show it can also bias estimates of basic scene properties. Mirror (reflective) symmetry can be detected in as little as 50 ms, in both natural and artificial visual scenes, and even when embedded within cluttered backgrounds [1]. In terms of its biological relevance, symmetry is a key determinant in mate selection; the degree of symmetry in a face is positively associated with perceived healthiness and attractiveness ratings [3]. In short, symmetry processing mechanisms are an important part of the neural machinery of vision. We reveal that the importance of symmetry extends beyond the processing of shape and objects. Mirror symmetry biases our perception of scene content, with symmetrical patterns appearing to have fewer components than their asymmetric counterparts. This demonstrates an interaction between two fundamental dimensions of visual analysis: symmetry [1] and number [4]. We propose that this numerical underestimation results from a processing bias away from the redundant information within mirror symmetrical displays, extending existing theories regarding redundancy in visual analysis [5,6]. PMID- 25829007 TI - Circadian biology: the early bird catches the morning shift. AB - Shift work misaligns the environment and the body's internal clock. A new study suggests that this 'social jet lag' can be remedied by a 'personalized schedule', an intervention that may help reduce circadian misalignment and pathologies in shift workers. PMID- 25829008 TI - Stomatal closure: the old guard takes up the SLAC. AB - Flowering plant stomata close through passive dehydration or by active pumping of anions through SLAC, a phospho-activated membrane channel. A new study reports that moss likely utilise this same mechanism, and thus supports an early origin for SLAC-mediated active stomatal control. PMID- 25829009 TI - Neurobiology: imaging prey capture circuits in zebrafish. AB - Two recent studies used a virtual hunting assay and functional imaging to identify prey-capture circuits in zebrafish. Together they show that the optic tectum and a pretectal region are two retinorecipient areas important for the recognition and capture of prey. PMID- 25829010 TI - Epithelial cell division: keeping aneuploidy levels in check. AB - Aneuploidy is deleterious at the cellular and organismal level and can promote tumorigenesis. Two new studies in Drosophila imaginal discs underscore the cellular and tissue-wide mechanisms that prevent the accumulation of aneuploid cells in symmetrically dividing epithelial tissues upon changes in centrosome number. PMID- 25829011 TI - Synaptic dynamics: how network activity affects neuron communication. AB - Synaptic responses are generally studied in the absence of spontaneous spiking, contrasting with the situation in the intact brain. A new study shows that even small increases in spontaneous network firing can significantly affect the properties and dynamics of excitatory evoked response in sensory neocortex. PMID- 25829012 TI - Small RNAs: artificial piRNAs for transcriptional silencing. AB - Technologies have been developed in animal germ cells that produce artificial piRNAs from transgenes in piRNA clusters to silence target genes by cleaving their transcripts. A new study provides a simple way to generate artificial piRNAs to direct de novo DNA methylation in mice. PMID- 25829013 TI - Bioluminescence: a fungal nightlight with an internal timer. AB - A recent study shows that green light emission by Neonothopanus gardneri mushrooms, endemic to coconut forests of Northern Brazil, is controlled by a circadian clock. Furthermore, insects are attracted by the light, raising the possibility that bioluminescence functions in spore dispersal and fungal dissemination. PMID- 25829014 TI - Evolution: tinkering within gene regulatory landscapes. AB - Recently evolved enhancers dominate mammalian gene regulatory landscapes. Mostly exapted from ancestral DNA sequences, many are linked to genes under positive selection. Just as RNA-seq some years ago, unbiased enhancer mapping is on the verge of changing evolutionary research. PMID- 25829015 TI - Membrane trafficking: returning to the fold(ER). AB - Retrieval mechanisms are essential to dynamically maintain the composition and functional homeostasis of secretory organelles. A recent study has identified a novel class of cargo receptor that retrieves a specific subset of escaped ER folding machinery from the Golgi. PMID- 25829016 TI - Enhancers: holding out for the right promoter. AB - Some transcriptional enhancers work best with one type of promoter, while ignoring others. How widespread is such specificity across the genome? A new study finds that, in a fair fight, most enhancers prefer to activate promoters resembling those of their parent genes. PMID- 25829017 TI - The augmin connection in the geometry of microtubule networks. AB - Microtubules mediate important cellular processes by forming highly ordered arrays. Organization of these networks is achieved by nucleating and anchoring microtubules at centrosomes and other structures collectively known as microtubule-organizing centers (MTOCs). However, the diverse microtubule configurations found in different cell types may not be generated and maintained by MTOCs alone. Work over the last few years has revealed a mechanism that has the capacity to generate cell-type-specific microtubule arrays independently of a specific organizer: nucleation of microtubules from the lateral surface of pre existing microtubules. This type of nucleation requires cooperation between two different multi-subunit protein complexes, augmin and the gamma-tubulin ring complex (gammaTuRC). Here we review recent molecular insight into microtubule dependent nucleation and discuss the possibility that the augmin-gammaTuRC module, initially described in mitosis, may broadly contribute to microtubule organization also in non-mitotic cells. PMID- 25829018 TI - Capture of Prey, Feeding, and Functional Anatomy of the Jaws in Velvet Worms (Onychophora). AB - Onychophorans are carnivorous, terrestrial invertebrates that occur in tropical and temperate forests of the Southern Hemisphere and around the Equator. Together with tardigrades, onychophorans are regarded as one of the closest relatives of arthropods. One of the most peculiar features of onychophorans is their hunting and feeding behavior. These animals secrete a sticky slime, which is ejected via a pair of slime-papillae, to entangle the prey. After the prey has been immobilized, its cuticle is punctured using a pair of jaws located within the mouth. These jaws constitute internalized appendages of the second body segment and are innervated by the deutocerebrum; thus, they are homologous to the chelicerae of chelicerates, and to the (first) antennae of myriapods, crustaceans, and insects. The jaws are also serial homologs of the paired claws associated with each walking limb of the trunk. The structure of the jaws is similar in representatives of the two major onychophoran subgroups, the Peripatidae and Peripatopsidae. Each jaw is characterized by an outer and an inner blade; while the outer blade consists only of a large principal tooth and up to three accessory teeth, the inner blade bears numerous additional denticles. These denticles are separated from the remaining part of the inner jaw by a diastema and a soft membrane only in peripatids. The onychophoran jaws are associated with large apodemes and specialized muscles that enable their movement. In contrast to the mandibles of arthropods, the onychophoran jaws are moved along, rather than perpendicular to, the main axis of the body. Our elemental analysis reveals an increased incorporation of calcium at the tip of each blade, which might provide rigidity, whereas there is no evidence for incorporation of metal or prominent mineralization. Stability of the jaw might be further facilitated by the cone-in-cone organization of its cuticle, as each blade consists of several stacked, cuticular elements. In this work, we summarize current knowledge on the jaws of onychophorans, which are a characteristic feature of these animals. PMID- 25829020 TI - High Expression of Human Leukocyte Antigen-G is Associated with a Poor Prognosis in Patients with PDAC. AB - Pancreatic Adenocarcinoma (PDAC) is one of the most deadly malignant tumors worldwide. A variety of mechanisms are involved in PDAC biological behaviors, of which, the mechanisms of immune escape may be a pivotal hallmark. HLA-G is a tolerant molecule implicated in tumor escape and serves as a prognostic biomarker in tumors. Our study evaluated the expression of HLA-G in PDAC and explored its clinical significance. In a cohort of 122 PDAC patients, 78 patents (63.9%) exhibited high level of HLA-G tumor tissues. Multivariate analysis suggested that HLA-G level was an independent predictor for OS (HR = 3.894, 95% CI = 2.380 6.370, p <0.001). High level of HLA-G significantly correlated with PDAC aggressive features, such as more advanced stage (TNM Stage II) (p<0.001), extrapancreatic infiltration (T3 stage) (p<0.001), lymph node involvement (p=0.019) and poor differentiation (p=0.010). In western blot analysis, almost all of the tumor cell lines (5/6) expressed high levels of HLA-G. In ELISA analysis, the level of plasma sHLA-G in PDAC patients were significantly increased than in healthy control (P=0.0037). Further analysis revealed the level of sHLA-G inversely related to numbers of peripheral activated T cells (CD8+CD28+ T cells), which may indicate that sHLA-G inactivates T cell responses resulting in tumor immune escape. In conclusion, tumor-derived HLA-G may indicate the mechanism of immune escape and impaired PDAC clinical outcome, especially in early-stage patients, which may also be a potential therapeutic target. PMID- 25829019 TI - Crocodilian Forebrain: Evolution and Development. AB - Organization and development of the forebrain in crocodilians are reviewed. In juvenile Caiman crocodilus, the following features were examined: identification and classification of dorsal thalamic nuclei and their respective connections with the telencephalon, presence of local circuit neurons in the dorsal thalamic nuclei, telencephalic projections to the dorsal thalamus, and organization of the thalamic reticular nucleus. These results document many similarities between crocodilians and other reptiles and birds. While crocodilians, as well as other sauropsids, demonstrate several features of neural circuitry in common with mammals, certain striking differences in organization of the forebrain are present. These differences are the result of evolution. To explore a basis for these differences, embryos of Alligator misissippiensis were examined to address the following. First, very early development of the brain in Alligator is similar to that of other amniotes. Second, the developmental program for individual vesicles of the brain differs between the secondary prosencephalon, diencephalon, midbrain, and hindbrain in Alligator. This is likely to be the case for other amniotes. Third, initial development of the diencephalon in Alligator is similar to that in other amniotes. In Alligator, alar and basal parts likely follow a different developmental scheme. PMID- 25829021 TI - Crystal structure, vibrational spectra and DFT simulations of 2-fluoro-4 bromobenzaldehyde. AB - Molecular structure and properties of 2-fluoro-4-bromobenzaldehyde (FBB, C7H4BrFO) was experimentally investigated by X-ray diffraction technique and vibrational spectroscopy. Experimental results on the molecular structure of FBB were supported with computational studies using the density functional theory, with the Becke-3-Lee-Yang-Parr functional and the 6-311+G(3df,p) basis set. Molecular dimer formed by the intermolecular hydrogen bonding was investigated. Potential energy distribution analysis of normal modes was performed to identify characteristic frequencies. FBB crystallizes in orthorhombic space group P2(1)2(1)2(1) with the O-trans conformation. In order to investigate halogen effect, the chloro- (CBB) and bromo- (BBB) analogs of FBB have also been studied theoretically. It is observed that all compounds prefer the stable O-trans conformation. Although the free energy difference between the O-cis and O-trans conformers is less than 2.5 kcal/mol, the free energy rotational barrier is at least 7.4 kcal/mol. There is a good agreement between the experimentally determined structural parameters, and vibrational frequencies of FBB and those predicted theoretically. PMID- 25829023 TI - Oral cyclosporine A treatment is feasible after myeloablative conditioning in allogeneic hematopoietic stem cell transplantation. AB - WHAT IS KNOWN AND OBJECTIVE: The target level and route of administration of cyclosporine A (CsA) differ between transplantation centres. It is unclear whether oral CsA is sufficient to maintain target level of CsA. CASE SUMMARY: We retrospectively analysed data from 48 adult patients, who underwent myeloablative hematopoietic stem cell transplantation. Twenty-one patients (44%) tolerated CsA orally throughout the transplantation period without increased incidence of acute graft versus host disease(aGVHD). Low concentration of CsA in week 2 was associated with increased incidence of aGVHD. WHAT IS NEW AND CONCLUSION: Oral administration of CsA is safe, less time-consuming and economically advantageous. Close monitoring of CsA concentration is important. PMID- 25829022 TI - Primary central nervous system diffuse large B-cell lymphoma has poorer immune cell infiltration and prognosis than its peripheral counterpart. AB - AIMS: Primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNSL) is an ominous disease with a poor prognosis. The brain is an immune-privileged sanctuary, and this may contribute to an ineffective host immune response and thus a poorer outcome. The aim of this study was therefore to study the difference in the immune composition in PCNSL and non-CNS diffuse large B-cell lymphoma (DLBCL), and the role of the immune response in PCNSL prognosis. METHODS AND RESULTS: Thirty-two biopsy specimens of PCNSL and 30 specimens of low-stage non-CNS DLBCL from immunocompetent patients formed the study group. The density and distribution of immune cells, including dendritic cells (dendritic cell specific lysosomal-associated membrane protein-positive and S100-positive), effector/memory T cells (CD45RO-positive), and cytotoxic T cells (granzyme B positive), and the expression of HLA-DR by lymphoma cells, were evaluated immunohistochemically. PCNSL patients showed poorer overall survival (P = 0.032). On comparison of the PCNSL and DLBCL biopsy specimens, the PCNSL cells showed less HLA-DR expression (P = 0.003), and there were fewer S100-positive cells (P < 0.01), and effector T cells (P = 0.026) infiltrating PCNSL than infiltrating DLBCL. For PCNSL patients, fewer cytotoxic T cells in the background constituted a poor prognostic factor (P = 0.004). Intratumoral S100-positive cell infiltration was positively correlated with T-cell infiltration, and a T-cell rimming pattern. CONCLUSIONS: In PCNSL, the baseline antitumour immune response is less as compared with non-CNS DLBCL, and this response may play a role in the poorer prognosis. Adjuvant dendritic cell and T-cell immunotherapy may further boost treatment responses in PCNSL patients. PMID- 25829024 TI - Fuel poverty increases risk of mould contamination, regardless of adult risk perception & ventilation in social housing properties. AB - INTRODUCTION: Fuel poverty affects 2.4 million UK homes leading to poor hygrothermal conditions and risk of mould and house dust mite contaminations, which in turn increases risk of asthma exacerbation. For the first time we assess how fuel poverty, occupants' risk perception and use of mechanical ventilation mediate the risk of mould contamination in social housing. METHODS: Postal questionnaires were sent to 3867 social housing properties to collect adult risk perception, and demographic and environmental information on occupants. Participant details were linked to data pertaining to the individual properties. Multiple logistic regression was used to calculate odds ratios and confidence intervals while allowing for clustering of individuals coming from the same housing estate. We used Structured Equation Modelling and Goodness of Fit analysis in mediation analyses to examine the role of fuel poverty, risk perception, use of ventilation and energy efficiency. RESULTS: Eighteen percent of our target social housing populations (671 households) were included into our study. High risk perception (score of 8-10) was associated with reduced risk of mould contamination in the bedrooms of children (OR 0.5 95% CI; 0.3-0.9) and adults (OR 0.4 95% CI; 0.3-0.7). High risk perception of living with inadequate heating and ventilation reduced the risk of mould contamination (OR 0.5 95% CI; 0.3-0.8 and OR 0.5 95% CI; 0.3-0.7, respectively). Participants living with inadequate heating and not heating due to the cost of fuel had an increased risk of mould contamination (OR 3.4 95% CI; 2.0-5.8 and OR 2.2 95% CI; 1.5-3.2, respectively). Increased risk perception and use of extractor fans did not mediate the association between fuel poverty behaviours and increased risk of mould contamination. DISCUSSION: Fuel poverty behaviours increased the risk of mould contamination, which corresponds with existing literature. For the first time we used mediation analysis to assess how this association maybe modified by occupant behaviours. Increased risk perception and use of extractor fans did not modify the association between fuel poverty and mould contamination. This suggests that fuel poor populations may not benefit from energy efficiency interventions due to ineffective heating and ventilation practices of those occupants residing participating households. Our findings may be modified by a complex interaction between occupant behaviours and the built environment. We found that participant age, occupancy, SES, pets, drying washing indoors, geographic location, architectural design/age of the property, levels of insulation and type of heating regulated risk of mould contamination. CONCLUSION: Fuel poverty behaviours affected around a third of participating households and represent a risk factor for increased exposures to damp and mouldy conditions, regardless of adult risk perception, heating and ventilation practices. This requires multidisciplinary approach to assess the complex interaction between occupant behaviours, risk perception, the built environment and the effective use of heating and ventilation practices. STUDY IMPLICATIONS: Our findings have implications for housing policies and future housing interventions. Effective communication strategies focusing on awareness and perception of risk may help address indoor air quality issues. This must be supported by improved household energy efficiency with the provision of more effective heating and ventilation strategies, specifically to help alleviate those suffering from fuel poverty. PMID- 25829025 TI - Acupuncture: a cause of mediastinal abscess presenting as axillary infection. PMID- 25829026 TI - Andrew A. Benson, 1917-2015. AB - On January 16, 2015, Professor Andrew Alm Benson, one of the leading plant biochemists of the twentieth century, died in La Jolla, California, at the age of 97; he was born on September 24, 1917. Benson was known especially for his pioneering studies on photosynthesis (CO2 assimilation, carbon reduction cycle) and plant lipids (phospholipid phosphatidyl glycerol; and the sulfolipid, sulfoquinovosyl diglyceride). A photograph of Benson is shown in Fig. 1. Fig. 1 Photograph of Andrew A. Benson. SOURCE: Annual Review of Plant Biology, Vol. 53, 2002, published with permission. PMID- 25829027 TI - Repetitive light pulse-induced photoinhibition of photosystem I severely affects CO2 assimilation and photoprotection in wheat leaves. AB - It was previously found that photosystem I (PSI) photoinhibition represents mostly irreversible damage with a slow recovery; however, its physiological significance has not been sufficiently characterized. The aim of the study was to assess the effect of PSI photoinhibition on photosynthesis in vivo. The inactivation of PSI was done by a series of short light saturation pulses applied by fluorimeter in darkness (every 10 s for 15 min), which led to decrease of both PSI (~60 %) and photosystem II (PSII) (~15 %) photochemical activity. No PSI recovery was observed within 2 days, whereas the PSII was fully recovered. Strongly limited PSI electron transport led to an imbalance between PSII and PSI photochemistry, with a high excitation pressure on PSII acceptor side and low oxidation of the PSI donor side. Low and delayed light-induced NPQ and P700(+) rise in inactivated samples indicated a decrease in formation of transthylakoid proton gradient (DeltapH), which was confirmed also by analysis of electrochromic bandshift (ECSt) records. In parallel with photochemical parameters, the CO2 assimilation was also strongly inhibited, more in low light (~70 %) than in high light (~45 %); the decrease was not caused by stomatal closure. PSI electron transport limited the CO2 assimilation at low to moderate light intensities, but it seems not to be directly responsible for a low CO2 assimilation at high light. In this regard, the possible effects of PSI photoinhibition on the redox signaling in chloroplast and its role in downregulation of Calvin cycle activity are discussed. PMID- 25829028 TI - Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in 2005 on selective serotonin reuptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards migraine prevention. Another updated review is under development to cover tension-type headache.Migraine is a common disorder. The chronic forms are associated with disability and have a high economic impact. In view of discoveries about the role of serotonin and other neurotransmitters in pain mechanisms, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of migraine. OBJECTIVES: To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic migraine in adults. SEARCH METHODS: For the original review, we searched MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), and Headache Quarterly (1990 to 2003). For this update, we applied a revised search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10), MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. SELECTION CRITERIA: We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older of either sex with migraine. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data (migraine frequency, index, intensity, and duration; use of symptomatic/analgesic medication; days off work; quality of life; mood improvement; cost-effectiveness; and adverse events) and assessed the risk of bias of trials. The primary outcome of this updated review is migraine frequency. MAIN RESULTS: The original review included eight studies on migraine. Overall, we now include 11 studies on five SSRIs and one SNRI with a total of 585 participants. Six studies were placebo controlled, four compared a SSRI or SNRI to amitriptyline, and one was a head-to head comparison (escitalopram versus venlafaxine). Most studies had methodological or reporting shortcomings (or both): all studies were at unclear risk of selection and reporting bias. Follow-up rarely extended beyond three months. The lack of adequate power of most of the studies is also a major concern.Few studies explored the effect of SSRIs or SNRIs on migraine frequency, the primary endpoint. Two studies with unclear reporting compared SSRIs and SNRIs to placebo, suggesting a lack of evidence for a difference. Two studies compared SSRIs or SNRIs versus amitriptyline and found no evidence for a difference in terms of migraine frequency (standardised mean difference (SMD) 0.04, 95% confidence interval (CI) -0.72 to 0.80; I(2) = 72%), or other secondary outcomes such as migraine intensity and duration.SSRIs or SNRIs were generally more tolerable than tricyclics. However, the two groups did not differ in terms of the number of participants who withdrew due to adverse advents or for other reasons (one study, odds ratio (OR) 0.39, 95% CI 0.10 to 1.50 and OR 0.42, 95% CI 0.13 to 1.34).We did not find studies comparing SSRIs or SNRIs with pharmacological treatments other than antidepressants (e.g. antiepileptics and anti hypertensives). AUTHORS' CONCLUSIONS: Since the last version of this review, the new included studies have not added high quality evidence to support the use of SSRIs or venlafaxine as preventive drugs for migraine. There is no evidence to consider SSRIs or venlafaxine as more effective than placebo or amitriptyline in reducing migraine frequency, intensity, and duration over two to three months of treatment. No reliable information is available at longer-term follow-up. Our conclusion is that the use of SSRIs and SNRIs for migraine prophylaxis is not supported by evidence. PMID- 25829032 TI - Recent advances in laboratory testing of cerebrospinal fluid improve the care of patients with meningitis. PMID- 25829033 TI - Reflections on the evolving role of Infection Services in New Zealand. PMID- 25829034 TI - Time to modernise response to sexually transmitted infections. PMID- 25829035 TI - Epidemiology and diagnostic testing for meningitis in adults as the meningococcal epidemic declined at Middlemore Hospital. AB - AIMS: To describe changes in epidemiology and diagnostic techniques for adult meningitis at Middlemore Hospital following the decline of the meningococcal epidemic. METHODS: Retrospective audit of cases of meningitis from 2000 to 2009. RESULTS: Microbiologically-confirmed diagnosis (MCD) was established in 296 of 743 episodes (40%), most commonly enterovirus (123/296, 42%), Neisseria meningitidis (43/296, 15%) and Streptococcus pneumoniae (34/296, 11%). N. meningitidis meningitis declined and herpes viruses increased over time, without significant change in overall meningitis case numbers. By 2009, S. pneumoniae constituted a greater proportion of cases than N. meningitidis. Cerebrospinal fluid (CSF) polymerase chain reaction (PCR) and pneumococcal immunochromatographic testing (PICT) increased over time as did the proportion of cases with MCD. CSF Gram stain was positive in 45% (53/118) and CSF culture made MCD in 37% (44/118) of confirmed bacterial episodes (CBE). PCR provided MCD in 59% (26/54) of CBE and 99% (168/170) of viral episodes. CSF PICT was tested in 76% (26/34) of S. pneumoniae meningitis (positive in 92% (24/26). CONCLUSIONS: As the epidemic waned, local incidence of meningococcal meningitis decreased without significant decreasing meningitis overall. Empiric treatment for meningitis in New Zealand adults should routinely include pneumococcal cover. Increased PCR testing increases MCD in meningitis. PMID- 25829036 TI - Lymphogranuloma venereum in men who have sex with men: evidence of local transmission in New Zealand. AB - Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by Chlamydia trachomatis. Five laboratory confirmed cases of LGV were detected in MSM (men who have sex with men) in the upper North Island; four in Auckland between September and December 2013 and a fifth case was detected in Waikato in June 2014. The absence of a recent travel history for four cases supports the likelihood of local transmission of this uncommon infection. PMID- 25829037 TI - Synopsis of New Zealand's inaugural Influenza Symposium - influenza is a severe vaccine- preventable disease. AB - Influenza is a vaccine-preventable disease that can lead to serious acute respiratory illnesses and other complications. Influenza viruses are widespread in wild avian species and infect several animal species in addition to humans. Constant evolutionary changes to the influenza virus make the disease challenging to control. In November 2014, the Immunisation Advisory Centre held New Zealand's inaugural Influenza Symposium (NZiS) to focus upon influenza and vaccine strategies in New Zealand. International and local experts discussed advances in vaccine effectiveness, safety and disease prevalence and impact. Disease surveillance and vaccine effectiveness studies are identifying those at greatest risk from influenza to target vaccination campaigns. Influenza vaccine safety is closely monitored in order to improve public confidence. In New Zealand, around 27% of the total population are vaccinated against influenza annually, with 67% coverage for those aged 65 years and over who are eligible to funded vaccine. Seasonal influenza vaccination is vigorously promoted each year to help to improve vaccine uptake. However, there are inequalities in disease impact, with the elderly and very young, socioeconomically deprived and those with Maori and Pacific Island ethnicity remaining at-risk of serious disease and hospitalisation, which may be addressed by further improving access to influenza vaccine. PMID- 25829038 TI - Why do patients attend Dunedin's free clinic? An audit of general practice activity using the ICPC-2 classification system. AB - AIM: To describe the reasons for socially vulnerable patients at Dunedin's Free Clinic visiting their general practitioner, using the International Classification of Primary Care, Second Edition (ICPC-2). METHOD: An audit of electronic medical notes at Dunedin's Free Clinic for a 13-week period, to profile the health needs of patients and associated general practice activity RESULTS: There were 9.0 visits per patient over 12 months at the Free Clinic. An average of 1.2 presenting complaints or requests was made per visit. The most frequent "reasons for encounter" (RFE) at the Free Clinic were requests for prescriptions and Sickness Benefit medical certificates. An average of 1.9 diagnostic or therapeutic procedures was recorded per consultation at the Free Clinic. CONCLUSION: Patients at Dunedin's Free Clinic had a high rate of prescription and Sickness Benefit medical certificate requests. However, they brought on average fewer RFEs and received fewer than expected "processes of care" than patients in the NatMedCa study. PMID- 25829039 TI - Plasmid-mediated AmpC beta-lactamase-producing Escherichia coli causing urinary tract infection in the Auckland community likely to be resistant to commonly prescribed antimicrobials. AB - AIM: To estimate the prevalence and characterise plasmid-mediated AmpC beta lactamase (PMACBL)- producing Escherichia coli in the Auckland community. METHOD: All cefoxitin non-susceptible (NS) E. coli identified at the two Auckland community laboratories between 1 January and 31 August 2011 were referred to ESR for boronic acid double-disc synergy testing, to detect the production of AmpC beta-lactamase, and polymerase chain reaction (PCR) to identify the presence of PMACBL genes. PMACBL-producing isolates were typed using pulsed-field gel electrophoresis (PFGE), and PCR was used to determine their phylogenetic group and to identify multilocus sequence type (ST)131. Antimicrobial susceptibility testing and detection of extended-spectrum beta-lactamases (ESBLs) were performed according to the Clinical and Laboratory Standards Institute recommendations. RESULTS: 101 (51%) and 74 (37%) of 200 non-duplicate cefoxitin-NS E. coli were PMACBL producers or assumed hyper-producers of chromosomal AmpC beta-lactamase, respectively. The prevalence of PMACBL-producing E. coli was 0.4%. PMACBL producing E. coli were significantly less susceptible to norfloxacin, trimethoprim and nitrofurantoin than E. coli that produced neither a PMACBL nor an ESBL. Very few (4%) PMACBL-producing E. coli co-produced an ESBL. Most (88%) of the PMACBL-producing isolates had a CMY-2-like PMACBL. The PMACBL-producing E. coli isolates were diverse based on their PFGE profiles, 44% belonged to phylogenetic group D, and only four were ST131. 100 of the 101 PMACBL-producing E. coli were cultured from urine, and were causing urinary tract infection (UTI) in the majority of patients. The median patient age was 56 years and most (94%) of the patients were women. A greater proportion of patients with community acquired UTI caused by PMACBL-producing E. coli received a beta-lactam antimicrobial than patients with community-acquired UTI caused by other non-AmpC, non-ESBL-producing E. coli. Thirty-six (43%) patients with community-acquired UTI due to PMACBL-producing E. coli were neither hospitalised nor had any antimicrobial treatment in the previous 6 months. CONCLUSION: The prevalence of PMACBL-producing E. coli was relatively low in the Auckland community, but has increased in recent years. Typing revealed that the majority of the PMACBL producing E. coli in the Auckland region were genetically unrelated meaning that a point source or direct person to person transmission are not drivers of local community spread currently. The isolates were more resistant to non-beta-lactam antimicrobials than other non-AmpC, non-ESBL-producing E. coli, leaving few treatment options. The majority of the PMACBL-producing E. coli isolates seemed to be acquired in the community and were most frequently isolated from women with UTI. A large proportion of patients with community-acquired UTI had not been hospitalised nor had any antimicrobial treatment in the previous 6 months. PMID- 25829041 TI - Medical image. Epiploic appendages. PMID- 25829040 TI - Colonisation with Staphylococcus aureus and Streptococcus pyogenes in New Zealand preschool children. AB - AIM: To describe colonisation patterns of Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes) among pre-school children in New Zealand. METHOD: Anterior nasal, oropharyngeal, and antecubital fossa swabs were collected from a diverse sample of 139 New Zealand children aged 4 years. Swabs were cultured for S. aureus and S. pyogenes. S. aureus isolates were tested for antibiotic susceptibility. RESULTS: S. aureus colonisation was more prevalent than S. pyogenes colonisation; 54% of the children were colonised with S. aureus whereas only 16% were colonised with S. pyogenes, at one or more sampling sites (P<0.0001). S. aureus was present in a larger proportion of swabs obtained from the anterior nasal (39%, P<0.0001) or oropharynx (32%, P=0.0002) than from the antecubital fossa (14%). S. pyogenes was present in a larger proportion of swabs obtained from the oropharynx (16%) than either the anterior nasal (4%, P=0.001) or the antecubital fossa (2%, P<0.0001). CONCLUSION: S. aureus and S. pyogenes are prevalent at superficial sites in preschool children in NZ, with S. aureus colonisation more prevalent than S. pyogenes colonisation. Colonisation frequency varies by site for both pathogens; S. aureus is more prevalent in the anterior nares and oropharynx while S. pyogenes is more prevalent in the oropharynx. PMID- 25829042 TI - Medical image. Terra firma-forme dermatosis. PMID- 25829043 TI - Health effects of water fluoridation: a response to the letter by Menkes et al. PMID- 25829044 TI - Infrastructure for supporting physical activity: a pilot survey of the quality of street-connecting walkways at night. PMID- 25829045 TI - Lies, damned lies and graphs. PMID- 25829046 TI - Rotavirus vaccine: dare to hope. PMID- 25829047 TI - Portrayal of violence, weapons, antisocial behaviour and alcohol: study of televised music videos in New Zealand. PMID- 25829048 TI - Effect of magnesium sulphate on sugammadex reversal time for neuromuscular blockade: a randomised controlled study. AB - Magnesium potentiates neuromuscular blockade. Sugammadex reverses rocuronium induced blockade. The aim of this study was to determine the effect of pre treatment with magnesium sulphate on sugammadex reversal time for neuromuscular blockade. Seventy-three patients were randomly assigned to receive magnesium sulphate (40 mg.kg(-1) ) or saline intravenously. After anaesthetic induction, continuous train-of-four monitoring was performed and rocuronium was administered (0.6 mg.kg(-1) ). When a second twitch appeared, the patients received sugammadex (2 mg.kg(-1) ). The median (IQR [range]) reversal time of moderate neuromuscular blockade to a train-of-four ratio of 0.9 facilitated by sugammadex was 115 (93 177.5 [68-315]) s in the magnesium group and 120 (105-140 [70-298]) s in the saline group (p = 0.79). The median (IQR [range]) clinical duration was 45 (35.5 53 [22-102]) min in the magnesium group and 37 (31-43 [19-73]) min in the saline group (p = 0.031). Pre-treatment with magnesium did not significantly affect sugammadex reversal time of moderate neuromuscular blockade induced by rocuronium. PMID- 25829049 TI - A novel dissolution method for evaluation of polysaccharide based colon specific delivery systems: A suitable alternative to animal sacrifice. AB - The most extensively used test for predicting in-vivo release kinetics of a drug from its orally administered dosage forms is dissolution testing. For polysaccharide based, colon targeted oral delivery systems, the entire path of the gut traversed by the dosage form needs to be simulated for assessing its in vivo dissolution pattern. This includes the dissolution testing sequentially in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and simulated colonic fluid (SCF). For SGF and SIF, simple and standardized composition is well known. However, preparation of SCF requires addition of either the colonic contents of rodents or human faecal slurry. A method is proposed, wherein a mixture of five probiotics cultured in the presence of a prebiotic under anaerobic conditions is able to surrogate the colonic fluid. Release profiles of drug from colon targeted delivery systems in this medium were studied and compared to those generated in the conventionally used media containing rodent caecal contents and human faecal slurry. The results from the three studies were found to be quite similar. These findings suggest that the proposed medium may prove to be useful not only as a biorelevant and discriminatory method but may also help in achieving the 3Rs objective regarding the ethical use of animals. PMID- 25829050 TI - Vitamin Bc -Bearing Hydrophilic Photosensitizer Conjugate for Photodynamic Cancer Theranostics. AB - The accurate diagnosis and proper therapy for cancer are essential to improve the success rate of cancer treatment. Here, we demonstrated that the vitamin Bc bearing hydrophilic photosensitizer conjugate folic acid-polyethylene glycol pheophorbideA (FA-PEG-PheoA) has been synthesized for the intracellular diagnosis and photodynamic therapy of a tumor. The synthesized vitamin Bc -bearing hydrophilic photosensitizer conjugate has been characterized for the folic acid receptor expressing the ability to target tumor cells, which is facilitated by the chemical conjugation with folic acid. The vitamin Bc -bearing hydrophilic photosensitizer conjugate internalization mechanism was identified through a competitive inhibition test with free folic acid. We optimized the laser sensitive, cytotoxicity changeable, vitamin Bc -bearing hydrophilic photosensitizer conjugate concentration, which is non-cytotoxic under normal conditions and specifically cytotoxic toward cancer cells (maximum 69.15%) under laser irradiation conditions used for theranostic agents. The cancer therapeutic and diagnosis effects of synthesized conjugate were confirmed in MDA-MB-231 cells and MDA-MB-231-bearing mice. As a result, the vitamin Bc -bearing hydrophilic photosensitizer conjugate exhibited a highly photodynamic therapeutic effect, which enabled the selective detection of a folic acid receptor expressing cancer using optical imaging. PMID- 25829055 TI - Demographic, behavioral, dietary, and socioeconomic characteristics related to persistent organic pollutants and mercury levels in pregnant women in Japan. AB - Persistent organic pollutants and mercury are known environmental chemicals that have been found to be ubiquitous in not only the environment but also in humans, including women of reproductive age. The purpose of this study was to evaluate the association between personal lifestyle characteristics and environmental chemical levels during the perinatal period in the general Japanese population. This study targeted 322 pregnant women enrolled in the Hokkaido Study on Environment and Children's Health. Each participant completed a self-administered questionnaire and a food-frequency questionnaire to obtain relevant information on parental demographic, behavioral, dietary, and socioeconomic characteristics. In total, 58 non-dioxin-like polychlorinated biphenyls, 17 dibenzo-p-dioxins and dibenzofuran, and 12 dioxin-like polychlorinated biphenyls congeners, perfluorooctane sulfonate, perfluorooctanoic acid, and mercury were measured in maternal samples taken during the perinatal period. Linear regression models were constructed against potential related factors for each chemical concentration. Most concentrations of environmental chemicals were correlated with the presence of other environmental chemicals, especially in the case of non-dioxin-like polychlorinated biphenyls and, polychlorinated dibenzo-p-dioxins and dibezofurans and dioxin-like polychlorinated biphenyls which had similar exposure sources and persistence in the body. Maternal smoking and alcohol habits, fish and beef intake and household income were significantly associated with concentrations of environmental chemicals. These results suggest that different lifestyle patterns relate to varying exposure to environmental chemicals. PMID- 25829051 TI - PKPD modelling to predict altered disposition of 1alpha,25-dihydroxyvitamin D3 in mice due to dose-dependent regulation of CYP27B1 on synthesis and CYP24A1 on degradation. AB - BACKGROUND AND PURPOSE: Concentrations of 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], the active ligand of the vitamin D receptor, are tightly regulated by CYP27B1 for synthesis and CYP24A1 for degradation. However, the dose dependent pharmacokinetic (PK)-pharmacodynamic (PD) relationship between these enzymes and 1,25(OH)2 D3 concentrations has not been characterized. EXPERIMENTAL APPROACH: The pharmacokinetics of 1,25(OH)2 D3 were evaluated after administration of single (2, 60 and 120 pmol) and repeated (2 and 120 pmol q2d *3) i.v. doses to male C57BL/6 mice. mRNA expression of CYP27B1 and CYP24A1 was examined by quantitative PCR and 1,25(OH)2 D3 concentrations were determined by enzyme immunoassay. KEY RESULTS: CYP27B1 and CYP24A1 changes were absent for the 2 pmol dose and biexponential decay profiles showed progressively shorter terminal half-lives with increasing doses. Fitting with a two-compartment model revealed decreasing net synthesis rates and increasing total clearances with dose, consistent with a dose-dependent down-regulation of renal CYP27B1 and the induction of renal/intestinal CYP24A1 mRNA expression. Upon incorporation of PD parameters for inhibition of CYP27B1 and induction of CYP24A1 to the simple two compartment model, fitting was significantly improved. Moreover, fitted estimates for the 2 pmol dose, together with the PD parameters as modifiers, were able to predict profiles reasonably well for the higher (60 and 120 pmol) doses. Lastly, an indirect response model, which considered the synthesis and degradation of enzymes, adequately described the PK and PD profiles. CONCLUSIONS AND IMPLICATIONS: The unique PK of exogenously administered 1,25(OH)2 D3 led to changes in PD of CYP27B1 and CYP24A1, which hastened the clearance of 1,25(OH)2 D3 . PMID- 25829057 TI - Plasma-engineered MoS2 thin-film as an efficient electrocatalyst for hydrogen evolution reaction. AB - Herein, for the first time, we reported a general approach of plasma engineering to tune the surface properties and edge reactive sites for greatly improving HER (hydrogen evolution) activity of MoS2. We show that the Ar or O2 plasma can be used to generate a large number of physical and chemical defects in 2D crystals to modify the electronic properties and increase the number of active sites in MoS2. Electrocatalytic studies show that the plasma-treated MoS2 exhibits significantly enhanced electrocatalytic activity for HER. PMID- 25829056 TI - Accumulation of organochlorines in the European clam (Ruditapes decussatus) and sediment of the Oualidia lagoon (Morocco). AB - This study focused on the analysis of organochlorine pesticides and PCBs in tissue samples of the clam, Ruditapes decussatus, in the Oualidia lagoon. Tissue assays were conducted during February to December 2005 and sediment (October 2005) was also tested. 13 organochlorine compounds and eight PCBs congeners were investigated, is HCB, gamma-HCH, chlordane, cis-chlordane and trans-nonachlor, DDT and its metabolites DDD, DDE, heptachlor, its epoxide, mirex and PCBs (PCB28 + 50, PCB52, PCB101, PCB 118, PCB138, PCB153, PCB180). Analysis of these compounds was performed using a gas chromatography capillary column and an electron capture detector. Organochlorine contamination of clams and sediments in the lagoon did not exceed tolerable thresholds according to European standards. The levels of tPCB, tDDT and tOCP in clams are high at 49.4, 22.2, and 7.1 ng g( 1) dw respectively. Concentrations of trans nonachlor and mirex are low compared to other chlorinated pesticides. PCB28 + 50, PCB52 and PCB101 show typical values in sediment, at 18.5, 10.8 and 17.8 ng g(-1) dw respectively. PMID- 25829058 TI - An LC-MS/MS method for determination of calceorioside B with cardiomyocyte protective activity in rat plasma and application to a pharmacokinetic study. AB - A simple, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for the determination of calceorioside B (CLB) in rat plasma. Detection was performed on a Thermo Scientific Hypersil Gold chromatography column using isocratic elution with a mobile phase of methanol-5 m m ammonium acetate-formic acid (70:30:0.1, v/v/v). Mass spectrometry was performed in selection reaction monitoring mode using a positive electrospray ionization interface. Good linearity was found for CLB in plasma in the linear range of 1.00-500 ng/mL (r > 0.9960). The validated method was successfully applied to the pharmacokinetic study of CLB in rats. PMID- 25829059 TI - UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation. AB - UDP-sugars, which are indispensable for protein glycosylation reactions in cellular secretory pathways, also act as important extracellular signaling molecules. We discuss here the broadly expressed P2Y14 receptor, a G-protein coupled receptor targeted by UDP sugars, and the increasingly diverse set of physiologic responses discovered recently functioning downstream of this receptor in many epithelia as well as in immune, inflammatory, and other cells. PMID- 25829060 TI - Dual targeting of the androgen receptor and hypoxia-inducible factor 1alpha pathways synergistically inhibits castration-resistant prostate cancer cells. AB - Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 alpha (HIF-1alpha) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1alpha signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1alpha inhibition was achieved by siRNA silencing HIF-1alpha or via chetomin, a disruptor of HIF-1alpha-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIF-signaling; conversely, specific HIF-1alpha target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1alpha inhibition attenuated AR regulated and HIF-1alpha-mediated gene transcription. The combination of enzalutamide and HIF-1alpha inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1alpha siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1alpha inhibition resulted in synergistic inhibition of AR dependent and gene-specific HIF-dependent expression and prostate cancer cell growth. PMID- 25829061 TI - Single-port laparoscopic resection for diverticular disease: experiences with more than 300 consecutive patients. AB - BACKGROUND: Single-port laparoscopic surgery (SILS) is a new minimally invasive technique, which has been developed to minimize the surgical access trauma. For colorectal resection, the access trauma can be limited to the one incision, which is needed for specimen extraction anyways, but dissection might be more demanding than in multiport laparoscopic surgery. The aim of this study was to evaluate the usefulness of SILS for the treatment of diverticular disease of the sigmoid colon. METHODS: Between July 2009 and December 2013, a total of 329 consecutive patients with intended SILS sigmoid colectomy for complicated or frequently recurring diverticulitis were studied. Clinical data were collected in a prospective database. Telephone follow-ups were performed to evaluate long-term morbidity and quality of life. RESULTS: Of the 329 patients (139 male) with intended SILS sigmoid colectomy, 309 were successfully operated on in SILS technique, while 20 (6.1%) were converted to open surgery. The mean duration of surgery was 153.5 (65-434) min. Total morbidity rate was 18.3%. Anastomotic leakage was the most serious complication occurring in 13 patients (leak rate 4%) with one consecutive death (mortality rate 0.3%). Quality of life had significantly improved 6 months after surgery in comparison with the preoperative value. At a mean follow-up of 18.6 months, 16 patients (4.9%) had incisional hernia and one patient had recurrent diverticulitis. CONCLUSION: In spite of almost 5% incisional hernia 6 months after surgery, single-incision sigmoid colectomy for diverticulitis is feasible and save and is therefore an alternative to multiport laparoscopic surgery. Further trials are necessary to evaluate its benefits over multiport laparoscopic surgery. PMID- 25829062 TI - Effect of a laparoscopic instrument with rotatable handle piece on biomechanical stress during laparoscopic procedures. AB - OBJECTIVE: To investigate the effect of a pistol grip laparoscopic instrument with a rotatable handle piece (rot-HP) on biomechanical stress and precision as well as a possible interaction between the instrument and working height (WH). BACKGROUND: Biomechanical stress induced by laparoscopic surgery (LS) is associated with work-related upper limb musculoskeletal disorders in surgeons. Ergonomic handle designs of laparoscopic instruments may reduce the risk of musculoskeletal disorders. METHODS: Without LS experience, 57 healthy subjects (30 women; 27 men, median age: 26) were observed while performing a laparoscopic exercise. Subjects had to pick up coloured pins and place them into a colour coded wooden set-up inside a pelvitrainer. The exercise was performed at two WHs using the rot-HP and a standard laparoscopic (fixed) handle piece in randomized sequence. Biomechanical stress was monitored via surface electromyography (sEMG) on fife muscles from the upper limb and shoulder region. Further, the wrist angle (palmar and dorsi flexion) and posture of the dominant upper arm were recorded. Precision was assessed using the number of validly placed pins and process time. RESULTS: sEMG parameters and upper arm postures indicated no differences in biomechanical stress related to either laparoscopic handle piece. The higher WH was associated with higher trapezius and deltoid activity and elevated arm postures (p < 0.05). Neutral wrist positions were more frequent using the rot-HP, and the lower WH resulted in slightly more neutral wrist positions. Precision was similar during all experimental conditions. CONCLUSIONS: The rot-HP did not decrease biomechanical stress in the shoulder or lower arm muscles. However, wrist angle position may be optimized without affecting precision. Long-term effects of the rot-HP on preventing complaints of the upper extremity should be evaluated. Low WH is recommended to reduce biomechanical stress in the shoulder during laparoscopic surgery. PMID- 25829063 TI - Feasibility, efficacy and safety of stent insertion as a palliative treatment for malignant strictures in the cervical segment of the esophagus and the hypopharynx. AB - BACKGROUND: 50% of esophageal cancers are inoperable at the time of diagnosis, and around 15% involve the cervical esophagus. The hypopharynx is often involved by these malignancies as well. Palliation of cervical esophageal malignancies through stent insertion is considered limited due to technical challenges, poor patient tolerance and high complication rate. The aim of this study is to review our experience with stent insertion in the cervical segment of the esophagus and to evaluate outcome differences between stent insertions involving or sparing the hypopharynx. METHODS: We retrospectively reviewed data on 69 consecutive patients that underwent stent insertion for malignant strictures in the cervical esophagus at our Department. Patients were divided according to involvement or sparing of the lower hypopharynx. Dysphagia severity was measured with the Mellow-Pinkas scale before the procedure and on monthly follow-ups. Any complication and its management were recorded. The main outcome parameters were as follows: dysphagia improvement, rate of successful dysphagia palliation (i.e., a reduction of the score to 0 or 1 after stent insertion) and complication rate. Multivariable analysis was carried out to assess the influence of patient- and procedure related factors on the outcome of the procedure. RESULTS: Stent insertion was achieved in 100% patients. At 4 weeks, dysphagia score improved from a median of 3-0 (p < 0.001), and a successful palliation was achieved in 76.8% patients. The 30-day mortality rate was 14.5%. Successful palliation throughout the follow-up was achieved in 72.9% of the surviving patients. Complications occurred in 31.9% patients. Dilation before stent insertion was associated with a less efficient short-term dysphagia palliation (OR 6.77, 95% CI 1.46-31.29, p = 0.02). CONCLUSIONS: Stent insertion is a safe and effective palliative treatment for malignant cervical esophageal strictures. Results are consistent even in patients with hypopharyngeal lesions. Dilation should be avoided before stent insertion. PMID- 25829064 TI - One- and ten-year outcome of laparoscopic anterior 120 degrees versus total fundoplication: a double-blind, randomized multicenter study. AB - BACKGROUND: Nissen fundoplication is an effective treatment for gastroesophageal reflux disease (GERD) but can cause adverse effects like flatulence and dysphagia. The aim was to compare laparoscopic anterior 120 degrees fundoplication (APF) to total fundoplication (Nissen) concerning flatulence and other adverse effects, in a randomized blinded study. METHODS: Seventy-two patients were randomized to APF (n = 36) or Nissen (n = 36). Gastroscopy, 24-h pH monitoring and evaluation for symptoms and quality of life using questionnaires (GSRS, PGWB and 7-graded Likert scales) were performed preoperatively, at 1 and 10 years postoperatively. Patients and the researchers were blinded to operative method. RESULTS: When entering the study, most patients had mild-moderate reflux disease according to the symptom score, the 24-h pH measurements, and frequency and grade of esophagitis. At 1-year (n = 68) flatulence, dysphagia, heartburn and acid regurgitation did not differ between groups. More patients could belch (p = 0.005), and pH monitoring showed a higher time with pH < 4 in the APF group (p = 0.006). At 10 years (n = 61), the APF group reported less dysphagia (p < 0.001), more heartburn (p = 0.019) and more patients could belch (p = 0.012) and vomit (p < 0.001) compared to the Nissen. No difference remained at 10 years in pH monitoring (n = 23) between groups. Symptoms of heartburn and acid regurgitation were less than preoperatively in both groups (p < 0.001). No revisional operations were performed. CONCLUSIONS: Both procedures offer good long-term control of reflux symptom, with modest post-fundoplication symptoms. Anterior 120 degrees fundoplication results in less dysphagia, better ability to belch and vomit than total fundoplication at 10-year follow-up. The results suggest that APF could be an alternative to Nissen fundoplication in the surgical treatment of mild-moderate GERD. PMID- 25829065 TI - A blinded assessment of video quality in wearable technology for telementoring in open surgery: the Google Glass experience. AB - BACKGROUND: The goal of telementoring is to recreate face-to-face encounters with a digital presence. Open-surgery telementoring is limited by lack of surgeon's point-of-view cameras. Google Glass is a wearable computer that looks like a pair of glasses but is equipped with wireless connectivity, a camera, and viewing screen for video conferencing. This study aimed to assess the safety of using Google Glass by assessing the video quality of a telementoring session. METHODS: Thirty-four (n = 34) surgeons at a single institution were surveyed and blindly compared via video captured with Google Glass versus an Apple iPhone 5 during the open cholecystectomy portion of a Whipple. Surgeons were asked to evaluate the quality of the video and its adequacy for safe use in telementoring. RESULTS: Thirty-four of 107 invited surgical attendings (32%) responded to the anonymous survey. A total of 50% rated the Google Glass video as fair with the other 50% rating it as bad to poor. A total of 52.9% of respondents rated the Apple iPhone video as good. A significantly greater proportion of respondents felt Google Glass video quality was inadequate for telementoring versus the Apple iPhone's (82.4 vs 26.5%, p < 0.0001). Intraclass correlation coefficient was 0.924 (95% CI 0.660-0.999, p < 0.001). CONCLUSION: While Google Glass provides a great breadth of functionality as a wearable device with two-way communication capabilities, current hardware limitations prevent its use as a telementoring device in surgery as the video quality is inadequate for safe telementoring. As the device is still in initial phases of development, future iterations or competitor devices may provide a better telementoring application for wearable devices. PMID- 25829066 TI - Outcomes of patients with early gastric cancer who underwent double endoscopic intraluminal surgery. AB - BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) has been used to treat patients with nonulcerated early gastric cancers of 2 cm or less, because the incidence of lymph node metastasis is negligible. However, the standard ESD procedure is long, complex, and associated with high complication rates. To overcome these limitations, we devised a double endoscopic intraluminal operation (DEILO) and assessed its efficacy and safety for superficial gastric neoplasms in a preliminary prospective study. METHODS: The DEILO procedure was performed on 101 patients with gastric cancers. Two endoscopes were simultaneously inserted into the stomach. One endoscope was used to lift the lesion, and the other was used to excise the lesion. RESULTS: The DEILO technique was performed successfully, and en bloc resection was achieved for 98 (97.0%) of 101 patients. Histologically curative resection was achieved for 85 lesions (84.2%). The mean operating time was 70 min (range 20-178 min). Perforation occurred in four patients (4.0%), all of whom were successfully treated nonsurgically. Three patients developed postoperative hemorrhage, which was controlled endoscopically. CONCLUSION: The DEILO procedure appears to shorten the operating time for ESD, with efficacy and complication rates comparable with the standard procedure. PMID- 25829067 TI - Risk stratification and management of non-curative resection after endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND: Non-curative resection after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) can contribute to local recurrence or lymphatic and distant metastasis of the tumor. We stratified the risk of local recurrence according to the histological characteristics in non-curative resection after ESD for EGC. METHODS: Among 892 EGCs treated with ESD, 152 (17.0%) were classified as non-curative resection based on the histology after ESD. The clinical outcomes and risk factors associated with local recurrence were analyzed retrospectively in non-curative resections. RESULTS: Of 152 non-curative resections, 46 (30.3%) were stratified as Group 1 (incomplete resection and met the ESD criteria), 31 (20.4%) as Group 2 (complete resection and exceeded the ESD criteria), 41 (27.0%) as Group 3 (incomplete resection and exceeded the ESD criteria), and 34 (22.4%) as Group 4 (lymphovascular invasion regardless of complete resection). Group 3 [odds ratio (OR) 3.991; p = 0.015] and Group 4 (OR 4.487; p = 0.014) had higher rates of local recurrence after non-curative resection. In those high-risk groups, endoscopic surveillance without additional treatment detected significantly more local recurrence than in those receiving additional treatment (p = 0.029). CONCLUSION: Risk stratification for non-curative resection is important for EGC prognosis after ESD. Moreover, additional treatment for non curative resection influences long-term outcomes, especially in high-risk groups. PMID- 25829068 TI - Redefining early gastric cancer. AB - BACKGROUND: The problem is that current definitions of early gastric cancer allow the inclusion of regional lymph node metastases. The increasing use of endoscopic submucosal dissection to treat early gastric cancer is a concern because regional lymph nodes are not addressed. The aim of the study was thus to critically evaluate current evidence with regard to tumour-specific factors associated with lymph node metastases in "early gastric cancer" to develop a more precise definition and improve clinical management. METHODS: A systematic and comprehensive search of major reference databases (MEDLINE, EMBASE, PubMed and the Cochrane Library) was undertaken using a combination of text words "early gastric cancer", "lymph node metastasis", "factors", "endoscopy", "surgery", "lymphadenectomy" "mucosa", "submucosa", "lymphovascular invasion", "differentiated", "undifferentiated" and "ulcer". All available publications that described tumour-related factors associated with lymph node metastases in early gastric cancer were included. RESULTS: The initial search yielded 1494 studies, of which 42 studies were included in the final analysis. Over time, the definition of early gastric cancer has broadened and the indications for endoscopic treatment have widened. The mean frequency of lymph node metastases increased on the basis of depth of infiltration (mucosa 6% vs. submucosa 28%), presence of lymphovascular invasion (absence 9% vs. presence 53%), tumour differentiation (differentiated 13% vs. undifferentiated 34%) and macroscopic type (elevated 13% vs. flat 26%) and tumour diameter (<=2 cm 8% vs. >2 cm 25%). CONCLUSION: There is a need to re-examine the diagnosis and staging of early gastric cancer to ensure that patients with one or more identifiable risk factor for lymph node metastases are not denied appropriate chemotherapy and surgical resection. PMID- 25829069 TI - Hereditary geniospasm in a Korean family. PMID- 25829070 TI - Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy. AB - BACKGROUND: Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic features (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and decreased aldehyde dehydrogenase (ALDH) activity in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4 dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern. METHODS: DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N = 15), sporadic PD (N = 17), and control subjects (N = 18). RESULTS: Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p < 0.0001), DOPAC (97% and 95%, p < 0.0001), NE (91% and 74%, p < 0.0001), and DHPG (81% and 74%, p < 0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not. CONCLUSIONS: MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which might be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach. PMID- 25829071 TI - Zolpidem withdrawal status dystonicus in the patient with advanced Parkinson's disease. PMID- 25829073 TI - Helsinki redux. PMID- 25829072 TI - Physiological roles of miR-155. AB - miR-155 is involved in non-coding microRNAs found in humans, mice and chickens of which the sequence is conserved. Historically, miR-155 was identified as a B-cell integration cluster (bic), which induces B-cell leucosis in chickens, by its activation through viral promoter insertion. Subsequent studies have shown that transgenic mice expressing miR-155 in B cells generated lymphoma, showing that miR-155 is oncogenic. Biochemical investigation identifies many substrates of miR 155, and one of them in B cells and macrophages is the SH2-domain containing inositol-5'-phosphatase 1. A deficiency of miR-155 in the immune system causes attenuated immune functions. Clinically, several types of malignancy including diffuse large B-cell lymphoma have high miR-155 expression levels. PMID- 25829074 TI - Protective equipment and sport-related concussion: letter to the editor. PMID- 25829075 TI - Protective equipment and sport-related concussion: response. PMID- 25829076 TI - Corrigendum. PMID- 25829077 TI - Genotoxic and immunotoxic potential effects of selected psychotropic drugs and antibiotics on blue mussel (Mytilus edulis) hemocytes. AB - The potential toxicity of pharmaceuticals towards aquatic invertebrates is still poorly understood and sometimes controversial. This study aims to document the in vitro genotoxicity and immunotoxicity of psychotropic drugs and antibiotics on Mytilus edulis. Mussel hemocytes were exposed to fluoxetine, paroxetine, venlafaxine, carbamazepine, sulfamethoxazole, trimethoprim and erythromycin, at concentrations ranging from MUg/L to mg/L. Paroxetine at 1.5 MUg/L led to DNA damage while the same concentration of venlafaxine caused immunomodulation. Fluoxetine exposure resulted in genotoxicity, immunotoxicity and cytotoxicity. In the case of antibiotics, trimethoprim was genotoxic at 200 MUg/L and immunotoxic at 20 mg/L whereas erythromycin elicited same detrimental effects at higher concentrations. DNA metabolism seems to be a highly sensitive target for psychotropic drugs and antibiotics. Furthermore, these compounds affect the immune system of bivalves, with varying intensity. This attests the relevance of these endpoints to assess the toxic mode of action of pharmaceuticals in the aquatic environment. PMID- 25829078 TI - Binding properties of palmatine to DNA: spectroscopic and molecular modeling investigations. AB - Palmatine, an isoquinoline alkaloid, is an important medicinal herbal extract with diverse pharmacological and biological properties. In this work, spectroscopic and molecular modeling approaches were employed to reveal the interaction between palmatine and DNA isolated from herring sperm. The absorption spectra and iodide quenching results indicated that groove binding was the main binding mode of palmatine to DNA. Fluorescence studies indicated that the binding constant (K) of palmatine and DNA was ~ 10(4)L.mol(-1). The associated thermodynamic parameters, DeltaG, DeltaH, and DeltaS, indicated that hydrogen bonds and van der Waals forces played major roles in the interaction. The effects of chemical denaturant, thermal denaturation and pH on the interaction were investigated and provided further support for the groove binding mode. In addition to experimental approaches, molecular modeling was conducted to verify binding pattern of palmatine-DNA. PMID- 25829079 TI - Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord. AB - Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors; however, neuropathic pain is one of the main limiting complications of OXL. The purpose of this study was to examine the underlying mechanisms by which neuropathic pain is induced by OXL in a rat model. Our results demonstrated that blocking spinal proteinase-activated receptor 2 (PAR2) and transient receptor potential vanilloid 1 (TRPV1) attenuated pain responses evoked by mechanical stimulation and decreased the releases of substance P and CGRP in the superficial dorsal horn of the spinal cord. The attenuating effect on mechanical pain was significantly smaller in OXL-rats than that in control rats. Blocking PAR2 also attenuated a heightened cold sensitivity evoked by OXL; whereas blocking TRPV1 had little effects on OXL-evoked hypersensitive cold response. Our data also showed that OXL increased the protein expressions of PAR2 and TRPV1 in the superficial dorsal horn. In addition, blocking PAR2 decreased TRPV1 expression in OXL-rats. Overall, our data suggest that upregulated expression of PAR2 in the superficial dorsal horn contributes to mechanical hyperalgesia and cold hypersensitivity; whereas amplified TRPV1 plays a role in regulating mechanical hyperalgesia, but not cold hypersensitivity after administration of OXL. We further suggest that TRPV1 is likely one of the signaling pathways for PAR2 to play a role in regulating OXL-induced neuropathic pain. PMID- 25829080 TI - Tuberculous optic neuritis: A case report. PMID- 25829081 TI - Fatal intracerebral haemorrhage following intravenous thrombolysis for acute ischaemic stroke: A hidden role for cerebral amyloid angiopathy? PMID- 25829082 TI - Heparin-responsive angiopathy in the central nervous system caused by intravascular large B-cell lymphoma. PMID- 25829083 TI - 18F FDG PET/CT and Head and Neck Cancer: Patient Management and Outcomes. AB - There is a growing body of evidence that point to the value of 18F fluoro deoxyglucose-PET/CT in the management of head and neck cancer (HNC) patients and predicting patient-related outcomes. FDG-PET/CT changes the baseline staging (compared with CT or MR imaging), guides appropriate therapy selection, separates the responders and non-responders for therapy assessment, adds value to clinical assessment in follow-up, and predicts patient survival outcomes. FDG-PET/CT can identify the recurrences in earlier stages and individualize follow-up regimens in HNC patients. This article reviews the value of FDG-PET/CT in management strategy and survival outcome of HNC patients. PMID- 25829084 TI - Lung cancer. AB - (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) plays a key role in the evaluation of undiagnosed lung nodules, when primary lung cancer is strongly suspected, or when it has already been diagnosed by other techniques. Although technical factors may compromise characterization of small or highly mobile lesions, lesions without apparent FDG uptake can generally be safely observed, whereas FDG-avid lung nodules almost always need further evaluation. FDG-PET/CT is now the primary staging imaging modality for patients with lung cancer who are being considered for curative therapy with either surgery or definitive radiation therapy. PMID- 25829085 TI - PET Imaging of Breast Cancer: Role in Patient Management. AB - Breast cancer is the most common malignancy in females. Imaging plays a critical role in diagnosis, staging and surveillance, and management of disease. Fluorodeoxyglucose (FDG) PET the imaging is indicated in specific clinical setting. Sensitivity of detection depends on tumor histology and size. Whole body FDG PET can change staging and management. In recurrent disease, distant metastasis can be detected. FDG PET imaging has prognostic and predictive value. PET/MR is evolving rapidly and may play a role management, assessment of metastatic lesions, and treatment monitoring. This review discusses current PET modalities, focusing on of FDG PET imaging and novel tracers. PMID- 25829086 TI - PET with Fluorodeoxyglucose F 18/Computed Tomography in the Clinical Management and Patient Outcomes of Esophageal Cancer. AB - PET with fluorodeoxyglucose F 18/computed tomography ((18)F-FDG PET/CT) has evolved into an indispensable imaging technique in the management of patients with esophageal cancer. Staging with (18)F-FDG PET/CT is strongly associated with overall survival and certain (18)F-FDG PET/CT parameters predict patient survival. Current evidence supporting the validity of the use of (18)F-FDG PET/CT in the tumor delineation process for radiation treatment planning in patients with esophageal cancer is still limited. It is useful in determining treatment response after neoadjuvant therapy and thereby has an impact on management. (18)F FDG PET/CT plays a role in the diagnosis of recurrent disease in patients with a background of clinical suspicion. PMID- 25829087 TI - Role of 2-Deoxy-2-[18F]-fluoro-d-glucose-PET/Computed Tomography in Lymphoma. AB - The role of PET and PET/computed tomography (CT) has evolved significantly in the last few decades. 2-Deoxy-2-[18F]-fluoro-d-glucose (FDG)-PET/CT is now an integral part of the management of patients with lymphoma. FDG-PET/CT at the time of initial staging can help in appropriate staging of the patients. Both interim and end-of-therapy PETs have significant prognostic value in patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma and more accurately assess for the presence of residual malignancy than anatomic imaging. The impact of interim FDG-PET/CT on risk-adapted strategies is an area of active investigation and the results of ongoing clinical trials will be informative. PMID- 25829088 TI - Multiple myeloma. AB - This article presents a review of multiple myeloma, precursor states, and related plasma cell disorders. The clinical roles of fluorodeoxyglucose PET/computed tomography (CT) and the potential to improve the management of patients with multiple myeloma are discussed. The clinical and research data supporting the utility of PET/CT use in evaluating myeloma and other plasma cell dyscrasias continues to grow. PMID- 25829089 TI - PET/Computed Tomography and Patient Outcomes in Melanoma. AB - The performance of fludeoxyglucose F 18 (FDG)-PET/computed tomography (CT) in the initial and follow-up evaluation of patients with melanoma is well established. Groups are beginning to investigate whether the inclusion of FDG-PET/CT into a staging or surveillance algorithm results in an improvement in patient outcome and whether such an imaging program would be cost-effective. PMID- 25829091 TI - Value of Fluorodeoxyglucose PET/Computed Tomography Patient Management and Outcomes in Thyroid Cancer. AB - "Fluorodeoxyglucose (FDG) PET/computed tomography (CT) is used most frequently in the surveillance of iodine-refractory differentiated thyroid cancer with increased thyroglobulin level after therapy. This article evaluates the impact of FDG-PET/CT on clinical management and the prognostic implications of a positive scan. In the studies reviewed, FDG-PET/CT changed the course of management in 14% to 78% of patients with suspected recurrence, and a positive scan was associated with poorer survival. Similar conclusions are supported in the literature for anaplastic and medullary thyroid cancers, although these are based on fewer studies on account of the lower prevalence of these subtypes." PMID- 25829092 TI - Radiotherapy planning. AB - Incorporation of PET/computed tomography (CT) in radiotherapy planning plays a critical role in assisting gross tumor volume delineation for radiotherapy planning and delivery. As radiotherapy techniques evolve to become more conformal with the increasing use of intensity-modulated radiotherapy and stereotactic body radiotherapy, whereby sharp dose gradients exist between the target and adjacent normal tissue, accurate contouring of tumor targets is vital for the success of radiotherapy to achieve cure and locoregional control. This article outlines the integration of PET/CT into radiotherapy planning for head and neck, lung, and other solid tumors. PMID- 25829090 TI - Prognostic Utility of PET in Prostate Cancer. AB - Many standard nonimaging-based prediction tools exist for prostate cancer. However, these tools may be limited in individual cases and need updating based on the improved understanding of the underlying complex biology of the disease and the emergence of the novel targeted molecular imaging methods. A new platform of automated predictive tools that combines the independent molecular, imaging, and clinical information can contribute significantly to patient care. Such a platform will also be of interest to regulatory agencies and payers as more emphasis is placed on supporting those interventions that have quantifiable and significant beneficial impact on patient outcome. PMID- 25829093 TI - PET/CT: Adding Value to Patient Outcomes and Health Care Delivery. PMID- 25829094 TI - Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites. AB - PURPOSE: Bendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non Hodgkin's lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug-drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies. METHODS: A literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion. RESULTS: Bendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t 1/2 (~40 min) as the effective t 1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites gamma hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug-drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m(2) is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure-efficacy response relationship has been observed. CONCLUSIONS: Altogether, the findings support dosing based on body surface area for most patient populations. PMID- 25829095 TI - Erratum to: Bivalirudin Versus Heparin Plus Glycoprotein IIb/IIIa Inhibitors in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials. PMID- 25829096 TI - Revised force-field parameters for chlorophyll-a, pheophytin-a and plastoquinone 9. AB - Biological photosynthetic machineries, such as photosystem I, photosystem II, or the bacterial reaction center, use cofactor molecules that absorb light or directly participate in chemical reactions. Accurate description of the structure of the cofactors, and of their interactions with protein groups, is an important step toward understanding how photosynthetic machineries work. Here we revisit the classical force field parameters for chlorophyll-a, pheophytin-a and plastoquinone-9. We present systematic quantum mechanical and classical mechanical computations that lead to a good description of the structure and non bonded interactions of these cofactors. PMID- 25829098 TI - Erratum to: Selenium as a Feed Supplement for Heat-Stressed Poultry: a Review. PMID- 25829097 TI - Molecular docking and molecular dynamics simulation studies of Trypanosoma cruzi triosephosphate isomerase inhibitors. Insights into the inhibition mechanism and selectivity. AB - Trypanosoma cruzi (T. cruzi) triosephosphate isomerase (TcTIM) is a glycolytic enzyme essential for parasite survival and has been considered an interesting target for the development of new antichagasic compounds. The homodimeric enzyme is catalytically active only as a dimer. Interestingly, significant differences exist between the human and parasite TIMs interfaces with a sequence identity of 52%. Therefore, compounds able to specifically disrupt TcTIM but not Homo sapiens TIM (hTIM) dimer interface could become selective antichagasic drugs. In the present work, the binding modes of 1,2,4-thiadiazol, phenazine and 1,2,6 thiadiazine derivatives to TcTIM were investigated using molecular docking combined with molecular dynamics (MD) simulations. The results show that phenazine and 1,2,6-thiadiazine derivatives, 2 and 3, act as dimer-disrupting inhibitors of TcTIM having also allosteric effects in the conformation of the active site. On the other hand, the 1,2,4-thiadiazol derivative 1 binds into the active site causing a significant decrease in enzyme mobility in both monomers. The loss of conformational flexibility upon compound 1 binding suggests that this inhibitor could be preventing essential motions of the enzyme required for optimal activity. The lack of inhibitory activity of 1 against hTIM was also investigated and seems to be related with the high mobility of hTIM which would hinder the formation of a stable ligand-enzyme complex. This work has contributed to understand the mechanism of action of this kind of inhibitors and could result of great help for future rational novel drug design. PMID- 25829099 TI - Whether Metal Element-Containing Herbal Formula Angong Niuhuang Pill Is Safe for Acute Brain Disorders? AB - "Angong Niuhuang Pill" (AGNH Pill) has been used as patented herbal formula for treatment of acute brain disorders including ischemic stroke, hemorrhage stroke, and trauma brain injury in traditional Chinese medicine for a thousand years. It is widely used in treatment of many diseases. As AGNH Pill contains metal elements named realgar and cinnabar, whether AGNH Pill is safe attracts great concerns. To address this question, we reviewed adverse drug reactions (ADR) and adverse events (AE) to assess the safety of AGNH Pill clinically. We searched PubMed, Embase, Cochrane library, TOXNET, and Chinese databases CNKI and Wanfang for articles published between January 1974 and January 2015. A total of 49 cases contained in 10 articles were included in this study. We were unable to determine the frequency of ADR/AE induced by AGNH Pill due to the lack of complete production and market information provided by pharmaceutical manufacturers and hospitals. Based on current literature data, we estimated that the risk of ADR/AE from AGNH Pill administration was low. The majority of ADR/AE was attributed to the improper use of AGNH Pill, such as use in children with overdosage or use with incompatible drugs. We were unable to distinguish whether incidents were ADR or AE because of the poor reports. To date, published evidence indicates that AGNH Pill appears to carry a relatively low risk of ADR/AE. As the quality of clinical assessment for the safety of AGNH Pill is poor, it is desirable to conduct well-designed randomized clinical trials to assess its safety for the treatment of acute brain disorders. PMID- 25829100 TI - Effect of co-morbid depression on neurocognitive functioning in patients with obsessive-compulsive disorder: a study from India. AB - OBJECTIVE: To study neuropsychological function in subjects with obsessive compulsive disorder (OCD) with and without co-morbid depression in comparison with healthy controls (HC). METHODS: The 3 sample groups included subjects with OCD without depression (OCD group, n = 30); subjects with OCD and depression (OCDD group, n = 20); and HC (n = 25). All 3 groups were matched for age, gender, and years of education, and they were assessed on the following: Trail Making Tests A and B, Verbal Fluency Test, PGI Memory Scale, Stroop test, Tower of London Test, Raven's Standard Progressive Matrices, Wisconsin Card Sorting Test, and the Object Alternation Test. RESULTS: Both OCD and OCDD groups performed more poorly than HC, whereas the OCDD group performed worse than OCD group. Besides, OCD and OCDD groups had significantly poorer performance on tests of attention, memory, executive functions, verbal fluency, and intelligence. The OCDD group performed worse than the OCD group notably on Verbal Fluency Test, PGI memory test, and Object Alternation Test. CONCLUSION: On tests of neurocognitive functioning, the performance of the OCDD group was poorer than the OCD group, and both performed poorer than HC, suggesting that OCD is associated with neurocognitive dysfunction and that this is exacerbated in the presence of depression. PMID- 25829101 TI - Transformation of a metaphor: semantic shift in a Cantonese term 'Chi Sin' denoting insanity. AB - OBJECTIVES: The historical evolution of the existing terms used to describe insanity may be able to shed light on the formation of stigma towards psychosis patients. In Hong Kong, a widely used Cantonese term for insanity 'Chi Sin' provides a unique example because of its neutral original sense, as it literally means misconnection in a network circuit. We attempt to trace the origin and subsequent evolution of the term 'Chi Sin' from its early use to the present day to understand how local Hong Kong people have attached increasingly negative connotations to this scientific term since the mid-20th century. METHODS: We sampled as many newspapers and magazines published in Hong Kong from 1939 to June 2014 as possible, and sampled 7 popular local movies from the 1950s and 1960s. We also searched all the newspapers published in Hong Kong, Macau, Taiwan, and Mainland China from January 1998 to June 2014, and searched several other local historical resources. RESULTS: In one early use of 'Chi Sin' in 1939, the term was only used in a technical sense to describe 'short circuiting'. We found that the development of the telephone system, the Strowger system, in Hong Kong is closely related to the evolution of the semantics of the term 'Chi Sin'. CONCLUSIONS: The original meaning of short circuitry of the term 'Chi Sin' is no longer used, and it has become a dead metaphor through repeated use with negative emotional connotations. This illustrates some of the factors facilitating the emergence of a metaphor with subsequent semantic drift. PMID- 25829102 TI - Concurrent validation of a neurocognitive assessment protocol for clients with mental illness in job matching as shop sales in supported employment. AB - OBJECTIVES: Occupational therapists play a major role in the assessment and referral of clients with severe mental illness for supported employment. Nonetheless, there is scarce literature about the content and predictive validity of the process. In addition, the criteria of successful job matching have not been analysed and job supervisors have relied on experience rather than objective standards in recruitment. This study aimed to explore the profile of successful clients working in 'shop sales' in a supportive environment using a neurocognitive assessment protocol, and to validate the protocol against 'internal standards' of the job supervisors. METHODS: This was a concurrent validation study of criterion-related scales for a single job type. The subjective ratings from the supervisors were concurrently validated against the results of neurocognitive assessment of intellectual function and work-related cognitive behaviour. RESULTS: A regression model was established for clients who succeeded and failed in employment using supervisor's ratings and a cutoff value of 10.5 for the Performance Fitness Rating Scale (R(2) = 0.918, F[41] = 3.794, p = 0.003). Classification And Regression Tree was also plotted to identify the profile of cases, with an overall accuracy of 0.861 (relative error, 0.26). CONCLUSION: Use of both inference statistics and data mining techniques enables the decision tree of neurocognitive assessments to be more readily applied by therapists in vocational rehabilitation, and thus directly improve the efficiency and efficacy of the process. PMID- 25829103 TI - Effectiveness of psycho-educational intervention in improving outcome of unipolar depression: results from a randomised clinical trial. AB - OBJECTIVES: Depressive disorders are one of the leading components of the global burden of disease with a prevalence of up to 14% in the general population. Numerous studies have demonstrated that pharmacotherapy combined with non pharmacological measures offer the best treatment approach. Psycho-education as an intervention has been studied mostly in disorders such as schizophrenia and dementia, less so in depressive disorders. The present study aimed to assess the impact of psycho-education of patients and their caregivers on the outcome of depression. METHODS: A total of 80 eligible depressed subjects were recruited and randomised into 2 groups. The study group involved an eligible family member and all were offered individual structured psycho-educational modules. Another group (controls) received routine counselling. The subjects in both groups also received routine pharmacotherapy and counselling from the treating clinician and were assessed at baseline, 2, 4, 8, and 12 weeks using the Hamilton Depression Rating Scale (HDRS), Global Assessment of Functioning (GAF), and Psychological General Well-Being Index (PGWBI). Results from both groups were compared using statistical methods including Chi-square test, Fisher's exact test, Student's t test, Pearson's correlation coefficient, as well as univariate and multiple regression analyses. RESULTS: Baseline socio-demographic and assessment measures were similar in both groups. The study group had consistent improvement in terms of outcome measures with HDRS, GAF, and PGWBI scores showing respective mean change of -15.08, 22, and 60 over 12 weeks. The comparable respective changes in the controls were -8.77, 18.1, and 43.25. CONCLUSION: Structured psycho-education combined with pharmacotherapy is an effective intervention for people with depressive disorders. Psycho-education optimises the pharmacological treatment of depression in terms of faster recovery, reduction in severity of depression, and improvement in subjective wellbeing and social functioning. PMID- 25829104 TI - Prodromal psychosis: a case series of ten symptomatic patients. AB - This case series provides an account of 10 patients with prodromal psychosis in Hong Kong over the course of 12 months between 2012 and 2014. Patterns of symptoms and functioning levels were noted each month and overall presentation was classified into 4 categories. Four patients' conditions were classified as fluctuating, 3 patients as improved, 2 patients as no change, and 1 patient as transition into psychosis. The noted observations were compared to the current conceptualisation of prodromal psychosis according to the clinical staging model of McGorry and colleagues. This case series provides insights into the condition in an Asian population and provides background data to inform future clinical research and mental health services. PMID- 25829105 TI - MWCNT uptake in Allium cepa root cells induces cytotoxic and genotoxic responses and results in DNA hyper-methylation. AB - Advances in nanotechnology have led to the large-scale production of nanoparticles, which, in turn, increases the chances of environmental exposure. While humans (consumers/workers) are primarily at risk of being exposed to the adverse effect of nanoparticles, the effect on plants and other components of the environment cannot be ignored. The present work investigates the cytotoxic, genotoxic, and epigenetic (DNA methylation) effect of MWCNT on the plant system- Allium cepa. MWCNT uptake in root cells significantly altered cellular morphology. Membrane integrity and mitochondrial function were also compromised. The nanotubes induced significant DNA damage, micronucleus formation and chromosome aberration. DNA laddering assay revealed the formation of internucleosomal fragments, which is indicative of apoptotic cell death. This finding was confirmed by an accumulation of cells in the sub-G0 phase of the cell cycle. An increase in CpG methylation was observed using the isoschizomers MspI/HpaII. HPLC analysis of DNA samples revealed a significant increase in the levels of 5-methyl-deoxy-cytidine (5mdC). These results confirm the cyto genotoxic effect of MWCNT in the plant system and simultaneously highlight the importance of this epigenetic study in nanoparticle toxicity. PMID- 25829106 TI - Electrocortical effects of a disgust placebo in children. AB - The electroencephalogram has been widely used to study voluntary emotion regulation (ER), whereas automatic ER has hardly been investigated. This experiment focused on automatic changes of disgust feelings and event-related potentials due to placebo treatment. Twenty-eight disgust-prone 8- to 13-year-old girls were presented with disgusting, fear-eliciting and neutral pictures once with and once without a placebo (syrup presented with the suggestion that it is able to ease disgust symptoms). In the disgust condition, the placebo reduced experienced disgust and increased frontal late positivity (400-1000 ms after picture onset). A similar electrocortical placebo effect was obtained for the fear pictures. These findings suggest that the placebo had the function of a safety signal which helped the children to direct their automatic attention to the aversive stimuli and to overcome visual avoidance. Future studies should integrate behavioral designs and should use additional psychophysiological measures (e.g., eye-tracking) in order to substantiate this interpretation. PMID- 25829107 TI - Characterization of biomimetic calcium phosphate labeled with fluorescent dextran for quantification of osteoclastic activity. AB - Bone resorbing osteoclasts represent an important therapeutic target for diseases associated with bone and joint destruction, such as rheumatoid arthritis, periodontitis, and osteoporosis. The quantification of osteoclast resorptive activity in vitro is widely used for screening new anti-resorptive medications. The aim of this paper was to develop a simplified semi-automated method for the quantification of osteoclastic resorption using fluorescently labeled biomimetic mineral layers which can replace time intensive, often subjective and clearly non sustainable use of translucent slices of tusks from vulnerable or endangered species such as the elephant. Osteoclasts were formed from RAW 264.7 mouse monocyte cell line using the pro-resorptive cytokine receptor activator of nuclear factor kappa-B ligand (RANKL). We confirmed that fluorescent labeling did not interfere with the biomimetic features of hydroxyapatite, and developed an automated method for quantifying osteoclastic resorption. Correlation between our assay and traditional manual measurement techniques was found to be very strong (R(2)=0.99). In addition, we modified the technique to provide depth and volume data of the resorption pits by confocal imaging at defined depths. Thus, our method allows automatic quantification of total osteoclastic resorption as well as additional data not obtainable by the current tusk slice technique offering a better alternative for high throughput screening of potential antiresorptives. PMID- 25829108 TI - Long bone maturation is driven by pore closing: A quantitative tomography investigation of structural formation in young C57BL/6 mice. AB - During mammalian growth, long bones undergo extensive structural reorganization, transforming from primitive shapes in the limb buds into mature bones. Here we shed light on the steps involved in structural formation of the mineralized tissue in midshafts of C57BL/6 femurs, shortly after birth. By combining 3D micrometer-resolution X-ray microtomography with 2D histology, we study the transformation of the tissue from a partially-mineralized scaffold into a compact bone structure. We identify three growth phases that take place during murine long bone maturation: During a patterning phase (I) mineralized struts form a loosely connected foam-like cortical network. During a transitioning phase (II), the extensive non-mineralized tracts vanish, transforming the foam into a fully continuous mass, by 14 days of age. Concomitantly, closed porosity increases to about ~ 1.4%, and stays at this level, also found in maturity. During a shaping phase (III), the bones gradually attain their characteristic intricate adult form. Architectured mineral depositioning--first in open foamy scaffolds, and later into solid bone material--is presumably a compromise between the mechanical needs of providing support to the body, and the biological requirements of vascularization and extensive nutritional needs in the early stages of bone formation. PMID- 25829109 TI - Everyone Swims: a community partnership and policy approach to address health disparities in drowning and obesity. AB - Well-known disparities exist in rates of obesity and drowning, two public health priorities. Addressing these disparities by increasing access to safe swimming and water recreation may yield benefits for both obesity and injury prevention. Everyone Swims, a community partnership, brought community health clinics and water recreation organizations together to improve policies and systems that facilitated learning to swim and access to swimming and water recreation for low income, diverse communities. Based in King County, Washington, Everyone Swims launched with Centers for Disease Control and Prevention grant funding from 2010 to 2012. This partnership led to multiple improvements in policies and systems: higher numbers of clinics screening for swimming ability, referrals from clinics to pools, more scholarship accessibility, and expansion of special swim programs. In building partnerships between community health/public health and community recreation organizations to develop systems that address user needs in low-income and culturally diverse communities, Everyone Swims represents a promising model of a structured partnership for systems and policy change to promote health and physical activity. PMID- 25829110 TI - Preventing unintentional injuries in the home using the Health Impact Pyramid. AB - Injuries continue to be the leading cause of death for the first four decades of life. These injuries result from a confluence of behavioral, physical, structural, environmental, and social factors. Taken together, these illustrate the importance of taking a broad and multileveled approach to injury prevention. Using examples from fall, fire, scald, and poisoning-related injuries, this article illustrates the utility of an approach that incorporates a social environmental perspective in identifying and selecting interventions to improve the health and safety of individuals. Injury prevention efforts to prevent home injuries benefit from multilevel modifications of behavior, public policy, laws and enforcement, the environment, consumer products and engineering standards, as demonstrated with Frieden's Health Impact Pyramid. A greater understanding, however, is needed to explain the associations between tiers. While interventions that include modifications of the social environment are being field-tested, much more work needs to be done in measuring social-environmental change and in evaluating these programs to disentangle what works best. PMID- 25829111 TI - Influencing organizations to promote health: applying stakeholder theory. AB - Stakeholder theory may help health promoters to make changes at the organizational and policy level to promote health. A stakeholder is any individual, group, or organization that can influence an organization. The organization that is the focus for influence attempts is called the focal organization. The more salient a stakeholder is and the more central in the network, the stronger the influence. As stakeholders, health promoters may use communicative, compromise, deinstitutionalization, or coercive methods through an ally or a coalition. A hypothetical case study, involving adolescent use of harmful legal products, illustrates the process of applying stakeholder theory to strategic decision making. PMID- 25829112 TI - Building the evidence base for population-level interventions: barriers and opportunities. AB - Population-level interventions focused on policy, systems, and environmental change strategies are increasingly being used to affect and improve the health of populations. At the same time, emphasis on implementing evidence-based public health practices and programming is increasing, particularly at the federal level. Valuing strategies in the population health domain without the benefit of demonstrated efficacy through highly rigorous methods introduces an inherent tension between planning and acting on the best evidence available, waiting for more rigorous evidence to emerge, as well as exploring innovative ways to evaluate and model evidence-based strategies. This article describes the creation of a resource that helps public health practitioners use current evidence for strategic decision making while building the evidence base for population-level interventions. The resource addresses topics of current discussion in the field of evaluating population-level interventions, including the tension between internal and external validity, the need to include measures of health equity, and the balance between fidelity to the intervention and adaptation to the community context. The resource is intended to advance development of evidence in the field by providing practitioners, project managers, and evaluators with a practical guide for using, reviewing, and adding to the existing evidence base. PMID- 25829113 TI - Reflections on structural change: where do we go from here? PMID- 25829114 TI - Developing evidence for structural approaches to build a culture of health: a perspective from the Robert Wood Johnson Foundation. AB - We believe that reframing the conversation to creating a culture around health rather than focusing on discrete actions or activities will capture national consciousness and enable us to make new progress as a nation. Thus, in 2014, the Robert Wood Johnson Foundation (RWJF) announced a new vision to help build a "Culture of Health" to enable everyone in our diverse society to lead healthier lives now and for generations to come. In supporting the development of this supplement of Health Education & Behavior, RWJF sought to contribute to a better understanding of the ways in which policy, environmental, and financial approaches can contribute to such a Culture of Health. However, while this supplement issue of Health Education & Behavior stands as a testament to the fact that a broad evidence base, rather than a single approach to health improvement, is necessary to have an impact on social change, more empirical evidence is needed on structural approaches if we are to be successful in understanding and improving health outcomes for individuals, families, communities, states, and nations. PMID- 25829115 TI - The impact of policy, environmental, and educational interventions: a synthesis of the evidence from two public health success stories. AB - Motor vehicle safety and tobacco control are among the greatest public health achievements of the 20th century, according to the Centers for Disease Control and Prevention. As the number of miles traveled in the United States multiplied 10 times from the 1920s to the 1990s, the annual motor vehicle crash death rate per vehicle mile traveled decreased by 90%. Similarly, tobacco-related deaths from heart disease, stroke, and cancer were rapidly mounting over the first two thirds of the 20th century. Then, in the last third of the century, tobacco consumption decreased by more than 50%, and rates of heart disease and stroke deaths, and later cancer deaths, declined similarly. This analysis addresses the central question of what lessons can be learned from these success stories that will help public health professionals successfully tackle new and emerging health behavior problems of today and tomorrow? Surveillance, research, multilevel interventions, environmental modifications, and strong policies were key to reducing motor vehicle- and tobacco-related health problems. Generating public support and advocacy, and changing social norms also played critical roles in promoting the safer and smoke-free behaviors. Lessons learned include the need for evidence-based practices and interventions that are ecologically comprehensive with an emphasis on changing environmental determinants and capitalizing on the concept of reciprocal determinism. The analysis concludes with a description of how the PRECEDE-PROCEED planning framework can be used to apply the lessons from motor vehicle safety and tobacco control to other public health threats. PMID- 25829116 TI - Working from the inside out: a case study of Mackay Safe Community. AB - Mackay Whitsunday Safe Community (MWSC) was established in 2000 in response to high rates of injury observed in the region. MWSC assumed an ecological perspective, incorporating targeted safety promotion campaigns reinforced by supportive environments and policy. By involving the community in finding its own solutions, MWSC attempted to catalyze structural, social, and political changes that empowered the community and, ultimately, individuals within the community, to modify their environment and their behavior to reduce the risk of injury. A community network consisting of 118 members and an external support network of 50 members was established. A social network analysis conducted in 2000 and 2004 indicated that the network doubled its cohesiveness, thereby strengthening its ability to collaborate for mutual benefit. However, while MWSC was rich in social resources, human and financial resources were largely controlled by external agencies. The bridging and linking relationships that connected MWSC to its external support network were the social mechanism MWSC used to access the resources it required to run programs. These boundary-spanning relationships accessed an estimated 6.5 full-time equivalents of human resources and US$750,000 in 2004 that it used to deliver a suite of injury control and safety promotion activities, associated with a 33% reduction in injury deaths over the period 2002 to 2010. MWSC can only be understood in its ecological context. The productivity of MWSC was vulnerable to the changing policy priorities of external sponsoring agents and critically dependent on the advocacy skills of its leaders. PMID- 25829117 TI - New approaches for moving upstream: how state and local health departments can transform practice to reduce health inequalities. AB - Growing evidence shows that unequal distribution of wealth and power across race, class, and gender produces the differences in living conditions that are "upstream" drivers of health inequalities. Health educators and other public health professionals, however, still develop interventions that focus mainly on "downstream" behavioral risks. Three factors explain the difficulty in translating this knowledge into practice. First, in their allegiance to the status quo, powerful elites often resist upstream policies and programs that redistribute wealth and power. Second, public health practice is often grounded in dominant biomedical and behavioral paradigms, and health departments also face legal and political limits on expanding their scope of activities. Finally, the evidence for the impact of upstream interventions is limited, in part because methodologies for evaluating upstream interventions are less developed. To illustrate strategies to overcome these obstacles, we profile recent campaigns in the United States to enact living wages, prevent mortgage foreclosures, and reduce exposure to air pollution. We then examine how health educators working in state and local health departments can transform their practice to contribute to campaigns that reallocate the wealth and power that shape the living conditions that determine health and health inequalities. We also consider health educators' role in producing the evidence that can guide transformative expansion of upstream interventions to reduce health inequalities. PMID- 25829119 TI - Policy and environmental approaches in health promotion: what is the state of the evidence? PMID- 25829118 TI - Policy, systems, and environmental change in the Mississippi Delta: considerations for evaluation design. AB - Community-level policy, systems, and environmental (PSE) change strategies may offer an economical and sustainable approach to chronic disease prevention. The rapidly growing number of untested but promising PSE strategies currently underway offers an exciting opportunity to establish practice-based evidence for this approach. This article presents lessons learned from an evaluation of a community-based PSE initiative targeting stroke and cardiovascular disease prevention in the Mississippi Delta. Its purpose is to describe one approach to evaluating this type of PSE initiative, to stimulate discussion about best practices for evaluating PSE strategies, and to inform future evaluation and research efforts to expand practice-based evidence. The evaluation used a descriptive mixed-methods design and focused on the second year of a multisectoral, multiyear initiative. Cross-sectional data were collected in the summer and fall of 2010 using four data collection instruments: a grantee interview guide (n = 32), a health council member survey (n = 256), an organizational survey (n = 60), and a grantee progress report (n = 26). Fifty eight PSE changes were assessed across five sectors: health, faith, education, worksite, and community/city government. PSE strategies aligned with increased access to physical activity opportunities, healthy food and beverage options, quality health care, and reduced exposure to tobacco. Results showed that grantees were successful in completing a series of steps toward PSE change and that sector-specific initiatives resulted in a range of PSE changes that were completed or in progress. Considerations for designing evaluations of community based PSE initiatives are discussed. PMID- 25829120 TI - Economic disruption and childhood obesity: distraction, disconnection, displacement of children's health, and a need for social change. AB - Using and adopting Simon Szreter's framework on how economic growth had a deleterious effect on children's health during the Industrial Revolution, this article presents a parallel argument that economic growth, in modern times, also has disrupted the lives of our children expressed by increasing rates of childhood obesity. A comprehensive perspective is presented that describes how economic growth in postindustrial United States has distracted our nation's attention away from a public health's concern for the health of children and social justice. The new normal of childhood obesity represents a disconnection from the harmful reality of childhood obesity and displaces the value of childhood health too far behind adult's pursuits of utility. To provide children a fair opportunity to health, and to help children secure their own future liberty and utility, children need to be able to achieve "just levels" of health that would ordinarily exist if remediable injustices that threaten health were reasonably addressed and eliminated. PMID- 25829121 TI - Conflict and compromise in public health policy: analysis of changes made to five competitive food legislative proposals prior to adoption. AB - Competitive foods in schools have historically been scrutinized for their ubiquity and poor nutritional quality, leading many states to enact legislation limiting the availability and accessibility of these items. Evaluations of these policy approaches show their promise in improving the healthfulness of school food environments, considered an important strategy for reducing childhood obesity. Yet little is known about the decision-making processes by which such legislation is formed and adopted. Using a comparative case study design, this study describes and analyzes the policy formation processes surrounding five state-level competitive food bills introduced in 2009-2010. Data for each case were drawn from multiple key informant interviews and document reviews. Case studies were conducted, analyzed, and written independently using a standard protocol and were subsequently compared for recurring and unique themes. Abbreviated case studies and summary tables are provided. Results indicate that bill cost is a major barrier to achieving strong, health-promoting policy change. Additionally, findings reveal that supporters of stronger competitive food policies often concede to changes that weaken a bill in order to neutralize opposition and achieve stakeholder buy-in. These challenges suggest that continued research on the development, implementation, and evaluation of public health policies can contribute to the advancement of new strategies for effective health promotion. PMID- 25829122 TI - A natural experiment opportunity in two low-income urban food desert communities: research design, community engagement methods, and baseline results. AB - A growing body of evidence has highlighted an association between a lack of access to nutritious, affordable food (e.g., through full-service grocery stores [FSGs]), poor diet, and increased risk for obesity. In response, there has been growing interest among policy makers in encouraging the siting of supermarkets in "food deserts," that is, low-income geographic areas with low access to healthy food options. However, there is limited research to evaluate the impact of such efforts, and most studies to date have been cross-sectional. The Pittsburgh Hill/Homewood Research on Eating, Shopping, and Health (PHRESH) is a longitudinal quasi-experimental study of a dramatic change (i.e., a new FSG) in the food landscape of a low-income, predominantly Black neighborhood. The study is following a stratified random sample of households (n = 1,372), and all food venues (n = 60) in both intervention and control neighborhoods, and the most frequently reported food shopping venues outside both neighborhoods. This article describes the study design and community-based methodology, which focused simultaneously on the conduct of scientifically rigorous research and the development and maintenance of trust and buy-in from the involved neighborhoods. Early results have begun to define markers for success in creating a natural experiment, including strong community engagement. Baseline data show that the vast majority of residents already shop at a FSG and do not shop at the nearest one. Follow-up data collection will help determine whether and how a new FSG may change behaviors and may point to the need for additional interventions beyond new FSGs alone. PMID- 25829123 TI - Upending the social ecological model to guide health promotion efforts toward policy and environmental change. AB - Efforts to change policies and the environments in which people live, work, and play have gained increasing attention over the past several decades. Yet health promotion frameworks that illustrate the complex processes that produce health enhancing structural changes are limited. Building on the experiences of health educators, community activists, and community-based researchers described in this supplement and elsewhere, as well as several political, social, and behavioral science theories, we propose a new framework to organize our thinking about producing policy, environmental, and other structural changes. We build on the social ecological model, a framework widely employed in public health research and practice, by turning it inside out, placing health-related and other social policies and environments at the center, and conceptualizing the ways in which individuals, their social networks, and organized groups produce a community context that fosters healthy policy and environmental development. We conclude by describing how health promotion practitioners and researchers can foster structural change by (1) conveying the health and social relevance of policy and environmental change initiatives, (2) building partnerships to support them, and (3) promoting more equitable distributions of the resources necessary for people to meet their daily needs, control their lives, and freely participate in the public sphere. PMID- 25829124 TI - Impact of Baltimore Healthy Eating Zones: an environmental intervention to improve diet among African American youth. AB - This study assessed the impact of a youth-targeted multilevel nutrition intervention in Baltimore City. The study used a clustered randomized design in which 7 recreation centers and 21 corner stores received interventions and 7 additional recreation centers served as comparison. The 8-month intervention aimed to increase availability and selection of healthful foods through nutrition promotion and education using point-of purchase materials such as posters and flyers in stores and interactive sessions such as taste test and cooking demonstrations. Two hundred forty-two youth-caregiver dyads residing in low income areas of Baltimore City recruited from recreation centers were surveyed at baseline using detailed instruments that contained questions about food-related psychosocial indicators (behavioral intentions, self-efficacy, outcome expectancies, and knowledge), healthful food purchasing and preparation methods, and anthropometric measures (height and weight). The Baltimore Healthy Eating Zones intervention was associated with reductions in youth body mass index percentile (p = .04). In subgroup analyses among overweight and obese girls, body mass index for age percentile decreased significantly in girls assigned to the intervention group (p = .03) and in girls with high exposure to the intervention (p = .013), as opposed to those in comparison or lower exposure groups. Intervention youth significantly improved food-related outcome expectancies (p = .02) and knowledge (p < .001). The study results suggest that the Baltimore Healthy Eating Zones multilevel intervention had a modest impact in reducing overweight or obesity among already overweight low-income African American youth living in an environment where healthful foods are less available. Additional studies are needed to determine the relative impact of health communications and environmental interventions in this population, both alone and in combination. PMID- 25829125 TI - Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis. AB - Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease with genotypic and phenotypic heterogeneity, sometimes translating into delayed diagnosis and treatment. In particular, cases of intermediate severity often constitute a diagnostic challenge and represent good candidates for exome sequencing. Here, we describe the tortuous path to identification of the molecular defect in two siblings, in which osteopetrosis diagnosed in early childhood followed a milder course, allowing them to reach the adult age in relatively good conditions with no specific therapy. No clearly pathogenic mutation was identified either with standard amplification and resequencing protocols or with exome sequencing analysis. While evaluating the possible impact of a 3'UTR variant on the TCIRG1 expression, we found a novel single nucleotide change buried in the middle of intron 15 of the TCIRG1 gene, about 150 nucleotides away from the closest canonical splice site. By sequencing a number of independent cDNA clones covering exons 14 to 17, we demonstrated that this mutation reduced splicing efficiency but did not completely abrogate the production of the normal transcript. Prompted by this finding, we sequenced the same genomic region in 33 patients from our unresolved ARO cohort and found three additional novel single nucleotide changes in a similar location and with a predicted disruptive effect on splicing, further confirmed in one of them at the transcript level. Overall, we identified an intronic region in TCIRG1 that seems to be particularly prone to splicing mutations, allowing the production of a small amount of protein sufficient to reduce the severity of the phenotype usually associated with TCIRG1 defects. On this basis, we would recommend including TCIRG1 not only in the molecular work-up of severe infantile osteopetrosis but also in intermediate cases and carefully evaluating the possible effects of intronic changes. PMID- 25829126 TI - The relationship between skull morphology, masticatory muscle force and cranial skeletal deformation during biting. AB - The human skull is gracile when compared to many Middle Pleistocene hominins. It has been argued that it is less able to generate and withstand high masticatory forces, and that the morphology of the lower portion of the modern human face correlates most strongly with dietary characteristics. This study uses geometric morphometrics and finite element analysis (FEA) to assess the relationship between skull morphology, muscle force and cranial deformations arising from biting, which is relevant in understanding how skull morphology relates to mastication. The three-dimensional skull anatomies of 20 individuals were reconstructed from medical computed tomograms. Maximal contractile muscle forces were estimated from muscular anatomical cross-sectional areas (CSAs). Fifty-nine landmarks were used to represent skull morphology. A partial least squares analysis was performed to assess the association between skull shape and muscle force, and FEA was used to compare the deformation (strains) generated during incisor and molar bites in two individuals representing extremes of morphological variation in the sample. The results showed that only the proportion of total muscle CSA accounted for by the temporalis appears associated with skull morphology, albeit weekly. However, individuals with a large temporalis tend to possess a relatively wider face, a narrower, more vertically oriented maxilla and a lower positioning of the coronoid process. The FEAs showed that, despite differences in morphology, biting results in similar modes of deformation for both crania, but with localised lower magnitudes of strains arising in the individual with the narrowest, most vertically oriented maxilla. Our results suggest that the morphology of the maxilla modulates the transmission of forces generated during mastication to the rest of the cranium by deforming less in individuals with the ability to generate proportionately larger temporalis muscle forces. PMID- 25829127 TI - N-Isopropylacrylamide-modified polyethylenimine-mediated p53 gene delivery to prevent the proliferation of cancer cells. AB - In this paper, N-isopropylacrylamide-modified polyethylenimine (PEN) was constructed through Michael addition and employed as a carrier to achieve the p53 gene delivery, using HeLa (p53wt) and PC-3 cells (p53null) as models. After PEN mediated p53 transfection, expression level of p53 in HeLa and PC3 cells was up regulated at both mRNA and protein levels. Due to the exogenous p53 expression, the inhibition of cell proliferation was observed through MTT analysis, attributing to the activation of apoptosis and cell cycle arrest. Using flow cytometric analysis, early apoptotic ratios of 54.95% and 27.06% after PEN mediated p53 transfection were detected in PC-3 and HeLa cells, respectively, indicating that PC-3 cells were more sensitive to the exogenous p53 transfection than HeLa cells. Meanwhile, G1 phase arrest was detected in PC-3 cells while a unique G2 phase arrest was identified in HeLa cells after p53 transfection. Through Western blotting, activity analysis of caspase-3, caspase-8 and caspase-9 and mitochondrial membrane potential measurement, the apoptosis induced by PEN mediated p53 transfection was conducted in a mitochondria-dependent apoptosis pathway. These results demonstrated that PEN could successfully mediate the p53 gene delivery and up-regulate the cellular p53 expression level, triggering a significant p53-dependent anti-proliferative effect on tumor cells. PMID- 25829128 TI - Folate mediated self-assembled phytosterol-alginate nanoparticles for targeted intracellular anticancer drug delivery. AB - Self-assembled core/shell nanoparticles (NPs) were synthesized from water-soluble alginate substituted by hydrophobic phytosterols. Folate, a cancer-cell-specific ligand, was conjugated to the phytosterol-alginate (PA) NPs for targeting folate receptor-overexpressing cancer cells. The physicochemical properties of folate phytosterol-alginate (FPA) NPs were characterized by nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug, was entrapped inside prepared NPs by dialysis method. The identification of prepared FPA NPs to folate-receptor-overexpressing cancer cells (KB cells) was confirmed by cytotoxicity and folate competition assays. Compared to the pure DOX and DOX/PA NPs, the DOX/FPA NPs had lower IC50 value to KB cells because of folate-receptor-mediated endocytosis process and the cytotoxicity of DOX/FPA NPs to KB cells could be competitively inhibited by free folate. The cellular uptake and internalization of pure DOX and DOX/FPA NPs was confirmed by confocal laser scanning microscopy image and the higher intracellular uptake of drug for DOX/FPA NPs over pure DOX was observed. The FPA NPs had the potential as a promising carrier to target drugs to cancer cells overexpressing folate receptors and avoid cytotoxicity to normal tissues. PMID- 25829129 TI - Apolipoprotein B-100-targeted negatively charged nanoliposomes for the treatment of dyslipidemia. AB - BACKGROUND: Anionic nanoliposomes can interact with serum lipoproteins and regulate lipid metabolism through several mechanisms. This study aimed to evaluate the lipid-modifying effects of anionic immunoliposomes targeted against apoB, an important component of atherogenic lipoproteins. METHODS: Two sets of nanoliposomes (20mM) were prepared with low (including soy phosphatidylcholine [SPC] and egg phosphatidylglycerol [EPG]) and high (including hydrogenated soy phosphatidylcholine [HSPC] and distearoyl phosphatidylglycerol [DSPG]) phase transition temperature values without cholesterol. In each set, the anionic phospholipid (EPG or DSPG) constituted 75% of total phospholipid content. Immunoliposomes were prepared by conjugating a monoclonal antibody against apoB 100 to the liposomal surface using a post-insertion technique. Fluorescently labeled immunoliposomes were assessed for their uptake by J774.A1 macrophages. Lipid-modifying effects of immunoliposomes were tested at different doses (50, 100 or 200MUmole/g weight) using a tyloxapol-induced hyperlipidemic mouse model. Blood sampling was performed 1h after the injection of each immunoliposomal formulation. RESULTS: ApoB-targeted HSPC/DSPG and SPC/EPG nanoliposomes were both taken up by cultured macrophages but the uptake rate was higher with the former formulation. Both immunoliposomal formulations significantly reduced serum LDL cholesterol concentrations of hyperlipidemic animals at all tested doses (p<0.001) and this effect lasted for at least 48h. Significant reductions of serum levels of apoB, non-HDL-C, total cholesterol and triglycerides, and elevations of HDL-C levels were also observed. CONCLUSION: Intravenous injection of a single dose of apoB-targeted anionic nanoliposomes improves serum lipid profile parameters. These findings might have implications for the treatment of patients with severe dyslipidemias or statin intolerance. PMID- 25829130 TI - Radiosensitizing effect of zinc oxide and silica nanocomposites on cancer cells. AB - Nanoparticulates responsive to X-rays offer increased efficacy of radiation therapy. However, successful demonstrations of such nanoparticle use are limited so far due to lack of significant radiosensitizing effects or poor nanoparticle stability in a biological system. Zinc oxide (ZnO) is the most promising biocompatible material for medicinal applications. In this paper, we report preparation and characterization of scintillating ZnO/SiO2 core-shell nanoparticles. The ZnO/SiO2 nanoparticles absorb ultraviolet (UV) radiation (below 360nm) and emit green fluorescence (400-750nm, maximum 550nm). Under X-ray irradiation (200kVp), the nanoparticles scintillate emitting luminescence in the region 350-700nm (maximum 420nm). The synthesized ZnO/SiO2 nanoparticles are stable in a biologically relevant environment (water and cell growth medium). The potential of the ZnO/SiO2 nanoparticles for radiosensitization is demonstrated in human prostate adenocarcinoma cell lines (LNCaP and Du145). The nanoparticles enhance radiation-induced reduction in cell survival about 2-fold for LNCaP and 1.5-fold for Du145 cells. Radiosensitizing effect can be attributed to X-ray induced radiocatalysis by the nanoparticles. PMID- 25829131 TI - Cubosome formulations stabilized by a dansyl-conjugated block copolymer for possible nanomedicine applications. AB - We present here an innovative, fluorescent, monoolein-based cubosome dispersion. Rather than embedded within the monoolein palisade, the fluorescent imaging agent, namely dansyl, was conjugated to the terminal ethylene oxide moieties of the block copolymer Pluronic F108. We discuss the physicochemical and photophysical properties of this fluorescent Pluronic and of a cubosome formulation stabilized by a mixture of dansyl-conjugated and non-conjugated Pluronic, also including an anticancer drug (quercetin). Furthermore, we performed biocompatibility tests against HeLa cells to assess internalization and cytotoxicity features of this nanoparticles aqueous dispersion. Cryo-TEM, SAXS, and DLS analysis, proved the bicontinuous cubic inner nanostructure and the morphology of this fluorescent cubosome dispersion, while photophysical measurements and biocompatibility results basically validate their potential use for theranostic nanomedicine applications. PMID- 25829132 TI - Mortality from alcohol consumption and alcohol use disorder: Findings from the Vietnam Experience Study. AB - BACKGROUND: To examine the relationship of alcohol consumption, alcohol use disorder and mortality. METHOD: A cohort of 4316 male former Vietnam-era US army personnel participating in telephone survey and medical examination in middle age (mean age 38.3 years) in 1985-1986 was used. Alcohol consumption was reported in face-to-face interview on medical history and information on DSM-III alcohol use disorder was obtained from structured psychiatric interview (using the Diagnostic Interview Schedule). Mortality hazard during 15 years of follow-up was assessed with Cox proportional hazard regression modeling. RESULT: A total of 4251 individuals participated in the psychiatric interview and the medical history interview. Of these 998 were abstainers, and for the remaining 3253 we calculated weekly average consumption and monthly frequency of binge drinking. A total of 1988 had alcohol dependence, abuse or both. There were 237 deaths during follow up. A J-shaped association was found for both consumption and binging. In multivariable analysis jointly modeling average consumption and disorder, and binging and disorder, increased mortality remained significant for both very high consumption (Hazard Ratio (HR) 1.62, 95% Confidence Intervals [1.02-2.57]) for drinking 29 or more drinks per week, and frequent bingeing HR 1.81 [1.03-3.18] for bingeing 16 or more times per month). CONCLUSION: This study showed that alcohol consumption measures were associated with mortality, partly independent from the potential confounding effect of alcohol use disorder, which is an established risk factor for mortality. This further highlights the importance of alcohol consumption measures in public health. PMID- 25829133 TI - Highly Efficient AuPd/Carbon Nanotube Nanocatalysts for the Electro-Fenton Process. AB - Development of novel nanocatalysts for the highly efficient in situ synthesis of H2 O2 from H2 and O2 in the electro-Fenton (EF) process has potential for the remediation of water pollution. In this work, AuPd/carbon nanotube (CNT) nanocatalysts were successfully synthesized by the facile aggregation of AuPd bimetals on CNTs. Characterization by X-ray diffraction, transmission electron microscopy, and X-ray photoelectron spectroscopy indicated that pure AuPd bimetallic heterogeneous nanospheres (~20 nm) were well dispersed outside the CNTs, which resulted in better catalytic performance than Pd/CNTs alone: 0.36 M H2 O2 was synthesized; 0.05 M Fe(2+) optimally initiated the EF process due to the superior in situ Fe(2+) regeneration; and the organic pollutant removal reached 100 % at 37 min, with a pseudo-first-order kinetic constant k1 =0.051 min(-1) . Moreover, structural insights before/after catalysis revealed that Au strengthened the construction of the nanocrystals, avoided negative deactivation caused by AuPd agglomeration, and immobilized the active Pd(111). The catalytic stability of AuPd/CNTs over ten cycles implied long durability and promising applications of this material. PMID- 25829135 TI - The Cardiac Rehabilitation Inventory: A New Method of Tailoring Patient Support. AB - BACKGROUND: Uptake and adherence to cardiac rehabilitation (CR) are low, and a contributing factor to this may be the practical difficulties of providing a tailored CR environment suited to individual preferences and needs. OBJECTIVE: The aim of this study was to develop and test a short questionnaire that CR practitioners can use to understand individual patient need and tailor support accordingly. METHODS: A conceptual framework of engagement in CR was derived from a comprehensive literature review and the content analysis of semistructured interviews with 15 CR patients. The conceptual framework was used to construct the first version of the Cardiac Rehabilitation Inventory (CRI), which comprised 42 items. Responses on the CRI were measured using a 5-point Likert scale. The CRI was administered to 380 phase III and IV CR patients, and factor analysis (FA) was used to identify salient CR engagement factors. RESULTS: The simplest structure found using FA was three 6-item subscales that all had good levels of internal consistency (Cronbach's alpha) and were labeled (a) outcome anxiety, alpha = .726; (2) process anxiety, alpha = .724; and (3) autonomy, alpha = .653. The 3-factor CRI model was verified using confirmatory FA (CMin/df = 3.2, root mean-square error of approximation = 0.073). Attenders were found to have higher levels of outcome anxiety than nonattenders (P < .001), and precontemplator nonattenders were found to have lower autonomy compared with attenders (P < .001). Standard multiple regression analysis indicated outcome anxiety was a strong predictor of CR intentions (r = 0.716), followed by autonomy (r = 0.110) and process anxiety (r = 0.031). CONCLUSIONS: The CRI is a reliable method of measuring CR outcome anxiety, process anxiety, and autonomy. These CRI measurements provide rehabilitation practitioners with valuable information that can help provide individual tailored support. PMID- 25829134 TI - Trajectories of premorbid childhood and adolescent functioning in schizophrenia spectrum psychoses: A first-episode study. AB - Evidence of social and behavioral problems preceding the onset of schizophrenia spectrum psychoses is consistent with a neurodevelopmental model of these disorders. Here we predict that individuals with a first episode of schizophrenia spectrum psychoses will evidence one of three patterns of premorbid adjustment: an early deficit, a deteriorating pattern, or adequate or good social adjustment. Participants were 164 (38% female; 31% black) individuals ages 15-50 with a first episode of schizophrenia-spectrum psychoses. Premorbid adjustment was assessed using the Cannon-Spoor Premorbid Adjustment Scale. We compared the fit of a series of growth mixture models to examine premorbid adjustment trajectories, and found the following 3-class model provided the best fit with: a "stable-poor" adjustment class (54%), a "stable-good" adjustment class (39%), and a "deteriorating" adjustment class (7%). Relative to the "stable-good" class, the "stable-poor" class experienced worse negative symptoms at 1-year follow-up, particularly in the social amotivation domain. This represents the first known growth mixture modeling study to examine premorbid functioning patterns in first episode schizophrenia-spectrum psychoses. Given that the stable-poor adjustment pattern was most prevalent, detection of social and academic maladjustment as early as childhood may help identify people at increased risk for schizophrenia spectrum psychoses, potentially increasing feasibility of early interventions. PMID- 25829136 TI - The Prevalence and Associated Distress of Physical and Psychological Symptoms in Patients With Advanced Heart Failure Attending a South African Medical Center. AB - BACKGROUND: Despite the high prevalence of heart failure in low- and middle income countries, evidence concerning patient-reported burden of disease in advanced heart failure is lacking. OBJECTIVE: The aim of this study is to measure patient-reported symptom prevalence and correlates of symptom burden in patients with advanced heart failure. METHODS: Adult patients diagnosed with New York heart Association (NYHA) stage III or IV heart failure were recruited from the emergency unit, emergency ward, cardiology ward, general medicine wards, and outpatient cardiology clinic of a public hospital in South Africa. Patients were interviewed by researchers using the Memorial Symptom Assessment Scale-Short Form, a well-validated multidimensional instrument that assesses presence and distress of 32 symptoms. RESULTS: A total of 230 patients (response, 99.1%), 90% NYHA III and 10% NYHA IV (12% newly diagnosed), with a mean age of 58 years, were included. Forty-five percent were women, 14% had completed high school, and 26% reported having no income. Mean Karnofsky Performance Status Score was 50%. Patients reported a mean of 19 symptoms. Physical symptoms with a high prevalence were shortness of breath (95.2%), feeling drowsy/tired (93.0%), and pain (91.3%). Psychological symptoms with a high prevalence were worrying (94.3%), feeling irritable (93.5%), and feeling sad (93.0%). Multivariate linear regression analyses, with total number of symptoms as dependent variable, showed no association between number of symptoms and gender, education, number of healthcare contacts in the last 3 months, years since diagnosis, or comorbidities. Increased number of symptoms was significantly associated with higher age (b = 0.054, P = .042), no income (b = -2.457, P = .013), and fewer hospitalizations in the last 12 months (b = -1.032, P = .017). CONCLUSIONS: Patients with advanced heart failure attending a medical center in South Africa experience high prevalence of symptoms and report high levels of burden associated with these symptoms. Improved compliance with national and global treatment recommendations could contribute to reduced symptom burden. Healthcare professionals should consider incorporating palliative care into the care for these patients. PMID- 25829137 TI - Subclinical Carotid Atherosclerosis in Asymptomatic Subjects With Type 2 Diabetes Mellitus. AB - BACKGROUND: Subjects with type 2 diabetes mellitus are considered to be at high risk for cardiovascular disease. The identification of carotid atherosclerosis is a validated surrogate marker of cardiovascular disease. Nurses are key professionals in the improvement and intensification of cardiovascular preventive strategies. AIMS: The aim is to study the presence of carotid atherosclerosis in a group of asymptomatic subjects with type 2 diabetes mellitus and no previous clinical cardiovascular disease. METHODS: A total of 187 patients with type 2 diabetes mellitus and 187 age- and sex-matched subjects without type 2 diabetes mellitus were studied in this cross-sectional, observational, cohort study. Standard operational procedures were applied by the nursing team regarding physical examination and carotid ultrasound assessment. Common, bulb, and internal carotid arteries were explored by measuring intima-media thickness and identifying atherosclerotic plaques. RESULTS: Carotid intima-media thickness (c IMT) and carotid plaque prevalence were significantly greater in diabetic subjects than in the control group. Carotid plaques and c-IMT were more frequent in men than in women and increased with increasing age. In the multivariate analysis, age, gender, waist circumference, systolic blood pressure, and hypercholesterolemia were positively associated with c-IMT, whereas age, gender, and weight were positively associated with carotid plaque. CONCLUSION: The current nurse-led study shows that subjects with type 2 diabetes mellitus have a high prevalence of subclinical atherosclerosis that is associated with cardiovascular risk factors. PMID- 25829138 TI - Mechanisms of Cardiovascular Injury in Type 2 Diabetes and Potential Effects of Dipeptidyl Peptidase-4 Inhibition. AB - BACKGROUND: Cardiovascular (CV) disease is the major cause of mortality and morbidity in patients with type 2 diabetes mellitus (T2DM). The pathogenesis of CV disease in T2DM is complex and multifactorial and involves direct and indirect injury to the vasculature and heart. The impact of intensive glucose-lowering therapy with antihyperglycemic agents on CV outcomes is not clear, and questions remain as to which glucose-lowering agents may be beneficial to CV health in patients with T2DM. PURPOSE: This review discusses findings regarding the known mechanisms of CV injury in T2DM and current knowledge regarding the potential cardioprotective effects of dipeptidyl peptidase-4 (DPP-4) inhibitors. CONCLUSIONS: Dipeptidyl peptidase-4 inhibitors are relatively new antihyperglycemic agents. Their main mechanism of action is to inhibit the degradation of the incretin hormones glucagon-like peptide-1 and glucose dependent insulinotropic peptide by DPP-4. By increasing levels of glucagon-like peptide-1, glucose-dependent insulin secretion is enhanced, glucagon secretion is suppressed, and the rate of gastric emptying is decreased. Dipeptidyl peptidase-4 also degrades other substances that are important in the regulation of CV function and inflammation. Animal studies, small observational studies in humans, and analyses of clinical trial data suggest that DPP-4 inhibitors may have beneficial CV effects. Recent prospectively designed CV outcomes trials with saxagliptin and alogliptin in patients with T2DM and high CV risk presented evidence that these DPP-4 inhibitors neither increased nor decreased adverse CV outcomes in this select patient population. CLINICAL IMPLICATIONS: Dipeptidyl peptidase-4 inhibitors are promising therapies for the treatment of T2DM. Able to improve glycemic control without the risk of weight gain or hypoglycemia, they provide a safe alternative to sulfonylureas and are an effective adjunct to metformin. To date, this class of drugs seems to be at least neutral in terms of CV effects. Time will tell if these findings translate into a benefit for our patients. PMID- 25829139 TI - Validation of the Critical-Care Pain Observation Tool and Vital Signs in Relation to the Sensory and Affective Components of Pain During Mediastinal Tube Removal in Postoperative Cardiac Surgery Intensive Care Unit Adults. AB - BACKGROUND: The Critical-Care Pain Observation Tool (CPOT) is a behavioral scale recommended in clinical practice guidelines for the assessment of pain in nonverbal intensive care unit (ICU) adults. Although the CPOT has been validated in various ICU patient groups, its association with the affective component of pain has not yet been explored, and in most studies, turning was the used nociceptive procedure. AIM: In this study, we aim to validate the use of the CPOT and vital signs in association with the sensory and affective components of pain during mediastinal tube removal (MTR) in postoperative cardiac surgery ICU adults. METHODS: A sample of 125 patients participated in this prospective repeated-measures, within-subject study. A total of 6 assessments of the main study variables (CPOT scores and patients' self-reports of pain intensity and unpleasantness) were completed by trained research assistants while patients were in the ICU. Assessments were done before, during, and 15 minutes after the nonnociceptive procedure (ie, noninvasive blood pressure taking [NIBP]) and nociceptive procedure (ie, MTR). RESULTS: Discriminant validation of the scale use was supported as higher CPOT scores were obtained during MTR (mean [SD], 2.74 [1.61]) compared with NIBP (mean [SD], 0.50 [0.747]) (t124 = 14.33, P < .001). Similarly, higher values were recorded for mean arterial pressure and heart and respiratory rates during MTR compared with NIBP (P < .01). During MTR, CPOT scores correlated significantly with self-report of pain intensity (r = 0.419, P < .01) and unpleasantness (r = 0.313, P < .01), supporting criterion and convergent validation. Conversely, vital signs did not correlate with either self report. CONCLUSIONS: Study findings confirmed the validity of the CPOT for the assessment of the sensory and affective components of pain in the postcardiac surgery ICU adults. Vital signs were not specific to pain and should be used only as cues to begin further assessment of pain using validated instruments for this purpose. PMID- 25829140 TI - Recent developments in superhydrophobic graphene and graphene-related materials: from preparation to potential applications. AB - In the past decade, graphene has revealed a cornucopia of both fundamental science and potential applications due to its exceptional electrical, mechanical, thermal, and optical properties. Recently, increasing effort has been devoted to exploiting its new features, for example, wetting properties. Benefitting from its inherent material properties, graphene shows great potential for the fabrication of superhydrophobic surfaces, which could be potentially used for various anti-water applications. In this review, we summarize the recent developments in superhydrophobic graphene and graphene-related materials. Preparation strategies using pure graphene, graphene oxide, and graphene/polymer hybrids are presented and their potential applications are discussed. Finally, our own perspective of this dynamic field, including both current challenges and future demands, has been discussed. It is anticipated that the cooperation of the numerous merits of graphene and superhydrophobicity will lead to new opportunities for high-performance multifunctional devices. PMID- 25829141 TI - Host Langerin (CD207) is a receptor for Yersinia pestis phagocytosis and promotes dissemination. AB - Yersinia pestis is a Gram-negative bacterium that causes plague. After Y. pestis overcomes the skin barrier, it encounters antigen-presenting cells (APCs), such as Langerhans and dendritic cells. They transport the bacteria from the skin to the lymph nodes. However, the molecular mechanisms involved in bacterial transmission are unclear. Langerhans cells (LCs) express Langerin (CD207), a calcium-dependent (C-type) lectin. Furthermore, Y. pestis possesses exposed core oligosaccharides. In this study, we show that Y. pestis invades LCs and Langerin expressing transfectants. However, when the bacterial core oligosaccharides are shielded or truncated, Y. pestis propensity to invade Langerhans and Langerin expressing cells decreases. Moreover, the interaction of Y. pestis with Langerin expressing transfectants is inhibited by purified Langerin, a DC-SIGN (DC specific intercellular adhesion molecule 3 grabbing nonintegrin)-like molecule, an anti-CD207 antibody, purified core oligosaccharides and several oligosaccharides. Furthermore, covering core oligosaccharides reduces the mortality associated with murine infection by adversely affecting the transmission of Y. pestis to lymph nodes. These results demonstrate that direct interaction of core oligosaccharides with Langerin facilitates the invasion of LCs by Y. pestis. Therefore, Langerin-mediated binding of Y. pestis to APCs may promote its dissemination and infection. PMID- 25829142 TI - Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia. AB - People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia. PMID- 25829143 TI - Cocaine Decreases Metabotropic Glutamate Receptor mGluR1 Currents in Dopamine Neurons by Activating mGluR5. AB - Midbrain dopamine neurons are important mediators of reward and movement and are sensitive to cocaine-induced plasticity. After even a single injection of cocaine, there is an increase in AMPA-dependent synaptic transmission. The present study examines cocaine-induced plasticity of mGluR-dependent currents in dopamine neurons in the substantia nigra. Activation of mGluR1 and mGluR5 resulted in a mixture of inward and outward currents mediated by a nonselective cation conductance and a calcium-activated potassium conductance (SK), respectively. A single injection of cocaine decreased the current activated by mGluR1 in dopamine neurons, and it had no effect on the size of the mGluR5 mediated current. When the injection of cocaine was preceded by treatment of the animals with a blocker of mGluR5 receptors (MPEP), cocaine no longer decreased the mGluR1 current. Thus, the activation of mGluR5 was required for the cocaine mediated suppression of mGluR1-mediated currents in dopamine neurons. The results support the hypothesis that mGluR5 coordinates a reduction in mGluR1 functional activity after cocaine treatment. PMID- 25829145 TI - Downward trends in the prevalence of childhood overweight in two pilot towns taking part in the VIASANO community-based programme in Belgium: data from a national school health monitoring system. AB - BACKGROUND: Multilevel approaches involving environmental strategies are considered to be good practice to help reduce the prevalence of childhood overweight. OBJECTIVES: The objective of this study was to evaluate the effects of VIASANO, a community-based programme using the EPODE methodology, on the prevalence of overweight in two pilot towns in Belgium. METHODS: We analysed data from a national school health monitoring system to compare changes in the prevalence of overweight and obesity over a 3-year period (2007-2010) in children aged 3-4 and 5-6 years in the pilot towns with those of children of the same ages from the whole French-speaking community of Belgium. Heights and weights of all participants were measured by trained school nurses using a standardized method. RESULTS: The prevalence of overweight (-2.1%) and overweight + obesity (-2.4%) decreased in the pilot towns, but remained stable in the comparison population (+0.1% and +0.2%, respectively). After adjustment for lack of homogeneity between the study populations, there was a trend towards a decrease in overweight (P = 0.054) and overweight + obesity (P = 0.058) in the pilot towns compared with the general population. CONCLUSIONS: These results suggest that a community-based programme, such as VIASANO, may be a promising strategy for reducing the prevalence of childhood overweight even over a short period of time. PMID- 25829144 TI - Progressive Brain Atrophy and Cortical Thinning in Schizophrenia after Commencing Clozapine Treatment. AB - Despite evidence that clozapine may be neuroprotective, there are few longitudinal magnetic resonance imaging (MRI) studies that have specifically explored an association between commencement of clozapine treatment for schizophrenia and changes in regional brain volume or cortical thickness. A total of 33 patients with treatment-resistant schizophrenia and 31 healthy controls matched for age and gender underwent structural MRI brain scans at baseline and 6 9 months after commencing clozapine. MRI images were analyzed using SIENA (Structural Image Evaluation, using Normalization, of Atrophy) and FreeSurfer to investigate changes over time in brain volume and cortical thickness respectively. Significantly greater reductions in volume were detected in the right and left medial prefrontal cortex and in the periventricular area in the patient group regardless of treatment response. Widespread further cortical thinning was observed in patients compared with healthy controls. The majority of patients improved symptomatically and functionally over the study period, and patients who improved were more likely to have less cortical thinning of the left medial frontal cortex and the right middle temporal cortex. These findings demonstrate on-going reductions in brain volume and progressive cortical thinning in patients with schizophrenia who are switched to clozapine treatment. It is possible that this gray matter loss reflects a progressive disease process irrespective of medication use or that it is contributed to by switching to clozapine treatment. The clinical improvement of most patients indicates that antipsychotic-related gray matter volume loss may not necessarily be harmful or reflect neurotoxicity. PMID- 25829146 TI - Analyzing transmission dynamics of cholera with public health interventions. AB - Cholera continues to be a serious public health concern in developing countries and the global increase in the number of reported outbreaks suggests that activities to control the diseases and surveillance programs to identify or predict the occurrence of the next outbreaks are not adequate. These outbreaks have increased in frequency, severity, duration and endemicity in recent years. Mathematical models for infectious diseases play a critical role in predicting and understanding disease mechanisms, and have long provided basic insights in the possible ways to control infectious diseases. In this paper, we present a new deterministic cholera epidemiological model with three types of control measures incorporated into a cholera epidemic setting: treatment, vaccination and sanitation. Essential dynamical properties of the model with constant intervention controls which include local and global stabilities for the equilibria are carefully analyzed. Further, using optimal control techniques, we perform a study to investigate cost-effective solutions for time-dependent public health interventions in order to curb disease transmission in epidemic settings. Our results show that the basic reproductive number (R0) remains the model's epidemic threshold despite the inclusion of a package of cholera interventions. For time-dependent controls, the results suggest that these interventions closely interplay with each other, and the costs of controls directly affect the length and strength of each control in an optimal strategy. PMID- 25829147 TI - Complete hierarchies of SIR models on arbitrary networks with exact and approximate moment closure. AB - We first generalise ideas discussed by Kiss et al. (2015) to prove a theorem for generating exact closures (here expressing joint probabilities in terms of their constituent marginal probabilities) for susceptible-infectious-removed (SIR) dynamics on arbitrary graphs (networks). For Poisson transmission and removal processes, this enables us to obtain a systematic reduction in the number of differential equations needed for an exact 'moment closure' representation of the underlying stochastic model. We define 'transmission blocks' as a possible extension of the block concept in graph theory and show that the order at which the exact moment closure representation is curtailed is the size of the largest transmission block. More generally, approximate closures of the hierarchy of moment equations for these dynamics are typically defined for the first and second order yielding mean-field and pairwise models respectively. It is frequently implied that, in principle, closed models can be written down at arbitrary order if only we had the time and patience to do this. However, for epidemic dynamics on networks, these higher-order models have not been defined explicitly. Here we unambiguously define hierarchies of approximate closed models that can utilise subsystem states of any order, and show how well-known models are special cases of these hierarchies. PMID- 25829148 TI - Impedance technology reveals correlations between cytotoxicity and lipophilicity of mono and bimetallic phosphine complexes. AB - Label free impedance technology enables the monitoring of cell response patterns post treatment with drugs or other chemicals. Using this technology, a correlation between the lipophilicity of metal complexes and the degree of cytotoxicity was observed. Au(L1)Cl (1), AuPd(L1)(SC4H8)Cl3 (1a) and Au(L2)Cl (2) [L1 = diphenylphosphino-2-pyridine; L2 = 2-(2-(diphenylphosphino)ethyl)-pyridine] were synthesised, in silico drug-likeness and structure-activity relationship monitored using impedance technology. Dose dependent changes in cytotoxicity were observed for the metal complexes resulting in IC50s of 12.5 +/- 2.5, 18.3 +/- 8.3 and 16.9 +/- 0.5 uM for 1, 1a and 2 respectively in an endpoint assay. When a real time impedance assay was used, dose-dependent responses depicting patterns that suggested slower uptake (at a toxic 20 uM) and faster recovery of the cells (at the less toxic 10 uM) of the bimetallic complex (1a) compared to the monometallic complexes (1 and 2) was observed. These data agreed with the ADMET findings of lower aqueous solubility of 1a and non-ideal lipophilicity (AlogP98 of 6.55) over more water soluble 1 and 2 with ideal lipophilicity (4.91 and 5.03 respectively) values. The additional coordination of a Pd atom to the nitrogen atom of a pyridine ring, the sulfur atom of a tetrahydrothiophene moiety and two chlorine atoms in 1a could be contributing to the observed differences when compared to the monometallic complexes. This report presents impedance technology as a means of correlating drug-likeness of lipophilic phosphine complexes containing similar backbone structures and could prove valuable in filtering drug like compounds in a drug discovery project. PMID- 25829149 TI - Methemoglobin reduction by NADH-cytochrome b(5) reductase in Propsilocerus akamusi larvae. AB - For oxygen respiration, a methemoglobin (metHb) reduction system is needed in the cell because metHb cannot bind oxygen. We examined the insect Propsilocerus akamusi larvae to elucidate the metHb reduction system in an organism that inhabits an oxygen-deficient environment. NADH-dependent reduction of metHb in coelomic fluid suggested the coexistence of cytochrome b5 reductase (b5R) and cytochrome b5 with hemoglobin in the fluid and that these proteins were involved in physiological metHb reduction in the larvae. The presence of b5R was revealed by purifying b5R to homogeneity from the midge larvae. Using purified components, we showed that larval metHb was reduced via the NADH-b5R (FAD)-cytochrome b5 metHb pathway, a finding consistent with that in aerobic vertebrates, specifically humans and rabbits, and b5R function between mammal and insect was conserved. b5R was identified as a monomeric FAD-containing enzyme; it had a molecular mass of 33.2 kDa in gel-filtration chromatography and approximately 37 kDa in SDS-PAGE analysis. The enzyme's optimal pH and temperature were 6.4 and 25 degrees C, respectively. The apparent Km and Vmax values were 345 MUM and 160 MUmol min(-1) mg(-1), respectively, for ferricyanide and 328 MUM and 500 MUmol min(-1) mg(-1), respectively, for 2,6-dichlorophenolindophenol. The enzyme reaction was inhibited by benzoate, p-hydroxymercuribenzoate, iodoacetamide, and iodoacetate, and was not inhibited by metal ions or EDTA. PMID- 25829150 TI - Molecular cloning and tissue expression of uncoupling protein 1, 2 and 3 genes in Chinese perch (Siniperca chuatsi). AB - Uncoupling proteins (UCPs) are mitochondrial anion carrier proteins, which play important roles in several physiological processes, including thermogenesis, reactive oxygen species generation, growth, lipid metabolism and insulin secretion. Although the roles of UCPs are well understood in mammals, little is known in fish. To investigate the thermogenesis roles in Chinese perch (Siniperca chuatsi), we cloned the UCP1, 2 and 3. The UCP1 consisted of six exons and five introns, and the UCP2 consisted of eight exons and seven introns. The UCP1 was primarily expressed in liver, UCP2 was ubiquitously expressed, and UCP3 was primarily expressed in muscle. The mRNA levels of UCP1 and UCP2 in liver, and UCP3 in muscle were significantly increased after prolonged cold exposure, but did not change after prolonged heat exposure, suggesting that Chinese perch might have a mechanism of response to cold environment, but not to hot environment. The intestinal UCP1 mRNA level was significantly up-regulated after prolonged heat exposure, while the UCP2 mRNA level was significantly up-regulated after prolonged cold exposure, suggesting that the two paralogs might play different roles in intestine of Chinese perch. In addition, the phylogenetic analysis could shed new light on the evolutionary diversification of UCP gene family. PMID- 25829151 TI - cfMSP-1, an extremely acidic matrix protein involved in shell formation of the scallop Chlamys farreri. AB - Matrix proteins play an important role in biomineralization by mollusks. In this study, we cloned and characterized an acidic protein (pI=3.36) homolog of cfMSP-1 that is highly expressed in the mantle transcriptome of the scallop Chlamys farreri. RT-PCR and in situ hybridization showed that cfMSP-1 is specifically expressed in the outer fold of the mantle edge and pallial part. The expression level of cfMSP-1 remarkably increased and then reduced gradually to a value that is ~2-fold higher than basal levels after shell notching. Knock-down expression of cfMSP-1 in adults via dsRNA injection gave a disordered folia surface. Both shell notching and RNAi experiments indicated that cfMSP-1 plays an essential role in the formation of the folia of C. farreri. PMID- 25829152 TI - US aims to cut antibiotic use in new five year plan to combat antibiotic resistant bacteria. PMID- 25829153 TI - Collagenase Clostridium Histolyticum versus Limited Fasciectomy for Dupuytren's Contracture: Outcomes from a Multicenter Propensity Score Matched Study. AB - BACKGROUND: Controversy exists about the relative effectiveness of injectable collagenase (collagenase clostridium histolyticum) and limited fasciectomy in the treatment of Dupuytren's contracture. The authors compared the effectiveness of both techniques in actual clinical practice. METHODS: This study evaluated all subjects treated with collagenase clostridium histolyticum or limited fasciectomy for metacarpophalangeal and/or proximal interphalangeal joint contractures between 2011 and 2014 at seven practice sites. The authors compared the degree of residual contracture (active extension deficit), Michigan Hand Outcomes Questionnaire scores, and adverse events at follow-up visits occurring between 6 and 12 weeks after surgery or the last injection with the use of propensity score matching. RESULTS: In 132 matched subjects who were treated with collagenase (n = 66) or fasciectomy (n = 66), the degree of residual contracture at follow-up for affected metacarpophalangeal joints was not significantly different (13 degrees versus 6 degrees; p = 0.095) and affected proximal interphalangeal joints had significantly worse residual contracture in the collagenase group compared with those in the fasciectomy group (25 degrees versus 15 degrees; p = 0.010). Collagenase subjects experienced fewer serious adverse events than did fasciectomy subjects and reported larger improvements in the Michigan Hand Outcomes Questionnaire subscores evaluating satisfaction with hand function, activities of daily living, and work performance. CONCLUSIONS: This propensity score-matched study showed that collagenase clostridium histolyticum was not significantly different from limited fasciectomy in reducing metacarpophalangeal joint contractures, whereas proximal interphalangeal joint contractures showed slightly better reduction following limited fasciectomy. Collagenase provided a more rapid recovery of hand function than did fasciectomy and was associated with fewer serious adverse events. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25829154 TI - So, You Want to Improve Your Plastic Surgery Papers? Introducing PRS' Friendly EQUATOR Reporting Guidelines. PMID- 25829155 TI - A Cadaveric Study of the Arterial Blood Supply of the Labia Minora. AB - BACKGROUND: Labiaplasty has become a rather common operation. The main complication of the different surgical techniques is the dehiscence of the suture line. The dehiscence rate varies among the different techniques, and this may imply that the vascular anatomy is not respected in some cases. The detailed arterial anatomy of labia minora is not well described, so the aim of the authors was to describe this anatomy with a cadaveric study. METHODS: Eleven fresh cadavers were dissected, and arterial study was made with injected computed tomography scans and rotational angiography. At the end, a cast of the arterial network was made and chemically exposed to verify the radiological findings. RESULTS: The findings of this study allowed identification of a dominant central artery that was named "C" artery, two posterior arteries named "P1" and "P2," and one small anterior artery, "A." Furthermore, a connection between the anterior system of the external pudendal artery and the posterior system of the internal pudendal artery was confirmed. CONCLUSIONS: The arterial network of the labia minora was identified with this study. This may help surgeons orientate the wedge excision when they perform labiaplasties. More precisely, when this wedge is placed at the most anterior part of the labia minora, the least perfused area is removed, and a posterior flap is created that will preserve a robust blood perfusion. PMID- 25829156 TI - A Prospective Randomized Outcomes Comparison of Two Temple Migraine Trigger Site Deactivation Techniques. AB - BACKGROUND: The authors compared the reduction of migraine headache frequency, days, severity, and duration after surgical decompression versus avulsion of the zygomaticotemporal branch of the trigeminal nerve for treatment of temporal migraine headache. METHODS: Twenty patients with bilateral temporal migraine headache were randomized to undergo avulsion of the zygomaticotemporal branch of the trigeminal nerve on one side and decompression via fasciotomy and removal of the zygomaticotemporal artery on the other side. Results were analyzed after a minimum of 12 months of follow-up. RESULTS: Nineteen patients completed the study. The patients experienced greater than 50 percent improvement in frequency, migraine days, severity, and duration in 34 of the 38 operative sites (89 percent). Complete elimination of symptoms was noted in 21 of the 38 operative sites (55 percent). In the decompression group, migraine frequency was reduced from 14.6 to 2.2 per month, migraine days from 14.1 to 2.3, severity from 7.0 to 2.9, duration from 9.6 to 4.8 hours, and Migraine Headache Index score from 42 to 2.9. In the neurectomy group, frequency decreased from 14.2 to 1.9 per month, migraine days from 14.1 to 2.3, severity from 6.8 to 2.6, migraine duration from 10.1 to 5.3 hours, and the Migraine Headache Index score from 41 to 2.5. There was no statistical significance in reduced migraine headache frequency, days, severity, and duration between the two groups. CONCLUSIONS: Neurectomy and decompression of the zygomaticotemporal branch of the trigeminal nerve are both appropriate treatment for temporal migraine headache. If decompression fails to provide sufficient relief, neurectomy is another option. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I. PMID- 25829157 TI - Unilateral Cleft Lip Repair Using the Anatomical Subunit Approximation: Modifications and Analysis of Early Results in 100 Consecutive Cases. AB - BACKGROUND: The anatomical subunit approximation for unilateral cleft lip repair has gained acceptance; however, outcomes have not been reported since the original description. The purpose of this article is to report the experience using this technique. METHODS: One hundred two consecutive patients underwent primary cleft lip repair performed by a single surgeon over a 3-year period. Objective analysis involved anthropometric measurements performed on preoperative and postoperative three-dimensional images. Subjective analysis involved Asher McDade scores by blinded independent surgeons. Observational insights were gained by review of surgical records. Anthropometric measurements were expressed as ratios of the cleft side to the noncleft side. Differences in ratios were assessed by using the rank sum test. Differences in Asher-McDade scores were assessed using the Mann-Whitney test. RESULTS: Demographic, cleft type, cleft extent, and cleft severity were consistent with our center's norms. The mean age at surgery was 6 months and the mean inferior triangle used was 1.8 +/- 0.9 mm. Anthropometric ratios were significantly improved postoperatively and approached 1, regardless of initial cleft severity. Ten subjects who underwent repair early in the experience were compared with 10 subjects who underwent repair late in the experience. There was no significant difference in postoperative anthropometric measures or Asher-McDade scores. CONCLUSIONS: The anatomical subunit approximation for unilateral cleft lip repair in a single-surgeon series can achieve improvements in anthropometric measures and early favorable postoperative form. The technique could be applied to all cleft types and there was little change in outcome with greater surgeon experience. Long-term follow-up is necessary. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25829158 TI - Studies in Fat Grafting: Part V. Cell-Assisted Lipotransfer to Enhance Fat Graft Retention Is Dose Dependent. AB - BACKGROUND: Cell-assisted lipotransfer has shown much promise as a technique for improving fat graft take. However, the concentration of stromal vascular fraction cells required to optimally enhance fat graft retention remains unknown. METHODS: Human lipoaspirate was processed for both fat transfer and harvest of stromal vascular fraction cells. Cells were then mixed back with fat at varying concentrations ranging from 10,000 to 10 million cells per 200 MUl of fat. Fat graft volume retention was assessed by means of computed tomographic scanning over 8 weeks, and then fat grafts were explanted and compared histologically for overall architecture and vascularity. RESULTS: Maximum fat graft retention was seen at a concentration of 10,000 cells per 200 MUl of fat. The addition of higher number of cells negatively impacted fat graft retention, with supplementation of 10 million cells producing the lowest final volumes, lower than fat alone. Interestingly, fat grafts supplemented with 10,000 cells showed significantly increased vascularity and decreased inflammation, whereas fat grafts supplemented with 10 million cells showed significant lipodegeneration compared with fat alone CONCLUSIONS: : The authors' study demonstrates dose dependence in the number of stromal vascular fraction cells that can be added to a fat graft to enhance retention. Although cell-assisted lipotransfer may help promote graft survival, this effect may need to be balanced with the increased metabolic load of added cells that may compete with adipocytes for nutrients during the postgraft period. PMID- 25829159 TI - The New Accreditation Council for Graduate Medical Education Next Accreditation System Milestones Evaluation System: What Is Expected and How Are Plastic Surgery Residency Programs Preparing? AB - BACKGROUND: The Accreditation Council for Graduate Medical Education Next Accreditation System milestones were implemented for plastic surgery programs in July of 2014. Forward progress through the milestones is an indicator of trainee appropriate development, whereas regression or stalling may indicate the need for concentrated, targeted training. METHODS: Online software at www.surveymonkey.com was used to create a survey about the program's approaches to milestones and was distributed to program directors and administrators of 96 Accreditation Council for Graduate Medical Education-approved plastic surgery programs. RESULTS: The authors had a 63.5 percent response rate (61 of 96 plastic surgery programs). Most programs report some level of readiness, only 22 percent feel completely prepared for the Next Accreditation System milestones, and only 23 percent are completely satisfied with their planned approach for compliance. Seventy-five percent of programs claim to be using some form of electronic tracking system. Programs plan to use multiple tools to capture and report milestone data. Most programs (44.4 percent) plan to administer evaluations at the end of each rotation. Over 70 percent of respondents believe that the milestones approach would improve the quality of resident training. However, programs were less than confident that their current compliance systems would live up to their full potential. CONCLUSIONS: The Next Accreditation System has been implemented nationwide for plastic surgery training programs. Milestone-based resident training is a new paradigm for residency training evaluation; programs are in the process of making this transition to find ways to make milestone data meaningful for faculty and residents. PMID- 25829160 TI - Electronic structure investigations of 4-aminophthal hydrazide by UV-visible, NMR spectral studies and HOMO-LUMO analysis by ab initio and DFT calculations. AB - Combined experimental and theoretical studies were conducted on the molecular structure and vibrational spectra of 4-AminoPhthalhydrazide (APH). The FT-IR and FT-Raman spectra of APH were recorded in the solid phase. The molecular geometry and vibrational frequencies of APH in the ground state have been calculated by using the ab initio HF (Hartree-Fock) and density functional methods (B3LYP) invoking 6-311+G(d,p) basis set. The optimized geometric bond lengths and bond angles obtained by HF and B3LYP method show best agreement with the experimental values. Comparison of the observed fundamental vibrational frequencies of APH with calculated results by HF and density functional methods indicates that B3LYP is superior to the scaled Hartree-Fock approach for molecular vibrational problems. The difference between the observed and scaled wave number values of most of the fundamentals is very small. A detailed interpretation of the NMR spectra of APH was also reported. The theoretical spectrograms for infrared and Raman spectra of the title molecule have been constructed. UV-vis spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies, were performed by time dependent density functional theory (TD-DFT) approach. Finally the calculations results were applied to simulated infrared and Raman spectra of the title compound which show good agreement with observed spectra. And the temperature dependence of the thermodynamic properties of constant pressure (Cp), entropy (S) and enthalpy change (DeltaH0->T) for APH were also determined. PMID- 25829161 TI - Preparation and characterization of host-guest system between inosine and beta cyclodextrin through inclusion mode. AB - Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a beta-N9-glycosidic bond. Inosine is commonly found in tRNAs. Inosine (INS) has been used widely as an antiviral drug. The inclusion complex of INS with beta-CDx in solution phase is studied by ground and excited state with UV-visible and fluorescence spectroscopy, respectively. A binding constant and stoichiometric ratio between INS and beta-CDx are calculated by BH equation. The lifetime and relative amplitude of INS is increases with increasing the concentrations of beta-CDx, confirms the formation of inclusion complex in liquid state. The solid complexes are prepared by kneading method (KM) and co-precipitation method (CP). The solid complex is characterized by Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), powder X-ray diffraction (XRD) and differential scanning colorimetry (DSC). CP method gives the solid product with good yield than that of physical mixture and KM method. The structure of complex is proposed based on the study of Patch - Dock server. PMID- 25829162 TI - S values for 131I based on the ICRP adult voxel phantoms. AB - To improve the estimates of organ doses from nuclear medicine procedures using (131)I, the authors calculated a comprehensive set of (131)I S values, defined as absorbed doses in target tissues per unit of nuclear transition in source regions, for different source and target combinations. The authors used the latest reference adult male and female voxel phantoms published by the International Commission on Radiological Protection (ICRP Publication 110) and the (131)I photon and electron spectra from the ICRP Publication 107 to perform Monte Carlo radiation transport calculations using MCNPX2.7 to compute the S values. For each phantom, the authors simulated 55 source regions with an assumed uniform distribution of (131)I. They computed the S values for 42 target tissues directly, without calculating specific absorbed fractions. From these calculations, the authors derived a comprehensive set of S values for (131)I for 55 source regions and 42 target tissues in the ICRP male and female voxel phantoms. Compared with the stylised phantoms from Oak Ridge National Laboratory (ORNL) that consist of 22 source regions and 24 target regions, the new data set includes 1662 additional S values corresponding to additional combinations of source-target tissues that are not available in the stylised phantoms. In a comparison of S values derived from the ICRP and ORNL phantoms, the authors found that the S values to the radiosensitive tissues in the ICRP phantoms were 1.1 (median, female) and 1.3 (median, male) times greater than the values based on the ORNL phantoms. However, for several source-target pairs, the difference was up to 10-fold. The new set of S values can be applied prospectively or retrospectively to the calculation of radiation doses in adults internally exposed to (131)I, including nuclear medicine patients treated for thyroid cancer or hyperthyroidism. PMID- 25829163 TI - Feasibility of combined unipolar and bipolar voltage maps to improve sensitivity of endomyocardial biopsy. AB - BACKGROUND: Endomyocardial biopsy (EMB) has a low sensitivity. Electroanatomic voltage mapping (EVM) is effective in guiding EMB thanks to its ability in identifying and locating low-voltage regions. The analysis of unipolar EVM can correlate with epicardial pathological involvement. We evaluated the unipolar EVM in EMB areas to determine whether it can increase EMB sensitivity in diagnosing epicardial diseases. METHODS AND RESULTS: We performed endocardial bipolar EVM guided EMBs in 29 patients and we analyzed unipolar EVM at withdrawal sites. Eighty myocardial samples were collected (mean, 2.8+/-0.9; median, 3 fragments per patient) and 60 were suitable for histological analysis. Ten specimens (17%) were collected from an area with discordant normal bipolar/low-voltage unipolar EVM and they were diagnostic or suggestive for arrhythmogenic right ventricular dysplasia/cardiomyopathy in 6 patients, for myocarditis and sarcoidosis in 1 patient each. Six samples (10%) were collected from an area with discordant low voltage bipolar/normal unipolar EVM and they showed nonspecific features. The sensitivity of unipolar EVMs for a diagnostic biopsy finding EMB was significantly higher compared with bipolar EVMs analyzed according to samples (P<0.01) and patients (P=0.008). The specificity of unipolar EMB was better than bipolar EMB when analyzed for all samples (P=0.0014) but the difference did not reach statistical significance when analyzed by patient (P=0.083). The diagnostic yield was 63.3% for the bipolar and 83.3% for the unipolar EVM. CONCLUSIONS: These findings suggest that use of a combined bipolar/unipolar map may be able to improve the diagnostic yield of endomyocardial ventricular biopsy. PMID- 25829164 TI - Acute and chronic performance evaluation of a novel epicardial pacing lead placed by percutaneous subxiphoid approach in a canine model. AB - BACKGROUND: Endovascularly implanted leads risk vascular injury and endocarditis, and can be difficult to locate in desired positions for LV pacing. We evaluated the acute and long-term stability, electric performance and histopathology of a percutaneously placed intrapericardial lead (IPL). METHODS AND RESULTS: Twelve adult mongrel dogs underwent defibrillator implants incorporating IPLs. Successful uncomplicated percutaneous implantation of an IPL was achieved in all. Early fluoroscopic shift noted with 3 of 6 of the initial version IPL-1 was not seen with the modified IPL-2. Mean+/-95% confidence interval bipolar capture threshold at 0.5-ms pulse width for the IPL increased from 0.69+/-0.14 V at implant to 1.50+/-0.34 V (P=0.003) at 12 weeks. The 12-week thresholds were higher for IPL compared with right ventricular endocardial leads (0.75+/-0.33 V; P=0.001) but not different compared with coronary sinus leads (1.33+/-0.58 V; P=0.994). IPL impedance increased from 742+/-46 Omega at implant to 1066+/-207 Omega at 12 weeks (P=0.007). R-wave amplitude at 12 weeks was 8.37+/-1.52 mV. There was no important phrenic nerve stimulation from IPL pacing. Histopathology in 8 animals showed adequate adhesion of the electrodes or mesh to the epicardium without damage to underlying vasculature. There was no evidence for late pericardial inflammation or effusion. CONCLUSIONS: The IPL demonstrated adequate stability of position and acceptable electric parameters without chronic pericardial inflammation in this canine model and offers a potential alternative to endocardial pacing leads. PMID- 25829165 TI - Thoracoscopic tunnel technique for anatomical lung resections: a 'fissure first, hilum last' approach with staplers in the fissureless patient. AB - OBJECTIVES: To minimize air leak after anatomical lung resections, many video assisted thoracic surgery (VATS) surgeons use a 'fissureless' technique, using staplers to divide the hilar bronchovascular structures first and the main part of the fissure last. We describe a cohort of 198 consecutive patients operated with an alternative fissureless technique, opening the fissure completely with staplers at an early stage of the VATS anatomical lung resection. METHODS: To open the incomplete fissure first and with staplers, a tunnel dissection is started anterior between the triangle of pulmonary veins and the parenchyma. After identification of the pulmonary artery, the anvil of a first stapler is placed on top of the artery and the anterior part of the fissure is divided. Dissection between artery and parenchyma is continued until the fissure is completely stapled. From a prospectively managed single institution database, we retrieved 405 patients scheduled for VATS anatomical resection between October 2009 and December 2014. The patients were categorized in four consecutive periods: a learning curve with the first 50 cases of VATS lobectomy technique (LC), a period of consecutive 'hilum first, fissure last' (HF), a transition group (TG) during which both techniques were used and a period of consecutive 'fissure first, hilum last' (FF). RESULTS: No significant differences in operating time, frequency of prolonged air leak or hospital stay were observed between HF (n = 45) and FF (n = 198). Chest tubes were removed earlier in the FF period (6.9 vs 5.2 days, P = 0.025). Excluding the learning curve, we found 2 patients (2.8%) operated 'hilum first' with an intraoperative complication that potentially could have been avoided by a 'fissure first' technique. CONCLUSIONS: By making a tunnel between the bronchovascular structures and parenchyma from anteriorly to posteriorly, one can open the fissure completely with staplers at an early stage of an anatomical lung resection. This combines the advantages of both the 'fissureless' hilum first technique and classic (open) fissure first dissection, i.e. minimal air leak and optimal anatomical overview before bronchovascular structures are divided, potentially avoiding inadvertent transections. A cohort of 198 consecutive patients operated with this alternative fissureless technique demonstrates the feasibility and non-inferiority regarding hospital stay, chest tube duration, operation time and complications in comparison with the hilum first technique. PMID- 25829166 TI - Phenotypic switching of vascular smooth muscle cells in animal model of rat thoracic aortic aneurysm. AB - OBJECTIVES: To explore if there is phenotypic switching in the vascular smooth muscle cells (vSMCs) of rat thoracic aortic aneurysms and the role it plays in the process of aneurysm formation. METHODS: Male SD white rats were assigned randomly to the aneurysm group (AG) and control group (CG). The animal aneurysm model was obtained by soaking the peri-adventitia with porcine pancreatic elastase (PPE). The rats in the CG were given saline to provide contrast. A vascular ultrasound was used to monitor the diameter of the aneurysm. Specimens were stained with haematoxylin and eosin (HE), and alpha-SMA, SM-MHC, matrix metalloproteinase (MMP)-2 and MMP-9 were detected with immunohistochemistry staining. alpha-SMA, SM-MHC, MMP-2 and MMP-9 were conducted with western blot. vSMCs taken from the descending aorta of both of the CG and AG were separated and cultured until Passage 3. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method were used to analyse cell proliferation. Western blot was used to evaluate MMP-2, MMP-9 expression and flow cytometry was employed to assess cell apoptosis. RESULTS: Vascular ultrasound showed obvious dilatation of soaked descending aorta. HE staining showed thickening of thoracic aorta and disarrangement of cells after soaking with PPE. Immunohistochemistry staining showed high expression of MMP-2 and MMP-9 but low expression of SM-MHC and alpha SMA in the AG. Tissue western blot analysis of the AG showed that the protein gray value was high in MMP-2 and MMP-9, but low in alpha-SMA and SM-MHC, which had statistical differences compared with CG with a P-value of <0.05. MTT analysis showed vSMC proliferation activity was higher in the AG than in the CG. Flow cytometry analysis revealed that cell apoptosis between the control and aneurysm groups had significant statistical differences. CONCLUSIONS: There is vSMC phenotypic switching in animal models as seen through the rat thoracic aortic aneurysms. This may play an important role in the formation of aneurysms. Our findings are relevant to human aneurysms and may be conducive in the research of aortic aneurysm pathology and treatment. PMID- 25829167 TI - Monitoring Compliance to Promote Quality Assurance: Development of a Mental Health Clinical Chart Audit Tool in Belize, 2013. AB - Belize trained psychiatric nurse practitioners (PNPs) in the early 1990s to provide mental health services throughout the country. Despite overwhelming success, the program is limited by lack of monitoring, evaluation, and surveillance. To promote quality assurance, we developed a chart audit tool to monitor mental healthcare delivery compliance for initial psychiatric assessment notes completed by PNPs. After reviewing the Belize Health Information System electronic medical record system, we developed a clinical audit tool to capture 20 essential components for initial assessment clinical notes. The audit tool was then piloted for initial assessment notes completed during July through September of 2013. One hundred and thirty-four initial psychiatric interviews were audited. The average chart score among all PNPs was 9.57, ranging from 3 to 15. Twenty three charts-or 17.2%-had a score of 14 or higher and met a 70% compliance benchmark goal. Among indicators most frequently omitted included labs ordered and named (15.7%) and psychiatric diagnosis (21.6%). Explicit statement of medications initiated with dose and frequency occurred in 47.0% of charts. Our findings provide direction for training and improvement, such as emphasizing the importance of naming labs ordered, medications and doses prescribed, and psychiatric diagnoses in initial assessment clinical notes. We hope this initial assessment helps enhance mental health delivery compliance by prompting creation of BHIS templates, development of audits tools for revisit follow-up visits, and establishment of corrective actions for low-scoring practitioners. These efforts may serve as a model for implementing quality assurance programming in other low resource settings. PMID- 25829168 TI - Transport characteristics of organic solvents through carbon nanotube filled styrene butadiene rubber nanocomposites: the influence of rubber-filler interaction, the degree of reinforcement and morphology. AB - The transport behaviour of some aromatic and aliphatic solvents through carbon nanotube filled styrene butadiene rubber composites has been investigated. The aim of the present work is to investigate the role of the sorption technique in analysing the compatibility and the reinforcing effect of MWCNTs as a filler in the SBR matrix. It also focuses on the investigation of the relationship between the dispersion of CNTs in the SBR matrix and its transport behaviour. The diffusion and transport of organic solvents through the membranes have been investigated in detail as a function of CNT content, nature of solvent and temperature in the range of 28-60 degrees C. Solvent uptake, diffusion, sorption and permeation constants were investigated and were found to decrease with the increase of CNT loading. Transport properties could be related to the morphology of the nanocomposites. At high concentration CNT particles form a local filler filler network in the rubber matrix. As a result, the transport of solvent molecules through the polymer is hindered. The rubber-solvent interaction parameter, enthalpy and entropy of sorption have also been estimated from the transport data. The values of rubber-solvent interaction parameters obtained from the diffusion experiments have been used to calculate the molecular mass between the crosslinks of the network polymer. The better reinforcement at higher filler loading was confirmed from the cross-link density values. The extent of reinforcement was evaluated using Kraus and Cunneen and Russel equations. The Affine and Phantom models for chemical crosslinks were used to predict the mobility of the crosslinks. The Phantom model gave better fitting indicating that the chains can move freely through one another, i.e. the junction points fluctuate over time around their mean position without any hindrance from the neighbouring molecule. The diffusivity datas of the systems have shown dependence on the temperature and microstructure of the nanocomposite. Finally, the diffusion data have been compared with theoretical predictions. PMID- 25829169 TI - Biosynthesis and characterisation of silver nanoparticles using Sphingomonas paucimobilis sp. BDS1. AB - Sphingomonas is a novel and abundant microbial resource for biodegradation of aromatic compounds. It has great potential in environment protection and industrial production. The use of microorganisms for the synthesis of nanoparticles is in the limelight of modern nanotechnology, since it is cost effective, non-toxic and friendly to the ever-overwhelmed environment. In this paper, the biosynthesis of silver nanoparticles (AgNPs) using Sphingomonas paucimobilis sp. BDS1 under ambient conditions was investigated for the first time. Biosynthesised AgNPs were characterised with powder ultraviolet-visible spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscopy and energy dispersive X-ray spectroscopy. The overall results revealed that well-dispersed face centred cubic spherical AgNPs in the range of 50-80 nm were produced on the surface of Sphingomonas paucimobilis sp. BDS1, after challenging pure wet biomass with silver nitrate solution. This suggests that the capture of silver ions may be a complex process of physical and chemical adsorption and the proteins on the surface of the bacteria may play the role of reduction and stabilising agent with regard to the result of FTIR. PMID- 25829170 TI - Fabrication of long-acting drug release property of hierarchical porous bioglasses/polylactic acid fibre scaffolds for bone tissue engineering. AB - Hierarchical porous fibre scaffolds with mesoporous bioglasses (MBGs) and polylactic acid (PLA) were successfully fabricated by the electrospinning method. These compound scaffolds possess macropores with sizes of about 100 nm because of the solvent evaporation from the fibre and the mesoporous structure ( ~4.0 nm) originated from MBGs. The biomineralisation ability was investigated in simulated body fluid. The fibre structure is beneficial for inducing the growth of hydroxyapatite. In addition, compared with pure MBGs, the materials (MP-1 and MP 2) exhibit a long-acting drug release process up to 140 h and the drug release process corresponds with the Fickian diffusion mechanism. With the special fibre morphology and the hierarchical porous structure, the MBGs/PLA fibre scaffolds are expected to have potential application for bone tissue repair and regeneration. PMID- 25829171 TI - Gold nanoparticles: novel catalyst for the preparation of direct methanol fuel cell. AB - The authors report the biosynthesis of gold nanoparticles (Au-NPs) using plant pathogenic Phoma glomerata (MTCC 2210). The synthesis of nanoparticles was characterised by visual observation followed UV-visible spectrophotometric analysis, Fourier transform infrared spectroscopy and nanoparticle tracking analysis. Later, direct methanol fuel cell (DMFC) was constructed using two chambers (anodic chamber and cathodic chamber). These Au-NPs as catalysts have various advantages over the other catalysts that are used in the DMFC. Most importantly, it is cheaper as compared with other catalysts like platinum, and showed higher catalytic activity because of its effective surface structure. Being nano in size, it provides more surface area for the attachment of reactant molecules (methanol molecules). The DMFC catalysed by Au-NPs are found to be suitable to replace lithium ion battery technology in consumer electronics like cell phones, laptops and so on due to the fact that they can produce a high amount of energy in a small space. As long as fuel and air are supplied to the DMFC, it will continue to produce power, so it does not need to be recharged. The use of Au-NPs as catalyst in DMFC has not been reported in the past; it is reported here the first time. PMID- 25829172 TI - Synthesis of silver nanoparticles by Phoma gardeniae and in vitro evaluation of their efficacy against human disease-causing bacteria and fungi. AB - The authors report the biological synthesis of silver nanoparticles (NPs) by Phoma gardeniae (ITCC 4554). The detection of silver NP formation was done by visual observation, and UV-vis spectrophotometer analysis. Further, these mycogenic silver NPs were characterised by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and nanoparticle tracking and analysis system. The TEM analysis revealed the formation of spherical and polydispersed NPs within the range of 10-30 nm. FTIR analysis confirmed the presence of proteins as capping agents. They also evaluated the antimicrobial activity of silver NPs against Candida albicans, Salmonella choleraesuis, Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. They found remarkable inhibition of Escherichia coli followed by Staphylococcus aureus, Candida albicans, Salmonella choleraesuis and Pseudomonas aeruginosa as compared with antibiotics. The main aim of the present study was to synthesise mycogenic silver NPs by P. gardeniae and to evaluate their antimicrobial activity in order to find their potential against human pathogenic microbes. PMID- 25829173 TI - Electrospun scaffold containing TGF-beta1 promotes human mesenchymal stem cell differentiation towards a nucleus pulposus-like phenotype under hypoxia. AB - The study was aimed at evaluating the effect of electrospun scaffold containing TGF-beta1 on promoting human mesenchymal stem cells (MSCs) differentiation towards a nucleus pulposus-like phenotype under hypoxia. Two kinds of nanofibrous scaffolds containing TGF-beta1 were fabricated using uniaxial electrospinning (Group I) and coaxial electrospinning (Group II). Human MSCs were seeded on both kinds of scaffolds and cultured in a hypoxia chamber (2% O2), and then the scaffolds were characterised. Cell proliferation and differentiation were also evaluated after 3 weeks of cell culture. Results showed that both kinds of scaffolds shared similar diameter distributions and protein release. However, Group I scaffolds were more hydrophilic than that of Group II. Both kinds of scaffolds induced the MSCs to differentiate towards the nucleus pulposus-type phenotype in vitro. In addition, the expression of nucleus pulposus-associated genes (aggrecan, type II collagen, HIF-1alpha and Sox-9) in Group I increased more than that of Group II. These results indicate that electrospinning nanofibrous scaffolds containing TGF-beta1 supports the differentiation of MSCs towards the pulposus-like phenotype in a hypoxia chamber, which would be a more appropriate choice for nucleus pulposus regeneration. PMID- 25829174 TI - Molecular dynamic simulation of Ca2+-ATPase interacting with lipid bilayer membrane. AB - In biomedical and drug delivery treatments, protein Ca2+-ATPase in the lipid bilayer (plasma) membrane plays a key role by reducing multidrug resistance of the cancerous cells. The lipid bilayer membrane and the protein Ca2+-ATPase were simulated by utilising the Gromacs software and by applying the all-atom/united atom and coarse-grained models. The initial structure of Ca2+-ATPase was derived from X-ray diffraction and electron microscopy patterns and was placed in a simulated bilayer membrane of dipalmitoylphosphatidylcholine. The conformational changes were investigated by evaluating the root mean square deviation, root mean square fluctuation, order parameter, diffusion coefficients, partial density, thickness and area per lipid. PMID- 25829175 TI - DNA adduct identification using gold-aptamer nanoprobes. AB - The optical and physico-chemical properties of gold nanoparticles (AuNPs) have prompted new and improved approaches which have greatly evolved the fields of biosensing and molecular detection. In this study, the authors took advantage of AuNPs' ease of modification and functionalised it with selected DNA aptamers using a salt aging method to produce gold-aptamer nanoprobes. After characterisation, these nanoprobes were subsequently used for biomolecular detection of glycidamide (GA)-guanine (Gua) adducts generated in vitro. The results are based on differences in nanoprobe stabilisation against salt-induced aggregation, similar to the non-cross-linking method developed by Baptista for discrimination of specific sequences. Alkylated Guas were efficiently discriminated from deoxyguanosine and GA in solution. Despite this, a clear identification of DNA adducts derived from genomic DNA alkylation has proven to be a more challenging task. PMID- 25829176 TI - High-throughput assay and engineering of self-cleaving ribozymes by sequencing. AB - Self-cleaving ribozymes are found in all domains of life and are believed to play important roles in biology. Additionally, self-cleaving ribozymes have been the subject of extensive engineering efforts for applications in synthetic biology. These studies often involve laborious assays of multiple individual variants that are either designed rationally or discovered through selection or screening. However, these assays provide only a limited view of the large sequence space relevant to the ribozyme function. Here, we report a strategy that allows quantitative characterization of greater than 1000 ribozyme variants in a single experiment. We generated a library of predefined ribozyme variants that were converted to DNA and analyzed by high-throughput sequencing. By counting the number of cleaved and uncleaved reads of every variant in the library, we obtained a complete activity profile of the ribozyme pool which was used to both analyze and engineer allosteric ribozymes. PMID- 25829178 TI - An update on LNCipedia: a database for annotated human lncRNA sequences. PMID- 25829177 TI - Robust meta-analysis of gene expression using the elastic net. AB - Meta-analysis of gene expression has enabled numerous insights into biological systems, but current methods have several limitations. We developed a method to perform a meta-analysis using the elastic net, a powerful and versatile approach for classification and regression. To demonstrate the utility of our method, we conducted a meta-analysis of lung cancer gene expression based on publicly available data. Using 629 samples from five data sets, we trained a multinomial classifier to distinguish between four lung cancer subtypes. Our meta-analysis derived classifier included 58 genes and achieved 91% accuracy on leave-one-study out cross-validation and on three independent data sets. Our method makes meta analysis of gene expression more systematic and expands the range of questions that a meta-analysis can be used to address. As the amount of publicly available gene expression data continues to grow, our method will be an effective tool to help distill these data into knowledge. PMID- 25829179 TI - Nature journal's plan to fast track paper for a fee prompts resignation from editorial board. PMID- 25829181 TI - GP fails in attempt to reverse decision to suspend his practice. PMID- 25829180 TI - A Prospective, Longitudinal Study of the Effect of Remission on Cortical Thickness and Hippocampal Volume in Patients with Treatment-Resistant Depression. AB - BACKGROUND: Magnetic resonance imaging studies have provided evidence of structural modifications in cortical-limbic regions in major depressive disorder. To date, however, few studies have tracked structural changes in patients during treatment. This prospective, longitudinal imaging study investigated associations between brain structure and clinical responsiveness in a sample of patients with treatment-resistant major depressive disorder during an approximate 1-year follow up period. METHODS: FreeSurfer software was used to extract volume or cortical thickness values from 6 regions of interest (hippocampus, rostral middle frontal gyrus, orbitofrontal cortex, rostral and caudal anterior cingulate cortices, and inferior temporal gyrus) in patients (n = 26) and matched healthy controls (n = 28). Regions of interest were selected based on previous evidence of potential associations between morphometric characteristics in these regions and treatment response or remission. Analyses were conducted to compare volume and cortical thickness in patients and controls at baseline imaging, determine whether patients' brain structure at treatment initiation was associated with response over follow-up, and compare longitudinal changes in volume and cortical thickness in patients who achieved sustained 6-month remission (Montgomery-Asberg Depression Rating Scale Score <=12) with nonremitters. RESULTS: Patients and controls showed no structural differences at baseline. Among patients, thicker right caudal anterior cingulate cortex at baseline was associated with greater symptom improvement over follow-up. Remitters and nonremitters showed subtle changes in volume and thickness over time in opposing directions, with increased hippocampal volume and cortical thickness in the rostral middle frontal gyrus, orbitofrontal cortex, and inferior temporal gyrus in remitters, and decreased volume or thickness in these regions in nonremitters. CONCLUSIONS: The results suggest that longitudinal structural trajectories may differ in major depressive disorder patients according to their clinical response to treatment. PMID- 25829182 TI - Effect of titanium carbonitride (Ti(C,N)) decomposition on failure mechanisms in Inconel 617 alloy. AB - Titanium Carbonitride (Ti(C,N)) decomposition in Inconel 617 alloy creep-exposed at 650 degrees C for 574 hours is reported using analytical electron microscopy techniques. Cr-enriched M23C6-type carbides enveloped in fine gamma prime particles thought to be precipitated from the decomposition reaction are observed in the alloy. The morphology of the M23C6 carbides is irregular and blocky and the particle size up to 5 MUm, whereas the morphology of gamma prime particles is mostly spherical and up to 30 nm in size. Intergranular carbides are mostly secondary precipitates of the M23Cc type (M predominantly Cr) and these respond to solution heat treatment and precipitate on the grain boundaries as a result of ageing. The ability of intragranular MX to decompose is sensitive to the N content, high N resists decomposition. Decomposed intragranular MX provides an excess source of C which can react locally with Cr to form heat treatable intragranular fine Cr23C6 precipitates. M6C can segregate in interdendritic locations during melting which may be the reason for high content of Mo in M23C6. These precipitates are generally very small and contribute to an additional hardening effect and are the reason for the onset of voiding and cracking along the grain boundaries that ultimately lead to a reduced creep rupture life. PMID- 25829183 TI - Toll-like receptor 4 inhibition in lung ischemia-reperfusion injury: Time for a clinical trial? PMID- 25829184 TI - STAT4 genetic polymorphisms association with spontaneous clearance of hepatitis B virus infection. AB - STAT4 signal pathway plays an important role in IFN-gamma-mediated antiviral activity. Recent studies show an association of STAT4 polymorphisms with hepatitis B virus (HBV) infection. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility of spontaneous clearance of HBV in a Chinese Han population. Genomic DNA from 288 cases with chronic HBV infection and 288 controls who spontaneously recovered from HBV infection was analyzed for five SNPs in the STAT4 gene (rs7574865, rs7572482, rs7582694 rs11889341, and rs8179673).Our analysis revealed that all the minor alleles of the four SNPs (rs7574865, rs7582694, rs11889341, and rs8179673) had an association with overall decreased risk to HBV infection [p = 0.040, OR 0.762 (95 % CI 0.593-0.981); p = 0.011, OR 0.686 (95 % CI 0.535-0.878); p = 0.023, OR 0.751 (95 % CI 0.586-0.962); p = 0.002, OR 0.670 (95 % CI 0.521-0.861), respectively]. The major alleles of the four SNPs were found to be associated with increased risk of HBV-related cirrhosis and hepatocellular carcinoma. Furthermore, the haplotype GGGCT constructed from the five SNPs was found to have a highly significant association with chronic HBV infection when compared to the controls who spontaneously recovered from HBV infection [p = 0.031, OR 1.368 (95 % CI 1.028-1.818)]. These findings indicate that STAT4 minor allele may be associated with the spontaneous clearance of HBV, whereas the major allele may be associated with the progress of the HBV-related liver disease. PMID- 25829185 TI - Evaluation of right ventricular function performed by 3D-echocardiography in scleroderma patients. AB - The impairment of the right ventricle (RV) in systemic sclerosis (SSc) is usually related to pulmonary arterial hypertension (PAH). New echocardiographic techniques, such as 3-dimensional echocardiography (3DE) and 2-dimensional speckle tracking (2DSTE), allow an accurate evaluation of the RV function. The aim of this study was to evaluate the RV function using 3DE and 2DSTE in SSc patients with no history of heart disease and no PAH. Forty-five SSc patients, 42 females and 3 males, 28 with limited cutaneous SSc (lcSSc) and 17 with diffuse cutaneous SSc (dcSSc), were studied. Forty-three age- and gender-matched healthy subjects were enrolled as controls. All of them underwent a 3DE and 2DSTE ecocardiographic evaluation of the RV function. Systolic pulmonary arterial pressure (sPAP) and total pulmonary vascular resistance (tPVR) were also estimated by power doppler. RV echocardiographic parameters were compared in the different subsets of SSc patients. A statistical analysis was performed by t test, ANOVA and multiple logistic regression. RV areas in 2DSTE and volumes in 3DE were higher and RV function parameters were reduced in SSc patients compared with controls. Also sPAP and tVPR were higher, but they did not reach pathological values. Echocardiographic alterations were more pronounced in patients with lcSSc. 3DE and 2DSTE echocardiography allowed us to detect morphological and functional alterations of the RV in a group of SSc patients with no clinical signs of heart disease and no PAH. These patients had significantly higher sPAP and tPVR than healthy controls without reporting values compatible with PAH. These data suggest that RV alterations are related to a pressure overload rather than to an intrinsic myocardial involvement in SSc. PMID- 25829186 TI - Adherence to recommendations for cervical and breast cancer screening in systemic sclerosis. AB - The aim of the study was to evaluate the adherence of systemic sclerosis (SSc) female patients to cervix and breast cancer screening procedures, as suggested by local guidelines. A cohort of 84 SSc women was asked if they had undergone mammography and Pap test during the previous 2- and 3-year intervals, as indicated according to the Italian recommendations. The results were compared with those collected in patients affected by other chronic rheumatic disorders and in the general population. More than 85% of SSc women declared to comply with an age-related cervix and breast cancer screening schedule. The data were similar to those collected in patients affected by other chronic rheumatic disorders, whereas the subjects belonging to the general population reported to undergo breast cancer screening more frequently. Among SSc women, neither the educational level, nor the lung and skin involvement influenced their cancer screening program compliance. Only a positive history of ischemic digital ulcers seemed to interfere with mammography. Our study reported a very high percentage of SSc female patients who adhered to programs for the early detection of cervical and breast cancer. The significant adherence to guidelines may be due to the schedule adopted by the local health public service, which regularly invites eligible subjects by mail to undergo cancer screening at no charge. PMID- 25829187 TI - Elevated serum levels of macrophage migration inhibitory factor and stem cell growth factor beta in patients with idiopathic and systemic sclerosis associated pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) can be idiopathic or secondary to autoimmune diseases, and it represents one of the most threatening complications of systemic sclerosis (SSc). Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory functions that appears to be involved in the pathogenesis of hypoxia-induced PH. In SSc patients, high serum levels of MIF have been associated with the development of ulcers and PAH. Stem cell growth factor beta (SCGF beta) is a human growth factor that, together with MIF, is involved in the pathogenesis of chronic spinal cord injury. The aim of our study was to measure serum levels of MIF in patients with idiopathic and SSc-associated PAH. We enrolled 13 patients with idiopathic PAH and 15 with SSc-associated PAH. We also selected 14 SSc patients without PAH and 12 normal healthy controls, matched for sex and age. PAH was confirmed by right hearth catheterism (mPAP>25 mmHg). MIF and SCGF beta levels were measured by ELISA. We found significantly higher circulating levels of MIF and of SCGF beta in patients with idiopathic PAH (P=0.03 and P=0.004) and with PAH secondary to SSc (P=0.018 and P=0.023) compared to SSc patients without PAH. Higher levels of MIF were found in those patients with an higher New York Heart Association (NYHA) class (P=0.03). We can hypothesize that MIF and SCGF beta are able to play a role in PAH, both idiopathic or secondary, and in the future they may be evaluated as useful biomarkers and prognostic factors for this serious vascular disease. PMID- 25829188 TI - Ex vivo and in vitro production of pro-inflammatory cytokines in Blau syndrome. AB - The objective was to study both ex vivo and in vitro secretion of pro inflammatory cytokines in patients affected by Blau syndrome (BS) and carrying p.E383K mutation in the CARD15/NOD2 gene associated with the disease. For ex vivo studies, peripheral blood mononuclear cells (PBMCs), serum from three patients and healthy controls have been collected. PBMCs have been cultured in the presence or absence of inflammatory enhancers, such as lipopolysaccharide (LPS) and muramyl dipeptide (MDP). The levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were assayed by either immunoassay or array-based system. For in vitro studies, different constructs were created cloning human wild-type and p.E383K-mutated NOD2 cDNA into the expression vector pCMV-Tag2c. HEK293 cell lines were stably transfected, cultured with or without MDP and IL-8 level was assayed in their surnatants. Statistical analysis in both studies was performed using non-parametric tests. Both ex vivo and in vitro studies have not identified a significant increase in secretion of the analyzed proinflammatory cytokines. p.E383K-mutated NOD2 transfected cells express low level of IL-8. The ex vivo basal level results from both serum and PBMCs surnatants present similar levels of IL-1beta, IL-6, TNF alpha and IFN-gamma in patients and controls. The presence of the stimulant agents (LPS and MDP), either individual or paired, does not lead to significant increases in all cytokines concentrations in patients compared to controls. Taken together, the ex vivo and in vitro data suggest that there is not a primary mediation of IL-1beta and other pro-inflammatory cytokines in BS patients carrying p.E383K. PMID- 25829189 TI - Why golimumab in the treatment of psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis? AB - Golimumab is an anti-TNF monoclonal antibody administred subcutaneously once a month and produced with an innovative technology that minimizes immunogenicity. This paper reviews and updates the main studies on the efficacy, safety and pharmacoeconomic aspects of treatment with golimumab of psoriatic arthritis, ankylosing spondylitis and rheumatoid arthritis. PMID- 25829190 TI - Are biological drugs safe in pregnancy? AB - The introduction of biological therapies has significantly improved the outcome of inflammatory rheumatic diseases. As most of these diseases affect women and men in childbearing age, some concerns have been voiced as to the safety of these drugs in relation to reproduction and pregnancy. Data from many hundreds of pregnancies in patients affected by inflammatory bowel disease and inflammatory arthritis have suggested that exposure to anti-TNF therapies at conception and/or during pregnancy is not associated with adverse pregnancy outcomes or any increase in congenital abnormalities. However, the exposure to anti-TNFalpha agents, particularly to monoclonal antibodies, in late pregnancy is associated with high drug levels in the newborn and their long-term effects on children remain unknown. Therefore, limiting the use of anti-TNFalpha to the first 30 weeks of pregnancy is recommended to reduce fetal exposure. Live-virus vaccines should be given only when levels of anti-TNFalpha drugs are undetectable in the serum of infants. Studies suggest that many of these drugs do enter breast milk in small amounts, but the extent to which the infant absorbs them is less clear. Limited reports have not suggested adverse pregnancy outcomes in women whose partners were exposed to anti-TNF therapies at the time of conception. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab and belimumab are limited and their use in pregnancy cannot currently be recommended. PMID- 25829191 TI - Change perspective to increase diagnostic accuracy of ultrasonography in calcium pyrophosphate dehydrate deposition disease! A new approach: the axial scan of the meniscus. AB - Ultrasonography (US) is a relevant tool in the study of calcium pyrophosphate dihydrate (CPP) deposition disease. However, differential diagnosis of hyperechoic deposits within the fibrocartilage can be difficult; moreover, US study is limited by the need of an adequate acoustic window. We describe a US scanning technique that offers a new viewpoint in the study of knee meniscal structure: a longitudinal scan performed according to the long axis of meniscus. This technique proves to be particularly useful for the identification of CPP deposition, but could also improve the US diagnostic utility and accuracy in other meniscal pathologies. PMID- 25829192 TI - Ribosomal protein L11- and retinol dehydrogenase 11-induced erythroid proliferation without erythropoietin in UT-7/Epo erythroleukemic cells. AB - Erythropoiesis is the process of proliferation, differentiation, and maturation of erythroid cells. Understanding these steps will help to elucidate the basis of specific diseases associated with abnormal production of red blood cells. In this study, we continued our efforts to identify genes involved in erythroid proliferation. Lentivirally transduced UT-7/Epo erythroleukemic cells expressing ribosomal protein L11 (RPL11) or retinol dehydrogenase 11 (RDH11) could proliferate in the absence of erythropoietin, and their cell-cycle profiles revealed G0/G1 prolongation and low percentages of apoptosis. RPL11-expressing cells proliferated more rapidly than the RDH11-expressing cells. The antiapoptotic proteins BCL-XL and BCL-2 were expressed in both cell lines. Unlike the parental UT-7/Epo cells, the expression of hemoglobins (Hbs) in the transduced cells had switched from adult to fetal type. Several signal transduction pathways, including STAT5, were highly activated in transduced cells; furthermore, expression of the downstream target genes of STAT5, such as CCND1, was upregulated in the transduced cells. Taken together, the data indicate that RPL11 and RDH11 accelerate erythroid cell proliferation by upregulating the STAT5 signaling pathway with phosphorylation of Lyn and cyclic AMP response element-binding protein (CREB). PMID- 25829193 TI - Stroke and death prediction with CHA2DS2-vasc score after myocardial infarction in patients without atrial fibrillation. AB - AIMS: The CHA2DS2-VASc score is widely used to stratify the risk of stroke in patients with nonvalvular atrial fibrillation. The aim of the study was to assess whether the CHA2DS2-VASc score might be useful to identify patients at a high risk of ischemic stroke and death among individuals after acute myocardial infarction and with no history of atrial fibrillation. METHODS: We analysed consecutive patients with acute myocardial infarction admitted to our centre between 2003 and 2008. On the basis of the CHA2DS2-VASc score, four groups were distinguished: low-risk (1 point), intermediate-risk (2-3 points), high-risk (4-5 points) and very high-risk (>5 points). Data on long-term follow-up were screened to identify patients who experienced stroke or died during remote observation. RESULTS: Out of 2980 registry participants, 333 were excluded because of atrial fibrillation and/or ongoing therapy with oral anticoagulants. Finally, 2647 individuals were included into the analysis. An ischemic stroke occurred in 71 (2.68%) patients, whereas 439 (16.58%) died during a median follow-up of 41.5 months. The risk of stroke and death increased four-fold in the high-risk group compared with the low-risk group (P < 0.001). Every point in the CHA2DS2-VASc score was independently associated with 41% increase in stroke risk and 23% increase in mortality rate (for both P < 0.001). CONCLUSION: The mortality rate and risk of stroke were strongly associated with the CHA2DS2-VASc scores. Hence, this scoring system could be useful to identify high-risk patients with no history of atrial fibrillation, in whom additional preventive measures might be beneficial to improve the outcome. PMID- 25829194 TI - Should prenatal hydronephrosis that resolves before birth be followed postnatally? Analysis and comparison to persistent prenatal hydronephrosis. AB - BACKGROUND: Prenatal ultrasonography has greatly enhanced detection of congenital genitourinary abnormalities. However, although persistent prenatal hydronephrosis (PPH) is typically imaged and followed postnatally, it remains unclear if prenatal hydronephrosis that resolves in utero (RPH) should be similarly managed. We determined postnatal abnormalities associated with RPH and compared these to those associated with PPH. METHODS: We performed a retrospective review of all consecutive patients evaluated for prenatal hydronephrosis over 24 months. Patients were followed prenatally with serial ultrasounds and postnatally with ultrasonography and a voiding cystourethrogram. RESULTS: Of the consecutive 165 patients enrolled in the study, 72 had RPH. The average prenatal anterior posterior renal pelvis length was significantly longer in patients with PPH (5.5 mm) than in those with RPH (4.9 mm) (p = 0.01). Recurrent postnatal hydronephrosis occurred in 44% of patients with RPH, with eventual resolution in 34% of those affected. In comparison, 29% of PPH cases resolved postnatally. Mean time to resolution was statistically shorter for PPH (116 days) than for RPH (175 days) (p = 0.01). Seven PPH patients required surgery, while no RPH patients needed intervention (difference was statistically significant). CONCLUSIONS: A significant number of RPH children had postnatal hydronephrosis. Despite a slower resolution time, no children with RPH required intervention. Although RPH may recur postnatally, the significantly lower chance of intervention being required suggests that these children may not require postnatal imaging. PMID- 25829195 TI - Patient access to health care and medicines across low-income countries. AB - This study explores the issue of demand for health care and medicines in low income country settings. Using the World Health Survey, multivariate analysis of cross-sectional household data from 35 low-income countries found that when ill, patient demand for health care to visit a clinic or hospital is inelastic ranging from -0.19 to 0.11. The main determinants of health seeking behaviour include having insurance, having a chronic condition, high household expenditure, and marital status. Women, the educated and those living in urban settings are more likely to seek care in a clinic. These findings suggest low-income patients will experience access problems, raising important policy implications to improve access to health care and medicines in these settings. PMID- 25829197 TI - No vote in US Congress on proposal to create new pathway for approving antibiotics. PMID- 25829196 TI - Endothelial protective genes induced by statin are mimicked by ERK5 activation as triggered by a drug combination of FTI-277 and GGTI-298. AB - BACKGROUND: Statins are potent inhibitors of cholesterol biosynthesis and are clinically beneficial in preventing cardiovascular diseases, however, the therapeutic utility of these drugs is limited by myotoxicity. Here, we explored the mechanism of statin-mediated activation of ERK5 in the human endothelium with the goal of identifying compounds that confer endothelial protection but are nontoxic to muscle. METHODS: An ERK5-one hybrid luciferase reporter transfected into COS-7 cells with pharmacological and molecular manipulations dissected the signaling pathway leading to statin activation of ERK5. qRT-PCR of HUVEC cells documented the transcriptional activation of endothelial-protective genes. Lastly, morphological and cellular ATP analysis, and induction of atrogin-1 in C2C12 myotubes were used to assess statin-induced myopathy. RESULTS: Statin activation of ERK5 is dependent on the cellular reduction of GGPPs. Furthermore, we found that the combination of FTI-277 (inhibitor of farnesyl transferase) and GGTI-298 (inhibitor of geranylgeranyl transferase I) mimicked the statin-mediated activation of ERK5. FTI-277 and GGTI-298 together recapitulated the beneficial effects of statins by transcriptionally upregulating anti-inflammatory mediators such as eNOS, THBD, and KLF2. Finally, C2C12 skeletal myotubes treated with both FTI-277 and GGTI-298 evoked less morphological and cellular changes recognized as biomarkers of statin-associated myopathy. CONCLUSIONS: Statin-induced endothelial protection and myopathy are mediated by distinct metabolic intermediates and co inhibition of farnesyl transferase and geranylgeranyl transferase I confer endothelial protection without myopathy. GENERAL SIGNIFICANCE: The combinatorial FTI-277 and GGTI-298 drug regimen provides a promising alternative avenue for endothelial protection without myopathy. PMID- 25829198 TI - Relationship between subclinical cardiac troponin I elevation and culprit lesion characteristics assessed by optical coherence tomography in patients undergoing elective percutaneous coronary intervention. AB - BACKGROUND: The prevalence of subclinical, cardiac troponin I (cTnI) elevation in stable patients undergoing elective percutaneous coronary intervention and its relationship to culprit lesion characteristics assessed by optical coherence tomography (OCT) are unknown. METHODS AND RESULTS: We studied 206 native de novo culprit coronary lesions from 206 patients with stable angina pectoris who underwent OCT before elective percutaneous coronary intervention. Patients were divided into 2 groups according to the presence (cTnI group; n=47; 22.8%) or absence (non-cTnI group; n=159; 77.2%) of cTnI >=0.03 ng/mL at admission. The clinical and OCT findings were compared between these 2 groups. No significant difference was found in the clinical presentation between the groups except for the serum C-reactive protein levels and presence of multivessel disease. By OCT, cTnI elevation was associated with the presence of thin-cap fibroatheromas, a greater lipid arc, and a longer lipid length. In a multivariable analysis, the presence of positive C-reactive protein levels (odds ratio, 4.38; 95% confidence interval, 1.90-10.08; P=0.001) and OCT-derived thin-cap fibroatheromas (odds ratio, 2.89; 95% confidence interval, 1.22-6.86; P=0.016) were independent predictors of cTnI elevation. Periprocedural myocardial injury, defined as postpercutaneous coronary intervention peak cTnI levels >1.0 ng/mL (5* the upper reference limit), occurred more often in patients with cTnI elevation at admission (cTnI group: 41% versus non-cTnI group: 18%; P=0.001). CONCLUSIONS: The presence of subclinical cTnI elevation at admission was not uncommon and was associated with OCT-derived unstable plaque morphology in patients undergoing elective percutaneous coronary intervention, and may help to identify patients with stable angina pectoris at high risk for periprocedural myocardial injury. PMID- 25829199 TI - A retrospective study of end-to-side venous anastomosis for free flap in extremity reconstruction. AB - INTRODUCTION: The success of end-to-side (ETS) venous anastomosis primarily depends on several mandatory factors including recipient vessel selection and reconstruction site. This retrospective study was designed to analyze the success rate of ETS venous anastomosis for free flap extremity reconstruction. METHODS: Between 2009 and 2011, ETS venous anastomosis was performed in 117 patients to reconstruct soft tissue defects of extremity at Nanjing Drum Tower Hospital. The patients were divided into three groups: (1) only one large recipient vein left, (2) two deep venas, (3) one deep vein and one superficial vein. Medical records and the follow-up data were retrospectively reviewed. The success rates of the three groups were compared with Chi-squared test. RESULTS: Totally, 5, 52, and 60 patients were included in Group 1, Group 2, and Group 3, respectively. The overall surgery success rate was 96.6% (113/117) with four failures: zero in Group 1, two in Group 2 (2/52, 3.8%) and two in Group 3 (2/60, 3.3%), due to venous thrombosis. The re-anastomosis rate in re-exploration in Group 1, 2 and 3 was 0%, 1.9% (1/52), and 1.7% (1/60), respectively. No complication was observed during the operation. DISCUSSION: No statistical difference was observed in flap failure rate among the three different types of ETS anastomosis. This suggests that differences of the ETS anastomosis surgical site might not affect the surgery success rate. CONCLUSION: These results confirmed that the success rate of ETS anastomosis was not affected by the local conditions of surgery site. PMID- 25829200 TI - Body Surface Area: A new predictive factor of mortality and pancreatic fistula after pancreaticoduodenectomy: A cohort-study. AB - INTRODUCTION: To assess the role of Body Surface Area (BSA) in predicting pancreatic fistula and mortality after pancreaticoduodenectomy. METHODS: The data of patients who underwent pancreaticoduodenectomy between January 1992 to December 2012 at the University Hospital of Caen were collected prospectively and analyzed retrospectively. Pancreatic fistula was determined according to the ISPGF (International Study Group for Pancreatic Fistula) criteria. The Clavien and Dindo classification was used for grading post-operative complications and BSA was calculated according to the Boyd formula. Patients were classified as "large" and "non-large" using a BSA value >=1.82 to define the large group and the non-large group. The primary end points were post-operative mortality rate, and the rate and grade of post-operative pancreatic fistula. RESULTS: 411 patients underwent pancreaticoduodenectomy with a mean age of 61.2 (+/-12.1) year. Six patients (1.45%) died post-operatively. Patients with a BSA >=1.82 had a significantly higher risk of post-operative death: OR 3.55 [1.43-8.80] (p < 0.0005). Eighty-five patients (20.7%) developed a post-operative pancreatic fistulas. The grade A pancreatic fistula rate was 87.1%. Patients with a BSA >=1.82 had a significantly higher risk of developing overall post-operative pancreatic fistula (p < 0.038). Multivariate analysis showed that "large" patients (1.86, 95%CI[1.09-3.92], p = 0.0229), soft pancreas (6.5, 95%CI[2.39 9.31], p = 0.0155) and a BMI >= 25 (1.09, 95%CI[1.031-1.163], p = 0.0407) were independent risk factors of pancreatic fistula. CONCLUSION: Body Surface Area is a useful factor after pancreaticoduodenectomy to predict mortality and post operative fistula. PMID- 25829201 TI - Mycolic acid-containing bacteria activate heterologous secondary metabolite expression in Streptomyces lividans. PMID- 25829202 TI - Synthesis and antibacterial evaluation of some teicoplanin pseudoaglycon derivatives containing alkyl- and arylthiosubstituted maleimides. AB - Bis-alkylthio maleimido derivatives have been prepared from teicoplanin pseudoaglycon by reaction of its primary amino group with N-ethoxycarbonyl bis alkylthiomaleimides. Some of the new derivatives displayed excellent antibacterial activity against resistant bacteria. PMID- 25829203 TI - Curricular and pedagogical implications for the Carnegie Study, educating nurses: a call for radical transformation. PMID- 25829204 TI - Factors affecting mobility in community-dwelling older Koreans with chronic illnesses. AB - PURPOSE: This descriptive study aims to describe the levels of mobility in community-dwelling older Koreans with chronic illnesses, and to examine the associations of their mobility with sleep patterns, physical activity and physical symptoms including fatigue and pain. METHODS: The participants were a total of 384 community-dwelling older adults recruited from three senior centers in Seoul, Korea. Measures included mobility assessed using 6-minute walk test (6MWT), physical activity behavior, sleep profiles, fatigue and pain. Data were collected from July to December 2012. RESULTS: The mean 6MWT distance was 212.68 meters. Over 90% of the study participants (n = 373) were classified as having impaired mobility using 400 meters as the cutoff point diagnostic criteria of normal mobility in 6MWT. The 6MWT distance was 246.68 meters for participants in their 60s, 212.32 meters for those in their 70s, and 175.54 meters for those in their 80s. Significant predictors of mobility included younger age, taking mediation, regular physical activity, female gender, higher income, higher fatigue and better perception on sleep duration, which explained 18% of the total variance of mobility. CONCLUSIONS: A high-risk group for mobility limitation includes low income, sedentary older men who are at risk for increased fatigue and sleep deficit. Further research should incorporate other psychological and lifestyle factors such as depression, smoking, drinking behavior, and/or obesity into the prediction model of mobility to generate specific intervention strategies for mobility enhancement recommendations for older adults. PMID- 25829205 TI - Teamwork and clinical error reporting among nurses in Korean hospitals. AB - PURPOSE: To examine levels of teamwork and its relationships with clinical error reporting among Korean hospital nurses. METHODS: The study employed a cross sectional survey design. We distributed a questionnaire to 674 nurses in two teaching hospitals in Korea. The questionnaire included items on teamwork and the reporting of clinical errors. We measured teamwork using the Teamwork Perceptions Questionnaire, which has five subscales including team structure, leadership, situation monitoring, mutual support, and communication. Using logistic regression analysis, we determined the relationships between teamwork and error reporting. RESULTS: The response rate was 85.5%. The mean score of teamwork was 3.5 out of 5. At the subscale level, mutual support was rated highest, while leadership was rated lowest. Of the participating nurses, 522 responded that they had experienced at least one clinical error in the last 6 months. Among those, only 53.0% responded that they always or usually reported clinical errors to their managers and/or the patient safety department. Teamwork was significantly associated with better error reporting. Specifically, nurses with a higher team communication score were more likely to report clinical errors to their managers and the patient safety department (odds ratio = 1.82, 95% confidence intervals [1.05, 3.14]). CONCLUSIONS: Teamwork was rated as moderate and was positively associated with nurses' error reporting performance. Hospital executives and nurse managers should make substantial efforts to enhance teamwork, which will contribute to encouraging the reporting of errors and improving patient safety. PMID- 25829206 TI - Resilience and work-life balance in first-line nurse manager. AB - PURPOSE: The aim of this study was to explore how first-line nurse managers constructed the meaning of resilience and its relationship to work-life balance for nurses in Korea. METHODS: Participants were 20 first-line nurse managers working in six university hospitals. Data were collected through in-depth interviews from December 2011 to August 2012, and analyzed using Strauss and Corbin's grounded theory method. RESULTS: Analysis revealed that participants perceived work-life balance and resilience to be shaped by dynamic, reflective processes. The features consisting resilience included "positive thinking", "flexibility", "assuming responsibility", and "separating work and life". This perception of resilience has the potential to facilitate a shift in focus from negative to positive experiences, from rigidity to flexibility, from task centered to person-centered thinking, and from the organization to life. CONCLUSIONS: Recognizing the importance of work-life balance in producing and sustaining resilience in first-line nurse managers could increase retention in the Korean nursing workforce. PMID- 25829207 TI - Mapping and changing informal nurse leadership communication pathways in a health system. AB - PURPOSE: Social network analysis (SNA) is increasingly being used to provide a visual and quantitative analysis of relationships among groups of staff and other subjects of interest. This paper examines the role SNA can play in identifying existing networks, and measures the impact of participation in brief task-focused project groups on the underlying communication pathways. METHODS: An SNA of a closed group of nurse leaders was conducted in a health system in Scotland, UK. Data were collected on two occasions 6 months apart. Analysis of both whole network and individual node-based (nurse leader) measures were undertaken. RESULTS: Analysis revealed that the initial network structure was related to functional departments. By establishing task and finish groups, network density and other key measures could be improved. CONCLUSIONS: SNA is a useful tool in mapping existing networks and evaluating how these can be strengthened through the use of task orientated project work. This easy-to-use technique can provide useful insights and a means of targeting management action to improve communication pathways in a moderately large and complex nurse leadership group. Further clinical and academic potential uses of the technique are suggested. PMID- 25829208 TI - A qualitative approach of psychosocial adaptation process in patients undergoing long-term hemodialysis. AB - PURPOSE: Professional hemodialysis (HD) nursing tends to be task-oriented and lack consideration of the client's viewpoint. This study aims to interpret the process of psychosocial adaptation to dealing with HD in people with end-stage renal disease (ESRD). METHODS: A grounded theory guided this study. Theoretical sampling included 15 people receiving HD at the HD center of a hospital from July to November 2010. Participants received an information sheet in writing, a verbal invitation, and informed consent forms before interviews were conducted. A constant comparative data analysis was analyzed using open, axial and selective coding. The computer software ATLAS.ti assisted data management. Credibility, transferability, dependability, and confirmability ensured the rigor of study process. RESULTS: This study identified "adopting life with hemodialysis", which captures the process of the psychosocial adaptation in people with ESRD as one transformation. Four categories that evolved from "adopting HD life" are (a) slipping into, (b) restricted to a renal world, (c) losing self control, and (d) stuck in an endless process. CONCLUSIONS: The findings of this investigation indicate the multidimensional requirements of people receiving maintenance dialysis, with an emphasis on the deficiency in psychosocial and emotional care. The study's findings contribute to clinical practice by increasing the understanding of the experience of chronic HD treatment from the recipient's viewpoint. The better our understanding, the better the care provided will meet the needs of the people receiving HD. PMID- 25829209 TI - Efficacy of chronic disease self-management program in older Korean adults with low and high health literacy. AB - PURPOSE: We evaluated the efficacy of the Chronic Disease Self-management Program (CDSMP) among older Korean adults and investigated the question of whether the effects differed according to their levels of health literacy. METHODS: Measures of self efficacy, physical activity, physical health, and mental health were assessed at baseline, and at 6-week, and 18-week follow up for the CDSMP intervention group (n = 23) and control group (n = 31) according to their health literacy status. RESULTS: The older adults in the CDSMP intervention group showed significantly higher levels of self efficacy and physical activity at follow up. Participants with low health literacy had greater benefits from the intervention than had those with high health literacy. CONCLUSIONS: The CDSMP is a beneficial intervention for older Korean adults with chronic disease. Healthcare professionals should encourage older Korean adults with chronic illness to participate in the CDSMP, in particular for those with low health literacy. PMID- 25829210 TI - Health-related quality of life in symptomatic postmyocardial infarction patients with left ventricular dysfunction. AB - PURPOSE: Symptoms of postmyocardial infarction (post-MI) patients at risk for progression to heart failure are often ignored, and lack of symptom recognition or misinterpretation may diminish health-related quality of life (HRQoL). This study was conducted to evaluate the differences in HRQoL by symptom experience and determine factors that predict diminished HRQoL in post-MI patients. METHODS: Using a descriptive correlational study design, post-MI patients with left ventricular dysfunction (ejection fraction < 50%) completed face-to-face interviews for symptoms, HRQoL, covariates including self-care compliance, New York Heart Association class, and demographic and clinical questionnaires. RESULTS: A total of 105 post-MI patients participated (mean age 65 years, 79.0% male, mean ejection fraction 43.6%, New York Heart Association class III/IV 33.3%). Mean length of time after the cardiac event was 48 months. Patients reported four or more symptoms, with fatigue being the most common symptom (63.8%), followed by shortness of breath (56.2%), weakness (54.3%), and dizziness (51.4%). HRQoL was moderately poor, with a mean score of 44.38 +/- 27.66. There was no significant relationship between self-care compliance and HRQoL. Patients who were female, with low monthly income, and had lower functional capacity and more symptoms had worse HRQoL, after controlling for age and length of time after the event (adjusted R(2) = 0.53, p < .001). CONCLUSIONS: A need for transitional care that assists post-MI patients take an active involvement in symptom monitoring arises so that they can get into the system earlier and benefit from treatment, and eventually achieve desirable HRQoL. PMID- 25829211 TI - Effects of self-esteem improvement program on self-esteem and peer attachment in elementary school children with observed problematic behaviors. AB - PURPOSE: The purpose of this study was to investigate the effects of a self esteem improvement program on self-esteem and peer attachment in elementary school children with observed problematic behaviors. METHODS: This study is a quasi-experimental study with a nonequivalent control group pretest-post-test design. A total of 47 fourth grade elementary school students participated in this study. The program was provided for 45 minutes once a week; a total of 12 sessions were completed with a group in the classroom for the experimental group. Child Problem-Behavior Screening Questionnaire was used to measure problematic behavior. Self-esteem was measured using the Rosenberg's Self-esteem Questionnaire, and peer attachment was measured using the Inventory of Parent and Attachment. Measuring was performed right after the program was done (post 1) and 1 month after the program was finished (post 2). To compare the differences in self-esteem and peer attachment between groups, repeated measures analysis of variance was used. RESULTS: Most participants in the experimental group were 10 years old (62.5%, range 10-11), male (52.0%) and with middle grade point average (64.0%). The self-esteem scores in the experimental group were significantly higher than those of the control group (F = 26.64, p < .001). The peer attachment scores in the experimental group were significantly higher than those of the control group (F = 6.48, p = .014). CONCLUSIONS: The self-esteem improvement program in this study improved the self-esteem and peer attachment in elementary school children. The self-esteem program helped acknowledge the peer's name and increased their connections. The program needs to be considered as a formal and consistent program. PMID- 25829212 TI - Factors affecting fatigue in patients with type II diabetes mellitus in Korea. AB - PURPOSE: This study aimed to characterize and identify the factors affecting fatigue in patients with type II diabetes mellitus in Korea. METHODS: A total of 180 patients with type II diabetes mellitus were recruited from the outpatient clinic of a tertiary care hospital. For data collection, a questionnaire survey of diabetes history, hypoglycemia symptoms, and fatigue was conducted between January and February 2011. Data were analyzed using t test, analysis of variance, Pearson's correlation, and hierarchical multiple regression. RESULTS: The mean fatigue and hypoglycemia symptom scores of patients with type II diabetes mellitus were 2.88 +/- 0.61 and 6.18 +/- 12.60, respectively. Hypoglycemia symptoms (p = .004), disease duration (p < .001), and age (p < .001) correlated positively with fatigue. Hierarchical multiple regression analysis revealed that hypoglycemia symptoms was the variable positively influencing fatigue in patients with type II diabetes mellitus after adjustment for influences of demographic and clinical characteristic variables. CONCLUSIONS: Hypoglycemia symptoms were confirmed to be a predictor of fatigue. Consequently, it is essential to consider age, and disease duration as well as hypoglycemia symptoms to intervene fatigue effectively among patients with type II diabetes mellitus. PMID- 25829213 TI - Geriatric hospital nurses' perceived barriers to research utilization and empowerment. AB - PURPOSE: The quality of nursing care in geriatric hospitals has been of concern. Nurses need to provide evidence-based nursing using best available research findings in order to maximize the quality of care. Research utilization is a major part of evidence-based nursing practice. Empowerment is an important factor that may influence the context of nursing practice. The purpose of this study was to identify the barriers to research utilization in nursing practice and its relationship to empowerment perceived by registered nurses (RNs) in geriatric hospitals. METHODS: A descriptive, correlational design was used. A total of 147 RNs from six geriatric hospitals in K province of Korea participated. The BARRIERS scale and the Conditions of Work Empowerment Questionnaire-II were administered to identify perceived barriers to the use of research findings and the level of perceived empowerment respectively. RESULTS: Participants rated that research reports being written in English constituted the greatest barrier to the use of research findings. The score was the highest for the Communication domain, suggesting the greatest barrier, and the lowest for the Adopter domain. Subscales of the Conditions of Work Empowerment Questionnaire-II were significant predictors of the Adopter, Organization, and Communication domains of the BARRIERS scale. CONCLUSIONS: This study found that RNs in geriatric hospitals perceived that interpreting and understanding research reports in English was the greatest barrier to the use of research findings. Administrators and nurse managers of geriatric hospitals need to provide RNs with opportunities to participate in research-related activities and to empower RNs in order to facilitate research utilization. PMID- 25829214 TI - A predictive model of health outcomes for young people with type 2 diabetes. AB - PURPOSE: This study was conducted to develop and test a hypothetical model to predict health outcomes in young people with type 2 diabetes. METHODS: Data were collected from 190 adults aged 23-45 with type 2 diabetes mellitus who visited the endocrinology outpatient department of the two university hospitals in South Korea from November 2, 2012 to March 7, 2013. Data collection used the structured questionnaires and patient medical records. The descriptive and correlation statistics were analyzed using PASW 18.0 and structural equation modeling procedure was performed using the AMOS 18.0 program. RESULTS: The fit of the hypothetical model was appropriate with the ratio of the chi-square statistic to degrees of freedom at 17.00, goodness-of-fit index at .975, adjusted goodness-of fit index at .930, root mean square error of approximation at .061, normed fit index at .926, Turker-Lewis index at .929, comparative fit index at .966. Behavioral skills were a critical factor that directly affects self-management behaviors. Through behavioral skills, motivation had a statistically significant indirect effect on self-management behavior. Self-management behavior had a statistically significant direct effect on health outcome. Through self management behavior, behavioral skills had a statistically significant indirect effect on health outcome. These variables explained 17.9% of the total variance for the health outcome in young people with type 2 diabetes. CONCLUSIONS: The results suggest that self-management behavior could be improved through nursing interventions promoting personal motivation (positive attitude), social motivation (social support), and behavioral skills (self efficacy), which can result in better health outcomes for young people with type 2 diabetes. PMID- 25829215 TI - The monitoring medicines project: a multinational pharmacovigilance and public health project. AB - The Monitoring Medicines project (MM), funded by the FP-7 EU framework, was carried out between 2009 and 2013 by a consortium of 11 partners. The objectives were to support and strengthen consumer reporting of adverse drug reactions (ADRs); expand the role and scope of national pharmacovigilance centres concerning medication errors; promote improved use of pharmacovigilance data; and develop methods to complement spontaneous reporting. The work was organised into four themes: patient reporting; medication errors; drug dependence, counterfeit and substandard medicines and clinical risk estimation; and active and targeted spontaneous pharmacovigilance. MM differed from some other major pharmacovigilance initiatives by having participants from developing countries in Asia and Africa and in leaning towards public health and communicable diseases. MM brought together stakeholders including WHO, drug regulators, pharmacovigilance centres, consumers, public health and disease specialists and patient safety networks. Resources and methodologies developed directly by, or with support from, MM include electronic systems/tools for consumer ADR reporting and cohort event monitoring; publication by WHO of handbooks on consumer reporting, medication errors and pharmacovigilance for TB medicines; methodologies for detecting drug dependence and substandard or counterfeit medicines in ADR databases; and a database on HIV treatment risks with a risk assessment tool. MM enabled stakeholders to achieve more than if they had worked alone in pursuit of patient safety. PMID- 25829216 TI - Risks and benefits of triple oral anti-thrombotic therapies after acute coronary syndromes and percutaneous coronary intervention. AB - The key pathophysiological process underlying symptomatic coronary artery disease, including acute coronary syndromes (ACS), is usually a rupture or an erosion of an atherosclerotic plaque, followed by platelet activation and subsequent thrombus formation. Early clinical trials showed benefit with long term aspirin treatment, and later-based on large clinical trials-dual anti platelet therapy (DAPT), initially with clopidogrel, and more recently with prasugrel or ticagrelor, has become the established treatment in the post-ACS setting and after percutaneous coronary intervention (PCI). Treatment with DAPT is recommended for both ST-elevation myocardial infarction and non-ST-elevation ACS, as well as after PCI with stenting, in American and European clinical guidelines. Notwithstanding the benefits observed with DAPT, including third generation P2Y12 receptor inhibitors plus aspirin, ACS patients remain at high risk for a recurrent cardiovascular event, suggesting that other treatment strategies, including the addition of a third oral anti-platelet agent or a novel oral anticoagulant (NOAC) to standard DAPT regimens, may provide additional benefit for post-ACS patients and for patients undergoing PCI. Adding a third anti-thrombotic agent to DAPT after an ACS event or a PCI procedure has been shown to have modest benefit in terms of ischemic event reduction, but has consistently been associated with increased bleeding complications. Therefore, the quest to optimize anti-thrombotic therapies post-ACS and post-PCI continues unabated but is tempered by the historical experiences to date that indicate that careful patient and dose selection will be critical features of future randomized trials. PMID- 25829217 TI - Indoleamine 2,3-dioxygenase is upregulated in the brain of rats with acute pancreatitis. AB - BACKGROUND: Acute pancreatitis (AP) has an effect on both inflammatory/autoimmune processes and psychological states, but the pathophysiological causes of pancreatic encephalopathy in the brain are unclear. We hypothesized that the peripheral immune/inflammatory response during AP can affect indolamine 2,3 dioxygenase (IDO) expression and serotonin content in the brain. METHODS: About 210 male Sprague Dawley rats were randomly divided into five groups: control (0 h) and 6 h, 24 h, 48 h and 72 h experimental groups. Acute pancreatitis was induced by an injection of a sodium taurocholate solution via a cannulated bile pancreatic duct. We measured the plasma TNF-alpha and IL-6 levels; serotonin, 5 HIAA and the protein concentration levels of IDO and monoamine oxidase A (MAO-A) were evaluated in the striatum, hippocampus and left prefrontal cortex. RESULTS: The IL-6 and the TNF-alpha levels increased in the 24 h, 48 h and 72 h groups. The IDO concentrations of both the 72 h group in the hippocampus and 48 h, 72 h groups in the prefrontal cortex increased; in the corpus striatum, the IDO concentrations fluctuated without statistical significance. The MAO-A protein concentration of the 6 h and 24 h groups decreased in the striatum, hippocampus and prefrontal cortex. There were no statistically significant differences found in the serotonin and 5-HIAA concentrations. CONCLUSIONS: During the process of AP, cytokines, such as IL-6 and TNF-alpha, may play a role in activation of neuronal pathways utilizing the metabolic enzyme IDO, which may play an important role in determining the mental symptomatology accompanying AP. PMID- 25829218 TI - Hindlimb Skeletal Muscle Function and Skeletal Quality and Strength in +/G610C Mice With and Without Weight-Bearing Exercise. AB - Osteogenesis imperfecta (OI) is a heterogeneous heritable connective tissue disorder associated with reduced bone mineral density and skeletal fragility. Bone is inherently mechanosensitive, with bone strength being proportional to muscle mass and strength. Physically active healthy children accrue more bone than inactive children. Children with type I OI exhibit decreased exercise capacity and muscle strength compared with healthy peers. It is unknown whether this muscle weakness reflects decreased physical activity or a muscle pathology. In this study, we used heterozygous G610C OI model mice (+/G610C), which model both the genotype and phenotype of a large Amish OI kindred, to evaluate hindlimb muscle function and physical activity levels before evaluating the ability of +/G610C mice to undergo a treadmill exercise regimen. We found +/G610C mice hindlimb muscles do not exhibit compromised muscle function, and their activity levels were not reduced relative to wild-type mice. The +/G610C mice were also able to complete an 8-week treadmill regimen. Biomechanical integrity of control and exercised wild-type and +/G610C femora were analyzed by torsional loading to failure. The greatest skeletal gains in response to exercise were observed in stiffness and the shear modulus of elasticity with alterations in collagen content. Analysis of tibial cortical bone by Raman spectroscopy demonstrated similar crystallinity and mineral/matrix ratios regardless of sex, exercise, and genotype. Together, these findings demonstrate +/G610C OI mice have equivalent muscle function, activity levels, and ability to complete a weight-bearing exercise regimen as wild-type mice. The +/G610C mice exhibited increased femoral stiffness and decreased hydroxyproline with exercise, whereas other biomechanical parameters remain unaffected, suggesting a more rigorous exercise regimen or another exercise modality may be required to improve bone quality of OI mice. PMID- 25829219 TI - Rapid and sensitive detection of multiple microRNAs in cell lysate by low-fouling surface plasmon resonance biosensor. AB - We report an ultra-low fouling surface plasmon resonance imaging (SPRi) biosensor for the rapid simultaneous detection of multiple miRNAs in erythrocyte lysate (EL) at subpicomolar levels without need of RNA extraction. The SPRi chips were coated with ultra-low fouling functionalizable poly(carboxybetaine acrylamide) (pCBAA) brushes having optimized thicknesses and directly functionalized with amino-modified oligonucleotide probes. We have characterized the effect of the brush thickness on the probe loading capacity: a loading capacity of ~9.8*10(12) probes/cm(2) was achieved for pCBAA having a thickness of ~40 nm. The probe functionalized sensor also exhibited a high resistance to fouling from ~90% EL samples (<2 ng/cm(2)). A two-step detection assay was employed for multiplexed miRNA detection in EL. Specifically, the assay consisted of (i) a sandwich-type hybridization of the probe-functionalized pCBAA with target miRNA in EL (bound to biotinylated oligonucleotides) and (ii) the capture of streptavidin functionalized gold nanoparticles to the aforementioned biotinylated probes. We have demonstrated that this approach enables the detection of miRNAs in EL at concentrations as low as 0.5 pM. Finally, we have confirmed the detection of four endogenous miRNAs representing a set of potential miRNA biomarkers of myelodysplastic syndrome (MDS) in clinical EL samples (miR-16, miR-181, miR-34a, and miR-125b). The results revealed significantly higher levels of miR-16 in all the clinical EL samples compared to the other measured miRNAs. PMID- 25829220 TI - A carbon dot-based "off-on" fluorescent probe for highly selective and sensitive detection of phytic acid. AB - We herein report a facile, one-step pyrolysis synthesis of photoluminescent carbon dots (CDs) using citric acid as the carbon source and lysine as the surface passivation reagent. The as-prepared CDs show narrow size distribution, excellent blue fluorescence and good photo-stability and water dispersivity. The fluorescence of the CDs was found to be effectively quenched by ferric (Fe(III)) ions with high selectivity via a photo-induced electron transfer (PET) process. Upon addition of phytic acid (PA) to the CDs/Fe(III) complex dispersion, the fluorescence of the CDs was significantly recovered, arising from the release of Fe(III) ions from the CDs/Fe(III) complex because PA has a higher affinity for Fe(III) ions compared to CDs. Furthermore, we developed an "off-on" fluorescence assay method for the detection of phytic acid using CDs/Fe(III) as a fluorescent probe. This probe enables the selective detection of PA with a linear range of 0.68-18.69 MUM and a limit of detection (signal-to-noise ratio is 3) of 0.36 MUM. The assay method demonstrates high selectivity, repeatability, stability and recovery ratio in the detection of the standard and real PA samples. We believe that the facile operation, low-cost, high sensitivity and selectivity render this CD-based "off-on" fluorescent probe an ideal sensing platform for the detection of PA. PMID- 25829221 TI - DNA biosensor-based on fluorescence detection of E. coli O157:H7 by Au@Ag nanorods. AB - A novel DNA sensor for the detection of the Escherichia coli O157:H7 (E. coli O157:H7) eaeA gene was constructed using surface enhanced fluorescence (SEF). The spacing distance dependence nature of Au@Ag nanorods surface enhanced fluorescence was investigated when the cy3-labled single strand DNA(ssDNA) and the stem-loop DNA probe modified on the nanorods was co-hybridized. The result revealed that the fluorescence intensity reached the maximum value with the spacing distance of about 10nm between cy3 and the Au@Ag nanorods surface. Based on this result, a fluorescence "ON/OFF" switch for detecting the eaeA gene of E. coli O157:H7 was constructed. Under optimal conditions, the DNA sensor produced a linear range from 10(-17) to 10(-11) M with a correlation coefficient of 0.9947 and a detection limit of 3.33*10(-18) M, and was also found to be specific in targeting eaeA. The DNA sensor demonstrated a new strategy of combining eaeA recognition and Au@Ag nanorods for fluorescence signal enhancement, and increased sensitivity in the detection of bacterial specific genes. PMID- 25829222 TI - Fluorescence analysis of 6-mercaptopurine with the use of a nano-composite consisting of BSA-capped Au nano-clusters and core-shell Fe3O4-SiO2 nanoparticles. AB - A magnetic and fluorescent nano-composite was prepared. It comprised of a core of Fe3O4 nanoparticles (NPs), a silica shell and satellitic Au nano-clusters (AuNCs) capped with bovine serum albumin (BSA). This nano-composite has many desirable properties, e.g. magnetism, red emission, high water solubility, and high resistance to photo-bleaching. On addition of the analyte, 6-mercaptopurine (6 MP) or indeed other similar thiols, AuNCs formed aggregates because the existing cross-links within the Fe3O4 NPs@SiO2 and AuNC structure were broken in favor of the gold-thiol bonds. On suitable irradiation of such aggregates, red fluorescence was emitted at 613 nm. It decreased significantly as a function of the added 6-MP concentration, and the quenching ratio (F0 - F) / F0 was related linearly to the concentration of 6-MP in the range of 0.01 to 0.5 MUmol L(-1). The detection limit was 0.004 MUmol L(-1) (S/N=3). The method was strongly selective for 6-MP in the presence of oxidants, phenols, heavy-metal ions, and especially bio-thiols. PMID- 25829223 TI - Development of immunochromatographic strip test using fluorescent, micellar silica nanosensors for rapid detection of B. abortus antibodies in milk samples. AB - Presence of bacteria such as Brucella spp. in dairy products is an immense risk to public health. Point of care immunoassays are rapid in that they can quickly screen various samples in a relatively short amount of time, are sensitive, specific and offer a great advantage in accurate and fast diagnosis of infectious diseases. We have fabricated a point of care rapid diagnostic assay that employs fluorescent, micellar silica nanosensors capable of specifically detecting Brucella IgG antibodies in milk samples of afflicted animals. Currently, point of care detection assays are not commercially available for field testing of farm animals using milk samples. The nanosensing allows precise detection of antibodies with low sample volumes (50 MUl). We demonstrate recognition of B. abortus antibodies through capture by fluorescent silica nanosensors using spiked and raw milk samples validated by ELISA and PCR. The test results are accurate and repeatable with high sensitivity and specificity, and a short assay time of 10 min for antigenic recognition and do not require any sample processing procedures such as isolation and separation. Additionally, well defined antigenic components and surface biomarkers of various disease causing microbes can be broadly incorporated within the purview of this technology for accurate and rapid detection of suspected bovine pathological conditions, and can largely enable rapid field testing that can be implemented in farms and food industry. PMID- 25829224 TI - Highly amplified detection of visceral adipose tissue-derived serpin (vaspin) using a cognate aptamer duo. AB - A cognate aptamer duo for visceral adipose tissue-derived serpin (vaspin) which distinctively bind to two different sites on vaspin with high affinity and specificity were successfully developed by using graphene oxide-based systematic evolution of ligands by exponential enrichment (GO-SELEX), which offers immobilization-free screening of aptamers. The specific and simultaneous bindings of this aptamer duo (V1 and V49 aptamers) to the different sites of vaspin were confirmed by circular dichroism (CD) analysis and both sandwich-type surface plasmon resonance (SPR) and quantum dot labelled fluorescence imaging analysis (V1 aptamer serves as primary capturing aptamer and V49 aptamer as secondary signalling aptamer or vice versa). With this vaspin cognate aptamer duo on SPR platform, the detection of the target vaspin were improved to the limit of detection down to 3.5 ng/ml in buffer and 4.7 ng/ml in human serum samples. This cognate aptamer duo based biosensor could be utilized in the early diagnosis of type-2 diabetes. PMID- 25829225 TI - Reaction Optimization, Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1-Diborylalkanes via Suzuki-Miyaura Cross Coupling. AB - A method for enantioselective desymmetrization of 1,1-diborylalkanes through a stereoselective Pd-catalyzed Suzuki-Miyaura cross-coupling has been thoroughly optimized. The most effective ligand was found to be a alpha,alpha,alpha,alpha tetra-aryl-1,3-dioxolane-4,5-dimethanol (TADDOL)-derived phosphoramidite. Results show that in order to achieve high selectivity, a suitable balance between the sterics of the aryl groups and the amino group on the ligand must be achieved. While the base has been known to facilitate transmetallation in cross-coupling reactions, mechanistic studies on this desymmetrization process reveal that the base, in the presence of KHF2, likely plays an additional role in the hydrolysis of the pinacol boronates to the corresponding boronic acids. Through an in depth optimization of the chiral ligand and mechanistic studies, it was possible to obtain ee values over 90% for several aryl bromides and to develop a reliably scalable process (up to one gram of 1,1-diborylalkane substrate). PMID- 25829226 TI - Successful treatment of a patient with SAPHO syndrome with certolizumab pegol. PMID- 25829227 TI - Health-related quality of life among children, young people and adults with esophageal atresia: a review of the literature and recommendations for future research. AB - PURPOSE: Esophageal atresia (EA) is a rare congenital malformation requisite of surgical treatment. Survival rates have significantly increased in recent decades, but treated children are at risk of chronic morbidity. This study aims to review the literature on health-related quality of life (HRQOL) in patients with EA and describe the questionnaires used. METHODS: A literature search was conducted in Pubmed, Cinahl and PsycINFO, from inception to January 2015. A meta analysis of studies investigating HRQOL in patients with EA compared to healthy references was performed. The effect size was calculated as Cohen's d. RESULTS: Twelve articles (published 1995-2014) describing HRQOL among children, young people and adults were identified. Only European studies were found, and these had variable sample sizes (8-128). Overall HRQOL was reported to be reduced in five of the seven studies that compared overall HRQOL with a healthy reference population. Impaired physical or general health was described in eight articles. In the meta-analysis, eight eligible studies provided 16 estimates of the effect of EA, six of which reached statistical significance for worse HRQOL (p < 0.05). Using Cohen's criteria, the pooled estimate of the effect of EA was small for overall and physical HRQOL, and <0.2 for the mental and social HRQOL components. Altogether, 15 different questionnaires were used, and none were condition specific for EA. CONCLUSIONS: Different findings are reported; however, this study suggests that patients with EA may have a reduced HRQOL. Moreover, HRQOL is not adequately measured in this group. Additional research is required. PMID- 25829228 TI - VEGF can protect against blood brain barrier dysfunction, dendritic spine loss and spatial memory impairment in an experimental model of diabetes. AB - Clinical and experimental studies have shown a clear link between diabetes, vascular dysfunction and cognitive impairment. However, the molecular underpinnings of this association remain unclear. Since vascular endothelial growth factor (VEGF) signaling is important for maintaining vascular integrity and function, we hypothesized that vascular and cognitive impairment in the diabetic brain could be related to a deficiency in VEGF signaling. Here we show that chronic hyperglycemia (~8weeks) in a mouse model of type 1 diabetes leads to a selective reduction in the expression of VEGF and its cognate receptor (VEGF R2) in the hippocampus. Correlating with this, diabetic mice showed selective deficits in spatial memory in the Morris water maze, increased vessel area, width and permeability in the dentate gyrus/CA1 region of the hippocampus and reduced spine densities in CA1 neurons. Chronic low dose infusion of VEGF in diabetic mice was sufficient to restore VEGF signaling, protect them from memory deficits, as well as vascular and synaptic abnormalities in the hippocampus. These findings suggest that a hippocampal specific reduction in VEGF signaling and resultant vascular/neuronal defects may underlie early manifestations of cognitive impairment commonly associated with diabetes. Furthermore, restoring VEGF signaling may be a useful strategy for preserving hippocampal-related brain circuitry in degenerative vascular diseases. PMID- 25829230 TI - Personality and breast cancer risk and survival: the Miyagi cohort study. AB - It has long been hypothesized that personality is associated with breast cancer risk and survival. The present population-based prospective cohort study in Japan tested this hypothesis. To investigate the association of personality with breast cancer risk, a total of 15,107 women aged 40-64 years who completed the Eysenck Personality Questionnaire-Revised (EPQ-R) Short Form were followed from 1990 to 2007. To assess the association of personality with survival after breast cancer, 250 identified cases were further followed up from the date of diagnosis to 2008, and 45 all-cause deaths were documented. Study subjects were categorized into four groups based on the quartile points of scores ranging between 0 and 12 on each EPQ-R subscale (extraversion, neuroticism, psychoticism, and lie), and the hazard ratio (HR) for each category was computed using the lowest category as reference. Multivariate analysis revealed no association between any of the four personality subscales and the risk of breast cancer. In the analysis on survival, no significant association was found between any of these subscales and the risk of death, although breast cancer cases with a higher score of extraversion tended to have a lower risk of death (P for trend = 0.07; HR for highest score level = 0.38). Exclusion of 32 cases diagnosed in the first 3 years of follow-up did not largely change the results with regard to either breast cancer risk or survival. The present findings suggest that personality does not impact significantly on the development and progression of breast cancer. PMID- 25829229 TI - Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study. AB - BACKGROUND: Antiplatelet agents are widely used for cardiovascular disea ses, but their pleiotropic effects in sepsis are controversial. OBJECTIVE: To investigate the association between antiplatelet agents and the survival benefit for sepsis patients. DESIGN: A nationwide population-based cohort and nested case-control study. SETTING: Taiwan National Health Insurance database. PARTICIPANTS: All patients (age >=18 years) who were hospitalized for sepsis between January 2000 and December 2010. MEASUREMENTS: Conditional logistic regression was used to adjust for confounding. Adjusted odd ratios (ORs) were used to compare the mortality rate due to sepsis in antiplatelet drug users and nonusers. RESULTS: Of 683,421 included patients, 229,792 (33.6 %) patients died during hospitalization for sepsis, and the rest (64.4 %) survived to discharge. Use of antiplatelet agents before admission was associated with a lower risk of mortality in sepsis patients (aOR 0.82, 95 % confidence interval [CI] 0.81-0.83, P < 0.001). By using another case-control study design, the beneficial effect was more significant in current users (aOR 0.78, 95 % CI 0.76-0.79) than in recent users (aOR 0.88, 95 % CI 0.85-0.91), but was not significant in past users (aOR 1.00, 95 % CI 0.98 1.02). LIMITATIONS: Observational study. CONCLUSIONS: Prior use of antiplatelet agents was associated with a survival benefit in sepsis patients. PMID- 25829231 TI - Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma. AB - Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR+Asthma). To determine the pathophysiologic features of AR and AR+Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR+Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR+Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR+Asthma cases. Moreover, we found significant correlations of fractional exhaled nitric oxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma. PMID- 25829234 TI - Utility of eosin Y as a complexing reagent for the determination of citalopram hydrobromide in commercial dosage forms by fluorescence spectrophotometry. AB - An accurate, selective and sensitive spectrofluorimetric method was developed for the determination of citalopram hydrobromide in commercial dosage forms. The method was based on the formation of a fluorescent ion-pair complex between citalopram hydrobromide and eosin Y in the presence of a disodium hydrogen phosphate/citric acid buffer solution of pH 3.4 that was extractable in dichloromethane. The extracted complex showed fluorescence intensity at lambdaem = 554 nm after excitation at 259 nm. The calibration curve was linear over at concentrations of 2.0-26.0 ug/mL. Under optimized experimental conditions, the proposed method was validated as per ICH guidelines. The effect of common excipients used as additives was tested and the tolerance limit calculated. The limit of detection for the proposed method was 0.121 MUg/mL. The proposed method was successfully applied to the determination of citalopram hydrobromide in commercial dosage forms. The results were compared with the reference RP-HPLC method. PMID- 25829233 TI - Cbl-b-deficient mice express alterations in trafficking-related molecules but retain sensitivity to the multiple sclerosis therapeutic agent, FTY720. AB - The variable response to therapy in multiple sclerosis (MS) suggests a need for personalized approaches based on individual genetic differences. GWAS have linked CBLB gene polymorphisms with MS and recent evidence demonstrated that these polymorphisms can be associated with abnormalities in T cell function and response to interferon-beta therapy. Cbl-b is an E3 ubiquitin ligase that regulates T cell activation and Cbl-b-deficient (Cbl-b(-/-)) mice show T cell abnormalities described in MS patients. We now show that Cbl-b(-/-) T cells demonstrate significant lymph node trafficking abnormalities. We thus asked whether the MS-approved drug, FTY720, postulated to trap T cells in lymphoid tissues, is less effective in the context of Cbl-b dysfunction. We now report that FTY720 significantly inhibits EAE in Cbl-b(-/-) mice. Our results newly document a role for Cbl-b in T cell trafficking but suggest nevertheless that MS patients with Cbl-b abnormalities may still be excellent candidates for FTY720 treatment. PMID- 25829232 TI - T cell PKCdelta kinase inactivation induces lupus-like autoimmunity in mice. AB - Genetic and environmental factors contribute to the onset and progression of lupus. CD4+ T cells from patients with active lupus show a decreased ERK signaling pathway, which causes changes in gene expression. The defect points to its upstream regulator, PKCdelta, which exhibits a deficient activity due to oxidative stress. Our aim was to investigate the effect of a defective PKCdelta in the development of lupus. We generated a double transgenic C57BL6 * SJL mouse that expresses a doxycycline-induced dominant negative PKCdelta (dnPKCdelta) in T cells. The transgenic mice displayed decreased T cell ERK signaling, decreased DNMT1 expression and overexpression of methylation sensitive genes involved in the exaggerated immune response in the pathogenesis of lupus. The mice developed anti-dsDNA autoantibodies and glomerulonephritis with IgG deposition. The study indicates common pathogenic mechanisms with human lupus, suggesting that environmentally-mediated T cell PKCdelta inactivation plays a causative role in lupus. PMID- 25829235 TI - Enhanced thermoelectric properties of Ga-doped In2O3 ceramics via synergistic band gap engineering and phonon suppression. AB - Ga doped In2O3-based thermoelectric materials were prepared by spark plasma sintering (SPS) using sintered powders in the low temperature solid phase. The solubility of Ga in In2O3 is about 10 at%, much larger than other elements such as Ge, Ce, etc. The larger solubility of Ga allows us to optimize the thermal and electrical transport properties of Ga doped In2O3 in a wider window. While tuning the concentration of dopants, the thermoelectric performance of Ga doped In2O3 was enhanced through a synergistic approach combining band-gap engineering and phonon suppression. The power factor increases from ~0.5 * 10(-4) to ~9.6 * 10( 4) W mK(-2) at 700 degrees C while thermal conductivity reduces from ~4 to ~2 W mK(-1) at 700 degrees C in In1.9Ga0.1O3. The maximum ZT of 0.37, increased by a factor of 4 from the pristine In2O3, is achieved in In1.9Ga0.1O3 at 700 degrees C. PMID- 25829236 TI - Cardiovascular recovery from psychological and physiological challenge and risk for adverse cardiovascular outcomes and all-cause mortality. AB - OBJECTIVE: Exaggerated cardiovascular (CV) reactivity to laboratory challenge has been shown to predict future CV morbidity and mortality. CV recovery has been less studied and has yielded inconsistent findings, possibly due to the presence of moderators. Reviews on the relationship between CV recovery and CV outcomes have been limited to cross-sectional studies and have not considered methodological factors. We performed a comprehensive meta-analytic review of the prospective literature investigating CV recovery to physical and psychological challenge and adverse CV outcomes. METHODS: We searched PsycINFO and PubMed for prospective studies investigating the relationship between CV recovery and adverse CV outcomes. Studies were coded for variables of interest and for effect sizes. We conducted a random-effects weighted meta-analysis. Moderators were examined with analysis of variance-analog and meta-regression analyses. RESULTS: Thirty-seven studies met the inclusion criteria (n = 125,386). Impaired recovery from a challenge predicted adverse CV outcomes (summary effect, r = 0.17, p < .001). Physical challenge was associated with larger predictive effects than psychological challenge. Moderator analyses revealed that recovery measured at 1 minute postexercise, passive recovery, use of mortality as an outcome measure, and older sample age were associated with larger effects. CONCLUSIONS: Poor recovery from laboratory challenges predicts adverse CV outcomes, with recovery from exercise serving as a particularly strong predictor of CV outcomes. The overall effect size for recovery and CV outcomes is similar to that observed for CV reactivity and suggests that the study of recovery may have incremental value for understanding adverse CV outcomes. PMID- 25829238 TI - The association between depressive disorder and cardiac autonomic control in adults 60 years and older. AB - BACKGROUND: Altered cardiac autonomic control has often been reported in depressed persons and might play an important role in the increased risk for cardiovascular disease (CVD). A negative association between cardiac autonomic control and depression might become specifically clinically relevant in persons 60 years or older as CVD risk increases with age. METHODS: This study included data of 321 persons with a depressive disorder and 115 controls participating in the Netherlands Study of Depression in Older Persons (mean age = 70.3 years, 65.7% female). Respiratory sinus arrhythmia (RSA), heart rate (HR), and preejection period (PEP) were measured and compared between depressed persons and controls. In addition, the role of antidepressants and clinical characteristics (e.g., age of depression onset and comorbid anxiety) was examined. RESULTS: Compared with controls, depressed persons had lower RSA (mean [standard error of the mean] = 23.5 [1.2] milliseconds versus 18.6 [0.7] milliseconds, p = .001, d = 0.373) and marginally higher HR (73.1 [1.1] beats/min versus 75.6 [0.6] beats/min, p = .065, d = 0.212), but comparable PEP (113.9 [2.1] milliseconds versus 112.0 [1.2] milliseconds, p = .45, d = 0.087), fully adjusted. Antidepressants strongly attenuated the associations between depression and HR and RSA. Antidepressant-naive depressed persons had similar HR and RSA to controls, whereas users of antidepressants showed significantly lower RSA. In addition, tricyclic antidepressant users had higher HR (p < .001, d = 0.768) and shorter PEP (p = .014, d = 0.395) than did controls. CONCLUSIONS: Depression was not associated with cardiac autonomic control, but antidepressants were in this sample. All antidepressants were associated with low cardiac parasympathetic control and specifically tricyclic antidepressants with high cardiac sympathetic control. PMID- 25829237 TI - Socioeconomic status, daily affective and social experiences, and inflammation during adolescence. AB - OBJECTIVE: To assess the relation between socioeconomic status (SES) and inflammation during adolescence and determine whether daily affective and social experiences across a 15-day period mediate this relation. METHODS: Adolescents (n = 316) completed daily diary reports of positive affect, negative affect, and negative social interactions for 15 days and provided whole blood spot samples for the assessment of C-reactive protein (CRP). Parents provided information on SES, including the highest level of education they and their spouses completed and household income. RESULTS: Lower parent education was associated with higher levels of adolescent CRP, controlling for age, sex, ethnicity, and body mass index (beta = -.12, p = .031). Mean daily positive affect, negative affect, and negative social interactions were examined as potential mediators of this association. In these models, parent education was no longer associated with adolescent CRP (beta = -.09, p = .12), and only positive affect was related to CRP (beta = -.12, p = .025). Bootstrapping confirmed the mediating role of positive affect (indirect effect = -0.015, 95% confidence interval = -0.038 to 0.002). CONCLUSIONS: Adolescents with less educated parents tended to have higher levels of CRP, which may be explained by their lower levels of positive affect. Findings suggest that a lack of positive affect may be a pathway by which SES confers early risk for poor health in adulthood. It is possible that adolescents who display positive affect during daily life in circumstances of relatively adverse socioeconomic circumstances may have better health outcomes related to lower inflammatory factors. PMID- 25829239 TI - Effects of long-term sertraline treatment and depression on coronary artery atherosclerosis in premenopausal female primates. AB - OBJECTIVES: Major depressive disorder and coronary heart disease often co-occur in the same individuals. Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for depression and other disorders, but their effects on coronary heart disease risk remain unclear. We determined the effects of an SSRI on coronary artery atherosclerosis (CAA) in an established nonhuman primate model used to clarify the association between depression and CAA. METHODS: Forty-two adult female cynomolgus macaques consuming a Western diet were characterized during an 18-month pretreatment phase and assigned to SSRI (sertraline hydrochloride 20 mg/kg, per os, once a day) or placebo balanced on pretreatment depression, body weight (BW), and iliac artery atherosclerosis extent measured via biopsy. After 18 months, CAA extent was measured using histomorphometry. RESULTS: Before and during treatment, depressed monkeys had lower BW, body mass index, and plasma high-density lipoprotein cholesterol, and higher heart rates during the pretreatment (p < .01) but not the treatment phase (p = .17). There were no pretreatment differences between the sertraline and placebo groups. Sertraline reduced anxious behavior but had no effect on BW, body mass index, heart rate, plasma lipids, or depression. CAA, analyzed by a 2 (depressed, nondepressed) * 2 (placebo, sertraline) * 3 (coronary arteries) analysis of covariance adjusted for pretreatment iliac atherosclerosis, was greater in depressed than in nondepressed monkeys (p < .036), and in sertraline than in placebo-treated monkeys (p = .040). The observed CAA extent in depressed monkeys treated with sertraline was 4.9 times higher than that in untreated depressed monkeys, and 6.5 times higher than that in nondepressed monkeys, on average. CONCLUSIONS: Depressed animals developed more CAA, and long-term treatment with sertraline resulted in more extensive CAA. PMID- 25829241 TI - Can exaggerated stress reactivity and prolonged recovery predict negative health outcomes? The case of cardiovascular disease. AB - Researchers and laypersons have long argued that stress is bad for health, particularly when responses are large, prolonged, and frequent. By extension, individuals who have the largest and the most prolonged responses are assumed to have worse outcomes than do less reactive persons. Research in animals has been supportive of the connection between stress and poor health, but evidence in humans has been slow to accumulate. The current issue of Psychosomatic Medicine presents a meta-analysis of 33 studies of delayed recovery from stress and its association with poor cardiovascular disease outcomes and all-cause mortality. The analysis supports the contention that slower recovery to baseline after exercise or psychological stress may predict earlier death due to all causes. This finding raises questions for psychosomatic theories of disease and points the direction for further study of how or whether to incorporate reactivity measures into standard risk profiles. PMID- 25829240 TI - Divorce and health: current trends and future directions. AB - OBJECTIVE: Social relationships play a vital role in health and well-being, and it follows that loss experiences can be highly stressful for some people. This article reviews what is known about the association between marital separation, divorce, and health outcomes. METHODS: Key findings in the area of divorce and health are discussed, and the review outlines a series of specific questions for future research. In particular, the article integrates research in social epidemiology with research in social psychophysiology. The former approach provides a broad-based estimate of the association between marital status and health outcomes, whereas the latter approach studies mechanisms of action and individual differences associated with increased risk for poor outcomes. RESULTS: The experience of separation or divorce confers risk for poor health outcomes, including a 23% higher mortality rate. However, most people cope well and are resilient after their marriage or long-term relationship ends. Despite the fact that resilience is the most common response, a small percentage of people (approximately 10%-15%) struggle quite substantially, and it seems that the overall elevated adverse health risks are driven by the poor functioning of this group. Several candidate mechanisms and novel (ambulatory) assessment techniques that may elucidate the poor outcomes among people who adapt poorly to separation are discussed. CONCLUSIONS: To increase knowledge on the association between divorce and health, three primary areas require more research: a) genetic and third variable explanations for divorce-related health outcomes, (b) better studies of objective social behavior after separation, and (c) increased attention to interventions targeting high-risk adults. PMID- 25829243 TI - Characterization of colostrum from dams of BLV endemic dairy herds. AB - Bovine Leukemia Virus (BLV) is endemic in Argentina, where the individual prevalence is higher than 80% in dairy farms. The aim of this work was to find preliminary evidence to know if the high level of infection of the dam would implicate a higher challenge to her own offspring. We collected 65 sets of samples consisting of dam's blood and colostrum from two heavily infected dairy farms, and investigated the correlation between the dam's blood proviral load and the presence of provirus in colostrum. We also described the dual antibody/provirus profile in the colostrum. Provirus was detected in 69.23% of the colostrum samples, mostly from dams with a high proviral load, 36/45 (80%). Colostrum proviral load was significantly higher in dams with high blood proviral load (p<0.0001). Provirus was detected in colostrum samples all along the antibody distribution, even in those with a low amount of antibodies. These results show that even when high blood proviral load dams offer higher levels of infected cells to their offspring through colostrum they also offer higher levels of protection of antibodies. On the contrary, low blood proviral load dams also offer infected cells but a poor content of antibodies, suggesting that these animals could play an important role in the epidemiological cycle of transmission. PMID- 25829242 TI - Mutant Rep protein of the porcine circovirus type 2 N-glycosylation:23-25aa, 256 258aa mutation reduced virus replication but 286-288aa mutation enhanced virus replication in PK-15 cells. AB - Porcine circovirus type 2 (PCV2) Rep protein and the splice variant Rep' protein impact genome replication. The Rep protein contains three potential N glycosylation at positions 23-25aa (NPS), 256-258aa (NQT) and 286-288aa (NAT). Three double copy infectious clones with Rep protein N-glycosylation at positions mutations 23-25aa (DPS), 256-258aa (DQT) and 286-288aa (DAT) were constructed and their function in virus replication in PK-15 cells was investigated. The results showed that the double copy infectious clone with N-glycosylation site mutation could be rescued in vitro and 23-25aa, 256-258aa mutation reduced virus replication but 286-288aa mutation enhanced virus replication. PMID- 25829244 TI - Decidual expression and localization of human surfactant protein SP-A and SP-D, and complement protein C1q. AB - Surfactant proteins SP-A and SP-D, and complement protein C1q are soluble innate immune pattern recognizing molecules. SP-A, SP-D and C1q have an overall similar structure composed of an N-terminal triple-helical collagen region that is followed by a trimeric globular domain. While SP-A and SP-D belong to the collectin family (collagen containing lectin), C1q is the first recognition subcomponent of the classical pathway of the complement system. Recently, SP-A, SP-D and C1q have been considered to play important roles in early and late pregnancy. However, their expression in early human decidua has not been examined. Here, we investigated whether SP-A, SP-D and C1q are expressed within first trimester decidua in humans and their expression is associated with trophoblasts and decidual stromal cells. Decidual samples from women undergoing elective vaginal termination of pregnancy during first trimester were obtained from 25 subjects. Immunohistochemical studies using anti-human SP-A, anti-human SP-D and anti-human C1q antibodies were performed on decidual tissue sections along with anti-vimentin and cytokeratin-7 antibodies to identify stromal cells and trophoblasts. The expression was also examined by immunostaining and PCR using decidual and stromal cells. C1q expression was significantly higher when compared to SP-A and SP-D in the first trimester human decidua. Double immunostaining revealed that all stromal cells and trophoblasts expressed SP-A, SP-D and C1q, while only few invasive trophoblasts expressed C1q. Thus, expression of SP-A, SP-D and C1q in human decidua during first trimester suggests potential role of SP-A, SP-D and C1q during the early stages of pregnancy including implantation, trophoblast invasion and placental development. PMID- 25829245 TI - Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages. AB - Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-gamma and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy. PMID- 25829247 TI - Design and synthesis of analogues of natural products. AB - In this article strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples. Proven strategies include diverted total synthesis (DTS), function-oriented synthesis (FOS), biology-oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis. The latter includes mutasynthesis, the synthesis of natural products encoded by silent genes, and propionate scanning. Most of the examples from our group fall in the quite general concept of DTS. Thus, in case an efficient strategy to a natural product is at hand, modifications are possible at almost any stage of a synthesis. However, even for compounds of moderate complexity, organic synthesis remains a bottle neck. Unless some method for predicting the biological activity of a designed molecule becomes available, the design and synthesis of natural product analogues will remain what it is now, namely it will largely rely on trial and error. PMID- 25829248 TI - Comparisons of hospitalization rates among younger atrial fibrillation patients receiving different antiarrhythmic drugs. AB - BACKGROUND: Antiarrhythmic drugs (AADs) are used to reduce the frequency, severity, and duration of atrial fibrillation (AF) events, which should reduce hospitalizations; however, little is known about the associations between different AADs and hospitalization-particularly among younger AF patients without structural heart disease. METHODS AND RESULTS: Using MarketScan(r) claims data, we identified AF patients without coronary artery disease or heart failure who received their first AAD prescription (amiodarone, sotalol, dronedarone, or Class Ic) within 14 days post-first AF encounter. The primary outcome was time from first AAD prescription to AF hospitalization, and secondary outcomes included time to cardiovascular and all-cause hospitalizations. We used inverse probability-weighted estimators to adjust for differences in treatment allocation in the Cox proportional hazards model for each outcome. Among 8562 AF patients with a median age of 56 years (interquartile range 49, 61), risk of AF hospitalization was greater with dronedarone than Class Ic (hazard ratio [HR] 1.59; 95% confidence interval 1.13-2.24), amiodarone (HR 2.63; 1.77-3.89), and sotalol (HR 1.72; 1.17-2.54), but lower with amiodarone versus Class Ic (HR 0.68; 0.57-0.80) and sotalol (HR 0.63; 0.53-0.75). Risk of cardiovascular hospitalization was lower with amiodarone than Class Ic (HR 0.80; 0.70-0.92), but not non-AF cardiovascular hospitalization (HR 1.26; 1.01-1.57). There was no difference in all-cause hospitalization between amiodarone, Class Ic, and sotalol. CONCLUSIONS: Differences in hospitalization rates were found between AADs in younger AF patients without structural heart disease. Amiodarone had the lowest risk of AF hospitalization and dronedarone had the greatest risk. Additional research is needed to better understand associations between AADs and hospitalization risk. PMID- 25829246 TI - Face processing in autism spectrum disorders: From brain regions to brain networks. AB - Autism spectrum disorder (ASD) is characterized by reduced attention to social stimuli including the human face. This hypo-responsiveness to stimuli that are engaging to typically developing individuals may result from dysfunctioning motivation, reward, and attention systems in the brain. Here we review an emerging neuroimaging literature that emphasizes a shift from focusing on hypo activation of isolated brain regions such as the fusiform gyrus, amygdala, and superior temporal sulcus in ASD to a more holistic approach to understanding face perception as a process supported by distributed cortical and subcortical brain networks. We summarize evidence for atypical activation patterns within brain networks that may contribute to social deficits characteristic of the disorder. We conclude by pointing to gaps in the literature and future directions that will continue to shed light on aspects of face processing in autism that are still under-examined. In particular, we highlight the need for more developmental studies and studies examining ecologically valid and naturalistic social stimuli. PMID- 25829249 TI - Effect of super short pulse Er:YAG laser on human dentin--Scanning electron microscopy analysis. AB - This study evaluated the effect of different pulse widths in the morphological characteristics of human dentin irradiated with Er:YAG in cavity preparation protocols and dentin pretreatment. Dentin discs with 2 mm thickness were obtained from 18 human molars. The experimental groups were composed from two variables: (1) clinical protocol-cavity preparation (E = 200 mJ/20 Hz)-and pretreatment (E = 80 mJ/2 Hz); and (2) pulse duration-50, 300, and 600 MUs. This formed six experimental groups (n = 3): G1 (E = 200 mJ/20 Hz/50 MUs); G2 (E = 200 mJ/20 Hz/300 MUs); G3 (E = 200 mJ/20 Hz/600 MUs); G4 (E = 80 mJ/2 Hz/50 MUs); G5 (E = 80 mJ/2 Hz/300 MUs); G6 (E = 80 mJ/2 Hz/600 MUs). The samples were irradiated with the Er:YAG laser by noncontact mode at a focal distance of 7 mm from the target point under continuous water spray (60% water and 40% air). After the irradiation, they were processed for scanning electron microscopy (SEM). Morphological analysis showed an irregular dentin surface, absence of smear layer with opening of the exposure of dentinal tubules and protruding peritubular dentin-without indications of changes for all protocols used. Regardless of the analyzed experimental group, the dentin surface showed a microretentive morphology characteristic of ablation. The G1 and G4 showed a rougher surface when compared to other groups. Finally, we concluded that the pulse width can influence the morphological characteristics of the irradiated dentin tested in different clinical indications. The larger surface irregularity caused by regulation with less pulse width (50 us) seems more appropriate to get a microretentive pattern necessary for successful adhesives restoration procedures. PMID- 25829251 TI - MiR-101 reverses the hypomethylation of the LMO3 promoter in glioma cells. AB - LIM-only protein 3 (LMO3), a member of the LIM-only protein group, is a new DNA methylation gene that was identified in gliomas via the MeDIP-Chip in our previous study. In this study, we found that LIM-only protein 3 (LMO3) is hypomethylated and overexpressed in glioma cells and tissues. The overexpression of LMO3 was correlated with a poor prognosis in glioma patients, and LMO3 was indirectly inhibited by the tumor suppressor miR-101, which is a potential prognosis marker of gliomas. MiR-101 decreased the expression of LMO3 by reversing the methylation status of the LMO3 promoter and by inhibiting the presence of the methylation-related histones H3K4me2 and H3K27me3 and increasing the presence of H3K9me3 and H4K20me3 on the promoter. It was determined that miR 101 decreases the occupancy of H3K27me3 by inhibiting EZH2, DNMT3A and EED and decreases the H3K9me3 occupancy on the LMO3 promoter via SUV39H1, SUV39H2, G9a and PHF8. Furthermore, miR-101 suppresses the expression of LMO3 by decreasing USF and MZF1. PMID- 25829252 TI - CD133 initiates tumors, induces epithelial-mesenchymal transition and increases metastasis in pancreatic cancer. AB - CD133 has been implicated as a cancer stem cell (CSC) surface marker in several malignancies including pancreatic cancer. However, the functional role of this surface glycoprotein in the cancer stem cell remains elusive. In this study, we determined that CD133 overexpression induced "stemness" properties in MIA-PaCa2 cells along with increased tumorigenicity, tumor progression, and metastasis in vivo. Additionally, CD133 expression induced epithelial-mesenchymal transition (EMT) and increased in vitro invasion. EMT induction and increased invasiveness were mediated by NF-kappaB activation, as inhibition of NF-kappaB mitigated these effects. This study showed that CD133 expression contributes to pancreatic cancer "stemness," tumorigenicity, EMT induction, invasion, and metastasis. PMID- 25829253 TI - Response to Denosumab Treatment for 2 Years in an Adolescent With Osteoradionecrosis. AB - Radiotherapy, an essential component of cancer treatment, is not without risk to bone, particularly to the immature or growing skeleton. Known side effects range from post-radiation osteitis to osteoradionecrosis. We report the case of a 14 year-old male patient undergoing denosumab treatment, a new antiresorptive agent, for osteoradionecrosis. The patient exhibited fractures and associated pain and functional limitations secondary to radiation for the treatment of an embryonal rhabdomyosarcoma of prostate grade III administered at age 5 years. After treatment with denosumab, the pain disappeared, bone remodeling markers dramatically declined, bone mass increased, and pathological bone scan findings resolved without adverse effects or new fractures. PMID- 25829255 TI - Challenges in developing a cross-serotype rhinovirus vaccine. AB - A great burden of disease is attributable to human rhinovirus (HRV) infections which are the major cause of the common cold, exacerbations of both asthma and chronic obstructive pulmonary disease (COPD), and are associated with asthma development. Despite this there is currently no vaccine for HRV. The first vaccine studies showed some promise in terms of serotype-specific protection against cold symptoms, but antigenic heterogeneity amongst the >150 HRVs has been regarded as a major barrier to effective vaccine development and has resulted in little progress over 50 years. Here we review those vaccine studies conducted to date, discuss the difficulties posed by antigenic heterogeneity and describe some recent advances in generating cross-reactive antibodies and T cell responses using peptide immunogens. PMID- 25829254 TI - Affinity selection of epitope-based vaccines using a bacteriophage virus-like particle platform. AB - Display of epitopes on virus-like particles (VLPs) is a highly effective technique for enhancing the immunogenicity of antigens that are poorly immunogenic in their native context. VLP-based vaccines can be used to elicit long-lasting, high-titer antibody responses against diverse target antigens, even self-antigens. Most VLP platform-based vaccines are rationally engineered; specific target epitopes or domains are arrayed so that they are displayed at high-valency on the surface of VLPs. In this review, we describe an alternate technique for vaccine discovery using VLPs. This strategy, analogous to filamentous phage display, allows bacteriophage VLP-based vaccines to be identified from a vast library of potential vaccines by affinity selection. This technology integrates epitope discovery and immunization functions into a single platform. PMID- 25829256 TI - Lessons from Reverse Vaccinology for viral vaccine design. AB - Although almost 15 years have passed since the birthdate of Reverse Vaccinology (RV), there are very limited applications of this approach to viral vaccines discovery. Undeniably, RV presents a series of advantages as it can virtually identify all potential antigens coded by a genome, irrespective of their abundance, phase of expression and immunogenicity. Additionally, it can be applied to all pathogens, including those that cannot be grown in vitro. In this review we summarize the few examples of RV application to viruses, in particular the Herpesviridae, and report the advantage and limitations of this approach. Next we focus on the novel approaches and additional technologies to vaccine development including structure based approach (Structural Vaccinology [SV]), synthetic biology and some examples of their application in the development of viral vaccines. PMID- 25829258 TI - Do microsporidia function as "biological weapon" for Harmonia axyridis under natural conditions? AB - Invasive alien species, such as the multicoloured Asian ladybird Harmonia axyridis, are often regarded as major drivers of biodiversity loss. Therefore understanding which characteristics or mechanisms contribute to their invasive success is important. Here the role of symbiotic microsporidia in the hemolymph of H. axyridis was investigated in the context of intraguild predation between wild-caught H. axyridis and the native ladybird species Coccinella septempunctata. The microsporidia were recently discussed to contribute to the unpalatability of Harmonia for other coccinellids during intraguild predation and to function as "biological weapons". In the present study, visual detection of microsporidia in hemolymph samples revealed that 73.5% of H. axyridis were infected. Intraguild predation experiments between larvae of the two species showed a significant competitive advantage for H. axyridis, even against larger larvae of C. septempunctata. Adult C. septempunctata always killed and fed on H. axyridis larvae. However only 11.4% (4 of 47) of C. septempunctata that fed on infected H. axyridis died within 4 months. In contrast to previous studies this suggests that microsporidia or harmonine, the chemical defense compound of H. axyridis, do not lead to death of C. septempunctata preying on larvae of H. axyridis. Instead our results support the idea that competitive advantage during intraguild predation greatly facilitates the success of H. axyridis and that this may help this highly invasive species to outcompete native species. The impact of microsporidia on Harmonia itself as well as on interspecific interactions require further studies. PMID- 25829257 TI - Association of AluYb8 insertion/deletion polymorphism in the MUTYH gene with mtDNA maintain in the type 2 diabetes mellitus patients. AB - A common AluYb8-element insertion/deletion polymorphism of the MUTYH gene (AluYb8MUTYH) is a novel genetic risk factor for type 2 diabetes mellitus (T2DM). In the present study, mtDNA sequencing analysis indicated that the mtDNA sequence heteroplasmy was not associated with AluYb8MUTYH polymorphism. To better understand the genetic risk for T2DM, we investigated the association of this polymorphism with mtDNA content, mtDNA breakage and mtDNA transcription in the leukocytes of T2DM patients. The mtDNA content and unbroken mtDNA were significantly increased in the mutant patients than in the wild-type patients (P <0.05, respectively). However, no association between mtDNA transcription and AluYb8MUTYH variant was observed. The results suggested that the AluYb8MUTYH variant was associated with an altered mtDNA maintain in T2DM patients. The high level of mtDNA content observed in the mutant patients may have resulted from inefficient base excision repair of mitochondrial MUTYH and a compensatory mechanism that is triggered by elevated oxidative stress. PMID- 25829250 TI - Insights into the key roles of proteoglycans in breast cancer biology and translational medicine. AB - Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer. PMID- 25829259 TI - Affordable and rapid HPTLC method for the simultaneous analysis of artemisinin and its metabolite artemisinic acid in Artemisia annua L. AB - Artemisinin (AN) and artemisinic acid (AA), valuable phyto-pharmaceutical molecules, are well known anti-malarials, but their activities against diseases like cancer, schistosomiasis, HIV, hepatitis-B and leishmaniasis are also being reported. For the simultaneous estimation of AN and AA in the callus and leaf extracts of A. annua L. plants, we embarked upon a simple, rapid, selective, reliable and fairly economical high performance thin layer chromatography (HPTLC) method. Experimental conditions such as band size, chamber saturation time, migration of solvent front and slit width were critically studied and the optimum conditions were selected. The separations were achieved using toluene-ethyl acetate, 9:1 (v/v) as mobile phase on pre-coated silica gel plates, G 60F254 . Good resolution was achieved with Rf values of 0.35 +/- 0.02 and 0.26 +/- 0.02 at 536 nm for AN and 626 nm for AA, respectively, in absorption-reflectance mode. The method displayed a linear relationship with r(2) value 0.992 and 0.994 for AN and AA, respectively, in the concentration range of 300-1500 ng for AN and 200 1000 ng for AA. The method was validated for specificity by obtaining in-situ UV overlay spectra and sensitivity by estimating limit of detection (30 ng for AN and 15 ng for AA) and limit of quantitation (80 ng for AN and 45 ng for AA) values. The accuracy was checked by the recovery studies conducted at three different levels with the known concentrations and the average percentage recovery was 101.99% for AN and 103.84% for AA. The precision was analyzed by interday and intraday precision and was 1.09 and 1.00% RSD for AN and 1.22 and 6.05% RSD for AA. The analysis of statistical data substantiates that this HPTLC method can be used for the simultaneous estimation of AN and AA in biological samples. PMID- 25829260 TI - Global role of the membrane protease LonB in Archaea: Potential protease targets revealed by quantitative proteome analysis of a lonB mutant in Haloferax volcanii. AB - The membrane-associated LonB protease is essential for viability in Haloferax volcanii, however, the cellular processes affected by this protease in archaea are unknown. In this study, the impact of a lon conditional mutation (down regulation) on H. volcanii physiology was examined by comparing proteomes of parental and mutant cells using shotgun proteomics. A total of 1778 proteins were identified (44% of H. volcanii predicted proteome) and 142 changed significantly in amount (>=2 fold). Of these, 66 were augmented in response to Lon deficiency suggesting they could be Lon substrates. The "Lon subproteome" included soluble and predicted membrane proteins expected to participate in diverse cellular processes. The dramatic stabilization of phytoene synthase (57 fold) in concert with overpigmentation of lon mutant cells suggests that Lon controls carotenogenesis in H. volcanii. Several hypothetical proteins, which may reveal novel functions and/or be involved in adaptation to extreme environments, were notably increased (300 fold). This study, which represents the first proteome examination of a Lon deficient archaeal cell, shows that Lon has a strong impact on H. volcanii physiology evidencing the cellular processes controlled by this protease in Archaea. Additionally, this work provides a platform for the discovery of novel targets of Lon proteases. BIOLOGICAL SIGNIFICANCE: The proteome of a Lon-deficient archaeal cell was examined for the first time showing that Lon has a strong impact on H. volcanii physiology and evidencing the proteins and cellular processes controlled by this protease in Archaea. This work will facilitate future investigations aiming to address Lon function in archaea and provides a platform for the discovery of endogenous targets of the archaeal type Lon as well as novel targets/processes regulated by Lon proteases. This knowledge will advance the understanding on archaeal physiology and the biological function of membrane proteases in microorganisms. PMID- 25829261 TI - Analysis of the molecular response of Pseudomonas putida KT2440 to the next generation biofuel n-butanol. AB - To increase the efficiency of biocatalysts a thorough understanding of the molecular response of the biocatalyst to precursors, products and environmental conditions applied in bioconversions is essential. Here we performed a comprehensive proteome and phospholipid analysis to characterize the molecular response of the potential biocatalyst Pseudomonas putida KT2440 to the next generation biofuel n-butanol. Using complementary quantitative proteomics approaches we were able to identify and quantify 1467 proteins, corresponding to 28% of the total KT2440 proteome. 256 proteins were altered in abundance in response to n-butanol. The proteome response entailed an increased abundance of enzymes involved in n-butanol degradation including quinoprotein alcohol dehydrogenases, aldehyde dehydrogenases and enzymes of fatty acid beta oxidation. From these results we were able to construct a pathway for the metabolism of n butanol in P. putida. The initial oxidation of n-butanol is catalyzed by at least two quinoprotein ethanol dehydrogenases (PedE and PedH). Growth of mutants lacking PedE and PedH on n-butanol was significantly impaired, but not completely inhibited, suggesting that additional alcohol dehydrogenases can at least partially complement their function in KT2440. Furthermore, phospholipid profiling revealed a significantly increased abundance of lyso-phospholipids in response to n-butanol, indicating a rearrangement of the lipid bilayer. BIOLOGICAL SIGNIFICANCE: n-butanol is an important bulk chemical and a promising alternative to gasoline as a transportation fuel. Due to environmental concerns as well as increasing energy prices there is a growing interest in sustainable and cost-effective biotechnological production processes for the production of bulk chemicals and transportation fuels from renewable resources. n-butanol fermentation is well established in Clostridiae, but the efficiency of n-butanol production is mainly limited by its toxicity. Therefore bacterial strains with higher intrinsic tolerance to n-butanol have to be selected as hosts for n butanol production. Pseudomonas bacteria are metabolically very versatile and exhibit a high intrinsic tolerance to organic solvents making them suitable candidates for bioconversion processes. A prerequisite for a potential production of n-butanol in Pseudomonas bacteria is a thorough understanding of the molecular adaption processes caused by n-butanol and the identification of enzymes involved in n-butanol metabolization. This work describes the impact of n-butanol on the proteome and the phospholipid composition of the reference strain P. putida KT2440. The high proteome coverage of our proteomics survey allowed us to reconstruct the degradation pathway of n-butanol and to monitor the changes in the energy metabolism of KT2440 induced by n-butanol. Key enzymes involved in n butanol degradation identified in study will be interesting targets for optimization of n-butanol production in Pseudomonads. The present work and the identification of key enzymes involved in butanol metabolism may serve as a fundament to develop new or improve existing strategies for the biotechnological production of the next-generation biofuel n-butanol in Pseudomonads. PMID- 25829262 TI - Proteomics profiling of ethylene-induced tomato flower pedicel abscission. AB - The control of abscission is an important agricultural concern because of its substantial effect on crop yield and quality. Changes in gene expression are correlated with the ethylene-mediated execution of abscission. However, only few large-scale proteomic studies focused on tomato pedicel abscission. Isobaric tag for relative and absolute quantification labeling was used to examine the protein and phosphoprotein changes in the tomato pedicel AZ (AZ) treated with ethylene or 1-methylcyclopropene. Among the 1429 quantified proteins, 383 unique peptides corresponding to 166 proteins showed higher than 1.5-fold change in abundance. A total of 450 phosphopeptides were detected, among which 85 phosphopeptides corresponding to 73 phosphoproteins were significantly regulated (>1.5-fold abundance change) in response to ethylene. Protein and phosphoprotein sets showed 26 similar proteins. Six phosphorylation motifs were extracted from the 138 phosphorylation sites. By analyzing translational and modification levels, we found that the modification level was not due to the translational changes. Comparison between the protein and phosphoprotein functions revealed that the proteins acted mainly in the metabolic process and showed catalytic activity, whereas most of the phosphoproteins showed signaling and transporting activities. Data revealed the unique features of the AZ phosphoproteomics, thereby suggesting the involvement of a complex network of kinase-substrate and phosphatase substrate interactions in response to ethylene. Some phosphorylation sites from calcium-dependent protein kinase (CDPK5(S523)), CDPK5(S527), and SRL3(S329) were also found to perform protective functions for AZ and to be helpful in ethylene signal transduction. BIOLOGICAL SIGNIFICANCE: Organ abscission has both positive and negative roles. Abscission is conducive for the fall of ripe fruits and the release and dispersion of seeds, but abscission has been a major limiting factor for crop productivity. Hence, more details about the process may aid in the regulation of organ abscission. However, at present, the detailed mechanism of abscission is still unclear. In tomato, several transcriptome analyses were performed using pedicels as materials. Yet, no large-scale proteomics and phosphoproteomic studies of abscission zone have been reported so far. Hence, in this present study, we determined the ethylene-induced changes in the proteomics and phosphoproteomics of tomato flower AZ tissue using the isobaric tag for relative and absolute quantification (iTRAQ). Proteomics data from both data sets revealed the differentially expressed proteins that are associated with the translational and modification levels relevant to abscission mechanism. Two key proteins (CDPK (CDPK5(S523) and CDPK5(S527)) and SRL3(S329)) among ethylene signal transduction and defense-related proteins were obtained from the phosphoproteins. The set of tomato phosphorylation sites presented in this work is useful in at least two ways. First, as a database resource, the data would facilitate research on the identified phosphoproteins. Second, the identified sites of the related proteins could provide enough knowledge for further experiments. Hence, our results contribute to the understanding of the mechanism of abscission in plants. PMID- 25829263 TI - New educational approach for patients on warfarin improves knowledge and therapy control. AB - BACKGROUND: Patient education is essential for a safe and efficient oral anticoagulant treatment. We examined if a newly launched booklet with information on anticoagulant treatment with warfarin improved patient knowledge and the time spent in the therapeutic-range (TTR). METHODS: Standardized questionnaire was administered to 235 consecutive patients on warfarin to assess their baseline knowledge and readministered it 2 months after they received the booklet. A control group of 51 patients was interviewed only after the booklet had been distributed. RESULTS: Patient's knowledge at the baseline was unsatisfying (mean questionnaire score: 11/16) and a substantial progress was achieved after the educational intervention (mean questionnaire score: 13/16, p = 0.001). TTR is significantly increased after the intervention (63.4 +/- 22.3 vs. 74.6 +/- 23.8 %; p < 0.01). The mean questionnaire score and TTR after education were not different in the intervention and the control group. CONCLUSIONS: Knowledge about oral anticoagulant treatment and TTR is increased after the issue of the booklet in the majority of patients. However, for a small group of patients with unimproved knowledge new forms of education are needed. PMID- 25829264 TI - Serotypes and genotypes of invasive pneumococci in the central part of Slovenia. AB - To investigate epidemiology of invasive pneumococcal disease (IPD) in the central part of Slovenia in a population with no routine pneumococcal vaccination, we carried out serotyping of isolates by sequential multiplex polymerase chain reaction (PCR) and genotyping by repetitive sequence-based PCR (rep-PCR) and some by multilocus sequence typing. IPD was confirmed in 134 (26.5 %) of 510 acutely ill patients, either by a positive blood culture or real-time PCR (rt-PCR). In 94 patients, isolates were available for typing (24 from blood and 70 from nasopharynx). They belonged to 12 different serotypes; the most prevalent were 14 (27.6 % isolates), 9V, 3 (12.7 % each), 7F (9.5 %), 19A, and 1 (7.4 % each) followed by 4, 6A/B, 19F, 23F, 18C, and 33F. Genotyping yielded 34 rep-PCR genotypes and 13 subtypes; six were found in serotype 14, one in 9V, four each in 3, 19A, and 6A/B, three each in 7F and 1, and two each in 4, 19F, 23F, and 18C. Serotype 9V was the most homogenous and 14 and 19A were heterogenous and had two divergent clonal groups each. The most common genotypes belonged to virulent widespread clones, like ST162, ST9, ST15, ST156, ST191, and ST1377; however, sporadic clones were also observed. PMID- 25829265 TI - Finding the balance between capture and control: Oculomotor selection in early deaf adults. AB - Previous work investigating the consequence of bilateral deafness on attentional selection suggests that experience-dependent changes in this population may result in increased automatic processing of stimulus-driven visual information (e.g., saliency). However, adaptive behavior also requires observers to prioritize goal-driven information relevant to the task at hand. In order to investigate whether auditory deprivation alters the balance between these two components of attentional selection, we assessed the time-course of overt visual selection in deaf adults. Twenty early-deaf adults and twenty hearing controls performed an oculomotor additional singleton paradigm. Participants made a speeded eye-movement to a unique orientation target, embedded among homogenous non-targets and one additional unique orientation distractor that was more, equally or less salient than the target. Saliency was manipulated through color. For deaf participants proficiency in sign language was assessed. Overall, results showed that fast initiated saccades were saliency-driven, whereas later initiated saccades were goal-driven. However, deaf participants were overall slower than hearing controls at initiating saccades and also less captured by task-irrelevant salient distractors. The delayed oculomotor behavior of deaf adults was not explained by any of the linguistic measures acquired. Importantly, a multinomial model applied to the data revealed a comparable evolution over time of the underlying saliency- and goal-driven processes between the two groups, confirming the crucial role of saccadic latencies in determining the outcome of visual selection performance. The present findings indicate that prioritization of saliency-driven information is not an unavoidable phenomenon in deafness. Possible neural correlates of the documented behavioral effect are also discussed. PMID- 25829266 TI - The European Medicines Agency's strategies to meet the challenges of Alzheimer disease. AB - Regulatory agencies have a key role in facilitating the development of new drugs for Alzheimer disease, particularly given the challenges associated with early intervention. Here, we highlight the strategies of the European Medicines Agency to help address such challenges. PMID- 25829267 TI - The Roadmap Epigenomics Project opens new drug development avenues. PMID- 25829268 TI - HDAC inhibitors still need a home run, despite recent approval. PMID- 25829272 TI - Trial watch: Multikinase-targeting therapy finds potential niche in thyroid cancer. PMID- 25829273 TI - The breast cancer market. PMID- 25829274 TI - Anticancer drugs: On-site CAR parking. PMID- 25829275 TI - Muscular dystrophy: New exon-skipping strategy rescues dystrophin. PMID- 25829276 TI - Cancer: An epigenetic target for synthetic lethality. PMID- 25829277 TI - Inflammatory diseases: Starving inflammation. PMID- 25829282 TI - Parasite infection: Parasite-targeting compound sets identified and ready to go. PMID- 25829284 TI - Kinases: a remote control in inflammasome activity. PMID- 25829283 TI - Mitigating risk in academic preclinical drug discovery. AB - The number of academic drug discovery centres has grown considerably in recent years, providing new opportunities to couple the curiosity-driven research culture in academia with rigorous preclinical drug discovery practices used in industry. To fully realize the potential of these opportunities, it is important that academic researchers understand the risks inherent in preclinical drug discovery, and that translational research programmes are effectively organized and supported at an institutional level. In this article, we discuss strategies to mitigate risks in several key aspects of preclinical drug discovery at academic drug discovery centres, including organization, target selection, assay design, medicinal chemistry and preclinical pharmacology. PMID- 25829285 TI - SPR analysis of the interaction between a recombinant protein of unknown function in Leishmania infantum immobilised on dendrimers and antibodies of the visceral leishmaniasis: A potential use in immunodiagnosis. AB - In this work, an SPR immunosensor was developed to elucidate the reaction kinetics between a protein of unknown function in Leishmania infantum (hypothetical C1 protein) and specific antibodies of the visceral leishmaniasis (VL). A platform, which is based on layer-by-layer assembly was formed by cysteamine in combination with a fourth-generation poly(amidoamine) dendrimer (PAMAM(G4)) on gold surface for the immobilisation of the protein. This film resulted in amplification of the signal of SPR. Then, a kinetic model based on a bivalent ligation suggested that the reaction between the C1 protein and the anti C1 antibody occurs in two steps. The value of the equilibrium dissociation constant (KD1*KD2=1.64*10(-7) mol L(-1)) demonstrated high binding affinity between the biomolecules. Furthermore, low limits of detection (LOD=7.37 nmol L( 1)) and quantification (LOQ=7.83 nmol L(-1)) were presented with the proposed SPR immunosensor. Afterwards, the addition of real samples consisting of positive and negative canine sera for VL was accompanied by high sensitivity and selectivity by SPR immunosensor. Therefore, this study quantitatively demonstrated the strong antigenic character of a hypothetical protein and consequently its potential use in the immunodiagnosis of the VL. PMID- 25829287 TI - Consolidated Action Plan to Prevent and Combat Multidrug- and Extensively Drug resistant Tuberculosis in the WHO European Region 2011-2015: Cost-effectiveness analysis. AB - Drug-resistant tuberculosis (TB) has increased at an alarming rate in the WHO European Region. Of the 27 countries worldwide with a high burden of multidrug resistant-TB (MDR-TB), 15 are in the European Region. An estimated 78,000 new cases of MDR-TB occur annually in the Region, of which approximately 10% are extensively drug-resistant (XDR)-TB. In response, the WHO Regional Office for Europe developed a Consolidated Action Plan to Prevent and Combat Multidrug- and Extensively Drug-resistant Tuberculosis (2011-2015). Our objective was to analyse the cost-effectiveness of implementing the plan, with the expected achievements of diagnosing 85% of estimated MDR-TB cases and treating at least 75% successfully. A transmission model, using epidemiological data reported to WHO was developed to calculate expected achievements. WHO-CHOICE database was used for cost analyses. The highly cost-effective plan is expected to prevent the emergence of 250,000 new MDR-TB and 13,000 XDR-TB patients respectively, saving US$7 billion and 120,000 lives. The plan and accompanying Resolution were fully endorsed by the sixty-first session of the WHO Regional Committee for Europe in 2011. Member States need to continuously improve health system performance and address TB determinants. Research and development of new medicines, tools and patient-friendly services are also crucial. PMID- 25829286 TI - MadR1, a Mycobacterium tuberculosis cell cycle stress response protein that is a member of a widely conserved protein class of prokaryotic, eukaryotic and archeal origin. AB - Stress-induced molecular programs designed to stall division progression are nearly ubiquitous in bacteria, with one well-known example being the participation of the SulA septum inhibiting protein in the SOS DNA damage repair response. Mycobacteria similarly demonstrate stress-altered growth kinetics, however no such regulators have been found in these organisms. We therefore set out to identify SulA-like regulatory proteins in Mycobacterium tuberculosis. A bioinformatics modeling-based approach led to the identification of rv2216 as encoding for a protein with weak similarity to SulA, further analysis distinguished this protein as belonging to a group of uncharacterized growth promoting proteins. We have named the mycobacterial protein encoded by rv2216 morphology altering division regulator protein 1, MadR1. Overexpression of madR1 modulated cell length while maintaining growth kinetics similar to wild-type, and increased the proportion of bent or V-form cells in the population. The presence of MadR1-GFP at regions of cellular elongation (poles) and morphological differentiation (V-form) suggests MadR1 involvement in phenotypic heterogeneity and longitudinal cellular growth. Global transcriptional analysis indicated that MadR1 functionality is linked to lipid editing programs required for growth and persistence. This is the first report to differentiate the larger class of these conserved proteins from SulA proteins and characterizes MadR1 effects on the mycobacterial cell. PMID- 25829288 TI - Effect of variable soil texture, metal saturation of soil organic matter (SOM) and tree species composition on spatial distribution of SOM in forest soils in Poland. AB - In this study we investigated the effect of fine (phi<0.05mm) fraction, i.e., silt+clay (FF) content in soils, site moisture, metal (Al and Fe) of soil organic matter (SOM) and forest species composition on the spatial distribution of carbon (C) pools in forest soils at the landscape scale. We established 275 plots in regular 200*200m grid in a forested area of 14.4km(2). Fieldwork included soil sampling of the organic horizon, mineral topsoil and subsoil down to 40cm deep. We analysed the vertical and horizontal distribution of soil organic carbon (SOC) stocks, as well as the quantity of physically separated fractions including the free light (fLF), occluded light (oLF) and mineral associated fractions (MAF) in the mineral topsoil (A, AE) horizons. Distribution of C in soils was predominantly affected by the variation in the FF content. In soils richer in the FF more SOC was accumulated in mineral horizons and less in the organic horizons. Accumulation of SOC in mineral soil was also positively affected by the degree of saturation of SOM with Al and Fe. The increasing share of beech influenced the distribution of C stock in soil profiles by reducing the depth of O horizon and increasing C stored in mineral soil. The content of FF was positively correlated with the content of C in MAF and fLF fractions. The content of oLF and MAF fractions was also positively influenced by a higher degree of metal saturation, particularly Al. Our results confirmed that Al plays an important role in the stabilization of SOM inside aggregates (CoLF) and as in CMAF fractions. We also found a significant, positive effect of beech on the CfLF and fir on the CoLF content. PMID- 25829289 TI - Methodology to assess and map the potential development of forest ecosystems exposed to climate change and atmospheric nitrogen deposition: A pilot study in Germany. AB - A methodology for mapping ecosystems and their potential development under climate change and atmospheric nitrogen deposition was developed using examples from Germany. The methodology integrated data on vegetation, soil, climate change and atmospheric nitrogen deposition. These data were used to classify ecosystem types regarding six ecological functions and interrelated structures. Respective data covering 1961-1990 were used for reference. The assessment of functional and structural integrity relies on comparing a current or future state with an ecosystem type-specific reference. While current functions and structures of ecosystems were quantified by measurements, potential future developments were projected by geochemical soil modelling and data from a regional climate change model. The ecosystem types referenced the potential natural vegetation and were mapped using data on current tree species coverage and land use. In this manner, current ecosystem types were derived, which were related to data on elevation, soil texture, and climate for the years 1961-1990. These relations were quantified by Classification and Regression Trees, which were used to map the spatial patterns of ecosystem type clusters for 1961-1990. The climate data for these years were subsequently replaced by the results of a regional climate model for 1991-2010, 2011-2040, and 2041-2070. For each of these periods, one map of ecosystem type clusters was produced and evaluated with regard to the development of areal coverage of ecosystem type clusters over time. This evaluation of the structural aspects of ecological integrity at the national level was added by projecting potential future values of indicators for ecological functions at the site level by using the Very Simple Dynamic soil modelling technique based on climate data and two scenarios of nitrogen deposition as input. The results were compared to the reference and enabled an evaluation of site-specific ecosystem changes over time which proved to be both, positive and negative. PMID- 25829290 TI - An integrated crop model and GIS decision support system for assisting agronomic decision making under climate change. AB - The semi-arid tropical (SAT) regions of India are suffering from low productivity which may be further aggravated by anticipated climate change. The present study analyzes the spatial variability of climate change impacts on groundnut yields in the Anantapur district of India and examines the relative contribution of adaptation strategies. For this purpose, a web based decision support tool that integrates crop simulation model and Geographical Information System (GIS) was developed to assist agronomic decision making and this tool can be scalable to any location and crop. The climate change projections of five global climate models (GCMs) relative to the 1980-2010 baseline for Anantapur district indicates an increase in rainfall activity to the tune of 10.6 to 25% during Mid-century period (2040-69) with RCP 8.5. The GCMs also predict warming exceeding 1.4 to 2.4 degrees C by 2069 in the study region. The spatial crop responses to the projected climate indicate a decrease in groundnut yields with four GCMs (MPI-ESM MR, MIROC5, CCSM4 and HadGEM2-ES) and a contrasting 6.3% increase with the GCM, GFDL-ESM2M. The simulation studies using CROPGRO-Peanut model reveals that groundnut yields can be increased on average by 1.0%, 5.0%, 14.4%, and 20.2%, by adopting adaptation options of heat tolerance, drought tolerant cultivars, supplemental irrigation and a combination of drought tolerance cultivar and supplemental irrigation respectively. The spatial patterns of relative benefits of adaptation options were geographically different and the greatest benefits can be achieved by adopting new cultivars having drought tolerance and with the application of one supplemental irrigation at 60days after sowing. PMID- 25829291 TI - Multi-year ozone concentration and its spectra in Shanghai, China. AB - The periodic properties of surface ozone variation were studied at five stations with different environmental conditions in Shanghai based on multi-year observations of ozone concentration and UV radiation using spectral decomposition methods. The spectra of surface ozone have distinct peaks at semi-diurnal, diurnal, intraseasonal, semiannual, annual, and quasi-biennial periods. The spectra for the frequency band larger than the semi-diurnal follow a -5/3 power law at all the stations. The diurnal peak values for all stations in different years are similar to each other, while the semi-diurnal peak values are somewhat different among the stations. The peak value of semi-diurnal cycle at the station Dongtan (ecological environment area) is smaller than that at the other stations. The monthly mean of surface ozone has a significant seasonal variation with a maximum in May, a secondary maximum in fall, a lower value in summer (July and August), and a minimum in December or January. However the seasonal variation of UV radiation monthly mean shows a relatively higher value in summer (July and August), and for other months it is closely related to the ozone monthly mean. These secondary peaks of the ozone monthly mean in fall might be caused by the UV radiation coming back to its relevant value after falling off during the Asia summer monsoon; it was not related to biomass burning. The intraseasonal cycling of ozone might be related to the MJO (Madden-Julian Oscillation). Further studies are needed to understand the relationship between the local ozone intraseasonal variation and the MJO. The quasi-biennial variation of ozone in Shanghai might be a local reflection of climate change and could be associated with ENSO (El-Nino Southern Oscillation). Further studies will be needed to understand the relationship of the quasi-biennial variation of ozone to ENSO. PMID- 25829292 TI - Concentration and transportation of heavy metals in vegetables and risk assessment of human exposure to bioaccessible heavy metals in soil near a waste incinerator site, South China. AB - There is limited study focusing on the bioaccumulation of heavy metals in vegetables and human exposure to bioaccessible heavy metals in soil. In the present study, heavy metal concentrations (Cr, Ni, Cu, Pb and Cd) were measured in five types of vegetables, soil, root, and settled air particle samples from two sites (at a domestic waste incinerator and at 20km away from the incinerator) in Guangzhou, South China. Heavy metal concentrations in soil were greater than those in aerial parts of vegetables and roots, which indicated that vegetables bioaccumulated low amount of heavy metals from soil. The similar pattern of heavy metal (Cr, Cd) was found in the settled air particle samples and aerial parts of vegetables from two sites, which may suggest that foliar uptake may be an important pathway of heavy metal from the environment to vegetables. The highest levels of heavy metals were found in leaf lettuce (125.52MUg/g, dry weight) and bitter lettuce (71.2MUg/g) for sites A and B, respectively, followed by bitter lettuce and leaf lettuce for sites A and B, respectively. Swamp morning glory accumulated the lowest amount of heavy metals (81.02MUg/g for site A and 53.2MUg/g for site B) at both sites. The bioaccessibility of heavy metals in soil ranged from Cr (2%) to Cu (71.78%). Risk assessment showed that Cd and Pb in soil samples resulted in the highest non-cancer risk and Cd would result in unacceptable cancer risk for children and risk. The non-dietary intake of soil was the most important exposure pathway, when the bioaccessibility of heavy metals was taken into account. PMID- 25829293 TI - Distribution of phthalates, pesticides and drug residues in the dissolved, particulate and sedimentary phases from transboundary rivers (France-Belgium). AB - Various drug residues, pesticides and phthalates are ubiquitous in the environment. Their presence in the environment has attracted considerable attention due to their potential impacts on ecosystem functioning and on public health. In this work, 14 drug residues, 24 pesticides and 6 phthalates have been quantified in three matrices (in the dissolved phase, associated to suspended solid matter (SSM), and in sediment) collected from fifteen watercourses and rivers located in a highly industrialized zone at the cross-border area of Northern France and Belgium. The extractions have been carried out using accelerated solvent extraction (ASE) for solid matrices (SSM and sediment) and using solid phase extraction (SPE) for liquid matrix. The final extract was analyzed using GC-MS technique. Among the three classes of compounds, phthalates have been found at highest level compared to pesticides and drug residues. The Sigma6PAE concentrations were ranging from 17.2+/-2.58 to 179.1+/-26.9MUgL(-1) in dissolved phase, from 2.9+/-0.4 to 21.1+/-3.2MUgL(-1) in SSM and from 1.1+/-0.2 to 11.9+/-1.8MUgg(-1)dw in sediment. The Sigma14drug residue concentrations were lower than 1.3MUgL(-1) in the dissolved phases, lower than 30ngL(-1) associated to SSM and from nondetectable levels to 60.7+/-9.1ngg(-1)dw in sediment. For pesticides, all compounds were below the LOQ values in dissolved phase and in sediment, and only EPTC could be quantified in SSM. PMID- 25829294 TI - Mesocosm validation of the marine No Effect Concentration of dissolved copper derived from a species sensitivity distribution. AB - The Predicted No Effect Concentration (PNEC) for dissolved copper based on the species sensitivity distribution (SSD) of 24 marine single species tests was validated in marine mesocosms. To achieve this, the impact of actively maintained concentrations of dissolved copper on a marine benthic and planktonic community was studied in 18 outdoor 4.6m(3) mesocosms. Five treatment levels, ranging from 2.9 to 31MUg dissolved Cu/L, were created in triplicate and maintained for 82days. Clear effects were observed on gastropod and bivalve molluscs, phytoplankton, zooplankton, sponges and sessile algae. The most sensitive biological endpoints; reproduction success of the bivalve Cerastoderma edule, copepod population development and periphyton growth were significantly affected at concentrations of 9.9MUg Cu/L and higher. The No Observed Effect Concentration (NOEC) derived from this study was 5.7MUg dissolved Cu/L. Taking into account the DOC concentration of the mesocosm water this NOEC is comparable to the PNEC derived from the SSD. PMID- 25829295 TI - Pain characteristics and analgesic treatment in an aged adult population: a 4 week retrospective analysis of advanced cancer patients followed at home. AB - BACKGROUND: Studies of cancer pain management in older people are lacking and more information is needed. OBJECTIVES: The aim of this study was to assess the possible differences in pain intensity, pain mechanisms, breakthrough pain (BTP) medications and use of opioids between adult cancer patients and older cancer patients. METHODS: A retrospective review of computerized charts was undertaken for advanced cancer patients in the home-care setting. Pain intensity, pain mechanisms, the presence of BTP, analgesic treatments in the last 4 weeks of life, and frequency of change in opioid or route of administration were measured. Patients were divided into two groups: adults (<65 years, A), and aged (>=65 years, O). Within the latter group, three subgroups were assessed: old (65-74 years, O1), older (75-84 years, O2), and the oldest (>=85 years, O3). RESULTS: A total of 412 patients were available for analysis. No differences in Karnofsky status and survival in the two age groups were found (p=0.2 and p=0.09, respectively). No differences in pain intensity were observed among age subgroups. The O3 group presented a lower prevalence of BTP in comparison with other groups. Significant changes in opioid doses were reported with an inverse relationship with age (p=0.0001). Opioid switching was less frequently present in the older patients (p<0.005). CONCLUSION: Careful opioid titration may achieve adequate analgesia in older patients by using lower doses of opioids, with a lower rate of opioid switching. The prevalence of BTP was only shown to be lower in the oldest group (O3). PMID- 25829296 TI - The inability of older adults to recall their drugs and medical conditions. AB - BACKGROUND/OBJECTIVES: Previous research has shown that many older adults without known cognitive impairment are unable to recall basic knowledge about their medical history. We sought to determine whether older adult patients in our own clinic population were able to recall their drug regimens and medical conditions from memory. METHODS: Patients aged 65 years or older with no known cognitive impairment, dementia, or memory loss who were presenting for routine outpatient follow-up in our medical school neurology and general medicine clinics were recruited. Each patient was asked to recall the number and names of their presently prescribed drugs and their associated medical conditions. Each patient was also administered a Mini-Mental State Examination (MMSE) cognitive screening test (range 0-30). RESULTS: Most patients were unable to recall their drug regimens or their medical conditions. Of 99 patients taking drugs, only 22% correctly named their drugs from memory, and only 34% correctly named their medical conditions associated with the drugs. Fewer than half (49%) correctly recalled the number of drugs they were taking. Poor recall performance was evident even in high-cognitive (MMSE>27) patients. CONCLUSION: The accuracy of recall memory in older adults regarding their drugs and medical conditions may be poor, which has important implications towards medication reconciliation within meaningful-use doctrine. Clinicians treating older adults should be very cautious before relying on their patients' memories for accurate recall of their medical conditions, their drug regimens, and even the number of drugs they are taking. PMID- 25829297 TI - Synthesis, Structure, and Air-stable N-type Field-Effect Transistor Behaviors of Functionalized Octaazanonacene-8,19-dione. AB - Increasing the length of N-heteroacenes or their analogues is highly desirable because such materials could have great potential applications in organic electronics. In this report, the large pi-conjugated N-heteroquinone 6,10,17,21 tetra-((triisopropylsilyl)ethynyl)-5,7,9,11,16,18,20,22-octaazanonacene-8,19 dione (OANQ) has been synthesized and characterized. The as-prepared OANQ shows high stability under ambient conditions and has a particularly low LUMO level, which leads to it being a promising candidate for air-stable n-type field-effect transistors (FETs). In fact, FET devices based on OANQ single crystals have been fabricated and an electron mobility of up to 0.2 cm(2) V(-1) s(-1) under ambient conditions is reported. More importantly, no obvious degradation was observed even after one month. Theoretical calculations based on the single crystal are consistent with the measured mobility. PMID- 25829298 TI - A randomised, placebo-controlled, Phase II, dose-ranging trial of once-daily treatment with olodaterol, a novel long-acting beta2-agonist, for 4 weeks in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Olodaterol is a novel long-acting beta2-agonist (LABA) with >=24-h duration of action in preclinical and clinical studies. OBJECTIVE: This Phase II, multicentre, randomised, double-blind, placebo-controlled, parallel-group, dose finding study evaluated four doses of once-daily olodaterol over 4 weeks in patients with chronic obstructive pulmonary disease (COPD), based on efficacy, safety and pharmacokinetic parameters. METHODS: Patients received olodaterol inhalation solution or placebo via Respimat(r) Soft MistTM inhaler once daily for 4 weeks. Pulmonary function testing was performed pre-dose (trough) and up to 3 or 6 h post-dose, depending on visit. Primary end point was change from baseline in trough forced expiratory volume in 1 s (FEV1) after 4 weeks' treatment. Secondary end points included change from baseline in peak FEV1 and FEV1 area under the curve from 0 to 6 h. RESULTS: 405 patients with COPD were randomised and assigned to treatment. Mean baseline post-bronchodilator FEV1 was 1.50 L (54% predicted). All olodaterol doses provided statistically significant increases in trough FEV1 compared to placebo (2 MUg: 0.061 L [p = 0.0233]; 5 MUg: 0.097 L [p = 0.0003]; 10 MUg: 0.123 L [p < 0.0001]; 20 MUg: 0.132 L [p < 0.0001]). A clear dose-response relationship was demonstrated regarding pulmonary function; the two highest olodaterol doses (10 and 20 MUg) formed the plateau of the dose-response curve. All olodaterol doses were well tolerated, with no dose-dependent safety effects. CONCLUSION: Once-daily olodaterol demonstrated 24-h bronchodilator efficacy, confirming its potential as a once-daily LABA for the management of COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00452400. PMID- 25829299 TI - Detection of tyrosine sulfation on proteins. AB - Tyrosine sulfation is a post-translational modification (PTM) where a sulfate group is added to a tyrosine moiety. This PTM is responsible for strengthening interaction between proteins. One of the drawbacks of studying this PTM is the lack of an antibody that can detect all tyrosine-sulfated proteins. In addition, due to the labile nature of the tyrosine sulfate, other techniques such as mass spectrometry cannot be used to study this PTM unless special modification procedures are used. This requires considerable skill and knowledge of mass spectrometry. This unit describes an in vitro technique that can be used to study tyrosine-sulfated proteins by radiolabeling the recombinant protein. The protein is then subject to barium hydroxide hydrolysis and thin-layer electrophoresis (TLE). Co-localization of radioactive tyrosine-sulfate with nonradioactive tyrosine sulfate standard spiked in before TLE analysis identifies a protein as tyrosine-sulfated protein. The advantage of this technique is that, it identifies all tyrosine-sulfated proteins without any bias and is the only technique that identifies the tyrosine sulfate residues in the protein. PMID- 25829300 TI - Selective Proteomic Proximity Labeling Assay Using Tyramide (SPPLAT): A Quantitative Method for the Proteomic Analysis of Localized Membrane-Bound Protein Clusters. AB - This manuscript describes a new and general method to identify proteins localized into spatially restricted membrane microenvironments. Horseradish peroxidase (HRP) is brought into contact with a target protein by being covalently linked to a primary or secondary antibody, an antigen or substrate, a drug, or a toxin. A biotinylated tyramide-based reagent is then added. In the presence of HRP and hydrogen peroxide, the reagent is converted into a free radical that only diffuses a short distance before covalently labeling proteins within a few tens to hundreds of nanometers from the target. The biotinylated proteins can then be isolated by standard affinity chromatography and identified by liquid chromatography (LC) and mass spectrometry (MS). The assay can be made quantitative by using stable isotope labeling with amino acids in cell culture (SILAC) or isobaric tagging at the peptide level. PMID- 25829301 TI - Preparing protein extracts for quantitative two-dimensional gel comparison. AB - This unit describes basic protocols for efficient and reproducible protein solubilization from a variety of biological samples, including cultured animal cells and tissues, plant cells and tissues, bacteria, nuclei, other subcellular organelles, plasma, serum, and other biological fluids. The optimized extraction process is strongly sample dependent and cannot be described for every type of sample. Instead, typical protocols are provided as general guidelines and illustrate good starting points for optimization of sample preparation. These solubilization procedures take into account the constraints imposed by two dimensional electrophoresis and are thus well suited for proteomic approaches. PMID- 25829302 TI - Overview of the purification of recombinant proteins. AB - When the first version of this unit was written in 1995, protein purification of recombinant proteins was based on a variety of standard chromatographic methods and approaches, many of which were described and mentioned throughout Current Protocols in Protein Science. In the interim, there has been a shift toward an almost universal usage of the affinity or fusion tag. This may not be the case for biotechnology manufacture where affinity tags can complicate producing proteins under regulatory conditions. Regardless of the protein expression system, questions are asked as to which and how many affinity tags to use, where to attach them in the protein, and whether to engineer a self-cleavage system or simply leave them on. We will briefly address some of these issues. Also, although this overview focuses on E.coli, protein expression and purification, other commonly used expression systems are mentioned and, apart from cell breakage methods, protein purification methods and strategies are essentially the same. PMID- 25829303 TI - Protein purification using PDZ affinity chromatography. AB - PDZ domains function in nature as protein-binding domains within scaffold and membrane-associated proteins. They comprise approximately 90 residues and undergo specific, high-affinity interactions with complementary C-terminal peptide sequences, other PDZ domains, and/or phospholipids. We have previously shown that the specific, strong interactions of PDZ domains with their ligands make them well suited for use in affinity chromatography. This unit provides protocols for the PDZ affinity chromatography procedure that are applicable for the purification of proteins that contain PDZ domains or PDZ domain-binding ligands, either naturally or introduced by genetic engineering. We detail the preparation of affinity resins composed of PDZ domains or PDZ domain peptide ligands coupled to solid supports. These resins can be used to purify proteins containing endogenous or genetically introduced PDZ domains or ligands, eluting the proteins with free PDZ domain peptide ligands. PMID- 25829304 TI - Walking and running in the desert ant Cataglyphis fortis. AB - Path integration, although inherently error-prone, is a common navigation strategy in animals, particularly where environmental orientation cues are rare. The desert ant Cataglyphis fortis is a prominent example, covering large distances on foraging excursions. The stride integrator is probably the major source of path integration errors. A detailed analysis of walking behaviour in Cataglyphis is thus of importance for assessing possible sources of errors and potential compensation strategies. Zollikofer (J Exp Biol 192:95-106, 1994a) demonstrated consistent use of the tripod gait in Cataglyphis, and suggested an unexpectedly constant stride length as a possible means of reducing navigation errors. Here, we extend these studies by more detailed analyses of walking behaviour across a large range of walking speeds. Stride length increases linearly and stride amplitude of the middle legs increases slightly linearly with walking speed. An initial decrease of swing phase duration is observed at lower velocities with increasing walking speed. Then it stays constant across the behaviourally relevant range of walking speeds. Walking speed is increased by shortening of the stance phase and of the stance phase overlap. At speeds larger than 370 mm s(-1), the stride frequency levels off, the duty factor falls below 0.5, and Cataglyphis transitions to running with aerial phases. PMID- 25829307 TI - Assessing clinical reasoning in anesthesiology: Making the case for the Script Concordance Test. PMID- 25829308 TI - Pulse pressure respiratory variation to predict fluid responsiveness: From an enthusiastic to a rational view. PMID- 25829309 TI - The Script Concordance Test in anesthesiology: Validation of a new tool for assessing clinical reasoning. AB - OBJECTIVE: To evaluate whether the Script Concordance Test (SCT) can discriminate between levels of experience among anesthesiology residents and attending physicians. STUDY TYPE: Multicenter (Toulouse, Nantes, Bordeaux and Limoges), prospective, observational study. PATIENTS AND METHODS: A SCT made of 60 items was used to evaluate "junior residents" (n=60), "senior residents" (n=47) and expert anesthesiologists (n=10). RESULTS: There were no missing data in our study. Mean scores (+/-SD) were 69.9 (+/-6.1), 73.1 (+/-6.5) and 82.0 (+/-3.5) out of a potential score of 100 for "junior residents", "senior residents" and expert anesthesiologists, respectively. Results were statistically different between the 3 groups (P=0.001) using the Kruskall-Wallis test. The Cronbach's alpha score was 0.63. CONCLUSIONS: The SCT is a valid and useful tool for discriminating between anesthesia providers with varying levels of experience in anesthesiology. It may be a useful tool for documenting the progression of reasoning during anesthesia residency. PMID- 25829310 TI - Residents in tutored practice exchange groups have better medical reasoning as measured by the script concordance test: A pilot study. AB - BACKGROUND: This pilot study attempted to evaluate the impact of a practice exchange group (PEG) tutored by a senior anaesthesiologist on clinical reasoning performance of anaesthesiology residents for uncertain situations. Changes in clinical reasoning were measured by script concordance tests (SCT). METHODS: First, a curriculum, with educational objectives and assessment tools, was proposed to all residents at the beginning of their 6-month training. The first group (control) consisted of residents undergoing a 6-month rotation without PEG training. The second group (PEG group) consisted of the residents starting a new rotation 6 months later, who followed a weekly PEG session. In both groups, clinical reasoning was assessed in the same manner, with SCTs, multiple-choice questions (MCQs) and questions with short answers. The primary outcome measurement of this study was the SCT results in the group with PEG training (PEG group) in comparison with those without (control group). RESULTS: The performance in the SCT, expressed as the degree of concordance with the panel [95% confidence interval or CI], was better in the PEG group including 19 residents (72 [68 to 76] %) as compared to the control group including 17 residents (60 [57 to 63] % P<0.001). Performances (mean [95% CI]) in MCQs and short answers were better in the PEG group (64 [57 to 71] and 74 [68 to 72] %, respectively) when compared with the control group (32 [28 to 36]% [P<0.001] and 60 [52 to 68] % [P<0.01], respectively). CONCLUSION: Our pilot study suggested that a senior-directed, peer conducted educational training might improve the clinical reasoning of anaesthesia residents as measured by the SCT. PMID- 25829312 TI - Evaluation of the knowledge base of French intensivists and anaesthesiologists as concerns the interpretation of respiratory arterial pulse pressure variation. AB - OBJECTIVE: The aims of the study were to assess the knowledge of intensivists and/or anaesthesiologists concerning respiratory arterial pulse pressure variation (PPV) and to define the criteria used to indicate a fluid challenge. STUDY DESIGN: A prospective observational study. PATIENTS AND METHODS: Intensivists and anaesthesiologists from one region of France were evaluated for their knowledge about the prerequisites (continuous arterial pressure monitoring, regular sinus rhythm, mechanical ventilation without spontaneous breathing) and confounding factors shifting the threshold value of PPV (low tidal volume, decreased pulmonary compliance, low heart rate/respiratory rate ratio, right ventricular dysfunction, and/or intra-abdominal hypertension) using clinical vignettes. Criteria used by physicians to indicate a fluid challenge were also collected. RESULTS: One hundred and forty-five physicians were included in the study. Among them, 87 (60%) knew prerequisites but none of them had full knowledge of all confounding factors. Criteria used to perform a fluid challenge were mainly PPV and the passive leg-raising test for the residents and PPV, blood pressure, oliguria and hydric balance for the qualified physicians. CONCLUSIONS: PPV was widely employed to indicate a fluid challenge and 60% of the physicians knew the prerequisites. However, the physicians did not correctly interpret all confounding factors. PMID- 25829311 TI - Arterial pulse pressure variation suitability in critical care: A French national survey. AB - OBJECTIVE: Arterial pulse pressure variation (PPV) has been used as an accurate index to predict fluid responsiveness. However, many confounding factors have been recently described. The aims of this study were to assess the conditions of applicability of PPV in intensive care units (ICU). STUDY DESIGN: A one-day French national survey. PATIENTS AND METHODS: A form assessing the suitability of PPV was completed by practitioners for each critically-ill patient included on a set day. RESULTS: Four hundred and sixty-five patients were included in 36 ICUs. A regular sinus rhythm was noted in 408 (88%) patients and the presence of an arterial line in 324 (70%) patients. One hundred and twenty-seven (27%) patients were mechanically ventilated without spontaneous breathing. Only six patients (1.3%) had no confounding factors modifying the threshold value of the PPV. CONCLUSION: The incidence of ICU patients in whom PPV was suitable and without confounding factors were respectively 18% and 1.3% in this one-day French national survey. PMID- 25829313 TI - French survey of the first three-years of liver transplantation activity from uncontrolled donors deceased after cardiac death. AB - OBJECTIVE: To assess the first three years of French activity related to liver transplantation from uncontrolled donation after cardiac death (uDCD). STUDY DESIGN: Prospective and observational study in the three active centres authorized by the French Biomedicine Agency. PATIENTS AND METHODS: All patients deceased between 2010 and 2012 after an uncontrolled cardiac arrest admitted to one of three centres (Pitie-Salpetriere, Saint-Louis or Bicetre hospitals, AP-HP, Paris, France) and potentially eligible for liver recovery were included. Abdominal normothermic oxygenated recirculation (ANOR) was used for graft preservation. RESULTS: One hundred twenty-six potential uDCD donors were identified as eligible for liver recovery after hospital admission. The main causes of organ recovery failure were technical failure related to ANOR (29 patients, 23%), refusal of consent (39 patients, 31% of potential uDCD donors and 40% of asked relatives) and abnormal hepatic transaminases up to 200 UI.L(-1) during ANOR (24 patients, 19%). Finally, 11 livers were transplanted. Process efficiency was 9% [95% CI: 4-15%]. One-year recipient survival was 82%, [95% CI: 48-98%] and one-year graft survival was 64% [95% CI: 31-89%]. CONCLUSION: Liver transplantation from uDCD donors is achievable in France, despite low process efficiency. PMID- 25829314 TI - Implementation of lung ultrasound in polyvalent intensive care unit: Impact on irradiation and medical cost. AB - OBJECTIVE: To determine the effect of implementing a daily lung ultrasound round on the number of chest radiographs and chest computed tomography (CT) scans in a polyvalent intensive care unit (ICU). STUDY DESIGN: Retrospective study comparing two consecutive periods. PATIENTS: All patients hospitalized for longer than 48 hours in a polyvalent ICU. METHODS: Implementation of a daily lung ultrasound round after a short educational program. The number of chest radiographs and chest CT scans and the patient outcome were measured before (group PRE) and after (group POST) the implementation of a daily lung ultrasound round. RESULTS: No demographic difference was found between the two groups, with the exception of a higher severity score in the group POST. For each ICU stay, the number of chest radiographs was 10.3 +/- 12.4 in the group PRE and 7.7 +/- 10.3 in the group POST, respectively (P<0.005) The number of chest CT scans was not reduced in the group POST, as compared with the group PRE (0.5 +/- 0.7 CT scan/patient/ICU stay versus 0.4 +/- 0.6 CT scan/patient/ICU stay, P=0.01). The ICU mortality was similar in both groups (21% versus 22%, P=0.75) CONCLUSION: The implementation of a daily lung ultrasound round was associated with a reduction in radiation exposure and medical cost without altering patient outcome. PMID- 25829315 TI - Diagnosis and management of the postoperative surgical and medical complications of bariatric surgery. AB - Perioperative complications following bariatric surgery (BS) have been poorly analysed and their management is not clearly assessed. The associated frequency of ICU admission is difficult to estimate. Among surgical complications, digestive perforations are the most frequent. The most common postoperative complications of sleeve gastrectomy are fistulas, but bleeding on the stapling line is also commonly reported. Complication rates are higher after Roux-en-Y gastric bypass, mainly due to anastomotic leaks. Medical complications are mainly thromboembolic or respiratory complications. All these surgical and medical complications are not easily detected; clinical signs can be atypical or insidious, often resulting in delayed management. Respiratory signs can be predominant and lead erroneously to pulmonary or thromboembolic diseases. Diagnostic criteria are based on minor clinical signs, tachycardia being probably the most frequent one. Lately, complications are revealed by haemodynamic instability, respiratory failure or renal dysfunction and radiographic findings. Management decision according to these abnormal signs is based on a combined multidisciplanary approach including surgical and/or endoscopic procedures and medical care, depending on the nature and severity of the surgical complication. Medical management is based on supportive ICU care of organ dysfunctions, curative anticoagulation if required, nutritional support, and appropriate anti infective therapy. Pharmacological data are limited in morbidly obese patients and the appropriate doses are debated, especially for anti-infective agents. Complicated BS cases have a poor outcome, probably largely related to delayed diagnosis and reoperation. PMID- 25829316 TI - Treatment of intra-abdominal haemorrhagic shock by Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). AB - PURPOSE: Haemorrhagic shock is commonly encountered in the emergency room and is associated with high morbidity and mortality. For intra-thoracic and intra abdominal bleeding, treatment usually requires either surgery or an interventional radiologic procedure. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) has already been described for pelvic fractures and intra abdominal haemorrhages. In this case report, we present the use of REBOA in a patient admitted for haemorrhagic shock due to a ruptured splenic artery aneurysm. CASE REPORT: We describe the case of a 35-year-old male with suspected massive pulmonary embolism. Prior to diagnostic confirmation by CT-scan, the patient suffered several cardiac arrests. CT-scan revealed a massive haemoperitoneum secondary to a ruptured aneurysm of the splenic artery. Because of refractory hypotension despite maximal conventional therapy, we used REBOA before patient transfer to the operating room for splenectomy. CONCLUSIONS: This case underlines the feasibility of REBOA and discusses its role in uncontrollable intra-abdominal haemorrhagic shock. PMID- 25829317 TI - Accidental injection of patent blue dye during gynaecological surgery: Lack of knowledge constitutes a system error. AB - The authors report a case in which an intravenous injection of Patent Blue V dye instead of Indigo Carmine was given during routine gynaecological surgery. The patient presented with temporary arterial (spurious) desaturation and skin discoloration over a 48-hour period. Pharmacological differences between these dyes are described. Root cause analysis based on the ALARM (Association of Litigation and Risk Management) model is presented. The authors emphasise that use of this model should not be limited solely to describing and correcting well known systems errors such as working conditions or teamwork and communication. Furthermore, they conclude that insufficient knowledge must also be recognised as a systems error and as such should be sought out and corrected using similar strategies to those used to discover other contributory factors, without allocation of blame to any individual. PMID- 25829318 TI - Early diagnosis of Sheehan's syndrome. PMID- 25829319 TI - Guidelines on the use of ultrasound guidance for vascular access. AB - Insertion of vascular access is a common procedure with potential for iatrogenic events, some of which can be serious. The spread of ultrasound scanners in operating rooms, intensive care units and emergency departments has made ultrasound-guided catheterisation possible. The first guidelines were published a decade ago but are not always followed in France. The French Society of Anaesthesia and Intensive Care has decided to adopt a position on this issue through its Guidelines Committee in order to propose a limited number of simple guidelines. The method used was the GRADE((r)) method using the most recently published meta-analyses as the source of references. The level of evidence found ranged from low to high and all the positive aspects associated with ultrasound guidance, i.e. fewer traumatic complications at puncture, probably or definitely outweigh the potential adverse consequences regardless of whether an adult or child is involved and regardless of the site of insertion. PMID- 25829320 TI - Novel biallelic OTOGL mutations in a Chinese family with moderate non-syndromic sensorineural hearing loss. AB - OBJECTIVE: Autosomal recessive non-syndromic hearing loss (DFNB) is a genetically heterogeneous disorder. So far, 55 pathogenic genes have been identified. In this study, we aim to characterize the clinical feature and the genetic cause of a Chinese DFNB family. METHODS: Whole exome sequencing was performed on the proband. Co-segregation between the hearing loss phenotype and the potential causative mutations was verified in all family members by Sanger sequencing. RESULTS: Audiologic profiles of the affected family members revealed a moderate hearing loss mainly affecting higher frequencies. Novel biallelic OTOGL mutations, c.6467C>A (p.Ser2156*) and c.6474dupA (p.Ser2159Metfs*2), were identified in this family segregating with the childhood onset DFNB. Both mutations were predicted to cause either nonsense mediated mRNA decay or premature terminations of protein synthesis. CONCLUSIONS: We identified novel biallelic OTOGL mutations in a Chinese DFNB family. To the best of our knowledge, this is the first report of OTOGL mutations causing hearing loss in the East Asian population. Our finding enriched the mutation spectrum of OTOGL associated hearing loss. PMID- 25829321 TI - Modified Sistrunk operation: New concept for management of thyroglossal duct cyst. AB - OBJECTIVE: To describe a method of hyoid cartilage division during Sistrunk operation for management of thyroglossal duct cyst (TGDC) and compare postoperative outcomes with those of conventional hyoid bone cutting. METHODS: Fifty-nine patients who received operative treatment for TGDC from January 2005 to July 2013 were enrolled. The degree of fusion in the cartilaginous portion of the hyoid was evaluated by preoperative neck computed tomography and classified into (1) non-fusion, (2) partial fusion, and (3) complete fusion. Techniques of hyoid management, division of the cartilaginous portion of the hyoid or conventional hyoid bone cutting, during Sistrunk operation were analyzed according to the fusion classification. RESULTS: Of the 59 patients, 27 were pediatric patients and 32 were adults. In 32 adults undergoing TGDC, there were 13 cases (41%) of complete hyoid fusion and 7 (22%) of non-fusion. A total of 20 adult patients (63%) were treated with the cartilage division. Among the pediatric patients, 96% of cases were classified as non-fusion of the hyoid, and all of these were treated with the cartilage division. Patients who were treated with the cartilage division showed better postoperative results. However, there were no statistical differences. CONCLUSIONS: Our cartilage division technique at Sistrunk operation for TGDC is feasible and comparable to conventional hyoid cutting with regard to postoperative results. PMID- 25829322 TI - Is there a need for a histological examination of the adenoid tissue after adenoidectomy? AB - OBJECTIVES: In Germany there is no uniform practice regarding the histological examination of removed tissue after an adenoidectomy. In addition, the unique benefits of routine histological examination of adenoid tissue cannot be ascertained from current literature due to varying opinion and evidence. METHODS: This study was approved by the Medical Association and Ethics Committee in Cottbus, Brandenburg, Germany. We evaluated the pre- and intra-operative examination findings (direct and indirect epipharyngoscopy, digital palpation, intraoperative macroscopic assessment and examination of removed tissue) and the histopathological findings of excised adenoid tissue. A statistical analysis of obtained results was undertaken thereafter. RESULTS: It was found that in all young patients included in the study, the histological results invariably represented lymphoepithelial hypertrophic mucosa with a varying inflammatory response, matching a clinical picture of adenoid vegetation and in keeping with the pre- and intraoperative investigations and findings. CONCLUSION: The characteristic history of adenoid vegetation in combination with a classic pre- and intraoperative clinical examination and an inconspicuous macroscopic examination of removed tissue, renders routine histopathological workup dispensable. On suspicion of deviant pathology a histopathological examination is recommended and should be undertaken. PMID- 25829323 TI - Iron supplementation associates with low mortality in pre-dialyzed advanced chronic kidney disease patients receiving erythropoiesis-stimulating agents: a nationwide database analysis. AB - BACKGROUND: A risk/benefit analysis of iron supplementation in pre-dialysis advanced chronic kidney disease (CKD) patients has not been conducted. We aim to assess the effectiveness and the safety of iron supplementation in patients with CKD Stage 5 who have not yet received dialysis (CKD 5 ND). METHODS: A prospective cohort study was conducted based on the Taiwan National Health Insurance Research Database. From 1 January 2000 to 30 June 2009, we enrolled 31 971 adult patients who had a serum creatinine >6 mg/dL and a haematocrit <28% and who were treated with erythropoiesis-stimulating agents (ESAs). All patients were further divided into two groups with or without iron supplementation within 90 days after starting ESA therapy. Patient follow-up took place until dialysis, death before initiation of dialysis or 31 December 2009. The primary outcomes were death before initiating dialysis, hospitalization before death or long-term dialysis. RESULTS: After propensity score matching, the patients who received iron supplementation were associated with a lower risk of all-cause death [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.80-0.90] compared with non users. The survival benefit of iron use was consistent across the majority of dosage groups, except for those who were treated with monthly IV iron >200 mg. Moreover, compared with the non-users, the iron users were associated with a lower risk of hospitalizations (HR, 0.97; 95% CI, 0.94-0.99) but with a higher risk of faster progression to end-stage renal disease (HR, 1.05; 95% CI, 1.01 1.08). CONCLUSIONS: Iron supplementation is associated with 15% risk reduction in death among CKD 5 ND patients who received ESA treatment. Randomized studies are needed to validate this association. PMID- 25829324 TI - Glutamate receptors in the kidney. AB - l-Glutamate (l-Glu) plays an essential role in the central nervous system (CNS) as an excitatory neurotransmitter, and exerts its effects by acting on a large number of ionotropic and metabotropic receptors. These receptors are also expressed in several peripheral tissues, including the kidney. This review summarizes the general properties of ionotropic and metabotropic l-Glu receptors, focusing on N-methyl-d-aspartate (NMDA) and Group 1 metabotropic glutamate receptors (mGluRs). NMDA receptors are expressed in the renal cortex and medulla, and appear to play a role in the regulation of renal blood flow, glomerular filtration, proximal tubule reabsorption and urine concentration within medullary collecting ducts. Sustained activation of NMDA receptors induces Ca(2+) influx and oxidative stress, which can lead to glomerulosclerosis, for example in hyperhomocysteinemia. Group 1 mGluRs are expressed in podocytes and probably in other cell types. Mice in which these receptors are knocked out gradually develop albuminuria and glomerulosclerosis. Several endogenous agonists of l-Glu receptors, which include sulfur-containing amino acids derived from l homocysteine, and quinolinic acid (QA), as well as the co-agonists glycine and d serine, are present in the circulation at concentrations capable of robustly activating ionotropic and metabotropic l-Glu receptors. These endogenous agonists may also be secreted from renal parenchymal cells, or from cells that have migrated into the kidney, by exocytosis or by transporters such as system x( )(c), or by transporters involved in ammonia secretion. l-Glu receptors may be useful targets for drug therapy, and many selective orally-active compounds exist for investigation of these receptors as potential drug targets for various kidney diseases. PMID- 25829325 TI - Short-Form 12 or Short-Form 36 to measure quality-of-life changes in dialysis patients? AB - BACKGROUND: Short-Form 36 (SF-36) is a self-report health-related quality-of-life (HRQOL) questionnaire, widely used in dialysis patients. It consists of physical and mental component scores (PCS/MCS), ranging from 0 to 100. To improve efficiency, the Short-Form 12 (SF-12) was developed to reproduce PCS and MCS. We assessed the ability of SF-12 versus SF-36 to detect change over time, and the association of SF-12 versus SF-36 with short-term and long-term mortality in dialysis patients. METHODS: Patients were selected from the Netherlands Cooperative Study on the Adequacy of Dialysis (N = 1379), a prospective follow-up study among incident dialysis patients (62.1% HD) who completed SF-36 measurements every 6 months. Changes in scores of SF-12 versus SF-36 were compared with intra-class correlation coefficients (ICCs). Subsequently, Bland Altman plots were used to assess limits of agreement. Relationship with mortality was assessed with Cox models with and without a time-dependent variable, adjusted for age, sex, ethnicity, comorbidity and dialysis modality at baseline. RESULTS: ICC for change in scores was 0.90 for MCS and 0.84 for PCS. Mean difference was 0.1 and 0.2, respectively, and limits of agreement were -8.3 to 8.4 for MCS change in scores and -8.8 to 9.2 for PCS. Adjusted hazard ratio's for mortality per 5 units increment were 0.87 (95% CI: 0.84-0.91) for MCS12, 0.87 (95% CI: 0.84 0.90) for MCS36, 0.79 (95% CI: 0.76-0.83) for PCS12 and 0.75 (95% CI: 0.71-0.78) for PCS36. CONCLUSIONS: SF-12 can be used to detect change in HRQOL in cohort studies on dialysis patients. SF-12 and SF-36 were similarly associated with short-term and long-term mortality. However, the wide limits of agreement indicate that SF-12 and SF-36 can give different scores on the individual level, suggesting that for individual purposes SF-36 instead of SF-12 should be used. PMID- 25829326 TI - Hyperuricemia-induced inflammasome and kidney diseases. AB - Classically, urate nephropathy has been postulated to cause kidney disease by depositing intraluminal crystal in the collecting duct. Recently, molecular mechanisms of inflammasome have been investigated. Urate-induced inflammasome pathway is comprised of urate crystal uptake into intracellular lysosomes and subsequent lysosomal rupture with mitochondrial reactive oxygen species (ROS) production, which activates the NLRP3 inflammasome. Against the lysosomal rupture and mitochondrial ROS production, autophagy acts to protect proximal tubular cells by isolating them from expanding the inflammation. In addition, increased cellular urate, directly or indirectly via xanthine oxidase-induced oxidative stress, may be associated with inflammasome. In addition to the traditional therapy against hyperuricemia, management of urate-induced inflammasome or augmentation of autophagy may offer the new effective therapies. PMID- 25829327 TI - Discoidin domain receptor-1 and periostin: new players in chronic kidney disease. AB - The incidence and prevalence of chronic kidney disease represents an important problem for public health. In renal diseases, the main histologic alterations derive from the development of renal fibrosis which results from the loss of the balance between pro- and anti-fibrotic factors. Tyrosine kinase receptors (RTKs) and matricellular proteins (MPs) are nowadays studied as potential modulators of renal injury. RTKs regulate cell cycle, migration, metabolism and cellular differentiation. Discoidin domain receptor-1 (DDR-1) is an RTK that has been extensively studied in cancer, and lung and renal diseases. It modulates inflammatory recruitment, extracellular matrix deposition and fibrosis; in renal diseases, it appears to act independently of the underlying disease. MPs regulate cell-matrix interactions and matrix accumulation, cellular adhesion and migration, and expression of inflammatory cells. Periostin is an MP, mainly studied in bone, heart, lung and cancer. Several studies demonstrated that it mediates cell-matrix interactions, migration of inflammatory cells and development of fibrosis. Recently, it has been reported in several nephropathies. In this review, we discuss the potential pathological roles of DDR-1 and periostin focussing on the kidney in both experimental models and human diseases. PMID- 25829328 TI - Microorganisms responsible for periprosthetic knee infections in England and Wales. AB - PURPOSE: This study aimed to delineate epidemiology of infecting microorganism genus in first-time revision knee arthroplasty for indication of periprosthetic joint infection in England and Wales using linked registry data. METHODS: From the National Joint Registry database for England and Wales, a consecutive series of primary knee arthroplasties performed between April 2003 and January 2014 that went on to have a revision for periprosthetic infection were identified (n = 2810). Each case was then linked to microbiology data held by Public Health England in order to identify infecting microorganism at time of revision surgery established from intra-operative cultures. Following data linkage, 403 culture results at time of revision surgery were identified in a group of 331 patients. The demographic characteristics of five microorganism groups were compared: pure staphylococcus (single genus), pure streptococcus (single genus), other gram positive infections (single genus), gram-negative infections (single genus) and mixed genus infections. RESULTS: Staphylococcus species was the most common organism genus isolated after revision of a primary implant for infection and present in 72 % of cases overall (71.3 % of patients with a single-genus infection and 76.8 % of patients with mixed genus infection). A pure staphylococcal infection was present in 59 % of all cases. A single-genus infection was responsible for infection in 83.1 % of cases, and mixed genera were responsible in 16.9 % of cases. A significant difference was observed for mean age at primary procedure in the cohort of patients where there was an isolated pure streptococcal infection (73.2 years) when compared to gram-negative infections (65.0 years). No other significant differences were observed between microorganism groups in terms of BMI, gender, ASA grade, indication for primary procedure and primary implant characteristics. CONCLUSION: Staphylococci were the most commonly isolated organism species responsible for periprosthetic infection of primary arthroplasty in England and Wales. This information can be used by surgeons to benchmark and audit their own practice against national, publicly available data. Furthermore, this study has shown that even when using the largest national databases available, there is a substantial volume of missing data. Antimicrobial resistance represents a growing clinical problem with significant health and social costs. In order to counteract this threat, this study would advocate the consolidation of national microbial data in order to guide effective strategies towards targeting and combating the threat of antimicrobial resistance. LEVEL OF EVIDENCE: IV. PMID- 25829329 TI - Youhaiella tibetensis gen. nov., sp. nov., isolated from subsurface sediment. AB - A Gram-reaction-negative bacterial strain, designated fig4(T), was isolated from a subsurface sediment core of Qiangtang Basin permafrost in China. Cells were catalase- and oxidase-positive and rods. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain fig4(T )was a member of the family Hyphomicrobiaceae and was most closely related to members of the genera Pelagibacterium, Vasilyevaea and Devosia with 93.8-96.2% sequence similarities. The major cellular fatty acids were C16 : 0, C18 : 0, 11-methyl C18 : 1 omega7c, C19 : 0 cyclo omega8c and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The major respiratory quinone was Q-10 and the major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and two unknown glycolipids. The DNA G+C content was 60.7 mol%. Based on the phenotypic, phylogenetic and genotypic data, strain fig4(T) is considered to represent a novel species of a new genus in the family Hyphomicrobiaceae, for which the name Youhaiella tibetensis gen. nov., sp. nov. is proposed. The type strain is fig4(T) ( = CGMCC 1.12719(T) = JCM 19854(T)). PMID- 25829330 TI - Bacillus taiwanensis sp. nov., isolated from a soil sample from Taiwan. AB - A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium (FJAT 14571(T)) was isolated from a soil sample in Taiwan. Strain FJAT-14571(T) grew at 20-40 degrees C (optimum 35 degrees C), pH 6-10 (optimum pH 8) and 0-2% (w/v) NaCl (optimum 0%). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain FJAT-14571(T) was a member of the genus Bacillus and was most closely related to Bacillus oceanisediminis DSM 24771(T) (96.2%). DNA-DNA relatedness between strain FJAT-14571(T) and B. oceanisediminis DSM 24771(T) was low (32.0% +/- 0.88%). The diagnostic diamino acid of the peptidoglycan of strain FJAT 14571(T) was meso-diaminopimelic acid and the predominant menaquinone was MK-7 (96.6%). The major cellular fatty acids were iso-C15 : 0 (46.4%), anteiso-C15 : 0 (7.6%), iso-C17 : 0 (8.2%) and iso-C16 : 0 (10.0 %) and the DNA G+C content was 40.8 mol%. Phenotypic, chemotaxonomic and genotypic properties clearly indicated that strain FJAT-14571(T) represents a novel species within the genus Bacillus, for which the name Bacillus taiwanensis sp. nov. is proposed. The type strain is FJAT-14571(T) ( = DSM 27845(T) = CGMCC1.1 2698(T)). PMID- 25829331 TI - Microbacterium enclense sp. nov., isolated from sediment sample. AB - A novel bacterium (strain NIO-1002(T)) belonging to the genus Microbacterium was isolated from a marine sediment sample in Chorao Island, Goa Province, India. Its morphology, physiology, biochemical features and 16S rRNA gene sequence were characterized. Cells of this strain were Gram-stain-positive, non-motile, non spore-forming rods that formed yellow-pigmented colonies. It grew in 0-12% (w/v) NaCl and at 25-37 degrees C, with optimal growth at 30 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain NIO-1002(T) is associated with members of the genus Microbacterium, with highest sequence similarity with Microbacterium hominis CIP 105731(T) (98.1%) and Microbacterium testaceum KCTC 9103(T) (98.0%). Within the phylogenetic tree, this novel strain shared a branching point with M. hominis CIP 105731(T). The DNA G+C content was 66.5 mol% and DNA-DNA hybridization relatedness between NIO-1002(T), M. hominis CIP 105731(T) and M. testaceum KCTC 9103(T) was 39.0 +/- 2.0% and 41.0 +/- 2.0%, respectively. The major fatty acids were ai-C15 : 0, i-C16 : 0 and ai-C17 : 0 and the diamino acid in the cell-wall peptidoglycan of NIO-1002(T) was lysine. Data obtained from DNA-DNA hybridization and chemotaxonomic phenotypic analysis support the conclusion that strain NIO-1002(T) represents a novel species within the genus Microbacterium. The name Microbacterium enclense sp. nov. is proposed, with NIO-1002(T) ( = NCIM 5454(T) = DSM 25125(T) = CCTCC AB 2011120(T)) as the type strain. PMID- 25829332 TI - Staphylococcus petrasii subsp. pragensis subsp. nov., occurring in human clinical material. AB - Seven coagulase-negative, oxidase-negative and novobiocin-susceptible staphylococci assigned tentatively as Staphylococcus petrasii were investigated in this study in order to elucidate their taxonomic position. All strains were initially shown to form a genetically homogeneous group separated from remaining species of the genus Staphylococcus by using a repetitive sequence-based PCR fingerprinting with the (GTG)5 primer. Phylogenetic analysis based on 16S rRNA gene, hsp60, rpoB, dnaJ, gap and tuf sequences showed that the group is closely related to Staphylococcus petrasii but separated from the three hitherto known subspecies, S. petrasii subsp. petrasii, S. petrasii subsp. croceilyticus and S. petrasii subsp. jettensis. Further investigation using automated ribotyping, MALDI-TOF mass spectrometry, fatty acid methyl ester analysis, DNA-DNA hybridization and extensive biotyping confirmed that the analysed group represents a novel subspecies within S. petrasii, for which the name Staphylococcus petrasii subsp. pragensis subsp. nov. is proposed. The type strain is NRL/St 12/356(T) ( = CCM 8529(T) = LMG 28327(T)). PMID- 25829333 TI - CRF1 and CRF2 receptors in the bed nucleus of the stria terminalis modulate the cardiovascular responses to acute restraint stress in rats. AB - The corticotropin-releasing factor (CRF) is involved in behavioral and physiological responses to emotional stress through its action in several limbic structures, including the bed nucleus of the stria terminalis (BNST). Nevertheless, the role of CRF1 and CRF2 receptors in the BNST in cardiovascular adjustments during aversive threat is unknown. Therefore, in the present study we investigated the involvement of CRF receptors within the BNST in cardiovascular responses evoked by acute restraint stress in rats. For this, we evaluated the effects of bilateral treatment of the BNST with selective agonists and antagonists of either CRF1 or CRF2 receptors in the arterial pressure and heart rate increase and the decrease in tail skin temperature induced by restraint stress. Microinjection of the selective CRF1 receptor antagonist CP376395 into the BNST reduced the pressor and tachycardiac responses caused by restraint. Conversely, BNST treatment with the selective CRF1 receptor agonist CRF increased restraint-evoked arterial pressure and HR responses and reduced the fall in tail skin temperature response. All effects of CRF were inhibited by local BNST pretreatment with CP376395. The selective CRF2 receptor antagonist antisalvagine 30 reduced the arterial pressure increase and the fall in tail skin temperature. The selective CRF2 receptor agonist urocortin-3 increased restraint-evoked pressor and tachycardiac responses and reduced the drop in cutaneous temperature. All effects of urocortin-3 were abolished by local BNST pretreatment with antisalvagine-30. These findings indicate an involvement of both CRF1 and CRF2 receptors in the BNST in cardiovascular adjustments during emotional stress. PMID- 25829334 TI - Thymoquinone and its therapeutic potentials. AB - Herbal medicine has attracted great attention in the recent years and is increasingly used as alternatives to chemical drugs. Several lines of evidence support the positive impact of medicinal plants in the prevention and cure of a wide range of diseases. Thymoquinone (TQ) is the most abundant constituent of the volatile oil of Nigella sativa seeds and most properties of N sativa are mainly attributed to TQ. A number of pharmacological actions of TQ have been investigated including anti-oxidant, anti-inflammatory, immunomodulatory, anti histaminic, anti-microbial and anti-tumor effects. It has also gastroprotective, hepatoprotective, nephroprotective and neuroprotective activities. In addition, positive effects of TQ in cardiovascular disorders, diabetes, reproductive disorders and respiratory ailments, as well as in the treatment of bone complications as well as fibrosis have been shown. In addition, a large body of data shows that TQ has very low adverse effects and no serious toxicity. More recently, a great deal of attention has been given to this dietary phytochemical with an increasing interest to investigate it in pre-clinical and clinical researches for assessing its health benefits. Here we report on and analyze numerous properties of the active ingredient of N. sativa seeds, TQ, in the context of its therapeutic potentials for a wide range of illnesses. We also summarize the drug's possible mechanisms of action. The evidence reported sugests that TQ should be developed as a novel drug in clinical trials. PMID- 25829335 TI - Glycogen synthase kinase-3 beta (GSK-3beta) signaling: Implications for Parkinson's disease. AB - Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3beta), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (alpha-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3beta in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3beta has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3beta inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3beta and several cellular processes involved in the pathogenesis of PD, including the accumulation of alpha-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK 3beta inhibitors as a potential therapeutic strategy in PD. PMID- 25829336 TI - Gold(I)-catalyzed selective heterocyclization of propargylic thioureas: mechanistic study of competitive gold-activation mode. AB - A new selective gold(I)-catalyzed intramolecular heterocyclization of propargylic thioureas has been developed, efficiently affording two kinds of cycloadducts in moderate to excellent yields with a broad substrate scope. Further mechanistic investigations indicate that competitive different gold activation modes feature in these cyclization processes. Kinetic experiments reveal that the gold activation mode is influenced by the ligand of the gold catalyst and the reaction conditions. PMID- 25829337 TI - Visceral pain and gastrointestinal microbiome. AB - A complex set of interactions between the microbiome, gut and brain modulate responses to visceral pain. These interactions occur at the level of the gastrointestinal mucosa, and via local neural, endocrine or immune activity; as well as by the pro-duction of factors transported through the circulatory system, like bacterial metabolites or hormones. Various psychological, in-fectious and other stressors can disrupt this harmonious relationship and alter both the microbiome and visceral pain responses. There are critical sensitive periods that can impact visceral pain responses in adulthood. In this review we provide a brief background of the intestinal microbiome and emerging concepts of the bidirectional interactions between the micro-biome, gut and brain. We also discuss recent work in animal models, and human clinical trials using prebiotics and probiotics that alter the microbiome with resultant alterations in visceral pain responses. PMID- 25829338 TI - Thrombolytic efficacy and enzymatic activity of rt-PA-loaded echogenic liposomes. AB - Echogenic liposomes (ELIP), that can encapsulate both recombinant tissue-type plasminogen activator (rt-PA) and microbubbles, are under development to improve the treatment of thrombo-occlusive disease. However, the enzymatic activity, thrombolytic efficacy, and stable cavitation activity generated by this agent has yet to be evaluated and compared to another established ultrasound-enhanced thrombolytic scheme. A spectrophotometric method was used to compare the enzymatic activity of the rt-PA incorporated into ELIP (t-ELIP) to that of rt-PA. An in vitro flow model was employed to measure the thrombolytic efficacy and dose of ultraharmonic emissions from stable cavitation for 120-kHz ultrasound exposure of three treatment schemes: rt-PA, rt-PA and the perfluorocarbon-filled microbubble Definity((r)), and t-ELIP. The enzymatic activity of rt-PA incorporated into t-ELIP was 28 % that of rt-PA. Thrombolytic efficacy of t-ELIP or rt-PA and Definity((r)) was equivalent when the dose of t-ELIP was adjusted to produce comparable enzymatic activity. Sustained bubble activity was nucleated from Definity but not from t-ELIP exposed to 120-kHz ultrasound. These results emphasize the advantages of encapsulating a thrombolytic and the importance of incorporating an insoluble gas required to promote sustained, stable cavitation activity. PMID- 25829339 TI - Synthesis, characterization and luminescent properties of europium complexes with 2,4,6-tris-(2-pyridyl)-s-triazine as highly efficient sensitizers. AB - Using 2,4,6-tris-(2-pyridyl)-s-triazine (TPTZ) as a neutral ligand, and p hydroxybenzoic acid, terephthalic acid and nitrate as anion ligands, five novel europium complexes have been synthesized. These complexes were characterized using elemental analysis, rare earth coordination titrations, UV/vis absorption spectroscopy and infrared spectroscopy. Luminescence spectra, luminescence lifetime and quantum efficiency were investigated and the mechanism discussed in depth. The results show that the complexes have excellent emission intensities, long emission lifetimes and high quantum efficiencies. The superior luminescent properties of the complexes may be because the triplet energy level of the ligands matches well with the lowest excitation state energy level of Eu(3+). Moreover, changing the ratio of the ligands and metal ions leads to different luminescent properties. Among the complexes, Eu2(TPTZ)2(C8H4O4)(NO3)4(C2H5OH).H2O shows the strongest luminescence intensity, longest emission lifetime and highest quantum efficiency. PMID- 25829341 TI - Editor's note. PMID- 25829340 TI - Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. PMID- 25829342 TI - Utilization of nutrition-focused physical assessment in identifying micronutrient deficiencies. AB - Heightened interest in and utilization of parts of the nutrition-focused physical assessment (NFPA) have increased with recent guidelines in defining malnutrition and the call to awareness among healthcare practitioners to recognize, document, and intervene in malnourished patients. Furthermore, an increased prevalence of nutrient deficiencies has been reported in surgical weight loss patients, those with various acute and chronic diseases, and the elderly requiring physical assessment and examination skills to identify these deficiencies. The registered dietitian nutritionist (RDN) can use the NFPA to note physical findings to use along with the other domains in the nutrition assessment to determine the nutrition-related diagnosis, while other nutrition professionals can use the NFPA findings to determine a differential diagnosis. This article outlines the NFPA and how to determine physical findings related to micronutrient deficiencies, which can have a profound impact on overall nutrition status. PMID- 25829343 TI - Phase angle as a prognostic marker in patients with critical illness. AB - BACKGROUND: Phase angle (PA) is interpreted as an indicator of cell membrane integrity and a prognostic indicator in some clinical situations. This study aims to evaluate PA as a prognostic marker in critically ill patients admitted to the intensive care unit (ICU) and associate this marker with length of hospital stay, mortality, and clinical scores. METHODS: A cohort study was conducted with 95 patients aged >=18 years admitted to the ICU, who were assessed in terms of prognostic indexes (Acute Physiology and Chronic Health Evaluation II [APACHE II] and Sequential Organ Failure Assessment [SOFA]), clinical evolution (ICU discharge, death, and length of ICU stay), and PA. RESULTS: Patients were predominantly male (63.1%) and had a mean age of 63.7 +/- 14.6 years; length of stay of 4 days (range, 3-9 days); mortality of 15.8%; mean APACHE II and SOFA scores of 17.3 +/- 8.2 and 6.1 +/- 3.1 points, respectively; and mean PA of 4.91 +/- 1.36 degrees . An association was observed between females and PA <5.1 degrees (P = .035), which was the cutoff point determined from the receiver operating characteristic curve. PA was correlated with APACHE II score (r = 0.241; P = .02). This correlation became moderate only when patients without sepsis were considered (r = -0.506; P < .001). CONCLUSIONS: PA seems to be a good prognostic marker for patients without sepsis. The weak correlation between PA and APACHE II score and the lack of association with other clinical outcomes are limitations for interpreting the prognostic value of PA in the entire study sample. PMID- 25829344 TI - Starved for attention: the prevalence and quality of nutrition-related research in gastroenterology. PMID- 25829345 TI - Interactive effects of explicit emergent structure: a major challenge for cognitive computational modeling. AB - David Marr's (1982) three-level analysis of computational cognition argues for three distinct levels of cognitive information processing-namely, the computational, representational, and implementational levels. But Marr's levels are-and were meant to be-descriptive, rather than interactive and dynamic. For this reason, we suggest that, had Marr been writing today, he might well have gone even farther in his analysis, including the emergence of structure-in particular, explicit structure at the conceptual level-from lower levels, and the effect of explicit emergent structures on the level (or levels) that gave rise to them. The message is that today's cognitive scientists need not only to understand how emergent structures-in particular, explicit emergent structures at the cognitive level-develop but also to understand how they feed back on the sub structures from which they emerged. PMID- 25829346 TI - A 12-MONTH, SINGLE-MASKED, RANDOMIZED CONTROLLED STUDY OF EYES WITH PERSISTENT DIABETIC MACULAR EDEMA AFTER MULTIPLE ANTI-VEGF INJECTIONS TO ASSESS THE EFFICACY OF THE DEXAMETHASONE-DELAYED DELIVERY SYSTEM AS AN ADJUNCT TO BEVACIZUMAB COMPARED WITH CONTINUED BEVACIZUMAB MONOTHERAPY. AB - PURPOSE: To determine whether a dexamethasone intravitreal implant 0.7 mg (dexamethasone delivery system [DDS], Ozurdex) combined with bevacizumab 1.25 mg (Avastin) provides greater benefit than bevacizumab monotherapy in eyes with diabetic macular edema with incomplete response to multiple antivascular endothelial growth factor injections. METHODS: Eyes with diabetic macular edema were randomly assigned to receive combination therapy (bevacizumab plus DDS) or bevacizumab monotherapy. Combination therapy eyes received intravitreal bevacizumab at baseline, DDS at Month 1, and subsequent DDS (at Months 5 and 9), whereas monotherapy eyes received bevacizumab (monthly) if indicated. Eyes were eligible for retreatment if the central subfield thickness measured >250 MUm, and Early Treatment of Diabetic Retinopathy Study visual acuity was <80 letters (20/25). RESULTS: Forty eyes of 30 patients were enrolled. The mean visual acuity changes from baseline to 12 months were similar in the 2 groups (combined: +5.4 letters; bevacizumab: +4.9 letters; difference = 0.2 letters, 95% confidence interval = -5.9 to 6.3; P = 0.75). The mean reduction in central subfield thickness was greater in the combination group (-45 MUm vs. -30 MUm, difference = 69 MUm, 95% confidence interval = 9-129; P = 0.03) and more patients in the combination group had central subfield thickness <250 MUm. The combined treatment group received three fewer supplemental injections of bevacizumab, but this was counterbalanced by the need for an average of 2.1 DDS injections. CONCLUSIONS: The dexamethasone implant combined with bevacizumab significantly improves visual acuity and significantly improves macular morphology in eyes with refractory diabetic macular edema, although visual acuity changes are not superior to continued bevacizumab monotherapy. PMID- 25829347 TI - PLASMA CONCENTRATIONS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN RETINOPATHY OF PREMATURITY AFTER INTRAVITREAL BEVACIZUMAB INJECTION. AB - PURPOSE: To investigate the changes in plasma concentrations of vascular endothelial growth factor (VEGF), insulin growth factor (IGF-1), erythropoietin, pigment epithelium-derived factor, and IgG1 after bevacizumab intravitreal injection in infants with retinopathy of prematurity. METHODS: Eleven eyes from six infants who received intravitreal injection of bevacizumab were enrolled in this study. At preinjection and postinjection 1, 2, 3, 4, 5, 6, 7, and 8 weeks, 0.5 mL of blood was collected from each infant. The plasma concentrations of VEGF, insulin growth factor, erythropoietin, pigment epithelium-derived factor, and IgG1 were measured by enzyme-linked immunosorbent assay. Five patients received simultaneous bilateral bevacizumab injection; one patient received unilateral injection. RESULTS: Of the infants who received intravitreal bevacizumab injection, two were males and four were females. The mean gestational age was 26 +/- 2 weeks. The mean birth weight was 870 g. The mean plasma VEGF concentration before bevacizumab injection was 2.05 +/- 3.00 ng/mL; plasma level decreased significantly to 0.16 +/- 0.10 ng/mL and to 0.14 +/- 0.14 ng/mL (P = 0.028) after 1 week and 2 weeks, respectively. Moreover, the plasma concentrations of VEGF did not return to the original level in any of the samples until 8 weeks after the injection. However, mean plasma IgG1, erythropoietin, insulin growth factor, and PEDF concentrations did not change significantly during the interval between preinjection and any other follow-up time points. CONCLUSION: Intravitreal bevacizumab injections significantly reduce plasma VEGF concentration in infants with retinopathy of prematurity over a 7-week period. PMID- 25829348 TI - DIRECTIONAL OPTICAL COHERENCE TOMOGRAPHY PROVIDES ACCURATE OUTER NUCLEAR LAYER AND HENLE FIBER LAYER MEASUREMENTS. AB - PURPOSE: The outer nuclear layer (ONL) contains photoreceptor nuclei, and its thickness is an important biomarker for retinal degenerations. Accurate ONL thickness measurements are obscured in standard optical coherence tomography (OCT) images because of Henle fiber layer (HFL). Improved differentiation of the ONL and HFL boundary is made possible by using directional OCT, a method that purposefully varies the pupil entrance position of the OCT beam. METHODS: Fifty seven normal eyes were imaged using multiple pupil entry positions with a commercial spectral domain OCT system. Cross-sectional image sets were registered to each other and segmented at the top of HFL, the border of HFL and the ONL and at the external limiting membrane. Thicknesses of the ONL and HFL were measured and analyzed. RESULTS: The true ONL and HFL thicknesses varied substantially by eccentricity and between individuals. The true macular ONL thickness comprised an average of 54.6% of measurements that also included HFL. The ONL and HFL thicknesses at specific retinal eccentricities were poorly correlated. CONCLUSION: Accurate ONL and HFL thickness measurements are made possible by the optical contrast of directional OCT. Distinguishing these individual layers can improve clinical trial endpoints and assessment of disease progression. PMID- 25829350 TI - PERIPAPILLARY ATROPHY WITH LARGE DEHISCENCES IN BRUCH MEMBRANE IN PSEUDOXANTHOMA ELASTICUM. AB - PURPOSE: To describe a new set of findings in eyes with pseudoxanthoma elasticum, specifically large defects in Bruch membrane. METHODS: Retrospective review of the optical coherence tomography image obtained with the Heidelberg Spectralis of the posterior pole of patients with pseudoxanthoma elasticum. Large dehiscences in Bruch membrane were defined as any defect in Bruch membrane greater than 250 um in diameter that was not contiguous with a visible angioid streak. RESULTS: There were 28 eyes of 14 patients, with a mean age of 53.6 years; 10 were female. Large dehiscences in Bruch membrane were seen in nine eyes of six patients, and all were within peripapillary atrophy manifested by loss of the choroid and retinal pigment epithelium. The edges of Bruch membrane showed an abrupt termination in the optical coherence tomography images, and often with an upturned edge surrounding the region devoid of Bruch membrane. The mean refractive error of the patients was -2.1 diopters (D) in the right eye and -2.5 D in the left. CONCLUSION: Pseudoxanthoma elasticum shares peripapillary atrophy and large dehiscences of Bruch membrane with pathologic myopia. Although theories of pathologic myopia involve stresses from ocular expansion, those of pseudoxanthoma elasticum typically do not. The Bruch membrane defect in pseudoxanthoma elasticum may be related to fragility secondary to abnormal calcification and to the surrounding abiotrophy of surrounding affected tissues of the posterior pole of the eye. PMID- 25829349 TI - INTRAOPERATIVE SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING AFTER INTERNAL LIMITING MEMBRANE PEELING IN IDIOPATHIC EPIRETINAL MEMBRANE WITH CONNECTING STRANDS. AB - PURPOSE: To report the intraoperative optical coherence tomography findings in idiopathic epiretinal membrane (ERM) with connecting strands and to describe the postoperative outcomes. METHODS: A retrospective, case series study within a prospective observational intraoperative optical coherence tomography imaging study was performed. Epiretinal membranes with connecting strands were characterized on preoperative spectral domain optical coherence tomography images and assessed against corresponding intraoperative (after internal limiting membrane [ILM] peeling) and postoperative spectral domain optical coherence tomography images. RESULTS: Eleven locations of the connecting strands in 7 eyes were studied. The connecting strands had visible connections from the inner retinal surface to the ERM in all locations, and the reflectivity was moderate in 8 locations and high in 3 locations. After ERM and ILM peeling, disconnected strands were identified in all of the intraoperative optical coherence tomography images. The reflectivity of the remaining intraoperative strands was higher than that of the preoperative lesions and appeared as "finger-like" and branching projections. The remaining disconnected lesions were contiguous with the inner retinal layers. Postoperatively, the intraoperative lesions disappeared completely in all locations, and recurrent formation of ERM was not identified in any eyes. CONCLUSION: In ERM eyes with connecting strands, intraoperative spectral domain optical coherence tomography imaging showed moderately to highly reflective sub-ILM finger-like lesions that persist immediately after membrane and ILM peeling. Postoperatively, the hyperreflective lesions disappeared spontaneously without localized nerve fiber layer loss. The sub-ILM connecting strands may represent glial retinal attachments. PMID- 25829351 TI - Copper-catalysed cross-coupling: an untapped potential. AB - Copper is emerging as a viable catalytic metal for cross-coupling reactions to construct carbon-carbon (C-C) bonds. Recent revelations that Cu-catalysts can execute with high efficacy the cross-couplings of a variety of organometallic reagents, including organomagnesium, organoboron, organosilicon, organoindium and organomanganese, with alkyl, aryl and heteroaryl halides clearly demonstrate the versatility of Cu-based catalytic systems in conducting these reactions. In addition, Cu-catalysts are exhibiting a unique reactivity pattern that allows ligandless cross-coupling for aryl-heteroaryl and heteroaryl-heteroaryl bond formation, a transformation that generally requires special custom-designed ligands with Pd-catalysts. This review summarises early discoveries and subsequent advancements made in the area of Cu-catalysed cross-couplings of organometallic reagents with organohalides to form C-C bonds. PMID- 25829352 TI - Stereoselective synthesis of the Halaven C14-C26 fragment from D-quinic acid: crystallization-induced diastereoselective transformation of an alpha-methyl nitrile. AB - Crystallization-induced diastereoselective transformation (CIDT) of an alpha methyl nitrile completes an entirely non-chromatographic synthesis of the halichondrin B C14-C26 stereochemical array. The requisite alpha-methyl nitrile substrate is derived from D-quinic acid through a series of substrate-controlled stereoselective reactions via a number of crystalline intermediates that benefit from a rigid polycyclic template. Therefore, all four stereogenic centers in the Halaven C14-C26 fragment were derived from the single chiral source D-quinic acid. PMID- 25829353 TI - Effect of leaf incubation temperature profiles on Agrobacterium tumefaciens mediated transient expression. AB - Agrobacterium tumefaciens-mediated transient expression is known to be highly dependent on incubation temperature. Compared with early studies that were conducted at constant temperature, we examined the effect of variable leaf incubation temperature on transient expression. As a model system, synthetic endoglucanase (E1) and endoxylanase (Xyn10A) genes were transiently expressed in detached whole sunflower leaves via vacuum infiltration for biofuel applications. We found that the kinetics of transient expression strongly depended on timing of the temperature change as well as leaf incubation temperature. Surprisingly, we found that high incubation temperature (27-30 degrees C) which is suboptimal for T-DNA transfer, significantly enhanced transient expression if the high temperature was applied during the late phase (Day 3-6) of leaf incubation whereas incubation temperature in a range of 20-25 degrees C for an early phase (Day 0-2) resulted in higher production. On the basis of these results, we propose that transient expression is governed by both T-DNA transfer and protein synthesis in plant cells that have different temperature dependent kinetics. Because the phases were separated in time and had different optimal temperatures, we were then able to develop a novel two phase optimization strategy for leaf incubation temperature. Applying the time-varying temperature profile, we were able to increase the protein accumulation by fivefold compared with the control at a constant temperature of 20 degrees C. From our knowledge, this is the first report illustrating the effect of variable temperature profiling for improved transient expression. PMID- 25829354 TI - Fixation and Immunolabeling of Brain Slices: SNAPSHOT Method. AB - Acute brain slices are widely used in neuroscience because this preparation enables pharmacological interventions in a timely manner, similar to what is currently done in cultured cell studies, while preserving the natural cytoarchitecture. However, compared with cells in culture and thin cryostat sections, acute brain slices are not commonly used for immunolabeling because of poor fixation and antibody penetration. Thus, we have established a novel protocol to overcome these issues. We named this protocol SNAPSHOT (StaiNing of dynAmic ProcesseS in HOt-fixed Tissue) because it describes a simple approach for preserving the morphology of fine dynamic cellular processes at the exact time of fixation and for improving the penetration of antibodies. We have previously shown that SNAPSHOT preserves the ultrastructure of the tissue and allows for a uniform immunolabeling throughout a 300 MUm thick slice. SNAPSHOT has recently proven to be beneficial in addressing several unique biological questions. PMID- 25829355 TI - Tracking neuronal migration in adult brain slices. AB - Neuronal migration is one of the fundamental processes underlying the proper assembly and function of neural circuitry. The majority of neuronal precursors are generated far away from their sites of integration and need to migrate substantial distances to reach their final destination. Neuronal migration occurs not only in the embryonic brain but also in a few regions of the adult brain such as the olfactory bulb (OB). The mechanisms orchestrating cell migration in the adult brain are, however, poorly understood, despite their clinical relevance. Here we describe a method for time-lapse imaging of cell migration in acute brain slices. This method, combined with genetic and/or pharmacological manipulations of different molecular pathways, makes it possible to determine the dynamics and molecular mechanisms of cell migration in the adult brain. In addition, time lapse imaging in acute brain slices makes it possible to monitor cell movement in a microenvironment that closely resembles in vivo conditions and to study neuroblast displacement along with other cellular elements such as astrocytes and blood vessels. PMID- 25829356 TI - Latent sensitization: a model for stress-sensitive chronic pain. AB - Latent sensitization is a rodent model of chronic pain that reproduces both its episodic nature and its sensitivity to stress. It is triggered by a wide variety of injuries ranging from injection of inflammatory agents to nerve damage. It follows a characteristic time course in which a hyperalgesic phase is followed by a phase of remission. The hyperalgesic phase lasts between a few days to several months, depending on the triggering injury. Injection of MU-opioid receptor inverse agonists (e.g., naloxone or naltrexone) during the remission phase induces reinstatement of hyperalgesia. This indicates that the remission phase does not represent a return to the normal state, but rather an altered state in which hyperalgesia is masked by constitutive activity of opioid receptors. Importantly, stress also triggers reinstatement. Here we describe in detail procedures for inducing and following latent sensitization in its different phases in rats and mice. PMID- 25829357 TI - Matrix Metalloproteinase 14 Overexpression Is Correlated with the Progression and Poor Prognosis of Nasopharyngeal Carcinoma. AB - BACKGROUND AND AIMS: Matrix metalloproteinase 14 (MMP14) has been identified to play a significant role in several types of cancers, but little is known about the significance of MMP14 in nasopharyngeal carcinoma (NPC) patients. The aim of this study was to explore the association of MMP14 expression with clinicopathologic features and prognosis in NPC. METHODS: MMP14 mRNA and protein expressions were examined in NPC and nasopharyngeal tissues through real-time PCR and immunohistochemistry. Meanwhile, the relationship of MMP14 expression levels with clinical features and prognosis of NPC patients was analyzed. RESULTS: MMP14 mRNA expression was markedly higher in NPC tissues than in nasopharyngeal epithelium tissues (p = 0.002). Using immunohistochemistry, staining for MMP14 protein was found in the normal nasopharyngeal epithelial cells and malignant epithelial cells, but increased expression of MMP14 was observed in NPC samples compared with normal nasopharyngeal epithelium samples (p = 0.027). In addition, high levels of MMP14 protein were positively correlated with the status of clinical stage (p = 0.009), N classification (p = 0.006), and distant metastasis (p = 0.005) of NPC patients. Patients with higher MMP14 expression had a significantly shorter overall survival time than did patients with low MMP14 expression. Multivariate analysis indicated that the level of MMP14 expression was an independent prognostic indicator (p < 0.001) for the survival of patients with NPC. CONCLUSIONS: MMP14 overexpression is a potentially unfavorable prognostic factor for NPC patients. PMID- 25829358 TI - Histology of the heterostracan dermal skeleton: Insight into the origin of the vertebrate mineralised skeleton. AB - Living vertebrates are divided into those that possess a fully formed and fully mineralised skeleton (gnathostomes) versus those that possess only unmineralised cartilaginous rudiments (cyclostomes). As such, extinct phylogenetic intermediates of these living lineages afford unique insights into the evolutionary assembly of the vertebrate mineralised skeleton and its canonical tissue types. Extinct jawless and jawed fishes assigned to the gnathostome stem evidence the piecemeal assembly of skeletal systems, revealing that the dermal skeleton is the earliest manifestation of a homologous mineralised skeleton. Yet the nature of the primitive dermal skeleton, itself, is poorly understood. This is principally because previous histological studies of early vertebrates lacked a phylogenetic framework required to derive evolutionary hypotheses. Nowhere is this more apparent than within Heterostraci, a diverse clade of primitive jawless vertebrates. To this end, we surveyed the dermal skeletal histology of heterostracans, inferred the plesiomorphic heterostracan skeleton and, through histological comparison to other skeletonising vertebrate clades, deduced the ancestral nature of the vertebrate dermal skeleton. Heterostracans primitively possess a four-layered skeleton, comprising a superficial layer of odontodes composed of dentine and enameloid; a compact layer of acellular parallel-fibred bone containing a network of vascular canals that supply the pulp canals (L1); a trabecular layer consisting of intersecting radial walls composed of acellular parallel-fibred bone, showing osteon-like development (L2); and a basal layer of isopedin (L3). A three layered skeleton, equivalent to the superficial layer L2 and L3 and composed of enameloid, dentine and acellular bone, is possessed by the ancestor of heterostracans + jawed vertebrates. We conclude that an osteogenic component is plesiomorphic with respect to the vertebrate dermal skeleton. Consequently, we interpret the dermal skeleton of denticles in chondrichthyans and jawless thelodonts as independently and secondarily simplified. J. Morphol. 276:657-680, 2015. (c) 2015 The Authors Journal of Morphology Published by Wiley Periodicals, Inc. PMID- 25829359 TI - Ungoutedly time for a change. PMID- 25829360 TI - Spectroscopic study on the interaction of bovine serum albumin with zinc(II) phthalocyanine. AB - The interaction between the photosensitive antitumour drug, 2(3),9(10),16(17),23(24)-tetra-(((2 aminoethylamino)methyl)phenoxy)phthalocyaninato-zinc(II) (ZnPc) and bovine serum albumin (BSA) has been investigated using various spectroscopic methods. This work may provide some useful information for understanding the interaction mechanism of anticancer drug-albumin binding and gain insight into the biological activity and metabolism of the drug in blood. Based on analysis of the fluorescence spectra, ZnPc could quench the intrinsic fluorescence of BSA and the quenching mechanism was static by forming a ground state complex. Meanwhile, the Stern-Volmer quenching constant (KSV), binding constant (Kb), number of binding sites (n) and thermodynamic parameters were obtained. Results showed that the interaction of ZnPc with BSA occurred spontaneously via hydrogen bond and van der Waal's force. According to Foster's non-radioactive energy transfer theory, the energy transfer from BSA to ZnPc occurred with high possibility. Synchronous fluorescence and circular dichroism (CD) spectra also demonstrated that ZnPc induced the secondary structure of and conformation changes in BSA, especially alpha helix. PMID- 25829361 TI - Chemical synthesis of phosphorylated ubiquitin and diubiquitin exposes positional sensitivities of e1-e2 enzymes and deubiquitinases. AB - Modification of ubiquitin by phosphorylation extends the signaling possibilities of this dynamic signal, as it could affect the activity of ligases and the processing of ubiquitin chains by deubiquitinases. The first chemical synthesis of phosphorylated ubiquitin and of Lys63-linked diubiquitin at the proximal, distal or both ubiquitins is reported. This enabled the examination of how such a modification alters E1-E2 activities of the ubiquitination machinery. It is found that E1 charging was not affected, while the assembly of phosphorylated ubiquitin chains was differentially inhibited with E2 enzymes tested. Moreover, this study shows that phosphorylation interferes with the recognition of linkage specific antibodies and the activities of several deubiquitinases. Notably, phosphorylation in the proximal or distal ubiquitin unit has differential effects on specific deubiquitinases. These results support a unique role of phosphorylation in the dynamics of the ubiquitin signal. PMID- 25829362 TI - Cohort Profile: The Barwon Infant Study. AB - The modern environment is associated with an increasing burden of non communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population derived birth cohort study (n = 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2- and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [peter.vuillermin@deakin.edu.au]. PMID- 25829363 TI - Evaluating the interaction between UCOE and DHFR-linked amplification and stability of recombinant protein expression. AB - Chinese hamster ovary (CHO) cells are widely used in the biopharmaceutical industry. In the creation of mammalian cell lines plasmid DNA carrying the gene of-interest integrates randomly into the host cell genome, which results in variable levels of gene expression between cell lines due to gene silencing mechanisms. In addition, cell lines often show unstable protein production during long-term culture. This means that a large number of clones need to be screened in order to isolate stable, high producing cell lines making mammalian cell line development a long and laborious process. In this study an expression platform incorporating a Ubiquitous Chromatin Opening Element (UCOE; which are proposed to maintain chromatin in an open state) has been utilised for the expression of eGFP in CHO cells. Cell lines containing a UCOE vector, showed a significantly higher and more consistent eGFP expression than the non-UCOE cell lines without DHFR amplification. To further improve recombinant protein production cell lines were amplified with methotrexate (MTX). UCOE cell lines showed improved growth in MTX therefore amplification to 250 nM MTX was achieved following a one-step amplification procedure. However, non-UCOE cell lines showed higher levels of eGFP production following MTX amplification. In addition, UCOE cell lines did not improve stability during long-term culture in the absence of selective pressure. Stable eGFP production was achieved for all cell lines when MTX is present. Finally, UCOE cell lines displayed more consistent response to external stimuli than non-UCOE cell lines, suggesting that UCOE cell lines are less prone to clonal variability. PMID- 25829364 TI - Silent Synapses Speak Up: Updates of the Neural Rejuvenation Hypothesis of Drug Addiction. AB - A transient but prominent increase in the level of "silent synapses"--a signature of immature glutamatergic synapses that contain only NMDA receptors without stably expressed AMPA receptors--has been identified in the nucleus accumbens (NAc) following exposure to cocaine. As the NAc is a critical forebrain region implicated in forming addiction-associated behaviors, the initial discoveries have raised speculations about whether and how these drug-induced synapses mature and potentially contribute to addiction-related behaviors. Here, we summarize recent progress in recognizing the pathway-specific regulations of silent synapse maturation, and its diverse impacts on behavior. We provide an update of the guiding hypothesis--the "neural rejuvenation hypothesis"--with recently emerged evidence of silent synapses in cocaine craving and relapse. PMID- 25829365 TI - Continuous daily use of cilostazol prevents in-stent restenosis following carotid artery stenting: serial angiographic investigation of 229 lesions. AB - BACKGROUND: Several studies have reported that cilostazol (CLS) may reduce in stent restenosis (ISR) after carotid artery stenting (CAS). However, it is not known for how long CLS must be continued to prevent ISR. METHODS: We retrospectively reviewed a prospectively collected database of patients who underwent elective CAS and follow-up angiography at 3 months and 1 year after the procedure. ISR was defined as stenosis of 50% or greater on digital subtraction angiography. The cumulative incidence rates of angiographic ISR were compared between the three groups, divided according to duration of CLS use : (1) patients who were maintained on CLS for 12 months or more after CAS (12M CLS group, n=70), (2) patients who were treated with CLS for the first 3 months after CAS (3M CLS group, n=23), and (3) patients who did not receive CLS (no CLS group, n=136). RESULTS: A total of 229 lesions in 199 patients were included in our analysis. During a median follow-up of 365 days, ISR was detected in 15 lesions. The cumulative ISR rates overall and in the 12M CLS, 3M CLS, and no CLS groups were 5.6%, 0%, 5.0%, and 8.4%, respectively, at 1 year, and the log rank test showed that there was a significant difference between the three groups (p<0.05). Cox regression analysis demonstrated that the 12M CLS group had a significantly lower risk of ISR than the 3M CLS group (adjusted relative risk (aRR) 3.06e-10, 95% CI 0 to 0.51, p<0.05) and the no CLS group (aRR 1.41e-10, 95% CI 0 to 0.15, p<0.001), whereas no difference was found between the 3M CLS group and the no CLS group. CONCLUSIONS: An overall cumulative ISR rate of 5.6% was documented angiographically at 1 year after CAS. Continuous daily use of CLS (for at least 1 year) may have a beneficial effect on long term prevention of ISR. PMID- 25829366 TI - The Bundled Payments for Care Improvement Initiative. AB - The Affordable Care Act enters its fifth year firmly entrenched in our national consciousness. One method that has entered the vernacular for achieving cost savings is accountable care. There are other approaches that are less well known. The Bundled Payments for Care Improvement Initiative has the potential to significantly impact neurointerventionalists. We review that initiative here. PMID- 25829367 TI - Pd nanoparticles on ZnO-passivated porous carbon by atomic layer deposition: an effective electrochemical catalyst for Li-O2 battery. AB - Uniformly dispersed Pd nanoparticles on ZnO-passivated porous carbon were synthesized via an atomic layer deposition (ALD) technique, which was tested as a cathode material in a rechargeable Li-O2 battery, showing a highly active catalytic effect toward the electrochemical reactions-in particular, the oxygen evolution reaction. Transmission electron microscopy (TEM) showed discrete crystalline nanoparticles decorating the surface of the ZnO-passivated porous carbon support in which the size could be controlled in the range of 3-6 nm, depending on the number of Pd ALD cycles performed. X-ray absorption spectroscopy (XAS) at the Pd K-edge revealed that the carbon-supported Pd existed in a mixed phase of metallic palladium and palladium oxide. The ZnO-passivated layer effectively blocks the defect sites on the carbon surface, minimizing the electrolyte decomposition. Our results suggest that ALD is a promising technique for tailoring the surface composition and structure of nanoporous supports for Li O2 batteries. PMID- 25829368 TI - Correction. Overweight and obesity on the island of Ireland: an estimation of costs. PMID- 25829369 TI - Educational interventions for improving control of blood pressure in patients with hypertension: a systematic review protocol. AB - INTRODUCTION: The aim of this review is to evaluate the effectiveness of educational interventions on improving the control of blood pressure in patients with hypertension. METHODS: Randomised controlled trials including patients over 18 years of age, regardless of sex and ethnicity, with a diagnosis of hypertension (either treated or not treated with antihypertensive medications) will be assessed in our analysis. We will electronically search four databases: MEDLINE, CINAHL, PEDro and ScienceDirect. There will be no language restrictions in the search for studies. The data will be extracted independently by two authors using predefined criteria. Disagreements will be resolved between the authors. The risk of bias will be assessed using the Cochrane risk of bias tool. After searching and screening of the studies, we will run a meta-analysis of the included randomised controlled trials. We will summarise the results as risk ratio for dichotomous data and mean differences for continuous data. ETHICS AND DISSEMINATION: The review will be published in a journal. The findings from the review will also be disseminated electronically and at conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO CRD4201401071. PMID- 25829370 TI - Levels, trends and reasons for unmet need for family planning among married women in Botswana: a cross-sectional study. AB - OBJECTIVES: The objectives of this study are: (1) to estimate the prevalence of unmet need for family planning among married women using Botswana Family Health Survey 2007 data and (2) to identify risk factors for unmet need for family planning among married women. DESIGN: This study used secondary data from a cross sectional survey that was conducted to provide a snapshot of health issues in Botswana. SETTING: Nationally representative population survey data. PARTICIPANTS: 2601 married or in union women aged 15-49 years who participated in the 2007 Botswana Family Health Survey were included in the analysis. PRIMARY OUTCOME: Unmet need for family planning, which was defined as the percentage of all fecund married women who are not using a method of contraception even though they do not want to get pregnant. RESULTS: Married women who had unmet need for family planning were 9.6% in 2007. Most of the unmet need was for limiting (6.7%) compared to spacing (2.9%). Unmet need for family planning was more likely to be among women whose partners disapproved of family planning, non-Christians, had one partner and had never discussed family planning with their partner. Women of low parity, aged 25-34 years, and greater exposure to mass media, were less likely to have experienced unmet need. The patterns and magnitude of covariates differed between unmet need for limiting and for spacing. CONCLUSIONS: The prevalence of unmet need for family planning was low in Botswana compared to other sub-Saharan African countries. The findings from this study reemphasise the importance of women's empowerment and men's involvement in women's sexual and reproductive healthcare needs and services. Different approaches are needed to satisfy the demand for family planning for spacing and limiting. PMID- 25829371 TI - Impaired mental well-being and psychosocial risk: a cross-sectional study in female nursing home direct staff. AB - OBJECTIVES: The present study sought to quantify the impaired mental well-being and psychosocial stress experienced by nursing home staff and to determine the relationship between impaired mental well-being assessed on the 12-item General Health Questionnaire (GHQ-12) and exposure to psychosocial stress assessed on Siegrist's effort/reward and overcommitment model. METHODS: A transverse study was conducted in France on 2471 female employees in 105 nursing homes for the elderly. Personal and occupational data were collected by questionnaire for 668 housekeepers, 1454 nursing assistants and 349 nurses. RESULTS: 36.8% of participants (n=896) showed impaired mental well-being, 42.7% (n=1039) overcommitment and 9% (n=224) effort/reward imbalance. Overcommitment (prevalence ratio (PR)=1.27; 95% CI (1.21 to 1.34)) and effort-reward imbalance (PR=1.19; 95% CI (1.12 to 1.27)) were significantly associated with presence of impaired mental well-being after adjustment for personal factors (age and private life events). Taking effort and reward levels into account, the frequency of impaired mental well-being was highest in case of exposure to great extrinsic effort and low rewards of any type: esteem, PR=3.53, 95% CI (3.06 to 4.08); earnings, PR=3.48, 95% CI (2.99 to 4.06); or job security, PR=3.30, 95% CI (2.88 to 3.78). Participants in situations of overcommitment and of effort/reward imbalance were at the highest risk of impaired mental well-being: PR=3.86, 95% CI (3.42 to 4.35). CONCLUSIONS: Several changes in nursing home organisation can be suggested to reduce staff exposure to factors of psychosocial stress. Qualitative studies of the relation between impaired mental well-being and psychosocial stress in nursing home staff could guide prevention of impaired mental well-being at work. PMID- 25829372 TI - National Audit of Seizure management in Hospitals (NASH): results of the national audit of adult epilepsy in the UK. AB - OBJECTIVES: About 100,000 people present to hospitals each year in England with an epileptic seizure. How they are managed is unknown; thus, the National Audit of Seizure management in Hospitals (NASH) set out to assess prior care, management of the acute event and follow-up of these patients. This paper describes the data from the second audit conducted in 2013. SETTING: 154 emergency departments (EDs) across the UK. PARTICIPANTS: Data from 4544 attendances (median age of 45 years, 57% men) showed that 61% had a prior diagnosis of epilepsy, 12% other neurological problems and 22% were first seizure cases. Each ED identified 30 consecutive adult cases presenting due to a seizure. PRIMARY AND SECONDARY OUTCOME MEASURES: Details were recorded of the patient's prior care, management at hospital and onward referral to neurological specialists onto an online database. Descriptive results are reported at national level. RESULTS: Of those with epilepsy, 498 (18%) were on no antiepileptic drug therapy and 1330 (48%) were on monotherapy. Assessments were often incomplete and witness histories were sought in only 759 (75%) of first seizure patients, 58% were seen by a senior doctor and 57% were admitted. For first seizure patients, advice on further seizure management was given to 264 (27%) and only 55% were referred to a neurologist or epilepsy specialist. For each variable, there was wide variability among sites that was not explicable. For the sites who partook in both audits, there was a trend towards better care in 2013, but this was small and dwarfed by the intersite variability. CONCLUSIONS: These results have parallels with the Sentinel Audit of Stroke performed a decade earlier. There is wide intersite variability in care covering the entire care pathway, and a need for better organised and accessible care for these patients. PMID- 25829373 TI - Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial. AB - INTRODUCTION: Finding therapeutic alternatives to carbapenems in infections caused by extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) is imperative. Although fosfomycin was discovered more than 40 years ago, it was not investigated in accordance with current standards and so is not used in clinical practice except in desperate situations. It is one of the so-called neglected antibiotics of high potential interest for the future. METHODS AND ANALYSIS: The main objective of this project is to demonstrate the clinical non inferiority of intravenous fosfomycin with regard to meropenem for treating bacteraemic urinary tract infections (UTI) caused by ESBL-EC. This is a 'real practice' multicentre, open-label, phase III randomised controlled trial, designed to compare the clinical and microbiological efficacy, and safety of intravenous fosfomycin (4 g/6 h) and meropenem (1 g/8 h) as targeted therapy for this infection; a change to oral therapy is permitted after 5 days in both arms, in accordance with predetermined options. The study design follows the latest recommendations for designing trials investigating new options for multidrug resistant bacteria. Secondary objectives include the study of fosfomycin concentrations in plasma and the impact of both drugs on intestinal colonisation by multidrug-resistant Gram-negative bacilli. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Andalusian Coordinating Institutional Review Board (IRB) for Biomedical Research (Referral Ethics Committee), which obtained approval from the local ethics committees at all participating sites in Spain (22 sites). Data will be presented at international conferences and published in peer reviewed journals. DISCUSSION: This project is proposed as an initial step in the investigation of an orphan antimicrobial of low cost with high potential as a therapeutic alternative in common infections such as UTI in selected patients. These results may have a major impact on the use of antibiotics and the development of new projects with this drug, whether as monotherapy or combination therapy. TRIAL REGISTRATION NUMBER: NCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014. PMID- 25829374 TI - Protocol for a pre-implementation and post-implementation study on shared decision-making in the surgical treatment of women with early-stage breast cancer. AB - BACKGROUND: The majority of patients diagnosed with early-stage breast cancer are in a position to choose between having a mastectomy or lumpectomy with radiation therapy (breast-conserving therapy). Since the long-term survival rates for mastectomy and for lumpectomy with radiation therapy are comparable, patients' informed preferences are important for decision-making. Although most clinicians believe that they do include patients in the decision-making process, the information that women with breast cancer receive regarding the surgical options is often rather subjective, and does not invite patients to express their preferences. Shared decision-making (SDM) is meant to help patients clarify their preferences, resulting in greater satisfaction with their final choice. Patient decision aids can be very supportive in SDM. We present the protocol of a study to beta test a patient decision aid and optimise strategies for the implementation of SDM regarding the treatment of early-stage breast cancer in the actual clinical setting. METHODS/DESIGN: This paper concerns a pre-implementation and post-implementation study, lasting from October 2014 to June 2015. The intervention consists of implementing SDM using a patient decision aid. The intervention will be evaluated using qualitative and quantitative measures, acquired prior to, during and after the implementation of SDM. Outcome measures are knowledge about treatment, perceived SDM and decisional conflict. We will also conduct face-to-face interviews with a sample of these patients and their care providers, to assess their experiences with the implementation of SDM and the patient decision aid. ETHICS AND DISSEMINATION: This protocol was approved by the Maastricht University Medical Centre (MUMC) ethics committee. The findings will be disseminated through peer-reviewed journal articles and presentations at national conferences. Findings will be used to finalise a multi-faceted implementation strategy to test the implementation of SDM and a patient decision aid in terms of cost-effectiveness, in a multicentre cluster randomised controlled trial (RCT). STUDY REGISTRATION NUMBER: NTR4879. PMID- 25829375 TI - Cortisol and Inflammatory Biomarkers Predict Poor Treatment Response in First Episode Psychosis. AB - BACKGROUND: Cortisol and inflammatory markers have been increasingly reported as abnormal at psychosis onset. The main aim of our study was to investigate the ability of these biomarkers to predict treatment response at 12 weeks follow-up in first episode psychosis. METHODS: In a longitudinal study, we collected saliva and blood samples in 68 first episode psychosis patients (and 57 controls) at baseline and assessed response to clinician-led antipsychotic treatment after 12 weeks. Moreover, we repeated biological measurements in 39 patients at the same time we assessed the response. Saliva samples were collected at multiple time points during the day to measure diurnal cortisol levels and cortisol awakening response (CAR); interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha, and interferon-gamma (IFN-gamma) levels were analyzed from serum samples. Patients were divided into Non-Responders (n = 38) and Responders (n = 30) according to the Remission symptom criteria of the Schizophrenia Working Group Consensus. RESULTS: At first onset, Non-Responders had markedly lower CAR (d = 0.6, P = .03) and higher IL-6 and IFN-gamma levels (respectively, d = 1.0, P = .003 and d = 0.9, P = .02) when compared with Responders. After 12 weeks, Non Responders show persistent lower CAR (P = .01), and higher IL-6 (P = .04) and IFN gamma (P = .05) when compared with Responders. Comparison with controls show that these abnormalities are present in both patients groups, but are more evident in Non-Responders. CONCLUSIONS: Cortisol and inflammatory biomarkers at the onset of psychosis should be considered as possible predictors of treatment response, as well as potential targets for the development of novel therapeutic agents. PMID- 25829376 TI - Interaction Between Functional Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis. AB - Both cannabis use and the dopamine receptor (DRD2) gene have been associated with schizophrenia, psychosis-like experiences, and cognition. However, there are no published data investigating whether genetically determined variation in DRD2 dopaminergic signaling might play a role in individual susceptibility to cannabis associated psychosis. We genotyped (1) a case-control study of 272 patients with their first episode of psychosis and 234 controls, and also from (2) a sample of 252 healthy subjects, for functional variation in DRD2, rs1076560. Data on history of cannabis use were collected on all the studied subjects by administering the Cannabis Experience Questionnaire. In the healthy subjects' sample, we also collected data on schizotypy and cognitive performance using the Schizotypal Personality Questionnaire and the N-back working memory task. In the case-control study, we found a significant interaction between the rs1076560 DRD2 genotype and cannabis use in influencing the likelihood of a psychotic disorder. Among cannabis users, carriers of the DRD2, rs1076560, T allele showed a 3-fold increased probability to suffer a psychotic disorder compared with GG carriers (OR = 3.07; 95% confidence interval [CI]: 1.22-7.63). Among daily users, T carrying subjects showed a 5-fold increase in the odds of psychosis compared to GG carriers (OR = 4.82; 95% CI: 1.39-16.71). Among the healthy subjects, T carrying cannabis users had increased schizotypy compared with T carrying cannabis-naive subjects, GG cannabis users, and GG cannabis-naive subjects (all P <= .025). T carrying cannabis users had reduced working memory accuracy compared with the other groups (all P <= .008). Thus, variation of the DRD2, rs1076560, genotype may modulate the psychosis-inducing effect of cannabis use. PMID- 25829378 TI - Non-structural carbohydrate profiles and ratios between soluble sugars and starch serve as indicators of productivity for a bioenergy grass. AB - There is a pressing need to find a sustainable alternative to fossil fuels that will not compromise food security or require extensive use of agrochemicals. Miscanthus is a perennial energy grass predominantly used for combustion but with the current advancement of ligno-cellulosic fermentation technologies there is an interest in using Miscanthus for bioethanol production. Currently, the only commercially grown genotype of Miscanthus is M.* giganteus; a high yielding, interspecific hybrid of M. sacchariflorus and M. sinensis. As M.* giganteus is a sterile triploid, it cannot be used as a parent so Miscanthus breeding effort is focused on producing new interspecific varieties that out-perform M.* giganteus. The carbohydrate profiles of four genotypes of Miscanthus, including M. sacchariflorus (Sac-5), M.* giganteus (Gig-311), M. sinensis (Sin-11) and M. sinensis (Goliath), were characterized at replicated field sites in Aberystwyth, West Wales and Harpenden, south-east England. Our hypothesis was that a distinctive carbohydrate profile underlies enhanced biomass accumulation. Biomass accumulation is greatest when day-lengths and solar intensity are highest; so, observations were made in the middle of UK summer (July) for 2 years. Gig-311 had a greater abundance of fructose in its stems at both sites, and both Gig-311 and Sac-5 had low abundance of starch. At both sites, the highest yielding genotype was Gig-311 and Sac-5 was also high yielding at Harpenden, but performed comparatively poorly at Aberystwyth. At both sites Gig-311 had a distinctly high concentration of fructose, low starch and a high ratio of soluble sugars: starch, and at Harpenden, Sac-5 was similar. We conclude that the abundance of starch and fructose and a greater partitioning of soluble sugars, relative to starch, are candidate biomarkers of productivity in Miscanthus. PMID- 25829377 TI - Physical Exercise Keeps the Brain Connected: Biking Increases White Matter Integrity in Patients With Schizophrenia and Healthy Controls. AB - It has been shown that learning a new skill leads to structural changes in the brain. However, it is unclear whether it is the acquisition or continuous practicing of the skill that causes this effect and whether brain connectivity of patients with schizophrenia can benefit from such practice. We examined the effect of 6 months exercise on a stationary bicycle on the brain in patients with schizophrenia and healthy controls. Biking is an endemic skill in the Netherlands and thus offers an ideal situation to disentangle the effects of learning vs practice. The 33 participating patients with schizophrenia and 48 healthy individuals were assigned to either one of two conditions, ie, physical exercise or life-as-usual, balanced for diagnosis. Diffusion tensor imaging brain scans were made prior to and after intervention. We demonstrate that irrespective of diagnosis regular physical exercise of an overlearned skill, such as bicycling, significantly increases the integrity, especially of motor functioning related, white matter fiber tracts whereas life-as-usual leads to a decrease in fiber integrity. Our findings imply that exercise of an overlearned physical skill improves brain connectivity in patients and healthy individuals. This has important implications for understanding the effect of fitness programs on the brain in both healthy subjects and patients with schizophrenia. Moreover, the outcome may even apply to the nonphysical realm. PMID- 25829379 TI - Improving methods to evaluate the impacts of plant invasions: lessons from 40 years of research. AB - Methods used to evaluate the ecological impacts of biological invasions vary widely from broad-scale observational studies to removal experiments in invaded communities and experimental additions in common gardens and greenhouses. Different methods provide information at diverse spatial and temporal scales with varying levels of reliability. Thus, here we provide a synthetic and critical review of the methods used to evaluate the impacts of plant invasions and provide recommendations for future research. We review the types of methods available and report patterns in methods used, including the duration and spatial scale of studies and plant functional groups examined, from 410 peer-reviewed papers published between 1971 and 2011. We found that there has been a marked increase in papers published on plant invasion impacts since 2003 and that more than half of all studies employed observational methods while <5 % included predictive modelling. Most of the studies were temporally and spatially restricted with 51 % of studies lasting <1 year and almost half of all studies conducted in plots or mesocosms <1 m(2). There was also a bias in life form studied: more than 60 % of all studies evaluated impacts of invasive forbs and graminoids while <16 % focused on invasive trees. To more effectively quantify invasion impacts, we argue that longer-term experimental research and more studies that use predictive modelling and evaluate impacts of invasions on ecosystem processes and fauna are needed. Combining broad-scale observational studies with experiments and predictive modelling may provide the most insight into invasion impacts for policy makers and land managers seeking to reduce the effects of plant invasions. PMID- 25829380 TI - Dominant plant taxa predict plant productivity responses to CO2 enrichment across precipitation and soil gradients. AB - The Earth's atmosphere will continue to be enriched with carbon dioxide (CO2) over the coming century. Carbon dioxide enrichment often reduces leaf transpiration, which in water-limited ecosystems may increase soil water content, change species abundances and increase the productivity of plant communities. The effect of increased soil water on community productivity and community change may be greater in ecosystems with lower precipitation, or on coarser-textured soils, but responses are likely absent in deserts. We tested correlations among yearly increases in soil water content, community change and community plant productivity responses to CO2 enrichment in experiments in a mesic grassland with fine- to coarse-textured soils, a semi-arid grassland and a xeric shrubland. We found no correlation between CO2-caused changes in soil water content and changes in biomass of dominant plant taxa or total community aboveground biomass in either grassland type or on any soil in the mesic grassland (P > 0.60). Instead, increases in dominant taxa biomass explained up to 85 % of the increases in total community biomass under CO2 enrichment. The effect of community change on community productivity was stronger in the semi-arid grassland than in the mesic grassland, where community biomass change on one soil was not correlated with the change in either the soil water content or the dominant taxa. No sustained increases in soil water content or community productivity and no change in dominant plant taxa occurred in the xeric shrubland. Thus, community change was a crucial driver of community productivity responses to CO2 enrichment in the grasslands, but effects of soil water change on productivity were not evident in yearly responses to CO2 enrichment. Future research is necessary to isolate and clarify the mechanisms controlling the temporal and spatial variations in the linkages among soil water, community change and plant productivity responses to CO2 enrichment. PMID- 25829381 TI - Palliative care patients' perceptions of the work involved in understanding and managing the network of care provision surrounding them. AB - OBJECTIVE: To explore the work carried out for cancer palliative care patients in understanding and dealing with the often large network of care provision surrounding them. METHOD: Qualitative thematic analysis of interviews with 24 patients (aged 48-85 years) with 15 different types/sites of cancer and palliative care needs. RESULTS: The main theme of 'patient work-their strategies and project management' is presented. Subthemes included: being organised and keeping records; planning ahead and coordinating care; information gathering; understanding the hierarchy and knowing who the key people are; strategies to remember names and roles; understanding and 'working the system'. Insights are given into the work carried out on patients' behalf by family, although it was unclear who would do this work if no family was available. Some of the challenges faced by patients and families are identified. These included limited information; uncertainty when care is transferred between different teams or locations; deciding who to contact and how; and negotiating through gatekeepers. CONCLUSIONS: The number and variety of people contributing to the care of a cancer palliative care patient can be difficult for patients and family to comprehend. Work is required by patients or family on their behalf to achieve the level of understanding required to become accomplished at navigating the system and project managing their care organisation, and is probably influenced by role expectations and previous experience. Much of this additional, often hidden, workload for patients and family could probably be reduced with clear, timely information provision by health professionals. PMID- 25829387 TI - Transaxillary thyroidectomies: a comparative learning experience of robotic vs endoscopic thyroidectomies. AB - OBJECTIVE: Robotic and endoscopic approaches have become more accepted in thyroid surgery, with current literature documenting the experience of high-volume centers. We adopted both approaches concurrently, and this series presents our initial experience to assess the more practical option for low- to moderate volume centers starting out with transaxillary thyroidectomies. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic center. SUBJECTS AND METHODS: Over a period of 4 years, 101 patients underwent transaxillary thyroidectomies, of whom 48 underwent robotic thyroidectomy and 53 underwent endoscopic thyroidectomy. Data analysis includes patient characteristics, procedure time, thyroid pathology, and postoperative complications. A survey was conducted among surgeons to assess the subjective experience. RESULTS: Endoscopic hemithyroidectomies had a significantly shorter duration of operation (145.8 minutes) vs that of robotic hemithyroidectomies (193.6 minutes), P < .001. The mean time taken for the first 5 hemithyroidectomies vs the last 5 hemithyroidectomies showed a greater drop in the endoscopic group (49.1%) vs the robotic group (18.6%). There were 2 cases of transient recurrent laryngeal nerve injury. In the surgeon survey, the endoscopic technique was perceived to have less need for peripheral support, while the robotic technique was preferred for its shorter learning curve. CONCLUSION: In terms of outcome, both techniques are comparable at least in the initial phase. Based on our early experience, the endoscopic technique may be less intuitive with a longer learning curve, although at steady state, it may be the quicker procedure. This is relevant for low- to moderate-volume centers starting their transaxillary thyroidectomy program. PMID- 25829388 TI - A swallow preservation protocol improves function for veterans receiving chemoradiation for head and neck cancer. AB - OBJECTIVE: Determine the efficacy of a swallow preservation protocol (SPP) on maintaining swallow function in patients undergoing chemoradiation (CRT) or radiation therapy alone (RT) for head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Retrospective case series. SETTING: Veterans Affairs medical center. SUBJECTS AND METHODS: Patients treated with CRT or RT for HNSCC between February 2006 and November 2013 were studied. Those enrolled in the SPP participated in swallowing, jaw, and tongue exercises during cancer therapy. The comparator group received no swallowing intervention during CRT. A previously described functional outcome swallowing scale (FOSS; 0 = no symptoms and 5 = nonoral feeding for all nutrition) was used to quantify dysphagia prior to and at the completion of cancer therapy, and an analysis was performed to compare swallowing function. RESULTS: Forty-one (all male; mean age, 66 years) and 66 patients (all male; mean age, 61 years) were included in the SPP and comparator groups, respectively. In the SPP group, mean pre- and posttreatment FOSS scores were 2.2 and 2.2, respectively, while the corresponding scores in the comparator group were 1.8 and 2.7, respectively, with posttreatment FOSS scores being significantly worse than pretreatment FOSS scores in the comparator group only. CONCLUSION: Patients enrolled in the SPP demonstrated preserved swallowing function over the course of cancer treatment compared with a comparator group. This confirms the importance of early evaluation and intervention for dysphagia prior to and during CRT or RT alone. PMID- 25829389 TI - Standardized outcome and reporting measures in pediatric head and neck lymphatic malformations. AB - OBJECTIVE: To develop general and site-specific treatment effect and outcome measures to standardize the reporting of head and neck lymphatic malformation (HNLM) treatments. STUDY DESIGN: Consensus statement/expert opinion. SETTING: Multiple tertiary academic institutions. SUBJECTS AND METHODS: The modified Delphi method is an iterative process of collecting expert opinions, refining opinions through discussion and feedback, statistically aggregating opinions, and using these aggregates to generate consensus opinion in the absence of other data. The modified Delphi method was used by a multi-institutional group of otolaryngology and interventional radiology experts in the field of vascular anomalies to formulate a list of recommended reporting outcomes for the study and treatment of head and neck lymphatic malformations. RESULTS: Through 3 rounds of iteration, 10 expert panelists refined 98 proposed outcome measures and 9 outcome categories to a final consensus set of 50 recommended outcome measures in 3 global categories (general, demographics, and treatment complications) and 5 site specific categories (orbit, oral cavity, pharynx, larynx, and neck). CONCLUSIONS: We propose the first consensus set of standardized reporting measures for clinical and treatment outcomes in studies of HNLMs. Consistent outcome measures across future studies will facilitate comparison of treatment options and allow systematic review. We hope that these guidelines facilitate the design and reporting of subsequent HNLM studies. PMID- 25829390 TI - Ambulatory thyroidectomy: a multistate study of revisits and complications. AB - OBJECTIVE: Determine rates and reasons for revisits after ambulatory adult thyroidectomy. STUDY DESIGN: Cross-sectional analysis of multistate ambulatory surgery and hospital databases. SETTING: Ambulatory surgery data from the State Ambulatory Surgery Databases of California, Florida, Iowa, and New York for calendar years 2010 and 2011. SUBJECTS AND METHODS: Ambulatory thyroidectomy cases were linked to state ambulatory, emergency, and inpatient databases for revisit encounters occurring within 30 days. The numbers of revisits, mortality, and associated diagnoses were analyzed. RESULTS: A total of 25,634 cases of ambulatory thyroid surgery were identified: 44.2% total thyroidectomy (TT) and 55.8% partial thyroidectomy (PT). Common indications for surgery included goiter/cyst (39.5%), benign/uncertain neoplasm (24.2%), and malignant neoplasm (24.0%). The 30-day revisit rate was 7.2% (n = 1858; 61.8% emergency department, 22.4% inpatient admission, and 15.8% ambulatory surgery center). The most common diagnosis at revisit was hypocalcemia (20.8% of revisits), followed by wound hematoma/seroma/bleeding (7.1%). Higher rates of revisit, hypocalcemia, and hematoma/seroma/bleeding were seen in patients undergoing TT (P < .016 for all). Sixteen patients had bleeding less than 24 hours after the index procedure (0.1% overall, 0.9% of revisits). Most hypocalcemia and hematoma/bleeding occurred over the first postoperative week. Three deaths occurred within 30 days of the index procedure. CONCLUSION: In carefully selected patients, ambulatory thyroidectomy demonstrates a good postoperative morbidity and mortality profile. Common reasons for revisits included hypocalcemia and bleeding/seroma/hematoma, which occurred with relatively high frequencies as late as a week after surgery. Quality improvement measures should be targeted at lowering revisit rates and safely managing complications. PMID- 25829391 TI - Characterization of Vestibulopathy in Individuals with Type 2 Diabetes Mellitus. AB - OBJECTIVE: Previous observational studies suggest higher rates of vestibular dysfunction among patients with type 2 diabetes mellitus (DM) compared with those without diabetes. This study aims to functionally localize vestibular dysfunction in adults with type 2 DM. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: Adults 50 years of age and older with >=10-year history of type 2 DM were recruited (December 2011 February 2013, n = 25). Vestibular function was assessed by cervical and ocular vestibular-evoked myogenic potentials (VEMPs), testing the saccule and utricle, respectively. Head thrust dynamic visual acuity testing assessed semicircular canal (SCC) function in all canal planes. Results were compared with nondiabetic age-matched controls (n = 25). RESULTS: Subjects were 64.7 +/- 7.6 years old, were 40% female, and had a mean hemoglobin A1c of 8.3% +/- 1.7%. SCC dysfunction was more common than otoconial organ dysfunction, with 70% of subjects with DM demonstrating impaired performance of at least 1 SCC (DeltalogMAR >=0.18) and 50% demonstrating otoconial organ impairment (absent ocular VEMP and/or cervical VEMP). Adults with type 2 DM had poorer lateral and superior SCC performance (P < .05) but similar posterior SCC performance compared with controls (P = .16). Both cervical VEMP peak-to-peak amplitude and ocular VEMP n1 amplitude were also decreased with diabetes (P < .01). CONCLUSION: Adults with type 2 DM have poorer performance on tests of vestibular function related to both SCC and otoconial organ function compared with nondiabetic age-matched adults. Future studies are needed to better understand the relationship between vestibular function and functional disability in persons with diabetes. PMID- 25829392 TI - Health service use and costs associated with excess weight in older adults in Germany. AB - BACKGROUND: excess weight is a risk factor for numerous co-morbidities that predominantly occur in later life. This study's purpose was to analyse the association between excess weight and health service use/costs in the older population in Germany. METHODS: this cross-sectional analysis used data of n = 3,108 individuals aged 58-82 from a population-based prospective cohort study. Body mass index (BMI) and waist-to-height ratio (WHtR) were calculated based on clinical examinations. Health service use was measured by a questionnaire for a 3 month period. Corresponding costs were calculated applying a societal perspective. RESULTS: 21.8% of the sample were normal weight, 43.0% overweight, 25.5% obese class 1 and 9.6% obese class >=2 according to BMI. In 42.6%, WHtR was >=0.6. For normal weight, overweight, obese class 1 and obese class >=2 individuals, mean costs (3-month period) of outpatient care were 384?, 435?, 475? and 525? (P < 0.001), mean costs of inpatient care were 284?, 408?, 333? and 652? (P = 0.070) and mean total costs 716?, 891?, 852? and 1,244? (P = 0.013). For individuals with WHtR <0.6 versus >=0.6, outpatient costs were 401? versus 499? (P < 0.001), inpatient costs 315? versus 480? (P = 0.016) and total costs 755? versus 1,041? (P < 0.001). Multiple regression analyses controlling for sociodemographic variables showed a significant effect of obesity on costs of outpatient care (class 1: +72?; class >=2: +153?) and total costs (class >=2: +361?) while the effect of overweight was not significant. WHtR >=0.6 significantly increased outpatient costs by +79? and total costs by +189?. CONCLUSIONS: excess weight is associated with increased service use and cost in elderly individuals, in particular in obese class >=2 individuals. PMID- 25829394 TI - Performance of influenza-specific triage tools in an H1N1-positive cohort: P/F ratio better predicts the need for mechanical ventilation and critical care admission. AB - BACKGROUND: Pandemic influenza presents a major threat to global health and socioeconomic well-being. Future demand for critical care may outstrip supply and force clinicians to triage patients for admission. We evaluated the Simple Triage Scoring System (STSS), Ontario Health Plan for an Influenza Epidemic (OHPIP) and PaO2 /FiO2 (P/F) ratio to determine utility in predicting need for mechanical ventilation. METHODS: We conducted a retrospective case note review of patients admitted to two centres, Royal Liverpool University Hospital and Countess of Chester Hospital, during the UK influenza pandemic of 2010-11. Demand for critical care during this period forced hospitals in Cheshire and Merseyside to implement escalation policies and increase capacity. Inclusion criteria were polymerase chain reaction-confirmed H1N1 influenza and age >18 years. Exclusion criteria were no evidence of treatment for influenza, patient not admitted to hospital or the inability to locate case notes. RESULTS: One hundred and one patients were included, 29 were admitted to critical care and 23 required mechanical ventilation. The P/F ratio predicted the need for mechanical ventilation with a receiver operating characteristic area under the curve (ROC AUC) of 0.885 (CI 0.817-0.952). Predictive ability was not reduced when the P/F ratio had to be estimated using the Pandharipande tool. The STSS score predicted the need for mechanical ventilation [ROC AUC 0.798 (CI 0.704-0.891)]. The reverse triage component of the OHPIP tool was a poor predictor of patient outcome. CONCLUSIONS: The P/F ratio was a better predictor of need for mechanical ventilation than STSS. The P/F ratio is a simple and accepted determinant of hypoxaemia and should be used if secondary triaging becomes necessary during future influenza pandemics. PMID- 25829385 TI - International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. AB - Since the discovery of Toll, in the fruit fly Drosophila melanogaster, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future. PMID- 25829393 TI - Evidence for a link between gut microbiota and hypertension in the Dahl rat. AB - The gut microbiota plays a critical role in maintaining physiological homeostasis. This study was designed to evaluate whether gut microbial composition affects hypertension. 16S rRNA genes obtained from cecal samples of Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats were sequenced. Bacteria of the phylum Bacteroidetes were higher in the S rats compared with the R rats. Furthermore, the family S24-7 of the phylum Bacteroidetes and the family Veillonellaceae of the phylum Firmicutes were higher in the S rats compared with the R rats. Analyses of the various phylogenetic groups of cecal microbiota revealed significant differences between S and R rats. Both strains were maintained on a high-salt diet, administered antibiotics for ablation of microbiota, transplanted with S or R rat cecal contents, and monitored for blood pressure (BP). Systolic BP of the R rats remained unaltered irrespective of S or R rat cecal transplantation. Surprisingly, compared with the S rats given S rat cecal content, systolic BP of the S rats given a single bolus of cecal content from R rats was consistently and significantly elevated during the rest of their life, and they had a shorter lifespan. A lower level of fecal bacteria of the family Veillonellaceae and increased plasma acetate and heptanoate were features associated with the increased BP observed in the S rats given R rat microbiota compared with the S rats given S rat microbiota. These data demonstrate a link between microbial content and BP regulation and, because the S and R rats differ in their genomic composition, provide the necessary basis to further examine the relationship between the host genome and microbiome in the context of BP regulation in the Dahl rats. PMID- 25829395 TI - Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. AB - BACKGROUND: This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR >=80 ml min(-1)). METHODS: Sugammadex 4 mg kg(-1) was administered at 1-2 post-tetanic counts for reversal of rocuronium NMB. Primary efficacy variable was time from sugammadex to recovery to train-of-four (T4/T1) ratio 0.9. Equivalence between groups was demonstrated if two-sided 95% CI for difference in recovery times was within -1 to +1 min interval. Pharmacokinetics of rocuronium and overall safety were assessed. RESULTS: The intent-to-treat group comprised 67 patients (renal n=35; control n=32). Median (95% CI) time from sugammadex to recovery to T4/T1 ratio 0.9 was 3.1 (2.4-4.6) and 1.9 (1.6-2.8) min for renal patients vs controls. Estimated median (95% CI) difference between groups was 1.3 (0.6-2.4) min; thus equivalence bounds were not met. One control patient experienced acceleromyography-determined NMB recurrence, possibly as a result of premature sugammadex (4 mg kg(-1)) administration, with no clinical evidence of NMB recurrence observed. Rocuronium, encapsulated by Sugammadex, was detectable in plasma at day 7 in 6 patients. Bioanalytical data for sugammadex were collected but could not be used for pharmacokinetics. CONCLUSIONS: Sugammadex 4 mg kg(-1) provided rapid reversal of deep rocuronium-induced NMB in renal and control patients. However, considering the prolonged sugammadex rocuronium complex exposure in patients with severe renal impairment, current safety experience is insufficient to support recommended use of sugammadex in this population. CLINICAL TRIAL REGISTRATION: NCT00702715. PMID- 25829397 TI - Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. AB - PURPOSE: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. EXPERIMENTAL DESIGN: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). RESULTS: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut(+) cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14-0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut(-) cfDNA subgroup (HR, 0.83; 95% CI, 0.65-1.04, P = 0.1076). For patients with EGFR mut(+) cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut(+) cfDNA versus cycle 3 EGFR mut(-) patients, respectively (HR, 0.32; 95% CI, 0.21-0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31-0.84, P = 0.0066). CONCLUSIONS: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes. PMID- 25829396 TI - The Impact of Macrophage- and Microglia-Secreted TNFalpha on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment. AB - PURPOSE: Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM. EXPERIMENTAL DESIGN: Quantitative flow cytometry of mice with intracranial gliomas (+/-oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNFalpha-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFalpha on virus replication. TNFalpha blocking antibodies were used to evaluate the impact of TNFalpha on oHSV therapy in vivo. RESULTS: Flow-cytometry analysis revealed a 7.9 fold increase in macrophage infiltration after virus treatment. Tumor infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFalpha in response to infected glioma cells in vitro and in vivo. Using TNFalpha-blocking antibodies and macrophages derived from TNFalpha-knockout mice, we discovered TNFalpha induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFalpha from the tumor microenvironment with TNFalpha-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors. CONCLUSIONS: The results of these studies suggest that FDA approved TNFalpha inhibitors may significantly improve the efficacy of oncolytic virus therapy. PMID- 25829398 TI - Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia. AB - PURPOSE: Bruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes. EXPERIMENTAL DESIGN: Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199), and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed. RESULTS: The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted in high cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2. CONCLUSIONS: Our biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL. PMID- 25829399 TI - Diffuse Large B-cell Lymphoma Classification Tied Up Nicely with a "String". AB - Molecular classification of diffuse large B-cell lymphoma (DLBCL) is a critical biologic, prognostic, and predictive distinction. Since the discovery of two molecular types of DLBCL in otherwise morphologically indistinguishable cases, numerous methodologies for making this distinction have been published. A method and technical platform may now be reaching consensus. PMID- 25829400 TI - Correlation between Prostate-Specific Antigen Kinetics and Overall Survival in Abiraterone Acetate-Treated Castration-Resistant Prostate Cancer Patients. AB - PURPOSE: We constructed a biomarker-survival modeling framework to explore the relationship between prostate-specific antigen (PSA) kinetics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients following oral administration of 1,000 mg/day of abiraterone acetate (AA). EXPERIMENTAL DESIGN: The PSA-survival modeling framework was based on data from two phase III studies, COU-AA-301 (chemotherapy pretreated, n = 1,184) and COU-AA 302 (chemotherapy naive, n = 1,081), and included a mixed-effects tumor growth inhibition model and a Cox proportional hazards survival model. RESULTS: The effect of AA on PSA kinetics was significant (P < 0.0001) and comparable between the chemotherapy-naive and -pretreated patients. PSA kinetics [e.g., PSA nadir, PSA response rate (>=30%, 50%, and 90%), time to PSA progression, PSA doubling time (PSADT)] were highly associated with OS in both populations. The model-based posttreatment PSADT had the strongest association with OS (HR ~0.9 in both populations). The models could accurately predict survival outcomes. After adjusting for PSA kinetic endpoints, the treatment effect of AA on survival was no longer statistically significant in both studies, and the Prentice criteria of surrogacy were met for the PSA kinetic endpoints. A strong correlation was also observed between PSA and radiographic progression-free survival. CONCLUSIONS: The analysis revealed a consistent treatment effect of AA on PSA kinetics and strong associations between PSA kinetics and OS in chemotherapy-pretreated and -naive patients, thereby providing a rationale to consider PSA kinetics as surrogacy endpoints to indicate clinical benefit in AA-treated patients with mCRPC regardless of chemotherapy treatment. PMID- 25829401 TI - A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment. AB - PURPOSE: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome. EXPERIMENTAL DESIGN: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r(2) = 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5 year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma. RESULTS: We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001). CONCLUSIONS: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome. PMID- 25829403 TI - Comparative cytotoxicity and genotoxicity of cobalt (II, III) oxide, iron (III) oxide, silicon dioxide, and aluminum oxide nanoparticles on human lymphocytes in vitro. AB - Despite the extensive use of nanoparticles (NPs) in various fields, adequate knowledge of human health risk and potential toxicity is still lacking. The human lymphocytes play a major role in the immune system, and it can alter the antioxidant level when exposed to NPs. Identification of the hazardous NPs was done using in vitro toxicity tests and this study mainly focuses on the comparative in vitro cytotoxicity and genotoxicity of four different NPs including cobalt (II, III) oxide (Co3O4), iron (III) oxide (Fe2O3), silicon dioxide (SiO2), and aluminum oxide (Al2O3) on human lymphocytes. The Co3O4 NPs showed decrease in cellular viability and increase in cell membrane damage followed by Fe2O3, SiO2, and Al2O3 NPs in a dose-dependent manner after 24 h of exposure to human lymphocytes. The oxidative stress was evidenced in human lymphocytes by the induction of reactive oxygen species, lipid peroxidation, and depletion of catalase, reduced glutathione, and superoxide dismutase. The Al2O3 NPs showed the least DNA damage when compared with all the other NPs. Chromosomal aberration was observed at 100 ug/ml when exposed to Co3O4 NPs and Fe2O3 NPs. The alteration in the level of antioxidant caused DNA damage and chromosomal aberration in human lymphocytes. PMID- 25829402 TI - Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma. AB - PURPOSE: The human endogenous retrovirus (HERV-K) envelope (env) protein is a tumor-associated antigen (TAA) expressed on melanoma but not normal cells. This study was designed to engineer a chimeric antigen receptor (CAR) on T-cell surface, such that they target tumors in advanced stages of melanoma. EXPERIMENTAL DESIGN: Expression of HERV-K protein was analyzed in 220 melanoma samples (with various stages of disease) and 139 normal organ donor tissues using immunohistochemical (IHC) analysis. HERV-K env-specific CAR derived from mouse monoclonal antibody was introduced into T cells using the transposon-based Sleeping Beauty (SB) system. HERV-K env-specific CAR(+) T cells were expanded ex vivo on activating and propagating cells (AaPC) and characterized for CAR expression and specificity. This includes evaluating the HERV-K-specific CAR(+) T cells for their ability to kill A375-SM metastasized tumors in a mouse xenograft model. RESULTS: We detected HERV-K env protein on melanoma but not in normal tissues. After electroporation of T cells and selection on HERV-K(+) AaPC, more than 95% of genetically modified T cells expressed the CAR with an effector memory phenotype and lysed HERV-K env(+) tumor targets in an antigen-specific manner. Even though there is apparent shedding of this TAA from tumor cells that can be recognized by HERV-K env-specific CAR(+) T cells, we observed a significant antitumor effect. CONCLUSIONS: Adoptive cellular immunotherapy with HERV-K env-specific CAR(+) T cells represents a clinically appealing treatment strategy for advanced-stage melanoma and provides an approach for targeting this TAA on other solid tumors. PMID- 25829404 TI - Long-term results of adipose-derived stem cell therapy for the treatment of Crohn's fistula. AB - A previous phase II clinical trial of adipose-derived stem cell (ASC) therapy for fistulae associated with Crohn's disease, a devastating condition with a high recurrence rate, demonstrated safety and therapeutic potential with a 1-year sustained response. In the present study, 41 of the 43 phase II trial patients were followed for an additional year, regardless of response in the initial year. At 24 months, complete healing was observed in 21 of 26 patients (80.8%) in modified per protocol analysis and 27 of 36 patients (75.0%) in modified intention-to-treat analysis. No adverse events related to ASC administration were observed. Furthermore, complete closure after initial treatment was well sustained. These results strongly suggest that autologous ASCs may be a novel treatment option for Crohn's fistulae. PMID- 25829406 TI - Should the governments of 'developed' countries be held responsible for equalizing the indigenous health gap? AB - Across the globe there is significant variation between and within indigenous populations in terms of world view, culture, and socio-political forces. However, many indigenous groups do share a striking commonality: greater rates of non communicable diseases and shorter life expectancies than non-indigenous compatriots. Notably, this health gap persists for 'developed' countries, including Australia, Canada, New Zealand and the United States. The question of who is responsible for equalizing the gap is complicated. Using Australia as an exemplar context, this commentary will present arguments 'for' and 'against' the governments of developed nations being held liable for closing the indigenous health gap. We will discuss the history and nature of the health gap, actions needed to 'close the gap', and which party has the necessary resources to do so. PMID- 25829405 TI - Perceptions of barriers and facilitators in physical activity participation among women in Thiruvananthapuram City, India. AB - BACKGROUND: Despite the known benefits of physical activity, very few people, especially women, are found to engage in regular physical activity. This study explored the perceptions, barriers and facilitators related to physical activity among women in Thiruvananthapuram City, India. METHODS: Four focus group discussions were conducted among individuals between 25 and 60 years of age, in a few areas of Thiruvananthapuram City Corporation limits in Kerala, preparatory to the design of a physical activity intervention trial. An open-ended approach was used and emergent findings were analyzed and interpreted. RESULTS: Women associated physical activity mostly with household activities. The majority of the women considered their activity level adequate, although they engaged in what the researchers concluded were quite low levels of activity. Commonly reported barriers were lack of time, motivation, and interest; stray dogs; narrow roads; and not being used to the culture of walking. Facilitators of activity were seeing others walking, walking in pairs, and pleasant walking routes. Walking was reported as the most feasible physical activity by women. CONCLUSION: Physical activity promotion strategies among women should address the prevailing cultural norms in the community, and involve social norming and overcoming cultural barriers. They should also target the modifiable determinants of physical activity, such as improving self-efficacy, improving knowledge on the adequacy of physical activity and its recommendations, facilitating goal-setting, and enhancing social support through peer support and group-based activities. PMID- 25829407 TI - Pseudoparticle neutralization assay for detecting ebola- neutralizing antibodies in biosafety level 2 settings. PMID- 25829408 TI - Thyroid function in pregnancy: what is normal? AB - BACKGROUND: Gestational thyroid dysfunction is common and associated with maternal and child morbidity and mortality. During pregnancy, profound changes in thyroid physiology occur, resulting in different thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals compared to the nonpregnant state. Therefore, international guidelines recommend calculating trimester- and assay-specific reference intervals per center. If these reference intervals are unavailable, TSH reference intervals of 0.1-2.5 mU/L for the first trimester and 0.2-3.0 mU/L for the second trimester are recommended. In daily practice, most institutions do not calculate institution-specific reference intervals but rely on these fixed reference intervals for the diagnosis and treatment of thyroid disorders during pregnancy. However, the calculated reference intervals for several additional pregnancy cohorts have been published in the last few years and show substantial variation. CONTENT: We provide a detailed overview of the available studies on thyroid function reference intervals during pregnancy, different factors that contribute to these reference intervals, and the maternal and child complications associated with only minor variations in thyroid function. SUMMARY: There are large differences in thyroid function reference intervals between different populations of pregnant women. These differences can be explained by variations in assays as well as population-specific factors, such as ethnicity and body mass index. The importance of using correct reference intervals is underlined by the fact that even small subclinical variations in thyroid function have been associated with detrimental pregnancy outcomes, including low birth weight and pregnancy loss. It is therefore crucial that institutions do not rely on fixed universal cutoff concentrations, but calculate their own pregnancy-specific reference intervals. PMID- 25829409 TI - Personal home care workers' role in hospital: a qualitative study. AB - OBJECTIVES: Unlike in most high-income countries, in Israel personal (social) care of elderly patients in hospitals is provided either by relatives or friends, or, for those patients with live-in assistance at home, by their home care workers. Our aim was to understand the explicit and implicit roles of live-in carers and whether any difficulties occurred. METHODS: Interviews in the internal medicine unit of Hadassah Hospital with 17 patients, 16 relatives, 20 home care workers and 20 nurses. Data were subjected to categorical content analysis. RESULTS: Three major themes emerged: the development of teamwork with relatives and nurses; the varied roles of home care workers including nursing care, emotional care, and monitoring and supervision of the patient; and the conflicts and challenges associated with having a care worker related to their physical presence and the care worker's own social needs. CONCLUSIONS: Israel partially addresses its nursing shortage by allowing paid home care workers to take an active role in the care of hospitalized older adults. This can have both a positive and a negative impact on the role and perception of nursing. PMID- 25829410 TI - Variations in the persistence of health expenditures and the implications for the design of capitation payments in Taiwan. AB - OBJECTIVES: The National Health Insurance (NHI) system in Taiwan launched a trial capitation provider payment programme in 2011, with the capitation formula based on patients' average NHI expenditure in the previous year. This study seeks to examine the concentration and persistence of health care expenditure among the elderly, and to assess the performance of the current capitation formula in predicting future high-cost users. METHODS: This study analysed NHI expenditures for a nationally representative sample of people aged 65 years and over who took part in Taiwan's National Health Interview Survey, 2005. Expenditure concentration was assessed by the proportion of NHI expenditures attributable to four groups by expenditure percentile. Four transition probability matrixes examined changes in a person's position in the expenditure percentiles and generalized estimation equation models were estimated to identify significant predictors of a patient being in the top 10% of users. RESULTS: Between 2005 and 2009, the top 10% of users on average accounted for 55% of total NHI expenditures. Of the top 10% in 2005, 39% retained this position in 2006. However, expenditure persistence was the highest (77%) among the bottom 50% of users. NHI expenditure percentiles in both the baseline year and the prior year, and chronic conditions all significantly predicted future high expenditures. The model including chronic conditions performed better in predicting the top 10% of users (c-statistics increased from 0.772 to 0.904) than the model without. CONCLUSIONS: Given the increase in predictive ability, adding chronic conditions and baseline health care use data to Taiwan's capitation payment formula would correctly identify more high users. PMID- 25829411 TI - Influence of translaminar pressure dynamics on the position of the anterior lamina cribrosa surface. AB - PURPOSE: To determine how the translaminar pressure difference (TLPD) and gradient (TLPG) influence the position of anterior lamina cribrosa (LC) surface. METHODS: Twenty-six eyes of 26 healthy subjects were subjected to enhanced-depth imaging volume scanning of the optic nerve using spectral-domain optical coherence tomography (SD-OCT). The anterior LC surface depth (LCD) relative to the Bruch's membrane (BM) opening was measured at 11 equidistant planes, and the LC thickness (LCT) was measured at three locations (superior midperipheral, midhorizontal, and inferior midperipheral). Intraocular pressure and lumbar cerebrospinal fluid pressure (CSFP) were measured on the same day as the SD-OCT examination. The TLPD was defined as the difference between IOP and CSFP (i.e., IOP-CSFP), and the TLPG as the TLPD divided by LCT (i.e., TLPD/LCT). RESULTS: Subjects were aged 63.4 +/- 8.0 years and comprised 12 males and 14 females. Regression analyses revealed a significant association between a larger mean LCD and male sex (P = 0.002), and between a larger central LCD and male sex (P <= 0.012), larger TLPD (P = 0.048), and higher TLPG (P = 0.029). There was no significant association between IOP, CSFP, and LCT, and either the mean LCD (P = 0.438, 0.368, and 0.416, respectively) or central LCD (P = 0.284, 0.085, and 0.144, respectively). CONCLUSIONS: A larger central LCD was associated with larger TLPD and higher TLPG in healthy eyes, which indicates that the translaminar pressure dynamics may play a role in the position of the anterior LC surface relative to BM opening in healthy human eyes. PMID- 25829412 TI - Optimal number of angle images for calculating anterior angle volume and iris volume measurements. AB - PURPOSE: We determined the optimal number of angle images required to obtain reliable measurements of trabecular-iris circumferential volume (TICV) and iris volume (IV) using swept-source Fourier domain anterior segment optical coherence tomography (SSFD-ASOCT) scans in narrow angle eyes. METHODS: Scleral spur landmarks (SSL) were manually identified on ASOCT angle images from 128 meridians from each of 24 eyes with chronic primary angle closure (PAC) spectrum of disease. The anterior and posterior corneal curves, and the anterior and posterior iris surfaces were identified automatically by the anterior chamber analysis and interpretation (ACAI) software, then manually examined and edited by the reader if required. Trabecular-iris circumferential volume at 750 MUm from SSL (TICV750) and IV were subsequently calculated using varying numbers of angle images. Threshold error was determined to be less than the lower 95% confidence limit of mean absolute percent error (MAPE) of the change in TICV or IV resulting from laser peripheral iridotomy, which would be 17% for TICV and 5% for IV, based on previous studies. The optimal number of angle images was the smallest number of images where MAPE was less than this threshold for TICV and IV. RESULTS: A total of 32 equally-spaced angle images (16 meridians) was required to estimate TICV750 and 16 angle images (8 meridians) to estimate IV. Both were within 4.6% and 1.6% of MAPE, respectively. CONCLUSIONS: It is possible to determine TICV and IV parameters reliably in narrow angles without evaluating all 128 meridians obtained with SSFD-ASOCT. PMID- 25829413 TI - Decorin Prevents Retinal Pigment Epithelial Barrier Breakdown Under Diabetic Conditions by Suppressing p38 MAPK Activation. AB - PURPOSE: The purpose of this study was to determine the effect of decorin on the barrier function of human retinal pigment epithelial (RPE) cells under high glucose (HG) plus hypoxia conditions. METHODS: Human RPE (ARPE-19) cells were cultured for 18 days in normal glucose (5.5 mM) or HG (25 mM) medium. In addition, to mimic the hypoxic impact which occurs in diabetic retinopathy, cells were treated with 100 MUM CoCl2 during the last 2 days of the experiment. Decorin, 100 nM, was applied 1 hour before CoCl2 was added. Retinal pigment epithelial barrier function was evaluated by measuring transepithelial electrical resistance (TER) and apical-basolateral permeability of fluorescein isothiocyanate (FITC)-dextran. The content and distribution of tight junction proteins (claudin-1, occludin, and zonula occludens-1 [ZO-1]) were examined by Western blotting and immunofluorescence. p38 mitogen-activated protein kinase (MAPK) phosphorylation was evaluated by Western blotting, and small interfering RNA transfection to p38 MAPK was also performed in ARPE-19 monolayers. RESULTS: High-glucose plus hypoxia significantly increased FITC-dextran permeability, paralleled by decreased TER. Decorin reversed both of these effects. High-glucose plus hypoxia-induced reduction and disorganization of occludin and ZO-1 were also reversed by decorin. Decorin prevented the activation of p38 MAPK induced by hypoxia. Silence of p38 MAPK by RNA interference also inhibited the breakdown of ARPE-19 cell monolayer induced by HG plus hypoxia. CONCLUSIONS: Retinal pigment epithelial barrier disruption induced by HG plus hypoxia was prevented by decorin through suppression of p38 MAPK activation, which could present a new therapeutic strategy for inhibition of diabetic macular edema. PMID- 25829414 TI - Chronic ocular hypertension induced by circumlimbal suture in rats. AB - PURPOSE: To induce chronic intraocular pressure (IOP) elevation in rat eyes by circumlimbal suture. METHODS: Anesthetized (isoflurane) Long-Evans rats underwent unilateral circumlimbal suture implantation while the fellow eyes served as untreated controls (n = 15). A sham group (n = 8) received the same procedure except that the suture was loosely tied. Intraocular pressure, electroretinography (ERG), and optical coherence tomography (OCT) were monitored for 15 weeks, after which retinal histology and immunofluorescence staining for glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule-1 (Iba-1) were undertaken. RESULTS: Both IOP and ERG remained unaltered in the sham and all control eyes over 15 weeks. In the ocular hypertensive eye, IOP spiked from 17 +/- 1 to 58 +/- 3 mm Hg immediately after suture application, recovering to 32 +/- 2 mm Hg by 24 hours, and remained elevated by 7 to 10 mm Hg above baseline for 15 weeks. At week 2, there was a small reduction of ERG components involving the photoreceptor a-wave, bipolar cell b-wave, and ganglion cell-mediated scotopic threshold response (pSTR). The reduction in a- and b-wave remained stable, while the pSTR became more affected from week 8 onward (P < 0.05). By week 12, there was progressive retinal nerve fiber layer (RNFL) thinning. At week 15, GFAP expression was upregulated in inner retina and on Muller cells. The ganglion cell dysfunction was associated with RNFL thinning and cell loss in the ganglion cell layer. CONCLUSIONS: Circumlimbal suture provides a simple and cost-effective way to induce mild chronic ocular hypertension in rat eyes. This model produces preferential ganglion cell dysfunction and RNFL reduction. PMID- 25829416 TI - Assessing the effectiveness of low vision rehabilitation in children: an observational study. AB - PURPOSE: To evaluate the change in visual functioning (VF) using the L. V. Prasad Functional Vision Questionnaire II (LVP-FVQ II) following multidisciplinary low vision rehabilitation (LVR) services in children with low vision (LV). METHODS: Children with LV referred for the first time to the Centre for Sight Enhancement were administered the LVP-FVQ II at baseline and at 3 to 4 months' follow-up to assess the outcomes of LVR. Participants' responses to the LVP-FVQ II at baseline and follow-up were transformed into interval-level estimates of VF using Rasch analysis. Cohen's d values (effect size) were used to estimate the magnitude of change in VF. RESULTS: A total of 183 participants completed the rehabilitation (mean age, 11.9 years; male, 57%). More than one-half of the participants had retinal disorders (55%) and most were moderately visually impaired (<20/60 20/200, 76.5%). Using the LVP-FVQ II, significant improvement in VF after rehabilitation was recorded (P < 0.0001) and the increase in VF (SD) was 1.20 (1.82) logits. Using Cohen's d, the magnitude of the improvement in LVR intervention at follow-up was found to be 0.75, indicating nearly large treatment effect. CONCLUSIONS: Ours is the first study to provide strong evidence that LVR services result in nearly large and significant improvements in the overall VF in children with LV, regardless of the cause of LV. These results should encourage eye care professionals to refer children with LV to LVR services. Further investigation is needed to determine if the improvement in VF can be sustained over a longer duration (>4 months). PMID- 25829415 TI - A Novel Approach of Daunorubicin Application on Formation of Proliferative Retinopathy Using a Porous Silicon Controlled Delivery System: Pharmacodynamics. AB - PURPOSE: Proliferative vitreoretinopathy (PVR) is the most common cause of poor visual outcomes in association with retinal detachment surgeries and ocular trauma. Daunorubicin (DNR) has shown the strongest efficacy in proliferation inhibition in vitro. However, clinical studies have shown only mild effect owing to limitations of narrow therapeutic window and short vitreous half-life. METHODS: Three milligrams of DNR-loaded particles were intravitreally injected into 18 pigmented rabbits, and vitreous samples were collected up to 84 days for analysis. Thirty-seven rabbits were used for a dose-escalation (1, 3, 6 mg) safety and efficacy study in a rabbit PVR model using a pretreatment design. RESULTS: Loading efficiency of DNR was 108.55 +/- 12 MUg per 1 mg particles. Eighty-four days of follow-up did not reveal any adverse reaction. Pharmacokinetic analysis demonstrated a vitreous half-life of 29 days with a maximum DNR concentration of 178 ng/mL and a minimum concentration of 29 ng/mL at day 84. Daunorubicin-loaded porous silicon (pSi) particles were dosed 8 to 9 weeks before PVR induction, and PVR severity score was dose dependent (Spearman rho = -0.25, P = 0.0005). Proliferative vitreoretinopathy with tractional retinal detachment was 88% in the control group, 63% in the low-dose group, 14% in the medium-dose group, and 0% in the high-dose group (Cochran-Armitage Trend Test, Z = 8.99, rho = -0.67, P < 0.0001). CONCLUSIONS: Daunorubicin-loaded pSi particles can safely reside in the vitreous for at least 3 months. The pSi-based delivery expanded the therapeutic window of DNR by a factor of 862 and drove down the minimum effective concentration by a factor of 175. PMID- 25829417 TI - Long-Term Reproducibility of Macular Ganglion Cell Analysis in Clinically Stable Glaucoma Patients. AB - PURPOSE: To investigate the long-term reproducibility of macular ganglion cell analysis in clinically stable glaucoma patients using spectral-domain optical coherence tomography (SD-OCT). METHODS: One hundred nine eyes of 109 clinically stable open-angle glaucoma patients with a localized retinal nerve fiber layer (RNFL) defect and a corresponding macular ganglion cell-inner plexiform layer (GCIPL) defect were included in this retrospective, longitudinal study. Clinical stability was defined as showing no change on serial structural (stereo-disc and RNFL photography) and functional (visual field progression analysis) assessments. Three serial SD-OCT (Cirrus-HD) peripapillary and macular scans taken at 6-month intervals were analyzed. Intraclass correlation coefficient (ICC), coefficient of variation (CV), test-retest standard deviation (TRTSD), and tolerance limit of area and angular width of GCIPL defect and GCIPL thickness measurements were assessed. RESULTS: The ICC of the GCIPL thickness parameters ranged from 0.966 to 0.992, and the CV from 2.0% to 5.5%. The TRTSD was the lowest for the average GCIPL thickness (1.45 MUm), the highest for the minimum GCIPL thickness (3.42 MUm), and varied from 1.54 to 2.16 MUm for the sectoral measurements. The ICC, CV, and TRTSD were 0.993, 3.9%, and 5.32 degrees for angular width, and 0.930, 6.7%, and 0.27 mm2 for area of GCIPL defect. Measurement variances (TRTSD) for the GCIPL measurements showed no significant association with the glaucomatous severity. CONCLUSIONS: The macular GCIPL thickness and deviation maps showed excellent long-term intervisit reproducibility. Macular ganglion cell analysis can be considered as an effective means of monitoring glaucomatous progression in macula. PMID- 25829418 TI - Proteomics Differentiate Between Thyroid-Associated Orbitopathy and Dry Eye Syndrome. AB - PURPOSE: In patients with thyroid-associated orbitopathy (TAO), the dry eye syndrome occurs frequently, and symptoms and signs of both disorders overlap making early and accurate differential diagnosis difficult. A differentiation via specific markers is warranted. METHODS: Tear fluid samples of 120 subjects with TAO, TAO + dry eye, dry eye, and controls were collected. The samples were measured using matrix-assisted laser desorption ionization mass spectrometry. The identified proteins were tested with antibody microarrays. RESULTS: Proteomics identified deregulated proteins in TAO and dry eye. Compared with dry eye, proline-rich protein 1 (PROL1, P = 0.002); uridine diphosphate (UDP)-glucose dehydrogenase (UGDH, P = 0.017); calgranulin A (S10A8, P < 0.0001); transcription activator BRG1 (SMCA4, P < 0.0001); annexin A1 (P = 0.007); cystatin (P = 0.009); heat shock protein 27 (P = 0.03); and galectin (P = 0.04) were markedly downregulated in TAO. Compared with healthy controls, PROL1 (P < 0.05.); proline rich protein 4 (PRP4, P < 0.05), S10A8 (P = 0.004) and SMCA4 (P = 0.002) were downregulated in TAO. In contrast, the proteins midasin and POTE-ankyrin-domain family-member I were upregulated in TAO versus healthy controls (P < 0.05). Protein dysregulation was associated with inflammatory response and cell death. Antibody microarray confirmed significant changes of PRP4, PROL1, and UGDH between TAO and dry eye or healthy controls (P < 0.01). The presence of these three proteins was negatively correlated with smoking (P < 0.05). CONCLUSIONS: Proteomics of tear fluid demonstrated an upregulation of inflammatory proteins versus a downregulation of protective proteins in TAO, and a significantly different protein panel in TAO versus dry eye and/or controls. The spectrum of inflammatory and protective proteins might be a useful indicator for disease activity and ocular surface disease in patients with TAO. PMID- 25829419 TI - How dangerous a toy can be? The magnetic effect. AB - During the last decade, there has been a significant increase in the number of magnetic toys available for children. Two or more magnets separate from each other along the gastrointestinal course can attract each other across bowel walls, resulting in pressure necrosis, bowel perforations and fistulas formation. This has led to an increasing number of case reports describing serious complications from ingesting more than one magnet. We report the ingestion of a large number of magnets from one toy (>60 pieces). Our patient presented with generalised peritonitis and shock. During emergency laparotomy, she was found to have gross abdominal contamination with multiple bowel perforations and fistulae. This report emphasises the danger of such toys and how important that parents, physicians and manufacturers are aware of such fatal hazards that can arise from 'unsupervised' ingestion of these 'nice-looking' toys. PMID- 25829420 TI - Why was this child not brought? PMID- 25829421 TI - Infant sleep-related deaths: why do parents take risks? PMID- 25829423 TI - Epigenome maps offer clues to disease origins. PMID- 25829422 TI - Using digital multimedia to improve parents' and children's understanding of clinical trials. AB - OBJECTIVE: Data show that many research subjects have difficulty understanding study information using traditional paper consent documents. This study, therefore, was designed to evaluate the effect of an interactive multimedia program on improving parents' and children's understanding of clinical trial concepts and participation. METHODS: Parents (n=148) and children (n=135) were each randomised to receive information regarding clinical trials using either a traditional paper format (TF) or an interactive iPad program (IP) with inline exercises. Participants' understanding of the information was assessed using semistructured interviews prior to (pretest) and after (post-test) receiving the information. Participants also completed a short survey to assess their perceptions of information delivery and satisfaction with the process. RESULTS: Regardless of the mode of information delivery, all participants demonstrated improved pretest to post-test understanding. While there were no statistical differences in parents' post-test understanding between the TF and IP groups, children in the IP group had significantly greater post-test understanding compared with children in the TF group (11.65 (4.1) vs 8.85 (4.1) (2.8, 1.4, 4.2) 0-18 scale where 18=complete understanding). Furthermore, the IP was found to be significantly 'easier to follow' and 'more effective' in presenting information compared with the TF. CONCLUSIONS: Results demonstrated the importance of providing information regarding clinical trial concepts to parents and children. Importantly, the ability of interactive multimedia to improve understanding of clinical trial concepts and satisfaction with information delivery, particularly among children, supports this approach as a novel and effective vehicle for enhancing the informed consent process. PMID- 25829424 TI - HIF2alpha-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma. AB - Two hallmarks of clear-cell renal cell carcinoma (ccRCC) are constitutive hypoxia inducible factor (HIF) signaling and abundant intracellular lipid droplets (LD). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF2alpha, but not HIF1alpha, activation. HIF2alpha-dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2-dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF2alpha modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival. SIGNIFICANCE: We demonstrate that HIF2alpha promotes lipid storage, ER homeostasis, and cell viability in ccRCC via upregulation of the LD coat protein PLIN2, revealing a novel function for the well-documented "clear-cell" phenotype and identifying ER stress as a targetable vulnerability created by HIF2alpha/PLIN2 suppression in this common renal malignancy. PMID- 25829426 TI - ERS guidelines, statements and technical standards published in the ERJ in 2014: a year in review. PMID- 25829427 TI - Lung cancer diagnosis in the emergency department. PMID- 25829425 TI - MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2. AB - We have recently recapitulated metastasis of human PTEN/TP53-mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell cell communication by IL6 drives the AKT-MYC switch through activation of the AKT suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation. Similarly, in tissues, peak proliferation in Pten/Trp53-mutant primary and metastatic prostate cancer does not correlate with activated AKT, but with STAT3/MYC activation instead. Mechanistically, MYC strongly activates the AKT phosphatase PHLPP2 in primary cells and prostate cancer metastasis. We show genetically that Phlpp2 is essential for dictating the proliferation of MYC-mediated AKT suppression. Collectively, our data reveal competition between two proto-oncogenes, MYC and AKT, which ensnarls the Phlpp2 gene to facilitate MYC-driven prostate cancer metastasis after loss of Pten and Trp53. SIGNIFICANCE: Our data identify IL6 detection as a potential causal biomarker for MYC-driven metastasis after loss of PTEN and p53. Second, our finding that MYC then must supersede AKT to drive cell proliferation points to MYC inhibition as a critical part of PI3K pathway therapy in lethal prostate cancer. PMID- 25829428 TI - Treatment of COPD and the TOnado trial: a tempest in a teapot? PMID- 25829429 TI - Biomarkers in COPD: the search continues! PMID- 25829430 TI - Number needed to treat: enigmatic results for exacerbations in COPD. PMID- 25829433 TI - Salmeterol/fluticasone combination instead of indacaterol or vice-versa? PMID- 25829434 TI - Salmeterol/fluticasone combination instead of indacaterol or vice-versa? PMID- 25829435 TI - Sleep medicine certification for physicians in Spain. PMID- 25829431 TI - An official American Thoracic Society/European Respiratory Society statement: research questions in COPD. AB - Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) research statement is to describe evidence related to diagnosis, assessment and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centred outcomes. PMID- 25829436 TI - Inherent weaknesses of the current ICD coding system regarding idiopathic pulmonary fibrosis. PMID- 25829438 TI - Cryolipolysis: The Importance of Scientific Evaluation of a New Technique. PMID- 25829439 TI - pH Regulation by NHX-Type Antiporters Is Required for Receptor-Mediated Protein Trafficking to the Vacuole in Arabidopsis. AB - Protein trafficking requires proper ion and pH homeostasis of the endomembrane system. The NHX-type Na(+)/H(+) antiporters NHX5 and NHX6 localize to the Golgi, trans-Golgi network, and prevacuolar compartments and are required for growth and trafficking to the vacuole. In the nhx5 nhx6 T-DNA insertional knockouts, the precursors of the 2S albumin and 12S globulin storage proteins accumulated and were missorted to the apoplast. Immunoelectron microscopy revealed the presence of vesicle clusters containing storage protein precursors and vacuolar sorting receptors (VSRs). Isolation and identification of complexes of VSRs with unprocessed 12S globulin by 2D blue-native PAGE/SDS-PAGE indicated that the nhx5 nhx6 knockouts showed compromised receptor-cargo association. In vivo interaction studies using bimolecular fluorescence complementation between VSR2;1, aleurain, and 12S globulin suggested that nhx5 nhx6 knockouts showed a significant reduction of VSR binding to both cargoes. In vivo pH measurements indicated that the lumens of VSR compartments containing aleurain, as well as the trans-Golgi network and prevacuolar compartments, were significantly more acidic in nhx5 nhx6 knockouts. This work demonstrates the importance of NHX5 and NHX6 in maintaining endomembrane luminal pH and supports the notion that proper vacuolar trafficking and proteolytic processing of storage proteins require endomembrane pH homeostasis. PMID- 25829440 TI - Arabidopsis BIRD Zinc Finger Proteins Jointly Stabilize Tissue Boundaries by Confining the Cell Fate Regulator SHORT-ROOT and Contributing to Fate Specification. AB - Plant cells cannot rearrange their positions; therefore, sharp tissue boundaries must be accurately programmed. Movement of the cell fate regulator SHORT-ROOT from the stele to the ground tissue has been associated with transferring positional information across tissue boundaries. The zinc finger BIRD protein JACKDAW has been shown to constrain SHORT-ROOT movement to a single layer, and other BIRD family proteins were postulated to counteract JACKDAW's role in restricting SHORT-ROOT action range. Here, we report that regulation of SHORT ROOT movement requires additional BIRD proteins whose action is critical for the establishment and maintenance of the boundary between stele and ground tissue. We show that BIRD proteins act in concert and not in opposition. The exploitation of asymmetric redundancies allows the separation of two BIRD functions: constraining SHORT-ROOT spread through nuclear retention and transcriptional regulation of key downstream SHORT-ROOT targets, including SCARECROW and CYCLIND6. Our data indicate that BIRD proteins promote formative divisions and tissue specification in the Arabidopsis thaliana root meristem ground tissue by tethering and regulating transcriptional competence of SHORT-ROOT complexes. As a result, a tissue boundary is not "locked in" after initial patterning like in many animal systems, but possesses considerable developmental plasticity due to continuous reliance on mobile transcription factors. PMID- 25829441 TI - Cytoplastic Glyceraldehyde-3-Phosphate Dehydrogenases Interact with ATG3 to Negatively Regulate Autophagy and Immunity in Nicotiana benthamiana. AB - Autophagy as a conserved catabolic pathway can respond to reactive oxygen species (ROS) and plays an important role in degrading oxidized proteins in plants under various stress conditions. However, how ROS regulates autophagy in response to oxidative stresses is largely unknown. Here, we show that autophagy-related protein 3 (ATG3) interacts with the cytosolic glyceraldehyde-3-phosphate dehydrogenases (GAPCs) to regulate autophagy in Nicotiana benthamiana plants. We found that oxidative stress inhibits the interaction of ATG3 with GAPCs. Silencing of GAPCs significantly activates ATG3-dependent autophagy, while overexpression of GAPCs suppresses autophagy in N. benthamiana plants. Moreover, silencing of GAPCs enhances N gene-mediated cell death and plant resistance against both incompatible pathogens Tobacco mosaic virus and Pseudomonas syringae pv tomato DC3000, as well as compatible pathogen P. syringae pv tabaci. These results indicate that GAPCs have multiple functions in the regulation of autophagy, hypersensitive response, and plant innate immunity. PMID- 25829442 TI - Natural variation in epigenetic pathways affects the specification of female gamete precursors in Arabidopsis. AB - In angiosperms, the transition to the female gametophytic phase relies on the specification of premeiotic gamete precursors from sporophytic cells in the ovule. In Arabidopsis thaliana, a single diploid cell is specified as the premeiotic female gamete precursor. Here, we show that ecotypes of Arabidopsis exhibit differences in megasporogenesis leading to phenotypes reminiscent of defects in dominant mutations that epigenetically affect the specification of female gamete precursors. Intraspecific hybridization and polyploidy exacerbate these defects, which segregate quantitatively in F2 populations derived from ecotypic hybrids, suggesting that multiple loci control cell specification at the onset of female meiosis. This variation in cell differentiation is influenced by the activity of ARGONAUTE9 (AGO9) and RNA-DEPENDENT RNA POLYMERASE6 (RDR6), two genes involved in epigenetic silencing that control the specification of female gamete precursors. The pattern of transcriptional regulation and localization of AGO9 varies among ecotypes, and abnormal gamete precursors in ovules defective for RDR6 share identity with ectopic gamete precursors found in selected ecotypes. Our results indicate that differences in the epigenetic control of cell specification lead to natural phenotypic variation during megasporogenesis. We propose that this mechanism could be implicated in the emergence and evolution of the reproductive alternatives that prevail in flowering plants. PMID- 25829443 TI - Patient and carer experiences of clinical uncertainty and deterioration, in the face of limited reversibility: A comparative observational study of the AMBER care bundle. AB - BACKGROUND: Clinical uncertainty is emotionally challenging for patients and carers and creates additional pressures for those clinicians in acute hospitals. The AMBER care bundle was designed to improve care for patients identified as clinically unstable, deteriorating, with limited reversibility and at risk of dying in the next 1-2 months. AIM: To examine the experience of care supported by the AMBER care bundle compared to standard care in the context of clinical uncertainty, deterioration and limited reversibility. DESIGN: A comparative observational mixed-methods study using semi-structured qualitative interviews and a followback survey. SETTING/PARTICIPANTS: Three large London acute tertiary National Health Service hospitals. Nineteen interviews with 23 patients and carers (10 supported by AMBER care bundle and 9 standard care). Surveys completed by next of kin of 95 deceased patients (59 AMBER care bundle and 36 standard care). RESULTS: The AMBER care bundle was associated with increased frequency of discussions about prognosis between clinicians and patients (chi(2) = 4.09, p = 0.04), higher awareness of their prognosis by patients (chi(2) = 4.29, p = 0.04) and lower clarity in the information received about their condition (chi(2) = 6.26, p = 0.04). Although the consistency and quality of communication were not different between the two groups, those supported by the AMBER care bundle described more unresolved concerns about caring for someone at home. CONCLUSION: Awareness of prognosis appears to be higher among patients supported by the AMBER care bundle, but in this small study this was not translated into higher quality communication, and information was judged less easy to understand. Adequately powered comparative evaluation is urgently needed. PMID- 25829444 TI - Burnout, psychological morbidity and use of coping mechanisms among palliative care practitioners: A multi-centre cross-sectional study. AB - BACKGROUND: The prevalence of burnout, psychological morbidity and the use of coping mechanisms among palliative care practitioners in Singapore have not been studied. AIM: We aimed to study the prevalence of burnout and psychological morbidity among palliative care practitioners in Singapore and its associations with demographic and workplace factors as well as the use of coping mechanisms. DESIGN: This was a multi-centre, cross-sectional study of all the palliative care providers within the public healthcare sector in Singapore. SETTING/PARTICIPANTS: The study was conducted in hospital palliative care services, home hospice and inpatient hospices in Singapore. The participants were doctors, nurses and social workers. RESULTS: The prevalence of burnout among respondents in our study was 91 of 273 (33.3%) and psychological morbidity was 77 (28.2%). Working >60 h per week was significantly associated with burnout (odds ratio: 9.02, 95% confidence interval: 2.3-35.8, p = 0.002) and psychological morbidity (odds ratio: 7.21, 95% confidence interval: 1.8-28.8, p = 0.005). Home hospice care practitioners (41.5%) were more at risk of developing psychological morbidity compared to hospital-based palliative care (17.5%) or hospice inpatient care (26.0%) (p = 0.007). Coping mechanisms like physical well-being, clinical variety, setting boundaries, transcendental (meditation and quiet reflection), passion for one's work, realistic expectations, remembering patients and organisational activities were associated with less burnout. CONCLUSION: Our results reveal that burnout and psychological morbidity are significant in the palliative care community and demonstrate a need to look at managing long working hours and promoting the use of coping mechanisms to reduce burnout and psychological morbidity. PMID- 25829445 TI - Does ketamine target olfactory receptors in the brain? AB - The findings of Ho et al. in this issue of Science Signaling suggest that the anesthetic ketamine binds to and activates select olfactory receptors in mouse brain, raising the possibility that ketamine targets a similar set of GPCRs in humans. PMID- 25829446 TI - PTEN inhibits PREX2-catalyzed activation of RAC1 to restrain tumor cell invasion. AB - The tumor suppressor PTEN restrains cell migration and invasion by a mechanism that is independent of inhibition of the PI3K pathway and decreased activation of the kinase AKT. PREX2, a widely distributed GEF that activates the GTPase RAC1, binds to and inhibits PTEN. We used mouse embryonic fibroblasts and breast cancer cell lines to show that PTEN suppresses cell migration and invasion by blocking PREX2 activity. In addition to metabolizing the phosphoinositide PIP3, PTEN inhibited PREX2-induced invasion by a mechanism that required the tail domain of PTEN, but not its lipid phosphatase activity. Fluorescent nucleotide exchange assays revealed that PTEN inhibited the GEF activity of PREX2 toward RAC1. PREX2 is a frequently mutated GEF in cancer, and examination of human tumor data showed that PREX2 mutation was associated with high PTEN expression. Therefore, we tested whether cancer-derived somatic PREX2 mutants, which accelerate tumor formation of immortalized melanocytes, were inhibited by PTEN. The three stably expressed, somatic PREX2 cancer mutants that we tested were resistant to PTEN mediated inhibition of invasion but retained the ability to inhibit the lipid phosphatase activity of PTEN. In vitro analysis showed that PTEN did not block the GEF activity of two PREX2 cancer mutants and had a reduced binding affinity for the third. Thus, PTEN antagonized migration and invasion by restraining PREX2 GEF activity, and PREX2 mutants are likely selected in cancer to escape PTEN mediated inhibition of invasion. PMID- 25829447 TI - Molecular recognition of ketamine by a subset of olfactory G protein-coupled receptors. AB - Ketamine elicits various neuropharmacological effects, including sedation, analgesia, general anesthesia, and antidepressant activity. Through an in vitro screen, we identified four mouse olfactory receptors (ORs) that responded to ketamine. In addition to their presence in the olfactory epithelium, these G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are distributed throughout the central nervous system. To better understand the molecular basis of the interactions between ketamine and ORs, we used sequence comparison and molecular modeling to design mutations that (i) increased, reduced, or abolished ketamine responsiveness in responding receptors, and (ii) rendered nonresponding receptors responsive to ketamine. We showed that olfactory sensory neurons (OSNs) that expressed distinct ORs responded to ketamine in vivo, suggesting that ORs may serve as functional targets for ketamine. The ability to both abolish and introduce responsiveness to ketamine in GPCRs enabled us to identify and confirm distinct interaction loci in the binding site, which suggested a signature ketamine-binding pocket that may guide exploration of additional receptors for this general anesthetic drug. PMID- 25829448 TI - T lymphocyte regulation by mevalonate metabolism. AB - Whereas resting T cells, which have low metabolic requirements, use oxidative phosphorylation (OXPHOS) to maximize their generation of ATP, activated T cells, similar to tumor cells, shift metabolic activity to aerobic glycolysis, which also fuels mevalonate metabolism. Both sterol and nonsterol derivatives of mevalonate affect T cell function. The intracellular availability of sterols, which is dynamically regulated by different classes of transcription factors, represents a metabolic checkpoint that modulates T cell responses. The electron carrier ubiquinone, which is modified with an isoprenoid membrane anchor, plays a pivotal role in OXPHOS, which supports the proliferation of T cells. Isoprenylation also mediates the plasma membrane attachment of the Ras, Rho, and Rab guanosine triphosphatases, which are involved in T cell immunological synapse formation, migration, proliferation, and cytotoxic effector responses. Finally, multiple phosphorylated mevalonate derivatives can act as danger signals for innate-like gammadelta T cells, thus contributing to the immune surveillance of stress, pathogens, and tumors. We highlight the importance of the mevalonate pathway in the metabolic reprogramming of effector and regulatory T cells. PMID- 25829449 TI - The glenoid component in anatomic shoulder arthroplasty. AB - Ideal management of the glenoid in anatomic shoulder arthroplasty remains controversial. Glenoid component loosening remains a common source of clinical concern and, in young, active patients, implantation of a glenoid prosthesis is often avoided. Efforts to decrease glenoid loosening have resulted in changes to prosthetic design and implantation techniques. Currently, a wide variety of glenoid component options are available, including metal-backed or all polyethylene, bone ingrowth or ongrowth, inset, and augmented designs. Additionally, several alternatives are available for the young, active patient, including hemiarthroplasty, nonprosthetic resurfacing, and tissue interposition. Many recent clinical and biomechanical studies have examined these implant options. A thorough knowledge of glenoid anatomy, pathology, implant options, indications, and principles of implantation is necessary to optimize the outcome following anatomic shoulder arthroplasty. PMID- 25829450 TI - Evaluation and management of the painful total ankle arthroplasty. AB - Total ankle arthroplasty (TAA) is an increasingly popular treatment option for patients with end-stage ankle arthritis. Although improved short- and long-term clinical and radiographic outcomes have been achieved with TAA, revision surgery may be necessary in the setting of aseptic loosening, subsidence, impingement, arthrofibrosis, or infection. Factors such as patient selection, implant design, and surgical technique can all contribute to TAA failure. Treatment of patients with a painful TAA is complex and requires careful consideration of symptom history, workup, and nonsurgical and surgical treatment options. Surgical management of failed TAA includes arthrodesis, revision surgery, or below-knee amputation. PMID- 25829451 TI - Beyond fruit-flies: population genomic advances in non-Drosophila arthropods. AB - Understanding the evolutionary processes driving the adaptive differentiation of populations is of broad interest in biology. Genome-wide nucleotide polymorphisms provide the basis for population genetic studies powered by advances in high throughput sequencing technologies. These advances have led to an extension of genome projects to a variety of non-genetic model organisms, broadening our view on the evolution of gene families and taxonomic-restricted novelties. Here, we review the progress of genome projects in non-Drosophila arthropods, focusing on advances in the analysis of large-scale polymorphism data and functional genomics and examples of population genomic studies. PMID- 25829452 TI - Glucose Tolerance Is Improved in Mice Invalidated for the Nuclear Receptor HNF 4gamma: A Critical Role for Enteroendocrine Cell Lineage. AB - Intestine contributes to energy homeostasis through the absorption, metabolism, and transfer of nutrients to the organism. We demonstrated previously that hepatocyte nuclear receptor-4alpha (HNF-4alpha) controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4gamma, the other HNF-4 form highly expressed in intestine, is much less studied. In HNF-4gamma knockout mice, we detect an exaggerated insulin peak and improvement in glucose tolerance during oral but not intraperitoneal glucose tolerance tests, highlighting the involvement of intestine. Moreover, the enteroendocrine L-type cell lineage is modified, as assessed by the increased expression of transcription factors Isl1, Foxa1/2, and Hnf4a, leading to an increase of both GLP-1-positive cell number and basal and stimulated GLP-1 plasma levels potentiating the glucose-stimulated insulin secretion. Using the GLP-1 antagonist exendin (9-39), we demonstrate a direct effect of GLP-1 on improved glucose tolerance. GLP-1 exerts a trophic effect on pancreatic beta-cells, and we report an increase of the beta-cell fraction correlated with an augmented number of proliferative islet cells and with resistance to streptozotocin-induced diabetes. In conclusion, the loss of HNF-4gamma improves glucose homeostasis through a modulation of the enteroendocrine cell lineage. PMID- 25829453 TI - Perilipin 5-Driven Lipid Droplet Accumulation in Skeletal Muscle Stimulates the Expression of Fibroblast Growth Factor 21. AB - Perilipin 5 (PLIN5) is a lipid droplet protein and is highly expressed in oxidative tissue. Expression of the PLIN5 gene is regulated by peroxisome proliferator-activated receptor-alpha, fasting, and exercise. However, the effect of increased muscle PLIN5 expression on whole-body energy homeostasis remains unclear. To examine this, we developed a mouse line with skeletal muscle PLIN5 overexpression (MCK-Plin5). We show that MCK-Plin5 mice have increased energy metabolism and accumulate more intramyocellular triacylglycerol but have normal glucose and insulin tolerance. MCK-Plin5 mice fed high-fat chow manifest lower expression of inflammatory markers in their liver and increased expression of "browning" factors in adipose tissue. This muscle-driven phenotype is, at least in part, mediated by myokines; the MCK-Plin5 mice have 80-fold higher FGF21 gene expression in muscle and increased serum FGF21 concentration. The increase in FGF21 occurs mainly in muscles with a predominance of fast-twitch fibers, suggesting that fiber type-specific lipid storage may be part of the mechanism conferring metabolic protection in MCK-Plin5 mice. In conclusion, upregulating the PLIN5 level in skeletal muscle drives expression of the FGF21 gene in fast twitch fibers and is metabolically protective. These findings provide insight into the physiology of PLIN5 and the potential contribution of its upregulation during exercise. PMID- 25829455 TI - The Effectiveness of Aftercare for Juvenile and Young Adult Offenders. AB - This study examined the New Perspectives Aftercare Program (NPAP) for serious juvenile and young adult offenders in The Netherlands. Participants (n = 127) were randomly assigned to NPAP (n = 66) or existing aftercare services ("treatment as usual" [TAU], n = 61). The aim was to determine whether NPAP was effective in decreasing cognitive distortions and criminal thinking patterns and increasing prosocial skills of the juveniles compared with TAU. No direct intervention effects were found on any of the outcome measures. Moderator analyses, however, showed several interaction effects of ethnicity and coping skills for both NPAP and TAU youths. Furthermore, NPAP dropouts displayed significantly more indirect aggression at posttest compared with youths dropping out from TAU. Possible explanations for the mostly null effects are discussed, including implications for further research, policy, and practice. PMID- 25829454 TI - Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes. AB - Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing beta-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity. PMID- 25829456 TI - Adaptation of the Texas Implementation Medication Algorithm for Bipolar Disorder in Adult Female Offenders. AB - Use of medication algorithms in the correctional setting may facilitate clinical decision making, improve consistency of care, and reduce polypharmacy. The objective of the present study was to evaluate effectiveness of algorithm (Texas Implementation of Medication Algorithm [TIMA])-driven treatment of bipolar disorder (BD) compared with Treatment as Usual (TAU) in the correctional environment. A total of 61 women inmates with BD were randomized to TIMA (n = 30) or TAU (n = 31) and treated over a 12-week period. The outcome measures included measures of BD symptoms, comorbid symptomatology, quality of life, and psychotropic medication utilization. In comparison with TAU, TIMA-driven treatment reduced polypharmacy, decreased overall psychotropic medication utilization, and significantly decreased use of specific classes of psychotropic medication (antipsychotics and antidepressants). This pilot study confirmed the feasibility and benefits of algorithm-driven treatment of BD in the correctional setting, primarily by enhancing appropriate use of evidence-based treatment. PMID- 25829457 TI - Reentry Programming for High-Risk Offenders: Insights From Participants. AB - The mass increase in imprisonment of the last two decades has led to an increasing number of adults released from prison. Scholarly accounts of prisoner reentry have demonstrated that incarcerated individuals face barriers on release from prison and that intervention programs are necessary to assist their transition to the community. Here, we build from the insights of previous research by examining how high-risk offenders perceive a reentry program. Using a qualitative approach, our findings suggest that procedural and substantive justice affect their satisfaction and involvement with the program. This study highlights the importance of providing employment opportunities, social support, and fair and respectful delivery of services to assist incarcerated individuals transitioning to the community. PMID- 25829458 TI - Severe antiphospholipid syndrome and cardiac surgery: Perioperative management. AB - Antiphospholipid syndrome is an antiphospholipid antibody-mediated prothrombotic state leading to arterial and venous thrombosis. This condition alters routine in vitro coagulation tests, making results unreliable. Antiphospholipid syndrome patients requiring cardiac surgery with cardiopulmonary bypass present a unique challenge in perioperative anticoagulation management. We describe 3 patients with antiphospholipid syndrome who had successful heart valve surgery at our institution. We have devised an institutional protocol for antiphospholipid syndrome patients, and all 3 patients were managed according to this protocol. An algorithm-based approach is recommended because it improves team work, optimizes treatment, and improves patient outcome. PMID- 25829459 TI - Axillary Lymphadenopathy: An Outstanding Presentation for Breast Implant Associated ALK-Negative Anaplastic Large Cell Lymphoma. AB - Till date, there is only one reported case of breast implant-associated ALK negative anaplastic large cell lymphoma (ALCL) with an axillary presentation that followed an aggressive behavior. We report the case of a 50-year-old female presenting with an axillary lymphadenopathy 8 years after breast prostheses implantation. Clinical examination, ultrasound, and magnetic resonance imaging detected no mammary lesions. The lymph node showed intrasinusoidal infiltration by large pleomorphic cells expressing CD30 and lacking ALK-immunoreactivity. Tumor staging was negative. Cells with identical features were found in the ipsilateral periprosthetic capsule. The patient was treated with CHOP and radiotherapy, and she is alive without evidence of disease after a 30-month follow-up. The diagnosis of an ALK-negative ALCL in an axillary lymph node of a patient with ipsilateral breast prosthesis and negative staging should prompt removal of the implant with capsulectomy, since the pathological study of this specimen allows the correct diagnosis with important prognostic implications. PMID- 25829460 TI - Recommendations to improve the usability of drug-drug interaction clinical decision support alerts. AB - OBJECTIVE: To establish preferred strategies for presenting drug-drug interaction (DDI) clinical decision support alerts. MATERIALS AND METHODS: A DDI Clinical Decision Support Conference Series included a workgroup consisting of 24 clinical, usability, and informatics experts representing academia, health information technology (IT) vendors, healthcare organizations, and the Office of the National Coordinator for Health IT. Workgroup members met via web-based meetings 12 times from January 2013 to February 2014, and two in-person meetings to reach consensus on recommendations to improve decision support for DDIs. We addressed three key questions: (1) what, how, where, and when do we display DDI decision support? (2) should presentation of DDI decision support vary by clinicians? and (3) how should effectiveness of DDI decision support be measured? RESULTS: Our recommendations include the consistent use of terminology, visual cues, minimal text, formatting, content, and reporting standards to facilitate usability. All clinicians involved in the medication use process should be able to view DDI alerts and actions by other clinicians. Override rates are common but may not be a good measure of effectiveness. DISCUSSION: Seven core elements should be included with DDI decision support. DDI information should be presented to all clinicians. Finally, in their current form, override rates have limited capability to evaluate alert effectiveness. CONCLUSION: DDI clinical decision support alerts need major improvements. We provide recommendations for healthcare organizations and IT vendors to improve the clinician interface of DDI alerts, with the aim of reducing alert fatigue and improving patient safety. PMID- 25829461 TI - Comparison of consumers' views on electronic data sharing for healthcare and research. AB - New models of healthcare delivery such as accountable care organizations and patient-centered medical homes seek to improve quality, access, and cost. They rely on a robust, secure technology infrastructure provided by health information exchanges (HIEs) and distributed research networks and the willingness of patients to share their data. There are few large, in-depth studies of US consumers' views on privacy, security, and consent in electronic data sharing for healthcare and research together. OBJECTIVE: This paper addresses this gap, reporting on a survey which asks about California consumers' views of data sharing for healthcare and research together. MATERIALS AND METHODS: The survey conducted was a representative, random-digit dial telephone survey of 800 Californians, performed in Spanish and English. RESULTS: There is a great deal of concern that HIEs will worsen privacy (40.3%) and security (42.5%). Consumers are in favor of electronic data sharing but elements of transparency are important: individual control, who has access, and the purpose for use of data. Respondents were more likely to agree to share deidentified information for research than to share identified information for healthcare (76.2% vs 57.3%, p < .001). DISCUSSION: While consumers show willingness to share health information electronically, they value individual control and privacy. Responsiveness to these needs, rather than mere reliance on Health Insurance Portability and Accountability Act (HIPAA), may improve support of data networks. CONCLUSION: Responsiveness to the public's concerns regarding their health information is a pre-requisite for patient-centeredness. This is one of the first in-depth studies of attitudes about electronic data sharing that compares attitudes of the same individual towards healthcare and research. PMID- 25829462 TI - Reference intervals for plasma-free amino acid in a Japanese population. AB - BACKGROUND: Plasma amino acid concentrations vary with various diseases. Although reference intervals are useful in daily clinical practice, no reference intervals have been reported for plasma amino acids in a large Japanese population. METHODS: Reference individuals were selected from 7685 subjects examined with the Japanese Ningen Dock in 2008. A total of 1890 individuals were selected based on exclusion criteria, and the reference samples were selected after the outlier samples for each amino acid concentration were excluded. The lower limit of the reference intervals for the plasma amino acid concentrations was set at the 2.5th percentile and the upper limit at the 97.5th percentile. RESULTS: By use of the nested analysis of variance, we analysed a large dataset of plasma samples and the effects of background factors (sex, age and body mass index [BMI]) on the plasma amino acid concentrations. Most amino acid concentrations were related to sex, especially those of branched-chained amino acid. The citrulline, glutamine, ornithine and lysine concentrations were related to age. The glutamate concentration was related to body mass index. CONCLUSIONS: The concentrations of most amino acids are more strongly related to sex than to age or body mass index. Our results indicate that the reference intervals for plasma amino acid concentrations should be stratified by sex when the background factors of age and body mass index are considered. PMID- 25829463 TI - Photosynthetic energy conversion efficiency: setting a baseline for gauging future improvements in important food and biofuel crops. AB - The conversion efficiency (epsilon(c)) of absorbed radiation into biomass (MJ of dry matter per MJ of absorbed photosynthetically active radiation) is a component of yield potential that has been estimated at less than half the theoretical maximum. Various strategies have been proposed to improve epsilon(c), but a statistical analysis to establish baseline epsilon(c) levels across different crop functional types is lacking. Data from 164 published epsilon(c) studies conducted in relatively unstressed growth conditions were used to determine the means, greatest contributors to variation, and genetic trends in epsilon(c )across important food and biofuel crop species. epsilon(c) was greatest in biofuel crops (0.049-0.066), followed by C4 food crops (0.046-0.049), C3 nonlegumes (0.036-0.041), and finally C3 legumes (0.028-0.035). Despite confining our analysis to relatively unstressed growth conditions, total incident solar radiation and average growing season temperature most often accounted for the largest portion of epsilon(c) variability. Genetic improvements in epsilon(c), when present, were less than 0.7% per year, revealing the unrealized potential of improving epsilon(c) as a promising contributing strategy to meet projected future agricultural demand. PMID- 25829464 TI - Epigenetic Mechanisms Are Critical for the Regulation of WUSCHEL Expression in Floral Meristems. AB - The floral meristem (FM), which develops from the inflorescence meristem upon completion of the floral transition, terminates after producing a defined number of floral organs. This is in contrast to the shoot apical meristem, which is active throughout the entire life span of plants. WUSCHEL (WUS) encodes a homeodomain-containing protein and plays a critical role in shoot apical meristem, inflorescence meristem, and FM establishment and maintenance as well as FM determinacy. Although many genes have been implicated in FM determinacy through the regulation of WUS expression, precisely how these genes are coordinated to regulate WUS and consequently dictate FM fate remains unclear. Emerging lines of evidence indicate that epigenetic mechanisms, such as histone modification, chromatin remodeling, noncoding RNAs, and DNA methylation, play vital roles in meristem maintenance and termination. Here, recent findings demonstrating the involvement of the epigenetic network in the regulation of WUS expression in the context of FM determinacy are summarized and discussed. PMID- 25829465 TI - The gymnosperm cytochrome P450 CYP750B1 catalyzes stereospecific monoterpene hydroxylation of (+)-sabinene in thujone biosynthesis in western redcedar. AB - Western redcedar (WRC; Thuja plicata) produces high amounts of oxygenated thujone monoterpenoids associated with resistance against herbivore feeding, particularly ungulate browsing. Thujones and other monoterpenoids accumulate in glandular structures in the foliage of WRC. Thujones are produced from (+)-sabinene by sabinol and sabinone. Using metabolite analysis, enzyme assays with WRC tissue extracts, cloning, and functional characterization of cytochrome P450 monooxygenases, we established that trans-sabin-3-ol but not cis-sabin-3-ol is the intermediate in thujone biosynthesis in WRC. Based on transcriptome analysis, full-length complementary DNA cloning, and characterization of expressed P450 proteins, we identified CYP750B1 and CYP76AA25 as the enzymes that catalyze the hydroxylation of (+)-sabinene to trans-sabin-3-ol. Gene-specific transcript analysis in contrasting WRC genotypes producing high and low amounts of monoterpenoids, including a glandless low-terpenoid clone, as well as assays for substrate specificity supported a biological role of CYP750B1 in alpha- and beta thujone biosynthesis. This P450 belongs to the apparently gymnosperm-specific CYP750 family and is, to our knowledge, the first member of this family to be functionally characterized. In contrast, CYP76AA25 has a broader substrate spectrum, also converting the sesquiterpene farnesene and the herbicide isoproturon, and its transcript profiles are not well correlated with thujone accumulation. PMID- 25829466 TI - The Experiences and Perceptions of Street-Involved Youth Regarding Emergency Department Services. AB - Street-involved (SI) youth comprise a substantial component of the urban homeless population. Despite being significant users of hospital emergency department (ED) services for acute and ongoing health needs, little is known about their experiences of ED care and the factors affecting their ED use. This study used a grounded theory and community-based approach to examine these issues. Focus groups and individual interviews were facilitated with 48 SI youth between ages 15 and 26 years, recruited in hospital or through community agencies serving SI youth in a major Western Canadian city. Results demonstrate that SI youth often perceived suboptimal care and experienced long waiting periods that led to many avoiding or prematurely exiting the ED. Service gaps appeared to have a negative bearing on their care and health outcomes. Findings invite a critical review of ED care processes, structures, and staff interactions in the aim of enhancing ED services to SI youth. PMID- 25829467 TI - On the Brink of Genuinely Collaborative Care: Experience-Based Co-Design in Mental Health. AB - Inpatient mental health services in the United Kingdom are currently dissatisfactory for service-users and staff. For young people with psychosis, being hospitalized is often distressing, and can lead to disengagement with mental health services. This article describes how we took three qualitative research studies about hospitalization in early psychosis (exploring the perspectives of service-users, parents, and staff) and translated them into service improvements developed in collaboration with a range of stakeholders, including service-users, carers, community and inpatient staff, and management. We used an adapted form of experience-based co-design (EBCD), a participatory action-research method for collaboratively improving health care services. The use of EBCD is still relatively novel in mental health settings, and we discuss how we adapted the methodology, and some of the implications of using EBCD with vulnerable populations in complex services. We reflect on both the disappointments and successes and give some recommendations for future research and methodological development. PMID- 25829468 TI - Assessing the consistency of public human tissue RNA-seq data sets. AB - Sequencing-based gene expression methods like RNA-sequencing (RNA-seq) have become increasingly common, but it is often claimed that results obtained in different studies are not comparable owing to the influence of laboratory batch effects, differences in RNA extraction and sequencing library preparation methods and bioinformatics processing pipelines. It would be unfortunate if different experiments were in fact incomparable, as there is great promise in data fusion and meta-analysis applied to sequencing data sets. We therefore compared reported gene expression measurements for ostensibly similar samples (specifically, human brain, heart and kidney samples) in several different RNA-seq studies to assess their overall consistency and to examine the factors contributing most to systematic differences. The same comparisons were also performed after preprocessing all data in a consistent way, eliminating potential bias from bioinformatics pipelines. We conclude that published human tissue RNA-seq expression measurements appear relatively consistent in the sense that samples cluster by tissue rather than laboratory of origin given simple preprocessing transformations. The article is supplemented by a detailed walkthrough with embedded R code and figures. PMID- 25829470 TI - How many digits should be reported in forensic breath alcohol measurements? AB - Uncertainty is an inherent property of all measurements. The magnitude of this uncertainty will determine the number of meaningful digits that should be reported in a measurement result. Several statistical arguments are considered providing evidence that three digit truncated results are more appropriate than two since the first significant digit of the combined uncertainty (standard deviation) in breath alcohol measurement is found in the third decimal place. Probably, the most compelling reason for reporting three digits is the significant reduction in combined uncertainty compared with the use of two digits. For a breath alcohol concentration of 0.089 g/210 L, the combined uncertainty for two digit results is ~0.0042 g/210 L, compared with 0.0031 g/210 L for three digit results. The historical practice of reporting two digit truncated results in forensic breath alcohol analysis has been largely based on the use of analog scale instruments with 0.01 g/210 L scale resolution. With today's modern digital instrumentation, this practice should be reconsidered. While the focus of this paper is on breath alcohol analysis, the general principles will apply to any quantitative analytical measurement. PMID- 25829469 TI - Adapting bioinformatics curricula for big data. AB - Modern technologies are capable of generating enormous amounts of data that measure complex biological systems. Computational biologists and bioinformatics scientists are increasingly being asked to use these data to reveal key systems level properties. We review the extent to which curricula are changing in the era of big data. We identify key competencies that scientists dealing with big data are expected to possess across fields, and we use this information to propose courses to meet these growing needs. While bioinformatics programs have traditionally trained students in data-intensive science, we identify areas of particular biological, computational and statistical emphasis important for this era that can be incorporated into existing curricula. For each area, we propose a course structured around these topics, which can be adapted in whole or in parts into existing curricula. In summary, specific challenges associated with big data provide an important opportunity to update existing curricula, but we do not foresee a wholesale redesign of bioinformatics training programs. PMID- 25829471 TI - A novel lamin A/C gene missense mutation (445 V > E) in immunoglobulin-like fold associated with left ventricular non-compaction. AB - AIMS: Two LMNA mutations (R644C and R190W) have been associated with familial and sporadic left ventricular non-compaction (LVNC). However, the mechanisms underlying these associations have not been elucidated. METHODS AND RESULTS: Genomic DNA was isolated from peripheral blood leucocytes and analysed by direct sequencing. Human embryonic kidney 293 cells were transfected with either wild type or mutant LMNA and SCN5A for whole-cell patch-clamp experiment and fluorescence microscopy. Point mutation modeling for mutant LMNA was also performed. One novel LVNC-associated mutation (V445E) in beta2 sheet of immunoglobulin (Ig)-like fold was found in the proband and his father. We also found that the peak current of sodium channel was markedly reduced in mutant LMNA compared with WT while the activation, inactivation, and recovery curves were not significantly altered. The mutant lamin A/C were aggregated into multiple highlighted particles. Three beta sheets and multiple side chains in Ig-like fold were altered due to the replacement of a valine by glutamic acid. CONCLUSION: Our data associated a novel lamin A/C mutation (V445E) with a sudden death form of familial LVNC. The reduced sodium current in mutant LMNA may account for the advent of malignant ventricular arrhythmias. The altered structures of three beta sheets and side chains may partially explain the aggregation of lamin A/C protein subjacent to the nuclear envelope. PMID- 25829472 TI - Apical vs. non-apical right ventricular pacing in cardiac resynchronization therapy: a meta-analysis. AB - AIMS: Cardiac resynchronization therapy (CRT) has been shown to improve outcomes in patients with heart failure. The optimal site of right ventricular (RV) stimulation in CRT has not been established. We aimed to conduct a meta-analysis of randomized-controlled trials and observational studies comparing the mid- and long-term effects of RV apical (RVA) and non-apical (RVNA) pacing on CRT outcomes. METHODS: We systematically searched the Cochrane library, EMBASE, and MEDLINE databases for studies evaluating RVA vs. RVNA pacing in CRT with regards to left ventricular end-systolic volume (LVESV) reduction, functional status improvement (defined as >=1 New York Heart Association class improvement), and the clinical outcome of mortality or cardiovascular hospitalization. Effect estimates [standardized mean difference (SMD) and odds ratio (OR) with 95% confidence intervals (CI)] were pooled using random-effect models. RESULTS: Twelve studies comprising 2670 patients (1655 with an apical and 1015 with a non apical RV lead position) were included. In meta-analyses, LVESV reduction and functional status improvement were similar in patients with RVA and RVNA pacing (SMD 0.13, 95% CI: -0.24 to 0.50, P = 0.48; OR 1.08, 95% CI: 0.81 to 1.45, P = 0.60, respectively). Data regarding mortality and hospitalizations could not be pooled due to a small number of relevant studies with significant heterogeneity. CONCLUSION: Our meta-analysis suggests that in CRT patients the effects of RVA or RVNA pacing on LV remodelling and functional status are similar. Mortality and morbidity outcomes with different RV lead positions should be further assessed in randomized clinical trials. PMID- 25829474 TI - The SAMe-TT2R2 score and quality of anticoagulation in atrial fibrillation: a simple aid to decision-making on who is suitable (or not) for vitamin K antagonists. PMID- 25829473 TI - A Brugada syndrome proband with compound heterozygote SCN5A mutations identified from a Chinese family in Singapore. AB - AIMS: Brugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the alpha-subunit of the sodium ion channel Nav1.5, are present in 15-30% of BrS cases. SCN5A remains by far, the highest yielding gene for BrS. We studied a young male who presented with syncope at age 11. This proband was screened for possible disease causing SCN5A mutations. The inheritance pattern was also examined amongst his first-degree family members. METHODS AND RESULTS: The proband had a baseline electrocardiogram that showed Type 2 BrS changes, which escalated to a characteristic Type I BrS pattern during a treadmill test before polymorphic ventricular tachycardia onset at a cycle length of 250 ms. Mutational analysis across all 29 exons in SCN5A of the proband and first-degree relatives of the family revealed that the proband inherited a compound heterozygote mutation in SCN5A, specifically p.A226V and p.R1629X from each parent. To further elucidate the functional changes arising through these mutations, patch-clamp electrophysiology was performed in TSA201 cells expressing the mutated SCN5A channels. The p.A226V mutation significantly reduced peak sodium current (INa) to 24% of wild type (WT) whereas the p.R1629X mutation abolished the current. To mimic the functional state in our proband, functional expression of the compound variants A226V + R1629X resulted in overall peak INa of only 13% of WT (P < 0.01). CONCLUSION: Our study is the first to report a SCN5A compound heterozygote in a Singaporean Chinese family. Only the proband carrying both mutations displayed the BrS phenotype, thus providing insights into the expression and penetrance of BrS in an Asian setting. PMID- 25829475 TI - Slow pathway ablation in abdominal visceral heterotaxy with azygos continuation. PMID- 25829476 TI - Breastfeeding Support in a Community Pharmacy: Improving Access through the Well Babies at Walgreens Program. AB - Well Babies at Walgreens is a unique community-based corporate partnership program that offers breastfeeding support by a lactation professional in a private room at the pharmacy. Walgreens is a community pharmacy chain with more than 8000 locations in the United States, Puerto Rico, and the US Virgin Islands. The primary goal of Well Babies is to support breastfeeding women using a model that is expandable to other Walgreens pharmacy sites. The Well Babies program offers drop-in services, with a professional consultation by a lactation consultant and baby weight check, if desired. Well Babies creators are developing a business plan for Walgreens and a toolkit that would help other stores implement the program. An additional goal is to improve continuity of care for breastfeeding by engaging pharmacists as vital members of the health care team. Offering breastfeeding support at a pharmacy improves access and encourages support persons to attend while simultaneously allowing the family to complete other errands. This initiative included education for pharmacists to improve the recommendations they make for breastfeeding mothers and to improve awareness among pharmacists of the benefits associated with breastfeeding and the need to preserve the breastfeeding relationship. The first drop-in location opened in April 2012. Grant funding from the US Centers for Disease Control and Prevention, awarded to the Indiana State Department of Health, made it possible to open a second drop-in location in June 2013. Future plans include developing an employee lactation program and expanding Well Babies at Walgreens at other store locations. PMID- 25829477 TI - Changes in Breastfeeding Attitudes in a Metropolitan Community in Tennessee. AB - BACKGROUND: The Southern United States has low breastfeeding rates, particularly among African Americans. Breastfeeding rates are influenced by community attitudes and norms. OBJECTIVE: This study aimed to examine changes in breastfeeding attitudes and demographic factors related to these attitudes. METHODS: Cross-sectional data from a community-based survey, repeated annually from 2004 to 2008, were analyzed. Univariable analysis examined trends over time and log binomial regression estimated the strength of the association between year of the survey, demographic factors, and outcome responses related to the survey questions. RESULTS: After adjusting for sex, race, marital status, age, and education, compared to 2004, 2008 respondents were 26% more likely to rate breastfeeding as extremely important compared to formula feeding (prevalence ratio [PR] = 1.26; 95% confidence interval [CI], 1.10-1.43). Similarly, 2008 respondents were 29% more likely to rate the importance of breastfeeding for long term health as extremely important (PR = 1.29; 95% CI, 1.14-1.46). Comfort levels with breastfeeding outside the home also increased. Respondents to the 2008 survey were more likely to report that they were comfortable with a mother breastfeeding in their workplace (PR = 1.20; 95% CI, 1.11-1.31) and in a mall or restaurant (PR = 1.15; 95% CI, 1.06-1.26). After controlling for demographic factors, there were no significant differences in responses between African Americans and other races. CONCLUSION: Despite significantly lower breastfeeding rates among African Americans, this analysis revealed significant positive changes in attitudes regarding breastfeeding between 2004 and 2008, regardless of race. These changes in attitude coincided with increased breastfeeding initiation rates, suggesting that federal, state, and local breastfeeding promotion efforts had an effect. PMID- 25829478 TI - Breastfeeding Self-Efficacy, Mood, and Breastfeeding Outcomes among Primiparous Women. AB - BACKGROUND: A link between postpartum mood and breastfeeding has been established in the literature, but little is known about the relationship of breastfeeding self-efficacy (BSE) to breastfeeding and mood outcomes, particularly in primiparous women. OBJECTIVES: The purpose of this study was to prospectively evaluate the relationship among BSE, mood, and breastfeeding outcomes in primiparous women. A secondary purpose was to explore self-reported reasons for difficult emotional adjustment during the transition to motherhood. METHODS: Primiparous women who initiated breastfeeding were surveyed at 2 days, 6 weeks, and 6 months postpartum. Breastfeeding self-efficacy, depressive symptoms, work status, breastfeeding difficulties, partner support, and use of lactation services were included in a hierarchical multiple regression analysis. Women who identified as emotionally distressed provided open-ended responses identifying the main cause of their stress. RESULTS: High BSE at 2 days postpartum predicted positive emotional adjustment and fewer depressive symptoms at 6 weeks postpartum, as well as more exclusive breastfeeding at 6 months postpartum. Among distressed mothers, breastfeeding concerns were among the most commonly named reasons for stress, along with lack of sleep, lack of social support, and overwhelming learning demands involved with being a new parent. CONCLUSION: Breastfeeding perceptions are associated with emotional health and breastfeeding outcomes. Bolstering women's early BSE may be an important goal for multiple dimensions of postpartum health. PMID- 25829479 TI - 80-kVp CT angiography for endovascular aneurysm repair follow-up with halved contrast medium dose and preserved diagnostic quality. AB - BACKGROUND: Follow-up of endovascular aneurysm repair (EVAR) with life-long computed tomography angiography (CTA) surveillance exposes patients with impaired renal function to repeated risks of contrast medium-induced nephropathy (CIN). PURPOSE: To retrospectively compare vascular attenuation, image noise, contrast to-noise ratio (CNR), subjective image quality and effective radiation dose (mSv) for CTA with a 16-multirow detector CT (MDCT) equipment at 80 kVp after EVAR using a contrast medium (CM) dose that is half of that used at 120 kVp. MATERIAL AND METHODS: Forty patients with estimated glomerular filtration rate (eGFR) <45 mL/min underwent 80-kVp CTA with 160 mg I/kg, and 40 patients with eGFR >=45 mL/min 120-kVp CTA with 320 mg I/kg (maximum dose weight, 80 kg). Arterial phase analysis included vascular attenuation, image noise and CNR, and calculated effective dose. Subjective image quality was assessed on a 4-point scale by two blinded readers at three different levels as well as overall. RESULTS: Median values in the 80/120 kVp cohorts were: age, 74-75 years; body weight, 77/80 kg; BMI 24/27 kg/m(2); CM dose, 13/25 gram-iodine; gram-iodine/GFR ratio, 0.35/0.38; mean aortic attenuation, 313/326 HU; image noise, 26/32 HU; CNR 10-11; subjective image quality score, 3.0-3.5 (Reader 1) and 3.0-3.3 (Reader 2); number of non diagnostic examinations, 0/1; and effective dose, 4.5/5.1 mSv. There was no statistically significant difference in aortic CNR and effective dose between the 80 and 120 kVp cohorts. CONCLUSION: 80 kVp 16-MDCT with halved CM dose tailored to body weight for CTA follow-up of EVAR may provide satisfactory diagnostic results compared to common standards and be beneficial for patients at risk of CIN, though the present CT equipment may limit the use of the method to patients below 90 kg or with a BMI below 35 kg/m(2). PMID- 25829480 TI - How reliable is routine lumbar spine MRI for detection of renal cysts? Correlation with abdominal CT. AB - BACKGROUND: Incidental renal cysts are a very common finding in routine lumbar spine magnetic resonance imaging (MRI). However, there is no report of the renal cyst detection rate on routine lumbar spine MRI. PURPOSE: To determine the renal cyst detection rate in routine lumbar spine MRI based on findings of abdominal computed tomography (CT), and to investigate if the largest renal cyst seen by abdominal CT could be also detected by routine lumbar spine MRI. MATERIAL AND METHODS: A retrospective study was conducted of 70 patients who underwent both routine lumbar spine MRI and abdominal CT between December 2011 and January 2014. The detection rate of all renal cysts>5 mm as well as the largest renal cyst seen by abdominal CT were assessed in routine lumbar spine MRI. RESULTS: On routine lumbar spine MRI, the detection rate of renal cysts was 46.5% (73/157) for>5-mm renal cysts and 68.0% (34/50) for>10-mm renal cysts, correlating with abdominal CT. The detection rate of the largest renal cyst seen by abdominal CT was 60.0% (27/45). Non-detection of the largest renal cyst could be caused by upper positioning (n = 7), lateral positioning (n = 6), or relatively small cyst size (n = 5). CONCLUSION: Approximately half of renal cysts>5 mm and two-thirds of renal cysts>10 mm were detected on routine lumbar spine MRI. However, radiologists should be aware that kidney lesions may not be included in the scan coverage of routine lumbar spine MRI. PMID- 25829481 TI - Why do psychiatric patients have higher cancer mortality rates when cancer incidence is the same or lower? AB - OBJECTIVE: Studies of overall cancer incidence and mortality in psychiatric patients have had mixed results. Some have reported lower than expected cancer incidence or mortality, while others have found no association or an increased risk depending on sample, psychiatric diagnosis, cancer site and methodology. Few studies have compared cancer incidence and mortality using the same population and methodology. METHOD: A population-based record-linkage analysis to compare cancer incidence and mortality in psychiatric patients with that for the general Queensland population, using an historical cohort to calculate age- and sex standardised rate ratios and hazard ratios. Mental health records were linked with cancer registrations and death records from 2002 to 2007. RESULTS: There were 89,992 new cancer cases, of which 3349 occurred in people with mental illness. Cancer incidence was the same as the general population for most psychiatric disorders. Rates were actually lower for dementia (hazard ratio = 0.77; 95% confidence interval = [0.67, 0.88]) and schizophrenia (hazard ratio = 0.84; 95% confidence interval = [0.72, 0.98]). By contrast, mortality was increased in psychiatric patients (hazard ratio = 2.27; 95% confidence interval = [2.15, 2.39]) with elevated hazard ratios for all the main psychiatric diagnoses. CONCLUSIONS: Lifestyle, such as alcohol or tobacco use, would not explain our findings that people with mental illness are no more likely than the general population to develop cancer but more likely to die of it. Other factors may be the difficulty in differentiating medically explained and unexplained symptoms, greater case fatality or inequity in access to specialist procedures. The study highlights the need for improved cancer screening, detection and intervention in this population. PMID- 25829483 TI - Portrayal of violent male psychiatric patients by entertainment media and the stigma of psychiatric illness. PMID- 25829482 TI - Gender differences in depressive symptom profiles and patterns of psychotropic drug usage in Asian patients with depression: Findings from the Research on Asian Psychotropic Prescription Patterns for Antidepressants study. AB - OBJECTIVES: The purpose of this study was to investigate whether there were gender-specific depressive symptom profiles or gender-specific patterns of psychotropic agent usage in Asian patients with depression. METHOD: Clinical data from the Research on Asian Psychotropic Prescription Patterns for Antidepressant study (1171 depressed patients) were used to determine gender differences by analysis of covariates for continuous variables and by logistic regression analysis for discrete variables. In addition, a binary logistic regression model was fitted to identify independent clinical correlates of the gender-specific pattern on psychotropic drug usage. RESULTS: Men were more likely than women to have loss of interest (adjusted odds ratio = 1.379, p = 0.009), fatigue (adjusted odds ratio = 1.298, p = 0.033) and concurrent substance abuse (adjusted odds ratio = 3.793, p = 0.008), but gender differences in other symptom profiles and clinical features were not significant. Men were also more likely than women to be prescribed adjunctive therapy with a second-generation antipsychotic (adjusted odds ratio = 1.320, p = 0.044). However, men were less likely than women to have suicidal thoughts/acts (adjusted odds ratio = 0.724, p = 0.028). Binary logistic regression models revealed that lower age (odds ratio = 0.986, p = 0.027) and current hospitalization (odds ratio = 3.348, p < 0.0001) were independent clinical correlates of use of second-generation antipsychotics as adjunctive therapy for treating depressed Asian men. CONCLUSION: Unique gender-specific symptom profiles and gender-specific patterns of psychotropic drug usage can be identified in Asian patients with depression. Hence, ethnic and cultural influences on the gender preponderance of depression should be considered in the clinical psychiatry of Asian patients. PMID- 25829484 TI - Tropisetron for postoperative cognitive decline. PMID- 25829485 TI - The paradoxes of doubting in obsessive-compulsive disorder. PMID- 25829486 TI - Association between topiramate use and serum bicarbonate levels in a veteran population. AB - BACKGROUND: Topiramate has been associated with metabolic acidosis secondary to decreased serum bicarbonate. Product labeling recommends serum bicarbonate monitoring at baseline and periodically thereafter. OBJECTIVE: The study objective was to assess changes in serum bicarbonate within the first year of topiramate use in an outpatient veteran population. METHODS: This was a single center, retrospective study conducted at the Iowa City Veterans Affairs Health Care System. Inclusion criteria required a minimum of 1 topiramate outpatient prescription between October 1, 1999, and August 31, 2012, and at least 1 serum bicarbonate level within 12 months prior to topiramate initiation. Patients with topiramate nonadherence, concurrent use of sodium bicarbonate or oral carbonic anhydrase inhibitors, and individual serum bicarbonate values obtained during inpatient hospitalizations were excluded. Change in bicarbonate was evaluated using a paired t test. Decreases in bicarbonate of >=5 mEq/L, values <20 mEq/L, days to lowest value, and correlation between adverse drug reactions (ADRs) and topiramate discontinuation were evaluated. RESULTS: Of 546 patients reviewed, 350 were included in the analysis. There was a statistically significant decrease of 2.7 mEq/L in bicarbonate following initiation of topiramate. Only 1 patient had a bicarbonate value <17 mEq/L. There was no association between bicarbonate decrease >=5 mEq/L and ADRs. CONCLUSIONS: A statistically significant reduction in bicarbonate levels occurred with topiramate, which was clinically insignificant. ADR occurrence did not correlate with bicarbonate levels <17 mEq/L or a decrease >=5 mEq/L. Our results indicate that serum bicarbonate levels should only be monitored before topiramate initiation and in patients presenting with symptoms suggestive of acidosis. PMID- 25829487 TI - Macular structure-function relationship at various spatial locations in glaucoma. AB - BACKGROUND/AIMS: To study whether the structure-function (S-F) relationship in glaucoma differs according to macular location using spectral-domain optical coherence tomography (SD-OCT) and standard automated perimetry 10-2 and 24-2 visual fields (VFs). METHODS: We enrolled 151 eyes of 151 healthy, preperimetric and perimetric glaucomatous subjects. Macular ganglion cell-inner plexiform layer thicknesses at different parafoveal locations were measured using Cirrus SD-OCT. The mean sensitivity of 10-2 and 24-2 VFs was recorded in the decibel and 1/L scales. The topographic relationships between structure and function were assessed at different parafoveal and hemimacular locations using 'weighted' correlation coefficients. The strength of S-F relationships between macular ganglion cell-inner plexiform layer thickness measurements and VF mean sensitivity in various parafoveal locations and in superior and inferior hemimacula was compared using Steiger's test. RESULTS: The temporal parafoveal sector showed a significantly greater S-F relationship in each hemimacula compared with other parafoveal sectors (p<0.05). The inferior hemimacula showed a significantly greater S-F relationship than superior hemimacula (p<0.001). CONCLUSIONS: The strength of the S-F associations at the temporal parafoveal location is significantly greater than that of the central or nasal parafoveal location in each hemimacula. The strength of the S-F association is significantly greater in the inferior hemimacula than in the superior hemimacula. PMID- 25829488 TI - Defining the ideal femtosecond laser capsulotomy. AB - PURPOSE: We define the ideal anterior capsulotomy through consideration of capsular histology and biomechanics. Desirable qualities include preventing posterior capsular opacification (PCO), maintaining effective lens position (ELP) and optimising capsular strength. METHODS: Laboratory study of capsular biomechanics and literature review of histology and published clinical results. RESULTS: Parameters of ideal capsulotomy construction include complete overlap of the intraocular lens to prevent PCO, centration on the clinical approximation of the optical axis of the lens to ensure concentricity with the capsule equator, and maximal capsular thickness at the capsulotomy edge to maintain integrity. CONCLUSIONS: Constructing the capsulotomy centred on the clinical approximation of the optical axis of the lens with diameter 5.25 mm optimises prevention of PCO, consistency of ELP and capsular strength. PMID- 25829489 TI - Phosphatidylserine decarboxylase 1 autocatalysis and function does not require a mitochondrial-specific factor. AB - Phosphatidylethanolamine (PE) is a major cellular phospholipid that can be made by four separate pathways, one of which resides in the mitochondrion. The mitochondrial enzyme that generates PE is phosphatidylserine decarboxylase 1 (Psd1p). The pool of PE produced by Psd1p, which cannot be compensated for by the other cellular PE metabolic pathways, is important for numerous mitochondrial functions, including oxidative phosphorylation and mitochondrial dynamics and morphology, and is essential for murine development. To become catalytically active, Psd1p undergoes an autocatalytic processing step involving a conserved LGST motif that separates the enzyme into alpha and beta subunits that remain non covalently attached and are anchored to the inner membrane by virtue of the membrane-embedded beta subunit. It was speculated that Psd1p autocatalysis requires a mitochondrial-specific factor and that for Psd1p to function in vivo, it had to be embedded with the correct topology in the mitochondrial inner membrane. However, the identity of the mitochondrial factor required for Psd1p autocatalysis has not been identified. With the goal of defining molecular requirements for Psd1p autocatalysis, we demonstrate that: 1) despite the conservation of the LGST motif from bacteria to humans, only the serine residue is absolutely required for Psd1p autocatalysis and function; 2) yeast Psd1p does not require its substrate phosphatidylserine for autocatalysis; and 3) contrary to a prior report, yeast Psd1p autocatalysis does not require mitochondrial specific phospholipids, proteins, or co-factors, because Psd1p re-directed to the secretory pathway undergoes autocatalysis normally and is fully functional in vivo. PMID- 25829490 TI - Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine. AB - The N-methyl-d-aspartate (NMDA) subtype of the ionotropic glutamate receptors is the primary mediator of calcium-permeable excitatory neurotransmission in the central nervous system. Subunit composition and binding of allosteric modulators to the amino-terminal domain determine the open probability of the channel. By using luminescence resonance energy transfer with functional receptors expressed in CHO cells, we show that the cleft of the amino-terminal domain of the GluN2B subunit, which has a lower channel open probability, is on average more closed than the GluN2A subunit, which has a higher open probability. Furthermore, the GluN1 amino-terminal domain adopts a more open conformation when coassembled with GluN2A than with GluN2B. Binding of spermine, an allosteric potentiator, opens the amino-terminal domain cleft of both the GluN2B subunit and the adjacent GluN1 subunit. These studies provide direct structural evidence that the inherent conformations of the amino-terminal domains vary based on the subunit and match the reported open probabilities for the receptor. PMID- 25829491 TI - Nuclear localization and functional characteristics of voltage-gated potassium channel Kv1.3. AB - It is widely known that ion channels are expressed in the plasma membrane. However, a few studies have suggested that several ion channels including voltage gated K(+) (Kv) channels also exist in intracellular organelles where they are involved in the biochemical events associated with cell signaling. In the present study, Western blot analysis using fractionated protein clearly indicates that Kv1.3 channels are expressed in the nuclei of MCF7, A549, and SNU-484 cancer cells and human brain tissues. In addition, Kv1.3 is located in the plasma membrane and the nucleus of Jurkat T cells. Nuclear membrane hyperpolarization after treatment with margatoxin (MgTX), a specific blocker of Kv1.3 channels, provides evidence for functional channels at the nuclear membrane of A549 cells. MgTX-induced hyperpolarization is abolished in the nuclei of Kv1.3 silenced cells, and the effects of MgTX are dependent on the magnitude of the K(+) gradient across the nuclear membrane. Selective Kv1.3 blockers induce the phosphorylation of cAMP response element-binding protein (CREB) and c-Fos activation. Moreover, Kv1.3 is shown to form a complex with the upstream binding factor 1 in the nucleus. Chromatin immunoprecipitation assay reveals that Sp1 transcription factor is directly bound to the promoter region of the Kv1.3 gene, and the Sp1 regulates Kv1.3 expression in the nucleus of A549 cells. These results demonstrate that Kv1.3 channels are primarily localized in the nucleus of several types of cancer cells and human brain tissues where they are capable of regulating nuclear membrane potential and activation of transcription factors, such as phosphorylated CREB and c-Fos. PMID- 25829492 TI - Importin beta2 Mediates the Spatio-temporal Regulation of Anillin through a Noncanonical Nuclear Localization Signal. AB - The compartmentalization of cell cycle regulators is a common mechanism to ensure the precise temporal control of key cell cycle events. For instance, many mitotic spindle assembly factors are known to be sequestered in the nucleus prior to mitotic onset. Similarly, the essential cytokinetic factor anillin, which functions at the cell membrane to promote the physical separation of daughter cells at the end of mitosis, is sequestered in the nucleus during interphase. To address the mechanism and role of anillin targeting to the nucleus in interphase, we identified the nuclear targeting motif. Here, we show that anillin is targeted to the nucleus by importin beta2 in a Ran-dependent manner through an atypical basic patch PY nuclear localization signal motif. We show that although importin beta2 binding does not regulate anillin's function in mitosis, it is required to prevent the cytosolic accumulation of anillin, which disrupts cellular architecture during interphase. The nuclear sequestration of anillin during interphase serves to restrict anillin's function at the cell membrane to mitosis and allows anillin to be rapidly available when the nuclear envelope breaks down to remodel the cellular architecture necessary for successful cell division. PMID- 25829493 TI - Direct Evidence for the Formation of Precatenanes during DNA Replication. AB - The dynamics of DNA topology during replication are still poorly understood. Bacterial plasmids are negatively supercoiled. This underwinding facilitates strand separation of the DNA duplex during replication. Leading the replisome, a DNA helicase separates the parental strands that are to be used as templates. This strand separation causes overwinding of the duplex ahead. If this overwinding persists, it would eventually impede fork progression. In bacteria, DNA gyrase and topoisomerase IV act ahead of the fork to keep DNA underwound. However, the processivity of the DNA helicase might overcome DNA gyrase and topoisomerase IV. It was proposed that the overwinding that builds up ahead of the fork could force it to swivel and diffuse this positive supercoiling behind the fork where topoisomerase IV would also act to maintain replicating the DNA underwound. Putative intertwining of sister duplexes in the replicated region are called precatenanes. Fork swiveling and the formation of precatenanes, however, are still questioned. Here, we used classical genetics and high resolution two dimensional agarose gel electrophoresis to examine the torsional tension of replication intermediates of three bacterial plasmids with the fork stalled at different sites before termination. The results obtained indicated that precatenanes do form as replication progresses before termination. PMID- 25829494 TI - Heat shock inhibition of CDK5 increases NOXA levels through miR-23a repression. AB - Hyperthermia is a proteotoxic stress that is lethal when exposure is extreme but also cytoprotective in that sublethal exposure leads to the synthesis of heat shock proteins, including HSP70, which are able to inhibit stress-induced apoptosis. CDK5 is an atypical cyclin-dependent kinase family member that regulates many cellular functions including motility and survival. Here we show that exposure of a human lymphoid cell line to hyperthermia causes CDK5 insolubilization and loss of tyrosine-15 phosphorylation, both of which were prevented in cells overexpressing HSP70. Inhibition of CDK5 activity with roscovitine-sensitized cells to heat induced apoptosis indicating a protective role for CDK5 in inhibiting heat-induced apoptosis. Both roscovitine and heat shock treatment caused increased accumulation of NOXA a pro-apoptotic BH3-only member of the BCL2 family. The increased abundance of NOXA by CDK5 inhibition was not a result of changes in NOXA protein turnover. Instead, CDK5 inhibition increased NOXA mRNA and protein levels by decreasing the expression of miR-23a, whereas overexpressing the CDK5 activator p35 attenuated both of these effects on NOXA and miR-23a expression. Lastly, overexpression of miR-23a prevented apoptosis under conditions in which CDK5 activity was inhibited. These results demonstrate that CDK5 activity provides resistance to heat-induced apoptosis through the expression of miR-23a and subsequent suppression of NOXA synthesis. Additionally, they indicate that hyperthermia induces apoptosis through the insolubilization and inhibition of CDK5 activity. PMID- 25829495 TI - Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia. AB - Sirtuins are evolutionarily conserved NAD(+)-dependent acetyl-lysine deacetylases that belong to class III type histone deacetylases. In humans, seven sirtuin isoforms (Sirt1 to Sirt7) have been identified. Sirtinol, a cell-permeable lactone ring derived from naphthol, is a dual Sirt1/Sirt2 inhibitor of low potency, whereas EX-527 is a potent and selective Sirt1 inhibitor. Here we demonstrate that Sirt1, Sirt2, and Sirt3 are expressed in enucleate platelets. Both sirtinol and EX-527 induced apoptosis-like changes in platelets, as revealed by enhanced annexin V binding, reactive oxygen species production, and drop in mitochondrial transmembrane potential. These changes were associated with increased phagocytic clearance of the platelets by macrophages. Expression of acetylated p53 and the conformationally active form of Bax were found to be significantly higher in both sirtinol- and EX-527-treated platelets, implicating the p53-Bax axis in apoptosis induced by sirtuin inhibitors. Administration of either sirtinol or EX-527 in mice led to a reduction in both platelet count and the number of reticulated platelets. Our results, for the first time, implicate sirtuins as a central player in the determination of platelet aging. Because sirtuin inhibitors are being evaluated for their antitumor activity, this study refocuses attention on the potential side effect of sirtuin inhibition in delimiting platelet life span and management of thrombosis. PMID- 25829496 TI - Different ligands of the TRPV3 cation channel cause distinct conformational changes as revealed by intrinsic tryptophan fluorescence quenching. AB - TRPV3 is a thermosensitive ion channel primarily expressed in epithelial tissues of the skin, nose, and tongue. The channel has been implicated in environmental thermosensation, hyperalgesia in inflamed tissues, skin sensitization, and hair growth. Although transient receptor potential (TRP) channel research has vastly increased our understanding of the physiological mechanisms of nociception and thermosensation, the molecular mechanics of these ion channels are still largely elusive. In order to better comprehend the functional properties and the mechanism of action in TRP channels, high-resolution three-dimensional structures are indispensable, because they will yield the necessary insights into architectural intimacies at the atomic level. However, structural studies of membrane proteins are currently hampered by difficulties in protein purification and in establishing suitable crystallization conditions. In this report, we present a novel protocol for the purification of membrane proteins, which takes advantage of a C-terminal GFP fusion. Using this protocol, we purified human TRPV3. We show that the purified protein is a fully functional ion channel with properties akin to the native channel using planar patch clamp on reconstituted channels and intrinsic tryptophan fluorescence spectroscopy. Using intrinsic tryptophan fluorescence spectroscopy, we reveal clear distinctions in the molecular interaction of different ligands with the channel. Altogether, this study provides powerful tools to broaden our understanding of ligand interaction with TRPV channels, and the availability of purified human TRPV3 opens up perspectives for further structural and functional studies. PMID- 25829497 TI - Reduced Expression of EXTL2, a Member of the Exostosin (EXT) Family of Glycosyltransferases, in Human Embryonic Kidney 293 Cells Results in Longer Heparan Sulfate Chains. AB - Heparan sulfate proteoglycans are ubiquitously located on cell surfaces and in the extracellular matrices. The negatively charged heparan sulfate chains interact with a multitude of different proteins, thereby influencing a variety of cellular and developmental processes, for example cell adhesion, migration, tissue morphogenesis, and differentiation. The human exostosin (EXT) family of genes contains five members: the heparan sulfate polymerizing enzymes, EXT1 and EXT2, and three EXT-like genes, EXTL1, EXTL2, and EXTL3. EXTL2 has been ascribed activities related to the initiation and termination of heparan sulfate chains. Here we further investigated the role of EXTL2 in heparan sulfate chain elongation by gene silencing and overexpression strategies. We found that siRNA mediated knockdown of EXTL2 in human embryonic kidney 293 cells resulted in increased chain length, whereas overexpression of EXTL2 in the same cell line had little or no effect on heparan sulfate chain length. To study in more detail the role of EXTL2 in heparan sulfate chain elongation, we tested the ability of the overexpressed protein to catalyze the in vitro incorporation of N acetylglucosamine and N-acetylgalactosamine to oligosaccharide acceptors resembling unmodified heparan sulfate and chondroitin sulfate precursor molecules. Analysis of the generated products revealed that recombinant EXTL2 showed weak ability to transfer N-acetylgalactosamine to heparan sulfate precursor molecules but also, that EXTL2 exhibited much stronger in vitro N acetylglucosamine-transferase activity related to elongation of heparan sulfate chains. PMID- 25829499 TI - The association between peer, parental influence and tobacco product features and earlier age of onset of regular smoking among adults in 27 European countries. AB - BACKGROUND: Factors that influence smoking initiation and age of smoking onset are important considerations in tobacco control. We evaluated European Union (EU) wide differences in the age of onset of regular smoking, and the potential role of peer, parental and tobacco product design features on the earlier onset of regular smoking among adults <40 years old in 27 EU countries. METHODS: We analysed data from 4442 current and former smokers aged 15-39 years, collected for the Eurobarometer 77.1 survey (2012). Respondents reported their age at regular smoking onset and factors that influenced their decision to start smoking, including peer influence, parental influence and features of tobacco products. Multi-variable logistic regression, adjusted for age; geographic region; education; difficulty to pay bills; and gender, was used to assess the role of the various pro-tobacco influences on early onset of regular smoking (i.e. <18 years). RESULTS: Among ever smokers, the mean age of onset of regular smoking was 16.6 years, ranging from 15.8 to 18.8 years in member countries. 68.1% responded that they started smoking regularly when they were <18 years old. Ever smokers who reported they were influenced by peers (OR = 1.70; 95%CI 1.30 2.20) or parents (OR = 1.60; 95%CI 1.21-2.12) were more likely to have started smoking regularly <18 years old. No significant association between design and marketing features of tobacco products and an early initiation of regular smoking was observed (OR = 1.04; 95%CI 0.83-1.31). CONCLUSIONS: We identified major differences in smoking initiation patterns among EU countries, which may warrant different approaches in the prevention of tobacco use. PMID- 25829498 TI - Role of nucleotide binding and GTPase domain dimerization in dynamin-like myxovirus resistance protein A for GTPase activation and antiviral activity. AB - Myxovirus resistance (Mx) GTPases are induced by interferon and inhibit multiple viruses, including influenza and human immunodeficiency viruses. They have the characteristic domain architecture of dynamin-related proteins with an N-terminal GTPase (G) domain, a bundle signaling element, and a C-terminal stalk responsible for self-assembly and effector functions. Human MxA (also called MX1) is expressed in the cytoplasm and is partly associated with membranes of the smooth endoplasmic reticulum. It shows a protein concentration-dependent increase in GTPase activity, indicating regulation of GTP hydrolysis via G domain dimerization. Here, we characterized a panel of G domain mutants in MxA to clarify the role of GTP binding and the importance of the G domain interface for the catalytic and antiviral function of MxA. Residues in the catalytic center of MxA and the nucleotide itself were essential for G domain dimerization and catalytic activation. In pulldown experiments, MxA recognized Thogoto virus nucleocapsid proteins independently of nucleotide binding. However, both nucleotide binding and hydrolysis were required for the antiviral activity against Thogoto, influenza, and La Crosse viruses. We further demonstrate that GTP binding facilitates formation of stable MxA assemblies associated with endoplasmic reticulum membranes, whereas nucleotide hydrolysis promotes dynamic redistribution of MxA from cellular membranes to viral targets. Our study highlights the role of nucleotide binding and hydrolysis for the intracellular dynamics of MxA during its antiviral action. PMID- 25829500 TI - An exploration of antecedents of positive affect among the elderly: a cross sectional study. AB - BACKGROUND: Positive affect contributes to the healthy life style, which, in turn, explains life satisfaction and psychological well-being among the elderly. Existent literature has reinforced that physical activity participation influences development of positive affect for the elderly. Because of the increased life constraints and physical problems, however, maintenance of positive affect might be challenging for elderly people. METHODS: Data were drawn from a sample of the Survey of Health, Ageing and Retirement in Europe. A total sample of 3845 males and 3912 females aged between 65 and 103 years from 16 European countries was analyzed. Perception of life constraints, health problems, physical activity engagement and positive affect were measured by a structured questionnaire. Confirmatory factor analysis and a technique of structural equation modelling were employed using Amos 18 to examine the hypothesized relationships between study variables. RESULTS: Perceived life constraints and physical problems significantly affected the acquisition of positive affect among the elderly. Physical activity was found to have a significant path coefficient towards the measure of positive attitude and emotion. Physical activity was also a significant mediator between physical problems and positive affect. CONCLUSIONS: This study extended our understanding of how the perception of life constraints and health problems influence the elderly's daily experience. Study finding reinforced the goodness of physical activity participation to enhance positive affect among the elderly. We should administer sustainable and evidence based physical activity including interventions and infrastructure to improve positive affect and psychological well-bing among the elderly. PMID- 25829501 TI - Unmet care needs of people with a neurological chronic disease: a cross-sectional study in Italy on Multiple Sclerosis. AB - BACKGROUND: Community-based studies are required to accurately describe the supportive services needed by people with multiple sclerosis (MS). METHODS: A total of 1205 people with MS participated in a cross-sectional study evaluating their unmet health and social care needs through a questionnaire collecting information used in the study. It was specifically developed by a multi disciplinary team. RESULTS: Overall, 79% of the responders declared at least one health or social care needs. The most prevalent health care need was the psychological support (27.5%), whereas the transport was the social care need more frequent (over 41%) in our sample. The multivariate analysis highlighted that unmet health care needs depended mainly on clinical factors such as disease stage, influenced by disease duration, and disability degree, whereas the social care needs were related to both clinical and socio-demographic factors. CONCLUSION: These findings suggest that MS needs significantly change over time during the disease development and to find the best way to personalize PwMS management is crucial. Moreover, more public funding directed at improving the health-related quality of life of people with MS is needed. For this reason, we think that these results will provide important information and baseline data on how to build the national service strategies thereby making healthcare planning more efficient. PMID- 25829502 TI - Transitions between health care settings in the final three months of life in four EU countries. AB - BACKGROUND: Transitions between care settings may be related to poor quality in end-of-life care. Yet there is a lack of cross-national population-based data on transitions at the end of life. METHOD: International mortality follow-back study with data collection in Belgium, Netherlands, Italy and Spain (2009-11) via existing representative epidemiological surveillance networks of general practitioners (GPs). All general practitioners reported weekly, on a standardized registration form, every deceased patient (>=18 years) in their practice and identified those who died 'non-suddenly'. RESULTS: Among 4791 non-sudden deaths in Belgium, Netherlands, Italy and Spain, 59%, 55%, 60% and 58%, respectively, were transferred between care settings at least once in the final 3 months of life (10%, 8%, 10% and 13% in final 3 days of life); 10%, 5%, 8% and 12% were transferred three times or more (P < 0.001 in multivariate analyses adjusting for country differences in age, sex, cause of death, presence of dementia). In all countries, transitions were more frequent among patients residing at home (61 73%) than among patients residing in a care home (33-40%). Three months before death 5-7% of patients were in hospital, and this rose to 27-39% on the day of death. Patient wishes were cited as the reason for the last transition before death in 27%, 39%, 9% and 6% of cases in Belgium, Netherlands, Italy and Spain, respectively (P < 0.001). CONCLUSION: End-of-life transitions between health care settings are common across EU countries, in particular late hospitalizations for people residing at home. Frequency, type and reasons for terminal hospitalizations vary between countries. PMID- 25829503 TI - Seven years' mortality in Roma and non-Roma patients after coronary angiography. AB - BACKGROUND: Ethnicity is associated with differences in clinical course and outcomes of cardiac disease, often in association with a poorer socioeconomic position. The aim of this study was to compare the mortality after coronary angiography (CAG) of Roma and non-Roma patients matched for education and adjusted for gender and age. METHODS: In total, 816 patients were included in the study (167 Roma and 649 non-Roma). Data on socio-demographic background, disease history, use of drugs, coronary findings and type of treatment were obtained from medical records. Mortality was assessed up to seven years after CAG. Kaplan-Meier curves of mortality were plotted, and differences between the Roma and non-Roma patients were assessed using log-rank tests, matched for education and adjusted for gender and age. RESULTS: Mortality after CAG was significantly higher among Roma than non-Roma (log-rank test chi(2) = 7.59, P < 0.01) and remained so after matching for education and adjustment for gender, age, history of previous myocardial infarction and abnormal CAG (hazard ratio: 2.07, 95% confidence interval: 1.13-3.82). CONCLUSION: Mortality after CAG is higher among Roma, and this is not due to differences in age, gender or education. These results warrant further reconsideration of the management of Roma cardiac patients. PMID- 25829504 TI - The ballad of financial dependency: sponsoring in public health professional societies. PMID- 25829505 TI - European accreditation and the future public health workforce. AB - BACKGROUND: In 2011 the Agency for Public Health Education Accreditation (APHEA) was initially launched focusing on Master level (second cycle) education. METHODS: Between 2012 and 2013 the Association of Schools of Public Health in the European Region, APHEA and partner schools conducted a study on the compliance of Master level programmes of public health to the accreditation criteria. A web based survey of second cycle programmes of public health across 29 countries was conducted using the APHEA criteria. The 29 countries were categorized into four regions: Northern, Southern, Central and Eastern and Western. We applied a Chi square test to identify regional differences with regard to the compliance of the programmes to the criteria. RESULTS: Data from 51 out of 71 schools contacted were analyzed. The compliance to the two themes of student and faculty exchange and quality management were lowest for programmes of public health throughout the EHEA. There were significant differences in the compliance between the regions with higher compliance in the Northern European region. CONCLUSIONS: Student and faculty exchange and quality management are essential for schools and programmes of public health to improve the quality of their education through expanding international knowledge and the pertinence of skills taught within European and national contexts. The results show that there are intrinsic issues with exchange and quality management as well as the role of national accreditation agencies in defining public health education for the future workforce. PMID- 25829506 TI - Age-related socio-economic and geographic disparities in breast cancer stage at diagnosis: a population-based study. AB - BACKGROUND: This study aimed to determine the impact of socio-economic and geographic disparities on disease stage at diagnosis according to age in breast cancer (BC) patients. Secondary purpose was to describe survival METHODS: All women with primary invasive BC, diagnosed from 1998 to 2009 in the department of Cote d'Or were retrospectively selected using data from the Cote d'Or BC registry. European transnational ecological deprivation index (French European Deprivation Index) was used to measure the socio-economic environment. Relationships between socio-geographic deprivation and disease stage at diagnosis according to age were assessed by a multilevel ordered logistic regression model. Relative survival rates (RSRs) were given at 5 years according to tumour and patients characteristics. RESULTS: In total, 4364 women were included. In multivariable analysis, socio-economic deprivation was associated with disease stage at diagnosis. Women aged between 50 and 74 years and living in deprived areas were more often diagnosed with advanced tumour stages (stages II/III vs. I or stages IV vs. II/III) with odds ratio = 1.27 (1.01-1.60). RSRs were lowest in women living in the most deprived area compared with those living in most affluent area with RSR = 88.4% (85.9-90.4) and 92.6% (90.5-94.2), respectively. CONCLUSIONS: Socio-economic factors affected tumour stage at diagnosis and survival. Living in a deprived area was linked to advanced-stage BC at diagnosis only in women aged 50-74 years. This is probably due to the socio-economic disparities in participation in organized BC screening programmes. Furthermore, living in deprived area was associated with a poor survival rate. PMID- 25829507 TI - Smoking and obesity among pregnant women in Iceland 2001-2010. AB - BACKGROUND: The prevalence of smoking during pregnancy in Western societies has decreased in the last decades, whereas prevalence of overweight and obesity has increased. Our objective was to study secular trends and patterns of smoking and body weight among pregnant women in Iceland, during a period of dramatic changes in the nation's economy. METHODS: On the basis of the Medical Birth Registry, we used a random sample of 1329 births between 1 January 2001 and 31 December 2010. Information on smoking, body mass index and background factors during pregnancy was retrieved from the Medical Birth Register and maternity records. Trends in smoking, overweight, obesity and body mass index were assessed using logistic and linear regression analyses. Logistic regression analysis was used to examine the annual odds of smoking and obesity and by socio-demographic characteristics. RESULTS: We found a decrease in the prevalence of continued smoking during pregnancy from 12.4% in 2001 to 7.9% in 2010 [odds ratio (OR) = 0.94, 95% confidence interval (CI) (0.88-1.00)], particularly among women with Icelandic citizenship [OR = 0.92, 95% CI (0.86-0.98)], whereas no changes in obesity [OR = 1.02, 95% CI (0.96-1.07)] were observed. The highest prevalence of maternal smoking and obesity was observed in 2005-06. CONCLUSION: Our results indicate that smoking during pregnancy decreased among Icelandic women in 2001-10, whereas an initial increase in obesity prevalence seemed to level off towards the end of the observation period. Interestingly, we found that both of these maternal risk factors reached their highest prevalence in 2005-06, which coincides with a flourishing period in the nation's economy. PMID- 25829508 TI - "Data were saturated . . . ". PMID- 25829509 TI - Acceptable care? Illness constructions, healthworlds, and accessible chronic treatment in South Africa. AB - Achieving equitable access to health care is an important policy goal, with access influenced by affordability, availability, and acceptability of specific services. We explore patient narratives from a 5-year program of research on health care access to examine relationships between social constructions of illness and the acceptability of health services in the context of tuberculosis treatment and antiretroviral therapy in South Africa. Acceptability of services seems particularly important to the meanings patients attach to illness and care, whereas-conversely-these constructions appear to influence what constitutes acceptability and hence affect access to care. We highlight the underestimated role of individually, socially, and politically constructed healthworlds; traditional and biomedical beliefs; and social support networks. Suggested policy implications for improving acceptability and hence overall health care access include abandoning patronizing approaches to care and refocusing from treating "disease" to responding to "illness" by acknowledging and incorporating patients' healthworlds in patient-provider interactions. PMID- 25829510 TI - Neuronal redox imbalance results in altered energy homeostasis and early postnatal lethality. AB - Redox imbalance is believed to contribute to the development and progression of several neurodegenerative disorders. Our aim was to develop an animal model that exhibits neuron-specific oxidative stress in the CNS to study the consequences and eventually find clues regarding the pathomechanisms of oxidative insults in neuronal homeostasis. We therefore generated a novel neuron-specific superoxide dismutase 2 (SOD2)-deficient mouse by deleting exon 3 of the SOD2 gene using CamKIIalpha promoter-driven Cre expression. These neuron-specific SOD2 knockout (SOD2(nko)) mice, although born at normal frequencies, died at the age of 4 weeks with critical growth retardation, severe energy failure, and several neurologic phenotypes. In addition, SOD2(nko) mice exhibited severe neuronal alterations such as reactive astrogliosis, neuronal cell cycle inhibition, and induction of apoptosis. JNK activation and stabilization of p53, as a result of reactive oxygen species accumulation, are most likely the inducers of neuronal apoptosis in SOD2(nko) mice. It is remarkable that hypothalamic regulation of glucose metabolism was affected, which in turn induced necrotic brain lesions in SOD2(nko) mice. Taken together, our findings suggest that exclusive deficiency of SOD2 in neurons results in an impaired central regulation of energy homeostasis that leads to persistent hypoglycemia, hypoglycemia-related neuropathology, and an early lethality of the mutant mice. PMID- 25829511 TI - 2014 winners: Anne-Lise Gaffuri and Elizabeth Crowell. PMID- 25829514 TI - Cooperative functions of the two F-BAR proteins Cip4 and Nostrin in the regulation of E-cadherin in epithelial morphogenesis. PMID- 25829513 TI - Cavin family proteins and the assembly of caveolae. AB - Caveolae are an abundant feature of the plasma membrane in many cells. Until recently, they were generally considered to be membrane invaginations whose formation primarily driven by integral membrane proteins called caveolins. However, the past decade has seen the emergence of the cavin family of peripheral membrane proteins as essential coat components and regulators of caveola biogenesis. In this Commentary, we summarise recent data on the role of cavins in caveola formation, highlighting structural studies that provide new insights into cavin coat assembly. In mammals, there are four cavin family members that associate through homo- and hetero-oligomerisation to form distinct subcomplexes on caveolae, which can be released into the cell in response to stimuli. Studies from several labs have provided a better understanding of cavin stoichiometry and the molecular basis for their oligomerisation, as well as identifying interactions with membrane phospholipids that may be important for caveola function. We propose a model in which coincident, low-affinity electrostatically controlled protein-protein and protein-lipid interactions allow the formation of caveolae, generating a meta-stable structure that can respond to plasma membrane stress by release of cavins. PMID- 25829515 TI - Physician under the knife. PMID- 25829512 TI - Autophagosome dynamics in neurodegeneration at a glance. AB - Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration. PMID- 25829516 TI - Inference of purifying and positive selection in three subspecies of chimpanzees (Pan troglodytes) from exome sequencing. AB - We study genome-wide nucleotide diversity in three subspecies of extant chimpanzees using exome capture. After strict filtering, Single Nucleotide Polymorphisms and indels were called and genotyped for greater than 50% of exons at a mean coverage of 35* per individual. Central chimpanzees (Pan troglodytes troglodytes) are the most polymorphic (nucleotide diversity, thetaw = 0.0023 per site) followed by Eastern (P. t. schweinfurthii) chimpanzees (thetaw = 0.0016) and Western (P. t. verus) chimpanzees (thetaw = 0.0008). A demographic scenario of divergence without gene flow fits the patterns of autosomal synonymous nucleotide diversity well except for a signal of recent gene flow from Western into Eastern chimpanzees. The striking contrast in X-linked versus autosomal polymorphism and divergence previously reported in Central chimpanzees is also found in Eastern and Western chimpanzees. We show that the direction of selection statistic exhibits a strong nonmonotonic relationship with the strength of purifying selection S, making it inappropriate for estimating S. We instead use counts in synonymous versus nonsynonymous frequency classes to infer the distribution of S coefficients acting on nonsynonymous mutations in each subspecies. The strength of purifying selection we infer is congruent with the differences in effective sizes of each subspecies: Central chimpanzees are undergoing the strongest purifying selection followed by Eastern and Western chimpanzees. Coding indels show stronger selection against indels changing the reading frame than observed in human populations. PMID- 25829517 TI - Syphilis serology in pregnancy: an eight-year study (2005-2012) in a large teaching maternity hospital in Dublin, Ireland. AB - All cases of positive syphilis serology detected in antenatal and peripartum screening in a large teaching maternity hospital in inner city Dublin, Ireland over an eight-year period (2005-2012 inclusive) were reviewed and included in our study. Demographic, antenatal registration, laboratory (including co-infections), partner serology, treatment and delivery data were recorded in our database. Infant follow-up, treatment and outcome data were also collected. During this period, 194 women had positive syphilis serology, of which 182 completed their pregnancies at the institution. This accounts for 0.28% of the total number of women completing their pregnancies during this time (N = 66038); 79 had no previous diagnosis of infection. There was one case of re-infection during pregnancy. Thirty-two women were co-infected with human immunodeficiency virus, hepatitis B or hepatitis C. There was one case suggestive of congenital syphilis infection. Our study is a comprehensive analysis of the diagnosis, management and clinical outcomes of women testing positive for syphilis infection in pregnancy. It reveals the relatively high prevalence of syphilis infection in the population utilising the maternity services in north inner-city Dublin. It re-enforces the importance of continued active surveillance to prevent morbidity and mortality associated with maternal syphilis infection. It also highlights the importance of strategies such as re-testing high-risk groups and definitive screening of spouse serology. PMID- 25829518 TI - Management of recalcitrant Trichomonas vaginalis in pregnancy: a case report. AB - A case report of a pregnant woman with recalcitrant Trichomonas vaginalis is described. This case was managed with suppressive treatment with metronidazole during pregnancy and cleared with paromomycin vaginal treatment after delivery. PMID- 25829521 TI - Extending the quality and safety agenda from parenteral to oral chemotherapy. PMID- 25829520 TI - The Virtual Short Physical Performance Battery. AB - BACKGROUND: Performance-based and self-report instruments of physical function are frequently used and provide complementary information. Identifying older adults with a mismatch between actual and perceived function has utility in clinical settings and in the design of interventions. Using novel, video-animated technology, the objective of this study was to develop a self-report measure that parallels the domains of objective physical function assessed by the Short Physical Performance Battery (SPPB)-the virtual SPPB (vSPPB). METHODS: The SPPB, vSPPB, the self-report Pepper Assessment Tool for Disability, the Mobility Assessment Tool-short form, and a 400-m walk test were administered to 110 older adults (mean age = 80.6+/-5.2 years). One-week test-retest reliability of the vSPPB was examined in 30 participants. RESULTS: The total SPPB (mean [+/-SD] = 7.7+/-2.8) and vSPPB (7.7+/-3.2) scores were virtually identical, yet moderately correlated (r = .601, p < .05). The component scores of the SPPB and vSPPB were also moderately correlated (all p values <.01). The vSPPB (intraclass correlation = .963, p < .05) was reliable; however, individuals with the lowest function overestimated their overall lower extremity function while participants of all functional levels overestimated their ability on chair stands, but accurately perceived their usual gait speed. CONCLUSION: In spite of the similarity between the SPPB and vSPPB, the moderate strength of the association between the two suggests that they offer unique perspectives on an older adult's physical function. PMID- 25829519 TI - Effect of HIV diagnosis disclosure on psychosocial outcomes in Thai children with perinatal HIV infection. AB - A provider-assisted, counselling-based, paediatric HIV disclosure model was developed and implemented at two tertiary-care hospitals in Bangkok, Thailand. All undisclosed perinatally acquired HIV-infected children, aged 7-18 years, and their caretakers were offered the four-step disclosure service, including: screening, readiness assessments and preparation, disclosure sessions, and follow up evaluations. To assess psychosocial outcomes of disclosure, we compared the scores of the Children Depression Inventory and the PedsQL 4.0TM at baseline and at two-month and six-month follow-up visits, and compared the scores of the Child Behavioral Checklist at baseline and at six-month follow-up. Disclosure was made to 186 children, 160 of whom completed post-disclosure assessments. The median Children's Depression Inventory score in 135 children decreased significantly from 11 at baseline to 8 at two-month and six-month follow-up (p < 0.01). The median PedsQL 4.0TM scores in 126 children increased significantly from 78 at baseline to 80 at two-month and 84 at six-month follow-up (p = 0.04). The median Child Behavioral Checklist scores were not significantly changed. In conclusion, paediatric HIV diagnosis disclosure using this model was found to have positive effect on the children's mood and quality of life, and no negative effect on children's behaviours. This disclosure programme should be expanded to improve the psychosocial health of HIV-infected children. PMID- 25829522 TI - Cost-related health literacy: a key component of high-quality cancer care. PMID- 25829523 TI - Transforming data from information to quality improvement: a panel discussion with electronic health record vendors. PMID- 25829524 TI - Oncology pharmaceutical funding in New Zealand: a different approach and a proposal. PMID- 25829525 TI - Processes of discontinuing chemotherapy for metastatic non-small-cell lung cancer at the end of life. AB - PURPOSE: Administration of chemotherapy close to death is widely recognized as poor-quality care. Prior research has focused on predictors and outcomes of chemotherapy administration at the end of life. This study describes processes of chemotherapy discontinuation and examines their relationships with timing before death, hospice referral, and hospital death. PATIENTS AND METHODS: We reviewed health records of a prospective cohort of 151 patients with newly diagnosed metastatic non-small-cell lung cancer who participated in a trial of early palliative care. Chemotherapy treatments during final regimen were qualitatively analyzed to identify categories of discontinuation processes. We then quantitatively compared predictors and outcomes of the process categories. RESULTS: A total of 144 patients died, with 81 and 48 receiving intravenous (IV) and oral chemotherapies as their final regimen, respectively. Five processes were identified for IV chemotherapy: definitive decisions (19.7%), deferred decisions or breaks (22.2%), disruptions for radiation therapy (22.2%), disruptions resulting from hospitalization (27.2%), and no decisions (8.6%). The five processes occurred at significantly different times before death and, except for definitive decisions, ultimate decisions for no further chemotherapy and referral to hospice were often made months later. Among patients receiving oral chemotherapy, 83.3% (40 of 48) were switched from IV to oral delivery as their final regimen, sometimes concurrent with or even after hospice referral. CONCLUSION: Date of last chemotherapy is not a proxy for when a decision to stop treatment is made. Patients with metastatic non-small-cell lung cancer stop their final chemotherapy regimen via different processes, which significantly vary in time before death and subsequent end-of-life care. PMID- 25829526 TI - Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines. PMID- 25829527 TI - Prostate cancer survivorship care guidelines: American Society of Clinical Oncology practice guideline endorsement. PMID- 25829528 TI - Systematic Review and Meta-Analysis of Anxious and Depressive Symptoms in Caregivers of Children With Asthma. AB - OBJECTIVE: To provide a review of the literature comparing anxious and depressive symptoms in caregivers of children with asthma with caregivers of healthy children. METHOD: A systematic search identified 25 studies from 17 articles, reporting outcomes on 4,300 caregivers of children with asthma and 25,064 caregivers of healthy children. RESULTS: Overall, anxious (d = 0.50) and depressive symptoms (d = 0.44) were higher in caregivers of children with asthma compared with caregivers of healthy children. Age, site of recruitment, and whether the asthma diagnosis was medically confirmed were included as potential moderators. The relationship between parental psychopathology and asthma was stronger in those with medically confirmed asthma and participants recruited from clinical settings. Other moderators were not significant. CONCLUSIONS: Caregivers of children with asthma appear to have greater anxious and depressive symptoms than caregivers of healthy children, but the reasons are unclear. More research that investigates modifiable factors that may moderate this association is urgently needed. PMID- 25829530 TI - The varying influence of socioeconomic deprivation on breast cancer screening uptake in London. AB - BACKGROUND: We assessed the relationship between screening uptake and socioeconomic deprivation for London women aged 50-52 invited to their first routine screening appointment between 2006 and 2009. METHODS: We examined uptake for London overall and within six screening areas, using deprivation quintile, based on post code of residence. RESULTS: After adjustment for age, area and ethnicity, overall uptake decreased with increasing deprivation (adjusted odds ratio (OR) = 0.95, P < 0.001). However, in two screening areas with lower uptake, women living in deprived areas had higher uptake than women from affluent areas. CONCLUSIONS: These potential inequalities in early diagnosis across London require further investigation. PMID- 25829529 TI - Amiloride and GMQ Allosteric Modulation of the GABA-A rho1 Receptor: Influences of the Intersubunit Site. AB - Amiloride, a diuretic used in the treatment of hypertension and congestive heart failure, and 2-guanidine-4-methylquinazoline (GMQ) are guanidine compounds that modulate acid-sensing ion channels. Both compounds have demonstrated affinity for a variety of membrane proteins, including members of the Cys-loop family of ligand-gated ion channels, such as the heteromeric GABA-A alphabetagamma receptors. The actions of these guanidine compounds on the homomeric GABA-A rho1 receptor remains unclear, especially in light of how many GABA-A alphabetagamma receptor modulators have different effects in the GABA-A rho1 receptors. We sought to characterize the influence of amiloride and GMQ on the human GABA-A rho1 receptors using whole-cell patch-clamp electrophysiology. The diuretic amiloride potentiated the human GABA-A rho1 GABA-mediated current, whereas GMQ antagonized the receptor. Furthermore, a GABA-A second transmembrane domain site, the intersubunit site, responsible for allosteric modulation in the heteromeric GABA-A receptors mediated amiloride's positive allosteric actions. In contrast, the mutation did not remove GMQ antagonism but only changed the guanidine compound's potency within the human GABA-A rho1 receptor. Through modeling and introduction of point mutations, we propose that the GABA-A rho1 intersubunit site plays a role in mediating the allosteric effects of amiloride and GMQ. PMID- 25829531 TI - Lesion regression rate based on RECIST: prediction of treatment outcome in patients with head and neck cancer treated with chemoradiotherapy compared with FDG PET-CT. AB - The aim of this study was to evaluate whether the lesion regression rate (DeltaLR) based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria could be used for the prediction of treatment outcome in head and neck squamous cell carcinoma (HNSCC) patients treated with chemoradiotherapy (CRT) compared with FDG PET-CT. A total of 33 patients underwent MRI and PET-CT at pretreatment and at 8 weeks after CRT. We assessed the treatment outcome by analyzing the following parameters: the RECIST criteria, DeltaLR, the European Organization for Research and Treatment of Cancer (EORTC) criteria, and pretreatment SUVmax of the primary tumor and node. The correlation between the analysis of the parameters and the results of the long-term follow-up of the patients was determined. The RECIST did not significantly correlate with locoregional control (LRC) or survival. The DeltaLR was significantly lower for the lesions with locoregional failure (LRF) than for those with LRC. A threshold DeltaLR of 48% revealed a sensitivity of 72.7% and specificity of 77.3% for the prediction of LRF. Progression-free survival (PFS) of patients with DeltaLR >= 48% was significantly better than that of patients with DeltaLR < 48% (P = 0.001), but not overall survival. There was a significant correlation between LRC and the EORTC (P = 0.02). The patients who achieved a complete response by the EORTC criteria showed significantly better PFS and overall survival (P = 0.01 and 0.04, respectively). The DeltaLR was inferior to FDG PET-CT with respect to the prediction of patient survival; however, it may be useful for selecting patients in need of more aggressive monitoring after CRT. PMID- 25829533 TI - Fournier's gangrene secondary to an acutely inflamed appendix herniating into the deep inguinal ring. AB - Fournier's gangrene (FG) requires prompt recognition and management. We report the case of a 68-year-old man who presented with extensive pain and purple discolouration from the right iliac fossa to perineum. Computed tomography demonstrated gas within the right hemiscrotum extending into the inguinal canal and right buttock, with a right pelvic fluid and air collection. At debridement necrotic fluid was arising from the superficial inguinal ring so laparotomy was performed, revealing a grossly inflamed appendix herniating into the inguinal canal; a right hemicolectomy was performed. Unfortunately, the patient went into cardiac arrest and passed away on the operating table. Histological analysis demonstrated acute-on-chronic inflammation involving the appendix. The condition where appendicitis is implicated in FG is usually due to retroperitoneal rupture and tracking into the perineal spaces. This is the first case reported of an inflamed appendix herniating into the inguinal canal and thus causing FG. PMID- 25829532 TI - Abundance of BER-related proteins depends on cell proliferation status and the presence of DNA polymerase beta. AB - In mammalian cells, murine N-methylpurine DNA glycosylase (MPG) removes bases damaged spontaneously or by chemical agents through the process called base excision repair (BER). In this study, we investigated the influence of POL beta deficiency on MPG-initiated BER efficiency and the expression levels of BER related proteins in log-phase and growth-arrested (G(0)) mouse embryonic fibroblasts (MEFs). G(0) wild-type (WT) or POL beta-deficient (Pol beta-KO) cells showed greater resistance to methyl methanesulfonate than did log-phase cells, and repair of methylated bases was less efficient in the G(0) cells. Apex1 mRNA expression was significantly lower in Pol beta-KO or G(0) WT MEFs than in log phase WT MEFs. Moreover, although Mpg mRNA levels did not differ significantly among cell types, MPG protein levels were significantly higher in log-phase WT cells than in log-phase Pol beta-KO cells or either type of G(0) cells. Additionally, proliferating cell nuclear antigen protein levels were also reduced in log-phase Pol beta-KO cells or either type of G(0) cells. These results indicated that MPG-initiated BER functions mainly in proliferating cells, but less so in G(0) cells, and that POL beta may be involved in regulation of the amount of intracellular repair proteins. PMID- 25829534 TI - Maximizing the diagnostic yield from bone marrow aspirate material using the cell block technique on clot sections. AB - BACKGROUND: Paraffin section of bone-marrow aspirate (clot section) is one of several components of bone marrow biopsy. Improper acquisition of aspirate material results in lack of diagnostic tissue and a waste of resources. OBJECTIVE: To detail a novel cell block method of aspirated marrow as a way to ensure maximum yield. This is of particular value when the material gathered via core biopsy is inadequate. METHOD: We used the cell block method to evaluate paraffin-embedded sections of hematopoietic tissue from bone marrow aspirate. RESULTS: The range of diagnoses possible from an adequate clot section parallels those from a comparable core biopsy. Examples of an adequate clot section include lesions assessed by routine hematoxylin-eosin (H&E) staining, special and immunohistochemistry (IHC) stains, and molecular diagnostic studies such as fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). CONCLUSION: A bone marrow clot section comprised of sinusoidal blood is inadequate for morphological interpretation and is a waste of resources. Hence, we recommend the cell block technique for procurement; this method ensures maximum capture of material needed to establish a diagnosis. PMID- 25829535 TI - Tuberculosis-resistant transgenic cattle. PMID- 25829536 TI - Equation-free modeling unravels the behavior of complex ecological systems. PMID- 25829537 TI - Climate change and California drought in the 21st century. PMID- 25829538 TI - Do the spatial frequencies of grid cells mold the firing fields of place cells? PMID- 25829540 TI - Novel Epac fluorescent ligand reveals distinct Epac1 vs. Epac2 distribution and function in cardiomyocytes. AB - Exchange proteins directly activated by cAMP (Epac1 and Epac2) have been recently recognized as key players in beta-adrenergic-dependent cardiac arrhythmias. Whereas Epac1 overexpression can lead to cardiac hypertrophy and Epac2 activation can be arrhythmogenic, it is unknown whether distinct subcellular distribution of Epac1 vs. Epac2 contributes to differential functional effects. Here, we characterized and used a novel fluorescent cAMP derivate Epac ligand 8-[Pharos 575]-2'-O-methyladenosine-3',5'-cyclic monophosphate (Phi-O-Me-cAMP) in mice lacking either one or both isoforms (Epac1-KO, Epac2-KO, or double knockout, DKO) to assess isoform localization and function. Fluorescence of Phi-O-Me-cAMP was enhanced by binding to Epac. Unlike several Epac-specific antibodies tested, Phi O-Me-cAMP exhibited dramatically reduced signals in DKO myocytes. In WT, the apparent binding affinity (Kd = 10.2 +/- 0.8 uM) is comparable to that of cAMP and nonfluorescent Epac-selective agonist 8-(4-chlorophenylthio)-2-O methyladenosine-3'-,5'-cyclicmonophosphate (OMe-CPT). Phi-O-Me-cAMP readily entered intact myocytes, but did not activate PKA and its binding was competitively inhibited by OMe-CPT, confirming its Epac specificity. Phi-O-Me cAMP is a weak partial agonist for purified Epac, but functioned as an antagonist for four Epac signaling pathways in myocytes. Epac2 and Epac1 were differentially concentrated along T tubules and around the nucleus, respectively. Epac1-KO abolished OMe-CPT-induced nuclear CaMKII activation and export of transcriptional regulator histone deacetylase 5. In conclusion, Epac1 is localized and functionally involved in nuclear signaling, whereas Epac2 is located at the T tubules and regulates arrhythmogenic sarcoplasmic reticulum Ca leak. PMID- 25829541 TI - T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. AB - During infection, the release of damage-associated molecular patterns, so-called "alarmins," orchestrates the immune response. The alarmin IL-33 plays a role in a wide range of pathologies. Upon release, IL-33 signals through its receptor ST2, which reportedly is expressed only on CD4(+) T cells of the Th2 and regulatory subsets. Here we show that Th1 effector cells also express ST2 upon differentiation in vitro and in vivo during lymphocytic choriomeningitis virus (LCMV) infection. The expression of ST2 on Th1 cells was transient, in contrast to constitutive ST2 expression on Th2 cells, and marked highly activated effector cells. ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell intrinsic impairment of LCMV-specific Th1 effector responses in both mixed bone marrow-chimeric mice and adoptive cell transfer experiments. ST2-deficient virus specific CD4(+) T cells showed impaired expansion, Th1 effector differentiation, and antiviral cytokine production. Consequently, these cells mediated little virus-induced immunopathology. Thus, IL-33 acts as a critical and direct cofactor to drive antiviral Th1 effector cell activation, with implications for vaccination strategies and immunotherapeutic approaches. PMID- 25829542 TI - Inversion of Sonic hedgehog action on its canonical pathway by electrical activity. AB - Sonic hedgehog (Shh) is a morphogenic protein that operates through the Gli transcription factor-dependent canonical pathway to orchestrate normal development of many tissues. Because aberrant levels of Gli activity lead to a wide spectrum of diseases ranging from neurodevelopmental defects to cancer, understanding the regulatory mechanisms of Shh canonical pathway is paramount. During early stages of spinal cord development, Shh specifies neural progenitors through the canonical signaling. Despite persistence of Shh as spinal cord development progresses, Gli activity is switched off by unknown mechanisms. In this study we find that Shh inverts its action on Gli during development. Strikingly, Shh decreases Gli signaling in the embryonic spinal cord by an electrical activity- and cAMP-dependent protein kinase-mediated pathway. The inhibition of Gli activity by Shh operates at multiple levels. Shh promotes cytosolic over nuclear localization of Gli2, induces Gli2 and Gli3 processing into repressor forms, and activates cAMP-responsive element binding protein that in turn represses gli1 transcription. The regulatory mechanisms identified in this study likely operate with different spatiotemporal resolution and ensure effective down-regulation of the canonical Shh signaling as spinal cord development progresses. The developmentally regulated intercalation of electrical activity in the Shh pathway may represent a paradigm for switching from canonical to noncanonical roles of developmental cues during neuronal differentiation and maturation. PMID- 25829543 TI - Combinatorial proteomic analysis of intercellular signaling applied to the CD28 T cell costimulatory receptor. AB - Systematic characterization of intercellular signaling approximating the physiological conditions of stimulation that involve direct cell-cell contact is challenging. We describe a proteomic strategy to analyze physiological signaling mediated by the T-cell costimulatory receptor CD28. We identified signaling pathways activated by CD28 during direct cell-cell contact by global analysis of protein phosphorylation. To define immediate CD28 targets, we used phosphorylated forms of the CD28 cytoplasmic region to obtain the CD28 interactome. The interaction profiles of selected CD28-interacting proteins were further characterized in vivo for amplifying the CD28 interactome. The combination of the global phosphorylation and interactome analyses revealed broad regulation of CD28 and its interactome by phosphorylation. Among the cellular phosphoproteins influenced by CD28 signaling, CapZ-interacting protein (CapZIP), a regulator of the actin cytoskeleton, was implicated by functional studies. The combinatorial approach applied herein is widely applicable for characterizing signaling networks associated with membrane receptors with short cytoplasmic tails. PMID- 25829546 TI - Retraction for Cox et al., Pan-viral-microRNA screening identifies interferon inhibition as a common function of diverse viruses. PMID- 25829544 TI - The coreceptor CD4 is expressed in distinct nanoclusters and does not colocalize with T-cell receptor and active protein tyrosine kinase p56lck. AB - CD4 molecules on the surface of T lymphocytes greatly augment the sensitivity and activation process of these cells, but how it functions is not fully understood. Here we studied the spatial organization of CD4, and its relationship to T-cell antigen receptor (TCR) and the active form of Src kinase p56lck (Lck) using single and dual-color photoactivated localization microscopy (PALM) and direct stochastic optical reconstruction microscopy (dSTORM). In nonactivated T cells, CD4 molecules are clustered in small protein islands, as are TCR and Lck. By dual color imaging, we find that CD4, TCR, and Lck are localized in their separate clusters with limited interactions in the interfaces between them. Upon T-cell activation, the TCR and CD4 begin clustering together, developing into microclusters, and undergo a larger scale redistribution to form supramolecluar activation clusters (SMACs). CD4 and Lck localize in the inner TCR region of the SMAC, but this redistribution of disparate cluster structures results in enhanced segregation from each other. In nonactivated cells these preclustered structures and the limited interactions between them may serve to limit spontaneous and random activation events. However, the small sizes of these island structures also ensure large interfacial surfaces for potential interactions and signal amplification when activation is initiated. In the later activation stages, the increasingly larger clusters and their segregation from each other reduce the interfacial surfaces and could have a dampening effect. These highly differentiated spatial distributions of TCR, CD4, and Lck and their changes during activation suggest that there is a more complex hierarchy than previously thought. PMID- 25829547 TI - Scattering-layer-induced energy storage function in polymer-based quasi-solid state dye-sensitized solar cells. AB - Photo-self-charging cells (PSCs) are compact devices with dual functions of photoelectric conversion and energy storage. By introducing a scattering layer in polymer-based quasi-solid-state dye-sensitized solar cells, two-electrode PSCs with highly compact structure were obtained. The charge storage function stems from the formed ion channel network in the scattering layer/polymer electrolyte system. Both the photoelectric conversion and the energy storage functions are integrated in only the photoelectrode of such PSCs. This design of PSC could continuously output power as a solar cell with considerable efficiency after being photo-charged. Such PSCs could be applied in highly-compact mini power devices. PMID- 25829545 TI - CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction. AB - Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction. PMID- 25829548 TI - An acoustic filter based on layered structure. AB - Acoustic filters (AFs) are key components to control wave propagation in multi frequency systems. We present a design which selectively achieves acoustic filtering with a stop band and passive amplification at the high- and low frequencies, respectively. Measurement results from the prototypes closely match the design predictions. The AF suppresses the high frequency aliasing echo by 14.5 dB and amplifies the low frequency transmission by 8.0 dB, increasing an axial resolution from 416 to 86 MUm in imaging. The AF design approach is proved to be effective in multi-frequency systems. PMID- 25829549 TI - Silicon on-chip bandpass filters for the multiplexing of high sensitivity photonic crystal microcavity biosensors. AB - A method for the dense integration of high sensitivity photonic crystal (PC) waveguide based biosensors is proposed and experimentally demonstrated on a silicon platform. By connecting an additional PC waveguide filter to a PC microcavity sensor in series, a transmission passband is created, containing the resonances of the PC microcavity for sensing purpose. With proper engineering of the passband, multiple high sensitivity PC microcavity sensors can be integrated into microarrays and be interrogated simultaneously between a single input and a single output port. The concept was demonstrated with a 2-channel L55 PC biosensor array containing PC waveguide filters. The experiment showed that the sensors on both channels can be monitored simultaneously from a single output spectrum. Less than 3 dB extra loss for the additional PC waveguide filter is observed. PMID- 25829550 TI - A new approach to cancer. PMID- 25829552 TI - Laparoscopic-assisted extirpation of falciform ligament hemangiosarcoma in a dog. AB - An 8-year-old, spayed female, bichon frise dog had incidental nodules within its falciform ligament identified on routine abdominal ultrasonography. A laparoscopic-assisted technique provided both a diagnostic and a therapeutic treatment option. A histopathological diagnosis of hemangiosarcoma was made. This is the second case reporting hemangiosarcoma of the falciform fat. PMID- 25829553 TI - Anthrax vaccine associated deaths in miniature horses. AB - During a widespread anthrax outbreak in Canada, miniature horses were vaccinated using a live spore anthrax vaccine. Several of these horses died from an apparent immune-mediated vasculitis temporally associated with this vaccination. During the course of the outbreak, other miniature horses from different regions with a similar vaccination history, clinical signs, and necropsy findings were found. PMID- 25829554 TI - Multiorgan dysfunction syndrome secondary to joint supplement overdosage in a dog. AB - A 5-year-old spayed female Bernese mountain dog, with a chief complaint of vomiting and melena ingested approximately 200 nutritional joint supplement tablets. Despite aggressive therapy, the patient developed a coagulopathy, pancreatitis, peritonitis, acute kidney injury, and was euthanized. Postmortem examination revealed myocardial necrosis, pneumonia, centrilobular hemorrhage and necrosis of the liver, vasculitis, and acute tubular necrosis. PMID- 25829556 TI - The use of equine surfactant and positive pressure ventilation to treat a premature alpaca cria with severe hypoventilation and hypercapnia. AB - A 5-hour-old, premature alpaca cria was presented with failure to nurse, weakness, hypoglycemia, hypercapnia, and respiratory distress. The cria was treated with 3 doses of fresh, crude equine surfactant, positive pressure ventilation, and supplemental intranasal oxygen. Recovery to discharge was uneventful, and the cria regained apparently normal respiratory function. Three years after hospital discharge, the alpaca was a healthy adult. PMID- 25829555 TI - Cranial vena cava syndrome secondary to cryptococcal mediastinal granuloma in a cat. AB - The successful management of cranial vena cava syndrome with suspected secondary chylothorax due to mediastinal cryptococcal granuloma in a 4-year-old male domestic shorthair cat is described. Treatment included long-term antifungal medication, short-term corticosteroids, intermittent thoracocentesis, rutin, octreotide, and enalapril. PMID- 25829557 TI - Effects of incision closure method on infection prevalence following tibial plateau leveling osteotomy in dogs. AB - The goal of this study was to retrospectively investigate the effect of incisional closure with either stainless steel skin staples or intradermal poliglecaprone 25 on the prevalence of surgical site infection following tibial plateau leveling osteotomy in dogs. Medical records were reviewed for dogs treated with unilateral tibial plateau leveling osteotomy at Memphis Veterinary Specialists between 2006 and 2013. Procedures (n = 306) from 242 dogs were included in the study. The association of potential risk factors with the occurrence of postoperative infection was assessed using logistic regression. A value of P < 0.05 was considered significant. Weight and administration of postoperative antimicrobials were found to significantly influence surgical site infection prevalence. No significant association was noted between closure method and prevalence of postoperative infection. PMID- 25829558 TI - Ceratohyoidectomy for treatment of equine temporohyoid osteoarthopathy (15 cases). AB - This study investigated 15 horses diagnosed with temporohyoid osteoarthopathy (THO) and treated by ceratohyoidectomy between 2004 and 2012. The presenting complaint, duration and nature of the clinical signs, additional diagnostic procedures, and complications were reviewed retrospectively. Long-term follow-up on horses was used to determine prognosis. All horses were diagnosed by guttural pouch endoscopy. Follow-up was available for 14 horses that survived to discharge. Eight of 10 horses that were used athletically prior to surgery returned to previous levels of use. Persisting clinical signs included mild facial nerve paralysis (3/14; 21.4%) or head tilt (6/14; 42.8%) but these were not functionally limiting. It was concluded that equine THO affects a wide range of breeds, disciplines, and ages of horses, and has a variety of presenting clinical signs most commonly associated with vestibular and facial nerves. Prognosis following ceratohyoidectomy is good for resolution of ataxia but some cranial nerve deficits may persist. PMID- 25829559 TI - Comparison of cardiorespiratory variables in dorsally recumbent horses anesthetized with guaifenesin-ketamine-xylazine spontaneously breathing 50% or maximal oxygen concentrations. AB - This study compared cardiorespiratory variables in dorsally recumbent horses anesthetized with guaifenesin-ketamine-xylazine and spontaneously breathing 50% or maximal (> 90%) oxygen (O2) concentrations. Twelve healthy mares were randomly assigned to breathe 50% or maximal O2 concentrations. Horses were sedated with xylazine, induced to recumbency with ketamine-diazepam, and anesthesia was maintained with guaifenesin-ketamine-xylazine to effect. Heart rate, arterial blood pressures, respiratory rate, lithium dilution cardiac output (CO), inspired and expired O2 and carbon dioxide partial pressures, and tidal volume were measured. Arterial and mixed-venous blood samples were collected prior to sedation (baseline), during 30 minutes of anesthesia, 10 minutes after disconnection from O2, and 30 minutes after standing. Shunt fraction, O2 delivery, and alveolar-arterial O2 partial pressures difference [P(A-a)O2] were calculated. Recovery times were recorded. There were no significant differences between groups in cardiorespiratory parameters or in P(A-a)O2 at baseline or 30 minutes after standing. Oxygen partial pressure difference in the 50% group was significantly less than in the maximal O2 group during anesthesia. PMID- 25829561 TI - The Ontario Veterinary College after World War II: 1945-1953. PMID- 25829560 TI - Antimicrobial resistance trends among canine Escherichia coli isolates obtained from clinical samples in the northeastern USA, 2004-2011. AB - Our objectives were to describe the antimicrobial susceptibility of Escherichia coli isolates from dogs in the northeastern USA and to identify temporal trends in resistance to selected antimicrobial agents. Data were collected retrospectively for all canine E. coli isolates from clinical samples submitted to Cornell University's Animal Health Diagnostic Center between January 1, 2004 and December 31, 2011. Antimicrobial susceptibility testing was performed on 3519 canine E. coli isolates; frequency of resistance to each agent ranged from 0.4% (amikacin) to 34.3% (ampicillin). No trends were evident among urinary isolates, but cephalosporin resistance remained consistently high. Among non-urinary isolates, there was evidence of a significantly increasing trend in prevalence of resistance to several agents, including cephalosporins, enrofloxacin, and tetracycline. These data suggest that some of the most commonly used antimicrobial agents in companion animal practice are becoming less effective against canine E. coli infections outside the urinary tract. PMID- 25829562 TI - Efficacy of needle-free injection on antibody production against Clostridium chauvoei in beef calves under field conditions. AB - This study compared needle-free and needle-based injection devices for vaccination of calves against Clostridium chauvoei in warm and cold conditions. Both devices elicited comparable antibody responses in calves. Needle-free injection devices can be used to vaccinate calves provided appropriate precautions are taken in cold weather. PMID- 25829563 TI - Hereditary hyperplastic gingivitis in North American farmed silver fox (Vulpes vulpes). AB - Hereditary hyperplastic gingivitis is a progressive growth of gingival tissues in foxes resulting in dental encapsulation. It is an autosomal recessive condition displaying a gender-biased penetrance, with an association with superior fur quality. This disease has been primarily described in European farmed foxes. Here we document its emergence in Canada. PMID- 25829564 TI - The popularity paradox. PMID- 25829565 TI - Weighty communication challenges. PMID- 25829566 TI - Direct observations of field-induced assemblies in magnetite ferrofluids. AB - Evolution of microstructures in magnetite-based ferrofluids with weak dipolar moments (particle size <= 10 nm) is studied with an emphasis on examining the effects of particle concentration (phi) and magnetic field strength (H) on the structures. Nanoparticles are dispersed in water at three different concentrations, phi = 0.15%, 0.48%, and 0.59% (w/v) [g/ml%] and exposed to uniform magnetic fields in the range of H = 0.05-0.42 T. Cryogenic transmission electron microscopy is employed to provide in-situ observations of the field induced assemblies in such systems. As the magnetic field increases, the Brownian colloids are observed to form randomly distributed chains aligned in the field direction, followed by head-to-tail chain aggregation and then lateral aggregation of chains termed as zippering. By increasing the field in low concentration samples, the number of chains increases, though their length does not change dramatically. Increasing concentration increases the length of the linear particle assemblies in the presence of a fixed external magnetic field. Thickening of the chains due to zippering is observed at relatively high fields. Through a systematic variation of concentration and magnetic field strength, this study shows that both magnetic field strength and change in concentration can strongly influence formation of microstructures even in weak dipolar systems. Additionally, the results of two commonly used support films on electron microscopy grids, continuous carbon and holey carbon films, are compared. Holey carbon film allows us to create local regions of high concentrations that further assist the development of field-induced assemblies. The experimental observations provide a validation of the zippering effect and can be utilized in the development of models for thermophysical properties such as thermal conductivity. PMID- 25829567 TI - Flaxseed-a potential functional food source. AB - There is currently much interest in phytochemicals as bioactive molecules of food. Functional foods are an emerging field in food science due to their increasing popularity among health conscious consumers. Flaxseed is cultivated in many parts of world for fiber, oil as well as for medicinal purposes and also as nutritional product. In this review, nutrients, anti-nutrients, functional properties, processing, metabolism and health benefits of bioactive molecules viz., essential fatty acids, lignans and dietary fiber of flaxseed are discussed. PMID- 25829568 TI - Date canning: a new approach for the long time preservation of date. AB - Dramatic growth in date (Phoenix dactylifera L.) production, makes it clear to apply proper methods to preserve this nutritious fruit for a long time. Numerous methods have been used to gain this goal in recent years that can be classified into non-thermal (fumigation, ozonation, irradiation, and packaging) and thermal (heat treatment, cold storage, dehydration, jam etc.) processing methods. In this paper these methods were reviewed and novel methods for date preservation were presented. PMID- 25829569 TI - Evaluation of antioxidant activities of bioactive compounds and various extracts obtained from saffron (Crocus sativus L.): a review. AB - Saffron (Crocus sativus L. stigma), the most valuable medicinal food product, belongs to the Iridaceae family which has been widely used as a coloring and flavoring agent. These properties are basically related to its crocins, picrocrocin and safranal contents which have all demonstrated health promoting properties. The present review article highlights the phytochemical constituents (phenolic and flavonoid compounds, degraded carotenoid compounds crocins and crocetin) that are important in antioxidant activity of saffron extracts. However, the synergistic effect of all the bioactive components presence in saffron gave a significant antioxidant activity similar to vegetables rich in carotenoids. Our study provides an updated overview focused on the antioxidant activity of saffron related to its bioactive compounds to design the different functional products in food, medicine and cosmetic industries. PMID- 25829570 TI - Oxygen absorbers in food preservation: a review. AB - The preservation of packaged food against oxidative degradation is essential to establish and improve food shelf life, customer acceptability, and increase food security. Oxygen absorbers have an important role in the removal of dissolved oxygen, preserving the colour, texture and aroma of different food products, and importantly inhibition of food spoilage microbes. Active packaging technology in food preservation has improved over decades mostly due to the sealing of foods in oxygen impermeable package material and the quality of oxygen absorber. Ferrous iron oxides are the most reliable and commonly used oxygen absorbers within the food industry. Oxygen absorbers have been transformed from sachets of dried iron powder to simple self-adhesive patches to accommodate any custom size, capacity and application. Oxygen concentration can be effectively lowered to 100 ppm, with applications spanning a wide range of food products and beverages across the world (i.e. bread, meat, fish, fruit, and cheese). Newer molecules that preserve packaged food materials from all forms of degradation are being developed, however oxygen absorbers remain a staple product for the preservation of food and pharmaceutical products to reduce food wastage in developed nations and increased food security in the developing & third world. PMID- 25829571 TI - Rheological behaviour of enzyme clarified sapota (Achras sapota L) juice at different concentration and temperatures. AB - Rheological behaviour of enzyme clarified sapota (Achras sapota L.) juice at different temperatures (10 to 85 degrees C) and total soluble solid content (10.2 to 55.6 degrees brix) corresponding to a water activity (aw) (0.986 to 0.865) was studied using controlled stress rheometer by coaxial cylinders attachment. The rheological parameter shear stress (Pa) was measured upto a shear rate of 1,000 s(-1). The investigation showed that the enzyme clarified sapota juice and its concentrates behaved like a Newtonian liquid and the viscosity (eta) values were in the range 4.340 to 56.418 mPa s depending upon temperature and concentration studied. The temperature dependency of viscosity of enzyme clarified sapota juice was described by Arrhenius equation (r > 0.94) and activation energy (Ea) for viscous flow was in the range 5.218 to 25.439 KJ/mol depending upon concentration. The effect of total soluble solid content on flow activation energy was described by exponential relationship (r > 0.95, rmse% <13.5, p < 0.01) and that of water activity was described by power law relation (r > 0.99, rmse% <5.80, p < 0.01). The effect of total soluble solid content on viscosity of enzyme clarified sapota juice followed second order exponential type relationship (r > 0.99, rmse% < 3.53) at the temperature used. The effect of water activity on viscosity of enzyme clarified sapota juice followed power law equation (r > 0.98, rmse% < 4.38). A single equation representing combined effect of temperature and total soluble solid content/water activity on viscosity of enzyme clarified sapota was established. PMID- 25829572 TI - Aqueous extract of some indigenous medicinal plants inhibits glycation at multiple stages and protects erythrocytes from oxidative damage-an in vitro study. AB - Azadirachta indica, Emblica officinalis, Syzygium cumini and Terminalia bellirica are common in Indian system of traditional medicine for the prevention of diabetes and its complications. The aim of the present study was to comprehensively and comparatively investigate the antiglycation potential of these plant extracts at multiple stages and their possible protective effect against glycated albumin mediated toxicity to erythrocytes. Antiglycation activities of these plant extracts was measured by co-incubation of plant extract with bovine serum albumin-fructose glycation model. The multistage glycation markers- fructosamines (early stage), protein carbonyls (intermediate stage) and AGEs (late stage) are investigated along with measurement of thiols and beta aggregation of albumin using amyloid-specific dyes-Congo red and Th T. Protection of erythrocytes from glycated albumin induced toxicity by these plant extracts was assessed by measuring erythrocytes hemolysis, lipid peroxidation, reduced glutathione and intracellular antioxidant capacity. Total phenolics, reducing power and antioxidant activities of the plant extracts were also measured. In vitro glycation assays showed that plant extracts exerted site specific inhibitory effects at multiple stages, with T. bellirica showing maximum attenuation. In erythrocytes, along with the retardation of glycated albumin induced hemolysis and lipid-peroxidation, T. bellirica considerably maintained cellular antioxidant potential. Significant positive correlations were observed between erythrocyte protection parameters with total phenolics. These plant extracts especially T. bellirica prevents glycation induced albumin modifications and subsequent toxicity to erythrocytes which might offer additional protection against diabetic vascular complications. PMID- 25829573 TI - Antioxidant activities and phenolic contents of three red seaweeds (Division: Rhodophyta) harvested from the Gulf of Mannar of Peninsular India. AB - The antioxidant activities of methanol extract and its solvent fractions (n hexane, dichloromethane and ethyl acetate) of three red seaweeds (Hypnea musciformis, H. valentiae, and Jania rubens) collected from the Gulf of Mannar of South eastern coast of India were evaluated, using different in vitro systems, viz., DPPH, ABTS, HO radical scavenging activities, H2O2 scavenging ability, Fe(2+) ion chelating ability and reducing potential. Folin-Ciocalteu method was used to determine the total phenolic content of the extracts/fractions, and the results were expressed as mg of gallic acid equivalent (GAE)/g of the seaweed extracts/fractions. Thiobarbituric acid-reactive substances (TBARS) inhibition assay was employed to assess the ability of the seaweed extracts/fractions to inhibit lipid oxidation. Ethyl acetate (EtOAc) fractions of H. musciformis exhibited significantly higher total phenolic content (205.5 mg GAE/g), DPPH. scavenging activity (IC50 0.6 mg/mL), ABTS(.+) scavenging activity (IC50 0.51 MUg/mL), Fe(2+) chelating ability (IC50 0.70 mg/mL), H2O2 scavenging activity (IC50 0.39 mg/mL), reducing ability (Abs700 nm 1.46) and lipid peroxidation inhibitory ability (2.71 MDAEC/kg) (P < 0.05) compared to its n-hexane, DCM fractions, crude MeOH extract and MeOH extracts/fractions of H. valentiae and J. rubens. DCM fraction of J. rubens showed significantly higher hydroxyl radical scavenging activity (IC50 0.55 mg/mL) compared with H. musciformis and H. valentiae (P < 0.05). This study indicated the potential use of red seaweeds, in particular, H. musciformis as candidate species to be used as food supplement for increasing the shelf-life of food industry, and candidates in combating carcinogenesis and inflammatory diseases. PMID- 25829574 TI - Alternation of secondary metabolites and quality attributes in Valencia Orange fruit ( Citrus sinensis ) as influenced by storage period and edible covers. AB - Flavonoids (FGs) are a large group of polyphenolic compounds with low molecular weight, found in free and glycozidic forms in plants. Citrus fruits can be used as a food supplement containing hesperidin and flavonoids to prevent infections and boost the immune system in human body. The aim of this study was the investigation of the effect of clove oil and storage period on the amount of hesperidin and naringin component in orange peel (cv. Valencia). Four treatments including clove oil (1 %), wax, mixture of wax-clove oil, control and storage period were applied. Treated fruits were stored at 7 degrees C and 85 % relative humidity for 3 months and naringin, hesperidin, antioxidant activity, total pheenolic compounds, TSS, Vitamin C, fruits weight loss, pH, acidity and carbohydrates content were measured every 3 weeks. The amount of hesperidin and naringin was determined using high performance liquid chromatography at the detection wavelength of 285 nm. Antioxidant activity was measured using the 1, 1 diphenyl-2-picrylhydrazyl-hydrate (DPPH) free radical scavenging assay. Total phenolic compounds were measured using the Folin-Ciocalteu micro method. Results showed that naringin and hesperidin were decreased during storage. Different treatment only had significant effect on the amount of hesperidin while storage period affected both of narigin and hesperidin. Results of correlation study, indicated strong relation between antioxidant activity and amount of naringin and hesperidin during storage time. However, at the end of storage period, the amount of hesperidin and naringin were diminished independent of different covers. Probably anaerobic condition caused such reduction. Results showed that the amount of TSS, fruit hardness, weight loss, total sugar and fructose content were increased during storage period while total acidity, pH and glucose content showed descending trend during storage periods. In conclusion, hesperidin and naringin of peels can be used as suitable quality indexes indicating proper conditions for storage. PMID- 25829575 TI - Effect of containers on the quality of Chemlali olive oil during storage. AB - This study is undertaken to determine the storage stability of Chemlali extra virgin olive oil (EVOO) in different containers such as clear and dark glass bottles, polyethylene (PE) and tin containers. The different oil samples were stored under light at room temperature. Quality parameters monitored during a 6 month-storage period included: acidity, peroxide value (PV), spectrophotometric indices (K232 and K270), chlorophyll and carotene pigments, fatty acids and sterol compositions, total phenols, Rancimat induction time as well as sensory evaluation. Tin containers and dark glass bottles recorded the lowest oxidation values. In addition, oil packed in tin containers and dark glass bottles showed better physicochemical and organoleptic characteristics than that stored in clear glass bottles and PE containers. A significant decrease (p < 0.05) in the antioxidant contents (carotenes, chlorophylls and total phenols) was observed in the oil stored in the clear glass bottles and PE containers. Such results proved that the storage of oil in tin containers and dark glass bottles appeared most adequate, and showed a gradual loss of quality during storage, especially in PE containers and clear glass bottles. This study has shown that the best packaging materials for the commercial packing of Chemlali extra-virgin olive oil are tin containers and dark glass bottles. PMID- 25829576 TI - Effect of cinnamon powder addition during conching on the flavor of dark chocolate mass. AB - In the present study, refined dark chocolate mix was conched with the addition of finely powdered cinnamon in a laboratory-style conching machine to evaluate its aroma profile both analytically and sensorially. The analytical determinations were carried out by a combination of solid phase micro extraction (SPME)-gas chromatography (GC)-mass spectroscopy (MS) and-olfactometry(O), while the sensory evaluation was made with trained panelists. The optimum conditions for the SPME were found to be CAR/PDMS as the fiber, 60 degrees C as the temperature, and 60 min as the time. SPME analyses were carried out at 60 degrees C for 60 min with toluene as an internal standard. 26 compounds were monitored before and after conching. The unconched sample had a significantly higher fruity odor value than the conched sample. This new product was highly acceptable according to the overall inclination test. However some of textural properties, such as coarseness, and hardness were below the general preference. PMID- 25829577 TI - Standardized extract of Withania somnifera (Ashwagandha) markedly offsets rotenone-induced locomotor deficits, oxidative impairments and neurotoxicity in Drosophila melanogaster. AB - Withania somnifera (Ashwagandha, WS) or Indian ginseng possesses multiple pharmacological properties which are mainly attributed to the active constituents, withanolides. Despite its extensive usage as a memory enhancer and a nerve tonic, few attempts have been made to ascertain its usage in the management of Parkinson's disease. In the present study, we investigated the neuroameliorative effects of WS in a rotenone (ROT) model of Drosophila melanogaster (Oregon-K). Initially, we ascertained the ability of WS-enriched diet (0-0.05 %) to protect against ROT induced lethality and locomotor phenotype in adult male flies. Further, employing a co-exposure paradigm, we investigated the propensity of WS to offset ROT-induced oxidative stress, mitochondrial dysfunctions and neurotoxicity. WS conferred significant protection against ROT induced lethality, while the survivor flies exhibited improved locomotor phenotype. Biochemical investigations revealed that ROT-induced oxidative stress was significantly diminished by WS enrichment. WS caused significant elevation in the levels of reduced GSH/non-protein thiols. Furthermore, the altered activity levels of succinate dehydrogenase, MTT, membrane bound enzymes viz., NADH cytochrome-c reductase and succinate-cytochrome-c reductase were markedly restored to normalcy. Interestingly, ROT-induced perturbations in cholinergic function and depletion in dopamine levels were normalized by WS. Taken together these data suggests that the neuromodulatory effect of WS against ROT- induced neurotoxicity is probably mediated via suppression of oxidative stress and its potential to attenuate mitochondrial dysfunctions. Our further studies aim to understand the underlying neuroprotective mechanisms of WS and withanolides employing neuronal cell models. PMID- 25829578 TI - Antioxidant activity and anti-exercise-fatigue effect of highly denatured soybean meal hydrolysate prepared using neutrase. AB - Highly denatured soybean meal is a by-product of soybean oil extraction obtained through high-temperature desolventization. High-temperature treatment can result in soybean protein denaturation. Compare with ordinary soybean meal, the protein structure of highly denatured soybean meal has changed. Highly denatured soybean meal was pretreated with thermal treatment or ultrasonication, and then hydrolyzed with neutrase. The ultrasonicated hydrolysate exhibited better antioxidant activity than the thermally treated hydrolysate. The ultrasonication increased 1,1-diphenyl-2-pycryl hydrazyl (DPPH) radical scavenging activity by 8.31 % and reduction capacity by 10.19 %. The highly denatured soybean meal hydrolysate ultrasonicated at 400 W exhibited the highest antioxidant activity. The DPPH radical scavenging activity was 56.22 % and reduction capacity was 0.717. The ultrasonicated hydrolysate at 400 W was fractionated using ultrafiltration into three fractions: I (>10 kDa), II (5 kDa to 10 kDa), and III (<5 kDa). The in vitro antioxidant activity and others in vivo anti-exercise fatigue effect of the three fractions (I, II, and III) were determined. Fraction III exhibited the highest DPPH radical scavenging activity and reduction capacity, improved the hemoglobin and hepatic glycogen content and reduced blood urea nitrogen and blood lactic acid. Fraction III improved the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) and reduced the malonaldehyde (MDA) content in mouse livers. Therefore, the highly denatured soybean meal hydrolysate has an anti-oxidative effect and it significantly alleviates exercise-fatigue in mice. Amino acids of hydrolysate were determined. Results showed that the antioxidant activity and anti-exercise-fatigue effect were related to the amino acid compositions. PMID- 25829579 TI - Antioxidants and antioxidant enzymes status of rats fed on n-3 PUFA rich Garden cress (Lepidium Sativum L) seed oil and its blended oils. AB - Garden cress (Lepidium sativum L) seed oil (GCO) is a rich source of alpha linolenic acid (ALA, 33.6 %) and the oil has a fairly balanced SFA, MUFA and PUFA ratio. In this study we have investigated the effect of GCO and its blends with n 6 PUFA rich edible vegetable oils sunflower oil (SFO), rice bran oil (RBO) and sesame oil (SESO) on antioxidant status of oils and antioxidative enzymes in Wistar rats. Physical blending of GCO with n-6 PUFA rich vegetable oils (SFO, RBO and SESO) increased content of natural antioxidants such as tocopherols, oryzanol and lignans, decreased the n-6/n-3 PUFA ratio and improved the radical scavenging activity of blended oils. Dietary feeding of GCO and its blended oils for 60 days, increased the tocopherols levels (12.2-21.6 %) and activity of antioxidant enzymes namely catalase, glutathione peroxidase (GPx), but did not affect the activity of glutathione reductase (GR), superoxide dismutase (SOD) and glutathione S-transferase (GST) in liver compared to native oil fed rats. Thus, blending of GCO with other vegetable oil decreased n-6/n-3 PUFA ratio (>2.0) and dietary feeding of GCO blended oils increased the antioxidant status and activity of antioxidant enzymes (catalase and GPx) in experimental rats. PMID- 25829580 TI - Microwave assisted dehulling of black gram (Vigna mungo L). AB - This article summarises the results of the investigation of application of microwave exposure on the dehulling characteristics of the black gram and the properties of the dehulled grains. Black gram was exposed to 3 microwave power levels, viz., 450, 630 and 810 W for 7 different exposure, ranging from 60 to 150 s at an interval of 15 s with a view to determine the suitable combination of dosage in order to get the maximum yield with little change in colour. Related changes in properties were also studied. It was observed that the surface temperature of the grain increased with the increase in microwave power level from 450 to 810 W as well as exposure time from 60 to 150 s in the range from 58 to 123 degrees C while the dehulling time reduced from 445 to 170 s. The dehulling yield increased with increasing microwave dosage in the beginning and reached to the maximum value followed by decreasing trend. The colour of the dehulled grain changed slowly up to a microwave dosage of 972 J/g after that it changed vividly darker than the control. The dehulling and dhal yields and colour change were polynomial functions of microwave dosage. The highest yield of 73.7 % was achieved at about 972 J/g with a little change in colour (CIELAB DeltaE* value of 2.58). The corresponding dehulling time, cooking time and losses during dehulling were respectively 185 s, 10 min and 15.1 % as compared to 492 s, 20 min and 31.5 % for control respectively. It is concluded that a dosage of about 972 J/g was the best for the black gram dehulling at a rate of 630 W or higher power level. PMID- 25829581 TI - Thin-layer modeling of convective and microwave-convective drying of oyster mushroom (Pleurotus ostreatus). AB - Oyster mushroom samples were dried under selected convective, microwave convective drying conditions in a recirculatory hot-air dryer and microwave assisted hot-air dryer (2.45 GHz, 1.5 kW) respectively. Only falling rate period and no constant rate period, was exhibited in both the drying technique. The experimental moisture loss data were fitted to selected semi-theoretical thin layer drying equations. The mathematical models were compared according to three statistical parameters, i.e. correlation coefficient, reduced chi-square and residual mean sum of squares. Among all the models, Midilli et al. model was found to have the best fit as suggested by 0.99 of square correlation coefficient, 0.000043 of reduced-chi square and 0.0023 of residual sum of square. The highest effective moisture diffusivity varying from 10.16 * 10(-8) to 16.18 * 10(-8) m(2)/s over the temperature range was observed in microwave-convective drying at an air velocity of 1.5 m/s and the activation energy was calculated to be 16.95 kJ/mol. The above findings can aid to select the most suitable operating conditions, so as to design drying equipment accordingly. PMID- 25829582 TI - The arils characterization of five different pomegranate (Punica granatum) genotypes stored after minimal processing technology. AB - In this study, the quality of minimally processed different Iranian pomegranate genotypes was investigated during storage at 4 degrees C for 14 days. The results showed that at the end of storage time, the lowest microbial count was found on the arils of "Torsh Syabe Lorestan" genotype. There was a significant difference in titratable acidity, total soluble solids, total anthocyanin, catechin, and quercetin content in most genotypes after 14-day cold storage; while no difference was found between studied genotypes in antioxidant capacity, total phenolic, and flavonoid content. In general, total phenolic content and antioxidant capacity of pomegranate arils gradually decreased over storage time. Diphenolase activity of polyphenol oxidase (PPO) enzyme with dopamine hydrochloride substrate and peroxidase (POD) decreased over storage time, whereas diphenolase activity of PPO with pyrocatechol substrate significantly increased. The lowest diphenolase activity with dopamine hydrochloride and pyrocatechol substrates, as well as POD activity was found in Torsh Syabe Lorestan. The results suggested that the genotype of Torsh Syabe Lorestan, which showed the lowest microbial count on the arils and enzymes, could be more appropriate for minimal processing technology. PMID- 25829583 TI - Influence of calcium fortification on physical and rheological properties of sucrose-free prebiotic milk chocolates containing inulin and maltitol. AB - In the present study, chocolates were investigated that had been prepared according to the composition specified as a result of this previous work (9.00 % w/w inulin and 34.0 % w/w maltitol) Certain physical (particle size distribution [PSD], brightness, chroma, water activity and hardness) and rheological features of the samples resulting from the addition of calcium carbonate in different quantities (300, 450, 600, 750 and 900 mg calcium carbonate to 100 mg milk chocolate) were studied. Both the Herschel-Bulkley and Casson models were used to investigate the rheological findings. It was determined by comparing certain rheological (rate index, Casson yield stress and Casson viscosity) and physical (chroma and hardness) parameters that samples containing 409.5 mg calcium (nearly 41.0 % of the RDA of calcium) per 100 g chocolate did not show significant differences from samples from the control group. Furthermore, these calcium containing samples were shown to exhibit positive differences in other physical properties (brightness and water activity) that could be noteworthy and significant with respect to visual quality and shelf life. PMID- 25829584 TI - Concise and informative title: evaluation of selected spices in extending shelf life of paneer. AB - Black pepper, cardamom, cinnamon and clove were tested for their relative efficacy in improving shelf life of paneer. All the spices were incorporated in paneer @ 0 (control), 0.2, 0.4, 0.6, 0.8 and 1.0 % by wt. of expected yield of paneer. Addition of black pepper, cardamom or clove at the rate of 0.6 % by weight or cinnamon at the rate of 0.4 % by weight was found to be acceptable. Therefore, paneer was prepared by incorporating black pepper, cardamom and clove i.e. Bp, Ca and Cl @ 0.6 % and cinnamon (Ci) @ 0.4 % by wt. of expected yield of paneer. All the paneer samples viz. Bp, Ca, Cl and Ci were subjected to sensory evaluation when fresh and after interval of 7 days during storage at 7 +/- 1 degrees C up to 28 days. Results indicated that control remained acceptable up to 7 days, Bp up to 14 days of storage and Cl up to 21st day of storage. The overall acceptability score of Ca remained well above the acceptable level even on 28th day of the storage. Results of changes in chemical characteristics indicate that amongst all the spices studied, cardamom had maximum ability to control the rate of increase in acidity, free fatty acids content and soluble nitrogen content in paneer during storage. The order of the relative effectiveness in enhancing shelf life of paneer was cardamom > cinnamon > clove > black pepper. The effect of cardamom on microbial counts of paneer viz. standard plate counts (SPC), yeast and mould count and coliform count were evaluated. Among the spices studied, cardamom was found to be the best spice to improve shelf life of paneer up to 28 days of storage at 7 +/- 1 degrees C. PMID- 25829585 TI - Effects of salicylic acid and putrescine on storability, quality attributes and antioxidant activity of plum cv. 'Santa Rosa'. AB - Plum fruit has a short shelf life with a rapid deterioration in quality after harvest. The primary goal of this study is to investigate and compare the effect of putrescine and salicylic acid on quality properties and antioxidant activity of plum during storage. The plum fruits (cv. 'Santa Rosa') were harvested at the mature ripe stage, and dipped in different concentrations of putrescine (1, 2, 3 and 4 mmol/L) and salicylic acid (1, 2, 3 and 4 mmol/L), as well as distilled water (control) for 5 min. The fruits were then packed in boxes with polyethylene covers and stored at 4 degrees C with 95 % relative humidity for 25 days. A factorial trial based on completely randomized block design with 4 replications was carried out. The weight loss, fruit firmness, total soluble solids, titratable acidity, pH, maturity index, ascorbic acid, total phenolics and antioxidant activity at 0, 5, 10, 15, 20 and 25 days after harvest were recorded. During the storage period, the weight loss, total soluble solids, pH and maturity index increased significantly while the fruit firmness, titratable acidity, ascorbic acid, total phenolics and antioxidant activity decreased significantly (P < 0.05) for all treatments. Statistically significant differences were observed between different treatments (putrescine, salicylic acid and control) in all measured parameters. The data showed that the weight loss and softening of the plum fruits were decreased significantly by the use of putrescine and salicylic acid. Also, exogenous treatments of putrescine and salicylic acid are found to be effective in maintaining titratable acidity, ascorbic acid, total phenolics and antioxidant activity in plum fruits during storage at 4 degrees C. It was concluded that postharvest treatment of plum fruit with putrescine and salicylic acid were effective on delaying the ripening processes and can be used commercially to extend the shelf life of plum fruit with acceptable fruit quality. PMID- 25829586 TI - The encapsulation of flavourzyme in nanoliposome by heating method. AB - The main objective of this study was to use heating method (HM) to prepare liposome without employing any chemical solvent or detergent. Plackett-Burman design (PBD) was applied for the screening of significant process variables including the lecithin proportion, the cholesterol/lecithin ratio, the pH of solution for liposome preparation, the enzyme/lecithin ratio, the stirring time, the process temperature, the speed of stirrer, the ratio of stirrer to the tank diameter, the application of homogenization, the method of adding enzyme and centrifugation conditions on the encapsulation efficiency (EE %) of liposome and the activity of liposomal Flavourzyme (LAPU(-1)) (P < 0.05). Then, the response surface methodology based on the central composite design (CCD) was applied for the evaluation of the impacts of the significant mentioned variables on the EE (%) and the activity of the liposomal Flavourzyme. The results indicated that the lecithin proportion and the stirring time were the major influential variables for both responses. The most suitable formulation of the Flavourzyme-loaded liposome is 4.5 % lecithin, 45 degrees C temperature, 5 % Flavourzyme/lecithin ratio, 30 min stirring time and medium pH of 6. Under suitable operating conditions, the EE of liposome and the activity of the liposomal Flavourzyme were achieved as 26.5 % and 9.96 LAPU ml(-1), respectively. AFM technique and size distribution clearly showed the diameter of 189 nm for the spherical shape of the Flavourzyme- loaded nanoliposome. PMID- 25829587 TI - Angiotensin I-Converting Enzyme inhibitory and antioxidant activities and surfactant properties of protein hydrolysates as obtained of Amaranthus hypochondriacus L. grain. AB - Even though some research has been carried out on surfactant properties of amaranth protein hydrolysates, their bio-functionality has not been studied yet. In this work amaranth grain Alb 1 and Glob were hydrolyzed (Alb 1H, Glob H) and foams and emulsions at optimal conditions (t, E/S, pH5) were prepared in order to assess techno-functional properties such as foaming (F) and emulsifying (E) (capacity (C) and stability (S)). FC and EC were much better for Glob H than for Alb H. Angiotensin I-converting enzyme-inhibitory activity was higher for Alb 1H (roughly 50 %) than that of Glob H (roughly 30 %). Scavenging of radicals activity (DPPH. or ABTS. (+) ) of Alb 1H and Glob H, at 2 mg/mL, was similar (approx. 40 %), but lower than Alb 1 (approx. 70 %), which was the best antioxidant. The low reducing power showed that hydrolysates barely donate an electron or hydrogen. Chelating activity on Cu(2+) was lower than that exhibited by Fe(2+,) which was remarkable, approx. 80 % as long as DH% > 10 %, where hydrolysates displayed high solubility (Alb 1H = 85 %, Glob H = 70 %) because of occurrence of 1-10 kDa peptides. Amaranth foams and emulsions prepared with protein hydrolysates have a potential as a nutraceutical food. PMID- 25829588 TI - Chemical characterisation and application of acid whey in fermented milk. AB - Acid whey is a by-product from cheese processing that can be employed in beverage formulations due to its high nutritional quality. The objective of the present work was to study the physicochemical characterisation of acid whey from Petit Suisse-type cheese production and use this by-product in the formulation of fermented milk, substituting water. In addition, a reduction in the fermentation period was tested. Both the final product and the acid whey were analysed considering physicochemical determinations, and the fermented milk was evaluated by means of sensory analysis, including multiple comparison and acceptance tests, as well as purchase intention. The results of the physicochemical analyses showed that whey which was produced during both winter and summer presented higher values of protein (1.22 and 0.97 %, w/v, respectively), but there were no differences in lactose content. During the autumn, the highest solid extract was found in whey (6.00 %, w/v), with larger amounts of lactose (4.73 %, w/v) and ash (0.83 %, w/v). When analysing the fermented milk produced with added acid whey, the acceptance test resulted in 90 % of acceptance; the purchase intention showed that 54 % of the consumers would 'certainly buy' and 38 % would 'probably buy' the product. Using acid whey in a fermented milk formulation was technically viable, allowing by-product value aggregation, avoiding discharge, lowering water consumption and shortening the fermentation period. PMID- 25829589 TI - Effect of conjugated linoleic acid enrichment on the quality characteristics of Turkish dry fermented sausage. AB - The effects of conjugated linoleic acid (CLA) enrichment on lipid oxidation, the fatty acid profile, physico-chemical, sensory and microbiological features of sucuk were investigated. The control sucuk did not contain CLA, however, other groups contained 0.5 %, 1 %, 1.5 %, 2 %, 2.5 %, and 3 % CLA, respectively. The results indicated that CLA concentration was increased in sucuk with CLA addition (p < 0.05). CLA concentration decreased (p < 0.05) during the fermentation period, but did not alter during the storage. Lipid oxidation gradually increased with the increasing of storage in all treatments (p < 0.05). However, addition of CLA decreased lipid oxidation compared to control (p < 0.05). With regard to color, higher L* values were observed in 2 % CLA treatment group compared to other treatments during storage (p < 0.05). Moreover, CLA addition resulted in increased a* values in sucuk (p < 0.05). With the addition of CLA, saturated fatty acids in sucuk decreased and poly-unsaturated fatty acids and conjugated linoleic acids increased (p < 0.05). PMID- 25829590 TI - Identification of phenolic compounds in polyphenols-rich extract of Malaysian cocoa powder using the HPLC-UV-ESI-MS/MS and probing their antioxidant properties. AB - The antioxidant components of cocoa powder, which is rich in polyphenols, were isolated using column chromatography and high performance liquid chromatography. Polyphenolic compounds were then characterized by high-performance liquid chromatography/Ultraviolet and electronspray ionization-tandem mass spectrometry (HPLC-UV-/ESI-MS-MS). As a result, five phenolic compounds were detected. In this study we also investigated scavenging or the total antioxidant capacity (%) of cocoa polyphenol (CP) fractionated from cocoa powder extract. 114.0 mg/g of gallic acid -equivalent phenolics and 94.3 mg/g catechin- equivalent flavonoids were quantified in this extract. Their free radical-scavenging activity was assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay, beta-carotene bleaching test, and xanthine oxidase inhibitory activity (OX). Total antioxidant capacity (TAC) was further assessed against the myoglobin-induced oxidation of 6 hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid (ABTS) and expressed as Trolox equivalent. A high correlation between TAC and phenolic contents indicated that phenolic compounds from cocoa were a major contributor of antioxidant activity (0.967 <= r <= 1.00). CP extract had significantly (P < 0.05) potential antioxidant activities with various concentrations. These results suggest that Polyphenols-rich cocoa extract possess prominent medical properties and can be exploited as natural drug to treat free radical associated diseases. PMID- 25829591 TI - Quality characteristics of no added sugar ready to drink milk supplemented with mango pulp. AB - Removal of sugar as a sweetener and its replacement by a high potency sweetener introduces a number of sensory and technical challenges particularly diminution in mouthfeel. Thick consistency of pulpy fruits could be exploited to compensate for the loss of viscosity and mouthfeel in sugar substituted beverages. The investigation was undertaken to study the effect of mango pulp supplementation on the quality of flavoured low calorie milk drinks using sucralose as sugar substitute. The effect of 0.0 to 100 % sugar replacement on total solids (TS), total soluble solids (TSS), specific gravity, viscosity and sensory scores was studied. Sugar replacement considerably decreased TS, TSS, viscosity and sensory scores. The mango flavoured milk drinks(MFDs) prepared by replacing sugar with sucralose and adding 10 % mango pulp in milk of 0.5 % fat and 8.5 % milk solid not-fat. MFD were pasteurized and stored at refrigeration temperature for shelf life studies. A significant (p < 0.01) loss in the viscosity, ascorbic acid and reducing sugar content of pasteurized MFD was noticed during the storage period of 10 days at 5.0 +/- 0.1 degrees C. However, the titratable acidity increased to undesirable levels in MFD after 8 days which rendered it unacceptable. Standard plate count and yeast and mold count of MFDs increased during storage. The shelf life of the pasteurized MFD was found to be 8 days at 5.0 +/- 0.1 degrees C. PMID- 25829592 TI - Development and quality evaluation of dehydrated chicken meat rings using spent hen meat and different extenders. AB - It is recommended that for effective utilization of spent hen meat, it should be converted into value added or shelf stable meat products. Since we are lacking in cold chain facilities, therefore there is imperative need to develop shelf stable meat products. The present study was envisaged with the objective to develop dehydrated chicken meat rings utilizing spent hen meat with different extenders. A basic formulation and processing conditions were standardized for dehydrated chicken meat rings. Extenders such as rice flour, barnyard millet flour and texturized soy granule powder at 5, 10 and 15 % levels were incorporated separately replacing the lean meat in pre standardized dehydrated chicken meat ring formulation. On the basis of physico-chemical properties and sensory scores optimum level of incorporation was adjudged as 10 %, 10 % and 5 % for rice flour, barnyard millet flour and texturized soy granule powder respectively. Products with optimum level of extenders were analysed for physico-chemical and sensory attributes. It was found that a good quality dehydrated chicken meat rings can be prepared by utilizing spent hen meat at 90 % level, potato starch 3 % and refined wheat flour 7 % along with spices, condiments, common salt and STPP. Addition of an optimum level of different extenders such as rice flour (10 %), barnyard millet flour (10 %) and TSGP (5 %) separately replacing lean meat in the formulation can give acceptable quality of the product. Rice flour was found to be the best among the three extenders studied as per the sensory evaluation. PMID- 25829593 TI - Comparison of thawing assisted by low-intensity ultrasound on technological properties of pork Longissimus dorsi muscle. AB - The objective of the present study was to analyses technological and textural properties of pork thawed by low intensity ultrasound compared to meat thawed conventionally in air (control) or by immersion in water. The pork thawing was done by means of a generator of constant frequency, with adjusting ultrasound intensity, coupled with a transducer plate and a water bath. The frequency of 25 kHz and the intensity of 0.6 W/cm(2) allowed reducing by 87 % the time required for thawing from -5 degrees C to -1 degrees C as well as the overall thawing time as compared to thawing in air. Using intensity of 0.2, 0.4, and 0.6 W/cm(2) thawing rates were 0.62, 0.73, 1 degrees C/min, versus 0.16 degrees C/min in the control. The textural and technological properties of meat thawed by ultrasound are not impaired by the significant lowering of thawing time; there were no large mass loss or modification of meat ultrastructure as compared to control. PMID- 25829594 TI - Influence of watermelon seed protein concentrates on dough handling, textural and sensory properties of cookies. AB - Fruit processing wastes contain numerous by products of potential use in food & allied industry. Watermelon seeds represent a major by-product of the processing waste and contain high amount of nutritional proteins. Protein rich cereal based products are in demand due to their health promoting benefits. With this aim, wheat flour was fortified with watermelon seed protein concentrates (2.5 %, 5 %, 7.5 % and 10 % levels) to prepare cookies with desirable physical, nutritional, and textural and sensory properties. Substitution levels of 5 % and 10 % significantly (p <= 0.05) increased the dough stability and mixing tolerance index, however pasting properties and dough extensibility decreased considerably above 5 % substitution levels. Cookie fracture force (kg) increased significantly (p <= 0.05) above 5 % fortification levels. Cookie spread factor (W/T) increased from 2.5 % to 7.5 % fortification levels, further increase showed negative impact. Sensory scores of the cookies showed that protein concentrate may be added up to 7.5 % fortification levels. This study revealed that watermelon protein concentrates can be fortified with protein concentrates upto 5-7.5 % levels in cookies to improve their protein quality. PMID- 25829595 TI - Enhanced bactericidal effect of enterocin A in combination with thyme essential oils against L. monocytogenes and E. coli O157:H7. AB - The combined effects of enterocin A with Thymus vulgaris essential oils (EOs) against Listeria monocytogenes and Escherichia coli O157:H7 were investigated in vitro by enumeration of surviving populations of testing pathogens and minimal inhibitory concentration (MIC) determination. Enterocin A was purified to homogeneity by RP-HPLC from the culture fluid of Enterococcus strain and thyme EOs were extracted from local Thymus vulgaris plants. The major constituent of thyme EOs oils determined by GC-MS was thymol (78.4 %). Combination of enterocin A with thyme EOs showed an enhanced bactericidal effect against Listeria monocytogenes. Checkerboard assay and isobologram construction displayed a synergistic interaction between these compounds against Listeria (FIC index <0.5). Moreover, the MIC value of enterocin A has fallen fivefold (from 4.57 to 0.9 MUg/ml), while the MIC of thyme EOs decreased threefold (from 3.6 to 1.2 MUg/ml). Treatments with enterocin A alone did not affect the growth of the enteric pathogen E. coli O157:H7. However, the addition of thyme EOs and enterocin A yielded a synergistic antimicrobial effect against E. coli (MIC thyme EOs decrease from 2.2 to 0.71 MUg/ml). This is the first report on the combined effect of enterocin A and thyme EOs against food pathogen bacteria. This combination could be useful in food bio-preservation. PMID- 25829596 TI - Quantitative analysis of flavonoids, sugars, phenylalanine and tryptophan in onion scales during storage under ambient conditions. AB - A comprehensive quantitative analysis of flavonoids, sugars, phenylalanine, and tryptophan have been carried out in different onion scales during storage at ambient temperature (20-23 degrees C) and relative humidity (60-80 %). Depending on the length of storage, dry matter content and composition shows variation inside the onion bulbs. Inner sprouts were observed on longitudinally cut bulbs after 2 months and visible sprouts appeared after 5 months of storage. The bulbs lost 20 to 30 % of their weight at the end of the storage. Higher dry matter content was observed in the inner scales. Significantly high content of quercetin in inner scales and high level of quercetin-3,4'-O-diglucoside and quercetin-4'-O monoglucoside in outer scales was observed during a 7 months storage. During storage period, high content of fructose and glucose was observed in the middle scales while sucrose was high in the inner scales. There was no particular trend observed within analyzed amino acids. However, the content of phenylalanine was higher than tryptophan. PMID- 25829597 TI - Physico-chemical properties of gelatin from bighead carp (Hypophthalmichthys nobilis) scales by ultrasound-assisted extraction. AB - In this study, gelatin was extracted from bighead carp (Hypophthalmichthys nobilis) scales by water bath (WB) and ultrasound bath (UB) at 60 degrees C for 1 h, 3 h and 5 h, named WB1, WB3, WB5, UB1, UB3 and UB5, respectively. The physicochemical properties of gelatin were investigated. The result indicated that gelatin extracted from bighead carp scales had a high protein content (84.15 ~ 91.85 %) with moisture (7.11 ~ 13.65 %), low ash content (0.31 ~ 0.97 %). All extracted gelatin contained alpha-and beta-chains as the predominant components. Gelatin extracted by UB obtained much higher yield (30.94-46.67 %) than that of WB (19.15-36.39 %). More voids and less sheets of gelatin structure were observed, when the gelatin was extracted by UB for longer time. Gelatin of UB assisted extraction normally exhibited lower gel strength and melting points than that of WB, which may be resulted from the protein degradation reflected by the FTIR spectra and higher free amino group content. However, there was no significant difference between WB1 and UB1. Therefore, the ultrasound assisted extraction in a short time was a promising method to enhance the yield and obtain gelatin with high quality. PMID- 25829598 TI - Nutritional composition, antinutritional factors, bioactive compounds and antioxidant activity of guava seeds (Psidium Myrtaceae) as affected by roasting processes. AB - The purpose of this study was to explore the influences of roasting process on the nutritional composition and nutritive value, antinutritional factors, bioactive compounds and antioxidant activity of guava seeds. Roasting process caused significant (P <= 0.05) decreases in moisture content, crude protein, crude fiber, ash and mineral contents, isoleucine, arginine, glutamic and total aromatic and sulfur amino acids, antinutritional factors (tannins and phytic acid) and flavonoids, while oil content increased. Subjecting guava seeds to 150 degrees C for 10, 15 and 20 min increased the total essential amino acids from 35.19 g/100 g protein in the raw sample to 36.96, 37.30 and 37.47 g/100 g protein in roasted samples, respectively. Protein efficiency ratio (PER) of guava seeds roasted at 150 degrees C for 10, 15 and 20 min were about 1.08, 1.14 and 1.18 times as high as that in unroasted seeds. Lysine was the first limiting amino acid, while leucine was the second limiting amino acid in raw and roasted guava seeds. Total phenolic contents was significantly (P <= 0.05) increased by roasting at 150 degrees C for 10 min. However, roasting at 150 degrees C for 15 and 20 min caused significant decrease in the phenolic content of guava seeds. Guava seeds subjected to roasting process showed higher DPPH radical scavenging and reducing power activities. PMID- 25829599 TI - Effect of nisin as a biopreservative agent on quality and shelf life of vacuum packaged rainbow trout (Oncorhynchus mykiss) stored at 4 degrees C. AB - Effect of nisin on biochemical and microbial quality and shelf life of vacuum packaged rainbow trout (Oncorhynchus mykiss) during 16 days storage at 4 degrees C was investigated. According to the obtained results, nisin treated fish showed lower (p < 0.05) and acceptable biochemical (Peroxide value, thiobarbituric acid index, pH, and total volatile base nitrogen) and bacteriological (total viable counts, psychrotrophic viable counts, and lactic acid bacteria) attributes up to 16 days storage at 4 degrees C compared with those treated without nisin. Furthermore, FAs composition analysis indicated that presence of the nisin preserved nutritional quality of fish lipid, so that nisin treated samples contained higher percentage (p > 0.05) of essential FAs such as eicosapentaenoic acid and docosahexaenoic acid. This study concluded that treatment of the vacuum packaged rainbow trout with nisin resulted in improvement of quality and extension of shelf life of the fish from 12 to 16 days at 4 degrees C. PMID- 25829600 TI - Cultivar characterization of stone fruits for their minimal processing. AB - Due to their physicochemical properties, minimal processing of fruits is challenging because of their quick quality loss. Therefore, several preservative steps are needed, such as washing treatments, modified atmosphere packaging, cultivar selection, etc. The latter is an important pre-harvest condition due to the fact that many functional compounds and enzymes are dependent on the cultivar. The aim of this study was to compare the minimal processing adaptation of different stone fruits (nectarine, peach, and plum), focusing on visual and functional quality. The fruit underwent minimal processing in a clean room (temperature and relative humidity were kept at 8 degrees C and 70 %, respectively) and was washed during 2 min into 2 % w/v ascorbic acid, 1 % w/v citric acid, and 1 % w/v calcium lactate solution. To sum up, nectarine and peach offered a better adaptation, and medium-season cultivars had higher quality maintenance. Nevertheless, late cultivars should not be ruled out before hand on account of their remarkable functional content. PMID- 25829601 TI - Optimization of beta-cyclodextrin-based flavonol extraction from apple pomace using response surface methodology. AB - The present study investigated five cyclodextrins (CDs) for the extraction of flavonols from apple pomace powder and optimized beta-CD based extraction of total flavonols using response surface methodology. A 2(3) central composite design with beta-CD concentration (0-5 g 100 mL(-1)), extraction temperature (20 72 degrees C), extraction time (6-48 h) and second-order quadratic model for the total flavonol yield (mg 100 g(-1) DM) was selected to generate the response surface curves. The optimal conditions obtained were: beta-CD concentration, 2.8 g 100 mL(-1); extraction temperature, 45 degrees C and extraction time, 25.6 h that predicted the extraction of 166.6 mg total flavonols 100 g(-1) DM. The predicted amount was comparable to the experimental amount of 151.5 mg total flavonols 100 g(-1) DM obtained from optimal beta-CD based parameters, thereby giving a low absolute error and adequacy of fitted model. In addition, the results from optimized extraction conditions showed values similar to those obtained through previously established solvent based sonication assisted flavonol extraction procedure. To the best of our knowledge, this is the first study to optimize aqueous beta-CD based flavonol extraction which presents an environmentally safe method for value-addition to under-utilized bio resources. PMID- 25829602 TI - Roller milling process for fractionation of fenugreek seeds (Trigonella foenumgraecum) and characterization of milled fractions. AB - The fenugreek seed is the richest source of soluble and insoluble fiber and also known for its medicinal and functional properties. The major objective of this present study is fractionation of the fenugreek by roller milling method and characterization of roller milled fractions. The effects of moisture conditioning on fenugreek roller milling were studied using standard methods. The results observed were increase in coarse husk from 33.75-42.46 % and decrease in flour yield from 49.52-41.62 % with increase in addition of moisture from 12-20 %. At 16 % conditioning moisture, the yield of coarse husk was 40.87 % with dietary fiber and protein content of 73.4 % and 6.96 % respectively. The yellowness value (b) for the coarse husk (29.68) found to be lowest at 16 % conditioning moisture compared to the other coarse husk samples, showing maximum clean separation. The fiber fractions showed the viscosity of 6,392 cps at 2 % w/v concentration. The flour fraction was higher in protein (41.83 %) and fat (13.22 %) content. Roller milling process of fenugreek was able to produce > 40 % of coarse husk with 73.4 % dietary fiber (25.56 % soluble & 47.84 % insoluble) and > 48 % flour with 41.83 % protein content, where as the whole fenugreek contained 22.5 % protein & 51.25 % dietary fiber. Thus roller milling has proved to be a valuable method for the fractionation of fenugreek to obtain fiber and protein rich fractions. PMID- 25829603 TI - Efficacy of Angelica archangelica essential oil, phenyl ethyl alcohol and alpha- terpineol against isolated molds from walnut and their antiaflatoxigenic and antioxidant activity. AB - Mold association, aflatoxin B1 contamination as well as oxidative deterioration of agri-food items during storage and processing are some global task for food industries. In view of the adverse effects of some synthetic preservatives on treated food items and subsequently on consumers health, recently plant based chemicals are encouraged by food industries as better alternatives of synthetics. The present study recommends the combination (1:1:1) of Angelica archangelica essential oil: Phenyl ethyl alcohol (PEA): alpha- terpineol as botanical preservative against molds, aflatoxin contamination and oxidative deterioration of walnut samples. Eight mold species were procured from stored walnut samples, including some aflatoxigenic Aspergillus flavus strains. The combination inhibited growth of aflatoxigenic strain Aspergillus flavus NKDW-7 and aflatoxin B1 production at 2.25 and 2.0 MUL mL(-1) respectively. The IC50 value of the combination was recorded as 3.89 MUL mL(-1), showing strong antioxidant potential. The antifungal action of the combination showed > 90 % decrease in ergosterol content in plasma membrane of A. flavus at 2.0 MUL mL(-1). The LD50 of the combination, through oral administration on mice, was 9562.9 MUL kg(-1) body weight, indication favourable safety profile as a plant based preservative. The combination may be recommended as safe preservative against molds, aflatoxin contamination and oxidative deterioration of walnut samples. PMID- 25829604 TI - In vitro and in vivo activity of essential oils against major postharvest pathogens of Kinnow (Citrus nobilis * C. deliciosa) mandarin. AB - The present study envisages the influence of essential oils namely lemon grass, eucalyptus, clove and neem on Kinnow mandarin with the objective to combat major post harvest diseases and to prolong its availability for longer time in the season. For this, in vitro and in vivo studies were conducted. Poisoned food technique was used for in vitro studies, and for in vivo studies, Kinnow fruit were pre-inoculated with pathogens (Penicillium digitatum and P. italicum), treated with different essential oils and then stored at 5 degrees C +/-1 degrees C temperature and 85-90 % RH). Our results indicated that all essential oils inhibited the growth (colony diameter) of both pathogens over untreated PDA plates, but the inhibition was the strongest by lemon grass oil. Similarly, under in vivo conditions, all essential oils influenced decay incidence, decay loss, lesion diameter, respiration rate, ethylene evolution, overall acceptability and physiological loss in weight but lemon grass was the most effective. And also the incidence of Penicillium italicum was more noticed in fruits than P. digitatum, however, it was reverse under in vitro conditions. The decay rot at all stages of storage was less in EOs treated fruits than untreated fruits, thereby increasing their storage life significantly. Thus, it is evident from our studies that essential oils have the potential to control green and blue mold without causing any injury or harmful effects on Kinnow mandarin, and EOs can be recommended as a safe method for extending its storage life while maintaining fruit quality. PMID- 25829605 TI - Effect of antioxidant tertiary butyl hydroquinone on the thermal and oxidative stability of sesame oil (sesamum indicum) by ultrasonic studies. AB - The aim of the current investigation is to evaluate the efficiency of tertiary butyl hydroquinone (TBHQ) as an antioxidant in sesame oil (sesamum indicum) by density, viscosity and ultrasonic velocity. The effects of varying amounts of TBHQ on the oxidation stability of sesame oil have been investigated. The antioxidant incorporated sesame oil system and control edible oil were subjected to heating at 180 +/- 5 degrees C continuously for a period of 4 h per day for consecutive 4 days. The parameters used to assess the thermal degradation and oxidation properties of the oils include ultrasonic velocity, viscosity, density and peroxide value. The fatty acid compositions of the oils were measured by gas chromatography. Adiabatic compressibility, intermolecular free length, relaxation time and acoustic impedance have been calculated from experimental data. Viscosity, density and ultrasonic velocity change in control oil is from 3.6553 * 10(-2) to 11.1729 * 10(-2) Nsm(-2), 912.59 to 940.31 kg/m(3) and 1,421 to 1,452 m/s respectively and in sesame oil with 200 ppm TBHQ is from 3.6793 * 10(-2) to 6.4842 * 10(-2) Nsm(-2), 913.78 to 922.45 kg/m(3) and 1,421 to 1,431 m/s respectively for 16 h of heat treated oil. The ultrasonic results obtained have shown reduction in thermal degradation and improvement in oxidation stability of antioxidant loaded oil in comparison to base oil. Hence, it can be recommended that sesame oil with 200 ppm TBHQ can be used for frying without adverse effect on physical properties. The ultrasonic velocity can be used for assessment of stability of frying oil. PMID- 25829606 TI - Effects of different postharvest treatments on the physiology and quality of 'Xiaobai' apricots at room temperature. AB - The effect of postharvest treatments on storage characteristics of harvested apricots in relation to fruit quality was investigated. 'Xiaobai' apricots treated with 1-methylcyclopropene (1-MCP), chlorine dioxide (ClO2), calcium, and heat in sealed container and then stored at 20 degrees C with 90 % relative humidity (RH) for 10 days. Results showed that the treatments could reduce respiration production and MDA content, delay softening, postharvest decay, the decrease of soluble solids (SSC), and visual changes. Furthermore, the polyphenol oxidase (PPO), polygalacturonase (PG), and pectin methylesterase (PME), superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) activities were reduced by treatments. Taken together, it is suggested that ClO2 treatment might be an effective way to maintain the quality of apricot fruit except 1-MCP treatment. PMID- 25829607 TI - Organoleptic and glycemic properties of chickpea-wheat composite breads. AB - Prevalence of obesity and type-2-diabetes requires dietary manipulation. It was hypothesized that wheat-legume-composite breads will reduce the spike of blood glucose and increase satiety. Four pan bread samples were prepared: White bread (WB) as standard, Whole-wheat bread (WWB), WWB supplemented with chickpea flour at 25 % (25%ChB) and 35 % (35%ChB) levels. These breads were tested in healthy female subjects for acceptability and for effect on appetite, blood glucose, and physical discomfort in digestion. The breads were rated >5.6 on a 9-point hedonic scale with WB significantly higher than all other breads. No difference in area under the curve (AUC) for appetite was found, but blood glucose AUC was reduced as follows: 35%ChB < WB and WWB, WB >25%ChB = WWB or 35%ChB. We conclude that addition of chickpea flour at 35 % to whole wheat produces a bread that is acceptable to eat, causing no physical discomfort and lowers the glycemic response. PMID- 25829608 TI - Effect of different alkali treatments on the chemical composition, physical properties, and microstructure of pidan white. AB - Changes in chemical composition, physical property and microstructure of pidan white treated with 4.5 % NaOH or 5.5 % KOH were monitored during pickling up to 4 weeks, and followed by aging for another 2 weeks. As the pickling and ageing times increased, moisture content of pidan white decreased and salt content increased for both (4.5 % NaOH and 5.5 % KOH) treatments (P < 0.05). Free alkalinity and pH of pidan white treated with 4.5 % NaOH increased as pickling proceeded, but decreased during ageing for both pickling treatments (P < 0.05). At week 4 of pickling, pidan white treated with 5.5 % KOH had higher hardness, cohesiveness, gumminess and chewiness than those treated with 4.5 % NaOH. After ageing, higher springiness, elastic modulus (G') and viscous modulus (G") were generally found in pidan white treated with 5.5 % KOH (P < 0.05). As the pickling time increased, lower L*, b* values and higher a* value were observed in pidan white from both treatments (P < 0.05). As visualized by scanning electron microscope, the aggregation of egg proteins took place in pidan white gels, irrespective of pickling treatments used. Nevertheless, closer and more orderly protein aggregates with denser network were founded in pidan white treated with 5.5 % KOH. PMID- 25829609 TI - Antimicrobial activity of turmeric extract and its potential use in food industry. AB - The present study investigates the antimicrobial and preservative potentials of turmeric extracts for food industry. Turmeric extracts prepared in n-hexane, water, chloroform and ethanol were applied to meals as preservatives and antibacterial agent. The samples were assessed microbiologically (total bacterial, total fungal and total coliform counts) and organoleptically (color, odor, taste) at day zero and after 15 days intervals. Meals autoclaved for shorter time (5 min) and treated with combination of 1 % or 2 % turmeric extract preserved for longer period. These results were comparable with samples autoclaved for longer period (15 min) with out turmeric extract. The antibacterial activities of different turmeric extracts were also tested against Escherichia coli, Staphylococcus aureus, Salmonella typhi and Candida albicans by disc diffusion method. Water extracted samples of turmeric stored at room temperature inhibited the growth of Escherichia coli and Salmonella typhi while aqueous extract autoclaved at 121 degrees C for 30 min reduced the growth of Escherichia coli and Staphylococcus aureus. Methanol extracted samples stored at room temperature or autoclaved at 121 degrees C was effective to control the growth of all microbes under study. Chloroform and n-hexane extracts (stored at room temperature) showed weak activity against all tested microbes. PMID- 25829610 TI - Evolution of antioxidants in dietary fiber powder produced from white cabbage outer leaves: effects of blanching and drying methods. AB - White cabbage outer leaves, which are usually discarded both during industrial processing and selling in a consumer market, have proven to be a good source of dietary fiber (DF) as well as antioxidants and can be effectively transformed into functional DF powder. In the past, however, only hot air drying was used to prepare DF powder from cabbage outer leaves although it is well recognized that this drying technique could lead to much quality degradation of a dried product. This work was therefore aimed at studying the evolution of selected important antioxidants, e.g., phenolic compounds and vitamin C, in white cabbage outer leaves during vacuum drying at 60, 70 and 80 degrees C. The effect of pretreatment viz. steam blanching was also evaluated. The results showed that there were losses of antioxidants during steam blanching; vacuum dried blanched leaves nevertheless contained higher antioxidant contents and activity than dried unblanched leaves. Losses of antioxidants during vacuum drying were also noted to be less than those during hot air drying. Overall, the results showed that there were no differences in the antioxidants retention among all the tested conditions performed in this study. Therefore, the most suitable condition for the production of antioxidant DF powder from cabbage outer leaves is vacuum drying at 80 degrees C as this condition requires the minimum specific energy consumption. PMID- 25829611 TI - Quality characteristics of low fat chicken nuggets: effect of salt substitute blend and pea hull flour. AB - Effect of salt substitution (Treat I) and added pea hull flour (PHF) at 8 (Treat II), 10 (Treat-III) and 12 % (Treat-IV) levels on the quality of low fat chicken nuggets (Control) was investigated. Replacement of NaCl significantly affected (P < 0.05) emulsion and product pH, emulsion stability, cooking yield, ash content while PHF had additional effect on moisture and protein. Dietary fibre content in the product significantly (P < 0.05) increased at each level of PHF. The colour parameters remained similar to control due to salt replacement while added PHF decreased their values. Textural properties were lower (P < 0.05) in the treated products. Addition of PHF significantly (P < 0.05) decreased cholesterol and glycolipids contents at 8 % and 12 % levels, respectively. Sensory evaluation exhibited that 40 % NaCl can efficiently be replaced and 8 % PHF can be incorporated as a source of fibre in low fat chicken nuggets without significant effect on various attributes. PMID- 25829612 TI - Standardization of Fat:SNF ratio of milk and addition of sprouted wheat fada (semolina) for the manufacture of halvasan. AB - Traditional Indian Dairy Products such as Halvasan are manufactured in India using an age old practice. For manufacture of such products industrially, a standard formulation is required. Halvasan is a region specific, very popular heat desiccated milk product but has not been studied scientifically. Fat and Solids-not-fat (SNF) plays an important role in physico-chemical, sensory, textural characteristics and also the shelf life of any milk sweet. Hence for process standardization of Halvasan manufacture, different levels of Fat:SNF ratios i.e. 0.44, 0.55, 0.66 and 0.77 of milk were studied so that an optimum level yielding best organoleptic characteristics in final product can be selected. The product was made from milk standardized to these ratios of Fat:SNF and the product was manufactured as per the method tentatively employed on the basis of characterization of market samples of the product in laboratory. Based on the sensory results obtained, a Fat:SNF ratio of 0.66 for the milk has been selected. In the similar way, for standardizing the rate of addition of fada (semolina); 30, 40, 50 and 60 g fada (semolina) per kg of milk were added and based on the sensory observations, the level of fada (semolina) addition @50 gm/kg of milk was adjudged the best for Halvasan manufacture and hence selected. PMID- 25829613 TI - Influence of drying temperature on dietary fibre, rehydration properties, texture and microstructure of Cape gooseberry (Physalis peruviana L.). AB - The effects of air drying temperature on dietary fibre, texture and microstructure of the Cape gooseberry fruits during convective dehydration in the range of 50-90 oC were investigated. The ratio of insoluble dietary fibre to soluble dietary fibre was higher than 7:1 for all dehydrated samples. At 50 oC tissue structure damage was evidenced leading to the maximum water holding capacity (47.4 +/- 2.8 g retained water/100 g water) and the lowest rehydration ratio (1.15 +/- 0.06 g absorbed water/g d.m.). Texture analysis showed effects of drying temperatures on TPA parameters. Changes in microstructure tissue were also observed at the studied drying temperatures. Hot air drying technology leads not only to fruit preservation but also increases and adds value to Cape gooseberry, an asset to develop new functional products. PMID- 25829614 TI - Comparative evaluation of antioxidant and insecticidal properties of essential oils from five Moroccan aromatic herbs. AB - This study describes the antioxidant and insecticidal activities of essential oils (EOs) of Mentha suaveolens subsp. timija, Thymus satureioides, Achillea ageratum, Cotula cinerea and Salvia officinalis widely used in Morocco as flavorings, food additives and preservatives. Sixty seven components were identified accounting for more than 95.0 % of the total oils. M. suaveolens subsp. timija oil had as main components menthone and pulegone. A. ageratum oil was particularly rich in artemisyl acetate and yomogi alcohol. The essential oil of T. satureioides was characterized by high contents of carvacrol and borneol. C. cinerea oil contained trans-thujone and cis-verbenyl acetate as major constituents, whereas S. officinalis oil was characterized by trans-thujone and camphor. Antioxidant activities were examined by means of 2,2-diphenyl-1 picrylhydrazyl radical (DPPH), reducing power, beta-carotene/linoleic acid bleaching and ABTS radical tests. In all assays, the highest antioxidant potency was observed in T. satureioides EO with IC50 values ranging from 0.15 +/- 0.36 MUg mL(-1) to 0.23 +/- 0.67 MUg mL(-1) across the four assays. The in vitro evaluation of the insecticidal activity showed that M. suaveolens subsp. timija EO present the highest insecticidal efficiency against adults of Tribolium castaneum with LD50 and LD90 values of 0.17 MUL cm(-2) and 0.26 MUL cm(-2), respectively and LT50, LT90 values ranged from 44.19 h to 2.98 h and 98.14 h to 6.02 h, respectively. Our data support the possible use of T. satureioides oil as potential antioxidant agent, while M. suaveolens subsp. timija oil can be developed as a new natural bio-insecticide. PMID- 25829615 TI - Physical and chemical characteristics of goldenberry fruit (Physalis peruviana L.). AB - Some physical and chemical characteristics of goldenberry fruit (Physalis peruviana L.) were investigated. These characteristics are necessary for the design of equipments for harvesting, processing, transportation, sorting, separating and packing. The fruit length, diameter, geometric and arithmetic mean diameters, sphericity, surface area, projected areas (vertical-horizontal) and aspect ratio of goldenberries were determined as 17.52 mm, 17.31 mm, 17.33 mm, 17.38 mm, 98.9 %, 0.949 cm(2), 388.67-387.85 mm(2) and 0.988, respectively. The mass of fruit, bulk density, fruit density, porosity and fruit hardness were 3.091 g, 997.3 kg/m(3), 462.3 kg/m(3), 53.61 % and 8.01 N, respectively. The highest static coefficient of friction was observed on rubber surface, followed by stainless steel sheet, aluminum sheet, and plywood materials. The dry matter, water soluble dry matter, ash, protein, oil, carbohydrate, titratable acidity, pH, total sugar, reducing sugar, antioxidant capacity were 18.67 %, 14.17 %, 2.98 %, 1.66 %, 0.18 %, 13.86 %, 1.26 %, 6.07, 63.90 g/kg, 31.99 g/kg and 57.67 %, respectively. The fresh fruits have 145.22 mg gallic acid equivalent (GAE)/100 g total phenol content and skin colour data represented as L*, a*, b*, Chroma (C) and Hue angle (alpha) were 49.92, 25.11, 50.23, 56.12 and 63.48, respectively. PMID- 25829616 TI - Antioxidant, DNA protective efficacy and HPLC analysis of Annona muricata (soursop) extracts. AB - Annona muricata is a naturally occurring edible plant with wide array of therapeutic potentials. In India, it has a long history of traditional use in treating various ailments. The present investigation was carried out to characterize the phytochemicals present in the methanolic and aqueous leaf extracts of A. muricata, followed by validation of its radical scavenging and DNA protection activities. The extracts were also analyzed for its total phenolic contents and subjected to HPLC analysis to determine its active metabolites. The radical scavenging activities were premeditated by various complementary assays (DRSA, FRAP and HRSA). Further, its DNA protection efficacy against H2O2 induced toxicity was evaluated using pBR322 plasmid DNA. The results revealed that the extracts were highly rich in various phytochemicals including luteolin, homoorientin, tangeretin, quercetin, daidzein, epicatechin gallate, emodin and coumaric acid. Both the extracts showed significant (p < 0.05) radical scavenging activities, while methanolic extract demonstrated improved protection against H2O2-induced DNA damage when compared to aqueous extract. A strong positive correlation was observed for the estimated total phenolic contents and radical scavenging potentials of the extracts. Further HPLC analysis of the phyto constituents of the extracts provides a sound scientific basis for compound isolation. PMID- 25829617 TI - Optimization of the extraction of total flavonoids from Scutellaria baicalensis Georgi using the response surface methodology. AB - The response surface methodology (RSM) was used to optimize the conditions for total flavonoid extraction from Scutellaria baicalensis Georgi. The influences of the ethanol concentration, extraction time, temperature, and the liquid-solid ratio on flavonoid yield were investigated. Based on ANOVA results, a second order quadratic polynomial model could be applied to characterize the extraction process. The following optimal extraction conditions were identified: ethanol concentration, 52.98 %; extraction time, 2.12 h; extraction temperature, 62.46 degrees C; and liquid-solid ratio, 35.23. The predicted extraction yield was 19.437 mg/g when these optimal conditions were used. The proposed method was successfully employed to extract flavonoids from S. baicalensis. PMID- 25829618 TI - Characterization of collagen from emu (Dromaius novaehollandiae) skins. AB - Collagen from emu skins as a by-product was prepared. The skins were hardly solubilized in acetic acid, however were successfully solubilized on digestion with 10 % pepsin (w/w) for 4 days. The yield of pepsin-solubilized collagen (PSC) was about 27.3 %, on a raw weight basis. By SDS-PAGE and CM-Toyopearl 650 M column chromatography, the presence of a fourth subunit that was previously designated alpha4 was confirmed. The denaturation temperature of the PSC was 31.5 degrees C, about 6-7 degrees C lower than that from the porcine skins. ATR-FTIR analysis indicated that the helical arrangements of the PSC from emu skins existed and its structures of PSC were changed slightly due to the loss of N- and C-terminus domains in similar to that from the porcine skins. That is, the PSC from emu skins did not possess telopeptide chains as major portion of antigenic sites in collagen. The present study indicates that a large quantity of emu skins as by-products have potential as a good alternative source of high-quality collagen for industrial purposes in the foods, cosmetics, and pharmaceutical and biomedical fields. PMID- 25829619 TI - Zinc enrichment of whole potato tuber by vacuum impregnation. AB - Zinc is a nutritionally essential truce element, and thus zinc deficiency (ZD) severely affects human health. More than 25% of the world's population is at risk of ZD. This study was initiated to examine the use of the vacuum impregnation (VI) technique for enriching zinc content of whole potatoes; the effect of vacuum time, restoration time, steam-cooking and storage at 4 degrees C on the zinc content of VI whole potatoes was evaluated. Whole potato tubers were immersed in a 9 g/100 g zinc (zinc gluconate) solution. Vacuum pressure of 1,000 Pa was applied for 0-120 min, and atmospheric pressure restoration for 0-4 h. Experimental results showed that the zinc content of VI potatoes increased with vacuum and restoration time. Moreover, VI-cooked unpeeled or peeled potatoes had 63-94 times and 47-75 times higher zinc contents than un-VI-cooked unpeeled or peeled potatoes, respectively. The world daily potato consumption (86 g) of the VI-cooked unpeeled and peeled potatoes provided adult men with 130-148% and 100 135% of the recommended daily allowance (RDA) of zinc, respectively. Also, the daily potato consumption of the unpeeled and peeled potatoes supplied adult women with 178-203% and 137-185% of the RDA level, respectively. In addition, the VI potatoes had 40 times higher zinc contents through 30 days of storage at 4 degrees C, compared with un-VI-treated potatoes. This study indicated that VI treatment of whole potatoes was useful for enriching the zinc content. PMID- 25829620 TI - Effect of spinach powder on physico-chemical, rheological, nutritional and sensory characteristics of chapati premixes. AB - Effect of spinach powder on the physico-chemical, rheological, nutritional and sensory characteristics on chapati premixes was studied by incorporating spinach powder at different concentrations from 1 % to 10 % based on wheat flour. Addition of 5 % of spinach powder to wheat flour was found to be optimum for chapati preparation. Effect of incorporation of spinach powder on the alveo consistographic, mixographic and pasting characteristics were studied. It was observed that peak viscosity, breakdown viscosity significantly decreases whereas, peak time, tenacity increases with the increase in the concentration of spinach powder from 1 % to 10 % in chapati premixes. Addition of spinach powder also significantly affects the textural qualities of the chapaties. Premixes and prepared chapaties were also studied for chlorophyll content, total carotenoids,vitamins and minerals. PMID- 25829621 TI - Gum cordia as carrier of antioxidants: effects on lipid oxidation of peanuts. AB - Performance of antioxidants is improved by incorporating them into polymer matrix such as polysaccharides based edible coatings. Gum cordia, an anionic polysaccharide extracted from the fruits of Cordia.myxa could be used as carrier of antioxidants by virtue of its strong adhering and emulsifying properties. This study aimed to explore the potential of gum cordia as carrier of antioxidants when applied as edible coating on peanuts. Gum Cordia was compared with carboxymethyl cellulose (CMC) in delivering of antioxidants: butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and ascorbic acid (AA). Coated and uncoated peanuts were stored at 35 degrees C for 126 days and coating carrier effectiveness was measured by following lipid oxidation using chemical parameters (peroxide value and thiobarbituric acid reactive species) and sensory evaluation (oxidized flavor). Significant differences (p < 0.05) between coated and uncoated samples were observed. Gum cordia was found better than CMC to deliver the antioxidants. Gum cordia based coating in combination with BHA/BHT exhibited highest protection (290 % higher shelf life than control) based on peroxide value (40 meq.O2 kg(-1)) followed by gum codia plus BHT (244 %), gum cordia plus BHA (232 %), CMC plus BHA/BHT (184 %), CMC plus BHA (139 %), CMC plus BHT (119 %), gum cordia plus AA (96 %) and CMC plus AA (46 %). PMID- 25829622 TI - Aspartame: safety and stability in kalakand. AB - Aspartame was used in the manufacture of kalakand instead of sucrose. Sensory evaluation revealed that aspartame when used in the preparation of kalakand at a level of 0.065 % scored the highest in terms of sweetness perception and resembled control. Aspartame sweetened kalakand possessed the same desirable sweetness, colour, body and texture/consistency and mouthfeel even after 7 days of storage at 6-8 degrees C. Significant increase in titratable acidity of control as well as aspartame sweetened kalakand was observed during storage. However, only a slight drop in pH was observed in all samples on storage. The titratable acidity was higher in aspartame sweetened products than the corresponding control samples. Lightness (L*) was less in control samples with sucrose than the aspartame sweetened kalakand during storage. Total plate counts were higher in aspartame sweetened kalakand than its corresponding control throughout the storage period. Total plate counts increased linearly for both aspartame sweetened kalakand and control. A solid phase extraction method was standardized for the isolation of aspartame in kalakand. HPLC analytical conditions were standardized for separation of aspartame and its degradation products diketopiperazine and L-phenylalanine. HPLC analysis revealed that aspartame did not degrade in kalakand during storage establishing its stability in these products. PMID- 25829623 TI - Effect of temperature and relative humidity on the water vapour permeability and mechanical properties of cassava starch and soy protein concentrate based edible films. AB - The effect of temperature and relative humidity on the water vapour permeability (WVP) and mechanical properties of cassava starch and soy protein concentrate (SPC) based edible films containing 20 % glycerol level were studied. Tensile strength and elastic modulus of edible films increased with increase in temperature and decreased with increase in relative humidity, while elongation at break decreased. Water vapour permeability of the films increased (2.6-4.3 g.mm/m(2).day.kPa) with increase in temperature and relative humidity. The temperature dependence of water vapour permeation of cassava starch-soy protein concentrate films followed Arrhenius relationship. Activation energy (Ea) of water vapour permeation of cassava starch-soy protein concentrate edible films ranged from 1.9 to 5.3 kJ/mol (R (2) >= 0.93) and increased with increase in SPC addition. The Ea values were lower for the bio-films than for polyvinylidene chloride, polypropylene and polyethylene which are an indication of low water vapour permeability of the developed biofilms compared to those synthetic films. PMID- 25829624 TI - Antioxidant and antibacterial activity of Rhoeo spathacea (Swartz) Stearn leaves. AB - The decoction and infusion of Rhoeo spathacea (Swartz) Stearn leaves have been recognized as a functional food particularly in South America, but has not yet gained international popularity as a beverage. The primary aim of this study was to establish the viability of R. spathacea aqueous leaf extracts as a beverage, in terms of its antioxidant activity and antibacterial activity. The antioxidant contents of aqueous and methanol leaf extracts were evaluated by the total phenolic content (TPC) and total flavonoid content (TFC) assays. The antioxidant activities measured were DPPH radical scavenging activity (FRS), ferric reducing power (FRP) and ferrous ion chelating (FIC) activity. The aqueous leaf extracts in the forms of decoction and infusion, were found to have comparable TPC and antioxidant activity with other herbal teas previously reported by our research group. Both decoction and infusion also exhibited antibacterial activity against six species of Gram positive and four species of Gram negative bacteria, notably methicillin-resistant Staphylococcus aureus and Neisseria gonorrhoeae. A total of four different known phenolic compounds were identified by HPLC and MS, three of which have not been previously reported to be found in this plant. Both the decoction and infusion of the leaves R. spathacea have potential to be popularized into a common beverage. PMID- 25829625 TI - Potential utilization of Citrullus lanatus var. Colocynthoides waste as a novel source of pectin. AB - The Citrullus lanatus var. Colocynthoides is an ancestor type of watermelon. It was investigated as a new source of pectin. It was cultivated in Egypt for seeds only, while the remaining fruits are discarded as waste. Effect of different extraction conditions such as pH, solid: liquid ratio, temperature and extraction time on pectin yield of Citrullus lanatus var. Colocynthoides waste was investigated in the present study. The highest yield (19.75 % w/w) was achieved at pH 2, solid: liquid ratio1:15 and 85 degrees C, for 60 min. Methylation degree and galacturonic acid content of extracted pectin were 55.25 %, w/w and 76.84 %, w/w. The main neutral sugars were galactose followed by arabinose and rhamnose. In addition, glucose, xylose and mannose existed as constituents in the pectin hydrolysate. The results indicated that Citrullus lanatus var. Colocynthoide waste is a potential new source of pectin. PMID- 25829626 TI - Assessment of transesterified palm olein and Moringa oleifera oil blends as vanaspati substitutes. AB - This study aimed to investigate the suitability of Moringa oleifera oil and palm olein blends as vanaspati substitutes on the basis of physico-chemical and sensory characteristics. Blends were prepared either by blending Moringa oleifera oil or palm olein at 25:75, 50:50, 75:25, and 100 ratios, transesterified by Rhizopus miehei, compared with market vanaspati, designated as T1, T2, T3, T4 and T5, respectively. The blends were filled in 3-layer polyethylene pouch packs, stored at ambient temperature, sampled at every at 0, 90 and 180-days for the assessment of storage stability. The melting point and iodine value of T2 and control were 36.8, 37.2 degrees C and 62.2, 51.8, with no effect on free fatty acids content, peroxide, anisidine values and color of the deodorized stuffs. C18:1 content of T2 was 59.7 % with no trans fatty acids. Trans fatty acid content of the market vanaspati was 22.9 %. The addition of Moringa oleifera oil improved the induction period of the blends strongly inhibited the formation of primary and secondary oxidation products. The overall acceptability score of French fries prepared in T2 was 81 % of the total score (9). Blend containing 50 % palm olein and 50 % Moringa oleifera oil can be used in the formulation of a functional shelf stable fat that can be used as a vanaspati substitute. PMID- 25829627 TI - Single step aqueous two-phase extraction for downstream processing of C phycocyanin from Spirulina platensis. AB - C-phycocyanin, a natural food colorant, is gaining importance worldwide due to its several medical and pharmaceutical applications. In the present study, aqueous two-phase extraction was shown to be an attractive alternative for the downstream processing of C-phycocyanin from Spirulina platensis. By employing differential partitioning, C-phycocyanin selectively partitioned to the polymer rich (top) phase in concentrated form and contaminant proteins to the salt rich (bottom) phase. This resulted in an increase in the product purity (without losing much of the yield) in a single step without the need of multiple processing steps. Effect of process parameters such as molecular weight, tie line length, phase volume ratio, concentration of phase components on the partitioning behavior of C-phycocyanin was studied. The results were explained based on relative free volume of the phase systems. C-phycocyanin with a purity of 4.32 and yield of about 79 % was obtained at the standardized conditions. PMID- 25829628 TI - Choice of solvent extraction technique affects fatty acid composition of pistachio (Pistacia vera L.) oil. AB - Pistachio (Pistacia vera L.) oil has important nutritional and therapeutic properties because of its high concentration of essential fatty acids. The extraction method used to obtain natural compounds from raw material is critical for product quality, in particular to protect nutritional value. This study compared the fatty acid composition of pistachio oil extracted by two conventional procedures, Soxhlet extraction and maceration, analyzed by a gas chromatography-flame ionization detector (GC-FID). Four solvents with different polarities were tested: n-hexane (Hx), dichloromethane (DCM), ethyl acetate (EtAc) and ethanol (EtOH). The highest unsaturated fatty acid content (88.493 %) was obtained by Soxhlet extraction with EtAc. The Soxhlet method extracted the most oleic and linolenic acids (51.99 % and 0.385 %, respectively) although a higher concentration (36.32 %) of linoleic acid was extracted by maceration. PMID- 25829629 TI - Proteolytic and ACE-inhibitory activities of probiotic yogurt containing non viable bacteria as affected by different levels of fat, inulin and starter culture. AB - In this study, the effects of fat (0.5 %, 3.2 % and 5.0 %), inulin (0.0 and 1.0 %) and starter culture (0.0 %, 0.5 %, 1.0 % and 1.5 %) on the angiotensin converting enzyme (ACE)-inhibitory activity of probiotic yogurt containing non viable bacteria were assessed. Proteolytic activities of bacteria were also investigated. Yogurts were prepared either using a sole yogurt commercial culture including Streptococcus thermophilus and Lactobacillus delbrueckii subs. bulgaricus or bifidobacterium animalis BB-12 and Lactobacillus acidophilus La5 in addition to yogurt culture. Relative degrees of proteolysis were found to be considerably higher in yogurt samples than UHT milk as the control. Both regular and probiotic yogurts showed considerable ACE-inhibitory activities. Results showed that degree of proteolysis was not influenced by different fat contents, while was increased by high concentration of starter culture (1.5 % w/w) and reduced by inulin (1 % w/w). ACE-inhibitory activities of yogurt were also negatively affected by the presence of inulin and high levels of fat (5 % w/w). Moreover, yogurt containing probiotic bacteria showed higher inhibitory against ACE in comparison to the yogurt prepared with non-probiotic strains. PMID- 25829630 TI - A validated dispersive liquid-liquid microextraction method for extraction of ochratoxin A from raisin samples. AB - A method based on dispersive liquid-liquid microextraction (DLLME) was developed for the quantitative extraction of Ochratoxin A (OTA) from raisin samples. The influence of various parameters on the recovery of OTA such as type and volume of DLLME extractant, centrifuging and sonication time, also volume of deionized water was investigated. Recovery values under the optimum conditions were between 68.6 and 85.2 %, the inner and intra-day precision expressed as relative standard deviation (RSD%, n = 3), were less than 15 % at spiking levels of 2.5-30 MUg kg( 1). Linearity was studied from 0.5 to 30 MUg L(-1), and the limits of detection (LOD) and quantification (LOQ) were 0.7 and 2.0 MUg kg(-1), respectively. Real samples were analyzed by DLLME method and compared with confirmative immunoaffinity Column Chromatography (IAC) clean-up. Low cost, simplicity of operation, speed and minimum consumption of organic solvent were the main advantages of proposed method. The mean contamination of samples was 0.88 MUg kg( 1) that was lower than European Legal Limit. PMID- 25829631 TI - Antimicrobial activities of active component isolated from Lawsonia inermis leaves and structure-activity relationships of its analogues against food-borne bacteria. AB - The antimicrobial activities of Lawsonia inermis leaf extract and 2-hydroxy-1,4 naphthoquinone analogues against food-borne bacteria. The antimicrobial activities of five fractions derived from the methanol extract of Lawsonia inermis leaves were evaluated against 7 food-borne bacteria. 2-Hydroxy-1,4 naphthoquinone was isolated by chromatographic analyses. 2-Hydroxy-1,4 naphthoquinone showed the strong activities against Bacillus cereus, Listeria monocytogenes, Salmonella enterica, Shigella sonnei, Staphylococcus epidermidis, and S. intermedius, but exerted no growth-inhibitory activities against S. typhimurium. The antimicrobial activities of the 2-hydroxy-1,4-naphthoquinone analogues were tested against 7 food-borne bacteria to establish structure activity relationships. Hydroxyl (2-hydroxy-1,4-naphthoquinone and 5-hydroxy-1,4 naphthoquinone), methoxy (2-methoxy-1,4-naphthoquinone), and methyl (2-methyl-1,4 naphthoquinone, and 5-hydroxy-2-methyl-1,4-naphthoquinone) functional groups on the 1,4-naphthoquinone skeleton possessed potent activities, whereas bromo (2 bromo-1,4-naphthoquinone and 2,3-dibromo-1,4-naphthoquione) and chloro (2,3 dichloro-1,4-naphthoquinone) exhibited no activity against 7 food-borne bacteria. The L. inermis leaf extract and 2-hydroxy-1,4-naphthoquinone analogues should be useful as natural antimicrobial agents against food-borne bacteria. PMID- 25829632 TI - Comparison of essential oil composition and antimicrobial activity of Coriandrum sativum L. extracted by hydrodistillation and microwave-assisted hydrodistillation. AB - Coriander (Coriandrum sativum L.), is an annual herb in the Apiaceae family which disperses in Mediterranean and Middle Eastern regions. The Coriander essential oil has been used in food products, perfumes, cosmetics and pharmaceutical industries for its flavor and odor. In Iran, fruits of Coriander used in pickle, curry powders, sausages, cakes, pastries, biscuits and buns. The aim of this study was to investigate microwave radiation effects on quality, quantity and antimicrobial activity of essential oil of Coriander fruits. The essential oils were obtained from the Coriander fruits by hydrodistillation (HD) and Microwave assisted hydrodistillation (MAHD) then, the oils were analyzed by GC and GC-MS. Antimicrobial activities of essential oils were evaluated against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans by microdilution method. The results indicated that the HD and MAHD essential oils (EO) were dominated by monoterpenoids such as linalool, geranyl acetate and gamma terpinene. The major compound in both EO was linalool which its amount in HD and MAHD was 63 % and 66 %, respectively. The total amount of monoterpenes hydrocarbons in HD EO differ significantly with the amount in MAHD EO (12.56 % compare to 1.82 %). HD EO showed greater activity against Staphylococcus aureus and Candida albicans than MAHD EO. Moreover, their activities against Ecoli and P. aeruginosa were the same with Minimum Inhibitory Concentration (MIC) 0.781 and 6.25 MUL mL(-1), respectively. By using MAHD method, it was superior in terms of saving energy and extraction time, although the oil yield and total composition decrease by using this method. PMID- 25829633 TI - Relationships between antioxidant compounds and antioxidant activities of tartary buckwheat during germination. AB - Relationships of changes between major non-enzymatic antioxidant compounds and antioxidant capacities of tartary buckwheat during germination were evaluated by means of correlation analysis and principal component analysis in this paper. The changes of antioxidant compounds, including vitamin C, vitamin E, flavonoids, carotenoids, and chlorophyll, and antioxidant activities were detected. A good accumulation in the content of vitamin C (0.71 mg/g), total flavonoids (19.53 mg rutin/g), and rutin (11.34 mg/g) was found after 7-day germination, but germination decreased the vitamin E activity. Germination improved the activities of buckwheat extracts to scavenge DPPH, ABTS, and superoxide free radicals by 107, 144, and 88 %, respectively. Furthermore, the correlation and principal component analysis showed that the vitamin C, total flavonoids, and rutin contents were closely related positively with free radicals scavenging properties, indicating that the compounds which play a key role in the elevated antioxidant activities during germination consisted of vitamin C, total flavonoids, and rutin, but not vitamin E and quercetin. PMID- 25829634 TI - Roller milled black gram (Phaseolus mungo) semolina and its influence on the quality characteristics of high protein pasta. AB - Black gram (Phaseolus mungo) was roller milled into semolina (BGS) and was substituted at 25, 50 and 75 % levels in vermicelli making in this investigation. There was an increase in ash and protein content as the inclusion of BGS in blends increased. The quality characteristics of pasta showed marginal increase in cooking loss up to 50 % level of BGS. The firmness value did not change much up to 50 % BGS in pasta. At 75 % level of BGS, the cooking loss and stickiness value were highest (6.10 % and 0. 90 N) whereas firmness value and overall quality score were lowest (4 N and 27.5/40) indicating that the pasta had mushy, indiscrete, sticky strands and had a prominent beany odour making it unacceptable. Hence 50 % BGS was considered optimum in vermicelli. The pasta made with 50 % BGS inclusion had a protein and dietary fiber content of 15.30 % and 8 % as against the control value of 11.30 and 4.20 % respectively. PMID- 25829635 TI - Chemical composition and antioxidant activity of ultrasound-assisted extract of the endemic plant Haberlea rhodopensis Friv. AB - The antioxidant capacity of extracts from leaves of Haberlea rhodopensis Friv. obtained by a highly efficient and simple method of the ultrasound-assisted extraction was investigated. The total polyphenolic content was determined spectrophotometrically using the Folin - Ciocalteu's phenol reagent and the polyphenols composition was analyzed by HPLC method. Antioxidant activity of the extract was evaluated as 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2-azinobis-3 ethyl benxothiazoline-6-sulphonic acid (ABTS) cation decolorization activity assays and the ferric reducing/antioxidant power method (FRAP). The total phenolics of the extract were determined to be 148.71 +/- 5.33 mg GAE on a dry weight basis. The HPLC analysis showed a large number of flavonoids and phenolic acids present in the ultrasound ethanol extract of H. rhodopensis. Results also revealed that the major flavonoids were luteolin (2730.18 MUg/g DW), hesperidin (928.56 MUg/g DW) and kaempferol (578.52 MUg/g DW), whereas the most abundant phenolic acids identified in the extract were ferulic acid (630.48 MUg/g DW) and sinapic acid (580.80 MUg/g DW). DPPH(*) and ABTS(*+) values were 0.803 +/- 0.007 and 0.769 +/- 0.040 mmol TE/g DW, respectively and FRAP values were 1.362 +/- 0.05 mmol TE/g DW. PMID- 25829636 TI - Application of ultrasound to microencapsulation of coconut milk fat by spray drying method. AB - Mixtures of coconut milk and gelatin solution were treated by ultrasound, mixed with maltodextrin and subsequently spray-dried to yield powder. The effects of ultrasonic power and sonication time on the microencapsulation efficiency (ME) and microencapsulation yield (MY) of coconut fat were investigated. The results indicated that increase in ultrasonic power from 0 to 5.68 W/g and in sonication time from 0 to 2.5 min augmented ME and MY of coconut fat. However, treatment with sonication power higher than 5.68 W/g led to a drop in fat ME and MY, mainly due to aggregation of fat particles and that blocked the adsorption of gelatin molecules on the particle surface. PMID- 25829637 TI - Occurrence of mislabeling in meat products using DNA-based assay. AB - Considering that the authentication of food contents is one of the most important issues for the food quality sector, and given the increasing demand for transparency in the meat industry followed the horsemeat scandal in Europe, this study investigates processed-meat products from Italian markets and supermarkets using the mitochondrial cytochrome b gene qualitative PCR identification system in order to verify any species substitution or mislabeling. The results revealed a high substitution rate among the meat products, highlighting a mislabeling rate of 57 %, and consequently, considerable discordance with the indications on the labels, which raises significant food-safety and consumer-protection concerns. PMID- 25829638 TI - Influence of moisture, particle size and pulse flour composition on phase transition behavior of rice flour. AB - Study on the phase transition characteristics is an important parameter in extrusion processing. The influence of Moisture Content (MC), particle size and level of cereal-pulse blend on the glass transition (Tg) and melt (Tm) temperatures of a ready to eat cereal-pulse formulation was determined. All samples were moisture conditioned in a 9 to 27 % with 3 % interval. Tg and Tm were measured by phase transition analyser (PTA). A substantial decrease in Tg and Tm was observed as moisture content level increased from 9 to 27 %. However Tg and Tm values could not be clearly defined below 9 % moisture content and above 27 % moisture content. The Tg and Tm values of the cereal-pulse formulation were found to be increased with increasing pulse composition (5 to 30 % with 5 % interval). Increase in particle size (150, 180, 212, 300, 425 and 500 MU) exhibited significant increase effect on Tg while less significant effect on Tm. This may be due to crystalline regions which play a role in cross linking amorphous regions of the polymeric network and thus suppress the mobility of amorphous regions. The observed differences in Tg and Tm induced by the moisture content, concentration of Bengal gram and particle size will be useful in simulation and optimization of barrel temperature set during extrusion processing. PMID- 25829639 TI - Antibiotic utilization improvement with the Nanosphere Verigene Gram-Positive Blood Culture assay. AB - New technologies offer rapid identification of organisms and antimicrobial resistance markers in blood cultures several hours faster than conventional methods. We sought to determine whether implementation of the Verigene(r) Gram Positive Blood Culture (BC-GP) assay paired with a well-defined results reporting algorithm would lead to earlier deescalation of empiric therapy for inpatients with methicillin-sensitive Staphylococcus aureus (MSSA) and vancomycin-resistant Enterococcus (VRE) bacteremia. The algorithm design focused on lessening the demand for pharmacist time by using electronic communications where possible. Our study compared inpatients with MSSA and VRE bacteremia from the time period before (pre-BC-GP) and after (post-BC-GP) implementation of the assay on June 25, 2013. The time from blood draw to identification and susceptibility results was decreased by 36.4 hours (P < 0.001) in the post-BC-GP group. The mean time from collection to the first dose of optimal antibiotics was reduced in the post-BC-GP group by 18.9 hours (P = 0.004) overall, with a 20.6-hour reduction (P = 0.009) for patients with MSSA and a 20.7-hour reduction (P = 0.077) for patients with VRE. Additionally, the percent of patients on empiric therapy who were placed on optimal antibiotics at any time after the Gram stain result was available increased from 64% (45/70) pre-BC-GP to 80% (43/54) post-BC-GP. The BC-GP led to an increased rate of deescalation of empiric antibiotics and a reduction in the time to optimal antibiotics for patients with MSSA and VRE bacteremia. PMID- 25829640 TI - The SUCCESS model for laboratory performance and execution of rapid molecular diagnostics in patients with sepsis. AB - Successful performance and execution of rapid diagnostics in a clinical laboratory hinges heavily on careful validation, accurate and timely communication of results, and real-time quality monitoring. Laboratories must develop strategies to integrate diagnostics with stewardship and evidence-based clinical practice guidelines. We present a collaborative SUCCESS model for execution and monitoring of rapid sepsis diagnostics to facilitate timely treatment. Six months after execution of the Verigene Gram-Positive Blood Culture (BC-GP) and the AdvanDx PNA-FISH assays, data were collected on 579 and 28 episodes of bacteremia and fungemia, respectively. Clinical testing was executed using a SUCCESS model comprising the following components: stewardship, utilization of resources, core strategies, concierge services, education, support, and surveillance. Stewardship needs were identified by evaluating the specialty services benefiting from new testing. Utilization of resources was optimized by reviewing current treatment strategies and antibiogram and formulary options. Core strategies consisted of input from infectious disease leadership, pharmacy, and laboratory staff. Concierge services included automated Micro eUpdate and physician-friendly actionable reports. Education modules were user specific, and support was provided through a dedicated 24/7 microbiology hotline. Surveillance was performed by daily audit by the director. Using the SUCCESS model, the turnaround time for the detailed report with actionable guidelines to the physician was ~3 hours from the time of culture positivity. The overall correlation between rapid methods and culture was 94% (546/579). Discrepant results were predominantly contaminants such as a coagulase-negative staphylococci or viridans streptococci in mixed cultures. SUCCESS is a cost effective and easily adaptable model for clinical laboratories with limited stewardship resources. PMID- 25829641 TI - Impact of the DASH diet on endothelial function, exercise capacity, and quality of life in patients with heart failure. AB - Endothelial dysfunction has been recognized as a pathophysiologic mechanism in the progression of heart failure (HF). However, little attention has been given to the ability of dietary approaches to improve endothelial function. This study examined the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on endothelial function, exercise capacity, and quality of life in patients with chronic symptomatic (stage C) HF. Forty-eight patients were randomized to follow the DASH diet (n = 24) or the general HF dietary recommendations (n = 24). Endothelial function was assessed by measuring large and small arterial elasticity (LAE and SAE) at rest. Exercise capacity (measured with the 6-minute walk test) and quality of life (measured with the Minnesota Living with Heart Failure Questionnaire) at baseline and 3 months were also evaluated. Patients were older adults with an average HF duration of 5 years. LAE at 1 month improved significantly in the DASH diet group (P < 0.01). Overall LAE and SAE scores at 3 months also improved; however, the net changes were not statistically significant. The DASH group had better exercise capacity (292 m vs 197 m; P = 0.018) and quality of life scores (21 vs 39; P = 0.006) over time, while sodium intake levels at 1, 2, and 3 months were comparable between the groups. Adhering to the DASH diet improved arterial compliance initially and improved exercise capacity and quality of life scores at 3 months. The DASH diet may be an important adjunctive therapy for patients with symptomatic HF. PMID- 25829642 TI - A survey-based analysis of symptoms in patients with postural orthostatic tachycardia syndrome. AB - Postural orthostatic tachycardia syndrome (POTS) is a type of dysautonomia seen most commonly in young women and children. It is defined as an increase in heart rate of 30 beats per minute (bpm) or more within 10 minutes of standing in adults, or by 40 bpm or more in children in the absence of orthostatic hypotension. In addition to typical autonomic symptoms, POTS patients report a wide range of subjective complaints in multiple organ systems, though the exact frequencies are unclear. To address the symptom frequency, we had 39 patients with POTS at our institution complete an intake form consisting of a list of 37 symptoms. The most frequently reported symptoms included palpitations, lightheadedness, and headache, although sleep disturbances, gastrointestinal complaints, sensitivity to temperature, and rash were also common. PMID- 25829643 TI - An interactive web-based project to stimulate internal medicine resident reading using board-type questions. AB - Since restricted resident work hours have reduced resident participation in traditional educational activities, we wanted to evaluate e-mail-based education in an internal medicine residency. One internal medicine faculty member sent four clinical case-based questions per week to all internal medicine residents over a 10-month period (132 questions total). The mean percentage of participation on a set of questions was 69% (range, 43% to 97%). The mean percentage of correct answers on all questions for all residents was 70% (range, 15% to 100%). Seventy three percent of the question sets resulted in an electronic interaction between the residents and the faculty sponsor. Based on an anonymous survey, 96% of the residents found the program useful. The faculty sponsor spent 60 to 150 minutes per week on this activity. We think that this program increased overall reading since it did not replace any traditional activity; further, it provided practice with board-type questions. This approach can supplement the educational curriculum for internal medicine training. PMID- 25829645 TI - History of neurologic examination books. AB - The objective of this study was to create an annotated list of textbooks dedicated to teaching the neurologic examination. Monographs focused primarily on the complete neurologic examination published prior to 1960 were reviewed. This analysis was limited to books with the word "examination" in the title, with exceptions for the texts of Robert Wartenberg and Gordon Holmes. Ten manuals met the criteria. Works dedicated primarily to the neurologic examination without a major emphasis on disease description or treatment first appeared in the early 1900s. Georg Monrad-Krohn's "Blue Book of Neurology" ("Blue Bible") was the earliest success. These treatises served the important purpose of educating trainees on proper neurologic examination technique. They could make a reputation and be profitable for the author (Monrad-Krohn), highlight how neurology was practiced at individual institutions (McKendree, Denny-Brown, Holmes, DeJong, Mayo Clinic authors), and honor retiring mentors (Mayo Clinic authors). PMID- 25829646 TI - Cecal adenocarcinoma presenting as colonic intussusception in adulthood. AB - Intussusception occurs when a proximal segment of intestine invaginates into a distal segment. It is a common cause of intestinal obstruction in children but is infrequent in adults. A 77-year-old woman presented with a 1-month history of intermittent abdominal pain associated with nausea and distended abdomen. Imaging showed a complex elongated sausage-shaped mass in the transverse colon with no obstructive pattern or free air. Surgery confirmed colonic intussusception in addition to a palpable cecal mass requiring a right hemicolectomy. Histologic study demonstrated adenocarcinoma in situ within a tubulovillous adenoma. Surgical excision of the affected intestine is the recommended treatment of choice. PMID- 25829644 TI - The acute respiratory distress syndrome. AB - The acute respiratory distress syndrome (ARDS) is a major cause of acute respiratory failure. Its development leads to high rates of mortality, as well as short- and long-term complications, such as physical and cognitive impairment. Therefore, early recognition of this syndrome and application of demonstrated therapeutic interventions are essential to change the natural course of this devastating entity. In this review article, we describe updated concepts in ARDS. Specifically, we discuss the new definition of ARDS, its risk factors and pathophysiology, and current evidence regarding ventilation management, adjunctive therapies, and intervention required in refractory hypoxemia. PMID- 25829647 TI - Large-volume barium aspiration. AB - We present a case of large-volume barium aspiration in a 56-year-old woman with stage IV tongue squamous cell carcinoma and longstanding dysphagia. The patient rapidly developed hypoxemic respiratory failure from the resultant chemical pneumonitis. However, her respiratory status improved with supportive care alone in 48 hours. Barium aspiration is rare and often produces dramatic radiographic findings, but is generally associated with a favorable prognosis. PMID- 25829648 TI - Effect of resection of an orbital arteriovenous malformation on central venous pressure. AB - We report the first utilization of intraoperative central venous pressure (CVP) monitoring in the resection of an orbital arteriovenous malformation. A 24-year old woman with a history of a left orbital mass who had previously undergone resection of a cranio-orbital arteriovenous malformation presented with gradual recurrence in the left orbit. She visited the emergency department with sudden vision loss, which resolved over several hours. This transient vision loss was thought to be due to a steal phenomenon from the ophthalmic artery due to the residual vascular malformation. Further surgical resection was undertaken. A preoperative angiogram identified residual feeding vessels, and the larger vessels were embolized. At the start of the procedure, her CVP was elevated (29 mm Hg), as measured by a central venous line. The remaining feeding vessels were surgically ligated, and an intraoperative arteriogram confirmed their successful ablation. At the conclusion of the procedure, the CVP had decreased to 9 mm Hg. PMID- 25829649 TI - Acute nonrheumatic streptococcal myocarditis resembling ST-elevation acute myocardial infarction in a young patient. AB - Acute myocarditis can be induced by various concomitant disease processes including infections. Most of these cases are viral in origin; however, bacterial infections are also implicated to a lesser degree. Group A streptococcus is a frequent culprit in bacterial-induced myocarditis. Its diagnosis is suspected by the presence of signs and symptoms of rheumatic fever as established by the Jones criteria. The development and refinement of current diagnostic tools has improved our ability to identify specific pathogens. It has been found that group A streptococcus may be responsible for more cases of infection-induced acute myocarditis than previously thought, and often without the clinical features of rheumatic fever. We present the case of a 43-year-old man hospitalized with chest pain that was initially diagnosed as an acute ST-elevation myocardial infarction. Further evaluation confirmed that his chief complaint was due to acute nonrheumatic streptococcal myocarditis. PMID- 25829650 TI - Invited Commentary: What is the definition of SPAM? Even if you cannot define it, you must recognize it! PMID- 25829651 TI - Cardiac arrhythmias during myocardial infarction. PMID- 25829652 TI - Takotsubo cardiomyopathy associated with hyperthyroidism treated with thyroidectomy. AB - Takotsubo cardiomyopathy is an uncommon clinical entity, also called apical ballooning syndrome, characterized by transient systolic dysfunction of the apical and/or mid segments of the left ventricle. We report a case that highlights takotsubo syndrome in the setting of thyrotoxicosis that required thyroidectomy. The association of takotsubo syndrome and hyperthyroidism has been reported before. We found 13 previously reported cases of thyrotoxicosis-induced cardiomyopathy, most associated with Grave's disease and none treated with thyroidectomy. Awareness of this possible association is important in establishing the diagnosis and instituting proper management. PMID- 25829653 TI - Ventricular tachycardic storm with a chronic total coronary artery occlusion treated with percutaneous coronary intervention. AB - A 66-year-old man with a history of coronary artery disease was evaluated due to ventricular tachycardic (VT) storm. The patient continued to have frequent recurrences of VT despite treatment with amiodarone and lidocaine. Since the ventricular arrhythmia could be related to myocardial ischemia related to a chronic total occlusion (CTO) of the right coronary artery, the patient underwent successful percutaneous coronary intervention of the CTO, followed by implantable cardioverter defibrillator implantation. He had no further episodes of VT during his hospital stay. After 9 months of follow-up, he had no further chest pain or clinically apparent recurrent ischemia. Interrogation of his defibrillator has shown brief nonsustained episodes of ventricular tachycardia, but the patient has not required delivery of a shock. The temporal association between treatment of the CTO and resolution of the VT, as well as the lack of recurrence of sustained VT, suggest a causative link between underlying ischemia produced by a chronically occluded coronary artery and provocation of VT and lend supportive evidence to this treatment approach. PMID- 25829654 TI - Myocardial ischemic hyperacute T-wave oversensing leading to a defibrillator shock storm. AB - Appropriate sensing is essential for the normal functioning of an implantable cardioverter defibrillator (ICD). T-wave oversensing is a potential clinical problem in ICD patients that may result in inappropriate shocks. Oversensing may have various underlying causes and can be treated with noninvasive or invasive means. We present the case of a 45-year-old man presenting with shock storm as a result of T-wave oversensing. Workup revealed a hemodynamically significant stenosis of the left anterior descending artery treated with percutaneous coronary intervention and drug-eluting stent placement. This resulted in the resolution of T-wave missensing and restoration of normal ICD functioning. PMID- 25829655 TI - Usefulness of percutaneous closure of patent foramen ovale for hypoxia. AB - We report a patient with hypoxia secondary to a right-to-left shunt through a patent foramen ovale, following aortic root, valve, and arch replacement due to an aortic dissection in the setting of the Marfan syndrome. Following the operation, he failed extubation twice due to hypoxia. An extensive workup revealed a right-to-left shunt previously not seen. The patent foramen ovale was closed using a percutaneous closure device. Following closure, our patient was extubated without difficulty and has done well postoperatively. PMID- 25829656 TI - Mitral stenosis and acute ST elevation myocardial infarction. AB - We describe a patient who presented with acute (inferior wall) ST elevation myocardial infarction. Her echocardiogram showed severe mitral stenosis with ball valve thrombus in the left atrial body and thrombus in the left atrial appendage. Coronary angiogram revealed thromboembolic material in the right coronary artery. Mitral valve replacement was scheduled. PMID- 25829657 TI - Effectiveness of exclusion of a persistent sciatic artery aneurysm with an AmplatzerTM plug. AB - Persistent sciatic artery is a rare developmental anomaly. In its complete form, it provides the major arterial supply to the lower leg since the femoral system is hypoplastic. These unique arteries are prone to aneurysm formation and most commonly present with complications related to aneurysm formation, which can lead to limb loss. We encountered a 68-year-old man presenting with bilateral lower extremity ischemia who was found to have bilateral persistent sciatic artery aneurysms. One aneurysm had already thrombosed, but the other was still patent. We treated this patient with a hybrid open and endovascular repair on the patent side. The aneurysm was excluded with an AmplatzerTM plug (St. Jude Medical, Inc., St. Paul, MN) followed by a femoropopliteal bypass with saphenous vein in situ to revascularize the lower leg. To our knowledge, this is only the second report of a persistent sciatic artery aneurysm successfully treated with Amplatzer plug occlusion. PMID- 25829658 TI - Immune thrombocytopenia associated with consumption of tonic water. AB - Thrombocytopenic purpura can develop from an induced antibody response that destroys platelets. Megakaryocyte production may also play a role. Although the inciting antigen is usually not identified, it is important to consider medications. This article presents the case of a man who developed sudden onset of severe thrombocytopenia associated with the ingestion of quinine-containing tonic water. PMID- 25829659 TI - Paraneoplastic cerebellar ataxia and the paraneoplastic syndromes. AB - Paraneoplastic cerebellar ataxia, also known as paraneoplastic cerebellar degeneration, is one of the wide array of paraneoplastic neurological syndromes in which neurological symptoms are indirectly caused by an underlying malignancy, most commonly gynecological, breast, or lung cancer or Hodgkin's lymphoma. We describe a patient with severe cerebellar dysfunction attributed to a paraneoplastic neurological syndrome. The case highlights the need to look for paraneoplastic syndromes-both to discover malignancies early, at a treatable stage, and, as in our case, to address very distressing symptoms for the patient's relief even if the malignancy is not curable. PMID- 25829660 TI - Carcinoma of the lungs causing enlarged kidneys. AB - Bilateral enlarged kidneys can be caused by a number of conditions. Renal metastasis is included in the differential diagnosis. We report a case of a 67 year-old woman with a 6-month history of productive cough and unintentional weight loss. Cavitary pulmonary lesions and bilateral enlarged kidneys were noted on imaging studies. Hematuria, azotemia, and proteinuria were present. Renal biopsy showed squamous carcinoma cells invading normal-appearing glomeruli and atrophic tubules. The invasive squamous cells stained negative for CK7 and CK 20. Lung biopsy confirmed squamous cell carcinoma. Our case shows that in patients with renal enlargement, even with the absence of a focal mass, renal metastasis should be considered, especially in those with suspected or diagnosed malignancy elsewhere. PMID- 25829661 TI - Mixed epithelial and stromal tumors of the kidney discovered incidentally at autopsy. AB - Mixed epithelial and stromal tumors (MEST) of the kidney are uncommon neoplasms that were added to the World Health Organization's renal tumor classification in 2004. These entities are biphasic and contain both epithelial and mesenchymal components. MEST most commonly occur in women. Presented are two cases of MEST incidentally discovered at autopsy. PMID- 25829662 TI - Superior sagittal sinus thrombosis as the initial presentation of renal cell carcinoma. AB - We describe a 68-year-old man who presented with headaches, nausea, and dizziness and was found to have a superior sagittal sinus venous thrombosis on magnetic resonance imaging. His initial hypercoagulable workup was negative. Computed tomography of the abdomen revealed a large mass originating from the kidney. A radical nephrectomy was performed at an outside hospital, and histological study of the excised mass disclosed clear cell renal carcinoma. PMID- 25829663 TI - Hepatocellular carcinoma with extension to the heart via the inferior vena cava. AB - Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide. Most cases of HCC are associated with cirrhosis from various causes such as alcohol or viral hepatitis. Most patients are symptomatic as a result of cirrhosis itself or secondary to tumor extension. These tumors have an affinity for the vasculature and often invade the portal system. HCC rarely causes invasion of the inferior vena cava or the heart. We, however, present a case of HCC in a patient without cirrhosis who remained asymptomatic despite having tumor extension to the heart by way of the inferior vena cava. The mean survival in patients with intracardiac extension with or without aggressive treatment or intervention is approximately 4 months, but our patient greatly exceeded survival expectations after treatment with sorafenib. PMID- 25829665 TI - Facts and ideas from anywhere. PMID- 25829664 TI - Leprosy in a texan. AB - A 69-year-old man from Texas with an unremarkable past medical history presented with a 2-year history of a diffuse, spreading annular eruption involving most of his trunk. He noticed progressive numbness of his hands and feet but no other systemic symptoms. He had never traveled outside of the United States. Skin biopsy confirmed a diagnosis of leprosy, and he was initiated on appropriate therapy. PMID- 25829666 TI - Pediatric surgery in India: Time now for review. PMID- 25829667 TI - Disorders of sex development: The quintessence of perennial controversies-III - DSD, transgenders and the judgment by the Hon'ble Supreme Court of India. PMID- 25829668 TI - Study of prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. AB - AIMS: Study on prognostic significance of antenatal ultrasonography and renin angiotensin system activation in predicting disease severity in posterior urethral valves. MATERIALS AND METHODS: Antenatally diagnosed hydronephrosis patients were included. Postnatally, they were divided into two groups, posterior urethral valve (PUV) and non-PUV. The studied parameters were: Gestational age at detection, surgical intervention, ultrasound findings, cord blood and follow up plasma renin activity (PRA) values, vesico-ureteric reflux (VUR), renal scars, and glomerular filtration rate (GFR). RESULTS: A total of 25 patients were included, 10 PUV and 15 non-PUV. All infants with PUV underwent primary valve incision. GFR was less than 60 ml/min/1.73 m(2) body surface area in 4 patients at last follow-up. Keyhole sign, oligoamnios, absent bladder cycling, and cortical cysts were not consistent findings on antenatal ultrasound in PUV. Cord blood PRA was significantly higher (P < 0.0001) in PUV compared to non-PUV patients. Gestational age at detection of hydronephrosis, cortical cysts, bladder wall thickness, and amniotic fluid index were not significantly correlated with GFR while PRA could differentiate between poor and better prognosis cases with PUV. CONCLUSIONS: Ultrasound was neither uniformly useful in diagnosing PUV antenatally, nor differentiating it from cases with non-PUV hydronephrosis. In congenital hydronephrosis, cord blood PRA was significantly higher in cases with PUV compared to non-PUV cases and fell significantly after valve ablation. Cord blood PRA could distinguish between poor and better prognosis cases with PUV. PMID- 25829669 TI - Laparoscopic repair of Morgagni's hernia: An innovative approach. AB - AIM: To review our experience of laparoscopic repair of Morgagni's hernia (MH) using transfascial sutures. MATERIALS AND METHODS: This is a retrospective review of patients presenting to the first author with the diagnosis of MH over a 15 year period. The variables analyzed included demographic data, clinical presentation, and operative details. RESULTS: In all there were five male with a median age of 2 years. They were asymptomatic and MH was detected incidentally by observing an air-filled density in the right cardiophrenic angle on plain X-ray of the chest. Computed tomography (CT) confirmed the diagnosis in all patients. All patients underwent laparoscopic repair of MH using transfascial sutures. The average operative time was 75 min. Oral feeding was started 6 h after surgery and patients were discharged on either 3(rd) or 4(th) postoperative day. Postoperative follow-up X-ray confirmed the intact repair. CONCLUSIONS: Laparoscopic repair of MH using transfascial sutures is an easy and effective solution. Multiple horizontal mattress sutures taking full thickness of abdominal wall muscles with the edge of the diaphragm leads to a strong repair. As sutures are tied extracorporeally, the technique is easily reproducible. PMID- 25829670 TI - The Bracka two-stage repair for severe proximal hypospadias: A single center experience. AB - BACKGROUND: Surgical correction of severe proximal hypospadias represents a significant surgical challenge and single-stage corrections are often associated with complications and reoperations. Bracka two-stage repair is an attractive alternative surgical procedure with superior, reliable, and reproducible results. PURPOSE: To study the feasibility and applicability of Bracka two-stage repair for the severe proximal hypospadias and to analyze the outcomes and complications of this surgical technique. MATERIALS AND METHODS: This prospective study was conducted from January 2011 to December 2013. Bracka two-stage repair was performed using inner preputial skin as a free graft in subjects with proximal hypospadias in whom severe degree of chordee and/or poor urethral plate was present. Only primary cases were included in this study. All subjects received three doses of intra-muscular testosterone 3 weeks apart before first stage. Second stage was performed 6 months after the first stage. Follow-up ranged from 6 months to 24 months. RESULTS: A total of 43 patients operated for Bracka repair, out of which 30 patients completed two-stage repair. Mean age of the patients was 4 years and 8 months. We achieved 100% graft uptake and no revision was required. Three patients developed fistula, while two had metal stenosis. Glans dehiscence, urethral stricture and the residual chordee were not found during follow-up and satisfactory cosmetic results with good urinary stream were achieved in all cases. CONCLUSION: The Bracka two-stage repair is a safe and reliable approach in select patients in whom it is impractical to maintain the axial integrity of the urethral plate, and, therefore, a full circumference urethral reconstruction become necessary. This gives good results both in terms of restoration of normal function with minimal complication. PMID- 25829671 TI - A study of the effect of caudal epidural block on bispectral index targeted propofol requirement in children: A comparative study. AB - Caudal epidural block is one of the most commonly performed neuraxial block techniques with reliable peri-operative and post-operative analgesia in pediatric patients. In our randomized, prospective, double-blinded, open level, parallel group study, we have established the effect of caudal epidural block on maintenance requirement of intravenous (IV) propofol in targeted bispectral (BIS) monitored patients. CONTEXT: Neuraxial anesthesia exhibits sedative properties that may reduce the requirement for general anesthesia. TIVA with propofol has been administered as an established method of maintaining general anesthesia in children. Caudal analgesia being a type of neuraxial block, also seems to reduce the requirement of sedative hypnotics in pediatric patients. Numerous studies show that for patients, administered with caudal epidural block, they require reduced intra-operative volatile inhalation anesthetics. In the present study, we have established the anesthetic sparing effect of Caudal Epidural Analgesia in children undergoing infra-umbilical surgical procedure and calculated the efficacy of propofol-infusion in maintaining adequate depth of anesthesia. AIMS: (1) To study and compare the dose requirements of propofol using caudal epidural analgesia. (2) To calculate the efficacy of propofol as maintenance anesthetic agent in both groups and to compare hemodynamic stability of patients in both the techniques. SETTINGS AND DESIGN: In our study, after administering general anesthesia to pediatric patients, we have administered caudal analgesia and IV analgesia to monitor the requirement of intra-operative propofol infusion using BIS monitor with a target value of 40-60 in both groups. MATERIALS AND METHODS: 82 patients (aged between 3 and 6 years) have been selected undergoing infra umbilical surgery and randomly allocated into two groups containing 41 patients in each group. Both the groups group B and group A then intubated with glycopyrrolate, 2 mg/kg injection fentanyl, propofol till loss of verbal contact and atracurium at the rate of 0.5 mg/kg and group B has been administered caudal epidural blockade with 1 ml/kg 0.2% ropivacaine. Propofol infusion at the rate of 10 mg/kg/h is given as maintenance. BIS value has been recorded throughout and propofol requirement at the end of surgery has been calculated. STATISTICAL ANALYSIS USED: Numerical variables between groups have been analyzed using the Student's t-test and the Mann-Whitney U-test as applicable. Categorical variables have been analyzed using the Pearson's Chi-square test. P < 0.05 is considered statistically significant. RESULTS: Consumption of propofol at the start of operation in the group A is 2.9 +/- 0.17 and group B is 2.91 +/- 0.17, which is not statistically significant (P > 0.05), whereas at the end of the operation in the group A is 11.33 +/- 0.17 and group B is 7.83 +/- 0.63, which is statistically significant (P < 0.05). Incidence of adverse effects is statistically insignificant between the two groups. The time for administration of rescue analgesic is 2.1 +/- 0.88 in group A and 6.5 +/- 0.17 in group B, which is statistically significant due to caudal analgesia. CONCLUSIONS: We conclude that in BIS-monitored patients (3-6 years) with infra-umbilical surgeries have shown a reduction in consumption of IV propofol due to caudal epidural blockade. PMID- 25829672 TI - A rare case of bilateral cystic nephroma associated with embryonal rhabdomyosarcoma of the penile urethra. AB - Bilateral cystic nephroma is an extremely rare benign renal neoplasm. Here we present a case of bilateral cystic nephroma in a four month old boy who subsequently developed embryonal rhabdomyosarcoma of the urethra. Both tumors were successfully treated. To our knowledge this is the first reported case of this association which could be related to Dicer-1 mutation. PMID- 25829673 TI - Continent cutaneous diversion and external genitalia reconstruction in a child with severe variety urogenital sinus and ambiguous genitalia. AB - The diagnosis and management of a child with ambiguous genitalia and severe variety of urogenital sinus with a high vesico-vaginal confluence is challenging. This 4-year-old female child had solitary right kidney with ectopic ureter opening in high variety of urogenital sinus with hypo-plastic urinary bladder and incontinence. We describe genitourinary reconstruction with complete functional rehabilitation in this child. This complex problem was managed with continent urinary diversion with Penn pouch and refashioning of external genitalia, rendering continence and near normal female external genitalia. The child and parents are happy with continence and aesthetically normal external genitalia. PMID- 25829674 TI - Esophageal lung resection and prosthesis placement in a preterm neonate. AB - This report describes a successful outcome in a preterm baby with an esophageal atresia and tracheo-esophageal fistula, who initially underwent a primary esophageal repair; but a persistent nonexpanding lung on the side of surgery led to further investigations. A further diagnosis of an esophageal lung resulted in pneumonectomy and prophylactic placement of an intra-thoracic prosthesis to prevent post-pneumonectomy syndrome. To the best of our knowledge, this is the first report of a prophylactic placement of an intra-thoracic prosthesis in a neonate with the condition of esophageal atresia and tracheo-esophageal fistula and associated esophageal lung. PMID- 25829675 TI - Multiple singing magnet ingestion leading to pressure necrosis of the small bowel. AB - Multiple Magnet ingestion may cause a number of sinister complications. We report a case of multiple singing magnets ingestion by a 2-year-old girl resulting in intestinal obstruction and pressure necrosis of the small bowel. A bunch of seven magnets present in the small bowel was removed operatively. PMID- 25829676 TI - Esophageal lung: A rare type of communicating bronchopulmonary foregut malformation, case report with review of literature. AB - A 2-year-old female child was referred from a private hospital as a case of recurrent lower respiratory tract infections (LRTI). The chest X ray revealed a hypoplastic right lung and further workup led to the diagnosis of esophageal lung - a rare type of communicating bronchopulmonary foregut malformation. A right posterolateral thoracotomy was done, anamolous bronchial communication with esophagus disrupted, esophageal fistula repaired and the lung resected. Postoperatively, diet was allowed from day 7. The patient tolerated the diet well. Repeat dye study revealed no leak and subsequently the patient was discharged on day 10. PMID- 25829677 TI - Solitary crossed ectopia with vesicoureteric junction obstruction: A rare case report. AB - Solitary crossed renal ectopia (SCRE) is a very rare anomaly of urinary tract. Most cases are diagnosed incidentally. We report a case of SCRE associated with vesicoureteric junction obstruction in a 7-year-old child which has not been reported in the literature till date. PMID- 25829678 TI - Patent vitellointestinal duct with ileal prolapse in a newborn. PMID- 25829679 TI - Primary hydatid cyst of fronto-temporo-zygomatic region: A rare presentation. PMID- 25829680 TI - Is Stephen-fowler staged approach the correct answer for orchidopexy in a peeping testis? PMID- 25829681 TI - Type V congenital pouch colon: A need to expand the scope of the definition. PMID- 25829682 TI - Biotoxicity of commonly used root canal sealers: A meta-analysis. AB - INTRODUCTION: The main objective of a root canal sealer is to provide a fluid tight seal. The purpose of this systematic meta-analysis was to determine the relative toxicity of commonly used root canal sealers like zinc oxide eugenol, calcium hydroxide, and resin-based sealers. MATERIALS AND METHODS: An online search was conducted in peer-reviewed journals listed in PubMed, Cochrane, EBSCO, and IndMed databases between 2000 and 2012). Statistical analysis was carried out by using analysis of variance (ANOVA) followed by post-hoc comparison by Bonferroni method. The comparison between toxicity at 24 h and between 3 and 7 days was done by using paired t-test for each sealer. RESULTS: At 24 h, the relative biotoxicity of the three sealers reported was insignificant (P- value 0.29), but the difference in toxicity was found significant (P < 0.001) after 3 days. CONCLUSION: Calcium hydroxide sealer and zinc oxide eugenol were found to be significantly biotoxic as compared to resin-based sealers after 3 days. PMID- 25829683 TI - The self-adjusting file instrumentation results in less debris extrusion apically when compared to WaveOne and ProTaper NEXT. AB - AIM: The present ex vivo study aimed to evaluate the debris extrusion after instrumenting the root canals by three different files systems. MATERIALS AND METHODS: Sixty extracted human mandibular premolars with single canals were selected and randomly divided into three groups (n = 20) for instrumentation with three different files. Group 1: WaveOne (primary) single reciprocating file (WO; Dentsply Maillefer, Ballaigues, Switzerland) (25/08), Group 2: Self-adjusting file (SAF; ReDent-Nova, Ra'anana, Israel) (1.5 mm), and Group 3: ProTaper NEXT X1 and X2 (PTN; Dentsply Tulsa Dental, Tulsa, OK) (25/06). Debris extruding by instrumentation were collected into pre-weighed Eppendorf tubes. These tubes were then stored in an incubator at 70 degrees C for 5 days. The tubes were then weighed to obtain the final weight, with the extruded debris. Statistical analysis for the debris extruded apically was performed using one-way analysis of variance and post hoc Tukey's test. RESULTS: The statistical analysis showed a significant difference between all the three groups tested (P < 0.01). The following post hoc Tukey's test confirmed that Group 2 (SAF) exhibited significantly least (P < 0.01) debris extrusion between the three groups tested. CONCLUSIONS: The SAF resulted in significantly less extrusion of debris when compared to reciprocating WO and rotary PTN. PMID- 25829684 TI - Biological and chemical-physical properties of root-end filling materials: A comparative study. AB - AIM: The purpose of the study is to evaluate and compare the biological and chemical-physical properties of four different root-end filling materials. MATERIALS AND METHODS: Cytotoxicity towards murine odontoblasts cells (MDPC-23) was evaluated using the Transwell insert methodology by Alamar blue test. Streptococcus salivarius, S. sanguis, and S. mutans strains were selected to evaluate the antimicrobial activity by agar disc diffusion test. Solubility was determined after 24 h and 2 months. pH values were measured after 3 and 24 h. To evaluate radiopacity, all materials were scanned on a GE Healthcare Lunar Prodigy. RESULTS: Excellent percentage of vitality were obtained by mineral trioxide aggregate (MTA)-based materials and Biodentine. MTA-Angelus, ProRoot MTA, and Intermediate Restorative Material (IRM) showed the highest values for the inhibition zones when tested for S. mutans, while Biodentine showed the largest inhibition zone when tested for S. sanguis. All the materials fulfilled the requirements of the International Standard 6876, demonstrating low solubility with a weight loss of less than 3%. No significant reduction in pH value was demonstrated after 24 h. ProRoot MTA and MTA-Angelus showed the highest values of radiographic density. CONCLUSIONS: The differences showed by the root-end filling materials tested do not cover completely the ideal clinical requests. PMID- 25829685 TI - Three-dimensional finite element analysis of stress distribution in a tooth restored with metal and fiber posts of varying diameters: An in-vitro study. AB - OBJECTIVE: To compare stress distribution in a tooth restored with metal and fiber posts of varying diameters (1.2 and 1.4 mm) by means of three-dimensional finite element analysis (3D-FEA). MATERIALS AND METHODS: Four 3D-FEA models were constructed: (1) fiber post (1.2 and 1.4 mm) and (2) metal post (1.2 and 1.4 mm). The material properties were assigned and a force of 100 N was applied at 45 degrees angle to the longitudinal axis of the tooth onto the palatal surface incisal to the cingulum. Analysis was run and stress distribution pattern was studied. RESULTS: Maximum stresses in the radicular tooth structure for fiber post were higher than that for metal post. In the former models, stresses in the tooth structure were slightly reduced with increase in fiber post diameter. CONCLUSIONS: To reduce stress in the remaining radicular tooth structure, it is better to use a fiber post of a large diameter. PMID- 25829686 TI - Influence of addition of calcium oxide on physicochemical properties of Portland cement with zirconium or niobium oxide. AB - CONTEXT: Calcium oxide (CaO) may be added to mineral trioxide aggregate (MTA) or Portland cement (PC) to improve physicochemical and biological properties. AIMS: To evaluate the physicochemical properties of PC associated with radiopacifiers and CaO. MATERIALS AND METHODS: MTA Angelus, PC + 30% zirconium oxide (Zr), or 30% niobium oxide (Nb) associated with 10 or 20% of CaO were evaluated. Gilmore needles were used to evaluate initial and final setting time. Compressive strength was evaluated after the periods of 24 hours and 21 days. pH was analyzed after 3, 12, 24 hours, 7, 14, 21 days. Solubility and flow tests were performed based on the ISO 6876. The data obtained were submitted to analysis of variance and Tukey tests (P <= 0.05). RESULTS: The associations with 10% CaO showed greater strength that the associations with 20% CaO. The shortest initial setting time was observed for the association PC + Zr + 20% CaO and MTA. All the cements presented alkaline pH. The flow of all cements was similar. The highest solubility was found in the associations with 20% CaO. CONCLUSION: The addition of CaO to PC favored the alkaline property and the PC + Zr + 20% CaO presented setting time similar to MTA. PMID- 25829687 TI - Marginal adaptation of mineral trioxide aggregate (MTA) to root dentin surface with orthograde/retrograde application techniques: A microcomputed tomographic analysis. AB - BACKGROUND: Achieving a good apical seal for root canals is known to be associated with good mineral trioxide aggregate (MTA) adaptation to dentin. AIMS: This study aims to compare the marginal adaptation of MTA with root dentin between orthograde and retrograde application techniques using microcomputed tomography (micro-CT) analysis. SETTINGS AND DESIGN: Fifty-two single-rooted human teeth were divided into four equal groups: (Group 1) Retrograde MTA (RMTA), (Group 2) Orthograde MTA (OMTA), (Group 3) Etched RMTA (ERMTA), and (Group 4) Etched OMTA (EOMTA). MATERIALS AND METHODS: For Group 1, 3-mm retrograde cavities were prepared and filled with MTA. For Group 2, the apical 6 mm of the canals were filled with MTA and sealed with sealer cement and warm gutta-percha. In Groups 3 and 4, canals were treated the same as Groups 1 and 2, respectively, except that before placing the MTA, canals were irrigated with 17% ethylenediaminetetraacetic acid (EDTA). After 48 hours, all the teeth were analyzed using a micro-CT scanner. STATISTICAL ANALYSIS: Mean dentin-MTA contact and the mean length and width of each gap was analysed using one-way analysis of variance (ANOVA). Statistical significance was set at an alpha level of 5%. RESULTS: No significant difference in gap volumes was observed in the dentin-MTA adaptation in both orthograde and retrograde application techniques. However, significant difference in the gap volumes was observed between RMTA and ERMTA (P = 0.045). Etching significantly improved the MTA-Dentin adaptation (P < 0.05). The type of application technique did not significantly improve the dentin-MTA adaptation, instead with the use of 17% EDTA, a significant improvement could be achieved. CONCLUSION: Within the limitations of the present study, it concludes that MTA adaptation to dentin tooth structure is not significantly different between an orthograde and retrograde approach. However, the use of EDTA significantly improved the MTA-Dentin adaptation. PMID- 25829688 TI - Effect of temperature, curing time, and filler composition on surface microhardness of composite resins. AB - AIM: The aim of this study was to evaluate the microhardness of two composite resins when subjected to three different temperatures and three different light curing times. MATERIALS AND METHODS: Two composites were used; Filtek Z250 and Grandio. Three different temperatures (23, 37, and 55(o)C) were used, utilizing a composite warmer. The heated samples were immediately injected into cylindrical molds (6 mm * 2 mm) and the top surface of the specimens was polymerized for 10, 20, and 40 sec, using a Quartz-Tungsten-Halogen light-curing unit (QTH LCU). Vickers microhardness measurements were performed from both the top and bottom surface of the specimens, following dry storage for 24 hours in the dark. Statistical analysis were performed using one-way analysis of variance (ANOVA) and Tukey post-hoc test at a level of significance of a = 0.05. RESULTS: The results indicated that there was an increase in microhardness as the temperature of the composite was increased for either the top or the bottom surface (P < 0.05). Furthermore, there was a general increase in microhardness for both composites as curing time increased (P < 0.05). The type of composites did not influence the surface microhardness (P > 0.05). CONCLUSIONS: Temperature of composites affects their surface microhardness. Also, light-curing time influence microhardness values of the composites tested. PMID- 25829689 TI - Effect of technique of sealer agitation on percentage and depth of MTA Fillapex sealer penetration: A comparative in-vitro study. AB - AIM: To compare the effect of three root canal sealer activation techniques on percentage and depth of sealer penetration of MTA Fillapex and AH Plus sealers. MATERIALS AND METHODS: Sixty teeth prepared till F5 ProTaper size were divided into three equal groups on the basis of sealer activation technique (G1: Ultrasonics, G2: Lentulo spiral, and G3: Counter-clockwise rotary motion). Each group was further divided into two equal subgroups on the basis of type of sealer used: AH Plus (Denstply, Konstanz, Germany) or MTA Fillapex (Angelus, Londrina, PR, Brazil) and obturated with gutta-percha. Horizontal sections at 3 and 6 mm from the apex were obtained and the percentage and depth of penetration of sealers into dentinal tubules were measured using confocal laser scanning microscopy (CLSM). Statistical analysis was performed utilizing Kruskal-Wallis and Mann-Whitney U tests with a significance level of 5%. RESULTS: G1 showed significantly (P < 0.001) high percentage and depth of sealer penetration than G2 and G3 while the difference was insignificant (P > 0.05) between G2 and G3. CONCLUSION: Percentage and depth of sealer penetration are influenced by the type of sealer used sealer activation technique and by the root canal level. Ultrasonic method of sealer activation and MTA Fillapex showed the best results. PMID- 25829690 TI - Evaluation of push-out bond strength of endosequence BC sealer with lateral condensation and thermoplasticized technique: An in vitro study. AB - AIMS: To evaluate and compare the push-out bond strength of root filled with Endosequence BC, AH Plus and Endomethasone N sealers using lateral condensation and thermoplasticized technique. MATERIALS AND METHODS: Thirty mandibular premolars with completely formed roots were selected. Teeth were decoronated, working length was determined. Instrumentation and irrigation were performed. Teeth were then obturated with Group 1-Cold lateral compaction (n = 15) or Group 2-Thermoplasticized technique (n = 15). Each group was again subdivided into three depending on the sealers used. Teeth in each subgroup were then sectioned perpendicularly to the long axis to obtain a disc of 2 mm each, which were then subjected to micro push-out test. Data was analyzed with ANOVA. RESULTS: AH Plus sealer in Group 1 showed the maximum (4.77 +/- 1.67 MPa) push-out bond strength among the three sealers and between two groups. The mean strength of Bioceramic sealer was lower in Group 1 (2.62 +/- 0.76 MPa) and higher in Group 2 (3.52 +/- 0.69 MPa). CONCLUSIONS: The push-out bond strength of Endosequence BC sealer was lower than the AH Plus root canal sealer with cold lateral condensation technique. PMID- 25829691 TI - Comparative evaluation of antimicrobial efficacy of QMixTM 2 in 1, sodium hypochlorite, and chlorhexidine against Enterococcus faecalis and Candida albicans. AB - AIM/OBJECTIVE: The aim of this study is to compare the antimicrobial efficacy of QMixTM 2 in 1, sodium hypochlorite (NaOCl), and chlorhexidine (CHX) against Enterococcus faecalis and Candida albicans. MATERIALS AND METHODS: Eighty freshly extracted, single-rooted human mandibular premolar teeth were instrumented and autoclaved. Samples were divided into two groups of 40 teeth each based on the type of microorganism used. Group I was inoculated with E. faecalis and Group II with C. albicans and incubated for 3 days. Each group was subdivided into four subgroups based on the type of irrigant used. Group IA, IIA, 5.25% NaOCl; Group IB, IIB, 2% CHX; Group IC, IIC, QMixTM 2 in 1; and Group ID, IID, 0.9% saline (the control group). Ten microliters of the sample from each canal was taken and was placed on Brain Heart Infusion agar and Sabouraud dextrose agar. The plates were incubated at 37 degrees C for 24 h and colony forming units (CFUs) that were grown were counted. Data was analyzed with analysis of variance (ANOVA) followed by post-hoc Games-Howell test. RESULTS: The greatest antimicrobial effects were observed in samples treated with QMixTM 2 in 1 (P < 0.001). No statistical significant difference was found between 5.25% NaOCl and 2% CHX (P > 0.001) against E. faecalis and C. albicans. CONCLUSION: QMixTM 2 in 1 demonstrated significant antimicrobial efficacy against E. faecalis and C. albicans. PMID- 25829692 TI - Assessment of apical seal obtained after irrigation of root end cavity with MTAD followed by subsequent retrofilling with MTA and Biodentine: An in vitro study. AB - INTRODUCTION: The present study is designed to assess the apical seal obtained after root end cavity irrigation with MTAD and retrograde filling with mineral trioxide aggregate (MTA) and Biodentine. MATERIALS AND METHODS: Sixty extracted maxillary central incisors were instrumented and obturated. Apical 3 mm of all the roots were resected and retrograde preparations of 3 mm were made in all the teeth using ultrasonic tips. Thirty root end preparations were irrigated with MTAD for 5 min (Group 1), while 30 were irrigated with saline for 5 min (Group 2). Each main group was subdivided into two subgroups containing 15 samples each. Samples under each subgroup were then filled either with MTA (1A and 2A) or Biodentine (1B and 2B). The amount of microleakage was assessed using a UV spectrophotometer. RESULTS: Statistical analysis suggest a significant difference (P < 0.005) between group 1A and 2A and between the groups 1B and 2B (P < 0.1). There was a significant difference (P < 0.005) between group 1A and 1B and also between group 2A and 2B. CONCLUSION: Irrigation with MTAD significantly improved the apical seal of Biodentine, but it increased the microleakage in MTA-filled root end cavities. Also the apical seal obtained with Biodentine was superior to that obtained with MTA. PMID- 25829693 TI - Comparative evaluation of surface hardness and depth of cure of silorane and methacrylate-based posterior composite resins: An in vitro study. AB - AIM: This in vitro study was carried out to compare the effect of LED light curing system on polymerization and hardness of silorane-based and methacrylate based posterior composite resin. MATERIALS AND METHODS: A total of 40 samples, 20 of silorane-based composite Filtek P-90 and 20 of methacrylate-based composite Heliomolar HB measuring 2 mm thickness and 8 mm diameter were prepared using Teflon molds and cured using LED curing light. The samples were polished and tested in Knoop hardness tester using a 50-gram load and dwell time of 15 seconds on top and bottom surfaces. The percentage depth of cure was calculated, and statistical analysis was performed using two-way ANOVA test and Student t- test. RESULTS: Higher statistically significant values were seen for both the top and bottom surface hardness in silorane-based resins than methacrylate-based resins on LED light curing. CONCLUSION: Greater depth of cure was achieved in silorane based posterior composite than in methacrylate-based posterior composite resins with a statistically significant difference. PMID- 25829694 TI - Comparison of fracture resistance and failure pattern of endodontically treated premolars with different esthetic onlay systems: An in vitro study. AB - AIM: To compare the fracture resistance and modes of failures of three different aesthetic MOD onlays on endodontically treated premolars. MATERIALS AND METHODS: Forty sound maxillary premolars were selected of which 10 untreated teeth were taken as control (Group I). The other thirty premolars were subjected to standardized MOD onlay preparations and root canal treatments and divided into 3 equal groups. Onlays were prepared in Group II- Indirect composite, Group III- Lithium Disilicate ceramic and Group IV- Full Zirconia. All onlays were cemented using Multilink Automix. All the 40 samples were subjected to fracture resistance testing on Universal testing machine. Also fractured specimens were observed under stereo-microscope for modes of failure. RESULTS: Group IV presented the highest fracture resistance. Groups II and III presented no significant difference in fracture resistance from each other (P > 0.05). Group II and Group III showed significantly lower fracture resistance values than Group I. Coming to modes of failure, only Group IV had showed no cracks in any of the restorations. CONCLUSION: Full Zirconia MOD onlays increased the fracture resistance of endodontically treated premolars to a significantly higher level than the sound teeth. PMID- 25829695 TI - Effect of three different antioxidants on the shear bond strength of composite resin to bleached enamel: An in vitro study. AB - OBJECTIVE: The effect of 10% sodium ascorbate, 10% grape seed extract, and 10% pine bark extract on the shear bond strength of composite resin to bleached enamel was evaluated. MATERIALS AND METHODS: Ninety recently extracted human premolars were divided into six groups of 15 teeth each. Except Group I (negative control), the labial enamel surface of all specimens in the other groups were bleached with 37.5% hydrogen peroxide. After bleaching, Group II specimens were stored in artificial saliva for 3weeks before composite bonding. Immediately following bleaching; Groups III, IV, and V specimens were treated with antioxidants 10% sodium ascorbate, 10% grape seed extract, and 10% pine bark extract, respectively, for 10 min and bonded with composite resin. In Group VI (positive control), the composite bonding was done immediately after bleaching. All specimens were stored in deionized water for 24 h at 37?C before shear bond strength testing. The data obtained were tabulated and statistically analyzed using analysis of variance (ANOVA) and Duncan's multiple range test. RESULTS: The unbleached teeth showed the highest shear bond strength followed by the bleached teeth treated with the antioxidant 10% pine bark extract. CONCLUSION: Within the limitations of this study, it was observed that the use of antioxidants effectively reversed the compromised bond strength of bleached enamel. Among the antioxidants, 10% pine bark extract application after bleaching showed better bond strength. PMID- 25829696 TI - Solubility of a new calcium silicate-based root-end filling material. AB - INTRODUCTION: The purpose of this study was to compare solubility of a new calcium silicate-based cement, Biodentine with three commonly used root-end filling materials viz. glass-ionomer cement (GIC), intermediate restorative material (IRM), and mineral trioxide aggregate (MTA). MATERIALS AND METHODS: Twenty stainless steel ring molds were filled with cements corresponding to four groups (n = 5). The weight of 20 dried glass bottles was recorded. Samples were transferred to bottles containing 5 ml of distilled water and stored for 24 h. The bottles were dried at 105?C and weighed. This procedure was repeated for 3, 10, 30, and 60 days. Data was analyzed with one-way analysis of variance (ANOVA) test (P < 0.05). RESULTS: Biodentine demonstrated significantly higher solubility than MTA for 30- and 60-day immersion periods. Statistical difference was noted between the solubility values of Biodentine samples amongst each of the five time intervals. CONCLUSIONS: Biodentine exhibited higher solubility in comparison with all other cements. PMID- 25829698 TI - Evaluation of minimal inhibitory concentration of two new materials using tube dilution method: An in vitro study. AB - AIM: The aim of the study is to evaluate and compare the antimicrobial efficacy of two new materials MTA Plus and Biodentine with ProRoot MTA using tube dilution method. MATERIALS AND METHODS: The materials used were ProRoot MTA (Dentsply), MTA Plus (compounded by Prevest Denpro, Jammu, India for Avalon Biomed Inc, USA) and a calcium silicate based material Biodentine (Septodont, Saint-Maur-des Fosses, France). Doubling dilutions of the material were prepared in Sabouraud's dextrose broth (SDB) and Brain Heart Infusion (BHI) broth for Candida albicans and Enterococcus faecalis, respectively. The minimal concentration at which inhibition of microorganism occurred was measured and noted as minimal inhibitory concentration (MIC) of the material. RESULTS: There was no statistically significant difference between the materials against C. albicans. Biodentine was statistically significant than MTA Plus against E. faecalis (P-value-0.022). ProRoot MTA was statistically significant at different time intervals against E. faecalis (P-value-0.001). CONCLUSION: ProRoot MTA and Biodentine proved to have antimicrobial property. MTA Plusproved as a good antifungal agent. PMID- 25829697 TI - Comparison of variation in the light curing cycle with a time gap and its effect on polymerization shrinkage, degree of conversion and microhardness of a nanohybrid composite. AB - BACKGROUND: Giving a time gap and distance during curing can decrease the polymerization shrinkage. AIM: To evaluate the effect of time gap and distance between the curing tip and restoration on the polymerization shrinkage, degree of monomer conversion (DOC), and microhardness of a nanohybrid composite. MATERIALS AND METHODS: A total of 50 standardized cylindrical specimens (Z350, 3M ESPE) were fabricated using a brass mould. The curing was done in contact with the sample surface for 20 seconds in the control group. In the four experimental groups, curing was initiated at 1-cm distance, followed by variation in the time gap and the curing cycle. The polymerization shrinkage, DOC, microhardness was calculated. STATISTICAL ANALYSIS: One-way analysis of variance (ANOVA) and post hoc-Dunnett test were used to analyze the data. RESULTS: Curing at 1-cm distance for 10 seconds with a gap of 10 seconds and finishing the curing cycle with 20 seconds at 0 cm proved to be an appropriate technique to reduce the polymerization shrinkage without significantly affecting the DOC and microhardness. CONCLUSION: A simple innovative modification of varying the distance of curing and a time gap in the curing cycle can decrease the polymerization shrinkage without affecting the DOC and microhardness. PMID- 25829699 TI - Management of synodontia between dilacerated permanent maxillary central incisor and supernumerary tooth with aid of cone-beam computed tomography. AB - A malformed tooth characterized by one or more developmental disturbances is often difficult to treat. When such teeth are present in anterior region, they pose a technical challenge for the clinician to restore esthetics as well as function. This case describes endodontic, surgical, and restorative management of fused and dilacerated maxillary central incisor. Cone-beam computed tomography (CBCT) was used in the present case to aid in understanding of complicated tooth morphology and managing the case successfully. PMID- 25829700 TI - Single C-shaped canal in mandibular first molar: A case report. AB - The variability of root canal system morphology presents a continuous challenge to endodontic diagnosis and therapeutics. There have been reports of teeth with multiple roots and canals as also those with lesser number of root and root canals. Variations of root canal systems need not always be in the form of extra canals. Clinicians should be aware that there is a possibility of existence of fewer numbers of roots and root canals than normal, which presents varied canal anatomy and poses a challenge to the clinician's expertise. This case report deals with the management of an unusual case of C-shaped canal in mandibular molar with two buccally fused roots. Cone-beam computed tomography (CBCT) was employed to confirm the extension of the unusual anatomy. The Self Adjusting File (SAF) system was used to ensure complete cleaning of the canal system. One-year follow-up of the case showed good healing. The clinician should expect to encounter unusual features when performing endodontic treatment. Use of diagnostic aids like CBCT, improved magnification with dental operating microscope, and the use of novel file systems like SAF ensure success. PMID- 25829702 TI - Message from the president association of surgeons of India. PMID- 25829701 TI - SHARONLAY - A new onlay design for endodontically treated premolar. AB - Root-canal-treated teeth are structurally compromised as a result of loss of tooth structure due to caries, iatrogenic cavity preparation, and dehydration. Given that a direct relationship exists between the amount of remaining tooth structure and the ability to resist occlusal forces, it is vital to provide a restoration allowing cuspal coverage as soon as possible following completion of the root canal treatment. A decision to provide a full crown or an onlay depends on the remaining tooth structure; if the cuspal width to length ratio is 1:2 or more, an onlay can be placed. When the ratio is less than 1:2, a full crown has to be planned. In single-rooted teeth requiring post-endodontic restoration cast post and core or a prefabricated post can provide resistance to fracture with comparable results. However, in case of premolars contradictory to the practice of providing only cuspal coverage through Onlays, it would in addition require cervical reinforcement also to counter horizontal forces acting in cervical region. A new onlay design SHARONLAY patented design with I.P. no 1956475 dated 27/04/2010 with a post extending into the radicular portion of the premolar providing the required reinforcement in a conservative manner and protecting it against both vertical and horizontal forces is proposed herewith. PMID- 25829703 TI - Severe Colonic Complications requiring Sub-Total Colectomy in Acute Necrotizing Pancreatitis-A Retrospective Study of 8 Patients. AB - Colonic involvement in acute pancreatitis is associated with high mortality. Diagnosis of colonic pathology complicating acute pancreatitis is difficult. The treatment of choice is resection of the affected segment. The aim of this study is to evaluate the feasibility of aggressive surgical approach when colonic complication is suspected. Retrospectively, 8 patients with acute necrotizing pancreatitis and colonic complications (2006-2010) were reviewed. Eight patients with acute necrotizing pancreatitis requiring colonic resection were evaluated. Presentation was varied, including rectal bleeding (2), clinical deterioration during severe pancreatitis (4), colonic contrast leak on CT scan (1) and large bowel obstruction (1). Typically, patients with severe acute pancreatitis had colonic pathology obscured and unrecognized initially because of the ongoing, fulminant inflammatory process. All eight patients underwent Sub-total colectomy & ileostomy for suspected imminent or overt ischemia/perforation, based on the outer aspect of the colon. There was one mortality due to severe sepsis and multiorgan dysfunction syndrome. All other patients recovered well and later underwent closure of the stoma. Recognition of large bowel involvement may be difficult because of nonspecific symptoms or be masked by the systemic features of a critical illness. Clinicians should be aware that acute pancreatitis may erode or inflame the large bowel, resulting in lifethreatening colonic necrosis, bleeding or perforation. In our series of eight patients, we observed that mortality can be reduced by this aggressive surgical approach. We recommend a low threshold for colonic resection due to unreliable detection of ischemia or imminent perforation by outside inspection during surgery for acute necrotizing pancreatitis. PMID- 25829704 TI - Left atrial and left ventricular diastolic function after the maze procedure for atrial fibrillation in mitral valve disease: degenerative versus rheumatic. AB - The present study was aimed to compare the left atrial and left ventricular diastolic functions amongst the rheumatic and degenerative mitral valve disease patients in atrial fibrillation who reverted to normal sinus rhythm following Cox maze procedure. We prospectively investigated the left atrial and left ventricular function with Doppler echocardiography, by dividing into the rheumatic (N = 105) and the degenerative group (N = 47). Over the follow-up period (mean: 4.4 +/- 1.2 years in the rheumatic group, 4.8 +/- 1.3 years in the degenerative group), the rheumatic group showed statistically significant decrease in A' velocity and E' velocity, on contrary to degenerative group (A' velocity: mean decrease of 0.43 +/- 0.13 cm/s in the rheumatic group, mean increase of 0.57 +/- 0.11 cm/s in the degenerative group, p = 0.029, E' velocity: mean decrease of 0.23 +/- 0.17 cm/s in the rheumatic group, mean increase of 0.21 +/- 0.15 cm/s in the degenerative group, p = 0.031). In addition, the rheumatic group showed statistically significant increase in E/E' ratio than the degenerative group (mean increase of 4.49 +/- 1.98 in the rheumatic group, mean increase of 1.74 +/- 1.52 in the degenerative group, p = 0.047). Despite successful sinus rhythm restoration, the progressive loss of LA function as well as LV diastolic function is more prominent in the rheumatic group than the degenerative group. Therefore, differentiated strategies for postoperative surveillance are needed according to the pathology of mitral valve disease. PMID- 25829705 TI - The relationship between holding time and the bacterial load on surgical instruments. AB - The aim of this investigation was to determine the bacterial load on used instruments and to evaluate the relationship between the bacterial load and the holding time prior to cleaning. Thirty six sets were evaluated to establish the average number of bacteria per square centimeter. For the experimental study, three different bacteria were prepared in sheep blood and used to contaminate sterile stainless steel pieces with the surface of 10 cm(2). After incubation at room temperature for 2, 4, 6, 8, 12, 24, 36, and 48 h, colonies were counted and compared to time zero. Bacterial counts were between 10 and 250 CFU/cm(2), depending on the operation site. Bacterial load was found to have increased after 6 h. An increase of 3log10 CFU/cm(2) was measured after 12 h. It is imperative to clean surgical instruments in the first 6 h to ensure effective disinfection and sterility. PMID- 25829706 TI - To study serum iron levels in patients of gall bladder stone disease and to compare with healthy individuals. AB - Gallstone disease is a common gastrointestinal problem in day-to-day practice. The Old concept that a typical gallstone sufferer is fat, fertile, flatulent female of 50. This is partially true as the disease has been found in women soon after their first delivery who are thin and underweight and in males also. Conditions that favor the formation of cholesterol gallstones are super saturation of bile with cholesterol, kinetically favorable nucleation and presence of cholesterol crystals in the gall bladder long enough to agglomerate into a stone. Recent studies have defined the role of trace elements (Fe, Ca, Zn and Cu) and defective pH in the formation of gallstones. The aim of the study was to correlate iron-deficiency anemia with gallstone disease. To estimate the serum ferritin level as a diagnostic tool of iron deficiency anemia in patients with gallstone disease, this prospective study of 100 patients was conducted over a period of 24 months in the Department of General Surgery, Jaipur Golden Hospital, New Delhi, India. Serum cholesterol, iron and ferritin levels were compared in patients having gallstones and healthy individuals. A low serum iron level is a factor in bile super saturation with respect to cholesterol, leading to gallstone formation. PMID- 25829707 TI - Can Subepididymal Orchiectomy Re-emerge as the Treatment of Choice in Patients with Advanced Prostatic Carcinoma? AB - To study the effectiveness of bilateral subepididymal orchiectomy compared to bilateral simple and subcapsular orchiectomy in terms of androgen ablation, control of disease progression and esthetic superiority. 114 patients of advanced prostatic carcinoma (T3, T4, M1) were randomized to 3 groups- Group A: bilateral simple orchiectomy (38 patients), Group B: bilateral subcapsular orchiectomy (38 patients), & Group C: bilateral subepididymal orchiectomy (38 patients). Serum PSA and serum testosterone values were checked pre-operatively and at 3 months follow-up. Patients' esthetic satisfaction was scored on a quality of life scale of 1-5. In Groups A, B and C, at 3 months the post-operative mean serum testosterone values were 34.7, 38.1 and 36.7 ng/dl (p = 0.0524); and mean serum PSA values were 4.2, 3.9 and 3.4 ng/ml (p = 0.09) respectively, the differences not being statistically significant. On esthetic satisfaction scale the average scores were 1.8, 2.7 and 4.0 respectively, the difference being highly significant (p < 0.0001). Subepididymal orchiectomy maintains esthetic appearance of scrotum and provides superior patient satisfaction as compared to standard total and subcapsular orchiectomy, while achieving equal efficacy. Bilateral sub epididymal orchiectomy may thus be considered procedure of choice to achieve androgen ablation in advanced prostatic carcinoma. PMID- 25829708 TI - Comparison of inguinal hernia repairs performed with lichtenstein, rutkow robbins, and gilbert double layer graft methods. AB - Tension-free repairs are performed commonly in inguinal hernia operations. The objective of the present study is to compare the outcomes of three different tension-free repair methods known as Lichtenstein, Rutkow-Robbins, and Gilbert double layer. One-hundred and fifty patients diagnosed with inguinal hernia were randomly split into three groups. The comparisons across groups were carried out in terms of operation length, postoperative pain, femoral vein flow velocity, early and late complications, recurrence rates, length of hospital stay, time required to return to work, and cost analysis. No difference was found between the groups regarding age, gender, type and classification of hernia, postoperative pain, and late complications (p > 0.05). Operation length was 53.70 +/- 12.32 min in the Lichtenstein group, 44.29 +/- 12.37 min in the Rutkow Robbins group, and 45.21 +/- 14.36 min in the Gilbert group (p < 0.05). Mean preoperative and postoperative femoral vein flow velocity values were 13.88 +/- 2.237 and 13.42 +/- 2.239 cm/s for Lichtenstein group, 12.64 +/- 2.98 and 12.16 +/- 2.736 cm/s for Rutkow-Robbins group, and 16.02 +/- 3.19 and 15.52 +/- 3.358 cm/s for the Gilbert group, respectively. Statistical difference was found between all the groups (p < 0.001). However, no difference was determined between the groups regarding the decrease rates (p = 0.977). Among early complications, hematoma was observed in one (2 %) patient of Lichtenstein group, five (10 %) patients of Rutkow-Robbins group, and three (6 %) patients of Gilbert group (p = 0.033). Cost analysis produced the following results for Lichtenstein, Rutkow Robbins, and Gilbert groups: US $157.94 +/- 50.05, $481.57 +/- 11.32, and $501.51 +/- 73.59, respectively (p < 0.001). Lichtenstein operation was found to be more advantageous compared with the other techniques in terms of cost analysis as well as having unaffected femoral blood flow. Therefore, we believe that Lichtenstein repair is still the most appropriate surgical option in patients diagnosed with inguinal hernia. PMID- 25829709 TI - Palliative radiotherapy in esophageal cancer. AB - The present study was undertaken to evaluate the efficacy of radiotherapy in palliation of dysphagia in patients with squamous cell carcinoma (SCC) of esophagus and to see the quality of life (QoL) following radiotherapy. This was a prospective clinical study done between September 2006 and May 2008. All consecutive patients with SCC of the esophagus, who are not candidates for definitive treatment, were included in the study. Dysphagia and QoL were assessed using modified Takita's grading and modified questionnaire based on EORTC QLQ 30 respectively. External beam radiotherapy (EBRT) was delivered to all patients using linear accelerator 6 Mv photons. Patients who had good response with EBRT were further subjected to intraluminal brachytherapy (ILBT) at 700 cGy using Iridium-192. The cumulative dose each patient received was 65 Gy. Patients were followed up at 6 weeks from completion of treatment to look for any difference in dysphagia grade and QoL following therapy. Thirty-three patients were included in the study. The mean age among males and females was 60.9 and 49.8 years, respectively. Nineteen patients (57.6 %) received EBRT followed by ILBT; the remaining patients received only EBRT. Seven were lost during follow-up, and seven (21.2 %) died during the study period of 6 weeks. Nineteen (57.6 %) were followed up. On follow-up endoscopy, evidence of residual stricture was observed in 57.9 %, and growth in 36.8 %. Of the patients, 27.8 % had biopsy-confirmed residual disease. The median dysphagia score decreased from 4 to 3 after treatment (p = 0.002) in 17 (89.5 %) patients. The mean QoL score improved from 107.5 to 114.1 at 6-week follow-up. Following radiotherapy, 26.3 % had persistent chest pain, increased cough with expectoration in 15.8 %, and hyperpigmentation of skin in 10.5 %. Radiotherapy gives significant relief of dysphagia and improves QoL in 90 % of patients with SCC of esophagus. However, following radiotherapy, a number of patients will have persistent stricture, ulceration, and residual disease. PMID- 25829710 TI - Reconstruction of chest wall using a two-layer prolene mesh and bone cement sandwich. AB - Wide surgical resection is the most effective treatment for the vast majority of chest wall tumors. This study evaluated the clinical success of chest wall reconstruction using a Prolene mesh and bone cement prosthetic sandwich. The records of all patients undergoing chest wall resection and reconstruction were reviewed. Surgical indications, the location and size of the chest wall defect, diaphragm resection, pulmonary performance, postoperative complications, and survival of each patient were recorded. From 1998 to 2008, 43 patients (27 male, 16 female; mean age of 48 years) underwent surgery in our department to treat malignant chest wall tumors: chondrosarcoma (23), osteosarcoma (8), spindle cell sarcoma (6), Ewing's sarcoma (2), and others (4). Nine sternectomies and 34 antero-lateral and postero-lateral chest wall resections were performed. Postoperatively, nine patients experienced respiratory complications, and one patient died because of respiratory failure. The overall 4-year survival rate was 60 %. Chest wall reconstruction using a Prolene mesh and bone cement prosthetic sandwich is a safe and effective surgical procedure for major chest wall defects. PMID- 25829711 TI - Pulsion Diverticulum of the Oesophagus: More than just an Out Pouch. AB - Oesophageal diverticulum is divided into two types based on the aetiology: the pulsion and the traction diverticula. Pulsion diverticulum occurs due to increased intraluminal pressure. This can be of three types based on the location along the oesophagus: the Zenker's diverticulum (ZD), the mid-oesophageal diverticulum (MD) and the epiphrenic diverticulum (ED). A PubMed search was conducted for the words 'pulsion', 'diverticulum' and 'oesophagus' for all studies published from January 1980 to March 2013 in the English language. A total of 31 studies were identified, and out of which, five were not included in the review. The pulsion diverticulum of the oesophagus is an uncommon disorder. Its aetiology is related to the motility disorders of the oesophagus. Patients usually present with chest-related symptoms or oesophageal symptoms, which are related to the underlying motility disorder. Evaluation includes barium studies, gastrointestinal endoscopy, CT scan and oesophageal manometry. Surgery is the treatment of choice for symptomatic and large diverticula, although the outcome in asymptomatic patients is unknown. The surgical options include diverticulectomy or diverticulopexy with an adequate myotomy. Most patients with ZD are now treated by using endoscopic techniques, although no randomised trial has shown its superiority over the open technique. Minimally invasive surgery has also been used for patients with MD and ED. Although isolated case series has shown good improvement in symptoms and reduction in mortality with minimally invasive techniques in patients with ED, its role in thoracic oesophageal diverticulum is debated. PMID- 25829712 TI - Surgical trauma and immune functional changes following major lung resection. AB - Video-assisted thoracic surgery (VATS) has evolved greatly over the last two decades. VATS major lung resection for early stage non-small cell lung carcinoma (NSCLC) has been shown to result in less postoperative pain, less pulmonary dysfunction postoperatively, shorter hospital stay, and better patient tolerance to adjuvant chemotherapy compared with patients who underwent thoracotomy. Several recent studies have even reported improved long-term survival in those who underwent VATS major lung resection for early stage NSCLC when compared with open technique. Interestingly, the immune status and autologous tumor killing ability of lung cancer patients have previously been associated with long-term survival. VATS major lung resection can result in an attenuated postoperative inflammatory response. Furthermore, the minimal invasive approach better preserve patients' postoperative immune function, leading to higher circulating natural killer and T cells numbers, T cell oxidative activity, and levels of immunochemokines such as insulin growth factor binding protein 3 following VATS compared with thoracotomy. Apart from host immunity, the angiogenic environment following surgery may also have a role in determining cancer recurrence and possibly survival. Whether differences in immunological and biochemical mediators contribute significantly towards improved clinical outcomes following VATS major lung resection for lung cancer remains to be further investigated. Future studies will also need to address whether the reduced access trauma from advanced thoracic surgical techniques, such as single-port VATS, can further attenuate the postoperative inflammatory response. PMID- 25829713 TI - Facial dog attack injuries. AB - The exposed position of the face makes it vulnerable to dog bite injuries. This fact combined with the short stature of children makes them a high-risk group for such attacks. In contrast to wounds inflicted by assaults and accidents, dog bite wounds are deep puncture type wounds compounded by the presence of pathologic bacteria from the saliva of the attacking dog. This, combined with the presence of crushed, devitalized tissue makes these wounds highly susceptible to infection. Key to successful management of such wounds are meticulous cleansing of the wound, careful debridement, primary repair, appropriate antibiotic therapy, and rabies and tetanus immunization where indicated. This review presents an overview of the epidemiology, presentation, management of such emergencies, and the recent advances in the care of such patients. PMID- 25829714 TI - Synchronous Jejunal Metastasis Presenting as Intussusception in a Case of Advanced RCC: a Rare Presentation. AB - Renal cell carcinoma (RCC) may metastasize to almost any organ, but metastasis to the small bowel is very rare. Factors responsible for a resistant behavior of small bowel wall are still not clear. Small bowel metastasis from RCC may cause obstruction, bleeding, and perforation. RCC metastasis to the small bowel presenting as intussusception is extremely rare. Only 20 cases of small bowel intussusceptions caused by metastatic RCC have been reported worldwide. Here, we are reporting this rare case of RCC with simultaneous solitary metastasis in jejunum which presented as intussusceptions and which was treated with simultaneous radical nephrectomy, jejunal resection, and anastomosis. PMID- 25829715 TI - Haemophilic pseudotumour: surgical management of a rare case. AB - Haemophilia is a common cause of genetically inherited bleeding disorders. Pseudotumours occur in 1-2 % of persons with severe forms of haemophilia. These are a result of repeated haemorrhage into soft tissues, subperiosteum or a site of bone fracture with inadequate resorption of the extravasated blood. There are a number of therapeutic alternatives for this dangerous condition: surgical removal, percutaneous management, irradiation, embolization etc. In this case report, we describe the natural history, clinical course and successful surgical management of a patient with haemophilia who presented with a massive pseudotumour. We also briefly review the relevant literature on the various therapeutic modalities that have been implemented in the management of this rare complication. Though surgeons may be averse to operate on haemophiliacs, primary surgical management as done in our case may prove to be the definitive treatment option for such patients. PMID- 25829716 TI - Management of cardiac injury by stab wounds on the right lateral chest wall: a case report. AB - The report presented a 20-year-old male case with multiple stab wounds on the right lateral chest wall, and a latent heart injury was found during the right lateral thoracotomy. A laceration on the right ventricle was verified by a median sternoctomy and repaired using an Inforce suture. The clinicians should not neglect the lower probability of life-threatening thoracic injuries following stab wounds to the chest, despite the initial location of anatomy. PMID- 25829717 TI - Desmoplastic Small Round Cell Tumor (DSRCT): an Unusual Intra-abdominal Tumor. AB - Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal tumor commonly seen in adolescents and young adult males. It is an important differential diagnosis in these patients presenting with abdominal masses and/or GI obstruction. The management and prognosis improve if preoperative diagnosis can be established. PMID- 25829718 TI - Omphalocele major with absent lower limb. AB - A newborn delivered by Caesarian section presented with an absent anterior abdominal wall and visible bowel loops and liver. The defect was covered by a thin membrane. The patient had associated absent left lower limb and right foot fusion defect. The patient was haemodynamically stable; general condition was average. No genito-urinary abnormality was detected. The anal opening was present normally, and the patient passed meconium immediately after birth. A diagnosis of omphalocele major with amelia was made. The patient was initially managed by topical application of povidone-iodine for eschar formation and epithelisation of the sac. The patient was discharged after 1 week with advice for regular follow up. PMID- 25829719 TI - Impalement injury with transanal prolapse of bowel content due to intraperitoneal rectal tear. AB - A 48-eight-year-old female patient came with prolapse of small intestines per rectum (Fig. 1) due to impalement injury with iron rod at a construction site. As the patient was hemodynamically unstable, she was taken for emergency laparotomy. A large rent in the intraperitoneal rectum was found (Fig. 2), with prolapse of intestines. Luckily for the patient, there was no other intra-abdominal organ injury. As there was no fecal contamination at all, a decision against proximal colostomy was made. The rent was closed in two layers after re-placing the small bowel contents with thorough lavage. Patient made a swift recovery thereafter. PMID- 25829720 TI - Bezoar: an unusual palpable mass in the right iliac fossa. AB - A 64-year-old gentleman presented with a 12-h history of right iliac fossa pain. On examination, the patient had a tender 8 * 6 cm mass in the right iliac fossa with localised peritonitis. The working diagnosis at this time was an appendix mass or caecal cancer. A computed tomography scan revealed the characteristic 'bird's nest' appearance of a bezoar. On further questioning, the patient confessed to regularly 'binging' on grapes. The patient described passing the mass and his symptoms completely resolved. This appears to be the only documented case of a bezoar affecting the ascending colon. PMID- 25829721 TI - "One-stop hybrid procedure" in the treatment of vascular injury of lower extremity. AB - As a new surgical technique, "one-stop hybrid procedure" is rarely applied in trauma patients. This paper aims to explore its role in vascular injury of the lower extremity. Vascular intervention combined with open surgery was performed to treat three cases of vessel injuries of the lower extremity in our hybrid operating room. One patient with stab injury to the left femoral vein was treated by temporary artery blocking after excluding arterial injury by angiography, followed by blocking surgery and debridement and repair of the injured vein. The other two patients with drug addiction history, who were found to have pricking injuries to the femoral artery combined with local infection, were successfully treated by endovascular techniques and open debridement. One-stop hybrid procedure in treating vascular injury patients could simplify the operation procedure, reduce operative risk, and achieve good curative effect. PMID- 25829722 TI - Schwannoma of parapharyngeal space: a case report. AB - The incidence of schwannoma in the head and neck region is between 25 and 45 %. The vestibular nerve is involved in most cases followed by the parapharyngeal space. Schwannoma, also known as neurilemmoma, is a benign neoplasm that originates from the Schwann cells. These cells form the myelin sheath around myelinated peripheral axons. Here, we report a case of parapharyngeal space schwannoma in a 27-year-old female. PMID- 25829723 TI - Data conflicts: the dwindling power of a study. PMID- 25829724 TI - Study methodology: crux of a research article. PMID- 25829725 TI - 18-F flourodeoxy glucose positron emission tomography-computed tomography imaging: A viable alternative to three phase bone scan in evaluating diabetic foot complications? AB - BACKGROUND: This paper is based on the initial findings from a prospective ongoing study to evaluate the efficacy of flourodeoxy glucose positron emission tomography-computed tomography (FDG-PET CT) in diabetic foot evaluation. OBJECTIVE: The aim was to compare the diagnostic accuracies of three phase bone scan (TPBS) and FDG PET-CT (FDG-PET) in diabetic foot evaluation. METHODS: Seventy-nine patients with complicated diabetic foot (osteomyelitis/cellulitis, Charcot's neuropathy) were prospectively investigated. TPBS (15 mci methylene di phosphonate [MDP] intravenous [IV]), followed by FDG-PET (5 mci IV) within 5 days were performed in all patients. Based on referral indication, patients grouped into Group I, n = 36, (?osteomyelitis/cellulitis) and Group II, n = 43 (?Charcot's neuropathy). Interpretation was based on intensity, extent, pattern of MDP and FDG uptake (standardized uptake value) along with CT correlation. Findings were compared with final diagnostic outcome based on bone/soft tissue culture in Group I and clinical, radiological or scintigraphic followup in Group II. RESULTS: Group I: For diagnosing osteomyelitis, TP: TN: FP: FN were 14:5:2:2 by FDG PET and 13:02:05:03 by TPBS respectively. Sensitivity, specificity, positive predictive value and negative predictive value (NPV) of FDG-PET were 87.5%, 71%, 87.5% and 71% and 81.25%, 28.5%, 72% and 40% for TPBS, respectively. Group II: charcot's: cellulitis: Normal were 22:14:7 by FDG PET and 32:5:6 by TPBS, respectively. CONCLUSION: Flourodeoxy glucose PET-CT has a higher specificity and NPV than TPBS in diagnosing pedal osteomyelitis. TPBS, being highly sensitive is more useful than FDG-PET in detecting Charcot's neuropathy. PMID- 25829726 TI - Three phase bone scan interpretation based upon vascular endothelial response. AB - OBJECTIVES: A new method of interpretation of Three Phase Bone Scan (TPBS) scan based upon the normal physiological vascular endothelial related response. MATERIALS AND METHODS: Fifty cases of TPBS were evaluated. Thirteen were normal. In remaining 37 positive studies, 20 showed localized hyperemic response. All localized hyperemic responses except one with vascular endothelial dysfunction were without infection (95.0%). Infection could be ruled out in absence of generalized massive flow and pool response. All 17 cases with generalized massive hyperemic response had infection, consistent with infection or CRPS/RSD. Micro bacterial or histological confirmation of infection was obtained in 11 cases. All 11 cases with confirmed infection showed generalized massive hyperemic response (100.0%). Two were CRPS/RSD and 2 cases were of cellulitis (100.0%). Among remaining 2, one refused surgery and other was lost to follow-up. Additionally, 20 published cases in the literature of osteomyelitis were also analyzed. Nineteen cases of bone and joint infection, (osteomyelitis/arthritis/cellulitis) except one with endothelial dysfunction showed generalized massive increased flow and pool response (95.0%). All published cases of osteomyelitis in the literature showed generalized massive hyperemic response (100.0%). RESULTS: The data clearly indicated that 100% of the cases of bone infection (osteomyelitis/arthritis/cellulitis) and cases of CRPS/RSD showed generalized massive flow and pool pattern. Infection could be ruled out in absence of generalized massive flow and pool response. All 100% published cases of osteomyelitis in the literature showed positive vascular endothelial response. CONCLUSION: By incorporating the concept of vascular endothelial related response causing massive vasodilatation in infection, the interpretation of the TPBS can be more precised as it is based upon the normal physiology. Larger studies are recommended. PMID- 25829727 TI - Effects of low-dose capecitabine on Samarium-153-EDTMP therapy for painful bone metastases. AB - INTRODUCTION: Samarium-153 (Sm-153)-EDTMP is routinely used for pain palliation in skeletal metastasis, however most patients report partial response. Many strategies have been contemplated to make radiation therapy for pain more effective, one of them being the use of radiosensitizers. Capecitabine is a chemotherapeutic drug and is routinely combined with external beam radiation to make the target more radio-sensitive. Aim of the study was to evaluate whether combining capecitabine in radiosensitizing dose with Sm-153-EDTMP produces superior analgesia compared to Sm alone. MATERIALS AND METHODS: Forty-four patients with skeletal metastases from various primaries were randomized into two groups: The study group received 1 mCi/kg Sm-153-EDTMP plus capecitabine (1,650 mg/m(2)) orally for 8 days (equivalent to four t 1/2 of (153)Sm-EDTMP) and the control arm received 1 mCi/kg Sm-153-EDTMP plus placebo for the 8 days. After treatment, the patients were followed up for 12 weeks to evaluate the degree and duration of pain palliation and hematologic toxicity. RESULTS: All 44 patients reported different degrees of pain relief with none reporting complete pain relief for the entire duration of 12 weeks posttherapy observation period. However the level of pain relief obtained in study arm was significantly better than the control arm with mean posttherapy pain score being 1.29 +/- 1.05 and 3.59 +/- 2.77 respectively with P of 0.001. Transient and mild hematologic toxicity, as determined by World Health Organization criteria, was apparent in both arms without significant differences. CONCLUSION: The addition of a low-dose of capecitabine significantly enhances the analgesic effect of Sm-153 without any additional side effects. PMID- 25829728 TI - Rate of thyroglossal duct remnant visualization after total thyroidectomy for differentiated thyroid carcinoma and its impact on clinical outcome of radioactive iodine (I-131) ablation. AB - OBJECTIVES: The rate and impact of thyroglossal duct remnant (TGDR) visualization in patients with hypothyroidism after total thyroidectomy for differentiated thyroid carcinoma (DTC) have not yet been fully determined. The aim of this study was to assess the rate of TGDR visualization in post total thyroidectomy whole body scan (WBS) for DTC and to evaluate its impact on the outcome of I-131 ablation. METHODS: A total of 60 consecutive DTC patients (51 papillary thyroid Ca., and 9 Follicular thyroid Ca.), underwent total thyroidectomy, followed by WBS (using I-131 in 28 patients and I-123 in 32 patients), neck ultrasound (US), thyroglobulin (Tg) and Tg anti-bodies (TgAb) assay after 40 days and subsequent I 131 ablation. At 6 months later follow-up I-131 WBS, neck U/S, Tg and TgAb were performed following suspension of L-thyroxine for 1-month (thyroid stimulating hormone [TSH] >30 MUIU/ml) in 53 patients and following recombinant human TSH stimulation in seven patients. RESULTS: Of the studied 60 patients, 19/60 (31.7%) had a linear or focal radioactivity at the superior midline of the neck, suggesting TGDR (Group 1), and 41/60 (68.3%) had no uptake to suggest TGDR (Group 2). No significant difference regarding age, gender and histopathology between both groups. Neck US showed no evidence of thyroid tissue in the superior midline of the neck in both groups, and only a small or no residual thyroid tissue in patients of Group 1. There was a significant successful I-131 ablation rate among patients of group 1 compared to group 2 (79% in Group 1 vs. 41.5% in Group 2) (P = 0.007). CONCLUSIONS: Thyroglossal duct remnant visualization on WBS of hypothyroid subjects after total thyroidectomy suggests presence of only a small or no residual functioning thyroid tissue at the thyroid bed and can predict a good response to I-131 ablation. PMID- 25829729 TI - Deviation in the predefined calibration factors of the dose calibrators and the associated inaccuracy in the radioactivity measurements of beta-gamma emitters. AB - AIM: To determine whether the predefined calibration factors of the dose calibrators can provide accurate radioactivity measurements of beta-gamma emitters used in routine therapeutic nuclear medicine procedures. MATERIALS AND METHODS: Two models of dose calibrators were used in the present study for radioactivity measurements of (153)Sm ethylenediamine-N, N, N', N'-tetrakis methylene phosphonic acid (EDTMP) and (177)Lu (EDTMP). A known (precalibrated) activity of each of the two beta emitters received by us from our National Supplier for administration to the patients with extensive bony metastases for bone pain palliation, was used for experiments. RESULTS: When we used the manufacturers' provided dial setting of 450 * 10, each of the dose calibrators underestimated the radioactivity of (177)Lu by about 9.0%. Dial settings of 403 * 10 and 408 * 10 for (177)Lu on CRC-15R and CRC-ultra dose calibrators respectively were calculated experimentally using an iterative approach. The radioactivity measurements made at these settings provided an excellent agreement with the specified values. Likewise, a dial setting of 230 for each of the two dose calibrators was calculated for (153)Sm, which provided a good agreement between the experimentally derived radioactivity values and the certified values. A deviation of +/- 5.0% was observed when radioactivity of (177)Lu and (153)Sm was measured over a wide range (4.0 MBq to 2.1 GBq) for time intervals equivalent to 4.5 half-lives of each of the two radionuclides. A deviation of +/- 5% was observed when radioactivity was counted in different dilution volumes and in syringes of varying size. CONCLUSION: These variations could lead to a cumulative error of about 20.0% toward the inaccuracy in the radioactivity measurements of the beta-gamma emitters and thus predefined calibration factors of the dose calibrators may require experimental re-setting of these parameters and periodic checking to provide accurate radioactivity estimates of beta-gamma emitters in a given clinical setting. PMID- 25829730 TI - Characterization of parallel-hole collimator using Monte Carlo Simulation. AB - OBJECTIVE: Accuracy of in vivo activity quantification improves after the correction of penetrated and scattered photons. However, accurate assessment is not possible with physical experiment. We have used Monte Carlo Simulation to accurately assess the contribution of penetrated and scattered photons in the photopeak window. MATERIALS AND METHODS: Simulations were performed with Simulation of Imaging Nuclear Detectors Monte Carlo Code. The simulations were set up in such a way that it provides geometric, penetration, and scatter components after each simulation and writes binary images to a data file. These components were analyzed graphically using Microsoft Excel (Microsoft Corporation, USA). Each binary image was imported in software (ImageJ) and logarithmic transformation was applied for visual assessment of image quality, plotting profile across the center of the images and calculating full width at half maximum (FWHM) in horizontal and vertical directions. RESULTS: The geometric, penetration, and scatter at 140 keV for low-energy general-purpose were 93.20%, 4.13%, 2.67% respectively. Similarly, geometric, penetration, and scatter at 140 keV for low-energy high-resolution (LEHR), medium-energy general purpose (MEGP), and high-energy general-purpose (HEGP) collimator were (94.06%, 3.39%, 2.55%), (96.42%, 1.52%, 2.06%), and (96.70%, 1.45%, 1.85%), respectively. For MEGP collimator at 245 keV photon and for HEGP collimator at 364 keV were 89.10%, 7.08%, 3.82% and 67.78%, 18.63%, 13.59%, respectively. CONCLUSION: Low energy general-purpose and LEHR collimator is best to image 140 keV photon. HEGP can be used for 245 keV and 364 keV; however, correction for penetration and scatter must be applied if one is interested to quantify the in vivo activity of energy 364 keV. Due to heavy penetration and scattering, 511 keV photons should not be imaged with HEGP collimator. PMID- 25829731 TI - Splenic and lymph nodal involvement in sarcoidosis mimicking lymphoma on fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography. AB - Sarcoidosis is a multisystemic disease presenting with well-defined, bilateral, symmetric hilar and right paratracheal lymph node enlargement. Recently, fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) has been used to stage and detect occult site of active inflammation in sarcoidosis. F-18 FDG PET/CT has become a cornerstone imaging modality in the modern lymphoma management, which can present with generalized lymphadenopathy including mediastinal. We present a case series, which shows how sarcoidosis can be a "great mimic of lymphoma" on F-18 FDG PET/CT and how histopathology is essential in diagnosing sarcoidosis and ruling out lymphoma. PMID- 25829732 TI - Role of dual time fluorodeoxyglucose (FDG) positron emission tomography-computed tomography in identifying co-existing inflammatory and malignant disease: Who holds it (FDG) longer? AB - 18-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is an integral part of imaging in the follow-up of head and neck malignancies. Very often distinguishing inflammatory/infective from malignant recurrence cannot be made confidently with standard uptake value (SUV) alone, as inflammatory lesions have shown to have a very high SUV, and in some cases both can co-exist. In such doubtful cases, dual time PET-CT (3-5 h delayed) is of paramount importance in confidently differentiating inflammatory/infective from a malignant cause. PMID- 25829733 TI - Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of primary pulmonary angiosarcomas. AB - Angiosarcoma is a malignant vascular tumor that originates from the mesenchymal cells which have undergone angioblastic differentiation. Pulmonary angiosarcomas are invariably (>90%) metastatic tumors form primaries of the skin, bone, liver, breast, or heart. Primary pulmonary angiosarcomas are exceedingly rare, with just about 20 cases being reported in the literature. We report an additional case with a brief review of the literature of a primary pulmonary angiosarcoma in a 26 year-old lady who presented with intractable hemoptysis. In addition, we highlight the potential of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography as an important diagnostic tool in the evaluation of this tumor and thus contribute to the existing sparse literature on this fascinating yet devastating disease. PMID- 25829734 TI - Metabolic flare phenomenon on 18 fluoride-fluorodeoxy glucose positron emission tomography-computed tomography scans in a patient with bilateral breast cancer treated with second-line chemotherapy and bevacizumab. AB - Increase in radiopharmaceutical uptake is an indicator of progression of disease. Paradoxical increase in the radiopharmaceutical uptake also occurs during favorable response to therapy, which is designated as flare phenomenon. Flare phenomenon is well documented on bone scinitgraphy when initially noted lesions show increased radiotracer uptake after therapy is instituted. This happens despite favorable response to the treatment. The osteoblastic activity associated with healing response of bone tumors is the cause of flare phenomenon. Recently, metabolic flare phenomenon has been described in patients with breast cancer who undergo hormonal therapy. Changes in the hormonal level during initial part of the treatment is the cause of metabolic flare. We describe a patient with bilateral breast cancer who underwent second line chemotherapy along with bevacizumab. Serial positron emission tomography scans done showed interesting phenomenon of metabolic flare. PMID- 25829735 TI - FDG PET/CT detects benign neurofibromas presenting as nodal masses: Imaging hallmarks of a diagnostic "red herring". AB - Multi-modality positron emission tomography/computed tomography (PET/CT) with 18F fluoro-deoxy-glucose (FDG) depicts the enhancement pattern and metabolic intensity of lesions. Benign lesions with multiplicity, like neurofibromas often mimic similar appearing malignant neoplasms. We, report, a similar case where FDG PET/CT shows imaging hallmarks for diagnosing benign neurofibromas, in a patient with clinical presentation of lymphoma. PMID- 25829736 TI - Paget's disease of pelvis mimicking metastasis in a patient with lung cancer evaluated using staging and follow-up imaging with fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography. AB - Paget's disease of bone is a benign disease, of uncertain etiology, characterized by an accelerated turnover, that is, bone resorption and formation. Paget's disease may be present in up to 5% of the population, and the majority of cases are asymptomatic. We report the imaging findings of Paget's disease of pelvis discovered incidentally in patient with lung cancer evaluated by fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for staging. FDG PET-CT scan showed intense uptake in the right lung lower lobe primary and mediastinal lymph nodes. Furthermore, increased uptake noted in left hemipelvis suggestive of Paget's disease. He underwent follow-up FDG PET-CT after chemotherapy showed decrease in lung mass and mediastinal nodes. However, the uptake in left hemipelvis remains same confirming Paget's disease. PMID- 25829737 TI - Hepatic metastasis arising from diverse primary pathologies diagnosed on 99mTc Methylene diphosphonate bone scan. AB - We are presenting two cases that illustrate nonosseous localization of 99mTc Methylene diphosphonate (MDP) in hepatic metastases arising from varied primary pathology and review of the literature. This series emphasizes the evidence of MDP localization in hepatic metastases arising from adenocarcinoma of rectum and infiltrating duct cell carcinoma of the breast. PMID- 25829738 TI - Missing sentinel lymph node in cutaneous melanoma. AB - The American Society of Clinical Oncology guidelines recommend sentinel lymph node biopsy (SLNB) for all patients with melanoma tumors of intermediate thickness (between 1 and 4 mm). In case of patients with thick melanoma tumors (>4 mm), SLNB may be recommended as well, for staging purposes and to facilitate regional disease control. We report a case of an 82-year-old man, undergone excision of a cutaneous melanoma of the right thigh, which shows some limitation of SLNB in thick melanoma. Lymphoscintigraphy, performed as single-photon emission computed tomography/computed tomography (SPECT/CT), failed to identify the real sentinel lymph node, as tracer uptake was seen in A right inguinal node. Due to the presence on CT co-registered images of another suspicious node (with no radiopharmaceutical uptake) in the crural region, and considering the "high risk" pathologic features of the removed primary lesion, a 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) staging scan was planned. PET/CT showed high metabolic activity in the suspected crural lymphadenopathy. Histopathology demonstrated massive invasion of the crural ("sentinel") node and no metastatic cells in the inguinal node. This report highlights both the higher accuracy of lymphoscintigraphy, when performed as SPECT/CT and the potential utility of 18F-FDG PET/CT in regional staging. PMID- 25829739 TI - Primary malignant melanoma of the esophagus. AB - Primary malignant melanoma most commonly originates from the skin; other less common extra cutaneous sites include squamous mucous membranes, uvea, retina, leptomeninges, genitourinary tract, digestive tract, biliary tract, and upper respiratory tract. Primary melanoma of the gastrointestinal tract is exceedingly rare. We are reporting a histo-pathologically proven rare case of primary malignant melanoma of the esophagus and its findings on fluorodeoxyglucose positron emission tomography and computed tomography. PMID- 25829740 TI - Mycosis fungoides: Positron emission tomography/computed tomography in staging and monitoring the effect of therapy. AB - A 58-year-old woman, diagnosed as a case of mycosis fungoides (MF), underwent [18F]-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) examination. The study revealed intense FDG uptake in a large ulceroproliferative right thigh lesion, indurated plaques in the chest wall and left thigh, along with multiple sites of cutaneous involvement, axillary and inguinal lymphadenopathy. The patient underwent chemotherapy with CHOP regimen, radiotherapy for the right thigh lesion, along with topical corticosteroids and emollients for the disseminated cutaneous involvement. Repeat [18F]-FDG PET/CT study performed a year later, showed near complete disease regression specifically of the ulceroproliferative lesion and indurated cutaneous plaques, no change in lymphadenopathy, and a subtle diffuse progression of the remaining cutaneous lesions. A multidisciplinary approach to the diagnosis, staging and treatment of MF has long been suggested for optimizing outcomes from management of patients with this disease. This case highlights the potential role of incorporating PET/CT as a single modality imaging technique in the staging and assessment of response to therapy. PMID- 25829741 TI - Rare case of axillary lymph node metastasis in papillary thyroid carcinoma detected using Iodine-131 whole-body scintigraphy and single-photon emission computed tomography/computed tomography. AB - Differentiated thyroid cancer is, usually, associated with an excellent prognosis and indolent course. Distant metastases are rare events at the onset of thyroid cancer. Among these presentations, metastasis to the axillary lymph nodes is even more unusual. Only few cases of papillary carcinoma with axillary nodal metastasis were previously reported in the literature. We present a 38-year-old female who underwent Iodine-131 whole-body scintigraphy, after total thyroidectomy and bilateral neck lymph node dissection for papillary carcinoma of thyroid, showed intense uptake in the remnant thyroid, lung metastasis, left cervical and left axillary lymph nodes. Excision of left axillary lymph nodes confirmed metastatic papillary carcinoma. PMID- 25829742 TI - Unusual sites of metastatic recurrence of osteosarcoma detected on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography. AB - Osteosarcoma (OS) is the most common nonhematolymphoid primary bone malignancy characterized by osteoid or new bone formation. Lungs and bones are the most common sites of metastases. We report a case where unusual sites of the soft tissue recurrence from OS were detected on restaging fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan done post 6 years of disease free interval. PMID- 25829744 TI - Lymphoscintigraphy combined with single-photon emission computed tomography computed tomography (SPECT-CT): A very effective imaging approach for identification of the site of leak in postoperative chylothorax. AB - Post operative chylothorax is a known complication of various thoracic surgeries. It needs identification of precise site of leak in the thoracic duct. Lymphosicintigraphy can identify chyle leak but cannot delineate exact site of leak. SPECT-CT is precise in anatomic localisation and hence SPECT-CT should be combined with every lymphoscintigraphy in evaluation of clinically suspected case of post operative chylothorax. We report such a case. PMID- 25829743 TI - Non heamoptytic massive Rasmussen's pulmonary artery aneurysm caused by aggressive cavitating squamous cell carcinoma metastasis. AB - The authors report an extremely rare occurrence of a massive aneurysm of a major pulmonary artery branch vessel caused by adjacent necrotizing aggressive squamous cell carcinoma metastatic mediastinal nodes. Despite the huge size, there was no hemoptysis due to the walling off effect by the necrotic nodes. PMID- 25829745 TI - Mediastinal ectopic benign colloid goitre detected using iodine-131 whole body scintigraphy and single-photon emission computed tomography-computed tomography. AB - Ectopic thyroid tissue primarily occurs along the course of the embryologic migration of the thyroid gland. Mediastinal thyroid may be differentiated into primary and secondary form. Primary mediastinal goiters are quite rare, occurring in <1% of all goiters. We present findings of 29-year-old female, case of papillary carcinoma of the thyroid who underwent iodine-131 whole body scintigraphy after total thyroidectomy showed a primary mediastinal mass lesion along with residual thyroid. She underwent mediastinal mass excision through sternotomy and biopsy confirmed as ectopic nodular colloid goiter with no malignancy. PMID- 25829746 TI - Bone single-photon emission computed tomography and three-dimensional computed tomography in the diagnosis of low costal variation and pathologies. AB - In general, there are five lumbar vertebras in normal human subjects. But occasionally there are six. In such a situation, a radiologist need to discern between lumbarization of S1 (S1 vertebra becomes segmented and mimics L5) or due to hypoplastic 12(th) ribs, hence the T12 vertebra is wrongly assumed to be L1. These interesting images serve a multimodality approach to right aplasia/left hypoplasia of 12(th) rib, injury of left 11(th) rib and subluxation of left 11(th) Costovertebral joint in a patient with lumbar back pain. PMID- 25829747 TI - F-18 fluoro-d-glucose positron emission tomography/computed tomography in a patient with corticobasal degeneration. AB - Corticobasal degeneration is a rare neurodegenerative disorder that often eludes clinical diagnosis. The present case shows the F-18 fluoro-d-glucose positron emission tomography/computed tomography (PET/CT) of a 62-year-old man with a progressive movement disorder with asymmetric features. PET/CT examination showed a markedly right-brain hemispheric hypometabolism also involving basal ganglia. PMID- 25829748 TI - Cold spot in the uniform Co-57 image may not necessarily be due to photomultiplier tube failure or variations in photomultiplier tube tuning: A technical note. PMID- 25829749 TI - Microbial infection imaging: A novel diagnostic approach. PMID- 25829750 TI - Flowtron foot-pumps for prevention of venous thromboembolism in total hip and knee replacement. AB - INTRODUCTION: Mechanical prophylaxis with foot-pumps provides an interesting alternative to chemical agents in the prevention of venous thomboembolism following major orthopaedic surgery procedures. The aim of this prospective study was to assess efficacy and safety of the Flowtron((r)) foot-pumps system following total hip and knee replacement. The foot pumps were used as main tool for prevention of thromboembolic events, in most cases in association with a variety of chemicals. METHODS: The primary endpoint of the study was to assess the incidence of deep vein thrombosis and pulmonary embolism after total hip and knee replacement. The secondary endpoints included postoperative bleeding, swelling, bruising and wound ooze. RESULTS: 424 consecutive patients were included in the study. Symptomatic deep vein thrombosis was detected in 7 patients (1.6%). All symptomatic deep vein thromboses were detected after discharge before the six week follow-up clinic. Five non-fatal pulmonary embolisms occurred (1.2%). Only one patient presented a major wound bleeding (0.2%). The mean difference of swelling of thigh pre-versus postoperatively was only 22.8 mm. DISCUSSION: In conclusion, thromboembolism prophylaxis after total hip and knee replacement using Flowtron((r)) foot-pumps as main prevention tool of an individualised protocol appears effective and safe. This is the first clinical report related to this popular brand of foot pumps. PMID- 25829751 TI - Optimization of multiple quality characteristics in bone drilling using grey relational analysis. AB - PURPOSE: Drilling of bone is common during bone fracture treatment to fix the fractured parts with screws wires or plates. Minimally invasive drilling of the bone has a great demand as it helps in better fixation and quick healing of the broken bones. The purpose of the present investigation is to determine the optimum cutting condition for the minimization of the temperature, force and surface roughness simultaneously during bone drilling. METHOD: In this study, drilling experiments have been performed on bovine bone with different conditions of feed rate and drill rotational speed using full factorial design. Optimal level of the drilling parameters is determined by the grey relational grade (GRG) obtained from the GRA as the performance index of multiple quality characteristics. The effect of each drilling parameter on GRG is determined using analysis of variance (ANOVA) and the results obtained are validated by confirmation experiment. RESULTS: Grey relational analysis showed that the investigation with feed rate of 40 mm/min and spindle speed of 500 rpm has the highest grey relational grade and is recommended setting for minimum temperature, force and surface roughness simultaneously during bone drilling. Feed rate has the highest contribution (59.49%) on the multiple performance characteristics followed by the spindle speed (37.69%) as obtained from ANOVA analysis. CONCLUSIONS: The use of grey relational analysis will simplify the complex process of optimization of the multi response characteristics in bone drilling by converting them into a single grey relational grade. The use of the above suggested methodology can greatly minimize the bone tissue injury during drilling. PMID- 25829752 TI - Development and validation of the French version of a tool assessing patient's expectations in lower limb osteoarthritis. AB - OBJECTIVE: The Hospital for Special Surgery (HSS) Hip Replacement Expectations Survey and Knee Replacement Expectations Survey are validated tools developed to measure patients' preoperative expectations for hip and knee arthroplasty. These instruments have possible uses in both daily practice and research. Our objective was to assess the test-retest reliability and the construct validity of the French version of the surveys. METHODS: Patients scheduled for total hip (n = 82) or knee replacement (n = 61) aged 38-90 years were included. All completed the HSS Hip or Knee Replacement Expectations Survey and the Expectation WOMAC to determine concurrent validity. The test-retest reliability was assessed using the intraclass coefficient correlation (ICC), the Bland and Altman Method and the coefficient of variation; the internal consistency was assessed by the Cronbach alpha coefficient. The construct validity was investigated using the Pearson correlation coefficient and floor and ceiling effects by percentage frequency of lowest or highest possible score achieved by respondents. RESULTS: 143 patients scheduled for hip or knee arthroplasty were included. The reliability was excellent between the test and the rested total score, with an ICC of 0.902 (0.853-0.936) and CV of 4.06% for the French Hip Replacement Expectations Survey and 0.865 (0.786-0.917) and CV of 7.7% for the French Knee Replacement Expectations Survey, without bias. The Cronbach alpha coefficient was 0.72 for hip Survey and 0.82 for knee Survey showing a good internal consistency. Pearson correlation coefficients of 0.45 and 0.48 between Expectations WOMAC and HSS, respectively for hip Survey and knee Survey, were observed but with systematic bias. The lowest possible score was not reported by any patient and only three patients (3.66%) scheduled for hip arthroplasty reported the highest possible score. CONCLUSIONS: The French version of the HSS Hip or Knee Replacement Expectations Survey is a reliable and valid questionnaire and compares favourably with the original English version. Therefore, this new version may help French speaking clinicians to evaluate expectations before lower limb arthroplasty. PMID- 25829753 TI - Navigation in TKA surgery - Evolutionary technique or blind alley? PMID- 25829754 TI - Tibial rotation kinematics subsequent to knee arthroplasty. AB - BACKGROUND: The use of computer assisted joint replacement has facilitated precise intraoperative measurement of knee kinematics. The changes in "screw home mechanism" (SHM) resulting from Total Knee Arthroplasty (TKA) with different prostheses and constraints has not yet been accurately described. METHODS: A pilot study was first completed. Intraoperative kinematic data was collected two groups of 15 patients receiving different prostheses. RESULTS: On average, patients lost 5.3 degrees of ER (SD = 6.1 degrees ). There was no significant difference between the prostheses or different prosthetic constraints. CONCLUSIONS: There significant loss of SHM after TKA. Further research is required to understand its impact on patient function. PMID- 25829755 TI - 3D patient-specific model of the tibia from CT for orthopedic use. AB - OBJECTIVES: 3D patient-specific model of the tibia is used to determine the torque needed to initialize the tibial torsion correction. METHODS: The finite elements method is used in the biomechanical modeling of tibia. The geometric model of the tibia is obtained from CT images. The tibia is modeled as an anisotropic material with non-homogeneous mechanical properties. CONCLUSIONS: The maximum stress is located in the shaft of tibia diaphysis. With both meshes are obtained similar results of stresses and displacements. For this patient-specific model, the torque must be greater than 30 Nm to initialize the correction of tibial torsion deformity. PMID- 25829756 TI - Selective hemiepiphyseodesis for patellar instability with associated genu valgum. AB - BACKGROUND/AIMS: Patellar instability limits activity and promotes arthritis. Correcting genu valgum with selective hemiepiphyseodesis can treat patellar instability. METHODS: We retrospectively reviewed 26 knees with patellar instability and associated genu valgum that underwent hemiepiphyseodesis. RESULTS: Average anatomic lateral distal femoral angle (aLDFA) significantly corrected. Symptoms improved in all patients. All competitive athletes returned to sports. One complication occurred. CONCLUSIONS: In genu valgum, the patella seeks an abnormal mechanical axis, resulting in patellar instability. By correcting the mechanical axis with hemiepiphyseodesis, patellar instability symptoms improve and patients return to sports. Complications are rare. Selective hemiepiphyseodesis is recommended when treating patellar instability with associated genu valgum. PMID- 25829757 TI - Ultrasound vs. MRI in the assessment of rotator cuff structure prior to shoulder arthroplasty. AB - BACKGROUND/AIMS: We compared the accuracy of US to 3 T Tesla MRI for the detection of rotator cuff and long biceps tendon pathologies before joint replacement. METHODS: 45 patients were prospectively included. RESULTS: For the supraspinatus tendon, the accuracy of US when using MRI as reference was 91.1%. For the infraspinatus tendon, the accuracy with MRI as reference was 84.4%. The subscapularis tendon was consistently assessed by US and MRI in 35/45 patients (accuracy 77.8%). For the long biceps tendon the accuracy was 86.7%. CONCLUSION: US detection of rotator cuff and biceps tendon integrity is comparable to MRI and should be preferred in revision cases. PMID- 25829758 TI - Achondroplasia and limb lengthening: Results in a UK cohort and review of the literature. AB - AIMS: We aim to review the results, complications and outcomes of a single surgeon's series of lower limb lengthening in patients with achondroplasia. METHODS: Ten achondroplastic children underwent limb lengthening. The patients, medical records and radiographs were reviewed. RESULTS: The average age at the time of the index operation was 7.8 years. A single surgeon undertook all procedures. The average total length gain was 20.5 cm. The commonest complication was a fractured femur after removal of the frame. CONCLUSION: Although complication rates were high (70%), none were left with any long-term sequelae and all were pleased with the results. PMID- 25829759 TI - An unusual complex karyotype in myopericytoma. AB - INTRODUCTION: Myopericytoma is a perivascular neoplasm commonly found in the skin and soft tissue of extremities. These lesions often exhibit concentric vascular proliferation of spindle shaped myoid cells. METHODS/RESULTS: We present a case of a 76-year old male who was diagnosed with myopericytoma and subsequent cytogenetic analysis found a highly abnormal karyotype. This karyotype includes cytogenetic mutations that have not been described in previous case studies of myopericytoma. CONCLUSIONS: Some of these aberrations occur on genes that are involved in hedgehog signaling as well as pericyte proliferation, indicating a potential pericyte origin for myopericytoma tumors. PMID- 25829760 TI - New free radical scavenging neolignans from fruits of Piper attenuatum. AB - OBJECTIVE: The aim was to study and identify free radicals scavenging and antihyperglycemic principles in fruit of Piper attenuatum. MATERIALS AND METHODS: Bioassay guided identification of extracts possessing potent free radical scavenging activity, and isolation of compounds was done. Chloroform extract of P. attenuatum possessing potent radical scavenging activity was also evaluated for antihyperglycemic activity following oral glucose tolerance test in rats. RESULTS: Nine neolignans namely, denudatin B (1), iso-4', 5'-dimethoxy-3, 4 methylenedioxy-2'-oxo-Delta(3',5',8')-8.1'-lignan (2), lancifolin D (3), denudatin A (4), wallichinin (5), piperenone (6), lancifolin C (7), 2-oxo-piperol B (8), piperkadsin A (9) and a crotepoxide (10) was identified in Chloroform extract of P. attenuatum. Neolignans (1-9) displayed potent 2, 2'-azino-bis (3 ethylbenzothiazoline-6-sulphonic acid) radical and piperkadsin A (9) also displayed 1, 1-diphenyl-2-picrylhydrazyl radical scavenging activity. Analysis of structure-activity relationship revealed that presence of furan ring and methoxy groups is an important criterion to influence 2, 2'-azino-bis (3 ethylbenzothiazoline-6-sulphonic acid) radical scavenging potentials. Chloroform extract of P. attenuatum fruit could not display antihyperglycemic activity following oral glucose tolerance test in rats. CONCLUSION: Neolignans present in P. attenuatum fruits are potent free radical scavengers and this is the first report identifying these compounds and activities in this fruit. PMID- 25829761 TI - Anti-arthritic activity of Fu-Fang-Lu-Jiao-Shuang on collagen-induced arthritis in Balb/c mice and its underlying mechanisms. AB - BACKGROUND: Rheumatoid arthritis (RA) is a common, autoimmune disorder characterized by progressive multiple joint destruction, deformity, disability and premature death in most patients. Fu-Fang-Lu-Jiao-Shuang (FFLJS) is an effective traditional Chinese medicine, which has long been used clinically to treat RA patients. OBJECTIVE: The objective of this study is aimed to evaluate the anti-rheumatic effects of FFLJS on collagen induced arthritis (CIA) model, as well as the underlying mechanisms, which have not previously been explored. MATERIALS AND METHODS: CIA was induced by immunization with type II collagen (CII) in male Balb/c mice. The mice in the onset of arthritis were treated daily with FFLJS (125 or 500 mg/kg) or 1% carboxymethyl cellulose-Na for 28 days. Paw thickness and arthritic score were evaluated to confirm the anti-arthritic effect of FFLJS on CIA in mice. Levels of anti-CII antibody, proinflammatory cytokines interleukin-1 (IL-1) beta, IL-17, and tumor necrosis factor-alpha (TNF-alpha) as well as prostaglandin E-2 (PGE-2) in serum and histological changes in the ankle joint were also analyzed. In addition, expressions of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitors of matrix metalloproteases-1 (TIMP-1) in synovial tissue were also detected to further study the molecular mechanism of the anti-arthritic effects of FFLJS. RESULTS: During therapeutic treatment, FFLJS significantly reduced paw thickness and arthritic score in CIA mice, decreased the amounts of TNF-alpha, IL-1 beta, IL-17, PGE-2 and anti-CII antibody in serum. In addition, FFLJS treatment could prevent the bone destruction by reducing the expression of MMP-1 and MMP-3, increasing the expression of TIMP-1 in synovial tissue of CIA mice. CONCLUSION: These findings offer the convincing evidence for the first time that the anti-rheumatic effects of FFLJS might be related to down regulation of TNF-alpha, IL-1 beta, IL-17 and PGE-2 levels for acute arthritis, and regulation of MMP-1, MMP-3 and TIMP-1 protein expression for chronic arthritis. PMID- 25829762 TI - Shikonin induces apoptosis in the human gastric cancer cells HGC-27 through mitochondria-mediated pathway. AB - BACKGROUND: Gastric cancer (GC) is one of the most frequently occurring digestive tract cancers and fewer chemotherapeutic drugs for GC have shown promising results. In this study, we investigated the anti-tumor activity of shikonin, a natural compound isolated from the Chinese plant Lithospermum erythrorhizon, against the human GC cell line HGC-27. MATERIALS AND METHODS: HGC-27 cells treated with shikonin at a concentration of 30MUM or above showed significant growth inhibition compared to control cells. Shikonin-treated cells also underwent apoptosis as detected by flow cytometric analysis and microscopic examination of cellular morphology. Further investigation into the underlying mechanism of apoptosis by western blot showed that the shikonin promoted the activation of poly-(ADP-ribose)-polymerase, caspase-3 and caspase-9 following 24 h or 48 h of treatment time, as well as the activation of caspase-8, but only after 48 h of treatment time. Furthermore, the levels of mitochondrial membrane potential, B-cell lymphoma 2 (Bcl-2) and Bcl-extra large were reduced following shikonin treatment while the level of Bax was increased. In addition, shikonin also caused a significant reduction of the protein Survivin, while having little effect on the expression on X-linked inhibitor of apoptosis protein. CONCLUSION: Taken together, these results showed that the shikonin exhibited its anti-tumor activity against HGC-27 cells through inhibiting cell growth and promoting apoptosis by targeting mitochondrial-related signaling pathway. Our finding may represent a positive step in finding a natural and effective compound that could be important implication for future development of chemotherapeutic and/or chemopreventive agent against GC. PMID- 25829763 TI - The enriched fraction of Elephantopus scaber Triggers apoptosis and inhibits multi-drug resistance transporters in human epithelial cancer cells. AB - BACKGROUND: Medicinal plants have played an important role in the development of clinically useful anticancer agents. Elephantopus scaber (Asteraceae) (ES) is widely used in Indian traditional system of medicine for the treatment of various ailments including cancer. OBJECTIVE: To investigate anticancer effects of ES in human epithelial cancer cells. MATERIALS AND METHODS: Cytotoxicity of ethanolic extract of ES (ES-ET) and its fractions, such as ES Petroleum ether fraction (ES PET), ES Dichloromethane fraction (ES DCM), n Butyl alcohol fraction (ES-BT), and ES-Rest (ES-R) were assessed in human epithelial cancer cell lines using sulforhodamine B (SRB) assay. Acridine orange/ethidium bromide assay and Hoechst 33342 assays were used to gauge induction of apoptosis. Cell cycle analysis and micronuclei assay were used to assess cell cycle specific pharmacological effects and drug induced genotoxicty. Further, the ability of ES to inhibit multi drug resistant (MDR) transporters (ABC-B1 and ABC-G2) was determined by Rhodamine (Rho) and Mitoxantrone (MXR) efflux assays. RESULTS: The enriched fraction of ES (ES DCM) possessed dose-dependent potent cytotoxicity in human epithelial cancer cells. Further, treatment of cancer cells (HeLa, A549, MCF-7, and Caco-2) with ES DCM showed hall mark properties of apoptosis (membrane blebbing, nuclear condensation etc.). Similarly, ES DCM caused enhanced sub G0 content and micronuclei formation indicating the induction of apoptosis and drug induced genotoxicity in cancer cells, respectively. Interestingly, ES DCM inhibited MDR transporters (ABC B1 and ABC G2) in cancer cells. CONCLUSION: The enriched fraction of ES imparted cytotoxic effects, triggered apoptosis, induced genotoxicity, and inhibited MDR transporters in human epithelial cancer cells. Thus, ES appears to be potential anticancer agent. PMID- 25829764 TI - Methyl gallate isolated from Spondias pinnata exhibits anticancer activity against human glioblastoma by induction of apoptosis and sustained extracellular signal-regulated kinase 1/2 activation. AB - BACKGROUND: Spondias pinnata has been reported for its efficient anticancer effects, but the studies were mostly focused on its extract. OBJECTIVE: Since its bioactive compounds are largely unknown, this study was designed to characterize the lead components present in it and their anticancer activity against human glioblastoma cell line (U87). MATERIALS AND METHODS: Major compounds from the ethyl acetate fraction were isolated by column chromatography and their anticancer potentials against U87 cells were evaluated. Furthermore, flow cytometric and immunoblotting analyses were performed to demonstrate the mechanism of apoptosis inducing activity of methyl gallate (MG) against U87 cell line. RESULTS: Four major compounds were isolated from the ethyl acetate fraction. Amongst these, two compounds showed promising activities and with the help of different spectroscopic methods they were identified as gallic acid and MG. Flow cytometric studies revealed that MG-induced apoptosis in U87 cells dose dependently; the same was confirmed by activation of caspases through cleavage of endogenous substrate poly (adenosine diphosphate-ribose) polymerase. MG treatment also induced the expression of p53 and B-cell lymphoma-2-associated X and cleavage of BH3 interacting-domain with a concomitant decrease in B-cell lymphoma 2 expression. Moreover, MG-induced sustained phosphorylation of extracellular signal-regulated kinase (ERK1/2) in U87 cells with no change in the phosphorylation of other mitogen-activated protein kinases (c-Jun N-terminal of stress-activated protein kinases, p38). CONCLUSION: MG is a potent antioxidant and it induces sustained ERK1/2 activation and apoptosis in human glioblastoma U87, and provide a rationale for evaluation of MG for other brain carcinoma cell lines for the advancement of glioblastoma therapy. PMID- 25829765 TI - Comparative evaluation of standardized alcoholic, hydroalcoholic, and aqueous extracts of Phyllanthus maderaspatensis Linn. against galactosamine-induced hepatopathy in albino rats. AB - BACKGROUND: Phyllanthus maderaspatensis species (Euphorbiaceae) has been used in folk medicine of many countries as a remedy against several pathological conditions including jaundice and hepatitis. This study is an attempt to evaluate hepatoprotective activity of P. maderaspatensis against galactosamine-induced toxicity and also investigation of polyphenols in each extract. MATERIALS AND METHODS: The extraction of P. maderaspatensis as per Ayurveda was simultaneously standardized and quantified for biochemical markers viz., polyphenols: Kaempferol, quercetin, catechin, rutin, and ellagic acid by high-performance thin layer chromatography. Hepatotoxicity was induced albino adult rats by intraperitoneal injection of galactosamine (400 mg/kg). The quantified aqueous, hydroalcoholic and alcoholic extract of P. maderaspatensis (200 and 400 mg/kg body weight/day) were compared for evaluation of hepatoprotective potential, which were assessed in terms of reduction in histological damage, change in serum enzymes such as aspartate amino transaminase, alanine amino transaminase and alkaline phosphatase and increase thiobarbituric acid reactive substances. RESULTS AND DISCUSSION: The hydroalcoholic extract was found to contain comparatively high amount of kaempferol, quercetin, catechin, rutin, and ellagic acid which are responsible for hepatoprotection. Antioxidant parameters such as glutathione, catalase, and superoxide dismutase activity in liver tissues were restored toward the normalization more significantly by the hydroalcoholic extract when compared with other extracts. The biochemical observations were supplemented with histopathological examination. CONCLUSION: The hydroalcoholic extract standardized with respect to known biomarkers may be considered as a potent extract against hepatotoxicity. PMID- 25829766 TI - Attenuation of reactive oxygen/nitrogen species with suppression of inducible nitric oxide synthase expression in RAW 264.7 macrophages by bark extract of Buchanania lanzan. AB - BACKGROUND: Oxidative stress is one of the most critical factors implicated in disease conditions. Buchanania lanzan Spr. (Anacardiaceae) bark powder preparation has been reported for treating an inflammatory condition in the Ayurvedic Pharmacopoeia of India. OBJECTIVE: In the present study, we investigate the effect of the bark methanol extract (BLM) on reactive oxygen/nitrogen species (ROS/RNS), the expression of protein and mRNA of inducible nitric oxide synthase (iNOS) in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) and sodium nitroprusside (SNP) to provide scientific validation of the above said medicinal property. MATERIALS AND METHODS: The capacity to quench ROS and RNS was evaluated by 5-(and-6) chloromethyl-20,70-dichlorodihydrofluorescein diacetate acetyl ester fluorescence and nitrite estimations in LPS/SNP-stimulated macrophages respectively. The protein and transcript expression of iNOS was evaluated through Western Blot and reverse transcription-polymerase chain reaction (RT-PCR) analysis respectively. RESULTS: Macrophages pretreated with BLM (>100 MUg/mL) for 24 h, stimulated with LPS for the last 18 h of experimental duration recorded a significantly (P < 0.05) reduced levels of ROS (3.45-fold) against LPS-stimulated conditions (5.7-fold). SNP-stimulation resulted in increased NO accumulation (17-fold) which was neutralized by BLM at >100 MUg/ml (1.6-fold) credited to a reduced protein and mRNA expression of iNOS as recorded by Western blots and RT-PCR results respectively. The reversed-phase liquid chromatography-diode array detection analysis identified the presence of 4 hydroxybenzoic acid, quercetin and p-coumaric acid (Rt values 5.444, 5.569 and 9.580 respectively). CONCLUSIONS: The potential of BLM inhibiting ROS/RNS production validates the medical use of bark, could find beneficial application under conditions of immune stimulation and/or bacterial infection. PMID- 25829767 TI - Preconditioning with glycyrrhizic, ferulic, paeoniflorin, cinnamic prevents rat hearts from ischemia/reperfusion injury via endothelial nitric oxide pathway. AB - OBJECTIVE: The objective was to investigate the endothelial nitric oxide synthase (eNOS/NO) pathway is involved or not in the protective effects of glycyrrhizic, ferulic, paeoniflorin, cinnamic (GFPC) in myocardial ischemia-reperfusion injury Sprague-Dawley rats. MATERIALS AND METHODS: Ischemia-reperfusion (I/R) model was made by ligating the left anterior descending branch of the coronary artery for 30 min and releasing for 120 min, then the left ventricular apical was fixed and sliced, morphological changes of myocardial microvascular endothelial cell (MMVEC) was observed by electron microscopy, apoptosis index of MMVEC was observed by means of TUNEL, serum NO was tested by methods of nitrate reduction, lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) was detected by automatic biochemical analyzer; Phosphorylated eNOS (PeNOS) and inducible NOS (iNOS) protein were measured by means of western blot. RESULTS: In positive product control group, the serum levels of NO, LDH, CK-MB significantly increased (P < 0.05); MMVEC apoptosis was significantly decreased (P < 0.05); incidence of area at risk decreased significantly (P < 0.05); PeNOS protein increased (P < 0.05); iNOS protein decreased significantly (P < 0.05). CONCLUSION: Ischemic preconditioning of GFPC from GFPC plays a protective role in I/R heart through regulating the eNOS/NO signal pathway by increasing the PeNOS protein expression and decreasing the expression of iNOS protein. PMID- 25829768 TI - Simultaneous determination three phytosterol compounds, campesterol, stigmasterol and daucosterol in Artemisia apiacea by high performance liquid chromatography diode array ultraviolet/visible detector. AB - BACKGROUND: Artemisia apiacea is a traditional herbal medicine using treatment of eczema and jaundice in Eastern Asia, including China, Korea, and Japan. OBJECTIVE: An accurate and sensitive analysis method using high performance liquid chromatography-diode array ultraviolet/visible detector and liquid chromatography-mass spectrometry for the simultaneous determination of three phytosterol compounds, campesterol, stigmasterol and daucosterol in A. apiacea was established. MATERIALS AND METHODS: The analytes were separated on a Shiseido C18 column (5 MUm, 4.6 mm I.D. *250 mm) with gradient elution of 0.1% trifluoroacetic acid and acetonitrile. The flow rate was 1 mL/min and detection wavelengths were set at 205 and 254 nm. RESULTS: Validation of the method was performed to demonstrate its linearity, precision and accuracy. The calibration curves showed good linearity (R (2) > 0.9994). The limits of detection and limits of quantification were within the ranges 0.55-7.07 MUg/mL and 1.67-21.44 MUg/mL, respectively. And, the relative standard deviations of intra- and inter-day precision were <2.93%. The recoveries were found to be in the range of 90.03 104.91%. CONCLUSION: The developed method has been successfully applied to the analysis for quality control of campesterol, stigmasterol and daucosterol in A. apiacea. PMID- 25829769 TI - A new method for identification of natural, artificial and in vitro cultured Calculus bovis using high-performance liquid chromatography-mass spectrometry. AB - OBJECTIVE: Calculus bovis have been widely used in Chinese herbology for the treatment of hyperpyrexia, convulsions, and epilepsy. Nowadays, due to the limited source and high market price, the substitutes, artificial and in vitro cultured Calculus bovis, are getting more and more commonly used. The adulteration phenomenon is serious. Therefore, it is crucial to establish a fast and simple method in discriminating the natural, artificial and in vitro cultured Calculus bovis. Bile acids, one of the main active constituents, are taken as an important indicator for evaluating the quality of Calculus bovis and the substitutes. Several techniques have been built to analyze bile acids in Calculus bovis. Whereas, as bile acids are with poor ultraviolet absorbance and high structural similarity, effective technology for identification and quality control is still lacking. METHODS: In this study, high-performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (LC/MS/MS) was applied in the analysis of bile acids, which effectively identified natural, artificial and in vitro cultured Calculus bovis and provide a new method for their quality control. RESULTS: Natural, artificial and in vitro cultured Calculus bovis were differentiated by bile acids analysis. A new compound with protonated molecule at m/z 405 was found, which we called 3alpha, 12alpha dihydroxy-7-oxo-5alpha-cholanic acid. This compound was discovered in in vitro cultured Calculus bovis, but almost not detected in natural and artificial Calculus bovis. A total of 13 constituents was identified. Among them, three bio markers, including glycocholic acid, glycodeoxycholic acid and taurocholic acid (TCA) were detected in both natural and artificial Calculus bovis, but the density of TCA was different in two kinds of Calculus bovis. In addition, the characteristics of bile acids were illustrated. CONCLUSIONS: The HPLC coupled with tandem MS (LC/MS/MS) method was feasible, easy, rapid and accurate in identifying natural, artificial and in vitro cultured Calculus bovis. PMID- 25829770 TI - Effects of Pogostemon cablin Blanco extract on hypoxia induced rabbit cardiomyocyte injury. AB - BACKGROUND: Pogostemonis Herba, the dried aerial part of Pogostemon cablin Blanco, is a well-known materia medica in Asia that is widely used for syndrome of gastrointestinal dysfunctions. OBJECTIVE: This study was undertaken to examine whether Pogostemon cablin extract (PCe) might have any beneficial effect on hypoxia induced rabbit cardiomyocyte injury. MATERIALS AND METHODS: Isolated cardiomyocytes were divided into three groups and the changes of cell viability in cardiomyocytes of hypoxic and hypoxia/reoxygenation group were determined. The effect of PCe on reactive oxygen species (ROS) generation, intracellular formation of ROS was also measured by monitoring the 2',7'-dichlorofluorescein fluorescence. RESULTS: PCe effectively protected the cells against both the hypoxia and reoxygenation induced injury, and the protective effect of PCe is not mediated by interaction with adenosine triphosphate-sensitive K(+) channels. In the presence of PCe, production of ROS under chemical hypoxia was remarkably reduced which suggests that PCe might exert its effect as a ROS scavenger. CONCLUSION: The present study provides clear evidence for the beneficial effect of PCe on cardiomyocyte injury during hypoxia or reoxygenation following prolonged hypoxia. PMID- 25829771 TI - Quantitative analysis of the eight major compounds in the Samsoeum using a high performance liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometer. AB - BACKGROUND: Samsoeum was traditionally used for treatment of a respiratory disease. OBJECTIVE: The simultaneous determination of eight major compounds, ginsenoside Rg3, caffeic acid, puerarin, costunolide, hesperidin, naringin, glycyrrhizin, and 6-gingerol in the Samsoeum using a high-performance liquid chromatography (HPLC) coupled with diode array detection (DAD) and an electrospray ionization mass spectrometer was developed for an accurate and reliable quality assessment. MATERIALS AND METHODS: Eight compounds were qualitative identified based on their mass spectra and by comparing with standard compounds and quantitative analyzed by HPLC-DAD. Separation of eight compounds was carried out on a LUNA C18 column (S-5 MUm, 4.6 mm i.d. *250 mm) with gradient elution composed of acetonitrile and 0.1% trifluoroacetic acid. RESULTS: The data showed good linearity (R (2) > 0.9996). The limits of detection and the limits of quantification were <0.53 MUg and 1.62 MUg, respectively. Inter- and Intra-day precisions (expressed as relative standard deviation values) were within 1.94% and 1.91%, respectively. The recovery of the method was in the range of 94.24 107.90%. CONCLUSION: The established method is effective and could be applied to quality control of Samsoeum. PMID- 25829773 TI - The influences of inorganic elements in soil on the development of famous - region Atractylodes lancea (Thunb.) DC. AB - BACKGROUND: Atractylodes lancea (Thunb.) DC., is an important medicinal plant in China. Recently, researches of A. Lancea were focused on chemical composition and genetics, only a few were concerned with soil factors. OBJECTIVE: The aim was to discuss the relationship between geo-herbalism of A. Lancea (Thunb.) DC. and inorganic elements in soil. MATERIALS AND METHODS: The contents of 15 kinds of inorganic elements in the rhizoma of A. Lancea (Thunb.) DC. and soils from various regions were determined with inductively coupled plasma-optical emission spectrometer and the data were analyzed with Statistical Package for the Social Sciences 20.0 software. RESULTS: The contents of inorganic elements in rhizoma of A. Lancea and in soil with different geological background were different. The soils in the famous region contained high aluminum, iron, sodium and low sulfur content. The rhizoma of A. Lancea contained high aluminum, lithium, manganese and low iron, sulfur content. The famous-region crude drugs had a strong tendency to accumulate selenium, manganese. Ten characteristic elements of A. Lancea were K, Ca, S, Al, Li, Ti, Mn, Pb, Ni, SE. CONCLUSION: The contents of inorganic elements in rhizoma of A. Lancea showed a significant positive interrelationship with those in soil. It was identified that inorganic elements play an important role in forming authenticity A. Lancea (Thunb.) DC. PMID- 25829772 TI - Sesamol, a lipid lowering agent, ameliorates aluminium chloride induced behavioral and biochemical alterations in rats. AB - BACKGROUND: Sesame oil from the seeds of Sesamum indicum Linn. (Pedaliaceae) has been used traditionally in Indian medical practice of Ayurveda in the treatment of central nervous system disorders and insomnia. A few published reports favor the anti-dementia effect of sesamol (SML), an active constituent of sesame oil. OBJECTIVE: Thus, the present study was aimed to explore the anti-dementia effect and possible mechanism (s) of SML in aluminium chloride (AlCl3)-induced cognitive dysfunction model in rodents with special emphasis on memory centers viz., hippocampus and frontal cortex. METHODS: Male Wistar rats were exposed to AlCl3 (175 mg/kg p.o.) for 60 days. SML (10 and 20 mg/kg) and rivastigmine (1 mg/kg) were administered orally 45 min before administration of AlCl3 for 60 days. Spatial memory was assessed using Morris water maze test. After 60 days of treatment animals were sacrificed, hippocampus and frontal cortex were collected and analyzed for acetylcholinesterase (AChE) activity, tumor necrosis factor (TNF alpha) level, antioxidant enzymes (Glutathione, catalase), lipid peroxidation, and nitrite level. The circulating triglycerides, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels were also analyzed. RESULTS: SML significantly prevented behavioral impairments in aluminium-exposed rats. Treatment with SML reversed the increased cholesterol, triglycerides and LDL while raised the HDL levels. SML significantly corrected the effect of AlCl3 on AChE activity. Further, SML reversed the elevated nitric oxide, TNF-alpha and reduced antioxidant enzymes in hippocampus and frontal cortex. CONCLUSION: The present study suggests the neuro-protection by SML against cognitive dysfunction induced by environmental toxin (AlCl3) in hippocampus and frontal cortex. PMID- 25829774 TI - Ethyl acetate extract from marine sponge Hyattella cribriformis exhibit potent anticancer activity by promoting tubulin polymerization as evidenced mitotic arrest and induction of apoptosis. AB - BACKGROUND: Marine sponges are important sources of bioactive compounds. OBJECTIVE: This study investigated the anticancer properties of Hyattella cribriformis ethyl acetate (EA) fraction in various cancer and normal cell lines. MATERIALS AND METHODS: anticancer assay was carried out in 15 cell lines to evaluate the anticancer potential of the EA fraction. Impact on cell cycle distribution was determined using flow cytometry. The fraction was investigated for interfering microtubules assembly in both in vitro and cellular assay. Further studies were conducted to determine the fraction induced cell death (apoptosis) using calcein/propidium iodide dual staining, activated caspase-3 and phosphorylation of Bcl-2 protein at Ser70. DNA fragmentation assay was performed to confirm the apoptosis. RESULTS: EA fraction exhibited potent inhibition of cancer cell growth and resulted in 50% growth inhibition (GI50) of 0.27 MUg/mL in A673 cell line. Sarcoma (MG-63, Saos-2) and ovarian (SK-OV-3 and OVCAR-3) cancer cell lines also showed superior anticancer activity GI50 of 1.0 MUg/mL. Colon and breast cancer cell lines exhibited moderate GI compare other cancer cell lines and normal human lung fibroblast showed GI50 of 15.6 MUg/mL. EA fraction showed potent G2/M phase arrest in A673 cell line and induced apoptosis at 48 h exposure. EA fraction promoted microtubule polymerization in tubulin polymerization assay and increased level of polymerized tubulin in the HeLa cells. Fraction induced the activation of caspase-3 and phosphorylation of Bcl-2 anti-apoptotic protein. Fraction induced DNA fragmentation in HeLa cells as evidence of apoptosis. CONCLUSION: Marine sponge H. cribriformis EA fraction exhibited potent anticancer activity through tubulin polymerization and induction of apoptosis. PMID- 25829775 TI - Identification of longevity, fertility and growth-promoting properties of pomegranate in Caenorhabditis elegans. AB - BACKGROUND: Pomegranate (Punica granatum L.) is commonly consumed as fresh fruit and fruit juice. It is also used in the production of jam, wine, food coloring agent, and flavor enhancer. OBJECTIVE: The aim of this study was to identify the possible longevity, fertility and growth promoting properties of different ethanolic extract concentrations of pomegranate in Caenorhabditis elegans, which is increasingly popular and has proven to be a very useful experimental model organism for aging studies as well as for testing antioxidants and other compounds for effects on longevity. MATERIALS AND METHODS: In this study, five experimental groups (20, 10, 5, 2.5 and 1.25 mg pomegranate extract/mL and one control group) were used to determine the most effective dose of pomegranate in terms of longevity, fertility and growth parameters. RESULTS: It was seen that, pomegranate extracts up to the concentration of 5 mg/mL, had the potential to promote for the longevity, formation of new generations, fertility of new generations and growth properties of C. elegans although higher concentrations significantly reduced these parameters. CONCLUSION: these findings indicated that pomegranate could be used as a supplement to enhance longevity, fertility and growth rate for the other living organisms and human beings, but the dose should be carefully adjusted to avoid adverse effects. PMID- 25829777 TI - Evaluation of extraction method on the chemical composition in Apeiba tibourbou Aubl's extracts. AB - BACKGROUND: The extraction method of bioactive compounds is an important step in the manufacturing of herbal medicines, because secondary metabolites with therapeutic potential are usually found in small quantities in plant materials. OBJECTIVE: Due the potential of Apeiba tibourbou Aubl, this study aimed to evaluate the impact of the extraction method on the quality of herbal extract and optimize the extraction of fatty acid, rosmarinic (Ra) and caffeic (Ca) acid from A. tibourbou. MATERIALS AND METHODS: Determinations of residual moisture (Rm), proteins (Pt), lipids (Lp), total fiber (Tf), and carbohydrate (Cy) were performed in triplicate samples according assessment of antioxidant capacity. Extraction of fatty acids was carried out by two different methods: (i) By shoxlet and (ii) bligh and dyer. The optimized conditions were determined by surface response methodology (RSM), and the criterion of desirability was the maximum extraction of Ra and Ca. RESULTS: The method of bligh and dyer was able to extraction more total Lp than the shoxlet. However, the extraction of fatty acid was different for the two methods. The optimized conditions to extract RA and Ca was calculated by RSM, 42 degrees C, 30% (alcohol degree) and 24 min, this conditions maximize simultaneously the extraction of Ca (0, 04%) and Ry (1.89). CONCLUSION: It was observed that the extraction method alters the chemical composition of extract, and it is possible to extract Ca and Ra from A. tibourbou's leaves using ultrasound-assisted extraction. PMID- 25829776 TI - Simultaneous quantification of six alkaloid components from commercial stemonae radix by solid phase extraction-high-performance liquid chromatography coupled with evaporative light scattering detector. AB - BACKGROUND: Stemonae radix has been applied in traditional Chinese medicine for centuries. Alkaloids are the main active ingredient in stemonae radix, so their composition and concentration levels are directly linked to clinic effects. OBJECTIVE: The objective was to develop an analytical method with multiple markers for quality survey of commercial stemonae radix. MATERIALS AND METHODS: A method for simultaneous determination of six compounds in commercial stemonae radix was performed using solid-phase extraction and high-performance liquid chromatography coupled with evaporative light scattering detector. The separation was carried out on an Agilent TC-C18 column with 0.1% acetonitrile solution of triethylamine aqueous solution and acetonitrile as the mobile phase under gradient elution within 70 min. The hierarchical clustering analysis (HCA) was successfully used to classify the samples in accordance with their chemical constituents. RESULTS: Linearity (R(2) > 0.9990), intra- and inter-day precision (relative standard deviations <4%), limit of detection (0.011-0.086 MUg/mL), limit of quantification (0.033-0.259 MUg/mL) of the six alkaloids were determined, and the recoveries were between 96.6% and 103.7%. The method was successfully applied to analysis 36 batches of commercial stemonae radix. All the samples could be classified into five clusters by HCA. CONCLUSION: This article provides an accurate and simple analytical method for quality survey of commercial stemonae radix. Because of the significant chemical variations, careful selection of Stemona sources with obvious antitussive value but devoid of croomine followed by good agricultural practice and good manufacturing practice process is suggested. PMID- 25829778 TI - In vitro regeneration and Agrobacterium tumefaciens-mediated genetic transformation in asakura-sanshoo (Zanthoxylum piperitum (L.) DC. F. inerme Makino) an important medicinal plant. AB - CONTEXT: Asakura-sanshoo (Zanthoxylum piperitum [L.] DC. f. inerme Makino) is an important medicinal plant in East Asia. Transgenic technique could be applied to improve plant traits and analyze gene function. However, there is no report on regeneration and genetic transformation in Asakura-sanshoo. AIMS: To establish a regeneration and Agrobacterium tumefaciens-mediated genetic transformation system in Asakura-sanshoo, which could be used for cultivar improvement and gene function analysis. SETTINGS AND DESIGN: The various combinations of indole-3 butyric acid (IBA), 6-benzylaminopurine (BA) and naphthalene acetic acid (NAA) were explored for the optimal plant regeneration from petiole and stem of Asakura sanshoo. The half-strength woody plant medium (WPM) with different concentrations of NAA and IBA was used to induce root. For genetic transformation, A. tumefaciens strain EHA-105 harboring the plasmid pBin-Ex-H-ipt which carries the isopentenyl transferase (ipt) gene, beta-glucuronidase (GUS) gene and kanamycin resistance gene neomycin phosphotransferase II (NPTII) were used. The transformation efficiency was detected by the kanamycin resistant frequency. MATERIALS AND METHODS: Petioles and stems were obtained from the in vitro cultured Asakura-sanshoo. The petiole and stem segments were precultured for 3 days, and then inflected using the bacterium at the concentration of OD600 0.5 0.8 for 10 min, followed by 3 days co-cultivation. Selection of the transgenic plants was carried out after 7 days the regeneration using gradient kanamycin at 30 mg/L and 50 mg/L, respectively. Successful transformed plants were confirmed by GUS histochemical assays, polymerase chain reaction (PCR), reverse transcription-PCR (RT-PCR), and Southern blotting analysis. RESULTS: The highest shoots regeneration was obtained on WPM supplement with 0.5 mg/L BA and 0.2 mg/L NAA. The optimal rooting medium was half strength macro-element WPM. The kanamycin resistant frequency of petiole and stem was 24.66% and 25.93%, respectively. Thirty-five shoots in thousands adventitious buds were confirmed through GUS histochemical assays, PCR, RT-PCR, and Southern blotting. The regeneration shoot per explants elevated 5.85 fold compared with the wild-type plants. CONCLUSIONS: Individual transgenic Asakura-sanshoo lines were obtained. In this paper, it first revealed the expression of ipt gene significantly promoted the adventitious buds induction in Asakura-sanshoo as the same action as in other plants. PMID- 25829779 TI - Effects of Valerianae Radix et Rhizoma extract on psychological stress in mice. AB - BACKGROUND: The aim of this study was to identify the effects of Valerianae Radix et Rhizoma water extract (VRe) originated from Valeriana fauriei Briquet on reducing psychological stress (PS) on mice. OBJECTIVE: Mice were put under PS with communication box method: Restraining mice and forcing to see other mice underfoot shock stress. MATERIALS AND METHODS: Measurements on plasma corticosterone, noradrenaline and lipid peroxidation, and elevated plus-maze (EPM) tests were carried out to determine the effect of VRe administration on physiological and behavioral responses of mice. RESULTS: VRe showed anxiolytic effects in plasma corticosterone, noradrenaline, and EPM transfer latency levels, but it did not show any significant effects on the other indicators. CONCLUSION: V. fauriei, which has been used as a natural anxiolytic drug, exerts positive effects in the communication box induced PS in mice. PMID- 25829780 TI - Antiradical and antidiabetic properties of standardized extract of Sunderban mangrove Rhizophora mucronata. AB - BACKGROUND: Mangroves have the ability to grow where no other vascular plants survive. Rhizophora mucronata is a true mangrove and traditionally used to treat diabetes and its allied complications. OBJECTIVES: In the present study, we standardized the 80% methanolic standardized extract of R. mucronata leaves (RH) and found out its antiradical and antidiabetic activities. MATERIALS AND METHODS: The methanolic extract of R. mucronata leaves (RH) was standardized and quantified for phenolics, flavonoinds, gallic acid, quercetin, and coumarin. The reducing abilities and antiradical activities of RH were performed in vitro methods like, 1,1-diphenyl-2-picrylhydrazyl, nitric oxides, superoxides, hydroxyl, and ABTS (2,2'-azino-bis-3-ethyl benzthiazoline-6-sulphonic acid). Thereafter, RH was evaluated for it antidiabetic potentialities on streptozotocin (STZ)-induced type-2 diabetes. STZ (90 mg/kg, intraperitoneal) was administered to 2 days old pups to induce diabetes. RH was fed at doses of 50 and 100 mg/kg and glibenclamide (positive control) at 5 mg/kg, when the rats were 6 weeks old and continued for 10 weeks. Fasting glucose was monitored before and after the treatment. Further, lipid peroxides and reduced glutathione level were estimated on rat liver. RESULTS: The results obtained from this study revealed RH possesses flavonoinds and also gallic acid, quercetin, and coumarin. Further, it has antiradical activities. It has also reduced blood glucose level in type-2 diabetic rats and reduced the formation of lipid peroxidation in liver. RH enhanced the level of glutathione in liver tissue. CONCLUSION: RH exhibits source of natural antioxidants and great potentialities as an antidiabetic agent by improving the hyperglycemia through its antiradical action. PMID- 25829781 TI - Effect of co-administration of Angelicae gigantis radix and Lithospermi radix on rat hepatic injury induced by carbon tetrachloride. AB - BACKGROUND: Co-administration of Angelicae gigantis radix (AGR) and Lithospermi radix (LR) has been commonly applied to patients to treat cardiac and hepatic disorders. Individual bioactivities of these herbal medicines have been widely investigated, but the hepatoprotective effects of co-treatment of AGR and LR have yet to be clarified. OBJECTIVE: The present study investigated the protective effects of extracts of AGR and LR on carbon tetrachloride (CCl4) induced hepatic injury. MATERIALS AND METHODS: In this study, we measured the hepatoprotective activity of individual and co-treatment of the two herbal medicines on hepatic injury induced by CCl4 by measuring different biochemical parameters such as serum aspartate aminotransaminase (AST) and serum alanine aminotransaminase (ALT). Microarray technology also used to compare ontological difference with individual and co-treatment of these two. RESULTS: Combined treatment with AGR and LR (AGR + LR) decreased AST and ALT level in serum which demonstrate hepatoprotective effect of the therapy. When the effect of AGR and LR according to treatment conditions was measured, co-treatment showed the most prominent effect on hepatic injury by CCl4 rather than individual treatment condition. We further defined gene set that could be the molecular target of herbal effect on hepatic injury by CCl4 using bioinformatical analysis of interaction network. Highly recovered genes by treating AGR + LR play significant roles in response to hepatic injury induced by CCl4. CONCLUSION: Combined treatment with AGR and LR showed synergistic protective effects on the CCl4-induced rat hepatic tissue injury. PMID- 25829782 TI - Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B Pathway. AB - Quercetin can inhibit the growth of cancer cells with the ability to act as chemopreventers. Its cancer-preventive effect has been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis as well as the antioxidant functions. Nuclear factor kappa-B (NF-kappaB) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Inhibitors of NF-kappaB pathway have shown potential anti-tumor activities. However, it is not fully elucidated in colon cancer. In this study, we demonstrate that quercetin induces apoptosis in human colon cancer CACO-2 and SW-620 cells through inhibiting NF-kappaB pathway, as well as down-regulation of B-cell lymphoma 2 and up-regulation of Bax, thus providing basis for clinical application of quercetin in colon cancer cases. PMID- 25829783 TI - Bacopa monnieri promotes longevity in Caenorhabditis elegans under stress conditions. AB - BACKGROUND: Bacopa monnieri (L.) Pennell, commonly known as Brahmi is an important medicinal plant traditionally used as memory enhancer and antiepileptic agent. OBJECTIVE: The present study investigated antioxidant and stress resistance potentials of B. monnieri aqueous extract (BMW) using Caenorhabditis elegans animal model system. MATERIALS AND METHODS: The antioxidant activity of the BMW was measured using in vitro (DPPH, reducing power and total polyphenol content) and in vivo (DCF-DA assay) assays. The antistress potential of BMW (0.1, 0.01, and 0.001 mg/ml) was evaluated through thermal stress (37 degrees C) and oxidative stress (10 mM paraquat) using C. elegans. Quantification of the HSP 16.2 level was done using CL2070 transgenic worms. RESULTS: Present study reveals that BMW possess in vitro and in vivo antioxidant activities. BMW significantly enhanced stress tolerance and increased the mean lifespan of worms during thermal and oxidative stress, although it did not extend lifespan at 20 degrees C and attenuated age dependent decline in physiological behaviors. Moreover, it was shown that BMW was able to up-regulate expression of stress associated gene hsp 16.2, which significantly (P < 0.001) extends the mean lifespan of worms under stress conditions. CONCLUSION: The study strongly suggests that BMW acts as an antistressor and potent reactive oxygen species scavenger which enhances the survival of the worms in different stress conditions. PMID- 25829784 TI - Yin-Chen-Hao-Tang alleviates biliary obstructive cirrhosis in rats by inhibiting biliary epithelial cell proliferation and activation. AB - BACKGROUND: Yin-Chen-Hao-Tang (YCHT) consists of three aqueous extracts from Artemisia capillaris, Gardenia sp., and prepared Rheum rhabarbarum (rhubarb) (3:2:1). YCHT is characterized by its anti-inflammatory properties in liver regulation and relief of jaundice. We aimed to study the effects and mechanisms of action of YCHT on biliary obstructive cirrhosis. MATERIALS AND METHODS: Secondary biliary fibrosis was induced in rats by bile duct ligation (BDL) and scission. One week after BDL, rats were randomly divided into a saline-treated BDL or YCHT-treated BDL group for 4 weeks. Liver function and hepatic hydroxyproline (Hyp) content were assessed. Types I and IV collagen (Col-IV), laminin, fibronectin, alpha smooth muscle actin (alpha-SMA), and proliferating cell nuclear antigen protein and messenger ribonucleic acid (mRNA) expression were assessed with immunohistochemistry and real-time polymerase chain reaction. RESULTS: In the YCHT-treated BDL group, serum total bilirubin, total bile acids, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase were lower than those in the sham-operated BDL group. The proliferation of bile ducts in hepatic tissues and the Hyp content and Col deposition were also significantly lower than those in control rats. In addition, alpha-SMA and Col-IV staining was less obvious, and mRNA expression of Procol alpha1 (IV), platelet derived growth factor subunit B (PDGF)-B, connective tissue growth factor, and transforming growth factor-beta in proliferative biliary epithelial cells (BECs) in the YCHT-treated BDL group was significantly lower than those in controls. CONCLUSIONS: YCHT effectively reduces the formation of biliary obstructive cirrhosis mainly via inhibition of BEC proliferation by down regulation of PDGF-B mRNA expression, inhibition of BEC profibrogenic paracrines, and the epithelial-mesenchymal transition pathological process. PMID- 25829785 TI - In vivo antitumor potential of Ipomoea pes-caprae on melanoma cancer. AB - BACKGROUND: The incidence of skin cancers is rising gradually. The treatment of melanoma is also necessary to prevent the spread of cancer to other body organs. Scientific literatures have not documented any evidence of the antitumor potential of Ipomoea pes-caprae on melanoma. AIM OF THE STUDY: Explore in vivo antitumor potential of I. pes-caprae on melanoma cancer. MATERIALS AND METHODS: Petroleum ether (60 degrees C-80 degrees C), methanolic and aqueous extracts, and swaras prepared from the whole herb of I. pes-caprae were assessed for their antitumor activity. The extracts and swaras at doses of 25 and 50 mg/kg b. wt. were administered intraperitoneal along with chemo and radiotherapy for 40 days for exploring antitumor activity against melanoma cancer (B16F10) in male C57BL mice. The results obtained from tumor volume, and histopathological studies were compared with the control and dacarbazine used as a standard. RESULTS: Antitumor effect of I. pes-caprae extracts and swaras on melanoma cancer was found to be significant (P < 0.01) compared to normal control. The tumor volume inhibition against tumor-bearing mice, although differed from each other, was concentration dependent. Administration of plant extracts and swaras from the day 1 since tumor inducted. The induction of tumor was found delayed by 10-15 days and the tumor volume on the day 40 was similar to the Dacarbazine treatment used as a standard. CONCLUSION: The results obtained from the tumor volume and histopathological studies clearly revealed the antitumor potential of I. pes-caprae on melanoma cancer. PMID- 25829786 TI - Cytotoxic activity of ten algae from the Persian Gulf and Oman Sea on human breast cancer cell lines; MDA-MB-231, MCF-7, and T-47D. AB - BACKGROUND: Seaweeds have proven to be a promising natural source of bioactive metabolites for drug development. OBJECTIVE: This study aimed to monitor the ethanol extract of ten algae from the Persian Gulf and Oman Sea, for their in vitro cytotoxic activity on three human breast cancer cell lines. MATERIALS AND METHODS: Three human breast cancer cell lines including MDA-MB-231(ER(-)), MCF 7(ER(+)), and T-47D (ER(+)) were treated by different concentrations of total ethanol (90%) algae extracts and the cytotoxic effects were evaluated by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Doxorubicin (Ebewe, Austria) was used as a positive control. After 72 h of incubation, the cytotoxic effect of the algae was calculated and presented as 50%-inhibitory concentration (IC50). RESULTS: The results indicated Gracilaria foliifera and Cladophoropsis sp. to be the most active algae in terms of cytotoxic effects on the investigated cancer cell lines. The IC50 values against MDA-MB-231, MCF-7, and T-47D cells were, respectively, 74.89 +/- 21.71, 207.81 +/- 12.07, and 203.25 +/- 30.98 ug/ml for G. foliifera and 66.48 +/- 4.96, 150.86 +/- 51.56 and >400 ug/ml for Cladophoropsis sp. The rest of the algal extracts were observed not to have significant cytotoxic effects in the concentration range from 6.25 ug/ml to 400 ug/ml. CONCLUSION: Our data conclusively suggest that G. foliifera and Cladophoropsis sp. may be good candidates for further fractionation to obtain novel anticancer substances. Moreover, stronger cytotoxic effects on estrogen negative breast cancer cell line (MDA-MB-231(ER(-))) in comparison to estrogen positive cells (MCF-7 and T-47D) suggest that the extract of G. foliifera and Cladophoropsis sp. may have an estrogen receptor/progesterone receptor independent mechanism for their cellular growth inhibition. PMID- 25829787 TI - Chemical constituents and bioactivities of Glinus oppositifolius. AB - OBJECTIVES: To isolate the secondary metabolites from the dichloromethane (DCM) extracts of Glinus oppositifolius; to test for the cytotoxicity of a new triterpene, oppositifolone (1); and to test for the hypoglycemic, analgesic, and antimicrobial potentials of 1, DCM and aqueous leaf extracts of G. oppositifolius. METHODS: The compounds were isolated by silica gel chromatography and identified by nuclear magnetic resonance spectroscopy. The cytotoxicity potential of 1 was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Triterpene 1, DCM, and aqueous leaf extracts were tested for hypoglycemic potential using the oral glucose tolerance test; analgesic potential using the tail-flick assay, and antimicrobial potential using the disc diffusion method. RESULTS: The DCM extracts of G. oppositifolius afforded 1, squalene, spinasterol, oleanolic acid, phytol, and lutein from the leaves; squalene and spergulagenin A from the stems; and spinasterol from the roots. Triterpene 1 was cytotoxic against human colon carcinoma 116 with an IC50 value of 28.7 but did not exhibit cytotoxicity against A549. The aqueous leaf extract at 200 mg/kg body weight (BW) exhibited hypoglycemic activity with a pronounced % blood glucose reduction of 70.76% +/-17.4% within 0.5 h after introduction. The DCM leaf extract showed a lower % blood glucose reduction of 18.52% +/-13.5% at 200 mg/kg BW within 1.5 h after introduction, while 1 did not exhibit hypoglycemic activity. The samples did not exhibit analgesic property and were inactive against multiple drug resistant bacterial pathogens. CONCLUSION: The compounds responsible for the hypoglycemic activity of G. oppositifolius which are fast acting (0.5 h) are found in the aqueous leaf extract. PMID- 25829788 TI - Comparing and authenticating on anatomical aspects of Abrus cantoniensis and Abrus mollis by microscopy. AB - BACKGROUND: Abrus cantoniensis is popularly used as traditional Chinese medicine and a cool tea in South of China. However, due to diminishing source of A. cantoniensis, it is usually interchanged or adulterated with other species of Abrus genus because of the limited knowledge in identification and differentiation. Especially, Abrus mollis is widely mixed on herbal markets and pharmaceutical preparation. OBJECTIVE: To ensure safety and efficacy, a detailed comparison was undertaken to carry out an anatomical and micro-morphological study of two species of A. cantoniensis and A. mollis. MATERIALS AND METHODS: Microscopic characteristics of roots, leaves and stems, including transverse sections and the crude drug powder, were observed using a light microscope according to the usual microscopic techniques. RESULTS: The basic diagnostic features of A. cantoniensis include that stem is extremely thin; xylem vessels of root are radially arranged in 10 or more bundles; pith is hollow in stem, and the palisade tissue is made up of two layers of palisade cells. Furthermore, scanning electron microscopy was used to compare nonglandular hairs and the stomata of the leaflet surface. A table of the key authentication parameters based on the analyzed microscopic characteristics was drawn up. CONCLUSION: The study demonstrated that the microscopy and related techniques provided a systematic method that is convenient, feasible, and can be unambiguously applied to the authentication of the species of Abrus. PMID- 25829789 TI - Evaluation of Antidiabetic and Antihyperlipidemic Effects of Hydroalcoholic Extract of Leaves of Ocimum tenuiflorum (Lamiaceae) and Prediction of Biological Activity of its Phytoconstituents. AB - OBJECTIVE: The aim was to evaluate the anti-diabetic and anti-hyperlipidemic effects of hydroalcoholic extract of leaves of Ocimum tenuiflorum (Lamiaceae) and prediction of biological activities of its phytoconstituents using in vivo anti diabetic model and in silico analysis respectively. MATERIALS AND METHODS: The leaves of O. tenuiflorum were extracted with 60% ethanol, and the extract was used for further pharmacological screening. The acute toxicity of the extract was evaluated as per the guidelines set by the Organization for Economic Co-operation and Development, revised draft guidelines 423. The oral anti-diabetic activity of the hydroalcoholic extract of O. tenuiflorum (125, 250 and 500 mg/kg) was studied against streptozotocin (STZ) (50 mg/kg; i.p.) + nicotinamide (120 mg/kg; i.p.) induced diabetes mellitus. The animals were treated with the investigational plant extract and standard drug (glibenclamide) for 21 consecutive days and the effect of hydroalcoholic extract of O. tenuiflorum on blood glucose levels was measured at regular intervals. At the end of the study, blood samples were collected from all the animals for biochemical estimation, then the animals were sacrificed and the liver and kidney were collected for organ weight analysis. Prediction for pharmacological and toxicological properties of phytoconstituents of O. tenuiflorum was carried out using online web tools such as online pass prediction and lazar toxicity prediction. RESULTS: The hydroalcoholic extract of O. tenuiflorum showed significant anti-diabetic and anti-hyperlipidemic activity at 250 and 500 mg/kg, and this effect was comparable with that of glibenclamide. Predicted biological activities of phytoconstituents of O. tenuiflorum showed presence of various pharmacological actions, which includes anti-diabetic and anti-hyperlipidemic activities. Prediction of toxicological properties of phytoconstituents of O. tenuiflorum did not show any major toxic effects. CONCLUSION: The hydroalcoholic extract of O. tenuiflorum showed significant anti diabetic and anti-hyperlipidemic activity against STZ + nicotinamide induced diabetes mellitus in rats. Further studies are required to confirm the anti diabetic and anti-hyperlipidemic activities of individual phytoconstituents of O. tenuiflorum. PMID- 25829790 TI - Psidium guajava Linn. leaf extract affects hepatic glucose transporter-2 to attenuate early onset of insulin resistance consequent to high fructose intake: An experimental study. AB - BACKGROUND: Insulin resistance (IR) is amalgam of pathologies like altered glucos metabolism, dyslipidemia, impaired glucose tolerance, non-alcoholic fatty liver disease, and associated with type-II diabetes and cardiometabolic diseases. One of the reasons leading to its increased and early incidence is understood to be a high intake of processed fructose containing foods and beverages by individuals, especially, during critical developmental years. OBJECTIVE: To investigate the preventive potential of aqueous extract of Psidium guajava leaves (PG) against metabolic pathologies, vis-a-vis, IR, dyslipidemia, hyperleptinemia and hypertension, due to excess fructose intake initiated during developmental years. MATERIALS AND METHODS: Post-weaning (4 weeks old) male rats were provided fructose (15%) as drinking solution, ad libitum, for 8 weeks and assessed for food and water/fructose intake, body weight, fasting blood sugar, mean arterial pressure, lipid biochemistry, endocrinal (insulin, leptin), histopathological (fatty liver) and immunohistochemical (hepatic glucose transporter [GLUT2]) parameters. Parallel treatment groups were administered PG in doses of 250 and 500 mg/kg/d, po * 8 weeks and assessed for same parameters. Using extensive liquid chromatography-mass spectrometry protocols, PG was analyzed for the presence of phytoconstituents like Myrecetin, Luteolin, Kaempferol and Guavanoic acid and validated to contain Quercetin up to 9.9%w/w. RESULTS: High fructose intake raised circulating levels of insulin and leptin and hepatic GLUT2 expression to promote IR, dyslipidemia, and hypertension that were favorably re set with PG. Although PG is known for its beneficial role in diabetes mellitus, for the first time we report its potential in the management of lifelong pathologies arising from high fructose intake initiated during developmental years. PMID- 25829791 TI - Development of phytovesicles containing triterpenoids from Samadera indica. AB - INTRODUCTION: Samadera indica belonging to Simaroubaceae family is being used traditionally for many diseases including arthritis, edema, itching, skin diseases, constipation, and general debility. OBJECTIVE: The effectiveness of any drug delivery system depends upon its ability to deliver the active components at therapeutic level. In this study, a novel phyto vesicular formulation for the enhanced topical delivery of methanol extract of S. indica in order to treat skin infections was developed. MATERIALS AND METHODS: The methanol extract fraction of leaves of S. indica which showed more antifungal activity was purified to separate an antifungal compound. Phytovesicles were formulated using the more antifungal fraction in order to treat topical and deep seated fungal infections. Pytovesicles were prepared using 1:2 molar ratio of antifungal triterpenoid from S. indica (AFTSI)-phosphatidylcholine by film hydration method. RESULTS AND DISCUSSION: Chloroform 100% fraction of methanol extract of S. indica showed more activity against the fungus Candida albicans. Further purification gave a fraction with minimum inhibitory concentration value of 15.6 mg/ml against C. albicans and showed positive test for triterpenoids. The fraction was named as AFTSI. A compound (20 mg) was isolated from this fraction at an RF value. The phytovesicle gel formulated using AFTSI showed enhanced skin permeability and antifungal activity. CONCLUSION: The study demonstrated that the phytovesicular gel developed using methanol extract of S. indica would be beneficial for treating deep seated fungal infections. PMID- 25829792 TI - Serum total antioxidant capacity in oral carcinoma patients. AB - CONTEXT: Oxidative stress is a major determinant in carcinogenesis and serum total antioxidant capacity (TAC) indirectly reflects the level of oxidative stress. Although oral cancer is the third most frequent cancer in Indian population, there are no standard noninvasive marker for early detection and monitoring therapeutic response in oral cancer patients. AIMS: This study was carried out to investigate implications of serum TAC in oral cancer by evaluating pre- and post-operative levels in oral cancer patients. SETTINGS AND DESIGNS: It was a prospective single blinded study. SUBJECTS AND METHODS: Serum TAC was measured using ferric-reducing antioxidant power assay. Pre- and post-operative values were estimated and compared in 30 oral cancer patients who underwent surgery. STATISTICAL ANALYSIS USED: Paired t-test was used to compare pre- and post-operative values. RESULTS: Compared to the normal value, both pre- and post operative serum TAC were significantly low in oral cancer patients. However, there was no statistically significant difference between pre- and postoperative levels. CONCLUSIONS: In this study, low mean serum TAC was detected in oral cancer patients. However, its diagnostic and prognostic significance in oral cancer needs further investigation. PMID- 25829793 TI - Anti-inflammatory and antiarthritic activity of UNIM-301 (a polyherbal unani formulation) in Wistar rats. AB - BACKGROUND: UNIM-301 is a polyherbal formulation used in the Unani system of medicine for the treatment of joint pain and rheumatoid arthritis (RA). OBJECTIVE: The objective was to evaluate the anti-inflammatory and antiarthritic activity of UNIM-301 in carrageenan-induced paw edema and complete Freund's Adjuvant (CFA) induced arthritis. MATERIALS AND METHODS: The anti-inflammatory and antiarthritic activity of UNIM-301 was evaluated using carrageenan-induced paw edema and CFA induced animal arthritis models, respectively, in doses of 250, 500, and 1000 mg/kg body weight. Anti-inflammatory activity of UNIM-301 was evaluated using carrageenan-induced paw edema model using a digital plethysmometer. Anti-arthritic activity was evaluated using CFA induced arthritis, and joint sizes were measured at regular intervals using a micrometer screw gauge. Serum was collected and subjected to estimation of pro-inflammatory cytokine. Indomethacin 3 mg/kg body weight) was used as a standard drug in both the models. The acute and chronic toxicity study was carried out to evaluate the safety of the test drug. RESULTS: UNIM-301 treatment produced a dose-dependent reduction in paw edema and paw thickness in carrageenan-induced paw edema and CFA induced arthritis, respectively, as compared to control. UNIM 301 also reduced the expression of pro-inflammatory mediator in a dose-dependent manner as compared to control. CONCLUSION: The result of the present study suggests that anti-inflammatory and anti-arthritic activity of UNIM-301, which might be accredited to inhibitory activity on pro-inflammatory cytokines to its various individual constituents. PMID- 25829794 TI - A study of Nigella sativa induced growth inhibition of MCF and HepG2 cell lines: An anti-neoplastic study along with its mechanism of action. AB - OBJECTIVE: To evaluate the anticancer potential of seeds of Nigella sativa using MCF and HepG2 cell lines along with its mechanism of action. MATERIALS AND METHODS: (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and acridine orange/ethidium bromide nuclear staining technique were selected to evaluate anticancer potential and mechanism of action of test extract. RESULTS: Aqueous extract of N.sativa at a test dose of 180 mg and 300 mg was identified to be the best as anticancer agent against MCF and HepG2 cell lines among different solvent test extract where doxorubicin and cisplatin were employed as standard references. DISCUSSION: Further study including separation and characterization of active principles in the aqueous extract shall prove beneficial. PMID- 25829795 TI - Assessment of in vitro cytotoxicity and in vivo antitumor activity of Sphaeranthus amaranthoides burm.f. AB - BACKGROUND: A number of plants have been used in Indian system of medicine such as ayurveda, unani and siddha, but most of these plants were not explored properly. Sphaeranthus amaranthoides (SA) Burm.f., is one such plant used as an energizer in siddha. OBJECTIVE: To evaluate the anticancer effect of chloroform extract of the whole plant of SA Burm.f. against Ehrlich ascites carcinoma bearing Swiss albino mice. MATERIALS AND METHODS: The anticancer effect of chloroform extract was investigated in Swiss albino mice bearing Ehrlich ascites carcinoma at two different dose levels. Acute toxicity studies were also performed to determine the safety of the extract. Mice injected with Ehrlich ascites carcinoma cells were treated with the extract of doses 200 and 400 mg/kg body weight and standard 5-fluorouracil 20 mg/kg body weight for 15 consecutive days. Animals were sacrificed on day 15 for determination of anticancer activity by evaluating tumor volume, nonviable and viable tumor cell count and hematological parameters. RESULTS: Mice treated with the extract showed a significant decrease in tumor volume and viable cell count and an increase in nonviable cell count and mean survival time. The hematological parameters were also found to be restored to a normal level. CONCLUSION: The results indicate that the chloroform extract was producing anticancer activity comparable with that of the standard 5-fluorouracil. PMID- 25829796 TI - Nucleotide sequence of Phaseolus vulgaris L. alcohol dehydrogenase encoding cDNA and three-dimensional structure prediction of the deduced protein. AB - BACKGROUND: Common beans (Phaseolus vulgaris L.) are widely consumed as a source of proteins and natural products. However, its yield needs to be increased. In line with the agenda of Phaseomics (an international consortium), work of expressed sequence tags (ESTs) generation from bean pods was initiated. Altogether, 5972 ESTs have been isolated. Alcohol dehydrogenase (AD) encoding gene cDNA was a noticeable transcript among the generated ESTs. This AD is an important enzyme; therefore, to understand more about it this study was undertaken. OBJECTIVE: The objective of this study was to elucidate P. vulgaris L. AD (PvAD) gene cDNA sequence and to predict the three-dimensional (3D) structure of deduced protein. MATERIALS AND METHODS: positive and negative strands of the PvAD cDNA clone were sequenced using M13 forward and M13 reverse primers to elucidate the nucleotide sequence. Deduced PvAD cDNA and protein sequence was analyzed for their basic features using online bioinformatics tools. Sequence comparison was carried out using bl2seq program, and tree-view program was used to construct a phylogenetic tree. The secondary structures and 3D structure of PvAD protein were predicted by using the PHYRE automatic fold recognition server. RESULTS: The sequencing results analysis showed that PvAD cDNA is 1294 bp in length. It's open reading frame encodes for a protein that contains 371 amino acids. Deduced protein sequence analysis showed the presence of putative substrate binding, catalytic Zn binding, and NAD binding sites. Results indicate that the predicted 3D structure of PvAD protein is analogous to the experimentally determined crystal structure of s-nitrosoglutathione reductase from an Arabidopsis species. CONCLUSIONS: The 1294 bp long PvAD cDNA encodes for 371 amino acid long protein that contains conserved domains required for biological functions of AD. The predicted deduced PvAD protein's 3D structure reflects the analogy with the crystal structure of Arabidopsis thaliana s nitrosoglutathione reductase. Further study is required to validate the predicted structure. PMID- 25829798 TI - In vivo anti-inflammatory and antiarthritic activities of aqueous extracts from Thymelaea hirsuta. AB - BACKGROUND: The aerial parts of Thymelaea hirsuta (TH) are used as a decoction in the treatment of different pathologies in folk medicine in Morocco. OBJECTIVE: The aqueous extracts were evaluated for its anti-inflammatory activity and in inhibition of adjuvant induction arthritis in male Wistar rats. MATERIALS AND METHODS: The anti-inflammatory activity was carried out using carrageenan-induced rat paw edema model, and the antiarthritic activity was carried out using complete Freund's adjuvant-induced arthritis model. RESULTS: The plant extract (500 mg/kg body weight) exhibited significant activity in acute inflammation produced 60% of inhibition after 4 h as compared with that of the standard anti inflammatory drug, the diclofenac (100 mg/kg) which showed 40% of inhibition. In arthritis model, the extract produced 85% inhibition after 18 days when compared with the diclofenac (10 mg/kg; 72%). CONCLUSION: These results indicate that the aqueous extract of TH had an anti-inflammatory activity and inhibited the induction of adjuvant arthritis in male Wistar rats. PMID- 25829797 TI - Analysis of common bean (Phaseolus vulgaris L., genotype BAT93) calmodulin cDNA using computational tools. AB - BACKGROUND: Common bean (Phaseolus vulgaris L.) is an important part of the human diet and serves as a source of natural products. Identification and understanding of genes in P. vulgaris is important for its improvement. Characterization of expressed sequence tags (ESTs) is one of the approaches in understanding the expressed genes. For the understanding of genes expression in P. vulgaris pod tissue, research work of ESTs generation was initiated by constructing cDNA libraries using 5-day and 20-day old bean-pod-tissues. Altogether, 5972 cDNA clones were isolated to have ESTs. While processing ESTs, we found a transcript for calmodulin (CaM) gene. It is an important gene that encodes for a calcium binding protein and known to express in all eukaryotic cells. Hence, this study was undertaken to analyse and annotate it. OBJECTIVE: The objective of this study was to analyze and annotate P. vulgaris CaM (PvCaM) gene cDNA and its deduced protein (amino acids) sequence. MATERIALS AND METHODS: Both strands of PvCaM cDNA clone were sequenced using M13 forward and reverse primer to elucidate the nucleotide sequence. The cDNA sequence and deduced protein sequence were analyzed and annotated using bioinformatics tools available online. The secondary structures and three-dimensional (3D) structure of PvCaM protein were predicted using the Phyre automatic fold recognition server. RESULTS: Results showed that PvCaM cDNA is 818 bp in length. The cDNA analysis results showed that it contains an open reading frame that encodes for 149 amino acid residues. The deduced protein sequence analysis results showed the presence of conserved domains required for CaM function. The predicted secondary structures and 3D structure are analogous to the Solanum tuberosum CaM. CONCLUSIONS: This study analyzed and annotated PvCaM cDNA and protein. However, in order to obtain a complete understanding of PvCaM protein, further study on its expression, structure and regulation is essential. PMID- 25829799 TI - It is time for doctors to start seeing the signs and hearing the cries of abused children as professional guardians. PMID- 25829800 TI - Vaccination policy in Korean armed forces: current status and future challenge. AB - Infectious diseases have historically resulted in suspended or cancelled military operations. Vaccination for disease prevention is a critical component of the military's force readiness doctrine. Until recently, Korea had not recognized the importance of vaccinating military personnel. However, a 2011 meningococcal disease outbreak at an army recruit training center led to dramatic changes in the paradigm of traditional medical practice in the Korean armed forces. A new vaccination policy was formed by a 2012 Military Healthcare Service Act. Since then, Neisseria meningitidis, hepatitis A, and measles-mumps-rubella vaccines have been routinely administered to all new recruits early in basic training to ensure protection against these diseases. All active-duty soldiers also receive seasonal influenza vaccination annually. Despite quantitative improvements in vaccination policies, several instances of major infectious diseases and adverse vaccine reactions have threatened soldier health. In the future, vaccination policies in the Korean armed forces should be based on epidemiologic data and military medical research for vaccine use and safety management. PMID- 25829801 TI - Rewarding peer reviewers: maintaining the integrity of science communication. AB - This article overviews currently available options for rewarding peer reviewers. Rewards and incentives may help maintain the quality and integrity of scholarly publications. Publishers around the world implemented a variety of financial and nonfinancial mechanisms for incentivizing their best reviewers. None of these is proved effective on its own. A strategy of combined rewards and credits for the reviewers1 creative contributions seems a workable solution. Opening access to reviews and assigning publication credits to the best reviews is one of the latest achievements of digitization. Reviews, posted on academic networking platforms, such as Publons, add to the transparency of the whole system of peer review. Reviewer credits, properly counted and displayed on individual digital profiles, help distinguish the best contributors, invite them to review and offer responsible editorial posts. PMID- 25829802 TI - The initial hyperglycemia in acute type II pyrethroid poisoning. AB - This retrospective observational case series study was conducted to describe the clinical feature of acute type II pyrethroid poisoning, and to investigate whether hyperglycemia at presentation can predict the outcome in patients with type II pyrethroid poisoning. This study included 104 type II pyrethroid poisoned patients. The complication rate and mortality rate was 26.9% and 2.9% in type II pyrethroid poisoned patients. The most common complication was respiratory failure followed by acidosis and hypotension. In non-diabetic type II pyrethroid poisoned patients, patients with complications showed a higher frequency of hyperglycemia, abnormalities on the initial X ray, depressed mentality, lower PaCO2 and HCO3- levels, and a higher WBC and AST levels at the time of admission compared to patients without complication. Hyperglycemia was an independent factor for predicting complications in non-diabetic patients. Diabetic patients had a significantly higher incidence of complications than non-diabetic patients. However, there was no significant predictive factor for complications in patients with diabetes mellitus probably because of small number of diabetes mellitus. In contrast to the relatively low toxicity of pyrethroids in mammals, type II pyrethroid poisoning is not a mild disease. Hyperglycemia at presentation may be useful to predict the critical complications in non-diabetic patients. PMID- 25829803 TI - Pediatric medication error reports in Korea adverse event reporting system database, 1989-2012: comparing with adult reports. AB - Children have dynamic process of maturation and substantial changes in growth and development which eventually make the drug safety profiles different from adults. Medication errors (MEs) in pediatrics are reported to occur three times more likely than adults. The aims of this study were to identify the characteristics of pediatric MEs in Korea at national level and help raise awareness of risks from the MEs in pediatrics. We conducted a descriptive analysis with the pediatric ME reports in Korea Adverse Event Reporting System (KAERS) database from 1989 to 2012 and 208 ME reports in pediatrics were found. Based on KAERS database, the proportion of reported pediatric ME in adverse drug event (ADE) reports was 2.73 times (95% CI, 2.35-3.17) higher than that of adult ME. In 208 ME reports, we found a total of 236 ME-related terms within 19 types of MEs. The most common type of MEs was "accidental overdose" (n=58, 24.6%), followed by "drug maladministration" (n=50, 21.2%) and "medication error" (n=41, 17.4%). After the narratives of ME reports were reviewed, we noticed that most of them did no harm to patients, but some cases were needed for medical treatment. Our data suggest that MEs in pediatrics are not negligible in Korea. We expect that this study would increase the awareness of the problem in pediatric MEs and induce the need for further development of an effective national ME preventing system in Korea. PMID- 25829804 TI - A phase 2 multi-center, open-label, switch-over trial to evaluate the safety and efficacy of Abcertin(r) in patients with type 1 Gaucher disease. AB - Gaucher disease is a lysosomal storage disease for which enzyme replacement therapy has proven to be effective. A switch-over clinical trial was performed to evaluate the efficacy and safety of Abcertin(r) (ISU Abxis, Seoul, Korea) in subjects with type 1 Gaucher disease who were previously treated with imiglucerase. Five Korean patients with type 1 Gaucher disease were enrolled. Previous doses of imiglucerase ranged from 30 to 55 U/kg every other week. The same dose of Abcertin(r) was administered to all patients for 24 weeks. Primary efficacy endpoints were changes in hemoglobin levels and platelet counts, and the secondary efficacy endpoints included changes in liver and spleen volumes, serum biomarkers, skeletal status and bone mineral density (BMD). During the study period, no statistically significant changes were observed in all parameters including hemoglobin levels and platelet counts, liver and spleen volumes, skeletal status and BMD. Abcertin(r) administration was continued in three patients for another 24 weeks as an extension of the study. Hemoglobin levels and platelet counts were maintained in all three patients. In conclusion, the efficacy and safety of Abcertin(r) are similar to those of imiglucerase, and Abcertin(r) is an effective therapeutic agent for patients with type 1 Gaucher disease (Clinical Trial Registry No. NCT02053896 at www.clinicaltrials.gov). PMID- 25829805 TI - Clinicopathological features of prostate ductal carcinoma: matching analysis and comparison with prostate acinar carcinoma. AB - We evaluated the clinicopathological features and prognosis of 29 cases of prostate ductal carcinoma was considered to be an aggressive subtype of prostate acinar carcinoma. We selected 29 cases who were diagnosed prostate ductal carcinoma and had a radical prostatectomy (RP). The acinar group (n = 116) was selected among 3,980 patients who underwent a prostatectomy. The acinar group was matched to the ductal group for prostate specific antigen (PSA), clinical stage, Gleason score, and age. The mean (range) of the follow-up periods for the ductal and acinar group was 23.8 +/- 20.6 and 58 +/- 10.5 months, respectively. The mean age of the prostate ductal and acinar carcinoma patients was 67.3 and 67.0 yr and the mean PSA level was 14.7 and 16.2 ng/mL, respectively. No statistical differences were evident between groups in terms of the final pathologic stage or positive resection margin rate other than the postoperative Gleason score. A greater proportion of the ductal group demonstrated a postoperative Gleason score >= 8 in comparison with the acinar group (P = 0.024). Additionally, we observed significant prognostic difference in our patient series in biochemical recurrence. The ductal group showed a poorer prognosis than the acinar group (P = 0.016). There were no differences significantly in terms of final pathology and rate of positive resection margin, but a greater proportion of the ductal group demonstrated a Gleason score >= 8 than the acinar group after matching for PSA, Gleason score in biopsy and clinical stage. The ductal group also showed a poorer prognosis. PMID- 25829806 TI - Increased expression of forkhead box M1 is associated with aggressive phenotype and poor prognosis in estrogen receptor-positive breast cancer. AB - Fox transcription factors play a critical role in the regulation of a variety of biological processes. While FoxM1 behaves like the oncogenic transcription factor, FoxO3a is known as a tumor suppressor by inhibiting FoxM1. This study aimed to investigate the clinicopathological significance of FoxM1 and FoxO3a expression in breast cancer. Expression of FoxM1 and FoxO3a were analyzed by immunohistochemical staining on tissue microarray sections from 236 breast cancer patients, and correlated with various clinicopathological characteristics. Overexpression of FoxM1 correlated with adverse clinicopathological features, such as larger tumor size, lymph node metastasis, advanced tumor stage, and lymphovascular invasion. The Kaplan-Meier survival curves revealed no prognostic significance of FoxM1 expression. However, in subgroup analyses with patients of estrogen receptor (ER) positive breast cancers, FoxM1 overexpression associated with poor disease free and overall survival. No association was found between FoxO3a and FoxM1 expression. Regarding clinicopathological variables, the only association between histologic grade and FoxO3a was observed. In conclusion, FoxM1 overexpression was significantly associated with aggressive phenotypes and poor prognosis of ER-positive breast cancer. These findings suggest the possible role of FoxM1 as a prognostic biomarker and putative target of anti-cancer therapy. PMID- 25829807 TI - Meta-analysis of predictive clinicopathologic factors for lymph node metastasis in patients with early colorectal carcinoma. AB - The objective of this study was to conduct a meta-analysis to determine risk factors that may facilitate patient selection for radical resections or additional resections after a polypectomy. Eligible articles were identified by searches of PUBMED, Cochrane Library and Korean Medical Database using the terms (early colorectal carcinoma [ECC], lymph node metastasis [LNM], colectomy, endoscopic resection). Thirteen cohort studies of 7,066 ECC patients who only underwent radical surgery have been analysed. There was a significant risk of LNM when they had submucosal invasion (>= SM2 or >= 1,000 um) (odds Ratio [OR], 3.00; 95% confidence interval [CI], 1.36-6.62, P = 0.007). Moreover, it has been found that vascular invasion (OR, 2.70; 95% CI, 1.95-3.74; P < 0.001), lymphatic invasion (OR, 6.91; 95% CI, 5.40-8.85; P < 0.001), poorly differentiated carcinomas (OR, 8.27; 95% CI, 4.67-14.66; P < 0.001) and tumor budding (OR, 4.59; 95% CI, 3.44-6.13; P < 0.001) were significantly associated with LNM. Furthermore, another analysis was carried out on eight cohort studies of 310 patients who underwent additional surgeries after an endoscopic resection. The major factors identified in these studies include lymphovascular invasion on polypectomy specimens (OR, 5.47; 95% CI, 2.46-12.17; P < 0.001) and poorly or moderately differentiated carcinomas (OR, 4.07; 95% CI, 1.08-15.33; P = 0.04). For ECC patients with >= SM2 or >= 1,000 um submucosal invasion, vascular invasion, lymphatic invasion, poorly differentiated carcinomas or tumor budding, it is deemed that a more extensive resection accompanied by a lymph node dissection is necessary. Even if the lesion is completely removed by an endoscopic resection, an additional surgical resection should be considered in patients with poorly or moderately differentiated carcinomas or lymphovascular invasion. PMID- 25829808 TI - Addition of N-terminal pro-B-type natriuretic peptide levels to electrocardiography criteria for detection of left ventricular hypertrophy: the ARIRANG study. AB - The utility of electrocardiography (ECG) in screening for left ventricular hypertrophy (LVH) in general populations is limited mainly because its low sensitivity. B-type natriuretic peptide (BNP) is released due to the remodeling processes of LVH and could improve the diagnostic accuracy for the ECG criteria for LVH. We hypothesized that addition of BNP levels to ECG criteria could aid LVH detection compared with ECG alone in a general population. We enrolled consecutive 343 subjects from a community-based cohort. LVH was defined as LV mass index > 95 g/m(2) for females and > 115 g/m(2) for males according to echocardiography. The area under the receiver operator characteristic (ROC) curve to detect LVH was 0.55 (95% confidence interval [CI], 0.50-0.61) in Sokolow-Lyon criteria and 0.53 (0.47-0.59) in the Cornell voltage criteria. After addition of N-terminal-proBNP levels to the model, the corresponding areas under the ROC were 0.63 (0.58-0.69) and 0.64 (0.59-0.69), respectively. P values for the comparison in areas under the ROC for models with and without N-terminal-proBNP levels were < 0.001. These data suggest that addition of N-terminal-proBNP levels to ECG criteria could significantly improve the diagnostic accuracy of LVH in general populations. PMID- 25829809 TI - The effect of admission at weekends on clinical outcomes in patients with non-ST segment elevation acute coronary syndrome and its contributing factors. AB - We investigated the effects of weekend admission on adverse cardiac events in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Patients with NSTE-ACS treated with percutaneous coronary intervention (PCI) were divided into a "weekend group" and a "weekday group" according to the emergency room arrival time. The primary outcome was 30-day major adverse cardiac events (MACE) including cardiac death, recurrent myocardial infarction, repeat revascularization, and urgent PCI. Of 577 patients, 168 patients were allocated to the weekend and 409 patients to the weekday group. The incidence of 30-day MACE was significantly higher in the weekend group (Crude: 15.5% vs. 7.3%, P = 0.005; propensity score matched: 12.8% vs. 4.8%, P = 0.041). After adjustment for all the possible confounding factors, in Cox proportional hazard regression analysis, weekend admission was associated with a 2.1-fold increased hazard for MACE (HR, 2.13; 95% CI, 1.26-3.60, P = 0.005). These findings indicate that weekend admission of patients with NSTE-ACS is associated with an increase in 30 day adverse cardiac event. PMID- 25829810 TI - Safety and efficacy of a novel, fenestrated aortic arch stent graft with a preloaded catheter for supraaortic arch vessels: an experimental study in Swine. AB - Thoracic endovascular aortic repair (TEVAR) shows limitations in cases in which the aortic pathology involves the aortic arch. The study aims were to test a fenestrated aortic arch stent graft (FASG) with a preloaded catheter for the supraaortic arch vessels and to perform a preclinical study in swine to evaluate the safety and efficacy of this device. Six FASGs with 1 preloaded catheter and 5 FASGs with 2 preloaded catheters were advanced through the iliac artery in 11 swines. The presence of endoleaks and the patency and deformity of the grafts were examined with computed tomography (CT) at 4 weeks postoperatively. A postmortem examination was performed at 8 weeks. The mean procedure time for the one and two FASG groups was 30.2 (27.9-34.5) min and 43.1 (39.2-53.7) min. The mean time for the selection of the carotid artery was 4.8 (4.2-5.5) min and 6.2 (4.6-9.4) min. Major adverse event was observed in one of 11 pigs. One pig died at 4 weeks likely because of the effects of the high dose of ketamine, while the remaining 10 pigs survived 8-week. For both the one and two FASG groups, no endoleaks, no disconnection, no occlusion of the stent grafts were observed in the CT findings and the postmortem gross findings. The procedure with the FASG could be performed safely in a relatively short procedure time and involved an easy technique. The FASG is found to be safe and convenient in this preclinical study with swine. PMID- 25829811 TI - Effects of high-dose atorvastatin pretreatment in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a cardiac magnetic resonance study. AB - It is uncertain that atorvastatin pretreatment can reduce myocardial damage in patients undergoing primary percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). The aim of this study was to investigate the effects of atorvastatin pretreatment on infarct size measured by contrast-enhanced magnetic resonance imaging (CE-MRI) in STEMI patients. Patients undergoing primary PCI for STEMI within 12 hr after symptom onset were randomized to an atorvastatin group (n=30, 80 mg before PCI and for 5 days after PCI) or a control group (n=37, 10 mg daily after PCI). The primary end point was infarct size evaluated as the volume of delayed hyperenhancement by CE-MRI within 14 days after the index event. The median infarct size was 19% (IQR 11.1%-31.4%) in the atorvastatin group vs. 16.3% (7.2%-27.2%) in the control group (P=0.27). The myocardial salvage index (37.1% [26.9%-58.7%] vs. 46.9% [39.9-52.4], P=0.46) and area of microvascular obstruction (1.1% [0%-2.0%] vs. 0.7% [0%-1.8%], P=0.37) did not differ significantly between the groups. Frequency of the hemorrhagic and transmural infarctions was not significantly different in the 2 groups. Pretreatment with a high-dose atorvastatin followed by further treatment for 5 days in STEMI patients undergoing primary PCI failed to reduce the extent of myocardial damage or improve myocardial salvage. PMID- 25829812 TI - One-year prognosis and the role of brain natriuretic peptide levels in patients with chronic cor pulmonale. AB - Data on the clinical outcomes and role of brain natriuretic peptide (BNP) levels in patients with chronic cor pulmonale are limited. A total of 69 patients with chronic cor pulmonale, admitted for dyspnea (January 2007 to September 2011) to three university hospitals, were retrospectively reviewed. All of the patients had right ventricular (RV) dysfunction on echocardiography. The median age was 70.0 yr, and chronic obstructive pulmonary disease (40.6%) and tuberculosis destroyed lung (TDL, 27.5%) were the leading causes of chronic cor pulmonale. At the 1-yr follow-up, the mortality rate was 15.9%, and the readmission rate was 53.7%; patients with TDL had higher mortality (31.6% vs. 10.0%; P=0.059) and readmission rates (78.9% vs. 43.8%; P=0.009) than those with non-TDL diseases. The area under the receiver operating characteristic curve for admission BNP levels to predict readmission was 0.788 (95% confidence interval [CI], 0.673 0.904), and the sensitivity and specificity of the cut-off value were 80.6% and 77.4%, respectively. In multivariate analysis, high admission BNP levels were a significant risk factor for subsequent readmission (hazard ratio, 1.049; 95% CI, 1.005-1.094). Additionally, admission BNP levels were well correlated with cardiac troponin I (r=0.558), and delta BNP also correlated with delta RV systolic pressure (n=25; r=0.562). In conclusion, among hospitalized patients with chronic cor pulmonale, admission high BNP levels are a significant risk factor for subsequent readmission. Therefore, more intensive monitoring and treatment are needed in patients with higher BNP levels. PMID- 25829813 TI - Validity of the ages and stages questionnaires in Korean compared to Bayley Scales of infant development-II for screening preterm infants at corrected age of 18-24 months for neurodevelopmental delay. AB - This study aimed to evaluate the validity of the ages and stages questionnaire in Korean (ASQ 1st edition, Korean Questionnaires, Seoul Community Rehabilitation Center, 2000) for premature infants. The study population consisted of 90 premature infants born between January 1, 2005, and December 31, 2011, who were tested using the ASQ (Korean) and Bayley Scales of Infant Development (BSID) (II) at a corrected age of 18-24 months. The validity of the ASQ (Korean) using cut off values set at < -2 SD was examined by comparing it to the BSID (II) components, namely, the mental developmental index (MDI) or psychomotor developmental index (PDI), which were both set at < 85. The calculation of the sensitivities, specificities, positive predictive values, and negative predictive values of the ASQ (Korean) components revealed that they detected infants with neurodevelopmental delay with low sensitivity and positive predictive values, however, the communication domain showed moderate correlations with MDI. The failure in more than one domain of the ASQ (Korean) was significantly correlated with the failure in MDI. The ASQ (Korean) showed low validity for screening neurodevelopmentally delayed premature infants. PMID- 25829814 TI - Risk factors for late-onset hyponatremia and its influence on neonatal outcomes in preterm infants. AB - Late-onset hyponatremia (LOH), hyponatremia occurring after two weeks of age with the achievement of full feeding, is the result of a negative sodium balance caused by inadequate salt intake or excessive salt loss due to immature renal or intestinal function in preterm infants. The aims of our study were to identify the risk factors for LOH and its influence on neonatal outcomes. This was a retrospective cohort analysis of 161 preterm infants born before 34 weeks of gestation between June 2009 and December 2010 at Seoul National University Hospital. LOH was defined as a sodium level <= 132 mEq/L or 133-135 mEq/L with oral sodium supplementation. LOH occurred in 49 (30.4%) of the studied infants. A lower gestational age, a shorter duration of parenteral nutrition, the presence of respiratory distress syndrome, the use of furosemide, and feeding with breast milk were significant risk factors for LOH. In terms of neonatal outcomes, the infants with LOH had longer hospital stays and higher risks of bronchopulmonary dysplasia and retinopathy of prematurity requiring surgery. LOH lasting at least 7 days significantly increased moderate to severe bronchopulmonary dysplasia, periventricular leukomalacia, and extra-uterine growth retardation. LOH is commonly observed in preterm infants; it may be a risk factor for bronchopulmonary dysplasia and retinopathy of prematurity or a marker of illness severity. PMID- 25829815 TI - Neurocognitive outcome in survivors of childhood acute lymphoblastic leukemia: experience at a tertiary care hospital in Korea. AB - This study was conducted to investigate long-term neurocognitive outcomes and to determine associated risk factors in a cohort of Korean survivors of childhood acute lymphoblastic leukemia (ALL). Forty-two survivors of ALL were compared with 42 healthy controls on measures of a neurocognitive test battery. We analysed potential risk factors (cranial irradiation, sex, age at diagnosis, elapsed time from diagnosis, and ALL risk group) on neurocognitive outcomes. ALL patients had lower, but non-significant full-scale intelligence quotient (FSIQ, 107.2+/-12.2 vs. 111.7+/-10.2), verbal intelligence quotient (VIQ, 107.7+/-13.6 vs. 112.2+/ 11.4), and performance intelligence quotient (PIQ, 106.3+/-14.2 vs. 110.1+/-10.7) scores than healthy controls. However, patients treated with cranial irradiation performed significantly lower on FSIQ (102.2+/-8.1), VIQ (103.3+/-11.7), and PIQ (101.4+/-13.2) compared to non-irradiated patients and healthy controls. ALL patients also had poor attention, concentration, and executive functions. Among ALL survivors, cranial irradiation was a risk factor for poor FSIQ, being male was a risk factor for poor PIQ, and younger age was a risk factor for poor attention. Therefore, the delayed cognitive effects of ALL treatment and its impact on quality of life require continuing monitoring and management. PMID- 25829816 TI - Coronary heart disease in moyamoya disease: are they concomitant or coincidence? AB - The purpose of this study was to determine the prevalence and characteristics of symptomatic coronary heart disease (CHD) in patients with moyamoya disease (MMD). This retrospective study evaluated 456 patients who received examination for MMD between 1995 and 2012. We reviewed the patients' medical history and coronary imaging, including conventional coronary angiography and coronary computed tomography angiogram (CTA). Among 456 patients with MMD, 21 (4.6%) patients were found to have symptomatic CHD. Ten patients were treated with coronary artery bypass graft or percutaneous coronary intervention for unstable angina or myocardial infarction. Eleven were treated with medication for stable angina (n = 6) and variant angina with mild degree of stenosis (n = 5).The median age of these patients was 44 yr (range, 27-59). The median Framingham score at diagnosing MMD was < 1% (range, < 1%-16%). The old age was associated with CHD in uni- and multivariate analyses (P = 0.021, OR, 1.053; 95% CI, 1.008-1.110). Considering low age of onset and low stroke risk factor, CHD might be a systemic manifestation that is clinically relevant to MMD. PMID- 25829817 TI - Baseline predictors of visual acuity and retinal thickness in patients with retinal vein occlusion. AB - This study investigated the baseline predictors of best corrected visual acuity (BCVA) and central retinal thickness (CRT) at 6 months in patients with treatment naive branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). This multicenter, interventional case series included 208 BRVO and 123 CRVO patients with follow-up period of 6 months or more. Outcome measures of BCVA (logMAR) included absolute change from baseline and a gain or loss of >= 0.3 from baseline. Outcome measures of CRT included absolute change from baseline and a measurement of <= 250 um or >= 400 um at 6 months. Univariate and multiple regression analyses were done to find baseline predictors. For BRVO, younger age, worse baseline BCVA, and shorter duration of symptom were associated with more gain in BCVA. For CRVO, worse baseline BCVA was associated with more gain in BCVA. For CRT outcomes, higher baseline CRT predicted greater decrease at 6 months in both BRVO and CRVO. Younger age and better baseline BCVA were associated with an increased likelihood of measurement of a <= 250 um outcome for BRVO and CRVO, respectively. For CRVO, smoking was associated with greater decrease from baseline and decreased likelihood of measurement of a CRT >= 400 um at 6 months. In conclusion, several baseline factors including age, symptom duration, and baseline BCVA and CRT are associated with BCVA and CRT outcomes at 6 months, which may help to predict disease course for RVO patients. PMID- 25829818 TI - Trend in hip fracture incidence and mortality in Korea: a prospective cohort study from 2002 to 2011. AB - This prospective longitudinal cohort study was to assess the 10-yr hip fracture incidence and mortality trend of person >=50 yr of age between 2002 and 2011 of eight hospitals in Jeju Island. Sex-specific incidence rate (per 100,000 person years) were calculated based on that estimated for the population in the United States in 2008. Poisson and logistic regressions were used to examine trends in incidence and mortality. There was a 101% increase in the number of hip fractures from 151 in 2002 to 304 in 2011. The crude incidence of hip fractures in the Jeju population >=50 yr of age increased from 126.6/100,000 to 183.7/100,000. The fracture incidence in the population standardized to the 2008 population in the United States increased from 100.6/100,000 for men and 194.4/100,000 for women in 2002 to 114.2/100,000 for men and 278.4/100,000 for women in 2011. The annual increasing incidence rate of hip fracture was 4.3% (5.3% in women and 2.2% in men). Poisson regression did not show significant trends in the mortality rates for all age groups or for both genders. The total number of hip fractures increased two-fold and the incidence rate of hip fractures increased markedly during the 10-yr study period. PMID- 25829819 TI - Perioperative complications of orthopedic surgery for lower extremity in patients with cerebral palsy. AB - Because complications are more common in patients with cerebral palsy (CP), surgeons and anesthesiologists must be aware of perioperative morbidity and be prepared to recognize and treat perioperative complications. This study aimed to determine the incidence of and risk factors for perioperative complications of orthopedic surgery on the lower extremities in patients with CP. We reviewed the medical records of consecutive CP patients undergoing orthopedic surgery. Medical history, anesthesia emergence time, intraoperative body temperature, heart rate, blood pressure, immediate postoperative complications, Gross Motor Function Classification System (GMFCS) level, Cormack-Lehane classification, and American Society of Anesthesiologists physical status classification were analyzed. A total of 868 patients was included. Mean age at first surgery was 11.8 (7.6) yr. The incidences of intraoperative hypothermia, absolute hypotension, and absolute bradycardia were 26.2%, 4.4%, and 20.0%, respectively. Twenty (2.3%) patients had major complications, and 35 (4.0%) patients had minor complications postoperatively. The incidences of intraoperative hypothermia, absolute hypotension, and major postoperative complications were significantly higher in patients at GMFCS levels IV and V compared with patients at GMFCS levels I to III (P<0.001). History of pneumonia was associated with intraoperative absolute hypotension and major postoperative complications (P<0.001). These results revealed that GMFCS level, patient age, hip reconstructive surgery, and history of pneumonia are associated with adverse effects on intraoperative body temperature, the cardiovascular system, and immediate postoperative complications. PMID- 25829822 TI - How to encourage best peer reviewers: an empiric approach. PMID- 25829820 TI - Ethical issues recognized by critical care nurses in the intensive care units of a tertiary hospital during two separate periods. AB - This research aimed to investigate the changes in ethical issues in everyday clinical practice recognized by critical care nurses during two observation periods. We conducted a retrospective analysis of data obtained by prospective questionnaire surveys of nurses in the intensive care units (ICU) of a tertiary university-affiliated hospital in Seoul, Korea. Data were collected prospectively during two different periods, February 2002-January 2003 (Period 1) and August 2011-July 2012 (Period 2). Significantly fewer cases with ethical issues were reported in Period 2 than in Period 1 (89 cases [2.1%] of 4,291 ICU admissions vs. 51 [0.5%] of 9,302 ICU admissions, respectively; P < 0.001). The highest incidence of cases with identified ethical issues in both Periods occurred in MICU. The major source of ethical issues in Periods 1 and 2 was behavior-related. Among behaviorrelated issues, inappropriate healthcare professional behavior was predominant in both periods and mainly involved resident physicians. Ethical issue numbers regarding end-oflife (EOL) care significantly decreased in the proportion with respect to ethical issues during Period 2 (P = 0.044). In conclusion, the decreased incidence of cases with identified ethical issues in Period 2 might be associated with ethical enhancement related with EOL and improvements in the ICU care environment of the studied hospital. However, behaviorrelated issues involving resident physicians represent a considerable proportion of ethical issues encountered by critical care nurses. A systemic approach to solve behavior-related issues of resident physicians seems to be required to enhance an ethical environment in the studied ICU. PMID- 25829821 TI - Multiple muscular variations in the neck, upper extremity, and lower extremity biased toward the left side of a single cadaver. AB - Although numerous reports have found accessory or supernumerary muscles throughout the human body, multiple appearances of these variations biased toward one side of body are rare. We report a 76-yr-old male cadaver with an accessory head of the biceps brachii and palmaris profundus, and a muscular slip between the biceps femoris and semitendinosus on the left side in addition to a bilateral accessory belly of the digastric muscle. No remarkable nervous, vascular, or visceral variation accompanied these variations. An interruption of normal somitogenesis or myogenesis may be a cause of these variations. PMID- 25829823 TI - Deep anterior lamellar keratoplasty using irradiated acellular cornea with amniotic membrane transplantation for intractable ocular surface diseases. AB - PURPOSE: To report the clinical outcomes of deep anterior lamellar keratoplasty (DALK) when sterile gamma-irradiated acellular corneal tissues (VisionGraft) are used in combination with amniotic membrane transplantation (AMT) for intractable ocular surface diseases. METHODS: The medical records of fifteen patients who had DALK with AMT were retrospectively reviewed. Indications for surgery included ocular burn, bacterial keratitis, herpes simplex virus keratitis, corneal opacity with Stevens-Johnson syndrome, Mooren's ulcer, idiopathic myxoid degeneration of corneal stroma, and recurrent band keratopathy. DALK was performed using partial thickness acellular corneal tissue and a temporary amniotic membrane patch was added at the end of the operation. RESULTS: All cases that underwent DALK with AMT became epithelialized within 2 postoperative weeks. Twelve patients showed favorable outcomes without graft rejection, corneal opacification, or neovascularization. The other three grafts developed corneal opacification and neovascularization, and required additional penetrating keratoplasty (PK). Unlike the results of previous PKs, there were no graft rejections and the graft clarity was well-maintained in these three cases for at least 8 months after PK. CONCLUSIONS: DALK using sterile acellular corneal tissues in combination with AMT may be a good therapeutic strategy for treating intractable ocular surface diseases because of lowered immune rejection, fibroblast activation, and facilitation of epithelialization. Furthermore, DALK can help stabilize the ocular surface, prolong graft survival, and may allow better outcomes when combined with subsequent PK. PMID- 25829824 TI - Hyperhomocysteinemia, a biochemical tool for differentiating ischemic and nonischemic central retinal vein occlusion during the early acute phase. AB - PURPOSE: The purpose of the study was to differentiate ischemic central retinal vein occlusion (CRVO) from nonischemic CRVO during the early acute phase using plasma homocysteine as a biochemical marker. METHODS: Fasting plasma homocysteine, serum vitamin B12, and folate levels were measured in 108 consecutive unilateral elderly adult (age >50 years) ischemic CRVO patients in the absence of local and systemic disease and compared with a total of 144 age and sex matched nonischemic CRVO patients and 120 age and sex matched healthy control subjects. RESULTS: Homocysteine level was significantly increased in the patients with ischemic CRVO in comparison with nonischemic CRVO patients (p = 0.009) and also in comparison with control subjects (p < 0.001). Analysis also showed that hyperhomocysteinemia was associated with increased incidence of ischemic CRVO (odds ratio, 18) than that for nonischemic CRVO (odds ratio, 4.5). Serum vitamin B12 and folate levels were significantly lower (p < 0.001) in CRVO patients compared to the control but were not significantly different between nonischemic and ischemic CRVO patients (p > 0.1). CONCLUSIONS: Hyperhomocysteinemia can be regarded as useful in differentiating nonischemic and ischemic CRVO during the early acute phase in absence of local and systemic disease in the elderly adult (age >50 years) population. PMID- 25829825 TI - Association between microperimetric parameters and optical coherent tomographic findings in various macular diseases. AB - PURPOSE: To analyze the correlation between microperimetric parameters and optical coherent tomographic findings in the eyes of patients with macular diseases. METHODS: A total of 64 eyes were included in this retrospective cross sectional study. Differences in the macular integrity index and microperimetric parameters were analyzed according to types of outer retinal band defects. Correlations between average threshold values and retinal thickness in the corresponding areas were analyzed. Finally, microperimetric parameters were compared between inner and outer retinal lesions. RESULTS: Measures of best corrected visual acuity, macular integrity index, and average threshold values were significantly worse in eyes with defects in the ellipsoid portion of the photoreceptor inner segment (ISe), the cone outer segment tip (COST), and the external limiting membrane (ELM) than in eyes without ISe, COST, and ELM defects. Also, visual functionality is more significantly impacted by ELM defects than by other hyper-reflective band defects. There was a significant negative correlation between retinal thickness and the average threshold of the corresponding area in the Early Treatment Diabetic Retinopathy Study grid. Microperimetric parameters in the eyes of patients with inner retinal lesions were better than in the eyes of patients with outer retinal lesions. CONCLUSIONS: The macular integrity index may be a useful factor for reflecting the functional aspects of macular diseases. Specifically, ELM, ISe, and COST defects are significantly associated with poor retinal sensitivity and macular integrity index values that suggest abnormalities. Among eyes with these particular defects, the visual functionality of patients is most sensitively impacted by ELM defects. This finding suggests that microperimetric parameters are sensitive and useful for evaluating functional abnormalities in the eyes of patients with macular disease, particularly in patients with outer retinal pathology. PMID- 25829826 TI - Comparison of risk factors for initial central scotoma versus initial peripheral scotoma in normal-tension glaucoma. AB - PURPOSE: To investigate the risk factors for initial central scotoma (ICS) compared with initial peripheral scotoma (IPS) in normal-tension glaucoma (NTG). METHODS: Fifty-six NTG patients (56 eyes) with an ICS and 103 NTG patients (103 eyes) with an IPS were included. Retrospectively, the differences were assessed between the two groups for baseline characteristics, ocular factors, systemic factors, and lifestyle factors. Also, the mean deviation of visual field was compared between the two groups. RESULTS: Patients from both ICS and IPS groups were of similar age, gender, family history of glaucoma, and follow-up periods. Frequency of disc hemorrhage was significantly higher among patients with ICS than in patients with IPS. Moreover, systemic risk factors such as hypotension, migraine, Raynaud's phenomenon, and snoring were more prevalent in the ICS group than in the IPS group. There were no statistical differences in lifestyle risk factors such as smoking or body mass index. Pattern standard deviation was significantly greater in the ICS group than in the IPS group, but the mean deviation was similar between the two groups. CONCLUSIONS: NTG Patients with ICS and IPS have different profiles of risk factors and clinical characteristics. This suggests that the pattern of initial visual field loss may be useful to identify patients at higher risk of central field loss. PMID- 25829827 TI - Surgical results of trabeculectomy and Ahmed valve implantation following a previous failed trabeculectomy in primary congenital glaucoma patients. AB - PURPOSE: To compare the surgical results of trabeculectomy and Ahmed glaucoma valve implantation after a previous failed trabeculectomy. METHODS: A retrospective comparative case series review was performed on 31 eye surgeries in 20 patients with primary congenital glaucoma who underwent trabeculectomy or Ahmed glaucoma valve implantation after a previous failed trabeculectomy with mitomycin C. RESULTS: The preoperative mean intraocular pressure was 25.5 mmHg in the trabeculectomy group and 26.9 mmHg in the Ahmed glaucoma valve implantation group (p = 0.73). The 48-month postoperative mean intraocular pressure was 19.6 mmHg in the trabeculectomy group and 20.2 mmHg in the Ahmed glaucoma valve implantation group (p = 0.95). The 12-month trabeculectomy success rate was 69%, compared with 64% for Ahmed glaucoma valve implantation, and the 48-month success rates were 42% and 36% for trabeculectomy and valve implantation, respectively. The success rates following the entire follow-up period were not significantly different between the two groups (p > 0.05 by log rank test). Postoperative complications occurred in 25% of the trabeculectomy-operated eyes and 9% of the Ahmed-implanted eyes (p = 0.38). CONCLUSIONS: There was no significant difference in surgical outcome between the trabeculectomy and Ahmed glaucoma valve implantation groups, neither of which had favorable results. However, the trabeculectomy group demonstrated a higher prevalence of adverse complications such as post-operative endophthalmitis. PMID- 25829828 TI - Clinical outcomes of individualized botulinum neurotoxin type A injection techniques in patients with essential blepharospasm. AB - PURPOSE: To assess the clinical outcomes following botulinum neurotoxin type A (BoNT-A) treatment with an individualized injection technique based on the types of spasms and to compare the results of the individualized injection technique with those of the conventional injection technique in the same patients. METHODS: From November 2011 to July 2013, 77 BoNT-A injections were performed in 38 patients. Eighteen patients were treated with conventional BoNT-A injections before 2011, and 20 patients were referred to our hospital for unsatisfactory results after a conventional injection technique. We classified the patients by spasm-dominant sites: the lateral orbital area, representing the orbital orbicularis-dominant group (ODG); the glabella, representing the corrugator dominant group (CDG); and the ptosis, representing the palpebral part of the orbicularis-dominant group (PDG). We increased the injection dose into the spasm dominant sites of the blepharospasm groups. We assessed subjective symptom scores (functional disability score, FDS) after treatment. RESULTS: This study included 38 patients (26 women, 12 men; mean age, 60.6 +/- 10.9 years). There were 21 patients in the ODG, 10 patients in the CDG, and 7 patients in the PDG. Mean ages were 59.7 +/- 12.6, 59.8 +/- 8.5, and 66.8 +/- 9.0 years, and mean BoNT-A injection dose was 38.8 +/- 11.2, 38.8 +/- 11.2, and 38.8 +/- 10.8 U in each group, respectively (p = 0.44, 0.82 Kruskal-Wallis test). Mean FDS after injection was 1.7 +/- 0.7 in the ODG, 1.4 +/- 0.8 in the CDG, and 1.2 +/- 0.3 in the PDG. There were significant differences in reading and job scale among the three groups. In a comparison between the conventional and individualized injection techniques, there was a significant improvement in mean FDS and in the reading scale in the PDG with the individualized injection technique. The success rate was 92.1% in the conventional injection group and 94.1% in the individualized injection group. CONCLUSIONS: The individualized injection technique of BoNT-A according to the spasm-dominant site is an effective and safe treatment method for essential blepharospasm patients. PMID- 25829829 TI - Functional magnetic resonance imaging findings in Meares-Irlen syndrome: a pilot sudy. AB - PURPOSE: To investigate patterns of functional magnetic resonance imaging (fMRI) activation during sentence reading before and after wearing color-tinted lenses. METHODS: A total of 15 Meares-Irlen syndrome patients with a mean age of 23.4 years (range, 13 to 42 years) with no history of neurological or psychiatric disorders were scanned using a 3T MR scanner (Siemens, Tim-Trio, Germany). Each patient underwent two sessions of fMRI imaging (before and after MISViS color tinted lens application). The fMRI paradigm included a block design of 20 seconds of rest (cross), 20 seconds of activation (sentence reading), and ten blocks (a total of 200 echo-planar image volumes) repeated for each session. Data preprocessing and analyses were performed using the SPM8 software package. RESULTS: The reading speed of patients improved more than 20% while wearing the selected lenses. When compared to the before-lens session, the after-lens session identified significant regions of activation in the left middle and superior temporal gyri (paired t-test; maximal z score, 5.38; Montreal Neurological Institute coordinate, -60 / -39 / 0; threshold at p < 0.05; corrected for multiple comparisons using family-wise error). No region of activation at the same threshold was found in the before-lens session as compared to the after-lens session. CONCLUSIONS: In the current study, we confirmed activation in the left middle and superior temporal gyri during sentence reading after wearing color tinted lenses. These results could explain the effectiveness of color-tinted lenses in patients with Meares-Irlen syndrome. PMID- 25829830 TI - Normative data of videonystagmography in young healthy adults under 40 years old. AB - PURPOSE: The purpose of this study was to establish a set of normative data values for saccade movements using videonystagmography and to evaluate the effects of manual correction on this data. METHODS: We examined 25 healthy subjects (9 men and 16 women). All tests were carried out by one well-instructed physician. Errors such as the wrong detection of the inflection point, missing movement, and prediction occurred during some tests. Thus, the same physician manually corrected the data by deleting error data from row results. RESULTS: We established a set of normative data for horizontal saccade movements (amplitude size 15 and 30 degrees) for mean peak velocity, latency, and accuracy. Manual correction only impacted latency and accuracy at 30 degrees horizontal, which is likely related to possible errors during the test. CONCLUSIONS: The present study provides clinically useful videonystagmography-based normative data for clinicians regarding saccade movements in Korean individuals. PMID- 25829831 TI - Efficacy of the mineral oil and hyaluronic acid mixture eye drops in murine dry eye. AB - PURPOSE: To investigate the therapeutic effects of mineral oil (MO) and hyaluronic acid (HA) mixture eye drops on the tear film and ocular surface in a mouse model of experimental dry eye (EDE). METHODS: Eye drops consisting of 0.1% HA alone or mixed with 0.1%, 0.5%, or 5.0% MO were applied to desiccating stress induced murine dry eyes. Tear volume, corneal irregularity score, tear film break up time (TBUT), and corneal fluorescein staining scores were measured at 5 and 10 days after treatment. Ten days after treatment, goblet cells in the conjunctiva were counted after Periodic acid-Schiff staining. RESULTS: There was no significant difference in the tear volume between desiccating stress-induced groups. The corneal irregularity score was lower in the 0.5% MO group compared with the EDE and HA groups. The 0.5% and 5.0% MO groups showed a significant improvement in TBUT compared with the EDE group. Mice treated with 0.1% and 0.5% MO mixture eye drops showed a significant improvement in fluorescein staining scores compared with the EDE group and the HA group. The conjunctival goblet cell count was higher in the 0.5% MO group compared with the EDE group and HA group. CONCLUSIONS: The MO and HA mixture eye drops had a beneficial effect on the tear films and ocular surface of murine dry eye. The application of 0.5% MO and 0.1% HA mixture eye drops could improve corneal irregularity, the corneal fluorescein staining score, and conjunctival goblet cell count compared with 0.1% HA eye drops in the treatment of EDE. PMID- 25829832 TI - Bilateral macula-involving metastatic infection resulting from septic embolization. PMID- 25829833 TI - Bilateral sequential optic neuritis in Behcet's syndrome. PMID- 25829834 TI - Inferior rectus muscle restriction after sub-Tenon's anesthesia. PMID- 25829835 TI - Massive exudative retinal detachment following photodynamic therapy and intravitreal bevacizumab injection in retinal capillary hemangioma. PMID- 25829836 TI - Fast Implementation for Normal Mixed Effects Models With Censored Response. AB - We propose an EM algorithm for computing the maximum likelihood and restricted maximum likelihood for linear and nonlinear mixed effects models with censored response. In contrast with previous developments, this algorithm uses closed-form expressions at the E-step, as opposed to Monte Carlo simulation. These expressions rely on formulas for the mean and variance of a truncated multinormal distribution, and can be computed using available software. This leads to an improvement in the speed of computation of up to an order of magnitude. A wide class of mixed effects models is considered, including the Laird-Ware model, and extensions to different structures for the variance components, heteroscedastic and autocorrelated errors, and multilevel models. We apply the methodology to two case studies from our own biostatistical practice, involving the analysis of longitudinal HIV viral load in two recent AIDS studies. The proposed algorithm is implemented in the R package lmec. An appendix which includes further mathematical details, the R code, and datasets for examples and simulations are available as the online supplements. PMID- 25829837 TI - The effect of in-plane arterial curvature on blood flow and oxygen transport in arterio-venous fistulae. AB - Arterio-Venous Fistulae (AVF) are the preferred method of vascular access for patients with end stage renal disease who need hemodialysis. In this study, simulations of blood flow and oxygen transport were undertaken in various idealized AVF configurations. The objective of the study was to understand how arterial curvature affects blood flow and oxygen transport patterns within AVF, with a focus on how curvature alters metrics known to correlate with vascular pathology such as Intimal Hyperplasia (IH). If one subscribes to the hypothesis that unsteady flow causes IH within AVF, then the results suggest that in order to avoid IH, AVF should be formed via a vein graft onto the outer-curvature of a curved artery. However, if one subscribes to the hypothesis that low wall shear stress and/or low lumen-to-wall oxygen flux (leading to wall hypoxia) cause IH within AVF, then the results suggest that in order to avoid IH, AVF should be formed via a vein graft onto a straight artery, or the inner-curvature of a curved artery. We note that the recommendations are incompatible-highlighting the importance of ascertaining the exact mechanisms underlying development of IH in AVF. Nonetheless, the results clearly illustrate the important role played by arterial curvature in determining AVF hemodynamics, which to our knowledge has been overlooked in all previous studies. PMID- 25829838 TI - Sumatrellachelonica gen. n., sp. n., a new remarkable genus and species from Indonesia, Sumatra (Acari, Uropodina, Oplitidae). AB - A new genus Sumatrella gen. n. is described and illustrated based on the new species Sumatrellachelonica sp. n. collected in Sumatra, Indonesia. The new genus belongs to the family Oplitidae based on its hypertrichous internal malae and the absence of strongly sclerotized structures on the dorsal shield. The new genus is closely related to the genus Chelonuropoda Sellnick, 1954 but the transverse furrow on ventral idiosoma close to coxae IV and the strongly sclerotized C shaped dorsal line are missing in the new genus. These characters can be found in species of Chelonuropoda. PMID- 25829839 TI - The distribution and taxonomy of Lissotriton newts in Turkey (Amphibia, Salamandridae). AB - Two and perhaps three taxa of Lissotriton newt occur in Turkey. Their species status is controversial. The distribution of these taxa and the taxonomic status of each are reviewed and discussed. A database of 128 Turkish Lissotriton localities was compiled and species distribution models were constructed. We reiterate that the presence of Lissotriton (vulgaris) lantzi in Turkey is disputed and needs confirmation. The range of Lissotriton (vulgaris) kosswigi is restricted to north-western Anatolia - given the small global range of this Turkey endemic, a closer look at its conservation status is warranted. The distribution of Lissotritonvulgarisschmidtleri covers western Asiatic and European Turkey. The findings support an allopatric distribution of the Turkish Lissotriton species. We reflect on the biological significance of previously reported morphological intermediates between Lissotriton (vulgaris) kosswigi and Lissotritonvulgarisschmidtleri in the light of the recent proposal to recognize kosswigi at the species level. The available data are in line with species status for Lissotriton (vulgaris) lantzi and Lissotriton (vulgaris) kosswigi. Although Lissotritonvulgarisschmidtleri is a genetically diverged taxon as well, the extent of gene flow with parapatric European Lissotriton taxa is as yet unknown. PMID- 25829841 TI - Phylogenetic analysis of the sharpshooter genus Subrasaca Young, 1977 (Hemiptera, Cicadellidae, Cicadellini). AB - The South American sharpshooter genus Subrasaca comprises 14 species. Some species of this genus are quite common in the Brazilian Atlantic Rainforest. In this paper, a phylogenetic analysis of Subrasaca, based on a matrix of 20 terminal taxa and 72 morphological characters of the head, thorax, and male and female genitalia, is presented. The analysis yielded six equally most parsimonious trees (197 steps, CI = 0.6091, RI = 0.5722, and RC = 0.3486). The results suggest that Subrasaca is a monophyletic taxon, although the genus branch is not robust. The clade showing the highest bootstrap and Bremer scores is formed by species with longitudinal dark brown to black stripes on the forewings (Subrasacabimaculata, Subrasacaconstricta, Subrasacacurvovittata, and Subrasacaflavolineata), followed by Subrasacaatronasa + Subrasacaaustera. PMID- 25829840 TI - The systematics of Echinorhynchus Zoega in Muller, 1776 (Acanthocephala, Echinorhynchidae) elucidated by nuclear and mitochondrial sequence data from eight European taxa. AB - The acanthocephalan genus Echinorhynchus Zoega in Muller, 1776 (sensuYamaguti 1963) is a large and widespread group of parasites of teleost fish and malacostracan crustaceans, distributed from the Arctic to the Antarctic in habitats ranging from freshwaters to the deep-sea. A total of 52 species are currently recognised based on the conventional morphological species concept; however, the true diversity in the genus is masked by cryptic speciation. The considerable diversity within Echinorhynchus is an argument for subdividing the genus if monophyletic groups with supporting morphological characters can be identified. With this objective in mind, partial sequences of two genes with different rates of evolution and patterns of inheritance (nuclear 28S rRNA and mitochondrial cytochrome c oxidase subunit I) were used to infer the phylogenetic relationships among eight taxa of Echinorhynchus. These included representatives of each of three genus group taxa proposed in a controversial revision of the genus based on cement gland pattern, namely Echinorhynchus (sensu stricto), Metechinorhynchus Petrochenko, 1956 and Pseudoechinorhynchus Petrochenko, 1956. These groupings have previously been rejected by some authorities, because the diagnostic character is poorly defined; this study shows that Echinorhynchus (sensu stricto) and Metechinorhynchus are not natural, monophyletic groups. A revision of Echinorhynchus will require tandem molecular phylogenetic and morphological analyses of a larger sample of taxa, but this study has identified two morhological characters that might potentially be used to define new genera. The estimated phylogeny also provides insight into the zoogeographical history of Echinorhynchus spp. We postulate that the ancestral Echinorhynchus had a freshwater origin and the genus subsequently invaded the sea, probably several times. The freshwater taxa of the Echinorhynchusbothniensis Zdzitowiecki & Valtonen, 1987 clade may represent a reinvasion of freshwater by one or more ancestral marine species. PMID- 25829842 TI - Three new species of Epicephala Meyrick (Lepidoptera, Gracillariidae) associated with Phyllanthusmicrocarpus (Benth.) (Phyllanthaceae). AB - Three new species of Epicephala Meyrick, 1880 are described based on specimens reared from fruits of Phyllanthusmicrocarpus (Benth.): Epicephalamicrocarpa sp. n. and Epicephalalaeviclada sp. n. from Guangxi and Hainan, and Epicephalatertiaria sp. n. from Guangdong and Guangxi. Photographs of adults and illustrations of genital structures are provided. PMID- 25829843 TI - A new genus and species of tettigarctid cicada from the early Miocene of New Zealand: Paratettigarctazealandica (Hemiptera, Auchenorrhyncha, Tettigarctidae). AB - A new genus and species of primitive cicada (Hemiptera: Tettigarctidae) is described from the early Miocene of southern New Zealand. Paratettigarctazealandica gen. et sp. n. is the first cicada (Cicadoidea) fossil from New Zealand and exhibits wing venation patterns typical for the subfamily Tettigarctinae. It differs from other fossil taxa and the extant genus Tettigarcta in the early divergence of CuA2 from the nodal line in the forewing, its parallel-sided subcostal cell, the early bifurcation of vein M and long apical cells of the hindwing, and in wing pigmentation patterns. PMID- 25829844 TI - On the desmitracheate "micronetine" genus Nippononeta Eskov, 1992 (Araneae, Linyphiidae). AB - The desmitracheate system in a "micronetine" genus Nippononeta Eskov, 1992 is recognized for the first time in the present study. This makes the subfamilial placement of this genus problematic. A morphological study was conducted for Nippononetakurilensis Eskov, 1992 (the type species of Nippononeta) and Nippononetacoreana (Paik, 1991). Characters of genitalia and tracheal system, as well as some somatic characters were studied in detail by using scanning electronic microscopy (SEM), and compared with those of Agyneta. Updated descriptions of the genus Nippononeta and its two species are presented. Putative synapomorphies for Nippononeta and Agyneta are provided, as well as some putative synapomorphies shared by the two genera. The results imply that both scaped epigynum and desmitracheate tracheal system are probably homoplastic. The placement of Nippononeta and Agyneta within Linyphiidae need to be resolved in future studies. PMID- 25829845 TI - Description of a new soft scale insect of the genus Pulvinaria Targioni Tozzetti (Hemiptera, Coccoidea, Coccidae) from Bogota, Colombia. AB - A new soft scale (Hemiptera: Coccoidea: Coccidae) species, Pulvinariacaballeroramosae Tanaka & Kondo, sp. n., is described from specimens collected on twigs of Ficussoatensis Dugand (Moraceae) in Bogota, Colombia. The new species resembles Pulvinariadrymiswinteri Kondo & Gullan, described from Chile on Drimyswinteri J.R. Forst. & G. Forst. (Winteraceae), but differs in the distribution of preopercular pores on the dorsum, the presence of dorsal tubular ducts, dorsal microducts, and reticulation on the anal plates; and in its feeding habits, i.e., Pulvinariacaballeroramosae feeds on the twigs whereas Pulvinariadrymiswinteri feeds on the leaves of its host. A key to the Colombian species of Pulvinaria Targioni Tozzetti is provided. PMID- 25829846 TI - Morphological and molecular study of Symphyla from Colombia. AB - The symphylans are a poorly studied group. In Colombia the number of symphylan species is unknown with only Scutigerellaimmaculata (Symphyla: Scutigerellidae) being reported previously. The aim of this research was to collect and identify the symphylan pests of flower crops in Colombia. Morphological descriptions showed that our specimens shared more than one of the characters that define different genera within Scutigerellidae. The COI barcode haplotype showed interspecific level genetic divergence with Scutigerellacauseyae (at least 23%) and Hanseniella sp. (22%). Furthermore, our Colombian symphylans shared the same COI haplotype as some Symphyla found in Cameroon indicating a wide geographical distribution of this taxon. Our results suggest the presence of a new genus or subgenus in the class Symphyla. PMID- 25829847 TI - Integrative taxonomy of New World Euplectrus Westwood (Hymenoptera, Eulophidae), with focus on 55 new species from Area de Conservacion Guanacaste, northwestern Costa Rica. AB - 90 species of Euplectrus are treated: 55 newly described, all from Area de Conservacion Guanacaste (ACG), and 35 previously described species, of which 20 occur in ACG. Three of the previously described species (Euplectrusbrasiliensis Ashmead, Euplectrushircinus (Say), Euplectrusronnai (Brethes)) have unknown status, owing to missing or severely damaged type material. The new species, all authored by C. Hansson, are: Euplectrusalejandrovalerioi, Euplectrusalexsmithi, Euplectrusalvarowillei, Euplectrusandybennetti, Euplectrusandydeansi, Euplectrusannettewalkerae, Euplectrusbillbrowni, Euplectrusbobwhartoni, Euplectruscarlosarmientoi, Euplectruscarlrettenmeyeri, Euplectruscharlesmicheneri, Euplectruscharlesporteri, Euplectruschrisdarlingi, Euplectruschrisgrinteri, Euplectruscorriemoreauae, Euplectrusdaveroubiki, Euplectrusdavesmithi, Euplectrusdavidwahli, Euplectrusdianariasae, Euplectrusdonquickei, Euplectruseowilsoni, Euplectrusgarygibsoni, Euplectrusgavinbroadi, Euplectrusgerarddelvarei, Euplectrushenrytownesi, Euplectrushowelldalyi, Euplectrushugokonsi, Euplectrusiangauldi, Euplectrusjacklonginoi, Euplectrusjesusugaldei, Euplectrusjimwhitfieldi, Euplectrusjjrodriguezae, Euplectrusjohnheratyi, Euplectrusjohnlasallei, Euplectrusjohnnoyesi, Euplectrusjosefernandezi, Euplectruslubomirmasneri, Euplectrusmarkshawi, Euplectrusmikegatesi, Euplectrusmikeschauffi, Euplectrusmikesharkeyi, Euplectrusninazitaniae, Euplectruspammitchellae, Euplectruspaulhansoni, Euplectruspaulheberti, Euplectruspaulhurdi, Euplectrusphilwardi, Euplectrusrobbinthorpi, Euplectrusronaldzunigai, Euplectrusroysnellingi, Euplectrusscottshawi, Euplectrussondrawardae, Euplectrussydneycameronae, Euplectrusvictoriapookae, Euplectruswonyoungchoi. The species are described or redescribed, and thoroughly and uniformly illustrated, and included in two identification keys, one for females and one for males. Lectotypes are designated for eight species: Euplectruscatocalae Howard (?), Euplectrusjunctus Gahan (?), Euplectrusleucotrophis Howard (?), Euplectrusmarginatus Ashmead (?), Euplectruspachyscaphus Girault (?), Euplectrusplatyhypenae Howard (?), Euplectrussemimarginatus Girault (?), Heteroscapusronnai Brethes (?). One synonym is established: Euplectruswalteri Schauff is a junior synonym of Euplectrustestaceipes (Cameron). Brief image notes and host records are provided on the natural history of the wasps as well as the details of their morphology. Hosts are known for 74 Euplectrus species. PMID- 25829848 TI - Annotated type catalogue of the Chrysididae (Insecta, Hymenoptera) deposited in the collection of Radoszkowski in the Polish Academy of Sciences, Krakow. AB - A critical and annotated catalogue of 183 types of HymenopteraChrysididae belonging to 124 taxa housed in the Radoszkowski collection is given. Radoszkowski type material from other institutes has also been checked. Six lectotypes are designated in Krakow (ISEA-PAN): Chrysisacceptabilis Radoszkowski, 1891; Chrysispersica Radoczkowsky, 1881; Chrysisdaphnis Mocsary, 1889; Chrysislagodechii Radoszkowski, 1889; Chrysisremota Mocsary, 1889 and Chrysisvagans Radoszkowski, 1877. The lectotype of Brugmoiapellucida Radoszkowski, 1877 is designated in Moscow (MMU). Four new combinations are proposed: Philoctetesararaticus (Radoszkowski, 1890), comb. n.; Pseudomalushypocrita (du Buysson, 1893), comb. n.; Chrysiseldari (Radoszkowski, 1893), comb. n.; and Chrysuramlokosewitzi (Radoszkowski, 1889), comb. n.. Ten new synonyms are given: Chrysisauropunctata Mocsary, 1889, syn. n. of Chrysisangolensis Radoszkovsky, 1881; Chrysischrysochlora Mocsary, 1889, syn. n. and Chrysisviridans Radoszkowski, 1891, syn. n. of Chrysiskeriensis Radoszkowski, 1887; Chrysisangustifronsvar.ignicollis Trautmann, 1926, syn. n. of Chrysiseldari (Radoszkowski, 1893); Chrysismaracandensisvar.simulatrix Radoszkowski, 1891, syn. n. of Chrysismaracandensis Radoszkowski, 1877; Chrysispulchra Radoszkovsky, 1880, syn. n. of Spinoliadallatorreana (Mocsary, 1896); Chrysisrubricollis du Buysson, 1900, syn. n. of Chrysiseldari (Radoszkowski, 1893); Chrysissubcoerulea Radoszkowski, 1891, syn. n. of Chrysischlorochrysa Mocsary, 1889; Chrysistherates Mocsary, 1889, syn. n. of Chrysisprincipalis Smith, 1874; and Notozuskomarowi Radoszkowski, 1893, syn. n. of Elampusobesus (Mocsary, 1890). One species is revaluated: Chrysischalcochrysa Mocsary, 1887. Chrysiskizilkumiana Rosa is the new name for Chrysisuljanini Radoszkowski & Mocsary, 1889 nec Radoszkowski, 1877. Pictures of seventy-seven type specimens are given. PMID- 25829849 TI - The Diplommatinidae of Fiji - a hotspot of Pacific land snail biodiversity (Caenogastropoda, Cyclophoroidea). AB - The minute (adult size 1.3-4.8 mm) land snail species of the family Diplommatinidae in the Fiji archipelago are revised based on historical material and modern (1998-99) collections targeting limestone outcrops on the largest island, Viti Levu, and several smaller islands in the Lau group. The forty-two species (including 30 new species) belong to the genera Moussonia Semper, 1865, Palaina Semper, 1865 and Diancta Martens, 1867, which are briefly characterized and keyed. The diagnostic structure of the inner lamellar system of each species is illustrated. All species except one are endemic to Fiji. In Viti Levu, the 12 localities surveyed each had 1-13 (average 5) species of Diplommatinidae; ten species were each found at a single site only. In the Lau islands, five islands were visited, with 1-4 species per island; four species are known from single islands. The number of historically known species not recollected in 1998-99 (7 species), the number of single-site occurrences (14 species), and the numerous islands - including limestone islands - that have not been surveyed at all, indicate that the 42 species of Diplommatinidae currently known from Fiji represent perhaps only half of the Fiji diplommatinid fauna. Such numbers approach the diplommatinid diversity of Palau (39 described and more than 60 undescribed species), and surpasses by far the diversity of other South Pacific archipelagos of comparable land area (New Caledonia, Vanuatu, Samoa). Nomenclatural acts: Lectotypes designated: Diplommatinafuscula, Diplommatinafusculavar.vitiana, Diplommatinagodeffroyana, Diplommatinagodeffroyanavar.latecostata, Diplommatinatuberosa, Diplommatinamartensivar.macrostoma, all Mousson, 1870. Neotypes designated: Diplommatinasubregularis, Diplommatinaascendens, Diplommatinaquadrata, all Mousson, 1870. New species: Dianctaaurea sp. n., Dianctaaurita sp. n., Dianctabasiplana sp. n., Dianctacontroversa sp. n., Dianctadensecostulata sp. n., Dianctadextra sp. n., Dianctadilatata sp. n., Dianctadistorta sp. n., Dianctapulchella sp. n., Dianctarotunda sp. n., Dianctasubquadrata sp. n., Dianctatrilamellata sp. n., Moussoniaacuta sp. n., Moussoniabarkeri sp. n., Moussoniabrodieae sp. n., Moussonialongipalatalis sp. n., Moussoniaminutissima sp. n., Moussoniaobesa sp. n., Moussoniapolita sp. n., Moussoniauncinata sp. n., Moussoniavitianoides sp. n., Palainaalberti sp. n., Palainaflammulata sp. n., Palainaglabella sp. n., Palainakitteli sp. n., Palainalabeosa sp. n., Palainaparietalis sp. n., Palainasulcata sp. n., Palainatruncata sp. n., Palainatuberosissima sp. n. PMID- 25829850 TI - Peruvian oribatid mites (Acari, Oribatida) from the German Biological Expedition, with description of a new species of the genus Pergalumna. AB - The present study is based on oribatid mite material (Acari, Oribatida) collected during the German Expedition in 2011 in Peru. An annotated checklist of identified oribatid mites, including 16 species from 14 genera and 8 families, is provided. Thirteen species and two genera (Notohermannia, Zetomimus) are recorded for the first time in Peru; the genus Notohermannia and species Notohermanniaobtusa are recorded for the first time in the Neotropical region. A new species of the genus Pergalumna (Galumnidae), Pergalumnaparaboliviana sp. n., is described. The new species is most similar to Pergalumnaboliviana Ermilov, 2013 from Bolivia, however, it differs from the latter by the body size, morphology of porose areas A1 and the presence of interlamellar setae. PMID- 25829851 TI - A new species of Scolopocryptops Newport: a troglobitic scolopocryptopine centipede from a remarkable siliciclastic area of eastern Brazil (Scolopendromorpha, Scolopocryptopidae, Scolopocryptopinae). AB - We describe Scolopocryptopstroglocaudatus sp. n., a new troglobitic scolopocryptopine centipede species. The species was found in a remarkable siliciclastic karst area of Eastern Brazil, in three caves of the Chapada da Diamantina, in the state of Bahia. Scolopocryptopstroglocaudatus sp. n. is close to Scolopocryptopsmiersii Newport, 1845 and Scolopocryptopsferrugineusmacrodon (Kraepelin, 1903) but differs from them by troglomorphic features, such as depigmentation, long appendages and a thin cuticle. This new species is the second troglobitic scolopocryptopine described and is the first discovered in Brazil. PMID- 25829852 TI - Review of Canadian species of the genus Mocyta Mulsant & Rey (Coleoptera, Staphylinidae, Aleocharinae), with the description of a new species and a new synonymy. AB - Six species of the genus Mocyta Mulsant & Rey are reported from Canada: Mocytaamblystegii (Brundin), Mocytabreviuscula (Maklin), Mocytadiscreta (Casey), Mocytafungi (Gravenhorst), Mocytaluteola (Erichson), and Mocytasphagnorum Klimaszewski & Webster, sp. n. New provincial and state records include: Mocytabreviuscula - Saskatchewan and Oregon; Mocytadiscreta - Quebec, Ontario and Saskatchewan; Mocytaluteola - New Brunswick, Quebec, Ontario, Massachusetts and Minnesota; and Mocytafungi - Saskatchewan. Mocytasphagnorum is described from eastern Canada from specimens captured in Newfoundland, New Brunswick, Quebec and Ontario. Mocytanegligens Mulsant and Rey, a native European species suspected of occurring in Canada, is excluded from the Nearctic fauna based on comparison of European types with similarly coloured Canadian specimens, which are now identified as Mocytaluteola. The European species, Mocytagilvicollis (Scheerpeltz), is synonymized with another European nominal species, Mocytanegligens, based on examination of type material of the two species. Lectotypes are designated for Eurypronotadiscreta Casey, Athetagilvicollis Scheerpeltz, Homalotaluteola Erichson, Colpodotanegligens Mulsant and Rey, Acrotonaprudens Casey and Dolosotaredundans Casey. The latter species is here synonymized with Mocytaluteola. A review of the six Nearctic species is provided, including keys to species and closely related genera, colour habitus images, images of genitalia, biological information and maps of their distributions in Canada. PMID- 25829853 TI - No need to replace an "anomalous" primate (Primates) with an "anomalous" bear (Carnivora, Ursidae). AB - By means of mitochondrial 12S rRNA sequencing of putative "yeti", "bigfoot", and other "anomalous primate" hair samples, a recent study concluded that two samples, presented as from the Himalayas, do not belong to an "anomalous primate", but to an unknown, anomalous type of ursid. That is, that they match 12S rRNA sequences of a fossil Polar Bear (Ursusmaritimus), but neither of modern Polar Bears, nor of Brown Bears (Ursusarctos), the closest relative of Polar Bears, and one that occurs today in the Himalayas. We have undertaken direct comparison of sequences; replication of the original comparative study; inference of phylogenetic relationships of the two samples with respect to those from all extant species of Ursidae (except for the Giant Panda, Ailuropodamelanoleuca) and two extinct Pleistocene species; and application of a non-tree-based population aggregation approach for species diagnosis and identification. Our results demonstrate that the very short fragment of the 12S rRNA gene sequenced by Sykes et al. is not sufficiently informative to support the hypotheses provided by these authors with respect to the taxonomic identity of the individuals from which these sequences were obtained. We have concluded that there is no reason to believe that the two samples came from anything other than Brown Bears. These analyses afforded an opportunity to test the monophyly of morphologically defined species and to comment on both their phylogenetic relationships and future efforts necessary to advance our understanding of ursid systematics. PMID- 25829854 TI - A new species of Cyanea (Campanulaceae, Lobelioideae), from the Ko'olau Mountains of O'ahu, Hawaiian Islands. AB - Cyaneakonahuanuiensis Sporck-Koehler, M. Waite, A.M. Williams, sp. nov., a recently documented, narrowly endemic species from the Hawaiian Island of O'ahu, is described and illustrated with photographs from the field. The closest likely relatives to the species, current conservation needs, and management future are discussed. It is currently known from 20 mature plants from two subpopulations and is restricted to a drainage below the Konahua-nui summit (K1), the highest summit of the Ko'olau Mountains, located on Windward O'ahu. It differs from all other Cyanea species by its combination of densely pubescent leaves, petioles, and flowers; sparsely pubescent to glabrous stems, long calyx lobes, and staminal column being adnate to the corolla. PMID- 25829856 TI - Species richness and macronutrient content of wawo worms (Polychaeta, Annelida) from Ambonese waters, Maluku, Indonesia. AB - The aims of this research were to: (1) investigate the species richness of wawo worms, and to (2) analyze macronutrient content of the worms. Wawo worms were sampled using a fishing net on March 18(th)-19(th), 2014, from Ambonese waters, Maluku. As many as 26 wawo species belonging to 5 families were identified. Palola sp. was identified as the most abundant species of wawo, followed by Lysidiceoele, Horst 1905, Eunice spp. and nereidids. Results of the proximate analysis reveal that female epitokes of Palola sp. contain 10.78 % ash, 10.71 % moisture, 11.67 % crude fat, 54.72 % crude protein and 12.12 % carbohydrate. PMID- 25829855 TI - PASSIFOR: A reference library of DNA barcodes for French saproxylic beetles (Insecta, Coleoptera). AB - Saproxylic beetles - associated with dead wood or with other insects, fungi and microorganisms that decompose it - play a major role in forest nutrient cycling. They are important ecosystem service providers and are used as key bio-indicators of old-growth forests. In France alone, where the present study took place, there are about 2500 species distributed within 71 families. This high diversity represents a major challenge for specimen sorting and identification. The PASSIFOR project aims at developing a DNA metabarcoding approach to facilitate and enhance the monitoring of saproxylic beetles as indicators in ecological studies. As a first step toward that goal we assembled a library of DNA barcodes using the standard genetic marker for animals, i.e. a portion of the COI mitochondrial gene. In the present contribution, we release a library including 656 records representing 410 species in 40 different families. Species were identified by expert taxonomists, and each record is linked to a voucher specimen to enable future morphological examination. We also highlight and briefly discuss cases of low interspecific divergences, as well as cases of high intraspecific divergences that might represent cases of overlooked or cryptic diversity. PMID- 25829857 TI - Thirteen new records of ferns from Brazil. AB - Thirteen fern species are reported for the first time for Brazil. Among the new records, eight are from Acre state (Cyatheasubincisa, Cyclodiumtrianae, Elaphoglossumstenophyllum, Hypoderrisbrauniana, Pleopeltisstolzei, Thelypterisarcana, Thelypteriscomosa, Thelypterisvaldepilosa), two are from Para state (Polypodiumflagellare, Tectariaheracleifolia), one from Minas Gerais state (Alsophilasalvinii), one from Ceara state (Campyloneurumcostatum) and one from Bahia state (Thelypterisrolandii). Part of the species shows a disjunct occurrence or illustrates floristic relations between Brazilian and Andean Mountains or Central American Mountains. PMID- 25829858 TI - Vascular plant community composition from the campos rupestres of the Itacolomi State Park, Brazil. AB - Camposrupestres are rare and endangered ecosystems that accommodate a species rich flora with a high degree of endemism. Here, we make available a dataset from phytosociological surveys carried out in the Itacolomi State Park, Minas Gerais, southeastern Brazil. All species in a total of 30 plots of 10 x 10 m from two study sites were sampled. Their cardinality, a combination of cover and abundance, was estimated. Altogether, we registered occurrences from 161 different taxa from 114 genera and 47 families. The families with the most species were Poaceae and Asteraceae, followed by Cyperaceae. Abiotic descriptions, including soil properties such as type, acidity, nutrient or aluminum availability, cation exchange capacity, and saturation of bases, as well as the percentage of rocky outcrops and the mean inclination for each plot, are given. This dataset provides unique insights into the campo rupestre vegetation, its specific environment and the distribution of its diversity. PMID- 25829859 TI - Checklist of fabaceae lindley in balaghat ranges of maharashtra, India. AB - The present paper provides an enumeration of leguminous taxa of Balaghat Ranges of Maharashtra along with their habits, phenological deta and voucher specimen numbers. During the present work, a total of 123 species, 4 subspecies and 17 varieties of Fabaceae have been recorded for Balaghat Ranges of Maharashtra, of which 119 taxa are occurring in wild while 25 are under cultivation. The members of Fabaceae are dominant in herbaceous vegetation of the Balaghat Ranges. There are more species in genera like Crotalaria (23 taxa), Indigofera (16 taxa), Alysicarpus (14 taxa), Vigna (11 taxa) and Desmodium (8 taxa). Twelve taxa are endemic to India of which Indigoferadeccanensis falls into Critically Endangered IUCN Red data category. The legumes of Balaghat Ranges have many actual and potential uses such as food, fodder and sources of edible oil, natural dyes, industrial lubricants, timber and medicines. About 19 leguminous taxa are wild relatives of food and fodder crops have resistance to pests and diseases, and abiotic stresses such as drought and salinity, can be used for crop improvement. PMID- 25829860 TI - Updated list of the mosquitoes of Colombia (Diptera: Culicidae). AB - BACKGROUND: A revised list of the mosquitoes (Diptera: Culicidae) known to occur in Colombia is presented. A total of 324 species from 28 genera of Culicidae are included. The species names are organized in alphabetical order according to the current generic and subgeneric classification, along with their authorship. The list is compiled in order to support mosquito research in Colombia. NEW INFORMATION: Our systematic review and literature survey found, by 16 February 2015, 13 records of culicid species previously overlooked by mosquito catalogs for Colombia: Anophelescostai da Fonseca & da Silva Ramos, 1939, An.fluminensis Root, 1927, An.malefactor Dyar & Knab, 1907, An.shannoni Davis, 1931, An.vargasi Galbadon, Cova Garcia & Lopez, 1941, Culexmesodenticulatus Galindo & Mendez, 1961, Haemagoguscapricornii Lutz, 1904, Isostomyiaespini (Martini, 1914), Johnbelkinialeucopus (Dyar & Knab, 1906), Mansoniaindubitans Dyar & Shannon, 1925, Psorophorasaeva Dyar & Knab, 1906, Sabethesglaucodaemon (Dyar & Shannon, 1925), and Wyeomyiaintonca Dyar & Knab, 1909. Moreover, Wyeomyia (Dendromyia) luteoventralis Theobald, 1901 is recorded for Colombia for the first time. This work provides important insights into mosquito diversity in Colombia, using the current nomenclature and phylogenetic rankings. PMID- 25829861 TI - Vignapandeyana (Fabaceae), a new species from northern Western Ghats, India. AB - BACKGROUND: Vigna subg. Ceratotropis (Piper) Verdc. represents a homogenous and distinct group of species with highly specialized complex floral characters. It is most diverse in Asia. India, with 24 species, represents a secondary center of species diversity of the subgenus. NEW INFORMATION: A new species, Vignapandeyana RD Gore, SP Gaikwad & SD Randive, is described from hill slopes of the northern Western Ghats of India. It resembles Vignayadavii Gaikwad et al. and Vignadalzelliana (Kuntze) Verdc. but differs from the latter in its dimorphic shoots (some subterranean, with cleistogamous flowers) and densely hairy pods, from the former by its curved style, flattened style beak, foveolate seed coat and absence of standard protuberance and horn-like keel pocket in cleistogamous flowers. PMID- 25829862 TI - Review of Anasillomos Londt, 1983 with the description of a new species (Insecta: Diptera: Asilidae). AB - The southern African assassin-fly genus Anasillomos Londt, 1983 is reviewed. A new species, Anasillomosjuergeni sp. n., is described from the Namib desert and represents the second species in the genus. Descriptions/re-descriptions, photographs, and identification keys are provided to aid in the identification. Distribution, occurrence in biodiversity hotspots sensu Conservation International, and seasonal incidence are discussed. PMID- 25829863 TI - Additions to the myxobiota of the Aland Islands. AB - Six myxomycete species new to the Aland Islands are presented: Comatrichaelegans, Cribrariaintricata, Didymiumminus, Hemitrichiaclavata, Liceavariabilis and Trichiafavoginea. The record of Cribrariaintricata is the third in Finland. Specimens were collected in September 2014. Altogether the number of myxomycete species found from the Aland Islands is now 55. PMID- 25829864 TI - First report of Dicopuslongipes (Subba Rao) (Hymenoptera: Chalcidoidea) from India with new distribution data on some species. AB - Dicopuslongipes (Subba Rao) (Hymenoptera: Chalcidoidea: Mymaridae) is recorded from India for the first time. New additional distribution records of Mymaridae from the southern Indian states of Tamil Nadu and Kerala are documented. PMID- 25829865 TI - History of research in Japan on electrocardiography in the racehorse. AB - Since the first recording of electrocardiograms (ECGs) of a horse in Japan was carried out in 1944, studies on ECGs have been performed intensively. During the early stages of research from the 1950s to 1960s, leads to use for ECG recording were evaluated using several different approaches including unipolar leads, bipolar limb leads, and bipolar chest leads. Based on these studies, the AB lead, which is oriented along the long axis of the heart, became the standard reference method in Japan. Electrodes of the AB lead are placed on the upper 1/4th point along a straight line between the withers and the left shoulder blade (base: B), and 10 cm posterior to the left olecranon (apex: A). The incidence of equine arrhythmias among racehorses has been surveyed, and details of the electrocardiographic characteristics of several arrhythmias have been investigated. In particular, atrial fibrillation (AF) has been extensively studied, and papers have reported findings such as that paroxysmal AF occurs during racing and described electrocardiographic changes that occur at the onset of AF during exercise. Development of a radiotelemetry system for ECG recording enabled the first recording of equine ECGs during galloping in 1964, the detection of arrhythmias, and calculation of heart rate during exercise. Studies on comparative and developmental changes of ECGs have described characteristics of the equine ECGs. Future research on changes in cardiac function, including autonomic function, that occur with aging may lead to new developments in equine electrocardiography and contribute to improving the health and welfare of the horse. PMID- 25829866 TI - Anti-Mullerian hormone as an indicator of hemi-castrated unilateral cryptorchid horses. AB - Anti-Mullerian hormone (AMH), a glycoprotein secreted from the fetal testis, is responsible for regression of the Mullerian duct in the male fetus. The aim of this study was to evaluate the usefulness of serum AMH as a biomarker for diagnosis of cryptorchidism in horses. Serum AMH concentrations were measured in intact stallions, hemi-castrated unilateral cryptorchid stallions, and geldings. In addition, expression of AMH was characterized in cryptorchid testes by immunohistochemistry. Serum AMH was detected in intact stallions (n=11, 13.3 +/- 1.8 ng/ml) and in hemi-castrated cryptorchid stallions (n=8, 17.6 +/- 3.0 ng/ml), but not in geldings (n=6, all data were below the limit of detection). Immunolabeling for AMH was detected in Sertoli cells of undescended testes from cryptorchid horses as well as those of normal testes. Our findings indicate that the cryptorchid testis after hemi-castration secretes AMH and that serum AMH concentrations may be a useful biomarker for diagnosis of equine cryptorchidism. PMID- 25829867 TI - Prevalence and Antibiogram study of Rhodococcus equi in equines of Jammu and Kashmir, India. AB - The present study was conducted to determine the prevalence of Rhodococcus equi infection in equines of Jammu and Kashmir, India, and evaluate the zoonotic threat posed by this organism to equine owners and tourists. One hundred and forty-one samples (98 samples from adult animals >=5 years old and 43 samples from foals less than 6 months old) were collected in duplicate from nasopharyngeal tract of equines for isolation and direct PCR. A total of 12 isolates of R. equi were recovered, of which 9 were from foals and 3 from adult animals. Therefore, the present study recorded prevalence rates of 20.93% and 3.06% among foals and adult equines respectively. The prevalence rates were found to be 25.58% and 4.08% by 16S rRNA species-specific PCR among foals and adult animals respectively. Thus, the PCR-based assay was found to be more sensitive and helped in quick detection of R. equi than the culture based method which is time consuming and laborious. However, the culture-based method is still preferred due to some limitations of PCR. The antibiogram of the isolates revealed that erythromycin and rifampicin were the most effective antimicrobials with 100% sensitivity, followed by amoxicillin (66.67%), lincomycin (58.3%) and kanamycin (58.3%). The results also revealed that resistance was highest for penicillin G (50%), followed by kanamycin (25%) and streptomycin (25%). PMID- 25829868 TI - Development of loop-mediated isothermal amplification methods for detecting Taylorella equigenitalis and Taylorella asinigenitalis. AB - Taylorella equigenitalis is a causative bacterium of contagious equine metritis (CEM), and Taylorella asinigenitalis is species belonging to genus Taylorella. The authors developed two loop-mediated isothermal amplification (LAMP) methods, Te-LAMP and Ta-LAMP, for detecting T. equigenitalis and T. asinigenitalis, respectively. Using experimentally spiked samples, Te-LAMP was as sensitive as a published semi-nested PCR method, and Ta-LAMP was more sensitive than conventional PCR. Multiplex LAMP worked well without nonspecific reactions, and the analytical sensitivities of multiplex LAMP in the spiked samples were almost equivalent to those of Te-LAMP and Ta-LAMP. Therefore, the LAMP methods are considered useful tools to detect T. equigenitalis and/or T. asinigenitalis, and preventive measures will be rapidly implemented if the occurrence of CEM is confirmed by the LAMP methods. PMID- 25829869 TI - Functional activity of peripheral blood eosinophils in allergen-induced late phase airway inflammation in asthma patients. AB - OBJECTIVE: We aimed to investigate peripheral blood eosinophil chemotaxis, generation of spontaneous reactive oxygen species (ROS), and apoptosis in patients with allergic asthma after bronchial allergen challenge. MATERIAL AND METHODS: A total of 18 patients with allergic asthma (AA), 14 with allergic rhinitis (AR), and 10 healthy subjects (HS) underwent bronchial challenge with a specific allergen extract. Eosinophils from peripheral blood were isolated 24 h before as well as 7 and 24 h after bronchial allergen challenge. Chemotaxis, spontaneous ROS production in eosinophils, and apoptosis were analyzed by flow cytometry. Serum and induced sputum IL-5 levels were measured by ELISA; the cell count in sputum was analyzed by the May-Grunwald-Giemsa method. RESULTS: Before bronchial allergen challenge, peripheral blood eosinophil chemotaxis, spontaneous ROS production was enhanced and eosinophil apoptosis was reduced in the patients with AA as compared with AR patients and HS (P < 0.05). Meanwhile, eosinophil chemotaxis and ROS generation markedly increased in the patients with AA 7 h and 24 h after challenge compared with other groups and baseline values (P < 0.05). The percentage of apoptotic eosinophils in the patients with AA decreased at 7 h as well as 24 h after challenge when compared with other groups and the baseline values (P < 0.05). There was a significant correlation between the migrated peripheral blood eosinophil count and the sputum eosinophil count (Rs = 0.89, P < 0.0001) and the sputum IL-5 level (Rs = 0.68, P = 0.002) at 24 h after bronchial challenge only in the patients with AA. Furthermore, the percentage of peripheral blood apoptotic eosinophils significantly correlated with eosinophil count in sputum (Rs = -0.53, P = 0.02), and ROS production correlated with the serum IL-5 levels (Rs = 0.71, P = 0.01). CONCLUSION: During allergen-induced late-phase airway inflammation, peripheral blood eosinophils demonstrated further alterations of their functional activity manifested by enhanced spontaneous ROS production, increased chemotaxis, and diminished apoptosis in patients with AA. PMID- 25829870 TI - From the Editor's Desk. PMID- 25829871 TI - Letters to the editor. PMID- 25829872 TI - Bioethics in practice - a quarterly column about medical ethics: ebola and medical ethics - ethical challenges in the management of contagious infectious diseases. PMID- 25829873 TI - Clinical Images - A Quarterly Column: Rare Neonatal Look at Chiari II Thoracic Myelomeningocele. PMID- 25829874 TI - The importance of colorectal cancer screening. PMID- 25829875 TI - Long-term effects of a diabetes boot cAMP on measures of diabetic care. AB - BACKGROUND: Diabetic patients should receive self-management education to improve self-care and quality of life but are frequently unable to attend such programs because of the time commitment. We instituted an intensive 2-hour Diabetes Boot Camp to provide this education in a condensed time frame. The objective was to determine the long-term effect of the boot camp on mean hemoglobin A1c (HgA1c) levels in patients with diabetes compared to diabetic patients receiving the standard of care. METHODS: The Diabetes Boot Camp population was defined as all diabetic patients referred to the boot camp from the 10 highest utilizing physicians between August 2009 and August 2010. A control population was randomly selected from these same physicians' diabetic patients during the same period. Baseline and postintervention HgA1c measurements on the same patients in both groups were extracted from the electronic medical record. Subpopulations studied included those with HgA1c >=9% and <9% at baseline. To evaluate long-term effects, we compared HgA1c levels 3 years later (between July 1, 2012 and December 31, 2012) for all groups. RESULTS: Using comparison-over-time analysis, the overall boot camp group (n=69) showed a mean decrease in HgA1c from 8.57% (SD +/- 2.32%) to 7.76% (SD +/- 1.85%) vs an increase from 7.92% (SD +/- 1.58%) to 8.22% (SD +/- 1.82%) in the control group (n=107, P<0.001). Mean length of follow up was 3.2 (SD +/- 0.54) years. CONCLUSION: An intensive 2-hour multidisciplinary diabetes clinic was associated with significant long-term improvements in glycemic control in diabetic participants of the clinic. PMID- 25829876 TI - Robotic-assisted laparoscopic donor nephrectomy: decreasing length of stay. AB - BACKGROUND: The number of robotic operations performed with the da Vinci Surgical System has increased during the past decade. This system allows for greater maneuverability and control than hand-assisted laparoscopic procedures, resulting in less tissue manipulation and irritation. METHODS: We retrospectively analyzed the results of 100 consecutive robotic-assisted laparoscopic donor nephrectomies and compared them to our most recent 20 hand-assisted laparoscopic donor nephrectomies. RESULTS: Between May 2008 and June 2012, 120 laparoscopic donor nephrectomies were performed at Ochsner Clinic Foundation. Of those, 100 live kidney donors underwent robotic-assisted laparoscopic donor nephrectomies. Surgical time and hospital length of stay improved after the first 20 patients receiving robotic-assisted laparoscopic nephrectomies, which was considered the learning curve. Sixty percent of patients who underwent robotic-assisted laparoscopic donor nephrectomies were released on postoperative day 1 compared to 45% of patients who underwent hand-assisted laparoscopic techniques. CONCLUSION: In our experience, robotic-assisted laparoscopic donor nephrectomy resulted in decreased postoperative length of stay that decreased the global cost of the procedure and allowed our institution to admit more patients. PMID- 25829877 TI - Posttransplant nephrocalcinosis is associated with poor renal allograft function: a single-center experience. AB - BACKGROUND: Nephrocalcinosis, characterized by intratubular and/or parenchymal deposition of calcium phosphate and calcium oxalate crystals, is frequently seen in renal allograft biopsies; however, the clinical consequence of this histologic finding remains unknown. Kidney transplant recipients with good allograft function usually demonstrate improvement in biochemical parameters; however, persistent hyperparathyroidism remains prevalent in this population of patients. We identified renal allografts with nephrocalcinosis and evaluated the effects on renal allograft function and survival. METHODS: We conducted a single-center, retrospective review of kidney allograft biopsies performed at our center from December 1, 2006 to November 30, 2012. Biopsies with nephrocalcinosis as the primary diagnosis were included in the final analysis. Biochemical parameters at the time of biopsy included serum creatinine, phosphate, calcium, intact parathyroid hormone (iPTH), 25-hydroxy vitamin D, and albumin. Serum creatinine was measured at 1, 3, 6, and 12 months after nephrocalcinosis was diagnosed. The use of calcimimetics, vitamin D analogs, active vitamin D, and bisphosphonates was also reviewed. RESULTS: We identified 12 patients with nephrocalcinosis as the primary diagnosis on renal biopsy. The average age of these patients was 52.2 +/- 11.9 years, and the average time since transplantation was 2.3 +/- 2.7 years. The baseline serum creatinine was 1.37 +/- 0.4 mg/dL before the onset of acute kidney injury (AKI). Mean iPTH and 25-hydroxy vitamin D at the time of AKI were 495.66 +/- 358.9 pg/mL and 19.9 +/- 13.3 ng/mL, respectively. Renal function deteriorated in all patients, and mean serum creatinine at 12-month follow up was 2.37 +/- 1.3 mg/dL (P=0.028). One patient progressed to end-stage renal disease at the end of the study period. CONCLUSION: The histologic finding of nephrocalcinosis is associated with poor renal allograft function. Metabolic abnormalities including hyperparathyroidism persist in renal allograft recipients despite normal allograft function and may be associated with the development of nephrocalcinosis in renal transplant recipients. PMID- 25829878 TI - Addressing the process improvement science knowledge and skills of program directors and associate program directors. AB - BACKGROUND: Process improvement (PI) science is relatively new to healthcare and has only recently been introduced to medical education. Most residency faculty lack training or experience in PI science activities. We assessed the impact of PI science education on the knowledge and attitudes of a group of residency and fellowship program directors and associate program directors using their respective Accreditation Council for Graduate Medical Education annual program evaluations (APEs) as an experiential object. METHODS: For this pre/post study, 16 program directors and 7 associate program directors were surveyed before and after 4 didactic modules. The APEs for the 2 years prior to the intervention and in the fall after the intervention were analyzed. Mentoring in the use of these skills in the preparation of the APEs was provided. RESULTS: The participants demonstrated improved knowledge in some areas and increased awareness of deficits in other areas. APE quality did not show consistent improvement following the intervention. CONCLUSION: The PI science knowledge and skill gaps of program directors and associate program directors are likely to impact the content and success of residency curricula. The designed PI science curriculum was slightly effective. Using the APE as the experiential object was convenient, but the APE was not the best project for a PI exercise. New, effective strategies and interventions to develop expertise in PI science are important as programs grapple with meeting new requirements, ensuring quality programs, and preparing residents and fellows for practice. PMID- 25829879 TI - Enhancing resilience among new nurses: feasibility and efficacy of a pilot intervention. AB - BACKGROUND: Orientation is one of the most stressful times in a registered nurse's career. Little information is available regarding the efficacy of stress management approaches among new nurses. The purpose of this study was to examine outcomes of the implementation of a brief Stress Management and Resiliency Training (SMART) program within a nurse orientation program. METHODS: In this randomized controlled pilot study, self-reported measures of stress, mindfulness, anxiety, and resilience were measured at baseline and 12 weeks following the intervention. For each group, the mean change from baseline to week 12 was evaluated using the paired t test. The change from baseline was compared between groups using the 2-sample t test. Feasibility of integrating the SMART program into the nurse orientation program was also analyzed. RESULTS: Of the 55 participants enrolled, 40 (73%) completed the study. Mindfulness and resilience scores improved in the intervention group and declined in the control group, while stress and anxiety scores decreased in the intervention group and increased in the control group. The between-group change in each outcome, however, was not statistically significant. CONCLUSIONS: Integrating the SMART program within the nurse orientation program is feasible. While changes between groups were not significant, trends in the results indicate that the program has the potential for efficacy. Future research with larger numbers is indicated with a revised version of the program to increase its effect size. PMID- 25829880 TI - Drug-induced acute pancreatitis: a review. AB - BACKGROUND: The majority of drug-induced pancreatitis cases are mild to moderate in severity, but severe and even fatal cases can occur. Management of drug induced pancreatitis requires withdrawal of the offending agent and supportive care. METHODS: This review focuses on differential diagnosis, clinical presentation, drug-mediated effects, treatments, and mechanisms of pancreatitis, with an emphasis on drug-induced pancreatitis. RESULTS: Although only a minority of cases associated with acute pancreatitis are linked to drugs, clinical presentation and mechanisms of injury to the pancreas are not well understood by clinicians in terms of individual drug effects in the mediation or modulation of injury to the pancreas. In recent years, a large number of commonly prescribed medications has been linked to drug-induced pancreatitis pathogenesis. Although mechanisms are proposed, the exact cause of injury is either not well understood or controversial. CONCLUSION: Future investigation into the mechanisms of pancreatitis and an appreciation by clinicians of the drugs commonly linked to the condition will help establish earlier diagnosis and quicker cessation of offending drugs in the treatment of drug-induced acute pancreatitis. PMID- 25829881 TI - iPhone and iPad Use in Orthopedic Surgery. AB - BACKGROUND: Thousands of healthcare mobile applications (apps) are available, and physicians are increasingly recognizing that mobile technology can improve their workflow and allow them to practice medicine in a better and/or more efficient manner. METHODS: This article highlights apps compatible with the iPhone and iPad and their utility to the busy orthopedic surgeon. RESULTS: Currently available apps address every aspect of healthcare: patient management, reference, education, and research. CONCLUSION: Key aspects of helpful apps include low cost (preferably free), a user-friendly interface, and simplicity. PMID- 25829882 TI - Rhabdomyolysis: pathogenesis, diagnosis, and treatment. AB - BACKGROUND: Rhabdomyolysis is a complex medical condition involving the rapid dissolution of damaged or injured skeletal muscle. METHODS: This review focuses on the epidemiology, pathophysiology, causes, presentation, diagnosis, complications, management, and anesthetic considerations related to rhabdomyolysis. RESULTS: Any form of muscle damage--and by extension any entity that causes muscle damage--can initiate rhabdomyolysis. One of the most important treatment goals when rhabdomyolysis is suspected is avoiding acute kidney injury. CONCLUSION: All clinicians should be aware of common causes, diagnosis, and treatment options. PMID- 25829883 TI - Distended bladder presenting with altered mental status and venous obstruction. AB - BACKGROUND: New onset or acute worsening of bilateral lower extremity swelling is commonly caused by venous congestion from decompensated heart failure, pulmonary disease, liver dysfunction, or kidney insufficiency. A thromboembolic event, lymphatic obstruction, or even external compression of venous flow can also be the culprit. CASE REPORT: We report the case of an 83-year-old male with a history of myelodysplastic syndrome that progressed to acute myeloid leukemia, bipolar disorder, and benign prostatic hypertrophy. He presented with altered mental status and new onset lower extremity edema caused by acute bladder outflow obstruction. Computed tomography of the abdomen and pelvis showed the patient's distended bladder compressing bilateral external iliac veins. CONCLUSION: Insertion of a Foley catheter resulted in several liters of urine output and marked improvement in his lower extremity edema and mental status a few hours later. Our extensive workup failed to reveal a cause of the patient's acute change in mental status, and we attributed it to a concept known as cystocerebral syndrome. PMID- 25829884 TI - Resolution of refractory superior mesenteric artery syndrome with laparoscopic duodenojejunostomy: pediatric case series with spectrum of clinical imaging. AB - BACKGROUND: Superior mesenteric artery (SMA) syndrome is an uncommon condition resulting in partial small bowel obstruction because of external compression of the third portion of the duodenum between the SMA anteriorly and the aorta posteriorly. SMA syndrome often presents with postprandial nausea, bilious vomiting, and abdominal pain with associated weight loss. Onset of symptoms can be acute (occurring in the setting of rapid weight loss because of trauma/surgery) or can be vague and chronic over many years. CASE REPORTS: We present two cases of female adolescents who presented with symptoms of duodenal obstruction attributed to SMA syndrome. Both failed conservative treatment with weight gain and underwent successful laparoscopic duodenojejunostomy procedures with resolution of duodenal obstruction. CONCLUSION: In the differential diagnosis of persistent nausea and bilious vomiting, even in the setting of an eating disorder, SMA syndrome should be considered. Upper gastrointestinal examination is the primary modality for diagnosing SMA syndrome, but ultrasound is an inexpensive, rapid screening tool for patients with unexplained abdominal pain. Abdominal computed tomography may also be helpful in selected patients. Conservative therapy consisting of nutritional support to enhance weight gain is usually sufficient and is accomplished with placement of a nasojejunal feeding tube past the point of duodenal compression. When conservative therapy fails, laparoscopic duodenojejunostomy can provide definitive relief of the obstruction. PMID- 25829885 TI - Transient glaucoma after an epidural steroid injection: a case report. AB - BACKGROUND: Steroids are recognized as a beneficial treatment for various medical conditions, yet clinically relevant side effects of steroids are common and problematic, ranging from a minor case of acne to a potentially life-threatening Addisonian crisis. In anesthetic medicine, the use of epidural steroid injections (ESIs) for chronic low back pain and other radicular pain-related conditions has become standard practice in interventional pain management. CASE REPORT: We report the case of a patient who experienced sudden bilateral blurred vision after receiving an ESI and required urgent ophthalmic interventions and follow-up care. The main clinical findings from this case showed that the patient had high intraocular pressure (IOP) that caused unexpected short-term vision loss. The symptom resolved after 31/2 months without ophthalmic treatment. CONCLUSION: Clinicians should inform patients about the possibility of visual complications associated with pain procedures involving steroids. Among the high-risk groups with predisposing factors, such as uncontrolled hypertension and diabetes mellitus, routine eye tests that include measuring IOP prior to ESI should be recommended as a preventive measure. Alternative pain management therapies should be considered if possible. Comprehensive planning of patient care will also ensure safety and prevent unwanted outcomes, particularly with high-risk patients receiving steroids for pain procedures. PMID- 25829886 TI - Acute idiopathic heart failure following laparoscopic myotomy for achalasia of the esophagus. AB - BACKGROUND: Stress-induced cardiomyopathy, also known as takotsubo cardiomyopathy, is not fully understood. It is thought to occur in patients who have signs and symptoms consistent with acute myocardial infarction but display no obstructive coronary lesions during heart catheterization. Characteristics include transient left ventricular dysfunction, wall motion abnormalities on echocardiogram, new electrocardiographic ST-segment changes, and the occurrence of a precipitating stressor. CASE REPORT: We present a patient who underwent Heller myotomy and suffered acute heart failure in the immediate postoperative period. Left heart catheterization revealed clean coronary arteries, and the patient fully recovered days later. While difficult to fully exclude drug-related causes, we believe this case to be consistent with takotsubo cardiomyopathy. CONCLUSION: This unusual postoperative complication following uneventful laparoscopic surgery should be kept in mind when unsuspected cardiovascular compromise is seen in the early perioperative recovery period. In addition to the rare occurrence of acute coronary ischemia syndromes and possible perioperative pulmonary embolic events, cardiovascular decompensation related to acute stress syndromes or idiopathic pharmacologic responses must be considered. Even patients who seem most healthy can have complications that warrant immediate attention and treatment. PMID- 25829887 TI - Musical hallucinations in a patient with presbycusis: a case report. AB - BACKGROUND: Musical hallucinations are a rare subtype of auditory hallucination characterized by the perception of musical sounds, instrumental music, or songs. They are most commonly seen in older women with age-related hearing loss but are also associated with neurologic and psychiatric conditions. The underlying pathophysiology is poorly understood and likely multifactorial. CASE REPORT: A 74 year-old woman presented with subjective hearing loss 2-3 years in duration with a recent development of hearing continuous patriotic and children's songs playing in her head. After extensive interviewing and the documentation of a normal otologic/comprehensive head and neck examination, audiologic evaluation revealed evidence of a symmetric high-frequency sensorineural hearing loss consistent with presbycusis. She was counseled on the use of ambient noise and offered a trial of binaural hearing amplification. CONCLUSION: The diagnosis of musical hallucinations requires the consideration of numerous possible etiologies. Treatment varies widely, but many patients improve with the use of ambient noise and hearing amplification. Lack of response requires the consideration of pharmacologic treatments such as anticonvulsants, antipsychotics, and anticholinesterases. It is important to reassure patients with a nonpsychiatric etiology that use of these drugs does not imply psychiatric illness. PMID- 25829888 TI - Multiple unilateral traumatic carotid-cavernous sphenoid sinus fistulas with associated massive epistaxis: a consequence of parkour. AB - BACKGROUND: Traumatic carotid-cavernous fistulas (CCFs) present the clinician with diagnostic and surgical challenges. Extension of a CCF into the sphenoid sinus presents additional management difficulties. Endovascular interventions using various thrombogenic materials such as balloons, coils, or liquids are effective treatment strategies. Ideally, these techniques are used to obliterate the fistula while maintaining the patency of the parent artery. CASE REPORT: We present a rare case of traumatic carotid-cavernous sphenoid sinus fistulas complicated by multiple tears in the internal carotid artery with direct communication to the cavernous and sphenoid sinus. As a result, the patient developed massive epistaxis requiring emergent endovascular intervention. A total of 87 detachable coils were placed into the cavernous and sphenoid sinuses via transarterial and transvenous routes in a staged procedure, resulting in complete obliteration of the patient's multiple fistulas. CONCLUSION: To our knowledge, this is the first reported case of multiple fistulous tears in the internal carotid artery with extension to the cavernous and sphenoid sinus. This report emphasizes the importance of early diagnosis and neurosurgical intervention. PMID- 25829889 TI - Early precursor of mixed endocrine-exocrine tumors of the gastrointestinal tract: histologic and molecular correlations. AB - BACKGROUND: Mixed endocrine-exocrine tumors display histologic features of endocrine and glandular differentiation. Unlike in collision tumors, the two components are thought to arise from a monoclonal precursor. Evidence from molecular testing supports the monoclonal theory and suggests that the exocrine component may give rise to the endocrine component but not vice versa. CASE REPORT: We report a case of an adenomatous polyp in the large intestine that had groups of endocrine cells arising from the crypt bases of the adenomatous (exocrine) epithelium. To our knowledge, ours is only the second report of an adenomatous polyp in which groups of microcarcinoid endocrine cells were recognized. The histologic findings in our case correlate with the molecular findings described in mixed endocrine-exocrine tumors. CONCLUSION: Our description may represent the primordial stage of a mixed endocrine-exocrine neoplasm. PMID- 25829890 TI - Intrahepatic stones from congenital biliary dilatation. AB - BACKGROUND: Congenital or primary intrahepatic bile duct (IHBD) dilatation is a rare disorder with symptoms of abdominal pain and hepatomegaly that usually presents in childhood and adolescence. Recurrent cholangitis, liver abscesses, septicemia, and biliary cirrhosis may result secondary to biliary sludge and hepatolithiasis. CASE REPORT: We present a case of IHBD dilatation with hepatolithiasis cured with surgical resection and discuss the management of this disease. CONCLUSION: IHBD dilatation should be treated, as chronic biliary stasis and hepatolithiasis can lead to infection and recurrent cholangitis that can progress to cholangiocarcinoma. Treatment for IHBD dilatation usually involves multiple modalities including medical therapy, but ultimately resection of the diseased segments or lobes is required given the increased risk of malignancy. PMID- 25829891 TI - Simultaneous bilateral nonarteritic anterior ischemic optic neuropathy in a patient with a history of diffuse large B-cell lymphoma. AB - BACKGROUND: Nonarteritic anterior ischemic optic neuropathy (NAAION) has a poorly understood etiology, and the onset of simultaneous bilateral NAAION in a patient <50 years without identifiable systemic risk factors is rare. CASE REPORT: We present the case of a patient with acute painless monocular vision loss and bilateral optic disc edema who subsequently developed painless vision loss in the fellow eye. The patient's history was significant for diffuse large B-cell lymphoma, and our pressing diagnostic concern was to determine if his vision loss and bilateral optic disc changes represented lymphomatous infiltrates. A complete ocular exam demonstrated findings consistent with simultaneous bilateral NAAION. After an extensive systemic workup for malignancy with central nervous system involvement, vasculitis, and other entities associated with NAAION, we determined that the patient's primary risk factor for developing bilateral ischemic optic neuropathies was his crowded optic discs. CONCLUSION: This case supports the hypothesis that a crowded optic disc is a sufficient primary risk factor for developing NAAION. PMID- 25829893 TI - 15(th) Annual Southern Hospital Medicine Conference Abstracts. PMID- 25829892 TI - Management challenges in the passing-through technique using a fogarty catheter to remove an endobronchial foreign body from an infant. AB - BACKGROUND: Foreign body aspiration (FBA) is a potentially life-threatening condition in children, and removal of an aspirated bead can be difficult. CASE REPORT: An 11-month-old male infant presented with a history of choking 6 days prior to admission. FBA was suspected, and initial examination revealed a bead occluding the left main bronchus. The surgeon tried to retrieve the foreign body, but the patient developed coughing episodes with desaturation. The patient was intubated and a bronchoscopy was performed with a flexible bronchoscope. A Fogarty catheter was passed through the bronchoscope and then advanced through the bead opening. The distal balloon was inflated, and the bead was removed as the Fogarty catheter was withdrawn. CONCLUSION: We successfully removed an aspirated bead from an infant using the passing-through technique with a Fogarty catheter. Maintaining spontaneous ventilation for as long as possible and good coordination between the anesthesiologist and surgeon are crucial in such cases. PMID- 25829895 TI - Bariatric anesthesia ladder. PMID- 25829894 TI - Dynamic knee joint function in children with juvenile idiopathic arthritis (JIA). AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is a chronic illness with a high risk of developing long-term disability. Disease activity is currently being monitored and quantified by ACR core set. Here, joint inflammation is determined; however joint function is the crucial component for developing disability. The aim of this study was to quantify and compare dynamic joint function in healthy and arthritic knee joints and to evaluate response to improvement. METHODS: A single center cohort study of consecutive children presenting to the rheumatology outpatient clinic was performed to measure dynamic knee joint function. Serial measures were performed if possible. Splint fixed electrogoniometers were used to measure dynamic knee joint function including ROM and flexion and extension torque. RESULTS: A total of 54 children were tested including 44 with JIA, of whom eight had to be excluded for non-JIA-related knee problems. The study included 36 JIA patients of whom eight had strictly unilateral knee arthritis, and nine controls. Dynamic joint function ROM and torque depended on age and bodyweight, as demonstrated in healthy joints. ROM and torques were significant lower in arthritic compared to unaffected knee joints in children with unilateral arthritis and across the cohort. Importantly, extension torque was the most sensitive marker of impaired joint function. Follow up measurements detected responsiveness to change in disease activity. CONCLUSIONS: Measuring dynamic joint function with electrogoniometers is feasible and objective. Active ROM and torque during flexion and extension of arthritic knee joints were significant lower compared to unaffected. In dynamic joint measurement extension torque is a sensitive marker for disease activity. PMID- 25829896 TI - Conscious sedation for middle ear surgeries: A comparison between fentanyl propofol and fentanyl-midazolam infusion. AB - INTRODUCTION AND AIM: Middle ear surgeries can be performed under local anesthesia and sedation and can be well tolerated by the patient with minimal discomfort. This study was undertaken to compare two techniques of conscious sedation, intravenous midazolam, and propofol infusion for tympanoplasty. MATERIALS AND METHODS: Forty patients scheduled for right or left tympanoplasty. American Society of Anesthesiologists I or II in age group 18-75 years were included in the study. The patients were randomly allocated into one of the two groups to receive either propofol (group I) or midazolam (group II). RESULTS: The mean duration of anesthesia was 116.00 +/- 33.94 min in group I, while 97.50 +/- 30.76 min in group II (P = 0.07). The modified Ramsay sedation scale was not statistically significant in both the groups. In group I, 70% of the patients and 95% of the patients in group II had amnesia during the surgery (P = 0.091). The mean visual analog scale (VAS) score for surgeons and patients was not statistically significant in both the groups. In group I there was a positive correlation between the total dose of fentanyl and VAS score for surgeons (P = 0.02). There was also a positive correlation between the total dose of propofol and VAS score for surgeons (P = 0.034) and patients (P = 0.039) in group I. CONCLUSION: Though propofol had shown a faster recovery and less nausea vomiting, we need a larger sample size to conclude, which of the technique is better. Both the techniques are safe, simple and versatile and provide excellent sedation with rapid trouble free recovery. PMID- 25829897 TI - A randomized controlled prospective study comparing a low dose bupivacaine and fentanyl mixture to a conventional dose of hyperbaric bupivacaine for cesarean section. AB - CONTEXT: Hormonal and mechanical factors make obstetric patients need strict dose calculations of local anesthetics intrathecally for spinal anesthesia. Any greater dose of local anesthetics can cause hemodynamic instability, maternal morbidity and any lesser dose can produce inadequate block. Hence, we hypothesized in our study that by using low dose of bupivacaine with fentanyl can maintain stable hemodynamics and provide better analgesia. AIM: The aim was to compare the hemodynamics and duration of analgesia using a low dose (7.5 mg) bupivacaine fentanyl mixture to a conventional dose (10 mg) of hyperbaric bupivacaine for cesarean section. SETTINGS AND DESIGN: Double-blinded, randomized, controlled prospective study was conducted at a tertiary academic hospital from 2008 to 2011. MATERIALS AND METHODS: Fifty singleton parturient, scheduled for elective caesarean section were randomly allocated into two groups. Study group (group-S) received a combination of 25 MUg fentanyl and 7.5 mg of hyperbaric bupivacaine, whereas the control group (group-C) received 10 mg of hyperbaric bupivacaine. Maternal hemodynamics, sensory and motor block, duration of analgesia and the Apgar score of the newborn were compared between the groups. STATISTICAL ANALYSIS USED: Observational descriptive statistics, statistical package for social sciences (SPSS Inc. Released 2006, SPSS for Windows, Version 15.0. Chicago), paired t-test was used as applicable. RESULTS: The blood pressure significantly decreased with >25% fall from the baseline in group-C (98.76 +/- 8.36) than in group-S (117.32 +/- 12.21) with P < 0.001. The duration of effective analgesia was significantly prolonged in the study group than in the control group (P < 0.001). CONCLUSION: The combination of low dose bupivacaine and fentanyl in comparison to bupivacaine alone is hemodynamically stable and prolonged duration of analgesia in caesarean section. PMID- 25829898 TI - Caudal epidural blockade for major orthopedic hip surgery in adolescents. AB - BACKGROUND: There continues to be a significant focus on the value of regional and neuraxial anesthesia techniques for adjunctive use when combined with general anesthesia. The reported advantages include decreased patient opiate exposure, decreased medication-related adverse effects, decreased postanesthesia recovery room time and hospital stay, and increased patient satisfaction. MATERIALS AND METHODS: The authors present a case-controlled series evaluating the use of a single caudal epidural injection prior to incision as an adjunct to general anesthesia for the open repair of slipped capital femoral epiphysis. Opiate consumption, pain scores, and hospital stay were compared between the two cohorts of 16 adolescent patients. All patients received a demand-only patient-controlled opiate delivery system. RESULTS: Although the failed block rate was high (31%), there was decreased opioid use in the perioperative arena as well as during the first 24 postoperative hours in patients who had a successful caudal epidural block. Furthermore, discharge home was possible in 27% of patients who received a caudal epidural block compared to 0% of patients who did not receive a caudal block. CONCLUSION: The potential utility of caudal epidural block as an adjunct to general anesthesia during major hip surgery in adolescents is presented. Factors resulting in a failed block in this patient population as well as the use of the ultrasound as an added modality to increase block success are reviewed. PMID- 25829899 TI - Role of regional anesthesia for placement of peritoneal dialysis catheter under ultrasound guidance: Our experience with 52 end-stage renal disease patients. AB - AIM: The number of patients with end-stage renal disease (ESRD) has shown a consistent rise in India in recent years. Continuous ambulatory peritoneal dialysis (CAPD) remains one of the safe and effective forms of treatment. In this study, we have tried to assess the effectiveness of field block technique for analgesia during catheter placement surgery until 24 h postoperatively, also, if it can obviate the need for general anesthesia in these high-risk patients. MATERIALS AND METHODS: We studied 52 ESRD patients from 2010 to 2012 who were posted for CAPD catheterization in the Department of Urology, Care Hospital, Hyderabad, India. Under ultrasound guidance, "unilateral posterior" and "unilateral subcostal" transversus abdominis plane block anesthesia were given for the placement of CAPD catheter. Patient's intra-operative pain and post operative pain were recorded with visual analog scores (VAS) and analyzed. RESULTS: All patients in our study belonged to American Society of Anesthesiologists category 2 or 3 with multiple co-morbidities. 41 out of 52 patients required no supplemental analgesia during the procedure; 8 patients needed additional infiltration of local anesthetic during skin incisions. Three patients required supplemental analgesia and were considered as failure. A VAS of two was noted in 30 patients and 1 in 19 Patients. No Patient had significant pain 24 h post operatively. No local complication was noted in any patient. CONCLUSION: CAPD Catheterization under regional field block remains safe and effective options for ESRD patients. PMID- 25829900 TI - Comparison of acute physiology and chronic health evaluation II and Glasgow Coma Score in predicting the outcomes of Post Anesthesia Care Unit's patients. AB - CONTEXT: Acute physiology and chronic health evaluation II (APACHE II) is one of the most general classification systems of disease severity in Intensive Care Units and Glasgow Coma Score (GCS) is one of the most specific ones. AIMS: The aim of the current study was to assess APACHE II and GCS ability in predicting the outcomes (survivors, non-survivors) in the Post Anesthesia Care Unit's (PACU). SETTINGS AND DESIGN: This was an observational and prospective study of 150 consecutive patients admitted in the PACU during 6-month period. MATERIALS AND METHODS: Demographic information recorded on a checklist, also information about severity of disease calculated based on APACHE II scoring system in the first admission 24 h and GCS scale. STATISTICAL ANALYSIS USED: Logistic regression, Hosmer-Lemeshow test and receiver operator characteristic (ROC) curves were used in statistical analysis (95% confidence interval). RESULTS: Data analysis showed a significant statistical difference between outcomes and both APACHE II and Glasgow Coma Score (GCS) (P < 0.0001). The ROC-curve analysis suggested that the predictive ability of GCS is slightly better than APACHE II in this study. For GCS the area under the ROC curve was 86.1% (standard error [SE]: 3.8%), and for APACHE II it was 85.7% (SE: 3.5%), also the Hosmer-Lemeshow statistic revealed better calibration for GCS (chi(2) = 5.177, P = 0.521), than APACHE II (chi(2) = 10.203, P = 0.251). CONCLUSIONS: The survivors had significantly lower APACHE II and higher GCS compared with non-survivors, also GCS showed more predictive accuracy than APACHE II in prognosticating the outcomes in PACU. PMID- 25829901 TI - Response to low-dose intrathecal clonidine in septuagenarians undergoing sub umbilical surgeries: A study. AB - Clonidine, an alpha-2-adrenergic agonist, may have a clinically relevant analgesic action but also a hypotensive action, when administered spinally. AIM: To evaluate the analgesic and circulatory effects of low-dose intrathecal clonidine co-administered with hyperbaric bupivacaine in septuagenarian patients undergoing sub-umbilical surgeries. MATERIALS AND METHODS: A total of 20 patients within the age group of 70-80 years of either sex, enrolled in this study, were randomly divided into groups of 10 each. Group I received clonidine 7.5 MUg as an adjuvant to 15 mg of hyperbaric bupivacaine and Group II (control group) received 15 mg of bupivacaine with saline to make volume in the two solutions equal. RESULT: The level of subarachnoid block was comparable in the two groups. Duration of motor blockade was longer in the clonidine group (221.4 +/- 35.92 min) compared with the control group (112.3 +/- 12.45 min). Request for 1(st) dose of analgesic was earlier in the control group (135.5 +/- 28.52 min) than the clonidine group (295 +/- 18.85 min). Mean arterial pressure (clonidine 77.67 +/- 6.47 vs. control 93.87 +/- 3.03, P = 0.0002) and heart rate (clonidine 65.2 +/- 5.20 vs. control 77.4 +/- 6.06, P = 0.003) were significantly lower (P < 0.05) in the clonidine group compared with the control group from 20 mins after the block to the end of 3 h. In the clonidine group, 3 patients had postoperative headache, 4 had intra-operative shivering. 2 patients in the clonidine group also developed hypotension and 1 bradycardia and 1 of them developed bradyapnea along with acute hypotension 5 min after shifting to the postoperative ward and later recovered on resuscitation. In the control group 2 patients had bradycardia, 6 had intra operative shivering and 3 had postoperative headache. CONCLUSION: We conclude that addition of clonidine in the dose of 7.5 MUg to bupivacaine significantly increases the duration of spinal analgesia with clinically insignificant influence on hemodynamic parameters. PMID- 25829902 TI - Dexmedetomidine as an adjuvant to ropivacaine in supraclavicular brachial plexus block. AB - CONTEXT: Dexmedetomidine as an adjuvant to local anesthetics in peripheral nerve blocks has been used in only a few studies. AIMS: We aimed at assessing the effect of dexmedetomidine as an adjuvant to ropivacaine in supraclavicular brachial plexus block. SETTINGS AND DESIGN: Random, controlled, and triple blind. MATERIALS AND METHODS: Sixty American Society of Anesthesiologist grade I and II patients of either sex scheduled for elective upper limb surgery under supraclavicular brachial plexus block were divided into three equal groups in a prospective randomized double-blind controlled manner. For block patients in Group C received 0.5% ropivacaine (30cc), 0.5% ropivacaine with 50 MUg dexmedetomidine (30cc) in Group D and 0.5% ropivacaine (30cc) in Group D-IV along with intravenous infusion of 50 MUg dexmedetomidine in normal saline. STATISTICAL ANALYSIS USED: IBM-SPSS software version 17, Chi-square test, Mann-Whitney U test. RESULTS: Demographic profile and surgical characteristics were similar in all the three groups. Sensory block and motor block onset was earlier in group D than in group D-IV and group C. The sensory block and motor block duration was also prolonged in group D when compared with group D-IV and group C. The duration of analgesia was significantly longer in group D and D-IV when compared to group C. CONCLUSIONS: Dexmedetomidine as an adjuvant to 0.5%ropivacaine in ultrasound guided brachial plexus block shortens the sensory as well as motor block onset time, prolongs sensory and motor block duration and also increases the duration of analgesia. The action of dexmedetomidine most probably is local rather than centrally mediated. PMID- 25829903 TI - The safety of ultrasound guided central venous cannulation in patients with liver disease. AB - BACKGROUND: Central venous cannulation (CVC) is frequently required during the management of patients with liver disease with deranged conventional coagulation parameters (CCP). Since CVC is known to be associated with vascular complications, it is standard practice to transfuse Fresh-Frozen Plasma or platelets to correct CCP. These CCP may not reflect true coagulopathy in liver disease. Additionally CVC when performed under ultrasound guidance (USG-CVC) in itself reduces the incidence of complications. AIM: To assess the safety of USG CVC and to evaluate the incidence of complications among liver disease patients with coagulopathy. SETTING AND DESIGN: An audit of all USG-CVCs was performed among adult patients with liver disease in a tertiary care center. MATERIALS AND METHODS: Data was collected for all the adult patients (18-60 years) of either gender suffering from liver disease who had required USG-CVC. Univariate and multivariate regression analysis was done to identify possible risk factors for complications. RESULTS: The mean age of the patients was 42.1 +/- 11.6 years. Mean international normalized ratio was 2.17 +/- 1.16 whereas median platelet count was 149.5 (range, 12-683) * 10(9)/L. No major vascular or non-vascular complications were recorded in our patients. Overall incidence of minor vascular complications was 18.6%, of which 13% had significant ooze, 10.3% had hematoma formation and 4.7% had both hematoma and ooze. Arterial puncture and multiple attempts were independent risk factors for superficial hematoma formation whereas low platelet count and presence of ascites were independent risk factors for significant oozing. CONCLUSION: Ultrasound guidance -CVC in liver disease patients with deranged coagulation is a safe and highly successful modality. PMID- 25829904 TI - Behavioral and emotional effects of repeated general anesthesia in young children. AB - BACKGROUND: Preclinical and clinical data suggest the possibility of neurotoxicity following exposure of young children to general anesthetics with subsequent behavioral disturbances. The aim of the study was to determine the overall effect of repeated general anesthesia on behavior and emotions of young children aged 11/2-5 years old, compared to healthy children. MATERIALS AND METHODS: Thirty-five children underwent repeated anesthesia and surgery were matched with the same number of healthy children who attended vaccination clinic, as a control group. Both groups were administered the child behavior checklist (CBCL) 11/2-5 years and Diagnostic and Statistical Manual of Mental Disorders (DSM) oriented scale. Behavior data were collected through a semi-structured questionnaire. RESULTS: The CBCL score revealed that children with repeated anesthesia were at risk to become anxious or depressed (relative risk [RR]; 95% confidence interval [CI] = 11 [1.5-80.7]), to have sleep (RR; 95% CI = 4.5 [1.1 19.4]), and attention problems (RR; 95% CI = 8 [1.1-60.6]). There was no difference in the risk between the two groups regarding emotionally reactive, somatic complaints, withdrawn problems, aggressive behavior, internalizing or externalizing problems. On DSM scale, children with repeated anesthesia were at risk to develop anxiety problems (RR; 95% CI = 3.7 [1.1-12.0]), and attention deficit/hyperactivity problems (RR; 95% CI = 3 [1.1-8.4]). There was no difference in the risk between the two groups regarding affective, pervasive developmental and oppositional defiant problems. CONCLUSION: Young children who undergone repeated surgical procedures under general anesthesia were at risk for subsequent behavioral and emotional disturbances. Proper perioperative pain management, social support, and avoidance of unpleasant surgical experiences could minimize these untoward consequences. PMID- 25829905 TI - Comparison of intraoperative brain condition, hemodynamics and postoperative recovery between desflurane and sevoflurane in patients undergoing supratentorial craniotomy. AB - BACKGROUND: Post operative recovery has been reported to be faster with desflurane than sevoflurane anesthesia in previous studies. The use of desflurane is often criticized in neurosurgery due to the concerns of cerebral vasodilation and increase in ICP and studies comparing desflurane and sevoflurane in neurosurgey are scarce. So we compared the intraoperative brain condition, hemodynamics and postoperative recovery in patients undergoing elective supratentorial craniotomy receiving either desflurane or sevoflurane. MATERIALS AND METHODS: Fifty three patients between 18-60yr undergoing elective supratentorial craniotomy receiving N2O and oxygen (60%:40%) and 0.8-1.2 MAC of either desflurane or sevoflurane were randomized to group S (Sevoflurane) or group D (Desflurane). Subdural intra cranial pressure (ICP) was measured and brain condition was assessed.. Emergence time, tracheal extubation time and recovery time were recorded. Cognitive behavior was evaluated with Short Orientation Memory Concentration Test (SOMCT) and neurological outcome (at the time of discharge) was assessed using Glasgow Outcome Score (GOS) between the two groups. RESULTS: The emergence time [Group D 7.4 +/- 2.7 minutes vs. Group S 7.8 +/- 3.7 minutes; P = 0.65], extubation time [Group D 11.8 +/- 2.8 minutes vs. Group S 12.9 +/- 4.9 minutes; P = 0.28] and recovery time [Group D 16.4 +/- 2.6 minutes vs. Group S 17.1 +/- 4.8 minutes; P = 0.50] were comparable between the two groups. There was no difference in ICP [Group D; 9.1 +/- 4.3 mmHg vs. Group S; 10.9 +/- 4.2 mmHg; P = 0.14] and brain condition between the two groups. Both groups had similar post-operative complications, hospital and ICU stay and GOS. CONCLUSION: In patients undergoing elective supratentorial craniotomy both sevoflurane and desflurane had similar intra-operative brain condition, hemodynamics and post operative recovery profile. PMID- 25829906 TI - Postoperative pain assessment using four behavioral scales in Pakistani children undergoing elective surgery. AB - BACKGROUND: Several measurement tools have been used for assessment of postoperative pain in pediatric patients. Self-report methods have limitations in younger children and parent, nurse or physician assessment can be used as a surrogate measure. These tools should be tested in different cultures as pain can be influenced by sociocultural factors. The objective was to assess the inter rater agreement on four different behavioral pain assessment scales in our local population. MATERIALS AND METHODS: This prospective, descriptive, observational study was conducted in Pakistan. American Society of Anesthesiologists I and II children, 3-7 years of age, undergoing elective surgery were enrolled. Four pain assessment scales were used, Children's Hospital of Eastern Ontario Pain Scale (CHEOPS), Toddler Preschool Postoperative Pain Scale (TPPPS), objective pain scale (OPS), and Face, Legs, Activity, Cry, Consolability (FLACC). After 15 and 60 min of arrival in the postanesthesia care unit (PACU), each child evaluated his/her postoperative pain by self-reporting and was also independently assessed by the PACU nurse, PACU anesthetist and the parent. The sensitivity and specificity of the responses of the four pain assessment scales were compared to the response of the child. RESULTS: At 15 min, sensitivity and specificity were >60% for doctors and nurses on FLACC, OPS, and CHEOPS scales and for FLACC and CHEOPS scale for the parents. Parents showed poor agreement on OPS and TPPS. At 60 min, sensitivity was poor on the OPS scale by all three observers. Nurses showed a lower specificity on FLACC tool. Parents had poor specificity on CHEOPS and rate of false negatives was high with TPPS. CONCLUSIONS: We recommend the use of FLACC scale for assessment by parents, nurses, and doctors in Pakistani children aged between 3 and 7. PMID- 25829907 TI - A comparative evaluation of the effect of intravenous dexmedetomidine and clonidine on intraocular pressure after suxamethonium and intubation. AB - BACKGROUND: In patients with penetrating eye injury and a full stomach, suxamethonium is still used for rapid sequence induction of anesthesia. But its use is associated with the rise in intraocular pressure (IOP) and this can result in permanent vision loss in these patients. Dexmedetomidine and clonidine are two alpha-2 adrenergic agonist drugs which prevent the rise in IOP. The aim of this study is to compare the efficacy of intravenous (i.v.) dexmedetomidine and clonidine in preventing an increase in IOP after administration of suxamethonium and tracheal intubation. MATERIALS AND METHODS: Sixty patients undergoing elective nonophthalmic surgery under general anesthesia were included in this clinical study. Patients were randomly assigned into three groups to receive 0.5 mcg/kg dexmedetomidine (Group D), 2 mcg/kg clonidine (Group C) or normal saline (Group S) as premedication i.v. over a period of 10 min before induction. IOP, heart rate, and mean arterial pressure were recorded before and after premedication, after suxamethonium, after intubation and then after 5 min. RESULTS: Following administration of dexmedetomidine and clonidine IOP decreased in both groups. After suxamethonium IOP increased in all three groups but it never crossed the baseline in Group D and C. After laryngoscopy and intubation IOP again increased in all three groups but in dexmedetomidine group it never crossed the baseline whereas in clonidine group it was significantly higher than the baseline. CONCLUSION: Single i.v. dose of dexmedetomidine premedication (0.5 mcg/kg) blunt the IOP and hemodynamic response to suxamethonium injection and tracheal intubation more effectively than single i.v. dose of clonidine premedication (2 mcg/kg). PMID- 25829908 TI - Comparison between general anesthesia and spinal anesthesia in attenuation of stress response in laparoscopic cholecystectomy: A randomized prospective trial. AB - BACKGROUND: Laparoscopy though minimally invasive produces significant hemodynamic surge and neuroendocrine stress response. Though general anesthesia (GA) is the conventional technique, now-a-days, regional anesthesia has been accepted for laparoscopic diagnostic procedures, and its use is also being extended to laparoscopic surgeries. OBJECTIVE: The aim was to compare the hemodynamic surge and neuroendocrine stress response during laparoscopic cholecystectomy (LC) under GA and spinal anesthesia (SA) in American Society of Anesthesiologists (ASA) PS 1 patients. MATERIALS AND METHODS: Thirty ASA physical status I patients, aged 18-65 years were randomly allocated into two equal groups of 15 each. Group A received GA with controlled ventilation. Patients were preoxygenated for 5 min with 100/5 oxygen, premedicated with midazolam 0.03 mg/kg intravenous (i.v), fentanyl 2 mcg/kg i.v; induction was done with thiopentone 3-5 mg/kg i.v; intubation was achieved after muscle relaxation with 0.5 mg/kg atracurium besylate i.v. Anesthesia was maintained with 1-2% sevoflurane and N2O:O2 (60:40) and intermittent i.v injection of atracurium besylate. Group B SA with 0.5% hyperbaric bupivacaine and 25 MUg fentanyl along with local anesthetic instillation in the subdiaphragmatic space. Mean arterial pressure, heart rate (HR), oxygen saturation, end tidal carbon-dioxide were recorded. Venous blood was collected for cortisol assay before induction and 30 min after pneumoperitoneum. All data were collected in Microsoft excel sheet and statistically analyzed using SPSS software version 16 (SPSS Inc., Chicago, IL, USA). All numerical data were analyzed using Student's t-test and paired t-test. Any value <0.05 was taken as significant. RESULTS: Mean arterial pressure and mean HR and postpneumoperitoneum cortisol level were lower in group B than group A though the difference was not statistically significant in hemodynamic parameters but significant in case of cortisol. CONCLUSION: Spinal anesthesia administered for LC maintained comparable hemodynamics compared to GA and did not produce any ventilatory depression. It also produced less neuroendocrine stress response as seen by reduction in the level of serum cortisol in ASA PS 1 patients put for LC. PMID- 25829909 TI - Does a single specialty intensive care unit make better business sense than a multi-specialty intensive care unit? A costing study in a trauma center in India. AB - CONTEXT: Though intensive care units (ICUs) only account for 10% of hospital beds, they consume nearly 22% of hospital resources. Few definitive costing studies have been conducted in Indian settings that would help determine appropriate resource allocation. AIM: To evaluate and compare the cost of intensive care delivery between multi-specialty and neurosurgery ICU in an apex trauma care facility in India. MATERIALS AND METHODS: The study was conducted in a polytrauma and neurosurgery ICU at a 203 bedded level IV trauma care facility in New Delhi, India from May, 2012 to June 2012. The study was cross-sectional, retrospective, and record-based. Traditional costing was used to arrive at the cost for both direct and indirect cost estimates. The cost centers included in study were building cost, equipment cost, human resources, materials and supplies, clinical and nonclinical support services, engineering maintenance cost, and biomedical waste management. STATISTICAL ANALYSIS: Fisher's two-tailed t-test. RESULTS: Total cost/bed/day for the multi-specialty ICU was Rs. 14,976.9/ and for the neurosurgery ICU was Rs. 14,306.7/-, manpower constituting nearly half of the expenditure in both ICUs. The cost center wise and overall difference in the cost among the ICUs were statistically significant. CONCLUSIONS: Quantification of expenditure in running an ICU in a trauma center would assist healthcare decision makers in better allocation of resources. Although multi specialty ICUs are more expensive, other factors will also play a role in defining the kind of ICU that need to be designed. PMID- 25829910 TI - Influence of GlideScope assisted endotracheal intubation on intraocular pressure in ophthalmic patients. AB - BACKGROUND: Traditional Macintoch laryngoscopy is known to cause a rise in intraocular pressure (IOP), tachycardia and hypertension. These changes are not desirable in patients with glaucoma and open globe injury. GlideScope is a video laryngoscope that functions independent of the line of sight, reduces upward lifting forces for glottic exposure and requires less cervical neck movement for intubation, making it less stimulating than Macintosh laryngoscopy. AIM: The aim was to assess the variations in IOP and hemodynamic changes after GlideScope assisted intubation. MATERIALS AND METHODS: After approval of the local Institutional Research and Ethical Board and informed patient consent, 50 adult American Society of Anesthesiologist I and II patients with normal IOP were enrolled in a prospective, randomized study for ophthalmic surgery requiring tracheal intubation. In all patients, trachea was intubated using either GlideScope or Macintoch laryngoscope. IOP of nonoperated eye, heart rate and blood pressure were measured as baseline, 1 min after induction, 1 min and 5 min after tracheal intubation. RESULTS: IOP was not significantly different between groups before and after anesthetic induction and 5 min after tracheal intubation (P = 0.217, 0.726, and 0.110 respectively). The only significant difference in IOP was at 1 min after intubation (P = 0.041). No significant difference noted between groups in mean arterial pressure (P = 0.899, 0.62, 0.47, 0.82 respectively) and heart rate (P = 0.21, 0.72, 0.07, 0.29, respectively) at all measurements. CONCLUSION: GlideScope assisted tracheal intubation shown lesser rise in IOP at 1 min after intubation in comparison to Macintoch laryngoscope, suggesting that GlideScope may be preferable to Macintosh laryngoscope. PMID- 25829911 TI - Fascia Iliaca block as the sole anesthesia technique in a patient with recent myocardial infarction for emergency femoral thrombectomy. AB - Acute limb ischemia is a surgical emergency that precludes prolonged preoperative cardiac evaluation. A 70-year-old female with recent myocardial infarction was posted for emergency transfemoral thrombectomy. We discuss the perioperative anesthetic considerations in these case. Fascia iliaca block can be used as sole anesthesia technique for transfemoral thrombectomy in high-risk patients. PMID- 25829912 TI - Anesthetic concerns in a huge congenital sublingual swelling obscuring airway access. AB - Presence of intraoral pathology poses a great challenge during management of pediatric airway. We report management of big intraoral cystic swelling physically occupying the entire oral cavity restricting access to airway. Preintubation aspiration of swelling was done to decrease its size and make room for airway manipulation, followed by laryngoscopy and intubation in lateral position. Airway patency is at risk in postoperative period also, in this case, though the swelling decreased in size postoperatively but presence of significant edema required placement of tongue stitch and modified nasopharyngeal airway. Case report highlights simple maneuvers to manage a difficult case. PMID- 25829913 TI - Stellate ganglion block can relieve symptoms and pain and prevent facial nerve damage. AB - Ramsay hunt syndrome[1] is a varicella zoster virus infection of the geniculate ganglion of the facial nerve. It is typically associated with a red rash and blister (inflamed vesicles or tiny water filled sacks in the skin) in or around the ear and eardrum and sometimes on the roof of the mouth or tongue. Corticosteroid, oral acyclovir, and anticonvulsant are used for treatment of this. In addition to this sympathetic neural blockade via stellate ganglion block is used to prevent facial nerve damage and relieve symptoms. We present a case of Ramsay hunt syndrome in which pain and symptoms are not relieved by oral medication but by daily sittings of stellate ganglion block with local anesthetic and steroid, pain, and other symptoms are relieved, and facial nerve damage is prevented. PMID- 25829914 TI - Simultaneous cesarean delivery and craniotomy in a term pregnant patient with traumatic brain injury. AB - The management of pregnant patients with traumatic brain injury is challenging. A multidisciplinary team approach is mandatory, and management should be individualized according to the type and extent of injury, maternal status, gestational age, and fetal status. We report a 27-year-old term primigravida presenting after head injury with Glasgow coma scale score 11 and anisocoria. Depressed temporal bone fracture and acute epidural hematoma were diagnosed, necessitating an urgent neurosurgery. Her fetus was viable with no signs of distress and no detected placental abnormalities. Cesarean delivery was performed followed by craniotomy in the same setting under general anesthesia with good outcome of the patient and her baby. PMID- 25829915 TI - Novel management of methylene blue extravasation: A case report and review of literature. AB - Methylene blue is a highly irritant drug and has been used intraoperatively. Its accidental extravasation can lead to tissue necrosis. In this report, a unique management is described, and the patient recovered without any morbidity. PMID- 25829916 TI - Cauda equina syndrome after repeated spinal attempts: A case report and review of the literature. AB - Spinal and epidural blocks are widely used for cesarean section. Spinal hematoma causing cauda equina syndrome is a rare complication after spinal anesthesia (SA), but can lead to severe neurological deficit. It is usually associated with difficult SA and requires surgical decompression in most of the cases. PMID- 25829917 TI - I-gel assisted fiberoptic intubation in a child with Morquio's syndrome. AB - Morquio's syndrome, also known as mucopolysaccharidosis type IV is an autosomal recessive disorder, caused by deficiency of n-acetylgalactosamine-6-sulphate. Anesthetic management of this syndrome is a great challenge, especially in pediatric age group as "cannot ventilate, cannot intubate" scenario can be encountered by anesthesiologist due to the possibility of total airway collapse. Herewith, we are reporting a case of child with Morquio's syndrome where I-gel assisted fiber-optic intubation was used for safe endotracheal intubation. PMID- 25829918 TI - Comments on "Fatal colchicine intoxication". PMID- 25829919 TI - Ultrafluoro guided caudal epidural injection: An innovative blend of two traditional techniques. PMID- 25829920 TI - Retromolar intubation: A better alternative to submental intubation or tracheostomy for dental occlusion by intermaxillary fixation. PMID- 25829921 TI - Ultrasound out of plane approach for pulsed radiofrequency treatment of post herniorrhaphy pain: Synchronizing treatment and imaging modality. PMID- 25829922 TI - Iatrogenic ascending aortic obstruction in the neonate: Significance of pressure gradients across the aorta. PMID- 25829923 TI - Fiberoptic endotracheal intubation through a supraglottic conduit using an exchange catheter. PMID- 25829924 TI - Right sided congenital diaphragmatic hernia: A rare neonatal emergency. PMID- 25829925 TI - Low oxygen saturation: Really a hypoxia? PMID- 25829926 TI - Pericardial effusion: Real and false. PMID- 25829927 TI - Mishap due to look alike ampule: Matter of serious concern. PMID- 25829928 TI - Capno cannula is useful for sedation management in patients undergoing esophagogastroduodenoscopy. PMID- 25829929 TI - Erratum: 0.5% levobupivacaine versus 0.5% ropivacaine: Are they different in ultrasound-guided sciatic block?: Erratum. AB - [This corrects the article on p. 3 in vol. 9, PMID: 25558190.]. PMID- 25829930 TI - Comparison of three different techniques of low-dose-rate seed implantation for prostate cancer. AB - PURPOSE: Three different techniques of low-dose-rate seed implantation for prostate cancer have been used since its use started in our hospital. The purpose of this study was to compare the results of the three different techniques. MATERIAL AND METHODS: The data of 305 prostate cancer patients who underwent low dose-rate seed implantation were retrospectively analyzed. Pre-plan technique (n = 27), intraoperative pre-plan technique (n = 86), and interactive plan technique (n = 192) were tried in chronological order. The prescribed dose was set at 145 Gy. RESULTS: Median follow-up was 66 months (range: 12-94 months). The 5-year biochemical control rate was 95.5% (pre-plan group: 100%, intraoperative pre-plan group: 90.7%, interactive plan group: 97.0%; p = 0.08). Dosimetric parameters were generally increased from the pre-plan group to the interactive group. The differences in some dosimetric parameters between the planning phase and the CT analysis were significantly reduced with the interactive plan compared to the other techniques. The interactive plan showed a significant reduction of the seed migration rate compared to the two other groups. Acute genitourinary toxicity, acute gastrointestinal toxicity, frequency, and urinary retention increased gradually from the pre-plan period to the interactive plan period. CONCLUSIONS: There was no significant difference in biochemical control among the three groups. Dose-volume parameters were increased from the pre-plan technique to the interactive plan technique. However, this may not necessarily be due to technical improvements, since dose escalation was started during the same period. Lower seed migration rates and the smaller differences between the planning phase and CT analysis with the interactive plan technique suggest the superiority of this technique to the two other techniques. PMID- 25829931 TI - High-dose-rate brachytherapy delivered in two fractions as monotherapy for low risk prostate cancer. AB - PURPOSE: High-dose-rate (HDR) brachytherapy has been accepted as an effective and safe method to treat prostate cancer. The aim of this study was to describe acute toxicity following HDR brachytherapy to the prostate, and to examine the association between dosimetric parameters and urinary toxicity in low-risk prostate cancer patients. MATERIAL AND METHODS: Patients with low-risk prostate cancer were given HDR brachytherapy as monotherapy in two 12.5 Gy fractions. Planning objectives for the planning target volume (PTV) were V100% >= 90% and V150% <= 35%. Planning objectives for organs at risk were V75% <= 1 cc for the bladder, rectum and perineum, and V125% <= 1 cc for the urethra. Toxicity was assessed three months after treatment using the Common Terminology Criteria for Adverse Events. RESULTS: Seventy-three patients were included in the analysis. Thirty-three patients (45%) reported having any type of toxicity in the three months following HDR brachytherapy. Most toxicity cases (26%) were grade 1 urinary toxicity. Mean coverage index was 0.89 and mean V100 was 88.85. Doses administered to the urethra were associated with urinary toxicity. Patients who received more than 111.3% of the prescribed dose in 1 cc of the urethra were four times more likely to have urinary toxicity compared to patients receiving less than 111.3% (OR = 4.71, 95% CI: 1.43-15.6; p = 0.011). CONCLUSIONS: High-dose rate brachytherapy administered as monotherapy for prostate cancer proved to be a safe alternative treatment for patients with low-risk prostate cancer. Urinary toxicity was associated with the dose administered to 1 cc and 0.1 cc of the urethra and was remarkably inferior to the reported toxicity in similar studies. PMID- 25829932 TI - Influence of zonal dosimetry on prostate brachytherapy outcomes. AB - PURPOSE: To examine the influence of zone-specific dosimetry on outcomes during permanent prostate implantation (PI), where the peripheral zone (PZ) and transitional zone (TZ) may receive varying radiation doses. MATERIAL AND METHODS: Four hundred and sixteen patients treated with I-125 PI (target dose: 144 Gy) between 1996 and 2003 were included in this Institutional Review Board (IRB) approved, retrospective analysis. Whole prostate (WP), TZ, and PZ were contoured, and zone-specific D90 and V100 were computed. Their influence on biochemical failure (BF) was evaluated using Cox proportional hazards analysis. RESULTS: The median age and initial prostate-specific antigen (PSA) was 68 years and 6.1 ng/ml, respectively, and the median follow-up time was 8.8 years. There were 329 subjects with Gleason score (GS) 6 disease (79.1%), and 82 subjects had GS 7 disease (19.7%). Androgen deprivation therapy (ADT) was used in 20.4% of patients. Median D90 and V100% in the WP, PZ, and TZ were 141.2 Gy, 156.1 Gy, and 134.5 Gy; and 88.8%, 93.3%, and 84.2%, respectively. Ten-year rates for biochemical recurrence-free survival, distant metastasis-free survival, and prostate cancer-specific mortality were 82.4%, 92.4%, and 0.97% respectively. Only initial PSA, GS7+ disease, ADT, and PSA frequency were significant on multivariate analysis. Ten-year rates of grade 3 or higher GU and GI toxicity was 10.9% and 1.8%, respectively. TZ V200 and TZ V300 were significantly associated with late genitourinary toxicity. CONCLUSIONS: The TZ received significantly lower doses of radiation compared to the PZ. On multivariate analysis, no dosimetric parameter was associated with efficacy. Higher TZ doses may be associated with higher late GU toxicity without improving efficacy. PMID- 25829933 TI - Comparison of radiation dose to the left anterior descending artery by whole and partial breast irradiation in breast cancer patients. AB - PURPOSE: Breast conserving surgery (BCS) followed by whole breast irradiation (WBI) is the standard of care for breast cancer patients. However, there is a risk of coronary events with WBI therapy. In this study, we compared the radiation dose in the left anterior descending artery (LAD) in patients receiving partial breast irradiation (PBI) with WBI. MATERIAL AND METHODS: We evaluated consecutive patients who underwent adjuvant radiotherapy after BCS between October 2008 and July 2014. Whole breast irradiation patients received 50 Gy in fractions of 2 Gy to the entire breast. Partial breast irradiation was performed using multicatheter brachytherapy at a dose of 32 Gy in eight fractions. The mean and maximal cumulative doses to LAD were calculated. The radiotherapeutic biologically effective dose of PBI was adjusted to WBI, and radiation techniques were compared. RESULTS: Of 379 consecutive patients with 383 lesions receiving radiotherapy (151 WBI and 232 PBI lesions), 82 WBI and 100 PBI patients were analyzed. In WBI patients, the mean and maximal cumulative doses for left-sided breast cancer (2.13 +/- 0.11 and 8.19 +/- 1.21 Gy, respectively) were significantly higher than those for right-sided (0.37 +/- 0.02 and 0.56 +/- 0.03 Gy, respectively; p < 0.0001). In PBI patients with left-sided breast cancer, the doses for tumors in inner quadrants or central location (2.54 +/- 0.21 and 4.43 +/- 0.38 Gy, respectively) were significantly elevated compared to outer quadrants (1.02 +/- 0.17 and 2.10 +/- 0.29 Gy, respectively; p < 0.0001). After the adjustment, the doses in PBI patients were significantly reduced in patients with tumors only in outer quadrants (1.12 +/- 0.20 and 2.43 +/- 0.37 Gy, respectively; p = 0.0001). CONCLUSIONS: Tumor control and dose to LAD should be considered during treatment since PBI may reduce the risk of coronary artery disease especially in patients with lateral tumors in the left breast. PMID- 25829934 TI - The incidence of fat necrosis in balloon-based breast brachytherapy. AB - PURPOSE: To investigate the incidence of and potential risk factors for fat necrosis in high dose-rate (HDR) balloon-based breast brachytherapy (BBB). MATERIAL AND METHODS: Fifty-four patients were treated postoperatively with HDR BBB between May 2007 and December 2010. Median age was 71 years (range: 50-88 years). Median tumor size was 1 cm (range: 0.1-2.7 cm). Forty-four had invasive histology; 43% were grade 1, 24% grade 2, and 15% grade 3. The median margin size was 0.7 cm (range: 0.1-1.5 cm). RESULTS: With a median follow-up of 2.9 years (range: 0.5-5.2 years), local control was 98% with one in-breast failure, and overall survival was 89%. Fifty percent of patients experienced fat necrosis. Seven patients were symptomatic, with the remainder detected by mammography alone. Two patients required surgical resection with pathology confirming fat necrosis; 1 required i.v. steroids. At 1, 3, and 5 years following treatment, estimated cumulative incidences of fat necrosis were 7.5%, 52.7%, and 60.6%. Breast laterality, location, tumor size, histology, margin size, balloon volume, skin distance, skin dose, and number of dwell positions were not significantly associated with fat necrosis on univariate analysis. CONCLUSIONS: In this retrospective review of HDR-BBB, we found a 50% incidence of both asymptomatic and symptomatic fat necrosis. Only three patients, however, required intervention. None of the risk factors considered were significantly associated with fat necrosis. Further studies evaluating factors associated with fat necrosis for patients undergoing HDR-BBB are necessary to appropriately assess the risks associated with treatment. PMID- 25829935 TI - High-dose-rate vaginal brachytherapy with chemotherapy for surgically staged localized uterine serous carcinoma. AB - PURPOSE: To evaluate our institutional experience combining carboplatin paclitaxel (C/T) chemotherapy with high-dose-rate (HDR) intra-vaginal brachytherapy (IVB) following comprehensive surgical staging in localized uterine serous carcinoma (USC). MATERIAL AND METHODS: Institutional chart review identified 56 patients with FIGO 2009 stage I-II USC treated between 2000-2010. Patients underwent total hysterectomy, bilateral salpingo-oopherectomy, and comprehensive surgical staging including pelvic and para-aortic lymph node dissection, omentectomy, and peritoneal cytology. Chemotherapy was 6 cycles of C/T, and the IVB dose was 14 Gy in 2 fractions, prescribed to 0.5 cm from the cylinder surface. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS) and overall survival (OS). RESULTS: The median follow-up time was 49 months (range: 9-145). The 5-yr RFS and OS were 85% and 93%, respectively. In all cases of recurrence (n = 8), the first site of failure was extra-pelvic. There were no isolated vaginal recurrences, however, there was one vaginal apex recurrence recorded at 19 months in a patient with simultaneous lung metastases. Thus, the 2-year vaginal RFS was 98%. CONCLUSIONS: Excellent vaginal/pelvic control rates were observed. Further study of HDR brachytherapy dose and fractionation in combination with chemotherapy is worthwhile. PMID- 25829937 TI - A novel intracavitary applicator design for the treatment of deep vaginal fornices: preliminary dose metrics and geometric analysis. AB - PURPOSE: To investigate the dose distributions associated with a novel balloon sleeve placed over a standard cylinder applicator. MATERIAL AND METHODS: A computed tomography (CT) scan of a sleeve balloon shaped to inflate into the vaginal fornices was used to digitize 1-, 3-, and 5-catheter configurations. Point doses for rectum, apex, and fornix were calculated and compared to the values associated with a standard cylinder plan not targeting the vaginal fornices. Inflation of the sleeve balloon in the vaginal fornices and dose coverage with constraints to the rectum, bladder, and sigmoid D2cc were evaluated. RESULTS: Rectum, apex, and fornix doses were respectively 76%, 119%, and 44% for a standard cylinder; 190%, 310%, and 93% for a 1-catheter configuration; 98%, 109%, and 109% for a 3-catheter configuration; and 91%, 107%, and 96% for the 5-catheter configuration. In a patient analysis, expansion of the sleeve balloon into the vaginal fornices was confirmed. The 5-catheter configurations were associated with best coverage of the fornices and acceptable doses to rectum, bladder, and sigmoid. CONCLUSIONS: A 1-catheter configuration cannot be used clinically due to high rectal and apex dose. In theoretical analysis, the 3- and 5-catheter configurations showed > 96% coverage to the vaginal fornices with a clinically acceptable rectal dose. In a treatment simulation in a patient, a 5-catheter configuration showed 90% coverage of the fornices with acceptable doses to the organs at risk. The treatment of deep vaginal fornices results in an increased rectal dose compared to a standard cylinder plan. PMID- 25829936 TI - Uterine perforation and its dosimetric implications in cervical cancer high-dose rate brachytherapy. AB - PURPOSE: To retrospectively assess the incidence of sub-serosal and uterine perforation of intra-uterine tandem in intracavitary high-dose-rate (HDR) brachytherapy for cervical cancer, and to evaluate its dosimetric implications on computed tomography (CT)-based treatment planning. MATERIAL AND METHODS: Computed tomography images and brachytherapy plans of cervical cancer patients treated from February 2006 to December 2012 were reviewed for sub-optimal implants (sub serosal and uterine perforation), and their correlation with cancer FIGO stage and patients' age. For each patient, the plans showing sub-optimal insertion of intra-uterine tandem were analyzed and compared to plans with adequate insertion. The difference in dose coverage of clinical-target-volume (CTV) and variation of the dose delivered to organs-at-risk (OARs) rectum and bladder were evaluated. RESULTS: A total of 231 brachytherapy plans for 82 patients were reviewed. We identified 12 (14.6%) patients and 14 (6%) applications with uterine perforation, and 12 (14.6%) patients and 20 (8.6%) applications with sub-serosal insertion of tandem. Data analysis showed that advanced stage correlates with higher incidence of sub-optimal implants (p = 0.005) but not the age (p = 0.18). Dose-volume histograms (DVHs) analysis showed large variations for CTV dose coverage: D90 significantly decreased with average of -115.7% +/- 134.9% for uterine perforation and -65.2% +/- 82.8% for sub-serosal insertion (p = 0.025). The rectum and bladder dose assessed by D2cc increased up to 70.3% and 43.8%, respectively, when sub-optimal insertion of uterine tandem occurred. CONCLUSIONS: We report a low incidence of uterine perforation and sub-serosal insertion of uterine tandem in intracavitary HDR brachytherapy for cervical cancer. However, the effects on treatment plan dosimetry can be considerably detrimental. Therefore, we recommend image-guided insertion, at least for the challenging cases. PMID- 25829938 TI - Multi-axis dose accumulation of noninvasive image-guided breast brachytherapy through biomechanical modeling of tissue deformation using the finite element method. AB - PURPOSE: Noninvasive image-guided breast brachytherapy delivers conformal HDR (192)Ir brachytherapy treatments with the breast compressed, and treated in the cranial-caudal and medial-lateral directions. This technique subjects breast tissue to extreme deformations not observed for other disease sites. Given that, commercially-available software for deformable image registration cannot accurately co-register image sets obtained in these two states, a finite element analysis based on a biomechanical model was developed to deform dose distributions for each compression circumstance for dose summation. MATERIAL AND METHODS: The model assumed the breast was under planar stress with values of 30 kPa for Young's modulus and 0.3 for Poisson's ratio. Dose distributions from round and skin-dose optimized applicators in cranial-caudal and medial-lateral compressions were deformed using 0.1 cm planar resolution. Dose distributions, skin doses, and dose-volume histograms were generated. Results were examined as a function of breast thickness, applicator size, target size, and offset distance from the center. RESULTS: Over the range of examined thicknesses, target size increased several millimeters as compression thickness decreased. This trend increased with increasing offset distances. Applicator size minimally affected target coverage, until applicator size was less than the compressed target size. In all cases, with an applicator larger or equal to the compressed target size, > 90% of the target covered by > 90% of the prescription dose. In all cases, dose coverage became less uniform as offset distance increased and average dose increased. This effect was more pronounced for smaller target-applicator combinations. CONCLUSIONS: The model exhibited skin dose trends that matched MC generated benchmarking results within 2% and clinical observations over a similar range of breast thicknesses and target sizes. The model provided quantitative insight on dosimetric treatment variables over a range of clinical circumstances. These findings highlight the need for careful target localization and accurate identification of compression thickness and target offset. PMID- 25829939 TI - Thromboembolic events following brachytherapy: case reports. AB - Pulsed-dose-rate (PDR) brachytherapy is a recent brachytherapy modality combining the radiobiological advantages of low-dose-rate (LDR) brachytherapy with increased possibilities of dose optimization and radiation safety. However, treatment duration remains protracted, as the prescribed dose is typically delivered through pulses that do not exceed 0.5 Gy/h for critical organs. It is frequently used for the treatment of gynaecological malignancies. Although, the relationship between thrombosis and cancer is well known, specific data on thromboembolic events during brachytherapy are scarce. We report two cases of major thromboembolic events during brachytherapy treatment for gynaecological malignancies. We discuss the possible causal relationship between brachytherapy procedures and the occurrence of thromboembolic events, drawing a preventive practical attitude. PMID- 25829940 TI - A case report of ultrasound-guided interstitial brachytherapy for abdominal wall metastases of ovarian cancer. AB - PURPOSE: To report the treatment effect of interstitial brachytherapy for abdominal wall metastases of ovarian cancer. MATERIAL AND METHODS: The patient is a 44-year-old female with a diagnosis of stage IA ovarian cancer. After surgery and two cycles of chemotherapy with paclitaxel and carboplatin, the patient noticed dull pain in the lower abdomen and found a mass located in the subcutaneous tissue, below the operative incision. A diagnostic biopsy showed abdominal wall metastases. After external radiotherapy with a dose of 39.6 Gy in 22 fractions, the residual tumor was treated with interstitial brachytherapy under ultrasound guidance. The brachytherapy dose was 18 Gy in 6 fractions of 3 Gy each. RESULTS: After 3 weeks of brachytherapy, the tumor had disappeared completely. Interstitial brachytherapy was feasible. CONCLUSIONS: Interstitial brachytherapy may be a proposed treatment strategy for inoperable superficial metastases, especially for low radiosensitivity cancer. PMID- 25829941 TI - University Cooperation Platform (UCP) between Christian-Albrechts-University Kiel (Germany) and Chiang Mai University (Thailand): implementation of image-guided gynecological brachytherapy. AB - Starting in 1999, the University Cooperation Platform (UCP) implemented an exchange program of researchers and clinicians/physicists between the Christian Albrechts-University Kiel in Germany and Chiang Mai University in Thailand, to initiate a sustainable base for long-term development of image-guided brachytherapy and in general for high-technology radiotherapy in Chiang Mai. A series of UCP protocols, based constructively on each other, were performed and evaluated at intermediate term follow-up. The first protocol, addressing computed tomography (CT)-optimized brachytherapy for advanced cervical cancer (n = 17), showed a significant reduction of D2cc for the bladder and sigmoid (p < 0.001) while maintaining a very high dose in D90 high-risk clinical target volume (HR CTV) in comparison with standard point-based planning. In addition, after a follow-up of 19 months no tumor relapse was observed. The second UCP protocol, testing the impact of magnetic resonance imaging (MRI) guidance (n = 15) in patients with cervical cancer, proved significantly smaller D2cc doses for the bladder, rectum, and sigmoid (p = 0.003, p = 0.015, and p = 0.012), and secured highly curative mean doses in D90 HR-CTV of 99.2 Gy. The acute and late toxicity was excellent without any observed grade 3 or higher morbidity. In the third protocol, the combination of image-guided brachytherapy (IGBT) and whole pelvis intensity-modulated external beam radiotherapy (WP-IMRT) (n = 15) reaffirmed the significant reduction of D2cc doses for the bladder, rectum, and sigmoid (p = 0.001 or p < 0.001) along with high equivalent dose at 2 Gy (EQD2) in the HR-CTV, and demonstrated very low acute therapy-related toxicity in absence of grade 3 morbidity. The implementation of transabdominal ultrasound (TAUS) was the focus of the fourth UCP project aiming a more generous potential use of image-guidance on long-term, and enhancing the quality of soft tissue assessment complementary to conventionally planned gynecological brachytherapy. Analyses in 29 patients revealed significantly reduced OARs doses in bladder with a total EQD2 > 80 Gy for bladder in only 17.2% versus 62.1% in conventional planning, and in rectum EQD2 > 75 Gy in 44.8% versus 79.3%, respectively. In conclusion, analyses revealed excellent results for the high-dose-rate IGBT in patients with advanced gynecological cancer both by using CT and MRI, and/or the combination with WP IMRT. They also define MRI as gold standard for soft tissue assessment and to determine more accurately HR-CTV. The use of TAUS-guidance adds quality aspects to the "classical" conventional X-ray based planning, especially in terms of real time measures and adequate soft tissue information, and may lower significantly the dose in OARs. The review of all UCP-results reconfirms the importance of the established program that will continue to operate with subsequent projects. PMID- 25829942 TI - Multi-capillary column-ion mobility spectrometry (MCC-IMS) as a new method for the quantification of occupational exposure to sevoflurane in anaesthesia workplaces: an observational feasibility study. AB - BACKGROUND: Occupational exposure to sevoflurane has the potential to cause health damage in hospital personnel. Workplace contamination with the substance mostly is assessed by using photoacoustic infrared spectrometry with detection limits of 10 ppbv. Multi-capillary column-ion mobility spectrometry (MCC-IMS) could be an alternative technology for the quantification of sevoflurane in the room air and could be even more accurate because of potentially lower detection limits. The aim of this study was to test the hypothesis that MCC-IMS is able to detect and monitor very low concentrations of sevoflurane (<10 ppbv) and to evaluate the exposure of hospital personnel to sevoflurane during paediatric anaesthesia and in the post anaesthesia care unit (PACU). METHODS: A MCC-IMS device was calibrated to several concentrations of sevoflurane and limits of detection (LOD) and quantification (LOQ) were calculated. Sevoflurane exposure of hospital personnel was measured at two anaesthesia workplaces and time-weighted average (TWA) values were calculated. RESULTS: The LOD was 0.0068 ppbv and the LOQ was 0.0189 ppbv. During paediatric anaesthesia the mean sevoflurane concentration was 46.9 ppbv (8.0 - 314.7 ppbv) with TWA values between 5.8 and 45.7 ppbv. In the PACU the mean sevoflurane concentration was 27.9 ppbv (8.0 - 170.2 ppbv) and TWA values reached from 8.3 to 45.1 ppbv. CONCLUSIONS: MCC-IMS shows a significantly lower LOD and LOQ than comparable methods. It is a reliable technology for monitoring sevoflurane concentrations at anaesthesia workplaces and has a particular strength in quantifying low-level contaminations of sevoflurane. The exposure of the personnel working in these areas did not exceed recommended limits and therefore adverse health effects are unlikely. PMID- 25829943 TI - Markets, breastfeeding and trade in mothers' milk. AB - This introduction to a special issue on the economics of breastfeeding draws attention to the lack of economic justice for women. Human milk is being bought and sold. Commodifying and marketing human milk and breastfeeding risk reinforcing social and gender economic inequities. Yet there are potential benefits for breastfeeding, and some of the world's poorest women might profit. How can we improve on the present situation where everyone except the woman who donates her milk benefits? Breastfeeding is a global food production system with unsurpassed capacity to promote children's food security and maternal and child health, but it is side-lined by trade negotiators who seek instead to expand world markets for cow's milk-based formula. Regulators focus on potential risks of feeding donated human milk, rather than on health risks of exposing infants and young children to highly processed bovine milk. Similarly, policymakers aspire to provide universal health care access that may be unaffordable when two thirds of the world's children are not optimally nourished in infancy, resulting in a global double burden of infectious and chronic disease. Universal breastfeeding requires greater commitment of resources, but such investment remains lacking despite the cost effectiveness of breastfeeding protection, support and promotion in and beyond health services. Women invest substantially in breastfeeding but current policy - epitomised by the G20 approach to the 'gender gap' - fails to acknowledge the economic value of this unpaid care work. Economic incentives for mothers to optimally breastfeed are dwarfed by health system and commercial incentives promoting formula feeding and by government fiscal policies which ignore the resulting economic costs. 'The market' fails to protect breastfeeding, because market prices give the wrong signals. An economic approach to the problem of premature weaning from optimal breastfeeding may help prioritise global maternity protection as the foundation for sustainable development of human capital and labour productivity. It would remove fiscal subsidies for breast milk substitutes, tax their sale to recoup health system costs, and penalise their free supply, promotion and distribution. By removing widespread incentives for premature weaning, the resources would be available for the world to invest more in breastfeeding. PMID- 25829944 TI - Research prospects in BioPsychoSocial medicine: new year reflections on the "Cross-Boarder Dialogue" paradigm. PMID- 25829945 TI - Adaptation of Scheffersomyces stipitis to hardwood spent sulfite liquor by evolutionary engineering. AB - BACKGROUND: Hardwood spent sulfite liquor (HSSL) is a by-product of acid sulfite pulping process that is rich in xylose, a monosaccharide that can be fermented to ethanol by Scheffersomyces stipitis. However, HSSL also contains acetic acid and lignosulfonates that are inhibitory compounds of yeast growth. The main objective of this study was the use of an evolutionary engineering strategy to obtain variants of S. stipitis with increased tolerance to HSSL inhibitors while maintaining the ability to ferment xylose to ethanol. RESULTS: A continuous reactor with gradually increasing HSSL concentrations, from 20% to 60% (v/v), was operated for 382 generations. From the final obtained population (POP), a stable clone (C4) was isolated and characterized in 60% undetoxified HSSL. C4 isolate was then compared with both the parental strain (PAR) and POP. Both POP and C4 were able to grow in 60% undetoxified HSSL, with a higher capability to withstand HSSL inhibitors than PAR. Higher substrate uptake rates, 7% higher ethanol efficiency and improved ethanol yield were obtained using C4. CONCLUSION: S. stipitis was successfully adapted to 60% (v/v) undetoxified eucalyptus HSSL. A stable isolate, C4, with an improved performance in undetoxified HSSL compared to PAR was successfully obtained from POP. Owing to its improved tolerance to inhibitors, C4 may represent a major advantage for the production of bioethanol using HSSL as substrate. PMID- 25829946 TI - Cellobiohydrolase and endoglucanase respond differently to surfactants during the hydrolysis of cellulose. AB - BACKGROUND: Non-ionic surfactants such as polyethylene glycol (PEG) can increase the glucose yield obtained from enzymatic saccharification of lignocellulosic substrates. Various explanations behind this effect include the ability of PEG to increase the stability of the cellulases, decrease non-productive cellulase adsorption to the substrate, and increase the desorption of enzymes from the substrate. Here, using lignin-free model substrates, we propose that PEG also alters the solvent properties, for example, water, leading the cellulases to increase hydrolysis yields. RESULTS: The effect of PEG differs for the individual cellulases. During hydrolysis of Avicel and PASC with a processive monocomponent exo-cellulase cellobiohydrolase (CBH) I, the presence of PEG leads to an increase in the final glucose concentration, while PEG caused no change in glucose production with a non-processive endoglucanase (EG). Also, no effect of PEG was seen on the activity of beta-glucosidases. While PEG has a small effect on the thermostability of both cellulases, only the activity of CBH I increases with PEG. Using commercial enzyme mixtures, the hydrolysis yields increased with the addition of PEG. In parallel, we observed that the relaxation time of the hydrolysis liquid phase, as measured by LF-NMR, directly correlated with the final glucose yield. PEG was able to boost the glucose production even in highly concentrated solutions of up to 150 g/L of glucose. CONCLUSIONS: The hydrolysis boosting effect of PEG appears to be specific for CBH I. The mechanism could be due to an increase in the apparent activity of the enzyme on the substrate surface. The addition of PEG increases the relaxation time of the liquid-phase water, which from the data presented points towards a mechanism related to PEG water interactions rather than PEG-protein or PEG-substrate interactions. PMID- 25829947 TI - Human lung myofibroblast TGFbeta1-dependent Smad2/3 signalling is Ca(2+) dependent and regulated by KCa3.1 K(+) channels. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a common and invariably lethal interstitial lung disease with poorly effective therapy. Blockade of the K(+) channel KCa3.1 reduces constitutive alpha-SMA and Smad2/3 nuclear translocation in IPF-derived human lung myofibroblasts (HLMFs), and inhibits several transforming growth factor beta 1 (TGFbeta1)-dependent cell processes. We hypothesized that KCa3.1-dependent cell processes also regulate the TGFbeta1 dependent Smad2/3 signalling pathway in HLMFs. HLMFs obtained from non-fibrotic controls (NFC) and IPF lungs were grown in vitro and examined for alphaSMA expression by immunofluorescence, RT-PCR, and flow cytometry. Two specific and distinct KCa3.1 blockers (TRAM-34 200 nM and ICA-17043 [Senicapoc] 100 nM) were used to determine their effects on TGFbeta1-dependent signalling. Expression of phosphorylated and total Smad2/3 following TGFbeta1 stimulation was determined by Western blot and Smad2/3 nuclear translocation by immunofluorescence. RESULTS: KCa3.1 block attenuated TGFbeta1-dependent Smad2/3 phosphorylation and nuclear translocation, and this was mimicked by lowering the extracellular Ca(2+) concentration. KCa3.1 block also inhibited Smad2/3-dependent gene transcription (alphaSMA, collagen type I), inhibited KCa3.1 mRNA expression, and attenuated TGFbeta1-dependent alphaSMA protein expression. CONCLUSIONS: KCa3.1 activity regulates TGFbeta1-dependent effects in NFC- and IPF-derived primary HLMFs through the regulation of the TGFbeta1/Smad signalling pathway, with promotion of downstream gene transcription and protein expression. KCa3.1 blockers may offer a novel approach to treating IPF. PMID- 25829948 TI - Mining severe drug-drug interaction adverse events using Semantic Web technologies: a case study. AB - BACKGROUND: Drug-drug interactions (DDIs) are a major contributing factor for unexpected adverse drug events (ADEs). However, few of knowledge resources cover the severity information of ADEs that is critical for prioritizing the medical need. The objective of the study is to develop and evaluate a Semantic Web-based approach for mining severe DDI-induced ADEs. METHODS: We utilized a normalized FDA Adverse Event Report System (AERS) dataset and performed a case study of three frequently prescribed cardiovascular drugs: Warfarin, Clopidogrel and Simvastatin. We extracted putative DDI-ADE pairs and their associated outcome codes. We developed a pipeline to filter the associations using ADE datasets from SIDER and PharmGKB. We also performed a signal enrichment using electronic medical records (EMR) data. We leveraged the Common Terminology Criteria for Adverse Event (CTCAE) grading system and classified the DDI-induced ADEs into the CTCAE in the Web Ontology Language (OWL). RESULTS: We identified 601 DDI-ADE pairs for the three drugs using the filtering pipeline, of which 61 pairs are in Grade 5, 56 pairs in Grade 4 and 484 pairs in Grade 3. Among 601 pairs, the signals of 59 DDI-ADE pairs were identified from the EMR data. CONCLUSIONS: The approach developed could be generalized to detect the signals of putative severe ADEs induced by DDIs in other drug domains and would be useful for supporting translational and pharmacovigilance study of severe ADEs. PMID- 25829949 TI - Sites of disease as predictors of outcome in metastatic renal cell carcinoma patients treated with first-line sunitinib or sorafenib. AB - BACKGROUND: This study investigated whether the effectiveness of first-line tyrosine-kinase inhibitors was associated with sites of disease in patients with metastatic renal cell carcinoma (mRCC). METHODS: A retrospective cohort of consecutive mRCC patients receiving first-line sorafenib (SO) or sunitinib (SU) was analyzed. RESULTS: In total, 203 patients received SO and 99 SU. In patients with liver metastasis, SU was associated with a 18% higher risk of time-to treatment failure (TTF), and a 39% higher risk of death than SO: conversely, patients without liver metastases who received SU showed a 46% decreased risk of TTF and 62% decreased risk of death. CONCLUSIONS: mRCC patients with liver metastases treated with first-line SO showed a better outcome compared with SU, while mRCC patients without liver metastases treated with first-line SU showed a better outcome compared with SO. PMID- 25829950 TI - A report of a regional service for post-prostatectomy urinary incontinence: a model for best practice? AB - INTRODUCTION: Post-prostatectomy incontinence (PPI) is a potentially highly significant complication of a common urological procedure. Pathophysiology may be multifactorial but most commonly involves urinary sphincter weakness. The gold standard treatment for severe incontinence is artificial urinary sphincter but multiple alternatives exist. The growing incidence of PPI has led to the development of a specialized regional service dedicated to management. PATIENTS AND METHODS: In 2004 a regional referral protocol for PPI was established with a dedicated clinic at a single centre for assessment and management including videourodynamics, pelvic floor rehabilitation, biofeedback and a consultant with a specialist interest in PPI surgery. Data regarding all in-house and tertiary referrals to this clinic between 2004 and 2011 were analysed with patients categorized by symptom severity. RESULTS: A total of 267 patients were referred to the post-prostatectomy service (mean age 66.6, range 49-83 years) with numbers increasing year on year. Two-thirds of these were tertiary referrals: 27.7% of referrals were for mild symptoms, 35.2% moderate and 33.3% severe. One-third of referrals were made within 2 years of the primary procedure. Just over half of referred patients underwent invasive treatment including 24.3 artificial sphincter (24.3%) and male slings (22.8%). 7.5% patients were managed with medication, 14.6% were managed conservatively with containment therapy only. One fifth remain under assessment or have deferred treatment. CONCLUSION: PPI is of increasing personal and societal impact which should be identified early and supported. Investigation and management can be standardized and intervention at a high volume centre achieved by early specialist referral. PMID- 25829951 TI - The double urethra: revisiting the surgical classification. AB - AIM: The aim of this article was to describe our experience with 14 patients with double urethra. PATIENTS AND METHODS: We retrospectively examined the patients' records including their clinical presentations, investigations, operative findings, and outcome. In addition to Effmann's classification, we used a newly proposed classification that depends on the orientation of the double urethral channels. RESULTS: During the last 15 years, 18 patients were diagnosed to have double urethra at our pediatric surgical unit. We excluded four patients with 'Y type' urethral duplication. The remaining 14 patients were divided into either sagittal or collateral duplication. Their age at presentation ranged from the neonatal period to 9 years. The sagittal urethral duplication included 12 male patients. All patients had two urethral channels, one above the other. The dorsal urethral channel was always characterized by poor function and ectopic course. The ventral channel was always the more functioning urethra, with a normal course from the urinary bladder to end either at an orthotopic meatus (subgroup A), or more proximally in a hypospadiac location (subgroup B). The collateral urethral duplication included two patients. Both patients were associated with duplication of the urinary bladder and the external genitalia as a part of caudal duplication syndrome. In this group, both urethrae had comparable function, lying side by side, and each draining a separate urinary bladder. CONCLUSION: The double urethra is a diverse spectrum comprising different pathologies. Our proposed classification system of duplicated urethras is clinically relevant as it guides surgical management and allows prognostication of outcome. PMID- 25829952 TI - Management of idiopathic retroperitoneal fibrosis from the urologist's perspective. AB - INTRODUCTION: Idiopathic retroperitoneal fibrosis (IRF) is a rare disease characterized by a fibrotic reaction that affects retroperitoneal organs, especially the urinary tract. In this review we analyze the current imaging techniques, morphological characteristics, clinical aspects and therapeutic aspects of idiopathic retroperitoneal disease. METHODS: A PubMed search was conducted in December 2013 to find original articles, bibliographic reviews and series reports published in the past 15 years on idiopathic retroperitoneal fibrosis, its management and outcomes by combining terms like retroperitoneal fibrosis, periaortitis, treatment and autoimmune. A total of 89 articles were included in this review that referred strictly to IRF. We analyzed the imaging tools used for diagnostic and the decision making protocol used by physicians in the management of IRF. RESULTS: A computerized tomography (CT) scan represents the most commonly used imaging technique for diagnosis. Magnetic resonance imaging (MRI) is unable to differentiate more accurately between benign and malignant retroperitoneal fibrosis (RF) than a CT scan. Biopsy remains the most reliable diagnostic tool for IRF. However, the histological characteristics of IRF are not yet well-defined and the protocol for biopsy is not standardized in terms of template, number of biopsies and the immunohistochemical panel needed for positive diagnosis. The most common treatment reported is corticosteroid therapy alone or in combination with other immunosuppressants, whereas surgical treatment is reserved for severe cases. Indwelling ureteric stents represent the most common procedure for renal drainage, but their efficacy is questionable. Open ureterolysis remains the gold standard for surgical treatment, but its purpose is only to resolve the ureteric obstruction, not to treat the retroperitoneal fibrosis. Laparoscopic and robotic approaches have been reported to be feasible, but no prospective, comparative trials have been performed due to the rarity of the disease. Surgical technique is not standardized and the outcome of the treatment only evaluates the recovery of the renal function. CONCLUSIONS: The imaging procedures available today are unable to accurately differentiate between idiopathic and malignant RF. A biopsy is mandatory to confirm the diagnosis, but there is no consensus regarding the template, timing and number of biopsies needed to exclude malignancy. Open ureterolysis represents the main surgical treatment for cases with severe IRF, and laparoscopic or robotic approach may be an option in selected cases. The recovery of the renal function is a surrogate for evaluating the success of the treatment. More clinical studies are needed in order standardize the protocol for diagnostic, treatment and follow up after medical or surgical management. PMID- 25829953 TI - Association of Intact dupA (dupA1) rather than dupA1 cluster with duodenal ulcer in Indian population. AB - BACKGROUND: The duodenal ulcer promoting gene (dupA) and dupA cluster in Helicobacter pylori have been described as a risk factor for duodenal ulcer development in some populations. Polymorphic gene dupA can be divided into two groups, intact dupA1 (long or short type based on the presence or absence of 615 bp extra sequences at the 5' region) having complete reading frame and other truncated dupA2 having frame-shift mutation. This study was aimed to elucidate the role of dupA of H. pylori and their clusters in the disease manifestation of Indian population. METHODS: A total of 170 H. pylori strains were screened for the presence of dupA, dupA alleles and dupA cluster by PCR and sequencing. Pro inflammatory cytokine (IL-8) with different dupA variant H. pylori stimulated gastric epithelial cells (AGS cells) was measured by ELISA. RESULTS: A total of 50 strains (29.4%) were positive for dupA among the tested 170 strains. The prevalence of dupA1 in duodenal ulcer (DU) and non-ulcer dyspepsia (NUD) populations was found to be 25.5% (25/98) and 11.1% (8/72), respectively and 16.4% (28/170) of the tested strains had dupA1, cagA and vacAs1m1 positive. The distribution of long and short type dupA1 has not been significantly associated with the disease outcome. The dupA cluster analysis showed that 10.2% (10/98) and 8.3% (6/72) strains were positive among DU and NUD, respectively. IL-8 production was significantly higher in dupA1(+) , cagA (+), vacA (+) (902.5 +/- 79.01 pg/mL) than dupA2 (+) , cagA (+) , vacA (+) (536.0 +/- 100.4 pg/mL, P = 0.008) and dupA (-), cagA (+), vacA (+) (549.7 +/- 104.1 pg/mL, P = 0.009). Phylogenetic analysis of dupA indicated that the Indian H. pylori strains clustered with East Asian strains but distinct from Western strains. This is the first known genetic element of Indian H. pylori that is genetically closer to the East Asian strains but differed from the Western strains. CONCLUSIONS: The intact dupA1 was significantly associated with DU than NUD (P = 0.029) but the dupA1 cluster has no role in the disease manifestation at India (P = 0.79). Thus, dupA1 can be considered as a biomarker for DU patients in India. PMID- 25829954 TI - Therapeutic effects of prolotherapy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. AB - OBJECTIVES: Prolotherapy is an injection-based complementary treatment, which has shown promising results in the treatment of different musculoskeletal disorders. The aim of this study was to determine the therapeutic efficacy of dextrose prolotherapy on pain, range of motion, and function in patients with knee osteoarthritis (OA). METHODS: In this single-arm prospective study, participants with symptomatic moderate knee osteoarthritis underwent prolotherapy with intra articular injection of 20% dextrose water at baseline, and at 4 weeks and 8 weeks later. Patients were followed for 24 weeks. Pain severity at rest and activity, according to the visual analog scale (VAS), articular range of motion (ROM), and Western Ontario and McMaster Universities arthritis index (WOMAC) scores were measured at baseline, 4, 8, and 24 weeks later. RESULTS: A total of 24 female patients (average age: 58.37 +/- 11.8 years old) received 3-monthly injection therapies. Before the treatment, the mean articular range of motion was 105.41 +/ 11.22 degrees . Mean VAS scale at rest and activity was 8.83 +/- 1.37 and 9.37 +/- 1.31, respectively. At the end of week 24, knee ROM increased by 8 degrees . Pain severity in rest and activity decreased to 4.87 +/- 1.39, 45.86%, and 44.23%, respectively (p < 0.001). Total WOMAC score and its subcategories showed a continuous improvement trend in all the evaluation sessions, so that at the end of the study, the total score decreased by 30.5 +/- 14.27 points (49.58%) (p < 0.001). Improvements of all parameters were considerable until week 8, and were maintained throughout the study period. CONCLUSIONS: Prolotherapy with three intra-articular injections of hypertonic dextrose given 4 weeks apart for selected patients with knee OA, resulted in significant improvement of validated pain, ROM, and WOMAC-based function scores, when baseline levels were compared at 24 weeks. Further studies with randomized controlled trials involving a comparison group are suggested to confirm these findings. PMID- 25829956 TI - Distal biceps reconstruction 13 years post-injury. AB - Distal biceps tendon ruptures are relatively rare injuries most commonly caused by an eccentric contraction of the biceps brachii. The majority of complete ruptures receive early surgical intervention, however, some patients do present in a delayed fashion. There are many surgical options at this time for acute and chronic injuries, and this case report describes an Achilles allograft reconstruction in a male who sustained a complete tear 13 years prior to presentation. At 12-month follow up, he had regained full function of his dominant extremity as evidence by returning to work with no limitations and by a Disabilities of the Arm, Shoulder, and Hand (DASH) score of zero. We are unaware of a successfully surgically reconstructed distal biceps tendon of this chronicity. As the literature on this subject is sparse, this case report gives credence to the idea that certain patients with a chronic distal biceps rupture should be considered for operative reconstruction and not relegated to continued failed conservative treatment. Discussed are the surgical treatment options and controversies for chronic distal biceps ruptures, and we review various outcome studies using different surgical techniques. PMID- 25829955 TI - Diagnosis and therapeutic options for peripheral vasculitic neuropathy. AB - Vasculitis can affect the peripheral nervous system alone (nonsystemic vasculitic neuropathy) or can be a part of primary or secondary systemic vasculitis. In cases of pre-existing systemic vasculitis, the diagnosis can easily be made, whereas suspected vasculitic neuropathy as initial or only manifestation of vasculitis requires careful clinical, neurophysiological, laboratory and histopathological workout. The typical clinical syndrome is mononeuropathia multiplex or asymmetric neuropathy, but distal-symmetric neuropathy can frequently be seen. Standard treatments include steroids, azathioprine, methotrexate and cyclophosphamide. More recently the B-cell antibody rituximab and intravenous immunoglobulins have shown to be effective in some vasculitic neuropathy types. PMID- 25829957 TI - Cardiopulmonary exercise testing in the assessment of exertional dyspnea. AB - Dyspnea on exertion is a commonly encountered problem in clinical practice. It is usually investigated by resting tests such as pulmonary function tests and echocardiogram, which may at times can be non-diagnostic. Cardiopulmonary exercise testing (CPET) measures physiologic parameters during exercise which can enable accurate identification of the cause of dyspnea. Though CPET has been around for decades and provides valuable and pertinent physiologic information on the integrated cardiopulmonary responses to exercise, it remains underutilized. The objective of this review is to provide a comprehensible overview of the underlying principles of exercise physiology, indications and contraindications of CPET, methodology and interpretative strategies involved and thereby increase the understanding of the insights that can be gained from the use of CPET. PMID- 25829958 TI - Lights and shadows of non-invasive mechanical ventilation for chronic obstructive pulmonary disease (COPD) exacerbations. AB - Despite the overwhelming evidence justifying the use of non-invasive ventilation (NIV) for providing ventilatory support in chronic obstructive pulmonary disease (COPD) exacerbations, recent studies demonstrated that its application in real life settings remains suboptimal. European clinical audits have shown that 1) NIV is not invariably available, 2) its availability depends on countries and hospital sizes, and 3) numerous centers declare their inability to provide NIV to all of the eligible patients presenting throughout the year. Even with an established indication, the use of NIV in acute respiratory failure due to COPD exacerbations faces important challenges. First, the location and personnel using NIV should be carefully selected. Second, the use of NIV is not straightforward despite the availability of technologically advanced ventilators. Third, NIV therapy of critically ill patients requires a thorough knowledge of both respiratory physiology and existing ventilatory devices. Accordingly, an optimal team-training experience, the careful selection of patients, and special attention to the selection of devices are critical for optimizing NIV outcomes. Additionally, when applied, NIV should be closely monitored, and endotracheal intubation should be promptly available in the case of failure. Another topic that merits careful consideration is the use of NIV in the elderly. This patient population is particularly fragile, with several physiological and social characteristics requiring specific attention in relation to NIV. Several other novel indications should also be critically examined, including the use of NIV during fiberoptic bronchoscopy or transesophageal echocardiography, as well as in interventional cardiology and pulmonology. The present narrative review aims to provide updated information on the use of NIV in acute settings to improve the clinical outcomes of patients hospitalized for COPD exacerbations. PMID- 25829959 TI - The association between glucose levels and hospital outcomes in patients with acute exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Corticosteroids used for chronic obstructive pulmonary disease (COPD) exacerbations can cause hyperglycemia in hospitalized patients, and hyperglycemia may be associated with increased mortality, length of stay (LOS), and re admissions in these patients. MATERIALS AND METHODS: We did three retrospective studies using charts from July 2008 through June 2009, January 2006 through December 2010, and October 2010 through March 2011. We collected demographic and clinical information, laboratory results, radiographic results, and information on LOS, mortality, and re-admission. RESULTS: Glucose levels did not predict outcomes in any of the studied cohorts, after adjustment for covariates in multivariable analysis. The first database included 30 patients admitted to non intensive care unit (ICU) hospital beds. Six of 20 non-diabetic patients had peak glucoses above 200 mg/dl. Nine of the ten diabetic patients had peak glucoses above 200 mg/dl. The maximum daily corticosteroid dose had no apparent effect on the glucose levels. The second database included 217 patients admitted to ICUs. The initial blood glucose was higher in patients who died than those who survived using bivariate analysis (P = 0.015; odds ratio, OR, 1.01) but not in multivariable analysis. Multivariable logistic regression analysis also demonstrated that glucose levels did not affect LOS. The third database analyzing COPD re-admission rates included 81 patients; the peak glucose levels were not associated with re-admission. CONCLUSIONS: Our data demonstrate that COPD patients treated with corticosteroids developed significant hyperglycemia, but the increase in blood glucose levels did not correlate with the maximum dose of corticosteroids. Blood glucose levels were not associated with mortality, LOS, or re-admission rates. PMID- 25829960 TI - Factors associated with poor asthma control in the outpatient clinic setting. AB - BACKGROUND/OBJECTIVES: The goal of the study was to assess asthma control using asthma control test (ACT) and to explore the factors that effects asthma control among participants with bronchial asthma in the outpatient clinic setting. METHODS: This cross-sectional descriptive study was conducted in the outpatient primary care clinic at King Abdulaziz Medical City in Riyadh. Adult patients who were diagnosed with bronchial asthma by their primary treating physician were recruited over a 6-month period. Patients completed the ACT and questionnaires, which identified factors that affect asthma control. RESULTS: Four hundred asthmatic patients (n = 400) were enrolled, and 70% of these patients were women. Fifty-four percent of patients inappropriately used the inhaler device. The estimated prevalence of uncontrolled asthma at the time of the study was 39.8%. Inappropriate device use by the patient was more frequently associated with uncontrolled asthma (P-value = 0.001). Active smoking (P-value = 0.007), passive smoking (P-value = 0.019), unsealed mattress (P-value = 0.030), and workplace triggers (P-value = 0.036) were also associated with uncontrolled asthma. However, the extent of asthma control did not appear to be related to the existence of regular follow-ups, bedroom carpets, outpatient clinic visits, age, body mass index (BMI), or duration of asthma. CONCLUSIONS: The present study identified a high prevalence of uncontrolled asthma in the primary outpatient clinic setting and common risk factors that may contribute to poor asthma control. PMID- 25829961 TI - Chronic obstructive pulmonary disease severity is associated with severe pneumonia. AB - CONTEXT: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder, and various aspects of COPD may be associated with the severity of pneumonia in such patients. AIMS: We examined the risk factors associated with severe pneumonia in a COPD population. MATERIALS AND METHODS: We performed a retrospective observational study using a prospectively collected database of pneumonia patients who were admitted to our hospital through emergency department between 2008 and 2012. Patients with hospital-acquired pneumonia and those with an immunocompromised status were excluded. RESULTS: Of 148 pneumonia patients with COPD for whom chest computed tomography (CT) scans were available, 106 (71.6%) and 42 (28.4%) were classified as non-severe and severe pneumonia, respectively. Multivariate logistic regression analysis revealed that the severity of airflow limitation [odds ratio (OR), 2.751; 95% confidence interval (CI), 1.074-7.050; P = 0.035] and the presence of emphysema on a chest CT scan (OR, 3.366; 95% CI, 1.104-10.265; P = 0.033) were independently associated with severe pneumonia in patients with COPD. CONCLUSIONS: The severity of COPD including the airflow limitation grade and the presence of pulmonary emphysema were independently associated with the development of severe pneumonia. PMID- 25829962 TI - Reliability and validity of an arabic version of the dyspnea-12 questionnaire for Saudi nationals with chronic obstructive pulmonary disease. AB - BACKGROUND: Dyspnea is a distressing symptom experienced by people with chronic obstructive pulmonary disease (COPD). The dyspnea-12 (D-12) questionnaire comprises of 12 items and assesses the quality of this symptom, its severity and the emotional response. The original (English) version of the D-12 is reliable and valid for the measurement of dyspnea in pulmonary diseases. AIM: To translate the D-12 into Arabic and determine whether this version is reliable and valid in Saudi nationals with COPD. METHODS: The D-12 was translated into Arabic version and reviewed by an expert panel before being back-translated into English. The Arabic version was administered to five patients with COPD to test whether it was easily understood after which a final Arabic version was produced. Thereafter, 40 patients with COPD (aged 63 ? 9 years; 33 [82.5%] males; forced expiratory volume in one second (FEV 1) 47 ? 16% predicted) completed the D-12, the COPD Assessment Test (CAT) and the Chronic Respiratory Disease Questionnaire (CRDQ). Lung function and 6-minute walk distance were also measured. The D-12 was re administered two weeks later. RESULTS: The Arabic version of the D-12 demonstrated good reliability over the two administration (intraclass correlation coefficient = 0.94, P = 0.01). Strong associations were demonstrated between the (1) total score for the D-12 and the CAT, (2) quality sub-score of the D-12 and the CAT and (3) emotional response sub-score of the D-12 and emotional function domain of the CRDQ (r >= 0.6, all P < 0.01). CONCLUSION: The Arabic version of the D-12 is a reliable and valid instrument in Saudi nationals with COPD. PMID- 25829963 TI - Excessive dynamic airway collapse in a small cohort of chronic obstructive pulmonary disease patients. AB - INTRODUCTION: The prevalence of EDAC (Excessive Dynamic Airway Collapse) has not been studied specifically in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: The aim of this study was to investigate the prevalence of EDAC in COPD and to determine whether there are clinical factors or functional variables that could influence the degree of expiratory collapse of central airways. METHODS: Prospective observational study of a group of patients with COPD. The degree of tracheobronchial collapse was evaluated by low-dose dynamic airway computed tomography (CT). We recorded clinical and pulmonary function tests data, quality of life and BODE index. RESULTS: This study included 53 patients with COPD, 46 (87%) males, mean age 65 (SD, 9) years. CONCLUSIONS: The prevalence of EDAC observed in a sample of patients with different levels of COPD severity is low. The degree of dynamic central airway collapse was not related to the patient's epidemiological or clinical features, and did not affect lung function, symptoms, capacity for effort, or quality of life. PMID- 25829964 TI - Poor asthma education and medication compliance are associated with increased emergency department visits by asthmatic children. AB - BACKGROUND: Acute exacerbations of bronchial asthma remain a major cause of frequent Emergency Department (ED) visits by pediatric patients. However, other factors including psychosocial, behavioural and educational, are also reportedly associated with repetitive ED visits. Therefore, it is necessary to determine whether such visits are justifiable. OBJECTIVE: The objective of this cross sectional study was to identify risk factors associated with visits to ED by asthmatic children. METHODS: Asthmatic children (n = 297) between 1-17 years old were recruited and information collected at the time of visiting an ED facility at two major hospitals. RESULTS: Asthmatic patients visited the ED 3.9 ? 3.2 times-per-year, on average. Inadequately controlled asthma was perceived in 60.3% of patients. The majority of patients (56.4%) reported not receiving education about asthma. Patients reflected misconceptions about the ED department, including the belief that more effective treatments are available (40.9%), or that the ED staff is better qualified (27.8%). About half of patients (48.2%) visited the ED because of the convenience of being open 24 hours, or because they are received immediately (38.4%). Uncontrolled asthma was associated with poor education about asthma and/or medication use. Patients educated about asthma, were less likely to stop corticosteroid therapy when their symptoms get better (OR:0.55; 95% CI:0.3-0.9; P = 0.04). CONCLUSION: This study reports that most patients had poor knowledge about asthma and were using medications improperly, thus suggesting inefficient application of management action plan. Unnecessary and frequent visits to the ED for asthma care was associated with poor education about asthma and medication use. Potential deficiencies of the health system at directing patients to the proper medical facility were uncovered and underline the necessity to improve education about the disease and medication compliance of patients and their parents/guardians. PMID- 25829965 TI - Determinants of functional status among survivors of severe sepsis and septic shock: One-year follow-up. AB - RATIONALE: Sepsis is a leading cause of intensive care unit (ICU) admissions worldwide and a major cause of morbidity and mortality. Limited data exist regarding the outcomes and functional status among survivors of severe sepsis and septic shock. OBJECTIVES: This study aimed to determine the functional status among survivors of severe sepsis and septic shock a year after hospital discharge. METHODS: Adult patients admitted between April 2007 and March 2010 to the medical-surgical ICU of a tertiary hospital in Saudi Arabia, were included in this study. The ICU database was investigated for patients with a diagnosis of severe sepsis or septic shock. Survival status was determined based on hospital discharge. Patients who required re-admission, stayed in ICU for less than 24 hours, had incomplete data were all excluded. Survivors were interviewed through phone calls to determine their functional status one-year post-hospital discharge using Karnofsky performance status scale. RESULTS: A total of 209 patients met the eligibility criteria. We found that 38 (18.1%) patients had severe disability before admission, whereas 109 (52.2%) patients were with severe disability or died one-year post-hospital discharge. Only one-third of the survivors had good functional status one-year post-discharge (no/mild disability). After adjustment of baseline variables, age [adjusted odds ratio (aOR) = 1.03, 95% confidence interval (CI) = 1.01-1.04] and pre-sepsis functional status of severe disability (aOR = 50.9, 95% CI = 6.82-379.3) were found to be independent predictors of functional status of severe disability one-year post-hospital discharge among survivors. CONCLUSIONS: We found that only one-third of the survivors of severe sepsis and septic shock had good functional status one-year post-discharge (no/mild disability). Age and pre-sepsis severe disability were the factors that highly predicted the level of functional status one-year post-hospital discharge. PMID- 25829966 TI - Prognostic value of serum procalcitonin and C-reactive protein levels in critically ill patients who developed ventilator-associated pneumonia. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) is an important cause of mortality and morbidity in critically ill patients. We sought to determine the prognostic value of procalcitonin (PCT) and C-reactive protein (CRP) kinetics in critically ill patients who developed VAP. METHODS: Patients who were admitted to the intensive care unit (ICU) and developed VAP were eligible. Patients were followed for 28 days after the pneumonia diagnosis and blood samples for PCT and CRP were collected on the day of the pneumonia diagnosis (D0), and days 3 (D3) and 7 (D7) after the diagnosis. Patients were grouped as survivors and non survivors, and the mean PCT and CRP values and their kinetics were assessed. RESULTS: In total, 45 patients were enrolled. Of them, 22 (48.8%) died before day 28 after the pneumonia diagnosis. There was no significant difference between the survivor and non-survivor groups in terms of PCT on the day of pneumonia diagnosis or CRP levels at any point. However, the PCT levels days 3 and 7 were significantly higher in the non-survivor group than the survivor group. Whereas PCT levels decreased significantly from D0 to D7 in the survivor group, CRP did not. A PCT level above 1 ng/mL on day 3 was the strongest predictor of mortality, with an odds ratio of 22.6. CONCLUSION: Serum PCT was found to be a superior prognostic marker compared to CRP in terms of predicting mortality in critically ill patients who developed VAP. The PCT level on D3 was the strongest predictor of mortality in VAP. PMID- 25829967 TI - A case of near fatal asthma: The role of ECMO as rescue therapy. AB - We report a case of an adolescent with near fatal asthma (NFA). He presented with severe hypoxemia and lifethreatening acidemia, who failed to respond to conventional therapy. His hospital course was complicated by barotrauma and hemodynamic instability. Early introduction of extracorporeal membrane oxygenation (ECMO) led to dramatic improvement in gas exchange and lung mechanics. This case illustrates the important role of ECMO as salvage therapy in NFA. PMID- 25829968 TI - Clinical description of human bocavirus viremia in children with LRTI, Eastern Province, Saudi Arabia. AB - Human bocavirus (HBoV) is a major etiology of lower respiratory tract infection (LRTI) in young children. We tested 149 patients admitted to King Fahd Hospital of the University with diagnosis of LRTI. Viremia caused by the different studied viruses was detected in 31.5% of the total cases by Real-time Polymerase chain reaction. We report five patients who were positive for HBoV in serum samples. Clinical presentation ranged from mild to severe disease as one of them required admission to intensive care unit. Wheezing was a striking feature in most of our patients, but fever was not a consistent finding. PMID- 25829969 TI - Neural mechanisms of negative reinforcement in children and adolescents with autism spectrum disorders. AB - BACKGROUND: Previous research has found accumulating evidence for atypical reward processing in autism spectrum disorders (ASD), particularly in the context of social rewards. Yet, this line of research has focused largely on positive social reinforcement, while little is known about the processing of negative reinforcement in individuals with ASD. METHODS: The present study examined neural responses to social negative reinforcement (a face displaying negative affect) and non-social negative reinforcement (monetary loss) in children with ASD relative to typically developing children, using functional magnetic resonance imaging (fMRI). RESULTS: We found that children with ASD demonstrated hypoactivation of the right caudate nucleus while anticipating non-social negative reinforcement and hypoactivation of a network of frontostriatal regions (including the nucleus accumbens, caudate nucleus, and putamen) while anticipating social negative reinforcement. In addition, activation of the right caudate nucleus during non-social negative reinforcement was associated with individual differences in social motivation. CONCLUSIONS: These results suggest that atypical responding to negative reinforcement in children with ASD may contribute to social motivational deficits in this population. PMID- 25829970 TI - Premature aging of leukocyte DNA methylation is associated with type 2 diabetes prevalence. AB - BACKGROUND: Type 2 diabetes mellitus (T2D) is highly prevalent in Middle-Eastern and North African Arab populations, but the molecular basis for this susceptibility is unknown. Altered DNA methylation levels were reported in insulin-secreting and responding tissues, but whether methylation in accessible tissues such as peripheral blood is associated with T2D risk remains an open question. Age-related alteration of DNA methylation level was reported in certain methylation sites, but no association with T2D has been shown. Here we report on a population-based study of 929 men and women representing the East Jerusalem Palestinian (EJP) Arab population and compare with the findings among Israeli Ashkenazi Jews. This is the first reported epigenetic study of an Arab population with a characteristic high prevalence of T2D. RESULTS: We found that DNA methylation of a prespecified regulatory site in peripheral blood leukocytes (PBLs) is associated with impaired glucose metabolism and T2D independent of sex, body mass index, and white blood cell composition. This CpG site (Chr16: 53,809,231-2; hg19) is located in a region within an intron of the FTO gene, suspected to serve as a tissue-specific enhancer. The association between PBL hypomethylation and T2D varied by age, revealing differential patterns of methylation aging in healthy and diabetic individuals and between ethnic groups: T2D patients displayed prematurely low methylation levels, and this hypomethylation was greater and occurred earlier in life among Palestinian Arabs than Ashkenazi Jews. CONCLUSIONS: Our study suggests that premature DNA methylation aging is associated with increased risk of T2D. These findings should stimulate the search for more such sites and may pave the way to improved T2D risk prediction within and between human populations. PMID- 25829971 TI - Somatic cancer mutations in the MLL3-SET domain alter the catalytic properties of the enzyme. AB - BACKGROUND: Somatic mutations in epigenetic enzymes are frequently found in cancer tissues. The MLL3 H3K4-specific protein lysine monomethyltransferase is an important epigenetic enzyme, and it is among the most recurrently mutated enzymes in cancers. MLL3 mainly introduces H3K4me1 at enhancers. RESULTS: We investigated the enzymatic properties of MLL3 variants that carry somatic cancer mutations. Asn4848 is located at the cofactor binding sites, and the N4848S exchange renders the enzyme inactive. Tyr4884 is part of an aromatic pocket at the active center of the enzyme, and Y4884C converts MLL3 from a monomethyltransferase with substrate preference for H3K4me0 to a trimethyltransferase with H3K4me1 as preferred substrate. Expression of Y4884C leads to aberrant H3K4me3 formation in cells. CONCLUSIONS: Our data show that different somatic cancer mutations of MLL3 affect the enzyme activity in distinct and opposing manner highlighting the importance of experimentally studying the effects of somatic cancer mutations in key regulatory enzymes in order to develop and apply targeted tumor therapy. PMID- 25829972 TI - Reporting and handling of missing data in predictive research for prevalent undiagnosed type 2 diabetes mellitus: a systematic review. AB - Missing values are common in health research and omitting participants with missing data often leads to loss of statistical power, biased estimates and, consequently, inaccurate inferences. We critically reviewed the challenges posed by missing data in medical research and approaches to address them. To achieve this more efficiently, these issues were analyzed and illustrated through a systematic review on the reporting of missing data and imputation methods (prediction of missing values through relationships within and between variables) undertaken in risk prediction studies of undiagnosed diabetes. Prevalent diabetes risk models were selected based on a recent comprehensive systematic review, supplemented by an updated search of English-language studies published between 1997 and 2014. Reporting of missing data has been limited in studies of prevalent diabetes prediction. Of the 48 articles identified, 62.5% (n = 30) did not report any information on missing data or handling techniques. In 21 (43.8%) studies, researchers opted out of imputation, completing case-wise deletion of participants missing any predictor values. Although imputation methods are encouraged to handle missing data and ensure the accuracy of inferences, this has seldom been the case in studies of diabetes risk prediction. Hence, we elaborated on the various types and patterns of missing data, the limitations of case-wise deletion and state-of the-art methods of imputations and their challenges. This review highlights the inexperience or disregard of investigators of the effect of missing data in risk prediction research. Formal guidelines may enhance the reporting and appropriate handling of missing data in scientific journals. PMID- 25829973 TI - [Severe pneumonia with bronchial involvement complicating varicella in an immunocompetent adult]. PMID- 25829974 TI - [Spinal cord compression due to metastases]. PMID- 25829975 TI - Ovarian tuberculosis masquerading as ovarian cancer in HIV infected patient: a plea to avoid unnecessary surgery. AB - Female patients who present with adnexial mass and weight loss should not be presumed to have ovarian carcinoma until after extensive investigation. This is to avoid the mistake of radical surgery with its attendant morbidity and mortality. An important disease to consider in our environment is ovarian TB that respond well to medication. A 35 year old HIV-1 positive house wife presented with fever, persistent vomiting, progressive weight loss, vague abdominal pain and swelling. Patient occasionally ingest unpasteurized milk since childhood but had no sustained contact with adult with chronic cough. She had no menstrual abnormality. Imaging studies revealed right ovarian mass measuring 11.8 cm x 10 cm. Right ovarian malignancy was highly suspected, for which she underwent exploratory laporotomy. Histopathology result was consistent with tuberculous granuloma. Chest radiograph was normal. Her CD4 count was 541 cells/ul. Patient was commenced on anti tuberculotic therapy based on the Nigerian National TB control and she responded well. Tuberculosis of the ovary can masquerade as ovarian cancer, especially among HIV patients in regions where TB-HIV co infections is endemic, it should be ruled out before performing extended surgery. PMID- 25829976 TI - [Diagnostic and therapeutic management of lymph node tuberculosis in Tunisia]. PMID- 25829977 TI - [Place of double arthrodesis in the management of irreducible talipes equinovarus]. PMID- 25829978 TI - Spontaneous subdural hematoma associated with preeclampsia: a case report and litterature review. AB - A patient with pre-eclampsia at 31 weeks' gestation developed neurologic signs. Computerized tomography revealed a large cranial subdural hematoma. This diagnostic should be considered in any pre-eclamptic patient demonstrating neurological symptoms and must be treated effectively because of the poor maternel and fetal prognosis. Our patient was succesfully treated. PMID- 25829979 TI - Vitamin D, allergies and asthma: focus on pediatric patients. AB - In recent years, the interest of the scientific world towards vitamin D gradually increased, and several studies have been conducted to dissect its possible role in modulating the development/course of allergic diseases. Also, Vitamin D supplementation has been assessed as a beneficial approach for treating allergies in some, but not all studies. We reviewed herein the available and relevant literature concerning the possible links between Vitamin D, its supplementation and allergic diseases. A literature search was made independently by the Authors, identifying articles for a narrative review. As per literature, Vitamin D plays a key role in calcium and phosphate metabolism, and it is essential for bone health in infants, children and adolescents. However, there is presently insufficient evidence to support vitamin D supplementation for prevention or treatment of allergic diseases in infants, children and adolescents, concerning allergic rhinitis, asthma, food allergy and atopic dermatitis. PMID- 25829980 TI - Current status and future perspectives of immunotherapy in Latin America and Cuba. AB - Most Latin-American countries use subcutaneous immunotherapy (SCIT) extracts from the United States and Europe and sublingual immunotherapy (SLIT) from Europe, with the exception of Argentina, Brazil, Cuba and Mexico. The number of researches on immunotherapy (IT) in Latin America has increased extensively in the last years. Only few Latin American countries have their own guidelines on IT, and, in general, the economic resources for medical research on IT are still low in the area. A global approach for the future of IT in Latin America includes to improve standardization, quality control and the production of allergen products, to develop IT guidelines and clinical investigation by the highest number of countries, to improve the regulatory status for allergens products in the area, and to expand IT accessibility for low-income patients. In Cuba, the first registered allergen vaccines were developed and registered in 2006: a standardized (in biologic units) and freeze dried product for SCIT, with a sublingual version developed in 2009. As much as 23.000 IT treatments were applied in 2011, all provided to patients free of charge. In 2012, Cuban researchers developed an IT vaccine with adjuvant for subcutaneous route, which uses Neisseria meningitidis proteoliposome as an adjuvant, added to the purified Dermatophagoides siboney major allergens: Der s1 and Der s2. Since December 2012, this vaccine is in Phase I clinical trial, evaluating its safety, tolerability and immunogenicity in asthmatic patients sensitized to this allergen. Cuban perspectives on IT includes to work on new indications for IT, to investigate the preventive effect and cost-effectiveness for the current vaccines, to develop new products with mixed formulas of house dust mites for SLIT, to complete the phase I and II clinical study for dust mite plus adjuvant vaccine, to develop allergen vaccines for fungi allergy and to complete the Cuban guideline for allergen IT management. PMID- 25829981 TI - Comparative efficacy of non-sedating antihistamine updosing in patients with chronic urticaria. PMID- 25829982 TI - A World Allergy Organization international survey on physical activity as a treatment option for asthma and allergies. AB - BACKGROUND: Physical exercise has been shown to improve asthma symptoms, QoL, exercise capacity, bronchial hyperresponsiveness and lung function and is recommended as a supplementary treatment to pharmacotherapy for asthma. Clinicians are well placed to promote physically active lifestyles, but their role and practice towards promoting physically active lifestyles among patients has not been fully investigated. This study was designed to investigate the knowledge, propensity, attitude and practices of clinicians towards the promotion of physical activity among patients with asthma and allergies. METHODS: Two hundred and eighty clinicians (mean age; 46 +/- 13 years; with a clinical experience of practice for 15 +/- 7 years) participated in a global survey. The survey comprised a 29-item questionnaire, which gathered information on attitudes of the clinicians towards promoting physical activity, their knowledge and their beliefs regarding evidence for benefits of physical activity as a supplementary treatment in patients with asthma and allergies. RESULTS: Almost all respondents were aware of the strong evidence in favor of physical activity for the psychological well-being, weight control, decreased risk of diabetes, ischemic heart disease and arterial hypertension. Evidence for reduction in the risk for developing asthma and for better asthma control were reported by 60.0% and 85.4% of participants, respectively. The majority (85.0%) of clinicians strongly agreed that promoting physical activity is important to health care, although 95.5% considered they required more educational training. Although two thirds of them usually recommended exercise to their asthmatic/allergic patients, only 24.0% reported having previous training on the subject of such counseling. Almost all believed that effective counseling about a healthy diet, exercise and weight management would be easier if the clinician himself/herself was physically fit and healthy. CONCLUSIONS: The results of this global survey indicate that clinicians working in the field of allergy and respiratory diseases are well aware of the evidence supporting the benefits of physical activity for asthma and allergic diseases although they need more training in such counseling. Therefore, concerted efforts are needed towards educating clinicians towards promoting physical activity and weight management, as a supplementary treatment for asthma and allergies. PMID- 25829983 TI - A proposal to prevent omissions and delays of antiparkinsonian drug administration in hospitals. PMID- 25829984 TI - Readmission for infective endocarditis after ischemic stroke or transient ischemic attack. AB - BACKGROUND AND PURPOSE: Providers vary in their thresholds for obtaining blood cultures in patients with ischemic stroke or transient ischemic attack (TIA). We assessed the rate of missed diagnoses of infective endocarditis (IE) in patients discharged with stroke or TIA before blood culture results could have been available. METHODS: Using administrative claims data, we performed a retrospective cohort study of all patients discharged from nonfederal California emergency departments or acute care hospitals from 2005 through 2011 with stroke (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 433.x1, 434.x1, or 436 in any position) or TIA (ICD-9-CM code 435 in the primary diagnosis position). We excluded patients with a length of stay >2 days to focus on those discharged before conclusive blood culture results could have been available. Our outcome was hospitalization within 14 days with a new diagnosis of IE (ICD-9-CM codes 391.1 or 421.x in any position). RESULTS: Among 173 966 eligible patients, 24 were subsequently hospitalized for IE-a readmission rate of 1.4 per 10 000 (95% confidence interval [CI], 0.8-1.9 per 10 000). Multiple logistic regression identified the following potential associations with readmission: prosthetic valve: odds ratio (OR), 15.8 (95% CI, 1.9-129.0); other valvular disease: OR, 1.5 (95% CI, 0.2-10.8); urinary tract infection: OR, 3.5 (95% CI, 1.0-12.3; P = .05). CONCLUSIONS: In patients with acute cerebral ischemia discharged before blood culture results could have been available, the rate of subsequent IE was negligible. These findings argue against the liberal use of blood cultures for the routine evaluation of stroke or TIA. PMID- 25829985 TI - The role of magnetic resonance imaging in management of patients with nonlobar hypertensive intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Despite the increased use and availability of magnetic resonance imaging (MRI), its role in hypertensive intracerebral hemorrhage (ICH) remains uncertain. In this retrospective study, we assessed the utility of MRI in diagnosis and management of patients with hypertensive ICH. METHODS: We retrospectively reviewed the charts of patients with ICH presenting to our hospital over an 18-month period. We included patients who presented with hypertensive ICH in typical locations and excluded lobar hemorrhages. We further isolated cases that had undergone MRI. Collected data included mean age, gender, location of hematoma, neuroradiologist's interpretative report of the MRI, and management steps taken in response to the results of the MRI. Logistic regression was used to determine whether the overall yield of MRI in these patients was significant. RESULTS: We found 222 patients with ICH in our database. Forty-eight patients met our inclusion criteria, of which 24 had brain MRI done as a part of their hospital workup. Brain MRI obtained in 2 (8%) of the 24 patients revealed abnormalities that led to a change in management. The diagnostic yield of MRI and the management decisions that followed were both insignificant. CONCLUSIONS: The diagnostic yield of brain MRI in patients with nonlobar hypertensive ICH is low and does not result in significant changes in management. PMID- 25829986 TI - An acute stroke evaluation app: a practice improvement project. AB - A point-of-care workflow checklist in the form of an iOS (iPhone Operating System) app for use by stroke providers was introduced with the objective of standardizing acute stroke evaluation and documentation at 2 affiliated academic medical centers. Providers used the app in unselected, consecutive patients undergoing acute stroke evaluation in an emergency department or hospital setting between August 2012 and January 2013 and August 2013 and February 2014. Satisfaction surveys were prospectively collected pre- and postintervention from residents, staff neurologists, and clinical data specialists. Residents (20 preintervention and 16 postintervention), staff neurologists (6 pre and 5 post), and clinical data specialists (4 pre and 4 post) participated in this study. All 16 (100%) residents had increased satisfaction with their ability to perform an acute stroke evaluation postintervention but only 9 (56%) of 16 felt the app was more help than hindrance. Historical controls aligned with preintervention results. Staff neurologists conveyed increased satisfaction with resident presentations and decision making when compared to preintervention surveys. Stroke clinical data specialists estimated a 50% decrease in data abstraction when the app data were used in the clinical note. Concomitant effect on door-to needle (DTN) time at 1 site, although not a primary study measure, was also evaluated. At that 1 center, the mean DTN time decreased by 16 minutes when compared to the corresponding months from the year prior. The point-of-care acute stroke workflow checklist app may assist trainees in presenting findings in a standardized manner and reduce data abstraction time. The app may help reduce DTN time, but this requires further study. PMID- 25829987 TI - Hashimoto encephalopathy or neurosarcoidosis? A case report. AB - Hashimoto encephalopathy (HE) is a rare autoimmune disease characterized by symptoms of acute or subacute encephalopathy associated with increased antithyroid antibody levels. Neurosarcoidosis is also a rare entity that occurs in less than 5% of patients with systemic sarcoidosis. Neurosarcoidosis usually presents with cranial neuropathies, myelopathy, or new-onset seizure. We report a case of a 49-year-old caucasian woman, previously healthy, who initially presented for a workup of a new-onset seizure. She had a gradually progressive course with neurocognitive decline and recurrent partial seizures refractory to conventional antiepileptic drugs. Her seizures responded well to a course of intravenous immunoglobulin. She was subsequently diagnosed with HE and pulmonary sarcoidosis based on serological and pathological studies. She improved neurologically once the seizures were controlled. Hashimoto encephalopathy is a rare condition that is potentially treatable and presents with various neuropsychiatric manifestations. It is a diagnosis of exclusion that requires a strong clinical suspicion and is often underrecognized. PMID- 25829988 TI - The "starfield" pattern of cerebral fat embolism from bone marrow necrosis in sickle cell crisis. AB - Sickle cell disease may manifest with cerebrovascular and systemic complications. Sickle crisis that results in avascular necrosis of long bones with resultant cerebral fat embolism syndrome is rare and has a characteristic "starfield" pattern on MRI. This "starfield" MRI pattern should raise suspicion for sickle cell crisis in patients without a known history of the disease, which can lead to earlier sickle cell red blood cell exchange transfusion and treatment. We present a case of a male who presented emergently with acute seizure, coma with a characteristic MRI pattern, which lead to the diagnosis of avascular bone marrow necrosis and cerebral fat embolism syndrome from sickle cell crisis. PMID- 25829990 TI - Magnetic resonance imaging corticospinal tract hyperintensities in progressive supranuclear palsy. PMID- 25829991 TI - The resolution of central variant of posterior reversible encephalopathy syndrome. PMID- 25829989 TI - Emerging treatments for motor rehabilitation after stroke. AB - Although numerous treatments are available to improve cerebral perfusion after acute stroke and prevent recurrent stroke, few rehabilitation treatments have been conclusively shown to improve neurologic recovery. The majority of stroke survivors with motor impairment do not recover to their functional baseline, and there remains a need for novel neurorehabilitation treatments to minimize long term disability, maximize quality of life, and optimize psychosocial outcomes. In recent years, several novel therapies have emerged to restore motor function after stroke, and additional investigational treatments have also shown promise. Here, we familiarize the neurohospitalist with emerging treatments for poststroke motor rehabilitation. The rehabilitation treatments covered in this review will include selective serotonin reuptake inhibitor medications, constraint-induced movement therapy, noninvasive brain stimulation, mirror therapy, and motor imagery or mental practice. PMID- 25829992 TI - Hyperhomocysteinemia and MTHFR polymorphisms as antenatal risk factors of white matter abnormalities in two cohorts of late preterm and full term newborns. AB - Higher total homocysteine (tHcy) levels, and C677T and A1298C methylenetetrahydrofolate (MTHFR) polymorphisms, have been reported in preterm or full term newborns with neonatal encephalopathy following perinatal hypoxic ischemic insult. This study investigated the causal role of tHcy and MTHFR polymorphisms together with other acquired risk factors on the occurrence of brain white matter abnormalities (WMA) detected by cranial ultrasound scans (cUS) in a population of late preterm and full term infants. A total of 171 newborns (81 M, 47.4%), 45 (26.3%) born <37 wks, and 126 (73.7%) born >=37 wks were recruited in the study. cUS detected predominant WMA pattern in 36/171 newborns (21.1%) mainly characterized by abnormal periventricular white matter signal and mild-to-moderate periventricular white matter volume loss with ventricular dilatation (6/36, 16.6%). WMA resulted in being depending on tHcy levels (P < 0.014), lower GA (P < 0.000), lower Apgar score at 1 minutes (P < 0.000) and 5 minutes (P < 0.000), and 1298AC and 677CT/1298AC genotypes (P < 0.000 and P < 0.000). In conclusion, both acquired and genetic predisposing antenatal factors were significantly associated with adverse neonatal outcome and WMA. The role of A1298C polymorphism may be taken into account for prenatal assessment and treatment counseling. PMID- 25829993 TI - Stem cell research and ethics: an update. PMID- 25829995 TI - The effect of low-dose intravenous ketamine on postoperative pain following cesarean section with spinal anesthesia: a randomized clinical trial. AB - OBJECTIVES: Low-dose ketamine has been considered a good substitute for opioids for controlling postoperative pain. The purpose of this study was to determine the effect of low-dose intravenous ketamine following cesarean section with spinal anesthesia on postoperative pain and its potential complications. METHODS: One hundred and sixty pregnant women volunteered to participate in this randomized controlled trial. Participants were randomly divided into two groups (n=80 for each group). Five minutes after delivery, the experimental group received 0.25mg/kg ketamine while the control group received the same amount of normal saline. RESULTS: There was a significant difference between the two groups in the severity of pain at one, two, six, and 12 hours following surgery. Postoperative pain was significantly less severe in the experimental group. Compared to the control group, the experimental group felt pain less frequently and therefore asked for analgesics less often. On average, the number of doses of analgesics used for the participants in the experimental group was significantly less than the number of doses used for the control group. Analgesic side effects (including nausea, itching, and headache) were not significantly different between the two groups. However, vomiting was significantly more prevalent in the control group and hallucination was more common in the experimental group. CONCLUSION: We conclude that administration of low doses of ketamine after spinal anesthesia reduces the need for analgesics and has fewer side effects than using opioids. Further studies are required to determine the proper dose of ketamine which offers maximum analgesic effect. Furthermore, administration of low-dose ketamine in combination with other medications in order to minimize its side effects warrants further investigation. PMID- 25829994 TI - Excessive daytime sleepiness and unintended sleep episodes associated with Parkinson's disease. AB - This article looks at the issues of excessive daytime sleepiness and unintended sleep episodes in patients with Parkinson's disease (PD) and explores the reasons why patients might suffer from these symptoms, and what steps could be taken to manage them. During the last decade, understanding of sleep/wake regulation has increased. Several brainstem nuclei and their communication pathways in the ascending arousing system through the hypothalamus and thalamus to the cortex play key roles in sleep disorders. Insomnia is the most common sleep disorder in PD patients, and excessive daytime sleepiness is also common. Excessive daytime sleepiness affects up to 50% of PD patients and a growing body of research has established this sleep disturbance as a marker of preclinical and premotor PD. It is a frequent and highly persistent feature in PD, with multifactorial underlying pathophysiology. Both age and disease-related disturbances of sleep-wake regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also contribute to excessive daytime sleepiness. Effective management of sleep disturbances and excessive daytime sleepiness can greatly improve the quality of life for patients with PD. PMID- 25829996 TI - The Cystic Fibrosis Symptom Progression Survey (CF-SPS) in Arabic: A Tool for Monitoring Patient's Symptoms. AB - OBJECTIVE: Our study aimed to develop a survey that could be used by nurses during regular cystic fibrosis (CF) clinic visits, providing clinicians with a standardized means of longitudinally assessing and monitoring symptom progression in their patients. In addition, the use of this survey would provide an opportunity for patient engagement and relationship building, thereby enhancing patient education and improving adherence to treatment. This is the first such survey designed specifically for use in Arab populations. . METHODS: The Cystic Fibrosis Symptom Progression Survey (CF-SPS) was developed using previously published patient reported outcomes relating to pulmonary exacerbations in CF. It contains 10 items that provide a patient-focused account of symptoms. The survey was translated into Arabic and was completed by 12 patients on 139 occasions over 22 months. The psychometric properties of the survey were evaluated, as was the relationship between the survey findings and other known clinical measures of health status in CF. . RESULTS: The CF-SPS performs well as a psychometrically valid clinical tool, with good internal consistency as determined by Cronbach's alpha analysis. Our results suggest that the CF-SPS is able to identify significant declines in health status in line with routine clinical patient assessment (chest sounds, body mass index and admissions). As such it is a useful tool that can support clinical decision making in the care of Arabic speaking CF patients. . CONCLUSION: We recommend the CF-SPSa (Arabic version) as a valid tool for the longitudinal monitoring of symptom progression in CF in Arabic speaking populations. PMID- 25829997 TI - Adolescents and adults with congenital heart diseases in oman. AB - OBJECTIVES: The aim of our study was to examine the spectrum, demographics, and mortality rate among adolescents and adults with congenital heart diseases (CHD) in Oman. METHODS: Data was collected retrospectively from the Royal Hospital, Muscat, electronic health records for all patients with a diagnosis of CHD aged 13 years and above. Data was analyzed according to the type of CHD and in hospital mortality was assessed using Kaplan-Meier survival analysis. RESULTS: A total of 600 patients with CHD were identified, among them 145 (24%) were aged 18 years or below. The median age was 24 years. The majority of patients had a simple form of CHD. Atrial and ventricular septal defects together constituted 62.8% of congenital heart diseases. Most patients were clustered in Muscat (32%) and the Batinah regions (31.1%) of Oman. Patients with tetralogy of Fallot and Fontan had shorter survival time than recorded in the published literature. CONCLUSION: Mostly simple forms of CHD in younger patients was observed. The survival rate was significantly shortened in more complex lesions compared to simple lesions. A national data registry for CHD is needed to address the morbidities and mortality associated with the disease. PMID- 25829998 TI - Frequency of obstructive sleep apnea syndrome among patients with epilepsy attending a tertiary neurology clinic. AB - OBJECTIVES: Epilepsy is a common neurological disorder with a median lifetime prevalence of 14 per 1000 subjects. Sleep disorders could influence epileptic seizure. The most common sleep disorder is obstructive sleep apnea syndrome (OSAS) which occurs in 2% of adult women and 4% of adult men in the general population. The aim of this study is to estimate the frequency of OSAS among patients with epilepsy and to study the seizure characteristics among those patients with co-morbid OSAS. METHODS: Patients with a confirmed diagnosis of epilepsy who attended the Sultan Qaboos University Hospital neurology clinic were recruited for the study between June 2011 and April 2012. Patients were screened for OSAS by direct interview using the validated Arabic version of the Berlin questionnaire. Patients identified as high-risk underwent polysomnography. RESULTS: A total of 100 patients with epilepsy (55 men and 45 women) were screened for OSAS. Generalized and focal seizure was found in 67% of male and 27% of female patients. Six percent of the participants had epilepsy of undetermined type. Only 9% of the sample was found to have high risk of OSAS based on the Berlin questionnaire. No significant correlation was found between risk of OSAS, type of epilepsy, and anti-epileptic drugs. CONCLUSION: The risk of OSAS was marginally greater in patients with epilepsy compared to the general population with the overall prevalence of 9%. PMID- 25829999 TI - The Relationship between Body Mass Index and Periodontitis in Arab Patients with Type 2 Diabetes Mellitus. AB - OBJECTIVE: Our study sought to evaluate the association between periodontitis and body mass index (BMI) among patients with type 2 diabetes mellitus. . METHODS: In this cross-sectional case control study analysis of 186 diabetic patients, 112 patients had a body mass index >=30kg/m(2) and 74 control patients had BMI <30kg/m(2). All participants underwent oral examinations including a full mouth recording of clinical attachment level (CAL). Information regarding HbA1c levels and high-sensitivity C-reactive protein (hs-CRP) were also gathered. . RESULTS: Over half (61%) of patients had a BMI >=30. Of these 52% had CAL less than 2mm. Multivariate logistic regression analysis showed that there was no association between BMI and CAL. In addition, hs-CRP levels were significantly and positively associated with CAL (OR:1.06, 95% CI: 1.01, 1.12; p=0.007). . CONCLUSION: Among patients with type 2 diabetes mellitus, there was no association between periodontitis and BMI. More studies are needed to further explore this relationship taking into consideration additional lifestyle factors. PMID- 25830000 TI - Impact of acne on quality of life of students at sultan qaboos university. AB - OBJECTIVE: The purpose of this study was to assess the impact of acne on the quality of life. Its secondary objective was to assess the influence of gender of students and severity of symptoms on the quality of life. . METHODS: A cross sectional study was conducted on 100 students at Sultan Qaboos University (SQU) (40 males and 60 females) diagnosed with acne who attended the Student Clinic during a period of three months from September to December 2009. The Acne Quality Of Life index (Acne-QoL) questionnaire was used to assess the patient's quality of life in four different domains: self-perception, social, emotional, and acne symptoms. . RESULTS: Acne affected all areas of the patients, quality of life with the emotional domain found to be the most affected. Overall, female patients reported more adverse QoL effects. The mean score for self-perception for female students was 2.5 and 2.8 for males (p=0.300). The role-social domain approached a significant difference between genders (p=0.078). There was a statistically significant correlation between severity of acne symptoms and the other three domains. The correlation was highest between acne symptoms score and self perception score. . CONCLUSION: This study showed that acne affects the quality of life of affected SQU students treated by primary care physicians at the Student Clinic. Therefore, physicians should take into account the effect of acne on the persons' quality of life when individualizing treatment. PMID- 25830001 TI - Quality of diabetes care at outpatient clinic, sultan qaboos university hospital. AB - OBJECTIVE: To assess the clinical care of type 2 diabetes mellitus (T2D) patients at Sultan Qaboos University Hospital (SQUH), a countrywide tertiary referral center in Muscat, Oman. . METHODS: We performed a retrospective, observational, cross-sectional study using a total of 673 Omani T2D patients from the Diabetes and Family Medicine Clinics at SQUH. We collected patient data from June 2010 to February 2012 from the Hospital Information System (HIS). Patients had to be Omani, aged more than 18 years old, and have T2D with active follow-up and at least three visits within one year to be included in the study. Ninety-three percent of the patients (n=622) were on oral hypoglycemic drugs and/or insulin, and 70% were on statins. Patients' anthropometric data, biochemical investigations, blood pressure, and duration of diabetes were recorded from the HIS. . RESULTS: Using the recommended standards and guidelines of medical care in diabetes (American Diabetes Association and the American National Cholesterol Education Program III NCDP NIII standards), we observed that 22% of the patients achieved a HbA1C goal of <7%, 47% achieved blood pressure goal of <140/80mm Hg, 48% achieved serum low density lipoprotein cholesterol goal of <2.6mmol/L, 67% achieved serum triglycerides goal of <1.7 mmol/L, 59% of males and 43% of females achieved high density lipoprotein cholesterol goals (males>1.0; females >1.3mmol/L). Almost 60% of the patients had urinary microalbumin/creatinine ratio within the normal range. . CONCLUSIONS: The clinical outcomes of the care that T2D patients get at SQUH were lower than those reported in Europe and North America. However, it is similar to those reported in other countries in the Arabian Gulf. PMID- 25830002 TI - Acute myocardial infarction after switching from warfarin to dabigatran. AB - Dabigatran etexilate is a recently approved direct thrombin inhibitor (DTI), which is superior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). However, dabigatran use is associated with an increased risk of myocardial infarction (MI) compared to warfarin. The mechanisms for this association effect remain speculative. We present a case of an acute MI and cardiac arrest in a patient with chronic AF who had been recently switched from warfarin to dabigatran. Urgent coronary angiography, at St. Michael's hospital (Toronto, Canada), revealed evidence of thromboembolism to the distal posterior descending artery. The patient was treated medically and switched back from dabigatran to warfarin. He did well and was discharged after an uneventful stay in the coronary care unit. PMID- 25830003 TI - Hughes-stovin syndrome and massive hemoptysis: a management challenge. AB - Hughes-Stovin syndrome is a very rare clinical entity characterized by pulmonary artery aneurysms and deep vein thrombosis (DVT). Here we report the case of a 53 year-old man, admitted to Sultan Qaboos University Hospital, Muscat, Oman, with bilateral pulmonary artery aneurysms and lower-limb DVT who developed massive hemoptysis. He was managed successfully with high-dose steroids in combination with cyclophosphamide. PMID- 25830004 TI - Post-aural Nodular Fasciitis. AB - Nodular fasciitis is a rare benign lesion. Here we report a case of post auricular nodular fasciitis, which was misdiagnosed by fine-needle aspiration cytology (FNAC) as pleomorphic adenoma. An 18-year-old male presented at Al Nahdha Hospital, physical examination revealed a right post aural firm immobile mass. Radiology suggested the presence of a hypo-dense to iso-dense subcutaneous mass. The swelling was excised and sent for histopathological examination which suggested the diagnosis of nodular fasciitis. FNAC reported pleomorphic adenoma of unusual location should raise the suspicion of nodular fasciitis. PMID- 25830005 TI - Extrahepatic biliary cystadenoma: a rare cause of biliary obstruction. AB - Biliary cystadenoma is a rare tumor of the biliary tree and a rare cause of obstructive jaundice. Most are intrahepatic, and pure extrahepatic biliary cystadenoma is less common. Cases are more common in women. Unless suspected, diagnosis of extrahepatic biliary cystadenoma is often delayed. Here, we report the case of a young woman with extrahepatic biliary cystadenoma who presented at Raja Isteri Pengiran Anak Saleha Hospital with obstructive jaundice initially thought to be due to a large biliary stone based on the endoscopic cholangiogram image. She was successfully managed with resection of the cystadenoma. PMID- 25830006 TI - Localized acral hypertrophy. PMID- 25830007 TI - Allergic rhinitis in oman and malaysia: the similarities and differences. PMID- 25830008 TI - Control or placebo group in a clinical trial. PMID- 25830009 TI - Motivating factors associated with receipt of asymptomatic colonoscopy screening. AB - BACKGROUND: Colonoscopy is the preferred screening method for colorectal cancer (CRC). This study aimed to identify factors motivating a beneficial health behavior, that is, the decision to complete a colonoscopy. METHODS: We surveyed 91 primarily urban minority health care workers who were ineligible for a large randomized controlled trial due to self-reported asymptomatic colonoscopy screening. Participants were asked an open-ended question about what made them get screened. Responses were classified as external or internal motivations. RESULTS: The most commonly reported external motivation was a primary care physician's recommendation (n = 60, 65.9%). Other external motivations were familiarity with CRC or polyps through family or work (n = 16, 17.6%) and pressure from relatives or friends (n = 8, 8.8%). Seventeen respondents were deemed self-motivated; these individuals were more likely have income over $50K/year (P < 0.05) and to be US born (P = 0.05); they were more likely to mention being age-appropriate for screening (P < 0.05); knew more people who had colonoscopies (P < 0.001); they were less likely to believe that most of the age appropriate population in New York City has been screened (P < 0.01) and less likely to be deterred from colonoscopy by work schedule (P < 0.001) or by having to take a powerful laxative (P < 0.001). CONCLUSIONS: A primary care physician's recommendation may be the most prevalent motivating factor in patients' decisions to receive a colonoscopy, but a subgroup seeks CRC screening on their own. Analysis of the motivations of individuals who have sought colonoscopy screening may offer useful insights into motivating those who have not. PMID- 25830010 TI - Road map to organ donation in Tamil Nadu: an excellent model for India. PMID- 25830011 TI - Preventive role of estradiol on kidney injury induced by renal ischemia reperfusion in male and female rats. AB - BACKGROUND: Renal ischemia-reperfusion (RIR) is the main cause of renal failure. The incidence of RIR injury seems to be gender-related due to female sex hormone; estrogen. This study was designed to investigate the protective role of estrogen against RIR injury in male and ovariectomized female rats. METHODS: Thirty-nine Wistar rats were used in this study as male and ovariectomized female rats in the sham-operated, RIR, and estradiol-treated plus RIR groups. The RIR was induced by clamping the renal vessels for 45 min and then 24 h of reperfusion. All animals finally were sacrificed for the measurements. RESULTS: The serum levels of creatinine and blood urea nitrogen and kidney tissue damage score significantly increased in both male and female RIR rats (P < 0.05). Estradiol however significantly attenuated theses parameters (P < 0.05) toward normal levels in female (P < 0.05), but not in male rats. Kidney weight increased in both genders and estradiol intensified it in the male rats (P < 0.05). Uterus weight was increased by estradiol in female rats (P < 0.05) and testis weight did not alter in male rats. CONCLUSIONS: Estradiol demonstrated a protective role against RIR injury in female rats; however, estradiol as an antioxidant could not protect the male kidney from RIR injury. PMID- 25830012 TI - Reliability of gingival blood sample to screen diabetes in dental hospital. AB - BACKGROUND: Early detection and treatment of diabetes mellitus may reduce the burden of diabetes and its complications. Screening of undiagnosed diabetes with gingival blood sample in patients attending to the dental hospital and to check the reliability with standard method. METHODS: Five hundred and fifty new patients age ranged from 30 to 50 years were randomly selected. Of 550 patients examined, gingival blood samples of 454 patients were collected from bleeding site and analyzed with self-monitoring device. Blood glucose values were recorded. In addition, all the patients were advised for the second visit with overnight fasting for fasting Blood glucose assessment. Among them, 442 patients returned for fasting blood glucose assessment in laboratory with blood glucose analyzer. RESULTS: In the total of 454 patients gingival blood glucose assessment with self-monitoring device, 64 patients showed >=200 mg/dL, which indicates diabetes, and the other 390 patients showed <=200 mg/dL, which indicates patients are not diabetic. Whereas, the results of the laboratory blood glucose analysis, 24 (5.43%) patients showed >=126 mg/dL, 36 (8.14%) patients showed 100-125 mg/dL and the other 382 patients are not diabetic. Comparison of blood glucose measurements by two methods showed sensitivity 96.66% and specificity 99.47%. CONCLUSIONS: The results of the present study showed blood obtained from periodontal pocket probing is a reliable sample to screen diabetes in periodontal disease population. Early diagnosis of diabetes in the dental hospitals can help improve the patient's oral health and overall health status by helping patients avoid or reduce complications from diabetes. PMID- 25830013 TI - Use of biosimilar filgrastim compared with lenograstim in autologous haematopoietic stem-cell transplant and in sibling allogeneic transplant. AB - OBJECTIVES: Biosimilar filgrastim was compared with lenograstim for autologous haematopoietic stem-cell transplant (HSCT) in patients with haematological malignancies. Data from a separate group of sibling donors who underwent allogeneic HSCT are also reported. METHODS: Patients with lymphoma or multiple myeloma (MM) who underwent autologous HSCT with biosimilar filgrastim were compared with a historical control group of patients who received lenograstim. Peripheral blood (PB) cells counts were monitored after 7-8 consecutive days of granulocyte-colony stimulating factor (G-CSF) injection and apheresis was performed on day 8 if PB CD34+ cell count was ?10 cells/ul. The target PB CD34+ cell doses were ?2.0 * 10(6)/kg (lymphoma), ?4.0 * 10(6)/kg (MM ?60 years old) or ?8.0 * 10(6)/kg (MM <60 years old). RESULTS: A total of 259 patients were included in the autologous HSCT comparison (biosimilar filgrastim, n = 104; lenograstim, n = 155). In patients with lymphoma and older MM patients (?60 years old), no significant differences were observed between groups with regard to stem cell mobilization parameters. However, in MM patients <60 years old, all parameters were significantly superior in the biosimilar filgrastim group, including the need for 1 rather than 2 apheresis procedures. No significant differences were observed between groups in median number of days to absolute neutrophil count (ANC) or platelet recovery. In the allogeneic setting, 47 sibling donors received biosimilar filgrastim. Mean CD34+ count at the first apheresis was 6.1 * 10(6)/kg. A total of 13 donors needed a second apheresis and 4 required a third. Among recipients, median days to ANC recovery was 16 (10-28) and to platelet recovery was 13 (9-54). CONCLUSIONS: Biosimilar filgrastim is as effective as lenograstim for autologous HSCT in patients with lymphoma or MM patients ?60 years old. However, mobilization with biosimilar filgrastim appeared to be superior to that with lenograstim in younger MM patients. PMID- 25830015 TI - Targeting polo-like kinase 1 in acute myeloid leukemia. AB - Polo-like kinase 1 (Plk1) plays a number of important roles in the passage of cells through mitosis. It is expressed at high levels in a variety of malignancies, including acute myeloid leukemia (AML). Inhibition of Plk1 results in cell cycle arrest and apoptosis, and has anti-tumor effects in pre-clinical models. A number of Plk1 inhibitors have been developed, some of which have entered clinical trials. Of these, volasertib (BI6727) has been most extensively studied clinically in AML. Volasertib has demonstrated antileukemic activity in AML, both as a single agent and when combined with low-dose cytarabine. It is well tolerated, with the major toxicity being reversible myelosuppression. A recently completed phase III clinical trial in older AML patients will address the question of whether adding this agent to low-dose cytarabine is associated with a survival advantage. PMID- 25830014 TI - Novel agents for the treatment of childhood acute leukemia. AB - Together, acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) make up approximately one-third of all pediatric cancer diagnoses. Despite remarkable improvement in the treatment outcomes of these diseases over the past several decades, the prognosis for certain high-risk groups of leukemia and for relapsed disease remains poor. However, recent insights into different types of 'driver' lesions of leukemogenesis, such as the aberrant activation of signaling pathways and various epigenetic modifications, have led to the discovery of novel agents that specifically target the mechanism of transformation. In parallel, emerging approaches in cancer immunotherapy have led to newer therapies that can exploit and harness cytotoxic immunity directed against malignant cells. This review details the rationale and implementation of recent and specifically targeted therapies in acute pediatric leukemia. Topics covered include the inhibition of critical cell signaling pathways [BCR-ABL, FMS-like tyrosine kinase 3 (FLT3), mammalian target of rapamycin (mTOR), and Janus-associated kinase (JAK)], proteasome inhibition, inhibition of epigenetic regulators of gene expression [DNA methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and disruptor of telomeric signaling-1 (DOT1L) inhibitors], monoclonal antibodies and immunoconjugated toxins, bispecific T-cell engaging (BiTE) antibodies, and chimeric antigen receptor-modified (CAR) T cells. PMID- 25830016 TI - Treatment-related acute myeloid leukemia in a chronic lymphocytic leukemia patient: role of fludarabine? PMID- 25830018 TI - Reconstructing a comprehensive transcriptome assembly of a white-pupal translocated strain of the pest fruit fly Bactrocera cucurbitae. AB - BACKGROUND: Bactrocera cucurbitae is a serious global agricultural pest. Basic genomic information is lacking for this species, and this would be useful to inform methods of control, damage mitigation, and eradication efforts. Here, we have sequenced, assembled, and annotated a comprehensive transcriptome for a mass rearing sexing strain of this species. This forms a foundational genomic and transcriptomic resource that can be used to better understand the physiology and biochemistry of this insect as well as being a useful tool for population genetics. FINDINGS: A transcriptome assembly was constructed containing 17,654 transcript isoforms derived from 10,425 unigenes. This transcriptome size is similar to reports from other Tephritid species and probably includes about 70 80% of the protein-coding genes in the genome. The dataset is publicly available in NCBI and GigaDB as a resource for researchers. CONCLUSIONS: Foundational knowledge on the protein-coding genes in B. cucurbitae will lead to improved resources for this species. Through comparison with a model system such as Drosophila as well as a growing number of related Tephritid transcriptomes, improved strategies can be developed to control this pest. PMID- 25830017 TI - RNA-Seq analysis and annotation of a draft blueberry genome assembly identifies candidate genes involved in fruit ripening, biosynthesis of bioactive compounds, and stage-specific alternative splicing. AB - BACKGROUND: Blueberries are a rich source of antioxidants and other beneficial compounds that can protect against disease. Identifying genes involved in synthesis of bioactive compounds could enable the breeding of berry varieties with enhanced health benefits. RESULTS: Toward this end, we annotated a previously sequenced draft blueberry genome assembly using RNA-Seq data from five stages of berry fruit development and ripening. Genome-guided assembly of RNA-Seq read alignments combined with output from ab initio gene finders produced around 60,000 gene models, of which more than half were similar to proteins from other species, typically the grape Vitis vinifera. Comparison of gene models to the PlantCyc database of metabolic pathway enzymes identified candidate genes involved in synthesis of bioactive compounds, including bixin, an apocarotenoid with potential disease-fighting properties, and defense-related cyanogenic glycosides, which are toxic. Cyanogenic glycoside (CG) biosynthetic enzymes were highly expressed in green fruit, and a candidate CG detoxification enzyme was up regulated during fruit ripening. Candidate genes for ethylene, anthocyanin, and 400 other biosynthetic pathways were also identified. Homology-based annotation using Blast2GO and InterPro assigned Gene Ontology terms to around 15,000 genes. RNA-Seq expression profiling showed that blueberry growth, maturation, and ripening involve dynamic gene expression changes, including coordinated up- and down-regulation of metabolic pathway enzymes and transcriptional regulators. Analysis of RNA-seq alignments identified developmentally regulated alternative splicing, promoter use, and 3' end formation. CONCLUSIONS: We report genome sequence, gene models, functional annotations, and RNA-Seq expression data that provide an important new resource enabling high throughput studies in blueberry. PMID- 25830019 TI - Improving functional magnetic resonance imaging reproducibility. AB - BACKGROUND: The ability to replicate an entire experiment is crucial to the scientific method. With the development of more and more complex paradigms, and the variety of analysis techniques available, fMRI studies are becoming harder to reproduce. RESULTS: In this article, we aim to provide practical advice to fMRI researchers not versed in computing, in order to make studies more reproducible. All of these steps require researchers to move towards a more open science, in which all aspects of the experimental method are documented and shared. CONCLUSION: Only by sharing experiments, data, metadata, derived data and analysis workflows will neuroimaging establish itself as a true data science. PMID- 25830020 TI - A rare presentation of gastric outlet obstruction (GOO) - The Bouveret's syndrome. AB - INTRODUCTION: Bouveret's Syndrome is a rare cause of Gastric outlet obstruction (GOO) caused by a gall stone which has migrated into the duodenal bulb from a bilioduodenal fistula. It is an uncommon condition and only a few cases have been reported in the medical literature till to date. PRESENTATION OF CASE: We report a case of a 45 year old woman who presented to us with recurrent pain in the upper abdomen for the last 8 years, and that progressed to develop symptoms of gastric outlet obstruction. An upper gastrointestinal endoscopy revealed duodenal ulceration with a stony hard lesion in the first part of duodenum. An contrast enhanced computed tomography (CECT) scan of the abdomen performed later confirmed the presence of cholecystoduodenal fistula and a gall-stone in proximal jejunum. DISCUSSION: Bouveret's syndrome is a case of gastric outlet obstruction caused by the impaction of a large gall stone in the duodenum as a result of a cholecystoduodenal fistula. It constitutes 1-3% of cases of gall stone ileus which in turn complicates only 0.3-4% cases of cholelithisasis. Bouveret's syndrome is managed surgically. CONCLUSION: Bouveret's syndrome being an uncommon condition may pose a difficulty in diagnosis and dilemma in managing such patients. An awareness is hence essential. PMID- 25830021 TI - Caecal diverticulitis: Presentation and management. AB - INTRODUCTION: While left sided colonic diverticular disease is common in Western countries, right sided colonic diverticular disease is rare. With increasing migration from Asia, many western countries including Australia, are now seeing more right sided diverticular disease, of which caecal diverticulitis is the commonest. This study aims to determine the incidence of caecal diverticulitis in patients presenting with colonic diverticulitis, as well as identify the symptoms and clinical features that may aid in making a pre-operative diagnosis. METHODS: Data was collected using the Queen Elizabeth II Hospital medical records database identifying patients diagnosed with colonic diverticulitis and, more specifically, those with caecal diverticulitis from January 2007 to December 2013. Only those patients who had confirmed caecal diverticulitis on imaging studies or at laparoscopy on their first admission were included in this study. RESULTS: A total of 632 patients with colonic diverticulitis were admitted to our institution over a seven-year period, of which 13 patients had caecal diverticulitis (2.06%). Of the 13 patients, twelve were of Asian background and ten were considered young (<=50 years of age). The main complaints were right sided abdominal pain (n = 11, 84.6%) and diarrhoea (n = 5, 38.5%). Nine were diagnosed using computed tomography (n = 9/10, 90%), three on laparoscopy and one using ultrasound (n = 1/2, 50%). Ten patients were treated successfully by conservative means. DISCUSSION: A high index of suspicion in Asian patients with atypical symptoms of appendicitis, especially diarrhoea, may provide the diagnosis of caecal diverticulitis. PMID- 25830022 TI - A molecular survey of Australian and North American termite genera indicates that vertical inheritance is the primary force shaping termite gut microbiomes. AB - BACKGROUND: Termites and their microbial gut symbionts are major recyclers of lignocellulosic biomass. This important symbiosis is obligate but relatively open and more complex in comparison to other well-known insect symbioses such as the strict vertical transmission of Buchnera in aphids. The relative roles of vertical inheritance and environmental factors such as diet in shaping the termite gut microbiome are not well understood. RESULTS: The gut microbiomes of 66 specimens representing seven higher and nine lower termite genera collected in Australia and North America were profiled by small subunit (SSU) rRNA amplicon pyrosequencing. These represent the first reported culture-independent gut microbiome data for three higher termite genera: Tenuirostritermes, Drepanotermes, and Gnathamitermes; and two lower termite genera: Marginitermes and Porotermes. Consistent with previous studies, bacteria comprise the largest fraction of termite gut symbionts, of which 11 phylotypes (6 Treponema, 1 Desulfarculus-like, 1 Desulfovibrio, 1 Anaerovorax-like, 1 Sporobacter-like, and 1 Pirellula-like) were widespread occurring in >=50% of collected specimens. Archaea are generally considered to comprise only a minority of the termite gut microbiota (<3%); however, archaeal relative abundance was substantially higher and variable in a number of specimens including Macrognathotermes, Coptotermes, Schedorhinotermes, Porotermes, and Mastotermes (representing up to 54% of amplicon reads). A ciliate related to Clevelandella was detected in low abundance in Gnathamitermes indicating that protists were either reacquired after protists loss in higher termites or persisted in low numbers across this transition. Phylogenetic analyses of the bacterial communities indicate that vertical inheritance is the primary force shaping termite gut microbiota. The effect of diet is secondary and appears to influence the relative abundance, but not membership, of the gut communities. CONCLUSIONS: Vertical inheritance is the primary force shaping the termite gut microbiome indicating that species are successfully and faithfully passed from one generation to the next via trophallaxis or coprophagy. Changes in relative abundance can occur on shorter time scales and appear to be an adaptive mechanism for dietary fluctuations. PMID- 25830024 TI - Outcomes of a rapid refeeding protocol in Adolescent Anorexia Nervosa. AB - BACKGROUND: The impact of severe malnutrition and medical instability in adolescent Anorexia Nervosa (AN) on immediate health and long-term development underscores the need for safe and efficient methods of refeeding. Current refeeding guidelines in AN advocate low initial caloric intake with slow increases in energy intake to avoid refeeding syndrome. This study demonstrates the potential for more rapid refeeding to promote initial weight recovery and correct medical instability in adolescent AN. METHODS: Seventy-eight adolescents with AN (12-18 years), hospitalised in two specialist paediatric eating disorder units, for medical instability (bradycardia, hypotension, hypothermia, orthostatic instability and/or cardiac arrhythmia) were followed during a 2.5 week admission. Patients were refed using a standardised protocol commencing with 24-72 hours of continuous nasogastric feeds (ceased with daytime medical stability) and routine oral phosphate supplementation, followed by nocturnal feeds and a meal plan of 1200-2400 kcal/day aiming for a total caloric intake of 2400-3000 kcal/day. Along with indicators of medical stability, weight, phosphate and glucose levels were recorded. RESULTS: All patients gained weight in week one (M = 2.79 kg, SD = 1.27 kg) and at subsequent measurement points with an average gain of 5.12 kg (SD = 2.96) at 2.5 weeks. No patient developed hypophosphatemia, hypoglycaemia, or stigmata of the refeeding syndrome. CONCLUSIONS: The refeeding protocol resulted in immediate weight gain and was well tolerated with no indicators of refeeding syndrome. There were no significant differences in outcomes between the treatment sites, suggesting the protocol is replicable. TRIAL REGISTRATION: Australian Clinical Trials Register number: ACTRN012607000009415. PMID- 25830025 TI - A case series investigation of association between co-morbid psychiatric disorder and the improvement in body mass index among patients with anorexia nervosa and eating disorder not otherwise specified of the anorexia nervosa type. AB - BACKGROUND: Anorexia nervosa and eating disorder not otherwise specified* (not fulfilling Anorexia Nervosa DSM IV criteria) are increasing in Singapore. Patients with eating disorders may also present with other psychiatric disorders such as depression and anxiety. The paper aims to investigate the association of co-morbid psychiatric disorders with the improvement of body mass index (BMI) in these patients. METHODS: A retrospective cohort analysis of 182 patients with anorexia and eating disorder not otherwise specified at a tertiary hospital was done. The clinical course of co-morbid psychiatric disorders was correlated with the improvement of body mass index. RESULTS: 109 patients were included in the analysis and the mean BMI on resolution of co-morbid psychiatric disorders was BMI 16.9. There is a significant association between the BMI groups and the resolution of co-morbid psychiatric disorders, chi2 = 10.2, p = .03. Patients in BMI group 5 (BMI 16.6 - 18.5) were noted to be significantly less likely to resolve their psychiatric co-morbidity compared to the other 4 groups. (OR = 0.323). CONCLUSION: Patients with anorexia nervosa and eating disorders not otherwise specified were at increased risk of having co-morbid psychiatric disorders and the clinical course of co-morbid psychiatric disorders appeared to correlate with improved BMI. Specifically patients with BMI < 16.5 with co-morbid psychiatric disorders were more likely to recover from their co-morbid psychiatric disorder with nutritional rehabilitation than patients with a higher BMI. PMID- 25830026 TI - Identification of Propionibacterium avidum from a breast abscess: an overlooked etiology of clinically significant infections. AB - We report the case of a 37-year-old previously healthy woman diagnosed with a breast abscess due to Propionibacterium avidum after breast reduction surgery. This case emphasizes the potential pathogenicity and morbidity associated with this commensal skin organism. PMID- 25830027 TI - Palaeomicrobiology meets forensic medicine: time as a fourth-dimension for the crime scene. AB - The unrelenting progress of laboratory techniques is rapidly unleashing the huge potential of palaeomicrobiology. That bodies are often found in poor condition is common to both palaeomicrobiology and forensic medicine, and this might stimulate them towards a joint quest to extract reproducible data for reliable specimens. PMID- 25830028 TI - Butyricimonas virosa: the first clinical case of bacteraemia. AB - The strictly anaerobic Gram-negative bacteria Butyricimonas species have recently been described in human faeces and have to our knowledge not been isolated in infectious clinical materials. We report the first case of Butyricimonas virosa bacteraemia in a 72-year-old man with colon adenocarcinoma, who underwent aortic aneurysm replacement surgery. PMID- 25830029 TI - First detection of KPC-3-producing Klebsiella pneumoniae in Albania. PMID- 25830030 TI - Evaluation of normal tissue exposure in patients receiving radiotherapy for pancreatic cancer based on RTOG 0848. AB - BACKGROUND: Pancreatic cancer is a highly aggressive malignancy. Chemoradiotherapy (CRT) is utilized in many cases to improve locoregional control; however, toxicities associated with radiation can be significant given the location of the pancreas. RTOG 0848 seeks to evaluate chemoradiation using either intensity-modulated radiation therapy (IMRT) or 3D conformal photon radiotherapy (3DCRT) modalities as an adjuvant treatment. The purpose of this study is to quantify the dosimetric changes seen when using IMRT or 3D CRT photon modalities, as well as proton radiotherapy, in patients receiving CRT for cancer of the pancreas treated per RTOG 0848 guidelines. MATERIALS: Ten patients with pancreatic head adenocarcinoma treated between 2010 and 2013 were evaluated in this study. All patients were simulated with contrast-enhanced CT imaging. Separate treatment plans using IMRT and 3DCRT as well as proton radiotherapy were created for each patient. All planning volumes were created per RTOG 0848 protocol. Dose-volume histograms (DVH) were calculated and analyzed in order to compare plans between the three modalities. The organs at risk (OAR) evaluated in this study are the kidneys, liver, small bowel, and spinal cord. RESULTS: There was no difference between the IMRT and 3DCRT plans in dose delivered to the kidneys, liver, or bowel. The proton radiotherapy plans were found to deliver lower mean total kidney doses, mean liver doses, and liver D1/3 compared to the IMRT plans. The proton plans also gave less mean liver dose, liver D1/3, bowel V15, and bowel V50 in comparison to the 3DCRT. CONCLUSIONS: For patients receiving radiotherapy per ongoing RTOG 0848 for pancreatic cancer, there was no significant difference in normal tissue sparing between IMRT and 3DCRT treatment planning. Therefore, the choice between the two modalities should not be a confounding factor in this study. The proton plans also demonstrated improved OAR sparing compared to both IMRT and 3DCRT treatment plans. PMID- 25830031 TI - Efficacy of platinum chemotherapy agents in the adjuvant setting for adenosquamous carcinoma of the pancreas. AB - BACKGROUND: Pancreatic adenosquamous carcinoma (PASC) accounts for only 1-4% of all exocrine pancreatic cancers and carries a particularly poor prognosis. This retrospective study was performed to determine whether inclusion of a platinum agent as part of adjuvant therapy is associated with improved survival in patients with resected PASC. METHODS: Records of all patients who underwent pancreatic resection at Johns Hopkins Hospital from 1986 to 2012 were reviewed to identify those with PASC. Multivariable Cox proportional hazards modeling was used to assess for significant associations between patient characteristics and survival. RESULTS: In total, 62 patients (1.1%) with resected PASC were identified among 5,627 cases. Median age was 68 [interquartile range (IQR), 57 77] and 44% were female. Multivariate analysis revealed that, among all patients (n=62), the following factors were independently predictive of poor survival: lack of adjuvant therapy [hazard ratio (HR) =3.6; 95% confidence interval (CI), 1.8-7.0; P<0.001], margin-positive resection (HR =3.5; 95% CI, 1.8-6.8; P<0.001), lymph node involvement (HR =3.5; 95% CI, 1.5-8.2; P=0.004), and age (HR =1.0; 95% CI, 1.0-1.1; P=0.035). There were no significant differences between patients who did and did not receive adjuvant therapy following resection (all P>0.05). A second multivariable model included only those patients who received adjuvant therapy (n=39). Lack of inclusion of a platinum agent in the adjuvant regimen (HR =2.4; 95% CI, 1.0-5.8; P=0.040) and larger tumor diameter (HR =1.3; 95% CI, 1.0 1.6; P=0.047) were independent predictors of inferior survival. CONCLUSIONS: Addition of a platinum agent to adjuvant regimens for resected PASC may improve survival among these high-risk patients, though collaborative prospective investigation is needed. PMID- 25830032 TI - Intensity-modulated radiotherapy following null-margin resection is associated with improved survival in the treatment of intrahepatic cholangiocarcinoma. AB - BACKGROUND: The current study is the first to examine the effectiveness and toxicity of postoperative intensity-modulated radiotherapy (IMRT) in the treatment of intrahepatic cholangiocarcinoma (ICC) abutting the vasculature. Specifically, we aim to assess the role of IMRT in patients with ICC undergoing null-margin (no real resection margin) resection. METHODS: Thirty-eight patients with ICC adherent to major blood vessels were included in this retrospective study. Null-margin resection was performed on all patients; 14 patients were further treated with IMRT. The median radiation dose delivered was 56.8 Gy (range, 50-60 Gy). The primary endpoints were overall survival (OS) and disease free survival (DFS). RESULTS: At a median follow-up of 24.6 months, the median OS and DFS of all patients (n=38) were 17.7 months (95% CI, 13.2-22.2) and 9.9 months (95% CI, 2.8-17.0), respectively. Median OS was 21.8 months (95% CI, 15.5 28.1) among the 14 patients in the postoperative IMRT group and 15.0 months (95% CI, 9.2-20.9) among the 24 patients in the surgery-only group (P=0.049). Median DFS was 12.5 months (95% CI, 6.8-18.2) in the postoperative IMRT group and 5.5 months (95% CI, 0.7-12.3) in the surgery-only group (P=0.081). IMRT was well tolerated. Acute toxicity included one case of Grade 3 leukopenia; late toxicity included one case of asymptomatic duodenal ulcer discovered through endoscopy. CONCLUSIONS: The study results suggest that postoperative IMRT is a safe and effective treatment option following null-margin resections of ICC. Larger prospective and randomized trials are necessary to establish postoperative IMRT as a standard practice for the treatment of ICC adherent to major hepatic vessels. PMID- 25830034 TI - HER2 expression in gastric and oesophageal cancer: a meta-analytic review. AB - BACKGROUND: Since the advent and the success of adjuvant medical therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the form of trastuzumab there has been increasing interest in the development of similar therapies in other solid organ malignancies including gastric cancer and oesophageal cancer. Over the years, multiple observational studies have been inconsistent. Several meta-analyses have been published looking at the association between HER2 and gastric cancer and oesophageal cancer. This review aims to summarize the meta-analytic evidence for the association between HER2 in gastric and oesophageal cancer. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane Library, Google Scholar, Science Direct, and Web of Science. RESULTS: Of the articles selected, only nine studies met full criteria. Six of them reviewed the role of HER2 in gastric cancer and the remaining three reviewed its role in oesophageal cancer. CONCLUSIONS: The current evidence regarding the role of HER2 is unclear. However, it clearly plays a key role in the pathogenesis of gastric and oesophageal carcinomas. Targeted therapy towards this subgroup (despite variable frequency and association with survival) would offer a mortality benefit and improve survival. PMID- 25830033 TI - Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for (90)Y resin microspheres. AB - BACKGROUND: Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-((90)Y)-labeled resin microspheres. METHODS: Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fisher's exact test and Kaplan-Meier estimates, respectively. RESULTS: Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade >=3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2(nd)-line, 3(rd)-line, or 4(th)-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. >=1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy. CONCLUSIONS: Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received >=3 prior lines of chemotherapy. PMID- 25830035 TI - Factors influencing response to neoadjuvant chemoradiation and outcomes in rectal cancer patients: tertiary Indian cancer hospital experience. AB - BACKGROUND: In the treatment of rectal cancers several randomized trials have demonstrated benefits of neoadjuvant chemoradiotherapy (NACRT) in downstaging as well as survival among these patients. We investigated the patient and tumor related variables dictating the outcomes in these patients. METHODS: Biopsy proven treatment naive 182 rectal cancer patients underwent NACRT from June 2006 to December 2010. The entire patients received long course conventionally fractionated external beam radiotherapy with concurrent oral Capecitabine. At 6 weeks from completion of NACRT clinico-radiological assessment was carried out for surgical feasibility. All patients were given postoperative adjuvant chemotherapy either single agent or multi drug regimen depending upon biopsy report. RESULTS: Among 182 patients, 131 (72%) underwent surgery and initial T stage and signet ring cell morphology were major determinant of operability. Among the 131 operated patients at median follow up of 36 months, 94 (72%) are alive and disease free. With a median follow up of 42 months the 5-year disease free survival (DFS) and overall survival (OS) was 60% and 77%. The majority of the failures were distal but with more advanced disease at presentation both local and distal failures were similar. While assessing survival by multivariate analysis patients having positive nodes post-surgery had a significantly poorer DFS (P=0.001), while signet ring cell morphology and pre-treatment carcino embryonic antigen (CEA) levels strongly influenced OS (P=0.03). CONCLUSIONS: The outcome of our patients were similar to World Literature and signet ring cell morphology, pre-treatment CEA level, and pathological nodal staging all were influential in determining survival. Besides this, the study also highlights the fact that tumours with signet ring cell morphology appearing in younger population with poor survival needs prospective evaluation for more intense CRT regimen and aggressive surgical resections. PMID- 25830036 TI - Low bone mineral density linked to colorectal adenomas: a cross-sectional study of a racially diverse population. AB - BACKGROUND: Epidemiologic studies suggest that lower bone mineral density (BMD) is associated with an increased risk for colorectal adenoma/cancer, especially in postmenopausal women. The aim of this study is to investigate the association between osteopenia and/or osteoporosis and colorectal adenomas in patients from a New York community hospital. METHODS: We performed a cross-sectional observational study on 200 patients who underwent screening colonoscopies and bone density scan (dual-energy X-ray absorptiometry) at Nassau University Medical Center from November 2009 to March 2011. Among these, 83 patients were identified as osteoporosis (T score of -2.5 or below) and 67 were osteopenia (T score between -1.0 and -2.5). Logistic regression model was performed to assess the association between osteopenia and/or osteoporosis and colorectal adenomas. RESULTS: Among the patients with osteopenia and osteoporosis, the mean ages were 59.1 years [standard deviation (SD) =8.9] and 61.5 (SD =8.9), respectively. There were 94.0%, 85.1% and 74.7% women, respectively, in normal BMD, osteopenia and osteoporosis groups. The prevalence of colorectal adenomas was 17.9% and 25.3% in the osteopenia and osteoporosis groups, respectively, and 18.0% in the normal BMD group. After adjustment for potential confounders including age, sex, race, body mass index (BMI), tobacco use, alcohol use, history of diabetes, hypertension, or dyslipidemia, osteoporosis was found to be associated with presence of colorectal adenomas more than 2, compared to the normal BMD group. No significant associations were found for the prevalence, size, and location of adenomas. CONCLUSIONS: Our study suggests that osteoporosis is significantly associated with the presence of multiple colorectal adenomas. Prospective studies with a larger sample size are warranted in the future. PMID- 25830037 TI - Evolution of imaging in rectal cancer: multimodality imaging with MDCT, MRI, and PET. AB - Magnetic resonance imaging (MRI), multidetector computed tomography (MDCT), and positron emission tomography (PET) are complementary imaging modalities in the preoperative staging of patients with rectal cancer, and each offers their own individual strengths and weaknesses. MRI is the best available radiologic modality for the local staging of rectal cancers, and can play an important role in accurately distinguishing which patients should receive preoperative chemoradiation prior to total mesorectal excision. Alternatively, both MDCT and PET are considered primary modalities when performing preoperative distant staging, but are limited in their ability to locally stage rectal malignancies. This review details the role of each of these three modalities in rectal cancer staging, and how the three imaging modalities can be used in conjunction. PMID- 25830038 TI - Review of systemic therapies for locally advanced and metastatic rectal cancer. AB - Rectal cancer, along with colon cancer, is the second leading cause of cancer related deaths in the U.S. Up to a quarter of patients have metastatic disease at diagnosis and 40% will develop metastatic disease. The past 10 years have been extremely exciting in the treatment of both locally advanced and metastatic rectal cancer (mRC). With the advent of neoadjuvant chemoradiation, increased numbers of patients with locally advanced rectal cancer (LARC) are surviving longer and some are seeing their tumors shrink to sizes that allow for resection. The advent of biologics and monoclonal antibodies has propelled the treatment of mRC further than many could have hoped. Combined with regimens such as FOLFOX or FOLFIRI, median survival rates have been increased to an average of 23 months. However, the combinations of chemotherapy regimens seem endless for rectal cancer. We will review the major chemotherapies available for locally advanced and mRC as well as regimens currently under investigation such as FOLFOXIRI. We will also review vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors as single agents and in combination with traditional chemotherapy regimens. PMID- 25830039 TI - Management of oligometastatic rectal cancer: is liver first? AB - Twenty percent of patients with rectal cancer present with synchronous liver metastases at the time of initial diagnosis. These patients can be treated with a curative intent, although the choice and sequence of treatment modalities are not well established and are commonly debated in multi-disciplinary tumor boards. In this article we review clinical evidence for various treatment approaches and attempt to formulate a pathway for clinicians to use in evaluating and managing these patients. PMID- 25830040 TI - Impact of the immune system and immunotherapy in colorectal cancer. AB - The development of cancer is a multi-step process involving the gradual loss of regulation over the growth and functional capabilities of normal cells. Much research has been focused on the numerous cell intrinsic factors that govern this process; however, recent attention has turned to understanding the cell extrinsic factors in the tumor microenvironment that appear equally critical to the progression and treatment of cancer. One critical component of the tumor microenvironment is the immune system and it has become increasingly evident that the immune system plays an integral role in preventing and promoting the development of cancer. Understanding the immune cell types and pathways involved in this process has enabled the development of novel biomarkers for prognosis and accelerated the development of immune-based therapeutics, both of which have the potential to forever change the treatment paradigms for colorectal cancer (CRC). In this review, we discuss the impact of the immune system on the initiation, progression and treatment of cancer, specifically focusing on CRC. PMID- 25830041 TI - Non-operative therapies for colorectal liver metastases. AB - Locoregional therapies for colorectal liver metastases complement systemic therapy by providing an opportunity for local control of hepatic spread. The armamentarium for liver-directed therapy includes ablative therapies, embolization, and stereotactic body radiation therapy. At this time, prospective studies comparing these modalities are limited and decision-making relies on a multidisciplinary approach for optimal patient management. Herein, we describe multiple therapeutic non-surgical procedures and an overview of the results of these treatments. PMID- 25830042 TI - Predicting complete response: is there a role for non-operative management of rectal cancer? AB - Pre-operative chemoradiotherapy followed by a total mesorectal excision (TME) is the standard of care for patients with locally advanced (stage II or III) rectal cancer. Approximately 20% of patients may achieve a pathologic complete response after chemoradiation therapy (CRT), which has been shown to be associated with better oncologic outcomes. Whether surgery can be avoided in this population is an area of active investigation. Recent studies demonstrated feasibility and safety of non-operative management in patients with clinical complete response (cCR) after chemoradiotherapy. In this article, we set out to review the current data on non-operative management and to identify areas requiring further investigation, including improvement in imaging for reassessment after CRT and identifying the optimal time frame for restaging. As the field moves forward with non-operative management in select patients with rectal cancer, there continues to be a need to better understand the prognostic factors and biomarkers that may more accurately characterize patients who are qualified for this "wait-and-see" approach and thereby avoid overtreatment, potentially leading to improvements in long-term quality of life. PMID- 25830043 TI - Exploring signet-ring cells in pregnant female. AB - INTRODUCTION: Primary signet-ring cell carcinoma (SRCC) of the colon and rectum are rare form, which present at an advanced stage and have poor prognosis. Different treatment policies of SRCC during different gestational age of pregnancy are explored from the literature. CASE STUDY: A 26-year-old young pregnant female with 10-week gestation presented with constipation and blood in stools and on per rectal examination a tender circumferential stricture was present 2 cm above the anal verge. Magnetic resonant imaging (MRI) pelvis of the patient revealed rectal thickening, the biopsy of which revealed characteristic appearance of "linitis plastica" and diagnosed as poorly differentiated adenocarcinoma with signet ring morphology with wide spread positivity for cytokeratin & p53. With this diagnosis, patient underwent medical termination of pregnancy (MTP). DISCUSSION: SRCC of the colon comprises about only 1% of all cases of colon cancer. When compared with other types of adenocarcinoma, patients with SRCC in the colon are younger and more likely to experience lymph node metastasis. Its incidence in pregnancy is estimated to be less than 0.1%. Certainly, any pregnant patient who reports rectal bleeding or has hemoccult positive stool on examination deserves careful evaluation to rule out cancer. The complex treatment of colorectal cancer in pregnancy is based on the gestational age of the fetus, tumor stage and need for emergent vs. elective management. PMID- 25830045 TI - Liver regeneration following repeat SBRT. AB - Liver stereotactic body radiation therapy (SBRT) is an emerging treatment option for oligometastases and may confer a survival benefit in select patients. Herein, we document the first case of liver regeneration (LR) following repeat right hepatic lobe SBRT in a woman with breast cancer metastases. Retraction of the treated lobe was significant with a near 50% volume reduction. Compensatory contralateral lobe hypertrophy was noted with a 320% volume increase. The overall liver volume remained stable, within +/-5% of baseline. This case indicates that repeat liver SBRT can be delivered safely to individual patients and that compensatory contralateral lobe hypertrophy is observed to maintain a functional liver volume. PMID- 25830044 TI - Numb chin syndrome secondary to leptomeningeal carcinomatosis from gastric adenocarcinoma. AB - Numb chin syndrome (NCS) can be a sign of malignancy. Its association with gastric adenocarcinoma is rare. We report a case of a 27-year-old Hispanic female that presented with complaint of left sided headache associated with numbness of the left side of chin and lower gingiva. Initial brain MRI, whole body gallium scan, high resolution CT of chest and elevated protein in the CSF were suggestive of sarcoidosis. She was treated with IV steroids with transient clinical improvement. Two weeks later, her symptoms worsened and further evaluation revealed the diagnosis of a poorly differentiated metastatic gastric adenocarcinoma with leptomeningeal involvement. This case report aims to emphasize the importance of identifying NCS as a possible indication of an underlying malignant condition. Reported cases of NCS associated with metastatic gastric adenocarcinoma are very rare. PMID- 25830046 TI - A 26-year-old female with metastatic primary gastrointestinal malignancy presenting as menorrhagia. AB - Krukenberg tumor is a metastatic malignant tumor of the ovary arising from a wide variety of primary sources, with the stomach being the most common. The presenting symptoms are non-specific and the primary source is often un identified. Here, we describe a case of a 26-year-old Hispanic gravida 4, para 3 female who presented to our hospital with dysuria, pelvic pain and irregular, heavy menstrual cycles for three months duration. An endometrial biopsy was suggestive of carcinosarcoma. The patient underwent debulking surgery with partial cystectomy and bladder repair. A week later, she presented with hematemesis and an endoscopic biopsy revealed a diagnosis of poorly differentiated gastric adenocarcinoma. The tissue specimen obtained during the initial surgery was identified as Krukenberg tumor. The patient underwent adjuvant chemotherapy with FOLFOX along with gastrectomy with intraperitoneal chemotherapy. PMID- 25830047 TI - Exfoliative erythroderma as a paraneoplastic presentation of adenocarcinoma of the gallbladder. AB - We report a case of a 71-year-old Caucasian male presenting with an exfoliative skin rash all over his body. The patient was also found to have a huge gall bladder mass extending into the liver that turned out to be adenocarcinoma of the gall bladder on biopsy. Gall bladder cancer usually presents with abdominal pain, swelling or jaundice. We report only the second case in literature of a gall bladder adenocarcinoma presenting with exfoliative erythroderma as its paraneoplastic presentation. PMID- 25830048 TI - Retroperitoneal nodular fasciitis: a benign etiology on the differential diagnosis of malignant gastric outlet obstruction. AB - Nodular fasciitis is a relatively rare, benign and proliferative lesion that is not typically found in the retroperitoneal (RP) space and has not been previously reported as a cause of gastric outlet obstruction (GOO). GOOs are frequently associated with malignancies, however, benign etiologies should be considered as well. We report the first case of GOO secondary to nodular fasciitis in the form of a spontaneously regressing RP mass that was initially concerning for malignancy. PMID- 25830049 TI - Transition of a pancreatic neuroendocrine tumor from ghrelinoma to insulinoma: a case report. AB - Pancreatic neuroendocrine tumors (PNETs) are rare with an incidence of 1 in 100,000 populations. PNETs can present either as a functional or non-functional tumor. In functional tumors the symptoms are a result of hormones such as insulin, gastrin, glucagon and vasoactive intestinal peptide (VIP) or others. Ghrelin is a 28 amino acid peptide discovered in 1999 and is thought to be involved in various physiologic and pathologic processes. Due to relatively recent discovery of this hormone, its functions in normal homeostasis and its association with various pathologic processes are still being uncovered. PNETs are a rare entity and the natural history of disease is not well known. We have presented a first ever case of metastatic PNET which presented as a ghrelinoma and later transformed into a symptomatic insulinoma. This case gives us a glimpse into an unusual variant of metastatic PNET. It also tells us that change in functional tumor biology can sometime be more morbid than the metastatic disease itself. PMID- 25830050 TI - Erratum to A case of esophageal squamous cell intraepithelial neoplasia with positivity for type 16 human papillomavirus successfully treated with radiofrequency ablation. AB - [This corrects the article on p. E36 in vol. 5, PMID: 24772344.]. PMID- 25830051 TI - Extramedullary plasmacytoma of the gallbladder diagnosed by endoscopic ultrasound fine needle aspiration (EUS-FNA). AB - Extramedullary plasmacytoma (EMP) is a rare entity that can exist independently or in conjunction with underlying plasma cell myeloma (PCM). When there is underlying multiple myeloma, the presence of EMP portends a poor prognosis. The most common locations for an EMP include the gastrointestinal tract, pleura, testis, skin, peritoneum, liver, endocrine glands and lymph nodes; involvement of the gallbladder is exceedingly rare with only five other cases reported and only one of which was associated with PCM. EMP of the gallbladder can manifest as acute cholecystitis, biliary obstruction, or may be asymptomatic. Treatment is traditionally surgical resection plus adjuvant chemotherapy or autologous stem cell transplant. We present a case of a 53-year-old man with PCM who was found to have a gallbladder mass on imaging and underwent endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) of the mass, which was diagnostic of a plasma cell neoplasm. PMID- 25830052 TI - A case of cardiac metastasis from uterine cervical carcinoma. AB - Cases of cardiac metastasis from uterine cervical carcinoma are rare. While they are occasionally found on autopsy, antemortem recognition is extremely rare. We confirmed a case of cardiac metastasis from cervical carcinoma antemortem, because we observed a decrease in platelet count during the course of treatment. The patient was a 27-year-old woman diagnosed with stage Ib1 uterine cervical carcinoma. Radical hysterectomy with pelvic lymphadenectomy was performed. Para aortic lymph node metastasis was detected on positron emission tomography/computed tomography (PET-CT). Adjuvant chemotherapy was started, and most of the metastatic lesions disappeared. Pelvic lymph node recurrence was suspected on PET-CT during continued chemotherapy; therefore, treatment was shifted to radiation therapy. Tumor shrinkage was recognized, and the initial therapy was completed. A noticeable decrease in platelet count was recognized seven months after treatment. Multidetector CT was performed, and an intracardiac tumor was detected. The patient did not desire any further treatment. She died three weeks after the intracardiac tumor was confirmed. Few previous autopsy studies have reported cardiac metastasis from cervical carcinoma. Thus, it is necessary to consider the possibility of cardiac metastasis for patients diagnosed with terminal cervical carcinoma. PMID- 25830053 TI - Pleomorphic adenoma of breast: a radiological and pathological study of a common tumor in an uncommon location. AB - Pleomorphic adenoma occurs commonly in the major salivary glands but is uncommonly encountered in the breast. In both of these locations, the tumor is typically grossly circumscribed and has a "mixed" histological appearance, being composed of myoepithelial and epithelial components amid a myxochondroid matrix. Herein, we report a case of pleomorphic adenoma of the breast which was preoperatively thought to represent a fibroadenoma on clinical and radiological grounds. It is the rarity of the tumor in the breast, rather than its histological appearance, that causes diagnostic difficulty. PMID- 25830055 TI - Quercetin Down-regulates IL-6/STAT-3 Signals to Induce Mitochondrial-mediated Apoptosis in a Nonsmall- cell Lung-cancer Cell Line, A549. AB - OBJECTIVES: Quercetin, a flavonoid compound, has been reported to induce apoptosis in cancer cells, but its anti-inflammatory effects, which are also closely linked with apoptosis, if any, on non-small-cell lung cancer (NSCLC) have not so far been critically examined. In this study, we tried to determine if quercetin had any demonstrable anti-inflammatory potential, which also could significantly contribute to inducing apoptosis in a NSCLC cell line, A549. METHODS: In this context, several assays, including cytotoxicity, flow cytometry and fluorimetry, were done. Gene expression was analyzed by using a western blot analysis. RESULTS: Results revealed that quercetin could induce apoptosis in A549 cells through mitochondrial depolarization by causing an imbalance in B-cell lymphoma 2/ Bcl2 Antagonist X (Bcl2/Bax) ratio and by down-regulating the interleukine-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway. An analysis of the data revealed that quercetin could block nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activity at early hours, which might cause a down-regulation of the IL-6 titer, and the IL-6 expression, in turn, could inhibit p-STAT3 expression. Down regulation of both the STAT3 and the NF-kappaB expressions might, therefore, cause down-regulation of Bcl2 activity because both are major upstream effectors of Bcl2. Alteration in Bcl2 responses might result in an imbalance in the Bcl2/Bax ratio, which could ultimately bring about mitochondria mediated apoptosis in A549 cells. CONCLUSION: Overall, the finding of this study indicates that a quercetin induced anti-inflammatory pathway in A549 cells appeared to make a significant contribution towards induction of apoptosis in NSCLC and, thus, may have a therapeutic use such as a strong apoptosis inducer in cancer cells. PMID- 25830054 TI - Loranthus ferrugineus: a Mistletoe from Traditional Uses to Laboratory Bench. AB - OBJECTIVES: Loranthus ferrugineus (L. ferrugineus) from Loranthaceae, a mistletoe, is a medicinal herb used for a variety of human ailments. Traditionally, decoctions of this parasitic shrub have been mainly used to treat high blood pressure (BP) and gastrointestinal complaints; usage which is supported by experimental based pharmacological investigations. Nonetheless, there is still limited data available evaluating this plant's traditions, and few studies have been scientifically translated toward evidence based phytomedicine. We therefore provide a concise review of the currently available L. ferrugineus literature and discuss potential directions for future areas of investigation. METHODS: We surveyed available literature covering ethnopharmacological usage of L. ferrugineus and discussed relevant findings, including important future directions and shortcomings for the medicinal values of this parasitic shrub. RESULTS: Evidence based pharmacological approaches significantly covered the medicinal application of L. ferrugineus for hypertension and gastrointestinal complaint management, with a particular focus on the active hydrophilic extract of this herb. CONCLUSION: Understanding the sites of action of this plant and its beneficial effects will provide justification for its use in old traditional treatments, and potentially lead to the development of therapies. Other medicinal applicative areas of this parasitic shrub, such as wound healing, gerontological effects, and antiviral and anticancer activities, are yet to be researched. PMID- 25830056 TI - Behaviors of providers of traditional korean medicine therapy and complementary and alternative medicine therapy for the treatment of cancer patients. AB - OBJECTIVES: In Korea, cancer is one of the most important causes of death. Cancer patients have sought alternative methods, like complementary and alternative medicine (CAM) together with Western medicine, to treat cancer. Also, there are many kinds of providers of CAM therapy, including providers of Korean oriental medicine therapy. The purpose of this study is to identify the behaviors of Korean oriental medicine therapy and CAM therapy providers who treat cancer patients and to provide background knowledge for establishing a new policy with the management and quality control of CAM. METHODS: Structured and well organized questionnaires were made, and 350 persons were surveyed concerning the providers of CAM or Korean oriental medicine. The questionnaires were collected and analyzed. RESULTS: The questionnaires (182) were collected. The questionnaires identified a total of 73 known providers, such as medicinal professionals or other providers of CAM suppliers, 35.6% of whom had had experience with treating cancer patients (52.6% vs. 29.6%). The treatment methods were a little different: alternative therapy and nutritional therapy being preferred by medicinal professionals and mind body modulation therapy and alternative therapy being preferred by other CAM providers. Four patients (7.4%) experienced side effects, and 6 patients (12.5%) experienced legal problems. As the method for managing the therapy, CAM providers, medicinal professionals, and other CAM providers had different viewpoints. For example, some CAM providers stated that both legislation and an official education on CAM or a national examination were needed as a first step to establish the provider's qualifications and that as a second step, a license test was needed for quality control. To the contrary, medicinal professionals stated that a license test was needed before legislation. CONCLUSION: Adequate management and quality control of CAM providers is thought to involve both education and legislation. PMID- 25830057 TI - Repeated Intramuscular-dose Toxicity Test of Watersoluble Carthami Flos (WCF) Pharmacopuncture in Sprague-Dawley Rats. AB - OBJECTIVES: Water-soluble carthami flos (WCF) is a new mixture of Carthami flos (CF) pharmacopuncture. We conducted a 4-week toxicity test of repeated intramuscular injections of WCF in Sprague-Dawley rats. METHODS: Forty male and 40 female rats were divided into 4 groups of 10 male and 10 female SD rats: The control group received 0.5 mL/animal/day of normal saline whereas the three experimental groups received WCF at doses of 0.125, 0.25, and 0.5 mL/animal/day, respectively. For 4 weeks, the solutions were injected into the femoral muscle of the rats alternating from side to side. Clinical signs, body weights, and food consumption were observed; opthalmological examinations and urinalyses were performed. On day 29, blood samples were taken for hematological and clinical chemistry analyses. Then, necropsy was conducted in all animals to observe weights and external and histopathological changes in the bodily organs. All data were tested using a statistical analysis system (SAS). RESULTS: No deaths were observed. Temporary irregular respiration was observed in male rats of the experimental group for the first 10 days. Body weights, food consumptions, opthalmological examinations, urinalyses, clinical chemistry analyses, organ weights and necropsy produced no findings with toxicological meaning. In the hematological analysis, delay of prothrombin time (PT) was observed in male rats of the 0.25- and the 0.5- mL/animal/day groups. In the histopathological test, a dose-dependent inflammatory cell infiltration into the fascia and panniculitis in perimuscular tissues was observed in all animals of the experimental groups. However, those symptoms were limited to local injection points. No toxicological meanings, except localized changes, were noted. CONCLUSION: WCF solution has no significant toxicological meaning, but does produce localized symptoms. No observed adverse effect level (NOAEL) of WCF in male and female rats is expected for doses over 0.5 mL/animal/day. PMID- 25830058 TI - Stability Test and Quantitative and Qualitative Analyses of the Amino Acids in Pharmacopuncture Extracted from Scolopendra subspinipes mutilans. AB - OBJECTIVES: Scolopendra subspinipes mutilans (S. subspinipes mutilans) is known as a traditional medicine and includes various amino acids, peptides and proteins. The amino acids in the pharmacopuncture extracted from S. subspinipes mutilans by using derivatization methods were analyzed quantitatively and qualitatively by using high performance liquid chromatography (HPLC) over a 12 month period to confirm its stability. METHODS: Amino acids of pharmacopuncture extracted from S. subspinipes mutilans were derived by using O-phthaldialdehyde (OPA) & 9-fluorenyl methoxy carbonyl chloride (FMOC) reagent and were analyzed using HPLC. The amino acids were detected by using a diode array detector (DAD) and a fluorescence detector (FLD) to compare a mixed amino acid standard (STD) to the pharmacopuncture from centipedes. The stability tests on the pharmacopuncture from centipedes were done using HPLC for three conditions: a room temperature test chamber, an acceleration test chamber, and a cold test chamber. RESULTS: The pharmacopuncture from centipedes was prepared by using the method of the Korean Pharmacopuncture Institute (KPI) and through quantitative analyses was shown to contain 9 amino acids of the 16 amino acids in the mixed amino acid STD. The amounts of the amino acids in the pharmacopuncture from centipedes were 34.37 ppm of aspartate, 123.72 ppm of arginine, 170.63 ppm of alanine, 59.55 ppm of leucine and 57 ppm of lysine. The relative standard deviation (RSD %) results for the pharmacopuncture from centipedes had a maximum value of 14.95% and minimum value of 1.795% on the room temperature test chamber, the acceleration test chamber and the cold test chamber stability tests. CONCLUSION: Stability tests on and quantitative and qualitative analyses of the amino acids in the pharmacopuncture extracted from centipedes by using derivatization methods were performed by using HPLC. Through research, we hope to determine the relationship between time and the concentrations of the amino acids in the pharmacopuncture extracted from centipedes. PMID- 25830059 TI - Single-dose Intramuscular Injection Toxicology of Danggui Pharmacopuncture (DGP) in Sprague-Dawley Rats. AB - OBJECTIVES: The purpose of the study is to assess both the approximate lethal dose and the single dose intramuscular injection toxicity of Danggui (Angelica gigantis radix) pharmacopuncture (DGP) in Sprague-Dawley (SD) rats. METHODS: The experiments were conducted at the good laboratory practice (GLP) laboratory, Biotoxtech Co., which is a laboratory approved by the ministry of food and drug safety (MFDS). The study was performed according to the GLP regulation and the toxicity test guidelines of the MFDS (2009) after approval of the institutional animal care and use committee of Biotoxtech. Single doses of DGP were injected intramuscularly into the rats in three test groups of 6 week old SD rats (5 male and 5 female rats per groups) in the amounts of 0.1, 0.5, and 1.0 mL/animal for groups 2, 3, and 4, respectively, and normal saline solution in the amount of 1.0 mL/animal was injected intramuscularly into the rats (5 male and 5 female rats) in the control group. Observations of the general symptoms and weight measurements were performed during the 14 day observation period after the injection. Hematologic and serum biochemical examination, necropsy, and a local tolerance test at the injection site were done after the observation period. RESULTS: No death was observed in three test groups (0.1, 0.5 and 1.0 mL/animal group). In addition, the injection of DGP had no effect on general symptoms, weights, hematologic and serum biochemical examination, and necropsy. The results from the local tolerance tests at injection site showed no treatment related effects in the SD rats. CONCLUSION: The results of single dose intramuscular injection of DGP suggest that the approximate lethal dose is above 1.0 mL/animal for both male and female SD rats and that intramuscular injection of DGP may be safe. PMID- 25830060 TI - Toxicity of Eun-bi San Pharmacopuncture Injection in the Muscle of Rats. AB - OBJECTIVES: This study was carried out to analyze the single-dose toxicity of Eun Bi San pharmacopuncture injected into the muscle of Sprague-Dawley (SD) rats. METHODS: All experiments were performed at Biotoxtech, an institution certified to conduct non-clinical studies under the Good Laboratory Practice (GLP) regulations. Six week old SD rats reared by ORIENTBIO were chosen for this pilot study. The reason SD rats were chosen is that they have been widely used in safety tests in the field of medicine, so the results can be easily compared with many other databases. The Eun-Bi San pharmacopuncture was made in a clean room at the Korean Pharmacopuncture Institute (KPI, K-GMP). The constituents of the Eun Bi San pharmacopuncture are Angelicae gigantis radix, Strychni semen and Glycyrrhizae radix. These were extracted at low temperature and low pressure in an aseptic room at the KPI. Doses of Eun- Bi San pharmacopuncture, 0.25, 0.5 and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. This study was performed under the approval of the Institutional Animal Ethics Committee of Biotoxtech Co., Ltd. RESULTS: No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To determine if abnormalities existed in any organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues. CONCLUSION: The results of this study suggest that treatment with Eun-Bi San pharmacopuncture is relatively safe and that its clinical use may be beneficial. Further evaluations and studies on this subject will be needed to provide more concrete evidence in support of these conclusions. PMID- 25830061 TI - Ganoderma Lucidum Pharmacopuncture for Teating Ethanol-induced Chronic Gastric Ulcers in Rats. AB - OBJECTIVES: The stomach is a sensitive digestive organ that is susceptible to exogenous pathogens from the diet. In response to such pathogens, the stomach induces oxidative stress, which might be related to the development of both gastric organic disorders such as gastritis, gastric ulcers, and gastric cancer, and functional disorders such as functional dyspepsia. This study was accomplished to investigate the effect of Ganoderma lucidum pharmacopuncture (GLP) on chronic gastric ulcers in rats. METHODS: The rats were divided into 4 groups of 8 animals each: the normal, the control, the normal saline (NP) and the GLP groups. In this study, the modified ethanol gastritis model was used. The rats were administrated 56% ethanol orally every other day. The dose of ethanol was 8 g/kg body weight. The normal group received the same amount of normal saline instead of ethanol. The NP and the GLP groups were treated with injection of saline and GLP respectively. The control group received no treatment. Two local acupoints CV12 () and ST36 () were used. All laboratory rats underwent treatment for 15 days. On last day, the rats were sacrificed and their stomachs were immediately excised. RESULTS: Ulcers of the gastric mucosa appeared as elongated bands of hemorrhagic lesions parallel to the long axis of the stomach. In the NP and GLP groups, the injuries to the gastric mucosal injuries were not as severe as they were in the control group. Wound healings of the chronic gastric ulcers was promoted by using GLP and significant alterations of the indices in the gastric mucosa were observed. Such protection was demonstrated by gross appearance, histology and immunehistochemistry staining for Bcl-2 associated X (BAX), B-cell lymphoma 2 (Bcl-2) and Transforming growth factor-beta 1 (TGF-beta1). CONCLUSION: These results suggest that GLP at CV12 and ST36 can provide significant protection to the gastric mucosa against an ethanol induced chronic gastric ulcer. PMID- 25830062 TI - Acupuncture in patients with a vertebral compression fracture: a protocol for a randomized, controlled, pilot clinical trial. AB - OBJECTIVES: A vertebral compression fracture (VCF) is characterized by back pain and fracture of a vertebral body on spinal radiography. VCFs of the thoraco lumbar spine are common in the elderly. In general, appropriate analgesics should be prescribed to reduce pain and, thus, promote early mobilization. The ideal treatment approach for VCFs has not been determined. In Korea, acupuncture and herbal medication have been used to treat VCFs for many years. There is empirical evidence that acupuncture might benefit patients with a VCF. However, no randomized, controlled, clinical trials evaluating the efficacy and the safety of acupuncture for treating a VCF have been published. Therefore, we designed a randomized, controlled, pilot, clinical trial to obtain information for the design of a further full scale trial. METHODS: A five week protocol for a randomized, controlled, pilot, clinical trial is presented. Fourteen patients will be recruited and randomly allocated to two groups: a control group receiving interlaminar epidural steroid injections once a week for three weeks, and an experimental group receiving interlaminar epidural steroid injections plus acupuncture treatment (three acupuncture sessions per week for three weeks, nine sessions in total). The primary outcomes will be the pain intensity (visual analogue scale and PainVision(TM) system). The secondary outcome measurements will be the answers on the short form McGill pain questionnaire and the oswestry disability index. Assessments will be made at baseline and at one, three, and five weeks. The last assessment (week five) will take place two weeks after treatment cessation. This study will provide both an indication of feasibility and a clinical foundation for a future large scale trial. The outcomes will provide additional resources for incorporating acupuncture into existing treatments, such as nonsteroidal anti-inflammatory medications, narcotics and vertebral augmentation. This article describes the protocol. PMID- 25830063 TI - Obesity as a Possible Risk Factor for Lost-time Injury in Registered Nurses: A Literature Review. AB - Time-loss injuries are still a major occurrence in Canada, injuring thousands of Canadian workers each year. With obesity rates on the rise across the country, as well as around the world, it is important that the possible effects of obesity in the workplace be fully understood, especially those effects linked to lost-time injuries. The aim of this paper was to evaluate predictors of workplace lost-time injuries and how they may be related to obesity or high body mass index by examining factors associated with lost-time injuries in the health care sector, a well-studied industry with the highest number of reported time loss injuries in Canada. A literature review focusing on lost-time injuries in Registered Nurses (RNs) was conducted using the keywords and terms: lost time injury, workers' compensation, occupational injury, workplace injury, injury, injuries, work, workplace, occupational, nurse, registered nurse, RN, health care, predictors, risk factors, risk, risks, cause, causes, obese, obesity, and body mass index. Data on predictors or factors associated with lost-time injuries in RNs were gathered and organized using Loisel's Work Disability Prevention Management Model and extrapolated upon using existing literature surrounding obesity in the Canadian workplace. PMID- 25830064 TI - Ergonomic evaluation of biomechanical hand function. AB - The human hand is a complex structure that performs various functions for activities of daily living and occupations. This paper presents a literature review on the methodologies used to evaluate hand functions from a biomechanics standpoint, including anthropometry, kinematics, kinetics, and electromyography (EMG). Anthropometry describes the dimensions and measurements of the hand. Kinematics includes hand movements and the range of motion of finger joints. Kinetics includes hand models for tendon and joint force analysis. EMG is used on hand muscles associated with hand functions and with signal-processing technology. PMID- 25830065 TI - Low-Oxygen Atmosphere and its Predictors among Agricultural Shallow Wells in Northern Thailand. AB - BACKGROUND: In 2006, three farmers died at the bottom of an agricultural shallow well where the atmosphere contained only 6% oxygen. This study aimed to document the variability of levels of oxygen and selected hazardous gases in the atmosphere of wells, and to identify ambient conditions associated with the low oxygen situation. METHODS: A cross-sectional survey, conducted in June 2007 and July 2007, measured the levels of oxygen, carbon monoxide, hydrogen sulfide, and explosive gas (percentage of lower explosive limit) at different depths of the atmosphere inside 253 wells in Kamphaengphet and Phitsanulok provinces. Ambient conditions and well use by farmers were recorded. Carbon dioxide was measured in a subset of wells. Variables independently associated with low-oxygen condition (<19.5%) were identified using multivariate logistic regression. RESULTS: One in five agricultural shallow wells had a low-oxygen status, with oxygen concentration decreasing with increasing depth within the well. The deepest-depth oxygen reading ranged from 0.0% to 20.9%. Low levels of other hazardous gases were detected in a small number of wells. The low-oxygen status was independently associated with the depth of the atmosphere column to the water surface [odds ratio (OR) = 13.5 for 8-11 m vs. <6 m], depth of water (OR = 0.17 for 3-<8 m vs. 0-1 m), well cover (OR = 3.95), time elapsed since the last rainfall (OR = 7.44 for >2 days vs. <1 day), and location of well in sandy soil (OR = 3.72). Among 11 wells tested, carbon dioxide was detected in high concentration (>25,000 ppm) in seven wells with a low oxygen level. CONCLUSION: Oxygen concentrations in the wells vary widely even within a small area and decrease with increasing depth. PMID- 25830066 TI - Shift work and occupational stress in police officers. AB - BACKGROUND: Shift work has been associated with occupational stress in health providers and in those working in some industrial companies. The association is not well established in the law enforcement workforce. Our objective was to examine the association between shift work and police work-related stress. METHODS: The number of stressful events that occurred in the previous month and year was obtained using the Spielberger Police Stress Survey among 365 police officers aged 27-66 years. Work hours were derived from daily payroll records. A dominant shift (day, afternoon, or night) was defined for each participant as the shift with the largest percentage of total time a participant worked (starting time from 4:00 AM to 11:59 AM, from 12 PM to 7:59 PM, and from 8:00 PM to 3:59 AM for day, afternoon, and night shift, respectively) in the previous month or year. Analysis of variance and covariance were used to examine the number of total and subscale (administrative/professional pressure, physical/psychological danger, or organizational support) stressful events across the shift. RESULTS: During the previous month and year, officers working the afternoon and night shifts reported more stressful events than day shift officers for total stress, administrative/professional pressure, and physical/psychological danger (p < 0.05). These differences were independent of age, sex, race/ethnicity, and police rank. The frequency of these stressful events did not differ significantly between officers working the afternoon and night shifts. CONCLUSION: Non-day shift workers may be exposed to more stressful events in this cohort. Interventions to reduce or manage police stress that are tailored by shift may be considered. PMID- 25830067 TI - Evaluation of Coordination of Emergency Response Team through the Social Network Analysis. Case Study: Oil and Gas Refinery. AB - BACKGROUND: The purpose of this study was to examine the cohesions status of the coordination within response teams in the emergency response team (ERT) in a refinery. METHODS: For this study, cohesion indicators of social network analysis (SNA; density, degree centrality, reciprocity, and transitivity) were utilized to examine the coordination of the response teams as a whole network. The ERT of this research, which was a case study, included seven teams consisting of 152 members. The required data were collected through structured interviews and were analyzed using the UCINET 6.0 Social Network Analysis Program. RESULTS: The results reported a relatively low number of triple connections, poor coordination with key members, and a high level of mutual relations in the network with low density, all implying that there were low cohesions of coordination in the ERT. CONCLUSION: The results showed that SNA provided a quantitative and logical approach for the examination of the coordination status among response teams and it also provided a main opportunity for managers and planners to have a clear understanding of the presented status. The research concluded that fundamental efforts were needed to improve the presented situations. PMID- 25830068 TI - Healthcare Work and Organizational Interventions to Prevent Work-related Stress in Brindisi, Italy. AB - BACKGROUND: Organizational changes that involve healthcare hospital departments and care services of health districts, and ongoing technological innovations and developments in society increasingly expose healthcare workers (HCWs) to work related stress (WRS). Minimizing occupational exposure to stress requires effective risk stress assessment and management programs. METHODS: The authors conducted an integrated analysis of stress sentinel indicators, an integrated analysis of objective stress factors of occupational context and content areas, and an integrated analysis between nurses and physicians of hospital departments and care services of health districts in accordance with a multidimensional validated tool developed in Italy by the National Network for the Prevention of Work-Related Psychosocial Disorders. The purpose of this retrospective observational study was to detect and analyze in different work settings the level of WRS resulting from organizational changes implemented by hospital healthcare departments and care services of health districts in a sample of their employees. RESULTS: The findings of the study showed that hospital HCWs seemed to incur a medium level risk of WRS that was principally the result of work context factors. The implementation of improvement interventions focused on team development, safety training programs, and adopting an ethics code for HCWs, and it effectively and significantly reduced the level of WRS risk in the workplace. CONCLUSION: In this study HCW resulted to be exposed to occupational stress factors susceptible to reduction. Stress management programs aimed to improve work context factors associated with occupational stress are required to minimize the impact of WRS on workers. PMID- 25830069 TI - Integrating building information modeling and health and safety for onsite construction. AB - BACKGROUND: Health and safety (H&S) on a construction site can either make or break a contractor, if not properly managed. The usage of Building Information Modeling (BIM) for H&S on construction execution has the potential to augment practitioner understanding of their sites, and by so doing reduce the probability of accidents. This research explores BIM usage within the construction industry in relation to H&S communication. METHODS: In addition to an extensive literature review, a questionnaire survey was conducted to gather information on the embedment of H&S planning with the BIM environment for site practitioners. RESULTS: The analysis of responses indicated that BIM will enhance the current approach of H&S planning for construction site personnel. CONCLUSION: From the survey, toolbox talk will have to be integrated with the BIM environment, because it is the predominantly used procedure for enhancing H&S issues within construction sites. The advantage is that personnel can visually understand H&S issues as work progresses during the toolbox talk onsite. PMID- 25830070 TI - Safety management practices in small and medium enterprises in India. AB - BACKGROUND: Small and medium enterprises (SMEs) are often the main pillar of an economy. Minor accidents, ergonomics problems, old and outdated machinery, and lack of awareness have created a need for implementation of safety practices in SMEs. Implementation of healthy working conditions creates positive impacts on economic and social development. METHODS: In this study, a questionnaire was developed and administered to 30 randomly chosen SMEs in and around Mumbai, Maharashtra, and other states in India to evaluate safety practices implemented in their facilities. The study also looked into the barriers and drivers for technology innovation and suggestions were also received from the respondent SMEs for best practices on safety issues. RESULTS: In some SMEs, risks associated with safety issues were increased whereas risks were decreased in others. Safety management practices are inadequate in most SMEs. Market competitiveness, better efficiency, less risk, and stringent laws were found to be most significant drivers; and financial constraints, lack of awareness, resistance to change, and lack of training for employees were found to be main barriers. CONCLUSION: Competition between SMEs was found to be major reason for implementation of safety practices in the SMEs. The major contribution of the study has been awareness building on safety issues in the SMEs that participated in the project. PMID- 25830071 TI - Cold exposure and health effects among frozen food processing workers in eastern Thailand. AB - Frozen food processing workers work under a cold environment which can cause several adverse health effects.This study explored factors affecting workers' health in the frozen food industry in Thailand. Participants comprised 497 workers exposed to a cold working environment and 255 office workers who served as the controls. Data were collected by a survey on the work environment, and the interview of workers for abnormal symptoms. The exposed group had the following characteristics: 52.7% male, overall average age of 27 (SD 6.6) years old, attained elementary education (Grade 4 and Grade 6) (54.1%), married (48.9%), smokers (21.3%), alcohol consumption (31.0%), duration of work was between 1 and 5 years (65.2%), working 6 days a week (82.7%), 1-5 hours of overtime per week (33.8%), office workers (33.9%); work category: sizing (6.9%), peeling (28.3%) dissecting (22.2%), and in the warehouse (8.6%). The temperature in the work environment ranged from 17.2 degrees C to 19.2 degrees C in most sections, -18.0 degrees C in the warehouse, and 25 degrees C in the office areas. Warehouse workers had more abnormal symptoms than controls including repeated pain in the musculoskeletal system (OR 11.9; 95% CI 6.12-23.45), disturbance throughout the body (OR 4.60; 95% CI 2.00-10.56), respiratory symptoms (OR 9.73; 95% CI 3.53 26.80), episodic finger symptoms (OR 13.51; 95% CI 5.17-35.33). The study results suggest that workers' health should be monitored especially with regard to back and muscle pain, respiratory symptoms, episodic finger symptoms, and cardiovascular symptoms. Health promotion campaigns such as antismoking and reduction of alcohol consumption should be established because smoking and alcohol consumption are contributing factors to the pathogenesis of Raynaud's phenomenon and peripheral vascular disorders such as hypertension and heart disease. PMID- 25830072 TI - Evaluation of microbial load in oropharyngeal mucosa from tannery workers. AB - BACKGROUND: Animal skin provides an ideal medium for the propagation of microorganisms and it is used like raw material in the tannery and footware industry. The aim of this study was to evaluate and identify the microbial load in oropharyngeal mucosa of tannery employees. METHODS: The health risk was estimated based on the identification of microorganisms found in the oropharyngeal mucosa samples. The study was conducted in a tanners group and a control group. Samples were taken from oropharyngeal mucosa and inoculated on plates with selective medium. In the samples, bacteria were identified by 16S ribosomal DNA analysis and the yeasts through a presumptive method. In addition, the sensitivity of these microorganisms to antibiotics/antifungals was evaluated. RESULTS: The identified bacteria belonged to the families Enterobacteriaceae, Pseudomonadaceae, Neisseriaceae, Alcaligenaceae, Moraxellaceae, and Xanthomonadaceae, of which some species are considered as pathogenic or opportunistic microorganisms; these bacteria were not present in the control group. Forty-two percent of bacteria identified in the tanners group are correlated with respiratory diseases. Yeasts were also identified, including the following species: Candida glabrata, Candida tropicalis, Candida albicans, and Candida krusei. Regarding the sensitivity test of bacteria identified in the tanners group, 90% showed sensitivity to piperacillin/tazobactam, 87% showed sensitivity to ticarcillin/clavulanic acid, 74% showed sensitivity to ampicillin/sulbactam, and 58% showed sensitivity to amoxicillin/clavulanic acid. CONCLUSION: Several of the bacteria and yeast identified in the oropharyngeal mucosa of tanners have been correlated with infections in humans and have already been reported as airborne microorganisms in this working environment, representing a health risk for workers. PMID- 25830073 TI - High-intensity Fitness Training Among a National Sample of Male Career Firefighters. AB - Obesity and fitness have been identified as key health concerns among USA firefighters yet little is known about the current habits related to exercise and diet. In particular, high-intensity training (HIT) has gained increasing popularity among this population but limited quantitative data are available about how often it is used and the relationship between HIT and other outcomes. Using survey methodology, the current study evaluated self-reported HIT and diet practice among 625 male firefighters. Almost one-third (32.3%) of participants reported engaging in HIT. Body composition, as measured by waist circumference and percentage body fat, was significantly related to HIT training, with HIT participants being approximately half as likely to be classified as obese using body fat [odds ratio (OR) = 0.52, 95% confidence interval (CI) = 0.34-0.78] or waist circumference (OR = 0.61, 95% CI = 0.37-0.98). Those who engaged in HIT were more than twice as likely as those who did not (OR = 2.24, 95% CI = 1.42 3.55) to meet fitness recommendations. Findings highlight directions for future prevention and intervention efforts. PMID- 25830074 TI - Letter on oral health of stone mine workers. PMID- 25830075 TI - Electronic Cigarettes: Vulnerability of Youth. AB - Electronic cigarettes have become popular and are heavily promoted as a safer cigarette and an aid to quit smoking. Although they may have value in reducing cigarette use among smokers, they are of limited value in smoking cessation and pose many problems, particularly in children. Nicotine is highly addictive and affects virtually all cells in the body. It is particularly harmful to developing brains and other organs. The electronic nicotine delivery systems are largely uncontrolled and safety risks are manifold. Initiating nicotine use and increasing dependence in the population may be linked with increased tobacco and other addictive substance abuse even if the individual electronic cigarette delivers less harm than a combustible cigarette does. PMID- 25830076 TI - Geographical, environmental and pathophysiological influences on the human blood transcriptome. AB - Gene expression variation provides a read-out of both genetic and environmental influences on gene activity. Geographical, genomic and sociogenomic studies have highlighted how life circumstances of an individual modify the expression of hundreds and in some cases thousands of genes in a co-ordinated manner. This review places such results in the context of a conserved set of 90 transcripts known as Blood Informative Transcripts (BIT) that capture the major conserved components of variation in the peripheral blood transcriptome. Pathophysiological states are also shown to associate with the perturbation of transcript abundance along the major axes. Discussion of false negative rates leads us to argue that simple significance thresholds provide a biased perspective on assessment of differential expression that may cloud the interpretation of studies with small sample sizes. PMID- 25830077 TI - Is Helicobacter Pylori Associated with an Increased Complication Rate after Sleeve Gastrectomy? AB - Introduction: Few studies have reported the prevalence and consequences of infection with Helicobacter pylori among obese patients undergoing sleeve gastrectomy. This study reviewed whether infection with H. pylori has any association with postoperative complications. This study also examined whether there was any difference in postoperative percent excess weight loss (%EWL). Materials and Methods: In this retrospective study, the pathology reports of 400 patients who underwent sleeve gastrectomy between 2008 and 2013 at the authors' institution were reviewed. Data examined included the demographics, perioperative and postoperative complications, and %EWL in the follow-up period. Results: In 68 of 400 patients (17%), H. pylori was positive in the specimen. In the H. pylori negative group, 332 patients were eligible for follow-up. No perioperative and postoperative (30 days) complications were registered in the H. pylori positive group. There was one postoperative leak in the H. pylori negative group. No other complications were reported in patients during the 36 months follow-up. There were no significant differences between groups in terms of %EWL during postoperative follow-up. Conclusions: In this study, the prevalence of H. pylori infection among sleeve gastrectomy patient was 17%. H. pylori did not seem to have any influence on postoperative outcomes or %EWL. H. pylori did not increase perioperative complications. PMID- 25830078 TI - Stricture Rate after Laparoscopic Roux-en-Y Gastric Bypass with a 21-mm Circular Stapler versus a 25-mm Linear Stapler. AB - Background: Obesity is estimated to affect more than one and a half billion adults. Laparoscopic Roux-en-Y gastric bypass (LRYGB) has become one of the preferred weight loss procedures. However, complications can occur. Strictures at the gastrojejunal anastomosis lead to clinical symptoms such as vomiting, dysphagia, and patient discomfort. The stricture rate has been correlated with the size and type of stapler used. Methods: A retrospective review of the clinical records of patients who underwent LRYGB was performed between 2003 and 2010. A comparison was made between a 21-mm circular stapler technique and a 25 mm linear stapler technique. Results: The stricture rate for the 21-mm circular stapler group was 7.12% and comparable to the national average. Using the 25-mm linear stapler, this complication rate significantly decreased to 1.09% (p<0.0004; odds ratio 6.5; [95% confidence interval 1.96-33.83]). Conclusions: Stricture after LRYGB is a serious complication. This study found that with a change in technique, this complication can be decreased considerably. PMID- 25830080 TI - An English vocabulary learning support system for the learner's sustainable motivation. AB - In English vocabulary learning, continuation is an important factor; however, many learners are not good at continuing learning because they tend to prefer amusement or rest. Our proposed system is targeting learners who are eager to learn but are not able to continue learning for various reasons. We especially focused on English vocabulary learning, and described an approach for learners who have difficulty with continuing learning. Our developed application aggressively supports the learners' sustainable motivation by gamification techniques and an efficient difficulty setting method. PMID- 25830079 TI - Evaluating the Effect of Drain Site on Abdominal Pain after Laparoscopic Gastric Bypass Surgery for Morbid Obesity: A Randomized Controlled Trial. AB - Background: Most morbidly obese patients complain of abdominal pain after laparoscopic gastric bypass (LGBP) surgery. In this study, the relationship between the prevalence and severity of pain and the drain site was assessed. Methods: Fifty morbidly obese patients undergoing LGBP surgery were selected, and a drain was randomly inserted postoperatively to the left 5 mm port in 25 cases and to the right in the other 25. All patients filled out a questionnaire, including a visual analog scale for the quality and quantity of pain, exacerbating and alleviating factors and its relation to patient's positioning, in the first 24 hours, first week, and first month after the operation. Result: In both groups, all patients had abdominal pain 24 hours after the operation. However, in the right-sided drain group, most patients (52%) experienced mild pain, whereas most patients (56%) in the left-sided drain group had severe pain (p=0.028). At weeks 1 and 4, there was no significant difference between the two groups in terms of severity of pain (p=0.068 and 0.875, respectively, for both times). After the first 24 hours and first week, the mean pain score was significantly lower in the right-sited drain group compared to the left-sited drain group (p=0.012 and 0.006). Conclusion: Early abdominal pain after LGBP surgery is significantly reduced in the right-sided drain group. PMID- 25830081 TI - MEO based secured, robust, high capacity and perceptual quality image watermarking in DWT-SVD domain. AB - The aim of this paper is to present multiobjective evolutionary optimizer (MEO) based highly secured and strongly robust image watermarking technique using discrete wavelet transform (DWT) and singular value decomposition (SVD). Many researchers have failed to achieve optimization of perceptual quality and robustness with high capacity watermark embedding. Here, we achieved optimized peak signal to noise ratio (PSNR) and normalized correlation (NC) using MEO. Strong security is implemented through eight different security levels including watermark scrambling by Fibonacci-Lucas transformation (FLT). Haar wavelet is selected for DWT decomposition to compare practical performance of wavelets from different wavelet families. The technique is non-blind and tested with cover images of size 512x512 and grey scale watermark of size 256x256. The achieved perceptual quality in terms of PSNR is 79.8611dBs for Lena, 87.8446 dBs for peppers and 93.2853 dBs for lake images by varying scale factor K1 from 1 to 5. All candidate images used for testing namely Lena, peppers and lake images show exact recovery of watermark giving NC equals to 1. The robustness is tested against variety of attacks on watermarked image. The experimental demonstration proved that proposed method gives NC more than 0.96 for majority of attacks under consideration. The performance evaluation of this technique is found superior to all existing hybrid image watermarking techniques under consideration. PMID- 25830082 TI - Presence and distribution of mosquito larvae predators and factors influencing their abundance along the Mara River, Kenya and Tanzania. AB - Among all the malaria controlling measures, biological control of mosquito larvae may be the cheapest and easiest to implement. This study investigated baseline predation of immature mosquitoes by macroinvertebrate predators along the Mara River, determined the diversity of predators and mosquito larvae habitats and the range of their adaptive capacity to water physico-chemical parameters. Between July and August 2011, sampling sites (n=39) along the Mara River were selected and investigated for the presence of macroinvertebrate predators and mosquito larvae. The selected sampling sites were geocoded and each dipped 20 times using standard mosquito larvae dipper to sample mosquito larvae, while a D-frame dip net was used to capture the macroinvertebrate predators. Water physico-chemical parameters (dissolved oxygen, temperature, pH, conductivity, salinity and turbidity) were taken in situ at access points, while hardness and alkalinity were measured titrimetically. The influence of macroinvertebrate predator occurrence was correlated with mosquito larvae and water quality parameters using Generalized Linear Model (GLM). Predators (n=297) belonging to 3 orders of Hemiptera (54.2%), Odonata (22.9%) and Coleoptera (22.9%), and mosquito larvae (n=4001) belonging to 10 species, which included An.gambiae s.l (44.9%), Culex spp. (34.8%) and An. coustani complex (13.8%), An. maculipalpis (3.6%), An. phaorensis (1.2%), An. funestus group (0.5%), An. azaniae (0.4%), An. hamoni (0.3%), An. christyi (0.3%), An. ardensis (0.08%), An. faini (0.07%), An. sergentii (0.05%) and 0.05% of Aedes mosquito larvae which were not identified to species level, due to lack of an appropriate key, were captured from different habitats along the Mara river. It was established that invasion of habitats by the macroinvertebrate predators were partially driven by the presence of mosquito larvae (p < 0.001), and the prevailing water physico-chemical parameters (DO, temperature, and turbidity, p <0.001). Understanding abiotic and biotic factors which favour mosquitoes and macroinveterbrate co-occurrence may contribute to the control of malaria. PMID- 25830083 TI - Phyllopertha horticola (Coleoptera: Scarabaeidae) larvae in eastern Austrian mountainous grasslands and the associated damage risk related to soil, topography and management. AB - The soil-dwelling larvae of several Scarabaeidae species (white grubs), like the cockchafer (Melolontha melolontha) and the garden chafer (Phyllopertha horticola), are serious pests in European cultivated grassland, reducing grass yield and destroying the turf by root-feeding. Nevertheless, the factors responsible for the development of large grub populations and the associated damage risk are poorly understood. The objectives of the study were to survey grub densities in grassland sites with different damage histories and find correlations with environmental and management variables. Data on grub densities were collected at 10 farms in the eastern Austrian Alps in September and October 2011. At each farm, one recently damaged site (high risk) and one site at which grub damage had never been observed by the farmers (undamaged site = low risk; each site: 500 m(2)) were sampled. All sites were dominated by P. horticola (99% of 1,422 collected individuals; maximum density 303 grubs/m(2)), which indicates that grub damage there is mainly caused by that species. Recently damaged sites tended to higher grub densities than undamaged sites. However, 3 out of 10 undamaged sites harbored high grub populations as well. Humus content together with the depth of the A-horizon significantly explained 38% of P. horticola grub density variance, with highest densities in deeper humus-rich soils. The risk of grub damage was positively connected to the humus content and negatively related to the cutting frequency. For the investigated mountainous grassland sites, these results suggest an important role of humus for the development of high grub densities and an effect of management intensity on grub damage. PMID- 25830084 TI - Multiple extra-ischemic hemorrhages following intravenous thrombolysis in a patient with Trousseau syndrome: case study. AB - BACKGROUND: Intracerebral hemorrhage is the most feared complication of intravenous thrombolysis for acute ischemic stroke. Such hemorrhage usually occurs within or at the margin of ischemic or manifestly infarcted brain tissue. A patient with Trousseau syndrome who developed multiple extra-ischemic hemorrhages following intravenous thrombolysis is described. CASE DESCRIPTION: An 80-year-old Japanese man with no other underlying disease was diagnosed with unresectable advanced lung cancer (stage IV) without brain metastasis and had not yet been treated. The patient suddenly presented with disturbance of consciousness, right hemiplegia, and total aphasia, and was admitted to our hospital. Magnetic resonance imaging revealed acute cerebral infarction extending from the basal ganglia to the corona radiata of the left cerebrum and multiple small areas of bilateral cerebral cortices. Cardiogenic cerebral embolism was considered among the differential diagnoses, but the brain natriuretic peptide level was within the normal range, and no arrhythmias such as atrial fibrillation were observed. With no other causes, the patient was diagnosed with Trousseau syndrome due to hypercoagulability associated with the advanced lung cancer. The patient received intravenous tissue plasminogen activator (t-PA) at 96 minutes after onset of symptoms. His symptoms partially improved, but they suddenly deteriorated at 84 minutes after the thrombolysis. A computed tomography (CT) scan immediately after the neurological deterioration revealed a subcortical hemorrhage in the left occipital lobe. A repeat CT scan the day after onset showed enlargement of the left occipital hemorrhage and two new subcortical hemorrhages in the right frontal and right temporal lobes. These hemorrhages were located in areas remote from the acute ischemic lesions. CONCLUSION: To the best of our knowledge, this is the first reported case of multiple extra-ischemic hemorrhages following intravenous thrombolysis in a patient with Trousseau syndrome. The course of this case suggests that intravenous t-PA administration for acute ischemic stroke with Trousseau syndrome may be associated with a higher risk of intracranial hemorrhage. PMID- 25830086 TI - Genome-wide analysis of the AP2/ERF gene family in Salix arbutifolia. AB - AP2/ERF genes encode transcriptional regulators with a variety of functions in plant growth and development and in response to biotic and abiotic stresses. To date, there are no detailed classification and expression profiles for AP2/ERF genes in Salix. In this study, a comprehensive computational analysis identified 173 AP2/ERF superfamily genes in willow (Salix arbutifolia), by using in silico cloning methods with the use of the AP2/ERF conserved domain amino acid sequence of Arabidopsis thaliana as a probe. Based on the results of phylogenetic analyses and the number of AP2/ERF domains, the AP2/ERF genes were classified into four groups: AP2, RAV, ERF and Soloist. The expression profile was analyzed using transcriptome data from different tissues. A comparative analysis of AP2/ERF superfamily genes among Salix, Populus and Arabidopsis was performed. The Salix DREB, AP2 and RAV groups had a similar number to those in Arabidopsis, and the size of the ERF subfamily in Salix was about 1.4-fold that of Arabidopsis. The Salix DREB subfamily was smaller compared to Populus, while the other families were similar in size to those in Populus. These results will be useful for future functional analyses of the ERF family genes. PMID- 25830085 TI - Lysine nutrition in swine and the related monogastric animals: muscle protein biosynthesis and beyond. AB - Improving feed efficiency of pigs with dietary application of amino acids (AAs) is becoming increasingly important because this practice can not only secure the plasma AA supply for muscle growth but also protect the environment from nitrogen discharge with feces and urine. Lysine, the first limiting AA in typical swine diets, is a substrate for generating body proteins, peptides, and non-peptide molecules, while excess lysine is catabolized as an energy source. From a regulatory standpoint, lysine is at the top level in controlling AA metabolism, and lysine can also affect the metabolism of other nutrients. The effect of lysine on hormone production and activities is reflected by the change of plasma concentrations of insulin and insulin-like growth factor 1. Lysine residues in peptides are important sites for protein post-translational modification involved in epigenetic regulation of gene expression. An inborn error of a cationic AA transporter in humans can lead to a lysinuric protein intolerance condition. Dietary deficiency of lysine will impair animal immunity and elevate animal susceptibility to infectious diseases. Because lysine deficiency has negative impact on animal health and growth performance and it appears that dietary lysine is non-toxic even at a high dose of supplementation, nutritional emphasis should be put on lysine supplementation to avoid its deficiency rather than toxicity. Improvement of muscle growth of monogastric animals such as pigs via dietary lysine supply may be due to a greater increase in protein synthesis rather than a decrease in protein degradation. Nevertheless, the underlying metabolic and molecular mechanisms regarding lysine effect on muscle protein accretion merits further clarification. Future research undertaken to fully elucidate the metabolic and regulatory mechanisms of lysine nutrition could provide a sound scientific foundation necessary for developing novel nutritional strategies to enhance the muscle growth and development of meat animals. PMID- 25830087 TI - Successful treatment of an invasive fungal infection caused by Talaromyces sp. with voriconazole. AB - Invasive fungal infections (IFI) are on the rise due to increasing numbers of immunosuppressed and critically ill patients. A malignant-looking pulmonary nodule in an immunosuppressed patient may indeed be caused by a fungal organism. We report a patient, who was eventually diagnosed with an IFI caused by an agent of hyalohyphomycosis, Talaromyces sp. determined via molecular methods and succesfully treated with voriconazole. PMID- 25830088 TI - Disseminated Conidiobolus incongruus in a dog: A case report and literature review. AB - Conidiobolomycosis is a rare fungal disease of both humans and animals, occurring mainly in tropical and subtropical climates. We describe a disseminated fungal infection in a young, apparently immunocompetent dog who initially presented for antibiotic resistant pneumonia. Histopathology and mycology identified a Conidiobolus sp., further confirmed as Conidiobolus incongruus through DNA sequencing of D1/D2 regions. This is the first report of this species causing disease in dogs and the fifth reported infection in animals. PMID- 25830089 TI - Clic4, a novel protein that sensitizes beta-cells to apoptosis. AB - OBJECTIVES: Chloride intracellular channel protein 4 (Clic4) is a ubiquitously expressed protein involved in multiple cellular processes including cell-cycle control, cell differentiation, and apoptosis. Here, we investigated the role of Clic4 in pancreatic beta-cell apoptosis. METHODS: We used betaTC-tet cells and islets from beta-cell specific Clic4 knockout mice (betaClic4KO) and assessed cytokine-induced apoptosis, Bcl2 family protein expression and stability, and identified Clic4-interacting proteins by co-immunoprecipitation and mass spectrometry analysis. RESULTS: We show that cytokines increased Clic4 expression in betaTC-tet cells and in mouse islets and siRNA-mediated silencing of Clic4 expression in betaTC-tet cells or its genetic inactivation in islets beta-cells, reduced cytokine-induced apoptosis. This was associated with increased expression of Bcl-2 and increased expression and phosphorylation of Bad. Measurement of Bcl 2 and Bad half-lives in betaTC-tet cells showed that Clic4 silencing increased the stability of these proteins. In primary islets beta-cells, absence of Clic4 expression increased Bcl-2 and Bcl-xL expression as well as expression and phosphorylation of Bad. Mass-spectrometry analysis of proteins co immunoprecipitated with Clic4 from betaTC-tet cells showed no association of Clic4 with Bcl-2 family proteins. However, Clic4 co-purified with proteins from the proteasome suggesting a possible role for Clic4 in regulating protein degradation. CONCLUSIONS: Collectively, our data show that Clic4 is a cytokine induced gene that sensitizes beta-cells to apoptosis by reducing the steady state levels of Bcl-2, Bad and phosphorylated Bad. PMID- 25830090 TI - Chronic hyperglycemia downregulates GLP-1 receptor signaling in pancreatic beta cells via protein kinase A. AB - OBJECTIVE: Glucagon-like peptide 1 (GLP-1) enhances insulin secretion and protects beta-cell mass. Diabetes therapies targeting the GLP-1 receptor (GLP 1R), expressed in numerous tissues, have diminished dose-response in patients with type 2 diabetes compared with healthy human controls. The aim of this study was to determine the mechanistic causes underlying the reduced efficacy of GLP-1R ligands. METHODS: Using primary mouse islets and the beta-cell line MIN6, outcomes downstream of the GLP-1R were analyzed: Insulin secretion; phosphorylation of the cAMP-response element binding protein (CREB); cAMP responses. Signaling systems were studied by immunoblotting and qRT-PCR, and PKA activity was assayed. Cell surface localization of the GLP-1R was studied by confocal microscopy using a fluorescein-tagged exendin-4 and GFP-tagged GLP-1R. RESULTS: Rodent beta-cells chronically exposed to high glucose had diminished responses to GLP-1R agonists including: diminished insulin secretory response; reduced phosphorylation of (CREB); impaired cAMP response, attributable to chronically increased cAMP levels. GLP-1R signaling systems were affected by hyperglycemia with increased expression of mRNAs encoding the inducible cAMP early repressor (ICER) and adenylyl cyclase 8, reduced PKA activity due to increased expression of the PKA-RIalpha subunit, reduced GLP-1R mRNA expression and loss of GLP-1R from the cell surface. To specifically examine the loss of GLP 1R from the plasma membrane a GLP-1R-GFP fusion protein was employed to visualize subcellular localization. Under low glucose conditions or when PKA activity was inhibited, GLP-1R-GFP was found at the plasma membrane. Conversely high glucose, expression of a constitutively active PKA subunit, or exposure to exendin-4 or forskolin led to GLP-1R-GFP internalization. Mutation of serine residue 301 of the GLP-1R abolished the glucose-dependent loss of the receptor from the plasma membrane. This was associated with a loss of an interaction between the receptor and the small ubiquitin-related modifier (SUMO), an interaction that was found to be necessary for internalization of the receptor. CONCLUSIONS: These data show that glucose acting, at least in part, via PKA leads to the loss of the GLP-1R from the cell surface and an impairment of GLP-1R signaling, which may underlie the reduced clinical efficacy of GLP-1R based therapies in individuals with poorly controlled hyperglycemia. PMID- 25830091 TI - LKB1 and AMPKalpha1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia. AB - AIMS/HYPOTHESIS: Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear. METHODS: Here, we ablated LKB1 (alphaLKB1KO), or the catalytic alpha subunits of AMPK (alphaAMPKdKO, -alpha1KO, -alpha2KO), selectively in ~45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre. RESULTS: Blood glucose levels in male alphaLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). alphaLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in alphaAMPKalpha1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in alphaLKB1KO, alphaAMPKdKO, and -alpha1KO, but not -alpha2KO islets. CONCLUSIONS/INTERPRETATION: An LKB1-dependent signalling cassette, involving but not restricted to AMPKalpha1, is required in pancreatic alpha cells for the control of glucagon release by glucose. PMID- 25830092 TI - FTO is necessary for the induction of leptin resistance by high-fat feeding. AB - OBJECTIVE: Loss of function FTO mutations significantly impact body composition in humans and mice, with Fto-deficient mice reported to resist the development of obesity in response to a high-fat diet (HFD). We aimed to further explore the interactions between FTO and HFD and determine if FTO can influence the adverse metabolic consequence of HFD. METHODS: We studied mice deficient in FTO in two well validated models of leptin resistance (HFD feeding and central palmitate injection) to determine how Fto genotype may influence the action of leptin. Using transcriptomic analysis of hypothalamic tissue to identify relevant pathways affected by the loss of Fto, we combined data from co immunoprecipitation, yeast 2-hybrid and luciferase reporter assays to identify mechanisms through which FTO can influence the development of leptin resistant states. RESULTS: Mice deficient in Fto significantly increased their fat mass in response to HFD. Fto (+/-) and Fto (-/-) mice remained sensitive to the anorexigenic effects of leptin, both after exposure to a HFD or after acute central application of palmitate. Genes encoding components of the NFkB signalling pathway were down-regulated in the hypothalami of Fto-deficient mice following a HFD. When this pathway was reactivated in Fto-deficient mice with a single low central dose of TNFalpha, the mice became less sensitive to the effect of leptin. We identified a transcriptional coactivator of NFkB, TRIP4, as a binding partner of FTO and a molecule that is required for TRIP4 dependent transactivation of NFkB. CONCLUSIONS: Our study demonstrates that, independent of body weight, Fto influences the metabolic outcomes of a HFD through alteration of hypothalamic NFkB signalling. This supports the notion that pharmacological modulation of FTO activity might have the potential for therapeutic benefit in improving leptin sensitivity, in a manner that is influenced by the nutritional environment. PMID- 25830093 TI - TRAP-seq defines markers for novel populations of hypothalamic and brainstem LepRb neurons. AB - OBJECTIVE: Leptin acts via its receptor (LepRb) on multiple subpopulations of LepRb neurons in the brain, each of which controls specific aspects of energy balance. Despite the importance of LepRb-containing neurons, the transcriptome and molecular identity of many LepRb subpopulations remain undefined due to the difficulty of studying the small fraction of total cells represented by LepRb neurons in heterogeneous brain regions. Here we sought to examine the transcriptome of LepRb neurons directly and identify markers for functionally relevant LepRb subsets. METHODS: We isolated mRNA from mouse hypothalamic and brainstem LepRb cells by Translating Ribosome Affinity Purification (TRAP) and analyzed it by RNA-seq (TRAP-seq). RESULTS: TRAP mRNA from LepRb cells was enriched for markers of peptidergic neurons, while TRAP-depleted mRNA from non LepRb cells was enriched for markers of glial and immune cells. Genes encoding secreted proteins that were enriched in hypothalamic and brainstem TRAP mRNA revealed subpopulations of LepRb neurons that contained neuropeptide-encoding genes (including prodynorphin, Pdyn) not previously used as functional markers for LepRb neurons. Furthermore, Pdyn (cre) -mediated ablation of Lepr (flox) in Pdyn-expressing neurons (LepRb (Pdyn) KO mice) blunted energy expenditure to promote obesity during high-fat feeding. CONCLUSIONS: TRAP-seq of CNS LepRb neurons defines the LepRb neuron transcriptome and reveals novel markers for previously unrecognized subpopulations of LepRb neurons. PMID- 25830095 TI - Enhanced insulin signaling in density-enhanced phosphatase-1 (DEP-1) knockout mice. AB - OBJECTIVE: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. METHODS: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj (-/-) (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. RESULTS: High-fat diet fed-Ptprj (-/-) mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj ( /-) mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj (-/-) mice. CONCLUSION: Together, these data establish DEP-1 as novel negative regulator of insulin signaling. PMID- 25830094 TI - Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance. AB - OBJECTIVE: The peptide hormone adropin regulates fuel selection preferences in skeletal muscle under fed and fasted conditions. Here, we investigated whether adropin treatment can ameliorate the dysregulation of fuel substrate metabolism, and improve aspects of glucose homeostasis in diet-induced obesity (DIO) with insulin resistance. METHODS: DIO C57BL/6 mice maintained on a 60% kcal fat diet received five intraperitoneal (i.p.) injections of the bioactive peptide adropin(34-76) (450 nmol/kg/i.p.). Following treatment, glucose tolerance and whole body insulin sensitivity were assessed and indirect calorimetry was employed to analyze whole body substrate oxidation preferences. Biochemical assays performed in skeletal muscle samples analyzed insulin signaling action and substrate oxidation. RESULTS: Adropin treatment improved glucose tolerance, enhanced insulin action and augmented metabolic flexibility towards glucose utilization. In muscle, adropin treatment increased insulin-induced Akt phosphorylation and cell-surface expression of GLUT4 suggesting sensitization of insulin signaling pathways. Reduced incomplete fatty acid oxidation and increased CoA/acetyl-CoA ratio suggested improved mitochondrial function. The underlying mechanisms appear to involve suppressions of carnitine palmitoyltransferase-1B (CPT-1B) and CD36, two key enzymes in fatty acid utilization. Adropin treatment activated pyruvate dehydrogenase (PDH), a rate-limiting enzyme in glucose oxidation, and downregulated PDH kinase-4 (PDK-4) that inhibits PDH. Along with these changes, adropin treatment downregulated peroxisome proliferator-activated receptor-gamma coactivator-1alpha that regulates expression of Cpt1b, Cd36 and Pdk4. CONCLUSIONS: Adropin treatment of DIO mice enhances glucose tolerance, ameliorates insulin resistance and promotes preferential use of carbohydrate over fat in fuel selection. Skeletal muscle is a key organ in mediating adropin's whole-body effects, sensitizing insulin signaling pathways and altering fuel selection preference to favor glucose while suppressing fat oxidation. PMID- 25830096 TI - Angiotensin type 1a receptors in the forebrain subfornical organ facilitate leptin-induced weight loss through brown adipose tissue thermogenesis. AB - OBJECTIVE: Elevations in brain angiotensin-II cause increased energy expenditure and a lean phenotype. Interestingly, the metabolic effects of increased brain angiotensin-II mimic the actions of leptin, suggesting an interaction between the two systems. Here we demonstrate that angiotensin-type 1a receptors (AT1aR) in the subfornical organ (SFO), a forebrain structure emerging as an integrative metabolic center, play a key role in the body weight-reducing effects of leptin via brown adipose tissue (BAT) thermogenesis. METHODS: Cre/LoxP technology coupled with targeted viral delivery to the SFO in a mouse line bearing a conditional allele of the Agtr1a gene was utilized to determine the interaction between leptin and SFO AT1aR in metabolic regulation. RESULTS: Selective deletion of AT1aR in the SFO attenuated leptin-induced weight loss independent of changes in food intake or locomotor activity. This was associated with diminished leptin induced increases in core body temperature, blunted upregulation of BAT thermogenic markers, and abolishment of leptin-mediated sympathetic activation to BAT. CONCLUSIONS: These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation. PMID- 25830097 TI - The expression of dominant negative TCF7L2 in pancreatic beta cells during the embryonic stage causes impaired glucose homeostasis. AB - OBJECTIVE: Disruption of TCF7L2 in mouse pancreatic beta-cells has generated different outcomes in several investigations. Here we aim to clarify role of beta cell TCF7L2 and Wnt signaling using a functional-knockdown approach. METHODS: Adenovirus-mediated dominant negative TCF7L2 (TCF7L2DN) expression was conducted in Ins-1 cells. The fusion gene in which TCF7L2DN expression is driven by P TRE3G was utilized to generate the transgenic mouse line TCF7L2DN Tet . The double transgenic line was created by mating TCF7L2DN Tet with Ins2-rtTA, designated as betaTCFDN. beta-cell specific TCF7L2DN expression was induced in betaTCFDN by doxycycline feeding. RESULTS: TCF7L2DN expression in Ins-1 cells reduced GSIS, cell proliferation and expression of a battery of genes including incretin receptors and beta-cell transcription factors. Inducing TCF7L2DN expression in betaTCFDN during adulthood or immediately after weaning generated no or very modest metabolic defect, while its expression during embryonic development by doxycycline feeding in pregnant mothers resulted in significant glucose intolerance associated with altered beta-cell gene expression and reduced beta cell mass. CONCLUSIONS: Our observations support a cell autonomous role for TCF7L2 in pancreatic beta-cells suggested by most, though not all, investigations. betaTCFDN is a novel model for further exploring the role of TCF7L2 in beta-cell genesis and metabolic homeostasis. PMID- 25830098 TI - The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. AB - OBJECTIVE: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation and fibrosis. There are currently no targeted therapies for NASH. We developed a liver-specific LXR inverse agonist, SR9238, which effectively reduces hepatic lipogenesis in models of obesity and hepatic steatosis. We hypothesized that suppression of lipogenesis, which is pathologically elevated in NASH may suppress progression of hepatic steatosis to NASH. METHODS: NASH was induced in B6 V-lep (ob)/J (ob/ob) mice using a custom complete rodent diet (HTF) containing high amounts of trans-fat, fructose, and cholesterol. Once NASH was induced, mice were treated with SR9238 for one month by i.p. injection. Plasma lipid levels and liver health were analyzed by clinical chemistry. QPCR, western blot, and immunohistochemistry were used to assess disease severity. RESULTS: Ob/ob mice are obese and diabetic thus they are commonly used as models for the study of metabolic diseases. These mice quickly developed the NASH phenotype when provided the HTF diet. The mice develop hepatic steatosis, severe hepatic inflammation and fibrosis on the HTF diet. Treatment with SR9238 significantly reduced the severity of hepatic steatosis and most importantly reduced hepatic inflammation and ameliorated hepatic fibrosis. CONCLUSIONS: Here, we demonstrate that an LXR inverse agonist, SR9238, is effective in reduction of hepatic steatosis, inflammation and fibrosis in an animal model of NASH. These results have important implications for the development of therapeutics for treatment NASH in humans. PMID- 25830099 TI - Ventral dermatitis in rowi (Apteryx rowi) due to cutaneous larval migrans. AB - The rowi is a critically endangered species of kiwi. Young birds on a creche island showed loss of feathers from the ventral abdomen and a scurfy dermatitis of the abdominal skin and vent margin. Histology of skin biopsies identified cutaneous larval migrans, which was shown by molecular sequencing to be possibly from a species of Trichostrongylus as a cause of ventral dermatitis and occasional ulcerative vent dermatitis. The predisposing factors that led to this disease are suspected to be the novel exposure of the rowi to parasites from seabirds or marine mammals due to the island creche and the limited management of roost boxes. This is the first instance of cutaneous larval migrans to be recorded in birds. Severe and fatal complications of the investigation resulted in the death of eight birds of aspergillosis and pulmonary complications associated with the use of bark as a substrate in hospital. Another bird died of renal failure during the period of hospitalisation despite oral and intravenous fluid therapy. The initiating cause of the renal failure was not determined. These complications have the potential to undermine the working relationship between wildlife veterinarians and conservation managers. This case highlights that intensive conservation management can result in increased opportunities for novel routes of cross-species pathogen transmission. PMID- 25830100 TI - Evidence for intercontinental parasite exchange through molecular detection and characterization of haematozoa in northern pintails (Anas acuta) sampled throughout the North Pacific Basin. AB - Empirical evidence supports wild birds as playing a role in the interhemispheric exchange of bacteria and viruses; however, data supporting the redistribution of parasites among continents are limited. In this study, the hypothesis that migratory birds contribute to the redistribution of parasites between continents was tested by sampling northern pintails (Anas acuta) at locations throughout the North Pacific Basin in North America and East Asia for haemosporidian infections and assessing the genetic evidence for parasite exchange. Of 878 samples collected from birds in Alaska (USA), California (USA), and Hokkaido (Japan) during August 2011-May 2012 and screened for parasitic infections using molecular techniques, Leucocytozoon, Haemoproteus, and Plasmodium parasites were detected in 555 (63%), 44 (5%), and 52 (6%) samples, respectively. Using an occupancy modeling approach, the probability of detecting parasites via replicate genetic tests was estimated to be high (rho > 0.95). Multi-model inference supported variation of Leucocytozoon parasite prevalence by northern pintail age class and geographic location of sampling in contrast to Haemoproteus and Plasmodium parasites for which there was only support for variation in parasite prevalence by sampling location. Thirty-one unique mitochondrial DNA haplotypes were detected among haematozoa infecting northern pintails including seven lineages shared between samples from North America and Japan. The finding of identical parasite haplotypes at widely distributed geographic locations and general lack of genetic structuring by continent in phylogenies for Leucocytozoon and Plasmodium provides evidence for intercontinental genetic exchange of haemosporidian parasites. Results suggest that migratory birds, including waterfowl, could therefore facilitate the introduction of avian malaria and other haemosporidia to novel hosts and spatially distant regions. PMID- 25830101 TI - History and development of research on wildlife parasites in southern Africa, with emphasis on terrestrial mammals, especially ungulates. AB - The history of wildlife parasitology in South Africa, and to some extent southern Africa, is reviewed, giving a brief overview of the early years and following its development from the founding of the Onderstepoort Veterinary Institute in 1908 until the turn of the century. An emphasis is placed on game species. The main findings on protozoan parasites, including those of carnivores, are presented, starting in the 1890s and leading up to the first decade of the 21st century. Important developments with regard to the studies of arthropod and helminth parasites took place during a period of three decades, starting from the 1970s. Because of the sheer volume of work done by parasitologists during this time, this particular part of the overview concentrates on South African authors or authors working in South Africa at the time, and is limited to hosts that are members of the order Perissodactyla and the superorder Cetartiodactyla. PMID- 25830103 TI - A sylvatic lifecycle of Echinococcus equinus in the Etosha National Park, Namibia. AB - Various species of Echinococcus have been described in the past from wild mammals of sub-Saharan Africa. However, it is only recently, that a few isolates have become available for molecular identification; therefore, the involvement of wildlife in the lifecycles of the various cryptic species within Echinococcus granulosus sensu lato is still only partially known. A preliminary survey was undertaken in Etosha National Park, Namibia, from August to October 2012. Faecal samples were obtained from 34 individual wild carnivores, and metacestodes were collected from carcasses of 18 culled herbivores. Single eggs and metacestode tissue were lysed and identified from sequences of the mitochondrial nad1 gene. In case of metacestodes, the cox1 gene was additionally sequenced and haplotype networks were constructed. Echinococcus equinus was found in lions (4 of 6), black-backed jackals (2 of 7) and Burchell's zebras (11 of 12). The frequency of this parasite in the absence of domestic dogs, horses and donkeys strongly indicates its transmission in a wildlife cycle. Further, a variety of sequences were obtained from eggs and cysticerci from lions, cheetahs, caracals, spotted hyenas and oryx, which most closely clustered with species of Taenia. Only 3 of them, 2 of lion and 1 of hyena origin, could be allocated to Hydatigera (=Taenia) taeniaeformis (lion), Taenia regis (lions and oryx) and Taenia cf. crocutae (spotted hyena and oryx). PMID- 25830102 TI - Wildlife reservoirs for vector-borne canine, feline and zoonotic infections in Austria. AB - Austria's mammalian wildlife comprises a large variety of species, acting and interacting in different ways as reservoir and intermediate and definitive hosts for different pathogens that can be transmitted to pets and/or humans. Foxes and other wild canids are responsible for maintaining zoonotic agents, e.g. Echinococcus multilocularis, as well as pet-relevant pathogens, e.g. Hepatozoon canis. Together with the canids, and less commonly felids, rodents play a major role as intermediate and paratenic hosts. They carry viruses such as tick-borne encephalitis virus (TBEV), bacteria including Borrelia spp., protozoa such as Toxoplasma gondii, and helminths such as Toxocara canis. The role of wild ungulates, especially ruminants, as reservoirs for zoonotic disease on the other hand seems to be negligible, although the deer filaroid Onchocerca jakutensis has been described to infect humans. Deer may also harbour certain Anaplasma phagocytophilum strains with so far unclear potential to infect humans. The major role of deer as reservoirs is for ticks, mainly adults, thus maintaining the life cycle of these vectors and their distribution. Wild boar seem to be an exception among the ungulates as, in their interaction with the fox, they can introduce food-borne zoonotic agents such as Trichinella britovi and Alaria alata into the human food chain. PMID- 25830104 TI - Prevalence and genetic diversity of haematozoa in South American waterfowl and evidence for intercontinental redistribution of parasites by migratory birds. AB - To understand the role of migratory birds in the movement and transmission of haematozoa within and between continental regions, we examined 804 blood samples collected from eleven endemic species of South American waterfowl in Peru and Argentina for infection by Haemoproteus, Plasmodium, and/or Leucocytozoon blood parasites. Infections were detected in 25 individuals of six species for an overall apparent prevalence rate of 3.1%. Analysis of haematozoa mitochondrial DNA revealed twelve distinct parasite haplotypes infecting South American waterfowl, four of which were identical to lineages previously observed infecting ducks and swans sampled in North America. Analysis of parasite mitochondrial DNA sequences revealed close phylogenetic relationships between lineages originating from waterfowl samples regardless of continental affiliation. In contrast, more distant phylogenetic relationships were observed between parasite lineages from waterfowl and passerines sampled in South America for Haemoproteus and Leucocytozoon, suggesting some level of host specificity for parasites of these genera. The detection of identical parasite lineages in endemic, South American waterfowl and North American ducks and swans, paired with the close phylogenetic relationships of haematozoa infecting waterfowl on both continents, provides evidence for parasite redistribution between these regions by migratory birds. PMID- 25830105 TI - Endoparasites in a Norwegian moose (Alces alces) population - Faunal diversity, abundance and body condition. AB - Many health surveillance programs for wild cervids do not include routine parasite screening despite evidence that gastrointestinal parasites can affect wildlife population dynamics by influencing host fecundity and survival. Slaughter weights of moose in some regions of Norway have been decreasing over recent decades but any role of parasites has not yet been considered. We investigated parasite faunal diversity of moose in Hedmark, SE Norway, by faecal analysis and identification of adult abomasal and caecal nematodes during the autumn hunting season. We related parasite prevalence and abundance to estimates of body condition, gender and age. We identified 11 parasite groups. Moose had high abomasal gastrointestinal nematode (GIN) burdens and all individuals were infected. Ostertagia antipini and Spiculopteragia alcis were the most prevalent abomasal GINs identified. O. leptospicularis and Telodorsagia circumcincta were also identified in the abomasa while a range of other GIN and Moniezia sp. eggs, and coccidia, Dictyocaulus sp. and Protostrongylid larvae were found in faeces. Female moose had higher mean abomasal nematode counts than males, particularly among adults. However, adult males had higher faecal egg counts than adult females which may reflect reduction in faecal volume with concentration of eggs among males during the rut. We found no strong evidence for the development of acquired immunity to abomasal nematodes with age, although there was a higher Protostrongylid and Moniezia infection prevalence in younger animals. High burdens of several parasites were associated with poor body condition in terms of slaughter weight relative to skeletal size but unrelated to visually evaluated fat reserves. Given findings from earlier experimental studies, our results imply sub-clinical effects of GI parasite infection on host condition. Managers should be aware that autumn faecal egg counts and field assessments of fat reserves may not be reliable indicators of parasitism and may underestimate impacts on wildlife populations. PMID- 25830106 TI - Ectoparasites of the critically endangered insular cavy, Cavia intermedia (Rodentia: Caviidae), southern Brazil. AB - Cavia intermedia is a rodent species critically endangered and is found only on a 10 hectare island off the southern Brazilian coast. To identify the ectoparasites of C. intermedia, 27 specimens (14 males and 13 females), representing approximately 65% of the estimated total population, were captured and examined. A total of 1336 chewing lice of two species were collected: Gliricola lindolphoi (Amblycera: Gyropidae) and Trimenopon hispidum (Amblycera: Trimenoponidae). In addition, chiggers Arisocerus hertigi (Acari: Trombiculidae) and Eutrombicula sp. (Acari: Trombiculidae) were collected from the ears of all captured animals. This low species richness compared to those for other Cavia species is expected for island mammals. Although the results presented here are not conclusive about the relationship between C. intermedia and ectoparasites, this low species richness found might be reflected in a low level of investment by the hosts in the basal immune defense, since investments in white blood cell production by mammals are influenced by the diversity of parasites in the environment. Additionally, considering that it might result in host vulnerability to other parasites that might be introduced through exotic or migratory host species, the monitoring of C. intermedia, including parasitological and immunological assessments, is recommended as a key component of conservation efforts. PMID- 25830107 TI - Occurrence and seasonality of internal parasite infection in elephants, Loxodonta africana, in the Okavango Delta, Botswana. AB - It is known from studies in a wide range of wild and domestic animals, including elephants, that parasites can affect growth, reproduction and health. A total of 458 faecal samples from wild elephants were analysed using a combination of flotation and sedimentation methods. Coccidian oocysts (prevalence 51%), and nematode (77%) and trematode (24%) eggs were found. Species were not identified, though trematode egg morphology was consistent with that of the intestinal fluke Protofasciola robusta. The following factors were found to have a significant effect on parasite infection: month, year, sex, age, and group size and composition. There was some evidence of peak transmission of coccidia and nematodes during the rainy season, confirmed for coccidia in a parallel study of seven sympatric domesticated elephants over a three month period. Nematode eggs were more common in larger groups and nematode egg counts were significantly higher in elephants living in maternal groups (mean 1116 eggs per gram, standard deviation, sd 685) than in all-male groups (529, sd 468). Fluke egg prevalence increased with increasing elephant age. Preservation of samples in formalin progressively decreased the probability of detecting all types of parasite over a storage time of 1-15 months. Possible reasons for associations between other factors and infection levels are discussed. PMID- 25830108 TI - The role of wildlife in the transmission of parasitic zoonoses in peri-urban and urban areas. AB - During the last 100 years in many countries of the world, there have been dramatic changes in natural/rural landscapes due to urbanization. Since many wildlife species are unable to adapt to these alterations in their environment, urbanization is commonly responsible for a decline of biodiversity in areas of urban development. In contrast, some wild animal species are attracted to peri urban and urban habitats due to the availability of an abundant food supply and the presence of structures in which to shelter. Urban foxes and/or raccoons are common sights in many peri-urban and urban areas of Europe where they can reach far higher population densities than in their natural habitats. The same is true for foxes and dingoes in some urban areas of Australia. Unfortunately, some of these highly adaptable species are also hosts for a number of parasites of public health and veterinary importance. Due to the complexity of many parasitic life cycles involving several host species, the interactions between wild animals, domestic animals and humans are not fully understood. The role of potential hosts for transmission of a zoonotic disease in urban or peri-urban areas cannot be extrapolated from data obtained in rural areas. Since more than 75% of human diseases are of zoonotic origin, it is important to understand the dynamics between wildlife, domestic animal species and humans in urbanized areas, and to conduct more focused research on transmission of zoonotic parasites including arthropod vectors under such conditions. PMID- 25830109 TI - (macro-) Evolutionary ecology of parasite diversity: From determinants of parasite species richness to host diversification. AB - The present review summarized the factors or determinants that may explain parasite diversity among host species and the consequences of this parasite diversity on the evolution of host-life history traits. As host-parasite interactions are asymmetrical exploited-exploiter relationships, ecological and epidemiological theories produce hypotheses to find the potential determinants of parasite species richness, while life-history theory helps for testing potential consequences on parasite diversity on the evolution of hosts. This review referred only to studies that have specifically controlled or took into account phylogenetic information illustrated with parasites of mammals. Several points needing more investigation were identified with a special emphasis to develop the metabolic theory of epidemiology. PMID- 25830111 TI - Competing invaders: Performance of two Anguillicola species in Lake Bracciano. AB - Anguillicola crassus is one of the most successful parasitic invasive species as it has spread from its original habitat in East Asia throughout the world and has acquired five new eel host species in the course of its invasion within the last three decades. Records from an Italian lake indicate that this species has even displaced an established population of its close relative A. novaezelandiae originating from New Zealand. In order to analyze the reasons for its high invasive potential, this review highlights recent studies, which substantiate the selective advantages of A. crassus over A. novaezelandiae. Laboratory infection experiments revealed that A. crassus features a less synchronized development compared to A. novaezelandiae in the European eel, which enables this species to emit eggs over a longer period of time. Differences in the time period required for first egg output and in the maturation process of second stage larvae in intermediate hosts could also be detected, which may lead to differences in infection potential. Finally, microsatellite analyses have shown that hybridization processes are possible, but might only occur between A. crassus males and A. novaezelandiae females. Taken as a whole, the sum of minor selective advantages and differences in life cycle traits could have considerably contributed to a replacement of one species by the other. PMID- 25830112 TI - Enhanced understanding of ectoparasite-host trophic linkages on coral reefs through stable isotope analysis. AB - Parasitism, although the most common type of ecological interaction, is usually ignored in food web models and studies of trophic connectivity. Stable isotope analysis is widely used in assessing the flow of energy in ecological communities and thus is a potentially valuable tool in understanding the cryptic trophic relationships mediated by parasites. In an effort to assess the utility of stable isotope analysis in understanding the role of parasites in complex coral-reef trophic systems, we performed stable isotope analysis on three common Caribbean reef fish hosts and two kinds of ectoparasitic isopods: temporarily parasitic gnathiids (Gnathia marleyi) and permanently parasitic cymothoids (Anilocra). To further track the transfer of fish-derived carbon (energy) from parasites to parasite consumers, gnathiids from host fish were also fed to captive Pederson shrimp (Ancylomenes pedersoni) for at least 1 month. Parasitic isopods had delta(13)C and delta(15)N values similar to their host, comparable with results from the small number of other host-parasite studies that have employed stable isotopes. Adult gnathiids were enriched in (15)N and depleted in (13)C relative to juvenile gnathiids, providing insights into the potential isotopic fractionation associated with blood-meal assimilation and subsequent metamorphosis. Gnathiid-fed Pedersen shrimp also had delta(13)C values consistent with their food source and enriched in (15)N as predicted due to trophic fractionation. These results further indicate that stable isotopes can be an effective tool in deciphering cryptic feeding relationships involving parasites and their consumers, and the role of parasites and cleaners in carbon transfer in coral-reef ecosystems specifically. PMID- 25830113 TI - Biodiversity of frog haemoparasites from sub-tropical northern KwaZulu-Natal, South Africa. AB - Since South Africa boasts a high biodiversity of frog species, a multispecies haemoparasite survey was conducted by screening the blood from 29 species and 436 individual frogs. Frogs were collected at three localities in sub-tropical KwaZulu-Natal, a hotspot for frog diversity. Twenty per cent of the frogs were infected with at least one of five groups of parasites recorded. Intraerythrocytic parasites comprising Hepatozoon, Dactylosoma, and viral or bacterial organisms, as well as extracellular parasites including trypanosomes and microfilarid nematodes were found. A significant difference (P < 0.01) in the prevalence of parasitaemia was found across species, those semi-aquatic species demonstrating the highest, followed by semi-terrestrial frog species. None of those species described as purely terrestrial and aquatic were infected. Hepatozoon and Trypanosoma species accounted for most of the infections, the former demonstrating significant differences in intensity of infection across species, families and habitat types (P = 0.028; P = 0.006; P = 0.007 respectively). Per locality, the first, the formally protected Ndumo Game Reserve, had the highest biodiversity of haemoparasite infections, with all five groups of parasites recorded. The other two sites, that is the area bordering the reserve and the Kwa Nyamazane Conservancy, had a lower diversity with no parasite infections recorded and only Hepatozoon species recorded respectively. Such findings could be ascribed to the anthropogenic impact on the latter two sites, the first by the rural village activities, and the second by the bordering commercial sugar cane agriculture. Future studies should include both morphological and molecular descriptions of the above parasites, as well as the identification of potential vectors, possibly clarifying the effects human activities may have on frog haemoparasite life cycles and as such their biodiversity. PMID- 25830114 TI - Reproductive strategies of the kangaroo leech, Marsupiobdella africana (Glossiphoniidae). AB - The Kangaroo Leech, Marsupiobdella africana, is a hermaphroditic organism, with insemination taking place by the planting of a spermatophore on another leech. Spermatophores are mostly planted on the anterior of the recipient leech, but not always. Several spermatophores may be planted by different leeches on a single recipient. The spermatophore consists of two side by side lobes. Within minutes from planting of the spermatophore, the contents are squeezed out and into the body of the recipient. Sperm are believed to find the way to the ova by following chemical cues. Kangaroo Leeches display advanced parental care by transferring fertilized eggs from the reproductive opening to a brood pouch on the ventral side. Fully developed leeches may copulate after detaching from the amphibian host Xenopus laevis, or from the Cape River Crab Potamonautes perlatus with which it maintains a phoretic association. PMID- 25830110 TI - A review of Theileria diagnostics and epidemiology. AB - An extensive range of serological and molecular diagnostic assays exist for most of the economically important Theileira species such as T. annulata, T. equi, T. lestoquardi, T. parva, T. uilenbergi and other more benign species. Diagnostics of Theileria is considered with regard to sensitivity and specificity of current molecular and serological assays and their use in epidemiology. In the case of serological assays, cross-reactivity of genetically closely related species reduces the use of the gold standard indirect fluorescent antibody test (IFAT). Development of antigen-specific assays does not necessarily address this problem, since closely related species will potentially have similar antigens. Even so, serological assays remain an important line of enquiry in epidemiological surveys. Molecular based assays have exploded in the last decade with significant improvements in sensitivity and specificity. In this review, the current interpretation of what constitute a species in Theileria and its impact on accurate molecular diagnostics is considered. Most molecular assays based on conventional or real-time PCR technology have proven to be on standard with regard to analytical sensitivity. However, consideration of the limits of detection in regard to total blood volume of an animal indicates that most assays may only detect >400,000 parasites/L blood. Even so, natural parasitaemia distribution in carrier-state animals seems to be above this limit of detection, suggesting that most molecular assays should be able to detect the majority of infected individuals under endemic conditions. The potential for false-negative results can, however, only be assessed within the biological context of the parasite within its vertebrate host, i.e. parasitaemia range in the carrier-state that will support infection of the vector and subsequent transmission. PMID- 25830115 TI - Complex interactions within the ectoparasite community of the eastern rock sengi (Elephantulus myurus). AB - Concomitant infection with more than one parasite species is the rule in nature. Since co-infecting parasites are exploiting the same host, interspecific interactions at the infracommunity level are likely. The nature of such interactions can be expected to affect the distribution of parasites within host populations. Intraspecific interactions within the infracommunity are not easily discernible from cross-sectional studies and the focus of most of these studies lies on relationships between endoparasitic micro- and macroparasites. In the current study of the ectoparasite community of wild eastern rock sengis (Elephantulus myurus) we experimentally reduced tick and flea infestations and monitored ectoparasite burdens over the course of three years. We found a number of within-taxon facilitating interactions between tick species that might be the result of decreasing immune responses with increasing tick burden. In contrast, inter-taxon relationships appeared to be dominated by antagonistic relationships likely to be linked to competition over feeding sites. Only one of the observed interspecific interactions was reciprocal. Our experimental manipulation revealed additional antagonistic relationships that cross-sectional studies would not have captured. In addition, we found substantial long-term changes in the sengi ectoparasite community as a result of our experimental manipulation suggesting carry-over effects of our treatment. This study is the first that evaluates interspecific interactions within the entire ectoparasite community exploiting a mammalian host in Africa and highlights the complexity of interspecific interactions within an ectoparasite community. PMID- 25830116 TI - Long-term surgery outcome for epilepsy and psychogenic nonepileptic seizures in a child with anterior cingulate gyrus dysplasia. AB - We present the case of a 13-year-old child with nocturnal frontal lobe epilepsy (NFLE) related to a right cingulate gyrus cortical dysplasia, who also presented with psychogenic nonepileptic seizures (PNES) and interictal antisocial behavior. The association of drug-resistant epilepsy with behavioral disorders is well established, but the role of epilepsy surgery in these patients is still controversial, especially in children. The key finding is represented by the excellent long-term outcome on both epilepsy and behavioral dysfunction after the surgical excision of the cingulate gyrus cortical dysplasia. PMID- 25830117 TI - The effect of magnesium sulfate on motor and sensory axillary plexus blockade. AB - BACKGROUND: Magnesium is a physiologic cation that blocks neuromuscular transmission and does not allow the nerve to be stimulated. OBJECTIVES: This study investigates the effect of adding magnesium sulfate to lidocaine to extend the duration of sensory and motor blocks of the axillary plexus in orthopedic surgeries of the upper extremities. PATIENTS AND METHODS: This controlled randomized double-blind study was performed on patients who were candidates for orthopedic surgery of the upper extremities. A total of 60 patients between 18-60 years with ASA Class 1 or 2 participated in the study. One group received lidocaine (5 mg/kg) with magnesium sulfate 20% (3 mL) as the case group, while the second group received lidocaine (5 mg/kg) with normal saline (3 mL) as a placebo to block the axillary plexus using the trans-arterial technique. The duration of the sensory and motor block of the axillary plexus was monitored and evaluated using the pinprick and modified Bromage scale. RESULTS: A total of 60 patients were included in the study with 30 patients having received lidocaine plus magnesium and the other 30 patients having received lidocaine plus normal saline. The mean sensory block duration in the case group was 248.83 +/- 18.36 and in control group was 204.67 +/- 22.62. The mean motor block duration in the case group was 207.0 +/- 16.64 and in control group was 147.33 +/- 21.52 (both P < 0.0001). The mean onset of sensory block in case group was 15.5 +/- 3.79 and the onset block in control group was 10.33 +/- 4.13 (P < 0.0001). The mean onset of motor block in case group was 20.66 +/- 4.09 and the onset block in control group was 19.73 +/- 26.18 (P < 0.848). CONCLUSIONS: The addition of magnesium sulfate to lidocaine increased the duration of motor and sensory axillary block in the upper extremities during surgeries when compared to the use of lidocaine alone. PMID- 25830118 TI - Premedication with oral pregabalin for the prevention of acute postsurgical pain in coronary artery bypass surgery. AB - BACKGROUND: For coronary artery bypass grafting (CABG) sternotomy should be performed. The pain after surgery is severe and requires medical intervention. Use of the analgesics is limited by their side effects and studies suggest that prevention with some medications before surgery is effective in controlling the postoperative pain. OBJECTIVES: We investigated the efficacy of pregabalin administration before surgery in the treatment of acute postoperative pain after CABG surgery. PATIENTS AND METHODS: Sixty patients indicated for elective CABG surgery were randomly allocated to two groups. One group received placebo and the other received 150 mg of oral pregabalin before surgery. Heart rates, blood pressure, respiratory rate, intensive care unit (ICU) stay duration, morphine consumption, and pain score according to the visual analog scale (VAS) were measured and recorded at 4, 12, and 24 hours of surgery. RESULTS: Pregabalin consumption did not alter hemodynamic parameters and was safe in patients after CABG. Its consumption was associated with significant reduction in the pain score (P values were 0.035, 0.026, and 0.047 respectively at 4, 12, and 24 hours of surgery). Its use was not associated with changes in the morphine consumption at 4, 12, and 24 hours of surgery (P > 0.05). CONCLUSIONS: Premedication with studied dose of pregabalin is effective for the prevention of postoperative pain in patients after CABG and has no adverse effects. Trials with other treating schedule and doses of the drug should be performed to determine the best treatment plan. PMID- 25830119 TI - The effect of intra-articular meperidine and bupivacaine 0.5% on postoperative pain of arthroscopic knee surgery; a randomized double blind clinical trial. AB - BACKGROUND: Arthroscopic knee surgeries have a painful postoperative course, which often necessitates acute pain management. Among different analgesia techniques, Intra-articular injection is the technique of choice for many pain specialists, based on its confined effect to the surgical site (knee), lack of systemic effects and promotion of safe early ambulation. OBJECTIVES: The aim of this study was to compare analgesic effects of intra-articular meperidine, bupivacaine 0.5% or their combination after knee arthroscopic surgery. PATIENTS AND METHODS: Sixty ASA class I-II patients' candidates for arthroscopy knee surgery enrolled in a randomized double blind study to receive either 20 mL of bupivacaine 0.5%; 100 mg meperidine (diluted in normal saline) or bupivacaine 0.5% along with 100 mg meperidine. A written informed consent was obtained from all patients. Postoperative analgesia duration, VAS at 2, 6, 12 and 24 hours, the first analgesic request time, total fentanyl consumption in first 24 hours, patients' satisfaction and adverse effects were recorded. RESULTS: The bupivacaine-meperidine group had better duration of postoperative analgesia (P = 0.001), latter first analgesic request (P <= 0.001), lower total fentanyl consumption in first 24 hours after the operation (P = 0.001), less mean VAS at 2 hours (P = 0.001) and more patients' overall satisfaction (P = 0.01) compared with each medication alone. VAS at 6, 12 and 24 postoperative hours were not different between the groups of study. No adverse effects were observed. CONCLUSIONS: Although postoperative intra-articular meperidine is a better alternative for bupivacaine, their combination could improve their analgesic effects compared with each other alone. PMID- 25830120 TI - Attention-deficit/hyperactivity disorder in children undergoing peritoneal dialysis. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder. This disorder is more prevalent in some chronic disease. OBJECTIVES: The aim of this study was to investigate ADHD in children with end-stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD) and to compare the results with those of healthy children. PATIENTS AND METHODS: This case-control study was conducted for six months (December 22, 2013 to June 21, 2014) on five to 16-year-old children, visiting the Pediatric Dialysis Unit of Amirkabir Hospital, Arak, Iran, and Taleghani Hospital, Kermanshah, Iran. A total of 100 children with ESRD who had undergone CAPD for at least six months and 100 healthy children were included in this study as case and control groups, respectively. ADHD was diagnosed by Conner's Parent Rating Scale-48 (CPRS-48) and DSM-IV-TR criteria, and was confirmed through consultation by psychologist. Data were analyzed by Binomial test in SPSS 18. RESULTS: The ADHD inattentive type was observed in 16 cases (16%) with CAPD and five controls (5%) (P = 0.01). Moreover, ADHD hyperactive-impulsive type was observed in 27 cases (27%) with CAPD and seven controls (9%) (P = 0.002). Despite these significant differences, no children were diagnosed with ADHD combined type among all subjects. CONCLUSIONS: Inattentive type and hyperactive-impulsive type of ADHD are more prevalent in children with ESRD undergoing CAPD. Therefore screening methods for ADHD is necessary in these patients. PMID- 25830121 TI - Eltrombopag: a new treatment option for chronic refractory adult immune thrombocytopenia. PMID- 25830122 TI - Is cord blood worth saving for public or private banking? PMID- 25830123 TI - Splenic rupture in primary amyloidosis with chronic neutrophilic leukemia. PMID- 25830124 TI - Spontaneous bilateral suburothelial hemorrhage in immune thrombocytopenic purpura. PMID- 25830126 TI - Efficacy and safety of eltrombopag in adult refractory immune thrombocytopenia. AB - BACKGROUND: Eltrombopag is a thrombopoietin receptor agonist with excellent treatment outcomes in immune thrombocytopenia (ITP). Here, we analyzed the dose of eltrombopag required to achieve and maintain safe platelet counts in Korean ITP patients. METHODS: Adult refractory ITP patients (<30,000 platelets/uL) were enrolled. Eltrombopag doses were increased to achieve a target platelet count (>=50,000 cells/uL). After achieving the target platelet count, the dose of concomitant ITP medications and eltrombopag was reduced to identify the lowest effective dose required to maintain the platelet count. RESULTS: Among 18 patients, 66.7% achieved complete response, 5.6% achieved platelet counts between 50,000 and 100,000 cells/uL, and 27.8% failed to achieve the target platelet count. The median ITP duration was significantly shorter in patients who achieved the target platelet count. The initial dose required to achieve the target platelet count was 25 mg/d. The adjusted maintenance doses were 25 mg twice per week or 25 mg/d. After discontinuation, 83.3% relapsed, and the median relapse free survival was 15 days. Two relapsed and 1 failed patient switched to romiplostim. The response to romiplostim was similar to eltrombopag. During eltrombopag treatment, 38.9% showed hepatobiliary laboratory anomalies. Among 9 follow-up bone marrow examinations, 1 revealed fibrosis after 1 year of treatment. CONCLUSION: Eltrombopag was well tolerated with excellent treatment outcomes in refractory adult ITP patients. Low-dose eltrombopag effectively maintained the target platelet count. However, some patients required longer or higher-dose treatment to maintain the target platelet count, especially in heavily pretreated or longer ITP cases. PMID- 25830125 TI - Use of lenalidomide in the management of relapsed or refractory multiple myeloma: expert recommendations in Korea. AB - Multiple myeloma (MM) is the third most common hematologic malignancy in Korea. Historically, the incidence of MM in Korea has been lower than that in Western populations, although there is growing evidence that the incidence of MM in Asian populations, including Korea, is increasing rapidly. Despite advances in the management of MM, patients will ultimately relapse or become refractory to their current treatment, and alternative therapeutic options are required in the relapsed/refractory setting. In Korea, although lenalidomide/dexamethasone is indicated for the treatment of relapsed or refractory MM (RRMM) in patients who have received at least one prior therapy, lenalidomide is reimbursable specifically only in patients with RRMM who have failed bortezomib-based treatment. Based on evidence from pivotal multinational clinical trials as well as recent studies in Asia, including Korea, lenalidomide/dexamethasone is an effective treatment option for patients with RRMM, regardless of age or disease status. Adverse events associated with lenalidomide/dexamethasone, including hematologic toxicity, venous thromboembolism, fatigue, rash, infection, and muscle cramps, are largely predictable and preventable/manageable with appropriate patient monitoring and/or the use of standard supportive medication and dose adjustment/interruption. Lenalidomide/dexamethasone provides an optimal response when used at first relapse, and treatment should be continued long term until disease progression. With appropriate modification of the lenalidomide starting dose, lenalidomide/dexamethasone is effective in patients with renal impairment and/or cytopenia. This review presents updated evidence from the published clinical literature and provides recommendations from an expert panel of Korean physicians regarding the use of lenalidomide/dexamethasone in patients with RRMM. PMID- 25830127 TI - Promoter methylation and expression levels of selected hematopoietic genes in pediatric B-cell acute lymphoblastic leukemia. AB - BACKGROUND: Precursor B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common neoplasm in children and is characterized by genetic and epigenetic aberrations in hematopoietic transcription factor (TF) genes. This study evaluated promoter DNA methylation and aberrant expression levels of early- and late-acting hematopoietic TF genes homeobox A4 and A5 (HOXA4 and HOXA5), Meis homeobox 1 (MEIS1), T-cell acute lymphocytic leukemia 1 (TAL1), and interferon regulatory factors 4 and 8 (IRF4 and IRF8) in pediatric B-cell ALL. METHODS: Blood samples of 38 ALL patients and 20 controls were obtained. DNA was treated with sodium bisulfite and DNA methylation level of HOXA4, HOXA5, MEIS1, TAL1, IRF4, and IRF8 was assessed using quantitative methylation-specific polymerase chain reaction (PCR). Relative gene expression was measured using quantitative reverse transcription-PCR. RESULTS: Aberrant methylation of TAL1, IRF8, MEIS1, and IRF4 was observed in 26.3%, 7.9%, 5.3%, and 2.6% patients, respectively, but not in controls. HOXA4 and HOXA5 were methylated in some controls and hypermethylated in 16% and 5% patients, respectively. IRF8, MEIS1, and TAL1 expression was lower in patients than in controls. MEIS1 expression was inversely correlated with white blood cell (WBC) count. HOXA4 expression was down-regulated in patients with high risk according to the National Cancer Institute (NCI) classification. TAL1 methylation was slightly elevated in patients aged >9 years and in patients showing relapse, suggesting its potential prognostic value. CONCLUSION: Aberrant methylation and expression of the selected hematopoietic genes were correlated with demographic/clinical prognostic factors of pediatric ALL, such as age, WBC count, and NCI risk classification. PMID- 25830128 TI - Anti-leukemic properties of deferasirox via apoptosis in murine leukemia cell lines. AB - BACKGROUND: Although deferasirox (DFX) is reported to have anti-tumor effects, its anti-leukemic activity remains unclear. We evaluated the effect of DFX treatment on two murine lymphoid leukemia cell lines, and clarified the mechanisms underlying its potential anti-leukemic activity. METHODS: L1210 and A20 murine lymphoid leukemia cell lines were treated with DFX. Cell viability and apoptosis were evaluated by the 3-(4,5-dimethylthaizol-2-yl)-5-(3 carboxymethylphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and fluorescence-activated cell sorting (FACS) analysis, respectively. Immunoblotting was performed to detect the expression of key apoptotic proteins. RESULTS: In dose- and time-dependent manner, DFX decreased viability and increased apoptosis of murine leukemic cells. Fas expression was significantly higher in A20 cells than in L1210 cells at all DFX concentrations tested. Although both cell lines exhibited high caspase 3 and caspase 9 expression, a critical component of the intrinsic mitochondrial apoptotic pathway, expression was greater in L1210 cells. In contrast, caspase 8, a key factor in the extrinsic apoptotic pathway, showed greater expression in A20 cells. Cytochrome c expression was significantly higher in L1210 cells. In both cell lines, co-treatment with ferric chloride and DFX diminished the expression of these intracellular proteins, as compared to DFX treatment alone. CONCLUSION: Treatment with DFX increased caspase-dependent apoptosis in two murine lymphoid leukemia cell lines, with differing apoptotic mechanisms in each cell line. PMID- 25830130 TI - Comparative analysis of cellulose acetate hemoglobin electrophoresis and high performance liquid chromatography for quantitative determination of hemoglobin A2. AB - BACKGROUND: The present study is designed to evaluate the reliability and cost effectiveness of cellulose acetate Hb electrophoresis and high performance liquid chromatography (HPLC) in the determination of HbA2 levels. METHODS: The test population comprised 160 individuals divided into four groups: normal individuals, beta-thalassemia trait (BTT) patients, iron deficiency anemia (IDA) patients, and co-morbid patients (BTT with IDA). HbA2 levels determined using cellulose acetate Hb electrophoresis and HPLC were compared. RESULTS: HbA2 levels were found to be diagnostic for classical BTT using either method. In co-morbid cases, both techniques failed to diagnose all cases of BTT. The sensitivity, specificity, and Youden's index for detection of the co-morbid condition was 69% and 66% for HPLC and cellulose acetate Hb electrophoresis, respectively. CONCLUSION: This study revealed that semi-automated cellulose acetate Hb electrophoresis is more suitable for use in beta-thalassemia prevention programs in low-income countries like Pakistan. This technique is easily available, simple and cost effective. PMID- 25830129 TI - SOCS1 and SOCS3 are expressed in mononuclear cells in human cytomegalovirus viremia after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: The expression of the SOCS genes in cytomegalovirus (CMV) viremia after hematopoietic stem cell transplantation (HSCT) remains largely unexplored. METHODS: Using quantitative RT-PCR of mononuclear cells, we conducted pairwise comparison of SOCS1 and SOCS3 expression levels among a healthy donor group (N=55), a pre-HSCT group (N=17), and the recipient subgroup (N=107), which were divided according to the occurrence of CMV viremia and acute graft-versus-host disease (aGVHD). RESULTS: Compared to that in the healthy donor group, SOCS1 expression was higher in the CMV+ subgroup, especially in the CMV+GVHD- group, but decreased in the other subgroups. When compared to the expression in the pre HSCT group, SOCS1 expression was significantly higher in the CMV+ subgroup, especially in the CMV+GVHD+ subgroup. Meanwhile, compared to that in the healthy donor group, SOCS3 expression was significantly lower in all other groups. The CMV-GVHD- subgroup showed significantly lower SOCS3 expression compared to the CMV+ subgroup, the CMV+GVHD+ subgroup, and the CMV+GVHD- subgroup. CONCLUSION: We report differential expression of SOCS genes according to CMV viremia with acute GVHD occurrence after HSCT, suggesting that regulation of SOCS expression is associated with CMV viremia. PMID- 25830131 TI - HBV reactivation in a HBsAg-negative patient with multiple myeloma treated with prednisolone maintenance therapy after autologous HSCT. AB - Hepatitis B virus (HBV) reactivation has previously occurred in hepatitis B surface antigen-negative patients with malignant lymphoma who received rituximab based combination chemotherapy. However, few reports have described cases of HBV reactivation in patients with multiple myeloma thus far. We report a case of HBV reactivation in a patient with multiple myeloma treated with chemotherapy, autologous hematopoietic stem cell transplantation, and maintenance steroid therapy. For the HBV reactivation, the patient was treated with the antiviral agent entecavir. The clinical symptoms and laboratory findings improved after 3 months. Further studies should target the identification of patients at high risk of HBV reactivation in multiple myeloma treated with autologous hematopoietic stem cell transplantation and steroid therapy for maintenance and establish viral prophylaxis strategies, especially in Korea, in which HBV infection is endemic. PMID- 25830132 TI - Regenerating blasts masquerading as relapse in a patient with ALL following G-CSF therapy. PMID- 25830133 TI - A case of pediatric ALL with t(16;21)(p11.2;q22) and FUS-ERG rearrangement. PMID- 25830134 TI - Chronic eosinophilic leukemia with a FIP1L1-PDGFRA rearrangement: Two case reports and a review of Korean cases. PMID- 25830135 TI - Diffuse large B cell lymphoma with high M protein: an unusual finding. PMID- 25830136 TI - Atypical HUS caused by anti-complement factor H antibody: a hematologist's perspective. PMID- 25830137 TI - Forbidden fruit for athletes, but possible divine blessing for rehabilitation: testosterone. AB - Testosterone is regarded as an attractive supplement for obtaining masculinity and sexuality; however, there have been pros and cons regarding its application as a treatment. In addition, there is also conventional repulsion on adoption of testosterone to any kind of exercise to anyone with concern with sports. However, we should keep in mind that in terms of rehabilitation, our main concern is not fairness but efficiency. And there are obvious advantages of testosterone in recovery and rejuvenation. We aim to introduce the possibility of testosterone in recovery and rejuvenation and are to bring up a topic the application of testosterone in exercise rehabilitation. Considering the light and darkness in testosterone, moderate use of testosterone under professional medication counseling might be an effective possibility to those with sickness and illness and should be considered as a possible option to assist the recovery from frailty and illness. PMID- 25830138 TI - Treadmill exercise improves short-term memory by enhancing hippocampal cell proliferation in quinolinic acid-induced Huntington's disease rats. AB - Huntington's disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements called chorea. Quinolinic acid (QA) is an endogenous metabolite of tryptophan in the kynurenine pathway. QA induced alterations are similar to the symptoms of HD patients. Physical exercise has beneficial effects on the brain functions. Exercise increases production of neurotrophic factors in the brain and improves learning ability and memory function. In the present study, we investigated the effects of treadmill exercise short-term memory on QA-induced HD rats in relation with cell proliferation. For the induction of Huntington's animal model, 2 MUL of 100 nmol QA was intrastriatal injected into the rats. The rats in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 2 weeks. Step-down avoidance test was conducted for the determination of short-term memory. Cell proliferation in the hippocampal dentate gyrus was determined by 5 bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry. Western blot for brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were performed. In the present results, treadmill exercise alleviated QA-induced short-term memory impairment in HD rats. Treadmill exercise increased cell proliferation in the hippocampal dentate gyrus through enhancing BDNF expression in the HD rats. These results revealed that treadmill exercise is effective for the symptom improvement in the HD patients. PMID- 25830139 TI - Postnatal treadmill exercise attenuates prenatal stress-induced apoptosis through enhancing serotonin expression in aged-offspring rats. AB - Maternal stress during pregnancy affects negative impact on health of offspring. In the present study, we compared the effects of maternal treadmill exercise and offspring treadmill exercise on prenatal stress-induced apoptosis and serotonin expression in offspring. Stress to the pregnant rats was induced by exposure of maternal rats to the hunting dog in an enclosed room. Exposure time was 10 min, three times per day, with a 1-h interval between exposures. This regimen was maintained from the seventh day of gestation until delivery. The pregnant rats in the exercise group were forced to run on a motorized tread-mill for 30 min once a day, started 7 days after pregnancy until delivery. The offspring in the exercise group were forced to run on a motorized treadmill for 30 min once a day, started 4 weeks after birth for 4 weeks. In the present results, offspring exposed to prenatal stress exhibited lower Bcl-2 level and higher Bax level in the hippocampus, lower 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase (TPH) expression in the dorsal raphe, and higher c-Fos expression in the locus coeruleus compared to age-matched control rats. Treadmill exercise of offspring suppressed Bax expression and enhanced Bcl-2 expression in the hippocampus, increased 5-HT and TPH expression in the dorsal raphe, and enhanced c-Fos expression in the locus coeruleus of offspring. Tread-mill exercise of offspring suppressed prenatal stress-induced apoptosis and normalized prenatal stress induced alterations in serotonin synthesis and neuronal activation. However maternal treadmill exercise during pregnancy exerted no significant effect on offspring. PMID- 25830140 TI - Exercise facilitators and barriers following participation in a community-based exercise and education program for cancer survivors. AB - Cancer survivors participating in supervised exercise programs learn to exercise safely with oversight from care providers who monitor and facilitate their progress. This study investigated the long-term exercise participation levels and identified exercise barriers for graduates from a specialized cancer exercise and education program. Subjects were graduates from a 12-week supervised exercise program (www.canwellprogram.ca) who participated in a, prospective, long-term evaluation. Measures included: six-minute walk test (6-MWT), STEEP treadmill test, Functional Assessment Cancer Therapy-General (FACT-G), Edmonton Symptom Assessment System (ESAS), Godin Leisure-Time Exercise Questionnaire, and exercise barriers survey. Analysis was performed using the paired t -test. Fifty-seven (55% of eligible cohort) CanWell participants (mean age= 60; 74% females) were included in this study. Post program changes included statistically significant reductions in total min on the treadmill and a trend towards improvements in 6 MWT distance. No significant changes were recorded in total FACT-G or ESAS score, however functional well-being approached statistical significant improvements. The most commonly reported exercise barriers included fatigue, cost, and return to work. While most participants (86%) believed they were able to exercise, only 63% reported being able to progress their exercise. These finding demonstrated that although CanWell graduates have substantial support from exercise specialists and most have early success with exercise, environment-related factors diminish long-term independent adherence to exercise. Providing cancer survivors with the skills needed to monitor and progress their exercise routines, or access to "tune-ups" may increase exercise adherence and maximize benefits. PMID- 25830141 TI - A study on the effect of self bedside exercise program on resilience and activities of daily living for patients with hemiplegia. AB - The purpose of this study was to design a repeatable universal rehabilitation program in which patients with hemiplegia can participate voluntarily, complementing physical and occupational therapies to increase voluntary exercise practice rate. Also, this study attempted to identify the relationship between psychological resilience due to the implementation of self-bedside exercise and functional recovery of activity of daily living (ADL). 12 patients with hemiplegia voluntarily participated in 8 weeks of self-bedside exercise 5 times a day and more than 5 days a week. Their program implementation, resilience, activities of daily living (MBI), upper limb motor functions (MFT), and balance ability (BBS) were analyzed and compared before and after the program. Compared to before implementing the program, significant increases were found in resilience, MBI, BBS, and MFT in the affected side after the implementation, and the resilience scores showed statistically positive correlation in MBI and MFT. Also, the change in resilience before and after the program implementation showed a statistically positive correlation. Therefore, it can be concluded that the self-bedside exercise developed in this study had a positive effect on voluntary participation in exercise as well as resilience and ADL. However, many studies which complement the psychological aspects of hemiparetic patients with stroke are still needed. PMID- 25830142 TI - The effects of band exercise using proprioceptive neuromuscular facilitation on muscular strength in lower extremity. AB - The purpose of this study was to examine whether a six-week elastic band exercise program using proprioceptive neuromuscular facilitation (PNF) can increase isotonic strength of abductor muscles in the lower extremity. Twenty-eight healthy students from S university were divided into an experimental group and control group. Each group was participated in pre and post-measurement in isotonic strength using an isotonic analyzer, En-treeM. Experimental group performed elastic band exercise using PNF pattern for a six-weeks, in contrast, control group did not take any exercise. In the results of this study, isotonic strength measurements of abductor muscles in lower extremity in experimental group were significantly different after exercise, but control group did not show any significant changes. Therefore, we hope that resistive exercise would be very valuable for healthy people as well as the old people with weakened muscle strength. PMID- 25830143 TI - On school violence in Korean middle school, prevention and reaction measures. AB - This study is aiming to explore the practical and realistic measure in more variable way, which enables us to manage the problems about school violence we are currently facing as well as to overcome limitations in the current situation where we react only with punishments, mainly in the form of the law enforcement, supported by the police. This study was conducted on male and female students (n= 424) and teachers (n= 136) attending at the seven middle schools located in Seoul. The frequency analysis, one way ANOVA F-test, t -test, the multiple regression analysis were applied. Students recognize' harmful environmental cleanup' as an important variable or factor to reduce school violence. Also, both teachers and students are aware that 'regular survey on school violence' could reduce school violence. In conclusion, it is considered that as an effective and viable prevention measure against school violence, more attention and affection efforts need to be activated and addressed, on the part of home, school, and government, which will enable our young generations of students to be brought up, and take up the future of our country. PMID- 25830144 TI - Effects of participation in swimming lessons on health perception and belief. AB - This study was conducted to investigate the effects of the degree of participation in swimming lessons and the participation styles on health perception and belief. To do this, several analyses were conducted-statistical analysis, frequency analysis, factorial analysis, reliability analysis, correlation analysis, and regression analysis-using SPSS 18.0. A total of 300 copies of the questionnaire were distributed and after excluding those that are considered invalid, only 278 copies were used for the study. As a result, first, for the participants for "30 min-1 h," "1 h-2 h," and "more than 2 h" in time and "2-3 times a week" and "4-5 times a week" in frequency, swimming lessons in types had a significant effect on health interest and health concern. Second, participants for "30 min-1 h" and "1 h-2 h" in time and "hard' in intensity had a significant effect on resistance and sensitivity. Third, all frequencies and intensities excluding the participants for "15 min-30 min." and "swimming lessons" in types had a significant effect on perceived benefit. Fourth, all participants for a time period did not have a significant effect on the perceived disability, but they all had a significant effect on the former in terms of frequency and intensity. This being said, however, the participating types did not have any a significant effect. PMID- 25830145 TI - A follow-up study on the physique, body composition, physical fitness, and isokinetic strength of female collegiate Taekwondo athletes. AB - The purpose of the study was to analyze changes in physique, body composition, physical fitness, and isokinetic strength in female collegiate taekwondo athletes. The study included 14 subjects, of whom 8 were followed up throughout the study. Anthropometric characteristics included body weight, height, sitting height, circumferences, and bone width. Physical fitness parameters included flexibility, agility, muscle strength, muscular endurance, power, speed, and cardiorespiratory endurance. Peak torque, mean power, and H/Q ratio were analyzed by using Cybex 770. All data were analyzed by using the SAS statistical program. Paired t test was performed, with 0.05 as the significance level. The results indicated significant changes in body weight, and upper arm and flexed upper arm circumferences during the experimental period. Test scores for plate tapping, and sit and reach significantly increased, but that for power decreased. In addition, the peak power of right flexion at 180 degrees /sec was significantly increased, as well as the mean power of right and left flexion, and the H/Q ratio at 180 degrees /sec. PMID- 25830146 TI - The Dallas Heart Study using the probability sample technique for ethnicity and cardiovascular health differences. AB - The decrease in cardiovascular death rates in the United States has been slower in blacks than whites, especially in patients < 65 years of age. The Dallas Heart Study was designed as a single-site, multiethnic, population-based probability sample to produce unbiased comparison of cardiovascular health among multiple ethnicities. PMID- 25830147 TI - Left ventricular diastolic function and dysfunction: Central role of echocardiography. AB - Comprehensive and precise assessment of left ventricular (LV) systolic and diastolic function is necessary to establish, or exclude, heart failure as a cause or component of dyspnea. Echocardiography with Doppler readily assesses LV diastolic function; advantages include that echocardiography is non-invasive, does not require radiation, is portable, rapid, readily available, and in competent hands, can provide an accurate and comprehensive assessment of LV systolic and diastolic function. Correct assessment of LV diastolic function is relevant in patients with both depressed and preserved LV ejection fraction (EF >= 50%, and < 50%, respectively). Tissue Doppler (TD) imaging has been useful in demonstrating impaired LV relaxation in the setting of preserved LVEF, which, in the setting of increased cardiac volume, can result in elevated LV filling pressures, and dyspnea due to diastolic heart failure. TD imaging is not always critical in patients with depressed LVEF, since such patients by definition have impaired LV relaxation, and thus significant increases in volume will result in increases in LV filling pressure due to impaired LV compliance. Thus, in depressed LVEF, transmitral flow velocities (E and A, and E/A) and deceleration time, pulmonary venous Doppler, left atrial volume, and pulmonary artery (PA) pressures suffice for the accurate assessment of LV filling pressures. Overall, diastolic assessment by echo-Doppler can be readily achieved in by using a comprehensive diastolic assessment-incorporating many 2-dimensional, conventional and tissue Doppler variables-as opposed to relying on any single, diastolic parameter, which can lead to errors. PMID- 25830148 TI - Dronedarone-digoxin interaction in PALLAS: A foxglove connection? AB - In the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, dronedarone use was associated with an excess risk of stroke, cardiovascular death and hospitalizations. However, an increased level in the serum digoxin level was observed in the dronedarone arm, as it is a potent inhibitor of the P-glycoprotein transport system. The PALLAS subanalysis suggests that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These data are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation. One must consider other safer alternatives before prescribing digoxin in atrial fibrillation patients. PMID- 25830149 TI - 3D modelling of atrial and ventricular shape and function in a patient following the new modified Mustard operation. PMID- 25830150 TI - STABILITY and SOLID-TIMI 52: Lipoprotein associated phospholipase A2 (Lp-PLA2) as a biomarker or risk factor for cardiovascular diseases. AB - Lipoprotein associated phospholipase A2 (Lp-PLA2) - an enzyme with several pro inflammatory properties - has been hypothesized to be involved in the pathogenesis of atherosclerosis and plaque vulnerability. Lp-PLA2 activity has been demonstrated to be an independent predictor of coronary heart disease (CHD) and ischemic stroke. However, it has been recently reported that carriers of loss of function variants in PLA2G7 gene (encoding Lp-PLA2) had no lower CHD risk than non-carriers. The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY), and the Stabilization of Plaque Using Darapladib Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies are two phase III, randomized, placebo-controlled, clinical trials that were conducted to evaluate the clinical efficacy and safety of the Lp-PLA2 inhibitor (darapladib), against a background of optimal medical therapy, in patients with stable CHD and acute coronary syndrome, respectively. In both studies, darapladib failed to reduce the risk of major coronary events as compared to placebo. In addition, darapladib was associated with significantly higher rates of drug discontinuation, and adverse side effects such as diahrrea and malodorous feces, urine, and skin, as compared to placebo. These data suggest that Lp-PLA2 may be a biomarker of vascular inflammation rather than a causal pathway of cardiovascular (CV) diseases. It also challenges the notion that inhibition of Lp-PLA2 is a worthwhile approach in patients with CHD. Alternate therapies that target inflammation are awaited to reduce residual risk in patients with CV diseases. PMID- 25830151 TI - INHERIT (INHibition of the renin angiotensin system in hypertrophic cardiomyopathy and the Effect on hypertrophy-a Randomised Intervention Trial with losartan). AB - Early pharmacological interventions on transgenic models of hypertrophic cardiomyopathy (HCM) using angiotensin receptor blockers (ARBs) may be effective in preventing development of clinical phenotype or causing phenotype regression in early stages of disease. In the clinical setting, however, the effects of ARBs on HCM phenotype have been less consistent. INHERIT (INHibition of the renin angiotensin system in hypertrophic cardiomyopathy and the Effect on hypertrophy-a Randomised Intervention Trial with losartan) was designed to assess the effect of 100 mg of losartan in promoting the regression of LV hypertrophy in HCM. The primary end-point of the study was the reduction in LV mass assessed by MRI or computed tomography. After 12 months, no reduction in LV mass was observed in the losartan arm, and there was no difference in LV mass change with the placebo arm. The same was true for all secondary endpoints. The implications of these findings are discussed in the light of further, ongoing study targeting the HCM phenotype. PMID- 25830152 TI - DECAAF: Emphasizing the importance of MRI in AF ablation. AB - Atrial fibrillation ablation is a complex and challenging procedure. Appropriate patient selection is the most critical step to ensure safe and successful atrial fibrillation ablation procedure. The DECAAF study (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation) showed that atrial tissue fibrosis, as estimated by delayed enhancement magnetic resonance imaging, was independently associated with recurrent arrhythmia post atrial fibrillation ablation. Magnetic resonance imaging also detected left atrial volume and shape. Integrating the data provided by magnetic resonance imaging into the pre-procedural planning is crucial. PMID- 25830153 TI - Comparison of the contraceptive use and its related factors among women seeking repeat and first-time induced abortions in iran. AB - BACKGROUND: Abortion in Iran, like other Islamic countries is severely restricted except in a few exceptions. However, some women who have an unwanted or mistimed pregnancy are seeking abortion. OBJECTIVES: This study aimed to compare the contraceptive use and its related factors among repeat and first- time induced abortion seekers in Iran. PATIENTS AND METHODS: In this cross-sectional study, 417 married women (age range, 15-49 years) seeking abortion services at either a hospital or private office in Maku City, the northwest of Iran, were selected through convenience sampling between December 2010 and March 2011. All the subjects were asked about the contraceptive methods used during the three months before the current pregnancy and the use of any emergency contraception and forced sex. Women who mentioned reasons except than completing family size for their applying for abortion were excluded from the analysis. Characteristics of women were examined using chi-square and t test. T test and Mann-Whitney U test were used to compare contraceptive methods and the regularity of contraceptive use between repeat and first-time abortion seekers, respectively. RESULTS: About 33.8% of the repeat abortion-seekers and 76.8% of first-time abortion seekers were using male methods (withdrawal and condom). Utilization of an intrauterine device for birth control was higher among women seeking repeat abortion than in first-time abortion seekers (P = 0.003). All of 31 pill users in the repeat abortion-seeking group missed three or more pills per month for three times during the three months before contraception. The repeat abortion seekers had used condom more regularly than those in the first-time abortion seekers. Forced sex was more prevalent in the abortion seekers who had used male method. CONCLUSIONS: Using male methods are prevalent in abortion-seeker women. An increased focus is needed on training the regular use of pills and using the emergency contraception for all of the couples who are first-time abortion seekers. Moreover, information about the role of forced sex might be efficacious in decreasing illegally induced repeat abortion in couples who use condom or withdrawal methods. PMID- 25830154 TI - Sex differences in Acute Myocardial Infarction. PMID- 25830155 TI - Patients dignity in nursing. PMID- 25830156 TI - Severity of menopausal symptoms and related factors among 40 to 60 year-old women. PMID- 25830157 TI - Psychological violence in the health care settings in iran: a cross-sectional study. AB - BACKGROUND: Psychological violence is the most common form of workplace violence that can affect professional performance and job satisfaction of health care workers. Although several studies have been conducted in Iran, but there is no consensus regarding current status of such violence. OBJECTIVES: This study aimed to investigate the prevalence of psychological violence among healthcare workers employed at teaching hospitals in Iran. PATIENTS AND METHODS: In this cross sectional study, 5874 health professionals were selected using multistage random sampling. Data were collected using a self-administered questionnaire developed by the International Labor Organization, International Council of Nurses, World Health Organization, and Public Services International. Descriptive statistics were used to analyze the data. RESULTS: It was found that 74.7% of the participants were subjected to psychological violence during the past 12 months. Totally, 64.5% of psychological violence was committed by patients' families, but 50.9% of participants had not reported the violence, and 69.9% of them believed that reporting was useless. CONCLUSIONS: The results are indicative of high prevalence of psychological violence against healthcare workers. Considering non reporting of violence in more than half of participants, use of an appropriate reporting system and providing training programs for health professionals in order to prevent and manage workplace violence are essential. PMID- 25830158 TI - A comparison between foley and nelatone urinary catheters in causing urinary tract infection in animal models. AB - BACKGROUND: Urinary catheterization is one of the main measures used to treat and care for hospitalized patients. Several complications have been attributed to the presence of latex with routine Foley catheters. Therefore, some studies have recommended that Nelatone catheters be substituted for the ordinary Foley catheters to prevent these complications. OBJECTIVES: This study aimed to compare the rates of urinary tract infection (UTI) in rabbits catheterized either with Foley or with Nelatone catheters. MATERIALS AND METHODS: A randomized controlled trial was conducted on 60 rabbits that were randomly assigned to three groups of twenty. The first group was catheterized using Nelatone catheter; the second group was catheterized using Foley catheter and the third group was studied without performing any catheterization. After seven days, urine samples were collected using suprapubic aspiration and were sent to the laboratory for culture. Descriptive statistics were calculated. Moreover, chi-square and Fisher's exact tests were used for data analysis. RESULTS: At the end of the study, four cases in the Nelatone group and 12 cases in the Foley group presented with UTI (P = 0.01). No positive urine cultures were found in the control group. CONCLUSIONS: The Nelatone catheters, compared with the Foley ones, had a lower risk of UTI in the long term use. Verifying this claim by further studies can have an important role in reducing UTIs in patients using urinary catheters. PMID- 25830159 TI - How baloch women make decisions about the risks associated with different childbirth settings in southeast iran. AB - BACKGROUND: In Zahedan City in Southeast Iran, some women prefer to give birth at home despite the availability of the equipped hospitals and expert advice that hospital births are safer. OBJECTIVES: This study explains how Baloch women make decisions regarding the risks associated with childbirth at home versus a hospital. This study identifies and defines the factors that influence the choice of the place of delivery by Baloch women. MATERIALS AND METHODS: The article draws on data from a grounded theory. In particular, on in-depth interviews with 25 Baloch women, 21 of whom had planned home births and 4 planned hospital births in their most recent childbirth. RESULTS: Six categories emerged from the data as follows: 1) deliberation and risk assessment; 2) obstacles to hospital births; 3) preference for hospital births; 4) obstacles to homebirth; 5) preference for homebirth; and 6) risk management. The core category was deliberation and risk assessment. Our interviews showed that Baloch woman weighed the negative and positive aspects of each option when deciding on a childbirth setting. In this process, their assessment of risk included physical wellbeing and sociao-cultural values. Furthermore, their assessment of risk can, in some circumstances, result in delays or avoidance of having hospital childbirth. CONCLUSIONS: Managers and service providers need to know an ordinary woman's perception of risk to address the gap between current and desired childbirth services and encourage women to use current hospital services. PMID- 25830160 TI - Critical thinking skills in nursing students: a comparison between freshmen and senior students. AB - BACKGROUND: Critical thinking is one of the most important concepts in the field of education. Despite studies published on nursing students' critical thinking skills (CTS), some suggest that there is not enough evidence supporting the relationship between content of nursing education programs and nursing students' CTS. OBJECTIVES: Given the existing discrepancies, this study aimed to compare the critical thinking skills of freshmen and senior nursing students. PATIENTS AND METHODS: This comparative study was conducted on 150 undergraduate freshmen and senior nursing students in Kashan University of Medical Sciences, during 2012. The students in the first and the last semesters of their study in nursing were entered in the study using the census method. Data were collected using a questionnaire including questions on demographic data and the California Critical Thinking Skills Test, form B. Data analysis was performed using the SPSS v.13 software. Descriptive statistics were calculated. Moreover, independent sample t test and Spearman and Pearson's correlation coefficients were used in the data analysis. RESULTS: Both the freshmen and senior nursing students had low CTS. The mean critical thinking scores were 11.79 +/- 4.80 and 11.21 +/- 3.17 for the freshmen and the senior students, respectively (P = 0.511). Moreover, no significant correlation was found between the students' score in CTS and their age, gender, high school grade point average (GPA), rank in university entrance examination (RUEE) and interest in the nursing profession. CONCLUSIONS: The students were low skilled in critical thinking and their CTS did not significantly change during their nursing degree. Thus it may be concluded that the nursing education program did not affect the CTS of its students. Longitudinal studies are suggested for assessing nursing students' critical thinking over time. Moreover, revising the curriculum and preparing nursing educators for implementing innovative and active teaching strategies are suggested. PMID- 25830162 TI - Testing of action of direct flame on concrete. AB - The paper states results of experimental exposition of concrete test specimens to direct flame. Concrete test specimens made from various mixtures differing in the type of aggregate, binder, dispersed reinforcement, and technological procedure were subjected to thermal load. Physicomechanical and other properties of all test specimens were tested before exposition to open flame: density, compressive strength, flexural strength, moisture content, and surface appearance. The specimens were visually observed during exposition to open flame and changes were recorded. Exposed surface was photographically documented before thermal load and at 10-minute intervals. Development of temperature of the specimens was documented with a thermocamera. After exposition to thermal load and cooling down, concrete specimens were visually observed, network of cracks was photographically documented, and maximal depth of spalled area was measured. PMID- 25830161 TI - Comparing the effects of active and passive intradialytic pedaling exercises on dialysis efficacy, electrolytes, hemoglobin, hematocrit, blood pressure and health-related quality of life. AB - BACKGROUND: The effect of exercise during hemodialysis has been a controversial issue, however, there are just few studies about the effect of active exercise during hemodialysis. OBJECTIVES: This study aimed to compare the effects of passive and active intradialytic pedaling exercises on dialysis efficacy, electrolytes, hemoglobin, hematocrit, blood pressure and health-related quality of life in hemodialysis patients. PATIENTS AND METHODS: This quasi-experimental study was conducted on 16 hemodialysis patients in Akhavan hemodialysis center in Kashan from April to November 2013. Active or passive intradialytic pedaling exercise was performed using a Mini-Bike for 30 minutes during the first two hours of the dialysis sessions. The quality of life (QOL) was assessed before and after the intervention. Blood pressure was examined at the beginning and then hourly during the dialysis sessions. Dialysis efficacy, levels of phosphorus, calcium, sodium, potassium and Blood urea nitrogen (BUN) were measured at the end of the intervention. Kolmogorov-Smirnov test, paired t test, Wilcoxon signed rank and Friedman tests and repeated measure analysis of variancewere used to analyze the data. RESULTS: No significant changes were observed in serum potassium, phosphorus and calcium levels at the end of the passive exercise program compared to the baseline. However, phosphorus levels were significantly decreased in the active exercise program (P < 0.05). Moreover, the mean diastolic blood pressure was significantly decreased after the passive exercise (P = 0.039). Passive exercise did not significantly change the dialysis efficacy, urea reduction rate, hemoglobin and calcium levels. The mean overall QOL was 63.78 +/- 21.15 at the beginning of the study, which was increased to 77.07 +/- 21.14 at the end of eight weeks of the intradialytic exercise (P = 0.007). CONCLUSIONS: The passive intradialytic exercise had a positive effect on blood pressure. The active exercise could decrease the serum phosphorus and potassium levels. Moreover, both exercise programs could significantly improve the QOL. Both active and passive intradialytic exercises can have some beneficial effects. PMID- 25830163 TI - Repair Bond Strength of Aged Silorane-based Composite Using Intermediate Adhesive Systems Based on Different Monomers. AB - PURPOSE: To investigate the effect of pre-repair aging periods and intermediate adhesive systems based on different monomers on the repair bond strength of silorane-based resin composite. MATERIALS AND METHODS: A total of 32 Filtek P90 (3M ESPE) substrate specimens (4 mm diameter and 4 mm height) were made. Substrate specimens were grouped according to the pre-repair time periods into four groups (n = 8/group): 15 to 30 min, 24 h, 1 month, and 3 months. All substrate specimens were ground flat using a diamond stone and were etched using Scotchbond phosphoric acid etchant (3M ESPE). The specimens of each pre-repair time period were equally distributed among the two repair groups, using either silorane-based (P90 System Adhesive) or acrylamide-based (AdheSE One F, Ivoclar Vivadent) intermediate adhesive systems. Specimens of P90 System adhesive received Filtek P90 as the repair resin composite, and Tetric N-Ceram (Ivoclar Vivadent) was used with AdheSE One F specimens. Additional specimens were made from the repair resin composite materials to study the cohesive strength. Specimens were sliced into sticks (0.6 +/- 0.01 mm2) for microtensile bond strength testing (MUTBS). Modes of failure were determined. RESULTS: Two-way ANOVA with repeated measures revealed no significant effect for the pre-repair aging periods, intermediate adhesive systems based on different monomers, or their interaction on repair bond strength of silorane-based resin composite. CONCLUSION: Up to 3 months of pre-aging the repaired silorane-based resin composite had no negative effect on its repair bond strength, even when an intermediate adhesive system based on a different monomer (acrylamide) was used. PMID- 25830165 TI - Brain warfare: primates to humans? PMID- 25830164 TI - Bond Strength of Experimental Low-viscosity Resin Materials to Early Enamel Caries Lesions: Effect of Diluent/Solvent Addition. AB - PURPOSE: To evaluate the effect of different concentrations of monomers and solvents/diluents on the microtensile bond strength (MUTBS) bond strength of experimental low-viscosity resins (infiltrants) to enamel caries-like lesions (ECLL). MATERIALS AND METHODS: Flat enamel blocks obtained from sound human third molars were submitted to ECLL formation and randomly distributed into 9 groups (n = 10): G1: TEG-DMA 100%; G2: TEG-DMA 80%, ethanol 20%; G3; TEG-DMA 80%, HEMA 20%; G4: TEG-DMA 75%, UDMA 25%; G5: TEG-DMA 60%, UDMA 20%, ethanol 20%; G6: TEG-DMA 60%, UDMA 20%, HEMA 20%; G7: TEG-DMA 75%, bis-EMA 25%; G8: TEG-DMA 60%, bis-EMA 20%, ethanol 20%; G9: TEG-DMA 60%, bis-EMA 20%, HEMA 20%. After etching with 37% phosphoric acid for 60 s, experimental infiltrants were actively applied and photocured for 60 s, then stored in 100% humidity (24 h, 37 degrees C). Hourglass shaped specimens were obtained and the MUTBS test performed (MPa). The fracture patterns were assessed by SEM. Data were submitted to two way-ANOVA and Tukey's tests (alpha = 0.05). RESULTS: The highest MUTBS value was observed for G4 (TEG DMA/UDMA, 19.18 MPa) and the lowest for G5 (TEG-DMA/UDMA/ethanol, 9.00 MPa). A significant decrease in MUTBS was observed for all groups containing ethanol (G2, G5, and G8). The addition of HEMA did not affect MUTBS values. Most groups showed a high frequency of mixed failure between infiltrant and enamel. CONCLUSION: The addition of bis-EMA or UDMA to TEG-DMA-based infiltrants did not improve bond strength to carious enamel. The ethanol addition negatively affected the bonding strength of infiltrants to enamel caries-like lesions, regardless of the resin matrix composition of the infiltrant. PMID- 25830166 TI - Journeys in long-term care. PMID- 25830167 TI - Healthcare transitions of older adults: an overview for the general practitioner. AB - Healthcare transition refers to the care "hand-off" of a patient among providers and treatment settings. Older adults experience more frequent care transitions than younger patients due to the presence of co-morbidities, cognitive impairment, increased dependence and medication use. Hospitalization and subsequent readmission after discharge to a nursing home represents a unique care transition situation. It is estimated that as many as 60% of readmissions from nursing homes can be avoided. Poor communication between hospital and nursing home staff; delayed, inaccurate, or missing discharge summaries; lack of accurate medication reconciliation; pending test results; inappropriate follow-up; and poor education of patient and families all contribute to poor care transition quality, and increase the probability of rehospitalization. Interventions for improved care transitions are suggested. They focus on patient and family centered care effectiveness, minimizing adverse events, and increasing timely, accurate and complete communication. PMID- 25830168 TI - Health care transitions: perceptions from older patients in Rhode Island. AB - Health care transitions are often dangerous for older patients. Interviews with older adults about their health care moves in Rhode Island (RI) were conducted to develop an Internal Medicine (IM) curriculum designed to provide IM interns with insights about the impact of transitions on patients. This paper describes some ways patients talk about their transitional experiences. Following pilot interviews, 10 nursing home residents were interviewed about their care transitions, conversations with physicians, and advice to doctors beginning their careers. The interviews were analyzed to identify themes. Patients described multiple moves, often did not know what to expect, appreciated help from a family member and desired effective communications with physicians. Learning about patient experiences may help new physicians appreciate the experiences of transitions on patients. PMID- 25830169 TI - The goals of care conversation: a tool to improve patient care in the nursing home at the end of life. AB - Patients residing in nursing homes may undergo burdensome transitions in care during the final months of life. They may get care they do not want and are unlikely to benefit from. Patients and families may not understand prognosis or the potential benefits of treatment. A "goals of care" conversation can be the critical first step in identifying a patient's wishes and then developing a plan of care that honors those wishes. When the goal of care is to focus on comfort, hospice can be accessed. Hospice can help ensure that the patient's final time is spent in comfort and that the family's needs are attended to both before and after the patient dies. PMID- 25830170 TI - Hospice and palliative care in nursing homes: challenges and opportunities for enhanced access. AB - The use of hospice care in nursing homes (NHs) has grown exponentially, but an increasing concern is the lack of access to resident and family-centered palliative care when residents do not elect hospice, and in time periods prior to election. This concern is amplified by the high magnitude of palliative care needs present for NH residents (and their families) when the NH will be their final residence; and, it is amplified because of short hospice stays, half of which are 22 days or less. This manuscript describes the use of the Medicare hospice care in NHs and discusses the policy, staff and physician barriers to timely hospice referral. It also describes the challenges NHs face in expanding residents' access to palliative care. Opportunities and approaches for increasing palliative care expertise and practice in NHs are presented. PMID- 25830171 TI - Comparison of substance-use prevalence among Rhode Island and The Miriam Hospital Emergency Department patients to state and national general population prevalence estimates. AB - OBJECTIVES: Compare the prevalence of recent alcohol, tobacco, and drug use among patients from two Rhode Island emergency departments (EDs) to Rhode Island state and United States national general population estimates between 2010 and 2012. METHODS: Secondary analysis of ED patient data and the National Survey of Drug Use and Health. RESULTS: Alcohol was the most commonly reported substance, and prevalence of its use was higher among ED patients than those in the national, but not the Rhode Island, general population. Drug use was higher among ED patients than in the state and national general population. For ED patients, tobacco and opioid use was highest among 26-34 year-olds, alcohol and marijuana highest among 18-25 years-olds, and cocaine highest among 35-49 years-olds. CONCLUSION: Rhode Island Hospital and The Miriam Hospital ED patients report a greater prevalence of substance use than the national population and in many cases the state general population. PMID- 25830172 TI - Training family medicine residents to build and remodel a patient centered medical home in Rhode Island: a team based approach to PCMH education. AB - Primary Care practices in the United States are undergoing rapid transformation into Patient Centered Medical Homes (PCMHs), prompting a need to train resident physicians in this new model of primary care. However, few PCMH curricula are described or evaluated in the literature. We describe the development and implementation of an innovative, month-long, team-based, block rotation, integrated into the Brown Family Medicine Residency Program, within the context of statewide PCMH practice transformation in Rhode Island. The PCMH resident team (first-, second- and third-year residents) gain PCMH skills, with progressive levels of responsibility through residency. In addition to traditional supervised direct outpatient care, learning activities include: active participation in PCMH transformation projects, population health level patient management, quality improvement activities, interdisciplinary teamwork, chronic disease management (including leading group medical visits), and PCMH specific didactics paired with weekly projects. This new clinical block rotation and team holds promise as a model to train residents for future PCMH primary care practices. PMID- 25830173 TI - Too weak to move. PMID- 25830174 TI - Uninsurance is only half the problem: Underinsurance and healthcare-related financial burden in RI. PMID- 25830175 TI - Versatile electronic properties and exotic edge states of single-layer tetragonal silicon carbides. AB - Three single-layer tetragonal silicon carbides (SiCs), termed as T1, T2 and T3, are proposed by density functional theory (DFT) computations. Although the three structures have the same topological geometry, they show versatile electronic properties from a semiconductor (T1), a semimetal (T2) to a metal (T3). The versatile properties originate from the rich bonds between Si and C atoms. The nanoribbons of the three SiCs also show interesting electronic properties. Especially, T1 nanoribbons possess exotic edge states, where electrons only distribute on one edge's silicon or carbon atoms. The band gaps of the T1 nanoribbons are constant because of no interaction between the edge states. PMID- 25830176 TI - The ligand polyhedral model approach to the mechanism of complete carbonyl exchange in [Rh4(CO)12] and [Rh6(CO)16]. AB - The Ligand Polyhedral Model (LPM) is applied to the carbonyl scrambling observed on the NMR timescale for the two cluster carbonyls [Rh4(CO)12] and [Rh6(CO)16]. For [Rh4(CO)12] the NMR data is completely consistent with the libration of the Rh4 central core about a C3 - rotational axis within the icosahedral shell of twelve CO ligands leading to a single-step concerted exchange process. Rotation of the Rh4 unit is also found to lead to the formation of a new all terminally bonded isomer which retains the icosahedral shell of CO ligands. Importantly, this new isomer does not have the [Ir4(CO)12] structure which is known to possess an cube-octahedral ligand shell. With [Rh6(CO)16] and its substituted derivative [Rh6(CO)15L] exchange is considered to take place via a polyhedral inter conversion in which the external tetra-capped truncated tetrahedral shell of carbonyl ligands observed in the ground-state undergoes rearrangement first to the 2 : 6 : 6' : 2 complementary geometry and then returns to the ground-state structure. This leads to a single-step fully concerted CO exchange. The LPM approach also provides an understanding of the variation of activation energies observed in going from [Rh4(CO)12] to [Rh6(CO)16] and of the driving force to the fluxional process. PMID- 25830177 TI - Rotameric transformations in the photochemistry of TpM(CO)2(eta(3)-C3H4R), where Tp = tris(pyrazolyl)borate, M = Mo or W, and R = H or Me. AB - Low energy photolysis of TpM(CO)2(eta(3)-C3H4R), where Tp = tris(pyrazolyl)borate, M = Mo or W, and R = 2-H or 2-Me in PVC matrices at 85 K results in exo/gauche isomerism of the allyl ligand. This transformation comes in contrast to the behaviour observed in cyclopentadienyl analogues which undergo exo/endo isomerism. DFT computations reveal an eta(3) -> eta(1)* -> eta(3) mechanism for the allyl rotameric interconversion where the eta(1)*-allyl intermediate is generated upon MLCT excitation. PMID- 25830178 TI - Arginine-assisted immobilization of silver nanoparticles on ZnO nanorods: an enhanced and reusable antibacterial substrate without human cell cytotoxicity. AB - Silver-based hybrid nanomaterials are gaining interest as potential alternatives for conventional antimicrobial agents. Herein, we present a simple, facile and eco-friendly approach for the deposition of silver nanoparticles (AgNPs) on ZnO nanorods, which act as a nanoreactor for in situ synthesis and as an immobilizing template in the presence of arginine. The presence of arginine enhanced the stability of ZnO deposition on the glass substrate by hindering the dissolution of zinc under alkaline conditions. Various Ag/ZnO hybrid nanorod (HNR) samples were screened to obtain a high amount of silver immobilization on the ZnO substrate. Ag/ZnO HNRs displayed potent antibacterial ability and could achieve 100% kill for both Escherichia coli and Bacillus subtilis strains under various test conditions. The hybrid material mediated its dual mode of antibacterial action through direct contact-killing and release of silver ions/nanoparticles and showed superior bactericidal performance compared to pure ZnO nanorods and colloidal AgNPs. No significant decline in antibacterial efficacy was observed even after the same substrate was repeatedly reused multiple times. Interestingly, the amount of Ag and Zn release was much below their maximal limit in drinking water, thus preventing potential health hazards. Immobilized AgNPs showed no cytotoxic effects on the human hepatocarcinoma cell line (HepG2). Moreover, treating cells with the antibacterial substrate for 24 hours did not lead to significant generation of reactive oxygen species (ROS). The good biocompatibility and bactericidal efficacy would thus make it feasible to utilize this immobilization strategy for preparing new-generation antibacterial coatings. PMID- 25830179 TI - Regulatory and quality considerations for continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium. AB - This paper assesses the current regulatory environment, relevant regulations and guidelines, and their impact on continuous manufacturing. It summarizes current regulatory experience and learning from both review and inspection perspectives. It outlines key regulatory aspects, including continuous manufacturing process description and control strategy in regulatory files, process validation, and key Good Manufacturing Practice (GMP) requirements. In addition, the paper identifies regulatory gaps and challenges and proposes a way forward to facilitate implementation. PMID- 25830180 TI - Effect of hydrogen peroxide and/or Flavobacterium psychrophilum on the gills of rainbow trout, Oncorhynchus mykiss (Walbaum). AB - The immune response and morphological changes in the gills of rainbow trout fry after immersion in hydrogen peroxide (H2O2), Flavobacterium psychrophilum or combined exposure were examined. The gills were sampled 4, 48, 125 and 192 h after exposure, and the regulation of expression of the following genes was investigated using qPCR: IgT, IgM, CD8, CD4, MHC I, MHC II, IL-4/13A, TcR-beta, IL-10, IL-1beta, IL-17, SAA and FoxP3. Bacteria were not observed in haematoxylin and-eosin-stained gill tissue, but the presence of F. psychrophilum 16S rRNA was detected using qPCR. The 16S rRNA levels were correlated with gene expression. Although pretreatment with H2O2 before immersion in F. psychrophilum did not significantly alter the amount of bacteria found in the gill, the immune response was influenced: exposure to F. psychrophilum resulted in a negative correlation with expression of IL-17c1, MHC I and MHC II, while pretreatment with H2O2 resulted in a positive correlation with IL-4/13A and IgM. Exposure to either H2O2 or F. psychrophilum influenced the regulation of gene expression and damaged tissue. Exposure to both combined altered the immune response to infection and postponed healing of gill tissue. PMID- 25830181 TI - In memoriam: Dato Dr Khoo Kah-Lin--obituary. PMID- 25830182 TI - Retraction notice to 'Reduced syntaxin-5 in skeletal muscle of patients with type 2 diabetes. A link between lipid storage and insulin resistance' [Atherosclerosis (Supplements) 12 (2011) 33-34]. PMID- 25830183 TI - Response: Palliative cardiovascular care is not an oxymoron. PMID- 25830184 TI - Retraction statement: Analysis of association between the 5-HTTLPR and STin2 polymorphisms in the serotonin-transporter gene and clinical response to a selective serotonin reuptake inhibitor (sertraline) in patients with premature ejaculation. PMID- 25830185 TI - Retraction statement: A double-blind placebo-controlled study of the efficacy and safety of pentoxifylline in early chronic Peyronie's disease. PMID- 25830186 TI - Retraction statement: The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study. PMID- 25830187 TI - Integrated treatment for diabetes, depression gains notice, with help from ACA. PMID- 25830188 TI - Aging and cognitive decline in diabetes. PMID- 25830189 TI - Re: Yang SS-D, Zhao L-L, and Chang S-J. Early initiation of toilet training for urine was associated with early urinary continence and does not appear to be associated with bladder dysfunction. Neurourol Urodyn 2011;30:1253-7. PMID- 25830190 TI - Value-engineered translation: developing biotherapeutics that align with health system needs. PMID- 25830191 TI - AJMC Peer Exchange: nationwide, patient-centered strategy needed to battle obesity, T2DM. PMID- 25830192 TI - Benefits, risks of SGLT2 inhibitors explored at session. PMID- 25830193 TI - Can early use of insulin, GLP-1 halt diabetes progression? PMID- 25830194 TI - Sessions highlight strides in "artificial pancreas" technology. PMID- 25830195 TI - Results presented on motivating patients with diabetes. PMID- 25830196 TI - Diabetes navigator program reduces A1C levels for patients in Alabama. PMID- 25830197 TI - Afrezza, inhaled insulin, wins FDA approval. PMID- 25830198 TI - Liquid-based cytology sample showing leishmaniasis in bronchoalveolar lavage fluid. PMID- 25830199 TI - Interface methods for biological and biomedical problems. PMID- 25830200 TI - Immersed boundary model of aortic heart valve dynamics with physiological driving and loading conditions. AB - The immersed boundary (IB) method is a mathematical and numerical framework for problems of fluid-structure interaction, treating the particular case in which an elastic structure is immersed in a viscous incompressible fluid. The IB approach to such problems is to describe the elasticity of the immersed structure in Lagrangian form, and to describe the momentum, viscosity, and incompressibility of the coupled fluid-structure system in Eulerian form. Interaction between Lagrangian and Eulerian variables is mediated by integral equations with Dirac delta function kernels. The IB method provides a unified formulation for fluid structure interaction models involving both thin elastic boundaries and also thick viscoelastic bodies. In this work, we describe the application of an adaptive, staggered-grid version of the IB method to the three-dimensional simulation of the fluid dynamics of the aortic heart valve. Our model describes the thin leaflets of the aortic valve as immersed elastic boundaries, and describes the wall of the aortic root as a thick, semi-rigid elastic structure. A physiological left-ventricular pressure waveform is used to drive flow through the model valve, and dynamic pressure loading conditions are provided by a reduced (zero-dimensional) circulation model that has been fit to clinical data. We use this model and method to simulate aortic valve dynamics over multiple cardiac cycles. The model is shown to approach rapidly a periodic steady state in which physiological cardiac output is obtained at physiological pressures. These realistic flow rates are not specified in the model, however. Instead, they emerge from the fluid-structure interaction simulation. PMID- 25830201 TI - Axisymmetric multicomponent vesicles: A comparison of hydrodynamic and geometric models. AB - Using a mathematical model, we investigate the role of hydrodynamic forces on three-dimensional axisymmetric multicomponent vesicles. The equations are derived using an energy variation approach that accounts for different surface phases, the excess energy associated with surface domain boundaries, bending energy and inextensibility. The equations are high-order (fourth order) nonlinear and nonlocal. To solve the equations numerically, we use a nonstiff, pseudo-spectral boundary integral method that relies on an analysis of the equations at small scales. We also derive equations governing the dynamics of inextensible vesicles evolving in the absence of hydrodynamic forces and simulate numerically the evolution of this geometric model. We find that compared with the geometric model, hydrodynamic forces provide additional paths for relaxing inextensible vesicles. The presence of hydrodynamic forces may enable the dynamics to overcome local energy barriers and reach lower energy states than those accessible by geometric motion or energy minimization algorithms. Because of the intimate connection between morphology, surface phase distribution and biological function, these results have important consequences in understanding the role vesicles play in biological processes. PMID- 25830202 TI - Modeling TGF-mediated flow dynamics in a system of three coupled nephrons. AB - This paper focuses on a mathematical model of a system of three closely coupled nephrons and accompanying analytical and computational analysis. In our previous modeling efforts, we have shown how coupling magnifies the tendency of many coupled identical nephrons to oscillate owing to tubuloglomerular feedback (TGF) mechanism. However, in this study, our focus is on the coupled nonidentical nephrons and their dynamics due to the TGF system. Our detailed analytical and computational results suggest that systems of three nonidentical nephrons coupled to their nearest neighbors are prone to be found in an oscillatory state, relative to a single-nephron case with the same properties; however, their steady state regions are not necessarily as small as it was predicted from the system of many coupled identical nephrons cases. PMID- 25830203 TI - Numerical studies of problems in biophysics, biomechanics and mechanobiology. PMID- 25830204 TI - Numerical simulation of a thermodynamically consistent four-species tumor growth model. AB - In this paper, we develop a thermodynamically consistent four-species model of tumor growth on the basis of the continuum theory of mixtures. Unique to this model is the incorporation of nutrient within the mixture as opposed to being modeled with an auxiliary reaction-diffusion equation. The formulation involves systems of highly nonlinear partial differential equations of surface effects through diffuse-interface models. A mixed finite element spatial discretization is developed and implemented to provide numerical results demonstrating the range of solutions this model can produce. A time-stepping algorithm is then presented for this system, which is shown to be first order accurate and energy gradient stable. The results of an array of numerical experiments are presented, which demonstrate a wide range of solutions produced by various choices of model parameters. PMID- 25830205 TI - An active strain electromechanical model for cardiac tissue. AB - We propose a finite element approximation of a system of partial differential equations describing the coupling between the propagation of electrical potential and large deformations of the cardiac tissue. The underlying mathematical model is based on the active strain assumption, in which it is assumed that there is a multiplicative decomposition of the deformation tensor into a passive and active part holds, the latter carrying the information of the electrical potential propagation and anisotropy of the cardiac tissue into the equations of either incompressible or compressible nonlinear elasticity, governing the mechanical response of the biological material. In addition, by changing from a Eulerian to a Lagrangian configuration, the bidomain or monodomain equations modeling the evolution of the electrical propagation exhibit a nonlinear diffusion term. Piecewise quadratic finite elements are employed to approximate the displacements field, whereas for pressure, electrical potentials and ionic variables are approximated by piecewise linear elements. Various numerical tests performed with a parallel finite element code illustrate that the proposed model can capture some important features of the electromechanical coupling and show that our numerical scheme is efficient and accurate. PMID- 25830206 TI - Coupled electromechanical model of the heart: Parallel finite element formulation. AB - In this paper, a highly parallel coupled electromechanical model of the heart is presented and assessed. The parallel-coupled model is thoroughly discussed, with scalability proven up to hundreds of cores. This work focuses on the mechanical part, including the constitutive model (proposing some modifications to pre existent models), the numerical scheme and the coupling strategy. The model is next assessed through two examples. First, the simulation of a small piece of cardiac tissue is used to introduce the main features of the coupled model and calibrate its parameters against experimental evidence. Then, a more realistic problem is solved using those parameters, with a mesh of the Oxford ventricular rabbit model. The results of both examples demonstrate the capability of the model to run efficiently in hundreds of processors and to reproduce some basic characteristic of cardiac deformation. PMID- 25830207 TI - A continuum description of the damage process in the arterial wall of abdominal aortic aneurysms. AB - In the present work, we develop a three-dimensional isotropic finite-strain damage model for abdominal aortic aneurysm (AAA) wall that considers both the characteristic softening of the material caused by damage and the spatial variation of the material properties. A strain energy function is formulated that accounts for a hyperelastic, slightly compressible, isotropic material behavior during the elastic phase, whereas the damage process only contributes to the material response when the elastic limit of the AAA wall is exceeded. Material and damage parameters are obtained by fitting the strain energy function to the experimental data obtained by uniaxial tensile tests of freshly harvested AAA wall samples. The damage model extends the validity of the material law to a strain range of up to 50%. Purely elastic material laws for AAA wall are only valid for a strain range of up to 17%. In a series of finite element simulations of patient-specific AAAs, serving as numerical examples, we investigate the applicability of the damage model. The use of the damage model does not yield a more distinct identification of rupture-prone AAAs than other computational-based risk indices. However, the benefit of the finite-strain damage model is the potential capability to trigger growth and remodeling processes in mechanobiological models. PMID- 25830208 TI - Dynamics of the aortic arch submitted to a shock loading: Parametric study with fluid-structure models. AB - This work aims to present some fluid-structure models for analyzing the dynamics of the aorta during a brusque loading. Indeed, various lesions may appear at the aortic arch during car crash or other accident such as brusque falling. Aortic stresses evolution are simulated during the shock at the cross section and along the aorta. One hot question was that if a brusque deceleration can generate tissue tearing, or a shock is necessary to provoke such a damage. Different constitutive laws of blood are then tested whereas the aorta is assumed linear and elastic. The overall shock model is inspired from an experimental jig. We show that the viscosity has strong influence on the stress and parietal moments and forces. The nonlinear viscosity has no significant additional effects for healthy aorta, but modifies the stress and parietal loadings for the stenotic aorta. PMID- 25830209 TI - Computational model of soft tissues in the human upper airway. AB - This paper presents a three-dimensional finite element model of the tongue and surrounding soft tissues with potential application to the study of sleep apnoea and of linguistics and speech therapy. The anatomical data was obtained from the Visible Human Project, and the underlying histological data was also extracted and incorporated into the model. Hyperelastic constitutive models were used to describe the material behaviour, and material incompressibility was accounted for. An active Hill three-element muscle model was used to represent the muscular tissue of the tongue. The neural stimulus for each muscle group was determined through the use of a genetic algorithm-based neural control model. The fundamental behaviour of the tongue under gravitational and breathing-induced loading is investigated. It is demonstrated that, when a time-dependent loading is applied to the tongue, the neural model is able to control the position of the tongue and produce a physiologically realistic response for the genioglossus. PMID- 25830210 TI - Semi-automatic surface and volume mesh generation for subject-specific biomedical geometries. AB - An overview of surface and volume mesh generation techniques for creating valid meshes to carry out biomedical flows is provided. The methods presented are designed for robust numerical modelling of biofluid flow through subject-specific geometries. The applications of interest are haemodynamics in blood vessels and air flow in upper human respiratory tract. The methods described are designed to minimize distortion to a given domain boundary. They are also designed to generate a triangular surface mesh first and then volume mesh (tetrahedrons) with high quality surface and volume elements. For blood flow applications, a simple procedure to generate a boundary layer mesh is also described. The methods described here are semi-automatic in nature because of the fact that the geometries are complex, and automation of the procedures may be possible if high quality scans are used. PMID- 25830211 TI - Automated extraction of the femoral anatomical axis for determining the intramedullary rod parameters in total knee arthroplasty. AB - The automated extraction of anatomical reference parameters may improve speed, precision and accuracy of surgical procedures. In this study, an automated method for extracting the femoral anatomical axis (FAA) from a 3D surface mesh, based on geometrical entity fitting, is presented. This was applied to conventional total knee arthroplasty, which uses an intramedullary rod (FIR) to orient the femoral prosthesis with respect to the FAA. The orientation and entry point of a FIR with a length of 200 mm are automatically determined from the FAA, as it has been shown that errors in these parameters may lead to malalignment of the mechanical axis. Moreover, the effect of partially scanning the leg was investigated by creating reduced femur models and comparing the results with the full models. Precise measurements are obtained for 50 models by using a central and two outer parts, with lengths of 20 and 120 mm, which correspond to 58% of the mean femoral length. The deviations were less than 2 mm for the FAA, 2.8 mm for the FAA endpoints and 0.7 degrees and 1.3 mm for the FIR orientation and entry point. The computer-based techniques might eventually be used for preoperative planning of total knee arthroplasty. PMID- 25830212 TI - Human skull shape and masticatory induced stress: Objective comparison through the use of non-rigid registration. AB - Variation in masticatory induced stress, caused by shape changes in the human skull, is quantified in this article. A comparison on masticatory induced stress is presented subject to a variation in human skull shape. Non-rigid registration is employed to obtain appropriate computational domain representations. This procedure allows the isolation of shape from other variations that could affect the results. An added benefit, revealed through the use of non-rigid registration to acquire appropriate domain representation, is the possibility of direct and objective comparison and manipulation. The effect of mapping uncertainty on the direct comparison is also quantified. As shown in this study, exact difference values are not necessarily obtained, but a non-rigid map between subject shapes and numerical results gives an objective indication on the location of differences. PMID- 25830213 TI - Editorial comment. PMID- 25830214 TI - Editorial comment. PMID- 25830215 TI - Letting the data speak for themselves: a fully Bayesian approach to transcriptome assembly. AB - A novel method for transcriptome assembly, Bayesembler, provides greater accuracy without sacrifice of computational speed, and particular advantages for alternative transcripts expressed at low levels. PMID- 25830216 TI - [International Schizophrenia Research Society conference]. PMID- 25830217 TI - Dr Paul Batchelor responds. PMID- 25830218 TI - [Analysis on the removal efficiency and mechanisms of phosphorus by modified zeolites substrates coated with LDHs reacted by different metal compounds in laboratory-scale vertical-flow constructed wetlands]. AB - Six kinds of metal compounds which were CaCl2 , ZnCl2, MgCl2, FeCl3, AlCl3, and CoCl3 were formed nine kinds of different combinations in the alkaline conditions to synthesized LDHs (Layered Double Hydroxides), which were in-situ coated on the surface of zeolites. With the filling of the original and nine kinds of modified zeolites in the columns to simulate a laboratory-scale vertical-flow constructed wetland system, the experiments of purified phosphorus were conducted. Combined removal efficiency with adsorption isotherm data of the ten kinds of zeolites, mechanism for strengthening the removal rates of the phosphorus by the modified zeolites was studied. The results showed that compared with the original zeolites, the removal rates of the phosphorus by nine kinds of modified zeolites were enhanced with various degrees. In the cases of Zn involved in the modified zeolites, the removal efficiencies of phosphorus reached a high quality. Especially, the ZnFe-LDHs had the average removal rates of the total phosphorus, the dissolved phosphorus and the phosphate were over 90%, and its maximum adsorption capacity of the phosphorus was three times higher than that of the original zeolites. Therefore, by means of increasing the adsorption capacity and improving the chemical adsorption ability of phosphorus, the modification to coated LDHs on the zeolites reached the aim of strengthening the purification of the phosphorus. PMID- 25830219 TI - A PEGylation-Free Biomimetic Porphyrin Nanoplatform for Personalized Cancer Theranostics. AB - PEGylation (PEG) is the most commonly adopted strategy to prolong nanoparticles' vascular circulation by mitigating the reticuloendothelial system uptake. However, there remain many concerns in regards to its immunogenicity, targeting efficiency, etc., which inspires pursuit of alternate, non-PEGylated systems. We introduced here a PEG-free, porphyrin-based ultrasmall nanostructure mimicking nature lipoproteins, termed PLP, that integrates multiple imaging and therapeutic functionalities, including positron emission tomography (PET) imaging, near infrared (NIR) fluorescence imaging and photodynamic therapy (PDT). With an engineered lipoprotein-mimicking structure, PLP is highly stable in the blood circulation, resulting in favorable pharmacokinetics and biodistribution without the need of PEG. The prompt tumor intracellular trafficking of PLP allows for rapid nanostructure dissociation upon tumor accumulation to release monomeric porphyrins to efficiently generate fluorescence and photodynamic reactivity, which are highly silenced in intact PLP, thus providing an activatable mechanism for low-background NIR fluorescence imaging and tumor-selective PDT. Its intrinsic copper-64 labeling feature allows for noninvasive PET imaging of PLP delivery and quantitative assessment of drug distribution. Using a clinically relevant glioblastoma multiforme model, we demonstrated that PLP enabled accurate delineation of tumor from surrounding healthy brain at size less than 1 mm, exhibiting the potential for intraoperative fluorescence-guided surgery and tumor selective PDT. Furthermore, we demonstrated the general applicability of PLP for sensitive and accurate detection of primary and metastatic tumors in other clinically relevant animal models. Therefore, PLP offers a biomimetic theranostic nanoplatform for pretreatment stratification using PET and NIR fluorescence imaging and for further customized cancer management via imaging-guided surgery, PDT, or/and potential chemotherapy. PMID- 25830220 TI - Moving from opinion-based Homo Medicus to evidence-based Homo Cochrane. PMID- 25830221 TI - Performance of a receptive language test among young children in Madagascar. AB - Language tests developed and validated in one country may lose their desired properties when translated for use in another, possibly resulting in misleading estimates of ability. Using Item Response Theory (IRT) methodology, we assess the performance of a test of receptive vocabulary, the U.S.-validated Peabody Picture Vocabulary Test-Third Edition (PPVT-III), when translated, adapted, and administered to children 3 to 10 years of age in Madagascar (N = 1372), in the local language (Malagasy). Though Malagasy is considered a single language, there are numerous dialects spoken in Madagascar. Our findings were that test scores were positively correlated with age and indicators of socio-economic status. However, over half (57/96) of items evidenced unexpected response variation and/or bias by local dialect spoken. We also encountered measurement error and reduced differentiation among person abilities when we used the publishers' recommended stopping rules, largely because we lost the original item ordering by difficulty when we translated test items into Malagasy. Our results suggest that bias and testing inefficiency introduced from the translation of the PPVT can be significantly reduced with the use of methods based on IRT at both the pre testing and analysis stages. We explore and discuss implications for cross cultural comparisons of internationally recognized tests, such as the PPVT. PMID- 25830222 TI - Frugivorous bats maintain functional habitat connectivity in agricultural landscapes but rely strongly on natural forest fragments. AB - Anthropogenic changes in land use threaten biodiversity and ecosystem functioning by the conversion of natural habitat into agricultural mosaic landscapes, often with drastic consequences for the associated fauna. The first step in the development of efficient conservation plans is to understand movement of animals through complex habitat mosaics. Therefore, we studied ranging behavior and habitat use in Dermanura watsoni (Phyllostomidae), a frugivorous bat species that is a valuable seed disperser in degraded ecosystems. Radio-tracking of sixteen bats showed that the animals strongly rely on natural forest. Day roosts were exclusively located within mature forest fragments. Selection ratios showed that the bats foraged selectively within the available habitat and positively selected natural forest. However, larger daily ranges were associated with higher use of degraded habitats. Home range geometry and composition of focal foraging areas indicated that wider ranging bats performed directional foraging bouts from natural to degraded forest sites traversing the matrix over distances of up to three hundred meters. This behavior demonstrates the potential of frugivorous bats to functionally connect fragmented areas by providing ecosystem services between natural and degraded sites, and highlights the need for conservation of natural habitat patches within agricultural landscapes that meet the roosting requirements of bats. PMID- 25830223 TI - Predator-specific effects on incubation behaviour and offspring growth in great tits. AB - In birds, different types of predators may target adults or offspring differentially and at different times of the reproductive cycle. Hence they may also differentially influence incubation behaviour and thus embryonic development and offspring phenotype. This is poorly understood, and we therefore performed a study to assess the effects of the presence of either a nest predator or a predator targeting adults and offspring after fledging on female incubation behaviour in great tits (Parus major), and the subsequent effects on offspring morphological traits. We manipulated perceived predation risk during incubation using taxidermic models of two predators: the short-tailed weasel posing a risk to incubating females and nestlings, and the sparrowhawk posing a risk to adults and offspring after fledging. To disentangle treatment effects induced during incubation from potential carry-over effects of parental behaviour after hatching, we cross-fostered whole broods from manipulated nests with broods from unmanipulated nests. Both predator treatments lead to a reduced on- and off-bout frequency, to a slower decline in on-bout temperature as incubation advanced and showed a negative effect on nestling body mass gain. At the current state of knowledge on predator-induced variation in incubation patterns alternative hypotheses are feasible, and the findings of this study will be useful for guiding future research. PMID- 25830224 TI - Comparative effectiveness of tocilizumab with either methotrexate or leflunomide in the treatment of rheumatoid arthritis. AB - OBJECTIVE: In agreement with EULAR recommendations, a DMARD in combination with a biotherapy is the reference treatment because of the superior long-term clinical and radiographic outcomes. Methotrexate (MTX) is the cornerstone of combination therapy but is in some cases contra-indicated or poorly tolerated. This observational study aimed to compare the effectiveness and safety of TCZ in combination with either MTX or leflunomide (LEF) in the treatment of patients with active rheumatoid arthritis (RA) and an inadequate response to one or more DMARDs and/or biological agents in a real-world setting. METHODS: We performed an ambispective review of 91 patients with active RA who were routinely treated with TCZ plus MTX or LEF. A comparative study between the two combinations of treatment was performed at 6 months of follow-up considering 3 outcomes: improvement of RA disease activity, evolution of functional disability, and tolerability and side effect profile. RESULTS: Of the 91 patients, 62 received TCZ with MTX and 29 received TCZ with LEF. Eighty-one patients were followed for 6 months, and the remaining 10 patients discontinued treatment due to serious adverse events. At baseline, there were no significant differences between the groups in terms of the main clinical and laboratory data or in the number of previous DMARDs and biological agents used. At 6 months, there were no significant differences between the combinations in terms of disease activity and functional disability. Serious adverse events occurred in 11% and 10% of the patients treated in combination with MTX and LEF, respectively. CONCLUSION: Our preliminary data support the argument that LEF is an effective and safe (equivalent) alternative to MTX for combination treatment with TCZ. PMID- 25830225 TI - New genetic and linguistic analyses show ancient human influence on baobab evolution and distribution in Australia. AB - This study investigates the role of human agency in the gene flow and geographical distribution of the Australian baobab, Adansonia gregorii. The genus Adansonia is a charismatic tree endemic to Africa, Madagascar, and northwest Australia that has long been valued by humans for its multiple uses. The distribution of genetic variation in baobabs in Africa has been partially attributed to human-mediated dispersal over millennia, but this relationship has never been investigated for the Australian species. We combined genetic and linguistic data to analyse geographic patterns of gene flow and movement of word forms for A. gregorii in the Aboriginal languages of northwest Australia. Comprehensive assessment of genetic diversity showed weak geographic structure and high gene flow. Of potential dispersal vectors, humans were identified as most likely to have enabled gene flow across biogeographic barriers in northwest Australia. Genetic-linguistic analysis demonstrated congruence of gene flow patterns and directional movement of Aboriginal loanwords for A. gregorii. These findings, along with previous archaeobotanical evidence from the Late Pleistocene and Holocene, suggest that ancient humans significantly influenced the geographic distribution of Adansonia in northwest Australia. PMID- 25830226 TI - The activity of TcCYS4 modified by variations in pH and temperature can affect symptoms of witches' broom disease of cocoa, caused by the fungus Moniliophthora perniciosa. AB - The phytocystatins regulate various physiological processes in plants, including responses to biotic and abiotic stresses, mainly because they act as inhibitors of cysteine proteases. In this study, we have analyzed four cystatins from Theobroma cacao L. previously identified in ESTs libraries of the interaction with the fungus Moniliophthora perniciosa and named TcCYS1, TcCYS2, TcCYS3 and TcCYS4. The recombinant cystatins were purified and subjected to the heat treatment, at different temperatures, and their thermostabilities were monitored using their ability to inhibit papain protease. TcCYS1 was sensitive to temperatures above 50 degrees C, while TcCYS2, TcCYS3, and TcCYS4 were thermostable. TcCYS4 presented a decrease of inhibitory activity when it was treated at temperatures between 60 and 70 degrees C, with the greater decrease occurring at 65 degrees C. Analyses by native gel electrophoresis and size exclusion chromatography showed that TcCYS4 forms oligomers at temperatures between 60 and 70 degrees C, condition where reduction of inhibitory activity was observed. TcCYS4 oligomers remain stable for up to 20 days after heat treatment and are undone after treatment at 80 degrees C. TcCYS4 presented approximately 90% of inhibitory activity at pH values between 5 and 9. This protein treated at temperatures above 45 degrees C and pH 5 presented reduced inhibitory activity against papain, suggesting that the pH 5 enhances the formation of TcCYS4 oligomers. A variation in the titratable acidity was observed in tissues of T. cacao during the symptoms of witches' broom disease. Our findings suggest that the oligomerization of TcCYS4, favored by variations in pH, is an endergonic process. We speculate that this process can be involved in the development of the symptoms of witches' broom disease in cocoa. PMID- 25830227 TI - Impact of nutrition and salinity changes on biological performances of green and white sturgeon. AB - Green and white sturgeon are species of high conservational and economic interest, particularly in the San Francisco Bay Delta (SFBD) for which significant climate change-derived alterations in salinity and nutritional patterns are forecasted. Although there is paucity of information, it is critical to test the network of biological responses underlying the capacity of animals to tolerate current environmental changes. Through nutrition and salinity challenges, climate change will likely have more physiological effect on young sturgeon stages, which in turn may affect growth performance. In this study, the two species were challenged in a multiple-factor experimental setting, first to levels of feeding rate, and then to salinity levels for different time periods. Data analysis included generalized additive models to select predictors of growth performance (measured by condition factor) among the environmental stressors considered and a suite of physiological variables. Using structural equation modeling, a path diagram is proposed to quantify the main linkages among nutrition status, salinity, osmoregulation variables, and growth performances. Three major trends were anticipated for the growth performance of green and white sturgeon in the juvenile stage in the SFBD: (i) a decrease in prey abundance will be highly detrimental for the growth of both species; (ii) an acute increase in salinity within the limits studied can be tolerated by both species but possibly the energy spent in osmoregulation may affect green sturgeon growth within the time window assessed; (iii) the mechanism of synergistic effects of nutrition and salinity changes will be more complex in green sturgeon, with condition factor responding nonlinearly to interactions of salinity and nutrition status or time of salinity exposure. Green sturgeon merits special scientific attention and conservation effort to offset the effects of feed restriction and salinity as key environmental stressors in the SFBD. PMID- 25830229 TI - Problem-solving skills appraisal mediates hardiness and suicidal ideation among malaysian undergraduate students. AB - OBJECTIVES: Recent evidence suggests that suicidal ideation is increased among university students, it is essential to increase our knowledge concerning the etiology of suicidal ideation among university students. This study was conducted to examine the relationships between problem-solving skills appraisal, hardiness, and suicidal ideation among university students. In addition, this study was conducted to examine problem-solving skills appraisal (including the three components of problem-solving confidence, approach-avoidance style, and personal control of emotion) as a potential mediator between hardiness and suicidal ideation. METHODS: The participants consisted of 500 undergraduate students from Malaysian public universities. RESULTS: Structural Equation Modelling (SEM) estimated that undergraduate students with lower hardiness, poor problem-solving confidence, external personal control of emotion, and avoiding style was associated with higher suicidal ideation. Problem-solving skills appraisal (including the three components of problem-solving confidence, approach-avoidance style, and personal control of emotion) partially mediated the relationship between hardiness and suicidal ideation. CONCLUSION: These findings underline the importance of studying mediating processes that explain how hardiness affects suicidal ideation. PMID- 25830228 TI - Positive effects of voluntary running on metabolic syndrome-related disorders in non-obese hereditary hypertriacylglycerolemic rats. AB - While metabolic syndrome is often associated with obesity, 25% of humans suffering from it are not obese and the effect of physical activity remains unclear in such cases. Therefore, we used hereditary hypertriaclyglycerolemic (HHTg) rats as a unique model for studying the effect of spontaneous physical activity [voluntary running (VR)] on metabolic syndrome-related disorders, such as dyslipidemia, in non-obese subjects. Adult HHTg males were fed standard (CD) or high-sucrose (HSD) diets ad libitum for four weeks. Within both dietary groups, some of the rats had free access to a running wheel (CD+VR, HSD+VR), whereas the controls (CD, HSD) had no possibility of extra physical activity. At the end of the four weeks, we measured the effects of VR on various metabolic syndrome-associated parameters: (i) biochemical parameters, (ii) the content and composition of triacylglycerols (TAG), diacylglycerols (DAG), ceramides and membrane phospholipids, and (iii) substrate utilization in brown adipose tissue. In both dietary groups, VR led to various positive effects: reduced epididymal and perirenal fat depots; increased epididymal adipose tissue lipolysis; decreased amounts of serum TAG, non-esterified fatty acids and insulin; a higher insulin sensitivity index. While tissue ceramide content was not affected, decreased TAG accumulation resulted in reduced and modified liver, heart and skeletal muscle DAG. VR also had a beneficial effect on muscle membrane phospholipid composition. In addition, compared with the CD group, the CD+VR rats exhibited increased fatty acid oxidation and protein content in brown adipose tissue. Our results confirm that physical activity in a non-obese model of severe dyslipidemia has many beneficial effects and can even counteract the negative effects of sucrose consumption. Furthermore, they suggest that the mechanism by which these effects are modulated involves a combination of several positive changes in lipid metabolism. PMID- 25830230 TI - Nanodelivery: An Emerging Avenue for Nutraceuticals and Drug Delivery. AB - Aquaculture has been globally recognized as the fastest growing food production sector which plays a major role in meeting the increasing demand for animal protein requirement. A consensus is growing that a dramatic increase in aquaculture is needed to supply future aquatic food needs. However, there are sustained problems with the aquaculture like disease outbreaks, chemical pollution, the environmental destruction, and inefficient feed utilization. These altogether raise question mark on sustainability of aquaculture. In spite of the several strategy adopted on national and international level, as improved laboratory facilities, diagnostic expertise, and control and therapeutic strategies in order to handle disease outbreaks more effectively. Aquaculture industry is under uncertainty and the progress has not matched that of the rapidly developing aquaculture sector. In order to control disease prevalence and ensure better health of system and sustainable production, the sector demand more technical innovation for the drug use, disease treatment, water quality management, production of tailored fish for suiting better health, productivity drive by epigenetic and nutrigenomic interaction, better breeding success by efficient delivery of maturation and spawning inducing agent, nutraceutical delivery for rapid growth promotion and culture time reduction, successful use of autotransgenic, and effective vaccine. Nanotechnology has a tremendous potential to revolutionize agriculture and allied fields including aquaculture and fisheries. For these multiple purposes effort, importance of nanotechnology and nanodelivery of drugs, vaccine, nutraceutical, inducing hormones, and growth promoting anabolics open tremendous opportunity. The paper has been targeted to delineate the possible future application of nanodelivery for the aquaculture development. PMID- 25830232 TI - Current and novel therapeutic approaches in myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms with an annual incidence of 4.1 cases per 100,000 Americans. Patients with MDS suffer from chronic cytopenias that may lead to recurrent transfusions, infections, and increased risk for bleeding. They are also at risk for progression to acute myeloid leukemia. Allogeneic hematopoietic cell transplantation is the only potentially curative treatment for MDS, although 3 drugs have been approved by the US Food and Drug Administration for its treatment: lenalidomide, 5-azacitidine, and decitabine. These therapies can be effective in the relief of cytopenias, achievement of cytogenetic remissions, and reduction in bone marrow blasts. 5-azacitidine has also been shown to improve overall survival. However, there remain many unmet needs in the treatment of MDS. Breakthroughs in our understanding of the complex pathogenesis of MDS through epigenetic, genetic, immunologic, and other biological mechanisms have allowed us to develop new therapeutic strategies that can lead to improvements in outcomes in MDS. In this review, we aim to provide an overview of the evolution in classifcation and risk stratifcation in MDS and to illustrate how we can use this to guide us in tailoring therapeutic choices in this disease. Responses and outcomes related to com monly used MDS therapies will be discussed together with novel therapies that have evolved with the improved understanding of MDS pathophysiology. PMID- 25830231 TI - The Singapore Liver Cancer Recurrence (SLICER) Score for relapse prediction in patients with surgically resected hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection. METHODS: Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992-2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis. RESULTS: A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities. CONCLUSION: The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling. PMID- 25830233 TI - Palonosetron versus older 5-HT3 receptor antagonists for nausea prevention in patients receiving chemotherapy: a multistudy analysis. AB - BACKGROUND: No clinical standard currently exists for the optimal management of nausea induced by emetogenic chemotherapy, 7particularly delayed nausea. OBJECTIVES: To compare the effcacy and safety of palonosetron with older 5-HT3 receptor antagonists (RAs) in preventing chemotherapy-induced nausea. METHODS: Data were pooled from 4 similarly designed multicenter, randomized, double-blind, clinical trials that compared single intravenous doses of palonosetron 0.25 mg or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 MUg/kg, administered 30 minutes before moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). Pooled data within each chemotherapy category (MEC: n = 1,132; HEC: n = 1,781) were analyzed by a logistic regression model. Nausea endpoints were complete control rates (ie, no more than mild nausea, no vomiting, and no rescue medication), nausea-free rates, nausea severity, and requirement for rescue antiemetic/antinausea medication over 5 days following chemotherapy. Pooled safety data were summarized descriptively. RESULTS: Numerically more palonosetron-treated patients were nausea-free on each day, and fewer had moderate-severe nausea. Similarly, usage of rescue medication was less frequent among palonosetron-treated patients. Complete control rates for palonosetron and older 5-HT3 RAs in the acute phase were 66% vs 63%, 52% vs 42% in the delayed phase (24-120 hours), and 46% vs 37% in the overall phase. The incidence of adverse events was similar for palonosetron and older 5-HT3 RAs. LIMITATIONS: This post hoc analysis summarized data for palonosetron and several other 5-HT3 RAs but was not powered for statistical comparisons between individual agents. Because nausea is inherently subjective, the reliability of assessments of some aspects (eg, severity) may be infuenced by interindividual variability. CONCLUSION: Palonosetron may be more effective than older 5-HT3 RAs in preventing nausea, with comparable tolerability. DISCLOSURES AND FUNDING: Dr Schwartzberg is a consultant to and Dr Cox an employee at Esai. Mr Ballinari is a member of staff at and Dr Thorn consults for Helsinn Healthcare SA. Funding to support this study and the preparation of this manuscript was provided by Eisai Inc. PMID- 25830234 TI - Combined effect of insulin-like growth factor-1 and CC chemokine ligand 2 on angiogenic events in endothelial cells. AB - Therapeutic angiogenesis may be applied in medical conditions to promote stimulation of angiogenesis. Angiogenesis is a multistep process, which includes endothelial cell proliferation, migration, and tube formation, which is mediated by various angiogenic polypeptides. Thus, studies that elucidate the cellular mechanisms involved in these processes are necessary to develop novel therapeutic strategies. This study investigated the in vitro effects of the pro-angiogenic factors, insulin-like growth factor-1 (IGF-1) and/or chemokine (CC motif) ligand 2 (CCL2), on endothelial cells. Flow cytometry analysis showed that IGF-1 and CCL2 treatment did not interfere with IGF-1 receptor (IGF-1R) expression, but CCL2 treatment increased CCL2 receptor (CCR2) expression. Immunofluorescence analysis revealed that the IGF-1/CCL2 combination induced a greater increase in fibronectin deposition, but the treatments did not alter the expression of the fibronectin receptors, CD49e and CD44. The interaction of fibronectin with cytokines demonstrated that IGF-1/CCL2 promoted changes in intermediate F-actin remodeling that may result in increased endothelial cell adhesion and cell migration mediated by fibronectin. Furthermore, IGF-1/CCL2 stimulated endothelial cells, grown on fibronectin, to form capillary-like structures and intercellular lumina with greater luminal area. These data suggest that IGF-1/CCL2 combination and a fibronectin matrix may contribute to the angiogenesis process to stimulate adhesion, migration, and tube formation by endothelial cells as a result of F actin remodeling. PMID- 25830235 TI - Positional demands of professional rugby. AB - Rugby union is a physically intense intermittent sport coupled with high force collisions. Each position within a team has specific requirements which are typically based on speed, size and skill. The aim of this study was to investigate the contemporary demands of each position and whether they can explain changes in psychophysiological stress. Urine and saliva samples were collected before and after five selected Super 15 rugby games from 37 players. Total neopterin (NP), cortisol and immunoglobulin A were analysed by SCX-high performance liquid chromatography and enzyme linked immunosorbent assay. Global positioning system software provided distance data, while live video analysis provided impact data. All contemporary demands were analysed as events per minute of game time. Forwards were involved in more total impacts, tackles and rucks compared to backs (p < 0.001), while backs were involved in more ball carries and covered more total distance and distance at high speed per minute of game time (p < 0.01). Loose forwards, inside and outside backs covered significantly more distance at high speed (p < 0.01), while there was a negligible difference with number of impacts between the forward positions. There was also minimal difference between positions in the percentage change in NP, cortisol and sIgA. The results indicate distance covered and number of impacts per minute of game time is position-dependent whereas changes in psychophysiological stress are independent. This information can be used to adapt training and recovery interventions to better prepare each position based on the physical requirements of the game. PMID- 25830236 TI - Dissecting Lewis score under the light of fecal calprotectin; an analysis of correlation of score components with calprotectin levels in capsule endoscopy. AB - BACKGROUND: Lewis Score (LS) is an inflammatory score in small-bowel capsule endoscopy (SBCE). Fecal calprotectin (FC) is considered the non-invasive, 'gold standard' marker of gastrointestinal (GI) inflammation. Recently, we reported that LS shows only a moderate correlation with FC. In this study, we aim to evaluate which LS parameters have greater correlation with FC. METHODS: A retrospective, two-center study; 74 patients who underwent SBCE within 7 (median 1.5) days from a FC measurement. LS was calculated; univariate and multivariate analyses were performed, investigating LS correlation with FC, and which LS parameters had stronger correlation coefficient (rs) with FC. RESULTS: 74 patients had an FC measurement within 7 days of their SBCE examination (median 22 time-interval: 1.5 days; IQR: 5). Coefficient rs between LS and FC was moderate (0.454). In univariate analysis, the variables that gave the strongest association with FC were: the higher tertile subscore for ulcer, the summative ulcer subscore, the higher tertile ulcer score (only with descriptors of ulcer size and number), the summative ulcer score (only with descriptors of ulcer size and number), and subscores including various combinations of the stenosis descriptors. In multivariate analysis, the only positive predictor for FC was the higher tertile ulcer subscore (only with descriptors of ulcer size and number). CONCLUSION: LS shows only moderate correlation to FC. This is due to a) an inherent limitation of LS, and b) the notion of correlating the 2 parameters, and consideration should be given to development of a new, simplified (or composite) inflammation score/index for SBCE. PMID- 25830237 TI - [Stock based medicine: the patient waiting in a weary medical procedure]. AB - This essay attempts to bring on a new perspective for healthcare professionals regarding the problems that surround this institutionalized profession, based on a system of stock balances and not on the real needs of patients and their community. The healthcare professional not only engages in biomedical healing but also possesses knowledge and expertise regarding the dialectical process of health/disease. Thus, his or her practice and actions should be centered on social practices and not just the healing process. PMID- 25830238 TI - Menage a quoi? Optimal number of peer reviewers. AB - Peer review represents the primary mechanism used by funding agencies to allocate financial support and by journals to select manuscripts for publication, yet recent Cochrane reviews determined literature on peer review best practice is sparse. Key to improving the process are reduction of inherent vulnerability to high degree of randomness and, from an economic perspective, limiting both the substantial indirect costs related to reviewer time invested and direct administrative costs to funding agencies, publishers and research institutions. Use of additional reviewers per application may increase reliability and decision consistency, but adds to overall cost and burden. The optimal number of reviewers per application, while not known, is thought to vary with accuracy of judges or evaluation methods. Here I use bootstrapping of replicated peer review data from a Post-doctoral Fellowships competition to show that five reviewers per application represents a practical optimum which avoids large random effects evident when fewer reviewers are used, a point where additional reviewers at increasing cost provides only diminishing incremental gains in chance-corrected consistency of decision outcomes. Random effects were most evident in the relative mid-range of competitiveness. Results support aggressive high- and low end stratification or triaging of applications for subsequent stages of review, with the proportion and set of mid-range submissions to be retained for further consideration being dependent on overall success rate. PMID- 25830240 TI - Correction: Orai3 constitutes a native store-operated calcium entry that regulates non small cell lung adenocarcinoma cell proliferation. PMID- 25830239 TI - Co-chaperone p23 regulates C. elegans Lifespan in Response to Temperature. AB - Temperature potently modulates various physiologic processes including organismal motility, growth rate, reproduction, and ageing. In ectotherms, longevity varies inversely with temperature, with animals living shorter at higher temperatures. Thermal effects on lifespan and other processes are ascribed to passive changes in metabolic rate, but recent evidence also suggests a regulated process. Here, we demonstrate that in response to temperature, daf-41/ZC395.10, the C. elegans homolog of p23 co-chaperone/prostaglandin E synthase-3, governs entry into the long-lived dauer diapause and regulates adult lifespan. daf-41 deletion triggers constitutive entry into the dauer diapause at elevated temperature dependent on neurosensory machinery (daf-10/IFT122), insulin/IGF-1 signaling (daf-16/FOXO), and steroidal signaling (daf-12/FXR). Surprisingly, daf-41 mutation alters the longevity response to temperature, living longer than wild-type at 25 degrees C but shorter than wild-type at 15 degrees C. Longevity phenotypes at 25 degrees C work through daf-16/FOXO and heat shock factor hsf-1, while short lived phenotypes converge on daf-16/FOXO and depend on the daf-12/FXR steroid receptor. Correlatively daf-41 affected expression of DAF-16 and HSF-1 target genes at high temperature, and nuclear extracts from daf-41 animals showed increased occupancy of the heat shock response element. Our studies suggest that daf-41/p23 modulates key transcriptional changes in longevity pathways in response to temperature. PMID- 25830241 TI - Flexible, fast and accurate sequence alignment profiling on GPGPU with PaSWAS. AB - MOTIVATION: To obtain large-scale sequence alignments in a fast and flexible way is an important step in the analyses of next generation sequencing data. Applications based on the Smith-Waterman (SW) algorithm are often either not fast enough, limited to dedicated tasks or not sufficiently accurate due to statistical issues. Current SW implementations that run on graphics hardware do not report the alignment details necessary for further analysis. RESULTS: With the Parallel SW Alignment Software (PaSWAS) it is possible (a) to have easy access to the computational power of NVIDIA-based general purpose graphics processing units (GPGPUs) to perform high-speed sequence alignments, and (b) retrieve relevant information such as score, number of gaps and mismatches. The software reports multiple hits per alignment. The added value of the new SW implementation is demonstrated with two test cases: (1) tag recovery in next generation sequence data and (2) isotype assignment within an immunoglobulin 454 sequence data set. Both cases show the usability and versatility of the new parallel Smith-Waterman implementation. PMID- 25830242 TI - The effect of VoorZorg, the Dutch nurse-family partnership, on child maltreatment and development: a randomized controlled trial. AB - BACKGROUND: Child maltreatment is a great public health concern that has long term mental and physical health consequences and can result in death. We studied the effect of a nurse home visiting program on child maltreatment among young disadvantaged families in The Netherlands. This study is the first to investigate the effects of this program outside of the United States. METHODS: We conducted a single blind, parallel-group, randomized controlled trial that compared usual care with the nurse home visitation program, which began during pregnancy and continued until the children's second birthdays, in 460 disadvantaged women who were pregnant for the first time and <26 years of age. The primary outcome was the existence of a report about the child from a child protecting services agency (CPS reports). Secondary outcome measures included home environment and child behavior. RESULTS: Two hundred twenty-three participants were assigned to the control group, and 237 were assigned to the intervention group. Three years after birth, 19% of the children in the control group had a CPS report. The 11 percent of children in the intervention group with CPS files was significantly lower (relative risk 0.91, p-value 0.04). At 24 months, the intervention group scored significantly better on the IT-HOME. At 24 months after birth, the children in the intervention group exhibited a significant improvement in internalizing behavior (relative risk 0.56, p-value 0.04) but no evidence of a difference from the control group in externalizing behavior (relative risk 0.71, p-value 0.12). CONCLUSION: The number of CPS reports for the intervention group was significantly lower than that of the control group. Additionally, the long-term home environments were improved and internalizing behaviors of the children were lower in the intervention group. TRIAL REGISTRATION: Dutch Trial Register NTR854. PMID- 25830244 TI - Dark field transmission electron microscopy as a tool for identifying inorganic nanoparticles in biological matrices. AB - Dark field transmission electron microscopy has been applied herein to visualize the interactions of inorganic nanomaterials with biological systems. This new application of a known technique addresses a deficiency in status quo visualization techniques. High resolution and low noise images can be acquired to locate and identify crystalline nanoparticles in complex biological matrices. Moreover, through the composition of multiple images taken at different angular beam tilts, it is possible to image a majority of nanoparticles present at a site in dark field mode. This facilitates clarity regarding the internalization of nanomaterials in cellular systems. In addition, comparing dark field images recorded at different angular tilts yields insight into the character of nanoparticle faceting. PMID- 25830245 TI - It is my pleasure and great honor to serve as the guest editor for this issue. Introduction. PMID- 25830243 TI - Tobacco smoke activates human papillomavirus 16 p97 promoter and cooperates with high-risk E6/E7 for oxidative DNA damage in lung cells. AB - We have previously shown a functional interaction between human papillomavirus type 16 (HPV-16) E6 and E7 oncoproteins and cigarette smoke condensate (CSC) in lung cells suggesting cooperation during carcinogenesis. The molecular mechanisms of such interaction, however, remain to be elucidated. Here we first present evidence showing that cigarette smoke condensate (CSC) has the ability to activate the HPV-16 p97 promoter by acting on the long control region (LCR) in lung epithelial cells. Interestingly, we observed that CSC-induced p97 promoter activation occurs in a dose-dependent manner in both tumor A-549 (lung adenocarcinoma), H-2170 (bronchial carcinoma), SiHa or Hela (cervical carcinoma) cells but not in non-tumor BEAS-2B (bronchial) or NL-20 (alveolar) lung cells unless they ectopically expressed the HPV-16 E6 and E7 oncogenes. In addition, we also observed a significant increase of primary DNA damage in tumor and non-tumor CSC-treated lung cells expressing HPV-16 E6 and E7 oncogenes suggesting a cooperative effect in this process, even though the contribution of E7 was significantly higher. Taken together, our results strongly suggest that tobacco smoke is able to induce the activation of the HPV-16 p97 promoter in cooperation with HPV-16 E6 and E7 oncogenes that, in turn, sensitize lung cells to tobacco smoke-induced DNA damage. PMID- 25830246 TI - Update on botulinum neurotoxin use in aesthetic dermatology. AB - Botulinum toxins are among the most widely studied and versatile drugs in the medicinal market. Since their extraction from Clostridium botulinum, they have been harnessed and incorporated into different formulations with varied properties and actions. These products have been used to treat countless disorders such as musculoskeletal disorders, headaches, and eye disorders, among many others. In the realm of aesthetic cutaneous medicine, the evolution and creativity in the use of botulinum toxins has been swift and ever changing. Knowledge of the science and innovation behind this toxin enables the user to provide the patient with a variety of treatment options founded in evidence-based medicine. This review will highlight the properties and actions of the newer, more recent neurotoxin preparations, as well as some of the latest and novel therapeutic applications of botulinum toxins. PMID- 25830247 TI - Filler frontier: what's new and heading West to the US market. AB - The amount of fillers approved by the United States Food and Drug Administration (FDA) for use in facial volume augmentation is diminutive in comparison to filler products employed worldwide. In the near future, several new hyaluronic acid filler products will be available to the United States market. Already approved fillers include Belotero Balance for fine lines, Juvederm Voluma XC for midfacial volume loss replacement, and Restylane Silk for perioral lines and lip augmentation. Volbella, currently under FDA evaluation, will be used for fine line correction and lip augmentation. The physiochemical properties, best practices, clinical uses, and side effects of these fillers are discussed. Additionally, evolving techniques such as the use of blunt-tipped microcannulas are explained. PMID- 25830248 TI - Picosecond lasers: the next generation of short-pulsed lasers. AB - Selective photothermolysis, first discussed in the context of targeted microsurgery in 1983, proposed that the optimal parameters for specific thermal damage rely critically on the duration over which energy is delivered to the tissue. At that time, nonspecific thermal damage had been an intrinsic limitation of all commercially available lasers, despite efforts to mitigate this by a variety of compensatory cooling mechanisms. Fifteen years later, experimental picosecond lasers were first reported in the dermatological literature to demonstrate greater efficacy over their nanosecond predecessors in the context of targeted destruction of tattoo ink. Within the last 4 years, more than a decade after those experiments, the first commercially available cutaneous picosecond laser unit became available (Cynosure, Westford, Massachusetts), and several pilot studies have demonstrated its utility in tattoo removal. An experimental picosecond infrared laser has also recently demonstrated a nonthermal tissue ablative capability in soft tissue, bone, and dentin. In this article, we review the published data pertaining to dermatology on picosecond lasers from their initial reports to the present as well as discuss forthcoming technology. PMID- 25830249 TI - The evolution of laser surgery for acne and other scarring processes. AB - The treatment of acne scars is an important part of a laser specialist's practice. For the last 20 years, the technology available for this application has progressed from nonablative to ablative and eventually to fractional lasers that are effective for a range of scar types. Although patients with mild to severe acne scarring have long been good laser candidates, we are beginning to understand the use of lasers for severe traumatic scars which can be disfiguring and functionally limiting in nature. PMID- 25830250 TI - Convergence of anatomy, technology, and therapeutics: a review of laser-assisted drug delivers. AB - This is a very exciting time in cutaneous laser surgery with an ever-expanding therapeutic armamentarium and an increased sophistication of available technology. These recent trends have allowed for both a rapid development of interest and exploration of laser-assisted drug delivery and its potential applications. We review the current literature on anatomy, technology, and therapeutics as it relates to laser-assisted drug delivery. The focus of our review is on two areas of interest that have received much attention to date - photodynamic therapy in the treatment of actinic keratoses and nonmelanoma skin cancers as well as the treatment of scarring. We will also discuss potential complications of existing modalities used independently and in laser-assisted drug delivery and conclude with future indications for this burgeoning therapeutic methodology. PMID- 25830251 TI - Updates in noninvasive and minimally invasive skin tightening. AB - The demand for noninvasive and minimally invasive skin-tightening procedures is rising within the aesthetic world. Although these treatments will not replace surgery,a growing patient population is seeking results through low-risk procedures with associated minimal downtime.The technology within this realm is changing due to an increased ability to safely deliver energy to deeper tissue planes. Within the last year alone, research has led to the introduction of a subdermal radiofrequency device, advancements in minimally invasive lasers, and the use of microfocused ultrasound off the facial tissue. Through research studies, protocols are being optimized and clinical results are becoming more reliable. PMID- 25830252 TI - Men's aesthetic dermatology. AB - Cosmetic dermatology is continuing to see a dramatic increase in both procedures performed and technological advancements. Men's aesthetic dermatology is burgeoning with more men seeking cosmetic consultations and intervention. Whether it is targeted cosmeceuticals for men or male-specific procedures, dermatologists must be aware of this evolving demographic and understand the biological, anatomical, and psychological aspects that separate this cohort from their female counterparts. Cosmetic dermatology has moved beyond just applying the same techniques used for females onto males. The use of our cosmetic toolbox can differ for men in terms of technique and dosage. This article will review the state of men's aesthetic dermatology with. PMID- 25830253 TI - Home-use devices in aesthetic dermatology. AB - The world of aesthetic medicine is increasingly a consumer-driven market with a wide variety of home-use devices from which the consumer can choose for treating hair removal, hair loss, acne, facial rejuvenation, and other dermatologic conditions. Where these devices fit in the physician practice and consumer routine can be confusing, as scientific studies may be weak or lacking. The specifications, price, ease-of-use, maintenance, and technology can differ greatly between devices. Thus, the physician and consumer need to define exp. PMID- 25830254 TI - Dissection of the water cavity of yeast thioredoxin 1: the effect of a hydrophobic residue in the cavity. AB - The water cavity of yeast thioredoxin 1 (yTrx1) is an ancestral, conserved structural element that is poorly understood. We recently demonstrated that the water cavity is involved in the complex protein dynamics that are responsible for the catalytically relevant event of coupling hydration, proton exchange, and motion at the interacting loops. Its main feature is the presence of the conserved polar residue, Asp24, which is buried in a hydrophobic cavity. Here, we evaluated the role of the solvation of Asp24 as the main element that is responsible for the formation of the water cavity in thioredoxins. We showed that the substitution of Asp24 with a hydrophobic residue (D24A) was not sufficient to completely close the cavity. The dynamics of the D24A mutant of yTrx1 at multiple time scales revealed that the D24A mutant presents motions at different time scales near the active site, interaction loops, and water cavity, revealing the existence of a smaller dissected cavity. Molecular dynamics simulation, along with experimental molecular dynamics, allowed a detailed description of the water cavity in wild-type yTrx1 and D24A. The cavity connects the interacting loops, the central beta-sheet, and alpha-helices 2 and 4. It is formed by three contiguous lobes, which we call lobes A-C. Lobe A is hydrophilic and the most superficial. It is formed primarily by the conserved Lys54. Lobe B is the central lobe formed by the catalytically important residues Cys33 and Asp24, which are strategically positioned. Lobe C is the most hydrophobic and is formed by the conserved cis-Pro73. The central lobe B is closed upon introduction of the D24A mutation, revealing that independent forces other than solvation of Asp24 maintain lobes A and C in the open configuration. These data allow us to better understand the properties of this enzyme. PMID- 25830255 TI - Alternative for carpal tunnel injection: palmar injection site (Rankin's zone). AB - This study investigates an alternative approach for steroid injection into the carpal canal through a palmar site and its exposure of vital wrist structures to potential injury. The Rankin's zone entry site is more distally located than conventional sites. This cadaveric study investigated 28 wrists from 26 cadavers. Red latex dye was injected as a localizing aid. Layered dissections were performed to localize the needle tip with respect to vital wrist structures. Calipers measured the distance from the needle to nerves. Twenty-three of the 28 injections using this approach demonstrated dye solely within the carpal tunnel. One median nerve was punctured. The mean distance from the median nerve was 5.76 +/- 2.9 mm and 18.27 +/- 5.27 mm from the palmar cutaneous branch. This study suggests that the Rankin's zone approach might be utilized with diminished frequency of neural puncture. PMID- 25830256 TI - Morphometric analysis of distal interphalangeal joint and implications for arthrodesis with a headless compression screw. AB - Using radiographs of a cross section of patients, measurements of phalanges were done to aid in surgical planning for distal interphalangeal joint (DIPJ) arthrodesis using a headless compression screw. Measurements were performed of the distal and middle phalanx of all fingers and the proximal and distal phalanx of the thumb. Three independent reviewers measured 50 patients. The average measurements (in mm) of anteroposterior (AP) dimensions were as follows: for the thumb P1 and P2: 5.7 and 5.5, lateral 4.2 and 3.5; for the index P2 and P3 AP: 4.2 and 3.3, lateral 2.1 and 1.8; for the long P2 and P3 AP: 4.5 and 3.5, lateral 2.2 and 1.8; for the ring P2 and P3 AP: 4.3 and 3.1, lateral 1.8 and 1.7; and for the small P2 and P3 AP: 3.7 and 2.2, lateral 1.8 and 1.5. Careful surgical planning by measuring the involved digit and knowledge of screw size is paramount to avoid complications from DIPJ arthrodesis with a compression screw. PMID- 25830257 TI - Effect of body mass index on early outcomes of minimally invasive degenerative lumbar surgery. AB - This retrospective study examined the early outcomes of healthy weight and severely obese subjects who underwent minimally invasive (MI) fusion and decompression surgery for degenerative lumbar disease at one to two spinal levels. A single surgeon (D.A.) operated on all subjects. Subjects were categorized based on body mass index [normal (18.5-24.9 kg/m(2)) or severely obese (over 35 kg/m(2))]. Surgical data included blood loss, hospital length of stay, narcotic use, discharge disposition, and postoperative infection. Data were compared using Levene's test for equality of variances, t test for equality of means, Pearson chi-square test, and Cramer's V correlation test (alpha <= .05 for all). SPSS software was utilized for all tests. Significant differences between the groups included blood loss, hospital length of stay, and early narcotic use. In the early postoperative setting, healthy weight subjects went home sooner and lost less blood, but needed more narcotic prescriptions filled than their obese counterparts. The use of MI spinal surgery in the severely obese population provides manageable issues for the patient and no significant complications when compared with the healthy weight population, indicating that it is a good alternative for obese patients. PMID- 25830258 TI - Comparison of intramedullary fixation techniques in the maintenance of functional anatomy of the elbow after fixation of the proximal ulna. AB - The objective of this study was to compare intramedullary (IM) nail and IM screw fixation for reattachment of the proximal ulna. Preserved elbow anatomy served as the primary outcome and was defined as the distance between the coronoid process and the olecranon. A retrospective cohort study of 31 patients treated with IM fixation of the proximal ulna was performed. Radiographs were used to compare displacement distances between the coronoid process and the olecranon, with average follow-up of approximately 5 months. IM nail fixation corresponded to a mean displacement of -0.65 mm between the olecranon and coronoid process, versus 0.23 mm for IM screw fixation. No patients were identified with loss of reduction of bone fragments. Both IM fixation techniques maintained the functional anatomy of the elbow. Minimal displacement of bone fragments and no identified loss of reduction suggest that both techniques could be reasonable alternatives to more traditional approaches. PMID- 25830259 TI - Documentation of acute compartment syndrome during medical evacuation. AB - The purpose of this study is to evaluate the documentation of acute compartment syndrome (ACS) in combat casualties in an effort to identify potential areas for improvement. Medical records of U.S. service members wounded during the current conflicts in Afghanistan and Iraq who underwent fasciotomies were reviewed. Key descriptors including signs and symptoms of ACS were recorded. Injury severity scores and muscle excision at the time of fasciotomy were also included for analysis. Of 134 patients who met inclusion criteria, documentation was inadequate overall in 65 patients (49%). Fourteen (10%) had muscle excised at the time of fasciotomy, but this was not associated with a higher rate of inadequate documentation. This study demonstrates the need for improved awareness and documentation of impending compartment syndrome in the austere setting to improve the continuity of care during the medical evacuation process. PMID- 25830260 TI - Techniques for periarticular infiltration with liposomal bupivacaine for the management of pain after hip and knee arthroplasty: a consensus recommendation. AB - Periarticular infiltration analgesia when used as a component of multimodal analgesia regimen has been shown to provide excellent pain relief after major joint replacement surgery. Recently, a liposomal formulation of bupivacaine (Exparel) has been approved for administration into the surgical site to produce postsurgical analgesia. It is a sustained release preparation of bupivacaine that has been shown to provide pain relief for up to 72 hours with a single local administration. Because the success of infiltration technique depends on systematic, extensive, meticulous tissue injection before surgical wound closure, a group convened to address the best practice for periarticular injection techniques for hip and knee replacement surgery. This article provides recommendations for optimal solution for injection (i.e., drug combinations or ''cocktail'' and total volume) as well as detailed description (including illustrations) of the infiltration technique for primary, revision, and unicompartmental knee arthroplasty and primary and revision hip arthroplasty using various surgical approaches. PMID- 25830261 TI - Effect of setting of initial surgical drainage on outcome of finger infections. AB - This study sought to determine the optimal treatment setting (emergency department vs. operating room) for the initial incision and drainage of acute suppurative finger infections. A search of hospital medical records over a 5-year period identified 152 cases. In 108 cases (71%), a single drainage successfully resolved infection; 44 cases (29%) required multiple drainage procedures. Treatment setting did not decrease the risk for multiple procedures. Seventy-six cases (57%) of community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) were identified. Bivariate analysis identified CA-MRSA infection as a significant, independent risk factor for multiple procedures. Obtaining initial cultures correlated with a decreased need for multiple procedures. In conclusion, initial surgical drainage in the emergency department is a safe alternative to the operating room. However, patients with CA-MRSA infection have an increased risk for persistent infection requiring multiple procedures. Prompt organism identification and appropriate antibiotics following surgical drainage remain most crucial for the successful treatment of finger infections. PMID- 25830262 TI - A low-cost digital templating system for total hip arthroplasty. AB - Acetate templating for total hip arthroplasty (THA) is cumbersome and inaccurate. High cost hampers mainstream use of digital templating despite ease of use and accuracy. The aim of this study was to validate a low-cost digital THA templating system. Low-cost digital templating software was created using C# programming language. On the basis of power calculations, three surgeons templated 20 consecutive anteroposterior pelvis X-rays using this software against an industry standard. Intraclass correlation coefficient for both systems was approximately .90 for component size and femoral neck cut position. Bland-Altman plots demonstrated that both systems predicted actual implant size with similar accuracy. Interrater reliability was not significantly different between the two systems. This low-cost digital THA templating system is up to 12-fold lower in cost than currently available software with similar accuracy. PMID- 25830263 TI - Design comparison: manipulation after total knee arthroplasty. AB - Postoperative stiffness is a relatively uncommon issue in total knee arthroplasty (TKA). However, it can be a debilitating complication when it occurs. Manipulation under anesthesia (MUA) is commonly used as the primary treatment modality following failed physiotherapy. The Advance medial pivot knee (Wright Medical Technology) was created in an effort to prevent stiffness postoperatively and increase range of motion. The Evolution medial pivot knee is a second generation design that builds on the technology of the Advance knee. This article presents a retrospective review of prospectively collected data on 881 primary medial pivot knees (592 Advance knees, 289 Evolution knees). It was theorized that the design changes made to the Evolution knees might contribute toward reducing the need for MUA. It was found that the Evolution knees required significantly fewer manipulations under anesthesia (p = .036). The design modifications made to the Evolution knees may have contributed to the lower rate of MUA. PMID- 25830264 TI - Intraoperative frozen section analysis for failed metal-on-metal total hip arthroplasty: is it useful? AB - Recent failure mechanisms seen with metal-on-metal (MOM) total hip arthroplasty (THA) include a spectrum of inflammatory and immune-mediated reactions of lymphocyte predominance. Frozen section (FS) analysis has been used to evaluate joints for acute inflammation indicative of infection. However, the impact of the inflammatory response to metal debris on FS analysis is unknown and the usefulness of FS analysis in failed MOM THA has not been reported. This study investigated the impact of intraoperative FS analysis in evaluating the possibility of infection in 30 patients undergoing revision of a failed MOM THA. The authors' experience suggests that FS has acceptable specificity (96.6%) for infection in revision MOM surgery, although one false positive was noted in this series and the addition of FS did not provide obvious diagnostic utility. The authors believe that FS should be used selectively (if at all) in conjunction with other studies to avoid misdiagnosis in failed MOM THA. PMID- 25830265 TI - Radiation exposure in the young level 1 trauma patient: a retrospective review. AB - Computed tomography (CT) has become an increasingly popular and powerful tool for clinicians managing trauma patients with life-threatening injuries, but the ramifications of increasing radiation burden on individual patients are not insignificant. This study examines a continuous series of 337 patients less than 40 years old admitted to a level 1 trauma center during a 4-month period. Primary outcome measures included number of scans; effective dose of radiation from radiographs and CT scans, respectively; and total effective dose from both sources over patients' hospital stays. Several variables, including hospital length of stay, initial Glasgow Coma Scale score, and Injury Severity Score, correlated with greater radiation exposure. Blunt trauma victims were more prone to higher doses than those with penetrating or combined penetrating and blunt trauma. Location and mechanism of injury were also found to correlate with radiation exposure. Trauma patients as a group are exposed to high levels of radiation from X-rays and CT scans, and CT scans contribute a very high proportion (91.3% +/- 11.7%) of that radiation. Certain subgroups of patients are at a particularly high risk of exposure, and greater attention to cumulative radiation dose should be paid to patients with the above mentioned risk factors. PMID- 25830266 TI - Musculoskeletal ultrasound education: orthopaedic resident ability following a multimedia tutorial. AB - Musculoskeletal ultrasound (MSK-US) is a quick and effective imaging tool that can be utilized by orthopaedic surgeons to identify common musculoskeletal pathology such as ankle tendinopathy. This study evaluated the ability of 15 orthopaedic surgery residents to identify and measure ankle tendons after attending a multimedia tutorial on MSK-US. Afterwards, proficiency of usage was assessed by identification and quantification of three ankle tendons (Achilles, tibialis posterior, and flexor hallucis longus) in a cadaver limb. Resident comfort level and plan for future use were also assessed. After completing the tutorial, accuracy measuring the Achilles, tibialis posterior, and flexor hallucis longus tendons was 94.8%, 90.2%, and 90.1%, respectively. Resident comfort level improved from a level of 2.3 before the tutorial to 6.8 afterwards. Seventy-one percent of residents plan to use ultrasound in clinical practice. These results show that orthopaedic surgery residents can identify and assess tendon size via MSK-US with sufficient accuracy after a multimedia tutorial. PMID- 25830267 TI - Arthroscopy and manipulation versus home therapy program in treatment of adhesive capsulitis of the shoulder: a prospective randomized study. AB - This study determined in a prospective manner if arthroscopic shoulder capsular release can decrease the duration of adhesive capsulitis symptoms when compared with a nonoperative home therapy program. Patients randomized to the operative group underwent arthroscopic capsular release and manipulation of the shoulder. Immediately after surgery they began the same stretching program as the nonoperative group, which consisted of terminal range of motion low-grade stretches twice daily for at least 15 minutes per session for 3 months. Twenty six patients granted consent for the study (final analyses included 10 operative and 7 nonoperative). There were no statistical differences between the groups regarding gender, age (operative mean age, 51.5 +/- 11.1 years; nonoperative mean age, 52.0 +/- 6.8 years) or treatment outcome. This prospective, randomized study, which compared arthroscopic capsular release to a gentle home stretching program, demonstrated both treatment options to be effective treatment modalities. PMID- 25830268 TI - Achilles allograft reconstruction for chronic achilles tendinopathy. AB - Reconstruction of chronic rupture and resection of chronic tendinosis of the Achilles tendon can be challenging when there is insufficient tendon for repair. This article describes the demographics, diagnosis, surgical technique, and results of a series of patients having Achilles allograft reconstruction of the Achilles tendon. A retrospective chart review identified patients who required Achilles reconstruction. Between 2006 and 2013, 78 patients had surgical repair for Achilles rupture or resection of tendinosis. Eight patients required use of Achilles tendon allograft with calcaneal block. In all patients, there was insufficient viable tendon to repair by direct reattachment. The postdebridement gap was greater than 5 cm. All patients had good function at last follow-up. This series of patients undergoing Achilles allograft reconstruction technique demonstrated promising results and suggests that allograft reconstruction is a reasonable solution. PMID- 25830269 TI - Imaging of the Lisfranc injury. AB - Lisfranc ligament and joint injuries are relatively uncommon but can result from a variety of low- and high-impact trauma. Up to 20% of Lisfranc fracture dislocations are misdiagnosed or missed during the initial evaluation. Timely and accurate diagnosis of the injury and early anatomical reduction and stabilization of the Lisfranc joint are crucial to avoid long-term sequelae and functional impairment. Magnetic resonance imaging (MRI) is a sensitive and specific imaging modality and should be considered in injuries with equivocal physical and radiographic findings. In this article, the mechanism and the classification of the Lisfranc joint and ligament injuries are outlined, and imaging findings of different modalities are discussed with the emphasis on MRI. PMID- 25830270 TI - [Considerations on the evolution of the Spanish language in medicine]. PMID- 25830271 TI - Assessment of excitability at the brainstem and cortex in primary headaches with allodynia. AB - PURPOSE: The aims were to assess the excitability of motor cortex and trigeminal structures in patients with primary headaches experiencing allodynia and to investigate the alterations in interictal allodynia and blink reflex excitability after repetitive transcranial magnetic stimulation (rTMS). METHODS: Patients with strictly lateralized primary headaches were included, and Allodynia Symptom Checklist was used to detect allodynia. Paired transcranial magnetic stimulation and blink reflex recovery studies were performed on both sides. Ten Hertz or sham rTMS was applied on the motor cortex in patients with interictal allodynia. Allodynic symptoms were registered quantitatively, and blink reflex study was repeated after these trials. RESULTS: Seventeen of 34 patients with headache described allodynia. Our findings showed bilateral hyperexcitability of cortical and trigeminal structures in the allodynic group. Interictal allodynia, detected in 13 allodynic patients, improved after rTMS as compared with sham stimulation, and this effect appeared to be more evident in the late period. CONCLUSIONS: Bilateral increases in the cortical and trigeminal excitability were shown in patients with allodynia, and rTMS was effective for reducing clinical allodynia. The authors suggest that allodynic condition of the patients should be taken into account in the planning and evaluation of electrophysiological studies, and rTMS may be considered as a treatment alternative for troublesome allodynia. PMID- 25830272 TI - Severe hemispatial neglect as a manifestation of seizures and nonconvulsive status epilepticus: utility of prolonged EEG monitoring. AB - PURPOSE: Seizures and status epilepticus causing hemispatial neglect syndromes are seldom diagnosed, in part because, without motor signs, EEGs are not performed. Also, nonconvulsive seizures are often intermittent and missed on a single EEG. Two patients had severe neglect syndromes thought due to strokes. Correct diagnosis of epileptic seizures required longer-term EEG monitoring. METHODS: Review of clinical history, neurologic examination, imaging, and findings on prolonged EEG monitoring. RESULTS: A patient with a new onset of a profound left neglect had normal strength and language use, with no obvious clinical seizures. A right hemisphere embolic stroke was diagnosed, but MRI with diffusion-weighted imaging showed no evidence of ischemia. The initial EEG showed marked right parietal voltage suppression, with subsequent brief electrographic seizures and later, right parietal periodic discharges. The second patient had an earlier right subdural hematoma and focal motor seizures but was admitted with a new neglect syndrome and no clear clinical seizures. Head computed tomography showed no new lesion. EEG showed frequent right parieto-temporal epileptiform discharges and electrographic seizures. The neglect syndromes resolved with anticonvulsant treatment, but in both cases, electrographic seizures were intermittent, and there was no strict correlation between the clinical deficit and EEG manifestations of seizures. CONCLUSIONS: Infrequently, the sudden onset of new hemispatial neglect can be caused by nonconvulsive seizures and nonconvulsive status epilepticus, even when there is no weakness and no clear clinical seizure activity. Nonconvulsive status epilepticus can cause primarily perceptual and cognitive syndromes. The correlation between the clinical deficits and seizure activity on the EEG, however, is imprecise. A single EEG may miss seizure activity, and repeated or prolonged EEG recording may be necessary to make the diagnosis. PMID- 25830274 TI - Statistics: why meaningful statistics cannot be generated from a private practice. PMID- 25830273 TI - Our other vital organ. PMID- 25830275 TI - Massage therapy improves in vitro fertilization outcome in patients undergoing blastocyst transfer in a cryo-cycle. AB - CONTEXT: Massage therapy is increasingly used to relieve physical and mental discomfort and is suggested as a safe therapeutic modality, without any significant risks or any known side effects. Although a multitude of complementary therapies, such as acupuncture, are applied in reproductive medicine, no information is available with regard to the application of massage as an adjuvant therapy in assisted-reproduction techniques (ARTs). OBJECTIVES: This study was intended to assess the effectiveness of a deep relaxation (andullation) therapy based on oscillating vibrations when used prior to embryo transfer (ET) in in vitro fertilization (IVF) cryo-cycles. DESIGN: The research team designed a retrospective, observational study. Participants willing to undergo the massage treatment were allocated to the intervention (andullation) group. SETTING: The study was performed at the IVF Centers Prof. Zech-Bregenz in Bregenz, Austria. PARTICIPANTS: A total of 267 IVF patients, with a mean age of 36.3 y, participated in this single-center study. INTERVENTION: All patients receiving a transfer of vitrified and warmed blastocysts between January and December 2012 were included in the evaluation. Prior to ET, the andullation group received a standardized program of therapy-a 30-min, deep relaxation massage on an oscillating (vibrating) device, whereas the control group did not. OUTCOME MEASURES: To determine efficacy, the primary outcomes that the study measured were (1) pregnancy rates (PRs), by testing urine and obtaining a positive beta human chorionic gonadotropin (beta-hCG); and (2) ongoing, pregnancies (oPR), by observation of fetal heartbeat and birth rates (BR) as well as miscarriage rates. The patients' medical histories and types of infertility as well as the quality of the embryo transfers (ETs) were evaluated. RESULTS: In patients using the massage therapy prior to ET, significantly higher PRs, oPRs, and BRs were observed compared with the control group-PR: 58.9% vs 41.7%, P<.05; oPR: 53.6% vs 33.2%, P<.01; and BR: 32.0% vs 20.3%, P<.05. No differences were detected among groups for patients' ages, hormonal substitution protocols, endometrium structures and buildups, quality of transferred embryos, or quality of transfers. No adverse effects were noted in the massage group. CONCLUSIONS: The research team's results suggested that andullation therapy prior to blastocyst transfer in a cryo-cycle improves embryo implantation, most likely due to a reduction in stress (ie, a relaxation effect on patients), a reduction in uterine contractions, and, probably, an enhancement of the blood flow in the abdominal region. These findings provide support for use of andullation as a complementary therapy for ART. PMID- 25830276 TI - A broader conclusion to a well-conceived study: must it be massage before reproductive technology? PMID- 25830277 TI - Medical ozone and radiotherapy in a peritoneal, Erlich-ascites, tumor-cell model. AB - CONTEXT: Medical ozone therapy is used for treatment of inflammation in alternative and complementary medicine. It has been reported that the beneficial effects of radiotherapy increased with the addition of medical ozone therapy. OBJECTIVES: This study intended to investigate the antitumor and antiedema effects of ozone therapy when applied in different concentrations in mice with peritoneal carcinomatosis (PC) and to evaluate the contribution of medical ozone therapy to the outcomes for radiotherapy in vivo. DESIGN: Ehrlich ascites carcinoma (EAC) cells were inoculated intraperitoneally (IP) to develop peritoneal carcinomatosis in 60 adult male Swiss albino mice. The animals were divided into 5 groups. Groups 1 and 2 were treated IP for a period of 10 d with daily medical ozone therapy. Group 3 received radiotherapy into the abdomen for 5 d. Groups 4 and 5 were treated with medical ozone therapy for 10 d and radiotherapy for 5 d. Groups 1 and 4 received a 20 mg/L concentration of ozone and groups 2 and 5 received a 40 mg/L concentration. A sixth group acted as controls, and serum physiologic was given to them IP. OUTCOME MEASURES: Changes in body weight and abdominal circumference were measured daily for each mouse. Survival rates of the groups of mice were also determined. The results were compared between groups and were statistically analyzed. RESULTS: Changes in body weights and abdominal circumferences in the different groups were statistically different. The longest survival rates were found for groups 3 and 5, and survival rates for the 5 experimental groups were significantly higher than for the control group. CONCLUSIONS: Medical ozone therapy or radiotherapy was found to be effective when administered alone or concurrently to mice with PC, suggesting that medical ozone therapy might serve as a method of obtaining antiedema and antitumor effects, providing a longer survival time. PMID- 25830278 TI - Examining the association between patient-centered communication and provider avoidance, CAM use, and CAM-use disclosure. AB - CONTEXT: Patients' perceptions of the quality of their relationships with health care providers may influence their health care-seeking behaviors and future interactions with providers, including use of conventional health care, use of complementary and alternative medicine (CAM), and disclosure of CAM use. OBJECTIVE: The study examined the associations between perceived patient-centered communication and provider avoidance, CAM use, and CAM-use disclosure. DESIGN: This study used cross-sectional survey data from the Health Information National Trends Survey (HINTS) 3, a nationally representative survey of US adults collected between January 2008 and May 2008. OUTCOME MEASURES: Two questions asked about CAM use and CAM-use disclosure, and another asked about avoidance of doctors. For the independent variable, responses from 6 questions on patient centered communication were averaged to create a scale score ranging from 1-4. The research team conducted multiple logistic regressions of the 3 primary outcome measures, adjusting for sociodemographic characteristics, presence or absence of a regular source of care, insurance status, frequency of visits to providers, and health status. All analyses were weighted to make the results representative of the US population aged >=18 y. RESULTS: Approximately one-third of respondents (36%) had avoided seeing their doctors within the 12 mo prior to the survey. Approximately 24% had used CAM within the prior 12 mo, and 51.7% of CAM users had discussed their CAM use with their doctors. Higher levels of patient-centered communication were significantly associated with lower odds of provider avoidance (AOR=0.63; 95% CI=0.52, 0.76) and CAM use (AOR=0.60; 95% CI=0.46, 0.78) but were not associated with CAM-use disclosure. CONCLUSIONS: Findings suggest that patients may be more likely to avoid seeing their doctors and more likely to use CAM when they perceive low levels of patient-centered communication. Further research to understand the role of the characteristics of patient-provider relationships on provider avoidance, CAM use, and CAM-use disclosure is warranted. PMID- 25830279 TI - Antioxidant agents: a future alternative approach in the prevention and treatment of radiation-induced oral mucositis? AB - Radiotherapy is a therapeutic modality frequently employed for patients with head and neck cancer (HNC). It destroys tumor cells, but it is not selective, also affecting healthy tissues and producing adverse effects. One that stands out is oral mucositis because of the morbidity that it is capable of causing. This lesion is characterized by the presence of erythema, ulcerations, pain, opportunistic infections, and weight loss. These side effects can lead to serious situations that require the interruption of the antineoplastic treatment and can result in hospitalization and even death. The complex mechanisms linked to the pathogenesis of oral mucositis were recently established, and since then, the control of oxidative stress (OS) has been tied to the prevention and management of this disease. The authors have carried out a review of the literature about the use of antioxidant agents in the prevention and treatment of radiation induced oral mucositis, using the PubMed database. This review has shown that the research on use of antioxidants (AOX) has proved insufficient to justify suggesting the products in treatment protocols. Results are promising, however, and AOX may represent a future alternative in the prevention and treatment of oral mucositis. PMID- 25830280 TI - Mumijo attenuates chemically induced inflammatory pain in mice. AB - BACKGROUND: Mumijo (shilajit) has been well known in traditional medicine as a remedy for a number of diseases, such as bone fractures, wounds, inflammation, and headache. It is also widely used as an analgesic agent in folk medicine, but no scientific documentation exists concerning that effect. OBJECTIVE: The current study was conducted to evaluate the ability of mumijo to reduce sensitivity to painful stimuli when compared with morphine sulfate and sodium diclofenac. METHODS: A total of 176 animals were randomly and equally divided into 2 groups with 88 mice each-one for formalin test and the other for writhing test. For each test, the animals were allocated into 10 equal groups, based on the dosage of the analgesic, plus a negative control group, with 8 mice in each group. INTERVENTION: The analgesic effect of mumijo extract in doses of 0.75, 7.5, 75, and 750 mg/kg was assessed and compared witha group receiving distilled water-the negative control group, and that for groups receiving 1, 2, or 4 mg/kg of morphine sulfate or 10, 20, or 30 mg/kg of sodium diclofenac-the positive control groups. RESULTS: The results showed a significant decrease in pain intensity for all mice receiving doses of mumijo extract during a 1-h formalin test when compared with the distilled water group. For all the mumijo groups except the one receiving 750 mg/kg, the analgesic effect was significantly lower than that for the morphine sulfate group receiving 4 mg/kg. No significant differences existed between all mumijo and all diclofenac groups. In a writhing test, a significant inhibition of the pain response induced by acetic acid also occurred in all 4 mumijo-administered groups as opposed to the group receiving distilled water. No significant differences existed between the writhing response in groups receiving 75 and 750 mg/kg of mumijo and any doses of diclofenac or morphine. The comparison among the different doses of mumijo in the formalin test did not show any significant differences, but in the writhing test, the maximum dose showed a more effective analgesic action. CONCLUSION: The findings indicated a significant analgesic effect for mumijo extract on chronic pain in mice, occurring in a dose independent manner. PMID- 25830281 TI - Development of a modified yoga program for pulmonary hypertension: a case series. AB - BACKGROUND: Pulmonary hypertension (PH) is a hemodynamic condition in which the pressure in the bed of the pulmonary arteries is elevated. Although medications have improved both symptoms and mortality, PH remains a debilitating and devastating disease. Little is known about the effects of nonpharmacologic approaches, such as yoga and meditative breathing, in treatment of the disease. OBJECTIVE: Given the unique hemodynamic concerns of PH patients, the research team intended to describe the development and subsequent initiation of a therapeutic treatment plan that uses modified yoga and to evaluate its benefits and safety. DESIGN: This study was a case series with 3 PH patients of varying functional abilities. Each patient was provided with a DVD, access to YouTube video segments, and a download of the Yoga for PH application. The patients were asked to document their use of the home exercise regimen and journal around their subjective observations. They were also administered the Health Promoting Lifestyle Profile II (HPLPII) at the beginning and end of the 8 wk. SETTING: The study took place in a tertiary care, academic hospital in a large urban setting. PARTICIPANTS: In this case series, 3 patients with group 1 pulmonary arterial hypertension, with varying functional abilities, are described. INTERVENTION: Three discreet yoga programs were designed with modifications specific to PH patients: chair yoga, intermediate yoga with a chair assist, and experienced yoga. Patients were provided with a video, Yoga for PH, in the form of a DVD, a video on YouTube, and a downloadable application and were instructed to log activity and subjective markers of well-being. OUTCOME MEASURES: Subjective and objective effects on clinical, physical function, and psychological outcomes were measured. Subjective effects were identified through journaling as well as the self-administered questionnaire HPLPII. When available, 6-min walk distance (6MWD) testing and oxygen saturation were also used. RESULTS: The modified yoga program proved feasible, safe, and effective in the 3 described cases. Patients described decreases in anxiety and joint pain, with improvements in health promoting behaviors as measured by the HPLPII. Overall mean scores for health promoting lifestyle increased in each patient, though due to the small sample size, statistical significance cannot be measured. No patient experienced an adverse event associated with the practice. CONCLUSIONS: The modified yoga program for PH patients can provide a standardized, accessible starting point for further study on the feasibility, efficacy, and safety of such a program on a larger scale. PMID- 25830282 TI - James Forsythe, MD, HMD: the success of integrative cancer therapy based on chemosensitivity testing and insulin potentiation therapy. PMID- 25830283 TI - Incidence and survival of lacunar infarction in a southern Chinese population: A 7-year prospective study. AB - OBJECTIVE: Little attention has been paid to the epidemiological characteristics of lacunar infarction (LAC) in China before. This study aimed to examine the incidence and survival of LAC in a southern Chinese population. METHODS: From 2004-2010 in Changsha, two communities with a registered population of ~100 000 were selected and data from first-ever ischaemic stroke (IS) cases were prospectively collected. Then the epidemiological characteristics of LAC and non LAC were evaluated. RESULTS: During the study period, the age-standardized incidence increased at an annual rate of 0.7% (p < 0.001) for LAC and 2.0% (p < 0.001) for non-LAC. The mean annual age-standardized incidence of LAC and non-LAC was 28.2/100 000 and 45.0/100 000, respectively. Compared with non-LAC patients, the prevalence of hypertension, diabetes and hyperlipidemia was significantly higher in patients with LAC (p < 0.05). Although the 30-day fatality rate was significantly lower in patients with LAC than non-LAC (0.5% vs. 14.9%, p < 0.001), there was no significant difference in survival between the two groups (96.7% vs. 95.2%, p = 0.203) after excluding the patients who died within 1 year of stroke onset. CONCLUSION: LAC is a common stroke sub-type in southern China and the long-term prognosis is not benign. PMID- 25830285 TI - Scientific Abstracts of the Skin Disease Education Foundation's 15th Annual Las Vegas Dermatology Seminar. PMID- 25830284 TI - Fluctuation of the water environmental carrying capacity in a huge river connected lake. AB - A new method, with the non-fully mixed coefficient (NFMC) considered, was put forward to calculate the water environmental carrying capacity (WECC) for huge river-connected lakes, of which the hydrological conditions always vary widely during a year. Poyang Lake, the most typical river-connected lake and the largest freshwater lake in China, was selected as the research area. Based on field investigations and numerical simulation, the monthly pollutant degradation coefficients and non-fully mixed coefficients of different lake regions were determined to explore the WECCs of COD, TN and TP of Poyang Lake in a common water year. It was found that under the hydrological conditions of a common water year the total WECCs of COD, TN and TP in the lake were respectively 181.9 * 104 t, 33.3 * 104 t and 1.86 * 104 t. Due to the varied lake water volume and self purification ability, an evident temporal fluctuation of WECCs in Poyang Lake was observed. The dry seasons were characterized by a higher NFMCs but lower WECCs owing to the lower water level and degradation ability. Variation coefficients of COD and TN WECC were close to each other, of which the average level was about 58.5%, a little higher than that of TP. PMID- 25830286 TI - Immobilization of horseradish peroxidase on beta-cyclodextrin-capped silver nanoparticles: Its future aspects in biosensor application. AB - This study aimed to work out a simple and high-yield procedure for the immobilization of horseradish peroxidase on silver nanoparticle. Ultraviolet visible (UV-vis) and Fourier-transform infrared spectroscopy and transmission electron microscopy were used to characterize silver nanoparticles. Horseradish peroxidase was immobilized on beta-cyclodextrin-capped silver nanoparticles via glutaraldehyde cross-linking. Single-cell gel electrophoresis (Comet assay) was also performed to confirm the genotoxicity of silver nanoparticles. To decrease toxicity, silver nanoparticles were capped with beta-cyclodextrin. A comparative stability study of soluble and immobilized enzyme preparations was investigated against pH, temperature, and chaotropic agent, urea. The results showed that the cross-linked peroxidase was significantly more stable as compared to the soluble counterpart. The immobilized enzyme exhibited stable enzyme activities after repeated uses. PMID- 25830287 TI - Site-specific cassette exchange systems in the Aedes aegypti mosquito and the Plutella xylostella moth. AB - Genetically engineered insects are being evaluated as potential tools to decrease the economic and public health burden of mosquitoes and agricultural pest insects. Here we describe a new tool for the reliable and targeted genome manipulation of pest insects for research and field release using recombinase mediated cassette exchange (RMCE) mechanisms. We successfully demonstrated the established PhiC31-RMCE method in the yellow fever mosquito, Aedes aegypti, which is the first report of RMCE in mosquitoes. A new variant of this RMCE system, called iRMCE, combines the PhiC31-att integration system and Cre or FLP-mediated excision to remove extraneous sequences introduced as part of the site-specific integration process. Complete iRMCE was achieved in two important insect pests, Aedes aegypti and the diamondback moth, Plutella xylostella, demonstrating the transferability of the system across a wide phylogenetic range of insect pests. PMID- 25830288 TI - Neurofunctional correlates of ethical, food-related decision-making. AB - For consumers today, the perceived ethicality of a food's production method can be as important a purchasing consideration as its price. Still, few studies have examined how, neurofunctionally, consumers are making ethical, food-related decisions. We examined how consumers' ethical concern about a food's production method may relate to how, neurofunctionally, they make decisions whether to purchase that food. Forty-six participants completed a measure of the extent to which they took ethical concern into consideration when making food-related decisions. They then underwent a series of functional magnetic resonance imaging (fMRI) scans while performing a food-related decision-making (FRDM) task. During this task, they made 56 decisions whether to purchase a food based on either its price (i.e., high or low, the "price condition") or production method (i.e., with or without the use of cages, the "production method condition"), but not both. For 23 randomly selected participants, we performed an exploratory, whole-brain correlation between ethical concern and differential neurofunctional activity in the price and production method conditions. Ethical concern correlated negatively and significantly with differential neurofunctional activity in the left dorsolateral prefrontal cortex (dlPFC). For the remaining 23 participants, we performed a confirmatory, region-of-interest (ROI) correlation between the same variables, using an 8-mm3 volume situated in the left dlPFC. Again, the variables correlated negatively and significantly. This suggests, when making ethical, food related decisions, the more consumers take ethical concern into consideration, the less they may rely on neurofunctional activity in the left dlPFC, possibly because making these decisions is more routine for them, and therefore a more perfunctory process requiring fewer cognitive resources. PMID- 25830290 TI - Correction: Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay. PMID- 25830289 TI - What do Pneumocystis organisms tell us about the phylogeography of their hosts? The case of the woodmouse Apodemus sylvaticus in continental Europe and western Mediterranean islands. AB - Pneumocystis fungi represent a highly diversified biological group with numerous species, which display a strong host-specificity suggesting a long co-speciation process. In the present study, the presence and genetic diversity of Pneumocystis organisms was investigated in 203 lung samples from woodmice (Apodemus sylvaticus) collected on western continental Europe and Mediterranean islands. The presence of Pneumocystis DNA was assessed by nested PCR at both large and small mitochondrial subunit (mtLSU and mtSSU) rRNA loci. Direct sequencing of nested PCR products demonstrated a very high variability among woodmouse-derived Pneumocystis organisms with a total number of 30 distinct combined mtLSU and mtSSU sequence types. However, the genetic divergence among these sequence types was very low (up to 3.87%) and the presence of several Pneumocystis species within Apodemus sylvaticus was considered unlikely. The analysis of the genetic structure of woodmouse-derived Pneumocystis revealed two distinct groups. The first one comprised Pneumocystis from woodmice collected in continental Spain, France and Balearic islands. The second one included Pneumocystis from woodmice collected in continental Italy, Corsica and Sicily. These two genetic groups were in accordance with the two lineages currently described within the host species Apodemus sylvaticus. Pneumocystis organisms are emerging as powerful tools for phylogeographic studies in mammals. PMID- 25830292 TI - In vitro growth of Curcuma longa L. in response to five mineral elements and plant density in fed-batch culture systems. AB - Plant density was varied with P, Ca, Mg, and KNO3 in a multifactor experiment to improve Curcuma longa L. micropropagation, biomass and microrhizome development in fed-batch liquid culture. The experiment had two paired D-optimal designs, testing sucrose fed-batch and nutrient sucrose fed-batch techniques. When sucrose became depleted, volume was restored to 5% m/v sucrose in 200 ml of modified liquid MS medium by adding sucrose solutions. Similarly, nutrient sucrose fed batch was restored to set points with double concentration of treatments' macronutrient and MS micronutrient solutions, along with sucrose solutions. Changes in the amounts of water and sucrose supplementations were driven by the interaction of P and KNO3 concentrations. Increasing P from 1.25 to 6.25 mM increased both multiplication and biomass. The multiplication ratio was greatest in the nutrient sucrose fed-batch technique with the highest level of P, 6 buds/vessel, and the lowest level of Ca and KNO3. The highest density (18 buds/vessel) produced the highest fresh biomass at the highest concentrations of KNO3 and P with nutrient sucrose fed-batch, and moderate Ca and Mg concentrations. However, maximal rhizome dry biomass required highest P, sucrose fed-batch, and a moderate plant density. Different media formulations and fed batch techniques were identified to maximize the propagation and storage organ responses. A single experimental design was used to optimize these dual purposes. PMID- 25830291 TI - Sex differences in epidemiology and risk factors of acute coronary syndrome in Chinese patients with type 2 diabetes: a long-term prospective cohort study. AB - OBJECTIVE: Diabetic patients with acute coronary syndrome (ACS) are at higher risk of poor outcome than are non-diabetic patients with ACS. Few studies have focused on sex-related ACS incidence, ACS-related mortality or risk factors to affects sex specific ACS in Chinese with Type 2 diabetes mellitus (T2DM). Based on a hospital-based cohort of Chinese patients with T2DM, we aimed to investigate whether there was sex difference in ACS or ACS-related mortality or risk factors of ACS. METHODS: Totally 2,135 Hong Kong Chinese with T2DM were recruited during 1994-1996 and followed up until August 2012. We systematically analyzed sex related ACS incidence and ACS-related mortality and risk factors with chi2 squared test, descriptive statistics and survival analysis. RESULTS: Regular follow-up was completed in 2,105 subjects (98.6%), with a median period of 14.53 years. The occurrence of ACS was recorded among 414 patients (19.7%) and ACS related death among 104 patients (4.9%). ACS incidences increased with age in both men and women, and men had a higher prevalence of ACS than women across different age categories and different follow-up periods (log rank chi2=20.32, P<0.001). The transition of ACS incidences from slow to rapid increase were about 5 years earlier in men (at 51-55 years) than in women (55-60 years). Among ACS patients, cumulative ACS-related mortalities was similar between men and women (log rank chi2=0.063, P=0.802). Besides age and albuminuria, different profiles of risk factors accounted for the occurrence of ACS between men and women. CONCLUSIONS: Our findings demonstrated sex differences in ACS incidence and risk factors, but not in ACS-related mortality in Chinese patients withT2DM. These findings suggest that screening and prevention campaigns should be optimized for men and women, which may help to identify diabetic patients at higher risk of coronary heart disease. PMID- 25830293 TI - Managing marine plastic pollution: policy initiatives to address wayward waste. PMID- 25830294 TI - Factors that affect transfer of the IncI1 beta-lactam resistance plasmid pESBL 283 between E. coli strains. AB - The spread of antibiotic resistant bacteria worldwide presents a major health threat to human health care that results in therapy failure and increasing costs. The transfer of resistance conferring plasmids by conjugation is a major route by which resistance genes disseminate at the intra- and interspecies level. High similarities between resistance genes identified in foodborne and hospital acquired pathogens suggest transmission of resistance conferring and transferrable mobile elements through the food chain, either as part of intact strains, or through transfer of plasmids from foodborne to human strains. To study the factors that affect the rate of plasmid transfer, the transmission of an extended-spectrum beta-lactamase (ESBL) plasmid from a foodborne Escherichia coli strain to the beta-lactam sensitive E. coli MG1655 strain was documented as a function of simulated environmental factors. The foodborne E. coli isolate used as donor carried a CTX-M-1 harboring IncI1 plasmid that confers resistance to beta-lactam antibiotics. Cell density, energy availability and growth rate were identified as factors that affect plasmid transfer efficiency. Transfer rates were highest in the absence of the antibiotic, with almost every acceptor cell picking up the plasmid. Raising the antibiotic concentrations above the minimum inhibitory concentration (MIC) resulted in reduced transfer rates, but also selected for the plasmid carrying donor and recombinant strains. Based on the mutational pattern of transconjugant cells, a common mechanism is proposed which compensates for fitness costs due to plasmid carriage by reducing other cell functions. Reducing potential fitness costs due to maintenance and expression of the plasmid could contribute to persistence of resistance genes in the environment even without antibiotic pressure. Taken together, the results identify factors that drive the spread and persistence of resistance conferring plasmids in natural isolates and shows how these can contribute to transmission of resistance genes through the food chain. PMID- 25830296 TI - Adverse Event Reporting in Clinical Trials of Finasteride for Androgenic Alopecia: A Meta-analysis. AB - IMPORTANCE: Two meta-analyses conclude that finasteride treatment of androgenic alopecia (AGA) is safe but do not assess quality of safety reporting. OBJECTIVE: To assess safety reporting for clinical trial reports of finasteride for AGA. DATA SOURCES: MEDLINE, ClinicalTrials.gov, and a clinical data repository for an academic medical center. STUDY SELECTION: Published clinical trial reports for finasteride treatment of AGA. DATA EXTRACTION AND SYNTHESIS: For each trial, we assessed quality of adverse event reporting, extracted the number and type of adverse events in treatment and placebo groups, and assessed duration of safety evaluation and adequacy of blinding. Two observers independently extracted the data; differences were resolved by consensus. We assessed generalizability in a large cohort of men prescribed finasteride, 1.25 mg/d or less, by assessing for eligibility in the finasteride-AGA pivotal trials. MAIN OUTCOMES AND MEASURES: Quality was assessed as adequate, partially adequate, inadequate, or no events reported. We used funnel plots of the hazard ratio to assess bias. RESULTS: Of 34 clinical trials, none had adequate safety reporting, 19 were partially adequate, 12 were inadequate, and 3 reported no adverse events. Funnel plots were asymmetric with a bias toward lower odds ratio for sexual adverse effects, suggesting systematic underdetection. No reports assessed adequacy of blinding, 18 (53%) disclosed conflicts of interest, and 19 (56%) received funding from the manufacturer. Duration of drug safety evaluation was 1 year or less for 26 of 34 trials (76%). Of 5704 men in the clinical data repository who were treated for AGA with finasteride, 1.25 mg/d or less, for AGA, only 31% met inclusion criteria for the pivotal trials referenced in the manufacturer's full prescribing information and 33% took finasteride for more than 1 year. CONCLUSIONS AND RELEVANCE: Available toxicity information from clinical trials of finasteride in men with AGA is very limited, is of poor quality, and seems to be systematically biased. In a cohort of men prescribed finasteride for routine treatment of AGA, most would have been excluded from the pivotal studies that supported US Food and Drug Administration approval for AGA. Published reports of clinical trials provide insufficient information to establish the safety profile for finasteride in the treatment of AGA. PMID- 25830295 TI - Systematic mutagenesis of genes encoding predicted autotransported proteins of Burkholderia pseudomallei identifies factors mediating virulence in mice, net intracellular replication and a novel protein conferring serum resistance. AB - Burkholderia pseudomallei is the causative agent of the severe tropical disease melioidosis, which commonly presents as sepsis. The B. pseudomallei K96243 genome encodes eleven predicted autotransporters, a diverse family of secreted and outer membrane proteins often associated with virulence. In a systematic study of these autotransporters, we constructed insertion mutants in each gene predicted to encode an autotransporter and assessed them for three pathogenesis-associated phenotypes: virulence in the BALB/c intra-peritoneal mouse melioidosis model, net intracellular replication in J774.2 murine macrophage-like cells and survival in 45% (v/v) normal human serum. From the complete repertoire of eleven autotransporter mutants, we identified eight mutants which exhibited an increase in median lethal dose of 1 to 2-log10 compared to the isogenic parent strain (bcaA, boaA, boaB, bpaA, bpaC, bpaE, bpaF and bimA). Four mutants, all demonstrating attenuation for virulence, exhibited reduced net intracellular replication in J774.2 macrophage-like cells (bimA, boaB, bpaC and bpaE). A single mutant (bpaC) was identified that exhibited significantly reduced serum survival compared to wild-type. The bpaC mutant, which demonstrated attenuation for virulence and net intracellular replication, was sensitive to complement-mediated killing via the classical and/or lectin pathway. Serum resistance was rescued by in trans complementation. Subsequently, we expressed recombinant proteins of the passenger domain of four predicted autotransporters representing each of the phenotypic groups identified: those attenuated for virulence (BcaA), those attenuated for virulence and net intracellular replication (BpaE), the BpaC mutant with defects in virulence, net intracellular replication and serum resistance and those displaying wild-type phenotypes (BatA). Only BcaA and BpaE elicited a strong IFN-gamma response in a restimulation assay using whole blood from seropositive donors and were recognised by seropositive human sera from the endemic area. To conclude, several predicted autotransporters contribute to B. pseudomallei virulence and BpaC may do so by conferring resistance against complement-mediated killing. PMID- 25830297 TI - Optimizing tuberculosis case detection through a novel diagnostic device placement model: the case of Uganda. AB - BACKGROUND: Xpert MTB/RIF (Xpert) is being widely adopted in high TB burden countries. Analysis is needed to guide the placement of devices within health systems to optimize the tuberculosis (TB) case detection rate (CDR). METHODS: We used epidemiological and operational data from Uganda (139 sites serving 87,600 individuals tested for TB) to perform a model-based comparison of the following placement strategies for Xpert devices: 1) Health center level (sites ranked by size from national referral hospitals to health care level III centers), 2) Smear volume (sites ranked from highest to lowest volume of smear microscopy testing), 3) Antiretroviral therapy (ART) volume (sites ranked from greatest to least patients on ART), 4) External equality assessment (EQA) performance (sites ranked from worst to best smear microscopy performance) and 5) TB prevalence (sites ranked from highest to lowest). We compared two clinical algorithms, one where Xpert was used only for smear microscopy negative samples versus another replacing smear microscopy. The primary outcome was TB CDR; secondary outcomes were detection of multi-drug resistant TB, number of sites requiring device placement to achieve specified rollout coverage, and cost. RESULTS: Placement strategies that prioritized sites with higher TB prevalence maximized CDR, with an incremental rate of 6.2-12.6% compared to status quo (microscopy alone). Diagnosis of MDR-TB was greatest in the TB Prevalence strategy when Xpert was used in place of smear microscopy. While initial implementation costs were lowest in the Smear Volume strategy, cost per additional TB case detected was lowest in the TB prevalence strategy. CONCLUSION: In Uganda, placement of Xpert devices in sites with high TB prevalence yielded the highest TB CDR at the lowest cost per additional case diagnosed. These results represent novel use of program level data to inform the optimal placement of new technology in resource-constrained settings. PMID- 25830298 TI - Modulation of recombinant antigenic constructs containing multi-epitopes towards effective reduction of atherosclerotic lesion in B6;129S Ldlr(tm1Her)Apob(tm2Sgy)/J mice. AB - Atherosclerosis is increasingly recognized as a complex chronic inflammatory disease. Many more studies have extended vaccination against atherosclerosis by using epitopes from self-antigens or beyond and demonstrated that vaccination with antigens or derivatives could reduce the extent of the lesions in atherosclerosis-prone mice. Our previous study has demonstrated that construct AHHC [ApoB100688-707 + hHSP60303-312 + hHSP60153-163 + Cpn derived peptide (C)] significantly reduced atherosclerotic lesion. The aim of this study was to investigate whether AHHC can be modulated towards increased lesion reduction in mice by creating two other derivatives with a sequential epitope-substitution named RHHC in which A was replaced by an "R" (C5aR1-31) and RPHC with a further "H" (hHSP60303-312) conversion into "P" (protease-activated receptor-142-55) in mice. Antigenic epitopes were incorporated into a dendroaspin scaffold. Immunization of B6;129S-Ldlrtm1HerApobtm2Sgy/J mice with three constructs elicited production of high levels of antibodies against each epitope (apart from hHSP60153-163 and P which induced a low antibody response). Histological analyses demonstrated that the mice immunized with either RPHC or RHHC showed significant reductions in the size of atherosclerostic lesions compared to those with AHHC (69.5+/-1.1% versus 55.7+/-3.4%, P<0.01 or 65.6+/-1.3% versus 55.7+/-3.4%, P<0.01). Reduction of plaque size in the aortic sinus and descending aorta correlated with alterations in cellular immune responses when compared with controls. We conclude that a recombinant construct RPHC may provide new antigenic and structural features which are favorable for significant reduction in atherosclerotic lesion formation. This approach offers a novel strategy for developing anti-atherosclerotic agents. PMID- 25830299 TI - Na+/H+ exchanger isoform 1 induced cardiomyocyte hypertrophy involves activation of p90 ribosomal s6 kinase. AB - Studies using pharmacological and genetic approaches have shown that increased activity/expression of the Na+/H+ exchanger isoform 1 (NHE1) play a critical role in the pathogenesis of cardiac hypertrophy. Despite the importance of NHE1 in cardiac hypertrophy, severe cerebrovascular side effects were associated with the use of NHE1 inhibitors when administered to patients with myocardial infarctions. p90 ribosomal S6 Kinase (RSK), a downstream regulator of the mitogen-activated protein kinase pathway, has also been implicated in cardiac hypertrophy. We hypothesized that RSK plays a role in the NHE1 induced cardiomyocyte hypertrophic response. Infection of H9c2 cardiomyoblasts with the active form of the NHE1 adenovirus induced hypertrophy and was associated with an increase in the phosphorylation of RSK (P<0.05). Parameters of hypertrophy such as cell area, protein content and atrial natriuretic mRNA expression were significantly reduced in H9c2 cardiomyoblasts infected with active NHE1 in the presence of dominant negative RSK (DN-RSK) (P<0.05). These results confirm that NHE1 lies upstream of RSK. Increased phosphorylation and activation of GATA4 at Ser261 was correlated with increased RSK phosphorylation. This increase was reversed upon inhibition of RSK or NHE1. These findings demonstrate for the first time that the NHE1 mediated hypertrophy is accounted for by increased activation and phosphorylation of RSK, which subsequently increased the phosphorylation of GATA4; eventually activating fetal gene transcriptional machinery. PMID- 25830301 TI - Free-Standing and Transparent Graphene Membrane of Polyhedron Box-Shaped Basic Building Units Directly Grown Using a NaCl Template for Flexible Transparent and Stretchable Solid-State Supercapacitors. AB - Transparency has never been integrated into freestanding flexible graphene paper (FF-GP), although FF-GP has been discussed extensively, because a thin transparent graphene sheet will fracture easily when the template or substrate is removed using traditional methods. Here, transparent FF-GP (FFT-GP) was developed using NaCl as the template and was applied in transparent and stretchable supercapacitors. The capacitance was improved by nearly 1000-fold compared with that of the laminated or wrinkled chemical vapor deposition graphene-film-based supercapacitors. PMID- 25830300 TI - Spatial fluctuations in expression of the heterocyst differentiation regulatory gene hetR in Anabaena filaments. AB - Under nitrogen deprivation, filaments of the cyanobacterium Anabaena undergo a process of development, resulting in a one-dimensional pattern of nitrogen-fixing heterocysts separated by about ten photosynthetic vegetative cells. Many aspects of gene expression before nitrogen deprivation and during the developmental process remain to be elucidated. Furthermore, the coupling of gene expression fluctuations between cells along a multicellular filament is unknown. We studied the statistics of fluctuations of gene expression of HetR, a transcription factor essential for heterocyst differentiation, both under steady-state growth in nitrogen-rich conditions and at different times following nitrogen deprivation, using a chromosomally-encoded translational hetR-gfp fusion. Statistical analysis of fluorescence at the individual cell level in wild-type and mutant filaments demonstrates that expression fluctuations of hetR in nearby cells are coupled, with a characteristic spatial range of circa two to three cells, setting the scale for cellular interactions along a filament. Correlations between cells predominantly arise from intercellular molecular transfer and less from cell division. Fluctuations after nitrogen step-down can build up on those under nitrogen-replete conditions. We found that under nitrogen-rich conditions, basal, steady-state expression of the HetR inhibitor PatS, cell-cell communication influenced by the septal protein SepJ and positive HetR auto-regulation are essential determinants of fluctuations in hetR expression and its distribution along filaments. A comparison between the expression of hetR-gfp under nitrogen rich and nitrogen-poor conditions highlights the differences between the two HetR inhibitors PatS and HetN, as well as the differences in specificity between the septal proteins SepJ and FraC/FraD. Activation, inhibition and cell-cell communication lie at the heart of developmental processes. Our results show that proteins involved in these basic ingredients combine together in the presence of inevitable stochasticity in gene expression, to control the coupled fluctuations of gene expression that give rise to a one-dimensional developmental pattern in this organism. PMID- 25830302 TI - Mulberry leaf polysaccharides modulate murine bone-marrow-derived dendritic cell maturation. AB - Various components of mulberry leaves, such as iminosugars, flavonoids and polysaccharides, have been reported to exert anti-diabetic activity. The purpose of our present study was to examine the modulating effect of mulberry leaf polysaccharides (MLPs) on murine bone-marrow-derived dendritic cells (BMDCs). The ultrastructure, phenotype and functional maturation of BMDCs were studied using transmission electron microscopy (TEM), flow cytometry (FCM), and tested for phagocytosis, acid phosphatase (ACP) activity using an enzyme linked immunosorbent assay (ELISA). Our results demonstrated that MLPs could markedly induce BMDC maturation by up-regulating the expression of membrane phenotypic markers, such as CD80, CD86, CD83,CD40, and MHC II, down-regulating phagocytosis and ACP activity, and by enhancing the production of interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) secreted by BMDCs. We therefore concluded that MLPs can positively modulate BMDCs. PMID- 25830303 TI - Trees grow on money: urban tree canopy cover and environmental justice. AB - This study examines the distributional equity of urban tree canopy (UTC) cover for Baltimore, MD, Los Angeles, CA, New York, NY, Philadelphia, PA, Raleigh, NC, Sacramento, CA, and Washington, D.C. using high spatial resolution land cover data and census data. Data are analyzed at the Census Block Group levels using Spearman's correlation, ordinary least squares regression (OLS), and a spatial autoregressive model (SAR). Across all cities there is a strong positive correlation between UTC cover and median household income. Negative correlations between race and UTC cover exist in bivariate models for some cities, but they are generally not observed using multivariate regressions that include additional variables on income, education, and housing age. SAR models result in higher r square values compared to the OLS models across all cities, suggesting that spatial autocorrelation is an important feature of our data. Similarities among cities can be found based on shared characteristics of climate, race/ethnicity, and size. Our findings suggest that a suite of variables, including income, contribute to the distribution of UTC cover. These findings can help target simultaneous strategies for UTC goals and environmental justice concerns. PMID- 25830304 TI - No dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or G2019S mutant LRRK2 and in human fibroblasts. AB - Mutations within the LRRK2 gene have been identified in Parkinson's disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel transgenic mouse model expressing physiological levels of human wild type and G2019S-mutant LRRK2. No neuronal loss or neurodegeneration was detected in midbrain dopamine neurons at the age of 12 months. Postnatal hippocampal neurons derived from transgenic mice showed no alterations in the seven parameters examined concerning neurite outgrowth sampled automatically on several hundred neurons using high content imaging. Treatment with the kinase inhibitor LRRK2-IN-1 resulted in no significant changes in the neurite outgrowth. In human fibroblasts we analyzed whether pathogenic LRRK2 mutations change cytoskeleton functions such as cell adhesion. To this end we compared the adhesion characteristics of human skin fibroblasts derived from six PD patients carrying one of three different pathogenic LRRK2 mutations and from four age-matched control individuals. The mutant LRRK2 variants as well as the inhibition of LRRK2 kinase activity did not reveal any significant cell adhesion differences in cultured fibroblasts. In summary, our results in both human and mouse cell systems suggest that neither the expression of wild type or mutant LRRK2, nor the inhibition of LRRK2 kinase activity affect neurite complexity and cellular adhesion. PMID- 25830306 TI - Correction: cardiac mechanics and ventricular twist by three-dimensional strain analysis in relation to B-type natriuretic Peptide as a clinical prognosticator for heart failure patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0115260.]. PMID- 25830305 TI - Analyses of the transcriptome and metabolome demonstrate that HIF1alpha mediates altered tumor metabolism in clear cell renal cell carcinoma. AB - Hypoxia inducible factor 1 alpha (HIF1alpha) is a transcription factor that is frequently stabilized and active in human clear cell renal cell carcinoma (ccRCC). We have found that constitutively active HIF1alpha is sufficient to cause neoplastic transformation in a murine model of ccRCC termed the TRACK model. RNA sequencing (RNAseq) and untargeted metabolomics analyses of samples from TRACK kidneys demonstrate that HIF1alpha activates the transcription of genes that cause increased glucose uptake, glycolysis, and lactate production, as well as a decrease in the flux of pyruvate entering the tricarboxylic acid (TCA) cycle and a decrease in oxidative phosphorylation; these changes are identical to those observed in human ccRCC samples. These studies show that a constitutively active HIF1alpha promotes tumorigenesis in TRACK mice by mediating a metabolic switch to aerobic glycolysis, i.e., the Warburg effect, and suggest that TRACK mice are a valid model to test novel therapies targeting metabolic changes to inhibit human ccRCC. PMID- 25830307 TI - Metabolic and cardiovascular complications in the liver transplant recipient. AB - Metabolic syndrome (MS) is an established risk factor for atherosclerosis and cardiovascular disease that affects 20-30% of the adult population in the western world, correlating with increased incidence of cardiovascular disease. Survival following liver transplantation (LT) has been steadily improving over the last 2 decades, with graft loss becoming a relatively rare cause of morbidity and mortality post LT. The improvement in short-term survival following LT has resulted in an increased incidence of metabolic and cardiovascular complications, which affect the mid- and long term survival. Patients following LT typically gain weight and might develop diabetes, hypertension and dyslipidemia as a consequence of their immunosuppressive therapy and their lifestyle. In this paper we review the prevalence of metabolic and cardiovascular complications following LT, their impact on post-transplant morbidity and mortality and their optimal management. PMID- 25830308 TI - Detrusor myocyte autophagy protects the bladder function via inhibiting the inflammation in cyclophosphamide-induced cystitis in rats. AB - Autophagy, a highly conserved homeostatic cellular process that removes and recycles damaged proteins and organelles in response to cellular stress, is believed to play a crucial role in the immune response and inflammation. The role of autophagy in bladder cystitis, however, has not well been clarified. Here we investigate the role of detrusor myocytes autophagy (DMA) in cyclophosphamide induced cystitis animal model. 164 female Sprague-Dawley rats were randomized into three experimental groups and compared to three control groups, respectively. The expressions of microtubule-associated protein 1 light chain 3 (LC3), p-p70s6k (the phosphorylated form of ribosomal protein S6), SOD2 (superoxide dismutase 2) in the bladder muscular layer were measured using western blot. The co-location of LC3, alpha-smooth muscle actin (alpha-SMA), and autophagic vacuoles were investigated with double-labeled immunofluorescence and transmission electron microscopy (TEM). The expression of lL-1beta, IL-6, IL-8, malondialdehyde (MDA), and glutathione (GSH) in the detrusor layer were analyzed using ELISA. The bladder inflammation and the number of mast cells in the muscular layer were analyzed by histology. The bladder function was evaluated using cystometry. In cyclophosphamide-induced cystitis, autophagy was detected in detrusor myocytes by increased LC3, p-p70s6k expression, and autophagosomes. However, the presence of enhanced inflammation and oxidative stress in the cyclophosphamide-treated group suggest autophagy of detrusor myocytes may not be sufficiently activated. Inflammation and oxidative stress were significantly decreased and the bladder histology and micturition function were significantly improved with rapamycin (RAPA, autophagy agonist) pre-treatment. In contrast, inflammation and oxidative stress were dramatically increased and the bladder histology and function were negatively affected with chloroquine (CQ, autophagy blocker) pre-treated. These findings preferentially provide evidence of the association between DMA and cyclophosphamide-induced cystitis in rats. The autophagy agonist RAPA significantly decreased the inflammation and protected the bladder function, which might be considered as a potential treatment for interstitial cystitis. PMID- 25830310 TI - The importance of population growth and regulation in human life history evolution. AB - Explaining the evolution of human life history traits remains an important challenge for evolutionary anthropologists. Progress is hindered by a poor appreciation of how demographic factors affect the action of natural selection. I review life history theory showing that the quantity maximized by selection depends on whether and how population growth is regulated. I show that the common use of R, a strategy's expected lifetime number of offspring, as a fitness maximand is only appropriate under a strict set of conditions, which are apparently unappreciated by anthropologists. To concretely show how demography free life history theory can lead to errors, I reanalyze an influential model of human life history evolution, which investigated the coevolution of a long lifespan and late age of maturity. I show that the model's conclusions do not hold under simple changes to the implicitly assumed mechanism of density dependence, even when stated assumptions remain unchanged. This analysis suggests that progress in human life history theory requires better understanding of the demography of our ancestors. PMID- 25830309 TI - The association of statin use after cancer diagnosis with survival in pancreatic cancer patients: a SEER-medicare analysis. AB - BACKGROUND: Pancreatic cancer has poor prognosis and existing interventions provide a modest benefit. Statin has anti-cancer properties that might enhance survival in pancreatic cancer patients. We sought to determine whether statin treatment after cancer diagnosis is associated with longer survival in those with pancreatic ductal adenocarcinoma (PDAC). METHODS: We analyzed data on 7813 elderly patients with PDAC using the linked Surveillance, Epidemiology, and End Results (SEER) - Medicare claims files. Information on the type, intensity and duration of statin use after cancer diagnosis was extracted from Medicare Part D. We treated statin as a time-dependent variable in a Cox regression model to determine the association with overall survival adjusting for follow-up, age, sex, race, neighborhood income, stage, grade, tumor size, pancreatectomy, chemotherapy, radiation, obesity, dyslipidemia, diabetes, chronic pancreatitis and chronic obstructive pulmonary disease (COPD). RESULTS: Overall, statin use after cancer diagnosis was not significantly associated with survival when all PDAC patients were considered (HR = 0.94, 95%CI 0.89, 1.01). However, statin use after cancer diagnosis was associated with a 21% reduced hazard of death (Hazard ratio = 0.79, 95% confidence interval (CI) 0.67, 0.93) in those with grade I or II PDAC and to a similar extent in those who had undergone a pancreatectomy, in those with chronic pancreatitis and in those who had not been treated with statin prior to cancer diagnosis. CONCLUSIONS: We found that statin treatment after cancer diagnosis is associated with enhanced survival in patients with low-grade, resectable PDAC. PMID- 25830311 TI - The repertoire of archaea cultivated from severe periodontitis. AB - In previous studies, the abundance and diversity of methanogenic archaea in the dental microbiota have been analysed by the detection of specific DNA sequences by PCR-based investigations and metagenomic studies. Few data issued regarding methanogens actually living in dental plaque. We collected dental plaque specimens in 15 control individuals and 65 periodontitis patients. Dental plaque specimens were cultured in an anoxic liquid medium for methanogens in the presence of negative control tubes. Dental plaque methanogens were cultured from 1/15 (6.67%) control and 36/65 (55.38%) periodontitis patient samples (p<0.001). The cultures yielded Methanobrevibacter oralis in one control and thirty-one patients, Methanobrevibacter smithii in two patients and a potential new species named Methanobrevibacter sp. strain N13 in three patients with severe periodontitis. Our observations of living methanogens, strengthen previous observations made on DNA-based studies regarding the role of methanogens, in periodontitis. PMID- 25830312 TI - Heroin use is associated with suppressed pro-inflammatory cytokine response after LPS exposure in HIV-infected individuals. AB - BACKGROUND: Opioid use is associated with increased incidence of infectious diseases. Although experimental studies have shown that opioids affect various functions of immune cells, only limited data are available from human studies. Drug use is an important risk factor for HIV transmission; however no data are available whether heroin and/or methadone modulate immune response. Therefore, we examined the effect of heroin and methadone use among HIV-infected individuals on the production of cytokines after ex vivo stimulation with various pathogens. METHODS: Treatment naive HIV-infected individuals from Indonesia were recruited. Several cohorts of individuals were recruited: 1) using heroin 2) receiving methadone opioid substitution 3) using heroin over 1 year ago and 4) controls (never used opioids). Whole blood was stimulated with Mycobacterium tuberculosis, Candida albicans and LPS for 24 to 48 hours. Cytokine production (IL-1 beta, IL 6, IL-10, IFN-alpha, IFN-gamma and TNF-alpha) was determined using multiplex beads assay. RESULTS: Among 82 individuals, the cytokine levels in unstimulated samples did not differ between groups. Overall, heroin users had significantly lower cytokine response after exposure to LPS (p<0.05). After stimulation with either M. tuberculosis or C. albicans the cytokine production of all groups were comparable. CONCLUSION: The cytokine production after exposure to LPS is significantly down-regulated in HIV-infected heroin users. Interesting, methadone use did not suppress cytokine response, which could have implications guidelines of opioid substitution. PMID- 25830315 TI - Market Performance and Food Safety Compliance for Small Food Businesses: The Case of Fifth Town Artisan Cheese. AB - Few studies have investigated how small businesses in the food sector cope with federally mandated recalls. The available literature is also unclear as to how small businesses, particularly those in food production with limited resources, manage with newly approved regulations, while working to achieve commercial success. The aim of this paper is to address this information gap through the exploration of how one firm coped with a situation that threatened its existence. This study will explore links between small firms, supply-chain resources for small food businesses and food safety regimes. This study is based on a recall experienced by an artisan cheese maker in Prince Edward County in Ontario, Canada, called Fifth Town Cheese (FTC). A conceptual framework was developed and results are presented. Finally, the paper concludes with theoretical and managerial implications, and presents avenues for future research. PMID- 25830313 TI - Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast. AB - Topoisomerase 1 (Top1), a Type IB topoisomerase, functions to relieve transcription- and replication-associated torsional stress in DNA. We investigated the effects of Top1 on genome stability in Saccharomyces cerevisiae using two different assays. First, a sectoring assay that detects loss of heterozygosity (LOH) on a specific chromosome was used to measure reciprocal crossover (RCO) rates. Features of individual RCO events were then molecularly characterized using chromosome-specific microarrays. In the second assay, cells were sub-cultured for 250 generations and LOH was examined genome-wide using microarrays. Though loss of Top1 did not destabilize single-copy genomic regions, RCO events were more complex than in a wild-type strain. In contrast to the stability of single-copy regions, sub-culturing experiments revealed that top1 mutants had greatly elevated levels of instability within the tandemly-repeated ribosomal RNA genes (in agreement with previous results). An intermediate in the enzymatic reaction catalyzed by Top1 is the covalent attachment of Top1 to the cleaved DNA. The resulting Top1 cleavage complex (Top1cc) is usually transient but can be stabilized by the drug camptothecin (CPT) or by the top1-T722A allele. We found that increased levels of the Top1cc resulted in a five- to ten-fold increase in RCOs and greatly increased instability within the rDNA and CUP1 tandem arrays. A detailed analysis of the events in strains with elevated levels of Top1cc suggests that recombinogenic DNA lesions are introduced during or after DNA synthesis. These results have important implications for understanding the effects of CPT as a chemotherapeutic agent. PMID- 25830314 TI - Honey glycoproteins containing antimicrobial peptides, Jelleins of the Major Royal Jelly Protein 1, are responsible for the cell wall lytic and bactericidal activities of honey. AB - We have recently identified the bacterial cell wall as the cellular target for honey antibacterial compounds; however, the chemical nature of these compounds remained to be elucidated. Using Concavalin A-affinity chromatography, we found that isolated glycoprotein fractions (glps), but not flow-through fractions, exhibited strong growth inhibitory and bactericidal properties. The glps possessed two distinct functionalities: (a) specific binding and agglutination of bacterial cells, but not rat erythrocytes and (b) non-specific membrane permeabilization of both bacterial cells and erythrocytes. The isolated glps induced concentration- and time-dependent changes in the cell shape of both E. coli and B. subtilis as visualized by light and SEM microscopy. The appearance of filaments and spheroplasts correlated with growth inhibition and bactericidal effects, respectively. The time-kill kinetics showed a rapid, >5-log10 reduction of viable cells within 15 min incubation at 1xMBC, indicating that the glps induced damage of the cell wall was lethal. Unexpectedly, MALDI-TOF and electrospray quadrupole time of flight mass spectrometry, (ESI-Q-TOF-MS/MS) analysis of glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. The presence of high-mannose structures explained the lectin-like activity of MRJP1, while the presence of Jelleins in MRJP1 may explain cell wall disruptions. Thus, the observed damages induced by the MRJP1 to the bacterial cell wall constitute the mechanism by which the antibacterial effects were produced. Antibacterial activity of MRJP1 glps directly correlated with the overall antibacterial activity of honey, suggesting that it is honey's active principle responsible for this activity. PMID- 25830317 TI - Correction: association of dietary factors with presence and severity of tinnitus in a middle-aged UK population. AB - [This corrects the article DOI: 10.1371/journal.pone.0114711.]. PMID- 25830316 TI - HCV genotyping from NGS short reads and its application in genotype detection from HCV mixed infected plasma. AB - Genotyping of hepatitis C virus (HCV) plays an important role in the treatment of HCV. As new genotype-specific treatment options become available, it has become increasingly important to have accurate HCV genotype and subtype information to ensure that the most appropriate treatment regimen is selected. Most current genotyping methods are unable to detect mixed genotypes from two or more HCV infections. Next generation sequencing (NGS) allows for rapid and low cost mass sequencing of viral genomes and provides an opportunity to probe the viral population from a single host. In this paper, the possibility of using short NGS reads for direct HCV genotyping without genome assembly was evaluated. We surveyed the publicly-available genetic content of three HCV drug target regions (NS3, NS5A, NS5B) in terms of whether these genes contained genotype-specific regions that could predict genotype. Six genotypes and 38 subtypes were included in this study. An automated phylogenetic analysis based HCV genotyping method was implemented and used to assess different HCV target gene regions. Candidate regions of 250-bp each were found for all three genes that have enough genetic information to predict HCV genotypes/subtypes. Validation using public datasets shows 100% genotyping accuracy. To test whether these 250-bp regions were sufficient to identify mixed genotypes, we developed a random primer-based method to sequence HCV plasma samples containing mixtures of two HCV genotypes in different ratios. We were able to determine the genotypes without ambiguity and to quantify the ratio of the abundances of the mixed genotypes in the samples. These data provide a proof-of-concept that this random primed, NGS-based short read genotyping approach does not need prior information about the viral population and is capable of detecting mixed viral infection. PMID- 25830318 TI - Neurodevelopmental disorders and agricultural pesticide exposures: Shelton and Hertz-Picciotto respond. PMID- 25830321 TI - Cell-free DNA analysis for noninvasive examination of trisomy. AB - BACKGROUND: Cell-free DNA (cfDNA) testing for fetal trisomy is highly effective among high-risk women. However, there have been few direct, well-powered studies comparing cfDNA testing with standard screening during the first trimester in routine prenatal populations. METHODS: In this prospective, multicenter, blinded study conducted at 35 international centers, we assigned pregnant women presenting for aneuploidy screening at 10 to 14 weeks of gestation to undergo both standard screening (with measurement of nuchal translucency and biochemical analytes) and cfDNA testing. Participants received the results of standard screening; the results of cfDNA testing were blinded. Determination of the birth outcome was based on diagnostic genetic testing or newborn examination. The primary outcome was the area under the receiver-operating-characteristic curve (AUC) for trisomy 21 (Down's syndrome) with cfDNA testing versus standard screening. We also evaluated cfDNA testing and standard screening to assess the risk of trisomies 18 and 13. RESULTS: Of 18,955 women who were enrolled, results from 15,841 were available for analysis. The mean maternal age was 30.7 years, and the mean gestational age at testing was 12.5 weeks. The AUC for trisomy 21 was 0.999 for cfDNA testing and 0.958 for standard screening (P=0.001). Trisomy 21 was detected in 38 of 38 women (100%; 95% confidence interval [CI], 90.7 to 100) in the cfDNA-testing group, as compared with 30 of 38 women (78.9%; 95% CI, 62.7 to 90.4) in the standard-screening group (P=0.008). False positive rates were 0.06% (95% CI, 0.03 to 0.11) in the cfDNA group and 5.4% (95% CI, 5.1 to 5.8) in the standard-screening group (P<0.001). The positive predictive value for cfDNA testing was 80.9% (95% CI, 66.7 to 90.9), as compared with 3.4% (95% CI, 2.3 to 4.8) for standard screening (P<0.001). CONCLUSIONS: In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes. (Funded by Ariosa Diagnostics and Perinatal Quality Foundation; NEXT ClinicalTrials.gov number, NCT01511458.). PMID- 25830320 TI - Screening of the Pan-African natural product library identifies ixoratannin A-2 and boldine as novel HIV-1 inhibitors. AB - The continued burden of HIV in resource-limited regions such as parts of sub Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world. PMID- 25830324 TI - Use of cell-free DNA to screen for Down's syndrome. PMID- 25830323 TI - Copy-number variation and false positive prenatal aneuploidy screening results. AB - Investigations of noninvasive prenatal screening for aneuploidy by analysis of circulating cell-free DNA (cfDNA) have shown high sensitivity and specificity in both high-risk and low-risk cohorts. However, the overall low incidence of aneuploidy limits the positive predictive value of these tests. Currently, the causes of false positive results are poorly understood. We investigated four pregnancies with discordant prenatal test results and found in two cases that maternal duplications on chromosome 18 were the likely cause of the discordant results. Modeling based on population-level copy-number variation supports the possibility that some false positive results of noninvasive prenatal screening may be attributable to large maternal copy-number variants. (Funded by the National Institutes of Health and others.). PMID- 25830325 TI - Accurate description of DNA-based noninvasive prenatal screening. PMID- 25830322 TI - A Recombinant Vesicular Stomatitis Virus Ebola Vaccine. AB - BACKGROUND: The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. METHODS: We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. RESULTS: The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. CONCLUSIONS: This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV?G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .). PMID- 25830328 TI - Correction: Fc receptors for immunoglobulins and their appearance during vertebrate evolution. PMID- 25830327 TI - Leisure-Time Physical Activity Does not Attenuate the Association Between Occupational Sedentary Behavior and Obesity: Results From Alberta's Tomorrow Project. AB - BACKGROUND: Sedentary behavior has been proposed as a risk factor for obesity that is distinct from physical inactivity. This study aimed to examine the association between occupational sedentary behavior and obesity, and to determine if this association is independent of leisure-time physical activity (LTPA). METHODS: Fully employed participants enrolled between 2001 and 2008 to Alberta's Tomorrow Project, a prospective cohort study in Alberta, Canada, were studied (n = 12,409). Associations between occupational sedentary behavior and waist circumference (WC), waist-to-hip ratio (WHR), and body mass index (BMI) were examined using multiple binary and multinomial logistic regressions. RESULTS: In men, a positive association was observed between daily occupational sedentary hours and WC, WHR, BMI, and with high risk profiles that incorporated both BMI and WC (P < .01). Controlling for vigorous-intensity LTPA in all models strengthened associations between sedentary behavior and measures of obesity. In contrast, inverse associations were observed for occupational sedentary hours and WHR for women (P < .05). CONCLUSIONS: In fully employed men, occupational sedentary behavior was positively associated with obesity risk that was not attenuated by physical activity. In women, an increase in obesity risk was not observed with sedentary behavior. Gender differences in the health effects of sedentary behavior require further study. PMID- 25830329 TI - Modification of nitrate uptake pathway in plants affects the cadmium uptake by roots. AB - NRT1.1 is a dual-affinity nitrate (NO3(-)) transporter involved in both high- and low-affinity NO3(-) uptake in Arabidopsis plants. In a recent study, we showed that, under cadmium (Cd) exposure, blocking the NRT1.1-mediated NO3(-) uptake reduces Cd entry into roots, thus lowing Cd levels in plants and improving plant growth. In addition, we also found that the Cd levels in edible parts of 11 Chinese cabbage (Brassica rapa L. ssp. pekinensis) cultivars correlated well with the NO3(-) uptake rates of their roots. These results suggested that the NO3(-) uptake of roots negatively regulate Cd uptake. Modification of NO3(-) uptake in crops by modulating NO3(-) uptake pathway might provide a biological engineering approach to reducing Cd accumulation in edible organs, thus improving food safety. PMID- 25830326 TI - Phase 1 Trials of rVSV Ebola Vaccine in Africa and Europe. AB - BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.). PMID- 25830330 TI - Selection of reference genes for transcriptional analysis of edible tubers of potato (Solanum tuberosum L.). AB - Potato (Solanum tuberosum) yield has increased dramatically over the last 50 years and this has been achieved by a combination of improved agronomy and biotechnology efforts. Gene studies are taking place to improve new qualities and develop new cultivars. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) is a bench-marking analytical tool for gene expression analysis, but its accuracy is highly dependent on a reliable normalization strategy of an invariant reference genes. For this reason, the goal of this work was to select and validate reference genes for transcriptional analysis of edible tubers of potato. To do so, RT-qPCR primers were designed for ten genes with relatively stable expression in potato tubers as observed in RNA-Seq experiments. Primers were designed across exon boundaries to avoid genomic DNA contamination. Differences were observed in the ranking of candidate genes identified by geNorm, NormFinder and BestKeeper algorithms. The ranks determined by geNorm and NormFinder were very similar and for all samples the most stable candidates were C2, exocyst complex component sec3 (SEC3) and ATCUL3/ATCUL3A/CUL3/CUL3A (CUL3A). According to BestKeeper, the importin alpha and ubiquitin-associated/ts-n genes were the most stable. Three genes were selected as reference genes for potato edible tubers in RT-qPCR studies. The first one, called C2, was selected in common by NormFinder and geNorm, the second one is SEC3, selected by NormFinder, and the third one is CUL3A, selected by geNorm. Appropriate reference genes identified in this work will help to improve the accuracy of gene expression quantification analyses by taking into account differences that may be observed in RNA quality or reverse transcription efficiency across the samples. PMID- 25830331 TI - Whole-genome optical mapping and finished genome sequence of Sphingobacterium deserti sp. nov., a new species isolated from the Western Desert of China. AB - A novel Gram-negative bacterium, designated ZWT, was isolated from a soil sample of the Western Desert of China, and its phenotypic properties and phylogenetic position were investigated using a polyphasic approach. Growth occurred on TGY medium at 5-42 degrees C with an optimum of 30 degrees C, and at pH 7.0-11.0 with an optimum of pH 9.0. The predominant cellular fatty acids were summed feature 3 (C16:1omega7c/C16:1omega6c or C16:1omega6c/C16:1omega7c) (39.22%), iso-C15:0 (27.91%), iso-C17:0 3OH (15.21%), C16:0 (4.98%), iso-C15:0 3OH (3.03%), C16:0 3OH (5.39%) and C14:0 (1.74%). The major polar lipid of strain ZWT is phosphatidylethanolamine. The only menaquinone observed was MK-7. The GC content of the DNA of strain ZWT is 44.9 mol%. rDNA phylogeny, genome relatedness and chemotaxonomic characteristics all indicate that strain ZWT represents a novel species of the genus Sphingobacterium. We propose the name S. deserti sp. nov., with ZWT (= KCTC 32092T = ACCC 05744T) as the type strain. Whole genome optical mapping and next-generation sequencing was used to derive a finished genome sequence for strain ZWT, consisting of a circular chromosome of 4,615,818 bp in size. The genome of strain ZWT features 3,391 protein-encoding and 48 tRNA encoding genes. Comparison of the predicted proteome of ZWT with those of other sphingobacteria identified 925 species-unique proteins that may contribute to the adaptation of ZWT to its native, extremely arid and inhospitable environment. As the first finished genome sequence for any Sphingobacterium, our work will serve as a useful reference for subsequent sequencing and mapping efforts for additional strains and species within this genus. PMID- 25830332 TI - Notch1 is pan-endothelial at the onset of flow and regulated by flow. AB - Arteriovenous differentiation is a key event during vascular development and hemodynamic forces play an important role. Arteriovenous gene expression is present before the onset of flow, however it remains plastic and flow can alter arteriovenous identity. Notch signaling is especially important in the genetic determination of arteriovenous identity. Nevertheless, the effect of the onset of circulation on Notch expression and signaling has not been studied. The aim of this study is therefore to investigate the interaction of Notch1 signaling and hemodynamic forces during early vascular development. We find that the onset of Notch1 expression coincides with the onset of flow, and that expression is pan endothelial at the onset of circulation in mouse embryos and only becomes arterial-specific after remodeling has occurred. When we ablate flow in the early embryo, endothelial cells fail to express Notch1. We show that low and disturbed flow patterns upregulate Notch1 expression in endothelial cells in vitro, but that higher shear stress levels do not (>=10 dynes/cm2). Using siRNA, we knocked down Notch1 to investigate the role of Notch1 in mechanotransduction. When we applied shear stress levels similar to those found in embryonic arteries, we found an upregulation of Klf2, Dll1, Dll4, Jag1, Hey1, Nrp1 and CoupTFII but that only Dll4, Hey1, Nrp1 and EphB4 required Notch1 for flow-induced expression. Our results therefore indicate that Notch1 can modulate mechanotransduction but is not a critical mediator of the process since many genes mechanotransduce normally in the absence of Notch1, including genes involved in arteriovenous differentiation. PMID- 25830333 TI - Behavioural differences between single scandinavian brown bears (Ursus arctos) and females with dependent young when experimentally approached by humans. AB - Carnivore-human encounters that result in human injury present a conservation and management challenge and it is therefore important to understand under what conditions such incidents occur. Females with cubs are often involved when humans are injured by brown bears Ursus arctos. In Scandinavia, this is particularly true for unarmed recreational forest users. Our aim was to document behavioural differences between single bears and females with cubs in order to develop recommendations to minimize the risk of injuries to recreational forest users. We documented the reactions of GPS-collared females with cubs and single brown bears to experimental approaches by humans to 50 m from the bear on 42 and 108 occasions, respectively. The majority of females with cubs (95%) and single bears (89%) left when approached. Bears that left were passed at shorter distances and were in more open areas than those that stayed. Both groups had similar flight initiation distances, which were longer for bears that were active at the time of the disturbance. Females with cubs selected more open habitat than single bears, also for the new site they selected following disturbance. Females with cubs, particularly active females with cubs of the year, moved greater distances and spent more time active following the approach. Females with cubs and single bears were seen or heard in 26% and 14% of the approaches, respectively. None of the bears displayed any aggressive behaviour during the approaches. Females with cubs selected more open habitat, perhaps predisposing them to encountering people that are not involved in hunting activities, which might be the primary explanation why females with cubs are most frequently involved when unarmed people are injured by bears in Scandinavia. To mitigate injury risks, one must consider factors that bring bears closer to human activity in the first place. PMID- 25830336 TI - The effect of mixing entire male pigs prior to transport to slaughter on behaviour, welfare and carcass lesions. AB - Research is needed to validate lesions recorded at meat inspection as indicators of pig welfare on farm. The aims were to determine the influence of mixing pigs on carcass lesions and to establish whether such lesions correlate with pig behaviour and lesions scored on farm. Aggressive and mounting behaviour of pigs in three single sex pens was recorded on Day -5, -2, and -1 relative to slaughter (Day 0). On Day 0 pigs were randomly allocated to 3 treatments (n = 20/group) over 5 replicates: males mixed with females (MF), males mixed with males (MM), and males unmixed (MUM). Aggressive and mounting behaviours were recorded on Day 0 at holding on farm and lairage. Skin/tail lesions were scored according to severity at the farm (Day -1), lairage, and on the carcass (Day 0). Effect of treatment and time on behaviour and lesions were analysed by mixed models. Spearman rank correlations between behaviour and lesion scores and between scores recorded at different stages were determined. In general, MM performed more aggressive behaviour (50.4 +/- 10.72) than MUM (20.3 +/- 9.55, P < 0.05) and more mounting (30.9 +/- 9.99) than MF (11.4 +/- 3.76) and MUM (9.8 +/- 3.74, P < 0.05). Skin lesion scores increased between farm (Day -1) and lairage (P < 0.001), but this tended to be significant only for MF and MM (P = 0.08). There was no effect of treatment on carcass lesions and no associations were found with fighting/mounting. Mixing entire males prior to slaughter stimulated mounting and aggressive behaviour but did not influence carcass lesion scores. Carcass skin/tail lesions scores were correlated with scores recorded on farm (rskin = 0.21 and rtail = 0.18, P < 0.01) suggesting that information recorded at meat inspection could be used as indicators of pig welfare on farm. PMID- 25830335 TI - A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. AB - Aging is the most significant risk factor for a range of diseases, including many cancers, neurodegeneration, cardiovascular disease, and diabetes. Caloric restriction (CR) without malnutrition delays aging in diverse species, and therefore offers unique insights into age-related disease vulnerability. Previous studies suggest that there are shared mechanisms of disease resistance associated with delayed aging, however quantitative support is lacking. We therefore sought to identify a common response to CR in diverse tissues and species and determine whether this signature would reflect health status independent of aging. We analyzed gene expression datasets from eight tissues of mice subjected to CR and identified a common transcriptional signature that includes functional categories of mitochondrial energy metabolism, inflammation and ribosomal structure. This signature is detected in flies, rats, and rhesus monkeys on CR, indicating aspects of CR that are evolutionarily conserved. Detection of the signature in mouse genetic models of slowed aging indicates that it is not unique to CR but rather a common aspect of extended longevity. Mice lacking the NAD-dependent deacetylase SIRT3 fail to induce mitochondrial and anti-inflammatory elements of the signature in response to CR, suggesting a potential mechanism involving SIRT3. The inverse of this transcriptional signature is detected with consumption of a high fat diet, obesity and metabolic disease, and is reversed in response to interventions that decrease disease risk. We propose that this evolutionarily conserved, tissue-independent, transcriptional signature of delayed aging and reduced disease vulnerability is a promising target for developing therapies for age-related diseases. PMID- 25830338 TI - Correction: experiential thinking in creationism-a textual analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0118314.]. PMID- 25830337 TI - Serving first in isolation increases vegetable intake among elementary schoolchildren. AB - Many people want to eat healthier, but they often fail in these attempts. We report two field studies in an elementary school cafeteria that each demonstrate children eat more of a vegetable (carrots, broccoli) when we provide it first in isolation versus alongside other more preferred foods. We propose this healthy first approach succeeds by triggering one's inherent motivation to eat a single food placed in front of them, and works even though they have prior knowledge of the full menu available and no real time constraints. Consistent with this theory, and counter to simple contrast effects, an additional lab study found that presenting a food first in isolation had the unique ability to increase intake whether the food was healthy (carrots) or less healthy (M&M's). Our findings demonstrate the effectiveness of this simple intervention in promoting healthier eating, which should interest consumers, food marketers, health professionals, and policy makers. PMID- 25830339 TI - Antiviral Effect of Interferon Lambda Against Lymphocytic Choriomeningitis Virus. AB - Lambda interferons inhibit replication of many viruses, but their role in the inhibition of lymphocytic choriomeningitis virus (LCMV) infection remains unclear. In this study, we examined the antiviral effects of interferon (IFN) lambda2 and IFN-lambda3 against LCMV in A549 cells. We found that IFN-lambda2 is a more potent inhibitor of LCMV strain MX compared with IFN-lambda3, whereas both cytokines have similar antiviral effects against an immunosuppressive variant of LCMV, clone-13. We also demonstrated that the antiviral activity of IFN-lambda2 is more effective if it is delivered early rather than after establishment of a long-term infection, suggesting that virus replication is only partially responsive to the cytokine. In agreement with this observation, we showed that LCMV infection significantly reduces IFNLR1 mRNA expression in infected cells. In addition, LCMV infection, to some extent, compromises the signal transduction pathway of IFN-lambda2. This implies that IFN receptors as well as their downstream signaling components could be selectively targeted either directly by LCMV proteins or indirectly by cellular factor(s) that are induced or activated by LCMV infection. PMID- 25830340 TI - Invariant NKT cells act as an adjuvant to enhance Th2 inflammatory response in an OVA-induced mouse model of asthma. AB - BACKGROUND: Invariant natural killer T cells (iNKT cells) are a unique subset of T lymphocytes and are considered to play an important role in the development of allergic bronchial asthma. Recently, iNKT cells were shown to play an immunoregulatory role in CD4+ and CD8+ T cell-mediated adaptive immune response. Allergen-specific Th2 inflammatory responses are an important part of the adaptive immune response in asthma. However, the regulatory functions of the Th2 inflammatory response in asthma have not been studied in detail. METHOD: In this study, we have investigated the regulatory functions of iNKT cells on the Th2 inflammatory response in an ovalbumin (OVA)-induced murine model of asthma. RESULTS: Our results demonstrate that alpha-Galactosylceramide (alpha-GalCer) administration activated iNKT cells but could not induce the Th2 inflammatory response in wild-type (WT) mice. In the OVA-induced asthma model, alpha-GalCer administration and adoptive transfer of iNKT cells significantly augmented the Th2 inflammatory responses, including elevated inflammatory cell infiltration in the lung and bronchoalveolar lavage fluid (BALF); increased levels of IL-4, IL-5, and IL-13 in the BALF and splenocyte culture supernatant; and increased serum levels of OVA-specific IgE and IgG1. In addition, the Th2 inflammatory response was reduced, but not completely abrogated in CD1d-/- mice immunized and challenged with OVA, compared with WT mice. CONCLUSION: These results suggest that iNKT cells may serve as an adjuvant to enhance Th2 inflammatory response in an OVA-induced murine model of asthma. PMID- 25830341 TI - CAPER is vital for energy and redox homeostasis by integrating glucose-induced mitochondrial functions via ERR-alpha-Gabpa and stress-induced adaptive responses via NF-kappaB-cMYC. AB - Ever since we developed mitochondria to generate ATP, eukaryotes required intimate mito-nuclear communication. In addition, since reactive oxygen species are a cost of mitochondrial oxidative phosphorylation, this demands safeguards as protection from these harmful byproducts. Here we identified a critical transcriptional integrator which eukaryotes share to orchestrate both nutrient induced mitochondrial energy metabolism and stress-induced nuclear responses, thereby maintaining carbon-nitrogen balance, and preserving life span and reproductive capacity. Inhibition of nutrient-induced expression of CAPER arrests nutrient-dependent cell proliferation and ATP generation and induces autophagy mediated vacuolization. Nutrient signaling to CAPER induces mitochondrial transcription and glucose-dependent mitochondrial respiration via coactivation of nuclear receptor ERR-alpha-mediated Gabpa transcription. CAPER is also a coactivator for NF-kappaB that directly regulates c-Myc to coordinate nuclear transcriptome responses to mitochondrial stress. Finally, CAPER is responsible for anaplerotic carbon flux into TCA cycles from glycolysis, amino acids and fatty acids in order to maintain cellular energy metabolism to counter mitochondrial stress. Collectively, our studies reveal CAPER as an evolutionarily conserved 'master' regulatory mechanism by which eukaryotic cells control vital homeostasis for both ATP and antioxidants via CAPER-dependent coordinated control of nuclear and mitochondrial transcriptomic programs and their metabolisms. These CAPER dependent bioenergetic programs are highly conserved, as we demonstrated that they are essential to preserving life span and reproductive capacity in human cells-and even in C. elegans. PMID- 25830343 TI - Indications for Fetal Invasive Procedures at the End of an Era. AB - Purpose The introduction of first trimester screening has changed the attitude towards and the number of invasive procedures in prenatal medicine. We evaluated the indications in patients who underwent an invasive procedure before the introduction of the analysis of cell-free fetal DNA in maternal plasma in prenatal medicine. Materials and Methods 680 pregnant women between the 10th and 35th week of gestation were included in the study from July 1, 2010 to June 30, 2013. Retrospectively, we reviewed the data for indications, type, gestational age at the time of, and result of the invasive procedure. Results We performed 247 chorionic villus samplings (CVSs) and 433 amniocenteses (ACs) during the study interval. The main indication for CVS was an abnormal result from the first trimester screening (75 %), whereas in AC it was advanced maternal age (39 %). 33 % of all CVSs and 8 % of all ACs revealed an abnormal karyotype. All these findings were significantly different. Conclusion Despite the broad acceptance of first trimester screening, there are still women undergoing AC for advanced maternal age, whereas abnormal results from the first trimester screening are the most common indication for CVS. Based on our results, we can conclude that indications derived from first trimester findings have the highest positive predictive value. PMID- 25830344 TI - Ultrasound Evaluation of Carotid Atherosclerosis in Post-Radiotherapy Nasopharyngeal Carcinoma Patients, Type 2 Diabetics, and Healthy Controls. AB - Purpose To comprehensively evaluate and compare the degree of carotid atherosclerosis in patients treated with radiotherapy (RT) for nasopharyngeal carcinoma (NPC) and in patients with type 2 diabetes mellitus (DM), and using healthy subjects as controls. Materials and Methods The present study recruited 69 post-RT NPC patients without conventional cardiovascular risk factors, 70 type 2 diabetic patients without previous RT, and 76 healthy controls without conventional cardiovascular risk factors and previous RT. For each participant, 5 carotid atherosclerotic parameters, namely carotid intima-media thickness (CIMT), carotid arterial stiffness (CAS), presence of carotid plaque, carotid plaque score, and presence of >= 50 % carotid stenosis, were assessed using ultrasonography. The differences in these carotid atherosclerotic parameters between study groups were compared using ANCOVA or logistic regression after the adjustment for age and gender. Multiple comparisons were corrected using the Benjamini-Hochberg false discovery rate. Results Post-RT NPC patients and type 2 diabetics had a significantly higher CIMT, CAS and carotid plaque burden compared to the healthy subjects (corrected P-value, Pcor < 0.05). In addition, carotid atherosclerosis in post-RT NPC patients tended to be more severe with significantly higher CAS and carotid plaque burden than that in type 2 diabetics (Pcor < 0.05). Conclusion Neck RT for NPC is an independent risk factor of carotid atherosclerosis, and radiation induces more severe carotid atherosclerosis in post-RT NPC patients. Thus, assessment of carotid atherosclerosis using ultrasonography may be necessary for these patients and should be indicated in the routine follow-up of NPC. PMID- 25830345 TI - Complexity and health functionality of plant cell wall fibers from fruits and vegetables. AB - The prevalence of lifestyle-related diseases is increasing in developing countries with the causes for death starting to follow the same pattern in the developed world. Lifestyle factors including inadequate dietary intake of fruits and vegetables and over consumption of nutrient-poor processed foods, are considered to be major causal risk factors associated with increased susceptibility to developing certain diseases (Alldrick, 1998 ; Kiani, 2007 ). Recent epidemiological evidence confirms a strong association between dietary fiber and reduced all-cause mortality risk, as well as a risk reduction for a number of non-communicable diseases (Chuang et al., 2012 ). The relationship between dietary fiber and mortality has been described as "convincing observations that call for mechanistic investigations" (Landberg, 2012 ). In particular, the health protective roles played by dietary fibers of different origin are not well understood. Whilst Hippocrates was the earliest known physician to study the health benefits of fiber derived from grains (Burkitt, 1987 ), the functionality of fruit and vegetable fiber, especially in association with other compounds such as polyphenols and carotenoids, is an area of more recent interest. Hence the objective of this review is to assess the complexity and health-related functional role of plant cell wall (PCW) fibers from fruits and vegetables with a particular emphasis on interactions between cell walls and phytonutrients. PMID- 25830342 TI - Effects of lifestyle interventions that include a physical activity component in class II and III obese individuals: a systematic review and meta-analysis. AB - BACKGROUND: In class II and III obese individuals, lifestyle intervention is the first step to achieve weight loss and treat obesity-related comorbidities before considering bariatric surgery. A systematic review, meta-analysis, and meta regression were performed to assess the impact of lifestyle interventions incorporating a physical activity (PA) component on health outcomes of class II and III obese individuals. METHODS: An electronic search was conducted in 4 databases (Medline, Scopus, CINAHL and Sportdiscus). Two independent investigators selected original studies assessing the impact of lifestyle interventions with PA components on anthropometric parameters, cardiometabolic risk factors (fat mass, blood pressure, lipid and glucose metabolism), behaviour modification (PA and nutritional changes), and quality of life in adults with body mass index (BMI) >= 35 kg/m2. Estimates were pooled using a random-effect model (DerSimonian and Laird method). Heterogeneity between studies was assessed by the Cochran's chi-square test and quantified through an estimation of the I2. RESULTS: Of the 3,170 identified articles, 56 met our eligibility criteria, with a large majority of uncontrolled studies (80%). The meta-analysis based on uncontrolled studies showed significant heterogeneity among all included studies. The pooled mean difference in weight loss was 8.9 kg (95% CI, 10.2-7.7; p < 0.01) and 2.8 kg/m2 in BMI loss (95% CI, 3.4-2.2; p < 0.01). Long-term interventions produced superior weight loss (11.3 kg) compared to short-term (7.2 kg) and intermediate-term (8.0 kg) interventions. A significant global effect of lifestyle intervention on fat mass, waist circumference, blood pressure, total cholesterol, LDL-C, triglycerides and fasting insulin was found (p<0.01), without significant effect on HDL-C and fasting blood glucose. CONCLUSIONS: Lifestyle interventions incorporating a PA component can improve weight and various cardiometabolic risk factors in class II and III obese individuals. However, further high quality trials are needed to confirm this evidence, especially beyond weight loss. PMID- 25830346 TI - Increasing 3D Supramolecular Order by Decreasing Molecular Order. A Comparative Study of Helical Assemblies of Dendronized Nonchlorinated and Tetrachlorinated Perylene Bisimides. AB - A nonplanar, twisted, and flexible tetrachlorinated perylene bisimide (Cl4PBI) was functionalized with two AB3 minidendrons containing hydrogenated or semifluorinated dodecyl groups. The hydrogenated dendron was attached to the imide groups of Cl4PBI via m = 0, 1, and 2 methylenic units, whereas the dendron containing semifluorinated groups was attached via m = 3 or a di(ethylene oxide) linker (m = 2EO). The supramolecular structures of these compounds, determined by a combination of differential scanning calorimetry, X-ray diffraction, and solid state NMR, were compared with those of nonchlorinated planar and rigid PBI reported previously, which demonstrated the thermodynamically controlled formation of 2D periodic arrays at high temperatures and 3D arrays at low temperatures. The molecularly less ordered Cl4PBI containing hydrogenated dendrons self-organize into exclusively 3D crystalline periodic arrays under thermodynamic control for m = 0 and 2, while the more highly molecularly ordered PBI produced less stable and ordered 3D crystals and also 2D assemblies. This induction of a higher degree of 3D order in supramolecular assemblies of the less well-ordered molecular building blocks was unanticipated. The semifluorinated dendronized Cl4PBI with m = 3 formed a 2D columnar hexagonal array under kinetic control, whereas the compound with m = 2EO formed an unusual 2D honeycomb-like hexagonal phase under thermodynamic control. These Cl4PBI compounds provide a new route to stable crystalline assemblies via thermodynamic control at lower temperatures than previously obtained with PBI, thus generating 3D order in an accessible range of temperature of interest for structural analysis and for technological applications. PMID- 25830348 TI - The Institute of Medicine Report on Graduate Medical Education Funding: Implications for Surgical Training. PMID- 25830347 TI - Pharmacological inhibition of FTO. AB - In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO's demethylase activity could be therapeutically useful for the treatment of obesity. PMID- 25830349 TI - An improved perforator-based island flap: the heart balloon flap. AB - BACKGROUND: Reconstructive surgery has entered a "perforator flap era" with more surgeons performing successful perforator flap procedures. The perforator-based island flap is an extension of this perforator concept and one of the most successful. In perforator-rich or -reliable areas, this allows for primary closure of the donor site and the construction of highly customized flaps with little tissue waste. METHODS: The authors present a design modification of the perforator-based island flap used in 73 patients who underwent heart balloon perforator-based island flap reconstruction between 2008 and 2012. RESULTS: There were no reported cases of total flap necrosis. Marginal necrosis of the flap was noted in three cases, which resolved with simple dressings. The donor sites were closed primarily in all cases. CONCLUSIONS: The heart balloon perforator-based island flap enables tension-free closure of the donor site, reduces donor-site complications, and minimizes tissue waste. The resulting shape resembles a heart and gives rise to the flap's name. Key principles for success are perforators close to the defect, a flap axis that allows for primary donor-site closure, flap border adjacent to the defect that is smaller than the postresection defect, flap harvest until an adequate arc of rotation is obtained, primary closure of the donor site before flap inset, and preservation of a triangular area between the proximal apex of the flap and the defect. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25830350 TI - Peach water relations, gas exchange, growth and shoot mortality under water deficit in semi-arid weather conditions. AB - In this study the sensitivity of peach tree (Prunus persica L.) to three water stress levels from mid-pit hardening until harvest was assessed. Seasonal patterns of shoot and fruit growth, gas exchange (leaf photosynthesis, stomatal conductance and transpiration) as well as carbon (C) storage/mobilization were evaluated in relation to plant water status. A simple C balance model was also developed to investigate sink-source relationship in relation to plant water status at the tree level. The C source was estimated through the leaf area dynamics and leaf photosynthesis rate along the season. The C sink was estimated for maintenance respiration and growth of shoots and fruits. Water stress significantly reduced gas exchange, and fruit, and shoot growth, but increased fruit dry matter concentration. Growth was more affected by water deficit than photosynthesis, and shoot growth was more sensitive to water deficit than fruit growth. Reduction of shoot growth was associated with a decrease of shoot elongation, emergence, and high shoot mortality. Water scarcity affected tree C assimilation due to two interacting factors: (i) reduction in leaf photosynthesis (-23% and -50% under moderate (MS) and severe (SS) water stress compared to low (LS) stress during growth season) and (ii) reduction in total leaf area (-57% and -79% under MS and SS compared to LS at harvest). Our field data analysis suggested a Psistem threshold of -1.5 MPa below which daily net C gain became negative, i.e. C assimilation became lower than C needed for respiration and growth. Negative C balance under MS and SS associated with decline of trunk carbohydrate reserves--may have led to drought-induced vegetative mortality. PMID- 25830351 TI - Risk factors for Plasmodium falciparum gametocyte positivity in a longitudinal cohort. AB - Malaria transmission intensity is highly heterogeneous even at a very small scale. Implementing targeted intervention in malaria transmission hotspots offers the potential to reduce the burden of disease both locally and in adjacent areas. Transmission of malaria parasites from man to mosquito requires the production of gametocyte stage parasites. Cluster analysis of a 19-year long cohort study for gametocyte carriage revealed spatially defined gametocyte hotspots that occurred during the time when chloroquine was the drug used for clinical case treatment. In addition to known risk factors for gametocyte carriage, notably young age (<15 years old) and associated with a clinical episode, blood groups B and O increased risk compared to groups A and AB. A hotspot of clinical P. falciparum clinical episodes that overlapped the gametocyte hotspots was also identified. Gametocyte positivity was found to be increased in individuals who had been treated with chloroquine, as opposed to other drug treatment regimens, for a clinical P. falciparum episode up to 30 days previously. It seems likely the hotspots were generated by a vicious circle of ineffective treatment of clinical cases and concomitant gametocyte production in a sub-population characterized by an increased prevalence of all the identified risk factors. While rapid access to treatment with an effective anti-malarial can reduce the duration of gametocyte carriage and onward parasite transmission, localised hotspots represent a challenge to malaria control and eventual eradication. PMID- 25830353 TI - Retinal vessel segmentation: an efficient graph cut approach with retinex and local phase. AB - Our application concerns the automated detection of vessels in retinal images to improve understanding of the disease mechanism, diagnosis and treatment of retinal and a number of systemic diseases. We propose a new framework for segmenting retinal vasculatures with much improved accuracy and efficiency. The proposed framework consists of three technical components: Retinex-based image inhomogeneity correction, local phase-based vessel enhancement and graph cut based active contour segmentation. These procedures are applied in the following order. Underpinned by the Retinex theory, the inhomogeneity correction step aims to address challenges presented by the image intensity inhomogeneities, and the relatively low contrast of thin vessels compared to the background. The local phase enhancement technique is employed to enhance vessels for its superiority in preserving the vessel edges. The graph cut-based active contour method is used for its efficiency and effectiveness in segmenting the vessels from the enhanced images using the local phase filter. We have demonstrated its performance by applying it to four public retinal image datasets (3 datasets of color fundus photography and 1 of fluorescein angiography). Statistical analysis demonstrates that each component of the framework can provide the level of performance expected. The proposed framework is compared with widely used unsupervised and supervised methods, showing that the overall framework outperforms its competitors. For example, the achieved sensitivity (0:744), specificity (0:978) and accuracy (0:953) for the DRIVE dataset are very close to those of the manual annotations obtained by the second observer. PMID- 25830352 TI - Decidualization and syndecan-1 knock down sensitize endometrial stromal cells to apoptosis induced by embryonic stimuli. AB - Human embryo invasion and implantation into the inner wall of the maternal uterus, the endometrium, is the pivotal process for a successful pregnancy. Whereas disruption of the endometrial epithelial layer was already correlated with the programmed cell death, the role of apoptosis of the subjacent endometrial stromal cells during implantation is indistinct. The aim was to clarify whether apoptosis plays a role in the stromal invasion and to characterize if the apoptotic susceptibility of endometrial stromal cells to embryonic stimuli is influenced by decidualization and Syndecan-1. Therefore, the immortalized human endometrial stromal cell line St-T1 was used to first generate a new cell line with a stable Syndecan-1 knock down (KdS1), and second to further decidualize the cells with progesterone. As a replacement for the ethically inapplicable embryo all cells were treated with the embryonic factors and secretion products interleukin-1beta, interferon-gamma, tumor necrosis factor alpha, transforming growth factor-beta1 and anti-Fas antibody to mimic the embryo contact. Detection of apoptosis was verified via Caspase ELISAs, PARP cleavage and Annexin V staining. Apoptosis-related proteins were investigated via antibody arrays and underlying signaling pathways were analyzed by Western blot. Non decidualized endometrial stromal cells showed a resistance towards apoptosis which was rescinded by decidualization and Syndecan-1 knock down independent of decidualization. This was correlated with an altered expression of several pro- and anti-apoptotic proteins and connected to a higher activation of pro-survival Akt in non-differentiated St-T1 as an upstream mediator of apoptotis-related proteins. This study provides insight into the largely elusive process of implantation, proposing an important role for stromal cell apoptosis to successfully establish a pregnancy. The impact of Syndecan-1 in attenuating the apoptotic signal is particularly interesting in the light of an already described influence on pregnancy disorders and therefore might provide a useful clinical tool in the future to prevent pregnancy complications provoked by inadequate implantation. PMID- 25830355 TI - Acquired phototrophy through retention of functional chloroplasts increases growth efficiency of the sea slug Elysia viridis. AB - Photosynthesis is a fundamental process sustaining heterotrophic organisms at all trophic levels. Some mixotrophs can retain functional chloroplasts from food (kleptoplasty), and it is hypothesized that carbon acquired through kleptoplasty may enhance trophic energy transfer through increased host growth efficiency. Sacoglossan sea slugs are the only known metazoans capable of kleptoplasty, but the relative fitness contributions of heterotrophy through grazing, and phototrophy via kleptoplasts, are not well understood. Fitness benefits (i.e. increased survival or growth) of kleptoplasty in sacoglossans are commonly studied in ecologically unrealistic conditions under extended periods of complete darkness and/or starvation. We compared the growth efficiency of the sacoglossan Elysia viridis with access to algal diets providing kleptoplasts of differing functionality under ecologically relevant light conditions. Individuals fed Codium fragile, which provide highly functional kleptoplasts, nearly doubled their growth efficiency under high compared to low light. In contrast, individuals fed Cladophora rupestris, which provided kleptoplasts of limited functionality, showed no difference in growth efficiency between light treatments. Slugs feeding on Codium, but not on Cladophora, showed higher relative electron transport rates (rETR) in high compared to low light. Furthermore, there were no differences in the consumption rates of the slugs between different light treatments, and only small differences in nutritional traits of algal diets, indicating that the increased growth efficiency of E. viridis feeding on Codium was due to retention of functional kleptoplasts. Our results show that functional kleptoplasts from Codium can provide sacoglossan sea slugs with fitness advantages through photosynthesis. PMID- 25830354 TI - A strategy for O-glycoproteomics of enveloped viruses--the O-glycoproteome of herpes simplex virus type 1. AB - Glycosylation of viral envelope proteins is important for infectivity and interaction with host immunity, however, our current knowledge of the functions of glycosylation is largely limited to N-glycosylation because it is difficult to predict and identify site-specific O-glycosylation. Here, we present a novel proteome-wide discovery strategy for O-glycosylation sites on viral envelope proteins using herpes simplex virus type 1 (HSV-1) as a model. We identified 74 O linked glycosylation sites on 8 out of the 12 HSV-1 envelope proteins. Two of the identified glycosites found in glycoprotein B were previously implicated in virus attachment to immune cells. We show that HSV-1 infection distorts the secretory pathway and that infected cells accumulate glycoproteins with truncated O glycans, nonetheless retaining the ability to elongate most of the surface glycans. With the use of precise gene editing, we further demonstrate that elongated O-glycans are essential for HSV-1 in human HaCaT keratinocytes, where HSV-1 produced markedly lower viral titers in HaCaT with abrogated O-glycans compared to the isogenic counterpart with normal O-glycans. The roles of O-linked glycosylation for viral entry, formation, secretion, and immune recognition are poorly understood, and the O-glycoproteomics strategy presented here now opens for unbiased discovery on all enveloped viruses. PMID- 25830356 TI - Involvement of GluR2 up-regulation in neuroprotection by electroacupuncture pretreatment via cannabinoid CB1 receptor in mice. AB - We investigated whether glutamate receptor subunit 2 (GluR2) is involved in EA pretreatment-induced neuroprotection via cannabinoid CB1 receptors (CB1R) after global cerebral ischemia in mice. Two hours after electric acupuncture (EA) pretreatment, global cerebral ischemia (GCI) was induced by bilateral common carotid artery occlusion (BCCAO) for 20 min. The GluR2 expression was examined in the hippocampus after reperfusion. Cell survival, neuronal apoptosis, the Bax/Bcl 2 ratio and neurological scores were evaluated at 24 h after BCCAO in the presence or absence of the GluR2 inhibitor. Furthermore, the GluR2 was determined in the presence and absence of CB1R inhibitor. Our results showed EA pretreatment enhanced expression of GluR2 in the hippocampus 2 h after reperfusion. Moreover, EA pretreatment improved neurological outcome, promoted cell survival, inhibited neuronal apoptosis, and decreased the Bax/Bcl-2 ratio after reperfusion. GluR2 knockdown by GluR2 siRNA effectively reversed the beneficial effects of EA pretreatment. Furthermore, CB1R siRNA and two CB1R antagonists blocked the elevation of GluR2 expression by EA pretreatment, whereas the two CB1R agonists up-regulated GluR2 expression as EA pretreatment. In conclusion, GluR2 up regulation is involved in neuroprotection of EA pretreatment against GCI through CB1R, suggesting that GluR2 may be a novel target for stroke intervention. PMID- 25830359 TI - Isolation and characterization of two squalene epoxidase genes from Botryococcus braunii, race B. AB - The B race of the green microalga Botryococcus braunii produces triterpene hydrocarbons, botryococcenes and methylsqualenes that can be processed into jet fuels with high heating values. In this alga, squalene is also converted into membrane sterols after 2,3-epoxidation. In the present study, cDNA clones of two distinct squalene epoxidases (BbSQE-I and -II) were isolated. Predicted amino acid sequences encoded on these genes are 45% identical with each other. Introduction of BbSQE-I or -II into Saccharomyces cerevisie erg1 mutants resulted in the complementation of ergosterol auxotrophy. The relative expression level of SQE-II increased 3.5-fold from the early stage to the middle phase of a culture period of 42 days, while that of SQE-I was almost constant throughout the culture period. Southern blot analyses suggested that these genes are single-copied genes. This is the first report on the isolation of functional SQEs that are encoded in duplicated loci in the algal genome. PMID- 25830357 TI - Electroacupuncture prevents cognitive impairments by regulating the early changes after brain irradiation in rats. AB - Cognitive impairments severely affect the quality of life of patients who undergo brain irradiation, and there are no effective preventive strategies. In this study, we examined the therapeutic potential of electroacupuncture (EA) administered immediately after brain irradiation in rats. We detected changes in cognitive function, neurogenesis, and synaptic density at different time points after irradiation, but found that EA could protect the blood-brain barrier (BBB), inhibit neuroinflammatory cytokine expression, upregulate angiogenic cytokine expression, and modulate the levels of neurotransmitter receptors and neuropeptides in the early phase. Moreover, EA protected spatial memory and recognition in the delayed phase. At the cellular/molecular level, the preventative effect of EA on cognitive dysfunction was not dependent on hippocampal neurogenesis; rather, it was related to synaptophysin expression. Our results suggest that EA applied immediately after brain irradiation can prevent cognitive impairments by protecting against the early changes induced by irradiation and may be a novel approach for preventing or ameliorating cognitive impairments in patients with brain tumors who require radiotherapy. PMID- 25830360 TI - Gait Characteristics of People with Lateral Knee Osteoarthritis after ACL Reconstruction. AB - PURPOSE: Lateral knee osteoarthritis (OA) is common after anterior cruciate ligament reconstruction (ACLR), yet gait characteristics associated with lateral knee OA after ACLR are not well understood. This cross-sectional study aimed to compare knee, trunk, pelvis, hip, and ankle kinematics and moments between people with predominant lateral knee OA after ACLR and healthy controls. METHODS: Nineteen post-ACLR people with lateral knee OA and 25 healthy controls were recruited. Quantitative gait analysis was conducted during walking, and knee pain, confidence, and kinesiophobia were assessed. Between-group differences in peak kinematics and moments were evaluated, and Pearson correlations evaluated relations between biomechanical and patient-reported measures (P < 0.05). RESULTS: Participants with lateral knee OA after ACLR had greater peak knee flexion (mean difference, 3.5 degrees ; 95% confidence interval, 0.9-6.1) and lower knee internal rotation angles (-3.3 degrees ; -6.2 to -0.5) than the controls. Those with lateral knee OA also had greater peak pelvic anterior tilt (3.1 degrees , 0.4-5.9), hip flexion angles (5.1 degrees , 1.9-8.3), and peak ankle dorsiflexion moment (0.1 N.m.kg(-1), 0.0-0.2). In the lateral knee OA group, worse knee confidence and kinesiophobia were significantly correlated with greater peak trunk flexion angle (r = 0.654 and r = 0.535, respectively) and greater knee pain was significantly correlated with greater peak knee flexion angle (r = 0.535). CONCLUSIONS: Gait characteristics associated with lateral knee OA after ACLR differ from those in healthy individuals, predominantly in the sagittal plane. Increased sagittal plane knee and trunk kinematics seem to be related to worse knee pain, confidence, and kinesiophobia. These findings will assist the development of compartment-specific interventions for individuals with posttraumatic lateral knee OA. PMID- 25830358 TI - Mapping publication trends and identifying hot spots of research on Internet health information seeking behavior: a quantitative and co-word biclustering analysis. AB - BACKGROUND: The Internet has become an established source of health information for people seeking health information. In recent years, research on the health information seeking behavior of Internet users has become an increasingly important scholarly focus. However, there have been no long-term bibliometric studies to date on Internet health information seeking behavior. OBJECTIVE: The purpose of this study was to map publication trends and explore research hot spots of Internet health information seeking behavior. METHODS: A bibliometric analysis based on PubMed was conducted to investigate the publication trends of research on Internet health information seeking behavior. For the included publications, the annual publication number, the distribution of countries, authors, languages, journals, and annual distribution of highly frequent major MeSH (Medical Subject Headings) terms were determined. Furthermore, co-word biclustering analysis of highly frequent major MeSH terms was utilized to detect the hot spots in this field. RESULTS: A total of 533 publications were included. The research output was gradually increasing. There were five authors who published four or more articles individually. A total of 271 included publications (50.8%) were written by authors from the United States, and 516 of the 533 articles (96.8%) were published in English. The eight most active journals published 34.1% (182/533) of the publications on this topic. Ten research hot spots were found: (1) behavior of Internet health information seeking about HIV infection or sexually transmitted diseases, (2) Internet health information seeking behavior of students, (3) behavior of Internet health information seeking via mobile phone and its apps, (4) physicians' utilization of Internet medical resources, (5) utilization of social media by parents, (6) Internet health information seeking behavior of patients with cancer (mainly breast cancer), (7) trust in or satisfaction with Web-based health information by consumers, (8) interaction between Internet utilization and physician-patient communication or relationship, (9) preference and computer literacy of people using search engines or other Web-based systems, and (10) attitude of people (especially adolescents) when seeking health information via the Internet. CONCLUSIONS: The 10 major research hot spots could provide some hints for researchers when launching new projects. The output of research on Internet health information seeking behavior is gradually increasing. Compared to the United States, the relatively small number of publications indexed by PubMed from other developed and developing countries indicates to some extent that the field might be still underdeveloped in many countries. More studies on Internet health information seeking behavior could give some references for health information providers. PMID- 25830361 TI - Effects of Endurance Training at the Crossover Point in Women with Metabolic Syndrome. AB - INTRODUCTION: On the basis of theoretical evidence, intensity at the crossover point (COP) of substrate utilization could be considered as potential exercise intensity for metabolic syndrome (MetS). This study aimed to examine the effects of a training program at COP on exercise capacity parameters in women with MetS and to compare two metabolic indices (COP and the maximal fat oxidation rate point LIPOXmax(r)) with ventilatory threshold (VT). METHODS: Nineteen women with MetS volunteered to perform a 12-wk training program on a cycle ergometer, with intensity corresponding to COP. Pre- and posttraining values of anthropometric and exercise capacity parameters were compared to determine the effects of exercise training. The pre-post training change of COP, LIPOXmax(r), and VT were also investigated. RESULTS: After training, anthropometric parameters were significantly modified, with reduction of body mass (3.0% +/- 3.0%, P < 0.001), fat mass (3.3% +/- 3.4%, P < 0.001), and body mass index (3.2% +/- 3.4%, P < 0.001). Exercise capacity was improved after the training program, with significant increase of maximal power output (25.0% +/- 18.4%, P < 0.001) and maximal oxygen uptake (VO2max, 9.0% +/- 11.2%; P < 0.01). Lastly, when expressed in terms of power output, COP, LIPOXmax(r), and VT occurred at a similar exercise intensity, but the occurrence of these three indices is different when expressed in terms of oxygen uptake, HR, or RPE. CONCLUSIONS: This study highlights the effectiveness of a 12-wk training program at COP to improve physical fitness in women with MetS. The relations between metabolic indices and VT in terms of power output highlight the determination of VT from a shorter maximal exercise as a useful method for determining metabolic indices in MetS. PMID- 25830363 TI - Lower Limb Interjoint Postural Coordination One Year after First-Time Lateral Ankle Sprain. AB - INTRODUCTION: Longitudinal analyses of participants with a history of lateral ankle sprain are lacking. This investigation combined measures of lower limb interjoint coordination and stabilometry to evaluate static unipedal stance with the eyes open (condition 1) and closed (condition 2) in a group of participants with chronic ankle instability (CAI) compared to lateral ankle sprain "copers" (both recruited 12 months after sustaining an acute first-time lateral ankle sprain) and a group of noninjured controls. METHODS: Twenty-eight participants with CAI, 42 lateral ankle sprain "copers," and 20 noninjured controls completed three 20-s single-limb stance trials in conditions 1 and 2. An adjusted coefficient of multiple determination statistic was used to compare stance limb three-dimensional kinematic data for similarity to establish patterns of interjoint coordination. The fractal dimension of the stance limb center of pressure path was also calculated. RESULTS: Between-group analyses revealed that participants with CAI displayed notable increases in ankle-hip linked coordination compared with both lateral ankle sprain "copers" (-0.52 (1.05) vs 0.28 (0.9), P = 0.007) and controls (-0.52 (1.05) vs 0.63 (0.64), P = 0.006) in condition 1 and compared with controls only (0.62 (1.92) vs 0.1 (1.0) P = 0.002) in condition 2. Participants with CAI also exhibited a decrease in the fractal dimension of the center-of-pressure path during condition 2 compared with both controls and lateral ankle sprain "copers." CONCLUSIONS: Participants with CAI present with a hip-dominant strategy of eyes-open and eyes-closed static unipedal stance. This coincided with reduced complexity of the stance limb center of pressure path in the eyes-closed condition. PMID- 25830364 TI - Predictors of Beneficial Coronary Plaque Changes after Aerobic Exercise. AB - PURPOSE: It has been demonstrated that aerobic exercise induces beneficial changes in coronary atherosclerosis via reduced necrotic core and plaque burden. Clinical factors that may be associated with favorable exercise-induced intracoronary effects are unknown. METHODS: This study used post hoc analysis of associations between baseline clinical variables and reductions in coronary necrotic core and plaque burden after aerobic exercise intervention. Coronary plaque characteristics were measured with grayscale and radiofrequency intravascular ultrasound in 36 patients (median age, 58.5 yr; seven women) with stable CAD (SCAD) or non-ST elevation acute coronary syndrome (NSTE-ACS). Screening of clinical variables was performed with random forest analysis followed by multivariate linear regression. RESULTS: The only significant clinical variable for necrotic core reduction was clinical presentation of disease (SCAD vs NSTE-ACS, P = 0.011). The changes in necrotic core after exercise were -4.94 mm3 (-10.33; -1.33) in patients with SCAD and 1.03 mm3 ( 4.29; 3.71) in patients with NSTE-ACS (P = 0.01). Necrotic core was reduced in 17 patients (94%) with SCAD and eight patients (44%) with NSTE-ACS (P = 0.01). R2 for the model including baseline clinical presentation and baseline necrotic core volume was 0.90. There were no significant explanatory variables for plaque burden reduction. CONCLUSIONS: Exercise-induced plaque stabilization via reduced coronary necrotic core may be strongly dependent on clinical presentation of CAD. We hypothesized that an increased proinflammatory load renders patients with NSTE ACS more resistant to exercise-induced plaque stabilization than patients with SCAD. Furthermore, aerobic exercise may have a particular potential for inducing beneficial effects on coronary atherosclerosis in patients with SCAD compared with patients in the early phase after an acute coronary syndrome. PMID- 25830362 TI - MRS Evidence of Adequate O2 Supply in Human Skeletal Muscle at the Onset of Exercise. AB - PURPOSE: At exercise onset, intramuscular oxidative energy production responds relatively slowly in comparison with the change in adenosine triphosphate demand. To determine whether the slow kinetics of oxidative adenosine triphosphate production is due to inadequate O2 supply or metabolic inertia, we studied the kinetics of intramyocellular deoxygenation (deoxy-myoglobin (Mb)) and metabolism (phosphocreatine (PCr)) using proton (1H) and phosphorus (31P) magnetic resonance spectroscopy in six healthy subjects (33 +/- 5 yr). METHODS: Specifically, using dynamic plantarflexion exercise, rest to exercise and recovery were assessed at both 60% of maximum work rate (moderate intensity) and 80% of maximum work rate (heavy intensity). RESULTS: At exercise onset, [PCr] fell without delay and with a similar time constant (tau) at both exercise intensities (approximately 33 s). In contrast, the increase in deoxy-Mb was delayed at exercise onset by 5-7 s, after which it increased with kinetics (moderate tau = 37 +/- 9 s; heavy tau = 29 +/- 6 s) that was not different from tauPCr (P > 0.05). At cessation, deoxy-Mb recovered without time delay and more rapidly (tau = ~20 s) than PCr (tau = ~33 s) (P < 0.05). CONCLUSIONS: Using a unique combination of in vivo magnetic resonance spectroscopy techniques with high time resolution, this study revealed a delay in intramuscular deoxygenation at the onset of exercise and rapid reoxygenation kinetics upon cessation. Together, these data imply that intramuscular substrate-enzyme interactions, and not O2 availability, determine the exercise onset kinetics of oxidative metabolism in healthy human skeletal muscles. PMID- 25830366 TI - Chiral surfactant-type catalyst: enantioselective reduction of long-chain aliphatic ketoesters in water. AB - A series of amphiphilic ligands were designed and synthesized. The rhodium complexes with the ligands were applied to the asymmetric transfer hydrogenation of broad range of long-chained aliphatic ketoesters in neat water. Quantitative conversion and excellent enantioselectivity (up to 99% ee) was observed for alpha , beta-, gamma-, delta- and epsilon-ketoesters as well as for alpha- and beta acyloxyketone using chiral surfactant-type catalyst 2. The CH/pi interaction and the strong hydrophobic interaction of long aliphatic chains between the catalyst and the substrate in the metallomicelle core played a key role in the catalytic transition state. Synergistic effects between the metal-catalyzed site and the hydrophobic microenvironment of the core in the micelle contributed to high stereoselectivity. PMID- 25830365 TI - Tandem fusion of hepatitis B core antigen allows assembly of virus-like particles in bacteria and plants with enhanced capacity to accommodate foreign proteins. AB - The core protein of the hepatitis B virus, HBcAg, assembles into highly immunogenic virus-like particles (HBc VLPs) when expressed in a variety of heterologous systems. Specifically, the major insertion region (MIR) on the HBcAg protein allows the insertion of foreign sequences, which are then exposed on the tips of surface spike structures on the outside of the assembled particle. Here, we present a novel strategy which aids the display of whole proteins on the surface of HBc particles. This strategy, named tandem core, is based on the production of the HBcAg dimer as a single polypeptide chain by tandem fusion of two HBcAg open reading frames. This allows the insertion of large heterologous sequences in only one of the two MIRs in each spike, without compromising VLP formation. We present the use of tandem core technology in both plant and bacterial expression systems. The results show that tandem core particles can be produced with unmodified MIRs, or with one MIR in each tandem dimer modified to contain the entire sequence of GFP or of a camelid nanobody. Both inserted proteins are correctly folded and the nanobody fused to the surface of the tandem core particle (which we name tandibody) retains the ability to bind to its cognate antigen. This technology paves the way for the display of natively folded proteins on the surface of HBc particles either through direct fusion or through non-covalent attachment via a nanobody. PMID- 25830367 TI - Fighting while parasitized: can nematode infections affect the outcome of staged combat in beetles? AB - The effects of non-lethal parasites may be felt most strongly when hosts engage in intense, energy-demanding behaviors. One such behavior is fighting with conspecifics, which is common among territorial animals, including many beetle species. We examined the effects of parasites on the fighting ability of a saproxylic beetle, the horned passalus (Odontotaenius disjunctus, Family: Passalidae), which is host to a non-lethal nematode, Chondronema passali. We pitted pairs of randomly-chosen (but equally-weighted) beetles against each other in a small arena and determined the winner and aggression level of fights. Then we examined beetles for the presence, and severity of nematode infections. There was a non-significant tendency (p = 0.065) for the frequency of wins, losses and draws to differ between beetles with and without C. passali; non-parasitized individuals (n = 104) won 47% of their fights while those with the parasite (n = 88) won 34%, a 13% difference in wins. The number of nematodes in a beetle affected the outcome of fights between infected and uninfected individuals in an unexpected fashion: fighting ability was lowest in beetles with the lowest (p = 0.033), not highest (p = 0.266), nematode burdens. Within-fight aggression was highest when both beetles were uninfected and lowest when both were infected (p = 0.034). Collectively, these results suggest the nematode parasite, C. passali, is associated with a modest reduction in fighting ability in horned passalus beetles, consistent with the idea that parasitized beetles have lower energy available for fighting. This study adds to a small but growing body of evidence showing how parasites negatively influence fighting behavior in animals. PMID- 25830368 TI - High-throughput in vivo genotoxicity testing: an automated readout system for the somatic mutation and recombination test (SMART). AB - Genotoxicity testing is an important component of toxicity assessment. As illustrated by the European registration, evaluation, authorization, and restriction of chemicals (REACH) directive, it concerns all the chemicals used in industry. The commonly used in vivo mammalian tests appear to be ill adapted to tackle the large compound sets involved, due to throughput, cost, and ethical issues. The somatic mutation and recombination test (SMART) represents a more scalable alternative, since it uses Drosophila, which develops faster and requires less infrastructure. Despite these advantages, the manual scoring of the hairs on Drosophila wings required for the SMART limits its usage. To overcome this limitation, we have developed an automated SMART readout. It consists of automated imaging, followed by an image analysis pipeline that measures individual wing genotoxicity scores. Finally, we have developed a wing score based dose-dependency approach that can provide genotoxicity profiles. We have validated our method using 6 compounds, obtaining profiles almost identical to those obtained from manual measures, even for low-genotoxicity compounds such as urethane. The automated SMART, with its faster and more reliable readout, fulfills the need for a high-throughput in vivo test. The flexible imaging strategy we describe and the analysis tools we provide should facilitate the optimization and dissemination of our methods. PMID- 25830369 TI - Development and uniform evaluation of ropinirole osmotic pump tablets with REQUIP XL both in vitro and in beagle dogs. AB - REQUIP XL, prolonged release formulation of ropinirole hydrochloride (RH) in market, could release ropinirole constantly and showed satisfactory therapeutic effect and good compliance. REQUIP XL was composed of more than 10 kinds of excipients and prepared by Geomatrix technology, which was complex and laborious. The purpose of this study was to obtain a dosage form of RH with similar in vitro release profile and bioequivalence in vivo compared to REQUIP XL. Osmotic pump tablet combined with fast release phase was selected as the delivery system of RH and similar release curves were obtained in different media. The tablets were also administered to beagle dogs and the pharmacokinetic parameters were calculated using a non-compartmental model. Cmax, tmax, mean residence time (MRT), and area under the curve from 0 to 24 h (AUC0-24) were 3.97 +/- 0.53 ng/mL, 3.58 +/- 0.49 h, 8.29 +/- 0.93 h, and 35.20 +/- 8.11 ng/mL c h for ropinirole osmotic pump tablets (ROPT) and 4.15 +/- 1.07 ng/mL, 2.92 +/- 0.49 h, 7.84 +/- 1.09 h, and 34.34 +/- 10.06 ng/mL c h for REQUIP XL. The log-transformed mean Cmax and AUC0-24 of ROPT were about 92.15% and 102.49% relative to that of REQUIP XL, respectively. The 90% confidence intervals of Cmax and AUC0-24 for ROPT were 75.69-115.31% and 88.89-122.30%, respectively. So it could be concluded that ROPT was uniform with REQUIP XL both in vitro and in beagles and the release profiles of Geomatrix technology may be obtained by osmotic pump combined with fast release technology. PMID- 25830370 TI - Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design. AB - OBJECTIVE: Nisoldipine (ND) is a potential antihypertensive drug with low oral bioavailability. The aim was to develop an optimal formulation of ND-loaded solid lipid nanoparticles (ND-SLNs) for improved oral bioavailability and pharmacodynamic effect by using a two-factor, three-level central composite design. Glyceryl trimyristate (Dynasan 114) and egg lecithin were selected as independent variables. Particle size (Y1), PDI (Y2) and entrapment efficiency (EE) (Y3) of SLNs were selected as dependent response variables. METHODS: The ND SLNs were prepared by hot homogenization followed by ultrasonication. The size, PDI, zeta potential, EE, assay, in vitro release and morphology of ND-SLNs were characterized. Further, the pharmacokinetic (PK) and pharmacodynamic behavior of ND-SLNs was evaluated in male Wistar rats. RESULTS: The optimal ND-SLN formulation had particle size of 104.4 +/- 2.13 nm, PDI of 0.241 +/- 0.02 and EE of 89.84 +/- 0.52%. The differential scanning calorimetry and X-ray diffraction analyses indicated that the drug incorporated into ND-SLNs was in amorphous form. The morphology of ND-SLNs was found to be nearly spherical by scanning electron microscopy. The optimized formulation was stable at refrigerated and room temperature for 3 months. PK studies showed that 2.17-fold increase in oral bioavailability when compared with a drug suspension. In pharmacodynamic studies, a significant reduction in the systolic blood pressure was observed, which sustained for a period of 36 h when compared with a controlled suspension. CONCLUSION: Taken together, the results conclusively demonstrated that the developed optimal ND-SLNs caused significant enhancement in oral bioavailability along with pharmacodynamic effect. PMID- 25830373 TI - Dynamics of bimolecular reactions in solution. AB - Mechanisms of bimolecular chemical reactions in solution are amenable to study on picosecond timescales, both by transient absorption spectroscopy and by computer simulation. The dynamics of exothermic reactions of CN radicals and of Cl and F atoms with organic solutes in commonly used solvents are contrasted with the corresponding dynamics in the gas phase. Many characteristics of the gas-phase reaction dynamics persist in solution, such as efficient energy release to specific vibrational modes of the products. However, additional complexities associated with the presence of the solvent are open to investigation. These features of liquid-phase reactions include the role of solvent-solute complexes, solvent caging, coupling of the product motions to the solvent bath, thermalization of internally excited reaction products, incipient hydrogen bond formation, and involvement of charge-separated states that arise from proton transfer. PMID- 25830374 TI - DFT: A Theory Full of Holes? AB - This article is a rough, quirky overview of both the history and present state of the art of density functional theory. The field is so huge that no attempt to be comprehensive is made. We focus on the underlying exact theory, the origin of approximations, and the tension between empirical and nonempirical approaches. Many ideas are illustrated on the exchange energy and hole. Features unique to this article include how approximations can be systematically derived in a nonempirical fashion and a survey of warm dense matter. PMID- 25830371 TI - Experience-related structural changes of degenerated occipital white matter in late-blind humans - a diffusion tensor imaging study. AB - Late-blind humans can learn to understand speech at ultra-fast syllable rates (ca. 20 syllables/s), a capability associated with hemodynamic activation of the central-visual system. Thus, the observed functional cross-modal recruitment of occipital cortex might facilitate ultra-fast speech processing in these individuals. To further elucidate the structural prerequisites of this skill, diffusion tensor imaging (DTI) was conducted in late-blind subjects differing in their capability of understanding ultra-fast speech. Fractional anisotropy (FA) was determined as a quantitative measure of the directionality of water diffusion, indicating fiber tract characteristics that might be influenced by blindness as well as the acquired perceptual skills. Analysis of the diffusion images revealed reduced FA in late-blind individuals relative to sighted controls at the level of the optic radiations at either side and the right-hemisphere dorsal thalamus (pulvinar). Moreover, late-blind subjects showed significant positive correlations between FA and the capacity of ultra-fast speech comprehension within right-hemisphere optic radiation and thalamus. Thus, experience-related structural alterations occurred in late-blind individuals within visual pathways that, presumably, are linked to higher order frontal language areas. PMID- 25830375 TI - Electron transfer mechanisms of DNA repair by photolyase. AB - Photolyase is a flavin photoenzyme that repairs two DNA base damage products induced by ultraviolet (UV) light: cyclobutane pyrimidine dimers and 6-4 photoproducts. With femtosecond spectroscopy and site-directed mutagenesis, investigators have recently made significant advances in our understanding of UV damaged DNA repair, and the entire enzymatic dynamics can now be mapped out in real time. For dimer repair, six elementary steps have been characterized, including three electron transfer reactions and two bond-breaking processes, and their reaction times have been determined. A unique electron-tunneling pathway was identified, and the critical residues in modulating the repair function at the active site were determined. The dynamic synergy between the elementary reactions for maintaining high repair efficiency was elucidated, and the biological nature of the flavin active state was uncovered. For 6-4 photoproduct repair, a proton-coupled electron transfer repair mechanism has been revealed. The elucidation of electron transfer mechanisms and two repair photocycles is significant and provides a molecular basis for future practical applications, such as in rational drug design for curing skin cancer. PMID- 25830376 TI - Correction: decoding vigilance with NIRS. AB - [This corrects the article DOI: 10.1371/journal.pone.0101729.]. PMID- 25830377 TI - Does Helicobacter pylori eradication or proton pump inhibitor use benefit gastroesophageal reflux disease? PMID- 25830378 TI - Transcriptomic identification of ADH1B as a novel candidate gene for obesity and insulin resistance in human adipose tissue in Mexican Americans from the Veterans Administration Genetic Epidemiology Study (VAGES). AB - Type 2 diabetes (T2D) is a complex metabolic disease that is more prevalent in ethnic groups such as Mexican Americans, and is strongly associated with the risk factors obesity and insulin resistance. The goal of this study was to perform whole genome gene expression profiling in adipose tissue to detect common patterns of gene regulation associated with obesity and insulin resistance. We used phenotypic and genotypic data from 308 Mexican American participants from the Veterans Administration Genetic Epidemiology Study (VAGES). Basal fasting RNA was extracted from adipose tissue biopsies from a subset of 75 unrelated individuals, and gene expression data generated on the Illumina BeadArray platform. The number of gene probes with significant expression above baseline was approximately 31,000. We performed multiple regression analysis of all probes with 15 metabolic traits. Adipose tissue had 3,012 genes significantly associated with the traits of interest (false discovery rate, FDR <= 0.05). The significance of gene expression changes was used to select 52 genes with significant (FDR <= 10(-4)) gene expression changes across multiple traits. Gene sets/Pathways analysis identified one gene, alcohol dehydrogenase 1B (ADH1B) that was significantly enriched (P < 10(-60)) as a prime candidate for involvement in multiple relevant metabolic pathways. Illumina BeadChip derived ADH1B expression data was consistent with quantitative real time PCR data. We observed significant inverse correlations with waist circumference (2.8 x 10(-9)), BMI (5.4 x 10(-6)), and fasting plasma insulin (P < 0.001). These findings are consistent with a central role for ADH1B in obesity and insulin resistance and provide evidence for a novel genetic regulatory mechanism for human metabolic diseases related to these traits. PMID- 25830380 TI - Variability of the perception of dyspnea in healthy subjects assessed through inspiratory resistive loading. AB - OBJECTIVE: Few studies have evaluated the variability of the perception of dyspnea in healthy subjects. The objective of this study was to evaluate the variability of the perception of dyspnea in healthy subjects during breathing against increasing inspiratory resistive loads, as well as to assess the association between the level of perception of dyspnea and the level of physical activity. METHODS: This was a cross-sectional study involving healthy individuals 16 years of age or older. Subjects underwent inspiratory resistive loading testing, in which the level of perception of dyspnea was quantified with the modified Borg scale. We also determined body mass indices (BMIs), assessed maximal respiratory pressures, performed pulmonary function tests, applied the international physical activity questionnaire (IPAQ)-long form, and conducted six minute walk tests (6 MWTs). The level of perception of dyspnea was classified as low (Borg score < 2), intermediate (Borg score, 2-5), or high (Borg score > 5). RESULTS: We included 48 healthy subjects in the study. Forty-two subjects completed the test up to a load of 46.7 cmH2O/L/s. The level of perception of dyspnea was classified as low, intermediate, and high in 13, 19, and 10 subjects, respectively. The level of perception of dyspnea was not significantly associated with age, gender, BMI, IPAQ-long form score, maximal respiratory pressures, or pulmonary function test results. CONCLUSIONS: The scores for perceived dyspnea induced by inspiratory resistive loading in healthy subjects presented wide variability. The perception of dyspnea was classified as low in 31% of the subjects, intermediate in 45%, and high in 24%. There was no association between the level of perception of dyspnea and the level of physical activity (IPAQ or six-minute walk distance). PMID- 25830379 TI - Capsules, toxins and AtxA as virulence factors of emerging Bacillus cereus biovar anthracis. AB - Emerging B. cereus strains that cause anthrax-like disease have been isolated in Cameroon (CA strain) and Cote d'Ivoire (CI strain). These strains are unusual, because their genomic characterisation shows that they belong to the B. cereus species, although they harbour two plasmids, pBCXO1 and pBCXO2, that are highly similar to the pXO1 and pXO2 plasmids of B. anthracis that encode the toxins and the polyglutamate capsule respectively. The virulence factors implicated in the pathogenicity of these B. cereus bv anthracis strains remain to be characterised. We tested their virulence by cutaneous and intranasal delivery in mice and guinea pigs; they were as virulent as wild-type B. anthracis. Unlike as described for pXO2-cured B. anthracis, the CA strain cured of the pBCXO2 plasmid was still highly virulent, showing the existence of other virulence factors. Indeed, these strains concomitantly expressed a hyaluronic acid (HA) capsule and the B. anthracis polyglutamate (PDGA) capsule. The HA capsule was encoded by the hasACB operon on pBCXO1, and its expression was regulated by the global transcription regulator AtxA, which controls anthrax toxins and PDGA capsule in B. anthracis. Thus, the HA and PDGA capsules and toxins were co-regulated by AtxA. We explored the respective effect of the virulence factors on colonisation and dissemination of CA within its host by constructing bioluminescent mutants. Expression of the HA capsule by itself led to local multiplication and, during intranasal infection, to local dissemination to the adjacent brain tissue. Co-expression of either toxins or PDGA capsule with HA capsule enabled systemic dissemination, thus providing a clear evolutionary advantage. Protection against infection by B. cereus bv anthracis required the same vaccination formulation as that used against B. anthracis. Thus, these strains, at the frontier between B. anthracis and B. cereus, provide insight into how the monomorphic B. anthracis may have emerged. PMID- 25830381 TI - Efficacy and safety of fluticasone furoate/vilanterol (50/25 mcg; 100/25 mcg; 200/25 mcg) in Asian patients with chronic obstructive pulmonary disease: a randomized placebo-controlled trial. AB - BACKGROUND AND OBJECTIVE: Three strengths of fluticasone furoate/vilanterol (FF/VI) were previously evaluated for the treatment of chronic obstructive pulmonary disease (COPD) in a program of global Phase 3 studies that included only a small subgroup of Asian patients. This study further evaluated the efficacy and safety of the same three strengths of FF/VI exclusively in Asian patients. METHODS: A randomized, double-blind, placebo-controlled, parallel group, multicenter study. Patients with post-bronchodilator FEV1/FVC <=0.70, FEV1 <=70% predicted and modified Medical Research Council score >=2 were randomized (1:1:1:1) to placebo, FF/VI 50/25 mcg, 100/25 mcg or 200/25 mcg once daily via the ELLIPTA dry powder inhaler. The primary efficacy endpoint was change from baseline in trough FEV1 at Week 24. RESULTS: The intent-to-treat population comprised 643 patients. Statistically significant (p < 0.001) improvements in trough FEV1 were observed with all strengths of FF/VI versus placebo at Week 24 (0.14-0.19 L). Reduction of supplemental albuterol use was observed with all strengths of FF/VI versus placebo. The incidence of on-treatment adverse events (AEs) was 48% with FF/VI 200/25 mcg and 37-40% with other treatments. The incidence of on-treatment serious AEs was 4-9% with FF/VI treatments versus 9% with placebo; however, the study only covered a 6 month treatment period and was not powered to assess effects on exacerbations. No clinically significant treatment effects versus placebo were identified for electrocardiogram, vital signs, 24 hour urinary cortisol excretion and pneumonia. CONCLUSIONS: All strengths of FF/VI improved lung function with an acceptable safety profile. There is no evidence to suggest that dose adjustment may be required in Asian patients using FF/VI 100/25 mcg for the treatment of COPD. CLINICAL TRIAL REGISTRATION: NCT01376245. PMID- 25830382 TI - Plk1 phosphorylation of IRS2 prevents premature mitotic exit via AKT inactivation. AB - Insulin receptor substrate (IRS) proteins play important roles by acting as a platform in transducing signals from transmembrane receptors upon growth factor stimulation. Although tyrosine phosphorylation on IRS proteins plays critical roles in signal transduction, phosphorylation of IRS proteins on serine/threonine residues is believed to play various regulatory roles in IRS protein function. However, studies of serine/threonine phosphorylation of IRS proteins are very limited, especially for insulin receptor substrate 2 (IRS2), one member of the IRS protein family. In this study, we identify Polo-like kinase 1 (Plk1) as the responsible kinase for phosphorylation of IRS2 on two serine residues, Ser 556 and Ser 1098. Phosphorylation of IRS2 at these two serine residues by Plk1 prevents the activation of the PI3K pathway upon growth factor stimulation by inhibiting the binding between IRS2 and the PI3K pathway components and increasing the level of IRS2 protein degradation. Significantly, we show that IRS2 phosphorylation is cell cycle-regulated and that Plk1 phosphorylation of IRS2 prevents premature mitotic exit via AKT inactivation. PMID- 25830384 TI - Unconventional charge distribution in the planar wheel-type M(c)B6H6(-/0/+) (M = Mn, Fe and Co): central M with negative charges and peripheral boron ring with positive charges. AB - Planar wheel-type D6h M(c)B6H6(-/0/+) (M = Mn, Fe and Co for anion, neutral and cation, respectively.) clusters with a planar hexacoordinate transition-metal at the center of the boron ring were designed and investigated by density functional theory. These planar clusters are chemically stable as a result of their large binding energy, vertical ionization potential, and vertical electron affinity. The detailed natural population and molecular orbital analyses suggest that not only does the M atom donate electrons to the boron ring for participation in the pi-delocalized bonding, but also the boron ring donates electrons back to the M atom for the formation of the sigma-delocalized bonding, which leads to a strong aromaticity and unconventional charge distribution, i.e., the M atom is negatively charged, while the boron ring is positively charged. This study may open a new area in coordination chemistry for planar hexacoordinate transition metals and we expect further experimental exploration of their synthesis and potential applications. PMID- 25830383 TI - The antisaccade task: visual distractors elicit a location-independent planning 'cost'. AB - The presentation of a remote - but not proximal - distractor concurrent with target onset increases prosaccade reaction times (RT) (i.e., the remote distractor effect: RDE). The competitive integration model asserts that the RDE represents the time required to resolve the conflict for a common saccade threshold between target- and distractor-related saccade generating commands in the superior colliculus. To our knowledge however, no previous research has examined whether remote and proximal distractors differentially influence antisaccade RTs. This represents a notable question because antisaccades require decoupling of the spatial relations between stimulus and response (SR) and therefore provide a basis for determining whether the sensory- and/or motor related features of a distractor influence response planning. Participants completed pro- and antisaccades in a target-only condition and conditions wherein the target was concurrently presented with a proximal or remote distractor. As expected, prosaccade RTs elicited a reliable RDE. In contrast, antisaccade RTs were increased independent of the distractor's spatial location and the magnitude of the effect was comparable across each distractor location. Thus, distractor related antisaccade RT costs are not accounted for by a competitive integration between conflicting saccade generating commands. Instead, we propose that a visual distractor increases uncertainty related to the evocation of the response selection rule necessary for decoupling SR relations. PMID- 25830386 TI - Survival analysis and other clinical outcomes of immediate implant placement in sites with periapical lesions: systematic review. AB - PURPOSE: Immediate implantation has become one of the therapeutic options for replacement of a hopeless tooth. In the case of a tooth with a periapical lesion, this approach remains controversial. The aims of this article were to systematically review the evidence on immediate implants in sites with periapical lesions with reference to: (1) survival rates, (2) changes in crestal bone levels and marginal tissues, (3) complication rates, and (4) comparison of clinical outcomes with other implant treatments. MATERIALS AND METHODS: An electronic search was conducted in MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE for articles published between January 1990 and August 2013. Publications were screened, and data extraction and quality assessment were performed. Implant survival rates were calculated using predicted Kaplan-Meier survival analysis. Crestal bone level changes, soft tissue outcomes, complications, and procedure characteristics were analyzed descriptively. RESULTS: Initially, 301 articles were identified. Three prospective controlled trials of immediate implant placement in sites with periapical lesions with a follow-up period of at least 1 year were selected for the survival analysis. The predicted cumulative 5-year survival rate of immediate implants in sites with periapical lesions was 96.23%. Bone and gingival level changes were comparable to those of implants placed in sites without periapical pathology. The complication rates, reported in only one study, were 15.4% (2/13) in sites with periapical lesions and 6.7% (1/15) in healthy sites. CONCLUSION: Limited evidence suggests that immediate implant placement in sites with periapical lesions leads to clinical outcomes comparable to those of immediate implants in healthy sites. Additional prospective controlled trials with large sample sizes and long-term follow-up are needed to further investigate these results. PMID- 25830385 TI - Pathway as a pharmacological target for herbal medicines: an investigation from reduning injection. AB - As a rich natural resource for drug discovery, Traditional Chinese Medicine (TCM) plays an important role in complementary and alternative medical systems. TCM shows a daunting complexity of compounds featuring multi-components and multi targets to cure diseases, which thus always makes it extremely difficult to systematically explain the molecular mechanisms adequately using routine methods. In the present work, to reveal the systematic mechanism of herbal formulae, we developed a pathway-based strategy by combining the pathways integrating, target selection, reverse drug targeting and network analysis together, and then exemplified it by Reduning injection (RDN), a clinically widely used herbal medicine injection, in combating inflammation. The anti-inflammatory effects exerted by the major ingredients of RDN at signaling pathways level were systematically investigated. More importantly, our predicted results were also experimentally validated. Our strategy provides a deep understanding of the pharmacological functions of herbal formulae from molecular to systematic level, which may lead to more successful applications of systems pharmacology for drug discovery and development. PMID- 25830387 TI - Experimental evaluation of the effects of Ankaferd Blood Stopper and collagenated heterologous bone graft on bone healing in sinus floor augmentation. AB - PURPOSE: The aim of this study was to evaluate the effect of collagenated heterologous bone graft (CHBG) and Ankaferd Blood Stopper (ABS), a plant extract, on bone healing after sinus floor augmentation. MATERIALS AND METHODS: Thirty-six New Zealand rabbits were used. Bilateral sinus augmentation was performed, and 72 bone defects were created. The maxillary sinuses were grafted with four different biomaterials: blood clot (control group), CHBG (Apatos Mix, OsteoBiol, Tecnoss) (graft group), ABS (ABS group), and ABS + CHBG (ABS+graft group). The rabbits were sacrificed at 1, 4, and 8 weeks after surgery. Histochemical and immunohistochemical examinations were performed on all samples. Staining with hematoxylin-eosin and Masson trichrome was performed, and bone marker activity was evaluated. RESULTS: Lymphocyte infiltration was high at the first week in all groups and decreased from 1 to 8 weeks. All materials were biocompatible. Osteoclast numbers increased in the control group from 1 to 8 weeks and decreased in the other groups. There was no new bone formation in week 1 in all groups. New bone formation increased in all groups from 1 to 8 weeks, and at the fourth week, new bone formation was greater in the ABS and ABS+graft groups than in the other groups. There were osteoclasts around the bone graft materials, but degeneration of the graft was seen only in the ABS+graft group at week 8. CONCLUSION: ABS accelerates bone healing in sinus augmentation procedures and can be used alone or with CHBG. CHBG has osteoconductive properties, and ABS can accelerate bone graft degeneration. PMID- 25830388 TI - Measuring bone density at orthodontic miniscrew implantation sites using microcomputed tomography. AB - PURPOSE: This study was performed to determine the accuracy of measurements of bone mineral density (BMD) and cortical bone thickness (CBT) at miniscrew implantation sites in small animals and to verify the usefulness of in vivo microcomputed tomography (micro-CT). MATERIALS AND METHODS: Rat femurs were scanned before and after placing miniscrews using in vivo micro-CT. The images were superimposed using a subtraction method with bone volume measurement software. At each screw site, the total BMD was calculated as the average BMD of a cylinder 1.6 mm in diameter and 2.0 mm in depth, while the cortical BMD was the average BMD of a cylinder 1.6 mm in diameter and 1.0 mm in depth. CBT was measured three times on transaxial images of the rat femurs, and the average value was used. All miniscrews were placed using the maximum torque, verified with a digital torque tester. To verify the usefulness and accuracy of in vivo micro-CT, CBT on micro-CT images was compared with that measured on histologic sections. RESULTS: Significant correlations were observed between placement torque and cortical BMD (R = 0.572), total BMD (R = 0.732), and CBT (R = 0.788). There was a significant correlation between CBT measured via field-emission scanning electron microscopy images and CBT measured with in vivo micro-CT (R = 0.974). CONCLUSIONS: The BMD over a narrow range can be measured accurately in small animals with high reproducibility of the trabecular structure using a combination of high-resolution in vivo micro-CT and image superimposition using a three-dimensional subtraction method. PMID- 25830389 TI - Reliability of four zygomatic implant-supported prostheses for the rehabilitation of the atrophic maxilla: a systematic review. AB - PURPOSE: The reliability of oral rehabilitation by four zygomatic implants with no anterior support remains to be determined. The aim of this systematic review was to assess the predictability of this approach in regard to implant survival, technical and biologic complications, and quality of life. MATERIALS AND METHODS: An electronic literature search was conducted from September 2000 to November 2013. Human clinical trials in which oral rehabilitation was achieved by the use of four zygomatic implants with no additional placement of standard implants were included. The primary outcome was the survival rate of the zygomatic implants. In addition, random effects meta-analyses of the selected studies were applied to avoid potential bias caused by methodologic differences among studies. RESULTS: Zygomatic implant survival rate weighted mean (WM) was 96.7% (range, 95.8% to 99.9%), with a 95% confidence interval (CI) of 92.5% to 98.5%. Only a limited number of surgical complications were reported, with orbital perforation the most significant. Similar results were obtained for prosthetic complications (few occurrences). Additionally, patient satisfaction levels were shown to be high, approaching that of the general population. CONCLUSION: Data from the present systematic review suggest that maxillary rehabilitation by four zygomatic implants with no anterior support is a reliable approach. PMID- 25830390 TI - Microcomputed tomography-based assessment of retrieved dental implants. AB - PURPOSE: The aim of this study was to demonstrate the potential of microcomputed tomography (micro-CT) technology in the assessment of retrieved dental implants. Cases are presented to illustrate the value of micro-CT imaging techniques in determining possible mechanical causes for dental implant failures. MATERIALS AND METHODS: Eight retrieved dental implants were randomly selected from a pool and imaged using a micro-CT device. Source voltages (80 to 100 kV) and source-to detector distances (65 to 70 mm) were based on signal quality requirements with an additional criterion of achieving the highest resolution with the sample entirely in the field of view in the projection plane. One additional sample was chosen for histology and tomographic imaging so that the information contained therein could be compared. RESULTS: The micro-CT images displayed high contrast between the implant, bone, and background, with negligible metal artifacts. The micro-CT technology used in this study delivered excellent images of the retrieved implants. As a result of the quality and resolution (pixel size: 5.52 to 6.15 MUm) of the images, surface morphology as well as internal structures of the retrieved implants could be observed in great detail. The majority of the retrieved implants had increased wear, dents, pits, regular shallow scratches, and deep scratches in the implant-to-abutment engagement area. Furthermore, plastic deformations, microcracks, and brittle implant fractures were observed in two implants. CONCLUSION: The mechanical competence of dental implant components plays a major role in the success of implant treatment. When failures do occur, a nondestructive three-dimensional assessment of such failed implants and their components is helpful in understanding the underlying factors. Micro-CT was found to be a useful tool for the morphologic assessment of retrieved dental implants. PMID- 25830391 TI - Ridge preservation surgery after single and multiple adjacent tooth extractions: a microcomputed tomography study in dogs. AB - PURPOSE: The aim of this study was to determine, before implant placement, the outcome of ridge preservation surgery after extractions of one or more adjacent teeth on the dimensions of the edentulous ridge. MATERIALS AND METHODS: Nineteen extraction sites in four dogs were randomly divided into three groups: group 1 = single premolars (n = 7 sites); group 2 = two adjacent premolars (n = 6 sites); group 3 = three adjacent premolars (n = 6 sites). Extraction was followed by ridge preservation surgery using a combination of xenograft and collagen membrane after full-thickness flap reflection. All animals were sacrificed 4 months later, and each extraction site was sectioned in the sagittal plane so that alveolar bone measurements could be made in both the buccolingual and apicocoronal directions using microcomputed tomography. RESULTS: Mean buccolingual width of the ridges postsurgery was 4.80 +/- 2.78 mm, 4.98 +/- 2.65 mm, and 4.79 +/- 2.79 mm in groups 1, 2, and 3, respectively. The mean vertical distance from the cementoenamel junction to the crest of the ridge was 1.94 +/- 0.42 mm, 2.05 +/- 0.48 mm, and 2.60 +/- 0.67 mm in groups 1, 2, and 3, respectively. No statistically significant difference was seen between single and multiple extraction sites. CONCLUSION: Ridge preservation surgery results in a similar pattern of bone remodeling in the horizontal and vertical dimensions of the edentulous ridge after single and multiple adjacent tooth extractions. PMID- 25830392 TI - Digitally produced fiber-reinforced composite substructures for three-unit implant-supported fixed dental prostheses. AB - PURPOSE: This study aimed to evaluate the probability of survival, Weibull modulus, characteristic strength, and failure modes of computer-aided design/computer-assisted manufacture (CAD/CAM) fiber-reinforced composite (FRC) substructures used for implant-supported fixed dental prostheses (ISFDPs). MATERIALS AND METHODS: Three-unit ISFDPs (first molar pontic) fabricated as a monolithic composite piece or as composite veneered on a CAD/CAM FRC substructure with either a 12-mm2 or 3-mm2 connector area (n = 18 each) were subjected to step stress accelerated life testing in water. Use-level probability Weibull curves and the probability of survival were calculated. Fractographic analysis was performed under polarized light and scanning electron microscopy. RESULTS: Fatigue did not accelerate the failure of any group, whereas prosthesis strength was the main factor in increased failure (beta < 1). The probability Weibull contour plot showed no differences between the ISFDPs with 12 mm2 and the monolithic composite ISFDP in characteristic strength (eta = 643.5 N and 742.7 N, respectively) or Weibull modulus (6.7 and 5.8, respectively), whereas both were significantly higher than 3 mm2 (444.91 N and 9.57). The probability of survival was not statistically different between groups at 100,000 mission cycles at 300 N. Differences were observed in fatigue failures above 800 N; monolithic composite ISFDPs failed catastrophically, whereas those with CAD/CAM FRC substructures presented veneer/composite cohesive or adhesive failures. Cracks evolved from the occlusal contact toward the margins of the cohesively failed composite, and in CAD/CAM FRC prostheses, competing failure modes of cracks developing at the connector area with those at the indentation contact were observed. CONCLUSION: The probability of survival did not differ between CAD/CAM FRC with either 3-mm2 or 12-mm2 connector areas, monolithic composite, or metal ceramic ISFDPs previously tested under the same methodology. However, differences in failure modes were detected between groups. PMID- 25830393 TI - Systematic literature review of digital three-dimensional superimposition techniques to create virtual dental patients. AB - PURPOSE: Digital developments have led to the opportunity to compose simulated patient models based on three-dimensional (3D) skeletal, facial, and dental imaging. The aim of this systematic review is to provide an update on the current knowledge, to report on the technical progress in the field of 3D virtual patient science, and to identify further research needs to accomplish clinical translation. MATERIALS AND METHODS: Searches were performed electronically (MEDLINE and OVID) and manually up to March 2014 for studies of 3D fusion imaging to create a virtual dental patient. Inclusion criteria were limited to human studies reporting on the technical protocol for superimposition of at least two different 3D data sets and medical field of interest. RESULTS: Of the 403 titles originally retrieved, 51 abstracts and, subsequently, 21 full texts were selected for review. Of the 21 full texts, 18 studies were included in the systematic review. Most of the investigations were designed as feasibility studies. Three different types of 3D data were identified for simulation: facial skeleton, extraoral soft tissue, and dentition. A total of 112 patients were investigated in the development of 3D virtual models. CONCLUSION: Superimposition of data on the facial skeleton, soft tissue, and/or dentition is a feasible technique to create a virtual patient under static conditions. Three-dimensional image fusion is of interest and importance in all fields of dental medicine. Future research should focus on the real-time replication of a human head, including dynamic movements, capturing data in a single step. PMID- 25830394 TI - Comparison of the efficacy of different types of lasers for the treatment of peri implantitis: a systematic review. AB - PURPOSE: To evaluate the efficacy of various types of lasers (neodymium-doped yttrium-aluminum-garnet [Nd:YAG], carbon dioxide [CO2], diode, erbium/chromium doped yttrium-scandium-gallium-garnet [Er,Cr:YSGG], and erbium-doped yttrium aluminum-garnet [Er:YAG]) in the treatment of peri-implantitis and their use in surgical and nonsurgical procedures. MATERIALS AND METHODS: Human studies for the treatment of peri-implantitis with laser therapy, published between 2002 and January 2014, were collected utilizing the electronic databases PubMed, Ovid, MEDLINE, Cochrane, and Google Scholar. Two reviewers conducted the study selection, data collection, and validity assessment. RESULTS: Eight hundred twelve studies were selected in the initial title search; 13 studies were then chosen for this review. No human studies evaluated the effect of the Nd:YAG laser on peri-implantitis. The CO2 laser is reported to be safe and able to enhance bone regeneration. The diode laser (980 nm) seems to be effective in its bactericidal effect without changing the implant surface pattern. The Er,Cr:YSGG laser was reported to obtain bone regeneration around a failing implant in one case, while the Er:YAG laser exhibits a strong bactericidal effect against periodontopathic bacteria at a low energy level. CONCLUSION: Although lasers have shown promising results in reducing clinical signs of peri-implantitis, because of the limited sample sizes and short follow-up periods, no firm conclusion can be drawn at this moment. Hence, there is a need for more well-designed, longitudinal, randomized controlled clinical trials. PMID- 25830395 TI - Fracture strength study of internally connected zirconia abutments reinforced with titanium inserts. AB - PURPOSE: The implant-abutment connection area is known to be the weakest part of an internal-connection zirconia abutment and therefore the most likely to fracture. The aim of this study was to evaluate the complementary effect of a titanium insert on the fracture strength of a zirconia abutment. MATERIALS AND METHODS: Three types of abutments with internal connection structures were selected and assembled: titanium abutment-titanium abutment screw (Ti-Ti), zirconia abutment-titanium abutment screw (Zr-Ti), and zirconia abutment-titanium insert-titanium abutment screw (Zr+Ti-Ti). Fifteen abutments and 15 implants were used and divided into three groups of five specimens each. Compressive loading was applied to the specimens at 30 degrees off-axis with dislocation speed of 1 mm/min and was increased until deformation occurred. RESULTS: The Ti-Ti specimens showed the highest maximum fracture load, followed by the Zr+Ti-Ti specimens; the Zr-Ti assemblies were the weakest. Significant differences in fracture strength were found between the groups. All of the investigated Zr abutments fractured. However, in the Zr+Ti-Ti specimens, 60% of the Ti abutment screws fractured and 40% bent, whereas all of the abutment screws in the Zr-Ti group were only bent. CONCLUSION: The Ti insert, as a substitute for the weakest part of a Zr abutment in an implant with an internal friction connection, can reinforce the fracture strength of a Zr abutment. PMID- 25830396 TI - Assessment of implant cumulative survival rates in sites with different bone density and related prognostic factors: an 8-year retrospective study of 2,684 implants. AB - PURPOSE: This retrospective study was set to explore the influence of local bone density (BD) on implant cumulative survival rates (ICSRs) and to assess prognostic factors associated with implant failure at sites with different BD. MATERIALS AND METHODS: Between January 2005 and December 2011, 2,684 implants were placed in 1,377 patients and included in the study. Implants at sites with different BD were divided into four groups (G1 to G4) according to the Lekholm and Zarb classification, corresponding to bone types 1 to 4. ICSRs and the reasons for failure in each group were evaluated. Factors related to the local distribution of BD were also analyzed. A number of predictive variables were examined by univariate and multivariate analyses to evaluate prognostic factors and their influence on implant failure rates. RESULTS: In total, 45 implants were lost, resulting in ICSRs for G1 to G4 of 100%, 98.18%, 96.83%, and 92.25%, respectively. The main reasons for failure in each group were failed osseointegration and occlusal overloading. Low BD was associated with advanced age (> 50 years) and the posterior maxilla. Based on multivariate analysis, diabetes mellitus and nonthreaded implants were significant factors in the high BD group (G2), while advanced age, smoking, nonthreaded implants, and immediate loading were risk factors for the low-BD group (G3 and G4). CONCLUSION: BD is one of the most important factors influencing the long-term ICSR, which decreases with decreasing BD values. Accurate risk evaluation for sites with different BD before implantation will be beneficial to implant survival. PMID- 25830398 TI - Retrospective study of pterygoid implants in the atrophic posterior maxilla: implant and prosthesis survival rates up to 3 years. AB - PURPOSE: Few reports have evaluated cumulative survival rates of implants placed in the pterygoid region in the medium term. The objective of this study was to evaluate success rates of pterygoid implants and prostheses in patients treated in the atrophic posterior maxilla. MATERIALS AND METHODS: A retrospective study was performed of patients with an atrophic posterior maxilla rehabilitated with pterygoid implants between 1999 and 2010 and followed for at least 36 months after implant loading. Two outcome variables were considered: implant success and prosthesis success. The following predictor variables were recorded: sex, age, implant placement angulation, number and size of implants, prosthetic rehabilitation, bone loss, date of prosthesis delivery, and date of last follow up. A statistical model was used to estimate the survival rates and associated confidence intervals. Data were analyzed using the Kaplan-Meier method and log rank test to compare survival curves. RESULTS: A total of 238 titanium implants (172 anterior and 66 pterygoid) were placed in 56 patients. The 3-year overall pterygoid implant survival rate was 99%. The 3-year overall prosthesis survival rate was 97.7%. The mean bone loss around pterygoid implants after 3 years of loading was 1.21 mm (range, 0.31 to 1.75). All patients were wearing the prostheses at the most recent follow-up examination. CONCLUSION: Placement of implants in the pterygoid region is a viable alternative treatment modality for rehabilitation of patients with an atrophic posterior maxilla. PMID- 25830397 TI - Prediction of implant loss and marginal bone loss by analysis of dental panoramic radiographs. AB - PURPOSE: One of the major factors governing implant success is the quantity and density of the host bone. The aim of this work was to determine whether mandibular bone texture and cortical width measurements on plain radiographs could be associated with implant failure and/or marginal bone loss. MATERIALS AND METHODS: A statistical model was built to predict implant failure; it incorporated several radiographic features of cortical and cancellous bone texture, cortical width, and patient smoking habits. Cortical width measurements and texture measurements of cortical and cancellous bone were made on the panoramic radiographs of 460 subjects. These were used to predict implant failure and marginal bone loss after 5 years. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to determine the diagnostic accuracy of the variables in predicting implant failure and marginal bone loss. Additionally, for 91 of 460 subjects with periapical radiographs, marginal bone levels around implants were measured over a 5-year period. RESULTS: Of the 460 patients assessed for implant failure, 29 had failed implants (93.7% success rate). The ROC curve built from this model had a sensitivity of 62.1% and specificity of 67.5%. The AUC from the model was 0.690 (95% confidence interval [CI] 0.597 to 0.783). A model was also built to predict marginal bone loss. The ROC curve had 78.6% sensitivity and 74.6% specificity (AUC = 0.880, 95% CI = 0.810 to 0.953). Mandibular cortical width was not a significant predictor of either implant failure or bone loss. CONCLUSION: In a retrospective analysis 5 years after implant placement, features of cancellous and cortical bone of the mandible were significant in predicting implant failure and marginal bone loss in a sample of 460 patients. PMID- 25830399 TI - Influence of the crown-implant connection on the preservation of peri-implant bone: a retrospective multifactorial analysis. AB - PURPOSE: Control over marginal bone loss (MBL) and its progression is critical for preserving peri-implant tissue health. A moderate MBL over the first year has conventionally been associated with clinical success. However, different implants are associated with distinct amounts of MBL during their first functional year. Therefore, this study evaluated the MBL in pristine maxillary bone around implants with different types of implant-abutment connections and sought to determine the effect of other clinical factors on this tissue response. MATERIALS AND METHODS: Two hundred forty-six implants were placed in 101 patients with a mean age of 54.43 years. The MBL around two different types of implants (internal versus external prosthetic connection) was evaluated at 6 and 18 months after loading. Different variables were recorded to analyze their influence on radiographic parameters using a complex samples general linear model. RESULTS: At 18 months, MBL ranged from 0 to 3.56 mm; less than 1 mm was lost around 46.3% (mesial) and 40.2% (distal) of the implants, while no bone was lost around 19.5% (mesial) and 19.9% (distal). The MBL was significantly higher around external than internal connections (0.714 vs 0.516 mm/year, respectively). Age, smoking habit, and connection type were directly related to mesial and distal MBL at 6 and 18 months postloading. CONCLUSION: Implant design is a key factor in peri implant MBL. Age and smoking also play major roles in maintaining the stability of peri-implant bone. PMID- 25830400 TI - Effects of implant-based prostheses on mastication, nutritional intake, and oral health-related quality of life in partially edentulous patients: a paired clinical trial. AB - PURPOSE: This study evaluated the effects of different implant-based prostheses on swallowing threshold, dietary intake, and oral health-related quality of life (OHRQoL). MATERIALS AND METHODS: This prospective paired controlled clinical trial followed partially edentulous subjects, who sequentially used implant supported removable partial dentures and implant-supported fixed partial dentures (IFPDs). Swallowing threshold was assessed by counting the masticatory cycles and median particle size (X50) calculation. Nutritional intake was verified by a 3 day food record. OHRQoL was measured with the Oral Health Impact Profile (OHIP 49). Data were evaluated with repeated-measures analysis of variance. RESULTS: Twelve subjects (mean age 62.6 +/- 7.8 years; range, 55 to 87) took part in the study. IFPD treatment significantly reduced X50 values and the number of chewing cycles. Higher intake of fiber, calcium, and iron and lower consumption of cholesterol-rich food were observed after IFPD use. OHIP summary score and OHIP physical pain domain were lower with the IFPD. CONCLUSION: IFPD use leads to more efficient mastication and improves dietary intake and OHRQoL. This information will guide dentists to better clinical management of partially edentulous patients. PMID- 25830401 TI - Innovative approach to computer-guided surgery and fixed provisionalization assisted by screw-retained transitional implants. AB - PURPOSE: The objectives of this case series are to describe a novel clinical approach to treat completely edentulous patients and determine its viability. Computer-guided implant planning was used to create a screw-retained surgical template (ST) supported by transitional implants and a fixed screw-retained provisional prosthesis supported by the transitional implants at the time of definitive implant placement. MATERIALS AND METHODS: Five patients with at least one edentulous arch were treated. After the diagnostic tooth setup was performed, a duplicate with radiopaque acrylic resin was fabricated to serve as a surgical template (ST) for the placement of screw-form transitional implants and a radiographic guide (RG). Four transitional implants were strategically placed through the guide where they would not interfere with the future definitive implants. The transitional implants were used to support the RG during computed tomographic scanning. Subsequently, the RG was converted into a second ST based on three-dimensional virtual planning. Eight implants were placed by the computer guided system, and an immediate prefabricated fixed provisional was connected to the transitional implants. RESULTS: All the implants included in the study achieved primary stability and osseointegrated successfully. For 4 months, the transitional implants served successfully as abutments for the provisional prosthesis. CONCLUSION: This innovative clinical approach overcomes the limitations of a mucosa/bone-supported ST by offering fixed, reproducible support for the RG and ST by means of transitional implants. The delivery of a prefabricated screw-retained provisional on transitional implants allows for passive healing and minimum chairside adjustments. PMID- 25830402 TI - Clinical evaluation of marginal bone level change around multiple adjacent implants restored with splinted and nonsplinted restorations: a 10-year randomized controlled trial. AB - PURPOSE: The management of occlusal forces on implant restorations may influence their long-term prosthetic success. The purpose of this randomized controlled trial was to compare marginal bone level changes around adjacent splinted and nonsplinted implants, functionally loaded with cemented restorations, up to 10 years in maxillae. MATERIALS AND METHODS: During 2002 and 2003, all patients who received three adjacent implants in a private office and a university setting were included in this study. All implants featured an external-hexagon design and were placed in the posterior maxilla. Implants in the left maxilla were randomly selected to be restored with splinted cemented restorations; maxillary right implants were restored with nonsplinted cemented restorations. Marginal bone resorption was measured with intraoral radiographs yearly over a period of at least 10 years after placement of abutments and restorations. The amount of bone loss in each group was analyzed with the two-sample Wilcoxon rank-sum (Mann Whitney) test because variable bone loss was normally distributed at the fifth year only. RESULTS: One hundred thirty-two implants were placed in 44 patients. Three implants failed at stage-two surgery. Five years after initial loading, two patients moved away and were lost to follow-up (6 implants in total); three additional patients did not complete the study (9 implants in total). Of the remaining 114 implants, 60 left implants were restored with splinted cemented restorations and 54 right implants were restored with nonsplinted cemented restorations. At 10 years, the splinted group showed a mean of 1.2 mm (interquartile range: 0.2 mm) of bone loss; the nonsplinted group showed 1.3 mm (interquartile range: 0.2 mm). CONCLUSION: A significant difference in bone loss was seen between the two groups. However, the difference of 0.1 mm was not considered clinically meaningful. PMID- 25830403 TI - Biomechanical in vitro evaluation of two full-arch rehabilitations supported by four or five implants. AB - PURPOSE: The aim of this in vitro study was to evaluate the stress pattern on the abutments in two different full-arch implant-supported clinically equivalent prosthetic rehabilitations. MATERIALS AND METHODS: Two steel master casts were created and titanium implants were inserted in two different configurations. One configuration used four implants, with the distal implants tilted 30 degrees (4IMP configuration), and the other used five axially inclined implants (5IMP configuration). A straight multiunit abutment (MUA) was connected to every axial implant and a 30-degree angulated MUA was connected to each tilted implant. One titanium framework was fabricated for each configuration, with a 5-mm (4IMP configuration) or a 15-mm (5IMP configuration) distal cantilever length. Six cycles of vertical loading between 20 and 200 N were applied unilaterally at the most distal point of the frameworks on both sides. Readings of the deformations at the abutment level were obtained with the use of linear strain gauges. RESULTS: A similar pattern of deformation was seen in both configurations. The greatest compressive stress was measured by the strain gauge on the abutment closest to load application and was similar for the 4IMP and 5IMP configurations. The tensile stress measured on the same abutment was higher in the 5IMP configuration than in the 4IMP configuration. In terms of the distribution of stresses, the deformation measured on the central abutment in the 5IMP configuration was less than 10% of the overall stress in all the tested conditions. CONCLUSION: There was no difference in strain between the two different designs, so the use of tilted implants with angulated abutments to reduce cantilever length could be considered a viable clinical option. PMID- 25830404 TI - Immediate versus conventional loading with fixed full-arch prostheses in mandibles with failing dentition: a prospective controlled study. AB - PURPOSE: To compare immediate and conventional loading protocols for fixed full arch mandibular prostheses supported by immediate and nonimmediate implants. MATERIALS AND METHODS: A prospective controlled nonrandomized study with 12 months of follow-up included patients requiring fixed full-arch rehabilitations supported by immediate and nonimmediate implants. Eighteen patients were treated with conventional loading (control group), and 18 were treated with immediate loading (test group). Each patient received four to six implants; implants with insertion torque < 35 Ncm were excluded from the study and loaded conventionally. The following variables were assessed: implant success, biologic and prosthetic complications, success of the immediately loaded provisional prostheses, and marginal bone loss. Statistical analysis was performed with nonparametric tests (chi-square, Mann-Whitney, Kruskal-Wallis) with an alpha value of .05. RESULTS: Thirty-six patients consecutively enrolled in the study. Two control group patients failing to attend control visits and 12 implants that did not achieve an insertion torque of 35 Ncm were excluded. The final sample consisted of 34 patients and 183 implants (98 test and 85 control implants). Implant success rates were 99.0% (test) and 97.6% (control). Within the test group, success rates for immediate and nonimmediate implants were 100% and 97.6%, respectively. Differences were not statistically significant. All immediately loaded prostheses were successful. Five provisional fixed prostheses presented with loosened screws; all control group patients reported discomfort with the provisional denture. Average bone loss was 0.71 mm (standard deviation 0.25 mm) in the test group and 0.60 mm (standard deviation 0.28 mm) in the control group. CONCLUSION: No significant differences were seen in implant success and peri-implant marginal bone loss between immediate and conventional loading of mandibular fixed full arch prostheses supported by immediate and nonimmediate implants. Biologic and prosthetic complications were rare, and all immediately loaded provisional fixed prostheses performed successfully. PMID- 25830405 TI - Bone repair of surgical defects filled with autogenous bone and covered with demineralized bone matrix membrane or polytetrafluoroethylene membrane in rats. AB - PURPOSE: The aim of this study was to evaluate the behavior of a demineralized bone matrix membrane and a polytetrafluoroethylene (PTFE) membrane in the process of bone repair of surgical defects filled with autogenous bone in rats. MATERIALS AND METHODS: Sixty rats weighing approximately 250 g each were selected and separated into three groups: control group without membrane, demineralized bone matrix membrane group, and PTFE membrane group. Bilaterally, surgical defects of 2 mm in diameter were prepared in the tibiae. The defect in the left tibia was filled with particulate autogenous bone collected during the creation of the two defects and was left uncovered (control) or was covered with the membranes investigated by the present study. At 10 or 60 days postoperatively, the rats were euthanized and the left tibiae were submitted to routine laboratory processing for histomorphometric analysis. All groups were evaluated separately on the 10th and 60th days after surgery. The Kruskal-Wallis test was used for group comparison. RESULTS: The membrane-treated defects showed a delay in healing. Sites treated with demineralized bone matrix membrane showed, as early as day 10, more newly formed bone and slow replacement until day 60. At day 60, the sites covered with demineralized bone matrix membrane and with synthetic membrane showed statistically significant results. CONCLUSION: The demineralized bone matrix membrane proved to be biocompatible. In terms of newly formed bone area, both membranes showed similar performance. PMID- 25830406 TI - Clinical outcome of the use of fresh frozen allogeneic bone grafts for the reconstruction of severely resorbed alveolar ridges: preliminary results of a prospective study. AB - PURPOSE: The objectives of this study were to evaluate: (1) the clinical outcome of fresh frozen human allogeneic bone grafts (FFB) used for the reconstruction of severely atrophied edentulous ridges; (2) the survival rate of implants placed in the reconstructed areas; and (3) bone resorption. MATERIALS AND METHODS: During a 2-year period, 19 patients with severely atrophied partially or totally edentulous ridges who were candidates for an implant-supported prosthesis were consecutively enrolled and reconstructed with FFB iliac blocks. Five to 7 months later, 117 implants were placed in the reconstructed areas, and prosthetic rehabilitation was started 5 to 6 months afterward. RESULTS: The mean follow-up of patients after prosthetic loading was 27 months (range, 20 to 32 months). Prior to implant placement, graft exposure with partial or total loss of the graft occurred in four patients. After implant placement, bone graft exposures with partial loss of the grafts occurred in nine patients; in two patients, both grafts and implants were removed. The cumulative survival rate of implants was 90.2%. The mean (+/- standard deviation) graft resorption before implant placement was 0.98 +/- 0.77 mm (range, 0 to 4 mm), while these values were 1.21 +/- 1.05 mm (range, 0 to 6 mm) at loading, 1.55 +/- 1.57 mm (range, 0 to 8 mm) at 12 months, and 1.93 +/- 1.38 mm (range, 1 to 9 mm) at 24 months. CONCLUSION: Within the limits of this study (limited sample of patients and short follow-up), the reconstruction of severely atrophic edentulous ridges with FFB is associated with a relevant incidence of bone exposures and partial or total loss of the grafts, which may compromise the long-term survival of implants placed in the reconstructed areas. PMID- 25830407 TI - Osteogenesis of rat mesenchymal stem cells and osteoblastic cells on strontium doped nanohydroxyapatite-coated titanium surfaces. AB - PURPOSE: The aim of this study was to compare the promotion of osteogenesis in vitro on three types of titanium surfaces: a strontium-hydroxyapatite (Sr-HA) coated surface, a nano-HA-coated surface, and an uncoated roughened surface. MATERIALS AND METHODS: Sr-HA and HA were placed on disks with a roughened titanium surface by electrochemical deposition. MC3T3-E1 preosteoblast cells and rat bone mesenchymal stem cells were cultured on the Sr-HA, HA-coated, and uncoated roughened disks, and cell adhesion, proliferation, viability, osteogenic differentiation, and formation of mineralized nodules were measured at various time points. RESULTS: The Sr-HA coating produced by a simple electrochemical deposition treatment evidently enhanced the attachment, spreading, alkaline phosphatase activity, and extracellular matrix calcium mineralization of mouse bone mesenchymal stem cells and MC3T3-E1 cells compared with an untreated roughened titanium surface and a nano-HA-coated surface. CONCLUSION: This study suggests that a Sr-doped nano-HA coating produced through electrochemical deposition improves the osteoconductivity of a microrough titanium surface. PMID- 25830408 TI - In vitro and in vivo imaging of ultra-high-molecular-weight polyethylene orbital implants. AB - The aim of this study is to compare magnetic resonance imaging (MRI) with computed tomography (CT) for visualization of an orbital alloplastic prosthesis made of ultra-high-molecular-weight polyethylene (UHMW-PE) both in vitro and in vivo. A study of 15 test implants from UHMW-PE visualized in vitro in CT and MRI and an in vivo visualization in a patient who suffered from orbital injury and underwent reconstructive surgery is presented. The postsurgery MRI showed the UHMW-PE material clearly, with no significant artifacts. The surrounding tissues could be satisfactorily evaluated. The CT scans did not present the graft material. Both techniques were sufficient tools for in vitro evaluation of the shape and measurement of the prosthesis. PMID- 25830409 TI - Investigation of the electronic ground states for a reduced pyridine(diimine) uranium series: evidence for a ligand tetraanion stabilized by a uranium dimer. AB - The electronic structures of a series of highly reduced uranium complexes bearing the redox-active pyridine(diimine) ligand, (Mes)PDI(Me) ((Mes)PDI(Me) = 2,6 (2,4,6-Me3-C6H2-N?CMe)2C5H3N) have been investigated. The complexes, ((Mes)PDI(Me))UI3(THF) (1), ((Mes)PDI(Me))UI2(THF)2 (2), [((Mes)PDI(Me))UI]2 (3), and [((Mes)PDI(Me))U(THF)]2 (4), were examined using electronic and X-ray absorption spectroscopies, magnetometry, and computational analyses. Taken together, these studies suggest that all members of the series contain uranium(IV) centers with 5f (2) configurations and reduced ligand frameworks, specifically [(Mes)PDI(Me)](*/-), [(Mes)PDI(Me)](2-), [(Mes)PDI(Me)](3-) and [(Mes)PDI(Me)](4-), respectively. In the cases of 2, 3, and 4 no unpaired spin density was found on the ligands, indicating a singlet diradical ligand in monomeric 2 and ligand electron spin-pairing through dimerization in 3 and 4. Interaction energies, representing enthalpies of dimerization, of -116.0 and 144.4 kcal mol(-1) were calculated using DFT for the monomers of 3 and 4, respectively, showing there is a large stabilization gained by dimerization through uranium-arene bonds. Highlighted in these studies is compound 4, bearing a previously unobserved pyridine(diimine) tetraanion, that was uniquely stabilized by backbonding between uranium cations and the eta(5)-pyridyl ring. PMID- 25830410 TI - Potentiometric study of antioxidant activity: development and prospects. AB - The increasing interest in the study of the antioxidant activity of different objects is caused by an unbalance between the formation of reactive oxygen species (ROS) and the performance of the antioxidant system in humans under certain conditions, which leads to oxidative stress and pathological states of the organism. This article presents a brief critical review of the methods that are used to measure integrated antioxidant activity (AOA). It is shown that the most promising methods for measuring AOA are electrochemical ones, particularly potentiometry, as it best fits the nature of the processes causing oxidative stress. The article gives the theoretical rational for requirements that an oxidizer of antioxidants (AO) should meet. The work presents the thermodynamic grounds for the use of an earlier proposed mediator system, kinetics of chemical reactions between AO and the mediator system. In order to confirm reliability and accuracy of the results, numerous correlation studies were conducted, aiming to compare the data obtained with the use the proposed method and independent analytical methods. The article presents the results of the potentiometric study of AOA for a variety of objects, including individual antioxidant -> nutritional supplements -> food -> blood and blood fractions. PMID- 25830411 TI - Motor imagery and cortico-spinal excitability: A review. AB - Motor imagery (MI) has received a lot of interest during the last decades as its chronic or acute use has demonstrated several effects on improving sport performances or skills. The development of neuroimagery techniques also helped further our understanding of the neural correlates underlying MI. While some authors showed that MI, motor execution and action observation activated similar motor cortical regions, transcranial magnetic stimulation (TMS) studies brought great insights on the role of the primary motor cortex and on the activation of the cortico-spinal pathway during MI. After defining MI and describing the TMS technique, a short report of MI activities only at cortical level is provided. Then, a main focus on the specificities of cortico-spinal modulations during MI, investigated by TMS, is provided. Finally, a brief overview of sub-cortical mechanisms gives importance to the activation of peripheral neural structures during MI. PMID- 25830412 TI - Cutaneous vasculitis and inflammatory bowel diseases. AB - Extraintestinal manifestations occur in up to 40% of patients living with inflammatory bowel disease (IBD) and may precede the onset of gastrointestinal symptoms by many years. Vasculitides are considered rare cutaneous manifestations, but they often represent an important cause of morbidity and a relevant diagnostic issue in IBD. In addition, the increasing use of biological therapies for IBD may also play a pivotal role in the development of vascular disorders of different type. Hence, we provide a complete and in-depth review of the main features of cutaneous vasculitides observed in IBD, with a specific focus on their clinical presentation and possible pathophysiological mechanisms. PMID- 25830413 TI - Oral infections: clinical and biological perspectives. PMID- 25830414 TI - Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents. AB - Necrotic cell death triggers a range of biological responses including a strong adaptive immune response, yet we know little about the cellular pathways that control necrotic cell death. Inhibitor studies suggest that proteases, and in particular cathepsins, drive necrotic cell death. The cathepsin B-selective inhibitor CA-074-Me blocks all forms of programmed necrosis by an unknown mechanism. We found that cathepsin B deficiency does not prevent induction of pyroptosis and lysosome-mediated necrosis suggesting that CA-074-Me blocks necrotic cell death by targeting cathepsins other than cathepsin B. A single cathepsin, cathepsin C, drives necrotic cell death mediated by the lysosome destabilizing agent Leu-Leu-OMe (LLOMe). Here we present evidence that cathepsin C-deficiency and CA-074-Me block LLOMe killing in a distinct and cell type specific fashion. Cathepsin C-deficiency and CA-074-Me block LLOMe killing of all myeloid cells, except for neutrophils. Cathepsin C-deficiency, but not CA-074-Me, blocks LLOMe killing of neutrophils suggesting that CA-074-Me does not target cathepsin C directly, consistent with inhibitor studies using recombinant cathepsin C. Unlike other cathepsins, cathepsin C lacks endoproteolytic activity, and requires activation by other lysosomal proteases, such as cathepsin D. Consistent with this theory, we found that lysosomotropic agents and cathepsin D downregulation by siRNA block LLOMe-mediated necrosis. Our findings indicate that a proteolytic cascade, involving cathepsins C and D, controls LLOMe-mediated necrosis. In contrast, cathepsins C and D were not required for pyroptotic cell death suggesting that distinct cathepsins control pyroptosis and lysosome mediated necrosis. PMID- 25830415 TI - Tctex1d2 associates with short-rib polydactyly syndrome proteins and is required for ciliogenesis. AB - Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical for cilia assembly and function. Recently, mutations in WDR34 or WDR60 (candidate dynein intermediate chains) were identified in SRPS. We have identified and characterized Tctex1d2, which associates with Wdr34, Wdr60 and other dynein complex 1 and 2 subunits. Tctex1d2 and Wdr60 localize to the base of the cilium and their depletion causes defects in ciliogenesis. We propose that Tctex1d2 is a novel dynein light chain important for trafficking to the cilium and potentially retrograde IFT and is a new molecular link to understanding SRPS pathology. PMID- 25830416 TI - The effect of cluster size variability on statistical power in cluster-randomized trials. AB - The frequency of cluster-randomized trials (CRTs) in peer-reviewed literature has increased exponentially over the past two decades. CRTs are a valuable tool for studying interventions that cannot be effectively implemented or randomized at the individual level. However, some aspects of the design and analysis of data from CRTs are more complex than those for individually randomized controlled trials. One of the key components to designing a successful CRT is calculating the proper sample size (i.e. number of clusters) needed to attain an acceptable level of statistical power. In order to do this, a researcher must make assumptions about the value of several variables, including a fixed mean cluster size. In practice, cluster size can often vary dramatically. Few studies account for the effect of cluster size variation when assessing the statistical power for a given trial. We conducted a simulation study to investigate how the statistical power of CRTs changes with variable cluster sizes. In general, we observed that increases in cluster size variability lead to a decrease in power. PMID- 25830418 TI - Simplified process for preparation of schizophyllan solutions for biomaterial applications. AB - Schizophyllan is a biopolymer commercially produced for pharmaceutical and cosmetics uses. However, schizophyllan also has potential biomaterial applications. Schizophyllan is conventionally produced from glucose and recovered by diafiltration and ultrafiltration to produce a highly purified product. Here we demonstrate a simplified process for preparation of schizophyllan solutions for biomaterial applications. Schizophyllan was produced in 1.5-L bioreactors from distiller's dried grains with solubles (DDGS), an abundant coproduct of dry grind fuel ethanol production. Downstream processing eliminated filtration and concentration steps, providing solutions containing 4.2 +/- 0.3 g schizophyllan/L. Solutions contained high-molecular-weight schizophyllan and exhibited viscosity properties similar to those of commercial schizophyllan. Schizophyllan solutions showed promise as a component of biolubricants in friction and wear tests and by dynamic surface and interfacial tension measurements. PMID- 25830417 TI - Recent developments in imaging of pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (PNETs) are very rare, accounting for 1-2% of all pancreatic neoplasms. They are classified into functioning and non functioning and their behavior varies widely from benign to highly malignant. For their investigation, a variety of anatomical and functional imaging methods are available. Anatomical methods include computed tomography (CT), magnetic resonance imaging, and ultrasonography. Functional methods include scintigraphy and positron emission tomography (PET). A combination of anatomical and morphological methods results in the so-called hybrid imaging, such as PET/CT. We herein discuss the currently available imaging modalities for the investigation of PNETs and, more specifically, their applications in tumor detection and staging as well as in choice of therapy, imaging follow up and prediction of response, with emphasis on the recent developments. PMID- 25830419 TI - Lessons from the East--China's rapidly evolving health care system. PMID- 25830420 TI - Informed consent and the First Amendment. PMID- 25830421 TI - Antibiotic treatment strategies for community-acquired pneumonia in adults. AB - BACKGROUND: The choice of empirical antibiotic treatment for patients with clinically suspected community-acquired pneumonia (CAP) who are admitted to non intensive care unit (ICU) hospital wards is complicated by the limited availability of evidence. We compared strategies of empirical treatment (allowing deviations for medical reasons) with beta-lactam monotherapy, beta-lactam macrolide combination therapy, or fluoroquinolone monotherapy. METHODS: In a cluster-randomized, crossover trial with strategies rotated in 4-month periods, we tested the noninferiority of the beta-lactam strategy to the beta-lactam macrolide and fluoroquinolone strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval. RESULTS: A total of 656 patients were included during the beta-lactam strategy periods, 739 during the beta-lactam macrolide strategy periods, and 888 during the fluoroquinolone strategy periods, with rates of adherence to the strategy of 93.0%, 88.0%, and 92.7%, respectively. The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], -0.6 to 4.4) with the beta-lactam-macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, -2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. These results indicated noninferiority of the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies. CONCLUSIONS: Among patients with clinically suspected CAP admitted to non-ICU wards, a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam-macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality. (Funded by the Netherlands Organization for Health Research and Development; CAP-START ClinicalTrials.gov number, NCT01660204.). PMID- 25830423 TI - Demographic and epidemiologic drivers of global cardiovascular mortality. AB - BACKGROUND: Global deaths from cardiovascular disease are increasing as a result of population growth, the aging of populations, and epidemiologic changes in disease. Disentangling the effects of these three drivers on trends in mortality is important for planning the future of the health care system and benchmarking progress toward the reduction of cardiovascular disease. METHODS: We used mortality data from the Global Burden of Disease Study 2013, which includes data on 188 countries grouped into 21 world regions. We developed three counterfactual scenarios to represent the principal drivers of change in cardiovascular deaths (population growth alone, population growth and aging, and epidemiologic changes in disease) from 1990 to 2013. Secular trends and correlations with changes in national income were examined. RESULTS: Global deaths from cardiovascular disease increased by 41% between 1990 and 2013 despite a 39% decrease in age-specific death rates; this increase was driven by a 55% increase in mortality due to the aging of populations and a 25% increase due to population growth. The relative contributions of these drivers varied by region; only in Central Europe and Western Europe did the annual number of deaths from cardiovascular disease actually decline. Change in gross domestic product per capita was correlated with change in age-specific death rates only among upper-middle income countries, and this correlation was weak; there was no significant correlation elsewhere. CONCLUSIONS: The aging and growth of the population resulted in an increase in global cardiovascular deaths between 1990 and 2013, despite a decrease in age specific death rates in most regions. Only Central and Western Europe had gains in cardiovascular health that were sufficient to offset these demographic forces. (Funded by the Bill and Melinda Gates Foundation and others.). PMID- 25830424 TI - Clinical practice. Emergency contraception. PMID- 25830422 TI - A randomized trial of laparoscopic versus open surgery for rectal cancer. AB - BACKGROUND: Laparoscopic resection of colorectal cancer is widely used. However, robust evidence to conclude that laparoscopic surgery and open surgery have similar outcomes in rectal cancer is lacking. A trial was designed to compare 3 year rates of cancer recurrence in the pelvic or perineal area (locoregional recurrence) and survival after laparoscopic and open resection of rectal cancer. METHODS: In this international trial conducted in 30 hospitals, we randomly assigned patients with a solitary adenocarcinoma of the rectum within 15 cm of the anal verge, not invading adjacent tissues, and without distant metastases to undergo either laparoscopic or open surgery in a 2:1 ratio. The primary end point was locoregional recurrence 3 years after the index surgery. Secondary end points included disease-free and overall survival. RESULTS: A total of 1044 patients were included (699 in the laparoscopic-surgery group and 345 in the open-surgery group). At 3 years, the locoregional recurrence rate was 5.0% in the two groups (difference, 0 percentage points; 90% confidence interval [CI], -2.6 to 2.6). Disease-free survival rates were 74.8% in the laparoscopic-surgery group and 70.8% in the open-surgery group (difference, 4.0 percentage points; 95% CI, -1.9 to 9.9). Overall survival rates were 86.7% in the laparoscopic-surgery group and 83.6% in the open-surgery group (difference, 3.1 percentage points; 95% CI, -1.6 to 7.8). CONCLUSIONS: Laparoscopic surgery in patients with rectal cancer was associated with rates of locoregional recurrence and disease-free and overall survival similar to those for open surgery. (Funded by Ethicon Endo-Surgery Europe and others; COLOR II ClinicalTrials.gov number, NCT00297791.). PMID- 25830425 TI - Molecular physiology of water balance. PMID- 25830426 TI - Images in clinical medicine. Peritoneal loose body. PMID- 25830427 TI - Clinical problem-solving. A history lesson. PMID- 25830428 TI - Adipocytes armed against Staphylococcus aureus. PMID- 25830429 TI - Duration of dual antiplatelet therapy after drug-eluting stents. PMID- 25830430 TI - Duration of dual antiplatelet therapy after drug-eluting stents. PMID- 25830431 TI - Duration of dual antiplatelet therapy after drug-eluting stents. PMID- 25830432 TI - Duration of dual antiplatelet therapy after drug-eluting stents. PMID- 25830433 TI - Duration of dual antiplatelet therapy after drug-eluting stents. PMID- 25830434 TI - Duration of dual antiplatelet therapy after drug-eluting stents. PMID- 25830435 TI - Multiple-system atrophy. PMID- 25830436 TI - Multiple-system atrophy. PMID- 25830437 TI - Multiple-system atrophy. PMID- 25830438 TI - Multiple-system atrophy. PMID- 25830439 TI - Severe Ebola virus infection complicated by gram-negative septicemia. PMID- 25830440 TI - Severe Ebola virus infection complicated by gram-negative septicemia. PMID- 25830441 TI - A case of iced-tea nephropathy. PMID- 25830442 TI - Images in clinical medicine. Transdiaphragmatic intercostal herniation of the gallbladder. PMID- 25830443 TI - Physical Activity Enjoyment, Perceived Barriers, and Beliefs Among Adolescents With and Without Intellectual Disabilities. AB - BACKGROUND: Youths with intellectual disabilities (ID) exhibit low levels of physical activity, but the underlying contributors to behavior are unclear. We compared physical activity enjoyment, perceived barriers, beliefs, and self efficacy among adolescents with ID and typically developing (TD) adolescents. METHODS: A questionnaire was administered to 38 adolescents with ID (mean age, 16.8 years) and 60 TD adolescents (mean age, 15.3 years). Of the original 33 questionnaire items, 23 met the test-retest reliability criteria and were included in the group comparisons. RESULTS: Fewer adolescents with ID reported that they have someone with whom to do physical activity (64% vs 93%: P < .001), and a greater percentage of adolescents with ID perceived that physical activities were too hard to learn (41% vs 0%; P < .001). Fewer adolescents with ID believed that physical activity would be good for their health (92% vs 100%; P = .05). More adolescents with ID reported a dislike of individual physical activities (P = .02). A large percentage of adolescents with ID (84%) responded that they were good at doing physical activities, but the difference between groups was only of borderline significance (95% of TD adolescents, P = .06). CONCLUSIONS: Adolescents shared many of the same perceptions about physical activity, but some important differences between groups were identified. PMID- 25830445 TI - Effectiveness evaluation of existing noise controls in a deep shaft underground mine. AB - Noise exposures and hearing loss in the mining industry continue to be a major problem, despite advances in noise control technologies. This study evaluated the effectiveness of engineering, administrative, and personal noise controls using both traditional and in-ear dosimetry by job task, work shift, and five types of earplug. The noise exposures of 22 miners performing deep shaft-sinking tasks were evaluated during 56 rotating shifts in an underground mine. Miners were earplug-insertion trained, earplug fit-tested, and monitored utilizing traditional and in-ear dosimetry. The mean TWA8 noise exposure via traditional dosimetry was 90.1 +/- 8.2 dBA, while the mean in-ear TWA8 was 79.6 +/- 13.8 dBA. The latter was significantly lower (p < 0.05) than the Mine Safety and Health Administration (MSHA) personal exposure limit (PEL) of 90 dBA. Dosimetry mean TWA8 noise exposures for bench blowing (103.5 +/- 0.9 dBA), jumbo drill operation (103.0 +/- 0.8 dBA), and mucking tasks (99.6 +/- 4.7 dBA) were significantly higher (p < 0.05) than other tasks. For bench blowing, cable pulling, grinding, and jumbo drill operation tasks, the mean in-ear TWA8 was greater than 85 dBA. Those working swing shift had a significantly higher (p < 0.001) mean TWA8 noise exposure (95.4 +/- 7.3 dBA) than those working day shift. For percent difference between traditional vs. in-ear dosimetry, there was no significant difference among types of earplug used. Reflective of occupational hearing loss rate trends across the mining industry, this study found that, despite existing engineering and administrative controls, noise exposure levels exceeded regulatory limits, while the addition of personal hearing protection limited excessive exposures. PMID- 25830444 TI - 'Preconditioning' with low dose lipopolysaccharide aggravates the organ injury / dysfunction caused by hemorrhagic shock in rats. AB - METHODS: Male rats were 'pretreated' with phosphate-buffered saline (PBS; i.p.) or LPS (1 mg/kg; i.p.) 24 h prior to HS. Mean arterial pressure (MAP) was maintained at 30 +/- 2 mmHg for 90 min or until 25% of the shed blood had to be re-injected to sustain MAP. This was followed by resuscitation with the remaining shed blood. Four hours after resuscitation, parameters of organ dysfunction and systemic inflammation were assessed. RESULTS: HS resulted in renal dysfunction, and liver and muscular injury. At a first glance, LPS preconditioning attenuated organ dysfunction. However, we discovered that HS-rats that had been preconditioned with LPS (a) were not able to sustain a MAP at 30 mmHg for more than 50 min and (b) the volume of blood withdrawn in these animals was significantly less than in the PBS-control group. This effect was associated with an enhanced formation of the nitric oxide (NO) derived from inducible NO synthase (iNOS). Thus, a further control group in which all animals were resuscitated after 50 min of hemorrhage was performed. Then, LPS preconditioning aggravated both circulatory failure and organ dysfunction. Most notably, HS-rats pretreated with LPS exhibited a dramatic increase in NF-kappaB activation and pro inflammatory cytokines. CONCLUSION: In conclusion, LPS preconditioning predisposed animals to an earlier vascular decompensation, which may be mediated by an excess of NO production secondary to induction of iNOS and activation of NF kappaB. Moreover, LPS preconditioning increased the formation of pro-inflammatory cytokines, which is likely to have contributed to the observed aggravation of organ injury/dysfunction caused by HS. PMID- 25830447 TI - Cultural background and barriers to mental health care for African American adults. PMID- 25830446 TI - The RAISE early treatment program for first-episode psychosis: background, rationale, and study design. AB - OBJECTIVE: The premise of the National Institute of Mental Health Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) is to combine state-of-the-art pharmacologic and psychosocial treatments delivered by a well-trained, multidisciplinary team in order to significantly improve the functional outcome and quality of life for first-episode psychosis patients. The study is being conducted in non-academic (ie, real-world) treatment settings, using primarily extant reimbursement mechanisms. METHOD: We developed a treatment model and training program based on extensive literature review and expert consultation. Our primary aim is to compare the experimental intervention to "usual care" on quality of life. Secondary aims include comparisons on remission, recovery, and cost-effectiveness. Patients 15-40 years old with a first episode of schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder not otherwise specified, or brief psychotic disorder according to DSM-IV and no more than 6 months of treatment with antipsychotic medications were eligible. Patients are followed for a minimum of 2 years, with major assessments conducted by blinded, centralized raters using live, 2-way video. We selected 34 clinical sites in 21 states and utilized cluster randomization to assign 17 sites to the experimental treatment and 17 to usual care. Enrollment began in July 2010 and ended in July 2012 with 404 subjects. The results of the trial will be published separately. The goal of the article is to present both the overall development of the intervention and the design of the clinical trial to evaluate its effectiveness. CONCLUSIONS: We believe that we have succeeded in both designing a multimodal treatment intervention that can be delivered in real-world clinical settings and implementing a controlled clinical trial that can provide the necessary outcome data to determine its impact on the trajectory of early phase schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01321177. PMID- 25830448 TI - Impulsive versus planned suicide attempts: different phenotypes? PMID- 25830449 TI - Prevalence and correlates of past 12-month suicide attempt among adults with past year suicidal ideation in the United States. AB - OBJECTIVE: To examine the prevalence and correlates of attempting suicide in the past 12 months among adults with past-year suicidal ideation in the United States. METHOD: Data were from 229,600 persons aged 18 years or older who participated in the 2008-2012 National Survey on Drug Use and Health. Among them, 12,300 reported having past-year suicidal ideation, and over 2,000 of those reported attempting suicide within the past 12 months prior to survey interview. Descriptive analyses and pooled and stratified (by suicide plan and major depressive episode [MDE]) multivariate logistic regression models were applied. Major depressive episode was based on assessments of individual diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). RESULTS: Among persons aged 18 years or older in the United States, 3.8% reported having suicidal ideation in the past 12 months. Among past year suicidal ideators, 13.2% attempted suicide in the past 12 months. The prevalence of past 12-month suicide attempt among past-year ideators with MDE was higher than among those without MDE (14.1% vs 12.0%). Past 12-month suicide attempt was more common among ideators with a suicide plan than among ideators without a plan (37.0% vs 3.7%). However, the prevalence of suicide attempt was higher among ideators with a plan but without MDE than among ideators with a plan and MDE (42.1% vs 32.9%). Compared with ideators without a plan, ideators with a plan had a higher (adjusted odds ratio [AOR] = 2.2; 95% confidence interval [CI], 1.47-3.45) suicide attempt risk among those without MDE (AOR = 22.4; 95% CI,16.55 30.27) than among those with MDE (AOR = 10.7; 95% CI, 7.91-14.49). CONCLUSIONS: Among adult suicidal ideators, factors associated with their progression from ideation to suicide attempt may vary by their suicide plan and major depression status. Focusing attention on high-risk subgroups may be warranted. PMID- 25830450 TI - Insight into mental disorders and suicidal behavior: a qualitative and quantitative multimodal investigation. AB - OBJECTIVE: To investigate the association between insight into mental disorders and suicidal behavior. DATA SOURCES: English and French MEDLINE databases up to January 2014 were searched using suicide combined with awareness, consciousness, insight and anosognosia, unawareness, and awareness of illness. We also conducted a cross-sectional study comparing Mood Disorder Insight Scale (MDIS) and 24-item Hamilton Depression Rating Scale (HDRS-24), item 17, performance between 22 depressed (DSM-IV-TR criteria) suicide attempters and 22 patient controls. STUDY SELECTION: Study selection was based on the STROBE checklist. Selected studies were published in an English- or French-language peer-reviewed journal, included at least 1 measure of insight, and included patients with a history of suicidal behavior. Thirty-two studies were reviewed, of which 12 were longitudinal. DATA EXTRACTION: A review of the literature and meta-analysis of studies were conducted to compare insight in patients with versus those without a history of suicidal behavior. RESULTS: Most studies (25) were conducted in psychotic disorders. A small majority showed a positive association between 1 measure of insight and higher risk of suicidal ideas or acts in both psychotic and mood disorders. Our study found that suicide attempters, mostly female attempters, tended to have better insight into depression than patient controls according to the HDRS-24 (P = .06, effect size = 1.43 [95% CI, 0.77 to 2.09]) but not MDIS. Finally, a meta-analysis of 7 studies confirmed significantly better insight scores in suicide attempters, with a small effect size (Hedges g = -0.16 [95% CI, -0.3 to -0.03]). CONCLUSIONS: Overall, a significant but weak association was found between insight and the risk of suicidal behavior. We also raised methodological and conceptual concerns and discussed new measures (eg, test based). PMID- 25830451 TI - A role for profiles of patient-specific depression characteristics and socioeconomic factors in the prediction of antidepressant treatment outcome. PMID- 25830452 TI - Mr Jakubovski and Dr Bloch reply. PMID- 25830453 TI - Improving outcomes in patients with bipolar depression: a comprehensive review. AB - Only 3 medications are currently approved in the US for acute bipolar depression: 2 atypical antipsychotics and a combination atypical antipsychotic-selective serotonin reuptake inhibitor. Metabolic, neurologic, and hormonal adverse events are associated with all of the atypical antipsychotics approved for this indication. However, these agents differ in their propensity to cause weight gain or other side effects that significantly impact a patient's physical health and ability to function, and the selection of medication-which may also include a mood stabilizer-as well as other forms of treatment, will affect the outcome. It is important to design treatment based on individual needs. Evidence suggests that the collaborative care model, which incorporates individualized systematic treatment, may be more appropriate for the management of bipolar depression than the acute care model. PMID- 25830454 TI - The numbers needed to treat and harm (NNT, NNH) statistics: what they tell us and what they do not. AB - Research papers and research summaries frequently present information in the form of derived statistics such as the number needed to treat (NNT) and the number needed to harm (NNH). These statistics are not always correctly understood by the reader. This article explains what NNT and NNH mean; presents a simple, nontechnical explanation for the calculation of the NNT; addresses the interpretation of the NNT; considers applications of the NNT; and discusses the limitations of this statistic. The NNH is also briefly considered. PMID- 25830455 TI - Time trends in incidence rates of diagnosed attention-deficit/hyperactivity disorder across 16 years in a nationwide Danish registry study. AB - OBJECTIVE: To investigate time trends in incidence rates of first-time diagnosed attention-deficit/hyperactivity disorder (ADHD) in a nationwide sample aged 4-65 years across 16 years and identify potential contributing factors to these time trends. METHOD: Incidence rates of first-time diagnosed ADHD based on ICD-10 criteria in Danish psychiatric hospitals per 100,000 person years (PY) were calculated for the total population, the 2 sexes, and 4 age groups using data from the Danish Psychiatric Central Research Registry and annual census data. Time trends and the role of contributing factors were analyzed and identified using joinpoint regression procedures by calculating annual percent changes for the time period 1995-2010. RESULTS: A total of 20,281 patients were diagnosed with ADHD and incidence rates increased from 7.3 to 91.2 per 100,000 PY during the study period. Joinpoint analysis suggested that incidence rates for diagnosed ADHD rapidly increased from 1998 to 2002, peaked from 2002 to 2008, and slowed down from 2008 to 2010. Contributing factors to the observed time trends were a general increase in patients seen in psychiatry for any mental disorder and an increased awareness and recognition of ADHD in females, adolescents, and adults. CONCLUSIONS: These results provide empirical data needed in the public and professional debate often based on theoretical rather than empirical arguments. Results support the notion of increasing incidence rates of diagnosed ADHD and identify that contributing factors are a general increase in the number of patients assessed in psychiatry and an increased recognition of females, adolescents, and adults with ADHD. PMID- 25830457 TI - Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study. AB - OBJECTIVE: To estimate the frequency of mixed states in patients diagnosed with major depressive episode (MDE) according to conceptually different definitions and to compare their clinical validity. METHOD: This multicenter, multinational cross-sectional Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE)-II-MIX study enrolled 2,811 adult patients experiencing an MDE. Data were collected per protocol on sociodemographic variables, current and past psychiatric symptoms, and clinical variables that are risk factors for bipolar disorder. The frequency of mixed features was determined by applying both DSM-5 criteria and a priori described Research-Based Diagnostic Criteria (RBDC). Clinical variables associated with mixed features were assessed using logistic regression. RESULTS: Overall, 212 patients (7.5%) fulfilled DSM-5 criteria for MDE with mixed features (DSM-5-MXS), and 818 patients (29.1%) fulfilled diagnostic criteria for a predefined RBDC depressive mixed state (RBDC-MXS). The most frequent manic/hypomanic symptoms were irritable mood (32.6%), emotional/mood lability (29.8%), distractibility (24.4%), psychomotor agitation (16.1%), impulsivity (14.5%), aggression (14.2%), racing thoughts (11.8%), and pressure to keep talking (11.4%). Euphoria (4.6%), grandiosity (3.7%), and hypersexuality (2.6%) were less represented. In multivariate logistic regression analysis, RBDC-MXS was associated with the largest number of variables including diagnosis of bipolar disorder, family history of mania, lifetime suicide attempts, duration of the current episode > 1 month, atypical features, early onset, history of antidepressant-induced mania/hypomania, and lifetime comorbidity with anxiety, alcohol and substance use disorders, attention deficit/hyperactivity disorder, and borderline personality disorder. CONCLUSIONS: Depressive mixed state, defined as the presence of 3 or more manic/hypomanic features, was present in around one-third of patients experiencing an MDE. The valid symptom, illness course and family history RBDC criteria we assessed identified 4 times more MDE patients as having mixed features and yielded statistically more robust associations with several illness characteristics of bipolar disorder than did DSM-5 criteria. PMID- 25830456 TI - Assessing cognitive function in bipolar disorder: challenges and recommendations for clinical trial design. AB - OBJECTIVE: Neurocognitive impairment in schizophrenia has been recognized for more than a century. In contrast, only recently have significant neurocognitive deficits been recognized in bipolar disorder. Converging data suggest the importance of cognitive problems in relation to quality of life in bipolar disorder, highlighting the need for treatment and prevention efforts targeting cognition in bipolar patients. Future treatment trials targeting cognitive deficits will be met with methodological challenges due to the inherent complexity and heterogeneity of the disorder, including significant diagnostic comorbidities, the episodic nature of the illness, frequent use of polypharmacy, cognitive heterogeneity, and a lack of consensus regarding measurement of cognition and outcome in bipolar patients. Guidelines for use in designing future trials are needed. PARTICIPANTS: The members of the consensus panel (each of the bylined authors) were selected based upon their expertise in bipolar disorder. Dr Burdick is a neuropsychologist who has studied cognition in this illness for 15 years; Drs Ketter, Calabrese, and Goldberg each bring considerable expertise in the treatment of bipolar disorder, both within and outside of controlled clinical trials. This consensus statement was derived from work together at scientific meetings (eg, symposium presentation at the 2014 Annual Meeting of the American Society of Clinical Psychopharmacology, among others) and ongoing discussions by conference call. With the exception of the public presentations on this topic, these meetings were closed to outside participants. EVIDENCE: A literature review was undertaken by the authors to identify illness-specific challenges relevant to the design and conduct of treatment trials targeting neurocognition in bipolar disorder. Expert opinion from each of the authors guided the consensus recommendations. CONSENSUS PROCESS: Consensus recommendations, reached by unanimous opinion of the authors, are provided here as a preliminary guide for future trial design. Recommendations comprise exclusion of certain syndromal level comorbid diagnoses and current affective instability, restrictions on numbers and types of medications, and use of prescreening assessment to ensure enrollment of subjects with adequate objective evidence of baseline cognitive impairment. CONCLUSIONS: Clinical trials to address cognitive deficits in bipolar disorder face distinctive design challenges. As such trials move from proof-of concept to confirmation of clinical efficacy, it will be important to incorporate distinctive design modifications to adequately address these challenges and increase the likelihood of demonstrating cognitive remediation effects. The field is now primed to address these challenges, and a comprehensive effort to formalize best practice guidelines will be a critically important next step. PMID- 25830458 TI - Thinking about dying and trying and intending to die: results on suicidal behavior from a large Web-based sample. AB - OBJECTIVE: Suicide is an important worldwide public health problem. The aim of this study was to characterize risk factors of suicidal behavior using a large Web-based sample. METHOD: The data were collected by the Brazilian Internet Study on Temperament and Psychopathology (BRAINSTEP) from November 2010 to July 2011. Suicidal behavior was assessed by an instrument based on the Suicidal Behaviors Questionnaire. The final sample consisted of 48,569 volunteers (25.9% men) with a mean +/- SD age of 30.7 +/- 10.1 years. RESULTS: More than 60% of the sample reported having had at least a passing thought of killing themselves, and 6.8% of subjects had previously attempted suicide (64% unplanned). The demographic features with the highest risk of attempting suicide were female gender (OR = 1.82, 95% CI = 1.65 to 2.00); elementary school as highest education level completed (OR = 2.84, 95% CI = 2.48 to 3.25); being unable to work (OR = 5.32, 95% CI = 4.15 to 6.81); having no religion (OR = 2.08, 95% CI = 1.90 to 2.29); and, only for female participants, being married (OR = 1.19, 95% CI = 1.08 to 1.32) or divorced (OR = 1.66, 95% CI = 1.41 to 1.96). A family history of a suicide attempt and of a completed suicide showed the same increment in the risk of suicidal behavior. The higher the number of suicide attempts, the higher was the real intention to die (P < .05). Those who really wanted to die reported more emptiness/loneliness (OR = 1.58, 95% CI = 1.35 to 1.85), disconnection (OR = 1.54, 95% CI = 1.30 to 1.81), and hopelessness (OR = 1.74, 95% CI = 1.49 to 2.03), but their methods were not different from the methods of those who did not mean to die. CONCLUSIONS: This large Web survey confirmed results from previous studies on suicidal behavior and pointed out the relevance of the number of previous suicide attempts and of a positive family history, even for a noncompleted suicide, as important risk factors. PMID- 25830459 TI - Does indication drive use, or does use drive indication? PMID- 25830461 TI - Suicide in men. PMID- 25830460 TI - Cariprazine in bipolar disorders. PMID- 25830462 TI - Naturally occurring low-dose lithium in drinking water. PMID- 25830463 TI - Cognitive dysfunction in psychiatric illness: a neglected domain. PMID- 25830464 TI - Mixed depression: a farewell to differential diagnosis? PMID- 25830465 TI - "Mixed" depression: drawbacks of DSM-5 (and other) polythetic diagnostic criteria. PMID- 25830466 TI - Suicidology meets "Big Data". PMID- 25830467 TI - Culturally competent approaches to assessing ADHD in African American adults and overcoming cultural issues with patients and families. AB - To better diagnose and treat African American patients with ADHD, clinicians should consider the mental health field from a cultural and historical perspective. This perspective can aid clinicians in assessing patients' culturally informed resistance or ambivalence toward ADHD treatment and in adopting strategies for communicating with patients about their diagnosis and treatment. Clinicians must learn to recognize and manage their own biases as well as their patients' biases. Using a culturally competent approach is critical to assessing ADHD in African American adults and overcoming cultural issues with patients and their families. PMID- 25830468 TI - Identifying and addressing unmet therapeutic needs in MS. AB - Current disease-modifying treatments in multiple sclerosis (MS) are partially effective in reducing relapses and slowing disease progression, but these treatments do not restore function and are effective mainly in relapsing forms of MS. Unmet needs in MS include treatments for progressive forms of MS, agents with improved efficacy and safety profiles and that comprehensively manage MS symptoms, and medications with neuroprotective or remyelinating properties. Some adverse effects of disease-modifying agents could be reduced if medications are developed with more specific treatment targets, and research into the pathogenesis of MS may lead to agents that could restore myelin or protect nerves from inflammation. PMID- 25830469 TI - Effective communication strategies to help patients and caregivers cope with moderate-to-severe Alzheimer's disease. AB - As the number of people with Alzheimer's disease (AD) increases, clinicians must learn to educate patients and their caregivers about the communication problems associated with different stages of illness. Patients with AD will experience varying degrees of language impairments, concentration problems, and difficulty expressing themselves. Caregivers can learn to avoid common communication mistakes, such as correcting, reasoning with, and arguing with the person with AD. By equipping caregivers with strategies to aid verbal and nonverbal communication, clinicians can improve the interactions between patients with AD and their caregivers and lessen frustration on both sides. PMID- 25830470 TI - Worldwide Status of Fresh Fruits Irradiation and Concerns about Quality, Safety, and Consumer Acceptance. AB - Development of knowledge-based food preservation techniques have been a major focus of researchers in providing safe and nutritious food. Food irradiation is one of the most thoroughly investigated food preservation techniques, which has been shown to be effective and safe through extensive research. This process involves exposing food to ionizing radiations in order to destroy microorganisms or insects that might be present on and/or in the food. In addition, the effects of irradiation on the enzymatic activity and improvement of functional properties in food have also been well established. In the present review, the potential of food irradiation technology to address major problems, such as short shelf life, high-initial microbial loads, insect pest management (quarantine treatment) in supply chain, and safe consumption of fresh fruits was described. With improved hygienic quality, other uses, such as delayed ripening and enhanced physical appearance by irradiation were also discussed. Available data showed that the irradiation of fruits at the optimum dose can be a safe and cost-effective method, resulting in enhanced shelf life and hygienic quality with the least amount of compromise on the various nutritional attributes, whereas the consumer acceptance of irradiated fruits is a matter of providing the proper scientific information. PMID- 25830471 TI - Emissions and Cost Implications of Controlled Electric Vehicle Charging in the U.S. PJM Interconnection. AB - We develop a unit commitment and economic dispatch model to estimate the operation costs and the air emissions externality costs attributable to new electric vehicle electricity demand under controlled vs uncontrolled charging schemes. We focus our analysis on the PJM Interconnection and use scenarios that characterize (1) the most recent power plant fleet for which sufficient data are available, (2) a hypothetical 2018 power plant fleet that reflects upcoming plant retirements, and (3) the 2018 fleet with increased wind capacity. We find that controlled electric vehicle charging can reduce associated generation costs by 23%-34% in part by shifting loads to lower-cost, higher-emitting coal plants. This shift results in increased externality costs of health and environmental damages from increased air pollution. On balance, we find that controlled charging of electric vehicles produces negative net social benefits in the recent PJM grid but could have positive net social benefits in a future grid with sufficient coal retirements and wind penetration. PMID- 25830472 TI - Noninvasive biomarkers FibroTest and ActiTest versus liver biopsy in chronic hepatitis C patients: the Middle East experience. AB - BACKGROUND: The aim of this study was to compare noninvasive biomarkers, FibroTest and ActiTest in predicting fibrosis stage and inflammation grade in chronic hepatitis C (CHC) patients with liver biopsy (LB). METHODS: In 107 patients with CHC, levels of six serum biomarkers (alanine aminotransferase, gamma-glutamyl transpeptidase, total bilirubin, haptoglobin, apolipoprotein, alpha-2 macroglobulin) were determined at the time of LB. LB was evaluated by Metavir score for fibrosis and inflammation. Voluntary blood donors (n=106) were taken as controls for the study. RESULTS: Fibrosis estimated by Fibrotest was significantly higher in patients compared to control group. The observed area under the receiver operating characteristic curve (AUROC) for advanced fibrosis (F3, F4) adjusted according to the observed difference between advanced and non advanced fibrosis prevalence (DANA) was 0.80 (0.69-0.88) and the AUROC for cirrhosis (F4) was 0.94 (0.86-0.98). ActiTest AUROC for moderate to severe activity (A2A3) was 0.72 (0.61-0.81), and for severe activity (A3) was 0.88 (0.78 0.93). The diagnostic values in the group of good quality biopsy (n=41) showed Fibrotest AUROC (DANA-adjusted): for advanced fibrosis 0.90 (0.72-0.99); for cirrhosis 0.93 (0.76-0.98); and ctiTest AUROC: for moderate/severe activity 0.86 (0.67-0.94); and for severe activity 0.90 (0.76-0.93). There was good concordance between FibroTest and LB (with discordance for two or more stages in <20% for advanced fibrosis and <10% for cirrhosis) and between ActiTest and LB. Specificity for FibroTest and ActiTest in the control population were 95% and 100% respectively. CONCLUSIONS: Fibrotest and ActiTest had high observed and standardized diagnostic values for predicting fibrosis and activity respectively. PMID- 25830473 TI - Highly sensitive and selective microRNA detection based on DNA-bio-bar-code and enzyme-assisted strand cycle exponential signal amplification. AB - Herein, a highly sensitive and selective microRNA (miRNA) detection strategy using DNA-bio-bar-code amplification (BCA) and Nb.BbvCI nicking enzyme-assisted strand cycle for exponential signal amplification was designed. The DNA-BCA system contains a locked nucleic acid (LNA) modified DNA probe for improving hybridization efficiency, while a signal reported molecular beacon (MB) with an endonuclease recognition site was designed for strand cycle amplification. In the presence of target miRNA, the oligonucleotides functionalized magnetic nanoprobe (MNP-DNA) and gold nanoprobe (AuNP-DNA) with numerous reported probes (RP) can hybridize with target miRNA, respectively, to form a sandwich structure. After sandwich structures were separated from the solution by the magnetic field, the RP were released under high temperature to recognize the MB and cleaved the hairpin DNA to induce the dissociation of RP. The dissociated RP then triggered the next strand cycle to produce exponential fluorescent signal amplification for miRNA detection. Under optimized conditions, the exponential signal amplification system shows a good linear range of 6 orders of magnitude (from 0.3 pM to 3 aM) with limit of detection (LOD) down to 52.5 zM, while the sandwich structure renders the system with high selectivity. Meanwhile, the feasibility of the proposed strategy for cell miRNA detection was confirmed by analyzing miRNA-21 in HeLa lysates. Given the high-performance for miRNA analysis, the strategy has a promising application in biological detection and in clinical diagnosis. PMID- 25830475 TI - Car Licensing Trends of the Babyboomer Cohort (b. 1946-1965) Compared to Earlier Birth Cohorts: Effects on the Driving Population in the State of Victoria, Australia. AB - OBJECTIVE: The objective of this article was to explore trends in licensing among babyboomer older drivers in the state of Victoria, Australia. The study aims were to (1) compare the car licensing trends of the babyboomer cohort to that of previous birth cohorts and (2) predict the number of babyboomers licensed to drive a car in 2021 when the babyboomer cohort reaches an average age of 65 years. METHODS: The residential population of Victoria, Australia, for 2001-2013 was obtained from the Australian Bureau of Statistics; car licensing statistics were obtained from VicRoads. Birth cohorts from 1916 to 1975 were defined in 10 year birth-year intervals. Population size was modeled using logistic regression. License prevalence was modeled using a logit model. RESULTS: The babyboomer cohort (1946-1965) in Victoria is 1.7 times larger than the cohort before them. At age 60 years, license prevalence among babyboomers was higher than in previous cohorts: 88% in the 1936-1945 cohort vs. 96% in the 1946-1955 cohort. When the babyboomers reach 65 years (average) in 2021, we estimate there to be over twice as many license holders among them than in the preceding cohort (n = 1,300,094 vs. 630,830, respectively). CONCLUSIONS: Aging of the babyboomer cohort will have a greater impact on the driving population than on the general population, due to the multiplicative effect of cohort size and license prevalence. The impact of road user aging on burden of injury can be minimized by focusing prevention at crashes typical to older drivers, such as intersection crashes, and promoting car safety features among older drivers. PMID- 25830476 TI - Method validation for automated isolation of viable peripheral blood mononuclear cells. AB - BACKGROUND: This article is part of a series of publications providing formal method validation for biospecimen processing in the context of accreditation in laboratories and biobanks. We report the optimization and validation for fitness for-purpose of automated and manual protocols for isolating peripheral blood mononuclear cells (PBMCs) from whole blood, and compare the two methods. METHODS: The manual method was optimized for whole blood centrifugation speed, gradient type (Ficoll, Leucosep, CPT), and freezing method (Mr Frosty, Controlled Rate Freezing). Various parameters of the automated protocol using a CPT gradient on a Tecan liquid handler were optimized. Optimal protocols were validated in parallel for reproducibility and robustness. Optimization and validation were assessed in terms of cell yield, viability, recovery, white blood cell (WBC) subpopulation distribution, gene expression, and lymphoblastoid cell line (LCL) transformation. RESULTS: An initial centrifugation of whole blood at 2000 g was considered optimal for further processing, allowing isolation of plasma and PBMCs from a single sample. The three gradients gave similar outcomes in terms of cell yield, viability, and WBC subpopulation distribution. Ficoll showed some advantages and was selected for further evaluations. Optimization of the automated protocol script using a CPT gradient gave 61% cell recovery. No significant differences in quality, quantity, and WBC subpopulation distribution were seen between the two freezing methods, and Mr. Frosty was selected. The manual and automated protocols were reproducible in terms of quantity, recovery, viability, WBC subpopulation distribution, gene expression, and LCL transformation. Most (75%-100%) of the 13 robustness parameters were accepted for both methods with an 8 h pre centrifugation delay versus 38%-85% after 24 h. Differences identified between the automated and manual methods were not considered consequential. CONCLUSIONS: We validated the first fully automated method for isolating viable PBMCs, including RNA analysis and generation of LCLs. We recommend processing within 8 h of blood collection. PMID- 25830474 TI - Role of mannose-binding lectin deficiency in HIV-1 and schistosoma infections in a rural adult population in Zimbabwe. AB - BACKGROUND: Polymorphism in the MBL2 gene lead to MBL deficiency, which has been shown to increase susceptibility to various bacterial, viral and parasitic infections. We assessed role of MBL deficiency in HIV-1 and schistosoma infections in Zimbabwean adults enrolled in the Mupfure Schistosomiasis and HIV Cohort (MUSH Cohort). METHODS: HIV-1, S. haematobium and S. mansoni infections were determined at baseline. Plasma MBL concentration was measured by ELISA and MBL2 genotypes determined by PCR. We calculated and compared the proportions of plasma MBL deficiency, MBL2 structural variant alleles B (codon 54A>G), C (codon 57A>G), and D (codon 52T>C) as well as MBL2 promoter variants -550(H/L), 221(X/Y) and +4(P/Q) between HIV-1 and schistosoma co-infection and control groups using Chi Square test. RESULTS: We assessed 379 adults, 80% females, median age (IQR) 30 (17-41) years. HIV-1, S. haematobium and S. mansoni prevalence were 26%, 43% and 18% respectively in the MUSH baseline survey. Median (IQR) plasma MBL concentration was 800MUg/L (192-1936MUg/L). Prevalence of plasma MBL deficiency was 18% with high frequency of the C (codon 57G>A) mutant allele (20%). There was no significant difference in median plasma MBL levels between HIV negative (912MUg/L) and HIV positive (688MUg/L), p = 0.066. However plasma MBL levels at the assay detection limit of 20MUg/L were more frequent among the HIV-1 infected (p = 0.007). S. haematobium and S. mansoni infected participants had significantly higher MBL levels than uninfected. All MBL2 variants were not associated with HIV-1 infection but promoter variants LY and LL were significantly associated with S. haematobium infection. CONCLUSION: Our data indicate high prevalence of MBL deficiency, no evidence of association between MBL deficiency and HIV-1 infection. However, lower plasma MBL levels were protective against both S. haematobium and S. mansoni infections and MBL2 promoter and variants LY and LL increased susceptibility to S. haematobium infection. PMID- 25830477 TI - Polygenic Risk Score, Parental Socioeconomic Status, Family History of Psychiatric Disorders, and the Risk for Schizophrenia: A Danish Population-Based Study and Meta-analysis. AB - IMPORTANCE: Schizophrenia has a complex etiology influenced both by genetic and nongenetic factors but disentangling these factors is difficult. OBJECTIVE: To estimate (1) how strongly the risk for schizophrenia relates to the mutual effect of the polygenic risk score, parental socioeconomic status, and family history of psychiatric disorders; (2) the fraction of cases that could be prevented if no one was exposed to these factors; (3) whether family background interacts with an individual's genetic liability so that specific subgroups are particularly risk prone; and (4) to what extent a proband's genetic makeup mediates the risk associated with familial background. DESIGN, SETTINGS, AND PARTICIPANTS: We conducted a nested case-control study based on Danish population-based registers. The study consisted of 866 patients diagnosed as having schizophrenia between January 1, 1994, and December 31, 2006, and 871 matched control individuals. Genome-wide data and family psychiatric and socioeconomic background information were obtained from neonatal biobanks and national registers. Results from a separate meta-analysis (34,600 cases and 45,968 control individuals) were applied to calculate polygenic risk scores. EXPOSURES: Polygenic risk scores, parental socioeconomic status, and family psychiatric history. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs), attributable risks, liability R2 values, and proportions mediated. RESULTS: Schizophrenia was associated with the polygenic risk score (OR, 8.01; 95% CI, 4.53-14.16 for highest vs lowest decile), socioeconomic status (OR, 8.10; 95% CI, 3.24-20.3 for 6 vs no exposures), and a history of schizophrenia/psychoses (OR, 4.18; 95% CI, 2.57-6.79). The R2 values were 3.4% (95% CI, 2.1-4.6) for the polygenic risk score, 3.1% (95% CI, 1.9-4.3) for parental socioeconomic status, and 3.4% (95% CI, 2.1-4.6) for family history. Socioeconomic status and psychiatric history accounted for 45.8% (95% CI, 36.1 55.5) and 25.8% (95% CI, 21.2-30.5) of cases, respectively. There was an interaction between the polygenic risk score and family history (P = .03). A total of 17.4% (95% CI, 9.1-26.6) of the effect associated with family history of schizophrenia/psychoses was mediated through the polygenic risk score. CONCLUSIONS AND RELEVANCE: Schizophrenia was associated with the polygenic risk score, family psychiatric history, and socioeconomic status. Our study demonstrated that family history of schizophrenia/psychoses is partly mediated through the individual's genetic liability. PMID- 25830478 TI - Blunt Snout Bream (Megalobrama amblycephala) MyD88 and TRAF6: characterisation, comparative homology modelling and expression. AB - MyD88 and TRAF6 play an essential role in the innate immune response in most animals. This study reports the full-length MaMyD88 and MaTRAF6 genes identified from the blunt snout bream (Megalobrama amblycephala) transcriptome profile. MaMyD88 is 2501 base pairs (bp) long, encoding a putative protein of 284 amino acids (aa), including the N-terminal DEATH domain of 78 aa and the C-terminal TIR domain of 138 aa. MaTRAF6 is 5474 bp long, encoding a putative protein of 542 aa, including the N-terminal low-complexity region, RING domain (40 aa), a coiled coil region (64 aa) and C-terminal MATH domain (147 aa). Coding regions of MaMyD88 and MaTRAF6 genomic sequences consisted of five and six exons, respectively. Physicochemical and functional characteristics of the proteins were analysed. Alpha helices were dominant in the secondary structure of the proteins. Homology models of the MaMyD88 and MaTRAF6 domains were constructed applying the comparative modelling method. RT-qPCR was used to analyse the expression of MaMyD88 and MaTRAF6 mRNA transcripts in response to Aeromonas hydrophila challenge. Both genes were highly upregulated in the liver, spleen and kidney during the first 24 h after the challenge. While MyD88 and TRAF6 have been reported in various aquatic species, this is the first report and characterisation of these genes in blunt snout bream. This research also provides evidence of the important roles of these two genes in the blunt snout bream innate immune system. PMID- 25830479 TI - Identification and functional analysis of microRNAs and their targets in Platanus acerifolia under lead (Pb) stress. AB - MicroRNAs (miRNAs) play important regulatory roles in development and stress responses in plants. Lead (Pb) is a non-essential element that is highly toxic to living organisms. Platanus acerifolia is grown as a street tree in cities throughout temperate regions for its importance in improving the urban ecological environment. MiRNAs that respond to abiotic stresses have been identified in plants; however, until now, the influence of Pb stress on P. acerifolia miRNAs has not been reported. To identify miRNAs and predict their target genes under Pb stress, two small RNA and two degradome libraries were constructed from Pb treated and Pb-free leaves of P. acerifolia seedlings. After sequencing, 55 known miRNAs and 129 novel miRNAs were obtained, and 104 target genes for the miRNAs were identified by degradome sequencing. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to predict the functions of the targets. The expressions of eight differentially expressed miRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). This is the first report about P. acerifolia miRNAs and their target genes under Pb stress. This study has provided data for further research into molecular mechanisms involved in resistance of P. acerifolia to Pb stress. PMID- 25830480 TI - MicroRNA-16 modulates HuR regulation of cyclin E1 in breast cancer cells. AB - RNA binding protein (RBPs) and microRNAs (miRNAs or miRs) are post transcriptional regulators of gene expression that are implicated in development of cancers. Although their individual roles have been studied, the crosstalk between RBPs and miRNAs is under intense investigation. Here, we show that in breast cancer cells, cyclin E1 upregulation by the RBP HuR is through specific binding to regions in the cyclin E1 mRNA 3' untranslated region (3'UTR) containing U-rich elements. Similarly, miR-16 represses cyclin E1, dependent on its cognate binding sites in the cyclin E1 3'UTR. Evidence in the literature indicates that HuR can regulate miRNA expression and recruit or dissociate RNA induced silencing complexes (RISC). Despite this, miR-16 and HuR do not affect the other's expression level or binding to the cyclin E1 3'UTR. While HuR overexpression partially blocks miR-16 repression of a reporter mRNA containing the cyclin E1 3'UTR, it does not block miR-16 repression of endogenous cyclin E1 mRNA. In contrast, miR-16 blocks HuR-mediated upregulation of cyclin E1. Overall our results suggest that miR-16 can override HuR upregulation of cyclin E1 without affecting HuR expression or association with the cyclin E1 mRNA. PMID- 25830481 TI - Unfolding the unfolded protein response: unique insights into brain ischemia. AB - The endoplasmic reticulum (ER) is responsible for processing of proteins that are destined to be secreted, enclosed in a vesicle, or incorporated in the plasma membrane. Nascent peptides that enter the ER undergo a series of highly regulated processing steps to reach maturation as they transit the ER. Alterations in the intracellular environment that induce ER stress are thought to interrupt these processing steps, and result in unfolding of proteins in the ER. Accumulation of unfolded proteins concurrently activates three transmembrane stress sensors, IRE1, ATF6 and PERK, and is referred to as the Unfolded Protein Response (UPR). Our understanding of the mechanisms of UPR induction has been assembled primarily from experiments inducing ER stress with chemical and genetic manipulations. However, physiological stress often induces activation of ER stress sensors in a distinct manner from the canonical UPR. The unique activation profiles in vivo have prompted us to examine the mechanism of UPR activation in neurons following cerebral ischemia. PMID- 25830482 TI - Organocatalytic upgrading of furfural and 5-hydroxymethyl furfural to C10 and C12 furoins with quantitative yield and atom-efficiency. AB - There is increasing interest in the upgrading of C5 furfural (FF) and C6 5 hydroxymethyl furfural (HMF) into C10 and C12 furoins as higher energy-density intermediates for renewable chemicals, materials, and biofuels. This work utilizes the organocatalytic approach, using the in situ generated N,S heterocyclic carbene catalyst derived from thiazolium ionic liquids (ILs), to achieve highly efficient self-coupling reactions of FF and HMF. Specifically, variations of the thiazolium IL structure have led to the most active and efficient catalyst system of the current series, which is derived from a new thiazolium IL carrying the electron-donating acetate group at the 5-ring position. For FF coupling by this IL (0.1 mol %, 60 degrees C, 1 h), when combined with Et3N, furoin was obtained in >99% yield. A 97% yield of the C12 furoin was also achieved from the HMF coupling by this catalyst system (10 mol % loading, 120 degrees C, 3 h). On the other hand, the thiazolium IL bearing the electron-withdrawing group at the 5-ring position is the least active and efficient catalyst. The mechanistic aspects of the coupling reaction by the thiazolium catalyst system have also been examined and a mechanism has been proposed. PMID- 25830483 TI - A double-edged sword: the role of VEGF in wound repair and chemoattraction of opportunist pathogens. AB - Wound healing is a complex process essential to repairing damaged tissues and preventing infection. Skin is the first line of defense, a chief physical barrier to microbe entry. Wound healing is a physical rebuilding process, but at the same time it is an inflammatory event. In turn, molecules for wound repair are secreted by fibroblasts and others present at the wound site. Vascular endothelial growth factor (VEGF) is a critical cytokine that exhibits chemoattractant properties, recruiting other immune cells to the site. Although generally beneficial, VEGF may also act as a chemoattractant for invading microorganisms, such as Pseudomonas aeruginosa. P. aeruginosa is problematic during wound infection due to its propensity to form biofilms and exhibit heightened antimicrobial resistance. Here, we explored the influence of VEGF gradients (in a microfluidic device wound model) on the motility and chemotactic properties of P. aeruginosa. At lower concentrations, VEGF had little effect on motility, but as the maximal concentration within the gradient increased, P. aeruginosa cells exhibited directed movement along the gradient. Our data provide evidence that while beneficial, VEGF, in excess, may aid colonization by P. aeruginosa. This highlights the necessity for the efficient resolution of inflammation. Understanding the dynamics of wound colonization may lead to new/enhanced therapeutics to hasten recovery. PMID- 25830484 TI - Interaction of tRNA with eukaryotic ribosome. AB - This paper is a review of currently available data concerning interactions of tRNAs with the eukaryotic ribosome at various stages of translation. These data include the results obtained by means of cryo-electron microscopy and X-ray crystallography applied to various model ribosomal complexes, site-directed cross linking with the use of tRNA derivatives bearing chemically or photochemically reactive groups in the CCA-terminal fragment and chemical probing of 28S rRNA in the region of the peptidyl transferase center. Similarities and differences in the interactions of tRNAs with prokaryotic and eukaryotic ribosomes are discussed with concomitant consideration of the extent of resemblance between molecular mechanisms of translation in eukaryotes and bacteria. PMID- 25830486 TI - Calcium Handling Abnormalities as a Target for Atrial Fibrillation Therapeutics: How Close to Clinical Implementation? AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia with a substantial impact on morbidity and mortality. Antiarrhythmic drugs play a major role in rhythm-control therapy of AF. However, currently available agents exhibit limited efficacy and pronounced adverse effects, notably drug-induced proarrhythmia. Recent experimental studies have identified that Ca handling abnormalities are critical elements in AF pathophysiology with central roles in atrial ectopic activity, reentry, and atrial remodeling suggesting that Ca handling abnormalities could be promising targets for novel AF therapeutics. Here, we summarize key aspects of AF-related Ca-handling abnormalities, describe currently available compounds targeting atrial Ca handling, and highlight potential novel targets and experimental drugs currently under investigation. Finally, we assess how close AF therapeutics based on Ca-handling abnormalities are to clinical implementation. PMID- 25830485 TI - Role of Calcium-activated Potassium Channels in Atrial Fibrillation Pathophysiology and Therapy. AB - Small-conductance Ca(2+)-activated potassium (SK) channels are relative newcomers within the field of cardiac electrophysiology. In recent years, an increased focus has been given to these channels because they might constitute a relatively atrial-selective target. This review will give a general introduction to SK channels followed by their proposed function in the heart under normal and pathophysiological conditions. It is revealed how antiarrhythmic effects can be obtained by SK channel inhibition in a number of species in situations of atrial fibrillation. On the contrary, the beneficial effects of SK channel inhibition in situations of heart failure are questionable and still needs investigation. The understanding of cardiac SK channels is rapidly increasing these years, and it is hoped that this will clarify whether SK channel inhibition has potential as a new anti-atrial fibrillation principle. PMID- 25830488 TI - SNAP-Tag-Reactive Lipid Anchors Enable Targeted and Spatiotemporally Controlled Localization of Proteins to Phospholipid Membranes. AB - The natural mechanisms that direct proteins to membranes are typically complex, requiring multiple steps and accessory components. It would be advantageous to develop simplified methods to direct proteins of interest to phospholipid membranes in a single step. Here we report a modular method for membrane localization of proteins by using chemically modified phospholipid anchors capable of covalent attachment to O(6)-methylguanine DNA methyltransferase (SNAP tag) fusion proteins. To our knowledge, this is the first use of SNAP-tag reactions to modify benzylguanine-functionalized lipid membranes. We demonstrate that photocaged lipid precursors enable light-triggered spatial and temporal control over protein localization. The anchoring system is compatible with cell free expression, allowing for genetic targeting of proteins to lipid membranes of giant unilamellar vesicles. This technique can be used to control membrane curvature effects, similar to what has been previously observed with certain membrane-bound proteins. This work addresses a current need in synthetic biology for simplified and robust methods to control membrane localization of expressed proteins and shows promise as a general tool for protein targeting to lipid vesicles and cellular membranes. PMID- 25830490 TI - (Electro)Sensing of Phenicol Antibiotics-A Review. AB - The presence of residues from frequent antibiotic use in animal feed can cause serious health risks by contaminating products meant for human consumption such as meat and milk. The present paper gives an overview of the electrochemical methods developed for the detection of phenicol antibiotic residues (chloramphenicol, thiamphenicol, and florfenicol) in different kinds of foodstuffs. Electrochemical sensors based on different biomolecules and nanomaterials are described. The detection limit of various developed methods with their advantages and disadvantages will be highlighted. PMID- 25830489 TI - Immunogenicity and safety of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) co-administered with DTPa vaccine in Japanese children: A randomized, controlled study. AB - This phase III, randomized, open-label, multicenter study (NCT01027845) conducted in Japan assessed the immunogenicity, safety, and reactogenicity of 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD CV, given intramuscularly) co-administered with diphtheria-tetanus-acellular pertussis vaccine (DTPa, given subcutaneously). Infants (N=360 ) were randomized (2:1) to receive either PHiD-CV and DTPa (PHiD-CV group) or DTPa alone (control group) as 3-dose primary vaccination (3-4-5 months of age) and booster vaccination (17-19 months of age). Immune responses were measured before and one month after primary/booster vaccination and adverse events (AEs) were recorded. Post-primary immune responses were non-inferior to those in pivotal/efficacy European or Latin American pneumococcal protein D-conjugate vaccine studies. For each PHiD-CV serotype, at least 92.6% of infants post-primary vaccination and at least 97.7% of children post-booster had pneumococcal antibody concentrations >=0.2 MUg/ml, and at least 95.4% post-primary and at least 98.1% post-booster had opsonophagocytic activity (OPA) titers >=8 . Geometric mean antibody concentrations and OPA titers (except OPA titer for 6B) were higher post-booster than post-priming for each serotype. All PHiD-CV-vaccinated children had anti protein D antibody concentrations >=100 EL.U/ml one month post-primary/booster vaccination and all were seroprotected/seropositive against each DTPa antigen. Redness and irritability were the most common solicited AEs in both groups. Incidences of unsolicited AEs were comparable between groups. Serious AEs were reported for 47 children (28 in PHiD-CV group); none were assessed as vaccine related. In conclusion, PHiD-CV induced robust immune responses and was well tolerated when co-administered with DTPa in a 3-dose priming plus booster regimen to Japanese children. PMID- 25830492 TI - Brain activity and the perception of self-agency while viewing a video of hand grasping: a functional near-infrared spectroscopy study. AB - Self-agency is the recognition of one's own movement and plays a vital role in purposeful, voluntary movement. A sense of self-agency can be elicited in individuals who view their own simple finger movements as they are projected onto a screen and aligned with their actual hand position. Here, we examined whether individuals perceived self-agency when they viewed a video of a hand grasping a wooden cylinder and whether the perception of self-agency correlated with simultaneous changes in oxy-hemoglobin in the parietal or the prefrontal cortical areas. All participants reported the perception of self-agency, which was correlated with oxy-hemoglobin increases in the right prefrontal area. We conclude that self-agency also relates to hand-held objects displayed on video. PMID- 25830491 TI - Brainstem morphological changes in Alzheimer's disease. AB - As brainstem nuclei are interconnected with several cortical structures and regulate several autonomic, cognitive, and behavioral functions, it might be important to place the brainstem within an important pathologic core in the progression of Alzheimer's disease (AD). Although there have been several postmortem studies reporting neuropathological alterations of the brainstem in AD, there has been no in-vivo structural neuroimaging study of the brainstem in the patients with AD. The aim of this study was to investigate differences in the brainstem volume and shape between patients with AD and elderly normal controls. Fifty AD patients (the Clinical Dementia Rating Scale >= 1) and 50 normal controls were recruited, and the brainstem volumes and deformations were compared between the AD and the controls. Patients with AD showed significant total volume [(mean +/- SD) 21007 +/- 1640 mm] reduction in the brainstem compared with the controls [(mean +/- SD) 22530 +/- 1750 mm] (P<0.001). In addition, AD patients showed significant brainstem deformations in the upper posterior brainstem corresponding to the midbrain compared with the healthy individuals (false discovery rate corrected P<0.05). This study is the first to explore brainstem volume change and deformations in AD. These structural changes in the midbrain areas might be at the core of the underlying neurobiological mechanisms of brainstem dysfunction with relevance to their various cognitive and behavioral symptoms such as memory impairment, sleep, and emotional disturbance in AD. However, further longitudinal studies might be needed to confirm these findings. PMID- 25830493 TI - Differential motor and sensory functional recovery in male but not female adult rats is associated with remyelination rather than axon regeneration after sciatic nerve crush. AB - Peripheral nerve functional recovery after injuries relies on both axon regeneration and remyelination. Both axon regeneration and remyelination require intimate interactions between regenerating neurons and their accompanying Schwann cells. Previous studies have shown that motor and sensory neurons are intrinsically different in their regeneration potentials. Moreover, denervated Schwann cells accompanying myelinated motor and sensory axons have distinct gene expression profiles for regeneration-associated growth factors. However, it is unknown whether differential motor and sensory functional recovery exists. If so, the particular one among axon regeneration and remyelination responsible for this difference remains unclear. Here, we aimed to establish an adult rat sciatic nerve crush model with the nonserrated microneedle holders and measured rat motor and sensory functions during regeneration. Furthermore, axon regeneration and remyelination was evaluated by morphometric analysis of electron microscopic images on the basis of nerve fiber classification. Our results showed that Aalpha fiber-mediated motor function was successfully recovered in both male and female rats. Adelta fiber-mediated sensory function was partially restored in male rats, but completely recovered in female littermates. For both male and female rats, the numbers of regenerated motor and sensory axons were quite comparable. However, remyelination was diverse among myelinated motor and sensory nerve fibers. In detail, Abeta and Adelta fibers incompletely remyelinated in male, but not female rats, whereas Aalpha fibers fully remyelinated in both sexes. Our result indicated that differential motor and sensory functional recovery in male but not female adult rats is associated with remyelination rather than axon regeneration after sciatic nerve crush. PMID- 25830494 TI - Incremental Validity of the Trait Emotional Intelligence Questionnaire-Short Form (TEIQue-SF). AB - This study examined the incremental validity of the adult short form of the Trait Emotional Intelligence Questionnaire (TEIQue-SF) in predicting 7 construct relevant criteria beyond the variance explained by the Five-factor model and coping strategies. Additionally, the relative contributions of the questionnaire's 4 subscales were assessed. Two samples of Canadian university students completed the TEIQue-SF, along with measures of the Big Five, coping strategies (Sample 1 only), and emotion-laden criteria. The TEIQue-SF showed consistent incremental effects beyond the Big Five or the Big Five and coping strategies, predicting all 7 criteria examined across the 2 samples. Furthermore, 2 of the 4 TEIQue-SF subscales accounted for the measure's incremental validity. Although the findings provide good support for the validity and utility of the TEIQue-SF, directions for further research are emphasized. PMID- 25830495 TI - An Electrochemical Capacitor with Applicable Energy Density of 7.4 Wh/kg at Average Power Density of 3000 W/kg. AB - Electrochemical capacitors represent a new class of charge storage devices that can simultaneously achieve high energy density and high power density. Previous reports have been primarily focused on the development of high performance capacitor electrodes. Although these electrodes have achieved excellent specific capacitance based on per unit mass of active materials, the gravimetric energy densities calculated based on the weight of entire capacitor device were fairly small. This is mainly due to the large mass ratio between current collector and active material. We aimed to address this issue by a 2-fold approach of minimizing the mass of current collector and increasing the electrode performance. Here we report an electrochemical capacitor using 3D graphene hollow structure as current collector, vanadium sulfide and manganese oxide as anode and cathode materials, respectively. 3D graphene hollow structure provides a lightweight and highly conductive scaffold for deposition of pseudocapacitive materials. The device achieves an excellent active material ratio of 24%. Significantly, it delivers a remarkable energy density of 7.4 Wh/kg (based on the weight of entire device) at the average power density of 3000 W/kg. This is the highest gravimetric energy density reported for asymmetric electrochemical capacitors at such a high power density. PMID- 25830498 TI - Non-immune Hydrops fetalis due to Parvovirus B19 Infection in 2 Extremely Preterm Infants: Perinatal Management and Long-term Neurodevelopmental Outcome. AB - Parvovirus B19 (B19V) infection during pregnancy can lead to fetal damage and even fetal loss. In some cases a severe fetal anemia with hydrops fetalis occurs. An intrauterine red blood cell transfusion can reduce the mortality rate. Neurodevelopmental outcome after fetal B19V infection is affected by fetal anemia and presumably direct infection of the CNS. There are only a few studies on long term neurodevelopmental outcome after B19V infection induced hydrops fetalis. There are hardly any long-term data especially in preterm infants. We report on the long-term outcomes of 2 extremely preterm children after non-immune hydrops fetalis due to intrauterine B19V Infection. PMID- 25830496 TI - Alanine aminotransferase variants conferring diverse NUE phenotypes in Arabidopsis thaliana. AB - Alanine aminotransferase (AlaAT, E.C. 2.6.1.2), is a pyridoxal-5'-phosphate dependent (PLP) enzyme that catalyzes the reversible transfer of an amino group from alanine to 2-oxoglutarate to produce glutamate and pyruvate, or vice versa. It has been well documented in both greenhouse and field studies that tissue specific over-expression of AlaAT from barley (Hordeum vulgare, HvAlaAT) results in a significant increase in plant NUE in both canola and rice. While the physical phenotypes associated with over-expression of HvAlaAT have been well characterized, the role this enzyme plays in vivo to create a more N efficient plant remains unknown. Furthermore, the importance of HvAlaAT, in contrast to other AlaAT enzyme homologues in creating this phenotype has not yet been explored. To address the role of AlaAT in NUE, AlaAT variants from diverse sources and different subcellular locations, were expressed in the wild-type Arabidopsis thaliana Col-0 background and alaat1;2 (alaat1-1;alaat2-1) knockout background in various N environments. The analysis and comparison of both the physical and physiological properties of AlaAT over-expressing transgenic plants demonstrated significant differences between plants expressing the different AlaAT enzymes under different external conditions. This analysis indicates that the over-expression of AlaAT variants other than HvAlaAT in crop plants could further increase the NUE phenotype(s) previously observed. PMID- 25830499 TI - [Indication-Related Effectivity of Cervical Occlusion Techniques in Women with Threatening Preterm Birth]. AB - The aim of this study was to identify which operation technique [total cervical occlusion (TMV), cerclage (C) or combination of both (TMV+C)] would lead to the greatest pregnancy prolongation in 3 different collectives of patients at risk (history of preterm birth, cervical insufficiency, prolapsing membranes). In this retrospective data collection, 200 cervical occlusions performed between 1997 and 2010 were analysed. In patients with a history of preterm birth/stillbirth (n=80) a prophylactic TMV increased the lifebirth rate from 35% without TMV to 95% with TMV (p<0.001). The risk diminuation after TMV was - 60% for stillbirth (p<0.001) and - 30% for preterm birth (p=0.01). In this subcollective the TMV seemed to be more effective in pregnancy prolongation (days) than C (139 vs. 113 days), however the combination of both (C+TMV) did not add much benefit (142 days). In patients with cervical insuffiency (n=86) the pregnancy could be prolonged by 82 (C), 79 (TMV) und 109 days (C+TMV) (p=0.003-0.017) and in patients with membrane prolaps (n=34) by 63 (C), 61 (TMV) und 76 (C+TMV) days. According to present data, the combination of cerclage and TMV has the highest benefit on pregnancy prolongation. This analysis should provide a basis for randomised controlled studies on this topic. PMID- 25830501 TI - Pitfalls in the analysis of volatile breath biomarkers: suggested solutions and SIFT-MS quantification of single metabolites. AB - The experimental challenges presented by the analysis of trace volatile organic compounds (VOCs) in exhaled breath with the objective of identifying reliable biomarkers are brought into focus. It is stressed that positive identification and accurate quantification of the VOCs are imperative if they are to be considered as discreet biomarkers. Breath sampling procedures are discussed and it is suggested that for accurate quantification on-line real time sampling and analysis is desirable. Whilst recognizing such real time analysis is not always possible and sample collection is often required, objective recognition of the pitfalls involved in this is essential. It is also emphasized that mouth-exhaled breath is always contaminated to some degree by orally generated compounds and so, when possible, analysis of nose-exhaled breath should be performed. Some difficulties in breath analysis are mitigated by the choice of analytical instrumentation used, but no single instrument can provide solutions to all the analytical challenges. Analysis and interpretation of breath analysis data, however acquired, needs to be treated circumspectly. In particular, the excessive use of statistics to treat imperfect mass spectrometry/mobility spectra should be avoided, since it can result in unjustifiable conclusions. It is should be understood that recognition of combinations of VOCs in breath that, for example, apparently describe particular cancer states, will not be taken seriously until they are replicated in other laboratories and clinics. Finally, the inhibiting notion that single biomarkers of infection and disease will not be identified and utilized clinically should be dispelled by the exemplary and widely used single biomarkers NO and H2 and now, as indicated by recent selected ion flow tube mass spectroscopy (SIFT-MS) results, triatomic hydrogen cyanide and perhaps pentane and acetic acid. Hopefully, these discoveries will provide encouragement to research workers to be more open-minded on this important and desirable issue. PMID- 25830502 TI - A network centrality method for the rating problem. AB - We propose a new method for aggregating the information of multiple users rating multiple items. Our approach is based on the network relations induced between items by the rating activity of the users. Our method correlates better than the simple average with respect to the original rankings of the users, and besides, it is computationally more efficient than other methods proposed in the literature. Moreover, our method is able to discount the information that would be obtained adding to the system additional users with a systematically biased rating activity. PMID- 25830500 TI - [Knee-related Pain Problems during Pregnancy Correlate with an Increase in Body Weight. Results of a Prospective Study]. AB - PURPOSE: This study aimed to evaluate the incidence of knee pain or the intensification of knee-related problems during pregnancy. We hypothesised that the occurrence of knee problems correlates with an increase in body weight during pregnancy. METHODS: A total of 326 women (30(th)-40(th) week of pregnancy) were involved in this study. At onset of the pregnancy, the patients were 29.4 [95% CI 28.8-29.9] years of age. We asked all patients retrospectively about their anthropometric data at the beginning of pregnancy. All patients provided information about former knee problems, knee problems occurring after onset of pregnancy or any increase in these problems. These knee patients were re evaluated 6 weeks after childbirth. At follow-up, the patients were asked about their knee problems and about their body weight. RESULTS: At the beginning of pregnancy, the mean body weight was 68.0 kg (95% CI 64.4-69.6; range 41-117). The mean BMI of all patients was 24.5 kg/m2 (25% CI 23.9-25.0; range 17.0-26.0). The absolute body weight increased by 13.8 kg (95% CI 13.2-1.5; range 3-38). A total of 24 patients (7.4%) reported new knee problems during pregnancy. 2 patients reported an increase in knee-related problems during pregnancy (0.6%). The incidence of knee-related problems (new cases and increase of problems n=26) was 26/326 or 7.6/100 pregnancies. In patients without knee problems, the pregnancy related increase in the BMI (DeltaBMI) was 4.8 kg/m2 (95% CI 4.6-5.1, range 1.1 14.1). In cases with incident knee problems, the DeltaBMI was 5.9 kg/m2 (95% CI 4.9-6.9, range 2.1-11.8). The increase in body weight (Deltabody weight) in patients without knee problems was 13.5 kg (95% CI 12.9-14.2, range 3-38). Patients with incident knee pain experienced a Deltabody weight of 16.8 kg (95% CI 13.9-19.4, range 6-35). The differences in DeltaBMI and Deltabody weight were significant (p=0.009). A Deltabody weight >20 kg was a significant risk factor for pregnancy-related knee pain significant risk factor pregnancy related pain. A total of 23 incident cases (92%) underwent a follow-up interview 6 weeks after parturition. At this time, a total of 6 patients (26.1%) had not experienced further knee problems, whereas persistent knee problems were reported in the remaining patients (73.9%). Patients without any knee complaints [body weight 72.5 kg (CI 95% 60.9-83.9)] tended to have a lower body weight at follow-up than patients with persistent knee pain [85.5 kg (CI 95% 71.8-99.1), p=0.162]. CONCLUSION: There is a body weight-associated increase in the incidence of functional knee pain in pregnant women. In about one-third of the cases, knee problems persist after pregnancy and are associated with a residual increase in body weight. Thus, we conclude that body weight is a potential risk factor for functional knee pain. PMID- 25830504 TI - The popularity of benzodiazepines, their advantages, and inadequate pharmacological alternatives. PMID- 25830503 TI - A Web-based health promotion program for older workers: randomized controlled trial. AB - BACKGROUND: Recent evidence supports the efficacy of programs that promote improvements in the health practices of workers 50 years and older who are at higher risk for chronic diseases than younger workers are. Internet-based programs that promote healthy practices have also shown promise and, therefore, should be especially appropriate for workers aged 50 years and older. OBJECTIVE: The purpose of the research was to evaluate the effectiveness of HealthyPast50, a fully automated Web-based health promotion program based on social cognitive theory and aimed specifically at workers 50 years and older. METHODS: The randomized controlled trial was conducted across multiple US offices of a large global information technology company. The sample included 278 employees aged 50 to 68 who were recruited online and randomly assigned to the Web-based HealthyPast50 program or to a wait-list control condition. Self-report measures of diet, physical activity, stress, and tobacco use were collected online before and 3 months after the program group was given access to the program. Use data included number of log-ins and number of pages accessed. The primary analysis was multiple linear regression, following intent-to-treat principles with multiple imputation using the Markov chain Monte Carlo (MCMC) approach for nonmonotone missing data. Potential moderators from demographic characteristics and program dosage effects were assessed using multiple linear regression models. Additional analyses were conducted on complete (nonimputed) cases, excluding program participants who used the program for less than 30 minutes. RESULTS: Retention rates were good for both groups: 80.4% (111/138) for the program group and 94.3% (132/140) for the control group. Program group participants spent a mean of 102.26 minutes in the program (SD 148.32), logged in a mean of 4.33 times (SD 4.28), and viewed a mean of 11.04 pages (SD 20.08). In the analysis of the imputed dataset, the program group performed significantly better than the control group on diet behavioral change self-efficacy (estimated adjusted difference [Delta]=0.16, P=.048), planning healthy eating (Delta=0.17, P=.03), and mild exercise (Delta=1.03, P=.01). Moderator and dosage analyses of the dataset found no significant program effects. Analyses of the nonimputed dataset comparing program users with controls found additional significant program effects on eating practices (Delta=0.09, P=.03), exercise self-efficacy (Delta=0.12, P=.03), exercise planning (Delta=0.18, P=.03), and aging beliefs (Delta=0.17, P=.01). Moderator analysis of this dataset also found significant moderator effects of gender on multiple measures of exercise. CONCLUSIONS: A Web based health promotion program showed promise for making a significant contribution to the short-term dietary and exercise practices of older working adults. Gender effects suggest that the program effects on exercise are due mainly to improvements among women. PMID- 25830506 TI - Interferon-Gamma Increases Endothelial Permeability by Causing Activation of p38 MAP Kinase and Actin Cytoskeleton Alteration. AB - Interferon-gamma (IFN-gamma) is known to potentiate the progression of inflammatory diseases, such as inflammatory bowel disease and atherosclerosis. IFN-gamma has been found to disrupt the barrier integrity of epithelial and endothelial cell both in vivo and in vitro. However, the mechanisms of IFN-gamma underlying increased endothelial cell permeability have not been extensively elucidated. We reported that IFN-gamma exhibits a biphasic nature in increasing endothelial permeability. The changes observed in the first phase (4-8 h) involve cell retraction and rounding in addition to condensed peripheral F-actin without a significant change in the F-/G-actin ratio. However, cell elongation, stress fiber formation, and an increased F-/G-actin ratio were noticed in the second phase (16-24 h). Consistent with our finding from the permeability assay, IFN gamma induced the formation of intercellular gaps in both phases. A delayed phase of increased permeability was observed at 12 h, which paralleled the onset of cell elongation, stress fiber formation, and increased F-/G-actin ratio. In addition, IFN-gamma stimulated p38 mitogen-activated protein (MAP) kinase phosphorylation over a 24 h period. Inhibition of p38 MAP kinase by SB203580 prevented increases in paracellular permeability, actin rearrangement, and increases in the F-/G-actin ratio caused by IFN-gamma. Our results suggest that p38 MAP kinase is activated in response to IFN-gamma and causes actin rearrangement and altered cell morphology, which in turn mediates endothelial cell hyperpermeability. The F-/G-actin ratio might be involved in the regulation of actin distribution and cell morphology rather than the increased permeability induced by IFN-gamma. PMID- 25830509 TI - Correlated Conformational Motions of the KH Domains of Far Upstream Element Binding Protein Complexed with Single-Stranded DNA Oligomers. AB - Single-stranded DNA binding (SSB) proteins bind with single-stranded DNA (ss-DNA) segments that are generated as intermediates during DNA metabolic processes. The primary function of an SSB protein is to protect the ss-DNA from being degraded so that other enzymes can effectively act on it. We have performed atomistic molecular dynamics simulations of the two DNA binding K homology (KH) domains (KH3 and KH4) of the far upstream element (FUSE) binding protein (FBP) complexed with two ss-DNA oligomers in aqueous solutions. Attempts have been made to study the effects of complexation on the internal motions of the protein domains and the correlated dynamics of the amino acid residue side chains. In agreement with experiments, KH3 domain has been found to be relatively more flexible in the complexed state. The calculations reveal increased long-range anticorrelated motions among several amino acid residues in the complexed forms. Compared to the KH4 domain, noticeable increase in N-H dipole ordering on complexation has been observed for the KH3 domain. Importantly, it is demonstrated that the effects of the DNA strands on the side chain orientations of the arginine and lysine residues and their ordering and dynamics play critical roles in forming the complexes and their structural stability. PMID- 25830507 TI - Ubiquitous promoter-localization of essential virulence regulators in Francisella tularensis. AB - Francisella tularensis is a Gram-negative bacterium whose ability to replicate within macrophages and cause disease is strictly dependent upon the coordinate activities of three transcription regulators called MglA, SspA, and PigR. MglA and SspA form a complex that associates with RNA polymerase (RNAP), whereas PigR is a putative DNA-binding protein that functions by contacting the MglA-SspA complex. Most transcription activators that bind the DNA are thought to occupy only those promoters whose activities they regulate. Here we show using chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-Seq) that PigR, MglA, and SspA are found at virtually all promoters in F. tularensis and not just those of regulated genes. Furthermore, we find that the ability of PigR to associate with promoters is dependent upon the presence of MglA, suggesting that interaction with the RNAP-associated MglA-SspA complex is what directs PigR to promoters in F. tularensis. Finally, we present evidence that the ability of PigR (and thus MglA and SspA) to positively control the expression of genes is dictated by a specific 7 base pair sequence element that is present in the promoters of regulated genes. The three principal regulators of virulence gene expression in F. tularensis therefore function in a non-classical manner with PigR interacting with the RNAP-associated MglA-SspA complex at the majority of promoters but only activating transcription from those that contain a specific sequence element. Our findings reveal how transcription factors can exert regulatory effects at a restricted set of promoters despite being associated with most or all. This distinction between occupancy and regulatory effect uncovered by our data may be relevant to the study of RNAP-associated transcription regulators in other pathogenic bacteria. PMID- 25830510 TI - The preconception needs of women with severe mental illness: a consecutive clinical case series. AB - INTRODUCTION: Women with severe mental illness (SMI) are having babies at an increasing rate, but continue to face many challenges across the perinatal period. There is little research into the preconception needs of women with SMI and the aim of this study was to investigate the social circumstances, general health, mental health and reproductive health care needs in these at risk women. METHOD: Women with SMI referred for specialist preconception counselling at a tertiary obstetric hospital in 2012 were eligible to participate. The data source was a semi-structured study-specific interview schedule with open-ended questions incorporated into the routine assessment protocol. RESULTS: In a one-year period, 23 women were referred to the service and 22 consented to data from the interview being pooled for the study. All women were taking at least one psychotropic medication at the time of referral. Overall, 40% (n = 9) were aged at least 35 years, 36% (n = 8) smoked cigarettes daily and over half (54.5% n = 12) reported their body mass index as being in the overweight or obese range. Thematic analysis revealed the importance of maternal desire, and concerns relating to age and biological time pressure, the impact of the illness and medication on pregnancy and motherhood. CONCLUSION: Our data indicate that preconception counselling should be routine in the care of women with SMI of reproductive age, and should take into account the potential centrality of motherhood in the woman's rehabilitation, as well as the complex appraisals of risks, general health and support. PMID- 25830508 TI - Alcohol, binge drinking and associated mental health problems in young urban Chileans. AB - OBJECTIVE: To explore the link between alcohol use, binge drinking and mental health problems in a representative sample of adolescent and young adult Chileans. METHODS: Age and sex-adjusted Odds Ratios (OR) for four mental wellbeing measures were estimated with separate conditional logistic regression models for adolescents aged 15-20 years, and young adults aged 21-25 years, using population-based estimates of alcohol use prevalence rates from the Chilean National Health Survey 2010. RESULTS: Sixty five per cent of adolescents and 85% of young adults reported drinking alcohol in the last year and of those 83% per cent of adolescents and 86% of young adults reported binge drinking in the previous month. Adolescents who reported binging alcohol were also more likely, compared to young adults, to report being always or almost always depressed (OR 12.97 [95% CI, 1.86-19.54]) or to feel very anxious in the last month (OR 9.37 [1.77-19.54]). Adolescent females were more likely to report poor life satisfaction in the previous year than adolescent males (OR 8.50 [1.61-15.78]), feel always or almost always depressed (OR 3.41 [1.25-9.58]). Being female was also associated with a self-reported diagnosis of depression for both age groups (adolescents, OR 4.74 [1.49-15.08] and young adults, OR 4.08 [1.65-10.05]). CONCLUSION: Young people in Chile self-report a high prevalence of alcohol use, binge drinking and associated mental health problems. The harms associated with alcohol consumption need to be highlighted through evidence-based prevention programs. Health and education systems need to be strengthened to screen and support young people. Focussing on policy initiatives to limit beverage companies targeting alcohol to young people will also be needed. PMID- 25830511 TI - Early parental loss and self-rated health of older women and men: a population based, multi-country study. AB - OBJECTIVE: Death of a parent in childhood can diminish both the nurturing that promotes healthy development, and household income. We consider, for the first time, whether this adverse childhood experience is associated with self-rated health decades later, among seniors and whether this lifelong effect is different for women and men. METHODS: The International Mobility in Aging (IMIAS) study is a prospective cohort with survey information and biophysical measures and markers from 2000 community-dwelling 65-74 year olds in Canada, Colombia, Brazil and Albania. We assessed the independent impact of death of a parent, early hunger, and witnessing violence, while controlling for current income sufficiency and other early adversities on self-rated health using baseline (2012) IMIAS data. Regressions grouping and then separating women and men were compared. RESULTS: Approximately 17% of the 1991 participants had experienced early parental loss. Overall 56% rated their health as good however parental loss predicted poorer adult health, as did early hunger but not witnessing violence. Disaggregated analyses revealed that the health consequences of parental loss were significant only among men (p = 0.000 versus p = 0.210 for women) whereas early hunger predicted poor self-rated health for both (p = 0.000). CONCLUSION: Parental loss should be considered as a potent adverse childhood experience with life-long consequences for health. The gender difference in its effect, speaks to unidentified and modifiable traits that appear to be more common among women and that may build resilience to long-term harms of early parental death. PMID- 25830512 TI - A systematic review of the efficacy and safety experience reported for sorafenib in advanced renal cell carcinoma (RCC) in the post-approval setting. AB - BACKGROUND: Sorafenib was FDA approved in 2005 for treatment of renal cell carcinoma (RCC) based on the results of the pivotal phase 3 clinical trial, TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial). Since that time, numerous clinical studies have been undertaken that substantially broaden our knowledge of the use of sorafenib for this indication. METHODS: We systematically reviewed PubMed, Web of Science, Embase, Cochrane Library, and www.clinicaltrials.gov for prospective clinical studies using single agent sorafenib in RCC and published since 2005. Primary endpoints of interest were progression-free survival (PFS) and safety. PROSPERO International prospective register of systematic reviews #CRD42014010765. RESULTS: We identified 30 studies in which 2182 patients were treated with sorafenib, including 1575 patients who participated in randomized controlled phase 3 trials. In these trials, sorafenib was administered as first-, second- or third-line treatment. Heterogeneity among trial designs and reporting of data precluded statistical comparisons among trials or with TARGET. The PFS appeared shorter in second- vs. first-line treatment, consistent with the more advanced tumor status in the second-line setting. In some trials, incidences of grade 3/4 hypertension or hand-foot skin reaction (HFSR) were more than double that seen in TARGET (4% and 6%, respectively). These variances may be attributable to increased recognition of HFSR, or potentially differences in dose adjustments, that could be consequences of increased familiarity with sorafenib usage. Several small studies enrolled exclusively Asian patients. These studies reported notably longer PFS than was observed in TARGET. However, no obvious corresponding differences in disease control rate and overall survival were seen. CONCLUSIONS: Collectively, more recent experiences using sorafenib in RCC are consistent with results reported for TARGET with no marked changes of response endpoints or new safety signals observed. PMID- 25830513 TI - A common pathway to obesity and allergic asthma. PMID- 25830514 TI - The Dutch hypothesis meets genomics. PMID- 25830515 TI - Imaging to predict therapeutic outcomes. PMID- 25830516 TI - Show me the SNPs. How bacterial sex generates diversity in the cystic fibrosis lung. PMID- 25830517 TI - Bringing comfort to endobronchial ultrasound bronchoscopy. PMID- 25830518 TI - Global participation in core data sets for emerging pathogens. PMID- 25830519 TI - Continuous positive airway pressure plus weight loss for obstructive sleep apnea (OSA), association of cancer with OSA, and hypoglossal nerve stimulation for OSA treatment. PMID- 25830520 TI - Fulminant invasive tracheobronchial aspergillosis. PMID- 25830521 TI - Endothelial chromosome 13 deletion in congenital heart disease-associated pulmonary arterial hypertension dysregulates SMAD9 signaling. PMID- 25830523 TI - Attenuation of obstructive sleep apnea and overnight rostral fluid shift by physical activity. PMID- 25830522 TI - Genetic heterogeneity of circulating cells from patients with lymphangioleiomyomatosis with and without lung transplantation. PMID- 25830524 TI - No significant reduction in antibiotic treatment using a procalcitonin algorithm with low cutoff value in the intensive care unit? PMID- 25830526 TI - Expression of concern: Alveolar macrophages from overweight/obese subjects with asthma demonstrate a proinflammatory phenotype. PMID- 25830525 TI - Reply: No significant reduction in antibiotic treatment using a procalcitonin algorithm with low cutoff value in the intensive care unit? PMID- 25830528 TI - Web-Based Remote Monitoring Systems for Self-Managing Type 2 Diabetes: A Systematic Review. AB - This systematic review aims to evaluate evidence for viability and impact of Web based telemonitoring for managing type 2 diabetes mellitus. A review protocol included searching Medline, EMBASE, CINAHL, AMED, the Cochrane Library, and PubMed using the following terms: telemonitoring, type 2 diabetes mellitus, self management, and web-based Internet solutions. The technology used, trial design, quality of life measures, and the glycated hemoglobin (HbA1c) levels were extracted. This review identified 426 publications; of these, 19 met preset inclusion criteria. Ten quasi-experimental research designs were found, of which seven were pre-posttest studies, two were cohort studies, and one was an interrupted time-series study; in addition, there were nine randomized controlled trials. Web-based remote monitoring from home to hospital is a viable approach for healthcare delivery and enhances patients' quality of life. Six of these studies were conducted in South Korea, five in the United States, three in the United Kingdom, two in Taiwan, and one each in Spain, Poland, and India. The duration of the studies varied from 4 weeks to 18 months, and the participants were all adults. Fifteen studies showed positive improvement in HbA1c levels. One study showed high acceptance of the technology among participants. It remains challenging to identify clear evidence of effectiveness in the rapidly changing area of remote monitoring in diabetes care. Both the technology and its implementations are complex. The optimal design of a telemedicine system is still uncertain, and the value of the real-time blood glucose transmissions is still controversial. PMID- 25830527 TI - An Official American Thoracic Society/European Respiratory Society Statement: Research questions in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. METHODS: Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified. RESULTS: Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. CONCLUSIONS: Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes. PMID- 25830529 TI - Effects of estradiol, progestogens, and of tibolone on breast proliferation and apoptosis. AB - AIM: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue. METHODS: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging. RESULTS: There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis. CONCLUSIONS: The various progestogens can have more or less proliferative and pro apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation. PMID- 25830532 TI - Authors' reply. PMID- 25830531 TI - Plasmodium knowlesi genome sequences from clinical isolates reveal extensive genomic dimorphism. AB - Plasmodium knowlesi is a newly described zoonosis that causes malaria in the human population that can be severe and fatal. The study of P. knowlesi parasites from human clinical isolates is relatively new and, in order to obtain maximum information from patient sample collections, we explored the possibility of generating P. knowlesi genome sequences from archived clinical isolates. Our patient sample collection consisted of frozen whole blood samples that contained excessive human DNA contamination and, in that form, were not suitable for parasite genome sequencing. We developed a method to reduce the amount of human DNA in the thawed blood samples in preparation for high throughput parasite genome sequencing using Illumina HiSeq and MiSeq sequencing platforms. Seven of fifteen samples processed had sufficiently pure P. knowlesi DNA for whole genome sequencing. The reads were mapped to the P. knowlesi H strain reference genome and an average mapping of 90% was obtained. Genes with low coverage were removed leaving 4623 genes for subsequent analyses. Previously we identified a DNA sequence dimorphism on a small fragment of the P. knowlesi normocyte binding protein xa gene on chromosome 14. We used the genome data to assemble full-length Pknbpxa sequences and discovered that the dimorphism extended along the gene. An in-house algorithm was developed to detect SNP sites co-associating with the dimorphism. More than half of the P. knowlesi genome was dimorphic, involving genes on all chromosomes and suggesting that two distinct types of P. knowlesi infect the human population in Sarawak, Malaysian Borneo. We use P. knowlesi clinical samples to demonstrate that Plasmodium DNA from archived patient samples can produce high quality genome data. We show that analyses, of even small numbers of difficult clinical malaria isolates, can generate comprehensive genomic information that will improve our understanding of malaria parasite diversity and pathobiology. PMID- 25830530 TI - Interaction between fibronectin and beta1 integrin is essential for tooth development. AB - The dental epithelium and extracellular matrix interact to ensure that cell growth and differentiation lead to the formation of teeth of appropriate size and quality. To determine the role of fibronectin in differentiation of the dental epithelium and tooth formation, we analyzed its expression in developing incisors. Fibronectin mRNA was expressed during the presecretory stage in developing dental epithelium, decreased in the secretory and early maturation stages, and then reappeared during the late maturation stage. The binding of dental epithelial cells derived from postnatal day-1 molars to a fibronectin coated dish was inhibited by the RGD but not RAD peptide, and by a beta1 integrin neutralizing antibody, suggesting that fibronectin-beta1 integrin interactions contribute to dental epithelial-cell binding. Because fibronectin and beta1 integrin are highly expressed in the dental mesenchyme, it is difficult to determine precisely how their interactions influence dental epithelial differentiation in vivo. Therefore, we analyzed beta1 integrin conditional knockout mice (Intbeta1lox-/lox-/K14-Cre) and found that they exhibited partial enamel hypoplasia, and delayed eruption of molars and differentiation of ameloblasts, but not of odontoblasts. Furthermore, a cyst-like structure was observed during late ameloblast maturation. Dental epithelial cells from knockout mice did not bind to fibronectin, and induction of ameloblastin expression in these cells by neurotrophic factor-4 was inhibited by treatment with RGD peptide or a fibronectin siRNA, suggesting that the epithelial interaction between fibronectin and beta1 integrin is important for ameloblast differentiation and enamel formation. PMID- 25830533 TI - Involvement of the caleosin/peroxygenase RD20 in the control of cell death during Arabidopsis responses to pathogens. AB - Caleosins, mostly found in lipid droplets of seeds and leaves, are believed to play physiological roles through their enzymatic capacities to produce oxylipins. We recently identified the caleosin RD20 as a peroxygenase reducing endogenous fatty acid hydroperoxides into their corresponding alcohols. Such oxylipins confer tolerance to oxidative stress by decreasing reactive oxygen species accumulation and by minimizing cell death. RD20 expression being induced by pathogens, we have examined the mode of action of this caleosin in response to biotic stress. Plants overexpressing RD20 exhibited an alteration of their leaf cuticle wax components and an increased resistance to the fungus Alternaria brassicicola. Conversely, silencing RD20 led to an enhanced propagation of the fungus and to reduced severity of the damages caused by the inoculation of the bacteria Pseudomonas syringae pv tomato. We discuss these findings and propose that the major function of RD20 is to generate oxylipins modulating oxidative status and cell death. PMID- 25830534 TI - Understanding of the viscoelastic response of the human corneal stroma induced by riboflavin/UV-a cross-linking at the nano level. AB - PURPOSE: To investigate the viscoelastic changes of the human cornea induced by riboflavin/UV-A cross-linking using Atomic Force Microscopy (AFM) at the nano level. METHODS: Seven eye bank donor corneas were investigated, after gently removing the epithelium, using a commercial AFM in the force spectroscopy mode. Silicon cantilevers with tip radius of 10 nm and spring elastic constants between 26- and 86-N/m were used to probe the viscoelastic properties of the anterior stroma up to 3 um indentation depth. Five specimens were tested before and after riboflavin/UV-A cross-linking; the other two specimens were chemically cross linked using glutaraldehyde 2.5% solution and used as controls. The Young's modulus (E) and the hysteresis (H) of the corneal stroma were quantified as a function of the application load and scan rate. RESULTS: The Young's modulus increased by a mean of 1.1-1.5 times after riboflavin/UV-A cross-linking (P<0.05). A higher increase of E, by a mean of 1.5-2.6 times, was found in chemically cross-linked specimens using glutaraldehyde 2.5% (P<0.05). The hysteresis decreased, by a mean of 0.9-1.5 times, in all specimens after riboflavin/UV-A cross-linking (P<0.05). A substantial decrease of H, ranging between 2.6 and 3.5 times with respect to baseline values, was observed in glutaraldehyde-treated corneas (P<0.05). CONCLUSIONS: The present study provides the first evidence that riboflavin/UV-A cross-linking induces changes of the viscoelastic properties of the cornea at the scale of stromal molecular interactions. PMID- 25830535 TI - Transforming primary care residency training: a collaborative faculty development initiative among family medicine, internal medicine, and pediatric residencies. AB - PROBLEM: The scope and scale of developments in health care redesign have not been sufficiently adopted in primary care residency programs. APPROACH: The interdisciplinary Primary Care Faculty Development Initiative was created to teach faculty how to accelerate revisions in primary care residency training. The program focused on skill development in teamwork, change management, leadership, population management, clinical microsystems, and competency assessment. The 2013 pilot program involved 36 family medicine, internal medicine, and pediatric faculty members from 12 residencies in four locations. OUTCOMES: The percentage of participants rating intention to implement what was learned as "very likely to" or "absolutely will" was 16/32 (50%) for leadership, 24/33 (72.7%) for change management, 23/33 (69.7%) for systems thinking, 25/32 (75.8%) for population management, 28/33 (84.9%) for teamwork, 29/33 (87.8%) for competency assessment, and 30/31 (96.7%) for patient centeredness.Content analysis revealed five key themes: leadership skills are key drivers of change, but program faculty face big challenges in changing culture and engaging stakeholders; access to data from electronic health records for population management is a universal challenge; readiness to change varies among the three disciplines and among residencies within each discipline; focusing on patients and their needs galvanizes collaborative efforts across disciplines and within residencies; and collaboration among disciplines to develop and use shared measures of residency programs and learner outcomes can guide and inspire program changes and urgently needed educational research. NEXT STEPS: Revise and reevaluate this rapidly evolving program toward widespread engagement with family medicine, internal medicine, and pediatric residencies. PMID- 25830536 TI - Sociomateriality: a theoretical framework for studying distributed medical education. AB - Distributed medical education (DME) is a type of distance learning in which students participate in medical education from diverse geographic locations using Web conferencing, videoconferencing, e-learning, and similar tools. DME is becoming increasingly widespread in North America and around the world.Although relatively new to medical education, distance learning has a long history in the broader field of education and a related body of literature that speaks to the importance of engaging in rigorous and theoretically informed studies of distance learning. The existing DME literature is helpful, but it has been largely descriptive and lacks a critical "lens"-that is, a theoretical perspective from which to rigorously conceptualize and interrogate DME's social (relationships, people) and material (technologies, tools) aspects.The authors describe DME and theories about distance learning and show that such theories focus on social, pedagogical, and cognitive considerations without adequately taking into account material factors. They address this gap by proposing sociomateriality as a theoretical framework allowing researchers and educators to study DME and (1) understand and consider previously obscured actors, infrastructure, and other factors that, on the surface, seem unrelated and even unimportant; (2) see clearly how the social and material components of learning are intertwined in fluid, messy, and often uncertain ways; and (3) perhaps think differently, even in ways that disrupt traditional approaches, as they explore DME. The authors conclude that DME brings with it substantial investments of social and material resources, and therefore needs careful study, using approaches that embrace its complexity. PMID- 25830538 TI - The role of medical culture in the journey to resilience. AB - There is growing concern about the difficulty primary care practices are experiencing both recruiting and retaining practitioners. Frustrations stemming from integrating electronic medical records, satisfying external documentation requirements for oversight and billing, and the divide created between inpatient and ambulatory care teams all contribute to practitioner and staff burnout. Addressing the current culture of medical education and primary care is clearly an essential issue for health care leaders and medical educators.Using two experiences, a workshop on resilience with a large primary care practice group and a medical student studying for the United States Medical Licensing Examination Step 1, the author describes the cultural imperative, beginning in medical school, to sacrifice self-care for productivity and individual achievement. This approach has consequences for practitioners' levels of burnout and selecting primary care as a career. The author concludes by providing recommendations for both individual and organizational approaches to addressing these concerns. PMID- 25830537 TI - A facilitated peer mentoring program for junior faculty to promote professional development and peer networking. AB - PURPOSE: To explore the design, implementation, and efficacy of a faculty development program in a cohort of early career junior faculty. METHOD: Interested junior faculty members were divided into interdisciplinary small groups led by senior faculty facilitators. The groups met monthly for 1.5 hours to review a modular curriculum from 2011 to 2013. Using a survey at two time points (September 2011 and 2013) and an interim program evaluation, the authors collected data on participants' demographics, faculty interconnectedness, and self-reported knowledge, skills, and attitudes (KSA) in the domains of professional development and scholarship, including the ability to write career goals and align activities with those goals. RESULTS: A total of 104 junior faculty participated in the program. They demonstrated changes in self-reported KSA in the domains of professional development (P = .013, P = .001) and scholarship (P = .038, P = .015) with an increase in ability to write career goals (P < .001), ability to align activities with those goals (P < .001), and number of and amount of time spent pursuing activities related to those goals (P = .022). These changes were more significant among female faculty and were not affected by academic rank or time since last training. Interconnectedness among faculty increased during the period of study-the number of nodes and ties between nodes within the network increased. CONCLUSIONS: This facilitated peer mentoring program for junior faculty was effective in improving the KSA necessary to promote early career advancement and peer networking, especially for women. PMID- 25830539 TI - Air pollution and neonatal blood pressure: examining earlier exposures. PMID- 25830543 TI - New scenarios of Trypanosoma cruzi transmission in the Orinoco region of Colombia. AB - Rhodnius prolixus, a blood-sucking triatomine with domiciliary anthropophilic habits, is the main vector of Chagas disease. The current paradigm of Trypanosoma cruzi transmission in Columbia includes a sylvatic and domiciliary cycle co existing with domestic and sylvatic populations of reservoirs. The aim of this study is to evaluate the population densities and relative abundance of triatomines and mammals that may be involved in the sylvatic cycle of Chagas disease to clarify the epidemiological scenario in an endemic area in the province of Casanare. Insect vectors on Attalea butyracea palms were captured using both manual searches and bait traps. The capture of mammals was performed using Sherman and Tomahawk traps. We report an infestation index of 88.5% in 148 palms and an index of T. cruzi natural infection of 60.2% in 269 dissected insects and 11.9% in 160 captured mammals. High population densities of triatomines were observed in the sylvatic environment and there was a high relative abundance of reservoirs in the area, suggesting a stable enzootic cycle. We found no evidence of insect domiciliation. Taken together, these observations suggest that eco-epidemiological factors shape the transmission dynamics of T. cruzi, creating diverse scenarios of disease transmission. PMID- 25830545 TI - Material properties and constitutive modeling of infant porcine cerebellum tissue in tension at high strain rate. AB - BACKGROUND: The mechanical characterization of infant porcine cerebellum tissue in tension at high strain rate is crucial for modeling traumatic cerebellum injury, which is in turn helpful for understanding the biomechanics of such injuries suffered in traffic accidents. MATERIAL AND METHOD: In this study, the infant porcine cerebellum tissue was given three loading velocities, ie, 2s-1, 20s-1 and 100s-1 with up to 30% strain to investigate the tensile properties. At least six tensile tests for each strain rate were validly performed. Fung, Gent, Ogden and exponential models were applied to fit the constitutive equations, so as to obtain material parameters from the experimental data. RESULTS: The Lagrange stress of infant porcine cerebellum tissue in tension appeared to be no more than 3000Pa at each loading velocity. More specifically, the Lagrange stress at 30% strain was (393.7+/-84.4)Pa, (928.3+/-56.3)Pa and (2582.4+/-282.2)Pa at strain rates of 2s-1, 20s-1 and 100s-1, respectively. Fung (0.833<=R2<=0.924), Gent (0.797<=R2<=0.875), Ogden (0.859<=R2<=0.944) and exponential (0.930<=R2<=0.972) models provided excellent fitting to experimental data up to 30% strain. CONCLUSIONS: The infant cerebellum tissue shows a stiffer response with increase of the loading speed, indicating a strong strain-rate sensitivity. This study will enrich the knowledge on the material properties of infant brain tissue, which may augment the biofidelity of finite element model of human pediatric cerebellum. PMID- 25830546 TI - Development of a dry-reagent-based qPCR to facilitate the diagnosis of Mycobacterium ulcerans infection in endemic countries. AB - BACKGROUND: Buruli ulcer is a neglected tropical disease caused by Mycobacterium ulcerans. This skin disease is the third most common mycobacterial disease and its rapid diagnosis and treatment are necessary. Polymerase chain reaction (PCR) is considered to be the most sensitive method for the laboratory confirmation of Buruli ulcer. However, PCR remains expensive and involves reagents unsuitable for use in tropical countries with poor storage conditions, hindering the development of reliable quantitative PCR (qPCR) diagnosis. We aimed to overcome this problem by developing a ready-to-use dry qPCR mix for the diagnosis of M. ulcerans infection. METHODOLOGY/PRINCIPAL FINDINGS: We compared the efficiency of three different dry qPCR mixes, lyophilized with various concentrations of cryoprotectants, with that of a freshly prepared mixture, for the detection of a standard range of M. ulcerans DNA concentrations. We evaluated the heat resistance of the dry mixes, comparing them with the fresh mix after heating. We also evaluated one of the dry mixes in field conditions, by analyzing 93 specimens from patients with suspected Buruli ulcers. The dry mix was (i) highly resistant to heat; (ii) of similar sensitivity and efficiency to the fresh mix and (iii) easier to use than the fresh mix. CONCLUSIONS: Dry qPCR mixes are suitable for use in the diagnosis of M. ulcerans infection in endemic countries. The user-friendly format of this mix makes it possible for untrained staff to perform diagnostic tests with a limited risk of contamination. The possibility of using this mix in either vial or strip form provides considerable flexibility for the management of small or large amounts of sample. Thus, dry-mix qPCR could be used as a reliable tool for the diagnosis of Buruli ulcer in the field. PMID- 25830547 TI - "Why Not Stoichiometry" versus "Stoichiometry-Why Not?" Part III: Extension of GATES/GEB on Complex Dynamic Redox Systems. AB - In the third part of a series of articles issued under a common title, some examples of complex dynamic redox systems are presented and considered from analytical and physico-chemical viewpoints; the analysis is a leitmotiv for detailed, physico-chemical considerations. All attainable physico-chemical knowledge is involved in algorithms applied for resolution of the systems, realized with use of iterative computer programs. The first redox system (System I) is related to titration of FeSO4 + H2C2O4 with KMnO4 solution in acidic (H2SO4) medium, where simultaneous determination of both analytes from a single curve of potentiometric titration is possible. The possibility of the formation of precipitates (FeC2O4 and/or MnC2O4) in this system is taken into considerations. The second system (System II) relates to the complete analytical procedure involved in the iodometric determination of Cu; four consecutive steps of this analysis are considered. As a reasonable tool for explanation of processes occurring during simulated redox titration, speciation diagrams are suggested. This explanation is based on graphical presentation of results obtained from the calculations. The calculations made for this purpose are performed in accordance with principles of the generalized approach to electrolytic systems (GATES) with generalized electron balance (GEB) or GATES/GEB and realized with use of iterative computer programs offered by MATLAB. The reactions proceeding in this system can be formulated, together with their efficiencies, at any stage of the titration. Stoichiometry is considered as the derivative concept when put in context with GATES/GEB. The article illustrates the enormous possibilities and advantages offered by GATES/GEB. PMID- 25830548 TI - Iron starvation induces apoptosis in Rhizopus oryzae in vitro. AB - Mortality associated with mucormycosis remains high despite current antifungals. Iron-starvation strategies have been shown to have promising activity against Mucorales. We hypothesized that iron starvation enhances apoptosis in Rhizopus oryzae. Apoptosis was characterized in R. oryzae transformed with RNAi plasmid targeting FTR1 expression (iron permease mutant) or empty plasmid grown in iron rich (0.125% FeCl3) and iron depleted media (YNB+1mM ferrozine and 1 mM ascorbic acid). Increased apoptosis was observed with dihydrorhodamine-123 and rhodamine 123 staining in the iron starved mutant FTR1 when compared to empty plasmid, followed by increased extracellular ATP levels. In addition, DNA fragmentation and metacaspase activity were prominent in FTR1. In contrast, Rhizopus strains grown in iron-rich medium displayed minimal apoptosis. Our results demonstrate a metacaspase dependent apoptotic process in iron deprived condition and further support the role of iron starvation strategies as an adjunct treatment for mucormycosis, a mechanism by which iron starvation affects R. oryzae. PMID- 25830549 TI - Norwegian PUQE (Pregnancy-Unique Quantification of Emesis and nausea) identifies patients with hyperemesis gravidarum and poor nutritional intake: a prospective cohort validation study. AB - OBJECTIVE: The English questionnaire Pregnancy-Unique Quantification of Emesis and nausea (PUQE) identifies women with severe Hyperemesis Gravidarum. Our aim was to investigate whether scores from the translated Norwegian version; SUKK (SvangerskapsUtlost Kvalme Kvantifisering) was associated with severity of hyperemesis and nutritional intake. DESIGN: A prospective cohort validation study. SETTING: Hospital cohort of Hyperemesis Gravidarum (HG) patients from western Norway and healthy pregnant women from Bergen, Norway. SAMPLE: 38 women hospitalized due to HG and 31 healthy pregnant controls attending routine antenatal check-up at health centers. METHODS: Data were collected May 2013 January 2014. The study participants answered the Norwegian PUQE-questionnaire (scores ranging from 3 to 15) and registered prospectively 24-hours nutritional intake by a food list form. MAIN OUTCOME MEASURES: Differences of PUQE-scores, QOL-score and nutritional intake between hyperemesis patients and controls. RESULTS: Hyperemesis patients had shorter gestational age compared to controls (median 9.7 weeks; 95% CI 8.6-10.6 versus 11.9; 95% CI 10.1-12.9, p=0.004), and larger weight-change from pre-pregnant weight (loss of median 3 kg; 95% CI 3-4 versus gain of 2 kg; 95% CI 0.5-2, p<0.001) otherwise groups were similar regarding pre-pregnant BMI, age, gravidity, and inclusion weight. Compared to controls, hyperemesis patients had significant higher PUQE-score (median 13; 95% CI 11-14 vs. 7; 95% CI 4-8), lower QOL (median score 3; 95% CI 2-4 vs. 6; 95% CI 4.5-8) and lower nutritional intake (energy intake median 990 kcal/24 hours; 95% CI 709-1233 vs. 1652; 95% CI 1558-1880 all p<0.001). PUQE-score was inversely correlated to nutritional intake (-0.5, p<0.001). At discharge PUQE-score had fallen to median 6 (95% CI 5-8) and QOL score risen to 7 (95% CI 6-8) in the HG group, (both p<0.001 compared to admission values). CONCLUSION: PUQE-scoring has been validated as a robust indicator of severe hyperemesis gravidarum and insufficient nutritional intake in a Norwegian setting. PMID- 25830550 TI - B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity. AB - Chimeric antigen receptor (CAR) T-cell therapies have demonstrated durable and potentially curative therapeutic efficacy against B-cell leukemia in clinical trials. A CAR strategy can target any tumor surface antigens as long as an antigen-binding receptor can be generated. New CARs that target solid tumors and have the potential to target multiple tumor types are needed. In this study, B7H6, a ligand for the NK cell activating receptor NKp30, was targeted to create a CAR that targets multiple tumor types. B7H6 is expressed on various primary human tumors, including leukemia, lymphoma and gastrointestinal stromal tumors, but it is not constitutively expressed on normal tissues. B7H6-specific CAR T cells have robust cellular cytotoxicity and interferon-gamma secretion when co cultured with B7H6+ tumor cells, and they exhibit little self-reactivity to immature dendritic cells or pro-inflammatory monocytes. In vivo, B7H6-specific CAR T cells greatly enhanced the survival of RMA/B7H6 lymphoma-bearing mice. The long-term survivor mice were protected against a B7H6-deficient tumor re challenge. This CAR therapy also decreased tumor burden in a murine ovarian cancer model. In conclusion, B7H6-specific CARs have the potential to treat B7H6+ hematologic and solid tumors. PMID- 25830551 TI - Long-term and efficient expression of human beta-globin gene in a hematopoietic cell line using a new site-specific integrating non-viral system. AB - Targeted integration of a therapeutic gene at specific loci in safe genomic regions by a non-viral vector can restore the function of the damaged gene. This approach also minimizes the potential genotoxic effects of transferred DNA. In this study, we have developed a non-viral vector that functions according to site specific recombination (SSR). The vector contained a bacterial backbone and puromycin resistance gene (pur(r)), a beta-globin expressing cassette and an attB recombination site. We used phiC31 integrase to insert a copy of the vector into specific genomic locations of a human hematopoietic cell line. Site-specific integration of the vector with one or two copies in the transcriptionally active regions of the genome was confirmed. After genomic integration, we used Cre recombinase to remove the bacterial backbone and pur(r). This removal was verified by negative selection and genomic PCR screening. Following deletion of these sequences, the stable beta-chain expression was continued for several months in the absence of selective pressure. Consequently, this vector may potentially be a powerful tool for ex vivo correction of beta-globinopathies such as beta-thalassemia through successful genomic integration of a functional copy of the globin gene into the patient's target cells. PMID- 25830552 TI - Protective effects of non-anticoagulant activated protein C variant (D36A/L38D/A39V) in a murine model of ischaemic stroke. AB - Ischaemic stroke is caused by occlusive thrombi in the cerebral vasculature. Although tissue-plasminogen activator (tPA) can be administered as thrombolytic therapy, it has major limitations, which include disruption of the blood-brain barrier and an increased risk of bleeding. Treatments that prevent or limit such deleterious effects could be of major clinical importance. Activated protein C (APC) is a natural anticoagulant that regulates thrombin generation, but also confers endothelial cytoprotective effects and improved endothelial barrier function mediated through its cell signalling properties. In murine models of stroke, although APC can limit the deleterious effects of tPA due to its cell signalling function, its anticoagulant actions can further elevate the risk of bleeding. Thus, APC variants such as APC(5A), APC(Ca-ins) and APC(36-39) with reduced anticoagulant, but normal signalling function may have therapeutic benefit. Human and murine protein C (5A), (Ca-ins) and (36-39) variants were expressed and characterised. All protein C variants were secreted normally, but 5 20% of the protein C (Ca-ins) variants were secreted as disulphide-linked dimers. Thrombin generation assays suggested reductions in anticoagulant function of 50- to 57-fold for APC(36-39), 22- to 27-fold for APC(Ca-ins) and 14- to 17-fold for APC(5A). Interestingly, whereas human wt APC, APC(36-39) and APC(Ca-ins) were inhibited similarly by protein C inhibitor (t1/2 - 33 to 39 mins), APC(5A) was inactivated ~9-fold faster (t1/2 - 4 mins). Using the murine middle cerebral artery occlusion ischaemia/repurfusion injury model, in combination with tPA, APC(36-39), which cannot be enhanced by its cofactor protein S, significantly improved neurological scores, reduced cerebral infarct area by ~50% and reduced oedema ratio. APC(36-39) also significantly reduced bleeding in the brain induced by administration of tPA, whereas wt APC did not. If our data can be extrapolated to clinical settings, then APC(36-39) could represent a feasible adjunctive therapy for ischaemic stroke. PMID- 25830553 TI - The identification and characterization of specific ARF-Aux/IAA regulatory modules in plant growth and development. AB - The current model of auxin-inducible transcription describes numerous regulatory interactions between AUXIN RESPONSE FACTORs (ARFs) and Aux/IAAs. However, specific relationships between individual members of these families in planta remain largely uncharacterized. Using a systems biology approach, the entire suite of Aux/IAA genes directly regulated by the developmentally pivotal ARF MONOPTEROS (MP) was recently determined for multiple Arabidopsis tissue types. This study showed that MP directly targets distinct subclades of Aux/IAAs, revealing potential regulatory modules of redundantly acting Aux/IAAs involved in MP-dependent processes. Further, functional analyses indicated that the protein products of these targeted Aux/IAAs negatively feedback on MP. Thus, comprehensive identification of Aux/IAAs targeted by individual ARFs will generate biologically meaningful networks of ARF-Aux/IAA regulatory modules controlling distinct plant pathways. PMID- 25830555 TI - Molecular Detection of Foodborne Pathogens: A Rapid and Accurate Answer to Food Safety. AB - Food safety is a global health concern. For the prevention and recognition of problems related to health and safety, detection of foodborne pathogen is of utmost importance at all levels of food production chain. For several decades, a lot of research has been targeted at the development of rapid methodology as reducing the time needed to complete pathogen detection tests has been the primary goal of food microbiologists. With the result, food microbiology laboratories now have a wide array of detection methods and automated technologies such as enzyme immunoassay, polymerase chain reaction, and microarrays, which can cut test times considerably. Nucleic acid amplification strategies and advances in amplicon detection methodologies have been the key factors in the progress of molecular microbiology. A comprehensive literature survey has been carried out to give an overview in the field of foodborne pathogen detection. In this paper, we describe the conventional methods, as well as recent developments in food pathogen detection, identification, and quantification, with a major emphasis on molecular detection methods. PMID- 25830554 TI - The SKINT1-like gene is inactivated in hominoids but not in all primate species: implications for the origin of dendritic epidermal T cells. AB - Dendritic epidermal T cells, which express an invariant Vgamma5Vdelta1 T-cell receptor and account for 95% of all resident T cells in the mouse epidermis, play a critical role in skin immune surveillance. These gammadelta T cells are generated by positive selection in the fetal thymus, after which they migrate to the skin. The development of dendritic epidermal T cells is critically dependent on the Skint1 gene expressed specifically in keratinocytes and thymic epithelial cells, suggesting an indispensable role for Skint1 in the selection machinery for specific intraepithelial lymphocytes. Phylogenetically, rodents have functional SKINT1 molecules, but humans and chimpanzees have a SKINT1-like (SKINT1L) gene with multiple inactivating mutations. In the present study, we analyzed SKINT1L sequences in representative primate species and found that all hominoid species have a common inactivating mutation, but that Old World monkeys such as olive baboons, green monkeys, cynomolgus macaques and rhesus macaques have apparently functional SKINT1L sequences, indicating that SKINT1L was inactivated in a common ancestor of hominoids. Interestingly, the epidermis of cynomolgus macaques contained a population of dendritic-shaped gammadelta T cells expressing a semi invariant Vgamma10/Vdelta1 T-cell receptor. However, this population of macaque T cells differed from rodent dendritic epidermal T cells in that their Vgamma10/Vdelta1 T-cell receptors displayed junctional diversity and expression of Vgamma10 was not epidermis-specific. Therefore, macaques do not appear to have rodent-type dendritic epidermal T cells despite having apparently functional SKINT1L. Comprehensive bioinformatics analysis indicates that SKINT1L emerged in an ancestor of placental mammals but was inactivated or lost multiple times in mammalian evolution and that Skint1 arose by gene duplication in a rodent lineage, suggesting that authentic dendritic epidermal T cells are presumably unique to rodents. PMID- 25830556 TI - Enhanced production of protease by Pseudoalteromonas arctica PAMC 21717 via statistical optimization of mineral components and fed-batch fermentation. AB - The objective of this study was to statistically optimize the mineral components of the nutritional medium required for enhancing the production of a cold-active extracellular serine-type protease, W-Pro21717, by the Antarctic bacterium Pseudoalteromonas arctica PAMC 21717. Skim milk was identified as the major efficient inducer. Among the 12 components included in the unoptimized medium, skim milk, NaCl, Na2SO4, Fe(C6H5O7) (ferric citrate), and KCl were determined, by the Plackett-Burman and Box-Behnken design, to have a major effect on W-Pro21717 production. Fed-batch fermentation (5 L scale) using the mineral-optimized medium supplemented with concentrated skim milk (critical medium component) resulted in a W-Pro21717 activity of 53.4 U/L, a 15-fold increment in production over that obtained using unoptimized flask culture conditions. These findings could be applied to scale up the production of cold-active protease. PMID- 25830557 TI - Acute recanalization of carotid stenosis is not proper: an experimental ischaemic stroke study. AB - OBJECTIVES: In a rat common carotid artery (CCA) stenosis model, the author determined the function of blood-brain barrier (BBB) at different time points and established an optimal time for CCA recanalization in rats with CCA stenosis combined with cerebral infarction. METHODS: Common carotid artery severe stenosis combined with cerebral infarction was divided into two groups: CCA stenosis group (n = 48) and CCA stenosis recanalization group (n = 48). Common carotid artery stenosis recanalization was opened at time points of 1, 2, 3, 5, 7 and 14 days. Twenty-four hours after recanalization, neurological behaviour, motor function, brain water content and immunohistochemistry of laminin and fibronectin were used to assess brain injury. The peak systolic velocity (PSV) determined by colour Doppler flow imaging (CDFI) was used to assess blood flow of the CCA. RESULTS: In contrast to CCA stenosis without recanalization, in which severe neurological deficits and foot fault were observed at 1, 2 and 3 days, significantly less neurological deficits at 14 days and less foot fault placing at 5, 7 and 14 days were observed after recanalization (P < 0.05). Although the brain water content was enhanced in the recanalization group at the stage of 1-3 days (P < 0.05), a decrease in recanalization group at all time points (1-14 days) was found. Being consistent with reduced brain oedema, the expression of laminin and fibronectin gradually increased in both groups. However, at the early phase of 7-14 days (vs acute phase), the levels of basal laminar proteins were significantly (P < 0.05) enhanced by vascular recanalization in both the ischaemic core and penumbra. Peak systolic velocity of CCA after recanalization reached the control level without stenosis. CONCLUSIONS: Our study suggests that the optimal time to open the CCA stenosis complicating cerebral infarction is at or after 7 days of CCA stenosis. PMID- 25830559 TI - Structural Equation Modeling Supports a Moderating Role of Personality in the Relationship Between Physical Activity and Mental Health in College Women. AB - BACKGROUND: A positive association between physical activity and mental health is well established, particularly for lower symptoms of depression and anxiety among active adults. However, it is unclear whether the association is influenced by personality, which might moderate or otherwise explain the association. In addition, past studies have not confirmed the association using an objective measure of physical activity. OBJECTIVE: Our objective was to examine whether Extraversion and Neuroticism influence the association between mental health and physical activity measured by convergent self-reports and an accelerometer. METHODS: Structural equation modeling was used to test competing models of the relationships between personality, physical activity, and mental health in a sample of female undergraduates. RESULTS: In bivariate analysis, mental health was negatively related to Neuroticism and positively related to Extraversion, self-reported physical activity (which was related only to Extraversion, positively), and objective physical activity (which was related only to Neuroticism, negatively). In structural equation modeling, a 3-way interaction indicated that objective physical activity and mental health were unrelated in extraverts, but related positively in neurotic-introverts and negatively in stable-introverts. CONCLUSIONS: Higher levels of physical activity were associated with better mental health only in neurotic-introverts, who are at higher risk for mental health problems. PMID- 25830558 TI - The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. AB - The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent advances in research have described the importance of gut microbiota in influencing these interactions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies. PMID- 25830560 TI - Carotene Degradation and Isomerization during Thermal Processing: A Review on the Kinetic Aspects. AB - Kinetic models are important tools for process design and optimization to balance desired and undesired reactions taking place in complex food systems during food processing and preservation. This review covers the state of the art on kinetic models available to describe heat-induced conversion of carotenoids, in particular lycopene and beta-carotene. First, relevant properties of these carotenoids are discussed. Second, some general aspects of kinetic modeling are introduced, including both empirical single-response modeling and mechanism-based multi-response modeling. The merits of multi-response modeling to simultaneously describe carotene degradation and isomerization are demonstrated. The future challenge in this research field lies in the extension of the current multi response models to better approach the real reaction pathway and in the integration of kinetic models with mass transfer models in case of reaction in multi-phase food systems. PMID- 25830561 TI - Bone cells in birds show exceptional surface area, a characteristic tracing back to saurischian dinosaurs of the late Triassic. AB - BACKGROUND: Dinosaurs are unique among terrestrial tetrapods in their body sizes, which range from less than 3 gm in hummingbirds to 70,000 kg or more in sauropods. Studies of the microstructure of bone tissue have indicated that large dinosaurs, once believed to be slow growing, attained maturity at rates comparable to or greater than those of large mammals. A number of structural criteria in bone tissue have been used to assess differences in rates of osteogenesis in extinct taxa, including counts of lines of arrested growth and the density of vascular canals. METHODOLOGY/PRINCIPAL FINDINGS: Here, we examine the density of the cytoplasmic surface of bone-producing cells, a feature which may set an upper limit to the rate of osteogenesis. Osteocyte lacunae and canaliculi, the cavities in bone containing osteocytes and their extensions, were measured in thin-sections of primary (woven and parallel fibered) bone in a diversity of tetrapods. The results indicate that bone cell surfaces are more densely organized in the Saurischia (extant birds, extinct Mesozoic Theropoda and Sauropodomorpha) than in other tetrapods, a result of denser branching of the cell extensions. The highest postnatal growth rates among extant tetrapods occur in modern birds, the only surviving saurischians, and the finding of exceptional cytoplasmic surface area of the cells that produce bone in this group suggests a relationship with bone growth rate. In support of this relationship is finding the lowest cell surface density among the saurischians examined in Dinornis, a member of a group of ratites that evolved in New Zealand in isolation from mammalian predators and show other evidence of lowered maturation rates. PMID- 25830563 TI - Charging a capacitor from an external fluctuating potential using a single conical nanopore. AB - We explore the electrical rectification of large amplitude fluctuating signals by an asymmetric nanostructure operating in aqueous solution. We show experimentally and theoretically that a load capacitor can be charged to voltages close to 1 V within a few minutes by converting zero time-average potentials of amplitudes in the range 0.5-3 V into average net currents using a single conical nanopore. This process suggests that significant energy conversion and storage from an electrically fluctuating environment is feasible with a nanoscale pore immersed in a liquid electrolyte solution, a system characteristic of bioelectronics interfaces, electrochemical cells, and nanoporous membranes. PMID- 25830562 TI - Nrg1 is an injury-induced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish. AB - Heart regeneration is limited in adult mammals but occurs naturally in adult zebrafish through the activation of cardiomyocyte division. Several components of the cardiac injury microenvironment have been identified, yet no factor on its own is known to stimulate overt myocardial hyperplasia in a mature, uninjured animal. In this study, we find evidence that Neuregulin1 (Nrg1), previously shown to have mitogenic effects on mammalian cardiomyocytes, is sharply induced in perivascular cells after injury to the adult zebrafish heart. Inhibition of Erbb2, an Nrg1 co-receptor, disrupts cardiomyocyte proliferation in response to injury, whereas myocardial Nrg1 overexpression enhances this proliferation. In uninjured zebrafish, the reactivation of Nrg1 expression induces cardiomyocyte dedifferentiation, overt muscle hyperplasia, epicardial activation, increased vascularization, and causes cardiomegaly through persistent addition of wall myocardium. Our findings identify Nrg1 as a potent, induced mitogen for the endogenous adult heart regeneration program. PMID- 25830564 TI - Biomass pyrolysis for biochar or energy applications? A life cycle assessment. AB - The application of biochar as a soil amendment is a potential strategy for carbon sequestration. In this paper, a slow pyrolysis system for generating heat and biochar from lignocellulosic energy crops is simulated and its life-cycle performance compared with that of direct biomass combustion. The use of the char as biochar is also contrasted with alternative use options: cofiring in coal power plants, use as charcoal, and use as a fuel for heat generation. Additionally, the influence on the results of the long-term stability of the biochar in the soil, as well as of biochar effects on biomass yield, is evaluated. Negative greenhouse gas emissions are obtained for the biochar system, indicating a significant carbon abatement potential. However, this is achieved at the expense of lower energy efficiency and higher impacts in the other assessed categories when compared to direct biomass combustion. When comparing the different use options of the pyrolysis char, the most favorable result is obtained for char cofiring substituting fossil coal, even assuming high long-term stability of the char. Nevertheless, a high sensitivity to biomass yield increase is found for biochar systems. In this sense, biochar application to low-quality soils where high yield increases are expected would show a more favorable performance in terms of global warming. PMID- 25830565 TI - Nanodiscs as a Modular Platform for Multimodal MR-Optical Imaging. AB - Nanodiscs are monodisperse, self-assembled discoidal particles that consist of a lipid bilayer encircled by membrane scaffold proteins (MSP). Nanodiscs have been used to solubilize membrane proteins for structural and functional studies and deliver therapeutic phospholipids. Herein, we report on tetramethylrhodamine (TMR) tagged nanodiscs that solubilize lipophilic MR contrast agents for generation of multimodal nanoparticles for cellular imaging. We incorporate both multimeric and monomeric Gd(III)-based contrast agents into nanodiscs and show that particles containing the monomeric agent (ND2) label cells with high efficiency and generate significant image contrast at 7 T compared to nanodiscs containing the multimeric agent (ND1) and Prohance, a clinically approved contrast agent. PMID- 25830566 TI - Hepatic artery duplex Doppler ultrasound in severe alcoholic hepatitis and correlation with Maddrey's discriminant function. AB - BACKGROUND: Alcoholic hepatitis is associated with altered hepatic artery hemodynamics. Maddrey's discriminant function (MDF) can identify patients with poor prognosis (DF >32). We studied hepatic artery hemodynamic parameters of hepatic artery diameter (HAD), resistive index (RI) and pulsatility index (PI) in severe acute alcoholic hepatitis (SAAH) and for the presence of correlation of parameters with severity factor MDF. METHODS: A total of 20 consecutive SAAH patients defined as MDF >32 and a group of 20 alcoholic cirrhosis patients without alcoholic hepatitis formed the two study groups. Hepatic artery Doppler parameters HAD, RI, PI were determined after admission in the Gastroenterology Department, Government Medical College, Thiruvananthapuram, India. MDF score of SAAH was calculated at the time of admission to the hospital. RESULTS: The mean HAD showed statistically significant increase in SAAH compared with cirrhosis (3.96+/-0.51 vs. 2.86+/-0.41, P<0.001). There was statistically significant decrease in mean RI (0.49+/-0.08 vs. 0.81+/-0.09, P<0.001) and mean PI (1.67+/ 0.13 vs. 1.80+/-0.13, P<0.001) in SAAH compared with alcoholic cirrhosis. Statistically significant correlation between MDF and HAD (r=0.63, P<0.003) was found in SAAH. On linear regression, 36% of the variability in MDF could be independently predicted by HAD. CONCLUSION: Hepatic artery parameters of HAD, RI, PI had a significant difference in SAAH compared with alcoholic cirrhosis patients thereby being useful as a diagnostic tool. HAD showed correlation with MDF score assessing the severity of alcoholic hepatitis and may be a useful non invasive prognostic tool. PMID- 25830567 TI - Stanniocalicin 2 suppresses breast cancer cell migration and invasion via the PKC/claudin-1-mediated signaling. AB - Stanniocalcin (STC), a glycoprotein hormone, is expressed in a wide variety of tissues to regulate Ca2+ and PO4- homeostasis. STC2, a member of STC family, has been reported to be associated with tumor development. In this study, we investigated whether the expression of STC2 is associated with migration and invasion of breast cancer cells. We found that breast cancer cell line 231 HM transfected with STC2 shRNA displayed high motility, fibroblast morphology, and enhanced cell migration and invasion. Introduction of STC2 in 231 cells reduced cell migration and invasion. In response to irradiation, silencing of STC2 in 231 HM cells reduced apoptosis, whereas overexpression of STC2 in 231 cells promoted apoptosis, compared with in control cells. Mechanistic study showed that STC2 negatively regulated PKC to control the expression of Claudin-1, which subsequently induced the expressions of EMT-related factors including ZEB1, ZO-1, Slug, Twist, and MMP9. Suppression of PKC activity by using a PKC inhibitor (Go 6983) restored the normal motility of STC2-silenced cells. Furthermore, in vivo animal assay showed that STC2 inhibited tumorigenesis and metastasis of breast cancer cells. Collectively, these results indicate that STC2 may inhibit EMT at least partially through the PKC/Claudin-1-mediated signaling in human breast cancer cells. Thus, STC2 may be exploited as a biomarker for metastasis and targeted therapy in human breast cancer. PMID- 25830568 TI - Epidemiology of Road Traffic Injuries Treated in a Large Romanian Emergency Department in Tirgu-Mures Between 2009 and 2010. AB - OBJECTIVE: Road traffic injuries are one of the leading causes of preventable unintentional injury. The European Injury Database estimated that in European Union (EU)-27 countries, road traffic injuries account for 10% of all injuries treated in the emergency department or admitted to the hospital, accounting for 4.2 million victims each year. We examined the characteristics and outcomes of road traffic injuries treated in a large emergency department in Romania by different types of road users. METHODS: Secondary data analysis was conducted on a sample of patients who suffered a transport-related injury and received care at the Emergency Department of Mures County Emergency Hospital in Romania. Data was collected by 2 trained emergency physicians between March 2009 and July 2010, as part of the European Injury Database project. Information about demographics, mechanism, nature, place of occurrence, and activity of injury; treatment and follow-up; and mode of transport were described for 5 different categories of road users: animal-drawn vehicle (operator and passenger), passenger car (driver and passenger), motorcycle (driver and passenger), bicyclist, and pedestrian. RESULTS: A total of 2,782 patients were treated in the emergency department, of which 718 (25.8%) were road traffic injuries. The male-to-female ratio was 2:1. The highest percentage of patients were injured in passenger cars (49%), followed by motorcycles (16.7%). For both types of road users, the majority of patients were between the ages of 18 and 29. Pedestrian injuries accounted for 14.6%, of which a third were children up to the age of 17 and 40% were adults and elderly over the age of 50. The majority of patients were injured due to contact with a moving object (48.1%), followed by contact with static object (23.5%), then falling, stumbling, jumping, or being pushed (19.6%). Contusion and bruises (54.9%) were the most common diagnosis, followed by fractures (20.1%) and open wounds (10.2%) for all road user categories. The most common part of the body injured for all road user categories was the head region (42.3%). Of the 34.9% patients treated and admitted to the hospital, 30% had a length of stay between 4 and 7 days. CONCLUSIONS: Understanding the extent, nature, and characteristics of road traffic injuries may help to identify vulnerable road users in specific settings and implement the most effective prevention strategies targeting the most affected populations. PMID- 25830571 TI - Transitions in osteopathic medical education. PMID- 25830569 TI - Gender-specific prevalence and associated risk factors of high normal blood pressure and hypertension among multi-ethnic Chinese adolescents aged 8-18 years old. AB - AIM: To date, accurate reports about the prevalence of high normal blood pressure (BP) and hypertension among Chinese adolescents have been rare. We examine the sex-specific and age-specific prevalence of high normal BP and hypertension, and the associated risk factors among multi-ethnic Chinese adolescents from a large and representative sample. METHODS: 29,997 adolescents aged 8-18 years old received blood pressure measurement on one clinical visit. RESULTS: The overall prevalence was 4.15% for hypertension (4.73% for boys and 3.62% for girls) and 29.85% for high normal BP (33.40% for boys and 26.65% for girls). The odds ratios (ORs) increased with age, but the absolute changes of ORs were significantly different between boys and girls. Compared with that of the Han counterparts, the risk of high normal BP was 1.960-fold, 1.283-fold and 1.618-fold for Yi boys, Mongolian boys and Yi girls, respectively, whereas the OR was 0.440 for Tibetan boys, 0.492 for Tibetan girls and 0.794 for Korean girls. Compared with those of normal weight, overweight and obese adolescents had significantly increased risk of high normal BP (OR = 3.377 for obese boys and OR = 2.009 for overweight boys; OR = 2.865 for obese girls and OR = 1.738 for overweight girls). Rural adolescents had a higher risk of hypertension than those living in urban areas. CONCLUSION: The prevalence of high normal BP and hypertension was high in Chinese adolescents. Age, ethnicity, obesity, overweight, abnormal waist circumference, family history of cardiovascular diseases and dwelling at rural districts were significantly associated with pediatric high normal BP or hypertension. PMID- 25830572 TI - A structural examination of medical education reform. PMID- 25830573 TI - Single accreditation system: opportunity and duty to promote osteopathic training for all interested residency programs. PMID- 25830574 TI - The CAST model: enhancing medical student and resident clinical performance through feedback. PMID- 25830575 TI - Challenges of teaching live and distance audiences simultaneously. PMID- 25830576 TI - Developing technology-enhanced active learning for medical education: challenges, solutions, and future directions. AB - Growing up in an era of video games and Web-based applications has primed current medical students to expect rapid, interactive feedback. To address this need, the A.T. Still University-School of Osteopathic Medicine in Arizona (Mesa) has developed and integrated a variety of approaches using technology-enhanced active learning for medical education (TEAL-MEd) into its curriculum. Over the course of 3 years (2010-2013), the authors facilitated more than 80 implementations of games and virtual patient simulations into the education of 550 osteopathic medical students. The authors report on 4 key aspects of the TEAL-MEd initiative, including purpose, portfolio of tools, progress to date regarding challenges and solutions, and future directions. Lessons learned may be of benefit to medical educators at academic and clinical training sites who wish to implement TEAL-MEd activities. PMID- 25830577 TI - Innovative approach to teaching osteopathic manipulative medicine: the integration of ultrasonography. AB - CONTEXT: Noninvasive diagnostic methods and palpatory physical examination skills are especially important for osteopathic medical students intending to work in rural, underresourced, or underserved areas. The A.T. Still University-Kirksville College of Osteopathic Medicine integrates ultrasonography into the osteopathic manipulative medicine (OMM) courses required during the first 2 years of medical school, allowing students to learn the technology and to visualize anatomical structures and regions. OBJECTIVE: To assess the feasibility of integrating ultrasonography into the first-year and second-year OMM curriculum through the evaluation of students' success in demonstrating the technology and visualizing the anatomy. METHODS: As part of their OMM requirements at the A.T. Still University-Kirksville College of Osteopathic Medicine, all first- and second-year students in OMM courses were given ultrasonography assignments that required them to obtain images of musculoskeletal structures in different regions of the body. First-year students studied craniocervical structures and the thoracic, lumbar, and sacral regions. Second-year students studied the glenohumeral joint and the suprapatellar recess. The assignments focused on identifying structures of interest, making annotations, and measuring the structures of interest. Handouts with detailed instructions and a demonstration were provided before each assignment. RESULTS: A total of 183 first-year students and 165 second-year students participated. Of the first-year students, on average, 177 of 181 were able to successfully complete the assignments, with an average completion rate of 98%. The costotransverse joint assignment yielded the lowest completion rate (97%), and the craniocervical landmarks assignment had the highest completion rate (99%). Of the second-year students, 162 of 165 participants were able to successfully complete the assignments, with an average completion rate of 98%. Mean scores were the same for both second-year assignments. CONCLUSION: First year and second-year osteopathic medical students successfully demonstrated their use and understanding of ultrasonography and found their assigned structures using live ultrasound imaging. The skills gained through these assignments added another dimension to students' understanding of normal and pathologic musculoskeletal anatomy and vasculature. The integration of ultrasonography into OMM courses may have created a foundation for learning ultrasound-guided injection techniques. PMID- 25830578 TI - Comparison of COMLEX-USA scores, medical school performance, and preadmission variables between women and men. AB - CONTEXT: Previous studies by the author showed differences in preadmission variables and Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX USA) scores between women and men at the New York Institute of Technology College of Osteopathic Medicine (NYIT-COM). It is pertinent to reexamine the preadmission variables, medical school performance, and COMLEX-USA scores of women and men to determine whether these differences still exist. OBJECTIVE: To examine the relationship between student sex and performance on COMLEX-USA Level 1 and Level 2-Cognitive Evaluation (CE), performance during medical school, and preadmission academic variables at NYIT-COM. METHODS: Scores on COMLEX-USA Level 1 and COMLEX USA Level 2-CE, grades in all courses taken during the first 2 years of medical school, the National Board of Osteopathic Medical Examiners' clinical science subject examination scores, Medical College Admission Test (MCAT) scores, and undergraduate grade point averages (GPAs) were compared between women and men in the classes graduating between 2009 and 2012. RESULTS: Data from 748 students were analyzed. Men had statistically significantly higher scores than women on COMLEX-USA Level 1 in 2009 (540 vs 500; P<.001) and 2010 (537 vs 496; P<.001). No statistically significant difference in COMLEX-USA Level 2-CE scores was found between women and men. The performance of women and men was comparable during the first 2 years of medical school and on clinical science subject examinations in years 3 and 4. Men had statistically significantly higher MCAT scores than women, but no statistically significant differences were found between women's and men's undergraduate GPAs. CONCLUSION: Men were found to have higher scores than women on COMLEX-USA Level 1 and the MCAT. However, the reasons behind these data have yet to be elucidated. Although a stronger background in basic science could explain the discrepancy in scores between women and men, women were found to have equally high science GPAs and performed comparably to men in osteopathic medical school. The results were in agreement with previous studies at NYIT-COM. PMID- 25830579 TI - Relationship between residency placement and clerkship site enrollment: a retrospective analysis. AB - CONTEXT: Osteopathic medical students frequently engage in clinical clerkships away from their home teaching institution, which can help them decide on a residency program, gain additional experience in a new environment, and further their professional contacts. Conventional wisdom states that these audition clerkships are an important factor in residency placement, but the educational literature concerning the topic is lacking. OBJECTIVE: To determine the relationship between clerkship site enrollment and residency placement so that empirical guidelines can be established for osteopathic medical students in the process of making informed decisions about their clerkships, particularly during the fourth year. METHODS: A retrospective analysis was conducted. Data on clerkship and residency placement were compiled for the classes of 2008, 2009, and 2010 at the New York Institute of Technology College of Osteopathic Medicine, and chi2 goodness-of-fit analysis and chi2 tests of independence were used to explore relationships between clerkship and residency placement. RESULTS: Of 862 graduates, data were available for 812 (94.2%). Statistically significant relationships were noted between residency program status (osteopathic, allopathic, and military) and audition clerkship, with fewer graduates completing audition clerkships in allopathic programs and with more graduates completing audition clerkships in osteopathic and military residency programs than expected from an independent relationship. A total of 416 graduates (51.2%) did not enroll in the residency program where they completed their audition clerkship. A total of 352 graduates (43.3%) enrolled in the residency program where they completed their audition clerkship. An additional 44 graduates (5.4%) did not complete an audition clerkship in the discipline of their residency program but rotated at a hospital. A total of 364 graduates (44.8%) enrolled in osteopathic residency programs, 425 (52.3%) enrolled in allopathic programs, and 23 (2.8%) enrolled in military programs. CONCLUSION: Although the results of this study are specific to 1 medical school, they provide evidence to counter long-held beliefs that audition clerkships determine residency placement. PMID- 25830580 TI - Comprehensive Osteopathic Medical Licensing Examination-USA level 1 and level 2 cognitive evaluation preparation and outcomes. AB - The Comprehensive Osteopathic Medical Licensing Examination-USA (COMLEX-USA) assesses the competence of osteopathic physicians in training. It is designed to protect the public by setting minimum competence standards. All osteopathic medical students must pass COMLEX-USA Level 1, Level 2-Cognitive Evaluation, and Level 2-Performance Evaluation before being allowed to graduate from an osteopathic medical school. Residency training programs use COMLEX-USA scores as a major factor in deciding whom they will interview and admit into their programs. In addition, colleges of osteopathic medicine use student COMLEX-USA scores as an external assessment of their success in educating students. Because COMLEX-USA is a high-stakes examination series, it is important to understand predictive factors for performance. The authors review the literature on the relationship between COMLEX-USA scores and correlated student variables. Results from the Council on Osteopathic Student Government Presidents' survey on students' preparation methods and performance are also provided. PMID- 25830581 TI - International medical graduates in the US physician workforce. AB - International medical graduates (IMGs) play a vital role in the US health care system. These graduates represent 26% of physicians in practice and 24% of residents in specialty programs. All IMGs go through US medical licensing examination and credentialing verification to receive certification from the Educational Commission for Foreign Medical Graduates to become eligible to enter the US graduate medical education process. Compared with US graduates, IMGs tend to practice in primary care specialties and in underserved and rural areas. The author summarizes available data regarding IMGs in training and in practice to convey the role IMGs play in the US health care system. PMID- 25830582 TI - New colleges of osteopathic medicine, branch campuses, and additional locations- what is the difference? AB - The American Osteopathic Association Commission on Osteopathic College Accreditation (AOA COCA) is recognized by the US Secretary of Education as the only accrediting agency for predoctoral osteopathic medical education. To maintain its recognition with the US Secretary of Education, the AOA COCA is required to adhere to all federal laws and regulations associated with recognition of accrediting agencies. In this article, the authors discuss the development of new colleges of osteopathic medicine (COMs). They also discuss the development of additional locations and branch campuses of existing COMs and compare the 2 processes. Also included is a review of the AOA COCA- approved class sizes of the accredited COMs. PMID- 25830583 TI - The single graduate medical education accreditation system. AB - In 2014, the American Osteopathic Association, the American Association of Colleges of Osteopathic Medicine, and the Accreditation Council for Graduate Medical Education signed a historic Memorandum of Understanding, which creates a single accreditation system for graduate medical education. The present article outlines the history of the agreement and the 5-year transition process, which begins July 1, 2015, and ends June 30, 2020. PMID- 25830584 TI - Osteopathic postdoctoral training institutions' 2014 annual report. AB - In 2013, the Board of Trustees of the American Osteopathic Association approved the new mission and vision statements of osteopathic postdoctoral training institutions (OPTIs) to ensure that OPTIs were operating effectively as academic sponsors of osteopathic graduate medical education. Since then, OPTIs have made substantial strides in meeting and exceeding the new mandates. The authors discuss the revised OPTI accreditation standards, the OPTI annual report, and recent activities. PMID- 25830585 TI - Evolution of AOA specialty board certification. AB - The launch of Osteopathic Continuous Certification (OCC) signifes the next stage of the osteopathic board certification process. The OCC process replaces the old recertification system for all osteopathic physicians who earned time-limited certificates from American Osteopathic Association (AOA) certifying boards. All 18 AOA certifying boards are now engaged in the continuous certification process. With the advent of any new system, many questions and concerns will arise. The AOA Bureau of Osteopathic Specialists continues to evaluate its new certification system and prepare for modifcations in response to this feedback. PMID- 25830589 TI - Large paraesophageal hiatal hernia in a patient with chest pain. PMID- 25830591 TI - Modeling the Role of pH on Baltic Sea Cyanobacteria. AB - We simulate pH-dependent growth of cyanobacteria with an ecosystem model for the central Baltic Sea. Four model components-a life cycle model of cyanobacteria, a biogeochemical model, a carbonate chemistry model and a water column model-are coupled via the framework for aquatic biogeochemical models. The coupled model is forced by the output of a regional climate model, based on the A1B emission scenario. With this coupled model, we perform simulations for the period 1968 2098. Our simulation experiments suggest that in the future, cyanobacteria growth is hardly affected by the projected pH decrease. However, in the simulation phase prior to 1980, cyanobacteria growth and N2-fixation are limited by the relatively high pH. The observed absence of cyanobacteria before the 1960s may thus be explained not only by lower eutrophication levels, but also by a higher alkalinity. PMID- 25830590 TI - Evolutionary Aspects and Regulation of Tetrapyrrole Biosynthesis in Cyanobacteria under Aerobic and Anaerobic Environments. AB - Chlorophyll a (Chl) is a light-absorbing tetrapyrrole pigment that is essential for photosynthesis. The molecule is produced from glutamate via a complex biosynthetic pathway comprised of at least 15 enzymatic steps. The first half of the Chl pathway is shared with heme biosynthesis, and the latter half, called the Mg-branch, is specific to Mg-containing Chl a. Bilin pigments, such as phycocyanobilin, are additionally produced from heme, so these light-harvesting pigments also share many common biosynthetic steps with Chl biosynthesis. Some of these common steps in the biosynthetic pathways of heme, Chl and bilins require molecular oxygen for catalysis, such as oxygen-dependent coproporphyrinogen III oxidase. Cyanobacteria thrive in diverse environments in terms of oxygen levels. To cope with Chl deficiency caused by low-oxygen conditions, cyanobacteria have developed elaborate mechanisms to maintain Chl production, even under microoxic environments. The use of enzymes specialized for low-oxygen conditions, such as oxygen-independent coproporphyrinogen III oxidase, constitutes part of a mechanism adapted to low-oxygen conditions. Another mechanism adaptive to hypoxic conditions is mediated by the transcriptional regulator ChlR that senses low oxygen and subsequently activates the transcription of genes encoding enzymes that work under low-oxygen tension. In diazotrophic cyanobacteria, this multilayered regulation also contributes in Chl biosynthesis by supporting energy production for nitrogen fixation that also requires low-oxygen conditions. We will also discuss the evolutionary implications of cyanobacterial tetrapyrrole biosynthesis and regulation, because low oxygen-type enzymes also appear to be evolutionarily older than oxygen-dependent enzymes. PMID- 25830592 TI - Pregnancy outcome following maternal exposure to mirtazapine: a multicenter, prospective study. AB - This multicenter, observational prospective cohort study addresses the risk associated with exposure to mirtazapine during pregnancy. Pregnancy outcomes after exposure to mirtazapine were compared with 2 matched control groups: (1) exposure to any selective serotonin reuptake inhibitor (SSRI, control subjects with a psychiatric condition) and (2) no exposure to medication known to be teratogenic or any antidepressant (general control subjects). Data were collected by members of the European Network of Teratology Information Services between 1995 and 2011. Observations from 357 exposed pregnancies were compared with 357 pregnancies from each control group. The rate of major birth defects between the mirtazapine and the SSRI group did not differ significantly (4.5% vs 4.2%; odds ratio [OR], 1.1; 95% confidence interval [95% CI], 0.5-2.3; P = 0.9). A trend toward a higher rate of birth defects in the mirtazapine group compared with general control subjects (4.5% vs 1.9%; OR, 2.4; 95% CI, 0.9-6.3; P = 0.08) reached statistical significance after exclusion of chromosomal or genetic anomalies (4.1% vs 1.3%; OR, 3.3; 95% CI, 1.04-10.3; P = 0.03), but this difference became again nonsignificant if cases of exposure not comprising the first trimester were excluded from the analysis (3.4% vs 1.9%; OR, 1.8; 95% CI, 0.6-5.0; P = 0.26). The crude miscarriage rate did not differ significantly between the mirtazapine, the SSRI, and the general control groups (12.1% vs 12.0% vs 9.3%; P = 0.44). However, a higher rate of elective pregnancy termination was observed in the mirtazapine group compared with SSRI and general control subjects (7.8% vs 3.4% vs 5.6%; P = 0.03). This study did not observe a statistically significant difference in the rate of major birth defects after first-trimester exposure between mirtazapine, SSRI-exposed, and nonexposed pregnancies. A marginally higher rate of birth defects was, however, observed in the mirtazapine and SSRI groups compared with the low rate of birth defects in our general control subjects. Overall pregnancy outcome after mirtazapine exposure was similar to that of the SSRI-exposed control group. PMID- 25830593 TI - Suicide attempt during late pregnancy with quetiapine: nonfatal outcome despite severe intoxication. PMID- 25830594 TI - Efficacy and safety of sertindole in schizophrenia: a clinical review. AB - Sertindole is an atypical antipsychotic reintroduced into the European market in 2005 after a reevaluation of its risks and benefits, under the agreement that close electrocardiographic screening would be conducted. It has a high affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1 adrenergic receptors. Moreover, sertindole shows modest affinity for H1-histaminergic and muscarinic receptors. The pharmacological properties, clinical efficacy, safety, and tolerability of sertindole are covered in this article based on a literature review from 1990 to 2014. Given current available findings, sertindole is at least effective as haloperidol, risperidone, and olanzapine on schizophrenia symptoms. Regarding its efficacy on cognitive symptoms, sertindole effect is supported by both preclinical and clinical studies versus haloperidol and olanzapine; however, its role on cognition needs further clarification. Concerning safety and tolerability issues, sertindole is characterized by a low potential to cause sedation and extrapyramidal symptoms, and by an acceptable metabolic profile; nevertheless, cardiac safety remains a major concern, and the electrocardiographic monitoring should be carried out during treatment to substantially reduce cardiovascular risk. In conclusion, although it has an equivalent profile compared to other antipsychotic drugs, sertindole actually remains a second-line choice for schizophrenic patients intolerant to at least one other antipsychotic agent. PMID- 25830595 TI - Correction to Nematicidal activities of 4-quinolone alkaloids isolated from the aerial part of Triumfetta grandidens against Meloidogyne incognita. PMID- 25830596 TI - Blood lead levels in children aged 0-6 years old in Hunan Province, China from 2009-2013. AB - OBJECTIVES: The aim of this study is to describe blood lead levels (BLLs) and the prevalence of elevated blood lead levels (EBLLs) in children aged 0-6 years old and to analyze the BLL trend in children from 2009 to 2013 in China. METHODS: A total of 124,376 children aged 0-6 years old were recruited for this study from January 1st 2009 to December 31st 2013. Their blood lead levels were analyzed using atomic absorption spectrometry. RESULTS: The median BLL was 64.3 MUg/L (IQR: 49.6-81.0), and the range was 4.3-799.0 MUg/L. Blood lead levels were significantly higher in boys (66.0 MUg/L) than in girls (61.9 MUg/L) (P<0.001). The overall prevalence of BLLs>=100 MUg/L was 10.54% in children aged 0-6 years in Hunan Province. Between 2009 and 2013, the prevalence of EBLLs (>=100 MUg/L) decreased from 18.31% to 4.26% in children aged 0-6 years and increased with age. The prevalence of EBLLs has dramatically decreased in two stages (2009-2010 and 2012-2013), with a slight fluctuation in 2010 and 2011. CONCLUSIONS: Both BLLs and the prevalence of EBLLs in children aged 0-6 years old declined substantially from 2009 to 2013 in Hunan Province; however, both remain at unacceptably high levels compared to developed countries. Comprehensive strategies are required to further reduce blood lead levels in children. PMID- 25830597 TI - Circulatory endotoxin concentration and cytokine profile in response to exertional-heat stress during a multi-stage ultra-marathon competition. AB - Exertional-heat stress has the potential to disturb intestinal integrity, leading to enhanced permeability of enteric pathogenic micro-organisms and associated clinical manifestations. The study aimed to determine the circulatory endotoxin concentration and cytokine profile of ultra-endurance runners (UER, n=19) and a control group (CON, n=12) during a five stage 230km ultra-marathon (mean +/- SD: 27h38min +/- 3h55min) conducted in hot and dry environmental conditions (30oC to 40oC and 31% to 40% relative humidity). Body mass and tympanic temperature were measured, and venous blood samples were taken before (pre-stage) and immediately after (post-stage) each stage of the ultra-marathon for the analysis of gram negative bacterial endotoxin, C-reactive protein, cytokine profile (IL-6, IL 1beta, TNF-alpha, IFN-gamma, IL-10, and IL- 1ra), and plasma osmolality. Gastrointestinal symptoms and perceptive thermal tolerance rating were also monitored throughout competition. Mean exercise-induced body mass loss over the five stages ranged 1.0% to 2.5%. Pre- and poststage plasma osmolality in UER ranged277 to 282mOsmol/kg and 286 to 297 mOsmol/kg, respectively. Pre-stage concentrations of endotoxin (peak: 21% at Stage 5), C-reactive protein (889% at Stage 3), IL-6 (152% at Stage 2), IL-1beta (95% at Stage 5), TNF-alpha (168% at Stage 5), IFN-gamma (102% at Stage 5),IL-10 (1271% at Stage 3), and IL-1ra (106% at Stage 5) increased as the ultra-marathon progressed in UER; while no changes in CON were observed (except for IL-1beta, 71% at Stage 5). Pre- to post-stage increases were observed for endotoxin (peak: 22% at Stage 3), C-reactive protein (25% at Stage 1), IL-6 (238% at Stage 1), IL-1beta (64% at Stage 1), TNF-alpha (101% at Stage 1), IFN-gamma (39% at Stage 1), IL-10 (1100% at Stage 1), and IL 1ra(207% at Stage 1) concentrations in UER. Multi-stage ultra-marathon competition in the heat resulted in a modest circulatory endotoxaemia accompanied by a pronounced pro-inflammatory cytokinaemia by post-Stage 1, both of which were sustained throughout competition at rest (pre-stage) and after stage completion. Compensatory anti-inflammatory responses and other external factors (i.e., training status, cooling strategies, heat acclimatization, nutrition and hydration) may have contributed towards limiting the extent of pro-inflammatory responses in the current scenario. PMID- 25830598 TI - Iron bioavailability in iron-fortified cereal foods: The contribution of in vitro studies. AB - Iron deficiency anemia is the most common nutritional deficiency in humans. Not all dietary ingested iron, heme or nonheme, will be available to absorption and negative imbalance between iron requirements and absorption leads to iron deficiency and/or anemia. The recommended iron values usually are based on the genetic and on diet iron-bioavailability, which can be considered as the principal factor that change among the cultures and influences the distinct levels of recommendation among countries. Dietary changes present practical limitations due to be difficult to change food habits. The iron food fortification is considered more cost effective and economically more attractive than iron supplementation. There are many iron compounds available to be used in iron fortification. Cereals represent a target food group to iron fortification programs due to high consumption and the in vitro studies can be useful to estimate the relative iron bioavailability in large number of products in short time and with a low cost. Wheat flour baked into bread or not was the main product tested in in vitro bioavailability studies and ferrous sulfate was the principal iron compound used in the fortification studies. However, iron bioavailability from ferrous sulfate is lower than from other compounds, such FeNaEDTA or ferric pyrophosphate. The variables level of fortification, storage, level of extraction, baking and also the association or not with other chemical compound seems to influence the results obtained. PMID- 25830599 TI - Negative life events have detrimental effects on in-vitro fertlization outcome. AB - The aim of this study was to investigate the effect of negative life events on in vitro-fertilization (IVF) outcome. Depression and negative life events were measured using Beck Depression Inventory (BDI) and List of Recent Events in 83 women attending the IVF clinic of a tertiary research and education hospital with the diagnosis of unexplained infertility between January 2013 and August 2013. Demographic features, stimulation parameters, depression scores, and negative life events of pregnant and non-pregnant participants were compared and the relation between negative life events, depression scores, and IVF outcome was investigated. Women who did not achieve a pregnancy experienced more negative life events than women who became pregnant (77.2% vs. 23.1%) (p > 0.001). The number of patients with moderate-to-severe depression (BDI scores > 16) was higher in the non-pregnant group than pregnant group (49.1% vs. 26.9%), however the difference was not statistically significant (p = 0.057). Clinical pregnancy showed a significant moderate negative correlation with the number of negative life events (r = -0.513, p = 0.001), but the correlation between clinical pregnancy and BDI scores was not statistically significant (r = -0.209, p = 0.059). Stressful life events have a negative influence on the quality of life, which eventually affects in IVF outcome, possibly through maladaptive lifestyle behavior. PMID- 25830600 TI - The Energy Index Does Not Affect Local Control of Brain Metastases Treated by Gamma Knife Stereotactic Radiosurgery. AB - BACKGROUND: The energy index (EI) is a measure of dose homogeneity within a target volume calculated by the integral dose divided by the product of prescription dose and tumor volume. OBJECTIVE: To assess whether a higher EI is associated with greater local control for brain metastases (BMs) treated by Gamma Knife radiosurgery (GKRS). METHODS: We reviewed all patients treated with GKRS for BM at our institution between January 2009 and February 2014. Data on the prescription dose, prescription isodose line, minimum dose, mean dose, integral dose, tumor volume, and EI were collected. Tumor response was assessed by reviewing follow-up brain imaging studies and classified according to the Response Evaluation Criteria in Solid Tumors. Local control per lesion and dosimetric prognostic factors for local control were assessed by univariate and multivariate Cox proportional hazards regression analyses. RESULTS: Of 213 patients treated, 126 had follow-up imaging available with a median follow-up of 6 months. Three hundred seventy-three individual tumors were analyzed. Of these, 133 showed a complete response, 157 showed a partial response, 46 remained stable, and 37 developed local failure. Tumors with EI >=1.6 mJ.mL(-1).Gy(-1) showed a higher rate of complete response. Local control rates at 6, 11, and 17 months were 95.4%, 86.5%, and 81.5%, respectively. On univariate analysis, the following factors were associated with higher rates of local failure: prescription doses of 16 and 18 Gy compared with a prescription dose of 20 Gy. The following factors were associated with a greater rate of local control: maximum dose and mean dose. On multivariate analysis, the only statistically significant factor associated with a greater rate of local failure was prescription dose of 16 Gy compared with 20 Gy. CONCLUSION: GKRS for BM results in a high rate of local control with an 11-month rate of 86.5%. A higher EI was not significantly associated with a higher rate of local control on multivariate analysis. Prescription dose was found to be the only significant predictor of local control on multivariate analysis. PMID- 25830601 TI - Endovascular Treatment of Cavernous Sinus Dural Arteriovenous Fistula With Ipsilateral Inferior Petrosal Sinus Occlusion: A Single-Center Experience. AB - BACKGROUND: Although a transvenous route via the ipsilateral inferior petrosal sinus (IPS) is preferred in treating cavernous sinus dural arteriovenous fistula (CSdAVF), this option may be limited if an occluded ipsilateral IPS undermines microcatheter delivery to the cavernous sinus. OBJECTIVE: To describe our experience with endovascular treatment of CSdAVF complicated by ipsilateral IPS occlusion. METHODS: From January 2003 through September 2014, a total of 49 CSdAVFs with ipsilateral IPS occlusion were identified in 49 patients, who then underwent endovascular treatment. Clinical and radiologic data were retrospectively reviewed. RESULTS: Either transvenous (n = 38) or transarterial (n = 11) access was initially elected, the latter reserved for single-hole or dominant arterial feeder fistulas. Access via occluded ipsilateral IPS was usually attempted (n = 34) by transvenous approach, with a 54.3% success rate. Anterior (n = 3) or posterior (n = 1) facial vein was alternatively used. Direct surgical exposure of ophthalmic vein (n = 3) or radiosurgery (n = 4) was performed for access failure or unsuccessful occlusion by other means. In 46 fistulas (93.9%), complete occlusion was achieved, with no procedure-related morbidity or mortality. Postprocedural symptom improvement was noted in all but 2 patients, who separately experienced paradoxical worsening of cranial nerve palsy and access failure. CONCLUSION: In patients with CSdAVF and ipsilateral IPS occlusion, various treatment strategies may be applied (given angioanatomic suitability), resulting in excellent procedural and short-term follow-up results. Reopening of an occluded IPS is reasonable as an initial access attempt. PMID- 25830602 TI - The enigmatic psalterium: a review and anatomic study with relevance to callosotomy procedures. AB - BACKGROUND: Recalcitrant seizures after callosotomy procedures are challenging to treat. One commissure, the psalterium, has received little attention. OBJECTIVE: To review the literature on this structure, and with dissection, better elucidate its morphology and relationships. METHODS: Twenty adult cadaver brains underwent microsurgical dissection of the psalterium. Measurements included the size and distance from the splenium of the corpus callosum and posterior border of the hippocampus tail. Observations included the relationships between the psalterium and the vein of Galen and the fiber direction within this structure. RESULTS: The psalterium was identified in all specimens. It intimately contacted the undersurface of the splenium superiorly and the velum interpositum inferiorly. It was always in the midline. Just posterior to the psalterium, the internal cerebral veins were found leaving the velum interpositum to drain into the vein of Galen. In most specimens, the psalterium fibers traveled in the same plane as the commissural fibers of the splenium. Mean width of the psalterium was 11 mm; mean length was 13 mm. Average thickness in the midline was 1.4 mm, and at the lateral edges, it was generally thicker as it joined the fornix with an average of 2 mm. In 30%, efferents from the hippocampus were arranged in the form of a sheet bilaterally rather than the normal bundle-like formation forming the posterior crura. CONCLUSION: Better understanding of the commissures of the human brain, including the psalterium, might help the neurosurgeon during procedures near this structure. PMID- 25830603 TI - Interhospital Transfer of Neurosurgical Patients to a High-Volume Tertiary Care Center: Opportunities for Improvement. AB - BACKGROUND: Neurosurgical indications for patient transfer include absence of local or available neurosurgical coverage, subspecialty or interdisciplinary requirements, and family preference. Transfer of patients to regional centers will increase with further centralization of medical care. OBJECTIVE: To report the transfer records of a large tertiary care center to identify trends, failures, and opportunities to improve interhospital transfer of neurosurgical patients. METHODS: All consecutive, prospectively documented requests for interhospital patient transfer to the adult neurosurgical service of Emory University Hospitals were retrospectively identified from a centralized transfer center database for a 1-year study period. RESULTS: Requests for neurosurgical care constituted 1323 of the 9087 calls (14.6%); 81.1% of these requests were accepted, and a total of 984 patients (74.4%) arrived at our institutions. Patients arrived from 133 unique facilities throughout a catchment area of 66 287 sq miles. Although the median travel time for transfer patients was 36 minutes, the median interval between the request and patient arrival was 4 hours 2 minutes. The most frequent diagnoses were intracranial hemorrhage (31.8%), subarachnoid hemorrhage (31.2%), and intracranial tumor (15.2%). The overall diagnostic error rate was 10.3%. Only 42.5% of patients underwent neurosurgical intervention, and 57 patients admitted to intensive care were immediately transitioned to a lower level of care. CONCLUSION: Interhospital transfer requires a coordinated effort among hospital administrators, physicians, and staff to make complex decisions that govern this important and costly process. These data suggest common failures and numerous opportunities for improvement in transfer efficiency, diagnostic accuracy, triage, and resource allocation. PMID- 25830604 TI - Maximizing the petroclival region exposure via a suboccipital retrosigmoid approach: where is the intrapetrous internal carotid artery? AB - BACKGROUND: Recent reports have validated the use of retrosigmoid approach extensions to deal with petroclival lesions. OBJECTIVE: To describe the topographic retrosigmoid anatomy of the intrapetrous internal carotid artery (IICA), providing guidelines for maximizing the petroclival region exposure via this route. METHODS: The IICA was exposed bilaterally in 6 specimens via a retrosigmoid approach in the semisitting position. Its topographic relationship with pertinent posterolateral cranial base landmarks was quantified with neuronavigation. RESULTS: Safe exposure of the IICA and the surrounding inframeatal/petroclival regions was accomplished in all specimens. On average, the IICA genu was 15.08 mm anterolateral to the XI nerve in the jugular foramen, 16.18 mm anteroinferolateral to the endolymphatic sac, and 10.63 mm anteroinferolateral to the internal acoustic meatus. On average, the IICA horizontal segment was 9.92 mm inferolateral to the Meckel cave, and its midpoint was 19.96 mm anterolateral to the XI nerve in the jugular foramen. The mean distance from the IICA genu to the cochlea was 1.96 mm. The genu and the midpoint of the horizontal segment of the IICA were exposed at a depth of approximately 14.50 mm from the posterior pyramidal wall with the use of different drilling angles (49.74 degrees vs 39.54 degrees , respectively). CONCLUSION: Knowledge of the IICA general relationship with these landmarks (combined with a careful assessment of the preoperative imaging and with the use of intraoperative navigation and micro-Doppler) may help to enhance the inframeatal/petroclival region exposure via a retrosigmoid route, maximizing safe inframeatal and suprameatal petrous bone removal while minimizing neurovascular complications. PMID- 25830605 TI - Efficient Coupling of an Antenna-Enhanced nanoLED into an Integrated InP Waveguide. AB - Increasing power consumption in traditional on-chip metal interconnects has made optical links an attractive alternative. However, such a link is currently missing a fast, efficient, nanoscale light-source. Coupling nanoscale optical emitters to optical antennas has been shown to greatly increase their spontaneous emission rate and efficiency. Such a structure would be an ideal emitter for an on-chip optical link. However, there has never been a demonstration of an antenna enhanced emitter coupled to a low-loss integrated waveguide. In this Letter we demonstrate an optical antenna-enhanced nanoLED coupled to an integrated InP waveguide. The nanoLEDs are comprised of a nanoridge of InGaAsP coupled to a gold antenna that exhibits a 36* enhanced rate of spontaneous emission. Coupling efficiencies as large as 70% are demonstrated into an integrated waveguide. Directional antennas also demonstrate direction emission down one direction of a waveguide with observed front-to-back ratios as high as 3:1. PMID- 25830606 TI - Correction: Enzyme and voltage stimuli-responsive controlled release system based on beta-cyclodextrin-capped mesoporous silica nanoparticles. AB - Correction for 'Enzyme and voltage stimuli-responsive controlled release system based on beta-cyclodextrin-capped mesoporous silica nanoparticles' by Yu Xiao et al., Dalton Trans., 2015, 44, 4355-4361. PMID- 25830607 TI - Ultrafine particle content in exhaled breath condensate in airways of asthmatic children. AB - Air pollution triggers and exacerbates airway inflammation. Particulate material (PM) in ambient is characterized as being coarse (PM 10, aerodynamic diameter range 2.5-10 um), fine (PM 2.5, 2.5-0.1 um) and ultrafine (UFP, nano-sized, <0.1 um). It is known that smaller inhaled PM produced more inflammation than larger ones. Most data on human exposure to PM are based on environmental monitoring. We evaluated the effect of individual exposure to UFP on functional respiratory parameters and airway inflammation in 52 children aged 6-18 years referred to the Pulmonary and Allergic Diseases Laboratory due to respiratory symptoms. Spirometry, bronchial provocation challenge, induced sputum (IS), exhaled breath condensate (EBC) and franctional exhaled nitric oxide evaluations were performed by conventional methods. UFP content in EBC was analyzed by using a NanoSight Light Microscope LM20. The total EBC UFP content correlated with wheezing (r = 0.28, p = 0.04), breath symptom score (r = 0.3, p = 0.03), and sputum eosinophilia (R = 0.64, p = 0.005). The percent of EBC particles in the nano sized range also correlated with wheezing (r = 0.36, p = 0.007), breath symptom score (r = 0.33, p <= 0.02), and sputum eosinophilia (r = 0.72, p = 0.001). Respiratory symptoms and airway inflammation positively correlated to UFP content in EBC of symptomatic children. PMID- 25830608 TI - CIMIDx: Prototype for a Cloud-Based System to Support Intelligent Medical Image Diagnosis With Efficiency. AB - BACKGROUND: The Internet has greatly enhanced health care, helping patients stay up-to-date on medical issues and general knowledge. Many cancer patients use the Internet for cancer diagnosis and related information. Recently, cloud computing has emerged as a new way of delivering health services but currently, there is no generic and fully automated cloud-based self-management intervention for breast cancer patients, as practical guidelines are lacking. OBJECTIVE: We investigated the prevalence and predictors of cloud use for medical diagnosis among women with breast cancer to gain insight into meaningful usage parameters to evaluate the use of generic, fully automated cloud-based self-intervention, by assessing how breast cancer survivors use a generic self-management model. The goal of this study was implemented and evaluated with a new prototype called "CIMIDx", based on representative association rules that support the diagnosis of medical images (mammograms). METHODS: The proposed Cloud-Based System Support Intelligent Medical Image Diagnosis (CIMIDx) prototype includes two modules. The first is the design and development of the CIMIDx training and test cloud services. Deployed in the cloud, the prototype can be used for diagnosis and screening mammography by assessing the cancers detected, tumor sizes, histology, and stage of classification accuracy. To analyze the prototype's classification accuracy, we conducted an experiment with data provided by clients. Second, by monitoring cloud server requests, the CIMIDx usage statistics were recorded for the cloud based self-intervention groups. We conducted an evaluation of the CIMIDx cloud service usage, in which browsing functionalities were evaluated from the end user's perspective. RESULTS: We performed several experiments to validate the CIMIDx prototype for breast health issues. The first set of experiments evaluated the diagnostic performance of the CIMIDx framework. We collected medical information from 150 breast cancer survivors from hospitals and health centers. The CIMIDx prototype achieved high sensitivity of up to 99.29%, and accuracy of up to 98%. The second set of experiments evaluated CIMIDx use for breast health issues, using t tests and Pearson chi-square tests to assess differences, and binary logistic regression to estimate the odds ratio (OR) for the predictors' use of CIMIDx. For the prototype usage statistics for the same 150 breast cancer survivors, we interviewed 114 (76.0%), through self-report questionnaires from CIMIDx blogs. The frequency of log-ins/person ranged from 0 to 30, total duration/person from 0 to 1500 minutes (25 hours). The 114 participants continued logging in to all phases, resulting in an intervention adherence rate of 44.3% (95% CI 33.2-55.9). The overall performance of the prototype for the good category, reported usefulness of the prototype (P=.77), overall satisfaction of the prototype (P=.31), ease of navigation (P=.89), user friendliness evaluation (P=.31), and overall satisfaction (P=.31). Positive evaluations given by 100 participants via a Web-based questionnaire supported our hypothesis. CONCLUSIONS: The present study shows that women felt favorably about the use of a generic fully automated cloud-based self- management prototype. The study also demonstrated that the CIMIDx prototype resulted in the detection of more cancers in screening and diagnosing patients, with an increased accuracy rate. PMID- 25830609 TI - The popularity of benzodiazepines, their advantages, and inadequate pharmacological alternatives-reply. PMID- 25830612 TI - From the editor. PMID- 25830611 TI - EEG classification of different imaginary movements within the same limb. AB - The task of discriminating the motor imagery of different movements within the same limb using electroencephalography (EEG) signals is challenging because these imaginary movements have close spatial representations on the motor cortex area. There is, however, a pressing need to succeed in this task. The reason is that the ability to classify different same-limb imaginary movements could increase the number of control dimensions of a brain-computer interface (BCI). In this paper, we propose a 3-class BCI system that discriminates EEG signals corresponding to rest, imaginary grasp movements, and imaginary elbow movements. Besides, the differences between simple motor imagery and goal-oriented motor imagery in terms of their topographical distributions and classification accuracies are also being investigated. To the best of our knowledge, both problems have not been explored in the literature. Based on the EEG data recorded from 12 able-bodied individuals, we have demonstrated that same-limb motor imagery classification is possible. For the binary classification of imaginary grasp and elbow (goal-oriented) movements, the average accuracy achieved is 66.9%. For the 3-class problem of discriminating rest against imaginary grasp and elbow movements, the average classification accuracy achieved is 60.7%, which is greater than the random classification accuracy of 33.3%. Our results also show that goal-oriented imaginary elbow movements lead to a better classification performance compared to simple imaginary elbow movements. This proposed BCI system could potentially be used in controlling a robotic rehabilitation system, which can assist stroke patients in performing task-specific exercises. PMID- 25830613 TI - A multidisciplinary three-phase approach to improve the clinical utility of patient safety indicators. AB - PURPOSE: The AHRQ Patient Safety Indicators (PSIs) are used for calculation of risk-adjusted postoperative rates for adverse events. The payers and quality consortiums are increasingly requiring public reporting of hospital performance on these metrics. We discuss processes designed to improve the accuracy and clinical utility of PSI reporting in practice. METHODS: The study was conducted at a 793-bed tertiary care academic medical center where PSI processes have been aggressively implemented to track patient safety events at discharge. A three phased approach to improving administrative data quality was implemented. The initiative consisted of clinical review of all PSIs, documentation improvement, and provider outreach including active querying for patient safety events. RESULTS: This multidisciplinary effort to develop a streamlined process for PSI calculation reduced the reporting of miscoded PSIs and increased the clinical utility of PSI monitoring. Over 4 quarters, 4 of 41 (10%) PSI-11 and 9 of 138 (7%) PSI-15 errors were identified on review of clinical documentation and appropriate adjustments were made. CONCLUSION: A multidisciplinary, phased approach leveraging existing billing infrastructure for robust metric coding, ongoing clinical review, and frontline provider outreach is a novel and effective way to reduce the reporting of false-positive outcomes and improve the clinical utility of PSIs. PMID- 25830614 TI - Do hospital-acquired condition scores correlate with patients' perspectives of care? AB - Beginning in fiscal year 2015, the federal Hospital-Acquired Condition (HAC) Reduction Program requires the Centers for Medicare & Medicaid Services to reduce payments by 1% for hospitals in the top quartile of risk-adjusted national HAC scores. The HAC penalty underscores the need for hospitals to become increasingly quality- and safety-focused, which could negatively affect their performance on patient satisfaction with care, another key performance metric tied to reimbursement. Using publicly available data through the Centers for Medicare & Medicaid Services Hospital Compare program, we assessed the correlation between preliminary HAC scores and patients' perspectives of care, as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems survey. Higher quality of care (lower HAC score) was modestly associated with a better patient experience (r = -0.090, P < .001). Additional research is needed to ensure that national policy efforts are not working at cross purposes and there need not be a trade-off between delivering high quality of care and patient satisfaction. PMID- 25830615 TI - Pocket change: a simple educational intervention increases hospitalist documentation of comorbidities and improves hospital quality performance measures. AB - BACKGROUND: Complete documentation of patient comorbidities in the medical record is important for clinical care, hospital reimbursement, and quality performance measures. We designed a pocket card reminder and brief educational intervention aimed at hospitalists with the goal of improving documentation of 6 common comorbidities present on admission: coagulation abnormalities, metastatic cancer, anemia, fluid and electrolyte abnormalities, malnutrition, and obesity. METHODS: Two internal medicine inpatient teams led by 10 hospitalist physicians at an academic medical center received the educational intervention and pocket card reminder (n = 520 admissions). Two internal medicine teams led by nonhospitalist physicians served as a control group (n = 590 admissions). Levels of documentation of 6 common comorbidities, expected length of stay, and expected mortality were measured at baseline and during the 9-month study period. RESULTS: The intervention was associated with increased documentation of anemia, fluid and electrolyte abnormalities, malnutrition, and obesity in the intervention group, both compared to baseline and compared to the control group during the study period. The expected length of stay increased in the intervention group during the study period. CONCLUSIONS: A simple educational intervention and pocket card reminder were associated with improved documentation and hospital quality measures at an academic medical center. PMID- 25830616 TI - Utility of an integrated electronic suicide alert system in a psychiatric hospital. AB - Management of suicide-related behaviors in a hospital is challenging. This article (1) describes integration of an electronic suicide risk notification system to improve assessment of psychiatric inpatients, (2) details the manner in which these alerts complement standard of care, and (3) provides support of using aggregate data to inform administrative decision-making. Complementing routine clinical care and under the supervision of an assessment coordinator, adult inpatients at a specialty psychiatric hospital complete a computerized battery of outcome assessments throughout the course of their hospitalization. A critical item response notification system for suicide-related behaviors was implemented within the larger, assessment architecture, sending an alert e-mail to unit staff if patients endorsed suicidal ideation on any 1 of 6 critical items. Analysis of aggregate data over a 19-month period reveal a linear trend of increasing rate of suicide alerts from October 2012 to April 2013 (Phase A) with a stabilization at the heightened level from July 2013 to April 2014 (Phase B), R = 0.697, P = .007. Findings suggest that more nuanced training in the management of suicide-related behavior may be necessary and that traditional approaches to staffing may need to accommodate patient acuity. The communication innovation of this system is in line with the Joint Commission's emphasis on designing and implementing patient centered systems that enhance quality of care, including improved safety. PMID- 25830617 TI - Using quality improvement methods to change surgical practice: a case example of pediatric soft-tissue abscesses. AB - BACKGROUND: Surgical treatments of soft-tissue abscesses (STAs) include packing and ring drain (RD) and straight drain (SD) placement. Potential benefits of SDs include a single incision, less scarring, and no need for a follow-up appointment. We used a multidisciplinary quality improvement (QI) process to promote surgeon adoption of an STA drainage technique to improve efficiency and quality of care. SUBJECTS AND METHODS: Outcome measures included the proportion of STAs drained using SDs, the number of postoperative clinic visits, the proportion of patients requiring follow-up with a pediatric surgeon and other providers, and the postoperative complication rate, defined as need for an additional drainage procedure. RESULTS: After beginning the QI initiative, the proportion of STAs drained by SDs increased from 23% to 78% (P < .00001) and the proportion of patients requiring a surgical follow-up clinic appointment decreased from 71% to 32% (P < .00001). The mean number of surgical clinic visits per patient decreased from 0.79 to 0.39 visits per patient (P < .00001). Complication rates were similar between drain types (RD: 2.4%; SD: 1.7%; P = .57). This QI initiative produced a rapid sustained shift in surgeon practice with increased use of SDs, decreased number of follow-up visits, and no increase in complications. PMID- 25830618 TI - Tailoring your heart failure project for success in rural areas. AB - PURPOSE: The purpose of this project was to decrease heart failure (HF) readmissions in a rural community by redesigning the inpatient education model. METHODS: An integrated plan of care (ICP) was developed using 6 interventions, tailored to the needs of patients in this community. The interventions in this quality improvement project included (1) upgraded HF education for patients and families using teach-back methodology, (2) a discharge HF packet with survival skills, (3) nutrition education, (4) case management, (5) making appointments for patients with their primary care provider for a visit 5 to 7 days postdischarge and with their cardiologist for 2 weeks after discharge, and (6) a follow-up phone call to each patient within 48 hours postdischarge. RESULTS: Readmission rates decreased 36.9% with implementation of the ICP. Patients without the discharge teaching/packet were almost 7 times more likely to be readmitted. IMPLICATIONS: The IPC was effective in decreasing HF readmissions. CONCLUSIONS: These findings suggest that organizations should focus on developing their discharge teaching methods and ICP to meet the needs of their community. Projects such as these can be used for many chronic disease processes, not only HF. PMID- 25830619 TI - Senior alert: a quality registry to support a standardized, structured, and systematic preventive care process for older adults. AB - The average life expectancy and the proportion of the elderly in the Western countries are increasing. The care processes used for the elderly are known to differ between the care providers in Sweden. Accordingly, the need to develop a system to support the processes in order to attain a standardized, structured, and systematic approach to improve preventive care processes for the elderly has been called for. The County Council of Jonkoping developed a national Web-based quality registry, Senior Alert, with a focus on the following areas: falls, pressure ulcers, malnutrition, and oral health. The patients are evaluated using validated risk assessment instruments, and the care is planned, executed, evaluated. The registry supports the users to work with preventive care systematically and in a standardized way and provides feedback to the care providers on their preventive care processes. The registry helps the caregivers fulfill the preventive care according to the best available clinical knowledge and practice. The registry also provides the government and health care politicians with data for setting aims for elderly care. The registry is used in 90% of the municipalities and county councils throughout the country. The total number of risk assessments completed from 2009 to 2014 exceeded 1 000 000. PMID- 25830623 TI - Accurate evaluation of charge asymmetry in aqueous solvation. AB - Charge hydration asymmetry (CHA)-a characteristic dependence of hydration free energy on the sign of the solute charge-quantifies the asymmetric response of water to electric field at microscopic level. Accurate estimates of CHA are critical for understanding hydration effects ubiquitous in chemistry and biology. However, measuring hydration energies of charged species is fraught with significant difficulties, which lead to unacceptably large (up to 300%) variation in the available estimates of the CHA effect. We circumvent these difficulties by developing a framework which allows us to extract and accurately estimate the intrinsic propensity of water to exhibit CHA from accurate experimental hydration free energies of neutral polar molecules. Specifically, from a set of 504 small molecules we identify two pairs that are analogous, with respect to CHA, to the K(+) /F(-) pair-a classical probe for the effect. We use these "CHA-conjugate" molecule pairs to quantify the intrinsic charge-asymmetric response of water to the microscopic charge perturbations: the asymmetry of the response is strong, ~50% of the average hydration free energy of these molecules. The ability of widely used classical water models to predict hydration energies of small molecules correlates with their ability to predict CHA. PMID- 25830624 TI - Effects of losartan on expression of monocyte chemoattractant protein-1 (MCP-1) in hyperuricemic nephropathy rats. AB - The monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of progression of renal failure. This is based on the observations done both in various animal models of renal damage and in different types of human renal disease. During the development of non-infectious kidney stones, crystals are formed and deposited on the kidneys and the kidneys are surrounded by monocytes/macrophages. We have proposed that in response to crystal exposure, renal epithelial cells produce chemokines, which attract the monocytes/macrophages to the sites of crystal deposition. In this study, we investigated the expression of MCP-1 protein by SD rats exposed to oxonic acid (OA). Our study showed that hyperuricemia accelerates renal progression via a mechanism linked to high MCP-1 which may mediate the inflammation reaction of renal diseases induced by hyperuricemia. Losartan may retard the progression of advanced renal dysfunction, and the mechanism was partly due to blocking of renal inflammation induced by the uric acid. Because the number of experiments performed here is very few, results must be confirmed by more extensive studies with a larger sample size. PMID- 25830625 TI - Intranasally applied neuropeptide S shifts a high-anxiety electrophysiological endophenotype in the ventral hippocampus towards a "normal"-anxiety one. AB - The neurobiological basis of pathological anxiety and the improvement of its pharmacological treatment are a matter of intensive investigation. Here, using electrophysiological techniques in brain slices from animals of the high anxiety related behavior (HAB) and normal anxiety-related behavior (NAB) mouse model, we show that basal neurotransmission at ventral hippocampal CA3-CA1 synapses is weaker in HAB compared to NAB mice. We further demonstrate that paired-pulse facilitation (PPF) and long-term potentiation (LTP) at these synapses are more pronounced in slices from HAB animals. Based on previous findings, we also examined whether intranasal delivery of neuropeptide S (NPS), which increasingly emerges as a potential novel treatment option for anxiety symptoms occurring in a variety of diseases like anxiety disorders, posttraumatic stress disorder, and major depression, impacts on the high-anxiety electrophysiological endophenotype in HAB mice. Strikingly, we detected enhanced basal neurotransmission and reduced PPF and LTP in slices from NPS-treated HAB animals. Collectively, our study uncovers a multifaceted high-anxiety neurophysiological endophenotype in the murine ventral hippocampus and provides the first evidence that an intranasally applied neuropeptide can shift such an endophenotype in an anxiety-regulating brain structure towards a "normal"-anxiety one. PMID- 25830626 TI - Improvement of anti-tumor abilities on human non-small cell lung carcinoma by micellization and cross-linking of N-(2-hydroxypropyl) methacrylamide copolymers. AB - Non-small cell lung carcinoma is one of the most frequently occurred cancers with a very high rate of recurrence. Self-assembly N-(2-hydroxypropyl) methacrylamide (HPMA) micelles and cross-linked micelles were developed to improve antitumor ability of linear HPMA copolymer. The characters of HPMA micelles were investigated and compared using human non-small cell lung carcinoma 3-D culture model and nude mice xenograft model. Cross-linked micelles showed highest cytotoxicity on A549 cell monolayers after a short time treatment in vitro. Moreover, both of the two micelles exhibited better in vitro anti-tumor activity on A549 tumor spheroids than linear HPMA conjugates especially the cross-linked micelles. On BALB/c nude mice bearing A549 xenograft tumors, the cross-linked micelles exhibited the greatest tumor accumulation and the best anti-tumor activity due to the highly improved stabilities and the more pronounced enhanced permeability and retention (EPR) effect, which were followed by the non-cross linked micelles. Meanwhile, neither the two micelles nor the linear HPMA copolymers showed significant toxicity on the main organs of mice while free doxorubicin (DOX) showed obvious cardiac toxicity. All the results suggested that micellization improved the anti-tumor activity of HPMA copolymers on A549 human non-small cell lung carcinoma, furthermore, cross-linked HPMA copolymer micelles with pH-sensitivity and biodegradability showed more excellent anti-tumor activity. PMID- 25830628 TI - Working women and the menopause. AB - Women are living longer, working more and retiring later. About 45% of the over 50-year-old workforce in virtually all forms of employment are women, all of whom will experience the menopause and its symptoms, which in some women will be mild to moderate, whilst in others they may be severe and debilitating. About half of these women will find it somewhat, or fairly difficult, to cope with their work, about half will not be affected and only about 5% will be severely compromised. Poor concentration, tiredness, poor memory, depression, feeling low, lowered confidence, sleepiness and particularly hot flushes are all cited as contributing factors. As with any longstanding health-related condition, the need for support and understanding from line management is crucial and can make a major difference to how a woman will deal with the adverse impact the menopausal symptoms may have on her productivity, her job satisfaction and her efficiency. A number of plausible strategies have been proposed that can be realistically implemented in the workplace and which could certainly make a significant difference. Careful thought, planning, consideration and effort may be required but, if instituted, they will, in the final analysis, benefit both employer and employee. PMID- 25830627 TI - Novel disease susceptibility factors for fungal necrotrophic pathogens in Arabidopsis. AB - Host cells use an intricate signaling system to respond to invasions by pathogenic microorganisms. Although several signaling components of disease resistance against necrotrophic fungal pathogens have been identified, our understanding for how molecular components and host processes contribute to plant disease susceptibility is rather sparse. Here, we identified four transcription factors (TFs) from Arabidopsis that limit pathogen spread. Arabidopsis mutants defective in any of these TFs displayed increased disease susceptibility to Botrytis cinerea and Plectosphaerella cucumerina, and a general activation of non immune host processes that contribute to plant disease susceptibility. Transcriptome analyses revealed that the mutants share a common transcriptional signature of 77 up-regulated genes. We characterized several of the up-regulated genes that encode peptides with a secretion signal, which we named PROVIR (for provirulence) factors. Forward and reverse genetic analyses revealed that many of the PROVIRs are important for disease susceptibility of the host to fungal necrotrophs. The TFs and PROVIRs identified in our work thus represent novel genetic determinants for plant disease susceptibility to necrotrophic fungal pathogens. PMID- 25830630 TI - Giant esophageal gastrointestinal stromal tumor mimicking mediastinal tumor treated by thoracic approach. PMID- 25830629 TI - Sex differences between CRF1 receptor deficient mice following naloxone precipitated morphine withdrawal in a conditioned place aversion paradigm: implication of HPA axis. AB - BACKGROUND: Extinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R) and the different response of male and female mice in the expression and extinction of the aversive memory. METHODOLOGY/PRINCIPAL FINDING: We used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10-60 mg/kg). Negative state associated with naloxone (1 mg/kg s.c.)-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. No sex differences for CPA expression were found in wild type (n = 29) or CRF1R knockout (KO) mice (n = 29). However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH) levels observed in wild-type (n = 11) mice after CPA expression, were attenuated in CRF1R KO mice (n = 10). In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished. CONCLUSION/SIGNIFICANCE: These results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished. PMID- 25830631 TI - Impact of chain length on antibacterial activity and hemocompatibility of quaternary N-alkyl and n,n-dialkyl chitosan derivatives. AB - A highly efficient method for chemical modification of chitosan biopolymers by reductive amination to yield N,N-dialkyl chitosan derivatives was developed. The use of 3,6-O-di-tert-butyldimethylsilylchitosan as a precursor enabled the first 100% disubstitution of the amino groups with long alkyl chains. The corresponding mono N-alkyl derivatives were also synthesized, and all the alkyl compounds were then quaternized using an optimized procedure. These well-defined derivatives were studied for antibacterial activity against Gram positive S. aureus, E. faecalis, and Gram negative E. coli, P. aeruginosa, which could be correlated to the length of the alkyl chain, but the order was dependent on the bacterial strain. Toxicity against human red blood cells and human epithelial Caco-2 cells was found to be proportional to the length of the alkyl chain. The most active chitosan derivatives were found to be more selective for killing bacteria than the quaternary ammonium disinfectants cetylpyridinium chloride and benzalkonium chloride, as well as the antimicrobial peptides melittin and LL-37. PMID- 25830632 TI - Retraction: Maternal diesel inhalation increases airway hyperreactivity in ozone exposed offspring. PMID- 25830633 TI - News from the National Heart, Lung, and Blood Institute: Allowable content in new applications. PMID- 25830634 TI - Dominant negative RPW8.2 fusion proteins reveal the importance of haustorium oriented protein trafficking for resistance against powdery mildew in Arabidopsis. AB - Powdery mildew fungi form feeding structures called haustoria inside epidermal cells of host plants to extract photosynthates for their epiphytic growth and reproduction. The haustorium is encased by an interfacial membrane termed the extrahaustorial membrane (EHM). The atypical resistance protein RPW8.2 from Arabidopsis is specifically targeted to the EHM where RPW8.2 activates haustorium targeted (thus broad-spectrum) resistance against powdery mildew fungi. EHM specific localization of RPW8.2 suggests the existence of an EHM-oriented protein/membrane trafficking pathway during EHM biogenesis. However, the importance of this specific trafficking pathway for host defense has not been evaluated via a genetic approach without affecting other trafficking pathways. Here, we report that expression of EHM-oriented, nonfunctional RPW8.2 chimeric proteins exerts dominant negative effect over functional RPW8.2 and potentially over other EHM-localized defense proteins, thereby compromising both RPW8.2 mediated and basal resistance to powdery mildew. Thus, our results highlight the importance of the EHM-oriented protein/membrane trafficking pathway for host resistance against haustorium-forming pathogens such as powdery mildew fungi. PMID- 25830635 TI - alphaII-spectrin regulates invadosome stability and extracellular matrix degradation. AB - Invadosomes are actin-rich adhesion structures involved in tissue invasion and extracellular matrix (ECM) remodelling. alphaII-Spectrin, an ubiquitous scaffolding component of the membrane skeleton and a partner of actin regulators (ABI1, VASP and WASL), accumulates highly and specifically in the invadosomes of multiple cell types, such as mouse embryonic fibroblasts (MEFs) expressing SrcY527F, the constitutively active form of Src or activated HMEC-1 endothelial cells. FRAP and live-imaging analysis revealed that alphaII-spectrin is a highly dynamic component of invadosomes as actin present in the structures core. Knockdown of alphaII-spectrin expression destabilizes invadosomes and reduces the ability of the remaining invadosomes to digest the ECM and to promote invasion. The ECM degradation defect observed in spectrin-depleted-cells is associated with highly dynamic and unstable invadosome rings. Moreover, FRAP measurement showed the specific involvement of alphaII-spectrin in the regulation of the mobile/immobile beta3-integrin ratio in invadosomes. Our findings suggest that spectrin could regulate invadosome function and maturation by modulating integrin mobility in the membrane, allowing the normal processes of adhesion, invasion and matrix degradation. Altogether, these data highlight a new function for spectrins in the stability of invadosomes and the coupling between actin regulation and ECM degradation. PMID- 25830636 TI - Dietary factors associated with faecal consistency and other indicators of gastrointestinal health in the captive cheetah (Acinonyx jubatus). AB - Gastrointestinal diseases pose significant risks to captive cheetah survival and welfare. Multiple factors are thought to be associated with these diseases, but to date a comprehensive epidemiological survey of disease risk factors has not been conducted. A survey of diet and health parameters was completed for 184 captive cheetahs in 86 international facilities. Comparisons were made among dietary factors with respect to disease status and observed faecal consistency, incidence of vomiting and diarrhoea in the past 4 weeks. Extremely dry faeces were most common in cheetahs fed carcasses, but was still of low incidence (15%). Contrastingly, cheetahs fed commercially prepared diets had the highest prevalence of liquid faeces "always" or "often" (9%). Cheetahs fed raw meat diets had the highest prevalence of soft faeces with no shape (22%), as well as of firm and dry faeces (40%). No broad category of diet exerted any influence on the health parameters investigated. However, feeding of ribs at least once per week reduced the odds of diarrhoea (P = 0.020) and feeding of long bones (limbs) at least once per week was associated with a lower odds of vomiting (P = 0.008). Cheetahs fed muscle meat at least once per week had reduced odds of suffering from chronic gastritis (P = 0.005) or non-specific gastrointestinal disease (P < 0.001). The only factor identified as increasing the odds of chronic gastritis was feeding of horse "often" or "always" (P = 0.023). The findings of the current study build on existing empirical research to support a recommendation towards a greater inclusion of skeletal components. Current husbandry guidelines advocating the use of supplemented raw meat diets are likewise supported, but the use of horse meat, as well as commercially prepared diets for captive cheetahs, warrants caution until further research is conducted. PMID- 25830637 TI - New tool for EDC research: in vivo assay screens for estrogenic effects. PMID- 25830638 TI - The volume ratio of ground glass opacity in early lung CT predicts mortality in acute paraquat poisoning. AB - BACKGROUND: Pulmonary injury is the main cause of death in acute paraquat (PQ) poisoning. However, whether quantitative lung computed tomography (CT) can be useful in predicting the outcome of PQ poisoning remains unknown. We aimed to identify early findings of quantitative lung CT as predictors of outcome in acute PQ poisoning. METHODS: Lung CT scanning (64-slide) and quantitative CT lesions were prospectively measured for patients after PQ intoxication within 5 days. The study outcome was mortality during 90 days follow-up. Survival curves were derived by the Kaplan-Meier method, and mortality risk factors were analyzed by the forward stepwise Cox regression analysis. RESULTS: Of 97 patients, 41 (42.3%) died. Among the eight different types of lung CT findings which appeared in the first 5-day of PQ intoxication, four ones discriminated between survivors and non survivors including ground glass opacity (GGO), consolidation, pneumomediastinum and "no obvious lesion". With a cutoff value of 10.8%, sensitivity of 85.4% and specificity of 89.3%, GGO volume ratio is better than adopted outcome indicators in predicting mortality, such as estimated amount of PQ ingestion, plasma or urine PQ concentration, acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores. GGO volume ratios above 10.8% were associated with increased mortality (hazard ratio, 5.82; 95% confidence interval, 4.77-7.09; P < 0.001). CONCLUSIONS: The volume ratio of GGO exceeding 10.8% is a novel, reliable and independent predictors of outcome in acute PQ poisoning. PMID- 25830639 TI - Bioorganic fertilizer enhances soil suppressive capacity against bacterial wilt of tomato. AB - Tomato bacterial wilt caused by Ralstonia solanacearum is one of the most destructive soil-borne diseases. Many strategies have been taken to improve soil suppressiveness against this destructive disease, but limited success has been achieved. In this study, a novel bioorganic fertilizer revealed a higher suppressive ability against bacterial wilt compared with several soil management methods in the field over four growing seasons from March 2011 to July 2013. The application of the bioorganic fertilizer significantly (P<0.05) reduced disease incidence of tomato and increased fruit yields in four independent trials. The association among the level of disease incidence, soil physicochemical and biological properties was investigated. The soil treated with the bioorganic fertilizer increased soil pH value, electric conductivity, organic carbon, NH4+ N, NO3--N and available K content, microbial activities and microbial biomass carbon content, which were positively related with soil suppressiveness. Bacterial and actinomycete populations assessed using classical plate counts were highest, whereas R. solanacearum and fungal populations were lowest in soil applied with the bioorganic fertilizer. Microbial community diversity and richness were assessed using denaturing gel gradient electrophoresis profile analysis. The soil treated with the bioorganic fertilizer exhibited higher bacterial community diversity but lower fungal community diversity. Redundancy analysis showed that bacterial community diversity and richness negatively related with bacterial wilt suppressiveness, while fungal community richness positively correlated with R. solanacearum population. We concluded that the alteration of soil physicochemical and biological properties in soil treated with the bioorganic fertilizer induced the soil suppressiveness against tomato bacterial wilt. PMID- 25830641 TI - [Limits in the immunological and genetical investigation of recurrent abortion]. PMID- 25830640 TI - Antibiotic resistance modulation and modes of action of (-)-alpha-pinene in Campylobacter jejuni. AB - The aim of the study was to investigate the mode of action of (-)-alpha-pinene in terms of its modulation of antibiotic resistance in Campylobacter jejuni. Broth microdilution and ethidium bromide accumulation assays were used to evaluate the (-)-alpha-pinene antimicrobial activity, modulation of antimicrobial resistance, and inhibition of antimicrobial efflux. The target antimicrobial efflux systems were identified using an insertion mutagenesis approach, and C. jejuni adaptation to (-)-alpha-pinene was evaluated using DNA microarrays. Knock-out mutants of the key up-regulated transcriptional regulators hspR and hrcA were constructed to investigate their roles in C. jejuni adaptation to several stress factors, including osmolytes, and pH, using Biolog phenotypical microarrays. Our data demonstrate that (-)-alpha-pinene efficiently modulates antibiotic resistance in C. jejuni by decreasing the minimum inhibitory concentrations of ciprofloxacin, erythromycin and triclosan by up to 512-fold. Furthermore, (-)-alpha-pinene promotes increased expression of cmeABC and another putative antimicrobial efflux gene, Cj1687. The ethidium bromide accumulation was greater in the wild-type strain than in the antimicrobial efflux mutant strains, which indicates that these antimicrobial efflux systems are a target of action of (-)-alpha-pinene. Additionally, (-)-alpha-pinene decreases membrane integrity, which suggests that enhanced microbial influx is a secondary mode of action of (-)-alpha-pinene. Transcriptomic analysis indicated that (-)-alpha-pinene disrupts multiple metabolic pathways, and particularly those involved in heat-shock responses. Thus, (-)-alpha-pinene has significant activity in the modulation of antibiotic resistance in C. jejuni, which appears to be mediated by multiple mechanisms that include inhibition of microbial efflux, decreased membrane integrity, and metabolic disruption. These data warrant further studies on (-)-alpha-pinene to develop its use in the control of antibiotic resistance in Campylobacter. PMID- 25830642 TI - Efficacy of paraspinal anesthetic block in patients with chronic pelvic pain refractory to drug therapy: a randomized clinical trial. AB - PURPOSE: To determine whether paraspinal block reduces pain scores compared to placebo in women with chronic pelvic pain refractory to drug therapy. METHODS: Subjects with chronic pelvic pain due to benign conditions and refractory to drug therapy were invited to participate in a randomized, double blind, superiority trial at a tertiary reference center. Subjects were randomly allocated to receive paraspinal anesthetic block with 1% lidocaine without epinephrine or placebo (control). Lidocaine was injected along the spinal process of the painful segment in the supra- and interspinal ligaments using a 25G X 2" needle. Placebo consisted of introduction of the needle in the same segment without injecting any substance. The main outcome measured was the pain score based on a visual analog scale at T0 (baseline), T1 (within 15 min after the procedure) and T2 (one week after the procedure). Data were statistically analyzed by ANOVA and the 95% confidence interval (95%CI). RESULTS: Mean age was similar for both groups, i.e., 51.2 (paraspinal anesthetic block) and 51.8 years (control). A blind examiner measured the degree of pain according to the visual analog scale from 0 (no pain) to 10 (worst pain imaginable). Based on the visual analog scale, the mean pain scores of the paraspinal anesthetic block group at T0, T1 and T2 were 5.50 (SD=2.92; 95%CI 3.84-7.15), 2.72 (SD=2.10; 95%CI 1.53-3.90), and 4.36 (SD=2.37; 95%CI 1.89-6.82), respectively. The difference between T0 and T1 was statistically significant, with p=0.03. CONCLUSIONS: Paraspinal anesthetic block had a small effect on visual analog scale pain score immediately after the injections, but no sustained benefit after one week. Further studies are needed to determine the efficacy of paraspinal anesthetic block with different lidocaine doses for the treatment of visceral pain of other causes. PMID- 25830643 TI - [Reproductive outcomes after hysteroscopic septoplasty: a retrospective study]. AB - PURPOSE: To assess the reproductive outcomes after hysteroscopic septoplasty. METHODS: A retrospective observational study was performed with analysis of the medical records of 28 women with infertility or recurrent abortions undergoing hysteroscopic septoplasty. To evaluate reproductive outcomes we consulted the medical records of our hospital and of primary health care units between septoplasty and the present or first pregnancy. Primary outcomes were pregnancy rate, newborns, and abortions after septoplasty. Uterine septum was diagnosed by 2D or 3D ultrasound and classified according to the American Fertility Society. All procedures were performed in the follicular phase of the menstrual cycle using monopolar or bipolar energy and/or microscissors. To compare the reproductive outcomes before and after septoplasty we used Microsoft Excel and SPSS version 17. Fisher's exact test was considered statistically significant if p<0.05. RESULTS: Hysteroscopic septoplasty was performed in 20 patients (72%) with secondary infertility and in 8 patients (28%) with primary infertility. The septum was incompletely removed during the first hysteroscopy in 5 cases (18%), which required a second surgery. One case was complicated with minor uterine perforation. After hysteroscopic septoplasty, 64% of women became pregnant and 48% live neonates were delivered; 4% of the patients had a tubal pregnancy; and 19% had miscarriages. CONCLUSIONS: The results of this study are consistent with those described in the literature. Patients obtained a significant improvement of reproductive outcomes with a fivefold reduction in miscarriage rate after hysteroscopic septoplasty. PMID- 25830644 TI - Minimally invasive approach of tubo-ovarian abscesses. AB - PURPOSE: To evaluate the treatment outcome of tubo-ovarian abscesses managed by transvaginal ultrasound-guided aspiration. METHODS: Descriptive analysis of all patients with tubo-ovarian abscesses treated with a minimally invasive procedure, ultrasound-guided drainage, at the Department of Gynecology, Centro Hospitalar Vila Nova de Gaia/Espinho, during a period of 5 years (from June 2009 to June 2014). RESULTS: Twenty-six cases were included in the study. The mean age of the study group was 42.8 years. All patients were submitted to transvaginal ultrasound-guided aspiration and sclerosis with iodated solution, as well as received broad-spectrum intravenous antibiotics. The mean time from admission to drainage was 2.5 days. Cultures for aerobic and anaerobic pathogens were positive in 14 of the 26 cases. A complete response was noted in 23 of the 26 cases. No complications or morbidity were noted as a consequence of the drainage procedures. CONCLUSION: Minimally invasive treatment of tubo-ovarian abscesses by transvaginal ultrasound-guided drainage is an effective and safe approach. PMID- 25830645 TI - Fatigue and quality of life in breast cancer survivors: a comparative study. AB - PURPOSE: To assess fatigue and quality of life in disease-free breast cancer survivors in relation to a sample of age-matched women with no cancer history and to explore the relationship between fatigue and quality of life. METHODS: A cross sectional study was conducted in a sample of 202 consecutive disease-free Brazilian breast cancer survivors, all of whom had completed treatment, treated at 2 large hospitals. The patients were compared to age-matched women with no cancer history attending a primary health care center. The Piper Fatigue Scale Revised and the World Health Organization Quality of Life Instrument (WHOQOL BREF) were used to measure the fatigue and quality of life, respectively. Socio demographic and clinical variables were also obtained. The chi2 test, generalized linear model, and Spearman correlation coefficient were used for statistical purposes. The adopted level of significance was 5%. RESULTS: Breast cancer survivors experienced significantly greater total and subscale fatigue scores than comparison group (all p-values<0.05). In addition, survivors reported a poorer quality of life in physical (p=0.002), psychological (p=0.03), and social relationships (p=0.03) domains than comparison group. No difference was found for the environmental domain (p=0.08) for both groups. For survivors of breast cancer and for comparison group, the total and subscale fatigue scores were related to lower quality of life (all p-values<0.01). CONCLUSION: The findings of this study highlight the importance of assessing fatigue and quality of life in breast cancer survivors. PMID- 25830646 TI - [Mechanical method of induction of labor in high-risk pregnant women with previous cesarean section]. AB - PURPOSE: To describe the maternal and fetal outcomes with the use of the Foley catheter for induction of labor in high-risk pregnant women with previous caesarean section. METHODS: An interventive and descriptive study was conducted from November 2013 to June 2014. A total of 39 pregnant women at term, with a live fetus, cephalic presentation, estimated fetal weight <4,000 g, with previous cesarean section, medical indications for induction of labor, Bishop score <=6 and amniotic fluid index >5 cm were included. A number 16F Foley catheter was introduced for a maximum of 24 hours, and was considered to be satisfactory when the patient began labor within 24 hours. RESULTS: Labor was successfully induced in 79.5% of pregnant women. Nine women achieved vaginal delivery (23.1%), with a frequency of 18% of vaginal births occurring within 24 hours. The main indications for the induction of labor were hypertensive disorders (75%). The mean interval between the placement of the Foley catheter and the beginning of labor and delivery were 8.7+/-7.1 and 14.7+/-9.8 hours, respectively. Meconium stained amniotic fluid was observed in two patients; and an Apgar score <7 in the first minute was detected in 5 newborns (12.8%). CONCLUSIONS: The Foley catheter is an alternative for the induction of labor in women with previous caesarean section, despite the low vaginal delivery rate. PMID- 25830647 TI - Fetal heart rate responses during maternal resistance exercise: a pilot study. AB - PURPOSE: To determine fetal heart rate (FHR) responses to maternal resistance exercise for the upper and lower body at two different volumes, and after 25 minutes post-exercise. METHODS: Ten pregnant women (22-24 weeks gestation, 25.2+/ 4.4 years of age, 69.8+/-9.5 kg, 161.6+/-5.2 cm tall) performed, at 22-24, 28-32 and 34-36 weeks, the following experimental sessions: Session 1 was a familiarization with the equipment and the determination of one estimated maximum repetition. For sessions 2, 3, 4 and 5,FHR was determined during the execution of resistance exercise on bilateral leg extension and pec-deck fly machines, with 1 and 3 sets of 15 repetitions; 50% of the weight load and an estimated repetition maximum. FHR was assessed with a portable digital cardiotocograph. Results were analyzed using Student's t test, ANOVA with repeated measures and Bonferroni (alpha=0.05; SPSS 17.0). RESULTS: FHR showed no significant differences between the exercises at 22-24 weeks (bilateral leg extension=143.8+/-9.4 bpm, pec-deck fly=140.2+/-10.2 bpm, p=0.34), 28-30 weeks (bilateral leg extension=138.4+/-12.2 bpm, pec-deck fly=137.6+/-14.0 bpm, p=0.75) and 34-36 weeks (bilateral leg extension=135.7+/-5.8 bpm, pec-deck fly=139.7+/-13.3 bpm, p=0.38), between the volumes(bilateral leg extension at 22-24 weeks: p=0.36, at 28-30 weeks: p=0.19 and at 34-36 weeks: p=0.87; pec-deck fly at 22-24 weeks: p=0.43, at 28-30 weeks: p=0.61 and at 34-36 weeks: p=0.49) and after 25 minutes post-exercise. CONCLUSION: Results of this pilot study would suggest that maternal resistance exercise is safe for the fetus. PMID- 25830648 TI - [Prenatal management of congenital diaphragmatic hernia: present, past and future]. AB - The congenital diaphragmatic hernia is a defect in the formation of the diaphragm, which affects between 1:2,000 and 1:4,000 live births and represents 8% of major congenital anomalies. Medical advances in the last 30 years involving prenatal diagnosis, fetal intervention, neonatal surgical and clinical management have changed the survival of these patients. The historical evolution of these advances helps us to understand the effort in pursuit of better results of this defect, which is often lethal. Perspectives on the use of bioengineering and therapy involving stem cells may bring new hope for fetuses with congenital diaphragmatic hernia. PMID- 25830649 TI - Fluorescent Probes Used for Detection of Hydrogen Peroxide under Biological Conditions. AB - Hydrogen peroxide is a well-established precursor of reactive oxygen and nitrogen species that are known to contribute to oxidative stress-the crucial factor responsible for the course of a wide range of phy-sicochemical processes as well as the genesis of various diseases, such as cancer and neurodegenerative disorders. Thus, the development of sensitive and selective methods for the detection and quantitative determination of hydrogen peroxide is of great importance in monitoring the in vivo production of that species and elucidating its biological functions. This review highlights the progress that has been made in the development of fluorescent and luminescent probes (excluding nanoparticles) employed to monitor hydrogen peroxide under biological conditions. Attention was focused on probes developed in the past 10 years. PMID- 25830650 TI - Impact of daptomycin resistance on Staphylococcus aureus virulence. AB - Daptomycin resistance (DAP(R)) in Staphylococcus aureus is associated with mutations in genes that are also implicated in staphylococcal pathogenesis. Using a laboratory-derived series of DAP exposed strains, we showed a relationship between increasing DAP MIC and reduced virulence in a Galleria mellonella infection model. Point mutations in walK and rpoC led to cumulative reductions in virulence and simultaneous increases in DAP MIC. A point mutation to mprF did not impact on S.aureus virulence; however deletion of mprF led to virulence attenuation and hyper-susceptibility to DAP. To validate our findings in G. mellonella, we confirmed the attenuated virulence of select isolates from the laboratory-derived series using a murine septicaemia model. As a corollary, we showed significant virulence reductions for clinically-derived DAP(R) isolates compared to their isogenic, DAP-susceptible progenitors (DAP(S)). Intriguingly, each clinical DAP(R) isolate was persistent in vivo. Taken together, it appears the genetic correlates underlying daptomycin resistance in S. aureus also alter pathogenicity. PMID- 25830651 TI - Cooperative stabilization of the SIR complex provides robust epigenetic memory in a model of SIR silencing in Saccharomyces cerevisiae. AB - How alternative chromatin-based regulatory states can be made stable and heritable in order to provide robust epigenetic memory is poorly understood. Here, we develop a stochastic model of the silencing system in Saccharomyces cerevisiae that incorporates cooperative binding of the repressive SIR complex and antisilencing histone modifications, in addition to positive feedback in Sir2 recruitment. The model was able to reproduce key features of SIR regulation of an HM locus, including heritable bistability, dependence on the silencer elements, and sensitivity to SIR dosage. We found that antisilencing methylation of H3K79 by Dot1 was not needed to generate these features, but acted to reduce spreading of SIR binding, consistent with its proposed role in containment of silencing. In contrast, cooperative inter-nucleosome interactions mediated by the SIR complex were critical for concentrating SIR binding around the silencers in the absence of barriers, and for providing bistability in SIR binding. SIR-SIR interactions magnify the cooperativity in the Sir2-histone deacetylation positive feedback reaction and complete a double-negative feedback circuit involving antisilencing modifications. Thus, our modeling underscores the potential importance of cooperative interactions between nucleosome-bound complexes both in the SIR system and in other chromatin-based complexes in epigenetic regulation. PMID- 25830652 TI - Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment. AB - Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity. Taking this into account, we analyzed, using multiparametric flow cytometry, the co expression of the melanoma markers melanoma cell adhesion molecule and melanoma associated chondroitin sulphate proteoglycan and the tumor-initiating markers ATP binding cassette sub-family B member 5 (ABCB5), CD271, and receptor activator of NF-kappabeta (RANK) in individual circulating tumor cells (CTCs) from 40 late stage (III-IV) and 16 early-stage (I-II) melanoma patients. CTCs were heterogeneous within and between patients, with limited co-expression between the five markers analyzed. Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation. Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01). Moreover, the presence of ?5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01). Taken together, our results provide evidence of the heterogeneity among CTC subpopulations in melanoma and the differential response of these subpopulations to targeted therapy. PMID- 25830653 TI - A Drosophila Model of Epidermolysis Bullosa Simplex. AB - The blistering skin disorder epidermolysis bullosa simplex (EBS) results from dominant mutations in keratin 5 (K5) or keratin 14 (K14) genes, encoding the intermediate filament (IF) network of basal epidermal keratinocytes. The mechanisms governing keratin network formation and collapse due to EBS mutations remain incompletely understood. Drosophila lacks cytoplasmic IFs, providing a 'null' environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14(R125C) mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates in epithelial and non-epithelial fly tissues. Expression of K14(R125C)/K5 caused semi-lethality; adult survivors developed wing blisters and were flightless due to a lack of intercellular adhesion during wing heart development. This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for the development of EBS therapies. PMID- 25830655 TI - Correction: population biology of schistosoma mating, aggregation, and transmission breakpoints: more reliable model analysis for the end-game in communities at risk. AB - [This corrects the article DOI: 10.1371/journal.pone.0115875.]. PMID- 25830654 TI - Correlation between Reversal of DNA Methylation and Clinical Symptoms in Psoriatic Epidermis Following Narrow-Band UVB Phototherapy. AB - Epigenetic modifications by DNA methylation are associated with a wide range of diseases. Previous studies in psoriasis have concentrated on epigenetic changes in immune cells or in total skin biopsies that include stromal-associated changes. In order to improve our understanding of the role of DNA methylation in psoriasis, we sought to obtain a comprehensive DNA methylation signature specific for the epidermal component of psoriasis and to analyze methylation changes during therapy. Genome-wide DNA methylation profiling of epidermal cells from 12 patients undergoing narrow-band UVB phototherapy and 12 corresponding healthy controls revealed a distinct DNA methylation pattern in psoriasis compared with controls. A total of 3,665 methylation variable positions (MVPs) were identified with an overall hypomethylation in psoriasis patient samples. DNA methylation pattern was reversed at the end of phototherapy in patients showing excellent clinical improvement. Only 7% of phototherapy-affected MVPs (150 out of 2,108) correlate with nearby gene expression. Enrichment of MVPs in enhancers indicates tissue-specific modulation of the transcriptional regulatory machinery in psoriasis. Our study identified key epigenetic events associated with psoriasis pathogenesis and helps understand the dynamic DNA methylation landscape in the human genome. PMID- 25830656 TI - The prevalence of human T-lymphotropic virus infection among blood donors in southeast China, 2004-2013. AB - BACKGROUND: The human T-lymphotropic virus type 1 (HTLV-1) which is associated with the diseases of adult T-cell leukemia/lymphoma, HTLV-1 associated myelopathy / tropical spastic paraparesis (HAM/TSP) and HTLV-associated uveitis, can cause transfusion-transmitted infections. Although HTLV screening of blood donors was already routinely performed in developed countries, little is know about the HTLV prevalence among blood donors in developing countries which do not perform HTLV screening, such as China. OBJECTIVES &AIMS: To systematically characterize the prevalence of HTLV infection among bloods in southeast China. METHODS: A 10-year survey for HTLV prevalence in blood donors was performed in Xiamen, southeast China, during 2004-2013. The HTLV-1/2 of blood donations were screened by enzyme linked immunosorbent assay, following with confirmation by western blot assay and 9nucleic acid testing. The HTLV-1 prevalences in donors from different cities were calculated. Viral sequences derived from identified HTLV-positive cases were sequenced and analyzed. RESULTS: Among 253,855 blood donors, 43 were confirmed to be seropositive for HTLV-1 (16.9 per 100,000 95% CI: 12.3-22.8) and none HTLV-2 infection was found. The HTLV-1 prevalence varied significantly in donors from different cities. Donors from cities in Fujian province (24.3 per 100,000, 95%CI: 17.4-33.1) had a significantly higher (p=0.001) HTLV-1 seroprevalence than those who were born in non-Fujian cities (3.4 per 100,000, 95%CI: 0.7-9.8). Among nine cities in Fujian province, the highest prevalence was found in blood donors from Ningde (171.3 per 100,000, 95%CI: 91.3-292.8) which is a coastal city in the northeast of Fujian. Molecular characterization of viral sequences from 27 HTLV-1 carriers revealed 25 were Transcontinental subtype of genotype A and 2 were Japanese subtype of genotype A. Interestingly, 12 of 25 Transcontinental subtype sequences harbored a characteristic L55P mutation in viral gp46 protein, which was only presented in the Transcontinental subtype sequences from Japan and Taiwan but not in that from other countries. CONCLUSIONS: Although China is considered to be a non-endemic region for HTLV, the HTLV-1 prevalence in blood donors is significantly higher in Fujian province, southeast China. A higher prevalence of HTLV-1 in the Fujian may be attributed to endemic foci in the city of Ningde. PMID- 25830657 TI - Structural Characterization, Technological Functionality, and Physiological Aspects of Fungal beta-D-glucans: A Review. AB - beta-D-glucans are a (1->3)-linked glucose polymer with (1->6)-linked side chains and a major component of fungal cell walls. They exhibit structural integrity to the fungal cell wall. In addition, beta-glucans are widely used as food adjuvant in food and pharmaceutical industries because of their physico-chemical properties. Several studies have focused on different isolation processes of (1 >3) (1->6)-beta-glucan that could affect the physico-chemical and functional properties of beta-glucan such as chemical composition, solubility, viscosity, hydration properties, and oil binding capacity. Immunological activity is one of the most important properties of beta-glucans. Thus, they are effective in inhibiting growth of cancer cells and metastasis and preventing bacterial infection. In humans, beta-glucans reduce blood cholesterol, improve glucose absorption by body cells, and so help wound healing. This review described the prebiotic potentiality of fungal beta-D-glucans with the objective to detail the methodologies applied for their extraction, their structure and techno-functional properties, and finally their biological effects. PMID- 25830659 TI - Isolation and screening of endophytes from the rhizomes of some Zingiberaceae plants for L-asparaginase production. AB - Endophytes are described as microorganisms that colonize the internal tissues of healthy plants without causing any disease. Endophytes isolated from medicinal plants have been attracting considerable attention due to their high biodiversity and their predicted potential to produce a plethora of novel compounds. In this study, an attempt was made to isolate endophytes from rhizomes of five medicinal plants of Zingiberaceae family, and to screen the endophytes for L-asparaginase activity. In total, 50 endophytes (14 bacteria, 22 actinomycetes, and 14 fungi) were isolated from Alpinia galanga, Curcuma amada, Curcuma longa, Hedychium coronarium, and Zingiber officinale; of these, 31 endophytes evidenced positive for L-asparaginase production. All the L-asparaginase-positive isolates showed L asparaginase activity in the range of 54.17-155.93 U/mL in unoptimized medium. An endophytic fungus isolated from Curcuma amada, identified as Talaromyces pinophilus, was used for further experiments involving studies on the effect of certain nutritional and nonnutritional factors on L-asparaginase production in submerged fermentation. Talaromyces pinophilus initially gave an enzyme activity of 108.95 U/mL, but gradually reduced to 80 U/mL due to strain degeneration. Perhaps this is the first report ever on the production of L-asparaginase from endophytes isolated from medicinal plants of Zingiberaceae family. PMID- 25830660 TI - Planning Mediates Between Self-Efficacy and Physical Activity Among Motivated Young Adults. AB - BACKGROUND: Often, motivation to be physically active is a necessary precondition of action but still does not suffice to initiate the target behavior. Instead, motivation needs to be translated into action by a self-regulatory process. Self efficacy and planning are considered to be useful constructs that help to facilitate such translations. OBJECTIVE: The aim is to examine the roles of motivation, planning, and self-efficacy as well as the mechanisms that operate in the change of physical activity levels. METHODS: In a longitudinal observation study with 249 young adults, self-efficacy, planning, motivation, and physical activity were assessed at 2 points in time, 3 months apart. RESULTS: Planning served as a mediator between self-efficacy and physical activity, controlling for baseline activity. In addition to this indirect effect, a moderator effect was found between self-efficacy and stages of change on planning. The mediation operated only in motivated, but not in unmotivated students. CONCLUSIONS: A mediation from self-efficacy via planning to physical activity seems to be likely only when people are motivated to become more active. PMID- 25830661 TI - Herbal and plant therapy in patients with inflammatory bowel disease. AB - The use of herbal therapy in inflammatory bowel disease (IBD) is increasing worldwide. The aim of this study was to review the literature on the efficacy of herbal therapy in IBD patients. Studies on herbal therapy for IBD published in Medline and Embase were reviewed, and response to treatment and remission rates were recorded. Although the number of the relevant clinical studies is relatively small, it can be assumed that the efficacy of herbal therapies in IBD is promising. The most important clinical trials conducted so far refer to the use of mastic gum, tormentil extracts, wormwood herb, aloe vera, triticum aestivum, germinated barley foodstuff, and boswellia serrata. In ulcerative colitis, aloe vera gel, triticum aestivum, andrographis paniculata extract and topical Xilei san were superior to placebo in inducing remission or clinical response, and curcumin was superior to placebo in maintaining remission; boswellia serrata gum resin and plantago ovata seeds were as effective as mesalazine, whereas oenothera biennis had similar relapse rates as omega-3 fatty acids in the treatment of ulcerative colitis. In Crohn's disease, mastic gum, Artemisia absinthium, and Tripterygium wilfordii were superior to placebo in inducing remission and preventing clinical postoperative recurrence, respectively. Herbal therapies exert their therapeutic benefit by different mechanisms including immune regulation, antioxidant activity, inhibition of leukotriene B4 and nuclear factor kappa B, and antiplatelet activity. Large, double-blind clinical studies assessing the most commonly used natural substances should urgently be conducted. PMID- 25830662 TI - Short-term variation in occupational exposure to air contaminants. AB - Many industrial workers are exposed to air contaminants. A significant proportion of this exposure is found to occur as short peaks, a fact that has received limited attention in the literature. The present study focuses on short-term variation in air contaminant exposure measured at the level of seconds, linking exposure peaks to typical work situations in selected Swedish industries. The video exposure monitoring method was used to characterize this variation. Ten different videos were analyzed, from recordings varying in length between 15 and 34 minutes. Cumulative exposure for sampling intervals ranked from high to low, relative to the total exposure was calculated as a function of time. Measures of exposure variation included geometric standard deviation and maximum exposure divided by arithmetic mean. The results show that the characteristics of the variation differ between industrial situations. Samples from the stone, wood, and pharmaceutical industries generated the highest variation, implying that exposure peaks of short duration explain a large proportion of the total exposure. It can be concluded that video monitoring of exposure, combined with calculation of exposure variation as percentage of time accounting for given percentages of exposure, can help to reduce exposure to air contaminants in industrial situations by introducing more targeted control measures. PMID- 25830663 TI - Effect of High-pressure CO2 Processing on Bacterial Spores. AB - High-pressure CO2 (HPCD) is a nonthermal technology that can effectively inactivate the vegetative forms of pathogenic and spoilage bacteria, yeasts, and molds at pressures less than 30 MPa and temperatures in the range of 20 degrees C to 40 degrees C. However, HPCD alone at moderate temperatures (20-40 degrees C) is often insufficient to obtain a substantial reduction in bacterial spore counts because their structures are more complex than those of vegetative cells. In this review, we first thoroughly summarized and discussed the inactivation effect of HPCD treatment on bacterial spores. We then presented and discussed the kinetics by which bacterial spores are inactivated by HPCD treatment. We also summarized hypotheses drawn by different researchers to explain the mechanisms of spore inactivation by HPCD treatment. We then summarized the current research status and future challenges of spore inactivation by HPCD treatment. PMID- 25830664 TI - The efficacy of traditional Chinese Medical Exercise for Parkinson's disease: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Several studies assessed the efficacy of traditional Chinese medical exercise in the management of Parkinson's disease (PD), but its role remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the effect of traditional Chinese medical exercise for PD. METHODS: Seven English and Chinese electronic databases, up to October 2014, were searched to identify relevant studies. The PEDro scale was employed to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.1 software. RESULTS: Fifteen trials were included in the review. Tai Chi and Qigong were used as assisting pharmacological treatments of PD in the previous studies. Tai Chi plus medication showed greater improvements in motor function (standardized mean difference, SMD, -0.57; 95% confidence intervals, CI, -1.11 to -0.04), Berg balance scale (BBS, SMD, -1.22; 95% CI -1.65 to -0.80), and time up and go test (SMD, -1.06; 95% CI -1.44 to -0.68). Compared with other therapy plus medication, Tai Chi plus medication also showed greater gains in motor function (SMD, -0.78; 95% CI -1.46 to -0.10), BBS (SMD, -0.99; 95% CI -1.44 to -0.54), and functional reach test (SMD, -0.77; 95% CI -1.51 to 0.03). However, Tai Chi plus medication did not showed better improvements in gait or quality of life. There was not sufficient evidence to support or refute the effect of Qigong plus medication for PD. CONCLUSIONS: In the previous studies, Tai Chi and Qigong were used as assisting pharmacological treatments of PD. The current systematic review showed positive evidence of Tai Chi plus medication for PD of mild-to-moderate severity. So Tai Chi plus medication should be recommended for PD management, especially in improving motor function and balance. Qigong plus medication also showed potential gains in the management of PD. However, more high quality studies with long follow-up are warrant to confirm the current findings. PMID- 25830665 TI - Associations between subjective happiness and dry eye disease: a new perspective from the Osaka study. AB - IMPORTANCE: Dry eye disease has become an important health problem. A lack of concordance between self-reported symptoms and the outcome of dry eye examinations has raised questions about dry eye disease. OBJECTIVE: To explore the association between subjective happiness and objective and subjective symptoms of dry eye disease. DESIGN: The study adopted a cross-sectional design. SETTING: All the employees of a company in Osaka, Japan. PARTICIPANTS: 672 Japanese office workers using Visual Display Terminals (age range: 26-64 years). METHODS: The dry eye measurement tools included the Schirmer test, conjunctivocorneal staining, the tear film break-up time, as well as the administration of a dry eye symptoms questionnaire. Happiness was measured by the Subjective Happiness Scale. MAIN OUTCOME MEASURES: Dry eye examination parameters, dry eye symptoms questionnaires, and the Subjective Happiness Scale score. RESULTS: Of the 672 workers, 561 (83.5%) completed the questionnaires and examinations. The mean Subjective Happiness Scale score was 4.91 (SD = 1.01). This score was inversely correlated with the dry eye symptom score (r = -0.188, p < 0.001), but was not associated with objective findings which include conjunctivocorneal staining, low Schirmer test score, or low tear film break-up time. The level of subjective happiness was the lowest in the group without objective results, but reported subjective symptoms of dry eyes (p < 0.05). CONCLUSIONS AND RELEVANCE: There is evidence of the relationship between subjective happiness and self-reported symptoms of dry eyes. Findings of this study revealed a new perspective on dry eye disease, including the potential for innovative treatments of a specific population with dry eye disease. PMID- 25830667 TI - MALDI-MS Imaging Analysis of Fungicide Residue Distributions on Wheat Leaf Surfaces. AB - Improved retention and distribution of agrochemicals on plant surfaces is an important attribute in the biological activity of pesticide. Although retention of agrochemicals on plants after spray application can be quantified using traditional analytical techniques including LC or GC, the spatial distribution of agrochemicals on the plants surfaces has received little attention. Matrix assisted laser desorption/ionization (MALDI) imaging technology has been widely used to determine the distribution of proteins, peptides and metabolites in different tissue sections, but its application to environmental research has been limited. Herein, we probed the potential utility of MALDI imaging in characterizing the distribution of three commercial fungicides on wheat leaf surfaces. Using this MALDI imaging method, we were able to detect 500 ng of epoxiconazole, azoxystrobin, and pyraclostrobin applied in 1 MUL drop on the leaf surfaces using MALDI-MS. Subsequent dilutions of pyraclostrobin revealed that the compound can be chemically imaged on the leaf surfaces at levels as low as 60 ng of total applied in the area of 1 MUL droplet. After application of epoxiconazole, azoxystrobin, and pyraclostrobin at a field rate of 100 gai/ha in 200 L water using a track sprayer system, residues of these fungicides on the leaf surfaces were sufficiently visualized. These results suggest that MALDI imaging can be used to monitor spatial distribution of agrochemicals on leaf samples after pesticide application. PMID- 25830666 TI - Phenotypic dysregulation of microglial activation in young offspring rats with maternal sleep deprivation-induced cognitive impairment. AB - Despite the potential adverse effects of maternal sleep deprivation (MSD) on physiological and behavioral aspects of offspring, the mechanisms remain poorly understood. The present study was intended to investigate the roles of microglia on neurodevelopment and cognition in young offspring rats with prenatal sleep deprivation. Pregnant Wistar rats received 72 h sleep deprivation in the last trimester of gestation, and their prepuberty male offspring were given the intraperitoneal injection with or without minocycline. The results showed the number of Iba1(+) microglia increased, that of hippocampal neurogenesis decreased, and the hippocampus-dependent spatial learning and memory were impaired in MSD offspring. The classical microglial activation markers (M1 phenotype) IL-1beta, IL-6, TNF-alpha, CD68 and iNOS were increased, while the alternative microglial activation markers (M2 phenotype) Arg1, Ym1, IL-4, IL-10 and CD206 were reduced in hippocampus of MSD offspring. After minocycline administration, the MSD offspring showed improvement in MWM behaviors and increase in BrdU(+)/DCX(+) cells. Minocycline reduced Iba1(+) cells, suppressed the production of pro-inflammatory molecules, and reversed the reduction of M2 microglial markers in the MSD prepuberty offspring. These results indicate that dysregulation in microglial pro- and anti-inflammatory activation is involved in MSD-induced inhibition of neurogenesis and impairment of spatial learning and memory. PMID- 25830668 TI - Unique Surface Modification of Silica Nanoparticles with Polyethylenimine (PEI) for siRNA Delivery Using Cerium Cation Coordination Chemistry. AB - The discovery of RNA interference (RNAi) as a naturally occurring mechanism for gene knockdown has attracted considerable attention toward the use of small interfering RNAs (siRNAs) for therapeutic purposes. The main obstacles of harnessing siRNAs as drugs are their inefficient delivery to cells and off-target effect making clinical applications very challenging. The positively charged, branched 25 kDa polyethylenimine (b-PEI) polymer is widely regarded as one of the most efficient nonviral commercially available transfection agents. However, it has also been shown that 25 kDa b-PEI is highly cytotoxic and can readily lead to cell death. In this specific context, this study presents the preparation and characterization of innovative 25 kDa b-PEI-decorated polycationic silica nanoparticles (SiO2 NPs) for cellular siRNA delivery and subsequent gene silencing. A new method of b-PEI attachment onto the SiO2 NP surface has been developed that makes use of cerium(III) cations (Ce(3+)), a lanthanide group element, as an effective noncovalent inorganic linker between both polyNH2-SiO2 nanoparticle (SPA NPs) surface and polycationic 25 kDa b-PEI polymer. Two resulting novel SPA-Ce-PEI NPs consist of similar amounts of b-PEI, while possessing different amounts of Ce(3+). Various analytical techniques (TEM, DLS, zeta potential, ICP-AES, and TGA) have been used to deeply characterize NPs physicochemical qualities. The observed results of Ce(3+)-dependent gene silencing and cytotoxic activities led us to conclusions about the role of Ce(3+) N bonding during the chemical attachment of the 25 kDa b-PEI shell onto the NP surface. PMID- 25830669 TI - Hepatitis B immunization in healthcare workers. AB - BACKGROUND: Healthcare workers (HCWs) are at high risk for hepatitis B virus (HBV) infection. The aim of the study was to evaluate HBV immunization status and anti-HBs titer among HCWs. METHODS: AntiHBs titer was prospectively examined in all vaccinated of the 464 HCWs enrolled. A comparison was done between two groups who had received vaccination within or beyond 5 years (Group A >5 years, Group B <5 years) and also between those who received a booster dose, Group I (<1 year) and Group II (>1 year). RESULTS: 49.6% HCWs were vaccinated, 46.1% were unvaccinated, and 4.3% were partially vaccinated. Among HCWs, doctors had the highest vaccination rate of 92.5%, followed by medical students (62.4%), nursing staff (41.6%), technical staff (24.2%), administrative staff (12.1%), nursing students (8.5%), and grade IV/laundry staff (0%). Of the vaccinated HCWs, 30% had anti-HBs titer <10 mIU/mL, 10.8% between 10-100 mIU/mL, and 59.2% >100 mIU/mL. Mean anti-HBs titer between groups A and B was 334.8 and 649.2 mIU/mL, respectively (P<0.05); mean anti-HBs titer between groups I and II was 1742.7 and 629.2 mIU, respectively (P<0.002). CONCLUSION: A significant proportion of HCWs is unvaccinated. A fair proportion of fully vaccinated HCWs can have low titers to protect them against HBV infection. Measuring anti-HBs titer, administering a booster dose, and offering general screening for HBs antigen should be made compulsory for HCWs. PMID- 25830658 TI - Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers. AB - While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers. PMID- 25830670 TI - BAP1 missense mutation c.2054 A>T (p.E685V) completely disrupts normal splicing through creation of a novel 5' splice site in a human mesothelioma cell line. AB - BAP1 is a tumor suppressor gene that is lost or deleted in diverse cancers, including uveal mela!noma, malignant pleural mesothelioma (MPM), clear cell renal carcinoma, and cholangiocarcinoma. Recently, BAP1 germline mutations have been reported in families with combinations of these same cancers. A particular challenge for mutation screening is the classification of non-truncating BAP1 sequence variants because it is not known whether these subtle changes can affect the protein function sufficiently to predispose to cancer development. Here we report mRNA splicing analysis on a homozygous substitution mutation, BAP1 c. 2054 A&T (p.Glu685Val), identified in an MPM cell line derived from a mesothelioma patient. The mutation occurred at the 3rd nucleotide from the 3' end of exon 16. RT-PCR, cloning and subsequent sequencing revealed several aberrant splicing products not observed in the controls: 1) a 4 bp deletion at the end of exon 16 in all clones derived from the major splicing product. The BAP1 c. 2054 A&T mutation introduced a new 5' splice site (GU), which resulted in the deletion of 4 base pairs and presumably protein truncation; 2) a variety of alternative splicing products that led to retention of different introns: introns 14-16; introns 15-16; intron 14 and intron 16; 3) partial intron 14 and 15 retentions caused by activation of alternative 3' splice acceptor sites (AG) in the introns. Taken together, we were unable to detect any correctly spliced mRNA transcripts in this cell line. These results suggest that aberrant splicing caused by this mutation is quite efficient as it completely abolishes normal splicing through creation of a novel 5' splice site and activation of cryptic splice sites. These data support the conclusion that BAP1 c.2054 A&T (p.E685V) variant is a pathogenic mutation and contributes to MPM through disruption of normal splicing. PMID- 25830671 TI - Attitudes of Greek Drivers with Focus on Mobile Phone Use While Driving. AB - OBJECTIVE: This article investigates the attitudes and behavior of Greek drivers with specific focus on mobile phone use while driving. METHODS: The research is based on the data of the pan-European SARTRE 4 survey, which was conducted on a representative sample of Greek drivers in 2011. Analysis of the drivers' behavior was carried out by the statistical methods of factor and cluster analysis. RESULTS: According to the results of factor analysis, Greek drivers' responses in the selected questions were summarized into 4 factors, describing road behavior and accident involvement probability as well as their views on issues concerning other drivers' road behaviors, fatigued driving, enforcement of road safety, and mobile phone use while driving. The results of cluster analysis indicated 5 different groups of Greek drivers--the moderate, the optimistic, the conservative, the risky, and the reasonably cautious--and the characteristics of each group where identified. CONCLUSIONS: These results may be useful for the appropriate design of targeted road safety campaigns and other countermeasures. PMID- 25830673 TI - Structures of Ras superfamily effector complexes: What have we learnt in two decades? AB - The Ras superfamily small G proteins are master regulators of a diverse range of cellular processes and act via downstream effector molecules. The first structure of a small G protein-effector complex, that of Rap1A with c-Raf1, was published 20 years ago. Since then, the structures of more than 60 small G proteins in complex with their effectors have been published. These effectors utilize a diverse array of structural motifs to interact with the G protein fold, which we have divided into four structural classes: intermolecular beta-sheets, helical pairs, other interactions, and pleckstrin homology (PH) domains. These classes and their representative structures are discussed and a contact analysis of the interactions is presented, which highlights the common effector-binding regions between and within the small G protein families. PMID- 25830676 TI - Childhood trauma-specific reductions in limbic gray matter volume: still in the dark. PMID- 25830672 TI - Diffusion tensor magnetic resonance imaging of trigeminal nerves in relapsing herpetic keratouveitis. AB - BACKGROUND: Corneal hypoesthesia is the landmark of HSV and VZV keratitis and can lead to neurotrophic keratitis. Diffusion tensor imaging (DTI) is a new magnetic resonance imaging (MRI) derived technique, which offers possibilities to study axonal architecture. We aimed at assessing the potential impact of recurrent HSV or VZV-related keratitis on the axonal architecture of trigeminal nerves using DTI. DESIGN: Prospective non-interventional study. PARTICIPANTS: Twelve patients and 24 controls. METHODS: DTI using MRI of the trigeminal fibers and corneal esthesiometry using the Cochet-Bonnet esthesiometer were acquired for patients affected by unilateral and recurrent HSV or VZV-related keratitis (3 months after the last corneal inflammatory event), and control subjects with no history of ocular or neuronal disease affecting the trigeminal pathways. MAIN OUTCOME MEASURES: Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were compared between the 2 eyes of both patients and controls, and correlated with corneal esthesiometry. RESULTS: FA was lower in the trigeminal fibers ipsilateral to the affected eye compared to the non-affected side (0.39+/-0.02 versus 0.46+/-0.04, P=0.03). This difference was more important than the intra individual variability observed in controls. Concomitantly, the asymmetry in ADC results was significantly correlated with the loss of corneal sensitivity in the affected eye. CONCLUSIONS: Corneal hypoesthesia related to HSV and VZV keratitis is associated with persistent modifications in the architecture and functionality of the trigeminal fibers. These results add further explanation to the pathogenesis of HSV and VZV-induced neurotrophic keratitis, which may occur despite an apparent quiescence of the disease. PMID- 25830677 TI - Childhood trauma-specific reductions in limbic gray matter volume--reply. PMID- 25830679 TI - Seco-taondiol, an unusual meroterpenoid from the Chilean seaweed Stypopodium flabelliforme and its gastroprotective effect in mouse model. AB - Ten known meroterpenoids and the new meroterpenoid 7 were isolated from the Chilean seaweed Stypopodium flabelliforme as their acetylated derivatives. Furthermore, the known metabolite taondiol has been isolated for the first time from this species. The molecular structure of the new metabolite was determined by spectroscopic methods based on 1D- and 2D-NMR. Isolation of 7 represents a key step toward a better understanding of the biogenesis of this class of meroterpenoids. Among the meroditerpenoids isolated, stypodiol, isoepitaondiol, epitaondiol and sargaol exhibited gastroprotective activity on the HCl/Ethanol induced gastric lesions model in mice. Regarding the mode of gastroprotective action, the activity of epitaondiol was reversed significantly when animals were pretreated with indomethacin, N-ethylmaleimide and N-nitro-l-arginine methyl ester (L-NAME) suggesting that prostaglandins, sulfhydryl groups and nitric oxide are involved in their mode of gastroprotective action. In the case of sargaol the gastroprotective activity was attenuated with indomethacin and N-ethylmaleimide, which suggests that prostaglandins and sulfhydryl groups are also involved in the mode of action using this model. PMID- 25830680 TI - Co-processed chitin-mannitol as a new excipient for Oro-dispersible tablets. AB - This study describes the preparation, characterization and performance of a novel excipient for use in oro-dispersible tablets (ODT). The excipient (Cop-CM) consists of chitin and mannitol. The excipient with optimal physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w) and produced by roll compaction (RC). Differential scanning calorimetry (DSC), Fourier transform Infrared (FT-IR), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) techniques were used to characterize Cop-CM, in addition to characterization of its powder and ODT dosage form. The effect of particle size distribution of Cop-CM was investigated and found to have no significant influence on the overall tablet physical properties. The compressibility parameter (a) for Cop-CM was calculated from a Kawakita plot and found to be higher (0.661) than that of mannitol (0.576) due to the presence of the highly compressible chitin (0.818). Montelukast sodium and domperidone ODTs produced, using Cop-CM, displayed excellent physicochemical properties. The exceptional binding, fast wetting and superdisintegration properties of Cop-CM, in comparison with commercially available co-processed ODT excipients, results in a unique multifunctional base which can successfully be used in the formulation of oro dispersible and fast immediate release tablets. PMID- 25830681 TI - Low molecular weight chitosan-insulin polyelectrolyte complex: characterization and stability studies. AB - The aim of the work reported herein was to investigate the effect of various low molecular weight chitosans (LMWCs) on the stability of insulin using USP HPLC methods. Insulin was found to be stable in a polyelectrolyte complex (PEC) consisting of insulin and LMWC in the presence of a Tris-buffer at pH 6.5. In the presence of LMWC, the stability of insulin increased with decreasing molecular weight of LMWC; 13 kDa LMWC was the most efficient molecular weight for enhancing the physical and chemical stability of insulin. Solubilization of insulin-LMWC polyelectrolyte complex (I-LMWC PEC) in a reverse micelle (RM) system, administered to diabetic rats, results in an oral delivery system for insulin with acceptable bioactivity. PMID- 25830682 TI - First evidence that Ecklonia cava-derived dieckol attenuates MCF-7 human breast carcinoma cell migration. AB - We investigated the effect of Ecklonia cava (E. cava)-derived dieckol on movement behavior and the expression of migration-related genes in MCF-7 human breast cancer cell. Phlorotannins (e.g., dieckol, 6,6'-biecko, and 2,7"-phloroglucinol 6,6'-bieckol) were purified from E. cava by using centrifugal partition chromatography. Among the phlorotannins, we found that dieckol inhibited breast cancer cell the most and was selected for further study. RadiusTM-well was used to assess cell migration, and dieckol (1-100 uM) was found to suppress breast cancer cell movement. Metastasis-related gene expressions were evaluated by RT PCR and Western blot analysis. In addition, dieckol inhibited the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). On the other hand, it stimulated the expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. These results suggest that dieckol exerts anti-breast cancer activity via the regulation of the expressions of metastasis-related genes, and this is the first report on the anti breast cancer effect of dieckol. PMID- 25830684 TI - Evaluation of Anti-inflammatory Activity of Seeds of Phalaris canariensis. AB - Chloroform extract (ALC) from the seeds of Phalaris canariensis were assayed for antiinflammatory activity by carrageenan-induced oedema, cotton pellets-induced granuloma, histamine-induced inflammation, croton oil-induced oedema, activity of myeloperoxidase (MPO), adjuvant-induced arthritis, quantification of TNFalpha, IL 1beta, PGE2 and LTB4 and nitric oxide (NO) assay. ALC exhibited significant anti inflammatory activity in different chemically-induced edemas in a dose dependent manner. In the chronic model cotton pellets-induced granuloma showed decreased formation of granuloma tissue. Also caused inhibition of ear inflammation edema and influx of polymorphonuclear cells, as evidence by a decrease in ear thickness and reduced myeloperoxidase activity and inhibit mediators of inflammation as TNFalpha, IL-1beta, PGE2 and LTB4. When RAW 264.7 macrophages were treated with ALC together with LPS a significant inhibition of NO production was detected. These data provide evidence for antiinflammatory effect of P. canariensis by mechanisms that involve a reduced neutrophil influx and decreased production of inflammatory cytokines. PMID- 25830683 TI - Morphological and proteomic analyses reveal that unsaturated guluronate oligosaccharide modulates multiple functional pathways in murine macrophage RAW264.7 cells. AB - Alginate is a natural polysaccharide extracted from various species of marine brown algae. Alginate-derived guluronate oligosaccharide (GOS) obtained by enzymatic depolymerization has various pharmacological functions. Previous studies have demonstrated that GOS can trigger the production of inducible nitric oxide synthase (iNOS)/nitric oxide (NO), reactive oxygen species (ROS) and tumor necrosis factor (TNF)-alpha by macrophages and that it is involved in the nuclear factor (NF)-kappaB and mitogen-activated protein (MAP) kinase signaling pathways. To expand upon the current knowledge regarding the molecular mechanisms associated with the GOS-induced immune response in macrophages, comparative proteomic analysis was employed together with two-dimensional electrophoresis (2 DE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) and Western blot verification. Proteins showing significant differences in expression in GOS-treated cells were categorized into multiple functional pathways, including the NF-kappaB signaling pathway and pathways involved in inflammation, antioxidant activity, glycolysis, cytoskeletal processes and translational elongation. Moreover, GOS-stimulated changes in the morphologies and actin cytoskeleton organization of RAW264.7 cells were also investigated as possible adaptations to GOS. This study is the first to reveal GOS as a promising agent that can modulate the proper balance between the pro- and anti-inflammatory immune responses, and it provides new insights into pharmaceutical applications of polysaccharides. PMID- 25830685 TI - Epiploic appendagitis: a non-surgical cause of acute abdomen. PMID- 25830686 TI - Quantitative analysis of volatile metabolites released in vitro by bacteria of the genus Stenotrophomonas for identification of breath biomarkers of respiratory infection in cystic fibrosis. AB - The aim of the present study was to characterize the volatile metabolites produced by genotypically diverse strains of the Stenotrophomonas genus in order to evaluate their potential as biomarkers of lung infection by non-invasive breath analysis. Volatile organic compounds (VOCs) emitted from 15 clinical and five environmental strains belonging to different genogroups of Stenotrophomonas maltophilia (n = 18) and Stenotrophomonas rhizophila (n = 2) cultured in Mueller Hinton Broth (MHB) liquid media were analysed by gas chromatography mass spectrometry (GC-MS) and selected ion flow tube mass spectrometry (SIFT-MS). Several VOCs were detected in high concentration, including ammonia, propanol, dimethyl disulphide propanol and dimethyl disulphide. The GC-MS measurements showed that all 15 clinical strains produced similar headspace VOCs compositions, and SIFT-MS quantification showed that the rates of production of the VOCs by the genotypically distinct strains were very similar. All in vitro cultures of both the Stenotrophomonas species were characterised by efficient production of two isomers of methyl butanol, which can be described by known biochemical pathways and which is absent in other pathogens, including Pseudomonas aeruginosa. These in-vitro data indicate that methyl butanol isomers may be exhaled breath biomarkers of S. maltophilia lung infection in patients with cystic fibrosis. PMID- 25830687 TI - A mobile cloud-based Parkinson's disease assessment system for home-based monitoring. AB - BACKGROUND: Parkinson's disease (PD) is the most prevalent movement disorder of the central nervous system, and affects more than 6.3 million people in the world. The characteristic motor features include tremor, bradykinesia, rigidity, and impaired postural stability. Current therapy based on augmentation or replacement of dopamine is designed to improve patients' motor performance but often leads to levodopa-induced adverse effects, such as dyskinesia and motor fluctuation. Clinicians must regularly monitor patients in order to identify these effects and other declines in motor function as soon as possible. Current clinical assessment for Parkinson's is subjective and mostly conducted by brief observations made during patient visits. Changes in patients' motor function between visits are hard to track and clinicians are not able to make the most informed decisions about the course of therapy without frequent visits. Frequent clinic visits increase the physical and economic burden on patients and their families. OBJECTIVE: In this project, we sought to design, develop, and evaluate a prototype mobile cloud-based mHealth app, "PD Dr", which collects quantitative and objective information about PD and would enable home-based assessment and monitoring of major PD symptoms. METHODS: We designed and developed a mobile app on the Android platform to collect PD-related motion data using the smartphone 3D accelerometer and to send the data to a cloud service for storage, data processing, and PD symptoms severity estimation. To evaluate this system, data from the system were collected from 40 patients with PD and compared with experts' rating on standardized rating scales. RESULTS: The evaluation showed that PD Dr could effectively capture important motion features that differentiate PD severity and identify critical symptoms. For hand resting tremor detection, the sensitivity was .77 and accuracy was .82. For gait difficulty detection, the sensitivity was .89 and accuracy was .81. In PD severity estimation, the captured motion features also demonstrated strong correlation with PD severity stage, hand resting tremor severity, and gait difficulty. The system is simple to use, user friendly, and economically affordable. CONCLUSIONS: The key contribution of this study was building a mobile PD assessment and monitoring system to extend current PD assessment based in the clinic setting to the home-based environment. The results of this study proved feasibility and a promising future for utilizing mobile technology in PD management. PMID- 25830689 TI - Gene therapy for inherited diseases of liver metabolism. AB - Gene therapy is entering the stage of initial clinical development to treat a growing number of inherited metabolic diseases. This review outlines the development of liver-directed gene therapy for diseases caused by deficiencies of enzymes that are primarily expressed in the liver and discusses the disorders that appear most promising for clinical translation. PMID- 25830688 TI - Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia. AB - IMPORTANCE: Hemispheric specialization of the human brain is a marker of successful neurodevelopment. Altered brain asymmetry that has been repeatedly reported in schizophrenia may represent consequences of disrupted neurodevelopment in the disorder. However, a complete picture of functional specialization in the schizophrenic brain and its connectional substrates is yet to be unveiled. OBJECTIVES: To quantify intrinsic hemispheric specialization at cortical and subcortical levels and to reveal potential disease effects in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Resting-state functional connectivity magnetic resonance imaging has been previously used to quantitatively measure hemispheric specialization in healthy individuals in a reliable manner. We quantified the intrinsic hemispheric specialization at the whole brain level in 31 patients with schizophrenia and 37 demographically matched healthy controls from November 28, 2007, through June 29, 2010, using resting-state functional magnetic resonance imaging. RESULTS: The caudate nucleus and cortical regions with connections to the caudate nucleus had markedly abnormal hemispheric specialization in schizophrenia. Compared with healthy controls, patients exhibited weaker specialization in the left, but the opposite pattern in the right, caudate nucleus (P < .001). Patients with schizophrenia also had a disruption of the interhemispheric coordination among the cortical regions with connections to the caudate nucleus. A linear classifier based on the specialization of the caudate nucleus distinguished patients from controls with a classification accuracy of 74% (with a sensitivity of 68% and a specificity of 78%). CONCLUSIONS AND RELEVANCE: These data suggest that hemispheric specialization could serve as a potential imaging biomarker of schizophrenia that, compared with task-based functional magnetic resonance imaging measures, is less prone to the confounding effects of variation in task compliance, cognitive ability, and command of language. PMID- 25830690 TI - Crohn's disease in remission or simply smouldering? PMID- 25830691 TI - The Effect of Brief Exposure to Sub-Therapeutic Concentrations of Chlorhexidine Digluconate on the Susceptibility of Staphylococci to Platelet Microbicidal Protein. AB - BACKGROUND: Antiseptic agents are widely used in hospitals and are essential when prevention and control of nosocomial infections is required. It is necessary to consider several aspects that affect the biocide activity because they have direct impact on the nosocomial infection rate. Organisms belonging to the Staphylococcus genus are involved in such infections and chlorhexidine digluconate (CHXD) is one of the most used antiseptic agents for human and animal health. In the context of such infections, anti-bacterial peptides have been isolated from platelets and have been termed platelet microbicidal proteins (PMP). Platelet microbicidal proteins have been shown to enhance the bacterial inhibitory activities of sub-therapeutic concentrations of antibiotics. The main objective of this study was to investigate the effect of brief exposure to different sub-therapeutic concentrations of CHXD on the susceptibility of staphylococci to PMP. METHODS: The influence of brief exposure to three different sub-therapeutic concentrations of CHXD (0.005%, 0.0025%, and 0.00125%) on the subsequent staphylocidal effect of PMP was evaluated. RESULTS: Among all clinical staphylococcal strains studied, all isolates were considered to be resistant to the bactericidal action of PMP. Exposure of staphylococci to CHXD prior to PMP resulted in significantly increased staphylococcal killing compared with the killing achieved with PMP alone. This enhanced effect was most marked for concentrations of CHXD of 0.005%. CONCLUSION: The combined data indicate that PMP exerts cooperative bactericidal effect with CHXD. The anti-staphylococcal PMP and CHXD synergistic activity in vitro demonstrated in the present study make these molecules potentially useful for preventing endovascular catheter-associated infections. Future research based on animal and human models is needed to elucidate the in vivo efficacies and toxicities and utility in clinical practice. PMID- 25830692 TI - Proton Transfer Dynamics of 4'-N,N-Dimethylamino-3-hydroxyflavone Observed in Hydrogen-Bonding Solvents and Aqueous Micelles. AB - Photophysical studies on the 4'-N,N-dimethylamino-3-hydroxyflavone fluorophore were performed in hydrogen-bonding solvents. Both in hydrogen-bonding acids and bases, clear evidence of excited state intramolecular proton transfer (ESIPT) emerged from steady-state and time-resolved spectroscopies. The same was also observed for the fluorophores residing in the hydrophilic shell region of aqueous micelles, where they come into close contact with water molecules at the micelle water interface. Slow ~100 ps ESIPT time-constants were determined in these systems that correlated well with solvation dynamics. The slow ESIPT time constants are attributed to activated barrier crossing from the solvent-relaxed enol form to tautomer form in the excited state energy surface of the flavone. In contrast to the barrier-less ESIPT occurring in early (<1 ps) time-scales, this activated proton-transfer event necessarily requires extensive reorganization of flavone...solvent intermolecular hydrogen bonds, a process heavily modulated by the relatively slower dynamics of solvent relaxation around the excited fluorophore. PMID- 25830693 TI - High-performance inkjet-printed four-terminal microelectromechanical relays and inverters. AB - We report the first demonstration of inkjet-printed 4-terminal microelectromechanical (MEM) relays and inverters with hyper-abrupt switching that exhibit excellent electrical and mechanical characteristics. This first implementation of a printed 4-terminal device is critically important, since it allows for the realization of full complementary logic functions. The floated fourth terminal (body electrode), which allows the gate switching voltage to be adjusted, is bonded to movable channel beams via a printed epoxy layer in a planar structure, which can move downward together via the electrostatic force between the gate electrodes and body such that the channel can also actuate downward and touch the drain electrode. Because the body, channel, and drain electrodes are completely electrically separated, no detectable leakage or electrical interference between the electrodes is observed. The printed MEM relay exhibited an on-state resistance of only 3.48 Omega, immeasurable off-state leakage, subthreshold swing <1 mV/dec, and a stable operation over 10(4) cycles with a switching delay of 47 MUs, and the relay inverter exhibits abrupt transitions between on/off states. The operation of the printed 4-terminal MEM relay was also verified against the results of a 3-dimensional (3D) finite element simulation. PMID- 25830694 TI - BEVACIZUMAB LEVELS IN BREAST MILK AFTER LONG-TERM INTRAVITREAL INJECTIONS. AB - PURPOSE: The purpose of this study is to determine whether bevacizumab is detectable in the breast milk of nursing mothers. METHODS: Breast milk samples were collected from 2 patients receiving monthly intravitreal bevacizumab injections for choroidal neovascularization over the course of 16 months. Enzyme linked immunosorbent assay and Western blot analysis was used to determine the levels of bevacizumab in the milk samples. RESULTS: An enzyme-linked immunosorbent assay was developed using antibodies specific to bevacizumab in which the sensitivity threshold was 3 ng/mL. All breast milk samples assayed from the two patients actively undergoing treatment did not have detectable levels of bevacizumab. Samples collected 1.5 hours and 7 hours after an injection and 2 randomly chosen samples were negative by Western blot analysis. CONCLUSION: A sensitive assay to detect bevacizumab in breast milk samples assayed suggests that intravitreal injections do not result in detectable bevacizumab in breast milk. PMID- 25830695 TI - THE ROYAL COLLEGE OF OPHTHALMOLOGISTS' NATIONAL OPHTHALMOLOGY DATABASE STUDY OF VITREORETINAL SURGERY: Report 4, Epiretinal Membrane. AB - PURPOSE: To report pragmatic outcomes from a database study of epiretinal membrane surgery. METHODS: Prospective anonymized clinical audit data from electronic medical records were pooled over 10 years into a national database, from 1,131 primary epiretinal membrane operations, by 69 surgeons, in 16 U.K. vitreoretinal units. RESULTS: The median age of 1,131 patients was 71.6 years. A pars plana vitrectomy and epiretinal membrane peel were combined with internal limiting membrane peel in 17.0% of operations, and cataract surgery in 49.9%. Use of general anesthesia declined from 94.1% in 2001 to 28.9% in 2010. One or more intraoperative complication occurred in 9.8% (8.1% excluding cataract surgery complications). The median preoperative logarithm of the minimum angle of resolution (logMAR) visual acuity improved from 0.60 to 0.30 (Snellen 20/80 20/40) after a median follow-up of 7.0 months; 41.7% of eyes improved >=0.30 logMAR units (approximately 2 Snellen's lines). The percentages of eyes undergoing subsequent surgery were 3.3%, 1.0%, 0.4%, and 0.8% for epiretinal membrane, retinal detachment, macular hole, and other vitreoretinal indications, respectively. Excluding pseudophakic eyes, 51.7%, 73.2%, and 76.2% of eyes underwent cataract surgery within 1 year, 2 year, and 3 years respectively. CONCLUSION: These results may help vitreoretinal surgeons to benchmark their surgical outcomes, and patients to assess the risks and benefits of surgery. PMID- 25830696 TI - ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NAIVE IDIOPATHIC CHOROIDAL NEOVASCULARIZATION: A Comparative Study. AB - PURPOSE: To determine the clinical characteristics of patients with idiopathic choroidal neovascularization and to compare outcomes between intravitreal bevacizumab (IVB) and ranibizumab as therapy. METHODS: Retrospective analysis included demographics, the corrected distance visual acuity, details of the ocular examination, imaging, treatment, outcomes, and adverse events. Patients with minimum of 1-year follow-up were included in the study. Primary outcome measure was change in corrected distance visual acuity at the final visit compared with baseline. Secondary outcome measures were change in central macular thickness and subretinal fluid (if present) with treatment and adverse events. RESULTS: This study included 47 eyes of 45 patients with 30 males. Intravitreal bevacizumab group included 29 eyes (27 patients; with a median age of 39.4 +/- 7.3 years). Intravitreal ranibizumab group included 18 eyes (18 patients; median age: 36.8 +/- 9.3 years). Median baseline corrected distance visual acuity (logMAR) improved from 0.59 +/- 0.38 to 0.2 +/- 0.18 (P = 0.03) in intravitreal ranibizumab group and from 0.62 +/- 0.41 to 0.18 +/- 0.15 logMAR (P = 0.023) in intravitreal bevacizumab group. Median central macular thickness (in micrometers) improved from 315.11 +/- 75.24 to 228.24 +/- 67 (P = 0.036) in intravitreal bevacizumab group and from 327.24 +/- 61.56 to 208 +/- 53.42 (P = 0.031) in intravitreal ranibizumab group. There was no significant difference between groups in final corrected distance visual acuity (P = 0.31) or central macular thickness (P = 0.51). No adverse events were noted. CONCLUSION: Both intravitreal ranibizumab and intravitreal bevacizumab seem equally effective in treating idiopathic choroidal neovascularization with a good safety profile without recurrence. PMID- 25830697 TI - MULTIMODAL IMAGING FINDINGS AND MULTIMODAL VISION TESTING IN NEOVASCULAR AGE RELATED MACULAR DEGENERATION. AB - PURPOSE: To investigate the interactions among multimodal imaging findings and multimodal vision testing in neovascular age-related macular degeneration. METHODS: Patients enrolled in a prospective study of neovascular age-related macular degeneration with at least 3 previous intravitreal anti-vascular endothelial growth factor injections. Each patient underwent multimodal fundus imaging including spectral domain optical coherence tomography and fundus autofluorescence, and multimodal vision testing, including visual acuity, contrast sensitivity, reading speed, and microperimetry. RESULTS: There were 73 eyes of 49 consecutive patients enrolled. Generalized estimating equations' modelling showed that the significant independent predictors of visual acuity were the area of confluent hypoautofluorescence and involvement of the foveal center with either granular or confluent hypoautofluorescence (P < 0.001). Contrast sensitivity was negatively correlated with the area of confluent hypoautofluorescence (P < 0.001), involvement of the foveal center with granular hypoautofluorescence (P = 0.017), and subfoveal choroidal thickness (P = 0.042). The only significant predictor of reading speed was the size of confluent hypoautofluorescence (P < 0.001). The size of the defect in the ellipsoid zone (P < 0.001) and the presence of intraretinal fluid (P = 0.045) were correlated with microperimetry score. CONCLUSION: Confluent absence of autofluorescence was a highly significant predictor of vision testing and serves as an easy parameter to obtain in patients with neovascular age-related macular degeneration. PMID- 25830698 TI - INITIAL VERSUS DELAYED PHOTODYNAMIC THERAPY IN COMBINATION WITH RANIBIZUMAB FOR TREATMENT OF POLYPOIDAL CHOROIDAL VASCULOPATHY: The Fujisan Study. AB - PURPOSE: To compare the 1-year results of initial or deferred photodynamic therapy (PDT) combined with intravitreal ranibizumab (IVR) for eyes with polypoidal choroidal vasculopathy. METHODS: Prospectively, 72 men with treatment naive polypoidal choroidal vasculopathy were randomized to initial or later PDT combined with IVR. In both groups, 2 additional monthly IVR followed. From Month 3, PDT and IVR were administered according to the retreatment criteria. Mean changes in the best-corrected visual acuity between baseline and Month 12 and central retinal thickness, the rate of eyes showing regression of polypoidal lesions, and number of additional treatments were compared. RESULTS: The best corrected visual acuity increased by a mean of 8.1 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the initial PDT group and 8.8 ETDRS letters in the later PDT group, and there was a no significant difference (P = 0.59). The mean central retinal thickness decreased significantly in both groups but more so with combination therapy within the first 4 months; the difference was not significant at Month 12 (P = 0.30). The rate of eyes showing resolution of polypoidal lesions at 12 months was 62.1% in the initial PDT group and 54.8% in the later PDT group and again, there was no significant difference (P = 0.53). The mean number of additional IVR was 1.5 in initial PDT and 3.8 in later PDT; that of additional PDTs was 0.14 and 0.45, respectively, and they were significantly different (P < 0.001 and P = 0.013, respectively). CONCLUSION: Both initial and deferred PDT combined with IVR to treat polypoidal choroidal vasculopathy show the similar visual and anatomical improvements at 12 months. Initial PDT combination leads to significantly fewer additional treatments. PMID- 25830699 TI - Effectiveness of step therapy policies for specialty pharmaceuticals in immune disorders. AB - OBJECTIVE: To assess the effectiveness of managed care plans that limited access to infusion biologics via a step therapy policy. STUDY DESIGN: This was a retrospective cohort study using Symphony Health Solutions claims databases that included payer, prescription (Rx), diagnosis (Dx) and procedure (Px) information with unique anonymized patient identifiers. METHODS: The percentage of patients with claims for infusion and subcutaneous (SQ) biologics were evaluated across three increasingly restrictive cohorts: (1) patients in step therapy plans versus all others in the database (population), (2) patients in step therapy plans versus patients that were members of plans that were roughly matched (matched) and (3) a subsample of patients that were members of step therapy plans that had sufficient data for a pre/post analysis (pre/post). RESULTS: The population analysis comparison showed 5.1% fewer patients (p < 0.0001) with claims for infusion biologics among step therapy plans than among the overall plans. The more controlled matched and pre/post analyses showed a greater percentage of patients with claims for intravenous products in the plans with step therapy policies versus plans without step therapy policies, differences of +7.0% (p < 0.0001) and +2.8% (p = 0.0522), respectively. CONCLUSIONS: Policies designed to limit utilization of infusion biologics showed equivocal results. In the near term, the intended effects of implementing step therapy policies may be limited by relatively small numbers of patients that are affected relative to the total number of users. PMID- 25830700 TI - Omega 3 polyunsaturated fatty acids and the treatment of depression. AB - Depression is a common, recurrent, and debilitating illness that has become more prevalent over the past 100 years. This report reviews the etiology and pathophysiology of depression, and explores the role of omega 3 polyunsaturated fatty acids (n-3 PUFA) as a possible treatment. In seeking to understand depression, genetic factors and environmental influences have been extensively investigated. Research has led to several hypotheses for the pathophysiological basis of depression but a definitive pathogenic mechanism, or group thereof, has hitherto remained equivocal. To date, treatment has been based on the monoamine hypothesis and hence, selective serotonin reuptake inhibitors have been the most widely used class of medication. In the last decade, there has been considerable interest in n-3 PUFAs and their role in depression. These fatty acids are critical for development and function of the central nervous system. Increasing evidence from epidemiological, laboratory, and randomized placebo-controlled trials suggests deficiency of dietary n-3 PUFAs may contribute to development of mood disorders, and supplementation with n-3 PUFAs may provide a new treatment option. Conclusions based on systematic reviews and meta-analyses of published trials to date vary. Research into the effects of n-3 PUFAs on depressed mood is limited. Furthermore, results from such have led to conflicting conclusions regarding the efficacy of n-3 PUFAs in affecting reduction in symptoms of depression. PUFAs are generally well tolerated by adults and children although mild gastrointestinal effects are reported. There is mounting evidence to suggest that n-3 PUFAs play a role in depression and deserve greater research efforts. PMID- 25830701 TI - Transcriptome sequencing of mung bean (Vigna radiate L.) genes and the identification of EST-SSR markers. AB - Mung bean (Vigna radiate (L.) Wilczek) is an important traditional food legume crop, with high economic and nutritional value. It is widely grown in China and other Asian countries. Despite its importance, genomic information is currently unavailable for this crop plant species or some of its close relatives in the Vigna genus. In this study, more than 103 million high quality cDNA sequence reads were obtained from mung bean using Illumina paired-end sequencing technology. The processed reads were assembled into 48,693 unigenes with an average length of 874 bp. Of these unigenes, 25,820 (53.0%) and 23,235 (47.7%) showed significant similarity to proteins in the NCBI non-redundant protein and nucleotide sequence databases, respectively. Furthermore, 19,242 (39.5%) could be classified into gene ontology categories, 18,316 (37.6%) into Swiss-Prot categories and 10,918 (22.4%) into KOG database categories (E-value < 1.0E-5). A total of 6,585 (8.3%) were mapped onto 244 pathways using the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway database. Among the unigenes, 10,053 sequences contained a unique simple sequence repeat (SSR), and 2,303 sequences contained more than one SSR together in the same expressed sequence tag (EST). A total of 13,134 EST-SSRs were identified as potential molecular markers, with mono nucleotide A/T repeats being the most abundant motif class and G/C repeats being rare. In this SSR analysis, we found five main repeat motifs: AG/CT (30.8%), GAA/TTC (12.6%), AAAT/ATTT (6.8%), AAAAT/ATTTT (6.2%) and AAAAAT/ATTTTT (1.9%). A total of 200 SSR loci were randomly selected for validation by PCR amplification as EST-SSR markers. Of these, 66 marker primer pairs produced reproducible amplicons that were polymorphic among 31 mung bean accessions selected from diverse geographical locations. The large number of SSR-containing sequences found in this study will be valuable for the construction of a high-resolution genetic linkage maps, association or comparative mapping and genetic analyses of various Vigna species. PMID- 25830702 TI - A comparison of health outcomes in older versus younger adults following a road traffic crash injury: a cohort study. AB - BACKGROUND: Given the aging demographics of most developed countries, understanding the public health impact of mild/moderate road traffic crash injuries in older adults is important. We aimed to determine whether health outcomes (pain severity and quality of life measures) over 24 months differ significantly between older (65+) and younger adults (18-64). METHODS: Prospective cohort study of 364, 284 and 252 participants with mild/moderate injury following a vehicle collision at baseline, 12 and 24 months, respectively. A telephone-administered questionnaire obtained information on socio-economic, pre- and post-injury psychological and heath characteristics. RESULTS: At baseline, there were 55 (15.1%) and 309 (84.9%) participants aged >=65 and 18-64 years, respectively. At 12- and 24-month follow-up, older compared to younger participants who had sustained a mild/moderate musculoskeletal injury had lower physical functioning (3.9-units lower Short Form-12 Physical Composite Score, multivariable-adjusted p = 0.03 at both examinations). After multivariable adjustment, older (n = 45) versus younger (n = 207) participants had lower self perceived health status (8.1-units lower European Quality of Life-5 Dimensions Visual Acuity Scale scores at 24 months, p = 0.03), 24 months later. CONCLUSIONS: Older compared to younger participants who sustained a mild/moderate injury following a road-traffic crash demonstrated poorer physical functioning and general health at 24 months. PMID- 25830703 TI - A novel LTE scheduling algorithm for green technology in smart grid. AB - Smart grid (SG) application is being used nowadays to meet the demand of increasing power consumption. SG application is considered as a perfect solution for combining renewable energy resources and electrical grid by means of creating a bidirectional communication channel between the two systems. In this paper, three SG applications applicable to renewable energy system, namely, distribution automation (DA), distributed energy system-storage (DER) and electrical vehicle (EV), are investigated in order to study their suitability in Long Term Evolution (LTE) network. To compensate the weakness in the existing scheduling algorithms, a novel bandwidth estimation and allocation technique and a new scheduling algorithm are proposed. The technique allocates available network resources based on application's priority, whereas the algorithm makes scheduling decision based on dynamic weighting factors of multi-criteria to satisfy the demands (delay, past average throughput and instantaneous transmission rate) of quality of service. Finally, the simulation results demonstrate that the proposed mechanism achieves higher throughput, lower delay and lower packet loss rate for DA and DER as well as provide a degree of service for EV. In terms of fairness, the proposed algorithm shows 3%, 7 % and 9% better performance compared to exponential rule (EXP-Rule), modified-largest weighted delay first (M-LWDF) and exponential/PF (EXP/PF), respectively. PMID- 25830704 TI - Brown Adipose Tissue Transplantation Reverses Obesity in Ob/Ob Mice. AB - Increasing evidence indicates that brown adipose tissue (BAT) transplantation enhances whole-body energy metabolism in a mouse model of diet-induced obesity. However, it remains unclear whether BAT also has such beneficial effects on genetically obese mice. To address this issue, we transplanted BAT from C57/BL6 mice into the dorsal subcutaneous region of age- and sex-matched leptin deficient Ob/Ob mice. Interestingly, BAT transplantation led to a significant reduction of body weight gain with increased oxygen consumption and decreased total body fat mass, resulting in improvement of insulin resistance and liver steatosis. In addition, BAT transplantation increased the level of circulating adiponectin, whereas it reduced the levels of circulating free T3 and T4, which regulate thyroid hormone sensitivity in peripheral tissues. BAT transplantation also increased beta3-adrenergic receptor and fatty acid oxidation related gene expression in subcutaneous and epididymal (EP) white adipose tissue. Accordingly, BAT transplantation increased whole-body thermogenesis. Taken together our results demonstrate that BAT transplantation may reduce obesity and its related diseases by activating endogenous BAT. PMID- 25830705 TI - Bisphenol-A treatment during pregnancy in mice: a new window of susceptibility for the development of diabetes in mothers later in life. AB - Evidence now exists supporting the hypothesis that endocrine-disrupting chemicals (EDCs) can harmfully impact glucose metabolism. Thus, EDCs are beginning to be considered important contributors to the increased incidence of diabetes, obesity, or both. The possible effect of exposure to EDCs during pregnancy on glucose homeostasis in mothers later in life is presently unknown. Here we show that several months after delivery, mothers treated with the widespread EDC bisphenol-A (BPA) during gestation, at environmentally relevant doses, exhibit profound glucose intolerance and altered insulin sensitivity as well as increased body weight. These mice presented a decreased insulin secretion both in vivo and in vitro together with reduced pancreatic beta-cell mass. The proliferation capacity was decreased in association with a diminished expression of the cell cycle activators: cyclin D2 and cyclin-dependent kinase-4. In addition, the rate of beta-cells apoptosis was increased as well as the expression of the cell cycle inhibitors p16 and p53. Conversely, no effects on glucose metabolism or insulin sensitivity were observed when female nonpregnant mice were treated with BPA at the same doses. Taken together, these findings reveal that BPA exposure during gestation has harmful long-term implications in glucose metabolism for the mother. This finding highlights a new window of susceptibility for EDC exposure that may be important for the development of type 2 diabetes. PMID- 25830706 TI - Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels. AB - Somatostatin (SST) and cortistatin (CORT) are two highly related neuropeptides involved in the regulation of various endocrine secretions. In particular, SST and CORT are two primary negative regulators of GH secretion. Consequently, single SST or CORT knockout mice exhibit elevated GH levels; however, this does not lead to increased IGF-1 levels or somatic growth. This apparent lack of correspondence has been suggested to result from compensatory mechanisms between both peptides. To test this hypothesis, in this study we explored, for the first time, the consequences of simultaneously deleting endogenous SST and CORT by generating a double SST/CORT knockout mouse model and exploring its endocrine and metabolic phenotype. Our results demonstrate that simultaneous deletion of SST and CORT induced a drastic elevation of endogenous GH levels, which, surprisingly, did not lead to changes in growth rate or IGF-1 levels, suggesting the existence of additional factors/systems that, in the absence of endogenous SST and CORT, could counteract GH actions. Notably, elevation in circulating GH levels were not accompanied by changes in pituitary GH expression or by alterations in the expression of its main regulators (GHRH and ghrelin) or their receptors (GHRH receptor, GHS receptor, or SST/CORT receptors) at the hypothalamic or pituitary level. However, although double-SST/CORT knockout male mice exhibited normal glucose and insulin levels, they had improved insulin sensitivity compared with the control mice. Therefore, these results suggest the existence of an intricate interplay among the known (SST/CORT), and likely unknown, inhibitory components of the GH/IGF-1 axis to regulate somatic growth and glucose/insulin homeostasis. PMID- 25830707 TI - The clinical significance of endometrial fluid collection in asymptomatic postmenopausal women. AB - OBJECTIVE: This study assessed the clinical significance of endometrial fluid collection (EFC) in asymptomatic postmenopausal women. MATERIALS AND METHODS: A total of 564 postmenopausal females were enrolled into this retrospective study, of whom 141, with EFC, comprised the study group; the remaining 423 postmenopausal women (the three consecutive patients) who had been admitted to the menopause outpatient clinic for their routine annual check formed the control group. Data, including age, gravidity, parity, body mass index, hypertension, diabetes mellitus, menopause duration, endometrial thickness and histopathological endometrium results, were compared between groups using the SPSS for Windows software package (version 15.0; SPSS Inc., Chicago, IL, USA). RESULTS: There were no significant group differences in gravidity, parity, body mass index, rates of hypertension and diabetes mellitus, endometrial thickness or histopathological endometrium results. However, there were group differences in age (62.0 +/- 7.6 vs. 57.2 +/- 8.9 years, p < 0.001) and menopause duration (13.4 +/- 7.8 vs. 7.9 +/- 5.4 years, p < 0.001). CONCLUSION: The results indicate that EFC in asymptomatic postmenopausal women is a benign condition, influenced by older age and commensurately longer menopause duration due to a lack of hormonal stimulation. The presence of EFC by itself does not affect the decision to provide further evaluation; that is determined by the presence of confirmed risk factors (e.g. thickened endometrial stripe). However, further studies are needed to assess any long-term prognostic impact of this finding. PMID- 25830708 TI - Susceptibility of Ialpha- and Ibeta-Dominated Cellulose to TEMPO-Mediated Oxidation. AB - The susceptibility of Ialpha- and Ibeta-dominated cellulose to TEMPO-mediated oxidation was studied in this work since the cellulose Ialpha-allomorph is generally considered to be thermodynamically less stable and therefore more reactive than the cellulose Ibeta-allomorph. Highly crystalline Cladophora nanocellulose, which is dominated by the Ialpha-allomorph, was oxidized to various degrees with TEMPO oxidant via bulk electrolysis in the absence of co oxidants. Further, the Cladophora nanocellulose was thermally annealed in glycerol to produce its Ibeta-dominated form and then oxidized. The produced materials were subsequently studied using FTIR, CP/MAS (13)C NMR, XRD, and SEM. The solid-state analyses confirmed that the annealed Cladophora cellulose was successfully transformed from an Ialpha- to an Ibeta-dominated form. The results of the analyses of pristine and annealed TEMPO-oxidized samples suggest that Ialpha- and Ibeta-dominated cellulose do not differ in susceptibility to TEMPO oxidation. This work hence suggests that cellulose from different sources are not expected to differ in susceptibility to the oxidation due to differences in allomorph composition. PMID- 25830709 TI - Maximum principal strain as a criterion for prediction of orthodontic mini implants failure in subject-specific finite element models. AB - OBJECTIVE: To investigate the most reliable stress or strain parameters in subject-specific finite element (FE) models to predict success or failure of orthodontic mini-implants (OMIs). MATERIALS AND METHODS: Subject-specific FE analysis was applied to 28 OMIs used for anchorage. Each model was developed using two computed tomography data sets, the first taken before OMI placement and the second taken immediately after placement. Of the 28 OMIs, 6 failed during the first 5 months, and 22 were successful. The bone compartment was divided into four zones in the FE models, and peak stress and strain parameters were calculated for each. Logistic regression of the failure (vs success) of OMIs on the stress and strain parameters in the models was conducted to verify the ability of these parameters to predict OMI failure. RESULTS: Failure was significantly dependent on principal strain parameters rather than stress parameters. Peak maximum principal strain in the bone 0.5 to 1 mm from the OMI surface was the best predictor of failure (R(2) = 0.8151). CONCLUSIONS: We propose the use of the maximum principal strain as a criterion for predicting OMI failure in FE models. PMID- 25830710 TI - The effect of corticision on root resorption with heavy and light forces. AB - OBJECTIVE: To investigate the association between corticision and different force magnitudes with the amount of root resorption. METHODS: Forty-four male Wistar rats (7 week old) were evaluated after an orthodontic spring delivering either 10 or 100 g was placed on the left maxillary first molars to move molars mesially. Experimental rats were divided into four groups, with 11 animals in each group: (1) LF, no corticision and 10 g of orthodontic force; (2) LFC, corticision and 10 g of force; (3) HF, no corticision and 100 g of force; and (4) HFC, corticision and 100 g of force. Contralateral sides were used as unloaded controls. The total duration of the experimental period was 14 days. Two-dimensional (histomorphometric) and three-dimensional (volumetric, micro-focus X-ray computed tomography [microCT]) analysis of root craters were performed on maxillary first molars. RESULTS: Histomorphometric and microCT analysis revealed a significant amount of resorptive areas in the experimental groups when compared to unloaded controls. However, no significant difference was detected in the amount of resorption among the four experimental groups. CONCLUSIONS: At day 14, neither the amount of force nor the cortical incision caused significant effect on root resorption that was registered by histomorphometric or microCT analysis. PMID- 25830711 TI - Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review. AB - BACKGROUND: Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate. OBJECTIVE: To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury. METHODS: A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informacao em Ciencias da Saude, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies. RESULTS: The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review. CONCLUSION: On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions. PMID- 25830712 TI - 4-Second Exercise Test: Reference Values for Ages 18-81 Years. AB - BACKGROUND: Physiological reflexes modulated primarily by the vagus nerve allow the heart to decelerate and accelerate rapidly after a deep inspiration followed by rapid movement of the limbs. This is the physiological and pharmacologically validated basis for the 4-s exercise test (4sET) used to assess the vagal modulation of cardiac chronotropism. OBJECTIVE: To present reference data for 4sET in healthy adults. METHODS: After applying strict clinical inclusion/exclusion criteria, 1,605 healthy adults (61% men) aged between 18 and 81 years subjected to 4sET were evaluated between 1994 and 2014. Using 4sET, the cardiac vagal index (CVI) was obtained by calculating the ratio between the duration of two RR intervals in the electrocardiogram: 1) after a 4-s rapid and deep breath and immediately before pedaling and 2) at the end of a rapid and resistance-free 4-s pedaling exercise. RESULTS: CVI varied inversely with age (r = -0.33, p < 0.01), and the intercepts and slopes of the linear regressions between CVI and age were similar for men and women (p > 0.05). Considering the heteroscedasticity and the asymmetry of the distribution of the CVI values according to age, we chose to express the reference values in percentiles for eight age groups (years): 18-30, 31-40, 41-45, 46-50, 51-55, 56-60, 61-65, and 66+, obtaining progressively lower median CVI values ranging from 1.63 to 1.24. CONCLUSION: The availability of CVI percentiles for different age groups should promote the clinical use of 4sET, which is a simple and safe procedure for the evaluation of vagal modulation of cardiac chronotropism. PMID- 25830714 TI - Different heavy metals have various effects on Picea wilsonii pollen germination and tube growth. AB - Heavy metal pollution has became one of the realistic matters of globality. Previous reports indicated that heavy metals could significantly inhibit pollen germination and tube growth. In the present study, comparative studies on the effects of different heavy metals (As, Hg, Cd, Cr and Cu) on in-vitro picea wilsonii pollen germination and tube growth were carried out. Microscopic evaluation revealed that different heavy metals had various degree of toxicity on P. wilsonii pollen tube development. As showed the most toxic effects on pollen germination, which was followed by Hg and Cd, while Cr and Cu showed relatively lower toxicity. Besides, pollen tubes showed varying shapes in response to different heavy metal stress. Pollen tubes treated with Cd, Hg and As were usually characterized by irregularly increasing diameters and swelling tips with distinct cytoplasimic vacuolation. On the other hand, except for the slightly increased diameters, no obvious abnormal shape were observed in tubes treated with Cr or Cu. Lyso-Tracker Green staining indicated that only Cd-treated pollen tubes showed numerous vacuole-like acidic organelles, though cytoplasmic vacuolization were also observed in pollen tubes treated with Hg and A. In brief, our data indicated that different heavy metals have various effects on Picea wilsonii pollen germination and tube growth, and that in-vitro pollen culture might be used as a competent system for biomonitoring of air pollution. PMID- 25830715 TI - Polymer Brushes under Shear: Molecular Dynamics Simulations Compared to Experiments. AB - Surfaces coated with polymer brushes in a good solvent are known to exhibit excellent tribological properties. We have performed coarse-grained equilibrium and nonequilibrium molecular dynamics (MD) simulations to investigate dextran polymer brushes in an aqueous environment in molecular detail. In a first step, we determined simulation parameters and units by matching experimental results for a single dextran chain. Analyzing this model when applied to a multichain system, density profiles of end-tethered polymer brushes obtained from equilibrium MD simulations compare very well with expectations based on self consistent field theory. Simulation results were further validated against and correlated with available experimental results. The simulated compression curves (normal force as a function of surface separation) compare successfully with results obtained with a surface forces apparatus. Shear stress (friction) obtained via nonequilibrium MD is contrasted with nanoscale friction studies employing colloidal-probe lateral force microscopy. We find good agreement in the hydrodynamic regime and explain the observed leveling-off of the friction forces in the boundary regime by means of an effective polymer-wall attraction. PMID- 25830716 TI - Perchlorate: water and infant formulae contamination in France and risk assessment in infants. AB - Perchlorate ions ClO4(-), known to inhibit competitively the uptake of iodine by the thyroid, have been detected in drinking water in France as well as in infant formulae. A tolerable daily intake (TDI) has been established at 0.7 ug kg(-1) bw day(-1) based on the inhibition of iodine uptake. Due to this mechanism of action, the iodine status could strongly influence the biological effect of perchlorate. Perchlorate concentrations in water and infant formulae were measured and the exposure of children under 6 months of age calculated. It appeared that the TDI could be exceeded in some children. As the iodine status is not optimal within the entire French population, there appears to be a need to clarify the sources of perchlorate ultimately to decrease exposure. PMID- 25830717 TI - PET-MRI: clinical application of the new hybrid technology. AB - There is huge emphasis on noninvasive study of disease processes in the field of biomedical research. Combined PET-MRI allows simultaneous acquisition of physiologic information provided by PET images and morphologic and functional information obtained from MRI. The potential clinical and research applications of this technique in different organ systems and pathologies are promising (i.e. brain, cardiovascular, oncological, and inflammatory conditions). The purpose of this review is to illustrate the potential clinical advantages of this new technology, based on the authors' experience. PMID- 25830718 TI - Myxoid onychomatricoma: an unusual variant of a rare nail unit tumor. AB - A 57-year-old woman presented with a 3-year history of a thickened, yellowed, over-curved nail plate of the left second toe. The proximal nail fold had an associated nodule. When observed head-on, the distal nail plate demonstrated multiple circular perforations. Avulsion of the nail plate revealed a 0.7 cm pale white mass within the proximal nail matrix, which was excised. Histologic sections of the nail plate showed longitudinal cystic spaces associated with papillary projections of nail matrix epithelium. The parenchyma of the lesion demonstrated bland-appearing spindled cells in a prominent myxoid stroma with abundant mast cells. The spindled cells were focally positive for CD34 and factor XIIIa and negative for S100, pan-cytokeratin, desmin, smooth muscle actin, epithelial membrane antigen, and MART-1. Onychomatricoma (OM) is a rare nail unit biphasic fibroepithelial tumor with multiple radiating digitations lined by papillomatous matrix epithelium. The epithelial component is consisted of matrix cells that generate the thickened nail plate, and the digitations cause characteristic "wormwood" perforations of the nail plate. A fibrous stroma is characteristic with staining positive for CD34 and negative for CD99, epithelial membrane antigen, and S100. This case is unique with the presence of a prominent myxoid stroma associated with the fibrous component of the OM. Only 1 previous report of OM highlights a related finding of a myxocollagenous stroma. This purely myxoid variant represents a new distinct form of OM. Clinicopathologic correlation is essential to avoid confusion with other myxoid tumors such as a superficial acral myxoma, superficial angiomyxoma, or a digital myxoid cyst. PMID- 25830719 TI - Sebocyte-like cell primary cutaneous melanoma: a rare cytologic variant of malignant melanoma. AB - Although rising incidence rates of cutaneous melanoma have been observed during the last 4 decades in white populations worldwide, the sebocyte-like cell variant has been described only twice in the literature to date. In our case, a 64-year old man presented for evaluation of a changing pigmented lesion on the left upper back. Excision of the lesion revealed an invasive melanoma with a Breslow depth of 3.3 mm. Microscopic sections showed a predominantly dermal-based tumor composed of sheets and nests of enlarged epithelioid melanocytes, most of which showed an uncommon phenotype with multivacuolated cytoplasms and scalloped nuclei, features that gave them a strong resemblance to mature sebocytes. The lesional cells expressed S100 protein, Melan-A, and p16, whereas adipophilin was positive only within the sebocyte-like component of the neoplasm and showed focal nonspecific staining. The patient's sentinel lymph node biopsy was positive for micrometastases, although a subsequent position emission tomography scan was unremarkable. Sebocyte-like melanocytes are a rare distinctive type of melanocytes that can be found mostly in benign but also in malignant melanocytic lesions. They usually present focally within the lesions and, therefore, do not represent a diagnostic problem in nevus or primary cutaneous melanoma. However, when sebocyte-like melanocytes are the main cellular component of a melanocytic lesion or when they are found in the context of metastatic melanoma, they may create a potential diagnostic pitfall; for this reason, awareness of this cell type is important. PMID- 25830720 TI - Spiradenocarcinoma in Preexisting Spiradenoma With a Large In Situ Adenocarcinoma Component. AB - Spiradenocarcinoma is a very rare malignant tumor. In situ adenocarcinoma has recently been observed and defined by the preservation of a peripheral myoepithelial cell layer. The pathway for this phenomenon has been hypothesized to involve a sequence of adenomatous changes followed by atypical adenomatous changes, adenocarcinoma in situ, and invasive adenocarcinoma. However, there are no clearly defined morphological distinctions between atypical adenomatous changes and adenocarcinoma in situ. The authors present a case of spiradenocarcinoma in a preexisting spiradenoma in the left inguinal area of a 71 year-old woman. Adenomatous changes, atypical adenomatous changes, adenocarcinoma in situ, and invasive adenocarcinoma were found within the same lesion. The majority of the malignant component was an in situ adenocarcinoma. Although a loss of the myoepithelial cell layer and coalescing, irregular, glandular nests were present in several discrete foci, this case did not show infiltrative growth beyond the fibrous connective tissue. The authors speculate that this case represents a very early invasive spiradenocarcinoma lesion. We present this case to discuss the histological and/or immunohistochemical criteria of atypical adenomatous changes and to discuss the optimal treatment in cases with a disparity between the preservation of the whole architecture and the loss of the myoepithelial cell layer, which may be associated with favorable biological behavior. PMID- 25830721 TI - Chromoblastomycosis in a Diabetic Patient Without a History of Trauma. AB - Chromoblastomycosis (CBM) is a slowly progressive cutaneous and subcutaneous mycosis mostly seen in tropical and subtropical areas and Fonsecaea pedrosoi is the most common cause. The authors describe the case of a diabetic Haitian woman, presenting with a chronic verrucous plaque without any history of trauma. Her histopathologic results showed epidermal hyperplasia and sclerotic bodies, which are diagnostic for CBM. Her therapy began with itraconazole 200 mg tablets twice a day. The unique feature of this patient is the coincidence of diabetes and CBM. However, to the best of our knowledge, this is the first documented case of human CBM in Miami, FL, which develops the awareness regarding this diagnosis among doctors in this area. There should be a close communication between dermatologists and pathologists to make an early diagnosis of CBM and also adequate therapy, which both are fundamental to improve patient's quality of life. PMID- 25830722 TI - Interstitial Granulomatous Dermatitis: A Clinicopathological Study. AB - INTRODUCTION: Interstitial granulomatous dermatitis (IGD) is an uncommon granulomatous dermatitis occurring in the setting of highly reactive immune states, with a polymorphic clinical presentation. Because there is overlap with other entities [namely palisading neutrophilic granulomatous dermatitis (PNGD)], controversy exists regarding its classification. OBJECTIVE: To understand if there are features allowing clear-cut distinction between IGD and PNGD. MATERIAL AND METHODS: Retrospective analysis of 10 cases previously diagnosed as IGD or PNGD, from 2000 to 2013, with review of the histopathologic findings and clinical correlation. RESULTS: Six females and 4 males presented mostly with erythematous papules/nodules (n = 7) but also with erythematous annular plaques (n = 3). In 2 patients, the lesions coexisted. They were mostly distributed symmetrically on the limbs. Associated disease was observed in 6 patients. Regarding histopathology, an inflammatory infiltrate occupying the superficial and mid dermis was present in 40% of cases, with an interstitial component in all biopsies and a palisaded arrangement in 60%. Neutrophils and mononuclear cells were present in all cases in varying proportions. Necrobiosis was found in 70%, and leukocytoclasia was observed in 80% of biopsies. CONCLUSIONS: Coexistence of the interstitial and palisaded inflammatory patterns occurred in 90% of cases, with no correlation between tissue neutrophilia and the predominant pattern of the infiltrate. There was also no clear-cut correlation between the infiltrate pattern and semiologic aspect of the lesions. Therefore, the features described in our study suggest that IGD and PNGD belong to the same clinicopathological spectrum. PMID- 25830723 TI - Sigmund Freud and Moritz Kaposi: A Resurfaced Collision. PMID- 25830724 TI - Application of Ionic Liquids in Amperometric Gas Sensors. AB - This article presents an analysis of available literature data on metrological parameters of the amperometric gas sensors containing ionic liquids as an electrolyte. Four mechanism types of signal generation in amperometric sensors with ionic liquid are described. Moreover, this article describes the influence of selected physico-chemical properties of the ionic liquids on the metrological parameters of these sensors. Some metrological parameters are also compared for amperometric sensors with GDE and SPE electrodes and with ionic liquids for selected analytes. PMID- 25830726 TI - Low prevalence of rmpA and high tendency of rmpA mutation correspond to low virulence of extended spectrum beta-lactamase-producing Klebsiella pneumoniae isolates. AB - Invasive syndrome caused by Klebsiella pneumoniae (KP), including liver abscess, is mainly caused by community-acquired strains with characteristics of positive hypermucoviscosity (HV) phenotype and regulator of mucoid phenotype A (rmpA) and transcriptional activator (rmpA2) genes. Extended- spectrum beta-lactamase producing KP (ESBL-KP) is commonly nosocomial and rarely HV-positive. We aimed to explore the reasons of the rarer prevalence of HV phenotype, rmpA and rmpA2 as well as the virulence phenotype among the ESBL-KP isolates from clinical specimens than those non-ESBL isolates. The beta-lactamase genes, rmpA, rmpA2 and genes for K capsule serotype of 440 KP isolates were analyzed. The virulence of the isolates was characterized by the mouse lethality experiments. The prevalence rates of HV phenotype (~ 50% vs. < 10%) as well as rmpA and rmpA2 genes (~ 50-60% vs. < 20-30%) were significantly higher in non-ESBL group than in the ESBL group (p < 0.0001). Expression of HV phenotype in the rmpA-positive KP isolates was significantly rarer in the ESBL group than in non-ESBL group (33.3% vs. 91.9%, p < 0.0001). The frameshift mutations of rmpA and/or rmpA2 corresponded to negative HV phenotype of KP isolates that harbored the rmpA and/or rmpA2, resulting in variable mouse lethality (LD50, ~ 10(3) - >5 * 10(7) CFU). The mutation rates might significantly differ among KP isolates from various sources. Virulence was dependent on rmpA-related HV phenotype. In conclusion, ESBL-KP isolates were less hypermucoviscous and less virulent than non-ESBL KP isolates, mostly due to concurrently lower carriage and higher mutation rates of the rmpA and rmpA2 genes. PMID- 25830725 TI - Prolonged re-expression of the hypermethylated gene EPB41L3 using artificial transcription factors and epigenetic drugs. AB - Epigenetic silencing of tumor suppressor genes (TSGs) is considered a significant event in the progression of cancer. For example, EPB41L3, a potential biomarker in cervical cancer, is often silenced by cancer-specific promoter methylation. Artificial transcription factors (ATFs) are unique tools to re-express such silenced TSGs to functional levels; however, the induced effects are considered transient. Here, we aimed to improve the efficiency and sustainability of gene re expression using engineered zinc fingers fused to VP64 (ZF-ATFs) or DNA methylation modifiers (ZF-Tet2 or ZF-TDG) and/or by co-treatment with epigenetic drugs [5-aza-2'-deoxycytidine or Trichostatin A (TSA)]. The EPB41L3-ZF effectively bound its methylated endogenous locus, as also confirmed by ChIP-seq. ZF-ATFs reactivated the epigenetically silenced target gene EPB41L3 (~ 10-fold) in breast, ovarian, and cervical cancer cell lines. Prolonged high levels of EPB41L3 (~ 150-fold) induction could be achieved by short-term co-treatment with epigenetic drugs. Interestingly, for otherwise ineffective ZF-Tet2 or ZF-TDG treatments, TSA facilitated re-expression of EPB41L3 up to twofold. ATF-mediated re-expression demonstrated a tumor suppressive role for EPB41L3 in cervical cancer cell lines. In conclusion, epigenetic reprogramming provides a novel way to improve sustainability of re-expression of epigenetically silenced promoters. PMID- 25830727 TI - Dust emissions from cattle feed yards: a source of antibiotic resistance? PMID- 25830728 TI - Consolidacao e fortalecimento dos estudos qualitativos nas diversas vertentes da area de saude. PMID- 25830729 TI - Spectra of mothers of premature children about the educative circle of culture. AB - We sought to know the spectra of mothers of premature children regarding their experience with circle of culture of educational character and identifying the learning provided by the circle of culture about newborn care after hospital discharge. A descriptive study was performed in a hospital located in Fortaleza, Brazil. Three meetings of a circle of culture with 17 mothers of premature newborns were performed. The interpretation of the corpus was performed using thematic analysis. Emerged from the categories: Maternal experience in a circle of culture; Promoted social support among mothers through the circle of culture; and Learning provided by the circle of culture. It was concluded that teaching parents during the hospitalization of the child should be held in a way to involve parents in the care of the newborn, provide moments of health education, opportunities for support and dialogue between professionals and family. PMID- 25830730 TI - Health care to immigrant and Portuguese pregnant women in Portugal. AB - This study aimed to assess the care received and the barriers faced by immigrants and Portuguese pregnant women in Portugal. This is an exploratory qualitative study, resorting to applying semi-structured interviews to 60 immigrant and 22 Portuguese women. Content analysis supported by QSR Nvivo10 program was used. The study was approved by an Ethics Committee. The results showed four categories related to affective dimensions-relational, cognitive, technical-instrumental and health care policy for pregnant women. As for the barriers in health care, these were mentioned by some of the expectant mothers, especially immigrant women. Almost all, both immigrant and Portuguese, pregnant women were satisfied with the health care. PMID- 25830731 TI - Pregnancy and childbirth: What changes in the lifestyle of women who become mothers? AB - Pregnancy is a period influenced by the interaction of several factors, therefore this study aimed to identify changes in lifestyles due to pregnancy and childbirth in Portuguese and immigrant women in Portugal. This is a qualitative study, using the semi-structured interview, with eighty-two Portuguese and immigrant women. Content analysis was used, with verbatim classification supported by Nvivo 10. It was authorized by an Ethics Commission. Results revealed that the primary changes in lifestyles due to pregnancy were in eating habits (nutrition), daily activity, exposure to danger, sleep and rest patterns, social and family relationships, going out, self-care, work, clothing and footwear, travel, health monitoring and sexual activity and substances consumption. The main change after the birth, manifested by these women, was that their lives began to revolve around their baby. PMID- 25830732 TI - BETWEEN DREAMS AND REALITY: Migration of Brazilian women to Switzerland. AB - The general objective of this article was to study the process of illegal migration of Brazilian women to Switzerland and, more specifically, to analyze the motivations for migration, the difficulties found upon arrival, the circumstances that led them to get married and lastly an evaluation of the whole experience. The methodology was based in a qualitative approach. The participants were eight Brazilian women that illegally migrated to Switzerland but now are married with Swiss or European men. They responded to an interview focused in the objectives of the study. The appreciation of the data was realized with Minayo's Content Analysis. The motivations were related to a bettering of the financial situation. In the difficulties encountered, we can bring out illegality, language and prejudice. Regarding marriage, they married to stay legally in the country. Finally, the evaluation of the experience was negative for most participants. PMID- 25830733 TI - Violence as a research object and intervention in the health field: an analysis from the production of the Research Group on Gender, Health and Nursingi. AB - The study aimed to describe how violence is revealed in the production of the Research Group on Gender, Health and Nursing. This is a historical research of qualitative approach, which evaluated the production of the Research Group, through content analysis. The results show gender as a central category in determining violence and health practices. This aspect determines limitations on professional practices of coping, such as the invisibility of the problem. The female autonomy, the use of alcohol and drugs and social vulnerability play an important relation with the phenomenon and the bond is revealed as potentiality of health practices to address the problem. CONCLUSION: The gender perspective in nursing research is an innovative field and counter-hegemonic, a possibility to assume a meaning of praxis by transforming potential of understanding and modes of intervention in the phenomenon of gender violence. PMID- 25830734 TI - Understanding the experiences of caregivers of children with tuberculosis in directly observed therapy. AB - Objective To understand the situations and communications experienced by caregivers of children with tuberculosis (TB) with regard to directly observed therapy (DOT). Method A descriptive exploratory study with a qualitative approach was applied and developed in the ambulatory of Programa Einstein na Comunidade de Paraisopolis (PECP). The data were collected using semi-structured interviews of 13 caregivers of children with TB in DOT. The Collective Subject Discourse (CSD) method was used to analyze the data. Results Seven CSDs were identified and grouped into four categories: "Living in a difficult situation", "Changing the family routine", "Responsibility almost always fall son the mother", and "Adapting to the DOT". Conclusions The difficulties faced by the caregiver of the child at the beginning of DOT significantly changed the familiar routine. The responsibility for its continuity was assigned to the mother, who must adapt to the demands of the treatment and face the situation. PMID- 25830735 TI - In the context of a daycare center: nursing and their representations of child care as an educational act. AB - This study aimed to analyze the social representations in the professionals of technical staff, who work with children at USP daycare centers. Eight professionals of the nursing field underwent a semi-structured interview. The interviews were recorded and transcribed in their entirety and the content of the discourse was subjected to thematic-categorical analysis. The categories were transformed into variables and processed by the software Classification Hierarchique Classificatoire et Cohesitive (CHIC(r)) and analyzed by the hierarchical similarity tree. The results indicate that actions to promote health are reported as educational and transformative, in which health care gains new meaning through contextualized conceptions in the field of child education. We conclude that professionals attribute new meanings to their practices in the health care environment of daycare centers as their representations shifts from the logic of the biomedical field to a logic of educational care. In this sense, they perceive themselves as being challenged to establish an interaction with the children in terms of their activities related to the promotion of health and in an educational act. PMID- 25830736 TI - Cumulative Vulnerability: A Case Study on intrafamilial violence, Drug Addiction and Adolescent Pregnancy. AB - A pregnant adolescent's vulnerability increases when she is a victim of intrafamilial violence and drug addiction, which cause physical and biopsychosocial damage to the mother and her baby. Objective Present and analyze the case of an adolescent who is addicted to drugs, pregnant and the victim of lifelong intrafamilial violence. Method A case study based on a semi-structured interview conducted in the Obstetrics Emergency Unit at the Teaching Hospital of the University of Sao Paulo. The data were interpreted and analyzed using Content Analysis. Results intrafamilial violence experienced at the beginning of the adolescent's early relationships seriously affected her emotional maturity, triggering the development of psychopathologies and leaving her more susceptible to the use and abuse of alcohol and other drugs. The adolescent is repeating her history with her daughter, reproducing the cycle of violence. Conclusion Adolescent pregnancy combined with intrafamilial violence and drug addiction and multiplies the adolescent's psychosocial vulnerability increased the adolescent's vulnerability. PMID- 25830737 TI - Supplemental nursing staff's experiences at a Spanish hospital: Qualitative phenomenology research. AB - The objective of this study was to describe the Supplemental Nursing Staff's experiences at different hospital units. A qualitative phenomenological approach was conducted; a purposeful and theoretical sampling was implemented with supplemental nursing staff at Santa Barbara Hospital of Soria (Spain), to gain a more in-depth understanding of the Supplemental Nursing Staff 's experience. Data were collected by in-depth interviews and through a field notebook. Data were analyzed using the Giorgi proposal. Twenty-one nurses with a mean age of 46 years were included. Three main topics emerged from the data analysis: building the first contact, carving out a niche and establishing interprofessional/interpersonal relationships. We conclude that the experience of hosting the supplemental nursing staff in changing clinical environments is conditioned by various factors. It is necessary for nurses and hospital managers to establish clear objectives with regard to the supplemental nursing staff's role in the units. PMID- 25830738 TI - Primary Care Sensitive Hospitalization: users detect flaws on the access to services. AB - The aim of this study is to analyze and understand the reasons for the occurrence of sensitive hospitalizations in accordance with users. Qualitative study conducted with users who were admitted to Pedreira General Hospital, in Sao Paulo. The data was collected through semi structured interviews and thereafter, transcribed and processed in the electronic program Alceste. When analyzing the content, the access was seized fundamentally as an empirical category, bringing up problems that later deserved, from the Brazilian Ministry of Health, a specific Program to improve the quality and access to primary care. The hierarchical and pyramidal organization shape from the health system in the city of Sao Paulo can be one of the important aspects for the access matter and established as an important restricting factor in the primary care role in reducing or even preventing the occurrence of these hospitalizations. PMID- 25830739 TI - Distinct temporalities in the breast cancer disease process. AB - Comprehensive approach study aimed understanding the reflections and contrasts between personal time and medical therapy protocol time in the life of a young woman with breast cancer. Addressed as a situational study and grounded in Beth's life story about getting sick and dying of cancer at age 34, the study's data collection process employed interviews, observation and medical record analysis. The construction of the analytic-synthetic box based on the chronology of Beth's clinical progression, treatment phases and temporal perception of occurrences enabled us to point out a linear medical therapy protocol time identified by the diagnosis and treatment sequencing process. On the other hand, Beth's experienced time was marked by simultaneous and non-linear events that generated suffering resulting from the disease. Such comprehension highlights the need for healthcare professionals to take into account the time experienced by the patient, thus providing an indispensable cancer therapeutic protocol with a personal character. PMID- 25830740 TI - Perceptions and experiences of elderly residents in a nursing home. AB - The objective of this study was to evaluate the perception of the elderly residents of a long-stay nursing home on the process of institutionalization. We interviewed 14 subjects, five women and nine men, aged between 60 and 92 years. Data collection was conducted with a semi-structured sociodemographic interview, which presented the guiding question: "Tell me about how is your life, what do you do and how did you come to live here". From the analysis, we found topics related to feelings of abandonment, loneliness, anger, ingratitude, living with chronic pain, satisfaction of property in the nursing home, productivity and social relationship. Given the thematic analysis, it was possible to group them into three categories such as: what the elderly feel, what the elderly perceive and what the elderly desire. As a result, we need public policies that addresses to the service provided by institutions regarding elderly expectations. PMID- 25830741 TI - Chronic disease in the elderly: spirituality and coping. AB - This is an exploratory study using a qualitative methodology which aimed to identify and understand the role of spirituality in the management of chronic disease in the elderly. The discourse analysis revealed the following central themes: multidimensional impact of chronic diseases, coping and expectations of the elderly. Regarding coping with chronic diseases, the individual coping, social support and religiosity/spirituality/faith were analyzed. The results showed the changes brought about the diagnosis of chronic disease and its implications for the adaptation to the new way of life. The management of these changes is complex and many factors influence positively and negatively in order to deal with the new condition. The results showed that spirituality/religiosity /faith interfere positively in addressing the barriers and difficulties of life, strengthening the resilience of the patient, thus improving their quality of life. PMID- 25830742 TI - Perceptions of representatives of a committee against dengue in the health education actions, Goias, Brazil. AB - This study aimed to analyze how the educational actions of prevention and control of dengue are performed in Goias, from the perspective of representatives of the State Mobilization Committee against Dengue. It is a cross-sectional descriptive analytical study, carried out in Goiania with 43 representatives of public private institutions, members of the State Mobilization Committee against Dengue of Goias, in 2013. The data collection was done through questioning about the perception of health education for dengue prevention. Data were analyzed using content analysis and the WebQDA software. Three dimensions emerged from the analysis: educational aspects, management aspects, and community involvement. Respondents recognized the importance of health education for the prevention of dengue, and of the planning to strengthen the activities of the Committee. PMID- 25830743 TI - Modes of acquisition of health literacy skills in informal learning contexts. AB - In this article we try to analyze the learning processes of health literacy skills in informal contexts. We intend to broaden the understanding of the learning process beyond the formal contexts, thus contributing to the elucidation of health professionals on how individuals acquire and manage their knowledge in health matters. Given our goal, we use an analytic corpus constituted by one hundred autobiographical narratives written between 2006 and 2011, in educational contexts but with recognized potential for use in different scientific fields, including health. The results reveal the existence of three different types of modes of learning health literacy skills in informal context: : i) learning that takes place in action, in achieving daily tasks; ii) learning processes that result from problem solving; iii) learning that occurs in an unplanned manner, resulting from accidental circumstances and, in some cases, devoid of intentionality. PMID- 25830744 TI - Newspapers folha de sao paulo e correio braziliense: what they say about the program more doctors? AB - Analyzes publications related More Medical Program from July to September of 2013 and its impact on Correio Braziliense and Folha de Sao Paulo. This is a descriptive study using a qualitative-quantitative methodology. The analyzed and related data represent what the program takes in print. 363 publications were found, 262 in Folha de Sao Paulo and 101 in Correio. The word "Doctor" appeared in more titles, and Folha de Sao Paulo were 110 negative titles; to Correio neutral character was in 50 publications. In the character of news, 178 of these are pessimistic. The "neutral" and 101 representing "optimistic" 83. Was found that the media is critical to the impact of the program, but the truth is not apparent, but the opinion of journalists who wrote the stories related to the theme. PMID- 25830745 TI - Identity of care in a Psychosocial Care Center for Children and Adolescents who uses drugs. AB - Objective To associate the territory of identity with the production of care within a PCC focusing on children and adolescents with drug abuse and their institutional identity. Method We used the " process tracing methodology" in four research categories: focus groups, characterization of professionals, observing the everyday and interviewing two members of emblematic cases of the service. Results territory of identity of the institution, which operates the production of care is crossed by the difficulty of dealing with the complexity brought by the users and the performance of the PCC network. This paper is also permeated by different conceptions of care and small problematization of these issues in collective spaces of service. Conclusion The discussion in focus groups and other devices can be powerful resources to reframe the meaning of care and identity of collective service. PMID- 25830746 TI - Professional knowledge in primary health care of the person/family in mental distress: Le Boterf perspective. AB - Aim of this study was to identify knowing-doing actions constituted the practice of Family Health (FH), in view of nurses in relation to the person and family care in mental distress in terms of professional knowledge of Le Boterf. METHOD: Descriptive exploratory qualitative study, to deepen contruction of nurse in FH. The survey was conducted in 3 Units FH. RESULT: Doing a thematic analysis, came to the following categories: "Knowing how to act and react with relevance"; "Knowing how to combine resources and mobilize them in a professional context"; "Knowing how to interact with multiple knowledges"; "Knowing how to transpose"; "Knowing how to learn and knowing how to learn to learn"; "Knowing how to engage". FINAL CONSIDERATIONS: the greatest difficulty was "be able to transpose," and that the daily demand of the FH teams requires a lot of this knowledge. Little transposition of knowing-doing in real situations has been verified. PMID- 25830747 TI - Mental ill health in the elderly: medical students' social representations in the United Kingdom. AB - Objective This study aims to explore medical students' social representations of mental ill health in older adults. Method It comprises an exploratory and qualitative investigation based on the theory of social representations. Two focus groups with pre-clinical medics (group 1, N=4; group 2, N=4) and 10 individual interviews with clinical medical students were conducted. Thematic analysis at a latent level explored meanings and differences between groups. Results Three overarching themes reflect participants' representations of mental health problems in later life - mental ill health in old age, polarisation of care, and challenges to care. Primary health care appears as an important strategy to overcome barriers to mental health care in the community. Nevertheless, disqualifying representations, stigma and organization of services constitute the main challenges to quality mental health care in later life. Conclusion This paper highlights the need to address cultural and organizational barriers to promote quality care. PMID- 25830748 TI - Approach and treatment of suicidal behavior in the clinical practice of different groups of health professionals in Spain: results of the project euregena. AB - According to the WHO (World Health Organization) and the European Union, suicide is considered to be a health problem of prime importance and to be one of the principal causes of unnatural death. In Spain, the number of suicides has increased 12% since 2005 . The Research Project "European Regions Enforcing Actions against Suicide (EUREGENAS), funded by the Health Program 2008-2013, has as main objective the description of an integrated model of Mental Health orientated to the prevention of suicide. The differences that allow distinguishing the meaning of prevention in suicide behavior are described and explained through a qualitative methodological strategy and through the creation of discussion groups formed by different groups of health professionals. The results highlight the existing differences between the diverse health professionals who come more in contact with this problem and it shows as well the coincidence of meaning that suicide has to be considered as a priority in the field of health. PMID- 25830749 TI - Ethical dimension of circle Integrative Community Therapy on qualitative research. AB - This study discusses ethical issues in research involving human beings and seeks to understand the relationship between qualitative research and the ethical care guidelines for Integrative Community Therapy (ICT) circles based on Resolution 466/12 of the National Health Council of the Ministry of Health of Brazil. This is documentary research, which analyzed Resolution 466/12 and ICT circles seeking to make a connection between the ethical guidelines contained in both. The analysis of the corpus was directed toward the construction of the following results: the person's perception, cultural diversity and community. It also brings in consideration of the influence of the ethical dimension of the ICT circles on qualitative research. We conclude that ICT circles are innovative in the sense of the diversity of participants and respect for cultural and social differences. Thus, ICT circles promote acquisition of quality information for social research as well as compliance with the ethical guidelines outlined in Resolution No. 466/12. PMID- 25830750 TI - Nursing teaching strategies by encouraging students' questioning, argumentation and explanation. AB - Nursing students need to develop competences in the field of explanation, argumentation and questioning as they are pivotal to foster a relationship with their patients and achieve a greater humanisation of care. The objective of this paper is to analyse the perception of 1st-year nursing students with regard to the humanisation of care provided to patients by encouraging them to discuss real life episodes. The study is qualitative and content analysis used the students' questions, explanations and argumentation as core discourses. Among other conclusions, results point towards the importance of promoting activities that encourage the different nursing students' discourses and the ability to understand the humanisation and dehumanisation patterns arising from the real life episodes used as case study. PMID- 25830751 TI - The art and learning patterns of knowing in nursing. AB - Objective To identify the perception of the students about the use of art as a pedagogical strategy in learning the patterns of knowing in nursing; to identify the dimensions of each pattern valued in the analysis of pieces of art. Method Descriptive mixed study. Data collection used a questionnaire applied to 31 nursing students. Results In the analysis of the students' discourse, it was explicit that empirical knowledge includes scientific knowledge, tradition and nature of care. The aesthetic knowledge implies expressiveness, subjectivity and sensitivity. Self-knowledge, experience, reflective attitude and relationships with others are the subcategories of personal knowledge and the moral and ethics support ethical knowledge. Conclusion It is possible to learn patterns of knowledge through art, especially the aesthetic, ethical and personal. It is necessary to investigate further pedagogical strategies that contribute to the learning patterns of nursing knowledge. PMID- 25830752 TI - Nurse educators' perceptions of the way nursing students protect patient privacy. AB - The aim of this study was to assess the teaching-learning process related to patient privacy during the care process and the way nursing students' protect patient privacy. Descriptive/correlational study using a qualitative approach and nonprobability sampling of 19 nurse educators from two schools of nursing. Data was collected using semi-structured interviews. Data analysis was undertaken using the SPSS version 20 and Alceste 2010 programs. The study complied with ethical standards. Two classes were assigned (protection of patient privacy and care process) with four subcategories (protection, empathy, relational competencies and technoscientific competencies).The findings show the need to adopt a reflective approach to the teaching-learning process by using experiential learning activities and real-life activities. We believe that intimacy and the protection of privacy should be core themes of nurse education and training. PMID- 25830753 TI - Medical student in the family health strategy on the first years of college: perception of graduates. AB - There is a lack of knowledge about the effective value of the experience gained by medical students who participate in the Family Health Strategy (Estrategia Saude da Familia (ESF)) during the early stages of their medical training. This teaching strategy is based on learning by experiencing the problems that exist in real life. This study proposed to understand the value of this teaching strategy from the viewpoint of the students who had participated, after their graduation. The method adopted was a qualitative study conducted through interviews with students who graduated in the years 2009, 2010 and 2011. The data analysis used the hermeneutic dialectic technique as its model. The graduates considered that this experience enabled them to understand the organization and functioning of the health service and the context of the daily life of the users. This experience facilitated the doctor patient relationship, the development of clinical reasoning and the bond with the user. However the students emphasized that a lack of maturity prevented them gaining a higher level of benefit from the experience. Therefore, although the structure of the course is permeated by advances and challenges, it was concluded that this experience contributed to the student's learning of certain essential elements of medical training. PMID- 25830754 TI - Narrative interviews: an important resource in qualitative research. AB - Objetives This methodological study explain and emphasize the extent and fertility of the narrative interview in qualitative research. Methods To describe the narrative method within the qualitative research. Results The qualitative research method is characterized by addressing issues related to the singularities of the field and individuals investigated, being the narrative interviews a powerful method for use by researchers who aggregate it. They allow the deepening of research, the combination of life stories with socio-historical contexts, making the understanding of the senses that produce changes in the beliefs and values that motivate and justify the actions of possible informants. Conclusion The use of narrative is an advantageous investigative resource in qualitative research, in which the narrative is a traditional form of communication whose purpose is to serve content from which the subjective experiences can be transmitted. PMID- 25830755 TI - Nursing Supervision: Studying the "Case" of the phenomenon of interorganizational articulation Nursing School and Hospital. AB - The history of this research found a suitable ethos not only by the route of the researcher, but also by the current public policies of modernization and reform that are capable of regulating and transforming the educational and health systems, as well as their professional groups. The reflection meantime developed had raised a clear perception of the organizational change processes by which they interfered with the interorganizational coordination between School of Nursing and Hospital, where internship supervision would be the main protagonist, supported by the meanings that intervening actors have assigned to them. In this context, the search for explicit epistemological and methodological choices leads to look more attentively at the problem, ascertaining it, taking into account the organizational dimensions. In this regard, the choice of a case study was related to the fact that the method allowed to answer the purpose of knowing and understanding the interorganizational coordination phenomenon between School of Nursing and Hospital, namely through the supervision of internships. PMID- 25830756 TI - The Brazilian policy for reduction of accidents and violence aligns with international perspectives? AB - The study analyzed The Brazilian Policy for Reduction of Morbidity and Mortality from Accidents and Violence, in the socio-political perspective. We used as a base the chapter "Violence: a global public health problem" from the World Report on Violence and Health. The analysis revealed convergent and divergent elements of the Brazilian Policy in comparison with the international perspectives. We verified that the Brazilian Policy tried to converge to the international policies, however: it emphasizes the health promotion actions, but are limited to the context and behavior of individuals and individual communities; the performance of health professionals is expected without providing more structural investments, as the improvement in work conditions, the increase of financial and material resources; there are few clear definitions of the government and economical sector responsibilities. PMID- 25830757 TI - Model endophenotype for bipolar disorder: Qualitative Analysis, etiological factors, and research areas. AB - The aim of this study is to present an updated view of the writings on the endophenotype model for bipolar disorder using analytical methodologies. A review and analysis of networks was performed through descriptors and keywords that characterize the composition of the endophenotype model as a model of health. Information was collected from between 1992 and 2014, and the main thematic areas covered in the articles were identified. We discuss the results and question their cohesion, emphasizing the need to strengthen and identify the points of connection between etiological factors and characteristics that make up the model of endophenotypes for bipolar disorder. PMID- 25830758 TI - Competency-based training in nursing: limits and possibilities. AB - Objective To analyze the possibilities and limits of competency-based training in nursing. Method An integrative review of the literature on the subject was carried out, and an analysis was made of the results of a survey evaluating a nursing course based on areas of competency. A dialog was then established between the review and the results of the research. Results On the question of which theoretical type of competency the articles from the literature relate to, there is a predominance of the constructivist perspective, followed by the functionalist approach and the dialog-based approach. In the dialog between the literature and the research, limits and possibilities were observed in the development of a training by areas of competency. Conclusion The dialog-based approach to competency is the proposition that most approximates to the profile defined by the National Curriculum Guidelines for training in nursing, and this was also identified in the evaluation survey that was studied. However, it is found that there are aspects on better work is needed, such as: partnership between school and the workplace, the role of the teacher, the role of the student, and the process of evaluation. PMID- 25830759 TI - Symmetrical Versus Asymmetrical PresbyLASIK: Results After 18 Months and Patient Satisfaction. AB - PURPOSE: The aim of this study was to report visual, topographic, and satisfaction comparative results between symmetrical and asymmetrical presbyLASIK after 18 months. METHODS: Longitudinal, comparative case series of hyperopic presbyopes who underwent presbyLASIK, in a private clinical setting. Monovision symmetrical (plano target both eyes) versus asymmetrical [dominant eye (DE) = plano target; nondominant eye (NDE) = -0.50 diopter (D) target]. Pre- and postoperative variables included monocular and binocular, distance and near, uncorrected visual acuity (VA), best corrected visual acuity, spherical equivalent, addition (Add), topography SimK (Km), and topographic astigmatism. Topographic central corneal power increase was measured 3 and 18 months postoperatively. Data were reported as mean, range, and standard deviation and analyzed with Student t-test (P < 0.05 for statistical significance) and Pearson correlation coefficients. RESULTS: The symmetrical group consisted of 16 patients and the asymmetrical group of 14 patients, with a mean age of 53.5 +/- 2.3 and 51.9 +/- 2.5 years. Postoperative results, after 18 months, for symmetrical versus asymmetrical presbyLASIK were as follows: distance UCVA 0.8 +/-0.20; 0.9 +/- 0.2 (P < 0.01); near UCVA 0.9 +/- 0.2; 0.8 +/- 0.2 (P < 0.01); SE -0.20 +/- 0.50; -0.3 +/- 0.3D (P < 0.01); Add 0.5 +/- 0.5; 0.9 +/- 0.9 (P < 0.01); mean Km 44.8 +/- 1 D; 43.9 +/- 1.1 D (P < 0.01); mean central corneal power differential 1.4 +/- 0.8 D; 1.7 +/- 1.1 D (P < 0.01), respectively. Stability: -0.16 D, DE 0.13 D and NDE -0.16 D, and SE predictability -0.40; DE -0.28 D and NDE -0.53 D. Safety index 1.0; 1.0, efficacy distance VA 0.8; 0.9, and near VA 0.90; 0.8. More than 90% were within +/-0.50 D of the intended target. Twenty eyes required enhancement, and results were not significantly different. Mean satisfaction (0 10 points) for symmetrical patients was 7.0 +/- 2.6 and 7.3 +/- 2.8 points for asymmetrical patients. CONCLUSIONS: Symmetrical and asymmetrical presbyLASIK significantly improved distance UCVA, near UCVA, after 18 months. PMID- 25830760 TI - B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection. AB - We explored how B-lymphocytes influence in vitro T-cell alloresponses in patients with antibody-mediated rejection (AMR), testing whether B-cells would be preferentially involved in this group of patients. Peripheral blood mononuclear cells were collected from 65 patients having biopsy: 14 patients with AMR and 5 with no pathology on protocol; 38 with AMR and 8 with nonimmunologic damage on 'for cause'. Using enzyme-linked immunosorbent spot assays, we found interferon gamma production by indirect allorecognition in 45 of 119 total samples from the 65 patients. B-cells preferentially processed and presented donor alloantigens in samples from AMR patients. In a further 25 samples, B-cell-dependent allo specific reactivity was shown by depletion of CD25(+) cells and these individuals had higher percentages of CD4CD25hi cells. In 21 samples, reactivity was shown by depletion of CD19(+) cells, associated with polarized cytokine production toward IL-10 after polyclonal activation by IgG/IgM. Overall, this shows a significant contribution by B-cells to indirect donor-specific T-cell reactivity in vitro in patients with AMR. Active suppression by distinct phenotypes of T- or B-cells in approximately half of the patients indicates that chronic AMR is not characterized by a universal loss of immune regulation. Thus, stratified approaches that accommodate the heterogeneity of cell-mediated immunity might be beneficial to treat graft dysfunction. PMID- 25830761 TI - High prevalence of and potential mechanisms for chronic kidney disease in patients with acute intermittent porphyria. AB - Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors delta-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m(2) annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis. PMID- 25830762 TI - Perioperative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery. AB - Acute kidney injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine whether plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and postoperatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first postoperative log(H-FABP) was associated with severe AKI (adjusted odds ratio (OR) 5.39 (95% confidence interval (CI), 2.87-10.11) per unit increase), while preoperative log(H-FABP) was associated with any AKI (2.07 (1.48-2.89)) and mortality (1.67 (1.17-2.37)). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin. Thus, perioperative plasma H-FABP levels may be used for risk stratification of AKI and mortality following cardiac surgery. PMID- 25830763 TI - Interactions of DPP-4 and integrin beta1 influences endothelial-to-mesenchymal transition. AB - Integrin beta1 and dipeptidyl peptidase (DPP)-4 play roles in endothelial cell biology. Vascular endothelial growth factor (VEGF)-A inhibits endothelial-to mesenchymal transition (EndMT) through VEGF-R2, but through VEGF-R1 promotes EndMT by reducing the bioavailability of VEGF-A. Here we tested whether DPP-4 integrin beta1 interactions have a role in EndMT in the renal fibrosis of diabetic nephropathy. In streptozotocin-induced fibrotic kidneys in diabetic CD-1 mice, levels of endothelial DPP-4, integrin beta1, and phospho-integrin beta1 were all higher and associated with plasma cystatin C elevation. The DPP-4 inhibitor linagliptin ameliorated kidney fibrosis, reduced plasma cystatin C levels, and suppressed endothelial levels of DPP-4, integrin beta1, and phospho integrin beta1. In cultured endothelial cells, DPP-4 and integrin beta1 physically interacted. Suppression of DPP-4 by siRNA was associated with suppression of integrin beta1 and vice versa. Knockdown of either integrin beta1 or DPP-4 resulted in the silencing of TGF-beta2-induced TGF-beta receptor heterodimer formation, smad3 phosphorylation, and EndMT. DPP-4 negatively regulated endothelial viability signaling by VEGF-R2 suppression and VEGF-R1 induction in endothelial cells. Thus, DPP-4 and integrin beta1 interactions regulate key endothelial cell signal transduction in both physiological and pathological conditions including EndMT. Hence, inhibiting DPP-4 may be a therapeutic target for treating kidney fibrosis in diabetes. PMID- 25830764 TI - A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is marked by gradual renal cyst and kidney enlargement and ultimately renal failure. Magnetic resonance based, height-adjusted total kidney volume (htTKV) over 600 cc/m predicts the development of CKD stage 3 within 8 years in the Consortium for Radiologic Imaging in Polycystic Kidney Disease cohort. Here we compared simultaneous ultrasound and magnetic resonance imaging to determine whether ultrasound and kidney length (KL) predict future CKD stage 3 over longer periods of follow-up. A total of 241 ADPKD patients, 15-46 years, with creatinine clearance of 70 ml/min and above had iothalamate clearance, magnetic resonance, and ultrasound evaluations. Participants underwent an average of five repeat clearance measurements over a mean follow-up of 9.3 years. Ultrasound and magnetic resonance-based TKV and KL were compared using Bland-Altman plots and intraclass correlations. Each measure was tested to predict future CKD stage 3. Relatively strong intraclass correlations between ultrasound and magnetic resonance were found for both htTKV and KL (0.81 and 0.85, respectively). Ultrasound and magnetic resonance-based htTKV and KL predicted future CKD stage 3 similarly (AUC of 0.87, 0.88, 0.87, and 0.88, respectively). An ultrasound kidney length over 16.5 cm and htTKV over 650 ml/min had the best cut point for predicting the development of CKD stage 3. Thus, kidney length alone is sufficient to stratify the risk of progression to renal insufficiency early in ADPKD using either ultrasound or magnetic resonance imaging. PMID- 25830766 TI - Ultrahigh pressure extraction of bioactive compounds from plants-A review. AB - Extraction of bioactive compounds from plants is one of the most important research areas for pharmaceutical and food industries. Conventional extraction techniques are usually associated with longer extraction times, lower yields, more organic solvent consumption, and poor extraction efficiency. A novel extraction technique, ultrahigh pressure extraction, has been developed for the extraction of bioactive compounds from plants, in order to shorten the extraction time, decrease the solvent consumption, increase the extraction yields, and enhance the quality of extracts. The mild processing temperature of ultrahigh pressure extraction may lead to an enhanced extraction of thermolabile bioactive ingredients. A critical review is conducted to introduce the different aspects of ultrahigh pressure extraction of plants bioactive compounds, including principles and mechanisms, the important parameters influencing its performance, comparison of ultrahigh pressure extraction with other extraction techniques, advantages, and disadvantages. The future opportunities of ultrahigh pressure extraction are also discussed. PMID- 25830767 TI - Correction: characterization of the integration and modular excision of the integrative conjugative element PAISt in Streptomyces turgidiscabies Car8. PMID- 25830765 TI - Optimum AT1 receptor-neprilysin inhibition has superior cardioprotective effects compared with AT1 receptor blockade alone in hypertensive rats. AB - Neprilysin inhibitors prevent the breakdown of bradykinin and natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin II and endothelin-1. Here we studied the effects of a low and a high dose of the neprilysin inhibitor thiorphan on top of AT1 receptor blockade with irbesartan versus vehicle in TGR(mREN2)27 rats with high renin hypertension. Mean arterial blood pressure was unaffected by vehicle or thiorphan alone. Irbesartan lowered blood pressure, but after 7 days pressure started to increase again. Low- but not high-dose thiorphan prevented this rise. Only during exposure to low-dose thiorphan plus irbesartan did heart weight/body weight ratio, cardiac atrial natriuretic peptide expression, and myocyte size decrease significantly. Circulating endothelin-1 was not affected by low-dose thiorphan with or without irbesartan, but increased after treatment with high-dose thiorphan plus irbesartan. This endothelin-1 rise was accompanied by an increase in renal sodium hydrogen exchanger 3 protein abundance, and an upregulation of constrictor vascular endothelin type B receptors. Consequently, the endothelin type B receptor antagonist BQ788 no longer enhanced endothelin-1-induced vasoconstriction (indicative of endothelin type B receptor-mediated vasodilation), but prevented it. Thus, optimal neprilysin inhibitor dosing reveals additional cardioprotective effects on top of AT1 receptor blockade in renin-dependent hypertension. PMID- 25830768 TI - Identification of new genomospecies in the Mycobacterium terrae complex. AB - Members of the Mycobacterium terrae complex are slow-growing, non-chromogenic acid-fast bacilli found in the natural environment and occasionally in clinical material. These genetically closely-related members are difficult to differentiate by conventional phenotypic and molecular tests. In this paper we describe the use of whole genome data for the identification of four strains genetically similar to Mycobacterium sp. JDM601, a newly identified member of the M. terrae complex. Phylogenetic information from the alignment of genome-wide orthologous genes and single nucleotide polymorphisms show consistent clustering of the four strains together with M. sp. JDM601 into a distinct clade separate from other rapid and slow growing mycobacterial species. More detailed inter strain comparisons using average nucleotide identity, tetra-nucleotide frequencies and analysis of synteny indicate that our strains are closely related to but not of the same species as M. sp. JDM601. Besides the 16S rRNA signature described previously for the M. terrae complex, five more hypothetical proteins were found that are potentially useful for the rapid identification of mycobacterial species belonging to the M. terrae complex. This paper illustrates the versatile utilization of whole genome data for the delineation of new bacterial species and introduces four new genomospecies to add to current members in the M. terrae complex. PMID- 25830769 TI - Glowing seashells: diversity of fossilized coloration patterns on coral reef associated cone snail (Gastropoda: Conidae) shells from the Neogene of the Dominican Republic. AB - The biology of modern Conidae (cone snails)--which includes the hyperdiverse genus Conus--has been intensively studied, but the fossil record of the clade remains poorly understood, particularly within an evolutionary framework. Here, ultraviolet light is used to reveal and characterize the original shell coloration patterns of 28 species of cone snails from three Neogene coral reef associated deposits from the Cibao Valley, northern Dominican Republic. These fossils come from the upper Miocene Cercado Fm. and lower Pliocene Gurabo Fm., and range in age from about 6.6-4.8 Ma. Comparison of the revealed coloration patterns with those of extant species allow the taxa to be assigned to three genera of cone snails (Profundiconus, Conasprella, and Conus) and at least nine subgenera. Thirteen members of these phylogenetically diverse reef faunas are described as new species. These include: Profundiconus? hennigi, Conasprella (Ximeniconus) ageri, Conus anningae, Conus lyelli, Conus (Atlanticonus?) franklinae, Conus (Stephanoconus) gouldi, Conus (Stephanoconus) bellacoensis, Conus (Ductoconus) cashi, Conus (Dauciconus) garrisoni, Conus (Dauciconus?) zambaensis, Conus (Spuriconus?) kaesleri, Conus (Spuriconus?) lombardii, and Conus (Lautoconus?) carlottae. Each of the three reef deposits contain a minimum of 14-16 cone snail species, levels of diversity that are similar to modern Indo Pacific reef systems. Finally, most of the 28 species can be assigned to modern clades and thus have important implications for understanding the biogeographic and temporal histories of these clades in tropical America. PMID- 25830770 TI - Subclinical hypothyroidism is associated with increased risk for cancer mortality in adult Taiwanese-a 10 years population-based cohort. AB - BACKGROUND: The association between subclinical hypothyroidism (SCH) and cancer mortality is seldom discussed. METHODS: A total of 115,746 participants without thyroid disease history, aged 20 and above, were recruited from four nationwide health screening centers in Taiwan from 1998 to 1999. SCH was defined as a serum thyroid-stimulating hormone (TSH) level of 5.0-19.96 mIU/L with normal total thyroxine concentrations. Euthyroidism was defined as a serum TSH level of 0.47 4.9 mIU/L. Cox proportional hazards regression analyses were used to estimate the relative risks (RRs) of death from cancer for adults with SCH during a 10-year follow-up period. RESULTS: Among 115,746 adults, 1,841 had SCH (1.6%) and 113,905 (98.4%) had euthyroidism. There were 1,532 cancer deaths during the 1,034,082 person-years follow-up period. Adjusted for age, gender, body mass index, diabetes, hypertension, dyslipidemia, smoking, alcohol drinking, betel nut chewing, physical activity, income, and education level, the RRs (95% confidence interval) of cancer deaths among subjects with SCH versus euthyroid subjects were 1.51 (1.06 to 2.15). Cancer site analysis revealed a significant increased risk of bone, skin and breast cancer among SCH subjects (RR 2.79, (1.01, 7.70)). The risks of total cancer deaths were more prominent in the aged (RR 1.71, (1.02 to 2.87)), in females (RR 1.69 (1.08 to 2.65)), and in heavy smokers (RR 2.24, (1.19 to 4.21)). CONCLUSIONS: Subjects with SCH had a significantly increased risk for cancer mortality among adult Taiwanese. This is the first report to demonstrate the association between SCH and cancer mortality. PMID- 25830771 TI - The Malaria Parasite's Achilles' Heel: Functionally-relevant Invasion Structures. AB - Malaria parasites have their Achilles' heel; they are vulnerable in small parts of their relevant molecules where they can be wounded and killed. These are sporozoite and merozoite protein conserved high activity binding peptides (cHABPs), playing a critical role in binding to and invasion of host cells (hepatocytes and erythrocytes, respectively). cHABPs can be modified by specific amino acid replacement, according to previously published physicochemical rules, to produce analogues (mHABPs) having left-handed polyproline II (PPIIL)-like structures which can modulate an immune response due to fitting perfectly into the HLA-DRbeta1* peptide binding region (PBR) and having an appropriate presentation to the T-cell receptor (TCR). PMID- 25830773 TI - Generalised extreme value distributions provide a natural hypothesis for the shape of seed mass distributions. AB - Among co-occurring species, values for functionally important plant traits span orders of magnitude, are uni-modal, and generally positively skewed. Such data are usually log-transformed "for normality" but no convincing mechanistic explanation for a log-normal expectation exists. Here we propose a hypothesis for the distribution of seed masses based on generalised extreme value distributions (GEVs), a class of probability distributions used in climatology to characterise the impact of event magnitudes and frequencies; events that impose strong directional selection on biological traits. In tests involving datasets from 34 locations across the globe, GEVs described log10 seed mass distributions as well or better than conventional normalising statistics in 79% of cases, and revealed a systematic tendency for an overabundance of small seed sizes associated with low latitudes. GEVs characterise disturbance events experienced in a location to which individual species' life histories could respond, providing a natural, biological explanation for trait expression that is lacking from all previous hypotheses attempting to describe trait distributions in multispecies assemblages. We suggest that GEVs could provide a mechanistic explanation for plant trait distributions and potentially link biology and climatology under a single paradigm. PMID- 25830772 TI - 18F-Mefway PET imaging of serotonin 1A receptors in humans: a comparison with 18F FCWAY. AB - INTRODUCTION: The purpose of this research is to evaluate the prospects for the use of 4-(trans-18F-fluoranylmethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1 yl]ethyl]-N-pyridin-2-ylcyclohexane-1-carboxamide (18F-Mefway) in comparison to 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2 pyridyl)cyclohexanecarboxamide (18F-FCWAY) for the quantification of 5-HT1A receptors in human subjects. METHOD: Five healthy male controls were included for two positron emission tomography (PET) studies: 18F-FCWAY PET after the pretreatment with 500 mg of disulfiram and two months later, 18F-Mefway PET without disulfiram. Regional time-activity curves (TACs) were extracted from nine cortical and subcortical regions in dynamic PET images. Using cerebellar cortex without vermis as reference tissue, in vivo kinetics for both radioligands were compared based on the distribution volume ratio (DVR) calculated by non-invasive Logan graphical analysis and area under the curve ratio of the TACs (AUC ratio). RESULT: Although the pattern of regional uptakes in the 18F-Mefway PET was similar to that of the 18F-FCWAY PET (highest in the hippocampus and lowest in the cerebellar cortex), the amount of regional uptake in 18F-Mefway PET was almost half of that in 18F-FCWAY PET. The skull uptake in 18F-Mefway PET was only 25% of that in 18F-FCWAY PET with disulfiram pretreatment. The regional DVR values and AUC ratio values for 18F-Mefway were 17-40% lower than those of 18F FCWAY. In contrast to a small overestimation of DVR values by AUC ratio values (< 10%) in 18F-FCWAY PET, the overestimation bias of AUC ratio values was much higher (up to 21%) in 18F-Mefway PET. CONCLUSION: As 18F-Mefway showed lower DVR values and greater overestimation bias of AUC ratio values, 18F-Mefway may appear less favorable than 18F-FCWAY. However, in contrast to 18F-FCWAY, the resistance to in vivo defluorination of 18F-Mefway obviates the need for the use of a defluorination inhibitor. Thus, 18F-Mefway may be a good candidate PET radioligand for 5-HT1A receptor imaging in human. PMID- 25830774 TI - Dose-dependent effects of allopurinol on human foreskin fibroblast cells and human umbilical vein endothelial cells under hypoxia. AB - Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1alpha protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1alpha mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells. PMID- 25830775 TI - Multi-scale compositionality: identifying the compositional structures of social dynamics using deep learning. AB - OBJECTIVE: Social media exhibit rich yet distinct temporal dynamics which cover a wide range of different scales. In order to study this complex dynamics, two fundamental questions revolve around (1) the signatures of social dynamics at different time scales, and (2) the way in which these signatures interact and form higher-level meanings. METHOD: In this paper, we propose the Recursive Convolutional Bayesian Model (RCBM) to address both of these fundamental questions. The key idea behind our approach consists of constructing a deep learning framework using specialized convolution operators that are designed to exploit the inherent heterogeneity of social dynamics. RCBM's runtime and convergence properties are guaranteed by formal analyses. RESULTS: Experimental results show that the proposed method outperforms the state-of-the-art approaches both in terms of solution quality and computational efficiency. Indeed, by applying the proposed method on two social network datasets, Twitter and Yelp, we are able to identify the compositional structures that can accurately characterize the complex social dynamics from these two social media. We further show that identifying these patterns can enable new applications such as anomaly detection and improved social dynamics forecasting. Finally, our analysis offers new insights on understanding and engineering social media dynamics, with direct applications to opinion spreading and online content promotion. PMID- 25830776 TI - Spatio-temporal analysis of the accuracy of tropical multisatellite precipitation analysis 3B42 precipitation data in mid-high latitudes of China. AB - Satellite-based precipitation data have contributed greatly to quantitatively forecasting precipitation, and provides a potential alternative source for precipitation data allowing researchers to better understand patterns of precipitation over ungauged basins. However, the absence of calibration satellite data creates considerable uncertainties for The Tropical Rainfall Measuring Mission (TRMM) Multisatellite Precipitation Analysis (TMPA) 3B42 product over high latitude areas beyond the TRMM satellites latitude band (38 degrees NS). This study attempts to statistically assess TMPA V7 data over the region beyond 40 degrees NS using data obtained from numerous weather stations in 1998-2012. Comparative analysis at three timescales (daily, monthly and annual scale) indicates that adoption of a monthly adjustment significantly improved correlation at a larger timescale increasing from 0.63 to 0.95; TMPA data always exhibits a slight overestimation that is most serious at a daily scale (the absolute bias is 103.54%). Moreover, the performance of TMPA data varies across all seasons. Generally, TMPA data performs best in summer, but worst in winter, which is likely to be associated with the effects of snow/ice-covered surfaces and shortcomings of precipitation retrieval algorithms. Temporal and spatial analysis of accuracy indices suggest that the performance of TMPA data has gradually improved and has benefited from upgrades; the data are more reliable in humid areas than in arid regions. Special attention should be paid to its application in arid areas and in winter with poor scores of accuracy indices. Also, it is clear that the calibration can significantly improve precipitation estimates, the overestimation by TMPA in TRMM-covered area is about a third as much as that in no-TRMM area for monthly and annual precipitation. The systematic evaluation of TMPA over mid-high latitudes provides a broader understanding of satellite-based precipitation estimates, and these data are important for the rational application of TMPA methods in climatic and hydrological research. PMID- 25830777 TI - Purification and biochemical characterization of an extracellular serine peptidase from Aspergillus terreus. AB - Peptidases are important because they play a central role in pharmaceutical, food, environmental, and other industrial processes. A serine peptidase from Aspergillus terreus was isolated after two chromatography steps that showed a yield of 15.5%. Its molecular mass was determined to be 43 kD, by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). This peptidase was active between pH 5.0 to 8.0 and had maximum activity at pH 7.0, at 45 degrees C. When exposited with 1 M of urea, the enzyme maintained 100% activity and used azocasein as substrate. The N-terminal (first 15 residues) showed 33% identity with the serine peptidase of Aspergillus clavatus ES1. The kinetics assays showed that subsite S2 did not bind polar basic amino acids (His and Arg) nonpolar acidic amino acids (Asp and Glu). The subsite S1 showed higher catalytic efficiency than the S2 and S3 subsites. PMID- 25830778 TI - Ohmic Heating: Concept and Applications-A Review. AB - Ohmic heating, also known as Joule heating, electrical resistance heating, and direct electrical resistance heating, is a process of heating the food by passing electric current. In ohmic heating the energy is dissipated directly into the food. Electrical conductivity is a key parameter in the design of an effective ohmic heater. A large number of potential applications exist for ohmic heating, including blanching, evaporation, dehydration, fermentation, sterilization, pasteurization, and heating of foods. Beyond heating, applied electric field under ohmic heating causes electroporation of cell membranes, which increase extraction rates, and reduce gelatinization temperature and enthalpy. Ohmic heating results in faster heating of food along with maintenance of color and nutritional value of food. Water absorption index, water solubility index, thermal properties, and pasting properties are altered with the application of ohmic heating. Ohmic heating results in pre-gelatinized starches, which reduce energy requirement during processing. But its higher initial cost, lack of its applications in foods containing fats and oils, and less awareness limit its use. PMID- 25830779 TI - The spectrum of HBV/HCV coinfection: epidemiology, clinical characteristics, viralinteractions and management. AB - Monoinfection with either hepatitis B (HBV) or C virus (HCV) represents one of the major causes of chronic liver disease globally. However, in endemic areas a substantial number of patients are infected with both viruses mainly as a result of the common routes of transmission. Numerous studies have demonstrated that dually infected patients carry a greater risk of advanced liver disease, cirrhosis and hepatocellular carcinoma compared with monoinfected patients. The choice of treatment is based on the virological profile of each patient taking into account the dominant virus pattern. In predominant HCV, standard combination treatment with pegylated interferon and ribavirin has proven equally effective in HBV/HCV-coinfected patients as well as in HCV-monoinfected patients. Strikingly, approximately 60% of patients with inactive HBV infection before HCV treatment may present HBV reactivation while others experience hepatitis B surface antigen seroconversion after clearing HCV, demonstrating the complexity of the interaction between the two viruses during the follow up. The therapeutic strategies for the predominant HBV dually infected patients are more vague, although high genetic barrier nucleos(t)ide analogues play an indisputable role. Finally, the recently approved combination treatments for chronic hepatitis C containing direct-acting antivirals may definitely change the treatment protocols in the future although there is no experience with these drugs in dually infected patients until today. PMID- 25830780 TI - Prediction of new thermodynamically stable aluminum oxides. AB - Recently, it has been shown that under pressure, unexpected and counterintuitive chemical compounds become stable. Laser shock experiments (A. Rode, unpublished) on alumina (Al2O3) have shown non-equilibrium decomposition of alumina with the formation of free Al and a mysterious transparent phase. Inspired by these observations, we have explored the possibility of the formation of new chemical compounds in the system Al-O. Using the variable-composition structure prediction algorithm USPEX, in addition to the well-known Al2O3, we have found two extraordinary compounds Al4O7 and AlO2 to be thermodynamically stable in the pressure ranges 330-443 GPa and above 332 GPa, respectively. Both of these compounds at the same time contain oxide O(2-) and peroxide O2(2-) ions, and both are insulating. Peroxo-groups are responsible for gap states, which significantly reduce the electronic band gap of both Al4O7 and AlO2. PMID- 25830781 TI - Antibiotic body burden of Chinese school children: a multisite biomonitoring based study. AB - To explore the antibiotic body burden of Chinese school children, total urinary concentrations (free and conjugated) of 18 representative antibiotics (5 macrolides, 2 beta-lactams, 3 tetracyclines, 4 quinolones, and 4 sulfonamides) were measured by ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry among 1064 school students recruited from 3 economically and geographically distinct areas in east China in 2013. All 18 antibiotics were detected in urine samples with the detection frequencies ranging from 0.4 to 19.6%. The antibiotics were detected in 58.3% of urine samples overall, and this detection frequency reached at 74.4% in one study site. Of them, 47.8% of the urine samples had a sum of mass concentration of all antibiotics between 0.1 (minimum) and 20.0 ng/mL, and 8 antibiotics had their concentrations of above 1000 ng/mL in some urine samples. Three veterinary antibiotics, 4 human antibiotics, and 11 human/veterinary antibiotics were found overall in 6.3, 19.9, and 49.4% of urine samples, respectively. The detection frequencies and concentration levels of antibiotics in urine samples differed by study areas. Concerning mixed exposures, a total of 137 combinations of antibiotics and 20 combinations of antibiotic categories were found overall. Two or more antibiotics or categories were concurrently detected in more than 20% of urine samples. On the basis of a usage analysis, contaminated food or environment might be relevant exposure sources for tetracyclines, quinolones, and sulfonamides. PMID- 25830782 TI - Patterns of impact resulting from a 'sit less, move more' web-based program in sedentary office employees. AB - PURPOSE: Encouraging office workers to 'sit less and move more' encompasses two public health priorities. However, there is little evidence on the effectiveness of workplace interventions for reducing sitting, even less about the longer term effects of such interventions and still less on dual-focused interventions. This study assessed the short and mid-term impacts of a workplace web-based intervention (Walk@WorkSpain, W@WS; 2010-11) on self-reported sitting time, step counts and physical risk factors (waist circumference, BMI, blood pressure) for chronic disease. METHODS: Employees at six Spanish university campuses (n=264; 42+/-10 years; 171 female) were randomly assigned by worksite and campus to an Intervention (used W@WS; n=129; 87 female) or a Comparison group (maintained normal behavior; n=135; 84 female). This phased, 19-week program aimed to decrease occupational sitting time through increased incidental movement and short walks. A linear mixed model assessed changes in outcome measures between the baseline, ramping (8 weeks), maintenance (11 weeks) and follow-up (two months) phases for Intervention versus Comparison groups. RESULTS: A significant 2 (group) * 2 (program phases) interaction was found for self-reported occupational sitting (F[3]=7.97, p=0.046), daily step counts (F[3]=15.68, p=0.0013) and waist circumference (F[3]=11.67, p=0.0086). The Intervention group decreased minutes of daily occupational sitting while also increasing step counts from baseline (446+/-126; 8,862+/-2,475) through ramping (+425+/-120; 9,345+/ 2,435), maintenance (+422+/-123; 9,638+/-3,131) and follow-up (+414+/-129; 9,786+/-3,205). In the Comparison group, compared to baseline (404+/-106), sitting time remained unchanged through ramping and maintenance, but decreased at follow-up (-388+/-120), while step counts diminished across all phases. The Intervention group significantly reduced waist circumference by 2.1cms from baseline to follow-up while the Comparison group reduced waist circumference by 1.3cms over the same period. CONCLUSIONS: W@WS is a feasible and effective evidence-based intervention that can be successfully deployed with sedentary employees to elicit sustained changes on "sitting less and moving more". PMID- 25830783 TI - Fibroscan versus simple noninvasive screening tools in predicting fibrosis in high-risk nonalcoholic fatty liver disease patients from Western India. AB - BACKGROUND: The aim of the study was to determine the efficacy of Fibroscan versus noninvasive markers, i.e. nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS); Aspartate-aminotransferase (AST)/platelet ratio (APRI); and AST/Alanine-aminotransferase (AAR) as a screening tool in NAFLD patients with high risk of liver fibrosis. METHODS: This is a single-center study carried out in patients attending the outpatient department for dyspepsia and diagnosed with fatty liver on ultrasound. Liver biopsy was advised in diabetics, metabolic syndrome, body mass index >30 kg/m2, raised transaminases and hypothyroidism. Fibroscan, APRI, AAR and NFS were calculated. Area under the curve (AUROC), negative (NPV) and positive predictive values (PPV) were calculated for each diagnostic test. RESULTS: Of the 1500 patients screened, 110 with the above described risk factors underwent liver biopsy (stage 3/4 fibrosis = 38). Diabetes predicted severe fibrosis (stage 3/4). Sensitivity, specificity, PPV, NPV and AUROC for Fibroscan at value 12 kPa were 0.9, 0.8, 0.70, 0.93 and 0.91 respectively for predicting stage 3/4 fibrosis. With increase in severity of liver fibrosis there was stepwise increase in Fibroscan values (P=0.000038, Kruskal-Wallis test). Sensitivity, specificity, PPV and NPV for AAR and NFS at cutoff of 1.5 and 0.676 were 0.8, 1.0, 1.0 and 0.92 and 0.8, 1.0, 1.0 and 0.92 respectively. CONCLUSION: Fibroscan, NFS and AAR are simple noninvasive markers of fibrosis that can be utilized as screening tools in patients with high risk for fibrosis to determine the need for biopsy. The cutoff of Fibroscan for stage 3/4 fibrosis was 12 kPa. PMID- 25830784 TI - Correction: novel biogenic aggregation of moss gemmae on a disappearing African glacier. AB - [This corrects the article DOI: 10.1371/journal.pone.0112510.]. PMID- 25830785 TI - Analysis of acetohydroxyacid synthase1 gene in chickpea conferring resistance to imazamox herbicide. AB - Chickpea (Cicer arietinum L.) production in the Canadian prairies is challenging due to a lack of effective weed management mainly because of poor competition ability of the crop and limited registered herbicide options. Chickpea genotype with resistance to imidazolinone (IMI) herbicides has been identified. A point mutation in the acetohydroxyacid synthase1 (AHAS1) gene at C581 to T581, resulting in an amino acid substitution from Ala194 to Val194 (position 205, standardized to arabidopsis), confers the resistance to imazamox in chickpea. However, the molecular mechanism leading to the resistance is not fully understood. In many plant species, contrasting transcription levels of AHAS gene has been implicated in the resistant and susceptible genotypes in response to IMI. The objectives of this research were to compare the AHAS gene expression and AHAS enzyme activity in resistant and susceptible chickpea cultivars in response to imazamox herbicide treatment. Results from RT-qPCR indicated that there is no significant change in the transcript levels of AHAS1 between the susceptible and the resistant genotypes in response to imazamox treatment. Protein hydrophobic cluster analysis, protein-ligand docking analysis, and AHAS enzyme activity assay all indicated that the resistance to imazamox in chickpea is due to the alteration of interaction of the AHAS1 enzyme with the imazamox herbicide. PMID- 25830786 TI - Closing the health gap in a generation: exploring the association between household characteristics and schooling status among orphans and vulnerable children in Swaziland. AB - Swaziland has one of the highest HIV/AIDS prevalences in the world, which has contributed to many Swazi children being left as "orphans and vulnerable children" (OVC). In 2010, there were 78,000 AIDS orphans in the country and the number is expected to increase given the current HIV prevalence. The WHO aims to close the gap in a generation and eliminate health inequality; as a result the Swazi Government began in 2005 to provide financial support to the education of OVC. Prior research has indicated that household characteristics are some of the major determinants with respect to schooling status among children. We have examined the association between household characteristics and schooling status of OVC. Schooling status may vary by gender and by age, as well as by other sociodemographic factors, in sub-Saharan African societies, and therefore we have also included a comprehensive set of appropriate variables in all of our multivariate analyses. Using existing data from the Swaziland Multiple Indicator Cluster Survey 2010, a total of 5890 children aged 7-18 years old were analyzed. The results from the multivariate logistic regressions showed that non-OVC were more likely than OVC to be in school (OR = 2.18, p < 0.001), even after taking other variables into considerations. The OVC in socioeconomically disadvantaged households, such as those with lower levels of household wealt, and those who resided in an urban area, were less likely to be in school. These findings suggest that education programs for OVC need to be household-appropriate. PMID- 25830787 TI - Role of sleep disturbances in occupational accidents among women. AB - OBJECTIVES: This population-based cohort study was performed to assess the association between sleep disturbances and the risk of occupational accidents among women. METHODS: Data were collected by questionnaires on two different occasions (2000 and 2010) and data on work injuries were also collected from Swedish government records (ISA). Insomnia symptoms were defined as having severe or very severe problems with (i) difficulty initiating sleep, (ii) difficulty maintaining sleep, or (iii) early morning awakening. Symptom of obstructive sleep apnea syndrome (OSAS) was defined as reporting both snoring and daytime sleepiness. Working-age respondents (20-67 years of age) who responded to both baseline and follow-up questionnaires and had worked for part or all of the 10 year follow-up period (N=4320) were included in the study. RESULTS: Of the subjects responding to the questionnaire, 12.2% reported >=1 accident and 6.3% reported an accident requiring sick leave in the government register. Blue-collar workers and night and shift work were more common in the group with occupational accidents. Subjects with insomnia symptoms both at baseline and follow-up (persistent insomnia symptoms) ran a higher risk of being involved in an self reported occupational accident [adjusted OR (OR adj) 1.5, 95% confidence interval (95% CI) 1.2-2.0] after adjusting for age, body mass index, smoking, alcohol dependency, white- or blue-collar worker, years at work, night work, and physical activity. Persistent insomnia symptoms did not reach statistical significance as an independent predictor of register-reported occupational accident with sick leave (OR adj1.4, 95% CI 0.99-2.1). No significant association was found between symptoms of OSAS and self-reported or register-based occupational accidents. CONCLUSIONS: Persistent insomnia symptoms were associated with an increased risk of self-reported occupational accidents, while no significant association was found with occupational accidents with sick leave reported to government register. PMID- 25830788 TI - The absolute configuration of salicortin, HCH-salicortin and tremulacin from Populus trichocarpa * deltoides Beaupre. AB - The absolute configuration of salicortin, HCH-salicortin and tremulacin, isolated from leaves of Populus trichocarpa * deltoides Beaupre, was determined by comparing spectroscopic data of these compounds with those of idescarpin, isolated from leaves of Idesia polycarpa. All compounds were characterized by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and circular dichroism spectroscopy. It was found that the hydroxy cyclohexenonoyl (HCH) moiety in all compounds is (S)-configured. In addition, it was shown that leaves of Idesia polycarpa contain high amounts of (-)-idescarpin (1.1%, based on dry weight). PMID- 25830789 TI - A review of heterogeneous photocatalysis for water and surface disinfection. AB - Photo-excitation of certain semiconductors can lead to the production of reactive oxygen species that can inactivate microorganisms. The mechanisms involved are reviewed, along with two important applications. The first is the use of photocatalysis to enhance the solar disinfection of water. It is estimated that 750 million people do not have accessed to an improved source for drinking and many more rely on sources that are not safe. If one can utilize photocatalysis to enhance the solar disinfection of water and provide an inexpensive, simple method of water disinfection, then it could help reduce the risk of waterborne disease. The second application is the use of photocatalytic coatings to combat healthcare associated infections. Two challenges are considered, i.e., the use of photocatalytic coatings to give "self-disinfecting" surfaces to reduce the risk of transmission of infection via environmental surfaces, and the use of photocatalytic coatings for the decontamination and disinfection of medical devices. In the final section, the development of novel photocatalytic materials for use in disinfection applications is reviewed, taking account of materials, developed for other photocatalytic applications, but which may be transferable for disinfection purposes. PMID- 25830790 TI - New flavonolignan glycosides from the aerial parts of Zizania latifolia. AB - Two new flavonolignan glycosides, tricin-4'-O-(threo-beta-guaiacylglyceryl) ether 7''-O-beta-D-glucopyranose (4) and tricin-4'-O-(erythro-beta-guaiacylglyceryl) ether 7''-O-beta-D-glucopyranose (5) were isolated from the roots of Zizania latifolia, together with tricin-7-O-beta-D-glucopyranose (1), tricin-4'-O-(threo beta-guaiacylglyceryl) ether 7-O-beta-D-glucopyranose (2), and tricin-4'-O (erythro-beta-guaiacylglyceryl) ether 7-O-beta-D-glucopyranose (3). Their structures were identified on the basis of spectroscopic techniques, including HR ESI/MS, 1D-NMR (1H, 13C, DEPT), 2D-NMR (gCOSY, gHSQC, gHMBC), and IR spectroscopy. PMID- 25830792 TI - Developing effective leadership competencies in military social workers. AB - Military social workers are facing transformative times in that demand for military social work has increased and become more complex, challenging, and diverse due to the last 13 years of combat experiences. Developing military social work leaders must be deliberate, continuous, and progressive in order to impact and improve organizational performance in the healthcare delivery system. The transformational leadership model has been proven to be effective in both the military and social service organizations. The strength of this leadership model coincides well with the values of the social work profession. Incorporating leadership development in a clinical Master of Social Work program has the potential to improve service provision and offer strategies for military social workers to effectively manage the ongoing challenges in the field of social work. PMID- 25830791 TI - Design, synthesis, and insecticidal activity of some novel diacylhydrazine and acylhydrazone derivatives. AB - In this study a series of diacylhydrazine and acylhydrazone derivatives were designed and synthesized according to the method of active group combination and the principles of aromatic group bioisosterism. The structures of the novel derivatives were determined on the basis on 1H-NMR, IR and ESI-MS spectral data. All of the compounds were evaluated for their in vivo insecticidal activity against the third instar larvae of Spodoptera exigua Hiibner, Helicoverpa armigera Hubner, Plutella xyllostella Linnaeus and Pieris rapae Linne, respectively, at a concentration of 10 mg/L. The results showed that all of the derivatives displayed high insecticidal activity. Most of the compounds presented higher insecticidal activity against S. exigua than the reference compounds tebufenozide, metaflumizone and tolfenpyrad, and approximately identical insecticidal activity against H. armigera, P. xyllostella and P. rapae as the references metaflumizone and tolfenpyrad. PMID- 25830793 TI - Evolution of the combat and operational stress control detachment. AB - Medical units designed to provide combat and operational stress control services have evolved since World War II into the current Combat and Operational Stress Control (COSC) detachments. Yet the structure of these COSC detachments differ greatly between what is authorized in the table of organization and equipment (TO&E) and what is doctrinally described in the current field manual guiding combat and operational stress control operations. We therefore explore the evolution of the COSC detachment, compare the organizations found in current doctrine with that currently authorized on the TO&E, and conclude with a proposed structure of a modern COSC detachment that is functionally modular with more clear chains of command. PMID- 25830794 TI - The psychosocial challenges of conducting counterinsurgency operations. AB - Counterinsurgency (COIN) operations have served as the fundamental component of the nation's military strategy. Without the established boundaries of conventional operations, switching between diplomatic and combative roles can expose Soldiers to unique stressors when conducting COIN operations. An exploratory study of descriptive data obtained from a retrospective records review of 140 service members deployed to Operation Enduring Freedom identified and described problems in psychosocial functioning. Behavioral health records for the first 7 months of the deployment and throughout the first year of redeployment were reviewed. The most common problems reported by Soldiers were operational stress characterized by anxiety, fear, irritability, frustration, and isolation. Additionally, most of the Soldiers engaged services for psychosocial challenges within the first year of returning from deployment. Establishing reliable access to behavioral healthcare has emerged as an essential component of total force protection in COIN deployments. PMID- 25830795 TI - Sleep and the use of energy products in a combat environment. AB - BACKGROUND: The use of energy products appears to be widespread among deployed personnel, presumably to combat fatigue and sleep deprivation. However, these products have been associated with unpleasant side effects and adverse events, including insomnia, mood swings, fatigue, cardiac arrest, and even death. OBJECTIVE: To quantify the sleep habits and energy products used among deployed service members in Afghanistan from 2010-2011. METHODS: Participants completed an anonymous survey querying their demographic information, sleep habits, combat exposure, and energy product use. RESULTS: Respondent data: 83% experienced some degree of insomnia; 28% were using a prescription or over-the-counter sleep aid; 81% reported using at least one energy product daily. The most frequently consumed energy products were caffeinated coffee and soda. Only 4 energy products were used more frequently during deployment than prior to deployment: Rip-It, Tiger, Hydroxycut, and energy drink powders. On average, respondents who increased their use consumed only 2 more servings per week during deployment than they had prior to deployment. Only degree of combat exposure, not quantity of energy products consumed, predicted degree of insomnia. CONCLUSION: Energy product consumption by service members during deployment was not dramatically different than predeployment and was not associated with insomnia. PMID- 25830796 TI - Telebehavioral health: practical application in deployed and garrison settings. PMID- 25830797 TI - Effectiveness of Telebehavioral Health Program Nurse Case Managers (NCM): Data Collection Tools and the Process for NCM-Sensitive Outcome Measures. AB - As a part of our nation's pursuit of improvements in patient care outcomes, continuity of care, and cost containment, the case manager has become a vital member on interdisciplinary teams and in health care agencies. Telebehavioral health programs, as a relatively new method of delivering behavioral health care, have recently begun to incorporate case management into their multidisciplinary teams. To determine the efficacy and efficiency of healthcare programs, program managers are charged with the determination of the outcomes of the care rendered to patient populations. However, programs that use telehealth methods to deliver care have unique structures in place that impact ability to collect outcome data. A military medical center that serves the Pacific region developed surveys and processes to distribute, administer, and collect information about a telehealth environment to obtain outcome data for the nurse case manager. This report describes the survey development and the processes created to capture nurse case manager outcomes. Additionally, the surveys and processes developed in this project for measuring outcomes may be useful in other settings and disciplines. PMID- 25830798 TI - Military service member and veteran self reports of efficacy of cranial electrotherapy stimulation for anxiety, posttraumatic stress disorder, insomnia, and depression. AB - Cranial electrotherapy stimulation (CES) is being prescribed for service members and veterans for the treatment of anxiety, posttraumatic stress disorder (PTSD), insomnia and depression. The purpose of this study was to examine service members' and veterans' perceptions of the effectiveness and safety of CES treatment. Service members and veterans (N=1,514) who had obtained a CES device through the Department of Defense or Veterans Affairs Medical Center from 2006 2011 were invited to participate in the web based survey via email. One hundred fifty-two participants returned questionnaires. Data were analyzed using descriptive statistics. Participants reported clinical improvement of 25% or more from using CES for anxiety (66.7%), PTSD (62.5%), insomnia (65.3%) and depression (53.9%). The majority of these participants reported clinical improvement of 50% or more. Respondents also perceived CES to be safe (99.0%). Those individuals who were not taking any prescription medication rated CES more effective than the combined CES and prescription medication group. CES provides service members and veterans with a safe, noninvasive, nondrug, easy to use treatment for anxiety, PTSD, insomnia, and depression that can be used in the clinical setting or self directed at home. PMID- 25830799 TI - Raising the clinical standard of care for suicidal soldiers: an army process improvement initiative. AB - From 2004 to 2008, the suicide rate among US Army Soldiers increased 80%, reaching a record high in 2008 and surpassing the civilian rate for the first time in recorded history. In recent years, the rate of Army suicides rose again; the year 2012 reflects the highest rate of military suicides on record. There is a need to assess current behavioral health practices to identify both effective and ineffective practices, and to adapt services to meet the needs of the Army behavioral health patient population. This paper discusses a process improvement initiative developed in an effort to improve clinical processes for suicide risk mitigation in an Army behavioral health clinic located in the catchment area of the US Army Southern Regional Medical Command. PMID- 25830800 TI - Mild traumatic brain injury in the military: improving the referral/consultation process. AB - BACKGROUND: Clinical practice inconsistencies in the identification and referral of patients suspected of mild traumatic brain injury have been identified within primary care clinics in a major military medical center. OBJECTIVE: To determine if the use of an overprinted communication tool would improve the referral/consultation process between identified clinics in one Army medical center. DESIGN: The consultation/referral process was evaluated following an educational presentation regarding the use of a situation, background, assessment, and recommendation (SBAR) communication form. Data were collected from consultation charts before and after two months of use of the SBAR communication form. RESULTS: The communication tool improved capture of dates of injury, prior treatment, history of testing, patient education, and request for therapy. CONCLUSION: Findings from this project demonstrated that a communication tool such as the TBI-SBAR would be beneficial for use in primary care clinics. PMID- 25830801 TI - Directorate of treatment programs: providing behavioral health services at the US Disciplinary Barracks. PMID- 25830802 TI - The effects of military deployment on early child development. AB - PURPOSE: The purpose of this observational, point prevalence study is to determine if parental deployment affects the cognitive, social and emotional development of preschool age children in the military family. METHODS: Demographic information was collected and an age-appropriate Ages and Stages Questionnaire (ASQ-3) and Ages and Stages Social-Emotional Inventory (ASQ:SE) were administered. The primary outcome measure was the failure rates on the developmental instruments. RESULTS: We identified 151 parents of eligible children; 95 children had a parent that deployed during their lifetime. We found a significant difference in ASQ-3 failure rates for children in the deployed group compared to those in the nondeployed group. Children of deployed parents were at least twice as often to fail the ASQ-3 or ASQ:SE developmental screen compared to children whose parents did not deploy. 30.5% of children in the deployed group failed the ASQ-3 screen while 12.5% of children who did not have a deployed parent failed (P=.009). On the ASQ:SE developmental screen, 16.8% of children who had a parent deploy failed versus 5.4% of children who did not have a parent deploy (P=.031). CONCLUSIONS: This study suggests that parental deployment is related to adverse risk for developmental delays in children in military families. The psychological burden on military children could be life long or require significant resources to address. These adverse outcomes could be possibly mitigated by early detection of developmental delay and firm attention to aggressive screening techniques in military communities. PMID- 25830803 TI - The effect of deployment, distress, and perceived social support on Army spouses' weight status. AB - This study examined the relationship between deployment status, psychological distress, perceived social support, age, rank, and gender with Army spouses' (N=1863) weight status. We posited that spouses of deployed Soldiers have a higher body mass index (BMI) than spouses of nondeployed Soldiers; spouses with higher psychological distress scores have a higher BMI than those with lower distress scores; and spouses with low social support scores have higher BMIs than those with higher social support scores. METHOD: Secondary analysis of data from the 2008 Active Duty Spouse Survey was used to examine the relationship between weight status (health versus overweight or obese) and Army spouses' deployment status, demographic characteristics, psychological distress, and perceived social support. RESULTS: Deployment status and weight status were not related (P=.097). Male spouses were significantly more likely than female spouses to be overweight or obese. Psychological distress increased in direct correlation with increased age, and as perceived social support decreased, the incidents of being overweight or obese increased. CONCLUSIONS: Findings suggest several risk factors are associated with being overweight or obese: male spouse, noncommissioned officers in the ranks of E5 through E9, older age, higher psychological distress scores, and lower perceived social support scores. The risk factors support the use of the Army Surgeon General's Performance Triad of sleep, activity, and nutrition as a tool to assist Army personnel and Department of the Army civilians in teaching spouses awareness and methods of changing behaviors that may result in choosing healthy options. PMID- 25830804 TI - Applying the Korem Profiling System to domestic violence. AB - Soldiers involved in domestic violence are a focus of concern for the US Army. The Family Advocacy Program is designed to prevent and intervene to mitigate future violence. Some of the Family Advocacy Program assessment tools are limited in their ability to identify contributing factors of situational couple violence. This article proposes incorporating the Korem Profiling System, a rapid assessment tool, to help identify underlying causes of situational couple violence and provide appropriate interventions to prevent future incidents. PMID- 25830805 TI - Understanding the student veterans' college experience: an exploratory study. AB - OBJECTIVE: Students with active duty military experience are a unique and growing population on college campuses in the United States. This study explores student veterans' perceptions of their transition to and experience in higher education. METHOD: This mixed methods study used a sample of 10 active military and reserve component student veterans to explore their perceptions of their personal strengths, challenges, factors impacting participation in university resource programs, and suggestions for ideal resources to support their academic success. RESULTS: Content analysis yielded primary themes such as the strength of self discipline, the challenge of social interactions, and the desire for programs that connect student-veterans and assist with social integration. CONCLUSION: Implications for education, retention, and transition from active duty are discussed. PMID- 25830806 TI - Mental health outreach and screening among returning veterans: are we asking the right questions? AB - This study looked at predictors of mental health treatment utilization in a unique cohort of recently separated Veterans coming to the Department of Veterans Affairs (VA) (N=152). This convenience sample voluntarily completed questionnaires, which included mental health screening tools, during an outreach event at a large urban VA Medical Center. Researchers reviewed computerized medical records of these consenting participants to record VA treatment utilization. There is a statistically significant association between posttraumatic stress disorder screening results, functional impairment, and treatment-seeking. Certain functional impairments increase the odds of participation in VA mental health care. These include problems with school and/or work (odds ratio (OR)=2.8), physical fights (OR=2.8), physical health problems (OR=3.0), financial difficulties (OR=3.0), irritability/anger (OR=3.4), isolation (OR=3.8), drug use (OR=5.7), and problems with social support (OR=7.0). This study concluded that asking about symptoms alone may not capture the breadth and nature of Veterans' postdeployment difficulties. PMID- 25830807 TI - Analyzing large gene expression and methylation data profiles using StatBicRM: statistical biclustering-based rule mining. AB - Microarray and beadchip are two most efficient techniques for measuring gene expression and methylation data in bioinformatics. Biclustering deals with the simultaneous clustering of genes and samples. In this article, we propose a computational rule mining framework, StatBicRM (i.e., statistical biclustering based rule mining) to identify special type of rules and potential biomarkers using integrated approaches of statistical and binary inclusion-maximal biclustering techniques from the biological datasets. At first, a novel statistical strategy has been utilized to eliminate the insignificant/low significant/redundant genes in such way that significance level must satisfy the data distribution property (viz., either normal distribution or non-normal distribution). The data is then discretized and post-discretized, consecutively. Thereafter, the biclustering technique is applied to identify maximal frequent closed homogeneous itemsets. Corresponding special type of rules are then extracted from the selected itemsets. Our proposed rule mining method performs better than the other rule mining algorithms as it generates maximal frequent closed homogeneous itemsets instead of frequent itemsets. Thus, it saves elapsed time, and can work on big dataset. Pathway and Gene Ontology analyses are conducted on the genes of the evolved rules using David database. Frequency analysis of the genes appearing in the evolved rules is performed to determine potential biomarkers. Furthermore, we also classify the data to know how much the evolved rules are able to describe accurately the remaining test (unknown) data. Subsequently, we also compare the average classification accuracy, and other related factors with other rule-based classifiers. Statistical significance tests are also performed for verifying the statistical relevance of the comparative results. Here, each of the other rule mining methods or rule-based classifiers is also starting with the same post-discretized data-matrix. Finally, we have also included the integrated analysis of gene expression and methylation for determining epigenetic effect (viz., effect of methylation) on gene expression level. PMID- 25830808 TI - A hybrid biomechanical intensity based deformable image registration of lung 4DCT. AB - Deformable image registration (DIR) has been extensively studied over the past two decades due to its essential role in many image-guided interventions (IGI). IGI demands a highly accurate registration that maintains its accuracy across the entire region of interest. This work evaluates the improvement in accuracy and consistency by refining the results of Morfeus, a biomechanical model-based DIR algorithm. A hybrid DIR algorithm is proposed based on, a biomechanical model based DIR algorithm and a refinement step based on a B-spline intensity-based algorithm. Inhale and exhale reconstructions of four-dimensional computed tomography (4DCT) lung images from 31 patients were initially registered using the biomechanical DIR by modeling contact surface between the lungs and the chest cavity. The resulting deformations were then refined using the intensity-based algorithm to reduce any residual uncertainties. Important parameters in the intensity-based algorithm, including grid spacing, number of pyramids, and regularization coefficient, were optimized on 10 randomly-chosen patients (out of 31). Target registration error (TRE) was calculated by measuring the Euclidean distance of common anatomical points on both images after registration. For each patient a minimum of 30 points/lung were used. Grid spacing of 8 mm, 5 levels of grid pyramids, and regularization coefficient of 3.0 were found to provide optimal results on 10 randomly chosen patients. Overall the entire patient population (n = 31), the hybrid method resulted in mean +/- SD (90th%) TRE of 1.5 +/- 1.4 (2.9) mm compared to 3.1 +/- 1.9 (5.6) using biomechanical DIR and 2.6 +/ 2.5 (6.1) using intensity-based DIR alone. The proposed hybrid biomechanical modeling intensity based algorithm is a promising DIR technique which could be used in various IGI procedures. The current investigation shows the efficacy of this approach for the registration of 4DCT images of the lungs with average accuracy of 1.5 mm. PMID- 25830809 TI - Use of Electroconvulsive Therapy in Adolescents With Treatment-Resistant Depressive Disorders: A Case Series. AB - OBJECTIVES: This study presents a comprehensive case series of adolescents who received electroconvulsive therapy (ECT) for treatment-resistant depression. METHODS: Conducting a chart review, we identified 13 adolescents who had ECT for treatment of depression over a 5-year interval (2008-2013) at a Canadian tertiary care psychiatric hospital. Details about participants' clinical profile, index course of ECT, outcome, side effects, and comorbidities were extracted and analyzed. RESULTS: Thirteen adolescents aged 15 to 18 years, received a mean of 14 (SD, 4.5) ECT sessions per patient. Based on the Beck Depression Inventory-II at baseline and after treatment with ECT, a reliable improvement was observed in 10 patients, with 3 achieving full recovery. Through mixed effects linear modeling, we found a decrease of 0.96 points (95% CI, -1.31 to -0.67, P < 0.001) on the Beck Depression Inventory-II total score for every ECT treatment received. The Montreal Cognitive Assessment was used for monitoring of cognitive function throughout the treatment. Adverse effects included transient subjective cognitive impairment (n = 11), headache (n = 10), muscular pain (n = 9), prolonged seizure (n = 3), and nausea and/or vomiting (n = 3). CONCLUSIONS: A clinically significant improvement was observed for 10 (77%) adolescents receiving ECT for treatment-resistant depression. These observations suggest that ECT is a potential treatment option for refractory depression in selected adolescents. More data are needed to draw conclusions about efficacy and possible predictors of treatment response. PMID- 25830810 TI - Apps seeking theories: results of a study on the use of health behavior change theories in cancer survivorship mobile apps. AB - BACKGROUND: Thousands of mobile health apps are now available for use on mobile phones for a variety of uses and conditions, including cancer survivorship. Many of these apps appear to deliver health behavior interventions but may fail to consider design considerations based in human computer interface and health behavior change theories. OBJECTIVE: This study is designed to assess the presence of and manner in which health behavior change and health communication theories are applied in mobile phone cancer survivorship apps. METHODS: The research team selected a set of criteria-based health apps for mobile phones and assessed each app using qualitative coding methods to assess the application of health behavior change and communication theories. Each app was assessed using a coding derived from the taxonomy of 26 health behavior change techniques by Abraham and Michie with a few important changes based on the characteristics of mHealth apps that are specific to information processing and human computer interaction such as control theory and feedback systems. RESULTS: A total of 68 mobile phone apps and games built on the iOS and Android platforms were coded, with 65 being unique. Using a Cohen's kappa analysis statistic, the inter-rater reliability for the iOS apps was 86.1 (P<.001) and for the Android apps, 77.4 (P<.001). For the most part, the scores for inclusion of theory-based health behavior change characteristics in the iOS platform cancer survivorship apps were consistently higher than those of the Android platform apps. For personalization and tailoring, 67% of the iOS apps (24/36) had these elements as compared to 38% of the Android apps (12/32). In the area of prompting for intention formation, 67% of the iOS apps (34/36) indicated these elements as compared to 16% (5/32) of the Android apps. CONCLUSIONS: Mobile apps are rapidly emerging as a way to deliver health behavior change interventions that can be tailored or personalized for individuals. As these apps and games continue to evolve and include interactive and adaptive sensors and other forms of dynamic feedback, their content and interventional elements need to be grounded in human computer interface design and health behavior and communication theory and practice. PMID- 25830811 TI - Risk of Suicide Following Deliberate Self-poisoning. AB - IMPORTANCE: Suicide is the tenth leading cause of death in the United States, and its rate has risen by 16% in the past decade. Deliberate self-poisoning is the leading method of attempted suicide. Unlike more violent methods, which are almost universally fatal, survival following self-poisoning is common, providing an opportunity for secondary prevention. However, the long-term risk of suicide following a first episode of self-poisoning is unknown. OBJECTIVE: To determine the risk of suicide and mortality from other causes following a first self poisoning episode. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study using multiple linked health care databases. We identified all individuals with a first self-poisoning episode in Ontario, Canada, from April 1, 2002, through December 31, 2010, and followed up all surviving participants until December 31, 2011, or death, whichever occurred first. For each individual with a deliberate self-poisoning episode, we randomly selected 1 control from the same population with no such history, matched for age (within 3 months), sex, and calendar year. MAIN OUTCOMES AND MEASURES: The primary analysis examined the risk of suicide following discharge after self-poisoning. The secondary analyses explored factors associated with suicide and examined the risk of death caused by accidents or any other cause. RESULTS: We identified 65 784 patients (18 482 [28.1%] younger than 20 years) who were discharged after a first self-poisoning episode. During a median follow-up of 5.3 years (interquartile range, 3.1-7.6 years), 4176 died, including 976 (23.4%) by suicide. The risk of suicide following self-poisoning was markedly increased relative to controls (hazard ratio, 41.96; 95% CI, 27.75-63.44), corresponding to a suicide rate of 278 vs 7 per 100 000 person-years, respectively. The median time from hospital discharge to completed suicide was 585 days (interquartile range, 147-1301 days). Older age, male sex, multiple intervening self-poisoning episodes, higher socioeconomic status, depression, and recent psychiatric care were strongly associated with suicide. Patients with a self-poisoning episode were also more likely to die because of accidents (hazard ratio, 10.45; 95% CI, 8.10-13.47) and all causes combined (hazard ratio, 5.55; 95% CI, 5.12-6.02). CONCLUSIONS AND RELEVANCE: A first self-poisoning episode is a strong predictor of subsequent suicide and premature death. Most suicides occur long after the index poisoning, emphasizing the importance of longitudinal, sustained secondary prevention initiatives. PMID- 25830812 TI - Labor pain relief for parturients: We can do better: Retraction. AB - [This retracts the article on p. 1 in vol. 9, PMID: 25558189.] PMID- 25830813 TI - Effect of cigarette design on biomarkers of exposure, puffing topography and respiratory parameters. AB - Despite the lack of evidence, many reports exist which have implied that smokers inhale low-yield cigarette smoke more deeply than that of high-yield cigarettes. The objective of this study was to investigate the effect of short-term switching between smoker's own brand and test cigarettes with different smoke yields on puffing topography, respiratory parameters and biomarkers of exposure. Participants were randomly assigned to smoke either a Test Cigarette-High Tar (TCH), for two days, and then switched to a Test Cigarette-Low Tar (TCL), for two days or the reverse order (n = 10 each sequence). Puffing topography (CReSS microdevice), respiratory parameters (inductive plethysmography) and biomarkers of exposure (BOE, urinary nicotine equivalents - NE and blood carboxyhemoglobin - COHb) were measured at baseline and on days 2 and 4. The average puffs per cigarette, puff volume and puff durations were statistically significantly lower, and inter-puff interval was significantly longer for the TCH compared to the TCL groups. Respiratory parameters were not statistically significantly different between the TCH and TCL groups. Post-baseline NE and COHb were statistically significantly lower in the TCL compared to the TCH groups. Under the conditions of this study, we found no indication of changes in respiratory parameters, particularly inhalation time and volume, between study participants smoking lower versus higher yield cigarettes. Likewise, the BOE provides no indication of deeper inhalation when smoking low- versus high-yield cigarettes. These findings are consistent with the published literature indicating smoking low-yield cigarettes does not increase the depth of inhalation. PMID- 25830815 TI - Factors Affecting Surgical Site Infection Rates in Hepatobiliary Surgery. AB - BACKGROUND: There are several studies regarding risk factors affecting surgical site infections (SSIs); nevertheless, there are an insufficient number of studies focusing on risk factors for SSI in hepatobiliary (HPB) surgery. In this study, we aimed to determine risk factors related to HPB surgery. METHODS: A total of 1,418 patients were included in this study, all of whom underwent hepatobiliary system surgery in a five-year period between January 2005 and December 2009. Demographic data, patient- and surgery-related risk factors, and laboratory parameters were analyzed retrospectively from a database maintained prospectively. RESULTS: The overall incidence of SSI was 3.94% for HPB surgery. In multivariable analysis, blood transfusion (OR: 20.9), the presence of surgical drains (OR: 10.7), a pre-operative hospital stay of more than eight days (OR: 8.1), diabetes mellitus (OR: 6.2), chronic obstructive pulmonary disease (OR: 6.127), inappropriate antimicrobial prophylaxis (OR: 6), obesity (OR: 3.2), the presence of an external-internal biliary drainage catheter (OR: 2), and a direct bilirubin concentrations more than 15 mg/dL (OR: 1.4) were determined as independent risk factors related to SSI. E.coli and Enterococcus spp. were the pathogens isolated most commonly in SSIs. CONCLUSIONS: Most of the independent risk factors for hepatobiliary system surgery are similar to those for other general abdominal surgical procedures. The presence of an external-internal biliary drainage catheter and direct bilirubin concentrations higher than 15 mg/dL were found to be specific risk factors for HPB surgery. PMID- 25830814 TI - Propofol causes vasodilation in vivo via TRPA1 ion channels: role of nitric oxide and BKCa channels. AB - BACKGROUND: Transient receptor potential (TRP) ion channels of the A1 (TRPA1) and V1 (TRPV1) subtypes are key regulators of vasomotor tone. Propofol is an intravenous anesthetic known to cause vasorelaxation. Our objectives were to examine the extent to which TRPA1 and/or TRPV1 ion channels mediate propofol induced depressor responses in vivo and to delineate the signaling pathway(s) involved. METHODS: Mice were subjected to surgery under 1.5-2.5% sevoflurane gas with supplemental oxygen. After a stable baseline in mean arterial pressure (MAP) was achieved propofol (2.5, 5.0, 10.0 mg/kg/min) was administered to assess the hemodynamic actions of the intravenous anesthetic. The effect of nitric oxide synthase (NOS) inhibition with L-NAME and/or calcium-gated K+ channel (BKCa) inhibition with Penetrim A (Pen A), alone and in combination, on propofol-induced decreases in mean arterial pressure were assessed in control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). RESULTS: Propofol decreased MAP in control mice and this effect was markedly attenuated in TRPA1-/- and TRPAV-/- mice but unaffected in TRPV1-/-mice. Moreover, pretreatment with L-NAME or Pen A attenuated the decrease in MAP in control and TRPV1-/- mice, and combined inhibition abolished the depressor response. In contrast, the markedly attenuated propofol-induced depressor response observed in TRPA1-/- and TRPAV-/- mice was unaffected by pre-treatment with Pen A or L-NAME when used either alone or in combination. CONCLUSION: These data demonstrate for the first time that propofol induced depressor responses in vivo are predominantly mediated by TRPA1 ion channels with no involvement of TRPV1 ion channels and includes activation of both NOS and BKCa channels. PMID- 25830816 TI - Theoretical Characterization of the Flavin-Based Fluorescent Protein iLOV and its Q489K Mutant. AB - The iLOV protein is one of the most promising members of the family of engineered flavin-based fluorescent proteins (FbFPs), considered as an alternative to the green fluorescent protein family. We modeled the spectral properties of iLOV using quantum chemistry, quantum mechanics/molecular mechanics (QM/MM), and molecular dynamics approaches. Computational results predict that the conserved Gln489 side chain in iLOV adopts two almost equally populated conformations, Glnin and Glnout, altering hydrogen bonding near the flavin chromophore. Formation of the flavinN5-Gln489 and flavinO4-Gln489 hydrogen bonds in the case of Glnin accounts for the pronounced shifts of the flavin absorption and fluorescence maxima to the longer wavelengths. Following these results, we propose to introduce a point mutation in iLOV, Q489K, with the aim to obtain a more red-shifted variant. According to our simulations, this mutation should lead to a considerable, about 50 nm, red shift of the absorption and emission band maxima, thus introducing a new color in the FbFP palette. PMID- 25830817 TI - Electronic properties of electrical vortices in ferroelectric nanocomposites from large-scale ab initio computations. AB - An original ab initio procedure is developed and applied to a ferroelectric nanocomposite, in order to reveal the effect of electrical vortices on electronic properties. Such procedure involves the combination of two large-scale numerical schemes, namely, the effective Hamiltonian (to incorporate ionic degrees of freedom) and the linear-scaling three-dimensional fragment method (to treat electronic degrees of freedom). The use of such procedure sheds some light into the origin of the recently observed current that is activated at rather low voltages in systems possessing electrical vortices. It also reveals a novel electronic phenomena that is a systematic control of the type of the band alignment (i.e., type I versus type II) within the same material via the temperature-driven annihilation/formation of electrical topological defects. PMID- 25830818 TI - Epidemiology of irritable bowel syndrome. PMID- 25830819 TI - Teamwork skills in actual, in situ, and in-center pediatric emergencies: performance levels across settings and perceptions of comparative educational impact. AB - INTRODUCTION: Pediatric emergencies require effective teamwork. These skills are developed and demonstrated in actual emergencies and in simulated environments, including simulation centers (in center) and the real care environment (in situ). Our aims were to compare teamwork performance across these settings and to identify perceived educational strengths and weaknesses between simulated settings. We hypothesized that teamwork performance in actual emergencies and in situ simulations would be higher than for in-center simulations. METHODS: A retrospective, video-based assessment of teamwork was performed in an academic, pediatric level 1 trauma center, using the Team Emergency Assessment Measure (TEAM) tool (range, 0-44) among emergency department providers (physicians, nurses, respiratory therapists, paramedics, patient care assistants, and pharmacists). A survey-based, cross-sectional assessment was conducted to determine provider perceptions regarding simulation training. RESULTS: One hundred thirty-two videos, 44 from each setting, were reviewed. Mean total TEAM scores were similar and high in all settings (31.2 actual, 31.1 in situ, and 32.3 in-center, P = 0.39). Of 236 providers, 154 (65%) responded to the survey. For teamwork training, in situ simulation was considered more realistic (59% vs. 10%) and more effective (45% vs. 15%) than in-center simulation. DISCUSSION: In a video-based study in an academic pediatric institution, ratings of teamwork were relatively high among actual resuscitations and 2 simulation settings, substantiating the influence of simulation-based training on instilling a culture of communication and teamwork. On the basis of survey results, providers favored the in situ setting for teamwork training and suggested an expansion of our existing in situ program. PMID- 25830820 TI - Simulated patients' perspectives of and perceived role in medical students' professional identity development. AB - INTRODUCTION: Much has been written about medical students' professional identity formation, the process of "becoming" a doctor. During their training, medical students interact with a range of teachers and trainers. Among these are simulated patients (SPs) who role-play patients, assisting students with their communication, procedural, and physical examination skills. With SPs regularly interacting with students, this qualitative study explored their views of students' emerging professional identities at one Australian medical school. SPs' contributions to developing professional identities were also explored. METHODS: Fourteen SPs were interviewed individually or in pairs. After template analysis of the transcripts using a priori themes, a follow-up focus group (n = 7) was arranged. FINDINGS: Although being older (implying maturity and more life experience) and exposure to real patients and previous health care experience were identified as contributing to developing an identity as a doctor, SPs recognized that for some, an existing professional identity might impede the development of a new identity. Simulated patients were of the opinion that they contributed to students' professional identities by creating a supportive environment for honing skills, which they did by realistically role-playing patient scripts, by making their bodies available, and by providing feedback as "patients." CONCLUSIONS: Through their authentic portrayal of patients and through their feedback, we are of the opinion that our SPs can contribute to students' developing identities as doctors. As lay individuals who often encounter students longitudinally, we believe that SPs offer a particular lens through which to view students' emerging identities as future doctors. PMID- 25830821 TI - Suffering to change. PMID- 25830822 TI - Quality and Safety Aspects of Cereals (Wheat) and Their Products. AB - Cereals and, most specifically, wheat are described in this chapter highlighting on their safety and quality aspects. Moreover, wheat quality aspects are adequately addressed since they are used to characterize dough properties and baking quality. Determination of dough properties is also mentioned and pasta quality is also described in this chapter. Chemometrics-multivariate analysis is one of the analyses carried out. Regarding production weighing/mixing of flours, kneading, extruded wheat flours, and sodium chloride are important processing steps/raw materials used in the manufacturing of pastry products. Staling of cereal-based products is also taken into account. Finally, safety aspects of cereal-based products are well documented with special emphasis on mycotoxins, acrylamide, and near infrared methodology. PMID- 25830823 TI - Accurate and inexpensive prediction of the color optical properties of anthocyanins in solution. AB - The simulation of the color optical properties of molecular dyes in liquid solution requires the calculation of time evolution of the solute absorption spectra fluctuating in the solvent at finite temperature. Time-averaged spectra can be directly evaluated by combining ab initio Car-Parrinello molecular dynamics and time-dependent density functional theory calculations. The inclusion of hybrid exchange-correlation functionals, necessary for the prediction of the correct transition frequencies, prevents one from using these techniques for the simulation of the optical properties of large realistic systems. Here we present an alternative approach for the prediction of the color of natural dyes in solution with a low computational cost. We applied this approach to representative anthocyanin dyes: the excellent agreement between the simulated and the experimental colors makes this method a straightforward and inexpensive tool for the high-throughput prediction of colors of molecules in liquid solvents. PMID- 25830825 TI - Primary prevention of cardiovascular disease with hormone replacement therapy. AB - Many peri- and postmenopausal women suffer from a reduced quality of life due to menopausal symptoms and preventable diseases. The importance of cardiovascular disease in women must be emphasized, as it is the leading cause of mortality and morbidity in women. It is well known that female hormones contribute to the later onset of cardiovascular disease in women. The effect of estrogens has for decades been understood from observational studies of postmenopausal women treated with hormone replacement therapy (HRT). Later, treatment with HRT was disregarded due to the fear of side-effects and an ambiguity of the cardiovascular advantages. Accumulating knowledge from the large number of trials and studies has elucidated the cause for the disparity in results. In this paper, the beneficial effects of HRT, with emphasis on cardiovascular disease are explained, and the relative and absolute risks of side-effects are discussed. PMID- 25830824 TI - Patients' perspectives of accessibility and digital delivery of factual content provided by official medical and surgical specialty society websites: a qualitative assessment. AB - BACKGROUND: Health care websites provide a valuable resource of health information to online consumers, especially patients. Official surgical and medical society websites should be a reliable first point of contact. OBJECTIVE: The primary aim of this study was to quantitatively assess medical and surgical society websites for content and highlight the essential features required for a high-quality, user-friendly society website. METHODS: Twenty specialty association websites from each of the regions, Australia, UK, Canada, Europe, and the USA were selected for a total of 100 websites. Medical and surgical specialities were consistent across each region. Each website was systematically and critically analysed for content and usability. RESULTS: The average points scored per website was 3.2 out of 10. Of the total (N=100) websites, 12 scored at least 7 out of 10 points and 2 scored 9 out of 10. As well, 35% (35.0/100) of the websites had an information tab for patients on their respective homepages while 38% (38.0/100) had download access to patient information. A minority of the websites included different forms of multimedia such as pictures and diagrams (24.0/100, 24%) and videos (18.0/100, 18%). CONCLUSIONS: We found that most society websites did not meet an adequate standard for delivery of information. Half of the websites were not patient accessible, with the primary focus being for health professionals. As well, most required logins for information access. Specialty health care societies should create patient-friendly websites that would be beneficial to all online consumers. PMID- 25830827 TI - Introduction to the 57th annual Thomas L. Petty Aspen Lung Conference: Rebuilding the injured lung. PMID- 25830826 TI - Bovine immunoglobulin/protein isolate binds pro-inflammatory bacterial compounds and prevents immune activation in an intestinal co-culture model. AB - Intestinal barrier dysfunction is associated with chronic gastrointestinal tract inflammation and diseases such as IBD and IBS. Serum-derived bovine immunoglobulin/protein isolate (SBI) is a specially formulated protein preparation (>90%) for oral administration. The composition of SBI is greater than 60% immunoglobulin including contributions from IgG, IgA, and IgM. Immunoglobulin within the lumen of the gut has been recognized to have anti inflammatory properties and is involved in maintaining gut homeostasis. The binding of common intestinal antigens (LPS and Lipid A) and the ligand Pam3CSK4, by IgG, IgA, and IgM in SBI was shown using a modified ELISA technique. Each of these antigens stimulated IL-8 and TNF-alpha cytokine production by THP-1 monocytes. Immune exclusion occurred as SBI (<=50 mg/mL) bound free antigen in a dose dependent manner that inhibited cytokine production by THP-1 monocytes in response to 10 ng/mL LPS or 200 ng/mL Lipid A. Conversely, Pam3CSK4 stimulation of THP-1 monocytes was unaffected by SBI/antigen binding. A co-culture model of the intestinal epithelium consisted of a C2BBe1 monolayer separating an apical compartment from a basal compartment containing THP-1 monocytes. The C2BBe1 monolayer was permeabilized with dimethyl palmitoyl ammonio propanesulfonate (PPS) to simulate a damaged epithelial barrier. Results indicate that Pam3CSK4 was able to translocate across the PPS-damaged C2BBe1 monolayer. However, binding of Pam3CSK4 by immunoglobulins in SBI prevented Pam3CSK4 translocation across the damaged C2BBe1 barrier. These results demonstrated steric exclusion of antigen by SBI which prevented apical to basal translocation of antigen due to changes in the physical properties of Pam3CSK4, most likely as a result of immunoglobulin binding. This study demonstrates that immunoglobulins in SBI can reduce antigen associated inflammation through immune and steric exclusion mechanisms and furthers the mechanistic understanding of how SBI might improve immune status and reduce inflammation in various intestinal disease states. PMID- 25830829 TI - Epithelial-mesenchymal interactions in fibrosis and repair. Transforming growth factor-beta activation by epithelial cells and fibroblasts. AB - Transforming growth factor-beta (TGF-beta) plays a central role in driving tissue fibrosis. TGF-beta is secreted in a latent form, held latent by noncovalent association of the active cytokine with a peptide derived from cleavage of the N terminal domain of the same gene product, and needs to be activated extracellularly to exert any of its diverse biological effects. We have shown that two of the three mammalian isoforms of TGF-beta, TGF-beta1 and TGF-beta3, depend on interactions with cell surface integrins for activation. We found that the integrin alphavbeta6 is highly induced on injured alveolar epithelial cells, potently induces TGF-beta activation, and is critical for the development of pulmonary fibrosis and acute lung injury. However, although TGF-beta drives fibrosis in virtually every anatomic site, alphavbeta6-mediated TGF-beta activation is much more restricted. For example, alphavbeta6 is not induced on injured hepatocytes and plays little or no role in cirrhosis induced by repetitive hepatocyte injury. Fibroblasts are highly contractile cells that express multiple integrins closely related to alphavbeta6, which share the promiscuous alphav subunit, so we reasoned that perhaps one or more of these alphav integrins on fibroblasts might substitute for alphavbeta6 and activate the TGF-beta required to drive liver fibrosis. Indeed, deletion of the alphav subunit from activated fibroblasts protected mice from carbon tetrachloride-induced liver fibrosis. Importantly, these same mice were protected from bleomycin-induced pulmonary fibrosis and renal fibrosis caused by unilateral ureteral obstruction, despite the presence of epithelial alphavbeta6 in these mice. These results suggest that the generation and maintenance of sufficient quantities of active TGF-beta to cause tissue fibrosis in multiple organs probably depends on at least two sources-TGF-beta activation by injured epithelial cells that drives fibroblast expansion and activation and an amplification step that involves TGF beta activation by an alphav integrin on activated fibroblasts. These results suggest that intervening at either of these steps could be useful for the treatment of fibrotic diseases. PMID- 25830828 TI - Mechanisms of alveolar epithelial injury, repair, and fibrosis. AB - The challenge facing many fibrotic lung diseases is that these conditions usually present late, often after several decades of repetitive alveolar epithelial injury, during which functional alveolar units are gradually obliterated and replaced with nonfunctional connective tissue. The resulting fibrosis is often progressive and, in the case of idiopathic pulmonary fibrosis (IPF), invariably leads to respiratory insufficiency and, ultimately, the premature death of affected individuals. Recent years have seen a greater appreciation of the relative importance of chronic inflammation as a driver of fibrotic responses. Current evidence suggests that IPF arises as a result of repetitive epithelial injury and a highly aberrant wound healing response in genetically susceptible and aged individuals. Nonspecific anti-inflammatory agents offer no clinical benefit, but the potential contribution of maladaptive immune responses in determining outcome is gaining increasing recognition. The importance of key differences in the tissue-regenerative potential in young versus aged individuals is also beginning to be more fully appreciated. Moreover, there is considerable overlap in the mechanisms underlying tissue repair and cancer, and patients with IPF are at heightened risk of developing lung cancer. Progressive fibrosis and cancer may therefore represent the extremes of a highly dysregulated tissue injury response. This brief review focuses on some of this evidence and on our current understanding of abnormal tissue repair responses after chronic epithelial injury in the specific context of IPF. PMID- 25830831 TI - Mechanisms and clinical consequences of acute lung injury. AB - Acute respiratory distress syndrome (ARDS) was first described in 1967, and since then there have been a large number of studies addressing its pathogenesis and therapies. Despite intense research efforts, very few therapies for ARDS have been shown to be effective other than the use of lung protection strategies. The scarcity of therapeutic choices is related to the intricate pathogenesis of the syndrome and to insensitive and aspecific criteria to diagnose this profound acute respiratory failure. The aim of this paper is to summarize advances of new ARDS definitions and provide an overview of new relevant signaling pathways that mediate acute lung injury. PMID- 25830830 TI - Matrix, mesenchyme, and mechanotransduction. AB - The extracellular matrix (ECM) of the lung serves as both a scaffold for resident cells and a mechanical support for respiratory function. The ECM is deposited during development and undergoes continuous turnover and maintenance during organ growth and homeostasis. Cells of the mesenchyme, including the tissue resident fibroblast, take a leading role in depositing and organizing the matrix and do so in an anatomically distinct fashion, with differing composition, organization, and mechanical properties within the airways, vessels, and alveoli of the lung. Recent technological advancements have allowed the lung's ECM biochemical composition and mechanical properties to be studied with improved resolution, thereby identifying novel disease-related changes in ECM characteristics. In parallel, efforts to study cells seeded on normal and disease-derived matrices have illustrated the powerful role the ECM can play in altering key functions of lung resident cells. The mechanical properties of the matrix have been identified as an important modifier of cell-matrix adhesions, with matrices of pathologic stiffness promoting profibrotic signaling and cell function. Ongoing work is identifying both mechanically activated pathways in mesenchymal cells and disease related ECM molecules that biochemically regulate cell function. Uncovering the control systems by which cells respond to and regulate the matrix, and the failures in these systems that underlie aberrant repair, remains a major challenge. Progress in this area will be an essential element in efforts to engineer functional lung tissue for regenerative approaches and will be key to identifying new therapeutic strategies for lung diseases characterized by disturbed matrix architecture. PMID- 25830832 TI - Lung extracellular matrix and fibroblast function. AB - Extracellular matrix (ECM) is a tissue-specific macromolecular structure that provides physical support to tissues and is essential for normal organ function. In the lung, ECM plays an active role in shaping cell behavior both in health and disease by virtue of the contextual clues it imparts to cells. Qualities including dimensionality, molecular composition, and intrinsic stiffness all promote normal function of the lung ECM. Alterations in composition and/or modulation of stiffness of the focally injured or diseased lung ECM microenvironment plays a part in reparative processes performed by fibroblasts. Under conditions of remodeling or in disease states, inhomogeneous stiffening (or softening) of the pathologic ECM may both precede modifications in cell behavior and be a result of disease progression. The ability of ECM to stimulate further ECM production by fibroblasts and drive disease progression has potentially significant implications for mesenchymal stromal cell-based therapies; in the setting of pathologic ECM stiffness or composition, the therapeutic intent of progenitor cells may be subverted. Taken together, current data suggest that lung ECM actively contributes to health and disease; thus, mediators of cell-ECM signaling or factors that influence ECM stiffness may represent viable therapeutic targets in many lung disorders. PMID- 25830833 TI - Characteristic patterns in the fibrotic lung. Comparing idiopathic pulmonary fibrosis with chronic lung allograft dysfunction. AB - Tissue fibrosis, a major cause of death worldwide, leads to significant organ dysfunction in any organ of the human body. In the lung, fibrosis critically impairs gas exchange, tissue oxygenation, and immune function. Idiopathic pulmonary fibrosis (IPF) is the most detrimental and lethal fibrotic disease of the lung, with an estimated median survival of 50% after 3-5 years. Lung transplantation currently remains the only therapeutic alternative for IPF and other end-stage pulmonary disorders. Posttransplant lung function, however, is compromised by short- and long-term complications, most importantly chronic lung allograft dysfunction (CLAD). CLAD affects up to 50% of all transplanted lungs after 5 years, and is characterized by small airway obstruction with pronounced epithelial injury, aberrant wound healing, and subepithelial and interstitial fibrosis. Intriguingly, the mechanisms leading to the fibrotic processes in the engrafted lung exhibit striking similarities to those in IPF; therefore, antifibrotic therapies may contribute to increased graft function and survival in CLAD. In this review, we focus on these common fibrosis-related mechanisms in IPF and CLAD, comparing and contrasting clinical phenotypes, the mechanisms of fibrogenesis, and biomarkers to monitor, predict, or prognosticate disease status. PMID- 25830834 TI - A human breathing lung-on-a-chip. AB - Here we describe a microphysiological system that replicates the functional unit of the living human lung. This human "breathing lung-on-a-chip" microdevice provides unique capabilities to reconstitute three-dimensional microarchitecture, dynamic mechanical activity, and integrated physiological function of the alveolar-capillary interface. We demonstrate the potential of this microengineered biomimetic model for screening environmental particulates and modeling complex human disease processes. PMID- 25830835 TI - Using nature's platform to engineer bio-artificial lungs. AB - Native lung extracellular matrix can be isolated from cadaveric organs via perfusion decellularization and provides a novel scaffold material for lung engineering. Based on this platform, several proof-of-principle studies have demonstrated the feasibility of whole organ recellularization and culture in rodent models and have helped us better understand the numerous challenges in up scaling to clinically relevant tissues. Standardized protocols to generate whole lung scaffolds of porcine and human scale have been reported, but our understanding of the remaining extracellular matrix components and their properties is incomplete. Effective recellularization will require the isolation and in vitro expansion of clinically relevant cell sources, either from primary or stem cell-derived populations, and techniques to effectively deliver these populations throughout the lung scaffold. Ultimately, only tightly controlled recapitulation of tissue development and repair in vitro will enable us to mature lung grafts to function before implantation. Although substantial progress has been made, we are only beginning to grasp the complexity of this exciting new technology. PMID- 25830836 TI - Embryonic and induced pluripotent stem cells for lung regeneration. AB - The discovery of embryonic and induced pluripotent stem cells (ESCs and iPSCs) has ushered in an exciting new era of regenerative medicine. Human pluripotent stem cells can be "directed" in vitro toward lung epithelium by applying specific stepwise combinations of growth factors that recapitulate the molecular mechanisms of respiratory development in animal models. In a relatively short time, there has been significant progress in deriving lung epithelium from ESCs/iPSCs. These directed differentiation protocols include high concentrations of activin A to induce definitive endoderm followed by dual inhibition of bone morphogenic protein and TGF-beta signaling pathways to produce anterior foregut endoderm. Subsequent stimulation of Wnt, bone morphogenic protein, and fibroblast growth factor signaling leads to lung epithelial lineage specification, identified by the expression of Nkx2.1. These cells subsequently express other markers of the developing lung and a variety of lung epithelial subtypes. The major limitation in the field currently is deriving and characterizing mature, functional lung epithelium. The generation of iPSCs is now well established, and researchers have generated iPSCs from patients with acquired and inherited lung diseases. This platform offers unparalleled opportunities to model lung development and disease using human cells. PMID- 25830837 TI - Therapeutic potential of mesenchymal stromal cells for acute respiratory distress syndrome. AB - Based on preclinical data, cell-based therapy with bone marrow-derived mesenchymal stem (stromal) cells (MSCs) is a potentially attractive new therapeutic option for treating patients with the acute respiratory distress syndrome. Small and large animal models of acute lung injury from endotoxin, live bacteria, and sepsis have shown that MSCs can decrease lung injury and increase survival. The mechanisms for benefit are mediated in part by paracrine release of several antiinflammatory cytokines, keratinocyte growth factor, angiopoietin-1, as well as the release of antimicrobial peptides. There is also evidence that MSCs can transfer mitochondria and restore normal bioenergetics to injured alveolar epithelium. Some of the beneficial effects are mediated by microvesicles. A phase 1 safety and dose-escalation trial was completed and a randomized, double-blind clinical trial is currently underway. PMID- 25830838 TI - Confronting the frustrations of negative clinical trials in acute respiratory distress syndrome. AB - Despite robust successes in trials of mechanical ventilation, pharmacologic interventions in acute respiratory distress syndrome have been disappointing. Although ineffective therapy remains the compelling explanation for these negative trials, other possible explanations exist. These negative trials, better termed "statistically negative trials" or "indeterminate trials," cannot prove that a therapy is ineffective. It is important for clinicians and investigators to appreciate the alternative explanations for negative trials of potentially effective therapies because these indicate options for improving clinical trials in acute respiratory distress syndrome. These options can be organized into strategies that increase sample size, increase the signal from the therapy, and reduce the noise or variation in the study. Each of the strategies to improve the likelihood of a positive clinical trial poses a potential tradeoff in generalizability, cost, sample size, signal, or noise. PMID- 25830839 TI - Rebuilding the injured lung. AB - The 57th annual Thomas L. Petty Aspen Lung Conference, entitled "Rebuilding the Injured Lung," was held from June 4 to 7, 2014 at the Gant Conference Center in Aspen, Colorado. Investigators from a wide range of disciplines and perspectives convened to discuss the biology of lung injury, how the lung repairs itself, how and why repair fails, and how the repair process can be enhanced. Among the challenges identified in the course of the conference was how to develop more predictive experimental models that capture the multidimensional complexity of lung injury and repair in a tractable manner. From such approaches that successfully fuse the biological and physical sciences, the group envisioned that new therapies for acute and chronic lung injury would emerge. The discussion of experimental therapeutics ranged from pharmaceuticals and cells that interdict fibrosis and enhance repair to a de novo lung derived from stem cells repopulating a decellularized matrix. PMID- 25830857 TI - Acute effects of continuous positive airway pressure on pulse pressure in CHF. PMID- 25830855 TI - Conceptual approaches to lung injury and repair. AB - Lung injury and repair is a broad topic that includes many cell types and is relevant to the pathogenesis of most lung diseases. Here, we focus on injury and repair of the alveolus, the principal function of which is to achieve gas exchange. The many cell types and structures present in the alveolus are discussed, with emphasis on their interactions in both health and disease. We define injury as damage resulting in impaired gas exchange; physiologic repair, then, requires restoration of normal alveolar architecture and function. The role of inflammation in both injury and repair of structural alveolar cells, particularly epithelial cells, as well as mechanisms of resolution of inflammation will be addressed. Finally, emphasis is placed on the importance of addressing quantitatively the dynamic and complex multidirectional interactions between the many alveolar cell types and structures in three dimensions over time and in relating such mechanistic studies to physiologic outcomes and human disease. PMID- 25830858 TI - Case 2/2015 a 33-year-old woman with double right ventricular chamber and ventricular septal defect. PMID- 25830859 TI - Giant left atrial thrombus with double coronary vascularization. PMID- 25830860 TI - Mitral valve aneurysm secondary to probable infective endocarditis. PMID- 25830861 TI - Body dissatisfaction and mirror exposure: evidence for a dissociation between self-report and physiological responses in highly body-dissatisfied women. AB - BACKGROUND: Weight and shape concerns are widespread in the general population. Mirror exposure has been used to reduce body dissatisfaction but little is known about the mechanisms which underlie this therapeutic technique. The present study examined emotional, cognitive, and psychophysiological responses, in women with high and low levels of body dissatisfaction, exposed to their own bodies in a mirror. METHOD: Forty-two university-attending women (21 high body-dissatisfied (HBD) and 21 low body-dissatisfied (LBD)), were confronted with their own body during four 5-min trials in which participants were instructed to focus their attention on different parts of their body under standardized conditions. Emotional and cognitive measures were taken after each exposure trial. Heart rate (HR) and skin conductance (SC) were recorded continuously. RESULTS: HBD women experienced more negative emotions and cognitions following body exposure compared to LBD women but, conversely, showed a reduced physiological reaction in terms of HR and SC. In both groups greater physiological responses were observed looking at the thighs, buttocks, and abdomen. Extent of negative emotions and cognitions were positively associated with HR and/or SC in LBD women but no associations were observed in HBD women. CONCLUSION: The dissociation between self-report and psychophysiological measures in HBD women supports the existence of a passive-behavioral inhibited coping style in HBD women and suggests deficiencies in the generation of physiological correlates of emotion related to body dissatisfaction. PMID- 25830862 TI - Meta-analysis of microRNA-146a rs2910164 G>C polymorphism association with autoimmune diseases susceptibility, an update based on 24 studies. AB - BACKGROUND: Published data showed that the susceptibility of autoimmune diseases (ADs) was associated with the polymorphism rs2910164 in microRNA-146a (miR-146a). However, the results remain controversial so far. Two meta-analyses published in 2013 and 2014 came to opposite conclusions. In order to derive a more precise estimation of the relationship, we performed this meta-analysis. METHODS: We searched the PubMed, OvidSP and CNKI databases (published prior to September 8th, 2014) and extracted data from eligible studies. The procedure of meta-analysis was performed by using the Stata 12.0 software. Random effect model or fixed effect model were chosen respectively, according to the between study heterogeneities. RESULTS: A total of 24 case-control studies, 11 more than previous meta-analysis on this topic, were involved. We took stratified analyses by different ethnicities and different types of diseases in different genetic models. In Caucasian subgroup, significant increased risks of GC genotype and GC+CC genotype with ADs susceptibility were found in heterozygote model (GC vs GG, OR = 1.38, 95% CI 1.04-1.83, p = 0.024) and dominant model (GC+CC vs GG, OR = 1.37, 95% CI 1.01-1.85, p = 0.041), respectively. Meanwhile, in other disease subgroup, significant increased risks of C allele, CC genotype and GC+CC genotype were found in allele model (C vs G, OR = 1.16, 95% CI 1.04-1.31, p = 0.010), homozygote model (CC vs GG, OR = 1.42, 95% CI 1.10-1.84, p = 0.006) and dominant model (GC+CC vs GG, OR = 1.25, 95% CI 1.04-1.51, p = 0.020), respectively. CONCLUSIONS: MiR-146a rs2910164 G>C polymorphism was associated with the susceptibility of ADs. PMID- 25830863 TI - PDH45 overexpressing transgenic tobacco and rice plants provide salinity stress tolerance via less sodium accumulation. AB - Salinity stress negatively affects the crop productivity worldwide, including that of rice. Coping with these losses is a major concern for all countries. The pea DNA helicase, PDH45 is a unique member of helicase family involved in the salinity stress tolerance. However, the exact mechanism of the PDH45 in salinity stress tolerance is yet to be established. Therefore, the present study was conducted to investigate the mechanism of PDH45-mediated salinity stress tolerance in transgenic tobacco and rice lines along with wild type (WT) plants using CoroNa Green dye based sodium localization in root and shoot sections. The results showed that under salinity stress root and shoot of PDH45 overexpressing transgenic tobacco and rice accumulated less sodium (Na(+)) as compared to their respective WT. The present study also reports salinity tolerant (FL478) and salinity susceptible (Pusa-44) varieties of rice accumulated lowest and highest Na(+) level, respectively. All the varieties and transgenic lines of rice accumulate differential Na(+) ions in root and shoot. However, roots accumulate high Na(+) as compared to the shoots in both tobacco and rice transgenic lines suggesting that the Na(+) transport in shoot is somehow inhibited. It is proposed that the PDH45 is probably involved in the deposition of apoplastic hydrophobic barriers and consequently inhibit Na(+) transport to shoot and therefore confers salinity stress tolerance to PDH45 overexpressing transgenic lines. This study concludes that tobacco (dicot) and rice (monocot) transgenic plants probably share common salinity tolerance mechanism mediated by PDH45 gene. PMID- 25830864 TI - Single Molecule Investigation of Glycine-Chlorite Interaction by Cross-Correlated Scanning Probe Microscopy and Quantum Mechanics Simulations. AB - In this work, we studied the interaction of glycine with the (001) surface of chlorite mineral at a single molecule level by cross-correlating scanning probe microscopy (SPM) and ab initio quantum mechanics (QM) investigations. Chlorite mineral is particularly interesting and peculiar for the interaction with organic molecules because it presents an alternated stacking of brucite-like (hydrophobic) and talc-like (hydrophilic) layers of different polarities. Brucite like is positive, whereas talc-like is negative. The experimental atomic force microscopy (AFM) observations show that glycine is stably and selectively adsorbed on the brucite-like layer, organized in monolayers with different patterns. The sizes of single molecules of glycine measured by AFM are in agreement with those calculated by QM. Glycine molecules were found to align both at the edges and on the terraces of the brucitic surface. QM simulations confirmed the AFM observations that glycine molecule is adsorbed with high adsorption energy preferentially with its plane parallel to the (001) brucite like surface. QM also provided the geometry conformation of the molecule and the bonding scheme between glycine and brucite surface. This kind of data can be very helpful both to biotechnological applications of this substrate and to depict some important processes that might have been occurred in prebiotic environments. PMID- 25830865 TI - Tissue distribution and residue depletion of metronidazole in rainbow trout (Oncorhynchus mykiss). AB - Tissue distribution and residue depletion of metronidazole (MNZ) was studied in rainbow trout (Oncorhynchus mykiss) following oral administration of MNZ in feed at the average dose of 25 mg kg(-1) body weight day(-1) for 7 days at 11 +/- 2 degrees C. The MNZ concentration in feed was 0.25% while daily feed intake was 1% of body weight. The concentrations of MNZ and its main metabolite, hydroxymetronidazole (MNZOH), in fish tissues were determined by LC-MS/MS. The drug was well distributed in tissues with maximum concentrations on day 1 post administration. At this time, the mean MNZ concentrations in muscle, skin, kidney, liver and gill were 14,999, 20,269, 15,070, 10,102 and 16,467 ug kg(-1) respectively. MNZ was converted into MNZOH with the ratio of MNZOH:MNZ up to 7% in all fish tissues throughout the withdrawal period. This shows that MNZ itself is the main residue in rainbow trout. MNZ was detected at the level close to the decision limit (0.20 ug kg(-1)) in muscle, skin and muscle with adhering skin up to 42 days, while in kidney, liver and gill it was up to 28 days post administration. MNZOH was eliminated more rapidly from fish tissues and it was present in muscle alone up to 21 days. The elimination half-lives of MNZ and MNZOH in rainbow trout tissues were 1.83-2.53 and 1.24-2.12 days, respectively. When muscle without skin was analysed, higher MNZ and MNZOH concentrations were detected, and for a longer period of time, than in muscle with adhering skin. Thus muscle alone could be more appropriate for the effective residue control of MNZ in rainbow trout. For the same reason, it is also essential to ensure direct cooling immediately after sampling, since MNZ and its metabolite degrade in fish muscle and skin stored in non-freezing conditions. PMID- 25830866 TI - Remifentanil-acute opioid tolerance and opioid-induced hyperalgesia: a systematic review. AB - The use of opioids may seem to be a double-edged sword; they provide straight analgesic and antihyperalgesic effects initially, but subsequently are associated with the expression of acute opioid tolerance (AOT) and opioid-induced hyperalgesia (OIH) that have been reported in experimental studies and clinical observations. It has been suggested that opioids can induce an acute tolerance and hyperalgesia in dose- and/or time-dependent manners even when used within the clinically accepted doses. Recently, remifentanil has been used for pain management in clinical anesthesia and in the intensive care units because of its rapid onset and offset. We reviewed articles analyzing AOT and/or OIH by remifentanil and focused on the following issues: (1) evidence of remifentanil inducing AOT and/or OIH and (2) importance of AOT and/or OIH in considering the reduction of remifentanil dosage or adopting preventive modulations. Twenty-four experimental and clinical studies were identified using electronic searches of MEDLINE (PubMed, Ovid, Springer, and Elsevier). However, the development of AOT and OIH by remifentanil administration remains controversial. There is no sufficient evidence to support or refute the existence of OIH in humans. PMID- 25830868 TI - Successful Treatment of Life-Threatening Interstitial Lung Disease Secondary to Antisynthetase Syndrome Using Rituximab: A Case Report and Review of the Literature. AB - We are presenting a case of antisynthetase syndrome (ASS) that manifested with severe interstitial pneumonitis in the presence of anti-Jo-1 and Ro (SSA) antibodies. Our patient developed respiratory failure with high oxygen requirements despite treatment by high-dose steroids. The patient was then treated with rituximab. This treatment led to significant improvement in the patient condition, with resolution of the ground glass opacities on high resolution computerized tomography and near normalization of pulmonary function tests. In this communication, we performed a literature review and summarized previous reports pertinent to using of rituximab to treat interstitial lung disease (ILD) secondary to ASS by searching the PubMed database from 1980 to 2014. We were able to find 14 reports that included total of 45 patients with ILD secondary to ASS. A significant improvement in ILD was reported in the majority of reported patients who received rituximab, while there was only 1 mortality related to Pneumocystis jirovecii pneumonia. Rituximab treatment was tolerated well in the majority of cases. It is our conclusion that rituximab can be considered a therapeutic option in ILD secondary to ASS based on our experience with this case and the currently available evidence in the literature. Nevertheless, there is a need for additional controlled studies to assess the efficacy and safety of rituximab in ILD secondary to ASS compared with other immunosuppressive regimens. PMID- 25830867 TI - Case Study: Ticagrelor in PLATO and Prasugrel in TRITON-TIMI 38 and TRILOGY-ACS Trials in Patients With Acute Coronary Syndromes. AB - Cross-trial comparisons are typically inappropriate as there are often numerous differences in study designs, populations, end points, and loading doses of the study drugs. These differences are clearly reflected in the most recent updates to the European Society of Cardiology (ESC) non-ST elevation acute coronary syndrome (NSTE-ACS) and ST elevation myocardial infarction (STEMI) guidelines, which include recommendations for the use of the antiplatelet agents ticagrelor, prasugrel, and clopidogrel, based in part on results from the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38, TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY-ACS) and PLATelet inhibition and patient Outcomes (PLATO) trials. Here, we describe each of these trials in detail and explain the differences between them that make direct comparisons difficult. In conclusion, this information, along with the current guidelines and recommendations, will assist clinicians in deciding the most appropriate treatment pathway for their patients with NSTE-ACS and STEMI. PMID- 25830869 TI - Clinical Predictors Associated With Warfarin Sensitivity. AB - Our study aimed to identify predictors of warfarin sensitivity like demographic, clinical, and genetic data from a previously collected cohort of patients (n = 4272) with a stable warfarin dose who were able to achieve an observed international normalized ratio of 2-3. Predictors of warfarin sensitivity (dose <=21 mg/wk) were identified using a 2-stage approach. First, bivariate analysis, using analysis of variance for continuous variables and chi test for categorical variables, was performed to identify possible predictors of warfarin sensitivity (P < 0.05). Second, logistic regression with backward stepwise selection was then performed using predictors identified in bivariate analysis step to produce final model containing independent predictors at P < 0.05. Increased warfarin sensitivity was associated with increased age; CYP2C9 genotypes 2/3, 1/3, and 3/3; VKORC1 genotypes AA and AG; and amiodarone use. Decreased warfarin sensitivity (ie, weekly warfarin dose of >21 mg) was associated with increased height, increased weight, having diabetes mellitus, VKORC1 genotype GG, and CYP2C9 genotype 1/1. In conclusion, we identified patients' characteristics associated with warfarin sensitivity. This project is expected to improve patient care by identifying patients who need a low warfarin dose before warfarin administration. Early identification of this subset of patients helps minimize the incidence of bleeding. PMID- 25830870 TI - Decision-making on childhood vaccination by highly educated parents. AB - OBJECTIVE To analyze the sociocultural aspects involved in the decision-making process of vaccination in upper-class and highly educated families. METHODS A qualitative approach based on in-depth interviews with 15 couples from the city of Sao Paulo, Southeastern Brazil, falling into three categories: vaccinators, late or selective vaccinators, and nonvaccinators. The interpretation of produced empirical material was performed through content analysis. RESULTS The study showed diverse and particular aspects surrounding the three groups' decisions whether to vaccinate their children. The vaccinators' decision to vaccinate their children was spontaneous and raised no questions. Most late or selective vaccinators experienced a wide range of situations that were instrumental in the decision to delay or not apply certain vaccines. The nonvaccinator's decision making process expressed a broader context of both criticism of hegemonic obstetric practices in Brazil and access to information transmitted via social networks and the internet. The data showed that the problematization of vaccines (culminating in the decision to not vaccinate their children) occurred in the context of humanized birth, was protagonized by women and was greatly influenced by health information from the internet. CONCLUSIONS Sociocultural aspects of the singular Brazilian context and the contemporary society were involved in the decision-making on children's vaccination. Understanding this process can provide a real basis for a deeper reflection on health and immunization practices in Brazil in light of the new contexts and challenges of the world today. PMID- 25830871 TI - Weather parameters and nosocomial bloodstream infection: a case-referent study. AB - OBJECTIVE To evaluate if temperature and humidity influenced the etiology of bloodstream infections in a hospital from 2005 to 2010. METHODS The study had a case-referent design. Individual cases of bloodstream infections caused by specific groups or pathogens were compared with several references. In the first analysis, average temperature and humidity values for the seven days preceding collection of blood cultures were compared with an overall "seven-days moving average" for the study period. The second analysis included only patients with bloodstream infections. Several logistic regression models were used to compare different pathogens and groups with respect to the immediate weather parameters, adjusting for demographics, time, and unit of admission. RESULTS Higher temperatures and humidity were related to the recovery of bacteria as a whole (versus fungi) and of gram-negative bacilli. In the multivariable models, temperature was positively associated with the recovery of gram-negative bacilli (OR = 1.14; 95%CI 1.10;1.19) or Acinetobacter baumannii (OR = 1.26; 95%CI 1.16;1.37), even after adjustment for demographic and admission data. An inverse association was identified for humidity. CONCLUSIONS The study documented the impact of temperature and humidity on the incidence and etiology of bloodstream infections. The results correspond with those from ecological studies, indicating a higher incidence of gram-negative bacilli during warm seasons. These findings should guide policies directed at preventing and controlling healthcare associated infections. PMID- 25830872 TI - Treatment of depression in older adults beyond fluoxetine. AB - This review aimed to discuss the importance of the comprehensive treatment of depression among older adults in Brazil. The abuse of selective serotonin reuptake inhibitors, including fluoxetine hydrochloride, as antidepressants has been considered a serious public health problem, particularly among older adults. Despite the consensus on the need for a comprehensive treatment of depression in this population, Brazil is still unprepared. The interface between pharmacotherapy and psychotherapy is limited due to the lack of healthcare services, specialized professionals, and effective healthcare planning. Fluoxetine has been used among older adults as an all-purpose drug for the treatment of depressive disorders because of psychosocial adversities, lack of social support, and limited access to adequate healthcare services for the treatment of this disorder. Preparing health professionals is a sine qua non for the reversal of the age pyramid, but this is not happening yet. PMID- 25830873 TI - Targeted Exome Sequencing of Deafness Genes After Failure of Auditory Phenotype Driven Candidate Gene Screening. AB - OBJECTIVE: To demonstrate the efficacy and advantages of targeted exome sequencing (TES) of known deafness genes in cases with failed or misleading auditory phenotype-driven candidate gene screening. STUDY DESIGN: Prospective cohort survey. SETTING: Otolaryngology department of a tertiary referral hospital. PATIENTS: Six hearing-impaired probands with seemingly non-syndromic features from six deaf families were enrolled in this study after failure of genetic diagnosis using auditory phenotype-driven candidate gene screening. INTERVENTION: TES of known deafness genes was performed in the six probands, and a final causative variant was pursued using subsequent filtering steps. MAIN OUTCOME MEASURE: Potential causative variants determined using TES were confirmed by previously introduced filtering steps. RESULTS: We detected causative variants in three (50%) of six families, and these variants were in the COCH, PAX3, and GJB2 genes. Additionally, we also recapitulated the recent finding from other report arguing for the non-pathogenic potential of MYO1A variant. CONCLUSIONS: TES of a deafness panel provides a comprehensive genetic screening tool that can be implemented without being misled by the audiogram configuration information and can complement incomplete clinical physical examinations. In addition, the secondary incidental finding obtained by TES contributes useful information regarding the deafness field. PMID- 25830874 TI - Dexamethasone Regulates Cochlear Expression of Deafness-associated Proteins Myelin Protein Zero and Heat Shock Protein 70, as Revealed by iTRAQ Proteomics. AB - AIM: Using proteomics, we aimed to identify the proteins differentially regulated by dexamethasone in the mouse cochlea based on mass-spectrometry data. BACKGROUND: Glucocorticoid therapy is widely used for many forms of sensorineural hearing loss; however, the molecular mechanism of its action in the cochlea remains poorly understood. METHODS: Dexamethasone or control saline was intratympanically applied to the cochleae of mice. Twelve hours after application, proteins differentially regulated by dexamethasone in the cochlea were analyzed by isobaric Tag for Relative and Absolute Quantitation (iTRAQ)-mass spectrometry. Next, dexamethasone-dependent regulation of these proteins was verified in the cochleae of mice with noise-induced hearing loss (NIHL) and systemic administration of dexamethasone by western blotting. Immunolocalizations of these proteins were examined in cochleae with NIHL. RESULTS: A total of 247 proteins with a greater than 95% confidence interval of protein identification were found, and 11 differentially expressed proteins by dexamethasone were identified by the iTRAQ-mass spectrometry. One protein, myelin protein zero (Mpz), was upregulated (1.870 +/- 0.201-fold change, p < 0.01) at 6 hours post systemic dexamethasone and noise exposure in a mouse model of NIHL. Heat shock protein 70 (Hsp70) was downregulated (0.511 +/- 0.274-fold change, p < 0.05) at 12 hours post-systemic dexamethasone. Immunohistochemistry confirmed Mpz localization to the efferent and afferent processes of the spiral neurons, whereas Hsp70 showed a more ubiquitous expression pattern in the cochlea. CONCLUSION: Both Mpz and Hsp70 have been reported to be closely associated with sensorineural hearing loss in humans. Dexamethasone significantly modulated the expression levels of these proteins in the cochleae of mice. PMID- 25830875 TI - Head-shaking and Vibration-induced Nystagmus During and Between the Attacks of Unilateral Meniere's Disease. AB - OBJECTIVE: To aid in defining each phase of Meniere's disease (MD) and underlying vestibular pathophysiology by analyzing the evolving patterns of spontaneous, head-shaking (HSN), and vibration-induced nystagmus (VIN) during and between the attacks of MD. STUDY DESIGN: Retrospective case series review. METHODS: We analyzed the patterns of HSN and VIN during 123 attacks from 87 patients who had definite unilateral MD and underwent recording of eye movements both during and between the attacks using video-oculography. RESULTS: HSN tended to beat toward the lesion side during the irritative phase (80.0%) and toward the healthy side during the paretic phase (82.9%). In contrast, VIN was more commonly induced during the irritative phase (63.7%) and more likely beat toward the healthy side irrespective of the phases evaluated (84.3%). Directional dissociation may occur between HSN and VIN, especially during the irritative phase when HSN mostly beat to the lesion side, but VIN is toward the healthy side. CONCLUSION: The characteristic patterns of HSN and VIN during each phase of MD would aid in defining the acute phases of MD and understanding the underlying vestibular pathophysiology. PMID- 25830876 TI - The maternal-age-associated risk of congenital heart disease is modifiable. AB - Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn. Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease. PMID- 25830884 TI - New cosmogenic burial ages for Sterkfontein Member 2 Australopithecus and Member 5 Oldowan. AB - The cave infills at Sterkfontein contain one of the richest assemblages of Australopithecus fossils in the world, including the nearly complete skeleton StW 573 ('Little Foot') in its lower section, as well as early stone tools in higher sections. However, the chronology of the site remains controversial owing to the complex history of cave infilling. Much of the existing chronology based on uranium-lead dating and palaeomagnetic stratigraphy has recently been called into question by the recognition that dated flowstones fill cavities formed within previously cemented breccias and therefore do not form a stratigraphic sequence. Earlier dating with cosmogenic nuclides suffered a high degree of uncertainty and has been questioned on grounds of sediment reworking. Here we use isochron burial dating with cosmogenic aluminium-26 and beryllium-10 to show that the breccia containing StW 573 did not undergo significant reworking, and that it was deposited 3.67 +/- 0.16 million years ago, far earlier than the 2.2 million year flowstones found within it. The skeleton is thus coeval with early Australopithecus afarensis in eastern Africa. We also date the earliest stone tools at Sterkfontein to 2.18 +/- 0.21 million years ago, placing them in the Oldowan at a time similar to that found elsewhere in South Africa at Swartkans and Wonderwerk. PMID- 25830885 TI - Corrigendum: Deterministic direct reprogramming of somatic cells to pluripotency. PMID- 25830878 TI - Early reprogramming regulators identified by prospective isolation and mass cytometry. AB - In the context of most induced pluripotent stem (iPS) cell reprogramming methods, heterogeneous populations of non-productive and staggered productive intermediates arise at different reprogramming time points. Despite recent reports claiming substantially increased reprogramming efficiencies using genetically modified donor cells, prospectively isolating distinct reprogramming intermediates remains an important goal to decipher reprogramming mechanisms. Previous attempts to identify surface markers of intermediate cell populations were based on the assumption that, during reprogramming, cells progressively lose donor cell identity and gradually acquire iPS cell properties. Here we report that iPS cell and epithelial markers, such as SSEA1 and EpCAM, respectively, are not predictive of reprogramming during early phases. Instead, in a systematic functional surface marker screen, we find that early reprogramming-prone cells express a unique set of surface markers, including CD73, CD49d and CD200, that are absent in both fibroblasts and iPS cells. Single-cell mass cytometry and prospective isolation show that these distinct intermediates are transient and bridge the gap between donor cell silencing and pluripotency marker acquisition during the early, presumably stochastic, reprogramming phase. Expression profiling reveals early upregulation of the transcriptional regulators Nr0b1 and Etv5 in this reprogramming state, preceding activation of key pluripotency regulators such as Rex1 (also known as Zfp42), Dppa2, Nanog and Sox2. Both factors are required for the generation of the early intermediate state and fully reprogrammed iPS cells, and thus represent some of the earliest known regulators of iPS cell induction. Our study deconvolutes the first steps in a hierarchical series of events that lead to pluripotency acquisition. PMID- 25830887 TI - Materials science: Unique wrinkles as identity tags. PMID- 25830886 TI - Cardiology: Race for healthy hearts. PMID- 25830880 TI - The evolutionary history of lethal metastatic prostate cancer. AB - Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer. PMID- 25830888 TI - Corrigendum: Derivation of novel human ground state naive pluripotent stem cells. PMID- 25830889 TI - Reducing the energy cost of human walking using an unpowered exoskeleton. AB - With efficiencies derived from evolution, growth and learning, humans are very well-tuned for locomotion. Metabolic energy used during walking can be partly replaced by power input from an exoskeleton, but is it possible to reduce metabolic rate without providing an additional energy source? This would require an improvement in the efficiency of the human-machine system as a whole, and would be remarkable given the apparent optimality of human gait. Here we show that the metabolic rate of human walking can be reduced by an unpowered ankle exoskeleton. We built a lightweight elastic device that acts in parallel with the user's calf muscles, off-loading muscle force and thereby reducing the metabolic energy consumed in contractions. The device uses a mechanical clutch to hold a spring as it is stretched and relaxed by ankle movements when the foot is on the ground, helping to fulfil one function of the calf muscles and Achilles tendon. Unlike muscles, however, the clutch sustains force passively. The exoskeleton consumes no chemical or electrical energy and delivers no net positive mechanical work, yet reduces the metabolic cost of walking by 7.2 +/- 2.6% for healthy human users under natural conditions, comparable to savings with powered devices. Improving upon walking economy in this way is analogous to altering the structure of the body such that it is more energy-effective at walking. While strong natural pressures have already shaped human locomotion, improvements in efficiency are still possible. Much remains to be learned about this seemingly simple behaviour. PMID- 25830890 TI - Metabolism: Growth in the fat lane. PMID- 25830892 TI - Cancer: The complex seeds of metastasis. PMID- 25830891 TI - In vivo genome editing using Staphylococcus aureus Cas9. AB - The RNA-guided endonuclease Cas9 has emerged as a versatile genome-editing platform. However, the size of the commonly used Cas9 from Streptococcus pyogenes (SpCas9) limits its utility for basic research and therapeutic applications that use the highly versatile adeno-associated virus (AAV) delivery vehicle. Here, we characterize six smaller Cas9 orthologues and show that Cas9 from Staphylococcus aureus (SaCas9) can edit the genome with efficiencies similar to those of SpCas9, while being more than 1 kilobase shorter. We packaged SaCas9 and its single guide RNA expression cassette into a single AAV vector and targeted the cholesterol regulatory gene Pcsk9 in the mouse liver. Within one week of injection, we observed >40% gene modification, accompanied by significant reductions in serum Pcsk9 and total cholesterol levels. We further assess the genome-wide targeting specificity of SaCas9 and SpCas9 using BLESS, and demonstrate that SaCas9 mediated in vivo genome editing has the potential to be efficient and specific. PMID- 25830894 TI - Urinary biomarkers as exposure surrogates: controlling for possible bias. PMID- 25830895 TI - Strategies to avoid Shiga toxin effects. PMID- 25830893 TI - Fatty acid carbon is essential for dNTP synthesis in endothelial cells. AB - The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. PMID- 25830896 TI - Comparing and Contrasting Three Cultural Food Customs from Nigeria and Analyzing the Nutrient Content of Diets from These Cultures with the Aim of Proffering Nutritional Intervention. AB - Nigeria is a multicultural country with a diverse cultural food. Most Nigerians' cultural diet is based on staple food accompanied by stew. In the South West and Eastern region (where Yorubas and Igbos are the dominant ethnic groups), staple foods are yam and cassava by-product (garri, fufu and lafun) with vegetables prepared as stew, often over cooked, thereby losing essential micronutrients. In Northern Nigeria (where the Hausas and Fulanis are the dominant ethnic groups), grains such as sorghum, millet form the main diet; these are served with palm oil based soup made with tomatoes and okra. Meat is sometimes added. Among the Hausas, meat is usually reserved for special occasions. Various types of malnutrition prevalent in developing countries such as Nigeria are iron deficiency anemia (ID/A), protein-energy malnutrition (PEM), Vitamin A deficiency (VAD), iodine deficiency disorder (IDD). The proposed long-term measure by the Federal government of Nigeria for the resolution of these various types of malnutrition is dietary diversification. A review of the literature on Nigerian cultural diets identified gaps in knowledge with respect to the nutritional values of Nigerian ethnic diets. PMID- 25830898 TI - Allopurinol and the incidence of bladder cancer: a Taiwan national retrospective cohort study. AB - Our aim is to investigate the risk association between allopurinol use and cancer incidence among gout patients using clinical evidence. Newly diagnosed male patients with gout, 20 years or older, were included after excluding those who had a diagnosis of type 2 diabetes, and were followed up for 12 years in a retrospective cohort study of one million outpatients of a national database. The gout patients were matched to male controls by age and first diagnosis date of gout disease. We then estimated the risk associations between incident cancers and duration of allopurinol use by Cox hazard regression, age-adjusted standardized incidence ratio, and incidence per 1000 person-years. A total of 24 050 gout patients and 76 129 controls were included. The incidence of all-cause cancers for gout patients and controls was 8.26 cases and 7.49 cases/1000 person years, respectively; it was markedly increased in gout patients who used allopurinol for over 90 days. The hazard ratio of all-cause cancers was 1.21 (95% confidence interval=1.03-1.42, P=0.019) after adjustment for age and 2.26 for bladder cancer (95% confidence interval=1.32-3.87, P=0.003) on comparing those who used allopurinol for over 90 days with nonusers. Meanwhile, other cancers did not show the same significant result. We concluded that those who used allopurinol for a long duration had a higher occurrence of both bladder cancer and all-cause cancers in clinical evidence. PMID- 25830897 TI - Influence of sample return time and ambient temperature on the performance of an immunochemical faecal occult blood test with a new buffer for colorectal cancer screening. AB - The haemoglobin concentration measured by faecal immunochemical tests (FIT) may be decreased in cases of delayed sample return or high temperature. It is an issue of great importance. The aim of this study was to investigate the effects of sample return time and of season on the performance of an FIT (FOB-Gold) with a new buffer. The study included 20 371 participants involved in the French organized colorectal cancer (CRC) screening programme. The probability of a positive screening test, detection rates and positive predictive values for CRC and advanced adenoma were analysed according to sample return time and season of screening. A sample of positive FIT was stored for 7 days in an incubator at 20 degrees C or 30 degrees C. The positivity rate was 4.1% for a sample return time of up to 3 days, 4.1% for 4-5 days and 4.6% for 6-7 days (P=0.25). In multivariate analysis, there was no association between positivity rates, detection rates and positive predictive values for CRC and advanced adenoma and the sample return time or the season of screening. At a constant temperature of 20 degrees C, there was a decrease in the haemoglobin concentration of 5.1% after 7 days. The decrease reached 20.5% at a temperature of 30 degrees C. It was only 4.5% during the first 4 days of storage in the incubator. With the new buffer, delay in sample return or season did not affect the clinical outcome. When temperatures reach 30 degrees C, the faecal sample must be returned promptly. PMID- 25830899 TI - The RAB GTPase RABA1e localizes to the cell plate and shows distinct subcellular behavior from RABA2a under Endosidin 7 treatment. AB - Cytokinesis in plants requires the activity of RAB GTPases to regulate vesicle mediated contribution of material to the developing cell plate. While some plant RAB GTPases have been shown to be involved in cell plate formation, many still await functional assignment. Here, we report cell plate localization for YFP RABA1e in Arabidopsis thaliana and use the cytokinesis inhibitor Endosidin 7 to provide a detailed description of its localization compared to YFP-RABA2a. Differences between YFP-RABA2a and YFP-RABA1e were observed in late-stage cell plates under DMSO control treatment, and became more apparent under Endosidin 7 treatment. Taken together, our results suggest that individual RAB GTPases might make different contributions to cell plate formation and further demonstrates the utility of ES7 probe to dissect them. PMID- 25830900 TI - Different Analytical Procedures for the Study of Organic Residues in Archeological Ceramic Samples with the Use of Gas Chromatography-mass Spectrometry. AB - The analysis of the composition of organic residues present in pottery is an important source of information for historians and archeologists. Chemical characterization of the materials provides information on diets, habits, technologies, and original use of the vessels. This review presents the problem of analytical studies of archeological materials with a special emphasis on organic residues. Current methods used in the determination of different organic compounds in archeological ceramics are presented. Particular attention is paid to the procedures of analysis of archeological ceramic samples used before gas chromatography-mass spectrometry. Advantages and disadvantages of different extraction methods and application of proper quality assurance/quality control procedures are discussed. PMID- 25830903 TI - Random forests in non-invasive sensorimotor rhythm brain-computer interfaces: a practical and convenient non-linear classifier. AB - There is general agreement in the brain-computer interface (BCI) community that although non-linear classifiers can provide better results in some cases, linear classifiers are preferable. Particularly, as non-linear classifiers often involve a number of parameters that must be carefully chosen. However, new non-linear classifiers were developed over the last decade. One of them is the random forest (RF) classifier. Although popular in other fields of science, RFs are not common in BCI research. In this work, we address three open questions regarding RFs in sensorimotor rhythm (SMR) BCIs: parametrization, online applicability, and performance compared to regularized linear discriminant analysis (LDA). We found that the performance of RF is constant over a large range of parameter values. We demonstrate - for the first time - that RFs are applicable online in SMR-BCIs. Further, we show in an offline BCI simulation that RFs statistically significantly outperform regularized LDA by about 3%. These results confirm that RFs are practical and convenient non-linear classifiers for SMR-BCIs. Taking into account further properties of RFs, such as independence from feature distributions, maximum margin behavior, multiclass and advanced data mining capabilities, we argue that RFs should be taken into consideration for future BCIs. PMID- 25830902 TI - A novel Werner Syndrome mutation: pharmacological treatment by read-through of nonsense mutations and epigenetic therapies. AB - Werner Syndrome (WS) is a rare inherited disease characterized by premature aging and increased propensity for cancer. Mutations in the WRN gene can be of several types, including nonsense mutations, leading to a truncated protein form. WRN is a RecQ family member with both helicase and exonuclease activities, and it participates in several cell metabolic pathways, including DNA replication, DNA repair, and telomere maintenance. Here, we reported a novel homozygous WS mutation (c.3767 C > G) in 2 Argentinian brothers, which resulted in a stop codon and a truncated protein (p.S1256X). We also observed increased WRN promoter methylation in the cells of patients and decreased messenger WRN RNA (WRN mRNA) expression. Finally, we showed that the read-through of nonsense mutation pharmacologic treatment with both aminoglycosides (AGs) and ataluren (PTC-124) in these cells restores full-length protein expression and WRN functionality. PMID- 25830904 TI - Interactive near-real-time high-resolution imaging for MR-guided lumbar interventions using ZOOM imaging in an open 1.0 Tesla MRI system--initial experience. AB - PURPOSE: Different techniques for magnetic resonance-guided lumbar interventions have been introduced in recent years. Appropriate pulse sequence design is crucial since high spatial resolution often comes at the cost of lower temporal resolution. The purpose of this study was to evaluate the value of accelerated reduced field of view (ZOOM)-based imaging sequences for lumbar interventions. METHODS: ZOOM imaging was used in 31 interventions (periradicular, facet joint, epidural infiltrations, and discography) performed in 24 patients (10 women, 14 men; age 43 +/- 13.3 years). Signal-to-noise ratio and contrast-to-noise ratio (CNR) were determined and retrospectively compared with standard preinterventional (T2 weighted), peri-interventional (proton density), and postinterventional (spectral presaturation with inversion recovery [SPIR]) imaging. Needle artifacts were assessed by direct measurement as well as with parallel and perpendicular needle profiles. Puncture times were compared to similar interventions previously performed in our department. RESULTS: No significant differences in signal intensities (standard/ZOOM: 152.0/151.6; p=0.136) and CNR values (2.0/4.0; p=0.487) were identified for T2-weighted sequences. The needle artifact signal intensity was comparable (648.1/747.5; p=0.172) for peri-interventional imaging. Standard interventional (fat needle: 43.8/23.4; p<0.001; muscle needle: 6.2/2.4; p<0.001) and SPIR sequences (43.3/13.9; p=0.010) showed a higher CNR than corresponding ZOOM sequences did. Needle artifacts were larger in ZOOM (2.4 mm/2.9 mm; p=0.005). The profiles revealed that ZOOM imaging delivers more overall signal intensity. The turning points of both profiles were comparable. ZOOM reduced intervention times significantly (329.1 s/228.5 s; p=0.026). CONCLUSION: ZOOM imaging is a feasible interactive sequence for lumbar interventions. It ameliorates the tradeoff between image quality and temporal resolution. Moreover, the sequence design reduces intervention times significantly. PMID- 25830905 TI - Spuriously high platelet counts by various automated hematology analyzers in a patient with disseminated intravascular coagulation. PMID- 25830906 TI - An integrative review: instructional strategies to improve nurses' retention of cardiopulmonary resuscitation priorities. AB - Recognizing and responding to a cardiac arrest in the hospital setting is a high stress, high anxiety event for all healthcare providers. It requires the performance of several basic, but extremely important cardiopulmonary resuscitation (CPR) skills and response priorities. If not executed correctly and in a timely manner, a bad outcome may result. Poor retention of cardiopulmonary resuscitation skills and priorities is well documented in the literature. An integrative review of the evidence was conducted to answer the question, "Is there a more effective training method to improve nurses' retention of CPR priorities during an in hospital cardiac arrest as compared to traditional American Heart Association training? "This review evaluated high fidelity and low fidelity simulation training, online or computer-based training and video instruction as potential teaching strategies focusing on CPR priorities. The role of deliberate practice is discussed. The strongest evidence suggests that a teaching plan employing brief, frequent, repetitive or deliberate practice used in collaboration with low fidelity or high fidelity simulation may be a potential strategy to improve nurses' retention of CPR priorities over time. PMID- 25830907 TI - 3-MCPD: A Worldwide Problem of Food Chemistry. AB - 3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been widely investigated for decades. This paper presents an overview of current knowledge about 3-MCPD, including its formation routes, occurrence in various foodstuffs, analytical approach, toxicological aspects, and future research perspectives. So far, 3-MCPD was determined in its free and bound form in thermally treated foods, edible oils and fats, and infant foods including human breast milk. Contaminants in infant foods and human breast milk were highlighted in this paper as a serious problem as they can pose a potential hazard for infants. The analytical approach of 3-MCPD determination has been modified for over a decade. Nowadays, the method based on determining the derivative of this compound by using gas chromatography and mass spectrometry is widely used. However, there is still a big need for developing new methods that would produce repeatable results. Some of the toxicologic aspects associated with 3-MCPD still remain unknown. A number of studies on the carcinogenicity and genotoxicity of 3 MCPD were carried out on rodents; however, no clinical studies on humans have been reported so far. Moreover, both detrimental effect on kidneys and antifertility activity have been widely reported. The knowledge of 3-MCPD absorption into body fluids and tissues and its metabolic pathways is based on sometimes conflicting data derived from different studies. In conclusion, although a lot of research has been carried out on 3-MCPD, there is still a need for further research in this area. PMID- 25830908 TI - A process optimization study on ultrasonic extraction of paclitaxel from Taxus cuspidata. AB - This study aimed to improve the extraction rate of paclitaxel from Taxus cuspidata in order to determine the most effective combination of ultrasonic extraction and thin-layer chromatography-ultraviolet (TLC-UV) rapid separation method. The study was performed using the Box-Behnken test design to conduct single-factor experiments using ultrasonic extraction of paclitaxel from Taxus cuspidata. The study showed ethanol to be the best extraction solvent. When mixed with dichloromethane (1:1), the ratio of material to liquid was 1:50 when using an ultrasonic time of 1 hr at a power of 200 W. The correction coefficient K for the separation and detection of paclitaxel using the TLC-UV spectrophotometric method was 0.009152. Multifactor experiments determined the effect of the rate of liquid to material (X1), ultrasonic time (X2), and ultrasonic power (X3) on extraction using extraction volume as the dependent variable. Response surface analysis allowed a regression equation to be obtained, with the optimal conditions for extraction when the rate of liquid to material was 53.23 mL/g as an ultrasonic time of 1.11 hr and an ultrasonic power of 207.88 W. Using these parameters, the average amount of extracted paclitaxel was about 130.576 ug/g, which was significantly better than for other extraction methods. PMID- 25830909 TI - Direct healthcare cost of obesity in brazil: an application of the cost-of illness method from the perspective of the public health system in 2011. AB - BACKGROUND: Obesity is a global public health problem and a risk factor for several diseases that financially impact healthcare systems. OBJECTIVE: To estimate the direct costs attributable to obesity (body mass index {BMI} >= 30 kg/m2) and morbid obesity (BMI >= 40 kg/m2) in adults aged >= 20 incurred by the Brazilian public health system in 2011. SETTINGS: Public hospitals and outpatient care. METHODS: A cost-of-illness method was adopted using a top-down approach based on prevalence. The proportion of the cost of each obesity-associated comorbidity was calculated and obesity prevalence was used to calculate attributable risk. Direct healthcare cost data (inpatient care, bariatric surgery, outpatient care, medications and diagnostic procedures) were extracted from the Ministry of Health information systems, available on the web. RESULTS: Direct costs attributable to obesity totaled US$ 269.6 million (1.86% of all expenditures on medium- and high-complexity health care). The cost of morbid obesity accounted for 23.8% (US$ 64.2 million) of all obesity-related costs despite being 18 times less prevalent than obesity. Bariatric surgery costs in Brazil totaled US$ 17.4 million in 2011. The cost of morbid obesity in women was five times higher than it was in men. CONCLUSION: The cost of morbid obesity was found to be proportionally higher than the cost of obesity. If the current epidemic were not reversed, the prevalence of obesity in Brazil will increase gradually in the coming years, as well as its costs, having serious implications for the financial sustainability of the Brazilian public health system. PMID- 25830910 TI - Diversity dynamics in Nymphalidae butterflies: effect of phylogenetic uncertainty on diversification rate shift estimates. AB - The species rich butterfly family Nymphalidae has been used to study evolutionary interactions between plants and insects. Theories of insect-hostplant dynamics predict accelerated diversification due to key innovations. In evolutionary biology, analysis of maximum credibility trees in the software MEDUSA (modelling evolutionary diversity using stepwise AIC) is a popular method for estimation of shifts in diversification rates. We investigated whether phylogenetic uncertainty can produce different results by extending the method across a random sample of trees from the posterior distribution of a Bayesian run. Using the MultiMEDUSA approach, we found that phylogenetic uncertainty greatly affects diversification rate estimates. Different trees produced diversification rates ranging from high values to almost zero for the same clade, and both significant rate increase and decrease in some clades. Only four out of 18 significant shifts found on the maximum clade credibility tree were consistent across most of the sampled trees. Among these, we found accelerated diversification for Ithomiini butterflies. We used the binary speciation and extinction model (BiSSE) and found that a hostplant shift to Solanaceae is correlated with increased net diversification rates in Ithomiini, congruent with the diffuse cospeciation hypothesis. Our results show that taking phylogenetic uncertainty into account when estimating net diversification rate shifts is of great importance, as very different results can be obtained when using the maximum clade credibility tree and other trees from the posterior distribution. PMID- 25830911 TI - Characterization of phospho-(tyrosine)-mimetic calmodulin mutants. AB - Calmodulin (CaM) phosphorylated at different serine/threonine and tyrosine residues is known to exert differential regulatory effects on a variety of CaM binding enzymes as compared to non-phosphorylated CaM. In this report we describe the preparation and characterization of a series of phospho-(Y)-mimetic CaM mutants in which either one or the two tyrosine residues present in CaM (Y99 and Y138) were substituted to aspartic acid or glutamic acid. It was expected that the negative charge of the respective carboxyl group of these amino acids mimics the negative charge of phosphate and reproduce the effects that distinct phospho (Y)-CaM species may have on target proteins. We describe some physicochemical properties of these CaM mutants as compared to wild type CaM, after their expression in Escherichia coli and purification to homogeneity, including: i) changes in their electrophoretic mobility in the absence and presence of Ca2+; ii) ultraviolet (UV) light absorption spectra, far- and near-UV circular dichroism data; iii) thermal stability in the absence and presence of Ca2+; and iv) Tb3+-emitted fluorescence upon tyrosine excitation. We also describe some biochemical properties of these CaM mutants, such as their differential phosphorylation by the tyrosine kinase c-Src, and their action as compared to wild type CaM, on the activity of two CaM-dependent enzymes: cyclic nucleotide phosphodiesterase 1 (PDE1) and endothelial nitric oxide synthase (eNOS) assayed in vitro. PMID- 25830912 TI - Four-dimensional characterization of thrombosis in a live-cell, shear-flow assay: development and application to xenotransplantation. AB - BACKGROUND: Porcine xenografts are a promising source of scarce transplantable organs, but stimulate intense thrombosis of human blood despite targeted genetic and pharmacologic interventions. Current experimental models do not enable study of the blood/endothelial interface to investigate adhesive interactions and thrombosis at the cellular level under physiologic conditions. The purpose of this study was to develop and validate a live-cell, shear-flow based thrombosis assay relevant to general thrombosis research, and demonstrate its potential in xenotransplantation applications. METHODOLOGY/PRINCIPAL FINDINGS: Confluent wild type (WT, n = 48) and Gal transferase knock-out (GalTKO, which resist hyperacute rejection; n = 11) porcine endothelia were cultured in microfluidic channels. To mimic microcirculatory flow, channels were perfused at 5 dynes/cm2 and 37 degrees C with human blood stained to fluorescently label platelets. Serial fluorescent imaging visualized percent surface area coverage (SA, for adhesion of labeled cells) and total fluorescence (a metric of clot volume). Aggregation was calculated by the fluorescence/SA ratio (FR). WT endothelia stimulated diffuse platelet adhesion (SA 65 +/- 2%) and aggregation (FR 120 +/- 1 a.u.), indicating high-grade thrombosis consistent with the rapid platelet activation and consumption seen in whole-organ lung xenotransplantation models. Experiments with antibody blockade of platelet aggregation, and perfusion of syngeneic and allo incompatible endothelium was used to verify the biologic specificity and validity of the assay. Finally, with GalTKO endothelia thrombus volume decreased by 60%, due primarily to a 58% reduction in adhesion (P < 0.0001 each); importantly, aggregation was only marginally affected (11% reduction, P < 0.0001). CONCLUSIONS/SIGNIFICANCE: This novel, high-throughput assay enabled dynamic modeling of whole-blood thrombosis on intact endothelium under physiologic conditions, and allowed mechanistic characterization of endothelial and platelet interactions. Applied to xenogeneic thrombosis, it enables future studies regarding the effect of modifying the porcine genotype on sheer-stress-dependent events that characterize xenograft injury. This in-vitro platform is likely to prove broadly useful to study thrombosis and endothelial interactions under dynamic physiologic conditions. PMID- 25830913 TI - Predictive simulation generates human adaptations during loaded and inclined walking. AB - Predictive simulation is a powerful approach for analyzing human locomotion. Unlike techniques that track experimental data, predictive simulations synthesize gaits by minimizing a high-level objective such as metabolic energy expenditure while satisfying task requirements like achieving a target velocity. The fidelity of predictive gait simulations has only been systematically evaluated for locomotion data on flat ground. In this study, we construct a predictive simulation framework based on energy minimization and use it to generate normal walking, along with walking with a range of carried loads and up a range of inclines. The simulation is muscle-driven and includes controllers based on muscle force and stretch reflexes and contact state of the legs. We demonstrate how human-like locomotor strategies emerge from adapting the model to a range of environmental changes. Our simulation dynamics not only show good agreement with experimental data for normal walking on flat ground (92% of joint angle trajectories and 78% of joint torque trajectories lie within 1 standard deviation of experimental data), but also reproduce many of the salient changes in joint angles, joint moments, muscle coordination, and metabolic energy expenditure observed in experimental studies of loaded and inclined walking. PMID- 25830914 TI - Transcriptome analysis in patients with chronic kidney disease on hemodialysis disclosing a key role for CD16+CX3CR1+ monocytes. AB - The risk for cardiovascular morbidity and mortality is increased in chronic kidney disease; in this process micro-inflammation plays an essential role. Responsible mechanisms remain to a large extent unidentified. In this pilot study transcriptome analysis of peripheral blood monocytes was used to identify in an unprejudiced manner which factors could be discriminative for cardiovascular disease in patients with chronic kidney disease on hemodialysis. Forty gender- and age-matched, non-diabetic, non-smoking subjects with CRP < 20 mg/L were recruited: 9 healthy controls, 11 patients with eGFR > 60 mL/min/1.73m2 and a history of cardiovascular event (CVE), 10 patients with chronic kidney disease stage 5 on hemodialysis without previous cardiovascular event (CKD5HD) and 10 with a previous cardiovascular event (CKD5HD/CVE). Monocytes were isolated and their mRNA was submitted to focused transcriptome analysis using a macroarray platform containing ca. 700 genes associated with macrophage functional capacity. The macroarray data indicated 9 genes (8 upregulated and 1 downregulated) with a significant differential expression in CKD5HD/CVE vs. CVE alone, after excluding genes differentially expressed in CKD5HD vs. CONTROL: For FCGR3A (CD16) and CX3CR1 (chemokine receptor) the upregulation vs. control and vs. CVE could be confirmed by quantitative RT-PCR for all CKD5HD patients. Furthermore, CX3CR1 relative expression on monocytes correlated with CRP. Flow cytometric analysis of purified monocytes confirmed a significant increase in the percentage of CD16 positive monocytes in all CKD5HD patients vs. control and CVE. The present study indicates the importance of a specific pro-inflammatory monocyte subpopulation, positive for CD16 and the co-expressed chemokine receptor, CX3CR1, discriminative for CKD5HD patients. PMID- 25830915 TI - A stochastic delay differential model of cerebral autoregulation. AB - Mathematical models of the cardiovascular system and of cerebral autoregulation (CAR) have been employed for several years in order to describe the time course of pressures and flows changes subsequent to postural changes. The assessment of the degree of efficiency of cerebral auto regulation has indeed importance in the prognosis of such conditions as cerebro-vascular accidents or Alzheimer. In the quest for a simple but realistic mathematical description of cardiovascular control, which may be fitted onto non-invasive experimental observations after postural changes, the present work proposes a first version of an empirical Stochastic Delay Differential Equations (SDDEs) model. The model consists of a total of four SDDEs and two ancillary algebraic equations, incorporates four distinct delayed controls from the brain onto different components of the circulation, and is able to accurately capture the time course of mean arterial pressure and cerebral blood flow velocity signals, reproducing observed auto correlated error around the expected drift. PMID- 25830916 TI - Micronutrients in HIV: a Bayesian meta-analysis. AB - BACKGROUND: Approximately 28.5 million people living with HIV are eligible for treatment (CD4<500), but currently have no access to antiretroviral therapy. Reduced serum level of micronutrients is common in HIV disease. Micronutrient supplementation (MNS) may mitigate disease progression and mortality. OBJECTIVES: We synthesized evidence on the effect of micronutrient supplementation on mortality and rate of disease progression in HIV disease. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central, AMED and CINAHL databases through December 2014, without language restriction, for studies of greater than 3 micronutrients versus any or no comparator. We built a hierarchical Bayesian random effects model to synthesize results. Inferences are based on the posterior distribution of the population effects; posterior distributions were approximated by Markov chain Monte Carlo in OpenBugs. PRINCIPAL FINDINGS: From 2166 initial references, we selected 49 studies for full review and identified eight reporting on disease progression and/or mortality. Bayesian synthesis of data from 2,249 adults in three studies estimated the relative risk of disease progression in subjects on MNS vs. control as 0.62 (95% credible interval, 0.37, 0.96). Median number needed to treat is 8.4 (4.8, 29.9) and the Bayes Factor 53.4. Based on data reporting on 4,095 adults reporting mortality in 7 randomized controlled studies, the RR was 0.84 (0.38, 1.85), NNT is 25 (4.3, infinity). CONCLUSIONS: MNS significantly and substantially slows disease progression in HIV+ adults not on ARV, and possibly reduces mortality. Micronutrient supplements are effective in reducing progression with a posterior probability of 97.9%. Considering MNS low cost and lack of adverse effects, MNS should be standard of care for HIV+ adults not yet on ARV. PMID- 25830917 TI - Uptake of mass drug administration programme for schistosomiasis control in Koome Islands, Central Uganda. AB - INTRODUCTION: Schistosomiasis is one of the neglected tropical diseases targeted for elimination in Uganda through the Mass Drug Administration (MDA) programme. Praziquantel has been distributed using community resource persons in fixed sites and house-to-house visits; however the uptake is still below target coverage. In 2011/2012 MDA exercise, uptake stood at 50% yet WHO target coverage is 75% at community level. We assessed the uptake of MDA and the associated factors in Koome Islands, Central Uganda. METHODS: In March 2013, we conducted a mixed methods cross sectional study in 15 randomly selected villages. We interviewed a total of 615 respondents aged 18 years and above using semi structured questionnaires and five key informants were also purposively selected. Univariate and multivariate analysis was done. MDA uptake was defined as self reported swallowing of praziquantel during the last (2012) MDA campaign. We conducted key informant interviews with Ministry of Health, district health personnel and community health workers. RESULTS: Self reported uptake of praziquantel was 44.7% (275/615), 95% confidence interval (CI) 40.8-48.7%. Of the 275 community members who said they had swallowed praziquantel, 142 (51.6%) reported that they had developed side effects. Uptake of MDA was more likely if the respondent was knowledgeable about schistosomiasis transmission and prevention (adjusted odds ratio [AOR] 1.85, 95% CI 1.22-2.81) and reported to have received health education from the health personnel (AOR 5.95, 95% CI 3.67-9.65). Service delivery challenges such as drug shortages and community health worker attrition also influenced MDA in Koome Islands. CONCLUSIONS: Uptake of MDA for schistosomiasis control in Koome was sub optimal. Lack of knowledge about schistosomiasis transmission and prevention, inadequate health education and drug shortages are some of the major factors associated with low uptake. These could be addressed through routine health education and systematic drug supply for the successful elimination of schistosomiasis on the islands. PMID- 25830918 TI - The neural basis of risky choice with affective outcomes. AB - Both normative and many descriptive theories of decision making under risk are based on the notion that outcomes are weighted by their probability, with subsequent maximization of the (subjective) expected outcome. Numerous investigations from psychology, economics, and neuroscience have produced evidence consistent with this notion. However, this research has typically investigated choices involving relatively affect-poor, monetary outcomes. We compared choice in relatively affect-poor, monetary lottery problems with choice in relatively affect-rich medical decision problems. Computational modeling of behavioral data and model-based neuroimaging analyses provide converging evidence for substantial differences in the respective decision mechanisms. Relative to affect-poor choices, affect-rich choices yielded a more strongly curved probability weighting function of cumulative prospect theory, thus signaling that the psychological impact of probabilities is strongly diminished for affect-rich outcomes. Examining task-dependent brain activation, we identified a region-by condition interaction indicating qualitative differences of activation between affect-rich and affect-poor choices. Moreover, brain activation in regions that were more active during affect-poor choices (e.g., the supramarginal gyrus) correlated with individual trial-by-trial decision weights, indicating that these regions reflect processing of probabilities. Formal reverse inference Neurosynth meta-analyses suggested that whereas affect-poor choices seem to be based on brain mechanisms for calculative processes, affect-rich choices are driven by the representation of outcomes' emotional value and autobiographical memories associated with them. These results provide evidence that the traditional notion of expectation maximization may not apply in the context of outcomes laden with affective responses, and that understanding the brain mechanisms of decision making requires the domain of the decision to be taken into account. PMID- 25830920 TI - [(Pb6I8){Mn(CO)5}6](2-): an octahedral (M6X8)-like cluster with inverted bonding. AB - [BMIm]2[{PbMn(CO)5)}6I8] (BMIm: 1-butyl-3-methylimidazolium) is obtained by ionic liquid mediated reaction of PbI2 and Mn2(CO)10. Central is a cubelike (Pb6I8) unit containing a nonfilled Pb6 octahedron. Each Pb of this (Pb6I8) unit is terminated on its outside by Mn(CO)5, exhibiting Pb-Mn metal-to-metal bonding (280 pm). Structurally, the (Pb6I8) unit is similar to the well-known octahedral (M6Xn) cluster-type family (M = Zr, Nb, Ta, Mo, W; X = Cl, Br, I). In contrast to most similar cluster compounds, such as W6Br12 ([W6Br8]Br2/1Br4/2, according to Niggli notation) or the carbonyl cluster [Sn6{Cr(CO5)6}](2-), however, the nonfilled central Pb6 octahedron in [{PbMn(CO)5)}6I8](2-) does not exhibit any metal-to-metal bonding. Structure and bonding of the title compound are validated by single-crystal structure analysis, energy-dispersive X-ray analysis (EDX), infrared spectroscopy (FT-IR), and density functional theory (DFT) calculations. Based on the isolobal principle, electronegativity considerations, bond lengths, and DFT calculations including Mulliken population analysis and natural population analysis (NPA), in sum, the charge distribution of Pb is best reflected by an oxidation state of +1. PMID- 25830922 TI - Efficient synthesis of C-N-coupled heterobiaryls by sequential N-H functionalization reactions. AB - C-N-coupled heterobiaryls were synthesized by sequential N-H functionalization reactions: stereoselective rhodium-catalyzed N-H insertion, followed by regioselective palladium-catalyzed C-H amination. Because of the good substrate scope and excellent selectivity, the developed method presents a novel approach for the synthesis of heterobiaryls, which are potent antibiotics. PMID- 25830921 TI - Evaluating outcomes used in cardiothoracic surgery interventional research: a systematic review of reviews to develop a core outcome set. AB - BACKGROUND: When planning clinical trials, it is a key element to choose appropriate outcomes that ensure the comparability of effects of interventions in ways that minimise bias. We hypothesise that outcome measures in cardiothoracic surgical trials are inconsistent and without standard. Therefore, comparing the relative effectiveness of interventions across studies is problematic. We surmise that cardiothoracic research has focused habitually on the identification of risk factors and on the reduction of adverse outcomes with less consideration of factors that contribute to well being and positive health outcomes (salutogenesis). METHODS AND FINDINGS: We conducted a systematic review of reviews to determine both the type and number of outcomes reported in current cardiothoracic surgery interventional research, in order to identify a list of potential outcomes for a minimum core outcome set (COS). Special focus was placed on outcomes that emphasise salutogenesis. We interpreted salutogenic outcomes as those relating to optimum and/or positive health and well being. We searched Issue 7 (July 2014) of the Cochrane Database of Systematic Reviews. Systematic reviews of randomised trials on non-minimal-invasive off- or on-pump cardiothoracic surgery (elective and emergency, excluding transplants) investigating pre-, intra- or postsurgical interventions related to the outcome of the procedure were eligible for inclusion. We excluded protocols and withdrawn systematic reviews. Two review authors extracted outcome data independently. Unique lists of salutogenically and non-salutogenically focused outcomes were established. 15 systematic reviews involving 371 randomized trials and 58,253 patients were included in this review. Applied definitions of single and composite endpoints varied significantly, and patient-centred, salutogenically focused outcomes were seldom reported. One third of included reviews did not assess patient-centred outcomes at all; all other reviews were unable to perform meta-analyses due to an absence of data or heterogeneity in outcome measures. This compares to 36 non-salutogenically focused outcome domains representing 121 individual non-salutogenically focused outcomes, whereof 50% were assessed only once. Measures of mortality, cerebrovascular complications and hospitalisation were reported most frequently. Two reviews chose a composite endpoint as primary outcome. Pooled analysis of composite endpoints was not possible, as the required data was not reported per patient in all components. CONCLUSION: In cardiothoracic surgical trials, choice and definition of non-salutogenically focused single and composite outcomes are inconsistent. There is an absence of patient centred, salutogenically focused outcome parameters in cardiac trials. We recommend the development of a core outcome set of salutogenically focused and non-salutogenically focused outcomes for cardiothoracic surgical research. PMID- 25830919 TI - Whole-brain mapping of inputs to projection neurons and cholinergic interneurons in the dorsal striatum. AB - The dorsal striatum integrates inputs from multiple brain areas to coordinate voluntary movements, associative plasticity, and reinforcement learning. Its projection neurons consist of the GABAergic medium spiny neurons (MSNs) that express dopamine receptor type 1 (D1) or dopamine receptor type 2 (D2). Cholinergic interneurons account for a small portion of striatal neuron populations, but they play important roles in striatal functions by synapsing onto the MSNs and other local interneurons. By combining the modified rabies virus with specific Cre- mouse lines, a recent study mapped the monosynaptic input patterns to MSNs. Because only a small number of extrastriatal neurons were labeled in the prior study, it is important to reexamine the input patterns of MSNs with higher labeling efficiency. Additionally, the whole-brain innervation pattern of cholinergic interneurons remains unknown. Using the rabies virus-based transsynaptic tracing method in this study, we comprehensively charted the brain areas that provide direct inputs to D1-MSNs, D2-MSNs, and cholinergic interneurons in the dorsal striatum. We found that both types of projection neurons and the cholinergic interneurons receive extensive inputs from discrete brain areas in the cortex, thalamus, amygdala, and other subcortical areas, several of which were not reported in the previous study. The MSNs and cholinergic interneurons share largely common inputs from areas outside the striatum. However, innervations within the dorsal striatum represent a significantly larger proportion of total inputs for cholinergic interneurons than for the MSNs. The comprehensive maps of direct inputs to striatal MSNs and cholinergic interneurons shall assist future functional dissection of the striatal circuits. PMID- 25830923 TI - A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. AB - We investigated roles for spinal neurons expressing the neurokinin-1 receptor (NK1R) and/or gastrin-releasing peptide receptor (GRPR) in a mouse model of ovalbumin (OVA)-induced chronic atopic dermatitis. Mice receiving repeated topical application of OVA exhibited atopic-like skin lesions and behavioral signs of chronic itch including spontaneous scratching, touch-evoked scratching (alloknesis), and enhancement of chloroquine-evoked scratching (hyperknesis). Substance P-saporin (SP-SAP) and bombesin-saporin (BB-SAP) were intrathecally injected into OVA-sensitized mice to neurotoxically ablate NK1R- or GRPR expressing spinal neurons, respectively. SP-SAP diminished the expression of NK1R in the superficial spinal dorsal horn and significantly attenuated all behavioral signs of chronic itch. BB-SAP reduced the spinal dorsal horn expression of GRPR and significantly attenuated hyperknesis, with no effect on spontaneous scratching or alloknesis. To investigate whether NK1R-expressing spinal neurons project in ascending somatosensory pathways, we performed a double-label study. The retrograde tracer, Fluorogold (FG), was injected into either the somatosensory thalamus or lateral parabrachial nucleus. In the upper cervical (C1 2) spinal cord, most neurons retrogradely labeled with FG were located in the dorsomedial aspect of the superficial dorsal horn. Of FG-labeled spinal neurons, 89% to 94% were double labeled for NK1R. These results indicate that NK1R expressing spinal neurons play a major role in the expression of symptoms of chronic itch and give rise to ascending somatosensory projections. Gastrin releasing peptide receptor-expressing spinal neurons contribute to hyperknesis but not to alloknesis or ongoing itch. NK1R-expressing spinal neurons represent a potential target to treat chronic itch. PMID- 25830925 TI - Perioperative use of pregabalin for acute pain-a systematic review and meta analysis. AB - Evidence supporting postoperative pain management using pregabalin as an adjunct intervention across various surgical pain models is lacking. The objective of this systematic review was to evaluate "model-specific" comparative effectiveness and harms of pregabalin following a previously published systematic review protocol. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through August 2013. Data were screened and single extraction with independent verification and dual risk of bias assessment was performed. Quality of evidence (QoE) was rated using the GRADE approach. Primary outcomes were pain relief at rest and on movement and reduction in postoperative analgesic consumption. A total of 1423 records were screened, and 43 studies were included. Perioperative pregabalin resulted in: 16% (95% confidence interval [CI], 9%-21%) reduction in analgesic consumption (moderate QoE, 24 trials) and a small reduction in the magnitude of pain in surgeries associated with pronociceptive pain. Per 1000 patients, 10 more will experience blurred vision (95% CI, 5-20 more; moderate QoE, 17 trials) and 41 more sedation (95% CI, 13-77 more, 17 trials). To prevent 1 case of perioperative nausea and vomiting, the number needed to treat is 11 (95% CI: 7-28, 25 trials). Inadequate evidence addressed outcomes of enhanced recovery and serious harms. Pregabalin analgesic effectiveness is largely restricted to surgical procedures associated with pronociceptive mechanisms. The clinical significance of observed pregabalin benefits must be weighed against the uncertainties about serious harms and enhanced recovery to inform the careful selection of surgical patients. Recommendations for future research are proposed. PMID- 25830924 TI - Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation. AB - High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has analgesic effect; however, the efficacy of other cortical targets and the mode of action remain unclear. We examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, we assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (P = 0.0071) or the sham (P = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than those at pretreatment baseline (P = 0.0127 for the intensity of pain and P = 0.0074 for the interference of pain) or after the S1/M1 (P = 0.001 and P = 0.0001) and sham (P = 0.0491 and P = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS. PMID- 25830926 TI - The relationship between adolescents' pain catastrophizing and attention bias to pain faces is moderated by attention control. AB - This study considered the attentional functioning of adolescents with varying levels of pain catastrophizing. Specifically, we investigated the relationship between pain catastrophizing and attention bias to pain facial expressions. Furthermore, drawing on dual process models in the context of pain, we investigated the moderating role of attention control on this relationship. Adolescents (N = 73; age, 16-18 years) performed a dot-probe task in which facial expressions of pain and neutral expressions were presented for 100 milliseconds and 1250 milliseconds. Participants also completed self-report pain catastrophizing and attention control measures. We found that although there was no main effect of pain catastrophizing on attention bias towards pain faces, attention control did significantly moderate this relationship. Further analysis revealed that lower levels of attention control were significantly associated with increasing attentional vigilance towards pain faces only within high catastrophizing adolescents. In addition, we found that poorer attention control was related to increased attention bias for pain faces (regardless of pain catastrophizing level) when these faces were presented for relatively longer durations (ie, 1250 milliseconds) but not for short durations (ie, 100 milliseconds). This study supports a dual process model of attentional processes in pain, thus replicating previous findings within the psychopathology literature but extending them to the study of pain. Theoretical and clinical implications of our findings are discussed. PMID- 25830927 TI - Acute and chronic pain associated with leprosy. PMID- 25830929 TI - Development and Validation of an HPLC-UV Assay to Quantify Plasma Levels of Sulfametrol: A Preferential Antibiotic in Children. AB - BACKGROUND: Sulfonamides in combination with trimethoprim are frequently used antibiotics. They work synergistic. In infections with Pneumocystis jiroveci or Stenotrophomonas maltophilia, higher dosages are indicated than in other infections. Therapeutic drug monitoring (TDM) is warranted to assure the efficacy while limiting toxicity. Although trimethoprim in combination with sulfamethoxazole is the most common combination with established TDM target concentrations, the intravenous formulation is not suited for children because of its additives ethanol and propylene glycol to increase solubility. An alternative can be sulfametrol in combination with trimethoprim. When sulfametrol was introduced in the hospital, there was a need for a TDM method for sulfametrol. METHODS: A High Pressure Liquid Chromatography-Ultraviolet (HPLC-UV) detection method for sulfametrol determination in plasma was developed and validated according to the International Conference on Harmonization guidelines. Linearity, limit of detection, lower limit of quantification, recovery, process efficiency, selectivity, within-run precision, between-run precision, and sample stability were tested. RESULTS: All tested parameters met the required criteria. For linearity, r was 0.9948, lower limit of quantification was 10 mg/L, and limit of detection was 6 mg/L. Recovery was 100.4% and process efficiency 94.4%. Selectivity was met with no interfering peaks at the retention time of 4.2 minutes. Between-run precision and within-run precision were evaluated by replicating quality control levels, resulting in a within-run relative average standard deviation of 0.8% and a between-run relative standard deviation of 2.3%. Recovery of the samples after storing 8 days was 101.9% and recovery of already tested vials was 98.8% after 48 hours. CONCLUSIONS: In conclusion, an HPLC-UV method for sulfametrol determination in human plasma was developed and validated. The method is fast, accurate, reproducible, and has a short analysis time. It is now being used in routine TDM in our clinic. PMID- 25830928 TI - Evidence of field-evolved resistance of Spodoptera frugiperda to Bt corn expressing Cry1F in Brazil that is still sensitive to modified Bt toxins. AB - Brazil ranked second only to the United States in hectares planted to genetically modified crops in 2013. Recently corn producers in the Cerrado region reported that the control of Spodoptera frugiperda with Bt corn expressing Cry1Fa has decreased, forcing them to use chemicals to reduce the damage caused by this insect pest. A colony of S. frugiperda was established from individuals collected in 2013 from Cry1Fa corn plants (SfBt) in Brazil and shown to have at least more than ten-fold higher resistance levels compared with a susceptible colony (Sflab). Laboratory assays on corn leaves showed that in contrast to SfLab population, the SfBt larvae were able to survive by feeding on Cry1Fa corn leaves. The SfBt population was maintained without selection for eight generations and shown to maintain high levels of resistance to Cry1Fa toxin. SfBt showed higher cross-resistance to Cry1Aa than to Cry1Ab or Cry1Ac toxins. As previously reported, Cry1A toxins competed the binding of Cry1Fa to brush border membrane vesicles (BBMV) from SfLab insects, explaining cross-resistance to Cry1A toxins. In contrast Cry2A toxins did not compete Cry1Fa binding to SfLab-BBMV and no cross-resistance to Cry2A was observed, although Cry2A toxins show low toxicity to S. frugiperda. Bioassays with Cry1AbMod and Cry1AcMod show that they are highly active against both the SfLab and the SfBt populations. The bioassay data reported here show that insects collected from Cry1Fa corn in the Cerrado region were resistant to Cry1Fa suggesting that resistance contributed to field failures of Cry1Fa corn to control S. frugiperda. PMID- 25830930 TI - Generic Olanzapine Substitution in Patients With Schizophrenia: Assessment of Serum Concentrations and Therapeutic Response After Switching. AB - BACKGROUND: Several reports of loss of efficacy or adverse effects have been described after generic substitution of antipsychotics. To date, studies comparing serum drug levels in patients switched to generic antipsychotics in a standard clinical setting are lacking. The aim of this study was to investigate if switching to generic olanzapine in patients affected by schizophrenia is associated with differences in its serum concentrations and therapeutic response. METHODS: Preswitching and postswitching serum olanzapine concentrations were compared in schizophrenic outpatients who were switched from a chronic treatment with branded olanzapine to the same dose of its generic alternative. The Positive and Negative Syndrome Scale was concurrently administered to assess modifications in schizophrenia symptom control. RESULTS: A total of 25 patients (13 women and 12 men, mean age 41.2 +/- 12.8 years) concluded the study. Mean olanzapine dose was 12.2 +/- 5.4 mg/d. The mean olanzapine serum concentrations decreased from 27.7 +/- 14.4 ng/mL during treatment with the branded formulation to 22.6 +/- 12.3 ng/mL after switching to the generic formulation (P < 0.01). The log transformed ratio of generic/brand-name olanzapine serum concentration at steady state was 0.81 (90% confidence interval: 0.72-0.91). The total Positive and Negative Syndrome Scale scores did not significantly change after switching from branded to generic formulation (49.6 +/- 8.3 versus 48.6 +/- 9.5, P = 0.777). No patient exhibited disease relapse or required dose adjustment after switching. CONCLUSIONS: Significantly lower serum olanzapine concentrations were found after switching from branded to generic olanzapine. Although these modifications did not significantly impair schizophrenia symptoms control, it cannot be excluded that a longer exposure to lower olanzapine serum concentrations may result in relapse of schizophrenic symptoms. Generic substitution should be considered as an indication for therapeutic drug monitoring in psychiatry. PMID- 25830932 TI - Indium Tin Oxide-Free Transparent Conductive Electrode for GaN-Based Ultraviolet Light-Emitting Diodes. AB - Transparent conducting electrodes are important components of highly efficient ultraviolet light-emitting diodes (UV LEDs). Indium tin oxide (ITO) is commonly used to form a current spreading layer, but its UV-range optical transparency is limited with a low sheet resistance. We demonstrate a simple solution-based coating technique to obtain large-area, highly uniform, and conductive silver nanowire-based electrodes that exhibit UV-range optical transparency better than that of ITO for the same sheet resistance. The UV LEDs fabricated using this current spreading layer showed improved optical power emission as well as improvement in electrical properties. PMID- 25830931 TI - Association between the CD24 Ala57Val polymorphism and risk for multiple sclerosis and systemic lupus erythematosus: a meta-analysis. AB - The cluster of differentiation 24 (CD24) Ala57Val polymorphism has been implicated as a risk factor for multiple sclerosis (MS) and systemic lupus erythematosus (SLE); however, genetic studies have produced controversial results. A meta-analysis was performed on this topic. We used odds ratio (OR) and 95% confidence interval (95% CI) to investigate the strength of association. Eleven studies from nine publications consisting of 2466 cases and 2650 controls were included. The results suggested that the CD24 Val/Val genotypes were associated with an increased risk of MS in all study subjects and Caucasians (OR = 2.28, 95% CI: 1.68-3.10, Pz < 0.001 and OR = 2.30, 95% CI: 1.66-3.20, Pz < 0.001, respectively). Sensitivity analysis showed that no individual study was found to be significantly biasing the pooled results. Although meta-analysis also suggested an association between the CD24 Val/Val genotypes and SLE risk in Caucasians (OR = 1.71, 95% CI: 1.31-2.24, Pz < 0.001), sensitivity analysis demonstrated that the association was not statistically significant after removing a Spanish study. In conclusion, this meta-analysis suggests that the CD24 Ala57Val polymorphism is associated with an increased risk of MS in Caucasians. However, the available evidence is not sufficient to support an association between the CD24 Ala57Val polymorphism and SLE risk. PMID- 25830933 TI - Producing The Lancet and University College London Commission on Culture and Health. PMID- 25830934 TI - Impact of Device-Associated Infection on Trauma Patient Outcomes at a Major Trauma Center. AB - BACKGROUND: Catheter-associated urinary tract infection (CAUTI) and ventilator associated pneumonia (VAP) are considered performance measures. We analyzed the incidence, prevalence, and risk of CAUTI and VAP in trauma patients, as well as the demographic and injury factors related to these infections and their relative risks of negative outcomes (prolonged length of stay [LOS], sepsis, and death). METHODS: Trauma registry data were analyzed (age >18 y; LOS >24 h) from January 1, 2007, to December 31, 2011. Demographics and injury location, severity, and type were analyzed relative to outcomes along with device-associated infection, as defined by the U.S. Centers for Disease Control and Prevention. The outcomes analyzed were intensive care unit (ICU) and hospital LOS, sepsis, and in-hospital death. Multivariable logistic regression was then used to identify the factors contributing to sepsis, including device-associated infections. RESULTS: The included population (n=10,755) was 66.6% male and had a mean age of 45.1 y, with blunt trauma in 91.8% and a median Injury Severity Score (ISS) of 10 points. Patients developing CAUTI (n=324; 3.0%; p<0.005) were more likely to be female (59.4%), had a higher median ISS (20.5), and were older (56.7 years). Patients with VAP (n=161; 1.5%; p<0.005) had a higher median ISS (27). Patients with sepsis (n=149; 1.4%; p<0.005) had a higher median ISS (24.0) and were older (52.3 y). Sepsis was associated with prolonged LOS and death, as expected (p<0.005). In multivariable analysis, independent predictors of sepsis were CAUTI (odds ratio [OR] 16.15; p<0.001), VAP (OR 6.95; p<0.001), ISS (OR 1.05 per unit; p<0.001), age (OR 1.02 per year; p<0.001), and penetrating, abdominal, pelvic, or chest injury. CONCLUSION: Development of CAUTI and VAP are significantly associated with a higher risk of sepsis in trauma patients after adjustment for age and injury type, location, and severity. This study suggests the importance of device associated infections as vectors for sepsis in trauma and highlights the importance of prevention initiatives. PMID- 25830935 TI - Perioperative bleeding in patients undergoing liver transplantation. AB - Liver transplantation (LT) remains one of the most challenging surgical procedures. For many years uncontrolled bleeding and catastrophic haemorrhages were one of the major causes of perioperative mortality and morbidity. During the past fifty years or so, significant progress in surgical techniques and perioperative management has led to a marked change in transfusion practice over time, where up to 79.6% of LTs in experienced transplant centers are performed without any blood product transfusion. Despite this, perioperative bleeding and transfusion requirements remain potent predictors of patient's mortality, as well as postoperative complications and graft survival. The major impact of blood product transfusion on LT recipient outcomes implies that all patients on waiting lists should be carefully screened for the presence of risk factors of perioperative bleeding. Although multiple predictors of transfusion requirements during LT have been identified, no predictive model validated across centers has been constructed. The most suitable strategies to reduce intraoperative blood loss in this group should be employed on a case-to-case basis. This paper aims to summarize the most up-to-date evidence in the management of haemostasis in LT recipients. PMID- 25830936 TI - A combination of KingVision video-laryngoscope and flexible fibroscope for awake intubation in patient with laryngeal tumor--case report and literature review. PMID- 25830937 TI - Pyeloduodenal fistula diagnosed by esophagogastroduodenoscopy. PMID- 25830938 TI - Malnutrition in South Asia-A Critical Reappraisal. AB - Malnutrition continues to be a major public health challenge especially in South Asian developing countries. The aim of the present review is to spotlight the magnitude of the prevalence of malnutrition and its dynamics in South Asian region and to suggest potential approaches for the prevention and control of this issue of public health significance. An extensive review of literature, covering malnutrition and its determinants, health and economic consequences and pragmatic preventive strategies was performed on computer based bibliographic databases (PubMed, Google Scholar, Scopus, Medline and Sciencedirect.com ) to retrieve abstracts and full texts for India, Pakistan, Bangladesh, Sri Lanka and Nepal. All relevant titles and abstracts were examined and evaluated for malnutrition and its prevalence in South Asia. The results revealed malnutrition to be a major public health problem and a potential cause of high disease burden and mortality in South Asia. Compelling evidence suggests malnutrition to be the leading cause of stunting, wasting and underweight with drastic economic consequences among vulnerable populations. Reduced cognitive performance and low productivity have also been associated with micronutrients malnutrition. Suboptimal breastfeeding, inadequate food supply, micronutrient deficiencies, low household income, poor health care system, increased healthcare costs, illiteracy, unhygienic and substandard living, inappropriate child's care and the caregiver, food insecurity and on top of that vicious cycle of poverty, have been recognized as principal indicators for growing malnutrition prevalence in South Asia. Global organizations, local governments, program managers, NGOs, academia, industry in particular and the society at large need to take up the challenge to completely confiscate malnutrition from the region for economic prosperity and a healthier future. PMID- 25830939 TI - Ethanolamine oleate versus botulinum toxin in the treatment of idiopathic achalasia. AB - BACKGROUND: Botulinum toxin (BT) injection reduces lower esophageal sphincter pressure and alleviates symptoms in idiopathic achalasia (IA). Ethanolamine oleate (EO) has also been introduced for the treatment of IA. We compared the long-term efficacy of BT and EO injections in the treatment of IA. METHODS: A total of 189 IA patients were evaluated prospectively, of whom 21 were unwilling to undergo or were poor candidates for pneumatic balloon dilation and Heller myotomy and were enrolled in the study. Eleven patients were treated by BT, and 10 by EO injections. Patients were followed up by achalasia symptom score (ASS), timed barium esophagogram (TBE), and high-resolution manometry at baseline and post-treatment. A good initial response was defined as a decrease in ASS to 4 or less, and a reduction in barium column height and volume in TBE by >50%. RESULTS: All 10 EO group patients and 10 of 11 BT group patients showed a good initial response. Four EO group relapsers and 6 BT group relapsers were managed effectively by re-injections. Mean duration of follow up was 27.38 months. On completion of the study, a sustained good response was seen in 9 and 6 patients in EO and BT groups, respectively (P=0.149). CONCLUSION: This study revealed that BT and EO have comparable efficacy in the treatment of IA. However, the cost of EO is about 2 times lower than BT. PMID- 25830940 TI - Retraction notice to "Antimicrobial secondary metabolites from marine gastropod egg capsules and egg masses". AB - [This retracts the article DOI: 10.1016/S2221-1691(12)60253-6.][This retracts the article DOI: 10.1016/S2221-1691(12)60253-6.]. PMID- 25830941 TI - Risk of Suicide Among US Military Service Members Following Operation Enduring Freedom or Operation Iraqi Freedom Deployment and Separation From the US Military. AB - IMPORTANCE: A pressing question in military suicide prevention research is whether deployment in support of Operation Enduring Freedom or Operation Iraqi Freedom relates to suicide risk. Prior smaller studies report differing results and often have not included suicides that occurred after separation from military service. OBJECTIVE: To examine the association between deployment and suicide among all 3.9 million US military personnel who served during Operation Enduring Freedom or Operation Iraqi Freedom, including suicides that occurred after separation. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort design used administrative data to identify dates of deployment for all service members (October 7, 2001, to December 31, 2007) and suicide data (October 7, 2001, to December 31, 2009) to estimate rates of suicide-specific mortality. Hazard ratios were estimated from time-dependent Cox proportional hazards regression models to compare deployed service members with those who did not deploy. MAIN OUTCOMES AND MEASURES: Suicide mortality from the Department of Defense Medical Mortality Registry and the National Death Index. RESULTS: Deployment was not associated with the rate of suicide (hazard ratio, 0.96; 99% CI, 0.87-1.05). There was an increased rate of suicide associated with separation from military service (hazard ratio, 1.63; 99% CI, 1.50-1.77), regardless of whether service members had deployed or not. Rates of suicide were also elevated for service members who separated with less than 4 years of military service or who did not separate with an honorable discharge. CONCLUSIONS AND RELEVANCE: Findings do not support an association between deployment and suicide mortality in this cohort. Early military separation (<4 years) and discharge that is not honorable were suicide risk factors. PMID- 25830942 TI - Development of small diameter nanofiber tissue engineered arterial grafts. AB - The surgical repair of heart and vascular disease often requires implanting synthetic grafts. While synthetic grafts have been successfully used for medium to-large sized arteries, applications for small diameter arteries (<6 mm) is limited due to high rates of occlusion by thrombosis. Our objective was to develop a tissue engineered vascular graft (TEVG) for small diameter arteries. TEVGs composed of polylactic acid nanofibers with inner luminal diameter between 0.5 and 0.6 mm were surgically implanted as infra-renal aortic interposition conduits in 25 female C17SCID/bg mice. Twelve mice were given sham operations. Survival of mice with TEVG grafts was 91.6% at 12 months post-implantation (sham group: 83.3%). No instances of graft stenosis or aneurysmal dilatation were observed over 12 months post-implantation, assessed by Doppler ultrasound and microCT. Histologic analysis of explanted TEVG grafts showed presence of CD31 positive endothelial monolayer and F4/80-positive macrophages after 4, 8, and 12 months in vivo. Cells positive for alpha-smooth muscle actin were observed within TEVG, demonstrating presence of smooth muscle cells (SMCs). Neo-extracellular matrix consisting mostly of collagen types I and III were observed at 12 months post-implantation. PCR analysis supports histological observations. TEVG group showed significant increases in expressions of SMC marker, collagen-I and III, matrix metalloproteinases-2 and 9, and itgam (a macrophage marker), when compared to sham group. Overall, patency rates were excellent at 12 months after implantation, as structural integrity of these TEVG. Tissue analysis also demonstrated vessel remodeling by autologous cell. PMID- 25830944 TI - Antioxidant activity and nutritional status in anorexia nervosa: effects of weight recovery. AB - Few studies are focused on the antioxidant status and its changes in anorexia nervosa (AN). Based on the hypothesis that renutrition improves that status, the aim was to determine the plasma antioxidant status and the antioxidant enzymes activity at the beginning of a personalized nutritional program (T0) and after recovering normal body mass index (BMI) (T1). The relationship between changes in BMI and biochemical parameters was determined. Nutritional intake, body composition, anthropometric, hematological and biochemical parameters were studied in 25 women with AN (19.20 +/- 6.07 years). Plasma antioxidant capacity and antioxidant enzymes activity were measured. Mean time to recover normal weight was 4.1 +/- 2.44 months. Energy, macronutrients and micronutrients intake improved. Catalase activity was significantly modified after dietary intake improvement and weight recovery (T0 = 25.04 +/- 1.97 vs. T1 = 35.54 +/- 2.60 MUmol/min/mL; p < 0.01). Total antioxidant capacity increased significantly after gaining weight (T0 = 1033.03 +/- 34.38 vs. T1 = 1504.61 +/- 99.73 MUmol/L; p < 0.01). Superoxide dismutase activity decreased (p < 0.05) and glutathione peroxidase did not change. Our results support an association between nutrition improvement and weight gain in patients with AN, followed by an enhancement of antioxidant capacity and catalase antioxidant system. PMID- 25830945 TI - Monounsaturated fatty acids-rich diets in hypercholesterolemic-growing rats. AB - The effects of replacing dietary saturated fat by different monounsaturated fatty acid (omega-9MUFA) sources on serum lipids, body fat and bone in growing hypercholesterolemic rats were studied. Rats received one of the six different diets: AIN-93G (control, C); extra virgin olive oil (OO) + C; high-oleic sunflower oil (HOSO) + C or atherogenic diet (AT) for 8 weeks; the remaining two groups received AT for 3 weeks and then, the saturated fat was replaced by an oil mixture of soybean oil added with OO or HOSO for 5 weeks. Rats consuming MUFA rich diets showed the highest body fat, hepatic index and epididymal, intestinal and perirenal fat, and triglycerides. T-chol and non-HDL-chol were increased in HOSO rats but decreased in OO rats. Bone mineral content and density were higher in both OO and HOSO groups than in AT rats. This study casts caution to the generalization of the benefits of MUFA for the treatment of hypercholesterolemia. PMID- 25830946 TI - Validation of a food frequency questionnaire for use in Italian adults living in Sicily. AB - The objective of this study was to validate two interviewer-led food frequency questionnaires (FFQs) of very different lengths: a medium-length FFQ (medium-FFQ) of 36 items and a short-length FFQ (short-FFQ) of 18 items, intending to measure levels of intakes in a local population. Both FFQs were validated against intakes derived from a 3-day dietary record (3-day DR). Sixty-five non-diabetic adults with no known cardiovascular, renal or other systemic diseases were included. High correlation coefficients between the FFQ and the 3-day DR (0.45-0.73) were observed for energy intake, carbohydrates and lipid and protein intake. Bland Altman plots showed good agreement between the methods. Low (0.26-0.37) correlation coefficients of the different nutrient intakes obtained with the short-FFQ and the 3-day DR were observed, with the exception of alcohol intake (rho = 0.49). This study showed promising evidence for the use of a medium-FFQ as a potentially useful tool for investigating the relationship between habitual diet and diseases in clinical and research settings. PMID- 25830947 TI - Impact of probiotics during weaning on the metabolic and inflammatory profile: follow-up at school age. AB - We hypothesised that feeding the probiotic Lactobacillus paracasei ssp. paracasei F19 (LF19) (dep. nr LMG P-17806) during weaning would program the metabolic and inflammatory profile and studied its association with previously assessed body composition. In a double-blind, placebo-controlled trial, 179 infants were randomised to daily feeding of cereals with or without LF19 10(8) CFU from 4 to 13 months of age. At age 8-9 years, 120 children were re-assessed. Using high sensitivity multiplex immunoassay technology and ELISA, we found that overweight/obese children had increased plasma C-peptide, plasminogen activator inhibitor-1, leptin and serum high-sensitivity C-reactive protein (hsCRP) after overnight fasting compared with normal weight children, independently of LF19. After excluding the obese, leptin and hsCRP were still increased, revealing an aberrant metabolic and inflammatory state already in overweight, pre-pubertal children. Higher body mass index z-score, sagittal abdominal diameter, truncal and total body fat % were associated with an aberrant metabolic and inflammatory profile, emphasising the need for early prevention strategies although no programming effect of LF19 was observed. PMID- 25830943 TI - B vitamins, homocysteine and bone health. AB - Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated. This review will explore the emerging evidence of the supporting role of certain B Vitamins as modifiable factors associated with bone health. Individuals with high levels of homocysteine (hcy) exhibit reduced bone mineral density (BMD), alteration in microarchitecture and increased bone fragility. The pathophysiology caused by high serum homocysteine is not completely clear regarding fractures, but it may involve factors, such as bone mineral density, bone turnover, bone blood flow and collagen cross-linking. It is uncertain whether supplementation with B Vitamins, such as folate, Vitamin B1, and Vitamin B6, could decrease hip fracture incidence, but the results of further clinical trials should be awaited before a conclusion is drawn. PMID- 25830948 TI - Black soybean extract reduces fatty acid contents in subcutaneous, but not in visceral adipose triglyceride in high-fat fed rats. AB - It is known that black soybean (BS) extract, rich in polyphenols, has beneficial effects against obesity, inflammation and insulin resistance. However, detailed effects of BS on lipid metabolism have not been documented well. In the present study, we compared fatty acid composition in visceral and subcutaneous adipose tissues of high-fat fed (HFF) rats and BS administered HFF rats. Black soybean administration for 6 weeks influenced neither body nor adipose tissue weights, blood glucose, plasma insulin levels, or insulin sensitivity. However, BS reduced several saturated (C14:0 and C16:0), monounsaturated (C14:1n-5 and C18:1n-9) and n-6 polyunsaturated (C18:2n-6, C20:3n-6, C20:4n-6 and C22:4n-6) fatty acid contents in subcutaneous fat without any change in n-3 polyunsaturated fatty acid contents. No such effect was observed in fatty acid composition in visceral fat. Long-chain fatty acids are involved in regulation of inflammation. Therefore, those reduced fatty acids may be linked to the effects on suppressing inflammation. PMID- 25830950 TI - Access to tuberculosis services for individuals with disability in rural Malawi, a qualitative study. AB - Tuberculosis occurs in all populations, but with higher prevalence in poor contexts. Vulnerable groups, including individuals with disability, run a particular risk due to poorer access to information and health services. Studying access to tuberculosis services for vulnerable groups in poor contexts may provide useful insight into the quality of such services in low-income contexts. This article aims to present a contextual understanding of access to tuberculosis services for people with disabilities in one district in southern Malawi. A qualitative method with semi-structured interviews and site observations was applied. In all, 89 participants were interviewed: 47 persons with disability, 11 parents/guardians of youths with disability, and the remaining 31 comprising eight health workers, four community rehabilitation assistants and volunteers, and 19 leaders in the community.Our main findings are that lack of information and knowledge, and considerable confusion related to tuberculosis, its cause and how to protect oneself, are major barrier to accessing services. Disease awareness and personal risk perception are key factors in this regard. Further findings concerns the pathways to tuberculosis related health services, in particular having a test and completing the treatment. The combination of lack of knowledge and barriers in accessing tests implies substantial availability and access problems.It is of importance to understand the combined impact of individual, social, contextual, and systems barriers to fully address the complexity of accessing tuberculosis services for vulnerable groups in poor populations. Lack of disability specific strategies in the local health services may be part of the reason why individuals with disability to not access such services. PMID- 25830949 TI - Current endoscopic ultrasound-guided approach to incidental subepithelial lesions: optimal or optional? AB - Subepithelial lesions (SEL) are identified during endoscopic procedures on a regular basis. They can occur anywhere in the gastrointestinal (GI) tract and are located beneath the normal epithelial layer, which explains why a tissue diagnosis is difficult to obtain with routine biopsies. Endoscopic ultrasound (EUS) is used to further characterize these lesions. EUS can distinguish intramural lesion from extramural compression. Furthermore, it allows allocation of intramural lesions to a specific layer of the GI wall and offers additional information as to whether a lesion could be benign or malignant. EUS also assists in choosing the optimal means of tissue acquisition. The choice of tissue acquisition is based on a number of factors, such as tumor size, EUS features, and location within the GI tract or within a specific layer of the GI wall. Furthermore, local expertise and patient factors should be considered when deciding whether tissue acquisition, surgical intervention or follow up is recommended. In this review we offer an EUS-guided approach to the evaluation of incidental SEL based on current evidence and point out areas of uncertainty, which explain why the proposed algorithmic approach may be optional rather than optimal. PMID- 25830952 TI - Diabetes Text-Message Self-Management Support Program (SMS4BG): A Pilot Study. AB - BACKGROUND: The increasing prevalence of diabetes and costly long-term complications associated with poor glycemic control are issues facing health services worldwide. Diabetes self-management, with the support of health care providers, is critical for successful outcomes, however, frequent clinical contact is costly. Text messages via short message service (SMS) have the advantage of instant transmission at low cost and, given the ubiquity of mobile phones, may be the ideal platform for the delivery of diabetes self-management support. A tailored text message-based diabetes support intervention called Self Management Support for Blood Glucose (SMS4BG) was developed. The intervention incorporates prompts around diabetes education, management, and lifestyle factors (healthy eating, exercise, and stress management), as well as blood glucose monitoring reminders, and is tailored to patient preferences and clinical characteristics. OBJECTIVE: To determine the usability and acceptability of SMS4BG among adults with poorly controlled diabetes. METHODS: Adults (aged 17 to 69 years) with type 1 (n=12) or type 2 diabetes (n=30), a hemoglobin A1c (HbA1c) over 70 mmol/mol (8.6%), and who owned a mobile phone (n=42) were recruited to take part in a 3-month pilot study of SMS4BG. At registration, participants selected the modules they would like to receive and, where appropriate, the frequency and timing of blood glucose monitoring reminders. Patient satisfaction and perceptions of the usability of the program were obtained via semistructured phone interviews conducted at completion of the pilot study. HbA1c was obtained from patient records at baseline and completion of the pilot study. RESULTS: Participants received on average 109 messages during the 3-month program with 2 participants withdrawing early from the study. Follow-up interviews were completed with 93% of participants with all reporting SMS4BG to be useful and appropriate to their age and culture. Participants reported a range of perceived positive impacts of SMS4BG on their diabetes and health behaviors. HbA1c results indicated a positive impact of the program on glycemic control with a significant decrease in HbA1c from baseline to follow-up. CONCLUSIONS: A tailored text message-based intervention is both acceptable and useful in supporting self management in people with poorly controlled diabetes. A randomized controlled trial of longer duration is needed to assess the efficacy and sustainability of SMS4BG. PMID- 25830951 TI - Intravenous infusion of monocytes isolated from 2-week-old mice enhances clearance of Beta-amyloid plaques in an Alzheimer mouse model. AB - Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (Abeta) senile plaques and tau-associated neurofibrillary tangles. Other disease features include neuroinflammation and cholinergic neurodegeneration, indicating their possible importance in disease propagation. Recent studies have shown that monocytic cells can migrate into the AD brain toward Abeta plaques and reduce plaque burden. The purpose of this study was to evaluate whether the administration of intravenous infusions of 'young' CD11b-positive (+) monocytes into an AD mouse model can enhance Abeta plaque clearance and attenuate cognitive deficits. Peripheral monocytes were isolated from two-week-old wildtype mice using the Pluriselect CD11b+ isolation method and characterized by FACS analysis for surface marker expression and effective phagocytosis of 1 MUm fluorescent microspheres, FITC-Dextran or FITC-Abeta1-42. The isolated monocytes were infused via the tail vein into a transgenic AD mouse model, which expresses the Swedish, Dutch/Iowa APP mutations (APPSwDI). The infusions began when animals reached 5 months of age, when little plaque deposition is apparent and were repeated again at 6 and 7 months of age. At 8 months of age, brains were analyzed for Abeta+ plaques, inflammatory processes and microglial (Iba1) activation. Our data show that infusions of two-week-old CD11b+ monocytes into adult APPSwDI mice results in a transient improvement of memory function, a reduction (30%) in Abeta plaque load and significantly in small (<20 MUm) and large (>40 MUm) plaques. In addition, we observe a reduction in Iba1+ cells, as well as no marked elevations in cytokine levels or other indicators of inflammation. Taken together, our findings indicate that young CD11b+ monocytes may serve as therapeutic candidates for improved Abeta clearance in AD. PMID- 25830953 TI - Electrical Properties and Defect Chemistry of In-Doped TiO2 in Terms of the Jonker Formalism. AB - The present work considers the semiconducting properties of In-doped TiO2 in terms of the Jonker formalism applied for both electrical conductivity and thermoelectric power data determined simultaneously in equilibrium with the gas phase of controlled oxygen activity. It is shown that the electrical properties of In-doped TiO2 annealed in oxidizing conditions [p(O2) > 10 Pa] can be described by the Jonker formalism very well. However, annealing of In-doped TiO2 in strongly reducing conditions [p(O2) < 10(-10) Pa], imposed by the gas phase involving hydrogen, results in a deviation of the experimental data from the Jonker's theoretical model derived for the Maxwell-Boltzmann statistics. This departure is considered in terms of the effect of hydrogen on the formation of structural domains, which are expected to be entirely different from those of oxidized TiO2 in terms of its electronic properties. It is argued that In-doped TiO2 annealed in the gas phase involving hydrogen exhibits a high concentration of donor-type ionic defects, which lead to the formation of high concentration of electrons. The related semiconducting properties are inconsistent with the model of classical semiconductor where the electrons are described by the Maxwell Boltzmann statistics. It is concluded that strong interactions within the electron gas lead, in consequence, to the behavior resembling correlated transport of electrons. The obtained results suggest that indium incorporation into the rutile structure of TiO2 results in the formation of structural properties that exhibit extraordinary charge transport. PMID- 25830954 TI - Investigation of recovery of volatiles of Bidens tripartita L. using solid-phase extraction trap in supercritical fluid extraction. AB - Recovery of Bidens tripartita L. volatiles using supercritical CO2 extraction with solid-phase trap was performed in this study. Three points were analyzed: the impact of rinse solvent (heptane, methanol or acetonitrile) for analytes desorption from the trap; the impact of the amount of plant material used for extraction; the release of volatiles from plant matrix using multiple extraction. alpha-Pinene, p-cymene, beta-ocimene, and beta-elemene were predominant in all extracts prepared in different ways. beta-Ocimene was the main compound (40-46%) in all extracts despite of the solvent used. No significant difference between the amount of alpha-pinene observed using different trap desorption solvent, while heptane desorbed significantly higher amounts (12-31%) of other compounds. The composition of volatiles using different amount of sample showed both qualitative and quantitative differences. The study showed different extraction extent of the main compounds during the first and repeated extractions. PMID- 25830955 TI - Theoretical considerations regarding the thione-thiol tautomerism in 2-(5 mercapto-1,3,4-thiadiazol-2-ylthio)acetic acid. AB - The acidity constants Ka1 and Ka2 of 2-(5-mercapto-1,3,4-thiadiazol-2 ylthio)acetic acid have been determined both by experimental and theoretical methods. pKa computations at B3LYP/6-311+G(d,p) level of theory were carried out for the two tautomeric forms, thiol and thione, of the above-mentioned acid. Comparisons between the experimental and theoretical values led to the establishing of the most stable tautomer of 2-(5-mercapto-1,3,4-thiadiazol-2 ylthio)acetic acid in aqueous solution. Also, a DFT study regarding the reactivity, aromaticity and population analysis of the two tautomers has been performed. PMID- 25830956 TI - Spectroscopic methods and theoretical studies of bromoacetyl substituted derivatives of bile acids. AB - The structure of seven bromoacetic substituted derivatives of bile acids are characterized by 1H MMR, 13C NMR, 2D NMR, FT-IR and mass spectrometry (ESI-MS) as well as PM5 semiempirical and B3LYP ab initio methods. Estimation of the pharmacotherapeutic potential has been accomplished for the synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). PMID- 25830957 TI - Composite electrodes with carbon supported Ru nanoparticles for H2O2 detection. AB - A new carbon paste electrode (CPE) incorporating Ru - nanoparticles (RuNP) stabilized on graphite powder was developed for H(2)O(2) amperometric detection. Cyclic voltammetric measurements, performed in phosphate buffer solutions at different potential scan rates and different potential ranges were carried out in order to evaluate the electrochemical behavior of the CPE-RuNP modified electrodes. From amperometric measurements performed at -0.1 V vs. Ag/AgCl, KClsat, the electrocatalytic efficiency toward H(2)O(2) reduction was evaluated and it was found in the range: 28.47% (CPE) < 94.81% (CPE-RuNP (2.5:1)) < 118.19 % (CPE-RuNP (2.5:3)) < 152.43% (CPE-RuNP (2.5:2), recommending the new electrodes as promising sensors for hydrogen peroxide detection. PMID- 25830958 TI - Theoretical and experimental study of organic nano-material for acetate anion based on 1, 10-phenanthroline. AB - New phenanthroline derivatives (1, 2, 3, 4) containing phenol groups have been synthesized and optimized. The nano-material of compound 2 was also developed. Their binding properties were evaluated for various biological anions (F(-), Cl( ), Br(-), I(-), AcO(-) and H(2)PO(4)(-)) by theoretical investigation, UV-vis, fluorescence, (1)HNMR titration experiments and these compounds all showed strong binding ability for AcO(-) without the interference of other anions tested. The anion binding ability could be regularized by electron push-pull properties of the ortho- or para- substituent on benzene. Theoretical investigation analysis revealed the effect of intramolecular hydrogen bond existed between -OH and other atoms in the structure of these compounds. PMID- 25830959 TI - Development and validation of chromatographic methods for simultaneous determination of ibuprofen and famotidine in presence of related substances in pharmaceutical formulations. AB - Two validated methods for the simultaneous determination of ibuprofen and famotidine in the presence of ibuprofen impurity (4-isobutylacetophenone) and or famotidine degradation products were described. The first method was a simple TLC method where separation was performed on silica gel platesusing ethyl acetate: methanol: ammonia (9:2:1, by volume) as a mobile phase. Rf values were found to be 0.40, 0.94, 0.66, 0.27, 0.83 for ibuprofen, 4-isobutylacetophenone, famotidine, famotidine acid and basic degradation products, respectively. The second method is by HPLC on C18 column using methanol: phosphate buffer pH 3 (80:20, v/v) as a mobile phase. Retention times were found to be 2.2, 9.9, and 8.6 for famotidine, ibuprofen, and 4-isobutylacetophenone, respectively. Both methods were validated according to the ICH guidelines and applied for the determination of the two drugs in pure powder and combined dosage form without interference from the excipients. PMID- 25830960 TI - The influence of Co/Sr and Fe/Sr driers on film formation of high solid alkyd coatings. AB - High solid (HS) alkyd resins with low amount of volatile organic compounds (VOC) were developed as the result of new VOC solvent directive that limit the amount of VOC in decorative paints. Due to specific chemical structure of HS alkyd resins and possible deterioration of some applicative properties the optimal combination of driers is an important subject of research. In our present work we studied the influence of iron (Fe) and cobalt (Co) surface driers with strontium (Sr) through drier on the film formation of HS alkyd coatings. The kinetics of autoxidation was analysed using FT-IR spectroscopy. Further, applicative properties like drying time and film hardness were examined. In the end, electrochemical impedance spectroscopy (EIS) was used to evaluate the quality of cured HS alkyd coating films after exposure in the humidity chamber. It was established that the addition of the Sr drier to surface driers accelerates the film formation process. As higher amounts of the Sr drier were added, final drying times were reduced and film hardness increased. The highest quality of cured films were observed for Co/Sr and Fe/Sr drier combination at 1:1 concentration ratio. PMID- 25830961 TI - A Four-step Synthesis of Novel (S)-1-(heteroaryl)-1-aminoethanes from (S)-Boc alanine. AB - A series of (S)-1-(pyrimidin-4-yl)-, and regioisomeric (S)-1-(pyrazolo[1,5 a]pyrimidin-7-yl)-, and (S)-1-(pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-amines were prepared by cyclisation of (S)-N-Boc-alanine-derived ynone with N,N-1,3 dinucleophiles, such as amidines and alpha-aminoazoles, followed by acidolytic removal of the Boc group. Stereoselective catalytic hydrogenation of (S)-1 (pyrazolo[1,5-a]pyrimidin-7-yl)ethanamines lead to saturation of the pyrimidine ring to afford ~4:1 mixture of diastereomeric 4,5,6,7-tetrahydropyrazolo[1,5 a]pyrimidines. The structures of novel compounds were elucidated with NMR. PMID- 25830962 TI - Quality by design based optimization of a high performance liquid chromatography method for assay determination of low concentration preservatives in complex nasal formulations. AB - The effects of seven different chromatographic parameters and five sample preparation parameters in a high performance liquid chromatography (HPLC) method for assay determination of benzalkonium chloride (BKC) in a nasal formulation were evaluated using two fractional factorial experimental designs. The design space of the analytical method was modeled using Umetrics Modde software and the optimal method conditions were predicted. The optimum HPLC chromatographic conditions were obtained using a Luna CN column (150 x 4.6 mm, 3 um). The results show that mobile phase pH, amount of acetonitrile in the mobile phase and column temperature are the most important factors in obtaining good separation of BKC homologs from an interfering peak. In the sample preparation step, the use of an aqueous solution for dissolving the samples was the most important factor since it eliminated the interfering effect of the active compound. The optimal method was validated for linearity, accuracy and precision. The use of experimental designs enables obtaining the maximum amount of information with the least possible number of experiments. Such designs are an economical manner in evaluating a variety of different factors and their interactions. PMID- 25830963 TI - Initial conditioning of polymer eelectrolyte membrane fuel cell by temperature and potential cycling. AB - Polymer electrolyte membrane fuel cells need initial conditioning, activation or break-in the first time they are operated after being assembled. During this period performance of the fuel cell improves until it reaches its nominal performance. The exact mechanism of this initial conditioning is not completely understood, but it is assumed that during the conditioning process the polymer membrane, as well as the polymer in the catalyst layer, get humidified, and the number of active catalyst sites increases. Activation procedure proposed here consists of temperature and potential cycling. Temperature cycling is a new approach for the conditioning and the idea is to rapidly cool the running cell at some point to allow the membrane to equilibrate with condensed water which should result in higher intake of water within the membrane. The results show that proposed procedure is better or at least comparable to some conventional procedures for the initial conditioning. PMID- 25830964 TI - Synthesis, X-ray structural and thermal analysis of a novel copper compound containing dissymmetric independent 5- and 6-coordinate CuL(H2O)n (n = 2, 3) units and hydrogen bond bridges. AB - The synthesis, thermogravimetric and X-ray structure analysis of a highly unusual copper compound prepared from a chiral tridentate Schiff base ligand is reported. The title compound [CuL(H(2)O(2)]. CuL(H(2)O(3)].H(2)O crystallizes in the orthorhombic crystal system in space group P2(1)2(1)2(1) with Z = 4. Two independent CuL(H(2)O)(n) complexes are present in the same unit cell, one five- and the other six- coordinate. The five-coordinate copper(II) centre occupies a distorted square-pyramidal geometry whereas the six-coordinate copper(II) centre has a distorted octahedral geometry. The independent copper complexes and the uncoordinated water molecule are joined together with intermolecular hydrogen bonds in a two-dimensional supramolecular network which lies parallel to the ab plane. PMID- 25830965 TI - N-Functionalized L-proline anchored MCM-41: a novel organic-inorganic hybrid material for solvent-free aminolysis of styrene oxide under microwave irradiation. AB - A novel organic-inorganic hybrid material, namely L-prol-N-pMCM-41, was synthesized via two steps by covalently anchoring N-functionalized proline derivative (L-prol-N-pTMS) into the pore channels of MCM-41 silica. The prepared material was characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), nitrogen adsorption-desorption isotherm, Brunauer-Emmett-Teller (BET) surface area analysis, and Fourier Transform Infrared spectroscopy (FTIR). The immobilized catalyst demonstrated moderate to high catalytic activity and excellent regioselectivity for the ring opening of styrene oxide with aniline derivatives under microwave irradiation and solvent-free conditions. The catalyst could be rapidly separated from the reaction mixture and reused up to five runs with good conversion and high regioselectivity. PMID- 25830966 TI - CuI nanoparticles as a remarkable catalyst in the synthesis of benzo[b][1,5]diazepines: an eco-friendly approach. AB - Highly efficient CuI nanoparticles catalyzed one-pot synthesis of some benzo[b][1,5]diazepine derivatives via multi-component condensation of aromatic diamines, Meldrum's acid and isocyanides. The present approach creates a variety of benzo[b][1,5]diazepines as pharmaceutical and biologically active heterocyclic compounds in excellent yields and short reaction times. The salient features of the copper iodide nanoparticles are: easy preparation, cost-effective, high stability, low loading and reusability of the catalyst. The prepared copper iodide nanoparticles were fully characterized by XRD, EDX, FT-IR, SEM and TEM analysis. PMID- 25830967 TI - Application of mesoporous SBA-15 silica functionalized with 4-amino-2 mercaptopyrimidine for the adsorption of Cu(II), Zn(II), Cd(II), Ni(II), and Pb(II) from water. AB - This work reports the sol-gel synthesis of a SBA-15 silica, and its functionalization with 4-amino-2-mercaptopyrimidine to perform adsorption of metal species from aqueous media. The functionalization of the material was confirmed by FTIR and superficial area measurements. The final material was tested through batch experiments to uncover its adsorptive properties towards the adsorption of Cu(II), Cd(II), Zn(II), Pb(II) and Ni(II). Contact time and pH conditions were investigated, and the material presented slow adsorption kinetics, which was best described by the pseudo-second order model. In addition, at pH 5 - 6, the adsorption of the metal ions was favored. Under optimized conditions, the material had its maximum adsorption capacities determined for all metal species studied, and the obtained values were 13.0 umol g(-1) for Zn(II), 12.3 umol g(-1) for Cu(II), 3.45 umol g(-1) for Ni(II), 2.45 umol g(-1) for Pb(II) and 0.60 umol g(-1) for Cd(II). The capacity differences between each metal ion were discussed in terms of their ionic radii and Person's soft/hard acids/bases concept. PMID- 25830968 TI - Synthesis, structure characterization, DNA binding, and cleavage properties of mononuclear and tetranuclear cluster of copper(II) complexes. AB - Two copper(II) complexes, cluster 1, and mononuclear 2, have been synthesized by reacting acetylacetone and benzohydrazide (1:1 ratio for 1 and 1:2 ratio for 2) with CuCl(2) in a methanol solution. In 2, which is a new complex, the ligand acts as a tetradentate which binds the metal ion via two amide-O atoms and two imine-N atoms providing an N(2)O(2) square-planar around the copper(II) ion. The absorption spectra data evidence strongly suggested that the two copper(II) compounds could interact with CT-DNA (intrinsic binding constant, K(b) = 0.45*10(4) M-1 for 1 and K(b) = 2.39*10(4) M-1 for 2). The super coiled plasmid pBR322 DNA cleavage ability was studied with 1 and 2 in the presence and absence of H(2)O(2) as an oxidant. In both the absence and the presence of an oxidizing agent, complex 2 exhibited no nuclease activity. However, even in the absence of an oxidant, complex 1 exhibited significant DNA cleavage activity. PMID- 25830969 TI - Relation of the aged gels microstructure on the zeolite a particulate properties. AB - The microstructure of the starting hydrogel has extremely important role in the synthesis of the microporous materials. Due to the fact that very limited number of experimental methods (techniques) can be used for gel analysis, there are still a lot of missing informations about the processes on molecular level, which occur before and during the nuclei formation. In this paper, various methods were used in characterization of pretreated (aged) hydrogel before the process of its hydrothermal transformation to zeolite A. Results show the changes in chemical composition and in microstructure of the solid phase (FTIR, PALS, BET, DTG), indicating that the structure of the ordered phase (potential nuclei) within gel matrix (completely amorphous according to PXRD patterns) is rather of different structural units typical for FAU and SOD (or their mixture) than the final product (LTA) only! PMID- 25830970 TI - Convenient synthesis, characterization, cytotoxicity and toxicity of pyrazole derivatives. AB - 3-Methyl-1H-pyrazol-5(4H)-one (1) was used as a template to develop new anticancer compounds and investigate their SAR. The ring modification of compound 1 occurred through its reaction with aromatic aldehydes and different reagents to afford the corresponding 6-oxopyrano[2,3-c]pyrazoles4a-c and their amino analogues 6-aminopyrano[2,3-c]pyrazoles6a-c, 8; the pyrazolopyrano[2,3 b]pyridines 10a-c and the chromenopyrano[2,3-c]pyrzolones13, 14. The reaction of compound 1 with thiourea and appropriate aromatic aldehydes afforded the pyrazolo[3,4-d]pyrimidine derivatives 17a-c. On the other hand, the pyrazolo[3,4 d]thiazole derivatives 22a-d were obtained via the reaction of 1 with sulpher and aryl isothiocyanates in presence of triethylamine. The reaction of compound 1 with phenylisothiocyanate followed by treatment with the a-halocarbonyl compounds 24a-c afforded the thiazole derivatives 25a-c. The synthesized products were evaluated for their cytotoxicity against cancer and normal cell lines. Most compounds showed significant anticancer activity without affecting the normal fibroblast cells. The toxicity of the mostpontent cytotoxic compounds was measured using Brine-Shrimp Lethality Assay. PMID- 25830971 TI - Determination of nitrites in water by in-electrode coulometric titration in reticulated vitreous carbon electrode. AB - Nitrite in water samples was determined by in-electrode coulometric titration in a reticulated vitreous carbon (RVC) electrode of 100 ppi porosity. The sample was mixed with dilute sulphuric acid and sodium sulphate, filled into a flow cell with the porous electrode and nitrite was oxidised to nitrate by constant current of 5 uA at which the potential of the electrode was monitored. The limits of detection and quantification were found to be 0.4 and 1.2 ug/L, respectively. The repeatability and reproducibility were 2.2 % and 2.6 %, respectively. The bias at 100 ug/L were found to be 0.3 %. The duration of the measurement is 2-3 min depending on the nitrite concentration. There were few interferences only, neutral and cationic surfactants decreased and increased slightly the signal, respectively. Humic acids above 30 mg/L increased the signal by 10 %. Drinking and surface water samples were analysed and the results matched well those from the photometric method. PMID- 25830972 TI - Spectrophotometric studies of 4-[N'-(4-imino-2-oxo-thiazolidin-5-ylidene) hydrazino]-benzenesulfonic acid as a reagent for the determination of palladium. AB - The spectrophotometric behavior of a new, first-time synthesized reagent - 4-[N' (4-imino-2-oxo-thiazolidin-5-ylidene)hydrazino]-benzenesulfonic acid (ITHBA), has been investigated. A simple, rapid, accurate, selective and sensitive method for the spectrophotometric determination of Pd(II) ions using this reagent was developed. The optimal conditions for the formation of the complexes were found. The molar absorptivity at lambda = 438 nm is 7.5 * 10(3) L mol(-1) cm(-1), and Beer's law is observed for the concentrations ranging from 0.2-2.2 ug mL-1Pd(II). The effects of extraneous ions were investigated. The method proved to be successful in determination of palladium in the intermetallides and resistor. The accuracy of spectrophotometric palladium assay in real objects with 4-[N'-(4 imino-2-oxo-thiazolidin-5-ylidene)-hydrazino]-benzenesulfonic acid has been confirmed by voltammetric or atomic absorption spectroscopy method. PMID- 25830973 TI - Synthesis and antitumor evaluation of novel dihydropyrimidine, thiazolo[3,2 a]pyrimidine and pyrano[2,3-d]pyrimidine derivatives. AB - A simple and efficient method has been developed for the synthesis of 4,5-dihydro 2-mercapto-4-oxo-6-substituted arylpyrimidine derivatives (2a-e) and their fused rings (3b, 4b, 5b & 6b) and also 1,4-dihydro-2-mercaptopyrimidine derivatives (7a e) & (9a-e) using triethylamine as a catalyst. The structure of the newly synthesized compounds was confirmed on the basis of their spectral data and elemental analysis. All the synthesized compounds were evaluated for their in vitro anticancer activity against six human cancer cell lines and normal fibroblasts. Thirteen of the tested compounds: 2a-e, 3b, 4b, 5b, 7d, 8, 9a, 9c and 9d exhibited significant cytotoxicity against most cell lines. Among these derivatives compounds 2a, 3b and 9c are the most potent, they exhibited cytotoxic effect against the six cancer cell lines with IC(50) values < 330 nM compared to the standard CHS 828. Normal fibroblast cells (WI38) were affected to a much lesser extent (IC(50) >10,000 nM). PMID- 25830974 TI - The effect of tyrosine residues on alpha-synuclein fibrillation. AB - Aggregation of the intrinsically disordered protein alpha-synuclein into ordered amyloid fibrils is implicated in the pathogenesis of Parkinson's disease. To unravel the role of Tyr residues in alpha-synuclein fibrillation, we prepared recombinant N-terminal (Y39A) and C-terminal (Y(125,133,136)A) mutants of alpha synuclein and examined their fibrillation propensities by thioflavin T and 1 anilinonaphthalene-8-sulfonate (ANS) fluorescent probes, SDS-PAGE and atomic force microscopy. We demonstrate that in contrast to wild-type alpha-synuclein, both mutants show large, but comparable delays in the fibrillation process and exhibit enhanced hydrophobicity during fibril-like assembly. Both Tyr mutants form fibril-like structures after prolonged incubation periods, which are morphologically distinct from those of the wild-type protein. Our results suggest that the N-terminal and C-terminal Tyr residues of alpha-synuclein are important primarily for the initiation of the fibrillation process. PMID- 25830975 TI - Artificial neural network approach to modelling of metal contents in different types of chocolates. AB - The relationships between the contents of various metals in different types of chocolates were studied using chemometric approach. Chemometric analysis was based on the application of artificial neural networks (ANN). ANN was performed in order to select the significant models for predicting the metal contents. ANN equations, that represent the content of one metal as a function of the contents of other metals were established. The statistical quality of the generated mathematical models was determined by standard statistical measures and cross validation parameters. High agreement between experimental and predicted values, obtained in the validation procedure, indicated the good quality of the models. The obtained results indicate the possibility of predicting the metal contents in different types of chocolate. PMID- 25830976 TI - Ion pair-dispersive liquid-liquid microextraction coupled to microsample injection system-flame atomic absorption spectrometry for determination of gold at trace level in real samples. AB - A novel ion pair-dispersive liquid-liquid microextraction (IP-DLLME) of gold followed by its determination with microsample injection system-flame atomic absorption spectrometry (MIS-FAAS) detection was developed. The extraction method was based on the reaction of anionic tetrachloro gold(III) complex with the cationic form of Rhodamine B to give a violet ion pair complex, which is extracted from 1.0 mol L(-1) HCl solution of 8.0 mL to fine droplets of chloroform of 500 uL. A Plackett-Burman experimental design of MINITAB statistical program was employed to optimize the influence of main parameters to be controlled in DLLME. After optimizing the extraction conditions, gold was quantitatively recovered by preconcentration factor of 40, limit of detection (LOD) of 1.8 MUg L(-1) and relative standard deviation of less than 6.8%. The proposed method was successfully applied to the preconcentration and determination of gold in some samples such as tap water, waste water, copper electrolysis solution and copper wire coated nickel. PMID- 25830977 TI - Dialkyltin(IV)bis(O-tolyl/benzyldithiocarbonate) complexes: spectroscopic, thermogravemetric, antifungal and crystal analysis of n-Bu2Sn(S2COCH2C6H5)2. AB - Novel compounds of dimethyl- and dibutyltin(IV) with O tolyl/benzyldithiocarbonates were successfully obtained by the reaction of Me(2)SnC(l2) and n-Bu(2)SnCl(2) with sodium salt of O tolyl/benzyldithiocarbonates, [o-, m- and p-CH(3)C(6)H(4)OCS(2)Na and C(6)H(5)CH(2)OCS(2)Na], in 1:2 molar ratio in dry toluene. The structure of these newly synthesized complexes has been examined by elemental analysis, FT-IR, multinuclear NMR ((1)H, (13)C and (119)Sn) spectroscopy. The thermal behaviour of the complex (8) has been studied by TGA/DTA analysis. The complex (8), n Bu2Sn(S2COCH2C6H5)2, crystallizes in the monoclinic space group C2/c, in which tin adopts a distorted octahedron or skew trapezoidal bipyramidal geometry accompanied by two n-butyl chains and the two dithiocarbonate ligands coordinated in an anisobidentate fashion. Antifungal activities against fungus Fusarium sp. of these organotin(IV) derivatives exhibited enhanced activity compared to the free ligands. PMID- 25830978 TI - Bioacid hydroconversion over Co, Ni, Cu Mono- and indium-doped bimetallic catalysts. AB - Caprylic acid (CA) as model reactant was selectively reduced in a flow-through reactor in hydrogen stream at 21 bar total pressure and 240-360 degrees C over alumina loaded with the adjacent Co, Ni, Cu host and In guest metals. The main target of this research is the recognition of efficient cobalt catalysts for carboxylic group hydroconversion compared to more familiar nickel and copper composites. The catalysts were activated in H(2) flow at 21 bar and 450 degrees C. By variation of main metal or modification with indium, mono- or bimetallic catalysts can be obtained with low hydrodecarbonylation activity and high alcohol selectivity. These composites have higher hydrodeoxygenation (HDO) activity and alcohol selectivity than the conventional commercial catalysts applied for fatty alcohol production. Great variety of catalytic behavior indicates complexity of the surface reactions determined by several interacting factors. PMID- 25830979 TI - Two binuclear cyanide-bridged Cr(III)-Mn(III) complexes based-on [Cr(2,2' bipy)(CN)4]- building block: synthesis, crystal structures and magnetic properties. AB - Tetracyanide building block [Cr(2,2'-bipy)(CN)(4)]- and two bicompartimental Schiff-base based manganese(III) compounds have been employed to assemble cyanide bridged heterometallic complexes, resulting in two cyanide-bridged CrIII-MnIII complexes: [Mn(L(1))(H(2)O)][Cr(2,2'-bipy)(CN)(4)].CH(3)OH.2.5H(2)O (1) and [Mn(L(2))(H(2)O)][Cr(2,2'-bipy)(CN)(4)].CH(3)OH.(3)H(2)O (2) (L1 = N,N'-(1,3 propylene)-bis(3-methoxysalicylideneiminate), L2 = N,N'-ethylene-bis(3 ethoxysalicylideneiminate)). Single X-ray diffraction analysis shows their similar cyanide-bridged binuclear structures, in which the cyanide precursor acting as monodentate ligand connects the manganese(III) ion. The binuclear complexes are self-complementary through coordinated aqua ligand and the free O4 compartment from the neighboring complex, giving H-bond linking dimer structure. Investigation over magnetic properties reveals the antiferromagnetic magnetic coupling between the cyanide-bridged Cr(III) and Mn(III) ions. A best-fit to the magnetic susceptibilities of these two complexes leads to the magnetic coupling constants J = -5.95 cm(-1), j = -0.61 cm(-1) (1) and J = -4.15 cm(-1), j = -0.57 cm(-1) (2), respectively. PMID- 25830980 TI - New platinum(II) complexes of cycloalkanespiro-5-(2-thiohydantoins). Synthesis and quantum chemical investigation. AB - Synthesis and characterization of new Pt(II) complexes of cyclohexanespiro-5-(2 thiohydantoin) (L1) and cycloheptanespiro-5-(2-thiohydantoin) (L2) are discussed. The new complexes are studied by elemental analysis, IR, ATR FTIR spectroscopy. The free ligands are investigated by UV-Vis, FT-IR, (1)H NMR, (13)C NMR and Raman spectroscopy. The ground-state equilibrium geometries of the ligands L1 and L2 and their complexes with Pt(II) are optimized at the BLYP/CEP-31G theoretical level. PMID- 25830981 TI - Fast determination of diesel fuel oxidation stability by 1H NMR spectroscopy. AB - (1)H NMR spectroscopy and multiple linear regression analysis were used to determine diesel fuel oxidation stability. Oxidation stability is one of the most important properties which affect diesel fuel characteristics and quality. It has been demonstrated that integrated peak intensities of certain functional groups in (1)H NMR spectra correlated well with the oxidation stability. This approach is fast, nondestructive and requires small amounts of samples. It has a potential to be used as an alternative to existing standard methods. PMID- 25830982 TI - Saponification reaction system: a detailed mass transfer coefficient determination. AB - The saponification of an aromatic ester with an aqueous sodium hydroxide was studied within a heterogeneous reaction medium in order to determine the overall kinetics of the selected system. The extended thermo-kinetic model was developed compared to the previously used simple one. The reaction rate within a heterogeneous liquid-liquid system incorporates a chemical kinetics term as well as mass transfer between both phases. Chemical rate constant was obtained from experiments within a homogeneous medium, whilst the mass-transfer coefficient was determined separately. The measured thermal profiles were then the bases for determining the overall reaction-rate. This study presents the development of an extended kinetic model for considering mass transfer regarding the saponification of ethyl benzoate with sodium hydroxide within a heterogeneous reaction medium. The time-dependences are presented for the mass transfer coefficient and the interfacial areas at different heterogeneous stages and temperatures. The results indicated an important role of reliable kinetic model, as significant difference in k(L)a product was obtained with extended and simple approach. PMID- 25830983 TI - The effect of ultrasonic pretreatment and sample preparation on the extraction yield of antioxidant compounds and activity of black currant fruits. AB - The aim of the study was to evaluate the efficiency of an ultrasonic pretreatment at different amplitudes and extraction times, on the content of antioxidant compounds (phenolics, anthocyanins, ascorbic acid) and total antioxidant capacity of black currant fruits. Additionally, the influence of sample preparation (frozen storage/drying) was evaluated. Extraction was performed in 60% ethanol with 0.15% HCl at a solvent-to-sample ratio of 15/1. Our results show that the ultrasonic pretreatment proved particularly useful for the recovery of high amounts of total anthocyanins in freeze-dried samples, ascorbic acid in frozen and oven air-dried samples, and total antioxidant capacity in freeze-dried and oven air-dried samples. The total phenolics content was not significantly influenced by the ultrasonic pretreatment. Freeze-drying increased the content of targeted compounds, to a very high significant level (p < 0.001) for anthocyanins and ascorbic acid. Oven air-drying at 45 degrees C drastically decreased the ascorbic acid content. Ultrasonication enhanced the extraction yield of black currant valuable compounds in strong relation to the operating conditions. PMID- 25830984 TI - Skin changes after bariatric surgery. AB - Today, obesity is considered an epidemic all over the world and it is recognized as one of the major public health problems. Bariatric surgery is considered an appropriate therapeutic option for obesity with progressively increasing demands. The changes resulting from massive weight loss after bariatric surgery are related to numerous complications. This article will present the dermatological alterations that can be found after bariatric surgery. They will be subdivided into dermatoses that are secondary to metabolic and nutritional disorders, those derived from cutaneous structural modifications after major weight loss and the influence the latter may have in improving of certain dermatoses. PMID- 25830985 TI - Evaluation of the social, clinical and laboratorial profile of patients diagnosed with leprosy in a reference center in Sao Paulo. AB - BACKGROUND: Leprosy is the main infectious cause of disability. It is said to be eradicated in Sao Paulo since 2005, but diagnosis is still late. OBJECTIVES: To investigate the social, clinical and laboratorial profile of leprosy patients diagnosed between 01/2007 and 12/2011, in a reference center in Sao Paulo. METHODS: Retrospective descriptive study. Data of all new leprosy cases diagnosed between 01/2007 and 12/2011 were raised in Sao Paulo. RESULTS: 103 men and 71 women were diagnosed, most of them were multibacillary. Mean age at diagnosis was 49 yrs; 2,2% were children; 70% had incomplete primary education; 50% were referred without diagnostic suspicion of leprosy. Mean time since first symptoms/signs and diagnosis was 2 years; 64% of patients had some degree of disability, and 26% had grade 2. 23 cases were diagnosed only after being summoned, and 80% of these had no disability. Agreement between the Ridley and Jopling and the WHO classification was 75% (kappa index = 0.44). Serology for IgM anti-PGL1 (87 patients) showed a mean value of 0.25, and an association between MB classification and test positivity (p <0.001). CONCLUSIONS: Leprosy diagnosis in Sao Paulo is late. The disease mainly affected the socially disadvantaged and economically active population. Failure to detect the disease (41% in the last 10 years) could be due to the lack of suspicion and to decentralization. For the classification of patients with advanced leprosy, both the WHO and R&J classifications proved to be helpful tools. PMID- 25830986 TI - Dermoscopic and clinical features of pigmented skin lesions of the genital area. AB - BACKGROUND: The dermoscopic features of vulvar melanosis lesions are well known. To our knowledge, there are only a few case reports about dermoscopic features of pigmented genital lesions in male patients. OBJECTIVE: To evaluate dermoscopic and clinical characteristics of benign lesions of the genital area in both males and females, and to assess the distinguishing dermoscopic criteria of vulvar melanosis and atypical melanocytic nevi of the genital type. METHODS: 68 patients with pigmented genital lesions were included in this observational study (28 male and 40 female). A punch biopsy was taken from all pigmented lesions and histopathological examination was performed on all specimens. RESULTS: We histopathologically diagnosed: genital melanosis in 40 lesions, atypical melanocytic nevi of the genital type in 15 lesions, melanocytic nevi in 9 lesions, seborrheic keratosis in 4 lesions. The most frequent locations were the glans penis (19 patients, 67.9%) in males and the labia minora (19 patients, 47.5%) in females. The mean age of patients with atypical nevi (28,6 +/- 11,36) was significantly lower than the mean age of patients with genital melanosis (47,07 +/- 15,33). CONCLUSIONS: Parallel pattern is prominent in genital melanosis, ring-like pattern is only observed in genital melanosis. Most pigmented lesions on the genital area are solitary. Blue-white veil and irregular dots are only observed in AMNGT. According to these results, we propose that histopathological examination is performed, especially if blue-white veil and irregular dots are found by dermoscopy. PMID- 25830987 TI - Epidemiology of melanoma in the South of Brazil: study of a city in the Vale do Itajai from 1999 to 2013. AB - BACKGROUND: Cutaneous melanoma is a highly aggressive malignancy with increasing incidence worldwide. The southern Brazilian state of Santa Catarina has one of the highest incidence rates of melanoma in the country. OBJECTIVE: To evaluate the epidemiological profile of melanoma patients in a southern city of Brazil. METHODS: a cross-sectional retrospective study was conducted, aiming to detect the clinical and histopathological characteristics of cutaneous melanoma diagnosed in the city of Brusque - SC, between 1999 and 2013. RESULTS: A total of 213 cases in 212 individuals were studied. More than 50% of the patients were females (p< 0.05). The trunk was the most commonly affected site (p< 0.05), followed by the upper limbs. Nodular and superficial spreading melanomas were the most commonly detected in histological analyses. They did not differ statistically in frequency, but were more prevalent than other histopathological subtypes (p< 0.05). There was no statistically significant difference between invasive and noninvasive melanomas (p= 0.2441). Among the invasive melanomas, those with Breslow thicknesses < 1 mm and between 1-2mm were more prevalent (p< 0.05). CONCLUSIONS: In this study we found a higher frequency of melanomas in female patients and patients aged over 51. The trunk was the most commonly affected site. Nodular and superficial spreading melanomas prevailed. Among invasive melanomas, those with Breslow thicknesses < 2 mm were the most frequent. This paper highlights the epidemiological profile of melanoma patients in the city and may help to identify and aid in the follow-up of those who are most likely to present the disease. PMID- 25830988 TI - Quality of life index in autoimmune bullous dermatosis patients. AB - BACKGROUND: Autoimmune bullous dermatoses are complex diseases triggered by autoantibodies action against epidermal antigens or the dermoepidermal junction. Blisters and vesicles that evolve with erosion areas characterize them. Although rare, they present high morbidity, affecting the quality of life of patients. OBJECTIVES: To assess the magnitude of autoimmune bullous dermatoses on life quality of patients treated in a public university service in countryside of Brazil. METHODS: This cross-sectional study was based on an inquiry with autoimmune bullous dermatoses patients assisted at outpatient university referral service. Elements related to quality of life were evaluated by the Dermatology Life Quality Index, as well as clinical and demographic data. RESULTS: The study evaluated 43 patients with pemphigus foliaceus, 32 with pemphigus vulgaris, 6 with bullous pemphigoid and 3 with dermatitis herpetiformis. The average age was 48 +/- 16 years and 34 (40%) were female. The median score (p25-p75) of the Dermatology Life Quality Index was 16 (9-19), classified as "severe impairment" of life quality, in which the greater impact was related to symptoms and feelings, daily and leisure activities. CONCLUSIONS: Autoimmune bullous dermatoses inflict severe impairment of quality of life for patients followed by a public outpatient clinic in the countryside of Brazil. PMID- 25830990 TI - Teledermatology protocol for screening of skin cancer. AB - BACKGROUND: Telemedicine refers to the use of technology as improvement of healthcare delivery to places where distance becomes an obstacle. Its use represents a great potential for dermatology, a specialty whose visual analysis phase is essential in diagnosis. OBJECTIVES: To analyze the compatibility index of skin cancer diagnoses between primary care and teledermatology, and to validate a protocol for standardization of digital imaging to obtain the reports in teledermatology. METHODS: An observational cross-sectional study developed through the census of 333 examination requests, received between January/2012 and July/2012, in the Center for Telemedicine and Telehealth of SES-SC. We used a protocol for photographic lesion standardization, consisting of three steps (panoramic photo, close-up with ruler and dermoscopy). After collection, the data were sent to a virtual site on the Internet, and recorded with the use of an electronic health record containing the images, the skin phototype and demographic characteristics. RESULTS: The level of compatibility between the diagnosis of skin cancer in Santa Catarina's primary care and the diagnosis proposed by teledermatology was 19.02%. Proportionally, it was 21.21% for BCC, 44.44% for SCC and 6.98% for MM. The protocol was statistically significant (p <0.05), with an OR of 38.77. CONCLUSION: The rate of diagnostic compatibility of skin cancer was low and the use of the protocol optimized the chance of validating requests for examination. PMID- 25830989 TI - Melasma and assessment of the quality of life in Brazilian women. AB - BACKGROUND: Melasma is a chronic, acquired hyperpigmentation disease on sun exposed areas of the skin, which affects patients' quality of life. OBJECTIVE: To assess the impact on the quality of life of women living in Florianopolis, Brazil, through questionnaire (MelasQol), and investigate the clinical aspects and risk factors for melasma, correlating them with the MelasQol scores. METHODS: This study was performed on 51 melasma patients cared for at the University Hospital of the Universidade Federal de Santa Catarina. The variables included were: age, gender, age of onset of melasma, Fitzpatrick phototype (I-VI), duration and family history of melasma, onset of melasma during pregnancy, use of hormonal contraceptive, thyroid disorder and distribution of melasma. The MelasQoL questionnaire, validated for Brazilian Portuguese (MelasQoL-BP), was applied. RESULTS: The mean age was 38.43+/-6.75 years. All patients were women. The most common Fitzpatrick skin phototypes were III (49.02%) and IV (33.33%). Melasma had a mean age of onset of 29.18+/-7.05 years and a mean duration of 9.25+/-6.18 years. The majority of patients did not have familial history of melasma (50.98%). Melasma onset was associated with pregnancy (45.10%). The MelasQoL-BP analysis revealed significant emotional impact on patients, such as feeling bothered (94.11%), frustrated and embarrassed (64.71%), and depressed (52.94%) about their skin appearance, as well as unattractive (78.43%). No social impact was observed (P>0.05). CONCLUSION: Melasma has a strong emotional impact on quality of life, resulting especially from feelings about skin appearance. PMID- 25830991 TI - Sebaceous hyperplasia: systemic treatment with isotretinoin. AB - The study aimed to verify the therapeutic action of isotretinoin in the treatment of sebaceous hyperplasia. During two months, 20 patients with sebaceous hyperplasia took isotretinoin at a dosage of 1mg/kg per day. Their skin lesions were counted and photographed before and after treatment and re-evaluated two years later. The average number of sebaceous hyperplasia lesions before treatment was 24 per patient. At the end of two months of therapy, the number of lesions decreased to 2 per patient. The statistically analyzed data showed a reduction in the number of lesions following isotretinoin use (p < 0.05). Two years after the end of the treatment, the average number of sebaceous hyperplasia lesions was 4 per patient. There were no severe side effects. Thus, the data analysis suggests that isotretinoin is a safe and effective drug for treating the disease under study. PMID- 25830992 TI - Nutritional aspects of children and adolescents with epidermolysis bullosa: literature review. AB - Epidermolysis Bullosa is a genetic disorder that affects mainly the skin, however, all others systems are influenced. The nutritional care of children and adolescents with Epidermolysis Bullosa is a key treatment strategy, since the energy needs are increased due to the disease's metabolism, burdening the immune system and cicatrization process, symptoms caused by the disease hinder the intake and adequate absorption of nutrients, which may result in inadequate growth and development. Because this is a rare disease, there are few professionals who know the characteristics of both the clinical evolution and nutritional and dietary treatments. This literature review discusses the latest knowledge on energy and specific nutrient requirements to the dietary treatment and monitoring of children and adolescents with Epidermolysis Bullosa. PMID- 25830993 TI - Mammary and extramammary Paget's disease. AB - Paget's disease, described by Sir James Paget in 1874, is classified as mammary and extramammary. The mammary type is rare and often associated with intraductal cancer (93-100% of cases). It is more prevalent in postmenopausal women and it appears as an eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration and inversion of the nipple. It must be distinguished from erosive adenomatosis of the nipple, cutaneous extension of breast carcinoma, psoriasis, atopic dermatitis, contact dermatitis, chronic eczema, lactiferous ducts ectasia, Bowen's disease, basal cell carcinoma, melanoma and intraductal papilloma. Diagnosis is histological and prognosis and treatment depend on the type of underlying breast cancer. Extramammary Paget's disease is considered an adenocarcinoma originating from the skin or skin appendages in areas with apocrine glands. The primary location is the vulvar area, followed by the perianal region, scrotum, penis and axillae. It starts as an erythematous plaque of indolent growth, with well-defined edges, fine scaling, excoriations, exulcerations and lichenification. In most cases it is not associated with cancer, although there are publications linking it to tumors of the vulva, vagina, cervix and corpus uteri, bladder, ovary, gallbladder, liver, breast, colon and rectum. Differential diagnoses are candidiasis, psoriasis and chronic lichen simplex. Histopathology confirms the diagnosis. Before treatment begins, associated malignancies should be investigated. Surgical excision and micrographic surgery are the best treatment options, although recurrences are frequent. PMID- 25830994 TI - Alopecia secondary to anti-tumor necrosis factor-alpha therapy. AB - Biologic drugs represent a substantial progress in the treatment of chronic inflammatory immunologic diseases. However, its crescent use has revealed seldom reported or unknown adverse reactions, mainly associated with anti-tumor necrosis factor (anti-TNF). Psoriasiform cutaneous reactions and few cases of alopecia can occur in some patients while taking these drugs. Two cases of alopecia were reported after anti-TNF therapy. Both also developed psoriasiform lesions on the body. This is the second report about a new entity described as 'anti-TNF therapy related alopecia', which combines clinical and histopathological features of both alopecia areata and psoriatic alopecia. The recognition of these effects by specialists is essential for the proper management and guidance of these patients. PMID- 25830995 TI - Concurrence of Sweet's syndrome, pathergy phenomenon and erythema nodosum-like lesions. AB - We report the case of a 54-year-old woman with concurrent Sweet's syndrome, pathergy phenomenon and eythema nodosum-like lesions associated with suppurative tonsillitis. Tender, violaceous and highly edematous papules and plaques were detected on the forearms and legs, some of which were pseudovesicular. Similar edematous papules were detected on the dorsum of the hands at the sites of intravenous injection. Biopsies of a plaque on the forearm and a papule at the site of intravenous injection confirmed the presence of Sweet's syndrome. Multiple, tender, violet-red, subcutaneous erythematous nodules were revealed on the legs. A biopsy taken from a nodule on the leg revealed septal panniculitis. To our knowledge, no patient with concurrent Sweet's syndrome, pathergy phenomenon, and erythema nodosum-lesions had been reported yet in previous literature. PMID- 25830996 TI - Bed bug dermatitis, description of two cases in Rio de Janeiro, Brazil. AB - Bed bugs are hematophagous insects which due to their morphological and biological characteristics are able to easily adapt themselves to human households. The authors describe two cases of dermatitis caused by bed bug bites in the city of Rio de Janeiro, Brazil. Patients presented linear lesions in the usual "breakfast, lunch and dinner" arrangement, suggesting this diagnosis. A visit to their dwellings showed infestation of insects identified as Cimex hemipterus. The knowledge of these insects by the dermatological community will contribute to an accurate diagnosis as well as subsidize the dissemination of information aiming for prevention. PMID- 25830997 TI - Kikuchi's disease of the xanthomathous type with cutaneous manifestations. AB - Kikuchi's disease is a benign, self-limiting disease, whose pathogenesis remains unknown. Patients most often present with cervical lymphadenopathy, sometimes associated with fever and leukopenia. It has been reported that up to 40% of patients with Kikuchi's disease have also cutaneous eruptions, but no specific skin changes have been described. Kikuchi's disease can be subclassified into three histologic subtypes: a proliferative type, a necrotizing type and a xantomathous type. Most patients with Kikuchi's disease require no specific treatment, because the disease regresses spontaneously, within a few weeks to months. We report a case of a 31-year-old woman with xanthomatous type of Kikuchi's disease, whose first manifestation was the onset of erythematous papules with central suppuration on her face and on her left hand. PMID- 25830998 TI - Brazilian spotted fever: the importance of dermatological signs for early diagnosis. AB - Brazilian spotted fever is an acute febrile infectious disease caused by Rickettsia rickettsii, transmitted by tick bite. As this disease is rare and has high mortality rates in Brazil, the clinical aspects and epidemiological data may help the diagnosis. We report a case of Brazilian spotted fever in a 19-year-old patient who presented maculopapular exanthema in the palmar region and upper limbs, lymphadenopathy, fever, chills, headache, conjunctival hyperemia, nausea, vomiting, dyspnea, myalgia, developing neurological signs and abdominal pain. He was treated with doxycycline with clinical improvement. We emphasize the importance of the recognition of this disease by dermatologists as cutaneous manifestations are the key findings to establish early diagnosis and prevent complications. PMID- 25830999 TI - Majocchi's granuloma - case report. AB - We report the case of a three-year-old child who, following long term treatment with topical corticosteroids and their associations for a case of ringworm on the face developed a form of folliculitis known as Majocchi's Granuloma. Treatment with oral Griseofulvin was successful. PMID- 25831000 TI - Primary cutaneous histoplasmosis developed in the penis of an immunocompetent patient. AB - A 70-year-old male presenting a 3-month history of genital painless erythematous nodules in the balanopreputial sulcus was referred to our service. Histopathological exam presented a chronic dermatitis with epithelioid granulomas and Grocott staining revealed numerous fungal structures with a suggestive morphology of Histoplasma sp. Cultures evidenced Histoplasma capsulatum var. capsulatum. Treatment with oral itraconazole led to complete remission of lesions. PMID- 25831001 TI - O to Z flaps in facial reconstructions. AB - Local flaps are the standard procedure to reconstruct facial defects. As it occurs in any surgical procedure, the incision should be planned so that scars are located in the minimum skin tension lines. We report two cases of O to Z flaps in the supra and infraciliary regions. One of them is a hatchet flap. PMID- 25831002 TI - Cutaneous Lymphangioma circumscriptum - dermoscopic features. AB - Lymphangiomas are congenital lymphatic malformations and cutaneous lymphangioma circumscriptum is the most common type. It is clinically characterized by clusters of translucent vesicles and the presence of dermoscopically yellow lacunae surrounded by pale septa, as well as reddish to bluish lacunae. In our case, the recently described hypopyon-like feature manifested, aiding in the sometimes difficult differential diagnosis of cutaneous lymphangioma circumscriptum with vascular lesions, further highlighting the importance of dermoscopy in what can be a diagnostic challenge. PMID- 25831003 TI - Onychomatricoma: a tumor unknown to dermatologists. AB - A sixty-one year old white female was referred to the Dermatology Department to treat an ingrown nail in the inner corner of the left hallux. Examination of the entire nail unit showed the presence of xanthonychia in the outer corner besides thickening and increase in the transverse curvature of the nail plate. Dermoscopy and nuclear magnetic resonance of the free edge of the nail plate detected characteristic signs of onychomatricoma, a diagnosis that was later confirmed by anatomopathological exam. PMID- 25831004 TI - Lacaziosis - unusual clinical presentation. AB - Lacaziosis or Jorge Lobo's disease is a fungal, granulomatous, chronic infectious disease caused by Lacazia loboi, which usually affects the skin and subcutaneous tissue. It is characterized by slow evolution and a variety of cutaneous manifestations with the most common clinical expression being nodular keloid lesions that predominate in exposed areas. We report the case of a patient who had an unusual clinical presentation, with a single-plated lesion on the back. Histopathological examination confirmed the diagnosis of Lacaziosis. PMID- 25831005 TI - Syndrome in question. Immunoglobulin light chain amyloidosis. AB - Immunoglobulin light chain amyloidosis is the most common acquired systemic amyloidosis. Its presentation is often insidious and progressive, which may delay diagnosis. The authors describe a rare case of immunoglobulin light chain amyloidosis in a 34-year-old man with scleroderma-like manifestation substantiated by multifarious laboratory investigations and the histopathologic feature of involved skin lesions stained with Congo red and crystal violet. This helps to maintain a high clinical suspicion of the disease when confronting similar skin presentation. PMID- 25831006 TI - Characterization of sporotrichosis cases treated in a dermatologic teaching unit in the state of Sao Paulo - Brazil, 2003 - 2013. AB - We conducted a transversal retrospective study with secondary data collection from 25 cases of sporotrichosis, treated at a teaching unit in inner Sao Paulo (Brazil), between the years 2003-2013. We found that the prevalence was higher in men (72%), rural workers (44%) and those living in rural areas (60%), with an average age of 42.48 years. The median between the onset of lesions and diagnosis was six weeks. Lesions predominated in the upper limbs (92%), and were classified as lymphocutaneous (80%) and fixed cutaneous (20%) forms. Clinical cure was observed in 62.5% of the cases treated with potassium iodide and 100% of cases treated with itraconazole. PMID- 25831007 TI - Shiitake dermatitis. AB - Shiitake Dermatitis is a skin eruption that resembles whiplash marks and occurs after consumption of raw shiitake mushrooms. It is caused by a toxic reaction to lentinan, a thermolabil polysaccharide which decomposes upon heating. We report the second case of this dermatitis in Brazil. A 25-year-old man presented with linearly arranged erythematous, pruritic papules on the trunk and limbs, after ingestion of a salad containing raw shiitake mushrooms. The eruption was self limited, resolving within 10 days of onset. The recognition of this entity gains importance due to the increased consumption of shiitake mushrooms in occidental countries. PMID- 25831008 TI - Bullous pemphigoid and neurological disease: statistics from a dermatology service. AB - Bullous pemphigoid (BP) is an autoimmune, acquired, cutaneous disease caused by the production of autoantibodies against hemidesmosomes' components in the basement membrane. The estimated incidence in Europe ranges from 7 to 43 cases per million inhabitants per year. Several studies have reported an association between BP and neurological disorders (ND). Our cohort of Bullous pemphigoid and ND is the first in Brazil and showed a significantly high prevalence of neurological and/or psychiatric diseases, especially cerebrovascular accident (CVA) and dementia, in agreement with the prevalence reported in several studies published in the medical literature in recent years. PMID- 25831009 TI - Disseminated lichen sclerosus in a child: a case report. PMID- 25831010 TI - Renal involvement in Malignant Atrophic Papulosis (Degos Disease). PMID- 25831011 TI - Erratum. PMID- 25831012 TI - Long-distance autophagy. PMID- 25831013 TI - Mitophagy is primarily due to alternative autophagy and requires the MAPK1 and MAPK14 signaling pathways. AB - In cultured cells, not many mitochondria are degraded by mitophagy induced by physiological cellular stress. We observed mitophagy in HeLa cells using a method that relies on the pH-sensitive fluorescent protein Keima. With this approach, we found that mitophagy was barely induced by carbonyl cyanide m-chlorophenyl hydrazone treatment, which is widely used as an inducer of PARK2/Parkin-related mitophagy, whereas a small but modest amount of mitochondria were degraded by mitophagy under conditions of starvation or hypoxia. Mitophagy induced by starvation or hypoxia was marginally suppressed by knockdown of ATG7 and ATG12, or MAP1LC3B, which are essential for conventional macroautophagy. In addition, mitophagy was efficiently induced in Atg5 knockout mouse embryonic fibroblasts. However, knockdown of RAB9A and RAB9B, which are essential for alternative autophagy, but not conventional macroautophagy, severely suppressed mitophagy. Finally, we found that the MAPKs MAPK1/ERK2 and MAPK14/p38 were required for mitophagy. Based on these findings, we conclude that mitophagy in mammalian cells predominantly occurs through an alternative autophagy pathway, requiring the MAPK1 and MAPK14 signaling pathways. PMID- 25831014 TI - Shiga toxins induce autophagic cell death in intestinal epithelial cells via the endoplasmic reticulum stress pathway. AB - Shiga toxins (Stxs) are a family of cytotoxic proteins that lead to the development of bloody diarrhea, hemolytic-uremic syndrome, and central nervous system complications caused by bacteria such as S. dysenteriae, E. coli O157:H7 and E. coli O104:H4. Increasing evidence indicates that macroautophagy (autophagy) is a key factor in the cell death induced by Stxs. However, the associated mechanisms are not yet clear. This study showed that Stx2 induces autophagic cell death in Caco-2 cells, a cultured line model of human enterocytes. Inhibition of autophagy using pharmacological inhibitors, such as 3 methyladenine and bafilomycin A1, or silencing of the autophagy genes ATG12 or BECN1 decreased the Stx2-induced death in Caco-2 cells. Furthermore, there were numerous instances of dilated endoplasmic reticulum (ER) in the Stx2-treated Caco 2 cells, and repression of ER stress due to the depletion of viable candidates of DDIT3 and NUPR1. These processes led to Stx2-induced autophagy and cell death. Finally, the data showed that the pseudokinase TRIB3-mediated DDIT3 expression and AKT1 dephosphorylation upon ER stress were triggered by Stx2. Thus, the data indicate that Stx2 causes autophagic cell death via the ER stress pathway in intestinal epithelial cells. PMID- 25831016 TI - The Controversy Surrounding Surgical Care Improvement Project-Venous Thromboembolism Process Measures. PMID- 25831017 TI - Development, physical properties and clinical applicability of a mechanical Multileaf Collimator for the use in Cobalt-60 radiotherapy. AB - According to the Directory of Radiotherapy Centres (DIRAC) there are 2348 Cobalt 60 (Co-60) teletherapy units worldwide, most of them in low and middle income countries, compared to 11046 clinical accelerators. To improve teletherapy with Co-60, a mechanical Multi-Leaf Collimator (MLC) was developed, working with pneumatic pressure and thus independent of electricity supply. Instead of tungsten, brass was used as leaf material to make the mechanical MLC more affordable. The physical properties and clinical applicability of this mechanical MLC are presented here. The leakage strongly depends on the fieldsize of the therapy unit due to scatter effects. The maximum transmission through the leaves measured 2.5 cm from the end-to-end gap, within a field size of 20 cm * 30 cm defined by jaws of the therapy unit at 80 cm SAD, amounts 4.2%, normalized to an open 10 cm * 10 cm field, created by the mechanical MLC. Within a precollimated field size of 12.5 cm * 12.5 cm, the end-to-end leakage is 6.5% normalized to an open 10 cm * 10 cm field as well. This characteristic is clinically acceptable considering the criteria for non-IMRT MLCs of the International Electrotechnical Commission (IEC 60601-2-1). The penumbra for a 10 cm * 10 cm field was measured to be 9.14 mm in plane and 8.38 mm cross plane. The clinical applicability of the designed mechanical MLC was affirmed by measurements relating to all relevant clinical properties such as penumbra, leakage, output factors and field widths. Hence this novel device presents an apt way forward to make radiotherapy with conformal fields possible in low-infrastructure environments, using gantry based Co-60 therapy units. PMID- 25831015 TI - AU4S: a novel synthetic peptide to measure the activity of ATG4 in living cells. AB - ATG4 plays a key role in autophagy induction, but the methods for monitoring ATG4 activity in living cells are limited. Here we designed a novel fluorescent peptide named AU4S for noninvasive detection of ATG4 activity in living cells, which consists of the cell-penetrating peptide (CPP), ATG4-recognized sequence "GTFG," and the fluorophore FITC. Additionally, an ATG4-resistant peptide AG4R was used as a control. CPP can help AU4S or AG4R to penetrate cell membrane efficiently. AU4S but not AG4R can be recognized and cleaved by ATG4, leading to the change of fluorescence intensity. Therefore, the difference between AU4S- and AG4R-measured fluorescence values in the same sample, defined as "F-D value," can reflect ATG4 activity. By detecting the F-D values, we found that ATG4 activity paralleled LC3B-II levels in rapamycin-treated cells, but neither paralleled LC3B II levels in starved cells nor presented a correlation with LC3B-II accumulation in WBCs from healthy donors or leukemia patients. However, when DTT was added to the system, ATG4 activity not only paralleled LC3B-II levels in starved cells in the presence or absence of autophagy inhibitors, but also presented a positive correlation with LC3B-II accumulation in WBCs from leukemia patients (R(2) = 0.5288). In conclusion, this study provides a convenient, rapid, and quantitative method to monitor ATG4 activity in living cells, which may be beneficial to basic and clinical research on autophagy. PMID- 25831018 TI - Density functional theory study on the cross-linking of mussel adhesive proteins. AB - The water-resistant adhesion of mussel adhesive proteins (MAPs) to a wet surface requires a cross-linking step, where the catecholic ligands of MAPs coordinate to various transition-metal ions. Fe(III), among the range of metal ions, induces particularly strong cross-linking. The molecular details underlying this cross linking mediated by transition-metal ions are largely unknown. Of particular interest is the metal-ligand binding energy, which is the molecular origin of the mechanical properties of cross-linked MAPs. Using density functional theory, this study examined the structures and binding energies of various trivalent metal ions (Ti-Ga) forming coordination complexes with a polymeric ligand similar to a MAP. These binding energies were 1 order of magnitude larger than the physisorption energy of a catechol molecule on a metallic surface. On the other hand, the coordination strength of Fe(III) with the ligand was not particularly strong compared to the other metal ions studied. Therefore, the strong cross linking in the presence of Fe(III) is ascribed to its additional ability as an oxidant to induce covalent cross-linking of the catecholic groups of MAPs. PMID- 25831019 TI - Characterisation and potential migration of silver nanoparticles from commercially available polymeric food contact materials. AB - The potential for consumer exposure to nano-components in food contact materials (FCMs) is dependent on the migration of nanomaterials into food. Therefore, characterising the physico-chemical properties and potential for migration of constituents is an important step in assessing the safety of FCMs. A number of commercially available food storage products, purchased domestically within the United States and internationally, that claim to contain nanosilver were evaluated. The products were made of polyethylene, polypropylene and polyphenylene ether sulfone and all contained silver (0.001-36 mg kg(-1) of polymer). Silver migration was measured under various conditions, including using 3% acetic acid and water as food simulants. Low concentrations (sub-ppb levels) of silver were detected in the migration studies generally following a trend characterised by a surface desorption phenomenon, where the majority of the silver migration occurred in the first of three consecutive exposures. Silver nanoparticles were not detected in food simulants, suggesting that the silver migration may be due solely to ionic silver released into solution from oxidation of the silver nanoparticle surface. The absence of detectable silver nanoparticles was consistent with expectations from a physico-chemical view point. For the products tested, current USFDA guidance for evaluating migration from FCMs was applicable. PMID- 25831020 TI - Social media as a sensor of air quality and public response in China. AB - BACKGROUND: Recent studies have demonstrated the utility of social media data sources for a wide range of public health goals, including disease surveillance, mental health trends, and health perceptions and sentiment. Most such research has focused on English-language social media for the task of disease surveillance. OBJECTIVE: We investigated the value of Chinese social media for monitoring air quality trends and related public perceptions and response. The goal was to determine if this data is suitable for learning actionable information about pollution levels and public response. METHODS: We mined a collection of 93 million messages from Sina Weibo, China's largest microblogging service. We experimented with different filters to identify messages relevant to air quality, based on keyword matching and topic modeling. We evaluated the reliability of the data filters by comparing message volume per city to air particle pollution rates obtained from the Chinese government for 74 cities. Additionally, we performed a qualitative study of the content of pollution related messages by coding a sample of 170 messages for relevance to air quality, and whether the message included details such as a reactive behavior or a health concern. RESULTS: The volume of pollution-related messages is highly correlated with particle pollution levels, with Pearson correlation values up to .718 (n=74, P<.001). Our qualitative results found that 67.1% (114/170) of messages were relevant to air quality and of those, 78.9% (90/114) were a firsthand report. Of firsthand reports, 28% (32/90) indicated a reactive behavior and 19% (17/90) expressed a health concern. Additionally, 3 messages of 170 requested that action be taken to improve quality. CONCLUSIONS: We have found quantitatively that message volume in Sina Weibo is indicative of true particle pollution levels, and we have found qualitatively that messages contain rich details including perceptions, behaviors, and self-reported health effects. Social media data can augment existing air pollution surveillance data, especially perception and health-related data that traditionally requires expensive surveys or interviews. PMID- 25831021 TI - Thienothiophenes, dithienothiophenes, and thienoacenes: syntheses, oligomers, polymers, and properties. PMID- 25831023 TI - Friedreich's ataxia--a case of aberrant transcription termination? AB - Reduced expression of the mitochondrial protein Frataxin (FXN) is the underlying cause of Friedreich's ataxia. We propose a model of premature termination of FXN transcription induced by pathogenic expanded GAA repeats that links R-loop structures, antisense transcription, and heterochromatin formation as a novel mechanism of transcriptional repression in Friedreich's ataxia. PMID- 25831024 TI - Diffusion weighted imaging and apparent diffusion coefficient in 3 tesla magnetic resonance imaging of breast lesions. AB - OBJECTIVE: To evaluate the utility of diffusion-weighted-imaging (DWI) and apparent-diffusion-coefficient (ADC) in a 3T magnetic-resonance-imaging (MRI) study of breast cancer. In particular, the study aims to classify ADC-values according to histology either for benign or malignant lesions. METHODS: 110 Breast MRI with MRI-DWI sequences and quantitative evaluation of the ADC were retrospectively reviewed. Results obtained with MRI-DWI and with biopsy were analyzed and ADC values were compared to histological results. RESULTS: MRI showed a 95.5% sensitivity and a 83.7% specificity. The mean ADC values of benign and malignant lesions were 2.06 +/- 0.19 and 1.03 +/- 0.07 mm(2)/s, respectively (p < .05). CONCLUSIONS: DWI and ADC-values could help distinguishing malignant and benign breast masses. PMID- 25831025 TI - Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings. AB - This paper is a review of the work of my former academic group of research in the past 15 years, in the field of cognition enhancers (also called nootropics) that identified two very potent molecules: Unifiram and Sunifiram that for a variety of reasons were not protected by a patent. Some 12 years after their disclosure (2000) I casually found that on the web, there were dozens of sites offering Unifiram and Sunifiram as drugs that improve cognition in healthy individuals even if only few preclinical studies were done and their long-term toxicity was unknown. PMID- 25831022 TI - Genetic code expansion enables live-cell and super-resolution imaging of site specifically labeled cellular proteins. AB - Methods to site-specifically and densely label proteins in cellular ultrastructures with small, bright, and photostable fluorophores would substantially advance super-resolution imaging. Recent advances in genetic code expansion and bioorthogonal chemistry have enabled the site-specific labeling of proteins. However, the efficient incorporation of unnatural amino acids into proteins and the specific, fluorescent labeling of the intracellular ultrastructures they form for subdiffraction imaging has not been accomplished. Two challenges have limited progress in this area: (i) the low efficiency of unnatural amino acid incorporation that limits labeling density and therefore spatial resolution and (ii) the uncharacterized specificity of intracellular labeling that will define signal-to-noise, and ultimately resolution, in imaging. Here we demonstrate the efficient production of cystoskeletal proteins (beta actin and vimentin) containing bicyclo[6.1.0]nonyne-lysine at genetically defined sites. We demonstrate their selective fluorescent labeling with respect to the proteome of living cells using tetrazine-fluorophore conjugates, creating densely labeled cytoskeletal ultrastructures. STORM imaging of these densely labeled ultrastructures reveals subdiffraction features, including nuclear actin filaments. This work enables the site-specific, live-cell, fluorescent labeling of intracellular proteins at high density for super-resolution imaging of ultrastructural features within cells. PMID- 25831026 TI - 2-alkyl(aryl)-quinazolin-4(3H)-thiones, 2-R-(quinazolin-4(3H)-ylthio)carboxylic acids and amides: synthesis, molecular docking, antimicrobial and anticancer properties. AB - In this study, a series of novel 2-alkyl(aryl)-quinazolin-4(3H)-thiones, 2-R (quinazolin-4(3H)-ylthio)carboxylic acids and amides were synthesized and evaluated for antimicrobial and anticancer activities. Their structure was confirmed by elemental analysis and spectral data (FT-IR, LC-MS, (1)H-NMR). Antimicrobial activity was tested in vitro against Staphylococcus aureus, Enterococcus faecalis, Enterobacter aerogenes, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, Candida albicans and NCI in vitro preliminary anticancer activity against nine different cancer types. The most active antibacterial and antifungal compounds were: 2.1, 2.2 and 2.4. The introduction of the carboxylic acid or amide residue into the fourth position of quinazolin-4(3H)-thione resulted in the absence of antimicrobial activity. Substance 3.8 inhibited renal cancer UO-31 line and 2.18 - leukemia CCRF-CEM. The results of in silico molecular docking for DHFR and CK2 kinase had no correlation with in vitro properties, proposing the presence of other biological activity pathways. PMID- 25831027 TI - Intranasal midazolam for the emergency management of hypercyanotic spells in tetralogy of Fallot. AB - The case of a 2-month-old boy with previously diagnosed tetralogy of Fallot who was brought to the emergency department with a hypercyanotic spell is described. Because partly of the difficulty of intravenous placement, especially in an infant crying with marked hypernea and deeply cyanotic, intranasal midazolam was administered. Before 3 minutes of hypernea terminated increasing the oxygen saturation successfully and intravenous line was easily placed with the baby remaining in calm. Sedation is an important step in the management of patients with cyanotic spells. Intranasal midazolam offers an alternative use as an initial method of calming the child that was effective in a patient with a severe cyanotic spell because of tetralogy of Fallot in the emergency department. PMID- 25831028 TI - Primary hyperparathyroidism: an uncommon cause of hip pain. AB - Hip pain is a common complaint in a pediatric emergency department. The causes of hip pain are diverse and generally include traumatic and infectious causes. We report a case of hip pain caused by deep soft tissue infection associated with hypercalcemia and primary hyperparathyroidism. Atypical presentation of primary hyperparathyroidism may result in a delay in diagnosis. PMID- 25831029 TI - Recurrent rhabdomyolysis in a teenager with psychosis-intermittent hyponatremia polydipsia syndrome. AB - OBJECTIVE: To report a case of recurrent hyponatremia and rhabdomyolysis in a teenager with psychogenic polydipsia. CASE SUMMARY: A 16-year-old boy was admitted with recurrent episodes of hyponatremia and rhabdomyolysis secondary to psychogenic polydipsia. He was treated with hypertonic saline, intravenous fluids, and supportive care. DISCUSSION: Psychogenic polydipsia is a condition characterized by compulsive drinking. Severe hyponatremia is a rare, but serious complication in patients with psychogenic polydipsia. Failure in cell volume regulatory mechanisms, defective osmoregulation, defective urinary dilution, and enhanced secretion of vasopressin are believed to play a role in the development of hyponatremia. Rhabdomyolysis can complicate severe hyponatremia, although the exact mechanism is not known. Antipsychotic drugs are also implicated in rhabdomyolysis. CONCLUSIONS: Severe hyponatremia and rhabdomyolysis can complicate psychogenic polydipsia. Patients receiving antipsychotic drugs with concomitant severe hyponatremia need to be monitored for rhabdomyolysis. PMID- 25831030 TI - Amatoxin-containing mushroom (Lepiota brunneoincarnata) familial poisoning. AB - Serious to fatal toxicity may occur with amanitin-containing mushrooms ingestions. A Lepiota brunneoincarnata familial poisoning with hepatic toxicity is reported. In such poisonings, acute gastroenteritis may be firstly misdiagnosed leading to delay in preventing liver dysfunction by silibinin or penicillin G. Mushroom picking finally requires experience and caution. PMID- 25831031 TI - Cervical lung herniation complicating a case of acute asphyxial asthma in a child. AB - The abrupt onset of respiratory failure secondary to asthma, known as acute asphyxial asthma (AAA) in adults, is uncommonly reported in children. Here, we report a case of a child with the acute onset of respiratory failure consistent with AAA complicated by the finding of a neck mass during resuscitation. This 11 year-old boy with a history of asthma initially presented in respiratory failure with altered mental status after the complaint of difficulty in breathing minutes before collapsing at home. Initially, his respiratory failure was thought to be secondary to status asthmaticus, and treatment was initiated accordingly. However, a neck mass noted during the resuscitation was cause for concern, and other etiologies for his respiratory failure were considered, including an airway obstructing neck mass. After pediatric surgery and anesthesia consultation for intubation and possible tracheostomy placement, general anesthesia was induced in the operating room with an inhaled anesthetic, with prompt resolution of the bronchspasm and decompression of the neck mass. Review of the imaging and clinical course ultimately yielded a diagnosis of cervical lung herniation as the etiology of his neck mass. We report this case of AAA and cervical lung herniation and a review of the literature of these 2 uncommon phenomena in children. PMID- 25831032 TI - Massive spontaneous intraperitoneal hemorrhage in a young female with chronic immune thrombocytopenic purpura masquerading as ruptured ovarian cyst: successful nonsurgical management of this rare catastrophic event. AB - Chronic immune thrombocytopenic purpura has mild bleeding manifestations and severe bleeding requiring hospitalization is rare. We are reporting a case of a 19-year-old girl with chronic immune thrombocytopenic purpura who presented with spontaneous massive hemoperitoneum without any identifiable source of hemorrhage. We chose nonsurgical treatment over laparotomy, and the patient was managed successfully with parenteral steroids and platelet transfusion. In young women presenting with massive hemoperitoneum, undiagnosed immune thrombocytopenia should be considered as an etiology. In absence of any identifiable source of hemoperitoneum, these patients may not require laparotomy and treatment with intravenous corticosteroid and platelet transfusions may be preferrable and lifesaving. PMID- 25831033 TI - Long-acting reversible contraception in the pediatric emergency department: clinical implications and common challenges. AB - Long-acting reversible contraception (LARC) is recommended as first-line contraception for adolescents and young adults. As the use of LARC increases, pediatric emergency medicine clinicians should be able to recognize different types of LARC and address their common adverse effects, adverse reactions, and complications. This continuing medical education activity provides an overview of LARC and will assist clinicians in the evaluation and management of patients with LARC-associated complaints. PMID- 25831035 TI - Therapeutic hypothermia in children after cardiac arrest: a systematic review and meta-analysis. AB - BACKGROUND: Therapeutic hypothermia (TH) has been shown to be effective in resuscitation of some adults following cardiac arrest and infants with hypoxic ischemic encephalopathy, but has not been well studied in children. OBJECTIVES: The purpose of this systematic review/meta-analysis was to examine mortality, neurologic outcomes, and adverse events in children following use of TH. RESULTS: A search of PubMed, the Cumulative Index to Nursing and Allied Health Literature, and the Institute for Scientific Information's Web of Knowledge from 1946 to 2014 yielded 6 studies (3 retrospective and 3 prospective cohort studies) that met our inclusion criteria. Quantitative synthesis of mortality following TH (136 subjects) was 44% (95% confidence interval, 32-57) with 28% (95% confidence interval, 11-53) of survivors (42 subjects) demonstrating poor neurologic outcome. The most frequently reported adverse events were electrolyte imbalances and pneumonia. CONCLUSIONS: Evidence is insufficient to support the advantage of TH compared with normothermia in pediatric resuscitation. The adverse event profile appears to be different than that reported in adults. Further studies are needed before TH may be considered a standard protocol for children after cardiac arrest. PMID- 25831036 TI - Identification of optic disc elevation and the crescent sign using point-of-care ocular ultrasound in children. AB - Point-of-care ocular ultrasound has been used to detect papilledema. In previous studies, investigators have evaluated only optic nerve sheath diameter as a screen for increased intracranial pressure. In this series of 4 children, we demonstrate 2 additional optic nerve abnormalities using point-of-care ocular ultrasound: optic disc elevation and the crescent sign. Assessing the optic nerve for each of these 3 findings may assist the examiner in detecting papilledema. PMID- 25831037 TI - Pediatric emergency medicine fellowship programs. PMID- 25831038 TI - ECGs in the ED. PMID- 25831039 TI - Effects of emergency department crowding on the delivery of timely care in an inner-city hospital in the Netherlands. AB - BACKGROUND: The impact of delays in emergency department (ED) care has not been described in European countries where ED crowding is not universally recognized. The aim of this study was to determine the relationship of ED crowding with delays in triage and treatment, and 24-h mortality in patients admitted to the ED. METHODS: Five years of data from adults admitted to the hospital were analysed retrospectively from an inner-city ED in the Netherlands. Variables included the following: crowded versus noncrowded time, time to triage, triage category, time to treatment, age, 24-h mortality and 10-day mortality. RESULTS: A total of 39 110 patients met the inclusion criteria. ED crowding occurred 30.8% of the time. There were no differences in mortality between patients arriving during crowding versus those arriving during noncrowding. Delays in triage during ED crowding occurred 29.7% of the time versus 14.6% during noncrowding. Delays in treatment occurred 11.7 and 7.3% of the time during crowding and noncrowding, respectively. CONCLUSION: In this hospital, ED crowding results in increased times to triage and to treatment, not in increased 24-h or 10-day mortality. PMID- 25831041 TI - Genetic diversity and population structure analysis between Indian red jungle fowl and domestic chicken using microsatellite markers. AB - The present study was conducted to assess the genetic diversity, population structure, and relatedness in Indian red jungle fowl (RJF, Gallus gallus murgi) from northern India and three domestic chicken populations (gallus gallus domesticus), maintained at the institute farms, namely White Leghorn (WL), Aseel (AS) and Red Cornish (RC) using 25 microsatellite markers. All the markers were polymorphic, the number of alleles at each locus ranged from five (MCW0111) to forty-three (LEI0212) with an average number of 19 alleles per locus. Across all loci, the mean expected heterozygosity and polymorphic information content were 0.883 and 0.872, respectively. Population-specific alleles were found in each population. A UPGMA dendrogram based on shared allele distances clearly revealed two major clusters among the four populations; cluster I had genotypes from RJF and WL whereas cluster II had AS and RC genotypes. Furthermore, the estimation of population structure was performed to understand how genetic variation is partitioned within and among populations. The maximum ?K value was observed for K = 4 with four identified clusters. Furthermore, factorial analysis clearly showed four clustering; each cluster represented the four types of population used in the study. These results clearly, demonstrate the potential of microsatellite markers in elucidating the genetic diversity, relationships, and population structure analysis in RJF and domestic chicken populations. PMID- 25831042 TI - 100% citrus juice: Nutritional contribution, dietary benefits, and association with anthropometric measures. AB - Citrus juices such as 100% orange (OJ) and grapefruit juice (GJ) are commonly consumed throughout the world. This review examines the contributions of OJ and GJ to nutrient intake, diet quality, and fruit intake, and supports citrus juices as nutrient-dense beverages. This review also explores the research examining associations between OJ and GJ intake and anthropometric measures. Citrus juices are excellent sources of vitamin C and contribute other key nutrients such as potassium, folate, magnesium, and vitamin A. OJ intake has been associated with better diet quality in children and adults. OJ intake has not been associated with adverse effects on weight or other body measures in observational studies in children and adults. In adults, some observational studies report more favorable body mass index or body measure parameters in OJ consumers compared to nonconsumers. Intervention studies in adults report no negative impacts of OJ or GJ consumption on anthropometric measures, although these measures were typically not the primary outcomes examined in the studies. Moderate consumption of citrus juices may provide meaningful nutritional and dietary benefits and do not appear to negatively impact body weight, body composition, or other anthropometric measures in children and adults. PMID- 25831043 TI - Insights into Campylobacter jejuni colonization of the mammalian intestinal tract using a novel mouse model of infection. AB - A lack of relevant disease models for Campylobacter jejuni has long been an obstacle to research into this common enteric pathogen. We recently published that mice deficient in Single IgG Interleukin-1 related receptor (SIGIRR), a repressor of MyD88-dependent innate immune signaling, were highly susceptible to enteric infection by murine bacterial pathogens. Subsequently, we successfully employed these mice as an animal model for the human pathogen C. jejuni and gained substantial new insights into infection by this pathogen. The infected mice developed significant intestinal inflammation, primarily via TLR4 stimulation. Furthermore, the resulting gastroenteritis was dependent on C. jejuni pathogenesis as bacterial strains suffering mutations in key virulence factors were attenuated in causing disease. The ability to infect SIGIRR deficient mice with C. jejuni sheds new light onto how these bacteria colonize the mucus layer of the intestinal tract, invade epithelial cells, and raises new prospects for studying the virulence strategies and pathogenesis of C. jejuni. PMID- 25831044 TI - High-yield production of lipoglycopeptide antibiotic A40926 using a mutant strain Nonomuraea sp. DP-13 in optimized medium. AB - The lipoglycopeptide antibiotic A40926 produced by Nonomuraea sp. is a complex of structurally related components differing in the fatty acid moiety. Besides showing an intrinsic antibacterial activity, A40926 is the precursor of the semisynthetic antibiotic Dalvance. In this work, A40926 production by a mutant strain Nonomuraea sp. DP-13 was investigated. It was found that A40926 production was markedly promoted by using poorly assimilated carbon source maltodextrin and nitrogen source soybean meal. Addition of Cu(2+) resulted in a stimulation of A40926 production, but Co(2+) had an inhibitory effect. L-Leucine addition greatly improved total A40926 production and modified the complex composition toward factor B0. An optimized production medium IM-3 was developed and a maximum A40926 production of 1096 mg/L was obtained in the 10-L fermenter. This was the highest A40926 productivity so far reported. PMID- 25831045 TI - Beetle feeding induces a different volatile emission pattern from black poplar foliage than caterpillar herbivory. AB - Herbivore-induced plant volatile emission is often considered to be attacker species-specific, but most experimental evidence comes from short lived herbaceous species. In a recent study we showed that black poplar (Populus nigra) trees emit a complex blend of volatiles from damaged leaves when they are attacked by generalist gypsy moth (Lymantria dispar) caterpillars. Minor nitrogenous volatiles were especially characteristic of this blend. Here we show that attack on P. nigra by a beetle species, Phratora vulgatissima (Coleoptera, Chrysomelidae), led to the emission of the same compounds as already observed after caterpillar herbivory, but with striking quantitative changes in the blend. The consequences for attraction of herbivore enemies are discussed. PMID- 25831046 TI - Methods for the Determination of Endocrine-Disrupting Phthalate Esters. AB - Phthalates are endocrine disruptors frequently occurring in the general and industrial environment and in many industrial products. Moreover, they are also suspected of being carcinogenic, teratogenic, and mutagenic, and they show diverse toxicity profiles depending on their structures. The European Union and the United States Environmental Protection Agency (US EPA) have included many phthalates in the list of priority substances with potential endocrine-disrupting action. They are: dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butylbenzyl phthalate (BBP), diethylhexyl phthalate (DEHP), di iso-nonyl phthalate (DINP), di-iso-decyl phthalate (DIDP), di-n-decyl phthalate (DnDP), and dioctyl phthalate (DOP). There is an ever-increasing demand for new analytical methods suitable for monitoring different phthalates in various environmental, biological, and other matrices. Separation and spectrometric methods are most frequently used. However, modern electroanalytical methods can also play a useful role in this field because of their high sensitivity, reasonable selectivity, easy automation, and miniaturization, and especially low investment and running costs, which makes them suitable for large-scale monitoring. Therefore, this review outlines possibilities and limitations of various analytical methods for determination of endocrine-disruptor phthalate esters in various matrices, including somewhat neglected electroanalytical methods. PMID- 25831047 TI - Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer. AB - Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes. PMID- 25831048 TI - Cisplatin fails to induce puma mediated apoptosis in mucosal melanomas. AB - OBJECTIVES: Mucosal melanomas (MM) are aggressive subtypes of common melanomas. It remains unclear whether limitations in their resectability or their distinctive molecular mechanisms are responsible for the aggressive phenotype. METHODS: In total, 112 patients with cutaneous melanomas (CM) and 27 patients with MM were included. Clinical parameters were analysed using Chi square, Fisher exact and student's t-test. Survival rates were calculated by Kaplan-Meier. Analysis of p53, p21, Mdm2, Hipk2, Gadd45, Puma, Bax, Casp9 and Cdk1 via quantitative PCR and immunohistochemistry (IHC) was performed. TP53 induction after cisplatin treatment was analysed in 10 cell lines (melanocytes, four MM and five CM) using western blot (WB) and qPCR. RESULTS: The overall/recurrence-free survival differed significantly between MM (40 months and 30 months) and CM (90 months and 107 months; p < 0.001). IHC and WB confirmed high p53 expression in all melanomas. Hipk2 and Gadd45 showed significantly higher expressions in CM (p < 0.005; p = 0.004). QPCR and WB of wild-type cell lines demonstrated no differences for p53, p21, Mdm2, Bax and Casp9. WB failed to detect Puma in MM, while Cdk1 regulation occurred exclusively in MM. CONCLUSIONS: The aggressive phenotype of MM did not appear to be due to differential expressions of p53, p21, Mdm2, Bax or Casp9. A non-functional apoptosis in MM may have further clinical implications. PMID- 25831049 TI - Anti-tumour effects of antibodies targeting the extracellular cysteine-rich region of the receptor tyrosine kinase EphB4. AB - EphB4 is a membrane-bound receptor tyrosine kinase (RTK) commonly over-produced by many epithelial cancers but with low to no expression in most normal adult tissues. EphB4 over-production promotes ligand-independent signaling pathways that increase cancer cell viability and stimulate migration and invasion. Several studies have shown that normal ligand-dependent signaling is tumour suppressive and therefore novel therapeutics which block the tumour promoting ligand independent signaling and/or stimulate tumour suppressive ligand-dependent signaling will find application in the treatment of cancer. An EphB4-specific polyclonal antibody, targeting a region of 200 amino acids in the extracellular portion of EphB4, showed potent in vitro anti-cancer effects measured by an increase in apoptosis and a decrease in anchorage independent growth. Peptide exclusion was used to identify the epitope targeted by this antibody within the cysteine-rich region of the EphB4 protein, a sequence defined as a potential ligand interacting interface. Addition of antibody to cancer cells resulted in phosphorylation and subsequent degradation of the EphB4 protein, suggesting a mechanism that is ligand mimetic and tumour suppressive. A monoclonal antibody which specifically targets this identified extracellular epitope of EphB4 significantly reduced breast cancer xenograft growth in vivo confirming that EphB4 is a useful target for ligand-mimicking antibody-based anti-cancer therapies. PMID- 25831051 TI - Experimental shifts in intraclutch egg color variation do not affect egg rejection in a host of a non-egg-mimetic avian brood parasite. AB - Avian brood parasites lay their eggs in the nests of other birds, and impose the costs associated with rearing parasitic young onto these hosts. Many hosts of brood parasites defend against parasitism by removing foreign eggs from the nest. In systems where parasitic eggs mimic host eggs in coloration and patterning, extensive intraclutch variation in egg appearances may impair the host's ability to recognize and reject parasitic eggs, but experimental investigation of this effect has produced conflicting results. The cognitive mechanism by which hosts recognize parasitic eggs may vary across brood parasite hosts, and this may explain variation in experimental outcome across studies investigating egg rejection in hosts of egg-mimicking brood parasites. In contrast, for hosts of non-egg-mimetic parasites, intraclutch egg color variation is not predicted to co vary with foreign egg rejection, irrespective of cognitive mechanism. Here we tested for effects of intraclutch egg color variation in a host of nonmimetic brood parasite by manipulating egg color in American robins (Turdus migratorius), hosts of brown-headed cowbirds (Molothrus ater). We recorded robins' behavioral responses to simulated cowbird parasitism in nests where color variation was artificially enhanced or reduced. We also quantified egg color variation within and between unmanipulated robin clutches as perceived by robins themselves using spectrophotometric measures and avian visual modeling. In unmanipulated nests, egg color varied more between than within robin clutches. As predicted, however, manipulation of color variation did not affect rejection rates. Overall, our results best support the scenario wherein egg rejection is the outcome of selective pressure by a nonmimetic brood parasite, because robins are efficient rejecters of foreign eggs, irrespective of the color variation within their own clutch. PMID- 25831050 TI - Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients. AB - Zipper-interacting Protein Kinase (ZIPK) belongs to the death-associated protein kinase family. ZIPK has been characterized as a tumor suppressor in various tumors, including gastric cancer. On the other hand, ZIPK also promotes cell survival. In this study, both in vitro and in vivo assays indicated that ZIPK promoted cell growth, proliferation, migration, invasion, tumor formation and metastasis in nude mice. ZIPK induced epithelial-mesenchymal transition (EMT) with increasing expression of beta-catenin, mesenchymal markers, Snail and Slug, and with decreasing expression of E-cadherin. Furthermore, ZIPK activated the AKT/IkappaB/NF-kappaB pathway, which can promote EMT and metastasis. Additionally, ZIPK expression was detected in human primary gastric cancer and their matched metastatic lymph node samples by immunohistochemistry. Increased expression of ZIPK in lymph node metastases was significantly associated with stage VI and abdominal organ invasion. Survival analysis revealed that patients with increased ZIPK expression in metastatic lymph nodes had poor disease specific survival. Taken together, our study reveals that ZIPK is a pro-oncogenic factor, which promotes cancer metastasis. PMID- 25831052 TI - In situ observation of meniscus shape deformation with colloidal stripe pattern formation in convective self-assembly. AB - Vertical convective self-assembly is capable of fabricating stripe-patterned structures of colloidal particles with well-ordered periodicity. To unveil the mechanism of the stripe pattern formation, in the present study, we focus on the meniscus shape and conduct in situ observations of shape deformation associated with particulate line evolution. The results reveal that the meniscus is elongated downward in a concave fashion toward the substrate in accordance with solvent evaporation, while the concave deformation is accelerated by solvent flow, resulting in the rupture of the liquid film at the thinnest point of the meniscus. The meniscus rupture triggers the meniscus to slide off from the particulate line, followed by the propagation of the sliding motion of the three phase contact line, resulting in the formation of stripe spacing. PMID- 25831053 TI - Multimodality imaging to predict response to systemic treatment in patients with advanced colorectal cancer. AB - AIM: Aim of this study was to investigate the potential of 18F-FDG PET, diffusion weighted imaging (DWI) and susceptibility-weighted (T2*) MRI to predict response to systemic treatment in patients with colorectal liver metastases. The predictive values of pretreatment measurements and of early changes one week after start of therapy, were evaluated. METHODS: Imaging was performed prior to and one week after start of first line chemotherapy in 39 patients with colorectal liver metastases. 18F-FDG PET scans were performed on a PET/CT scanner and DWI and T2* were performed on a 1.5T MR scanner. The maximum standardized uptake values (SUV), total lesion glycolysis (TLG), apparent diffusion coefficient (ADC) and T2* value were assessed in the same lesions. Up to 5 liver metastases per patient were analyzed. Outcome measures were progression free survival (PFS), overall survival (OS) and size response. RESULTS: Pretreatment, high SUVmax, high TLG, low ADC and high T2* were associated with a shorter OS. Low pretreatment ADC value was associated with shorter PFS. After 1 week a significant drop in SUVmax and rise in ADC were observed. The drop in SUV was correlated with the rise in ADC (r=-0.58, p=0.002). Neither change in ADC nor in SUV was predictive of PFS or OS. T2* did not significantly change after start of treatment. CONCLUSION: Pretreatment SUVmax, TLG, ADC, and T2* values in colorectal liver metastases are predictive of patient outcome. Despite sensitivity of DWI and 18F-FDG PET for early treatment effects, change in these parameters was not predictive of long term outcome. PMID- 25831054 TI - Control of origin of sesame oil from various countries by stable isotope analysis and DNA based markers--a pilot study. AB - The indication of origin of sesame seeds and sesame oil is one of the important factors influencing its price, as it is produced in many regions worldwide and certain provenances are especially sought after. We joined stable carbon and hydrogen isotope analysis with DNA based molecular marker analysis to study their combined potential for the discrimination of different origins of sesame seeds. For the stable carbon and hydrogen isotope data a positive correlation between both isotope parameters was observed, indicating a dominant combined influence of climate and water availability. This enabled discrimination between sesame samples from tropical and subtropical/moderate climatic provenances. Carbon isotope values also showed differences between oil from black and white sesame seeds from identical locations, indicating higher water use efficiency of plants producing black seeds. DNA based markers gave independent evidence for geographic variation as well as provided information on the genetic relatedness of the investigated samples. Depending on the differences in ambient environmental conditions and in the genotypic fingerprint, a combination of both analytical methods is a very powerful tool to assess the declared geographic origin. To our knowledge this is the first paper on food authenticity combining the stable isotope analysis of bio-elements with DNA based markers and their combined statistical analysis. PMID- 25831055 TI - Effects of acute restraint stress, prolonged captivity stress and transdermal corticosterone application on immunocompetence and plasma levels of corticosterone on the cururu Toad (Rhinella icterica). AB - Glucocorticoid steroids modulate immunocompetence in complex ways with both immunoenhancing and immunosuppressive effects in vertebrates exposed to different stressors. Such bimodal effects have been associated with variation in duration and intensity of the stress response. Given that natural populations have been exposed to a multitude of stressors, a better understanding of the functional association between duration and intensity of the stress response, the resulting changes in glucocorticoid plasma levels and their impact on different aspects of immunocompetence emerges as a cornerstone for vertebrate conservation strategies. We investigated the effects of a restraint challenge (with and without movement restriction), long-term captivity, and transdermal corticosterone application on plasma levels of corticosterone (hereinafter referred to as CORT) and different parameters of innate immunocompetence in the male cururu toads (Rhinella icterica). We show that for R. icterica restraint for 24h proved to be a stressful condition, increasing CORT by 3-fold without consistent immunological changes. However, the application of a more intense stressor (restraint with movement restriction), for the same period, potentiated this response resulting in a 9-fold increase in CORT, associated with increase Neutrophil/Lymphocyte ratio (N:L) and a lower bacterial killing ability (BKA). Transdermal application of corticosterone efficiently mimics repeated acute stress response events, without changing the immune parameters even after 13 days of treatment. Interestingly, long-term captivity did not mitigate the stress response, since the toads maintained 3-fold increased CORT even after 3 months under these conditions. Moreover, long-term captivity in the same condition increased total leukocyte count (TLC) and generated an even greater decrease in BKA, suggesting that consequences of the stress response can be aggravated by time in captivity. PMID- 25831056 TI - Visceral leishmaniasis and immunocompromise as a risk factor for the development of visceral leishmaniasis: a changing pattern at the hospital for tropical diseases, london. AB - METHODS AND PRINCIPAL FINDINGS: A retrospective study of imported VL to the HTD, London including patients diagnosed and/or managed at the HTD between January 1995 and July 2013. We analyse patient demographics, risk factors for developing VL, diagnosis, investigation, management and outcome. Twenty-eight patients were treated for VL at the HTD over an 18 year period. The median age at VL diagnosis was 44 years (range 4-87 years) with a male to female ratio of 2:1. Most patients were British and acquired their infection in the Mediterranean basin. The median time from first symptom to diagnosis was six months with a range of 1-12 months and diagnosis included microscopic visualisation of leishmania amastigotes, positive serological tests (DAT and k39 antibody) or identification of leishmania DNA. Nineteen patients had some form of immunocompromise and this has increased proportionally compared to previously described data. Within the immunocompromised group, the ratio of those with autoimmune disease has increased. Immunocompromised patients had lower cure and higher relapse rates. CONCLUSIONS: The rise of VL in patients with immunocompromise secondary to autoimmune disease on immunomodulatory drugs presents new diagnostic and therapeutic challenges. VL should be a differential diagnosis in immunocompromised patients with pyrexia of unknown origin returning from travel in leishmania endemic areas. PMID- 25831057 TI - Representative literature on the phytonutrients category: Phenolic acids. AB - Research concerning the benefits derived from dietary polyphenols, a significant class within the family of phytonutrients, has increased considerably in the last decade. Prior to the late 1990s, the nutritional spotlight focused on the antioxidant capabilities of carotenoids, vitamins, and minerals. More recently, however, research has emerged in strong support of the antioxidant capacity of polyphenols and their role in the prevention and/or treatment of certain cancers, diabetes, cardiovascular diseases, and inflammation. Polyphenols are categorized according to the nature of their carbon skeleton, ranging from basic phenolic molecules to highly complex compounds, such as flavonoids, the most common and widely studied of all phenolic compounds. The most prevalent phenolic acids include ellagic acid, gallic acid, tannic acid, and capsaicin. PMID- 25831058 TI - Behavioral cost & overdominance in Anopheles gambiae. AB - In response to the widespread use of control strategies such as Insecticide Treated Nets (ITN), Anopheles mosquitoes have evolved various resistance mechanisms. Kdr is a mutation that provides physiological resistance to the pyrethroid insecticides family (PYR). In the present study, we investigated the effect of the Kdr mutation on the ability of female An. gambiae to locate and penetrate a 1cm-diameter hole in a piece of netting, either treated with insecticide or untreated, to reach a bait in a wind tunnel. Kdr homozygous, PYR resistant mosquitoes were the least efficient at penetrating an untreated damaged net, with about 51% [39-63] success rate compared to 80% [70-90] and 78% [65-91] for homozygous susceptible and heterozygous respectively. This reduced efficiency, likely due to reduced host-seeking activity, as revealed by mosquito video-tracking, is evidence of a recessive behavioral cost of the mutation. Kdr heterozygous mosquitoes were the most efficient at penetrating nets treated with PYR insecticide, thus providing evidence for overdominance, the rarely-described case of heterozygote advantage conveyed by a single locus. The study also highlights the remarkable capacity of female mosquitoes, whether PYR-resistant or not, to locate holes in bed-nets. PMID- 25831061 TI - Genome-wide DNA methylation modified by soy phytoestrogens: role for epigenetic therapeutics in prostate cancer? AB - In prostate cancer, DNA methylation is significantly associated with tumor initiation, progression, and metastasis. Previous studies have suggested that soy phytoestrogens might regulate DNA methylation at individual candidate gene loci and that they play a crucial role as potential therapeutic agents for prostate cancer. The purpose of our study was to examine the modulation effects of phytoestrogens on a genome-wide scale in regards to DNA methylation in prostate cancer. Prostate cancer cell lines DU-145 and LNCaP were treated with 40 MUM of genistein and 110 MUM of daidzein. DNMT inhibitor 5-azacytidine (2 MUM) and the methylating agent budesonide (2 MUM) were used to compare their demethylation/methylation effects with phytoestrogens. The regulatory effects of phytoestrogens on DNA methylation were analyzed by using a methyl-DNA immunoprecipitation method coupled with Human DNA Methylation Microarrays (MeDIP chip). We observed that the methylation profiles of 58 genes were altered by genistein and daidzein treatments in DU-145 and LNCaP prostate cancer cells. In addition, the methylation frequencies of the MAD1L1, TRAF7, KDM4B, and hTERT genes were remarkably modified by genistein treatment. Our results suggest that the modulation effects of phytoestrogens on DNA methylation essentially lead to inhibition of cell growth and induction of apoptosis. Genome-wide methylation profiling reported here suggests that epigenetic regulation mechanisms and, by extension, epigenetics-driven novel therapeutic candidates warrant further consideration in future "omics" studies of prostate cancer. PMID- 25831062 TI - PTPRD is homozygously deleted and epigenetically downregulated in human hepatocellular carcinomas. AB - PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5 azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5'UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology. PMID- 25831059 TI - The placental protein syncytin-1 impairs antiviral responses and exaggerates inflammatory responses to influenza. AB - BACKGROUND: Pregnancy increases susceptibility to influenza. The placenta releases an immunosuppressive endogenous retroviral protein syncytin-1. We hypothesised that exposure of peripheral monocytes (PBMCs) to syncytin-1 would impair responses to H1N1pdm09 influenza. METHODS AND FINDINGS: Recombinant syncytin-1 was produced. PBMCs from non-pregnant women (n=10) were exposed to H1N1pdm09 in the presence and absence of syncytin-1 and compared to responses of PBMCs from pregnant women (n=12). PBMCs were characterised using flow cytometry, release of interferon (IFN)-alpha, IFN-lambda, IFN-gamma, IL-10, IL-2, IL-6 and IL-1beta were measured by cytometric bead array or ELISA. Exposure of PBMCs to H1N1pdm09 resulted in the release of IFN-alpha, (14,787 pg/mL, 95% CI 7311-22,264 pg/mL) IFN-lambda (1486 pg/mL, 95% CI 756-2216 pg/mL) and IFN-gamma (852 pg/mL, 95% CI 193-1511 pg/mL) after 48 hours. This was significantly impaired in pregnant women (IFN-alpha; p<0.0001 and IFN-lambda; p<0.001). Furthermore, in the presence of syncytin-1, PBMCs demonstrated marked reductions in IFN-alpha and IFN lambda, while enhanced release of IL-10 as well as IL-6 and IL-1beta. CONCLUSIONS: Our data indicates that a placental derived protein, syncytin-1 may be responsible for the heightened vulnerability of pregnant women to influenza. PMID- 25831060 TI - The promise of multi-omics and clinical data integration to identify and target personalized healthcare approaches in autism spectrum disorders. AB - Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare. PMID- 25831063 TI - A systematic gene-gene and gene-environment interaction analysis of DNA repair genes XRCC1, XRCC2, XRCC3, XRCC4, and oral cancer risk. AB - Oral cancer is the sixth most common cancer worldwide with a high mortality rate. Biomarkers that anticipate susceptibility, prognosis, or response to treatments are much needed. Oral cancer is a polygenic disease involving complex interactions among genetic and environmental factors, which require multifaceted analyses. Here, we examined in a dataset of 103 oral cancer cases and 98 controls from Taiwan the association between oral cancer risk and the DNA repair genes X ray repair cross-complementing group (XRCCs) 1-4, and the environmental factors of smoking, alcohol drinking, and betel quid (BQ) chewing. We employed logistic regression, multifactor dimensionality reduction (MDR), and hierarchical interaction graphs for analyzing gene-gene (G*G) and gene-environment (G*E) interactions. We identified a significantly elevated risk of the XRCC2 rs2040639 heterozygous variant among smokers [adjusted odds ratio (OR) 3.7, 95% confidence interval (CI)=1.1-12.1] and alcohol drinkers [adjusted OR=5.7, 95% CI=1.4-23.2]. The best two-factor based G*G interaction of oral cancer included the XRCC1 rs1799782 and XRCC2 rs2040639 [OR=3.13, 95% CI=1.66-6.13]. For the G*E interaction, the estimated OR of oral cancer for two (drinking-BQ chewing), three (XRCC1-XRCC2-BQ chewing), four (XRCC1-XRCC2-age-BQ chewing), and five factors (XRCC1-XRCC2-age-drinking-BQ chewing) were 32.9 [95% CI=14.1-76.9], 31.0 [95% CI=14.0-64.7], 49.8 [95% CI=21.0-117.7] and 82.9 [95% CI=31.0-221.5], respectively. Taken together, the genotypes of XRCC1 rs1799782 and XRCC2 rs2040639 DNA repair genes appear to be significantly associated with oral cancer. These were enhanced by exposure to certain environmental factors. The observations presented here warrant further research in larger study samples to examine their relevance for routine clinical care in oncology. PMID- 25831064 TI - Terminal ileum hemosiderosis secondary to prolonged oral iron ingestion. PMID- 25831065 TI - Apple fruit diameter and length estimation by using the thermal and sunshine hours approach and its application to the digital orchard management information system. AB - In apple cultivation, simulation models may be used to monitor fruit size during the growth and development process to predict production levels and to optimize fruit quality. Here, Fuji apples cultivated in spindle-type systems were used as the model crop. Apple size was measured during the growing period at an interval of about 20 days after full bloom, with three weather stations being used to collect orchard temperature and solar radiation data at different sites. Furthermore, a 2-year dataset (2011 and 2012) of apple fruit size measurements were integrated according to the weather station deployment sites, in addition to the top two most important environment factors, thermal and sunshine hours, into the model. The apple fruit diameter and length were simulated using physiological development time (PDT), an indicator that combines important environment factors, such as temperature and photoperiod, as the driving variable. Compared to the model of calendar-based development time (CDT), an indicator counting the days that elapse after full bloom, we confirmed that the PDT model improved the estimation accuracy to within 0.2 cm for fruit diameter and 0.1 cm for fruit length in independent years using a similar data collection method in 2013. The PDT model was implemented to realize a web-based management information system for a digital orchard, and the digital system had been applied in Shandong Province, China since 2013. This system may be used to compute the dynamic curve of apple fruit size based on data obtained from a nearby weather station. This system may provide an important decision support for farmers using the website and short message service to optimize crop production and, hence, economic benefit. PMID- 25831066 TI - Combining Raman and FT-IR spectroscopy with quantitative isotopic labeling for differentiation of E. coli cells at community and single cell levels. AB - There is no doubt that the contribution of microbially mediated bioprocesses toward maintenance of life on earth is vital. However, understanding these microbes in situ is currently a bottleneck, as most methods require culturing these microorganisms to suitable biomass levels so that their phenotype can be measured. The development of new culture-independent strategies such as stable isotope probing (SIP) coupled with molecular biology has been a breakthrough toward linking gene to function, while circumventing in vitro culturing. In this study, for the first time we have combined Raman spectroscopy and Fourier transform infrared (FT-IR) spectroscopy, as metabolic fingerprinting approaches, with SIP to demonstrate the quantitative labeling and differentiation of Escherichia coli cells. E. coli cells were grown in minimal medium with fixed final concentrations of carbon and nitrogen supply, but with different ratios and combinations of (13)C/(12)C glucose and (15)N/(14)N ammonium chloride, as the sole carbon and nitrogen sources, respectively. The cells were collected at stationary phase and examined by Raman and FT-IR spectroscopies. The multivariate analysis investigation of FT-IR and Raman data illustrated unique clustering patterns resulting from specific spectral shifts upon the incorporation of different isotopes, which were directly correlated with the ratio of the isotopically labeled content of the medium. Multivariate analysis results of single-cell Raman spectra followed the same trend, exhibiting a separation between E. coli cells labeled with different isotopes and multiple isotope levels of C and N. PMID- 25831068 TI - Correction: Implementation of a surgical safety checklist: interventions to optimize the process and hints to increase compliance. PMID- 25831067 TI - Increased rates of pregnancy complications in women with celiac disease. AB - BACKGROUND: Celiac disease is an immune-mediated small bowel disorder that develops in genetically susceptible individuals upon exposure to dietary gluten. Celiac disease could have extra-intestinal manifestations that affect women's reproductive health. The aim of this study was to investigate fertility and outcomes of pregnancy among women with celiac disease. METHODS: In a retrospective cohort study, we analyzed information collected from patients at a tertiary care celiac center and from members of 2 national celiac disease awareness organizations. Women without celiac disease were used as controls. Women completed an anonymous online survey, answering 43 questions about menstrual history, fertility, and outcomes of pregnancy (329 with small bowel biopsy-confirmed celiac disease and 641 controls). RESULTS: Of the 970 women included in the study, 733 (75.6%) reported that they had been pregnant at some point; there was no significant difference between women with celiac disease (n=245/329, 74.5%) and controls (488/641, 76.1%; P=0.57). However, fewer women with celiac disease than controls (79.6% vs. 84.8%) gave birth following 1 or more pregnancies (P=0.03). Women with celiac disease had higher percentages of spontaneous abortion than controls (50.6% vs. 40.6%; P=0.01), and of premature delivery (23.6% vs. 15.9% among controls; P=0.02). The mean age at menarche was higher in the celiac disease group (12.7 years) than controls (12.4 years; P=0.01). CONCLUSIONS: In a retrospective cohort analysis examining reproductive features of women with celiac disease, we associated celiac disease with significant increases in spontaneous abortion, premature delivery, and later age of menarche. PMID- 25831069 TI - Do Written Disclosures of Serious Events Increase Risk of Malpractice Claims? One Health Care System's Experience. AB - OBJECTIVE: This study aimed to determine whether Pennsylvania ACT 13 of 2002 (Mcare) requiring the written and verbal disclosure of "serious events" was accompanied by increased malpractice claims or compensation costs in a large U.S. health system. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of malpractice claims. The secondary outcome was the amount paid for compensation of malpractice claims. The analyses tested the relationship between the rate of serious event disclosures and the outcome variables, adjusted for the year of the event, category of claim, and the degree of "harm" related to the event. RESULTS: There were 15,028 serious event disclosures and 1302 total malpractice claims among 1,587,842 patients admitted to UPMC hospitals from May 17, 2002, to June 30, 2011. As the number of serious event disclosures increased, the number of malpractice claims per 1000 admissions remained between 0.62 and 1.03. Based on a matched analysis of claims that were disclosed and those that were not (195 pairs), disclosure status was significantly associated with increased claim payout (disclosures had 2.71 times the payout; 95% confidence interval, 1.56 4.72). Claims with higher harm levels H and I were independently associated with higher payouts than claims with lower harm levels A to D (11.15 times the payout; 95% confidence interval, 2.30-54.07). CONCLUSIONS AND RELEVANCE: Implementation of a mandated serious event disclosure law in Pennsylvania was not associated with an overall increase in malpractice claims filed. Among events of similar degree of harm, disclosed events had higher compensation paid compared with those that had not been disclosed. PMID- 25831070 TI - Heart disease prevention in children: the road to 2020. PMID- 25831071 TI - Outcome after discontinuation of nucleot(s)ide analogues in chronic hepatitis B: relapse rate and associated factors. AB - The introduction of nucleot(s)ide analogues (NAs) for oral antiviral therapy has dramatically improved the clinical outcome of patients with chronic hepatitis B. NAs appear to be safe and induce potent suppression of viral replication. However, they are associated with a low rate of HBsAg seroclearance, the gold standard of successful treatment, and also with a relatively high rate of virological relapse after discontinuation. As a result, long-term treatment is needed. The optimal duration of NA treatment currently remains unclear, nevertheless in some patients NA treatment can be stopped with a relatively low probability of relapse. Whether NAs are able to induce a sustained off-treatment response is an important area for research. This article reviews the relapse rate after cessation of treatment with NAs in chronic hepatitis B patients with the goal of identifying possible predictive factors of relapse. PMID- 25831073 TI - Shape-selective oriented cerium oxide nanocrystals permit assessment of the effect of the exposed facets on catalytic activity and oxygen storage capacity. AB - The catalytic performance of a range of nanocrystalline CeO2 samples, prepared to have different morphologies, was measured using two accepted indicators; oxygen storage and diesel soot combustion. The same powders were characterized in detail by HR-TEM, XRD, XPS, and Raman methods. The study demonstrates that activity is determined by the relative fraction of the active crystallographic planes, not by the specific surface area of the powders. The physical study is a step toward quantitative evaluation of the relative contribution to activity of the different facets. The synthetic protocol permits fabrication of CeO2 nanostructures with preferentially grown active planes, and therefore has potential in developing catalytic applications and in nanocompositing. PMID- 25831072 TI - Antibiotic use: a cross-sectional survey assessing the knowledge, attitudes and practices amongst students of a school of medicine in Italy. AB - BACKGROUND: Since antibiotic resistance has become a worldwide public health concern and is in part related to physicians' lack of knowledge, it is essential to focus our attention on healthcare profession students. The present study aims at evaluating the knowledge and attitudes of the School of Medicine's students towards antibiotic usage and antibiotic resistance. METHODS: In December 2013, a cross sectional study was conducted amongst medical, dental, nursing and other health care profession students of the School of Medicine at the University of Torino. Students of all the academic years took part in this study. Questionnaires were submitted during regular lectures (only students who attended courses on one specific day were surveyed) and the data collected was analyzed using StataMP11 statistical software. RESULTS: Overall, 1,050 students were interviewed. The response rate was 100%. Around 20% of the sample stated that antibiotics are appropriate for viral infections and 15% of the students that they stop taking those drugs when symptoms decrease. Results of the multivariate analyses showed that females were more likely than males to take antibiotics only when prescribed (OR 1.43, 95% CI 1.04-1.98). Interestingly, students with a relative working in a health-related field, as well as those who took at least one course of antibiotics in the last year, had a lower probability of taking those drugs only under prescription (OR = 0.69 95% CI: 0.49-0.97 and OR = 0.38 95% CI: 0.27-0.53, respectively). CONCLUSION: The present paper shows how healthcare profession students do not practice what they know. Since those students will be a behavioral model for citizens and patients, it is important to generate more awareness around this issue throughout their studies. It would be advisable to introduce a specific course and training on antibiotics in the core curriculum of the School of Medicine. PMID- 25831074 TI - Structural revision of (+)-uprolide F diacetate confirmed by asymmetric total synthesis. AB - A new structure for the cytotoxic cembranolide uprolide F diacetate (UFD) was proposed, and an enantioselective total synthesis was accomplished to confirm that our revised structure correctly represented the natural UFD and its absolute configuration. Our synthesis features a late-stage, highly efficient, and diastereoselective Nozaki-Hiyama-Kishi macrocyclization (95% yield) and an unexpected reagent-controlled reversible translactonization, which, being the first example within the cembranolide family, might have biogenetic implications and be of great importance to synthetic studies of the alpha-methylene-gamma lactone-bearing cembranolides. PMID- 25831075 TI - 1D magnetic interactions in Cu(II) oxovanadium phosphates (VPO), magnetic susceptibility, DFT, and single-crystal EPR. AB - We report the crystal face indexing and molecular spatial orientation, magnetic properties, electron paramagnetic resonance (EPR) spectra, and density functional theory (DFT) calculations of two previously reported oxovanadium phosphates functionalized with Cu(II) complexes, namely, [Cu(bipy)(VO2)(PO4)]n (1) and [{Cu(phen)}2(VO2(H2O)2)(H2PO4)2 (PO4)]n (2), where bipy = 2,2'-bipyridine and phen = 1,10-phenanthroline, obtained by a new synthetic route allowing the growth of single crystals appropriate for the EPR measurements. Compounds 1 and 2 crystallize in the triclinic group P1 and in the orthorhombic Pccn group, respectively, containing dinuclear copper units connected by two -O-P-O- bridges in 1 and by a single -O-P-O- bridge in 2, further connected through -O-P-O-V-O- bridges. We emphasize in our work the structural aspects related to the chemical paths that determine the magnetic properties. Magnetic susceptibility data indicate bulk antiferromagnetism for both compounds, allowing to calculate J = 43.0 cm(-1) (dCu-Cu = 5.07 A; J defined as Hex(i,j) = -J Si.Sj), considering dinuclear units for 1, and J = -1.44 cm(-1) (dCu-Cu = 3.47 A) using the molecular field approximation for 2. The single-crystal EPR study allows evaluation of the g matrices, which provide a better understanding of the electronic structure. The absence of structure of the EPR spectra arising from the dinuclear character of the compounds allows estimation of weak additional exchange couplings |J'| > 0.3 cm(-1) for 1 (dCu-Cu = 5.54 A) and a smaller value of |J'| >= 0.15 cm(-1) for 2 (dCu-Cu = 6.59 A). DFT calculations allow evaluating two different exchange couplings for each compound, specifically, J = -36.60 cm(-1) (dCu-Cu = 5.07 A) and J' = 0.20 cm(-1) (dCu-Cu =5.54 A) for 1 and J = -1.10 cm(-1) (dCu-Cu =3.47 A) and J' = 0.01 cm(-1) (dCu-Cu = 6.59 A) for 2, this last value being in the range of the uncertainties of the calculations. Thus, these values are in good agreement with those provided by magnetic and single-crystal EPR measurements. PMID- 25831076 TI - Prevalence and management of back pain in adolescent idiopathic scoliosis patients: A retrospective study. AB - BACKGROUND: Back pain (BP) has often been associated with adolescent idiopathic scoliosis (AIS), which is a three-dimensional deviation of the vertebral column. In adolescents, chronic pain appears to be a predictor of health care utilization and has a negative impact on physical, psychological and family well-being. In this population, BP tends to be persistent and may be a predictor of BP in adulthood. OBJECTIVE: To document the prevalence and management of BP in AIS patients. METHODS: A retrospective chart review of AIS patients who were referred to Sainte-Justine University Teaching Hospital (Montreal, Quebec) from 2006 to 2011 was conducted. RESULTS: A total of 310 randomly selected charts were reviewed. Nearly one-half of the patients (47.3%) mentioned that they experienced BP, most commonly in the lumbar (19.7%) and thoracic regions (7.7%). The type of BP was documented in only 36% (n=112) of the charts. Pain intensity was specified in only 21% (n=65) of the charts. In approximately 80% (n=248) of the charts, no pain management treatment plan was documented. CONCLUSIONS: The prevalence of BP was moderately high among the present sample of adolescents with AIS. An improved system for documenting BP assessment, type, treatment plan and treatment effectiveness would improve pain management for these patients. PMID- 25831077 TI - Patients' recall of diagnostic and treatment information improves with use of the Pain Explanation and Treatment Diagram in an outpatient chronic pain clinic. AB - BACKGROUND: To maximize the benefit of therapies, patients must understand their condition, recall treatment suggestions and comply with treatments. The Pain Explanation and Treatment Diagram (PETD) is a one-page worksheet that identifies risk factors (health-related habits, sleep, exercise, ergonomics and psychosocial factors) involved in chronic pain. Clinician and patient complete the PETD together, and the clinician notes recommended treatments and lifestyle changes. OBJECTIVES: To examine the effect of use of the PETD on patient recall of diagnostic and treatment information on the sheet. METHODS: The present study was a cross-sectional analysis. Patients with chronic musculoskeletal pain seen by one physiatrist at an outpatient pain clinic in a university-affiliated hospital between 2009 and 2012 (all of whom received the PETD) were eligible. A structured telephone interview lasting approximately 1 h was used to determine recall of PETD diagnostic and treatment information. RESULTS: Of the 84 eligible patients, 46 were contacted and 29 completed the telephone interview. Participants recalled an average of 12.2% (95% CI 7.8% to 17.4%) of items without prompting and 48.5% (95% CI 42.0% to 53.5%) when prompted. Participants who referred to the PETD at home (n=13) recalled significantly more items than those who did not (n=15) (17.6% [95% CI 11.1% to 23.9%] versus 5.2% [95% CI 3.0% to 14.5%], P=0.004); when prompted, the rates increased to 54.3% (95% CI 48.3% to 61.2%) and 41.2% (95% CI 34.7% to 50.7%), respectively (P=0.032). CONCLUSIONS: The PETD is a promising, feasible and inexpensive tool that can improve patients' recall of diagnostic- and treatment-related information. PMID- 25831078 TI - Development of a cell system for siRNA screening of pathogen responses in human and mouse macrophages. AB - Macrophages play a critical role in the innate immune response to pathogen infection, but few tools exist for systematic dissection of these responses using modern genome-wide perturbation methods. To develop an assay platform for high throughput analysis of macrophage activation by pathogenic stimuli, we generated reporter systems in human and mouse macrophages with dynamic readouts for NF kappaB and/or TNF-alpha responses. These reporter cells show responsiveness to a broad range of TLR ligands and to gram-negative bacterial infection. There are significant challenges to the use of RNAi in innate immune cells, including efficient small RNA delivery and non-specific immune responses to dsRNA. To permit the interrogation of the macrophage pathogen response pathways with RNAi, we employed the stably expressed reporter genes to develop efficient siRNA delivery protocols for maximal target gene silencing with minimal activation of the innate macrophage response to nucleic acids. We demonstrate the utility of these macrophage cell systems for siRNA screening of pathogen responses by targeting components of the human and mouse TLR pathways, and observe species specific perturbation of signaling and cytokine responses. Our approach to reporter cell development and siRNA delivery optimization provides an experimental paradigm with significant potential for developing genetic screening platforms in mammalian cells. PMID- 25831080 TI - Employing XIAP to enhance the duration of antigen expression and immunity against an avian influenza H5 DNA vaccine. AB - DNA vaccine represents a powerful approach for prevention of avian H5N1 influenza infection. Yet, DNA vaccine-induced immune responses might be limited by the short duration of antigen expression. As a strategy to enhance adaptive immune responses elicited by a hemagglutinin 5 (H5) DNA vaccine, we explored the effect of co-administration of a DNA encoding X-linked inhibitor of apoptosis protein (XIAP) as a modulator of apoptosis and a stimulator of inflammatory signaling. In cultured cells as early as 24 hours (h), we found that the DNA vaccine encoded H5 antigen was a potent stimulator of apoptosis, and the H5 pro-apoptotic activity was significantly suppressed by the co-expression of full-length XIAP or mutant XIAP (DeltaRING). However, full-length XIAP showed a higher potency than mutant XIAP (DeltaRING) in the inhibition of H5-induced apoptosis. We also compared the immunizing ability of transmembrane and secretory forms of H5. Mice vaccinated (twice with 3-week intervals) with the secretory form of H5 showed higher hemagglutination inhibition (HI) antibody titers than mice vaccinated with the transmembrane form of H5. Furthermore, co-administration of XIAP with the secretory form of H5 resulted into a stronger antibody response than the transmembrane form of H5. Our findings suggest that in the design of DNA vaccines for a given pro-apoptotic antigen, using an anti-apoptotic molecular adjuvant and the secretory form of antigen may be a greater stimulus to induce immune responses. PMID- 25831079 TI - Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB. AB - Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. Activation of the aryl hydrocarbon receptor (AhR) protects adult and newborn mice against hyperoxic lung injury by mediating increases in the expression of phase I (cytochrome P450 (CYP) 1A) and phase II (NADP(H) quinone oxidoreductase (NQO1)) antioxidant enzymes (AOE). AhR positively regulates the expression of RelB, a component of the nuclear factor-kappaB (NF kappaB) protein that contributes to anti-inflammatory processes in adult animals. Whether AhR regulates the expression of AOE and RelB, and protects fetal primary human lung cells against hyperoxic injury is unknown. Therefore, we tested the hypothesis that AhR-deficient fetal human pulmonary microvascular endothelial cells (HPMEC) will have decreased RelB activation and AOE, which will in turn predispose them to increased oxidative stress, inflammation, and cell death compared to AhR-sufficient HPMEC upon exposure to hyperoxia. AhR-deficient HPMEC showed increased hyperoxia-induced reactive oxygen species (ROS) generation, cleavage of poly(ADP-ribose) polymerase (PARP), and cell death compared to AhR sufficient HPMEC. Additionally, AhR-deficient cell culture supernatants displayed increased macrophage inflammatory protein 1alpha and 1beta, indicating a heightened inflammatory state. Interestingly, loss of AhR was associated with a significantly attenuated CYP1A1, NQO1, superoxide dismutase 1(SOD1), and nuclear RelB protein expression. These findings support the hypothesis that decreased RelB activation and AOE in AhR-deficient cells is associated with increased hyperoxic injury compared to AhR-sufficient cells. PMID- 25831081 TI - Fascin regulates TLR4/PKC-mediated translational activation through miR-155 and miR-125b, which targets the 3' untranslated region of TNF-alpha mRNA. AB - Fascin is a well-known cytoskeletal regulatory protein that, as a substrate of protein kinase C (PKC), is involved in PKC-mediated translational regulation of TNF-alpha in macrophages stimulated with lipopolysaccharide (LPS). The regulatory effects of fascin targeted the 3'-untraslated region (UTR) of the TNF-alpha mRNA, and suppression of PKC activity or fascin expression resulted in specific blockage of the LPS-induced translational activation of the mRNA. In an effort to identify the molecular mechanism of this fascin-mediated translational regulation, the expression levels of micro-RNA (miRNA) after stimulation of the toll-like receptor 4 (TLR4) signaling pathways were analyzed in cells with down regulation of fascin. The LPS-induced translation of TNF-alpha is known to be regulated by miR-155 and miR-125b, which have positive and negative effects, respectively. Interestingly, suppression of fascin expression reversed LPS induced down-regulation of miR-125b and abolished the LPS-induced increase in miR 155. Furthermore, introduction of miR-155 precursor, blocking of miR-125b activity, or introduction of a mutation into the miR-125b binding site of the TNF alpha 3'-UTR restored translational activation in cells with suppressed fascin expression. These data indicate that fascin regulates translation through miR-155 and miR-125b, which target 3' UTR in TNF-alpha mRNA. PMID- 25831082 TI - Fukuyoa paulensis gen. et sp. nov., a new genus for the globular species of the dinoflagellate Gambierdiscus (Dinophyceae). AB - The marine epiphytic dinoflagellate Gambierdiscus is a toxicologically important genus responsible for ciguatera fish poisoning, the principal cause of non bacterial illness associated with fish consumption. The genus currently contains species exhibiting either globular or anterior-posteriorly compressed morphologies with marked differences in cell shape and plate arrangement. Here we report a third globular, epiphytic and tychoplanktonic species from the coasts of Ubatuba, Brazil. The new species can be distinguished from G. yasumotoi and G. ruetzleri by its broader first apical plate that occupies a larger portion of the epitheca. Accordingly, phylogenetic trees from small subunit (SSU) and large subunit (LSU) ribosomal DNA sequences also showed strongly supported separation of the new species from the G. yasumotoi/G. ruetzleri group albeit with short distance. The molecular phylogenies, which included new sequences of the planktonic species Goniodoma polyedricum, further indicated that the globular species of Gambierdiscus formed a tight clade, clearly separated (with strong bootstrap support) from the clade of lenticular species including the type for Gambierdiscus. The morphological and molecular data in concert support the split of Gambierdiscus sensu lato into two genera. Gambierdiscus sensu stricto should be reserved for the species with lenticular shapes, highly compressed anterioposteriorly, with short-shank fishhook apical pore plate, large 2' plate, low and ascending cingular displacement, and pouch-like sulcal morphology. The new genus name Fukuyoa gen. nov. should be applied to the globular species, slightly laterally compressed, with long-shank fishhook apical pore plate, large 1' plate, greater and descending cingular displacement, and not pouch-like vertically-oriented sulcal morphology. Fukuyoa contains the new species Fukuyoa paulensis gen. et sp. nov., and F. yasumotoi comb. nov. and F. ruetzleri comb. nov. PMID- 25831083 TI - Highly sensitive measurement of liquid density in air using suspended microcapillary resonators. AB - We report the use of commercially available glass microcapillaries as micromechanical resonators for real-time monitoring of the mass density of a liquid that flows through the capillary. The vibration of a suspended region of the microcapillary is optically detected by measuring the forward scattering of a laser beam. The resonance frequency of the liquid filled microcapillary is measured for liquid binary mixtures of ethanol in water, glycerol in water and Triton in ethanol. The method achieves a detection limit in an air environment of 50 ug/mL that is only five times higher than that obtained with state-of-the-art suspended microchannel resonators encapsulated in vacuum. The method opens the door to novel advances for miniaturized total analysis systems based on microcapillaries with the add-on of mechanical transduction for sensing the rheological properties of the analyzed fluids without the need for vacuum encapsulation of the resonators. PMID- 25831084 TI - PAD-MAC: primary user activity-aware distributed MAC for multi-channel cognitive radio networks. AB - Cognitive radio (CR) has emerged as a promising technology to solve problems related to spectrum scarcity and provides a ubiquitous wireless access environment. CR-enabled secondary users (SUs) exploit spectrum white spaces opportunistically and immediately vacate the acquired licensed channels as primary users (PUs) arrive. Accessing the licensed channels without the prior knowledge of PU traffic patterns causes severe throughput degradation due to excessive channel switching and PU-to-SU collisions. Therefore, it is significantly important to design a PU activity-aware medium access control (MAC) protocol for cognitive radio networks (CRNs). In this paper, we first propose a licensed channel usage pattern identification scheme, based on a two-state Markov model, and then estimate the future idle slots using previous observations of the channels. Furthermore, based on these past observations, we compute the rank of each available licensed channel that gives SU transmission success assessment during the estimated idle slot. Secondly, we propose a PU activity-aware distributed MAC (PAD-MAC) protocol for heterogeneous multi-channel CRNs that selects the best channel for each SU to enhance its throughput. PAD-MAC controls SU activities by allowing them to exploit the licensed channels only for the duration of estimated idle slots and enables predictive and fast channel switching. To evaluate the performance of the proposed PAD-MAC, we compare it with the distributed QoS-aware MAC (QC-MAC) and listen-before-talk MAC schemes. Extensive numerical results show the significant improvements of the PAD-MAC in terms of the SU throughput, SU channel switching rate and PU-to-SU collision rate. PMID- 25831085 TI - A non-chemical system for online weed control. AB - Non-chemical weed control methods need to be directed towards a site-specific weeding approach, in order to be able to compete the conventional herbicide equivalents. A system for online weed control was developed. It automatically adjusts the tine angle of a harrow and creates different levels of intensity: from gentle to aggressive. Two experimental plots in a maize field were harrowed with two consecutive passes. The plots presented from low to high weed infestation levels. Discriminant capabilities of an ultrasonic sensor were used to determine the crop and weed variability of the field. A controlling unit used ultrasonic readings to adjust the tine angle, producing an appropriate harrowing intensity. Thus, areas with high crop and weed densities were more aggressively harrowed, while areas with lower densities were cultivated with a gentler treatment; areas with very low densities or without weeds were not treated. Although the weed development was relatively advanced and the soil surface was hard, the weed control achieved by the system reached an average of 51% (20% 91%), without causing significant crop damage as a result of harrowing. This system is proposed as a relatively low cost, online, and real-time automatic harrow that improves the weed control efficacy, reduces energy consumption, and avoids the usage of herbicide. PMID- 25831086 TI - A robust method to detect zero velocity for improved 3D personal navigation using inertial sensors. AB - This paper proposes a robust zero velocity (ZV) detector algorithm to accurately calculate stationary periods in a gait cycle. The proposed algorithm adopts an effective gait cycle segmentation method and introduces a Bayesian network (BN) model based on the measurements of inertial sensors and kinesiology knowledge to infer the ZV period. During the detected ZV period, an Extended Kalman Filter (EKF) is used to estimate the error states and calibrate the position error. The experiments reveal that the removal rate of ZV false detections by the proposed method increases 80% compared with traditional method at high walking speed. Furthermore, based on the detected ZV, the Personal Inertial Navigation System (PINS) algorithm aided by EKF performs better, especially in the altitude aspect. PMID- 25831087 TI - Maximum stress estimation model for multi-span waler beams with deflections at the supports using average strains. AB - The safety of a multi-span waler beam subjected simultaneously to a distributed load and deflections at its supports can be secured by limiting the maximum stress of the beam to a specific value to prevent the beam from reaching a limit state for failure or collapse. Despite the fact that the vast majority of accidents on construction sites occur at waler beams in retaining wall systems, no safety monitoring model that can consider deflections at the supports of the beam is available. In this paper, a maximum stress estimation model for a waler beam based on average strains measured from vibrating wire strain gauges (VWSGs), the most frequently used sensors in construction field, is presented. The model is derived by defining the relationship between the maximum stress and the average strains measured from VWSGs. In addition to the maximum stress, support reactions, deflections at supports, and the magnitudes of distributed loads for the beam structure can be identified by the estimation model using the average strains. Using simulation tests on two multi-span beams, the performance of the model is evaluated by estimating maximum stress, deflections at supports, support reactions, and the magnitudes of distributed loads. PMID- 25831088 TI - The application of a piezo-resistive cardiorespiratory sensor system in an automobile safety belt. AB - Respiratory and heart failure are conditions that can occur with little warning and may also be difficult to predict. Therefore continuous monitoring of these bio-signals is advantageous for ensuring human health. The car safety belt is mainly designed to secure the occupants of the vehicle in the event of an accident. In the current research a prototype safety belt is developed, which is used to acquire respiratory and heart signals, under laboratory conditions. The current safety belt is constructed using a copper ink based nonwoven material, which works based on the piezo-resistive effect due to the pressure exerted on the sensor as a result of expansion of the thorax/abdomen area of the body for respiration and due to the principle of ballistocardiography (BCG) in heart signal sensing. In this research, the development of a theoretical model to qualitatively describe the piezo-resistive material is also presented in order to predict the relative change in the resistance of the piezo-resistive material due to the pressure applied. PMID- 25831089 TI - Simple Method to Genotype the ACTN3 r577x Polymorphism. AB - The alpha-actinin-3 r577x polymorphism (rs1815739) is one of the most important polymorphisms associated with athletic performance. This single-nucleotide mutation leads to a premature stop codon, resulting in a nonfunctional protein product. The presence of the dominant R allele is associated with full power skeletal muscle contraction. Homozygosity for the X allele is correlated with more efficient energy disposure. Restriction fragment length polymorphism and real-time polymerase chain reaction (PCR) are the standard methods used to genotype this polymorphism, but they are expensive and require special equipments. Here, we present a simple and cost-efficient method to genotype the ACTN3 r577x polymorphism by a single PCR. External primers yield a 690-bp product that indicates the template quality. Internal primers produce a 413-bp product if the R allele is present and a 318-bp product if the X allele is present. Our four primer genotyping PCR was validated by the standard real-time PCR, generally used to genotype this single-nucleotide polymorphism, demonstrating the accuracy of this method. This protocol is perfect for small- or large-scale cohort genotyping of the ACTN3 r577x polymorphism. PMID- 25831090 TI - The Challenge of Antimicrobial Resistance in Managing Intra-Abdominal Infections. AB - BACKGROUND: In recent years, there has been a worldwide increase in infections caused by microorganisms resistant to multiple antimicrobial agents. METHODS: In the past few decades, an increased prevalence of infections caused by antibiotic resistant pathogens, including Enterococcus spp., carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, extended-spectrum beta lactamase (ESBL)-producing Escherichia coli and Klebsiella spp., carbapenemase producing Klebsiella pneumoniae, and resistant Candida spp., also has been observed among intra-abdominal infections (IAIs). RESULTS: The increasing prevalence of multi-drug resistance is responsible for a substantial increase in morbidity and mortality rates associated with IAIs. CONCLUSIONS: It is necessary for every surgeon treating IAIs to understand the underlying epidemiology and clinical consequences of antimicrobial resistance. Emergence of drug resistance, combined with the lack of new agents in the drug development pipeline, indicates that judicious antimicrobial management will be necessary to preserve the utility of the drugs available currently. PMID- 25831091 TI - Erythematous Papules on the Forearms. PMID- 25831092 TI - Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intragastric alcohol administration. AB - Acetaldehyde (ACH) associated with alcoholic beverages is Group 1 carcinogen to humans (IARC/WHO). Aldehyde dehydrogenase (ALDH2), a major ACH eliminating enzyme, is genetically deficient in 30-50% of Eastern Asians. In alcohol drinkers, ALDH2-deficiency is a well-known risk factor for upper aerodigestive tract cancers, i.e., head and neck cancer and esophageal cancer. However, there is only a limited evidence for stomach cancer. In this study we demonstrated for the first time that ALDH2 deficiency results in markedly increased exposure of the gastric mucosa to acetaldehyde after intragastric administration of alcohol. Our finding provides concrete evidence for a causal relationship between acetaldehyde and gastric carcinogenesis. A plausible explanation is the gastric first pass metabolism of ethanol. The gastric mucosa expresses alcohol dehydrogenase (ADH) enzymes catalyzing the oxidation of ethanol to acetaldehyde, especially at the high ethanol concentrations prevailing in the stomach after the consumption of alcoholic beverages. The gastric mucosa also possesses the acetaldehyde-eliminating ALDH2 enzyme. Due to decreased mucosal ALDH2 activity, the elimination of ethanol-derived acetaldehyde is decreased, which results in its accumulation in the gastric juice. We also demonstrate that ALDH2 deficiency, proton pump inhibitor (PPI) treatment, and L-cysteine cause independent changes in gastric juice and salivary acetaldehyde levels, indicating that intragastric acetaldehyde is locally regulated by gastric mucosal ADH and ALDH2 enzymes, and by oral microbes colonizing an achlorhydric stomach. Markedly elevated acetaldehyde levels were also found at low intragastric ethanol concentrations corresponding to the ethanol levels of many foodstuffs, beverages, and dairy products produced by fermentation. A capsule that slowly releases L-cysteine effectively eliminated acetaldehyde from the gastric juice of PPI-treated ALDH2 active and ALDH2-deficient subjects. These results provide entirely novel perspectives for the prevention of gastric cancer, especially in established risk groups. PMID- 25831094 TI - Care Models of eHealth Services: A Case Study on the Design of a Business Model for an Online Precare Service. AB - BACKGROUND: With a growing population of health care clients in the future, the organization of high-quality and cost-effective service providing becomes an increasing challenge. New online eHealth services are proposed as innovative options for the future. Yet, a major barrier to these services appears to be the lack of new business model designs. Although design efforts generally result in visual models, no such artifacts have been found in the literature on business model design. This paper investigates business model design in eHealth service practices from a design perspective. It adopts a research by design approach and seeks to unravel what characteristics of business models determine an online service and what are important value exchanges between health professionals and clients. OBJECTIVE: The objective of the study was to analyze the construction of care models in-depth, framing the essential elements of a business model, and design a new care model that structures these elements for the particular context of an online pre-care service in practice. METHODS: This research employs a qualitative method of an in-depth case study in which different perspectives on constructing a care model are investigated. Data are collected by using the visual business modeling toolkit, designed to cocreate and visualize the business model. The cocreated models are transcribed and analyzed per actor perspective, transactions, and value attributes. RESULTS: We revealed eight new actors in the business model for providing the service. Essential actors are: the intermediary network coordinator connecting companies, the service dedicated information technology specialists, and the service dedicated health specialist. In the transactions for every service providing we found a certain type of contract, such as a license contract and service contracts for precare services and software products. In addition to the efficiency, quality, and convenience, important value attributes appeared to be: timelines, privacy and credibility, availability, pleasantness, and social interaction. Based on the in-depth insights from the actor perspectives, the business model for online precare services is modeled with a visual design. A new care model of the online precare service is designed and compiled of building blocks for the business model. CONCLUSIONS: For the construction of a care model, actors, transactions, and value attributes are essential elements. The design of a care model structures these elements in a visual way. Guided by the business modeling toolkit, the care model design artifact is visualized in the context of an online precare service. Important building blocks include: provision of an online flow of information with regular interactions to the client stimulates self-management of personal health and service-dedicated health expert ensure an increase of the perceived quality of the eHealth service. PMID- 25831093 TI - The benefits of social influence in optimized cultural markets. AB - Social influence has been shown to create significant unpredictability in cultural markets, providing one potential explanation why experts routinely fail at predicting commercial success of cultural products. As a result, social influence is often presented in a negative light. Here, we show the benefits of social influence for cultural markets. We present a policy that uses product quality, appeal, position bias and social influence to maximize expected profits in the market. Our computational experiments show that our profit-maximizing policy leverages social influence to produce significant performance benefits for the market, while our theoretical analysis proves that our policy outperforms in expectation any policy not displaying social signals. Our results contrast with earlier work which focused on showing the unpredictability and inequalities created by social influence. Not only do we show for the first time that, under our policy, dynamically showing consumers positive social signals increases the expected profit of the seller in cultural markets. We also show that, in reasonable settings, our profit-maximizing policy does not introduce significant unpredictability and identifies "blockbusters". Overall, these results shed new light on the nature of social influence and how it can be leveraged for the benefits of the market. PMID- 25831095 TI - Jahn-Teller distortion in polyoligomeric silsesquioxane (POSS) cations. AB - We investigated the symmetry breaking mechanism in cubic octa-tert-butyl silsesquioxane and octachloro silsesquioxane monocations (Si8O12(C(CH3)3)8(+) and Si8O12Cl8(+)) using density functional theory (DFT) and group theory. Under Oh symmetry, these ions possess (2)T2g and (2)Eg electronic states and undergo different symmetry breaking mechanisms. The ground states of Si8O12(C(CH3)3)8(+) and Si8O12Cl8(+) belong to the C3v and D4h point groups and are characterized by Jahn-Teller stabilization energies of 3959 and 1328 cm(-1), respectively, at the B3LYP/def2-SVP level of theory. The symmetry distortion mechanism in Si8O12Cl8(+) is Jahn-Teller type, whereas in Si8O12(C(CH3)3)8(+) the distortion is a combination of both Jahn-Teller and pseudo-Jahn-Teller effects. The distortion force acting in Si8O12(C(CH3)3)8(+) is mainly localized on one Si-(tert-butyl) group, while in Si8O12Cl8(+) it is distributed over the oxygen atoms. The main distortion forces acting on the Si8O12 core arise from the coupling between the electronic state and the vibrational modes, identified as 9t2g + 1eg + 3a2u for the Si8O12(C(CH3)3)8(+) and 1eg + 2eg for Si8O12Cl8(+). PMID- 25831096 TI - Influence of poly-L-lactic acid scaffold's pore size on the proliferation and differentiation of dental pulp stem cells. AB - The aim of this study was to evaluate the influence of the poly-L-lactic acid (PLLA)-based scaffold's pore size on the proliferation and differentiation of dental pulp stem cells (DPSCs). The scaffolds were prepared in pulp chambers of 1 mm-thick tooth slices from third molars using salt crystals (150-250 um or 251 450 um) as porogen. DPSC (1x105 cells) were seeded in the scaffolds with different pore sizes, and cultured in 24-well plates. The cell proliferation was evaluated using the WST-1 assay after 3-21 days. Furthermore, RT-PCR was used to assess the differentiation of the DPSCs into odontoblasts, using markers of odontoblastic differentiation (DSPP, DSP-1 and MEPE). RNA from human odontoblasts was used as control. Cell proliferation rate was similar in both scaffolds except at the 14th day period, in which the cells seeded in the scaffolds with larger pores showed higher proliferation (p<0.05). After 21 days DPSCs seeded in both evaluated scaffolds were able of expressing odontoblastic markers DMP-1, DSPP and MEPE. In summary, both scaffolds tested in this study allowed the proliferation and differentiation of DPSCs into odontoblast-like cells. PMID- 25831097 TI - Antifungal susceptibility in vitro determined by the Etest(r) for Candida obtained from the oral cavity of irradiated and elderly individuals. AB - This study aimed to evaluate the in vitro antifungal susceptibility of Candida species of head-and-neck-irradiated patients (Group 1), non-institutionalized (Group 2) and institutionalized elders (Group 3) using Etest(r) methodology. Candida was isolated from saliva and presumptively identified by CHROMagar Candida(r), confirmed by morphological criteria, carbohydrate assimilation (API 20C AUX(r)) and genetic typing (OPE 18). The collection was made from 29, 34 and 29 individuals (Groups 1, 2 and 3, respectively) with 67 isolates. Etest(r) strips (ketoconazole, itraconazole, fluconazole, amphotericin B and flucytosine) on RPMI (Roswell Park Memorial Institute) agar, on duplicate, were used to evaluate susceptibility. ATTC (American Type Culture Collection) 10231 (Candida albicans) was used as quality control. Among the 67 isolates of Candida species, most were susceptible to azoles, flucytosine and amphotericin B. None of the isolates showed resistance and dose-dependent susceptibility to amphotericin B. There were nine strains resistant to itraconazole, six to fluconazole and two to ketoconazole and ten dose-dependent, mainly to flucytocine. The highest MIC (minimum inhibitory concentration) to C. albicans, C. tropicalis, C. parapsilosis was 2.671 MUg.mL-1, 8.104 MUg.mL-1, 4.429 MUg.mL-1, all for flucytosine. C. krusei and C. glabrata were associated with higher MIC for azoles and C. glabrata with higher MIC to flucytosine. In summary, susceptibility to all tested antifungal agents was evident. The isolates were more resistant to itraconazole and dose-dependent to flucytosine. A comparison of C. albicans in the three groups showed no outliers. Higher MIC was associated with C. krusei and C. glabrata. PMID- 25831098 TI - Different extracts of Zingiber officinale decrease Enterococcus faecalis infection in Galleria mellonella. AB - Dried, fresh and glycolic extracts of Zingiber officinale were obtained to evaluate the action against G. mellonella survival assay against Enterococcus faecalis infection. Eighty larvae were divided into: 1) E. faecalis suspension (control); 2) E. faecalis + fresh extract of Z. officinale (FEO); 3) E. faecalis + dried extract of Z. officinale (DEO); 4) E. faecalis + glycolic extract of Z. officinale (GEO); 5) Phosphate buffered saline (PBS). For control group, a 5 MUL inoculum of standardized suspension (107 cells/mL) of E. faecalis (ATCC 29212) was injected into the last left proleg of each larva. For the treatment groups, after E. faecalis inoculation, the extracts were also injected, but into the last right proleg. The larvae were stored at 37 degrees C and the number of dead larvae was recorded daily for 168 h (7 days) to analyze the survival curve. The larvae were considered dead when they did not show any movement after touching. E. faecalis infection led to the death of 85% of the larvae after 168 h. Notwithstanding, in treatment groups with association of extracts, there was an increase in the survival rates of 50% (GEO), 61% (FEO) and 66% (DEO) of the larvae. In all treatment groups, the larvae exhibited a survival increase with statistically significant difference in relation to control group (p=0.0029). There were no statistically significant differences among treatment groups with different extracts (p=0.3859). It may be concluded that the tested extracts showed antimicrobial activity against E. faecalis infection by increasing the survival of Galleria mellonella larvae. PMID- 25831099 TI - Use of traditional Indian plants in the inhibition of caries-causing bacteria- Streptococcus mutans. AB - The aim of the study was to comparatively evaluate the antibacterial activity of six Indian plant extracts and 0.2% chlorhexidine against clinical strains of Streptococcus mutans, which were isolated from the plaque samples of 45 pediatric patients. Six plant extracts were prepared in three different forms, namely aqueous extracts, organic solvent-based extracts and crude (raw) extracts. The antimicrobial sensitivity testing was done by agar well diffusion method. Antimicrobial activity of the extracts was determined by measuring the mean zones of inhibition (mm) produced against the bacterial isolates. Results showed that crude garlic extract exhibited greater antibacterial activity than chlorhexidine. Aqueous extract of amla and organic solvent-based extract of ginger showed the maximum antibacterial activity against S. mutans, whereas aqueous extract of tulsi and organic solvent based extract of amla showed the minimum antibacterial activity. This study suggests that plant extracts like garlic in crude form, amla as aqueous infusion and ginger as alcoholic tincture have potential for the control of S. mutans. These extracts can be used as an alternative remedy for dental caries prevention or in the form of mouthwash, which is safe and economical. PMID- 25831100 TI - Clinical evaluation of residual tetrasodium pyrophosphate released from two different anticalculus flosses. AB - The aim of this study was to compare the residual content of tetrasodium pyrophosphate released by two different anticalculus dental flosses (Reach PP(r)- entangled polypropylene floss and Reach NT(r)--texturized nylon) in the oral cavity. Ten healthy individuals (aged between 18 and 30 years) were enrolled in this randomized crossover clinical investigation. Participants received instructions on daily dental flossing and the interventions were randomly performed in 2 different groups (NT or PP) of five individuals each according to the dental flosses. Individuals were instructed to use each dental floss with a total of six slides on the two interproximal aspects of target teeth (3 slides on each interproximal aspect). A washout period of one week was used before start flossing interventions and after each type of dental floss to prevent any bias related to the exposure to any product that contained the active ingredient. Samples were collected by #35 sterilized absorbent paper points from interdental fluid after flossing and assessed by ion chromatography. The levels of residual tetrasodium pyrophosphate were evaluated by means of binomial generalized linear model proportions and canonical link function. Both dental flosses were effective in tetrasodium pyrophosphate release at therapeutic levels in the interdental gingival crevicular fluid for a period of up to 2 h after use. No significant differences were found between both groups (p>0.05). It may be concluded that both material composition and physical structure of the new dental floss did not affect the release or the maintenance of anticalculus agent at therapeutic levels for a period of up to 2 h after single use. PMID- 25831101 TI - Surface characteristics of reciprocating instruments before and after use--a SEM analysis. AB - The presence of debris, defects and deformations of endodontic reciprocating instruments before and after chemical-mechanical preparation (MCP) was analyzed using scanning electron microscopy (SEM). The following 26 instruments were divided into 2 groups: Waveone (n=13) and Reciproc (n=13) and examined by SEM (150 x magnification) prior to canal preparation at 2 and 4 mm from the tip. The instruments were used in the preparation of mesial root canals of 26 extracted human permanent mandibular molars. The instruments were then washed in ultrasonic bath and subjected to new microscopic analysis of debris and deformation by a score that used the presence or absence of irregular edges, grooves, microcavities and burrs as criteria. After the SEM analysis and with the scores of the examiners, the collected data were subjected to descriptive statistical analysis using the Kruskall-Walis and Mann Whitney test at a 5% significance level. All instruments examined presented debris before and after use. A statistically significant difference was found for defects and deformation between the groups (p<0.05). The presence of defects and deformities was higher in the WaveOne instruments, and Reciproc instruments presented a lower rate. PMID- 25831102 TI - Influence of cariogenic challenge on bond strength stability of dentin. AB - The aim of this study was to evaluate the effect of cariogenic challenge on the microtensile bond strength values (MUTBS) of dentin pre-treated with chlorhexidine digluconate (CHX) or sodium hypochlorite (NaOCl). Thirty-six sound molars were selected and randomly assigned to 3 dentin pre-treatments (distilled water - control, 2% CHX and 10% NaOCl) and 4 aging protocols (24h control, biofilm without cariogenic challenge, biofilm with cariogenic challenge, and 18 month water storage). The same etch-and-rinse adhesive system and composite resin were used for all groups (n=30 beams). For the biofilm groups, dental microcosm biofilms originated from saliva of a healthy donor were grown on the samples with a defined medium enriched with mucin, with or without 10% sucrose, according to the group. After the experimental period, the microtensile test was performed. Data were analyzed with ANOVA followed by Tukey test (p<0.05). The pre-treatment did not influence MUTBS for all aging conditions (p=0.188), but the type of aging affected the bond strength (p<0.001). Cariogenic challenge and water storage aging affected the bond stability resulting in a decrease of the MUTBS, but the pre-treatments did not influence the MUTBS. PMID- 25831103 TI - Demineralization and hydrogen peroxide penetration in teeth with incipient lesions. AB - The aim of this study was to evaluate the demineralization and hydrogen peroxide (HP) penetration in teeth with incipient lesions submitted to bleaching treatment. For analysis of HP penetration, sound and demineralized enamel/dentin discs were placed in artificial pulp chambers containing acetate buffer solution. After bleaching treatment, this solution was subjected for analysis of optical density by spectrophotometry and the disc surfaces were analyzed with scanning electron microscopy (SEM) and polarized light microscopy (PLM). The remaining discs were subjected for cross-sectional hardness analysis at different depths. Data were analyzed by repeated measures ANOVA and PLSD Fisher test (a=0.05). It was observed that previously demineralized teeth showed greater HP penetration (p<0.05). The bleaching treatment caused changes to a depth of 20 um in sound enamel and up to 90 um in demineralized enamel. SEM and PLM images revealed that the bleaching treatment caused superficial changes that were considerably more accentuated in previously demineralized teeth. It may be concluded that the enamel mineralization level influences HP penetration and the bleaching agent contributed to increase the demineralization depth. PMID- 25831104 TI - Does the moment of fiber post cutting influence on the retention to root dentin? AB - Despite several advantages associated with pre-fabricated glass-fiber posts, the coronal portion of these posts must be cut to allow their use in various clinical situations. However, cutting the cemented post can generate stress on the bonding interface and affect the bond strength. The aim of this study was to investigate the effect the of fiber post cutting on the bond strength of root canals. Sixty bovine incisor roots were included in resin cylinders with simulated periodontal ligaments. Glass-fiber posts were luted using regular resin cement RelyX ARC (3M ESPE) or self-adhesive cement RelyX Unicem (3M ESPE). The posts were cut prior to cementation, immediately after luting or after building up the core (n=10). After storage for 24 h, the samples were cut and subject to push-out testing using a mechanical testing machine (EMIC DL 2000). Data were analyzed using two-way ANOVA (resin cement x moment of post cutting) and Tukey's post hoc test (alpha=0.05). The moment of fiber post cutting did not affect the bond strength when Unicem was used. However, the bond strength was reduced when ARC was used and when the post was cut immediately. In conclusion, the moment of fiber post cutting may affect the retention of root canal posts when a regular resin cement is used. PMID- 25831105 TI - Effect of ceramic thickness and composite bases on stress distribution of inlays- a finite element analysis. AB - The purpose of this study was to determine the effect of cavity depth, ceramic thickness, and resin bases with different elastic modulus on von Mises stress patterns of ceramic inlays. Tridimensional geometric models were developed with SolidWorks image software. The differences between the models were: depth of pulpal wall, ceramic thickness, and presence of composite bases with different thickness and elastic modulus. The geometric models were constrained at the proximal surfaces and base of maxillary bone. A load of 100 N was applied. The stress distribution pattern was analyzed with von Mises stress diagrams. The maximum von Mises stress values ranged from 176 MPa to 263 MPa and varied among the 3D-models. The highest von Mises stress value was found on models with 1-mm thick composite resin base and 1-mm-thick ceramic inlay. Intermediate values (249 250 MPa) occurred on models with 2-mm-thick composite resin base and 1-mm-thick ceramic inlay and 1-mm-thick composite resin base and 2-mm-thick ceramic inlay. The lowest values were observed on models restored exclusively with ceramic inlay (176 MPa to 182 MPa). It was found that thicker inlays distribute stress more favorably and bases with low elastic modulus increase stress concentrations on the internal surface of the ceramic inlay. The increase of ceramic thickness tends to present more favorable stress distribution, especially when bonded directly onto the cavity without the use of supporting materials. When the use of a composite base is required, composite resin with high elastic modulus and reduced thickness should be preferred. PMID- 25831106 TI - Surface treatments for repair of feldspathic, leucite - and lithium disilicate reinforced glass ceramics using composite resin. AB - The aim of this study was to evaluate the efficacy of different surface conditioning methods on the microtensile bond strength of a restorative composite repair in three types of dental ceramics: lithium disilicate-reinforced, leucite reinforced and feldspathic. Twelve blocks were sintered for each type of ceramic (n=3) and stored for 3 months in distilled water at 37 degrees C. The bonding surface of ceramics was abraded with 600-grit SiC paper. Surface treatments for each ceramic were: GC (control) - none; GDB - diamond bur #30 um; GHF - hydrofluoric acid (10%); GT- tribochemical silica coating (45-MUm size particles). Treatments were followed by cleaning with phosphoric acid 37% for 20 s + silane + adhesive. The composite resin was used as restorative material. After repair, samples were subjected to thermocycled ageing (10,000 cycles between 5 degrees C and 55 degrees C for 30 s). Thereafter, the samples were sectioned into 1.0 mm2 sticks and tested for microtensile bond strength with 0.5 mm/min crosshead speed. Data were compared by two-way ANOVA and Tukey's test (alpha=0.05). The superficial wear with diamond bur proved to be suitable for feldspathic porcelain and for leucite-reinforced glass ceramic while hydrofluoric acid-etching is indicated for repairs in lithium disilicate-reinforced ceramic; tribochemical silica coating is applicable to leucite-reinforced ceramic. Predominance of adhesive failures was observed (>85% in all groups). In conclusion, the success of surface treatments depends on the type of ceramic to be repaired. PMID- 25831107 TI - Compressive resistance of abutments with different diameters and transmucosal heights in Morse-taper implants. AB - The aim of this study was to evaluate the compressive resistance under oblique loads of abutments with two different diameters and transmucosal heights used for cement-retained implant-supported prostheses in Morse-taper implants. Forty Morse taper implants were divided into four groups with different abutment sizes for cement-retained prostheses in order to perform the compressive test. The groups were divided by abutment diameter and transmucosal height as follows: Group 1: 4.5 x 2.5 mm; Group 2: 4.5 x 3.5 mm; Group 3: 3.3 x 2.5 mm; and Group 4: 3.3 x 3.5 mm. An oblique compressive loading test was performed on each sample located in a platform at 30 degrees using a universal testing machine with a load cell of 1,000 kgf and 0.5 mm/min speed until achieving the deformation of abutment's neck. The compressive resistance and its mechanical behavior were recorded for each group and the data were analyzed using ANOVA, the Shapiro-Wilk and Scheffe tests. In addition, the detailed damage of all samples was recorded with a conventional camera linked to the endoscopic equipment. Significant differences were observed among the groups, except between Groups 2 and 3 (p>0.005). All the abutments showed permanent deformations in the upper region and at the transmucosal portion, but the threads of the screws were intact. Fractures were only identified in Groups 3 and 4. Stronger mechanical behavior and compressive resistance was observed in the abutments with 4.5 mm diameter and 2.5 mm transmucosal height. PMID- 25831108 TI - Cytotoxicity of universal, self-etching and etch-and-rinse adhesive systems according to the polymerization time. AB - This in vitro study evaluated in fibroblast cultures the direct cytotoxicity of universal, self-etching and etch-and-rinse adhesive systems according to the polymerization time. Paper discs were impregnated with adhesives and light-cured (10, 20 or 40 s). The discs were then immersed in culture medium to obtain the eluates for the experimental groups (A1-Single Bond 2; A2-Scotchbond Multi purpose; A3-Clearfil SE Bond; A4 Scotchbond Universal). As a negative control, paper discs were immersed in culture medium only. After 24 h or 7 days, the eluate obtained was applied on fibroblast culture. Cell viability, cell morphology, membrane damage and the presence of residual monomers were evaluated by MTT assay, SEM, flow cytometry and high-performance liquid chromatography (HPLC), respectively. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests (?=0.05). All adhesive systems significantly reduced 33-51% cell metabolism when compared to the negative control, regardless of polymerization time, storage period and adhesive system. Moreover, the adhesives caused intense morphological alterations and cell membrane damage. Toxicity was directly related to the presence of residual monomers in the eluates. Residual monomers and additional components are capable of reducing mitochondrial activity, causing morphological alterations and disruption of the cell membrane in fibroblasts, regardless of the polymerization time. This study highlights that despite the more complex composition of the universal adhesive system, its biological response was not more toxic when compared with other systems, even when the shortest polymerization time was tested in cell culture. PMID- 25831110 TI - Effects of coffee intake and intraperitoneal caffeine on bone repair process--a histologic and histometric study. AB - Studies have suggested that caffeine acts on bone promoting an increase of calcium excretion, inhibition of osteoblast proliferation and delay in tissue repair process, raising the risk of fractures, osteoporosis, periodontal disease and affecting the success of bone reconstructive procedures. The aim of this study was to analyze histomorphometrically the process of alveolar bone healing after tooth extraction in rats subjected to daily intake of boiled coffee or intraperitoneal administration of caffeine. Forty-five male rats were divided according to the treatment in Control group (C); Coffee group (CO) - treated with coffee since birth; and Caffeine (CAF) - intraperitoneal injection of aqueous solution of caffeine 1.5% (0.2 mL/100g body weight) for 30 days. When weighing between 250-300 g they were anesthetized, subjected to extraction of the maxillary right incisor, and euthanized 7, 21 and 42 days after surgery for histological assessments of bone volume and the quality of formed bone in the dental socket. The qualitative results demonstrated larger amounts of blood clot and immature bone in animals under treatment of pure caffeine compared to coffee and control. Histometric analysis revealed that coffee treatment led to a 40% drop in bone formation, and caffeine a 60% drop in comparison to control animals (ANOVA p<=0.01). It was concluded that both the daily ingestion of coffee and the intraperitoneal administration of caffeine in rats delayed the alveolar bone reparative process after tooth extraction, and this effect was more aggressive when pure caffeine was used. PMID- 25831109 TI - Serum adipokine levels and their relationship with fatty acids in patients with chronic periodontitis. AB - Adipokines are present in inflammatory processes and may be directly related to periodontal disease. Moreover, their activities may be regulated by fatty acids. The goal of this study was to quantify the concentrations of the main adipokines, leptin, adiponectin and resistin, and the docosahexaenoic (DHA), docosapentaenoic (DPA), eicosapentaenoic (EPA) and arachidonic (AA) fatty acids, in patients with generalized chronic periodontitis. As a secondary objective, the ratios of these substances in the blood of these patients were evaluated. The study included 15 systemically healthy patients with generalized chronic periodontitis (test group) and 15 patients with gingivitis (control group). Medical and periodontal parameters and blood samples were collected. Serum concentrations of fatty acids were analyzed by gas chromatography and adipokines by multiplex bead immunoassay. There was no significant difference in adipokines between groups. However, there was a tendency for lower values of adiponectin in periodontitis patients. Regarding the fatty acids, they were significantly higher in the test group compared with controls. The res/DHA, res/AA, adipon/DHA, adipon/AA and adipon/DPA ratios were significantly lower in the test group. There was no significant correlation between adipokines and clinical parameters and between adipokines and fatty acids levels. It was concluded that generalized chronic periodontitis patients showed significantly higher levels of fatty acids in comparison to gingivitis; adiponectin revealed a trend to lower values in the periodontitis group, even after Ancova correction. The ratios suggest a minor proportion of adiponectin and resistin in relation to the fatty acids in patients with generalized chronic periodontitis. PMID- 25831111 TI - Is the masticatory function changed in patients with temporomandibular disorder? AB - Patients with temporomandibular disorders (TMD) often complain and have limitation in masticatory function, which can be affected by a complex interaction of factors. The aim of this study was analyze the masticatory function in patients with TMD using surface electromyography (EMG) and masticatory efficiency (ME). Twenty-seven patients with TMD and 25 considered control (n), aged between 18 and 60 years, paired by age and gender, were evaluated according to RDC/TMD. In both groups were performed: EMG with chewing gum, clinical evaluation of habitual chewing with stuffed cookie (CE) (number of chewing strokes and time) and analysis of ME with fuchsin beads. Nonparametric statistical analyses were used (Mann-Whitney) for comparisons between groups, with 5% significance level. For all variables, the TMD group showed higher values than the control, with statistical significance for ME (p<0.0001), number of chewing strokes (p=0.04), chewing time (p=0.009), right masseter EMG activity (p=0.05), left masseter (p=0.005), right anterior temporal (p=0.05) and left anterior temporal (p=0.001). The conclusion is that patients with TMD showed changed chewing pattern, but without impairment of masticatory function. PMID- 25831112 TI - Accuracy of two cephalometric analyses in the treatment of patients with skeletal class III malocclusion. AB - The aim of the present study was to compare the treatment plan outlined from the diagnosis obtained by two different cephalometric analyses with the clinical decision made for surgical treatment of patients with skeletal Class III malocclusion. For this purpose, 82 skeletal Class III patients were evaluated, divided into three groups according to the surgical procedure performed for dentofacial deformity correction. Their preoperative cephalometric radiographs were submitted to McNamara and Steiner cephalometric analyses. The association of variables was evaluated by Kappa correlation (alpha=5%). The agreement between indication of surgical procedures performed based on clinical decision and surgical treatment indicated based on the evaluation of McNamara and Steiner cephalometric analyses were not significant (p=0.609 and p=0.544, respectively). McNamara and Steiner analyses showed reasonable agreement with each other as to the diagnosis, but did not agree with the clinical decision to treat skeletal CIII patients. Both tests were equally inaccurate in the indication of the surgical treatment. PMID- 25831113 TI - Use of a titanium mesh "shelter" combined with the soft tissue matrix expansion (tent pole) grafting in the reconstruction of a severely resorbed edentulous mandible. Technical note. AB - Patients wearing complete dentures for a long time usually exhibit lack of bone and keratinized mucosa in the bearing area due to bone resorption. The patients suffering from this phenomenon usually have unstable and non-retentive complete denture, which result in constant trauma to the mucosa, pain, functional limitations and worsening of facial esthetics. An innovative technique has been described in which a novel surgical approach using osseointegrated dental implants as "tent poles" was applied concomitant with particulate autogenous bone graft. The authors claim that the control and maintenance of the surgically expanded soft tissue volume should prevent graft resorption in the long term. Nevertheless, resorption of the bone graft is usually more significant where the bone mass is poorer, in the mandibular body. This paper describes a case of severely resorbed edentulous mandible in which the "tent pole" technique was applied with some modifications. Use of the titanium mesh "shelters" and two additional implants was effective in "protecting" the bone graft in the posterior portion of the mandibular body increasing bone mass volume in this area. Furthermore, we believe that this kind of graft "protection" on the whole residual alveolar ridge can increase the width of bone mass gain optimizing the "tent pole" technique. PMID- 25831114 TI - Influence of inner circular sealing area impression method on the retention of complete dentures. AB - The aims of the present study were to describe an impression method of "inner circular sealing area" and to evaluate the effect of the method on retention, aesthetics and comfort of complete dentures, which lack labial base for patients with maxillary protrusions. Three patients were subjected to the experiment, and two sets of complete maxillary dentures were made for each patient; the first set was made without labial base via an inner circular sealing area method (experimental group) and the second had an intact base that was made with conventional methods (control group). Retention force tests were implemented with a tensile strength assessment device to assess the retention and a visual analogue scale (VAS) was used to evaluate the comfort between the two groups. Results showed larger retention force, better aesthetics and more comfort in the experimental group. The improved two-step impression method formed an inner circular sealing area that prevented damage to the peripheral border seal effect of the denture caused by incomplete bases and obtained better denture retention. PMID- 25831115 TI - Uncommon oral cleft in Wolf-Hirschhorn syndrome. AB - Wolf-Hirschhorn syndrome (WHS) is a syndrome with craniofacial and systemic abnormalities, which is related to 4p deletion. A 3-month old girl with an undiagnosed syndrome was referred for evaluation of the cleft lip and palate. Hypotonia, short stature, cardiac malformation, hypertrophied clitoris, and atypical thumb of both hands was observed. Microcephaly, low-set ear, prominent glabella, downslanting palpebral fissures, a characteristic "Greek warrior helmet" appearance, micrognathia, ears with pits/tags and bilateral incomplete cleft lip apart from incomplete cleft palate were observed as craniofacial findings. With clinical diagnosis of WHS, blood was subjected to karyotyping, which showed a 4p15.2 deletion, consistent with the condition. Here is reported the case of this WHS patient with an uncommon oral cleft extending the phenotypic spectrum of the disorder. The child was referred to a multidisciplinary team to reparative surgery of the cleft lip and palate. The patient is on regular medical follow-up and will be further assisted by dentists, physical therapists, occupational therapists and psychologists. The genotype-phenotype correlation of the affected patient with previous WSH syndrome reports is described. PMID- 25831116 TI - Ligand-Dependent Nanoparticle Clustering within Lipid Membranes Induced by Surrounding Medium. AB - The interactions between hydrophobic or semihydrophobic gold and silver nanoparticles (NPs) and a dimyristoylphosphatidylcholine (DMPC) bilayer as a model cell membrane in two ionic solutions result in the structural reorganization within the bilayer manifested as locally increased nanomechanical compaction in the vicinity of NP clusters as well as changed overall thermotropic properties. The effects of NP surface charge and hydrophobicity were examined using AFM imaging, force spectroscopy and IR spectroscopy. The NP clustering occurred during hydration process of dry films containing both the DMPC molecules and the NPs by the mechanism in which the number of bilayer deformations was reduced by NP clustering. The force spectroscopy showed increased bilayer density around (semi)hydrophobic NP clusters and thus locally increased lateral compaction of the bilayer. The strengthening effect was observed for both the silver and the gold NPs in a high ionic strength solution such as seawater, while it was absent under physiological conditions. The local lipid rearrangement induces the long-range lipid reorganization resulting in the bilayer phase transition shifting toward lower or higher temperatures depending on the solution ionic strength (at the most by -1.0 degrees C in phosphate buffered saline and at the most by +0.5 degrees C in seawater). PMID- 25831117 TI - [How are thyroid nodules diagnosed?]. AB - The prevalence of thyroid nodules in Germany - depending on the diagnostic technique used - ranges from 20 to 50 %. The overall incidence increases, partly because by the use of modern ultrasound modalities ever smaller morphological changes are detected. Most nodules are asymptomatic - and therefore often incidental findings. In this article you will learn how to identify and differentiate thyroid nodules using different diagnostic tests. PMID- 25831118 TI - [Therapy of thyroid nodules]. AB - Thyroid nodules are frequent in Germany. In about every fourth person thyroid nodules can be detected. Most of them are benign. Signs for malignancy are hypoechogenicity, microcalcifications, an unregular margin and increased blood perfusion. There is no strict indication for the treatment of benign nodules. In most cases iodine supplementation is sufficient. A combination therapy with levothyroxine and iodine is more efficient for the treatment of larger nodules. Subclinical hyperthyroidism caused by an adenoma does not necessarily need to be treated, whereas manifest hyperthyroidism needs to treated in most cases with antithyroid drug therapy. Radioiodine therapy is the classical indication for the treatment of unifocal autonomous adenomas. A largely increased thyroid gland with and without uni- / multifocal adenomas are often operated. PMID- 25831119 TI - Antimicrobial activity of coriander oil and its effectiveness as food preservative. AB - ABTRACT Foodborne illness represents a major economic burden worldwide and a serious public health threat, with around 48 million people affected and 3,000 death each year only in the USA. One of the possible strategies to reduce foodborne infections is the development of effective preservation strategies capable of eradicating microbial contamination of foods. Over the last years, new challenges for the food industry have arisen such as the increase of antimicrobial resistance of foodborne pathogens to common preservatives and consumers demand for naturally based products. In order to overcome this, new approaches using natural or bio-based products as food preservatives need to be investigated. Coriander (Coriandrum sativum L.) is a well-known herb widely used as spice, or in folk medicine, and in the pharmacy and food industries. Coriander seed oil is the world's second most relevant essential oil, exhibiting antimicrobial activity against Gram-positive and Gram-negative bacteria, some yeasts, dermatophytes and filamentous fungi. This review highlights coriander oil antimicrobial activity and possible mechanisms of action in microbial cells and discusses the ability of coriander oil usage as a food preservative, pointing out possible paths for the successful evolution for these strategies towards a successful development of a food preservation strategy using coriander oil. PMID- 25831121 TI - A sunken ship of the desert at the river Danube in Tulln, Austria. AB - Rescue excavations recovered a skeleton that resurrect the contemporary dramatic history of Austria in the 17th century as troops besieged Vienna in the second Osmanic-Habsburg war. Unique for Central Europe is the evidence of a completely preserved camel skeleton uncovered in a large refuse pit. The male individual of slender stature indicates a few but characteristic pathological changes revealing not a beast of burden but probably a valuable riding animal. Anatomical and morphometrical analyses suggest a hybrid confirmed by the ancient DNA analyses resulting in the presence of a dromedary in the maternal and a Bactrian camel in the paternal line. PMID- 25831122 TI - Rumor diffusion and convergence during the 3.11 earthquake: a twitter case study. AB - We focus on Internet rumors and present an empirical analysis and simulation results of their diffusion and convergence during emergencies. In particular, we study one rumor that appeared in the immediate aftermath of the Great East Japan Earthquake on March 11, 2011, which later turned out to be misinformation. By investigating whole Japanese tweets that were sent one week after the quake, we show that one correction tweet, which originated from a city hall account, diffused enormously. We also demonstrate a stochastic agent-based model, which is inspired by contagion model of epidemics SIR, can reproduce observed rumor dynamics. Our model can estimate the rumor infection rate as well as the number of people who still believe in the rumor that cannot be observed directly. For applications, rumor diffusion sizes can be estimated in various scenarios by combining our model with the real data. PMID- 25831124 TI - Determining Chances for Survival in Intrahepatic Cholangiocarcinoma. PMID- 25831123 TI - Cyclin-dependent kinase five mediates activation of lung xanthine oxidoreductase in response to hypoxia. AB - BACKGROUND: Xanthine oxidoreductase (XOR) is involved in oxidative metabolism of purines and is a source of reactive oxygen species (ROS). As such, XOR has been implicated in oxidant-mediated injury in multiple cardiopulmonary diseases. XOR enzyme activity is regulated, in part, via a phosphorylation-dependent, post translational mechanism, although the kinase(s) responsible for such hyperactivation are unknown. METHODS AND RESULTS: Using an in silico approach, we identified a cyclin-dependent kinase 5 (CDK5) consensus motif adjacent to the XOR flavin adenine dinucleotide (FAD) binding domain. CDK5 is a proline-directed serine/threonine kinase historically linked to neural development and injury. We tested the hypothesis that CDK5 and its activators are mediators of hypoxia induced hyperactivation of XOR in pulmonary microvascular endothelial cells (EC) and the intact murine lung. Using complementary molecular and pharmacologic approaches, we demonstrated that hypoxia significantly increased CDK5 activity in EC. This was coincident with increased expression of the CDK5 activators, cyclin dependent kinase 5 activator 1 (CDK5r1 or p35/p25), and decreased expression of the CDK5 inhibitory peptide, p10. Expression of p35/p25 was necessary for XOR hyperactivation. Further, CDK5 physically associated with XOR and was necessary and sufficient for XOR phosphorylation and hyperactivation both in vitro and in vivo. XOR hyperactivation required the target threonine (T222) within the CDK5 consensus motif. CONCLUSIONS AND SIGNIFICANCE: These results indicate that p35/CDK5-mediated phosphorylation of T222 is required for hypoxia-induced XOR hyperactivation in the lung. Recognizing the contribution of XOR to oxidative injury in cardiopulmonary disease, these observations identify p35/CDK5 as novel regulators of XOR and potential modifiers of ROS-mediated injury. PMID- 25831125 TI - Systems Medicine 2.0: potential benefits of combining electronic health care records with systems science models. AB - BACKGROUND: The global burden of disease is increasingly dominated by non communicable diseases.These diseases are less amenable to curative and preventative interventions than communicable disease. This presents a challenge to medical practice and medical research, both of which are experiencing diminishing returns from increasing investment. OBJECTIVE: Our aim was to (1) review how medical knowledge is generated, and its limitations, (2) assess the potential for emerging technologies and ideas to improve medical research, and (3) suggest solutions and recommendations to increase medical research efficiency on non-communicable diseases. METHODS: We undertook an unsystematic review of peer-reviewed literature and technology websites. RESULTS: Our review generated the following conclusions and recommendations. (1) Medical knowledge continues to be generated in a reductionist paradigm. This oversimplifies our models of disease, rendering them ineffective to sufficiently understand the complex nature of non-communicable diseases. (2) Some of these failings may be overcome by adopting a "Systems Medicine" paradigm, where the human body is modeled as a complex adaptive system. That is, a system with multiple components and levels interacting in complex ways, wherein disease emerges from slow changes to the system set-up. Pursuing systems medicine research will require larger datasets. (3) Increased data sharing between researchers, patients, and clinicians could provide this unmet need for data. The recent emergence of electronic health care records (EHR) could potentially facilitate this in real-time and at a global level. (4) Efforts should continue to aggregate anonymous EHR data into large interoperable data silos and release this to researchers. However, international collaboration, data linkage, and obtaining additional information from patients will remain challenging. (5) Efforts should also continue towards "Medicine 2.0". Patients should be given access to their personal EHR data. Subsequently, online communities can give researchers the opportunity to ask patients for direct access to the patient's EHR data and request additional study-specific information. However, selection bias towards patients who use Web 2.0 technology may be difficult to overcome. CONCLUSIONS: Systems medicine, when combined with large-scale data sharing, has the potential to raise our understanding of non communicable diseases, foster personalized medicine, and make substantial progress towards halting, curing, and preventing non-communicable diseases. Large scale data amalgamation remains a core challenge and needs to be supported. A synthesis of "Medicine 2.0" and "Systems Science" concepts into "Systems Medicine 2.0" could take decades to materialize but holds much promise. PMID- 25831126 TI - Changes to serum sample tube and processing methodology does not cause Intra Individual [corrected] variation in automated whole serum N-glycan profiling in health and disease. AB - INTRODUCTION: Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system. METHODS: 25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual. RESULTS: There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status. CONCLUSIONS: The three different serum sample tubes processed using the described methods cause minimal inter-individual variation in serum whole N-glycan profile when processed using an automated workstream. This has important implications for N-glycan biomarker discovery studies using different serum processing standard operating procedures. PMID- 25831127 TI - Optimization of anticancer exopolysaccharide production from probiotic Lactobacillus acidophilus by response surface methodology. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the Western world. Recently, much attention has been focused on decreasing the risk of CRC by consuming probiotics. In the present study, exopolysaccharide (EPS) extracted from Lactobacillus acidophilus was found to inhibit the growth of CaCo2 colon cancer cell line in a dose-dependent manner. The experiment was performed in both normoxic and hypoxic conditions, and EPS was found to reduce the survival of CaCo2 cell line in both the conditions. Quantitative polymerase chain reaction (qPCR) studies demonstrated that EPS treatment upregulated the expression of peroxisome proliferator activator receptor-gamma (PPAR-gamma) in both normoxia and hypoxia conditions, whereas it upregulated the expression of erythropoietin (EPO) in the normoxic condition, but there was no significant expression under hypoxic conditions. Hence, the EPS production was optimized by Plackett-Burman design followed by central composite rotatory design. The optimized production of EPS at 24 hr was found to be 400 mg/L. During batch cultivation the production peaked at 21 hr, resulting in an EPS concentration of 597 mg/L. PMID- 25831128 TI - Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1. AB - Prokineticins are angiogenic hormones that activate two G protein-coupled receptors: PKR1 and PKR2. PKR1 has emerged as a critical mediator of cardiovascular homeostasis and cardioprotection. Identification of non-peptide PKR1 agonists that contribute to myocardial repair and collateral vessel growth hold promises for treatment of heart diseases. Through a combination of in silico studies, medicinal chemistry, and pharmacological profiling approaches, we designed, synthesized, and characterized the first PKR1 agonists, demonstrating their cardioprotective activity against myocardial infarction (MI) in mice. Based on high throughput docking protocol, 250,000 compounds were computationally screened for putative PKR1 agonistic activity, using a homology model, and 10 virtual hits were pharmacologically evaluated. One hit internalizes PKR1, increases calcium release and activates ERK and Akt kinases. Among the 30 derivatives of the hit compound, the most potent derivative, IS20, was confirmed for its selectivity and specificity through genetic gain- and loss-of-function of PKR1. Importantly, IS20 prevented cardiac lesion formation and improved cardiac function after MI in mice, promoting proliferation of cardiac progenitor cells and neovasculogenesis. The preclinical investigation of the first PKR1 agonists provides a novel approach to promote cardiac neovasculogenesis after MI. PMID- 25831129 TI - Plastic accumulation in the Mediterranean sea. AB - Concentrations of floating plastic were measured throughout the Mediterranean Sea to assess whether this basin can be regarded as a great accumulation region of plastic debris. We found that the average density of plastic (1 item per 4 m2), as well as its frequency of occurrence (100% of the sites sampled), are comparable to the accumulation zones described for the five subtropical ocean gyres. Plastic debris in the Mediterranean surface waters was dominated by millimeter-sized fragments, but showed a higher proportion of large plastic objects than that present in oceanic gyres, reflecting the closer connection with pollution sources. The accumulation of floating plastic in the Mediterranean Sea (between 1,000 and 3,000 tons) is likely related to the high human pressure together with the hydrodynamics of this semi-enclosed basin, with outflow mainly occurring through a deep water layer. Given the biological richness and concentration of economic activities in the Mediterranean Sea, the affects of plastic pollution on marine and human life are expected to be particularly frequent in this plastic accumulation region. PMID- 25831130 TI - Adding vitamin E-TPGS to the formulation of Genexol-PM: specially mixed micelles improve drug-loading ability and cytotoxicity against multidrug-resistant tumors significantly. AB - Genexol-PM, produced by Samyang Company (Korea) is an excellent preparation of paclitaxel (PTX) for clinical cancer treatment. However, it cannot resolve the issue of multidrug resistance (MDR)-a significant problem in the administration of PTX to cancer patients. To increase the efficacy of Genexol-PM against MDR tumors, a mixed micelle capable of serving as a vehicle for PTX was developed, and two substances were chosen as carrier materials: 1) Polyethylene glycol polylactic acid (PEG-PLA), the original vehicle of Genexol-PM. 2) Vitamin E-TPGS, an inhibitor of P-glycoprotein (P-gp). P-gp has been proven to be the main cause of MDR. In vitro evaluation indicated that the mixed micelle was an ideal PTX delivery system for the treatment of MDR tumors; the mixed micelle also showed a significantly better drug-loading coefficient than Genexol-PM. PMID- 25831131 TI - Effects of nitrogen stress on the photosynthetic CO2 assimilation, chlorophyll fluorescence, and sugar-nitrogen ratio in corn. AB - A field experiment was conducted using three corn cultivars (Jingyu7, Nongda80, and Tangyu10) and three nitrogen (N) application rates (0, 75, and 150 kg N ha( 1)). The objectives of this study were to investigate the responses of photosynthetic CO2 assimilation (Ph), the maximum quantum yield of photosystem II (Fv/Fm), leaf dry weight (LDW), leaf nitrogen concentration (LNC), leaf sugar concentration (LSC), and the sugar-to-nitrogen concentration ratio (S/N) to N levels in three different field-grown corn cultivars on three sampling dates. The results showed that the LDW, Fv/Fm, Ph, LNC, and LSC increased with increasing N levels, and the variation patterns of Fv/Fm, Ph, and LNC were "low-high-low". In contrast, S/N decreased with increasing N levels, and its variation pattern was "high-low-high". The values of LDW, Fv/Fm, Ph, LNC, LSC, and S/N were greatest under high N conditions, followed by medium N conditions, and finally low N conditions. Significant interactions occurred between Ph, Fv/Fm, LNC, LSC, LDW, and S/N, with the exception of the interaction between LSC and S/N and between LSC and LDW. The correlation coefficients between Ph and S/N and between Fv/Fm and S/N were -0.714 and -0.798, respectively. PMID- 25831132 TI - Cannabinoid receptor 1 antagonism in hepatocellular carcinoma: killing two birds with one stone. PMID- 25831133 TI - Integrated medical-psychiatric outpatient care in functional gastrointestinal disorders improves outcome: a pilot study. AB - BACKGROUND AND OBJECTIVES: Functional gastrointestinal disorders have a multifactorial etiology, including somatic and psychosocial factors. We provide multidisciplinary outpatient consultations by a gastroenterologist and a psychiatrist using an integrated approach toward somatic and psychosocial factors in complex functional gastrointestinal disorders. The aim of this study was to determine the efficacy of this approach assessing gastrointestinal and psychiatric symptoms and quality of life. METHODS: All patients with complex functional gastrointestinal disorders visiting for consultation were included and treated with antidepressants, psychotherapy, or both, or given advice for treatment in their own region. Questionnaires testing gastrointestinal and psychiatric symptoms, and quality of life at first visit and after 6 and 12 months were completed. RESULTS: A total of 124 patients were included (70% women, mean age 48 years): 57% were diagnosed with irritable bowel syndrome and about 80% had a psychiatric diagnosis (50% anxiety disorder, 20% mood disorder). Of the patients, 57% were treated with antidepressants and psychotherapy, 6% with psychotherapy alone, and 38% received advice for treatment in their own region. After 1 year, patients showed significant improvement in all questionnaires, with the exception of those testing gastrointestinal symptoms, although there were significant improvements in these at 6 months. CONCLUSION: This is the first prospective study on the efficacy of an integrated medical-psychiatric outpatient care model in patients with complex functional gastrointestinal disorders, showing significant improvement in gastrointestinal and psychiatric symptoms as well as quality of life after 6 months. With the exception of improvement in gastrointestinal symptoms, improvement persisted at the 1-year follow-up. This indicates that longer follow-up focusing on gastrointestinal symptoms may be needed. PMID- 25831134 TI - Consumption of vegetables and fruit and the risk of inflammatory bowel disease: a meta-analysis. AB - To date, associations between consumption of vegetables and fruit and the risk of inflammatory bowel disease have been a controversial subject. Therefore, we carried out a meta-analysis to evaluate the associations. A comprehensive search was performed in PubMed, Embase, Web of Science, and the China National Knowledge Infrastructure to identify all relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random-effects or fixed-effects models were calculated. Publication bias was estimated using Egger's test and the funnel plot. A total of 14 case-control studies were included in this meta-analysis. On the basis of the highest versus the lowest analysis, consumption of vegetables was associated inversely with the risk of ulcerative colitis (UC) (OR=0.71, 95% CI 0.58-0.88, n=9 studies), but not with Crohn's disease (CD) (OR=0.66, 95% CI 0.40-1.09, n=8 studies). Higher consumption of fruit was associated inversely with the risk of UC (OR=0.69, 95% CI 0.49-0.96, n=8 studies) and CD (OR=0.57, 95% CI 0.44-0.74, n=10 studies). For intake of vegetables and the risk of CD, subgroup analysis showed a significant association for studies carried out in Europe (OR=0.36, 95% CI 0.23-0.57), but not in Asia (OR=1.00, 95% CI 0.50-2.03). No significant publication bias was found for the analysis of intake of vegetables and the risk of UC, intake of fruit and the risk of UC, and intake of vegetables and the risk of CD. This meta-analysis indicates that consumption of vegetables and fruit might be associated inversely with the risk of UC and CD, and the results need to be further confirmed. PMID- 25831135 TI - Rates of cirrhosis and hepatocellular carcinoma in chronic hepatitis B and the role of surveillance: a 10-year follow-up of 673 patients. AB - BACKGROUND AND OBJECTIVES: Development of cirrhosis and hepatocellular carcinoma (HCC) are critical milestones in the natural history of chronic hepatitis B virus (HBV) infection. There are no prospective data on the risk of these critical milestones in HBV patients in Singapore. The efficacy and justification of HCC surveillance is determined by the rate of HCC development. Our study aims to determine the rates of cirrhosis and HCC in HBV patients in Singapore and hence the appropriateness of HCC surveillance. MATERIALS AND METHODS: A total of 673 HBV patients were enrolled between March 2003 and March 2004 and followed up for 10 years with regular surveillance for HCC using alpha-fetoprotein and abdominal ultrasound. RESULTS: Overall, 62.6% of the patients were men, mean age 56.4 years. In all, 31% were hepatitis B e antigen-positive and 14.9% had cirrhosis at baseline. Seventy-four patients developed cirrhosis and 42 patients developed HCC after 10 years. The overall 10-year incidence of cirrhosis and HCC was 16.2% (1.6%/year) and 7.8% (0.8%/year), respectively. The overall incidence of HCC in cirrhotics was 29.7% (3.0%/year), highest within a year of diagnosis of cirrhosis (7.9%). The rate of cirrhosis was significantly higher in those aged more than 55 years (P=0.001). Sex and hepatitis B e antigen status did not affect the rate of cirrhosis. Factors with significantly higher overall rates of HCC were age 55 years or more (P=0.001), male sex (P=0.001), and baseline alpha-fetoprotein of 4.1 ug/l or more (P<0.0001). However, age more than 55 years was not significant in the development of HCC in cirrhotics. CONCLUSION: The rate of cirrhosis in HBV patients in Singapore is about 1.6% per year. The rate of HCC is about 0.8% per year overall and 3.0% per year in cirrhotics, which justifies HCC surveillance. PMID- 25831136 TI - A proposed role for selective autophagy in regulating auxin-dependent lateral root development under phosphate starvation in Arabidopsis. AB - Plants respond to limited soil nutrient availability by inducing more lateral roots (LR) to increase the root surface area. At the cellular level, nutrient starvation triggers the process of autophagy through which bulk degradation of cellular materials is achieved to facilitate nutrient mobilization. Whether there is any link between the cellular autophagy and induction of LR had remained unknown. We recently showed that the S-Domain receptor Kinase (ARK2) and U Box/Armadillo Repeat-Containing E3 ligase (PUB9) module is required for lateral root formation under phosphate starvation in Arabidopsis thaliana.(1) We also showed that PUB9 localized to autophagic bodies following either activation by ARK2 or under phosphate starvation and ark2-1/pub9-1 plants displayed lateral root defects with inability to accumulate auxin in the root tips under phosphate starvation.(1) Supplementing exogenous auxin was sufficient to rescue the LR defects in ark2-1/pub9-1 mutant. Blocking of autophagic responses in wild-type Arabidopsis also resulted in inhibition of both lateral roots and auxin accumulation in the root tips indicating the importance of autophagy in mediating auxin accumulation under phosphate starved conditions.(1) Here, we propose a model for ARK2/AtPUB9 module in regulation of lateral root development via selective autophagy. PMID- 25831137 TI - Drug-triggered and cross-linked self-assembling nanofibrous hydrogels. AB - Self-assembly of multidomain peptides (MDP) can be tailored to carry payloads that modulate the extracellular environment. Controlled release of growth factors, cytokines, and small-molecule drugs allows for unique control of in vitro and in vivo responses. In this study, we demonstrate this process of ionic cross-linking of peptides using multivalent drugs to create hydrogels for sustained long-term delivery of drugs. Using phosphate, heparin, clodronate, trypan, and suramin, we demonstrate the utility of this strategy. Although all multivalent anions result in good hydrogel formation, demonstrating the generality of this approach, suramin led to the formation of the best hydrogels per unit concentration and was studied in greater detail. Suramin ionically cross linked MDP into a fibrous meshwork as determined by scanning and transmission electron microscopy. We measured material storage and loss modulus using rheometry and showed a distinct increase in G' and G" as a function of suramin concentration. Release of suramin from scaffolds was determined using UV spectroscopy and showed prolonged release over a 30 day period. Suramin bioavailability and function were demonstrated by attenuated M1 polarization of THP-1 cells compared to positive control. Overall, this design strategy has allowed for the development of a novel class of polymeric delivery vehicles with generally long-term release and, in the case of suramin, cross-linked hydrogels that can modulate cellular phenotype. PMID- 25831140 TI - New beginnings. PMID- 25831139 TI - Farewell. PMID- 25831138 TI - Latent tuberculosis screening tests and active tuberculosis infection rates in Turkish inflammatory bowel disease patients under anti-tumor necrosis factor therapy. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha inhibitors increase the risk of tuberculosis (TB). The objective of the present study was to determine the rate of active TB infection in inflammatory bowel disease (IBD) patients receiving anti-TNF therapy and to determine the results of their latent TB infection (LTBI) screening tests during the follow up. METHODS: This is a retrospective observational study of IBD patients receiving anti-TNF therapy. Tuberculin skin test (TST), interferon-gamma release assay (IGRA), and chest radiography were used to determine LTBI. Active TB infection rate during anti-TNF treatment was determined. RESULTS: Seventy-six IBD patients (25 with ulcerative colitis, 51 with Crohn's disease; 53 male; mean age 42.0+/-12.4 years) were included. Forty four (57.9%) patients received infliximab and 32 (42.1%) adalimumab. Their median duration of anti-TNF therapy was 15 months. Forty-five (59.2%) patients had LTBI and received isoniazid (INH) prophylaxis. During the follow-up period, active TB was identified in 3 (4.7%) patients who were not receiving INH prophylaxis. There was a moderate concordance between the TST and the IGRA (kappa coefficient 0.44, 95% CI 0.24-0.76). Patients with or without immunosuppressive therapy did not differ significantly with respect to TST (P=0.318) and IGRA (P=0.157). CONCLUSION: IBD patients receiving anti-TNF therapy and prophylactic INH have a decreased risk of developing active TB infection. However, despite LTBI screening, the risk of developing active TB infection persists. PMID- 25831141 TI - Relationship of maternal perceptions of workplace breastfeeding support and job satisfaction. AB - OBJECTIVES: Decades of research supports the health benefits of breastfeeding. Prior research has shown that unsupportive work environments are frequently cited as reasons women abandon breastfeeding early. The objective of this study is to determine if mothers' perceptions of workplace lactation support are associated with job satisfaction. MATERIALS AND METHODS: Female employees of Seattle Children's Hospital (SCH) and a large corporation were e-mailed a survey to measure perceptions of workplace lactation support. Women were eligible to participate if they had a child born within the last 5 years. Questions were asked about lactation support across five domains; organization, manager, coworker, time, and physical environment. The main outcome was job satisfaction. Linear regression models were run to evaluate the association between workplace support scores and the outcome of interest. RESULTS: The survey was completed by 420 women at SCH and 131 women at the large corporation (response rate, 47%). Ninety-eight percent of study participants initiated breastfeeding, and most sustained breastfeeding for at least 6 months. Increased total workplace support score was associated with increased job satisfaction at both companies (p<0.001). Increased support scores within each domain were independently associated with increased job satisfaction (p values<0.005). When all domains were considered together, only manager and coworker supports were significant at SCH (p=0.04), and only time support was significant at the large corporation (p=0.01). The workplace support score was not significantly associated with breastfeeding duration at either institution. CONCLUSIONS: Improved lactation support in the workplace may improve new mothers' job satisfaction, which could be beneficial to businesses. PMID- 25831142 TI - Nintedanib: examining the development and mechanism of action of a novel triple angiokinase inhibitor. AB - Antiangiogenic agents are effective standard-of-care options in several malignancies, but are generally associated with only modest improvements in survival, as well as leading to additional toxicities. Furthermore, almost all patients develop acquired resistance to therapy, possibly due to the activation of alternative proangiogenic pathways. Here we discuss: the rationale for developing nintedanib, an agent that simultaneously inhibits signaling pathways activated by platelet-derived growth factor, FGF, as well as VEGF; how its distinctive inhibitory and pharmacokinetic profile could underlie promising efficacy and tolerability observed in Phase II trials in patients with relapsed/refractory non-small cell lung cancer, advanced ovarian cancer and metastatic colorectal cancer; the ongoing Phase III program that is assessing nintedanib in these areas of major unmet medical need; and recent progress in the development of biomarkers that may predict response to nintedanib. PMID- 25831144 TI - Magnetic resonance imaging of the carotid artery in long-term head and neck cancer survivors treated with radiotherapy. AB - BACKGROUND: In head and neck cancer (HNC) patients, long-term treatment-related complications include radiotherapy (RT)-induced carotid vasculopathy and stroke. The current study investigated the magnetic resonance imaging (MRI) characteristics of the carotid wall in long-term HNC survivors treated with RT. METHODS: MRI of the carotid arteries was performed within a prospective cohort of 42 HNC patients on average 7 years after RT. Two independent radiologists assessed maximal vessel wall thickness of common and internal carotid arteries. In case of wall thickening (>= 2 mm) the MRI signals as well as length of the thickened segment were assessed. RESULTS: Mean (SD) age of the 42 patients at baseline was 53 (13) years and mean (SD) follow-up time after RT was 6.8 (1.3) years. In total 62% were men and 60% had one or more cerebrovascular risk factors. Mean (SD) dose of RT on the common carotid arteries and internal carotid arteries was 57 Gy (11) and 61 Gy (10), respectively. Wall thickening was observed in 58% of irradiated versus 27% of non-irradiated common carotid arteries and 24% of irradiated versus 6% of non-irradiated internal carotid arteries (p < 0.05). Mean (SD) thickness of the irradiated and non-irradiated common carotid arteries was 2.5 (0.9) and 2 (0.7) mm (p = 0.02). Mean thickness of the irradiated and non-irradiated internal carotid arteries was 1.8 (0.8) and 1.5 mm (0.3) (n.s.). Mean length of the thickened vessel wall was 48 mm versus 36 mm in the irradiated versus non-irradiated common carotid arteries (p = 0.03) and 20 mm versus 15 mm in the irradiated versus non-irradiated internal carotid arteries (n.s.). No significant differences were observed for signal intensities of the vessel walls. CONCLUSIONS: Our study showed significantly more vessel wall thickening in irradiated versus non-irradiated carotid arteries years after RT for HNC, while no differences in signal intensities were observed. PMID- 25831143 TI - Is radiotherapy still necessary for diffuse large B-cell lymphoma therapy? PMID- 25831145 TI - Interactions between Starch, Lipids, and Proteins in Foods: Microstructure Control for Glycemic Response Modulation. AB - In real food, starch is usually forming part of a matrix with lipids and proteins. However, research on this ternary system and interactions between such food components has been scarce so far. The control of food microstructure is crucial to determine the product properties, including sensorial and nutritionals ones. This paper reviews the microstructural principles of interactions between starch, lipids, and proteins in foods as well as their effect on postprandial glycemic response, considering human intrinsic differences on postprandial glycemic responses. Several lines of research support the hypothesis that foods without rapidly digestible starch will not mandatorily generate the lowest postprandial glycemic response, highlighting that the full understanding of food microstructure, which modulates starch digestion, plays a key role on food design from a nutritional viewpoint. PMID- 25831146 TI - Continuous nanoflow-scanning electrochemical microscopy: voltammetric characterization and application for accurate and reproducible imaging of enzyme labeled protein microarrays. AB - The coupling of scanning electrochemical microscopy (SECM) to a continuous nanoflow (CNF) system is accomplished with the use of a microconcentric ring electrode/injector probe. The gold microring electrode encapsulated by a glass sheath is robust and can be beveled and polished. The CNF system, comprising a precision gas displacement pump and a rotary valve, is capable of delivering solution to the center of the SECM probe in the range of 1-150 nL/min. Major advantages of the CNF-SECM imaging mode over the conventional SECM generation/collection (G/C) mode include higher imaging resolution, immunity from interferences by species in the bulk solution or at other sites of the substrate, elimination of the feedback current that could interfere with the G/C data interpretation, and versatility of initiating surface reactions/processes via introducing different reactants into the flowing stream. Parameters such as flow rates, probe/substrate separations, and collection efficiencies are examined and optimized. Higher resolution, reproducibility, and accuracy are demonstrated through the application of CNF-SECM to horseradish peroxidase (HRP)-amplified imaging of protein microarrays. By flowing H2O2 and ferrocenemethanol through the injector and detecting the surface-generated ferriceniummethanol, human IgG spots covered with HPR-labeled antihuman IgG can be detected in the range of 13 nM 1.333 MUM with a detection limit of 3.0 nM. In addition, consistent images of microarray spots for selective and high-density detection of analytes can be attained. PMID- 25831147 TI - Medullary carcinoma of the colon: an adenocarcinoma with better prognosis. PMID- 25831148 TI - Abnormal Expression of miR-21 and miR-95 in Cancer Stem-Like Cells is Associated with Radioresistance of Lung Cancer. AB - This study demonstrated that miR-21 and miR-95 expression were significantly higher in the ALDH1(+)CD133(+)subpopulation than in the ALDH1(-)CD133(-) subpopulation of lung cancer cells. Combined delivery of anti-miR-21 and anti-miR 95 by calcium phosphate nanoparticles significantly inhibited tumor growth in a xenograft tumor model and sensitized radiotherapy. The anti-miRNAs significantly reduced miR-21 and miR-95 levels, increased PTEN, SNX1, and SGPP1 protein expression, but reduced Akt Ser(473) and Thr(308) phosphorylation. ALDH1(+)CD133(+) subpopulation of NSCLC tumor cells confers radioresistance due to high expression of miR-21 and miR-95. Targeting inhibition of miR-21 and miR 95 can inhibit tumor growth through elevating PTEN, SNX1, and SGPP1 expression and inhibiting Akt phosphorylation. PMID- 25831150 TI - Future challenges: general discussion. PMID- 25831151 TI - Primary Non-Hodgkin Lymphoma of the Breast: Ultrasonography, Elastography, Digital Mammography, Contrast-Enhanced Digital Mammography, and Pathology Findings. AB - Lymphomas constitute approximately 0.15% of malignant mammary neoplasms. Less than 0.5% of all malignant lymphomas involve the breast primarily. Primary non Hodgkin breast lymphoma is usually right sided. The combined therapy approach, with chemotherapy and radiotherapy, is the most successful treatment. Mastectomy offers no benefit in the treatment of primary non-Hodgkin breast lymphoma. To the author's knowledge, this is the first published case of primary non-Hodgkin breast lymphoma reported with conventional ultrasonography, elastography (both freehand and acoustic radiation force impulse imaging), digital mammography, contrast-enhanced digital mammography, and pathology findings. A 45-year-old woman presented with a lump in the right breast for 2 months. There was no evidence of systemic lymphoma or leukemia when the breast lesion was detected. Imaging findings were negative for lymphoma. Ipsilateral lymph nodes were not palpable. The mass was resected, and histopathology findings were diagnostic of non-Hodgkin lymphoma. Immunohistochemistry was confirmatory of non-Hodgkin lymphoma, diffuse large cell type of B-cell lineage. Although primary and secondary lymphomas of the breast are rare entities, they should be considered in the differential diagnosis of breast malignancies. PMID- 25831152 TI - A Case of Glomangiomatosis of the Ankle and Foot: Ultrasonographic Appearance Correlated With the Magnetic Resonance Imaging Findings. AB - Glomangiomatosis, a rare category of glomus tumors, comprises 2% to 3% of glomus tumors in adults. We report a case of glomangiomatosis in a 48-year-old man who underwent multiple excisions of recurrent soft tissue masses in the ankle and foot. Ultrasonography revealed multiple nodular soft tissue tumors and dilated vascular channels with increased blood flow, suggesting the presence of vascular tumors. Here, we discuss the ultrasonography imaging features of glomangiomatosis, which have not been previously reported, correlate them with magnetic resonance imaging findings, and provide a brief review of the literature. PMID- 25831153 TI - Synthesis and solid-state structural characterization of a series of aqueous heterometallic tridecameric group 13 clusters. AB - The synthesis and solid-state characterization of a complete series of new heterometallic aqueous nanoscale Ga/In tridecameric clusters is presented. These hydroxo-aquo species significantly expand the library of discrete, aqueous group 13 clusters. This report details the synthetic and structural characterization of these compounds, which are of interest as precursors (inks) for thin-film oxides with materials applications. Single-crystal X-ray diffraction (XRD) data show that the hexagonal unit cell lengths of these clusters fall within the range a, b = 20.134-20.694 A and c = 18.266-18.490 A. The unit cell volumes become larger (V = 6494-6774 A(3)) with increasing indium occupancy. The compositions of several Ga/In clusters determined by electron probe microanalysis and elemental analysis are in agreement with single-crystal XRD results. The transformation of the Ga/In clusters to metal oxides at high temperature was studied using variable temperature powder XRD. With heating, the Ga/In clusters with lower indium occupancies convert to the beta-Ga2O3 structure. For clusters with higher indium occupancies, phase separation occurs, and an In2O3 bixbyite-type structure forms. The stoichiometric control at the molecular level demonstrated herein is important in designing functional thin films of metal oxides due to the tunable nature of these heterometallic solution precursors. In addition, information about the solid-state structure of these compounds leads to a fundamental understanding of the materials properties of these clusters for future thin-film and precursor development. PMID- 25831154 TI - Trifluoromethyl sulfoxides from allylic alcohols and electrophilic SCF3 donor by [2,3]-sigmatropic rearrangement. AB - An electrophilic trifluoromethylthiolation of allylic alcohols produces the corresponding allylic trifluoromethanesulfenates, which spontaneously rearrange into trifluoromethyl sulfoxides via a [2,3]-sigmatropic rearrangement. The reaction is straightforward and proceeds in good to high yields for the preparation of various allylic trifluoromethyl sulfoxides. PMID- 25831155 TI - A cost-effective RNA sequencing protocol for large-scale gene expression studies. AB - RNA sequencing has increasingly become an indispensable tool for biological research. While sequencing costs have fallen dramatically in recent years, the current cost of RNA sequencing, nonetheless, remains a barrier to even more widespread adoption. Here, we present a simple RNA sequencing protocol with substantially reduced costs. This protocol uses as little as 10 ng of total RNA, allows multiplex sequencing of up to 96 samples per lane, and is strand specific. Extensive validation using human embryonic stem cells showed high consistency between technical replicates at various multiplexing levels. PMID- 25831156 TI - Electrode array extrusion through the posterior canal wall presenting as a delayed post-cochlear implant complication. AB - OBJECTIVES AND IMPORTANCE: Cochlear implantation is an established, reliable, and safe procedure with a low complication rate. Electrode array extrusion through the posterior aspect of external ear canal is a potential major complication of cochlear implant surgery that may result in revision surgery or explantation. Although there have been previous case reports of such extrusions through the tympanic membrane, this is the first well-documented report of an extrusion through the posterior canal wall which was previously intact. CLINICAL PRESENTATION: In this case report, we present a case of electrode array extruding through an initially intact posterior canal wall presenting as a delayed post operative complication in a 13-year old Asian boy. INTERVENTION: With reference to existing relevant literature, the case is discussed focusing on its management, possible contributing factors, and prevention strategies. CONCLUSION: Excessive thinning of the bony wall should be avoided as it can potentially break down. Abutment on the posterior canal wall by a coiled electrode array in the mastoid cavity exerting undue pressure on the bony wall can further contribute to additional stress. The implant surgeon must be cognizant of mastoid growth patterns in children. Life-long regular follow-up in implanted patients is crucial. PMID- 25831157 TI - The dormant virus: a rare case of herpes simplex virus hemorrhagic necrotizing enterocolitis. PMID- 25831158 TI - Selective nonoperative management of foramen of Winslow hernias. PMID- 25831159 TI - Peritoneal decortication: an innovative technique for treatment of obstructive sclerosing encapsulating peritonitis. PMID- 25831160 TI - Interval asymptomatic infected postpancreatic resection fluid collections managed with endoscopic ultrasound-guided drainage. PMID- 25831161 TI - Stump appendicitis after remote appendectomy. PMID- 25831162 TI - Management of a misplaced endovascular stent in pulmonary artery. PMID- 25831163 TI - The indication for colectomy does not influence the management of anastomotic leaks. PMID- 25831164 TI - Solid pseudopapillary tumor of the pancreas in a teenager. PMID- 25831165 TI - Intraoperative testing after end-to-end anastomotic stapling and its ability to detect sound anastomoses. PMID- 25831166 TI - Parathyroid cysts. PMID- 25831167 TI - Transcatheter coil embolization of renal artery pseudoaneurysm in a pediatric patient. PMID- 25831168 TI - Angiosarcoma of the colon. PMID- 25831169 TI - A decade of work-hour restrictions: increasing pass rate trends on the American Board of Urology Qualifying Examination. PMID- 25831170 TI - Abdominal aortic and iliac injury in blunt trauma: a single center's experience. PMID- 25831171 TI - The plight of the general surgeon: an analysis of urgent and emergent surgeries at a community hospital. PMID- 25831172 TI - Current treatment guidelines for postoperative surgical site infection: clinical considerations in the surgical care improvement project era. PMID- 25831173 TI - Cholangiocarcinoma: a pan-Pacific perspective. PMID- 25831174 TI - Oncologic management dilemma of locally advanced occult rectal cancer presenting as Fournier's gangrene. PMID- 25831175 TI - James Lawrence Cabell, one of the most influential of America's early surgeons. AB - Dr. James Lawrence Cabell was one of the most important, farsighted, and influential surgical educators and leaders in the United States in the 19th century. He was appointed as Chair of Surgery and Physiology at the University of Virginia by Thomas Jefferson's successor as Rector of the University, James Madison, and held that Chair for over 50 years, the longest tenure of any American medical academician. He was a founding member of the American Medical Association, the American Surgical Association, and the National Board of Health. He is best remembered as an articulate, incessant, and early proponent of public health and the delivery of quality health care in the United States. His legacy and that of his proteges has continued to influence health care in this country, especially in the realm of the prevention and treatment of infectious diseases, even into the present time. PMID- 25831176 TI - Can routine trauma bay chest x-ray be bypassed with an extended focused assessment with sonography for trauma examination? AB - The objective of this study was to investigate the feasibility of using ultrasound (US) in place of portable chest x-ray (CXR) for the rapid detection of a traumatic pneumothorax (PTX) requiring urgent decompression in the trauma bay. All patients who presented as a trauma alert to a single institution from August 2011 to May 2012 underwent an extended focused assessment with sonography for trauma (FAST). The thoracic cavity was examined using four-view US imaging and were interpreted by a chief resident (Postgraduate Year 4) or attending staff. US results were compared with CXR and chest computed tomography (CT) scans, when obtained. The average age was 37.8 years and 68 per cent of the patients were male. Blunt injury occurred in 87 per cent and penetrating injury in 12 per cent of activations. US was able to predict the absence of PTX on CXR with a sensitivity of 93.8 per cent, specificity of 98 per cent, and a negative predictive value of 99.9 per cent compared with CXR. The only missed PTX seen on CXR was a small, low anterior, loculated PTX that was stable for transport to CT. The use of thoracic US during the FAST can rapidly and safely detect the absence of a clinically significant PTX. US can replace routine CXR obtained in the trauma bay and allow more rapid initiation of definitive imaging studies. PMID- 25831177 TI - Radiocephalic fistulas for hemodialysis: a comparison of techniques. AB - The radiocephalic fistula dates back to the 1960s with good long-term survival and a low incidence of complications. The standard practice of creating an end cephalic vein to side radial artery fistula (ETS) has a high incidence of early thrombosis and failure to mature, which limits its efficacy. The hypothesis is that a 1.3- to 1.5-cm side-to-side with distal vein ligation anastomosis (STS) is associated with a lower early thrombosis rate and higher primary patency rate. We retrospectively evaluated all radiocephalic fistulas created at our hospital from January 1, 2012, to December 31, 2012, comparing a 1.3- to 1.5-cm STS anastomosis to the ETS anastomosis. Primary endpoints were patency at three and six months and the secondary outcome was suitability for cannulation. An ETS anastomosis resulted in an early thrombosis rate, 3-month cannulation rate, and 6-month primary patency rate of 14, 30, and 48 per cent, respectively. Outcomes from the STS technique were significantly improved with no early thrombosis (P < 0.05), 3 month cannulation rate of 67 per cent (P < 0.03), and a primary patency of 75 per cent (P = 0.03). A STS radiocephalic fistula with distal vein ligation is superior to the ETS radiocephalic fistula. Early thrombosis, 6-month primary patency, and cannulation rates were significantly improved. PMID- 25831178 TI - Chest radiography does not alter the treatment course for children after rigid bronchoscopy. AB - The purpose of this study was to evaluate the usefulness of chest radiography in the direction of postbronchoscopy clinical therapy. From 2001 to 2011, 368 rigid bronchoscopies were performed at a single institution in 221 children. Indications for bronchoscopy, concomitant bronchoscopic procedures, and results of postoperative chest radiography were evaluated. Rigid bronchoscopy was performed in children at a median age of 2.21 years (range, two days to 20 years). Chest radiography was performed at the discretion of the primary surgeon after 275 (74.7%) procedures. Malpositioning of the endotracheal or tracheostomy tube occurred in 1.5 per cent (n = three of 203) of ventilated patients postbronchoscopy. Pneumothorax occurred in 0.5 per cent (n = two of 368) of children and followed laser degranulation (n = one of 117 [0.9%]) and removal of an aspirated foreign body (n = one of 80 [1.3%]). Neither child required tube thoracostomy. Three children necessitated intraoperative tube thoracostomy placement for symptomatic pneumothoraces before radiographic assessment. No children sustained postprocedural complications in the absence of postbronchoscopy radiography. Postbronchoscopy chest radiography in the absence of defined symptomatology is not associated with a change in the postprocedural treatment course, suggesting selective application may be appropriate after at risk bronchoscopic interventions. Such practice will limit the future cost and radiation exposure associated with this common procedure. PMID- 25831179 TI - Pharyngostomy. AB - A retrospective analysis of a prospective observational study of a cohort of patients who required prolonged foregut/midgut decompression/intraluminal stenting and/or enteral nutritional support was conducted. Those patients were intolerant of protracted nasogastric intubation. They also manifested hostile peritoneal cavities and therefore were not candidates for a laparoendoscopic gastrostomy or jejunostomy. Accordingly, they underwent insertion of a pharyngogastric or pharyngojejunal tube. With patients properly positioned and anesthetized and with attention to the anatomy of the superior carotid cervical triangle, those pharyngostomies and cannulations were performed safely and efficiently. The tubes remained indefinitely or were changed/removed ad libitum. Morbidity was nil and no mortality attributable to the procedure was observed. Pharyngostomy should be part of the armamentarium of all general surgeons. PMID- 25831180 TI - High-resolution manometry findings in patients with an intrathoracic stomach. AB - Intrathoracic stomach is a rare finding. The real value of the high-resolution manometry (HRM) in the preoperative evaluation of these patients has not yet being fully tested. This study aims to evaluate: 1) the HRM pattern of patients with an intrathoracic stomach; and 2) HRM findings as predictors for prosthetic reinforcement of the hiatus. We reviewed 33 patients (27 women, mean age 66 years) with an intrathoracic stomach who underwent HRM. Fifteen patients did the HRM as part of preoperative workup and were operated on in our institution. All patients were submitted to a laparoscopic Nissen fundoplication. HRM results show that the lower esophageal sphincter (LES) was transposed in all patients. Hiatal hernia was diagnosed in 21 (63%) patients. The length of the hernia was 4 +/- 2 cm (range, 1 to 9 cm). LES oscillation was observed in 23 (69%) patients with a mean of 1 +/- 0.4 cm (range, 0.4 to 2 cm). Hiatal mesh reinforcement was necessary in five (33%) of the operated patients. HRM findings did not predict hiatal mesh reinforcement. Our results show that: 1) HRM has a poor sensibility for hiatal hernia diagnosis; 2) half of the patients with an intrathoracic stomach have a normal HRM; and 3) HRM does not predict mesh hiatal hernia repair. PMID- 25831181 TI - Risk factors of postoperative myocardial infarction after colorectal surgeries. AB - There are limited data regarding the specific risk factors of postoperative myocardial infarction (MI) in patients undergoing colorectal resectional surgery. We sought to identify risk factors of acute MI after colorectal resection operations. The National Inpatient Sample database was used to identify patients who had postoperative MI after colorectal resection operations between 2002 and 2010. Statistical analysis was performed to identify factors predictive of postoperative MI. We sampled a total of 2,513,124 patients undergoing colorectal resection, of whom 38,317 (1.5%) sustained a postoperative MI. Patients with postoperative MI had associated 28.5 per cent in-hospital mortality. Risk factors identified include (P < 0.01): history of congestive heart failure (odds ratio [OR], 8.18), chronic renal failure (OR, 3.86), age 70 years or older (OR, 3.68), peripheral vascular disorders (OR, 2.93), fluid and electrolyte disorders (OR, 2.69), emergency admission (OR, 2.56), preoperative weight loss (OR, 2.49), cardiac valvular disease (OR, 2.46), chronic lung disease (OR, 1.75), deficiency anemia (OR, 1.22), colorectal cancer (OR, 1.77), and hypertension (OR, 1.14). Postoperative MI occurs in less than 2 per cent of colorectal resections. However, patients sustaining postoperative MI are over six times more likely to die. Congestive heart failure and chronic renal failure are the strongest predictors of postoperative MI. PMID- 25831182 TI - The surgical anatomy of the inguinal lymphatics. AB - Knowledge of the lymphatic system plays critical importance in surgical oncology. The study of the lymphatic system and its role in tumor metastasis continues to advance with new anatomical and surgical studies, and with a new study, we can gain a better understanding on how aggressive surgeons need to be with nodal dissection while balancing the complications with overly aggressive approaches. The lymphatics of the inguinal region represent a network of lymph nodes and vessels, which act as the bridge among the lower extremities, pelvis, perineum, and rest of the body. These lymph nodes are of particular importance in the metastatic spread of genitourinary and lower gastrointestinal epithelial cancer to the inguinal nodes. The aim of this article is to reveal the literature with regard to the inguinal lymph nodes and their relation in various carcinomas. PMID- 25831183 TI - Medical student quality-of-life in the clerkships: a scale validation study. AB - Many aspects of medical school are stressful for students. To empirically assess student reactions to clerkship programs, or to assess efforts to improve such programs, educators must measure the overall well-being of the students reliably and validly. The purpose of the study was to develop and validate a measure designed to achieve these goals. The authors developed a measure of quality of life for medical students by sampling (public domain) items tapping general happiness, fatigue, and anxiety. A quality-of-life scale was developed by factor analyzing responses to the items from students in two different clerkships from 2005 to 2008. Reliability was assessed using Cronbach's alpha. Validity was assessed by factor analysis, convergence with additional theoretically relevant scales, and sensitivity to change over time. The refined nine-item measure is a Likert scaled survey of quality-of-life items comprised of two domains: exhaustion and general happiness. The resulting scale demonstrated good reliability and factorial validity at two time points for each of the two samples. The quality-of-life measure also correlated with measures of depression and the amount of sleep reported during the clerkships. The quality-of-life measure appeared more sensitive to changes over time than did the depression measure. The measure is short and can be easily administered in a survey. The scale appears useful for program evaluation and more generally as an outcome variable in medical educational research. PMID- 25831184 TI - Quality and extent of locum tenens coverage in pediatric surgical practices. AB - The prevalence and quality of locum tenens coverage in pediatric surgery have not been determined. An Internet-based survey of American Pediatric Surgical Association members was conducted: 1) practice description; 2) use and frequency of locum tenens coverage; 4) whether the surgeon provided such coverage; and 5) Likert scale responses (strongly disagree, disagree, neutral, agree, strongly agree) to statements addressing its acceptability and quality (two * five contingency table and chi(2) analyses, significance at P < 0.05). Three hundred sixteen of 1163 members (27.2% response rate) responded. One-fourth (24.1%) used a locum tenens regularly. Reasons were long-term inability to recruit a full-time surgeon (35.2%) and short-term vacancies (32.4%). One-fifth (20.4%) did locum tenens work; one-fourth (27.0%) plan to do so in the future. Two-thirds (64.2%) believe that surgical care in a locum tenens situation does not provide the same level of care as a full-time community-based surgeon. Most support locum tenens for short-term coverage (87.3%) and recruitment problems (72.1%), but not long term vacancies (38.8%; P < 0.001) or permanent coverage (27.0%; P < 0.001). locum tenens coverage is an established feature of pediatric surgery. Most view it as a stopgap solution to the surgical workforce shortage. PMID- 25831185 TI - Reasons for 30-day postoperative readmissions for Medicare patients at a community-based teaching hospital. AB - Healthcare reform initiatives have proposed reducing reimbursement for certain 30 day readmissions among Medicare patients. Our objective was to evaluate the incidence and reasons for 30-day postoperative readmissions at our institution. The medical records of Medicare patients who underwent surgery from January 1, 2010, through May 16, 2011, were reviewed. Statistical analysis included chi(2), Wilcoxon rank sum, and t tests. Two thousand eight hundred sixty-five patients were included; 199 (7%) had a 30-day readmission. The readmission group included a higher proportion of men (53.8 vs 43.6%, P = 0.005), and patients with an American Society of Anesthesiologists (ASA) Class 3 or greater (84 vs 66%, P < 0.001) versus the nonreadmission group. Mean index length of stay and operative time were longer in the readmitted versus nonreadmitted group (4.8 vs 2.8 days, P < 0.001; 122.8 vs 98.2 minutes, P < 0.001). Readmission reasons were surgically related (53%), surgically unrelated (35%), planned (7%), and patient-related (5%). Higher 30-day postoperative readmission rates were associated with male sex, higher ASA class, and longer index length of stay and operative time. Reasons for readmission included surgical- and patient-related factors. Decreased reimbursement should be discouraged for readmissions directly related to patient noncompliance. PMID- 25831186 TI - Synthetic mesh repair for incisional hernia treatment in high-risk patients for surgical site occurrences. AB - Patients with incisional hernias (IH) and risk factors for surgical site occurrences (SSOs) such as defined comorbidities and/or potential contaminations are considered to be treated with bioprosthetics. A retrospective analysis of consecutive patients who had undergone elective IH repair with synthetic mesh materials between 2009 and 2013 was conducted. Only patients who were classified into Grades II and III according to the classification of the Ventral Hernia Working Group (VHWG) were considered for the study. Primary outcome parameter was the incidence of SSO. The relationships among demographics, hernia characteristics, surgical technique, and SSOs were also evaluated. Overall, 108 patients were included (Grade II: 68, Grade III: 40). SSO was identified in 14 patients. Having two or more comorbidities (P = 0.04), an open sublay technique (P = 0.005), duration of operation (P = 0.02), larger hernia defects (P = 0.001), and using larger mesh sizes (P = 0.01) were associated with significantly higher rates of SSO. Affiliation to VHWG Grading II or III showed no impact on SSO occurrence. Synthetic mesh repair both in an "open sublay" and laparoscopic intraperitoneal technique is safe regarding patients with risk factors for SSO. The recommendations of the VHWG must be declined and a modification of the grading system is warranted overlooking a more liberal use of synthetic meshes. PMID- 25831187 TI - You cannot go home: routine concussion evaluation is not enough. AB - Traditional care of mild traumatic brain injury (MTBI) is to discharge patients from the emergency department (ED) if they have a Glasgow Coma Score (GCS) of 15 and a normal head computed tomography (CT) scan. However, this does not address short-term neurocognitive deficits. Our hypothesis is that a notable percentage of patients will need outpatient neurocognitive therapy despite a reassuring initial presentation. This is a retrospective review of patients with MTBI at an urban Level I trauma center. Inclusion criteria were a diagnosis of MTBI in patients 14 years old or older, GCS 15, negative head CT scan, a completed neurocognitive evaluation, blunt mechanism, and no confounding psychiatric comorbidities. Six thousand thirty-two patients were admitted over 18 months. Three hundred ninety-five patients met inclusion criteria. Average age was 38 years (range, 14 to 93 years), 64 per cent were male, and mean Injury Severity Score (ISS) was 8.1. Forty-one per cent were cleared for discharge without follow up. Twenty-seven per cent required ongoing neurocognitive therapy. Three per cent were deemed unsafe for discharge home. Of the patients cleared for discharge, 88 per cent had positive/questionable loss of consciousness (LOC), whereas 81 per cent who required additional therapy had positive/questionable LOC (P = 0.20). Age, gender, ISS, and alcohol use were compared between the groups and not found to be statistically different rendering them poor predictors for appropriate discharge from the ED. A surprisingly high percentage (27%) of patients who would have met traditional ED discharge criteria were found to have persistent deficits after neurocognitive testing and were referred for ongoing therapy. We provide evidence to suggest that we should take pause before discharging patients with MTBI without a cognitive evaluation. PMID- 25831188 TI - Use and accuracy of computed tomography scan in diagnosing perforated appendicitis. AB - Perforated appendicitis has major implications on patient care. The ability of computed tomography (CT) scan to distinguish perforation in the absence of phlegmon or abscess is unknown. The purpose of this study is to assess the use and accuracy of CT scans in diagnosing perforated appendicitis without phlegmon or abscess. A retrospective chart review of 102 patients who underwent appendectomy from 2011 to 2013 was performed. Patient demographics and operative and postoperative course were recorded. Two radiologists were then blinded to operative findings and CT scans reread and results correlated. Findings on CT scan were also analyzed for correlation with perforation. Univariate and multivariate statistical analysis was performed. Of the 102 patients, 49 were perforated and 53 nonperforated. Analysis of patient populations demonstrated patients with perforation were significantly older (45 vs 34 years, P = 0.002), had longer operative times (132 vs 81 minutes, P = 0.001), and longer length of stay (8.2 vs 1.5 days, P < 0.001). Nineteen perforations (37%) were correctly diagnosed by CT scan. The sensitivity of CT scan to detect perforation was 38 per cent, specificity 96 per cent, and positive predictive value of 90 per cent. After multivariate analysis of significant variables, three were demonstrated to significantly correlate with presence of perforation: presence of extraluminal air (odds ratio [OR], 28.9; P = 0.02); presence of intraluminal fecalith (OR, 5.7; P = 0.03); and wall thickness greater than 3 mm (OR, 3.2; P = 0.02). CT scan has a low sensitivity for diagnosing perforated appendicitis without abscess or phlegmon. Presence of extraluminal air bubbles, increased wall thickness, and intraluminal fecalith should increase suspicion for perforation and are highly correlated with outcomes after appendectomy. PMID- 25831189 TI - The ACT Alert: preliminary results of a novel protocol to assess geriatric head trauma patients on anticoagulation. AB - In busy emergency departments (EDs), elderly patients on anticoagulation (AC) sustaining minor injuries who are triaged to a lower priority for evaluation are at risk for potentially serious consequences. We sought to determine if a novel ED protocol prioritizes workup and improves outcome. In a Pennsylvania-verified Level II trauma center, the ACT (AntiCoagulation and Trauma) Alert was implemented in March 2012. Triage parameters include: age 65 years or older, AC agents, Glasgow Coma Score (GCS) 13 or greater, and head trauma 24 hours or less. ACT Alerts are announced overhead in the ED and require assessment by an ED physician, nurse, and phlebotomist in 15 minutes or less. Furthermore, they necessitate Point of Care international normalized ratio (INR) 20 minutes or less and head computed tomography (CT) scan 30 minutes or less. Positive CT findings mandate trauma service consultation. ACT Alert patients from March to December 2012 were compared with ED patients 65 years or older, GCS 13 or greater, on AC with the same chief complaints as ACT Alerts from June 2011 to February 2012 (control). A P value <= 0.05 was considered significant. Of 752 study patients, 415 were ACT and 337 were controls. There were no significant differences between groups in age, elevated INR, or head bleeds. ACT patients had significantly shorter median times from ED arrival to INR (ACT 13 minutes vs control 80 minutes; P < 0.001) and to head CT (ACT 35 minutes vs control 65 minutes; P < 0.001). Of admitted patients, ACT had a significantly shorter median length of stay (LOS) (ACT 3.7 days vs control 5.0 days; P < 0.001). Although trends toward improved outcome were noted, no statistically significant differences were identified. The ACT Alert improves ED throughput and reduces hospital LOS while effectively identifying at-risk, mildly head injured geriatric patients on AC. PMID- 25831190 TI - Outcomes of open splenectomy for hematologic malignancy with splenomegaly: a contemporary perspective. AB - Splenectomy for hematologic malignancy (HM) is considered a high-risk procedure, especially in cases of splenomegaly. We analyzed the postoperative course of 82 patients undergoing open splenectomy for HM-related splenomegaly (splenic craniocaudal length 15 cm or greater) in a high-volume center. Primary outcome measures were: perioperative clinical course, rate and severity of postoperative complications (Clavien-Dindo classification), and length of hospital stay. Risk factors analyzed for morbidity and mortality by logistic regression analysis were: gender, age, American Society of Anesthesiologists (ASA)grade, body mass index (BMI), steroidal treatment, preoperative white blood cell count, spleen size, spleen weight, and operative time. The postoperative mortality rate was 1.2 per cent. Only 15.9 per cent of patients required surgical, endoscopic, or radiological intervention after splenectomy (Grade 3 or greater complication). Overall postoperative morbidity rate (as Grade 2 or greater complication) was 52.4 per cent. Surgical complications, mainly bleeding, occurred in 40.2 per cent of patients and 32.9 per cent of patients required blood transfusion. Medical complication rate was 24.4 per cent. Pulmonary disorders were prevalent among medical complications. At multivariate analysis, only ASA score was an independent risk factor for postoperative complications. Open splenectomy can be performed in high-volume centers with low mortality and acceptable morbidity in patients with HM-related splenomegaly, provided that patients at highest risk of postoperative complication (ASA greater than 3) are carefully evaluated. PMID- 25831191 TI - Preservation of beta cell function after pancreatic islet autotransplantation: University of Chicago experience. AB - The aim of the study was to assess the rate of insulin independence in patients after total pancreatectomy (TP) and islet autotransplantation in our center. TP followed by islet autotransplantation was performed in 10 patients. Severe unrelenting pain associated with chronic pancreatitis was the major indication for surgery. Islets were isolated using the modified Ricordi method and infused through the portal vein. Exogenous insulin therapy was implemented for at least two months posttransplant to support islet engraftment and was subsequently weaned off, if possible. Median follow-up was 26 months (range, 2 to 60 months). Median islet yield was 158,860 islet equivalents (IEQ) (range, 40,203 to 330,472 IEQ) with an average islet yield of 2,478 IEQ/g (range, 685 to 6,002 IEQ/g) of processed pancreas. One patient developed transient partial portal vein thrombosis, which resolved without sequela. Five (50%) patients are currently off insulin with excellent glucose control and HbA1c below 6. Patients who achieved and maintained insulin independence were transplanted with significantly more islets (median, 202,291 IEQ; range, 145,000 to 330,474 IEQ) than patients who required insulin support (64,348 IEQ; range, 40,203 to 260,476 IEQ; P < 0.05). Patient body mass index and time of chronic pancreatitis prior transplant procedure did not correlate with the outcome. The remaining five patients, who require insulin support, had present C-peptide in blood and experience good glucose control without incidence of severe hypoglycemic episodes. Islet autotransplantation efficiently preserved beta cell function in selected patients with chronic pancreatitis and the outcome correlated with transplanted islet mass. PMID- 25831192 TI - Low retrieval rates of temporary inferior vena cava filters in trauma patients. PMID- 25831193 TI - Serum calcium changes in response to varied surgical procedures. PMID- 25831194 TI - Parameter estimation using macroscopic diffusion MRI signal models. AB - Macroscopic models of the diffusion MRI (dMRI) signal can be helpful to understanding the relationship between the tissue microstructure and the dMRI signal. We study the least squares problem associated with estimating tissue parameters such as the cellular volume fraction, the residence times and the effective diffusion coefficients using a recently developed macroscopic model of the dMRI signal called the Finite Pulse Karger model that generalizes the original Karger model to non-narrow gradient pulses. In order to analyze the quality of the estimation in a controlled way, we generated synthetic noisy dMRI signals by including the effect of noise on the exact signal produced by the Finite Pulse Karger model. The noisy signals were then fitted using the macroscopic model. Minimizing the least squares, we estimated the model parameters. The bias and standard deviations of the estimated model parameters as a function of the signal to noise ratio (SNR) were obtained. We discuss the choice of the b-values, the least square weights, the extension to experimentally obtained dMRI data as well noise correction. PMID- 25831195 TI - SNP identification from RNA sequencing and linkage map construction of rubber tree for anchoring the draft genome. AB - Hevea brasiliensis, or rubber tree, is an important crop species that accounts for the majority of natural latex production. The rubber tree nuclear genome consists of 18 chromosomes and is roughly 2.15 Gb. The current rubber tree reference genome assembly consists of 1,150,326 scaffolds ranging from 200 to 531,465 bp and totalling 1.1 Gb. Only 143 scaffolds, totalling 7.6 Mb, have been placed into linkage groups. We have performed RNA-seq on 6 varieties of rubber tree to identify SNPs and InDels and used this information to perform target sequence enrichment and high throughput sequencing to genotype a set of SNPs in 149 rubber tree offspring from a cross between RRIM 600 and RRII 105 rubber tree varieties. We used this information to generate a linkage map allowing for the anchoring of 24,424 contigs from 3,009 scaffolds, totalling 115 Mb or 10.4% of the published sequence, into 18 linkage groups. Each linkage group contains between 319 and 1367 SNPs, or 60 to 194 non-redundant marker positions, and ranges from 156 to 336 cM in length. This linkage map includes 20,143 of the 69,300 predicted genes from rubber tree and will be useful for mapping studies and improving the reference genome assembly. PMID- 25831196 TI - Human, oceanographic and habitat drivers of central and western Pacific coral reef fish assemblages. AB - Coral reefs around US- and US-affiliated Pacific islands and atolls span wide oceanographic gradients and levels of human impact. Here we examine the relative influence of these factors on coral reef fish biomass, using data from a consistent large-scale ecosystem monitoring program conducted by scientific divers over the course of >2,000 hours of underwater observation at 1,934 sites, across ~40 islands and atolls. Consistent with previous smaller-scale studies, our results show sharp declines in reef fish biomass at relatively low human population density, followed by more gradual declines as human population density increased further. Adjusting for other factors, the highest levels of oceanic productivity among our study locations were associated with more than double the biomass of reef fishes (including ~4 times the biomass of planktivores and piscivores) compared to islands with lowest oceanic productivity. Our results emphasize that coral reef areas do not all have equal ability to sustain large reef fish stocks, and that what is natural varies significantly amongst locations. Comparisons of biomass estimates derived from visual surveys with predicted biomass in the absence of humans indicated that total reef fish biomass was depleted by 61% to 69% at populated islands in the Mariana Archipelago; by 20% to 78% in the Main Hawaiian islands; and by 21% to 56% in American Samoa. PMID- 25831197 TI - Focus Groups Move Online: Feasibility of Tumblr Use for eHealth Curriculum Development. AB - BACKGROUND: Constructing successful online programs requires engaging potential users in development. However, assembling focus groups can be costly and time consuming. OBJECTIVE: The aim of this study is to assess whether Tumblr can be used to prioritize activities for an online younger worker risk reduction and health promotion program. METHODS: Younger summer parks and recreation employees were encouraged to visit Tumblr using weekly announcements and competitions. Each week, new activities were posted on Tumblr with linked survey questions. Responses were downloaded and analyzed. RESULTS: An average of 36 young workers rated each activity on its likeability and perceived educational value. The method was feasible, efficient, and sustainable across the summer weeks. Ratings indicated significant differences in likeability among activities (P<.005). CONCLUSIONS: Tumblr is a means to crowdsource formative feedback on potential curricular components when assembling an online intervention. This paper describes its initial use as well as suggestions for future refinements. PMID- 25831198 TI - Finasteride and the Uncertainties of Establishing Harms. PMID- 25831199 TI - Information and communication technology-enabled person-centered care for the "big five" chronic conditions: scoping review. AB - BACKGROUND: Person-centered information and communication technology (ICT) could encourage patients to take an active part in their health care and decision making process, and make it possible for patients to interact directly with health care providers and services about their personal health concerns. Yet, little is known about which ICT interventions dedicated to person-centered care (PCC) and connected-care interactions have been studied, especially for shared care management of chronic diseases. The aim of this research is to investigate the extent, range, and nature of these research activities and identify research gaps in the evidence base of health studies regarding the "big 5" chronic diseases: diabetes mellitus, cardiovascular disease, chronic respiratory disease, cancer, and stroke. OBJECTIVE: The objective of this paper was to review the literature and to scope the field with respect to 2 questions: (1) which ICT interventions have been used to support patients and health care professionals in PCC management of the big 5 chronic diseases? and (2) what is the impact of these interventions, such as on health-related quality of life and cost efficiency? METHODS: This research adopted a scoping review method. Three electronic medical databases were accessed: PubMed, EMBASE, and Cochrane Library. The research reviewed studies published between January 1989 and December 2013. In 5 stages of systematic scanning and reviewing, relevant studies were identified, selected, and charted. Then we collated, summarized, and reported the results. RESULTS: From the initial 9380 search results, we identified 350 studies that qualified for inclusion: diabetes mellitus (n=103), cardiovascular disease (n=89), chronic respiratory disease (n=73), cancer (n=67), and stroke (n=18). Persons with one of these chronic conditions used ICT primarily for self-measurement of the body, when interacting with health care providers, with the highest rates of use seen in chronic respiratory (63%, 46/73) and cardiovascular (53%, 47/89) diseases. We found 60 relevant studies (17.1%, 60/350) on person-centered shared management ICT, primarily using telemedicine systems as personalized ICT. The highest impact measured related to the increase in empowerment (15.4%, 54/350). Health-related quality of life accounted for 8%. The highest impact connected to health professionals was an increase in clinical outcome (11.7%, 41/350). The impacts on organization outcomes were decrease in hospitalization (12.3%, 43/350) and increase of cost efficiency (10.9%, 38/350). CONCLUSIONS: This scoping review outlined ICT-enabled PCC in chronic disease management. Persons with a chronic disease could benefit from an ICT-enabled PCC approach, but ICT-PCC also yields organizational paybacks. It could lead to an increase in health care usage, as reported in some studies. Few interventions could be regarded as "fully" addressing PCC. This review will be especially helpful to those deciding on areas where further development of research or implementation of ICT-enabled PCC may be warranted. PMID- 25831200 TI - Mechanisms involved in the vasorelaxant effects produced by the acute application of amfepramone in vitro to rat aortic rings. AB - Amfepramone (diethylpropion) is an appetite-suppressant drug used for the treatment of overweight and obesity. It has been suggested that the systemic and central activity of amfepramone produces cardiovascular effects such as transient ischemic attacks and primary pulmonary hypertension. However, it is not known whether amfepramone produces immediate vascular effects when applied in vitro to rat aortic rings and, if so, what mechanisms may be involved. We analyzed the effect of amfepramone on phenylephrine-precontracted rat aortic rings with or without endothelium and the influence of inhibitors or blockers on this effect. Amfepramone produced a concentration-dependent vasorelaxation in phenylephrine precontracted rat aortic rings that was not affected by the vehicle, atropine, 4 AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. The vasorelaxant effect of amfepramone was significantly attenuated by NG-nitro-L-arginine methyl ester (L-NAME) and tetraethylammonium (TEA), and was blocked by removal of the vascular endothelium. These results suggest that amfepramone had a direct vasorelaxant effect on phenylephrine-precontracted rat aortic rings, and that inhibition of endothelial nitric oxide synthase and the opening of Ca2+-activated K+ channels were involved in this effect. PMID- 25831201 TI - Puerarin protects against damage to spatial learning and memory ability in mice with chronic alcohol poisoning. AB - We evaluated the effect of puerarin on spatial learning and memory ability of mice with chronic alcohol poisoning. A total of 30 male C57BL/6 mice were randomly divided into model, puerarin, and control groups (n=10 each). The model group received 60% (v/v) ethanol by intragastric administration followed by intraperitoneal injection of normal saline 30 min later. The puerarin group received intragastric 60% ethanol followed by intraperitoneal puerarin 30 min later, and the control group received intragastric saline followed by intraperitoneal saline. Six weeks after treatment, the Morris water maze and Tru Scan behavioral tests and immunofluorescence staining of cerebral cortex and hippocampal neurons (by Neu-N) and microglia (by Ib1) were conducted. Glutamic acid (Glu) and gamma amino butyric acid (GABA) in the cortex and hippocampus were assayed by high-performance liquid chromatography (HPLC), and tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were determined by ELISA. Compared with mice in the control group, escape latency and distance were prolonged, and spontaneous movement distance was shortened (P<0.05) by puerarin. The number of microglia was increased in both the cortex and hippocampal dentate gyrus (P<0.01), and neurons were reduced only in the hippocampal dentate gyrus (P<0.01) in puerarin-treated mice. In the model group, Glu and GABA levels decreased (P<0.05), and Glu/GABA, TNF-alpha, and IL-1beta increased (P<0.01) with puerarin treatment, returning to near normal levels. In conclusion, puerarin protected against the effects of chronic alcohol poisoning on spatial learning and memory ability primarily because of anti-inflammatory activity and regulation of the balance of Glu and GABA. PMID- 25831202 TI - Caffeic acid improves cell viability and protects against DNA damage: involvement of reactive oxygen species and extracellular signal-regulated kinase. AB - Hormesis is an adaptive response to a variety of oxidative stresses that renders cells resistant to harmful doses of stressing agents. Caffeic acid (CaA) is an important antioxidant that has protective effects against DNA damage caused by reactive oxygen species (ROS). However, whether CaA-induced protection is a hormetic effect remains unknown, as is the molecular mechanism that is involved. We found that a low concentration (10 MUM) of CaA increased human liver L-02 cell viability, attenuated hydrogen peroxide (H2O2)-mediated decreases in cell viability, and decreased the extent of H2O2-induced DNA double-strand breaks (DSBs). In L-02 cells exposed to H2O2, CaA treatment reduced ROS levels, which might have played a protective role. CaA also activated the extracellular signal regulated kinase (ERK) signal pathway in a time-dependent manner. Inhibition of ERK by its inhibitor U0126 or by its specific small interfering RNA (siRNA) blocked the CaA-induced improvement in cell viability and the protective effects against H2O2-mediated DNA damage. This study adds to the understanding of the antioxidant effects of CaA by identifying a novel molecular mechanism of enhanced cell viability and protection against DNA damage. PMID- 25831203 TI - Adult male circumcision with a circular stapler versus conventional circumcision: A prospective randomized clinical trial. AB - Male circumcision is the most frequently performed procedure by urologists. Safety and efficacy of the circumcision procedure requires continual improvement. In the present study, we investigated the safety and efficacy of a new male circumcision technique involving the use of a circular stapler. In total, 879 consecutive adult male patients were randomly divided into 2 groups: 441 underwent stapler circumcision, and 438 underwent conventional circumcision. The operative time, pain score, blood loss volume, healing time, treatment costs, and postoperative complications were compared between the two groups. The operative time and blood loss volume were significantly lower in the stapler group than in the conventional group (6.8 +/- 3.1 vs 24.2 +/- 3.2 min and 1.8 +/- 1.8 vs 9.4 +/ 1.5 mL, respectively; P<0.01 for both). The intraoperative and postoperative pain scores were significantly lower in the stapler group than in the conventional group (0.8 +/- 0.5 vs 2.4 +/- 0.8 and 4.0 +/-0.9 vs 5.8 +/- 1.0, respectively; P<0.01 for both). Additionally, the stapler group had significantly fewer complications than the conventional group (2.7% vs 7.8%, respectively; P<0.01). However, the treatment costs in the stapler group were much higher than those in the conventional group (US$356.60 +/- 8.20 vs US$126.50 +/- 7.00, respectively; P<0.01). Most patients (388/441, 88.0%) who underwent stapler circumcision required removal of residual staple nails. Overall, the present study has shown that stapler circumcision is a time-efficient and safe male circumcision technique, although it requires further improvement. PMID- 25831205 TI - Circulating endothelial cells are increased in chronic myeloid leukemia blast crisis. AB - We measured circulating endothelial precursor cells (EPCs), activated circulating endothelial cells (aCECs), and mature circulating endothelial cells (mCECs) using four-color multiparametric flow cytometry in the peripheral blood of 84 chronic myeloid leukemia (CML) patients and 65 healthy controls; and vascular endothelial growth factor (VEGF) by quantitative real-time PCR in 50 CML patients and 32 healthy controls. Because of an increase in mCECs, the median percentage of CECs in CML blast crisis (0.0146%) was significantly higher than in healthy subjects (0.0059%, P<0.01) and in the accelerated phase (0.0059%, P=0.01). There were no significant differences in the percentages of CECs in chronic- or active-phase patients and healthy subjects (P>0.05). In addition, VEGF gene expression was significantly higher in all phases of CML: 0.245 in blast crisis, 0.320 in the active phase, and 0.330 in chronic phase patients than it was in healthy subjects (0.145). In conclusion, CML in blast crisis had increased levels of CECs and VEGF gene expression, which may serve as markers of disease progression and may become targets for the management of CML. PMID- 25831206 TI - Dynamic resistance training decreases sympathetic tone in hypertensive ovariectomized rats. AB - The aim of this study was to investigate the effects of resistance exercise training on hemodynamics and cardiac autonomic control in ovariectomized spontaneously hypertensive rats. Female rats were divided into 4 groups: sedentary control (SC), sedentary hypertensive (SH), sedentary hypertensive ovariectomized (SHO), and resistance-trained hypertensive ovariectomized (RTHO). Resistance exercise training was performed on a vertical ladder (5 days/week, 8 weeks) at 40-60% maximal load. Direct arterial pressure was recorded. Vagal and sympathetic tones were measured by heart rate (HR) responses to methylatropine (3 mg/kg, iv) and propranolol (4 mg/kg, iv). Ovariectomy resulted in additional increases in blood pressure in hypertensive rats and was associated with decreased vagal tone. Resistance exercise trained rats had lower mean arterial pressure than untrained rats (RTHO: 159+/-2.2 vs SHO: 177+/-3.4 mmHg), as well as resting bradycardia (RTHO: 332+/-9.0 vs SHO: 356+/-5 bpm). Sympathetic tone was also lower in the trained group. Moreover, sympathetic tone was positively correlated with resting HR (r=0.7, P<0.05). The additional arterial pressure increase in hypertensive rats caused by ovarian hormone deprivation was attenuated by moderate-intensity dynamic resistance training. This benefit may be associated with resting bradycardia and reduced cardiac sympathetic tone after training, which suggests potential benefits of resistance exercise for the management of hypertension after ovarian hormone deprivation. PMID- 25831207 TI - Comparative pathogenicity of Coxsackievirus A16 circulating and noncirculating strains in vitro and in a neonatal mouse model. AB - An enterovirus 71 (EV71) vaccine for the prevention of hand, foot, and mouth disease (HMFD) is available, but it is not known whether the EV71 vaccine cross protects against Coxsackievirus (CV) infection. Furthermore, although an inactivated circulating CVA16 Changchun 024 (CC024) strain vaccine candidate is effective in newborn mice, the CC024 strain causes severe lesions in muscle and lung tissues. Therefore, an effective CV vaccine with improved pathogenic safety is needed. The aim of this study was to evaluate the in vivo safety and in vitro replication capability of a noncirculating CVA16 SHZH05 strain. The replication capacity of circulating CVA16 strains CC024, CC045, CC090 and CC163 and the noncirculating SHZH05 strain was evaluated by cytopathic effect in different cell lines. The replication capacity and pathogenicity of the CC024 and SHZH05 strains were also evaluated in a neonatal mouse model. Histopathological and viral load analyses demonstrated that the SHZH05 strain had an in vitro replication capacity comparable to the four CC strains. The CC024, but not the SHZH05 strain, became distributed in a variety of tissues and caused severe lesions and mortality in neonatal mice. The differences in replication capacity and in vivo pathogenicity of the CC024 and SHZH05 strains may result from differences in the nucleotide and amino acid sequences of viral functional polyproteins P1, P2 and P3. Our findings suggest that the noncirculating SHZH05 strain may be a safer CV vaccine candidate than the CC024 strain. PMID- 25831208 TI - Expression of intronic miRNAs and their host gene Igf2 in a murine unilateral ureteral obstruction model. AB - The objective of this study was to determine the expression of miR-483 and miR 483* and the relationship among them, their host gene (Igf2), and other cytokines in a murine model of renal fibrosis. The extent of renal fibrosis was visualized using Masson staining, and fibrosis was scored 3 days and 1 and 2 weeks after unilateral ureteral obstruction (UUO). Expression of miR-483, miR-483* and various cytokine mRNAs was detected by real-time polymerase chain reaction (PCR). Expression of miR-483 and miR-483* was significantly upregulated in the UUO model, particularly miR-483 expression was the greatest 2 weeks after surgery. Additionally, miR-483 and miR-483* expression negatively correlated with Bmp7 expression and positively correlated with Igf2, Tgfbeta, Hgf, and Ctgf expression, as determined by Pearson's correlation analysis. Hgf expression significantly increased at 1 and 2 weeks after the surgery compared to the control group. This study showed that miR-483 and miR-483* expression was upregulated in a murine UUO model. These data suggest that miR-483 and miR-483* play a role in renal fibrosis and that miR-483* may interact with miR-483 in renal fibrosis. Thus, these miRNAs may play a role in the pathogenesis of renal fibrosis and coexpression of their host gene Igf2. PMID- 25831209 TI - Role of mitochondrial ATP-sensitive potassium channel-mediated PKC-epsilon in delayed protection against myocardial ischemia/reperfusion injury in isolated hearts of sevoflurane-preconditioned rats. AB - This study aimed to determine the role of mitochondrial adenosine triphosphate sensitive potassium (mitoKATP) channels and protein kinase C (PKC)-epsilon in the delayed protective effects of sevoflurane preconditioning using Langendorff isolated heart perfusion models. Fifty-four isolated perfused rat hearts were randomly divided into 6 groups (n=9). The rats were exposed for 60 min to 2.5% sevoflurane (the second window of protection group, SWOP group) or 33% oxygen inhalation (I/R group) 24 h before coronary occlusion. The control group (CON) and the sevoflurane group (SEVO) group were exposed to 33% oxygen and 2.5% sevoflurane for 60 min, respectively, without coronary occlusion. The mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD) was given 30 min before sevoflurane preconditioning (5-HD+SWOP group). Cardiac function indices, infarct sizes, serum cardiac troponin I (cTnI) concentrations, and the expression levels of phosphorylated PKC-epsilon (p-PKC-epsilon) and caspase-8 were measured. Cardiac function was unchanged, p-PKC-epsilon expression was upregulated, caspase-8 expression was downregulated, cTnI concentrations were decreased, and the infarcts were significantly smaller (P<0.05) in the SWOP group compared with the I/R group. Cardiac function was worse, p-PKC-epsilon expression was downregulated, caspase-8 expression was upregulated, cTnI concentration was increased and infarcts were larger in the 5-HD+SWOP group (P<0.05) compared with the SWOP group. The results suggest that mitoKATP channels are involved in the myocardial protective effects of sevoflurane in preconditioning against I/R injury, by regulating PKC-epsilon phosphorylation before ischemia, and by downregulating caspase-8 during reperfusion. PMID- 25831211 TI - Ultrasensitive colorimetric assay of cadmium ion based on silver nanoparticles functionalized with 5-sulfosalicylic acid for wide practical applications. AB - Low-level cadmium ion (Cd(2+)) exposure contributes much toward the causation of chronic disease. Due to its low permissible exposure limit, overexposures may occur even in situations where trace quantities of Cd(2+) exist. So far, no effective treatment for Cd(2+) toxicity has been reported. Prevention of further exposure is the most important step in management of patients suggestive of Cd(2+) intoxication. Development of sensors for Cd(2+) is of great interest to ensure early diagnosis and improve management. We propose here a simple, low-cost (0.1$ per sample) yet very sensitive (limit of detection is 3.0 nM) and selective colorimetric assay for rapid (2 min) determination of Cd(2+) based on 5 sulfosalicylic acid functionalized silver nanoparticles (SAA-AgNPs). This method shows excellent selectivity for Cd(2+) over the other 16 metal ions. It is also precise and highly reproducible in determining Cd(2+) in real samples such as tap water, milk, serum, and urine with recoveries ranging from 93 to 110%, indicating the wide practical application to samples suspected of Cd(2+) exposure. PMID- 25831210 TI - Estimation of salivary nitric oxide in oral precancer patients. AB - The role of nitric oxide (NO) in the initiation, promotion and progression of cancer has been the subject of speculation and conflicting reports in the literature. The high incidence of oral cancer and precancer has been linked to tobacco chewing and smoking habits; NO is considered an indicator of tobacco related diseases. We compared salivary NO levels in oral precancer and normal patients. Unstimulated whole saliva was collected from 15 patients with oral precancer (group 1) and 15 healthy age and sex matched subjects (group 2). Salivary nitrite levels were estimated using a colorimetric method and a spectrophotometer. The salivary nitrite concentration of group 2 (median = 4.21 MUg/ml) was significantly less than for group 1 (median = 12.91 MUg/ml). We have added evidence concerning involvement of NO in the pathogenesis of oral cancer, but whether it is a potentially carcinogenic agent at the concentration at which it is present in oral precancer patients requires further evaluation. PMID- 25831212 TI - Virulence profile: George N Belibasakis. PMID- 25831213 TI - A unifying model for adsorption and nucleation of vapors on solid surfaces. AB - Vapor interaction with solid surfaces is traditionally described with adsorption isotherms in the undersaturated regime and with heterogeneous nucleation theory in the supersaturated regime. A class of adsorption isotherms is based on the idea of vapor molecule clustering around so-called active sites. However, as the isotherms do not account for the surface curvature effects of the clusters, they predict an infinitely thick adsorption layer at saturation and do not recognize the existence of the supersaturated regime. The classical heterogeneous nucleation theory also builds on the idea of cluster formation, but describes the interactions between the surface and the cluster with a single parameter, the contact angle, which provides limited information compared with adsorption isotherms. Here, a new model of vapor adsorption on nonporous solid surfaces is derived. The basic assumption is that adsorption proceeds via formation of molecular clusters, modeled as liquid caps. The equilibrium of the individual clusters with the vapor phase is described with the Frenkel-Halsey-Hill (FHH) adsorption theory modified with the Kelvin equation that corrects for the curvature effect on vapor pressure. The new model extends the FHH adsorption isotherm to be applicable both at submonolayer surface coverages and at supersaturated conditions. It shows good agreement with experimental adsorption data from 12 different adsorbent-adsorbate systems. The model predictions are also compared against heterogeneous nucleation data, and they show much better agreement than predictions of the classical heterogeneous nucleation theory. PMID- 25831214 TI - Extensive temporal transcriptome and microRNA analyses identify molecular mechanisms underlying mitochondrial dysfunction induced by multi-walled carbon nanotubes in human lung cells. AB - Understanding toxicity pathways of engineered nanomaterials (ENM) has recently been brought forward as a key step in twenty-first century ENM risk assessment. Molecular mechanisms linked to phenotypic end points is a step towards the development of toxicity tests based on key events, which may allow for grouping of ENM according to their modes of action. This study identified molecular mechanisms underlying mitochondrial dysfunction in human bronchial epithelial BEAS 2B cells following exposure to one of the most studied multi-walled carbon nanotubes (Mitsui MWCNT-7). Asbestos was used as a positive control and a non carcinogenic glass wool material was included as a negative fibre control. Decreased mitochondrial membrane potential (MMP?) was observed for MWCNTs at a biologically relevant dose (0.25 MUg/cm(2)) and for asbestos at 2 MUg/cm(2), but not for glass wool. Extensive temporal transcriptomic and microRNA expression analyses identified a 330-gene signature (including 26 genes with known mitochondrial function) related to MWCNT- and asbestos-induced MMP?. Forty-nine of the MMP?-associated genes showed highly similar expression patterns over time (six time points) and the majority was found to be regulated by two transcription factors strongly involved in mitochondrial homeostasis, APP and NRF1. In addition, four miRNAs were correlated with MMP? and one of them, miR-1275, was found to negatively correlate with a large part of the MMP?-associated genes. Cellular processes such as gluconeogenesis, mitochondrial LC-fatty acid beta oxidation and spindle microtubule function were enriched among the MMP? associated genes and miRNAs. These results are expected to be useful in the identification of key events in ENM-related toxicity pathways for the development of molecular screening techniques. PMID- 25831215 TI - Free energy surface of the Michaelis complex of lactate dehydrogenase: a network analysis of microsecond simulations. AB - It has long been recognized that the structure of a protein creates a hierarchy of conformations interconverting on multiple time scales. The conformational heterogeneity of the Michaelis complex is of particular interest in the context of enzymatic catalysis in which the reactant is usually represented by a single conformation of the enzyme/substrate complex. Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of two forms of the cofactor nicotinamide adenine dinucleotide (NADH and NAD(+)). Recent experimental results suggest that multiple substates exist within the Michaelis complex of LDH, and they show a strong variance in their propensity toward the on-enzyme chemical step. In this study, microsecond scale all-atom molecular dynamics simulations were performed on LDH to explore the free energy landscape of the Michaelis complex, and network analysis was used to characterize the distribution of the conformations. Our results provide a detailed view of the kinetic network of the Michaelis complex and the structures of the substates at atomistic scales. They also shed light on the complete picture of the catalytic mechanism of LDH. PMID- 25831216 TI - Alginate lyase: Review of major sources and classification, properties, structure function analysis and applications. AB - Alginate lyases catalyze the degradation of alginate, a complex copolymer of alpha-L-guluronate and its C5 epimer beta-D-mannuronate. The enzymes have been isolated from various kinds of organisms with different substrate specificities, including algae, marine mollusks, marine and terrestrial bacteria, and some viruses and fungi. With the progress of structural biology, many kinds of alginate lyases of different polysaccharide lyases families have been characterized by obtaining crystal structures, and the catalytic mechanism has also been elucidated. Combined with various studies, we summarized the source, classification and properties of the alginate lyases from different polysaccharide lyases families. The relationship between substrate specificity and protein sequence was also investigated. PMID- 25831217 TI - Can fecal calprotectin better stratify Crohn's disease activity index? AB - BACKGROUND: Crohn's disease (CD) activity index (CDAI) is still widely used for monitoring clinical activity in CD patients, but is of little value as indicator of persistent inflammation in symptomless patients. Fecal calprotectin levels >=150 ug/g are strongly indicative of endoscopically and/or histologically active disease. Our aim was to study, in a large cohort of CD patients, the relationship between CDAI and fecal calprotectin levels. METHODS: CDAI and fecal calprotectin levels were evaluated in consecutive patients from a CD outpatient clinic. RESULTS: We enrolled 193 CD patients, of whom 38% with CDAI <150 had a calprotectin value >=150 ug/g, suggestive of active disease. A logistic regression model showed that for CDAI levels between 100 and 150, the estimated logistic probability of calprotectin >=150 ug/g increased progressively to 76%, reaching 94% where disease activity was localized in the colon. With a CDAI cut off >120, we found a high diagnostic accuracy of 72%, with 88% specificity and 50% sensitivity (positive predictive value: 76%, negative predictive value: 71%) to identify a calprotectin value >=150 ug/g. CONCLUSION: CDAI scores between 100 and 150 display an acceptable ability to quantify the risk of persistent inflammation as expressed by the high calprotectin level. PMID- 25831218 TI - Chemiluminescence efficiency of catalyzed 1,2-dioxetanone decomposition determined by steric effects. AB - The chemiluminescent decomposition of 1,2-dioxetanones (alpha-peroxylactones), catalyzed by an appropriate fluorescent activator, is an important simple model for efficient bioluminescent transformations. In this work, we report experimental data on the catalyzed decomposition of two spiro-substituted 1,2 dioxetanone derivatives, which support the occurrence of an intermolecular electron transfer from the activator to the peroxide. The low efficiency of the studied systems is associated with steric hindrance during the chemiexcitation sequence, rationalized using the concept of supermolecule formation between the peroxide and the catalyst. This approach explains the difference in the chemiexcitation efficiencies in the decomposition of four-membered cyclic peroxide derivatives: 1,2-dioxetanes, 1,2-dioxetanones, and 1,2-dioxetanedione (the intermediate in the peroxyoxalate reaction), which are the most important model compounds for excited-state formation in chemiluminescence and bioluminescence processes. PMID- 25831219 TI - Is there a need to increase the dose of efavirenz during concomitant rifampicin based antituberculosis therapy in sub-Saharan Africa? The HIV-TB pharmagene study. AB - AIMS: The current HIV treatment guidelines are inconsistent about the need for weight-based efavirenz dose adjustment during rifampicin containing antituberculosis (anti-TB) cotreatment. We investigated effect of rifampicin based anti-TB cotreatment on plasma efavirenz exposure and treatment outcome, considering effect of CYP2B6 genotype and bodyweight. PATIENTS & METHODS: HIV only (arm 1, n = 285) or TB-HIV (arm 2, n = 208) coinfected patients were enrolled and received efavirenz-based ART alone or with rifampicin-based anti-TB therapy, respectively. Plasma efavirenz concentrations at 4th and 16th weeks, viral load and CD4 cell count at 24th and 48th weeks were determined. RESULTS: The mean plasma efavirenz concentration at weeks 4 (p = 0.03) and 16 (p = 0.08) was inconsistently higher in arm 2 than arm 1, mainly in CYP2B6*6 carriers. Effect of bodyweight on efavirenz pharmacokinetics was significant only in arm 1, but not in arm 2. Proportion of patients with nondetectable viral load (<=50 copies/ml) at week 24 was higher in arm 1 than arm 2 patients (91.0 vs 76.3%; p = 0.002), but no significant difference was observed at week 48 (89.5 vs 87.8%; p = 0.22). CONCLUSION: Rifampicin-based anti-TB cotreatment has no significant influence on long-term efavirenz plasma exposure and efficacy. Hence, there is no need to increase the dose of efavirenz during concomitant rifampicin-based anti TB cotreatment in the sub-Saharan African population. PMID- 25831220 TI - Affordable Care Act and telemedicine. PMID- 25831221 TI - [Thumb Reconstruction after Oncological Resection of a Rare Aggressive Digital Papillary Adenocarcinoma: A Case Report]. AB - We present the case of a 44-year-old female with an aggressive digital papillary adenocarcinoma of the right thumb. Aggressive digital papillary adenocarcinomas are rare tumours originating from sweat glands of the skin on the hand or foot. The tumour was located at the extensor side and had been excised in 2 operations after diagnosis as an eccine hidradenoma, which is exceptional in this case. The tumour was radically excised and the defect was reconstructed using arthrodesis, and a retrogradely perfused pedicle radialis fascial flap with skin graft, due to which amputation was avoided. PMID- 25831222 TI - Coronary computed tomography angiography predicts subsequent cardiac outcome events: results of the Visipaque CCTA registry study. AB - OBJECTIVES: To evaluate the diagnostic performance and predictive value of coronary computed tomography angiography (CCTA) on subsequent cardiac outcomes. BACKGROUND: CCTA has been suggested as an alternative method to invasive coronary angiography for detection of and ruling out coronary artery disease (CAD). However, the usefulness of CCTA findings in predicting patient outcome in routine clinical practice is still uncertain. MATERIALS AND METHODS: A prospective, multicenter registry study of CCTA with a Visipaque injection 320 mg I/ml was carried out in symptomatic patients suspected of having CAD as part of their medical care. CCTA findings were used to guide patient management decisions. Patient cardiac outcomes were followed at 1, 6, and 12 months after the CCTA procedure for the occurrence of major adverse cardiac event (MACE) (cardiac death, nonfatal myocardial infarction, or unstable angina requiring hospitalization). All cardiac outcome events or deaths were adjudicated independently. RESULTS: Of 874 patients (mean age=59 years; 51% men) who received Visipaque, 857 were included in the efficacy analysis. Using cardiac outcomes as the endpoint, the sensitivity of CCTA was 96.1, 95.8, and 94.7%, specificity was 84.5, 86.6, and 87.0%, and negative predictive value more than 99.0% at 1, 6, and 12 months, respectively. At 12 months, the rate of MACE was 5.7% (10/174) in patients with a positive CCTA (one or more >=50% stenosis) and 0.1% (1/683) in patients with a negative CCTA (99.9% MACE-free survival rate). The Cox proportional hazards analysis with CCTA outcome, age, sex, reasons for CCTA, and cardiac risk factors as covariates showed a hazard ratio of 87.6 for positive versus negative CCTA (P=0.0001). CONCLUSION: CCTA is a highly accurate, noninvasive tool to detect or rule out subsequent cardiovascular events in patients with intermediate pretest probability of CAD or an uninterpretable/equivocal stress test. A positive CCTA finding contributed significantly toward the prediction of subsequent MACE whereas a negative CCTA carried excellent prognostic outcomes at 12 months. PMID- 25831223 TI - White blood cell counts in predicting cardiovascular events: the racial ratios. PMID- 25831224 TI - Quantitative aspects of the identification of Fe(ii) moieties in ZSM-5 zeolites with various pore hierarchies. AB - This work was attempted in order to provide a new and well-established approach for the quantification of Fe(2+) sites in zeolites. The experimental procedure was based on carbon monoxide and nitrogen monoxide sorption in Fe-exchanged ZSM-5 zeolites with different pore hierarchies, which was followed by IR spectroscopy. The values of the absorption coefficients of the respective monocarbonyl Fe(2+)(CO) and mononitrosyl Fe(2+)(NO) IR bands were obtained. In turn, the concentrations of Fe(ii) moieties of various kinds were calculated and discussed with regard to the composition (Si/Al and Fe/Al ratios) of the zeolites studied. PMID- 25831225 TI - Conversion of zirconacyclopentadienes into metalloles: Fagan-Nugent reaction and beyond. AB - Metalloles are derivatives of cyclopentadiene in which the methylene unit is replaced by a heteroatom, such as S, Se, Te, N, P, As, Sb, Bi, Si, Ge, Sn, B, Al, Ga, and so on. Many metallole derivatives have been widely used as photovoltaic cells, organic light emitting diodes (OLEDs), chemical sensors, electrochromic devices, microelectronic actuators, and organic field effect transistors (OFETs). In the meantime, many of them showed promising biological actives. Due to the similarity to cyclopentadiene, the anionic forms of metalloles were also widely explored in coordination chemistry. As a result, development of a general method for the formation of metalloles from available starting materials is highly desired. In this Account, we outline formation of various p-block element metalloles from zirconacyclopentadienes. The zirconacyclopentadienes can be easily prepared from two molecules of alkynes and a low-valent zirconocene species "Cp2Zr(II)" (Cp = cyclopentadienyl). Fagan and Nugent first reported the formation of main group metalloles from zirconacyclopentadiene, which provided a versatile approach for the construction of metalloles, especially for the formation of metalloles in heavier p-block elements. To further expand the substrate scope, a number of stepwise conversions were developed, which involve 1,4-dimetallo- or dihalo-1,3-butadiene as intermediates from zirconacyclopentadienes. Here, four processes are classified based on direct and indirect conversion of zirconacyclopentadienes into metalloles. Direct reaction of zirconacyclopentadienes with element halides afforded heterocycles of main group elements, which provided a versatile method for the synthesis of metalloles. Nonetheless, the reaction scope was restricted to heavier p-block elements such as S, Se, P, As, Sb, Bi, Ge, Sn, Ga, and In. And these reactions usually suffered low yields and long reaction time. Transmetalation of zirconacyclopentadiene with copper chloride greatly enriched the zirconacyclopentadiene chemistry. The synthesis of stannoles and pyrroles from zirconacyclopentadienes has been developed in the presence of CuCl. The direct reaction of the zirconacyclopentadienes with SiCl4 or R2SiCl2 does not give the desired silacyclopendadiene derivatives, even in the presence of CuCl. It can be circumvented by using dilithiated dienes from diiododienes, which are easily prepared by the iodination of zirconacyclopentadienes using CuCl as an additive. Finally, an umpolung strategy, reaction of electrophilic 1,4-diiodo-1,3-butadiene with nucleophilic amine or sulfide reagents, was successfully used in the formation of pyrroles and thiophenes. PMID- 25831226 TI - Alteration in the expression of cytochrome P450s (CYP1A1, CYP2E1, and CYP3A11) in the liver of mouse induced by microcystin-LR. AB - Microcystins (MCs) are cyclic heptapeptide toxins and can accumulate in the liver. Cytochrome P450s (CYPs) play an important role in the biotransformation of endogenous substances and xenobiotics in animals. It is unclear if the CYPs are affected by MCs exposure. The objective of this study was to evaluate the effects of microcystin-LR (MCLR) on cytochrome P450 isozymes (CYP1A1, CYP2E1, and CYP3A11) at mRNA level, protein content, and enzyme activity in the liver of mice the received daily, intraperitoneally, 2, 4, and 8 ug/kg body weight of MCLR for seven days. The result showed that MCLR significantly decreased ethoxyresorufin-O deethylase (EROD) (CYP1A1) and erythromycin N-demthylase (ERND) (CYP3A11) activities and increased aniline hydroxylase (ANH) activity (CYP2E1) in the liver of mice during the period of exposure. Our findings suggest that MCLR exposure may disrupt the function of CYPs in liver, which may be partly attributed to the toxicity of MCLR in mice. PMID- 25831228 TI - Directed assembly of single colloidal gold nanowires by AFM nanoxerography. AB - Ultrathin gold nanowires (NWs) dispersed in hexane were prepared by chemical reduction of HAuCl4 in oleylamine, along with nanospheres (NSs), side products of the reaction. X-ray photoelectron spectroscopy and small-angle X-ray scattering evidenced a stabilization of these nano-objects by oleylammonium chloride surfactants. The directed assembly of these nano-objects on surfaces was performed by atomic force microscopy (AFM) nanoxerography in a few seconds. Selective assembly of gold NWs only occurred on positively charged patterns, while NSs assembled more specifically on the negatively charged ones. This sorting suggests that the strong electric field generated by the charge patterns induced a negative effective charge on the gold NWs and a weak positive effective charge on the NSs. Such difference could be explained by the ion organization at the colloid surface, monolayered in the case of NWs, and bilayered in the case of NSs. By adjusting the design of the positive patterns and the experimental conditions of development, single gold nanowires were successfully assembled by AFM nanoxerography on predefined sites of surfaces without damaging them, opening the way for future electrical and mechanical characterizations. PMID- 25831227 TI - Clinical significance of microscopic melanoma metastases in the nonhottest sentinel lymph nodes. AB - IMPORTANCE: A practice gap exists in the surgical removal of sentinel lymph nodes, from removal of only the most radioactive (hottest) lymph node to removal of all lymph nodes with radioactivity greater than 10% of the hottest lymph node. OBJECTIVE: To determine the clinical significance of melanoma in sentinel lymph nodes that are not the hottest sentinel node and to determine the risk for disease progression based on sentinel lymph node status and primary tumor characteristics. DESIGN, SETTING, AND PARTICIPANTS: Consecutive patients with cutaneous melanoma with sentinel lymph nodes resected from January 5, 2004, to June 30, 2008, with a mean follow-up of 59 months, at Massachusetts General Hospital were included in this retrospective review. The last year of follow-up was 2012. The operative protocol led to resection of all sentinel lymph nodes with radioactivity greater than 10% of the hottest lymph node. The number of lymph nodes removed, technetium-99m counts for each sentinel lymph node, presence or absence of sentinel lymph node metastases, primary tumor characteristics, disease progression, and melanoma-specific survival were recorded. MAIN OUTCOMES AND MEASURES: Microscopic melanoma metastases in the hottest and nonhottest sentinel lymph nodes and factors that correlate with disease progression and mortality. RESULTS: A total of 1575 sentinel lymph nodes were analyzed in 475 patients. Ninety-one patients (19%) had positive sentinel lymph nodes. Of these, 72 (79%) had metastases in the hottest sentinel lymph node. Of 19 cases with tumor present, but not in the hottest sentinel lymph node, counts ranged from 26% to 97% of the hottest node. Progression occurred in 43% of patients with sentinel node metastasis, regardless of whether the hottest lymph node was positive. In patients with negative sentinel lymph nodes, 11% developed metastases beyond the sentinel lymph node basin and 3.4% recurred in the basin. Mitogenicity of the primary tumor was associated with mortality (odds ratio, 2.435; 95% CI, 1.351 4.391; P < .001). Removing only the hottest sentinel lymph node would have led to false-negative results in 19 of 475 (4%) of all patients and 19 of 91 patients (21%) with positive sentinel lymph nodes. The 8-year survival in patients with at least 1 positive sentinel lymph node was less than 55%. The presence of more than 1 mitosis per square millimeter in the primary cutaneous melanoma was associated with decreased survival. CONCLUSIONS AND RELEVANCE: Microscopic melanoma metastases was associated with disease progression and mortality, whether present in the hottest sentinel lymph node or not. These observations emphasize the importance of removing the less hot nodes, addressing a practice gap in the surgical approach to patients with melanoma. PMID- 25831229 TI - Green sample preparation for liquid chromatography and capillary electrophoresis of anionic and cationic analytes. AB - A sample preparation device for the simultaneous enrichment and separation of cationic and anionic analytes was designed and implemented in an eight-channel configuration. The device is based on the use of an electric field to transfer the analytes from a large volume of sample into small volumes of electrolyte that was suspended into two glass micropipettes using a conductive hydrogel. This simple, economical, fast, and green (no organic solvent required) sample preparation scheme was evaluated using cationic and anionic herbicides as test analytes in water. The analytical figures of merit and ecological aspects were evaluated against the state-of-the-art sample preparation, solid-phase extraction. A drastic reduction in both sample preparation time (94% faster) and resources (99% less consumables used) was observed. Finally, the technique in combination with high-performance liquid chromatography and capillary electrophoresis was applied to analysis of quaternary ammonium and phenoxypropionic acid herbicides in fortified river water as well as drinking water (at levels relevant to Australian guidelines). The presented sustainable sample preparation approach could easily be applied to other charged analytes or adopted by other laboratories. PMID- 25831230 TI - Increasing physical activity and exercise in lung cancer: reviewing safety, benefits, and application. AB - Lung cancer continues to be a difficult disease frequently diagnosed in late stages with a high mortality and symptom burden. In part because of frequent lung comorbidity, even lung cancer survivors often remain symptomatic and functionally limited. Though targeted therapy continues to increase treatment options for advanced-stage disease, symptom burden remains high with few therapeutic options. In the last several decades, exercise and physical activity have arisen as therapeutic options for obstructive lung disease and lung cancer. To date, exercise has been shown to reduce symptoms, increase exercise tolerance, improve quality of life, and potentially reduce length of stay and postoperative complications. Multiple small trials have been performed in perioperative non small-cell lung cancer patients, although fewer studies are available for patients with advanced-stage disease. Despite the increased interest in this subject over the last few years, a validated exercise regimen has not been established for perioperative or advanced-stage disease. Clinicians underutilize exercise and pulmonary rehabilitation as a therapy, in part because of the lack of evidence-based consensus as to how and when to implement increasing physical activity. This review summarizes the existing evidence on exercise in lung cancer patients. PMID- 25831231 TI - GNeosomes: Highly Lysosomotropic Nanoassemblies for Lysosomal Delivery. AB - GNeosomes, lysosomotropic lipid vesicles decorated with guanidinoneomycin, can encapsulate and facilitate the cellular internalization and lysosomal delivery of cargo ranging from small molecules to high molecular weight proteins, in a process that is exclusively dependent on cell surface glycosaminoglycans. Their cellular uptake mechanism and co-localization with lysosomes, as well as the delivery, release, and activity of internalized cargo, are quantified. GNeosomes are proposed as a universal platform for lysosomal delivery with potential as a basic research tool and a therapeutic vehicle. PMID- 25831232 TI - Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy. AB - Gastrointestinal stromal tumors (GIST) are driven mostly by oncogenic KIT or PDGFRA mutations. However, in 10-15% of all GIST, no such activating mutations can be found and these tumors are classified as 'wild-type GIST' (KIT/PDGFRA wt GIST). Subgroups of KIT/PDGFRA wt-GIST are driven by other sporadic mutations involving the RAS/RAF/MAP-kinase pathway, such as BRAF or KRAS mutations. Furthermore, KIT/PDGFRA wt-GIST are observed in the context of hereditary syndromes, such as neurofibromatosis Type 1, in which the lack of neurofibromin 1 also leads to the activation of the RAS/RAF/MAP-kinase pathway. Finally, the deficiency succinate dehydrogenase seems to play a major role in KIT/PDGFRA wt GIST. In conclusion, KIT/PDGFRA wt-GIST belong to different subgroups defined by diverse underlying genetic alterations leading to different biological phenotypes. The vast majority of KIT/PDGFRA wt-GIST will not respond to imatinib. Further research to unravel the pathogenesis of KIT/PDGFRA wt-GIST is prerequisite to the development of effective treatment strategies. PMID- 25831233 TI - Introduction to special issue in memorial of Nicki R. Crick: Development of peer victimization in children and adolescents. PMID- 25831234 TI - Racial and ethnic disparities in breastfeeding. AB - This article's aim is to review the literature on racial and ethnic disparities in breastfeeding rates and practices, address barriers to breastfeeding among minority women, conduct a systematic review of breastfeeding interventions, and provide obstetrician-gynecologists with recommendations on how they can help increase rates among minority women. In order to do so, the literature of racial and ethnic disparities in breastfeeding rates and barriers among minority women was reviewed, and a systematic review of breastfeeding interventions among minority women on PubMed and MEDLINE was conducted. Racial and ethnic minority women continue to have lower breastfeeding rates than white women and are not close to meeting the Healthy People 2020 goals. Minority women report many barriers to breastfeeding. Major efforts are still needed to improve breastfeeding initiation and duration rates among minority women in the United States. Obstetrician-gynecologists have a unique opportunity to promote and support breastfeeding through their clinical practices and public policy, and their efforts can have a meaningful impact on the future health of the mother and child. PMID- 25831235 TI - The anticancer and antiobesity effects of Mediterranean diet. AB - Cancers have been the leading cause of death worldwide and the prevalence of obesity is also increasing in these few decades. Interestingly, there is a direct association between cancer and obesity. Each year, more than 90,000 cancer deaths are caused by obesity or overweight. The dietary pattern in Crete, referred as the traditional Mediterranean diet, is believed to confer Crete people the low mortality rates from cancers. Nevertheless, the antiobesity effect of the Mediterranean diet is less studied. Given the causal relationship between obesity and cancer, the antiobesity effect of traditional Mediterranean diet might contribute to its anticancer effects. In this regard, we will critically review the anticancer and antiobesity effects of this diet and its dietary factors. The possible mechanisms underlying these effects will also be discussed. PMID- 25831236 TI - Gut bacteria require neutrophils to promote mammary tumorigenesis. AB - Recent studies suggest that gastrointestinal tract microbiota modulate cancer development in distant non-intestinal tissues. Here we tested mechanistic hypotheses using a targeted pathogenic gut microbial infection animal model with a predilection to breast cancer. FVB-Tg(C3-1-TAg)cJeg/JegJ female mice were infected by gastric gavage with Helicobacter hepaticus at three-months-of-age putting them at increased risk for mammary tumor development. Tumorigenesis was multifocal and characterized by extensive infiltrates of myeloperoxidase-positive neutrophils otherwise implicated in cancer progression in humans and animal models. To test whether neutrophils were important in etiopathogenesis in this bacteria-triggered model system, we next systemically depleted mice of neutrophils using thrice weekly intraperitoneal injections with anti-Ly-6G antibody. We found that antibody depletion entirely inhibited tumor development in this H. hepaticus-infected model. These data demonstrate that host neutrophil associated immune responses to intestinal tract microbes significantly impact cancer progression in distal tissues such as mammary glands, and identify gut microbes as novel targets for extra-intestinal cancer therapy. PMID- 25831239 TI - Introduction. PMID- 25831238 TI - Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma. AB - The deletion of 12p (del(12p)) has been described as a novel negative prognostic marker in multiple myeloma (MM) and has gained increasing attention in recent years. However, its impact on MM is still controversial. In this study, we comprehensively evaluated the clinical impact of 12p13 deletion using fluorescence in situ hybridization (FISH) on 275 newly diagnosed MM cases treated in a prospective, non-randomized clinical trial (BDH 2008/02). The results showed that deletion of 12p13 was detected in 10.5% of newly diagnosed cases and associated with multiple indicators for high tumor burden including ISS III, BM plasmacytosis larger than 50%, and renal lesion. Moreover, the cases with 12p13 deletion typically had higher incidence of del(17p), IGH translocation and t(4;14). Patients with del(12p) conferred significantly adverse prognosis for PFS and OS, even in patients subjected to bortezomib-based therapy. When adjusted to the established prognostic variables including del(13q), del(17p), t(4;14), amp(1q21), ISS stage and LDH, del(12p13) remained the powerful independent adverse factor for PFS (P = 0.007) and OS (P = 0.032). In addition, del(12p13) combined with high beta2-MG, high LDH and bone lesion can further identify subpopulations with high-risk features. Our results strongly supported that del(12p13) can be used as a valuable prognostic marker in MM. PMID- 25831237 TI - miR-340 suppresses glioblastoma multiforme. AB - Deregulation of microRNAs (miRs) contributes to tumorigenesis. Down-regulation of miR-340 is observed in multiple types of cancers. However, the biological function of miR-340 in glioblastoma multiforme (GBM) remains largely unknown. In the present study, we demonstrated that expression of miR-340 was downregulated in both glioma cell lines and tissues. Survival of GBM patients with high levels of miR-340 was significantly extended in comparison to patients expressing low miR-340 levels. Biological functional experiments showed that the restoration of miR-340 dramatically inhibited glioma cell proliferation, induced cell-cycle arrest and apoptosis, suppressed cell motility and promoted autophagy and terminal differentiation. Mechanistic studies disclosed that, miR-340 over expression suppressed several oncogenes including p-AKT, EZH2, EGFR, BMI1 and XIAP. Furthermore, ROCK1 was validated as a direct functional target miR-340 and silencing of ROCK1 phenocopied the anti-tumor effect of mR-340. Our findings indicate an important role of miR-340 as a glioma killer, and suggest a potential prognosis biomarker and therapeutic target for GBM. PMID- 25831240 TI - Intestinal Fatty Acid Binding Protein: A Sensitive Marker in Abdominal Surgery and Abdominal Infection. AB - BACKGROUND: Intestinal fatty acid binding protein (iFABP) is elevated in plasma by intestinal injury. We investigated the influence of surgical trauma and severe sepsis caused by abdominal and pulmonary infection on plasma iFABP concentrations. METHODS: Seventy-nine patients were included in this prospective observational study: 31 patients before elective major abdominal surgery (EMS), 33 patients with severe sepsis on admission to the intensive care unit (ICU), and 15 healthy volunteers who served as controls. Blood samples were taken before and after surgery for a period up to 5 d. RESULTS: Prior to surgery, EMS patients had increased iFABP concentrations in those patients with intestinal cancer compared with patients without intestinal cancer (217 pg/mL, interquartile range [IQR] I III 100-369 pg/mL versus 79 pg/mL, IQR I-III: 0-182 pg/mL; p<0.01) and with controls (114 pg/mL, IQR I-III: 103-124 pg/mL; p<0.01). Surgical trauma increased iFABP levels in patients without intestinal cancer (240 pg/mL, IQR I-III 111-305 pg/mL; p<0.01). Within 24 h after surgery, iFABP levels decreased to normal values. Patients with severe sepsis of abdominal origin had elevated concentrations compared with controls (324 pg/mL [IQR I-III 0-649 pg/mL]; p=0.05); in patients with pneumonia, iFABP levels were not significantly increased. Discrimination between intestinal- and pulmonary-induced sepsis was low (area under the curve [AUC] 0.693; 95% confidence interval 0.512-0.874). CONCLUSIONS: Surgical trauma and severe sepsis lead to elevated iFABP concentrations. However, intestinal malignant disease and in some patients severe sepsis caused by pneumonia also resulted in elevated iFABP concentrations. The results support the idea that epithelial injury of many causes leads to elevated concentrations of iFABP. The value of iFABP for differentiating pulmonary from intestinal sepsis is limited. PMID- 25831241 TI - Synchrotron-based and globar-sourced molecular (micro)spectroscopy contributions to advances in new hulless barley (with structure alteration) research on molecular structure, molecular nutrition, and nutrient delivery. AB - This paper aimed to review synchrotron-based and globar-sourced molecular infrared (micro)spectroscopy contributions to advances in new hulless barley (with structure alteration) research on molecular structure, molecular nutrition, and nutrient delivery in ruminants. It reviewed recent progress in barley varieties, its utilization for animal and human, inherent structure features and chemical make-up, evaluation and research methodology, breeding progress, rumen degradation, and intestinal digestion. The emphasis of this review was focused on the effect of alteration of carbohydrate traits of newly developed hulless barley on molecular structure changes and nutrient delivery and quantification of the relationship between molecular structure features and changes and truly absorbed nutrient supply to ruminants. This review provides an insight into how inherent structure changes on a molecular basis affect nutrient utilization and availability in ruminants. PMID- 25831242 TI - Stereotactic body radiotherapy for oligometastases confined to the para-aortic region: clinical outcomes and the significance of radiotherapy field and dose. AB - We retrospectively reviewed 88 patients with oligometases in the para-aortic region from any controlled primary tumor site who were treated with stereotactic body radiotherapy (SBRT). The 5-year local control, disease-free survival, and overall survival rates were 83%, 31%, and 41%, respectively. A 90% tumor-control probability was predicted at a biological effective dose of 90 Gy. Severe gastrointestinal toxicities (grade >=3) were observed in 2 of 88 patients (1%). The results of this study are limited by the retrospective nature of the study but could serve as the background and rationale for future prospective trials on SBRT-based treatment for oligometastses. PMID- 25831244 TI - Give leadership a try. PMID- 25831245 TI - Effect of 6-minute colonoscopy withdrawal time policy on polyp detection rate in a community hospital. AB - In 2002, a U.S. Multi-Society Task Force on colorectal cancer recommended a 6 minute or more withdrawal time as an indicator of a quality colonoscopy. In 2006, found a correlation between longer withdrawal time and an increased rate in the detection of adenomas. In January 2008, the endoscopy department at our institution adopted the Multi-Society Task Force recommendation. The aim of our study was to evaluate the effect of a minimal 6-minute withdrawal time policy at our institution on polyp detection rate. All colonoscopies performed for screening indications from April 2007 to September 2008 were reviewed retrospectively. Group I (pre-policy) was compared with Group II (post-policy). Data collected included age, gender, indication, polyp detection rate, size, and withdrawal time. Unpaired t tests evaluated pre- and postprocedure results. Fisher's exact tests were used to compare detection rates between withdrawal time less than 6 minutes and more than 6 minutes. Mann-Whitney U Tests were performed to analyze the significance between the number of polyps detected for withdrawal time less than 6 minutes versus more than 6 minutes. A total of 1,342 colonoscopies were available for analysis in Group I and 1,316 in Group II. Polyp detection rate was 46.6% in Group I versus 48.2% in Group II (p = .39), a non statistically significant difference; however, there was a trend toward identifying small- and medium-sized polyps in Group II. Small polyps can carry a risk of severe dysplasia (). Data were then analyzed for withdrawal time. The polyp detection rate was 20.9 in procedures that took less than 6 minutes versus 48.3 in those that took more than 6 minutes (p <= .01). In this study, a 6-minute or more withdrawal time increased the polyp detection rate by 133% for all polyp sizes, especially small and medium. Small polyps (5 mm or less) should be removed and not ignored. A 6-minute or more withdrawal time should be mandatory in those patients without a previous colon resection. PMID- 25831243 TI - Non-caloric artificial sweeteners and the microbiome: findings and challenges. AB - Non-caloric artificial sweeteners (NAS) are common food supplements consumed by millions worldwide as means of combating weight gain and diabetes, by retaining sweet taste without increasing caloric intake. While they are considered safe, there is increasing controversy regarding their potential ability to promote metabolic derangements in some humans. We recently demonstrated that NAS consumption could induce glucose intolerance in mice and distinct human subsets, by functionally altering the gut microbiome. In this commentary, we discuss these findings in the context of previous and recent works demonstrating the effects of NAS on host health and the microbiome, and the challenges and open questions that need to be addressed in understanding the effects of NAS consumption on human health. PMID- 25831246 TI - Have you had an ERCP lawsuit yet? AB - Endoscopic Retrograde CholangioPancreatography (ERCP) is the most dangerous procedure performed regularly by gastroenterologists. While serious adverse events cannot all be avoided, there are many ways to reduce the risk of their resulting in a lawsuit. The most important is for the endoscopist to communicate carefully and fully with patients and family members before the procedure providing truly informed consent-and afterwards, especially when there is a poor outcome. PMID- 25831247 TI - Accuracy of trained nurses in finding small bowel lesions at video capsule endoscopy. AB - The video capsule endoscopy is an accurate tool to investigate the entire small bowel. Currently, the nurse actively participates in the procedure from patient preparation to the video download, whereas a gastroenterologist interprets the endoscopic findings. However, few studies recently showed high accuracy of nurses in detecting lesions in the small bowel on video capsule endoscopy recordings. This prospective study aimed to assess the ability of experienced and trained nurses in detecting small bowel lesions as compared with gastroenterologists. Forty-six consecutive video capsule endoscopy procedures were analyzed. Overall, the nurse evaluation was highly (95.6%) accurate in detecting small bowel lesions, with a 100% concordance with the gastroenterologist for the relevant findings. In addition, the absence of lesions was confirmed by the endoscopist in all cases classified as negative by the nurse. Data of this study found that trained nurses, with a large experience in endoscopic features, correctly identified small bowel lesions on video capsule endoscopy recordings. Therefore, a trained nurse may accurately select the thumbnails of all mucosal irregularities that may be faster reviewed by the endoscopist for a final diagnosis. PMID- 25831248 TI - The impact of laparoscopic Nissen fundoplication on the long-term quality of life in patients with gastroesophageal reflux disease. AB - Laparoscopic Nissen fundoplication is now the most common surgical procedure for treatment of gastroesophageal reflux disease (GERD), offering promising long-term outcomes. Outcomes for 46 patients with GERD who underwent Nissen fundoplication during the last 5 years (November 2007-June 2012) were prospectively studied using a structured questionnaire that evaluated clinical symptom scores for heartburn, dysphagia, and satisfaction with clinical outcomes. Postoperative care of the patients including analgesia, median hospital stay, overall cost, and complications was also studied. Clinical follow-up data for 2 years after surgery were available for all 46 patients. Forty-two patients (91.3%) were satisfied with their quality of life and only eight patients (17.4%) continued to receive antacids after surgery. Dysphagia to solid and liquid occasionally appeared in 26.1% (N = 12) and 17.4% (N = 8) of patients, respectively. Laparoscopic Nissen fundoplication was an effective long-term treatment for GERD. The operation resulted in a significant reduction of symptoms and minimized the use of antacid drugs with a high degree of patient satisfaction. Although some patients may have returned to antacid treatment at late follow-up or continued to complain of mild discomfort, they were overall pleased with the outcome. PMID- 25831249 TI - A nurse-driven outpatient clinic for thiopurine-treated inflammatory bowel disease patients reduces physician visits and increases follow-up efficiency. AB - Patients on thiopurine therapy need frequent monitoring to prevent drug adverse events. To describe the structure and main results of a nurse-driven outpatient clinic (NDOC) program for the follow-up of patients receiving treatment with thiopurine immunosuppressants, we retrospectively reviewed patients' clinical charts on thiopurine drugs, azathioprine (AZA), and 6-mercaptopurine. We evaluated the efficacy of the NDOC by comparing the number of physician visits and the adequacy of laboratory controls for each patient before and after inclusion in the program. From January 2006 to December 2008, 179 patients were included. Of these, 102 had received thiopurines for at least 1 year before the start of the NDOC. Mean age was 42 +/- 15 years; 83 were female. In all, 137 of the 179 patients (76%) had Crohn disease. AZA was the most frequent drug used (97%). Mean time of follow-up was 2.03 +/- 0.9 years. Implementation of this program decreased the number of physician visits per year-from 4.6 +/- 1.9 to 2.4 +/- 1.3 (p < .001)-and the number of periods longer than 4 months without laboratory control (from 68% to 45%; p = .01). Leucopenia episodes and complications did not differ significantly before and after the start of the NDOC. Nurse-driven follow-up of these patients reduces physician visits while improving tightness of the follow-up. PMID- 25831250 TI - The removal of a gastric balloon: a case study. PMID- 25831251 TI - Gastrointestinal stromal tumor in Turcot syndrome. PMID- 25831252 TI - The state of the science of proton pump inhibitors causing osteoporotic changes in postmenopausal women. PMID- 25831253 TI - Reuse of single-use critical medical devices. PMID- 25831255 TI - Correction to Pb7Bi4Se13: a lillianite homologue with promising thermoelectric properties. PMID- 25831256 TI - Endoscopic ultrasound-guided transmural drainage of calcified pseudocyst in a patient with chronic calcific pancreatitis. PMID- 25831257 TI - Understanding the Radioactive Ingrowth and Decay of Naturally Occurring Radioactive Materials in the Environment: An Analysis of Produced Fluids from the Marcellus Shale. AB - BACKGROUND: The economic value of unconventional natural gas resources has stimulated rapid globalization of horizontal drilling and hydraulic fracturing. However, natural radioactivity found in the large volumes of "produced fluids" generated by these technologies is emerging as an international environmental health concern. Current assessments of the radioactivity concentration in liquid wastes focus on a single element-radium. However, the use of radium alone to predict radioactivity concentrations can greatly underestimate total levels. OBJECTIVE: We investigated the contribution to radioactivity concentrations from naturally occurring radioactive materials (NORM), including uranium, thorium, actinium, radium, lead, bismuth, and polonium isotopes, to the total radioactivity of hydraulic fracturing wastes. METHODS: For this study we used established methods and developed new methods designed to quantitate NORM of public health concern that may be enriched in complex brines from hydraulic fracturing wastes. Specifically, we examined the use of high-purity germanium gamma spectrometry and isotope dilution alpha spectrometry to quantitate NORM. RESULTS: We observed that radium decay products were initially absent from produced fluids due to differences in solubility. However, in systems closed to the release of gaseous radon, our model predicted that decay products will begin to ingrow immediately and (under these closed-system conditions) can contribute to an increase in the total radioactivity for more than 100 years. CONCLUSIONS: Accurate predictions of radioactivity concentrations are critical for estimating doses to potentially exposed individuals and the surrounding environment. These predictions must include an understanding of the geochemistry, decay properties, and ingrowth kinetics of radium and its decay product radionuclides. PMID- 25831258 TI - Improved beam angle arrangement in intensity modulated proton therapy treatment planning for localized prostate cancer. AB - PURPOSE: This study investigates potential gains of an improved beam angle arrangement compared to a conventional fixed gantry setup in intensity modulated proton therapy (IMPT) treatment for localized prostate cancer patients based on a proof of principle study. MATERIALS AND METHODS: Three patients with localized prostate cancer retrospectively selected from our institution were studied. For each patient, IMPT plans were designed using two, three and four beam angles, respectively, obtained from a beam angle optimization algorithm. Those plans were then compared with ones using two lateral parallel-opposed beams according to the conventional planning protocol for localized prostate cancer adopted at our institution. RESULTS: IMPT plans with two optimized angles achieved significant improvements in rectum sparing and moderate improvements in bladder sparing against those with two lateral angles. Plans with three optimized angles further improved rectum sparing significantly over those two-angle plans, whereas four angle plans found no advantage over three-angle plans. A possible three-beam class solution for localized prostate patients was suggested and demonstrated with preserved dosimetric benefits because individually optimized three-angle solutions were found sharing a very similar pattern. CONCLUSIONS: This study has demonstrated the potential of using an improved beam angle arrangement to better exploit the theoretical dosimetric benefits of proton therapy and provided insights of selecting quality beam angles for localized prostate cancer treatment. PMID- 25831259 TI - Hepatitis B infection and vaccination coverage in men who have sex with men consulting a Danish venereal disease clinic. AB - BACKGROUND: Vaccination guidelines from the Danish Health and Medicines Authority recommend vaccination of all men who have sex with men (MSM) against hepatitis B virus (HBV). The only existing data on HBV infection in Danish MSM stem from 1984: 58% of MSM attending venereal clinics in Copenhagen had a prior and 4% had a chronic HBV infection. The aim of this study was to provide up-to-date data on the prevalence of HBV infection and vaccination coverage among Danish MSM. METHODS: At the venereal clinic at Aarhus University Hospital, 1525 consecutive patients received a questionnaire covering risk group and vaccination status; moreover, HBV serology was performed. Prevalence proportions of serological signs of vaccination, infection, etc. were stratified according to self-reported risk group and vaccination status. RESULTS: In total, 141 patients were MSM. Among these, 14% (CI = 9-21%) were vaccinated, 7% (CI = 3-13%) had a prior infection and 1.4% (CI = 0.2-5%) were HBsAg positive. In patients recalling three doses of vaccination, 18% (CI = 11-26%) were anti-HBs negative and 0.8% (CI = 0.02-5%) were HBsAg positive. Similar data for other risk groups and the total clientele are presented. CONCLUSIONS: This study presents the first Scandinavian data on the prevalence of HBV infection and vaccination among MSM since the introduction of the vaccine. Danish health authorities should evaluate whether a carrier frequency of 1.4% and a vaccination coverage of 14% in MSM is acceptable or warrants intensified focus on vaccination. Prospective vaccination campaigns should consider prevaccination testing, since 18% of patients recalling three doses of vaccination were anti-HBs negative. PMID- 25831260 TI - Transfusion of D+ red blood cells to D- individuals in trauma situations. AB - To conserve D- red blood cells (RBCs), our facility developed a policy for transfusion of D+ units to D- patients, particularly in trauma situations. To our knowledge, this is the first study looking at D-mismatched RBC transfusion in trauma patients. We developed guidelines for the transfusion of D-mismatched RBCs. patients were followed by anti body screening and direct antiglobulin testing. Twenty-six patients were identified, and 57.7 percent of the cases were the result of trauma. Follow-up ranged from 7 to 455 days. The trauma cohort had a follow-up of 7 to 102 days. Overall, patients were transfused with 1 to 36 units of D-mismatched RBCs. Three patients produced alloanti-D, resulting in a 20 percent rate of antibody formation rate of 11.5 percent compared with 21.4 to 30.4 percent in previous studies. Approximately 58 percent of our study population was composed of trauma patients. Within that cohort, the formation of anti-D was 20 percent, similar to the rate seen in previous studies looking at primarily non-trauma populations. PMID- 25831261 TI - Allogeneic red blood cell adsorption for removal of warm autoantibody. AB - Adsorption studies are usually required to confirm or rule out the presence of underlying alloantibodies in samples containing warm autoantibody. Allogeneic adsorptions are necessary if the patient has been recently transfused. Most commonly, allogeneic adsorptions are performed using a trio of phenotyped reagent red blood cells to rule out clinically significant alloantibodies to common antigens. The adsorbing cells may be used untreated or treated with enzymes or with ZZAP before adsorption. Adsorption may also be performed using enhancement such as low-tonic strength saline or polyethylene glycol added to the mixture. Multiple adsorptions may be necessary to remove strongly reactive autoantibodies. Allogeneic adsorptions will not detect alloantibodies to high-prevalence antigens. PMID- 25831262 TI - Anti-Ge2: further evidence for lack of clinical significance. AB - Anti-Ge2 may be immune or naturally occurring, and it reacts with an antigen on glycophorin D. Ge2 is encoded by a gene, GYPC, which is located on the long arm of chromosome 2. Anti-Ge2 is usually an immunoblobulin G (IgG) antibody. In the available literature, we have not been able to find any reported cases of proven acute hemolytic transfusion reactions caused by Anti-Ge2. We present the case of a 67-year-old man with metastatic pancreatic carcinoma who had symptomatic anemia and a hemoglobin concentration of 6.3 g/dL. During pretransfusion testing, Anti Ge2 was identified in his serum. Only a single unit of compatible, Ge:-2 frozen red blood cells (RBCs) could be provided by the blood supplier. A second unit of crossmatched, least-incompatible, leukocyte-reduced RBCs, presumably Ge:-2, was also transfused. The transfusion was completed without incident, and the patient's hemoglobin concentration rose appropriately. Posttransfusion values for haptoglobin, lactate dehydrogenase, and urine hemoglobin were within normal limits. A monocyte monolayer assay performed on this anti-Ge2 supports the data that antibodies of this specificity do not cause hemolysis. The clinical and laboratory data obtained in our patient clearly indicated that no hemolysis of transformed RBCs occurred during and for 24 hours after transfusion. We believe that this report adds to a limited experience with anti-Ge2 and provides further evidence for concluding that, to all likelihood, this is not a clinically important RBC antibody. The risk of transfusing apparently "incompatible" (Ge:2) RBCs seems remote and should allow for timely administration of RBCs when treating patients with serious anemia. PMID- 25831263 TI - Polyethylene glycol antiglobulin test (PEG-AGT). AB - Polyethylene glycol (PEG) ws described in 1987 as a new technique for immunohematology testing. The original paper described its use in detection and identification of weakly reactive antibodies. PEG is used as an additive to enhance reactivity and to reduce incubation time when testing for unexpected antibodies. PEG can be used as an alternative to low-ionic-strength saline and whenever weak reactions are encountered. PMID- 25831264 TI - Validation of a blood group genotyping method based on high-resolution melting curve analysis. AB - The detection of polymorphism is the basis of blood group genotyping and phenotype prediction. Genotyping may be useful to determine blood groups when serologic results are unclear. The development and application of different methods for blood group genotyping may be needed as a substitute for blood group typing. The purpose of this study is to establish an approach for blood group genotyping based on a melting curve analysis of real-time polymerase chain reaction (PCR). Using DNA extracted from whole blood, we developed and validated a DNA typing method for detecting DO*01/DO*02, DO*01/DI*02, LU*01/LU*02, and GYPB*03/GYBP*04 alleles using a melting curve analysis. All assays were confirmed with a commercial reagent containing sequence-specific primers (PCR-SSP), and a cohort of the samples was confirmed with sequencing. Results for all blood groups were within the range of specificity and assay variability. Genotypes of 300 blood donors were fully consistent with PCR-SSP data. The obtained genotype distribution is in complete concordance with existing data for the Chinese population. There are several advantages for this approach of blood group genotyping: lower contamination rates with PCR products in this laboratory, ease of performance, automation potential, and rapid cycling time. PMID- 25831266 TI - Boundary-enhancement in propagation-based x-ray phase-contrast tomosynthesis improves depth position characterization. AB - Propagation-based x-ray phase-contrast (PB XPC) tomosynthesis combines the concepts of tomosynthesis and XPC imaging to realize the advantages of both for biological imaging applications. Tomosynthesis permits reductions in acquisition times compared with full-view tomography, while XPC imaging provides the opportunity to resolve weakly absorbing structures. In this note, an investigation of the depth resolving properties of PB XPC tomosynthesis is conducted. The results demonstrate that in-plane structures display strong boundary-enhancement while out-of-plane structures do not. This effect can facilitate the identification of in-plane structures in PB XPC tomosynthesis that could normally not be distinguished from out-of-plane structures in absorption based tomosynthesis. PMID- 25831265 TI - Working With Parents to Prevent Childhood Obesity: Protocol for a Primary Care Based eHealth Study. AB - BACKGROUND: Parents play a central role in preventing childhood obesity. There is a need for innovative, scalable, and evidence-based interventions designed to enhance parents' motivation to support and sustain healthy lifestyle behaviors in their children, which can facilitate obesity prevention. OBJECTIVE: (1) Develop an online screening, brief intervention, and referral to treatment (SBIRT) eHealth tool to enhance parents' concern for, and motivation to, support children's healthy lifestyle behaviors, (2) refine the SBIRT eHealth tool by assessing end-user acceptability, satisfaction, and usability through focus groups, and (3) determine feasibility and preliminary effectiveness of the refined SBIRT eHealth tool through a randomized controlled trial. METHODS: This is a three-phase, multi-method study that includes SBIRT eHealth tool development (Phase I), refinement (Phase II), and testing (Phase III). Phase I: Theoretical underpinnings of the SBIRT tool, entitled the Resource Information Program for Parents on Lifestyle and Education (RIPPLE), will be informed by concepts applied within existing interventions, and content will be based on literature regarding healthy lifestyle behaviors in children. The SBIRT platform will be developed in partnership between our research team and a third-party intervention development company. Phase II: Focus groups with parents, as well as health care professionals, researchers, and trainees in pediatrics (n=30), will explore intervention-related perceptions and preferences. Qualitative data from the focus groups will inform refinements to the aesthetics, content, structure, and function of the SBIRT. Phase III: Parents (n=200) of children-boys and girls, 5 to 17 years old-will be recruited from a primary care pediatric clinic while they await their children's clinical appointment. Parents will be randomly assigned to one of five groups-four intervention groups and one control group-as they complete the SBIRT. The randomization function is built into the tool. Parents will complete the eHealth SBIRT using a tablet that will be connected to the Internet. Subsequently, parents will be contacted via email at 1-month follow-up to assess (1) change in concern for, and motivation to, support children's dietary and physical activity behaviors (primary outcome), and (2) use of online resources and referrals to health services for obesity prevention (secondary outcome). RESULTS: This research was successfully funded and received ethics approval. Development of the SBIRT started in summer 2012, and we expect all study-related activities to be completed by fall 2016. CONCLUSIONS: The proposed research is timely and applies a novel, technology-based application designed to enhance parents concern for, and motivation to, support children's healthy lifestyle behaviors and encourage use of online resources and community services for childhood obesity prevention. Overall, this research builds on a foundation of evidence supporting the application of SBIRTs to encourage or "nudge" individuals to make healthy lifestyle choices. Findings from Phase III of this project will directly inform a cluster randomized controlled trial to study the effectiveness of our intervention across multiple primary care-based settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT02330588; http://clinicaltrials.gov/ct2/show/NCT02330588 (Archived by WebCite at http://www.webcitation.org/6WyUOeRlr). PMID- 25831268 TI - Communicating biopsy results to patients in a new technological era. PMID- 25831267 TI - Auxin as an inducer of asymmetrical division generating the subsidiary cells in stomatal complexes of Zea mays. AB - The data presented in this work revealed that in Zea mays the exogenously added auxins indole-3-acetic acid (IAA) and 1-napthaleneacetic acid (NAA), promoted the establishment of subsidiary cell mother cell (SMC) polarity and the subsequent subsidiary cell formation, while treatment with auxin transport inhibitors 2,3,5 triiodobenzoic acid (TIBA) and 1-napthoxyacetic acid (NOA) specifically blocked SMC polarization and asymmetrical division. Furthermore, in young guard cell mother cells (GMCs) the PIN1 auxin efflux carriers were mainly localized in the transverse GMC faces, while in the advanced GMCs they appeared both in the transverse and the lateral ones adjacent to SMCs. Considering that phosphatidyl inositol-3-kinase (PI3K) is an active component of auxin signal transduction and that phospholipid signaling contributes in the establishment of polarity, treatments with the specific inhibitor of the PI3K LY294002 were carried out. The presence of LY294002 suppressed polarization of SMCs and prevented their asymmetrical division, whereas combined treatment with exogenously added NAA and LY294002 restricted the promotional auxin influence on subsidiary cell formation. These findings support the view that auxin is involved in Z. mays subsidiary cell formation, probably functioning as inducer of the asymmetrical SMC division. Collectively, the results obtained from treatments with auxin transport inhibitors and the appearance of PIN1 proteins in the lateral GMC faces indicate a local transfer of auxin from GMCs to SMCs. Moreover, auxin signal transduction seems to be mediated by the catalytic function of PI3K. PMID- 25831270 TI - Fe protein-independent substrate reduction by nitrogenase MoFe protein variants. AB - The reduction of substrates catalyzed by nitrogenase normally requires nucleotide dependent Fe protein delivery of electrons to the MoFe protein, which contains the active site FeMo cofactor. Here, it is reported that independent substitution of three amino acids (beta-98(Tyr->His), alpha-64(Tyr->His), and beta-99(Phe >His)) located between the P cluster and FeMo cofactor within the MoFe protein endows it with the ability to reduce protons to H2, azide to ammonia, and hydrazine to ammonia without the need for Fe protein or ATP. Instead, electrons can be provided by the low-potential reductant polyaminocarboxylate-ligated Eu(II) (Em values of -1.1 to -0.84 V vs the normal hydrogen electrode). The crystal structure of the beta-98(Tyr->His) variant MoFe protein was determined, revealing only small changes near the amino acid substitution that affect the solvent structure and the immediate vicinity between the P cluster and the FeMo cofactor, with no global conformational changes observed. Computational normal mode analysis of the nitrogenase complex reveals coupling in the motions of the Fe protein and the region of the MoFe protein with these three amino acids, which suggests a possible mechanism for how Fe protein might communicate subtle changes deep within the MoFe protein that profoundly affect intramolecular electron transfer and substrate reduction. PMID- 25831269 TI - Know your audience: predictors of success for a patient-centered texting app to augment linkage to HIV care in rural Uganda. AB - BACKGROUND: Despite investments in infrastructure and evidence for high acceptability, few mHealth interventions have been implemented in sub-Saharan Africa. OBJECTIVE: We sought to (1) identify predictors of uptake of an mHealth application for a low-literacy population of people living with HIV (PLWH) in rural Uganda and (2) evaluate the efficacy of various short message service (SMS) text message formats to optimize the balance between confidentiality and accessibility. METHODS: The trial evaluated the efficacy of a SMS text messaging app to notify PLWH of their laboratory results and request return to care for those with abnormal test results. Participants with a normal laboratory result received a single SMS text message indicating results were normal. Participants with an abnormal test result were randomized to 1 of 3 message formats designed to evaluate trade-offs between clarity and privacy: (1) an SMS text message that stated results were abnormal and requested return to clinic ("direct"), (2) the same message protected by a 4-digit PIN code ("PIN"), and (3) the message "ABCDEFG" explained at enrollment to indicate abnormal results ("coded"). Outcomes of interest were (1) self-reported receipt of the SMS text message, (2) accurate identification of the message, and (3) return to care within 7 days (for abnormal results) or on the date of the scheduled appointment (for normal results). We fit regression models for each outcome with the following explanatory variables: sociodemographic characteristics, CD4 count result, ability to read a complete sentence, ability to access a test message on enrollment, and format of SMS text message. RESULTS: Seventy-two percent (234/385) of participants successfully receiving a message, 87.6% (219/250) correctly identified the message format, and 60.8% (234/385) returned to clinic at the requested time. Among participants with abnormal tests results (138/385, 35.8%), the strongest predictors of reported message receipt were the ability to read a complete sentence and a demonstrated ability to access a test message on enrollment. Participants with an abnormal result who could read a complete sentence were also more likely to accurately identify the message format (AOR 4.54, 95% CI 1.42-14.47, P=.01) and return to clinic appropriately (AOR 3.81, 95% CI 1.61-9.03, P=.002). Those who were sent a PIN-protected message were less likely to identify the message (AOR 0.11, 95% CI 0.03-0.44, P=.002) or return within 7 days (AOR 0.26, 95% CI 0.10-0.66, P=.005). Gender, age, and socioeconomic characteristics did not predict any outcomes and there were no differences in outcomes between those receiving direct or coded messages. CONCLUSIONS: Confirmed literacy at the time of enrollment was a robust predictor of SMS text message receipt, identification, and appropriate response for PLWH in rural Uganda. PIN-protected messages reduced odds of clinic return, but coded messages were as effective as direct messages and might augment privacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT 01579214; https://clinicaltrials.gov/ct2/show/NCT01579214 (Archived by WebCite at http://www.webcitation.org/6Ww8R4sKq). PMID- 25831271 TI - Enzyme-free and label-free signal amplification for monitoring endonuclease activity and inhibition via hybridization chain reaction. AB - A label-free and enzyme-free amplification protocol has been proposed for studying endonuclease activity and inhibition on the basis of the enzyme-digested product triggered hybridization chain reaction (HCR). Three hairpin oligonucleotides were designed as probes which could not open or hybridize with each other at room temperature until the initiator DNA was released by specific enzymatic cleavage in the presence of endonuclease to trigger the hybridization chain reaction. SYBR Green I was chosen as a signal probe which intercalated into the grooves of the nicked double DNA polymer, generating a substantially apparent increase in fluorescence intensity. Once the activity of endonuclease is inhibited by enzyme inhibitors, the efficiency of HCR will be greatly decreased. Therefore, screening of endonuclease inhibitors can be achieved effectively as well as the assay of endonuclease activity. Meanwhile, the assay of endonuclease activity and inhibition achieves a better performance as compared to the previous reports. Importantly, it is a more universal method that can be simply used to study activity and inhibition of other endonucleases by changing the specific recognition site. So, the protocol was proved to be a sensitive and cost effective approach for studying endonuclease activity and inhibition, and as such, it is promising for broad potential application in various biological reactions. PMID- 25831272 TI - Neurodevelopmental disorders and agricultural pesticide exposures. PMID- 25831273 TI - [Retrospective study comparing low-dose versus standard dose of bortezomib in patients with multiple myeloma]. AB - INTRODUCTION: Bortezomib is a selective inhibitor of the proteosoma that is used in multiple myeloma. In combination with other antineoplastic drugs, it has a well-documented impact in progression-free survival rates and overall survival rates with standard doses (1.3-1.5 mg/m(2)). However, up to 88% of patients on standard doses have unwanted side effects (neutropenia, neuropathy or anemia. Standard dose (1.3 mg/m(2)) is used in almost all patients and low dose (0.7-0.8 mg/m(2)) is reserved for patients with kidney disease and neuropathy. OBJECTIVE: We aim to describe clinical, cytological, and cytometric outcomes, as well as overall survival and side effects of low dose versus standard dose of bortezomib in our institution. METHODS: Retrospective, descriptive study based on data recovered from clinical charts of 48 multiple myeloma patients treated in our hospital between 2011 and 2013. We included data on age, gender, type of multiple myeloma, serum albumin, serum creatinine, beta 2 microglobulin, calcemia, imaging studies, disease stage, pre-and post-therapy bone marrow studies, adverse events and rate of progression. We also recorded events like date of death or of the last medical appointment. RESULTS: Forty-eight multiple myeloma patients were treated with bortezomib-cyclophosphamide-dexamethasone. Twenty-one patients received low dose and 27 patients were treated with the standard dose. No statistical differences between the two groups were found for clinical response (p=0.6), cytological response (p=0.28), flow cytometric response (p= 0.3), rate of adverse effects and overall survival rates. CONCLUSION: This retrospective analysis suggests that lower doses of bortezomib have similar effects in disease control measured by flow cytometry and cytology compared to standard doses in multiple myeloma patients. PMID- 25831274 TI - Cyberknife treatment for low and intermediate risk prostate cancer. AB - Cyberknife is an emerging treatment for early stage prostate cancer. Between October 2012 and January 2014, 32 patients were treated in our institution. Prescribed dose was 35-36.25 Gy in five fractions. Biochemical response was observed in 22 patients. Four patients experienced G2 acute genitourinary toxicity and in two cases we recorded G3 acute GU toxicity. 5 patients experienced G2 acute proctitis. At last follow up visit, all patients were still alive. 29 remained free of disease at last follow up appointment, while three developed a biochemical recurrence. Our experience confirms the efficacy and safety of Cyberknife for localized prostate cancer. PMID- 25831275 TI - Effects of Amendments on Growth and Uptake of Cd and Zn by Wetland Plants, Typha angustifolia and Colocasia esculenta from Contaminated Sediments. AB - A pot study was conducted to compare the effects of amendments (CaHPO4 and cow manure) on growth and uptake of Cd and Zn from contaminated sediments by two wetland plant species, Typha angustifolia and Colocasia esculenta. Contaminated sediments (Cd 33.2 mg kg(-1) and Zn 363 mg kg(-1)) were collected from Mae Tao basin, Mae Sot district, Tak province, Thailand. The experiment consisted of 4 treatments: control (uncontaminated sediment), Cd/Zn, Cd/Zn + 5% CaHPO4, and Cd/Zn + 10% cow manure. Plants were grown for 3 months in the greenhouse. The addition of CaHPO4 resulted in the highest relative growth rate (RGR) and highest Cd accumulation in both T. angustifolia and C. esculenta while the lowest RGR was found in C. esculenta grown in the cow manure treatment. Both plant species had higher concentrations of metals (Cd, Zn) in their belowground parts. None of the amendments affected Zn accumulation. C. esculenta exhibited the highest uptake of both Cd and Zn. The results clearly demonstrated the phytoremediation potential of C. esculenta and the enhancement of this potential by CaHPO4 amendment. PMID- 25831276 TI - Microscopic lensing by a dense, cold atomic sample. AB - We demonstrate that a cold, dense sample of Rb87 atoms can exhibit a micron-scale lensing effect, much like that associated with a macroscopically sized lens. The experiment is carried out in the fashion of traditional z-scan measurements but in much weaker fields and where close attention is paid to the detuning dependence of the transmitted light. The results are interpreted using numerical simulations and by modeling the sample as a thin lens with a spherical focal length. PMID- 25831277 TI - Label-free imaging of melanoma with nonlinear photothermal microscopy. AB - Nonlinear photothermal microscopy, in which the intensity of the pump heating beam is modulated at f and the photothermal signal is extracted from the probe beam with a lock-in amplifier referred to 2f, is applied to the imaging of mouse melanoma without any staining. The pump and probe pulses, with central wavelengths of 488 and 632 nm, and a pulse duration of ~100 ps, are filtered from a compact commercial supercontinuum fiber laser source. An auto-balanced detector is applied to accumulate the signal and remove the laser noise of the probe. The spatial resolution of the nonlinear photothermal imaging is enhanced by ~18% in both theoretical calculations and experiments, compared with a linear photothermal mechanism, and the resolution enhancement is theoretically ~42% compared with conventional optical microscopy. This imaging technique shows possibilities for the clinical evaluation of melanoma with a high contrast and spatial resolution. PMID- 25831278 TI - Simultaneous dual-wavelength photoacoustic radar imaging using waveform engineering with mismatched frequency modulated excitation. AB - The spectroscopic imaging capability of photoacoustics (PA) without the depth limitations of optical methods offers a major advantage in preclinical and clinical applications. Consecutive PA measurements with properly chosen wavelengths allow composition related information about blood or tissue. In this work, we propose and experimentally introduce modulation waveform engineering through the use of mismatched (uncorrelated or weakly correlated) linear frequency modulated signals for PA characterization and imaging. The feasibility of the method was tested on oxygen saturated hemoglobin and deoxygenated hemoglobin in vitro in a blood circulating rig. The method was also employed for in vivo imaging of a neck carcinoma tumor grown in a mouse thigh. The proposed method can increase the accuracy and speed of functional imaging by simultaneous PA probing with two wavelengths using portable laser-diode based PA imaging systems. PMID- 25831279 TI - Noise reduction in solid-state lasers using a SHG-based buffer reservoir. AB - The cancellation of resonant intensity noise, from a few kHz up to several GHz, is reported using a second-harmonic generation (SHG) buffer reservoir in a Nd:YAG solid-state laser. This approach is shown to be well suited and easily optimizable for reducing the excess noise lying at the laser relaxation oscillations as well as that originating from the beating between the lasing mode and nonlasing adjacent longitudinal modes. A thorough analysis of noise spectra of both laser and SHG signals confirms definitely that noise reduction is a consequence of a deep laser dynamics modification rather than noise evacuation mechanism. PMID- 25831280 TI - Mode-locked Er:Yb-doped double-clad fiber laser with 75-nm tuning range. AB - We demonstrate a widely tunable Er:Yb-doped double-clad multiple-soliton fiber laser based on nonlinear polarization rotation (NPR). Based on both an artificial birefringent filtering effect of the cavity and population inversion related gain variation, the central wavelength can be continuously tuned over 75 nm range (1545-1620 nm). Wavelength tunability is achieved by controlling both the linear loss of the cavity and the polarization controllers (PCs). This is the widest tunable range yet reported in tunable passively mode-locked erbium-doped fiber lasers. PMID- 25831281 TI - Analytical calculation of two-dimensional spectra. AB - We demonstrate an analytical calculation of two-dimensional (2D) coherent spectra of electronic or vibrational resonances. Starting with the solution to the optical Bloch equations for a two-level system in the 2D time domain, we show that a fully analytical 2D Fourier transform can be performed if the projection slice and Fourier-shift theorems of Fourier transforms are applied. Results can be fit to experimental 2D coherent spectra of resonances with arbitrary inhomogeneity. PMID- 25831282 TI - Elimination of artifacts derived from the residual birefringence of a phase modulator for circular dichroism by retardation domain analysis. AB - It is well known that various artifacts interfere with circular dichroism (CD) measurement using the polarization modulation technique. In this report, we propose a simple analysis method for eliminating the artifacts derived from the residual birefringence of a phase modulator. We consider the origin of the artifacts and find that those in CD can be distinguished by analyzing signals as a function of the retardation of the phase modulator using a Mueller matrix method. We experimentally obtain pure CD from a sample with CD and linear dichroism by applying retardation domain analysis. PMID- 25831283 TI - Improved resolution in SPR and MCWG microscopy by combining images acquired with distinct mode propagation directions. AB - In high-resolution surface plasmon (SPR) imaging, lateral resolution is limited along the direction of plasmon propagation by the longitudinal decay length. Though SPR systems can achieve sub-micrometer resolution, the decay length causes a degradation in the images in the direction of plasmon propagation akin to a blurring artifact, with ringing along resonant to nonresonant transition edges. We present a method to significantly reduce this effect based on combining images of a sample acquired with distinct guided-mode propagation directions. As SPR is a special case of the class of optical structures known as metal-clad waveguides (MCWG) that are also affected by the decay length, this work is broadly applicable. PMID- 25831284 TI - Incoherent wavefront reconstruction by a retroemission device. AB - This Letter addresses wavefront reconstruction by a retroemission device (REM). REM represents a lenslet array mounted on a substrate made of photoluminescent optical material, such as a polymer film impregnated with upconversion nanoparticles. An excitation light wavefront incident on the REM was sampled by the lenslet array piece-wise. Each wavelet at the lenslet aperture was converged into a voxel in the substrate, with its coordinates encoding the angle of incidence and curvature of the wavelet. Photoluminescence excited in the voxel was radiated isotropically, its back-propagating fraction was captured by the lenslet and transformed into a back-propagating wavelet, which contributed to reproduction of the entire incident wavefront with some fidelity. We experimentally proved the wavefront reconstruction based on REM, and present its theoretical model based on a Fresnel-Kirchhoff approximation. PMID- 25831285 TI - Optimum generation of annular vortices using phase diffractive optical elements. AB - An annular vortex of arbitrary integer topological charge q can be obtained at the Fourier domain of appropriate phase diffractive optical elements. In this context we prove that the diffractive element that generates the vortex with maximum peak intensity has the phase modulation of a propagation-invariant qth order Bessel beam. We discuss additional advantages of this phase element as annular vortex generator. PMID- 25831286 TI - Laser-diode-pumped thin-slice c-cut Nd:GdVO(4) multimode laser with coherent vector fields. AB - Spontaneous formation of coherent vector fields, which results from synchronization of longitudinal modes of orthogonally polarized transverse modes, has been observed in a laser-diode (LD)-pumped thin-slice c-cut Nd:GdVO(4) laser with reflective end faces operating under the multi-longitudinal mode oscillation condition. The suppression of antiphase dynamics inherent to multimode solid state lasers as well as the enhanced self-mixing interference effect as compared with a linearly polarized multimode laser have been identified. PMID- 25831287 TI - Experimental performance evaluation of analog signal transmission in a silicon microring resonator. AB - We experimentally evaluate the performance of analog signal transmission in a silicon microring resonator. The spurious free dynamic range (SFDR) of the second order harmonic distortion (SHD) and third-order harmonic distortion (THD) is used to assess the analog link. The performance dependence on the input signal wavelength and input signal power is comprehensively studied. The obtained results indicate that the analog signal transmission performance through microring resonator is mainly affected by the notch filtering effect for low level input signal power. Moreover, with the increase of input signal power, the enhanced nonlinear resonance in the microring resonator could cause the shift of the resonance wavelength, which might also impact on the analog signal transmission performance. PMID- 25831288 TI - 100.29-Gb/s direct detection optical OFDM/OQAM 32-QAM signal over 880 km SSMF transmission using a single photodiode. AB - We propose a novel guard-band-shared direct-detection (GBS-DD) scheme for a 100 Gb/s single-photodiode direct-detection transmission system. The 100.29 Gb/s signal is successfully transmitted over 880 km standard single mode fiber (SSMF) with Raman amplification under the 20% forward error correction (FEC) threshold within 52 GHz optical bandwidth. The signal is modulated with orthogonal frequency-division multiplexing/offset quadrature-amplitude-modulation 32-ary QAM (OFDM/OQAM 32-QAM). The signal-to-signal beat interference (SSBI) terms fall and overlap in the same guard band. Adopting the proposed approach, the bandwidth usage efficiency of the photodiode is greatly enhanced, which brings benefits on the data rate and transmission performance. PMID- 25831289 TI - Millijoule pulse energy 100-nanosecond Er-doped fiber laser. AB - We report, for the first time to our knowledge, on a single-mode millijoule-level 100-nanosecond Er-doped fiber laser operating near 1550 nm. The system features a newly developed 35-MUm-core Yb-free double-clad Er-doped fiber based on P(2)O(5) Al(2)O(3)-SiO(2) glass matrix and produces pulses with energy as high as 1 mJ at repetition rates of 1-10 kHz. PMID- 25831290 TI - Single-trial estimation of the cerebral metabolic rate of oxygen with imaging photoplethysmography and laser speckle contrast imaging. AB - Cortical cerebral metabolic rate of oxygen (CMRO(2)) could conventionally be measured by combining laser Doppler flowmetry and multispectral reflectance imaging across multiple trials of stimulation, which compromises the real-time capacity. Monitoring transient change of CMRO(2) has been challenging. In this Letter, imaging photoplethysmography (iPPG) and laser speckle contrast imaging were combined into a multi-modal optical imaging system for single-trial estimation of CMRO(2). In a physiologically stable experiment, the iPPG-based method showed a less than 4% variance in comparison with the conventional method over 20 trials, and its temporal stability could be comparable to that by conventional method over 6 trials. While the oxygen supply was decreased deliberately, the new method was able to detect the transient changes of CMRO(2) in real time, which could not be revealed by the conventional method. PMID- 25831291 TI - Phase correction for a distorted orbital angular momentum beam using a Zernike polynomials-based stochastic-parallel-gradient-descent algorithm. AB - A stochastic-parallel-gradient-descent algorithm (SPGD) based on Zernike polynomials is proposed to generate the phase correction pattern for a distorted orbital angular momentum (OAM) beam. The Zernike-polynomial coefficients for the correction pattern are obtained by monitoring the intensity profile of the distorted OAM beam through an iteration-based feedback loop. We implement this scheme and experimentally show that the proposed approach improves the quality of the turbulence-distorted OAM beam. Moreover, we apply phase correction patterns derived from a probe OAM beam through emulated turbulence to correct other OAM beams transmitted through the same turbulence. Our experimental results show that the patterns derived this way simultaneously correct multiple OAM beams propagating through the same turbulence, and the crosstalk among these modes is reduced by more than 5 dB. PMID- 25831292 TI - Electrically induced red, green, and blue scattering in chiral-nematic thin films. AB - Cholesteric liquid-crystalline materials are abundant in nature such as condensed phases of DNA, plant cell walls, and chiral biopolymers. These self-organized helical structures produce unique optical properties, giving rise to the selective Bragg reflection of colorful light. In this Letter, we focus on the focal conic state of cholesteric liquid crystals and report on stable, tunable, and reversible color switching among red, green, and blue in polymer-stabilized cholesteric films. The experimental results indicate that, with appropriate voltage pulses, the electrically induced color switching of all six routes can be realized in a single cell reflecting green light. The scattered transmissive color persists at zero voltage due to the polymer stabilization. PMID- 25831293 TI - Modeling light scattering by forsterite particles. AB - Laboratory optical measurements of forsterite particles reveal remarkably similar light-scattering responses in two samples that were thought to obey different size distributions. These measurements are modeled with irregularly shaped agglomerated debris particles having a refractive index of m=1.6+0.0005i that is representative of forsterite in the visible. Modeling closely reproduces the measurements of both samples, making retrieval of their size distributions possible. PMID- 25831294 TI - Multi-color carrier-envelope-phase stabilization for high-repetition-rate multi pulse coherent synthesis. AB - Using a zero-offset carrier-envelope locking technique, we have synthesized an octave-spanning composite frequency comb exhibiting 132-attosecond timing jitter between the constituent pulses over a one-second observation window. In the frequency domain, this composite comb has a modal structure and coherence which are indistinguishable from those of a comb that might be produced by a hypothetical single mode locked oscillator of equivalent bandwidth. The associated phase stability enables the participating multi-color pulse sequences to be coherently combined, representing an example of multi-pulse synthesis using a femtosecond oscillator. PMID- 25831295 TI - Nonlinear optimization of slot Si waveguides: TPA minimization with FOM(TPA) up to 4.25. AB - The chi(3) nonlinear properties of slotted crystalline silicon photonic waveguides filled with third-order nonlinear materials (NM) are studied by calculating the effective nonlinear susceptibilities associated to the silicon and cladding material, respectively. The adopted approach circumvents the assumptions that the introduced NM dominates the nonlinear behavior of the slotted waveguide and that strong light confinement in the slot allows neglecting the two-photon absorption (TPA) process in the silicon rails. Optimization of the geometry of silicon-slotted waveguides is performed on the basis of the nonlinear figure of merit (FOM(TPA)) of the guided mode, which is related to the balance between the Kerr and the TPA effects, allowing to reach a FOM(TPA)=4.25. The obtained results reveal the importance of properly choosing the waveguide width of the silicon rails in order to minimize the TPA effect even by tolerating a reduced overall nonlinearity. PMID- 25831296 TI - Free space self-similar beams. AB - It is well known that self-similar wave dynamics can happen with the coexistence of diffraction and nonlinearity. However, things are clearly different in linear systems, since simple extrapolation by approaching the nonlinear coefficient toward zero will lead to trivial solutions. Here, we show that a broad class of self-similar beams can propagate in linear wave systems governed by a paraxial wave equation or the free particle Schrodinger equation. The linearity of free space allows us to construct these beams by superposition, and eliminates instability problems. The technique of seeking exact or approximate solutions of the wave equations in transformed coordinates presented here should be a useful avenue toward the manipulation of wave propagation in various linear systems. PMID- 25831297 TI - Fiber in-line Mach-Zehnder interferometer based on an inner air-cavity for high pressure sensing. AB - We demonstrate a fiber in-line Mach-Zehnder interferometer based on an inner air cavity with open micro-channel for high-pressure sensing applications. The inner air-cavity is fabricated by combining femtosecond laser micromachining and the fusion splicing technique. The micro-channel is drilled on the top of the inner air-cavity to allow the high-pressure gas to flow in. The fiber in-line device is miniature, robust, and stable in operation and exhibits a high pressure sensitivity of ~8,239 pm/MPa. PMID- 25831298 TI - Low wavenumber efficient single-beam coherent anti-Stokes Raman scattering using a spectral hole. AB - We demonstrate an approach to detect low wavenumber vibrational signals based on single-beam coherent anti-Stokes Raman scattering (CARS) with a spectral hole. Using a 4f pulse shaper for both pulse shaping and signal collection, we achieve an enhanced efficiency in collecting back-reflected CARS signals. PMID- 25831299 TI - Experimental determination of generalized Stokes parameters. AB - A new technique to determine generalized Stokes parameters by making use of the speckle holographic technique and the two-point intensity correlation is proposed and experimentally demonstrated. Assuming Gaussian statistics and spatial stationarity, a speckle hologram is generated prior to the fourth-order correlation, i.e., the two-point intensity correlation. This measurement technique offers a complete retrieval of complex generalized Stokes parameters. The application of the proposed technique is experimentally demonstrated for two different, random source structures. PMID- 25831300 TI - Multi-directional 3D flame chemiluminescence tomography based on lens imaging. AB - Flame chemiluminescence tomography (FCT) has been widely used in flame diagnostics for three-dimensional (3D), spatially resolved measurements of instantaneous flame geometry and, to some extent, of species concentrations. However, in most studies, tomographic reconstructions are based on a traditional parallel projection model. Due to the light collection characteristics of a lens, a parallel projection model is not appropriate for the practical optical setups that are used for emission imaging, particularly at small F-numbers. Taking the light collection effect of the lens into account, this Letter establishes a complete and novel tomographic theory for a multi-directional tomography system consisting of a lens and CCD cameras. A modified camera calibration method is presented first. It determines the exact spatial locations and intrinsic parameters of the cameras. A 3D projection model based on the lens imaging theory is then proposed and integrated into the multiplicative algebraic reconstruction technique (MART). The new approach is demonstrated with a 12-camera system that is used to reconstruct the emission field of a propane flame, thereby resolving space and time. PMID- 25831301 TI - Wavefront sensorless adaptive optics based on the trust region method. AB - We present what is to the best of our knowledge the first implementation of a trust region method for derivative-free optimization (TRDF) in a wavefront sensorless (WFSless) adaptive optics (AO) system. We compare the trust region method with the simulated annealing (SA) algorithm and stochastic parallel gradient descent (SPGD) algorithm. The experimental results demonstrate that the trust region method is superior to both the SA algorithm and SPGD algorithm with respect to convergence rates. These results indicate that the trust region method is a promising approach for correcting static or slowly changing wavefront aberrations in practical applications. PMID- 25831302 TI - Compressing MUJ-level pulses from 250 fs to sub-10 fs at 38-MHz repetition rate using two gas-filled hollow-core photonic crystal fiber stages. AB - Compression of 250-fs, 1-MUJ pulses from a KLM Yb:YAG thin-disk oscillator down to 9.1 fs is demonstrated. A kagome-PCF with a 36-MUm core-diameter is used with a pressure gradient from 0 to 40 bar of krypton. Compression to 22 fs is achieved by 1200 fs2 group-delay-dispersion provided by chirped mirrors. By coupling the output into a second kagome-PCF with a pressure gradient from 0 to 25 bar of argon, octave spanning spectral broadening via the soliton-effect is observed at 18-W average output power. Self-compression to 9.1 fs is measured, with compressibility to 5 fs predicted. Also observed is strong emission in the visible via dispersive wave generation, amounting to 4% of the total output power. PMID- 25831303 TI - Brightness calibrates particle size in single particle fluorescence imaging. AB - This Letter provides a novel approach to quantify the particle sizes of highly bright semiconductor polymer dots (Pdots) for single-particle imaging and photobleaching studies. A quadratic dependence of single-particle brightness on particle size was determined by single-particle fluorescence imaging and intensity statistics. In terms of the same imaging conditions, the particle diameter can be quantified by comparing the individual brightness intensity with associated calibration curve. Based on this sizing method, photobleaching trajectories and overall photon counts emitted by single particles were analyzed. It is found that photobleaching rate constants of different sized Pdots are not strongly dependent on particle diameter except the sparsely occurring fluorescence blinking in certain dim particles and the rapid photobleaching component in some bright particles. The overall photon counts increase with increasing particle diameter. However, those larger than 30 nm deviate away from the increasing tendency. These results reveal the significance of selecting appropriate Pdots (<=30 nm) for single-particle imaging and tracking applications. PMID- 25831304 TI - Experimental demonstration of a novel indoor optical wireless localization system for high-speed personal area networks. AB - In this Letter, we propose a novel indoor localization system based on optical wireless technology. By using the same architecture as the high-speed full-duplex indoor optical wireless communication system, the "search and scan" process, and the added transmission power and beam footprint information in the "search and scan" message, indoor localization functionality is achieved. Proof-of-concept experiments are carried out, and results show that an average error of <15 cm is achieved with a localization beam size of 1 m. In addition, the major localization-accuracy-limiting factors are analyzed both theoretically and experimentally. When incorporated with the optical wireless communication system, high-speed indoor wireless personal area networks can be achieved. PMID- 25831305 TI - Diode end-pumped passively Q-switched Tm:YAP laser with 1.85-mJ pulse energy. AB - Passive Q switching of a Tm:YAP solid-state laser at 1935 nm with Cr:ZnSe and Cr:ZnS polycrystalline saturable absorbers is demonstrated for the first time, to the best of our knowledge. With Cr:ZnS, a maximum pulse energy of 1.85 mJ is obtained for a pulse duration of 35.8 ns, resulting in a peak power of 51.7 kW. With Cr:ZnSe, the achieved pulse energy of 1.55 mJ with a pulse duration of 42.2 ns leads to 36.7-kW peak power. These high pulse energies, together with the unique lasing wavelength at 1935 nm, make this laser a promising tool for biomedical and microsurgery applications. PMID- 25831306 TI - Fast electric field switched 2D-photonic liquid crystals. AB - We demonstrate field-induced 2D-photonic liquid crystals (LC). The 2D spatially periodic modulation of the LC director field is achieved using a geometry with two crossed interdigitated systems of electrodes located at opposite sides of the LC layer. With a special method of dual-field driving, a very fast switching between different spatially periodic LC director distributions is achieved. The director field distribution and potential use of these photonic crystals for fast switched multidirectional lasing is discussed. PMID- 25831307 TI - Fast-beam self-trapping in LiNbO(3) films by pyroelectric effect. AB - We report light-beam self-trapping triggered by the pyroelectric effect in an isolated ferroelectric thin film. Experiments are performed in an 8-MUm-thick congruent undoped LiNbO(3) film bonded onto a silicon wafer. Response time two orders of magnitude faster than in bulk LiNbO(3) is reported. The original underlying physics specific of this arrangement is discussed. PMID- 25831308 TI - Thermally induced light-scattering effects as responsible for the degradation of cholesteric liquid crystal lasers. AB - We have studied the degradation process of the laser emission in a cholesteric liquid crystal laser. We have found that there exists a negative correlation between the laser efficiency and the amount of light scattered by the liquid crystal sample in the illuminated area. The growth of scattering is attributed to the appearance of small imperfections generated in the sample as a result of certain thermal processes that involve the dye molecules. The scattering implies an increase of the coefficient of distributed losses, which is the main response of the rise of the laser threshold. PMID- 25831309 TI - Femtosecond laser writing of Bragg grating waveguide bundles in bulk glass. AB - Waveguide bundles in bulk glass materials, consisting of several parallel scans of refractive index modifications, have been generated with a low-repetition femtosecond laser. Additionally, Bragg grating (BG) structures for 840 and 1550 nm have been introduced by segmentation of the central scan. A spectral loss in the transmission signal of >36 dB was achieved at 1550 nm with a second-order Bragg grating waveguide (BGW) in fused silica, which corresponds to an intrinsic grating efficiency of >16 dB/cm. This is to our knowledge the strongest BG structure realized in glass with a femtosecond laser. The BGW were proven to be stable up to a temperature of 250 degrees C in fused silica. The diameter of the waveguide bundles can be adapted very easily for a broad range of wavelengths and have been demonstrated for diameters between 1 and 50 MUm. The transmission properties of the waveguide bundles are affected minorly by the insertion of BG structures, which opens the ability for adjusting the BGW for a broad range of wavelength in single-mode or multimode optical circuits. BGW have been realized successfully in fused silica, borosilicate glass (BOROFLOAT 33), and AF 32 eco Thin Glass from Schott. PMID- 25831311 TI - Tunable Q-factor silicon microring resonators for ultra-low power parametric processes. AB - A compact silicon ring resonator is demonstrated that allows simple electrical tuning of the ring coupling coefficient and Q-factor and therefore the resonant enhancement of on-chip nonlinear optical processes. Fabrication-induced variation in designed coupling fraction, crucial in the resonator performance, can be overcome using this post-fabrication trimming technique. Tuning of the microring resonator across the critical coupling point is demonstrated, exhibiting a Q factor tunable between 9000 and 96,000. Consequently, resonantly enhanced four wave mixing shows tunable efficiency between -40 and -16.3 dB at an ultra-low on chip pump power of 0.7 mW. PMID- 25831310 TI - Full characterization of dichroic samples from a single measurement by circular polarization orthogonality breaking. AB - We report a novel method to unambiguously determine the magnitude and orientation of linear dichroism in a simultaneous way. It is based on the use of a dedicated dual-frequency dual-polarization coherent source providing two orthogonal circularly polarized modes at the output. We show that the interaction of such a beam with dichroic media gives rise to a beatnote signal whose amplitude and phase enable the full determination of the diattenuation coefficient and axis orientation, respectively. The application of this method to polarimetric imaging provides single-shot sample characterization by its diattenuation coefficient and optical axis angle, with potential applications in biomedical imaging. PMID- 25831312 TI - Non-reciprocal transmission in photonic lattices based on unidirectional coherent perfect absorption. AB - A method for realizing asymmetric (one-way) transmission of discretized light in modulated, linear, and purely passive optical lattices is suggested, which exploits the idea of unidirectional coherent perfect absorption. The system consists of a linear photonic lattice of coupled resonators or waveguides, side coupled to a chain of lossy elements, in which light can avoid the occupation of the dissipative sites when propagating in one way, but not in the opposite one. Non-reciprocity requires modulation of the resonator/waveguide parameters, realizing a dissipative optical Aharonov-Bohm diode with non-reciprocal behavior. PMID- 25831313 TI - Determination of the basic optical parameters of ZnSnN(2). AB - Polycrystalline ZnSnN(2) thin films were successfully prepared by DC magnetron sputtering at room temperature. Both the as-deposited and annealed films showed n type conduction, with electron concentration varying between 1.6*10(18) and 2.3*10(17) cm(-3) and the maximum mobility of 3.98 cm(2) V(-1) s(-1). The basic optical parameters such as the refraction index, extinction coefficient, and absorption coefficient were precisely determined through the spectroscopic ellipsometry measurement and analysis. The optical bandgap of the ZnSnN(2)films was calculated to around 1.9 eV, with the absorption coefficient greater than 10(4) cm(-1) at wavelengths less than 845 nm. The easy-fabricated ZnSnN(2) possesses a sound absorption coefficient ranging from the ultraviolet through visible light and into the near-infrared, comparable to some typical photovoltaic materials such as GaAs, CdTe, and InP. PMID- 25831314 TI - Actively tunable Fano resonances based on colossal magneto-resistant metamaterials. AB - In this Letter, a periodic structure in which each unit cell consists of one manganese oxide (La(0.7)Ca(0.3)MnO(3)) strip and two gold strips is designed. By simulating the electromagnetic responses of the structure, we confirm that Fano resonances can be actively controlled in the infrared region by modulating the intensity of the external magnetic field applied to the structure. This is due to the colossal magneto-resistance of the La(0.7)Ca(0.3)MnO(3) material. Furthermore, a transmission phase can also be effectively tuned. The phase has a shift of DeltaPhi=1.05 rad at a frequency of 130 THz when the intensity of the external magnetic field varies from 5083 to 5193 kA/m. Such a tunable method has potential applications in controllable photoelectric elements. PMID- 25831315 TI - Performance enhancement in a-Si:H/MUc-Si:H tandem solar cells with periodic microstructured surfaces. AB - Here we report on an efficient light-coupling scheme with a periodic microstructured surface to enhance the performance of thin film silicon solar cells. The centerpiece of the surface structure is the hemispherical pit arrays (HPAs), which are fabricated using an inexpensive and scalable process. The integration of HPAs into micromorph tandem thin film silicon solar cells leads to superior broadband reflection suppression properties. With this design, the reflection losses of the tandem cell are reduced to only 1.5%. We demonstrate an efficiency increase from 11.67% to 12.23% compared to a conventional cell with a flat surface, with a 4.6% increase in short circuit current density. The surface microstructures reported here can be applied to a variety of photovoltaic devices to further improve their performance. PMID- 25831316 TI - Light-shift-modulated photon-echo. AB - We show that the AC-Stark shift (light-shift) is a powerful and versatile tool to control the emission of a photon-echo in the context of optical storage. As a proof-of-principle, we demonstrate that the photon-echo efficiency can be fully modulated by applying light-shift control pulses in an erbium-doped solid. The control of the echo emission is attributed to the spatial gradient induced by the light-shift beam. PMID- 25831317 TI - Strong enhancement of nano-sized circularly polarized light using an aperture antenna with V-groove structures. AB - We present a new type of aperture antenna with V-groove structures that are made of Au to enhance strong circularly polarized light (CPL). Simulations using the finite element method revealed that strong CPL was enhanced within the aperture with a diameter of 10 nm. The intensity of the electric field was enhanced and was 22,700 times greater than that of the incident light. The channel plasmon polaritons generated in the V-groove structures were responsible for the strong enhancement. The influence of the angle and length of the V-groove on the enhancement of the CPL was investigated. PMID- 25831318 TI - Self-adaptive vibrometry with CMOS-LCOS digital holography. AB - A self-adaptive interferometer based on digital holography is here reported for applications involving measurements of very small amplitude vibrations. The two beam coupling gain is optimized through an electronic feedback, while the dynamic character of the hologram allows reaching a high sensitivity of the interferometric measurements even in unstable environments and with strongly distorted wave-fronts. The frequency bandwidth of the adaptive interferometer and its spatial resolution are determined, respectively, by the maximum frame rate and the pixel size of the camera and of the spatial light modulator used to build the digital holographic setup. PMID- 25831319 TI - Diffraction of waves by a boundary between two half-planes with different resistivities. AB - The solution of the diffraction problem of waves by a junction between two resistive half-screens is obtained by using the wedge diffraction field expression, introduced by Maliuzhinets [Ann. Phys.461, 107 (1960)]. The two half planes, located at the same coordinate plane, have different surface resistivities. The new field expression is compared with the solution of Senior ["Diffraction by a material junction," http://deepblue.lib.umich.edu/handle/2027.42/21043] for the scattered waves. The important aspects of the approach are discussed in the light of the numerical results. PMID- 25831320 TI - Kinetics of optically pumped Kr metastables. AB - Optically-pumped atomic gas lasers that utilize metastable excited states of rare gas atoms (Rg(*)) have been demonstrated using both pulsed and CW pump sources. These devices resemble diode-pumped alkali vapor lasers, but have the advantage of using a chemically inert lasing medium. Collisional energy transfer is needed to sustain a population inversion, and He is used as the transfer agent. Consequently, values for the Kr(*)+He state-to-state energy transfer rate constants are needed for the analysis and prediction of laser performance characteristics. In the present study, we report He energy transfer rate constants for Kr(*) in the 5p[5/2](2), 5p[5/2](3), 5p[1/2](1), and 5s[3/2](1) states. PMID- 25831321 TI - Multiple quasi-phase-matching in nonlinear Raman-Nath diffraction. AB - The method of the superposition of a nonlinearity modulation is employed to design a two-dimensional (2D) nonlinear photonic lattice for efficient multiple quasi-phase-matched second harmonic generation in the process of nonlinear Raman Nath diffraction (NRND). An analytical solution is proposed to calculate the second harmonic intensity in rectangular 2D lattices. This approach can be useful for the generation of multiple second harmonic beams with the efficiency a few orders of magnitude higher than in the case of nonphase-matched generation via NRND. PMID- 25831322 TI - Effect of intrinsic surface roughness on the efficiency of intermodal phase matching in silica optical nanofibers. AB - We investigate the effect of intrinsic surface roughness associated to frozen thermal oscillations from the fiber fabrication process on the efficiency of third-harmonic generation via intermodal phase matching in silica nanofibers. Already a periodic wave with roughness of 0.2 nm reduces the efficiency by roughly 50% in a 1-mm optical nanofiber, with the divergence growing quadratically with distance. The surface wave period does not exhibit a large impact on the efficiency, due to averaging effects. However, both the location of the surface waves with respect to the phase matching radius as well as the surface wave amplitude have substantial effect on the efficiency, with the former presenting the possibility of transferring the power back to the pump wavelength. Simulations with a realistic superposition of random surface waves indicate that the conversion efficiency increases only for a few mm of propagation and reaches a maximum of less than 1%. PMID- 25831323 TI - Dual-mode-locking mechanism for an akinetic dispersive ring cavity swept source. AB - A fast dual-mode-locked akinetic optical swept source in the 1550-nm wavelength band is presented that is tested up to a sweep rate of 797 KHz. It comprises a voltage-controlled oscillator-driven wideband semiconductor optical amplifier (SOA) along with a dispersion compensation fiber, in a ring laser configuration. A Faraday rotating mirror is employed in the cavity as a reflective element in order to achieve better polarization control. By driving the SOA at a high-MHz frequency value multiple of the resonant frequency f(R), equal to the inverse round trip time, a first-mode locking mechanism is imposed. A second locking mechanism consists in sweeping the radio frequency of the locking signal at a rate slightly detuned from f(R). A dynamic linewidth of 0.8 nm is assessed by measuring the decay of interference signal strength versus optical path difference in a Mach-Zehnder interferometer. PMID- 25831324 TI - Phase noise measurement of wideband microwave sources based on a microwave photonic frequency down-converter. AB - An approach for phase noise measurement of microwave signal sources based on a microwave photonic frequency down-converter is proposed. Using the same optical carrier, the microwave signal under test is applied to generate two +1st-order optical sidebands by two stages of electro-optical modulations. A time delay is introduced between the two sidebands through a span of fiber. By beating the two +1st-order sidebands at a photodetector, frequency down-conversion is implemented, and phase noise of the signal under test can be calculated thereafter. The system has a very large operation bandwidth thanks to the frequency conversion in the optical domain, and good phase noise measurement sensitivity can be achieved since the signal degradation caused by electrical amplifiers is avoided. An experiment is carried out. The phase noise measured by the proposed system agrees well with that measured by a commercial spectrum analyzer or provided by the datasheet. A large operation bandwidth of 5-40 GHz is demonstrated using the proposed system. Moreover, good phase noise floor is achieved (-123 dBc/Hz at 1 kHz and -137 dBc/Hz at 10 kHz at 10 GHz), which is nearly constant over the full measurement range. PMID- 25831326 TI - Broadband near-to-shot-noise suppression of arbitrary cw-laser excess intensity noise in the gigahertz range. AB - Broadband near-to-shot-noise suppression of the intensity noise from a continuous wave (cw) fiber laser at 1550 nm is demonstrated at GHz-frequencies using feed forward phase-matched destructive noise interference impressed onto the optical signal with a fiber electro-optic power modulator. The scheme is independent of the laser frequency and therefore is suitable for tunable lasers. It can be used with some modifications after an optical fiber-amplifier boosting a cw laser signal. A noise residual of down to 2 dB above the shot-noise was measured, which is about 2 dB below the prediction with a rigorous noise model. While the total laser noise can be removed, inclusive shot noise, because the latter is still 10 dB above the thermal noise, the power splitter introduces some partition noise above the shot level. In that case, a sub-shot-noise suppression scheme should be possible by replacing the photon anti-correlation of the power splitter by the co correlation obtained from a paired photon or twin beam source. PMID- 25831325 TI - Impact of substrate pits on laser-induced damage performance of 1064-nm high reflective coatings. AB - The laser damage resistance of coatings in high-power laser systems depends significantly on the surface quality of the substrate. In our experiment, pits were precisely fabricated on the surface of fused silica substrate using a femtosecond laser processing bench. The HfO2/SiO2 high reflective coatings at 1064 nm were deposited by conventional e-beam evaporation onto fused silica substrates with and without pits, respectively. The internal crack that was induced by the substrate geometrical structure was first observed in our experiment. The laser-induced damage threshold test showed negative effects of the substrate pits on the laser resistance of high-reflective coatings. Simulations by the finite element method were carried out, and results demonstrated that the modulation of a high reflector multilayer geometry could lead to electrical-field amplification and reduce laser damage resistance. Combined with its poor mechanical properties, the pits on substrate could contribute to the occurrence of damages. PMID- 25831327 TI - Enhanced intermodal four-wave mixing for visible and near-infrared wavelength generation in a photonic crystal fiber. AB - We demonstrate experimentally an enhanced intermodal four-wave mixing (FWM) process through coupling positively chirped femtosecond pulses into the deeply normal dispersion region of the fundamental mode of an in-house fabricated photonic crystal fiber (PCF). In the intermodal phase-matching scheme, the energy of the pump waves at 800 nm in the fundamental mode is efficiently converted into the anti-Stokes waves around 553 nm and the Stokes waves within the wavelength range of 1445-1586 nm in the second-order mode. The maximum conversion efficiency of eta(as) and eta(s) of anti-Stokes and Stokes waves can be up to 21% and 16%, respectively. The Stokes frequency shift Omega is 5580 cm(-1). The fiber bending and intermodal walk-off effect of pulses do not have significant influence on the nonlinear optical process. PMID- 25831328 TI - Radiocarbon dioxide detection based on cavity ring-down spectroscopy and a quantum cascade laser. AB - Monitoring of radiocarbon (C14) in carbon dioxide is demonstrated using mid infrared spectroscopy and a quantum cascade laser. The measurement is based on cavity ring-down spectroscopy, and a high sensitivity is achieved with a simple setup. The instrument was tested using a standardized sample containing elevated levels of radiocarbon. Radiocarbon dioxide could be detected from samples with an isotopic ratio C14/C as low as 50 parts-per-trillion, corresponding to an activity of 5 kBq/m(3) in pure CO(2), or 2 Bq/m(3) in air after extraction of the CO(2) from an air sample. The instrument is simple, compact, and robust, making it the ideal tool for on-site measurements. It is aimed for monitoring radioactive gaseous emissions in a nuclear power environment, during the operation and decommissioning of nuclear power plants. Its high sensitivity also makes it the ideal tool for the detection of leaks in radioactive waste repositories. PMID- 25831329 TI - Fabrication of low-stray-light gratings by broad-beam scanning exposure in the direction perpendicular to the grating grooves. AB - Previous research on making low-stray-light gratings is mainly focused on process steps after the photoresist mask has been made. We propose to improve the quality of the photoresist mask directly in exposure. We present a broad-beam scanning exposure method along the grating vector (i.e., in the direction perpendicular to the grating grooves), utilizing a reference grating clamped below the substrate on the translation stage for phase and attitude locking. Scanning-exposed gratings with a size of 40 mm*40 mm are successfully made, which have straighter grooves and smoother surfaces, and their stray light levels around the first and second diffraction orders are decreased significantly. PMID- 25831330 TI - In vivo optical resolution photoacoustic microscopy using glancing angle deposited nanostructured Fabry-Perot etalons. AB - In this Letter, reflection-mode optical resolution photoacoustic microscopy (OR PAM) using glancing angle-deposited (GLAD) nanostructured Fabry-Perot interferometers (FPI) for in vivo applications is reported. GLAD is a single-step physical vapor deposition (PVD) technique used to fabricate porous nanostructured thin films. Using titanium dioxide, a transparent semiconductor with a high refractive index (n=2.4), the GLAD technique can be employed to fabricate samples with tailored nano-porosity, refractive index periodicities, and high Q-factor reflectance spectra. The OR-PAM in vivo images of chorioallantoic membrane (CAM) of 5-day chicken embryo model are demonstrated. The phantom study shows lateral resolution and signal-to-noise ratio better than 7 MUm and 35 dB, respectively. The sensitive GLAD FPI allows photoacoustic imaging down to a few-nJ pulse energy. To the best of our knowledge, this is the first time that a FPI-based reflection mode optical resolution photoacoustic imaging technique is demonstrated for in vivo applications. PMID- 25831331 TI - Third-harmonic generation microscopy reveals dental anatomy in ancient fossils. AB - Fossil teeth are primary tools in the study of vertebrate evolution, but standard imaging modalities have not been capable of providing high-quality images in dentin, the main component of teeth, owing to small refractive index differences in the fossilized dentin. Our first attempt to use third-harmonic generation (THG) microscopy in fossil teeth has yielded significant submicrometer level anatomy, with an unexpectedly strong signal contrasting fossilized tubules from the surrounding dentin. Comparison between fossilized and extant teeth of crocodilians reveals a consistent evolutionary signature through time, indicating the great significance of THG microscopy in the evolutionary studies of dental anatomy in fossil teeth. PMID- 25831332 TI - Frequency-agile dual-frequency lidar for integrated coherent radar-lidar architectures. AB - We propose a novel architecture for implementing a dual-frequency lidar (DFL) exploiting differential Doppler shift measurement. The two frequency tones, needed for target velocity measurements, are selected from the spectrum of a mode locked laser operating in the C-band. The tones' separation is easily controlled by using a programmable wavelength selective switch, thus allowing for a dynamic trade-off among robustness to atmospheric turbulence and sensitivity. Speed measurements for different tone separations equal to 10, 40, 80, and 160 GHz are demonstrated, proving the system's capability of working in different configurations. Thanks to the acquisition system based on an analog-to-digital converter and digital-signal processing, real-time velocity measurements are demonstrated. The MLL-based proposed architecture enables the integration of the DFL with a photonic-based radar that exploits the same laser for generating and receiving radio-frequency signal with high performance, thus allowing for simultaneous or complementary target observations by exploiting the advantages of both radar and lidar. PMID- 25831333 TI - Temperature characteristics of silicon core optical fiber Fabry-Perot interferometer. AB - Silicon core optical fiber expanded silicon photonics to specialty fiber platform. Although great challenges still exist for the fiber fabrication, the presence of semiconductor material has already given optical fiber new features and enormous possibilities for fiber-based devices and sensors. In this Letter, an all fiber silicon cavity Fabry-Perot interferometer was made by splicing silicon core silica cladding fiber with conventional single-mode silica fiber. The cavity shows high temperature sensitivity around 82 pm/ degrees C due to the larger thermo-optical coefficient of silicon material compared with that of silica material. PMID- 25831334 TI - Rogue waves in a normal-dispersion fiber laser. AB - Experimental evidence of rogue-wave formation in a normal-dispersion ytterbium fiber laser is reported. Spectral filtering is a primary component of pulse shaping in normal-dispersion lasers, and we find that the choice of filter dramatically influences the distribution of noise-pulse energies produced by these lasers. With an interference filter in the cavity, non-Gaussian distributions with pulses as large as 6 times the significant wave height are observed. These correspond to pulse energies as high as ~50 nJ. To our knowledge, the results presented are not accounted for by existing theoretical models of rogue-wave formation. PMID- 25831335 TI - Optical coherence photoacoustic microscopy for in vivo multimodal retinal imaging. AB - We developed an optical coherence photoacoustic microscopy (OC-PAM) system, which can accomplish optical coherence tomography (OCT) and photoacoustic microscopy (PAM) simultaneously by using a single pulsed broadband light source. With a center wavelength of 800 nm and a bandwidth of 30 nm, the system is suitable for imaging the retina. Generated from the same group of photons, the OCT and PAM images are intrinsically registered in the lateral directions. To test the capabilities of the system on multimodal ophthalmic imaging, we imaged the retina of pigmented rats. The OCT images showed the retinal structures with quality similar to conventional OCT, while the PAM images revealed the distribution of absorbers in the retina. Since the absorption of hemoglobin is relatively weak at around 800 nm, the NIR PAM signals are generated mainly from melanin in the posterior segment of the eye, thus providing melanin-specific imaging of the retina. PMID- 25831336 TI - 463-MHz fundamental mode-locked fiber laser based on few-layer MoS(2) saturable absorber. AB - We report on the passive-mode-locking operation of a fiber laser with a fundamental repetition rate of 463 MHz based on molybdenum disulfide (MoS(2)) saturable absorber (SA). By embedding MoS(2) into polyvinyl alcohol (PVA) thin film, MoS(2)-PVA SA was prepared with a modulation depth of 2.7% and a saturation intensity of 137 MW/cm(2). The mode-locked fiber laser-employed MoS(2)-PVA SA was achieved with center wavelength of 1556.3 nm, 3-dB bandwidth of 6.1 nm, output power of 5.9 mW, and an extinction ratio of up to 97 dB in the RF spectrum. The demonstration of mode-locking operation with high fundamental repetition rate and high spectral purity indicates that MoS(2)-PVA SA can be a good candidate for high-precision ultrafast applications. PMID- 25831337 TI - Heterogeneously integrated III-V laser on thin SOI with compact optical vertical interconnect access. AB - A new heterogeneously integrated III-V/Si laser structure is reported in this report that consists of a III-V ridge waveguide gain section on silicon, III-V/Si optical vertical interconnect accesses (VIAs), and silicon-on-insulator (SOI) nanophotonic waveguide sections. The III-V semiconductor layers are introduced on top of the 300-nm-thick SOI layer through low temperature, plasma-assisted direct wafer-bonding and etched to form a III-V ridge waveguide on silicon as the gain section. The optical VIA is formed by tapering the III-V and the beneath SOI in the same direction with a length of 50 MUm for efficient coupling of light down to the 600 nm wide silicon nanophotonic waveguide or vice versa. Fabrication details and specification characterizations of this heterogeneous III-V/Si Fabry Perot (FP) laser are given. The fabricated FP laser shows a continuous-wave lasing with a threshold current of 65 mA at room temperature, and the slope efficiency from single facet is 144 mW/A. The maximal single facet emitting power is about 4.5 mW at a current of 100 mA, and the side-mode suppression ratio is ~30 dB. This new heterogeneously integrated III-V/Si laser structure demonstrated enables more complex laser configuration with a sub-system on-chip for various applications. PMID- 25831338 TI - Brewster effect in metafilms composed of bi-anisotropic split-ring resonators. AB - The Brewster effect is extended to single-layer metafilms. In contrast to bulk media, the Brewster effect in metafilms can be realized by tailoring the radiation pattern of a distribution of meta-atoms rather than the effective medium parameters. A metafilm composed of bi-anisotropic split-ring resonators is designed based on the theory, and its characteristics are numerically analyzed. The simulation demonstrates that there exists a condition for which the polarization of the reflected wave becomes independent of the incident polarization at a particular angle of incidence. PMID- 25831339 TI - Volume integrated phase modulator based on funnel waveguides for reconfigurable miniaturized optical circuits. AB - We demonstrate the integration of a miniaturized 30(x) MUm*30(y) MUm*2.7(z) mm electro-optic phase modulator operating in the near-IR (lambda=980 nm) based on the electro-activation of a funnel waveguide inside a paraelectric sample of photorefractive potassium lithium tantalate niobate. The modulator forms a basic tassel in the realization of miniaturized reconfigurable optical circuits embedded in a single solid-state three-dimensional chip. PMID- 25831340 TI - Image quality improvement by the structured light illumination method in an optical readout cantilever array infrared imaging system. AB - The structured light illumination method is applied in an optical readout uncooled infrared imaging system to improve the IR image quality. The unavoidable nonuniform distribution of the initial bending angles of the bimaterial cantilever pixels in the focal plane array (FPA) can be well compensated by this method. An ordinary projector is used to generate structured lights of different intensity distribution. The projected light is divided into patches of rectangular regions, and the brightness of each region can be set automatically according to the deflection angles of the FPA and the light intensity focused on the imaging plane. By this method, the FPA image on the CCD plane can be much more uniform and the image quality of the IR target improved significantly. A comparative experiment is designed to verify the effectiveness. The theoretical analysis and experimental results show that the proposed structured light illumination method outperforms the conventional one, especially when it is difficult to perfect the FPA fabrication. PMID- 25831341 TI - Plane-wave decomposition of spatially random fields. AB - We investigate the uniqueness of the plane-wave decomposition of temporally deterministic, spatially random fields. Specifically, we consider the decomposition of spatially ergodic and, thus, statistically homogeneous fields. We show that when the spatial power spectrum is injective, the plane waves are the only possible coherent modes. Furthermore, the randomness of such fields originates in the spatial spectral phase, i.e., the phase associated with the coefficients of each plane wave in the expansion. By contrast, the spectral amplitude is deterministic and is specified by the spatial power spectrum. We end with a discussion showing how the results can be translated in full to the time domain. PMID- 25831342 TI - High-power femtosecond mid-infrared optical parametric oscillator at 7 MUm based on CdSiP(2). AB - We report a femtosecond optical parametric oscillator (OPO) for the mid-infrared (mid-IR), generating a record average power of 110 mW at 7 MUm. The OPO, based on CdSiP(2) (CSP) as the nonlinear crystal, provides idler wavelength tuning across 6540-7186 nm with spectral bandwidths >400 nm at -10 dB level over the entire range, and a maximum bandwidth of 478 nm at 6.9 MUm. To the best of our knowledge, this is the highest average power generated from a femtosecond OPO in the deep mid-IR. The OPO also provides near-IR signal wavelengths tunable across 1204-1212 nm with a usable power of 450 mW in 418-fs pulses at 1207 nm. The simultaneously measured signal and idler power exhibit a passive stability better than 1.6% rms and 3% rms, respectively. A mid-IR idler spectral stability with a standard deviation of the frequency fluctuations better than 40 MHz over 15 min, limited by the measurement resolution, is realized. Using the mid-IR idler from the CSP OPO, we perform Fourier-transform spectroscopy to detect liquid phase organic solvent, toluene (C(7)H(8)), in the molecular fingerprint region. PMID- 25831344 TI - Swept optical SSB-SC modulation technique for high-resolution large-dynamic-range static strain measurement using FBG-FP sensors. AB - This Letter presents a static strain demodulation technique for FBG-FP sensors using a suppressed carrier LiNbO(3) (LN) optical single sideband (SSB-SC) modulator. A narrow-linewidth tunable laser source is generated by driving the modulator using a linear chirp signal. Then this tunable single-frequency laser is used to interrogate the FBG-FP sensors with the Pound-Drever-Hall (PDH) technique, which is beneficial to eliminate the influence of light intensity fluctuation of the modulator at different tuning frequencies. The static strain is demodulated by calculating the wavelength difference of the PDH signals between the sensing FBG-FP sensor and the reference FBG-FP sensor. As an experimental result using the modulator, the linearity (R2) of the time-frequency response increases from 0.989 to 0.997, and the frequency-swept range (dynamic range) increases from hundreds of MHz to several GHz compared with commercial PZT-tunable lasers. The high-linearity time-wavelength relationship of the modulator is beneficial for improving the strain measurement resolution, as it can solve the problem of the frequency-swept nonlinearity effectively. In the laboratory test, a 0.67 nanostrain static strain resolution, with a 6 GHz dynamic range, is demonstrated. PMID- 25831343 TI - Reconfigurable nonblocking 4-port silicon thermo-optic optical router based on Mach-Zehnder optical switches. AB - We demonstrate a reconfigurable nonblocking 4-port silicon thermo-optic optical router based on Mach-Zehnder optical switches. For all optical links in its 9 routing states, the optical signal-to-noise ratios are larger than 15 dB in the wavelength range from 1525 to 1565 nm. Each optical link of the optical router can manipulate 50 wavelength-division-multiplexing channels with the data rate of 32 Gbps for each channel in the same wavelength range. Its average energy efficiency is about 16.3 fJ/bit, and its response time is about 19 MUs. PMID- 25831345 TI - Low-loss partial rib polarization rotator consisting only of silicon core and silica cladding. AB - We present a low-loss and small-footprint polarization rotator based on mode evolution. The polarization rotator is composed of an asymmetric-rib waveguide and a tapered waveguide, both of which consist only of a silicon core and a silica cladding. The rotator is fabricated under the same design rules as other device blocks, such as rib-waveguide phase shifters for photonic integration. The polarization rotator is fabricated using CMOS-based processes and provides polarization rotations with an on-chip insertion loss lower than 0.5 dB from transverse-electric (TE) to transverse-magnetic (TM) polarization and a loss lower than 1.0 dB from the TM to TE polarization in a 200 nm wavelength range extending over C and L bands. PMID- 25831346 TI - High-energy dissipative solitons generation from a large normal dispersion Er fiber laser. AB - We report on a passively mode-locked erbium-doped fiber laser featuring a large normal dispersion and emitting high-energy dissipative solitons. Mode-locking is stabilized by the combined actions of a high nonlinearity amplitude modulator and a narrow band spectral filter. The laser routinely delivers highly chirped pulses with more than 38 nJ energy that can be compressed down to 700 fs duration using bulk gratings. Numerical simulations confirm the experimental results and reveal the self-similar pulse evolution along the normal dispersion fibers included inside the cavity. PMID- 25831347 TI - Determining the vortex densities of random nondiffracting beams. AB - The evolutionary and statistical properties of the optical vortices that exist in random nondiffracting beams (RNDBs) are analyzed. It is found that the phase singularities (PSs) in the RNDBs originate from the zero rings of Bessel beams with the same ring-shaped spatial spectrum structure (but with zero phase fluctuations) as those of the RNDBs provided. It is also found that the average PS density or vortex density is determined by the average duration of the zero rings of the corresponding Bessel function. According to this model, we successfully derived, for the first time to our knowledge, an analytical formula for quantitatively predicting the PS density of the RNDBs. This formula could be helpful for understanding and designing RNDBs in their applications. PMID- 25831348 TI - 40-GHz photonic waveform generator by linear shaping of four spectral sidebands. AB - We show that the amplitude and phase shaping of only four sidebands of the optical spectrum is sufficient to synthesize parabolic, triangular, or flat-top pulse trains at high repetition rates. Selection of the symmetric carrier suppressed waveform is easily achieved by changing the phase difference between the inner and outer spectral lines. Experiments carried out at a repetition rate of 40 GHz confirm the high quality of the intensity profiles that are obtained. PMID- 25831350 TI - Nanobump microresonator. AB - We introduce a whispering gallery-mode (WGM) nanobump microresonator (NBMR) and develop its theory. This microresonator is formed by an asymmetric nanoscale-high deformation of the translationally symmetric optical fiber surface, which is employed in fabrication of surface nanoscale axial photonics (SNAP) structures. It is shown that an NBMR causes strong localization of WGMs near a closed ray (geodesic) at the fiber surface, provided that this ray is stable. Our theory explains and describes the experimentally observed localization of WGMs by NBMRs and is useful for the design and fabrication of SNAP devices. PMID- 25831349 TI - In vivo molecular contrast OCT imaging of methylene blue. AB - An 830-nm spectral-domain optical coherence tomography (OCT) system with an integrated 663-nm diode pump laser has been developed to enable molecular contrast OCT imaging of methylene blue (MB), a common vital dye used clinically. The introduction of the 663-nm diode laser, which acts as the pump in this implementation of pump-probe OCT (PPOCT), represents a minor modification to an otherwise typical OCT system. A newly developed background subtraction technique completely removes all background from intensity noise at the pump modulation frequency, simplifying the interpretation of PPOCT images. These developments have enabled the first in vivo imaging of MB with PPOCT. Volumetric images of a zebrafish, stained by submersion in a 0.01% (w/v) solution of MB for 6 h, show accumulation of MB in the mesonephros, the primordial filtration organ. PMID- 25831351 TI - Hydrated-electron resonance enhancement O-H stretching vibration of water hexamer at air-water interface. AB - Raman scattering of the O-H stretching vibration mode inside water, as well as near and at the air-water interface, was investigated by laser-induced breakdown (LIB). An intense and characteristic higher wavenumber Raman shift of the O-H vibration was observed at the air-water interface, which was attributed to the hydrated-electron resonance enhancement of the O-H stretching vibration mode of water hexamer. The hydrated electron in the water hexamer structure was formed by excess electrons injected into the gas-like phase with low hydrogen bond order under LIB. The electron-phonon coupled mechanism was discussed. PMID- 25831352 TI - Incoherent-light temporal stretching of high-speed intensity waveforms: comment. AB - Time lens and pinhole time camera imaging systems can effectively image both coherent and incoherent (large time-bandwidth product) waveforms. Broadband, coherent light pulses used to create quadratic phase modulation in the parametric time lens are but one class of several time lens mechanisms and are independent of the time-bandwidth nature of the input waveform unless derived from the same source in an experimental demonstration. Clarification of these points, made in an earlier paper [Opt. Lett.39, 4243 (2014)10.1364/OL.39.004243OPLEDP0146-9592], is presented. PMID- 25831353 TI - Incoherent-light temporal stretching of high-speed intensity waveforms: reply to comment. AB - This is a reply to the recent comment [Opt. Lett.40, 1438 (2015)10.1364/OL.40.001438OPLEDP0146-9592] by Brian H. Kolner. We offer some additional explanations for his clarifications. PMID- 25831354 TI - Two-photon-induced Forster resonance energy transfer in a hybrid material engineered from quantum dots and bacteriorhodopsin. AB - Energy transfer from nanostructures to biological supramolecular photosystems is an important fundamental issue related to the possible influence of nanoobjects on biological functions. We demonstrate here two-photon-induced Forster resonance energy transfer (FRET) from fluorescent CdSe/ZnS quantum dots (QDs) to the photosensitive protein bacteriorhodopsin (bR) in a QD-bR hybrid material. The two photon absorption cross section of QDs has been found to be about two orders of magnitude larger than that of bR. Therefore, highly selective two-photon excitation of QDs in QD-bR complexes is possible. Moreover, the efficiency of FRET from QDs to bR is sufficient to initiate bR photoconversion through two photon excitation of QDs in the infrared spectral region. The data demonstrate that the effective spectral range in which the bR biological function is excited can be extended beyond the band where the protein itself utilizes light energy, which could open new ways to use this promising biotechnological material. PMID- 25831355 TI - Closed-form expressions for nonparaxial accelerating beams with pre-engineered trajectories. AB - In this Letter, we propose a general real-space method for the generation of nonparaxial accelerating beams with arbitrary predefined convex trajectories. Our results lead to closed-form expressions for the required phase at the input plane. We present such closed-form results for a variety of caustic curves: beside circular, elliptic, and parabolic, we find for the first time general power-law and exponential trajectories. Furthermore, by changing the initial amplitude, we can design different intensity profiles along the caustic. PMID- 25831356 TI - Reconfigurable dual-channel all-optical logic gate in a silicon waveguide using polarization encoding. AB - A reconfigurable dual-channel all-optical logic gate is proposed and experimentally demonstrated using four-wave mixing in a silicon waveguide for polarization encoding signals. Six logic functions, XNOR, AND, NOR, XOR, AB-, and A-B are implemented at two different wavelength channels by adjusting the polarization states of two 10 Gb/s non-return-to-zero polarization-shift keying (NRZ-PolSK) signals modulated by 10-bit on-off keying (OOK) sequences. The eye diagrams of the logic signals are clearly observed, and the logic functions are well demonstrated as the two incident NRZ-PolSK signals are both modulated by the OOK sequences, which originate from 2(31)-1 pseudo-random binary sequences. PMID- 25831357 TI - Ultra-compact TE and TM pass polarizers based on vanadium dioxide on silicon. AB - Vanadium dioxide (VO(2)) is a metal-insulator transition (MIT) oxide recently used in plasmonics, metamaterials, and reconfigurable photonics. Because of the MIT, VO(2)shows great change in its refractive index allowing for ultra-compact devices with low power consumption. We theoretically demonstrate a transverse electric (TE) and a transverse magnetic (TM) pass polarizer with an ultra-compact length of only 1 MUm and tunable using the MIT of the VO2. During the insulating phase, both devices exhibit insertion losses below 2 dB at 1550 nm. Changing to the metallic phase, the unwanted polarization is attenuated above 15 dB while insertion losses are kept below 3 dB. Broadband operation over a range of 60 nm is also achieved. PMID- 25831358 TI - Simple way to analyze Brillouin spectra from turbid liquids. AB - The shape of the Brillouin light-scattering spectrum recorded from turbid liquids is distinctly distorted compared to that from a transparent sample. The reason for this is the multiple scattering of light within the medium. The usual expression for the Brillouin spectrum does not apply to the multiple scattering situation. In this Letter, we consider a Brillouin spectrum from opaque samples composed of a distribution of spectra resulting from elementary scattering events, each occurring in single scattering vector conditions. We introduce a one parameter test function to define the probability distribution of scattering events occurring at a given value of the scattering vector. The proposed procedure was tested on model liquids that consisted of suspensions of sub micrometer spherical particles of different size and concentration, dispersed in different carrier liquids and studied as a function of temperature. Our analysis made it possible to account for the effect of multiple scattering and to recover the values of mechanical parameters describing the pure solvents. PMID- 25831359 TI - Effect of scattering loss on connections between classical and quantum processes in second-order nonlinear waveguides. AB - We show that a useful connection exists between spontaneous parametric downconversion (SPDC) and sum frequency generation in nonlinear optical waveguides with arbitrary scattering loss, while the same does not hold true for SPDC and difference frequency generation. This result refines the relationship between these quantum and classical second-order nonlinear optical processes in waveguides, and identifies the most accurate characterization of a waveguide's quantum performance in the presence of loss based solely on classical measurements. PMID- 25831360 TI - Actively mode-locked Tm(3+)-doped silica fiber laser with wavelength-tunable, high average output power. AB - A diode-pumped, actively mode-locked high-power thulium (Tm3+)-doped double-clad silica fiber laser is demonstrated, providing an average output power in mode-locked (continuous wave) operation of 53 W (72 W) with a slope efficiency of 34% (38%). Mode-locking in the 6th-harmonic order was obtained by an acousto optic modulator driven at 66 MHz without dispersion compensation. The shortest measured output pulse width was 200 ps. Owing to a diffraction grating as cavity end mirror, the central wavelength could be tuned from 1.95 to 2.13 MUm. The measured beam quality in mode-locked and continuous wave operation has been close to the diffraction limit. PMID- 25831361 TI - Compact fiber-optic curvature sensor based on super-mode interference in a seven core fiber. AB - A compact, low loss, and highly sensitive optical fiber curvature sensor is presented. The device consists of a few-millimeter-long piece of seven-core fiber spliced between two single-mode fibers. When the optical fiber device is kept straight, a pronounced interference pattern appears in the transmission spectrum. However, when the device is bent, a spectral shift of the interference pattern is produced, and the visibility of the interference notches changes. This allows for using either visibility or spectral shift for sensor interrogation. The dynamic range of the device can be tailored through the proper selection of the length of the seven-core fiber. The effects of temperature and refractive index of the external medium on the response of the curvature sensor are also discussed. Linear sensitivity of about 3000 nm/mm(-1) for bending was observed experimentally. PMID- 25831362 TI - Hybrid M-mode-like OCT imaging of three-dimensional microvasculature in vivo using reference-free processing of complex valued B-scans. AB - We propose a novel OCT-based method for visualizing microvasculature in three dimension using reference-free processing of individual complex valued B-scans with highly overlapped A-scans. In the lateral direction of such a B-scan, the amplitude and phase of speckles corresponding to vessel regions exhibit faster variability and, thus, can be detected without comparison with other B-scans recorded in the same plane. This method combines elements of several existing OCT angiographic approaches and exhibits: (1) enhanced robustness with respect to bulk tissue motion with frequencies up to tens of Hz, (2) resolution of microcirculation images equal to that of structural images, and (3) possibility of quantifying the vessels in terms of their decorrelation rates. PMID- 25831363 TI - Time-dependent variation of fiber Bragg grating reflectivity in PMMA-based polymer optical fibers. AB - In this Letter, we investigate the effects of viscoelasticity on both the strength and resonance wavelength of two fiber Bragg gratings (FBGs) inscribed in microstructured polymer optical fiber (mPOF) made of undoped PMMA. Both FBGs were inscribed under a strain of 1% in order to increase the material photosensitivity. After the inscription, the strain was released, and the FBGs spectra were monitored. We initially observed a decrease of the reflection down to zero after which it began to increase. After that, strain tests were carried out to confirm the results, and finally the gratings were monitored for a further 120 days, with a stable reflection response being observed beyond 50 days. PMID- 25831364 TI - Heterogeneously integrated 2.0 MUm CW hybrid silicon lasers at room temperature. AB - Here we experimentally demonstrate room temperature, continuous-wave (CW), 2.0 MUm wavelength lasers heterogeneously integrated on silicon. Molecular wafer bonding of InP to Si is employed. These hybrid silicon lasers operate CW up to 35 degrees C and emit up to 4.2 mW of single-facet CW power at room temperature. III V tapers transfer light from a hybrid III-V/silicon optical mode into a Si waveguide mode. These lasers enable the realization of a number of sensing and detection applications in compact silicon photonic systems. PMID- 25831365 TI - Characterization and mitigation of phase-modulation-dependent loss of liquid crystal on silicon. AB - We characterize the phase-modulation-dependent loss (PMDL) arising from the commercial liquid crystal on silicon (LCOS) and find that it severely degrades the fidelity of mode-selective conversion and orbital-angular-momentum (OAM) generation, as well as the performance of LCOS-based wavelength-selective switch (WSS). For the LP11 mode conversion, an offset-launch technique is proposed to mitigate such effect. For the LPl,m (l>1) mode conversion, the superposition of OAMs with conjugation vortices is demonstrated to achieve perfect mode conversion. Experimental outcomes verify that both solutions are able to improve the fidelity quality factor by at least 15 dB. PMID- 25831366 TI - Few-mode fiber multi-parameter sensor with distributed temperature and strain discrimination. AB - We propose a unique few-mode fiber (FMF)-based multi-parameter optical-fiber sensor for distributed measurement of temperature and strain. We launch a pump and a probe signal through specific linearly polarized modes into a FMF, and monitor the Brillouin frequency shift (BFS) in each mode. By analyzing the temperature and strain coefficients of the BFS of the two lowest order (LP(01), LP(11)) modes, discrimination of temperature and strain are successfully demonstrated, with an accuracy of 1.2 degrees C and 21.9 MUepsilon. PMID- 25831367 TI - Fabrication of highly stable microfiber structures via high-substituted hydroxypropyl cellulose coating for device and sensor applications. AB - We demonstrate a cost-effective approach to fabricate stable microfiber structures taking advantage of high-substituted hydroxypropyl cellulose (H-HPC) coating. The microfibers are bent, twisted, or coiled to form desired geometries, and then the segments in contact are coated to resist the existing bending or twisting stresses to stabilize the structures. Coated devices including a twisted Sagnac interferometer, a ring resonator, and a Fabry-Perot cavity have been exhibited. Measured result suggests that the coated structures are highly stable over 20 days. The thin, low-index coating material allows for a strong evanescent field interaction between the mode field and ambient solution. As an example, the coated twisted Sagnac interferometer can act as a refractive-index sensor with a sensitivity as high as 2600 nm/RIU. The present technique is greatly beneficial for long-term working of microfiber devices and sensors and offers a possible approach for the development of integrated microphotonic devices and platforms. PMID- 25831368 TI - Multispectral opto-acoustic tomography of exercised muscle oxygenation. AB - Unlike near-infrared spectroscopy, multispectral opto-acoustic tomography (MSOT) has the potential to offer high-resolution imaging assessment of hemodynamics and blood saturation levels in muscle. However motion artifacts impede the real-time applications of the technique. We developed fast-MSOT with motion tracking that reduces motion artifacts. We used this algorithm to follow blood oxygenation level changes associated with muscle exercise in the muscle and the skin of healthy volunteers. PMID- 25831369 TI - Enhanced third-harmonic generation in Si-compatible epsilon-near-zero indium tin oxide nanolayers. AB - We experimentally demonstrate enhanced third-harmonic generation from indium tin oxide nanolayers at telecommunication wavelengths with an efficiency that is approximately 600 times larger than crystalline silicon (Si). The increased optical nonlinearity of the fabricated nanolayers is driven by their epsilon-near zero response, which can be tailored on-demand in the near-infrared region. The present material platform is obtained without any specialized nanofabrication process and is fully compatible with the standard Si-planar technology. The proposed approach can lead to largely scalable and highly integrated optical nonlinearities in Si-integrated devices for information processing and optical sensing applications. PMID- 25831370 TI - Narrow-spectral-linewidth silicon photonic wavelength-tunable laser with highly asymmetric Mach-Zehnder interferometer. AB - We propose a narrow-spectral-linewidth silicon photonic wavelength-tunable laser with a novel external wavelength-tunable filter, which consists of two silicon ring resonators with different circumferences and a highly asymmetric Mach Zehnder interferometer (MZI), the two optical paths of which have significantly different lengths. Calculations and experimental results indicated that the gain difference between longitudinal modes was increased by the highly asymmetric MZI. Consequently, a narrow spectral linewidth of 12 kHz and a stable single-mode oscillation were obtained. PMID- 25831371 TI - High-sensitivity and high-Q-factor glass photonic crystal cavity and its applications as sensors. AB - We investigate the properties of a planar photonic crystal cavity on glass and its applications as sensors. An airbridged twofold defect cavity on Schott glass background and Gorilla glass substrate has been designed for high Q-factor up to 4459. The average sensitivity of the cavity resonance to background refractive index is 388 nm/Refractive Index Unit. The resonant wavelength is sensitive to background temperature by 18.5 pm/ degrees C. The designed sensors show much higher sensitivity than those based on waveguide interferometers or photonic bandgap structures without cavity resonance. The results are also useful for experimental studies of glass photonic devices. PMID- 25831372 TI - Enhancing near-infrared light absorption in PtSi thin films for Schottky barrier IR detectors using moth-eye surface structures. AB - Si-based Schottky barrier infrared detectors typically use thin (1-10 nm) PtSi or Pd2Si layers grown on Si substrates as an absorption medium. Herein, we demonstrate the use of sub-wavelength moth-eye (ME) structures on the Si substrate of such detectors to enhance absorption of near infrared (NIR) light in the active PtSi layer to increase detector efficiency. Absorbance enhancement of 70%-200% in the lambda=1-2.5 MUm range is demonstrated in crystalline PtSi films grown via electron beam evaporation of Pt and subsequent vacuum annealing. Low total reflectance (<10%) was measured for ME films, demonstrating the efficacy of the ME effect. Effective medium approximation calculations show that absorption enhancement at short wavelengths is partially due to forward scattering, which increases the effective optical path length in PtSi. Results also suggest that ME structuring of substrates is a general and low-cost method to enhance absorption in a variety of IR material platforms used for back-illuminated detectors. PMID- 25831373 TI - Near-infrared electro-optic modulator based on plasmonic graphene. AB - We propose a novel scheme for an electro-optic modulator based on plasmonically enhanced graphene. As opposed to previously reported designs where the switchable absorption of graphene itself was employed for modulation, here a graphene monolayer is used to actively tune the plasmonic resonance condition through the modification of interaction between optical field and an indium tin oxide (ITO) plasmonic structure. Strong plasmonic resonance in the near infrared wavelength region can be supported by accurate design of ITO structures, and tuning the graphene chemical potential through electrical gating switches on and off the ITO plasmonic resonance. This provides much increased electro-absorption efficiency as compared to systems relying only on the tunable absorption of the graphene. PMID- 25831374 TI - Polarization controlled coupling and shaping of surface plasmon polaritons by nanoantenna arrays. AB - We demonstrate experimentally the use of ordered arrays of nanoantennas for polarization controlled plasmonic beam shaping and excitation. Rod- and cross shaped nanoantennas are used as local point-like sources of surface plasmon polaritons, and the desired phase of the generated plasmonic beam is set directly through their spatial arrangement. The polarization selectivity of the optical nanoantennas allows us to further control the excitation, enabling the realization of a variety of complex and functional plasmonic beam shaping elements. We demonstrate this concept by generating plasmonic self-accelerating beams, plasmonic bottle beams, and switchable dual-focii plasmonic lenses. The freedom in the design and arrangement of these nanoantennas enables us to specifically tailor and control the shapes, wavelengths, and coupling efficiencies of complex plasmonic beams. PMID- 25831375 TI - Slowing down light to 300 km/s in a deuterium-loaded fiber Bragg grating. AB - We report light propagation with a group velocity of only 300 km/s, a group index of 1010, and a group delay of 42 ns, in a strong apodized fiber Bragg grating 12.5 mm in length. The grating was fabricated in a deuterium-loaded fiber using a femtosecond laser and a phase mask, followed by annealing to reduce residual losses. Data analysis indicates a strong index modulation of 1.98*10(-3) and an ultra-low single-pass power loss of 0.010 dB. PMID- 25831376 TI - Polarization control of quantum dot emission by chiral photonic crystal slabs. AB - We investigate theoretically the polarization properties of the quantum dot's (QDs) optical emission from chiral photonic crystal structures made of achiral materials in the absence of external magnetic field at room temperature. The mirror symmetry of the local electromagnetic field is broken in this system due to the decreased symmetry of the chiral modulated layer. As a result, the radiation of randomly polarized QDs normal to the structure becomes partially circularly polarized. The sign and degree of circular polarization are determined by the geometry of the chiral modulated structure and depend on the radiation frequency. A degree of circular polarization up to 99% can be achieved for randomly distributed QDs, and can be close to 100% for some single QDs. PMID- 25831377 TI - Single-grating-mirror intracavity stretcher design for chirped pulse regenerative amplification. AB - We report for the first time, to the best of our knowledge, an innovative design concept for intracavity pulse stretching in a regenerative amplifier, employing a single "grating-mirror" based on a leaky-mode grating-waveguide design. The very compact and flexible layout allows for femtosecond pulses to be in principle easily stretched up to nanosecond durations. The design has been tested in a diode-pumped Yb:CALGO regenerative amplifier followed by a standard transmission grating compressor. Sub-200-fs pulses (stretched pulses ~110 ps) with 205-MUJ energy at 20-kHz repetition rate have been demonstrated. In order to prove the robustness and potential for energy scaling of leaky-mode grating-waveguide intracavity stretcher, we generated stretched pulses with energies of up to ~700 MUJ (400-ps long) at a lower repetition rate of 10 kHz. A simple model is proposed for the study of the cavity in presence of induced spatial chirp. PMID- 25831378 TI - Mounting with compliant cylinders for deformable mirrors. AB - A method is presented to mount large aperture unimorph deformable mirrors by compliant cylinders (CC). The CCs are manufactured from a soft silicone, and shear testing is performed in order to evaluate the Young's modulus. A scale mirror model is assembled to evaluate mount-induced change of piezoelectric deformation, and its applicability for tightly focusing mirrors. Experiments do not show any decrease of piezoelectric stroke. Further it is shown that the changes of surface fidelity by the attachment of the deformable mirror to its mount are neglectable. PMID- 25831379 TI - Shot-by-shot imaging of Hong-Ou-Mandel interference with an intensified sCMOS camera. AB - We report the first observation of Hong-Ou-Mandel (HOM) interference of highly indistinguishable photon pairs with spatial resolution. Direct imaging of two photon coalescence with an intensified sCMOS camera system clearly reveals spatially separated photons appearing pairwise within one of the two modes. With the use of the camera system, we quantified the number of pairs and recovered the full HOM dip yielding 96.3% interference visibility, as well as counted the number of coalesced pairs. We retrieved the spatial modes of both interfering photons by performing a proof-of-principle demonstration of a new, low-noise, high-resolution coincidence imaging scheme. PMID- 25831380 TI - Universal polarization terahertz phase controllers using randomly aligned liquid crystal cells with graphene electrodes. AB - We present a universal polarization terahertz (THz) phase controller using a randomly aligned liquid crystal (LC) cell with graphene electrodes. The LC cell was fabricated using a nematic LC and two quartz substrates that were coated with a monolayer of graphene as the transparent electrode. The LC in the cell was prepared without any alignment treatments and was randomly aligned. The size of the random domains and the width of the disclination lines in the LC layer were several tens of microns. These textures disappeared when an alternating voltage was applied to the LC through the graphene layers. Using a THz time domain spectroscopic technique, we investigated the complex transmittance of the LC cell. The LC cell was highly transparent in the THz frequency range, and there was little change in the transmittance with the applied voltage. This indicated that the scattering loss originating in the randomly aligned LC molecules was small for the THz waves. We also demonstrated that the THz phase shift could be controlled by the applied voltage. The amplitude of the phase shift was explained by the ordinary and extraordinary refractive indices of the LC. These LC cells with graphene electrodes can be used to realize universal polarization THz phase controllers because of the random alignment. PMID- 25831381 TI - Positive operator-valued measure reconstruction of a beam-splitter tree-based photon-number-resolving detector. AB - Here we present a reconstruction of the positive operator-value measurement of a photon-number-resolving detector comprised of three 50?50 beam-splitters in a tree configuration, terminated with four single-photon avalanche detectors. The four detectors' outputs are processed by an electronic board that discriminates detected photon number states from 0 to 4 and implements a "smart counting" routine to compensate for dead time issues at high count rates. PMID- 25831382 TI - Distributed feedback and random lasing in DCNP aggregates dispersed in a polymeric layer. AB - Here, we report on the realization of random lasing (RL) and distributed feedback (DFB) lasing in a layer of luminescent 3-(1,1-dicyanoethenyl)-1-phenyl-4,5 dihydro-1H-pyrazole (DCNP) organic nonlinear optical dye that has been dispersed in a poly(methyl methacrylate) (PMMA) matrix. The RL phenomenon appears due to the presence of spontaneously formed micro- and nano-crystals of DCNP in the bulk of the PMMA during the sample preparation. DFB can be realized in an optical system by using degenerated two-wave mixing in the pumping beams. The period of the interference pattern can be easily changed by changing the intersection angle of the pumping beams, resulting in a real time, fully reversible method of DFB lasing emission tuning. Because of the two neighboring stimulated emission bands of DCNP, it is possible to tune the lasing wavelength over a long range of about 65 nm. PMID- 25831383 TI - Stimulated Raman scattering and nonlinear focusing of high-power laser beams propagating in water. AB - The physical processes associated with propagation of a high-power (power > critical power for self-focusing) laser beam in water include nonlinear focusing, stimulated Raman scattering (SRS), optical breakdown, and plasma formation. The interplay between nonlinear focusing and SRS is analyzed for cases where a significant portion of the pump power is channeled into the Stokes wave. Propagation simulations and an analytical model demonstrate that the Stokes wave can re-focus the pump wave after the power in the latter falls below the critical power. It is shown that this novel focusing mechanism is distinct from cross phase focusing. The phenomenon of gain-focusing discussed here for propagation in water is expected to be of general occurrence applicable to any medium supporting nonlinear focusing and stimulated Raman scattering. PMID- 25831384 TI - First observation of the temperature-dependent light-induced response of Ge(25)As(10)Se(65) thin films. AB - Ge-rich ternary chalcogenide glasses (ChGs) exhibit photobleaching (PB) when illuminated with bandgap light. This effect originates from the combined effects of intrinsic structural changes and photo-oxidation. In a sharp contradiction to previous observations, in this Letter, we demonstrate, for the first time, that Ge-rich Ge(25)As(10)Se(65) ChG thin films exhibit photodarkening (PD) at 20 K and PB at 300 and 420 K after having been continuously illuminated for ~3 hours. The temporal evolution of PD/PB shows distinct characteristics at the temperature of illumination, and provides valuable information on the light-induced structural changes. Furthermore, structure-specific far-infrared (FIR) absorption measurements give direct evidence of different structural units involved in PD/PB at the contrasting temperatures. By comparing the light-induced effects in vacuum and air, we conclude that intrinsic structural changes dominate over photo oxidation in the observed PB in Ge(25)As(10)Se(65) ChG thin films. PMID- 25831385 TI - Microfluidic channels with ultralow-loss waveguide crossings for various chip integrated photonic sensors. AB - Traditional silicon waveguides are defined by waveguide trenches on either side of the high-index silicon core that leads to fluid leakage orifices for over layed microfluidic channels. Closing the orifices needs additional fabrication steps which may include oxide deposition and planarization. We experimentally demonstrated a new type of microfluidic channel design with ultralow-loss waveguide crossings (0.00248 dB per crossings). The waveguide crossings and all other on-chip passive-waveguide components are fabricated in one step with no additional planarization steps which eliminates any orifices and leads to leak free fluid flow. Such designs are applicable in all optical-waveguide-based sensing applications where the analyte must be flowed over the sensor. The new channel design was demonstrated in a L55 photonic crystal sensor operating between 1540 and 1580 nm. PMID- 25831386 TI - Kerr optical frequency comb generation in strontium fluoride whispering-gallery mode resonators with billion quality factor. AB - We report the fabrication for the first time of a strontium fluoride (SrF(2)) whispering-gallery mode resonator with quality factor in excess of 1 billion. The millimeter-size disk-resonator is polished until the surface roughness decreases down to a root-mean square value of 1.2 nm, as measured with a vertical scanning profilometer. We also demonstrate that this ultrahigh Q resonator allows for the generation of a normal-dispersion Kerr optical frequency comb at 1550 nm. PMID- 25831387 TI - Plasmon ruler with gold nanorod dimers: utilizing the second-order resonance. AB - The idea of utilizing the second-order plasmon resonance of gold nanorod pi dimers for plasmon rulers is introduced. We report on a qualitatively different dependence of the plasmon resonance shift on the interparticle distance for the first- and second-order longitudinal modes of the nanorods, extending the working range of plasmon rulers up to the distance values of approximately 400 nm. PMID- 25831388 TI - On-sky demonstration of optimal control for adaptive optics at Palomar Observatory. AB - High-order adaptive optics systems often suffer from significant computational latency, which ultimately limits the temporal error rejection bandwidth when classical controllers are employed. This Letter presents results from an on-sky, real-time implementation of an optimal controller on the PALM-3000 adaptive optics system at Palomar Observatory. The optimal controller is computed directly from open-loop wavefront measurements using a multichannel subspace system identification algorithm, and mitigates latency by explicitly predicting incident turbulence. Experimental results show a significant reduction in the residual wavefront error over the controlled spatial modes, illustrating the superior performance of the optimal control approach versus the nominal integral control architecture. PMID- 25831389 TI - Long-range micro-pulse aerosol lidar at 1.5 MUm with an upconversion single photon detector. AB - A micro-pulse lidar at eye-safe wavelength is constructed based on an upconversion single-photon detector. The ultralow-noise detector enables using integration technique to improve the signal-to-noise ratio of the atmospheric backscattering even at daytime. With pulse energy of 110 MUJ, pulse repetition rate of 15 kHz, optical antenna diameter of 100 mm and integration time of 5 min, a horizontal detection range of 7 km is realized. In the demonstration experiment, atmospheric visibility over 24 h is monitored continuously, with results in accordance with the weather forecasts. PMID- 25831391 TI - Twisted Gaussian Schell-model beams as series of partially coherent modified Bessel-Gauss beams. AB - We show that twisted Gaussian Schell-model (TGSM) beams can be represented through an incoherent superposition of partially coherent beams carrying optical vortices and whose cross-spectral densities are expressed in terms of modified Bessel functions. Moreover, starting from this result, we show that the modal expansion of the cross-spectral density of a TGSM source can be directly obtained through simple mathematics. PMID- 25831390 TI - Ultrafast all-optical technologies for bidirectional optical wireless communications. AB - In this Letter, a spherical retro-modulator architecture is introduced for operation as a bidirectional transceiver in passive optical wireless communication links. The architecture uses spherical retroreflection to enable retroreflection with broad directionality (2pi steradians), and it uses all optical beam interaction to enable modulation on ultrafast timescales (120 fs duration). The spherical retro-modulator is investigated from a theoretical standpoint and is fabricated for testing with three glasses, N-BK7, N-LASF9, and S-LAH79. It is found that the S-LAH79 structure provides the optimal refraction and nonlinearity for the desired retroreflection and modulation capabilities. PMID- 25831392 TI - Anti-Stokes photoluminescence in Ga/Bi co-doped sol-gel silica glass. AB - Unusual temperature dependence of the anti-Stokes photoluminescence (ASPL) at 734 nm was found in Ga/Bi co-doped sol-gel silica glass. While in the temperature range of 450-873 K, the behavior of ASPL is completely determined by the thermal population of the excited state levels, its intensity is continuously increasing with decreasing temperature in the range of 77-430 K. By measuring the pump power dependence of ASPL at 300 K, we show that the latter can be described via the two step intracenter excitation process and subsequent relaxation. Based on the measurements of temperature dependence of the excitation spectra of near infrared band (at 1140 nm) and that corresponding to the ASPL (at 734 nm), we propose a simple rate equation model to explain the unusual behavior of ASPL. PMID- 25831393 TI - High spatial resolution recording of near-infrared hologram based on photo induced phase transition of vanadium dioxide film. AB - We present a method to record near-infrared (NIR) hologram at high spatial resolution. This method up-converts the NIR holograms to visible holograms taking advantage of the photo-induced phase transition characteristic of vanadium dioxide (VO2) material, and subsequently, the visible holograms are recorded by a high-resolution visible CMOS sensor. Obviously the pitch of visible sensor is much smaller than NIR sensors, so our method can extremely increase the recording resolution of NIR holograms. The experiments demonstrate the effectiveness of our method. Our method can improve the viewing angle of NIR holography to observe large-scale objects and shorten the observation distance so that the application area of NIR holography is expanded. It has the potential to become a more effective NIR hologram recording method. PMID- 25831394 TI - Compensating thermal drift of hybrid silicon and lithium niobate ring resonances. AB - We present low-power compensation of thermal drift of resonance wavelengths in hybrid silicon and lithium niobate ring resonators based on the linear electro optic effect. Fabricated devices demonstrate a resonance wavelength tunability of 12.5 pm/V and a tuning range of 1 nm. A capacitive geometry and low thermal sensitivity result in the compensation of 17 degrees C of temperature variation using tuning powers at sub-nanowatt levels. The method establishes a route for stabilizing high-quality factor resonators in chip-scale integrated photonics subject to temperature variations. PMID- 25831395 TI - Toward integrated electrically controllable directional coupling based on dielectric loaded graphene plasmonic waveguide. AB - We propose and numerically analyze a mid-infrared electrically controllable plasmonic waveguide directional coupler that is composed of two parallel identical straight dielectric loaded graphene plasmonic waveguide and S-shaped waveguide bends. By varying the Fermi energy level of the graphene sheet, the maximum power coupled from the input waveguide to the cross-waveguide and the corresponding coupling length could be effectively tuned. Under different Fermi energy level, this directional coupler could serve as an electrically controlled optical switch or a 3-dB splitter around the wavelength of 10.5 MUm. Moreover, the size of the entire device is really in sub-wavelength scale making it very facilitative for high density integration. PMID- 25831396 TI - Thermal oscillatory behavior analysis and dynamic modulation of refractive index in microspherical resonator. AB - The thermal nonlinear effects in whispering-gallery-mode resonators are characterized by oscillatory behavior in the transmission spectrum. Although the thermal linewidth broadening is proven to be practical in mode-locking and dynamic control of the optical path, the oscillatory behavior always leads to instability of mode-locking and influences the control accuracy. We theoretically and experimentally illustrate the thermal oscillatory behavior using a model that combines slow and fast thermal relaxation processes of the microsphere and fluctuations of the pump wavelength. We also report dynamic modulation of the refractive index based on the fast thermal relaxation process. PMID- 25831397 TI - Tuning random lasing in photonic glasses. AB - We present a detailed numerical investigation of the tunability of a diffusive random laser when Mie resonances are excited. We solve a multimode diffusion model and calculate multiple light scattering in presence of optical gain that includes dispersion in both scattering and gain, without any assumptions about the beta parameter. This allows us to investigate a realistic photonic glass made of latex spheres and rhodamine and to quantify both the lasing wavelength tunability range and the lasing threshold. Beyond what is expected by diffusive monochromatic models, the highest threshold is found when the competition between the lasing modes is strongest and not when the lasing wavelength is furthest from the maximum of the gain curve. PMID- 25831398 TI - Arbitrary holographic spectral shaping of plasmonic broadband excitations. AB - We demonstrate a new method for controlling the broadband excitations of surface plasmons. This method is based on computer-generated holographic gratings and enables not only the coupling of the broadband illumination with surface plasmons, but also the arbitrary shaping of their spectra. As an example, we demonstrate several spectral shapes numerically and measure them experimentally, finding a good agreement with the simulation results. In addition, we show the potential for shaping the plasmonic spatial profile simultaneously with its spectral profile. This method may be useful for on-chip communication and light filtering as well as for sensing and temporal manipulation of ultrashort pulses. PMID- 25831399 TI - The importance of the "V"-Factor: Escherichia coli bacteremia and sepsis. PMID- 25831400 TI - Selective loss of younger erythrocytes from blood circulation and changes in erythropoietic patterns in bone marrow and spleen in mouse anemia induced by poly dispersed single-walled carbon nanotubes. AB - Administration of poly-dispersed acid-functionalized single-walled carbon nanotubes (AF-SWCNTs, 10 ug intravenously on alternate days) induced a sustained anemia in mice. Using a modified double in vivo biotinylation (DIB) technique, blood counts of reticulocytes and erythrocytes of different age groups were simultaneously enumerated in control and AF-SWCNT treated mice. A sustained reticulocytosis was observed in AF-SWCNT treated mice. Young erythrocytes (up to 7 days old) that are normally resistant to elimination in control mice were eliminated at a significant rate in AF-SWCNT treated mice. Old erythrocytes, however, accumulated in circulation indicating that younger erythrocytes were selectively eliminated from the blood circulation of AF-SWCNT treated mice. Cells representing various stages of erythroid differentiation in bone marrow and spleen were enumerated flow cytometrically by double staining with anti-Ter119 and anti-transferrin receptor (CD71) monoclonal antibodies. Proportion of erythroid cells was significantly reduced (up to 27%) in bone marrow (BM) indicating a fall in erythropoietic activity. A concomitant increase in the spleen erythroid population was however observed that could be a compensatory response. Changes in erythroid populations in bone marrow and spleen correlated with changes in erythroblast-A population in these organs that represent an early stage of erythroid differentiation. Uptake of intravenously administered fluorescence tagged AF-SWCNTs (FAF-SWCNTs) was relatively low (3-4%) in erythroid cells in bone marrow and spleen. A significantly higher proportion of pro erythroblasts and erythroblast-A (early stages of erythroid differentiation) took up FAF-SWCNTs. Uptake of AF-SWCNTs by early precursors of erythroid differentiation with toxic consequences may be a contributing factor in AF-SWCNT induced anemia. PMID- 25831401 TI - Acylcarnitine ester utilization by the hindlimb of warmblood horses at rest and following low intensity exercise and carnitine supplementation. AB - BACKGROUND: Acylcarnitines play an important role in fuel metabolism in skeletal muscle. OBJECTIVE: To assess acylcarnitine ester utilization by the hindlimb of horses at rest and following low intensity exercise and carnitine supplementation. ANIMALS AND METHODS: Acylcarnitine ester uptake by the hindlimb was investigated using the arteriovenous difference technique. Blood from six warmblood mares (mean age 12 +/- 3 (SD) years and weighing 538 +/- 39 kg) was collected simultaneously from the transverse facial artery and from the caudal vena cava. Food was withheld for 12 hours prior to exercise. Exercise comprised a standardized treadmill protocol consisting of 5 minutes of walk, 20 minutes of trot and thereafter another 5 minutes of walk. At the end of the first exercise day, three horses were given carnitine supplementation (100 mg/kg bodyweight), whereas the other horses received saline. The next day the exercise was repeated and blood samples collected similarly. Free carnitine and acylcarnitines were analyzed as their butyl ester derivatives in heparinized plasma by electrospray tandem mass spectrometry. Statistical analysis was performed using a general linear mixed model. RESULTS: C3-carnitine, C6-carnitine and C14:1-carnitine showed the largest average extraction by the hindlimb at rest and C3-carnitine, C5:1-carnitine and C16-carnitine immediately after low-intensity exercise. Carnitine supplementation significantly increased free carnitine, C5-carnitine and C8-carnitine extraction. CONCLUSION: Carnitine supplementation altered the extraction of acylcarnitines by the hindlimb in horses exercising at low intensity. CLINICAL IMPORTANCE: Findings might aid in optimizing performance and myopathy prevention of the equine athlete. PMID- 25831402 TI - Influence of Ankle Braces on the Maximum Strength of Plantar and Toe Flexor Muscles. AB - This study sought to investigate the influence of ankle braces on maximum strength of plantar and toe flexor muscles. 21 healthy participants volunteered, and their maximum isometric toe flexor muscle strength (TFS), plantar flexor muscle strength (PFS) and passive range of motion of the ankle joint (ROM) were measured. TFS, PFS and ROM were compared among barefoot as a control (BAR), ankle support (SUP) and ankle splint (SPL) conditions. TFS was significantly lower in SPL (90.7+/-32.5 N, p<0.0001) compared to BAR (117.3+/-39.5 N) and it was significantly lower in SPL than in SUP (110.5+/-36.7 N, p=0.0001), whereas it was not significantly different between SUP and BAR (p=0.2587). On the contrary, PFS and ROM were significantly lower in SUP (p=0.0087 for PFS; p=0.0095 for ROM) and SPL (p<0.0001 for PFS; p<0.0001 for ROM) compared to BAR, and they were significantly lower in SPL than in SUP (p=0.0073 for PFS; p<0.0001 for ROM). The ankle support could provide ankle joint stabilization without a large decrease in the muscle strength of the foot. The proper use of an ankle brace is required to prevent major impairment of the muscle functions of the ankle-foot complex. PMID- 25831403 TI - Countermovement Jump Performance with Increased Training Loads in Elite Female Rugby Athletes. AB - Countermovement jump (CMJ) performance is typically analyzed through single-point concentric-based variables (e. g., peak power or force and height). However, methodological approaches examining movement strategies may be more sensitive to neuromuscular fatigue. 12 elite female rugby sevens athletes undertook weekly CMJ testing throughout a 6-week training block involving progressively increased training loads. Athletes self-reported training load (TRIMP) and wellness daily. 22 CMJ variables were assessed, incorporating analyses of force, velocity, power and time measured during eccentric and concentric jump phases. Differences over time were examined using the magnitude of change (effect sizes; ES) compared to baseline. Pearson correlations examined relationships between CMJ variables, wellness and TRIMP. TRIMP displayed large increases (mean ES; weeks 2-6: 2.47). Wellness decreased in week 3 (-0.41), with small reductions following (weeks 4-6: -0.34). Flight time (weeks 3-6: -1.84), peak displacement (weeks 2-6: -2.24), time to peak force (weeks 3-6: 2.58), force at zero velocity (F@0V) (weeks 5-6: 1.28) displayed multiple changes indicative of diminished neuromuscular function. Wellness scores and max rate of force development (mean; r=0.32), F@0V (r=0.28) and flight time (r=0.34) displayed positive correlations. Intensified training decreased CMJ output and altered CMJ mechanics. Longitudinal neuromuscular fatigue monitoring of team-sport athletes appears improved through CMJ mechanics analysis. PMID- 25831404 TI - Can Heart Rate Variability be used to Estimate Gas Exchange Threshold in Obese Adolescents? AB - This study investigated the agreement and reliability of oxygen uptake (VO2), VO2 reserve (VO2 R), heart rate (HR) and power output at intensities corresponding to the gas exchange threshold (GET) and heart rate variability threshold (HRVT) during maximal cardiopulmonary exercise testing (CPET) in obese and eutrophic adolescents. A further aim was to establish whether the HRVT was able to detect changes in cardio-respiratory fitness in obese adolescents after 3 months of recreational soccer practice. First, 25 obese and 10 eutrophic adolescents (ages 12-17) visited the laboratory twice to perform cycling CPET to test the reliability of CPET outcomes at GET and HRVT. Furthermore, the level of agreement between GET and HRVT was determined for a subgroup of 10 obese adolescents after performing a 3-month recreational soccer program. No significant difference was found for VO2, %VO2 R, HR and power output at the GET and HRVT (P>0.05), which were equally able to detect improvements in aerobic fitness after the soccer intervention. Correlations between GET and HRVT for VO2 and %VO2 R ranged from 0.89 to 0.95 (P<0.001) and test-retest reliability ranged from 0.59 to 0.82 (P<0.006). Overall, HRVT seems to be a reliable alternative for prescribing aerobic exercise intensity in obese adolescents. PMID- 25831406 TI - Analytics of Quinine and its Derivatives. AB - The objective of this study was to perform a synthesis and analysis of the most important information on quinine and its derivatives, which are still very important in the treatment of malaria. The analysis of stereoisomers of quinine and its derivatives was conducted using two techniques, high-performance liquid chromatography and capillary electrophoresis. Particularly noteworthy is the technique used for the determination of isotachophoresis, referred to as one of the so-called green chemistry techniques. Particular attention was paid to properties and the use of quinine and its derivatives in the treatment of malaria. The analytical part will supplement knowledge about quinidine, quinine, and cinchonidine, and will contribute to the growth of research on the so-much needed drugs against malaria. PMID- 25831405 TI - H2N2 live attenuated influenza vaccine is safe and immunogenic for healthy adult volunteers. AB - H2N2 influenza viruses have not circulated in the human population since 1968, but they are still being regularly detected in the animal reservoir, suggesting their high pandemic potential. To prepare for a possible H2N2 pandemic, a number of H2N2 vaccine candidates have been generated and tested in preclinical and clinical studies. Here we describe the results of a randomized, double-blind placebo-controlled phase 1 clinical trial of an H2N2 live attenuated influenza vaccine (LAIV) candidate prepared from a human influenza virus isolated in 1966. The vaccine candidate was safe and well-tolerated by healthy adults, and did not cause serious adverse events or an increased rate of moderate or severe reactogenicities. The H2N2 vaccine virus was infectious for Humans. It was shed by 78.6% and 74.1% volunteers after the first and second dose, respectively, most probably due to the human origin of the virus. Importantly, no vaccine virus transmission to unvaccinated subjects was detected during the study. We employed multiple immunological tests to ensure the adequate assessment of the H2N2 pandemic LAIV candidate and demonstrated that the majority (92.6%) of the vaccinated subjects responded to the H2N2 LAIV in one or more immunological tests, including 85.2% of subjects with antibody responses and 55.6% volunteers with cell-mediated immune responses. In addition, we observed strong correlation between the H2N2 LAIV virus replication in the upper respiratory tract and the development of antibody responses. PMID- 25831407 TI - Predicting diffusion coefficients of chemicals in and through packaging materials. AB - Most of the physicochemical properties in polymers such as activity and partition coefficients, diffusion coefficients, and their activation with temperature are accessible to direct calculations from first principles. Such predictions are particularly relevant for food packaging as they can be used (1) to demonstrate the compliance or safety of numerous polymer materials and of their constitutive substances (e.g. additives, residues...), when they are used: as containers, coatings, sealants, gaskets, printing inks, etc. (2) or to predict the indirect contamination of food by pollutants (e.g. from recycled polymers, storage ambiance...) (3) or to assess the plasticization of materials in contact by food constituents (e.g. fat matter, aroma...). This review article summarizes the classical and last mechanistic descriptions of diffusion in polymers and discusses the reliability of semi-empirical approaches used for compliance testing both in EU and US. It is concluded that simulation of diffusion in or through polymers is not limited to worst-case assumptions but could also be applied to real cases for risk assessment, designing packaging with low leaching risk or to synthesize plastic additives with low diffusion rates. PMID- 25831409 TI - De Novo Cerebral Palsy Diagnosis in 9-Year-Old Soccer Player Presenting With Knee Pain. AB - A 9-year-old boy presented to our outpatient specialized sport and exercise medicine clinic complaining of a subacute onset of unilateral knee pain, after an increased level of soccer training. His knee examination was unremarkable. However, he demonstrated significant tenderness on palpation of his ipsilateral hip flexor and adductor tendons. Abnormalities in muscle tone and difficulty in relaxing and resisting the examiner properly were noted and lead to a complete neurological examination. It demonstrated multiple abnormalities such as increased tone and deep tendon reflexes, greater in lower than upper extremities, and abnormal patterning. A mild form of spastic diplegia was suspected and the patient was referred to a pediatric neurologist who confirmed our initial diagnosis. This case draws attention to the importance of maintaining a high level of suspicion for milder forms of diseases that can go unnoticed for years. PMID- 25831408 TI - Effectiveness Analysis of Active Stretching Versus Active Stretching Plus Low Frequency Electrical Stimulation in Children Who Play Soccer and Who Have the Short Hamstring Syndrome. AB - OBJECTIVE: To determine the effectiveness of active stretching (AS) versus AS plus electrical stimulation (stretching + TENS) in young soccer players with the short hamstring syndrome (SHS). DESIGN: Randomized, controlled, single-blind parallel clinical trial with 3 arms and a 2-month follow-up. The assignment ratio was 1:1:1. SETTING: The study involved young federated soccer players in the town of Jumilla, in the region of Murcia (Spain), who were controlled in a physiotherapy office in 2012. PARTICIPANTS: Fifty-one young soccer players (10-16 years) with SHS. INTERVENTIONS: Stretching + TENS, AS, and conventional stretching. MAIN OUTCOME MEASURES: Straight leg raise (SLR) test, popliteal angle with the passive knee extension (PKE) test, and the toe-touch test (TT). RESULTS: Significant results (P < 0.05) were group 1 versus 2: (1) SLR, -5.5 degrees right; (2) PKE, +10.2 degrees right and +6.2 degrees left; and (3) range of values of clinically relevant parameters (RVCRP): relative risk (RR), 0.35 to 0.38; relative risk reduction (RRR), 0.62 to 0.65; absolute risk reduction (ARR), 0.32 to 0.39; number needed to treat (NNT), 3 to 4. Group 1 versus 3: (1) SLR, 12.3 degrees right and -10 degrees left; (2) PKE, +12.9 degrees right and +8.5 degrees left; (3) TT, -8.9 cm; and (4) RVCRP: RR, 0.12 to 0.28; RRR, 0.72 to 0.88; ARR, 0.60 to 0.83; NNT, 2 to 2. Group 2 versus 3: (1) SLR, -6.8 degrees right and -6.2 degrees left; (2) TT, -6.7 cm; (3) RVCRP: RR, 0.44 to 0.53; RRR, 0.47 to 0.56; ARR, 0.40 to 0.56; NNT, 2 to 3. CONCLUSIONS: Stretching + TENS produces greater improvement than AS alone, and these are both better than conventional stretching. CLINICAL RELEVANCE: The use of electrical stimulation combined with AS is a relevant technique for habitual clinical practice that should be systematically integrated in children aged 10 to 16 years who play soccer and who have the SHS. PMID- 25831410 TI - Wobble Board Rehabilitation for Improving Balance in Ankles With Chronic Instability. AB - OBJECTIVE: To quantify improvements in clinical impairments using a wobble board rehabilitation protocol for chronic ankle instability (CAI). DESIGN: Prospective randomized controlled trial. SETTING: Laboratory. PATIENTS: Thirty-four participants with "giving way" and history of ankle sprains were randomly assigned to a rehabilitation group (REH) (170.22 +/- 8.71 cm; 75.57 +/- 13.55 kg; 22.94 +/- 2.77 years) or control group (CON) (168.57 +/- 9.81 cm; 77.19 +/- 19.93 kg; 23.18 +/- 3.64 years). INTERVENTIONS: Four weeks with no intervention for CON or wobble board rehabilitation for REH, consisting of 3 sessions per week of 5 repetitions. MAIN OUTCOME MEASURES: Dependent variables were preintervention and postintervention score on foot lift test (average number of errors), Time-in Balance Test (TBT) (longest time), Star Excursion Balance Test (SEBT) anteromedial, medial, and posteromedial (average reach distance normalized to leg length), side hop test (fastest time), and figure-of-eight hop test (fastest time). RESULTS: Main effects for time were significant for all measures (P < 0.05); but main effects for groups were not (P > 0.05) except for SEBT anteromedial reach direction. Significant interactions were found for all dependent measures (P < 0.05) except for TBT (P > 0.05). Post hoc testing of significant interactions showed REH improved performance at posttest, whereas CON did not. CONCLUSIONS: These findings demonstrate that a single intervention using a wobble board improved static and dynamic balance deficits associated with CAI. CLINICAL RELEVANCE: This approach provides a potentially more economical, time efficient, and space efficient means of improving clinical outcome measures associated with CAI in patients who are physically active. PMID- 25831411 TI - Are angiotensin-converting enzyme inhibitors or angiotensin 2 receptor antagonists effective in heart failure with preserved ejection fraction? AB - Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) constitute first line treatment for patients with heart failure with reduced ejection fraction. However, their role in patients with preserved ejection fraction remains controversial. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including five randomized trials. We combined the evidence using meta analysis and generated a summary of findings table following the GRADE approach. We concluded ACEI and ARB do not decrease mortality or hospitalization risk in this group of patients. PMID- 25831412 TI - Association Between Inpatient Surveillance and Venous Thromboembolism Rates After Hospital Discharge. AB - IMPORTANCE: Venous thromboembolism (VTE) surveillance practices in hospitals, but not adherence to Surgical Care Improvement Program VTE prophylaxis measures, have been reported to explain the variation in VTE rates in hospitals. OBJECTIVE: To examine the relationship between inpatient surveillance testing for VTE and postdischarge VTE rates at the hospital level to determine whether more frequent inpatient surveillance is associated with reduced occurrence of postdischarge VTEs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of a US national cohort of Veterans Affairs (VA) patients. National VA Surgical Quality Improvement Program outcome data were linked to VA administrative data on patients undergoing inpatient surgery from 2005 to 2009 and were included in the Surgical Care Improvement Program VTE measurement population. MAIN OUTCOMES AND MEASURES: Surveillance was identified using Current Procedural Terminology codes for diagnostic VTE imaging. Relationships between hospital-level surveillance and VTE rates were assessed with Pearson correlation coefficients, and the postdischarge VTE rate was modeled using linear regression, adjusting for hospital volume, inpatient VTE rate, inpatient surveillance rate, and case mix. RESULTS: Of 25 975 patients at 79 VA facilities, 296 (1.4%) experienced a VTE during the index hospitalization, and 114 (0.4%) experienced a postdischarge VTE within 30 days after surgery. The median length of stay was 11 days for those with a positive surveillance test result and 9 days for those with a negative test result. There was a positive correlation between inpatient surveillance and inpatient VTE rates (R = 0.33, P = .003) but no significant correlation of inpatient surveillance with either postdischarge surveillance (R = 0.11, P = .29) or postdischarge VTE rates (R = 0.03, P = .76). In an adjusted regression model of the postdischarge VTE rate, only the inpatient VTE rate was significant (beta = 0.13, P = .05). CONCLUSIONS AND RELEVANCE: Hospitals with higher VTE surveillance rates have higher inpatient VTE rates but not decreased postdischarge VTE rates. However, hospitals with higher inpatient VTE rates have higher postdischarge VTE rates, which suggests that surveillance may be influenced by higher observed rates and not surveillance practices alone. PMID- 25831413 TI - Anthrax in injecting drug users: the need for increased vigilance in the clinic. AB - The emergence of a previously unrecognized route of Bacillus anthracis infection over the last few years has led to concern: sporadic anthrax outbreaks among heroin users in northern Europe have demonstrated the severe pathology associated with the newly described 'injectional anthrax'. With a high case fatality rate and non-specific early symptoms, this is a novel clinical manifestation of an old disease. Lack of awareness of this syndrome among emergency room clinicians can lead to a delayed diagnosis among heroin users; indeed, for many health workers in developed countries, where infection by B. anthracis is rare, this may be the first time they have encountered anthrax infections. As the putative route of contamination of the heroin supply is potentially ongoing, it is important that clinicians and public health workers remain vigilant for early signs of injectional anthrax. PMID- 25831414 TI - Epidemiological features of irritable bowel syndrome and its subtypes among Iranian adults. AB - BACKGROUND: The epidemiological features of irritable bowel syndrome (IBS) have not been properly investigated in Iran. Also, worldwide there is limited knowledge about the characteristics of IBS subtypes. The aim of the study was to explore the epidemiological features of IBS and its subtypes among Iranian adults. METHODS: This is a cross-sectional study in Iranian adults living in Isfahan province. Demographic characteristics and common gastrointestinal symptoms were assessed using a self-administered modified Persian version of the Rome III questionnaire. RESULTS: In 4763 subjects aged 19-70 years the overall prevalence of IBS was 21.5%. IBS was more prevalent in women than men (24.0 vs. 18.3%, P<0.001). In multivariate analysis, being married was associated with 27% increased odds of IBS (95% confidence interval: 1.03-1.57, P<0.05). However, IBS was not associated with age (P=0.71) or educational attainment (P=0.61). Constipation-predominant IBS (IBS-C) was the most prevalent subtype of IBS followed by mixed IBS (IBS-M), diarrhea-predominant IBS (IBS-D), and unsubtyped IBS. Female gender was associated with IBS-C while male gender was associated with IBS-D and IBS-M. CONCLUSION: IBS is highly prevalent among Iranian adults, affecting particularly women in whom IBS-C is the most prevalent subtype. PMID- 25831415 TI - Anatomic and pathological characterization of choroidal melanoma using multimodal imaging: what is practical, what is needed? AB - Choroidal melanoma is the most frequently occurring intraocular tumor in adults. The aim of this work is to assess the potential of state-of-the art in-vivo and ex-vivo imaging modalities for the characterization of choroidal melanoma. Multimodal imaging of a choroidal melanoma was performed in a 53-year-old male patient. In-vivo ophthalmoscopy, ultrasound microscopy, duplex ultrasound, and 7.0 T MRI were performed. Ex-vivo examination of the enucleated eye included 7.0 and 9.4 T magnetic resonance microscopy as well as histopathology with hematoxylin and eosin staining. Imaging of choroidal melanoma with ultrahigh field MRI and duplex sonography provides detailed morphologic and functional information of the eye. High-spatial-resolution MRI at 9.4 T shows details of the internal texture of melanoma and other structures of the eye with an in-plane spatial resolution of 32 MUm. Ultrahigh field in-vivo MRI at 7.0 T and ex-vivo MRI at 7.0 and 9.4 T correlate well with histologic evaluation. In-vivo ultrahigh field MRI is an emerging technique for the characterization and staging of ocular tumors. The combination of in-vivo ultrahigh-field MRI and duplex sonography has the potential to complement or even substitute complex and invasive biopsies. PMID- 25831416 TI - A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. AB - The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed cell death-1, is pioneering the treatment for advanced melanoma. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immune-related nature. Reported dermatological side effects mostly comprise nonspecific rash and pruritus. This is a report of a 75-year-old man with metastatic melanoma who was initially administered pembrolizumab at 10 mg/kg every 3 weeks. He developed spongiotic dermatitis that was partially treated with topical steroids after cycle 3. Pembrolizumab cycles were stopped because of disease progression after cycle 6. On the 30-day follow-up, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows. Both punch skin biopsies (haematoxylin and eosin and direct immunofluorescence studies) confirmed a bullous pemphigoid diagnosis. He was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment, which was switched to dexamethasone following the diagnosis of new brain metastases. PMID- 25831417 TI - Ebola Virus Disease: Focus on Children. AB - Ebola virus is one of the most deadly pathogens known to infect humans. The current Ebola outbreak in West Africa is unprecedented in magnitude and duration and, as of November 30, 2014, shows no signs of abating. For the first time, cases of Ebola virus disease have been diagnosed in the US, originating from patients who traveled during the incubation period. The outbreak has generated worldwide concern. It is clear that U.S. physicians need to be aware of this disease, know when to consider Ebola and how to care for the patient as well as protect themselves. Children comprise a small percentage of all cases globally, likely because of their lower risk of exposure given social and cultural practices. Limited evidence is available on pediatric disease course and prognosis. In this article, we present an overview of the pathogen, its epidemiology and transmission, clinical and laboratory manifestations, treatment and infection control procedures, with an emphasis on what is known about Ebola virus disease in the pediatric population. PMID- 25831418 TI - Genetic analysis of invasive pneumococcal isolates from children in Ontario, Canada, 2007-2012. AB - BACKGROUND: Multilocus sequence typing (MLST) is commonly used to understand the genetic background of invasive pneumococcal disease (IPD) isolates. This study was conducted to identify serotype and genetic change among IPD isolates in Canadian children following vaccine use. METHODS: Clinical isolates collected from children <=5 years old of Ontario, Canada with IPD during 2007-2012 were characterized with serotyping, multilocus sequence typing and antimicrobial susceptibility testing. RESULTS: One year after 13-valent pneumococcal conjugate vaccine (PCV13) implementation, a decline in 19A and 7F was observed in 2012, coincident with the rise of serogroup 15 and 22F. Clonal complex (CC) 199, CC320 and CC695 are 3 major CCs in 19A (74%). From 2007 to 2012, clonal shift was detected in the 19A population as CC320 and CC199 declined, whereas CC695 rose to a majority. Genetically, serogroup 15 was composed of 2 CCs and 7 sequence types (STs), making it more diverse than serotypes 3, 7F and 22F. Interestingly, 60% of 15C isolates were a novel ST, suggesting high single nucleotide polymorphism frequency in house-keeping genes of 15C. Several newly appeared STs found in 19A and 15 indicate the possibility of recent serotype switching events. CONCLUSION: Genetic shift because of PCV13 impact may have resulted in the decline of 19A in IPD. Recent rise of serogroup 15 infections in children could be because of its selective advantage conferred by genetic diversity, frequent recombination in the population plus drug resistance potential related to CC63 genotype. Close monitoring of serotype replacement and genetic change in IPD among children post PCV13 is warranted. PMID- 25831419 TI - Immunodeficiency among children with recurrent invasive pneumococcal disease. AB - BACKGROUND: Recurrent invasive pneumococcal disease (rIPD) occurs mostly in children with an underlying disease, but some cases remain unexplained. Immunodeficiency has been described in children with rIPD, but the prevalence is unknown. We used a nationwide registry of all laboratory-confirmed cases of rIPD to identify cases of unexplained rIPD and examine them for immunodeficiency. METHODS: Cases of rIPD in children 0-15 years of age from 1980 to 2008 were identified. Children without an obvious underlying disease were screened for complement function, T-cell, B-cell, natural killer--cell counts and concentration of immunoglobulins. B-cell function was evaluated by measuring antibody response to polysaccharide-based pneumococcal vaccination and the extent of fraction of somatic hypermutation. Toll-Like receptor (TLR) signaling function and mutations in key TLR-signaling molecules were examined. RESULTS: In total, rIPD were observed in 54 children (68 cases of rIPD of 2192 IPD cases). Children with classical risk factors for IPD were excluded, and among the remaining 22 children, 15 were eligible for analysis. Of these 6 (40%) were complement C2 deficient. Impaired vaccination response was found in 6 children of whom 3 were C2 deficient. One patient had a severe TLR signaling dysfunction. No mutations in IRAK4, IKBKG or MYD88 were found. CONCLUSION: Of an unselected cohort of children with rIPD at least 11% were C2 deficient. Data suggest that screening for complement deficiencies and deficient antibody response to pneumococcal vaccines in patients with more than 1 episode of IPD is warranted. PMID- 25831420 TI - An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age. AB - BACKGROUND: A 9-valent human papillomavirus (9vHPV) vaccine has recently been reported to be safe and highly efficacious against infection and disease related to HPV6/11/16/18/31/33/45/52/58. We evaluated the immunogenicity and safety of the 9vHPV vaccine administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine). METHODS: This open label, randomized, multicenter study enrolled 1054 males and females ages 11-15 years. Subjects were randomly assigned to each group in a 1:1 ratio. Subjects received a 0.5 mL dose of 9vHPV vaccine intramuscularly at day 1, months 2 and 6 and a 0.5 mL dose of REPEVAX either on day 1 (concomitant vaccination group; n = 526) or at month 1 (nonconcomitant vaccination group, n = 528). Serologic responses for each vaccine component were tested by 1-sided tests of noninferiority between groups. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored. RESULTS: Noninferiority of anti-HPV geometric mean titers and seroconversion rates for all 9vHPV antigens were demonstrated for the concomitant group compared with the nonconcomitant group. Seroconversion rates for the 9vHPV vaccine types were >=99.8% in both groups at month 7. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, all polio and pertussis antigens for both groups. There were no vaccine-related serious AEs. CONCLUSION: Overall, concomitant administration of 9vHPV vaccine and REPEVAX was generally well tolerated and did not interfere with the immune response to either vaccine. This strategy would minimize the number of visits required to deliver each vaccine individually. PMID- 25831421 TI - Evidence of herd immunity and sustained impact of rotavirus vaccination on the reduction of rotavirus-related medical encounters among infants from 2006 through 2011 in the United States. AB - BACKGROUND: Rotavirus (RV) is the leading cause of severe acute gastroenteritis among young children. Since the US licensure of the pentavalent RV vaccine (RV5) and the monovalent RV vaccine (RV1), a decline of RV activity has been observed. OBJECTIVE: To describe patterns of RV-related health care utilization among infants receiving RV vaccines (RVVs). METHODS: A large national health insurance claims database was used to identify infants born from January 2002 through July 2011. From this cohort, infants were divided into three groups: (1) those who received a RVV, (2) those receiving a diphtheria, tetanus, and acellular pertussis (DTaP) vaccine before the introduction of RVV (February 2006), and (3) those receiving DTaP without a concurrent RVV during the period of RVV availability. Study outcomes were rotavirus gastroenteritis (RGE) and acute gastroenteritis. Longitudinal, seasonal RGE incidence patterns among the RVV cohort (n = 140,952) were compared with the referent DTaP-vaccine cohort (n = 131,529). RESULTS: More than 91% of administered RVV were RV5. Mean peak incidence of RV medical encounters in RV-vaccinated infants was 95-96% lower than among DTaP-vaccinated infants who did not receive RVV. RGE incidence among the non-RV-vaccinated DTaP recipients in the RVV-available period (110 per 100,000 infants) was lower than among DTaP recipients in the pre-RVV period (151 per 100,000 infants). The highest RGE incidence in the 2007-2011 period was among older non-RV-vaccinated infants. CONCLUSIONS: Analysis of a national medical claims database indicates a sustained and substantial decrease in the seasonal RV medical claims pattern after the introduction of RVV. This analysis also reveals evidence of herd immunity, although unvaccinated infants continue to be at risk and contribute to smaller seasonal peaks in RV disease activity. PMID- 25831422 TI - Important of Angiopoietic System in Evaluation of Endothelial Damage in Children with Crimean-Congo Hemorrhagic Fever. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) causes endothelial activation and dysfunction by affecting the endothelium directly or indirectly. In maintaining the vascular integrity, vascular endothelial growth factor (VEGF-A) and its receptor (VEGFR1) and angiopoietin-2 (Ang-2) and its receptor (Tie-2) are very important mediators. For this reason, we aimed at studying the association of Ang-2 and VEGF and their receptors Tie-2 and VEGFR1 with CCHF infection. METHODS: Thirty one CCHF patients and 31 healthy controls (HC) were included in the study. CCHF patients were classified into 2 groups in terms of disease severity (severe and nonsevere). VEGF-A, VEGFR1, Ang-2 and Tie-2 levels were measured in all groups. RESULT: Serum levels of Tie-2, Ang-2, VEGF-A and VEGFR1 were significantly increased in CCHF patients compared with the HC. Furthermore, serum Tie-2, Ang-2, VEGF and VEGFR1 levels were found to be significantly higher in the severe group than in the nonsevere and HC groups (P < 0.05 and P < 0.001, respectively). Also, Tie-2, Ang-2, VEGF-A and VEGFR1 levels were significantly higher in the nonsevere group than in the HC group (P < 0.05). CONCLUSION: Having statistically significant higher Ang-2, Tie-2, VEGF-A and VEGFR1 levels in the severe group when compared with the other groups suggested that VEGF-related Ang 2/Tie-2 system played a critical role in the pathogenesis of the disease, and these markers could be used as the severity criteria. PMID- 25831423 TI - Increased prevalence of elevated blood pressures in HIV-infected children, adolescents and young adults. AB - BACKGROUND: HIV-infected children and young adults have cardiovascular disease risk factors reflecting chronic infection and the effects of combination antiretroviral (ARV) therapy. We thus sought to characterize the prevalence of and risk factors for high blood pressure (HBP) in this population. METHODS: Retrospective chart review classified subjects aged 2-25 years based on a single clinic blood pressure (BP) reading as normal BP, pre-HBP or HBP. Variables suspected to contribute to elevated BP were compared including body mass index, tobacco use, medical comorbidities, ARV or other medication use, dyslipidemia, ethnicity and family history. RESULTS: In all, 47 of 266 subjects (18%) were found to have HBP. Among children and adolescents aged 2-17 years, 21 of 107 (20%) had HBP. Comorbidities believed to elevate BP, such as polycystic ovarian syndrome, obstructive sleep apnea or cocaine exposure, were significant risk factors for elevated BP, with 35% of subjects with these comorbidities having HBP, compared with 16% of subjects without (P = 0.01). Male gender and tobacco use were also risk factors associated with elevated BPs. HBP was more common in overweight subjects (26%) than not overweight (15%) but did not reach statistical significance (P = 0.15). ARV medication use and higher HIV-1 RNA were not associated with HBP. CONCLUSIONS: Our finding of 20% prevalence of HBP in a cohort of HIV-infected children represents a potentially alarming figure. The explanation for this finding is unclear, but even if it is because of comorbid conditions, the life-long cardiovascular risks associated with HIV infection and its management mandate the need for closer monitoring and possibly treatment of elevated BP in this population. PMID- 25831424 TI - Preparation and evaluation of luteolin-phospholipid complex as an effective drug delivery tool against GalN/LPS induced liver damage. AB - CONTEXT: The phyto-phospholipid complexation technique is a promising approach to improve the bioavailability and efficacy of flavonoids. OBJECTIVE: The objective of this study was to improve the bioavailability and efficacy of luteolin by phospholipid complexation against inflammatory liver damage. MATERIALS AND METHODS: The phospholipid complex of luteolin (LPC) was prepared by solvent evaporation accompanied by freeze drying. The physicochemical properties of LPC were investigated by means of spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Pharmacokinetic parameters in rats were determined and the hepatoprotective potential was assessed against D galactosamine and lipopolysaccharide (GalN/LPS) induced hepatic damage. RESULTS: LPC showed drug loading of 74.14% and average particle size 147.4 nm. The results of FTIR, thermal and diffraction studies confirmed the formation of complex. The aqueous/n-octanol solubility showed improvements. LPC showed an increase in relative in vivo bioavailability to 535.31% of pure luteolin. The histological and biochemical changes induced by GalN/LPS were significantly ameliorated by LPC. DISCUSSION: Hepatoprotective effect of LPC was more profound than luteolin with a particle size suitable for passive targeting of inflammatory sites. CONCLUSION: LPC was successfully formulated under optimized conditions and is an efficient drug delivery system for oral administration of luteolin with enhanced bioavailability and hepatoprotective potential. PMID- 25831425 TI - Balanced cell proliferation and expansion is essential for flowering stem growth control. AB - The postembryonic development of aboveground plant organs relies on a continuous supply of cells from the shoot apical meristem. Previous studies of developmental regulation in leaves and flowers have revealed the crucial role of coordinated cell proliferation and differentiation during organogenesis. However, the importance of this coordination has not been examined in flowering stems. Very recently, we attempted to identify regulatory factors that maintain flowering stem integrity. We found that the increased cell number in clavata (clv) mutants and the decreased cell size in de-etiolated (det)3-1 resulted in flowering stems that were thicker and thinner, respectively, than in wild-type (WT) plants. Interestingly, in the cell proliferation- and cell expansion-defective double mutant clv det3-1, the flowering stems often exhibited severe cracking, resulting in exposure of their inner tissues. In this study, further quantification of the cellular phenotypes in the cotyledons and leaves revealed no differences between det3-1 and clv3 det3-1. Together, the above findings suggest that the clv3 mutation in a det3-1 background primarily affects flowering stems, while its effect on other organs is likely negligible. We propose that the coordination between cell proliferation and differentiation is not only important during leaf development, but also plays a role in the growth control of Arabidopsis flowering stems. PMID- 25831426 TI - Ih channels control feedback regulation from amacrine cells to photoreceptors. AB - In both vertebrates and invertebrates, photoreceptors' output is regulated by feedback signals from interneurons that contribute to several important visual functions. Although synaptic feedback regulation of photoreceptors is known to occur in Drosophila, many questions about the underlying molecular mechanisms and physiological implementation remain unclear. Here, we systematically investigated these questions using a broad range of experimental methods. We isolated two Ih mutant fly lines that exhibit rhythmic photoreceptor depolarization without light stimulation. We discovered that Ih channels regulate glutamate release from amacrine cells by modulating calcium channel activity. Moreover, we showed that the eye-enriched kainate receptor (EKAR) is expressed in photoreceptors and receives the glutamate signal released from amacrine cells. Finally, we presented evidence that amacrine cell feedback regulation helps maintain light sensitivity in ambient light. Our findings suggest plausible molecular underpinnings and physiological effects of feedback regulation from amacrine cells to photoreceptors. These results provide new mechanistic insight into how synaptic feedback regulation can participate in network processing by modulating neural information transfer and circuit excitability. PMID- 25831427 TI - Usability and Feasibility of an mHealth Intervention for Monitoring and Managing Pain Symptoms in Sickle Cell Disease: The Sickle Cell Disease Mobile Application to Record Symptoms via Technology (SMART). AB - Patients with sickle cell disease frequently experience severe pain events that lead to unplanned healthcare utilization. Mobile health tools (mHealth) may help prevent these events by providing remote monitoring and self-management support. This article describes the feasibility of the Sickle cell disease Mobile Application to Record symptoms via Technology (SMART), an mHealth app developed to help sickle cell disease patients monitor and manage their day-to-day symptoms. Fifteen patients recorded their pain intensity using a paper visual analog scale (VAS) and then repeated this measurement using an electronic VAS pain measure on SMART. Patients continued using SMART to record clinical symptoms, pain intensity, location and perceived severity, and treatment strategies for at least 28 days. Patient median age was 29 years (range 16-54); 60.0% were male. There was a high intraclass correlation between pain measurements entered on the paper VAS and SMART on the iPhone and the iPad We found a strong association between patient perceived pain severity and pain intensity entries using SMART (b = 1.71; p < 0.01). Daily compliance with SMART entries was a mean 75.0%, with a high of 85.7% in week 1 and low of 57.9% in week 4; however, one-third (n = 5) of the patients were 100.0% compliant even in week 4. Patients who were over age 35 or used an iPad for the study had the highest compliance rates. This study showed that SMART is a useable and feasible method for monitoring daily pain symptoms among adolescents and adults with sickle cell disease-related pain. PMID- 25831428 TI - Our old and new scourges. PMID- 25831429 TI - Teacher-led relaxation response curriculum in an urban high school: impact on student behavioral health and classroom environment. AB - CONTEXT: Recent data suggest that severe stress during the adolescent period is becoming a problem of epidemic proportions. Elicitation of the relaxation response (RR) has been shown to be effective in treating anxiety, reducing stress, and increasing positive health behaviors. OBJECTIVE: The research team's objective was to assess the impact of an RR-based curriculum, led by teachers, on the psychological status and health management behaviors of high-school students and to determine whether a train-the-trainer model would be feasible in a high school setting. DESIGN: The research team designed a pilot study. SETTING: The setting was a Horace Mann charter school within Boston's public school system. PARTICIPANTS: Participants were teachers and students at the charter school. INTERVENTION: The team taught teachers a curriculum that included (1) relaxation strategies, such as breathing and imagery; (2) psychoeducation regarding mind body pathways; and (3) positive psychology. Teachers implemented this curriculum with students. OUTCOME MEASURES: The research team assessed changes in student outcomes (eg, stress, anxiety, and stress management behaviors) using preintervention/postintervention surveys, including the Perceived Stress Scale (PSS), the State-Trait Anxiety Inventory-Form Y (STAI-Y), the stress management subscale of the Health-promoting Lifestyle Profile II (HPLP-II), the Rosenberg Self-Esteem Scale (RSES), the Locus of Control (LOC) questionnaire, and the Life Orientation Test-Revised (LOTR). Classroom observations using the Classroom Assessment Scoring System (CLASS)-Secondary were also completed to assess changes in classroom environment. RESULTS: Using a Bonferroni correction (P < .007), the study found that students experienced a significant reduction (P < .001) in measures of state-level anxiety on the STAI from pre- to postintervention. The study also found an increase in the use of stress management behaviors at that point. Using a Bonferroni correction (P < .007), the study found that students had significantly less perceived stress (P < .001), less state anxiety (P < .001) and trait anxiety (P < . 001), and increased use of positive stress management behaviors (P < .004) at the follow-up assessment in the fall of the following year. Using a Bonferroni correction (P < .002), the study found a significant increase in overall classroom productivity (eg, increased time spent on activities and instruction from pre- to postintervention). CONCLUSIONS: This study showed that teachers can lead an RR curriculum with fidelity and suggests that such a curriculum has positive benefits on student emotional and behavioral health and on classroom functioning. PMID- 25831430 TI - Sutherland's legacy in the new millennium: the osteopathic cranial model and modern osteopathy. AB - The concept of cranial osteopathy was introduced by W. G. Sutherland, DO, and became the foundation for setting the rules for use of skull palpation and many other techniques in the many types of dysfunctional patterns that craniosacral therapy treats. Sutherland's theories enabled modern osteopathy to develop and improve. The mechanism of primary respiration as well as the motion of neurocranial and viscerocranial sutures are phenomena intrinsic to the field and can be found in every living organism, independent of thoracic breathing and cardiac impulse. The sphenobasilar synchondrosis (ie, the joint between the base of the occiput and the body of the sphenoid bone) is the pillar supporting the concepts of craniosacral therapy. This article compares the cranial model devised by Sutherland with the present, relevant scientific research, aiming at clarifying the possibility of applying the craniosacral model in the new millennium. PMID- 25831431 TI - Autism spectrum disorder and pet therapy. AB - Autism Spectrum Disorder (ASD) encompasses a wide range of social and mental afflictions that are difficult to treat. Due to a lack of established treatments for ASD, alternative therapies have been the primary form of intervention. One of these alternatives is pet therapy, a field that has experienced growing interest and has recently accumulated studies that investigate its efficacy. This article reviews and summarizes that effectiveness as well as the findings and limitations associated with pet therapy for ASD. The majority of research on ASD and pet therapy has examined children and has primarily used dogs and horses for therapy. Studies have shown positive effects for the therapy, including high satisfaction rates among the participants' families. Major limitations of studies in the current literature include the lack of control groups and small sample sizes. Future research should incorporate better study designs and large samples to validate pet therapy as an appropriate treatment for ASD. PMID- 25831432 TI - Acupuncture for the temporary treatment of essential tremor: a case report. AB - This case report describes the successful, temporary treatment of essential tremor in a 74-y-old Caucasian woman, using weekly acupuncture sessions for a 10 wk period. The outcome measures included the patient's (1) subjective evaluation of her percentage of improvement before and after weekly treatments, (2) subjective evaluation of her ability to write personal checks and to hold a cup with 1 hand to drink, and (3) improved ability to write handwriting samples in the university health center. The patient continued to maintain these benefits through monthly acupuncture sessions at 12 mo after the initial acupuncture treatment. PMID- 25831433 TI - Datis Kharrazian, DHSc, DC, FACN, CNS: neuroinflammation-ignited by toxic burden or immune reactivity? PMID- 25831434 TI - Maternal neuroendocrine serum levels in exclusively breastfeeding mothers. AB - BACKGROUND: Low milk supply is a common cause of early weaning, and supply issues are associated with dysregulation of thyroid function and prolactin. However, hormone levels compatible with successful breastfeeding are not well defined, limiting interpretation of clinical lab results. In this study we sought to quantify ranges for thyroid-stimulating hormone (TSH), free thyroxine (T4), total T4, and prolactin in a cohort of exclusively breastfeeding women. MATERIALS AND METHODS: Women planning to breastfeed were recruited in the third trimester of pregnancy. Maternal endocrine function was assessed before and after a breastfeeding session at 2 and 8 weeks postpartum. We used paired t tests to determine whether values changed from the 2- to 8-week visit. RESULTS: Of 52 study participants, 28 were exclusively breastfeeding, defined as only breastmilk feeds in the prior 7 days, at both the 2- and 8-week study visits. Endocrine function changed with time since delivery: the TSH level was higher, whereas total T4, free T4, and prolactin levels were lower, at the 8-week visit than at the 2-week visit (by paired t test, p<=0.01). We found a wide range of prolactin values at the 8-week visit, with a 5th percentile value of 9 ng/dL before feeding and 74 ng/dL at 10 minutes after feeding. CONCLUSIONS: Neuroendocrine function changes during the first 8 weeks after birth, and a wide range of values is compatible with successful breastfeeding. Further studies are needed to define reference values in breastfeeding women. PMID- 25831435 TI - Iron-doped nickel oxide nanocrystals as highly efficient electrocatalysts for alkaline water splitting. AB - Efficient electrochemical water splitting to hydrogen and oxygen is considered a promising technology to overcome our dependency on fossil fuels. Searching for novel catalytic materials for electrochemical oxygen generation is essential for improving the total efficiency of water splitting processes. We report the synthesis, structural characterization, and electrochemical performance in the oxygen evolution reaction of Fe-doped NiO nanocrystals. The facile solvothermal synthesis in tert-butanol leads to the formation of ultrasmall crystalline and highly dispersible FexNi1-xO nanoparticles with dopant concentrations of up to 20%. The increase in Fe content is accompanied by a decrease in particle size, resulting in nonagglomerated nanocrystals of 1.5-3.8 nm in size. The Fe content and composition of the nanoparticles are determined by X-ray photoelectron spectroscopy and energy-dispersive X-ray spectroscopy measurements, while Mossbauer and extended X-ray absorption fine structure analyses reveal a substitutional incorporation of Fe(III) into the NiO rock salt structure. The excellent dispersibility of the nanoparticles in ethanol allows for the preparation of homogeneous ca. 8 nm thin films with a smooth surface on various substrates. The turnover frequencies (TOF) of these films could be precisely calculated using a quartz crystal microbalance. Fe0.1Ni0.9O was found to have the highest electrocatalytic water oxidation activity in basic media with a TOF of 1.9 s(-1) at the overpotential of 300 mV. The current density of 10 mA cm(-2) is reached at an overpotential of 297 mV with a Tafel slope of 37 mV dec(-1). The extremely high catalytic activity, facile preparation, and low cost of the single crystalline FexNi1-xO nanoparticles make them very promising catalysts for the oxygen evolution reaction. PMID- 25831436 TI - Multiparameter optimization method and enhanced production of secreted recombinant single-chain variable fragment against the HIV-1 P17 protein from Escherichia coli by fed-batch fermentation. AB - The single-chain fragment variable (scFv) was used to produce a completely functional antigen-binding fragment in bacterial systems. The advancements in antibody engineering have simplified the method of producing Fv fragments and made it more efficient and generally relevant. In a previous study, the scFv anti HIV-1 P17 protein was produced by a batch production system, optimized by the sequential simplex optimization method. This study continued that work in order to enhance secreted scFv production by fed-batch cultivation, which supported high volumetric productivity and provided a large amount of scFvs for diagnostic and therapeutic research. The developments in cell culture media and process parameter settings were required to realize the maximum production of cells. This study investigated the combined optimization methods, Plackett-Burman design (PBD) and sequential simplex optimization, with the aim of optimize feed medium. Fed-batch cultivation with an optimal feeding rate was determined. The result demonstrated that a 20-mL/hr feeding rate of the optimized medium can increase cell growth, total protein production, and scFv anti-p17 activity by 4.43, 1.48, and 6.5 times more than batch cultivation, respectively. The combined optimization method demonstrated novel power tools for the optimization strategy of multiparameter experiments. PMID- 25831437 TI - Oculopharyngeal muscular dystrophy as a rare cause of dysphagia. AB - Oculopharyngeal muscular dystrophy (OPMD) is a rare cause for late-onset dysphagia. OPMD normally follows an autosomal dominant inheritance. Herein we describe a rare case of an autosomal recessive inheritance of OPMD. An 80-year old male presented with progressive dysphagia, frequent aspiration and change of voice getting inarticulate and hoarse. Physical examination showed ptosis of the right eyelid. Endoscopic and manometric investigation revealed a nonspecific motility disorder with hypopharyngeal esophageal hypotension. The severity of dysphagia became apparent when significant aspiration occurred during a barium swallow. Magnetic resonance imaging of the head ruled out a malignant or cerebral ischemic process. Based on the neurological examination, neurogenic muscular dystrophy was suspected and DNA analysis was performed. The analysis confirmed the extremely rare diagnosis of an autosomal recessive inheritance pattern of OPMD with homozygous (GCN)6(GCN)4(GCN) expansion of the poly-(A) binding protein nuclear 1 gene. As OPMD normally follows an autosomal dominant inheritance, consanguinity of the patient's parents was suspected. PMID- 25831439 TI - A conversation with Bill Paul. PMID- 25831438 TI - Microsatellite instability use in mismatch repair gene sequence variant classification. AB - Inherited mutations in the DNA mismatch repair genes (MMR) can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI) is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants) are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review. PMID- 25831440 TI - Louis Ptacek receives the 2015 ASCI/Stanley J. Korsmeyer Award. Interview by Sarah Jackson. PMID- 25831443 TI - Nuclear receptor PXR: discovery of a pharmaceutical anti-target. AB - Transcriptional induction of the gene encoding cytochrome P450 3A oxygenase (CYP3A) causes a prominent class of dangerous drug-drug interactions wherein one drug accelerates the metabolism of another. In our 1998 JCI paper, we reported the cloning of the human nuclear receptor PXR and demonstrated that it mediates CYP3A induction. We determined that PXR is expressed in liver, acts through a DNA response element located in the CYP3A promoter, and is activated by a structurally diverse collection of drugs that induce CYP3A. Our findings revealed the molecular basis for the CYP3A induction class of drug-drug interactions and provided a high-throughput means for screening out drug candidates with this activity. PMID- 25831444 TI - Retraction. Novel APC-like properties of human NK cells directly regulate T cell activation. PMID- 25831445 TI - A human immunodeficiency caused by mutations in the PIK3R1 gene. PMID- 25831442 TI - Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. AB - Membrane sphingolipids are metabolized to sphingosine-1-phosphate (S1P), a bioactive lipid mediator that regulates many processes in vertebrate development, physiology, and pathology. Once exported out of cells by cell-specific transporters, chaperone-bound S1P is spatially compartmentalized in the circulatory system. Extracellular S1P interacts with five GPCRs that are widely expressed and transduce intracellular signals to regulate cellular behavior, such as migration, adhesion, survival, and proliferation. While many organ systems are affected, S1P signaling is essential for vascular development, neurogenesis, and lymphocyte trafficking. Recently, a pharmacological S1P receptor antagonist has won approval to control autoimmune neuroinflammation in multiple sclerosis. The availability of pharmacological tools as well as mouse genetic models has revealed several physiological actions of S1P and begun to shed light on its pathological roles. The unique mode of signaling of this lysophospholipid mediator is providing novel opportunities for therapeutic intervention, with possibilities to target not only GPCRs but also transporters, metabolic enzymes, and chaperones. PMID- 25831441 TI - No quiet surrender: molecular guardians in multiple sclerosis brain. AB - The brain under immunological attack does not surrender quietly. Investigation of brain lesions in multiple sclerosis (MS) reveals a coordinated molecular response involving various proteins and small molecules ranging from heat shock proteins to small lipids, neurotransmitters, and even gases, which provide protection and foster repair. Reduction of inflammation serves as a necessary prerequisite for effective recovery and regeneration. Remarkably, many lesion-resident molecules activate pathways leading to both suppression of inflammation and promotion of repair mechanisms. These guardian molecules and their corresponding physiologic pathways could potentially be exploited to silence inflammation and repair the injured and degenerating brain and spinal cord in both relapsing-remitting and progressive forms of MS and may be beneficial in other neurologic and psychiatric conditions. PMID- 25831447 TI - Vitamin D status and glucose metabolism in youth. AB - This study aimed to review and synthesize the available scientific evidence on the relationship between serum 25(OH)D concentrations and glucose metabolism among adolescents. A total of 19 studies were included. Many studies did not find a relation between 25(OH)D concentrations and insulin sensitivity, but most studies have shown that vitamin D status influences glucose dysregulation in youth due to particularities of this life stage. Considering the prevalence of vitamin D deficiency and insufficiency were high among adolescents, the importance for vitamin D status correction in this young group, in which chronic diseases are not expected but getting every day more common, is mandatory. PMID- 25831448 TI - The equivalence of information-theoretic and likelihood-based methods for neural dimensionality reduction. AB - Stimulus dimensionality-reduction methods in neuroscience seek to identify a low dimensional space of stimulus features that affect a neuron's probability of spiking. One popular method, known as maximally informative dimensions (MID), uses an information-theoretic quantity known as "single-spike information" to identify this space. Here we examine MID from a model-based perspective. We show that MID is a maximum-likelihood estimator for the parameters of a linear nonlinear-Poisson (LNP) model, and that the empirical single-spike information corresponds to the normalized log-likelihood under a Poisson model. This equivalence implies that MID does not necessarily find maximally informative stimulus dimensions when spiking is not well described as Poisson. We provide several examples to illustrate this shortcoming, and derive a lower bound on the information lost when spiking is Bernoulli in discrete time bins. To overcome this limitation, we introduce model-based dimensionality reduction methods for neurons with non-Poisson firing statistics, and show that they can be framed equivalently in likelihood-based or information-theoretic terms. Finally, we show how to overcome practical limitations on the number of stimulus dimensions that MID can estimate by constraining the form of the non-parametric nonlinearity in an LNP model. We illustrate these methods with simulations and data from primate visual cortex. PMID- 25831450 TI - Determinants of weight gain prevention in young adult and midlife women: study design and protocol of a randomized controlled trial. AB - BACKGROUND: Treatment of overweight and obesity through body weight reduction has been monumentally ineffective as few individuals are able to sustain weight loss. Rather than treating weight gain once it has become problematic, prevention of weight gain over time may be more effective. OBJECTIVE: The aim of this research is to preclude the burden of adult obesity in women by identifying the determinants of weight gain prevention. The objective of this randomized controlled trial (RCT) is to compare a weight gain prevention intervention delivered by the registered dietitian versus counselor. METHODS: This is a 12 month parallel-arm weight gain prevention RCT designed to increase self-efficacy, self-regulation, outcome expectations and family and social support through the use of a nutrition education intervention in women, aged 18-45 years, from the Urbana-Champaign (Illinois, USA) area. Women have been randomized to registered dietitian, counselor or wait-list control groups (August 2014) and are undergoing weekly nutrition education sessions for four months, followed by monthly sessions for eight months (through August 2015). Outcome measures, including: (1) dietary intake, (2) physical activity, (3) anthropometric and blood pressure measurements, (4) biochemical markers of health, (5) eating behaviors and health perceptions, and (6) mediators of behavior change, were collected before the intervention began (baseline) and will be collected at 3, 6, 9, and 12 months of the study. RESULTS: In total, 87 women have been randomized to intervention groups, and 81 women have completed first week of the study. Results are expected in early 2016. CONCLUSIONS: This RCT is one of the first to examine weight gain prevention in women across normal, overweight, and obese body mass index categories. Results of this research are expected to have application to evidence based practice in weight gain prevention for women and possibly have implication for policy regarding decreasing the encumbrance of overweight and obesity in the United States. PMID- 25831451 TI - Multiple single-molecule magnet behaviors in dysprosium dinuclear complexes involving a multiple functionalized tetrathiafulvalene-based ligand. AB - The reaction between the 2-(1-(2,6-di(pyrazol-1-yl)-4-methylpyridyl)-4,5-(4,5 bis(propylthio)-tetrathiafulvalenyl)-1H-benzimidazol-2-yl)-pyridine ligand (L) and 2 equiv of Dy(hfac)3.2H2O (hfac(-) = 1,1,1,5,5,5-hexafluoroacetylacetonate) and 1 equiv each of Dy(hfac)3.2H2O and Dy(tta)3.2H2O (tta(-) = 2 thenoyltrifluoroacetonate) metallic precursors leads to two dinuclear complexes, [Dy2(hfac)6(L)].(CH2Cl2)2.C6H14 (1) and [Dy2(hfac)3(tta)3(L)] (2), respectively. Their X-ray structures reveal that the two coordination sites are occupied by one Dy(III) ion. The Dy(III) ion coordinated to the benzoimidazolylpyridine (bzip) moiety adopts a D4d coordination sphere, while the Dy(III) ion coordinated to the 2,6-di(pyrazol-1-yl)-4-pyridine (dpp) moiety is in a D3h surrounding. In a zero dc field, the dynamic magnetic measurements show a slow relaxation for the D4d eight-coordination Dy(III) magnetization for 1 and 2. Application of an external dc field induces multirelaxation signals of the magnetic susceptibility for both compounds. The low frequency and high frequency of the out-of-phase magnetic signals are attributed to the Dy(III) ion in D4d and D3h surroundings, respectively. The two complexes can be described as double induced-field mononuclear single-molecule magnets. PMID- 25831452 TI - Insight into Transannular Cyclization Reactions To Synthesize Azabicyclo[X.Y.Z]alkanone Amino Acid Derivatives from 8-, 9-, and 10-Membered Macrocyclic Dipeptide Lactams. AB - An efficient method for synthesizing different functionalized azabicyclo[X.Y.0]alkanone amino acid derivatives has been developed employing electrophilic transannular cyclizations of 8-, 9-, and 10-membered unsaturated macrocycles to form 5,5-, 6,5-, 7,5-, and 6,6-fused bicylic amino acids, respectively. Macrocycles were obtained by a sequence featuring peptide coupling of vinyl-, allyl-, homoallyl-, and homohomoallylglycine building blocks followed by ring-closing metathesis. X-ray crystallographic analyses of the 8-, 9-, and 10 membered macrocyclic lactam starting materials as well as certain bicyclic amino acid products provided insight into their conformational preferences as well as the mechanism for the diastereoselective formation of specific azabicycloalkanone amino acids by way of transannular iodolactamization reactions. PMID- 25831453 TI - Pushing the limits of aminocatalysis: enantioselective transformations of alpha branched beta-ketocarbonyls and vinyl ketones by chiral primary amines. AB - Enantioselective alpha-functionalizations of carbonyl compounds are fundamental transformations for the asymmetric synthesis of organic compounds. One of the more recent developments along this line is in aminocatalysis, which leads to the direct alpha-functionalization of simple aldehydes and ketones. However, most of the advances have been achieved with linear aldehydes and ketones as substrates. Effective aminocatalysis with alpha-branched carbonyls, particularly alpha branched ketones, has remained elusive. The primary difficulty arises from the space-demanding alpha-substituent, which impedes iminium/enamine formation. In 2005, synthetic organic chemists revived catalysis using primary amines, which brought new attention to these challenges, because of the conformational flexibility of primary amines. On the basis of early biomimetic studies by Hine, in 2007 we developed the bioinspired chiral primary amine catalysts featuring primary-tertiary diamines. This type of catalyst involves enamine/iminium catalysis, and we could apply this chemistry to all of the major types of ketones and aldehydes. In this Account, we present research from our laboratory that significantly expands aminocatalysis to include alpha-branched ketones such as beta-ketocarbonyls and alpha-substituted vinyl ketones. Our primary amine catalysis methodology, when used alone or in conjunction with metal catalysts, provides convenient access to both enantiopure alpha-tertiary and quaternary ketones, structures that are not available via other approaches. Our mechanistic studies showed that acidic additives play the critical role in facilitating catalytic turnover, most likely by shuttling protons during the enamine/iminium tautomerizations. These additives are also critical to induce the desired stereochemistry via ammonium N-H hydrogen bonding. Proton transfer by shuttling is also stereoselective, resulting in enantioselective enamine protonation as observed in the reactions of alpha-substituted vinyl ketones. In addition, we have carried out density functional theory studies that help to delineate the origins of the stereoselectivity in these reactions. PMID- 25831454 TI - Program and Abstracts Thirty-fifth Annual Meeting of the Surgical Infection Society Westlake Village, California April 15-18, 2015. PMID- 25831456 TI - Platelet Count After Chemotherapy is a Predictor for Outcome for Ovarian Cancer Patients. AB - Elevated platelet count occasionally is associated with gynecologic malignancies. We investigated the level of platelet count in 450 patients with gynecologic tumors. Ovarian cancer patients have increased platelet count associated with the course of treatment and disease progression. In multivariate analysis, the decrease of platelet count less than 25% after chemotherapy was an unfavorable prognostic factor for PFS (HR, 1.948; 95% CI, 1.083-3.505; p = 0.026) and overall survival (HR, 2.093; 95% CI, 1.022-4.287; p = 0.043). An insufficient decrease of the platelet count increased the risk of recurrence. Thus platelet count could be used for monitoring the disease progression and to predict treatment response. PMID- 25831457 TI - 'The biggest thing is trying to live for two people': Spousal experiences of supporting decision-making participation for partners with TBI. AB - PRIMARY OBJECTIVE: To understand how the spouses of individuals with severe TBI experience the process of supporting their partners with decision-making. DESIGN: This study adopted a constructivist grounded theory approach, with data consisting of in-depth interviews conducted with spouses over a 12-month period. Data were analysed through an iterative process of open and focused coding, identification of emergent categories and exploration of relationships between categories. PARTICIPANTS: Participants were four spouses of individuals with severe TBI (with moderate-severe disability). Spouses had shared committed relationships (marriage or domestic partnerships) for at least 4 years at initial interview. Three spouses were in relationships that had commenced following injury. MAIN OUTCOME AND RESULTS: Two main themes emerged from the data. The first identified the saliency of the relational space in which decision-making took place. The second revealed the complex nature of decision-making within the spousal relationship. CONCLUSIONS: Spouses experience decision-making as a complex multi-stage process underpinned by a number of relational factors. Increased understanding of this process can guide health professionals in their provision of support for couples in exploring decision-making participation after injury. PMID- 25831458 TI - Study of the one-photon and two-photon properties of two water-soluble terpyridines and their zinc complexes. AB - Two water soluble 2,2':6',2''-terpyridine derivatives (TPYOH and O3TPY) with a di(hydroxyethyl)amino or a long (2-(2-methoxyethoxy)ethoxy)benzyl group, respectively, were designed and synthesized. The two terpyridine ligands and their Zn(ii) complexes display strong one-photon fluorescence. An unusually large solvatochromism effect in ethanol and water was found, which was ascribed to their interactions with the solvent through hydrogen bonds. All the four compounds show evident two-photon absorption ability when evaluated by Z-scan technology. The free ligands could give distinct two-photon excited fluorescence, and the emission of O3TPY responded linearly with Zn(2+) under the excitation of a 780 nm femtosecond laser. Only the complex ZnO3TPY, which possesses a large pi conjugation system and suitable election-donating groups, displayed emission maxima at 595 nm when excited by a 680-880 nm laser. PMID- 25831460 TI - Erratum: A longitudinal cohort study of body mass index and childhood exposure to secondhand tobacco smoke and air pollution: the Southern California Children's Health Study. PMID- 25831459 TI - Complete topology of the RNF complex from Vibrio cholerae. AB - RNF is a redox-driven ion (Na(+) and in one case possibly H(+)) transporter present in many prokaryotes. It has been proposed that RNF performs a variety of reactions in different organisms, delivering low-potential reducing equivalents for specific cellular processes. RNF shares strong homology with the Na(+) pumping respiratory enzyme Na(+)-NQR, although there are significant differences in subunit and redox cofactor composition. Here we report a topological analysis of the six subunits of RNF from Vibrio cholerae. Although individual subunits from other organisms have previously been studied, this is the first complete, experimentally derived, analysis of RNF from any one source. This has allowed us to identify and confirm key properties of RNF. The putative NADH binding site in RnfC is located on the cytoplasmic side of the membrane. FeS centers in RnfB and RnfC are also located on the cytoplasmic side. However, covalently attached FMNs in RnfD and RnfG are both located in the periplasm. RNF also contains a number of acidic residues that correspond to functionally important groups in Na(+)-NQR. The acidic residues involved in Na(+) uptake and many of those implicated in Na(+) translocation are topologically conserved. The topology of RNF closely matches the topology represented in the newly published structure of Na(+)-NQR, consistent with the close relation between the two enzymes. The topology of RNF is discussed in the context of the current structural model of Na(+)-NQR, and the proposed functionality of the RNF complex itself. PMID- 25831461 TI - Spatially Resolved Doping Concentration and Nonradiative Lifetime Profiles in Single Si-Doped InP Nanowires Using Photoluminescence Mapping. AB - We report an analysis method that combines microphotoluminescence mapping and lifetime mapping data of single semiconductor nanowires to extract the doping concentration, nonradiative lifetime, and internal quantum efficiency along the length of the nanowires. Using this method, the doping concentration of single Si doped wurtzite InP nanowires are mapped out and confirmed by the electrical measurements of single nanowire devices. Our method has important implication for single nanowire detectors and LEDs and nanowire solar cells applications. PMID- 25831462 TI - Conditional Probability of Long-term Survival After Liver Resection for Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis of 535 Patients. AB - IMPORTANCE: Whereas conventional actuarial overall survival (OS) estimates rely exclusively on static factors determined around the time of surgery, conditional survival (CS) estimates take into account the years that a patient has already survived. OBJECTIVE: To define the CS of patients following liver resection for intrahepatic cholangiocarcinoma (ICC). DESIGN, SETTING, AND PARTICIPANTS: Between January 1, 1990, and December 31, 2013, a total of 535 patients who underwent resection of ICC were identified from an international multi-institutional database. In this retrospective international study conducted from January to June 2014, clinicopathological characteristics, operative details, and long-term survival data were analyzed. Conditional survival estimates were calculated as the probability of survival for an additional 3 years. INTERVENTION: Resection of ICC. MAIN OUTCOMES AND MEASURES: Overall survival and CS. RESULTS: While actuarial OS decreased over time from 39% at 3 years to 16% at 8 years (P = .002), the 3-year CS (CS3) increased over time among those patients who survived. The CS3 at 5 years-the probability of surviving to postoperative year 8 after having already survived to postoperative year 5-was 65% compared with 8-year OS of 16% (P = .002). Factors that were associated with worse OS included larger tumor size (hazard ratio [HR], 1.02; 95% CI, 1.00-1.05; P = .05), multifocal disease (HR, 1.49; 95% CI, 1.19-1.86; P = .01), lymph node metastasis (HR, 2.21; 95% CI, 1.67-2.93; P < .01), and vascular invasion (HR, 1.39; 95% CI, 1.10-1.75; P = .006). The calculated CS3 exceeded the actuarial survival for all high-risk subgroups. For example, patients with lymph node metastasis had an actuarial OS of 11% at 6 years vs a CS3 of 49% at 3 years (Delta38%). Similarly, patients with vascular invasion had an actuarial OS of 15% at 6 years compared with a CS3 of 50% at 3 years (Delta35%). CONCLUSIONS AND RELEVANCE: Conditional survival estimates may provide critical quantitative information about the changing probability of survival over time among patients undergoing liver resection for ICC. Therefore, such estimates can be of significant value to patients and health care professionals. PMID- 25831463 TI - Endothelial PAS domain-containing protein 1 confers TKI-resistance by mediating EGFR and MET pathways in non-small cell lung cancer cells. AB - Mutations in epidermal growth factor receptor (EGFR) rendering it constitutively active is one of the major causes for metastatic non-small-cell lung cancer (NSCLC), and EGFR-targeted therapies utilizing tyrosine kinase inhibitors (TKIs) are often used clinically as the first-line treatment. But approximately half of NSCLC patients develop resistance to these therapies, where the MET proto oncogene is amplified by EGFR through the hypoxia-inducible factor (HIF)-1alpha. Here we report that endothelial PAS domain-containing protein 1 (EPAS1), with 48% sequence identity to HIF-1alpha, specifically binds to TKI-resistant T790M EGFR, but not to wild-type EGFR, in NSCLC cell lines. Expression of EPAS1 enhances amplification of MET when simultaneously expressed with T790M EGFR but not with wild-type EGFR, and this enhancement is independent of ligand binding domain of EGFR. MET amplification requires EPAS1, since EPAS1 knock-down reduced MET levels. When NSCLC cells expressing T790M EGFR were treated with TKIs, reduced EPAS1 levels significantly enhanced the drug effect, whereas over-expression of EPAS1 increased the drug resistant effect. This EPAS1-dependent TKI-resistance was abolished by knocking-down MET, suggesting that EPAS1 does not cause TKI resistance itself but functions to bridge EGFR and MET interactions. Our findings suggest that EPAS1 is a key factor in the EGFR-MET crosstalk in conferring TKI resistance in NSCLC cases, and could be used as a potential therapeutic target in TKI-resistant NSCLC patients. PMID- 25831465 TI - Structured illumination microscopy improves visualization of lytic granules in HIV-1 specific cytotoxic T-lymphocyte immunological synapses. PMID- 25831464 TI - Immune Reconstitution in Severely Immunosuppressed Antiretroviral-Naive HIV-1 Infected Patients Starting Efavirenz, Lopinavir-Ritonavir, or Atazanavir Ritonavir Plus Tenofovir/Emtricitabine: Final 48-Week Results (The Advanz-3 Trial). AB - BACKGROUND: Few randomized clinical trials have investigated antiretroviral regimens in very advanced HIV-1-infected patients. The objective was to study the immune reconstitution in very immunosuppressed antiretroviral-naive, HIV-1 infected individuals by comparing an efavirenz-based regimen with 2 ritonavir boosted protease inhibitor regimens. METHODS: Randomized, controlled, open-label, multicenter clinical trial. Eighty-nine HIV-1-infected antiretroviral-naive patients with <100 CD4 cells per cubic millimeter were randomly assigned in a 1:1:1 ratio to efavirenz (n = 29), atazanavir/ritonavir (n = 30), or lopinavir/ritonavir (n = 30) combined with tenofovir plus emtricitabine. The primary outcome was median increase in CD4 cell count at week 48. Secondary end points were the proportion of patients with HIV-1 RNA <50 copies per milliliter, adverse events, disease progression, and death. RESULTS: In the on-treatment analysis, the median (interquartile range) increase in the CD4 count after 48 weeks was +193 (129-349) cells per microliter in the efavirenz arm, +197 (146 238) cells per microliter in the ritonavir-boosted atazanavir arm, and +205 (178 327) cells per microliter in the ritonavir-boosted lopinavir arm (P = 0.73). The percentage of patients achieving viral suppression was similar in all 3 treatment arms at 48 weeks {efavirenz, 85.71% [95% confidence interval (CI): 68.5 to 94.3]; atazanavir, 80% [95% CI: 62.7 to 90.5]; and lopinavir, 82.8% [95% CI: 65.5 to 92.4]; P = 0.88}. Bacterial translocation, inflammation, immune activation, and apoptotic markers, but not D-dimer, declined significantly and similarly in the 3 treatment arms. Adverse events had a similar incidence in all 3 antiretroviral regimens. No patients died. CONCLUSIONS: The immune reconstitution induced by an efavirenz-based regimen in very advanced HIV-1-infected patients was similar to that induced by a ritonavir-boosted protease inhibitor-based regimen (ClinicalTrials.gov registration number: NCT00532168). PMID- 25831467 TI - A triazole-bearing picket fence type nickel porphyrin as a cyanide selective allosteric host. AB - A triazole-bearing picket fence type nickel porphyrin (1) has been synthesized as a host compound for anion binding. Among the various anionic species examined, cyanide was the only one that affected a spectral change of 1. Moreover, 1 exhibited strong homotropic positive allosterism against cyanide binding due to an electronic effect as well as multiple hydrogen bonds formed between cyanide and the triazole groups. PMID- 25831468 TI - Prevalence of Subclinical Coronary Artery Disease in Middle-Aged, Male Marathon Runners Detected by Cardiac CT. AB - PURPOSE: To evaluate the prevalence of coronary artery disease (CAD) in middle aged, male marathon runners using coronary dual source CT angiography (DSCTA). MATERIALS AND METHODS: 50 male marathon runners older than 45 years (mean age: 52.7, standard deviation: 5.9 years, range: 45 to 67 years) received DSCTA including calcium scoring (CS) in addition to standard pre-participation screening. Based on standard risk factors, the risk for coronary events was calculated using the PROCAM score. Coronary status was defined using the following system: 1. absence of CAD (CS zero, no coronary plaques) 2. mild coronary atherosclerosis (CS > 0, coronary plaques with luminal narrowing < 50 %), 3. moderate coronary atherosclerosis (CS > 0, luminal narrowing > 50 %), 4. significant CAD (CS > 0, luminal narrowing > 75 %). RESULTS: The mean PROCAM score was 1.85 % (standard deviation = 1.56, range 0.39 to 8.47 %). 26/50 marathon runners had no atherosclerosis. 1 of the remaining 24 participants had significant CAD, 3 had moderate coronary atherosclerosis and 20 had mild coronary atherosclerosis. Treadmill exercise testing was unremarkable in terms of myocardial ischemia in all participants. Age, systolic blood pressure, personal minimum time, family history of cardiovascular disease and PROCAM score were factors associated with an increased risk for coronary atherosclerosis. CONCLUSION: Coronary atherosclerosis can be detected in almost 50 % of male marathon runners aged older than 45 years. In 24 % of the participants plaques were located in the proximal coronary system. However, only a minority of these persons have obstructive CAD. As expected, treadmill exercise testing failed to detect these persons that possibly have a higher risk for coronary events. KEY POINTS: * Coronary atherosclerosis can be detected in ~50 % of male marathon runners > 45 years. * Only a minority of these persons have obstructive CAD. * Treadmill exercise testing failed to detect these persons. * Cardiac CT might help to identify athletes with elevated risk for coronary events, especially in persons with a family history of coronary artery. PMID- 25831469 TI - Thrombectomy vs. Systemic Thrombolysis in Acute Embolic Stroke with High Clot Burden: A Retrospective Analysis. AB - PURPOSE: The efficacy of i. v. thrombolysis in acute stroke with high clot burden is limited. Successful recanalization is very unlikely if the thrombus length exceeds 7 mm. Thus this retrospective controlled study evaluated the efficacy and safety of neurothrombectomy in the treatment of acute embolic stroke in patients selected by a thrombus length of >= 8 mm using the stent retriever Trevo((r)) device. MATERIALS AND METHODS: 40 patients with acute occlusion of the anterior intracranial arteries with a thrombus length of >= 8 mm were treated with neurothrombectomy. We compared the outcome with a historical cohort of 42 patients with a thrombus length of >= 8 mm that received i. v. thrombolysis only. Clinical outcome was assessed by modified Rankin scale in both groups at discharge and on day 90. RESULTS: Patients did not differ in age, mRS on admission, thrombus length or time from symptom onset to i. v. thrombolysis, but the thrombectomy group had higher NIHSS on admission. Successful recanalization was achieved in 33/40 patients (83 %) with neurothrombectomy. 15 patients received i. v. thrombolysis prior to neurothrombectomy. Median mRS at discharge was 3.5 (1.25 - 5) vs. 5 (4 - 6; p < 0.01) and on day 90 3 (1 - 4) vs. 5 (4 - 6; p < 0.01). Symptomatic hemorrhage occurred in 3 vs. 7 patients. 3 vs. 17 patients died within 90 days (thrombectomy vs. control each). There were only a few intervention-related complications. CONCLUSION: Thrombectomy in acute stroke with high clot burden using the Trevo((r)) device has a low risk and improved clinical outcome compared to i. v. thrombolysis alone. Treatment selection by a clot length of >= 8 mm might be a powerful approach to improve the outcome of mechanical thrombectomy. KEY POINTS: * Clot length of >= 8 mm might be a valuable criterion for indicating neurothrombectomy. * Thrombolysis only in high clot burden is associated with poor clinical outcome. * Thrombectomy using the Trevo((r)) stent retriever is safe and effective. PMID- 25831470 TI - [Traumatic severance of the hypophyseal stalk - MRI image]. PMID- 25831472 TI - X-ray diffraction: instrumentation and applications. AB - X-ray diffraction (XRD) is a powerful nondestructive technique for characterizing crystalline materials. It provides information on structures, phases, preferred crystal orientations (texture), and other structural parameters, such as average grain size, crystallinity, strain, and crystal defects. X-ray diffraction peaks are produced by constructive interference of a monochromatic beam of X-rays scattered at specific angles from each set of lattice planes in a sample. The peak intensities are determined by the distribution of atoms within the lattice. Consequently, the X-ray diffraction pattern is the fingerprint of periodic atomic arrangements in a given material. This review summarizes the scientific trends associated with the rapid development of the technique of X-ray diffraction over the past five years pertaining to the fields of pharmaceuticals, forensic science, geological applications, microelectronics, and glass manufacturing, as well as in corrosion analysis. PMID- 25831471 TI - Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Pi-Pi Stacking Stabilized Polymeric Micelles. AB - Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achiv prolonged circulation kinetics. As a result, PTX deposition in tumors is increased, while drug exposure to healthy tissues is reduced. However, many PTX loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed PTX-loaded micelles which are stable without chemical cross-linking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to pi-pi stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl)methacrylamide) (mPEG-b p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid MUCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses, while they induced complete tumor regression in two different xenograft models (i.e., A431 and MDA-MB-468). Our findings consequently indicate that pi-pi stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index. PMID- 25831473 TI - Z-Selective Olefin Synthesis via Iron-Catalyzed Reductive Coupling of Alkyl Halides with Terminal Arylalkynes. AB - Selective catalytic synthesis of Z-olefins has been challenging. Here we describe a method to produce 1,2-disubstituted olefins in high Z selectivity via reductive cross-coupling of alkyl halides with terminal arylalkynes. The method employs inexpensive and nontoxic catalyst (iron(II) bromide) and reductant (zinc). The substrate scope encompasses primary, secondary, and tertiary alkyl halides, and the reaction tolerates a large number of functional groups. The utility of the method is demonstrated in the synthesis of several pharmaceutically relevant molecules. Mechanistic study suggests that the reaction proceeds through an iron catalyzed anti-selective carbozincation pathway. PMID- 25831474 TI - Clinical and pathological features of head and neck follicular dendritic cell sarcoma. AB - OBJECTIVES: Follicular dendritic cell sarcoma (FDCS) in the head and neck is uncommon. The etiology, pathogenesis, optimal treatment, and prognosis are not well understood. In this review, we investigated these features to deepen the understanding of the disease. METHODS: We reviewed FDCS in the head and neck in the English language literature through Medline. We analyzed the clinical characteristics, pathologic features, immunophenotypic profile, and treatments of FDCS. RESULTS: Of 137 reported cases of FDCS in the head and neck region, 127 included data on age and gender. Among those, 64 were females and 63 were males. The mean age was 46 years (9-79 years). In the 106 cases with complete follow-up data, fourteen patients (13.2%) had local recurrence. Fourteen patients (13.2%) had distant metastasis. The metastatic site involved the lung, liver, adrenal, rib, vertebral body, and iliac bone. The overall 5-year survival rate was 80.0%. Compared to nodal FDCS and extranodal FDCS, the overall 5-year survival rates were 71.1 and 85.3%, respectively, with no significance (P = 0.42), 0.8% waived treatment, 46.6% received surgery alone, 30.5% received surgery combined with postoperative radiotherapy, 8.4% received surgery combined with postoperative radiotherapy and chemotherapy, 7.6% received surgery combined with postoperative chemotherapy, 3.1% received chemotherapy alone, 2.2% received chemotherapy combined with radiotherapy, 0.8% received radiotherapy alone. CONCLUSIONS: FDCS in the head and neck is rare. There was no difference in the survival between nodal and extranodal FDCS. The optimal treatment was undetermined. PMID- 25831475 TI - Patients' preferences for biopsy result notification in an era of electronic messaging methods. AB - IMPORTANCE: Effective patient-physician communication is essential for optimal health care. Recent introduction of online patient portals to access test results are changing the communication landscape, but regulatory guidelines for the online release of biopsy results vary from state to state. OBJECTIVES: To assess patient preferences for receiving skin biopsy results to rule out melanoma and to compare those preferences to current physicians' practices for notification. DESIGN, SETTING, AND PARTICIPANTS: English-speaking individuals 18 years or older were recruited consecutively from melanoma clinics at 3 academic tertiary referral medical centers: University of California, San Francisco, University of Pennsylvania, and Duke University. Patients were surveyed from July 1, 2012, through July 31, 2013. A second survey of physicians at these institutions was conducted to assess physician notification practices. RESULTS: A total of 301 of 305 patients agreed to participate (98.7 response rate). Most of the patients (67.1%) preferred to speak directly with their physician by telephone to receive their skin biopsy results, followed by a distant second choice (19.5%) of being notified in person at a clinic visit. Voice message or online patient portal were each the preferred method of communication for 5.1% of patients. The most important consideration for patients was a communication modality that provided test results in the most rapid manner; 51.7% wanted a method that was rapid, and 7.8% preferred a method that was not only speedy but also allowed them an opportunity to ask questions. A total of 59.5% of the study participants would choose the same communication method regardless of the biopsy results, but 40.5% preferred a different mode of notification if their biopsy results revealed a malignant tumor. Younger and more highly educated patients favored the online portal. Of 84 physicians surveyed, 47 responded (56% response rate). Physicians' overall preferred method of contacting patients aligned with patient preference for speaking by telephone (56.5%). However, for benign results, 31.2% of physicians chose to speak by telephone, whereas patients preferred voicemail (32.1%). There was physician uncertainty as to guidelines regarding communication of test results. CONCLUSIONS AND RELEVANCE: Patient preference has shifted from face-to-face visit to discussion over the telephone because of a desire for rapid notification. Experience with online portal delivery of results favorably inclined patients toward that modality. We recommend that patients be queried regarding their notification preference on the biopsy consent form. PMID- 25831476 TI - Structures, physicochemical properties, and applications of amaranth starch. AB - Amaranth as a rediscovered "new" crop is becoming a research focus in the recent two decades. The major carbohydrate of some amaranth species is starch, which accounts up to around 60% of the dry grains. This review summarizes the present knowledge of the isolation, composition, structures, physiochemical properties, modifications, and applications of amaranth starches, and provides suggestions for research to further improve the utilization. PMID- 25831477 TI - Evening chronotype is associated with metabolic disorders and body composition in middle-aged adults. AB - CONTEXT: Chronotype is a trait determining individual circadian preference in behavioral and biological rhythm relative to external light-dark cycle. However, little is known about the relationship between chronotype and metabolic disorders. OBJECTIVE: The aim of this study was to examine whether late chronotype is related to metabolic abnormalities and body composition in middle aged adults, independent of sleep duration and lifestyle. DESIGN AND PARTICIPANTS: A total of 1620 participants aged 47-59 years were recruited from the Korean Genome and Epidemiology Study. MAIN OUTCOME MEASURES: Chronotype was assessed by the Morningness-Eveningness Questionnaire. Associations of chronotype with diabetes, metabolic syndrome, sarcopenia, and visceral obesity were analyzed. All participants underwent the oral glucose tolerance test, and body composition was measured with dual energy x-ray absorptiometry. Visceral obesity was designated as visceral fat area, measured by abdominal computed tomography, of >100 cm(2). RESULTS: Chronotype was classified as morning in 29.6% of subjects, evening in 5.9%, neither morning nor evening in 64.5%. Evening type, when compared with morning type, was significantly associated with diabetes (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.01-2.95), metabolic syndrome (OR, 1.74; 95% CI, 1.05-2.87), and sarcopenia (OR, 3.16; 95% CI, 1.36-7.33) after adjusting for confounding factors. Gender differences in the associations were evident. In men, evening type was associated with diabetes (OR, 2.98; 95% CI, 1.39-6.39) and sarcopenia (OR, 3.89; 95% CI, 1.33-11.33). Only metabolic syndrome was associated with evening type in women (OR, 2.22; 95% CI, 1.11-4.43). CONCLUSIONS: At the population level, evening chronotype was independently associated with diabetes, metabolic syndrome, and sarcopenia. These results support the importance of circadian rhythms in metabolic regulation. PMID- 25831478 TI - Microbial conversion of ginsenoside Rd from Rb1 by the fungus mutant Aspergillus niger strain TH-10a. AB - Ginsenoside Rd, one of the ginsenosides with significant pharmaceutical activities, is getting more and more attractions on its biotransformation. In this study, a novel fungus mutant, the Aspergillus niger strain TH-10a, which can efficiently convert ginsenoside Rd from Rb1, was obtained through screening survival library of LiCl and ultraviolet (UV) irradiation. The transformation product ginsenoside Rd, generated by removing the outer glucose residue from the position C20 of ginsenoside Rb1, was identified through high-performance liquid chromatography (HPLC) analysis. Factors for the microbial culture and biotransformation were investigated in terms of the carbon sources, the nitrogen sources, pH values, and temperatures. This showed that maximum mycelia growth could be obtained at 28 degrees C and pH 6.0 with cellobiose and tryptone as the carbon source and the nitrogen source, respectively. The highest transformation rate (~86%) has been achieved at 32 degrees C and pH 5.0 with the feeding time of substrate 48 hr. Also, Aspergillus niger strain TH-10a could tolerate even 40 mg/mL ginseng root extract as substrate with 60% bioconversion rate after 72 hr of treatment at the optimal condition. Our results highlight a novel ginsenoside Rd transformation fungus and illuminate its potentially practical application in the pharmaceutical industries. PMID- 25831480 TI - [Amphibians in Spanish popular medicine and the pharmacopoeia of Pliny and Dioscorides]. AB - This article presents a list of medical remedies based on the use of amphibians in Spanish popular medicine and in the classical world. It provides an overview of bibliography relative to folklore studies, ethnographic work and research on social or medical anthropology. It documents a total of 113 remedies and the use of nine species of amphibians, two from the family of caudates (urodeles) and seven anurans. Most of these remedies are based on the popular "preconception" about the influence of amphibians and healing by transmitting an illness to a living creature. The traditional use of certain threatened species is emphasized, an issue to bear in mind in decision-making in the field of conservation biology and environmental education. PMID- 25831481 TI - Total syntheses of the resorcylic acid lactone neocosmosin A and its enantiomer. AB - A total synthesis of the structure, 1, assigned to the recently reported resorcylic acid lactone (RAL) neocosmosin A has been established. Olefin-cross metathesis, ring-closing metathesis, palladium-catalyzed Meinwald rearrangement, and Mitsunobu esterification reactions were used as key steps. A late-stage and simple modification to the reaction sequence also provided compound ent-1 that, in fact, represents the true structure of the natural product. PMID- 25831482 TI - Fighting fire with fire: mass antimalarial drug administrations in an era of antimalarial resistance. AB - The emergence and spread of antimalarial resistance has been a major liability for malaria control. The spread of chloroquine-resistant Plasmodium falciparum strains had catastrophic consequences for people in malaria-endemic regions, particularly in sub-Saharan Africa. The recent emergence of artemisinin-resistant P. falciparum strains is of highest concern. Current efforts to contain artemisinin resistance have yet to show success. In the absence of more promising plans, it has been suggested to eliminate falciparum malaria from foci of artemisinin resistance using a multipronged approach, including mass drug administrations. The use of mass drug administrations is controversial as it increases drug pressure. Based on current knowledge it is difficult to conceptualize how targeted malaria elimination could contribute to artemisinin resistance, provided a full treatment course is ensured. PMID- 25831483 TI - "It's got to be on this page": age and cognitive style in a study of online health information seeking. AB - BACKGROUND: The extensive availability of online health information offers the public opportunities to become independently informed about their care, but what affects the successful retrieval and understanding of accurate and detailed information? We have limited knowledge about the ways individuals use the Internet and the personal characteristics that affect online health literacy. OBJECTIVE: This study examined the extent to which age and cognitive style predicted success in searching for online health information, controlling for differences in education, daily Internet use, and general health literacy. METHODS: The Online Health Study (OHS) was conducted at Johns Hopkins School of Public Health and Stanford University School of Medicine from April 2009 to June 2010. The OHS was designed to explore the factors associated with success in obtaining health information across different age groups. A total of 346 men and women aged 35 years and older of diverse racial and ethnic backgrounds participated in the study. Participants were evaluated for success in searching online for answers to health-related tasks/questions on nutrition, cancer, alternative medicine, vaccinations, medical equipment, and genetic testing. RESULTS: Cognitive style, in terms of context sensitivity, was associated with less success in obtaining online health information, with tasks involving visual judgment most affected. In addition, better health literacy was positively associated with overall success in online health seeking, specifically for tasks requiring prior health knowledge. The oldest searchers were disadvantaged even after controlling for education, Internet use, general health literacy, and cognitive style, especially when spatial tasks such as mapping were involved. CONCLUSIONS: The increasing availability of online health information provides opportunities to improve patient education and knowledge, but effective use of these resources depends on online health literacy. Greater support for those who are in the oldest cohorts and for design of interfaces that support users with different cognitive styles may be required in an age of shared medical decision making. PMID- 25831484 TI - Clinical effectiveness and cost-effectiveness of elemental nutrition for the maintenance of remission in Crohn's disease: a systematic review and meta analysis. AB - BACKGROUND: Although enteral nutrition has been shown to be a viable treatment option for the management of active Crohn's disease (CD), the evidence regarding its clinical benefits compared with standard treatments (e.g. steroids) for maintaining remission in patients with CD has been inconsistent. If enteral nutrition was to be effective, the use of drugs such as steroids and immunosuppressive drugs could be reduced, thereby reducing the likelihood of adverse events associated with these medications. OBJECTIVES: This systematic review aimed to assess the clinical effectiveness and cost-effectiveness of elemental nutrition (a type of enteral nutrition) for maintenance of remission in patients with CD. DATA SOURCES: Major bibliographic databases (e.g. MEDLINE, EMBASE, Cochrane Database of Systematic Reviews) were searched from inception to August/September 2013. Searches were not limited by study design, language or publication date. Websites for relevant organisations and references of included studies were checked. METHODS: Experimental randomised and non-randomised controlled trials (RCTs and nRCTs) reporting clinical effectiveness and cost effectiveness of elemental nutrition in the maintenance of remission in patients with CD were eligible. Study selection, data extraction and risk of bias (RoB) assessment were performed independently. Risk ratios (RRs) and mean differences (MDs) were pooled using a random-effects model. Heterogeneity was assessed via forest plots, Cochran's Q and the I2 statistics. Overall, quality of evidence for each outcome was rated using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Eight studies (three RCTs and five nRCTs) were included in the review. RCTs indicated a significant benefit of elemental nutrition vs. no intervention (an unrestricted diet) in maintaining remission at 24 months [one RCT; RR 2.06, 95% confidence interval (CI) 1.00 to 4.43; very low-grade evidence] and preventing relapse at 12-24 months post baseline (two RCTs; pooled RR 0.57, 95% CI 0.38 to 0.84; I2 = 0%; high-grade evidence). Similarly, three nRCTs showed significant benefits of elemental nutrition over no intervention in maintaining remission at 12-48 months and preventing relapse at 12 months post baseline (MD 1.20 months, 95% CI 0.35 to 2.04 months). The incidence of mucosal healing was not significantly different in the intervention and control groups (RR 2.70, 95% CI 0.62 to 11.72). Adherence to an elemental nutrition regime was significantly worse than adherence to polymeric nutrition (RR 0.68, 95% CI 0.50 to 0.92) and, when compared with other active treatments (medications, polymeric nutrition or a combination), elemental nutrition yielded non-significant results with wide 95% CIs, rendering these results inconclusive. Complications and adverse events were too sparse to allow meaningful comparisons. None of the studies reported cost-effectiveness of elemental nutrition. Owing to scarcity of data, subgroup and sensitivity analyses could not be performed to explore methodological and clinical sources of heterogeneity. LIMITATIONS: The findings warrant cautious interpretation given the limitations of the evidence in methodological quality (small samples, short follow-up) and the RoB in individual studies (lack of blinding, confounding). CONCLUSIONS: Limited evidence indicates potential benefits of elemental nutrition against no intervention in the maintenance of remission and prevention of relapse in adult patients with CD. There was a lack or insufficient evidence on adverse events and complications. Future large and long-term randomised trials are warranted to draw more definitive conclusions regarding the effects of elemental nutrition in maintaining remission in CD. TRIAL REGISTRATION: This study is registered as PROSPERO CRD42013005134. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25831486 TI - Microbiology of Fresh Produce: Route of Contamination, Detection Methods, and Remedy. AB - Fresh fruits and vegetables are an important part of a healthful diet. They provide vitamins, minerals and fiber to help keep our body healthy. Occasionally, fresh fruits and vegetables can become contaminated with harmful bacteria or viruses, which are also known as pathogens. The major family of pathogen associated with food are members of Enterobacteriaceae which commonly form a part of microbiological criteria and their presence is traditionally related to hygiene and safety of foods. Organic fertilizers, irrigation water quality and soil are major source of contamination. For removal of pathogens, various decontamination procedures are also followed to reduce microbial load on the fruits. These are chemical preservatives and irradiation. Microbiological study of fresh produce can be done by various phenotypic, biochemical and molecular techniques so that pathogen can properly be identified. The World Health Organization (WHO) developed global risk communication message and training materials to assist countries in strengthening their food educating programs. There is a need for improved surveillance systems on food-borne pathogens, on food products and on outbreaks so that comparable data are available from a wider range of countries. PMID- 25831487 TI - Quenched phonon drag in silicon nanowires reveals significant effect in the bulk at room temperature. AB - Existing theory and data cannot quantify the contribution of phonon drag to the Seebeck coefficient (S) in semiconductors at room temperature. We show that this is possible through comparative measurements between nanowires and the bulk. Phonon boundary scattering completely quenches phonon drag in silicon nanowires enabling quantification of its contribution to S in bulk silicon in the range 25 500 K. The contribution is surprisingly large (~34%) at 300 K even at doping of ~3 * 10(19) cm(-3). Our results contradict the notion that phonon drag is negligible in degenerate semiconductors at temperatures relevant for thermoelectric energy conversion. A revised theory of electron-phonon momentum exchange that accounts for a phonon mean free path spectrum agrees well with the data. PMID- 25831488 TI - Warming trend: how climate shapes Vibrio ecology. PMID- 25831489 TI - Modulation of orthogonal body waves enables high maneuverability in sidewinding locomotion. AB - Many organisms move using traveling waves of body undulation, and most work has focused on single-plane undulations in fluids. Less attention has been paid to multiplane undulations, which are particularly important in terrestrial environments where vertical undulations can regulate substrate contact. A seemingly complex mode of snake locomotion, sidewinding, can be described by the superposition of two waves: horizontal and vertical body waves with a phase difference of +/- 90 degrees . We demonstrate that the high maneuverability displayed by sidewinder rattlesnakes (Crotalus cerastes) emerges from the animal's ability to independently modulate these waves. Sidewinder rattlesnakes used two distinct turning methods, which we term differential turning (26 degrees change in orientation per wave cycle) and reversal turning (89 degrees ). Observations of the snakes suggested that during differential turning the animals imposed an amplitude modulation in the horizontal wave whereas in reversal turning they shifted the phase of the vertical wave by 180 degrees . We tested these mechanisms using a multimodule snake robot as a physical model, successfully generating differential and reversal turning with performance comparable to that of the organisms. Further manipulations of the two-wave system revealed a third turning mode, frequency turning, not observed in biological snakes, which produced large (127 degrees ) in-place turns. The two-wave system thus functions as a template (a targeted motor pattern) that enables complex behaviors in a high-degree-of-freedom system to emerge from relatively simple modulations to a basic pattern. Our study reveals the utility of templates in understanding the control of biological movement as well as in developing control schemes for limbless robots. PMID- 25831490 TI - Human RECQ1 helicase-driven DNA unwinding, annealing, and branch migration: insights from DNA complex structures. AB - RecQ helicases are a widely conserved family of ATP-dependent motors with diverse roles in nearly every aspect of bacterial and eukaryotic genome maintenance. However, the physical mechanisms by which RecQ helicases recognize and process specific DNA replication and repair intermediates are largely unknown. Here, we solved crystal structures of the human RECQ1 helicase in complexes with tailed duplex DNA and ssDNA. The structures map the interactions of the ssDNA tail and the branch point along the helicase and Zn-binding domains, which, together with reported structures of other helicases, define the catalytic stages of helicase action. We also identify a strand-separating pin, which (uniquely in RECQ1) is buttressed by the protein dimer interface. A duplex DNA-binding surface on the C terminal domain is shown to play a role in DNA unwinding, strand annealing, and Holliday junction (HJ) branch migration. We have combined EM and analytical ultracentrifugation approaches to show that RECQ1 can form what appears to be a flat, homotetrameric complex and propose that RECQ1 tetramers are involved in HJ recognition. This tetrameric arrangement suggests a platform for coordinated activity at the advancing and receding duplexes of an HJ during branch migration. PMID- 25831491 TI - A new regime of nanoscale thermal transport: Collective diffusion increases dissipation efficiency. AB - Understanding thermal transport from nanoscale heat sources is important for a fundamental description of energy flow in materials, as well as for many technological applications including thermal management in nanoelectronics and optoelectronics, thermoelectric devices, nanoenhanced photovoltaics, and nanoparticle-mediated thermal therapies. Thermal transport at the nanoscale is fundamentally different from that at the macroscale and is determined by the distribution of carrier mean free paths and energy dispersion in a material, the length scales of the heat sources, and the distance over which heat is transported. Past work has shown that Fourier's law for heat conduction dramatically overpredicts the rate of heat dissipation from heat sources with dimensions smaller than the mean free path of the dominant heat-carrying phonons. In this work, we uncover a new regime of nanoscale thermal transport that dominates when the separation between nanoscale heat sources is small compared with the dominant phonon mean free paths. Surprisingly, the interaction of phonons originating from neighboring heat sources enables more efficient diffusive-like heat dissipation, even from nanoscale heat sources much smaller than the dominant phonon mean free paths. This finding suggests that thermal management in nanoscale systems including integrated circuits might not be as challenging as previously projected. Finally, we demonstrate a unique capability to extract differential conductivity as a function of phonon mean free path in materials, allowing the first (to our knowledge) experimental validation of predictions from the recently developed first-principles calculations. PMID- 25831492 TI - Biochemical characterization of a Naegleria TET-like oxygenase and its application in single molecule sequencing of 5-methylcytosine. AB - Modified DNA bases in mammalian genomes, such as 5-methylcytosine ((5m)C) and its oxidized forms, are implicated in important epigenetic regulation processes. In human or mouse, successive enzymatic conversion of (5m)C to its oxidized forms is carried out by the ten-eleven translocation (TET) proteins. Previously we reported the structure of a TET-like (5m)C oxygenase (NgTET1) from Naegleria gruberi, a single-celled protist evolutionarily distant from vertebrates. Here we show that NgTET1 is a 5-methylpyrimidine oxygenase, with activity on both (5m)C (major activity) and thymidine (T) (minor activity) in all DNA forms tested, and provide unprecedented evidence for the formation of 5-formyluridine ((5f)U) and 5 carboxyuridine ((5ca)U) in vitro. Mutagenesis studies reveal a delicate balance between choice of (5m)C or T as the preferred substrate. Furthermore, our results suggest substrate preference by NgTET1 to (5m)CpG and TpG dinucleotide sites in DNA. Intriguingly, NgTET1 displays higher T-oxidation activity in vitro than mammalian TET1, supporting a closer evolutionary relationship between NgTET1 and the base J-binding proteins from trypanosomes. Finally, we demonstrate that NgTET1 can be readily used as a tool in (5m)C sequencing technologies such as single molecule, real-time sequencing to map (5m)C in bacterial genomes at base resolution. PMID- 25831493 TI - Cross-talk between PKA-Cbeta and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. AB - Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit beta (PKA-Cbeta) and nuclear factor-kappaB (NF-kappaB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cbeta phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cbeta-induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cbeta and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor. PMID- 25831494 TI - Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. AB - The Mre11-Rad50-Xrs2/NBS1 (MRX/N) nuclease/ATPase complex plays structural and catalytic roles in the repair of DNA double-strand breaks (DSBs) and is the DNA damage sensor for Tel1/ATM kinase activation. Saccharomyces cerevisiae Sae2 can function with MRX to initiate 5'-3' end resection and also plays an important role in attenuation of DNA damage signaling. Here we describe a class of mre11 alleles that suppresses the DNA damage sensitivity of sae2Delta cells by accelerating turnover of Mre11 at DNA ends, shutting off the DNA damage checkpoint and allowing cell cycle progression. The mre11 alleles do not suppress the end resection or hairpin-opening defects of the sae2Delta mutant, indicating that these functions of Sae2 are not responsible for DNA damage resistance. The purified M(P110L)RX complex shows reduced binding to single- and double-stranded DNA in vitro relative to wild-type MRX, consistent with the increased turnover of Mre11 from damaged sites in vivo. Furthermore, overproduction of Mre11 causes DNA damage sensitivity only in the absence of Sae2. Together, these data suggest that it is the failure to remove Mre11 from DNA ends and attenuate Rad53 kinase signaling that causes hypersensitivity of sae2Delta cells to clastogens. PMID- 25831495 TI - Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects. AB - Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-gamma response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset. PMID- 25831496 TI - T-cell receptor alpha enhancer is inactivated in alphabeta T lymphocytes. AB - The Tcra enhancer (Ealpha) is essential for Tcra locus germ-line transcription and primary Valpha-to-Jalpha recombination during thymocyte development. We found that Ealpha is inhibited late during thymocyte differentiation and in alphabeta T lymphocytes, indicating that it is not required to drive transcription of rearranged Tcra genes. Ealpha inactivation resulted in the disruption of functional long-range enhancer-promoter interactions and was associated with loss of Ealpha-dependent histone modifications at promoter and enhancer regions, and reduced expression and recruitment of E2A to the Ealpha enhanceosome in T cells. Enhancer activity could not be recovered by T-cell activation, by forced expression of E2A or by the up-regulation of this and other transcription factors in the context of T helper differentiation. Our results argue that the major function of Ealpha is to coordinate the formation of a chromatin hub that drives Valpha and Jalpha germ-line transcription and primary rearrangements in thymocytes and imply the existence of an Ealpha-independent mechanism to activate transcription of the rearranged Tcra locus in alphabeta T cells. PMID- 25831497 TI - The frequency natural antisense transcript first promotes, then represses, frequency gene expression via facultative heterochromatin. AB - The circadian clock is controlled by a network of interconnected feedback loops that require histone modifications and chromatin remodeling. Long noncoding natural antisense transcripts (NATs) originate from Period in mammals and frequency (frq) in Neurospora. To understand the role of NATs in the clock, we put the frq antisense transcript qrf (frq spelled backwards) under the control of an inducible promoter. Replacing the endogenous qrf promoter altered heterochromatin formation and DNA methylation at frq. In addition, constitutive, low-level induction of qrf caused a dramatic effect on the endogenous rhythm and elevated circadian output. Surprisingly, even though qrf is needed for heterochromatic silencing, induction of qrf initially promoted frq gene expression by creating a more permissible local chromatin environment. The observation that antisense expression can initially promote sense gene expression before silencing via heterochromatin formation at convergent loci is also found when a NAT to hygromycin resistance gene is driven off the endogenous vivid (vvd) promoter in the Deltavvd strain. Facultative heterochromatin silencing at frq functions in a parallel pathway to previously characterized VVD-dependent silencing and is needed to establish the appropriate circadian phase. Thus, repression via dicer-independent siRNA-mediated facultative heterochromatin is largely independent of, and occurs alongside, other feedback processes. PMID- 25831498 TI - Infection by Toxoplasma gondii, a severe parasite in neonates and AIDS patients, causes impaired anion secretion in airway epithelia. AB - The airway epithelia initiate and modulate the inflammatory responses to various pathogens. The cystic fibrosis transmembrane conductance regulator-mediated Cl(-) secretion system plays a key role in mucociliary clearance of inhaled pathogens. We have explored the effects of Toxoplasma gondii, an opportunistic intracellular protozoan parasite, on Cl(-) secretion of the mouse tracheal epithelia. In this study, ATP-induced Cl(-) secretion indicated the presence of a biphasic short circuit current (Isc) response, which was mediated by a Ca(2+)-activated Cl(-) channel (CaCC) and the cystic fibrosis transmembrane conductance regulator. However, the ATP-evoked Cl(-) secretion in T. gondii-infected mouse tracheal epithelia and the elevation of [Ca(2+)]i in T. gondii-infected human airway epithelial cells were suppressed. Quantitative reverse transcription-PCR revealed that the mRNA expression level of the P2Y2 receptor (P2Y2-R) increased significantly in T. gondii-infected mouse tracheal cells. This revealed the influence that pathological changes in P2Y2-R had on the downstream signal, suggesting that P2Y2-R was involved in the mechanism underlying T. gondii infection in airways. These results link T. gondii infection as well as other pathogen infections to Cl(-) secretion, via P2Y2-R, which may provide new insights for the treatment of pneumonia caused by pathogens including T. gondii. PMID- 25831499 TI - Phosphorylation of ORF1p is required for L1 retrotransposition. AB - Although members of the L1 (LINE-1) clade of non-LTR retrotransposons can be deleterious, the L1 clade has remained active in most mammals for ~100 million years and generated almost 40% of the human genome. The details of L1-host interaction are largely unknown, however. Here we report that L1 activity requires phosphorylation of the protein encoded by the L1 ORF1 (ORF1p). Critical phospho-acceptor residues (two serines and two threonines) reside in four conserved proline-directed protein kinase (PDPK) target sites. The PDPK family includes mitogen-activated protein kinases and cyclin-dependent kinases. Mutation of any PDPK phospho-acceptor inhibits L1 retrotransposition. The phosphomimetic aspartic acid can restore activity at the two serine sites, but not at either threonine site, where it is strongly inhibitory. ORF1p also contains conserved PDPK docking sites, which promote specific interaction of PDPKs with their targets. As expected, mutations in these sites also inhibit L1 activity. PDPK mutations in ORF1p that inactivate L1 have no significant effect on the ability of ORF1p to anneal RNA in vitro, an important biochemical property of the protein. We show that phosphorylated PDPK sites in ORF1p are required for an interaction with the peptidyl prolyl isomerase 1 (Pin1), a critical component of PDPK-mediated regulation. Pin1 acts via isomerization of proline side chains at phosphorylated PDPK motifs, thereby affecting substrate conformation and activity. Our demonstration that L1 activity is dependent on and integrated with cellular phosphorylation regulatory cascades significantly increases our understanding of interactions between L1 and its host. PMID- 25831500 TI - A viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism. AB - Viral glycoproteins mediate entry of enveloped viruses into cells and thus play crucial roles in infection. In herpesviruses, a complex of two viral glycoproteins, gH and gL (gH/gL), regulates membrane fusion events and influences virion cell tropism. Human cytomegalovirus (HCMV) gH/gL can be incorporated into two different protein complexes: a glycoprotein O (gO)-containing complex known as gH/gL/gO, and a complex containing UL128, UL130, and UL131 known as gH/gL/UL128-131. Variability in the relative abundance of the complexes in the virion envelope correlates with differences in cell tropism exhibited between strains of HCMV. Nonetheless, the mechanisms underlying such variability have remained unclear. We have identified a viral protein encoded by the UL148 ORF (UL148) that influences the ratio of gH/gL/gO to gH/gL/UL128-131 and the cell tropism of HCMV virions. A mutant disrupted for UL148 showed defects in gH/gL/gO maturation and enhanced infectivity for epithelial cells. Accordingly, reintroduction of UL148 into an HCMV strain that lacked the gene resulted in decreased levels of gH/gL/UL128-131 on virions and, correspondingly, decreased infectivity for epithelial cells. UL148 localized to the endoplasmic reticulum, but not to the cytoplasmic sites of virion envelopment. Coimmunoprecipitation results indicated that gH, gL, UL130, and UL131 associate with UL148, but that gO and UL128 do not. Taken together, the findings suggest that UL148 modulates HCMV tropism by regulating the composition of alternative gH/gL complexes. PMID- 25831501 TI - Structural mechanisms of DNA binding and unwinding in bacterial RecQ helicases. AB - RecQ helicases unwind remarkably diverse DNA structures as key components of many cellular processes. How RecQ enzymes accommodate different substrates in a unified mechanism that couples ATP hydrolysis to DNA unwinding is unknown. Here, the X-ray crystal structure of the Cronobacter sakazakii RecQ catalytic core domain bound to duplex DNA with a 3' single-stranded extension identifies two DNA dependent conformational rearrangements: a winged-helix domain pivots ~90 degrees to close onto duplex DNA, and a conserved aromatic-rich loop is remodeled to bind ssDNA. These changes coincide with a restructuring of the RecQ ATPase active site that positions catalytic residues for ATP hydrolysis. Complex formation also induces a tight bend in the DNA and melts a portion of the duplex. This bending, coupled with translocation, could provide RecQ with a mechanism for unwinding duplex and other DNA structures. PMID- 25831503 TI - Using wavelength and slope to infer the historical origin of semiarid vegetation bands. AB - Landscape-scale patterns of vegetation occur worldwide at interfaces between semiarid and arid climates. They are important as potential indicators of climate change and imminent regime shifts and are widely thought to arise from positive feedback between vegetation and infiltration of rainwater. On gentle slopes the typical pattern form is bands (stripes), oriented parallel to the contours, and their wavelength is probably the most accessible statistic for vegetation patterns. Recent field studies have found an inverse correlation between pattern wavelength and slope, in apparent contradiction with the predictions of mathematical models. Here I show that this "contradiction" is based on a flawed approach to calculating the wavelength in models. When pattern generation is considered in detail, the theory is fully consistent with empirical results. For realistic parameters, degradation of uniform vegetation generates patterns whose wavelength increases with slope, whereas colonization of bare ground gives the opposite trend. Therefore, the empirical finding of an inverse relationship can be used, in conjunction with climate records, to infer the historical origin of the patterns. Specifically, for the African Sahel my results suggest that banded vegetation originated by the colonization of bare ground during circa 1760-1790 or since circa 1850. PMID- 25831502 TI - Systematic identification of signal integration by protein kinase A. AB - Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring protein-protein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA. PMID- 25831504 TI - Continental erosion and the Cenozoic rise of marine diatoms. AB - Marine diatoms are silica-precipitating microalgae that account for over half of organic carbon burial in marine sediments and thus they play a key role in the global carbon cycle. Their evolutionary expansion during the Cenozoic era (66 Ma to present) has been associated with a superior competitive ability for silicic acid relative to other siliceous plankton such as radiolarians, which evolved by reducing the weight of their silica test. Here we use a mathematical model in which diatoms and radiolarians compete for silicic acid to show that the observed reduction in the weight of radiolarian tests is insufficient to explain the rise of diatoms. Using the lithium isotope record of seawater as a proxy of silicate rock weathering and erosion, we calculate changes in the input flux of silicic acid to the oceans. Our results indicate that the long-term massive erosion of continental silicates was critical to the subsequent success of diatoms in marine ecosystems over the last 40 My and suggest an increase in the strength and efficiency of the oceanic biological pump over this period. PMID- 25831505 TI - Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue. AB - Genome-wide association studies have implicated PLEXIN D1 (PLXND1) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 (col5a1). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans. PMID- 25831506 TI - The uncertain climate footprint of wetlands under human pressure. AB - Significant climate risks are associated with a positive carbon-temperature feedback in northern latitude carbon-rich ecosystems, making an accurate analysis of human impacts on the net greenhouse gas balance of wetlands a priority. Here, we provide a coherent assessment of the climate footprint of a network of wetland sites based on simultaneous and quasi-continuous ecosystem observations of CO2 and CH4 fluxes. Experimental areas are located both in natural and in managed wetlands and cover a wide range of climatic regions, ecosystem types, and management practices. Based on direct observations we predict that sustained CH4 emissions in natural ecosystems are in the long term (i.e., several centuries) typically offset by CO2 uptake, although with large spatiotemporal variability. Using a space-for-time analogy across ecological and climatic gradients, we represent the chronosequence from natural to managed conditions to quantify the "cost" of CH4 emissions for the benefit of net carbon sequestration. With a sustained pulse-response radiative forcing model, we found a significant increase in atmospheric forcing due to land management, in particular for wetland converted to cropland. Our results quantify the role of human activities on the climate footprint of northern wetlands and call for development of active mitigation strategies for managed wetlands and new guidelines of the Intergovernmental Panel on Climate Change (IPCC) accounting for both sustained CH4 emissions and cumulative CO2 exchange. PMID- 25831507 TI - Expanded palette of Nano-lanterns for real-time multicolor luminescence imaging. AB - Fluorescence live imaging has become an essential methodology in modern cell biology. However, fluorescence requires excitation light, which can sometimes cause potential problems, such as autofluorescence, phototoxicity, and photobleaching. Furthermore, combined with recent optogenetic tools, the light illumination can trigger their unintended activation. Because luminescence imaging does not require excitation light, it is a good candidate as an alternative imaging modality to circumvent these problems. The application of luminescence imaging, however, has been limited by the two drawbacks of existing luminescent protein probes, such as luciferases: namely, low brightness and poor color variants. Here, we report the development of bright cyan and orange luminescent proteins by extending our previous development of the bright yellowish-green luminescent protein Nano-lantern. The color change and the enhancement of brightness were both achieved by bioluminescence resonance energy transfer (BRET) from enhanced Renilla luciferase to a fluorescent protein. The brightness of these cyan and orange Nano-lanterns was ~20 times brighter than wild-type Renilla luciferase, which allowed us to perform multicolor live imaging of intracellular submicron structures. The rapid dynamics of endosomes and peroxisomes were visualized at around 1-s temporal resolution, and the slow dynamics of focal adhesions were continuously imaged for longer than a few hours without photobleaching or photodamage. In addition, we extended the application of these multicolor Nano-lanterns to simultaneous monitoring of multiple gene expression or Ca(2+) dynamics in different cellular compartments in a single cell. PMID- 25831508 TI - TRAPPII regulates exocytic Golgi exit by mediating nucleotide exchange on the Ypt31 ortholog RabERAB11. AB - The oligomeric complex transport protein particle I (TRAPPI) mediates nucleotide exchange on the RAB GTPase RAB1/Ypt1. TRAPPII is composed of TRAPPI plus three additional subunits, Trs120, Trs130, and Trs65. Unclear is whether TRAPPII mediates nucleotide exchange on RAB1/Ypt1, RAB11/Ypt31, or both. In Aspergillus nidulans, RabO(RAB1) resides in the Golgi, RabE(RAB11) localizes to exocytic post Golgi carriers undergoing transport to the apex, and hypA encodes Trs120. RabE(RAB11), but not RabO(RAB1), immunoprecipitates contain Trs120/Trs130/Trs65, demonstrating specific association of TRAPPII with RabE(RAB11) in vivo. hypA1(ts) rapidly shifts RabE(RAB11), but not RabO(RAB1), to the cytosol, consistent with HypA(Trs120) being specifically required for RabE(RAB11) activation. Missense mutations rescuing hypA1(ts) at 42 degrees C mapped to rabE, affecting seven residues. Substitutions in six, of which four resulted in 7- to 36-fold accelerated GDP release, rescued lethality associated to TRAPPII deficiency, whereas equivalent substitutions in RabO(RAB1) did not, establishing that the essential role of TRAPPII is facilitating RabE(RAB11) nucleotide exchange. In vitro, TRAPPII purified with HypA(Trs120)-S-tag accelerates nucleotide exchange on RabE(RAB11) and, paradoxically, to a lesser yet substantial extent, on RabO(RAB1). Evidence obtained by exploiting hypA1-mediated destabilization of HypA(Trs120)/HypC(Trs130)/Trs65 assembly onto the TRAPPI core indicates that these subunits sculpt a second RAB binding site on TRAPP apparently independent from that for RabO(RAB1), which would explain TRAPPII in vitro activity on two RABs. Using A. nidulans in vivo microscopy, we show that HypA(Trs120) colocalizes with RabE(RAB11), arriving at late Golgi cisternae as they dissipate into exocytic carriers. Thus, TRAPPII marks, and possibly determines, the Golgi-to post-Golgi transition. PMID- 25831509 TI - Single-molecule analysis of RAG-mediated V(D)J DNA cleavage. AB - The recombination-activating gene products, RAG1 and RAG2, initiate V(D)J recombination during lymphocyte development by cleaving DNA adjacent to conserved recombination signal sequences (RSSs). The reaction involves DNA binding, synapsis, and cleavage at two RSSs located on the same DNA molecule and results in the assembly of antigen receptor genes. We have developed single-molecule assays to examine RSS binding by RAG1/2 and their cofactor high-mobility group box protein 1 (HMGB1) as they proceed through the steps of this reaction. These assays allowed us to observe in real time the individual molecular events of RAG mediated cleavage. As a result, we are able to measure the binding statistics (dwell times) and binding energies of the initial RAG binding events and characterize synapse formation at the single-molecule level, yielding insights into the distribution of dwell times in the paired complex and the propensity for cleavage on forming the synapse. Interestingly, we find that the synaptic complex has a mean lifetime of roughly 400 s and that its formation is readily reversible, with only ~40% of observed synapses resulting in cleavage at consensus RSS binding sites. PMID- 25831510 TI - DNA-mediated engineering of multicomponent enzyme crystals. AB - The ability to predictably control the coassembly of multiple nanoscale building blocks, especially those with disparate chemical and physical properties such as biomolecules and inorganic nanoparticles, has far-reaching implications in catalysis, sensing, and photonics, but a generalizable strategy for engineering specific contacts between these particles is an outstanding challenge. This is especially true in the case of proteins, where the types of possible interparticle interactions are numerous, diverse, and complex. Herein, we explore the concept of trading protein-protein interactions for DNA-DNA interactions to direct the assembly of two nucleic-acid-functionalized proteins with distinct surface chemistries into six unique lattices composed of catalytically active proteins, or of a combination of proteins and DNA-modified gold nanoparticles. The programmable nature of DNA-DNA interactions used in this strategy allows us to control the lattice symmetries and unit cell constants, as well as the compositions and habit, of the resulting crystals. This study provides a potentially generalizable strategy for constructing a unique class of materials that take advantage of the diverse morphologies, surface chemistries, and functionalities of proteins for assembling functional crystalline materials. PMID- 25831511 TI - Evidence for tunneling in base-catalyzed isomerization of glyceraldehyde to dihydroxyacetone by hydride shift under formose conditions. AB - Hydrogen atom transfer reactions between the aldose and ketose are key mechanistic features in formose chemistry by which formaldehyde is converted to higher sugars under credible prebiotic conditions. For one of these transformations, we have investigated whether hydrogen tunneling makes a significant contribution to the mechanism by examining the deuterium kinetic isotope effect associated with the hydrogen transfer during the isomerization of glyceraldehyde to the corresponding dihydroxyacetone. To do this, we developed a quantitative HPLC assay that allowed us to measure the apparent large intrinsic kinetic isotope effect. From the Arrhenius plot of the kinetic isotope effect, the ratio of the preexponential factors AH/AD was 0.28 and the difference in activation energies Ea(D) - Ea(H) was 9.1 kJ.mol(-1). All these results imply a significant quantum-mechanical tunneling component in the isomerization mechanism. This is supported by multidimensional tunneling calculations using POLYRATE with small curvature tunneling. PMID- 25831512 TI - A multistage mathematical approach to automated clustering of high-dimensional noisy data. AB - A critical problem faced in many scientific fields is the adequate separation of data derived from individual sources. Often, such datasets require analysis of multiple features in a highly multidimensional space, with overlap of features and sources. The datasets generated by simultaneous recording from hundreds of neurons emitting phasic action potentials have produced the challenge of separating the recorded signals into independent data subsets (clusters) corresponding to individual signal-generating neurons. Mathematical methods have been developed over the past three decades to achieve such spike clustering, but a complete solution with fully automated cluster identification has not been achieved. We propose here a fully automated mathematical approach that identifies clusters in multidimensional space through recursion, which combats the multidimensionality of the data. Recursion is paired with an approach to dimensional evaluation, in which each dimension of a dataset is examined for its informational importance for clustering. The dimensions offering greater informational importance are given added weight during recursive clustering. To combat strong background activity, our algorithm takes an iterative approach of data filtering according to a signal-to-noise ratio metric. The algorithm finds cluster cores, which are thereafter expanded to include complete clusters. This mathematical approach can be extended from its prototype context of spike sorting to other datasets that suffer from high dimensionality and background activity. PMID- 25831513 TI - Structure of the paramyxovirus parainfluenza virus 5 nucleoprotein-RNA complex. AB - Parainfluenza virus 5 (PIV5) is a member of the Paramyxoviridae family of membrane-enveloped viruses with a negative-sense RNA genome that is packaged and protected by long filamentous nucleocapsid-helix structures (RNPs). These RNPs, consisting of ~2,600 protomers of nucleocapsid (N) protein, form the template for viral transcription and replication. We have determined the 3D X-ray crystal structure of the nucleoprotein (N)-RNA complex from PIV5 to 3.11-A resolution. The structure reveals a 13-mer nucleocapsid ring whose diameter, cavity, and pitch/height dimensions agree with EM data from early studies on the Paramyxovirinae subfamily of native RNPs, indicating that it closely represents one-turn in the building block of the RNP helices. The PIV5-N nucleocapsid ring encapsidates a nuclease resistant 78-nt RNA strand in its positively charged groove formed between the N-terminal (NTD) and C-terminal (CTD) domains of its successive N protomers. Six nucleotides precisely are associated with each N protomer, with alternating three-base-in three-base-out conformation. The binding of six nucleotides per protomer is consistent with the "rule of six" that governs the genome packaging of the Paramyxovirinae subfamily of viruses. PIV5-N protomer subdomains are very similar in structure to the previously solved Nipah-N structure, but with a difference in the angle between NTD/CTD at the RNA hinge region. Based on the Nipah-N structure we modeled a PIV5-N open conformation in which the CTD rotates away from the RNA strand into the inner spacious nucleocapsid-ring cavity. This rotation would expose the RNA for the viral polymerase activity without major disruption of the nucleocapsid structure. PMID- 25831514 TI - Dynamin 2-dependent endocytosis sustains T-cell receptor signaling and drives metabolic reprogramming in T lymphocytes. AB - Prolonged T-cell receptor (TCR) signaling is required for the proliferation of T lymphocytes. Ligation of the TCR activates signaling, but also causes internalization of the TCR from the cell surface. How TCR signaling is sustained for many hours despite lower surface expression is unknown. Using genetic inhibition of endocytosis, we show here that TCR internalization promotes continued TCR signaling and T-lymphocyte proliferation. T-cell-specific deletion of dynamin 2, an essential component of endocytosis, resulted in reduced TCR signaling strength, impaired homeostatic proliferation, and the inability to undergo clonal expansion in vivo. Blocking endocytosis resulted in a failure to maintain mammalian target of rapamycin (mTOR) activity and to stably induce the transcription factor myelocytomatosis oncogene (c-Myc), which led to metabolic stress and a defect in cell growth. Our results support the concept that the TCR can continue to signal after it is internalized from the cell surface, thereby enabling sustained signaling and cell proliferation. PMID- 25831515 TI - Tryptophan-independent auxin biosynthesis contributes to early embryogenesis in Arabidopsis. AB - The phytohormone auxin regulates nearly all aspects of plant growth and development. Tremendous achievements have been made in elucidating the tryptophan (Trp)-dependent auxin biosynthetic pathway; however, the genetic evidence, key components, and functions of the Trp-independent pathway remain elusive. Here we report that the Arabidopsis indole synthase mutant is defective in the long anticipated Trp-independent auxin biosynthetic pathway and that auxin synthesized through this spatially and temporally regulated pathway contributes significantly to the establishment of the apical-basal axis, which profoundly affects the early embryogenesis in Arabidopsis. These discoveries pave an avenue for elucidating the Trp-independent auxin biosynthetic pathway and its functions in regulating plant growth and development. PMID- 25831516 TI - Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. AB - Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell based screen for bactericidal compounds against Mycobacterium tuberculosis under nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicating M. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, including Bacillus subtilis and Enterococcus faecalis, and drug-sensitive and drug-resistant strains of Enterococcus faecium and Staphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistant S. aureus infection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens. PMID- 25831517 TI - Unilateral incompatibility gene ui1.1 encodes an S-locus F-box protein expressed in pollen of Solanum species. AB - Unilateral interspecific incompatibility (UI) is a postpollination, prezygotic reproductive barrier that prevents hybridization between related species when the female parent is self-incompatible (SI) and the male parent is self-compatible (SC). In tomato and related Solanum species, two genes, ui1.1 and ui6.1, are required for pollen compatibility on pistils of SI species or hybrids. We previously showed that ui6.1 encodes a Cullin1 (CUL1) protein. Here we report that ui1.1 encodes an S-locus F-box (SLF) protein. The ui1.1 gene was mapped to a 0.43-cM, 43.2-Mbp interval at the S-locus on chromosome 1, but positional cloning was hampered by low recombination frequency. We hypothesized that ui1.1 encodes an SLF protein(s) that interacts with CUL1 and Skp1 proteins to form an SCF-type (Skp1, Cullin1, F-box) ubiquitin E3 ligase complex. We identified 23 SLF genes in the S. pennellii genome, of which 19 were also represented in cultivated tomato (S. lycopersicum). Data from recombination events, expression analysis, and sequence annotation highlighted 11 S. pennellii genes as candidates. Genetic transformations demonstrated that one of these, SpSLF-23, is sufficient for ui1.1 function. A survey of cultivated and wild tomato species identified SLF-23 orthologs in each of the SI species, but not in the SC species S. lycopersicum, S. cheesmaniae, and S. galapagense, pollen of which lacks ui1.1 function. These results demonstrate that pollen compatibility in UI is mediated by protein degradation through the ubiquitin-proteasome pathway, a mechanism related to that which controls pollen recognition in SI. PMID- 25831518 TI - Molecular coevolution of a sex pheromone and its receptor triggers reproductive isolation in Schizosaccharomyces pombe. AB - The diversification of sex pheromones is regarded as one of the causes of prezygotic isolation that results in speciation. In the fission yeast Schizosaccharomyces pombe, the molecular recognition of a peptide pheromone by its receptor plays an essential role in sexual reproduction. We considered that molecular coevolution of a peptide-mating pheromone, M factor, and its receptor, Map3, might be realized by experimentally diversifying these proteins. Here, we report the successful creation of novel mating-type pairs by searching for map3 suppressor mutations that rescued the sterility of M-factor mutants that were previously isolated. Several strong suppressors were found to also recognize WT M factor. The substituted residues of these Map3 suppressors were mapped to F204, F214, and E249, which are likely to be critical residues for M-factor recognition. These critical residues were systematically substituted with each of the other amino acids by in vitro mutagenesis. Ultimately, we successfully obtained three novel mating-type pairs constituting reproductive groups. These novel mating-type pairs could not conjugate with WT maters. Furthermore, no flow of chromosomally integrated drug-resistance genes occurred between the novel and the WT mating pairs, showing that each experimentally created reproductive group [e.g., M factor(V5H) and Map3(F214H)] was isolated from the WT group. In conclusion, we have succeeded in creating an artificial reproductive group that is isolated from the WT group. In keeping with the biological concept of species, the artificial reproductive group is a new species. PMID- 25831519 TI - An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world's most devastating pathogens. PMID- 25831520 TI - SWI/SNF chromatin-remodeling complexes function in noncoding RNA-dependent assembly of nuclear bodies. AB - Paraspeckles are subnuclear structures that form around nuclear paraspeckle assembly transcript 1 (NEAT1) long noncoding RNA (lncRNA). Recently, paraspeckles were shown to be functional nuclear bodies involved in stress responses and the development of specific organs. Paraspeckle formation is initiated by transcription of the NEAT1 chromosomal locus and proceeds in conjunction with NEAT1 lncRNA biogenesis and a subsequent assembly step involving >40 paraspeckle proteins (PSPs). In this study, subunits of SWItch/Sucrose NonFermentable (SWI/SNF) chromatin-remodeling complexes were identified as paraspeckle components that interact with PSPs and NEAT1 lncRNA. EM observations revealed that SWI/SNF complexes were enriched in paraspeckle subdomains depleted of chromatin. Knockdown of SWI/SNF components resulted in paraspeckle disintegration, but mutation of the ATPase domain of the catalytic subunit BRG1 did not affect paraspeckle integrity, indicating that the essential role of SWI/SNF complexes in paraspeckle formation does not require their canonical activity. Knockdown of SWI/SNF complexes barely affected the levels of known essential paraspeckle components, but markedly diminished the interactions between essential PSPs, suggesting that SWI/SNF complexes facilitate organization of the PSP interaction network required for intact paraspeckle assembly. The interactions between SWI/SNF components and essential PSPs were maintained in NEAT1-depleted cells, suggesting that SWI/SNF complexes not only facilitate interactions between PSPs, but also recruit PSPs during paraspeckle assembly. SWI/SNF complexes were also required for Satellite III lncRNA-dependent formation of nuclear stress bodies under heat-shock conditions. Our data suggest the existence of a common mechanism underlying the formation of lncRNA-dependent nuclear body architectures in mammalian cells. PMID- 25831521 TI - Sexual selection drives evolution and rapid turnover of male gene expression. AB - The profound and pervasive differences in gene expression observed between males and females, and the unique evolutionary properties of these genes in many species, have led to the widespread assumption that they are the product of sexual selection and sexual conflict. However, we still lack a clear understanding of the connection between sexual selection and transcriptional dimorphism, often termed sex-biased gene expression. Moreover, the relative contribution of sexual selection vs. drift in shaping broad patterns of expression, divergence, and polymorphism remains unknown. To assess the role of sexual selection in shaping these patterns, we assembled transcriptomes from an avian clade representing the full range of sexual dimorphism and sexual selection. We use these species to test the links between sexual selection and sex-biased gene expression evolution in a comparative framework. Through ancestral reconstruction of sex bias, we demonstrate a rapid turnover of sex bias across this clade driven by sexual selection and show it to be primarily the result of expression changes in males. We use phylogenetically controlled comparative methods to demonstrate that phenotypic measures of sexual selection predict the proportion of male-biased but not female-biased gene expression. Although male-biased genes show elevated rates of coding sequence evolution, consistent with previous reports in a range of taxa, there is no association between sexual selection and rates of coding sequence evolution, suggesting that expression changes may be more important than coding sequence in sexual selection. Taken together, our results highlight the power of sexual selection to act on gene expression differences and shape genome evolution. PMID- 25831523 TI - Development of sedentary communities in the Maya lowlands: coexisting mobile groups and public ceremonies at Ceibal, Guatemala. AB - Our archaeological investigations at Ceibal, a lowland Maya site located in the Pasion region, documented that a formal ceremonial complex was built around 950 B.C. at the onset of the Middle Preclassic period, when ceramics began to be used in the Maya lowlands. Our refined chronology allowed us to trace the subsequent social changes in a resolution that had not been possible before. Many residents of Ceibal appear to have remained relatively mobile during the following centuries, living in ephemeral post-in-ground structures and frequently changing their residential localities. In other parts of the Pasion region, there may have existed more mobile populations who maintained the traditional lifestyle of the preceramic period. Although the emerging elite of Ceibal began to live in a substantial residential complex by 700 B.C., advanced sedentism with durable residences rebuilt in the same locations and burials placed under house floors was not adopted in most residential areas until 500 B.C., and did not become common until 300 B.C. or the Late Preclassic period. During the Middle Preclassic period, substantial formal ceremonial complexes appear to have been built only at a small number of important communities in the Maya lowlands, and groups with different levels of sedentism probably gathered for their constructions and for public rituals held in them. These collaborative activities likely played a central role in socially integrating diverse groups with different lifestyles and, eventually, in developing fully established sedentary communities. PMID- 25831522 TI - Sparse feature selection methods identify unexpected global cellular response to strontium-containing materials. AB - Despite the increasing sophistication of biomaterials design and functional characterization studies, little is known regarding cells' global response to biomaterials. Here, we combined nontargeted holistic biological and physical science techniques to evaluate how simple strontium ion incorporation within the well-described biomaterial 45S5 bioactive glass (BG) influences the global response of human mesenchymal stem cells. Our objective analyses of whole gene expression profiles, confirmed by standard molecular biology techniques, revealed that strontium-substituted BG up-regulated the isoprenoid pathway, suggesting an influence on both sterol metabolite synthesis and protein prenylation processes. This up-regulation was accompanied by increases in cellular and membrane cholesterol and lipid raft contents as determined by Raman spectroscopy mapping and total internal reflection fluorescence microscopy analyses and by an increase in cellular content of phosphorylated myosin II light chain. Our unexpected findings of this strong metabolic pathway regulation as a response to biomaterial composition highlight the benefits of discovery-driven nonreductionist approaches to gain a deeper understanding of global cell-material interactions and suggest alternative research routes for evaluating biomaterials to improve their design. PMID- 25831524 TI - Multiplexed metagenome mining using short DNA sequence tags facilitates targeted discovery of epoxyketone proteasome inhibitors. AB - In molecular evolutionary analyses, short DNA sequences are used to infer phylogenetic relationships among species. Here we apply this principle to the study of bacterial biosynthesis, enabling the targeted isolation of previously unidentified natural products directly from complex metagenomes. Our approach uses short natural product sequence tags derived from conserved biosynthetic motifs to profile biosynthetic diversity in the environment and then guide the recovery of gene clusters from metagenomic libraries. The methodology is conceptually simple, requires only a small investment in sequencing, and is not computationally demanding. To demonstrate the power of this approach to natural product discovery we conducted a computational search for epoxyketone proteasome inhibitors within 185 globally distributed soil metagenomes. This led to the identification of 99 unique epoxyketone sequence tags, falling into 6 phylogenetically distinct clades. Complete gene clusters associated with nine unique tags were recovered from four saturating soil metagenomic libraries. Using heterologous expression methodologies, seven potent epoxyketone proteasome inhibitors (clarepoxcins A-E and landepoxcins A and B) were produced from these pathways, including compounds with different warhead structures and a naturally occurring halohydrin prodrug. This study provides a template for the targeted expansion of bacterially derived natural products using the global metagenome. PMID- 25831526 TI - Mechanisms of hematin crystallization and inhibition by the antimalarial drug chloroquine. AB - Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-MUM concentration of chloroquine fully arrests layer generation and step advancement, which is ~10(4)* less than hematin's physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials. PMID- 25831527 TI - Criticality of metals and metalloids. AB - Imbalances between metal supply and demand, real or anticipated, have inspired the concept of metal criticality. We here characterize the criticality of 62 metals and metalloids in a 3D "criticality space" consisting of supply risk, environmental implications, and vulnerability to supply restriction. Contributing factors that lead to extreme values include high geopolitical concentration of primary production, lack of available suitable substitutes, and political instability. The results show that the limitations for many metals important in emerging electronics (e.g., gallium and selenium) are largely those related to supply risk; those of platinum group metals, gold, and mercury, to environmental implications; and steel alloying elements (e.g., chromium and niobium) as well as elements used in high-temperature alloys (e.g., tungsten and molybdenum), to vulnerability to supply restriction. The metals of most concern tend to be those available largely or entirely as byproducts, used in small quantities for highly specialized applications, and possessing no effective substitutes. PMID- 25831525 TI - TCR contact residue hydrophobicity is a hallmark of immunogenic CD8+ T cell epitopes. AB - Despite the availability of major histocompatibility complex (MHC)-binding peptide prediction algorithms, the development of T-cell vaccines against pathogen and tumor antigens remains challenged by inefficient identification of immunogenic epitopes. CD8(+) T cells must distinguish immunogenic epitopes from nonimmunogenic self peptides to respond effectively against an antigen without endangering the viability of the host. Because this discrimination is fundamental to our understanding of immune recognition and critical for rational vaccine design, we interrogated the biochemical properties of 9,888 MHC class I peptides. We identified a strong bias toward hydrophobic amino acids at T-cell receptor contact residues within immunogenic epitopes of MHC allomorphs, which permitted us to develop and train a hydrophobicity-based artificial neural network (ANN Hydro) to predict immunogenic epitopes. The immunogenicity model was validated in a blinded in vivo overlapping epitope discovery study of 364 peptides from three HIV-1 Gag protein variants. Applying the ANN-Hydro model on existing peptide-MHC algorithms consistently reduced the number of candidate peptides across multiple antigens and may provide a correlate with immunodominance. Hydrophobicity of TCR contact residues is a hallmark of immunogenic epitopes and marks a step toward eliminating the need for empirical epitope testing for vaccine development. PMID- 25831528 TI - Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription. AB - Lineage specification during development involves reprogramming of transcriptional states, but little is known about how this is regulated in vivo. The chromatin remodeler chomodomain helicase DNA-binding protein 1 (Chd1) promotes an elevated transcriptional output in mouse embryonic stem cells. Here we report that endothelial-specific deletion of Chd1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5. Mutant embryos contain normal numbers of E10.5 intraaortic hematopoietic clusters that express Runx1 and Kit, but these clusters undergo apoptosis and fail to mature into blood lineages in vivo and in vitro. Hematopoietic progenitors emerging from the aorta have an elevated transcriptional output relative to structural endothelium, and this elevation is Chd1-dependent. In contrast, hematopoietic specific deletion of Chd1 using Vav-Cre has no apparent phenotype. Our results reveal a new paradigm of regulation of a developmental transition by elevation of global transcriptional output that is critical for hemogenesis and may play roles in other contexts. PMID- 25831529 TI - Carbon monoxide as a metabolic energy source for extremely halophilic microbes: implications for microbial activity in Mars regolith. AB - Carbon monoxide occurs at relatively high concentrations (>=800 parts per million) in Mars' atmosphere, where it represents a potentially significant energy source that could fuel metabolism by a localized putative surface or near surface microbiota. However, the plausibility of CO oxidation under conditions relevant for Mars in its past or at present has not been evaluated. Results from diverse terrestrial brines and saline soils provide the first documentation, to our knowledge, of active CO uptake at water potentials (-41 MPa to -117 MPa) that might occur in putative brines at recurrent slope lineae (RSL) on Mars. Results from two extremely halophilic isolates complement the field observations. Halorubrum str. BV1, isolated from the Bonneville Salt Flats, Utah (to our knowledge, the first documented extremely halophilic CO-oxidizing member of the Euryarchaeota), consumed CO in a salt-saturated medium with a water potential of 39.6 MPa; activity was reduced by only 28% relative to activity at its optimum water potential of -11 MPa. A proteobacterial isolate from hypersaline Mono Lake, California, Alkalilimnicola ehrlichii MLHE-1, also oxidized CO at low water potentials (-19 MPa), at temperatures within ranges reported for RSL, and under oxic, suboxic (0.2% oxygen), and anoxic conditions (oxygen-free with nitrate). MLHE-1 was unaffected by magnesium perchlorate or low atmospheric pressure (10 mbar). These results collectively establish the potential for microbial CO oxidation under conditions that might obtain at local scales (e.g., RSL) on contemporary Mars and at larger spatial scales earlier in Mars' history. PMID- 25831530 TI - cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. AB - Interferon gamma-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling. PMID- 25831531 TI - Insight into the evolution and origin of leprosy bacilli from the genome sequence of Mycobacterium lepromatosis. AB - Mycobacterium lepromatosis is an uncultured human pathogen associated with diffuse lepromatous leprosy and a reactional state known as Lucio's phenomenon. By using deep sequencing with and without DNA enrichment, we obtained the near complete genome sequence of M. lepromatosis present in a skin biopsy from a Mexican patient, and compared it with that of Mycobacterium leprae, which has undergone extensive reductive evolution. The genomes display extensive synteny and are similar in size (~3.27 Mb). Protein-coding genes share 93% nucleotide sequence identity, whereas pseudogenes are only 82% identical. The events that led to pseudogenization of 50% of the genome likely occurred before divergence from their most recent common ancestor (MRCA), and both M. lepromatosis and M. leprae have since accumulated new pseudogenes or acquired specific deletions. Functional comparisons suggest that M. lepromatosis has lost several enzymes required for amino acid synthesis whereas M. leprae has a defective heme pathway. M. lepromatosis has retained all functions required to infect the Schwann cells of the peripheral nervous system and therefore may also be neuropathogenic. A phylogeographic survey of 227 leprosy biopsies by differential PCR revealed that 221 contained M. leprae whereas only six, all from Mexico, harbored M. lepromatosis. Phylogenetic comparisons indicate that M. lepromatosis is closer than M. leprae to the MRCA, and a Bayesian dating analysis suggests that they diverged from their MRCA approximately 13.9 Mya. Thus, despite their ancient separation, the two leprosy bacilli are remarkably conserved and still cause similar pathologic conditions. PMID- 25831532 TI - beta-Arrestin-biased signaling mediates memory reconsolidation. AB - A long-standing hypothesis posits that a G protein-coupled signaling pathway mediates beta-adrenergic nervous system functions, including learning and memory. Here we report that memory retrieval (reactivation) induces the activation of beta1-adrenergic beta-arrestin signaling in the brain, which stimulates ERK signaling and protein synthesis, leading to postreactivation memory restabilization. beta-Arrestin2-deficient mice exhibit impaired memory reconsolidation in object recognition, Morris water maze, and cocaine-conditioned place preference paradigms. Postreactivation blockade of both brain beta adrenergic Gs protein- and beta-arrestin-dependent pathways disrupts memory reconsolidation. Unexpectedly, selective blockade of the Gs/cAMP/PKA signaling but not the beta-arrestin/ERK signaling by the biased beta-adrenergic ligands does not inhibit reconsolidation. Moreover, the expression of beta-arrestin2 in the entorhinal cortex of beta-arrestin 2-deficient mice rescues beta1-adrenergic ERK signaling and reconsolidation in a G protein pathway-independent manner. We demonstrate that beta-arrestin-biased signaling regulates memory reconsolidation and reveal the potential for beta-arrestin-biased ligands in the treatment of memory-related disorders. PMID- 25831533 TI - Trichodesmium genome maintains abundant, widespread noncoding DNA in situ, despite oligotrophic lifestyle. AB - Understanding the evolution of the free-living, cyanobacterial, diazotroph Trichodesmium is of great importance because of its critical role in oceanic biogeochemistry and primary production. Unlike the other >150 available genomes of free-living cyanobacteria, only 63.8% of the Trichodesmium erythraeum (strain IMS101) genome is predicted to encode protein, which is 20-25% less than the average for other cyanobacteria and nonpathogenic, free-living bacteria. We use distinctive isolates and metagenomic data to show that low coding density observed in IMS101 is a common feature of the Trichodesmium genus, both in culture and in situ. Transcriptome analysis indicates that 86% of the noncoding space is expressed, although the function of these transcripts is unclear. The density of noncoding, possible regulatory elements predicted in Trichodesmium, when normalized per intergenic kilobase, was comparable and twofold higher than that found in the gene-dense genomes of the sympatric cyanobacterial genera Synechococcus and Prochlorococcus, respectively. Conserved Trichodesmium noncoding RNA secondary structures were predicted between most culture and metagenomic sequences, lending support to the structural conservation. Conservation of these intergenic regions in spatiotemporally separated Trichodesmium populations suggests possible genus-wide selection for their maintenance. These large intergenic spacers may have developed during intervals of strong genetic drift caused by periodic blooms of a subset of genotypes, which may have reduced effective population size. Our data suggest that transposition of selfish DNA, low effective population size, and high-fidelity replication allowed the unusual "inflation" of noncoding sequence observed in Trichodesmium despite its oligotrophic lifestyle. PMID- 25831534 TI - A functional role of Rv1738 in Mycobacterium tuberculosis persistence suggested by racemic protein crystallography. AB - Protein 3D structure can be a powerful predictor of function, but it often faces a critical roadblock at the crystallization step. Rv1738, a protein from Mycobacterium tuberculosis that is strongly implicated in the onset of nonreplicating persistence, and thereby latent tuberculosis, resisted extensive attempts at crystallization. Chemical synthesis of the L- and D-enantiomeric forms of Rv1738 enabled facile crystallization of the D/L-racemic mixture. The structure was solved by an ab initio approach that took advantage of the quantized phases characteristic of diffraction by centrosymmetric crystals. The structure, containing L- and D-dimers in a centrosymmetric space group, revealed unexpected homology with bacterial hibernation-promoting factors that bind to ribosomes and suppress translation. This suggests that the functional role of Rv1738 is to contribute to the shutdown of ribosomal protein synthesis during the onset of nonreplicating persistence of M. tuberculosis. PMID- 25831535 TI - Leader emergence through interpersonal neural synchronization. AB - The neural mechanism of leader emergence is not well understood. This study investigated (i) whether interpersonal neural synchronization (INS) plays an important role in leader emergence, and (ii) whether INS and leader emergence are associated with the frequency or the quality of communications. Eleven three member groups were asked to perform a leaderless group discussion (LGD) task, and their brain activities were recorded via functional near infrared spectroscopy (fNIRS)-based hyperscanning. Video recordings of the discussions were coded for leadership and communication. Results showed that the INS for the leader-follower (LF) pairs was higher than that for the follower-follower (FF) pairs in the left temporo-parietal junction (TPJ), an area important for social mentalizing. Although communication frequency was higher for the LF pairs than for the FF pairs, the frequency of leader-initiated and follower-initiated communication did not differ significantly. Moreover, INS for the LF pairs was significantly higher during leader-initiated communication than during follower-initiated communications. In addition, INS for the LF pairs during leader-initiated communication was significantly correlated with the leaders' communication skills and competence, but not their communication frequency. Finally, leadership could be successfully predicted based on INS as well as communication frequency early during the LGD (before half a minute into the task). In sum, this study found that leader emergence was characterized by high-level neural synchronization between the leader and followers and that the quality, rather than the frequency, of communications was associated with synchronization. These results suggest that leaders emerge because they are able to say the right things at the right time. PMID- 25831536 TI - Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase. AB - Mitochondrial ATP synthase is driven by chemiosmotic oxidation of pyruvate derived from glycolysis. Blood-stage malaria parasites eschew chemiosmosis, instead relying almost solely on glycolysis for their ATP generation, which begs the question of whether mitochondrial ATP synthase is necessary during the blood stage of the parasite life cycle. We knocked out the mitochondrial ATP synthase beta subunit gene in the rodent malaria parasite, Plasmodium berghei, ablating the protein that converts ADP to ATP. Disruption of the beta subunit gene of the ATP synthase only marginally reduced asexual blood-stage parasite growth but completely blocked mouse-to-mouse transmission via Anopheles stephensi mosquitoes. Parasites lacking the beta subunit gene of the ATP synthase generated viable gametes that fuse and form ookinetes but cannot progress beyond this stage. Ookinetes lacking the beta subunit gene of the ATP synthase had normal motility but were not viable in the mosquito midgut and never made oocysts or sporozoites, thereby abrogating transmission to naive mice via mosquito bite. We crossed the self-infertile ATP synthase beta subunit knockout parasites with a male-deficient, self-infertile strain of P. berghei, which restored fertility and production of oocysts and sporozoites, which demonstrates that mitochondrial ATP synthase is essential for ongoing viability through the female, mitochondrion carrying line of sexual reproduction in P. berghei malaria. Perturbation of ATP synthase completely blocks transmission to the mosquito vector and could potentially be targeted for disease control. PMID- 25831537 TI - Non-native plants add to the British flora without negative consequences for native diversity. AB - Plants are commonly listed as invasive species, presuming that they cause harm at both global and regional scales. Approximately 40% of all species listed as invasive within Britain are plants. However, invasive plants are rarely linked to the national or global extinction of native plant species. The possible explanation is that competitive exclusion takes place slowly and that invasive plants will eventually eliminate native species (the "time-to-exclusion hypothesis"). Using the extensive British Countryside Survey Data, we find that changes to plant occurrence and cover between 1990 and 2007 at 479 British sites do not differ between native and non-native plant species. More than 80% of the plant species that are widespread enough to be sampled are native species; hence, total cover changes have been dominated by native species (total cover increases by native species are more than nine times greater than those by non-native species). This implies that factors other than plant "invasions" are the key drivers of vegetation change. We also find that the diversity of native species is increasing in locations where the diversity of non-native species is increasing, suggesting that high diversities of native and non-native plant species are compatible with one another. We reject the time-to-exclusion hypothesis as the reason why extinctions have not been observed and suggest that non-native plant species are not a threat to floral diversity in Britain. Further research is needed in island-like environments, but we question whether it is appropriate that more than three-quarters of taxa listed globally as invasive species are plants. PMID- 25831538 TI - Family environment and the malleability of cognitive ability: a Swedish national home-reared and adopted-away cosibling control study. AB - Cognitive ability strongly aggregates in families, and prior twin and adoption studies have suggested that this is the result of both genetic and environmental factors. In this study, we used a powerful design--home-reared and adopted-away cosibling controls--to investigate the role of the rearing environment in cognitive ability. We identified, from a complete national Swedish sample of male male siblings, 436 full-sibships in which at least one member was reared by one or more biological parents and the other by adoptive parents. IQ was measured at age 18-20 as part of the Swedish military service conscription examination. Parental educational level was rated on a 5-point scale. Controlling for clustering of offspring within biological families, the adopted siblings had an IQ 4.41 (SE = 0.75) points higher than their nonadopted siblings. Each additional unit of rearing parental education was associated with 1.71 (SE = 0.44) units of IQ. We replicated these results in 2,341 male-male half-sibships, in which, controlling for clustering within families, adoption was associated with a gain of IQ of 3.18 (SE = 0.34) points. Each additional unit of rearing parental education was associated with 1.94 (SE = 0.18) IQ units. Using full- and half sibling sets matched for genetic background, we found replicated evidence that (i) rearing environment affects IQ measured in late adolescence, and (ii) a portion of the IQ of adopted siblings could be explained by the educational level of their adoptive parents. PMID- 25831539 TI - Motion of proximal histidine and structural allosteric transition in soluble guanylate cyclase. AB - We investigated the changes of heme coordination in purified soluble guanylate cyclase (sGC) by time-resolved spectroscopy in a time range encompassing 11 orders of magnitude (from 1 ps to 0.2 s). After dissociation, NO either recombines geminately to the 4-coordinate (4c) heme (tauG1 = 7.5 ps; 97 +/- 1% of the population) or exits the heme pocket (3 +/- 1%). The proximal His rebinds to the 4c heme with a 70-ps time constant. Then, NO is distributed in two approximately equal populations (1.5%). One geminately rebinds to the 5c heme (tauG2 = 6.5 ns), whereas the other diffuses out to the solution, from where it rebinds bimolecularly (tau = 50 MUs with [NO] = 200 MUM) forming a 6c heme with a diffusion-limited rate constant of 2 * 10(8) M(-1)?s(-1). In both cases, the rebinding of NO induces the cleavage of the Fe-His bond that can be observed as an individual reaction step. Saliently, the time constant of bond cleavage differs depending on whether NO binds geminately or from solution (tau5C1 = 0.66 MUs and tau5C2 = 10 ms, respectively). Because the same event occurs with rates separated by four orders of magnitude, this measurement implies that sGC is in different structural states in both cases, having different strain exerted on the Fe-His bond. We show here that this structural allosteric transition takes place in the range 1-50 MUs. In this context, the detection of NO binding to the proximal side of sGC heme is discussed. PMID- 25831540 TI - Jupiter's decisive role in the inner Solar System's early evolution. AB - The statistics of extrasolar planetary systems indicate that the default mode of planet formation generates planets with orbital periods shorter than 100 days and masses substantially exceeding that of the Earth. When viewed in this context, the Solar System is unusual. Here, we present simulations which show that a popular formation scenario for Jupiter and Saturn, in which Jupiter migrates inward from a > 5 astronomical units (AU) to a ~ 1.5 AU before reversing direction, can explain the low overall mass of the Solar System's terrestrial planets, as well as the absence of planets with a < 0.4 AU. Jupiter's inward migration entrained s ? 10-100 km planetesimals into low-order mean motion resonances, shepherding and exciting their orbits. The resulting collisional cascade generated a planetesimal disk that, evolving under gas drag, would have driven any preexisting short-period planets into the Sun. In this scenario, the Solar System's terrestrial planets formed from gas-starved mass-depleted debris that remained after the primary period of dynamical evolution. PMID- 25831541 TI - Area burned in the western United States is unaffected by recent mountain pine beetle outbreaks. AB - In the western United States, mountain pine beetles (MPBs) have killed pine trees across 71,000 km(2) of forest since the mid-1990s, leading to widespread concern that abundant dead fuels may increase area burned and exacerbate fire behavior. Although stand-level fire behavior models suggest that bark beetle-induced tree mortality increases flammability of stands by changing canopy and forest floor fuels, the actual effect of an MPB outbreak on subsequent wildfire activity remains widely debated. To address this knowledge gap, we superimposed areas burned on areas infested by MPBs for the three peak years of wildfire activity since 2002 across the western United States. Here, we show that the observed effect of MPB infestation on the area burned in years of extreme fire appears negligible at broad spatial extents. Contrary to the expectation of increased wildfire activity in recently infested red-stage stands, we found no difference between observed area and expected area burned in red-stage or subsequent gray stage stands during three peak years of wildfire activity, which account for 46% of area burned during the 2002-2013 period. Although MPB infestation and fire activity both independently increased in conjunction with recent warming, our results demonstrate that the annual area burned in the western United States has not increased in direct response to bark beetle activity. Therefore, policy discussions should focus on societal adaptation to the effects of recent increases in wildfire activity related to increased drought severity. PMID- 25831542 TI - Engineering three-dimensional hybrid supercapacitors and microsupercapacitors for high-performance integrated energy storage. AB - Supercapacitors now play an important role in the progress of hybrid and electric vehicles, consumer electronics, and military and space applications. There is a growing demand in developing hybrid supercapacitor systems to overcome the energy density limitations of the current generation of carbon-based supercapacitors. Here, we demonstrate 3D high-performance hybrid supercapacitors and microsupercapacitors based on graphene and MnO2 by rationally designing the electrode microstructure and combining active materials with electrolytes that operate at high voltages. This results in hybrid electrodes with ultrahigh volumetric capacitance of over 1,100 F/cm(3). This corresponds to a specific capacitance of the constituent MnO2 of 1,145 F/g, which is close to the theoretical value of 1,380 F/g. The energy density of the full device varies between 22 and 42 Wh/l depending on the device configuration, which is superior to those of commercially available double-layer supercapacitors, pseudocapacitors, lithium-ion capacitors, and hybrid supercapacitors tested under the same conditions and is comparable to that of lead acid batteries. These hybrid supercapacitors use aqueous electrolytes and are assembled in air without the need for expensive "dry rooms" required for building today's supercapacitors. Furthermore, we demonstrate a simple technique for the fabrication of supercapacitor arrays for high-voltage applications. These arrays can be integrated with solar cells for efficient energy harvesting and storage systems. PMID- 25831543 TI - Late Pleistocene horse and camel hunting at the southern margin of the ice-free corridor: reassessing the age of Wally's Beach, Canada. AB - The only certain evidence for prehistoric human hunting of horse and camel in North America occurs at the Wally's Beach site, Canada. Here, the butchered remains of seven horses and one camel are associated with 29 nondiagnostic lithic artifacts. Twenty-seven new radiocarbon ages on the bones of these animals revise the age of these kill and butchering localities to 13,300 calibrated y B.P. The tight chronological clustering of the eight kill localities at Wally's Beach indicates these animals were killed over a short period. Human hunting of horse and camel in Canada, coupled with mammoth, mastodon, sloth, and gomphothere hunting documented at other sites from 14,800-12,700 calibrated y B.P., show that 6 of the 36 genera of megafauna that went extinct by approximately 12,700 calibrated y B.P. were hunted by humans. This study shows the importance of accurate geochronology, without which significant discoveries will go unrecognized and the empirical data used to build models explaining the peopling of the Americas and Pleistocene extinctions will be in error. PMID- 25831545 TI - Tunable molecular orientation and elevated thermal stability of vapor-deposited organic semiconductors. AB - Physical vapor deposition is commonly used to prepare organic glasses that serve as the active layers in light-emitting diodes, photovoltaics, and other devices. Recent work has shown that orienting the molecules in such organic semiconductors can significantly enhance device performance. We apply a high-throughput characterization scheme to investigate the effect of the substrate temperature (Tsubstrate) on glasses of three organic molecules used as semiconductors. The optical and material properties are evaluated with spectroscopic ellipsometry. We find that molecular orientation in these glasses is continuously tunable and controlled by Tsubstrate/Tg, where Tg is the glass transition temperature. All three molecules can produce highly anisotropic glasses; the dependence of molecular orientation upon substrate temperature is remarkably similar and nearly independent of molecular length. All three compounds form "stable glasses" with high density and thermal stability, and have properties similar to stable glasses prepared from model glass formers. Simulations reproduce the experimental trends and explain molecular orientation in the deposited glasses in terms of the surface properties of the equilibrium liquid. By showing that organic semiconductors form stable glasses, these results provide an avenue for systematic performance optimization of active layers in organic electronics. PMID- 25831546 TI - Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells. AB - Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase eta (Pol eta) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol eta blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol eta-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR 93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol eta expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol eta-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol eta, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment. PMID- 25831548 TI - KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8. AB - A rare Mendelian syndrome--pseudohypoaldosteronism type II (PHA-II)--features hypertension, hyperkalemia, and metabolic acidosis. Genetic linkage studies and exome sequencing have identified four genes--with no lysine kinase 1 (wnk1), wnk4, Kelch-like 3 (KLHL3), and Cullin 3 (Cul3)--mutations of which all caused PHA-II phenotypes. The previous hypothesis was that the KLHL3-Cul3 ubiquitin complex acted on the wnk4-wnk1 kinase complex to regulate Na(+)/Cl(-) cotransporter (NCC) mediated salt reabsorption in the distal tubules of the kidney. Here, we report the identification of claudin-8 as a previously unidentified physiologic target for KLHL3 and provide an alternative explanation for the collecting duct's role in PHA-II. Using a tissue-specific KO approach, we have found that deletion of claudin-8 in the collecting duct of mouse kidney caused hypotension, hypokalemia, and metabolic alkalosis, an exact mirror image of PHA-II. Mechanistically, the phenotypes in claudin-8 KO animals were caused by disruption of the claudin-8 interaction with claudin-4, the paracellular chloride channel, and delocalization of claudin-4 from the tight junction. In mouse collecting duct cells, knockdown of KLHL3 profoundly increased the paracellular chloride permeability. Mechanistically, KLHL3 was directly bound to claudin-8, and this binding led to the ubiquitination and degradation of claudin-8. The dominant PHA-II mutation in KLHL3 impaired claudin-8 binding, ubiquitination, and degradation. These findings have attested to the concept that the paracellular pathway is physiologically regulated through the ubiquitination pathway, and its deregulation may lead to diseases of electrolyte and blood pressure imbalances. PMID- 25831550 TI - Sitting Time, Physical Activity, and Cardiorespiratory Fitness: Cooper Center Longitudinal Study Cohort. AB - BACKGROUND: Prolonged sitting time is associated with numerous health outcomes; however, the role of cardiorespiratory fitness (CRF) in these relationships is largely unexplored. The cross-sectional association between reported sitting time and measured CRF was examined in a large study of healthy men and women. METHODS: The analytic sample included 4658 men and 1737 women enrolled in the Cooper Center Longitudinal Study. Unadjusted and adjusted multivariable linear regression models were constructed to examine the association between sitting time and CRF, stratified by sex and meeting (or not) meeting physical activity (PA) guidelines. RESULTS: In men, CRF was not associated with sitting time after adjustment for potential confounders. In contrast, for women, after adjustment there was a significant association between increased sitting time and lower CRF (P for trend <.001). When stratified by meeting or not meeting PA guidelines, there was no association between sitting time and CRF in men. In women, this relationship was statistically significant regardless of PA category (both P for trend < .05). CONCLUSIONS: These results suggest that the association between sitting time and CRF varies by sex. Further, meeting PA guidelines does not appear to modify this relation in either sex. PMID- 25831549 TI - Epigenetics. Epigenetic inheritance uncoupled from sequence-specific recruitment. AB - Changes in histone posttranslational modifications are associated with epigenetic states that define distinct patterns of gene expression. It remains unclear whether epigenetic information can be transmitted through histone modifications independently of specific DNA sequence, DNA methylation, or RNA interference. Here we show that, in the fission yeast Schizosaccharomyces pombe, ectopically induced domains of histone H3 lysine 9 methylation (H3K9me), a conserved marker of heterochromatin, are inherited through several mitotic and meiotic cell divisions after removal of the sequence-specific initiator. The putative JmjC domain H3K9 demethylase, Epe1, and the chromodomain of the H3K9 methyltransferase, Clr4/Suv39h, play opposing roles in maintaining silent H3K9me domains. These results demonstrate how a direct "read-write" mechanism involving Clr4 propagates histone modifications and allows histones to act as carriers of epigenetic information. PMID- 25831547 TI - An ancestral bacterial division system is widespread in eukaryotic mitochondria. AB - Bacterial division initiates at the site of a contractile Z-ring composed of polymerized FtsZ. The location of the Z-ring in the cell is controlled by a system of three mutually antagonistic proteins, MinC, MinD, and MinE. Plastid division is also known to be dependent on homologs of these proteins, derived from the ancestral cyanobacterial endosymbiont that gave rise to plastids. In contrast, the mitochondria of model systems such as Saccharomyces cerevisiae, mammals, and Arabidopsis thaliana seem to have replaced the ancestral alpha proteobacterial Min-based division machinery with host-derived dynamin-related proteins that form outer contractile rings. Here, we show that the mitochondrial division system of these model organisms is the exception, rather than the rule, for eukaryotes. We describe endosymbiont-derived, bacterial-like division systems comprising FtsZ and Min proteins in diverse less-studied eukaryote protistan lineages, including jakobid and heterolobosean excavates, a malawimonad, stramenopiles, amoebozoans, a breviate, and an apusomonad. For two of these taxa, the amoebozoan Dictyostelium purpureum and the jakobid Andalucia incarcerata, we confirm a mitochondrial localization of these proteins by their heterologous expression in Saccharomyces cerevisiae. The discovery of a proteobacterial-like division system in mitochondria of diverse eukaryotic lineages suggests that it was the ancestral feature of all eukaryotic mitochondria and has been supplanted by a host-derived system multiple times in distinct eukaryote lineages. PMID- 25831551 TI - Physical Activity Predicts Higher Physical Function in Older Adults: The Osteoarthritis Initiative. AB - OBJECTIVES: Physical activity reduces mobility impairments in elders. We examined the association of physical activity on risk of subjective and objective physical function in adults with and at risk for osteoarthritis (OA). METHODS: Adults aged >= 60 years from the longitudinal Osteoarthritis Initiative, a prospective observational study of knee OA, were classified by sex-specific quartiles of Physical Activity Score for the Elderly scores. Using linear mixed models, we assessed 6-year data on self-reported health, gait speed, Late-Life Function and Disability Index (LLFDI) and chair stand. RESULTS: Of 2252 subjects, mean age ranged from 66 to 70 years. Within each quartile, physical component (PCS) of the Short Form-12 and gait speed decreased from baseline to follow-up in both sexes (all P < .001), yet the overall changes across PASE quartiles between these 2 time points were no different (P = .40 and .69, males and females, respectively). Decline in PCS occurred in the younger age group, but rates of change between quartiles over time were no different in any outcomes in either sex. LLFDI scores declined in the 70+ age group. Adjusting for knee extensor strength reduced the strength of association. CONCLUSIONS: Higher physical activity is associated with maintained physical function and is mediated by muscle strength, highlighting the importance of encouraging physical activity in older adults with and at risk for OA. PMID- 25831552 TI - Using Shared Treadmill Workstations to Promote Less Time Spent in Daily Low Intensity Physical Activities: A Pilot Study. AB - OBJECTIVE: Our objective was to test the feasibility of sharing treadmill workstations among office workers to reduce time spent at low intensity and explore changes in health outcomes after a 3-month intervention. METHODS: Twenty two office workers were asked to walk 2 hours per shift on a shared treadmill workstation for 3 months. Physical activity levels (ie, low, light, moderate, and vigorous), health-related measures (eg, sleep, blood pressure), treadmill usage information, and questions regarding participants' expectation and experiences were collected. RESULTS: Physical activity time at low intensity during workdays was reduced by 20.1% (P = .007) in the 71% of participants completing the study. Participants were 70% confident that they would keep using the treadmill workstations. Interestingly, systolic blood pressure, diastolic blood pressure, and sleep quality scores were significantly improved (P < .05). CONCLUSIONS: The use of such equipment to replace a few hours of sitting is feasible and might offer important health benefits. PMID- 25831553 TI - Impact of Policies on Physical Activity and Screen Time Practices in 50 Child Care Centers in North Carolina. AB - BACKGROUND: This study assessed physical activity and screen time policies in child-care centers and their associations with physical activity and screen time practices and preschool children's (3-5 years old) physical activity. METHODS: Data were from 50 child-care centers in North Carolina. Center directors reported on the presence/absence of written policies. Trained research assistants observed physical activity and screen time practices in at least 1 preschool classroom across 3 to 4 days. Children (N = 544) wore accelerometers to provide an objective measure of physical activity. RESULTS: Physical activity and screen time policies varied across centers. Observational data showed 82.7 min/d of active play opportunities were provided to children. Screen time provided did not exceed 30 min/d/child at 98% of centers. Accelerometer data showed children spent 38 min/d in moderate-to-vigorous physical activity and 206 min/d in sedentary activity. Policies about staff supervision of media use were negatively associated with screen time (P < .05). Contrary to expectation, policies about physical activity were associated with less time in physical activity. CONCLUSIONS: Clear strategies are needed for translating physical activity policies to practice. Further research is needed to evaluate the quality of physical activity policies, their impact on practice, and ease of operationalization. PMID- 25831554 TI - Association Between Television Viewing and Physical Activity in 10-Year-Old Brazilian Children. AB - BACKGROUND: Studies have found an association between television (TV) viewing and physical activity levels. The purpose of this study was to examine the association between TV viewing and physical activity in 10-year-old Brazilian children. METHODS: The sample consisted of 485 children. Self-reported TV viewing on weekdays and weekends was assessed by questionnaire. An Actigraph GT3X+ accelerometer was used to monitor the range of physical activity intensities (including moderate-to-vigorous physical activity; MVPA), sedentary behavior (SB) and steps/day over 7 days. RESULTS: Daily MVPA was highest among children viewing TV <1 hour/day (69 min) compared with children viewing 1 to 2 hours/day (61 min), 3 to 4 hours/day (55 min) and >= 5 hours/day (59 min) on weekdays (P = .0015). Differences in MVPA were not observed across TV categories on weekends. The prevalence of reaching 60 min/day of MVPA and 12,000 steps/day on weekdays was significantly greater in children viewing <= 2 hours/day (51.7% and 23.5%, respectively) compared with those viewing > 2 hours/day (38.6%, P = .0058; and 15.1%, P = .0291, respectively). There was no difference in SB across TV viewing categories. CONCLUSION: Time spent in MVPA and the frequency of meeting MVPA guidelines were significantly higher among children viewing <= 2 hours/day of TV on weekdays compared with those viewing more. PMID- 25831555 TI - Measurement Considerations of Peak Stepping Cadence Measures Using National Health and Nutrition Examination Survey 2005-2006. AB - BACKGROUND: This study examined the optimal measurement conditions to obtain reliable peak cadence measures using the accelerometer-determined step data from the National Health and Nutrition Examination Survey 2005-2006. METHODS: A total of 1282 adults (> 17 years) who provided valid accelerometer data for 7 consecutive days were included. The peak 1- and 30-minute cadences were extracted. The sources of variance in peak stepping cadences were estimated using Generalizability theory analysis. A simulation analysis was conducted to examine the effect of the inclusion of weekend days. The optimal number of monitoring days to achieve 80% reliability for peak stepping cadences were estimated. RESULTS: Intraindividual variability was the largest variance component of peak cadences for young and middle-aged adults aged < 60 years (50.55%-59.24%) compared with older adults aged >= 60 years (31.62%-41.72%). In general, the minimum of 7 and 5 days of monitoring were required for peak 1- and 30-minute cadences among young and middle-aged adults, respectively, whereas 3 days of monitoring was sufficient for older adults to achieve the desired reliability (0.80). The inclusion of weekend days in the monitoring frame may not be practically important. CONCLUSIONS: The findings could be applied in future research as the reference measurement conditions for peak cadences. PMID- 25831544 TI - Evidence for indigenous nitrogen in sedimentary and aeolian deposits from the Curiosity rover investigations at Gale crater, Mars. AB - The Sample Analysis at Mars (SAM) investigation on the Mars Science Laboratory (MSL) Curiosity rover has detected oxidized nitrogen-bearing compounds during pyrolysis of scooped aeolian sediments and drilled sedimentary deposits within Gale crater. Total N concentrations ranged from 20 to 250 nmol N per sample. After subtraction of known N sources in SAM, our results support the equivalent of 110-300 ppm of nitrate in the Rocknest (RN) aeolian samples, and 70-260 and 330-1,100 ppm nitrate in John Klein (JK) and Cumberland (CB) mudstone deposits, respectively. Discovery of indigenous martian nitrogen in Mars surface materials has important implications for habitability and, specifically, for the potential evolution of a nitrogen cycle at some point in martian history. The detection of nitrate in both wind-drifted fines (RN) and in mudstone (JK, CB) is likely a result of N2 fixation to nitrate generated by thermal shock from impact or volcanic plume lightning on ancient Mars. Fixed nitrogen could have facilitated the development of a primitive nitrogen cycle on the surface of ancient Mars, potentially providing a biochemically accessible source of nitrogen. PMID- 25831556 TI - Individual, Social, and Neighborhood Associations With Sitting Time Among Veterans. AB - BACKGROUND: Sedentary behavior is an increasingly recognized health risk factor, independent of physical activity. Although several correlates of sedentary behavior are known, little research has identified them among U.S. veterans, a population that faces disproportionate chronic disease burden. METHODS: A survey was mailed to 1997 randomly selected veterans at a large urban Veterans Affairs medical center in 2012 and remailed in 2013 to nonresponders, resulting in a 40% response rate. We examined individual-, social-, and neighborhood-level factors in association with self-reported sitting time. Factors correlated with sitting time at P < .05 were included in a multiple linear regression model. RESULTS: In the multivariate model, higher depression (B = 7.8), body mass index (B = 5.1), functional impairment (B = 4.2), and self-rated health (B = 68.5) were significantly associated with higher sitting time, and leisure time physical activity (B = -0.10) and being employed (B = -71.3) were significantly associated with lower sitting time. CONCLUSIONS: Individual-level, but not social- and neighborhood-level, variables were associated with sitting time in this population. This study identified individual-level targets for reducing sitting time and improving overall health among veterans. PMID- 25831557 TI - Erratum for "Femtosecond Laser-Assisted Keyhole Endokeratophakia: Correction of Hyperopia by Implantation of an Allogeneic Lenticule Obtained by SMILE From a Myopic Donor". PMID- 25831558 TI - Erratum for "Outcomes of Small Incision Lenticule Extraction (SMILE) in Low Myopia". PMID- 25831559 TI - Erratum for "JRS Standard for Reporting Astigmatism Outcomes of Refractive Surgery". PMID- 25831560 TI - Efficiency enhancement in polymer light-emitting diodes via embedded indium-tin oxide nanorods. AB - Indium-tin-oxide (ITO) nanorods were fabricated in 10 min from commercially available ITO substrate using wet chemical etching method. The optical properties of the ITO nanorods were investigated using transmission spectroscopy and dark field optical microscopy. The transmittance and light-scattering characteristics of the ITO nanorods were better than those of ITO film. The ITO nanorod layer was further used as a transparent anode in polymer light-emitting diodes (PLEDs). The brightness and current efficiency of the PLED with the ITO nanorod layer were enhanced. This performance enhancement can be attributed to the excellent optical and electrical properties of the ITO nanorod layer. PMID- 25831561 TI - Safe use of health information technology. PMID- 25831562 TI - Proceedings of the 14th Bergmeyer Conference, held from 3-5 March 2014, Eibsee, Germany. PMID- 25831563 TI - Proceedings of the XIIth Oxford Conference, August 17-20, 2012, Almelo, The Netherlands. PMID- 25831564 TI - [Future pespectives for hepatology: still a long way to go]. PMID- 25831565 TI - [The advances on the treatment of chronic hepatitis B: an update of 2014]. PMID- 25831566 TI - [Advances in clinical research of fatty liver disease during 2014]. PMID- 25831567 TI - [Report of the 2nd international conference of autoimmune liver diseases]. PMID- 25831568 TI - [Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures]. PMID- 25831569 TI - [Deactivation mechanisms of hepatic stellate cells and their implications for anti-hepatic fibrosis therapy]. PMID- 25831570 TI - Causes of mortality of captive Arabian gazelles (Gazella Arabica) at King Khalid Wildlife Research Centre, Kingdom of Saudi Arabia, from 1988 to 2011. AB - We investigated the causes of mortality of the Arabian gazelle (Gazella arabica) based on the necropsy records of 1218 captive animals at King Khalid Wildlife Research Centre, Saudi Arabia, from 1988 to 2011. The largest number of deaths was attributed to trauma (391, 32.1%). Trauma was subdivided into the following three categories: collisions with fences (144, 11.8%); predator activity (91, 7.5%), and exhibit-mate aggression (156, 12.8%). Respiratory infection was another important cause of mortality, accounting for 186 (15.3%) deaths. Respiratory infection was more prevalent during the winter season (November to March). Other causes of death included gastrointestinal diseases, such as clostridiosis and salmonellosis (108, 8.9%). Maternal neglect (104, 8.5%), chronic renal fibrosis (34, 2.8%), and stress-related pathologies (35, 2.9%), in particular, capture myopathy, were also important causes of mortality. Here, the importance of these findings for improvement of the captive management of this vulnerable Arabian species is discussed, and for the first time, salmonellosis in Arabian gazelles is reported. PMID- 25831571 TI - Clinical investigation into feed-related hypervitaminosis D in a captive flock of budgerigars (Melopsittacus undulatus): morbidity, mortalities, and pathologic lesions. AB - The Blank Park Zoo began suffering mortalities in the spring of 2012 within a flock of 229 captive budgerigars (Melopsittacus undulatus) housed in an interactive public-feeding aviary. Clinical signs in affected birds included weakness, posterior paresis, inability to fly, or acute death. Gross and microscopic lesions were not initially apparent in acutely affected deceased birds. Many birds had evidence of trauma, which is now hypothesized to have been related to the birds' weakness. Investigation into the cause(s) of morbidity and mortality were complicated by the opening of a new interactive enclosure. For this reason, environmental conditions and husbandry protocols were heavily scrutinized. Microscopic examination of dead budgies later in the course of the investigation revealed mineralization of soft tissues consistent with hypervitaminosis D. Pooled serum analysis of deceased birds identified elevated vitamin D3 levels. Vitamin D3 analysis was performed on the feed sticks offered by the public and the formulated maintenance diet fed to the flock. This analysis detected elevated levels of vitamin D3 that were 22.5-times the manufacturer's labeled content in the formulated diet. These findings contributed to a manufacturer recall of more than 100 formulated diets fed to a wide variety of domestic and captive wild animal species throughout the United States and internationally. This case report discusses the complexities of determining the etiology of a toxic event in a zoologic institution. PMID- 25831572 TI - Hydrocoelom and lymphedema in dendrobatid frogs at National Aquarium, Baltimore: 2003-2011. AB - Hydrocoelom and lymphedema are common in amphibians. In the family Dendrobatidae at the National Aquarium, Baltimore, prevalence was 3.19% from 2005 to 2011. Complete review of all cases in dendrobatids from 01 January 2003 to 01 June 2011 at the National Aquarium identified annual incidence rate, associated signs, diagnostic findings, therapeutics, and outcomes using medical record review. Associated etiologies were assessed via available necropsy and histopathology reports. Hydrocoelom was defined as coelomic distention with fluid; lymphedema was defined as fluid accumulation in the lymph spaces. These two syndromes could occur concurrently, and no association between case success (36.5% overall) or etiology was found to contrast hydrocoelom and lymphedema. Species susceptibility varied, with increased prevalence and incidence rate in Adelphobates castaneoticus, Dendrobates auratus, and Phyllobates spp. D. auratus also had reduced case success overall (26.0%). Females experienced hydrocoelom and/or lymphedema at an attack rate more than three times that of males. Fluid aspiration for culture was the most predictive antemortem diagnostic to find infectious etiologies, but antemortem diagnostics were largely noncontributory in identifying other causes of fluid accumulation. Enrofloxacin treatment increased case success more than fivefold when compared to those not treated and was the only treatment positively associated with case success. Infectious etiology, renal disease, and gastrointestinal disease, including parasitism, were seen commonly on postmortem evaluation of cases. These findings underscore the importance of the ability to individually track and treat cases, with fluid culture and initiation of enrofloxacin therapy (10 mg/kg p.o.q. 24 hr) seen as the best first steps after presentation with hydrocoelom or lymphedema. PMID- 25831573 TI - Evaluation of captive gibbons (Hylobates spp., Nomascus spp., Symphalangus spp.) in North American Zoological Institutions for Gibbon Ape Leukemia Virus (GALV). AB - This study evaluated 79 captive gibbons (Hylobates, Nomascus, and Symphalangus spp.) within 30 North American zoological institutions for evidence of exposure to and possible infection with gibbon ape leukemia virus (GALV). Enzyme-linked immunosorbent assays (ELISAs) on gibbon serum samples revealed the presence of antibodies against GALV antigens in 28% of animals, indicating previous exposure or possibly protective immunity to GALV. Virus detection in gibbon blood or serum using polymerase chain reaction (PCR) or co-culture of gibbon peripheral blood mononuclear cells with human cells was negative for all samples submitted. The majority (19/27, 70%) of animals with reported health conditions were clinically healthy at the time of sample collection. Historically accrued clinical data were used to assess association of diseases in gibbons antibody positive for GALV. The results suggest captive gibbons could mount an immune response to GALV and show no evidence of infection. There was no association with neoplastic conditions in seropositive animals. The potential role of gibbons as a reservoir for GALV and the role of GALV as an epizoonotic-zoonotic agent or as a contributor to gibbon ape morbidity and mortality are not substantiated by the study findings. PMID- 25831574 TI - Radiographic reference limits for cardiac width of budgerigars (Melopsittacus undulatus). AB - Primary and secondary cardiovascular diseases are not uncommon in birds. Although radiologic standards for heart width have been developed for mammals, they are still not available for many avian species. The purpose of this study was to establish normal reference values for cardiac size in budgerigar (Melopsittacus undulatus), one of the most popular pet bird species all over the world. After clinical and radiographic (lateral and ventrodorsal views) evaluations, 27 adult, clinically healthy budgerigars (10 females and 17 males) were included in this study. High-quality ventrodorsal and lateral radiographic projections were obtained. The cardiac and thoracic width, distance between third and fourth ribs, synsacrum width, coracoid width, and the distance between clavicle bones were measured on ventrodorsal radiographs. The ratio between cardiac width and other mentioned indices was calculated. Correlation of each anatomical index with the cardiac width was evaluated by linear regression model. Sex and weight were included in all models. Mean + SD of cardiac width was 10.8 +/- 0.6 mm, with lower and upper limits of 9.5 and 12.0 mm. The results showed a significant correlation between the cardiac width and the thoracic width (R2 = 0.28; P = 0.005). There were no significant associations between weight, sex, and the heart width. The values and ratios obtained in this study can be used as a reference of normal cardiac size of budgerigar in radiology for detection of cardiomegaly in this bird. PMID- 25831575 TI - Health assessment of free-living eastern box turtles (Terrapene carolina carolina) in and around the Maryland Zoo in Baltimore 1996-2011. AB - Health data for free-living eastern box turtles (Terrapene carolina carolina) at the Maryland Zoo in Baltimore were analyzed. One hundred and eighteen turtles were captured on or near zoo grounds over the course of 15 yr (1996-2011), with recapture of many individuals leading to 208 total evaluations. Of the 118 individuals, 61 were male, 50 were female, and 7 were of undetermined sex. Of the 208 captures, 188 were healthy, and 20 were sick or injured. Complete health evaluations were performed on 30 turtles with physical examination records, complete blood counts (CBCs), and plasma biochemistry profiles. Eight animals were sampled more than once, yielding 40 total samples for complete health evaluations of these 30 individuals. The 40 samples were divided into healthy (N=29) and sick (N=11) groups based on clinical findings on physical examination. Samples from healthy animals were further divided into male (N=17) and female (N= 12) groups. CBC and biochemistry profile parameters were compared between sick and healthy groups and between healthy males and females. Sick turtles had lower albumin, globulin, total protein (TP), calcium, phosphorous, sodium, and potassium than healthy animals. Sick turtles also had higher heterophil to lymphocyte ratios. Healthy female turtles had higher leukocyte count, eosinophil count, total solids, TP, globulin, cholesterol, calcium, and phosphorous than healthy males. Banked plasma from all 40 samples was tested for antibodies to Mycoplasma agassizii and Mycoplasma testudineum via enzyme-linked immunosorbent assay. One sample from a clinically healthy female was antibody positive for M. agassizii; none were positive for M. testudineum. This study provides descriptive health data for eastern box turtles and CBC and biochemistry profile information for T. carolina carolina at and near the Maryland Zoo in Baltimore. It also reports low serologic evidence of exposure to mycoplasmosis. PMID- 25831576 TI - Pharmacokinetics of a single subcutaneous dose of sustained release buprenorphine in northern elephant seals (Mirounga angustirostris). AB - Information regarding analgesics in pinnipeds is limited. This study aimed to establish the pharmacokinetic parameters of a single subcutaneous dose of sustained release buprenorphine (Buprenorphine SR) in juvenile northern elephant seals (Mirounga angustirostris) with regard to its potential to provide long lasting analgesia that requires infrequent dosing. Seals (n=26) were administered a single dose of sustained release buprenorphine at 0.12 mg/kg s.c. Blood samples were collected from the extradural intervertebral vein at 0 hr and at three or four of the following time points: 0.5, 1, 2, 6, 12, 24, 36, 48, 60, 96, 120, and 144 hr. Seals were examined daily for systemic and local adverse reactions. Plasma was analyzed by liquid chromatography tandem-mass spectrometry for buprenorphine and norbuprenorphine concentrations. A noncompartmental analysis for pharmacokinetic parameters was calculated using standard methods and equations. An average maximum concentration of 1.21 ng/ml (0.3-2.9 ng/ml) was detected 12 hr postadministration. Concentrations were quantifiable up to 144 hr postadministration but were below those expected to provide analgesia in some other species. No systemic adverse effects were noted in healthy seals receiving sustained release buprenorphine. Cellulitis or abscesses at the injection site were observed in 6/26 (23%) seals between 24 and 168 hr postadministration. Adverse local effects suggest that this drug should be used with caution in northern elephant seals. PMID- 25831577 TI - Isolation and genotypic characterization of Trueperella (Arcanobacterium) pyogenes recovered from active cranial abscess infections of male white-tailed deer (Odocoileus virginianus). AB - Trueperella (Arcanobacterium) pyogenes is a causative agent of suppurative infections in domestic and wild animals. In some populations of captive or free ranging white-tailed deer (Odocoileus virginianus), cranial abscess disease is an important source of mortality in adult males. Although the pathogenesis of this disease is poorly understood, T. pyogenes has been isolated from active infections with other opportunistic bacteria. In this study, bacteria associated with cranial abscess infections were identified, the prevalence of T. pyogenes associated with these infections was determined, and the presence of known virulence determinants in T. pyogenes isolates was ascertained. Using routine biochemical techniques seven bacterial species were identified from 65 samples taken from active cranial abscess infections of 65 male white-tailed deer. Trueperellapyogenes was recovered from 46 samples; in 32 samples it was the only bacterium species detected. Staphylococcus aureus was detected in 26 samples. From these samples, the presence of known and putative virulence genes of T. pyogenes--plo, nanH, nanP, cbpA, fimA, fimC, fimE, and fimG--was examined by conventional polymerase chain reaction. All T. pyogenes isolates were positive for the pyolysin genes plo, nanP, and fimA. Furthermore, nanH, fimA, fimC, and fimE were detected in over 70% of isolates. Of the isolates tested, 48% had genotypes containing all virulence genes except cbpA. The suggestive virulence potential of all isolates, coupled with the large number of pure cultures obtained, implies that T. pyogenes is a causative agent of cranial abscess disease. PMID- 25831578 TI - Hematologic and serum biochemical parameters of apparently healthy rescued formosan pangolins (Manis pentadactyla pentadactyla). AB - Natural habitats of pangolins are rapidly deteriorating because of extensive farming, logging, and human construction activities. In addition, the illegal trading of pangolins substantially accelerated the decline of the pangolins' population in southeastern Asia. The maintenance of confiscated pangolins in rescue centers is currently a daunting task for veterinarians and conservation biologists. There is limited information in the literature about the reference values regarding the physiology of pangolins. The purpose of this study is to establish reliable hematologic and serum biochemical reference values for the Formosan pangolin (Manis pentadactyla pentadactyla). Blood samples were collected from 51 apparently healthy pangolins from a population of 117 rescued pangolins at the Taipei Zoo. Sex-related differences were observed in platelet count, alanine aminotransferase level, mean corpuscular hemoglobin concentration, and total protein level. Age-related differences were also noted; juveniles have significantly higher platelet counts and alkaline phosphatase levels than their adult counter parts. The hematologic and serum biochemical reference values for the Formosan pangolin presented in this study can be applied in the medical care of this important species during rescue attempts. It is the first systematic report of blood parameters of apparently healthy pangolins and provides a basis for future investigation of this species. The reference values reported in this study may also be applicable to other pangolin species in the genus Manis. PMID- 25831579 TI - Diagnosis and management of tuberculosis (Mycobacterium tuberculosis) in an Asian elephant (Elephas maximus) with a newborn calf. AB - In 2006, five Asian elephants (Elephas maximus) were imported to Taronga Zoo, Australia, from Thailand. Pre-import and initial postarrival tuberculosis screening was performed by trunk wash (TW) culture and was negative for Mycobacterium tuberculosis. In April 2009, the ElephantTB STAT-PAK (SP) assay was used to test the elephants. A 15.5-yr-old pregnant cow was reactive. TW frequency for this cow was increased from annually to quarterly. TW cultures remained negative on all other elephants. In February 2010, the Dual Path Platform (DPP) VetTB assay was used for the first time, and the SP-reactive cow also reacted on the DPP. A SP was run concurrently and was reactive. All other elephants were nonreactive on both assays. Treatment was not initiated due to concern about the effect of antituberculous drugs on the fetus. Quarterly TW cultures continued. The cow gave birth on 2 November 2010. A routine TW on 24 November 2010 was culture positive for M. tuberculosis. Although previous shedding could not be ruled out, reactivation of latent infection or exacerbation of subclinical disease due to parturition was suspected. Treatment with isoniazid, pyrazinamide, rifampicin, and ethambutol commenced. A 12-mo treatment course was completed within a 15-mo period. The isolate was susceptible to these drugs and genotyped as a Beijing strain. Stored serum samples from 2004 and 2006 were tested retrospectively and were reactive on SP and DPP. TW, SP, and DPP screening frequency increased to monthly for the positive cow on commencement of treatment in January 2011. Monthly serum biochemistry indicated drug-induced hepatitis. Therapeutic drug monitoring was conducted to ensure therapeutic levels were achieved. The infant calf was reactive on DPP, but TW culture negative, and was not treated. Serial DPP results for the cow and calf during and after treatment indicated that the antibody levels were declining, suggesting a favorable response to therapy in the dam, and that the origin of the antibodies in the calf were maternal, rather than a response to infection. PMID- 25831580 TI - Successful management of hypertrophic cardiomyopathy in a Matschie's tree kangaroo (Dendrolagus matschiei). AB - A 3-yr-old, intact male Matschie's tree kangaroo (Dendrolagus matschiei) was examined for a 1-wk history of intermittent lethargy and tachypnea. An echocardiogram revealed concentric hypertrophy of the left ventricular free wall and interventricular septum. These findings were compared to measurements from healthy Matschie's tree kangaroos, supporting a diagnosis of hypertrophic cardiomyopathy. At the time of publication, the patient has been managed for over 11.5 yr, using a combination of enalapril, furosemide, diltiazem, and diet modifications. Hypertrophic cardiomyopathy should be considered as a differential diagnosis in tree kangaroos exhibiting signs of cardiovascular or respiratory distress. This case represents the first report of antemortem diagnosis and successful management of hypertrophic cardiomyopathy in a Matschie's tree kangaroo. PMID- 25831582 TI - Cystic urolithiasis in captive waxy monkey frogs (Phyllomedusa sauvagii). AB - The waxy monkey frog (Phyllomedusa sauvagii) is an arboreal amphibian native to arid regions of South America, and it has developed behavioral and physiologic adaptations to permit survival in dry environments. These adaptations include a uricotelic nitrogen metabolism and unique cutaneous lipid excretions to prevent evaporative water loss. Uroliths are a rare finding in amphibians. Six adult, presumed wild-caught waxy monkey frogs housed in a museum animal collection were diagnosed with cystic urolithiasis over a 7-yr period, and a single animal was diagnosed with four recurrent cases. Six cases were identified incidentally at routine physical or postmortem examination and four cases were identified during veterinary evaluation for coelomic distension, lethargy, anorexia, and increased soaking behavior. Calculi were surgically removed from three frogs via cystotomy, and a single frog underwent three cystotomies and two cloacotomies for recurrent urolithiasis. Two frogs died within the 24-hr postoperative period. Two representative calculi from a single frog were submitted for component analysis and found to consist of 100% ammonium urate. In the present report, cystic calculi are proposed to be the result of a high-protein diet based on a single invertebrate source, coupled with uricotelism, dehydration, increased cutaneous water loss, body temperature fluctuations facilitating supersaturation of urine, and subsequent accumulation and precipitation of urogenous wastes within the urinary bladder. Surgical cystotomy represents a short-term treatment strategy for this condition. Preventative measures, such as supplying a diversified and balanced diet in addition to environmental manipulation aimed at promoting adequate hydration, are anticipated to be more-rewarding management tools for cystic urolithiasis in the waxy monkey frog. PMID- 25831581 TI - Potential for serodiagnosis of tuberculosis in black rhinoceros (Diceros bicornis). AB - A case of fatal Mycobacterium tuberculosis infection was diagnosed postmortem in a captive 33-yr-old male black rhinoceros (Diceros bicornis) after a nonspecific illness in April 2013. Retrospective testing of sera from this individual revealed that it had been seroreactive by ElephantTB STAT-PAK, dual-path platform VetTB, and multi-antigen print immunoassay for over 12 yr prior to death. Although samples collected at the time of intradermal tuberculin test performed in October 2000 were nonreactive in all three serologic assays, the animal appeared to seroconvert approximately 2.5 wk after the skin test administration. The antibody response remained detectable for the duration of the animal's life (12+ yr), indicating ongoing immunologic stimulation. The current case report supports the use of serologic assays for diagnosis of TB in black rhinoceros and may provide information for earlier detection. However, further research is needed to develop tools for recognition of mycobacterial infections in rhinoceros. PMID- 25831583 TI - Uropygial gland squamous cell carcinoma in chinstrap (Pygoscelis antarcticus) and gentoo (Pygoscelis papua) penguins at the Wildlife Conservation Society's Central Park Zoo. AB - Uropygial, or preen, glands are found in a variety of avian species including penguins. These glands have a multitude of functions and can develop a variety of conditions including impaction, rupture, adenitis, squamous metaplasia, and neoplasia of various types, with squamous cell carcinoma the most commonly reported. A case series of uropygial gland squamous cell carcinoma in five penguins at the Wildlife Conservation Society's Central Park Zoo is described. Most birds were aged (>10 yr) with a history of chronic, recurrent uropygial gland problems including impaction, rupture, abscess formation, or a combination of conditions. Before and after neoplasia diagnosis, these cases were managed conservatively, and palliative care was provided. Because many of these cases were preceded by chronic inflammation, it is possible this inflammation predisposed the uropygial gland to neoplastic transformation, and more aggressive treatment early in the disease process may therefore be warranted. PMID- 25831584 TI - Clinical canine parvovirus type 2C infection in a group of Asian small-clawed otters (Aonyx cinerea). AB - Despite the occurrence of clinical disease in a wide range of carnivore hosts, only vague accounts of clinical canine parvovirus type 2 (CPV-2) in any otter species have been reported in the literature. Over the course of 25 days, nine Asian small-clawed otters (Aonyx cinerea) presented for evaluation of inappetence, lethargy, vomiting, and diarrhea. A diagnosis of canine parvovirus type 2c was made based on electron microscopy, polymerase chain reaction, and DNA sequencing of group fecal samples. Supportive care was provided based on individual clinical assessment and included subcutaneous crystalline fluid therapy, antiemetics, antibiotics, appetite stimulants, and a neuraminidase inhibitor. Five of the nine otters exhibited moderate to severe disease requiring treatment, and one case was fatal despite supportive efforts. In light of this case report, CPV-2 should be recognized as a potential cause of gastrointestinal disease in Asian small-clawed otters. PMID- 25831585 TI - Valvulopathy consistent with endocarditis in an Argentine boa (Boa constrictor occidentalis). AB - An Argentine boa (Boa constrictor occidentalis) of 5 yr 7 mo of age was presented for respiratory problems and regurgitation. Radiographs revealed evidence of cardiomegaly and pneumonia. Blood smear examination revealed the presence of intracytoplasmic inclusion bodies in peripheral lymphocytes, consistent with inclusion body disease. Cultures of a tracheal wash sample resulted in growth of Ochrobactrum intermedium and Pseudomonas putida. Echocardiographic examination revealed a large vegetative lesion on the right atrioventricular valve with valvular insufficiency, a mildly dilated right atrium, and pulmonary hypertension. Postmortem examination confirmed the presence of pneumonia and bacterial endocarditis with dystrophic mineralization of the right atrioventricular valve, associated with different bacteria than those cultured from the tracheal wash. The present case is the first report of endocarditis in a boa constrictor and contributes to the rare reports of cardiac disease in snakes. PMID- 25831586 TI - Disseminated Yersinia pseudotuberculosis infection in a paca (Cuniculus paca). AB - A 2-yr-old paca (Cuniculus paca) was presented for necropsy with a history of sudden death. GrosS examination revealed multifocal, transmural, well-demarcated, white, soft nodules scattered along the length of the small intestine. The liver also had similar nodules associated with the capsular and cut surface. Histologic evaluation of several organs, including the intestine, liver, lung, kidney, adrenal gland, and lymph nodes, was consistent with disseminated yersiniosis. In addition, aerobic bacterial culture of liver and lung tissue yielded heavy growth of Yersinia pseudotuberculosis. Yersinia pseudotuberculosis is a Gram-negative, enteric pathogen that can cause disease in a variety of terrestrial species including humans. Although systemic infection has been observed in rodent species, to our knowledge this is the first report of disseminated Y pseudotuberculosis in a paca. PMID- 25831587 TI - Focal bacterial meningitis following ascending bite wound infection leading to paraparesis in a captive California sea lion (Zalophus californianus). AB - Magnetic resonance imaging was performed on a 15-yr-old captive female California sea lion (Zalophus californianus) with a 2-wk history of progressive paraparesis and a 9-mo history of exudative skin lesion on the left thoracic wall. Magnetic resonance images showed a well-defined muscle infiltrating lesion ventrolateral to the seventh cervical to the third thoracic vertebra on the left side, which extended through the left intervertebral foramina C7 to T3 into the vertebral canal, causing spinal cord compression and displacement as well as inflammation of the spinal cord and nerves. This lesion surprisingly caused no forelimb deficits. Differential diagnoses included abscess formation or neoplasia. Pathologic examination revealed chronic focal purulent meningitis associated with widespread paraspinal fistulous inflammation originating from a chronic dermal ulcer. Mainly Escherichia coli var. haemolytica and Clostridium perfringens were identified as the underlying agents. PMID- 25831588 TI - Herpesvirus and calicivirus infection in a black-footed cat (Fels nigripes) family group following vaccination. AB - Preventive healthcare recommendations for zoo felids include vaccination against primary viral diseases that affect domestic felids. Although associated with a more-substantial immune response in their domestic counterparts, use of modified live virus vaccines (MLV) in nondomestic carnivores can result in vaccine-induced viral disease. This case report details a feline herpesvirus and calicivirus outbreak in two black-footed cat (Felis nigripes) kittens and their dam following use of an MLV in the kittens. Clinical signs included anorexia, nasal discharge, sneezing, and tachypnea. Patient history, clinical signs, real-time polymerase chain reaction results, and histopathologic evaluation of tissues confirmed the diagnosis. Although unable to definitively prove that the disease observed in these cases was caused by the MLV, there is strong temporal and circumstantial evidence that this was the case. This outbreak of feline upper respiratory infection following vaccination with a multivalent MLV resulted in significant morbidity and mortality, serving as an important reminder that recombinant or killed vaccines are the safest choice for use in nondomestic species, particularly in kittens. PMID- 25831589 TI - Analysis of a collagen II degradation protein C2C and a collagen II formation protein CP II in serum of Asian elephants (Elephas maximus). AB - Osteoarthritis is a major cause of chronic lameness in Asian elephants (Elephas maximus) in captivity worldwide. Radiology and other imaging technologies are of limited use in the early diagnosis of this condition in elephants. Collagen II is a major component of articular cartilage. The degradation and formation of collagen II can be monitored by the measurement of specific biomarkers in biologic fluids such as serum. It is possible that these biomarkers could also prove useful in identifying disease in elephants. In this study two commercially available immunoassays which measure a marker of collagen II degradation (C2C) and a marker of collagen II formation (CPII) were evaluated in Asian elephants. The ability of the assays to detect and measure C2C and CPII in the serum of Asian elephants was confirmed. Median serum concentration of C2C was 148 ng/L in nonlame elephants (n=33) and 91.2 ng/L in lame elephants (n=7). The difference was statistically significant (P=0.0002). Median serum concentration of CPII was 519.3 ng/L in nonlame elephants and 318.7 ng/L in lame elephants. The difference was also statistically significant (P=0.039). Whereas CPII concentrations in lame elephants mirrored findings from human and animal osteoarthritis studies, C2C concentrations did not. Further studies which evaluate these and other similar biomarkers are necessary to elucidate their usefulness in the diagnosis of osteoarthritis in proboscidae. PMID- 25831590 TI - Multifocal respiratory and vertebral mycobacteriosis in a red-tailed hawk (Buteo jamaicensis). AB - An adult, female, free-ranging red-tailed hawk (Buteo jamaicensis) was presented to a rehabilitation facility for an inability to stand. On examination, it displayed bilateral exaggeration of the pelvic limb reflexes with extensor muscle rigidity, intact superficial pain response, and positive withdrawal reflexes. A complete blood count identified moderate leukocytosis characterized by moderate heterophilia. No abnormalities were appreciable on radiographic evaluation. After initial improvement, it regressed and was euthanized 27 days after presentation. Necropsy and histologic investigation identified reduction in the diameter of the vertebral canal and spinal cord at cervical segments 8-9 with coalescing granulomas and intralesional acid-fast bacilli within the intertrabecular space, left side of the clavicular air sac, and cranial left lung. Bacterial culture and genetic sequencing from respiratory lesions identified Mycobacterium avium avium. Real time-polymerase chain reaction of paraffin-fixed spinal tissue tested positive for M. avium complex. Mycobacteriosis should be considered when peripheral neurologic deficits are present in raptors. PMID- 25831591 TI - Anesthetic management of a 4-month-old red fox (Vulpes vulpes) for orthopedic surgery. AB - A 4-mo-old red fox (Vulpes vulpes) was found recumbent after a vehicular accident. Radiology revealed several limb fractures and the fox underwent surgery after 24 hr of initial stabilization. Premedication consisted of dexmedetomidine and morphine. Anesthesia was induced with ketamine and midazolam and maintained with isoflurane. Lidocaine, bupivacaine, and morphine were administered epidurally and further analgesia was provided with meloxicam. The heart rate and respiratory rate of the fox remained stable during surgery and, except for a mild hypothermia, the recovery from anesthesia was uneventful. The postoperative pain scores were low and the animal was transported to a rehabilitation facility and eventually released to the wild. The low pain scores postoperatively should be attributed to the successful application of epidural anesthesia and analgesia. PMID- 25831592 TI - Milbemycin oxime (Interceptor) treatment of amphipod parasites (Hyperiidae) from several host jellyfish species. AB - Wild-caught crystal jellyfish (Aequorea victoria) arrived at the John G. Shedd Aquarium infested with hyperiid amphipods (Hyperia medusarum), which were inadvertently introduced into a system containing several jellyfish species. Affected systems were treated with milbemycin oxime (Interceptor tablets for dogs 51-100 lbs, Novartis Animal Health US, Inc., Greensboro, North Carolina 27408, USA), a treatment prescribed for red bug (Tegastes acroporanus) infestation in corals. Two treatments using one 25-mg aliquot of Interceptor per 10 gallons of tank water administered 6-7 days apart were completed. Overall, treatment to eradicate the parasite from the affected systems was successful. Further studies evaluating the tolerance of jellyfish to milbemycin oxime, particularly in small juvenile Eutonina indicans and Aurelia aurita, are warranted. Based on clinical observations, there were more negative effects associated with the treatment in the hydrozoans than in the scyphozoans. PMID- 25831593 TI - A successful transfusion in a tamandua (Tamandua tetradactyla) using both whole blood and blood replacement products. AB - A 10-yr-old tamandua (Tamandua tetradactyla) presented with severe lethargy and ataxia. Severe anemia (9% hematocrit) was diagnosed and ultimately resolved with the administration of a whole blood transfusion from conspecific and additional blood replacement products (Oxyglobin). This is the first described use of a whole blood transfusion in an edentate. PMID- 25831594 TI - Physical therapy as an adjunctive treatment for severe osteoarthritis in a Komodo dragon (Varanus komodoensis). AB - This case report describes a new physical therapy technique, specifically the Wolfe Kinetic Technique, as adjunctive therapy in the treatment of severe osteoarthritis in a 20-yr-old Komodo dragon (Varanus komodoensis). This animal was managed with oral analgesics for 3 yr with fair to minimal response over time. Due to worsening of lameness and mobility, physical therapy was initiated. Ten treatment sessions were administered at 1-wk intervals. Within 1 mo the Komodo dragon exhibited marked improvement in gait and function, increased responsiveness to his environment, and increased mobility which continued to improve over the subsequent sessions. Although outcomes could not be measured by standardized objective measures, this study provides a reference for treatment of future cases and a foundation for future research substantiating treatment practices in animal physical therapy. PMID- 25831595 TI - Ovariectomy due to a dermoid cyst in an orangutan (Pongo pygmaeus). AB - A large abdominal mass was identified during an elective preventative health examination in a 25-yr-old female hybrid orangutan (Pongo pygmaeus). Sonographically, the mass was fluid-filled and a presumptive diagnosis of a dermoid cyst or cystic teratoma of an ovary was made. Exploratory laparotomy, after assembly of a surgical team, confirmed that the 2.5-kg cystic mass was associated with the left ovary. Following ovariectomy, perioperative dissection of the mass revealed hair components, confirming the working diagnosis. Because the right ovary was slightly nodular and firmer than expected, and these germ cell tumors sometimes occur bilaterally, excision of the contralateral ovary was elected. Histopathology confirmed the left ovarian mass was a dermoid cyst; the right ovary contained a corpus hemorrhagicum but no evidence of neoplasia. Recovery was uneventful and the orangutan was prescribed hormone replacement therapy to mitigate potential problems associated with a chronic lack of estrogen and progesterone. This case report demonstrates the importance of elective examinations under anesthesia, even in well-trained great apes. PMID- 25831596 TI - Hypoadrenocorticism (Addison's disease) in a Hoffmann's two-toed sloth (Choloepus hoffmanni). AB - A 22-yr-old, captive-born, presumed female Hoffmann's two-toed sloth (Choloepus hoffmanni) presented in respiratory distress with severe dehydration and symptoms of hypotension. During treatment, dysphagia was noted and oral examination revealed enlarged palatine tonsils and mucosal plaques. Bloodwork showed a decreased sodium:potassium ratio, a low baseline cortisol, a decreased adrenocorticotropin response test, and a blunted aldosterone stimulation test. All values were compared to a healthy male Hoffmann's two-toed sloth at the same facility. Despite aggressive medical management and treatment for hypoadrenocorticism, the sloth was found deceased. Necropsy revealed abdominal effusion, multifocal plaques throughout the upper gastrointestinal tract, and testes. Histopathology showed marked adrenal cortical atrophy and intranuclear mucosal inclusions in the gastrointestinal tract; advanced molecular techniques did not uncover any viral etiologies. This is the first reported case of hypoadrenocorticism in a sloth. PMID- 25831597 TI - Obstructive cholelithiasis and cholecystitis in a kinkajou (Potos flavus). AB - A 14.5-yr-old female kinkajou (Potos flavus) was diagnosed with cholelithiasis after an episode of vomiting; diagnostics included biochemical analysis and abdominal ultrasound exam. Despite antimicrobial treatment, cholelithiasis led to cholecystitis. A cholecystotomy was performed to remove choleliths and inspissated bile. Morphological and spectroscopic properties of the choleliths were similar to those of gallstones from the brown pigment family and Streptococcus sp. and Escherichia coli were isolated from the bile. Biliary tract infection is directly related to pathogenesis of brown pigment gallstones. Serial ultrasound exams revealed that cholecystitis developed secondary to the presence of gallstones in the biliary tree. Despite full recovery postsurgery, the patient died 15 mo later from gallbladder necrosis. Based on the progression of this case, a cholecystectomy would be preferred over a cholecystotomy in similar cases, and the efficacy of long-acting antibiotics may not be adequate in nontarget species. Gallstones and biliary tract infection are rarely described in small domestic carnivores, and this is the first reported case in a kinkajou. PMID- 25831598 TI - Tibial plateau leveling osteotomy in a cape clawless otter (Aonyx capensis) with cranial cruciate ligament ruptures. AB - A 13-yr-old female Cape clawless otter (Aonyx capensis) presented with an acute mild right pelvic limb lameness that progressed to a non-weight-bearing lameness. Diagnosis of a ruptured cranial cruciate ligament (CCL) was made based on positive cranial drawer during physical examination and was supported by radiographs. A surgical repair with a tibial plateau leveling osteotomy (TPLO) and bone anchor with an OrthoFiber suture was performed. The tibial plateau angle was reduced from 30 to 5 degrees. The otter returned to normal function after 12 wk of exercise restriction. Twelve months after surgery, the left CCL ruptured and a TPLO was performed. No complications developed after either surgery, and the otter had an excellent return to function. This is the first report of a cranial cruciate ligament rupture and TPLO procedure in a mustelid, supporting its application to noncanid and felid species. PMID- 25831599 TI - A randomized clinical trial evaluating gingivitis and plaque reduction of an oscillating-rotating power brush with a new brush head with angled bristles versus a marketed sonic brush with self-adjusting technology. AB - PURPOSE: To compare the efficacy of an oscillating-rotating power toothbrush with a novel brush head incorporating angled CrissCross bristles (Oral-B Pro 7000 SmartSeries and Oral-B CrossAction brush head) versus a marketed sonic toothbrush (Colgate ProClinical A1500 with the Triple Clean brush head) in the reduction of gingivitis and plaque over a 6-week period. METHODS: This was a single center, randomized, open label, examiner-blind, 2-treatment, parallel group study. Study participants who met the entrance criteria were enrolled in the study and randomly assigned to one of the two toothbrush groups. Study participants brushed with their assigned toothbrush and a marketed fluoride dentifrice for 2 minutes twice daily at home for 6 weeks. Gingivitis and plaque were evaluated at baseline and Week 6. Gingivitis was assessed using the Modified Gingival Index (MGI) and Gingival Bleeding Index (GBI) and plaque was assessed using the Rustogi Modified Navy Plaque Index (RMNPI). Data was analyzed using the ANCOVA with baseline as the covariate. RESULTS: In total, 130 study participants were randomized to treatment resulting in 64 study participants per group completing the study. Both brushes produced statistically significant (P < 0.001) reductions in gingivitis and plaque measures relative to baseline. The oscillating-rotating,brush with the novel brush head demonstrated statistically significantly (P < 0.05) greater reductions in all gingivitis measures, as well as whole mouth and interproximal plaque measures, compared to the sonic toothbrush. The benefit for the oscillating- rotating brush over the sonic brush was 21.3% for gingivitis, 35.7% for gingival bleeding, 34.7% for number of bleeding sites, 17.4% for whole mouth plaque, and 21.2% for interproximal plaque. There were no adverse events reported or observed for either brush. PMID- 25831600 TI - Comparative bioavailability and antimicrobial activity of cetylpyridinium chloride mouthrinses in vitro and in vivo. AB - PURPOSE: Commercialized cetylpyridinium chloride (CPC) mouthrinses were compared for antimicrobial substantivity/bioavailability in an in vitro disk retention assay (DRA) and clinical antimicrobial activity in vivo in the plaque glycolysis and regrowth method (PGRM). METHODS: Formulations compared in this testing included commercially available CPC mouthrinses: Crest Pro Health (CPH), (containing 700 ppm formulated CPC); Colgate Total Puerto Rico (CT450), (containing 450 ppm formulated CPC); Colgate Total US (CT750), (containing 750 ppm formulated CPC); and Scope Mouthwash (SCP), (containing 450 ppm formulated CPC). A water control (CTR) was included in one of the PGRM clinical trials. Two separate clinical PGRM studies employed a controlled, double-blind, randomized, crossover design where qualified adult PGRM panelists were supplied with acclimation NaF dentifrice for use throughout the trials. On treatment days, subjects sampled baseline plaque and then rinsed with assigned mouthrinse following morning toothbrushing. Treated plaque samples were collected 15 and 45 minutes after rinsing. Sampled plaques were vortexed, normalized for biomass and incubated under standard conditions to assess glycolysis. pH response of treated plaques in incubation buffers were compared to baseline untreated plaque values and an Area Under Curve (AUC) composite/aggregate analysis of glycolysis inhibition was used for treatment comparisons. A laboratory disk retention substantivity/bioavailability assay measured adsorption affinity of CPC in mouthrinse for anionic cellulose disks in vitro. RESULTS: Clinical PGRM studies showed significant differences in antibacterial clinical efficacy of commercialized mouthrinses. Combining clinical study results reveals rank ordered efficacy CPH > CT750 > SCP > CT450 > CTR. Comparison of DRA to PGRM glycolysis showed a linear relation highlighting correlation of CPC bioavailability to clinical antimicrobial performance of CPC mouthrinses. PMID- 25831601 TI - Post-cementation colorimetric evaluation of the interaction between the thickness of ceramic veneers and the shade of resin cement. AB - PURPOSE: To evaluate the color parameters (CIELab*) after the cementation of ceramic disks of different thicknesses onto a resin substrate using four different shades of resin cements, and determine the color difference (DeltaE) between the adhesively cemented disks and a 10 mm-thick A1 shade ceramic control (target color). METHODS: Ceramic disks, simulating laminate veneers, with thicknesses of 0.5, 0.7 and 1.0 mm (shade A1, IPS Classic) were fabricated (n = 40) and cemented with a dual-cured resin cement (Variolink II, shades A1, bleach, opaque and transparent) onto 120 2 mm-thick resin composite substrates (shade A3.5, Adoro). Each ceramic disk was photocured for 80 seconds. The determination of the CIELab* parameters of each ceramic-cement-substrate set was performed with a spectrophotometer. A 10 mm-thick A1 ceramic disk was used as a control. The results for the color difference (DeltaE) obtained from L*, a* and b* parameters were analyzed using ANOVA and Tukey's test (alpha = 0.05). RESULTS: The DeltaE values ranged from 2.46 (1.0 mm, opaque cement) to 12.11 (0.5 mm, A1 cement). The opaque cement showed the lower DeltaE values, followed by the bleach, transparent and A1 cements. With respect to the thickness of the ceramic, color differences between the target color and the group with 1.0 mm ceramic disks were smaller for all cement shades tested. Only the combination of 1.0 mm ceramic disks cemented with the opaque cement was able to mask the background color (DeltaE < 3.7). The color differences between the control and the specimens cemented with opaque resin cement were smaller in comparison with the bleach, transparent and A1 cements. PMID- 25831602 TI - Wear and surface roughness of silorane composites after pH cycling and toothbrushing abrasion. AB - PURPOSE: To evaluate the effects of toothbrushing abrasion associated with pH cycling on the surface roughness and wear of methacrylate- and silorane-based resin composites. METHODS: Microhybrid methacrylate-based (Filtek Z250), nanofilled methacrylate-based (Filtek Supreme Ultra) and microhybrid silorane based (Filtek LS) composites were selected for this investigation. For each composite, two groups (n = 10) of rectangular specimens were made. The initial roughness (Ra) of all of the groups was evaluated based on the average of three random tracings with a profilometer, and each specimen had half of its surface protected with two layers of nail varnish to serve as controls. Half of the specimens of each resin were submitted to pH cycling, while the other half were stored in deionized water for 14 days. Subsequently, 100,000 strokes of simulated toothbrushing were performed. Final roughness and wear were measured with the same profilometer, and the values were submitted to ANOVA, Student's t-test and Tukey's test (P < 0.05). RESULTS: The data revealed an increase in surface roughness for Filtek Z250 and Filtek Supreme Ultra after toothbrushing, while Filtek LS showed the opposite behavior. Methacrylate-based composites presented lower wear values [Z250 (4.19 +/- 1.73 MUm); Supreme Ultra (4.16 +/- 0.95 MUm)], while the silorane-based composite presented increased surface roughness (11.51 +/- 5.69 MUm), particularly when submitted to pH cycling (15.31 +/- 5.41 MUm). Despite the good properties of silorane-based composites, particularly its smooth surface roughness even after pH cycling and toothbrushing abrasion, this composite still presented increased wear, which is an important issue for the development of new resin compositions. PMID- 25831603 TI - Fluoride content in breast milk after the use of fluoridated food supplement. A randomized clinical trial. AB - PURPOSE: To evaluate if the intake of a fluoridated food supplement in breastfeeding mothers increases the fluoride concentration in breast milk. METHODS: A double-blind randomized placebo-controlled study was designed. Two groups of women were formed: a fluoride group (n = 112), using a non-sucrose food supplement containing fluoride (1,500 MUg/l for each dose) and a control group (n = 116), using a non-sucrose food supplement without fluoride content. The women were followed for 6 weeks. Samples of breast milk were collected and analyzed using an ion-specific electrode. RESULTS: 85 women in the fluoride group and 83 in the control group concluded the trial. Fluoride concentrations in the two groups were statistically significantly different (515 MUg/l in the fluoride and 476 MUg/l in the control group P= 0.04) at the end of the experimental period. In the fluoride group, a statistically significant increment in fluoride concentration during the experimental period was also observed (from 468 +/- 104 MUg/l to 515 +/- 105 MUg/l). The use of a non-sucrose food supplement containing fluoride resulted in a significant increment in fluoride concentration in breast milk. PMID- 25831605 TI - Effect of different application frequencies of CPP-ACP and fluoride dentifrice on demineralized enamel: a laboratory study. AB - PURPOSE: To evaluate the effect of different application frequencies of dentifrices containing CPP-ACP and fluoride on enamel demineralization inhibition using a pH cycling model. METHODS: A total of 120 enamel blocks obtained from permanent human third molars were divided into eight groups according to the treatment and number of times that the dentifrice slurry was applied (three or five times): Control--Dentifrice without Fluoride (CO3 and CO5); Fluoride Dentifrice (FD3 and FD5--commercial dentifrice 1100 ppm as NaF); MI Paste (MP3 and MP5--Recaldent) and MI Paste Plus (MPP3 and MPP5--Recaldent 900 ppm as NaF). The specimens were alternately soaked in a demineralizing solution for 6 hours and in a remineralizing solution for 18 hours for 5 days. The treatments were applied three or five times for 60 seconds after the de-remineralization period. The dentifrice slurries were prepared with deionized water, in a 1:3 proportion (wt%). Demineralized enamel changes were analyzed by surface microhardness (SMH) and 3D-profilometry. Data were analyzed by two-way and one-way ANOVA and Tukey's HSD post hoc test (alpha = 0.05). RESULTS: The percentage change of SMH (%SMH) was similar for all treatment groups except between MP5 < CO3 and CO5 (P < 0.05). The enamel samples treated with CCP-ACP topical paste showed smoother surfaces than those of control and fluoride dentifrice. PMID- 25831606 TI - Esthetic evaluation of different approaches to treat gingival recession associated with non-carious cervical lesion treatment: a 2-year follow-up. AB - PURPOSE: To evaluate the esthetic outcome of four different approaches to treat gingival recession, associated with non-carious cervical lesion (combined defects) and the possible roles of patient-related factors in this esthetic outcome. METHODS: 78 combined defects were previously treated by: coronally advanced flap (CAF), CAF plus cervical restoration using resin-modified glass ionomer material (CAF+R), connective tissue graft (CTG) and CTG+R. After a follow up of 2 years, esthetic evaluations were performed using a modification of the Root Coverage Esthetic Score (MRES) and Qualitative Cosmetic Evaluation (QCE). Additionally, regression analyses were performed to evaluate the influence of patient-related factors in the final esthetic outcome. RESULTS: The MRES showed that CAF and CTG had statistically significantly better results, when compared to the other groups (P < 0.05). Similarly, the QCE showed that CAF and CTG, along with CAF+R presented better results, and CTG+R showed the poorest esthetic outcome. Regression analyses showed that the overall gingival inflammation (full mouth bleeding index--FMBI) was negatively associated with CTG MRES score (P = 0.04 and R = -0.48). This means that the greater the FMBI during the study period, the lower the final esthetic score. PMID- 25831607 TI - [Transparency in medicine: what are the stakes?]. PMID- 25831604 TI - Mechanisms regulating the degradation of dentin matrices by endogenous dentin proteases and their role in dental adhesion. A review. AB - PURPOSE: This systematic review provides an overview of the different mechanisms proposed to regulate the degradation of dentin matrices by host-derived dentin proteases, particularly as it relates to their role in dental adhesion. Significant developments have taken place over the last few years that have contributed to a better understanding of all the factors affecting the durability of adhesive resin restorations. The complexity of dentin-resin interfaces mandates a thorough understanding of all the mechanical, physical and biochemical aspects that play a role in the formation of hybrid layers. The ionic and hydrophilic nature of current dental adhesives yields permeable, unstable hybrid layers susceptible to water sorption, hydrolytic degradation and resin leaching. The hydrolytic activity of host-derived proteases also contributes to the degradation of the resin-dentin bonds. Preservation of the collagen matrix is critical to the improvement of resin-dentin bond durability. Approaches to regulate collagenolytic activity of dentin proteases have been the subject of extensive research in the last few years. A shift has occurred from the use of proteases inhibitors to the use of collagen cross-linking agents. Data provided by 51 studies published in peer-reviewed journals between January 1999 and December 2013 were compiled in this systematic review. RESULTS: Appraisal of the data provided by the studies included in the present review yielded a summary of the mechanisms which have already proven to be clinically successful and those which need further investigation before new clinical protocols can be adopted. PMID- 25831608 TI - [2014 update in general internal medicine]. AB - This article comments 9 original publications from year 2014 of interest for the primary care physician in the outpatient setting. The impact of diet such as nut consumption on health outcomes and mortality is developped, and the importance of dietary changes while taking statins is reminded. Red flags in low back pain and their predictive value are re-evaluated. An association between benzodiazepine use and Alzheimer dementia seems probable. New treatments for alcohol abuse, restless legs syndrome and type 2 diabetes are discussed. Finally, beta-bloquers' effects on respiratory function in asthmatic patients are beeing reexamined. PMID- 25831609 TI - [2014 literature findings in internal general medicine]. AB - The usual treatment of venous ulcers may be associated with statins intake. Antibiotics have only marginal utility in acute bronchitis. The prescription of paracetamol seems to have no benefit in the treatment of acute lower back pain. The absence of antithrombotic prophylaxis for distal fractures of the lower limbs seems to be safe for patients' health. The treatment of atraumatic lesions of the rotator cuff in patients >55 years should remain conservative. Arthroscopic surgery of non-traumatic tear of the medial meniscus seems to have no benefit. The family environment seems to be a protective factor to the mental health of adolescents. Screening for colorectal cancer in patients >75 years would save lives. PMID- 25831610 TI - [What is new in 2014 for the specialist in hospital internal medicine? The point of view of university hospital chief residents]. AB - The year 2014 was rich in significant advances in all areas of internal medicine. Many of them have an impact on our daily practice and on the way we manage one problem or another. From the use of the ultrasound for the diagnosis of pneumonia to the choice of the site of venous access and the type of line, and the increasing complexity of choosing an oral anticoagulant agent, this selection offers to the readers a brief overview of the major advances. The chief residents in the Service of internal medicine of the Lausanne University hospital are pleased to share their readings. PMID- 25831611 TI - [Internal medicine in the hospital setting]. AB - Management of all pathologies, and in particular that of the most frequent ones, should whenever possible be based on robust evidence and arguments. New studies published this year enable rationalizing of screening in certain clinical situations, more adequate treatment of others, and open the way for novel and apparently very effective treatments. Whether it be the screening of carotid stenosis, the treatment of pericarditis, of heart failure, of chronic obstructive lung disease or spontaneous bacterial peritonitis, paradigm changes are conceivable. This selective review of the literature summarizes certain studies published this year. PMID- 25831612 TI - [Ten years of literature review in general internal medicine--a first assessment]. AB - A group of family physicians in an outpatient clinic in Switzerland prospectively followed scientific literature for ten years. What to remember among the numerous articles retrieved and which paper really changed our practice? If many readings are quickly forgotten, some of them marked our minds and changed our habits. This article is a summary of our efforts to keep the essential tools in clinical practice. PMID- 25831613 TI - [Does treatment improve prognosis of heart failure with preserved ejection fraction?]. AB - Heart failure with preserved ejection fraction (HF-PEF) represents half of all heart failure. Morbi-mortality for HF-PEF is similar to that of reduced ejection fraction HF (HF-REF). Diagnosis of HF-REF is difficult because of the lack of highly specific criteria. It is based on the presence of signs and symptoms of heart failure, associated with a preserved or moderately decreased left ventricular function, the absence of left ventricular dilatation, and the presence of relevant structural disease such as left ventricular hypertrophy. Despite the use of prognosis modifying drugs commonly used for HF-REF, no therapeutic strategy has been shown to reduce morbi-mortality of HF-PEF. Evidence based guidelines are limited. Management of HF-PEF therefore resides in treatment of high blood pressure and cardiac rate, that of comorbidities, and the use of diuretics in case of congestion. PMID- 25831614 TI - [ORL]. AB - This 2014 version of news in ENT--established by reading more than 10,000 abstracts published in 2014--will focuss this year on two main topics that are trendy: Robotic surgery in ENT, and e-cigarette. Of course, other subjects will be treated as well, in the format of guidelines, like for otitis externa, tinnitus, ear grommets, Bell's palsy, children's sinusitis, topical treatments in sinusitis, or dangers of radiation on kids. Some interesting mobile applications will be as well presented. PMID- 25831615 TI - [Medical scarcity: Valais canton rises to the task]. PMID- 25831616 TI - [Pulmonary embolism in the pregnant woman]. PMID- 25831618 TI - [Charlie Hebdo, Mohammed and the Jesuit priests: the price of a laugh]. PMID- 25831617 TI - [Author's response]. PMID- 25831619 TI - [Such a sky...]. PMID- 25831620 TI - [Vincent Lambert or a new European equation, to let die]. PMID- 25831621 TI - [Ten kilos less for now or for next year?]. PMID- 25831622 TI - [The latest information on the forefront of the campaign against tobacco]. PMID- 25831623 TI - [The Swiss champion prosthesis implantation]. PMID- 25831624 TI - [Is assisted suicide in prison possible in Switzerland?]. PMID- 25831625 TI - [The new role of physicians]. PMID- 25831626 TI - New governor off to good start. PMID- 25831627 TI - Good nurses are heroes. PMID- 25831628 TI - Intensive care gets a boost in several Arkansas hospitals. Baptist Health's eICU care services adding to care for critical care patients. PMID- 25831629 TI - Hazardous alcohol use and alcohol use disorder. PMID- 25831630 TI - The Arkansas Hand Trauma Telemedicine System at work. PMID- 25831631 TI - Diffuse large B-cell lymphoma of the colon--a rare presentation. AB - Patients with diffuse large B-cell lymphoma (DLBCL) can present with nodal or extra-nodal disease. The most common extra-nodal site is the gastrointestinal tract, including the stomach or illeo-cecal region. Primary colonic diffuse large B-cell lymphoma (DLBCL) is uncommon and presents a unique diagnostic and therapeutic challenge. We present a case of a middle-aged man who presented with abdominal pain and pathological weight loss and underwent hemi-colectomy for suspected adenocarcinoma. Final pathology revealed DLBCL, completely changing the prognosis and subsequent management. We will discuss some of the aspects of this rare presentation and shed light on therapeutic strategies currently available. PMID- 25831632 TI - A diagnostic dilemma of new onset ascites: think beyond the liver. PMID- 25831633 TI - Non communicable diseases in Pakistan: burden, challenges and way forward for health care authorities. PMID- 25831634 TI - Nutritional assessment of adolescent girls living in Cherah union council. AB - OBJECTIVE: To assess the nutritional status of adolescent girls living in the Cherah union council, Islamabad and to determine the association between dietary intake and iron deficiency anaemia. METHODS: It was a cross sectional survey conducted in union council Cherah of Islamabad. Study participants comprised of 150 adolescent (11-19 years of age) girls selected by simple random sampling living in that area during the study period. RESULTS: It was observed that 7% of the adolescents were overweight, 46% were underweight and 1% were obese. Minimum weight of the participants was 23 kg, minimum haemoglobin was 5.6 g/dl, 67% had mild anaemia, 9% had moderate, 1% severe and 48% had normal haemoglobin. Association of food groups labeled as in USDA guideline with the haemoglobin level, was statistically insignificant except in the case of beef and liver intake (meat group) showing association of beef liver intake with haemoglobin level. CONCLUSION: Adolescent girls living in the union council were under weight and had mild to moderate anaemia. There was a significant association of the intake of meat with the haemoglobin level. PMID- 25831635 TI - Body mass index or body fat! Which is a better obesity scale for Pakistani population? AB - OBJECTIVE: To compare two methods of classifying obesity based on body mass index and body fat percentage. METHODS: The cross-sectional study was conducted from November 2012 to August 2013 at Jinnah Postgraduate Medical Centre, Karachi. Male and female volunteers between the ages 15-65 years were selected using simple random sampling. They were classified into different groups for body mass index and body fat percentage measured through bioelectrical impedance scale. The subjects were sub-grouped into underweight, normal weight, overweight and obese. SPSS 11 was used for statistical analysis. RESULTS: The mean age of the 828 healthy volunteers was 25.67+/-10.10 years. A total of 552 (66.6%) subjects had a higher body fat percentage and were misclassified by body mass index. Only 276 (33.3%) subjects had body fat percentage values corresponding to the body mass index classification. The difference in terms of categorising obesity was highly significant (p<0.001). Both body mass index and body fat percentage showed positive correlation with age (r=0.144; p=0.001) (r=0.261; p=0.001) and weight (r=0.578; p=0.001) (r=0.444; p=0.001) respectively. Moreover body fat percentage showed a significant positive association with gender (r=0.109; p=0.027) whereas BMI did not. CONCLUSIONS: Body fat percentage should be incorporated for a better understanding as well as categorising of obesity. PMID- 25831636 TI - Vitamin D and cardiometabolic risk factors in adult non-diabetic offspring of type 2 diabetic parents. AB - OBJECTIVE: To measure serum vitamin D levels and assess its correlation with the various components of metabolic syndrome in adult non-diabetic offsprings of type 2 diabetics. METHODS: The analytical cross-sectional study was conducted from February to December 2012 at the Department of Physiology and Cell Biology, University of Health Sciences, Lahore. Data on anthropometric and physiologic/biochemical parameters was collected. Fasting blood samples were collected and serum was analysed for fasting serum insulin, fasting blood sugar, lipid profile and vitamin D. SPSS 20 was used for statistical analysis. RESULTS: Of the total 88 subjects in the study, 40 (45.5%) were offsprings of type 2 diabetics and 48 (54.5%) were offsprings of non-diabetic parents. Vitamin D deficiency (<20 ng/ml) was observed in 86 (98.5%) of the subjects and 77 (87.5%) had vitamin D levels <15 ng/ml. Severe deficiency (<10 ng/ml) was seen in 61 (70%) subjects. Inverse correlation was observed between vitamin D and low density lipoprotein, total cholesterol, total cholesterol/high density lipoprotein ratio, Fasting Blood Sugar and homeostasis model assessment of insulin resistance. CONCLUSION: The subjects were severely deficient in vitamin D and its levels were inversely correlated with most of the components of metabolic syndrome. PMID- 25831637 TI - Test anxiety levels and related factors: students preparing for university exams. AB - OBJECTIVE: To assess test anxiety levels and related factors among students preparing for university exams. METHODS: The descriptive, cross-sectional study was conducted at Istanbul University, Turkey, and comprised students preparing for exams in two private courses for the 2010-11 academic year. Data was collected via an original questionnaire and the Test Anxiety Inventory. SPSS 20 was used for statistical analyses. RESULTS: Of the 1250 students who qualified for the study, the final sample size was 376 (30%). Of them, 210 (55.9%) were females, and 154 (41%) were 18 years old. Students' mean Test Anxiety Inventory scores were 39.44+/-11.34. Female students' overall test anxiety scores and mean emotionality subscale score were significantly higher than those of their male counterparts. Students whose mothers had an educational attainment between primary school n=170 (45.2%) and a high school diploma n=184 (48.9%), as well as those with four or more siblings n=49 (15%), had significantly higher mean overall Test Anxiety Inventory scores. CONCLUSION: Among other things, test anxiety is influenced by maternal educational level, type of high school, number of exams, and number of siblings. Preparing a relaxed study environment for students, providing the family monetary or social support, and encouraging participation in social activities are recommendedto decreajb anxiety in students preparing for university exams. PMID- 25831638 TI - Outcomes of splenectomy for idiopathic thrombocytopenic purpura in adults: a developing country perspective. AB - OBJECTIVE: To determine the outcome of splenectomy done in adult patients of Idiopathic Thrombocytopenic Purpura over a period of 10 years and, secondarily, to determine the predictors of complete response to therapy. METHODS: The retrospective review comprised of adult patients over 14 years of age who underwent open or laparoscopic splenectomy for Idiopathic Thrombocytopenic Purpura at Aga Khan University Hospital, Karachi, from January 2000 to December 2010. Data was reviewed in January 2011 by a surgical resident. Outcome was the response to splenectomy as per new definition of response set by the American Society of Haematology 2011 evidence based practice guidelines for Idiopathic Thrombocytopenic Purpura. Assessment of response was done within 1 to 2 months of splenectomy and after withholding concomitant treatment. SPSS 17 was used for statistical analysis. RESULTS: A total of 27 patients were found eligible. Of them, 2 (7.4%) were males and 25 (92.6%) were females with an overall mean age at the time of splenectomy of 30.8+/-6.3 years (range: 15-55 years). Out of 27 cases, 23 (85.18%) patients underwent open splenectomy, 3 (11%) laparoscopic and 1 (3.7%) had laparoscopic converted to open splenectomy. Complete response was achieved in 20 (74.1%) patients, whereas 5 (18.5%) had response and 2 (7.4%) had no response. None of the predictors of response to splenectomy were found significant. CONCLUSION: Response to splenectomy in adult Idiopathic Thrombocytopenic Purpura patients was comparable to reported rate in literature with relatively lower morbidity and mortality. Splenectomy is a safe treatment option especially in patients who succumb to adverse effects of medical therapy. PMID- 25831639 TI - Students' perceptions of educational environment of a private medical school in Pakistan. AB - OBJECTIVES: To measure the students' perceptions of educational environment of a medical school, to compare the perceptions of high, average and low academic achievers, and to explore the relation between these perceptions and their academic achievements in order to identify specific problem areas. METHODS: The cross-sectional study was conducted at Ziauddin University, Karachi, during the mid of the 2010-11 academic year using Dundee Ready Education Environment Measure inventory. Data was collected from 200 undergraduate medical students of all five years. Analysis was performed using both Inventory guidelines on SPSS19.0. RESULTS: Of the 200 students initially enrolled, completed forms were received from 168 (84%). The overall mean score was 117+/-8.3. Mean comparison of their perceptions on the overall score was significantly less (p<0.001) for the low achievers across all 5 years. Moderate positive correlation (r= 0.417) was found between perceptions and academic achievements. CONCLUSIONS: Students' perceptions of their educational environment were reasonably positive, indicating adequate satisfaction in most areas. Emphasis needs to be paid on the implementation of strong student support system across all medical schools to initiate timely remedial measures where needed. The learning environment should be evaluated regularly for quality improvement purposes. PMID- 25831640 TI - Diametral tensile strength of two dental composites when immersed in ethanol, distilled water and artificial saliva. AB - OBJECTIVE: To examine the effect of distilled water, artificial saliva and ethanol on the tensile strength of direct tooth-coloured restorative material. METHODS: The study was conducted at Dr. Ishrat ul Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences (DUHS), Karachi, from April 2011 to September 2012. The testing was performed at the Pakistan Council of Scientific and Industrial Research (PCSIR) laboratories. Two composite resins Filtek Z250 and Spectrum TPH were tested. Specimens (13 mm x 3 mm x 2 mm) of each material were prepared in the stainless steel mould according to the manufacturers' instructions and distributed into 3 equal groups: one immersed in distilled water, the other in artificial saliva, and the last one in ethanol for 24 hours. Tensile strength was determined after 24 hours in universal Instron Testing Machine. RESULTS: There were 72 specimens in all; 36 (50%) each for Filtek Z250 and Spectrum TPH. The three sub-groups in each case had 12 (33.3%) specimens. For the Filtek Z250, there was no statistically significant difference between immersion in distilled water and artificial saliva, but the ethanol group presented lower tensile strength (p<0.05). For the Spectrum TPH, samples immersed in ethanol and artificial saliva presented lower tensile strength compared to distilled water (p<0.05). CONCLUSION: The tested composite resins were affected by the immersion media and adversely affected the mechanical properties of composite resins. PMID- 25831641 TI - Carbohydrate (CHO), protein and fat intake of healthy Pakistani school children in a 24 hour period. AB - OBJECTIVE: To determine the frequency pattern of CHO, protein and fat intake in 24 hours by Pakistani school children of different socioeconomic and cultural backgrounds) 6 to 16 years of age. METHODS: The cross-sectional study was a multistage stratified sampling, done in a part of nationwide survey funded by the Higher Education Commission, Pakistan (HEC, Ref no: 20-441/R&D/2008). Sample collection of the study was done from 2006-2009, and growth centile charts have already been published (JPMA 2012; 62:367-77). This is the final paper of the completed project and includes data on only the nutritional status. Final statistical analysis of the nutrition aspect was done from 2012 to 2013 and comprised assessment of quality and quantity of CHO, protein and fats consumed by healthy schoolchildren in a 24 hrs recall (breakfast, brunch, lunch, tea time, dinner and bed time). Food records of 11, 237 school children were subjected to United States Department of Agriculture food exchange list. SPSS 18 was used for statistical analysis. RESULTS: The age range of the study subjects was 6-16 years, and they represented different areas of Pakistan. The consumption of CHO was high (range: 60-74%) compared to protein (10-12%) and fat (18-32%). CONCLUSION: Schoolchildren in Pakistan were found to be taking a deficient amount of protein and fat in their daily diet, while. CHO intake was higher than normal. PMID- 25831642 TI - Radical surgical management of periampullary duodenal adenocarcinoma: a single institution experience. AB - OBJECTIVE: To share a single-centre experience with radical resection of adenocarcinoma of the second part of duodenum. METHODS: The retrospective review was conducted at Shaukat Khanum Memorial Cancer Hospital, Lahore, and comprised data of patients who underwent pancreaticoduodenal resection for duodenal adenocarcinoma from January 1999 to December 2012. Patient characteristics and histopathological variables were assessed. Post-op complications, median disease free span and overall survival were assessed. Expected 5-year disease-free and overall survival were calculated using Kaplan Meier curves. RESULTS: Of the 12 patients whose records were included, 8 (66.6%) were men and 4 (33.33%) were women. Overall median age was 55 years (range: 38-70 years). Jaundice was the predominant symptom in 9 (75%) patients. Five complications were observed during the post-operative period. Median disease-free and overall survival was 14.5 (0 140) and 17.5 (1-140) months respectively. Expected 5-year disease-free and overall survival were 56% and 21% respectively. Patients who survived >24 months had underlying well differentiated tumours, negative surgical margins, absence of perineural invasion and pancreatic involvement. CONCLUSION: Peri-ampullary duodenal adenocarcinoma is a rare malignancy. In selected patients, pancreatic oduodenectomy produces acceptable results. PMID- 25831643 TI - Wound healing in rat skin subjected to loud noise stress; a light microscopic study. AB - OBJECTIVE: To determine the effect of loud noise stress on wound healing in a skin tissue. METHODS: The randomised control trial was conducted at the Department of Anatomy, College of Physicians and Surgeons Pakistan Regional Centre, Islamabad, from September 2007 to September 2008. The study comprised 240 male Sprague Dawley rats who were randomised into control group A and experimental group B. Each group comprised 120 animals. Main groups were further subdivided into four subgroups of 30 animals each. After induction of local anaesthesia a linear full thickness skin incision paravertebral to thoracic spine was made. The experimental group B was exposed to loud noise stimulus. The animals were decapitated 1, 3, 5 and 7 days after surgery. Histological data was collected in the incisional space of the wound. Polymorpho-nuclear leukocytes, macrophages, fibroblasts and blood vessels, were analysed quantitatively, whereas re-epithelialisation and content of collagen fibres in the incisional space were analysed qualitatively. RESULTS: Macrophages were decreased initially 3 days after surgery and were increased 5 and 7 days after surgery in the experimental subgroups. Similarly, blood vessels and fibroblast were significantly decreased in experimental subgroups 3 days after surgery, but were increased significantly in experimental subgroups 7 days after surgery. Nothing significant was found regarding re-epithlialisation and collagenisation of wound. CONCLUSION: Loud noise stress affects the important cells involved in the healing of the wound. Therefore, it is expected to have an impact on the stages of wound healing. PMID- 25831645 TI - Vitamin D levels in children diagnosed with acute otitis media. AB - OBJECTIVE: To investigate the relationship between Vitamin D deficiency and acute otitis media infection. METHODS: The randomised, single-blind, case-control study was conducted at the Paediatric Department of Ataturk University, Erzurum, Turkey, from January to April 2010. It comprised ambulatory children diagnosed with acute otitis media and healthy controls. The subjects were divided into groups according to their serum 25-hydroxy vitamin D levels. SPSS 18 was used for statistical analysis. RESULTS: Of the 169 subjects in the study, 88(52%) were the cases and 81(48%) were controls. The mean age of the cases was 6.21+/-3.4 years, and 6.18+/-3.12 years for the controls (p<0.951). Serum 25-hydroxy vitamin D levels in the cases and controls were 20.6+/-10.2 ng/mL and 23.8+/-10.3 ng/mL (p<0.05). There was no statistically significant difference between the groups in terms of parathormone and calcium levels (p>0.05). CONCLUSION: Serum 25-hydroxy vitamin D levels being significantly lower in children diagnosed with acute otitis media compared to the controls in two otherwise similar groups suggests that Vitamin D deficiency plays a role in otitis media infection. PMID- 25831644 TI - Modified Limberg's flap versus primary closure for treatment of pilonidal sinus disease: a comparative study. AB - OBJECTIVES: To compare the outcome of Rhomboid excision and Modified Limberg's flap closure with excision and primary closure for the treatment of Sacrococcygeal Pilonidal sinus. METHODS: The study was conducted at the Surgical Department of Mayo Hospital, Lahore, from 2009 to 2012. A total of 60 patients of pilonidal sinus were randomly divided into two equal groups. The patients were operated under general anaesthesia in prone position by Rhomboid excision and Modified Limberg's flap closure with a closed suction drain in group 1, and excision and primary closure over a drain in group 2. Patients were followed up for 12 months for surgical complications of the treatment. SPSS 17 was used for statistical analysis. RESULTS: In group 1 there were 27(90%) males and 3(10%) females, while group 2 had 28(93.3%) males and 2(6.7%) females. The infection rates were observed to be 2(7%) in group 1 and 8(26.6%) (p<0.038) in group 2. The recurrence rate was only 1(3.3%) in group 1 compared to 4(13.3%) in group 2. Average hospital stay was 1.63+/-0.67 days group 1 and 2.8+/-1.24 days in group 2. CONCLUSION: Modified Limberg's flap closure is an effective treatment modality for pilonidal sinus disease with 1.5 times less infection rate, 4 times less recurrence rate and 40% in-hospital time. PMID- 25831646 TI - Treatment of ganglions; a five year experience. AB - OBJECTIVE: To evaluate and determine the effectiveness of surgical excision, aspiration and injection in the treatment of symptomatic ganglions. METHODS: The prospective randomized control trial based on non-probability convenience sampling was conducted at the Department of Surgery, Combined Military Hospital, Sialkot, from June 2007 to August 2010, and at the Department of Surgery, Islam Teaching Hospital, Sialkot, from September 2010 to December 2012. The last patient was included in June 2012. Adult patients referred by general practitioners with ganglia of wrist, ankle and knee were included. All the patients were offered treatment options of intralesional steroid injection or excision of ganglion.The study population was distributed in two groups: Group I opted for aspiration and injection treatment, while Group II went for surgical treatment. A minimum follow-up of six months was mandatory for inclusion in the study. Data was compared and analyzed using SPSS version 22. RESULTS: The study had 173 patients with 187 ganglia. Group I had 143(76.4%) patients, while Group II had 44(23.3%). In the short term, 82(57.3%) of the patients achieved complete resolution after one episode of aspiration and injection, and success rate after second injection repeated after 3 weeks was 116(81%). Overall success rate of aspiration and injection of Triamcinolone acetonide six months after the treatment was 116(81%). On the surgical side the success rate was 41(93%). Complications like pain, joint stiffness and ugly scar were few and not significant. Comparison of failure rates of the two groups (19% vs 7%) showed significant difference (p<0.028). CONCLUSION: In symptomatic ganglia, surgical excision was a better treatment option as the failure rate was less compared to injection-aspiration. The injection treatment should be offered to those who are not willing for surgery, but they should be properly counselled about the chances of failure. PMID- 25831647 TI - Foetal central nervous system anomalies: frequency and foeto-maternal outcome. AB - OBJECTIVE: To assess the frequency and outcome in pregnant females suspected to have foetal central nervous system anomalies on the basis of ultrasonography. METHODS: The retrospective study was conducted at the Department of Obstetrics and Gynaecology, Armed Forces Hospital, Southern Region, Khamis Mushait, Saudi Arabia, and comprised all women who were diagnosed by ultrasound to have foetal central nervous system abnormalities during anomaly scan at 18-20 weeks between January 2009 and December 2012. Data was retrieved from patient files and reviewed for foetal and maternal outcome. RESULTS: Of the 31,754 live births at the hospital during the study period, 22,880(72%) pregnant women were sent for ultrasonography to have foetal central nervous system anomalies checked. Of them, 181(0.57%) women had positive scans. Mean maternal age was 29.8+/-7 years and the mean gestational age at diagnosis was 24.4+/-7 weeks. There were 35(19%) primigravida, 108(60%) Para 2 to 5, and 38(21%) more than Para 5. Overall, 102(56.4%) women delivered vaginally, while 50(27.6%) delivered by caesarean section. Mean gestational age at delivery was 37.5+/-4.2 weeks. Major anomalies included ventriculomegaly 95(52.2%) neural tube defect 31(17.03%), cisterna magna 17(9.34%), and acrania 12(6.6%). No termination of pregnancy was done due to legal and religious reasons. CONCLUSION: Antenatal detection of central nervous system anomalies by screening with ultrasonography helps make multidisciplinary management plans. PMID- 25831648 TI - Psychological problems among women with infertility problem: a comparative study. AB - OBJECTIVE: To explore the difference between anxiety and depression among infertile and fertile women. METHODS: The study was conducted in 2009 and comprised fertile and infertile women. The sample of infertile women was drawn from the Liaquat National Hospital, Patel Hospital, Infertility Concept and Zainub Hospital, located in urban areas of Karachi, while fertile women were drawn from the general population in urban Karachi. All the subjects had at least 10 years of education and were in the age range of 20-35 years. They two groups were further divided into two sub-groups of working and non-working women. Institute for Personality and Ability Testing Depression and Anxiety scales were used to assess depression and anxiety. SPSS 14.0 was used to analyse the data. RESULT: Of the 120 subjects, the two groups had 60(50%) each. The mean age of fertile women was 27.48+/-160.75 and that in the infertile group was 27.36+/ 160.75. Depression among fertile women was 21.85+/-10.98 compared to 32.01+/ 12.49 among the infertile women. Corresponding values for anxiety was 24.45+/ 9.63 and 36.20+/-12.51. The difference was significant. CONCLUSION: Women with infertility experience a greater psychological impact. PMID- 25831649 TI - Clinical course and outcome of acute severe asthma (status asthmaticus) in adults. AB - OBJECTIVE: To evaluate the clinical course and outcomes in patients with acute severe asthma in a tertiary care setting. METHODS: The retrospective cross sectional study was conducted at the Aga Khan University Hospital, Karachi, and comprised data of patients of age 16 and above who were admitted with a diagnosis of acute severe asthma from January 2000 to December 2013. These patients had undergone clinical evaluation to assess the severity of illness as well as the complications and eventual outcomes. SPSS 16 was used for statistical analysis. RESULTS: Of the 50 patients in the study, 41 (82%) were females. The overall mean age was 53.1+/-20.3 years. Ventilator support was required by 37(74%) patients. Presence of acidaemia was associated with the need for invasive ventilation (p<0.033) which in turn was associated with increased hospital stay (p<0.043). Complications were observed in 37(74%) patients, the most common being respiratory failure in 35(70%) and arrhythmias in 8(16%). Use of both non invasive and invasive ventilation was found to be significantly associated with development of complications (p<0.001 and p<0.009). A total of 4(8%) patients died. Presence of acidaemia was found to be significantly associated with mortality (p<0.032). CONCLUSION: Overt acidaemia at initial presentation in patients with acute severe asthma was significantly associated with higher rates of invasive ventilation leading to increased hospital stay, complications and higher mortality rate. PMID- 25831650 TI - Comparison of hypoglycaemia episodes in people with type-2 diabetes fasting in Ramazan, treated with vildaglipton or sulphonylurea: results of the Pakistani cohort of the VIRTUE study. AB - OBJECTIVE: To assess the effect of vildagliptin in comparison to sulphonylurea (SU) on hypoglycaemia in Muslim patients with type 2 diabetes mellitus fasting during Ramadan. METHODS: VIRTUE was a multicenter, prospective, observational study, which enrolled 244 patients from Pakistan who were re-analysed. All included patients were treated with vildagliptin (n=121) or SU (n=121) as add-on to metformin or as monotherapy for 16 weeks. The primary outcome of interest was to compare the proportion of patients with >=1 hypoglycaemic event (HE) during fasting between vildagliptin and SU cohort. Changes in HbA1c and body weight and treatment adherence were also measured. RESULTS: Of the 244 patients enrolled, 120 patients in the vildagliptin cohort (99.2%) and 119 patients in the SU cohort (98.3%) completed the study. Patients experiencing at least one HE were fewer with vildagliptin when compared with SUs (5.8% vs. 14.2%; p<0.033). The reduction in HbA1c was 0.3% with vildagliptin from a baseline of 7.6% and 0.1% with SU from a baseline of 7.4% (between-treatment difference: -0.1% p<0.054). A reduction of 0.3 kg was seen with vildagliptin treatment vs. 0.2 kg weight gain in the SU group. Adverse events were experienced by 15.7% in the vildagliptin cohort and 17.4% in the SU group. CONCLUSION: The treatment with vildagliptin was associated with fewer hypoglycaemic events compared with SUs and was well tolerated with good glycaemic and weight control in patients with T2DM fasting during Ramadan. PMID- 25831651 TI - Effect of late vs early clamping of the umbilical cord (on haemoglobin level) in full-term neonates. AB - Sixty term infants delivered vaginally were assigned randomly to one of the two management groups; early cord clamping (ECC) or delayed cord clamping (DCC). Six months after delivery, the children in both groups were called back for follow up. Blood samples were obtained for measuring haemoglobin (Hb), haematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), serum iron (SI), transferrin saturation (TS) and serum ferritin (SF) levels. The mean Hb, HCT, SI and TS at 6 months were significantly higher in the DCC group (95% confidence interval (CI); p<0.001, p<0.001, p<0.024 and p<0.009). The mean SF at 6 months was also higher in the DCC group but it was not significant (p<0.071). Polycythaemia, jaundice and other undesirable side-effects of DCC were not seen. PMID- 25831652 TI - Prevalence, correlates, and changes in tobacco use between 2006 and 2010 among 13 15 year Moroccan school attending adolescents. AB - Tobacco use is a preventable cause of disease and death globally. Adolescents using tobacco tend to continue its use in adulthood. Analysis of data from Moroccan Global School-based Student Health Surveys for 2006 and 2010 showed statistically significant differences in prevalence of current cigarette smoking as well as current use of other tobacco products, among school attending 13-15 year old boys and girls within the year 2006 and 2010; with boys having higher prevalence than girls in each year. Combined prevalence of cigarette smoking i.e. between both boys and girls showed statistically significant difference between 2006 and 2010; with a higher prevalence in 2010. Use of tobacco in multivariate analysis of 2010 data, was found to have statistically significant associations with anxiety disorders, gender, truancy, depression, suicidal ideation, inadequate parental monitoring, and parental smoking. PMID- 25831653 TI - Is it safe to be calcified? Porcelain gallbladder perforation and review of literature. AB - Calcification of the gallbladder wall (porcelain gallbladder) is an intense structure and uncommon manifestation seen in chronic cholecystitis and resulting from chronic inflammation of the gallbladder wall. Patients with porcelain gallbladder are usually considered not at risk of acute cholecystitis. However, sporadic cases of cholecystitis on porcelain gallbladder have been described in literature. Gallbladder perforation is a rare entity and may complicate on acute or chronic cholecystitis in a non-calcified gallbladder. We report an unusual case of acute cholecystitis with perforation in a porcelain gallbladder. PMID- 25831654 TI - A rare case of Palizaeus Merzbacher Disease in a female patient diagnosed radiologically. AB - Pelizaeus Merzbacher's Disease is an inherited X-linked recessive trait. Males have the disease, while females are usually carriers. We report the case of a 6 years-old girl who had nystagmus since birth and later on developed head nodding. She started talking at one year and walking at 18 months. Then she developed regression of milestones, with speech impairment and inability to walk which progressively worsened. Before presenting she had a generalised seizure. Her parents were second cousins. Family history was unremarkable. On examination she was awake, alert, there was bilateral horizontal nystagmus. Cranial nerve examination was normal. There was spastic paraparesis with bilateral extensor plantar response. Magnetic resonance imaging of the brain showed classical features of diffuse hypomyelination characteristic of Pelizaeus Merzbacher's Disease for this age group. PMID- 25831655 TI - Eagle syndrome; radiological evaluation and management. AB - Eagle syndrome is a rare condition where elongated temporal styloid processes, or calcified stylohyoid ligaments, are in conflict with the adjacent anatomical structures giving rise to a complex range of symptoms including otalgia, dysphagia, foreign body sensation in throat, pain along carotid artery distribution and others. Commonly, the syndrome is documented to be unilateral. However, bilateral cases are also reported though rarely. Multislice computed tomography scan with 3D reconstruction can be really helpful in diagnosing the elongated styloid processes and their mass effect on the surrounding adjacent anatomical structures. Scan is also helpful in deciding further management and guides the surgeon on how and from where to approach the surgery. We present here a case of a 37-years-old man with significantly enlarged and thickened bilateral styloid process causing significant characteristic symptoms. PMID- 25831656 TI - Accidental intrathecal administration of high dose diamorphine. AB - A case of accidental administration of high dose intrathecal diamorphine is reported in a patient who underwent total knee replacement. Initially a regional technique was planned for this patient, but due to inadvertent administration of three milligrams of diamorphine intrathecally, it was decided to convert the patient to have a general anaesthetic. Postoperatively, she was monitored in high dependency unit for 48 hours. Apart from two episodes of nausea and mild drowsiness, she did not develop any serious side effects and did not require naloxone. PMID- 25831657 TI - Giant nasolabial cyst. AB - Nasolabial (nasoalveolar) cysts are nonodontogenic soft tissue lesions derived from epithelial remanant of the nasolacrimal duct. These are generally slow growing painless lesions. Additionally, they can cause obstruction, facial deformity and pain. This case report evaluates the facial deformity and boat shaped resorption demonstrated on computerized tomography (CT) in a 28 years-old patient presenting with facial swelling and pain as a result of a nasolabial cyst. Nasolabial cysts must be kept in mind in patients suffering from facial deformity and infection as an underlying predisposing factor. Recurrences may be seen in cases not amenable to treatment by surgical excision. PMID- 25831658 TI - Palatal perforation, the most rarely observed complication after deviated septum surgery. AB - Numerous complications after septoplasty have been identified in the literature. Blindness and palatal perforation are among the rarest complications. The palatal perforation experienced by the presented patient was because he was not thoroughly examined before surgery. Secondly, we wanted to emphasize the fact that care must be taken during septoplasty operation, particularly while performing the intervention to the inferior septal area. PMID- 25831659 TI - Quaternary prevention and diabetes. PMID- 25831660 TI - Association of hypertension with stroke recurrence may depend on ischaemic stroke subtype. PMID- 25831661 TI - Plagiarism detection softwares: useful tools for medical writers and editors. PMID- 25831662 TI - Assessment of knowledge about childhood autism among medical students from private and public universities in Karachi. AB - OBJECTIVE: To assess the knowledge about childhood autism among fourth year medical students in public and private medical universities of a metropolitan city. METHODS: The cross-sectional descriptive study was conducted in Karachi from January to August 2012. Two medical universities--one each from public and private sectors--were selected using non-probability convenience sampling technique. Fourth year medical students present at the time of data collection were included in the study. Data collection was done by Knowledge About Childhood Autism Among Health Worker questionnaire from fourth year medical students. Data was analysed using SPSS 20. RESULTS: Of the 157 students in the study, 62(39.6%) were males and 95(60.4%) were females; 84(43.5%) were from public medical university and 73(46.5%) were from private university. Total mean score obtained out of the maximum 25 was 12.30+/-4.71. The mean score obtained by public medical students was 12.40+/-4.69 and 12.1+/-4.76 by those of private university. CONCLUSION: The scores reflected shortcoming in knowledge about childhood autism among the study population. In order to bridge knowledge deficit, awareness generation activities must be held more frequently. PMID- 25831663 TI - A day experience at Research Methodology Workshop held by PAME. PMID- 25831664 TI - Medical research and science culture in Pakistan. PMID- 25831665 TI - Clinical predictors of mortality in hospitalized patients with infective endocarditis at a tertiary care center in Pakistan. AB - OBJECTIVE: To evaluate the clinical characteristics and predictors of in-hospital mortality in patients with infective endocarditis at a tertiary care centre in Pakistan. METHODS: The cross-sectional study was conducted at the Aga Khan University Hospital, Karachi, from January 1, 2002, to December 31, 2006, and comprised 84 consecutive patients hospitalised with infective endocarditis,. All patients underwent verification of the diagnosis according to the Modified Duke criterion. Data was collected through a questionnaire and analysed using Student's t test, Chi square and Fisher's exact test. Univariate and multivariate logistic regression analysis was performed to assess predictors of mortality. RESULTS: Of the total, 53(63%) patients were male and 31(37%) female. The mean age of the patients was 42+17 years. Overall, 34(41%) patients had rheumatic valve disease as a predisposing condition. The most commonly affected valve was mitral in 43(51%) patients, and the most commonly isolated organism was methicillin-resistant staphylococcus aureus in 12(14.3%). Overall in-hospital mortality was 27(32.1%), while 18(21%) patients, developed congestive cardiac failure, 15(18%) developed arrhythmias, 16(19%) developed peripheral embolism and renal failure was present in 38(54%). Besides, 17(20%) patients underwent surgical intervention. The final multivariate model that can be used to predict mortality in this study consisted of the presence of neurological complications (p <0.001) Odds Ratio 7.26, Confidence Interval (2.27-23.18), congestive cardiac heart failure (p <0.023) Odds Ratio 5.39, Confidence Interval (1.26-23.04), and arrhythmias (p <0.034) Odds Ratio 4.21, Confidence Interval (1.11-15.88). CONCLUSION: Significant predictors of mortality in hospitalised patients with infective endocarditis in our study were the presence of neurological complications, congestive cardiac heart failure, and the presence of arrhythmias. PMID- 25831666 TI - Dermatological evaluation of counter irritant potential of human urine in rabbits. AB - OBJECTIVE: To confirm the effect of human urine in the treatment of wounds, burns and irritation. METHODS: The study was conducted at Bahauddin Zakariya University, Multan, in November 2013 and comprised 15 rabbits of either gender. Irritation was induced by clockwise frictional movement of fine sandpaper to the ear of the rabbits. The counter-irritant activity was determined by calculating the mean decrease in redness and erythema. A group of 3 rabbits each was used while experimenting with the main assay every time the concentration of irritants was increased. The ear treated with distilled water was used as a control. Sodium lauryl sulfate irritation model was also applied and the counter-irritant activity was evaluated. One-way analysis of variance followed by Bonferroni test were used for statistical analysis. RESULTS: The mean weight of the 15 rabbits was 1.5+/-SD kg. Urine (50 and 100ul) showed excellent counter-irritant activity when compared with control and standard dexamethasone. Both the doses showed counter-irritant activity, ranging between 76.84% and 95.68% in the sandpaper model, and 68.90% and 93.68% in the sodium lauryl sulfate model. CONCLUSION: Human urine countered the effect of irritation in experimental animals and can be an alternative way of countering irritation. PMID- 25831667 TI - Multi-drug resistant pseudomonas aeruginosa: a threat of nosocomial infections in tertiary care hospitals. AB - OBJECTIVE: To determine the resistance patterns of Pseudomonas aeruginosa to currently available anti-pseudomonal drugs and frequency of nosocomial infections caused by multi drug resistant Pseudomonas aeruginosa in hospitals. METHODS: Clinical isolates of Pseudomonas aeruginosa were collected from patients admitted in different hospitals of Karachi between July 2012 and June 2013. The isolates were identified by conventional and Analytical Profile Index 20NE kit methods while the antibiograms of these isolates were determined by Kirby-Bauer disc diffusion method. RESULTS: Of the 204 isolates, 79(39%) were obtained from intensive care units: Overall, 135(66%) isolates belonged to men, and 35(17.2%) belonged to 10-15 year age group. The overall antibiogram pattern showed high resistance to commonly used antibiotics like Ofloxacin 125(61.3%), Cefepime 117(57.3%), Ceftazidime 110(53.9%), Amikacin 108(53%). Of all the isolates, 129(63.2%) were considered multidrug resistant. The most effective antibiotics were Colistin, Polymyxin B and Meropenem. CONCLUSION: Increasing multidrug resistance among nosocomial pathogens is an alarming situation in a hospital setting and requires prompt management of these cases. PMID- 25831668 TI - Knowledge, attitude and practices regarding respiratory symptoms among textile workers of Karachi, Pakistan: a cross-sectional survey. AB - OBJECTIVES: To determine the prevalence and predictors of good knowledge, appropriate attitude and appropriate protective practices regarding respiratory symptoms among textile workers, and to determine the association of knowledge, attitude and practices with respiratory symptoms. METHODS: The cross-sectional study was conducted in 2009 and comprised male workers from 15 textile mills in and around Karachi. A structured and pre-tested questionnaire was used which included questions to explore the knowledge, attitude and practices regarding respiratory symptoms. SPSS 19 was used for statistical analysis. RESULTS: The study had a sample size of 372 and found prevalence of good knowledge to be in 182 (48.9%) workers and appropriate attitude in 302 (81%), while only 80 (21%) were practising these measures appropriately. Being educated and older than 38 years of age, belonging to Sindhi ethnicity, and working in the weaving section were significant (p<0.05) predictors of knowledge, attitude and practices. Generally, there was no significant association of knowledge, attitude and practices with respiratory symptoms (p>0.05). CONCLUSIONS: There was low prevalence of appropriate practices, high prevalence of good knowledge and attitude, indicating an interplay of several other social and environmental factors which need to be explored. PMID- 25831669 TI - Student's perceptions of educational environment across multiple undergraduate medical institutions in Pakistan using DREEM inventory. AB - OBJECTIVE: To objectively assess whether the medical education environment across Pakistan was at an acceptable standard and to determine factors influencing its perception. METHODS: The cross-sectional study was conducted from August to November 2012 at six undergraduate medical institutions across Pakistan. The Dundee Ready Education Environment Measure (DREEM) inventory having five subscales of perceptions of learning, teachers, atmosphere, academic self perceptions and social self-perceptions was administered anonymously to all the consenting medical students. Data was analysed using SPSS 17. RESULT: Of the 3045 questionnaires distributed, 2084(68.4%) were returned duly filled. Of all the respondents, 1311(63%) were females. Overall mean score found positive was 105.0+/-25.8 (Max: 200). Corresponding scores in the subscales were: student's perception of learning 25.1+/-7.2 (Max: 48); social self-perception 15.4+/-3.9 (Max: 28); academic self-perception l7.2+/-6.5 (Max: 32); perception of teachers being in need of some re-training 22.5+/-7.1 (Max: 44); and perception of atmosphere as having many issues needing a change 24.8+/-7.0 (Max: 48). Female students and pre-clinical year students perceived environment as more positive than male students (108.6+/-23.0 vs. 98.8+/-28.9 [p<0.001]) and students belonging to clinical years (108.0+/-24.0 vs. 03.3+/-26.5 [p<0.001]). CONCLUSION: Highest score was found in the domain of student's social self-perceptions and lowest in the domain of student's perception of teachers. Results can be used as a basis for planning and executing remedial measures needed to improve undergraduate medical education environment in Pakistan. PMID- 25831670 TI - Comparison of placebo and intrauterine lidocaine with/or without rectal diclofenac sodium suppositories used in office endometrial biopsy. AB - OBJECTIVE: To compare the effects of intrauterine lidocaine, intrauterine lidocaine plus rectal diclofenac, and a placebo on analgesia and to determine the satisfaction of patients and surgeons in cases of endometrial biopsy. METHODS: The double-blind, randomised, placebo-controlled study was conducted in the Department of Obstetrics and Gynaecology of the Ondokuz Mayis University, Samsun,Turkey, from April 2013 to January 2014, and comprised patients scheduled for in-office endometrial biopsy.They were divided into three groups: Group P, 5ml of 0.9% saline intrauterine; Group L, 5ml of 2% lidocaine intrauterine; and Group LD, 5ml of 2% lidocaine intrauterine +/- 10min before the procedure plus 50mg of rectal diclofenac sodium. Haemodynamic changes and visual analogue scale scores were recorded during the preoperative period, when the cervix was grasped with a tenaculum, immediately after intrauterine instillation, during uterine curettage and at postoperative 10 min. The patient and the surgeon were questioned about their satisfaction 15 min after the procedure. SPSS 21 was used for statistical analysis. RESULTS: The 90 patients in the study were divided into three equal groups of 30(33.33%) each. There were no statistically significant inter-group differences in age, bodyweight, parity, number of postmenopausal patients, haemodynamic parameters and American Society of Anesthesiologists scores (p>0.05 in all categories). In Group P, the visual analogue scale score estimated when the cervix was grasped with the tenaculum was lower when compared with Group L and Group LD (p=0.029 and p=0.007, respectively). At other measurement time points, the scores did not differ between the groups. The groups did not differ with respect to patient and surgeon satisfaction and complication rates (p>0.05). CONCLUSION: Intrauterine lidocaine or intrauterine lidocaine plus rectal diclofenac application had no effect on visual analogue scale scores, patient satisfaction and vasovagal reaction. PMID- 25831671 TI - The role of positron emission tomography in mediastinal staging of patients with non-small cell lung cancer. AB - OBJECTIVE: To examine the diagnostic accuracy of positron emission tomography/computed tomography in evaluating the mediastinum of patients with non small cell lung cancer compared to histopathology results. METHODS: The prospective study was conducted at the Department of Thoracic Surgery of the Pulmonary Hospital in Zakopane, Poland, from September 2008 to August 2012 and comprised patients with radiologically-suspected lung cancer. All patients underwent histological verification by either mediastinoscopy alone or thoracotomy with mediastinal lymphanedectomy. Computed tomography and positron emission tomography/computed tomography data sets were compared with the results of the histopathology examinations. RESULTS: There were 80 patients in the study. In the diagnosis of mediastinal lymph nodes, computed tomography was able to detect 9(11.25%) true-positive, 17(21.25%) false-positive, 40(50%) true-negative and 14(17.5%) false-negative cases. The sensitivity, specificity and accuracy of the method were found to be 39%, 70% and 61% respectively, while the positive and negative predictive values were 35% and 74%. Positron emission tomography/computed tomography yielded 15(18.75%) true-positive, 12(15%) false positive, 46(57.5%) true-negative and 7(8.75%) false-negative cases. Sensitivity was 68% while specificity was 79%. The accuracy was 96%, and the positive and negative predictive values were 55% and 87% respectively. CONCLUSION: Positron emission tomography/computed tomography had higher diagnostic accuracy than computed tomography in assessing mediastinal lymph nodes of patients with non small cell lung cancer. However, a positive test requires histopathology confirmation. PMID- 25831672 TI - Effect of smoking on serum xanthine oxidase and malondialdehyde levels in patients with acute myocardial infarction. AB - OBJECTIVE: To evaluate the effect of smoking on blood levels of xanthine oxidase and malondialdehyde in acute myocardial infarction patients. METHODS: The cross sectional study was conducted from June to November 2013 and comprised myocardial infarction in-patients at Liaquat University of Medical and Health Sciences Hospital, Jamshoro, and Isra University Hospital, Hyderabad. Serum samples from age and gender matched smoking and non-smoking patients were investigated for the levels of xanthine oxidase and malondialdehyde by kit methods. RESULTS: Of the 88 serum samples investigated, 68(77.3%) belonged to men and 20(22.7%) to women. Among the 44 smokers, 35(79.5%) were men and 9(20.5%) were women.The overall mean age of the group was 49.6+/-8.0 years. Among the 44 non-smokers, 33(75%) were men and 11(25%) women. The overall mean age of the group was 50.9+/-8.4 Years. Smokers compared to non-smokers had significantly raised mean serum xanthine oxidase (0.31+/-0.05 vs 0.28+/-0.03mg/dl; p<0.05) and malondialdehyde (32.29+/ 3.30 vs 30.30+/-2.87 umol/L; p<0.04) levels. CONCLUSION: Smokers as against the non-smokers were at higher risk of developing acute myocardial infarction owing to increased level of oxidative stress caused by smoking. PMID- 25831673 TI - Effect of phoenix dactyliferia (date palm) pit powder on nicotine induced spermatotoxicty in adult albino mice. AB - OBJECTIVE: To study the effect of Phoenix Dactyliferia pit powder on nicotine induced spermatotoxicty in adult albino mice. METHODS: The study was conducted at the University of Health Sciences, Lahore, from February to November 2012, and comprised adult male albino mice aged 6-8 weeks. The animals were divided into five equal groups. Group A consisted of controls who were treated with 1.5ml/kg of normal saline for 15 days, while nicotine 0.5mg/kg was administered intraperitoneally daily to experimental groups B, C and D for the first 15 days. Group B was sacrificed on the 15th day to confirm toxicity, whereas nicotine treatment was stopped in groups C and D. Group C was given normal saline (1.5ml/kg) whereas group D was given date palm pit powder 500mg/kg for the next 30 days. However, Group E was given nicotine 0.5mg/kg for 45 days and date palm pit powder was added orally from the 16th day and it continued daily till the end of the experiment. SPSS 18 was used for statistical analysis. RESULTS: The mean weight of each of the 40 animals in the study was 30+/-5gm, and all the five groups hacL8(20%) mice each. Group B exhibited features of toxicity evident by statistically significant decrease in Johnsen score (p<0.001) and diameter of seminiferous tubule (p<0.001). Group C showed partial reversal of toxic effects but these positive effects were less compared to group D which showed complete reversal of toxicity evident by statistically significant increase in Johnsen score (p<0.001) and diameter of seminiferous tubule (p<0.001). However, reversal of toxic effect was not evident in group E. CONCLUSION: Partial recovery from nicotine-induced spermatotoxicity occurred after withdrawal of nicotine treatment whereas near normal restoration of structure was seen with administration of date palm pit powder after the stoppage of nicotine. PMID- 25831674 TI - Role of interleukin-l 3 in conception after intracytoplasmic sperm injection. AB - OBJECTIVE: To identify the role of Interleukin-l Beta(IL-1beta) in patients undergoing intracytoplasmic sperm injection. METHODS: The quasi-experimental study was conducted at an infertility clinic in Islamabad from June 2010 to August 2011, and comprised couples opting for intracytoplasmic sperm injection. Down regulation of ovaries was followed by calculated stimulation, ovulation induction, oocytes retrieval, intracytoplasmic sperm injection, in vitro maturation of embryos and embryo transfer. Serum Interleukin-l Beta was measured by enzyme-linked immunosorbent assay onovulation induction day. Patients were grouped as non-pregnant with beta human chorionic gonadotropin 5-25 mlU/ml, pre clinical abortion; beta human chorionic gonadotropin >25 mlU/ml with no cardiac activity and clinical pregnancy with foetal heart confirmation by trans-vaginal scan after 4 weeks of transfer. SPSS 15 was used for statistical analysis. RESULTS: Of the total 323 patients initially registered, embryo transfer could be carried out in 282(87.30%). Clinical pregnancy was achieved in 101(36%) patients, clinical abortions was the result in 61(22%) cases, while 120(42%) subjects did not conceive at all. Clinical pregnancy was achieved in subjects with high mean Interleukin-l Beta levels; 155.84+/-51.65 compared to 41.81+/-11.77and 118.46+/ 35.62pg/mlin non-pregnant, preclinical abortion groups respectively (p=0.001). CONCLUSION: The production of Interleukin-I Beta was associated with oocyte maturation, fertilisation, endometrial receptivity and implantation in patients undergoing intracytoplasmic sperm injection. PMID- 25831675 TI - Frequency of metabolic syndrome in psychiatric patients, is this the time to develop a standardized protocol to reduce the morbidity from an acute care psychiatry unit. AB - OBJECTIVE: To determine the frequency of Metabolic Syndrome among psychiatric patients and to look for the correlation between the two medical conditions. METHODS: The cross-sectional study was conducted from February to April 2013 at the acute care psychiatry in-patient unit at Kingston General Hospital, Ontario, Canada, and comprised adult patients of both genders diagnosed under the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. For Metabolic Syndrome, definitions outlined by the International Diabetes Federation were used. The patients were divided into two groups on the basis of presence or absence of the Syndrome and were compared for clinical and demographic characteristics. SPSS 22 was used for statistical analysis. RESULTS: Of the 50 patients in the study, 24(48%) were found to have Metabolic Syndrome. Besides, 40 (80%) patients were taking atypical antipsychotics regardless of the diagnosis; 20(83%) among those with the Syndrome, and 20(77%) among those without it. CONCLUSIONS: Patients at high risk of developing metabolic syndrome need to be identified early so that an individualised care plan can be formulated. Identifying the variables to make a management plan is vital. PMID- 25831676 TI - Evaluation of the effect of smoking on complete blood counts, serum C-reactive protein and magnesium levels in healthy adult male smokers. AB - OBJECTIVE: To examine the effect of smoking on complete blood count, serum C reactive protein and magnesium levels in male smokers. METHODS: The prospective case-control study was conducted in two villages of Matiari district in rural Sindh, Pakistan, from July to December 2013, and comprised healthy adult male smokers and an equal number of matching non-smokers as controls.The complete blood count, serum C-reactive protein and magnesium levels in all the subjects were measured to assess the effect of smoking on these parameters. RESULTS: The two groups had 48 subjects each with an overall age range of 20-40 years. The results of complete blood count were comparable except for lymphocyte, which was significantly higher (p<0.001), and neutrophil, which was lower (p<0.001) in smokers than in the non-smokers. Serum C-reactive protein concentrations among the cases (14.62+/-0.16mg/L) compared to the controls (4.81+/-0.38mg/L) were significantly higher (p<0.001). However, reverse was true for serum magnesium levels which were significantly higher (p<0.001) in the controls (2.52+/ 0.18mg/L) as against the cases (1.09+/-0.38mg/dl).Serum C-reactive protein-to magnesium ratio was significantly higher (p<0.001) in smokers than in the non smokers. CONCLUSION: Lymphocyte count was higher while neutrophil count was lower in smokers. Smoking also caused significant increase in serum C-reactive protein concentration concomitant to decrease in magnesium concentration in the smokers. PMID- 25831678 TI - Power doppler ultrasonography guided and random prostate biopsy in prostate cancer diagnosis - a comparative study. AB - OBJECTIVE: To compare the diagnostic accuracy of power Doppler-guided targeted prostate biopsy and random sextant biopsy in the diagnosis of prostate cancer. METHODS: The prospective study was carried out at the Allama Iqbal Medical College and Jinnah Hospital, Lahore, Pakistan, from January to December, 2012, and comprised clinically suspected cases of carcinoma prostate. Power Doppler guided biopsies using automatic biopsy gun were obtained from the suspected targeted site. One to three cores per suspected site were obtained. Subsequently random sextant biopsies were performed in the same sitting. Six cores were obtained from 6 random sites using the same gun. Biopsies from both sources were processed for routine haematoxylin and eosin stainstained sections for histopathological examination. RESULTS: Of the 50 patients in the study, 30(60%) were diagnosed with power Doppler-guided biopsy as malignant, whereas random sextant biopsy could pick up 22(44%) cases. For benign prostatic hyperplasia, random sextant biopsy labelled 28(56%)as benign, whereas only 20 (40%) were labelled as benign with power Doppler-guided biopsy. Discrepancy in the results between the two procedures was observed in 14(28%) cases, and of them, 1 1(22%) were labelled as malignant on power Doppler-guided biopsy while histopathology of sextant biopsies labelled these as benign.The sextant biopsies rendered a specificity, sensitivity, negative predictive value, positive predictive value and diagnostic accuracy of 60.71%, 86.36%, 85%, 63.33% and 72% respectively. CONCLUSION: Random sextant biopsy in combination with power Doppler-guided targeted biopsy increases the rate of detection of prostate cancer whereas both procedures in isolation have low sensitivity and specificity for cancer detection. PMID- 25831677 TI - Ocular manifestation, complications and aetiological factors in Stevens-Johnson syndrome/toxic epidermal necrolysis. AB - OBJECTIVE: To describe the ocular manifestations of Stevens-Johnson Syndrome/Toxic Epidermal Necrosis among inpatients at a tertiary care hospital. METHODS: The retrospective observational descriptive study was carried out at the Aga Khan University Hospital, Karachi, and comprised data on age, gender, aetiology and ocular findings related to patients diagnosed with Stevens-Johnson Syndrome/Toxic Epidermal Necrosis between January 2000 and December 2011. SPSS 19 was used for statistical analysis. RESULTS: There were 87 patients; 48(55.2%) of them being males.The overall mean age was 33.2+/-22.2 years, ranging from 1 month to 84 years. The most common aetiology was idiopathic 20(23%) followed by non steroidal inflammatory drugs and anti-epileptics 11(12.6%) each. Besides, 84(96.6%) patients had oral mucosal involvement whereas 45(51.7%) had ocular and 27(31.0%) had genital-mucosal involvement. Glassroding was performed in 16(18.4%) patients due to minor conjunctival adhesions. CONCLUSION: Ocular manifestations of varying severity were frequent, with drugs being the most common aetiology. PMID- 25831679 TI - Prognosis of stroke in children after three months of regular physical therapy in Lahore. AB - OBJECTIVE: To evaluate the effects and significance of Proprioceptive Neuromuscular Facilitation exercises on stroke patients. METHODS: The prospective follow-up study was conducted from January, 2012, to June, 2012, and comprised randomly-selected patients at the Department of Neurology, Children Hospital and Institute of Child Health, Lahore, Using systematic sampling the patients were divided into two groups. Patients in group I were subjected to Proprioceptive Neuromuscular Facilitation therapy, while those in group II were treated by passive range of motion exercises only. All patients were followed up at months 1, 2 and 3. Data was collected through a questionnaire, while muscle strength was evaluated through Medical Research Council scale. All date was analysed using SPSS 20. RESULTS: There were 50 patients in the study who were all below 15 years of age. Muscle strength of affected side at baseline in the experimental group I was 2.36+/-0.49 and in the control group II it was 2.60+/-0.50. At the end of the three-month follow-up, it had considerably increased to 4.76+/-0.43 in group I while it was 3.80+/-0.50 in grgup II (p<0.0001) CONCLUSION: Proprioceptive Neuromuscular Facilitation technique was an effective method in terms of pain relief, stiffness reduction and functional improvement. PMID- 25831680 TI - Effectiveness of simple strategies in reducing multidrug resistant blood stream infections in Neonatal Intensive Care Unit of tertiary care hospital in Karachi, Pakistan. AB - OBJECTIVES: To report reduction in transmission of multidrug resistant organisms from the neonatal intensive care unit after the implementation of simple risk reduction strategies. METHODS: Using a pre-and-post design, the study was carried out from June 2010 to December 2011 at the neonatal intensive care unit of Aga Khan University Hospital, Karachi, which is 12-bed, level III facility. The intervention comprised hand washing certification for all staff, use of chlorhexidine instead of povodine iodine for skin preparation, use of non-sterile gloves for diaper change, implementation of barrier nursing for clinically suspected and culture-proven infections, provision of separate intubation and central line trolley for each room and limiting the use of umbilical catheters to 7 days. Data is reported for 3-month pre-intervention period, one-month implementation phase, and for 3-month post-intervention phase. Data for 12 months post-implementation is reported to show sustainability. RESULTS: The average pre intervention rates of bloodstream infections due to extended spectrurm 3 lactamase, Acinetobacter, Pseudomonas and methicillin resistant staphylococcus aureus were 4.7, 3.3, 1.2 and zero respectively. The average number of admissions during the 3 phases was almost similar (49, 46 and 53 respectively). There was sustained reduction in rates for all organisms 12 months after the intervention period. CONCLUSION: Nosocomial transmission of multi drug resistant organisms within the neonatal intensive care unit can be effectively reduced by adopting simple strategies. PMID- 25831681 TI - Botulinum-A Toxin's efficacy in the treatment of idiopathic overactive bladder. AB - The systematic literature review was carried out to point out the efficacy of botulinum type A toxin (BTX-A) intra-detrusor injections in adults with idiopathic overactive bladder (OAB) and urgency urinary incontinence (UUI). A PubMed search for clinical studies with BTX-A intra-detrusor injections in adults with OAB was performed.The studies showed improvements in quality of life by relieving symptoms (decreased urinary frequency, urgency episodes, incontinence and nocturia). Randomised controlled trials conducted in the preceding two years showed complete continence in patients treated with BTX-A in 22.9% to 55% cases. Following treatment, most studies showed an increase in post-void residual volume, a fact that may lead to urinary tract infections (UTIs) and urinary retention requiring catheterisation. BTX-A is an effective treatment for OAB and results in a significant improvement in the quality of life of patients. PMID- 25831682 TI - Rates of caesarian section and trials and success of vaginal birth after caesarean sections in secondary care hospital. AB - We planned to investigate the rates of Caesarean Section (CS), potential Vaginal Births After previous Caesarean Section (VBAC), and successful VBAC in a secondary care hospital. We conducted an analytical retrospective study at Aga Khan Hospital for Women, Karimabad, Karachi, from October 2011 to September 2012. Data related to total deliveries, Lower Segment CS (LSCS), attempted VBAC and successful VBAC was retrieved from medical records. Total number of deliveries were 3266. Of these, 1021(31.26%) deliveries were conducted by CS. A total of 365(11.1%) had a previous history of one CS and VBAC trial was given to 33(9%) of these pregnancies. The success rate of VBAC was 21 (63.6%). Our results highlight that despite having limited resources, our rates of CS, VBAC trials and successful VBACs were within reasonable limits when compared with international rates. PMID- 25831683 TI - U-turns and road safety - perspective from Karachi. AB - U-turn is a complex driving manoeuvre entailing 180-degree turn to change the direction of travel towards the opposite direction. A cross-sectional survey based on convenience sampling was conducted at 120 U-turns in Karachi from February to October 2013. Shopkeepers operating in the close vicinity of U-turns were interviewed. Out of the 120 U-turns studied, 87(72.5%) were without median and 33(27.5%) were with median. Weekly average number of people getting injured or dying as a result of roadside traffic accidents was statistically significant (p<0.05) between the two types of U-turns; with U-turns having median having more injured and dead roadside traffic accident victims. Results from our preliminary study indicate that U-turns with medians are more likely to contribute towards road traffic accident morbidity and mortality and hence compromise road safety. Public health and transportation professionals in the country need to work in concert for ensuring that roads are safe for travelling. PMID- 25831684 TI - Poland's syndrome: a case report and review of literature. AB - Poland's Syndrome is a rare congenital condition. It is classically characterised by absence of unilateral chest wall muscles and sometimes ipsilateralsymbrachydactyly (abnormally short and webbed fingers). The condition typically presents with unilateral absence of the sternal or breast bone portion of the pectoralis major muscle which may or may not be associated with the absence of nearby musculoskeletal structures. Most of the Poland Syndrome is sporadic. We report a 19-year-old patient with variant of Poland Syndrome. To the best of our knowledge, this is one of the few documented cases of a patient with Poland Syndrome reported from Bangladesh. PMID- 25831685 TI - Urethral duplication: a rare cause of recurrent urinary infection. AB - Urethral duplication is quite a rare congenital anomaly with ill-defined aetiology. Patients often present with penile deformity; recurrent urinary infections, urinary incontinence, serosal discharge from the accessory urethra, and difficulty in urinating. Urethral duplication is most commonly grouped according to the Efmann classification. It has 3 main types as Type I, II, and III. There is no consensus on its therapy. There are non-surgical solutions, including follow-up without therapy, as well as many surgical options, including urethral reconstruction. Anatomical urethra and the external sphincter should absolutely be delineated when a surgery is contemplated. We herein report the case of a two-year-old male patient referred to our clinic with recurrent urinary infection, bilateral hydronephrosis and difficulty in urinating who was diagnosed with urethral duplication. We discuss our findings with review of the relevant literature. PMID- 25831686 TI - Surviving shot through the heart: Management in two cases. AB - Penetrating cardiac injuries after gunshot are usually fatal and are very challenging to manage for surgeons even in fully- equipped centres. Such injuries can cause ventricular septal defect (VSD) or cardiac tamponade depending upon the distance, direction and velocity of the bullet. Stable patients can be subjected to investigations like computed tomography (CT) to avoid unnecessary intervention, but unstable patients should be rushed to the operating room. We discuss management in two cases of traversing bullet injury to the heart. In the first case, traumatic VSD was significant, requiring closure on cardiopulmonary bypass (CPB) along with repair of right and left ventricular injury. In the second case, only the repair of right and left ventricles was performed without CPB. They both had traversing bullet injury through the heart. PMID- 25831687 TI - Palmar initial lesion in pityriasisrosea. AB - Pityriasisrosea is a frequently encountered skin disease associated with typical erythematous-squamous lesions. Majority of the cases relate to patients between 10 and 35 years of age. In clinically typical cases, the disease appears with the initial lesion called herald patch. The initial lesion generally locates on trunk, neck and proximal extremities. However, it can rarely be seen on other body parts such as face, scalp, and genital region. The initial lesion located on palmar region has been just once presented in literature. In this study, we present a 22-year-old female patient with palmar initial lesion who was followed up with misdiagnosis until rashes appeared on her body. PMID- 25831688 TI - Secondary malignant melanoma in primary mediastinal germ cell tumour. AB - Secondary transformation in Germ Cell Tumours (GCT) is an extremely rare event. We report here a case of malignant melanoma arising in primary mediastinal GCT. A young male presented with new onset dyspnoea and a mediastinal mass. As serum alpha fetoprotein was raised, a diagnosis of primary mediastinal GCT was made. He achieved remission with standard chemotherapy and resection of the mass. After a year, he relapsed with widespread disease which on work-up revealed malignant melanoma. As examination for cutaneous melanoma was unremarkable, a diagnosis of mediastinal GCT with secondary transformation to melanoma was made. Exact origin of melanoma in GCTs is unknown, but these may occur from transformation of dermal elements or de-differentiation of germ cells to melanomas. Before making such a diagnosis, search for primary cutaneous melanoma is mandatory. No clear guidelines exist in literature for the treatment of secondary melanomas, so current management guidelines for cutaneous melanoma may be followed. PMID- 25831689 TI - Sulfonylureas. AB - This review describes the basic and clinical pharmacology of sulfonylureas. It undertakes a balanced assessment of the advantages and limitations of sulfonylureas, and compares the use of various sulfonylureas in different clinical situations. The authors suggest pragmatic guidance to facilitate safe and effective use of this class of drugs, and thus help make maximal use of this economical therapeutic option in resource challenged settings such as developed nations. PMID- 25831690 TI - Screening for diabetes. AB - This article discusses the rationale and method of screening for diabetes in a primary care setting. It describes guidelines laid down by international organizations, while adding pragmatic suggestions based upon reality in South Asian and other developing countries. PMID- 25831691 TI - Writing tips for medical students/researchers following a comparative study. PMID- 25831692 TI - The decrepit state of trauma care in under-developed healthcare settings and the need to integrate trauma rehabilitation as a continuum of care. PMID- 25831693 TI - Frequency of proven risk factors for deep vein thrombosis in clinical patients: Results of a study on patients being treated at a tertiary care hospital in Rawalpindi, Pakistan. AB - OBJECTIVE: To enlist the dominant risk factors predisposing patients to deep venous thrombosis. METHODS: The prospective study was conducted in surgical and medical departments of Combined Military Hospital, Rawalpindi, and Fauji Foundation, Islamabad, from January 2012 to December 2013. Patients having deep venous thrombosis of lower extremities by duplex scan were enrolled. After taking their detailed personal and biochemical history, frequency of risk factors was noted and graded accordingly. RESULTS: Of the total 120 patients, 71(59%) were males. Overall, left leg was involved in 53(44%), right leg in 34(28%) and both legs in 33(28%). Of the total, 68(57%) patients were >40 years of age. Immobility was the main cause of deep venous thrombosis in 18(15%), followed by surgical interventions in 10(8%). Pregnancy and post-partum thrombosis was the major cause in 9(8%) women. Only 6(5%) patients had natural predisposition to deep venous thrombosis. CONCLUSION: Immobility was an independent and important risk factor for deep venous thrombosis. Thromboprophylaxis is not routinely provided in most health centres in Pakistan, exposing patients to the risk. PMID- 25831694 TI - [Effects of epidural anesthesia on stress-induced immune supression during major corrective spine surgery]. AB - STUDY DESIGN: A prospective, randomized study wias performed to compare two anesthetic methods. OBJECTIVE: To evaluate the effect of epidural analgesia on postoperative pain, endocrine- metabolic and inflammatory stress response and cellular inmmune responses during major corrective spine surgetry. METHODS: The study included 350 patients aged 15 to 65 who were randomly allocated to two equal groups. Group I (n=205) had continuous epidural analgesia (E4) and sevoflurane anesthesia during surgety and continuous epidural analgesia with ropivacaine and fentanil after surgery; Group 2 (n= 145) had general anesthesia with sevoflurane and fentanil and systemic administration of opioids after surgery. Patient pain, PONV syndrome, mobility, and satisfaction were measured after surgery along with plasma levels ofcortisol, ghmcose, interleukins IL 1beta, IL-6, and IL-10 during and after surgemy C-reactive protein (CRP), and cell-surface receptor expression of immune cells (cluster of differentiation) HLA DR+/CD3-, HLA-DR+/CD3+, HILA-DR, CD3, CD4, CD8, CD16, CD19 CD16/56+, and CD16/56+/CD3+) were measured perioperatively. RESULTS: In group 1, there were significantly less pain, less nausea, earlier mobility, and higher satisfaction than those in group 2. Group I has also demonstrated significantly less plasma levels of glucose, cortisol, CRP, IL-lbeta, IL-6, IL-10 at various stages. The ratio of CD4/CD8 (p=0.001) and B cells (p=0.01) have increased by postoperative day 3 in group 1. NK-cells (CD16/56+) have decreased significantly by day 3 after surgery (p=0.001) compared to the group 2. T-lymphocytes, (CD3) have decreased in all patients, but they were significantly lower in patients receiving opioids, compared wiith EA. CONCLUSIONS: Polerfulr afferent stimulation in major corrective spine surgery accompanied by immunosuppression for at least a wieek after surgery. EA reduces the surgical stress response, prevents postoperative lymphocyte apoptosis and thus, increases stress and infectious resistance. PMID- 25831695 TI - [Effects of prolonged thoracic epidural analgesia on the frequency of postoperative atrial fibrillation in thoracic surgery]. AB - Postoperative atrial fibrillation (POAF) has remained one of the most common complications that occur following non-cardiac thoracic surgery. Although it is dificult to determine the true incidence ofPOAF due to various methodologies used to identify its occurrence, reported rates have varied between 12 and 67%. The occurrence of POAF is associated with significant morbidity, such as increased risk ofstroke, atrial thrombosis and systemic mbolism, postoperative mortality, and significant increases in hospital length of stay and costs. OBJECTIVES: We aimed to evahluate the impact of thoracic epidural analgesia on the frequency of POAF in patients undergone lung cancer surgery. MATERIALS AND METHODS: We performed a retrospective analysis of medical cards of472 patients over 55 y.o., undeigone luhmg surgery (lobectomy (LE) and pneumonectomy (PE)) due to oncological diseases. The patients' physical status was II-Ill according to ASA classification. The average duration of the operations was 204.3+/-59.4 min. The average blood loss was 393+/-198 ml. The patients were divided into two groups according to the type of anaesthesia during the surgery and type of pain management during postoperative period Each group was divided into subgroups according to the type ofsurgery (LE and P4E). The patients of the group-1 (N=300, average age 61.7+/-7.74years) received a general anaesthesia (GA) (fentanyl, ketamine, propofol, sevoflurane) with intercostal blockade with mixture of alcohol and nodvocain in the end ofsumgery and follow ing complex analgesia in postoperative period (opioid analgesics, NSAIDs). The patients of the group-2 (N= 172, average age 62.2+/-7.45 years) received a combined (CA) general anaesthesia (propofol, ketamine. fentanyl, sevoflurane) and thoracic epidural analgesia with ropivacaine 0.3%, fenianyl 4 ug/ml and epinephrine 2 ug/ ml. These patients received the epidural infusion of ropivacaine 0.2%, fentanyl 2 ug/mnl and epinephrine 2 ug/ml for 5-7 days after the surgery. In postoperative period all patients in both groups received standard systemic analgesia with opioid analgesics. NSAIDs, paracetamol. A fixation of POAF wias heldfrom the first day after the surgery and until a discharge according to clinical signs and ECG fJacts. RESULTS: In GA-group the frequency ofPOAF was 15.3% (46/300). The overall incidence of POAF did not differ between patients undergone pneumonectomy and lobectomy in GA (21.6% (16/74) vs. 13.7% (30/226), respectively (p=0.08)). In CA group the frequency of POAF was significantly reduced versus GA-group (8.7% (15/172) vs. 15.3% (46/300), respectively (p=0.04)). Patients mundergone pneumonectomy suffered from postoperative atrial fibrillation in 13.2% (9/68) of cases and lobectomy in 62% (6/104) of cases in CA (p=0.09). The frequency of POAF in patients undergone pneumonectomy did not differ significantly between the groups (p=0.19), but the frequency of postoperative atrial fibrillation in patients undergone lobectomy was significantly reduced in CA versus GA (p=0.04). CONCLUSIONS: Postoperative thoracic epidural analgesia significantly decreases the frequency of postoperative atrial fibrillation in patients undergoing extended lungs surgery and most effective in patients undergoing lobectomy. PMID- 25831696 TI - [Regional anaesthesia in women with morbid obesity in obstetrics and gynecology]. AB - The article deals with regional anaesthesia peculiarities in womnen wiith morbid obesity in obstetrics and gynecology. The articles discusses cases demonstating safety and effectiveness of low-dose comnbined spinal-epidural anaesthesia in these patients. PMID- 25831697 TI - [Correction of local anesthetic dosage in spinal anesthesia in pregnant women with obesity]. AB - INTRODUCTION: Intra-abdomninal pressure (IAP) is one of the reasons for reducing the volume of the subarachnoid space, the cerebrospinal fluid of pregnant iwomnen with obesity and as a result, a high spinal block in spinal anesthesia (SA), clinical manifestation of which is marked arterial hypotension. OBJECTIVE: To decrease the frequency and severity of arterial hypotension related to the conduct of SA due to the correction dose of local anesthetic with the level of intra-abdomninal pressure and timing of operative delivery MATERIAL AND METHODS: The study involved 252 women. To determine the physiological level of IAP at different stages of gestation used to study the level of IAP in 118 pregnant women with normal body weight. To explore the relationship of frequency of hypotension in the SA and the development of methodology for calculating the dose of local anesthetic in pregnant women examined 92 patients, 62 of whom were obese. To assess the adequacy of the developed technique further examined 42 obese women. RESULTS: it was determined that the gestation 38-40 weeks, the mean physiological IAP corresponds to 20 mm Hg, at the term of 35-37 weeks - 18 mm Hg at 32-34 weeks of pregnancy - 16 mnm Hg. Studies have shown that an adequate dose of local anesthetic for spinal anesthesia for operative delivery in pregnant women with obesity depends on the level of IAP The required dosage is determined by the percentage reduction for the difference between the actual level of IAP and the predicted IAP The required dosage 5.5% per mm Hg IAP is higher than the physiological norm. CONCLUSION: The developed method of calculating the dose of local anesthetic with the levels of IAP and gestational age prevents development of arterial hypertension, the optimum level of sensory block during SA for operative delivery obese women. PMID- 25831698 TI - [Oxidative stress in perioperative period of cesarean section]. AB - OBJECTIVE: To assess a pro- and antioxidant status in pregnant women at the system level in the perioperative period of cesarean section under regional and general anaesthesia. MATERIAL AND METHODS: 62 pregnant women aged 21 to 37 years (30,9 +/- 6,2 y,ears) undergone delivery by cesarean section under general (n = 33) and regional (29) anaesthesia (1-2 class ASA (American Society ofAnesthesiologists). Blood samples were collected immediately after placing patients on an operating table (T1), immediately after suturing the surgical wound (T2), and 12 (T3) and 24 (T4) hours after taking the first sample. We studied following parameters: superoxide dismutase (SOD), glutathione peroxidase (GP). reduced glutathione (RG), total antioxidant activity, active products that react with thiobarbituric acid (TBA-ap). RESULTS: In general anaesthesia cesarean critical period activation ofprooxidant and antlioxidant activity is the period T2. Activation prooxidant activity (TBA-ap) was stored at 12 and 24 hours after surgery. Increased antioxidant activity (SOD, GP) was observed in the period T2. which wass replaced by its inhibition to 24 hours. Reduced glutathione content (RG) was reduced during T2 remains at low values up to 24 hours. Regional anaesthesia did not change observed prooxidant (poorly marked increase antioxidant activity (SOD, GP), which persists up to 24 hours). Reduced glutathione content (RG) was reduced in the period T3. but recovered after 24 hours. CONCLUSION: The use of regional imnaesthesia and spontaneous breathing with atmospheric air during an elective caesarean section helps to avoid induction and manifestations of oxidative stress in pregnant women in the perioperative period and to fully implement the program early activation parturients after cesarean section. PMID- 25831699 TI - [Assessment of prophylaxis and treatment of blood loss in patients with pre eclampsia]. AB - OBJECTIVE: To improve treatment results of women with massive obstetrical blood loss. Subjects and methods: 96 female patients with average and heavy degree preeclampsia worsened massive blood developing were involved into the investigation. The women were divided into two groups: main (n=55) (basic) - it's patients were treated with complex of offered wiays control (n=41) - it's patients were evaluated retrospectively. During the investigation the parameters of hemostasis system and periphery blood values were performed as dynamic evaluations, acidity-basic state and water-electrolyte balance parameters, medical history were monitored. RESULTS: As a result of the investigation it was found out that these offered actions complex application about reducing massive obstetric blood accelerates restoration of clinic, bio-chemical paramnleters during the early post-operating period CONCLUSION: The application of the offered methods has reduced both inltraoperative blood loss in women with preeclamsia and use of blood components and the time spent on the hemostasis system correction for all the women of the base group. PMID- 25831700 TI - [New oral anticoagulants for thromboprophylaxis under routine use of tranexamic acid after hip joint arthroplasty]. AB - PURPOSE: To evaluate the efficacy and safety of the novel oral anticoagulants under conservative hemostasis with tranexamic acid in hip arthroplasty. MATERIAL AND METHODS: All patients received 40 mg of enoxaparin 12 hours prior to surgery and on the operating day, and then they received either 10 mg of rivaroxaban (40 patients), 220 mg of dabigatran (42 patients) or 40 mng of enoxaparin (39 patients). Tranexamic acid with doses of 10 - 20 mg/kg was administered to all patients: within 30 minutes prior to surgery and 6 hours after the first infision. The hemorrhagic and thrombotic complications in a hospital outpatient therapy and outcomes in 35 days after surgery were evaluated. RESULTS: Minor bleeding was observed only in the rivaroxaban group, the complications rate in hospital was 2.5%, among outpatients 3.1%. At hospital discharge the DVT was 12.5% in rivaroxaban group, 7% in dabigatran and 8% in enoxaparin group (p>0.05). Asymptomatic distal DVT was found in 82% of patients by ultrasound screening. CONCLUSION: The new oral anticoagulants are effective and safe for venous thromboembolism preventing after hip re placement. Routine use of tranexamic acid was not accompanied by increased risk of DVT PMID- 25831701 TI - [Autotransfusion of cord blood erythrocytes in newborns with malformations requiring early surgical intervention]. AB - PURPOSE: To evaluate the clinical efficacy of cord blood erythrocytes autotransfiusion for the correction of anemia in the intra-and postoperative periods in infants requiring early surgical correction of congenital malformations. METHODS: Washed autoemythrocytes from placental umbilical blood were transfused for correction of intra and post-operative anemias. Umbilical blood assembly was carried out after extraction of the child and navel intersection by the occluded mean by a vein puncture distal (placental) end of a navel by the drainage needle which is a part of special transfiusion system. Further blood in the marked containers was pitched in branch of gravitational surgery of blood where its centrifiugal separation on erythrocyte mass and plasma was made. Then concentrated red cells it was put on storage for 21 day in a cooler at temperature 40 degrees C. Directly ahead of autotransfusion concentrated red cells was exposed to washing out in sterile physiological solution and a filtration through the micromodular filter. Then the marked package with the washed erythrocytes was pitched in branch of surgery of newborns for the purpose offurther anttqtransfusion under indications. The transfusion autoerythrocytes was made according to reacting at the moment of carrying out of work to orders of Ministry of Health of the Russian Federation: to the Order of Ministry of Health of the Russian Federation from November, 25th, 2002 No 363 "About the statement of the Instruction on application of components of blood" and to the Order of Ministry of Health of the Russian Federation from April, 2nd, 2013 N 183n "About the statement of rules of clinical use of donor blood and (or) its components". RESULTS: Total 122 newborns received an autotransfiusion of washed erythrocytes of placental/umbilical cord blood for the correction of anemia in the department of neonatal surgery in the period from 2005 to 2013. 66 children who are in the first two weeks of life were performed surgical intervention for malformation of the gastrointestinal tract (gastorshizis (22), omphalocele (2). itestinal atresia (10), esophageal atresia or doubling (4)), congenital diaphragmatic hernia (15), space-occupying lesions (teratoma (6) and lymphangioma (3)) and other pathologies (adenomatous lung (1), the sequestration of the lung (2). ovarian cyst (1)). Control group consisted of39 infants operated on for similar malformations , which in the absence of prior communication harvested autologous red blood cells in the first three weeks of life sparkled donor erythrocytes. Inmost cases (57 newborns - 86.4%) of the amount harvested and transfused blood autokonmpo tov was sufficient for the relief ofanemia, despite the fact that the volume of transfused autoeritrotsitnoy mass per kilogram of body weight was almost two times lower than the amount of donor erythrocyte mass used in the comparison group. Additional donor transfusion of red blood cells in the group of children who had autotransfusion, it took nine newborns (13.6%). The main indications for repeated transfusions were clinical and laboratory signs of anemia, persisting after autotransfusion or resulting from repeated operations. After transfusion of washed autoerythrocytes value of clinical and biochemical. blood tests, urinalysis were within the age norm. Post transfusion reactions in children who have received a transfusion autoerythrocytes not mentioned CONCLUSION: The use of placental/umbilical cord blood autoe,ythrocyvtes in children requiring early surgical correction of congenital malformations can significantly reduce the need for donor red blood cells. Autologous red blood cells use is a safe and effective alternative to transfusion of donor red blood cells. PMID- 25831702 TI - [Hemodynamic effects of the alveolar recruitment maneuver in cardiosurgical patients with left ventricular systolic dysfunction]. AB - PURPOSE: To evaluate hemodynamic effects of the ahveolar recruitment maneuver (ARM) in cardiosurgical patients with left ventricular systolic dysfunction. MATERIALS AND METHODS: We estimate hemnodynamics data obtained during intraoprative ARM in 16 cardiosuigical patients with left ventricular systolic dysfunction. ARMA were applied due to hypoxemnia with PaO2/FiO2 less than 250 nmm Hg. after CPB termination and heparin neutralization. Patients with signs of right heart failure were excluded from the study ARM were carried out after sternum closing. ARM method: Pinsp was increased stepwise until achievement of the alveoli opening point. PEEP was used 5 cm H2O greater than the lower inflection point in "pressure - vohlume" loop. The average alveoli opening pressure was 44.7 +/- 2.5 cm H2O and the average PEEP was 12.8 +/- 1.7 cm H2O. Hemodynamic parameters were eva luated before ARM and at the point of alveoli opening. Pulmnonary artery pressure and cardiac output were evaluated by Swan Gant- catheter and thermodilution method Left ventricle contractility, preload and end-systolic (LVESWS) and end-diastolic (LVEDWS) wall stress were studied using TEE. t -test for dependent variables was used for statistical analysis. Data are presented as M +/- delta. RESULTS: During ARM stroke volumne index decreased from 36.5 +/- 4.2 to 33.5 +/- 3.9 ml/m2 (p <0.05). Left ventricle contractility was not changed (there were no reduction in the left ventricle fraction area change (FAC)). Descent of left ventricular preload was the main cause of cardiac output decrease: end-diastolic area of the left ventricle decreased friom 22.6 +/- 4.3 to 19.5 +/- 4.1 cm2 (p <0.05). Preload renduction was accompanied by paradoxical increase in PCWP associated with an increase in intirathoracic pressure: friom 10.8 +/- 4.6 to 13.8 +/- 4 mm Hg (P <0.001). There was decrease in intramural left ventricular afterload during ARM: LVESWS decreased from 50.6 +/- 11.5 to 39.5 +/- 10.6 cm * kdyn-2 (p <0.01), which also contributed to the decline of oxygen demand in systole. ARM did not lead to deterioration of left ventricular systolic dysfunction and increased doses of inotropic agents. PaO2/FiO2 increased from 238.3 +/- 11.7 to 301.7 +/-22.3 mm Hg (p<0.05). CONCLUSION: Reduction of left ventricular preload is the main cause of cardiac output decrease during ARM. Positive hemodynamic effects of ARM are afterload reduction and left ventricle oxygen demand reduction. Our study showed the possibility ofARM applying in cardioswrgical patients with moderate left ventricular systolic dysfunction. PMID- 25831703 TI - [Efficiency of high-volume hemofiltration in patients with severe sepsis and intracranial hypertension]. AB - We performed a retrospective study in 68 patients (144 procedures) with severe sepsis and intracranial hypertension measured by the pressure in the central retinal vein. The patients underwent high-volume hemofiltration (HV-HF) for extrarenal indications. Increased pressure in the central retinal vein was accompanied by critical points of cerebral perfusion pressure and the growth of neurological deficit with inhibition level of consciousness to coma 1. In this case, IHV-HF may be associated with the formation of the critical points of cerebral perfihsion and severe disorders of microcirculation and the lack of resolution of tissue hypoperfusion. In case of intracranial hypertension IHV-HF is not effective in the category of patients where there is a combination DeltapCO2 > 5.9 mm Hg level and GCS <10 points. PMID- 25831704 TI - [Early diagnosis of Takayasu's disease (clinical case report)]. AB - Nonspecific aortoarteritis (Takayasu s disease, obliterating aortoarteritis, disease of the missing pulse) is a systemic inflammatory disease of aorta and its branches, which leads to stenosis and ischemia of surrounding tissues. This disease is more common in young women and characterized by slowly progressive course with significant impairing quality of life. Etiology of the Takayasu's disease is unknown. Syndrome of the systemic inflammatory reaction with the clinical manifestations of the effects of lesions of the aorta and its branches at different anatomical levels (symptom: coarctation, abdominal ischemia, coronary, renovascular hypertension, lesions of the pulmonary artery) are criteria of this systematic process. Angiography can detect typical vascular changes due to a nonspecific aortoarteritis and remains the gold standard for its verification. The effectiveness of conservative therapy, surgical treatment, the prognosis for life is entirely determined by the detection of this insidious disease in the initial stages of its development. Until today, the early detection of non-specific aortoarteriite is not generally accepted and widely used, and therefore remain relevant. PMID- 25831705 TI - [Primary (idiopathic) pulmonary hypertension (Ayerza-Arrillaga syndrome) and pregnancy - intensive care and anesthesia management]. AB - The lecture deals with detailed information about the etiology, pathogenesis and clinical manifestations of primary (idiopathic) pulmonaiy hypertension, intensive treatment and anesthesia in pregnancy. PMID- 25831706 TI - [Using recombinant activated blood coagulation factor VII for treatment of hemorrhagic syndrome in patients with thrombocytopenia]. AB - The review deals with an analysis of the use of recombinant activated factor clotting VII (rFVIIa) for the treatment of hemorrhagic syndrome in patients with thrombocytopenia. The review discusses cases of rFVIIa use during bleeding of different localization and different invasive interventions, a frequency of thrombotic complications and causes of the rFVlIIa insufficiency. PMID- 25831707 TI - [Iron metabolism in women with anemia and eclampsia (Part I)]. AB - The review deals with a modern view of iron exchange in general and during pregnancy, in particular Different views on the mechanisms of the development of anemia in pregnancy are reflected. The protective role of anemia is noted, and also the opinion of the review authors to the negative role of prophylactic supplementation of iron is reflected. Are numerous and compelling scientific evidence pointing to the large number of negative prevention of iron. That questioned the usefulness of routine appointments for pregnant women with iron. According to a large number of studies assigning pregnant iron on the one hand, contributes to excessive activation of free radical oxidation, the accumulation of lipid peroxidation products and demonstrations of eclampsia, and from the other potentiates the bacterial aggression and development of purulent-septic diseases that generally leads to the development of complications in pregnancy. PMID- 25831708 TI - [Anaesthetic management of the infant with gastroschisis]. AB - The review deals with an analysis of articles about a gastroschisis, its firequency and outcomes of treatment. The review discusses the mortality in patients with gastroschisis in Russia and peculiarities of anaesthesia management and surgical treatment. PMID- 25831709 TI - [The methodology of therapeutic hypothermia in children born in a state of asphyxia]. AB - This guideline provides the diagnostic and treatment algorithm for newborns with gestational age over 35 weeks and weighing more than 1800g who has severe asphyxia in birth with the threat of severe or medium-severe hypoxic-ischemic encephalopathy. PMID- 25831710 TI - Prosthodontic rehabilitation for a patient with acromegaly. AB - Acromegaly is a condition which results from an excess of growth hormone produced by the pituitary gland after epiphyseal plate closure at puberty. The most common cause of acromegaly is a benign pituitary adenoma. Acromegaly is characterised by enlargement of the hands, feet, nose and ears; expansion of the skull and pronounced brow protrusion. From an oral standpoint, the most relevant symptoms are mandibular protrusion, spacing of the lower teeth and macroglossia. A 46 year old patient was referred to University Dental School and Hospital by her General Dental Practitioner. The patient had been diagnosed with acromegaly and was receiving medical care from a consultant endocrinologist. The patient was partially dentate with only her lower anterior dentition remaining. She was wearing a complete upper denture but was unable to function effectively due to a lack of occlusal support. Treatment comprised non-surgical periodontal management, construction of upper and lower removable prostheses in a class III relationship and composite restorations on the remaining lower teeth. PMID- 25831711 TI - Do head and neck cancer survivors attend a high street dentist on a regular basis? AB - Head and neck cancer (HNC) patients face complex oral health issues following treatment. The aims of this study were to determine the proportion of HNC patients attending their dentist regularly and investigate clinicodemographic characteristics associated with attendance. Two surveys asked about patient attendance patterns and dentition. Pre-treatment orthopantomographs were evaluated for those treated between 2007-2009. The response rate was 66% (444/672). 69% (305/444) saw a high street dentist regularly. 28% of edentulous patients attended regularly compared with 84% with natural teeth, p < 0.001. Associations at p < 0.001 with regular attendance were the leaving of formal education (> 16 years) and earlier clinical staging. HNC patients should be encouraged to see a dentist regularly for routine dental care and cancer surveillance in partnership with the cancer service. PMID- 25831712 TI - Colour stability of maxillofacial silicone elastomers: a review of the literature. AB - Colour degradation is a serious limitation of maxillofacial silicone elastomers and most silicone facial prostheses have to be remade within 1 year due to colour deterioration. A comprehensive review of the literature was completed using MEDLINE and PubMed Library databases. This was supplemented with a manual search of selected journals and textbooks. English language articles published in peer reviewed journals from 1966 to January 2012 in which colour stability of silicone elastomers was evaluated using standard research protocols were included. In all, 127 articles were identified and 23 met the inclusion criteria. Current literature reveals that average colour stability of maxillofacial silicone prostheses is 6-12 months, and inherent unstable nature of silicones is responsible for the color degradation. Opacifiers, oil pigments and inorganic colourants may have a protective effect on colour stability of prostheses. Organic colourants, ultraviolet (UV) light, cleansing solutions, dust and aging can adversely affect colour stability of silicone prostheses. A direct comparison between studies has not been possible, because of the differences in experimental set-up such as materials tested, colourants used, or method of aging. There appears to be a need for a standardised test protocol for colour stability of maxillofacial materials. Colour degradation limits the useful lifespan of maxillofacial silicones. Improvements in colour stability is possible with the use of certain nano opacifiers, UV absorbers, photoprotective agents, and use of inorganic pigments and metal oxides. PMID- 25831713 TI - Composite inlays: a systematic review. AB - The purpose of this study is to review the available literature related to composite inlays. Electronic databases published up to November 2013 were searched. Studies that evaluate composite resin inlays for the restoration of posterior teeth were selected. The studies should compare composite inlays against gold inlays, ceramic inlays and direct composite fillings regarding longevity, aesthetic quality and postoperative sensitivity or comparing the clinical effectiveness of them on premolars versus molars or on 1-2 surface preparations versus multi-surface preparations. Despite the heterogeneity of the available clinical trials composite inlays seem to be an effective method for the restoration of posterior teeth. PMID- 25831714 TI - The influence of implant location and position characteristics on peri-implant pathology.. AB - Peri-implant pathology is a multifactorial disease, incorporating biological and biomechanical components in its pathogenesis; however; few studies address the possible risk factors. This study investigated the effect of implant location and position characteristics on the occurrence of Peri-implant pathology. A total of 1350 patients with dental implants were included 270 patients with peri-implant pathology and 1080 healthy controls. Results demonstrated that in the absence of bacterial plaque and smoking, the variable proximity of the implant to other implants or teeth revealed a significant difference between groups with a protective effect, but not in the presence of bacterial plaque and smoking. PMID- 25831715 TI - Effect of increased post length due to the presence of the remaining coronal structure on the fracture strength of post-retained restorations. AB - This study evaluated the effects of the remaining coronal tissue and post type on the fracture strength of incisors. Sixty human maxillary central incisors were sectioned at the cemento-enamel junction or at 2 mm above this junction. The roots received cast cores and posts, fibre posts, or relined fibre posts (n = 10 each). A compressive load was applied over the cores untilfracture. In the absence of coronal structure, the fracture strength did not differ among the post types evaluated. In the presence of remaining coronal structure, the fracture strength was higher in specimens with cast cores and posts. PMID- 25831716 TI - Effect of air moisture content on adhesion to dentine: a comparison of dental air/water syringe tips. AB - This study aimed to evaluate the spray pattern and air moisture content produced by single-use syringe and multiple-use syringe tips. The drying efficacy was evaluated by analyzing the spray and by detecting the presence of moisture in the air blast through the tips. Single-use tips had a more consistent spray pattern and produced a moisture-free airflow compared to the multiple-use tips. The differences were statistically significant. Adhesion to dentine between tooth preparations dried with the two tips was evaluated using a tensile test. The differences were statistically insignificant. PMID- 25831717 TI - [Development of anti-cancer drug: past and future]. PMID- 25831718 TI - [Future drug treatment against cancer viewed from current statistical data]. PMID- 25831719 TI - [Current status and issues in early & exploratory oncology clinical trials in Japan]. PMID- 25831720 TI - [Classification of anti-cancer agents]. PMID- 25831721 TI - [Side effects of chemotherapy]. PMID- 25831722 TI - [Clinical practice guidelines for the adverse events in medical oncology]. PMID- 25831723 TI - [Points of management for elderly patients in chemotherapy]. PMID- 25831724 TI - [Important points of measures for side effects in children]. PMID- 25831725 TI - [Safety management in the outpatient chemotherapy unit]. PMID- 25831726 TI - [Report of serious adverse drug reaction induced by anti-cancer agents]. PMID- 25831727 TI - [Assessment of anticancer drug-induced adverse event]. PMID- 25831728 TI - [Reduction and withdrawal of chemotherapy]. PMID- 25831729 TI - [Drug interactions of anti-cancer agents]. PMID- 25831730 TI - [Prophylactic management for adverse events of cancer chemotherapy]. PMID- 25831731 TI - [Patient education for side effects of anti-cancer agents]. PMID- 25831732 TI - [Monitoring the side effects of cancer chemotherapy]. PMID- 25831733 TI - [Clinical pharmacology and toxicology of anticancer drugs]. PMID- 25831735 TI - [Pharmacogenomics of anti-cancer drugs for individual treatment]. PMID- 25831734 TI - [Biomarkers for the prediction of adverse events]. PMID- 25831737 TI - [Mechanisms and side effects of cytotoxic anticancer drugs]. PMID- 25831736 TI - [Exploratory biomarker analyses and companion diagnostics]. PMID- 25831738 TI - [Adverse events and those managements of alkylating agents]. PMID- 25831739 TI - [Platinum drugs]. PMID- 25831741 TI - [Purine analogs]. PMID- 25831740 TI - [Folate antagonist]. PMID- 25831742 TI - [Adverse effects of antimetabolite fluoropyrimidine analog]. PMID- 25831743 TI - [Cytidine]. PMID- 25831744 TI - [Microtubule polymerization inhibitors]. PMID- 25831745 TI - [Microtubule depolymerization inhibitor]. PMID- 25831746 TI - [DNA topoisomerase I--targeting drugs]. PMID- 25831747 TI - [Topoisomerase II inhibitors (anthracyclines)]. PMID- 25831748 TI - [Topoisomerase II interactive agents (except for anthracyclins)]. PMID- 25831749 TI - [Antitumor antibiotics]. PMID- 25831750 TI - [Antileukemic]. PMID- 25831751 TI - [Antimyeloma drugs]. PMID- 25831752 TI - [Action mechanisms of molecular target agents and their off-target toxicities; introduction]. PMID- 25831753 TI - [Anti-CD20 antibody]. PMID- 25831754 TI - [Anti-HER2 antibodies]. PMID- 25831755 TI - [Anti-CD33 monoclonal antibody drug conjugate--Gemtuzumab ozogamicin (GO)]. PMID- 25831756 TI - [Anti-EGFR antibodies]. PMID- 25831757 TI - [Anti-CCR4 monoclonal antibody]. PMID- 25831758 TI - [Anti-vascular endothelial growth factor antibody]. PMID- 25831759 TI - [Anti-RANKL antibody]. PMID- 25831760 TI - [Adverse events and supportive therapy of anti-HER2 targeted therapy]. PMID- 25831761 TI - [Side effects of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI)]. PMID- 25831762 TI - [Inhibitors for ABL, KIT and PDGFR tyrosine kinases--imatinib, nitotinib, and dasatinib]. PMID- 25831763 TI - [Notable adverse events of ALK inhibitors in patients with ALK rearranged non small-cell lung cancer]. PMID- 25831764 TI - [VEGFR inhibitor (multi-target kinase inhibitors)]. PMID- 25831765 TI - [Proteasome inhibitors]. PMID- 25831766 TI - [Toxicity management for mTOR inhibitors]. PMID- 25831767 TI - [HDAC inhibitor]. PMID- 25831768 TI - [Bisphosphonate]. PMID- 25831769 TI - [Somatostatin analog]. PMID- 25831770 TI - [Mechanism and side effect of endocrine therapy]. PMID- 25831771 TI - [Anti-estrogen agents]. PMID- 25831772 TI - [Toxicity of aromatase inhibitor]. PMID- 25831774 TI - [LH-RH derivative]. PMID- 25831773 TI - [Effect and adverse event of enzalutamide and abiraterone in prostate cancer]. PMID- 25831775 TI - [Major side effects of systemic glucocorticoid]. PMID- 25831776 TI - [Management of adverse events with interferon and interleukin-2]. PMID- 25831777 TI - [Febrile neutropenia]. PMID- 25831778 TI - [Appropriate use of granulocyte-colony stimulating factor]. PMID- 25831779 TI - [Anemia]. PMID- 25831780 TI - [Thrombocytopenia]. PMID- 25831781 TI - [Appetite loss]. PMID- 25831782 TI - [Chemotherapy-induced nausea, vomiting and diarrhea]. PMID- 25831783 TI - [Oral mucositis, stomatitis--oral management of cancer patients receiving chemotherapy]. PMID- 25831784 TI - [Constipation and ileus]. PMID- 25831785 TI - [Hepatotoxicity of chemotherapy]. PMID- 25831786 TI - [Reactivation of hepatitis B virus in patients treated with systemic chemotherapy]. PMID- 25831787 TI - [Gastrointestinal ulcer, gastrointestinal perforation]. PMID- 25831788 TI - [Interstitial lung disease]. PMID- 25831789 TI - [Heart failure]. PMID- 25831790 TI - [Arrhythmia, conduction disturbance]. PMID- 25831791 TI - [Hypertension]. PMID- 25831792 TI - [Cancer-associated thromboembolism--prophylaxis and therapy]. PMID- 25831793 TI - [Renal dysfunction]. PMID- 25831794 TI - [Proteinuria and bleeding due to anticancer drugs]. PMID- 25831795 TI - [Thyroid dysfunction (hypothyroidism and hyperthyroidism)]. PMID- 25831796 TI - [Chemotherapeutic agents and electrolyte imbalance]. PMID- 25831797 TI - [Dyslipidemia]. PMID- 25831798 TI - [Disorder of glucose metabolism (hypoglycemia, hyperglycemia)]. PMID- 25831799 TI - [SIADH (syndrome of inappropriate secretion of antidiuretic hormone)]. PMID- 25831800 TI - [Tumor lysis syndrome]. PMID- 25831801 TI - [Skin disorders]. PMID- 25831802 TI - [Hand-foot syndrome]. PMID- 25831803 TI - [Chemotherapy-induced alopecia]. PMID- 25831804 TI - [Skin damage by extravasation of chemotherapeutic agents]. PMID- 25831805 TI - [Peripheral neuropathy]. PMID- 25831807 TI - [Ototoxicity of cisplatin]. PMID- 25831806 TI - [Central nervous system neurotoxicity of anticancer chemotherapy]. PMID- 25831808 TI - [Dysgeusia]. PMID- 25831809 TI - [Corneal epithelial disorder, lacrimal drainage obstruction, and conjunctivitis]. PMID- 25831810 TI - [Drug-induced arthralgias and myalgias]. PMID- 25831811 TI - [Rhabdomyolysis]. PMID- 25831812 TI - [Mental illness]. PMID- 25831813 TI - [Chemotherapy related gonadotoxicity]. PMID- 25831814 TI - [Allergic reaction and anaphylaxis]. PMID- 25831815 TI - [Safety management of infusion reactions]. PMID- 25831816 TI - [Secondary malignant neoplasms]. PMID- 25831817 TI - [Growth failure]. PMID- 25831818 TI - [Management of adverse effects of standard regimens for small cell lung cancer]. PMID- 25831819 TI - [Management of side effects with platinum doublet chemotherapy used for treatment of non-small cell lung cancer]. PMID- 25831820 TI - [Management of anthracycline and taxane therapy-induced symptoms for the patients with breast cancer]. PMID- 25831821 TI - [Pertuzumab+trastuzumab+DTX therapy]. PMID- 25831822 TI - [Concurrent chemoradiotherapy with cisplatin for locally advanced squamous cell carcinoma of head and neck]. PMID- 25831823 TI - [5-FU+CDDP(FP) +cetuximab in recurrence/metastasis head and neck cancer]. PMID- 25831824 TI - [Strategies to minimize toxicities during chemoradiotherapy for esophageal cancer]. PMID- 25831825 TI - [S-1 plus cisplatin(SP) for advanced gastric cancer]. PMID- 25831826 TI - [Chemotherapy and trastuzumab for HER2 positive gastric cancer]. PMID- 25831827 TI - [Incidence and management of adverse events in FOLFOX plus bevacizumab therapy for colorectal cancer]. PMID- 25831828 TI - [Management for adverse events associated with FOLFIRI plus cetuximab or panitumumab]. PMID- 25831829 TI - [Supportive management of cisplatin and gemcitabine combination therapy for advanced biliary tract cancer]. PMID- 25831830 TI - [Adverse event and countermeasure with regard to FOLFIRINOX for pancreatic cancer]. PMID- 25831831 TI - [Ovarian cancer: TC therapy]. PMID- 25831832 TI - [Side effect and supportive care to combination of gemcitabine and cisplatin chemotherapy for the advanced urothelial cancer]. PMID- 25831833 TI - [Germ cell tumors]. PMID- 25831834 TI - [Radiation and temozolomide therapy]. PMID- 25831835 TI - [Ara-C]. PMID- 25831836 TI - [ATRAC therapy]. PMID- 25831837 TI - [Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab]. PMID- 25831838 TI - [Supportive care for patients with non-Hodgkin lymphoma receiving R-CHOP chemotherapy]. PMID- 25831839 TI - [Hodgkin lymphoma--ABVD regimen]. PMID- 25831840 TI - [Bortezomib-based triple combinations (VCD, PAD) for untreated patients with multiple myeloma]. PMID- 25831842 TI - [Osteosarcoma: ADM+CDDP therapy]. PMID- 25831841 TI - [Complications and managements in treatment of melphalan, prednisone and new agents]. PMID- 25831843 TI - [VDC (A) + IE alternate chemotherapy]. PMID- 25831844 TI - [Rhabdomyosarcoma--VAC regimen]. PMID- 25831845 TI - [Multidisciplinary approaches--the role of doctors]. PMID- 25831846 TI - [Oral management during cancer chemotherapy--imperative role of dentistry and oral surgery]. PMID- 25831847 TI - [Team medical care--role of the pharmacist]. PMID- 25831848 TI - [Nursing of patients with cancer receiving chemotherapy]. PMID- 25831849 TI - [Team medicine--supportive care team]. PMID- 25831850 TI - [Ethical perspective in clinical trials for drug development]. PMID- 25831851 TI - [Comprehensive geriatric assessment for elderly patients with cancer]. PMID- 25831852 TI - [Cost-effectiveness of cancer drug treatments]. PMID- 25831853 TI - [Safety measures of oncology drugs]. PMID- 25831854 TI - [Cancer treatment system and a new guideline for cancer treatment hospitals in Japan]. PMID- 25831855 TI - [Community Cancer Networks: establishing alliances between hospital specialists and community treatment professionals to support cancer patients in Japan]. PMID- 25831856 TI - Anisometry anterior cruciate ligament sport injury mechanism study: a finite element model with optimization method. AB - ACL damage is one the most frequent causes of knee injuries and thus has long been the focus of research in biomechanics and sports medicine. Due to the anisometric geometry and functional complexity of the ACL in the knee joint, it is usually difficult to experimentally study the biomechanics of ACLs. Anatomically ACL geometry was obtained from both MR images and anatomical observations. The optimal material parameters of the ACL were obtained by using an optimization-based material identification method that minimized the differences between experimental results from ACL specimens and FE simulations. The optimal FE model simulated biomechanical responses of the ACL during complex combined injury-causing knee movements, it predicted stress concentrations on the top and middle side of the posterolateral (PL) bundles. This model was further validated by a clinical case of ACL injury diagnosed by MRI and arthroscope, it demonstrated that the locations of rupture in the patient's knee corresponded to those where the stresses and moments were predicted to be concentrated. The result implies that varus rotation played a contributing but secondary role in injury under combined movements, the ACL elevation angle, is positive correlated with the tensional loading tolerance of the ACL. PMID- 25831857 TI - Mass transger in an eccentric annular region through diffusion. AB - The mass transfer in an eccentric annular region through diffusion by taking blood as a Newtonian fluid with the investigation of oxygen transfer and drug transport to the tissue cells in an eccentric catheterized artery is studied. The region bounded by eccentric circles in x-y plane is mapped conformally to concentric circles in xi - eta plane using a conformal mapping z = lambda/1 - zeta. The resulting governing equations are analytically solved by using transformation for the concentration. Numerical computations are carried out to understand the simultaneous effects of absorption parameter and eccentricity on the flow. The observation through the numerical computation reveals that, as absorption parameter and eccentricity enhances, the solute concentration diminishes. This mathematical model provides an insight for physiologists to understand the drug transport to the tissues in various clinical treatments of cardiovascular diseases. PMID- 25831858 TI - Experimental evaluation of fiber orientation based material properties of skeletal muscle in tension. AB - Biomechanical researches are essential to develop new techniques to improve the clinical relevance. Skeletal muscle generates the force which results in the motion of human body, so it is essential to study the mechanical and structural properties of skeletal muscle. Many researchers have carried out mechanical study of skeletal muscle with in-vivo testing. This work aims to examine anisotropic mechanical behavior of skeletal muscle with in vitro test (tensile test). It is important to understand the mechanical and structural behavior of skeletal muscle when it is subjected to external loading; the research aims to determine the structural properties of skeletal muscle by tensile.testing. Tensile testing is performed on 5 samples of skeletal muscle of a goat at the rate of 1 mm/min with fiber orientation along the length and 45 degrees inclined to the length. It is found that muscle is stiffer in the direction parallel to the muscle fiber than at 45 degrees to the muscle fibers. The tensile strength of the skeletal muscle along the fiber direction is 0.44 MPa at maximum load of 110 N and for direction 45 degrees inclined to the muscle fibers, the strength is 0.234 MPa at max load 43 N. The displacement of Muscle sample against the maximum load is small along the length of the muscle fiber i.e. under longitudinal elongation [15.257 mm] as compared to 45 degrees inclined to the length of skeletal muscle [17.775 mm] and under cross fiber elongation [19.7291 mm by FEA]. The testing is not performed for 90 degrees fiber orientation due to unavailability of soft tissue in cross fiber direction of the required specification, but finite element analysis is done on the skeletal muscle for the cross fiber orientation. As the fiber orientation within skeletal muscle differs with respect to the length of the muscle, the stiffness of skeletal muscle is also changing effectively. Hence skeletal muscle exhibits the anisotropic mechanical behavior. PMID- 25831859 TI - A Global Numerical analysis of the "central incisor/local maxillary bone" system using a meshless method. AB - In this work the maxillary central incisor is numerically analysed with an advance discretization technique--Natural Neighbour Radial Point Interpolation Method (NNRPIM). The NNRPIM permits to organically determine the nodal connectivity, which is essential to construct the interpolation functions. The NNRPIM procedure, based uniquely in the computational nodal mesh discretizing the problem domain, allows to obtain autonomously the required integration mesh, permitting to numerically integrate the differential equations ruling the studied physical phenomenon. A numerical analysis of a tooth structure using a meshless method is presented for the first time. A two-dimensional model of the maxillary central incisor, based on the clinical literature, is established and two distinct analyses are performed. First, a complete elasto-static analysis of the incisor/maxillary structure using the NNRPIM is evaluated and then a non-linear iterative bone tissue remodelling analysis of the maxillary bone, surrounding the central incisive, is performed. The obtained NNRPIM solutions are compared with other numerical methods solutions available in the literature and with clinical cases. The results show that the NNRPIM is a suitable numerical method to analyse numerically dental biomechanics problems. PMID- 25831860 TI - Mechanical modelling of confined cell migration across constricted-curved micro channels. AB - Confined migration is a crucial phenomenon during embryogenesis, immune response and cancer. Here, a two-dimensional finite element model of a HeLa cell migrating across constricted-curved micro-channels is proposed. The cell is modelled as a continuum with embedded cytoplasm and nucleus, which are described by standard Maxwell viscoelastic models. The decomposition of the deformation gradient is employed to define the cyclic active strains of protrusion and contraction, which are synchronized with the adhesion forces between the cell and the substrate. The micro-channels are represented by two rigid walls and exert an additional viscous force on the cell boundaries. Five configurations have been tested: 1) top constriction, 2) top-bottom constriction, 3) shifted top-bottom constriction, 4) embedded obstacle and 5) bending micro-channel. Additionally, for the first four micro-channels both sub-cellular and sub-nuclear constrictions have been obtained, while for the fifth micro-channel three types of bending have been investigated ('curved', 'sharp' and 'sharper'). For each configuration, several parameters such as the cell behaviour, the covered distance, the migration velocity, the ratio between the cell and the nucleus area as well as the cell substrate and cell-channel surfaces forces have been evaluated. The results show once more the fundamental role played by mechanics of both the cell and the environment. PMID- 25831861 TI - Effects of equiaxial strain on the differentiation of dental pulp stem cells without using biochemical reagents. AB - During orthodontic treatments, applied mechanical forces create strain and result in tooth movement through the alveolar bone. This response to mechanical strain is a fundamental biological reaction. The present study evaluated the effect of equiaxial strain within the range of orthodontic forces on the osteogenic differentiation of human dental pulp stem cells (hDPSCs). Following isolation and culture of hDPSCs, 3rd passage cells were transferred on a silicone membrane covered with collagen. Cell adhesion to the membrane was evaluated under scanning electron microscope (SEM). Cells were divided into three groups: the first group was placed in a conventional culture medium, transferred to an equiaxial stretching device (3% strain for 2 weeks). The positive control was placed in an osteogenic medium with no mechanical strain. The negative control group was placed in the conventional culture medium with no mechanical strain either. Study groups were evaluated for expression ofosteogenic markers (Alkaline phosphatase and Osteopontin) with immunofluorescence and real time PCR. SEM images revealed optimal adhesion of cells to the silicone membrane. Immunofluorescence study demonstrated that osteocalcin expression occurred after 2 weeks in the two groups under mechanical and chemical signals. After application of equiaxial strain, level of expression of osteogenic markers was significantly higher than in the negative and positive control groups. Based on the study results, static equiaxial strain which mimics the types of orthodontic forces can result in differentiation of hDPSCs to osteoblasts. The results obtained may be used in cell therapy and tissue engineering. PMID- 25831862 TI - Largest for-profit hospital chains. Ranked by 2013 revenue as reported to the U.S. Securities and Exchange Commission. PMID- 25831863 TI - Largest U.S. teaching hospitals. Ranked by total number of residents and interns based on Medicare cost report data, 2012. PMID- 25831864 TI - Largest children's hospitals. Ranked by number of staffed beds. PMID- 25831865 TI - Largest not-for-profit hospital systems. Ranked by total revenue for 2013. PMID- 25831866 TI - Largest revenue-cycle management firms. Ranked by total number of healthcare revenue-cycle contracts, 2013. PMID- 25831867 TI - Largest healthcare management consulting firms. Ranked by 2013 total provider revenue ($ in millions). PMID- 25831868 TI - Executive compensation--healthcare systems (Selected titles, ranked by average total cash compensation, 2014 ($ in thousands). PMID- 25831869 TI - Executive compensation--hospitals. Selected titles, ranked by average total cash compensation, 2014 ($ in thousands). PMID- 25831870 TI - Top-paid execs at publicly traded healthcare industry companies. Ranked by total compensation for 2013 as reported to the U.S. Securities and Exchange Commission. PMID- 25831871 TI - Largest national healthcare associations. Organizations ranked by 2012 revenue, based on Modern healthcare's review of IRS 990 filings. PMID- 25831872 TI - Largest healthcare financing companies. Ranked by amount of loans underwritten in 2013. PMID- 25831873 TI - Top business graduate schools for physician-executives. Data collected January April 2014 for the 2013-14 school year, ranked by number of-time students. PMID- 25831874 TI - Largest physician staffing firms. Ranked by number of physician recruiters as of March 2014. PMID- 25831875 TI - Physician compensation, 2013. PMID- 25831876 TI - Truven health 100 top hospitals: national benchmarks for success, 2014 (1 of 2). PMID- 25831877 TI - Largest vendors of electronic health-record systems. Ranked by number of providers where organization is the primary vendor. PMID- 25831879 TI - Most profitable U.S. medical-device companies. Ranked by 2013 profit margin. PMID- 25831878 TI - Most profitable U.S. health insurance companies. Ranked by 2013 profit margin. PMID- 25831880 TI - Most profitable U.S. drug and biologic companies. Ranked by 2013 profit margin. PMID- 25831881 TI - Largest healthcare law firms. Based on a blended score of healthcare lawyers employed in 2013 and AHLA membership as of June 5, 2014. PMID- 25831882 TI - Top architectural firms. Ranked by 2013 dollar volume. PMID- 25831883 TI - Top design/build companies. Ranked by 2013 dollar volume. PMID- 25831884 TI - Top development companies. Ranked by 2013 dollar volume. PMID- 25831885 TI - [Tale nucleases--new tool for genome editing]. AB - The ability to introduce targeted changes in the genome of living cells or entire organisms enables researchers to meet the challenges of basic life sciences, biotechnology and medicine. Knockdown of target genes in the zygotes gives the opportunity to investigate the functions of these genes in different organisms. Replacement of single nucleotide in the DNA sequence allows to correct mutations in genes and thus to cure hereditary diseases. Adding transgene to specific genomic.loci can be used in biotechnology for generation of organisms with certain properties or cell lines for biopharmaceutical production. Such manipulations of gene sequences in their natural chromosomal context became possible after the emergence of the technology called "genome editing". This technology is based on the induction of a double-strand break in a specific genomic target DNA using endonucleases that recognize the unique sequences in the genome and on subsequent recovery of DNA integrity through the use of cellular repair mechanisms. A necessary tool for the genome editing is a custom-designed endonuclease which is able to recognize selected sequences. The emergence of a new type of programmable endonucleases, which were constructed on the basis of bacterial proteins--TAL-effectors (Transcription activators like effector), has become an important stage in the development of technology and promoted wide spread of the genome editing. This article reviews the history of the discovery of TAL effectors and creation of TALE nucleases, and describes their advantages over zinc finger endonucleases that appeared earlier. A large section is devoted to description of genetic modifications that can be performed using the genome editing. PMID- 25831886 TI - [Essential functions of microRNAs in the reproductive organs of animals]. AB - The development of the reproductive organs and the gametogenesis of animals are complex and multistage processes that require the precise and effective regulation. In this review, we summarized the recent findings about essential functions of miRNAs in the regulation of gene expression during the differentiation of germ cells in spermatogenesis and oogenesis. Most probably, the main functions of the conservative and highly-expressed miRNAs in the reproductive organs of mammalian are the control of differentiation and proliferation of cells. Also we discussed the possible involvement of the germline-expressed miRNAs in the formation of the reproductive barriers and speciation. PMID- 25831887 TI - [Spatial organization of interphase chromosomes and the role of chromatin fiber dynamycs in the positioning of genome elements]. AB - Many studies are devoted to the analysis ofinterphase chromosome architecture due to the evidence of functional-dependent spatial organization of the genome. These studies are based on classical cytological methods as well as on biochemical approaches (3C, 4C, 5C, Hi-C) allowing for the detection of long-range interactions between fragments of chromatin fibers, including the genome-wide interactions. In this review, we discuss the results of these researches which make it possible to explain functional-dependent multilevel compartmentalization of the nucleous and unravel the principals of high-level chromatin organization. Special attention is paid to the enchancer-promoter interactions important for the regulation of gene expression. Accordingly, we consider the model of an active chromatin hub and the alternative model of an active chromatin compartment, which was proposed based on reconsideration of some steps of the 3C procedure. PMID- 25831888 TI - [Expression of sphingomyelin synthase 1 (SGMS1) gene varies in human lung and oesophagus cancer]. AB - The investigation of molecular mechanisms contributing to cancer progression is the burning problem ofcurrent research. Considerable attention has been given to the study of gene expression in cancer cells. Sphingomyelin synthase 1 gene (SGMS1) is one of the genes whose expression can be altered in cancer. SMS1 enzyme, encoded by this gene, catalyzes the synthesis of sphingomyelin and diacylglycerol from phosphatidylcholine and ceramide. SMS1 may maintain the balance between cell death and survival by regulating the formation of the pro apoptotic mediator ceramide and anti-apoptotic mediator diacylglycerol. In addition, the changes in sphingomyelin level and sphingomyelin synthase activity have been observed in cancers of many tissues. However the peculiarities of SGMS1 gene transcription have been insufficiently explored. In this work the expression of transcripts of SGMS1 has been investigated by the method of Real Time PCR in matched pairs of samples of human lung and oesophagus cancer and adjacent tissues without pathology. A significant decrease in SMS1 transcripts expression has been found in samples of human lung cancer. At the same time, in the samples of human oesophagus cancer and adjacent tissue, expression of SMS1 transcripts varies insignificantly: it is increased in 7 and decreased in 5 of 15 samples. The obtained results indicate that SGMS1 gene is differently expressed in cancers of different genesis. PMID- 25831889 TI - [Evolution conservativity of scar DNA localization in warm-blooded vertebrates isochores]. AB - In meiotic prophase I attached to the lateral elements of the synaptonemal complex chromatin fibrils form loops. SCARs DNA (Synaptonemal Complex Associated Regions of DNA) is a family of genomic DNA sequences tightly associated with the synaptonemal complex and lying at the loop basements. Isochore compositional fractions of the human and chicken genomes were used as 32P-labeled probes for hybridization with the SCARs DNA isolated previously from the spermatocyte nucleus of the golden hamster Mesocricetus auratus. The localization of sequences, similar to golden hamster SCARs DNA in the human and chicken genome isochores was established. It was concluded that SCARs DNA localization into isochore com- partments of examined genomes is evolutionary conservative. PMID- 25831890 TI - [Genetic loci for spleen weight and blood pressure in Isiah rats with inherited stress-induced arterial hypertension]. AB - Recently, the important role of the spleen function in hypertension development was demonstrated. In this study, the genetic control of absolute and relative spleen weight was investigated to reveal the genetic loci common for spleen traits and for arterial blood pressure at rest and under the emotional stress conditions in the ISIAH rats with inherited stress-induced arterial hypertension. The search for genetic loci for absolute and relative spleen weight was performed on 6-month old F2 (ISIAH x WAG) hybrid males derived from a cross of hypertensive ISIAH and normotensive WAG rats. One significant QTL mapped on chromosome 1 and 5 suggestive loci were found for relative spleen weight. Four suggestive loci were detected for absolute spleen weight. All detected loci were novel. The significant QTL on chromosome 1 was common for relative spleen weight and arterial blood pressure at rest and under the emotional stress conditions in ISIAH rats. The results suggest that the manifestation ofthe stress-sensitive arterial hypertension in ISIAH rats may be related to the changes in genetic control of the spleen function. PMID- 25831891 TI - [Changes in mitochondrial function induced by dequalinium precede oxidative stress and apoptosis in the human prostate cancer cell line PC-3]. AB - Mitochondria play central roles in diverse physiological and pathological conditions associated with cell survival and death. Delocalized lipophilic cations, such as dequalinium (DQA), are accumulated in cancer cells attracted by the highly negative mitochondrial transmembrane potential of these cells. DQA showed a potent anticancer activity in cells from different malignancies. Here, we report the effect of DQA on PC-3 prostate cancer cells. Incubation with DQA at concentrations between 1.5 and 100 microM from 24 to 48 h decreases cell viability. The decrease in cell viability together with a loss of mitochondrial transmembrane potential induced an increase in reactive oxygen species production and cell death via caspase-3 dependent apoptotic pathway. QA was shown to cause moderate to strong cell death in a time and concentration dependent manner, causing a most advantageous effect at a concentration of 10 microM applied for a long 48 h time period, which might be a consequence of the kinetics of intracellular DQA accumulation in mitochondria, but also of the mechanisms of DQA induced cell death. This data shows DQA as a promising agent against the human prostate cancer PC-3 cell line, activating the caspase-3 dependent apoptotic pathway. This fact might be beneficial for possible future applications in cancer therapy. PMID- 25831892 TI - [Delayed augmentation effect of cytokine production after hyperthermia stimuli]. AB - Heatstroke is considered an important condition that may contribute to endothelial cell damage. The aim of this study was to assess temporal profiles of the cytokine (IL-6 and IL-8) and mRNA production when endothelial cells undergo higher temperature stimuli. In the first group, human umbilical vascular endothelial cells (HUVECs)were cultured at 4 different temperatures (37, 38, 39 or 40 degrees C) for 1, 3 and 5 h. In the second group, HUVECs were cultured at 37 degrees C for 4 h or 23 h, after stimulation by heating for one hour at the same culture temperatures used in the first group (37 degrees C to 40 degrees C). After culturing, IL-6 and IL-8 mRNA and protein levels were measured. It has been found the cytokine mRNA levels being significantly higher (p < 0.001) in all cells incubated at higher temperatures than those in the control (cultivation at 37 degrees C). At the same time, the productionof IL-6 and 8 at a higher temperature (39, 40 degrees C) was significantly lower (p < 0.001) than at 37 degrees C (control), and the decrease was temperature dependent. However, IL-6 and IL-8 levels were significantly greater in the cells at 23 h after transient hyperthermic (40 degrees C, 1 h) stimulation than in control ones (p < 0.001).After a transient hyperthermia, the production of the cytokines in HUVECs is initially inhibited and then augmented. The results indicated that tissue injury might continue to develop after a hyperthermic event. There might be a potent risk for underestimation of cytokine induced tissue injury in the acute phase of a heatstroke. PMID- 25831893 TI - [Comparative analysis of heat shock promoters efficiency in two diptera species]. AB - Heat shock proteins (Hsp) provide cellular and whole body adaptation of animals to various adverse environmental conditions. Hsp70 is apparently the major player underlying biological adaptation in all organisms studied so far. In all animals the regulatory regions of studied heat shock genes include several conservative promoter elements HSEs (heat shock elements) that are necessary for binding of heat shock transcription factor (HSF). The promoter regions of hsp70 genes are extremely conserved and, hence, it was generally accepted that they are universal and can operate in species belonging to different phyla. In the present work we performed the comparative analysis which revealed characteristic differences in the hsp 70 promoters of two Diptera species: Drosophila melanogaster and highly thermotolerance soldier fly Stratiomys singularior. We measured promoters activity in D. melanogaster cell culture exploring in vitro luciferase reporter assay. The analysis demonstrated significantly higher strength ofD. melanogaster promoters in spite of the fact that comparable numbers of HSEs are present in both species. These drastic differences in the promoter strength are probably due to absence of GAF-binding sites, which are necessary for efficient functioning of D. melanogaster hsp70 promoters. In contrast, comparison of hsp83 promoters isolated from these two species does not show significant differences. Our results demonstrate existence of different evolutionary trends in the regulation of the hsp70 expression even within the same order (Diptera). PMID- 25831894 TI - [Chymotripsin-like activity and subunit composition of proteasomes in human cancers]. AB - Activity of the proteasome, polyfunctional enzymatic complex, is known to undergo changes during cancer development. This phenomenon is, probably, caused by the changes in subunit composition of proteasomes. In present work, we studied chymotrypsin-like activity of proteasomes, subunit composition and their association in breast cancer, head and neck squamous cell carcinoma, endometrial cancer, renal cancer, bladder cancer, stomach cancer and colorectal cancer. The increase of proteasome activity was revealed in most cancer tissues compared with adjacent tissues except for the renal cell carcinoma. Changes in proteasome activity in cancer tissues compared with correspondent normal tissues were accompanied by modification of its subunit composition. High proteasome activity was observed in combination with an increased expression of immune subunits and/or proteasome activator PA28, associated with activity of 20S proteasome. In breast cancer, head and neck squamous cell carcinoma, bladder cancer, stomach cancer and colorectal cancer we additionally found higher expression of Rpt6 subunit of 26S proteasome. Correlations between chymotrypsin like proteasome activity and subunit expressions were found in human cancer tissues. In summary, we suggest that proteasome ac- tivation and changes in its subunit composition plays an important role in cancer pathogenesis. PMID- 25831895 TI - [Involvement of serine/threonine protein kinases in cold stress response in the cyanobacterium Synechocystis sp. PCC 6803: functional characterization of a protein kinase Spke]. AB - Stress responses of the unicellular cyanobacterium Synechocystis are fulfilled via a number of regulatory systems, namely, two-component systems as well as through negative supercoiling of the genome DNA. We have studied an involvement of serine/threonine protein kinases (STPK) in the cyanobacterium Synechocystis cold stress response. A search for the STPK mutants allowed us to determine four protein kinases, SpkB, SpkD, SpkE and SpkG, which could regulate transcription under the low temperature. According to a proteome analysis, SpkE significantly affects the protein pattern in Synechocystis. Functional activity of the recombinant SpkE was confirmed in in vitro phosphorylation assay with a use of a set of potential protein kinase substrates. It have been demonstrated that the basic proteins are preferable substrates for the recombinant protein kinase SpkE. PMID- 25831896 TI - [Influence of the orthosteric ligands binding on the conformational dynamics of the B-2-adrenergic receptor by means of essential dynamics sampling simulation]. AB - The influence of binding of the orthosteric ligands on the conformational dynamics of the beta-2-adrenoreceptor was identified using the molecular dynamics method. It was found that there was alittle fraction of the active states of the receptor in its apo (ligand free) ensemble. Analysis of the MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion of its VI helix. Thus receptor's constitutive activity is the direct result of its conformational dynamics. On other hand binding of the full agonist resulted in the significant shift of the initial equilibrium towards its active state. Finally binding of the inverse agonist stabilized receptor in its inactive state. Its likely that the binding of the inverse agonists might be the universal way of the constitutive activity inhibition. Our results indicate that ligand binding rather redistribute prexisting conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) than cause induced fit in it. Therefore ensemble of the biological-relevant receptor conformations have been encoded in its spatial structure and individual conformations from that ensemble might be used by the cell according to the physiological behavior. PMID- 25831897 TI - [Correlation between macro- and micro-stability ch2 domains of human IGG2 and their biological activity. 1. Ansalysis the calorimetric and optical melting curves]. AB - Human myeloma immunoglobulin second subclass LOM and SIN, their Fc fragment and firstly obtained hFc fragment in which there is not only low portion of the hinge region, but also its core portion (Cys-Cys-Val-Glu-Cys-Pro-Pro-Cys), have been studied by number of physical methods (scanning calorimetry, fluorescence spectroscopy, analytical centrifugation). Joint analysis of calorimetric and optical melting curves revealed that only first (low-temperature) heat absorption peak at all the melting curves corresponds to the melting of the two CH2 domains. It was shown that CH2 domains of intact IgG2 are destabilized relative to those domains in hFc and Fc fragments. PMID- 25831898 TI - [Common features in arrangements of ribosomal protein S26e binding sites on its own pre-mRNA and the 18S rRNA]. AB - It is known that human ribosomal protein (rp) S26e can bind to the first intron of its own pre-mRNA and thereby inhibit its splicing. In this work, hydroxyl radical footprinting was applied for detailed mapping of the rpS26e binding site on an RNA transcript corresponding to the rpS26e pre-mRNA fragment containing the first intron flanked by the first exon and a part of the second exon sequences. Nucleotides of this RNA protected from hydroxyl radical attack in the presence of rpS26e were identified. Most of them are found in the region of the 3'-splice site of the first intron within a purine-rich sequence, which forms a loop connecting two helices in the predicted secondary structure of the rpS26e pre mRNA fragment, and the remaining nucleotides are located near the 5'-splice site. Comparison of arrangements of rpS26e binding sites on the pre-mRNA and 18S rRNA secondary structures reveals similar elements in the organization of these sites. It was found that both sites contain a structural motif, represented by an extended purine-rich loop between two helices, which could be recognized by rpS26e upon binding to these RNAs. The data obtained shed light on the structural aspects of RNA-protein interactions underlying autoregulation of human RPS26e gene expression at the splicing step. PMID- 25831899 TI - [SPC/E and TIP4P models for investigation of the conformational mobility of the insulin superfamily peptides]. AB - In this work we carried out a comparative analysis of the two most popular water models-SPC/E and TIP4P and estimated the ability of using ones for insulin superfamily peptides-proinsulin and insulin-like growth factors (IGF1 and IGF2). It was shown that root-mean-square deviations and radius of gyration had tend to be in reversed phase when both water models were used. Only IGF1 had a plateau after 9000 ps. In addition, it was shown that in spite of the general nature of insulin-like packing maintenance, there were some differences in the secondary structures, when we used TIP4P and SPC/E. These differences could influence on the overall molecule dynamics and the ability to accept necessary conformation for interaction with cognate receptors. On the basis of the received data we concluded that it is necessary to use several, not one, water models for the study of the peptides conformational mobility. PMID- 25831900 TI - [Phylogeny of beta-xylanases from Planctomycetes]. AB - Here, we present the results of a computational analysis of a group of hypothetical GH10 endo-beta-xylanases from the Planctomycetes, a bacterial phylum with poorly characterized functional capabilities. These proteins are encoded in all analyzed genomes of heterotrophic Planctomycetes and form a phylogenetically distinct and tight cluster. In addition, we determined nucleotide sequences for endo-beta-xylanase genes from five strains of Isosphaera-Singulisphaera group of the Planctomycetes. The trees constructed for the 16S rRNA genes and the inferred amino acid sequences of endo-beta-xylanases were highly congruent, thus suggesting the vertical transfer of endo-beta-xylanase genes and their functional importance in Planctomycetes. PMID- 25831901 TI - [Indicators of plasminogen activation system and growth factors in the tissue of nevi and skin melanoma]. AB - Skin melanoma is believed to result from malignization of an inborn or acquired pigmented nevus under the action of a number of causative agents. With regard to this, the comparative analysis of skin melanoma tissue samples taken from patients of both sexes and pigmented nevus tissue samples was performed by polarization fluoroimmunoassay. The study involved analyzing the activity of plasmin, plasminogen, concentration and activity of urokinase type plasminogen activator, tissue type plasminogen activator, plasminogen activator inhibitor, as well as the level of growth factors--vasculoendothelial one and its receptor, epidermal one and its receptor, transforming one, fibroblasts growth factor, insulin-like 1 and 2 growth factors. The detected changes indicate possible mechanisms of malignant transformation of skin nevi. The obtained results can be used for developing the risk evaluation methods for neoplastic transformation of nevi as well as prevention methods. PMID- 25831902 TI - [Molecular phylogeny of Siberian glossiphoniidae (Hirudinea)]. AB - The molecular phylogenetic analysis based on mtCOI nucleotide sequences of Siberian glossiphoniids and phylogenetically relative Palearctic species clearly demonstrated that Siberian representatives do not belong to G. complanata as previously thought, but has an autonomous taxonomic status. In addition, the revealed genetic distances enable to accept the mtCOI fragment as a suitable marker for molecular identification of the species within the Glossiphoniidae (Hirudinea). PMID- 25831903 TI - Determination of vertical dimension of occlusion by using the phonetic vowel "O" and "E". AB - BACKGROUND/AIM: The vertical dimension of occlusion is a very important parameter for proper reconstruction of the relationship between the jaws. The literature describes many methods for its finding, from the simple, easily applicable clinically, to quite complicated, with the use of one or more devices for determination. The aim of this study was to examine the possibility of determining the vertical dimension of occlusion using the vocals "O" and "E" with the control of values obtained by applying cognitive functions. METHODS: This investigation was performed with the two groups of patients. The first group consisted of 50 females and 50 males, aged 18 to 30 years. In this group the distance between the reference points (on top of the nose and chin) was measured in the position of the mandible in the vertical dimension of occlusion, the vertical dimension at rest and the pronunciation of the words "OLO" and "ELE". Checking the correctness of the particular value for the word "OLO" was also performed by the phonetic method with the application of cognitive exercises when the patients counted from 89 to 80. The obtained difference in the average values in determining the vertical dimension of occlusion and the "OLO" and "ELE" in the first group was used as the reference for determining the vertical dimension of occlusion in the second group of patients. The second group comprised of 31 edentulous persons (14 females and 17 males), aged from 54 to 85 years who had been made a complete denture. RESULTS: The average value obtained for the vertical dimension of rest for the entire sample was 2.16 mm, for the word "OLO" for the entire sample was 5.51 mm and for the word "ELE" for the entire sample was 7.47 mm. There was no statistically significant difference between the genders for the value of the vertical dimension at rest, "ELE" and "OLO". There was a statistically significant difference between the values f or the vertical dimension at rest, "OLO" and "ELE" for both genders. There was a statistically significant correlation between the value for the vertical dimension at rest, "OLO" and "ELE", for both groups of subjects. CONCLUSION: Determining the vertical dimension of occlusion requires 5.5 mm subtraction from the position of the mandible in pronunciation of the word "OLO" or 7.5 mm in pronunciation of the word "ELE". PMID- 25831904 TI - Morphometric analysis of the fascicular organisation of the optic nerve. AB - BACKGROUND/AIM: The optic nerve is anatomically observed in four segments: intrabulbar, orbital, canalicular, and cranial. According to the literature, the surface of the transversal cut of the nerve is different through it. The aim of this study was to evaluate the fascicular organisation of the optic nerve, throughout its three segments fromthe eye. METHODS: Five pairs of optic nerves, obtained from the autopsies were examined. Using Heidenhain's (azan) staining, the cuts were prepared for microscopy. Morphometric analysis was performed using the stereological methods for morphometric cytology--the Weible's testing system M42. The following measures were established: the surface of the transverse cut of the nerve, the entire surface of fasciculi, the entire surface of connective tissue and blood vessels, the number of fasciculi, the surface of a single fasciculus. RESULTS: The surface of the transverse cut of the nerve was found to grow from the orbital to the cranial segment, as well as the entire surface of fasciculi. While their number is significantly lower in the cranial segment, the number of fasciculi varied slightly between the orbital and the canalicular segment. The surface of a single fasciculus grows from the bulb to the chiasma. There is probable a cause to believe that this may be due to fusion of the "small" fasciculi in the orbitocranial direction. CONCLUSION: There are significant differences among the examined parameters of the different parts of the optic nerve. PMID- 25831905 TI - Radical cystectomy in eldery. AB - BACKGROUND/AIM: Radical cystectomy is the method of choice for the treatment of muscle invasive bladder cancer. This major surgery is associated with many complications, especially in older patients. The aim of this study was to analyze preoperative comorbidity, and intraoperative and postoperative complicatons in patients older than 75 years. METHODS: This clinical, retrospective study included 46 patients over 75 years, who underwent radical cystectomy. Indications for surgery, and complications during and after the surgery were followed up. RESULTS: Preoperatively, anemia caused by hematuria was registered in 76% of the patients. In 52% of the patients urine derivation was performed by ileal conduit, in 35% by ureterocutaneostomy and in 13% orthotopic ileal neobladder was created. The average duration of surgery was 190 (120-300) min. A total of 76% of the patients were treated by blood supstitution intraoperatively, average 630 (310 1230) mL. Concerning pathological stage of transitional cell carcinoma of urinary bladder, 26% of the patients had T2, 4% T3a, 52% T3b, and 14% T4a stage. In one case, planocellular carcinoma was diagnosed by patohistological examination, and in 2 cases prostate carcinoma was incidentally found. The average duration of hospitalization was 16 (8-35) days. CONCLUSION: The main reason for cystectomy in patients over 70-and 80 years was gross hematuria caused by bladder cancer, with consecutive anemia which could not be solved using endoscopic treat- ment or blood supstitution. As expected, a prolonged stay in hospital after cystectomy, and a higher rate of complications were recorded in this population. PMID- 25831907 TI - Social participation of women with breast cancer. AB - BACKGROUND/AIM: The general problems of persons with malignant diseases (stages of asthenia, chronic fatigue and exhaustion, followed by depression and anxiety) lead to a decrease in functional abilities and a declining quality of life. The aim of this study was to determine the level of difficulty, the type of required assistance and the level of satisfaction that derives from maintaining life habits. The study also examined the correlation between the level of accomplishment of life habits and the level of satisfaction with how they are maintained. METHODS: The research was conducted at the Military Medical Academy in Belgrade and in the "Get Together" Association of Women with Breast Cancer from June to September 2012 on a sample of 30 women. A standardised questionnaire, Assessment of Life Habits-LIFE-H v.3.0, was administered. RESULTS: The lowest level of maintaining normal activities was related to education, housing and recreation. The greatest need for support to maintain normal activities was in the domains of housing, interpersonal relationships and employment The greatest satisfaction in the accomplishment of normal activities was observed in the domains of mobility, nutrition and housing, and the lowest level of satisfaction was in the domains of recreation, communication and interpersonal relationships. The correlation between the level of accomplishment of normal activities and the level of satisfaction was the highest in the domains of general physical activity, responsibility and life in a community; the lowest level was in the domains of personal hygiene, housing, mobility, employment and recreation (p < 0.001). CONCLUSION: The results indicate that research participants found it more difficult to maintain their social activities than their everyday activities. This clearly indicates the necessity to develop and implement special advisory and educational programs aimed at preventing social exclusion and to strengthen and support personal resources in the area of the social roles of women with breast cancer. PMID- 25831906 TI - Campylobacter jejuni infection and IgE sensitization in up to 2-year-old infants. AB - BACKGROUND/AIM: The "hygiene hypothesis" addresses the correlation between the occurrence of atopy and the frequency of infections in the earliest age, explaining an increase in the incidence of atopic diseases by living in good, infection-free, hygienic conditions. The aim of our study was to determine the conection between atopy and Camplobacter infection, and to analyze the association between serum concentrations of total IgE and Campyobacter infection in relation to atopy in children up to two years. METHODS: A case control study was conducted with the sample of 98 infants of the average age of 8 months. Total serum IgE and Phadiatop infant multi-test were determined on Immunocap-100 (Phadia AB, Uppsala, Sweden). The presence of atopy was determined by detection of serum-specific IgE > 0.35 kUA/L (Phadiatop infant positive) and serum IgM, IgA, IgG levels against C j uni were determined by a quantitative immuno-enzyme test--SERION ELISA classic. RESULTS: Total IgE cut-off values > 15 kU/L point to atopy in infants, and tIgE cut-off values > or = 8.1 kU/L pointed to a Cj/uni infection in infants. Within the group of atopic children, tIgE levels > 29.8 kU/L point to C. jejuni infection, and within the group of non-atopic children, tIgE levels > or = 5.9 kU/L point to infection. Enteritis is not a predictor of C jejuni infection, because of a high frequency of asymptomatic cases of infection. The risk factors for C. jejuni infection are age and tIgE, and the protective factors are breastfeeding and atopy. CONCLUSION: C. jejuni infection increases the total serum IgE level, which is pre- dictive of infection, regardless of the presence of atopy. The presence of symptomatic C. jejuni infection reduces the risk of atopy in a child of the age of 5-24 months by the factor of 10. PMID- 25831908 TI - Estimating disability and quality of life after different degrees of hand and forearm trauma. AB - BACKGROUND/AIM: Hand injuries comprise up to one fourth of all injuries and require excellent skills and aggressive physical therapy with still a high potential to cause long term physical and functional disability which affects one's quality of life. The aim of this study was to evaluate disability and quality of life in patients with different degrees of hand and forearm injuries using the two different scoring sistems and to examine the correlation between them. METHODS: This retrospective study was performed among patients operated on at our clinic due to acute hand and forearm trauma during the period of two years. Four groups of patients were made according to the Modified Hand Injury Severity Score (MHISS). One year after the treatment, phone interviews were made with those patients to answer to the Disability of Arm Shoulder and Hand (quick DASH) score for estimating disability and to the World Health Organization Quality of Life BREF (WHOQoL-BREF) score to estimate the quality of life regerding four domains: physical, social, environmental and psychological. RESULTS: Out of 182 patients who satisfied the inclusion criteria, only 60 completely answered to the questionnaires, 46 (17%) men and 14 (23%) women. Most of the patients were in the group with moderate injuries according to the MHISS, followed by the group with major and severe injuries. A weak correlation was found between the MHISS and quick DASH score in the group with minor injuries, compared to no correlation between these parameters in other groups. The lowest quality of life was registered in the physical domain, while the highest in the social one. A negative correlation was found among the four domains of the WHOQoL BREF score and quick-DASH score in all the groups. CONCLUSION: Severity of hand and forearm injuries does not necessarily correlate with patient's perception of disability. The quality of life was less affected by severity of injury than by the patient's per- ception of disability. PMID- 25831909 TI - Continuing medical education in Serbia with particular reference to the Faculty of Medicine, Belgrade. AB - BACKGROUND/AIM: Continuing Medical Education (CME), conceptualised as lifelong learning (LLL) aims at improving human resources and continuing professional development. Various documents of European institutions underline its key importance. This paper therefore tries to analyse the current status of CME and the main deficits in the delivery of LLL courses at medical faculties in Serbia with special consideration of the Faculty of Medicine in Belgrade with detailed financial data available. METHODS: Data of 2,265 medical courses submitted in 2011 and 2012 for accredita- tion were made available, thereof 403 courses submitted by 4 medical faculties in Serbia (Belgrade, Kragujevac, Nil, Novi Sad). A subset of more detailed information on 88 delivered courses with 5,600 participants has been provided by the Faculty of Medicine, Belgrade. All data were transferred into an Excel file and analysed with XLSTAT 2009. To reduce the complexity and possible redundancy we performed a principal component analysis (PCA). Correlated component regression (CCR) models were used to identify determinants of course participation. RESULTS: During the 2-year period 12.9% of all courses were submitted on pre-clinical and 62.4% on clinical topics, 12.2% on public health, while 61.5% of all took place in Belgrade. The subset of the Faculty of Medicine, Belgrade comprised 3,471 participants registered with 51 courses accredited and delivered in 2011 and 2,129 participants with 37 courses accredited and delivered in 2012. The median number of participants per course for the entire period was 45; the median fee rates for participants were 5,000 dinars in 2011 and 8,000 in 2012, resulting together with donations--in a total income for both years together of 16,126,495.00 dinar or almost 144,000.00 euro. This allowed for a median payment of approximately 90 eur per hour lectured in 2011 and 49 euro in 2012. The 2 factors, D1 (performance) and D2 (attractiveness), identified in the PCA for Medical Faculties in Serbia, explain 71.8% of the variance. Most relevant are the duration of the courses, credit points" and hours per credit point gained by lecturers and participants respectively. In the PCA for Belgrade D1 and D2 explain 40.7% of the total variance. The CCR on the number of participants reveals the highest positive impact from the number of lecturers per course and the expenditure on amenities, the highest negative impact from the total income collected per participant. CONCLUSION: The faculties of medicine in Serbia should reconsider the entire structure of their organisation of CME, especially to improve the quantity and quality of registration limit the course fee rates per hour and reduce administrative and other costs request lecturing in CME programmes as obligatory for academic promotion and organise a focused marketing. PMID- 25831910 TI - Assessment of implant stability by resonant frequency analysis. PMID- 25831911 TI - Beta-lactam antibiotics use in intensive care units--the pathophysiological, pharmacokinetic, pharmacodynamic and pharmacoeconomic approach. PMID- 25831912 TI - Surgical treatment of dislocated fracture of the scapula column and glenoid: a 22 year follow-up. AB - INTRODUCTION: Most scapular fractures are caused by high-impact blunt injuries, often as the result of motor vehicle accidents, fall from height, etc. In 80% to 90% of cases, scapula fractures are associated with multiple injuries (clavicle fracture, rib fractures, humeral fracture, pulmonary injury, brachial plexus injury). CASE REPORT: We presented scapular fracture in a 27-years-old male who had sustained a work-related injury when a ground soil brick machine pressed him. Fracture line was identified on radiotherapy and computed tomography scan from the distal scapular angle enclosing scapular neck. The whole lateral part of the scapula was dislocated laterally from the scapular body. Scapular fracture was treated operatively. The posterior approach was used for reposition, while for fixation after reposition we used two Blunt clamps. We presented functional outcome 22 years after the injury and the surgical treatment. The patient can perform all physical activities, still works, and there is no need to remove the ostheosynthetic material as it causes no discomfort nor problems. The strength of the shoulder muscles is estimated as physician as the grade 5. CONCLUSION: Displaced intra- articular fractures of the scapula should be treated operatively, with open reduction and internal fixation. PMID- 25831913 TI - Bilateral triple renal pelvis: a case report. AB - INTRODUCTION: Triple renal pelvis is an extremely rare variation of the renal collecting system. To the authors' knowledge, bilateral triple renal pelvis has not yet been described in the literature. CASE REPORT: A 55-year-old man was hospitalized due to papillary bladder cancer, detected on ultrasonography. As incidental finding, intravenous urography revealed bilateral triple renal pelvis. Six weeks after transurethral resection of the bladder tumor (TURB) the patient was admitted again, for the second TURB. Computed to mography-urography confirmed the presence of bilateral triple renal pelvis. CONCLUSION: The unique case of bilateral triple renal pelvis was presented as an extremely rare variation of the renal collecting system. PMID- 25831914 TI - Unilateral galactocele in a male infant. AB - INTRODUCTION: Galactocele, generally occuring in young women during or after lactation, is an extremely rare cause of breast enlargement in infants and children of exclusively male gender. Only 26 cases have been published so far, including two our cases. CASE REPORT: We described unilateral, cystic, breast enlargement, without any endocrinologic and other abnormalities in a 29-month-old boy. A typical clinical and histopathologic presentation of galactocele was followed with a complete excision. CONCLUSION: This was a 27th well documented case of galactocele in a male infant with typical clinical and histopathologic presentation. There are several hypotheses regarding etiology of the lesion, but it is likely to be multifactorial. Because of its extreme rarity, there are some difficulties in differential diagnosis and treatment options of galactocele in male infants. PMID- 25831915 TI - Emotional stress as a cause of syncope and torsade de pointes in patients with long QT syndrome. AB - INTRODUCTION: Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by the prolongation of QT interval and high risk propensity of torsade de pointes (TdP) that can lead to syncope, cardiac arrest and sudden death. Episodes may be provoked by various stimuli depending on the type of the condition. CASE REPORT: A 25-year-old famele patient was hospitalized due to syncope that occurred immediately after her solo concert, first time in her life. The patient studied solo singing and after intensive preparations the first solo concert was organized. Electrocardiography (ECG) on admission registered frequent ventricular premature beats (VES), followed by polymorphic ventricular tachycardia--TdP that degenerated into ventricular fibrilation (VF). After immediate cardioversion magnesium and beta-blockers were administered. TdP was registered again several times preceded by VES. The corrected QT interval (QTc) was 516 msec. For secondary prevention of sudden cardiac death, a cardioverter defibrillator was implanted, and beta-blockers continued. After a 1-year follow up there were no recurrent episodes of TdP, and measured QTc was reduced to 484 msec. CONCLUSION: Patients with syncope following intensive emotional stress should be evaluated for malignant arrhythmias in the context of LQTS. PMID- 25831916 TI - Kidney failure as an unusual initial presentation of biclonal gammopathy (IgD multiple myeloma associated with light chain disease)--a case report. AB - INTRODUCTION: Immunoglobulin D (IgD) myeloma is a rare disease, about 2% of all myelomas, even rarer when accompanied with another multiple myeloma in biclonal gammopathy. We presented a case of biclonal gammopathy-as-sociated manifestation of IgD myeloma and light chain disease in a patient who initially had renal failure. CASE REPORT: 37-year-old male approximately one month before hospitalization began to feel malaise and fatigue along with decreased urination. Laboratory analysis revealed azotemia. A dialysis catheter was placed and hemodialysis started. The patient was then admitted to our hospital for further tests and during admission, objective examination revealed pronounced paleness with hepatosplenomegaly and hypertension (170/95 mmHg). Laboratory analysis showed erythrocyte sedimentation rate 122 mm/h, expressed anemic syndrome (Hb 71 g/L) and renal failure dialysis rank: creatinine 1,408 micromol/L, urea 31.7 mmol/L. There was two M components in serum protein electrophoresis: IgD lambda and free light chain lambda. Proteinuria was nephrotic rank (5.4 g/24 h), whose electrophoresis revealed 2 M components--massive in alpha 2 fraction of 71%; 7% in the discrete beta fraction, beta 2M / serum 110 mg / L, in urine 1.8 mg/L- extremely high; IgL kappa I lambda index 1:13 (reference value ratio 2:1). The findings pointed to double myeloma disease: IgD myeloma and Bence Jones lambda myeloma. Bone biopsy confirmed IgD myeloma lambda 100% infiltration medulla predominantly plasmablasts. The treatment continued with hemodialysis 3 times per week with chemotherapy protocol bortezomib, doxorubicin, dexamethasone. After 4 cycles of chemotherapy, there was a decrease of IgD, lamda-light chains, reduction in proteinuria (1.03 g/24 h), so hemodialysis was reduced to once per week. Six months after treatment initiation the patient underwent autologous bone marrow transplantation. In a 2-year follow-up period double myeloma disease showed complete remission. CONCLUSION: The presented rare form of double myeloma disease with initial renal insufficiency underscores the importance of careful observation and teamwork that can alter the course of this serious disease. PMID- 25831917 TI - Quo vadis homine? Or where the marriage goes? PMID- 25831918 TI - A comment on the article: Stosic S, Karanovic N. Health care economics in Serbia: current problems and changes. Vojnosanit Pregl 2014; 71(11): 1055-1061. PMID- 25831919 TI - Authors' reply. PMID- 25831920 TI - [Environment and health: priorities for preventive medicine]. AB - Contemporary environmental factors influencing the formation of the environment and public health have been analyzed The increasing chemical pollution of the environment (air water, soil, living environment), and the intensification of the impact of physical factors in the first place, "electromagnetic smog" associated with the widespread use of appliances and computer equipment, cellular threaten public health have been shown. In this connection, there were determined priorities and main directions of research in the platform "Preventive Environment", approved by Ministry of Health of Russia, which is based on the concept of the factor prevention of noninfectious diseases. PMID- 25831921 TI - [Application of a standardized-human biomonitoring methodology to assess prenatal exposure to mercury]. AB - World Health Organization (WHO), in cooperation with the Consortium to Perform Human Biomonitoring on a European Scale (COPHES), has developed a standardized methodology for human biomonitoring (HBM) surveys in maternities in order to assess prenatal exposure to mercury. To test this standard methodology and adapt it to Russian settings, a cross-sectional HBM survey involving 120 parturient women was conducted in six maternities of the Moscow Region. Levels of total mercury in maternal hair (geometric mean: 0.21 MUg/g, 95th percentile: 0.54 MUg/g), cord blood (0.89 MUg/L and 2.38 MUg/L, respectively) and maternal urine (0.27 MUg/L and 0.94 MUg/L) in this population were similar to those in other European countries with relatively low fish consumption. Consumption of all types of fish at least once per week during the third trimester of pregnancy compared to fish consumption less than once per month was associated with the increase of geometric mean level of total mercury: in hair by 31% (95% confidence interval: 4%, 66%) higher, in cord blood--by 38% (9%, 74%) and in maternal urine--by 36% (2%, 81%). No biomarker values exceeded levels recommended by WHO or national agencies in the USA and Germany. However; at the population level, adverse effects of prenatal exposures to mercury can still be substantial. PMID- 25831922 TI - [Health and environment: the need and opportunity for the evaluation of the influence of environmental factors on the state of the population genofond in Ukraine]. AB - In connection with the drastically changed the human environment, including in connection with pollution by mutagenic and teratogenic factors of different origin, the majority of the population, including in Ukraine, is posed in different living conditions in comparison with previous generations. The recognizance of epigenetic impacts and the possibility of their inheritance significantly increased the role of environmental factors in ensuring human health of both present and future generations. There has been proposed the system of assessment of the status and reproduction of the genofond of the population consisting of assessment of the level of natality, determination of the proportion of persons of optimal reproductive age and children, calculation of the frequency and risk of congenital malformations, spontaneous abortions of the first trimester of gestation, infertile marriages, as well as identification of priority risk factors of formation of pathology, analysis of anthropometric parameters of newborns and comparison them with data characterizing the previous generation. The work of the system is based on existing statistical databases, it requires qualitative level diagnostics and the accounting of congenital malformations, as well as creation registries of congenital malformations, spontaneous abortions and infertile marriages. PMID- 25831923 TI - [Summary of ongoing activities on environmental noise and health at the WHO regional office for Europe]. AB - The environmental noise is an important public health issue, according to recent assessment of the burden of diseases among environmental health risk factors in order of importance the environmental noise occupies the second place after air pollution. The World Health Organization (WHO) for the first time published its public health recommendations for the environmental noise in 1999 in the "WHO Guidelines for Community Noise (1999)". These recommendations found their development in WHO Night Noise Guidelines for Europe" (2009). From then onward there have been published new important data on the impact of the environmental noise on the health, that stipulated the revision of existing guidelines. Furthermore, both in the European Union (EU) Directive 2002/49/ EC and the Parma Declaration from 2010 there was pointed out the importance of renewal environmental noise recommendations. Responding to appearing interrogation, WHO Regional Office for Europe has recently initiated the process of the elaboration of new guiding principles known as "WHO Environmental Noise Guidelines for the European Region". The Guidelines will include a systematic review of most critical or important health consequences and also concentrate on health benefits of measures for the reducing noise levels. The Guidelines will consider noise coming from various noise sources such as aircraft, railroad, personal electronic devices and wind turbines. The Guidelines will also consider the particularity of such accommodations as residences, hospitals, and educational facilities. The work in the mentioned spheres is ongoing and the revised Guidelines are expected to be published in mid-2015. The Guidelines will provide up-to-date information on the health risks related to the environmental noise and evidence-based recommendations in order to support for WHO Member States in their efforts to prevent of the excessive noise and the struggle with their negative impact. PMID- 25831924 TI - [Field investigations of the air pollution level of populated territories]. AB - The assessment and management of air quality of settlements is one of the priorities in the field of environmental protection. In the management of air quality the backbone factor is the methodology of the organization, performance and interpretation of data of field investigations. The present article is devoted to the analysis of the existing methodological approaches and practical aspects of their application in the organization and performance of field investigations with the aim to confirm the adequacy of the boundaries of the sanitary protection zone in the old industrial regions, hygienic evaluation of the data of field investigations of the air pollution level. PMID- 25831925 TI - [Investigation of the air microbiota in the Saint Petersburg]. AB - Microbiological tests of air in hospitals are the very important constituent element in prophylaxis of health care-associated infections. The aim of the study is to assess air in hospitals accordingly to the microbiological standards. The results were analyzed for 1993-2011. There were 0.2-4.2% of the samples that did not meet the standard. The maximum amount of microorganisms was found while SanPiN 2.1.3.1375-03 was effective within validity period SanPiN 2.1.3.2630-10 didn't normalize fungus, resulting in the minimal amount of mold. The frequency of sampling did not affect the result. DISCUSSION: Moulds are the causative agents of invasive fungal infections. Fungi can cause nosocomial infections. There is description of method to isolate fungi in the guidelines for control MUK 4.2.2942-11. CONCLUSION: It is necessary to use a new procedure when assessing the air in hospitals. PMID- 25831926 TI - [Biochemical effects of chronic peroral administration of carbon nanotubes and activated charcoal in drinking water in rats]. AB - Chronic 6-month experiment was carried out in rats, which received drinking water with multi-walled carbon nanotubes (MWCNTs), diameter of 15-40 nm, length >= 2 mkm) or activated charcoal (AC, diameter of 10-100 mkm), blood samples of the animals were used for assessment of biochemical markers. Both coal compounds induced the appearance of signs of oxidative stress 2 weeks after the beginning of the experiment and alteration of serum markers of liver and renal damage, as well as changes of cortisol and protein serum concentrations later Thus, despite of known high (asbest-like) inhalation toxicity of carbon nanotubes in comparison with other carbon allotrops (fullerenes and black carbon), we have found similar effects of MWCNTs and carbon microparticles in orally treated rats. PMID- 25831927 TI - [Information hygiene and regulation of information for vulnerable groups of the population]. AB - Development of information society engenders the problem of hygienic regulation of information load for the population, first of all for vulnerable groups. There are presented international and Russian normative legal documents and experience in this area, there are described the negative effects of information (such as stress, depression, suicidal ideations). There are considered social psychological characteristics of vulnerable groups that requires their best protection from loads of information, doing harm, particularly in terms of reproductive health, family relationships, children, etc. There was noted the desirability of improvement of sanitary, legislation on the regulation of the information load on the population, especially in vulnerable groups, in terms of optimization of parameters of the signal-carriers on volume, brightness and the adequacy of the volume and content of information in radio and television broadcasting, in an urban environment and at the plant to preserve the health and well-being of the population. PMID- 25831928 TI - [Mycobiota of soil and anthropogenic substrates of the Yamal Peninsula]. AB - There are presented results of mycological examination of samples of soil and anthropogenic substrates, collected on the Yamal Peninsula. 40 species of micromycetes have been identified. The obtained results indicate to the qualitative difference in the complexes of micromycetes from soil and anthropogenic substrates in the examined area. On anthropogenic substrates dark colored fungi were dominated Predominant group were known destructors of different materials and commensal human pathogens also. In soil samples from different depths species of the genus Penicillium and fungi of the genus Fusarium dominated clearly, that is quite typical for tundra soils. There is noted a general downward trend in species diversity and abundance of micromycetes with the increasing of the depth of the soil and the frozen ground. In the surface layer of soil there may occur species capable to move to man-made materials. The data obtained shows the feasibility of using the structure of complexes of micromycetes as an indicator index of anthropogenic impact on Arctic ecosystems. PMID- 25831929 TI - [Effect of environmental factors on the formation of postvaccinal immunity]. AB - In the present article there are considered the features of the formation of post vaccination immunity in dependence on the level of anthropogenic load. The level of anthropogenic load on urban and rural areas on the base of the database of the Regional Foundation for Socio-hygienic monitoring of the Orenburg region has been determined. The assessment of the state of post-vaccination immunity was performed on average long-term indices in the indicator groups of children and adults. The distribution of the population throughout the strength of immunity to measles in dependence on area of residence has been determined. The relationship between the formation of post-vaccination immunity area of the residence has been established. In the population residing in urban areas the number of post- vaccination antibodies was significantly lower than that of the population in rural settlements. PMID- 25831930 TI - [Visual hygiene in LED lighting. Modern scientific imaginations]. AB - There are considered a classic and modern paradigm of perception of light and its impact on human health. To consider the perception of light as a complex self organizing synergistic system of compression of information in the process of its sequencing was supposed. This allowed to develop a complex of interrelated measures, which may become the basis for modern hygiene, and determine requirements for the led lamp with biologically adequate spectrum of the light, for which there were obtained patents in Russia, Europe and USA. PMID- 25831931 TI - [On the issue of the safety of reagents used for water treatment and purification]. AB - There was shown the actuality of the problem of the safety of reagents used for water treatment. There have been analyzed several composite reagents used in Russia in the Practice of Water-Supplying Treatment. In technical specifications for these reagents, there was no information on the origin, composition and properties of modifying additives 'M', the synthetic polyelectrolytes level (%). Up to date, there are no available analytical methods permitting to determine reliably the content of polymers and monomers at the levels actually present in water after application of synthetic polyelectrolytes. It is necessary to strengthen the control over the use of synthetic polyelectrolytes in water supplying practice. PMID- 25831932 TI - [Excessive loads on schoolchild: analysis of the hygienist]. AB - In the article there are presented the arguments of the hygienist in favor of the improvement the of pedagogical technologies inthe school for the maintenance of children's health. Recommendations expressed in this article are based on modern data of current domestic research and observations of domestic scientists hygienists, as well as on the analysis of the opinions of parents and teachers of the school. PMID- 25831933 TI - [The methods of assessment of health risk from exposure to radon and radon daughters]. AB - The critical analysis of existing models of the relationship dose-effect (RDE) for radon exposure on human health has been performed. Conclusion about the necessity and possibility of improving these models has been made. A new improved version ofthe RDE has been developed. A technique for assessing the human health risk of exposure to radon, including the method for estimating of exposure doses of radon, an improved model of RDE, proper methodology risk assessment has been described. Methodology is proposed for the use in the territory of Russia. PMID- 25831934 TI - [Experience of justification of hygienic standards of food safety with the use of criteria for the risk population health]. AB - In the article there is presented the experience of justification of hygienic standards of food safety with the use of criteria for the risk for population health. Health risk assessment under the impact of tetracyclines with food showed that the content of residual amounts of these antibiotics at the level of 10 mg/kg (permissible residual tetracycline accepted in Customs Union Member Countries (CUMC) will not increase the risk to public health, including the most sensitive groups of the population. The assessment ofthe health risk associated with the receipt of ractopamine with food, showed that eating foods containing ractopamine at ADI level (0-1 mg/kg body weight), and even at the limit of quantification levels in meat products, is inadmissible because of unacceptable risk of functional disorders and diseases of the cardiovascular system. The results of the substantiation of the permissible levels of nitrates content in crop production showed that at the level of exposure according to hygienic standards established in the CUMC as at the recommended and actual consumption levels of products ofplant origin, the health risk as carcinogenic and non carcinogenic, does not exceed acceptable levels. The results of the assessment of the risk associated with the permissible levels of L. monocytogenes in certain food groups showed that an exposure level of hygienic standards established in the CUMC, standards of Codex Alimentarius Commission and EU documents (before release to the market by the manufacturer) the health risk does not exceed the maximum permissible level of the appearance of serious diseases. Adoption of standards of Codex Alimentarius Commission and the EU (for handling products in the market) is not acceptable because it can lead to an unacceptable risk of listeriosis for the population of the Russian Federation as a whole, and for the most sensitive groups. PMID- 25831935 TI - [Assessment of the effect of environmental chemicals on the working population in mono-cities]. AB - There was made the characterization of the health risk for workers' of pulp and paper industry, under the simultaneous effects of chemicals in the residential and working area. The main adverse effect of chemicals that pollute the air and work environment is related with the impact on the respiratory system. Under the successive exposure (ambient air--air in the workplace) in the adult population working at the Arkhangelsk Pulp and Paper Mill, the risk of occurrence of respiratory diseases (HI = 18.5) and individual carcinogenic risk (CR = 9.7 x 10( 3)) have been rated as high and constitute 86-99% of the total risk. PMID- 25831936 TI - [Dynamics of adaptation processes and morbidity risk for the popupation of the territory of industrial cities]. AB - There was investigated the character of the adaptation processes in the population residing in conditions ofprolonged exposure to environmental pollution in the territory of the industrial cities of the Irkutsk region in order to identify the possible periodicity of their manifestations in the formation of the morbidity risk for the population of different age groups. Under conditions of prolonged exposure to air pollution and other adverse unfavorable factors of industrial cities in the population of all age groups long cyclic changes of adaptation processes in the body in the form of repeated 11-15-years cycles in which a period of relative destabilization of physiological functions with lowered resistance is replaced by the period with the state of elevated nonspecific resistance were established to be observed. Undulating changes of the dynamics of the relative risks of general morbidity should be considered in the assessment of the medical and environmental situation in the territory and making the managing decisions at the base on the data of public health monitoring. PMID- 25831937 TI - [Monitoring of the chemical composition of snow cover pollution in the Moscow region]. AB - Monitoring of snow cover pollution as an indicator of ambient air pollution in 20 districts in the Moscow region during 2009-2013 was performed. The identification with a quantitative assessment of a wide array of organic compounds and the control of the main physical and chemical and inorganic indices of snow water pollution were carried out. More than 60 organic substances for most of which there are no the hygienic standards were established. The assessment of pollution levels of basic inorganic indices was given by means of the comparing them with the average values in the snow cover in the European territory of Russia and natural content in areas not been exposed to human impact. PMID- 25831938 TI - [Ecologo-hygienic criteria and monitoring indices of oil-contaminated peaty soils]. AB - Intensive oil extraction in Khanty-Mansi Autonomous Okrug is not uncommon accompanied by emergency situations giving rise to the pollution of soil, surface and groundwater and causing an elevation in the population morbidity rate. The purpose of the study is to substantiate the basis for information value of hygienic indices of peat soils with low levels of oil contamination: from background values to exceeding the latters as much as 10-20 times, to apply in the study results in hygienic monitoring and oil regulation. The study was performed in accordance with the current methodological regulations. There was established the expediency of determination in transforming in the soil, composition of the petroleum hydrocarbons not only alkanes but arenes and resin asphaltene fractions, indices of phytotoxicity, translocation of petroleum products into plants testing of soil extracts on protozoa and invertebrates. PMID- 25831939 TI - [Distribution iodine deficiency diseases in coastal areas depending on geochemical conditions]. AB - In the Primorsky Krai there was performed a population ecological and hygienic analysis of the relationship between the content of chemical elements in the soil and thyroid morbidity in the population of the region. The assessment of the prevalence of iodine deficiency and iodine deficiency diseases was carried out on the basis of the impact of the priority environmental toxic (strontium, nickel, cadmium, lead, arsenic, tin) and essential (nickel, iron, germanium, molybdenum, zinc, selenium) trace elements on the level of iodine deficiency diseases. The level of thyroid pathology in the territory of Primorye was established to be the highest one in areas characterized by the severe iodine deficiency (Northwest geochemical zones), where the structure of thyroid diseases is presented mainly by diffuse nontoxic goiter. Thyroid diseases associated with iodine deficiency in the population of different age groups are the result of multiple and combined imbalance of trace elements, which causes a relative (secondary) iodine deficiency. Thyroid disease in Primorye are environmentally caused diseases of technogenic origin, they are a consequence of the relative iodine deficiency, when on the background of normal iodine supply an imbalance of zinc, iron, cobalt, manganese with excess of such toxic trace elements as lead, strontium, nickel and chromium takes place. Thyroid pathology associated with iodine deficiency, along with other environmentally dependent diseases can be considered as a marker of ecological environment trouble. PMID- 25831940 TI - [Features of sexual development of adolescent boys in cities of Caspian region of the Republic of Kazakhstan]. AB - The complex estimation of parameters of the sexual development of adolescent boys aged 14-16 years had been done in cities of Aktay and Atyrau, in Caspian region of Western Kazakhstan. Adolescent boys in cities of Caspian region of the Republic of Kazakhstan were found to have tendency to the delayed puberty according to Tanner score. Retarded sexual development is manifested by the some retardation in growth of genitals and escutcheon, in comparison with their peers from control group. The absence of differences in general physical development, as evidenced by anthropometry data, does not exclude the specific (elective) character of the impact of urbanogenic factors on growing male body, which is typical impact of hard metals salts. PMID- 25831941 TI - [Cytogenetical alterations in the workers of higher chemical hazard enterprises in accordance with duration of the employment period]. AB - Cytogenetical examination was performed in 135 workers of higher chemical hazard enterprises with the duration of the employment period from 1 to 23 years. Weak, but statistically significant correlations were observed between indices: the total rate of chromosome aberrations (CA) (Tau = 0.14, p < 0.05), the rate of single fragments (Tau = 0.12, p = 0.01), the rate of ring chronosomes (Tau= 0.12, p = 0.04), the rate of double fragments (Tau = 0.13, p = 0.02), the rate of chromosomal exchange aberrations of chromosome type (Tau = 0.13, p < 0.03) and "the rate of multiaberrant metaphases" (Tau = 0.2, p = 0.0008) and the duration of the employment period at the higher chemical hazard enterprises. The rates of all types of CA was significantly higher in the group with duration of the employment period more than 5 years the significant exceedance of the control level was observed only for the total rate of CA and the rate of single fragments. Other CA types do not significantly exceed control indices. The ratio of carriers of CA of exchange type in the long standing group was significantly higher than in the short standing group, in that ring chromosomes were observed in the long standing group. Differences in the ratio of persons with the normal and increased levels of CA were statistically significant. PMID- 25831942 TI - [Regularities in the development of the toxic process in dependence on the stages of disorganization and adaptation]. AB - At the based of the terms "disorganization" and "adaptation" there was studied the variation of the quantitative criterion of toxic effect--the threshold dose during the experiment with 222 chemicals with the oral toxicity. It is shown that the first manifestation of the effect may occur already in the 5th or 10th or 15th-20th day of intoxication. In the short-term and chronic experiments the dynamics of the toxic process on threshold effect level in time was established to be characterized by four types of models: the growth of the effect (reduction of the threshold doses)--14% of the substances, the absence of the changes in threshold doses--46% of the substances, the apparent weakening of the effect (increase of the threshold dose)--10% of the substances, undulating nature of the threshold doses changes (periodic rise and fall)--30% of the substances. The analysis of these differences with regard to the stage of disorganization and adaptation is carried out. The recommendations for clarifying the procedure of toxicological experiment depending on the dynamics of the toxic process at the threshold level are developed. PMID- 25831944 TI - [Screening of compounds of nitrofuran in imported meat raw materials]. AB - The article presents the results of screening studies of quantification of the nitrofuran drugs imported in raw meat (turkey, beef pork, veal, lamb, chicken). Identification was carried out by the detection ofsuch nitrofurans metabolites as: 1-aminogidantoin (AGD), 3-amino-2-oxazolidinone (AOZ) and 3-amino-5 morpholinomethyl-2-oxazolidinone (AMOZ). There are analyzed the positive and negative effects of nitrofuran drugs. The data for the establishment of the potential risks to human health when using contaminated raw meat metabolites of nitrofurans are discussed. These drugs are prohibited in livestock in Europe since 1995 due to the adverse effects (carcinogenic, mutagenic, teratogenic and toxic) on animals and the potential risk to humans. In the Russian Federation in accordance with SanPin 2.3.2.1078-01 01.01.2012 for the first time the was introduced rationing for nitrofurans (including furazolidone). PMID- 25831943 TI - [To the question of the optimization of methods for detection of vinyl chloride and 1,2-dichloroethane, and their metabolites in biological fluids in workers involved in production of polyvinyl chloride]. AB - There is considered the improvement of methodological approaches to the gas chromatographic methods- of the detection of vinyl chloride and 1,2 dichloroethane and their metabolites--chloroethanol and monochloroacetic acid in biological fluids. There were evaluated such metrological characteristics of methods, as repeatability, interlaboratoty precision, relevance and accuracy. The value of relative expanded uncertainty does not exceed 30%. There are reported optimal regimes of gas chromatographic analysis, conditions for sample preparation. The results of the contents ofthese chemical compounds and their metabolites in biological fluids from persons working in contact with chlorinated hydrocarbons are presented These techniques can be used for the detection ofthe fact of exposure to toxic substances, assessment of the level of exposure and biomonitoring. PMID- 25831945 TI - [Application of immuno-biochemical indices for the identification of the chronic pathology of the upper respiratory tract]. AB - A comprehensive survey of organized children aged 14-17 years residing in the industrial centers with moderate and high levels of air pollution was performed. On the base of the examination of otorhinolaryngologist in the each of cities there was selected the group of schoolchildren with chronic pathology of the upper respiratory tract at the stage of remission. In these groups there was performed the assessment of the informativeness of immuno-biochemical indices for the identification of pathology caused by the impact of man-made factors. The most informative (relative content of autoantibodies to beta2-glycoprotein-1, the average individual immunoreactivity, erythrocyte sedimentation rate, level of alpha1-antitrypsin) were used in the mathematical model, on the based of which it was possible to calculate the diagnostic coefficient, allowing to identify in the groups observed by ourselves, chronic pathology of upper respiratory tract, formed under the influence of ambient air pollution. The above approach can be used in the formation groups for health promotion of children exposed to the negative impact. PMID- 25831946 TI - [Qualitative evaluation of TAMARPP, the relapse prevention program for substance abusers at the Mental Health and Welfare Center]. AB - The development of an effective treatment system for patients with addiction related problems like substance abuse or pathological gambling is urgently needed. The purpose of this study was to clarify the therapeutic factors of the Tama Mental Health and Welfare Center Relapse Prevention Program (TAMARPP). The program is provided at the Tama Comprehensive Center for Mental Health and Welfare, which is operated publicly by the Tokyo Metropolitan Government. Seven personnel (3 clinical psychologists, 2 public health nurses, and 2 recovering counselors) searched the consultation records of 31 participants who had continued treatment longer than 1 year, and made a list of qualitative factors that may positively impact participant outcome. The following six factors were extracted: 1) a "no-blame" atmosphere that makes participants feel safe and free; 2) a mutual helping process that enables participants to empathize with one another; 3) an individual-centered approach that focuses on a participant's motivation to recover; 4) a psycho-educational process that establishes treatment goals; 5) a treatment goal that involves some type of social role; and 6) the referral of graduates to another long-term treatment program such as Narcotics Anonymous. Our results suggest the need of personnel to provide treatment as follows: 1) keep the circumstances safe; 2) use a method that matches the participant's motivation; 3) refer graduates to another in-depth treatment program; 4) emphasize the relationship between thinking, emotion, and behavior; and 5) improve the quality of life of the participant. The missions of our center, an official institution that runs such a program, are as follows: 1) to be the first place at which addicts seek aid during the early stage; 2) to cooperate with other facilities in order to provide social resources that support recovery; and 3) to support patients suffering from both addiction and comorbid psychiatric diseases. PMID- 25831947 TI - [Response to treatment of patients abusing the "dappou drug" who participated in a group relapse prevention program: a comparison with patients abusing methamphetamine]. AB - In this study, we compared the efficacy of a group relapse prevention program using the cognitive behavioral therapy-based workbook, Serigaya Methamphetamine Relapse Prevention Program (SMARPP), between patients abusing the so-called "dappou drugs" (designer drug in Japan, and those abusing methamphetamine (MAP). Both groups participated in the SMARPP at the Center Hospital, National Center of Neurology and Psychiatry. Results showed that, no significant differences were found in the rates of participation in the program or self-reported frequency of drug or alcohol use between the patients abusing "dappou drugs" or MAP. However, patients using "dappou drugs" reported no significant increase in their confidence in their ability to resist the temptation to use drugs on the self- report drug abuse scales after the SMARPP intervention, while patients abusing MAP reported a significant positive difference in their ability to resist temptation. In addition, insight into substance abuse problems and motivation to participate in further treatment slightly declined in those using "dappou drugs," while there was a significant increase reported by the patients using MAP. These results suggested that the SMARPP might not be as effective for patients abusing "dappou drugs" as for those abusing MAP. The development of a relapse prevention program specifically designed for patients abusing "dappou drugs" is required. PMID- 25831948 TI - [Association between norepinephrine transporter gene polymorphism and alcohol dependence in Japanese]. AB - Several studies have suggested that the norepinephrine transporter (NET) may play an important role in the pathogenesis of alcohol dependence. Therefore, in this study, we investigated whether the NET gene polymorphism is a susceptibility factor for alcohol dependence in 64 alcoholics and 73 healthy controls. In addition, we examined whether the combination of the NET and serotonin transporter genotypes are associated with alcohol dependence. The NET (1287G/A, 182T/C, and -3081A/T) and serotonin transporter (5-HTT3'UTR) genotypes were determined by the polymerase chain reaction (PCR)--restriction fragment length polymorphism (RFLP) method. No significant differences in genotype and allele frequencies of the NET and serotonin transporter gene polymorphisms were found between alcoholics and controls. The haplotype frequencies of the NET gene polymorphisms were not also significantly different between them. Furthermore, the combination of the NET and serotonin transporter genotypes had not significant effects on alcohol dependence. The present study suggests that the polymorphisms of 1287G/A, -182T/C and -3081A/T in NET gene are not.risk factors in alcohol dependence. PMID- 25831949 TI - [Investigation of community support measures for patients with comorbid substance use disorder and psychotic disorder: nationwide survey of drug addiction rehabilitation centers]. AB - In psychiatric care practice, patients are often seen who have difficulty with their social lives due to protracted psychiatric symptoms despite years without drug abuse. The difficulty of dealing with such cases and the lack of preparedness of the legal system leave circumstantial care as the only option. Western.countries have recently begun using the name 'concurrent disorder' as a diagnosis for patients deemed unable to recover solely through such treatment for drug addiction, signifying the presence of both a substance use disorder (SUD) and a mental health disorder. Various assessment and intervention methods are being investigated, and many studies have been reported. Based on the hypothesis that Drug Addiction Rehabilitation Center (DARC) are partly involved in supporting those with psychotic concurrent disorders (PSCD) in Japan, we conducted a survey to clarify the actual support for PSCD patients at DARC and the challenges they face. Surveys were administered to DARC-related institutions all over Japan (44 governing organizations and 66 institutions). Complete responses from 86 full-time employees and 445 DARC users were analyzed. DARC users were divided into two groups: psychiatric concurrent disorders (PSCD group, n = 178) and those without such symptoms (SUD group, n = 267), with the PSCD group accounting for 40% of the DARC users surveyed. Compared to the SUD group, the PSCD group was significantly less satisfied with their lifestyle and interpersonal relations at the DARC and a significantly higher proportion of the PSCD group requested assistance in communicating with others. When employees were presented with a hypothetical PSCD case and asked what was needed to deal with it, some responses were, "an institution that can treat both drug addiction and other mental health disorders," "a psychiatric care institution that provides 24 hour care," and "sufficient manpower and training." In the future, a treatment system must be established based on public medical institutions with a dedicated PSCD program that can provide medical care under legal observation. PMID- 25831950 TI - [Motivation for change and recidivism among prison inmates for drug-related offences]. AB - Programs for improving motivation to recover drug dependence were conducted in penal institutes in Japan. This study examined the effects of these programs, in order to increase their efficacy. Furthermore, relationship between increased motivation and prevention of recidivism was examined. The following programs had been conducted in penal institutions: (1) speed learning program using audio visual aids, (2) meeting program (meet a experienced person in recover), in cooperation with DARC (Drug Addiction Rehabilitation Center), and (3) relapse prevention program. Participants were female inmates (N = 94) that had taken part in one of the programs. In order to examine the relationship between motivation for change and recidivism, the motivation for change score was assessed before and after the treatment program. Furthermore, a followed-up was conducted to assess recidivism after release. Results indicated that all the programs resulted in improvements in motivation for change. However, motivation for change resulting from none of the programs had any significant effect on recidivism. The objectives of the treatment programs were reached as expected, since motivation for change improved after the treatment However, it is suggested that to prevent recidivism, more effective treatment methods for improving motivation to change are required. PMID- 25831951 TI - [Alcohol related problem in the workplace: trial of a screening and brief intervention program for risky drinking in the workplace, via the Internet]. AB - This report describes the effect of a screening and brief intervention via the Internet (6-month Total health Management Program: TMP, a kind of life evolution program), for improvement of alcohol related problem in the workplace. At a certain company, 2,096 employees were screened.using AUDIT-C and CAGE via the Internet (electronic screening). From those screened, 17 risky drinkers were picked up. The classification of "risky drinker" was determined based on employees scoring over six points on AUDIT-C and over two points on_ AGE. These employees were then called to one-day practical seminar program (including the program of food education, music therapy, aro-atherapy, body conditioning etc.). After which, during 6 months, they were followed up via e-mail every month. After the 6-month follow up, their results of AUDIT-C were significantly decreased. Additionally, aside from the frequency of drinking at bedtime, maximum alcohol consumption per day was also significantly decreased. The Visual Analogue Scale for anxiety captured the initial screen and then again after follow-up was reduced significantly. Moreover, quality-of-life index for sleep and dinner were both significantly improved as well..These results suggest that the SBI (screening and brief intervention: TMP) is effective for reducing drinking behavior, can be used to effectively elevate quality of life. PMID- 25831952 TI - [Concurrent inpatient smoking cessation and alcohol abstinence programs for alcoholics and their outcomes]. AB - Alcoholics have a high prevalence of nicotine dependence, and smoking is a major contributor to their high mortality. Three weeks after admission to an addiction center in Japan, 193 alcoholic men who were participating in an 11-week concurrent inpatient smoking cessation and alcohol abstinence programs filled out an anonymous self-report questionnaire regarding smoking and drinking, and 6 months after the completion of the programs, 83 patients were asked to respond to a mailed questionnaire about their smoking and drinking status. Of the 193 subjects, 73.3% were current smokers, but many were highly motivated in regard to both smoking cessation and alcohol abstinence. The subjects' scores on a 0 to 10 point scale for rating motivation and confidence in regard to smoking cessation and smoking urge were significantly correlated with each other and with their scores for motivation and confidence in regard to alcohol abstinence and drinking urge. Three weeks after admission, varenicline treatment was well-tolerated, and the varenicline group had a high rate of smoking cessation than the smoker group not treated with varenicline (67.7% vs. 44.6%, p = 0.012). Forty-six (55.4%) of the 83 subjects who were mailed the questionnaire responded, and the drinking category was 'totally abstinent' in 35 subjects (42.2%), and 'mostly abstinent' in another 4 subjects (4.8%). Seventeen (20.5%) of the 83 subjects were non smokers before treatment, but after treatment, 23 (50.0%) of the 46 responders and 20 (51.3%) of the 'totally or mostly abstinent' 39 responders were total or almost non-smokers. The response rate of 'totally or mostly abstinent' was higher among the 17 non-smokers before treatment than among the 66 smokers before treatment (70.6% vs. 40.9%, p = 0.033), and the age-adjusted odds ratio (95% confidence interval) for the response of 'totally or mostly abstinent' was 3.30 (1.03-10.56) for the non-smokers before treatment (vs. the smokers before treatment). In conclusion, smoking status had a great impact on the drinking status of treatment-seeking alcoholic men, and smoking cessation should be recommended to smoking alcoholics. PMID- 25831953 TI - Critical thresholds of liver function parameters for ketosis prediction in dairy cows using receiver operating characteristic (ROC) analysis. AB - BACKGROUND: Fatty liver syndrome and ketosis are important metabolic disorders in high-producing cows during early lactation with fatty liver usually preceding ketosis. To date, parameters for early prediction of the risk of ketosis have not been investigated in China. OBJECTIVE: To determine the predictive value of some parameters on the risk of ketosis in China. ANIMALS AND METHODS: In a descriptive study, 48 control and 32 ketotic Holstein Friesian cows were randomly selected from one farm with a serum beta-hydroxybutyrate (BHBA) concentration of 1.20 mmol/L as cutoff point. The risk prediction thresholds for ketosis were determined by receiver operating characteristic (ROC) analysis. RESULTS: In line with a high BHBA concentration, blood glucose concentration was significantly lower in ketotic cows compared to control animals (2.77 +/- 0.24 versus 3.34 +/- 0.03 mmol/L; P = 0.02). Thresholds were more than 0.76 mmol/L for nonesterified fatty acids (NEFA, with 65% sensitivity and 92% specificity), more than 104 U/L for aspartate aminotransferase (AST, 74% and 85%, respectively), less than 140 U/L for cholinesterase (CHE, 75% and 59%, respectively), and more than 3.3 umol/L for total bilirubin (TBIL, 58% and 83%, respectively). There were significant correlations between BHBA and glucose (R = -4.74), or CHE (R = -0.262), BHBA and NEFA (R = 0.520), or AST (R = 0.525), or TBIL (R = 0.278), or direct bilirubin (DBIL, R = 0.348). CONCLUSIONS: AST, CHE, TBIL and NEFA may be useful parameters for risk prediction of ketosis. CLINICAL IMPORTANCE: This study might be of value in addressing novel directions for future research on the connection between ketosis and liver dysfunction. PMID- 25831955 TI - Eccrine poroma on the helix: a rare anatomical presentation. PMID- 25831954 TI - Characterization of an alpha-l-fucosidase from the periodontal pathogen Tannerella forsythia. AB - The periodontal pathogen Tannerella forsythia expresses several glycosidases which are linked to specific growth requirements and are involved in the invasion of host tissues. alpha-l-Fucosyl residues are exposed on various host glycoconjugates and, thus, the alpha-l-fucosidases predicted in the T. forsythia ATCC 43037 genome could potentially serve roles in host-pathogen interactions. We describe the molecular cloning and characterization of the putative fucosidase TfFuc1 (encoded by the bfo_2737 = Tffuc1 gene), previously reported to be present in an outer membrane preparation. In terms of sequence, this 51-kDa protein is a member of the glycosyl hydrolase family GH29. Using an artificial substrate, p nitrophenyl-alpha-fucose (KM 670 MUM), the enzyme was determined to have a pH optimum of 9.0 and to be competitively inhibited by fucose and deoxyfuconojirimycin. TfFuc1 was shown here to be a unique alpha(1,2)-fucosidase that also possesses alpha(1,6) specificity on small unbranched substrates. It is active on mucin after sialidase-catalyzed removal of terminal sialic acid residues and also removes fucose from blood group H. Following knock-out of the Tffuc1 gene and analyzing biofilm formation and cell invasion/adhesion of the mutant in comparison to the wild-type, it is most likely that the enzyme does not act extracellularly. Biochemically interesting as the first fucosidase in T. forsythia to be characterized, the biological role of TfFuc1 may well be in the metabolism of short oligosaccharides in the periplasm, thereby indirectly contributing to the virulence of this organism. TfFuc1 is the first glycosyl hydrolase in the GH29 family reported to be a specific alpha(1,2)-fucosidase. PMID- 25831956 TI - Automated auditory response detection: Further improvement of the statistical test strategy by using progressive test steps of iteration. AB - OBJECTIVE: A common testing approach for automated ABR detection is to use a sequential test strategy. Repeated testing increases the error probability for a falsely detected response (Type I error rate). To compensate for this effect, the statistically critical test value must be increased with each test step. The aim of the study was to improve response detection by a reduction of the number of test steps using a progressively increasing test step of iteration, defined here as step width. DESIGN: A progressively increasing test step width was tested with and without the table-related testing (adjusting the critical test value to each test step) proposed by Sturzebecher & Cebulla (2013) . For this study the same data pool was used. STUDY SAMPLE: The investigation was performed on raw EEG data collected during routine clinical measurement of frequency-specific ASSR for hearing threshold assessment. RESULTS: The reduction of the test step number combined with a progressive test step width led to a significantly improved response detection. In combination with table-related testing a slight but not significant improvement compared to table-related testing alone was revealed. CONCLUSIONS: The proposed test strategy can improve the performance of objective hearing threshold assessment and of newborn hearing screening. PMID- 25831957 TI - Postnatal ontogeny of the cochlea and flight ability in Jamaican fruit bats (Phyllostomidae) with implications for the evolution of echolocation. AB - Recent evidence has shown that the developmental emergence of echolocation calls in young bats follow an independent developmental pathway from other vocalizations and that adult-like echolocation call structure significantly precedes flight ability. These data in combination with new insights into the echolocation ability of some shrews suggest that the evolution of echolocation in bats may involve inheritance of a primitive sonar system that was modified to its current state, rather than the ad hoc evolution of echolocation in the earliest bats. Because the cochlea is crucial in the sensation of echoes returning from sonar pulses, we tracked changes in cochlear morphology during development that included the basilar membrane (BM) and secondary spiral lamina (SSL) along the length of the cochlea in relation to stages of flight ability in young bats. Our data show that the morphological prerequisite for sonar sensitivity of the cochlea significantly precedes the onset of flight in young bats and, in fact, development of this prerequisite is complete before parturition. In addition, there were no discernible changes in cochlear morphology with stages of flight development, demonstrating temporal asymmetry between the development of morphology associated with echo-pulse return sensitivity and volancy. These data further corroborate and support the hypothesis that adaptations for sonar and echolocation evolved before flight in mammals. PMID- 25831958 TI - The WOR1 5' untranslated region regulates white-opaque switching in Candida albicans by reducing translational efficiency. AB - The human fungal pathogen Candida albicans undergoes white-opaque phenotypic switching, which enhances its adaptation to host niches. Switching is controlled by a transcriptional regulatory network of interlocking feedback loops acting on the transcription of WOR1, the master regulator of white-opaque switching, but regulation of the network on the translational level is not yet explored. Here, we show that the long 5' untranslated region of WOR1 regulates the white-opaque phenotype. Deletion of the WOR1 5' UTR promotes white-to-opaque switching and stabilizes the opaque state. The WOR1 5' UTR reduces translational efficiency and the association of the transcript with polysomes. Reduced polysome association was observed for additional key regulators of cell fate and morphology with long 5' UTR as well. Overall, we find a novel regulatory step of white-opaque switching at the translational level. This translational regulation is implicated for many key regulators of cell fate and morphology in C. albicans. PMID- 25831959 TI - Advancing a sociotechnical systems approach to workplace safety--developing the conceptual framework. AB - Traditional efforts to deal with the enormous problem of workplace safety have proved insufficient, as they have tended to neglect the broader sociotechnical environment that surrounds workers. Here, we advocate a sociotechnical systems approach that describes the complex multi-level system factors that contribute to workplace safety. From the literature on sociotechnical systems, complex systems and safety, we develop a sociotechnical model of workplace safety with concentric layers of the work system, socio-organisational context and the external environment. The future challenges that are identified through the model are highlighted. PRACTITIONER SUMMARY: Understanding the environmental, organisational and work system factors that contribute to workplace safety will help to develop more effective and integrated solutions to deal with persistent workplace safety problems. Solutions to improve workplace safety need to recognise the broad sociotechnical system and the respective interactions between the system elements and levels. PMID- 25831960 TI - Clinical symptoms associated with suicidality in patients with panic disorder. AB - BACKGROUND: Patients with panic disorder have higher rates of suicide than the general population. Among panic disorder subjects, early onset, female gender, alcohol abuse, and mood disorder increase the risk of suicidality. However, less is known about the unique relationships between discrete DSM-IV panic symptoms and higher suicidality. Therefore, in the current study we examined the panic symptom profile that is associated with higher suicidality in a sample of outpatients with panic disorder. METHODS: This cross-sectional study included 427 patients diagnosed with current panic disorder on the basis of the DSM-IV-TR. In order to assess the contribution of the clinical variables, a univariate logistic regression was carried out examining the relationships between the demographic variables, suicidality from the suicide module of the Korean version of the MINI International Neuropsychiatric Interview Plus, and DSM-IV panic symptoms. Additionally, a multivariate logistic regression was performed to identify specific panic symptoms that were significant risk factors for suicidality among patients with current panic disorder. RESULTS: We found that 74 (17.33%) panic disorder patients experienced high suicidality. Univariate analyses showed that high suicidality was significantly associated with a younger age (OR = 13.66; 95% CI 2.68-69.70), comorbid depressive disorders (OR = 4.57; 95% CI 2.57-8.11), and the following panic symptoms: palpitations (OR = 2.20; 95% CI 0.90-5.35), trembling (OR = 0.61; 95% CI 0.362-1.18), nausea or abdominal distress (OR = 1.77; 95% CI 0.96-3.27), fear of losing control or going crazy (OR = 2.18; 95% CI 1.12-4.23), and paresthesia (OR = 1.57; 95% CI 0.83-2.98). Multivariate logistic regression analyses demonstrated that specific panic symptoms, such as palpitations (adjusted OR = 2.69; 95% CI 1.08-6.73) and fear of losing control or going crazy (adjusted OR = 2.28; 95% CI 1.21-4.31), were related to suicidality after controlling for confounding factors. CONCLUSION: Some panic symptoms (e.g. palpitations and fear of losing control or going crazy) are associated with a risk of suicidality among patients with panic disorder. A priori identification of high-risk suicidal subjects could lead to effective treatment strategies for panic disorder. PMID- 25831961 TI - The IVIg dilemma: a way out? PMID- 25831962 TI - The WHO-5 Well-Being Index: a systematic review of the literature. AB - BACKGROUND: The 5-item World Health Organization Well-Being Index (WHO-5) is among the most widely used questionnaires assessing subjective psychological well being. Since its first publication in 1998, the WHO-5 has been translated into more than 30 languages and has been used in research studies all over the world. We now provide a systematic review of the literature on the WHO-5. METHODS: We conducted a systematic search for literature on the WHO-5 in PubMed and PsycINFO in accordance with the PRISMA guidelines. In our review of the identified articles, we focused particularly on the following aspects: (1) the clinimetric validity of the WHO-5; (2) the responsiveness/sensitivity of the WHO-5 in controlled clinical trials; (3) the potential of the WHO-5 as a screening tool for depression, and (4) the applicability of the WHO-5 across study fields. RESULTS: A total of 213 articles met the predefined criteria for inclusion in the review. The review demonstrated that the WHO-5 has high clinimetric validity, can be used as an outcome measure balancing the wanted and unwanted effects of treatments, is a sensitive and specific screening tool for depression and its applicability across study fields is very high. CONCLUSIONS: The WHO-5 is a short questionnaire consisting of 5 simple and non-invasive questions, which tap into the subjective well-being of the respondents. The scale has adequate validity both as a screening tool for depression and as an outcome measure in clinical trials and has been applied successfully across a wide range of study fields. PMID- 25831963 TI - The need to treat maternal pain in the breastfeeding mother: are opioids safe? PMID- 25831965 TI - Risk factors for delayed healing in venous leg ulcers: a review of the literature. AB - BACKGROUND: Chronic leg ulcers, remaining unhealed after 4-6 weeks, affect 1-3% of the population, with treatment costly and health service resource intensive. Venous disease contributes to approximately 70% of all chronic leg ulcers and these ulcers are often associated with pain, reduced mobility and a decreased quality of life. Despite evidence-based care, 30% of these ulcers are unlikely to heal within a 24-week period and therefore the recognition and identification of risk factors for delayed healing of venous leg ulcers would be beneficial. AIM: To review the available evidence on risk factors for delayed healing of venous leg ulcers. METHODS: A review of the literature in regard to risk factors for delayed healing in venous leg ulcers was conducted from January 2000 to December 2013. Evidence was sourced through searches of relevant databases and websites for resources addressing risk factors for delayed healing in venous leg ulcers specifically. RESULTS: Twenty-seven studies, of mostly low-level evidence (Level III and IV), identified risk factors associated with delayed healing. Risk factors that were consistently identified included: larger ulcer area, longer ulcer duration, a previous history of ulceration, venous abnormalities and lack of high compression. Additional potential predictors with inconsistent or varying evidence to support their influence on delayed healing of venous leg ulcers included: decreased mobility and/or ankle range of movement, poor nutrition and increased age. DISCUSSION: Findings from this review indicate that a number of physiological risk factors are associated with delayed healing in venous leg ulcers and that social and/or psychological risk factors should also be considered and examined further. CONCLUSION: The findings from this review can assist health professionals to identify prognostic indicators or risk factors significantly associated with delayed healing in venous leg ulcers. This will facilitate realistic outcome planning and inform implementation of appropriate early strategies to promote healing. PMID- 25831964 TI - Re-visiting the trans insertion model for complexin clamping. AB - We have previously proposed that complexin cross-links multiple pre-fusion SNARE complexes via a trans interaction to function as a clamp on SNARE-mediated neurotransmitter release. A recent NMR study was unable to detect the trans clamping interaction of complexin and therefore questioned the previous interpretation of the fluorescence resonance energy transfer and isothermal titration calorimetry data on which the trans clamping model was originally based. Here we present new biochemical data that underscore the validity of our previous interpretation and the continued relevancy of the trans insertion model for complexin clamping. PMID- 25831966 TI - Incidental cholecystectomy in patients with asymptomatic gallstones undergoing surgery for colorectal cancer. AB - BACKGROUND AND AIMS: The feasibility of incidental cholecystectomy during colorectal cancer (CRC) surgery has not been determined as yet. We aimed to investigate the feasibility of incidental cholecystectomy during CRC surgery. METHODS: The clinicopathologic data of patients who underwent CRC surgery between January 2004 and May 2011 were assessed. Patients with asymptomatic cholelithiasis were divided into groups that did and did not undergo incidental cholecystectomy. Their in-hospital morbidity and long-term biliary complications were compared. RESULTS: Of the 282 patients identified, 143 (50.7%) underwent incidental cholecystectomy and 139 (49.3%) were observed without cholecystectomy. The two groups were similar in clinical characteristics, except for gender and operation time. Only one patient (0.7%) in the cholecystectomy group experienced an intraoperative biliary complication. There was no significant difference in overall in-hospital morbidity between the two groups. After a median follow-up period of 33 months, long-term biliary complications developed in 12 patients (8.6%) in the observation group, with 9 undergoing cholecystectomy. CONCLUSIONS: Incidental cholecystectomy was not associated with increased postoperative morbidity, whereas previously asymptomatic patients were at substantial long-term risk of becoming symptomatic. Thus, in the absence of clear contraindications, concomitant cholecystectomy might be a desirable treatment option during CRC surgery in patients with asymptomatic gallstones. PMID- 25831967 TI - Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors). AB - Vortioxetine is an antidepressant that targets multiple pharmacologic modes of action at sites--or nodes--where serotonergic neurons connect to various brain circuits. These multimodal pharmacologic actions of vortioxetine lead to enhanced release of various neurotransmitters, including serotonin, at various nodes within neuronal networks. PMID- 25831969 TI - Spontaneous resolution of Julia-Kocienski intermediates facilitates phase separation to produce Z- and E-monofluoroalkenes. AB - The monofluoroalkene motif is important in drug development as it serves as a peptide bond isostere and is found in a number of biologically active compounds with various pharmacological activities. Direct olefination of carbonyl compound is a straightforward way to prepare monofluoroalkenes; however, these methods often result in a mixture of Z- and E-isomers that cannot be easily separated. We discovered a unique spontaneous resolving reaction that simultaneously addresses the problems in the synthesis and separation of Z- and E-monofluoroalkenes. The reaction is accompanied by a highly efficient spontaneous kinetic resolution and phase labeling of monofluoroalkene precursors which allows the separation of Z- and E-monofluoroalkenes by liquid-liquid extraction. The application of the method is demonstrated by the synthesis and separation of potential anticancer agents, which are inseparable by HPLC. PMID- 25831968 TI - Prevalence and correlates of anger in the community: results from a national survey. AB - INTRODUCTION: Little is known about the prevalence and correlates of anger in the community. METHODS: We used data derived from a large national sample of the U.S. population, which included more than 34,000 adults ages 18 years and older. We defined inappropriate, intense, or poorly controlled anger by means of self report of the following: (1) anger that was triggered by small things or that was difficult to control, (2) frequent temper outbursts or anger that lead to loss of control, or (3) hitting people or throwing objects in anger. RESULTS: The overall prevalence of inappropriate, intense, or poorly controlled anger in the U.S. population was 7.8%. Anger was especially common among men and younger adults, and was associated with decreased psychosocial functioning. Significant and positive associations were evident between anger and parental factors, childhood, and adulthood adverse events. There were strong associations between anger and bipolar disorder, drug dependence, psychotic disorder, borderline, and schizotypal personality disorders. There was a dose-response relationship between anger and a broad range of psychopathology. CONCLUSIONS: A rationale exists for developing screening tools and early intervention strategies, especially for young adults, to identify and help reduce anger. PMID- 25831970 TI - Metal complex modified azo polymers for multilevel organic memories. AB - Multilevel organic memories have attracted considerable interest due to their high capacity of data storage. Despite advances, the search for multilevel memory materials still remains a formidable challenge. Herein, we present a rational design and synthesis of a class of polymers containing an azobenzene-pyridine group (PAzo-py) and its derivatives, for multilevel organic memory storage. In this design, a metal complex (M(Phen)Cl2, M = Cu, Pd) is employed to modify the HOMO-LUMO energy levels of azo polymers, thereby converting the memory state from binary to ternary. More importantly, this approach enables modulating the energy levels of azo polymers by varying the coordination metal ions. This makes the achievement of high performance multilevel memories possible. The ability to tune the bandgap energy of azo polymers provides new exciting opportunities to develop new materials for high-density data storage. PMID- 25831971 TI - Corrigendum. PMID- 25831972 TI - Allergic sensitization to pegylated interferon-alpha results in drug eruptions. AB - BACKGROUND: The introduction of pegylated interferon (PEG-IFN)-alpha in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon (IFN)-alpha, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-alpha. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-alpha-induced drug eruptions. METHODS: Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study (n = 22). Subjects were tested for sensitivity to pegylated IFN-alpha2a , pegylated IFN alpha2b , or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests (LATs). Skin biopsies obtained from pegylated IFN alpha-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-alpha injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. RESULTS: A subset of patients suffering from pegylated IFN alpha-associated exanthemas displayed positive intradermal tests to PEG-IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN alpha-signature, whereas lesional skin of exanthemas showed induction of TH2 associated chemokines. CONCLUSIONS: Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG-IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional, nonpegylated drugs, enabling IFN-alpha therapy continuation without drug-associated skin eruptions. PMID- 25831974 TI - Interventional decentralized telemonitoring: bridging the gap between patient's device and physician's needs in well selected indications. AB - Telemedicine comprises different concepts aiming to close a spatial distance between practitioner, medical staff and patient. It's functionality can include mere data transmission but extend as well to triggering alarms or enable consultation and therapy suggestions. A special form of telemedicinal application is interventional decentralized telemonitoring. Here practitioner-patient communication is characterized by telemedicinial data collection driven therapy control and -optimization. To identify feasible indications for the employment of telemonitoring a detailed definition of communicated parameters, alarm rules and algorithms of intervention are required as well as a benefit-cost analysis. The quality of the telemedical application is determined by the medical quality of the resulting actions. PMID- 25831973 TI - A photofunctional bottom-up bis(dipyrrinato)zinc(II) complex nanosheet. AB - Two-dimensional polymeric nanosheets have recently gained much attention, particularly top-down nanosheets such as graphene and metal chalcogenides originating from bulk-layered mother materials. Although molecule-based bottom-up nanosheets manufactured directly from molecular components can exhibit greater structural diversity than top-down nanosheets, the bottom-up nanosheets reported thus far lack useful functionalities. Here we show the design and synthesis of a bottom-up nanosheet featuring a photoactive bis(dipyrrinato)zinc(II) complex motif. A liquid/liquid interfacial synthesis between a three-way dipyrrin ligand and zinc(II) ions results in a multi-layer nanosheet, whereas an air/liquid interfacial reaction produces a single-layer or few-layer nanosheet with domain sizes of >10 MUm on one side. The bis(dipyrrinato)zinc(II) metal complex nanosheet is easy to deposit on various substrates using the Langmuir-Schafer process. The nanosheet deposited on a transparent SnO2 electrode functions as a photoanode in a photoelectric conversion system, and is thus the first photofunctional bottom-up nanosheet. PMID- 25831975 TI - Lymphocyte 'homing' and chronic inflammation. AB - Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV-like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV-like vessel-mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others. PMID- 25831976 TI - Erratum to: Estimating the number of men who have sex with men by race/ethnicity at the county level in Texas. PMID- 25831977 TI - Reconstitution of biosynthetic machinery for the synthesis of the highly elaborated indole diterpene penitrem. AB - Penitrem A is one of the most elaborated members of the fungal indole diterpenes. Two separate penitrem gene clusters were identified using genomic and RNA sequencing data, and 13 out of 17 transformations in the penitrem biosynthesis were elucidated by heterologous reconstitution of the relevant genes. These reactions involve 1) a prenylation-initiated cationic cyclization to install the bicyclo[3.2.0]heptane skeleton (PtmE), 2) a two-step P450-catalyzed oxidative processes forming the unique tricyclic penitrem skeleton (PtmK and PtmU), and 3) five sequential oxidative transformations (PtmKULNJ). Importantly, without conventional gene disruption, reconstitution of the biosynthetic machinery provided sufficient data to determine the pathway. It was thus demonstrated that the Aspergillus oryzae reconstitution system is a powerful method for studying the biosynthesis of complex natural products. PMID- 25831978 TI - Protein SYCP2 is an ancient component of the metazoan synaptonemal complex. AB - During the first meiotic prophase, chromosome synapsis is mediated by the synaptonemal complex (SC), an evolutionarily conserved meiosis-specific structure. In mammals, 7 SC protein components have been identified so far. Despite some controversy in the past, we have shown that SC proteins are ancient in metazoans and very likely formed an ancestral SC structure in the ancestor of metazoans. Protein components SYCP1, SYCP3, SYCE2, and TEX12 were identified in basal-branching metazoans, while other components (SYCE1 and SYCE3) are more recent elements. However, the evolutionary history of mammalian SYCP2 is not known. Here, we investigated this aspect with the aid of bioinformatic tools as well as with RNA and protein expression analysis. We conclude that SYCP2 belongs to the group of ancient SC proteins that was already present in the common ancestor of metazoans more than 500 million years ago. PMID- 25831980 TI - [Psycho-somatic dialogue]. PMID- 25831981 TI - [Standardization of the German 16-item short version of the Inventory of Personality Organization (IPO-16)]. AB - Standardization of the German 16-item short version of the Inventory of Personality Organization (IPO-16). OBJECTIVES: The 16-item short version of the Inventory of Personality Organization (IPO-16) is a self-report measure assessing the severity of personality dysfunction. This study provides representative norms and determines the smallest real difference value for the IPO-16. METHODS: Standardization of the IPO-16 was based on a representative survey among the German general population (N = 2502). Retest reliability and the smallest real difference were assessed in a separate longitudinal online survey, whereby participants completed the IPO-16 three times at time intervals of 2 months (N = 495). RESULTS: The average IPO-16-mean score in the general population was 1.87. The influence of age and sex was small, albeit statistically significant.We therefore developed sex- and age-specific norms. The average retest reliability across 2 months was .85, and the smallest real difference was 0.66. CONCLUSIONS: The IPO-16 is a well-validated, and now standardized, screening instrument for the assessment of severity of personality dysfunction. It can be recommended for use in research and practice. PMID- 25831982 TI - [Psychodynamically oriented inpatient psychotherapy of depressive disorders - First findings from a naturalistic, multicenter study]. AB - OBJECTIVES: While the general effectiveness of psychodynamic psychotherapy in both outpatient and inpatient treatment has been proven, few studies document the effectiveness of clinical inpatient treatment of depression through psychodynamic psychotherapy. METHODS: This paper presents first results of a naturalistic multicenter intervention study. Included were female inpatients suffering from depressive symptoms who had been admitted to 15 psychodynamically oriented psychosomatic hospital units (N = 487). The mean duration of treatment was 61.8 days. Data were acquired at admission (T1) and discharge (T2). RESULTS: Our findings support previous evidence and show that psychodynamically oriented inpatient psychotherapy of depressive disorders is efficient. High pre-post effect sizes were documented in all psychometric instruments used (BDI, HAM-D, SCL-90-R, BSS, GAF). Initial subgroup comparisons reveal that the benefits for patients with comorbid personality disorder are significantly lower than for depressed patients without comorbid personality disorder. CONCLUSION: Psychodynamic inpatient psychotherapy, as practiced under naturalistic conditions, is an effective treatment of depression. Predictors of therapeutic effects within different therapeutic settings, however, remain unclear. The sustainability of the therapeutic effects found and their impact on psychodynamic relevant constructs have still to be proven. PMID- 25831983 TI - [Narcissism self-expression - the generation me?]. AB - OBJECTIVES: A self-report questionnaire to assess conflict was created from the conflict axis of the Operationalized Psychodynamic Diagnostics (Arbeitskreis OPD 2 2006; Arbeitskreis OPD-KJ-2 2013). METHODS: In a paper-pencil test we compared a sample of 501 assumed healthy teenagers of between 12 and 17 years, a sample of 31 adolescent psychosomatic inpatients, and a sample of 20 adolescents psychiatric inpatients. RESULTS: We found significant sex and age differences concerning narcissistic self-expression. Significant differences between the three groups as well as significant correlations with common clinical instruments (BSI,IPO, IIP) revealed narcissistic self-expression to be problematic. DISCUSSION: The questionnaire demonstrated a high level of reliability.Narcissistic self-expression is higher in the healthy control group, for male adolescents and older adolescents. There is, however, a significant correlation with psychological symptoms and interpersonal problems. PMID- 25831989 TI - Universal definition of myocardial infarction: clinical insights. AB - AIMS: The universal definition of myocardial infarction (MI) classifies acute ischaemia into different classes according to lesion mechanism. Our aim was to perform a detailed comparison between these different types of MI in terms of baseline characteristics, management and prognosis. METHODS AND RESULTS: An observational retrospective single-centre cohort study was performed, including 1,000 consecutive patients admitted for type 1 (76.4%) or type 2 MI (23.6%). Type 2 MI patients were older, had a higher prevalence of comorbidities and worse medical status at admission. In-hospital mortality did not differ significantly between the MI groups (8.8 vs. 9.7%, p = 0.602). However, mortality during follow up was almost 3 times higher in type 2 MIs (HR 2.75, p < 0.001). Type 2 MI was an independent all-cause mortality risk marker, adding discriminatory power to the GRACE model. Finally, important differences in traditional risk score performances (GRACE, CRUSADE) were found between both MI types. CONCLUSIONS: Several important baseline differences were found between these MI types. Regarding prognosis, long-term survival is significantly compromised in type 2 MIs, potentially translating patients' higher medical complexity and frailty. Distinction between type 1 and type 2 MI seems to have important implications in clinical practice and likely also in the results of clinical trials. PMID- 25831990 TI - Head and pelvis stride-to-stride oscillations in gait: validation and interpretation of measurements from wearable accelerometers. AB - Unstable gait is a risk factor for falls. Wearable accelerometers enable remote monitoring of daily walking. Here, new methods for measuring stride-to-stride oscillations are validated against optical motion capture, normative data determined, and dependency on walking speed investigated. Walks by 13 young people (mean age 32 years) at fast, usual, and slow speeds were completed. Accelerometers were attached to the head and pelvis and stride-to-stride oscillation velocity and displacement were measured. Continuous tilt corrections were applied, filter cut-offs scaled by step frequency, and thresholds optimized using optical motion capture as a reference. Oscillations depended on walking speed, accelerometer placement, and measurement axis. Vertical oscillations increased with walking speed (Pearson's r = 0.78-0.89) and were the most accurate (1.4-2.3% error). Mediolateral or anterioposterior oscillations were less accurate (5.9-19.5% error) and had more complex relationships with walking speed (increasing, decreasing, uncorrelated, and/or 'U-shaped' minimum at usual speed). In healthy gait, the head and pelvis undergo regular oscillations, measurable with accelerometers. The results suggest head oscillations in the transverse plane are attenuated by the trunk, and there may be advantages in minimizing stride-to-stride oscillations that coincide with self-selected usual pace. These methods may prove useful for remote assessment of changing health, mental status, and/or fall risk. PMID- 25831991 TI - The assessment of renalase: searching for the best predictor of early renal dysfunction by multivariate modeling in stable renal transplant recipients. AB - BACKGROUND: Renal transplant dysfunction has been shown to be an independent risk factor for cardiac, non-cardiovascular, and all-cause mortality in post transplantation follow-up. MATERIAL AND METHODS: We enrolled 73 renal transplant recipients who were more than 12 months post-renal transplant surgery, had stable graft function, and were on standard immunosuppression. The purpose of the study was to observe the relation between renal dysfunction and endothelial dysfunction parameters (nitrates, asymmetric and symmetric dimethylarginine, and endothelial nitric oxide synthase), and renalase, and to hypothesize the best predictor of early renal dysfunction by multivariate modeling. The other aim was to observe differences with regard to immunosuppression. RESULTS: Non-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate in transplant recipients with increased renalase concentration (p=0.026); age-adjusted odds ratio showed a significant risk of reduced glomerular filtration rate with increased renalase concentration (p=0.042), also after multivariable adjustment (p=0.032). Increased plasma endothelial nitric oxide synthase concentration was a protective factor for glomerular filtration rate (p=0.011). After adjustment for age (p=0.045), and after multivariate modeling, endothelial nitric oxide synthase was shown to be a protective factor for glomerular filtration rate (p=0.014). Significant differences in immunosuppression were found in plasma renalase in patients maintained on cyclosporine (p=0.027). CONCLUSIONS: Renalase was shown to be strong predictor of decreased glomerular filtration rate and was significantly higher in the group of patients on cyclosporine. Endothelial nitric oxide synthase was identified as a strong protective factor for kidney function. PMID- 25831992 TI - An irregular pulmonary nodule was confirmed diagnosis of aspiration pneumonia by finding plant cells through rapid on-site evaluation. AB - BACKGROUND: Rapid on-site evaluation (ROSE) is a method which is often used in quick-staining cytology in the tumour diagnostic field, and results in a significant decrease in diagnostic time and cost. However, we have not found any previous report on the ROSE method for diagnosing aspiration pneumonia. METHODS: We would like to discuss the case of a patient with an irregular pulmonary nodule in the left lower lobar bronchus who had a confirmed diagnosis of aspiration pneumonia through ROSE stained by Diff-Quik methods during bronchoscopy. RESULTS: Through ROSE, which we were able to perform within just 1 min, we observed the plant cells on the smear under the microscope. The Giemsa stain of the specimen, which would take much more time than Diff-Quik, also revealed the plant cells. CONCLUSION: ROSE for the specimen from the bronchoscopy could be done for the patient who has developed an unexplained pulmonary nodule and is helpful. If the non-human cells such as plant cells are found from the ROSE, aspiration pneumonia can be diagnosed immediately and the corresponding therapy may be performed, which may significantly shorten hospital stay, reduce hospital costs and improve patient outcomes. PMID- 25831993 TI - Effects of isometric quadriceps strength training at different muscle lengths on dynamic torque production. AB - This study aims to (1) determine whether isometric training at a short vs. long quadriceps muscle length affects concentric torque production; (2) examine the relationship between muscle hypertrophy and concentric torque; and (3) determine whether changes in fascicle length are associated with changes in concentric torque. Sixteen men performed isometric training at a short (SL, n = 8) or a long muscle length (LL, n = 8). Changes in maximal concentric torque were measured at 30, 60, 90, 120, 180, 240 and 300 rad . s(-1). The relationships between the changes in concentric torque, cross-sectional area, volume and fascicle length were tested. Concentric torque increased significantly after training only in LL and at angular velocities of 30 and 120 rad . s(-1) by 12-13% (P < 0.05). Muscle size increased in LL only, the changes were correlated (r = 0.73-0.93, P < 0.05) with the changes in concentric torque. Vastus lateralis (VL) fascicle length increased in both groups (5.4 +/- 4.9%, P = 0.001) but the change was not correlated with changes in concentric torque in either group. Isometric training induced increases in muscle size and concentric torque were best elicited by training at long muscle lengths. These results highlight a clear muscle length dependence of isometric training on dynamic torque production. PMID- 25831994 TI - Gender Role Attitudes and Male Adolescent Dating Violence Perpetration: Normative Beliefs as Moderators. AB - Commonly used dating violence prevention programs assume that promotion of more egalitarian gender role attitudes will prevent dating violence perpetration. Empirical research examining this assumption, however, is limited and inconsistent. The current study examined the longitudinal association between gender role attitudes and physical dating violence perpetration among adolescent boys (n = 577; 14 % Black, 5 % other race/ethnicity) and examined whether injunctive (i.e., acceptance of dating violence) and descriptive (i.e., beliefs about dating violence prevalence) normative beliefs moderated the association. As expected, the findings suggest that traditional gender role attitudes at T1 were associated with increased risk for dating violence perpetration 18 months later (T2) among boys who reported high, but not low, acceptance of dating violence (injunctive normative beliefs) at T1. Descriptive norms did not moderate the effect of gender role attitudes on dating violence perpetration. The results suggest that injunctive norms and gender role attitudes work synergistically to increase risk for dating violence perpetration among boys; as such, simultaneously targeting both of these constructs may be an effective prevention approach. PMID- 25831995 TI - The correct episiotomy: does it exist? A cross-sectional survey of four public Israeli hospitals and review of the literature. AB - INTRODUCTION AND HYPOTHESIS: Our objective was to assess episiotomy technique used in Israeli hospitals, to determine factors influencing incision parameters, and to review relevant up-to-date professional literature. METHODS: Using anonymous questionnaires, a survey was conducted among obstetricians and midwives in the four public hospitals in northern Israel over a 1-year period commencing in October 2013. In addition to demographic and professional data, the accoucheurs were asked to describe the technique they usually use to perform an episiotomy (length, angle, and distance of initiation point from midperineum). RESULTS: Overall, 84 obstetricians and 32 midwives participated in the survey. Only 37.6% reported performing a mediolateral episiotomy, while the rest described the lateral type, placing the initiation point at an average distance of 2.45 +/- 0.88 cm from the fourchette. Compared with midwives, obstetricians reported performing a significantly longer episiotomy (3.53 +/- 1.01 vs. 2.73 +/- 0.81 cm, p = 0.0002). CONCLUSIONS: According to our study and relevant literature review, the technique of episiotomy varies significantly between health professionals and is not uniformly congruent with international practice guidelines. In part, this is derived from unclear literature evidence and lack of consensus definition for proper technique of this procedure by the national guidelines. Thus, further higher-quality research, uniform protocols, and educational programs are needed to guide episiotomy practice. PMID- 25831996 TI - Transcriptional and morphological changes in the transition from mycetophagous to phytophagous phase in the plant-parasitic nematode Bursaphelenchus xylophilus. AB - Drastic physiological and morphological changes in parasites are crucial for the establishment of a successful infection. The nematode Bursaphelenchus xylophilus is the pathogenic agent of pine wilt disease, and little is known about the physiology and morphology in this nematode at the initial stage of infection. In this study, we devised an infection system using pine stem cuttings that allowed us to observe transcriptional and morphological changes in the host-infecting phytophagous phase. We found that 60 genes enriched in xenobiotic detoxification were up-regulated in two independent post-inoculation events, whereas down regulation was observed in multiple members of collagen gene families. After 48 h of inoculation, the tails in some of the adult females exposed to the host changed in morphology. These results suggest that B. xylophilus may change its physiology and morphology to protect itself and to adapt to the host pine wood environment. PMID- 25831997 TI - De novo formation of brain tumors in pediatric population following therapeutic cranial irradiation. AB - PURPOSE: Tumors of central nervous system (CNS) are accounted as the second most common tumors in childhood (21% of all cancers) following hematologic malignancies. The patients can suffer more than one cancer in their lifetime, and radiotherapy is claimed for de novo formation of a new tumor in years after treatment of an initial tumor. METHODS: We have retrospectively analyzed our database for defining radiotherapy-related de novo brain tumors operated in between January, 2000 and August, 2012. New tumors in the field of radiotherapy were included into the study. RESULTS: The retrospective analysis revealed six patients (two girls and four boys) eligible for further evaluation. The children were irradiated at an age in the range of 5 and 12 years (mean, 7.8). The primary diagnoses were hematological malignancies in two (acute lymphocytic leukemia and non-Hodgkin lymphoma (NHL)) and solid tumors in other four (two pilocytic astrocytoma, one craniopharyngioma, and one grade 3 astrocytoma). All patients received cranial radiotherapy. The mean latency period for the "second tumor" was 9.5 years. The pathological diagnoses for de novo new tumors were as follows: glial tumor (two cases), medulloblastoma (two cases), mesenchymal tumor (one case), and meningeal sarcoma (one case). All de novo tumors were high graded. Mean survival was 14.6 months. CONCLUSIONS: de novo brain tumors after irradiation has poor prognosis in neurosurgical practice. Vigilance and awareness for possibility of de novo new tumor are warranted for both families and physicians at follow-ups even years after the treatment of initial tumors. PMID- 25831999 TI - Computational Insight into Nickel-Catalyzed Carbon-Carbon versus Carbon-Boron Coupling Reactions of Primary, Secondary, and Tertiary Alkyl Bromides. AB - The nickel-catalyzed alkyl-alkyl cross-coupling (C-C bond formation) and borylation (C-B bond formation) of unactivated alkyl halides reported in the literature show completely opposite reactivity orders in the reactions of primary, secondary, and tertiary alkyl bromides. The proposed Ni(I) /Ni(III) catalytic cycles for these two types of bond-formation reactions were studied computationally by means of DFT calculations at the B3LYP level. These calculations indicate that the rate-determining step for alkyl-alkyl cross coupling is the reductive elimination step, whereas for borylation the rate is determined mainly by the atom-transfer step. In borylation reactions, the boryl ligand involved has an empty p orbital, which strongly facilitates the reductive elimination step. The inability of unactivated tertiary alkyl halides to undergo alkyl-alkyl cross-coupling is mainly due to the moderately high reductive elimination barrier. PMID- 25831998 TI - Pro-oxidant HDL predicts poor outcome in patients with ST-elevation acute coronary syndrome. AB - Oxidative stress affects clinical outcome in patients with ST-elevation acute coronary syndrome (STE-ACS). Although high-density lipoprotein (HDL) particles are generally considered protective, deleterious properties of HDL have been observed in patients with acute myocardial infarction. Here, we analysed the association between pro-oxidant HDL and all-cause mortality in STE-ACS patients. We determined the antioxidant function of HDL in 247 prospectively enrolled patients undergoing primary percutaneous coronary intervention for STE-ACS. Patients were stratified as by a pro-oxidant serum HDL oxidant index (HOI>= 1) or with an antioxidant serum HOI (HOL< 1) capacity. Multivariate regression analysis was used to relate HOI to survival. The median follow-up time was 23 months (IQR 14.4-40.0 months). Pro-oxidant HDL was observed in 44.1 % of STE-ACS patients and was independently associated with all-cause mortality with a hazard ratio of 3.30(95 %CI 1.50-7.27, p = 0.003). Mortality rates were higher in patients with baseline pro-oxidant HDL compared to patients with preserved HDL function at 30 days (11.9 % vs 2.2 %, p=0.002), and at 4 years (22.9 % vs 8.7 %, p=0.002). Elevated neutrophil counts were a strong and independent predictor for pro oxidant HDL with an odds ratio per standard deviation of 1.50 (95 %CI 1.11-2.03, p=0.008), as was history of prior acute myocardial infarction, elevated triglycerides levels and reduced glomerular filtration rate. In conclusion, pro oxidant HDL represents a strong and independent predictor of long-term as well as short-term all-cause mortality in STE-ACS patients. Elevated neutrophil counts predicted the presence of serum pro-oxidant HDL. The maintenance of HDL functions might be a promising therapeutic target in STE-ACS patients. PMID- 25832001 TI - Evaluation of serum osteopontin level and gene polymorphism as biomarkers: analyses from the Nordic Adjuvant Interferon alpha Melanoma trial. AB - Malignant melanoma is highly aggressive cancer with poor prognosis and few therapeutic options. Interferon alpha (IFN-alpha) has been tested as adjuvant immunotherapy in high-risk melanoma patients in a number of studies, but its beneficial role is controversial. Although IFN-alpha treatment can prolong relapse-free survival, the effect on overall survival is not significant. However, a small subset of patients benefits from the treatment, signifying the need for biomarkers able to identify a responding subgroup. Here we evaluated whether serum osteopontin (OPN) could function as a biomarker identifying patients with poor prognosis that might benefit from IFN-alpha. The choice of osteopontin was based on the knowledge about the dual role of this protein in cancer and immune response, an apparent association between OPN and IFN signaling and a prognostic value of OPN in multiple other tumor types. Serum samples from 275 high-risk melanoma patients enrolled in the Nordic Adjuvant IFN Melanoma trial were analyzed for circulating OPN concentrations and OPN promoter polymorphisms in position -443. The potential relation between serum OPN levels, the genotypes and survival in non-treated patients and patients receiving adjuvant IFN-alpha was investigated. Although slightly better survival was observed in the treated patients that had high levels of OPN, the difference was not statistically significant. In conclusion, serum OPN (its level or the genotype) cannot distinguish melanoma patients with poor prognosis, or patients that might benefit from adjuvant treatment with IFN-alpha. PMID- 25832002 TI - Growth arrest and DNA damage-inducible protein (GADD34) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine (DEN)-treated murine model. AB - Growth arrest and DNA damage-inducible protein (GADD34/Ppp1r15a) is induced by various stimuli including DNA damage and ER stress. DNA damage and oncogene activation, accompanied by tumor-specific DNA repair defects and a failure to stall the cell cycle, are early markers of hepatocellular carcinoma (HCC). However, whether GADD34 accounts for regulating HCC tumorigenesis remains elusive. Here, we demonstrated that GADD34 expression was upregulated in the liver of mice after exposure to a carcinogen, diethylnitrosamine (DEN). In both acute and chronic DEN treatment models, GADD34 deficiency not only decreased oncogene expression, but also reduced hepatic damage. Moreover, loss of GADD34 attenuated immune cell infiltration, pro-inflammatory cytokine expression and hepatic compensatory proliferation. Finally, GADD34-deficient mice showed impaired hepatocarcinogenesis. Thus, the process of DEN-induced HCC proceeded as follows. First, DEN treatment induced DNA damage in hepatocytes, resulting in elevated expression of GADD34 in the liver. The increased expression of GADD34 augmented hepatic necrosis followed by elevated expression of interleukin (IL) 1beta and monocyte chemoattractant protein 1. This process promoted immune cell infiltration and Kupffer cell/macrophage activation followed by production of reactive oxygen species and pro-tumorigenic cytokines such as IL-6 and tumor necrosis factor-alpha. The pro-tumorigenic cytokines stimulated compensatory proliferation of surviving and mutant hepatocytes. Together with oncogene c-Myc expression, these processes led to HCC. Our results suggest therapeutic opportunities for HCC by targeting GADD34-related pathways. PMID- 25832003 TI - Mitochondrial drugs come of age. PMID- 25832000 TI - Crosstalk of carcinoembryonic antigen and transforming growth factor-beta via their receptors: comparing human and canine cancer. AB - There is accumulating evidence that the transforming growth factor beta (TGF beta) and nuclear factor kappa-B (NFkappaB) pathways are tightly connected and play a key role in malignant transformation in cancer. Immune infiltration by regulatory T- and B-lymphocytes (Tregs, Bregs) has recently gained increased attention for being an important source of TGF-beta. There is a plethora of studies examining the pro-tumorigenic functions of carcinoembryonic antigen (CEA), but its receptor CEAR is far less studied. So far, there is a single connecting report that TGF-beta also may signal through CEAR. The crosstalk between cancer tissues is further complicated by the expression of CEAR and TGF beta receptors in stromal cells, and implications of TGF-beta in epithelial mesenchymal transition. Furthermore, tumor-infiltrating Tregs and Bregs may directly instruct cancer cells by secreting TGF-beta binding to their CEAR. Therefore, both TGF-beta and CEA may act synergistically in breast cancer and cause disease progression, and NFkappaB could be a common crossing point between their signaling. CEAR, TGF-beta1-3, TGF-beta-R types I-III and NFkappaB class I and II molecules have an outstanding human-canine sequence identity, and only a canine CEA homolog has not yet been identified. For these reasons, the dog may be a valid translational model patient for investigating the crosstalk of the interconnected CEA and TGF-beta networks. PMID- 25832004 TI - Impact of Kasai portoenterostomy on liver transplantation outcomes: A retrospective cohort study of 347 children with biliary atresia. AB - Biliary atresia (BA) is the main diagnosis leading to liver transplantation (LT) in children. When diagnosed early in life, a Kasai portoenterostomy (Kasai-PE) can prevent or postpone LT. Instances of previous operations can result in difficulties during the LT. We hypothesized that a previous Kasai-PE could affect LT outcomes. A retrospective cohort study of 347 BA patients submitted to LT between 1995 and 2013 at Hospital Sirio-Libanes and A. C. Camargo Cancer Center was conducted. Patients were divided into those with a previous Kasai portoenterostomy early failure (K-EF), Kasai portoenterostomy late failure (K LF), and those with no Kasai portoenterostomy (No-K). Primary outcomes were patient and graft survival. A total of 94 (27.1%) patients had a K-EF, 115 (33.1%) had a K-LF, and 138 (39.8%) had No-K before LT. Children in the K-LF group were older and had lower Pediatric End-Stage Liver Disease (PELD) scores. Patients in both K-EF and K-LF groups had more post-LT biliary complications. After Cox-multivariate analysis adjusting for confounding factors to determine the influence of Kasai-PE on patient and graft survival, the K-LF group had an 84% less probability of dying and a 55% less chance to undergo retransplantation. The K-LF group had a protective effect on posttransplant patient and graft survival. When properly performed, the Kasai procedure can postpone LT and positively affect outcomes. Having a K-EF and having not performed a Kasai-PE had the same effect in patient and graft survival; however, a previous Kasai-PE can increase post-LT complications as biliary complications and bowel perforations. PMID- 25832005 TI - Stem cell conditioned culture media attenuated albumin-induced epithelial mesenchymal transition in renal tubular cells. AB - BACKGROUND: Proteinuria-induced epithelial-mesenchymal transition (EMT) plays an important role in progressive renal tubulointerstitial fibrosis in chronic renal disease. Stem cell therapy has been used for different diseases. Stem cell conditioned culture media (SCM) exhibits similar beneficial effects as stem cell therapy. The present study tested the hypothesis that SCM inhibits albumin induced EMT in cultured renal tubular cells. METHODS: Rat renal tubular cells were treated with/without albumin (20 umg/ml) plus SCM or control cell media (CCM). EMT markers and inflammatory factors were measured by Western blot and fluorescent images. RESULTS: Albumin induced EMT as shown by significant decreases in levels of epithelial marker E-cadherin, increases in mesenchymal markers fibroblast-specific protein 1 and alpha-smooth muscle actin, and elevations in collagen I. SCM inhibited all these changes. Meanwhile, albumin induced NF-kappaB translocation from cytosol into nucleus and that SCM blocked the nuclear translocation of NF-kappaB. Albumin also increased the levels of pro inflammatory factor monocyte chemoattractant protein-1 (MCP)-1 by nearly 30 fold compared with control. SCM almost abolished albumin-induced increase of MCP-1. CONCLUSION: These results suggest that SCM attenuated albumin-induced EMT in renal tubular cells via inhibiting activation of inflammatory factors, which may serve as a new therapeutic approach for chronic kidney diseases. PMID- 25832006 TI - What Risk Factors Predict Recurrence of Heterotopic Ossification After Excision in Combat-related Amputations? AB - BACKGROUND: Heterotopic ossification (HO) is common after combat-related amputations and surgical excision remains the only definitive treatment for persistently symptomatic HO. There is no consensus in the literature regarding the timing of surgery, and recurrence frequency, reexcision, and complications have not been reported in large numbers of patients. QUESTIONS/PURPOSES: (1) What are the rates of symptomatic recurrence resulting in reexcision and other complications resulting in reoperation in patients with HO? (2) Is either radiographic or symptomatic recurrence dependent on timing and type of initial surgery, the experience of the surgeon in performing the procedure, the severity of preexcision HO, the presence of concomitant neurologic injury, or the use of postoperative HO prophylaxis? METHODS: Between March 2005 and March 2013 our institution treated 994 patients with 1377 combat-related major extremity amputations; of those, 172 amputations underwent subsequent excision of symptomatic HO. The mechanism of injury resulting in nearly all amputations (n = 168) was blast-related trauma. We reviewed medical records and radiographs to collect initial grade of HO, radiographic recurrence, complete compared with partial excision, concomitant neurologic injury, timing to initial surgery, surgeon experience, and use of postexcision prophylaxis with our primary study outcome being a return to the operating room (OR) for repeat excision of symptomatic HO. All 172 combat-related amputations were considered for this study irrespective of followup, which was noted to be robust, with 157 (91%) amputations having at least 6 months clinical followup by an orthopaedic surgeon or physiatrist (median, 20 months; range, 0-88 months). RESULTS: Eleven of 172 patients (6.5%) underwent reexcision of HO, and 67 complications resulting in return to the OR occurred in 53 patients (31%) of patients. Multivariate analysis of our primary outcome measure showed more frequent symptomatic recurrences requiring reexcision when initial excision was performed as a partial excision (p = 0.03; odds ratio [OR], 5.0; 95% confidence interval [CI], 1.2-29.6) or when the initial excision was performed within 180 days of injury (p = 0.047; OR, 4.1; 95% CI, 1.02-16.6). There was no association between symptomatic recurrence and HO grade, central nervous system injury, experience of the attending surgeon, or postoperative prophylaxis. Radiographic recurrence was observed when partial excisions (eight of 30 [27%]) were done compared with complete excisions (five of 77 [7%]; p = 0.008). CONCLUSIONS: HO is common after combat-related amputations, and patients undergoing surgical excision of HO for this indication often have complications that result in repeat surgical procedures. Partial excisions of immature lesions more often resulted in both symptomatic and radiographic recurrence. The likelihood of a patient undergoing reexcision can be minimized by performing a complete excision at least 180 days from injury to surgery with no evidence of a reduced risk of reexcision by waiting longer than 270 days. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25832007 TI - Total Femur Replacement After Tumor Resection: Limb Salvage Usually Achieved But Complications and Failures are Common. AB - BACKGROUND: Primary bone or soft tissue tumors of the femur sometimes present with severe and extensive bone destruction, leaving few limb-salvage options other than total femur replacement. However, there are few data available regarding total femur replacement and, in particular, regarding implant failures. QUESTIONS/PURPOSES: We asked: (1) What are the revision-free and overall implant survival rates of conventional total femur replacements in patients treated for sarcoma of the femur or soft tissues? (2) What are the revision-free and overall implant survival rates of expandable total femur replacements in skeletally immature patients? (3) Using the comprehensive International Society of Limb Salvage failure-mode classification, what types of complications occur with conventional and expandable total femur replacements? PATIENTS AND METHODS: Our retrospective, single-center cohort study was based on data prospectively collected for 50 patients who received a total femur replacement after tumor resection for indications other than carcinoma or metastatic disease. Of the 50 patients, six (12%) were lost to followup before 6 months. Ten of the remaining 44 patients received expandable implants. The mean followup was 57 months (range, 1-280 months) and 172 months (range, 43-289 months) for patients who underwent conventional and expandable total femur replacements, respectively. For implant survival, competing risk analyses were used. RESULTS: At 5 years, revision-free implant survival of conventional total femur replacements was 48% (95% CI, 0.37 0.73), and overall implant survival was 97% (95% CI, 0.004-0.20). Five-year revision-free implant survival of expandable total femur replacements was 30% (95% CI, 0.47-1.00) and overall implant survival was 100%. With conventional total femur replacements soft tissue failures occurred in 13 of 34 patients, structural failures in three, infection in six, and local tumor progression in one. No patient had aseptic loosening with conventional total femur replacements, but hip disarticulation occurred in two patients owing to extensive wound-healing problems and infection. With expandable total femur replacements soft tissue failure, aseptic loosening, and infection occurred in one patient each of 10, and structural failures in three of 10 (two periprosthetic fractures, one loosening of an enhanced tendon anchor). No hip disarticulations were performed. Additionally expandable total femur replacement-related failures included hip instability in eight of 10 patients, contractures attributable to massive scar tissue in six, and defect of the implant's expansion mechanism in four patients. CONCLUSIONS: Although the indications for total femoral resection are rare, we think that total femur replacement is a reasonable treatment option for reconstruction of massive femoral bone defects after tumor resection in adults and skeletally immature patients, and results in limb salvage in most patients. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 25832008 TI - miR-142-3p Is a Regulator of the TGFbeta-Mediated Vascular Smooth Muscle Cell Phenotype. AB - The transforming growth factor beta (TGFbeta) signaling pathway is critical for the promotion and maintenance of the contractile phenotype of vascular smooth muscle cells (VSMCs). Though multiple microRNAs (miRNAs) implicated in the regulation of the VSMC phenotype have been identified, the modulation of miRNAs in the VSMCs by TGFbeta signaling has not been fully described. In this study, we identified microRNA-142-3p (miR-142-3p) as a modulator of the VSMC phenotype in response to TGFbeta signaling. We show that miR-142-3p is induced upon TGFbeta signaling, leading to the repression of a novel target, dedicator of cytokinesis 6 (DOCK6). The downregulation of DOCK6 by miR-142-3p is critical for cell migration. Thus, this study demonstrates that miR-142-3p is a key regulator of the TGFbeta-mediated contractile phenotype of VSMCs that acts through inhibiting cell migration through targeting DOCK6. PMID- 25832010 TI - Harvest time residues of pendimethalin and oxyfluorfen in vegetables and soil in sugarcane-based intercropping systems. AB - Terminal residues of pendimethalin and oxyfluorfen applied in autumn sugarcane- and vegetables-based intercropping systems were analyzed in peas (Pisum sativum), cabbage (Brassica oleracea), garlic (Allium sativum), gobhi sarson (Brassica napus), and raya (Brassica juncea). The study was conducted in winter season in 2010-2011 and in 2011-2012 at Ludhiana, India. Pendimethalin at 0.56 kg and 0.75 kg ha(-1) was applied immediately after sowing of gobhi sarson, raya, peas, garlic, and 2 days before transplanting of cabbage seedlings. Oxyfluorfen at 0.17 kg and 0.23 kg ha(-1) was applied immediately after sowing of peas and garlic and 2 days before transplanting of cabbage seedlings intercropped in autumn sugarcane. Representative samples of these vegetables were collected at 75, 90, 100, and 165 days after application of herbicides and analyzed by high performance liquid chromatograph (HPLC) with diode array detector for residues. The residue level of pendimethalin and oxyfluorfen in mature vegetables was found to be below the limit of quantification which is 0.05 mg kg(-1) for both the herbicides. The soil samples were collected at 0, 7, 15, 30, 45, and 60 days after the application of their herbicides. The residues of herbicides in soil samples were found to be below the detectability limit of 0.05 mg kg(-1) after 60 days in case of pendimethalin and after 45 days in case of oxyfluorfen. PMID- 25832011 TI - Agricultural by-products as low-cost sorbents for the removal of heavy metals from dilute wastewaters. AB - n the last years, much attention has been focused on the use of low-cost adsorbents for the removal of Cu(II) and Zn(II) from contaminated waters. In this context, we studied the sorption performances of two kinds of by-products resulted from the agriculture: soy bran and mustard husk. The effects of contact time, the initial metal ion concentration, pH, sorbent mass, and temperature on the adsorption capacity of the agricultural by-products as sorbents were investigated. The thermodynamic parameters associated with the adsorption process indicated that the process is spontaneous and endothermic. Modeling of experimental adsorption isotherm data showed that non-linear Langmuir isotherm fits better than other isotherms. The obtained values for the separation factor, R L were less than one which supports that the adsorption process was favorable. The obtained results indicated that the soy bran has a higher sorption capacity toward zinc ions (74.02 mg g(-1)) than mustard husk (63.69 mg g(-1)). Therefore, there is a great requirement for the search of biomaterials that are cheap and easily available for the removal of heavy metal ions from wastewater. The studied sorbents have the advantage of very low cost and great availability for simple operational experiments. PMID- 25832009 TI - Preparation and characterization of polyclonal antibody against Kaposi's sarcoma associated herpesvirus lytic gene encoding RTA. AB - Replication and transcription activator (RTA) is a critical lytic protein encoded by Kaposi's sarcoma-associated herpesvirus (KSHV). To prepare rabbit polyclonal antibody against RTA, three antigenic polypeptides of KSHV RTA were initially synthesized. The fragment of RTA was cloned into p3FlagBsd to construct the recombinant plasmid, pRTA-Flag. 293 T and EA.hy926 cells were transfected with pRTA-Flag to obtain RTA-Flag fusion protein, which was detected using anti-Flag antibody. Next, New Zealand white rabbits were immunized with keyhole limpet hemocyanin-conjugated peptides to generate polyclonal antibodies against RTA. Enzyme-linked immunosorbent assays were performed to characterize the polyclonal antibodies, and the titers of the polyclonal antibodies against RTA were greater than 1:11,000. Western blotting and immunofluorescence assay revealed that the prepared antibody reacted specifically with the RTA-Flag fusion protein as well as the native viral protein in KSHV-infected primary effusion lymphoma cells. Collectively, our work successfully constructed the recombinant expression vector, pRTA-Flag, and prepared the polyclonal antibody against RTA, which was valuable for investigating the biochemical and biological functions of the critical KSHV lytic gene. PMID- 25832012 TI - A cross-sectional study of bleeding phenotype in haemophilia A carriers. AB - Haemophilia A carriers have historically been thought to exhibit normal haemostasis. However, recent data demonstrates that, despite normal factor VIII (FVIII), haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers exhibit an increase in clinically relevant bleeding. A cross-sectional study was performed comparing haemophilia A carriers to normal women. Questionnaire assessment included a general bleeding questionnaire, condensed MCMDM-1VWD bleeding assessment tool and Pictorial Bleeding Assessment Chart (PBAC). Laboratory assessment included complete blood count, prothrombin time, activated partial thromboplastin time, fibrinogen activity, FVIII activity ( FVIII: C), von Willebrand factor antigen level, ristocetin cofactor, platelet function analyser-100(TM) and ABO blood type. Forty-four haemophilia A carriers and 43 controls were included. Demographic features were similar. Laboratory results demonstrated a statistically significant difference only in FVIII: C (82.5 vs. 134%, P < 0.001). Carriers reported a higher number of bleeding events, and both condensed MCMDM-1 VWD bleeding scores (5 vs. 1, P < 0.001) and PBAC scores (423 vs. 182.5, P = 0.018) were significantly higher in carriers. Haemophilia A carriers exhibit increased bleeding symptoms when compared to normal women. Further studies are necessary to fully understand the bleeding phenotype in this population and optimize clinical management. PMID- 25832013 TI - Carbon nanoparticle-guided central lymph node dissection in clinically node negative patients with papillary thyroid carcinoma. AB - BACKGROUND: Distinguishing the involved lymph nodes from other tissues during surgery is critical for lymph node dissection. The purpose of this study was to assess the feasibility by using carbon nanoparticles as guidance for lymph node dissection in patients with papillary thyroid carcinoma (PTC). METHODS: Eighty one patients were injected with carbon nanoparticles (carbon nanoparticle group), whereas the other 81 patients were not (control group). Routine pathological examination was performed. RESULTS: The lymph node dissection and metastatic lymph node dissection rates of the carbon nanoparticle group were significantly higher than that of the control group. In the carbon nanoparticle group, the number of mistakenly dissected parathyroid gland, the case number of postoperative hypocalcemia, the case number of postoperative hypoparathyroidism, and the recovery time from hypocalcemia were 4, 6, 8, and 2.33 +/- 0.58 weeks, respectively, significantly less than 14, 17, 20, 3, and 3.8 +/- 0.92 weeks in the control group (p < .05). CONCLUSION: Carbon nanoparticles can be applied to more accurately guide the dissection of lymph nodes during thyroidectomy in patients with PTC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 840-845, 2016. PMID- 25832015 TI - Would protecting tropical forest fragments provide carbon and biodiversity cobenefits under REDD+? AB - Tropical forests store vast amounts of carbon and are the most biodiverse terrestrial habitats, yet they are being converted and degraded at alarming rates. Given global shortfalls in the budgets required to prevent carbon and biodiversity loss, we need to seek solutions that simultaneously address both issues. Of particular interest are carbon-based payments under the Reducing Emissions from Deforestation and Forest Degradation (REDD+) mechanism to also conserve biodiversity at no additional cost. One potential is for REDD+ to protect forest fragments, especially within biomes where contiguous forest cover has diminished dramatically, but we require empirical tests of the strength of any carbon and biodiversity cobenefits in such fragmented systems. Using the globally threatened Atlantic Forest landscape, we measured above-ground carbon stocks within forest fragments spanning 13 to 23 442 ha in area and with different degrees of isolation. We related these stocks to tree community structure and to the richness and abundance of endemic and IUCN Red-listed species. We found that increasing fragment size has a positive relationship with above-ground carbon stock and with abundance of IUCN Red-listed species and tree community structure. We also found negative relationships between distance from large forest block and tree community structure, endemic species richness and abundance, and IUCN Red-listed species abundance. These resulted in positive congruence between carbon stocks and Red-listed species, and the abundance and richness of endemic species, demonstrating vital cobenefits. As such, protecting forest fragments in hotspots of biodiversity, particularly larger fragments and those closest to sources, offers important carbon and biodiversity cobenefits. More generally, our results suggest that macroscale models of cobenefits under REDD+ have likely overlooked key benefits at small scales, indicating the necessity to apply models that include finer-grained assessments in fragmented landscapes rather than using averaged coarse-grained cells. PMID- 25832014 TI - Incidence of opioid-managed pelvic pain after hysteroscopic sterilization versus laparoscopic sterilization, US 2005-2012. AB - OBJECTIVE: Compare incidence of opioid-managed pelvic pain within 12 months after hysteroscopic and laparoscopic sterilization. METHODS: Using administrative claims, we identified women aged 18-49 years without recent history of childbirth who underwent hysteroscopic or laparoscopic sterilization between 2005 and 2012. We defined the outcome as >=2 diagnoses for pelvic pain and >=2 prescription fills for opioids. We calculated adjusted hazard ratios (HR) using Cox models and propensity score methods (matching and inverse-probability-of-treatment-weighting [IPTW]). RESULTS: We identified 71,875 eligible women (hysteroscopic n = 26,927 [37.5%], laparoscopic n = 44,948 [62.5%]). Of those, 236 (0.88%) hysteroscopic patients and 420 (0.93%) laparoscopic patients experienced the outcome (crude HR = 0.97, 95%CI: [0.83, 1.14]). Adjusted analyses also yielded near-null results (matched HR = 1.08, 95%CI [0.90, 1.31]; IPTW HR = 0.97, 95%CI [0.80, 1.18]). While most sensitivity analyses generated results close to the null, hazard ratios estimated using propensity score matching ranged from 0.65 to 1.53. CONCLUSIONS: Among women without recent history of childbirth, we did not find compelling evidence of a clinically meaningful increase in the incidence of pelvic pain requiring opioids during the year after hysteroscopic sterilization. However, effects observed in sensitivity analyses may merit further investigation. PMID- 25832018 TI - An essential piece of nursing's future: The continued development of the nurse practitioner as expert clinician and scientist. PMID- 25832016 TI - Preoperative anemia is associated with adverse outcome in patients with urothelial carcinoma of the bladder following radical cystectomy. AB - PURPOSE: Radical cystectomy (RC) can be associated with significant blood loss, whereas many patients are presenting with anemia preoperatively. To date, there is a lack of data addressing the impact of preoperative anemia (PA) on survival of patients undergoing RC for urothelial carcinoma of the bladder (UCB). METHODS: This retrospective multicenter study includes 684 patients with UCB undergoing RC with pelvic lymph node dissection. The median follow-up was 50 (IQR 29,78) months. Anemia was defined in line with the WHO classification (hemoglobin (Hb): male <=13 g/dL, female <=12 g/dL) and based on contemporary gender- and age adjusted classification (Hb: white male aged <60 years: <=13.7 g/dL; >=60 years: <=13.2 g/dL; white female of all ages <=12.2 g/dL). Univariable and multivariable Cox regression analyses were used to assess the effects of PA on oncological outcomes. RESULTS: A total of 269 (39.3 %) and 302 (44.2 %) patients were anemic according to the WHO classification versus contemporary classification. Age, increased ECOG performance status, advanced tumor stages, lymph node metastasis, positive surgical margin and anemia were associated with disease recurrence (DR), cancer-specific mortality (CSM) and all-cause mortality (ACM). In multivariable analysis, anemia was an independent predictor of DR, CSM and ACM (WHO and/or contemporary classification). Blood transfusion was significantly associated with ACM in both classifications of anemia. CONCLUSIONS: PA is significantly associated with worse oncological outcome in patients undergoing RC. Based on the additional unfavorable influence of blood transfusion, this emphasizes the importance of early diagnosis and correction of anemia and implementation of alternative methods of blood volume management. PMID- 25832019 TI - Oxidative rearrangement of cyclobutanone derived N,O-ketals leading to pyrrolidone derivatives. AB - A halogen-induced oxidative rearrangement of N,O-ketals prepared from cyclobutanones, leading to pyrrolidone derivatives, is developed. The reaction proceeds via an iminium ether intermediate and, depending on the reaction medium, two types of pyrrolidone derivative, containing a halogen atom or hydroxyl group, can be obtained. PMID- 25832020 TI - Prediction of the stability of meropenem in intravenous mixtures. AB - The purpose of this study was to predict the stability of meropenem in a mixed infusion. The hydrolysis of meropenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (kobs) of pH, SBS and L-cysteine, and fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25 degrees C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the characteristic pH curve. From these results, an equation was derived giving the residual ratio (%) of meropenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature, and in the pH range 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%). PMID- 25832021 TI - Synthesis of a carbon analogue of scytonemin. AB - The synthesis of a carbon analogue of scytonemin was accomplished on the basis of molybdenum-mediated intramolecular double Pauson-Khand type reaction of bis(allenyne), followed by the double aldol condensation of the formed double Pauson-Khand type adduct. PMID- 25832022 TI - Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor alpha. AB - A series of fatty acid amides were synthesized and their peroxisome proliferator activated receptor alpha (PPAR-alpha) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-alpha downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase, were determined by real-time reverse transcription polymerase chain reaction (RT-PCR) as PPAR-alpha agonistic activities. We prepared nine oleic acid amides. Their PPAR-alpha agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Delta(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-alpha antagonist, GW6471, inhibited the induction of the PPAR alpha downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-alpha agonists. PMID- 25832023 TI - Membrane anchor of cytochrome P450 reductase suppresses the uncoupling of cytochrome P450. AB - Cytochrome P450 reductase (CPR) is an important redox partner of microsomal CYPs. CPR is composed of a membrane anchor and a catalytic domain that contains FAD and flavin mononucleotide (FMN) as redox centers and mediates electron transfer to CYP. Although the CPR membrane anchor is believed to be requisite for interaction with CYP, its physiological role is still controversial. To clarify the role of the anchor, we constructed a mutant (Delta60-CPR) in which the N-terminal membrane anchor was truncated, and studied its effect on binding properties, electron transfer to CYP2C19, and drug metabolism. We found that Delta60-CPR could bind to and transfer electrons to CYP2C19 as efficiently as WT-CPR, even in the absence of lipid membrane. In accordance with this, Delta60-CPR could mediate metabolism of amitriptyline (AMT) and imipramine (IMP) in the absence of lipids, although activity was diminished. However, Delta60-CPR failed to metabolize omeprazole (OPZ) and lansoprazole (LPZ). To clarify the reason for this discrepancy in drug metabolism, we investigated the uncoupling reaction of the CYP catalytic cycle. By measuring the amount of H2O2 by-product, we found that shunt pathways were markedly activated in the presence of OPZ/LPZ in the Delta60 CPR mutant. Because H2O2 levels varied among the drugs, we conclude that the proton network in the distal pocket of CYP2C19 is perturbed differently by different drugs, and activated oxygen is degraded to become H2O2. Therefore, we propose a novel role for the membrane anchor as a suppressor of the uncoupling reaction in drug metabolism by CYP. PMID- 25832024 TI - Preparation of solid dispersion of dronedarone hydrochloride with Soluplus((r)) by hot melt extrusion technique for enhanced drug release. AB - In order to enhance the dissolution rate of dronedarone hydrochloride (DRN), a novel Soluplus((r)) (polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer)-based solid dispersion (SD) was formulated using a hot melt extrusion technique. The physical characteristics determined using scanning electron microscopy and X-ray powder diffraction, revealed that the active compound was molecularly dispersed in the amphiphilic polymer in a stable amorphous form. The dissolution rate of DRN from the tablet dosage form of SD extrudate consisted of the drug and Soluplus((r)) in a weight ratio of 1 : 1, and was obviously more rapid and higher than that of the intact drug and marketed product (Multaq((r)), Sanofi, U.S.A.) at pH 1.2, 4.0 and 6.8. This suggests that Soluplus((r))-based SD formula can be a promising approach for enhancing the dissolution and oral absorption of DRN with a simple preparation process. PMID- 25832025 TI - Novel use of pectin as a microneedle base. AB - Hydrocolloid pectin formulation was utilized as a novel base for fabricating biodegradable micro-needle (MN) arrays. The pectin MNs were, on average, found to be 897.71 +/- 3.48 um in height and 234.31 +/- 2.27 um in base width, with an inter base spacing of 498.66 +/- 1.60 um, and corresponding to an aspect ratio of 3.83 +/- 0.04. Bovine serum albumin (BSA) and pectin gel interaction was found to be dependent on the loaded protein amount. By contrast, regardless of the amount of BSA incorporated, pectin MNs competed with BSA to form a complex with Cu(2+) ions in a bicinchoninic acid (BCA) kit. The glass transition of the pectin MN base was found to be 145.15 +/- 12.09, with a delta Cp of 2.60 +/- 0.02 J g(-1) K(-1). Because pectin MNs are skin friendly and naturally occurring, with biodegradable and hydrocolloidal features, they are promising vehicle for the controlled release of macromolecules. PMID- 25832026 TI - Limonoids from the stem bark of Khaya senegalensis. AB - Six new limonoids with modified furan ring, khaysenelide A-F (1-6), together with six known limonoids (7-12) were isolated from the stem bark of Khaya senegalensis. The basic skeletons of these new limonoids belong to mexicanolide (1, 2) and rearrangement phragmalin (3-6), which were elucidated on the basis of spectroscopic methods including high resolution-electrospray ionization (HR-ESI) MS, one and two dimensional (1D and 2D)-NMR and confirmed by single-crystal X-ray crystallography using CuKalpha radiation of 1 and 3. Their absolute configurations were determined by the X-ray crystallography data and comparison of their electronic circular dichroism spectra. The inhibitory effect on nitric oxide (NO) production in lipopolysaccaride-activated RAW264.7 macrophages of new compounds was also tested. PMID- 25832027 TI - Gas-Phase Fragmentation Pathways of Mixed Addenda Keggin Anions: PMo12-nW nO 40 3 (n = 0-12). AB - We report a collision-induced dissociation (CID) investigation of the mixed addenda polyoxometalate (POM) anions, PMo(12-n)W(n)O(40)(3-) (n = 0-12). The anions were generated in solution using a straightforward single-step synthesis approach and introduced into the gas phase by electrospray ionization (ESI). Distinct differences in fragmentation patterns were observed for the range of mixed addenda POMs examined in this study. CID of molybdenum-rich anions, PMo(12 n)W(n)O(40)(3-) (n = 0-2), generates an abundant doubly charged fragment containing seven metal atoms (M) and 22 oxygen atoms (M(7)O(22)(2-)) and its complementary singly charged PM(5)O(18)(-) ion. In comparison, the doubly charged Lindqvist anion, (M(6)O(19)(2-)) and its complementary singly charged PM(6)O(21)( ) ion are the dominant fragments of Keggin POMs containing more than two tungsten atoms, PMo(12-n)W(n)O(40)(3-) (n = 3-12). The observed transition in the dissociation pathways with an increase in the number of W atoms in the POM may be attributed to the higher barrier of tungsten-rich anions towards isomerization. We present evidence that the observed distribution of Mo and W atoms in the major M(6)O(19)(2-) and M(7)O(22)(2-) fragment ions is different from that predicted by a random distribution, indicating substantial segregation of the addenda metal atoms in the POMs. Charge reduction of the triply charged precursor anion resulting in formation of doubly charged anions is also observed. This is a dominant pathway for mixed POMs having a majority (8-11) of W atoms and a minor channel for other precursors indicating a close competition between fragmentation and charge loss pathways in CID of POM anions. PMID- 25832028 TI - Probing the electron capture dissociation mass spectrometry of phosphopeptides with traveling wave ion mobility spectrometry and molecular dynamics simulations. AB - Electron capture dissociation mass spectrometry offers several advantages for the analysis of peptides, most notably that backbone c and z fragments typically retain labile modifications such as phosphorylation. We have shown previously that, in some cases, the presence of phosphorylation has a deleterious effect on peptide sequence coverage, and hypothesized that intramolecular interactions involving the phosphate group were preventing separation of backbone fragments. In the present work, we seek to rationalize the observed ECD behavior through a combination of ECD of model peptides, traveling wave ion mobility mass spectrometry and molecular dynamics simulations. The results suggest that for doubly protonated ions of phosphopeptide APLpSFRGSLPKSYVK a salt-bridge structure is favored, whereas for the doubly-protonated ions of APLSFRGSLPKpSYVK ionic hydrogen bonds predominate. PMID- 25832029 TI - Rapid Online Non-Enzymatic Protein Digestion Analysis with High Pressure Superheated ESI-MS. AB - Recently, we reported a new ESI ion source that could electrospray the super heated aqueous solution with liquid temperature much higher than the normal boiling point (J. Am. Soc. Mass Spectrom. 25, 1862-1869). The boiling of liquid was prevented by pressurizing the ion source to a pressure greater than atmospheric pressure. The maximum operating pressure in our previous prototype was 11 atm, and the highest achievable temperature was 180 degrees C. In this paper, a more compact prototype that can operate up to 27 atm and 250 degrees C liquid temperatures is constructed, and reproducible MS acquisition can be extended to electrospray temperatures that have never before been tested. Here, we apply this super-heated ESI source to the rapid online protein digestion MS. The sample solution is rapidly heated when flowing through a heated ESI capillary, and the digestion products are ionized by ESI in situ when the solution emerges from the tip of the heated capillary. With weak acid such as formic acid as solution, the thermally accelerated digestion (acid hydrolysis) has the selective cleavage at the aspartate (Asp, D) residue sites. The residence time of liquid within the active heating region is about 20 s. The online operation eliminates the need to transfer the sample from the digestion reactor, and the output of the digestive reaction can be monitored and manipulated by the solution flow rate and heater temperature in a near real-time basis. PMID- 25832030 TI - Determination of Noncovalent Binding Using a Continuous Stirred Tank Reactor as a Flow Injection Device Coupled to Electrospray Ionization Mass Spectrometry. AB - Described is a new method based on the concept of controlled band dispersion, achieved by hyphenating flow injection analysis with ESI-MS for noncovalent binding determinations. A continuous stirred tank reactor (CSTR) was used as a FIA device for exponential dilution of an equimolar host-guest solution over time. The data obtained was treated for the noncovalent binding determination using an equimolar binding model. Dissociation constants between vancomycin and Ac-Lys(Ac)-Ala-Ala-OH peptide stereoisomers were determined using both the positive and negative ionization modes. The results obtained for Ac-L-Lys(Ac)-D Ala-D-Ala (a model for a Gram-positive bacterial cell wall) binding were in reasonable agreement with literature values made by other mass spectrometry binding determination techniques. Also, the developed method allowed the determination of dissociation constants for vancomycin with Ac-L-Lys(Ac)-D-Ala-L Ala, Ac-L-Lys(Ac)-L-Ala-D-Ala, and Ac-L-Lys(Ac)-L-Ala-L-Ala. Although some differences in measured binding affinities were noted using different ionization modes, the results of each determination were generally consistent. Differences are likely attributable to the influence of a pseudo-physiological ammonium acetate buffer solution on the formation of positively- and negatively-charged ionic complexes. PMID- 25832031 TI - Identification of microRNAs associated with abdominal aortic aneurysms and peripheral arterial disease. AB - BACKGROUND: MicroRNAs are crucial in the regulation of cardiovascular disease and represent potential therapeutic targets to decrease abdominal aortic aneurysm (AAA) expansion. The aim of this study was to identify circulating microRNAs associated with AAA. METHODS: Some 754 microRNAs in whole-blood samples from 15 men with an AAA and ten control subjects were quantified using quantitative reverse transcriptase-PCR. MicroRNAs demonstrating a significant association with AAA were validated in peripheral blood and plasma samples of men in the following groups (40 in each): healthy controls, controls with peripheral arterial disease (PAD), men with a small AAA (30-54 mm), those with a large AAA (over 54 mm), and those following AAA repair. MicroRNA expression was also assessed in aortic tissue. RESULTS: Twenty-nine differentially expressed microRNAs were identified in the discovery study. Validation study revealed that let-7e (fold change (FC) 1.80; P = 0.001), miR-15a (FC -2.24; P < 0.001) and miR-196b (FC -2.26; P < 0.001) were downregulated in peripheral blood from patients with an AAA, and miR 411 was upregulated (FC 5.90; P = 0.001). miR-196b was also downregulated in plasma from the same individuals (FC -3.75; P = 0.029). The same miRNAs were similarly expressed differentially in patients with PAD compared with healthy controls. Validated and predicted microRNA targets identified through miRWalk revealed that these miRNAs were all regulators of AAA-related genes (vascular cell adhesion molecule 1, intercellular cell adhesion molecule 1, DAB2 interacting protein, alpha1-antitrypsin, C-reactive protein, interleukin 6, osteoprotegerin, methylenetetrahydrofolate reductase, tumour necrosis factor alpha). CONCLUSION: In this study, circulating levels of let-7e, miR-15a, miR 196b and miR-411 were differentially expressed in men with an AAA compared with healthy controls, but also differentially expressed in men with PAD. Modulation of these miRNAs and their target genes may represent a new therapeutic pathway to affect the progression of AAA and atherosclerosis. PMID- 25832033 TI - Phenotype of a child with Angelman syndrome born to a woman with Prader-Willi syndrome. AB - This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader-Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting. PMID- 25832032 TI - Wine and bone health: a review. AB - A light-to-moderate wine consumption has been shown to provide several beneficial effects on the skeletal system, including reduced risk of bone mass loss and fractures. Wine is rich in phenolic compounds, strong phytoestrogens and natural antioxidants, to which bone protection is mainly attributed. The objective of this review was to give an overview of the exact mechanisms by which wine consumption is involved in bone protection. We found a great variety of in vitro research on the beneficial effects of isolated wine phenolics on the skeletal system, with a significant lack of evidence of their in vivo effects. In addition, we found almost no studies investigating how wine, a mixture of these phenolics dissolved in ethanol, affects the skeletal system. Our results warrant further research on this interesting topic. PMID- 25832034 TI - Propensity-matched comparisons of clinical outcomes after transapical or transfemoral transcatheter aortic valve replacement: a placement of aortic transcatheter valves (PARTNER)-I trial substudy. AB - BACKGROUND: The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching. METHODS AND RESULTS: From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days; P<0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%; P=0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge, P=0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months, P<0.0001). CONCLUSIONS: The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF first access strategy for TAVR when anatomically feasible. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894. PMID- 25832035 TI - Impact of Therapy on Metabolic Syndrome in Young Adult Premenopausal Female Lupus Patients: Beneficial Effect of Antimalarials. AB - OBJECTIVE: There are no data about the main factors associated with metabolic syndrome in young premenopausal systemic lupus erythematosus (SLE) patients. The aim of the study was to evaluate the frequency of metabolic syndrome and disease- or therapy-related factors in premenopausal young SLE patients. METHODS: A total of 103 premenopausal SLE patients ages <40 years were selected and compared to 35 healthy premenopausal age-matched women. Metabolic syndrome was defined according to the 2009 Joint Interim Statement. RESULTS: A higher frequency of metabolic syndrome (22.3% versus 5.7%; P = 0.03) was observed in the SLE group. Metabolic syndrome-SLE patients had higher SLE Disease Activity Index scores (mean +/- SD 5.9 +/- 7.6 versus 1.9 +/- 2.7; P = 0.006), more frequently had previous renal disease (73.9% versus 51.2%; P = 0.05) and current renal disease (34.8% versus 10.0%; P = 0.008), and had higher current prednisone dose (median [range] 20 [0 60] versus 5 [0-60] mg/dl; P = 0.018) and cumulative prednisone dose (mean +/- SD 41.48 +/- 27.81 versus 24.7 +/- 18.66 gm; P = 0.023) than those without metabolic syndrome. Chloroquine was less frequently used in metabolic syndrome-SLE patients (65.2% versus 90.0%; P = 0.008). In multivariate analysis, only current chloroquine use (prevalence ratio [PR] 0.29, 95% confidence interval [95% CI] 0.13-0.64) and cumulative prednisone were associated with metabolic syndrome (PR 1.02, 95% CI 1.01-1.04). Further estimated prevalence analysis identified the fact that antimalarial use promoted continuous decrease in the progressive metabolic syndrome prevalence associated with glucocorticoid cumulative dose. CONCLUSION: The prevalence of metabolic syndrome is high in premenopausal young adult SLE patients. Chloroquine has a protective effect on the prevalence of metabolic syndrome in these patients, and this benefit counteracts the deleterious effect of glucocorticoids in a dose-dependent manner. PMID- 25832036 TI - Tribute to Penny Slattery (1962-2015). PMID- 25832037 TI - Point/counterpoint. GPU technology is the hope for near real-time Monte Carlo dose calculations. PMID- 25832038 TI - Large scale validation of the M5L lung CAD on heterogeneous CT datasets. AB - PURPOSE: M5L, a fully automated computer-aided detection (CAD) system for the detection and segmentation of lung nodules in thoracic computed tomography (CT), is presented and validated on several image datasets. METHODS: M5L is the combination of two independent subsystems, based on the Channeler Ant Model as a segmentation tool [lung channeler ant model (lungCAM)] and on the voxel-based neural approach. The lungCAM was upgraded with a scan equalization module and a new procedure to recover the nodules connected to other lung structures; its classification module, which makes use of a feed-forward neural network, is based of a small number of features (13), so as to minimize the risk of lacking generalization, which could be possible given the large difference between the size of the training and testing datasets, which contain 94 and 1019 CTs, respectively. The lungCAM (standalone) and M5L (combined) performance was extensively tested on 1043 CT scans from three independent datasets, including a detailed analysis of the full Lung Image Database Consortium/Image Database Resource Initiative database, which is not yet found in literature. RESULTS: The lungCAM and M5L performance is consistent across the databases, with a sensitivity of about 70% and 80%, respectively, at eight false positive findings per scan, despite the variable annotation criteria and acquisition and reconstruction conditions. A reduced sensitivity is found for subtle nodules and ground glass opacities (GGO) structures. A comparison with other CAD systems is also presented. CONCLUSIONS: The M5L performance on a large and heterogeneous dataset is stable and satisfactory, although the development of a dedicated module for GGOs detection could further improve it, as well as an iterative optimization of the training procedure. The main aim of the present study was accomplished: M5L results do not deteriorate when increasing the dataset size, making it a candidate for supporting radiologists on large scale screenings and clinical programs. PMID- 25832039 TI - A deformable head and neck phantom with in-vivo dosimetry for adaptive radiotherapy quality assurance. AB - PURPOSE: Patients' interfractional anatomic changes can compromise the initial treatment plan quality. To overcome this issue, adaptive radiotherapy (ART) has been introduced. Deformable image registration (DIR) is an important tool for ART and several deformable phantoms have been built to evaluate the algorithms' accuracy. However, there is a lack of deformable phantoms that can also provide dosimetric information to verify the accuracy of the whole ART process. The goal of this work is to design and construct a deformable head and neck (HN) ART quality assurance (QA) phantom with in vivo dosimetry. METHODS: An axial slice of a HN patient is taken as a model for the phantom construction. Six anatomic materials are considered, with HU numbers similar to a real patient. A filled balloon inside the phantom tissue is inserted to simulate tumor. Deflation of the balloon simulates tumor shrinkage. Nonradiopaque surface markers, which do not influence DIR algorithms, provide the deformation ground truth. Fixed and movable holders are built in the phantom to hold a diode for dosimetric measurements. RESULTS: The measured deformations at the surface marker positions can be compared with deformations calculated by a DIR algorithm to evaluate its accuracy. In this study, the authors selected a Demons algorithm as a DIR algorithm example for demonstration purposes. The average error magnitude is 2.1 mm. The point dose measurements from the in vivo diode dosimeters show a good agreement with the calculated doses from the treatment planning system with a maximum difference of 3.1% of prescription dose, when the treatment plans are delivered to the phantom with original or deformed geometry. CONCLUSIONS: In this study, the authors have presented the functionality of this deformable HN phantom for testing the accuracy of DIR algorithms and verifying the ART dosimetric accuracy. The authors' experiments demonstrate the feasibility of this phantom serving as an end-to-end ART QA phantom. PMID- 25832040 TI - Computer-aided detection of breast cancers using Haar-like features in automated 3D breast ultrasound. AB - PURPOSE: Automated 3D breast ultrasound (ABUS) has gained interest in breast imaging. Especially for screening women with dense breasts, ABUS appears to be beneficial. However, since the amount of data generated is large, the risk of oversight errors is substantial. Computer aided detection (CADe) may be used as a second reader to prevent oversight errors. When CADe is used in this fashion, it is essential that small cancers are detected, while the number of false positive findings should remain acceptable. In this work, the authors improve their previously developed CADe system in the initial candidate detection stage. METHODS: The authors use a large number of 2D Haar-like features to differentiate lesion structures from false positives. Using a cascade of GentleBoost classifiers that combines these features, a likelihood score, highly specific for small cancers, can be efficiently computed. The likelihood scores are added to the previously developed voxel features to improve detection. RESULTS: The method was tested in a dataset of 414 ABUS volumes with 211 cancers. Cancers had a mean size of 14.72 mm. Free-response receiver operating characteristic analysis was performed to evaluate the performance of the algorithm with and without using the aforementioned Haar-like feature likelihood scores. After the initial detection stage, the number of missed cancer was reduced by 18.8% after adding Haar-like feature likelihood scores. CONCLUSIONS: The proposed technique significantly improves our previously developed CADe system in the initial candidate detection stage. PMID- 25832041 TI - GPU-accelerated regularized iterative reconstruction for few-view cone beam CT. AB - PURPOSE: The present work proposes an iterative reconstruction technique designed for x-ray transmission computed tomography (CT). The main objective is to provide a model-based solution to the cone-beam CT reconstruction problem, yielding accurate low-dose images via few-views acquisitions in clinically acceptable time frames. METHODS: The proposed technique combines a modified ordered subsets convex (OSC) algorithm and the total variation minimization (TV) regularization technique and is called OSC-TV. The number of subsets of each OSC iteration follows a reduction pattern in order to ensure the best performance of the regularization method. Considering the high computational cost of the algorithm, it is implemented on a graphics processing unit, using parallelization to accelerate computations. RESULTS: The reconstructions were performed on computer simulated as well as human pelvic cone-beam CT projection data and image quality was assessed. In terms of convergence and image quality, OSC-TV performs well in reconstruction of low-dose cone-beam CT data obtained via a few-view acquisition protocol. It compares favorably to the few-view TV-regularized projections onto convex sets (POCS-TV) algorithm. It also appears to be a viable alternative to full-dataset filtered backprojection. Execution times are of 1-2 min and are compatible with the typical clinical workflow for nonreal-time applications. CONCLUSIONS: Considering the image quality and execution times, this method may be useful for reconstruction of low-dose clinical acquisitions. It may be of particular benefit to patients who undergo multiple acquisitions by reducing the overall imaging radiation dose and associated risks. PMID- 25832042 TI - Head phantoms for transcranial focused ultrasound. AB - PURPOSE: In the ongoing endeavor of fine-tuning, the clinical application of transcranial MR-guided focused ultrasound (tcMRgFUS), ex-vivo studies wlkiith whole human skulls are of great use in improving the underlying technology guiding the accurate and precise thermal ablation of clinically relevant targets in the human skull. Described here are the designs, methods for fabrication, and notes on utility of three different ultrasound phantoms to be used for brain focused ultrasound research. METHODS: Three different models of phantoms are developed and tested to be accurate, repeatable experimental options to provide means to further this research. The three models are a cadaver, a gel-filled skull, and a head mold containing a skull and filled with gel that mimics the brain and the skin. Each was positioned in a clinical tcMRgFUS system and sonicated at 1100 W (acoustic) for 12 s at different locations. Maximum temperature rise as measured by MR thermometry was recorded and compared against clinical data for a similar neurosurgical target. Results are presented as heating efficiency in units ( degrees C/kW/s) for direct comparison to available clinical data. The procedure for casting thermal phantom material is presented. The utility of each phantom model is discussed in the context of various tcMRgFUS research areas. RESULTS: The cadaveric phantom model, gel-filled skull model, and full head phantom model had heating efficiencies of 5.3, 4.0, and 3.9 degrees C/(kW/s), respectively, compared to a sample clinical heating efficiency of 2.6 degrees C/(kW/s). In the seven research categories considered, the cadaveric phantom model was the most versatile, though less practical compared to the ex vivo skull-based phantoms. CONCLUSIONS: Casting thermal phantom material was shown to be an effective way to prepare tissue-mimicking material for the phantoms presented. The phantom models presented are all useful in tcMRgFUS research, though some are better suited to a limited subset of applications depending on the researchers needs. PMID- 25832043 TI - Dosimetric characteristics of the novel 2D ionization chamber array OCTAVIUS Detector 1500. AB - PURPOSE: The dosimetric properties of the OCTAVIUS Detector 1500 (OD1500) ionization chamber array (PTW-Freiburg, Freiburg, Germany) have been investigated. A comparative study was carried out with the OCTAVIUS Detector 729 and OCTAVIUS Detector 1000 SRS arrays. METHODS: The OD1500 array is an air vented ionization chamber array with 1405 detectors in a 27 * 27 cm(2) measurement area arranged in a checkerboard pattern with a chamber-to-chamber distance of 10 mm in each row. A sampling step width of 5 mm can be achieved by merging two measurements shifted by 5 mm, thus fulfilling the Nyquist theorem for intensity modulated dose distributions. The stability, linearity, and dose per pulse dependence were investigated using a Semiflex 31013 chamber (PTW-Freiburg, Freiburg, Germany) as a reference detector. The effective depth of measurement was determined by measuring TPR curves with the array and a Roos chamber type 31004 (PTW-Freiburg, Freiburg, Germany). Comparative output factor measurements were performed with the array, the Semiflex 31010 ionization chamber and the Diode 60012 (both PTW-Freiburg, Freiburg, Germany). The energy dependence of the OD1500 was measured by comparing the array's readings to those of a Semiflex 31010 ionization chamber for varying mean photon energies at the depth of measurement, applying to the Semiflex chamber readings the correction factor kNR for nonreference conditions. The Gaussian lateral dose response function of a single array detector was determined by searching the convolution kernel suitable to convert the slit beam profiles measured with a Diode 60012 into those measured with the array's central chamber. An intensity modulated dose distribution measured with the array was verified by comparing a OD1500 measurement to TPS calculations and film measurements. RESULTS: The stability and interchamber sensitivity variation of the OD1500 array were within +/-0.2% and +/-0.58%, respectively. Dose linearity was within 1% over the range from 5 to 1000 MU. The effective point of measurement of the OD1500 for dose measurements in RW3 phantoms was determined to be (8.7 +/- 0.2) mm below its front surface. Output factors showed deviations below 1% for field sizes exceeding 4 * 4 cm(2). The dose per pulse dependence was smaller than 0.4% for doses per pulse from 0.2 to 1 mGy. The energy dependence of the array did not exceed +/-0.9%. The parameter sigma of the Gaussian lateral dose response function was determined as sigma6MV = (2.07 +/- 0.02) mm for 6 MV and sigma15MV = (2.09 +/- 0.02) mm for 15 MV. An IMRT verification showed passing rates well above 90% for a local 3 mm/3% criterion. CONCLUSIONS: The OD1500 array's dosimetric properties showed the applicability of the array for clinical dosimetry with the possibility to increase the spatial sampling frequency and the coverage of a dose distribution with the sensitive areas of ionization chambers by merging two measurements. PMID- 25832044 TI - Robustness of sweeping-window arc therapy treatment sequences against intrafractional tumor motion. AB - PURPOSE: Due to the potentially periodic collimator dynamic in volumetric modulated arc therapy (VMAT) dose deliveries with the sweeping-window arc therapy (SWAT) technique, additional manifestations of dosimetric deviations in the presence of intrafractional motion may occur. With a fast multileaf collimator (MLC), and a flattening filter free dose delivery, treatment times close to 60 s per fraction are clinical reality. For these treatment sequences, the human breathing period can be close to the collimator sweeping period. Compared to a random arrangement of the segments, this will cause a further degradation of the dose homogeneity. METHODS: Fifty VMAT sequences of potentially moving target volumes were delivered on a two dimensional ionization chamber array. In order to detect interplay effects along all three coordinate axes, time resolved measurements were performed twice--with the detector aligned in vertical (V) or horizontal (H) orientation. All dose matrices were then moved within a simulation software by a time-dependent motion vector. The minimum relative equivalent uniform dose EUDr,m for all breathing starting phases was determined for each amplitude and period. Furthermore, an estimation of periods with minimum EUD was performed. Additionally, LINAC logfiles were recorded during plan delivery. The MLC, jaw, gantry angle, and monitor unit settings were continuously saved and used to calculate the correlation coefficient between the target motion and the dose weighed collimator motion component for each direction (CC, LR, AP) separately. RESULTS: The resulting EUDr,m were EUDr,m(CCV) = (98.3 +/- 0.6)%, EUDr,m(CCH) = (98.6 +/- 0.5)%, EUDr,m(APV) = (97.7 +/- 0.9)%, and EUDr,m(LRH) = (97.8 +/- 0.9)%. The overall minimum relative EUD observed for 360(?) arc midventilation treatments was 94.6%. The treatment plan with the shortest period and a minimum relative EUD of less than 97% was found at T = 6.1 s. For a partial 120(?) arc, an EUDr,m = 92.0% was found. In all cases, a correlation coefficient above 0.5 corresponded to a minimum in EUD. CONCLUSIONS: With the advent of fast VMAT delivery techniques, nonrobust treatment sequences for human breathing patterns can be generated. These sequences are characterized by a large correlation coefficient between a target motion component and the corresponding collimator dynamic. By iteratively decreasing the maximum allowed dose rate, a low correlation coefficient and consequentially a robust treatment sequence are ensured. PMID- 25832045 TI - Ion chamber absorbed dose calibration coefficients, N(D,w), measured at ADCLs: distribution analysis and stability. AB - PURPOSE: To analyze absorbed dose calibration coefficients, ND,w, measured at accredited dosimetry calibration laboratories (ADCLs) for client ionization chambers to study (i) variability among ND,w coefficients for chambers of the same type calibrated at each ADCL to investigate ion chamber volume fluctuations and chamber manufacturing tolerances; (ii) equivalency of ion chamber calibration coefficients measured at different ADCLs by intercomparing ND,w coefficients for chambers of the same type; and (iii) the long-term stability of ND,w coefficients for different chamber types by investigating repeated chamber calibrations. METHODS: Large samples of ND,w coefficients for several chamber types measured over the time period between 1998 and 2014 were obtained from the three ADCLs operating in the United States. These are analyzed using various graphical and numerical statistical tests for the four chamber types with the largest samples of calibration coefficients to investigate (i) and (ii) above. Ratios of calibration coefficients for the same chamber, typically obtained two years apart, are calculated to investigate (iii) above and chambers with standard deviations of old/new ratios less than 0.3% meet stability requirements for accurate reference dosimetry recommended in dosimetry protocols. RESULTS: It is found that ND,w coefficients for a given chamber type compared among different ADCLs may arise from differing probability distributions potentially due to slight differences in calibration procedures and/or the transfer of the primary standard. However, average ND,w coefficients from different ADCLs for given chamber types are very close with percent differences generally less than 0.2% for Farmer-type chambers and are well within reported uncertainties. CONCLUSIONS: The close agreement among calibrations performed at different ADCLs reaffirms the Calibration Laboratory Accreditation Subcommittee process of ensuring ADCL conformance with National Institute of Standards and Technology standards. This study shows that ND,w coefficients measured at different ADCLs are statistically equivalent, especially considering reasonable uncertainties. This analysis of ND,w coefficients also allows identification of chamber types that can be considered stable enough for accurate reference dosimetry. PMID- 25832046 TI - X-ray computed tomography using curvelet sparse regularization. AB - PURPOSE: Reconstruction of x-ray computed tomography (CT) data remains a mathematically challenging problem in medical imaging. Complementing the standard analytical reconstruction methods, sparse regularization is growing in importance, as it allows inclusion of prior knowledge. The paper presents a method for sparse regularization based on the curvelet frame for the application to iterative reconstruction in x-ray computed tomography. METHODS: In this work, the authors present an iterative reconstruction approach based on the alternating direction method of multipliers using curvelet sparse regularization. RESULTS: Evaluation of the method is performed on a specifically crafted numerical phantom dataset to highlight the method's strengths. Additional evaluation is performed on two real datasets from commercial scanners with different noise characteristics, a clinical bone sample acquired in a micro-CT and a human abdomen scanned in a diagnostic CT. The results clearly illustrate that curvelet sparse regularization has characteristic strengths. In particular, it improves the restoration and resolution of highly directional, high contrast features with smooth contrast variations. The authors also compare this approach to the popular technique of total variation and to traditional filtered backprojection. CONCLUSIONS: The authors conclude that curvelet sparse regularization is able to improve reconstruction quality by reducing noise while preserving highly directional features. PMID- 25832047 TI - Development of a phantom to validate high-dose-rate brachytherapy treatment planning systems with heterogeneous algorithms. AB - PURPOSE: This work presents the development of a phantom to verify the treatment planning system (TPS) algorithms used for high-dose-rate (HDR) brachytherapy. It is designed to measure the relative dose in a heterogeneous media. The experimental details used, simulation methods, and comparisons with a commercial TPS are also provided. METHODS: To simulate heterogeneous conditions, four materials were used: Virtual WaterTM (VM), BR50/50TM, cork, and aluminum. The materials were arranged in 11 heterogeneity configurations. Three dosimeters were used to measure the relative response from a HDR (192)Ir source: TLD-100TM, Gafchromic((r)) EBT3 film, and an ExradinTM A1SL ionization chamber. To compare the results from the experimental measurements, the various configurations were modeled in the penelope/penEasy Monte Carlo code. Images of each setup geometry were acquired from a CT scanner and imported into BrachyVisionTM TPS software, which includes a grid-based Boltzmann solver AcurosTM. The results of the measurements performed in the heterogeneous setups were normalized to the dose values measured in the homogeneous Virtual WaterTM setup and the respective differences due to the heterogeneities were considered. Additionally, dose values calculated based on the American Association of Physicists in Medicine-Task Group 43 formalism were compared to dose values calculated with the AcurosTM algorithm in the phantom. Calculated doses were compared at the same points, where measurements have been performed. RESULTS: Differences in the relative response as high as 11.5% were found from the homogeneous setup when the heterogeneous materials were inserted into the experimental phantom. The aluminum and cork materials produced larger differences than the plastic materials, with the BR50/50TM material producing results similar to the Virtual WaterTM results. Our experimental methods agree with the penelope/penEasy simulations for most setups and dosimeters. The TPS relative differences with the AcurosTM algorithm were similar in both experimental and simulated setups. The discrepancy between the BrachyVisionTM, AcurosTM, and TG-43 dose responses in the phantom described by this work exceeded 12% for certain setups. CONCLUSIONS: The results derived from the phantom measurements show good agreement with the simulations and TPS calculations, using AcurosTM algorithm. Differences in the dose responses were evident in the experimental results when heterogeneous materials were introduced. These measurements prove the usefulness of the heterogeneous phantom for verification of HDR treatment planning systems based on model-based dose calculation algorithms. PMID- 25832049 TI - Models for predicting objective function weights in prostate cancer IMRT. AB - PURPOSE: To develop and evaluate the clinical applicability of advanced machine learning models that simultaneously predict multiple optimization objective function weights from patient geometry for intensity-modulated radiation therapy of prostate cancer. METHODS: A previously developed inverse optimization method was applied retrospectively to determine optimal objective function weights for 315 treated patients. The authors used an overlap volume ratio (OV) of bladder and rectum for different PTV expansions and overlap volume histogram slopes (OVSR and OVSB for the rectum and bladder, respectively) as explanatory variables that quantify patient geometry. Using the optimal weights as ground truth, the authors trained and applied three prediction models: logistic regression (LR), multinomial logistic regression (MLR), and weighted K-nearest neighbor (KNN). The population average of the optimal objective function weights was also calculated. RESULTS: The OV at 0.4 cm and OVSR at 0.1 cm features were found to be the most predictive of the weights. The authors observed comparable performance (i.e., no statistically significant difference) between LR, MLR, and KNN methodologies, with LR appearing to perform the best. All three machine learning models outperformed the population average by a statistically significant amount over a range of clinical metrics including bladder/rectum V53Gy, bladder/rectum V70Gy, and dose to the bladder, rectum, CTV, and PTV. When comparing the weights directly, the LR model predicted bladder and rectum weights that had, on average, a 73% and 74% relative improvement over the population average weights, respectively. The treatment plans resulting from the LR weights had, on average, a rectum V70Gy that was 35% closer to the clinical plan and a bladder V70Gy that was 29% closer, compared to the population average weights. Similar results were observed for all other clinical metrics. CONCLUSIONS: The authors demonstrated that the KNN and MLR weight prediction methodologies perform comparably to the LR model and can produce clinical quality treatment plans by simultaneously predicting multiple weights that capture trade-offs associated with sparing multiple OARs. PMID- 25832048 TI - Prospective estimation of organ dose in CT under tube current modulation. AB - PURPOSE: Computed tomography (CT) has been widely used worldwide as a tool for medical diagnosis and imaging. However, despite its significant clinical benefits, CT radiation dose at the population level has become a subject of public attention and concern. In this light, optimizing radiation dose has become a core responsibility for the CT community. As a fundamental step to manage and optimize dose, it may be beneficial to have accurate and prospective knowledge about the radiation dose for an individual patient. In this study, the authors developed a framework to prospectively estimate organ dose for chest and abdominopelvic CT exams under tube current modulation (TCM). METHODS: The organ dose is mainly dependent on two key factors: patient anatomy and irradiation field. A prediction process was developed to accurately model both factors. To model the anatomical diversity and complexity in the patient population, the authors used a previously developed library of computational phantoms with broad distributions of sizes, ages, and genders. A selected clinical patient, represented by a computational phantom in the study, was optimally matched with another computational phantom in the library to obtain a representation of the patient's anatomy. To model the irradiation field, a previously validated Monte Carlo program was used to model CT scanner systems. The tube current profiles were modeled using a ray-tracing program as previously reported that theoretically emulated the variability of modulation profiles from major CT machine manufacturers Li et al., [Phys. Med. Biol. 59, 4525-4548 (2014)]. The prediction of organ dose was achieved using the following process: (1) CTDIvol normalized-organ dose coefficients (horgan) for fixed tube current were first estimated as the prediction basis for the computational phantoms; (2) each computation phantom, regarded as a clinical patient, was optimally matched with one computational phantom in the library; (3) to account for the effect of the TCM scheme, a weighted organ-specific CTDIvol [denoted as CTDIvol organ,weighted] was computed for each organ based on the TCM profile and the anatomy of the "matched" phantom; (4) the organ dose was predicted by multiplying the weighted organ-specific CTDIvol with the organ dose coefficients (horgan). To quantify the prediction accuracy, each predicted organ dose was compared with the corresponding organ dose simulated from the Monte Carlo program with the TCM profile explicitly modeled. RESULTS: The predicted organ dose showed good agreements with the simulated organ dose across all organs and modulation profiles. The average percentage error in organ dose estimation was generally within 20% across all organs and modulation profiles, except for organs located in the pelvic and shoulder regions. For an average CTDIvol of a CT exam of 10 mGy, the average error at full modulation strength (alpha = 1) across all organs was 0.91 mGy for chest exams, and 0.82 mGy for abdominopelvic exams. CONCLUSIONS: This study developed a quantitative model to predict organ dose for clinical chest and abdominopelvic scans. Such information may aid in the design of optimized CT protocols in relation to a targeted level of image quality. PMID- 25832050 TI - Patch-based generation of a pseudo CT from conventional MRI sequences for MRI only radiotherapy of the brain. AB - PURPOSE: In radiotherapy (RT) based on magnetic resonance imaging (MRI) as the only modality, the information on electron density must be derived from the MRI scan by creating a so-called pseudo computed tomography (pCT). This is a nontrivial task, since the voxel-intensities in an MRI scan are not uniquely related to electron density. To solve the task, voxel-based or atlas-based models have typically been used. The voxel-based models require a specialized dual ultrashort echo time MRI sequence for bone visualization and the atlas-based models require deformable registrations of conventional MRI scans. In this study, we investigate the potential of a patch-based method for creating a pCT based on conventional T1-weighted MRI scans without using deformable registrations. We compare this method against two state-of-the-art methods within the voxel-based and atlas-based categories. METHODS: The data consisted of CT and MRI scans of five cranial RT patients. To compare the performance of the different methods, a nested cross validation was done to find optimal model parameters for all the methods. Voxel-wise and geometric evaluations of the pCTs were done. Furthermore, a radiologic evaluation based on water equivalent path lengths was carried out, comparing the upper hemisphere of the head in the pCT and the real CT. Finally, the dosimetric accuracy was tested and compared for a photon treatment plan. RESULTS: The pCTs produced with the patch-based method had the best voxel-wise, geometric, and radiologic agreement with the real CT, closely followed by the atlas-based method. In terms of the dosimetric accuracy, the patch-based method had average deviations of less than 0.5% in measures related to target coverage. CONCLUSIONS: We showed that a patch-based method could generate an accurate pCT based on conventional T1-weighted MRI sequences and without deformable registrations. In our evaluations, the method performed better than existing voxel-based and atlas-based methods and showed a promising potential for RT of the brain based only on MRI. PMID- 25832051 TI - Comparison of film measurements and Monte Carlo simulations of dose delivered with very high-energy electron beams in a polystyrene phantom. AB - PURPOSE: To measure radiation dose in a water-equivalent medium from very high energy electron (VHEE) beams and make comparisons to Monte Carlo (MC) simulation results. METHODS: Dose in a polystyrene phantom delivered by an experimental VHEE beam line was measured with Gafchromic films for three 50 MeV and two 70 MeV Gaussian beams of 4.0-6.9 mm FWHM and compared to corresponding MC-simulated dose distributions. MC dose in the polystyrene phantom was calculated with the EGSnrc/BEAMnrc and DOSXYZnrc codes based on the experimental setup. Additionally, the effect of 2% beam energy measurement uncertainty and possible non-zero beam angular spread on MC dose distributions was evaluated. RESULTS: MC simulated percentage depth dose (PDD) curves agreed with measurements within 4% for all beam sizes at both 50 and 70 MeV VHEE beams. Central axis PDD at 8 cm depth ranged from 14% to 19% for the 5.4-6.9 mm 50 MeV beams and it ranged from 14% to 18% for the 4.0-4.5 mm 70 MeV beams. MC simulated relative beam profiles of regularly shaped Gaussian beams evaluated at depths of 0.64 to 7.46 cm agreed with measurements to within 5%. A 2% beam energy uncertainty and 0.286 degrees beam angular spread corresponded to a maximum 3.0% and 3.8% difference in depth dose curves of the 50 and 70 MeV electron beams, respectively. Absolute dose differences between MC simulations and film measurements of regularly shaped Gaussian beams were between 10% and 42%. CONCLUSIONS: The authors demonstrate that relative dose distributions for VHEE beams of 50-70 MeV can be measured with Gafchromic films and modeled with Monte Carlo simulations to an accuracy of 5%. The reported absolute dose differences likely caused by imperfect beam steering and subsequent charge loss revealed the importance of accurate VHEE beam control and diagnostics. PMID- 25832052 TI - The use of atlas registration and graph cuts for prostate segmentation in magnetic resonance images. AB - PURPOSE: An automatic method for 3D prostate segmentation in magnetic resonance (MR) images is presented for planning image-guided radiotherapy treatment of prostate cancer. METHODS: A spatial prior based on intersubject atlas registration is combined with organ-specific intensity information in a graph cut segmentation framework. The segmentation is tested on 67 axial T2-weighted MR images in a leave-one-out cross validation experiment and compared with both manual reference segmentations and with multiatlas-based segmentations using majority voting atlas fusion. The impact of atlas selection is investigated in both the traditional atlas-based segmentation and the new graph cut method that combines atlas and intensity information in order to improve the segmentation accuracy. Best results were achieved using the method that combines intensity information, shape information, and atlas selection in the graph cut framework. RESULTS: A mean Dice similarity coefficient (DSC) of 0.88 and a mean surface distance (MSD) of 1.45 mm with respect to the manual delineation were achieved. CONCLUSIONS: This approaches the interobserver DSC of 0.90 and interobserver MSD 0f 1.15 mm and is comparable to other studies performing prostate segmentation in MR. PMID- 25832053 TI - Time-resolved dosimetry using a pinpoint ionization chamber as quality assurance for IMRT and VMAT. AB - PURPOSE: To develop a method to verify the dose delivery in relation to the individual control points of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) using an ionization chamber. In addition to more effective problem solving during patient-specific quality assurance (QA), the aim is to eventually map out the limitations in the treatment chain and enable a targeted improvement of the treatment technique in an efficient way. METHODS: Pretreatment verification was carried out for 255 treatment plans that included a broad range of treatment indications in two departments using the equipment of different vendors. In-house developed software was used to enable calculation of the dose delivery for the individual beamlets in the treatment planning system (TPS), for data acquisition, and for analysis of the data. The observed deviations were related to various delivery and measurement parameters such as gantry angle, field size, and the position of the detector with respect to the field edge to distinguish between error sources. RESULTS: The average deviation of the integral fraction dose during pretreatment verification of the planning target volume dose was -2.1% +/- 2.2% (1 SD), -1.7% +/- 1.7% (1 SD), and 0.0% +/- 1.3% (1 SD) for IMRT at the Radboud University Medical Center (RUMC), VMAT (RUMC), and VMAT at the Wellington Blood and Cancer Centre, respectively. Verification of the dose to organs at risk gave very similar results but was generally subject to a larger measurement uncertainty due to the position of the detector at a high dose gradient. The observed deviations could be related to limitations of the TPS beam models, attenuation of the treatment couch, as well as measurement errors. The apparent systematic error of about -2% in the average deviation of the integral fraction dose in the RUMC results could be explained by the limitations of the TPS beam model in the calculation of the beam penumbra. CONCLUSIONS: This study showed that time-resolved dosimetry using an ionization chamber is feasible and can be largely automated which limits the required additional time compared to integrated dose measurements. It provides a unique QA method which enables identification and quantification of the contribution of various error sources during IMRT and VMAT delivery. PMID- 25832054 TI - Markerless tracking of small lung tumors for stereotactic radiotherapy. AB - PURPOSE: (1) To validate retrospective markerless tracking software for small lung tumors by comparing tracked motion in 4-dimensional planning computed tomography (4DCT) derived kV projection images and known tumor motion in the same 4DCT. (2) To evaluate variability of tumor motion using kV projection images from cone-beam computed tomography (CBCT) scans acquired on different days. METHODS: Nonclinical tumor tracking software (TTS) used a normalized cross correlation algorithm to track the tumor on enhanced kV projection images (e.g., from a CBCT scan). The reference dataset consisted of digitally reconstructed radiographs (DRRs) from one phase of a planning 4DCT. TTS matches two in-plane coordinates and obtains the out-of-plane coordinate by triangulating with match results from other projections. (1) To validate TTS, tracking results were compared with known 4DCT tumor motion for two patients (A and B). Projection images (1 image/1 degrees ) were digitally reconstructed for each 4DCT phase. From these, kV projection series were composed simulating full breathing cycles every 20 degrees of gantry rotation [breathing period = 20 degrees /(6 degrees /s) = 3.33 s]. Reference templates were 360 "tumor enhanced" DRRs from the 4DCT expiration phase. TTS-derived tumor motion was compared to known tumor motion on 4DCT. (2) For five patients, TTS-assessed motion during clinical CBCT acquisition was compared with motion on the planning 4DCT, and the motion component in the Y (cranio-caudal)-direction was compared with the motion of an external marker box (RPM, real-time position management). RESULTS: (1) Validation results: TTS for case A (tumor 6.2 cm(3), 32 mm axial diameter) over 360 degrees showed mean motion X (medial-lateral) = 3.4, Y = 11.5, and Z (ventral-dorsal) = 4.9 mm (1 SD < 1.0 mm). Corresponding 4DCT motion was X = 3.1, Y = 11.3, and Z = 5.1 mm. Correlation coefficients between TTS tumor motion and displacement of the tumor's center of mass (CoM) on 4DCT were 0.64, 0.96, and 0.82 (X, Y, and Z, respectively). For case B (4.1 cm(3), 20 mm diameter), due to temporarily decreased tumor visibility preventing TTS from resolving the tumor, robust tracking data were only available between angles 300 degrees -40 degrees and 120 degrees -220 degrees . Mean motion according to TTS was X = 2.0, Y = 7.7, and Z = 8.2 mm (1 SD < 0.9 mm). Tumor motion on 4DCT was X = 1.8, Y = 7.6, and Z = 9.5 mm and correlation coefficients between TTS motion and CoM displacement were 0.59, 0.95, and 0.93 (X, Y, and Z, respectively). (2) CLINICAL RESULTS: TTS revealed a mean intrafraction variation in tumor motion in Y-direction of >2.0 mm (1 SD) in four of five patients. In addition, clinical tumor motion amplitude differed from that seen on planning 4DCT. Internal and external structures that create abrupt density change (e.g., table-top edge, interface between lung/mediastinum and lung/heart) were observed to prevent 360 degrees tracking of the tumor. Correlation coefficients between TTS motion in the Y-direction and the RPM signal (22 observations) ranged from 0.78 to 0.96. In 2D, 241 TTS matches at end inspiration and end-expiration were visually validated: mean difference was 0.8 mm (SD = 0.7) for both. CONCLUSIONS: TTS can track small lung tumors if these are visible in kV projections. A 4DCT dataset can be used to validate kV tracking of moving targets. TTS and 4DCT displacement agreed to within 2 mm. TTS and RPM motion were closely associated but tumor motion during CBCT can vary from the planning 4DCT. PMID- 25832055 TI - Noninvasive differential diagnosis of dental periapical lesions in cone-beam CT scans. AB - PURPOSE: This paper proposes a novel application of computer-aided diagnosis (CAD) to an everyday clinical dental challenge: the noninvasive differential diagnosis of periapical lesions between periapical cysts and granulomas. A histological biopsy is the most reliable method currently available for this differential diagnosis; however, this invasive procedure prevents the lesions from healing noninvasively despite a report that they may heal without surgical treatment. A CAD using cone-beam computed tomography (CBCT) offers an alternative noninvasive diagnostic tool which helps to avoid potentially unnecessary surgery and to investigate the unknown healing process and rate for the lesions. METHODS: The proposed semiautomatic solution combines graph-based random walks segmentation with machine learning-based boosted classifiers and offers a robust clinical tool with minimal user interaction. As part of this CAD framework, the authors provide two novel technical contributions: (1) probabilistic extension of the random walks segmentation with likelihood ratio test and (2) LDA-AdaBoost: a new integration of weighted linear discriminant analysis to AdaBoost. RESULTS: A dataset of 28 CBCT scans is used to validate the approach and compare it with other popular segmentation and classification methods. The results show the effectiveness of the proposed method with 94.1% correct classification rate and an improvement of the performance by comparison with the Simon's state-of-the-art method by 17.6%. The authors also compare classification performances with two independent ground-truth sets from the histopathology and CBCT diagnoses provided by endodontic experts. CONCLUSIONS: Experimental results of the authors show that the proposed CAD system behaves in clearer agreement with the CBCT ground-truth than with histopathology, supporting the Simon's conjecture that CBCT diagnosis can be as accurate as histopathology for differentiating the periapical lesions. PMID- 25832056 TI - Incorporating multislice imaging into x-ray CT polymer gel dosimetry. AB - PURPOSE: To evaluate multislice computed tomography (CT) scanning for fast and reliable readout of radiation therapy (RT) dose distributions using CT polymer gel dosimetry (PGD) and to establish a baseline assessment of image noise and uniformity in an unirradiated gel dosimeter. METHODS: A 16-slice CT scanner was used to acquire images through a 1 L cylinder filled with water. Additional images were collected using a single slice machine. The variability in CT number (NCT) associated with the anode heel effect was evaluated and used to define a new slice-by-slice background subtraction artifact removal technique for CT PGD. Image quality was assessed for the multislice system by evaluating image noise and uniformity. The agreement in NCT for slices acquired simultaneously using the multislice detector array was also examined. Further study was performed to assess the effects of increasing x-ray tube load on the constancy of measured NCT and overall scan time. In all cases, results were compared to the single slice machine. Finally, images were collected throughout the volume of an unirradiated gel dosimeter to quantify image noise and uniformity before radiation is delivered. RESULTS: Slice-by-slice background subtraction effectively removes the variability in NCT observed across images acquired simultaneously using the multislice scanner and is the recommended background subtraction method when using a multislice CT system. Image noise was higher for the multislice system compared to the single slice scanner, but overall image quality was comparable between the two systems. Further study showed NCT was consistent across image slices acquired simultaneously using the multislice detector array for each detector configuration of the slice thicknesses examined. In addition, the multislice system was found to eliminate variations in NCT due to increasing x ray tube load and reduce scanning time by a factor of 4 when compared to imaging a large volume using a single slice scanner. Images acquired through an unirradiated, active gel revealed NCT varies between the top and bottom of the 1 L cylinder as well as across the diameter of the cylinder by up to 7 HU. CONCLUSIONS: Multislice CT imaging has been evaluated for CT PGD and found to be the superior technique compared to single slice imaging in terms of the time required to complete a scan and the tube load characteristics associated with each scanning method. The implementation of multislice scanning is straightforward and expected to facilitate routine gel dosimetry measurements for complex dose distributions in modern RT centers. PMID- 25832057 TI - Dynamic 31P MR spectroscopy of plantar flexion: influence of ergometer design, magnetic field strength (3 and 7 T), and RF-coil design. AB - PURPOSE: Dynamic phosphorus magnetic resonance spectroscopy ((31)P MRS) during and after acute exercise enables the noninvasive in vivo determination of the mitochondrial capacity of skeletal muscle. Nevertheless, the lack of standardization in experimental setups leads to significant variations in published values of maximal aerobic capacity, even in the population of healthy volunteers. Thus, in this study, we aimed to assess the impact of the ergometer type (pneumatic and mechanical resistance construction), radiofrequency (RF)-coil diameter, and different magnetic field strengths (3 and 7 T) on the metabolic parameters measured by dynamic (31)P MRS during a plantar flexion isotonic exercise protocol within the same group of healthy volunteers. METHODS: Dynamic (31)P MRS measurements of the calf muscle in 11 volunteers (mean age, 36 +/- 13 yrs; mean BMI, 23.5 +/- 2.5 kg/m(2)), on a 3 T MR system with a custom-made mechanical ergometer in the first research laboratory (RL1) and on 3 and 7 T MR systems equipped with a commercial pneumatic ergometer in the second research laboratory (RL2), were performed at three different workloads. RF-coils differed slightly between the sites and MR systems used. The repeatability of the experimental protocol was tested in every setup. The basal concentrations of phosphocreatine (PCr), exercise-induced depletion of PCr (DeltaPCr), initial PCr resynthesis rate (VPCr), and mitochondrial capacity (Qmax) were calculated and compared between the research sites and field strengths. RESULTS: High repeatability of the measurement protocol was found in every experimental setup. No significant differences at any workload were found in these metabolic parameters assessed at different magnetic field strengths (3 T vs 7 T), using the same ergometer (in RL2) and a similar RF-coil. In the inter-research laboratory comparison at the same field strength (3 T), but with using different ergometers and RF-coils, differences were found in the concentration of PCr measured at rest and in the drop in PCr signal intensity. These differences translated into difference in the value of mitochondrial capacity at a workload of 15% of maximal voluntary contraction (MVC) force (0.45 +/- 0.16 mM/s vs 0.31 +/- 0.08 mM/s, in the RL1 and RL2, respectively). CONCLUSIONS: Metabolic parameters measured during exercise challenge by dynamic (31)P MRS do not depend upon the magnetic field strength used. For multicenter studies with different ergometers, it is important to set the same workload, measurement, and evaluation protocols, especially when the effects of very mild exercise (15% MVC) are to be compared. However, a higher workload (24% MVC) decreases the influence of imperfections and intersite differences for the assessed value of maximal mitochondrial capacity. PMID- 25832058 TI - Novel spirometry based on optical surface imaging. AB - PURPOSE: To evaluate the feasibility of using optical surface imaging (OSI) to measure the dynamic tidal volume (TV) of the human torso during free breathing. METHODS: We performed experiments to measure volume or volume change in geometric and deformable phantoms as well as human subjects using OSI. To assess the accuracy of OSI in volume determination, we performed experiments using five geometric phantoms and two deformable body phantoms and compared the values with those derived from geometric calculations and computed tomography (CT) measurements, respectively. To apply this technique to human subjects, an institutional review board protocol was established and three healthy volunteers were studied. In the human experiment, a high-speed image capture mode of OSI was applied to acquire torso images at 4-5 frames per second, which was synchronized with conventional spirometric measurements at 5 Hz. An in-house matlab program was developed to interactively define the volume of interest (VOI), separate the thorax and abdomen, and automatically calculate the thoracic and abdominal volumes within the VOIs. The torso volume change (TV C = DeltaVtorso = DeltaVthorax + DeltaVabdomen) was automatically calculated using full-exhalation phase as the reference. The volumetric breathing pattern (BPv = DeltaVthorax/DeltaVtorso) quantifying thoracic and abdominal volume variations was also calculated. Under quiet breathing, TVC should equal the tidal volume measured concurrently by a spirometer with a conversion factor (1.08) accounting for internal and external differences of temperature and moisture. Another matlab program was implemented to control the conventional spirometer that was used as the standard. RESULTS: The volumes measured from the OSI imaging of geometric phantoms agreed with the calculated volumes with a discrepancy of 0.0% +/- 1.6% (range -1.9% to 2.5%). In measurements from the deformable torso/thorax phantoms, the volume differences measured using OSI imaging and CT imaging were 1.2% +/- 2.1% (range -0.5% to 3.6%), with a linear regression fitting (slope = 1.02 and R(2) = 0.999). In volunteers, the relative error in OSI tidal volume measurement was -2.2% +/- 4.9% (range -9.2% to 4.8%) and a correlation of r = 0.98 was found with spirometric measurement. The breathing pattern values of the three volunteers were substantially different from each other (BPv = 0.15, 0.45, and 0.32). CONCLUSIONS: This study demonstrates the feasibility of using OSI to measure breathing tidal volumes and breathing patterns with adequate accuracy. This is the first time that dynamic breathing tidal volume as well as breathing patterns is measured using optical surface imaging. The OSI-observed movement of the entire torso could serve as a new respiratory surrogate in the treatment room during radiation therapy. PMID- 25832059 TI - Using Rose's metal alloy as a pinhole collimator material in preclinical small animal imaging: a Monte Carlo evaluation. AB - PURPOSE: Pinhole collimation is the most common method of high-resolution preclinical single photon emission computed tomography imaging. The collimators are usually constructed from dense materials with high atomic numbers, such as gold and platinum, which are expensive and not always flexible in the fabrication step. In this work, the authors have investigated the properties of a fusible alloy called Rose's metal and its potential in pinhole preclinical imaging. When compared to current standard pinhole materials such as gold and platinum, Rose's metal has a lower density and a relatively low effective atomic number. However, it is inexpensive, has a low melting point, and does not contract when solidifying. Once cast, the piece can be machined with high precision. The aim of this study was to evaluate the imaging properties for Rose's metal and compare them with those of standard materials. METHODS: After validating their Monte Carlo code by comparing its results with published data and the results from analytical calculations, they investigated different pinhole geometries by varying the collimator material, acceptance angle, aperture diameter, and photon incident angle. The penetration-to-scatter and penetration-to-total component ratios, sensitivity, and the spatial resolution were determined for gold, tungsten, and Rose's metal for two radionuclides, (99)Tc(m) and (125)I. RESULTS: The Rose's metal pinhole-imaging simulations show higher penetration/total and scatter/total ratios. For example, the penetration/total is 50% for gold and 75% for Rose's metal when simulating (99)Tc(m) with a 0.3 mm aperture diameter and a 60 degrees acceptance angle. However, the degradation in spatial resolution remained below 10% relative to the spatial resolution for gold for acceptance angles below 40 degrees and aperture diameters larger than 0.5 mm. CONCLUSIONS: Extra penetration and scatter associated with Rose's metal contribute to degradation in the spatial resolution, but this degradation is not always substantial. The most important factor besides the collimator material was the acceptance angle. This should be kept to a minimum to prevent unnecessary scatter and penetration. For (125)I, the difference in spatial resolution between gold and Rose's metal is very small, 2.2% in the worst-case scenario. Based on these results, the authors conclude that Rose's metal is an alternative to standard materials not only for low-energy photon imaging but also for medium-energy applications that require low-cost, flexible pinhole configurations and designs, and that can tolerate a degraded spatial resolution. PMID- 25832060 TI - Systematic calibration of an integrated x-ray and optical tomography system for preclinical radiation research. AB - PURPOSE: The cone beam computed tomography (CBCT) guided small animal radiation research platform (SARRP) has been developed for focal tumor irradiation, allowing laboratory researchers to test basic biological hypotheses that can modify radiotherapy outcomes in ways that were not feasible previously. CBCT provides excellent bone to soft tissue contrast, but is incapable of differentiating tumors from surrounding soft tissue. Bioluminescence tomography (BLT), in contrast, allows direct visualization of even subpalpable tumors and quantitative evaluation of tumor response. Integration of BLT with CBCT offers complementary image information, with CBCT delineating anatomic structures and BLT differentiating luminescent tumors. This study is to develop a systematic method to calibrate an integrated CBCT and BLT imaging system which can be adopted onboard the SARRP to guide focal tumor irradiation. METHODS: The integrated imaging system consists of CBCT, diffuse optical tomography (DOT), and BLT. The anatomy acquired from CBCT and optical properties acquired from DOT serve as a priori information for the subsequent BLT reconstruction. Phantoms were designed and procedures were developed to calibrate the CBCT, DOT/BLT, and the entire integrated system. Geometrical calibration was performed to calibrate the CBCT system. Flat field correction was performed to correct the nonuniform response of the optical imaging system. Absolute emittance calibration was performed to convert the camera readout to the emittance at the phantom or animal surface, which enabled the direct reconstruction of the bioluminescence source strength. Phantom and mouse imaging were performed to validate the calibration. RESULTS: All calibration procedures were successfully performed. Both CBCT of a thin wire and a euthanized mouse revealed no spatial artifact, validating the accuracy of the CBCT calibration. The absolute emittance calibration was validated with a 650 nm laser source, resulting in a 3.0% difference between simulated and measured signal. The calibration of the entire system was confirmed through the CBCT and BLT reconstruction of a bioluminescence source placed inside a tissue-simulating optical phantom. Using a spatial region constraint, the source position was reconstructed with less than 1 mm error and the source strength reconstructed with less than 24% error. CONCLUSIONS: A practical and systematic method has been developed to calibrate an integrated x-ray and optical tomography imaging system, including the respective CBCT and optical tomography system calibration and the geometrical calibration of the entire system. The method can be modified and adopted to calibrate CBCT and optical tomography systems that are operated independently or hybrid x-ray and optical tomography imaging systems. PMID- 25832061 TI - A new stationary gridline artifact suppression method based on the 2D discrete wavelet transform. AB - PURPOSE: In digital x-ray radiography, an antiscatter grid is inserted between the patient and the image receptor to reduce scattered radiation. If the antiscatter grid is used in a stationary way, gridline artifacts will appear in the final image. In most of the gridline removal image processing methods, the useful information with spatial frequencies close to that of the gridline is usually lost or degraded. In this study, a new stationary gridline suppression method is designed to preserve more of the useful information. METHODS: The method is as follows. The input image is first recursively decomposed into several smaller subimages using a multiscale 2D discrete wavelet transform. The decomposition process stops when the gridline signal is found to be greater than a threshold in one or several of these subimages using a gridline detection module. An automatic Gaussian band-stop filter is then applied to the detected subimages to remove the gridline signal. Finally, the restored image is achieved using the corresponding 2D inverse discrete wavelet transform. RESULTS: The processed images show that the proposed method can remove the gridline signal efficiently while maintaining the image details. The spectra of a 1D Fourier transform of the processed images demonstrate that, compared with some existing gridline removal methods, the proposed method has better information preservation after the removal of the gridline artifacts. Additionally, the performance speed is relatively high. CONCLUSIONS: The experimental results demonstrate the efficiency of the proposed method. Compared with some existing gridline removal methods, the proposed method can preserve more information within an acceptable execution time. PMID- 25832062 TI - Characterization and implementation of OSL dosimeters for use in evaluating the efficacy of organ-based tube current modulation for CT scans of the face and orbits. AB - PURPOSE: The purpose of this work was to characterize commercially available optically stimulated luminescent (OSL) dosimeters for general clinical applications and apply the results to the development of a method to evaluate the efficacy of a vendor-specific organ-based tube current modulation application for both phantom and clinical computed tomography (CT) scans of the face and orbits. METHODS: This study consisted of three components: (1) thorough characterization of the dosimeters for CT scans in phantom, including evaluations of depletion, fading, angular dependence, and conversion from counts to absorbed dose; (2) evaluation of the efficacy of using plastic glasses to position the dosimeters over the eyes in both phantom and clinical studies; and (3) preliminary dosimetry measurements made using organ-based tube current modulation in computed tomography dose index (CTDI) and anthropomorphic phantom studies. RESULTS: (1) Depletion effects were found to have a linear relationship with the output of the OSL dosimeters (R(2) = 0.96). Fading was found to affect dosimeter readings during the first two hours following exposure but had no effect during the remaining 60-h period observed. No significant angular dependence was observed for the exposure conditions used in this study (with p-values ranging from 0.9 to 0.26 for all t-tests). Dosimeter counts varied linearly with absorbed dose when measured in the center and 12 o'clock positions of the CTDI phantoms. These linear models of counts versus absorbed dose had overlapping 95% confidence intervals for the intercepts but not for the slopes. (2) When dosimeters were positioned using safety glasses, there was no adverse effect on image quality, and there was no statistically significant difference between this placement and placement of the dosimeters directly on the eyes of the phantom (p = 0.24). (3) When using organ-based tube current modulation, the dose to the lens of the eye was reduced between 19% and 43%, depending on the scan protocol used and the positioning of the phantom. Furthermore, the amount of dose reduction was significantly affected by the vertical position of the phantom, with the largest reduction in dose seen when the phantom was centered in the gantry. CONCLUSIONS: (1) An appropriate correction factor, specific to CT scanning, was developed to account for depletion and fading characteristics of the dosimeters. Additionally, an equation to convert dosimeter counts to absorbed dose was established. (2) The use of plastic safety glasses was validated as an appropriate positioning device when measuring dose to the lens of the eye. (3) The use of organ-based tube current modulation can reduce dose to the lens of the eye during CT scanning. The amount of dose reduction, however, is largely influenced by the positioning of the anatomy in the gantry. PMID- 25832063 TI - Dosimetric measurements of an n-butyl cyanoacrylate embolization material for arteriovenous malformations. AB - PURPOSE: The therapeutic regimen for cranial arteriovenous malformations often involves both stereotactic radiosurgery and endovascular embolization. Embolization agents may contain tantalum or other contrast agents to assist the neurointerventionalists, leading to concerns regarding the dosimetric effects of these agents. This study investigated dosimetric properties of n-butyl cyanoacrylate (n-BCA) plus lipiodol with and without tantalum powder. METHODS: The embolization agents were provided cured from the manufacturer with and without added tantalum. Attenuation measurements were made for the samples and compared to the attenuation of a solid water substitute using a 6 MV photon beam. Effective linear attenuation coefficients (ELAC) were derived from attenuation measurements made using a portal imager and derived sample thickness maps projected in an identical geometry. Probable dosimetric errors for calculations in which the embolized regions are overridden with the properties of water were calculated using the ELAC values. Interface effects were investigated using a parallel plate ion chamber placed at set distances below fixed samples. Finally, Hounsfield units (HU) were measured using a stereotactic radiosurgery CT protocol, and more appropriate HU values were derived from the ELAC results and the CT scanner's HU calibration curve. RESULTS: The ELAC was 0.0516 +/- 0.0063 cm(-1) and 0.0580 +/- 0.0091 cm(-1) for n-BCA without and with tantalum, respectively, compared to 0.0487 +/- 0.0009 cm(-1) for the water substitute. Dose calculations with the embolized region set to be water equivalent in the treatment planning system would result in errors of -0.29% and -0.93% per cm thickness of n-BCA without and with tantalum, respectively. Interface effects compared to water were small in magnitude and limited in distance for both embolization materials. CT values at 120 kVp were 2082 and 2358 HU for n-BCA without and with tantalum, respectively; dosimetrically appropriate HU values were estimated to be 79 and 199 HU, respectively. CONCLUSIONS: The dosimetric properties of the embolization agents are very close to those of water for a 6 MV beam. Therefore, treating the entire intracranial space as uniform in composition will result in less than 1% dosimetric error for n-BCA emboli smaller than 3.4 cm without added tantalum and n-BCA emboli smaller than 1.1 cm with added tantalum. Furthermore, when effective embolization can be achieved by the neurointerventionalist using n-BCA without tantalum, the dosimetric impact of overriding material properties will be lessened. However, due to the high attenuation of embolization agents with and without added tantalum for diagnostic energies, artifacts may occur that necessitate additional imaging to accurately identify the spatial extent of the region to be treated. PMID- 25832064 TI - Noninvasive estimation of the pressure profile in the male urethra using ultrasound imaging. AB - PURPOSE: Decreased prostatic compliance as a result of benign prostatic enlargement can result in bladder outlet obstruction. This changes the urethral pressure profile during voiding. In this study, the authors propose noninvasive estimation of this pressure profile. In four soft tissue mimicking models of the urethra with increasing degree of obstruction, the authors measured deformation of the wall during flow, using ultrasound imaging. Combined with estimates of the model compliance, the authors were able to estimate the pressure profile. METHODS: First, the compliances (Young's moduli) of the four models were derived by applying static luminal pressure and measuring the resulting strain of the tissue using an ultrasound imaging system. Next, continuous flow was applied to the models and the strain in the urethral wall was measured similarly. The luminal pressure profile was estimated from the strain (measured under continuous flow conditions) and the derived compliance (measured under static pressure conditions). The estimated pressures up- and downstream of the obstruction were compared with the corresponding measured pressures. In the obstructed region, the strain gradient was estimated using linear regression. RESULTS: The luminal pressure values estimated from the ultrasound data up- and downstream of the obstruction were not significantly different from the corresponding measured pressures. The general pressure profile showed a decrease along the length of the obstruction followed by a small increase after the obstruction. The strain gradient in the obstructed region reflected the decrease in urethral pressure and increased with flow rate and degree of obstruction. CONCLUSIONS: The results from this model study illustrate the feasibility of noninvasive estimation of the urethral pressure profile using ultrasound. This offers the prospect of a noninvasive, ultrasound based diagnostic tool for assessment of bladder outlet obstruction in men with lower urinary tract symptoms. PMID- 25832065 TI - Feasibility study of a dual detector configuration concept for simultaneous megavoltage imaging and dose verification in radiotherapy. AB - PURPOSE: To test the feasibility of a dual detector concept for comprehensive verification of external beam radiotherapy. Specifically, the authors test the hypothesis that a portal imaging device coupled to a 2D dosimeter provides a system capable of simultaneous imaging and dose verification, and that the presence of each device does not significantly detract from the performance of the other. METHODS: The dual detector configuration comprised of a standard radiotherapy electronic portal imaging device (EPID) positioned directly on top of an ionization-chamber array (ICA) with 2 cm solid water buildup material (between EPID and ICA) and 5 cm solid backscatter material. The dose response characteristics of the ICA and the imaging performance of the EPID in the dual detector configuration were compared to the performance in their respective reference clinical configurations. The reference clinical configurations were 6 cm solid water buildup material, an ICA, and 5 cm solid water backscatter material as the reference dosimetry configuration, and an EPID with no additional buildup or solid backscatter material as the reference imaging configuration. The dose response of the ICA was evaluated by measuring the detector's response with respect to off-axis position, field size, and transit object thickness. Clinical dosimetry performance was evaluated by measuring a range of clinical intensity modulated radiation therapy (IMRT) beams in transit and nontransit geometries. The imaging performance of the EPID was evaluated quantitatively by measuring the contrast-to-noise ratio (CNR) and spatial resolution. Images of an anthropomorphic phantom were also used for qualitative assessment. RESULTS: The measured off-axis and field size response with the ICA in both transit and nontransit geometries for both dual detector configuration and reference dosimetry configuration agreed to within 1%. Transit dose response as a function of object thickness agreed to within 0.5%. All IMRT test patterns and clinical IMRT beams had gamma pass rates of >=98% at 2%/2 mm criteria. In terms of imaging performance, the measured CNR and spatial resolution (f50) were 263.23 +/- 24.85 and 0.4025 +/- 1.25 * 10(-3) for dual detector configuration and 324 +/- 26.65 and 0.4141 +/- 1.14 * 10(-3) for reference imaging configuration, respectively. The CNR and spatial resolution were quantitatively worse in the dual detector configuration due to the additional backscatter. The difference in imaging performance was not visible in qualitative assessment of phantom images. CONCLUSIONS: Combining a commercially available ICA dosimetry device with a conventional EPID did not significantly detract from the performance of either device. Further improvements in imaging performance may be achieved with an optimized design. This study demonstrates the feasibility of a dual detector concept for simultaneous imaging and dosimetry in radiation therapy. PMID- 25832066 TI - An investigation into factors affecting the precision of CT radiation dose profile width measurements using radiochromic films. AB - PURPOSE: To investigate the impact of x-ray beam energy, exposure intensity, and flat-bed scanner uniformity and spatial resolution on the precision of computed tomography (CT) beam width measurements using Gafchromic XR-QA2 film and an off the-shelf document scanner. METHODS: Small strips of Gafchromic film were placed at isocenter in a CT scanner and exposed at various x-ray beam energies (80-140 kVp), exposure levels (50-400 mA s), and nominal beam widths (1.25, 5, and 10 mm). The films were scanned in reflection mode on a Ricoh MP3501 flat-bed document scanner using several spatial resolution settings (100 to 400 dpi) and at different locations on the scanner bed. Reflection measurements were captured in digital image files and radiation dose profiles generated by converting the image pixel values to air kerma through film calibration. Beam widths were characterized by full width at half maximum (FWHM) and full width at tenth maximum (FWTM) of dose profiles. Dependences of these parameters on the above factors were quantified in percentage change from the baselines. RESULTS: The uncertainties in both FWHM and FWTM caused by varying beam energy, exposure level, and scanner uniformity were all within 4.5% and 7.6%, respectively. Increasing scanner spatial resolution significantly increased the uncertainty in both FWHM and FWTM, with FWTM affected by almost 8 times more than FWHM (48.7% vs 6.5%). When uncalibrated dose profiles were used, FWHM and FWTM were over estimated by 11.6% and 7.6%, respectively. Narrower beam width appeared more sensitive to the film calibration than the wider ones (R(2) = 0.68 and 0.85 for FWHM and FWTM, respectively). The global and maximum local background variations of the document scanner were 1.2%. The intrinsic film nonuniformity for an unexposed film was 0.3%. CONCLUSIONS: Measurement of CT beam widths using Gafchromic XR-QA2 films is robust against x-ray energy, exposure level, and scanner uniformity. With proper film calibration and scanner resolution setting, it can provide adequate precision for meeting ACR and manufacturer's tolerances for the measurement of CT dose profiles. PMID- 25832067 TI - Technical note: Implementation of biological washout processes within GATE/GEANT4 -a Monte Carlo study in the case of carbon therapy treatments. AB - PURPOSE: The imaging of positron emitting isotopes produced during patient irradiation is the only in vivo method used for hadrontherapy dose monitoring in clinics nowadays. However, the accuracy of this method is limited by the loss of signal due to the metabolic decay processes (biological washout). In this work, a generic modeling of washout was incorporated into the GATE simulation platform. Additionally, the influence of the washout on the beta(+) activity distributions in terms of absolute quantification and spatial distribution was studied. METHODS: First, the irradiation of a human head phantom with a (12)C beam, so that a homogeneous dose distribution was achieved in the tumor, was simulated. The generated (11)C and (15)O distribution maps were used as beta(+) sources in a second simulation, where the PET scanner was modeled following a detailed Monte Carlo approach. The activity distributions obtained in the presence and absence of washout processes for several clinical situations were compared. RESULTS: Results show that activity values are highly reduced (by a factor of 2) in the presence of washout. These processes have a significant influence on the shape of the PET distributions. Differences in the distal activity falloff position of 4 mm are observed for a tumor dose deposition of 1 Gy (Tini = 0 min). However, in the case of high doses (3 Gy), the washout processes do not have a large effect on the position of the distal activity falloff (differences lower than 1 mm). The important role of the tumor washout parameters on the activity quantification was also evaluated. CONCLUSIONS: With this implementation, GATE/GEANT4 is the only open-source code able to simulate the full chain from the hadrontherapy irradiation to the PET dose monitoring including biological effects. Results show the strong impact of the washout processes, indicating that the development of better models and measurement of biological washout data are essential. PMID- 25832068 TI - Creation of an atlas of filter positions for fluence field modulated CT. AB - PURPOSE: Fluence field modulated CT (FFMCT) and volume of interest (VOI) CT imaging applications require adjustment of the profile of the x-ray fluence incident on a patient as a function of view angle. Since current FFMCT prototypes can theoretically take on an infinite number of configurations, measuring a calibration data set for all possible positions would not be feasible. The present work details a methodology for calculating an atlas of configurations that will span all likely body regions, patient sizes, patient positioning, and imaging modes. The hypothesis is that there exists a finite number of unique modulator configurations that effectively span the infinite number of possible fluence profiles with minimal loss in performance. METHODS: CT images of a head, shoulder, thorax, abdominal, wrist, and leg anatomical slices were dilated and contracted to model small, medium, and large sized patients. Additionally, the images were positioned from iso-center by three different amounts. The modulator configurations required to compensate for each image were computed assuming a FFMCT prototype, digital beam attenuator, (DBA), was set to equalize the detector exposure. Each atlas configuration should be different from the other atlas configurations. The degree of difference was quantified using the sum of the absolute differences in filter thickness between configurations. Using this metric, a set of unique wedge configurations for which no two configurations have a metric value smaller than some threshold can be constructed. Differences in the total number of incident photons between the unconstrained filters and the atlas were studied as a function of the number of atlas positions for each anatomical site and size/off-centering combination. RESULTS: By varying the threshold used in creating the atlas, it was found that roughly 322 atlas positions provided an incident number of photons within 20% of using 19,440 unique filters (the number of atlas entries ranged from 7213 to 1). Additionally, for VOI applications implemented with a single VOI region, the number of required filter configurations was expressed in a simple closed form solution. CONCLUSIONS: The methodology proposed in this work will enable DBA-FFMCT and DBA-VOI imaging in the clinic without the need for patient specific air-scans to be performed. In addition, the methodology proposed here is directly applicable to other modulator designs such as piecewise linear, TomoTherapy multi leaf collimators, 2D fluid arrays, and inverse geometry CT. PMID- 25832069 TI - Patient-bounded extrapolation using low-dose priors for volume-of-interest imaging in C-arm CT. AB - PURPOSE: Three-dimensional (3D) volume-of-interest (VOI) imaging with C-arm systems provides anatomical information in a predefined 3D target region at a considerably low x-ray dose. However, VOI imaging involves laterally truncated projections from which conventional reconstruction algorithms generally yield images with severe truncation artifacts. Heuristic based extrapolation methods, e.g., water cylinder extrapolation, typically rely on techniques that complete the truncated data by means of a continuity assumption and thus appear to be ad hoc. It is our goal to improve the image quality of VOI imaging by exploiting existing patient-specific prior information in the workflow. METHODS: A necessary initial step prior to a 3D acquisition is to isocenter the patient with respect to the target to be scanned. To this end, low-dose fluoroscopic x-ray acquisitions are usually applied from anterior-posterior (AP) and medio-lateral (ML) views. Based on this, the patient is isocentered by repositioning the table. In this work, we present a patient-bounded extrapolation method that makes use of these noncollimated fluoroscopic images to improve image quality in 3D VOI reconstruction. The algorithm first extracts the 2D patient contours from the noncollimated AP and ML fluoroscopic images. These 2D contours are then combined to estimate a volumetric model of the patient. Forward-projecting the shape of the model at the eventually acquired C-arm rotation views gives the patient boundary information in the projection domain. In this manner, we are in the position to substantially improve image quality by enforcing the extrapolated line profiles to end at the known patient boundaries, derived from the 3D shape model estimate. RESULTS: The proposed method was evaluated on eight clinical datasets with different degrees of truncation. The proposed algorithm achieved a relative root mean square error (rRMSE) of about 1.0% with respect to the reference reconstruction on nontruncated data, even in the presence of severe truncation, compared to a rRMSE of 8.0% when applying a state-of-the-art heuristic extrapolation technique. CONCLUSIONS: The method we proposed in this paper leads to a major improvement in image quality for 3D C-arm based VOI imaging. It involves no additional radiation when using fluoroscopic images that are acquired during the patient isocentering process. The model estimation can be readily integrated into the existing interventional workflow without additional hardware. PMID- 25832071 TI - Robust electromagnetically guided endoscopic procedure using enhanced particle swarm optimization for multimodal information fusion. AB - PURPOSE: Electromagnetically guided endoscopic procedure, which aims at accurately and robustly localizing the endoscope, involves multimodal sensory information during interventions. However, it still remains challenging in how to integrate these information for precise and stable endoscopic guidance. To tackle such a challenge, this paper proposes a new framework on the basis of an enhanced particle swarm optimization method to effectively fuse these information for accurate and continuous endoscope localization. METHODS: The authors use the particle swarm optimization method, which is one of stochastic evolutionary computation algorithms, to effectively fuse the multimodal information including preoperative information (i.e., computed tomography images) as a frame of reference, endoscopic camera videos, and positional sensor measurements (i.e., electromagnetic sensor outputs). Since the evolutionary computation method usually limits its possible premature convergence and evolutionary factors, the authors introduce the current (endoscopic camera and electromagnetic sensor's) observation to boost the particle swarm optimization and also adaptively update evolutionary parameters in accordance with spatial constraints and the current observation, resulting in advantageous performance in the enhanced algorithm. RESULTS: The experimental results demonstrate that the authors' proposed method provides a more accurate and robust endoscopic guidance framework than state-of the-art methods. The average guidance accuracy of the authors' framework was about 3.0 mm and 5.6 degrees while the previous methods show at least 3.9 mm and 7.0 degrees . The average position and orientation smoothness of their method was 1.0 mm and 1.6 degrees , which is significantly better than the other methods at least with (2.0 mm and 2.6 degrees ). Additionally, the average visual quality of the endoscopic guidance was improved to 0.29. CONCLUSIONS: A robust electromagnetically guided endoscopy framework was proposed on the basis of an enhanced particle swarm optimization method with using the current observation information and adaptive evolutionary factors. The authors proposed framework greatly reduced the guidance errors from (4.3, 7.8) to (3.0 mm, 5.6 degrees ), compared to state-of-the-art methods. PMID- 25832070 TI - Characterization of the nanoDot OSLD dosimeter in CT. AB - PURPOSE: The extensive use of computed tomography (CT) in diagnostic procedures is accompanied by a growing need for more accurate and patient-specific dosimetry techniques. Optically stimulated luminescent dosimeters (OSLDs) offer a potential solution for patient-specific CT point-based surface dosimetry by measuring air kerma. The purpose of this work was to characterize the OSLD nanoDot for CT dosimetry, quantifying necessary correction factors, and evaluating the uncertainty of these factors. METHODS: A characterization of the Landauer OSL nanoDot (Landauer, Inc., Greenwood, IL) was conducted using both measurements and theoretical approaches in a CT environment. The effects of signal depletion, signal fading, dose linearity, and angular dependence were characterized through direct measurement for CT energies (80-140 kV) and delivered doses ranging from ~5 to >1000 mGy. Energy dependence as a function of scan parameters was evaluated using two independent approaches: direct measurement and a theoretical approach based on Burlin cavity theory and Monte Carlo simulated spectra. This beam quality dependence was evaluated for a range of CT scanning parameters. RESULTS: Correction factors for the dosimeter response in terms of signal fading, dose linearity, and angular dependence were found to be small for most measurement conditions (<3%). The relative uncertainty was determined for each factor and reported at the two-sigma level. Differences in irradiation geometry (rotational versus static) resulted in a difference in dosimeter signal of 3% on average. Beam quality varied with scan parameters and necessitated the largest correction factor, ranging from 0.80 to 1.15 relative to a calibration performed in air using a 120 kV beam. Good agreement was found between the theoretical and measurement approaches. CONCLUSIONS: Correction factors for the measurement of air kerma were generally small for CT dosimetry, although angular effects, and particularly effects due to changes in beam quality, could be more substantial. In particular, it would likely be necessary to account for variations in CT scan parameters and measurement location when performing CT dosimetry using OSLD. PMID- 25832073 TI - CHERENCUBE: concept definition and implementation challenges of a Cherenkov-based detector block for PET. AB - PURPOSE: A new concept for a depth-of-interaction (DOI) capable time-of-flight (TOF) PET detector is defined, based only on the detection of Cherenkov photons. The proposed "CHERENCUBE" consists of a cubic Cherenkov radiator with position sensitive photodetectors covering each crystal face. By means of the spatial distribution of the detected photons and their time of arrival, the point of interaction of the gamma-ray in the crystal can be determined. This study analyzes through theoretical calculations and Monte Carlo simulations the potential advantages of the concept toward reaching a Cherenkov-only detector for TOF-PET with DOI capability. Furthermore, an algorithm for the DOI estimation is presented and the requirements for a practical implementation of the proposed concept are defined. METHODS: The Monte Carlo simulations consisted of a cubic crystal with one photodetector coupled to each one of the faces of the cube. The sensitive area of the detector matched exactly the crystal size, which was varied in 1 mm steps between 1 * 1 * 1 mm(3) and 10 * 10 * 10 mm(3). For each size, five independent simulations of ten thousand 511 keV gamma-rays were triggered at a fixed distance of 10 mm. The crystal chosen was PbWO4. Its scintillation properties were simulated, but only Cherenkov photons were analyzed. Photodetectors were simulated having perfect photodetection efficiency and infinite time resolution. For every generated particle, the analysis considered its creation process, parent and daughter particles, energy, origin coordinates, trajectory, and time and position of detection. The DOI determination is based on the distribution of the emission time of all photons per event. These values are calculated as a function of the coordinates of detection and origin for every photon. The common origin is estimated by finding the distribution with the most similar emission time-points. RESULTS: Detection efficiency increases with crystal size from 8.2% (1 * 1 * 1 mm(3)) to 58.6% (10 * 10 * 10 mm(3)) and decreases applying a photon detection threshold of 5/10/20 photons to 6.3%/4.3%/0.7% and 49.3%/30.4%/2.8%, respectively. The detection rate in the six photodetectors is uniform due to the nearly isotropic cone emission. Most cones originated after a photoelectric effect interaction, with two dominating peaks for the kinetic energy of the electron at 422.99 and 441.47 keV. The detection distance between same-event photons defines the spatial resolution of the detector required for individual photon recognition, with 20% of the detected photons having their closest neighbor within a distance of 5% of the length of the cube. Same-event photons are detected within a time window whose width is determined by the crystal size, with values of 30 and 150 ps for a 1 * 1 * 1 mm(3) and a 10 * 10 * 10 mm(3) cube, respectively. The DOI reconstruction has an accuracy of approximately 23% of the length of the cube, with an average value of 2.2 mm for a 10 * 10 * 10 mm(3) CHERENCUBE. CONCLUSIONS: The proposed concept requires a detector with high photodetection efficiency. The structure of the sensitive surface of the detector should be a two dimensional array of microcells, able to provide individual detection coordinates and time stamps. The microcell size determines the ability to recognize individual photons, influencing detection efficiency. The 3D DOI recognition relies on the accuracy of the time stamps and detection coordinates, without the need for a recognition of the projected patterns of photons. The refractive index of the material defines a detector intrinsic energy-based rejection of scattered PET events at the cost of reduced sensitivity. PMID- 25832072 TI - Effects of CT-based attenuation correction of rat microSPECT images on relative myocardial perfusion and quantitative tracer uptake. AB - PURPOSE: Our goal in this work was to investigate the impact of CT-based attenuation correction on measurements of rat myocardial perfusion with (99m)Tc and (201)Tl single photon emission computed tomography (SPECT). METHODS: Eight male Sprague-Dawley rats were injected with (99m)Tc-tetrofosmin and scanned in a small animal pinhole SPECT/CT scanner. Scans were repeated weekly over a period of 5 weeks. Eight additional rats were injected with (201)Tl and also scanned following a similar protocol. The images were reconstructed with and without attenuation correction, and the relative perfusion was analyzed with the commercial cardiac analysis software. The absolute uptake of (99m)Tc in the heart was also quantified with and without attenuation correction. RESULTS: For (99m)Tc imaging, relative segmental perfusion changed by up to +2.1%/-1.8% as a result of attenuation correction. Relative changes of +3.6%/-1.0% were observed for the (201)Tl images. Interscan and inter-rat reproducibilities of relative segmental perfusion were 2.7% and 3.9%, respectively, for the uncorrected (99m)Tc scans, and 3.6% and 4.3%, respectively, for the (201)Tl scans, and were not significantly affected by attenuation correction for either tracer. Attenuation correction also significantly increased the measured absolute uptake of tetrofosmin and significantly altered the relationship between the rat weight and tracer uptake. CONCLUSIONS: Our results show that attenuation correction has a small but statistically significant impact on the relative perfusion measurements in some segments of the heart and does not adversely affect reproducibility. Attenuation correction had a small but statistically significant impact on measured absolute tracer uptake. PMID- 25832074 TI - Adaptive beamlet-based finite-size pencil beam dose calculation for independent verification of IMRT and VMAT. AB - PURPOSE: The use of sophisticated dose calculation procedure in modern radiation therapy treatment planning is inevitable in order to account for complex treatment fields created by multileaf collimators (MLCs). As a consequence, independent volumetric dose verification is time consuming, which affects the efficiency of clinical workflow. In this study, the authors present an efficient adaptive beamlet-based finite-size pencil beam (AB-FSPB) dose calculation algorithm that minimizes the computational procedure while preserving the accuracy. METHODS: The computational time of finite-size pencil beam (FSPB) algorithm is proportional to the number of infinitesimal and identical beamlets that constitute an arbitrary field shape. In AB-FSPB, dose distribution from each beamlet is mathematically modeled such that the sizes of beamlets to represent an arbitrary field shape no longer need to be infinitesimal nor identical. As a result, it is possible to represent an arbitrary field shape with combinations of different sized and minimal number of beamlets. In addition, the authors included the model parameters to consider MLC for its rounded edge and transmission. RESULTS: Root mean square error (RMSE) between treatment planning system and conventional FSPB on a 10 * 10 cm(2) square field using 10 * 10, 2.5 * 2.5, and 0.5 * 0.5 cm(2) beamlet sizes were 4.90%, 3.19%, and 2.87%, respectively, compared with RMSE of 1.10%, 1.11%, and 1.14% for AB-FSPB. This finding holds true for a larger square field size of 25 * 25 cm(2), where RMSE for 25 * 25, 2.5 * 2.5, and 0.5 * 0.5 cm(2) beamlet sizes were 5.41%, 4.76%, and 3.54% in FSPB, respectively, compared with RMSE of 0.86%, 0.83%, and 0.88% for AB-FSPB. It was found that AB-FSPB could successfully account for the MLC transmissions without major discrepancy. The algorithm was also graphical processing unit (GPU) compatible to maximize its computational speed. For an intensity modulated radiation therapy (~12 segments) and a volumetric modulated arc therapy fields (~90 control points) with a 3D grid size of 2.0 * 2.0 * 2.0 mm(3), dose was computed within 3-5 and 10-15 s timeframe, respectively. CONCLUSIONS: The authors have developed an efficient adaptive beamlet-based pencil beam dose calculation algorithm. The fast computation nature along with GPU compatibility has shown better performance than conventional FSPB. This enables the implementation of AB FSPB in the clinical environment for independent volumetric dose verification. PMID- 25832075 TI - Estimated dose rates to members of the public from external exposure to patients with 131I thyroid treatment. AB - PURPOSE: Estimated dose rates that may result from exposure to patients who had been administered iodine-131 ((131)I) as part of medical therapy were calculated. These effective dose rate estimates were compared with simplified assumptions under United States Nuclear Regulatory Commission Regulatory Guide 8.39, which does not consider body tissue attenuation nor time-dependent redistribution and excretion of the administered (131)I. METHODS: Dose rates were estimated for members of the public potentially exposed to external irradiation from patients recently treated with (131)I. Tissue attenuation and iodine biokinetics were considered in the patient in a larger comprehensive effort to improve external dose rate estimates. The external dose rate estimates are based on Monte Carlo simulations using the Phantom with Movable Arms and Legs (PIMAL), previously developed by Oak Ridge National Laboratory and the United States Nuclear Regulatory Commission. PIMAL was employed to model the relative positions of the (131)I patient and members of the public in three exposure scenarios: (1) traveling on a bus in a total of six seated or standing permutations, (2) two nursing home cases where a caregiver is seated at 30 cm from the patient's bedside and a nursing home resident seated 250 cm away from the patient in an adjacent bed, and (3) two hotel cases where the patient and a guest are in adjacent rooms with beds on opposite sides of the common wall, with the patient and guest both in bed and either seated back-to-back or lying head to head. The biokinetic model predictions of the retention and distribution of (131)I in the patient assumed a single voiding of urinary bladder contents that occurred during the trip at 2, 4, or 8 h after (131)I administration for the public transportation cases, continuous first-order voiding for the nursing home cases, and regular periodic voiding at 4, 8, or 12 h after administration for the hotel room cases. Organ specific activities of (131)I in the thyroid, bladder, and combined remaining tissues were calculated as a function of time after administration. Exposures to members of the public were considered for (131)I patients with normal thyroid uptake (peak thyroid uptake of ~27% of administered (131)I), differentiated thyroid cancer (DTC, 5% uptake), and hyperthyroidism (80% uptake). RESULTS: The scenario with the patient seated behind the member of the public yielded the highest dose rate estimate of seated public transportation exposure cases. The dose rate to the adjacent room guest was highest for the exposure scenario in which the hotel guest and patient are seated by a factor of ~4 for the normal and differentiated thyroid cancer uptake cases and by a factor of ~3 for the hyperthyroid case. CONCLUSIONS: It was determined that for all modeled cases, the DTC case yielded the lowest external dose rates, whereas the hyperthyroid case yielded the highest dose rates. In estimating external dose to members of the public from patients with (131)I therapy, consideration must be given to (patient- and case-specific) administered (131)I activities and duration of exposure for a more complete estimate. The method implemented here included a detailed calculation model, which provides a means to determine dose rate estimates for a range of scenarios. The method was demonstrated for variations of three scenarios, showing how dose rates are expected to vary with uptake, voiding pattern, and patient location. PMID- 25832076 TI - Dose domain regularization of MLC leaf patterns for highly complex IMRT plans. AB - PURPOSE: The advent of automated beam orientation and fluence optimization enables more complex intensity modulated radiation therapy (IMRT) planning using an increasing number of fields to exploit the expanded solution space. This has created a challenge in converting complex fluences to robust multileaf collimator (MLC) segments for delivery. A novel method to regularize the fluence map and simplify MLC segments is introduced to maximize delivery efficiency, accuracy, and plan quality. METHODS: In this work, we implemented a novel approach to regularize optimized fluences in the dose domain. The treatment planning problem was formulated in an optimization framework to minimize the segmentation-induced dose distribution degradation subject to a total variation regularization to encourage piecewise smoothness in fluence maps. The optimization problem was solved using a first-order primal-dual algorithm known as the Chambolle-Pock algorithm. Plans for 2 GBM, 2 head and neck, and 2 lung patients were created using 20 automatically selected and optimized noncoplanar beams. The fluence was first regularized using Chambolle-Pock and then stratified into equal steps, and the MLC segments were calculated using a previously described level reducing method. Isolated apertures with sizes smaller than preset thresholds of 1-3 bixels, which are square units of an IMRT fluence map from MLC discretization, were removed from the MLC segments. Performance of the dose domain regularized (DDR) fluences was compared to direct stratification and direct MLC segmentation (DMS) of the fluences using level reduction without dose domain fluence regularization. RESULTS: For all six cases, the DDR method increased the average planning target volume dose homogeneity (D95/D5) from 0.814 to 0.878 while maintaining equivalent dose to organs at risk (OARs). Regularized fluences were more robust to MLC sequencing, particularly to the stratification and small aperture removal. The maximum and mean aperture sizes using the DDR were consistently larger than those from DMS for all tested number of segments. CONCLUSIONS: The fluence map to MLC segmentation conversion problem was formulated as a secondary optimization problem in the dose domain to minimize the smoothness-regularized dose discrepancy. The large scale optimization problem was solved using a primal-dual algorithm that transformed complicated fluences into maps that were more robust to the MLC segmentation and sequencing, affording fewer and larger segments with minimal degradation to dose distribution. PMID- 25832077 TI - Dose ratio proton radiography using the proximal side of the Bragg peak. AB - PURPOSE: In recent years, there has been a movement toward single-detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single-detector technique is the dose ratio method in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp falloff. The authors investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak. METHODS: Using the analytical approximation for the Bragg peak, the authors generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, the authors were able to generate lookup graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these lookup graphs, the authors investigated the applicability of the technique for a range of patient treatment sites. The authors validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam. RESULTS: Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation, it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm(2), for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root-mean-square-error of 1.6 mm WET. The noise in the measured images was found to be sigma = 1.2% (standard deviation) and theoretical predictions with a 1.96sigma noise level showed good agreement with the measured errors. CONCLUSIONS: After validating the theoretical approach with measurements, the authors have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains. PMID- 25832078 TI - Spectra of clinical CT scanners using a portable Compton spectrometer. AB - PURPOSE: Spectral information of the output of x-ray tubes in (dual source) computer tomography (CT) scanners can be used to improve the conversion of CT numbers to proton stopping power and can be used to advantage in CT scanner quality assurance. The purpose of this study is to design, validate, and apply a compact portable Compton spectrometer that was constructed to accurately measure x-ray spectra of CT scanners. METHODS: In the design of the Compton spectrometer, the shielding materials were carefully chosen and positioned to reduce background by x-ray fluorescence from the materials used. The spectrum of Compton scattered x-rays alters from the original source spectrum due to various physical processes. Reconstruction of the original x-ray spectrum from the Compton scattered spectrum is based on Monte Carlo simulations of the processes involved. This reconstruction is validated by comparing directly and indirectly measured spectra of a mobile x-ray tube. The Compton spectrometer is assessed in a clinical setting by measuring x-ray spectra at various tube voltages of three different medical CT scanner x-ray tubes. RESULTS: The directly and indirectly measured spectra are in good agreement (their ratio being 0.99) thereby validating the reconstruction method. The measured spectra of the medical CT scanners are consistent with theoretical spectra and spectra obtained from the x ray tube manufacturer. CONCLUSIONS: A Compton spectrometer has been successfully designed, constructed, validated, and applied in the measurement of x-ray spectra of CT scanners. These measurements show that our compact Compton spectrometer can be rapidly set-up using the alignment lasers of the CT scanner, thereby enabling its use in commissioning, troubleshooting, and, e.g., annual performance check ups of CT scanners. PMID- 25832079 TI - Spatially constrained incoherent motion method improves diffusion-weighted MRI signal decay analysis in the liver and spleen. AB - PURPOSE: To evaluate the effect of the spatially constrained incoherent motion (SCIM) method on improving the precision and robustness of fast and slow diffusion parameter estimates from diffusion-weighted MRI in liver and spleen in comparison to the independent voxel-wise intravoxel incoherent motion (IVIM) model. METHODS: We collected diffusion-weighted MRI (DW-MRI) data of 29 subjects (5 healthy subjects and 24 patients with Crohn's disease in the ileum). We evaluated parameters estimates' robustness against different combinations of b values (i.e., 4 b-values and 7 b-values) by comparing the variance of the estimates obtained with the SCIM and the independent voxel-wise IVIM model. We also evaluated the improvement in the precision of parameter estimates by comparing the coefficient of variation (CV) of the SCIM parameter estimates to that of the IVIM. RESULTS: The SCIM method was more robust compared to IVIM (up to 70% in liver and spleen) for different combinations of b-values. Also, the CV values of the parameter estimations using the SCIM method were significantly lower compared to repeated acquisition and signal averaging estimated using IVIM, especially for the fast diffusion parameter in liver (CVIV IM = 46.61 +/- 11.22, CVSCIM = 16.85 +/- 2.160, p < 0.001) and spleen (CVIV IM = 95.15 +/- 19.82, CVSCIM = 52.55 +/- 1.91, p < 0.001). CONCLUSIONS: The SCIM method characterizes fast and slow diffusion more precisely compared to the independent voxel-wise IVIM model fitting in the liver and spleen. PMID- 25832080 TI - Improvement of registration accuracy in accelerated partial breast irradiation using the point-based rigid-body registration algorithm for patients with implanted fiducial markers. AB - PURPOSE: To investigate image-registration errors when using fiducial markers with a manual method and the point-based rigid-body registration (PRBR) algorithm in accelerated partial breast irradiation (APBI) patients, with accompanying fiducial deviations. METHODS: Twenty-two consecutive patients were enrolled in a prospective trial examining 10-fraction APBI. Titanium clips were implanted intraoperatively around the seroma in all patients. For image-registration, the positions of the clips in daily kV x-ray images were matched to those in the planning digitally reconstructed radiographs. Fiducial and gravity registration errors (FREs and GREs, respectively), representing resulting misalignments of the edge and center of the target, respectively, were compared between the manual and algorithm-based methods. RESULTS: In total, 218 fractions were evaluated. Although the mean FRE/GRE values for the manual and algorithm-based methods were within 3 mm (2.3/1.7 and 1.3/0.4 mm, respectively), the percentages of fractions where FRE/GRE exceeded 3 mm using the manual and algorithm-based methods were 18.8%/7.3% and 0%/0%, respectively. Manual registration resulted in 18.6% of patients with fractions of FRE/GRE exceeding 5 mm. The patients with larger clip deviation had significantly more fractions showing large FRE/GRE using manual registration. CONCLUSIONS: For image-registration using fiducial markers in APBI, the manual registration results in more fractions with considerable registration error due to loss of fiducial objectivity resulting from their deviation. The authors recommend the PRBR algorithm as a safe and effective strategy for accurate, image-guided registration and PTV margin reduction. PMID- 25832081 TI - Determination of the optimal tolerance for MLC positioning in sliding window and VMAT techniques. AB - PURPOSE: Several authors have recommended a 2 mm tolerance for multileaf collimator (MLC) positioning in sliding window treatments. In volumetric modulated arc therapy (VMAT) treatments, however, the optimal tolerance for MLC positioning remains unknown. In this paper, the authors present the results of a multicenter study to determine the optimal tolerance for both techniques. METHODS: The procedure used is based on dynalog file analysis. The study was carried out using seven Varian linear accelerators from five different centers. Dynalogs were collected from over 100,000 clinical treatments and in-house software was used to compute the number of tolerance faults as a function of the user-defined tolerance. Thus, the optimal value for this tolerance, defined as the lowest achievable value, was investigated. RESULTS: Dynalog files accurately predict the number of tolerance faults as a function of the tolerance value, especially for low fault incidences. All MLCs behaved similarly and the Millennium120 and the HD120 models yielded comparable results. In sliding window techniques, the number of beams with an incidence of hold-offs >1% rapidly decreases for a tolerance of 1.5 mm. In VMAT techniques, the number of tolerance faults sharply drops for tolerances around 2 mm. For a tolerance of 2.5 mm, less than 0.1% of the VMAT arcs presented tolerance faults. CONCLUSIONS: Dynalog analysis provides a feasible method for investigating the optimal tolerance for MLC positioning in dynamic fields. In sliding window treatments, the tolerance of 2 mm was found to be adequate, although it can be reduced to 1.5 mm. In VMAT treatments, the typically used 5 mm tolerance is excessively high. Instead, a tolerance of 2.5 mm is recommended. PMID- 25832082 TI - Lung dynamic MRI deblurring using low-rank decomposition and dictionary learning. AB - PURPOSE: Lung dynamic MRI (dMRI) has emerged to be an appealing tool to quantify lung motion for both planning and treatment guidance purposes. However, this modality can result in blurry images due to intrinsically low signal-to-noise ratio in the lung and spatial/temporal interpolation. The image blurring could adversely affect the image processing that depends on the availability of fine landmarks. The purpose of this study is to reduce dMRI blurring using image postprocessing. METHODS: To enhance the image quality and exploit the spatiotemporal continuity of dMRI sequences, a low-rank decomposition and dictionary learning (LDDL) method was employed to deblur lung dMRI and enhance the conspicuity of lung blood vessels. Fifty frames of continuous 2D coronal dMRI frames using a steady state free precession sequence were obtained from five subjects including two healthy volunteer and three lung cancer patients. In LDDL, the lung dMRI was decomposed into sparse and low-rank components. Dictionary learning was employed to estimate the blurring kernel based on the whole image, low-rank or sparse component of the first image in the lung MRI sequence. Deblurring was performed on the whole image sequences using deconvolution based on the estimated blur kernel. The deblurring results were quantified using an automated blood vessel extraction method based on the classification of Hessian matrix filtered images. Accuracy of automated extraction was calculated using manual segmentation of the blood vessels as the ground truth. RESULTS: In the pilot study, LDDL based on the blurring kernel estimated from the sparse component led to performance superior to the other ways of kernel estimation. LDDL consistently improved image contrast and fine feature conspicuity of the original MRI without introducing artifacts. The accuracy of automated blood vessel extraction was on average increased by 16% using manual segmentation as the ground truth. CONCLUSIONS: Image blurring in dMRI images can be effectively reduced using a low-rank decomposition and dictionary learning method using kernels estimated by the sparse component. PMID- 25832083 TI - Monte Carlo simulation of PET and SPECT imaging of 90Y. AB - PURPOSE: Yittrium-90 ((90)Y) is traditionally thought of as a pure beta emitter, and is used in targeted radionuclide therapy, with imaging performed using bremsstrahlung single-photon emission computed tomography (SPECT). However, because (90)Y also emits positrons through internal pair production with a very small branching ratio, positron emission tomography (PET) imaging is also available. Because of the insufficient image quality of (90)Y bremsstrahlung SPECT, PET imaging has been suggested as an alternative. In this paper, the authors present the Monte Carlo-based simulation-reconstruction framework for (90)Y to comprehensively analyze the PET and SPECT imaging techniques and to quantitatively consider the disadvantages associated with them. METHODS: Our PET and SPECT simulation modules were developed using Monte Carlo simulation of Electrons and Photons (MCEP), developed by Dr. S. Uehara. PET code (MCEP-PET) generates a sinogram, and reconstructs the tomography image using a time-of flight ordered subset expectation maximization (TOF-OSEM) algorithm with attenuation compensation. To evaluate MCEP-PET, simulated results of (18)F PET imaging were compared with the experimental results. The results confirmed that MCEP-PET can simulate the experimental results very well. The SPECT code (MCEP SPECT) models the collimator and NaI detector system, and generates the projection images and projection data. To save the computational time, the authors adopt the prerecorded (90)Y bremsstrahlung photon data calculated by MCEP. The projection data are also reconstructed using the OSEM algorithm. The authors simulated PET and SPECT images of a water phantom containing six hot spheres filled with different concentrations of (90)Y without background activity. The amount of activity was 163 MBq, with an acquisition time of 40 min. RESULTS: The simulated (90)Y-PET image accurately simulated the experimental results. PET image is visually superior to SPECT image because of the low background noise. The simulation reveals that the detected photon number in SPECT is comparable to that of PET, but the large fraction (approximately 75%) of scattered and penetration photons contaminates SPECT image. The lower limit of (90)Y detection in SPECT image was approximately 200 kBq/ml, while that in PET image was approximately 100 kBq/ml. CONCLUSIONS: By comparing the background noise level and the image concentration profile of both the techniques, PET image quality was determined to be superior to that of bremsstrahlung SPECT. The developed simulation codes will be very useful in the future investigations of PET and bremsstrahlung SPECT imaging of (90)Y. PMID- 25832084 TI - Validation of an in-vivo proton beam range check method in an anthropomorphic pelvic phantom using dose measurements. AB - PURPOSE: In-vivo dosimetry and beam range verification in proton therapy could play significant role in proton treatment validation and improvements. In-vivo beam range verification, in particular, could enable new treatment techniques one of which could be the use of anterior fields for prostate treatment instead of opposed lateral fields as in current practice. This paper reports validation study of an in-vivo range verification method which can reduce the range uncertainty to submillimeter levels and potentially allow for in-vivo dosimetry. METHODS: An anthropomorphic pelvic phantom is used to validate the clinical potential of the time-resolved dose method for range verification in the case of prostrate treatment using range modulated anterior proton beams. The method uses a 3 * 4 matrix of 1 mm diodes mounted in water balloon which are read by an ADC system at 100 kHz. The method is first validated against beam range measurements by dose extinction measurements. The validation is first completed in water phantom and then in pelvic phantom for both open field and treatment field configurations. Later, the beam range results are compared with the water equivalent path length (WEPL) values computed from the treatment planning system XIO. RESULTS: Beam range measurements from both time-resolved dose method and the dose extinction method agree with submillimeter precision in water phantom. For the pelvic phantom, when discarding two of the diodes that show sign of significant range mixing, the two methods agree with +/-1 mm. Only a dose of 7 mGy is sufficient to achieve this result. The comparison to the computed WEPL by the treatment planning system (XIO) shows that XIO underestimates the protons beam range. Quantifying the exact XIO range underestimation depends on the strategy used to evaluate the WEPL results. To our best evaluation, XIO underestimates the treatment beam range between a minimum of 1.7% and maximum of 4.1%. CONCLUSIONS: Time-resolved dose measurement method satisfies the two basic requirements, WEPL accuracy and minimum dose, necessary for clinical use, thus, its potential for in-vivo protons range verification. Further development is needed, namely, devising a workflow that takes into account the limits imposed by proton range mixing and the susceptibility of the comparison of measured and expected WEPLs to errors on the detector positions. The methods may also be used for in-vivo dosimetry and could benefit various proton therapy treatments. PMID- 25832085 TI - Cardiorespiratory motion-compensated micro-CT image reconstruction using an artifact model-based motion estimation. AB - PURPOSE: Cardiac in vivo micro-CT imaging of small animals typically requires double gating due to long scan times and high respiratory rates. The simultaneous respiratory and cardiac gating can either be done prospectively or retrospectively. In any case, for true 5D imaging, i.e., three spatial dimensions plus one respiratory-temporal dimension plus one cardiac temporal dimension, the amount of information corresponding to a given respiratory and cardiac phase is orders of magnitude lower than the total amount of information acquired. Achieving similar image quality for 5D than for usual 3D investigations would require increasing the amount of data and thus the applied dose to the animal. Therefore, the goal is phase-correlated imaging with high image quality but without increasing the dose level. METHODS: To achieve this, the authors propose a new image reconstruction algorithm that makes use of all available projection data, also of that corresponding to other motion windows. In particular, the authors apply a motion-compensated image reconstruction approach that sequentially compensates for respiratory and cardiac motion to decrease the impact of sparsification. In that process, all projection data are used no matter which motion phase they were acquired in. Respiratory and cardiac motion are compensated for by using motion vector fields. These motion vector fields are estimated from initial phase-correlated reconstructions based on a deformable registration approach. To decrease the sensitivity of the registration to sparse view artifacts, an artifact model-based approach is used including a cyclic consistent nonrigid registration algorithm. RESULTS: The preliminary results indicate that the authors' approach removes the sparse-view artifacts of conventional phase-correlated reconstructions while maintaining temporal resolution. In addition, it achieves noise levels and spatial resolution comparable to that of nongated reconstructions due to the improved dose usage. By using the proposed motion estimation, no sensitivity to streaking artifacts has been observed. CONCLUSIONS: Using sequential double gating combined with artifact model-based motion estimation allows to accurately estimate respiratory and cardiac motion from highly undersampled data. No sensitivity to streaking artifacts introduced by sparse angular sampling has been observed for the investigated dose levels. The motion-compensated image reconstruction was able to correct for both, respiratory and cardiac motion, by applying the estimated motion vector fields. The administered dose per animal can thus be reduced for 5D imaging allowing for longitudinal studies at the highest image quality. PMID- 25832086 TI - Slit-scanning differential x-ray phase-contrast mammography: proof-of-concept experimental studies. AB - PURPOSE: The purpose of this work is to investigate the feasibility of grating based, differential phase-contrast, full-field digital mammography (FFDM) in terms of the requirements for field-of-view (FOV), mechanical stability, and scan time. METHODS: A rigid, actuator-free Talbot interferometric unit was designed and integrated into a state-of-the-art x-ray slit-scanning mammography system, namely, the Philips MicroDose L30 FFDM system. A dedicated phase-acquisition and phase retrieval method was developed and implemented that exploits the redundancy of the data acquisition inherent to the slit-scanning approach to image generation of the system. No modifications to the scan arm motion control were implemented. RESULTS: The authors achieve a FOV of 160 * 196 mm consisting of two disjoint areas measuring 77 * 196 mm with a gap of 6 mm between them. Typical scanning times vary between 10 and 15 s and dose levels are lower than typical FFDM doses for conventional scans with identical acquisition parameters due to the presence of the source-grating G0. Only minor to moderate artifacts are observed in the three reconstructed images, indicating that mechanical vibrations induced by other system components do not prevent the use of the platform for phase contrast imaging. CONCLUSIONS: To the best of our knowledge, this is the first attempt to integrate x-ray gratings hardware into a clinical mammography unit. The results demonstrate that a scanning differential phase contrast FFDM system that meets the requirements of FOV, stability, scan time, and dose can be build. PMID- 25832087 TI - Fiber-optic detector for real time dosimetry of a micro-planar x-ray beam. AB - PURPOSE: Here, the authors describe a dosimetry measurement technique for microbeam radiation therapy using a nanoparticle-terminated fiber-optic dosimeter (nano-FOD). METHODS: The nano-FOD was placed in the center of a 2 cm diameter mouse phantom to measure the deep tissue dose and lateral beam profile of a planar x-ray microbeam. RESULTS: The continuous dose rate at the x-ray microbeam peak measured with the nano-FOD was 1.91 +/- 0.06 cGy s(-1), a value 2.7% higher than that determined via radiochromic film measurements (1.86 +/- 0.15 cGy s( 1)). The nano-FOD-determined lateral beam full-width half max value of 420 MUm exceeded that measured using radiochromic film (320 MUm). Due to the 8 degrees angle of the collimated microbeam and resulting volumetric effects within the scintillator, the profile measurements reported here are estimated to achieve a resolution of ~0.1 mm; however, for a beam angle of 0 degrees , the theoretical resolution would approach the thickness of the scintillator (~0.01 mm). CONCLUSIONS: This work provides proof-of-concept data and demonstrates that the novel nano-FOD device can be used to perform real-time dosimetry in microbeam radiation therapy to measure the continuous dose rate at the x-ray microbeam peak as well as the lateral beam shape. PMID- 25832088 TI - Evolution of spatial resolution in breast CT at UC Davis. AB - PURPOSE: Dedicated breast computed tomography (bCT) technology for the purpose of breast cancer screening has been a focus of research at UC Davis since the late 1990s. Previous studies have shown that improvement in spatial resolution characteristics of this modality correlates with greater microcalcification detection, a factor considered a potential limitation of bCT. The aim of this study is to improve spatial resolution as characterized by the modulation transfer function (MTF) via changes in the scanner hardware components and operational schema. METHODS: Four prototypes of pendant-geometry, cone-beam breast CT scanners were designed and developed spanning three generations of design evolution. To improve the system MTF in each bCT generation, modifications were made to the imaging components (x-ray tube and flat-panel detector), system geometry (source-to-isocenter and detector distance), and image acquisition parameters (technique factors, number of projections, system synchronization scheme, and gantry rotational speed). RESULTS: Characterization of different generations of bCT systems shows these modifications resulted in a 188% improvement of the limiting MTF properties from the first to second generation and an additional 110% from the second to third. The intrinsic resolution degradation in the azimuthal direction observed in the first generation was corrected by changing the acquisition from continuous to pulsed x-ray acquisition. Utilizing a high resolution detector in the third generation, along with modifications made in system geometry and scan protocol, resulted in a 125% improvement in limiting resolution. An additional 39% improvement was obtained by changing the detector binning mode from 2 * 2 to 1 * 1. CONCLUSIONS: These results underscore the advancement in spatial resolution characteristics of breast CT technology. The combined use of a pulsed x-ray system, higher resolution flat-panel detector and changing the scanner geometry and image acquisition logic resulted in a significant fourfold improvement in MTF. PMID- 25832089 TI - Continuous table acquisition MRI for radiotherapy treatment planning: distortion assessment with a new extended 3D volumetric phantom. AB - PURPOSE: Accurate geometry is required for radiotherapy treatment planning (RTP). When considering the use of magnetic resonance imaging (MRI) for RTP, geometric distortions observed in the acquired images should be considered. While scanner technology and vendor supplied correction algorithms provide some correction, large distortions are still present in images, even when considering considerably smaller scan lengths than those typically acquired with CT in conventional RTP. This study investigates MRI acquisition with a moving table compared with static scans for potential geometric benefits for RTP. METHODS: A full field of view (FOV) phantom (diameter 500 mm; length 513 mm) was developed for measuring geometric distortions in MR images over volumes pertinent to RTP. The phantom consisted of layers of refined plastic within which vitamin E capsules were inserted. The phantom was scanned on CT to provide the geometric gold standard and on MRI, with differences in capsule location determining the distortion. MRI images were acquired with two techniques. For the first method, standard static table acquisitions were considered. Both 2D and 3D acquisition techniques were investigated. With the second technique, images were acquired with a moving table. The same sequence was acquired with a static table and then with table speeds of 1.1 mm/s and 2 mm/s. All of the MR images acquired were registered to the CT dataset using a deformable B-spline registration with the resulting deformation fields providing the distortion information for each acquisition. RESULTS: MR images acquired with the moving table enabled imaging of the whole phantom length while images acquired with a static table were only able to image 50%-70% of the phantom length of 513 mm. Maximum distortion values were reduced across a larger volume when imaging with a moving table. Increased table speed resulted in a larger contribution of distortion from gradient nonlinearities in the through-plane direction and an increased blurring of capsule images, resulting in an apparent capsule volume increase by up to 170% in extreme axial FOV regions. Blurring increased with table speed and in the central regions of the phantom, geometric distortion was less for static table acquisitions compared to a table speed of 2 mm/s over the same volume. Overall, the best geometric accuracy was achieved with a table speed of 1.1 mm/s. CONCLUSIONS: The phantom designed enables full FOV imaging for distortion assessment for the purposes of RTP. MRI acquisition with a moving table extends the imaging volume in the z direction with reduced distortions which could be useful particularly if considering MR-only planning. If utilizing MR images to provide additional soft tissue information to the planning CT, standard acquisition sequences over a smaller volume would avoid introducing additional blurring or distortions from the through-plane table movement. PMID- 25832090 TI - Automatic learning-based beam angle selection for thoracic IMRT. AB - PURPOSE: The treatment of thoracic cancer using external beam radiation requires an optimal selection of the radiation beam directions to ensure effective coverage of the target volume and to avoid unnecessary treatment of normal healthy tissues. Intensity modulated radiation therapy (IMRT) planning is a lengthy process, which requires the planner to iterate between choosing beam angles, specifying dose-volume objectives and executing IMRT optimization. In thorax treatment planning, where there are no class solutions for beam placement, beam angle selection is performed manually, based on the planner's clinical experience. The purpose of this work is to propose and study a computationally efficient framework that utilizes machine learning to automatically select treatment beam angles. Such a framework may be helpful for reducing the overall planning workload. METHODS: The authors introduce an automated beam selection method, based on learning the relationships between beam angles and anatomical features. Using a large set of clinically approved IMRT plans, a random forest regression algorithm is trained to map a multitude of anatomical features into an individual beam score. An optimization scheme is then built to select and adjust the beam angles, considering the learned interbeam dependencies. The validity and quality of the automatically selected beams evaluated using the manually selected beams from the corresponding clinical plans as the ground truth. RESULTS: The analysis included 149 clinically approved thoracic IMRT plans. For a randomly selected test subset of 27 plans, IMRT plans were generated using automatically selected beams and compared to the clinical plans. The comparison of the predicted and the clinical beam angles demonstrated a good average correspondence between the two (angular distance 16.8 degrees +/- 10 degrees , correlation 0.75 +/- 0.2). The dose distributions of the semiautomatic and clinical plans were equivalent in terms of primary target volume coverage and organ at risk sparing and were superior over plans produced with fixed sets of common beam angles. The great majority of the automatic plans (93%) were approved as clinically acceptable by three radiation therapy specialists. CONCLUSIONS: The results demonstrated the feasibility of utilizing a learning-based approach for automatic selection of beam angles in thoracic IMRT planning. The proposed method may assist in reducing the manual planning workload, while sustaining plan quality. PMID- 25832091 TI - Feasibility and robustness of dose painting by numbers in proton therapy with contour-driven plan optimization. AB - PURPOSE: To prove the ability of protons to reproduce a dose gradient that matches a dose painting by numbers (DPBN) prescription in the presence of setup and range errors, by using contours and structure-based optimization in a commercial treatment planning system. METHODS: For two patients with head and neck cancer, voxel-by-voxel prescription to the target volume (GTVPET) was calculated from (18)FDG-PET images and approximated with several discrete prescription subcontours. Treatments were planned with proton pencil beam scanning. In order to determine the optimal plan parameters to approach the DPBN prescription, the effects of the scanning pattern, number of fields, number of subcontours, and use of range shifter were separately tested on each patient. Different constant scanning grids (i.e., spot spacing = Deltax = Deltay = 3.5, 4, and 5 mm) and uniform energy layer separation [4 and 5 mm WED (water equivalent distance)] were analyzed versus a dynamic and automatic selection of the spots grid. The number of subcontours was increased from 3 to 11 while the number of beams was set to 3, 5, or 7. Conventional PTV-based and robust clinical target volumes (CTV)-based optimization strategies were considered and their robustness against range and setup errors assessed. Because of the nonuniform prescription, ensuring robustness for coverage of GTVPET inevitably leads to overdosing, which was compared for both optimization schemes. RESULTS: The optimal number of subcontours ranged from 5 to 7 for both patients. All considered scanning grids achieved accurate dose painting (1% average difference between the prescribed and planned doses). PTV-based plans led to nonrobust target coverage while robust optimized plans improved it considerably (differences between worst-case CTV dose and the clinical constraint was up to 3 Gy for PTV-based plans and did not exceed 1 Gy for robust CTV-based plans). Also, only 15% of the points in the GTVPET (worst case) were above 5% of DPBN prescription for robust-optimized plans, while they were more than 50% for PTV plans. Low dose to organs at risk (OARs) could be achieved for both PTV and robust-optimized plans. CONCLUSIONS: DPBN in proton therapy is feasible with the use of a sufficient number subcontours, automatically generated scanning patterns, and no more than three beams are needed. Robust optimization ensured the required target coverage and minimal overdosing, while PTV-approach led to nonrobust plans with excessive overdose. Low dose to OARs can be achieved even in the presence of a high-dose escalation as in DPBN. PMID- 25832092 TI - Development and evaluation of a method of calibrating medical displays based on fixed adaptation. AB - PURPOSE: The purpose of this work was to develop and evaluate a new method for calibration of medical displays that includes the effect of fixed adaptation and by using equipment and luminance levels typical for a modern radiology department. METHODS: Low contrast sinusoidal test patterns were derived at nine luminance levels from 2 to 600 cd/m(2) and used in a two alternative forced choice observer study, where the adaptation level was fixed at the logarithmic average of 35 cd/m(2). The contrast sensitivity at each luminance level was derived by establishing a linear relationship between the ten pattern contrast levels used at every luminance level and a detectability index (d') calculated from the fraction of correct responses. A Gaussian function was fitted to the data and normalized to the adaptation level. The corresponding equation was used in a display calibration method that included the grayscale standard display function (GSDF) but compensated for fixed adaptation. In the evaluation study, the contrast of circular objects with a fixed pixel contrast was displayed using both calibration methods and was rated on a five-grade scale. Results were calculated using a visual grading characteristics method. Error estimations in both observer studies were derived using a bootstrap method. RESULTS: The contrast sensitivities for the darkest and brightest patterns compared to the contrast sensitivity at the adaptation luminance were 37% and 56%, respectively. The obtained Gaussian fit corresponded well with similar studies. The evaluation study showed a higher degree of equally distributed contrast throughout the luminance range with the calibration method compensated for fixed adaptation than for the GSDF. The two lowest scores for the GSDF were obtained for the darkest and brightest patterns. These scores were significantly lower than the lowest score obtained for the compensated GSDF. For the GSDF, the scores for all luminance levels were statistically separated from the average value; three were lower and two were higher. For the compensated GSDF, three of the scores could not be separated from the average value. CONCLUSIONS: An observer study using clinically relevant displays and luminance settings has demonstrated that the calibration of displays according to the GSDF causes the perceived contrast to be unevenly distributed when using displays with a high luminance range. As the luminance range increases, the perceived contrast in the dark and bright regions will be significantly lower than the perceived contrast in the middle of the luminance range. A new calibration method that includes the effect of fixed adaptation was developed and evaluated in an observer study and was found to distribute the contrast of the display more evenly throughout the grayscale than the GSDF. PMID- 25832093 TI - Semiautomatic segmentation of atherosclerotic carotid artery wall volume using 3D ultrasound imaging. AB - PURPOSE: Rupture of atherosclerotic plaques in the carotid artery has been implicated in 20% of strokes. 3D ultrasound (US) imaging is emerging as an attractive method to quantify plaque burden and track changes in plaque longitudinally over time. However, plaque segmentation from US images is challenging because of poor boundary contrast and shadowing. The objective of this study is to develop and evaluate a semiautomatic segmentation algorithm with a novel stopping criterion for segmenting outer wall boundary (OWB) and lumen intima boundary (LIB) of common, internal, and external carotid artery from 3D US images for quantifying the vessel wall volume (VWV). METHODS: 3D US image volumes were acquired from ten subjects with asymptomatic carotid stenoses. Volumes were acquired using a mechanically scanned linear probe, and the reconstructed volume consisted of 21 slices acquired at an interslice distance of 1 mm. The authors used distance regularized level set method with edge-based energy, region-based energy, smoothness energy, and a novel stopping criterion to segment the LIB and OWB of carotid artery. The algorithm was initialized by six user-selected points on the LIB and OWB in seven 2D cross-sectional slices in each volume. An ellipse fitting and a stopping boundary-based energy is proposed to smooth the OWB contour and to stop leaking of the evolving contour, respectively. The algorithm was compared against ground truth boundaries generated from manual segmentations. The dice similarity coefficient (DSC), Hausdorff distance (HD), and modified HD (MHD) were used as error metrics. RESULTS: The authors' proposed stopping boundary energy-based stopping criterion was compared with percentage change of area and change of the MHD between evolving contours at successive iterations stopping criteria. The performance of the proposed algorithm was better than other two stopping criteria and yielded mean of LIBDSC = 88.78%, OWBDSC = 94.81%, LIBMHD = 0.26 mm, OWBMHD = 0.25 mm, LIBHD = 0.74 mm, and OWBHD = 0.80 mm. The Bland-Altman plot and correlation coefficient (r = 0.99) indicated a high agreement between ground truth and algorithm-generated boundaries. The coefficient of variation (COV) and minimum detectable change of the VWV are 5.2% and 57.2 mm(3) (5.18% of mean VWV), calculated from repeated measurements of the VWV by algorithm. The mean absolute distance between corresponding points of the algorithm-generated and the ground truth boundaries was 0.25 mm. CONCLUSIONS: The authors have developed a semiautomatic segmentation algorithm for measuring the VWV of the carotid artery using 3D US images with reduced operator interaction and computational time and higher reproducibility using a commercially available 3D US transducer. Their method is a step forward toward routine longitudinal monitoring of 3D plaque progression. PMID- 25832094 TI - FEM design and simulation of a short, 10 MV, S-band Linac with Monte Carlo dose simulations. AB - PURPOSE: Current commercial 10 MV Linac waveguides are 1.5 m. The authors' current 6 MV linear accelerator-magnetic resonance imager (Linac-MR) system fits in typical radiotherapy vaults. To allow 10 MV treatments with the Linac-MR and still fit within typical vaults, the authors design a 10 MV Linac with an accelerator waveguide of the same length (27.5 cm) as current 6 MV Linacs. METHODS: The first design stage is to design a cavity such that a specific experimental measurement for breakdown is applicable to the cavity. This is accomplished through the use of finite element method (FEM) simulations to match published shunt impedance, Q factor, and ratio of peak to mean-axial electric field strength from an electric breakdown study. A full waveguide is then designed and tuned in FEM simulations based on this cavity design. Electron trajectories are computed through the resulting radio frequency fields, and the waveguide geometry is modified by shifting the first coupling cavity in order to optimize the electron beam properties until the energy spread and mean energy closely match values published for an emulated 10 MV Linac. Finally, Monte Carlo dose simulations are used to compare the resulting photon beam depth dose profile and penumbra with that produced by the emulated 10 MV Linac. RESULTS: The shunt impedance, Q factor, and ratio of peak to mean-axial electric field strength are all matched to within 0.1%. A first coupling cavity shift of 1.45 mm produces an energy spectrum width of 0.347 MeV, very close to the published value for the emulated 10 MV of 0.315 MeV, and a mean energy of 10.53 MeV, nearly identical to the published 10.5 MeV for the emulated 10 MV Linac. The depth dose profile produced by their new Linac is within 1% of that produced by the emulated 10 MV spectrum for all depths greater than 1.5 cm. The penumbra produced is 11% narrower, as measured from 80% to 20% of the central axis dose. CONCLUSIONS: The authors have successfully designed and simulated an S-band waveguide of length of 27.5 cm capable of producing a 10 MV photon beam. This waveguide operates well within the breakdown threshold determined for the cavity geometry used. The designed Linac produces depth dose profiles similar to those of the emulated 10 MV Linac (waveguide-length of 1.5 m) but yields a narrower penumbra. PMID- 25832096 TI - Regional radiation dose susceptibility within the parotid gland: effects on salivary loss and recovery. AB - PURPOSE: Xerostomia is one of the most likely late toxic effects of radiotherapy treatment in patients with head-and-neck cancers. Modern treatment techniques can incorporate knowledge of complication risk into treatment plans. To this end, the authors attempt to quantify the regional radiotherapy dose-dependence of salivary output loss and recovery in a prospective study. METHODS: Salivary output was collected from patients undergoing radiotherapy treatment for head-and-neck cancers at the BC Cancer Agency between February 2008 and May 2013. Regional dose dependence (i.e., dose susceptibility) of loss and recovery is quantified using nonparametric (Spearman's rank correlation coefficients, local linear regression) and parametric (least-sum of squares, least-median of squares) techniques. RESULTS: Salivary flow recovery was seen in 79 of 102 patients considered (p < 0.0001, Wilcoxon sign rank test). Output loss was strongly correlated with left- and right parotid combined dose phi = min (DL, 45 Gy) + min (DR, 45 Gy), and can be accurately predicted. Median early loss (three months) was 72% of baseline, while median overall loss (1 yr) was 56% of baseline. Fitting an exponential model to whole parotid yields dose sensitivities A3m = 0.0604 Gy(-1) and A1y = 0.0379 Gy(-1). Recovery was not significantly associated with dose. Hints of lateral organ sub-segment dose-response dimorphism were observed. CONCLUSIONS: Sub-segmentation appears to predict neither loss nor recovery with any greater precision than whole parotid mean dose, though it is not any worse. Sparing the parotid to a combined dose phi of <50 Gy is recommended for a patient to keep ~40% of baseline function and thus avoid severe xerostomia at 12 months post-treatment. It seems unlikely that a population's mean recovery will exceed 20%-30% of baseline output at 1 yr after radiotherapy treatment using current (whole-organ based) clinical guidelines. PMID- 25832095 TI - Predicting adenocarcinoma recurrence using computational texture models of nodule components in lung CT. AB - PURPOSE: To investigate the importance of presurgical computed tomography (CT) intensity and texture information from ground-glass opacities (GGO) and solid nodule components for the prediction of adenocarcinoma recurrence. METHODS: For this study, 101 patients with surgically resected stage I adenocarcinoma were selected. During the follow-up period, 17 patients had disease recurrence with six associated cancer-related deaths. GGO and solid tumor components were delineated on presurgical CT scans by a radiologist. Computational texture models of GGO and solid regions were built using linear combinations of steerable Riesz wavelets learned with linear support vector machines (SVMs). Unlike other traditional texture attributes, the proposed texture models are designed to encode local image scales and directions that are specific to GGO and solid tissue. The responses of the locally steered models were used as texture attributes and compared to the responses of unaligned Riesz wavelets. The texture attributes were combined with CT intensities to predict tumor recurrence and patient hazard according to disease-free survival (DFS) time. Two families of predictive models were compared: LASSO and SVMs, and their survival counterparts: Cox-LASSO and survival SVMs. RESULTS: The best-performing predictive model of patient hazard was associated with a concordance index (C-index) of 0.81 +/- 0.02 and was based on the combination of the steered models and CT intensities with survival SVMs. The same feature group and the LASSO model yielded the highest area under the receiver operating characteristic curve (AUC) of 0.8 +/- 0.01 for predicting tumor recurrence, although no statistically significant difference was found when compared to using intensity features solely. For all models, the performance was found to be significantly higher when image attributes were based on the solid components solely versus using the entire tumors (p < 3.08 * 10( 5)). CONCLUSIONS: This study constitutes a novel perspective on how to interpret imaging information from CT examinations by suggesting that most of the information related to adenocarcinoma aggressiveness is related to the intensity and morphological properties of solid components of the tumor. The prediction of adenocarcinoma relapse was found to have low specificity but very high sensitivity. Our results could be useful in clinical practice to identify patients for which no recurrence is expected with a very high confidence using a presurgical CT scan only. It also provided an accurate estimation of the risk of recurrence after a given duration t from surgical resection (i.e., C-index = 0.81 +/- 0.02). PMID- 25832097 TI - Theoretical investigation of the design and performance of a dual energy (kV and MV) radiotherapy imager. AB - PURPOSE: In modern radiotherapy treatment rooms, megavoltage (MV) portal imaging and kilovoltage (kV) cone-beam CT (CBCT) imaging are performed using various active matrix flat-panel imager (AMFPI) designs. To expand the clinical utility of MV and kV imaging, MV AMFPIs incorporating thick, segmented scintillators and, separately, kV imaging using a beam's eye view geometry have been investigated by a number of groups. Motivated by these previous studies, it is of interest to explore to what extent it is possible to preserve the benefits of kV and MV imaging using a single AMFPI design, given the considerably different x ray energy spectra used for kV and MV imaging. In this paper, considerations for the design of such a dual energy imager are explored through examination of the performance of a variety of hypothetical AMFPIs based on x ray converters employing segmented scintillators. METHODS: Contrast, noise, and contrast-to noise ratio performances were characterized through simulation modeling of CBCT imaging, while modulation transfer function, Swank factor, and signal performance were characterized through simulation modeling of planar imaging. The simulations were based on a previously reported hybrid modeling technique (accounting for both radiation and optical effects), augmented through modeling of electronic additive noise. All designs employed BGO scintillator material with thicknesses ranging from 0.25 to 4 cm and element-to-element pitches ranging from 0.508 to 1.016 mm. A series of studies were performed under both kV and MV imaging conditions to determine the most advantageous imager configuration (involving front or rear x ray illumination and use of a mirror or black reflector), converter design (pitch and thickness), and operating mode (pitch-binning combination). RESULTS: Under the assumptions of the present study, the most advantageous imager design was found to employ rear illumination of the converter in combination with a black reflector, incorporate a BGO converter with a 0.508 mm pitch and a 2 cm thickness, and operate at full resolution for kV imaging and 2 * 2 binning mode for MV imaging. Such a dual energy imager design should provide soft tissue visualization at low, clinically practical doses under MV conditions, while helping to preserve the high spatial resolution and high contrast offered by kV imaging. CONCLUSIONS: The authors' theoretical investigation suggests that a dual energy imager capable of largely preserving the desirable characteristics of both kV and MV imaging is feasible. Such an imager, when coupled to a dual energy radiation source, could facilitate simplification of current treatment room imaging systems (as well as their associated quality assurance), and facilitate more precise integration of kV and MV imaging information by virtue of reduced geometric uncertainties. PMID- 25832098 TI - Dosimetric characterization of a microDiamond detector in clinical scanned carbon ion beams. AB - PURPOSE: To investigate for the first time the dosimetric properties of a new commercial synthetic diamond detector (PTW microDiamond) in high-energy scanned clinical carbon ion beams generated by a synchrotron at the CNAO facility. METHODS: The detector response was evaluated in a water phantom with actively scanned carbon ion beams ranging from 115 to 380 MeV/u (30-250 mm Bragg peak depth in water). Homogeneous square fields of 3 * 3 and 6 * 6 cm(2) were used. Short- and medium-term (2 months) detector response stability, dependence on beam energy as well as ion type (carbon ions and protons), linearity with dose, and directional and dose-rate dependence were investigated. The depth dose curve of a 280 MeV/u carbon ion beam, scanned over a 3 * 3 cm(2) area, was measured with the microDiamond detector and compared to that measured using a PTW Advanced Markus ionization chamber, and also simulated using fluka Monte Carlo code. The detector response in two spread-out-Bragg-peaks (SOBPs), respectively, centered at 9 and 21 cm depths in water and calculated using the treatment planning system (TPS) used at CNAO, was measured. RESULTS: A negligible drift of detector sensitivity within the experimental session was seen, indicating that no detector preirradiation was needed. Short-term response reproducibility around 1% (1 standard deviation) was found. Only 2% maximum variation of microDiamond sensitivity was observed among all the evaluated proton and carbon ion beam energies. The detector response showed a good linear behavior. Detector sensitivity was found to be dose-rate independent, with a variation below 1.3% in the evaluated dose-rate range. A very good agreement between measured and simulated Bragg curves with both microDiamond and Advanced Markus chamber was found, showing a negligible LET dependence of the tested detector. A depth dose curve was also measured by positioning the microDiamond with its main axis oriented orthogonally to the beam direction. A strong distortion in Bragg peak measurement was observed, confirming manufacturer recommendation on avoiding such configuration. Very good results were obtained for SOBP measurements, with a difference below 1% between measured and TPS-calculated doses. The stability of detector sensitivity in the observation period was within the experimental uncertainty. CONCLUSIONS: Dosimetric characterization of a PTW microDiamond detector in high-energy scanned carbon ion beams was performed. The results of the present study showed that this detector is suitable for dosimetry of clinical carbon ion beams, with a negligible LET and dose-rate dependence. PMID- 25832099 TI - Comment on "Comparison of patient specific dose metrics between chest radiography, tomosynthesis, and CT for adult patients of wide ranging body habitus" [Med. Phys. 41(2), 023901 (12pp.) (2014)]. PMID- 25832100 TI - Comment on "A protocol for EBT3 radiochromic film dosimetry using reflection dosimetry using scanning" [Med. Phys. 41(12), 122101 (6pp.) (2014)]. PMID- 25832103 TI - Competition among native and invasive Impatiens species: the roles of environmental factors, population density and life stage. AB - Many invasive species are considered competitively superior to native species, with the strongest competition expected in species with similar niches and/or in closely related species. However, competition outcome is strongly context dependent as competitive strength varies along environmental gradients, and life stages, and also depends on abundances. To explore the importance of these factors, we examined competition effects in an experiment with three Impatiens species (Balsaminaceae) widespread in central Europe and sharing similar life history characteristics and habitats: the native I. noli-tangere, and two invasive species, I. parviflora and I. glandulifera. We compared their competitive strength and reciprocal impacts under two levels of water and light availability, two overall planting densities and three competitor densities. We assessed species performance (ability to complete the life-cycle, biomass and fecundity) and temporal competition dynamics in a garden pot experiment. Environmental variables had lower explanatory power than overall planting and competitor density, which indicates the importance of competitive interactions when evaluating plant performance and potential invasion success. Despite poor and delayed germination, the invasive I. glandulifera attained dominance even at a high competitor density and was competitively superior across all treatments, exceeding the height of both congeners. Impatiens parviflora was competitively weakest, having a negligible impact on both native I. noli-tangere and invasive I. glandulifera. The intermediate competitive strength of the native I. noli tangere probably results from its intermediate height, and good germination rate and timing. The difference in height among species increased during the experiment when I. glandulifera was involved; this species continues growing until autumn, enhancing its competitive superiority. The results provide a mechanistic understanding for the competitive exclusion of native I. noli-tangere that occurs in stands with I. glandulifera, but the limited impact of I. parviflora on I. noli-tangere in their mixed stands. PMID- 25832102 TI - Immunogenicity of reduced dose priming schedules of serogroup C meningococcal conjugate vaccine followed by booster at 12 months in infants: open label randomised controlled trial. AB - OBJECTIVE: To determine whether the immunogenicity of a single dose infant priming schedule of serogroup C meningococcal (MenC) conjugate vaccine is non inferior to a two dose priming schedule when followed by a booster dose at age 12 months. DESIGN: Phase IV open label randomised controlled trial carried out from July 2010 until August 2013 SETTING: Four centres in the United Kingdom and one centre in Malta. PARTICIPANTS: Healthy infants aged 6-12 weeks followed up until age 24 months. INTERVENTIONS: In the priming phase of the trial 509 infants were randomised in a 10:10:7:4 ratio into four groups to receive either a single MenC cross reacting material 197 (CRM) dose at 3 months; two doses of MenC-CRM at 3 and 4 months; a single MenC-polysaccharide-tetanus toxoid (TT) dose at 3 months; or no MenC doses, respectively. Haemophilus influenzae type b (Hib)-MenC-TT vaccine was administered to all infants at 12 months of age. All infants also received the nationally routinely recommended vaccines. Blood samples were taken at age 5, 12, 13, and 24 months. MAIN OUTCOME MEASURE: MenC serum bactericidal antibody assay with rabbit complement (rSBA) one month after the Hib-MenC-TT vaccine. Non-inferiority was met if the lower 95% confidence limit of the difference in the mean log10 MenC rSBA between the single dose MenC-CRM and the two dose MenC-CRM groups was >-0.35. RESULTS: The primary objective was met: after a Hib-MenC-TT booster dose at 12 months of age the MenC rSBA geometric mean titres induced in infants primed with a single MenC-CRM dose were not inferior to those induced in participants primed with two MenC-CRM doses in infancy (660 (95% confidence interval 498 to 876) v 295 (220 to 398)) with a corresponding difference in the mean log10 MenC rSBA of 0.35 (0.17 to 0.53) that showed superiority of the single over the two dose schedule). Exploration of differences between the priming schedules showed that one month after Hib-MenC-TT vaccination, MenC rSBA >= 1:8 was observed in >96% of participants previously primed with any of the MenC vaccine schedules in infancy and in 83% of those who were not vaccinated against MenC in infancy. The MenC rSBA geometric mean titres induced by the Hib-MenC-TT boost were significantly higher in children who were primed with one rather than two MenC-CRM doses in infancy. Only priming with MenC TT, however, induced robust MenC bactericidal antibody after the Hib-MenC-TT booster that persisted until 24 months of age. CONCLUSIONS: MenC vaccination programmes with two MenC infant priming doses could be reduced to a single priming dose without reducing post-boost antibody titres. When followed by a Hib MenC-TT booster dose, infant priming with a single MenC-TT vaccine dose induces a more robust antibody response than one or two infant doses of MenC-CRM. Bactericidal antibody induced by a single Hib-MenC-TT conjugate vaccine dose at 12 months of age (that is, a toddler only schedule), without infant priming, is not well sustained at 24 months. Because of rapid waning of MenC antibody, programmes using toddler only schedules will still need to rely on herd protection to protect infants and young children.Trial registration Eudract No: 2009-016579-31; NCT01129518; study ID: 2008_06 (http://clinicaltrials.gov). PMID- 25832104 TI - Effects of dose rates on radiation-induced replenishment of intestinal stem cells determined by Lgr5 lineage tracing. AB - An understanding of the dynamics of intestinal Lgr5(+) stem cells is important for elucidating the mechanism of colonic cancer development. We previously established a method for evaluating Lgr5(+) stem cells by tamoxifen-dependent Lgr5-lineage tracing and showed that high-dose-rate radiation stimulated replenishment of colonic stem cells. In this study, we evaluated the effects of low-dose-rate radiation on stem cell maintenance. Tamoxifen (4OHT)-injected Lgr5 EGFP-IRES-Cre(ERT2) * ROSA-LSL-LacZ mice were used, LacZ-labeled colonic crypts were enumerated, and the loss of LacZ(+) crypts under low-dose-rate radiation was estimated. After 4OHT treatment, the number of LacZ-labeled Lgr5(+) stem cells was higher in the colon of infant mice than in adult mice. The percentage of LacZ labeled crypts in infant mice rapidly decreased after 4OHT treatment. However, the percentage of labeled crypts plateaued at ~2% at 4 weeks post-treatment and remained unchanged for up to 7 months. Thus, it will be advantageous to evaluate the long-term effects of low-dose-rate radiation. Next, we determined the percentages of LacZ-labeled crypts irradiated with 1 Gy administered at different dose rates. As reported in our previous study, mice exposed to high-dose-rate radiation (30 Gy/h) showed a marked replenishment (P = 0.04). However, mice exposed to low-dose-rate radiation (0.003 Gy/h) did not exhibit accelerated stem cell replenishment (P = 0.47). These findings suggest the percentage of labeled crypts can serve as a useful indicator of the effects of dose rate on the stem cell pool. PMID- 25832105 TI - Antibiotic discovery goes underground: The discovery of teixobactin could revitalise the search for new antibiotics based on the novel method the researchers used to identify the compound. PMID- 25832106 TI - Redistribution of the intra-acrosomal EGFP before acrosomal exocytosis in mouse spermatozoa. AB - Mammalian spermatozoa must undergo complex physiological and morphological alterations within the female reproductive tract before they become fertilization competent. Two important alterations are capacitation and the acrosome reaction (AR), by which spermatozoa become capable of penetrating the zona pellucida (ZP) of the oocyte. Although various biochemical stimulants have been reported to induce the AR, the true physiological inducer in vivo remains to be identified. Previously, it has been reported that most fertilizing spermatozoa undergo the AR before contacting the ZP and that only a small fraction of in vitro-capacitated spermatozoa can penetrate the ZP. Therefore, it is important to identify which capacitating spermatozoa undergo the AR in response to potential AR inducers such as progesterone. Here we show that spermatozoa undergo a dynamic rearrangement of the acrosome during in vitro capacitation. This involves the rapid movement of an artificially introduced soluble component of the acrosome, enhanced green fluorescent protein (EGFP), from the acrosomal cap region to the equatorial segment (EQ) of the sperm head. Spermatozoa exhibiting the EQ pattern were more sensitive to progesterone than were those without it. We suggest that spermatozoa that are ready to undergo acrosomal exocytosis can be detected by real-time EGFP imaging. This offers a promising new method for identifying where spermatozoa undergo the AR in the female reproductive tract in vivo. PMID- 25832107 TI - Comparison of the in vitro susceptibility of rifaximin versus norfloxacin against multidrug resistant bacteria in a hospital setting. A proof-of-concept study for use in advanced cirrhosis. PMID- 25832108 TI - Secreted frizzled-related protein 4 predicts progression of autosomal dominant polycystic kidney disease. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common autosomal dominant condition associated with renal cysts and development of renal failure. With the availability of potential therapies, one major obstacle remains the lack of readily available parameters that identify patients at risk for disease progression and/or determine the efficacy of therapeutic interventions within short observation periods. Increased total kidney volume (TKV) correlates with disease progression, but it remains unknown how accurate this parameter can predict disease progression at early stages. METHODS: To identify additional parameters that help to stratify ADPKD patients, we measured secreted frizzled related protein 4 (sFRP4) serum concentrations at baseline and over the course of 18 months in 429 ADPKD patients. RESULTS: Serum creatinine and sFRP4 as well as TKV increased over time, and were significantly different from baseline values within 1 year. CONCLUSION: Elevated sFRP4 levels at baseline predicted a more rapid decline of renal function at 2, 3 and 5 years suggesting that sFRP4 serum levels may provide additional information to identify ADPKD patients at risk for rapid disease progression. PMID- 25832109 TI - Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. PMID- 25832110 TI - The 6-min walk test in pulmonary arterial hypertension: only for bad news? PMID- 25832111 TI - Therapeutic alliance in antidepressant treatment: cause or effect of symptomatic levels? AB - BACKGROUND: Previous studies have shown that in psychotherapy alliance is a predictor of symptomatic change, even while accounting for the temporal precedence between alliance and symptoms. However, the extent to which alliance predicts outcomes in psychopharmacology is yet to be fully investigated considering the fact that alliance can be the result, rather than the cause, of symptomatic change. The current prospective study examined whether the alliance predicts outcomes in psychopharmacology, while controlling for previous symptomatic change throughout the course of treatment. METHODS: Data from a psychopharmacological randomized controlled trial for the treatment of adult major depression (n = 42), including the patients' rating of the alliance with the physicians, were analyzed. Multilevel models controlling for autoregressive lag of the dependent variable were used in all analyses to examine the effect of alliance on outcome. RESULTS: The effect of alliance on outcome, while controlling for prior symptomatic levels, was significant and restricted to the middle phase of treatment (week 4, p = 0.005), when most of the reductions in symptoms were observed. Exploratory analyses of the differences between placebo and medication conditions suggest that the differences between the patients in their average alliance levels predicted a greater reduction in symptoms in the placebo compared to the medication conditions (p = 0.008). The main limitation is the small cohort size. CONCLUSIONS: The findings suggest an effect of alliance on outcome in psychopharmacology, which is not merely the result of previous symptomatic levels. This effect may be more robust in conditions that do not include active treatment (placebo), possibly serving as a compensatory effect. PMID- 25832112 TI - The effect of trimetazidine added to pharmacological treatment on all-cause mortality in patients with systolic heart failure. AB - The anti-ischemic agent trimetazidine (TMZ) added to pharmacological treatment appears to have positive effects on cardiac parameters of patients with heart failure (HF) as a result of specific antioxidant properties. OBJECTIVES: We aimed to verify whether the marked improvement provided by TMZ in echocardiographic and clinical parameters was likely to translate into reduced all-cause mortality in systolic HF patients. METHODS: Meta-analysis of available published prospective randomized controlled trial (RCT) data (1967-2014) retrieved from PubMed, Web of Science and Cochrane Collaboration. RESULTS: A total of 326 patients from 3 RCTs were analyzed: 164 who received TMZ on top of pharmacological HF therapy and 162 controls. Study durations ranged from 12 to 48 months. The analysis had no publication bias and the studies were homogeneous (p = 0.442, I(2) = 0). The results show a significant effect of TMZ on the reduction of all-cause mortality (RR = 0.283, p < 0.0001). The rate of events attributable to the drug was lower with TMZ than it was among control patients. CONCLUSION: This meta-analysis suggests that in patients with HF, TMZ given as an add-on therapy is likely to provide a protective effect, reduce all-cause mortality and increase event-free survival, and could be an effective and useful adjunct to our armamentarium for the treatment of HF patients. PMID- 25832113 TI - Is the Proportion of Patients Diagnosed with Synchronous Stage IV Breast Cancer Who Survive More than Two Years Increasing over Time? AB - BACKGROUND: Studies have shown a moderate increase in survival over time among patients with stage IV breast cancer. Median survival is approximately 2 years. The aim of this study was to evaluate trends over time in survival of >2 years of patients with synchronous stage IV disease. METHODS: Using the SEER (Surveillance, Epidemiology and End Results) registry, we identified patients with synchronous stage IV breast cancer diagnosed between 1990 and 2007. Patients were divided into 3 groups according to the year of diagnosis (1990-1995, 1996 2000, and 2001-2007). The probability of survival of >2 years was computed within each group of diagnosis years. A multivariate logistic regression model was then fit to determine the association between year of diagnosis and probability of surviving >2 years after adjusting for important prognostic factors. RESULTS: 22,601 patients were identified, of whom 9,435 (41.7%) had an overall survival of >2 years. The probability of breast cancer-specific survival (BCSS) of >2 years was 40.1, 44, and 48.1% among patients diagnosed in the periods 1990-1995, 1996 2000, and 2001-2007, respectively (p < 0.001). In the multivariate model, the probability of BCSS of >2 years increased with the more recent year of diagnosis (OR 1.058, 95% CI 1.046-1.069, p < 0.001). Other factors significantly associated with an increased probability of surviving >2 years included surgery of the primary tumor, lower grade, younger age, hormone receptor-positive disease, and noninflammatory disease. CONCLUSION: Our results indicate that among the patients with synchronous stage IV breast cancer, the probability of BCSS of >2 years in the US has increased over time. Attributable factors may be the increasing number of efficacious agents and improved palliative care services over time. PMID- 25832115 TI - Influence of olive oil phenolic compounds on headspace aroma release by interaction with whey proteins. AB - The release of volatile compounds in an oil-in-water model system obtained from olive oil-whey protein (WP) pairing was investigated by considering the effect of phenolic compounds. Human saliva was used to simulate mouth conditions by retronasal aroma simulator (RAS) analysis. Twelve aroma compounds were quantified in the dynamic headspace by SPME-GC/MS. The results showed significant influences of saliva on the aroma release of virgin olive oil (VOO) volatiles also in the presence of WP. The interaction between WP and saliva leads to lower headspace release of ethyl esters and hexanal. Salivary components caused lower decrease of the release of acetates and alcohols. A lower release of volatile compounds was found in the RAS essay in comparison to that in orthonasal simulation of only refined olive oil (without addition of saliva or WP), with the exception of hexanal and 1-penten-3-one, where a significantly higher release was found. Our results suggest that the extent of retronasal odor (green, pungent) of these two volatile compounds is higher than orthonasal odor. An extra VOO was used to verify the release in model systems, indicating that WP affected aroma release more than model systems, while saliva seems to exert an opposite trend. A significant increase in aroma release was found when phenolic compounds were added to the system, probably due to the contrasting effects of binding of volatile compounds caused by WP, for the polyphenol-protein interaction phenomenon. Our study could be applied to the formulation of new functional foods to enhance flavor release and modulate the presence and concentrations of phenolics and whey proteins in food emulsions/dispersions. PMID- 25832116 TI - Uncontrolled head oscillations in people with Parkinson's disease may reflect an inability to respond to perturbations while walking. AB - Fall injuries in people with Parkinson's disease (PD) are a major health problem. Increased sway while walking is a risk factor and further understanding of this destabilizing gait change may assist with rehabilitation and help prevent falls.Here, stride-to-stride head oscillations are used to help characterise different aspects of gait impairment in 10 people with PD on medication (67 years, SD 4), 10 healthy age-matched (HAM) participants (66 years, SD 7), and 10 young (30 years, SD 7). A wearable accelerometer was used to analyse head oscillations during five repeat 17 m walks by each participant.People with PD had significantly faster transverse plane head oscillations than the HAM or young groups; both along mediolateral (PD 47.2 cm s(-1), HAM 32.5 cm s(-1), and young 32.7 cm s(-1)) and anterioposterior axes (PD 33.3 cm s(-1), HAM 24.5 cm s(-1), and young 20.6 cm s(-1)). These differences were uncorrelated with reduced vertical oscillation velocity (PD 15.5 cm s(-1), HAM 18.8 cm s(-1), and young 20.1 cm s(-1)) and reduced walking speed (PD 1.2 m s(-1), HAM 1.4 m s(-1), and young 1.4 m s(-1)).Increased transverse plane head oscillations in people with PD may reflect motor impairment and the inability to respond sufficiently to perturbations while walking, which appears to be distinct from gait hyperkinesia, reduced vertical oscillations, step length, and walking speed. PMID- 25832114 TI - Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions. AB - The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS. PMID- 25832117 TI - Premature pubarche before one year of age: distinguishing between mini-puberty variants and precocious puberty. AB - BACKGROUND: The aim of this study was to facilitate the distinction between the benign "mini-puberty of early infancy" and precocious puberty (PP). MATERIAL AND METHODS: We compared 59 patients (21 boys and 38 girls) seen for pubic hair development before one year of age diagnosed as mini-puberty to 13 patients (2 boys) in whom pubertal development before one year revealed a PP. RESULTS: The boys with mini-puberty presented with pubic hair development and prepubertal testicular volume, with low plasma testosterone concentrations. Their gonadotropin responses to gonadotropin releasing hormone (GnRH) test showed predominant luteinising hormone increase in 9/13. The girls presented with pubic hair development that was accompanied by breast development in 47% of cases, with low plasma estradiol concentrations. Their gonadotropin responses showed predominant follicle-stimulating hormone increase in the 17 evaluated. The patients with PP had organic central PP (5 hypothalamic hamartoma) or idiopathic central PP (n=6), or peripheral PP (one ovarian tumor and one congenital adrenal hyperplasia). The diagnosis was challenging only in 3 girls with idiopathic central PP presenting with prepubertal plasma estradiol concentrations and responses to GnRH test. CONCLUSIONS: The diagnosis of PP was easily determined based on the clinical presentation and the pubertal concentrations of testosterone in boys or of estradiol in girls, as was the diagnosis of central or peripheral origin of PP based on gonadotropin response to the GnRH test. Once PP is excluded, these patients need careful follow-up and physician consultation is needed if clinical pubertal signs progress. PMID- 25832118 TI - Psychological, social and familial factors associated with tobacco cessation among young adults. AB - BACKGROUND/AIMS: The younger individuals quit smoking, the greater the health benefits. We studied the role of adolescent and concurrent psychological, social and familial factors in successful tobacco cessation in a general population sample of French young adults. METHODS: Our data came from participants of the TEMPO cohort study and their parents (members of the GAZEL cohort study) in France. Among regular smokers (n = 678), Cox proportional hazards models were used to estimate hazard ratios of self-reported tobacco cessation of at least 12 months in relation to individual and socioenvironmental variables. RESULTS: On average, participants (mean: 28.9 years) smoked for 10.51 years (SD = 5.9); the majority had attempted to quit smoking at least once (59.5%). In multiple regression analyses, cannabis use in the preceding year and recent financial difficulties were both negatively associated with successful smoking cessation. Conversely, living with a partner and, for women only, recent pregnancy or childbirth were associated with an increased likelihood of tobacco cessation. CONCLUSIONS: This study highlights the importance of young adults' cannabis use, family situation and socioeconomic context with regard to their smoking behavior. Physicians and public health decision makers aiming to decrease the burden of tobacco smoking should take into consideration these social and behavioral factors. PMID- 25832119 TI - Intrinsic platelet reactivity before start with clopidogrel as predictor for on clopidogrel platelet function and long-term clinical outcome. AB - High on-clopidogrel platelet reactivity is associated with worse clinical outcome. Previous data suggest that intrinsic platelet reactivity before initiation of clopidogrel contributes significantly to on-clopidogrel platelet reactivity. It is unknown whether intrinsic reactivity can sufficiently predict on-clopidogrel reactivity and therefore identify patients with insufficient response to clopidogrel before initiation of treatment and at risk for worse clinical outcome. This analysis included 765 consecutive patients undergoing elective coronary stent implantation. Platelet reactivity was assessed by light transmission aggregometry (5 uM ADP) before administration of clopidogrel 600mg and after intake of first maintenance dose of clopidogrel on day 1 following coronary stenting. Patients were followed for up to seven years. The combined primary endpoint was death of any cause or non-fatal myocardial infarction. Intrinsic and on-clopidogrel platelet reactivity were significant correlated (r=0.31; p < 0.001). Among all tested clinical and genetic factors including the cytochrome P450 2C19*2 polymorphism, intrinsic platelet reactivity was the strongest predictor for on-clopidogrel platelet reactivity. However, intrinsic platelet reactivity could only explain 8 % of variability of on-clopidogrel platelet function. Only on-treatment platelet reactivity was predictive for long term clinical outcome (HR 1.47, 95 % CI 1.05-2.05; p = 0.02) whereas intrinsic platelet reactivity was not (HR 1.03, 95 % CI 0.74-1.43; p = 0.86). In conclusion, intrinsic platelet reactivity before initiation of clopidogrel is the strongest predictor of early on-clopidogrel platelet reactivity but can only explain a minor proportion of its variability and is not significantly associated with clinical outcome. Thus, baseline testing cannot substitute on-clopidogrel platelet function testing. PMID- 25832120 TI - TBX21-1993T/C (rs4794067) polymorphism is associated with increased risk of chronic periodontitis and increased T-bet expression in periodontal lesions, but does not significantly impact the IFN-g transcriptional level or the pattern of periodontophatic bacterial infection. AB - Th1-polarized host response, mediated by IFN-gamma, has been associated with increased severity of periodontal disease as well as control of periodontal infection. The functional polymorphism TBX21-1993T/C (rs4794067) increases the transcriptional activity of the TBX21 gene (essential for Th1 polarization) resulting in a predisposition to a Th-1 biased immune response. Thus, we conducted a case-control study, including a population of healthy controls (H, n = 218), chronic periodontitis (CP, n = 197), and chronic gingivitis patients (CG, n = 193), to investigate if genetic variations in TBX21 could impact the development of Th1 responses, and consequently influence the pattern of bacterial infection and periodontitis outcome. We observed that the polymorphic allele T was significantly enriched in the CP patients compared to CG subjects, while the H controls demonstrated and intermediate genotype. Also, investigating the putative functionality TBX21-1993T/C in the modulation of local response, we observed that the transcripts levels of T-bet, but not of IFN-gamma, were upregulated in homozygote and heterozygote polymorphic subjects. In addition, TBX21-1993T/C did not influence the pattern of bacterial infection or the clinical parameters of disease severity, being the presence/absence of red complex bacteria the main factor associated with the disease status and the subrogate variable probing depth (PD) in the logistic regression analysis. PMID- 25832121 TI - Defining the methodological challenges and opportunities for an effective science of sociotechnical systems and safety. AB - An important part of the application of sociotechnical systems theory (STS) is the development of methods, tools and techniques to assess human factors and ergonomics workplace requirements. We focus in this paper on describing and evaluating current STS methods for workplace safety, as well as outlining a set of six case studies covering the application of these methods to a range of safety contexts. We also describe an evaluation of the methods in terms of ratings of their ability to address a set of theoretical and practical questions (e.g. the degree to which methods capture static/dynamic aspects of tasks and interactions between system levels). The outcomes from the evaluation highlight a set of gaps relating to the coverage and applicability of current methods for STS and safety (e.g. coverage of external influences on system functioning; method usability). The final sections of the paper describe a set of future challenges, as well as some practical suggestions for tackling these. PRACTITIONER SUMMARY: We provide an up-to-date review of STS methods, a set of case studies illustrating their use and an evaluation of their strengths and weaknesses. The paper concludes with a 'roadmap' for future work. PMID- 25832122 TI - The role of stop-signal probability and expectation in proactive inhibition. AB - The subjective belief of what will happen plays an important role across many cognitive domains, including response inhibition. However, tasks that study inhibition do not distinguish between the processing of objective contextual cues indicating stop-signal probability and the subjective expectation that a stop signal will or will not occur. Here we investigated the effects of stop-signal probability and the expectation of a stop-signal on proactive inhibition. Twenty participants performed a modified stop-signal anticipation task while being scanned with functional magnetic resonance imaging. At the beginning of each trial, the stop-signal probability was indicated by a cue (0% or > 0%), and participants had to indicate whether they expected a stop-signal to occur (yes/no/don't know). Participants slowed down responding on trials with a > 0% stop-signal probability, but this proactive response slowing was even greater when they expected a stop-signal to occur. Analyses were performed in brain regions previously associated with proactive inhibition. Activation in the striatum, supplementary motor area and left dorsal premotor cortex during the cue period was increased when participants expected a stop-signal to occur. In contrast, activation in the right inferior frontal gyrus and right inferior parietal cortex activity during the stimulus-response period was related to the processing of contextual cues signalling objective stop-signal probability, regardless of expectation. These data show that proactive inhibition depends on both the processing of objective contextual task information and the subjective expectation of stop-signals. PMID- 25832123 TI - Hearing threshold levels for an otologically screened population in Spain. AB - OBJECTIVE: The aim of the present study was to provide thresholds data as a function of age for an otologically normal population in Spain, compared to the current ISO 7029 (2000) standard. DESIGN: A prospective study in an otologically screened population. STUDY SAMPLE: Data was collected from 1175 otologically normal persons aged between 5 and 90 years. Inclusion criteria involved those listed in ISO 389-1 (1998) and the 8253-1 (2010). Suitability for inclusion was evaluated through interview, based on a questionnaire, and physical examination. RESULTS: The hearing thresholds decreased slightly from 125 to 2000 Hz. From 2000 Hz onwards the thresholds increased; this increase being more pronounced with increasing frequency and age. No statistically significant sex differences were found. The hearing threshold levels in the present study were higher (poorer) than the ones provided by ISO 7029 (2000). CONCLUSIONS: Results from this study suggest that the thresholds listed in ISO 7029 (2000) may be too restrictive, and could be useful in formulating the ISO 7029 update. PMID- 25832124 TI - Traceability in newborn hearing screening via an auditory-evoked response simulator. PMID- 25832125 TI - Kohn's pores are not responsible for collateral ventilation between inflated and deflated segments: a microscopic study of pulmonary intersegmental septa in the human lung. AB - The composition of the pulmonary intersegmental septum has not been clearly identified by thoracic surgeons who regard Kohn's pores as the main channel that causes air leakage when determining the intersegmental septum by segmental ventilation. In this study, we aimed to examine this possible misinterpretation by focusing on a detailed description of the microscopic anatomy of the intersegmental septum. To accomplish this aim, 50 lung samples of the intersegmental septum from fresh cadavers without emphysema were studied by histological and electron microscopy. The findings of light microscopy and electron microscopy showed that the intersegmental septum is composed of three layers. The alveolar walls of adjacent segments serve as the superficial layer. They are integral, and no Kohn's pores were identified. The deep layer contains collagen fibres. As shown by our findings, Kohn's pores are absent within the intersegmental septum. Therefore, they could not be the main channel for the collateral ventilation between inflated and deflated lung segments during a pulmonary segmentectomy. PMID- 25832126 TI - Risk perceptions of smokeless tobacco among adolescent and adult users and nonusers. AB - The recent growth in smokeless tobacco (ST) consumption has raised questions about consumer risk perceptions of ST products, especially in high-risk vulnerable populations. This qualitative study examined risk perceptions of ST among adolescent and adult users and nonusers in Ohio Appalachia. Focus groups and interviews were held with adolescents (n = 53; M age = 17 years) and adults (n = 63; M age = 34 years) from four Ohio Appalachian counties. Participants were asked about their perceptions of ST-related health risks, ST safety, and the relative safety of ST compared with cigarettes. Transcriptions were coded independently by two individuals. Overall, participants were knowledgeable about health problems from ST use (e.g., oral cancers, periodontal disease). Nearly all participants stated that ST use is not safe; however, there was disagreement about its relative safety. Some perceived all tobacco products as equally harmful; others believed that ST is safer than cigarettes for either the user or those around the user. Disagreements about ST relative safety may reflect mixed public health messages concerning the safety of ST. Comprehensive consumer messages about the relative safety of ST compared with cigarettes are needed. Messages should address the effect of ST on the health of the user as well as those exposed to the user. PMID- 25832127 TI - Hepatitis From Spiroplasma sp. in an Immunocompromised Patient. AB - A 70-year-old lung transplant recipient patient was admitted with fever, nausea, abdominal pain, peripheral edema and pronounced weakness. An initial work-up for presumed infection revealed cholestatic hepatitis, leukocytosis and thrombocytopenia, but failed to detect a pathogen. An increased glucose uptake exclusively in the liver was demonstrated by positron emission tomography. Liver biopsy showed basophilic inclusions in the cytoplasm of hepatocytes. Broad- range 16S rRNA gene PCR followed by sequence analysis yielded Spiroplasma sp. in two independent blood samples and the liver biopsy, confirming Spiroplasma sp. as the causative agent. Antibiotic treatment with doxycycline and azithromycin led to complete recovery. PMID- 25832128 TI - Renal effects of coronary artery bypass graft surgery in diabetic and non diabetic patients: a study with urinary neutrophil gelatinase-associated lipocalin and serum cystatin C. AB - BACKGROUND/AIMS: Cardiac surgery and diabetes are major causes of acute kidney injury (AKI). We aimed to investigate the value of urinary neutrophil gelatinase associated lipocalin (NGAL) and serum cystatin C, as early biomarkers for prediction of AKI in diabetic and non-diabetic adult patients undergoing cardiac surgery. METHODS: 15 non-diabetic and 15 diabetic adult patients undergoing cardiac surgery were enrolled. Peri-operative clinical and laboratory variables were recorded. Urinary NGAL, serum cystatin C, serum creatinine (Cre) and blood urea nitrogen (BUN) were evaluated. RESULTS: AKI was detected in 4 patients in non-diabetic group and 12 patients in diabetic group. Urinary NGAL levels of diabetic and non-diabetic patients and serum cystatin C levels of diabetic patients exceed upper normal limits or cutoff values much earlier than BUN and Cre. cystatin C levels of non-diabetic patients remain unchanged. Cystatin C and NGAL levels of patients meeting AKI criteria and NGAL levels of patients not meeting AKI criteria exceeded upper normal limits or cut off values much earlier in than BUN and Cre. CONCLUSIONS: Measurement of cystatin C level in both diabetic and non-diabetic patients may reveal AKI earlier than NGAL and BUN. In diabetic patients, measurement of urinary NGAL and serum cystatin C levels may indicate AKI signs earlier than BUN and Cre. PMID- 25832129 TI - Evaluation of thyroid-stimulating hormone, total thyroxine, and free thyroxine concentrations in hyperthyroid cats receiving methimazole treatment. AB - BACKGROUND: Iatrogenic hypothyroidism (IH) after treatment of hyperthyroidism can impair renal function. No study compared the efficacy of measurement of serum free thyroxine by equilibrium dialysis (fT4ed) or thyroid-stimulating hormone (TSH) concentrations for monitoring cats receiving methimazole. OBJECTIVES: To (1) compare the ability of total T4 and fT4ed concentrations in conjunction with TSH to define thyroid function in hyperthyroid cats receiving methimazole, (2) determine the prevalence of IH in cats receiving methimazole, and (3) examine the relationship between thyroid axis hormones and serum creatinine concentration. ANIMALS: One hundred and twenty-five serum samples from hyperthyroid cats receiving methimazole and total T4 concentrations <=3.9 MUg/dL. METHODS: Total T4, fT4ed, and TSH concentrations were measured to evaluate thyroid status and serum creatinine concentration was measured to assess renal function. A low total T4 or fT4ed concentration in combination with an increased TSH concentration defined IH. RESULTS: Forty-one cats (33%) had increased TSH concentrations. Of cats with total T4 and fT4ed concentrations below the reference range, 68% and 73%, respectively, had TSH concentrations above the reference range. Only 18% of cats with a normal TSH concentration had an increased serum creatinine concentrations as compared to 39% of those with increased TSH concentrations (P < .001). CONCLUSIONS: Free T4ed does not identify more cats with potential IH as compared to total T4. The IH prevalence was approximately 20%. Measurement of TSH may be more helpful in indicating that azotemia, if present, is at least in part related to IH. Investigation is needed to define TSH assay utility in identifying possible subclinical IH. PMID- 25832130 TI - GENDER, WEIGHT, AND AGE EFFECTS ON PREVALENCE OF CAUDAL ABERRANT NASAL TURBINATES IN CLINICALLY HEALTHY ENGLISH BULLDOGS: A COMPUTED TOMOGRAPHIC STUDY AND CLASSIFICATION. AB - English Bulldogs have been reported to demonstrate abnormal growth and development of the nasal turbinates, which contribute to an increase in airway resistance and hence clinical signs of brachycephalic airway syndrome. The purpose of this prospective, cross-sectional study was to assess the prevalence and severity of caudal aberrant turbinate protrusion via CT studies of English Bulldogs with, according to the owners, none or minimal clinical signs of brachycephalic airway syndrome. An additional objective was to propose a classification scheme for describing the degree of caudal aberrant turbinate protrusion in English Bulldogs and to apply this scheme in assessing the effect of gender, weight, and age on prevalence and severity of turbinate protrusion. The nasal cavities of 40 clinically healthy English Bulldogs were examined. The prevalence of caudal aberrant turbinates in this group was 100%. Using our proposed classification scheme, Grade 1 (minimal) was detected in 7 of 40 (17.5%), Grade 2 (mild) in 28 of 40 (70%), and Grade 3 (moderate) in 5 of 40 (12.5%) English Bulldogs. No significant effect of gender, weight, and age on degree of protrusion was found. In conclusion, this study identified minimal to moderate protrusion of caudal aberrant turbinates toward the nasopharynx in all the sampled English Bulldogs, despite the absence of clinical signs of brachycephalic airway syndrome. PMID- 25832131 TI - Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. AB - BACKGROUND: While much is known about childhood atopic dermatitis, little is known about persistence of atopic dermatitis into adult life. We report, to our knowledge for the first time, the clinical course of atopic dermatitis in an unselected cohort of adolescents followed into adulthood. METHODS: The course of atopic dermatitis from adolescence to adulthood was studied prospectively in a cohort of unselected 8th-grade schoolchildren established in 1995 and followed up in 2010 with questionnaire and clinical examination. RESULTS: The lifetime prevalence of atopic dermatitis was high (34.1%), and a considerable number of adults still suffered from atopic dermatitis evaluated both by questionnaire (17.1%) and clinical examination (10.0%). Persistent atopic dermatitis was found in 50% of those diagnosed in school age, and persistent atopic dermatitis was significantly associated with early onset, childhood allergic rhinitis and hand eczema. A close association was also found with allergic contact dermatitis and increased specific IgE to Malassezia furfur, but not with filaggrin gene defect. CONCLUSION: Persistence of atopic dermatitis in adulthood is common and affects quality of life. Persistent atopic dermatitis is particularly prevalent in those with early onset, allergic rhinitis and hand eczema in childhood. It is important to recognizing atopic dermatitis as a common and disabling disease not only in children but also in adults. PMID- 25832132 TI - Distinct testicular steroidogenic response mechanisms between neonatal and adult heat-acclimated male rats. AB - BACKGROUND: In comparison to short-term gonad heat exposure, little is known about the molecular mechanisms that regulate testicular steroidogenesis during long-term whole body heat acclimation. MATERIAL AND METHODS: Testicular slices from neonatal (NHA) and adult (AHA) heat-acclimated Wistar rats were analysed in vitro to assess the mRNA expression and enzymatic activity of steroidogenic enzymes under basal and luteinising hormone (LH) or prolactin (PRL) stimulated conditions compared with control rats (CR). Furthermore, a de-acclimated group (DA) was created by transferring adult NHA rats to control conditions. RESULTS: Heat acclimation significantly increased plasma LH levels in the AHA group and LH and PRL in the NHA group compared with the CR group; however, after heat acclimation, the T and E2 levels did not differ from the control levels. All heat acclimated groups showed high basal intra-testicular steroid production in vitro. Moreover, basal Cyp11a1 and Hsd3b1 levels were upregulated in vitro in the NHA and DA groups versus the CR group. LH in vitro stimulation upregulated Cyp11a1 expression in the NHA and AHA groups and PRL stimulation upregulated Cyp17a1 levels in the NHA and DA groups compared with the basal expression levels. In the AHA group, decreased basal Star and CYP11A activities but increased HSD3B1 and CYP17A1 activities were found. CONCLUSION: Our data revealed that despite the similar steroid levels in plasma and secreted in vitro by neonatal and adult heat acclimated rat testicular slices, the molecular mechanisms underlying the steroidogenic response to heat acclimation during these different developmental stages were distinct. PMID- 25832133 TI - Age but not ABCD(2) score predicts any level of carotid stenosis in either symptomatic or asymptomatic side in transient ischaemic attack. AB - BACKGROUND: The ABCD(2) score is routinely used in assessment of transient ischaemic attack (TIA) to assess the risk of developing stroke. There remains uncertainty regarding whether the ABCD(2) score could be used to help predict extent of carotid artery stenosis (CAS). OBJECTIVES: We aimed to (i) collate and analyse all available published literature on this topic and (ii) compare the data from our local population to the existing evidence base. MATERIALS AND METHODS: We conducted a retrospective-observational study over a 6-month period using our East of England hospital-based TIA clinic data with a catchment population of ~750,000. We also searched the literature on studies reporting the association between ABCD(2) score and CAS. RESULTS: We included 341 patients in our observational study. The mean age in our cohort was 72.86 years (SD 10.91) with 52% male participants. ABCD(2) score was not significantly associated with CAS (p = 0.78). Only age > 60 years was significantly associated with ipsilateral (> 50%) and contralateral CAS (> 50% and > 70%) (p < 0.01) after controlling for other confounders. The systematic review identified four studies for inclusion and no significant association between ABCD(2) score and CAS was reported, confirming our findings. CONCLUSION: Our systematic review and observational study confirm that the ABCD(2) score does not predict CAS. However, our observational study has examined a larger number of possible predictors and demonstrates that age appears to be the single best predictor of CAS in patients presenting with a TIA. Selection of urgent carotid ultrasound scan thus should be based on individual patient's age and potential benefit of carotid intervention rather than ABCD(2) score. PMID- 25832134 TI - Stress analysis of the cervical spinal cord: Impact of the morphology of spinal cord segments on stress. AB - OBJECTIVE: Although there are several classifications for cervical myelopathy, these do not take differences between spinal cord segments into account. Moreover, there has been no report of stress analyses for individual segments to date. METHODS: By using the finite element method, we constructed 3-dimensional spinal cord models comprised of gray matter, white matter, and pia mater of the second to eighth cervical vertebrae (C2-C8). We placed compression components (disc and yellow ligament) at the front and back of these models, and applied compression to the posterior section covering 10%, 20%, 30%, or 40% of the anteroposterior diameter of each cervical spinal cord segment. RESULTS: Our results revealed that, under compression applied to an area covering 10%, 20%, or 30% of the anteroposterior diameter of the cervical spinal cord segment, sites of increased stress varied depending on the morphology of each cervical spinal cord segment. Under 40% compression, stress was increased in the gray matter, lateral funiculus, and posterior funiculus of all spinal cord segments, and stress differences between the segments were smaller. CONCLUSION: These results indicate that, under moderate compression, sites of increased stress vary depending on the morphology of each spinal cord segment or the shape of compression components, and also that the variability of symptoms may depend on the direction of compression. However, under severe compression, the differences among the cervical spinal segments are smaller, which may facilitate diagnosis. PMID- 25832135 TI - Physical capacity in performing daily activities is reduced in scleroderma patients with early lung involvement. AB - BACKGROUND AND AIMS: Patients with systemic sclerosis (SSc) often complain reduced capacity at submaximal exercise; conversely, physical capacity in performing daily duties has never been measured in SSc. The aim of this study is to evaluate this performance and its correlates, in patients with SSc compared with healthy controls, in a free-living setting. METHODS: Twenty-seven outpatients with stable SSc and 11 controls were recruited. Physical activity was assessed by portable multiple sensor device (SenseWear Armband) worn for at least 6 days. Physical activity duration (PAD; in minutes) for non-sedentary activities and physical activity level (PAL = total daily energy/resting energy expenditure) per day were calculated. Nutritional status was estimated by bioelectrical impedance analysis and pulmonary arterial hypertension excluded by echocardiography. RESULTS: Daily physical activities (243 +/- 145 min per day vs 397 +/- 142 min, respectively; P = 0.005) and PAL were significantly reduced in SSc compared with controls (1.5 +/- 0.4 vs 2 +/- 0.7, respectively; P = 0.019). Seventy-four per cent of SSc patients showed PAL < 1.70, whereas only 27% of controls were below this threshold for sedentary life style. Both PAD and PAL positively correlated with DLco. Patients and controls did not differ for spirometric parameters, body mass index, phase angle at bioelectrical impedance analysis, fat mass or fat-free mass indexes. In SSc, exercise capacity during daily activity was reduced compared with controls, and was associated with early evidence of functional decay (decreasing DLco) but not with malnutrition (undernutrition). CONCLUSIONS: A reduction of daily physical activity is already present even in early stages of lung involvement in SSc, characterized by unaltered spirometry and well-preserved nutritional status. PMID- 25832136 TI - The global challenge of women's health. PMID- 25832137 TI - Screening tests for gonorrhoea should first do no harm. PMID- 25832138 TI - New and emerging treatments for Parkinson disease. PMID- 25832139 TI - Survey identifies key dementia research priorities. PMID- 25832141 TI - Countdown for health to the post-2015 UN Sustainable Development Goals. PMID- 25832142 TI - With talk of Medicare reform, let's not neglect vertical equity. PMID- 25832143 TI - Targets and abuse: the price public health campaigners pay. PMID- 25832144 TI - The health of "emerging adults" in Australia: freedom, risk and rites of passage. PMID- 25832145 TI - Identified health concerns and changes in management resulting from the Healthy Kids Check in two Queensland practices. PMID- 25832146 TI - Identified health concerns and changes in management resulting from the Healthy Kids Check in two Queensland practices. PMID- 25832147 TI - The importance of molecular testing to confirm measles, mumps and rubella in immunised individuals. PMID- 25832148 TI - Better access to mental health care and the failure of the Medicare principle of universality. PMID- 25832149 TI - Survival of Indigenous Australians receiving renal replacement therapy: closing the gap? PMID- 25832150 TI - Pharmacological management of low milk supply with domperidone: separating fact from fiction. PMID- 25832152 TI - The imperative to prevent diabetes complications: a broadening spectrum and an increasing burden despite improved outcomes. AB - Diabetes mellitus and its complications are common; the complications are, of themselves, a major reason to manage diabetes. Recent data from Australia and similar developed health care systems overseas indicate that morbidity and mortality outcomes relating to diabetes complications are improving. However, these benefits are offset by increasing numbers of people diagnosed with diabetes, resulting in an increased disease burden with significant health care implications. Thus the imperative to prevent diabetes and diabetes complications has never been greater. Furthermore, the recognised spectrum of diabetes complications is broadening, especially complications relating to lipid levels, insulin resistance and the metabolic syndrome. Clinicians now need to be aware of both traditional complications (eg, nephropathy and cardiovascular disease) and non-traditional complications (eg, polycystic ovary syndrome, non-alcoholic fatty liver disease, some cancers and eating disorders). Complications outcomes could be further improved by decreasing the evidence-treatment gap - for example, by increasing personalisation of care in managing diabetes complications. PMID- 25832153 TI - Costs to Australian taxpayers of pharmaceutical monopolies and proposals to extend them in the Trans-Pacific Partnership Agreement. AB - Intellectual property (IP) protections proposed by the United States for the Trans-Pacific Partnership Agreement (TPPA) have sparked widespread alarm about the potential negative impact on access to affordable medicines. The most recently leaked draft of the IP chapter shows some shifts in the US position, presumably in response to ongoing resistance from other countries. While some problematic provisions identified in earlier drafts have been removed or mitigated, major concerns remain unresolved. Three of the greatest concerns for Australia in the recent draft include provisions that would further entrench secondary patenting and evergreening, lock in extensions to patent terms and extend monopoly rights over clinical trial data for certain medicines. Data from the 2013 Pharmaceutical Patents Review, and from various submissions made to it, show that pharmaceutical monopoly protections already cost Australian taxpayers hundreds of millions of dollars each year. Provisions still being considered for the TPPA would further entrench and extend costly monopolies, with serious implications for the budget bottom line and the sustainability of the Pharmaceutical Benefits Scheme. PMID- 25832154 TI - An incidentaloma not to be missed. PMID- 25832155 TI - Odds, risks and appropriate diagnosis of gestational diabetes. AB - The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) diagnostic process and criteria for gestational diabetes mellitus (GDM) have been recommended by the World Health Organization for adoption and were widely introduced into clinical practice in Australia from January 2015 - in Queensland, the Australian Capital Territory and variably across other states. The IADPSG criteria identify women at increased risk of a range of adverse pregnancy outcomes related to maternal hyperglycaemia. The relationship between maternal hyperglycaemia and adverse outcomes is continuous; however, one elevated glucose value is sufficient to impart a higher risk of pregnancy complications. We outline the background and statistical foundations of the IADPSG approach and refute the inference that invalid statistical reasoning underlies the IADPSG approach. The prevalence of GDM diagnosed by IADPSG criteria may be higher or lower than with other criteria, depending on the underlying population prevalence of fasting and post-glucose load hyperglycaemia, which in turn vary with ethnicity. Studies comparing previous Australian criteria to the IADPSG criteria suggest GDM prevalence may decrease or may increase by up to 35% in specific populations with the planned change in criteria. Pregnancy complications have multiple potential underlying causes. No set of glucose criteria will ever be able to fully separate women and babies at risk of pregnancy complications from those who are not. PMID- 25832156 TI - Odds, risks and appropriate diagnosis of gestational diabetes: comment. PMID- 25832157 TI - The cost of freezing general practice. AB - OBJECTIVES: We aimed to assess the effect on general practitioners' income, and the amount of any copayment required for GPs to recoup lost income, of two policies (individually and combined) proposed by the Australian Government: a continued indexation freeze of Medicare schedule fees; and a $5 rebate reduction (now retracted). DESIGN, SETTING AND PARTICIPANTS: Analysis of data from the Bettering the Evaluation and Care of Health (BEACH) program, a continuous cross sectional, national study of GP activity in Australia. We used data for April 2013 to March 2014 on direct encounters between patients and GPs for which at least one Medicare Benefits Schedule or Department of Veterans' Affairs general practice consultation item was claimable. MAIN OUTCOME MEASURES: The reduction in GP rebate income due to the policies and the size of any copayment needed to address this loss. RESULTS: The $5 rebate reduction would have reduced GPs' income by $219.53 per 100 consultations. This would have required a $4.81 copayment at all non-concessional patient consultations to recoup lost income. The freeze would cost GPs $384.32 in 2017-18 dollars per 100 consultations, requiring an $8.43 copayment per non-concessional patient consultation. Total estimated loss in rebate income to GPs would have been $603.85 in 2017-18 per 100 encounters, a reduction of 11.2%. The non-concessional consultation copayment required to cover lost income from both policies would have been $7-$8 in 2015 16, and $12-$15 by 2017-18. CONCLUSION: If both policies had gone ahead, GPs would have needed to charge substantially more than the suggested $5 copayment for consultations with non-concessional patients in order to maintain 2014-15 relative gross income. Even though the rebate reduction has been retracted, the freeze will have greater impact with time - nearly double the amount of the rebate reduction by 2017-18. For economic reasons, the freeze may still force GPs who currently bulk bill to charge copayments. PMID- 25832158 TI - Mapping the diagnosis of autism spectrum disorders in children aged under 7 years in Australia, 2010-2012. AB - OBJECTIVES: To investigate the frequency and age at diagnosis of autism spectrum disorder (ASD) in children aged under 7 years living in Australia. DESIGN AND PARTICIPANTS: Analysis of de-identified data on 15 074 children aged under 7 years registered with the Helping Children with Autism Package (HCWAP; a program that provides funding for access to early intervention and support services throughout Australia) between 1 July 2010 and 30 June 2012. MAIN OUTCOME MEASURES: Age at diagnosis of ASD as confirmed by a paediatrician, psychiatrist and/or multidisciplinary team assessment. RESULTS: The average age at diagnosis of ASD in children registered with the HCWAP is currently 49 months, with the most frequently reported age being 71 months. Differences were evident in age at diagnosis across states, with children in Western Australia and New South Wales being diagnosed at a younger age. Across Australia, 0.74% of the population of children aged under 7 years are currently diagnosed with ASD and registered with the HCWAP. A higher proportion of children were registered with the HCWAP in Victoria compared with other states. There was no difference in age at diagnosis between Indigenous and non-Indigenous Australians, but children from a culturally and linguistically diverse background were diagnosed 5 months earlier than other children. CONCLUSIONS: There may be a substantial gap between the age at which a reliable and accurate diagnosis of ASD is possible and the average age that children are currently diagnosed. The frequency of ASD diagnoses in Australia has increased substantially from previously published estimates. PMID- 25832159 TI - Gonorrhoea notifications and nucleic acid amplification testing in a very low prevalence Australian female population. AB - OBJECTIVES: To examine whether the rapid increase of gonorrhoea notifications in Victoria, Australia, identified by nucleic acid amplification test (NAAT) is supported by similar changes in diagnoses by culture, which has higher specificity, and to determine the proportion of tests positive among women tested. DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of Medicare reporting of dual NAATs in Victoria, Victorian Department of Health gonorrhoea notifications, and gonorrhoea culture data at the Melbourne Sexual Health Centre (MSHC), among women, 2008 to 2013. MAIN OUTCOME MEASURES: Gonorrhoea notifications and testing methods. RESULTS: Gonorrhoea cases identified by NAAT increased from 98 to 343 cases over the study period. Notifications by culture alone decreased from 19 to five cases. The proportion of NAATs positive for gonorrhoea in Victoria was low (0.2%-0.3%) and did not change over time (P for trend, 0.66). Similarly, the proportion of women tested at the MSHC for gonorrhoea who tested positive (0.4%-0.6%) did not change over time (P for trend, 0.70). Of untreated women who had a positive NAAT result for gonorrhoea and were referred to the MSHC, 10/25 were confirmed by culture. CONCLUSIONS: The positivity of gonorrhoea in women identified by culture remains stable over time. Using NAAT for gonorrhoea screening in low-prevalence populations will result in many false positives. Positive NAAT results among low-risk women should be regarded as doubtful, and confirmatory cultures should be performed. PMID- 25832160 TI - Reduced breast milk feeding subsequent to cosmetic breast augmentation surgery. AB - OBJECTIVE: To determine the effect of cosmetic breast augmentation on subsequent infant feeding. PARTICIPANTS, DESIGN AND SETTING: Population-based record linkage study of women giving birth in New South Wales, January 2006 - December 2011. Birth records were linked longitudinally to maternal hospitalisations up to 11 years before birth. Breast augmentation was identified by surgical procedure codes in hospital records. MAIN OUTCOME MEASURES: Any breast milk feeding at discharge from birth care, and among infants receiving any breast milk, exclusive breast milk feeding. The before-and-after effect of breast augmentation was assessed among women who had the surgery between births. RESULTS: Among 378 389 women who gave birth in the study period, 892 (0.2%) had prior breast augmentation. Among women with breast augmentation, 705 (79%) provided any breast milk to their infant at discharge, compared with 89% among women without augmentation. After adjusting for sociodemographic and pregnancy factors, infants of women with breast augmentation were less likely to receive breast milk at discharge than infants of women without augmentation (adjusted relative risk [ARR], 0.90; 95% CI, 0.87-0.93). However, infants receiving breast milk were not more or less likely to receive breast milk exclusively (ARR, 0.99; 95% CI, 0.97 1.01). Women with augmentation surgery between births changed their breastfeeding behaviour (reduced rates), while those with no augmentation or augmentation before both births did not. CONCLUSIONS: Reduced rates of breast milk feeding among women who have undergone breast augmentation underscore the importance of identifying, supporting and encouraging women who are vulnerable to a lower likelihood of breastfeeding. PMID- 25832161 TI - An unusual case of implantable cardioverter-defibrillator inhibition. PMID- 25832162 TI - Intravenous OxyContin-associated thrombotic microangiopathy treated successfully without plasma exchange. PMID- 25832163 TI - An unusual neurological complication from a garden-variety organism: post melioidosis parkinsonism. PMID- 25832164 TI - Disclosing genetic information to at-risk relatives: new Australian privacy principles, but uniformity still elusive. AB - There is growing understanding of the need for genetic information to be shared with genetic relatives in some circumstances. Since 2006, s 95AA of the Privacy Act 1988 (Cwlth) has permitted the disclosure of genetic information to genetic relatives without the patient's consent, provided that the health practitioner reasonably believes that disclosure is necessary to lessen or prevent a serious threat to the life, health or safety of the genetic relatives. Enabling guidelines were introduced in 2009. These were limited to the private sector, and excluded doctors working in the public sector at both Commonwealth and state and territory levels. Privacy legislation was amended in March 2014, and new Australian Privacy Principles, which replace the National Privacy Principles and Information Privacy Principles, now cover the collection and use of personal information. The Privacy Act and the Australian Privacy Principles now extend to practitioners employed by the Commonwealth but not to health practitioners working in state and territory public hospitals. In this article, I review these legislative developments and highlight the implications of the lack of uniformity and the consequent need for a collaborative, uniform approach by states and territories. PMID- 25832165 TI - Is research ethics regulation really killing people? AB - It has been argued that research ethics regulation is leading to loss of life by delaying life-saving research. For example, Whitney and Schneider argue that the delays to the ISIS-2 trial cost 6538 lives. This suggests that there are grounds for rejecting research ethics regulation. However, the methods adopted by critics are flawed because: they conflate regulatory delays with those due to genuine normative requirements that would be present even if the regulatory framework was not; and looking at the impact of regulation on a per-project basis is the wrong metric, because it neglects all the unsuccessful research and because delaying specific projects does not reduce the overall research done by researchers. Research ethics regulation does not lead to substantial losses of life, but we have strong obligations to make it as efficient as possible. PMID- 25832166 TI - Commercial in confidence: public health without confidence. PMID- 25832168 TI - Discoveries and advances in noncoding RNAs. PMID- 25832169 TI - Small RNA deep sequencing reveals the important role of microRNAs in the halophyte Halostachys caspica. AB - MicroRNAs (miRNAs), an extensive class of small regulatory RNAs, play versatile roles in plant growth and development as well as stress responses. However, the regulatory mechanism is unclear on miRNA-mediated response to abiotic stress in plants. Halostachys caspica is a halophytic plant species and a great model for investigating plant response to salinity stress. However, no research has been performed on miRNAs in H. caspica. In this study, we employed deep sequencing to identify both conserved and novel miRNAs from salinity-exposed H. caspica and its untreated control. Among the 13-19 million sequences generated from both treatments, a total of 170 conserved miRNAs, belonging to 151 miRNA families, were identified; among these miRNAs, 31 were significantly up-regulated and 48 were significantly down-regulated by salinity stress. We also identified 102 novel miRNAs from H. caspica; among them, 12 miRNAs were significantly up regulated and 13 were significantly down-regulated by salinity. qRT-PCR expression analysis validated the deep sequencing results and also demonstrated that miRNAs and their targeted genes were responsive to high salt stress and existed a negative expression correlation between miRNAs and their targets. miRNA target prediction, GO and KEGG analysis showed that miRNAs were involved in salt stress-related biological pathway, including calcium signalling pathway, MAPK signalling pathway, plant hormone signal transduction and flavonoid biosynthesis, etc. This suggests that miRNAs play an important role in plant salt stress tolerance in H. caspica. This result could be used to improve salt tolerance in crops and woods. PMID- 25832170 TI - Statistical monitoring of the hand, foot and mouth disease in China. AB - In a period starting around 2007, the Hand, Foot, and Mouth Disease (HFMD) became wide-spreading in China, and the Chinese public health was seriously threatened. To prevent the outbreak of infectious diseases like HFMD, effective disease surveillance systems would be especially helpful to give signals of disease outbreaks as early as possible. Statistical process control (SPC) charts provide a major statistical tool in industrial quality control for detecting product defectives in a timely manner. In recent years, SPC charts have been used for disease surveillance. However, disease surveillance data often have much more complicated structures, compared to the data collected from industrial production lines. Major challenges, including lack of in-control data, complex seasonal effects, and spatio-temporal correlations, make the surveillance data difficult to handle. In this article, we propose a three-step procedure for analyzing disease surveillance data, and our procedure is demonstrated using the HFMD data collected during 2008-2009 in China. Our method uses nonparametric longitudinal data and time series analysis methods to eliminate the possible impact of seasonality and temporal correlation before the disease incidence data are sequentially monitored by a SPC chart. At both national and provincial levels, our proposed method can effectively detect the increasing trend of disease incidence rate before the disease becomes wide-spreading. PMID- 25832171 TI - Factors affecting occurrence of twin pregnancy after double embryo transfer on day 3. AB - AIM: The aim of this study was to identify the risk factors of twin gestation in fresh double day-3 embryo transfer cycles. MATERIAL AND METHODS: Out of a total of 386 cycles of fresh double embryo transfers on day 3 between 2006 and 2013 at a single center, 72 women with single intrauterine gestational sac (GS) (single GS group) and 32 women with double GS (double-GS group) were identified. The patients' clinical characteristics and laboratory results were extracted from electronic medical records and were compared. RESULTS: The double-GS group had a significantly younger age (P = 0.012), and higher bodyweight (P = 0.033) compared with the single-GS group. The total number of blastomeres (P = 0.013) and cumulative embryo score (P = 0.012) were higher in the double-GS group. By receiver-operator curve analysis, maternal age <= 35 years, maternal bodyweight > 60 kg, total number of blastomeres > 14, and cumulative embryo score > 49 were the cut-off values to predict twin pregnancy. Among eight women with all four risk factors, the twin pregnancy rate was 87.5%. There was no twin pregnancy among seven women with no risk factors. CONCLUSION: Younger age, higher bodyweight, and better embryo quality are all associated with a higher incidence of twin pregnancy after double embryo transfer on day 3. Single embryo transfer might be advisable for couples with risk factors for twin pregnancy. PMID- 25832172 TI - Identification of psychological comorbidity in TMD-patients. AB - OBJECTIVES: The aim of the current study was to access the prevalence of depression among patients with Temporomandibular Joint Disorder (TMD) compared to patients with no current TMD. METHOD: Patients (92) and controls (90) answered questionnaires on subjective pain, severity of chronic pain, jaw disability, emotional well-being and depression, and a clinical examination was performed. RESULTS: Temporomandibular Joint Disorder patients reported higher disability of jaw function, compared to controls (p<0.001). The myoarthopathy subgroup (67.4%) had slightly more jaw disability than the myopathy subgroup (p>0.05). While 51% of TMD patients reported poor emotional well-being, only 7.8% of controls were affected (p<0.001). Clinical symptoms of depression were reported by 16% of TMD patients and not in the controls (p<0.001). Among TMD patients, a higher prevalence of depression was observed in the myopathy subgroup. DISCUSSION: A regular screening for psychological problems, using standardized questionnaires, should be integrated in clinical examination of TMD patients. PMID- 25832173 TI - Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV4 channels. AB - BACKGROUND AND PURPOSE: Eugenol, a vanilloid molecule found in some dietary plants, relaxes vasculature in part via an endothelium-dependent process; however, the mechanisms involved are unclear. Here, we investigated the endothelial cell-mediated mechanism by which eugenol modulates rat mesenteric artery contractility and systemic BP. EXPERIMENTAL APPROACH: The isometric tension of rat mesenteric arteries (size 200-300 MUm) was measured using wire myography; non-selective cation currents (ICat ) were recorded in endothelial cells using patch clamp electrophysiology. Mean arterial pressure (MAP) and heart rate (HR) were determined in anaesthetized rats. KEY RESULTS: Eugenol relaxed endothelium-intact arteries in a concentration-dependent manner and this effect was attenuated by endothelium denudation. L-NAME, a NOS inhibitor, a combination of TRAM-34 and apamin, selective blockers of intermediate and small conductance Ca(2+) -activated K(+) channels, respectively, and HC-067047, a TRPV4 channel inhibitor, but not indomethacin, a COX inhibitor, reduced eugenol-induced relaxation in endothelium-intact arteries. Eugenol activated HC-067047-sensitive ICat in mesenteric artery endothelial cells. Short interfering RNA (siRNA) mediated TRPV4 knockdown abolished eugenol-induced ICat activation. An i.v. injection of eugenol caused an immediate, transient reduction in both MAP and HR, which was followed by prolonged, sustained hypotension in anaesthetized rats. This sustained hypotension was blocked by HC-067047. CONCLUSIONS AND IMPLICATIONS: Eugenol activates TRPV4 channels in mesenteric artery endothelial cells, leading to vasorelaxation, and reduces systemic BP in vivo. Eugenol may be therapeutically useful as an antihypertensive agent and is a viable molecular candidate from which to develop second-generation TRPV4 channel activators that reduce BP. PMID- 25832174 TI - Crystal structures of Mycobacterial MeaB and MMAA-like GTPases. AB - The methylmalonyl Co-A mutase-associated GTPase MeaB from Methylobacterium extorquens is involved in glyoxylate regulation and required for growth. In humans, mutations in the homolog methylmalonic aciduria associated protein (MMAA) cause methylmalonic aciduria, which is often fatal. The central role of MeaB from bacteria to humans suggests that MeaB is also important in other, pathogenic bacteria such as Mycobacterium tuberculosis. However, the identity of the mycobacterial MeaB homolog is presently unclear. Here, we identify the M. tuberculosis protein Rv1496 and its homologs in M. smegmatis and M. thermoresistibile as MeaB. The crystal structures of all three homologs are highly similar to MeaB and MMAA structures and reveal a characteristic three domain homodimer with GDP bound in the G domain active site. A structure of Rv1496 obtained from a crystal grown in the presence of GTP exhibited electron density for GDP, suggesting GTPase activity. These structures identify the mycobacterial MeaB and provide a structural framework for therapeutic targeting of M. tuberculosis MeaB. PMID- 25832175 TI - Prevention of recurrence of tibia and ankle deformities after bone lengthening in children with type II fibular hemimelia. AB - PURPOSE: This study aimed to evaluate development of the tibia after Ilizarov lengthening and deformity correction depending on whether or not the simultaneous resection of fibular anlage was performed in children with fibular aplasia type II, who did not undergo early surgery. METHODS: The study analyses results of reconstructive treatment in 38 children at the age of over four years. Two groups of children are compared: bifocal tibial lengthening with the Ilizarov device (group I) and bifocal lengthening associated with resection of the fibular anlage (group II). The results were estimated at 12 months and in the long-term exceeding three years. RESULTS: Radiological data of measurement of the anatomical lateral distal tibial angle (aLDTA) show surgical correction of deformities achieved in both groups. During the further limb growth a tendency to normalisation of the aLDTA was observed only in the group II. Quick relapse of the angular deformities of the tibial shaft in the first group occurred mainly during further growth of the limb regardless of complete correction at the time of treatment. On the other hand, there were no recurrences of diaphyseal deformities in the group II. CONCLUSIONS: In children with congenital fibular deficiency of type II at the age of four years, the bone lengthening and deformity correction should be associated with fibular anlage resection. That approach improves conditions for distal tibia development and prevents or decreases significantly the recurrence of deformities of the tibia and ankle joint in long-term follow-up. PMID- 25832176 TI - Two potential fish glycerol-3-phosphate phosphatases. AB - Winter-acclimated rainbow smelt (Osmerus mordax Mitchill) produce high levels of glycerol as an antifreeze. A common pathway to glycerol involves the enzyme glycerol-3-phosphate phosphatase (GPP), but no GPP has yet been identified in fish or any other animal. Here, two phosphatases assembled from existing EST libraries (from winter-acclimated smelt and cold-acclimated smelt hepatocytes) were found to resemble a glycerol-associated phosphatase from a glycerol producing alga, Dunaliella salina, and a recently discovered GPP from a bacterium, Mycobacterium tuberculosis. Recombinant proteins were generated and were found to have GPP activity on the order of a few MUMol Pi/mg enzyme/min. The two enzymes have acidic pH optima (~5.5) similar to that previously determined for GPP activity in liver tissue, with about 1/3 of their peak activities at neutral pH. The two enzymes appear to account for the GPP activity of smelt liver, but due to their reduced activities at neutral pH, their contributions to glycerol production in vivo remain unclear. Similar enzymes may be active in a glycerol-producing insect, Dendroctonus ponderosae. PMID- 25832177 TI - Atypical femur fracture during bisphosphonate drug holiday: a case series. AB - Recent studies have noted an increased risk of low energy subtrochanteric and femoral shaft fractures termed "atypical femur fractures" (AFFs) associated with long-term bisphosphonate use. As such, many clinicians have begun recommending a "drug holiday" to reduce the risks associated with long-term bisphosphonate use. We present two cases of AFFs occurring during a 4-year or greater drug holiday following long-term bisphosphonate use. These findings highlight the need to reevaluate optimal bisphosphonate therapy duration, dosage, as well as initiation and duration of a drug holiday with continued monitoring in the prevention of AFFs. PMID- 25832178 TI - Fracture predictive ability of physical performance tests and history of falls in elderly women: a 10-year prospective study. AB - In a large cohort of elderly women followed for 10 years, we found that balance, gait speed, and self-reported history of fall independently predicted fracture. These clinical risk factors are easily evaluated and therefore advantageous in a clinical setting. They would improve fracture risk assessment and thereby also fracture prevention. INTRODUCTION: The aim of this study was to identify additional risk factors for osteoporosis-related fracture by investigating the fracture predictive ability of physical performance tests and self-reported history of falls. METHODS: In the population-based Osteoporosis Prospective Risk Assessment study (OPRA), 1044 women were recruited at the age of 75 and followed for 10 years. At inclusion, knee extension force, standing balance, gait speed, and bone mineral density (BMD) were examined. Falls the year before investigation was assessed by questionnaire. Cox proportional hazards regression analysis was used to determine fracture hazard ratios (HR) with BMD, history of fracture, BMI, smoking habits, bisphosphonate, vitamin D, glucocorticoid, and alcohol use as covariates. Continuous variables were standardized and HR shown for each standard deviation change. RESULTS: Of all women, 427 (41%) sustained at least one fracture during the 10-year follow-up. Failing the balance test had an HR of 1.98 (1.18-3.32) for hip fracture. Each standard deviation decrease in gait speed was associated with an HR of 1.37 (1.14-1.64) for hip fracture. Previous fall had an HR of 1.30 (1.03-1.65) for any fracture; 1.39 (1.08-1.79) for any osteoporosis related fracture; and 1.60 (1.03-2.48) for distal forearm fracture. Knee extension force did not show fracture predictability. CONCLUSION: The balance test, gait speed test, and self-reported history of fall all hold independent fracture predictability. Consideration of these clinical risk factors for fracture would improve the fracture risk assessment and subsequently also fracture prevention. PMID- 25832179 TI - Application of Five Light-Response Models in the Photosynthesis of Populus * Euramericana cv. 'Zhonglin46' Leaves. AB - The light-response curve of photosynthesis is an important tool used to study plant ecophysiology and can provide a scientific basis for the response of plant photosynthetic characteristics to environmental factors. At present, there are five common light-response models of photosynthesis. To gain deeper insight into the applicability of different light-response models of photosynthesis and the photosynthetic physiological characteristics of Populus euramericana cv. 'Zhonglin46', two typical light-response curves of photosynthesis in P. euramericana cv. 'Zhonglin46' leaves, one under drought stress and the other under control conditions, were measured using a CIRAS-2 portable photosynthesis system. The light-response data were divided into two groups: one set of data was used to fit light-response curves, and the other set of data was used to test them. The accuracy of the fitting and the predictions of the different models were evaluated by mean square error and mean absolute error. The results showed that the light-response curves of P. euramericana cv. 'Zhonglin46' under drought stress matched the light-saturated inhibition type and that those under the control condition matched the approaching light-saturation type. The two new models (i.e., the modified rectangular hyperbola model and modified exponential model) fit the two light-response curves and their characteristic parameters well, and the fitting results of the two models were similar. Conversely, the three traditional models (i.e., the rectangular hyperbola model, nonrectangular hyperbola model, and exponential model) did not fit the two light-response curves well; in particular, they overestimated the maximum net photosynthetic rate, underestimated the light saturation point (LSP), and did not fit the net photosynthetic rate during the light-saturated stage. The LSP calculated by the "linear method" combined with the traditional models was significantly lower than the measured values; additionally, the appropriate value of the proportional coefficient was difficult to determine, and the assumed value (empirical value) could easily lead to unreliable results by the "coefficient method". The "estimation method" based on the measured light-response data was still a relatively accurate, simple, and practical way to determine LSP. In addition, the nonrectangular hyperbolic model also had good accuracy and applicability in fitting the approaching light saturation curve on the basis of the "estimation method" to determine LSP. PMID- 25832180 TI - Rapid Simultaneous Detection of Anti-protozoan Drugs Using a Lateral-Flow Immunoassay Format. AB - This research describes the development of a multi-analyte lateral-flow immunoassay intended for the simultaneous detection of three anti-protozoan drugs (coccidiostats). These drugs, namely, halofuginone, toltrazuril and diclazuril, are used in the treatment of Eimeria spp. infections in cattle, pigs, chickens and turkeys. Coloured carboxylated microspheres were coated with each of the detection antibodies and employed in a lateral-flow assay format for detection of these residues in eggs. Using this approach, halofuginone was detectable at a limit of 10 ng/mL or greater, toltrazuril at 100 ng/mL and, similarly, diclazuril had a detection limit of 100 ng/mL, which is below the maximum allowed residue limit for all three as outlined by EU regulation. This simple cost-efficient assay and analysis method could pave the way for more efficient simultaneous monitoring of small-molecule residues in the future. PMID- 25832181 TI - Characterization of the bioactive metabolites from a plant growth-promoting rhizobacteria and their exploitation as antimicrobial and plant growth-promoting agents. AB - A plant growth-promoting bacterial strain, PM 105, isolated from a tea plantation soil from the North Eastern region of India was identified as Pseudomonas aeruginosa through classical and 16S ribosomal DNA (rDNA) gene sequencing. Further studies with this strain confirmed broad spectrum antifungal activity against ten human and plant pathogenic fungal pathogens viz. Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus tubingensis, Candida albicans, Colletotrichum gloeosporioides, Fusarium oxysporum, Pencillium expansum, Rhizoctonia solani, Trichophyton rubrum besides growth-promoting property in cowpea (Vigna unguiculata) and pigeon pea (Cajanus cajan). However, no antibacterial property was exhibited by this strain against the four test bacterial pathogens tested in agar overlay method. The crude bioactive metabolites produced by this strain were isolated with three different solvents that exhibited significant antimicrobial and plant growth-promoting activity. Chloroform extract recorded significant antimicrobial and plant growth-promoting activity. Three major compounds viz. 1-hydroxyphenazine, pyocyanin, and phenazine 1-carboxamide were purified and characterized from crude extracts of this strain by various spectral data. The purified compounds recorded prominent antimicrobial activity but failed to establish the plant growth promotion activity in test crop plants under gnotobiotic conditions. Pyocyanin recorded significant antimicrobial activity, and best activity was recorded against T. rubrum (29 mm), followed by P. expansum (28 mm). These results suggest the use of PM 105 as plant growth promoting agent in crop plants after successful field trials. PMID- 25832182 TI - [81th annual meeting of the german cardiac society - cardiac and circulation research, april 8. - 11. 2015, mannheim]. PMID- 25832183 TI - Tegumental ultrastructure of adult Quinqueserialis quinqueserialis (Trematoda: Notocotylidae): an intestinal parasite of muskrat (Ondatra zibethicus). AB - Ten adult Quinqueserialis quinqueserialis specimens were removed from the intestine of a naturally infected muskrat, and scanning electron microscopy was used to study the morphological characteristics of the trematodes. The mature trematode, which was easy to recognize by the monostome holdfast organ, with no anterior cone, measured 2200-2500 MUm in length by 900-1050 MUm in width. The body was elongated and tapering at the anterior end, but the posterior end was rounded, and in some specimens was slightly truncated. The mouth opening lay at the anterior end and was surrounded by the oral sucker, which was round, small to medium in size, and subterminal. The tegument of the rim and inside of the oral sucker was smooth and had two types of papillae, domed and rosette papillae. Around the oral sucker, tegument was covered with sharp, pointed spines. The common genital pore was located on the median line of the body, posterior to the oral sucker. The cirrus had smooth tegument at the base and was armed with numerous conical spines throughout its length. The ventral surface was concave and provided with five distinct longitudinal rows of ventral papillae, which extended from the anterior to the posterior end of the body. Each row consisted of 15 to 20 papillae, making 81 to 88 papillae in all. These papillae were variable in size. In most specimens, the papillae were simple knob-like structures, but in some cases, they appeared to be bi- or trifurcate. The tegument at the base of each ventral papilla showed minute spiny pattern, but it was smooth or folded on top and had small rosette and ciliated papillae. Tegument at the edges of the worm was smooth in the mid-parts, spiny on lateral parts, and included rosette papillae. The dorsal surface of the worm was smooth and slightly convex, and the tegument was provided with two large domed papillae in one third of the anterior end of the dorsal part, few thick spines in the mid-part, and excretory pore at the level just posterior to the end. No spines or papillae were seen around the excretory pore. PMID- 25832184 TI - Inhibition of return: A phenomenon in search of a definition and a theoretical framework. AB - In a study of scientific nomenclature, we explore the diversity of perspectives researchers endorse for the phenomenon of inhibition of return (IOR). IOR is often described as an effect whereby people are slower to respond to a target presented at a recently stimulated or inspected location as compared to a target presented at a new location. Since its discovery, scores of papers have been published on IOR, and researchers have proposed, accepted and rejected a variety of potential causes, mechanisms, effects and components for the phenomenon. Experts in IOR were surveyed about their opinions regarding various aspects of IOR and the literature exploring it. We found variety both between and within experts surveyed, suggesting that most researchers hold implicit, and often quite unique assumptions about IOR. These widely varied assumptions may be hindering the creation or acceptance of a central theoretical framework regarding IOR; and this variety may portend that what has been given the label "IOR" may be more than one phenomenon requiring more than one theoretical explanation. We wonder whether scientific progress in domains other than IOR might be affected by too broad (or perhaps too narrow) a range of phenomena to which our nomenclature is applied. PMID- 25832186 TI - Introducing a control condition in the classic oddball paradigm: Oddballs are overestimated in duration not only because of their oddness. AB - Three experiments assessed whether participants perceive infrequent stimuli (oddballs) to last longer than frequent ones (standards). The classical oddball paradigm was modified so that participants judged the duration of a target stimulus which could either be a standard or an oddball. The target was always the fifth stimulus in the stream and all stimuli were presented at predefined spatial positions. These modifications enabled a direct comparison of duration judgments for oddballs and standards. In Experiments 1 and 2 not only the duration of oddballs but also the duration of standards was overestimated by virtually the same amount. In other words, the overestimation of oddballs was not due to their oddness but reflected a different temporal dilation such as the negative time-order error. In Experiment 3, all stimuli were presented at the same spatial position. Again, both oddballs and standards were overestimated, however, oddballs more so. The present results highlight the importance of comparing the judged duration of oddballs and standards when evaluating the size of the genuine oddball effect. Furthermore, the findings suggest that the occurrence of temporal oddball effects can depend on spatial features of stimulus presentation. PMID- 25832187 TI - Effects of stimulus order on discrimination sensitivity for short and long durations. AB - Previous studies have shown that discrimination sensitivity in 2AFC tasks depends on the presentation order of the standard and comparison stimulus. The present study examined whether this so-called Type B effect generalizes across different standard magnitudes. Therefore, Experiment 1 employed an auditory duration discrimination task with short (100 ms) and long (1,000 ms) standard durations and a constant interstimulus interval (ISI) of 1,000 ms. For both standard durations, a clear Type B effect emerged. In Experiment 2, discrimination sensitivity was assessed for short (300 ms) and long (1,000 ms) ISIs and a constant standard duration of 100 ms, in order to examine whether the Type B effect diminishes or even reverses when both stimuli are presented in rapid succession, as was suggested by previous studies. In the short, but not the long ISI condition, the Type B effect was virtually eliminated. Taken together, the present experiments suggest that the Type B effect is robust across standard magnitude, but diminishes when the time interval between both stimuli is reduced. This result pattern is discussed within the framework of the Internal Reference Model and the Sensation Weighting Model. It is also demonstrated that both models provide a quantitative account of the present results. PMID- 25832185 TI - The long and the short of priming in visual search. AB - Memory affects visual search, as is particularly evident from findings that when target features are repeated from one trial to the next, selection is faster. Two views have emerged on the nature of the memory representations and mechanisms that cause these intertrial priming effects: independent feature weighting versus episodic retrieval of previous trials. Previous research has attempted to disentangle these views focusing on short term effects. Here, we illustrate that the episodic retrieval models make the unique prediction of long-term priming: biasing one target type will result in priming of this target type for a much longer time, well after the bias has disappeared. We demonstrate that such long term priming is indeed found for the visual feature of color, but only in conjunction search and not in singleton search. Two follow-up experiments showed that it was the kind of search (conjunction versus singleton) and not the difficulty, that determined whether long-term priming occurred. Long term priming persisted unaltered for at least 200 trials, and could not be explained as the result of explicit strategy. We propose that episodic memory may affect search more consistently than previously thought, and that the mechanisms for intertrial priming may be qualitatively different for singleton and conjunction search. PMID- 25832188 TI - Experience shapes our odor perception but depends on the initial perceptual processing of the stimulus. AB - The questions of whether configural and elemental perceptions are competitive or exclusive perceptual processes and whether they rely on independent or dependent mechanisms are poorly understood. To examine these questions, we modified perceptual experience through preexposure to mixed or single odors and measured the resulting variation in the levels of configural and elemental perception of target odor mixtures. We used target mixtures that were spontaneously processed in a configural or an elemental manner. The AB binary mixture spontaneously involved the configural perception of a pineapple odor, whereas component A smelled like strawberry and component B smelled like caramel. The CD mixture produced the elemental perceptions of banana (C) and smoky (D) odors. Perceptual experience was manipulated through repeated exposure to either a mixture (AB or CD) or the components (A and B or C and D). The odor typicality rating data recorded after exposure revealed different influences of experience on odor mixtures and single-component perception, depending both on the type of exposure (components or mixture) and the mixture's initial perceptual property (configural or elemental). Although preexposure to A and B decreased the pineapple typicality of the configural AB mixture, preexposure to AB did not modify its odor quality. In contrast, preexposure to the CD elemental mixture induced a quality transfer between the components. These results emphasize the relative plasticity of odor mixture perception, which is prone to experience-induced modulations but depends on the stimulus's initial perceptual properties, suggesting that configural and elemental forms of odor mixture perception rely on rather independent processes. PMID- 25832189 TI - Rhesus macaques (Macaca mulatta) exhibit the decoy effect in a perceptual discrimination task. AB - The asymmetric dominance effect (or decoy effect) is a form of context-dependent choice bias in which the probability of choosing one of two options is impacted by the introduction of a third option, also known as the decoy. Decoy effects are documented widely within the human consumer choice literature, and even extend to preference testing within nonhuman animals. Here, we extended this line of research to a perceptual discrimination task with rhesus monkeys to determine whether decoy stimuli would impact size judgments of rectangular stimuli. In a computerized task, monkeys attempted to choose the larger of two rectangles that varied in size and orientation (horizontally or vertically oriented). In probe trials, a third stimulus (the decoy) was presented that was smaller than the other two rectangles but matched the orientation of one of them. On half of the probe trials, the presented decoy matched the orientation of the larger stimulus, and on the other half, the decoy matched the orientation of the smaller stimulus. Monkeys rarely selected the decoy stimulus. However, their performance (selection of the largest rectangle) increased relative to the baseline trials (with only two choices) when the decoy was congruent in its orientation with the largest rectangle, but decreased relative to baseline when the decoy was incongruent with the largest rectangle. Thus, a decoy stimulus impacted monkeys' perceptual choice behavior even when it was not a viable choice option itself. These results are explained with regard to comparative evaluation mechanisms. PMID- 25832190 TI - Oculomotor Capture by New and Unannounced Color Singletons during Visual Search. AB - The surprise capture hypothesis states that a stimulus will capture attention to the extent that it is preattentively available and deviates from task expectancies. Interestingly, it has been noted by Horstmann (Psychological Science 13: 499-505. doi: 10.1111/1467-9280.00488, 2002, Human Perception and Performance 31: 1039-1060. doi: 10.1037/00961523.31.5.1039, 2005, Psychological Research, 70, 13-25, 2006) that the time course of capture by such classes of stimuli appears distinct from that of capture by expected stimuli. Specifically, attention shifts to an unexpected stimulus are delayed relative to an expected stimulus (delayed onset account). Across two experiments, we investigated this claim under conditions of unguided (Exp. 1) and guided (Exp. 2) search using eye movements as the primary index of attentional selection. In both experiments, we found strong evidence of surprise capture for the first presentation of an unannounced color singleton. However, in both experiments the pattern of eye movements was not consistent with a delayed onset account of attention capture. Rather, we observed costs associated with the unexpected stimulus only once the target had been selected. We propose an interference account of surprise capture to explain our data and argue that this account also can explain existing patterns of data in the literature. PMID- 25832191 TI - Vicarious experiences and detection accuracy while observing pain and touch: The effect of perspective taking. AB - In this study, we investigated the effects of observing pain and touch in others on vicarious somatosensory experiences and the detection of subtle somatosensory stimuli. Furthermore, the effect of taking a first- versus a third-person perspective was investigated. Undergraduates (N = 57) viewed videos depicting hands being pricked (pain), hands being touched by a cotton swab (touch), and control scenes (same approaching movement of a hand as in the other video categories, but without the painful/touching object) while experiencing vibrotactile stimuli themselves on the left, on the right, or on both hands. Participants reported the location at which they felt a somatosensory stimulus. The vibrotactile stimuli and visual scenes were applied in a spatially congruent or incongruent way, and other trials were presented without vibrotactile stimuli. The videos were depicted in first-person perspective and third-person perspective (i.e., the videos were shown upside down). We calculated the proportions of correct responses and false alarms (i.e., numbers of trials on which a vicarious somatosensory experience was reported congruent or incongruent to the site of the visual information). Pain-related scenes facilitated the detection of tactile stimuli and augmented the number of vicarious somatosensory experiences, as compared with observing the touch or control videos. Detection accuracy was higher for videos depicted in first-person perspective than for those in third person perspective. Perspective had no effect on the number of vicarious somatosensory experiences. This study indicates that somatosensory detection is particularly enhanced during the observation of pain-related scenes, as compared to the observation of touch or control videos. These research findings further demonstrate that perspective taking impacts somatosensory detection, but not the report of vicarious experiences. PMID- 25832193 TI - There is more to trial history than priming in attentional capture experiments. AB - We used contingent attentional capture to investigate whether capture in a given trial n was affected by the cue-target position relations in a preceding trial n 1. Typically, attentional capture by a cue facilitates reaction times for targets in valid conditions (with the cue and target at the same position) relative to invalid conditions (with the cue and target at different positions). Also, this validity effect holds for cues with a feature similar to the searched-for target features (i.e., matching cues), but not for cues dissimilar to the searched-for target features (i.e., nonmatching cues), a pattern termed contingent capture because capture is assumed to be contingent on the match between the cue and top down control settings. Here, we replicated this contingent-capture pattern with cues that were nonpredictive of the target position. In addition, we showed that during search for white onset targets, red nonmatching color cues also created a validity effect if the same nonmatching cue had been used as a valid cue in trial n-1 (Exps. 1 and 2). This intertrial contingency of the nonmatching cue's validity effect was also found if the cues and targets both changed their positions from trial to trial, rendering position priming unlikely (Exp. 2). A similar intertrial contingency was found for nonmatching white onset cues, but not for matching red color cues during search for red color targets (Exp. 3). These results are discussed in light of explanations of the contingent-capture effect and of intertrial contingencies. PMID- 25832192 TI - The effects of visual search efficiency on object-based attention. AB - The attentional prioritization hypothesis of object-based attention (Shomstein & Yantis in Perception & Psychophysics, 64, 41-51, 2002) suggests a two-stage selection process comprising an automatic spatial gradient and flexible strategic (prioritization) selection. The combined attentional priorities of these two stages of object-based selection determine the order in which participants will search the display for the presence of a target. The strategic process has often been likened to a prioritized visual search. By modifying the double-rectangle cueing paradigm (Egly, Driver, & Rafal in Journal of Experimental Psychology: General, 123, 161-177, 1994) and placing it in the context of a larger-scale visual search, we examined how the prioritization search is affected by search efficiency. By probing both targets located on the cued object and targets external to the cued object, we found that the attentional priority surrounding a selected object is strongly modulated by search mode. However, the ordering of the prioritization search is unaffected by search mode. The data also provide evidence that standard spatial visual search and object-based prioritization search may rely on distinct mechanisms. These results provide insight into the interactions between the mode of visual search and object-based selection, and help define the modulatory consequences of search efficiency for object-based attention. PMID- 25832194 TI - Visit-to-visit variability in systolic blood pressure is a risk factor for rapid loss of residual renal function in peritoneal dialysis patients. AB - Visit-to-visit systolic blood pressure variability (VTV-SBPV) is correlated with cardiovascular complications. However, it still remains unclear whether VTV-SBPV is related to cardiovascular outcomes in patients with peritoneal dialysis (PD), who often manifest hypertension. We, therefore, evaluated the association of VTV SBPV with all-cause mortality, cardiovascular complications, or the loss of residual renal function (RRF) that is a powerful predictor of mortality and morbidity in PD patients. We retrospectively reviewed the medical records for patients undergoing maintenance PD for at least 12 months at Seoul National University Hospital. The patients were divided into quartiles of VTV-SBPV based on the standard deviation of systolic blood pressure (SBP). We checked the SBP of the patients for up to 2 years after the initiation of PD. Among 216 PD patients, 16 primary outcome events (cardiovascular complications and all-cause mortality) occurred. VTV-SBPV was not associated with primary outcomes. During the follow up, RRF loss occurred in 46 patients. The hazard ratios (HRs) for the loss of RRF in the 4 quartiles of VTV-SBPV, based on the highest to the lowest variability, were as follows: 6.201 (95% CI: 1.982-19.401, p = 0.002), 2.542 (95% CI: 0.859 7.523, p = 0.092), and 2.133 (95% CI: 0.635-7.165, p = 0.246), respectively. The loss of RRF was more frequently detected in patients with higher VTV-SBPV. VTV SBPV was indicated as an independent risk factor for the loss of RRF. Therefore, the degree of variations in SBP should be carefully monitored to preserve the RRF of these patients. PMID- 25832195 TI - An Air-Stable DPP-thieno-TTF Copolymer for Single-Material Solar Cell Devices and Field Effect Transistors. AB - Following an approach developed in our group to incorporate tetrathiafulvalene (TTF) units into conjugated polymeric systems, we have studied a low band gap polymer incorporating TTF as a donor component. This polymer is based on a fused thieno-TTF unit that enables the direct incorporation of the TTF unit into the polymer, and a second comonomer based on the diketopyrrolopyrrole (DPP) molecule. These units represent a donor-acceptor copolymer system, p(DPP-TTF), showing strong absorption in the UV-visible region of the spectrum. An optimized p(DPP TTF) polymer organic field effect transistor and a single material organic solar cell device showed excellent performance with a hole mobility of up to 5.3 * 10( 2) cm(2)/(V s) and a power conversion efficiency (PCE) of 0.3%, respectively. Bulk heterojunction organic photovoltaic devices of p(DPP-TTF) blended with phenyl-C71-butyric acid methyl ester (PC71BM) exhibited a PCE of 1.8%. PMID- 25832197 TI - Electrochemical synthesis of ultrafast and gram-scale surfactant-free tellurium nanowires by gas-solid transformation and their applications as supercapacitor electrodes for p-doping of graphene transistors. AB - We herein report a gas-solid transformation mechanism for the surfactant-free synthesis of Te NWs at room temperature by electrolysis of bulk Bi2Te3 using H2Te gas. Te NWs, with an average diameter below 20 nm, grow along the [001] direction due to the unique spiral chains in the crystal structure and show an enhanced Raman scattering effect, a broad absorption band over the range of 350-750 nm and an emission band over the range of 400-700 nm in the photoluminescence spectrum. In terms of device applications, we demonstrate how Te NWs can be directly applied as a p-type dopant source in order to shift the Dirac point in ambipolar field effect graphene transistors. Finally, the favorable capacitive properties of Te NWs are established as supercapacitor electrodes with negligible internal resistance and excellent electrochemical reversibility and a specific capacitance of 24 F g(-1). PMID- 25832196 TI - Structural characterization of metal binding to a cold-adapted frataxin. AB - Frataxin is an evolutionary conserved protein that participates in iron metabolism. Deficiency of this small protein in humans causes a severe neurodegenerative disease known as Friedreich's ataxia. A number of studies indicate that frataxin binds iron and regulates Fe-S cluster biosynthesis. Previous structural studies showed that metal binding occurs mainly in a region of high density of negative charge. However, a comprehensive characterization of the binding sites is required to gain further insights into the mechanistic details of frataxin function. In this work, we have solved the X-ray crystal structures of a cold-adapted frataxin from a psychrophilic bacterium in the presence of cobalt or europium ions. We have identified a number of metal-binding sites, mainly solvent exposed, several of which had not been observed in previous studies on mesophilic homologues. No major structural changes were detected upon metal binding, although the structures exhibit significant changes in crystallographic B-factors. The analysis of these B-factors, in combination with crystal packing and RMSD among structures, suggests the existence of localized changes in the internal motions. Based on these results, we propose that bacterial frataxins possess binding sites of moderate affinity for a quick capture and transfer of iron to other proteins and for the regulation of Fe-S cluster biosynthesis, modulating interactions with partner proteins. PMID- 25832198 TI - delta-Tocopherol prevents methylglyoxal-induced apoptosis by reducing ROS generation and inhibiting apoptotic signaling cascades in human umbilical vein endothelial cells. AB - Methylglyoxal (MGO) is a highly reactive metabolite of glucose, which is known to cause damage and induce apoptosis in endothelial cells. Endothelial cell damage is implicated in the progression of diabetes-associated complications and atherosclerosis. Nuts are high in vitamin E. Consumption of nuts has been recommended for the prevention of cardiovascular disease. However, different nuts contain different forms of vitamin E, which can have different effects on endothelial cells. In this work, we investigated the protective effect of different isoforms of vitamin E on MGO-induced apoptosis in human umbilical vein endothelial cells (HUVECs). Among all forms of vitamin E, delta-tocopherol showed the highest effect on apoptosis of HUVECs. We also compared the anti-apoptotic activity of delta-tocopherol with that of alpha-tocopherol in MGO-treated HUVECs. Pretreatment with alpha- or delta-tocopherol significantly inhibited MGO-induced changes in cell morphology, cell death, and production of intracellular reactive oxygen species. delta-Tocopherol prevented MGO-induced apoptosis in HUVECs by increasing Bcl-2 expression and decreasing Bax expression. Interestingly, alpha tocopherol also inhibited these factors but to a lesser extent than delta tocopherol. MGO was found to activate mitogen-activated protein kinases (MAPKs). Compared to pretreatment with alpha-tocopherol, pretreatment with delta tocopherol more strongly inhibited the activation of MAPKs, such as JNK and ERK1/2. These findings suggest that delta-tocopherol may be a more effective regulator of MGO-induced apoptosis than alpha-tocopherol. PMID- 25832200 TI - Ultrafast optical tuning of ferromagnetism via the carrier density. AB - Interest in manipulating the magnetic order by ultrashort laser pulses has thrived since it was observed that such pulses can be used to alter the magnetization on a sub-picosecond timescale. Usually this involves demagnetization by laser heating or, in rare cases, a transient increase of magnetization. Here we demonstrate a mechanism that allows the magnetic order of a material to be enhanced or attenuated at will. This is possible in systems simultaneously possessing a low, tunable density of conduction band carriers and a high density of magnetic moments. In such systems, the thermalization time can be set such that adiabatic processes dominate the photoinduced change of the magnetic order--the three-temperature model for interacting thermalized electron, spin and lattice reservoirs is bypassed. In ferromagnetic Eu(1-x)Gd(x)O, we thereby demonstrate the strengthening as well as the weakening of the magnetic order by ~10% and within <=3 ps by optically controlling the magnetic exchange interaction. PMID- 25832201 TI - A rare case of medulloblastoma coexisting with multiple spinal intramedullary tumors. AB - Medulloblastoma is the most common primary central nervous system tumor of childhood. Medulloblastoma can metastasize along the neuraxis and to extraneural locations, but multiple intramedullary spinal metastases are very rare. The usual presenting clinical features are related to posterior fossa syndrome and/or hydrocephalus. We describe a unique case of medulloblastoma with multiple intramedullary lesions at the D-7 and D-12 levels. PMID- 25832203 TI - A brief behavioral intervention targeting mental health risk factors for vascular disease: a pilot study. PMID- 25832204 TI - Contributed review: quantum cascade laser based photoacoustic detection of explosives. AB - Detecting trace explosives and explosive-related compounds has recently become a topic of utmost importance for increasing public security around the world. A wide variety of detection methods and an even wider range of physical chemistry issues are involved in this very challenging area. Optical sensing methods, in particular mid-infrared spectrometry techniques, have a great potential to become a more desirable tools for the detection of explosives. The small size, simplicity, high output power, long-term reliability make external cavity quantum cascade lasers (EC-QCLs) the promising spectroscopic sources for developing analytical instrumentation. This work reviews the current technical progress in EC-QCL-based photoacoustic spectroscopy for explosives detection. The potential for both close-contact and standoff configurations using this technique is completely presented over the course of approximately the last one decade. PMID- 25832205 TI - A magnetic stirring setup for applications in ultrafast spectroscopy of photo sensitive solutions. AB - An exchange system is presented, which allows ultrafast experiments with high excitation rates (1 kHz) on samples with reaction cycles in the range of a few seconds and small sample volumes of about 0.3 ml. The exchange is accomplished using a commercially available cuvette by the combination of a special type of magnetic stirring with transverse translational motion of the sample cuvette. PMID- 25832206 TI - Time-of-flight Extreme Environment Diffractometer at the Helmholtz-Zentrum Berlin. AB - The Extreme Environment Diffractometer (EXED) is a new neutron time-of-flight instrument at the BER II research reactor at the Helmholtz-Zentrum Berlin, Germany. Although EXED is a special-purpose instrument, its early construction made it available for users as a general-purpose diffractometer. In this respect, EXED became one of the rare examples, where the performance of a time-of-flight diffractometer at a continuous source can be characterized. In this paper, we report on the design and performance of EXED with an emphasis on the unique instrument capabilities. The latter comprise variable wavelength resolution and wavelength band, control of the incoming beam divergence, the possibility to change the angular positions of detectors and their distance to the sample, and use of event recording and offline histogramming. These features combined make EXED easily tunable to the requirements of a particular problem, from conventional diffraction to small angle neutron scattering. The instrument performance is demonstrated by several reference measurements and user experiments. PMID- 25832207 TI - Switchable Q-switched and modelocked operation in ytterbium doped fiber laser under all-normal-dispersion configuration. AB - We have constructed an Yb-doped fiber laser in all-normal-dispersion configuration which can be independently operated in Q-switched or modelocked configuration with the help of a simple fiber optic ring resonator (FORR). In the presence of FORR, the laser operates in Q-switched mode producing stable pulses in the range of 1 MUs-200 ns with repetition rate in the range of 45 kHz-82 kHz. On the other hand, the laser can be easily switched to mode-locked operation by disjoining the FORR loop producing train of ultrashort pulses of ~5 ps duration (compressible to ~150 fs) at ~38 MHz repetition rate. The transmission characteristics of FORR in combination with the nonlinear polarization rotation for passive Q-switching operation is numerically investigated and experimentally verified. The laser can serve as a versatile seed source for power amplifier which can be easily configured for application in the fields that require different pulsed fiber lasers. PMID- 25832208 TI - PHARAO laser source flight model: design and performances. AB - In this paper, we describe the design and the main performances of the PHARAO laser source flight model. PHARAO is a laser cooled cesium clock specially designed for operation in space and the laser source is one of the main sub systems. The flight model presented in this work is the first remote-controlled laser system designed for spaceborne cold atom manipulation. The main challenges arise from mechanical compatibility with space constraints, which impose a high level of compactness, a low electric power consumption, a wide range of operating temperature, and a vacuum environment. We describe the main functions of the laser source and give an overview of the main technologies developed for this instrument. We present some results of the qualification process. The characteristics of the laser source flight model, and their impact on the clock performances, have been verified in operational conditions. PMID- 25832209 TI - Electron and recoil ion momentum imaging with a magneto-optically trapped target. AB - A reaction microscope (ReMi) has been combined with a magneto-optical trap (MOT) for the kinematically complete investigation of atomic break-up processes. With the novel MOTReMi apparatus, the momentum vectors of the fragments of laser cooled and state-prepared lithium atoms are measured in coincidence and over the full solid angle. The first successful implementation of a MOTReMi could be realized due to an optimized design of the present setup, a nonstandard operation of the MOT, and by employing a switching cycle with alternating measuring and trapping periods. The very low target temperature in the MOT (~2 mK) allows for an excellent momentum resolution. Optical preparation of the target atoms in the excited Li 2(2)P3/2 state was demonstrated providing an atomic polarization of close to 100%. While first experimental results were reported earlier, in this work, we focus on the technical description of the setup and its performance in commissioning experiments involving target ionization in 266 nm laser pulses and in collisions with projectile ions. PMID- 25832210 TI - A design study for a compact two stage in-flight separator with a high mass resolution and large acceptance. AB - The rare isotope beam separator with a large angular acceptance and energy acceptance is essential for examining the characteristics of unstable nuclei and exotic nuclear reactions. Careful design, however, is required to compensate for the effects of high order aberrations induced by large aperture magnets, which are used to collect rare isotopes obtained from a high energy primary heavy-ion beam hitting a target. In order to minimize the effect of the high order aberration, the optics was based on the mirror symmetry optics, which provides smaller high order aberrations, for the separation of (132)Sn produced by a fission reaction between the primary beam of (238)U and a relatively thick Pb target. The designed optics provides energy acceptance (full), horizontal angular acceptance, and vertical acceptance of approximately 8%, 60 mrad, and 130 mrad, respectively. PMID- 25832211 TI - An ion trap built with photonic crystal fibre technology. AB - We demonstrate a surface-electrode ion trap fabricated using techniques transferred from the manufacture of photonic-crystal fibres. This provides a relatively straightforward route for realizing traps with an electrode structure on the 100 micron scale with high optical access. We demonstrate the basic functionality of the trap by cooling a single ion to the quantum ground state, allowing us to measure a heating rate from the ground state of 787 +/- 24 quanta/s. Variation of the fabrication procedure used here may provide access to traps in this geometry with trap scales between 100 MUm and 10 MUm. PMID- 25832212 TI - Flexible attosecond beamline for high harmonic spectroscopy and XUV/near-IR pump probe experiments requiring long acquisition times. AB - We describe the versatile features of the attosecond beamline recently installed at CEA-Saclay on the PLFA kHz laser. It combines a fine and very complete set of diagnostics enabling high harmonic spectroscopy (HHS) through the advanced characterization of the amplitude, phase, and polarization of the harmonic emission. It also allows a variety of photo-ionization experiments using magnetic bottle and COLTRIMS (COLd Target Recoil Ion Momentum Microscopy) electron spectrometers that may be used simultaneously, thanks to a two-foci configuration. Using both passive and active stabilization, special care was paid to the long term stability of the system to allow, using both experimental approaches, time resolved studies with attosecond precision, typically over several hours of acquisition times. As an illustration, applications to multi orbital HHS and electron-ion coincidence time resolved spectroscopy are presented. PMID- 25832213 TI - Tunable beam displacer. AB - We report the implementation of a tunable beam displacer, composed of a polarizing beam splitter (PBS) and two mirrors, that divides an initially polarized beam into two parallel beams whose separation can be continuously tuned. The two output beams are linearly polarized with either vertical or horizontal polarization and no optical path difference is introduced between them. The wavelength dependence of the device as well as the maximum separation between the beams achievable is limited mainly by the PBS characteristics. PMID- 25832214 TI - A simplified scheme for generating narrow-band mid-ultraviolet laser radiation. AB - We report on the development and characterization of continuous, narrow-band, and tunable laser systems that use direct second-harmonic generation from blue and green diode lasers with an output power level of up to 11.1 mW in the mid ultraviolet. One of our laser systems was tuned to the mercury 6(1)S0 -> 6(3)P1 intercombination line at 253.7 nm. We could perform Doppler-free saturation spectroscopy on this line and were able to lock our laser to the transition frequency on long time scales. PMID- 25832215 TI - The resilient hybrid fiber sensor network with self-healing function. AB - This paper presents a novel resilient fiber sensor network (FSN) with multi-ring architecture, which could interconnect various kinds of fiber sensors responsible for more than one measurands. We explain how the intelligent control system provides sensors with self-healing function meanwhile sensors are working properly, besides each fiber in FSN is under real-time monitoring. We explain the software process and emergency mechanism to respond failures or other circumstances. To improve the efficiency in the use of limited spectrum resources in some situations, we have two different structures to distribute the light sources rationally. Then, we propose a hybrid sensor working in FSN which is a combination of a distributed sensor and a FBG (Fiber Bragg Grating) array fused in a common fiber sensing temperature and vibrations simultaneously with neglectable crosstalk to each other. By making a failure to a working fiber in experiment, the feasibility and effectiveness of the network with a hybrid sensor has been demonstrated, hybrid sensors could not only work as designed but also survive from destructive failures with the help of resilient network and smart and quick self-healing actions. The network has improved the viability of the fiber sensors and diversity of measurands. PMID- 25832216 TI - An in situ sample environment reaction cell for spatially resolved X-ray absorption spectroscopy studies of powders and small structured reactors. AB - An easy-to-use sample environment reaction cell for X-ray based in situ studies of powders and small structured samples, e.g., powder, pellet, and monolith catalysts, is described. The design of the cell allows for flexible use of appropriate X-ray transparent windows, shielding the sample from ambient conditions, such that incident X-ray energies as low as 3 keV can be used. Thus, in situ X-ray absorption spectroscopy (XAS) measurements in either transmission or fluorescence mode are facilitated. Total gas flows up to about 500 mln/min can be fed while the sample temperature is accurately controlled (at least) in the range of 25-500 degrees C. The gas feed is composed by a versatile gas-mixing system and the effluent gas flow composition is monitored with mass spectrometry (MS). These systems are described briefly. Results from simultaneous XAS/MS measurements during oxidation of carbon monoxide over a 4% Pt/Al2O3 powder catalyst are used to illustrate the system performance in terms of transmission XAS. Also, 2.2% Pd/Al2O3 and 2% Ag - Al2O3 powder catalysts have been used to demonstrate X-ray absorption near-edge structure (XANES) spectroscopy in fluorescence mode. Further, a 2% Pt/Al2O3 monolith catalyst was used ex situ for transmission XANES. The reaction cell opens for facile studies of structure function relationships for model as well as realistic catalysts both in the form of powders, small pellets, and coated or extruded monoliths at near realistic conditions. The applicability of the cell for X-ray diffraction measurements is discussed. PMID- 25832217 TI - 2-D energy analyzer for low energy electrons. AB - A 2-D electron energy analyzer is designed and constructed to measure the transverse and longitudinal energy distribution of low energy (<1 eV) electrons. The analyzer operates on the principle of adiabatic invariance and motion of low energy electrons in a strong longitudinal magnetic field. The operation of the analyzer is studied in detail and a design to optimize the energy resolution, signal to noise ratio, and physical size is presented. An energy resolution better than 6 meV has been demonstrated. Such an analyzer is a powerful tool to study the process of photoemission which limits the beam quality in modern accelerators. PMID- 25832218 TI - Development of an interpretive simulation tool for the proton radiography technique. AB - Proton radiography is a useful diagnostic of high energy density (HED) plasmas under active theoretical and experimental development. In this paper, we describe a new simulation tool that interacts realistic laser-driven point-like proton sources with three dimensional electromagnetic fields of arbitrary strength and structure and synthesizes the associated high resolution proton radiograph. The present tool's numerical approach captures all relevant physics effects, including effects related to the formation of caustics. Electromagnetic fields can be imported from particle-in-cell or hydrodynamic codes in a streamlined fashion, and a library of electromagnetic field "primitives" is also provided. This latter capability allows users to add a primitive, modify the field strength, rotate a primitive, and so on, while quickly generating a high resolution radiograph at each step. In this way, our tool enables the user to deconstruct features in a radiograph and interpret them in connection to specific underlying electromagnetic field elements. We show an example application of the tool in connection to experimental observations of the Weibel instability in counterstreaming plasmas, using ~10(8) particles generated from a realistic laser driven point-like proton source, imaging fields which cover volumes of ~10 mm(3). Insights derived from this application show that the tool can support understanding of HED plasmas. PMID- 25832219 TI - On the analysis of inhomogeneous magnetic field spectrometer for laser-driven ion acceleration. AB - We present a detailed study of the use of a non-parallel, inhomogeneous magnetic field spectrometer for the investigation of laser-accelerated ion beams. Employing a wedged yoke design, we demonstrate the feasibility of an in-situ self calibration technique of the non-uniform magnetic field and show that high precision measurements of ion energies are possible in a wide-angle configuration. We also discuss the implications of a stacked detector system for unambiguous identification of different ion species present in the ion beam and explore the feasibility of detection of high energy particles beyond 100 MeV/amu in radiation harsh environments. PMID- 25832220 TI - An analytical study of double bend achromat lattice. AB - In a double bend achromat, Chasman-Green (CG) lattice represents the basic structure for low emittance synchrotron radiation sources. In the basic structure of CG lattice single focussing quadrupole (QF) magnet is used to form an achromat. In this paper, this CG lattice is discussed and an analytical relation is presented, showing the limitation of basic CG lattice to provide the theoretical minimum beam emittance in achromatic condition. To satisfy theoretical minimum beam emittance parameters, achromat having two, three, and four quadrupole structures is presented. In this structure, different arrangements of QF and defocusing quadruple (QD) are used. An analytical approach assuming quadrupoles as thin lenses has been followed for studying these structures. A study of Indus-2 lattice in which QF-QD-QF configuration in the achromat part has been adopted is also presented. PMID- 25832221 TI - On the detection of mesospheric meteoric smoke particles embedded in noctilucent cloud particles with rocket-borne dust probes. AB - Mesospheric nanoparticles in the forms of water ice particles and meteoric smoke particles (MSPs) exist in the middle atmosphere where they often play a decisive role in cloud formation and in chemical processes. Direct in situ observations of mesospheric nanoparticles have been made possible by rocket probes developed during the last two decades. Although progress has been made in mapping properties such as electric charge, sizes, and interaction with the plasma and neutral gas, more observations are needed on the size distribution, chemical content, and structure of the MSP to determine their role in cloud formation and chemistry in the mesosphere and stratosphere. We here present the result of a detailed analysis of the performance of a new dust probe MUltiple Dust Detector (MUDD) [O. Havnes et al., J. Atmos Soll.-Terr. Phys. 118, 190 (2014); O. Havenes et al., ibid. (in press)], which should give information of the size distribution of MSP by fragmenting impacting ice particles and releasing a fraction of the MSP which most probably are embedded in them [O. Havnes and L. I. Naesheim, Ann. Geophys. 25, 623 (2007); M. E. Hervig et al., J. Atmos. Sol.-Terr. Phys. 84-85, 1 (2012)]. We first determine the electric field structure and neutral gas condition in the interior of the probe and from this compute, the dynamics and current contribution of the charged fragments to the currents measured as the probe scans the fragment energy. For the single MUDD probe flown in July 2011 on the PHOCUS payload, we find that the fragment currents at the three retarding potentials for MUDD of 0, 10, and 20 V correspond to fragment sizes of ?0.6 nm, >1.5 nm, and >1.8 nm if the fragments have a negative unit charge. We also discuss the optimum choice of retarding potentials in future flights of MUDD probes. By launching 2 to 3 mechanically identical MUDD probes but with different retarding potentials, we will obtain a much more detailed and reliable fragment (MSP) size distribution. PMID- 25832222 TI - Implementation of EPICS based vacuum control system for variable energy cyclotron centre, Kolkata. AB - The vacuum system of the Room Temperature (K = 130) Cyclotron of Variable Energy Cyclotron Centre is comprised of vacuum systems of main machine and Beam Transport System. The vacuum control system is upgraded to a PLC based Automated system from the initial relay based Manual system. The supervisory control of the vacuum system is implemented in Experimental Physics and Industrial Control System (EPICS). An EPICS embedded ARM based vacuum gauge controller is developed to mitigate the requirement of vendor specific gauge controller for gauges and also for seamless integration of the gauge controllers with the control system. A set of MS-Windows ActiveX components with embedded EPICS Channel Access interface are developed to build operator interfaces with less complex programming and to incorporate typical Windows feature, e.g., user authentication, file handling, better fonts, colors, mouse actions etc. into the operator interfaces. The control parameters, monitoring parameters, and system interlocks of the system are archived in MySQL based EPICS MySQL Archiver developed indigenously. In this paper, we describe the architecture, the implementation details, and the performance of the system. PMID- 25832223 TI - Impact of x-ray dose on the response of CR-39 to 1-5.5 MeV alphas. AB - The CR-39 nuclear track detector is used in many nuclear diagnostics fielded at inertial confinement fusion (ICF) facilities. Large x-ray fluences generated by ICF experiments may impact the CR-39 response to incident charged particles. To determine the impact of x-ray exposure on the CR-39 response to alpha particles, a thick-target bremsstrahlung x-ray generator was used to expose CR-39 to various doses of 8 keV Cu-Kalpha and Kbeta x-rays. The CR-39 detectors were then exposed to 1-5.5 MeV alphas from an Am-241 source. The regions of the CR-39 exposed to x rays showed a smaller track diameter than those not exposed to x-rays: for example, a dose of 3.0 +/- 0.1 Gy causes a decrease of (19 +/- 2)% in the track diameter of a 5.5 MeV alpha particle, while a dose of 60.0 +/- 1.3 Gy results in a decrease of (45 +/- 5)% in the track diameter. The reduced track diameters were found to be predominantly caused by a comparable reduction in the bulk etch rate of the CR-39 with x-ray dose. A residual effect depending on alpha particle energy is characterized using an empirical formula. PMID- 25832224 TI - An in-vacuo optical levitation trap for high-intensity laser interaction experiments with isolated microtargets. AB - We report on the design, construction, and characterisation of a new class of in vacuo optical levitation trap optimised for use in high-intensity, high-energy laser interaction experiments. The system uses a focused, vertically propagating continuous wave laser beam to capture and manipulate micro-targets by photon momentum transfer at much longer working distances than commonly used by optical tweezer systems. A high speed (10 kHz) optical imaging and signal acquisition system was implemented for tracking the levitated droplets position and dynamic behaviour under atmospheric and vacuum conditions, with +/-5 MUm spatial resolution. Optical trapping of 10 +/- 4 MUm oil droplets in vacuum was demonstrated, over timescales of >1 h at extended distances of ~40 mm from the final focusing optic. The stability of the levitated droplet was such that it would stay in alignment with a ~7 MUm irradiating beam focal spot for up to 5 min without the need for re-adjustment. The performance of the trap was assessed in a series of high-intensity (10(17) W cm(-2)) laser experiments that measured the X ray source size and inferred free-electron temperature of a single isolated droplet target, along with a measurement of the emitted radio-frequency pulse. These initial tests demonstrated the use of optically levitated microdroplets as a robust target platform for further high-intensity laser interaction and point source studies. PMID- 25832225 TI - Design and implementation of fractional order pole placement controller to control the magnetic flux in Damavand tokamak. AB - In this paper, a routine algorithm is presented to design a fractional order controller for tracking the reference model. Using this algorithm, a pole placement controller can be designed by assigning the desired integer and fractional order closed loop transfer functions. Considering the desired time response and using the generalized characteristic ratio assignment (CRA) method for fractional order systems and coefficient diagram method (CDM) for integer order systems, the desired closed loop system can be achieved. For various practical experiments, having the desired time responses is vital for magnetic flux in Damavand tokamak. To approach this, at first, the desired reference models are obtained based on CRA and CDM methods. After that, a fractional order pole placement controller is designed and simulated by this algorithm. At last, this controller is implemented on a digital signal processor to control the vertical magnetic flux of Damavand tokamak plant. The practical results show the satisfactory performance of the controller. PMID- 25832226 TI - A simple experimental method to determine magnetic field topology in toroidal plasma devices. AB - Estimation of the parallel wavenumber in plasma devices finds wide applications such as determining the nature of instabilities. This task is often challenging, especially in toroidal magnetic configurations. In the present work, a simple yet effective method of achieving accurate probe-alignment along the magnetic field lines is demonstrated in a simple magnetized toroidal device BETA (Basic Experiments in Toroidal Assembly). The alignment was achieved by aligning each probe to a tiny localized plasma source. Such an alignment is necessary for determining the parallel wavenumber precisely. The probe-alignment was confirmed further from the measurements in the plasma and the corresponding parallel wavenumber was found to be in good agreement with the analytical predictions. PMID- 25832227 TI - Dynamical programming based turbulence velocimetry for fast visible imaging of tokamak plasma. AB - An orthogonal dynamic programming (ODP) based particle image velocimetry (PIV) technique is developed to measure the time resolved flow field of the fluctuating structures at the plasma edge and scrape off layer (SOL) of tokamaks. This non intrusive technique can provide two dimensional velocity fields at high spatial and temporal resolution from a fast framing image sequence and hence can provide better insights into plasma flow as compared to conventional probe measurements. Applicability of the technique is tested with simulated image pairs. Finally, it is applied to tangential fast visible images of QUEST plasma to estimate the SOL flow in inboard poloidal null-natural divertor configuration. This technique is also applied to investigate the intricate features of the core of the run-away dominated phase following the injection of a large amount of neutrals in the target Ohmic plasma. Development of the ODP-PIV code and its applicability on actual plasma images is reported. PMID- 25832228 TI - Time-resolved ion velocity distribution in a cylindrical Hall thruster: heterodyne-based experiment and modeling. AB - Time-resolved variations of the ion velocity distribution function (IVDF) are measured in the cylindrical Hall thruster using a novel heterodyne method based on the laser-induced fluorescence technique. This method consists in inducing modulations of the discharge plasma at frequencies that enable the coupling to the breathing mode. Using a harmonic decomposition of the IVDF, one can extract each harmonic component of the IVDF from which the time-resolved IVDF is reconstructed. In addition, simulations have been performed assuming a sloshing of the IVDF during the modulation that show agreement between the simulated and measured first order perturbation of the IVDF. PMID- 25832229 TI - Characteristics of a molybdenum X-pinch X-ray source as a probe source for X-ray diffraction studies. AB - X-ray emission from a molybdenum X-pinch has been investigated as a potential probe for the high pressure states made in dynamic compression experiments. Studies were performed on a novel 300 kA, 400 ns generator which coupled the load directly to a low inductance capacitor and switch combination. The X-pinch load consisted of 4 crossed molybdenum wires of 13 MUm diameter, crossed at an angle of 62 degrees . The load height was 10 mm. An initial x-ray burst generated at the wire crossing point, radiated in the soft x-ray range (hupsilon < 10 keV). This was followed, 2-5 ns later, by at least one harder x-ray burst (hupsilon > 10 keV) whose power ranged from 1 to 7 MW. Time integrated spectral measurements showed that the harder bursts were dominated by K-alpha emission; though, a lower level, wide band continuum up to at least 30 keV was also present. Initial tests demonstrated that the source was capable of driving Laue diffraction experiments, probing uncompressed samples of LiF and aluminium. PMID- 25832230 TI - Plasma current start-up by the outer ohmic heating coils in the Saskatchewan TORus Modified (STOR-M) iron core tokamak. AB - A plasma current up to 15 kA has been driven with outer ohmic heating (OH) coils in the STOR-M iron core tokamak. Even when the inner OH coil is disconnected, the outer OH coils alone can induce the plasma current as primary windings and initial breakdown are even easier in this coil layout. This result suggests a possibility to use an iron core in a spherical tokamak to start up the plasma current without a central solenoid. The effect of the iron core saturation on the extension of the discharge pulse length has been estimated for further experiments in the STOR-M tokamak. PMID- 25832231 TI - Experimental demonstration of Martian soil simulant removal from a surface using a pulsed plasma jet. AB - A plasma jet produced in a small coaxial plasma gun operated at voltages up to 2 kV and working in pure carbon dioxide (CO2) at a few Torr is used to remove Martian soil simulant from a surface. A capacitor with 0.5 mF is charged up from a high voltage source and supplies the power to the coaxial electrodes. The muzzle of the coaxial plasma gun is placed at a few millimeters near the dusty surface and the jet is fired parallel with the surface. Removal of dust is imaged in real time with a high speed camera. Mars regolith simulant JSC-Mars-1A with particle sizes up to 5 mm is used on different types of surfaces made of aluminium, cotton fabric, polyethylene, cardboard, and phenolic. PMID- 25832232 TI - Open-frame system for single-molecule microscopy. AB - We present the design and construction of a versatile, open frame inverted microscope system for wide-field fluorescence and single molecule imaging. The microscope chassis and modular design allow for customization, expansion, and experimental flexibility. We present two components which are included with the microscope which extend its basic capabilities and together create a powerful microscopy system: A Convex Lens-induced Confinement device provides the system with single-molecule imaging capabilities, and a two-color imaging system provides the option of imaging multiple molecular species simultaneously. The flexibility of the open-framed chassis combined with accessible single-molecule, multi-species imaging technology supports a wide range of new measurements in the health, nanotechnology, and materials science research sectors. PMID- 25832233 TI - Charge collection microscopy of in-situ switchable PRAM line cells in a scanning electron microscope: technique development and unique observations. AB - An imaging method has been developed based on charge collection in a scanning electron microscope (SEM) that allows discrimination between the amorphous and crystalline states of Phase-change Random Access Memory (PRAM) line cells. During imaging, the cells are electrically connected and can be switched between the states and the resistance can be measured. This allows for electrical characterization of the line cells in-situ in the SEM. Details on sample and measurement system requirements are provided which turned out to be crucial for the successful development of this method. Results show that the amorphous or crystalline state of the line cells can be readily discerned, but the spatial resolution is relatively poor. Nevertheless, it is still possible to estimate the length of the amorphous mark, and also for the first time, we could directly observe the shift of the amorphous mark from one side of the line cell to the other side when the polarity of the applied (50 ns) RESET pulse was reversed. PMID- 25832234 TI - Characterization of three-dimensional structure using images. AB - The pair correlation function g(r) and the number density n for particles in a three-dimensional (3D) sample can be determined from a single two-dimensional (2D) image. The 2D image is obtained experimentally with a simple setup: a cross sectional slab of particles is illuminated with a laser sheet and imaged with a single camera. After image analysis, to find positions of particles in two dimensions, along with their brightness, one obtains g(r), also known as the radial distribution function. The key for attaining high accuracy is to use only the particles that are brighter than a filter level, which we refine to achieve greater accuracy. The density n is obtained from g(r). This method is demonstrated in a dusty plasma experiment. Accuracy is quantified using simulation data; errors of 2% for both the pair correlation function and the number density are achievable. The method is useful for dusty plasmas and colloids. PMID- 25832235 TI - A subsurface add-on for standard atomic force microscopes. AB - The application of ultrasound in an Atomic Force Microscope (AFM) gives access to subsurface information. However, no commercially AFM exists that is equipped with this technique. The main problems are the electronic crosstalk in the AFM setup and the insufficiently strong excitation of the cantilever at ultrasonic (MHz) frequencies. In this paper, we describe the development of an add-on that provides a solution to these problems by using a special piezo element with a lowest resonance frequency of 2.5 MHz and by separating the electronic connection for this high frequency piezo element from all other connections. In this sense, we support researches with the possibility to perform subsurface measurements with their existing AFMs and hopefully pave also the way for the development of a commercial AFM that is capable of imaging subsurface features with nanometer resolution. PMID- 25832236 TI - Nanomechanical and topographical imaging of living cells by atomic force microscopy with colloidal probes. AB - Atomic Force Microscopy (AFM) has a great potential as a tool to characterize mechanical and morphological properties of living cells; these properties have been shown to correlate with cells' fate and patho-physiological state in view of the development of novel early-diagnostic strategies. Although several reports have described experimental and technical approaches for the characterization of cellular elasticity by means of AFM, a robust and commonly accepted methodology is still lacking. Here, we show that micrometric spherical probes (also known as colloidal probes) are well suited for performing a combined topographic and mechanical analysis of living cells, with spatial resolution suitable for a complete and accurate mapping of cell morphological and elastic properties, and superior reliability and accuracy in the mechanical measurements with respect to conventional and widely used sharp AFM tips. We address a number of issues concerning the nanomechanical analysis, including the applicability of contact mechanical models and the impact of a constrained contact geometry on the measured Young's modulus (the finite-thickness effect). We have tested our protocol by imaging living PC12 and MDA-MB-231 cells, in order to demonstrate the importance of the correction of the finite-thickness effect and the change in Young's modulus induced by the action of a cytoskeleton-targeting drug. PMID- 25832237 TI - The ReactorAFM: non-contact atomic force microscope operating under high-pressure and high-temperature catalytic conditions. AB - An Atomic Force Microscope (AFM) has been integrated in a miniature high-pressure flow reactor for in-situ observations of heterogeneous catalytic reactions under conditions similar to those of industrial processes. The AFM can image model catalysts such as those consisting of metal nanoparticles on flat oxide supports in a gas atmosphere up to 6 bar and at a temperature up to 600 K, while the catalytic activity can be measured using mass spectrometry. The high-pressure reactor is placed inside an Ultrahigh Vacuum (UHV) system to supplement it with standard UHV sample preparation and characterization techniques. To demonstrate that this instrument successfully bridges both the pressure gap and the materials gap, images have been recorded of supported palladium nanoparticles catalyzing the oxidation of carbon monoxide under high-pressure, high-temperature conditions. PMID- 25832239 TI - Optoelectronic transport properties in amorphous/crystalline silicon solar cell heterojunctions measured by frequency-domain photocarrier radiometry: multi parameter measurement reliability and precision studies. AB - A theoretical one-dimensional two-layer linear photocarrier radiometry (PCR) model including the presence of effective interface carrier traps was used to evaluate the transport parameters of p-type hydrogenated amorphous silicon (a Si:H) and n-type crystalline silicon (c-Si) passivated by an intrinsic hydrogenated amorphous silicon (i-layer) nanolayer. Several crystalline Si heterojunction structures were examined to investigate the influence of the i layer thickness and the doping concentration of the a-Si:H layer. The experimental data of a series of heterojunction structures with intrinsic thin layers were fitted to PCR theory to gain insight into the transport properties of these devices. The quantitative multi-parameter results were studied with regard to measurement reliability (uniqueness) and precision using two independent computational best-fit programs. The considerable influence on the transport properties of the entire structure of two key parameters that can limit the performance of amorphous thin film solar cells, namely, the doping concentration of the a-Si:H layer and the i-layer thickness was demonstrated. It was shown that PCR can be applied to the non-destructive characterization of a-Si:H/c-Si heterojunction solar cells yielding reliable measurements of the key parameters. PMID- 25832238 TI - Flexible digital signal processing architecture for narrowband and spread spectrum lock-in detection in multiphoton microscopy and time-resolved spectroscopy. AB - The lock-in amplifier is a critical component in many different types of experiments, because of its ability to reduce spurious or environmental noise components by restricting detection to a single frequency and phase. One example application is pump-probe microscopy, a multiphoton technique that leverages excited-state dynamics for imaging contrast. With this application in mind, we present here the design and implementation of a high-speed lock-in amplifier on the field-programmable gate array (FPGA) coprocessor of a data acquisition board. The most important advantage is the inherent ability to filter signals based on more complex modulation patterns. As an example, we use the flexibility of the FPGA approach to enable a novel pump-probe detection scheme based on spread spectrum communications techniques. PMID- 25832240 TI - Cantilever stress measurements for pulsed laser deposition of perovskite oxides at 1000 K in an oxygen partial pressure of 10(-4) millibars. AB - An in situ stress measurement setup using an optical 2-beam curvature technique is described which is compatible with the stringent growth conditions of pulsed laser deposition (PLD) of perovskite oxides, which involves high substrate temperatures of 1000 K and oxygen partial pressures of up to 1 * 10(-4) millibars. The stress measurements are complemented by medium energy electron diffraction (MEED), Auger electron spectroscopy, and additional growth rate monitoring by a quartz microbalance. A shielded filament is used to allow for simultaneous stress and MEED measurements at high substrate temperatures. A computer-controlled mirror scans an excimer laser beam over a stationary PLD target. This avoids mechanical noise originating from rotating PLD targets, and the setup does not suffer from limited lifetime issues of ultra high vacuum (UHV) rotary feedthroughs. PMID- 25832241 TI - Two-step fabrication technique of gold tips for use in point-contact spectroscopy. AB - For a successful point-contact spectroscopy (PCS) measurement, metallic tips of proper shape and smoothness are essential to ensure the ballistic nature of a point-contact junction. Until recently, the fabrication of Au tips suitable for use in point-contact spectroscopy has remained more of an art involving a trial and error method rather than an automated scientific process. To address these issues, we have developed a technique with which one can prepare high quality Au tips reproducibly and systematically. It involves an electronic control of the driving voltages used for an electrochemical etching of a gold wire in a HCl glycerol mixture or a HCl solution. We find that a stopping current, below which the circuit is set to shut off, is a single very important parameter to produce an Au tip of desired shape. We present detailed descriptions for a two-step etching process for Au tips and also test results from PCS measurements using them. PMID- 25832242 TI - Combinatorial thin film composition mapping using three dimensional deposition profiles. AB - Many next-generation technologies are limited by material performance, leading to increased interest in the discovery of advanced materials using combinatorial synthesis, characterization, and screening. Several combinatorial synthesis techniques, such as solution based methods, advanced manufacturing, and physical vapor deposition, are currently being employed for various applications. In particular, combinatorial magnetron sputtering is a versatile technique that provides synthesis of high-quality thin film composition libraries. Spatially addressing the composition of these thin films generally requires elemental quantification measurements using techniques such as energy-dispersive X-ray spectroscopy or X-ray fluorescence spectroscopy. Since these measurements are performed ex-situ and post-deposition, they are unable to provide real-time design of experiments, a capability that is required for rapid synthesis of a specific composition library. By using three quartz crystal monitors attached to a stage with translational and rotational degrees of freedom, we measure three dimensional deposition profiles of deposition sources whose tilt with respect to the substrate is robotically controlled. We exhibit the utility of deposition profiles and tilt control to optimize the deposition geometry for specific combinatorial synthesis experiments. PMID- 25832243 TI - High-pressure generation using double stage micro-paired diamond anvils shaped by focused ion beam. AB - Micron-sized diamond anvils with a 3 MUm culet were successfully processed using a focused ion beam (FIB) system and the generation of high pressures was confirmed using the double stage diamond anvil cell technique. The difficulty of aligning two second-stage micro-anvils was solved via the paired micro-anvil method. Micro-manufacturing using a FIB system enables us to control anvil shape, process any materials, including nano-polycrystalline diamond and single crystal diamond, and assemble the sample exactly in a very small space between the second stage anvils. This method is highly reproducible. High pressures over 300 GPa were achieved, and the pressure distribution around the micro-anvil culet was evaluated by using a well-focused synchrotron micro-X-ray beam. PMID- 25832244 TI - Magneto-optical Kramers-Kronig analysis. AB - We describe a simple magneto-optical experiment and introduce a magneto-optical Kramers-Kronig analysis (MOKKA) that together allow extracting the complex dielectric function for left- and right-handed circular polarizations in a broad range of frequencies without actually generating circularly polarized light. The experiment consists of measuring reflectivity and Kerr rotation, or alternatively transmission and Faraday rotation, at normal incidence using only standard broadband polarizers without retarders or quarter-wave plates. In a common case, where the magneto-optical rotation is small (below ~0.2 rad), a fast measurement protocol can be realized, where the polarizers are fixed at 45(?) with respect to each other. Apart from the time-effectiveness, the advantage of this protocol is that it can be implemented at ultra-high magnetic fields and in other situations, where an in-situ polarizer rotation is difficult. Overall, the proposed technique can be regarded as a magneto-optical generalization of the conventional Kramers Kronig analysis of reflectivity on bulk samples and the Kramers-Kronig constrained variational analysis of more complex types of spectral data. We demonstrate the application of this method to the textbook semimetals bismuth and graphite and also use it to obtain handedness-resolved magneto-absorption spectra of graphene on SiC. PMID- 25832245 TI - Experimental measurement of characteristic I(c) (epsilon, theta, B) response in GdBa2Cu3Odelta coated conductor tapes under low magnetic field at 77 K. AB - The continued development in the design technology of practical superconducting devices adopting high temperature superconductors tapes has led to a deeper understanding of their electromechanical behaviors. Rare-earth-barium-copper oxide coated conductor (CC) tapes exhibit anisotropy of transport property (Ic) under magnetic field and its intrinsic strain effect is much significant depending on the orientation to the tape surface and the magnetic field intensity applied. Different experimental systems have already been developed to measure the relation of Ic with mechanical strain epsilon, magnetic field intensity B, and its angle of orientation, theta. However, few systems and instruments can measure these relationships simultaneously; either Ic-B-theta or Ic-epsilon-B is usually measured. In this study, a device which can measure these influences simultaneously based on a pair of permanent magnet systems was constructed and the characteristic responses of critical current Ic with strain, magnetic field, and its orientation with respect to the CC tape surface were investigated. The angular dependence of Ic with strain at 77 K in reactive co-evaporation by deposition and reaction GdBCO CC tapes has been measured using the permanent magnet system. The orientation angle of magnetic field with respect to the tape's surface was varied by rotating the rig fixture that holds a pair of permanent magnets. The strain sensitivity of Ic at different angles under low magnetic field was evaluated. As a result, a characteristic surface Ic (epsilon, theta, B) has been constructed as the characteristic response of Ic with strain and varying orientation under magnetic field. PMID- 25832246 TI - Systematic approach to using isentropic stress reverberation techniques in approximating equation of state. AB - Isentropic stress reverberations are used to obtain multiple Hugoniot states from a single plate impact experiment using a layered plate geometry, where a low impedance inner layer is embedded within a high impedance bulk structure. The mathematical framework used in this technique uses the classical Rankine-Hugoniot equations in the method of impedance matching, where the bulk material is required to have a known Hugoniot. Factors including the wave velocities in the materials, input pulse duration, inner layer thickness, and diameter of the test samples affect the number of states that can be generated from a single experiment. Experiments using 6061 aluminum and polycarbonate, respectively, as the bulk material and inner layer, accurately generated six Hugoniot states for the polycarbonate. Experiments using A572 grade 50 structural steel as the bulk material accurately generated ten Hugoniot states for the polycarbonate. For each experiment, the method can be used to generate a Hugoniot equation defining the material response of the inner layer within the domain encompassed by the specific test. The method is also confined to the low to moderate stress regions, within which Hugoniot and isentropic representations of the material are almost identical. PMID- 25832247 TI - Parallelization of photocatalytic gas-producing reactions. AB - High-throughput screening has been widely utilized in the pharmaceutical and manufacturing industry targeting the development of new molecules and materials for numerous applications. To enable more rapid progress in photocatalytic water splitting reactions, the construction of high-throughput combinatorial photoreactors enabling the parallel optimization of relevant compositions under varieties of experimental conditions seems appropriate. This contribution describes a 16-photoreactor apparatus permitting the kinetic evaluation of photocatalytic gas-producing reactions using head-space pressure, gas chromatography, and mass spectrometry operating in parallel, illustrated with molecular-based homogeneous photocatalytic H2-generating compositions. PMID- 25832248 TI - A high-temperature in situ cell with a large solid angle for fluorescence X-ray absorption fine structure measurement. AB - We present the design and performance of a high-temperature in situ cell with a large solid angle for fluorescence X-ray absorption fine structure (XAFS) spectra. The cell has a large fluorescence XAFS window (116 mm(phi)) near the sample in the cell, realizing a large half-cone angle of 56 degrees . We use a small heater (25 * 35 mm(2)) to heat the sample locally to 873 K. We measured a Pt-SnO2 thin layer on a Si substrate at reaction conditions having a high activity. In situ measurement enables the analysis of the difference XAFS spectra between before and during the reaction to reveal the structure change during the operation. PMID- 25832249 TI - A new method for evaluating the degeneration of articular cartilage using pulse echo ultrasound. AB - This paper presents a novel nondestructive ultrasonic technique for measuring the sound speed and acoustic impedance of articular cartilage using the pulsed Vz,t technique. Vz,t data include a series of pulsed ultrasonic echoes collected using different distances between the ultrasonic transducer and the specimen. The 2D Fourier transform is applied to the Vz,t data to reconstruct the 2D reflection spectrum Rtheta,omega. To obtain the reflection coefficient of articular cartilage, the Vz,t data from a reference specimen with a well-known reflection coefficient are obtained to eliminate the dependence on the general system transfer function. The ultrasound-derived aggregate modulus (Ha) is computed based on the measured reflection coefficient and the sound speed. In the experiment, 32 cartilage-bone samples were prepared from bovine articular cartilage, and 16 samples were digested using 0.25% trypsin solution. The sound speed and Ha of these cartilage samples were evaluated before and after degeneration. The magnitude of the sound speed decreased with trypsin digestion (from 1663 +/- 5.6 m/s to 1613 +/- 5.3 m/s). Moreover, the Young's modulus in the corresponding degenerative state was measured and was correlated with the ultrasound-derived aggregate modulus. The ultrasound-derived aggregate modulus was determined to be highly correlated with the Young's modulus (n = 16, r>0.895, p<0.003, Pearson correlation test for each measurement). The results demonstrate the effectiveness of using the proposed method to assess the changes in sound speed and the ultrasound-derived aggregate modulus of cartilage after degeneration. PMID- 25832251 TI - Development of pulsed neutron uranium logging instrument. AB - This article introduces a development of pulsed neutron uranium logging instrument. By analyzing the temporal distribution of epithermal neutrons generated from the thermal fission of (235)U, we propose a new method with a uranium-bearing index to calculate the uranium content in the formation. An instrument employing a D-T neutron generator and two epithermal neutron detectors has been developed. The logging response is studied using Monte Carlo simulation and experiments in calibration wells. The simulation and experimental results show that the uranium-bearing index is linearly correlated with the uranium content, and the porosity and thermal neutron lifetime of the formation can be acquired simultaneously. PMID- 25832250 TI - A device for rapid and quantitative measurement of cardiac myocyte contractility. AB - Cardiac contractility is the hallmark of cardiac function and is a predictor of healthy or diseased cardiac muscle. Despite advancements over the last two decades, the techniques and tools available to cardiovascular scientists are limited in their utility to accurately and reliably measure the amplitude and frequency of cardiomyocyte contractions. Isometric force measurements in the past have entailed cumbersome attachment of isolated and permeabilized cardiomyocytes to a force transducer followed by measurements of sarcomere lengths under conditions of submaximal and maximal Ca(2+) activation. These techniques have the inherent disadvantages of being labor intensive and costly. We have engineered a micro-machined cantilever sensor with an embedded deflection-sensing element that, in preliminary experiments, has demonstrated to reliably measure cardiac cell contractions in real-time. Here, we describe this new bioengineering tool with applicability in the cardiovascular research field to effectively and reliably measure cardiac cell contractility in a quantitative manner. We measured contractility in both primary neonatal rat heart cardiomyocyte monolayers that demonstrated a beat frequency of 3 Hz as well as human embryonic stem cell derived cardiomyocytes with a contractile frequency of about 1 Hz. We also employed the beta-adrenergic agonist isoproterenol (100 nmol l(-1)) and observed that our cantilever demonstrated high sensitivity in detecting subtle changes in both chronotropic and inotropic responses of monolayers. This report describes the utility of our micro-device in both basic cardiovascular research as well as in small molecule drug discovery to monitor cardiac cell contractions. PMID- 25832252 TI - Nested Helmholtz coil design for producing homogeneous transient rotating magnetic fields. AB - Electromagnets that can produce strong rotating magnetic fields at kHz frequencies are potentially very useful to exert rotating force on magnetic nanoparticles as small as few nanometers in size. In this article, the construction of a pulsed high-voltage rotating electromagnet is demonstrated based on a nested Helmholtz coil design. The energy for the coils is provided by two high-voltage discharge capacitors. The triggered spark gaps used in the experiments show sufficient accuracy to achieve the high frequency rotating magnetic field. The measured strength of the rotating magnetic field is 200 mT. This magnetic field is scalable by increasing the number of turns on the coils, by reducing the dimensions of the coils and by increasing the discharge current/voltage of the capacitors. PMID- 25832253 TI - Optically isolated, 2 kHz repetition rate, 4 kV solid-state pulse trigger generator. AB - This paper presents the design and operation characteristics of a solid-state high voltage pulse generator. Its primary utilization is aimed at triggering a gaseous spark gap with high repeatability. Specifically, the trigger generator is designed to achieve a risetime on the order of 0.1 kV/ns to trigger the first stage, trigatron spark gap of a 10-stage, 500 kV Marx generator. The major design components are comprised of a 60 W constant current DC-DC converter for high voltage charging, a single 4 kV thyristor, a step-up pulse transformer, and magnetic switch for pulse steepening. A risetime of <30 ns and pulse magnitude of 4 kV is achieved matching the simulated performance of the design. PMID- 25832254 TI - Developing instrumentation to characterize thermoelectric generator modules. AB - Based on the law of physics, known as "Seebeck effect," a thermoelectric generator (TEG) produces electricity when the temperature differential is applied across the TEG. This article reports a precision method in characterizing TEG modules. A precision instrument is constructed to study thermoelectric conversion in terms of output power and efficiency of TEG modules. The maximum allowable TEG module size is 150 mm, and the preferred size is from 30 mm to 60 mm. During measurements, the highest hot side temperature is 500 degrees C and the cold side temperature can be adjusted from room temperature to 100 degrees C. A mechanical structure is developed to control the pressure and parallelism of the clamping force of the TEG on both its hot and cold sides. A heat flux measurement module is installed at its cold side, and the heat flux through TEGs can be measured in position. Finally, the energy conversion efficiency of TEGs is calculated from experimental data of both an output power and a heat flux. PMID- 25832255 TI - A high power microwave triggered RF opening switch. AB - A 4-port S-band waveguide structure was designed and fabricated such that a signal of any amplitude (less than 1 MW) can be switched from a normally closed state, <0.5 dB insertion loss (IL), to an open state >30 dB IL by initiating plasma in a gas cell situated at the junction of this waveguide and one propagating a megawatt level magnetron pulse. The 90/10 switching time is as low as 20 ns with a delay of ~30 ns between the onset of the high power microwave pulse and the initial drop of the signal. Two ports of this device are for the high power triggering pulse while the other two ports are for the triggered signal in a Moreno-like coupler configuration. In order to maintain high isolation, these two sets of waveguides are rotated 90 degrees from each other with a TE111 resonator/plasma cell located at the intersection. This manuscript describes the design and optimization of this structure using COMSOL 4.4 at the design frequency of 2.85 GHz, comparison of simulated scattering parameters with measured "cold tests" (testing without plasma), and finally the temporal waveforms of this device being used to successfully switch a low power CW signal from 2 W to <5 mW on a sub-microsecond timescale. PMID- 25832256 TI - Using fast moving electrode to achieve overvoltage breakdown of gas switch stressed with high direct voltages. AB - A small-scale fast risetime gas switch attached to a 50 Omega pulse forming line is tested. It includes a fast moving electrode and a fixed electrode. For the applied direct voltages, such as 2.8 kV, 2.0 kV, and 1.0 kV, the risetimes of this switch are tested to be ~3.8 ns, ~2.3 ns, and ~1.1 ns, respectively, while the risetimes of a switch with two fixed electrodes are about ~10.1 ns, ~9.0 ns, and ~3.6 ns. The results of high-speed photography and laser interferometry reveal that the moving electrode will obviously shorten discharge spark length but almost will not change the inter-electrodes gas pressure. The reason of shortening spark length is the existence of the discharge time delay of gas switch. After moving to the static breakdown spacing, the fast moving electrode will move on for an additional distance within the discharge time delay, which makes gas switch achieve overvoltage breakdown under high direct voltages and therefore leads to shorter spark length and faster switch risetime. PMID- 25832257 TI - Post-assembly magnetization of a 100 kW high speed permanent magnet rotor. AB - A post-assembly magnetizing fixture has been designed and successfully used to magnetize the rotor of a 100 kW high speed permanent magnet synchronous motor. The rotor is a solid cylinder with outer diameter of 80 mm and total length of 515 mm. The permanent magnet material is samarium-cobalt (Sm2Co17) with saturation magnetizing field of 6 T. The mechanical stability of the magnetizing fixture has been studied as well as the general design methodology. The magnetizing coil is subdivided in order to reduce the electromagnetic force, and the coils are separately reinforced in different ways. The electromagnetic and structural optimization is performed by finite element analysis and verified by experiments. PMID- 25832258 TI - Experimental study on parasitic mode suppression using FeSiAl in Relativistic Klystron Amplifier. AB - Experimental study of parasitic mode suppression using electromagnetic attenuate material FeSiAl in an S-band Relativistic Klystron Amplifier (RKA) is presented in this paper. The FeSiAl powder is coated and sintered onto the inner surface of a drift tube which locates between the input and the middle cavity of the RKA. Cold tests show that the attenuate rate of the tube against parasitic mode TE11 is about 50%. Experiments carried out on the Torch-01 accelerator present that the tube is effective in suppressing the parasitic mode. Two typical outputs are obtained. When the diode voltage is on a moderate level, the RKA operates well and the parasitic mode is totally suppressed. The pulse length of the High Power Microwave (HPM) almost equals the electron beam pulse length and the HPM average output power is about 300 MW, with a power efficiency of 10%. When the diode voltage is on a higher level, the output power and efficiency rise but the parasitic mode oscillation occurred and the pulse length is shortened. By contrast, the parasitic mode oscillation is too strong for the RKA to operate normally with un-sintered drift tube. The experimental study implies that FeSiAl is effective in suppressing the parasitic mode oscillation in a certain extent. However, total suppression needs a deeper attenuate rate and further investigation. PMID- 25832259 TI - Low frequency noise elimination technique for 24-bit Sigma-Delta data acquisition systems. AB - Low frequency 1/f noise is one of the key limiting factors of high precision measurement instruments. In this paper, digital correlated double sampling is implemented to reduce the offset and low frequency 1/f noise of a data acquisition system with 24-bit sigma delta (Sigma-Delta) analog to digital converter (ADC). The input voltage is modulated by cross-coupled switches, which are synchronized to the sampling clock, and converted into digital signal by ADC. By using a proper switch frequency, the unwanted parasitic signal frequencies generated by the switches are avoided. The noise elimination processing is made through the principle of digital correlated double sampling, which is equivalent to a time shifted subtraction for the sampled voltage. The low frequency 1/f noise spectrum density of the data acquisition system is reduced to be flat down to the measurement frequency lower limit, which is about 0.0001 Hz in this paper. The noise spectrum density is eliminated by more than 60 dB at 0.0001 Hz, with a residual noise floor of (9 +/- 2) nV/Hz(1/2) which is limited by the intrinsic white noise floor of the ADC above its corner frequency. PMID- 25832260 TI - Reliable and integrated technique for determining resonant frequency in radio frequency resonators. Application to a high-precision resonant cavity-based displacement sensor. AB - This paper presents a reliable and integrated technique for determining the resonant frequency of radio frequency resonators, which can be of interest for different purposes. The approach uses a heterodyne scheme as phase detector coupled to a voltage-controlled oscillator. The system seeks the oscillator frequency that produces a phase null in the resonator, which corresponds to the resonant frequency. A complete explanation of the technique to determine the resonant frequency is presented and experimentally tested. The method has been applied to a high-precision displacement sensor based on resonant cavity, obtaining a theoretical nanometric precision. PMID- 25832261 TI - An integrated wire harp and readout electronics inside vacuum. AB - A wire harp is a well known instrument used in ion beam profile measurement and beam diagnostics. Till date, for beam instrumentation, the harp is placed inside the vacuum chamber or beam line in direct exposure to the beam profile to be measured, whereas the related readout electronics is placed outside somewhere at a convenient place. Here, a harp has been developed along with the readout electronics as an integrated part of it and both were placed inside the beam line vacuum (order of 10(-7) Torr) to make the system much simpler, easy to operate, and measure small beam current more accurately. The entire signal conversion and processing is done inside the vacuum unlike other systems; hence, the electronics is kept inside. This results in a lesser number (only 4 pin) of electrical connections (feedthrough) including power which otherwise would have required 32 feedthrough pins only for signal readout for a 13 * 13 (X * Y) channel harp. This paper describes a completely new approach to the design of a conventional beam harp widely used for beam instrumentation. PMID- 25832262 TI - Miniature coils for producing pulsed inplane magnetic fields for nanospintronics. AB - Nanospintronic and related research often requires the application of quickly rising magnetic field pulses in the plane of the studied planar structure. We have designed and fabricated sub-millimeter-sized coils capable of delivering pulses of the magnetic field up to ~500 Oe in the plane of the sample with the rise time of the order of 10 ns. The placement of the sample above the coil allows for easy access to its surface with manipulators or light beams for, e.g., Kerr microscopy. We use the fabricated coil to drive magnetic domain walls in 1 MUm wide permalloy wires and measure magnetic domain wall velocity as a function of the applied magnetic field. PMID- 25832263 TI - Free-space reflection method for measuring moisture content and bulk density of particulate materials at microwave frequency. AB - A measurement system based on free-space reflection method is designed for simultaneous and independent determination of moisture content and bulk density of particulate materials. The proposed system consists of microwave cavity oscillator, horn antenna, slide rail, sample holder, mixer, and digital meter. Sand and rice with different moisture contents and bulk densities are chosen as samples. Calibration models for moisture content and bulk density are proposed according to the measurement of the position of the minimum of the traveling standing wave and the ratio of the maximum-to-minimum field strength of the traveling-standing wave at different temperatures. The moisture constant, ranging from 0% to 24.6%, is obtained with a coefficient of determination (R(2)) greater than 0.982 and a standard error of prediction (SEP) value of less than 0.695%. The bulk density, ranging from 0.501 g/cm(3) to 1.822 g/cm(3), is determined with a R(2) >= 0.961 and a SEP value ranging from 0.0144 g/cm(3) to 0.0382 g/cm(3) for different samples. PMID- 25832264 TI - Estimation of channel mismatches in time-interleaved analog-to-digital converters based on fractional delay and sine curve fitting. AB - This paper proposes an algorithm to estimate the channel mismatches in time interleaved analog-to-digital converter (TIADC) based on fractional delay (FD) and sine curve fitting. Choose one channel as the reference channel and apply FD to the output samples of reference channel to obtain the ideal samples of non reference channels with no mismatches. Based on least square method, the sine curves are adopted to fit the ideal and the actual samples of non-reference channels, and then the mismatch parameters can be estimated by comparing the ideal sine curves and the actual ones. The principle of this algorithm is simple and easily understood. Moreover, its implementation needs no extra circuits, lowering the hardware cost. Simulation results show that the estimation accuracy of this algorithm can be controlled within 2%. Finally, the practicability of this algorithm is verified by the measurement results of channel mismatch errors of a two-channel TIADC prototype. PMID- 25832266 TI - Analyzing surface plasmon resonance data: choosing a correct biphasic model for interpretation. AB - Surface plasmon resonance (SPR) has been widely used as a label-free biophysical technique to quantitatively study biochemical processes. For the SPR data fitting using a single exponential function, the procedure to extract the rate constants is straightforward. However, there is no simple procedure for SPR data fitting with double exponential functions. A highly non-linear fitting procedure is, therefore, used to fit the biphasic SPR data with numerical solutions of the rate equations. This procedure requires some prior knowledge of the underlying interaction mechanism, and the extracted rate constants often have large uncertainties. In this report, we propose a new method of analyzing the biphasic SPR data using the three commonly employed biphasic models. Our method is based on a general analytical solution of the biphasic rate equations, which is much more transparent and straightforward than the highly non-linear numerical integration approach. Our method can be used to determine the underlying biphasic interaction mechanism from the analysis of the SPR data and to extract the rate constants with high confidence levels. We have illustrated the procedures with examples of the data analysis on simulated SPR profiles, and the results are discussed. PMID- 25832265 TI - A prototype hand-held tri-modal instrument for in vivo ultrasound, photoacoustic, and fluorescence imaging. AB - Multi-modality imaging is beneficial for both preclinical and clinical applications as it enables complementary information from each modality to be obtained in a single procedure. In this paper, we report the design, fabrication, and testing of a novel tri-modal in vivo imaging system to exploit molecular/functional information from fluorescence (FL) and photoacoustic (PA) imaging as well as anatomical information from ultrasound (US) imaging. The same ultrasound transducer was used for both US and PA imaging, bringing the pulsed laser light into a compact probe by fiberoptic bundles. The FL subsystem is independent of the acoustic components but the front end that delivers and collects the light is physically integrated into the same probe. The tri-modal imaging system was implemented to provide each modality image in real time as well as co-registration of the images. The performance of the system was evaluated through phantom and in vivo animal experiments. The results demonstrate that combining the modalities does not significantly compromise the performance of each of the separate US, PA, and FL imaging techniques, while enabling multi modality registration. The potential applications of this novel approach to multi modality imaging range from preclinical research to clinical diagnosis, especially in detection/localization and surgical guidance of accessible solid tumors. PMID- 25832267 TI - A standing wave linear ultrasonic motor operating in in-plane expanding and bending modes. AB - A novel standing wave linear ultrasonic motor operating in in-plane expanding and bending modes was proposed in this study. The stator (or actuator) of the linear motor was made of a simple single Lead Zirconate Titanate (PZT) ceramic square plate (15 * 15 * 2 mm(3)) with a circular hole (D = 6.7 mm) in the center. The geometric parameters of the stator were computed with the finite element analysis to produce in-plane bi-mode standing wave vibration. The calculated results predicted that a driving tip attached at midpoint of one edge of the stator can produce two orthogonal, approximate straight-line trajectories, which can be used to move a slider in linear motion via frictional forces in forward or reverse direction. The investigations showed that the proposed linear motor can produce a six times higher power density than that of a previously reported square plate motor. PMID- 25832268 TI - Efficient block processing of long duration biotelemetric brain data for health care monitoring. AB - In real time clinical environment, the brain signals which doctor need to analyze are usually very long. Such a scenario can be made simple by partitioning the input signal into several blocks and applying signal conditioning. This paper presents various block based adaptive filter structures for obtaining high resolution electroencephalogram (EEG) signals, which estimate the deterministic components of the EEG signal by removing noise. To process these long duration signals, we propose Time domain Block Least Mean Square (TDBLMS) algorithm for brain signal enhancement. In order to improve filtering capability, we introduce normalization in the weight update recursion of TDBLMS, which results TD-B normalized-least mean square (LMS). To increase accuracy and resolution in the proposed noise cancelers, we implement the time domain cancelers in frequency domain which results frequency domain TDBLMS and FD-B-Normalized-LMS. Finally, we have applied these algorithms on real EEG signals obtained from human using Emotive Epoc EEG recorder and compared their performance with the conventional LMS algorithm. The results show that the performance of the block based algorithms is superior to the LMS counter-parts in terms of signal to noise ratio, convergence rate, excess mean square error, misadjustment, and coherence. PMID- 25832269 TI - Design of a four-degree-of-freedom nano positioner utilizing electromagnetic actuators and flexure mechanisms. AB - Positioning devices are widely used in industrial applications. High precision is a key performance of the positioner and recently high precision positioners for advanced applications are required to satisfy other performances such as larger motion range, nanometer level precision, and multiple degree-of-freedom (DOF) motion within compact size. We propose a new 4-DOF high-precision positioner employing voice coil motors and flexure guides. Millimeter motion range and nano level resolution were achieved simultaneously, utilizing the frictionless characteristic of the voice coil motors and the flexures. The mathematical model describing static and dynamic behaviors of the positioner was developed and the design parameters were optimized to achieve the best performances. The proposed positioner was manufactured with the size of 180 * 180 * 30.7 mm(3) which was very compact. The experiment of feedback control showed the motion range more than 1.80 * 1.80 mm(2) in-plane and 0.3 mm vertically and the minimum resolution of 10 nm in-plane and 14 nm vertically. PMID- 25832270 TI - Tetrafluoroethane (R134a) hydrate formation within variable volume reactor accompanied by evaporation and condensation. AB - Vast size hydrate formation reactors with fast conversion rate are required for the economic implementation of seawater desalination utilizing gas hydrate technology. The commercial target production rate is order of thousand tons of potable water per day per train. Various heat and mass transfer enhancement schemes including agitation, spraying, and bubbling have been examined to maximize the production capacities in scaled up design of hydrate formation reactors. The present experimental study focused on acquiring basic knowledge needed to design variable volume reactors to produce tetrafluoroethane hydrate slurry. Test vessel was composed of main cavity with fixed volume of 140 ml and auxiliary cavity with variable volume of 0 ~ 64 ml. Temperatures at multiple locations within vessel and pressure were monitored while visual access was made through front window. Alternating evaporation and condensation induced by cyclic volume change provided agitation due to density differences among water and vapor, liquid and hydrate R134a as well as extended interface area, which improved hydrate formation kinetics coupled with latent heat release and absorption. Influences of coolant temperature, piston stroke/speed, and volume change period on hydrate formation kinetics were investigated. Suggestions of reactor design improvement for future experimental study are also made. PMID- 25832271 TI - A fluorescence XAFS measurement instrument in the soft X-ray region toward observation under operando conditions. AB - X-ray absorption fine structure (XAFS) measurements are widely used for the analysis of electronic structure. Generally, XAFS in the soft X-ray region is measured under vacuum, but chemical structures under vacuum are typically different from those under operando conditions, where chemical species exhibit their function. Here, we developed an XAFS measurement instrument, as a step toward operando fluorescent, which yields XAFS measurement using synchrotron radiation in the soft X-ray region. We applied this method to analyze the local electronic structure of the sulfur atoms in L-cysteine in different pH solutions. In water at pH 7, the hydrogen atom does not dissociate from the thiol (-SH) group in L-cysteine, which forms a structure surrounded by and interacting with water molecules. The XAFS spectrum of L-cysteine in solution was altered by changing the pH. At pH 9, the hydrogen atom dissociated and a thiolate anion was formed. Although the -SH group was oxidized to SO4 (2-) when L-cysteine was adsorbed on a metal surface and dried, no oxidation was observed in solution. This may be because the water molecules were densely packed and protected the -SH group from oxidation. Our results show that this instrument aimed toward operando fluorescence XAFS measurements in the soft X-ray region is useful for structural analysis of sulfur atoms in organic molecules in air and in solution. The instrument will be applied to the structural analysis of materials containing elements that have absorption edges in soft X-ray region, such as phosphorus and alkali metals (potassium and cesium). It will be also particularly useful for the analysis of samples that are difficult to handle under vacuum and materials that have specific functions in solution. PMID- 25832272 TI - Spatially resolved and observer-free experimental quantification of spatial resolution in tomographic images. AB - We present a novel framework and experimental method for the quantification of spatial resolution of a tomography system. The framework adopts the "black box" view of an imaging system, considering only its input and output. The tomography system is locally stimulated with a step input, viz., a sharp edge. The output, viz., the reconstructed images, is analysed by Fourier decomposition of their spatial frequency components, and the local limiting spatial resolution is determined using a cut-off threshold. At no point is an observer involved in the process. The framework also includes a means of translating the quantification region in the imaging space, thus creating a spatially resolved map of objectively quantified spatial resolution. As a case-study, the framework is experimentally applied using a gaseous propane phantom measured by a well established chemical species tomography system. A spatial resolution map consisting of 28 regions is produced. In isolated regions, the indicated performance is 4-times better than that suggested in the literature and varies by 57% across the imaging space. A mechanism based on adjacent but non-interacting beams is hypothesised to explain the observed behaviour. The mechanism suggests that, as also independently concluded by other methods, a geometrically regular beam array maintains maximum objectivity in reconstructions. We believe that the proposed framework, methodology, and findings will be of value in the design and performance evaluation of tomographic imaging arrays and systems. PMID- 25832273 TI - Hard disk drive based microsecond X-ray chopper for characterization of ionization chambers and photodiodes. AB - A fast X-ray chopper capable of producing ms long X-ray pulses with a typical rise time of few MUs was realized. It is ideally suited to investigate the temporal response of X-ray detectors with response times of the order of MUs to ms, in particular, any kind of ionization chambers and large area photo diodes. The drive mechanism consists of a brushless DC motor and driver electronics from a common hard disk drive, keeping the cost at an absolute minimum. Due to its simple construction and small dimensions, this chopper operates at home lab based X-ray tubes and synchrotron radiation sources as well. The dynamics of the most important detectors used in time resolved X-ray absorption spectroscopy, namely, ionization chambers and Passivated Implanted Planar Silicon photodiodes, were investigated in detail. The results emphasize the applicability of this X-ray chopper. PMID- 25832274 TI - A novel experimental approach to investigate radiolysis processes in liquid samples using collimated radiation sources. AB - Here is detailed a novel and low-cost experimental method for high-throughput automated fluid sample irradiation. The sample is delivered via syringe pump to a nozzle, where it is expressed in the form of a hanging droplet into the path of a beam of ionising radiation. The dose delivery is controlled by an upstream lead shutter, which allows the beam to reach the droplet for a user defined period of time. The droplet is then further expressed after irradiation until it falls into one well of a standard microplate. The entire system is automated and can be operated remotely using software designed in-house, allowing for use in environments deemed unsafe for the user (synchrotron beamlines, for example). Depending on the number of wells in the microplate, several droplets can be irradiated before any human interaction is necessary, and the user may choose up to 10 samples per microplate using an array of identical syringe pumps, the design of which is described here. The nozzles consistently produce droplets of 25.1 +/- 0.5 MUl. PMID- 25832275 TI - A compact time-of-flight mass spectrometer for ion source characterization. AB - A compact time-of-flight mass spectrometer with overall dimension of about 413 * 250 * 414 mm based on orthogonal injection and angle reflection has been developed for ion source characterization. Configuration and principle of the time-of-flight mass spectrometer are introduced in this paper. The mass resolution is optimized to be about 1690 (FWHM), and the ion energy detection range is tested to be between about 3 and 163 eV with the help of electron impact ion source. High mass resolution and compact configuration make this spectrometer useful to provide a valuable diagnostic for ion spectra fundamental research and study the mass to charge composition of plasma with wide range of parameters. PMID- 25832276 TI - Explosively driven air blast in a conical shock tube. AB - Explosively driven shock tubes present challenges in terms of safety concerns and expensive upkeep of test facilities but provide more realistic approximations to the air blast resulting from free-field detonations than those provided by gas driven shock tubes. Likewise, the geometry of conical shock tubes can naturally approximate a sector cut from a spherically symmetric blast, leading to a better agreement with the blast profiles of free-field detonations when compared to those provided by shock tubes employing constant cross sections. The work presented in this article documents the design, fabrication, and testing of an explosively driven conical shock tube whose goal was to closely replicate the blast profile seen from a larger, free-field detonation. By constraining the blast through a finite area, large blasts (which can add significant damage and safety constraints) can be simulated using smaller explosive charges. The experimental data presented herein show that a close approximation to the free field air blast profile due to a 1.5 lb charge of C4 at 76 in. can be achieved by using a 0.032 lb charge in a 76-in.-long conical shock tube (which translates to an amplification factor of nearly 50). Modeling and simulation tools were used extensively in designing this shock tube to minimize expensive fabrication costs. PMID- 25832277 TI - Tip localization of an atomic force microscope in transmission microscopy with nanoscale precision. AB - Since the atomic force microscope (AFM) has evolved into a general purpose platform for mechanical experiments at the nanoscale, the need for a simple and generally applicable localization of the AFM cantilever in the reference frame of an optical microscope has grown. Molecular manipulations like in single molecule cut and paste or force spectroscopy as well as tip mediated nanolithography are prominent examples for the broad variety of applications implemented to date. In contrast to the different kinds of superresolution microscopy where fluorescence is used to localize the emitter, we, here, employ the absorbance of the tip to localize its position in transmission microscopy. We show that in a low aperture illumination, the tip causes a significant reduction of the intensity in the image plane of the microscope objective when it is closer than a few hundred nm. By independently varying the z-position of the sample slide, we could verify that this diffraction limited image of the tip is not caused by a near field effect but is rather caused by the absorbance of the transmitted light in the low apex needle-like tip. We localized the centroid position of this tip image with a precision of better than 6 nm and used it in a feedback loop to position the tip into nano-apertures of 110 nm radius. Single-molecule force spectroscopy traces on the unfolding of individual green fluorescent proteins within the nano apertures showed that their center positions were repeatedly approached with very high fidelity leaving the specific handle chemistry on the tip's surface unimpaired. PMID- 25832278 TI - Photoacoustic signal and noise analysis for Si thin plate: signal correction in frequency domain. AB - Methods for photoacoustic signal measurement, rectification, and analysis for 85 MUm thin Si samples in the 20-20 000 Hz modulation frequency range are presented. Methods for frequency-dependent amplitude and phase signal rectification in the presence of coherent and incoherent noise as well as distortion due to microphone characteristics are presented. Signal correction is accomplished using inverse system response functions deduced by comparing real to ideal signals for a sample with well-known bulk parameters and dimensions. The system response is a piece wise construction, each component being due to a particular effect of the measurement system. Heat transfer and elastic effects are modeled using standard Rosencweig-Gersho and elastic-bending theories. Thermal diffusion, thermoelastic, and plasmaelastic signal components are calculated and compared to measurements. The differences between theory and experiment are used to detect and correct signal distortion and to determine detector and sound-card characteristics. Corrected signal analysis is found to faithfully reflect known sample parameters. PMID- 25832279 TI - A methodology for high resolution digital image correlation in high temperature experiments. AB - We propose a methodology for performing high resolution Digital Image Correlation (DIC) analysis during high-temperature mechanical tests. Specifically, we describe a technique for producing a stable, high-quality pattern on metal surfaces along with a simple optical system that uses a visible-range camera and a long-range microscope. The results are analyzed with a high-quality open-source DIC software developed by us. Using the proposed technique, we successfully acquired high-resolution strain maps of the crack tip field in a nickel superalloy sample at 1000 degrees C. PMID- 25832280 TI - Method for collecting thermocouple data via secured shell over a wireless local area network in real time. AB - This manuscript addresses the design, hardware details, construction, and programming of an apparatus allowing an experimenter to monitor and record high temperature thermocouple measurements of dynamic systems in real time. The apparatus uses wireless network technology to bridge the gap between a dynamic (moving) sample frame and the static laboratory frame. Our design is a custom solution applied to samples that rotate through large angular displacements where hard-wired and typical slip-ring solutions are not practical because of noise considerations. The apparatus consists of a Raspberry PI mini-Linux computer, an Arduino micro-controller, an Ocean Controls thermocouple multiplexer shield, and k-type thermocouples. PMID- 25832281 TI - Conduction-coupled Tesla transformer. AB - A proof-of-principle Tesla transformer circuit is introduced. The new transformer exhibits the high voltage-high power output signal of shock-excited transformers. The circuit, with specification of proper circuit element values, is capable of obtaining extreme oscillatory voltages. The primary and secondary portions of the circuit communicate solely by conduction. The destructive arcing between the primary and secondary inductors in electromagnetically coupled transformers is ubiquitous. Flashover is eliminated in the new transformer as the high-voltage inductors do not interpenetrate and so do not possess an annular volume of electric field. The inductors are remote from one another. The high voltage secondary inductor is isolated in space, except for a base feed conductor, and obtains earth by its self-capacitance to the surroundings. Governing equations, for the ideal case of no damping, are developed from first principles. Experimental, theoretical, and circuit simulator data are presented for the new transformer. Commercial high-temperature superconductors are discussed as a means to eliminate the counter-intuitive damping due to small primary inductances in both the electromagnetic-coupled and new conduction-coupled transformers. PMID- 25832282 TI - A novel design of Rogowski coil for measurement of nanosecond-risetime high-level pulsed current. AB - In pulsed power systems, pulsed currents with risetimes from nanosecond to microsecond can be effectively measured by self-integrating Rogowski coils. Appropriate design of the structure and the integrating resistor is crucial to the high-frequency response of a coil. In this paper, several novel designs of Rogowski coil's integrating resistors were proposed and tested. Experimental results showed that the optimized coil could response square waves with fronts of ~1.5 ns and had a sensitivity of ~0.75 V/kA. The maximal peak current was designed as 100 kA. PMID- 25832283 TI - Experimental apparatus with full optical access for combustion experiments with laminar flames from a single circular nozzle at elevated pressures. AB - The design and features of a high pressure chamber and burner that is suitable for combustion experiments at elevated pressures are presented. The high pressure combustion apparatus utilizes a high pressure burner that is comprised of a chamber burner module and an easily accessible interchangeable burner module to add to its flexibility. The burner is well suited to study both premixed and non premixed flames. The optical access to the chamber is provided through four viewports for direct visual observations and optical-based diagnostic techniques. Auxiliary features include numerous access ports and electrical connections and as a result, the combustion apparatus is also suitable to work with plasmas and liquid fuels. Images of methane flames at elevated pressures up to 25 atm and preliminary results of optical-based measurements demonstrate the suitability of the high pressure experimental apparatus for combustion experiments. PMID- 25832284 TI - High average power, highly brilliant laser-produced plasma source for soft X-ray spectroscopy. AB - In this work, a novel laser-produced plasma source is presented which delivers pulsed broadband soft X-radiation in the range between 100 and 1200 eV. The source was designed in view of long operating hours, high stability, and cost effectiveness. It relies on a rotating and translating metal target and achieves high stability through an on-line monitoring device using a four quadrant extreme ultraviolet diode in a pinhole camera arrangement. The source can be operated with three different laser pulse durations and various target materials and is equipped with two beamlines for simultaneous experiments. Characterization measurements are presented with special emphasis on the source position and emission stability of the source. As a first application, a near edge X-ray absorption fine structure measurement on a thin polyimide foil shows the potential of the source for soft X-ray spectroscopy. PMID- 25832285 TI - Note: self-biased magnetic field sensor using end-bonding magnetoelectric heterostructure. AB - A high sensitivity magnetic field sensor based on magnetoelectric (ME) coupling is presented. The ME sensor FeCuNbSiB/Nickel-PZT-FeCuNbSiB/Nickel is made by bonding magnetization-graded magnetostrictive materials FeCuNbSiB/Nickel at the free ends of the piezoelectric Pb(Zr1-x,Tix)O3 (PZT) plate. Experiments indicate that the proposed sensor has a zero-bias field sensitivity of 14.7 V/Oe at resonance, which is ~41.6 times larger than that of previous FeCuNbSiB-PZT FeCuNbSiB. Furthermore, without external biased field, it can detect dc magnetic field changes as small as ~9 nT near the resonant frequency. This proposed ME sensor provides new pathways to reducing or even eliminating the need of bias fields for ME sensors. PMID- 25832286 TI - Note: proton microbeam formation with continuously variable kinetic energy using a compact system for three-dimensional proton beam writing. AB - A compact focused gaseous ion beam system has been developed to form proton microbeams of a few hundreds of keV with a penetration depth of micrometer range in 3-dimensional proton beam writing. Proton microbeams with kinetic energies of 100-140 keV were experimentally formed on the same point at a constant ratio of the kinetic energy of the object side to that of the image side. The experimental results indicate that the beam diameters were measured to be almost constant at approximately 6 MUm at the same point with the kinetic energy range. These characteristics of the system were experimentally and numerically demonstrated to be maintained as long as the ratio was constant. PMID- 25832287 TI - Note: fast neutron efficiency in CR-39 nuclear track detectors. AB - CR-39 samples are commonly employed for fast neutron detection in fusion reactors and in inertial confinement fusion experiments. The literature reported efficiencies are strongly depending on experimental conditions and, in some cases, highly dispersed. The present note analyses the dependence of efficiency as a function of various parameters and experimental conditions in both the radiator-assisted and the stand-alone CR-39 configurations. Comparisons of literature experimental data with Monte Carlo calculations and optimized efficiency values are shown and discussed. PMID- 25832289 TI - Preoperative rosuvastatin protects patients with coronary artery disease undergoing noncardiac surgery. AB - OBJECTIVES: We explored whether preoperative rosuvastatin could protect the cardiac health of patients with coronary artery disease undergoing emergency, noncardiac surgery. METHODS: We randomized 550 noncardiac emergency surgery patients with stable coronary artery disease on long-term statin therapy to treatment with and without preoperative rosuvastatin. All patients received rosuvastatin after surgery. We evaluated the incidence of myocardial necrosis and major adverse cardiovascular and cerebrovascular events (MACCE) 30 days and 6 months after surgery. RESULTS: Creatinine kinase-myocardial band (CK-MB) isoform elevations occurred less frequently 12 and 24 h after noncardiac emergency surgery in the experimental group than in the control group (p = 0.029). After surgery, the incidence of MACCE was also lower in the experimental group than in the control group (p = 0.019). The difference was mainly due to the incidence of perioperative myocardial infarction (p = 0.029). Multivariable analysis found that rosuvastatin reload reduced the incidence of MACCE 52% 6 months after surgery (p = 0.03). CONCLUSIONS: Preoperative rosuvastatin reload therapy decreases the incidence of myocardial necrosis and MACCE after noncardiac emergency surgery in patients with stable coronary artery disease on long-term statin therapy. PMID- 25832290 TI - Can Genomic Amplification of Human Telomerase Gene and C-MYC in Liquid-Based Cytological Specimens Be Used as a Method for Opportunistic Cervical Cancer Screening? AB - OBJECTIVE: To evaluate the effectiveness of five methods including the ThinPrep cytological test (TCT), liquid-based cytology, the human papillomavirus (HPV) test, detection of the TERC and C-MYC genes and visual inspection with acetic acid/Lugol's iodine (VIA/VILI) for opportunistic cervical cancer screening, and to explore whether genomic amplification of the human telomerase gene and C-MYC in liquid-based cytological specimens can be used as a method for opportunistic cervical cancer screening. METHODS: Data were collected prospectively from 1,010 consecutive patients who visited the gynecology clinic and agreed to participate in opportunistic cervical cancer screening at our institution from November 2010 to July 2011. The five methods mentioned above were used for the screening in all cases. The histopathological diagnosis served as the gold standard for the evaluation. A comparison between the five screening methods for the diagnosis of high-grade cervical intraepithelial neoplasia (CIN II and III) was performed for their sensitivity, specificity, false-positive rate, false-negative rate, accuracy rate, positive likelihood ratio and negative likelihood ratio. A comprehensive comparison of the different combination programs for screening was performed according to the analysis of the receiver operating characteristic (ROC) curve area. The accuracy of the five screening methods for the diagnosis of high-grade CIN (CIN II and III) was compared in the different age groups. A joint model for the diagnosis using different combinations of the five methods was developed according to the analysis by the SAS 8.0 software. The model was used to evaluate the accuracy of the different combination programs for the diagnosis of high-grade CIN, and the results were confirmed by the histopathological examination. RESULTS: The sensitivity and specificity of the single screen method (TCT, HPV test, detection of the TERC and C-MYC genes, and VIA/VILI method) for CIN II was 80.9, 70.2, 72.3, 76.6, and 72.3%, as well as 98.0, 95.1, 96.3, 96.3, and 90.4%, respectively. The sensitivity of the single screening method in four different age groups (25-34, 35-44, 45-54 and 55-66 years) was as follows: TCT, 64.3, 90.9 76.5, and 85.7%; HPV test, 78.6, 72.7, 60.0, and 71.4%; the TERC gene, 50.0, 90.9, 80.0, and 71.4%; the C-MYC gene, 50.0, 90.9, 80.0, and 100%; VIA/VILI, 85.7, 81.8, 66.7, and 42.9%. The specificity was: TCT, 98.9, 98.1, 98.8, and 95.2%; HPV test, 96.7, 95.1, 92.2, and 100%; the TERC gene, 95.0, 98.9, 94.0, and 95.2%; the C-MYC gene, 97.2, 97.3, 93.4, and 97.6%; VIA/VILI, 91.2, 90.5, 89.8, and 88.1%, respectively. In the joint model for the diagnosis using different combinations, we found Logit (P) = 5.757 - 4.055 * TCT - 3.724 * HPV. The sensitivity and specificity in the combination program with TCT (primary screening) and HPV testing (adjunct screening) were 78.7 and 99.5%, while in the combination with HPV (primary) and TCT (adjunct), they were 53.2 and 99.7%, respectively. However, in the cytology-HPV parallel test, they were 97.9 and 93.4%. The ROC analysis revealed that the cytology-HPV parallel test is superior to the combinations of either TCT (primary) and HPV (adjunct) or HPV (primary) and TCT (adjunct; AUCTCT-HPV parallel test = 0.956; AUCTCT/primaryHPV/adjunct = 0.764). CONCLUSIONS: Opportunistic cervical cancer screening is a practical approach to improve the efficiency of cervical cancer screening. Although the accuracy of TCT is the highest of the five screening methods for the diagnosis of high-grade CIN, it is still subject to sample acquisition and the practitioner's skill and experience. Since the efficacy of VIA/VILI may vary in all ages, it is not recommended for menopausal and perimenopausal women. PMID- 25832291 TI - Clinical features and survival of asian pediatric patients with paroxysmal nocturnal hemoglobinuria: results from a single center in China. AB - OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children. To characterize the clinical presentations and survival, we performed a retrospective analysis of pediatric patients. METHODS: We reviewed 55 pediatric patients with PNH referred to our hospital from January 1990 through June 2012 to assess clinical presentations, survival, and differences among subcategories. RESULTS: The overall survival 10 years after diagnosis estimated via the Kaplan-Meier method was 77.6%. The cohort of patients was divided into subcategories of classic PNH, PNH/aplastic anemia (AA), and subclinical PNH (PNH sc)/AA based on the recently proposed PNH working clinical classification. We found that patients with classic PNH and PNH/AA had larger PNH clones and many more parameters of hemolysis, but patients with PNH-sc/AA had smaller PNH clones, fewer parameters of hemolysis, and a higher rate of bone marrow failure. Our results revealed a high rate of bone marrow failure and a low rate of hemoglobinuria at presentation. Furthermore, thrombotic events were not observed in our patients, which is significantly different from the rate seen in Caucasian patients. Additionally, pediatric patients with PNH may develop bone marrow cytogenetic abnormalities. CONCLUSION: This study provides insight into Chinese pediatric PNH patients and may aid in setting up individualized therapeutic regimens. PMID- 25832292 TI - Red, green, and blue luminescence by carbon dots: full-color emission tuning and multicolor cellular imaging. AB - A facile approach for preparation of photoluminescent (PL) carbon dots (CDs) is reported. The three resulting CDs emit bright and stable red, green and blue (RGB) colors of luminescence, under a single ultraviolet-light excitation. Alterations of PL emission of these CDs are tentatively proposed to result from the difference in their particle size and nitrogen content. Interestingly, up conversion (UC)PL of these CDs is also observed. Moreover, flexible full-color emissive PVA films can be achieved through mixing two or three CDs in the appropriate ratios. These CDs also show low cytotoxicity and excellent cellular imaging capability. The facile preparation and unique optical features make these CDs potentially useful in numerous applications such as light-emitting diodes, full-color displays, and multiplexed (UC)PL bioimaging. PMID- 25832293 TI - Isostrychnine synthesis mediated by hypervalent iodine reagent. AB - Althought there are several reported synthetic routes to strychnine, one of the most widely recognized alkaloids, we report an unexplored route with an oxidative dearomatizing process mediated by hypervalent iodine as the key step. The new syntheses of isostrychnine and strychnine have been achieved from an readily available phenol in nine and ten steps. In addition to the key step, these syntheses involve an aza Michael-ether-enol tandem transformation, two heck type cyclizations, a reductive isomerization, and a double reductive amination in cascade leading to the alkaloid main core. PMID- 25832294 TI - A rate-based transcutaneous CO2 sensor for noninvasive respiration monitoring. AB - The pain and risk of infection associated with invasive blood sampling for blood gas measurements necessitate the search for reliable noninvasive techniques. In this work we developed a novel rate-based noninvasive method for a safe and fast assessment of respiratory status. A small sampler was built to collect the gases diffusing out of the skin. It was connected to a CO2 sensor through gas impermeable tubing. During a measurement, the CO2 initially present in the sampler was first removed by purging it with nitrogen. The gases in the system were then recirculated between the sampler and the CO2 sensor, and the CO2 diffusion rate into the sampler was measured. Because the measurement is based on the initial transcutaneous diffusion rate, reaching mass transfer equilibrium and heating the skin is no longer required, thus, making it much faster and safer than traditional method. A series of designed experiments were performed to analyze the effect of the measurement parameters such as sampler size, measurement location, subject positions, and movement. After the factor analysis tests, the prototype was sent to a level IV NICU for clinical trial. The results show that the measured initial rate of increase in CO2 partial pressure is linearly correlated with the corresponding arterial blood gas measurements. The new approach can be used as a trending tool, making frequent blood sampling unnecessary for respiratory status monitoring. PMID- 25832295 TI - Solid-phase extraction coupled with ultra high performance liquid chromatography and electrospray tandem mass spectrometry for the highly sensitive determination of five iodinated X-ray contrast media in environmental water samples. AB - A highly sensitive method based on solid-phase extraction and ultra high performance liquid chromatography with electrospray tandem mass spectrometry has been developed for simultaneous determination of five iodinated X-ray contrast media in environmental water samples. Various solid-phase extraction cartridges have been evaluated and a combination of LiChrolute EN and ENVI-Carb solid phase extraction cartridges was selected for sample enrichment. The method was comprehensively validated on ground water, tap water, surface water, drinking water, and waste water by the conventional procedures: linearity, method detection limits, accuracy and precision, matrix effects. Good linearity (R(2) > 0.999), low detection limits (0.4-8.1 ng/L), satisfactory recoveries (55.1 109.5%) and precision (0.8-10.0% for intra-day precisions and 0.6-16.5% for inter day precisions) were obtained for all the target compounds. Iopamidol, iohexol, and diatrizoate in some matrices were affected by matrix effects, which were slightly eased by using the isotope-labeled internal standard. The developed method was successfully applied for real samples collected in Shanghai, China, with detected concentrations up to 2200 +/- 200 and 9000 +/- 1000 ng/L for iohexol and iopamidol, respectively. PMID- 25832296 TI - Genetic analyses benefit from using less heterogeneous phenotypes: an illustration with the hospital anxiety and depression scale (HADS). AB - Phenotypic heterogeneity of depression has been cited as one of the causes of the limited success to detect genetic variants in genome-wide studies. The 7-item Hospital Anxiety and Depression Scale (HADS-D) was developed to detect depression in individuals with physical health problems. An initial psychometric analysis showed that a short version ("HADS-4") is less heterogeneous and hence more reliable than the full scale, and correlates equally strong with a DSM-oriented depression scale. We compared the HADS-D and the HADS-4 to assess the benefits of using less heterogeneous phenotype measures in genetic analyses. We compared HADS D and HADS-4 in three separate analyses: (1) twin- and family-based heritability estimation, (2) SNP-based heritability estimation using the software GCTA, and (3) a genome-wide association study (GWAS). The twin study resulted in heritability estimates between 18% and 25%, with additive genetic variance being the largest component. There was also evidence for assortative mating and a dominance component of genetic variance, with HADS-4 having slightly lower estimates of assortment. Importantly, when estimating heritability from SNPs, the HADS-D did not show a significant genetic variance component, while for the HADS 4, a statistically significant amount of heritability was estimated. Moreover, the HADS-4 had substantially more SNPs with small P-values in the GWAS analysis than did the HADS-D. Our results underline the benefits of using more homogeneous phenotypes in psychiatric genetic analyses. Homogeneity can be increased by focusing on core symptoms of disorders, thus reducing the noise in aggregate phenotypes caused by substantially different symptom profiles. PMID- 25832297 TI - Clinical relevance of as-needed treatment with nalmefene in alcohol-dependent patients. AB - Nalmefene is the first drug approved for reduction of alcohol consumption. The aim of this study was to evaluate the clinical relevance of treatment with nalmefene in alcohol-dependent patients with a high drinking risk level from two randomised placebo-controlled 6-month studies (NCT00811720 and NCT00812461). Response criteria were based on alcohol consumption, Clinical Global Impression, and Short Form Health Survey mental component summary scores at month 6, analysed using logistic regression. The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios significantly in favour of nalmefene for all responder criteria; numbers-needed-to-treat ranged from 6 to 10. Significant differences from placebo in clinician-rated and patient reported outcomes, and liver enzymes further supported the clinical relevance of the treatment effect. In conclusion, this study supports the clinical relevance of nalmefene treatment in patients with alcohol dependence. Nalmefene may help to reduce the alcohol-related burden and the large treatment gap, with currently less than 10% of alcohol-dependent patients in Europe receiving treatment. PMID- 25832298 TI - Evidence for human norovirus infection of dogs in the United kingdom. AB - Human noroviruses (HuNoVs) are a major cause of viral gastroenteritis, with an estimated 3 million cases per year in the United Kingdom. HuNoVs have recently been isolated from pet dogs in Europe (M. Summa, C.-H. von Bonsdorff, and L. Maunula, J Clin Virol 53:244-247, 2012, http://dx.doi.org/10.1016/j.jcv.2011.12.014), raising concerns about potential zoonotic infections. With 31% of United Kingdom households owning a dog, this could prove to be an important transmission route. To examine this risk, canine tissues were studied for their ability to bind to HuNoV in vitro. In addition, canine stool samples were analyzed for the presence of viral nucleic acid, and canine serum samples were tested for the presence of anti-HuNoV antibodies. The results showed that seven different genotypes of HuNoV virus-like particles (VLPs) can bind to canine gastrointestinal tissue, suggesting that infection is at least theoretically possible. Although HuNoV RNA was not identified in stool samples from 248 dogs, serological evidence of previous exposure to HuNoV was obtained in 43/325 canine serum samples. Remarkably, canine seroprevalence for different HuNoV genotypes mirrored the seroprevalence in the human population. Though entry and replication within cells have not been demonstrated, the canine serological data indicate that dogs produce an immune response to HuNoV, implying productive infection. In conclusion, this study reveals zoonotic implications for HuNoV, and to elucidate the significance of this finding, further epidemiological and molecular investigations will be essential. PMID- 25832299 TI - Use of Whole-Genome Phylogeny and Comparisons for Development of a Multiplex PCR Assay To Identify Sequence Type 36 Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus sequence type 36 (ST36) strains that are native to the Pacific Ocean have recently caused multistate outbreaks of gastroenteritis linked to shellfish harvested from the Atlantic Ocean. Whole-genome comparisons of 295 genomes of V. parahaemolyticus, including several traced to northeastern U.S. sources, were used to identify diagnostic loci, one putatively encoding an endonuclease (prp), and two others potentially conferring O-antigenic properties (cps and flp). The combination of all three loci was present in only one clade of closely related strains of ST36, ST59, and one additional unknown sequence type. However, each locus was also identified outside this clade, with prp and flp occurring in only two nonclade isolates and cps in four. Based on the distribution of these loci in sequenced genomes, prp identified clade strains with >99% accuracy, but the addition of one more locus increased accuracy to 100%. Oligonucleotide primers targeting prp and cps were combined in a multiplex PCR method that defines species using the tlh locus and determines the presence of both the tdh and trh hemolysin-encoding genes, which are also present in ST36. Application of the method in vitro to a collection of 94 clinical isolates collected over a 4-year period in three northeastern U.S. states and 87 environmental isolates revealed that the prp and cps amplicons were detected only in clinical isolates identified as belonging to the ST36 clade and in no environmental isolates from the region. The assay should improve detection and surveillance, thereby reducing infections. PMID- 25832300 TI - Successful Combination of Nucleic Acid Amplification Test Diagnostics and Targeted Deferred Neisseria gonorrhoeae Culture. AB - Nucleic acid amplification tests (NAATs) are recommended for the diagnosis of N. gonorrhoeae infections because of their superior sensitivity. Increasing NAAT use causes a decline in crucial antimicrobial resistance (AMR) surveillance data, which rely on culture. We analyzed the suitability of the ESwab system for NAAT diagnostics and deferred targeted N. gonorrhoeae culture to allow selective and efficient culture based on NAAT results. We included patients visiting the STI Clinic Amsterdam, The Netherlands, in 2013. Patient characteristics and urogenital and rectal samples for direct N. gonorrhoeae culture, standard NAAT, and ESwab were collected. Standard NAAT and NAAT on ESwab samples were performed using the Aptima Combo 2 assay for N. gonorrhoeae and C. trachomatis. Two deferred N. gonorrhoeae cultures were performed on NAAT-positive ESwab samples after storage at 4 degrees C for 1 to 3 days. We included 2,452 samples from 1,893 patients. In the standard NAAT, 107 samples were N. gonorrhoeae positive and 284 were C. trachomatis positive. The sensitivities of NAAT on ESwab samples were 83% (95% confidence interval [CI], 75 to 90%) and 87% (95% CI, 82 to 90%), respectively. ESwab samples were available for 98 of the gonorrhea-positive samples. Of these, 82% were positive in direct culture and 69% and 56% were positive in the 1st and 2nd deferred cultures, respectively (median storage times, 27 and 48 h, respectively). Deferred culture was more often successful in urogenital samples or when the patient had symptoms at the sampling site. Deferred N. gonorrhoeae culture of stored ESwab samples is feasible and enables AMR surveillance. To limit the loss in NAAT sensitivity, we recommend obtaining separate samples for NAAT and deferred culture. PMID- 25832301 TI - Combat-Related Pythium aphanidermatum Invasive Wound Infection: Case Report and Discussion of Utility of Molecular Diagnostics. AB - We describe a 22-year-old soldier with 19% total body surface area burns, polytrauma, and sequence- and culture-confirmed Pythium aphanidermatum wound infection. Antemortem histopathology suggested disseminated Pythium infection, including brain involvement; however, postmortem PCR revealed Cunninghamella elegans, Lichtheimia corymbifera, and Saksenaea vasiformis coinfection. The utility of molecular diagnostics in invasive fungal infections is discussed. PMID- 25832302 TI - Colonization with Escherichia coli Strains among Female Sex Partners of Men with Febrile Urinary Tract Infection. AB - Of 23 unique Escherichia coli strains from 10 men with febrile urinary tract infections (UTIs) and their female sex partners, 6 strains (all UTI causing) were shared between partners. Molecularly, the 6 shared strains appeared more virulent than the 17 nonshared strains, being associated with phylogenetic group B2, sequence types ST73 and ST127, and multiple specific virulence genes. This indicates that UTIs are sometimes sexually transmitted. PMID- 25832303 TI - First Case Report of Campylobacter volucris Bacteremia in an Immunocompromised Patient. AB - We report a case of Campylobacter volucris bacteremia in an immunocompromised patient with polycythemia vera and alcoholic liver cirrhosis. To our knowledge, this is the first case report in which this organism has been isolated from a human clinical specimen. PMID- 25832304 TI - Development and Application of a gp60-Based Typing Assay for Cryptosporidium viatorum. AB - The apicomplexan intestinal parasites of the genus Cryptosporidium take a major toll on human and animal health and are frequent causes of waterborne outbreaks. Several species and genotypes can infect humans, including Cryptosporidium viatorum, which, to date, has only been found in humans. Molecular characterization of Cryptosporidium spp., critical to epidemiological analyses, is commonly based on gp60 gene analysis, which appears to require bespoke species or group-specific PCR primers due to extensive genetic diversity across the genus. In this study, we amplified, sequenced, and characterized the gp60 gene of C. viatorum for the first time. Moreover, we developed and validated a gp60 typing assay for this species and applied it to 27 isolates originating from Asia, Africa, and Central America. A single subtype family, XVa, was identified containing multiple alleles. PMID- 25832305 TI - Quality compared to quantity of life in laryngeal cancer: A time trade-off study. AB - BACKGROUND: The purpose of this study was to use time trade-off to assess the factors influencing patients' decisions in advanced laryngeal cancer. Time trade off is a well-established method of assessing how individuals value a particular health state. METHODS: We developed vignettes depicting life after chemoradiotherapy or laryngectomy. One hundred fourteen participants ranked them, assigned utility values, and rated the importance of survival on treatment choice. RESULTS: Chemoradiotherapy was preferred by 62% and laryngectomy by 38%. Chemoradiotherapy optimal outcome had the highest mean utility value (0.64) followed by total laryngectomy optimal outcome (0.56). Total laryngectomy poor outcome (0.33) was equivalent to chemoradiotherapy poor outcome (0.32).The average survival advantage required for a participant to change their preferred choice was 2.1 years. CONCLUSION: The functional treatment outcome had a greater effect on health state utility values than treatment modality. In many individuals, larynx conservation may not be the primary consideration in treatment preference. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E631-E637, 2016. PMID- 25832306 TI - Mirror Therapy and Transcutaneous Electrical Nerve Stimulation for Management of Phantom Limb Pain in Amputees - A Single Blinded Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Phantom limb pain (PLP) can be disabling for nearly two thirds of amputees. Hence, there is a need to find an effective and inexpensive treatment that can be self administered. Among the non-pharmacological treatment for PLP, transcutaneous electrical nerve stimulation (TENS) applied to the contralateral extremity and mirror therapy are two promising options. However, there are no studies to compare the two treatments. The purpose of this study is to evaluate and compare mirror therapy and TENS in the management of PLP in subjects with amputation. METHODS: The study was an assessor blinded randomized controlled trial conducted at Physiotherapy Gymnasium of Physical Medicine and Rehabilitation Department, Christian Medical College, Vellore. Twenty-six subjects with PLP consented to participate. An initial assessment of pain using visual analogue scale (VAS) and universal pain score (UPS) was performed by a therapist blinded to the treatment given. Random allocation into Group I-mirror therapy and Group II-TENS was carried out. After 4 days of treatment, pain was re assessed by the same therapist. The mean difference in Pre and Post values were compared among the groups. The change in pre-post score was analyzed using the paired t test. RESULTS: Participants of Group I had significant decrease in pain [VAS ( p = 0.003) and UPS ( p = 0.001)]. Group II also showed a significant reduction in pain [VAS ( p = 0.003) and UPS ( p = 0.002)]. However, no difference was observed between the two groups [VAS ( p = 0.223 and UPS ( p = 0.956)]. DISCUSSION: Both Mirror Therapy and TENS were found to be effective in pain reduction on a short-term basis. However, no difference between the two groups was found. Substantiation with long-term follow-up is essential to find its long term effectiveness. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25832307 TI - Revisiting the extrapolation of correlation energies to complete basis set limit. AB - The extrapolation scheme of correlation energy is revisited to evaluate the complete basis set limit from double-zeta (DZ) and triple-zeta levels of calculations. The DZ level results are adjusted to the standard asymptotic behavior with respect to the cardinal number, observed at the higher levels of basis sets. Two types of adjusting schemes with effective scaling factors, which recover errors in extrapolations with the DZ level basis set, are examined. The first scheme scales the cardinal number for the DZ level energy, while the second scheme scales the prefactor of the extrapolation function. Systematic assessments on the Gaussian-3X and Gaussian-2 test sets reveal that these calibration schemes successfully and drastically reduce errors without additional computational efforts. PMID- 25832308 TI - Right lobe split liver transplantation versus whole liver transplantation in adult recipients: A systematic review and meta-analysis. AB - Split liver transplantation (SLT) has proven to be an effective technique to reduce the mortality of children on the waiting list, but whether creating 2 split grafts from 1 standard-criteria whole liver would compromise outcomes of adult recipients remains uncertain. We conducted this meta-analysis to compare outcomes of right lobe SLT and whole liver transplantation (WLT) in adult patients. PubMed, Embase, and the Cochrane Library were searched for relevant articles published before December 2014. Outcomes assessed were patient survival (PS), graft survival (GS), and major surgical complications after transplantation. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to synthesize the results. Seventeen studies with a total of 48,457 patients met the full inclusion criteria. PS and GS rates were all found to be equivalent between SLT and WLT recipients. However, SLT was associated with higher rates of overall biliary complications (OR = 1.66; 95% CI = 1.29-2.15; P < 0.001), bile leaks (OR = 4.30; 95% CI = 2.97-6.23; P < 0.001), overall vascular complications (OR = 1.81; 95% CI = 1.29-2.53; P < 0.001), hepatic artery thromboses (OR = 1.71; 95% CI = 1.17-2.50; P = 0.005), and outflow tract obstructions (OR = 4.17; 95% CI = 1.75-9.94; P = 0.001). No significant difference was observed in incidences of biliary stricture, portal vein complications, postoperative bleeding requiring surgical treatments, primary nonfunction, and retransplantations. In subgroup analyses, biliary and vascular complications only increased after ex vivo SLT rather than in situ SLT, and SLT recipients had more retransplantations if they matched with WLT recipients in terms of urgent status. In conclusion, adult right lobe SLT was associated with increased biliary and vascular complications compared with WLT, but it did not show significant inferiority in PSs and GSs. PMID- 25832309 TI - Estimating the number of sudden cardiac deaths attributable to the use of domperidone in France. AB - PURPOSE: The aim of this study was to estimate of the number of sudden cardiac deaths attributable to the use of domperidone in France in 2012 METHODS: Computation of the attributable fraction, function of the increase in risk of sudden cardiac death induced by domperidone and of the exposure prevalence. Multiplying the attributable fraction by the risk of sudden cardiac death in the French population gives an estimation of the number of sudden cardiac deaths attributable to domperidone. RESULTS: The use of domperidone in France is the cause of 231 deaths per year in the population aged 18 years or over. CONCLUSIONS: This risk should be taken into consideration by clinicians when prescribing a drug which provides a minor benefit. PMID- 25832310 TI - Pentraxin 3 as a clinical marker in children with lower respiratory tract infection. AB - BACKGROUND: Pentraxin 3 (PTX-3) is an acute-phase protein that increases in the plasma during inflammation. OBJECTIVE: We aimed to evaluate the usefulness of PTX 3 as a clinical marker in children with lower respiratory tract infection (LRTI) and examine the correlation of PTX-3 with other biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT). METHODS: We enrolled 117 consecutive patients admitted to Seoul St. Mary's Hospital with LRTI using the WHO criteria. We recorded data on fever duration and peak temperature before admission, duration of fever after admission, respiratory rate, heart rate, oxygen saturation upon admission, duration of oxygen supplementation, and duration of hospital stay. Upon admission, white blood cell (WBC) count, erythrocyte sedimentation rate, CRP level were measured. Multiplex respiratory virus polymerase chain reaction was performed using nasal swabs. PTX-3, PCT, and various cytokines were measured after the study had been completed. RESULTS: We found that there was no significant difference in the level of PTX-3 according to the type of viral infection. PTX-3 levels showed a significant correlation with PCT levels, but not with levels of CRP. The level of PTX-3 showed a significant correlation with peak temperature and duration of fever before admission as well as interleukin (IL)-6 levels. PCT levels showed a significant correlation with IL 6 and granulocyte-colony stimulating factor levels, peak temperature, and duration of fever before admission, and duration of hospital stay. CRP levels showed a significant correlation with duration of fever before admission, total WBC count, and neutrophil count. PCT levels significantly predicted a hospital stay of 7 days or more. PTX-3, PCT, and CRP levels showed no correlation with any other clinical features. CONCLUSION: PTX-3 reflected disease severity but failed to predict length of hospital stay. Further studies evaluating the use of PTX-3 as a biomarker in mild LRTI would be useful. PMID- 25832311 TI - Reversal of anticoagulants: an overview of current developments. AB - Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors. PMID- 25832313 TI - Different cortical projections from three subdivisions of the rat lateral posterior thalamic nucleus: a single-neuron tracing study with viral vectors. AB - The lateral posterior thalamic nucleus (LP) is one of the components of the extrageniculate pathway in the rat visual system, and is cytoarchitecturally divided into three subdivisions--lateral (LPl), rostromedial (LPrm), and caudomedial (LPcm) portions. To clarify the differences in the dendritic fields and axonal arborisations among the three subdivisions, we applied a single-neuron labeling technique with viral vectors to LP neurons. The proximal dendrites of LPl neurons were more numerous than those of LPrm and LPcm neurons, and LPrm neurons tended to have wider dendritic fields than LPl neurons. We then analysed the axonal arborisations of LP neurons by reconstructing the axon fibers in the cortex. The LPl, LPrm and LPcm were different from one another in terms of the projection targets--the main target cortical regions of LPl and LPrm neurons were the secondary and primary visual areas, whereas those of LPcm neurons were the postrhinal and temporal association areas. Furthermore, the principal target cortical layers of LPl neurons in the visual areas were middle layers, but that of LPrm neurons was layer 1. This indicates that LPl and LPrm neurons can be categorised into the core and matrix types of thalamic neurons, respectively, in the visual areas. In addition, LPl neurons formed multiple axonal clusters within the visual areas, whereas the fibers of LPrm neurons were widely and diffusely distributed. It is therefore presumed that these two types of neurons play different roles in visual information processing by dual thalamocortical innervation of the visual areas. PMID- 25832312 TI - Impact of Certolizumab Pegol on Patient-Reported Outcomes in Patients With Axial Spondyloarthritis. AB - OBJECTIVE: Patient-reported outcomes (PROs) provide an opportunity to collect important information relating to patient well-being, which is often difficult for physicians to measure (e.g., quality of life, pain, fatigue, and sleep). Here we evaluate the effects of certolizumab pegol (CZP) on PROs during the 24-week, double-blind phase of the RAPID axial spondyloarthritis (SpA) trial, a phase 3 trial of axial SpA patients, including both ankylosing spondylitis (AS) and nonradiographic axial SpA patients. METHODS: A total of 325 patients with active axial SpA were randomized 1:1:1 to placebo, CZP 200 mg every 2 weeks, or CZP 400 mg every 4 weeks. The primary end point was the Assessment of SpondyloArthritis International Society criteria for 20% improvement in disease activity response at week 12, and has been reported previously. PROs included total back pain, nocturnal back pain, a daily pain diary, the Sleep Problems Index II (SPI) domain of the Medical Outcomes Study (MOS) Sleep Scale, fatigue, the Ankylosing Spondylitis Quality of Life (ASQOL) measure, and the Short Form 36-item (SF-36) health survey physical component summary (PCS), mental component summary (MCS), and domains. RESULTS: Patients treated with CZP reported significant improvements from week 1 for nocturnal back pain (placebo -0.6, CZP 200 mg every 2 weeks -1.9, and CZP 400 mg every 4 weeks -1.6; P < 0.001) and ASQOL (placebo -1.0, CZP 200 mg every 2 weeks -2.3, and CZP 400 mg every 4 weeks -1.9; P < 0.05) compared with placebo, while significant improvements in total back pain were seen from day 2. Patients treated with both CZP dosing regimens also had significantly greater improvements in fatigue, MOS-SPI, SF-36 PCS, MCS, and domains compared with placebo. Improvements were similar in both AS and nonradiographic axial SpA patients. CONCLUSION: Both CZP dosing schedules rapidly improved patient well being, as measured by PROs, including pain, fatigue, sleep, SF-36, and ASQOL in both AS and nonradiographic axial SpA patients. PMID- 25832314 TI - Duplication of HEY2 in cardiac and neurologic development. AB - HEY2 is a basic helix-loop-helix (bHLH) transcription factor that plays an important role in the developing mammalian heart and brain. In humans, nonsynonymous mutations in HEY2 have been described in patients with atrial ventricular septal defects, and a subset of individuals with chromosomal deletions involving HEY2 have cardiac defects and cognitive impairment. Less is known about the potential effects of HEY2 overexpression. Here, we describe a female child with tetralogy of Fallot who developed severe right ventricular outflow tract obstruction due to a combination of infundibular and valvular pulmonary stenosis. She was also noted to have hypotonia, lower extremity weakness, fine motor delay and speech delay. A copy number variation (CNV) detection analysis followed by real-time quantitative PCR analysis revealed a single gene duplication of HEY2. This is the only duplication involving HEY2 identified in our database of over 70,000 individuals referred for CNV analysis. In the developing heart, overexpression of HEY2 is predicted to cause decreased expression of the cardiac transcription factor GATA4 which, in turn, has been shown to cause tetralogy of Fallot. In mice, misexpression of Hey2 in the developing brain leads to inhibition of neurogenesis and promotion of gliogenesis. Hence, duplication of HEY2 may be a contributing factor to both the congenital heart defects and the neurodevelopmental problems evident in our patient. These results suggest that individuals with HEY2 duplications should be screened for congenital heart defects and monitored closely for evidence of developmental delay and/or cognitive impairment. PMID- 25832315 TI - Costly retaliation is promoted by threats to resources in women and threats to status in men. AB - What motivates people to act against their own self-interest? In men, what seems to be irrational decision-making in the short-term may be explained by other long term benefits; thus retaliation may not be motivated by tangible costs, but instead intangible psychological variables (e.g., status threats). In contrast, there is evidence that women are more sensitive to tangible costs than are men. In Experiment 1, using the Point Subtraction Aggression Paradigm (PSAP), we tested the prediction that in men, the frequency of provocation, and not the monetary loss (tangible cost), would be associated with retaliation, whereas women would be sensitive to the tangible costs. In keeping with the prediction, women (n = 80) who incurred greater tangible costs (irrespective of frequency) retaliated with more costly punishment, whereas men (n = 90) who were provoked more frequently (irrespective of tangible costs) retaliated with more costly punishment. In Experiment 2, we directly investigated whether women were more sensitive to threats to resources and men were more sensitive to threats to status, as suggested by the results of Experiment 1. Women's (n = 53) retaliation was greater when they reported it to be a means to protect their resources, and men's (n = 35) retaliation was greater when they reported it to be a means to protect their status. Thus, these results identify psychological variables that guide retaliation that is costly to the actor. Consistent with evolutionary perspectives, concerns about status appear to drive costly retaliatory behavior more so in men than in women. PMID- 25832316 TI - Primacy of surgery for colorectal cancer. AB - BACKGROUND: The optimal technique for curative resection of colonic cancer includes high ligation of the mesenteric vessels, wide excision of the colonic mesentery and prevention of tumour cell spillage. This article reports results from the authors' institution for patients in whom complete mesocolic excision was performed long before the term was coined. METHODS: Patients operated on for cure for primary adenocarcinoma of the colon between January 1994 and December 2004 were identified from a prospectively maintained, institutional review board approved, colorectal cancer registry. Medical records and operation notes were reviewed. The primary outcomes were recurrence (local and distal) and age adjusted 5-year survival. RESULTS: Some 1013 patients (560 men and 453 women) were identified, with a median age of 69 (range 21-96) years. The most common location of the cancer was the sigmoid colon (32.9 per cent), followed by the caecum (26.7 per cent) and ascending colon (17.0 per cent). Operations were performed laparoscopically in 134 patients (13.2 per cent). Median duration of hospital stay was 7 (range 1-64, mean 8.2) days. Overall morbidity and mortality rates were 13.5 and 2.2 per cent respectively; there were 20 anastomotic leaks (2.0 per cent). Some 282 patients (27.8 per cent) had stage I, 386 (38.1 per cent) stage II and 345 (34.1 per cent) stage III disease. Median lymph node yield was 28.3 (range 0-241, mean 28.3), and 12 or more nodes were examined in 88.1 per cent of patients. Adjuvant chemotherapy was administered to 277 patients (80.3 per cent) with stage III disease. Overall local and distant recurrence rates at 5 years were 5.1 and 17.1 per cent respectively. The 5-year local recurrence rate was 2.2, 5.3 and 7.7 per cent for American Joint Committee on Cancer stages I, II and III respectively. Corresponding distant recurrence rates were 4.0, 14.7 and 30.5 per cent. The 5-year overall cancer-free age-standardized survival rate was 85.3 per cent. Five-year age standardized survival rates for patients with disease stages I, II and III were 97.7, 90.8 and 69.8 per cent respectively. CONCLUSION: These data define modern results of surgery for colonic cancer with conservative use of chemotherapy. PMID- 25832317 TI - Regional differences in Clostridium difficile infections in relation to fluoroquinolone and proton pump inhibitor use, Finland, 2008-2011. AB - BACKGROUND: Several antimicrobial agents and proton pump inhibitors (PPIs) have been identified as risk factors for Clostridium difficile infections (CDIs). Nationwide laboratory-based surveillance of CDIs in Finland since 2008 has shown variation in regional CDI rates. We evaluated whether regional differences in CDI rates were associated with antibacterial and PPI use. METHODS: Data on mean annual incidence rates of CDIs during 2008-2011 in 21 healthcare districts (HDs) were obtained from the National Infectious Disease Register, consumption (median annual use) of antimicrobials and PPIs from the Finnish Medical Agency, availability of molecular diagnostics by a laboratory survey and data on ribotypes from the national reference laboratory. The association over the 4 years was measured by incidence rate ratio (IRR) and we performed both bivariate and multivariate analyses. RESULTS: During 2008-2011, PPI use increased 27% but fluoroquinolone use was stable. The level of fluoroquinolone use was strongly associated with the mean annual CDI incidence rate in different HDs over the 4 year period, but PPI use had less effect. The molecular diagnostics methodology and PCR ribotype 027 were not independently associated with CDI rate. The final multivariable model only included fluoroquinolone and PPI use; IRR for fluoroquinolones was 2.20 (95% confidence interval (CI), 1.32-3.67; p = 0.003). CONCLUSIONS: Fluoroquinolone use may play a role in regional differences in CDI rates. Although the use has not recently increased, regionally targeted antimicrobial stewardship campaigns promoting appropriate use of fluoroquinolones should still be encouraged since they may decrease the incidence of CDIs. PMID- 25832318 TI - Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features. AB - AIMS: Familial adenomatous polyposis (FAP) is a hereditary cancer predisposition syndrome caused by a germline APC mutation. A recent study showed the enrichment of pyloric gland adenomas (PGAs) of the stomach, in addition to fundic gland polyps (FGPs) and foveolar-type adenomas (FAs), in patients with FAP. In the present study, we analysed the genetic alterations in these FAP-associated gastric lesions. METHODS AND RESULTS: Mutational statuses of GNAS and KRAS, which are frequently mutated in sporadic PGAs, as well as those of APC, were examined in PGAs, FAs and FGPs in patients with FAP using Sanger sequencing. Our analysis identified GNAS mutations in five of six PGAs (83%), but in none of the three FAs or the 40 FGPs examined. KRAS mutations were identified in four PGAs (67%), one FA (33%) and one FGP (3%). Somatic truncating APC mutations were found in all PGAs (100%), two FAs (67%) and 14 FGPs (47%). We additionally analysed sporadic PGAs of the stomach and duodenum and identified truncating APC mutations in 11 of 25 lesions (44%). CONCLUSIONS: FAP-associated and sporadic PGAs not only show similar morphologies, but also share common genetic aberrations, including mutations of GNAS, KRAS and APC. PMID- 25832319 TI - Liking them thin: adolescents' favorite television characters and body image. AB - Considering the alarming worldwide increases in eating disorders among adolescents, thought to be linked with body image, this study uses social cognitive theory as a framework to combine the examination of adolescent body image with the topic of mediated characters. The study places a new focus in this realm on favorite television characters, extending past research on general social comparison tendencies or comparisons with unfamiliar mediated models. A survey of 756 students in Grades 7-8 and 10-11 identified their favorite same gender television characters as well as the adolescents' body image and social comparison with the characters. The survey was accompanied by a content analysis of the favorite characters and their body sizes. Adolescents' favorite television characters were mostly identified as thin or average in body size. The thinner the characters, the more adolescents self-compared with them. The discrepancy between the adolescents' body size and that of their favorite characters significantly and negatively predicted adolescents' body image both directly and indirectly through its relationship with social comparison with the character. The study finds that television characters are important references for adolescents and may serve as targets for social comparison in the context of body image. PMID- 25832320 TI - Developmental dyslexia: predicting individual risk. AB - BACKGROUND: Causal theories of dyslexia suggest that it is a heritable disorder, which is the outcome of multiple risk factors. However, whether early screening for dyslexia is viable is not yet known. METHODS: The study followed children at high risk of dyslexia from preschool through the early primary years assessing them from age 3 years and 6 months (T1) at approximately annual intervals on tasks tapping cognitive, language, and executive-motor skills. The children were recruited to three groups: children at family risk of dyslexia, children with concerns regarding speech, and language development at 3;06 years and controls considered to be typically developing. At 8 years, children were classified as 'dyslexic' or not. Logistic regression models were used to predict the individual risk of dyslexia and to investigate how risk factors accumulate to predict poor literacy outcomes. RESULTS: Family-risk status was a stronger predictor of dyslexia at 8 years than low language in preschool. Additional predictors in the preschool years include letter knowledge, phonological awareness, rapid automatized naming, and executive skills. At the time of school entry, language skills become significant predictors, and motor skills add a small but significant increase to the prediction probability. We present classification accuracy using different probability cutoffs for logistic regression models and ROC curves to highlight the accumulation of risk factors at the individual level. CONCLUSIONS: Dyslexia is the outcome of multiple risk factors and children with language difficulties at school entry are at high risk. Family history of dyslexia is a predictor of literacy outcome from the preschool years. However, screening does not reach an acceptable clinical level until close to school entry when letter knowledge, phonological awareness, and RAN, rather than family risk, together provide good sensitivity and specificity as a screening battery. PMID- 25832321 TI - Protecting the infant from unknown risks. PMID- 25832322 TI - Use of the amplatzer vascular plug II device to occlude different types of patent ductus arteriosus in pediatric patients. AB - INTRODUCTION: Transcatheter patent ductus arteriosus (PDA) closure is difficult in small patients in part due to the diverse PDA morphology. We describe a multicenter pediatric experience using the Amplatzer Vascular Plug II device (AVP II) to occlude PDA. METHODS: All patients undergoing transcatheter closure of PDA with AVP II from April 2008 until May 2012 were included. Clinical, angiographic, and echocardiographic data were collected. RESULTS: One hundred and seventy-seven procedures were performed. Median age was 14 months (2-180) with median weight 9.7 kg (4.7-68). The morphological PDA classification was Type A in 66 (37.1%), Type C in 27 (15.3%), Type D in 17 (9.6%), and Type E in 67 (37.9%). The median minimum PDA diameter was 2.6 mm (1.2-7.7 mm). The implanted device sizes were: 4 mm in 17 patients (9.6%), 6 mm in 81 (45.8%), 8 mm in 56 (31.6%), 10 mm in 18 (10.2%), and 12 mm in 5 (2.8%). The implanted device was mean of 2.6 + 0.7 times the ductus narrowest diameter and mean of 1 + 0.5 times the ductus largest diameter. Complications included: one severe left pulmonary artery stenosis and one device embolization. No aortic obstruction occurred. Closure was complete in the 175 remaining patients. CONCLUSIONS: The AVP II is an effective and safe device for PDA closure. It is particularly useful when dealing with nontypical PDA shapes and in small infants where it eliminated the risk of device-related aortic obstruction. The AVPII is an addition to the PDA device closure armamentarium in pediatric patients. PMID- 25832323 TI - ANATOMICAL STUDY OF CRANIAL NERVE EMERGENCE AND SKULL FORAMINA IN THE HORSE USING MAGNETIC RESONANCE IMAGING AND COMPUTED TOMOGRAPHY. AB - For accurate interpretation of magnetic resonance (MR) images of the equine brain, knowledge of the normal cross-sectional anatomy of the brain and associated structures (such as the cranial nerves) is essential. The purpose of this prospective cadaver study was to describe and compare MRI and computed tomography (CT) anatomy of cranial nerves' origins and associated skull foramina in a sample of five horses. All horses were presented for euthanasia for reasons unrelated to the head. Heads were collected posteuthanasia and T2-weighted MR images were obtained in the transverse, sagittal, and dorsal planes. Thin-slice MR sequences were also acquired using transverse 3D-CISS sequences that allowed mutliplanar reformatting. Transverse thin-slice CT images were acquired and multiplanar reformatting was used to create comparative images. Magnetic resonance imaging consistently allowed visualization of cranial nerves II, V, VII, VIII, and XII in all horses. The cranial nerves III, IV, and VI were identifiable as a group despite difficulties in identification of individual nerves. The group of cranial nerves IX, X, and XI were identified in 4/5 horses although the region where they exited the skull was identified in all cases. The course of nerves II and V could be followed on several slices and the main divisions of cranial nerve V could be distinguished in all cases. In conclusion, CT allowed clear visualization of the skull foramina and occasionally the nerves themselves, facilitating identification of the nerves for comparison with MRI images. PMID- 25832324 TI - Identification of two novel missense mutations causing severe factor XIII deficiency. PMID- 25832325 TI - Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization. AB - BACKGROUND: Evidence regarding drug provocation test (DPT) with antineoplastic and biological agents is scarce. Our aim was to assess the usefulness of including DPT as a paramount gold standard diagnostic tool (prior to desensitization). METHODS: Prospective, observational, longitudinal study with patients who, during a 3-year period, were referred to the Desensitization Program at Ramon y Cajal University Hospital. Patients underwent a structured diagnostic protocol by means of anamnesis, skin tests (ST), risk assessment, and DPT. Oxaliplatin-specific IgE was determined in oxaliplatin-reactive patients (who underwent DPT regardless of oxaliplatin-specific IgE results). Univariate analysis and multivariate analysis were used to identify predictors of the final diagnosis among several variables. RESULTS: A total of 186 patients were assessed. A total of 104 (56%) patients underwent DPT. Sixty-four percent of all DPTs were negative (i.e., hypersensitivity was excluded). Sensitivity for oxaliplatin-specific IgE (0.35 UI/l cutoff point) was 34%, specificity 90.3%, negative predictive value 45.9%, positive predictive value 85%, negative likelihood ratio 0.7, and positive likelihood ratio 3.5. CONCLUSIONS: These are the first reported data based on more than 100 DPTs with antineoplastic and biological agents (paclitaxel, oxaliplatin, rituximab, infliximab, irinotecan, and other drugs). Implementation of DPT in diagnostic protocols helps exclude hypersensitivity (in 36% of all referred patients), and avoids unnecessary desensitizations in nonhypersensitive patients (30-56% of patients, depending on culprit-drug). Drug provocation test is vital to validate diagnostic tools; consequently, quality data are shown on oxaliplatin-specific IgE and oxaliplatin ST in the largest series of oxaliplatin-reactive patients reported to date (74 oxaliplatin-reactive patients). Identifying phenotypes and predictors of a diagnosis of hypersensitivity may be helpful for tailored plans. PMID- 25832326 TI - Anti-inflammatory effects of tanshinone IIA on atherosclerostic vessels of ovariectomized ApoE mice are mediated by estrogen receptor activation and through the ERK signaling pathway. AB - AIMS: Estrogen plays a protective role in atherosclerosis. Our preliminary work demonstrated that the active conformation of Tanshinone IIA(TanIIA) is similar to the 17beta-estradiol and it can bind to the estrogen receptor. Here, we hypothesized that Tanshinone IIA might have anti-inflammatory and anti-oxidative effects in atherosclerosis, mediated through estrogen receptor activation. METHODS: Subjects for this study were 120 apoE(-/-) female mice and 20 C57/BL female mice. The apoE(-/-) mice were ovariectomized (OVX) and the C57/BL mice were sham ovariectomized. The sham OVX mice were maintained on a normal diet (NOR) group. The OVX apoE(-/-) mice were fed a high fat diet and randomly divided into 6 groups: Model (MOD) group which was fed a high fat diet only, E2 group were given estrogen (E2) 0.13 mg/kg/d; E2+ICI group were given E2:0.13 mg/kg/d and ICI182780:65 mg/kg/m; TLD group (TanIIA low dose) were given TanIIA: 30 mg/kg/d; THD group (TanIIA high dose) were given TanIIA:60 mg/kg/d; and TLD+ICI group were given TanIIA 30 mg/kg/d and ICI182780 65 mg/kg/m. After three months of treatment, the aorta and the blood of the mice from each group was collected. The aorta were used for testing the lipid deposition by using hematoxylin and eosin(HE) and oil red O staining and for testing the expression of p-ERK1/2 by Western blot. The blood was used for testing the serum cholesterol, superoxide dismutase (SOD), methane dicarboxylic aldehyde (MDA), nuclear factor kappa (NF kappaB), soluble intercellular cell adhesion molecule-1 (sICAM-1), activating protein-1 (AP-1), E-selectin and 17beta-estradiol in serum. RESULTS: Tanshinone IIA significantly reduced the lipid deposition in aorta, decreased the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL), MDA, NF-kappaB, sICAM-1, AP-1, and E-selectin in serum but increased the levels of high density lipoprotein (HDL) and SOD in serum. Tanshinone IIA also suppressed the expression of p-ERK1/2. Tanshinone IIA had no effect of level of serum 17beta-estradiol levels. All of the effects of Tanshinone IIA were similar to estrogen and were inhibited by the estrogen receptor antagonist ICI182780. CONCLUSION: Tanshinone IIA may play an anti inflammatory and anti-oxidative stress role in OVX atherosclerotic apoE(-/-) mice by activating the estrogen receptor through the ERK signaling pathway. Therefore, Tanshinone IIA, as a phytoestrogen, could be used for estrogen replacement therapy for cardiovascular disease of postmenopausal women. PMID- 25832327 TI - Fall-induced spinal cord injury: External causes and implications for prevention. AB - OBJECTIVE: To document the demographic and clinical profile of persons who sustained spinal cord injury (SCI) as a result of accidental falls and to determine the usual circumstances surrounding the fall-induced SCI. DESIGN: Cohort study. SETTING: 21 SCI Model Systems centers throughout the United States. PARTICIPANTS: 6,408 individuals with traumatic SCI between 2005 and 2014 were recruited from the National SCI Database. 1,877 (29%) of them were injuries caused by falls. INTERVENTIONS: Not applicable. OUTCOMES MEASURES: External causes of injury documented by the International Classification of Diseases, 10(th) revision, Clinical Modification (ICD-10-CM). RESULTS: Falls on the same level from slipping, tripping, and stumbling were the most common cause of fall induced SCI (20%), followed by falls from building (16%), stairs and steps (16%), and ladder (9%). People who were 61 years of age and older had the highest frequency of falls on the same level, while those aged 16-45 years had a higher percentage of falls from buildings, usually work-related. The mechanisms of falls also varied by sex and race. Associated injury and vertebral injury occurred frequently among falls from buildings and ladders. High falls were more likely to be work-related and result in thoracic and complete injury, while low falls were more commonly associated with cervical and motor functionally incomplete injury. CONCLUSION: The study findings of different mechanisms of falls by age, sex, race and medical consequences provide an insight for future interventions aimed at high risk persons, activities, and environmental factors for preventing or reducing fall-induced SCI. PMID- 25832328 TI - Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non-alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non-invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence-based therapeutic options, although the clinical evidence for long-term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan. PMID- 25832329 TI - Bronchial fibroepithelial polyp: a clinico-radiologic, bronchoscopic, histopathological and in-situ hybridisation study of 15 cases of a poorly recognised lesion. AB - BACKGROUND AND AIMS: Bronchial fibroepithelial polyp is an uncommon, poorly recognised lesion, lacking clear diagnostic criteria at histology, but possibly mimicking neoplastic growth on clinico-radiologic and histopathological grounds. The aim of this study was to define the clinico-pathological features, bronchoscopic appearance and treatment of bronchial fibroepithelial polyp. METHODS: We collected the largest series of bronchial fibroepithelial polyps (15 consecutive cases), including clinico-pathological, bronchoscopic, radiologic and histological features. RESULTS: Overall, there were 13 males and 2 females, with a mean age of 68 years at diagnosis. Eight patients were asymptomatic, whereas four presented with haemoptysis, two with fever, cough and pneumonia-like opacity, and one with dry recurrent cough. Mean size of the lesion was 6.5 mm (range, 2-20 mm) without any prevalence for segmental bronchi. Lesions larger than 10 mm were always symptomatic and visible at computed tomography scans. At bronchoscopy, the lesion appeared as a firm endobronchial nodule with hard consistency and glistening, whitish, smooth surface. A multilobulated and sepimentated surface was observed in the largest polyps. Whatever the size, histological features were quite similar in all cases, consisting in a polypoid lesion with a dense, collagenous, hypocellular stroma with some thin-walled, ectatic vessels and a regular respiratory mucosa on surface. In-situ hybridisation with human papillomavirus probe was negative in all the eight tested cases. CONCLUSION: Despite the benign behaviour of bronchial fibroepithelial polyps, it is important to fix some robust diagnostic criteria in order to avoid misdiagnoses leading to unnecessary aggressive treatment. Differential diagnosis mainly includes inflammatory polyps, hamartomas and papillomas. PMID- 25832330 TI - The impact of secondary pests on Bacillus thuringiensis (Bt) crops. AB - The intensification of agriculture and the development of synthetic insecticides enabled worldwide grain production to more than double in the last third of the 20th century. However, the heavy dependence and, in some cases, overuse of insecticides has been responsible for negative environmental and ecological impacts across the globe, such as a reduction in biodiversity, insect resistance to insecticides, negative effects on nontarget species (e.g. natural enemies) and the development of secondary pests. The use of recombinant DNA technology to develop genetically engineered insect-resistant crops could mitigate many of the negative side effects of insecticides. One such genetic alteration enables crops to express toxic crystalline (Cry) proteins from the soil bacteria Bacillus thuringiensis (Bt). Despite the widespread adoption of Bt crops, there are still a range of unanswered questions concerning longer term agro-ecosystem interactions. For instance, insect species that are not susceptible to the expressed toxin can develop into secondary pests and cause significant damage to the crop. Here, we review the main causes surrounding secondary pest dynamics in Bt crops and the impact of such outbreaks. Regardless of the causes, if nonsusceptible secondary pest populations exceed economic thresholds, insecticide spraying could become the immediate solution at farmers' disposal, and the sustainable use of this genetic modification technology may be in jeopardy. Based on the literature, recommendations for future research are outlined that will help to improve the knowledge of the possible long-term ecological trophic interactions of employing this technology. PMID- 25832332 TI - Prevalence of temporomandibular joint disorder among North Saudi University students. AB - OBJECTIVE: The aim of the current investigation was to study the prevalence of temporomandibular disorder (TMD) among university students of North Saudi Arabia. METHODS: A specifically constructed questionnaire was distributed to 489 university students to investigate the prevalence of temporomandibular joint (TMJ) findings among them. The study sample consisted of 346 males and 143 females (age range was 18-25 years). The data were analyzed, and probability values were set at p <= 0.05. RESULTS: A total of 49.7% of participants had at least one sign or symptom of TMD. Clicking was the most reported finding. Pain in or about the ears/cheeks was the second most common finding. In all, 24.3% of the participants reported one TMJ finding; meanwhile, 0.4% reported the presence of five concurrent TMJ signs and symptoms. Females reported more TMJ signs and symptoms than males (p < 0.05). Science and health students reported more TMD findings than humanitarian college students (p < 0.05). DISCUSSION: University students in north Saudi Arabia reported high prevalence of TMD. Also, students from science and health colleges reported higher prevalence of TMD findings than humanitarian college students. Clicking and pain are the most prevalent findings of TMD among university students. The results of this investigation highlight the need for additional research to shed more light on the risk factors and findings related to TMD. This will facilitate drawing adequate guidelines for prevention and management of TMD. PMID- 25832331 TI - Prenatally diagnosed monochorionic diamniotic triplet pregnancy. AB - We present an extremely rare case of monochorionic diamniotic (MD) triplet pregnancy diagnosed via ultrasonography at the end of the first trimester that resulted in delivery of three healthy newborns. Ultrasonography for a 34-year-old woman at 12 weeks of gestation showed three fetuses and one placenta with a T sign at the initial segment of the dividing membrane. Color Doppler examination revealed umbilical cord entanglement between two fetuses in one sac in addition to another sac containing one fetus. Therefore, this was diagnosed as MD triplet pregnancy. The triplets were delivered by cesarean section at 35 weeks of gestation and were healthy without neurological morbidities at the age of 28 days. Histopathological examination also revealed an MD triplet placenta. The possibility of MD triplet pregnancy should be recognized, although it is rare. PMID- 25832333 TI - Establishing an Explanatory Model for Mathematics Identity. AB - This article empirically tests a previously developed theoretical framework for mathematics identity based on students' beliefs. The study employs data from more than 9,000 college calculus students across the United States to build a robust structural equation model. While it is generally thought that students' beliefs about their own competence in mathematics directly impact their identity as a "math person," findings indicate that students' self-perceptions related to competence and performance have an indirect effect on their mathematics identity, primarily by association with students' interest and external recognition in mathematics. Thus, the model indicates that students' competence and performance beliefs are not sufficient for their mathematics identity development, and it highlights the roles of interest and recognition. PMID- 25832334 TI - Trends in intake and sources of caffeine in the diets of US adults: 2001-2010. AB - BACKGROUND: Coffee and tea are traditional sources of caffeine in the diet, but other sources, such as energy drinks, are now available. Because risks and benefits of caffeine use are dose dependent, the public health consequences of caffeine consumption cannot be determined without data on amounts currently consumed by the US population. OBJECTIVE: The objective was to obtain an up-to date, nationally representative estimate of caffeine consumption in adults. DESIGN: Dietary intake data from NHANES from 2001 to 2010 for adults >=19 y of age were used (n = 24,808). Acute and usual intake of caffeine was estimated from all caffeine-containing foods and beverages. Trends in consumption and changes in sources of caffeine were also examined. RESULTS: Eighty-nine percent of the adult US population consumed caffeine, with equal prevalence in men and women. Usual mean +/- SE per capita caffeine consumption when nonusers were included was 186 +/- 4 mg/d, with men consuming more than women (211 +/- 5 vs. 161 +/- 3 mg/d, P < 0.05). Usual intake in consumers was 211 +/- 3 mg/d, with 240 +/- 4 mg/d in men and 183 +/- 3 mg/d in women (P < 0.05); 46% was consumed in a single consumption event. In consumers, acute 90th and 99th percentiles of intake were 436 and 1066 mg/d, respectively. Consumption was highest in men aged 31-50 y and lowest in women aged 19-30 y. Beverages provided 98% of caffeine consumed, with coffee (~64%), tea (~16%), and soft drinks (~18%) predominant sources; energy drinks provided <1%, but their consumption increased substantially from 2001 to 2010. CONCLUSIONS: Although new caffeine-containing products were introduced into the US food supply, total per capita intake was stable over the period examined. PMID- 25832335 TI - Food sources of fat may clarify the inconsistent role of dietary fat intake for incidence of type 2 diabetes. AB - BACKGROUND: Dietary fats could affect glucose metabolism and obesity development and, thereby, may have a crucial role in the cause of type 2 diabetes (T2D). Studies indicated that replacing saturated with unsaturated fats might be favorable, and plant foods might be a better choice than animal foods. Nevertheless, epidemiologic studies suggested that dairy foods are protective. OBJECTIVE: We hypothesized that, by examining dietary fat and its food sources classified according to fat type and fat content, some clarification regarding the role of dietary fat in T2D incidence could be provided. DESIGN: A total of 26,930 individuals (61% women), aged 45-74 y, from the Malmo Diet and Cancer cohort were included in the study. Dietary data were collected by using a modified diet-history method. During 14 y of follow-up, 2860 incident T2D cases were identified. RESULTS: Total intake of high-fat dairy products (regular-fat alternatives) was inversely associated with incident T2D (HR for highest compared with lowest quintiles: 0.77; 95% CI: 0.68, 0.87; P-trend < 0.001). Most robust inverse associations were seen for intakes of cream and high-fat fermented milk (P-trend < 0.01) and for cheese in women (P-trend = 0.02). High intake of low-fat dairy products was associated with increased risk, but this association disappeared when low- and high-fat dairy were mutually adjusted (P-trend = 0.18). Intakes of both high-fat meat (P-trend = 0.04) and low-fat meat (P-trend < 0.001) were associated with increased risk. Finally, we did not observe significant association between total dietary fat content and T2D (P-trend = 0.24), but intakes of saturated fatty acids with 4-10 carbons, lauric acid (12:0), and myristic acid (14:0) were associated with decreased risk (P-trend < 0.01). CONCLUSIONS: Decreased T2D risk at high intake of high- but not of low-fat dairy products suggests that dairy fat partly could have contributed to previously observed protective associations between dairy intake and T2D. Meat intake was associated with increased risk independently of the fat content. PMID- 25832336 TI - Dietary patterns: from nutritional epidemiologic analysis to national guidelines. PMID- 25832338 TI - Plasma phospholipid very-long-chain saturated fatty acids: a sensitive marker of metabolic dysfunction or an indicator of specific healthy dietary components? PMID- 25832337 TI - Association between birth weight and objectively measured sedentary time is mediated by central adiposity: data in 10,793 youth from the International Children's Accelerometry Database. AB - BACKGROUND: Birth weight is an early correlate of disease later in life, and animal studies suggest that low birth weight is associated with reduced activity and increased sedentary time. Whether birth weight predicts later sedentary time in humans is uncertain. OBJECTIVES: We examined the relation between birth weight and sedentary time in youth and examined whether this association was mediated by central adiposity. DESIGN: We used pooled cross-sectional data from 8 observational studies conducted between 1997 and 2007 that consisted of 10,793 youth (boys: 47%) aged 6-18 y from the International Children's Accelerometry Database. Birth weight was measured in hospitals or maternally reported, sedentary time was assessed by using accelerometry (<100 counts/min), and abdominal adiposity (waist circumference) was measured according to WHO procedures. A mediation analysis with bootstrapping was used to analyze data. RESULTS: The mean (+/-SD) time spent sedentary was 370 +/- 91 min/d. Birth weight was positively associated with sedentary time (B = 4.04, P = 0.006) and waist circumference (B = 1.59, P < 0.001), whereas waist circumference was positively associated with sedentary time (B = 0.82, P < 0.001). Results of the mediation analysis showed a significant indirect effect of birth weight on sedentary time through waist circumference (B: 1.30; 95% bias-corrected CI: 0.94, 1.72), and when waist circumference was controlled for, the effect of birth weight on sedentary time was attenuated by 32% (B = 2.74, P = 0.06). CONCLUSION: The association between birth weight and sedentary time appears partially mediated by central adiposity, suggesting that both birth weight and abdominal adiposity may be correlates of sedentary time in youth. PMID- 25832339 TI - Egg consumption and risk of incident type 2 diabetes in men: the Kuopio Ischaemic Heart Disease Risk Factor Study. AB - BACKGROUND: The prevalence of type 2 diabetes (T2D) is increasing around the world. Eggs are a major source of cholesterol, which has been associated with elevated blood glucose and an increased risk of T2D. However, there are limited and conflicting data from prospective population studies on the association between egg consumption and risk of T2D. OBJECTIVE: We investigated the association between egg consumption and risk of incident T2D in middle-aged and older men from eastern Finland. DESIGN: The study included 2332 men aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Dietary intakes were assessed with 4-d food records at baseline. Incident T2D was assessed by self-administered questionnaires; by fasting and 2-h oral-glucose-tolerance-test blood glucose measurement at re-examination rounds 4, 11, and 20 y after baseline; and by record linkage to a hospital discharge registry and reimbursement register of diabetes medication expenses. Cox proportional hazards regression analyses were used to estimate associations with the risk of incident T2D. Associations with the metabolic risk markers at baseline and at the 4-y examinations were analyzed by ANCOVA. RESULTS: During an average follow-up of 19.3 y, 432 men developed T2D. After adjustment for potential confounders, those in the highest compared with the lowest egg intake quartile had a 38% (95% CI: 18%, 53%; P-trend across quartiles <0.001) lower risk of incident T2D. Analyses with metabolic risk markers also suggested an inverse association with fasting plasma glucose and serum C-reactive protein but not with serum insulin. The associations between cholesterol intake and risk of T2D, plasma glucose, serum insulin, and C-reactive protein were mainly nonsignificant, especially after accounting for egg consumption. CONCLUSION: Higher egg intake was associated with a lower risk of T2D in this cohort of middle-aged and older men. PMID- 25832340 TI - Flavonoid intake and all-cause mortality. AB - BACKGROUND: Flavonoids are bioactive compounds found in foods such as tea, chocolate, red wine, fruit, and vegetables. Higher intakes of specific flavonoids and flavonoid-rich foods have been linked to reduced mortality from specific vascular diseases and cancers. However, the importance of flavonoids in preventing all-cause mortality remains uncertain. OBJECTIVE: The objective was to explore the association between flavonoid intake and risk of 5-y mortality from all causes by using 2 comprehensive food composition databases to assess flavonoid intake. DESIGN: The study population included 1063 randomly selected women aged >75 y. All-cause, cancer, and cardiovascular mortalities were assessed over 5 y of follow-up through the Western Australia Data Linkage System. Two estimates of flavonoid intake (total flavonoidUSDA and total flavonoidPE) were determined by using food composition data from the USDA and the Phenol-Explorer (PE) databases, respectively. RESULTS: During the 5-y follow-up period, 129 (12%) deaths were documented. Participants with high total flavonoid intake were at lower risk [multivariate-adjusted HR (95% CI)] of 5-y all-cause mortality than those with low total flavonoid consumption [total flavonoidUSDA: 0.37 (0.22, 0.58); total flavonoidPE: 0.36 (0.22, 0.60)]. Similar beneficial relations were observed for both cardiovascular disease mortality [total flavonoidUSDA: 0.34 (0.17, 0.69); flavonoidPE: 0.32 (0.16, 0.61)] and cancer mortality [total flavonoidUSDA: 0.25 (0.10, 0.62); flavonoidPE: 0.26 (0.11, 0.62)]. CONCLUSIONS: Using the most comprehensive flavonoid databases, we provide evidence that high consumption of flavonoids is associated with reduced risk of mortality in older women. The benefits of flavonoids may extend to the etiology of cancer and cardiovascular disease. PMID- 25832341 TI - Bridging evidence from observational and intervention studies to identify flavonoids most protective for human health. PMID- 25832342 TI - Bobcats (Lynx rufus) as a Model Organism to Investigate the Effects of Roads on Wide-Ranging Carnivores. AB - We are using bobcats (Lynx rufus) as a model organism to examine how roads affect the abundance, distribution, and genetic structure of a wide-ranging carnivore. First, we compared the distribution of bobcat-vehicle collisions to road density and then estimated collision probabilities for specific landscapes using a moving window with road-specific traffic volume. Next, we obtained incidental observations of bobcats from the public, camera-trap detections, and locations of bobcats equipped with GPS collars to examine habitat selection. These data were used to generate a cost-surface map to investigate potential barrier effects of roads. Finally, we have begun an examination of genetic structure of bobcat populations in relation to major road networks. Distribution of vehicle-killed bobcats was correlated with road density, especially state and interstate highways. Collision models suggested that some regions may function as demographic sinks. Simulated movements in the context of the cost-surface map indicated that some major roads may be barriers. These patterns were supported by the genetic structure of bobcats. The sharpest divisions among genetically distinct demes occurred along natural barriers (mountains and large lakes) and in road-dense regions. In conclusion, our study has demonstrated the utility of using bobcats as a model organism to understand the variety of threats that roads pose to a wide-ranging species. Bobcats may also be useful as one of a group of focal species while developing approaches to maintain existing connectivity or mitigate the negative effects of roads. PMID- 25832343 TI - Valuing the benefits of creek rehabilitation: building a business case for public investments in urban green infrastructure. AB - In an effort to increase the livability of its cities, public agencies in Australia are investing in green infrastructure to improve public health, reduce heat island effects and transition toward water sensitive urban design. In this paper, we present a simple and replicable approach to building a business case for green infrastructure. This approach requires much less time and resources compared to other methods for estimating the social and economic returns to society from such investments. It is a pragmatic, reasonably comprehensive approach that includes socio-demographic profile of potential users and catchment analysis to assess the economic value of community benefits of the investment. The approach has been applied to a case study area in the City of Brimbank, a western suburb of Greater Melbourne. We find that subject to a set of assumptions, a reasonable business case can be made. We estimate potential public benefits of avoided health costs of about AU$75,049 per annum and potential private benefits of AU$3.9 million. The project area is one of the most poorly serviced areas in the municipality in terms of quality open spaces and the potential beneficiaries are from relatively low income households with less than average health status and education levels. The values of cultural (recreational benefits, avoided health costs, and increased property values) and regulating (reduction in heat island effect and carbon sequestration) ecosystem services were quantified that can potentially offset annual maintenance costs. PMID- 25832344 TI - Can a rapid underwater video approach enhance the benthic assessment capability of the national coastal condition assessment in the great lakes? AB - Over 400 sites were sampled in the nearshore of the U.S. Great Lakes during the U.S. National Coastal Condition Assessment (NCCA) field survey in summer 2010. Underwater video images were recorded in addition to routine NCCA benthic assessment measures. This paper has two objectives: (1) to develop a process to evaluate video performance with acceptance criteria, exploring reasons for poor images, and (2) to use acceptable videos in an example application with invasive mussels, evaluating the enhancement potential of video to supplement traditional grab sampling. A standard hierarchical protocol was developed to rank video performance based on quality and clarity. We determined controllable and uncontrollable factors affecting video performance. Moreover, specific thresholds limiting video were identified: >0.5/m for light extinction and >3.5 ug/L for chlorophyll a concentration. To demonstrate the utility and enhancement potential of video sampling, observed dreissenid presence from excellent (221 of 362 videos) videos was compared with NCCA benthic taxonomy, in the context of the statistically based NCCA survey. Including video increased the overall area estimate of the U.S. Great Lakes nearshore with invasive mussels by about 15% compared to PONAR alone; 44% (7570 km(2)) of the surveyed region had mussels. The proportion of the nearshore area having mussels varied from low (3.5%) in Lake Superior to >50% in the lower lakes. PONAR and video have unique strengths and weaknesses as sampling tools in the Great Lakes nearshore environment, but when paired were complimentary and thus provided a more thorough benthic condition assessment at lake and regional scales. PMID- 25832345 TI - Unravelling river system impairments in stream networks with an integrated risk approach. AB - Rivers are complex systems for which it is hard to make reliable assessments of causes and responses to impairments. We present a holistic risk-based framework for river ecosystem assessment integrating all potential intervening processes and functions. Risk approaches allow us to deal with uncertainty both in the construction of indicators for magnitude of stressors and in the inference of environmental processes and their impairment. Yet, here we go further than simply replacing uncertainty by a risk factor. We introduce a more accurate and rigorous notion of risk with a transcription of uncertainty in causal relationships in probability distributions for the magnitude of impairment and the weight of different descriptors, with an associated confidence in the diagnostic. We discuss how Bayesian belief networks and Bayesian hierarchical inference allow us to deal with this risk concept to predict impairments and potential recovery of river ecosystems. We developed a comprehensive approach for river ecosystem assessment, which offers an appealing tool to facilitate diagnosis of the likely causes of impairment and predict future conditions. The ability of the risk approaches to integrate multi-scale quantitative and qualitative descriptors in the identification of multiple stressor sources and pathways in the stream network, and their impairment of specific processes and structures is illustrated for the national-level risk analysis for hydromorphology and pesticide pollution. Not only does the risk-based framework provide a more complete picture of environmental impairments, but it also offers a comprehensive, user-friendly tool to instruct the decision process. PMID- 25832346 TI - Nationwide benthic macroinvertebrate assemblage multimetric indices: identifying inconsistencies and limitations in reporting stream impairment status, USA. AB - The objective of this study was to identify the current status of stream water quality assessment and reporting methods for four states in the Ohio River basin (Indiana, Ohio, Tennessee, and Virginia), as required by the 305(b) section of the United States (US) Clean Water Act. Specifically, we clarified the discrepancies that exist among stream-impairment status classified by benthic macroinvertebrate multimetric indices (MMIs) and depicted using Geographic Information Systems shapefiles. In addition, we provided guidance in solving some of the comparability problems that arise when developing state-specific MMIs and depicting stream-impairment status using Geographic Information Systems technology. The MMI variation among states and differences in shapefile formats resulted in a nationwide dataset, which cannot be directly compared. Incorporating the changes suggested in this study allow for a uniform assessment and reporting method nationwide. Successful implementation of these changes would strengthen the US Environmental Protection Agency efforts to identify impaired streams and sources of those impairments without the limitations of state-by state .developed assessment methods. PMID- 25832347 TI - Expression of Wnt/beta-catenin signaling, stem-cell markers and proliferating cell markers in rat whisker hair follicles. AB - The rat whisker hair follicle (HF) is a model for studying the reconstruction of the HF or dermal papilla (DP), and involves the Wnt/beta-catenin signaling pathway, which is a key pathway in HF development and HF cycling after birth. It has been reported that Wnt/catenin signaling plays an indispensable role in human or rat pelages development and postnatal growth. However, the distribution of some Wnt/beta-catenin signaling pathway factors and their relationship with the epithelial stem cell markers in whisker follicles has not been characterized. In this study, we investigated the immunolocalization of Wnt/catenin signaling pathway members, including Wnt10b, Wnt10a, Wnt5a, beta-catenin, and downstream lymphoid enhancer-binding factor 1 (LEF1) and transcription factor 3 (TCF3), as well as, HF stem-cell markers CD34, CK15 and proliferating cell nuclear antigen (PCNA) protein, in rat anagen phase whisker follicles. beta-catenin, Wnt5a, Wnt10b, Wnt10a, LEF1, and TCF3 were expressed in the outer root sheath (ORS), inner root sheath, matrix and hair shaft of anagen follicles. beta-catenin, Wnt10b, LEF1, and TCF3 were highly expressed and Wnt5a and Wnt10a weakly expressed in DP and dermal sheath (DS) regions. The expression of alpha-smooth muscle actin was strong in the lower DS and it was also detected in some DP cells. CD34, CK15 and PCNA were all expressed in the ORS; and CD34 and PCNA were also detected in the matrix, however CD34 was extensively expressed in DP and DS regions. Our studies located the position of Wnts, downstream LEF1 and TCF3 and stem cell marker proteins, which provide new information in understanding the role of the Wnt singaling pathway in whisker follicles' growth. PMID- 25832348 TI - Analysis of swine fecal microbiota at various growth stages. AB - Recent obesity studies in humans and rodents have suggested that host weight gain is significantly associated with energy harvesting efficiency which is regulated by gut microbiota. Antibiotic growth promoters have been banned as feed additives in many countries. In this study, we aimed to provide knowledge of swine fecal microbiota by analyzing bacterial 16S rRNA gene sequences. Our results showed that swine fecal bacterial composition varied at each growth stage. Bacteroidetes decreased as the swine gained weight and unclassified genera significantly increased at later growth stages. Operational taxonomic unit (OTU) distribution analysis showed that the bacterial community difference was most significant between growers and finishers, while analysis of shared OTUs indicated a greater proportion of common species between growers and finishers. The differential abundance test between growers and finishers detected that nearly half of the species were shared OTUs, suggesting that differential abundance of each bacterial species predominantly controls bacterial community differences. Although functions of these bacteria are yet to be identified, understanding differences in fecal microbiota between each growth stage will provide additional insights for further studies related to swine gut microbiota. PMID- 25832351 TI - The second neurocritical care research conference. PMID- 25832349 TI - Regional brain monitoring in the neurocritical care unit. AB - Regional multimodality monitoring has evolved over the last several years as a tool to understand the mechanisms of brain injury and brain function at the cellular level. Multimodality monitoring offers an important augmentation to the clinical exam and is especially useful in comatose neurocritical care patients. Cerebral microdialysis, brain tissue oxygen monitoring, and cerebral blood flow monitoring all offer insight into permutations in brain chemistry and function that occur in the context of brain injury. These tools may allow for development of individual therapeutic strategies that are mechanistically driven and goal directed. We present a summary of the discussions that took place during the Second Neurocritical Care Research Conference regarding regional brain monitoring. PMID- 25832352 TI - Transradial left ventricular endomyocardial biopsy: assessment of safety and efficacy. AB - BACKGROUND: We aimed at assessing the safety and efficacy of a systematic transradial approach for left ventricular endomyocardial biopsy using a new hydrophilic sheathless guiding catheter. METHODS AND RESULTS: Forty-two consecutive patients were included. The transradial success rate was 98% (41 of 42). In one case, cross over to femoral access due to irreversible spasm of the right radial artery was necessary. No radial spasm was observed in the other 41 patients. Depending on the indication, several other procedures, such as coronary angiography or ventricular angiography, were additionally performed through the same transradial access site. Median fluoroscopy time was 7.9 min. The mean dose area product was 1867 cGy * cm(2). All biopsy samples were graded as good or excellent quality. No patient had any complications. Immediate post-procedural ambulation could be achieved in all patients. Radial artery patency was confirmed by duplex sonography 24 h after removal of the guide. CONCLUSION: The present study demonstrates safety and efficacy of a systematic transradial access for left ventricular EMB using a highly hydrophilic sheathless guiding catheter. This is of clinical importance since this new technique may overcome critical limitations of the common approach. PMID- 25832350 TI - Multi-modality neuro-monitoring: conventional clinical trial design. AB - Multi-modal monitoring has become an integral part of neurointensive care. However, our approach is at this time neither standardized nor backed by data from randomized controlled trials. The goal of the second Neurocritical Care Research Conference was to discuss research priorities in multi-modal monitoring, what research tools are available, as well as the latest advances in clinical trial design. This section of the meeting was focused on how such a trial should be designed so as to maximize yield and avoid mistakes of the past. PMID- 25832353 TI - Analysis of Streptococcus agalactiae pan-genome for prevalence, diversity and functionality of integrative and conjugative or mobilizable elements integrated in the tRNA(Lys CTT) gene. AB - Streptococcus agalactiae is the first cause of invasive infections in human neonates and is also a major bovine and fish pathogen. High genomic diversity was observed in this species that hosts numerous mobile genetic elements, in particular elements transferable by conjugation. This works aims to evaluate the contribution of these elements to GBS genome diversity. Focusing on genomic islands integrated in the tRNA(Lys) (CTT) gene, a known hotspot of recombination, an extensive in silico search was performed on the sequenced genome of 303 strains of S. agalactiae isolated from different hosts. In all the isolates (except 9), whatever their origin (human, bovine, camel, dog, gray seal, dolphin, fish species or bullfrog), this locus carries highly diverse genomic islands transferable by conjugation such as integrative and conjugative elements (ICEs), integrative and mobilizable elements (IMEs), CIs-mobilizable elements (CIMEs) or composite elements. Transfer of an ICE from an ST67 bovine strain to a phylogenetically distant ST23 human isolate was obtained experimentally indicating that there was no barrier to ICE transfer between strains from different hosts. Interestingly, a novel family of putative IMEs that site specifically integrate in the nic site of oriT of ICEs belonging to Tn916/ICESt3 superfamily was detected in silico. These elements carry an antibiotic resistance gene (lsa(C)) already described to confer cross-resistance to lincosamides, streptogramins A and pleuromutilins. Further work is needed to evaluate the impact of these IMEs on the transfer of targeted ICEs and the mobility and the dissemination of these IMEs. PMID- 25832356 TI - New concept for occupational health development: 3 phases. AB - Occupational health development in a country can be classified into 3 phases as External, Internal (or Personal), and Social Environmental Phases. Occupational health usually focuses on work environment, but it cannot advance without controlling workers' health and cannot be achieved without a complimentary understanding of the social security system. Society may continue wasting social costs for determining whether a disease of workers is caused by or arising from work. In order to understand the status of occupational diseases in a country, one must know about the comprehensiveness of the social security system in that society. PMID- 25832354 TI - A novel satellite DNA isolated in Pecten jacobaeus shows high sequence similarity among molluscs. AB - The aim of this work is to investigate the sequence conservation and the evolution of repeated DNA in related species. Satellite DNA is a component of eukaryotic genomes and is made up of tandemly repeated sequences. These sequences are affected by high rates of mutation that lead to the occurrence of species specific satellite DNAs, which are different in terms of both quantity and quality. In this work, a novel repetitive DNA family, named PjHhaI sat, is described in Pecten jacobaeus. The quantitative analyses revealed a different abundance of this element in the molluscan species investigated in agreement with the "library hypothesis" even if, in this case, at a high taxonomic level. In addition, the qualitative analysis demonstrated an astonishing sequence conservation not only among scallops but also in six other molluscan species belonging to three classes. These findings suggest that the PjHhaI sat may be considered as the most ancients of DNA described so far, which remained "frozen" during molluscan evolution. The widespread distribution of this sat DNA in molluscs as well as its long evolutionary preservation open up questions on the functional role of this element. A future challenge might be the identification of proteins or molecules which interact with the PjHhaI sat. PMID- 25832357 TI - Benchmark study of the Mossbauer isomer shifts of Eu and Np complexes by relativistic DFT calculations for understanding the bonding nature of f-block compounds. AB - We have performed benchmark investigations into the bonding properties in lanthanide and actinide complexes to quantitatively estimate the covalency of f block compounds. Three different density functionals including BP86 (pure-GGA), B3LYP (hybrid-GGA) and B2PLYP (double hybrid-GGA) were employed for all-electron self-consistent field calculations compensated by the scalar-relativistic zero order regular approximation (ZORA) Hamiltonian with a relativistically contracted all-electron basis set. Ten Eu and ten Np complexes were employed as benchmark sets for the calculation of Mossbauer parameters for (151)Eu and (237)Np compounds. As a result of the linear fitting between the calculated electron densities at the nucleus (rho) and the experimental isomer shifts (delta(exp)), the calculations performed using the all-electron ZORA-B2PLYP level reproduced a change of electron density at the Mossbauer nucleus for both Eu and Np complexes with high correlation coefficients (R(2) > 0.90). Mulliken's population analyses indicated that the BP86 and B3LYP methods overestimated the covalency of both Eu and Np complexes due to the smaller amount of the exact Hartree-Fock exchange admixture included in BP86 and B3PLYP compared to that in the B2PLYP functional. By comparing Mulliken's electronic structure analyses with the experimental isomer shifts, we found that Mulliken's spin population values were good parameters to quantitatively estimate the bonding natures of Eu and Np complexes. PMID- 25832355 TI - Three symbol ungrounding problems: Abstract concepts and the future of embodied cognition. AB - A great deal of research has focused on the question of whether or not concepts are embodied as a rule. Supporters of embodiment have pointed to studies that implicate affective and sensorimotor systems in cognitive tasks, while critics of embodiment have offered nonembodied explanations of these results and pointed to studies that implicate amodal systems. Abstract concepts have tended to be viewed as an important test case in this polemical debate. This essay argues that we need to move beyond a pretheoretical notion of abstraction. Against the background of current research and theory, abstract concepts do not pose a single, unified problem for embodied cognition but, instead, three distinct problems: the problem of generalization, the problem of flexibility, and the problem of disembodiment. Identifying these problems provides a conceptual framework for critically evaluating, and perhaps improving upon, recent theoretical proposals. PMID- 25832358 TI - A Novel Quinoline Based Second-generation mTOR Inhibitor that Induces Apoptosis and Disrupts PI3K-Akt-mTOR Signaling in Human Leukemia HL-60 Cells. AB - Deregulation of the PI3K-Akt-mTOR pathway is unanimously pragmatic in a number of tumors. This pathway pedals proliferation, survival, translation, and coupled with tumor-associated endurance. Current efforts focus on the discovery and development of novel inhibitors of this pathway. We have discovered 6-(4 phenoxyphenyl)-N-phenylquinolin-4-amine [PQQ] as a potent mTOR inhibitor with IC50 value of 64nM in a cell-based and cell-free mTOR assay. Mechanistically, PQQ was found to be a strong PI3K-Akt-mTOR-p70S6K cascade inhibitor in Human promyelocytic leukemia HL-60 cells. Moreover, it was found to be dual mTORC1 and mTORC2 inhibitor that inhibit the entire mTOR kinase-dependent functions and feedback commencement of PI3K/Akt pathway. PQQ simultaneously induces apoptosis via mitochondrial dependant pathway, which was confirmed through a battery of the assays, e.g. cellular and nuclear microscopy, annexin-V assay, cell cycle analysis and loss of mitochondrial membrane potential. In summary, PQQ discovered as a novel second-generation mTOR inhibitor with significant cytotoxic and apoptotic potentials. Thus, it might be a significant lead structure for the development of mTOR-targeted based anti-cancer therapeutics. PMID- 25832359 TI - Comparative transcriptome analysis between csrA-disruption Clostridium acetobutylicum and its parent strain. AB - The genome of Clostridium acetobutylicum contains the gene encoding CsrA, a carbon storage regulator. We investigated the function of CsrA in C. acetobutylicum by insertionally inactivating the encoding gene, CA_C2209 using the ClosTron. Disruption of csrA obviously decreases the growth of the organism and reduces the yield of acetone, butanol and ethanol (ABEs). Like the csrA in Escherichia coli, RNA-seq and beta-galactosidase analysis revealed that csrA in C. acetobutylicum was closely involved in regulating multiple pathways including flagella assembly, oligopeptide transporting, iron uptake, and central carbon metabolism. It has also been newly demonstrated that csrA in C. acetobutylicum is related to the regulation of pathways involved in the phosphotransferase transporting systems, synthesis of riboflavin, and stage III sporulation. This research represented the first investigation of global regulation by CsrA in the strain belonging to Gram-positive bacteria through transcriptome analysis and provided the important theoretical evidence for improving solvent production by transcriptor engineering in C. acetobutylicum. PMID- 25832361 TI - Sulfur-infiltrated graphene-backboned mesoporous carbon nanosheets with a conductive polymer coating for long-life lithium-sulfur batteries. AB - Sandwich-type, two-dimensional hybrid nanosheets were fabricated by the infiltration of nanosized sulfur into graphene-backboned mesoporous carbon with a PPy nanocoating. They exhibit a high reversible capacity for as long as 400 cycles with an ultra slow decay rate of 0.05% per cycle at the high rate of 1-3 C due to the efficient immobilization of polysulfides. PMID- 25832360 TI - No deficit in neurocortical information processing in patients with cleft lip and palate. AB - BACKGROUND: Cleft lip and palate (CLP) represents the most common malformation of the midfacial region worldwide. It can be suggested that the facial stigmatization, the speech impediment, and the long-standing pressure of treatment cause a range of life stressors. Neurocortical information is influenced by physiological and psychological factors and varies significantly in patients suffering from chronic stress, anxiety, depression, or other psychopathological conditions following maladaptation. The aims of the present study were to investigate the neurocortical information processing of patients with CLP using the contingent negative variation (CNV) paradigm and to evaluate secondary psychopathology, anxiety, and depression. MATERIALS AND METHODS: Twenty five adults with CLP and 25 healthy volunteers, matched in age and gender, were investigated using recordings of the CNV. Initial CNV (iCNV), late CNV (lCNV), and total CNV (tCNV) as well as habituation slope of the iCNV were determined in each subject. Additionally, each participant had to complete the hospital anxiety and depression questionnaire (HADS) and the Symptom Checklist-90-R (SCL-90-R). RESULTS: Individuals with CLP did not differ significantly from healthy subjects according to any of the CNV parameters investigated. No correlations could be revealed between the measured items and the confounding factors age and gender. Additionally, there were no differences between the groups regarding depression and SCL-90-R; however, anxiety showed significant group differences on a subclinical level. CONCLUSIONS: These data suggest that subjects with CLP show normal neurocortical information processing. It seems likely that CLP and its treatment have no impact on psychosocial functioning and neurophysiological mechanisms of attention. CLINICAL RELEVANCE: The specific living conditions of patients with CLP do not result in disease-specific neurophysiological changes. PMID- 25832363 TI - Aspirin 'resistance', diabetes mellitus and no-reflow: the elusive role of individual susceptibility in myocardial reperfusion. PMID- 25832365 TI - Long-term effects of individual mindfulness-based cognitive therapy and cognitive behavior therapy for depressive symptoms in patients with diabetes: a randomized trial. PMID- 25832364 TI - Demonstration of entanglement-enhanced phase estimation in solid. AB - Precise parameter estimation plays a central role in science and technology. The statistical error in estimation can be decreased by repeating measurement, leading to that the resultant uncertainty of the estimated parameter is proportional to the square root of the number of repetitions in accordance with the central limit theorem. Quantum parameter estimation, an emerging field of quantum technology, aims to use quantum resources to yield higher statistical precision than classical approaches. Here we report the first room-temperature implementation of entanglement-enhanced phase estimation in a solid-state system: the nitrogen-vacancy centre in pure diamond. We demonstrate a super-resolving phase measurement with two entangled qubits of different physical realizations: an nitrogen-vacancy centre electron spin and a proximal (13)C nuclear spin. The experimental data shows clearly the uncertainty reduction when entanglement resource is used, confirming the theoretical expectation. Our results represent an elemental demonstration of enhancement of quantum metrology against classical procedure. PMID- 25832366 TI - Primary pure and nonsecreting embryonal carcinoma of the anterior third ventricle: a case report. AB - Central nervous system germ cell tumors (GCTs) account for less than 5% of primary brain tumors in children and adolescents but continue to attract much attention. To the best of our knowledge, a primary pure and nonsecreting embryonal carcinoma of the anterior third ventricle has never been previously reported. A 15-year-old boy presented with signs of increased intracranial pressure for the past 2 weeks complicated by 2 episodes of generalized tonic clonic seizures 1 day before admission. Neurological examination was normal, and funduscopic examination disclosed a grade II papilledema bilaterally. CT and MRI revealed a well-demarcated and enhancing mass within the anterior third ventricle associated with a left lateral ventricle hydrocephalus. There was no evidence of tumor within the pineal or suprasellar region, and systemic and cerebrospinal fluid evaluation demonstrated normal levels of alpha-fetoprotein and human chorionic gonadotropin. Radical surgery was advised, and total tumor resection was achieved via a transcallosal transforaminal approach. The postoperative course was uneventful, and the final histological diagnosis was a pure embryonal carcinoma. Further screening showed no other location, and adjunctive high-dose chemotherapy was administered. The patient has been symptom free with no clinical or radiological sign of progression at the most recent follow-up examination 2 years after surgery. Primary pure and nonsecreting embryonal carcinoma can develop within the anterior third ventricle and should be considered in the differential diagnosis of anterior third ventricular masses especially in young patients. Accurate identification, radical surgery and high-dose chemotherapy can result in better tumor control and improve the postoperative outcome. PMID- 25832367 TI - Risk stratification model in elderly patients with multiple myeloma: clinical role of magnetic resonance imaging combined with international staging system and cytogenetic abnormalities. AB - The International Staging System (ISS) does not take into consideration the clinical role of imaging modalities in multiple myeloma (MM), even though these are important. Some studies have indicated a lack of impact of ISS in MM patients who receive novel agents. Therefore, accessible novel risk stratification might be needed in elderly MM patients receiving conventional therapy or novel agents. We analyzed 198 newly diagnosed and symptomatic MM patients who were not eligible for transplantation. The initial treatment regimen was therapy with melphalan prednisone (MP, n = 44), thalidomide-cyclophosphamide-dexamethasone (n = 89) or bortezomib-MP (VMP, n = 65). The magnetic resonance imaging (MRI) pattern was normal in 34 patients, focal in 30 and diffuse/variegated in 134. High-risk cytogenetic abnormalities were not associated with the diffuse/variegated MRI pattern (p = 0.182). ISS stage III [progression-free survival (PFS) p = 0.005; overall survival (OS) p = 0.027], high-risk cytogenetic abnormalities (PFS p = 0.001; OS p < 0.001) and diffuse/variegated MRI pattern (PFS p < 0.001; OS p < 0.001) were independently associated with poorer PFS and OS. Patients were further stratified according to the 3 prognostic factors. The PFS and OS of the 3 groups differed significantly. The addition of the diffuse/variegated MRI pattern may improve the prognostic potential of the current staging system which includes ISS and cytogenetic abnormalities. PMID- 25832368 TI - Communication breakdown. PMID- 25832369 TI - Tree cheers. PMID- 25832370 TI - Walking 2.0. PMID- 25832371 TI - Change the cancer conversation. PMID- 25832383 TI - Neuron encyclopaedia fires up to reveal brain secrets. PMID- 25832384 TI - Global-warming limit of 2 degrees C hangs in the balance. PMID- 25832385 TI - UK election: Upstart parties set out science plans. PMID- 25832386 TI - Corrections. PMID- 25832387 TI - Mini enzyme moves gene editing closer to the clinic. PMID- 25832388 TI - Stopping deforestation: Battle for the Amazon. PMID- 25832389 TI - Evidence-based medicine: Save blood, save lives. PMID- 25832390 TI - Climate change: Embed the social sciences in climate policy. PMID- 25832394 TI - Outback palms: Aboriginal myth meets DNA analysis. PMID- 25832395 TI - Public spending: US Congress replies on NSF scrutiny. PMID- 25832397 TI - Evaporation: Evaluate risks of coating reservoirs. PMID- 25832398 TI - Quantum physics: Two-atom bunching. PMID- 25832399 TI - Biodiversity: Land use matters. PMID- 25832400 TI - Planetary science: Preventing stars from eating their young. PMID- 25832403 TI - Planet heating prevents inward migration of planetary cores. AB - Planetary systems are born in the disks of gas, dust and rocky fragments that surround newly formed stars. Solid content assembles into ever-larger rocky fragments that eventually become planetary embryos. These then continue their growth by accreting leftover material in the disk. Concurrently, tidal effects in the disk cause a radial drift in the embryo orbits, a process known as migration. Fast inward migration is predicted by theory for embryos smaller than three to five Earth masses. With only inward migration, these embryos can only rarely become giant planets located at Earth's distance from the Sun and beyond, in contrast with observations. Here we report that asymmetries in the temperature rise associated with accreting infalling material produce a force (which gives rise to an effect that we call 'heating torque') that counteracts inward migration. This provides a channel for the formation of giant planets and also explains the strong planet-metallicity correlation found between the incidence of giant planets and the heavy-element abundance of the host stars. PMID- 25832404 TI - Atomic Hong-Ou-Mandel experiment. AB - Two-particle interference is a fundamental feature of quantum mechanics, and is even less intuitive than wave-particle duality for a single particle. In this duality, classical concepts--wave or particle--are still referred to, and interference happens in ordinary space-time. On the other hand, two-particle interference takes place in a mathematical space that has no classical counterpart. Entanglement lies at the heart of this interference, as it does in the fundamental tests of quantum mechanics involving the violation of Bell's inequalities. The Hong, Ou and Mandel experiment is a conceptually simpler situation, in which the interference between two-photon amplitudes also leads to behaviour impossible to describe using a simple classical model. Here we report the realization of the Hong, Ou and Mandel experiment using atoms instead of photons. We create a source that emits pairs of atoms, and cause one atom of each pair to enter one of the two input channels of a beam-splitter, and the other atom to enter the other input channel. When the atoms are spatially overlapped so that the two inputs are indistinguishable, the atoms always emerge together in one of the output channels. This result opens the way to testing Bell's inequalities involving mechanical observables of massive particles, such as momentum, using methods inspired by quantum optics, and to testing theories of the quantum-to-classical transition. Our work also demonstrates a new way to benchmark non-classical atom sources that may be of interest for quantum information processing and quantum simulation. PMID- 25832402 TI - Global effects of land use on local terrestrial biodiversity. AB - Human activities, especially conversion and degradation of habitats, are causing global biodiversity declines. How local ecological assemblages are responding is less clear--a concern given their importance for many ecosystem functions and services. We analysed a terrestrial assemblage database of unprecedented geographic and taxonomic coverage to quantify local biodiversity responses to land use and related changes. Here we show that in the worst-affected habitats, these pressures reduce within-sample species richness by an average of 76.5%, total abundance by 39.5% and rarefaction-based richness by 40.3%. We estimate that, globally, these pressures have already slightly reduced average within sample richness (by 13.6%), total abundance (10.7%) and rarefaction-based richness (8.1%), with changes showing marked spatial variation. Rapid further losses are predicted under a business-as-usual land-use scenario; within-sample richness is projected to fall by a further 3.4% globally by 2100, with losses concentrated in biodiverse but economically poor countries. Strong mitigation can deliver much more positive biodiversity changes (up to a 1.9% average increase) that are less strongly related to countries' socioeconomic status. PMID- 25832405 TI - Orbital-specific mapping of the ligand exchange dynamics of Fe(CO)5 in solution. AB - Transition-metal complexes have long attracted interest for fundamental chemical reactivity studies and possible use in solar energy conversion. Electronic excitation, ligand loss from the metal centre, or a combination of both, creates changes in charge and spin density at the metal site that need to be controlled to optimize complexes for photocatalytic hydrogen production and selective carbon hydrogen bond activation. An understanding at the molecular level of how transition-metal complexes catalyse reactions, and in particular of the role of the short-lived and reactive intermediate states involved, will be critical for such optimization. However, suitable methods for detailed characterization of electronic excited states have been lacking. Here we show, with the use of X-ray laser-based femtosecond-resolution spectroscopy and advanced quantum chemical theory to probe the reaction dynamics of the benchmark transition-metal complex Fe(CO)5 in solution, that the photo-induced removal of CO generates the 16 electron Fe(CO)4 species, a homogeneous catalyst with an electron deficiency at the Fe centre, in a hitherto unreported excited singlet state that either converts to the triplet ground state or combines with a CO or solvent molecule to regenerate a penta-coordinated Fe species on a sub-picosecond timescale. This finding, which resolves the debate about the relative importance of different spin channels in the photochemistry of Fe(CO)5 (refs 4, 16 - 20), was made possible by the ability of femtosecond X-ray spectroscopy to probe frontier orbital interactions with atom specificity. We expect the method to be broadly applicable in the chemical sciences, and to complement approaches that probe structural dynamics in ultrafast processes. PMID- 25832406 TI - Rate that journal. PMID- 25832408 TI - PLD3 and sporadic Alzheimer's disease risk. PMID- 25832409 TI - Cruchaga & Goate reply. PMID- 25832410 TI - PLD3 variants in population studies. PMID- 25832411 TI - PLD3 in non-familial Alzheimer's disease. PMID- 25832412 TI - Cruchaga & Goate reply. PMID- 25832413 TI - PLD3 gene variants and Alzheimer's disease. PMID- 25832414 TI - Umpolung of methylenephosphonium ions in their manganese half-sandwich complexes and application to the synthesis of chiral phosphorus-containing ligand scaffolds. AB - Half-sandwich manganese methylenephosphonium complexes [Cp(CO)2Mn(eta(2) R2P=C(H)Ph)]BF4 were obtained in high yield through a straightforward reaction sequence involving a classical Fischer-type manganese complex and a secondary phosphine as key starting materials. The addition of various nucleophiles (Nu) to these species took place regioselectively at the double-bonded carbon center of the coordinated methylenephosphonium ligand R2P(+)=C(H)Ph to produce the corresponding chiral phosphine complexes [Cp(CO)2Mn(kappa(1)-R2P-C(H)(Ph)Nu)], from which the phosphines were ultimately recovered as free entities upon simple irradiation with visible light. The synthetic potential of this umpolung approach is illustrated herein by the preparation of novel chiral pincer-type phosphine NHC-phosphine ligand architectures. PMID- 25832415 TI - A qualitative study of the prodrome to first-episode major depressive disorder in adolescents. AB - BACKGROUND: Currently, we lack a clear picture of the evolution of major depressive disorder (MDD) in adolescents. The period of disturbance preceding MDD can be conceptualised as the prodrome. The aim of the study was to explore the prodrome of first-episode MDD retrospectively in a group of help-seeking adolescents using qualitative methodologies. SAMPLING AND METHODS: Consecutively referred adolescents (15-18 years of age) with first-episode MDD were recruited for this study from Orygen Youth Health, Melbourne, Vic., Australia. After using quantitative methodologies to confirm the index episode of MDD and measure the extent of recovery, the prodrome was investigated in depth using qualitative techniques. RESULTS: Twenty-nine adolescents (20 females and 9 males) and 7 informants (6 mothers and 1 grandmother) participated. All 29 participants had a prodrome of varying lengths (between 6 days and 4 years). The most noticeable symptoms initially were perplexity and confusion and, thereafter, sadness and irritability. A common pattern was a reduction in their ability to fulfil their role accompanied by guilt, self-blame and reduced self-esteem. Around half of the participants had increased thoughts of suicide and increased anxiety. There were gender differences in the patterns of symptoms noticed, with males more commonly noticing a change in how they related to the world and females more commonly noticing a change in the way that they related to others. All informants noticed a prodrome of varying lengths; in 2 cases longer, in 2 cases shorter and in 3 cases around the same time period as that noticed by the participant. The changes most commonly noticed by informants were sadness, upset, irritability and reduced self-esteem. The symptoms were fewer in number and sometimes varied from those noticed by the adolescents themselves. CONCLUSIONS: Whilst we recognise that this study is vulnerable to autobiographical bias, we took all reasonable measures to minimise this. Symptoms not included in the diagnostic criteria for depression were the earliest changes noticed by the adolescents themselves and are, therefore, potentially important in informing prevention strategies, as is the finding that there are gender differences in the patterns of changes noticed. In addition, parents may provide an additional avenue to help seeking. PMID- 25832416 TI - How to approach delusional infestation. PMID- 25832417 TI - Imidazolium salt ion pairs in solution. AB - The formation, stabilisation and reactivity of contact ion pairs of non-protic imidazolium ionic liquids (ILs) in solution are conceptualized in light of selected experimental evidence as well theoretical calculations reported mainly in the last ten years. Electric conductivity, NMR, ESI-MS and IR data as well as theoretical calculations support not only the formation of contact ion pairs in solution, but also the presence of larger ionic and neutral aggregates even when dissolved in solvents with relatively high dielectric constants, such as acetonitrile and DMSO. The presence of larger imidazolium supramolecular aggregates is favoured at higher salt concentrations in solvents of low dielectric constant for ILs that contain shorter N-alkyl side chains associated with anions of low coordination ability. The stability and reactivity of neutral contact species are also dependent on the nature of the anion, imidazolium substituents, and are more abundant in ILs containing strong coordinating anions, in particular those that can form charge transfer complexes with the imidazolium cation. Finally, some ILs display reactivities as contact ion pairs rather than solvent-separated ions. PMID- 25832418 TI - An improved crest factor minimization algorithm to synthesize multisines with arbitrary spectrum. AB - Multisine signal with a low crest factor (CF) can bring a high signal-to-noise ratio for fast frequency response function (FRF) estimation. Synthesis of a low CF multisine with the given amplitude spectrum depends on optimum selection of the initial phases of its cosinusoidal components. The solutions investigated can be generally divided into two branches: (1) the analytical method based on direct formula calculation; and (2) the numerical method based on iterative computations. The analytical method works well only for an equidistant and flat amplitude spectrum, while the numerical method can generally output better results, even for a sparse or non-flat spectrum, but the number of iterations might be huge. This paper presents an improved CF minimization algorithm to synthesize multisine signals based on the combination of the previous Schroeder analytical method and the Van der Ouderaa (VDO) iteration procedure. The improved algorithm adopts the Schroder phases as the iterative initial phases, and employs a logarithmic clip function of the iterative index i in the VDO iteration procedure. Comprehensive experiments of multisine synthesis on three types of cosinusoidal amplitude spectra are performed, and the resulting CFs remain the lowest level in all cases compared with the earlier methods. The proposed algorithm provides a fast and efficient solution to synthesize multisine with the lowest CF for an arbitrary user-prescribed spectrum. PMID- 25832419 TI - Developing a holistic policy and intervention framework for global mental health. AB - INTRODUCTION: There are significant gaps in the accessibility and quality of mental health services around the globe. A wide range of institutions are addressing the challenges, but there is limited reflection and evaluation on the various approaches, how they compare with each other, and conclusions regarding the most effective approach for particular settings. This article presents a framework for global mental health capacity building that could potentially serve as a promising or best practice in the field. The framework is the outcome of a decade of collaborative global health work at the Centre for Addiction and Mental Health (CAMH) (Ontario, Canada). The framework is grounded in scientific evidence, relevant learning and behavioural theories and the underlying principles of health equity and human rights. METHODS: Grounded in CAMH's research, programme evaluation and practical experience in developing and implementing mental health capacity building interventions, this article presents the iterative learning process and impetus that formed the basis of the framework. A developmental evaluation (Patton M.2010. Developmental Evaluation: Applying Complexity Concepts to Enhance Innovation and Use. New York: Guilford Press.) approach was used to build the framework, as global mental health collaboration occurs in complex or uncertain environments and evolving learning systems. RESULTS: A multilevel framework consists of five central components: (1) holistic health, (2) cultural and socioeconomic relevance, (3) partnerships, (4) collaborative action-based education and learning and (5) sustainability. The framework's practical application is illustrated through the presentation of three international case studies and four policy implications. Lessons learned, limitations and future opportunities are also discussed. CONCLUSION: The holistic policy and intervention framework for global mental health reflects an iterative learning process that can be applied and scaled up across different settings through appropriate modifications. PMID- 25832420 TI - Novel molecularly imprinted magnetic nanoparticles for the selective extraction of protoberberine alkaloids in herbs and rat plasma. AB - In this work, a novel magnetic nanomaterial functionalized with a molecularly imprinted polymer was prepared for the extraction of protoberberine alkaloids. Molecularly imprinted polymers were made on the surface of Fe3 O4 nanoparticles by using berberine as template, acetonitrile/water as porogen, acrylamide as functional monomer and ethylene glycol dimethacrylate as cross-linker. The optimized molar ratio of template/functional monomer was 1:7. The polymeric magnetic nanoparticles were characterized by transmission electron microscopy and Fourier transform infrared spectroscopy. The stability and adsorption capacity of the molecularly imprinted polymers were investigated. The molecularly imprinted polymers were used as a selective sorbent for the magnetic molecularly imprinted solid-phase extraction and determination of jatrorrhizine, palmatine, and berberine. Extraction parameters were studied including loading pH, sample volume, stirring speed, and extraction time. Finally, a magnetic molecularly imprinted solid-phase extraction coupled to high-performance liquid chromatography method was developed. Under the optimized conditions, the method showed good linear range of 0.1-150 ng/mL for berberine and 0.1-100 ng/mL for jatrorrhizine and palmatine. The limit of detection was 0.01 ng/mL for berberine and 0.02 ng/mL for jatrorrhizine and palmatine. The proposed method has been applied to determine protoberberine alkaloids in Cortex phellodendri and rat plasma samples. The recoveries ranged from 87.33-102.43%, with relative standard deviation less than 4.54% in Cortex phellodendri and from 102.22-111.15% with relative standard deviation less than 4.59% in plasma. PMID- 25832421 TI - The divergent roles of autophagy in ischemia and preconditioning. AB - Autophagy is an evolutionarily conserved and lysosome-dependent process for degrading and recycling cellular constituents. Autophagy is activated following an ischemic insult or preconditioning, but it may exert dual roles in cell death or survival during these two processes. Preconditioning or lethal ischemia may trigger autophagy via multiple signaling pathways involving endoplasmic reticulum (ER) stress, AMPK/TSC/mTOR, Beclin 1/BNIP3/SPK2, and FoxO/NF-kappaB transcription factors, etc. Autophagy then interacts with apoptotic and necrotic signaling pathways to regulate cell death. Autophagy may also maintain cell function by removing protein aggregates or damaged mitochondria. To date, the dual roles of autophagy in ischemia and preconditioning have not been fully clarified. The purpose of the present review is to summarize the recent progress in the mechanisms underlying autophagy activation during ischemia and preconditioning. A better understanding of the dual effects of autophagy in ischemia and preconditioning could help to develop new strategies for the preventive treatment of ischemia. PMID- 25832422 TI - Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway. AB - AIM: To investigate the effects of ginsenoside Rd (Rd) on neurogenesis in rat brain after ischemia/reperfusion injury (IRI). METHODS: Male SD rats were subjected to transient middle cerebral artery occlusion (MCAO) followed by reperfusion. The rats were injected with Rd (1, 2.5, and 5 mg.kg(-1).d(-1), ip) from d 1 to d 3 after MCAO, and with BrdU (50 mg.kg(-1).d(-1), ip) from d 3 to d 6, then sacrificed on 7 d. The infarct size and neurological scores were assessed. Neurogenesis in the brains was detected by BrdU, DCX, Nestin, and GFAP immunohistochemistry staining. PC12 cells subjected to OGD/reperfusion were used as an in vitro model of brain ischemia. VEGF and BDNF levels were assessed with ELISA, and Akt and ERK phosphorylation was measured using Western blotting. RESULTS: Rd administration dose-dependently decreased the infarct size and neurological scores in the rats with IRI. The high dose of Rd 5 (mg.kg(-1).d(-1)) significantly increased Akt phosphorylation in ipsilateral hemisphere, and markedly increased the number of BrdU/DCX and Nestin/GFAP double-positive cells in ischemic area, which was partially blocked by co-administration of the PI3 kinase inhibitor LY294002. Treatment with Rd (25, 50, and 100 MUmol/L) during reperfusion significantly increased the expression of VEGF and BDNF in PC12 cells with IRI. Furthermore, treatment with Rd dose-dependently increased the phosphorylation of Akt and ERK, and significantly decreased PC12 cell apoptosis, which were blocked by co-application of LY294002. CONCLUSION: Rd not only attenuates ischemia/reperfusion injury in rat brain, but also promotes neurogenesis via increasing VEGF and BDNF expression and activating the PI3K/Akt and ERK1/2 pathways. PMID- 25832423 TI - Chronic nicotine treatment enhances vascular smooth muscle relaxation in rats. AB - AIM: To investigate the effect of chronic nicotine treatment on vascular function and to identify the underlying mechanisms. METHODS: Adult rats were treated with nicotine (3 mg.kg(-1).d(-1), sc) for 6 weeks. After the rats were sacrificed, aortic rings were prepared for detecting vascular reactivity, and thoracic aorta and periaortic fat samples were collected for histological and molecular biology studies. RESULTS: Chronic nicotine treatment significantly reduced periaortic fat, and specifically enhanced smooth muscle relaxation without altering the aortic adventitial fat and endothelium function. Pretreatment with the soluble guanylyl cyclase inhibitor ODQ (3 MUmol/L) or PKG inhibitor Rp-8-Br-PET-cGMP (30 MUmol/L) abolished the nicotine-induced enhancement of smooth muscle relaxation, whereas the cGMP analogue 8-Br-cGMP could mimic the nicotine-induced enhancement of smooth muscle relaxation. However, the chronic nicotine treatment did not alter PKG protein expression and activity in aortic media. CONCLUSION: Chronic nicotine treatment enhances vascular smooth muscle relaxation of rats via activation of PKG pathway. PMID- 25832424 TI - C-reactive protein stimulates RAGE expression in human coronary artery endothelial cells in vitro via ROS generation and ERK/NF-kappaB activation. AB - AIM: The receptor for advanced glycation end-products (RAGE) plays an important role in development of atherosclerosis, and C-reactive protein (CRP) has been found to stimulate its expression in endothelial cells. In this study we investigated how CRP regulated the expression of RAGE in human coronary artery endothelial cells (HCAECs). METHODS: HCAECs were treated in vitro with CRP (50 MUg/mL) in combination with a variety of inhibitors. ROS generation was determined by immunocytochemistry and flow cytometry. The RAGE expression and phosphorylation of relevant signaling proteins were measured using Western blot analyses. RESULTS: CRP stimulated the expression of RAGE in the cells, accompanied by markedly increased ROS generation, phosphorylation of ERK1/2 and NF-kappaB p65, as well as translocation of NF-kappaB p65 to the nuclei. CRP also stimulated phosphorylation of JNK and p38 MAPK. Pretreatment of the cells with the ROS scavenger N-acetyl-L-cysteine, ERK inhibitor PD98059 or NF-kappaB inhibitor PDTC blocked CRP-stimulated RAGE expression, but pretreatment with the NADPH oxidase inhibitor DPI, JNK inhibitor SP600125 or p38 MAPK inhibitor SB203580 did not significantly alter CRP-stimulated RAGE expression. CONCLUSION: CRP stimulates RAGE expression in HCAECs in vitro via ROS generation and activation of the ERK/NF-kappaB signaling pathway. PMID- 25832425 TI - Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized, single-blind, crossover study. AB - AIM: To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. METHODS: This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. RESULTS: The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. CONCLUSION: Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH E14 TQT studies in Chinese volunteers. PMID- 25832426 TI - The protease inhibitor atazanavir blocks hERG K(+) channels expressed in HEK293 cells and obstructs hERG protein transport to cell membrane. AB - AIM: Atazanavir (ATV) is a HIV-1 protease inhibitor for the treatment of AIDS patients, which is recently reported to provoke excessive prolongation of the QT interval and torsades de pointes (TdP). In order to elucidate its arrhythmogenic mechanisms, we investigated the effects of ATV on the hERG K(+) channels expressed in HEK293 cells. METHODS: hERG K(+) currents were detected using whole cell patch clamp recording in HEK293 cells transfected with EGFP-hERG plasmids. The expression of hERG protein was measured with Western blotting. Two mutants (Y652A and F656C) were constructed in the S6 domain within the inner helices of hERG K(+) channels that were responsible for binding of various drugs. The trafficking of hERG protein was studied with confocal microscopy. RESULTS: Application of ATV (0.01-30 MUmol/L) concentration-dependently decreased hERG K(+) currents with an IC50 of 5.7+/-1.8 MUmol/L. ATV (10 MUmol/L) did not affect the activation and steady-state inactivation of hERG K(+) currents. Compared with the wild type hERG K(+) channels, both Y652A and F656C mutants significantly reduced the inhibition of ATV on hERG K(+) currents. Overnight treatment with ATV (0.1-30 MUmol/L) concentration-dependently reduced the amount of fully glycosylated 155 kDa hERG protein without significantly affecting the core glycosylated 135 kDa hERG protein in the cells expressing the WT-hERG protein. Confocal microscopy studies confirmed that overnight treatment with ATV obstructed the trafficking of hERG protein to the cell membrane. CONCLUSION: ATV directly blocks hERG K(+) channels via binding to the residues Y652 and F656 in the S6 domain, and indirectly obstructs the transport of the hERG protein to the cell membrane. PMID- 25832427 TI - Collateral circulation formation determines the characteristic profiles of contrast-enhanced MRI in the infarcted myocardium of pigs. AB - AIM: To investigate the relationship between the collateral circulation and contrast-enhanced MR signal change for myocardial infarction (MI) in pigs. METHODS: Pigs underwent permanent ligation of two diagonal branches of the left anterior descending artery. First-pass perfusion (FPP) MRI (for detecting myocardial perfusion abnormalities) and delayed enhancement (DE) MRI (for estimating myocardial infarction) using Gd-DTPA were performed at 2 h, 7 d and 4 weeks after the coronary occlusion. Myocardial blood flow (MBF) was evaluated using nonradioactive red-colored microspheres. Histological examination was performed to characterize the infarcts. RESULTS: Acute MI performed at 2 h afterwards was characterized by hypoenhancement in both FPP- and DE-MRI, with small and almost unchanged FPP-signal intensity (SI) and DE-SI due to negligible MBF. Subacute MI detected 7 d afterwards showed small but significantly increaseing FPP-SI, and was visible as a sluggish hyperenhancement in DE-MRI with considerably higher DE-SI compared to the normal myocardium; the MBF approached the half-normal value. Chronic MI detected at 4 weeks afterwards showed increasing FPP-SI comparable to the normal myocardium, and a rapid hyperenhancement in DE-MRI with even higher DE-SI; the MBF was close to the normal value. The MBF was correlated with FPP-SI (r=+0.94, P<0.01) and with the peak DE-SI (r=+0.92, P<0.01) at the three MI stages. Remodeled vessels were observed at intra-infarction and peri-infarction zones during the subacute and chronic periods. CONCLUSION: Progressive collateral recovery determines the characteristic profiles of contrast-enhanced MRI in acute, subacute and chronic myocardial infarction in pigs. The FPP- and DE-MRI signal profiles not only depend on the loss of tissue viability and enlarged interstitial space, but also on establishing a collateral circulation. PMID- 25832428 TI - The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway. AB - AIM: (-)-Epigallocatechin-3-gallate (EGCG) is one of the most abundant polyphenols in green tea with strong antioxidant activity and various therapeutic effects. In this study, we investigated the anti-fibrotic effects of EGCG and underlying mechanisms in bile duct-ligated (BDL) rats and a liver fibrosis model in vitro. METHODS: BDL rats were treated with EGCG (25 mg.kg(-1).d(-1), po) for 14 d, and then the serum, bile and liver samples were collected. Liver fibrosis was assessed by serum, urine and bile biochemistry analyses and morphological studies of liver tissues. TGF-beta1-stimulated human hepatic stellate LX-2 cells were used as a liver fibrosis model in vitro. The expression of liver fibrogenic genes and signaling proteins in the PI3K/Akt/Smad pathway was examined using Western blotting and/or real-time PCR. RESULTS: In BDL rats, EGCG treatment significantly ameliorates liver necrosis, inflammation and fibrosis, and suppressed expression of the genes associated with liver inflammation and fibrogenesis, including TNF-alpha, IL-1beta, TGF-beta1, MMP-9, alpha-SMA, and COL1A1. In LX-2 cells, application of EGCG (10, 25 MUmol/L) dose-dependently suppressed TGF-beta1-stimulated expression of COL1A1, MMP-2, MMP-9, TGF-beta1, TIMP1, and alpha-SMA. Furthermore, EGCG significantly suppressed the phosphorylation of Smad2/3 and Akt in the livers of BDL rats and in TGF-beta1 stimulated LX-2 cells. Application of LY294002, a specific inhibitor of PI3K, produced similar effects as EGCG did in TGF-beta1-stimulated LX-2 cells, but co application of EGCG and LY294002 did not produce additive effects. CONCLUSION: EGCG exerts anti-fibrotic effects in BDL rats and TGF-beta1-stimulated LX-2 cells in vitro via inhibiting the PI3K/Akt/Smad pathway. PMID- 25832430 TI - Seipin mutation at glycosylation sites activates autophagy in transfected cells via abnormal large lipid droplets generation. AB - AIM: Seipin is a protein that resides in endoplasmic reticulum, and involved in both lipid metabolic disorders and motor neuropathy. The aim of this study was to investigate the effects of mutant seipin on autophagy system and the morphology of lipid droplets in vitro. METHODS: HEK-293, H1299 and MES23.5 cells were transfected with the plasmids of mutated seipin at glycosylation sites (N88S or S90L) and GFP-LC3 plasmids. The cells were subjected to immunofluorescence and flow cytometry assays, and the cell lysates were subjected to immunoblot analysis. Nile Red was used to stain the lipid droplets in the cells. RESULTS: Overexpression of the mutated seipin proteins N88S or S90L activated autophagy in the 3 cell lines, and substantially altered the sub-cellular distribution of the autophagosome marker GFP-LC3, leading to a number of large vacuoles appearing in the cytoplasm. The sub-cellular location of GFP-LC3 and mutated seipin proteins highly overlapped. Moreover, and the mutated seipin proteins caused diffuse small lipid droplets to fuse into larger lipid droplets. Treatment of mutated seipin transfected cells with the autophagy inhibitor 3-MA (5 mmol/L) facilitated the fusion of mutated seipin-induced large vacuoles. The protein glycosylation inhibitor tunicamycin could mimic the mutated seipin-induced effects, and treatment of the wild-type seipin-transfected cells with tunicamycin (2.5 MUg/mL) produced similar morphological and biochemical properties as in the mutated seipin-transfected cells. CONCLUSION: The mutation of seipin at glycosylation sites disrupt its function in regulating lipid droplet metabolism, and the autophagy acts as an adaptive response to break down abnormal lipid droplets. The interruption of autophagy would accelerate the fusion of abnormal lipid droplets. PMID- 25832429 TI - 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice. AB - AIM: Sterol-regulatory element binding proteins (SREBPs) are major transcription factors that regulate liver lipid biosynthesis. In this article we reported a novel synthetic compound 2-(3-benzoylthioureido)-4,5,6,7 tetrahydrobenzo[b]thiophene-3-carboxylic acid (ZJ001) that inhibited the SREBP-1c pathway, and effectively reduced hepatic lipid accumulation in diet-induced obesity (DIO) mice. METHODS: A luciferase reporter driven by an SRE-containing promoter transfected into HepG2 cells was used to discover the compound. Two approaches were used to evaluate the lipid-lowering effects of ZJ001: (1) diet induced obesity (DIO) mice that were treated with ZJ001 (15 mg.kg(-1).d(-1), po) for 7 weeks; and (2) HepG2 cells and primary hepatocytes used as in vitro models. RESULTS: ZJ001 (10, 20 MUmol/L) dose-dependently inhibited the activity of SRE containing promoter. ZJ001 administration ameliorated lipid metabolism and improved glucose tolerance in DIO mice, accompanied by significantly reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. In HepG2 cells and insulin-treated hepatocytes, ZJ001 (10-40 MUmol/L) dose-dependently inhibited lipid synthesis, and reduced mRNA levels of SREBP-1C and SREBP-2, and their downstream genes. Furthermore, ZJ001 dose-dependently increased the phosphorylation of AMPK and regulatory-associated protein of mTOR (Raptor), and suppressed the phosphorylation of mTOR in insulin-treated hepatocytes. Moreover, ZJ001 increased the ADP/ATP ratio in insulin-treated hepatocytes. CONCLUSION: ZJ001 exerts multiple beneficial effects in diet-induced obesity mice. Its lipid lowering effects may result from the suppression of mTORC1, which regulates SREBP 1c transcription. The results suggest that the SREBP-1c pathway may be a potential therapeutic target for the treatment of lipid metabolic disorders. PMID- 25832431 TI - Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro. AB - AIM: To investigate the effects of physalin B insolated from Physalis divericata on human colon cancer cells in vitro and its anticancer mechanisms. METHODS: Human HCT116 colon cancer cell line was tested. Cell viability and apoptosis were detected, and relevant proteins were measured using Western blot analyses. Autophagosomes were observed in stable GFP-LC3 HCT116 cells. Localization of autophagosomes and lysosomes was evaluated in GFP-LC3/RFP-LAMP1-co-transfected cells. Microtubules and F-actin microfilaments were observed with confocal microscope. Mitochondrial ROS (mito-ROS) was detected with flow cytometry in the cells stained with MitoSox dye. RESULTS: Physalin B inhibited the viability of HCT116 cells with an IC50 value of 1.35 MUmol/L. Treatment of the cells with physalin B (2.5-10 MUmol/L) induced apoptosis and the cleavage of PARP and caspase-3. Meanwhile, physalin B treatment induced autophagosome formation, and accumulation of LC3-II and p62, but decreased Beclin 1 protein level. Marked changes of microtubules and F-actin microfilaments were observed in physalin B treated cells, which led to the blockage of co-localization of autophagosomes and lysosomes. Physalin B treatment dose-dependently increased the phosphorylation of p38, ERK and JNK in the cells, whereas the p38 inhibitor SB202190, ERK inhibitor U0126 or JNK inhibitor SP600125 could partially reduce physalin B-induced PARP cleavage and p62 accumulation. Moreover, physalin B treatment dose-dependently increased mito-ROS production in the cells, whereas the ROS scavenger NAC could reverse physalin B-induced effects, including incomplete autophagic response, accumulation of ubiquitinated proteins, changes of microtubules and F-actin, activation of p38, ERK and JNK, as well as cell death and apoptosis. CONCLUSION: Physalin B induces mito-ROS, which not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in HCT116 cells in vitro. PMID- 25832434 TI - Music in the Operating Room: "Can You Hear Me Now?". PMID- 25832432 TI - Transfer of the IL-37b gene elicits anti-tumor responses in mice bearing 4T1 breast cancer. AB - AIM: IL-37b has shown anti-cancer activities in addition to its anti-inflammatory properties. In this study, we investigated the effects of IL-37b on breast carcinoma growth in mice and to determine the involvement of T cell activation in the effects. METHODS: IL-37b gene was transferred into mouse breast carcinoma cell line 4T1 (4T1-IL37b cells), the expression of secretory IL-37b by the cells was detected, and the effects of IL-37b expression on the cell proliferation in vitro was evaluated. After injection of 4T1 cells or 4T1-IL37b cells into immunocompetent BALB/c mice, immunodeficient BALB/c nude mice and NOD-SCID mice, the tumor growth and survival rate were measured. The proliferation of T cells in vitro was also detected. RESULTS: IL-37b was detected in the supernatants of 4T1 IL37b cells with a concentration of 12.02 +/- 0.875 ng/mL. IL-37b expression did not affect 4T1 cell proliferation in vitro. BALB/c mice inoculated with 4T1-IL37b cells showed significant retardation of tumor growth. BALB/c mice inoculated with both 4T1 cells and mitomycin C-treated 4T1-IL37b cells also showed significant retardation of tumor growth. But the anti-cancer activity of IL-37b was abrogated in BALB/c nude mice and NOD-SCID mice inoculated with 4T1-IL37b cells. Recombinant IL-37b slightly promoted CD4(+) T cell proliferation without affecting CD8(+) T cell proliferation. CONCLUSION: IL-37b exerts anti-4T1 breast carcinoma effects in vivo by modulating the tumor microenvironment and influencing T cell activation. PMID- 25832435 TI - Predictors of Outcome among Pathological Gamblers Receiving Cognitive Behavioral Group Therapy. AB - AIMS: The aim of this study was to evaluate posttreatment changes of individuals with a diagnosis of gambling disorder (GD) treated with group cognitive behavioral therapy (CBT), to assess the potential moderator effect of sex on CBT outcome, and to explore the best predictors of posttreatment changes, relapse, and dropout rates. METHODS: A cohort design was applied with a prospective follow up. The sample comprised 440 patients and the CBT intervention consisted of 16 weekly outpatient group sessions and a 3-month follow-up period. RESULTS: Patients showed significant improvements in both the level of psychopathology and the severity of the gambling behavior. High self-transcendence and the involvement of the spouse or partner in the therapy predicted a higher risk of relapse. Younger age and low education predicted a higher risk of dropout. CONCLUSION: Many patients with GD can be treated with strategies to improve self control and emotional regulation, but other techniques should be incorporated to address the individual characteristics of each patient. This is particularly important in group therapy, in which the same treatment is applied to several patients simultaneously. The involvement of a family member needs to be carefully considered since it may have a negative effect on the response to treatment if not adequately managed. PMID- 25832436 TI - Emodin regulates bone remodeling by inhibiting osteoclastogenesis and stimulating osteoblast formation. AB - Bone remodeling, a physiological process in which new bone is formed by osteoblasts and the preexisting bone matrix is resorbed by osteoclasts, is vital for the maintenance of healthy bone tissue in adult humans. Imbalances in this process can cause various pathological conditions, including osteoporosis. Emodin, a naturally occurring anthraquinone derivative found in Asian herbal medicines, has numerous beneficial pharmacologic effects, including anticancer and antidiabetic activities. However, the effect of emodin on the regulation of osteoblast and osteoclast activity has not yet been investigated. We show here that emodin is a potential target for osteoporosis therapeutics, as treatment with this agent enhances osteoblast differentiation and bone growth and suppresses osteoclast differentiation and bone resorption. In this study, emodin suppressed receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL) induced osteoclast differentiation of bone marrow macrophages (BMMs) and the bone resorbing activity of mature osteoclasts by inhibiting RANKL-induced NF-kappaB, c Fos, and NFATc1 expression. Emodin also increased ALP, Alizarin Red mineralization activity, and the expression of osteoblastogenic gene markers, such as Runx2, osteocalcin (OCN), and ALP in mouse calvarial primary osteoblasts, as well as activated the p38-Runx2 pathway, which enhanced osteoblast differentiation. Moreover, mice treated with emodin showed marked attenuation of lipopolysaccharide (LPS)-induced bone erosion and increased bone-forming activity in a mouse calvarial bone formation model based on micro-computed tomography and histologic analysis of femurs. Our findings reveal a novel function for emodin in bone remodeling, and highlight its potential for use as a therapeutic agent in the treatment of osteoporosis that promotes bone anabolic activity and inhibits osteoclast differentiation. PMID- 25832437 TI - Role of RhoA/Rho kinase signaling pathway in microgroove induced stem cell myogenic differentiation. AB - In our previous report, the authors have demonstrated that direct laser machined microchannels would trigger upregulation of myogenic markers in human mesenchymal stem cells (hMSCs) through promotion of cell elongation. However, the molecular basis signaling pathways behind this observation remains unclear. In this work, three types of microchannels generated by femtosecond laser were utilized to investigate possible mechanisms behind the induction of hMSCs myogenesis by microchannels. The authors hypothesized that small G-proteins RhoA and Rac1 play a vital role on myogenesis of hMSCs through regulating cytoskeleton rearrangement, via cell tension signaling cascades. The RhoA and Rac1 activities were evaluated for cells cultured on the micropatterned substrates, using a flat unpatterned substrate as control. It was found that significant activation of RhoA GTPase was exhibited for cells cultured on narrow microchannels (20-20-20 and 30-30-20), while no obvious differences were obtained on wide ones (80-30 20). Meanwhile, no significant difference was found for Rac1 activities on all tested groups. To further deduce the role of RhoA signaling pathway in microchannel directed stem cell myogenesis, the effectors of Rho, Rho kinase (ROCK) was chosen to explore how cell shape regulate myogenesis of hMSCs cultured on laser micropatterned substrate. A pharmacological ROCK inhibitor, Y-27632, was used to treat the cells and the effect on RhoA activation was investigated. Our data on the role of RhoA/ROCK in regulating cell myogenic differentiation on lasered microchannels substrates may provide a mechanistic insight on hMSCs fate directed by substrate topography. PMID- 25832438 TI - Plasma jet's shielding gas impact on bacterial inactivation. AB - One of the most desired aims in plasma medicine is to inactivate prokaryotic cells and leave eukaryotic cells unharmed or even stimulate proliferation to promote wound healing. The method of choice is to precisely control the plasma component composition. Here the authors investigate the inactivation of bacteria (Escherichia coli) by a plasma jet treatment. The reactive species composition created by the plasma in liquids is tuned by the use of a shielding gas device to achieve a reactive nitrogen species dominated condition or a reactive oxygen species dominated condition. A strong correlation between composition of the reactive components and the inactivation of the bacteria is observed. The authors compare the results to earlier investigations on eukaryotic cells and show that it is possible to find a plasma composition where bacterial inactivation is strongest and adverse effects on eukaryotic cells are minimized. PMID- 25832439 TI - Measurement of retromolar space dimensions using dental pantomograms for intubation feasibility. AB - BACKGROUND: The purpose of this study was to measure the dimensions of the retromolar space of a patient population. If the dimensions were found to exceed the outside diameters of commonly used tracheal tubes, the results could increase use of the retromolar approach for oral intubation in patients with trismus. METHODS: We reviewed 311 dental pantomograms. Retromolar space height was measured from the lowest point of the maxillary tuberosity to the mandibular alveolar ridge. Width was measured from the last mandibular molar to the junction of the anterior border of the ramus with the body of the mandible. RESULTS: Mean height and width were 17.87 mm and 17.48 mm for the right space and 18.07 mm and 16.51 mm for the left. CONCLUSION: These dimensions were usually larger than the outside diameters of commonly used tracheal tubes. The retromolar approach can be considered an option for flexible fiberoptic intubation in patients with trismus. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E638-E642, 2016. PMID- 25832440 TI - Universal Breadwinner Versus Universal Caregiver Model: Fathers' Involvement in Caregiving and Well-Being of Mothers of Offspring with Intellectual Disabilities. AB - BACKGROUND: The universal breadwinner model means both parents are employed; while the universal caregiver model implies that the father's hours of caregiving are equal or higher to those of the mother. This study aims to examine the hypothesis that the universal caregiver model is more related to the overall well being of mothers of children with intellectual disabilities than the universal breadwinner model. METHODS: Face-to-face interview surveys were conducted in 2011 in Taiwan with 876 working-age mothers who had an offspring with intellectual disabilities. The survey included 574 mothers living with their husbands who became our participants. RESULTS: Both anova and regression analyses indicated that, compared with mothers in the universal breadwinner group, mothers in the universal caregiver group had higher levels of maternal marital and family life satisfaction, but not of work satisfaction and quality of life. CONCLUSIONS: An incentive policy is critical for supporting the fathers involved in lifelong caregiving and to promote the mothers' quality of life. PMID- 25832441 TI - Allotides: Proline-Rich Cystine Knot alpha-Amylase Inhibitors from Allamanda cathartica. AB - Cystine knot alpha-amylase inhibitors belong to a knottin family of peptidyl inhibitors of 30-32 residues and contain two to four prolines. Thus far, only four members of the group of cystine knot alpha-amylase inhibitors have been characterized. Herein, the discovery and characterization of five cystine knot alpha-amylase inhibitors, allotides C1-C5 (Ac1-Ac5) (1-5), from the medicinal plant Allamanda cathartica are reported using both proteomic and genomic methods. Proteomic analysis showed that 1-5 are 30 amino acids in length with three or four proline residues. NMR determination of 4 revealed that it has two cis- and one trans-proline residues and adopts two equally populated conformations in solution. Determination of disulfide connectivity of 2 by differential S reduction and S-alkylation provided clues of its unfolding process. Genomic analysis showed that allotide precursors contain a three-domain arrangement commonly found in plant cystine knot peptides with conserved residues flanking the processing sites of the mature allotide domain. This work expands the number of known cystine knot alpha-amylase inhibitors and furthers the understanding of both the structural and biological diversity of this type of knottin family. PMID- 25832442 TI - Likelihood-based inferences about the mean area under a longitudinal curve in the presence of observations subject to limits of detection. AB - Comparison of groups in longitudinal studies is often conducted using the area under the outcome versus time curve. However, outcomes may be subject to censoring due to a limit of detection and specific methods that take informative missingness into account need to be applied. In this article, we present a unified model-based method that accounts for both the within-subject variability in the estimation of the area under the curve as well as the missingness mechanism in the event of censoring. Simulation results demonstrate that our proposed method has a significant advantage over traditionally implemented methods with regards to its inferential properties. A working example from an AIDS study is presented to demonstrate the applicability of our approach. PMID- 25832443 TI - Moderate oral supplementation with docosahexaenoic acid improves platelet function and oxidative stress in type 2 diabetic patients. AB - Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 ( 35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2 isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes. PMID- 25832444 TI - Reduced prevalence of chronic tubal inflammation in tubal pregnancies after levonorgestrel emergency contraception failure. AB - PURPOSE: The aim of this study was to compare chronic fallopian tubal inflammatory disease and fibrosis between patients with general tubal pregnancy (TP) and TP with levonorgestrel (LNG) emergency contraception (EC) failure. METHODS: We retrospectively studied patients with general TP (n = 79) and TP following LNG-EC failure (n = 81) within the same conception cycle. Information on the gynecological features of each subject was collected. Pelvic inflammatory disease and associated sequelae were assessed by the serum Chlamydia trachomatis (CT) IgG test, laparoscopic evaluation of tubal damage, and histopathological observation of tube tissues. Chi-square and Student's t-tests were employed to determine the difference between the two groups. RESULTS: Compared with general TP, cases of TP following LNG-EC failure subjects were less likely to have a history of previous ectopic pregnancy (5.06% vs. 18.52%, p = 0.009) and adnexal surgery (6.33% vs. 22.22%, p = 0.010). Patients with TP following LNG-EC failure were less likely to have pelvic inflammatory disease and associated sequelae than those with general TP, as revealed by positive reaction to anti-CT IgG (18.18% vs. 35.94%, p = 0.031), assessment of tubal damage (grade I: 5.06% vs. 17.28%; grade II: 2.53% vs. 11.11%; grade III: 1.27% vs. 6.17%; p = 0.001), infiltration of chronic inflammatory cells (10.91% vs. 62.50%, p < 0.001), and positive Masson's staining (7.69% vs. 39.58%; p < 0.001). CONCLUSIONS: Compared with cases of general TP, cases of TP following LNG-EC failure exhibited reduced rates of CT infection, fallopian tubal inflammation, and/or fibrosis. PMID- 25832445 TI - Stable isotopic labeling-based quantitative targeted glycomics (i-QTaG). AB - Mass spectrometry (MS) analysis combined with stable isotopic labeling is a promising method for the relative quantification of aberrant glycosylation in diseases and disorders. We developed a stable isotopic labeling-based quantitative targeted glycomics (i-QTaG) technique for the comparative and quantitative analysis of total N-glycans using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We established the analytical procedure with the chemical derivatizations (i.e., sialic acid neutralization and stable isotopic labeling) of N-glycans using a model glycoprotein (bovine fetuin). Moreover, the i-QTaG using MALDI-TOF MS was evaluated with various molar ratios (1:1, 1:2, 1:5) of (13) C6 /(12) C6 -2 aminobenzoic acid-labeled glycans from normal human serum. Finally, this method was applied to direct comparison of the total N-glycan profiles between normal human sera (n = 8) and prostate cancer patient sera (n = 17). The intensities of the N-glycan peaks from i-QTaG method showed a good linearity (R(2) > 0.99) with the amount of the bovine fetuin glycoproteins. The ratios of relative intensity between the isotopically 2-AA labeled N-glycans were close to the theoretical molar ratios (1:1, 1:2, 1:5). We also demonstrated that the up-regulation of the Lewis antigen (~82%) in sera from prostate cancer patients. In this proof-of concept study, we demonstrated that the i-QTaG method, which enables to achieve a reliable comparative quantitation of total N-glycans via MALDI-TOF MS analysis, has the potential to diagnose and monitor alterations in glycosylation associated with disease states or biotherapeutics. PMID- 25832446 TI - Defining vulnerability in allogeneic transplants is more complicated than the two numerical digits of age. PMID- 25832447 TI - Effectiveness of Nonpharmacologic Interventions in Systemic Sclerosis: A Systematic Review. AB - OBJECTIVE: To systematically and comprehensively document the effectiveness of nonpharmacologic interventions on physical functioning and psychological well being in patients with systemic sclerosis (SSc). METHODS: Multiple electronic databases were searched for studies on the effectiveness of nonpharmacologic interventions in SSc. Randomized clinical trials (RCTs), controlled clinical trials (CCTs), and observational designs (ODs) with >=10 participants were included. Two reviewers independently assessed methodologic quality using the Downs and Black checklist. RESULTS: Twenty-three studies (9 RCTs, 4 CCTs, and 10 ODs) were included. Studies assessing comparable interventions were grouped, resulting in data for 16 different interventions. The total number of patients included per study ranged from 10 to 53. Seventeen different outcome domains were assessed, with hand function, limitations in activities, and quality of life being assessed most frequently. Three studies, all RCTs, were rated as high quality. These RCTs reported that 1) a multifaceted oral health intervention improves mouth hygiene, and additional orofacial exercises did not improve mouth opening, 2) a multidisciplinary team-care program improves limitations in activities, mouth opening, and hand grip strength, and 3) manual lymph drainage improves hand function, limitations in activities, and quality of life. CONCLUSION: The body of knowledge regarding nonpharmacologic care in SSc is very limited due to the wide variety in studied interventions and outcomes in the relatively uncommon but highly disabling disease. To structure and focus future research, an international consensus should be established to prioritize primary targets for nonpharmacologic treatment and the content of interventions and to agree on a core set of outcome measures. PMID- 25832448 TI - Osteoporosis: the evolution of a diagnosis. AB - The global trend towards increased longevity has resulted in ageing populations and a rise in diseases or conditions that primarily affect older persons. One such condition is osteoporosis (fragile or porous bones), which causes an increased fracture risk. Vertebral and hip fractures lead to increased morbidity and mortality and result in enormous healthcare costs. Here, we review the evolution of the diagnosis of osteoporosis. In an attempt to separate patients with normal bones from those with osteoporosis and to define the osteoporosis diagnosis, multiple factors and characteristics have been considered. These include pathology and histology of the disease, the endocrine regulation of bone metabolism, bone mineral density (BMD), fracture type or trauma severity, risk models for fracture prediction, and thresholds for pharmacological intervention. The femoral neck BMD -2.5 SDs cut-off for the diagnosis of osteoporosis is arbitrarily chosen, and there is no evidence to support the notion that fracture location (except vertebral fractures) or severity is useful to discriminate osteoporotic from normal bones. Fracture risk models (including factors unrelated to bone) dissociate bone strength from the diagnosis, and treatment thresholds are often based on health-economic considerations rather than bone properties. Vertebral fractures are a primary feature of osteoporosis, characterized by decreased bone mass, strength and quality, and a high risk of another such fracture that can be considerably reduced by treatment. We believe that the 2001 definition of osteoporosis by the National Institutes of Health Consensus Development Panel on Osteoporosis is still valid and useful: 'Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture'. PMID- 25832449 TI - Catatonia in an adolescent with velo-cardio-facial syndrome. AB - Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans and is probably the most frequent genetic cause of psychosis currently known. Many psychiatric disorders have been reported to occur in people with VCFS including, but not limited to schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD. This report describes the psychiatric onset and development of catatonia in an adolescent female with VCFS that was undiagnosed until 15 years of age. Catatonia may be a relatively common presentation in people with VCFS with treatment-refractory psychiatric manifestations. PMID- 25832450 TI - Sodium benzoate and potassium sorbate preservatives in food stuffs in Iran. AB - A high-performance liquid chromatography method was applied for the determination of the levels of benzoate and sorbate in 400 food samples, including pickled cucumbers, canned tomato pastes, sour cherry jams, soft drinks, fruit juices and dairy products (UF-Feta cheeses, Lighvan cheeses, lactic cheeses, yogurts and doogh). The results showed that 270 (67.5%) of all samples contained benzoate ranging from 11.9 to 288.5 mg kg(-1) in lactic cheese and fruit juice, respectively. The levels of sorbate in 98 (24.5%) of the samples were 20.1 to 284.3 mg kg(-1) in doogh and fruit juice, respectively. Moreover, benzoate was detected in all dairy products ranging from 11.9 mg kg(-1) in lactic cheese to 91.2 mg kg(-1) in UF-Feta cheese. A low concentration of benzoate could originate naturally, due to specific biochemical mechanisms during cheese, yogurt and doogh maturation. In conclusion, a minimum level for benzoate in dairy products should be defined in the legislation. PMID- 25832451 TI - Comparison of the sociodemographic characteristics of the large NutriNet-Sante e cohort with French Census data: the issue of volunteer bias revisited. AB - BACKGROUND: A recurring concern in traditional and in Web-based studies pertains to non-representativeness due to volunteer bias. We investigated this issue in an ongoing, large population-based e-cohort. METHODS: The sample included 122 912 individuals enrolled in the Internet-based, nutrition-focused NutriNet-Sante study between May 2009 and March 2014, with complete baseline data. Participants were recruited via recurrent multimedia campaigns and other traditional and online strategies. Individuals aged 18+ years, residing in France and having Internet access, were eligible for enrolment. Their sociodemographic characteristics were compared with the corresponding 2009 Census data via chi(2) goodness-of-fit tests. The effectiveness of statistical weighting of the e-cohort data was also explored. RESULTS: The sample exhibited marked geographical and sociodemographic diversity, including volunteers belonging to typically under represented subgroups in traditional surveys (unemployed, immigrants, the elderly). Nonetheless, the proportions of women, relatively well-educated individuals and those who are married or cohabiting, were notably larger compared with the corresponding national figures (women: 78.0% vs 52.4%; postsecondary education: 61.5% vs 24.9%; married or cohabiting: 70.8% vs 62.0%, respectively; all p<0.0001). CONCLUSIONS: There were notable sociodemographic differences between the general French population and this general population-based e-cohort, some of which were corrected by statistical weighting. The findings bear on the potential generalisability of future investigations in the context of e epidemiology. PMID- 25832452 TI - Clues to diagnosis for unusual mucosal pemphigus demonstrating undetectable anti desmoglein 3 serum antibodies by routine tests. AB - Pemphigus is an autoimmune blistering disease caused by immunoglobulin (Ig)G autoantibodies against desmogleins (Dsg). In mucosal-dominant pemphigus vulgaris (PV), anti-Dsg3 antibodies play a critical role in acantholysis. We followed two mucosal-dominant PV cases who suffered from refractory oral mucosal erosions. In these cases, anti-Dsg3 serum antibodies were not detected by indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). However, direct immunofluorescence showed the intercellular IgG deposition in the epidermis and histopathological findings revealed suprabasal acantholysis. In order to analyze the pathomechanisms in these cases, we first examined the Dsg3 expression patterns in lesional sites and compared them with those of typical mucosal dominant PV cases. In typical PV cases, the alteration of Dsg3 distribution was observed in lesional sites by immunostaining. The aggregation of Dsg3, which is the characteristic change in PV mucosal lesions, was observed as the initial change prior to acantholysis. In our cases, a clustering of Dsg3 was observed at mucosal lesions, and the expression levels of Dsg3 in acantholytic lesions were decreased, as observed in typical mucosal-dominant PV cases. Although anti-Dsg3 serum antibodies could not be detected by routine tests, anti-Dsg3 serum antibodies were detected by Dsg3 ELISA using 10-times more concentrated sera (highly sensitive ELISA). Moreover, purified and concentrated PV IgG showed high pathogenicity when examined by dissociation assay. In conclusion, the detection of morphological changes in Dsg3 distribution and highly sensitive ELISA method could be useful for the early diagnosis of PV recurrence. PMID- 25832453 TI - Complications associated with central venous access device in children with haemophilia: a nationwide multicentre study in Finland. AB - Children with haemophilia require venous access for regular infusion of coagulation factors. A central venous access device (CVAD) ensures long-term access but associates with infectious and non-infectious complications with proposed risk factors of young age at initial CVAD implantation and presence of an inhibitor. Our aim was to evaluate the incidence and risk factors for complications associated with CVAD usage in a retrospective nationwide multicentre study in five Finnish Paediatric Haemophilia Treatment Centers. Our study investigated 106 CVADs in 58 patients with 137 971 CVAD days. The median access survival was 1159 CVAD days, and most often a malfunction led to CVAD removal after a long survival (median of 1640 CVAD days). We detected a very low bloodstream infection rate (0.12/1000 CVAD days). The presence of neutralizing inhibitor was a significant risk factor for infection. Heparin vs. saline flushing did not influence the CVAD outcome. We detected a lower infection rate than previously reported, although 90% of the patients were very young (<2 years) at first insertion (median age = 1.02 year). Port access was frequent after initial implantation: six patients (10%) used the port daily for immune tolerance induction therapy and 74% at least twice weekly for prophylaxis. Young age did not increase the risk of infections, as 59% of the CVAD-related infections were recorded in children over 6 years of age. Our national experience confirms the safety of prophylactic factor concentrate administration via ports even in very young children. PMID- 25832454 TI - VALIDATION OF AN INDEXED RADIOTHERAPY HEAD POSITIONING DEVICE FOR USE IN DOGS AND CATS. AB - Setup variability affects the appropriate delivery of radiation and informs the setup margin required to treat radiation patients. Twenty-four veterinary patients with head and neck cancers were enrolled in this prospective, cross sectional study to determine the accuracy of an indexed board immobilization device for positioning. Couch position values were defined at the first treatment based on setup films. At subsequent treatments, patients were moved to the previously defined couch location, orthogonal films were acquired, table position was modified, and displacement was recorded. The mean systematic displacement, random displacement, overall displacement, and mean displacement values of the three-dimensional (3D) vector were calculated. Three hundred thirty-two pairs of orthogonal setup films were analyzed for displacement in cranial-caudal, lateral, and dorsal-ventral directions. The mean systematic displacements were 0.5, 0.8, and 0.5 mm, respectively. The mean random displacements were 1.0, 1.1, and 0.7 mm, respectively. The overall displacements were 1.1, 1.4, and 0.9 mm, respectively. The mean 3D vector value was 1.6 mm with a standard deviation of 1.2 mm. Ninety-five percent of the vectors were <3.6 mm. These values were compared to data obtained with a previously used immobilization device. A t-test was used to compare the two devices. The 3D vector, random displacement in all directions, and overall displacement in the cranial-caudal and dorsal-ventral directions were significantly smaller than displacements with the previous device. The precision and accuracy of the indexed board device was superior to the historical head and neck device. PMID- 25832455 TI - Comparison of an interferon-gamma release assay and the tuberculin skin test for diagnosis of latent tuberculosis in homeless people in Iran: a cross-sectional study. AB - BACKGROUND: The aim of this study was to evaluate of the concordance between the results of the tuberculin skin test (TST) and an interferon-gamma release assay (QuantiFERON test, QFT-GIT) for diagnosis of latent tuberculosis infection (LTBI) in homeless people in Tehran city, Iran. METHODS: This cross-sectional study was conducted from June to August 2012. Homeless people were eligible to participate in the study if they were 18-60 years old. RESULTS: Among 569 homeless people, 46.22% (95% confidence interval (CI) = 42.16-50.33%) and 20.39% (95% CI = 17.28 23.9%) were QFT-GIT and TST positive, respectively. Among these participants, the prevalence of LTBI with positivity of at least one of the tests was 52.2%. The overall agreement between QFT-GIT and TST was 62.21% (kappa = 0.21, 95% CI = 0.13 0.29, p < 0.001). Factors associated with positive results in QFT-GIT and TST were older age, being male, having a longer history of homelessness and having a history of incarceration in the last 10 years. CONCLUSIONS: A high prevalence of LTBI was seen among homeless people in this study. There was a poor concordance between QFT-GIT and TST among this group. To better assess the utility of QFT-GIT in detection of LTBI further studies with a low prevalence of LTBI in this group are recommended. PMID- 25832456 TI - Immunofluorescence assay for diagnosis of strongyloidiasis in immunocompromised patients. AB - BACKGROUND: Strongyloides stercoralis is a parasite that causes human strongyloidiasis. The disease ranges from asymptomatic to severe forms, which are often fatal in immunocompromised individuals. Laboratory diagnosis is challenging owing to limitations in the use of conventional parasitological techniques. The present study aimed to evaluate the indirect immunofluorescence assay (IFA) using infective larvae of S. venezuelensis as an antigen for the immunodiagnosis of human strongyloidiasis in immunocompromised patients. METHODS: Serum and stool samples from 200 immunocompromised patients (HIV-positive, HTLV-1-positive, and renal, liver, and/or bone marrow transplantation candidates) were used. Stool samples were examined using three parasitological methods: Lutz, Rugai, and culture agar plate. IFA was performed using sections of infective larvae of S. venezuelensis as antigens, and showed 95.4% sensitivity and 95.8% and specificity. RESULTS: Among the 200 patients, 17 (8.5%) were positive for S. stercoralis by at least one parasitological method, and 43 (21.5%) were positive by IFA. CONCLUSIONS: IFA can be used as a screening method for the detection of S. stercoralis in immunocompromised patients. PMID- 25832457 TI - Prevalence, antimicrobial susceptibility, and genetic diversity of Pseudomonas aeruginosa as intestinal colonizer in the community. AB - In this study we determined the prevalence of intestinal carriage, the antimicrobial susceptibility rates, and the genetic diversity of Pseudomonas aeruginosa in the community. From July 2010 to December 2011, a total of 2110 nonreplicate fecal samples from individuals living in Bavaria were collected. Samples were screened for P. aeruginosa by a selective medium and antimicrobial susceptibility was determined by disc diffusion technique. Genetic diversity was assessed by multilocus sequence typing (MLST). Intestinal colonization was detected in 31 of 2110 (1.47%) individuals. None of the isolates showed resistance to aztreonam, imipenem, meropenem, ciprofloxacin, amikacin or colistin. Twenty-five isolates could be assigned to 20 different sequence types (STs), whereas the remaining 6 could not be assigned. Interestingly, four isolates belonged to ST253. These data show that intestinal colonization by P. aeruginosa occurs in the community with high genetic diversity and low rates of antimicrobial resistance. PMID- 25832458 TI - Psychometric Confirmation of the Sexual Health Survey as a Useful Tool for College Health Professionals. AB - OBJECTIVE: To conduct a confirmatory factor analysis on the 17-item Sexual Health Survey (SHS), a comprehensive instrument designed to be used with college students. PARTICIPANTS: College students (N = 515) aged 18 to 26 years enrolled at a Midwest public university October 2009. METHODS: Confirmatory factor analysis with maximum likelihood estimation was performed to test the stability of the constructs. RESULTS: All factor loadings were significant (p < .001), ranging from .55 to .99 (standardized). The range of squared multiple correlations of items was .31 to .98, and the intercorrelations among the 5 factors were from -.03 to .52. These small to moderate levels of intercorrelation support discriminant validity of 5 constructs. CONCLUSIONS: This study supports the 5-factor version of the 17-item SHS as a viable scale that can measure sexual health overall and 5 distinct areas. College health professionals should consider use of this scale for assessment purposes and evaluation of programmatic efforts. PMID- 25832459 TI - Uncertainty and predictiveness determine attention to cues during human associative learning. AB - Prior research has suggested that attention is determined by exploiting what is known about the most valid predictors of outcomes and exploring those stimuli that are associated with the greatest degree of uncertainty about subsequent events. Previous studies of human contingency learning have revealed evidence for one or other of these processes, but differences in the designs and procedures of these studies make it difficult to pinpoint the crucial determinant of whether attentional exploitation or exploration will dominate. Here we present two studies in which we systematically manipulated both the predictiveness of cues and uncertainty regarding the outcomes with which they were associated. This allowed us to demonstrate, for the first time, evidence of both attentional exploration and exploitation within the same experiment. Moreover, while the effect of predictiveness persisted to influence the rate of novel learning about the same cues in a second stage, the effect of uncertainty did not. This suggests that attentional exploration is more sensitive to a change of context than is exploitation. The pattern of data is simulated with a hybrid attentional model. PMID- 25832460 TI - Nuclear SMAD2 restrains proliferation of glioblastoma. AB - AIMS: Although TGFbeta receptor signaling has been shown to play a role in regulation of the growth and metastasis of glioblastoma multiforme (GBM), the downstream pathway through either SMAD2 or SMAD3 has not been elucidated. In this study, we investigate whether nuclear SMAD2 can restrain the proliferation of glioblastoma. METHODS: A total of 23 resected specimens from GBM patients were collected for SMAD2 detection. Human GBM cell line A172, U87mg, D341m and Hs683 were maintained in Dulbecco's modified Eagle's medium and transfected with SMAD2 and SMAD3 shRNA plasmids. Gene expression was detected by RT-qPCR and Western and cell growth were detected by MTT assay. RESULTS: Our results showed that the phosphorylated SMAD2 (pSMAD2, the nuclear and functional form of SMAD2) levels in GBM were significantly lower than the paired normal brain tissue in patients. Depletion of SMAD2, but not SMAD3, significantly abolished the inhibitory effects of TGFbeta1 on the growth of GBM cells, possibly through pSMAD2-mediated increases in cell-cycle inhibitor, p27. CONCLUSION: Our data suggest that TGFbeta/SMAD2 signaling cascades restrains growth of GBM. PMID- 25832461 TI - Laparoscopic radical abdominal trachelectomy for the management of stage IB1 cervical cancer at 14 weeks' gestation: case report and review of the literature. PMID- 25832462 TI - Synchronous primary malignancies of the appendix and ovary causing carcinomatosis in one patient. AB - Associated tumors of the ovary and the appendix are commonly found in cases of pseudomyxoma peritonei (PP); the origin of these tumors are a continually debated topic. Outside of the setting of PP, this finding is exceedingly rare and there are no documented reports of two primary processes causing carcinomatosis in the absence of PP. Here, we present a patient who underwent cytoreductive surgery for peritoneal carcinomatosis presumptively secondary to ovarian carcinoma and who on pathological examination was found to have synchronous primary malignant processes of both the appendix and the ovary. This represents the first documented case of carcinomatosis resulting from two separate malignant processes in the absence of PP. PMID- 25832463 TI - Hemorrhagic giant cystic lymphangioma of the liver in an adult female. AB - An 18-year-old woman who presented with epigastric pain was diagnosed with rupture of a hepatic tumor and transported to our hospital. Contrast-enhanced computed tomography revealed a 13-cm, low-density giant mass in the left hepatic lobe and high-density ascites, indicating abdominal bleeding from the liver tumor. The patient underwent emergent celiac angiography, and the left hepatic artery, which was believed to feed the tumor, was embolized. After the patient's condition stabilized, she underwent left hepatic lobectomy. In addition, the enlarged lymph nodes of the hepatoduodenal ligament were dissected. On microscopic examination, immunohistochemical staining revealed that both the liver cyst and the enlarged lymph node were positive for the endothelial marker CD31 and lymphangial marker D2-40. The patient was pathologically diagnosed with cystic lymphangioma of the liver. She has now been followed up for almost 4 years after surgery without any sign of recurrence. PMID- 25832464 TI - Paget's disease of the male breast with underlying ductal carcinoma in situ ('DCIS'). AB - Male breast cancer accounts for 1% of all breast malignancies and 0.1% of all male cancer death. Like Paget's disease, DCIS is a rare form of male breast malignancy. We report a 69-year-male presenting with 3 years history of subtle of nipple symptoms and normal breast imaging. Punch biopsy of nipple established the diagnosis of Paget's disease and subsequent histology of mastectomy specimen revealed underlying DCIS. PMID- 25832465 TI - Assessment of angiographic coronary calcification and plaque composition in virtual histology intravascular ultrasound. AB - OBJECTIVES: We assessed the relation between coronary plaque composition and angiographic calcification by using virtual histology intravascular ultrasound (VH-IVUS). BACKGROUND: The plaque vulnerability according to angiographic calcification is unclear. METHODS: Subjects were 140 consecutive patients (145 lesions) undergoing VH-IVUS before percutaneous coronary intervention. Subjects were divided into 4 groups: no calcification group (n = 27), spotty group (n = 65) that had calcium deposits under 90 degrees in grayscale IVUS, intermediate group (n = 37) had calcium deposits with 90 degrees or more and under 180 degrees , and extensive group (n = 16) had calcium deposits with 180 degrees or more. RESULTS: The number of VH thin-cap fibroatheromas in spotty group was significantly larger than no calcification group, intermediate group, and extensive group (0.66 +/- 0.71 vs 0.22 +/- 0.42 [P < 0.01], 0.32 +/- 0.48 [P < 0.05], 0.13 +/- 0.34 [P < 0.01], respectively). Spotty group without angiographic calcification had significantly larger %necrotic core than with angiographic calcification (24.5 +/- 6.7% vs 19.9 +/- 7.2%, P < 0.05). Intermediate group without angiographic calcification had significantly larger necrotic core area than with angiographic calcification (2.5 +/- 0.9 mm(2) vs 1.7 +/- 0.9 mm(2) , P < 0.05). Extensive group with angiographic calcification had significantly larger %dense calcium than without angiographic calcification (18.3 +/- 4.0% vs 13.4 +/- 4.4%, P < 0.05). CONCLUSIONS: Lesions with spotty calcification was highly vulnerable in VH-IVUS. Spotty or intermediate plaque calcification without angiographic calcification was more vulnerable than those with angiographic calcification. Extensive plaque calcification with angiographic calcification had more dense calcium than those without angiographic calcification. PMID- 25832467 TI - The cell of origin of acral melanomas may be hiding in the sweat glands. PMID- 25832466 TI - Targeting the interleukin-11 receptor alpha in metastatic prostate cancer: A first-in-man study. AB - BACKGROUND: Receptors in tumor blood vessels are attractive targets for ligand directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Ralpha) in the human vasculature. METHODS: The authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Ralpha-based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate resistant prostate cancer. RESULTS: BMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m(2) ). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine. CONCLUSIONS: These biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. PMID- 25832468 TI - Premature rupture of membranes and neonatal respiratory morbidity at 32-41 weeks' gestation: a retrospective single-center cohort study. AB - AIM: To ascertain whether premature rupture of membranes (PROM) independently affects the risk of neonatal respiratory morbidity at 32-41 weeks' gestation because previous reports have given insufficient consideration to the mode of delivery and labor onset. METHODS: Data on 4,629 consecutive singleton infants were retrospectively collected. Respiratory morbidity was limited to respiratory distress syndrome and transient tachypnea of the newborn, both of which are related to prematurity. Delivery modes were divided into four groups based on the existence of PROM and of labor onset, and the respiratory morbidity was examined according to the number of weeks of gestational age. Multivariate analysis including PROM and delivery mode was conducted to examine the association of respiratory morbidity. RESULTS: Respiratory morbidity or a positive pressure requirement delivered after PROM and intact amniochorionic membranes accompanied by labor were similar at all weeks. Around 37 weeks, the absence of labor onset was associated with a risk of respiratory morbidity or positive pressure requirement. Significant respiratory risk was not associated with the incidence of PROM (adjusted odds ratio [aOR], 0.98; 95% confidence interval [CI], 0.52 1.83), interval from rupture to delivery (aOR, 1.00; 95% CI, 0.99-1.01), clinical chorioamnionitis, induction management, pregnancy-related complications, or neonatal sex. Delivery by Cesarean section and early gestational age presented a significant risk for respiratory morbidity. CONCLUSIONS: Neither PROM nor latency after PROM at 32-41 weeks affected neonatal respiratory morbidity. Avoiding Cesarean section instead of simply increasing the time to delivery may help to reduce respiratory morbidity. PMID- 25832469 TI - A biopsychosocial model for the management of patients with sickle-cell disease transitioning to adult medical care. AB - The lifespan of patients with sickle-cell disease (SCD) continues to increase, and most affected individuals in high-resource countries now live into adulthood. This necessitates a successful transition from pediatric to adult health care. Care for transitioning patients with SCD often falls to primary care providers who may not be fully aware of the many challenges and issues faced by patients and the current management strategies for SCD. In this review, we aim to close the knowledge gap between primary care providers and specialists who treat transitioning patients with SCD. We describe the challenges and issues encountered by these patients, and we propose a biopsychosocial multidisciplinary approach to the management of the identified issues. Examples of this approach, such as transition-focused integrated care models and quality improvement collaboratives, with the potential to improve health outcomes in adulthood are also described. PMID- 25832470 TI - Impact of medication adherence and persistence on clinical and economic outcomes in patients with type 2 diabetes treated with liraglutide: a retrospective cohort study. AB - INTRODUCTION: Adherence to diabetes medication has been linked to improved glycemic levels and lower costs, but previous research on adherence has typically involved oral antidiabetic medication or insulin. This study examines how adherence and persistence to once-daily liraglutide impact glycemic control and economic outcomes in a real-world population of adult type 2 diabetes (T2D) patients. METHODS: A retrospective cohort study using administrative claims data from July 2009 through September 2013. Patients aged >=18 years with T2D treated with liraglutide were identified (index date = first liraglutide prescription). Adherence was based on the proportion of days covered (PDC); with PDC >=0.80 classified as adherent. Non-persistent patients were those with a gap in therapy of >90 days. Lab results for glycated hemoglobin (A1C) were used to identify whether patients achieved target levels of <7.0% and <= 6.5%, or experienced a reduction of >=1.0% in A1C from pre-index (baseline) to post-index (follow-up). Logistic regression was used to estimate the likelihood of achieving the A1C goals, adjusted for baseline characteristics. Diabetes-related medical, pharmacy, and total costs were modeled and estimated for the adherence and persistence cohorts. RESULTS: A total of 1321 patients were identified. The mean PDC was 0.59 and 34% of patients were classified as adherent, while 60% were persistent over 12 months of follow-up. Adherent and persistent patients were more likely to achieve each of the A1C goals than their non-adherent and non-persistent counterparts after adjusting for patient characteristics. Adherence and persistence were associated with higher adjusted diabetes-related pharmacy and total healthcare costs during follow-up; whereas persistent patients had significantly lower diabetes-related medical costs than non-persistent patients. CONCLUSIONS: Adherence and persistence to liraglutide are associated with improved A1C outcomes. Persistent patients showed significantly lower medical costs versus those discontinuing liraglutide. Total healthcare costs were higher for adherent and persistent cohorts driven by higher pharmacy costs. PMID- 25832472 TI - NOGGIN: a new therapeutic target for PH? Focus on "Noggin inhibits hypoxia induced proliferation by targeting store-operated calcium entry and transient receptor potential cation channels". PMID- 25832471 TI - Age-related variation in mobility independence among wheelchair users with spinal cord injury: A cross-sectional study. AB - OBJECTIVE: To evaluate age-related variation in mobility independence among community-living wheelchair users with spinal cord injury (SCI). DESIGN: Community Survey (2011-2013) as part of the Swiss Spinal Cord Injury Cohort Study. SETTING: Community. PARTICIPANTS: Individuals aged 16 years or older with traumatic or non-traumatic SCI permanently residing in Switzerland and using a wheelchair for moving around moderate distances (10-100 m). INTERVENTIONS: Not applicable. OUTCOME MEASURES: Mobility-related items of the Spinal Cord Independence Measure-Self Report were matched to the three principal domains "changing basic body position," "transferring oneself" and "moving around." Binary outcomes ("independence" vs. "no independence") were created for every domain and analyzed using multivariable logistic regression (adjusted for sex, socioeconomic factors, SCI characteristics, and health conditions). RESULTS: Regression analyses (N = 949; 27% women; median age 51, interquartile range 41 61) showed a decline in the odds of independence (odds ratio; 95% confidence interval) with increasing age for "changing basic body position" (age 16-30 (reference), 31-45 (0.99; 0.53-1.83), 46-60 (0.64; 0.33-1.21), 61-75 (0.45; 0.22 0.92), 76+ (0.18; 0.07-0.44); P < 0.001), "transferring oneself" (age 16-30 (reference), 31-45 (0.77; 0.37-1.61), 46-60 (0.39; 0.18-0.84), 61+ (0.05; 0.02 0.14); P < 0.001), and "moving around" (age 16-30 (reference), 31-45 (0.79; 0.42 1.48), 46-60 (0.49; 0.26-0.94), 61-75 (0.49; 0.24-1.01), 75+ (0.11; 0.04-0.30); P < 0.001). CONCLUSIONS: Mobility independence was negatively associated with age in wheelchair users with SCI. Future longitudinal analyses are required to gain further insights into the causal factors for the age-related decline. PMID- 25832473 TI - Comparison of lisdexamfetamine and dextroamphetamine exposures reported to U.S. poison centers. AB - CONTEXT: Lisdexamfetamine is a pro-drug stimulant that requires the enzymatic hydrolysis of lysine from dexamphetamine for pharmacologic effects. There is limited information comparing non-therapeutic lisdexamfetamine and dextroamphetamine exposures. OBJECTIVE: The objective was to compare lisdexamfetamine exposures with dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. METHODS: A retrospective observational case series of single-substance exposures to lisdexamfetamine, dextroamphetamine/amphetamine extended release, or dextroamphetamine/amphetamine immediate release reported to the National Poison Data System from 2007 to 2012 was performed. Data were analyzed for demographics, reason, clinical effects, management site, and outcomes. RESULTS: There were 23,553 exposures: lisdexamfetamine (7,113), dextroamphetamine/amphetamine extended release (6,245), and dextroamphetamine/amphetamine immediate release (10,195). The most frequent clinical effects observed for lisdexamfetamine, dextroamphetamine/amphetamine extended release, and dextroamphetamine/amphetamine immediate release were agitation (19.8%, 21.7%, and 25.1%, respectively) and tachycardia (19.2%, 22.8%, and 23.9%, respectively). The reason was most often exploratory (93.4%) in children < 6 years and therapeutic error (65.6%) in children aged 6-12 years. In adolescents and adults most common reasons were suicide attempts (28.4%) followed by abuse (19.5%) and therapeutic errors (18.8%). Overall, 61.6% of cases were managed in a health care facility, with the majority treated in the emergency department only. The majority of cases (76.0%) experienced no or minor effects. More serious outcomes (moderate/major/death) occurred in 21.2% of lisdexamfetamine, 24.7% of dextroamphetamine/amphetamine extended release, and 25.5% of dextroamphetamine/amphetamine immediate release. There were 4 deaths (1 dextroamphetamine/amphetamine extended release and 3 dextroamphetamine/amphetamine immediate release). In patients aged 6 years and more, abuse/misuse was more frequently reported for dextroamphetamine/amphetamine immediate release (32.5%) and dextroamphetamine/amphetamine extended release (23.0%) than that for lisdexamfetamine (13.5%). The odds of abuse/misuse was 2.3 (95% confidence interval [CI]: 2.0-2.4) times higher for dextroamphetamine/amphetamine immediate release than that for lisdexamfetamine and dextroamphetamine/amphetamine extended release combined; the odds of dextroamphetamine/amphetamine extended release abuse/misuse was 1.9 (95% CI: 1.7 2.2) times higher than lisdexamfetamine. In 2011, the number of lisdexamfetamine abuse/misuse cases exceeded dextroamphetamine/amphetamine extended release by approximately 26% and plateaued in 2012, but was significantly lower (~75%) than dextroamphetamine/amphetamine immediate release. CONCLUSIONS: Toxic effects were similar for all three drugs. Although the majority of cases were treated at health care facilities, the majority of patients experienced no effects or minor toxicity. Serious outcomes occurred in approximately 21% of lisdexamfetamine and 25% of dextroamphetamine/amphetamine extended release and dextroamphetamine/amphetamine immediate release. Lisdexamfetamine may have less abuse potential, especially compared with the immediate-release dextroamphetamine/amphetamine formulation. PMID- 25832474 TI - Bilateral and Unilateral Total Extraperitoneal Inguinal Hernia Repair (TEP) have Equivalent Early Outcomes: Analysis of 9395 Cases. AB - INTRODUCTION: To date, no randomized controlled trials have been carried out to compare the perioperative outcome of unilateral and bilateral inguinal hernia repair using an endoscopic technique. In a Swiss registry study comparing unilateral with bilateral inguinal hernias, no further details were given regarding the nature of the intra- and postoperative complications. In addition, some authors have raised the issue of prophylactic repair of a clinically healthy other groin side. PATIENTS AND METHODS: In the Herniamed Registry, in total 9395 patients with a TEP were enrolled. These comprised 6700 patients with unilateral (71.31%) and 2695 patients (28.69%) with bilateral inguinal hernia repair. The outcome variables, analyzed in a multivariable model, were the intra- and postoperative as well as general complication rates, reoperation rate, duration of operation, and length of hospital stay. RESULTS: While no significant difference was found in the overall number of intraoperative complications between the unilateral and bilateral group (p=0.310), a significantly higher number of urinary bladder injuries in the bilateral TEP operation of 0.28% compared with 0.04% for unilateral TEP (p=0,008) were noted. The greater probability of reoperation (0.82% for unilateral vs. 1.78% for bilateral TEP; p<0,001) in the unadjusted analysis was confirmed in the multivariable model [OR 2.35 (1.504; 3.322); p=0.001]. A significantly higher intraoperative urinary bladder injury rate and reoperation rate because of postoperative surgical complications constitute a difference in the perioperative outcome between unilateral and bilateral TEP which that warrants attention. Based on these results, prophylactic operation of the healthy other groin should not be recommended. PMID- 25832475 TI - Changes in atopy prevalence and sibship effect in rural population at all ages. AB - BACKGROUND: We examined the associations of family size and birth order with atopy prevalence in rural Poland at two time periods. METHODS: Two cross sectional surveys were conducted in the same villages and a small town of lower Silesia at an interval of 9 years. In 2003, 1700 (88% of eligible individuals), and in 2012, 1730 (86%) inhabitants aged 5 years or more completed a questionnaire and had a skin prick test for atopy. RESULTS: There was an inverse association between family size and atopy in the village population in 2003; the prevalence of atopy was the highest for those with no siblings (15.2%) and decreased to 5.4% for those with three and more siblings (OR = 0.22; 0.07-0.66). In contrast, there was little or no such protective effect in the town population where the prevalence of atopy was much higher (7.3% in the villages, 20.0% in the town). Nine years later, the prevalence of atopy had increased in the village to be similar to that in the town (19.6% and 19.9% respectively), and the protective effects of family size and birth order in the villages were much weaker (OR = 0.64; 95% CI 0.33-1.27 for three or more siblings). Both protective effects were strongest among children. CONCLUSIONS: The protective effects of family size and birth order on atopy were much stronger in children than in adults and among those living in a village. They largely disappeared with the steep increase in atopy prevalence at all ages; this followed environmental changes on the village farms. PMID- 25832476 TI - Spatio-temporal regulation of the formation of the somatosensory system. AB - The somatosensory system in the brain has been widely used for investigating the mechanisms underlying neural circuit formation and developmental neural plasticity. In the primary somatosensory cortex (S1) of rodents, there are discrete cytoarchitectonic units called barrels. Reverse genetic analyses using knockout mice have revealed molecules that control spatial pattern formation of barrels in S1. Glutamatergic receptors such as the NMDA receptor and mGluR5, and molecules related to serotonin such as serotonin transporter and monoamine oxidase A are essential for the formation of barrels. In addition to the mechanisms of spatial pattern formation, those regulating the timing of developmental processes were uncovered recently. Barrels are formed soon after the birth of newborn mouse pups from their mothers, and it was shown that the timing of barrel formation was determined by the timing of the birth of mouse pups. The mechanisms downstream of birth were also examined. It would be intriguing to examine if the mechanisms found using the somatosensory system are applicable to other brain regions. PMID- 25832477 TI - Reduced Expression of miR-23a Suppresses A20 in TLR-stimulated Macrophages. AB - High levels of miR-23a expression in human primary macrophages suggested that miR 23a might have an important role in innate immune cells. Therefore, we investigated whether miR-23a regulates the secretion of cytokines by immune cells. Herein, we demonstrate that the expression of miR-23a was reduced in toll like receptor (TLR)-stimulated macrophages. By targeting A20, miR-23a could affect NF-kappaB activity and the expression of downstream NF-kappaB-target genes that encode proinflammatory mediators, such as IL-6 and TNF-alpha. In summary, our study describes a novel role for miR-23a in the regulation of inflammatory cytokine production in macrophages, which could yield new insights into the regulatory role of miRNAs in the inflammatory response. PMID- 25832478 TI - Anti-Asthmatic Effects of Ginsenoside Rb1 in a Mouse Model of Allergic Asthma Through Relegating Th1/Th2. AB - The aim of the study was to investigate the anti-asthma effects of ginsenoside Rb1 (Rb1) and its possible mechanisms. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (2 mg/kg), and Rb1 (10 and 20 mg/kg). Airway resistance (RI) was measured; histological studies were evaluated by the hematoxylin and eosin (HE) staining; Th1/Th2, ovalbumin (OVA) specific serum, and bronchoalveolar lavage fluid (BALF) IgE levels were evaluated enzyme-linked immunosorbent assay (ELISA); and T-bet/GATA3 proteins were evaluated by Western blot. Our study demonstrated that Rb1 inhibited OVA-induced increases in RI and eosinophil counts; interleukin (IL)-4 was recovered, and IFN gammalevel increased in bronchoalveolar lavage fluid. Histological studies demonstrated that Rb1 substantially inhibited OVA-induced eosinophilia in lung tissue. Western blot studies demonstrated that Rb1 substantially inhibited GATA3 and increased T-bet. These findings suggest that Rb1 may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. PMID- 25832479 TI - Sustained Disease Control with TOMOXIRI Regimen in a Patient with Metastatic Pancreatic Adenocarcinoma. PMID- 25832480 TI - Visceral Adiposity is a Risk Factor for Poor Prognosis in Colorectal Cancer Patients Receiving Adjuvant Chemotherapy. AB - BACKGROUND: Studies utilizing body mass index (BMI) have failed to show a consistent relationship between obesity and survival following treatment for colorectal cancer (CRC). Computerized tomography (CT) offers a reliable alternative approach to quantify body adiposity. We hypothesized that visceral obesity may negatively impact survival in CRC patients. AIMS AND METHODS: A retrospective review of CRC patients who received adjuvant chemotherapy at a single center during the period 2006-2009 identified from a prospectively maintained database. Visceral adiposity was determined by measuring visceral fat area (VFA) on preoperative staging CT. All patients were followed up to study completion or death. RESULTS: Sixty-two CRC patients with a mean age of 63.2 years received adjuvant chemotherapy and had imaging available for analysis. Thirty-five patients (56.5 %) had node positive disease. Thirty-one patients (50 %) were classified viscerally obese based on staging CT. 85.4 % of the patients completed adjuvant chemotherapy and visceral obesity was not associated with increased toxicity or failure to complete treatment. After a median follow-up of 65.2 months, patients with visceral obesity had a significantly lower overall survival (OS) (54.8 % vs 87.1 %, p = 0.004) and disease-free survival (DFS) (48.4 vs 77.4 %, p = 0.007) compared with patients without visceral obesity. There was no relationship between BMI and survival. Multivariate analysis using Cox proportional hazards model showed that visceral obesity was independently associated with reduced OS (Hazard ratio = 7.0; 95 % CI 2.0-24.6; p = 0.002). CONCLUSION: This study shows that visceral obesity increases the likelihood of a poor prognosis in CRC patients receiving adjuvant chemotherapy thus underlying the value of lifestyle interventions to minimize visceral obesity in this patient cohort. PMID- 25832481 TI - West Eurasian mtDNA lineages in India: an insight into the spread of the Dravidian language and the origins of the caste system. AB - There is no indication from the previous mtDNA studies that west Eurasian specific subclades have evolved within India and played a role in the spread of languages and the origins of the caste system. To address these issues, we have screened 14,198 individuals (4208 from this study) and analyzed 112 mitogenomes (41 new sequences) to trace west Eurasian maternal ancestry. This has led to the identification of two autochthonous subhaplogroups--HV14a1 and U1a1a4, which are likely to have originated in the Dravidian-speaking populations approximately 10.5-17.9 thousand years ago (kya). The carriers of these maternal lineages might have settled in South India during the time of the spread of the Dravidian language. In addition to this, we have identified several subsets of autochthonous U7 lineages, including U7a1, U7a2b, U7a3, U7a6, U7a7, and U7c, which seem to have originated particularly in the higher-ranked caste populations in relatively recent times (2.6-8.0 kya with an average of 5.7 kya). These lineages have provided crucial clues to the differentiation of the caste system that has occurred during the recent past and possibly, this might have been influenced by the Indo-Aryan migration. The remaining west Eurasian lineages observed in the higher-ranked caste groups, like the Brahmins, were found to cluster with populations who possibly arrived from west Asia during more recent times. PMID- 25832482 TI - Application of high-resolution mass spectrometry to measure low abundance isotope enrichment in individual muscle proteins. AB - Stable isotope-labeled amino acids have long been used to measure the fractional synthesis rate of proteins, although the mass spectrometry platforms used for such analyses have changed throughout the years. More recently, tandem mass spectrometers such as triple quadrupoles have been accepted as the standard platform for enrichment measurement due to their sensitivity and the enhanced specificity offered by multiple reaction monitoring (MRM) experiments. The limit in the utility of such platforms for enrichment analysis occurs when measuring very low levels of enrichment from small amounts of sample, particularly proteins isolated from two-dimensional gel electrophoresis (2D-GE), where interference from contaminant ions impacts the sensitivity of the measurement. We therefore applied a high-resolution orbitrap mass spectrometer to the analysis of [ring (13)C6]-phenylalanine enrichment in individual muscle proteins isolated with 2D GE. Comparison of samples analyzed on both platforms revealed that the high resolution MS has significantly improved sensitivity relative to the triple quadrupole MS at very low-level enrichments due to its ability to resolve interferences in the m/z dimension. At higher enrichment levels, enrichment measurements from the orbitrap platform showed significant correlation (R (2) > 0.5) with those of the triple quadrupole platform. Together, these results indicate that high-resolution MS platforms such as the orbitrap are not only as capable of performing isotope enrichment measurements as the more commonly preferred triple quadrupole instruments, but offer unparalleled advantages in terms of mass accuracy and sensitivity in the presence of similar-mass contaminants. PMID- 25832483 TI - A multi-residue method for the determination of seven polypeptide drug residues in chicken muscle tissues by LC-MS/MS. AB - A new multi-residue method for the determination of seven polypeptides, namely, polymixin B1, polymixin B2, polymixin E1 (colistin A), polymixin E2 (colistin B), enduracidin A (enramycin A), enduracidin B (enramycin B), and bacitracin A, in food of animal origin was developed and validated for chicken muscle tissue. Chicken muscle tissue was extracted with acidified methanol (1 % TFA). After homogenization, shaking, and centrifugation, the acidified methanol extract was decanted. A second extraction was performed with methanol (1 % TFA) and formic acid (1 %) 25:75, v/v. The pooled extract was cleaned up and concentrated on a solid-phase extraction cartridge. The retained analytes were eluted with methanol/acetonitrile. The extract was evaporated to dryness, reconstituted in mobile phase, filtered, and quantified by LC-MS/MS under ESI conditions. The method has a LOQ of 50.0 MUg/kg for polymixin E2 (colistin B), 39.0 MUg/kg for polymixin E1 (colistin A), 74.0 MUg/kg for polymixin B1, 71.0 MUg/kg for polymixin B2, 66.0 MUg/kg for enduracidin A, 50.0 MUg/kg for enduracidin B, and 30.0 MUg/kg for bacitracin A in chicken muscle tissues. This is the first sensitive, suitable, multi-residue method reported for the seven polypeptide drug residues in chicken muscle tissue. PMID- 25832484 TI - Fabrication of Robust and Antifouling Superhydrophobic Surfaces via Surface Initiated Atom Transfer Radical Polymerization. AB - Superhydrophobic surfaces were fabricated via surface-initiated atom transfer radical polymerization of fluorinated methacrylates on poly(ethylene terephthalate) (PET) fabrics. The hydrophobicity of the PET fabric was systematically tunable by controlling the polymerization time. The obtained superhydrophobic fabrics showed excellent chemical robustness even after exposure to different chemicals, such as acid, base, salt, acetone, and toluene. Importantly, the fabrics maintained superhydrophobicity after 2500 abrasion cycles, 100 laundering cycles, and long time exposure to UV irradiation. Also, the surface of the superhydrophobic fabrics showed excellent antifouling properties. PMID- 25832485 TI - One-dimensional haemodynamic modeling and wave dynamics in the entire adult circulation. AB - One-dimensional (1D) modeling is a powerful tool for studying haemodynamics; however, a comprehensive 1D model representing the entire cardiovascular system is lacking. We present a model that accounts for wave propagation in anatomically realistic systemic (including coronary and cerebral) arterial/venous networks, pulmonary arterial/venous networks and portal veins. A lumped parameter (0D) heart model represents cardiac function via a time-varying elastance and source resistance, and accounts for mechanical interactions between heart chambers mediated via pericardial constraint, the atrioventricular septum and atrioventricular plane motion. A non-linear windkessel-like 0D model represents microvascular beds, while specialized 0D models are employed for the hepatic and coronary beds. Model-derived pressure and flow waveforms throughout the circulation are shown to reproduce the characteristic features of published human waveforms. Moreover, wave intensity profiles closely resemble available in vivo profiles. Forward and backward wave intensity is quantified and compared along major arteriovenous paths, providing insights into wave dynamics in all of the major physiological networks. Interactions between cardiac function/mechanics and vascular waves are investigated. The model will be an important resource for studying the mechanics underlying pressure/flow waveforms throughout the circulation, along with global interactions between the heart and vessels under normal and pathological conditions. PMID- 25832486 TI - Conjuring the ghosts of missing children: a Monte Carlo simulation of reproductive restraint in Tokugawa Japan. AB - This article quantifies the frequency of infanticide and abortion in one region of Japan by comparing observed fertility in a sample of 4.9 million person-years (1660-1872) with a Monte Carlo simulation of how many conceptions and births that population should have experienced. The simulation uses empirical values for the determinants of fertility from Eastern Japan itself as well as the best available studies of comparable populations. This procedure reveals that in several decades of the eighteenth century, at least 40% of pregnancies must have ended in either an induced abortion or an infanticide. In addition, the simulation results imply a rapid decline in the incidence of infanticide and abortion during the nineteenth century, when in a reverse fertility transition, this premodern family planning regime gave way to a new age of large families. PMID- 25832488 TI - Do adverse childhood experiences affect surgical weight loss outcomes? AB - Bariatric surgery is an effective and enduring treatment for obesity; however, variation in weight loss may occur following surgery. Many factors beyond technical considerations may influence postoperative outcomes. A better understanding of the influence of adverse childhood experiences (ACE) on surgical weight loss may improve preoperative care. Demographic and preoperative and postoperative data were prospectively obtained for 223 patients undergoing bariatric surgery. All cases were completed laparoscopically without serious complication. Patients completed the ACE questionnaire, which assesses childhood maltreatment. Patients had an average age of 48 years and 77 % were female. There was a significant reduction from preoperative to 12-month postoperative BMI (45 to 31 kg/m(2), p <= 0.01). The average ACE score was 2.9 and these patients were more likely than population norms to have an ACE score >=4 (35.9 vs. 12.5 %, p < 0.001). There was a positive correlation between the number of preoperative comorbidities and preoperative ACE score (R = 0.112, p = 0.09). Patients with a high ACE score (>=6) vs. patients low ACE scores had a higher postoperative BMI at 6-months (36.9 vs. 33.4 kg/m(2), p = 0.03) and 12-months postoperatively (34.5 vs. 30.5 kg/m(2), p = 0.07). High ACE patients had higher total cholesterol (191 vs. 169 mg/dL, p = 0.02) and LDL cholesterol (116 vs. 94 mg/dL, p = 0.02) than low ACE patients 12-months postoperatively. A high preoperative ACE score decreases weight loss following bariatric surgery and may warrant an increased preoperative counseling. PMID- 25832489 TI - 1,3-Bis(2,4,6-trimethylphenyl)triazenides of potassium, magnesium, calcium, and strontium. AB - Metalation of 1,3-bis(2,4,6-trimethylphenyl)triazene () with KH, Mg(nBu)2, and [(L)2Ae{N(SiMe3)2}2] (Ae/L = Ca/thf, Sr/dme) yields the dinuclear complexes [(thf)2K{MU-N3(Mes)2}]2 () and [(dme)K{MU-N3(Mes)2}]2 () as well as mononuclear [(thf)2Mg{N3(Mes)2}2] (), [(tmeda)Mg(nBu){N3(Mes)2}] (), [(thf)2Ca{N3(Mes)2}2] (), and [(tmeda)Sr{N3(Mes)2}2] (), respectively, with high yields depending on applied stoichiometry and donor solvent [tetrahydrofuran (THF), 1,2 dimethoxyethane (DME), 1,2-bis(dimethylamino)ethane (TMEDA)]. The 1,3-bis(2,4,6 trimethylphenyl)triazene () forms a strand-like structure in the solid state, stabilized by N-HN hydrogen bridges and intermolecular pi-stacking of the mesityl groups. The 1,3-bis(2,4,6-trimethylphenyl)triazenide anions of the s-block metal complexes show charge delocalization within the triazaallylic systems and act as bidentate chelate ligands. PMID- 25832490 TI - Low-level mercury, omega-3 index and neurobehavioral outcomes in an adult US coastal population. AB - BACKGROUND: Neurodevelopmental effects of omega-3 fatty acids and mercury from fish consumption have been characterized in children. In contrast, neurobehavioral outcomes associated with fish are not well studied in adults. OBJECTIVE: This study of avid seafood consumers on Long Island (NY, USA) sought to define associations between mercury, seafood consumption, omega-3 fatty acids and neurobehavioral outcomes. METHODS: A computer-based test system was used to assess neurobehavioral function. Blood total Hg (Hg) and omega-3 index were measured in 199 adult avid seafood eaters, who also completed the neurobehavioral assessment and an extensive food and fish frequency and demographic questionnaire. RESULTS: For most of the outcomes considered, neither Hg nor omega 3 index was associated with neurobehavioral outcomes after adjustment for key confounding variables. Fish consumption, however, was associated with decreased odds of both self-reported fatigue (OR 0.85; 95 % CI 0.72, 1.01) and a constellation of neurologic symptoms (OR 0.79; 95 % CI 0.66, 0.96). CONCLUSIONS: Results from our study provide little evidence that omega-3 fatty acids or Hg is associated with cognitive function in adult avid seafood consumers. Larger studies are needed to confirm our finding of associations between fish consumption and decreased self-reported fatigue and neurologic impairment. PMID- 25832491 TI - Patterns of dietary habits in relation to obesity in Iranian adults. AB - PURPOSE: Findings from few studies that investigated the relation between dietary behaviors and obesity are inconsistent. We aimed to assess the relation between patterns of dietary habits, identified by latent class analysis (LCA), and obesity in a large sample of Iranian adults. METHODS: In a cross-sectional study on 7958 adults, dietary behaviors were assessed in five domains (meal patterns, eating rate, intra-meal fluid intake, meal-to-sleep interval, and fatty foods intake) using a pretested questionnaire. LCA was applied to identify classes of diet-related practices. Anthropometric measures were assessed through the use of a validated self-reported questionnaire. General and abdominal obesity were defined as a body mass index >= 30 kg/m(2), and a waist circumference >= 88 cm for women and >= 102 cm for men. RESULTS: General and abdominal obesity were prevalent in 9.7 and 27.7 % of the study population, respectively. We identified three distinct classes of eating rates (moderate, moderate to slow, and moderate to fast), two classes of meal patterns (regular and irregular), two classes of intra-meal fluid intake (moderate and more intra-meal drinking), three classes of meal-to-sleep interval (short, moderate, and long meal-to-sleep interval), and three classes of fatty food intake (low to moderate, moderate to high, and low intake of fatty foods). After adjustment for potential confounders, individuals with 'irregular meal pattern' were 21, 24, and 22 % more likely to be overweight/obese, abdominally overweight/obese, and abdominally obese, compared with those who had a 'regular meal pattern.' Individuals with 'more intra-meal drinking' had greater odds of overweight (OR 1.37; 1.19-1.458) and obesity (OR 1.51; 1.16-1.97) than those with 'moderate intra-meal drinking.' Moderate-to-high intake of fatty foods was inversely associated with abdominally overweight/obese (OR 0.85; 0.73-1.00) and abdominally obesity (OR 0.80; 0.68-0.96) compared with 'low-to-moderate intake of fatty foods.' No significant association was observed between eating rate, meal-to-sleep interval, and general or abdominal obesity, after controlling for confounders. CONCLUSION: Irregular meal pattern and more intra-meal drinking were associated with increased odds of general and abdominal obesity, whereas moderate-to-high intake of fatty foods was related to the decreased odds of central obesity among Iranian adults. PMID- 25832492 TI - Aspirin 'resistance': impact on no-reflow, platelet and inflammatory biomarkers in diabetics after ST-segment elevation myocardial infarction. AB - BACKGROUND: The no-reflow (NR) phenomenon exists despite percutaneous coronary intervention (PCI), and is especially prevalent in diabetics. The causes(s) of NR are not fully elucidated, but may be associated with impaired residual platelet and inflammatory reactivity during dual-antiplatelet therapy. OBJECTIVE: To assess the relationship between dual-antiplatelet therapy, NR and conventional biomarkers suggestive of platelet and inflammatory response in diabetics following ST-segment elevation myocardial infarction (STEMI) treated with PCI. METHODS: Sixty diabetics with (n = 27) and without NR (n = 33) were prospectively enrolled. All patients were treated with clopidogrel and aspirin. Platelet and inflammatory biomarkers were assessed serially in the peripheral blood and right atrium before and after PCI and then at 24 h, 7 days and 30 days. RESULTS: Arachidonic acid (AA)-induced platelet aggregation and the serum thromboxane B2 level before and after PCI (in the peripheral and right atrium blood) were significantly higher in the NR patients than in those with no NR. AA-induced aggregation >100 (AUC*min) before PCI predicted NR in diabetic patients with 96.2% sensitivity and 38.5% specificity (AUC 0.66; 95% CI 0.52-0.71; p = 0.029). There were no other correlations between NR and platelet reactivity (collagen, adenosine diphosphate, thrombin receptor agonist peptide-induced aggregation, vasodilator-stimulated phosphoprotein platelet reactivity index, soluble P selectin, soluble CD40 ligand, platelet-derived growth factor AB and the level of platelet-monocyte aggregates) or between NR and inflammatory indices (i.e. high sensitivity C-reactive protein, interleukin 6 and interleukin 10). CONCLUSION: An inadequate response to aspirin, but not to clopidogrel, may be associated with the occurrence of the NR phenomenon in diabetics with STEMI who have been treated with primary PCI. PMID- 25832493 TI - Trace element landscape of resting and activated human neutrophils on the sub micrometer level. AB - Every infection is a battle for trace elements. Neutrophils migrate first to the infection site and accumulate quickly to high numbers. They fight pathogens by phagocytosis and intracellular toxication. Additionally, neutrophils form neutrophil extracellular traps (NETs) to inhibit extracellular microbes. Yet, neutrophil trace element characteristics are largely unexplored. We investigated unstimulated and phorbol myristate acetate-stimulated neutrophils using synchrotron radiation X-ray fluorescence (SR-XRF) on the sub-micron spatial resolution level. PMA activates pinocytosis, cytoskeletal rearrangements and the release of NETs, all mechanisms deployed by neutrophils to combat infection. By analyzing Zn, Fe, Cu, Mn, P, S, and Ca, not only the nucleus but also vesicular granules were identifiable in the elemental maps. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) revealed a neutrophil-specific composition of Zn, Fe, Cu, and Mn in comparison with J774 and HeLa cells, indicating a neutrophil-specific metallome complying with their designated functions. When investigating PMA activated neutrophils, the SR-XRF analysis depicted typical subcellular morphological changes: the transformation of nucleus and granules and the emergence of void vacuoles. Mature NETs were evenly composed of Fe, P, S, and Ca with occasional hot spots containing Zn, Fe, and Ca. An ICP-MS-based quantification of NET supernatants revealed a NETosis-induced decrease of soluble Zn, whereas Fe, Cu, and Mn concentrations were only slightly affected. In summary, we present a combination of SR-XRF and ICP-MS as a powerful tool to analyze trace elements in human neutrophils. The approach will be applicable and valuable to numerous aspects of nutritional immunity. PMID- 25832494 TI - Efficient bulk heterojunction solar cells based on solution processed small molecules based on the same benzo[1,2-b:4, 5-b']thiophene unit as core donor and different terminal units. AB - We report the synthesis, characterization, and optical and electrochemical of properties of two novel molecules DRT3-BDT (1) and DTT3-BDT (2), comprising the same BDT central core (donor) and different end capped acceptor units, i.e. rhodanine with ethyl hexyl and thiazolidione with ethylhexyl, respectively, linked via an alkyl-substituted terthiophene (3 T) pi-conjugation bridge. The electrochemical properties of these small molecules indicate that their energy levels are compatible with energy levels of PC71BM for efficient exciton dissociation. These molecules have been used as electron donors along with PC71BM as an electron acceptor, for the fabrication of solution processed "small molecule" bulk heterojunction (BHJ) solar cells (smOPV). The device prepared from optimized 1:PC71BM(1:1) processed cast from DIO (3%v)/CF solvent exhibited a power conversion efficiency of 6.76% with Jsc = 11.92 mA cm(-2), Voc = 0.90 and FF = 0.63. The device with 2:PC71BM under the same conditions showed a lower PCE of 5.25% with Jsc = 10.52 mA cm(-2), Voc = 0.86 and FF = 0.56. The AFM, TEM and PL quenching measurements revealed that the high Jsc is a result of the appropriate morphology and exciton dissociation. The performances were compared for the devices based on two small molecules. The higher Jsc for device 1 was attributed to its better nanoscale phase separation, smooth surface and higher carrier mobility in the 1:PC71BM blend film. Moreover, the higher value of FF for the 1:PC71BM based device was ascribed to a good balance between the electron and hole mobilities. PMID- 25832495 TI - Malignant cause of ventriculoperitoneal shunt 'pseudocyst': a case report. AB - Abdominal pseudocysts are an uncommon complication of ventriculoperitoneal (VP) shunts. We present the case of a 4-year-old boy with a history of complicated hydrocephalus managed with a VP shunt due to sequelae of prematurity. The patient presented with abdominal distention, and a pseudocyst was diagnosed. Despite shunt externalization and aspiration, the pseudocyst continued to produce up to 1 liter of serosanguineous fluid per day. After MRI revealed malignant features within the pseudocyst, laparotomy was performed and the pseudocyst was partially excised. Pathology reports suggested sarcoma. The cystic mass grew back aggressively, accompanied by distant metastasis. The patient's condition deteriorated and he died from his disease. To our knowledge, this represents the first report of an abdominal malignancy mimicking a pseudocyst and causing VP shunt failure. PMID- 25832496 TI - The cardioprotective role of pentraxin 3. PMID- 25832497 TI - Association between Peroxisome Proliferator-activated Receptor Gamma Gene Polymorphisms and Atherosclerotic Diseases: A Meta-analysis of Case-control Studies. AB - AIM: The aim of this study was to perform a meta-analysis to investigate the association between PPARgamma rs1801282/rs3856806 polymorphisms and atherosclerotic diseases. METHODS: The meta-analysis was performed by searching the PubMed, Embase and Web of Science databases from the first available year to September 10, 2013. Additionally, reference lists from the identified articles, reviews and abstracts presented at the meetings of related scientific societies were also checked. All case-control studies investigating the association between PPARgamma rs1801282/rs3856806 polymorphisms and the risk of atherosclerotic disease were included. The association was assessed according to the odds ratio (OR) with a 95% confidence interval (CI). Publication bias was analyzed using Begg's funnel plot and Egger's regression test. RESULTS: A total of 29 studies reporting PPARgamma rs1801282/rs3856806 polymorphism were included in the final meta-analysis. Neither the rs1801282 (Pro12Ala) nor rs3856806 (C161T) polymorphisms showed any significant associations with susceptibility to atherosclerotic diseases. In the meta-analysis performed to assess the association between the rs3856806 gene polymorphism and atherosclerotic disease based on ethnicity and the type of disease, significant associations were found in the Caucasian subgroup, Asian, CAD and MI subgroups. CONCLUSIONS: The present data suggest that there is no statistical evidence of a significant association between the PPARgamma gene rs1801282/rs3856806 polymorphism and the risk of atherosclerotic disease. In contrast, the rs3856806 polymorphism was associated with an increased risk in the Caucasian and MI subgroups, whereas decreased risks were noted in the Asian and CAD subgroups. Due to significant between-study heterogeneity, further studies with a larger sample size involving homogeneous AS patients and well-matched controls are required in the future. PMID- 25832498 TI - Association between SLCO1B1 521 T>C and 388 A>G Polymorphisms and Statins Effectiveness: A Meta-Analysis. AB - AIM: Previous studies on the association between the SLCO1B1 521 T>C and 388 A>G polymorphisms and statin effectiveness have been inconsistent. We performed this meta-analysis to provide a more comprehensive estimation of this issue. METHODS: Multiple electronic literatues databases were searched on March 5th 2014. A quality assessment was performed using the Methodological Index for Non Randomized Studies (MINORS) criteria. A meta-analysis, sub-group analysis, sensitivity analysis (RevMan 5.2), publication bias measuring and meta-regression analysis were conducted utilizing the Stata software program (version 12.0). RESULTS: A total of 13 studies were included in the final meta-analysis, which included 7,079 participants. Overall, there was no statistically significant association in the four genetic models of hypolipidemic effect. For the 521 T>C polymorphism, significant associations were found for the long-term effectiveness of lowering the low-density lipoprotein cholesterol (LDL-C) and in non-Asian populations in the dominant model [(CC+TC vs. TT: mean difference (MD)=1.44, 95% CI: 0.25-2.64,p=0.02) and (CC+TC vs. TT: MD=1.38, 95% CI: 0.28-2.49, p=0.01)], the recessive model [(CC vs. TT+TC: MD=3.31, 95% CI: 0.09-6.54, p=0.04) and (CC vs. TT+TC: MD=2.83, 95% CI: 0.26-5.41, p=0.03)], and the homozygote comparison [(CC vs. TT: MD=3.68, 95% CI: 0.42-6.94,p=0.03) and (CC vs. TT: MD=3.33, 95% CI: 0.67-5.99, p=0.01)], respectively. There were no significant differences for the other analyses of the 521 T>C polymorphism or all the analyses of the 388 A>G polymorphism. CONCLUSIONS: The overall results suggest that the SLCO1B1 521 T>C and 388 A>G polymorphisms do not affect the lipid-lowering effectiveness of statins. However, allele C of the SLCO1B1 521 T>C polymorphism leads to an attenuated effect on lowering the LDL-C in non-Asian populations and the long term effectiveness of statin treatment. PMID- 25832499 TI - ACE Insertion/Deletion Polymorphism and Cardiovascular Effect of Hypercholesterolemia. PMID- 25832500 TI - Identification and Assessment of Octreotide Acylation in Polyester Microspheres by LC-MS/MS. AB - PURPOSE: Polyesters with hydrophilic domains, i.e., poly(D,L-lactic-co-glycolic co-hydroxymethyl glycolic acid) (PLGHMGA) and a multiblock copolymer of poly(epsilon-caprolactone)-PEG-poly(epsilon-caprolactone) and poly(L-lactide) ((PC-PEG-PC)-(PL)) are expected to cause less acylation of encapsulated peptides than fully hydrophobic matrices. Our purpose is to assess the extent and sites of acylation of octreotide loaded in microspheres using tandem mass spectrometry analysis. METHODS: Octreotide loaded microspheres were prepared by a double emulsion solvent evaporation technique. Release profiles of octreotide from hydrophilic microspheres were compared with that of PLGA microspheres. To scrutinize the structural information and localize the actual modification site(s) of octreotide, liquid chromatography ion-trap mass spectrometry (LC-ITMS) was performed on the acylated adducts. RESULTS: Hydrophilic microspheres showed less acylated adducts in comparison with PLGA microspheres. LC-MS/MS showed that besides the N-terminus and primary amine of lysine, the primary hydroxyl of the end group of octreotide was also subjected to acylation. Nucleophilic attack of the peptide can also occur to the carbamate bond presented in (PC-PEG-PC)-(PL) since 1,4-butanediisocyanate was used as the chain extender. CONCLUSIONS: Hydrophilic polyesters are promising systems for controlled release of peptide because substantially less acylation occurs in microspheres based on these polymers. LC-ITMS provided detailed structural information of octreotide modifications via mass analysis of ion fragments. PMID- 25832501 TI - Intermolecular Interactions and the Viscosity of Highly Concentrated Monoclonal Antibody Solutions. AB - PURPOSE: The large increase in viscosity of highly concentrated monoclonal antibody solutions can be challenging for downstream processing, drug formulation, and delivery steps. The objective of this work was to examine the viscosity of highly concentrated solutions of a high purity IgG1 monoclonal antibody over a wide range of protein concentrations, solution pH, ionic strength, and in the presence / absence of different excipients. METHODS: Experiments were performed with an IgG1 monoclonal antibody provided by Amgen. The steady-state viscosity was evaluated using a Rheometrics strain-controlled rotational rheometer with a concentric cylinder geometry. RESULTS: The viscosity data were well-described by the Mooney equation. The data were analyzed in terms of the antibody virial coefficients obtained from osmotic pressure data evaluated under the same conditions. The viscosity coefficient in the absence of excipients was well correlated with the third osmotic virial coefficient, which has a negative value (corresponding to short range attractive interactions) at the pH and ionic strength examined in this work. CONCLUSIONS: These results provide important insights into the effects of intermolecular protein-protein interactions on the behavior of highly concentrated antibody solutions. PMID- 25832502 TI - View of excellent ROAD from the CAR. PMID- 25832503 TI - Three-fold rotational defects in two-dimensional transition metal dichalcogenides. AB - As defects frequently govern the properties of crystalline solids, the precise microscopic knowledge of defect atomic structure is of fundamental importance. We report a new class of point defects in single-layer transition metal dichalcogenides that can be created through 60 degrees rotations of metal chalcogen bonds in the trigonal prismatic lattice, with the simplest among them being a three-fold symmetric trefoil-like defect. The defects, which are inherently related to the crystal symmetry of transition metal dichalcogenides, can expand through sequential bond rotations, as evident from in situ scanning transmission electron microscopy experiments, and eventually form larger linear defects consisting of aligned 8-5-5-8 membered rings. First-principles calculations provide insights into the evolution of rotational defects and show that they give rise to p-type doping and local magnetic moments, but weakly affect mechanical characteristics of transition metal dichalcogenides. Thus, controllable introduction of rotational defects can be used to engineer the properties of these materials. PMID- 25832505 TI - Cognitive behavioral therapy for obsessive-compulsive disorder secondary to second-generation antipsychotics. PMID- 25832506 TI - A chemically triggered and thermally switched dielectric constant transition in a metal cyanide based crystal. AB - A dielectric constant transition is chemically triggered and thermally switched in (HPy)2[Na(H2O)Co(CN)6] (2, HPy=pyridinium cation) by single-crystal-to-single crystal transformation and structural phase transition, respectively. Upon dehydration, (HPy)2[Na(H2O)2Co(CN)6] (1) transforms to its semi-hydrated form 2, accompanying a transition from a low-dielectric state to a high-dielectric state, and vice versa. This dielectric switch is also realized by a structural phase transition in 2 that occurs between room- and low-temperature phases, and which corresponds to high- and low-dielectric states, respectively. The switching property is due to the variation in the environment surrounding the HPy cation, that is, the hydrogen-bonding interactions and the crystal packing, which exert predominant influences on the dynamics of the cations that transit between the static and motional states. PMID- 25832504 TI - Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells. AB - The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2 dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours. PMID- 25832507 TI - Major publisher retracts 43 papers, alleging fake peer review. PMID- 25832508 TI - A rural, community-based suicide awareness and intervention program. AB - Suicide is a prominent public health issue in rural Australia and specifically in Tasmania, which has one of the highest suicide rates in the country. The Community Response to Eliminating Suicide (CORES) program was developed in rural Tasmania in response to a significant number of suicides over a short period of time. CORES is unique in that it is both a community-based and gatekeeper education model. CORES aims to build and empower communities to take ownership of suicide prevention strategies. It also aims to increase the individual community member's interpersonal skills and awareness of suicide risks, while building peer support and awareness of suicide prevention support services within the community itself. Pre- and post-test surveys after the CORES 1-day suicide awareness and intervention program (SAIP) showed significant increases in levels of comfort and confidence in discussing suicide with those who may be contemplating that action. CORES builds community capital through establishing new connections within communities. Establishment of local executive groups, funding and SAIP are key activities of successful CORES programs in communities around Australia. Over half of the initial leaders are still actively involved after a decade, which reflects positively on the quality and outcomes of the program. This study supports CORES as a beneficial and feasible community-based suicide intervention program for rural communities. PMID- 25832509 TI - Psychosomatic medicine in the 21st century: understanding mechanisms and barriers to utilization. AB - The psychosomatic approach arose in antiquity as mankind looked for explanations for illness and death. With the rise of modern medicine, the links between emotions and medical conditions, such as cardiac disease and diabetes, were described by astute clinical observers, but the mechanisms for these conditions were based on correlation from observations rather than on experimental design. Psychoanalytic theory was often utilized to explain many common diseases. For example, peptic ulcer disease was blamed upon anger and stress, but scientific methodology discovered Helicobacter pylori to be the significant causal factor of this disease and resulted in the development of more effective treatments. Nevertheless emotional factors are still linked to disease states and morbidity; for example, depression is a risk factor for mortality following myocardial infarction. Advances in neuroscience demonstrate that the reduction of telomere length by anxiety and stress leads to more rapid aging and potential disease vulnerability. Thus, neuroscientific probes may allow for the elucidation of psychosomatic mechanisms. Sadly, clinical barriers, in terms of time pressure upon physicians and the current separation of mental health services from primary care settings, continue the dualistic treatment of many conditions where psychological factors are important. It is not clear whether a mandate for the integration of behavioral health into primary care will remedy this partition and finally maximize a psychosomatic approach to medical care. PMID- 25832510 TI - Communication with patients suffering from serious physical illness. AB - Communication is the corner stone of the relationship with the patient in all medical settings with the main aims of creating a good inter-personal relationship, exchanging information, and making treatment-related decisions. In a rapidly changing cultural and social context, the paternalistic approach of doctors knowing the best and deciding what should be done for a patient has been replaced by a shared decision-making approach, with patients being advised to educate themselves, ask questions and influence the course of the discussion with their doctors. Thus, a need for an improvement in the communication skills of physicians is extremely important for patients affected by serious physical illness (e.g. cancer, HIV infection, multiple sclerosis, amyotrophic lateral sclerosis). Certain attitudes, behaviour and skills (e.g. capacity to impart confidence, being empathetic, providing a 'human touch', relating on a personal level, being forthright, being respectful, and being thorough) are part of effective communication. However, some specific aspects influencing doctor patient communication and relationships, such as personality variables, coping and attachment styles, as well as cultural factors, should also be taken in to account. The development of training curricula to help doctors acquire proper skills in communication is mandatory, since research has shown that training in communication may facilitate the effectiveness of a doctor-patient relationship and the patient's satisfaction with care and give a general sense of humanity, which is easily lost in a biotechnologically oriented medicine. PMID- 25832511 TI - Dimensional psychopharmacology in somatising patients. AB - Despite the recent DSM-5 review of somatoform disorders, which are now called somatic symptom and related disorders, the categorical definitions of these syndromes have inherent limitations because their causal mechanism or presumed aetiologies are still unknown. These limitations may affect everyday clinical practice and decision-making abilities. As a result, physicians have limited information at their disposal to treat these patients. Furthermore, the clinical presentations of somatic disorders may vary a lot. The purpose of this chapter is to illustrate a psychopathological dimensional approach to the somatising patient. This approach is constantly unconsciously applied in clinical practice using continuous variables, such as rating scales. Moreover, treatment strategies might be improved by adding a dimensional approach, simply recognising the prominent components of the presenting psychopathology of a given patient and addressing them with drugs according to their different mechanisms, targeting circuits and neurotransmitters. Some authors have proposed a shift from the nosological to functional application of psychotropic drugs, in which functional psychopharmacology will be dysfunction oriented and therefore inevitably geared towards utilising drug combinations. Here, we present a summary of the advantages of functional/dimensional psychopharmacology for the treatment of somatic symptoms and related disorders. PMID- 25832512 TI - Forensic issues in medical evaluation: competency and end-of-life issues. AB - Decision-making capacity is a common reason for psychiatric consultation that is likely to become more common as the population ages. Capacity assessments are frequently compromised by misconceptions, such as the belief that incapacity is permanent or that patients with dementia categorically lack capacity. This chapter will review the conceptual framework of decision-making capacity and discuss its application to medical decision-making. We will review selected developments in capacity assessment and recommend an approach to assessing decision-making capacity. We will discuss the unique challenges posed by end-of life care, including determining capacity, identifying surrogate decision-makers, and working with surrogate decision-makers. We will discuss clinical and legal approaches to incapacity, including advance directives, surrogate decision makers, and guardians. We will discuss the legal standards based on which surrogates make medical decisions and outline options for resolving disagreements between clinical staff and surrogate decision-makers. We will offer recommendations for approaching decision-making capacity assessments. PMID- 25832513 TI - Then and now ... HIV consultation psychiatry update. AB - Over the last 2 decades, human immunodeficiency virus (HIV) illness has transformed to a chronic disease model. However, challenges, including the effects of co-morbid illnesses and the challenge of preventing future spread of the disease, continue to confront those infected with HIV. Addictions remain an important problem and a serious contributor to overall morbidity and mortality in this population. This book chapter seeks to illustrate the new developments in the treatment of these addictions as well as provide an overview of the medical updates regarding HIV and hepatitis C virus exposure prophylaxis and how they relate to the consultant psychiatrist. PMID- 25832514 TI - Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues. AB - There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined. Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM. Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems' abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified. PMID- 25832515 TI - Fibromyalgia and chronic fatigue syndrome: management issues. AB - Fibromyalgia and chronic fatigue syndrome represent two of the most commonly encountered functional somatic syndromes in clinical practice. Both have been contentious diagnoses in the past, and this diagnostic dispute has resulted in a therapeutic nihilism that has been of great detriment to their management and to alleviation of the intense suffering and disability that they have caused their innumerable sufferers. A new age has dawned in terms of a better understanding of these syndromes' physiology and improved approaches to their management. Here, the diagnosis and management of these closely related disorders are discussed, with particular reference to the recent empirical evidence that has come to light as a consequence of neurophysiological insights and robustly designed randomised clinical trials. Much work remains to be done in this vein, but we are better placed to facilitate recovery from these disorders than we have been previously. Whilst remission should always be a goal, complete symptom resolution is not the norm, but 'moderate' improvements are certainly attainable with appropriate management. PMID- 25832517 TI - Coping with losses, grief, and mourning in prostate cancer. AB - Prostate cancer is a highly prevalent disease with a high likelihood of survival. If treated, survivors live with significant and lasting treatment-related side effects. Surgical treatment is associated with urinary incontinence and erectile dysfunction, and radiation leads to urinary and bowel irritability as well as erectile dysfunction. Patients who undergo hormonal treatment cope with sexual dysfunction, bone density loss, hot flashes, mood symptoms, and cardiac and metabolic disorders. Functional losses have a significant impact on patients and their partners' quality of life and are associated with distress and psychosocial morbidity. Psychosocial treatment is largely unavailable in usual care, but has been shown to reduce distress, to increase positive reappraisal of the illness, and to contribute to the recovery of sexual intimacy. Treatment for grief and mourning, typical reactions to loss, has not been introduced into psychosocial interventions but is increasingly recognized as a path toward a 'new normal' after prostate cancer treatment. PMID- 25832518 TI - Psychodermatology. AB - Psychodermatology is an underappreciated field that studies psychocutaneous disorders, which are conditions that have both dermatologic and psychiatric characteristics. Underlying psychiatric comorbidity is estimated to occur in up to one-third of dermatologic patients, and psychiatric illness may either be the cause or the consequence of dermatologic disease. Psychodermatologic patients lack insight and often do not recognize a psychiatric etiology for their symptoms and therefore comprise some of the most challenging cases to treat. Herein, we discuss the background and clinical presentation of the most commonly encountered psychodermatologic conditions, including delusional infestation, neurotic excoriations, factitial dermatitis, trichotillomania and body dysmorphic disorder, followed by practical diagnostic and therapeutic recommendations. PMID- 25832519 TI - Huntington's disease: looking beyond the movement disorder. AB - Although Huntington's disease is classically considered a motor disease, psychiatric, behavioral, and cognitive symptoms are often presenting signs of illness. Even in isolation, these comorbidities can lead to impairment in function and significant distress for patients and their families. Intended for treating psychiatrists, this review discusses the clinical presentation and treatment of Huntington's disease. PMID- 25832516 TI - Telomeres, early-life stress and mental illness. AB - Telomeres are structures of tandem TTAGGG repeats that are found at the ends of chromosomes and preserve genomic DNA by serving as a disposable buffer to protect DNA termini during chromosome replication. In this process, the telomere itself shortens with each cell division and can consequently be thought of as a cellular 'clock', reflecting the age of a cell and the time until senescence. Telomere shortening and changes in the levels of telomerase, the enzyme that maintains telomeres, occur in the context of certain somatic diseases and in response to selected physical stressors. Emerging evidence indicates that telomeres shorten with exposure to psychosocial stress (including early-life stress) and perhaps in association with some psychiatric disorders. These discoveries suggest that telomere shortening might be a useful biomarker for the overall stress response of an organism to various pathogenic conditions. In this regard, telomeres and their response to both somatic and psychiatric illness could serve as a unifying stress-response biomarker that crosses the brain/body distinction that is often made in medicine. Prospective studies will help to clarify whether this biomarker has broad utility in psychiatry and medicine for the evaluation of responses to psychosocial stressors. The possibility that telomere shortening can be slowed or reversed by psychiatric and psychosocial interventions could represent an opportunity for developing novel preventative and therapeutic approaches. PMID- 25832520 TI - Joint hypermobility, anxiety and psychosomatics: two and a half decades of progress toward a new phenotype. AB - The strong association between a heritable collagen condition and anxiety was an unexpected finding that we first described in 1988 at the Hospital del Mar in Barcelona. Since then, several clinical and nonclinical studies have been carried out. In this paper, after summarizing the concept and diagnosis of joint hypermobility (hyperlaxity), we review case-control studies in both directions (anxiety in joint hypermobility and joint hypermobility in anxiety disorders) as well as studies on nonclinical samples, review papers and one incidence study. The collected evidence tends to confirm the strength of the association described two and a half decades ago. The common mechanisms that are involved in this association include genetics, autonomic nervous system dysfunctions and interoceptive and exteroceptive processes. Considering clinical and nonclinical data, pathophysiological mechanisms and the presented nosological status, we suggest a new Neuroconnective phenotype, which around a common core Anxiety Collagen hyperlaxity, includes five dimensions: behavioral, psychopathology, somatic symptoms, somatosensory symptoms, and somatic illnesses. It is envisaged that new descriptions of anxiety disorders and of some psychosomatic conditions will emerge and that different nosological approaches will be required. The Neuroconnective model is a proposal that is under study and may be useful for clinical practice. PMID- 25832522 TI - Efficacy of Heroin-assisted Treatment In Belgium: A Randomised Controlled Trial. AB - BACKGROUND/AIMS: Heroin-assisted treatment (HAT) can improve the condition of heroin addicts still using street heroin after a methadone treatment. In Belgium, a new trial compared the efficacy of a HAT to existing methadone maintenance treatment. METHODS: In this randomised controlled trial, HAT was limited to 12 months. Participants were assessed every 3 months. They were responders if they showed improvement on the level of street heroin use, health or criminal involvement. RESULTS: 74 participants were randomised in the trial. The experimental group (n = 36) counted 30% of responders more than the control group (n = 38) at each assessment point (p < 0.05), except at 12 months where the difference (11%) was no longer significant (p = 0.35). Still, after 12 months, participants in the experimental group reported significantly greater improvements (p < 0.05) than the control group on the level of street heroin use and on the level of physical and mental health. Both groups reported significantly less criminal acts after 12 months (p < 0.001), but with no significant difference between the groups. CONCLUSIONS: This trial confirms the short-term efficacy of HAT for severe heroin addicts, who already failed methadone treatment. PMID- 25832523 TI - Gaining insight into soybean defense responses using functional genomics approaches. AB - Soybean pathogens significantly impact yield, resulting in over $4 billion dollars in lost revenue annually in the United States. Despite the deployment of improved soybean cultivars, pathogens continue to evolve to evade plant defense responses. Thus, there is an urgent need to identify and characterize gene networks controlling defense responses to harmful pathogens. In this review, we focus on major advances that have been made in identifying the genes and gene networks regulating defense responses with an emphasis on soybean-pathogen interactions that have been amenable to gene function analyses using gene silencing technologies. Further we describe new research striving to identify genes involved in durable broad-spectrum resistance. Finally, we consider future prospects for functional genomic studies in soybean and demonstrate that understanding soybean disease and stress tolerance will be expedited at an unprecedented pace. PMID- 25832524 TI - [Effect of premolar extractions on third molar angulation changes: a meta analysis]. AB - OBJECTIVE: To assess the effect of premolar extractions on third molar angulation changes in orthodontic patients. METHODS: The Cochrane library, PubMed, Embase, China Science and Technology Periodical Database, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM) and Wanfang database were searched from January 1, 1990 to May 20, 2014 to identify all the studies about third molar angulation changes in orthodontic patients with or without premolars extraction, which was assigned as a extraction group and a control group. Th e extraction group was further divided into a fi rst premolar extraction subgroup and a second premolar extraction subgroup. Literature filtering, data extraction and methodological quality evaluation were finished independently by two researchers. After cross checking, the disagreements were solved by discussion. Meta-analysis was carried out by RevMan 5.3.3 software. RESULTS: Ten studies involving 712 patients were included. Meta-analysis revealed that: compared with the control group, the changes of third molar angulation in maxillary and mandible in the extraction group were statistically significantly different (all P<0.05); the difference in angulation between the two groups was about 5.19 degrees in maxillary and 3.55 degrees in mandibul. As for the premolar extraction subgroups, there was no significant difference in mandibular third molar angulation between them (P>0.05). CONCLUSION: The orthodontic treatment involving first or second premolar extractions can improve the maxillary third molar angulation, and the second premolar extraction is the best option. PMID- 25832525 TI - [Association of D2 dopamine receptor gene -141C Ins/Del polymorphisms with heroin dependence in Chinese Han population: a meta-analysis]. AB - OBJECTIVE: To evaluate the association between D2 dopamine receptor gene -141C Ins/Del polymorphism and heroin dependence in Chinese Han population. METHODS: Chinese and foreign databases were searched for relevant articles published from the establishment of database to March 2014. Case-control studies on D2 dopamine receptor gene -141C Ins/Del polymorphism with heroin dependence in Chinese Han population were gathered with Meta-analysis by Stata 12.0 software after data abstraction. RESULTS: Seven case-control studies on association between D2 dopamine receptor gene -141C Ins/ Del polymorphism and heroin dependence were included, which covered 3 211 heroin dependence patients and 1 979 controls. Meta analysis results showed that the pooled odds ratio (OR), the 95% confidence interval (CI) and P value after combining genotypes were as follows: Ins/Ins vs Del/Del: OR=0.51, 95% CI: 0.27-0.96, P=0.017; Ins/Ins vs Ins/Del+Del/Del: OR=0.82, 95% CI: 0.72-0.94, P=0.448; Ins/Ins+ Ins/Del vs Del/Del: OR=0.53, 95% CI: 0.28-0.98, P=0.019; Ins/Del vs Del/Del: OR=0.59, 95% CI: 0.32-1.07, P=0.045; Ins vs Del: OR=0.79, 95% CI: 0.71-0.89, P=0.101). CONCLUSION: D2 dopamine receptor gene -141C Ins/Del polymorphism is associated with heroin dependence in Chinese Han population, and Chinese Han population with Ins allele gene deletion are at lower risk of heroin dependence. PMID- 25832526 TI - [Risk factors for schizophrenia patients with type 2 diabetes: a metaanalysis]. AB - OBJECTIVE: To investigate risk factors for schizophrenia patients with complication of type 2 diabetes mellitus and to provide scientific evidence for prevention and management of this disease. METHODS: Relevant studies on schizophrenia with type 2 diabetes mellitus in China were searched through PubMed, Medline, CBM, CNKI and VIP from 1997 to 2014. Meta-analysis was performed using RevMan 5.2 soft ware. RESULTS: A total of 26 studies involving 6 373 participants (including 957 cases and 5 416 controls) were included. The results of Meta-analysis showed that the risk factors for schizophrenic patients with complication of type 2 diabetes mellitus were: gender (female) (OR=1.28, 95%CI: 1.09-1.50), age (>= 40 year) (OR=6.02, 95%CI: 4.48-8.09), overweight (OR=2.32, 95%CI: 1.52-2.88), family history of diabetes (OR=6.12, 95%CI: 3.16-11.86), duration of schizophrenia (>10 years) (OR=3.60, 95%CI: 2.39-5.41), triglycerides (MD=0.38, 95%CI: 0.05-0.71). CONCLUSION: Male, old age, overweight, family history of diabetes, longer duration and high level of triglycerides are risk factors for schizophrenic patients with complication of diabetes mellitus. PMID- 25832527 TI - [Expression of RASAL2 in hepatocellular carcinoma and the clinical significance]. AB - OBJECTIVE: To detect the expression of RA SAL2 in patients with hepatocellular carcinoma (HCC), and to investigate the association of RASAL2 expression with pathological characteristics and prognosis. METHODS: Immunohistochemical SP method was used to detect the expression of RA SAL2 in 164 samples of HCC tissue and the adjacent tissue. Th e association of RA SAL2 expression with clinical features and prognosis was analyzed. RESULTS: The expression of RASAL2 in adjacent tissue was significantly increased compared to that in HCC tissue (P<0.001). The expression level of RASAL2 was associated with the degree of differentiation, tumor TNM stage and vascular invasion (P<0.001), but not associated with the level of AFP, tumor size, or the number of nodules (P>0.05). The 5 years recurrence-free survival (RFS) in patients with low expression of RASLA2 was significantly reduced compared with that in patients with high expression of RASLA2 (P<0.001). Cox analysis showed that low expression of RASLA2 was the independent factor for recurrence and death in HCC patients after surgery (P<0.001). CONCLUSION: Low expression of RRASAL2 is significantly associated with the poor prognosis of HCC, which is an independent factor for HCC prognosis. PMID- 25832528 TI - [Expressions of ASPP2, iASPP and p53 in cervical cancinoma and the significance]. AB - OBJECTIVE: To explore the role of apoptosis stimulating proteins of p53 2 (ASPP2) and inhibitory member of the ASPP family (iASPP) in the occurrence of cervical cancer and the relation between these two proteins and p53. METHODS: We used immunohistochemical method to detect the expression of ASPP2, iASPP, p53 in 51 patients with early cervical cancer tissue, 53 patients with cervical intraepithelial neoplasia (CIN) II-III, 48 patients with CIN I and 45 patients with normal cervical tissue. The relation among ASPP2, iASPP and p53 was analyzed. RESULTS: When p53 was negative, the positive expression rate of ASPP2 in the cervical cancer group, the CIN II-III group, the CIN I group and the normal cervix group was gradually increased. There was significant difference between the CIN II-III group or the cervical cancer group and the normal cervix (P<0.05), but no statistical difference was found among the other groups (P>0.05). The positive expression rate of iASPP in the 4 groups gradually reduced, and the difference was significant difference between the cervical cancer group or the CIN II-III group and the normal cervix group (P<0.05). When the p53 was positive, there was no significant change in the expression of ASPP2 and iASPP in every group (P>0.05). CONCLUSION: ASPP2 and iASPP may play an important role in the occurrence of early stage of cervical cancer by regulating the ability of wild type p53 in induction of apoptosis. ASPP2 and iASPP gene might be a potential molecular target for cervical carcinoma. PMID- 25832529 TI - [Separation culture and biological characteristics analysis for bone marrow derived mesenchymal stem cells from inbreed line miniature pig of Wuzhishan]. AB - OBJECTIVE: To establish a method to isolate, culture and identify bone marrow derived mesenchymal stem cells (BM-MSCs) from inbreed line miniature pig of Wuzhishan (ILMW) in vitro, to compare the biological characteristics of BM-MSCs derived from different pigs, and to supply BM-MSCs for investigating the repair mechanisms of renal injury in ILMW aft er unilateral ureteral obstruction. METHODS: Four or 10-months old ILMW (n=4 per group) were selected and 5 mL of bone marrow fluid was extracted at 1 cm position from iliac wing edge. Mononuclear cells were isolated by density gradient method, then were cultured in the complete medium containing 3 different kinds of fetal bovine serum (FBS) (10% FBS, 12% FBS or 15% FBS). The cells of Passage 1, Passage 3, Passage 5 or Passage 11 were collected to examine biological characteristics including morphology, phenotype, differentiation ability, growth curve and cell cycle. RESULTS: The BM MSCs were attached to the culture dishes, which were fibroblast-like or whirlpoollike. Primary cultured cells began the adherence at 18 h and entered a logarithmic phase in the 6th day. Eighty percent of them were fused in the 9th day. There were no obvious anomalies in the subcultured cells. The expressions in cell surface antigens of CD29, CD44 and CD90 were positive, while the expressions of CD34 and CD45 were negative. There was no statistically significant difference between cells from different generations (all P>0.05). Under condition of osteogenic induction, alizarin red staining was positive at the 18th day, and alcian blue staining was positive at the 21th day. Cell cycle examination showed that the rate of G0/G1 was about 81.45%. CONCLUSION: BM-MSCs of ILMW has advantages of earlier adherent time, more active proliferation, shorter cell subculture cycle, and stable biological characteristics after subculture, which is one of the best kinds of BM-MSCs coming from swine in mainland of China. PMID- 25832530 TI - [Posterior short-segment fusion to treat upper cervical vertebra trauma]. AB - OBJECTIVE: To investigate the strategies of posterior short-segment fixation and plant iliac fusion surgery, and the clinical efficacy of them on the treatment of upper cervical vertebra trauma. METHODS: Three hundred and thirty-four patients with upper cervical vertebra trauma admitted into our hospital from June, 2005 to April, 2010 were studied retrospectively. Thirty-six were treated by posterior short-segment fusion, which included 22 and 14 male and female patients, respectively. Among them, 23 or 6 patients were related to traffic or falling accident, 5 or 2 patients were related to crashing object or fight. The clinical efficacy was evaluated by head and neck pain VAS score, JOA scores of nerve function and the rate of graft bone fusion. RESULTS: The postoperative VAS scores were lower than that of pre-operation, and the difference was significant (P<0.001). The postoperative JOA scores of nerve function was superior to preoperative scores (P<0.05). During follow-up, no internal fixation failure happened while bony fusion could be seen. CONCLUSION: The method of posterior short-segment fixation and bone graft fusion in treating patients with cervical spine injury is highly efficacy, which possesses great clinical value. PMID- 25832531 TI - [Influential factors of treatment cost of antihypertensive drugs for hypertensive patient in community]. AB - OBJECTIVE: To explore the influential factors of treatment cost of antihypertensive drugs for hypertensive patient in community. METHODS: A total of 220 community health centers (CHCs) from 15 provinces were selected across China in view of geographical location, economic level and previous cooperative experience to implement standardized blood pressure management for hypertensive patients for 1 year, based on guidelines for prevention and control for hypertension in China (2009 Community-based revision). Baseline and follow-up information for each hypertensive patient under the care of these CHCs was collected. A total of 22 683 hypertensive patients in hypertension community standardization management were enrolled in this study. We used multivariate linear regression model to analyze the influential factors of treatment cost of antihypertensive drugs. RESULTS: Cultural degree, regional distribution, medical security system, the blood pressure classification, complications, and treatment options were statistically significant independent variables. CONCLUSION: In hypertension community standardization management, the blood pressure of hypertensive patients should be controlled in advance to reduce the economic burden, , the occurrence of complications should be reduced, and economic factors should also be considered when selecting a treatment option. PMID- 25832532 TI - [Comprehensive evaluation of postpartum depression and correlations between postpartum depression and serum levels of homocysteine in Chinese women]. AB - OBJECTIVE: To investigate whether the level of homocysteine in patients with postpartum depression is associated with depression index. METHODS: A total of 43 women with postpartum depression or with potential postpartum depression, who visited the psychological clinic of Maternal and Child Health Hospital of Hunan Province from June, 2012 to April, 2014, were enrolled in this study. They were evaluated by the Edinburgh Postnatal Depression Scale and Hamilton Depression Scale. Chinese Classification of Mental Disorder (the third edition) was used for their diagnosis. The depressive index was calculated by Edinburgh Postnatal Depression Scale, Hamilton Depression Scale, and clinical symptom scores, which was used to assess the level of depressive symptoms. The level of homocysteine in serum was detected by chemoluminescent method. Meanwhile, another 31 women, who visited the hospital without postpartum depression, were used as controls to compare with the 43 patients. RESULTS: The homocysteine level in the women with postpartum depression was significantly higher than that in the control group [(10.09 +/- 3.59) MUmol/L vs (8.57 +/- 1.59) MUmol/L, t=12.392, P=0.001]. The depression index was positively correlated with the level of homocysteine (r=0.231, P<0.05). CONCLUSION: The level of serum homocysteine is associated with postpartum depression, suggesting that the level of serum homocysteine might be a risk biomarker for postpartum depression. PMID- 25832533 TI - [Interactions between MAP4K1 and adaptor proteins]. AB - Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, also called hematopoietic progenitor kinase 1, HPK1) is a serine/threonine kinase. As a member of the MAP4K family, MAP4K1 is closely associated with various adaptor proteins such as caspase recruitment domain family member 11 (CARD11), hematopoietic cell-specific protein 1 (HS1), HPK1-interacting protein of 55 kD (HIP-55), growth factor receptor-bound protein 2 (GRB2) family, the linker for activated T-cells (LAT), SH2 domain containing leukocyte protein of 76 kD (SLP 76) family, homologues of the v-crk oncogene product (CRK) family, the B-cell adaptor molecule of 32 kD (BAM32), etc. It plays important roles in many immunoreactions, such as regulation of cellular proliferation and apoptosis, inhibition of TCR/BCR signaling and T/B/dendritic cells-mediated immune responses. Thus, MAP4K1 is involved in autoimmune diseases and plays a key role in tumor and inflammatory reaction. PMID- 25832534 TI - [Experience of laparoscopic repair in 5 patients with vesicovaginal fistula]. AB - OBJECTIVE: To explore new methods for laparoscopic repair of vesicovaginal fistula. METHODS: Five patients with vesicovaginal fistula in Xiangya Hospital, Central South University, were reviewed retrospectively from May 2013 to July 2014. All patients underwent laparoscopic repair surgery, and the surgical methods were analyzed. The operative time, intraoperative blood loss, and hospital stay time were recorded. The duration of follow-up was from 4 to 12 months. RESULTS: Th e surgical procedures for all 5 patients were successful. No open surgery was required. The operative time was 70~120 (mean: 97) min, the intraoperative blood loss was 40~70 (mean: 54) mL, the hospital stay time was 4~8 (mean: 5.8) days. During the follow up of 4~12 (mean: 7.6) months, no recurrence was observed. CONCLUSION: Laparoscopic repair of vesicovaginal fistula is a feasible and safe and effective procedure with less blood loss and shorter recovery time, which can minimize surgery damage and improve successful rate. PMID- 25832535 TI - [A preliminary study on mechanisms for urinary system disorders before and after ketamine withdrawal in rats]. AB - OBJECTIVE: To explore the mechanisms for urinary system disorders before and after ketamine withdrawal in rats and to evaluate the recovery degree of the urinary system damage after ketamine withdrawal. METHODS: Fifteen male healthy Sprague-Dawley rats were randomly divided into 3 groups: A control group, an experimental group, and a withdrawal group. The rats in the control group were given normal saline. The rats in the experimental group were given ketamine 30 mg/(kg.day) for 30 days. The rats in the withdrawal group were treated as the experimental group except for drug withdrawal for 2 weeks. In the experimental period, we randomly selected 1 rat of kidney, ureter, and bladder from each group to perform HE staining. The bladder tissues in each group were used to detect mRNA expression by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: 1) The behavior of ketamine-injected rats was obviously changed, but the weight of ketamine-induced rats was not changed. 2) As compared with the control group, the experimental and withdrawal groups showed infiltration of mononuclear inflammatory cells in the kidney tissues, the thinner epithelium of bladder and infiltration of submucosal mononuclear inflammatory cells under the optical microscope. 3) As compared with the control group, the expression of H1R mRNA was increased in the experimental group (P<0.05). As compared with the experimental group, H1R mRNA expression was significantly decreased in the withdrawal group (P<0.05). CONCLUSION: Ketamine abuse could induce behavior changes in rats. The infiltration of mononuclear inflammatory cells in kidney and bladder, the thinner bladder epithelial layer, and the increased H1R gene mRNA expression in bladder might be an important pathogenesis of KAUD. Ketamine withdrawal may effectively reverse the pathogenic process of KAUD. PMID- 25832536 TI - [Effect of percutaneous nephrostolithotomy combined with flexible ureteroscopy on renal function in elderly patients with renal calculi]. AB - OBJECTIVE: To detect the levels of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (Cys-C ) in blood and the level of kidney injury molecule 1 (KIM-1) in urine in elderly patients with renal calculi at diff erent times, and to explore the eff ect of percutaneous nephrostolithotomy (PCNL) combined with flexible ureteroscopy (FU) on early postoperative renal function. METHODS: A total of 46 patients with renal calculi were selected, and their blood or urine specimens were collected respectively at preoperative and postoperative 2, 12, 24, 48, and 72 h. The concentrations of NGAL, Cys-C, KIM-1 were detected. RESULTS: The levels of NGAL and Cys-C began to increase respectively at postoperative 2 and 12 h, and reached peak at postoperative 12 to 24 h. There was significant difference in the levels of NGAL and Cys-C between the postoperative 12 and 2 h or between postoperative 48 and 24 h (all P<0.05). The levels of NGAL and Cys-C began to decline and eventually returned to preoperative levels respectively at postoperative 48 and postoperative 72 h. The KIM-1 began to increase at postoperative 2 h and peaked at postoperative 24 h, which was significant difference between the postoperative 24 and 12 h or postoperative 48 and 24 h (both P<0.05). The level of KIM-1 began to decline and eventually returned to preoperative levels at postoperative 48 h. CONCLUSION: After the combined treatment of percutaneous nephrostolithotomy with flexible ureteroscopy, the concentrations of NGAL, Cys-C and KIM-1 are significantly increased, suggesting injuries on renal function. The time of renal tubular injury and recovery is earlier than that of renal glomerulus. PMID- 25832537 TI - [Treatment of the pediatric neck abscess and surgery scar by high negative pressure drainage system]. AB - OBJECTIVE: To explore the clinical significance of high negative pressure drainage system (PFM) in treatment of pediatric neck abscess and postoperative scar. METHODS: The clinical data of 35 children with neck abscess from June, 2012 to January, 2014 were retrospectively analyzed. According to the site of the abscess in children, a small incision drainage combined PFM were used, and the antibiotics were used at the same time to strengthen systemic support treatment. The complications were treated by the related departments, and the application of topical silicone gel incision after operation lasted for 3-6 months. RESULTS: Thirty-five children healed after the above treatment in 7-14 d. The effective cure rate was 100%. The post-operation followed up for 6 months -1 year and no surgical incision scar was found. CONCLUSION: Small incision drainage combined with PFM show the superiority of minimal invasion for the treatment of postoperative abscess drainage without the needs of replacing the gauze and drainage bottle, and physiological activities are not affected in the suffering children. The method can significantly reduce the pain of children during the change of medical prescription and the physician workload. It has the advantages of faster healing, shorter hospital staying, without obvious scar and abnormalities. The method is especially useful for deep and large abscess, and it is better than the traditional treatment methods. PMID- 25832538 TI - [Efficacy of health education on patients with hip replacement based on the Internet]. AB - OBJECTIVE: To evaluate the efficacy of health education on patients with hip replacement based on the Internet, and to establish a new health education model through modern technology. METHODS: A total of 300 patients with hip replacement from March to August, 2015 were enrolled in this study. The participants were divided into a control group and an experimental group according to months surgeries performed. Traditional education was applied in the control group while the multimedia source material plus the Internet platform of Joint Registration System were applied in the experimental group. Levels of anxiety, degree of satisfaction, and postoperative complications were analyzed. RESULTS: The levels of knowledge, attitude and behavior compliance in the patients of the experimental group were significantly improved, while the levels of postoperative anxiety were decreased compared with those in the control group (P<0.05). CONCLUSION: Education based on the Internet platform of Joint Registration System and the computer video could improve patients' knowledge, attitude, and behavior, which is worthy of clinical spread. PMID- 25832539 TI - Effect of social support and coping styles on the stress and mental health in relatives of patients with traumatic brain injury. AB - OBJECTIVE: To investigate the effect of social support and coping style on the stress and mental health in relatives of patients with traumatic brain injury. METHODS: The stress, mental health, social support and coping style were investigated in 300 relatives of patients with traumatic brain injury by Relative Stress Scale, Symptom Checklist-90, Social Support Rating Scale and Simplified Coping Style Questionnaire in Changsha City. RESULTS: The mental health problems in relatives of patients with traumatic brain injury were closely related to the levels of stress, the ways of coping and the social support. In addition to the direct eff ect of stress on mental health in relatives of patients, the ways of coping and social support functioned as a mediator in this regard. The value of mesomeric eff ect for coping styles and social support ranged from 23.6% to 43.0%, and social support had an advantage over the coping styles. CONCLUSION: Social support and coping styles should be considered in psychological nursing program to prevent and adjust the mental distress in relatives of patients with traumatic brain injury, which is beneficial to the treatment and recovery for patients. PMID- 25832540 TI - Spontaneous bacterial peritonitis caused by Aeromonas caviae in a patient with cirrhosis. AB - Spontaneous bacterial peritonitis (SBP) is a common complication of cirrhosis. Based on our current understanding of SBP, the most common etiologies for SBP in cirrhosis are Enterobacter and Streptococcal species. Th e Aeromonas species are ubiquitous in fresh or sea water. Aeromonas caviae is never identified as etiology in cases of SBP. A patient, who had a history of liver cirrhosis related to chronic hepatitis B virus infection for 1 year, presented with diarrhea. He had diarrhea 1 week later returned from coastal city. He was hospitalized and treated with norfloxacin after 7 days of severe symptoms, including fever, abdominal distention, and diarrhea. Analysis of the ascitic specimen revealed a white-cell count of 4.42 * 109 cells/L with 88% neutrophils. Analysis of stool specimen showed a white-cell count of 60 cells per high-power field. Th e patient started the injection of cefriaxone at a dose of 4 g/d. However, the situation was not improved. Th ree days later, stool and ascitic fluid culture showed positive for Aeromonas caviae. Antibiotic susceptibility testing revealed that imipenem, meropenem, amikacin, and cefoperazone-sulbactam were highly sensitive to the Aeromonas caviae. However, the bacilli resisted to ceftriaxone, ceftazidime, ampicillin-sulbactam, levofloxacin, and sulfamethoxazole. Ceftriaxone was then switched to imipenem. The patient was fully recovered 14 days later. Aeromonas caviae is a rare pathogen of SBP in cirrhosis. It resists to third-generation of cephalosporin and fluroquinolone, which are of frequently used dependent on clinical experience. It needs a special attention. PMID- 25832541 TI - Comparison of the urinary excretion of quercetin glycosides from red onion and aglycone from dietary supplements in healthy subjects: a randomized, single blinded, cross-over study. AB - Some intervention studies have shown that quercetin supplementation can regulate certain biomarkers, but it is not clear how the doses given relate to dietary quercetin (e.g. from onion). We conducted a two-period, two-sequence crossover study to compare the bioavailability of quercetin when administered in the form of a fresh red onion meal (naturally glycosylated quercetin) or dietary supplement (aglycone quercetin) under fasting conditions. Six healthy, non smoking, adult males with BMI 22.7 +/- 4.0 kg m(-2) and age 35.3 +/- 12.3 y were grouped to take the two study meals in random order. In each of the 2 study periods, one serving of onion soup (made from 100 g fresh red onion, providing 156.3 +/- 3.4 MUmol (47 mg) quercetin) or a single dose of a quercetin dihydrate tablet (1800 +/- 150 MUmol (544 mg) of quercetin) were administered following 3 d washout. Urine samples were collected up to 24 h, and after enzyme deconjugation, quercetin was quantified by LC-MS. The 24 h urinary excretion of quercetin (1.69 +/- 0.79 MUmol) from red onion in soup was not significantly different to that (1.17 +/- 0.44 MUmol) for the quercetin supplement tablet (P = 0.065, paired t test). This means that, in practice, 166 mg of quercetin supplement would be comparable to about 10 mg of quercetin aglycone equivalents from onion. These data allow intervention studies on quercetin giving either food or supplements to be more effectively compared. PMID- 25832542 TI - Ameliorating pathogenesis by removing an exon containing a missense mutation: a potential exon-skipping therapy for laminopathies. AB - Exon skipping, as a therapy to restore a reading frame or switch protein isoforms, is under clinical trial. We hypothesised that removing an in-frame exon containing a mutation could also improve pathogenic phenotypes. Our model is laminopathies: incurable tissue-specific degenerative diseases associated with LMNA mutations. LMNA encodes A-type lamins, that together with B-type lamins, form the nuclear lamina. Lamins contain an alpha-helical central rod domain composed of multiple heptad repeats. Eliminating LMNA exon 3 or 5 removes six heptad repeats, so shortens, but should not otherwise significantly alter, the alpha-helix. Human Lamin A or Lamin C with a deletion corresponding to amino acids encoded by exon 5 (Lamin A/C-Delta5) localised normally in murine lmna-null cells, rescuing both nuclear shape and endogenous Lamin B1/emerin distribution. However, Lamin A carrying pathogenic mutations in exon 3 or 5, or Lamin A/C Delta3, did not. Furthermore, Lamin A/C-Delta5 was not deleterious to wild-type cells, unlike the other Lamin A mutants including Lamin A/C-Delta3. Thus Lamin A/C-Delta5 function as effectively as wild-type Lamin A/C and better than mutant versions. Antisense oligonucleotides skipped LMNA exon 5 in human cells, demonstrating the possibility of treating certain laminopathies with this approach. This proof-of-concept is the first to report the therapeutic potential of exon skipping for diseases arising from missense mutations. PMID- 25832543 TI - Absolute determination of the gelling point of gelatin under quasi-thermodynamic equilibrium. AB - Thermodynamic studies on phase transformation of biopolymers in solution are useful to understand their nature and to evaluate their technological potentials. Thermodynamic studies should be conducted avoiding time-related phenomena. This condition is not easily achieved in hydrophilic biopolymers. In this contribution, the simultaneous effects of pH, salt concentration, and cooling rate (Cr) on the folding from random coil to triple helical collagen-like structures of gelatin were systematically studied. The phase transformation temperature at the absolute invariant condition of Cr = 0 degrees C/min (T(T)Cr=0) ) is introduced as a conceptual parameter to study phase transformations in biopolymers under quasi-thermodynamic equilibrium and avoiding interferences coming from time-related phenomena. Experimental phase diagrams obtained at different Cr are presented. The T(T)(Cr=0) compared with pH and TT(Cr=0) compared with [NaCl] diagram allowed to explore the transformation process at Cr = 0 degrees C/min. The results were explained by electrostatic interactions between the biopolymers and its solvation milieu. PMID- 25832545 TI - Asymptomatic 43-year-old man with family history of sudden death. PMID- 25832544 TI - FOXO3: A Major Gene for Human Longevity--A Mini-Review. AB - BACKGROUND: The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. OBJECTIVE: Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. METHODS: The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword. RESULTS: We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis. CONCLUSIONS: The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported. PMID- 25832546 TI - Influence of L-homoarginine as an analogue of L-arginine on the heat-induced aggregation of proteins. AB - The influence of l-homoarginine on the heat-induced aggregation of three model proteins, i.e. porcine, mink, and human growth hormones was investigated by circular dichroism spectroscopy. It was found that the effect of l-homoarginine as an analogue of arginine depends on the concentration of the additive as well as the protein itself. l-Homoarginine increased the onset temperature of heat induced aggregation of both porcine and mink growth hormones. However, the formation of human growth hormone aggregates was increased at low concentrations of l-homoarginine. Only at higher concentrations of the additive was the onset temperature of human growth hormone aggregation found to increase. Additional experiments of human growth hormone melting in the presence of histidine, lysine, and sodium chloride were performed. The effect of lysine was similar as in the presence of l-homoarginine. It follows that in protein formulations low concentrations of amino acids should be used with some precaution. At low concentration of additive, depending on the charge of both protein and amino acid used, the promotion of aggregation of unfolding intermediates may occur. PMID- 25832547 TI - Identifying Children with Intellectual Disabilities in the Tribal Population of Barwani District in State of Madhya Pradesh, India. AB - BACKGROUND: Low-and middle-income countries (LAMI) lack an integrated and systematic approach to identify people with intellectual disabilities. Screening surveys are considered resource-intensive; therefore, alternative approaches are needed. This study attempted to identify children up to age 18 years with intellectual disabilities through a mixed-method approach involving focus group interviews (FGIs) and door-to-door surveys. MATERIALS AND METHODS: Focus groups were conducted with the assistance and involvement of local leaders in four villages of Barwani district of Madhya Pradesh with a 99% tribal population in all four villages. A formal survey of the community was then conducted to determine the prevalence of intellectual disabilities based on a standardized screening instrument (NIMH-DDS). RESULTS: Thirty focus group interviews were conducted involving 387 participants (males 284, females 103) over a period of 13 days. The entire adult population (N = 8797) was then surveyed for intellectual disabilities using a standardized screening instrument. The data revealed a close similarity in the prevalence rates of intellectual disabilities, as determined by the two approaches (Focus Group Interviews, 5.22/1000 versus Survey, 5.57/1000). CONCLUSION: A qualitative method using FGIs successfully identified people with intellectual disabilities in an economically deprived tribal area, showing that a community-based approach provides a close estimate of intellectual disabilities based on a formal survey using standard diagnostic criteria. These data suggest that FGI, along with other qualitative data, could be helpful in designing and in serving as an entree for community-based interventions. PMID- 25832549 TI - Beyond stereoselectivity, switchable catalysis: some of the last frontier challenges in ring-opening polymerization of cyclic esters. AB - Metal-based catalysts and initiators have played a pivotal role in the ring opening polymerization (ROP) of cyclic esters, thanks to their high activity and remarkable ability to control precisely the architectures of the resulting polyesters in terms of molar mass, dispersity, microstructure, or tacticity. Today, after two decades of extensive research, the field is slowly reaching maturity. However, several challenges remain, while original concepts have emerged around new types or new applications of catalysis. This Review is not intended to comprehensively cover all of these aspects. Rather, it provides a personal overview of the very recent progress achieved in some selected, important aspects of ROP catalysis--stereocontrol and switchable catalysis. Hence, the first part addresses the development of new metal-based catalysts for the isoselective ROP of racemic lactide towards stereoblock copolymers, and the use of syndioselective ROP metal catalysts to control the monomer sequence in copolymers. A second part covers the development of ROP catalysts--primarily metal-based catalysts, but also organocatalysts--that can be externally regulated by the use of chemical or photo stimuli to switch them between two states with different catalytic abilities. Current challenges and opportunities are highlighted. PMID- 25832548 TI - Endogenous tissue factor pathway inhibitor has a limited effect on host defence in murine pneumococcal pneumonia. AB - Streptococcus (S.) pneumoniae is the most common causative pathogen in community acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia. PMID- 25832550 TI - The role of microRNA in nutritional control. AB - MicroRNAs (miRNAs) are one of a growing class of noncoding RNAs that are involved in the regulation of a wide range of metabolic processes including cellular differentiation, cell proliferation and apoptosis. The generation of miRNA is regulated in complex ways, for example by small interfering RNAs (small nucleolar and nuclear RNAs) and various other metabolites. This complexity of control is likely to explain how a relatively small part of the DNA that codes for proteins has enabled the evolution of such complex organisms as mammals. Non-protein coding DNA is therefore thought to carry the memory of early evolutionary steps that led to progressively complex metabolic controls. Clinically, miRNAs are becoming increasingly important following the recognition that some congenital abnormalities can be traced to defects in miRNA processing. The potential for manipulating metabolism and affecting disease processes by the pharmaceutical or biological targeting of specific miRNA pathways is now being tested. miRNAs are also released into the extracellular milieu after packaging by cells into nano sized extracellular vesicles. Such vesicles can be taken up by adjacent and possibly more distant cells, thereby allowing coordinated intercellular communication in specific tissues. Extracellular miRNAs found in the blood stream may also serve as novel biomarkers for both diagnosing specific forms of cancer and assessing the likelihood of metastasis, and as powerful prognostic indices for various cancers. Here, we discuss the role of intracellular and extracellular miRNAs in nutritional control of various (patho)physiological processes. In this review, we provide an update of the presentations from the 25th Marabou Symposium (Stockholm, 14-16 June 2013) entitled 'Role of miRNA in health and nutrition', attended by 50 international experts PMID- 25832551 TI - Plasma concentrations, analgesic and physiological assessments in horses with chronic laminitis treated with two doses of oral tramadol. AB - REASONS FOR PERFORMING STUDY: Laminitis is a painful disease for which adequate pain management remains a challenging and largely unmet medical need. OBJECTIVES: To investigate plasma concentrations, analgesic and physiological effects of 2 doses of tramadol in horses with chronic laminitis. STUDY DESIGN: Nonrandomised trial. METHODS: Four horses with naturally occurring chronic laminitis received 5 mg/kg bwt and then 10 mg/kg bwt tramadol orally every 12 h for one week with a one-week washout between. Noninvasive arterial blood pressure, heart and respiratory rates, intestinal sounds and forelimb off-loading frequency were evaluated before and during treatments. Plasma tramadol and metabolite (M1 and M2) concentrations were measured on predetermined days and times after the morning dosing. RESULTS: Forelimb off-loading frequency decreased significantly with 10 mg/kg bwt (40%, P = 0.02) but not with 5 mg/kg bwt (9%, P = 0.4). Physiological variables did not change significantly with either treatment. For 5 and 10 mg/kg bwt treatments, respectively, individual maximum plasma concentrations (MUg/l) ranged from 329 to 728 and 628 to 1330 (tramadol), 12-24 and 32-80 (M1), and 90-157 and 239-362 (M2). Respective median area under the concentration vs. time curves (h MUg/l) were 727 and 1426, 33 and 88, 303 and 1003. CONCLUSIONS: Twice daily oral tramadol at 10 mg/kg bwt may produce analgesic plasma levels in horses with chronic laminitis. PMID- 25832552 TI - Primary localized tracheobronchial amyloidosis presenting with massive hemoptysis: a case report and literature review. AB - Primary localized tracheobronchial amyloidosis (TBA) is a rare respiratory tract dysfunction, which is a heterogeneous group of diseases involving abnormal extracellular deposition of amyloid and autologous fibrillar protein material in beta-pleated sheets. A 64-year-old man was referred to our hospital because of hemoptysis. Physical examination showed decreased breath sounds in the right lung on auscultation. Chest computed tomography scan displayed multiple nodules with varied size in main bronchia around bilateral hilus of the lung. After admission, bronchoscopy was performed for this patient, and roughness of mucosa in trachea and multiple nodules in respiratory tract were observed. Through further tissue biopsy, the diagnosis of primary TBA was confirmed. PMID- 25832553 TI - The moderating effects of cannabis use and decision making on the relationship between conduct disorder and risky sexual behavior. AB - Risky sexual behavior (RSB) is a current public health concern affecting adolescents and young adults. Conduct disorder, cannabis use, and decision-making (DM) ability are interrelated constructs that are relevant to RSB; however, there is little research on the association of DM and RSB. Participants were 79 cannabis users assessed through self-report measures of RSB and mental health and a timeline follow-back procedure for substance use. DM ability was assessed via the Iowa Gambling Task. We found that more conduct disorder symptoms accounted for unique variance in measures of overall RSB and an earlier initiation of oral sex, even when taking into account DM and cannabis use. Amount of cannabis use and DM ability moderated the relationships between number of conduct disorder symptoms and number of oral sex partners and age of initiation for vaginal sex. An increase in conduct disorder symptoms was associated with more oral sex partners when DM was poor and fewer partners when DM was better; however, this relationship was only present at higher levels of cannabis use. Furthermore, when DM was poor, more conduct disorder symptoms predicted a younger age of initiation of vaginal sex, with the age decreasing as amount of cannabis use increased. Determining how DM influences RSB may assist in the identification of novel treatment approaches to reduce engagement in RSB. PMID- 25832554 TI - Effects of Concomitant Methotrexate on Large Joint Replacement in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors: A Multicenter Retrospective Cohort Study in Japan. AB - OBJECTIVE: To determine the effects of concomitant methotrexate (MTX) on the incidence of large joint replacement resulting from the progression of large joint destruction in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors. METHODS: A retrospective cohort study was performed using a multicenter registry. In total, 803 patients with RA who received etanercept or adalimumab were included. The first large joint replacement during treatment with etanercept or adalimumab was used as the outcome variable in predictive analyses. The cumulative incidence of large joint replacement was estimated using Kaplan-Meier curves, and the impact of concomitant MTX on the incidence of large joint replacement was assessed with Cox proportional hazards models. Propensity score matching was used to reduce selection bias. RESULTS: Of all patients, 601 (75%) received concomitant MTX at a median dosage of 8 mg/week (interquartile range 6-8). A total of 49 patients (62 joints) underwent large joint replacement during treatment with etanercept or adalimumab. The incidence of large joint replacement for patients with concomitant MTX was significantly lower than that for patients without MTX (P < 0.001). Multivariate analysis revealed that concomitant MTX independently predicted large joint replacement (hazard ratio 0.36, 95% confidence interval 0.20-0.65). Additionally, propensity score-matched analysis demonstrated that patients with concomitant MTX had a significantly lower incidence of large joint replacement than those without concomitant MTX (P = 0.032). CONCLUSION: Concomitant MTX reduces the incidence of large joint replacement in patients with RA treated with TNF inhibitors. PMID- 25832555 TI - Thermophilic production of polyhydroxyalkanoates by a novel Aneurinibacillus strain isolated from Gudao oilfield, China. AB - Polyhydroxyalkanoates (PHAs) are usually biosynthesized using mesophilic strains, but the fermentation processes often suffer from bacterial contamination. This work reports the screening of thermophilic bacteria capable of producing PHAs under elevated temperatures to reduce the contamination risk. Strain XH2 was isolated from an oilfield and identified as Aneurinibacillus sp. by morphology, physiological-biochemical characterization, and 16S rDNA phylogenetic analysis. This strain can produce PHA granules, which was detected by Nile red staining and transmission electron microscopic imaging. At 55 degrees C, 111.6 mg l(-1) of PHA was produced in a fermentation medium containing glucose, peptone, and yeast extract. If peptone was removed from the medium, the yield of PHA would be enhanced by 2.4 times. The main monomers of the PHA product were identified to be 3-hydroxybutyrate and 3-hydroxyvalerate with a molar ratio of 17.2:1 by gas chromatography-mass spectroscopy (GC-MS) and nuclear magnetic resonance analyses. Two minor homologues, 3-hydroxyoctanoate, and 3-hydroxy-4-phenylbutanoate, were tentatively identified by GC-MS as well. This is the first report of thermophilic PHA bacterial producer from the Firmicutes phylum. PMID- 25832556 TI - Tolerance of early oral feeding in patients subjected to total laryngectomy. AB - BACKGROUND: The purpose of this study was to assess the tolerance of early oral feeding after total laryngectomy. METHOD: A randomized multicenter study was conducted that included 89 individuals subjected to total laryngectomy. The participants were allocated to 2 groups: early (n = 44), early oral feeding; and late (n = 45), late oral feeding. The participants in the early group were assessed as to acceptance of oral feeding, and their food intake was quantified. RESULTS: In the early group, the total energy expenditure and protein needs were not met through oral feeding alone at any time during the first 7 postoperative days. The times to attain 25% and 50% of the total energy expenditure and protein needs by oral feeding after surgery were 4 and 7 days, respectively. CONCLUSION: The patients subjected to early oral feeding failed to meet their caloric and protein needs through that route alone during the first 4 postoperative days and required complementary nutrition through another route. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E643-E648, 2016. PMID- 25832559 TI - 2-acetyl-4-tetrahydroxybutylimidazole and 4-methylimidazole in caramel colours, vinegar and beverages in China. AB - A survey of 2-acetyl-4-tetrahydroxybutylimidazole (THI) and 4-methylimidazole (4 MeI) concentrations in caramel colours, vinegar and beverages from the Chinese market were performed by ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In total, 117 samples, 78 caramel colour samples, 23 vinegar samples and 16 beverage samples, were investigated. The results indicated that 4-MeI was found in all samples. THI was found in a part of the samples and also the level range was lower compared to 4-MeI. In caramel colour samples, the concentration level range of THI was 1.0-74.3 mg/kg and of 4-MeI was 1.5-1291.8 mg/kg. In vinegar samples, the concentration level range of THI was 13.3-119.2 ug/L and for 4-MeI 111.2-2077.8 ug/L. In beverage samples, THI was only found in two samples and the concentration level range of 4-MeI was 10.8-307.1 ug/L. THI and 4-MeI levels in vinegar and beverages were rather low compared with those in caramel colour samples. These observations can be helpful for evaluating individual exposure to THI and 4-MeI from caramel colours, vinegar and beverages in China. PMID- 25832560 TI - Values-based practice and phenomenological psychopathology: implications of existential changes in depression. AB - Values-based practice (VBP), developed as a partner theory to evidence-based medicine (EBM), takes into explicit consideration patients' and clinicians' values, preferences, concerns and expectations during the clinical encounter in order to make decisions about proper interventions. VBP takes seriously the importance of life narratives, as well as how such narratives fundamentally shape patients' and clinicians' values. It also helps to explain difficulties in the clinical encounter as conflicts of values. While we believe that VBP adds an important dimension to the clinician's reasoning and decision-making procedures, we argue that it ignores the degree to which values can shift and change, especially in the case of psychiatric disorders. VBP does this in three respects. First, it does not appropriately engage with the fact that a person's values can change dramatically in light of major life events. Second, it does not acknowledge certain changes in the way people value, or in their modes of valuing, that occur in cases of severe psychiatric disorder. And third, it does not acknowledge the fact that certain disorders can even alter the degree to which one is capable of valuing anything at all. We believe that ignoring such changes limits the degree to which VBP can be effectively applied to clinical treatment and care. We conclude by considering a number of possible remedies to this issue, including the use of proxies and written statements of value generated through interviews and discussions between patient and clinician. PMID- 25832557 TI - Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. AB - BACKGROUND: Curative therapy for childhood sarcoma presents challenges when complete resection is not possible. Ionizing radiation (XRT) is used as a standard modality at diagnosis or recurrence for childhood sarcoma; however, local recurrence is still problematic. Most childhood sarcomas are TP53 wild type at diagnosis, although approximately 5-10% have MDM2 amplification or overexpression. PROCEDURES: The MDM2 inhibitor, RG7388, was examined alone or in combination with XRT (20Gy given in 2 Gy daily fractions) to immune-deficient mice bearing Rh18 (embryonal) or a total of 30 Gy in 2 Gy fractions to mice bearing Rh30 (alveolar) rhabdomyosarcoma xenografts. RG7388 was administered by oral gavage using two schedules (daily *5; schedule 1 or once weekly; schedule 2). TP53-responsive gene products (p21, PUMA, DDB2, and MIC1) as well as markers of apoptosis were analyzed. RESULTS: RG7388 showed no significant single agent antitumor activity. Twenty Grays XRT induced complete regressions (CR) of Rh18 with 100 percent tumor regrowth by week 7, but no tumor regrowth at 20 weeks when combined with RG7388. RG7388 enhanced time to recurrence combined with XRT in Rh30 xenografts compared to 30 Gy XRT alone. RG7388 did not enhance XRT-induced local skin toxicity. Combination treatments induced TP53 responsive genes more rapidly and to a greater magnitude than single agent treatments. CONCLUSIONS: RG7388 enhanced the activity of XRT in both rhabdomyosarcoma models without increasing local XRT-induced skin toxicity. Changes in TP53-responsive genes were consistent with the synergistic activity of RG7388 and XRT in the Rh18 model. PMID- 25832558 TI - Neuropsychological and dimensional behavioral trait profiles in Costa Rican ADHD sib pairs: Potential intermediate phenotypes for genetic studies. AB - Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity. PMID- 25832561 TI - Intersectin1-S, a multidomain adapter protein, is essential for malignant glioma proliferation. AB - Glioblastomas, the most aggressive form of primary brain tumors with a tendency to invade surrounding healthy brain tissues, remains an incurable disease. Intersectin (ITSN) is a multidomain adapter protein implicated in endocytosis, exocytosis, and multiple signaling pathways. Prior research of ours has shown intersectin1-S (ITSN1-S) is critical for the migration and invasion of glioma cells by regulating several key proteins. In this study, we established ITSN1-S expression patterns in human tumor tissues. We discovered that ITSN1-S expression was positively correlated with histological grade of gliomas and with poor patient prognosis. We also found that the expression of ITSN1-S protein was essential to glioblastoma cell proliferation. Furthermore, through a series of expression constructs encoding different ITSN1-S domains, we identified the critical roles of ITSN1-S SH3 domains in the regulation of cell proliferation. This study also demonstrates evidence suggesting that the regulation of ITSN1-S on glioblastoma cells proliferation is through the Raf/MEK/ERK pathway. In conclusion, this study suggests critical roles of ITSN1-S in malignant glioma proliferation, indicating a potential usage of ITSN1-S in the therapeutic intervention as a novel molecular target. PMID- 25832562 TI - Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models. AB - In recent years prodrug strategy has been used extensively to improve the pharmacokinetic properties of compounds exhibiting poor bioavailability. Mechanistic understanding of the absorption and the role of intestine and liver in the activation of oral prodrugs is crucial. Enalapril, a carboxyl ester prodrug, is reported to be metabolized by human carboxylesterase-1 (CES1) but not by carboxylesterase-2 (CES2) to its active metabolite enalaprilat. Further, it has been reported that the small intestines of both rat and human contain mainly CES2. The objective of this work was to understand whether enalapril remains unchanged as it is absorbed through the intestine into the portal circulation. This was evaluated using different intestinal preparations, an in situ intestinal perfusion experiment and a portal vein cannulated rat model. No turnover of enalapril was seen with commercial rat intestinal S9 and microsomes, but reasonable turnover was observed with freshly prepared rat intestinal and mucosal homogenate and S9. In the intestinal perfusion study, both enalapril and enalaprilat were observed in the mesenteric plasma with the data suggesting 32% hydrolysis of enalapril in the intestine. In the portal vein cannulated rat, about 51% of enalapril absorbed into intestine was converted to enalaprilat. Overall, it was demonstrated that even though enalapril has been shown to be a specific substrate for CES1, it is converted to enalaprilat to a significant extent in the intestine. Such experimental techniques can be applied by other scientific groups who are working on prodrugs to determine the region and extent of activation. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25832563 TI - Noninvasive imaging technologies for cutaneous wound assessment: A review. AB - The ability to phenotype wounds for the purposes of assessing severity, healing potential and treatment is an important function of evidence-based medicine. A variety of optical technologies are currently in development for noninvasive wound assessment. To varying extents, these optical technologies have the potential to supplement traditional clinical wound evaluation and research, by providing detailed information regarding skin components imperceptible to visual inspection. These assessments are achieved through quantitative optical analysis of tissue characteristics including blood flow, collagen remodeling, hemoglobin content, inflammation, temperature, vascular structure, and water content. Technologies that have, to this date, been applied to wound assessment include: near infrared imaging, thermal imaging, optical coherence tomography, orthogonal polarization spectral imaging, fluorescence imaging, laser Doppler imaging, microscopy, spatial frequency domain imaging, photoacoustic detection, and spectral/hyperspectral imaging. We present a review of the technologies in use or development for these purposes with three aims: (1) providing basic explanations of imaging technology concepts, (2) reviewing the wound imaging literature, and (3) providing insight into areas for further application and exploration. Noninvasive imaging is a promising advancement in wound assessment and all technologies require further validation. PMID- 25832564 TI - Utilizing Geographic Information Systems and Spatial Video to Analyze Patterns of Secondhand Smoke Exposure on College Campuses. AB - OBJECTIVE: Innovatively apply geographic information system (GIS) software and spatial video cameras to examine hotspots of smoking and secondhand smoke (SHS) exposure on a college campus. PARTICIPANTS: Pedestrians on a large public university in the United States. METHODS: Spatial video cameras mounted on bicycles and GIS software captured and analyzed smoking on campus. Data were collected during times of heavy pedestrian traffic. Hotspot locations with high concentrations of observed smoking were identified. RESULTS: Using this innovative methodology, several hotspots were identified on campus where SHS exposure occurs frequently. These hotspots were in areas of high pedestrian traffic, thus indicating a potential for SHS exposure to many students. CONCLUSIONS: This paper demonstrates an innovative application of GIS and spatial video technology to understand outdoor smoking patterns on campus. These techniques can aid in program planning, decision-making, policy development, and enforcement. PMID- 25832565 TI - Outcome measurement in New Zealand. AB - This paper provides a detailed description and critique of the development of routine outcome measurement (ROM) within New Zealand's mental health and addiction services. The paper will include a brief description of the New Zealand setting and the events that led to routine outcome measures, demographic and diagnostic characteristics of the population in New Zealand, characteristics of the New Zealand mental health and addictions services, a description of the outcome measures and rationale for their selection, the information collection protocol for the outcome measures, outcome data completion rates and aggregated outcome reporting uses, barriers and facilitators to the adoption of routine outcome measures in New Zealand, and current status and next steps. PMID- 25832566 TI - Routine mental health outcome measurement in the UK. AB - This paper offers a short history of routine clinical outcomes measurement (RCOM) in UK mental health services. RCOM developments in primary and secondary care are described, with reference to measures currently in widespread use or likely to be implemented. Assessment procedure and completion rates are discussed. Some of the forces operating in this field are enumerated. Comparison is made with UK attempts at routine outcomes measurement in public education. This field is thus reviewed for lessons for RCOM, and opportunities and challenges considered. PMID- 25832567 TI - Of means and ends: mind and brain science in the twentieth century. PMID- 25832568 TI - Dredging and projecting the depths of personality: the thematic apperception test and the narratives of the unconscious. AB - ARGUMENT: The Thematic Apperception Test (TAT) was a projective psychological test created by Harvard psychologist Henry A. Murray and his lover Christina Morgan in the 1930s. The test entered the nascent intelligence service of the United States (the OSS) during the Second World War due to its celebrated reputation for revealing the deepest aspects of an individual's unconscious. It subsequently spread as a scientifically objective research tool capable not only of dredging the unconscious depths, but also of determining the best candidate for a management position, the psychological complexes of human nature, and the unique characteristics of a culture. Two suppositions underlie the utility of the test. One is the power of narrative. The test entails a calculated abuse of the subjects tested, based on their inability to interpret their own narrative. The form of the test requires that a subject fail to decipher the coded, unconscious meaning their narrative reveals. Murray believed the interpretation of a subject's narrative and the projection contained therein depended exclusively on the psychologist. This view of interpretation stems from the seemingly more reasonable belief of nineteenth-century Romantic thinkers that a literary text serves as a proxy for an author's deepest self. The TAT also supposes that there is something beyond consciousness closely resembling a psychoanalytic unconscious, which also has clear precedents in nineteenth-century German thought. Murray's views on literary interpretation, his view of psychology as well as the continuing prevalence of the TAT, signals a nineteenth-century concept of self that insists "on relations of depth and surface, inner and outer life" (Galison 2007, 277). It is clear the hermeneutic practice of Freud's psychoanalysis, amplified in Jung, drew on literary conceptions of the unconscious wider than those of nineteenth-century psychology. PMID- 25832569 TI - The birth of information in the brain: Edgar Adrian and the vacuum tube. AB - ARGUMENT: As historian Henning Schmidgen notes, the scientific study of the nervous system would have been "unthinkable" without the industrialization of communication in the 1830s. Historians have investigated extensively the way nerve physiologists have borrowed concepts and tools from the field of communications, particularly regarding the nineteenth-century work of figures like Helmholtz and in the American Cold War Era. The following focuses specifically on the interwar research of the Cambridge physiologist Edgar Douglas Adrian, and on the technology that led to his Nobel-Prize-winning research, the thermionic vacuum tube. Many countries used the vacuum tube during the war for the purpose of amplifying and intercepting coded messages. These events provided a context for Adrian's evolving understanding of the nerve fiber in the 1920s. In particular, they provide the background for Adrian's transition around 1926 to describing the nerve impulse in terms of "information," "messages," "signals," or even "codes," and for translating the basic principles of the nerve, such as the all-or-none principle and adaptation, into such an "informational" context. The following also places Adrian's research in the broader context of the changing relationship between science and technology, and between physics and physiology, in the first few decades of the twentieth century. PMID- 25832570 TI - Screening the psychological laboratory: Hugo Munsterberg, psychotechnics, and the cinema, 1892-1916. AB - ARGUMENT: According to Hugo Munsterberg, the direct application of experimental psychology to the practical problems of education, law, industry, and art belonged by definition to the domain of psychotechnics. Whether in the form of pedagogical prescription, interrogation technique, hiring practice, or aesthetic principle, the psychotechnical method implied bringing the psychological laboratory to bear on everyday life. There were, however, significant pitfalls to leaving behind the putative purity of the early psychological laboratory in pursuit of technological utility. In the Vocation Bureau, for example, psychological instruments were often deemed too intimidating for a public unfamiliar with the inner workings of experimental science. Similarly, when psychotechnical means were employed by big business in screening job candidates, ethical red flags were raised about this new alliance between science and capital. This tension was particularly evident in Munsterberg's collaboration with the Paramount Pictures Corporation in 1916. In translating psychological tests into short experimental films, Munsterberg not only envisioned a new mass medium for the dissemination of psychotechnics, but a means by which to initiate the masses into the culture of experimental psychology. PMID- 25832571 TI - Of psychometric means: Starke R. Hathaway and the popularization of the Minnesota Multiphasic Personality Inventory. AB - ARGUMENT: The Minnesota Multiphasic Personality Inventory (MMPI) was developed at the University of Minnesota, Minneapolis, in the 1930s and 1940s. It became a highly successful and highly controversial psychometric tool. In professional terms, psychometric tools such as the MMPI transformed psychology and psychiatry. Psychometric instruments thus readily fit into the developmental history of psychology, psychiatry, and neurology; they were a significant part of the narrative of those fields' advances in understanding, intervening, and treating people with mental illnesses. At the same time, the advent of such tools also fits into a history of those disciplines that records the rise of obsessional observational and evaluative techniques and technologies in order to facilitate patterns of social control that became typical during the Progressive Era in the United States and after. It was those patterns that also nurtured the resistance to psychometrics that emerged during the Vietnam War and after. PMID- 25832572 TI - The Surgical Elimination of Violence? Conflicting Attitudes towards Technology and Science during the Psychosurgery Controversy of the 1970s. AB - ARGUMENT: In the 1970s a public controversy erupted over the proposed use of brain operations to curtail violent behavior. Civil libertarians, civil rights and community activists, leaders of the anti-psychiatry movement, and some U.S. Congressmen charged psychosurgeons and the National Institute of Mental Health, with furthering a political project: the suppression of dissent. Several government-sponsored investigations into psychosurgery rebutted this charge and led to an official qualified endorsement of the practice while calling attention to the need for more "scientific" understanding and better ethical safeguards. This paper argues that the psychosurgery debate of the 1970s was more than a power struggle between members of the public and the psychiatric establishment. The debate represented a clash between a postmodern skepticism about science and renewed focus on ultimate ends, on the one hand, and a modern faith in standards and procedures, a preoccupation with means, on the other. These diverging commitments made the dispute ultimately irresolvable. PMID- 25832573 TI - Contending professions: sciences of the brain and mind in the United States, 1850 2013. AB - Argument This paper examines the intersecting histories of psychiatry and psychology (particularly in its clinical guise) in the United States from the second half of the nineteenth century to the present. It suggests that there have been three major shifts in the ideological and intellectual orientation of the "psy complex." The first period sees the dominance of the asylum in the provision of mental health care, with psychology, once it emerges in the early twentieth century, remaining a small enterprise largely operating outside the clinical arena, save for the development of psychometric technology. It is followed, between 1945 and 1980, by the rise of psychoanalytic psychiatry and the emergence of clinical psychology. Finally, the re-emergence of biological psychiatry is closely associated with two major developments: an emphasis that emerges in the late 1970s on rendering the diagnosis of psychiatric illnesses mechanical and predictable; and the long-term effects of the psychopharmacological revolution that began in the early 1950s. This third period has seen a shift the orientation of mainstream psychiatry away from psychotherapy, the end of traditional mental hospitals, and a transformed environment within which clinical psychologists ply their trade. PMID- 25832574 TI - Epilogue: the redux of postmodernity. PMID- 25832576 TI - [Improving Access to Evidence Based Interventions for Children and Adolescents with Mental Disorders After Child Abuse and Neglect]. AB - Victims of child abuse and neglect are more likely to develop emotional and behavioral problems than their non-abused peers. In many cases they do not receive evidence based treatments. Based on pilot studies and clinical experience, a structured and manualized case-management protocol was developed to provide child welfare professionals guidance, direction and support in helping these families find and engage in appropriate treatment. The protocol is described. A survey among child welfare workers indicates a lack of knowledge about mental disorders in victims of child abuse as well as an insufficient cooperation between the child welfare and the mental healthcare system. Child welfare workers who have applied the manual evaluate it positively. This study shows that the structured case-management can be implemented in a child welfare setting. PMID- 25832577 TI - [Knowledge of Emotion Regulation Strategies, Problem Behavior, and Prosocial Behavior in Preschool Age]. AB - The present study examines the relation between knowledge of emotion regulation strategies and social behavior in preschoolers. Knowledge of emotion regulation strategies of 210 children (mean age 55 months) was assessed. Teachers rated children's social behavior with SDQ. Linear regression analysis examined how knowledge of emotion regulation strategies influenced social behavior of children. Significant effects of gender on SDQ scales "prosocial behavior", "hyperactivity", "behavior problems", and SDQ total problem scale were identified. Age was a significant predictor of SDQ scales "prosocial behavior", "hyperactivity", "problems with peers" and SDQ total problem scale. Knowledge of emotion regulation strategies predicted SDQ total problem scores. Results suggest that deficits in knowledge of emotion regulation strategies are linked with increased problem behavior. PMID- 25832578 TI - [Efficacy of the "Tuebinger-Intensiv-Programm fur Eltern" in Treating Childhood Anxieties - A Pilot Study]. AB - Anxiety problems among young children are highly prevalent and related to family factors such as parenting behavior or parental psychological health. The current pilot study examined the effectiveness of the non-specific, short-term, behavioral-hypnotherapeutic parent training Tipe in treating abnormal childhood anxieties. Childhood anxiety, parenting behavior, parenting sense of competence, and psychological stress of the parents were measured at three points in time (pretest, posttest, 3-month follow-up). Obtained data was compared to a waiting list control condition. After participating, parents of the treatment condition reported less dysfunctional parenting behavior, less psychological stress, and higher parenting sense of competence. Their children were significantly less anxious. These effects were stable after three months. Families of the waiting list control condition, however, showed no significant changes. We conclude that a general behavioral-hypnotherapeutic parent training positively affects the course of childhood anxiety problems. PMID- 25832579 TI - [Creation of Speech in Adolescents]. AB - In therapeutic preliminary talks, the therapist and the adolescent person (the potential patient) are together trying to answer the question of the indication. This is why every preliminary talk is designed like a "trial therapeutical session". The study tries to answer the question of the cognitive organization of the verbalization from a sozio-scientific point of view. A sociological interpretative approach was chosen to analyse transcripts of recordings of 30 of such therapeutic preliminary sessions, which provide the foundation for the study. The sociological-interpretative method allows it to filter out several phenomenons of verbal interaction, as for example when there is an incongruity of the different perceptions of "everyday life" and "therapy". A speech-style model is used to evaluate the formal result of the indication (as well as of the therapy). PMID- 25832583 TI - Subvisible (2-100 MUm) Particle Analysis During Biotherapeutic Drug Product Development: Part 1, Considerations and Strategy. AB - Measurement and characterization of subvisible particles (defined here as those ranging in size from 2 to 100 MUm), including proteinaceous and nonproteinaceous particles, is an important part of every stage of protein therapeutic development. The tools used and the ways in which the information generated is applied depends on the particular product development stage, the amount of material, and the time available for the analysis. In order to compare results across laboratories and products, it is important to harmonize nomenclature, experimental protocols, data analysis, and interpretation. In this manuscript on perspectives on subvisible particles in protein therapeutic drug products, we focus on the tools available for detection, characterization, and quantification of these species and the strategy around their application. PMID- 25832585 TI - JFMS Open Reports - innovation in feline veterinary publishing. PMID- 25832584 TI - FBXL5 inhibits metastasis of gastric cancer through suppressing Snail1. AB - BACKGROUND/AIMS: The Snail family of transcription factors controls epithelial to mesenchymal transition (EMT), a process associated with tumorigenesis originated from epithelial cells. Snail1 is a member from Snail family and upregulation of Snail1 has been detected in gastric cancer (GC), suggesting a potential role of Snail1 in GC metastasis. We have recently reported that FBXL5 regulates cortactin by inducing its ubiquitylation and subsequent proteasomal degradation, resulting in inhibition of metastasis of GC. However, a role of FBXL4 in regulation of other EMT-associated proteins is not unknown. METHODS: The levels of FBXL5 and Snail1 as well as their relationship were determined in GC specimen. Co immunoprecipitation (IP) was performed to detect the interaction between Snail1 and FBXL5 in GC cells. The effects on Snail1 by FBXL5 were examined by overexpression of depletion of FBXL5 in GC cells. The invasiveness of the FBXL5 modified GC cells was examined in both scratch wound healing assay and transwell matrix penetration assay. RESULTS: FBXL5 also physiologically interacted with Snail1. FBXL5 inhibited Snail1 to suppress GC cell invasiveness. CONCLUSION: FBXL5 negatively regulates several EMT-enhancing factors. FBXL5 is an attractive novel target for inhibiting invasion and metastasis of GC cells. PMID- 25832586 TI - Practical use of opioids in cats: a state-of-the-art, evidence-based review. AB - RATIONALE: Recent recognition of the need to improve pain management in cats has led to the investigation of the pharmacokinetics and efficacy of opioid analgesic drugs in this species. The results of these studies may be difficult to interpret because the effect of these drugs varies with dose, route of administration and the method used to assess them. As equipotency of different opioids is not known, it is hard to compare their effects. Animals do not verbalise the pain they feel and, in cats, it may be more difficult to recognise signs of pain in comparison with other species such as dogs. AIM: This article reviews the use of opioid analgesics in cats. It must be remembered that not all drugs are licensed for use in cats, and that marketing authorisations vary between different countries. PMID- 25832587 TI - Epigenetic regulation by histone demethylases in hypoxia. AB - The response to hypoxia is primarily mediated by the hypoxia-inducible transcription factor (HIF). Levels of HIF are regulated by the oxygen-sensing HIF hydroxylases, members of the 2-oxoglutarate (2OG) dependent oxygenase family. JmjC-domain containing histone lysine demethylases (JmjC-KDMs), also members of the 2OG oxygenase family, are key epigenetic regulators that modulate the methylation levels of histone tails. Kinetic studies of the JmjC-KDMs indicate they could also act in an oxygen-sensitive manner. This may have important implications for epigenetic regulation in hypoxia. In this review we examine evidence that the levels and activity of JmjC-KDMs are sensitive to oxygen availability, and consider how this may influence their roles in early development and hypoxic disease states including cancer and cardiovascular disease. PMID- 25832588 TI - Across all solid organs, adolescent age recipients have worse transplant organ survival than younger age children: A US national registry analysis. AB - Univariate analyses suggest that adolescents have worse long-term allograft survival versus younger children across different SOT. This study's objective was to determine whether multivariate analyses of a large national database recording all deceased SOT (KI; LI; HR; LU) also show worse adolescent allograft survival in the different organs. Using data from the national Scientific Registry for Transplant Recipients in the USA for pediatric primary SOT from 1989 to 2010, we calculated median half-lives and constructed K-M graft survival curves. Recipient age at transplant (<12 or adolescent 12-17 yr) was fitted with other identical covariates into multivariate Cox proportional hazards models. In all SOT recipients, unadjusted graft survival curves demonstrated better graft survival for adolescents initially, followed by crossing of the lines, such that adolescent SOT recipients had worse survival after one yr (KI), 4.6 yr (LI), 4.4 yr (HR), and 1.6 yr (LU). Multivariate models of the post-cross period showed a significantly higher AHR for worse graft survival in adolescent age across all four SOTs: AHR 1.400 (KI), 1.958 (LI), 1.414 (HR), and 1.576 (LU). Improving adolescent long-term outcomes across all four organs will be a defining issue in the future. PMID- 25832589 TI - Dopamine D2 receptor blocker thioridazine induces cell death in human uterine cervical carcinoma cell line SiHa. AB - AIM: The aim of this study was to explore the correlation of dopamine D2 receptor (DRD2) and the development of uterine cervical cancer, and the effect of thioridazine (an antagonist of DRD2) on the SiHa cell line. MATERIAL AND METHODS: The expression of DRD2 in tissues was detected with immunohistochemistry. SiHa cells were exposed to different concentrations of thioridazine for 24 h, and then cell viability was determined. After 20-MUM thioridazine treatment for 24 h, the protein level of DRD2 in SiHa cells was analyzed by Western blots, apoptosis was detected with the phosphatidylserine externalization and comet assay, and necrosis was detected by measuring high-mobility group box 1 protein (HMGB1). RESULTS: The expression of DRD2 gradually increased from normal to cancer tissues (P < 0.01). In vitro, DRD2 blocker thioridazine treatment resulted in death of SiHa cells with the expression of DRD2 significantly regulated down (P < 0.05), and thioridazine significantly induced SiHa apoptosis (P = 0.016) and necrosis (P < 0.01). CONCLUSION: Higher DRD2 expression is closely associated with cervical cancer progression. After blocking DRD2, SiHa cell growth is significantly suppressed, indicating that DRD2 may function as a novel tumor marker and a potential therapeutic target for cervical cancer. PMID- 25832590 TI - Evaluating the effect of oral administration of Echinacea hydroethanolic extract on the immune system in dog. AB - This study was designed to evaluate the effects of oral administration of Echinacea hydroethanolic extract on the dog's immune system. The study was performed on 14 dogs that were referred to the veterinary clinic. These dogs were randomly allocated to two equal treatment groups. The first group received 1 ml of 5% Echinacea hydroethanolic extract two times a day for 2 months, and the second group received a placebo (water). To do haematology and immunology tests, the dogs were bled on days 0, 30 and 60. Blood tests, including packed cell volume (PCV), haemoglobin (Hb), red blood cell count (RBC), white blood cell count (WBC), counting neutrophils (Nut), lymphocytes (Lym), monocytes (Mon), eosinophils (Eos), basophils (Baso) and B cell, were performed. Furthermore, safety factor IgM and per cent of phagocytosis and phagocyte were measured from the blood sample. The results showed that in the group which received Echinacea PCV, Hb, RBC count, WBC count, Lym, Nut, the per cent of phagocytosis and IgM significantly increased (P < 0.05). Moreover, positive effects of Echinacea plant on the immune system were observed. There was a significant change in HTC, RBC, Hb over time in the group that received Echinacea and the per cent of phagocytosis and IgM (P < 0.05). The study establishes that these extracts might have appreciable immunostimulatory activity. However, further studies are required to confirm these findings. PMID- 25832591 TI - Transcatheter closure of patent ductus arteriosus in under 6 kg and premature infants. AB - BACKGROUND: Transcatheter closure of a patent ductus arteriosus (PDA) has always been considered risky for infants weighing <6 kg and preterms. We present our findings regarding transcatheter closures of PDA. METHODS: The inclusion criteria were a weight of <6 kg and the presence of PDA symptoms. The study subjects were divided into two groups: <6 kg and premature infants. RESULTS: A total of 69 infants were included. The mean ages and weights of the <6 kg and the preterms were 5.4 +/- 2.7 months and 30.3 +/- 19.9 days, and 4.6 +/- 0.8 and 1.7 +/- 0.3 kg, respectively. Type C PDAs were most frequently observed in the premature group, and type A was in <6 kg. Sixteen of the patients were premature infants, and 81.2% of them had an extremely low birth weight. All of the premature infants had comorbidities, and had been receiving respiratory support therapy. Transcatheter closure was successfully completed in 81.2% of the premature infants and 94.3% of the <6-kg infants. Major complications occurred in 4 patients (one death and three device embolizations). The patient's age was found to be the main risk factor. The most frequently used device was the Amplatzer duct occluder II in additional sizes (84.6%) in the preterms and the Amplatzer duct occluder I (34%) and II (34%) in the <6-kg group. CONCLUSION: The transcatheter closure of PDA is relatively safe and effective in preterms and in infants <6 kg. The selection of a suitable device based on the type of PDA is critical to the success of the procedure. PMID- 25832592 TI - Addressing apoptosis to tumor zip codes. PMID- 25832594 TI - Head and Neck Trauma: Introduction. PMID- 25832593 TI - Down-Regulation of Renal Gluconeogenesis in Type II Diabetic Rats Following Roux en-Y Gastric Bypass Surgery: A Potential Mechanism in Hypoglycemic Effect. AB - OBJECTIVE: This study was initiated to evaluate the effects of Roux-en-Y gastric bypass surgery on renal gluconeogenesis in type 2 diabetic rats and its relationship with hormonal parameters. METHODS: Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ; 35 mg/kg) combined with a high fat diet. They were then randomly divided into three groups: diabetes model group (DM group, n = 8), sham Roux-en-Y gastric bypass group (SRYGB group, n = 8), and Roux-en-Y gastric bypass group (RYGB group, n = 14). Another 8 normal rats comprised the normal control group (NC group, n = 8). Body weight, glucose, serum lipid, insulin, glucagon-like peptide-1 (GLP-1), leptin, and adiponectin were measured pre- and postoperatively. Glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor-alpha (IR-alpha), insulin receptor-beta (IR-beta), and glycogen synthase kinase 3 beta (Gsk3b) were measured in renal cortex by using RT-PCR and Western immune-blot analyses on the 4th week after operation. RESULTS: Following RYGB surgery, surgery-treated rats showed significantly improved oral glucose tolerance, dyslipidemia and insulin resistance as well as increased post-gavage insulin levels and serum circulating levels of GLP-1 and adiponectin. RT-PCR and Western immune-blot analyses showed PEPCK and G6Pase protein and mRNA to be significantly decreased in the renal cortex in the RYGB group (p < 0.05 vs. DM or SRYGB group); in addition, IR-alpha and Gsk3b phosphorylation levels increased in the RYGB group (p < 0.05 vs. DM or SRYGB group). CONCLUSION: Down-regulation of renal gluconeogenic enzymes might be a potential mechanism in hypoglycemia. An improved insulin signal pathway in the renal cortex and increased circulating adiponectin concentrations may contribute to the decline of renal gluconeogenesis following RYGB surgery. PMID- 25832595 TI - Antifungal efficacy of the cactaceae Opuntia stricta (Haworth) prickly pear ethanolic extract in controlling pikeperch Sander lucioperca (Linnaeus) egg saprolegniasis. PMID- 25832596 TI - Vascular medicine and phlebology: where do we intersect? PMID- 25832597 TI - Beyond Virchow's Triad: does cardiovascular inflammation explain the recurrent nature of venous thromboembolism? PMID- 25832598 TI - Association of foot and ankle characteristics with progression of venous disease. AB - Although risk factors have been identified for the cross-sectional prevalence of venous disease, few studies have investigated risk factors for venous disease progression. Therefore, the aim of this study was to investigate the relationship between foot and ankle characteristics and the progression of venous disease. A total of 1025 participants from the San Diego Population Study were assessed at baseline and at follow-up 11 years later. Risk factors were assessed by questionnaire and physical measurements, while venous disease was determined by physical examination and Duplex ultrasound. Change in venous disease from baseline to 11-year follow-up was characterized as stable or progression. Those with venous disease progression were less likely to spend increased time lying per day, more likely to have a history of hypertension, lie supine for a surgical procedure greater than an hour, and report an occupation that was professional, technical, administrative, or management. Those with a normal arch reported the greatest degree of plantar flexion. In multivariable logistic regression, including adjustment for weight-bearing arch characteristics, greater dorsiflexion (per 5 degrees) was significantly associated with progression of venous disease (OR = 1.11, p = 0.01). A weight-bearing flat arch compared to a weight-bearing normal arch was of borderline significance as a protective factor against progression of venous disease with adjustment for dorsiflexion (OR = 0.56, p = 0.07). Our results indicate that the ability to have higher levels of dorsiflexion is a risk factor for the progression of venous disease, and suggest a role for connective tissue laxity in the pathogenesis of venous disease. PMID- 25832599 TI - Low incidence of post-thrombotic syndrome in patients treated with new oral anticoagulants and percutaneous endovenous intervention for lower extremity deep venous thrombosis. AB - Post-thrombotic syndrome (PTS) is a common complication of deep venous thrombosis (DVT) of the iliofemoral venous system leading to significant morbidity and high health care costs. It has been recently shown that percutaneous endovenous intervention (PEVI) can effectively reduce the incidence of PTS. The role of new oral anticoagulants (NOACs) in combination with PEVI in the reduction of PTS has not been previously studied. This report sought to evaluate the role of PEVI plus NOACs in the reduction of PTS in acute symptomatic femoropopliteal and iliac DVT. We studied 127 patients with acute lower extremity DVT who had undergone PEVI plus administration of NOACs. All had received a minimum of 3 months of anticoagulation with a NOAC following PEVI. The mean follow-up was 22+/-5 months. The patients were evaluated for development of PTS, bleeding, recurrent venous thromboembolism (VTE), duration of hospitalization and mortality. There was no in hospital bleeding. The mean duration of hospitalization was 46+/-9 hours. DVT occurred in two patients who had been later switched to warfarin. There were four non-VTE-related deaths. PTS developed in five patients (3%), two of whom were those who had been switched to warfarin. Their mean Villalta score was 6.2+/-0.9. We conclude that the combination of PEVI plus NOAC and low dose aspirin is associated with a very low rate of PTS with the severity being only mild. This approach leads to very low rates of bleeding and recurrent VTE and promotes early discharge. PMID- 25832600 TI - A retrospective analysis of catheter-based thrombolytic therapy for acute submassive and massive pulmonary embolism. AB - Catheter-based thrombolysis (CBT) is emerging as an option for acute pulmonary embolism (PE). Although prior studies have demonstrated improvement in right ventricular function, little data is available regarding clinical patient outcomes. Our institution adopted CBT as an option for patients with submassive and massive PE and we evaluated its effect on patient outcomes. Two hundred and twenty-one patients who presented to our institution with submassive and massive PE were analyzed over three years by time period; 102 prior to the use of CBT and 119 during the time CBT was performed. The primary outcome was in-hospital major adverse clinical events (a composite of death, recurrent embolism, major bleeding, or stroke). Secondary outcomes were overall and ICU length of stay and individual components of the composite outcome. Mean age was 56.3+/-16 years with high rates of central PE (57.9%), RV dysfunction (37%), and myocardial necrosis (26%). Mean RV/LV ratio was 1.2. Thirty-two patients were treated with CBT. The composite endpoint occurred more frequently in the CBT era vs the pre-CBT era (21.0% vs 14.7%, p=0.23). After multivariate adjustment, CBT treatment demonstrated no effect on major adverse clinical events (OR 0.84, CI 0.22-3.22, p=0.80). CBT era patients had an unadjusted 37% increase in ICU days and 54% increase in total length of stay (p<0.001). Within the CBT era, CBT treatment resulted in an adjusted 190% increase in overall length of stay (p<0.001). CBT did not demonstrate improvement in hospital outcomes, despite adjustments of PE severity, and was associated with a significant increase in overall and ICU length of stay. PMID- 25832601 TI - Comparative efficacy of different modalities for treatment of right heart thrombi in transit: a pooled analysis. AB - The objective was to compare the efficacy of treatment options for right heart thrombi (RHT) in transit. All published reports between 1992 and 2013 were identified and pooled. We analyzed 328 patients with RHT and pulmonary embolism (PE). The treatments administered were none in 11 patients (3.4%), anticoagulation (AC) with heparin in 70 patients (21.3%), thrombolytics in 122 patients (37.2%), catheter-related treatments in five patients (1.5%) and surgical embolectomy in 120 patients (36.6%). The overall short-term mortality for the entire cohort was 23.2%. The mortality rate associated with no therapy was highest at 90.9%. The mortality associated with AC alone was significantly higher than surgical embolectomy or thrombolysis (37.1% vs 18.3% vs 13.7%, respectively). In univariate analysis, any therapy was better than no therapy with a favorable odds of 16.92 (95% CI 2.05-139.87) for AC, 61.76 (95% CI 7.42 513.81) for thrombolysis and 44.54 (95% CI 5.42-366.32) for surgical embolectomy. In multivariate analysis with age and hemodynamic status entered as covariates, thrombolytic therapy was better than AC with favorable odds of 4.83 (95% CI 1.52 15.36). Similarly, there was a trend in favor of surgical embolectomy with an odds of 2.61 (95% CI 0.90-7.58). The estimated probability of survival in hemodynamically unstable patients with AC, surgical embolectomy and thrombolysis was 47.7%, 70.45% and 81.5%, respectively. There was no significantly increased risk of complications with thrombolytic therapy. In conclusion, left untreated, patients with RHT and PE have very high mortality. Aggressive management with thrombolysis or surgical thrombectomy may be more effective than AC alone in the management of these patients. PMID- 25832602 TI - Venous thromboembolism: Predicting recurrence and the need for extended anticoagulation. AB - Initial treatment for venous thromboembolism (VTE) includes the acute and intermediate phases, usually lasting for 3 months. The choice to extend therapy beyond the initial 3-month window involves assessing a combination of risk factors for VTE recurrence and bleeding, along with weighing patient preferences. In some cases, such as VTE provoked by a reversible surgical risk factor, the recurrence risk is sufficiently low that most patients should not receive extended therapy. In other cases, such as VTE associated with malignancy, the recurrence risk is sufficiently high that treatment should be extended beyond the initial 3 months. However, a large number of patients fall into a grey zone where the decision on extended therapy is less clear-cut. In this review, we summarize the evidence for VTE recurrence risk and the role for extended anticoagulation given a variety of patient-specific factors and laboratory results. We also review the role of VTE risk prediction tools and provide a recommended algorithm for approaching the decision of extended anticoagulation therapy. Various agents available for extended VTE therapy, including warfarin, aspirin and the direct oral anticoagulant agents, are discussed. PMID- 25832604 TI - Venous leg ulceration pathophysiology and evidence based treatment. AB - Venous leg ulceration (VLU) is one of the most predominate medical disorders worldwide and in the western hemisphere it affects around 1.5% of the general population and up to 5% of the elderly population. Unfortunately, this trend will only increase given the growth of an aging population worldwide. Understanding its pathophysiology that begins with venous hemodynamic abnormalities and leads to inflammatory alterations with microcirculatory changes is critical to delivering effective curative therapy. As such, the main component to treatment is reversing the underlying venous hypertension and pro-inflammatory milieu using compression treatment along with various adjuvant therapies. Given its impact, a comprehensive multi-pronged approach to care, treatment and prevention is required to reverse the increasing trend that is observed worldwide. PMID- 25832605 TI - Venous thoracic outlet syndrome. AB - Venous thoracic outlet syndrome is a complex but rare disease that often can have excellent outcomes if quickly recognized and treated. The syndrome results from compression of the subclavian vein along its exit from the thoracic cavity and frequently affects young otherwise healthy patients. Modern diagnosis is made with a combination of clinical exam, appropriate non-invasive imaging, and, finally, contrast venography, which can be both diagnostic and therapeutic. Treatments have evolved over time to the point where patients can undergo less extensive procedures than previously performed and still maintain excellent outcomes. One of the most important predictors of outcome is the initiation of treatment within 14 days of symptoms. Hence, the importance of the accurate and prompt diagnosis of this syndrome in patients with an upper-extremity deep vein thrombotic episode cannot be further underscored. This review is a concise summary of the background and treatment algorithm for this patient population. PMID- 25832603 TI - Approach to chemotherapy-associated thrombosis. AB - Treatment of cancer patients with antineoplastic agents is associated with a heightened risk of thrombotic events, both arterial and venous. In this article, we review the specific agents that are implicated and the pathophysiological processes that are known to be associated with this prothrombotic state. We conclude with current recommendations for prophylactic antithrombotic therapy in these clinical situations. PMID- 25832606 TI - Thrombophilia. PMID- 25832608 TI - Comment on: A critical evaluation of the trigger point phenomenon: reply. PMID- 25832609 TI - Good response to tumour necrosis factor alpha blockade results in an angiogenic T cell recovery in rheumatoid arthritis patients. PMID- 25832610 TI - Inhibiting histone deacetylase 1 suppresses both inflammation and bone loss in arthritis. AB - OBJECTIVE: Histone deacetylase 1 (HDAC1) is highly expressed in the synovium of RA patients. Thus we aimed to investigate a novel HDAC inhibitor (HDACi), NW-21, designed to target HDAC1. The effect of NW-21 on osteoclast formation and activity, cytokine and chemokine expression in vitro and arthritis in mice was assessed. METHODS: The effects on human osteoclast formation and activity derived from human blood monocytes stimulated with receptor activator of nuclear factor kappaB ligand (RANKL) and M-CSF were assessed. The anti-inflammatory activity of NW-21 was assessed using human monocytes stimulated with either TNF-alpha or lipopolysaccharide for 24 h. mRNA expression of monocyte chemotactic protein 1 (MCP-1), TNF-alpha, macrophage inflammatory protein 1alpha (MIP-1alpha), IL-1 and RANTES (regulated on activation, normal T cell expressed and secreted) was assessed. The effect of NW-21 in the collagen antibody-induced arthritis model was assessed following daily oral administration at 5 mg/kg/day. The HDAC1 inhibitors NW-21 and MS-275 were compared with a broad-acting HDACi, 1179.4b. Effects on inflammation and bone were assessed using paw inflammation scoring, histology and live animal micro-CT. RESULTS: NW-21 suppressed osteoclast formation and activity as well as significantly reducing mRNA expression of MCP-1 and MIP-1alpha in monocytes stimulated by lipopolysaccharide or TNF-alpha (P < 0.05) in vitro. Only inhibitors that targeted HDAC1 (NW-21 and MS-275) reduced inflammation and bone loss in the arthritis model. CONCLUSION: The results indicate that inhibitors targeting HDAC1, such as NW-21 and MS-275, may be useful for treating RA, as such drugs can simultaneously target both inflammation and bone resorption. PMID- 25832611 TI - A comparative analysis of magnetic resonance imaging and high-resolution peripheral quantitative computed tomography of the hand for the detection of erosion repair in rheumatoid arthritis. AB - OBJECTIVES: To investigate whether MRI allows the detection of osteosclerosis as a sign of repair of bone erosions compared with high-resolution peripheral quantitative computed tomography (HR-pQCT) as a reference and whether the presence of osteosclerosis on HR-pQCT is linked to synovitis and osteitis on MRI. METHODS: A total of 103 RA patients underwent HR-pQCT and MRI of the dominant hand. The presence and size of erosions and the presence and extent (grades 0-2) of osteosclerosis were assessed by both imaging modalities, focusing on MCP 2 and 3 and wrist joints. By MRI, the presence and grading of osteitis and synovitis were assessed according to the Rheumatoid Arthritis MRI Score (RAMRIS). RESULTS: Parallel evaluation was feasible by both modalities on 126 bone erosions. Signs of osteosclerosis were found on 87 erosions by HR-pQCT and on 22 by MRI. False positive results (MRI(+)CT(-)) accounted for 3%, while false-negative results (MRI(-)CT(+)) accounted for 76%. MRI sensitivity for the detection of osteosclerosis was 24% and specificity was 97%. The semi-quantitative scoring of osteosclerosis was reliable between MRI and HR-pQCT [intraclass correlation coefficient 0.917 (95% CI 0.884, 0.941), P < 0.001]. The presence of osteosclerosis on HR-pQCT showed a trend towards an inverse relationship to the occurrence and extent of osteitis on MRI [chi(2)(1) = 3.285; phi coefficient = 0.124; P = 0.070] but not to synovitis [chi(2)(1) = 0.039; phi coefficient = 0.14; P = 0.844]. CONCLUSION: MRI can only rarely detect osteosclerosis associated with bone erosions in RA. Indeed, the sensitivity compared with HR pQCT is limited, while the specificity is high. The presence of osteitis makes osteosclerosis more unlikely, whereas the presence of synovitis is not related to osteosclerosis. PMID- 25832612 TI - Comment on: A critical evaluation of the trigger point phenomenon. PMID- 25832613 TI - Pregnancy outcome in patients with systemic vasculitis: a single-centre matched case-control study. AB - OBJECTIVE: To study the outcome of pregnancy in patients with systemic vasculitis (SV) compared with age-, BMI- and ethnicity-matched healthy pregnant controls. METHODS: Fifty-one pregnancies in 29 SV patients were retrospectively studied. There were nine patients with granulomatosis with polyangiitis (GPA), three with eosinophilic GPA, seven with Takayasu's arteritis, two with ANCA-positive vasculitis with renal involvement, two with Behcet's disease, three with urticarial vasculitis, one with primary cerebral vasculitis, one with relapsing polychondritis and one with IgA vasculitis. BVAS and the vasculitis damage index were evaluated retrospectively. Sixty-two healthy women with 156 pregnancies matched in a 2:1 ratio for age, BMI and ethnicity formed the control group. RESULTS: Median gestational age at delivery was lower in the SV group: 36 weeks and 2 days (34-42) vs controls 40 (37-42) weeks (P < 0.03). Median birth weight in the SV group was 3.0 kg (2.0-5.2), whereas that of the controls was 3.5 (2.28 4.32) kg (P = 0.004). The median customized birth weight centile was 38.6 in the SV group and 37.2 in the control group. In the SV group, 9 patients had 13 miscarriages, 3 had pre-eclampsia, and 2 had an intrauterine death. In the control group, 20 patients had 27 miscarriages, 1 had pre-eclamptic toxaemia, and 1 had an antepartum haemorrhage. Eight patients with SV flared during pregnancy and 11 flared after delivery. CONCLUSION: Patients with SV had a lower median gestational age, but customized birth weights were similar to those of healthy women. Women with SV may flare during pregnancy and the post-partum period and may experience significant pregnancy morbidity. PMID- 25832614 TI - Comment on: The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis: reply. PMID- 25832615 TI - Comment on: The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. PMID- 25832616 TI - A practical approach to acute hemiparesis in children. AB - Acute hemiparesis in children is a common clinical syndrome presenting to a variety of care settings. The recognition and the differential diagnosis is challenging, particularly in young children. Arterial ischaemic stroke (AIS) is the primary diagnosis to be considered as this requires emergency investigations and management; however, there are several conditions collectively described as 'stroke mimics' that need consideration. Accurate diagnosis is essential for appropriate management. Clinical data combined with neuroimaging are important for accurate diagnosis and management. This review and the accompanying illustrative case vignettes suggest a practical approach to differential diagnosis and management of children presenting with acute hemiparesis. PMID- 25832617 TI - U.S. General Population Estimate for "Excellent" to "Poor" Self-Rated Health Item. AB - BACKGROUND: The most commonly used self-reported health question asks people to rate their general health from excellent to poor. This is one of the Patient Reported Outcomes Measurement Information System (PROMIS) global health items. Four other items are used for scoring on the PROMIS global physical health scale. Because the single item is used on the majority of large national health surveys in the U.S., it is useful to construct scores that can be compared to U.S. general population norms. OBJECTIVE: To estimate the PROMIS global physical health scale score from the responses to the single excellent to poor self-rated health question for use in public health surveillance, research, and clinical assessment. DESIGN: A cross-sectional survey of 21,133 individuals, weighted to be representative of the U.S. general population. PARTICIPANTS: The PROMIS items were administered via a Web-based survey to 19,601 persons in a national panel and 1,532 subjects from PROMIS research sites. The average age of individuals in the sample was 53 years, 52 % were female, 80 % were non-Hispanic white, and 19 % had a high school degree or lower level of education. MAIN OUTCOME MEASURES: PROMIS global physical health scale. KEY RESULTS: The product-moment correlation of the single item with the PROMIS global physical health scale score was 0.81. The estimated scale score based on responses to the single item ranged from 29 (poor self-rated health, 2.1 SDs worse than the general population mean) to 62 (excellent self-rated health, 1.2 SDs better than the general population mean) on a T-score metric (mean of 50). CONCLUSIONS: This item can be used to estimate scores for the PROMIS global physical health scale for use in monitoring population health and achieving public health objectives. The item may also be used for individual assessment, but its reliability (0.52) is lower than that of the PROMIS global health scale (0.81). PMID- 25832618 TI - Horner's, Heterochromia, and Harlequins. PMID- 25832619 TI - Industry Collaboration and Primary Guest Authorship of High-Impact Randomized Clinical Trials: A Cross-Sectional Study. AB - BACKGROUND: Journals have increased disclosure requirements in recent years, in part to deter guest authorship. The prevalence of guest authorship among primary authors (first and last) in the current era of increased disclosure requirements is unknown. OBJECTIVES: Our aim was to examine the self-reported prevalence of guest authorship among primary authors from a sample of randomized clinical trials with and without industry funding and industry collaboration in the design, analysis or reporting of trials. DESIGN: Cross-sectional analysis of randomized, drug/device clinical trials with published details on the "Role of the Funding Source/Sponsor" published in high-impact biomedical journals between 1 December 2011 and 31 November 2012. Phase 1 or 2 trials, secondary trial analyses, and trials that were not listed on ClinicalTrials.gov were excluded. Primary guest authorship was defined, based on International Committee of Medical Journal Editors (ICMJE) criteria, when neither the first nor last author contributed to either of the following: 1) the design of the trial or the analysis/interpretation of data; or 2) drafting part or all of the manuscript. PARTICIPANTS: One hundred and sixty-eight randomized clinical trials that met inclusion criteria were included. MAIN OUTCOME MEASURES: We measured differences in the prevalence of guest authorship between trials with neither industry funding nor collaboration and 1) trials with industry funding without collaboration, and 2) trials with industry funding with collaboration. RESULTS: The overall prevalence of primary guest authorship was 6 % (10/168). Primary guest authorship was significantly more common in trials with industry funding with collaboration than in those with neither industry funding nor collaboration [13.2 % (10/76) vs. 0 % (0/39); p < 0.02]. Primary guest authorship did not differ between trials with industry funding without collaboration and trials with neither industry funding nor collaboration. CONCLUSIONS: Among a sample of randomized, drug/device clinical trials in high-impact biomedical journals, primary guest authorship was overall uncommon and occurred exclusively among trials with industry funding with collaboration. PMID- 25832620 TI - Not just pathophysiology.... PMID- 25832621 TI - Increased osteogenesis in osteoporotic bone marrow stromal cells by overexpression of leptin. AB - Osteoporosis leads to increased bone fractures and net bone loss, in part because of the dysfunction of bone marrow stromal cells (BMSCs). Leptin is an adipokine that plays important roles in many biological processes, including the regulation of the actions of mesenchymal stem cells. Our aim is to investigate the osteogenic effects of leptin in osteoporotic BMSCs in vitro and in vivo. The leptin gene was transferred into BMSCs isolated from osteoporotic rats by using recombinant adenoviruses. Once the gene and protein expression of leptin had been confirmed, MTT assays were performed; leptin overexpression was confirmed not to affect the viability of osteoporotic BMSCs. However, alkaline phosphatase (ALP) activity measurements, Alizarin red staining and analyses by quantitative real time reverse transcription with the polymerase chain reaction revealed that leptin upregulated ALP activity, mineral deposition and the mRNA levels of runt related transcription factor 2, ALP and collagen type I. Lastly, the effects of leptin on osteogenic differentiation were assessed in vivo. Cells transfected with leptin exhibited increased osteogenic differentiation and enhanced formation of bone-like structures. This study thus reveals, for the first time, that the overexpression of leptin in osteoporotic BMSCs (1) enhances their capacity to differentiate into osteoblasts and to form bone-like tissue and (2) might be a useful skeletal regenerative therapy in osteoporotic patients. PMID- 25832622 TI - Prolyl hydroxylase domain-2 silencing induced by hydrodynamic limb vein injection enhances vascular regeneration in critical limb ischemia mice through activation of multiple genes. AB - Therapeutic revascularization had been considered as the most potential strategy for treating ischemic diseases. Reconstruction of mature blood vessels, which is the key for functional revascularization, is a complex process involving multiple angiogenesis factors. Attempts had been made to promote functional revascularization by delivering vectors or other macromolecules that could positively regulate angiogenesis; however, the delivery method of these therapeutic angiogenesis factors had been mostly limited to direct intramuscular injection. In this study, we showed that compared to intramuscular injection, the hydrodynamic limb vein (HLV) injection of naked short-hairpin RNA expression plasmid targeting PHD2 (shPHD2) into critical himblimb ischemia mice could increase not only the expressions of HIF-dependent and HIF-independent angiogenic factors, but also tissue protective factors involved in various endogenous pathways more efficiently. We also found that PHD2-silencing enhanced innate endogenous recovery mechanism, as the expression levels of these factors had been slightly upregulated merely by the ischemic condition. Finally, we showed that HLV injection of shPHD2 promoted the formation of mature and functional vessels, and thus, enhances the recovery of ischemic hindlimbs more efficiently. These results suggest that HLV delivery of shPHD2 might become a promising treatment strategy to promote vascular regeneration in critical limb ischemia disease via enhancing innate endogenous pathways. PMID- 25832623 TI - Disrupting saccadic updating: visual interference prior to the first saccade elicits spatial errors in the secondary saccade in a double-step task. AB - When we explore the visual environment around us, we produce sequences of very precise eye movements aligning the objects of interest with the most sensitive part of the retina for detailed visual processing. A copy of the impending motor command, the corollary discharge, is sent as soon as the first saccade in a sequence is ready to monitor the next fixation location and correctly plan the subsequent eye movement. Neurophysiological investigations have shown that chemical interference with the corollary discharge generates a distinct pattern of spatial errors on sequential eye movements, with similar results also from clinical and TMS studies. Here, we used saccadic inhibition to interfere with the temporal domain of the first of two subsequent saccades during a standard double step paradigm. In two experiments, we report that the temporal interference on the primary saccade led to a specific error in the final landing position of the second saccade that was consistent with previous lesion and neurophysiological studies, but without affecting the spatial characteristics of the first eye movement. On the other hand, single-step saccades were differently influence by the flash, with a general undershoot, more pronounced for larger saccadic amplitude. These findings show that a flashed visual transient can disrupt saccadic updating in a double-step task, possibly due to the mismatch between the planned and the executed saccadic eye movement. PMID- 25832624 TI - Minimally invasive surgery for lumbar spinal stenosis. PMID- 25832625 TI - The Stability of Problem Behavior Across the Preschool Years: An Empirical Approach in the General Population. AB - This study examined the stability of internalizing and externalizing problems from age 1.5 to 6 years, while taking into account developmental changes in the presentation of problems. The study comprised a population-based cohort of 7,206 children (50.4 % boys). At ages 1.5, 3, and 6 years, mothers reported on problem behavior using the Child Behavior Checklist/1.5-5 (CBCL/1.5-5). At each age we performed latent profile analysis on the CBCL/1.5-5 scales. Latent transition analysis (LTA) was applied to study the stability of problem behavior. Profiles of problem behavior varied across ages. At each age, 82-87 % of the children did not have problems whereas approximately 2 % showed a profile of co-occurring internalizing and externalizing problems. This profile was more severe (with higher scores) at 6 years than at earlier ages. A predominantly internalizing profile only emerged at 6 years, while a profile with externalizing problems and emotional reactivity was present at each age. LTA showed that, based on profiles at 1.5 and 3 years, it was difficult to predict the type of profile at 6 years. Children with a profile of co-occurring internalizing and externalizing problems early in life were most likely to show problem behavior at 6 years. This study shows that the presentation of problem behavior changes across the preschool period and that heterotypic continuity of problems is very common among preschoolers. Children with co-occurring internalizing and externalizing problems were most likely to show persisting problems. The use of evidence-based treatment for these young children may prevent psychiatric problems across the life course. PMID- 25832627 TI - Happy birthday, Mr. President.... PMID- 25832626 TI - In vitro Induction of residual caries lesions in dentin: comparative mineral loss and nano-hardness analysis. AB - Artificially inducing dentinal lesions mimicking those remaining after selective excavation should allow to investigate the effects and limits of such selective excavation, for example regarding the mechanical properties of treated teeth or the remineralisation of sealed residual lesions. Such analyses might otherwise be limited by the variability of natural lesions or ethical and practical concerns. This study compared different demineralisation protocols for their suitability to induce lesions similar to natural residual caries. Twelve natural deep lesions were excavated until leathery dentin remained, and analysed for their mineral loss (DeltaZ), lesion depth (LD), mineral loss ratio (R), the slope of the mineral gradient and their nano-hardness profile. Artificial lesions were induced using four different demineralisation protocols (acetic acid pH = 4.95; 0.1 M lactic acid gel pH = 5.0; 0.5 M ethylenediaminetetraacetic acid pH = 7.2; Streptococcus mutans biofilms) and their depths monitored over different demineralisation times. Lesions with depths most according to those of natural lesions were analysed using transversal microradiography. Lesions induced by acetic acid solution did not significantly differ with regards to LD, DeltaZ, R and mineral profile. Seven dentin specimens were subsequently submitted to a moderately acidic (pH = 5.3) methylhydroxydiphosphonate-buffered acetate solution for 12 weeks. Natural and artificial residual lesions were similarly deep (mean +/- SD: LD = 626 +/- 212 and 563 +/- 88 um), demineralised (R = 19.5 +/- 4.7 and 29.8 +/- 4.1%), showed a flat and continuous mineral gradient (slope = 0.10 +/- 0.05 and 0.13 +/- 0.06 vol%/um) and did not significantly differ regarding their nano-hardness profile. The described protocol induces lesions with mineral content and mechanical properties similar to natural residual lesions. PMID- 25832628 TI - Prauserella endophytica sp. nov., an endophytic actinobacterium isolated from Tamarix taklamakanensis. AB - A novel endophytic actinobacterium, designated strain SP28S-3(T), was isolated from a surface-sterilized stem of Tamarix taklamakanensis collected from the southern edge of Taklamakan desert, Xinjiang, China. Strain SP28S-3(T) was found to show chemotaxonomic and morphological properties consistent with its classification in the genus Prauserella. The polar lipids were found to consist of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphoglycolipid, phosphatidylcholine, phosphatidylinositol, a glycolipid, an aminolipid and unidentified phospholipids. The major fatty acids (>10 %) were identified as iso-C16:0 and C16:0. The genomic DNA G+C content was determined to be 69.7 mol%. Phylogenetic analysis of strain SP28S-3(T) clearly showed that the strain had the highest similarity of 16S rRNA gene sequence with Prauserella coralliicola SCSIO 11529(T) (99.9 %), followed by Prauserella marina DSM 45268(T) (97.0 %) and is affiliated with the genus Prauserella. The low level (47.8 +/- 5.5 %) of DNA-DNA relatedness between strain SP28S-3(T) and P. coralliicola SCSIO 11529(T) combined with other polyphasic taxonomic evidence clearly support the conclusion that strain SP28S-3(T) represents a novel Prauserella species, for which the name Prauserella endophytica sp. nov. is proposed. The type strain is SP28S-3(T) (=DSM 46655(T) = CGMCC 4.7182 (T)). PMID- 25832629 TI - Enhanced Therapeutic siRNA to Tumor Cells by a pH-Sensitive Agmatine-Chitosan Bioconjugate. AB - Charge-conversional naturally occurring chitosan-agmatine bioconjugates are prepared by dimethylmaleic anhydride (DMA) modification and the nucleophilic reaction between tosyl of tosylated chitosan and primary amine of agmatine. These bioconjugates (CS-DM-Agm) are shown to condense siRNA into nanocomplexes, which are stable in the presence of serum at physical pH values. Furthermore, the surface charge of complexes can tune from negative to positive while pH is changed to weak acid tumor micromilieu, thus facilitating the target cancer cell internalization in resisting serum adsorption. More importantly, this smart biogenic system shows remarkable gene silencing efficiency and a high apoptotic rate of tumor cells both in vitro and in vivo, indicating its great potential for cancer therapy. PMID- 25832631 TI - Hypoxia decreases glucagon-like peptide-1 secretion from the GLUTag cell line. AB - Glucagon-like peptide-1 (GLP-1), an incretin hormone, is secreted from L cells located in the intestinal epithelium. It is known that intestinal oxygen tension is decreased postprandially. In addition, we found that the expression of hypoxia inducible factor-1alpha (HIF-1alpha), which accumulates in cells under hypoxic conditions, was significantly increased in the colons of mice with food intake, indicating that the oxygen concentration is likely reduced in the colon after eating. Therefore, we hypothesized that GLP-1 secretion is affected by oxygen tension. We found that forskolin-stimulated GLP-1 secretion from GLUTag cells, a model of intestinal L cells, is suppressed in hypoxia (1% O2). Forskolin stimulated elevations of preproglucagon (ppGCG) and proprotein convertase 1/3 (PC1/3) mRNA expression were decreased under hypoxic conditions. The finding that H89, a protein kinase A (PKA) inhibitor, inhibited the forskolin-stimulated increase of ppGCG and PC1/3 indicated that the cAMP-PKA pathway is involved in the hypoxia-induced suppression of the genes. Hypoxia decreased hexokinase 2 mRNA and protein expression and increased lactate dehydrogenase A mRNA and protein expression. Concomitantly, lactate production was increased and ATP production was decreased. Together, the results indicate that hypoxia decreases glucose utilization for ATP production, which probably causes a decrease in cAMP production and in subsequent GLP-1 production. Our findings suggest that the postprandial decrease in oxygen tension in the intestine attenuates GLP-1 secretion. PMID- 25832632 TI - Protective effects of bupivacaine against kainic acid-induced seizure and neuronal cell death in the rat hippocampus. AB - The excessive release of glutamate is a critical element in the neuropathology of epilepsy, and bupivacaine, a local anesthetic agent, has been shown to inhibit the release of glutamate in rat cerebrocortical nerve terminals. This study investigated whether bupivacaine produces antiseizure and antiexcitotoxic effects using a kainic acid (KA) rat model, an animal model used for temporal lobe epilepsy, and excitotoxic neurodegeneration experiments. The results showed that administering bupivacaine (0.4 mg/kg or 2 mg/kg) intraperitoneally to rats 30 min before intraperitoneal injection of KA (15 mg/kg) increased seizure latency and reduced the seizure score. In addition, bupivacaine attenuated KA-induced hippocampal neuronal cell death, and this protective effect was accompanied by the inhibition of microglial activation and production of proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in the hippocampus. Moreover, bupivacaine shortened the latency of escaping onto the platform in the Morris water maze learning performance test. Collectively, these data suggest that bupivacaine has therapeutic potential for treating epilepsy. PMID- 25832633 TI - Impact of CYP2C9 polymorphism found in the Chinese population on the metabolism of propofol in vitro. AB - The microsomal CYP2C9 alleles involved in the biotransformation of propofol, a widely used anesthetic agent, were investigated in vitro. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for propofol 4 hydroxylation were determined in recombinant human P450s CYP2C9 microsomes from Sf21 insects cells carrying CYP2C9*1 and other variants. Some of the variants showed decreased enzyme activity compared with the wild type, as previously reported. Two variants (CYP2C9*36 and *56) were found substantially to increase intrinsic clearance relative to the wild type variant. Most variants significantly (p<0.05) decreased intrinsic clearance of propofol compared with the wild type, except *11, *47, and *54. This study is the first to report these rare alleles for propofol metabolism, providing fundamental data for further clinical studies on CYP2C9 alleles for propofol metabolism in vivo. PMID- 25832634 TI - TGF-beta decreases the stability of IL-18-induced IFN-gamma mRNA through the expression of TGF-beta-induced tristetraprolin in KG-1 cells. AB - We have previously reported that transforming growth factor-beta (TGF-beta) down regulates interferon-gamma (IFN-gamma) production in an interleukin-18 (IL-18) treated mouse natural killer (NK) cell line, LNK5E6. In LNK5E6 cells, TGF-beta exhibited no inhibition of the IL-18-induced transcription of IFN-gamma, but did stimulate the degradation of IFN-gamma mRNA induced by IL-18. In the present study, we investigated the mechanism of the down-regulatory effects of TGF-beta on IFN-gamma mRNA expression in a human myelomonocytic cell line, KG-1, which produces IFN-gamma in response to IL-18 alone. Interestingly, IL-18 induced the production of the IFN-gamma through the stabilization of IFN-gamma mRNA, but not the enhanced transcription of IFN-gamma gene. The stability of IFN-gamma mRNA was regulated by mRNA destabilizing elements in the 3'untranslated region (UTR) of IFN-gamma mRNA, especially adenylate-uridylate (AU)-rich elements (AREs) in the 5' half of 3'UTR. Tristetraprolin (TTP), one of the ARE-binding proteins, destabilizes IFN-gamma mRNA, and IL-18 repressed the expression of TTP mRNA. Moreover, TGF-beta repressed the IL-18-induced expression of IFN-gamma mRNA through the induction of TTP mRNA to destabilize IFN-gamma mRNA. Our data is the first to reveal that the crosstalk between IL-18 and TGF-beta through the expression of TTP regulates the production of IFN-gamma. PMID- 25832635 TI - Stereoselective recognition of amethopterin enantiomers by the rat proton-coupled folate transporter. AB - The stereoselective transport of methotrexate (L-amethopterin, L-MTX) and its enantiomer (D-amethopterin, D-MTX) by the rat proton-coupled folate transporter (rPCFT) were examined using rPCFT-expressing HEK293 cells. The initial rate of uptake of [3H]-L-MTX by the rPCFT followed Michaelis-Menten kinetics, with a Km value of 2.1 uM. Dixon plots revealed that the uptake of L-MTX by the rPCFT was inhibited in a competitive manner by unlabeled L-MTX and D-MTX, with Ki values of approximately 1.3 and 150 uM, respectively. The initial rate of uptake of D-MTX by the rPCFT also followed Michaelis-Menten kinetics, with a Km value of 190 uM. The results of the current study demonstrate that the different enantiomers of MTX are transported in a highly stereoselective manner by the rPCFT, with the uptake clearance of L-MTX being approximately 46-fold greater than that of D-MTX. The observed stereoselectivity of the rPCFT was found to be comparable with that of the human PCFT. PMID- 25832636 TI - Versatile nuclear localization signal-based oligopeptide as a gene vector. AB - To develop a versatile nuclear-targeted gene vector, nuclear localization signal (NLS) oligopeptides combining cysteine (C), histidine (H), and stearic acid (STR) were investigated in this study. The original SV40 sequence (SV40: Pro-Lys-Lys Lys-Arg-Lys-Val) was selected as the NLS sequence, and physical characterizations of various NLS-based oligopeptides (CSV40C, STR-CSV40C, and STR-CH2SV40H2C), including mean diameter, zeta-potential, complex condensation, and decondensation, were evaluated. In addition, cellular and nuclear uptake of plasmid DNA (pDNA) and gene expression in COS7 and dendritic cells (JAWS II) were determined. As a result, C and STR enhanced formation of a smaller and more stable nano-complex with pDNA based on ionic interactions, the disulfide linkage and hydrophobic interactions. STR-CSV40C and STR-CH2SV40H2C had significantly higher cellular uptake ability and transfection efficiency than SV40 and CSV40C. In particular, STR-CH2SV40H2C had higher nuclear uptake and gene expression efficiency than STR-CSV40C. Furthermore, STR-CH2SV40H2C could deliver pDNA to the nuclei and had high gene expression efficiency in dendritic cells. Our results indicate that STR-CH2SV40H2C is a promising gene delivery system in non- or slow dividing cells. PMID- 25832637 TI - Metabolism of dextran sulfate sodium by intestinal bacteria in rat cecum is related to induction of colitis. AB - Ulcerative colitis induced by dextran sulfate sodium (DSS) is one of the most widely used experimental animal models. However, the mechanism responsible for the pathogenesis of the colitis is still unclear. The aim of the present study was to clarify the events occurring after administration of DSS to rats focusing on the relationship between the intestinal bacterial metabolism of DSS and the intestinal mucosal lesions in the model. Within 2 d after DSS administration, severe injury of the cecal mucosa was evident, together with bloody feces and blood in the cecum. However, these lesions were repressed by administration of antibiotics. On the other hand, DSS was found to be metabolized under anaerobic conditions upon incubation with cecal content in vitro, first being desulfated and then undergoing carbohydrate moiety degradation. However, no such metabolic process occurred when cecal content from rats that had been administered antibiotics was employed. These results indicate that the initial step of DSS induced ulcerative colitis is lesioning of the cecal mucosa, which is related to metabolism of DSS by intestinal bacteria. PMID- 25832638 TI - Administration of olanzapine as an antiemetic agent changes glucose homeostasis in cisplatin-treated rats. AB - We investigated the effects of olanzapine on cisplatin-induced pica (the consumption of non-nutrient materials such as kaolin) and glucose homeostasis in rats to clarify the effects of olanzapine when used as an anti-emetic drug. Rats were injected intraperitoneally (i.p.) with either 5 mg/kg cisplatin or saline. Additionally, 2 or 10 mg/kg olanzapine were administered i.p. to the rats 10 min before the administration of cisplatin and subsequently administered every 24 h for 3 d. Kaolin and food intake was measured using an automatic monitoring apparatus. Plasma glucose levels were measured by an enzyme electrode method. The plasma levels of insulin and intact proinsulin were measured by enzyme-linked immunosorbent assay (ELISA). The proinsulin-to-insulin (P/I) ratio was calculated. Cisplatin significantly increased kaolin intake, but decreased food intake and body weight up to 72 h. Olanzapine had no effect on these parameters. Neither olanzapine nor cisplatin alone had a significant effect on the plasma levels of glucose, insulin, or proinsulin. However, a combination of olanzapine and cisplatin significantly decreased plasma insulin levels, but increased plasma intact proinsulin levels and the P/I ratio. Our results suggest that an additive deterioration of insulin-secreting beta-cell function and disturbance of glucose homeostasis should be considered during treatment of patients with olanzapine for cisplatin-induced nausea and vomiting. PMID- 25832639 TI - Agonistic antibodies reveal the function of GPR56 in human glioma U87-MG cells. AB - GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) and is highly expressed in parts of tumor cells. The involvement of GPR56 in tumorigenesis has been reported. We generated agonistic monoclonal antibodies against human GPR56 and analyzed the action and signaling pathway of GPR56. The antibodies inhibited cell migration through the Gq and Rho pathway in human glioma U87-MG cells. Co immunoprecipitation analysis indicated that the interaction between the GPR56 extracellular domain and transmembrane domain was potentiated by agonistic antibodies. These results demonstrated that functional antibodies are invaluable tools for GPCR research and should open a new avenue for therapeutic treatment of tumors. PMID- 25832640 TI - Effect of high glucose levels on amyloid beta production in retinas of spontaneous diabetes mellitus Otsuka Long-Evans Tokushima fatty rats. AB - The accumulation of amyloid beta(1-42) peptide (Abeta(1-42)) in retina is implicated in the development of retinal ganglion cell apoptosis and diabetic retinopathy. In this study we demonstrate that spontaneous diabetes mellitus Otsuka Long-Evans Tokushima Fatty (OLETF) rats can be used as an animal model in studies to identify the expression of Abeta in diabetic retinas. In addition, we investigated the relation between glucose level and Abeta production in the retinas of OLETF rats. In the retinas of Long-Evans Tokushima Otsuka (LETO) rats used as normal controls and OLETF rats, no expression of neprilysin (NEP), which degrades Abeta, was detected, and the expression levels of genes associated with Abeta production (amyloid precursor protein, beta site APP cleaving enzyme, and presenilin) and Abeta(1-42) levels in the retinas of 60-week-old OLETF rats with diabetes mellitus were significantly higher than in 60-week-old LETO rat retinas. Furthermore, the increase in the expression levels of genes associated with Abeta production was enhanced by administration of glucose (3.0 g/kg; OGT test), and close relations between the retinal Abeta(1-42) level and plasma blood glucose and HbA1c were observed. In conclusion, we have found that Abeta accumulates easily in the retinas of LETO and OLETF rats due to the absence of NEP. In addition, we determined that the accumulation of Abeta(1-42) in the retinas of OLETF rats is promoted by high plasma glucose levels. Therefore OLETF rats may be a suitable model for studies to identify the expression of Abeta in diabetic retinas. PMID- 25832641 TI - Analysis of cysteine and histidine residues required for zinc response of the transcription factor human MTF-1. AB - Metal responsive element (MRE)-binding transcription factor-1 (MTF-1) is a zinc finger (ZF) transcription factor that plays a key role in heavy metal homeostasis by regulating relevant genes in response to metals. MTF-1 is known to be activated by heavy metals such as Zn and Cd, but the mechanism of activation remains unclear. In the present study, Cys and His residues of human MTF-1 (hMTF 1), some of which may be involved in interaction with metals or with each other, were screened for their contribution to Zn-dependent transcription. To avoid poor induction ratios of previous transfection assays, we re-examined experimental conditions to establish an assay able to correctly detect Zn-responsive transcription. Using this assay, a series of Cys and/or His substitution mutants were analyzed over the entire hMTF-1 molecule. In five out of the six ZFs (ZF1 to ZF5), Cys mutations that disrupt the ZF structure abolished response to Zn. Of these, ZF5 was shown for the first time to be essential for Zn-responsive transcription, despite it being unnecessary for Zn-induced DNA binding. These results indicate that Zn activation of hMTF-1 involves an additional process besides induction of DNA binding activity. Our assay also confirmed the importance of Cys in the acidic activation domain, as well as those in the C terminal Cys cluster, implicated in transcription in other studies. The identified Cys residues might contribute to metal response of hMTF-1 through direct metal binding and/or intramolecular interactions, analysis of which will be helpful in understanding the mechanism of metal response. PMID- 25832642 TI - Pseudokinase tribbles 1 (TRB1) negatively regulates tumor-suppressor activity of p53 through p53 deacetylation. AB - Tribbles 1 (TRB1) is one of the mammalian orthologs of Drosophila Tribbles, which regulates development and cell proliferation. TRB1 is suggested to act as a scaffold protein in signaling pathways for important cellular processes. TRB1 has also been identified as a myeloid oncogenic driver and mediates leukemogenesis through the mitogen-activated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway and CCAAT/enhancer binding protein (C/EBP) transcriptional factors. However, the physiological roles of TRB1 in solid tumors have not been clarified. Here, we show that TRB1 interacts with p53 and suppresses its tumor suppressor activity. TRB1 knockdown enhances transcriptional activity of p53 and decreases cell viability. Interestingly, TRB1 enhances histone deacety lase 1 (HDAC1)-mediated p53 deacetylation and decreases DNA binding of p53. These results suggest that TRB1 is involved in the proliferation of tumor cells by inhibiting the activities of tumor suppressor p53 in solid tumors. PMID- 25832643 TI - Pharmaceutical studies of levothyroxine sodium hydrate suppository provided as a hospital preparation. AB - The levothyroxine sodium hydrate suppository (L-T4-suppository) is provided as a hospital preparation for the treatment of hypothyroid patients with dysphagia in Japan because only oral preparations of levothyroxine sodium (L-T4) are approved for the treatment of hypothyroidism. However, it has been found that serum thyroxine and triiodothyronine levels do not increase as expected with the hospital preparation, requiring a higher dosage of L-T4 in the L-T4-suppository than in the oral preparations. In this study, to determine an effective thyroid gland hormone-replacement therapy for patients with dysphagia, the pharmaceutical properties of the L-T4-suppository were investigated. Suppositories containing 300 ug L-T4 in a base of Witepsol H-15 and Witepsol E-75 (ratio of 1 : 1) were prepared according to Chiba University Hospital's protocol. Content uniformity, stability, and suppository release were tested. The L-T4-suppository had uniform weight and content. The content and release property were stable over 90 d when the L-T4-suppository was stored at 4 degrees C and protected from light. The release rate of L-T4 increased as pH increased. However, no L-T4 was released below pH 7.2. The release rate of L-T4 decreased as temperature decreased. These findings suggest that the low level of release of L-T4 in the rectum under physiological conditions may be the cause of the low serum thyroxine and triiodothyronine levels following L-T4-suppository administration. PMID- 25832644 TI - Piceatannol lowers the blood glucose level in diabetic mice. AB - We previously found that passion fruit (Passiflora edulis) seeds contained a high amount of piceatannol (3,5,3',4'-trans-tetrahydroxystilbene), a natural analog of resveratrol (3,5,4'-trans-trihydroxystilbene). Resveratrol has been proposed as a potential anti-metabolic disorder compound, by its activation of sirtuin and AMP activated protein kinase. Many reports show that resveratrol ameliorates diet induced obesity and insulin resistance. However, it is not known whether piceatannol also affects diet-induced obesity. We explored the effect of piceatannol on high fat diet-fed mice. The results showed that piceatannol did not affect high fat diet-induced body weight gain or visceral fat gain in mice. However, piceatannol did reduce fasting blood glucose levels. Furthermore, to explore the potential of passion fruit seed extract containing piceatannol as a functional food, passion fruit seed extract was administered in a genetic diabetic mouse model (db/db mice). Single administration of passion fruit seed extract, as well as piceatannol reduced the blood glucose levels of these db/db mice. These results suggest that piceatannol and passion fruit seed extract may have potential application in the prevention of diabetes. PMID- 25832645 TI - Errata for biological and pharmaceutical bulletin. PMID- 25832646 TI - A survey of current trends in computational drug repositioning. AB - Computational drug repositioning or repurposing is a promising and efficient tool for discovering new uses from existing drugs and holds the great potential for precision medicine in the age of big data. The explosive growth of large-scale genomic and phenotypic data, as well as data of small molecular compounds with granted regulatory approval, is enabling new developments for computational repositioning. To achieve the shortest path toward new drug indications, advanced data processing and analysis strategies are critical for making sense of these heterogeneous molecular measurements. In this review, we show recent advancements in the critical areas of computational drug repositioning from multiple aspects. First, we summarize available data sources and the corresponding computational repositioning strategies. Second, we characterize the commonly used computational techniques. Third, we discuss validation strategies for repositioning studies, including both computational and experimental methods. Finally, we highlight potential opportunities and use-cases, including a few target areas such as cancers. We conclude with a brief discussion of the remaining challenges in computational drug repositioning. PMID- 25832648 TI - Loss of miR-200 family in 5-fluorouracil resistant colon cancer drives lymphendothelial invasiveness in vitro. AB - Invasive colorectal cancer is associated with poor prognosis requiring treatment with systemic chemotherapies usually including 5-fluorouracil. A consequence of prolonged treatment is the acquisition of resistance eventually resulting in the recurrence of highly metastatic cancer cells. To address the relationship between drug resistance and increased lymphatic metastatic potential, we used a 3D co culture model of colon tumour cell spheroids of parent CCL227 cells and subclones with gradually increasing resistance against 5-fluorouracil. From each investigated cell line, homogeneous tumour spheroids were generated in the presence of methylcellulose yielding emboli of ~700 um diameter. When invasive, tumour spheroids disrupt the continuous lymphendothelial cell (LEC) layer and generate a 'circular chemorepellent-induced defect' (CCID), reminiscent of the entry gates through which tumour emboli intravasate lymphatic vasculature. Here we provide evidence that increasingly chemoresistant colon cancer spheroids were strongly associated with enhanced intravasative properties. In naive CCL227 spheroids, miR-200 family members were released into exosomes thereby repressing the epithelial to mesenchymal transition-regulating transcription factors ZEB1 and SLUG in LEC. As a consequence of attenuated plasticity and migration of LEC, CCID formation was impaired. Loss of exosomal transferred miR-200c in resistant colon cells rendered LEC more susceptible to pro-migratory signals that were generated and directly transmitted by colon cancer spheroids. This observation indicates a common molecular axis in colon cancer and LEC where miR-200 family members act as regulators of ZEB proteins. The data support the notion that horizontal miR-200 signalling prevents the permeation of cells into adjacent epithelia and contributes to organ integrity. PMID- 25832649 TI - Novel ferrocene-based bifunctional amine-thioureas for asymmetric Michael addition of acetylacetone to nitroolefins. AB - An efficient method was developed to synthesize ferrocene-based bifunctional amine-thioureas bearing multiple hydrogen-bonding donors. Asymmetric Michael addition of acetylacetone to nitroolefins catalyzed by these novel bifunctional catalysts affords the Michael adducts in high yield and moderate to excellent enantioselectivities. Multiple hydrogen-bonds play an important role in accelerating the reaction. PMID- 25832647 TI - Molecular portraits: the evolution of the concept of transcriptome-based cancer signatures. AB - Cancer results from dysregulation of multiple steps of gene expression programs. We review how transcriptome profiling has been widely explored for cancer classification and biomarker discovery but resulted in limited clinical impact. Therefore, we discuss alternative and complementary omics approaches. PMID- 25832650 TI - A Community Health Clinic Breastfeeding-Friendly Pilot: What Can We Learn about the Policy Process? AB - BACKGROUND: Implementing evidence-based practices and policies for breastfeeding support in community clinics is a promising, but challenging, approach to reducing disparities in breastfeeding rates. OBJECTIVE: This study aimed to apply a policy process research framework to increase knowledge of factors that facilitate adoption and implementation of breastfeeding policy changes. METHODS: In 2013, Washington State piloted a process to encourage 8 clinics to adopt and implement steps to become breastfeeding friendly. Evaluation data were collected through interviews, project reports, training evaluations, and pre- and post-self assessments of achievement of the steps. RESULTS: In 6 months, clinics increased the breastfeeding-friendly steps that they were implementing from a median (interquartile range) of 1.5 (0-3) to 6 (5-7). Improvements were most likely in the steps that required the fewest resources and administrative changes. Barriers to implementation included misperceptions about breastfeeding and breastfeeding support; lack of administrative "buy-in"; need for organizational changes to accommodate actions like monitoring breastfeeding rates and allowing providers training time; and the social-political climate of the clinic. Several factors, including actions taken by public health practitioners, enhanced the change process. These included fostering supportive relationships, targeting technical assistance, and providing resources for planning and training. CONCLUSION: This pilot project demonstrates that it is possible to make changes in breastfeeding support practices and policies in community clinics. Recommendations to enhance future work include framing and marketing breastfeeding support in ways that resonate with clinic decision makers and enhancing training, resources, and advocacy to build capacity for internal and external systems changes to support breastfeeding best practices. PMID- 25832651 TI - Oxidative addition to gold(i): a new avenue in homogeneous catalysis with au. PMID- 25832652 TI - JAK Inhibition Impairs NK Cell Function in Myeloproliferative Neoplasms. AB - Ruxolitinib is a small-molecule inhibitor of the JAK kinases, which has been approved for the treatment of myelofibrosis, a rare myeloproliferative neoplasm (MPN), but clinical trials are also being conducted in inflammatory-driven solid tumors. Increased infection rates have been reported in ruxolitinib-treated patients, and natural killer (NK) cells are immune effector cells known to eliminate both virus-infected and malignant cells. On this basis, we sought to compare the effects of JAK inhibition on human NK cells in a cohort of 28 MPN patients with or without ruxolitinib treatment and 24 healthy individuals. NK cell analyses included cell frequency, receptor expression, proliferation, immune synapse formation, and cytokine signaling. We found a reduction in NK cell numbers in ruxolitinib-treated patients that was linked to the appearance of clinically relevant infections. This reduction was likely due to impaired maturation of NK cells, as reflected by an increased ratio in immature to mature NK cells. Notably, the endogenous functional defect of NK cells in MPN was further aggravated by ruxolitinib treatment. In vitro data paralleled these in vivo results, showing a reduction in cytokine-induced NK cell activation. Further, reduced killing activity was associated with an impaired capacity to form lytic synapses with NK target cells. Taken together, our findings offer compelling evidence that ruxolitinib impairs NK cell function in MPN patients, offering an explanation for increased infection rates and possible long-term side effects associated with ruxolitinib treatment. PMID- 25832653 TI - Optimizing a lupus autoantibody for targeted cancer therapy. AB - The specificity of binding by antibodies to target antigens is a compelling advantage to antibody-based cancer therapy, but most antibodies cannot penetrate cells to affect intracellular processes. Select lupus autoantibodies penetrate into cell nuclei, and the potential for application of these antibodies in cancer therapy is an emerging concept. Here, we show that a divalent lupus anti-DNA autoantibody fragment with enhancing mutations that increase its ability to penetrate cell nuclei and bind DNA causes accumulation of DNA double-strand breaks in and is highly and selectively toxic to cancer cells and tumors with defective homology-directed repair of DNA double-strand breaks. These findings provide proof of principle for the use of optimized lupus autoantibodies in targeted cancer therapy. PMID- 25832654 TI - NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation. AB - The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulated p21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted. PMID- 25832655 TI - CTLA-4+ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis. AB - The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, and the variability and extent of cetuximab-mediated cellular immunity is not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional and clinical impact on antitumor immunity in cetuximab-treated individuals. The frequency, immunosuppressive phenotype, and activation status of Treg and natural killer (NK) cells were analyzed in the circulation and tumor microenvironment of cetuximab-treated patients with HNSCC enrolled in a novel neoadjuvant, single agent cetuximab clinical trial. Notably, cetuximab treatment increased the frequency of CD4(+)FOXP3(+) intratumoral Treg expressing CTLA-4, CD39, and TGFbeta. These Treg suppressed cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and their presence correlated with poor clinical outcome in two prospective clinical trial cohorts. Cetuximab expanded CTLA-4(+)FOXP3(+) Treg in vitro, in part, by inducing dendritic cell maturation, in combination with TGFbeta and T-cell receptor triggering. Importantly, cetuximab-activated NK cells selectively eliminated intratumoral Treg but preserved effector T cells. In ex vivo assays, ipilimumab targeted CTLA-4(+) Treg and restored cytolytic functions of NK cells mediating ADCC. Taken together, our results argue that differences in Treg-mediated suppression contribute to the clinical response to cetuximab treatment, suggesting its improvement by adding ipilimumab or other strategies of Treg ablation to promote antitumor immunity. PMID- 25832657 TI - Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB. PMID- 25832656 TI - FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells. AB - The growth factor PDGF controls the development of glioblastoma (GBM), but its contribution to the function of GBM stem-like cells (GSC) has been little studied. Here, we report that the transcription factor FoxM1 promotes PDGFA-STAT3 signaling to drive GSC self-renewal and tumorigenicity. In GBM, we found a positive correlation between expression of FoxM1 and PDGF-A. In GSC and mouse neural stem cells, FoxM1 bound to the PDGF-A promoter to upregulate PDGF-A expression, acting to maintain the stem-like qualities of GSC in part through this mechanism. Analysis of the human cancer genomic database The Cancer Genome Atlas revealed that GBM expresses higher levels of STAT3, a PDGF-A effector signaling molecule, as compared with normal brain. FoxM1 regulated STAT3 transcription through interactions with the beta-catenin/TCF4 complex. FoxM1 deficiency inhibited PDGF-A and STAT3 expression in neural stem cells and GSC, abolishing their stem-like and tumorigenic properties. Further mechanistic investigations defined a FoxM1-PDGFA-STAT3 feed-forward pathway that was sufficient to confer stem-like properties to glioma cells. Collectively, our findings showed how FoxM1 activates expression of PDGF-A and STAT3 in a pathway required to maintain the self-renewal and tumorigenicity of glioma stem-like cells. PMID- 25832658 TI - Cortical pencil lining in neuroferritinopathy: a diagnostic clue. PMID- 25832659 TI - A blow to the head trauma--ALS hypothesis. PMID- 25832660 TI - Head injury does not alter disease progression or neuropathologic outcomes in ALS. AB - OBJECTIVES: To study the effects of head injury on disease progression and on neuropathologic outcomes in amyotrophic lateral sclerosis (ALS). METHODS: Patients with ALS were surveyed to obtain head injury history, and medical records were reviewed. Linear regression was performed to determine if head injury was a predictor for mean monthly decline of Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R), while controlling for confounders. Head injury history was obtained from family members of ALS autopsy cases. The frequency of tau proteinopathy, brain TDP-43 inclusions, and pathologic findings of Alzheimer disease (AD) were examined in ALS cases with head injury compared to cases without. Logistic regression was performed with each neuropathologic diagnosis as an outcome measure and head injury as a predictor variable. RESULTS: No difference was seen in rate of decline of the ALSFRS-R between patients with head injury (n = 24) and without (n = 76), with mean monthly decline of -0.9 for both groups (p = 0.18). Of 47 ALS autopsy cases (n = 9 with head injury, n = 38 without), no significant differences were seen in the frequency of tau proteinopathy (11% with head injury; 24% without), TDP-43 in the brain (44% with head injury; 45% without), or AD pathology (33% with head injury; 26% without). Independent logistic regression models showed head injury was not a predictor of tau pathology (p = 0.42) or TDP-43 in the brain (p = 0.99). CONCLUSIONS: Head injury was not associated with faster disease progression in ALS and did not result in a specific neuropathologic phenotype. The tau pathology described with chronic traumatic encephalopathy was found in ALS autopsy cases both with and without head injury. PMID- 25832662 TI - Suicide in stroke survivors: frequency and risk factors. PMID- 25832661 TI - Poststroke suicide attempts and completed suicides: a socioeconomic and nationwide perspective. AB - OBJECTIVE: We examined attempted and completed suicides after stroke to determine whether they were associated with socioeconomic status, other patient characteristics, or time after stroke. METHODS: This nationwide cohort study included stroke patients from Riksstroke (the Swedish Stroke Register) from 2001 to 2012. We used personal identification numbers to link the Riksstroke data with other national registers. Suicide attempts were identified by a record of hospital admission for intentional self-harm (ICD-10: X60-X84), and completed suicides were identified in the national Cause of Death Register. We used multiple Cox regression to analyze time from stroke onset to first suicide attempt. RESULTS: We observed 220,336 stroke patients with a total follow-up time of 860,713 person-years. During follow-up, there were 1,217 suicide attempts, of which 260 were fatal. This was approximately double the rate of the general Swedish population. Patients with lower education or income (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.11-1.68) for primary vs university and patients living alone (HR 1.73, 95% CI 1.52-1.97) had an increased risk of attempted suicide, and patients born outside of Europe had a lower risk compared to patients of European origin. Male sex, young age, severe stroke, and poststroke depression were other factors associated with an increased risk of attempted suicide after stroke. The risk was highest during the first 2 years after stroke. CONCLUSIONS: Both clinical and socioeconomic factors increase the risk of poststroke suicide attempts. This suggests a need for psychosocial support and suicide preventive interventions in high-risk groups of stroke patients. PMID- 25832663 TI - Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. AB - OBJECTIVE: Glycogen storage disease type IIIa (GSDIIIa) is classically regarded as a glycogenosis with fixed weakness, but we hypothesized that exercise intolerance in GSDIIIa is related to muscle energy failure and that oral fructose ingestion could improve exercise tolerance in this metabolic myopathy. METHODS: We challenged metabolism with cycle-ergometer exercise and measured substrate turnover and oxidation rates using stable isotope methodology and indirect calorimetry in 3 patients and 6 age-matched controls on 1 day, and examined the effect of fructose ingestion on exercise tolerance in the patients on another day. RESULTS: Total fatty acid oxidation rates during exercise were higher in patients than controls, 32.1 (SE 1.2) vs 20.7 (SE 0.5; range 15.8-29.3) MUmol/kg/min (p = 0.048), and oxidation of carbohydrates was lower in patients, 1.0 (SE 5.4) vs 38.4 (SE 8.0; range 23.0-77.1) MUmol/kg/min (p = 0.024). Fructose ingestion improved exercise tolerance in the patients. CONCLUSION: Similar to patients with McArdle disease, in whom muscle glycogenolysis is also impaired, GSDIIIa is associated with a reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation, and fructose ingestion improves exercise tolerance. Our results indicate that GSDIIIa should not only be viewed as a glycogenosis with fixed skeletal muscle weakness, but should also be considered among the glycogenoses presenting with exercise-related dynamic symptoms caused by muscular energy deficiency. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ingestion of fructose improves exercise tolerance in patients with GSDIIIa. PMID- 25832664 TI - Loss of PCLO function underlies pontocerebellar hypoplasia type III. AB - OBJECTIVE: To identify the genetic cause of pontocerebellar hypoplasia type III (PCH3). METHODS: We studied the original reported pedigree of PCH3 and performed genetic analysis including genome-wide single nucleotide polymorphism genotyping, linkage analysis, whole-exome sequencing, and Sanger sequencing. Human fetal brain RNA sequencing data were then analyzed for the identified candidate gene. RESULTS: The affected individuals presented with severe global developmental delay and seizures starting in the first year of life. Brain MRI of an affected individual showed diffuse atrophy of the cerebrum, cerebellum, and brainstem. Genome-wide single nucleotide polymorphism analysis confirmed the linkage to chromosome 7q we previously reported, and showed no other genomic areas of linkage. Whole-exome sequencing of 2 affected individuals identified a shared homozygous, nonsense variant in the PCLO (piccolo) gene. This variant segregated with the disease phenotype in the pedigree was rare in the population and was predicted to eliminate the PDZ and C2 domains in the C-terminus of the protein. RNA sequencing data of human fetal brain showed that PCLO was moderately expressed in the developing cerebral cortex. CONCLUSIONS: Here, we show that a homozygous, nonsense PCLO mutation underlies the autosomal recessive neurodegenerative disorder, PCH3. PCLO is a component of the presynaptic cytoskeletal matrix, and is thought to be involved in regulation of presynaptic proteins and synaptic vesicles. Our findings suggest that PCLO is crucial for the development and survival of a wide range of neuronal types in the human brain. PMID- 25832665 TI - Medicare payments to the neurology workforce in 2012. AB - OBJECTIVE: Little is known about how neurology payments vary by service type (i.e., evaluation and management [E/M] vs tests/treatments) and compare to other specialties, yet this information is necessary to help neurology define its position on proposed payment reform. METHODS: Medicare Provider Utilization and Payment Data from 2012 were used. These data included all direct payments to providers who care for fee-for-service Medicare recipients. Total payment was determined by medical specialty and for various services (e.g., E/M, EEG, electromyography/nerve conduction studies, polysomnography) within neurology. Payment and proportion of services were then calculated across neurologists' payment categories. RESULTS: Neurologists comprised 1.5% (12,317) of individual providers who received Medicare payments and were paid $1.15 billion by Medicare in 2012. Sixty percent ($686 million) of the Medicare payment to neurologists was for E/M, which was a lower proportion than primary providers (approximately 85%) and higher than surgical subspecialties (range 9%-51%). The median neurologist received nearly 75% of their payments from E/M. Two-thirds of neurologists received 60% or more of their payment from E/M services and over 20% received all of their payment from E/M services. Neurologists in the highest payment category performed more services, of which a lower proportion were E/M, and performed at a facility, compared to neurologists in lower payment categories. CONCLUSION: E/M is the dominant source of payment to the majority of neurologists and should be prioritized by neurology in payment restructuring efforts. PMID- 25832666 TI - Shining light on Medicare's values: the Medicare physician data release. PMID- 25832667 TI - Glycogen storage disease type III: the phenotype branches out. PMID- 25832668 TI - Impairments and comorbidities of polyneuropathy revealed by population-based analyses. AB - OBJECTIVE: To quantify polyneuropathy impairments and comorbidities utilizing the Rochester Epidemiology Project (2010 census = 148,201). METHODS: ICD-9-CM coding identified polyneuropathy cases (2006-2010) and their 5:1 age- and sex-matched controls. Mortality and impairments were evaluated while identifying and adjusting for Charlson Index comorbidities. RESULTS: Overall prevalence of polyneuropathy was 1.66%, and markedly rose to 6.6% in persons older than 60 years. Cases (n = 2,892) had more comorbidities than controls (n = 14,435) with higher median Charlson Index (6 vs 3, p < 0.001). Diabetes with end-organ disease represented the largest increased comorbidity in cases compared with controls (46.8% vs 6.5%). Diabetic polyneuropathy was the most common specific subtype (38.2%). Miscoded idiopathic cases and false-negative controls also commonly had diabetic polyneuropathy. Median modified Rankin Scale score was considerably higher for cases than controls (4 vs 1, p < 0.001). Multiple comorbidities were found associated with polyneuropathy after adjusting for diabetes co-occurrence, including pulmonary disease, dementia, and others. Polyneuropathy was an independent contributor to multiple functional impairments including difficulty walking (odds ratio [OR] = 1.9), climbing stairs (OR = 2.0), using an assistive device (OR = 2.0), fall tendency (OR = 2.4), work disability (OR = 4.2), lower limb amputations (OR = 3.9), and opioid use (OR = 2.7). Prevalent cases had a younger median age at death than controls (80 vs 86 years, p < 0.001), and incident cases had a 6-month shorter survival. CONCLUSIONS: Polyneuropathies have notable neurologic impairments beyond their identified multiple comorbidities. Life expectancy is shortened. Diabetic polyneuropathy is underidentified. The quantified extent of the disease burden and refined comorbidity associations emphasize that greater research efforts and health care initiatives are needed. PMID- 25832669 TI - Characterizing the surface-exposed proteome of Planococcus halocryophilus during cryophilic growth. AB - Planococcus halocryophilus OR1 is a bacterial isolate capable of growth at temperatures ranging from -15 to +37 degrees C. During sub-zero (cryophilic) growth, nodular features appear on its cell surface; however, the biochemical compositions of these features as well as any cold-adaptive benefits they may offer are not understood. This study aimed to identify differences in the cell surface proteome (surfaceome) of P. halocryophilus cells grown under optimal (24 degrees C, no added salt), low- and mid-salt (5 and 12 % NaCl, respectively) at 24 degrees C, and low- and mid-salt sub-zero (5 % NaCl at -5 degrees C and 12 % NaCl at -10 degrees C) culture conditions, for the purpose of gaining insight into cold-adapted proteomic traits at the cell surface. Mid-log cells were harvested, treated briefly with trypsin and the resultant peptides were purified followed by identification by LC-MS/MS analysis. One hundred and forty-four proteins were subsequently identified in at least one culture condition. Statistically significant differences in amino acid usage, a known indicator of cold adaptation, were identified through in silico analysis. Two proteins with roles in peptidoglycan (PG) metabolism, an N-acetyl-L-alanine amidase and a multimodular transpeptidase-transglycosylase, were detected, though each was only detected under optimal conditions, indicating that high-salt and high-cold stress each affect PG metabolism. Two iron transport-binding proteins, associated with two different iron transport strategies, were identified, indicating that P. halocryophilus uses a different iron acquisition strategy at very low temperatures. Here we present the first set of data that describes bacterial adaptations at the cellular surface that occur as a cryophilic bacterium is transitioned from optimal to near-inhibitory sub-zero culture conditions. PMID- 25832670 TI - Fund the service from a hypothecated tax. PMID- 25832671 TI - DNA Methylation in Memory Formation: Emerging Insights. AB - The establishment of synaptic plasticity and long-term memory requires lasting cellular and molecular modifications that, as a whole, must endure despite the rapid turnover of their constituent parts. Such a molecular feat must be mediated by a stable, self-perpetuating, cellular information storage mechanism. DNA methylation, being the archetypal cellular information storage mechanism, has been heavily implicated as being necessary for stable activity-dependent transcriptional alterations within the CNS. This review details the foundational discoveries from both gene-targeted and whole-genome sequencing studies that have brought DNA methylation to our attention as a chief regulator of activity- and experience-dependent transcriptional alterations within the CNS. We present a hypothetical framework to resolve disparate experimental findings regarding distinct manipulations of DNA methylation and their effect on memory, taking into account the unique impact activity-dependent alterations in DNA methylation potentially have on both memory-promoting and memory-suppressing gene expression. And last, we discuss potential avenues for future inquiry into the role of DNA methylation during remote memory formation. PMID- 25832672 TI - Graphene based enzymatic bioelectrodes and biofuel cells. AB - The excellent electrical conductivity and ease of functionalization make graphene a promising material for use in enzymatic bioelectrodes and biofuel cells. Enzyme based biofuel cells have attracted substantial interest due to their potential to harvest energy from organic materials. This review provides an overview of the functional properties and applications of graphene in the construction of biofuel cells as alternative power sources. The review covers the current state-of-the art research in graphene based nanomaterials (physicochemical properties and surface functionalities), the role of these parameters in enhancing electron transfer, the stability and activity of immobilized enzymes, and how enhanced power density can be achieved. Specific examples of enzyme immobilization methods, enzyme loading, stability and function on graphene, functionalized graphene and graphene based nanocomposite materials are discussed along with their advantages and limitations. Finally, a critical evaluation of the performance of graphene based enzymatic biofuel cells, the current status, challenges and future research needs are provided. PMID- 25832673 TI - A four-chamber in transit heart thrombus in a pregnant woman with acute pulmonary embolism. PMID- 25832674 TI - Reflecting on patient-centred care in pharmacy through an illness narrative. AB - Patient-centred care (PCC) is rapidly adopting a central position in discussions on the quality of healthcare, with patient-centredness deemed essential to transforming the healthcare system. PCC speaks to the quality of patient-provider relationships and has been defined as an approach to providing care that is respectful of and responsive to individual patient preferences, needs, and values, while ensuring that patient values guide all clinical decisions. However its place within pharmacy practice is unclear and is as yet undefined, particularly in relation to pharmaceutical care. Through my personal illness narrative, I briefly explore the visibility and evidence of PCC in the pharmacy literature as well as from personal experience of pharmacy care, and find it lacking. I conclude that an integrated, seamless understanding of PCC and the use of shared language within the health professions is essential in successful teamwork with both the patient and with other health professions. PMID- 25832675 TI - Primary non-adherence in Portugal: findings and implications. AB - BACKGROUND: Portugal is currently facing a serious economic and financial crisis, which is dictating some important changes in the health care sector. Some of these measures may potentially influence patients' access to medication and consequently adherence, which will ultimately impact on health status, especially in chronic patients. AIMS: This study aimed at providing a snapshot of adherence in patients with chronic conditions in Portugal between March and April 2012. SETTING: Community pharmacy in Portugal. METHOD: A cross-sectional pilot study was undertaken, where patients were recruited via community pharmacies to a questionnaire study evaluating the number of prescribed and purchased drugs and, when these figures were inconsistent, the reasons for this. MAIN OUTCOME MEASURES: Primary and secondary adherence measures. Failing to purchase prescription items was categorized as primary nonadherence. Secondary nonadherence was attributed to purchasing prescription items, but not taking medicines as prescribed. RESULTS: Data were collected from 375 patients. Primary nonadherence was identified in 22.8 % of patients. Regardless of the underlying condition, the most commonly reported reason for primary non-adherence was having spare medicines at home ("leftovers"), followed by financial problems. The latter appeared to be related to the class of medicines prescribed. Primary non adherence was associated with low income (<475 /month; p = 0.026). Secondary non-adherence, assessed by the 7-MMAS was detected in over 50 % of all patients, where unintentional nonadherence was higher than intentional nonadherence across all disease conditions. CONCLUSION: This study revealed that more than one fifth of chronic medication users report primary nonadherence (22.8 %) and more than 50 % report secondary nonadherence. Data indicates that the existence of spare medicines and financial constraints occurred were the two most frequent reasons cited for nonadherence (47, 6-64, 8 and 19-45.5 %, depending on the major underlying condition, respectively). PMID- 25832676 TI - Drug utilisation profile in the neonatal unit of a university hospital: a prospective observational study in Brazil. AB - BACKGROUND: Advances in neonatology have contributed to changes in the drug utilisation profile in neonates, both in the number of drugs and the pharmacotherapeutic groups. OBJECTIVE: To analyse drug use in the neonatal care unit of a teaching hospital in Brazil and to evaluate the associations among perinatal, clinical care and drug use data. SETTING: The neonatal care unit of a teaching hospital in Brazil. METHODS: A prospective observational study was conducted. Perinatal, clinical care and pharmacotherapy data were collected from the patients' medical records. Labelling information regarding neonatal use was analysed for prescribed drugs. The data were analysed using univariate descriptive statistics and quasi-Poisson regression. MAIN OUTCOME MEASURE: Frequency of drug use by gestational age. RESULTS: The study included 187 patients; 157 (84.0 %) received drugs. The mean gestational age was 35.8 weeks. The mean number of drugs prescribed per patient was 6.4. The number of drugs used was inversely correlated to gestational age and birth weight. The most commonly prescribed drugs belonged to the following anatomical therapeutic chemical groups: nervous system drugs, anti-infectives for systemic use, and alimentary tract and metabolism drugs. Information regarding neonatal use was given in the labelling of only 20.5 % of the prescribed drugs. Of these, only 9.5 % had information specific for preterm infants. CONCLUSIONS: Drug administration to neonates is frequently and inversely correlated to gestational age and birth weight. Neonates are exposed to different therapeutic classes, reflecting scientific advances in neonatology. In Brazil, the percentage of drugs with neonate-specific labelling information is low. Consequently, there is an evident need for efforts to guarantee effective and safe pharmacotherapy for neonates. PMID- 25832677 TI - Factors that affect adverse drug reaction reporting among hospital pharmacists in Western China. AB - BACKGROUND: Hospital pharmacists can make a considerable contribution to the spontaneous reporting system of adverse drug reactions. The factors that influence adverse drug reaction reporting among hospital pharmacists remain largely unknown in China. OBJECTIVE: This study aims to identify factors that affect hospital pharmacist-led adverse drug reaction reporting in Xi'an, and to obtain suggestions from pharmacists about how to improve the current adverse drug reaction reporting system. SETTING: Hospital settings throughout Xi'an, a region of Western China. METHOD: A matched case-control study was conducted on a population of 2,814 hospital pharmacists in Xi'an during 2011. Cases included all pharmacists who had reported at least one adverse drug reaction between 2008 and 2010 and agreed to participate in the study (186/204; 91.2 %); controls (n = 372) were pharmacists who had not reported any adverse drug reaction during the same period. A self-administered questionnaire was distributed to the participants. Logistic regression was performed to evaluate the association between indicator variables and the outcome of having reported at least one adverse drug reaction. MAIN OUTCOME MEASURE: Pharmacists' knowledge, attitude and practice towards adverse drug reaction reporting and factors affecting reporting. RESULTS: Higher professional title (adjusted OR 1.44; 95 % CI 1.07-1.94; p = 0.018), having received training about adverse drug reaction reporting (1.64; 1.04-2.57; p = 0.032), better knowledge about reporting (1.53; 1.12-2.08; p = 0.007), "lack of access to adverse drug reaction reporting form" (0.29; 0.12-0.72; p = 0.008) was independently associated with adverse drug reaction reporting. Clinical pharmacists were more likely to report an adverse drug reaction than dispensary pharmacists (1/adjusted OR 5.26; p < 0.001), pharmacy administrators (5.00; p = 0.003), and other technicians (5.56; p = 0.001). CONCLUSIONS: Higher professional title, having received training, mastering knowledge about reporting, and being a clinical pharmacist were positive predictors of pharmacist-led adverse drug reaction reporting. Lack of access to reporting forms was a negative predictor. Continuous training and establishing incentive mechanisms are needed to promote adverse drug reaction reporting among hospital pharmacists. PMID- 25832678 TI - Evaluation of restricted antibiotic use in a hospital in Romania. AB - BACKGROUND: Antibiotics are the most frequently used drugs among hospitalised patients. Antimicrobial resistance is a major health issue and therefore antibiotic consumption should be under strict surveillance. OBJECTIVE: To evaluate the use of restricted antibiotics in an academic hospital in Romania. METHODS: Retrospective evaluation of the use of 11 restricted antibiotics issued based on the antibiotics formularies for the year 2012. Therapeutic guidelines and the summary of product characteristics were used for the evaluation. The appropriateness antibiotics use was verified, according to three main criteria: appropriate indication (type of treatment, localization and type of infection), dose and duration of treatment. Descriptive statistics and multiple logistic regression analysis were performed. Results 664 prescribing formularies were analyzed, of these 319 were from the intensive care unit (48.04 %). The most prescribed antibiotics were vancomycin (171, 25.75 %), imipenem (151, 22.74 %) and meropenem (116, 17.47 %). Overall, 285 prescriptions (42.92 %) were considered inappropriate. Vancomycin, meropenem and imipenem were prescribed inappropriate in 49.71, 46.55 and 44.06 % of such cases. Of the total 285 prescriptions deemed as inappropriate, for 49.82 % the dose was incorrect, 20 % were inadequate in terms of treatment duration and 15.44 % were wrongly indicated. Inappropriate use was significantly higher among empirical prescriptions than the documented ones (69.75 vs. 30.25 %, p < 0.001). Multiple stepwise logistic regression identified that the duration of the treatment was significant for inappropriate antibiotic use (p < 0.05). The risk of inappropriate use in the case of empirical prescriptions is higher than for documented prescriptions (OR 5.78, p < 0.001, CI 3.65-9.15). CONCLUSIONS: the results suggest the need to intensify the control of the use of restricted antibiotics. The implementation of drug formularies in hospitals and the involvement of the clinical pharmacist may ensure rational antibiotic therapy. PMID- 25832680 TI - A blast from the past and foresight for the future of gynecologic oncology. PMID- 25832681 TI - Lebanon: an evolving hub for radiation therapy in the arab world. PMID- 25832682 TI - Relating proton treatments to photon treatments via the relative biological effectiveness-should we revise current clinical practice? PMID- 25832683 TI - The end of the hypoxic EPOch. PMID- 25832684 TI - Radium-223 in the treatment of osteoblastic metastases: a critical clinical review. AB - The element radium (Ra) was discovered by the Curies in 1898 and within a decade was in broad scientific testing for the management of several forms of cancer. The compound was known to give rise to a series of both high-energy particulate and penetrating gamma-emissions. The latter found an important role in early 20th century brachytherapy applications, but the short-range alpha-particles seemed much less useful. Although highly cytotoxic when released within a few cell diameters of critical cell nuclei, the dense double-strand break damage was poorly repaired, and concerns regarding treatment-related toxicities and secondary malignancies halted clinical development. Moreover, the most common isotope of Ra has an exceptionally long half-life (>1600 years for (226)Ra) that proved daunting when aiming for a systemic cancer therapy. Fortunately, other radium isotopes have more convenient half-lives while still producing cytotoxic alpha particles. Radium-223 dichloride has a half-life of 11.4 days, and this isotope was identified as an excellent candidate for radionuclide therapy of cancers metastatic to bone. The calcium-mimetic chemical properties of the radium allowed intravenous infusion with rapid uptake to sites of new bone formation. The highly efficient bone localization suggested a potential therapeutic role for osteoblastic bone metastases, and a series of phase 1, 2, and 3 clinical trials was undertaken to explore this possibility. This series of clinical explorations culminated in the ALSYMPCA trial, an international, placebo-controlled, phase 3 study that accrued 921 symptomatic men with bone-metastatic, castrate-resistant prostate cancer. Results of this trial demonstrated a prolongation of overall survival, and regulatory agencies around the world have now approved this product as a treatment for advanced prostate cancer. PMID- 25832685 TI - Long-term quality of life after swallowing and salivary-sparing chemo-intensity modulated radiation therapy in survivors of human papillomavirus-related oropharyngeal cancer. AB - PURPOSE: To evaluate long-term health-related quality of life (HRQOL) in 2 prospective studies of chemo-intensity modulated radiation therapy (chemo-IMRT) for oropharyngeal cancer (OPC). METHODS AND MATERIALS: Of 93 patients with stage III/IV OPC treated on prospective studies of swallowing and salivary organ sparing chemo-IMRT, 69 were eligible for long-term HRQOL assessment. Three validated patient-reported instruments, the Head and Neck QOL (HNQOL) questionnaire, the University of Washington quality of life (UWQOL) questionnaire, and the Xerostomia Questionnaire (XQ), previously administered from baseline through 2 years in the parent studies, were readministered at long term follow-up, along with the Short-Form 36. Long-term changes in HRQOL from before treatment and 2 years were evaluated. RESULTS: Forty patients (58%) with a median follow-up of 6.5 years participated, 39 of whom (97.5%) had confirmed human papillomavirus-positive OPC. Long term, no clinically significant worsening was detected in mean HRQOL scores compared with 2 years, with stable or improved HRQOL from before treatment in nearly all domains. "Moderate" or greater severity problems were uncommon, reported by 5% of patients for eating, 5% for swallowing, and 2.5% and 5% by HNQOL and UWQOL summary scores, respectively. Freedom from percutaneous endoscopic gastrostomy tube dependence and stricture dilation beyond 2 years was 97.5% and 95%, respectively. Eleven percent and 14% of patients reported "moderate" or "severe" long-term worsening in HNQOL Pain and Overall Bother domains, respectively, which were associated with mean dose to the cervical esophagus, larynx, and pharyngeal constrictors. CONCLUSIONS: At more than 6 years' median follow-up, OPC patients treated with swallowing and salivary organ-sparing chemo-IMRT reported stable or improved HRQOL in nearly all domains compared with both before treatment and 2-year follow-up. New late toxicity after 2 years was uncommon. Further emphasis on sparing the swallowing organs may yield additional HRQOL gains for long-term OPC survivors. PMID- 25832686 TI - Phase 2 study of docetaxel, cisplatin, and concurrent radiation for technically resectable stage III-IV squamous cell carcinoma of the head and neck. AB - PURPOSE: We investigated the efficacy and safety of weekly low-dose docetaxel and cisplatin therapy concurrent with conventionally fractionated radiation in patients with technically resectable stage III-IV squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Between March 2004 and October 2011, we enrolled 117 patients, of whom 116 were analyzable (43 had oropharyngeal cancer, 54 had hypopharyngeal cancer, and 19 had laryngeal cancer), and 85 (73%) had stage IV disease. Radiation consisted of 66 Gy in 33 fractions. Docetaxel, 10 mg/m(2), followed by cisplatin, 20 mg/m(2), administered on the same day were given once a week for 6 cycles. The primary endpoint was overall complete response (CR) rate after chemoradiation therapy. Human papillomavirus (HPV) DNA in oropharyngeal cancer was examined by PCR. RESULTS: Of 116 patients, 82 (71%) completed treatment per protocol; 102 (88%) received the full radiation therapy dose; and 90 (78%) and 12 (10%) patients received 6 and 5 chemotherapy cycles, respectively. Overall CR rate was 71%. After median follow-up of 50.9 months (range: 15.6-113.9 months for surviving patients), 2-year and 4-year overall survival rates were 82% and 68%, respectively. Cumulative 2-year and 4-year local failure rates were 27% and 28%, respectively, whereas distant metastasis rates were 15% and 22%, respectively. HPV status in oropharyngeal cancer was not associated with treatment efficacy. Acute toxicity included grade 3 and 4 in field mucositis in 73% and 5% of patients, respectively, whereas myelosuppression and renal injury were minimal. No patients died of toxicity. Feeding tube dependence in 8% and tracheostomy in 1% of patients were evident at 2 years postchemoradiation therapy in patients who survived without local treatment failure. CONCLUSIONS: Local control and survival with this regimen were satisfactory. Although acute toxicity, such as mucositis, was common, late toxicity, such as laryngoesophageal dysfunction, was minimal. Therapy using weekly low-dose docetaxel and cisplatin concurrent with radiation warrants further evaluation. PMID- 25832687 TI - Concurrent chemo-radiation with or without induction gemcitabine, Carboplatin, and Paclitaxel: a randomized, phase 2/3 trial in locally advanced nasopharyngeal carcinoma. AB - PURPOSE: To compare survival, tumor control, toxicities, and quality of life of patients with locally advanced nasopharyngeal carcinoma (NPC) treated with induction chemotherapy and concurrent chemo-radiation (CCRT), against CCRT alone. PATIENTS AND METHODS: Patients were stratified by N stage and randomized to induction GCP (3 cycles of gemcitabine 1000 mg/m(2), carboplatin area under the concentration-time-curve 2.5, and paclitaxel 70 mg/m(2) given days 1 and 8 every 21 days) followed by CCRT (radiation therapy 69.96 Gy with weekly cisplatin 40 mg/m(2)), or CCRT alone. The accrual of 172 was planned to detect a 15% difference in 5-year overall survival (OS) with a 5% significance level and 80% power. RESULTS: Between September 2004 and August 2012, 180 patients were accrued, and 172 (GCP 86, control 86) were analyzed by intention to treat. There was no significant difference in OS (3-year OS 94.3% [GCP] vs 92.3% [control]; hazard ratio 1.05; 1-sided P=.494]), disease-free survival (hazard ratio 0.77, 95% confidence interval 0.44-1.35, P=.362), and distant metastases-free survival (hazard ratio 0.80, 95% confidence interval 0.38-1.67, P=.547) between the 2 arms. Treatment compliance in the induction phase was good, but the relative dose intensity for concurrent cisplatin was significantly lower in the GCP arm. Overall, the GCP arm had higher rates of grades 3 and 4 leukopenia (52% vs 37%) and neutropenia (24% vs 12%), but grade 3 and 4 acute radiation toxicities were not statistically different between the 2 arms. The global quality of life scores were comparable in both arms. CONCLUSION: Induction chemotherapy with GCP before concurrent chemo-irradiation did not improve survival in locally advanced NPC. PMID- 25832688 TI - Phase 1/2 trials of Temozolomide, Motexafin Gadolinium, and 60-Gy fractionated radiation for newly diagnosed supratentorial glioblastoma multiforme: final results of RTOG 0513. AB - PURPOSE: The purpose of phase 1 was to determine the maximum tolerated dose (MTD) of motexafin gadolinium (MGd) given concurrently with temozolomide (TMZ) and radiation therapy (RT) in patients with newly diagnosed supratentorial glioblastoma multiforme (GBM). Phase 2 determined whether this combination improved overall survival (OS) and progression-free survival (PFS) in GBM recursive partitioning analysis class III to V patients compared to therapies for recently published historical controls. METHODS AND MATERIALS: Dose escalation in phase 1 progressed through 3 cohorts until 2 of 6 patients experienced dose limiting toxicity or a dose of 5 mg/kg was reached. Once MTD was established, a 1 sided 1-sample log-rank test at significance level of .1 had 85% power to detect a median survival difference (13.69 vs 18.48 months) with 60 deaths over a 12 month accrual period and an additional 18 months of follow-up. OS and PFS were estimated using the Kaplan-Meier method. RESULTS: In phase 1, 24 patients were enrolled. The MTD established was 5 mg/kg, given intravenously 5 days a week for the first 10 RT fractions, then 3 times a week for the duration of RT. The 7 patients enrolled in the third dose level and the 94 enrolled in phase 2 received this dose. Of these 101 patients, 87 were eligible and evaluable. Median survival time was 15.6 months (95% confidence interval [CI]: 12.9-17.6 months), not significantly different from that of the historical control (P=.36). Median PFS was 7.6 months (95% CI: 5.7-9.6 months). One patient (1%) experienced a grade 5 adverse event possibly related to therapy during the concurrent phase, and none experience toxicity during adjuvant TMZ therapy. CONCLUSIONS: Treatment was well tolerated, but median OS did not reach improvement specified by protocol compared to historical control, indicating that the combination of standard RT with TMZ and MGd did not achieve a significant survival advantage. PMID- 25832689 TI - Predictors of adverse cosmetic outcome in the RAPID trial: an exploratory analysis. AB - PURPOSE: To evaluate factors associated with adverse cosmesis outcome in breast cancer patients randomized to accelerated partial breast irradiation (APBI) using 3-dimensional conformal radiation therapy or whole-breast irradiation in the RAPID (Randomized Trial of Accelerated Partial Breast Irradiation) trial. METHODS AND MATERIALS: Subjects were trial participants with nurse-assessed global cosmetic scores at baseline and at 3 years. Adverse cosmesis was defined as a score of fair or poor. Cosmetic deterioration was defined as any adverse change in score from baseline to 3 years. The analysis is based on data from the previously reported interim analysis. Logistic regression models were used to assess the association of risk factors for these outcomes among all patients and those treated with APBI only. RESULTS: Clinicopathologic characteristics were similar between subjects randomized to APBI (n=569) or whole-breast irradiation (n=539). For all subjects, factors associated with adverse cosmesis at 3 years were older age, central/inner tumor location, breast infection, smoking, seroma volume, breast volume, and use of APBI; factors associated with cosmetic deterioration were smoking, seroma volume, and use of APBI (P<.05). For APBI subjects, tumor location, smoking, age, and seroma volume were associated with adverse cosmesis (P<.05), and smoking was associated with cosmetic deterioration (P=.02). An independent association between the V95/whole-breast volume ratio and adverse cosmesis (P=.28) or cosmetic deterioration (P=.07) was not detected. On further exploration a V95/whole-breast volume ratio <0.15 was associated with a lower risk of cosmetic deterioration (p=.04), but this accounted for only 11% of patients. CONCLUSION: In the RAPID trial, a number of patient tumor and treatment related factors, including the use of APBI, were associated with adverse cosmesis and cosmetic deterioration. For patients treated with APBI alone, the high-dose treatment volume was not independently associated with an adverse cosmetic outcome, and a useful clinical threshold could not be identified. PMID- 25832690 TI - Second malignancies after adjuvant radiation therapy for early stage breast cancer: is there increased risk with addition of regional radiation to local radiation? AB - PURPOSE: This study was undertaken to determine whether there was an increased risk of second malignancies (SM), particularly lung cancer, in early stage breast cancer patients treated with the addition of nodal fields to breast and/or chest wall radiation therapy (RT). MATERIALS AND METHODS: Subjects were stage I/II female breast cancer patients 20 to 79 years of age, diagnosed between 1989 and 2005 and treated with adjuvant RT at our institution. Patients were included if they survived and did not have SM within 3 years of diagnosis. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated to compare SM incidence to cancer incidence in the general sex- and age-matched populations. Secondary malignancy risks in patients treated with local RT (LRT) to the breast/chest wall were compared to those in patients treated with locoregional RT (LRRT) to the breast/chest wall and regional nodes, using multivariate regression analysis (MVA) to account for covariates. RESULTS: The cohort included 12,836 patients with a median follow-up of 8.4 years. LRRT was used in 18% of patients. The SIR comparing patients treated with LRT to the general population was 1.29 (CI: 1.21-1.38). No statistically significant increased incidence of in-field malignancies (SIR, 1.04; CI: 0.87-1.23) and lung cancers (SIR, 1.06; CI: 0.88-1.26) was detected. The SIR comparing patients treated with LRRT to the general population was 1.39 (CI: 1.17-1.64). No statistically significant increased incidence of in-field malignancies (SIR, 1.26; CI: 0.77-1.94) and lung cancers (SIR, 1.27; CI: 0.76-1.98) was detected. On MVA comparing LRRT to LRT, the adjusted hazard ratio was 1.20 for in-field malignancies (CI: 0.68-2.16) and 1.26 for lung cancer (CI: 0.67-2.36). The excess attributable risk (EAR) to regional RT was 3.1 per 10,000 person years (CI: -8.7 to 9.9). CONCLUSIONS: No statistically significant increased risk of second malignancy was detected after LRRT relative to that for LRT. The upper limit of the EAR was approximately 1% at 10 years. PMID- 25832691 TI - Magnetic resonance imaging assessment of spinal cord and cauda equina motion in supine patients with spinal metastases planned for spine stereotactic body radiation therapy. AB - PURPOSE: To assess motion of the spinal cord and cauda equina, which are critical neural tissues (CNT), which is important when evaluating the planning organ-at risk margin required for stereotactic body radiation therapy. METHODS AND MATERIALS: We analyzed CNT motion in 65 patients with spinal metastases (11 cervical, 39 thoracic, and 24 lumbar spinal segments) in the supine position using dynamic axial and sagittal magnetic resonance imaging (dMRI, 3T Verio, Siemens) over a 137-second interval. Motion was segregated according to physiologic cardiorespiratory oscillatory motion (characterized by the average root mean square deviation) and random bulk shifts associated with gross patient motion (characterized by the range). Displacement was evaluated in the anteroposterior (AP), lateral (LR), and superior-inferior (SI) directions by use of a correlation coefficient template matching algorithm, with quantification of random motion measure error over 3 separate trials. Statistical significance was defined according to P<.05. RESULTS: In the AP, LR, and SI directions, significant oscillatory motion was observed in 39.2%, 35.1%, and 10.8% of spinal segments, respectively, and significant bulk motions in all cases. The median oscillatory CNT motions in the AP, LR, and SI directions were 0.16 mm, 0.17 mm, and 0.44 mm, respectively, and the maximal statistically significant oscillatory motions were 0.39 mm, 0.41 mm, and 0.77 mm, respectively. The median bulk displacements in the AP, LR, and SI directions were 0.51 mm, 0.59 mm, and 0.66 mm, and the maximal statistically significant displacements were 2.21 mm, 2.87 mm, and 3.90 mm, respectively. In the AP, LR, and SI directions, bulk displacements were greater than 1.5 mm in 5.4%, 9.0%, and 14.9% of spinal segments, respectively. No significant differences in axial motion were observed according to cord level or cauda equina. CONCLUSIONS: Oscillatory CNT motion was observed to be relatively minor. Our results support the importance of controlling bulk patient motion and the practice of applying a planning organ-at risk margin. PMID- 25832692 TI - Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT. AB - PURPOSE: This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by (18)F-choline positron emission tomography/computed tomography (PET/CT). METHODS AND MATERIALS: Thirty patients with localized prostate cancer underwent (18)F-choline PET/CT before treatment. Two VMAT plans, plan79 Gy and plan100-105 Gy, were compared for each patient. The whole-prostate planning target volume (PTVprostate) prescription was 79 Gy in both plans, but plan100-105 Gy added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, defined by 60% and 70% of maximum prostatic uptake on (18)F-choline PET (IDLsuv60% and IDLsuv70%, respectively, with IDLsuv70% nested inside IDLsuv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP). RESULTS: Planning objectives and dose constraints proved feasible in 30 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDLsuv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan100-105 Gy had significantly higher TCP than plan79 Gy across all prostate regions for alpha/beta ratios ranging from 1.5 Gy to 10 Gy (P<.001 for each case). There were no significant differences in bladder and femoral head NTCP between plans and slightly lower rectal NTCP (endpoint: grade >= 2 late toxicity or rectal bleeding) was found for plan100-105 Gy. CONCLUSIONS: VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to a (18)F-choline PET-defined IDL. PMID- 25832693 TI - Evaluation of online/offline image guidance/adaptation approaches for prostate cancer radiation therapy. AB - PURPOSE: To evaluate online/offline image-guided/adaptive treatment techniques for prostate cancer radiation therapy with daily cone-beam CT (CBCT) imaging. METHODS AND MATERIALS: Three treatment techniques were evaluated retrospectively using daily pre- and posttreatment CBCT images on 22 prostate cancer patients. Prostate, seminal vesicles (SV), rectal wall, and bladder were delineated on all CBCT images. For each patient, a pretreatment intensity modulated radiation therapy plan with clinical target volume (CTV) = prostate + SV and planning target volume (PTV) = CTV + 3 mm was created. The 3 treatment techniques were as follows: (1) Daily Correction: The pretreatment intensity modulated radiation therapy plan was delivered after online CBCT imaging, and position correction; (2) Online Planning: Daily online inverse plans with 3-mm CTV-to-PTV margin were created using online CBCT images, and delivered; and (3) Hybrid Adaption: Daily Correction plus an offline adaptive inverse planning performed after the first week of treatment. The adaptive plan was delivered for all remaining 15 fractions. Treatment dose for each technique was constructed using the daily posttreatment CBCT images via deformable image registration. Evaluation was performed using treatment dose distribution in target and critical organs. RESULTS: Treatment equivalent uniform dose (EUD) for the CTV was within [85.6%, 100.8%] of the pretreatment planned target EUD for Daily Correction; [98.7%, 103.0%] for Online Planning; and [99.2%, 103.4%] for Hybrid Adaptation. Eighteen percent of the 22 patients in Daily Correction had a target dose deficiency >5%. For rectal wall, the mean +/- SD of the normalized EUD was 102.6% +/- 2.7% for Daily Correction, 99.9% +/- 2.5% for Online Planning, and 100.6% +/- 2.1% for Hybrid Adaptation. The mean +/- SD of the normalized bladder EUD was 108.7% +/- 8.2% for Daily Correction, 92.7% +/- 8.6% for Online Planning, and 89.4% +/- 10.8% for Hybrid Adaptation. CONCLUSIONS: Both Online Planning and Hybrid Adaptation can achieve comparable target coverage and normal tissue sparing and are superior to the Daily Correction technique. The Daily Correction technique using a 3-mm target margin in the pretreatment plan is not appropriate to compensate for residual variations in CBCT image-guided prostate cancer radiation therapy. PMID- 25832694 TI - Comparative assessment of liver tumor motion using cine-magnetic resonance imaging versus 4-dimensional computed tomography. AB - PURPOSE: To compare the extent of tumor motion between 4-dimensional CT (4DCT) and cine-MRI in patients with hepatic tumors treated with radiation therapy. METHODS AND MATERIALS: Patients with liver tumors who underwent 4DCT and 2 dimensional biplanar cine-MRI scans during simulation were retrospectively reviewed to determine the extent of target motion in the superior-inferior, anterior-posterior, and lateral directions. Cine-MRI was performed over 5 minutes. Tumor motion from MRI was determined by tracking the centroid of the gross tumor volume using deformable image registration. Motion estimates from 4DCT were performed by evaluation of the fiducial, residual contrast (or liver contour) positions in each CT phase. RESULTS: Sixteen patients with hepatocellular carcinoma (n=11), cholangiocarcinoma (n=3), and liver metastasis (n=2) were reviewed. Cine-MRI motion was larger than 4DCT for the superior inferior direction in 50% of patients by a median of 3.0 mm (range, 1.5-7 mm), the anterior-posterior direction in 44% of patients by a median of 2.5 mm (range, 1-5.5 mm), and laterally in 63% of patients by a median of 1.1 mm (range, 0.2-4.5 mm). CONCLUSIONS: Cine-MRI frequently detects larger differences in hepatic intrafraction tumor motion when compared with 4DCT most notably in the superior inferior direction, and may be useful when assessing the need for or treating without respiratory management, particularly in patients with unreliable 4DCT imaging. Margins wider than the internal target volume as defined by 4DCT were required to encompass nearly all the motion detected by cine-MRI for some of the patients in this study. PMID- 25832695 TI - Computed tomography number changes observed during computed tomography-guided radiation therapy for head and neck cancer. AB - PURPOSE: To investigate CT number (CTN) changes in gross tumor volume (GTV) and organ at risk (OAR) according to daily diagnostic-quality CT acquired during CT guided intensity modulated radiation therapy for head and neck cancer (HNC) patients. METHODS AND MATERIALS: Computed tomography scans acquired using a CT-on rails during daily CT-guided intensity modulated radiation therapy for 15 patients with stage II to IVa squamous cell carcinoma of the head and neck were analyzed. The GTV, parotid glands, spinal cord, and nonspecified tissue were generated on each selected daily CT. The changes in CTN distributions and the mean and mode values were collected. Pearson analysis was used to assess the correlation between the CTN change, organ volume reduction, and delivered radiation dose. RESULTS: Volume and CTN changes for GTV and parotid glands can be observed during radiation therapy delivery for HNC. The mean (+/-SD) CTNs in GTV and ipsi- and contralateral parotid glands were reduced by 6 +/- 10, 8 +/- 7, and 11 +/- 10 Hounsfield units, respectively, for all patients studied. The mean CTN changes in both spinal cord and nonspecified tissue were almost invisible (<2 Hounsfield units). For 2 patients studied, the absolute mean CTN changes in GTV and parotid glands were strongly correlated with the dose delivered (P<.001 and P<.05, respectively). For the correlation between CTN reductions and delivered isodose bins for parotid glands, the Pearson coefficient varied from -0.98 (P<.001) in regions with low-dose bins to 0.96 (P<.001) in high-dose bins and were patient specific. CONCLUSIONS: The CTN can be reduced in tumor and parotid glands during the course of radiation therapy for HNC. There was a fair correlation between CTN reduction and radiation doses for a subset of patients, whereas the correlation between CTN reductions and volume reductions in GTV and parotid glands were weak. More studies are needed to understand the mechanism for the radiation-induced CTN changes. PMID- 25832696 TI - Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness. AB - PURPOSE: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LETd) while keeping the radiobiologically weighted dose (DRBE) to the target the same. METHODS AND MATERIALS: The target is painted with LETd by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LETd within the target increases with increasing number of fields, D decreases to maintain the DRBE the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]). RESULTS: The LETd increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LETd led to a decrease of D with 5.3 +/- 0.6 Gy for 2STP, 4.4 +/- 0.7 Gy for 4STP, and 5.3 +/- 1.1 Gy for 7STP, keeping the Drbe at 90% of the volume (Drbe, 90) constant to FTP. CONCLUSIONS: LETd painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment. PMID- 25832698 TI - Lung cancer cell line screen links fanconi anemia/BRCA pathway defects to increased relative biological effectiveness of proton radiation. AB - PURPOSE: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. METHODS AND MATERIALS: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/MUm). For comparison, 250-kVp X rays and (137)Cs gamma-rays were used. To estimate the RBE of protons relative to (60)Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. RESULTS: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P<=.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. CONCLUSIONS: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation. PMID- 25832697 TI - High-density and very-low-density lipoprotein have opposing roles in regulating tumor-initiating cells and sensitivity to radiation in inflammatory breast cancer. AB - PURPOSE: We previously demonstrated that cholesterol-lowering agents regulate radiation sensitivity of inflammatory breast cancer (IBC) cell lines in vitro and are associated with less radiation resistance among IBC patients who undergo postmastectomy radiation. We hypothesized that decreasing IBC cellular cholesterol induced by treatment with lipoproteins would increase radiation sensitivity. Here, we examined the impact of specific transporters of cholesterol (ie lipoproteins) on the responses of IBC cells to self-renewal and to radiation in vitro and on clinical outcomes in IBC patients. METHODS AND MATERIALS: Two patient-derived IBC cell lines, SUM 149 and KPL4, were incubated with low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), or high-density lipoproteins (HDL) for 24 hours prior to irradiation (0-6 Gy) and mammosphere formation assay. Cholesterol panels were examined in a cohort of patients with primary IBC diagnosed between 1995 and 2011 at MD Anderson Cancer Center. Lipoprotein levels were then correlated to patient outcome, using the log rank statistical model, and examined in multivariate analysis using Cox regression. RESULTS: VLDL increased and HDL decreased mammosphere formation compared to untreated SUM 149 and KPL4 cells. Survival curves showed enhancement of survival in both of the IBC cell lines when pretreated with VLDL and, conversely, radiation sensitization in all cell lines when pretreated with HDL. In IBC patients, higher VLDL values (>30 mg/dL) predicted a lower 5-year overall survival rate than normal values (hazard ratio [HR] = 1.9 [95% confidence interval [CI]: 1.05-3.45], P=.035). Lower-than-normal patient HDL values (<60 mg/dL) predicted a lower 5-year overall survival rate than values higher than 60 mg/dL (HR = 3.21 [95% CI: 1.25-8.27], P=.015). CONCLUSIONS: This study discovered a relationship among the plasma levels of lipoproteins, overall patient response, and radiation resistance in IBC patients and IBC patient-derived cell lines. A more expansive study is needed to verify these observations. PMID- 25832699 TI - Ataxia telangiectasia-mutated gene polymorphisms and acute normal tissue injuries in cancer patients after radiation therapy: a systematic review and meta analysis. AB - PURPOSE: Studies of the association between ataxia telangiectasia-mutated (ATM) gene polymorphisms and acute radiation injuries are often small in sample size, and the results are inconsistent. We conducted the first meta-analysis to provide a systematic review of published findings. METHODS AND MATERIALS: Publications were identified by searching PubMed up to April 25, 2014. Primary meta-analysis was performed for all acute radiation injuries, and subgroup meta-analyses were based on clinical endpoint. The influence of sample size and radiation injury incidence on genetic effects was estimated in sensitivity analyses. Power calculations were also conducted. RESULTS: The meta-analysis was conducted on the ATM polymorphism rs1801516, including 5 studies with 1588 participants. For all studies, the cut-off for differentiating cases from controls was grade 2 acute radiation injuries. The primary meta-analysis showed a significant association with overall acute radiation injuries (allelic model: odds ratio = 1.33, 95% confidence interval: 1.04-1.71). Subgroup analyses detected an association between the rs1801516 polymorphism and a significant increase in urinary and lower gastrointestinal injuries and an increase in skin injury that was not statistically significant. There was no between-study heterogeneity in any meta analyses. In the sensitivity analyses, small studies did not show larger effects than large studies. In addition, studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence. Power calculations revealed that the statistical power of the primary meta-analysis was borderline, whereas there was adequate power for the subgroup analysis of studies with high incidence of acute radiation injuries. CONCLUSIONS: Our meta-analysis showed a consistency of the results from the overall and subgroup analyses. We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was dependent on the incidence of the injury. These support the evidence of an association between the rs1801516 polymorphism and acute radiation injuries, encouraging further research of this topic. PMID- 25832700 TI - A comparison of evidence-based estimates and empirical benchmarks of the appropriate rate of use of radiation therapy in ontario. AB - PURPOSE: Estimates of the appropriate rate of use of radiation therapy (RT) are required for planning and monitoring access to RT. Our objective was to compare estimates of the appropriate rate of use of RT derived from mathematical models, with the rate observed in a population of patients with optimal access to RT. METHODS AND MATERIALS: The rate of use of RT within 1 year of diagnosis (RT1Y) was measured in the 134,541 cases diagnosed in Ontario between November 2009 and October 2011. The lifetime rate of use of RT (RTLIFETIME) was estimated by the multicohort utilization table method. Poisson regression was used to evaluate potential barriers to access to RT and to identify a benchmark subpopulation with unimpeded access to RT. Rates of use of RT were measured in the benchmark subpopulation and compared with published evidence-based estimates of the appropriate rates. RESULTS: The benchmark rate for RT1Y, observed under conditions of optimal access, was 33.6% (95% confidence interval [CI], 33.0% 34.1%), and the benchmark for RTLIFETIME was 41.5% (95% CI, 41.2%-42.0%). Benchmarks for RTLIFETIME for 4 of 5 selected sites and for all cancers combined were significantly lower than the corresponding evidence-based estimates. Australian and Canadian evidence-based estimates of RTLIFETIME for 5 selected sites differed widely. RTLIFETIME in the overall population of Ontario was just 7.9% short of the benchmark but 20.9% short of the Australian evidence-based estimate of the appropriate rate. CONCLUSIONS: Evidence-based estimates of the appropriate lifetime rate of use of RT may overestimate the need for RT in Ontario. PMID- 25832701 TI - Readability of patient education materials from professional societies in radiation oncology: are we meeting the national standard? PMID- 25832702 TI - Revisiting cobalt 60 teletherapy. In regard to Page et Al. PMID- 25832703 TI - In reply to Ravichandran and Ravikumar. PMID- 25832704 TI - Elective nodal irradiation in early non-small cell lung cancer. In regard to Lao et al. PMID- 25832705 TI - In reply to Cihoric and Jeremic. PMID- 25832706 TI - Progression rate of silent corticotroph adenomas after stereotactic radiosurgery. In regard to Xu et al. PMID- 25832708 TI - Erratum to: Melidis C, Bosch WR, Izewska J, et al. Global harmonization of quality assurance naming conventions in radiation therapy Clinical Trials. Int J Radiat Oncol Biol Phys 2014;90:1242-1249. PMID- 25832707 TI - In reply to Chen and Chung. PMID- 25832709 TI - Erratum to: Rodrigues G, Oberije C, Senan S, et al. is intermediate radiation dose escalation with concurrent chemotherapy for stage III non-small cell lung cancer beneficial? A multi-institutional propensity score matched analysis. Int J Radiat Oncol Biol Phys 2015;91:133-139. PMID- 25832710 TI - Erratum to: Wallner PE, Anscher MS, Barker CA, et al. Current status and recommendations for the future of research, teaching, and testing in the biological sciences of radiation oncology: report of the American Society for Radiation Oncology Cancer Biology/Radiation Biology Task Force, executive summary. Int J Radiat Oncol Biol Phys 2014;88:11-17. PMID- 25832713 TI - Metabolic Profiling of Bacteria by Unnatural C-terminated D-Amino Acids. AB - Bacterial peptidoglycan is a mesh-like network comprised of sugars and oligopeptides. Transpeptidases cross-link peptidoglycan oligopeptides to provide vital cell wall rigidity and structural support. It was recently discovered that the same transpeptidases catalyze the metabolic incorporation of exogenous D amino acids onto bacterial cell surfaces with vast promiscuity for the side-chain identity. It is now shown that this enzymatic promiscuity is not exclusive to side chains, but that C-terminus variations can also be accommodated across a diverse range of bacteria. Atomic force microscopy analysis revealed that the incorporation of C-terminus amidated D-amino acids onto bacterial surfaces substantially reduced the cell wall stiffness. We exploited the promiscuity of bacterial transpeptidases to develop a novel assay for profiling different bacterial species. PMID- 25832714 TI - The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications. MATERIALS AND METHODS: This review is based on the material found on PubMed up to December 2014. 'Ras signaling, Ras dysregulation, Ras inhibition, MAPK pathway, cancer, hepatocarcinoma and liver cancer' alone or in combination were the main terms used for online research. RESULTS: Multiple mechanisms lead to the deregulation of the Ras pathway in liver cancer. Ras and Raf gene mutations are rare events in human hepatocarcinogenesis in contrast to experimental models in rodents. Downregulation of several Ras/MAPK pathway inhibitors such as GAPs, RASSF proteins, DUSP1, Sprouty and Spred proteins is largely implicated in the aberrant activation of this pathway in the context of wild-type Ras and Raf genes. Epigenetic or post-transcriptional mechanisms lead to the downregulation of these tumour suppressor genes. CONCLUSION: Ras/MAPK pathway effectors may be considered as potential therapeutic targets in the field of HCC. In particular after the arrival of sorafenib, more Ras/MAPK inhibitors have emerged and are still in preclinical or clinical investigation for HCC therapy. PMID- 25832715 TI - Ultrafast myoglobin structural dynamics observed with an X-ray free-electron laser. AB - Light absorption can trigger biologically relevant protein conformational changes. The light-induced structural rearrangement at the level of a photoexcited chromophore is known to occur in the femtosecond timescale and is expected to propagate through the protein as a quake-like intramolecular motion. Here we report direct experimental evidence of such 'proteinquake' observed in myoglobin through femtosecond X-ray solution scattering measurements performed at the Linac Coherent Light Source X-ray free-electron laser. An ultrafast increase of myoglobin radius of gyration occurs within 1 picosecond and is followed by a delayed protein expansion. As the system approaches equilibrium it undergoes damped oscillations with a ~3.6-picosecond time period. Our results unambiguously show how initially localized chemical changes can propagate at the level of the global protein conformation in the picosecond timescale. PMID- 25832717 TI - Recent progress in drug discovery for Parkinson's disease. PMID- 25832718 TI - Dopamine D3 agonists in the treatment of Parkinson's disease. AB - Parkinson's disease (PD) is t he second most common form of neurodegenerative disorders that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc) triggering profound motor perturbation, as well as cognitive, sensory and mood deficits. Although these symptoms can be improved using currently available dopamine replacement strategies, they are not able to slow the neurodegenerative process that underlies PD progression. Following the discovery of the D3 receptor from molecular cloning, it has gained much attention as a potential therapeutic target for the treatment of PD due to their localization in the limbic regions of the brain as well as pharmacologic similarity to the D2 receptor subtype. Of particular interest, D3 receptor-selective agonists appear to have neuroprotective effects apart from their ability to relieve PD symptoms. Owing to the distinct significance of D3 receptor in mediating diverse neurological effects, it represents a unique target for therapeutic intervention in PD with much less undesirable side effects. Herein, we review progress in the development of D3 receptor-selective agonist molecules having a broad spectrum of affinities, selectivities as well as unique pharmacological properties directed at slowing the neurodegeneration process. PMID- 25832716 TI - PSF: nuclear busy-body or nuclear facilitator? AB - PTB-associated splicing factor (PSF) is an abundant and essential nucleic acid binding protein that participates in a wide range of gene regulatory processes and cellular response pathways. At the protein level, PSF consists of multiple domains, many of which remain poorly characterized. Although grouped in a family with the proteins p54nrb/NONO and PSPC1 based on sequence homology, PSF contains additional protein sequence not included in other family members. Consistently, PSF has also been implicated in functions not ascribed to p54nrb/NONO or PSPC1. Here, we provide a review of the cellular activities in which PSF has been implicated and what is known regarding the mechanisms by which PSF functions in each case. We propose that the complex domain arrangement of PSF allows for its diversity of function and integration of activities. Finally, we discuss recent evidence that individual activities of PSF can be regulated independently from one another through the activity of domain-specific co-factors. PMID- 25832719 TI - Inhibitors of leucine-rich repeat kinase 2 (LRRK2): progress and promise for the treatment of Parkinson's disease. AB - Mutations in the gene for leucine-rich repeat kinase 2 (LRRK2) have been linked to several familial and sporadic late-onset cases of Parkinson's disease. The cumulative data for the effects of mutant forms of this enzyme on neuronal degradation and the pathophysiology of Parkinson's disease create a compelling case for drug discovery based on inhibition of the mutant forms of LRRK2. This review focuses on structure-activity relationships for inhibitors of LRRK2 and the data supporting a potential role of these agents in treating Parkinson's disease. PMID- 25832720 TI - Design and development of a novel supportive care product for the treatment of sialorrhea in Parkinson's disease. AB - Sialorrhea or excessive drooling is a significant medical issue in Parkinson's disease (PD) and neurodegenerative disorders, although it is often underreported by patients. Sialorrhea affects a large proportion of PD patients, ranging up to 78% in advanced stages, with many PD patients considering drooling as their worst non-motor symptom. Sialorrhea affects up to a million patients with diverse neurological impairments, including cerebral palsy, amyotrophic lateral sclerosis (ALS), Huntington's, survivors of stroke and severe traumatic brain injury. Numerous approaches have been attempted to treat sialorrhea in PD patients, including surgical procedures, prosthetic devices, botulinum injections, systemic anticholinergic drugs, and speech and behavioral therapy. A novel drug treatment (NH004) to control the symptoms of sialorrhea is under development. The active ingredient is the anticholinergic drug tropicamide. Anticholinergic drugs work by blocking acetylcholine muscarinic receptors and ultimately decreasing saliva secretion via the reduction of parasympathetic autonomic nervous system activity. The tropicamide is delivered in a thin film designed to adhere to the buccal mucosa and to slowly dissolve within the oral cavity, allowing the drug to reach the underlying salivary gland. A pilot study testing NH004 in PD patients has suggested a potentially useful sialorrhea-reducing effect with NH004 compared to placebo. The advantages of NH004 include local bioavailability with low systemic exposure, rapid onset of action and, importantly, convenience of use for patients. This review summarizes the current knowledge and impact of sialorrhea as a common non-motor symptom in PD, treatment options, the anticholinergic drug tropicamide, the design and development of the thin film drug delivery system, and NH004 for the treatment of sialorrhea. PMID- 25832721 TI - Agonists of the tissue-protective erythropoietin receptor in the treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disease affecting more than a million people in the USA alone. While there are effective symptomatic treatments for PD, there is an urgent need for new therapies that slow or halt the progressive death of dopaminergic neurons. Significant progress has been made in understanding the pathophysiology of PD, which has substantially facilitated the discovery efforts to identify novel drugs. The tissue-protective erythropoietin (EPO) receptor, EPOR/CD131, has emerged as one promising target for disease modifying therapies. Recombinant human EPO (rhEPO), several variants of EPO, EPO mimetic peptides, cell-based therapies using cells incubated with or expressing EPO, gene therapy vectors encoding EPO, and small molecule EPO mimetic compounds all show potential as therapeutic candidates. Agonists of the EPOR/CD131 receptor demonstrate potent anti-apoptotic, antioxidant, and anti-inflammatory effects and protect neurons, including dopaminergic neurons, from diverse insults in vitro and in vivo. When delivered directly to the striatum, rhEPO protects dopaminergic neurons in animal models of PD. Early-stage clinical trials testing systemic rhEPO have provided encouraging results, while additional controlled studies are required to fully assess the potential of the treatment. Poor CNS availability of proteins and challenges related to invasive delivery limit delivery of EPO protein. Several variants of EPO and small molecule agonists of the EPO receptors are making progress in preclinical studies and may offer solutions to these challenges. While EPO was initially discovered as the primary modulator of erythropoiesis, the discovery and characterization of the tissue-protective EPOR/CD131 receptor offer an opportunity to selectively target the neuroprotective receptor as an approach to identify disease-modifying treatments for PD. PMID- 25832722 TI - A Rare Case of an Intact Bone Plug Associated with a Gunshot Exit Wound. AB - This case study presents an unusual manifestation of gunshot trauma in skeletal tissue from a post-World War II human rights abuse sample uncovered in Vilnius, Lithuania. After briefly reviewing the typical wound appearance of projectile trauma in the cranium, we discuss the presence of an intact bone plug associated with a gunshot exit wound in an individual from the Tuskulenai Case. While this individual demonstrated typical gunshot entry and exit wounds to the cranium consistent with high-velocity trauma, the bone plug indicates that the projectile likely lost much of its kinetic energy while traveling through the cranium resulting in a low-velocity impact at the exit site. This study reviews a similar instance of a bone plug recovered from a bioarcheological sample in Peru and emphasizes the importance of thorough archeological excavations of mass graves. PMID- 25832724 TI - Secondary cranial vault remodeling for restenosis after primary sagittal synostosis repair. AB - The mainstay of treatment for single-suture cranial synostosis is cranial vault reconstruction. After primary cranial vault remodeling, patients are at risk for cranial restenosis and delayed intracranial hypertension, which may result in developmental delay or blindness. Synostosis patients are therefore generally monitored periodically for signs and symptoms of intracranial hypertension that may indicate a second cranial expansion procedure. The authors present a carefully illustrated case of a patient who presented 2 years after primary cranial vault reconstruction for sagittal synostosis with a decrease in head circumference percentile, recurrent cranial dysmorphism, papilledema, headaches and computed tomographic imaging findings consistent with cranial restenosis. These findings resolved after secondary cranial vault remodeling. The authors advocate a protocol of prospective routine clinical and radiographic follow-up after primary cranial vault repair for single-suture cranial synostosis, and illustrate the specific clinical and radiographic findings suggestive of this late complication in a representative individual patient. PMID- 25832723 TI - Associations of pre-transplant prescription narcotic use with clinical complications after kidney transplantation. AB - BACKGROUND: The impact of narcotic use before kidney transplantation on post transplant clinical outcomes is not well described. METHODS: We examined integrated national transplant registry, pharmacy records, and Medicare billing claims to follow 16,322 kidney transplant recipients, of whom 28.3% filled a narcotic prescription in the year before transplantation. Opioid analgesic fills were normalized to morphine equivalents (ME) and expressed as mg/kg exposures (approximate quartiles: 0.1-1.7, 1.8-5.4, 5.5-23.7, and >= 23.8 mg/kg, respectively). Post-transplant cardiovascular, respiratory, neurological, accidents, substance abuse, and noncompliance events were identified using diagnosis codes on Medicare billing claims. Adjusted associations of ME level with post-transplant complications were quantified by multivariate Cox regression. RESULTS: The incidence of complications at 3 years post-transplant among those with the highest pre-transplant ME exposure compared to no use included: ventricular arrhythmias, 1.1 vs. 0.2% (p < 0.001); cardiac arrest, 4.7 vs. 2.7% (p < 0.05); hypotension, 14 vs. 8% (p < 0.0001); hypercapnia, 1.6 vs. 0.9% (p < 0.05); mental status changes, 5.3 vs. 2.7% (p < 0.001); drug abuse/dependence, 7.0 vs. 1.7% (p < 0.0001); alcohol abuse, 1.8 vs. 0.6% (p = 0.0001); accidents, 0.9 vs. 0.3% (p < 0.05); and noncompliance, 3.5 vs. 2.3% (p < 0.05). In multivariate analyses, transplant recipients with the highest level of pre-transplant narcotic use had approximately 2 to 4 times the risks of post transplant ventricular arrhythmias, mental status changes, drug abuse, alcohol abuse, and accidents compared with non-users, and 35-45% higher risks of cardiac arrest and hypotension. CONCLUSION: Although associations may reflect underlying conditions or behaviors, high-level prescription narcotic use before kidney transplantation predicts increased risk of clinical complications after transplantation. PMID- 25832725 TI - Prognostic value of pro-inflammatory cytokine and pro-angiogenesis factor in differentiating malignant from benign exudative effusion. AB - BACKGROUND AND AIMS: The precise mechanism of pathogenesis in exudation of effusions is uncertain. Released factors in inflammation and malignancy of pleura are related to incremented permeability of the micro-pleural vessels. Angiopoietins (Ang) take part in development of angiogenesis and pleural inflammation. Interleukin-8 (IL-8) influences proliferation and tumor angiogenesis and it is expressed in cancer. The aims of this study were to investigate the relationship between inflammation, angiogenesis and etiologies of exudative effusions, and to evaluate the diagnostic value in differentiating malignant from benign. METHODS: The study includes 49 pleural fluid (PF) samples. Ang-2 and IL-8 in PF and serum were estimated. RESULTS: Ten patients were transudative and 39 patients were exudative fluid, subdivided into 16 benign and 23 malignant effusion. Ang-2 and IL-8 either fluid level or ratio were in significantly high in exudative more than in transudative fluid (P = 0.002). Ang 2 and IL-8 in PF were in high level than in serum of exudative and transudative. Ang-2 fluid level and ratio were significantly high in benign exudative effusion (P = 0.01, P = 0.05, respectively), while IL-8 level was significantly high in malignant exudative effusion (P = 0.04). Cut-off points for PF Ang-2 and IL-8 in differentiating malignant from benign exudative were 15.67 ng/mL, 325.54 pg/mL, respectively. CONCLUSION: Our results support the evidence that angiogenesis and inflammatory pathways are linked, and that inflammation and vascular permeability of pleura constitutes the pathogenic basis of the majority of exudative effusion. PMID- 25832726 TI - Segregation of ovarian cancer stage exploiting spectral biomarkers derived from blood plasma or serum analysis: ATR-FTIR spectroscopy coupled with variable selection methods. AB - Ovarian cancer is a solid tumor and a leading cause of mortality. Diagnostic tools for the detection of early stage (stage I) ovarian cancer are urgently needed. For this purpose, attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) coupled with variable selection methods, successive projection algorithm or genetic algorithm (GA) combined with linear discriminant analysis (LDA), were employed to identify spectral biomarkers in blood plasma or serum samples for accurate diagnosis of different stages of ovarian cancer, histological type and segregation based on age. Three spectral datasets (stage I vs. stage II-IV; serous vs. non-serous carcinoma; and, <=60 years vs. >60 years) were processed: sensitivity and specificity required for real-world diagnosis of ovarian cancer was achieved. Toward segregating stage I vs. stage II-IV, sensitivity and specificity (plasma blood) of 100% was achieved using a GA-LDA model with 33 wavenumbers. For serous vs. non-serous category (plasma blood), the sensitivity and specificity levels, using 29 wavenumbers by GA-LDA, were remarkable (up to 94%). For <=60 years and >60 years categories (plasma blood), the sensitivity and specificity, using 42 wavenumbers by GA-LDA, gave complete accuracy (100%). For serum samples, sensitivity and specificity results gave relatively high accuracy (up to 91.6% stage I vs. stage II-IV; up to 93.0% serous vs. non-serous; and, up to 96.0% <=60 years vs. >60 years) using several wavenumbers. These findings justify a prospective population-based assessment of biomarkers signatures using ATR-FTIR spectroscopy as a screening tool for stage of ovarian cancer. PMID- 25832728 TI - Quality Management in Scientific Publishing--the Importance to Critically Scrutinize Scientific Work. PMID- 25832727 TI - High-throughput protease activity cytometry reveals dose-dependent heterogeneity in PMA-mediated ADAM17 activation. AB - As key components of autocrine signaling, pericellular proteases, a disintegrin and metalloproteinases (ADAMs) in particular, are known to impact the microenvironment of individual cells and have significant implications in various pathological situations including cancer, inflammatory and vascular diseases. There is great incentive to develop a high-throughput platform for single-cell measurement of pericellular protease activity, as it is essential for studying the heterogeneity of protease response and the corresponding cell behavioral consequences. In this work, we developed a microfluidic platform to simultaneously monitor protease activity of many single cells in a time-dependent manner. This platform isolates individual microwells rapidly on demand and thus allows single-cell activity measurement of both cell-surface and secreted proteases by confining individual cells with diffusive FRET-based substrates. With this platform, we observed dose-dependent heterogeneous protease activation of HepG2 cells treated with phorbol 12-myristate 13-acetate (PMA). To study the temporal behavior of PMA-induced protease response, we monitored the pericellular protease activity of the same single cells during three different time periods and revealed the diversity in the dynamic patterns of single-cell protease activity profile upon PMA stimulation. The unique temporal information of single cell protease response can help unveil the complicated functional role of pericellular proteases. PMID- 25832729 TI - Long-Term Results of Various Operations for Lumbar Disc Herniation: Analysis of over 39,000 Patients. AB - OBJECTIVE: To determine the long-term follow-up of the various operations for lumbar disc herniation in a large patient population. SUBJECTS AND METHODS: Patients who had operations for lumbar disc herniation (microdiscectomy, endoscopic microdiscectomy and the 'classical operation', i.e. laminectomy/laminotomy with discectomy) were collected from the world literature. Patients who had follow-ups for at least 2 years were analyzed relative to the outcome. The outcome was graded by the patients themselves, and the operative groups were compared to one another. RESULTS: 39,048 patients collected from the world literature had had lumbar disc operations for disc herniations. The mean follow-up period was 6.1 years, and 30,809 (78.9%) patients reported good/excellent results. Microdiscectomy was performed on 3,400 (8.7%) patients. The mean follow-up was 4.1 years with 2,866 (84.3%) good/excellent results, while 1,101 (3.6%) patients had endoscopic microdiscectomy. There, the mean follow-up was 2.9 years with 845 (79.5%) good/excellent results. The classical operation was performed on 34,547 (88.5%) patients with a mean follow-up period of 6.3 years, and 27,050 (78.3%) patients had good/excellent results. These results mirror those with discectomy and the placement of prosthetic discs. CONCLUSIONS: The analysis of 39,048 patients with various operations for lumbar disc herniation revealed the same pattern of long-term results. Patients who had microdiscectomy, endoscopic microdiscectomy or the classical operation (laminectomy/laminotomy with discectomy) all had approximately 79% good/excellent results. None of the operative procedures gave a different outcome. l. PMID- 25832732 TI - gamma134.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia. PMID- 25832730 TI - Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin. AB - Sphingosine-1-phosphate (S1P) participates in inflammation; however, its role in leukocyte rolling is still unclear. Here we use intravital microscopy in inflamed mouse cremaster muscle venules and human endothelial cells to show that S1P contributes to P-selectin-dependent leukocyte rolling through endothelial S1P receptor 3 (S1P3) and Galphaq, PLCbeta and Ca(2+). Intra-arterial S1P administration increases leukocyte rolling, while S1P3 deficiency or inhibition dramatically reduces it. Mast cells involved in triggering rolling also release S1P that mobilizes P-selectin through S1P3. Histamine and epinephrine require S1P3 for full-scale effect accomplishing it by stimulating sphingosine kinase 1 (Sphk1). In a counter-regulatory manner, S1P1 inhibits cAMP-stimulated Sphk1 and blocks rolling as observed in endothelial-specific S1P1(-/-) mice. In agreement with a dominant pro-rolling effect of S1P3, FTY720 inhibits rolling in control and S1P1(-/-) but not in S1P3(-/-) mice. Our findings identify S1P as a direct and indirect contributor to leukocyte rolling and characterize the receptors mediating its action. PMID- 25832734 TI - Expression of the toxin-antitoxin genes yefM(Lrh), yoeB(Lrh) in human Lactobacillus rhamnosus isolates. AB - Lactobacilli are important microorganisms in various activities, for example, diary products, meat ripening, bread and pickles, but, moreover, are associated directly with human skin and cavities (e.g., mouth, gut, or vagina). Some of them are used as probiotics. Therefore, the molecular biological investigation of these bacteria is important. Earlier we described several toxin antitoxin systems (type II) in lactobacilli. Here, we describe the structure and transcriptional regulation of genes, encoding TA system YefM-YoeB(Lrh) in three strains of Lactobacillus rhamnosus comparing stationary and exponential growth phases, the influence of stress factors and mRNA stability. The same TA system is responding to physiological and stress conditions differently in related strains. Using primer extension and RLM-RACE methods we determined three transcription start sites of RNAs in the operon. The promoter region of the operon is preceded by a conserved BOX element occurring at multiple positions in the genomes of L. rhamnosus strains. Downstream of and partially overlapping with the 3' end of the yoeB(Lrh) toxin gene, a divergently transcribed unexpected RNA was detected. PMID- 25832735 TI - Development of theory-based knowledge translation interventions to facilitate the implementation of evidence-based guidelines on the early management of adults with traumatic spinal cord injury. AB - RATIONALE: Optimal, early management following a spinal cord injury (SCI) can limit individuals' disabilities and costs related to their care. Several knowledge syntheses were recently published to guide health care professionals with regard to early interventions in SCI patients. However, no knowledge translation (KT) intervention, selected according to a behaviour change theory, has been proposed to facilitate the use of SCI guidelines in an acute care setting. OBJECTIVES: To develop theory-informed KT interventions to promote the application of evidence-based recommendations on the acute care management of SCI patients. METHODS: The first four phases of the knowledge-to-action model were used to establish the study design. Knowledge selection was based on the Grading of Recommendations Assessment, Development and Evaluation system. Knowledge adaptation to the local context was sourced from the ADAPTE process. The theoretical domains framework oriented the selection and development of the interventions based on an assessment of barriers and enablers to knowledge application. RESULTS: Twenty-nine recommendations were chosen and operationalized in measurable clinical indicators. Barriers related to knowledge, skills, perceived capacities, beliefs about consequences, social influences, and the environmental context and resources theoretical domains were identified. The mapping of behaviour change techniques associated with those barriers led to the development of an online educational curriculum, interdisciplinary clinical pathways as well as policies and procedures. CONCLUSIONS: This research project allowed us developing KT interventions according to a thorough behavioural change methodology. Exposure to the generated interventions will support health care professionals in providing the best care to SCI patients. PMID- 25832733 TI - Tracking miRNAs' footprints in tumor-microenvironment interactions: Insights and implications for targeted cancer therapy. AB - In the past decades, cancer medicine studies have mainly focused on tumor cell biology as the main promoter of solid tumor progression. However, tumor biology does not explain the intertwinement and ambiguity of the tumors' territory. Recently, the approach of understanding cancer has shifted from investigating the biology of tumor cells to studying the microenvironment surrounding them. MicroRNAs (miRNAs), which play a role in exploiting indigenous stromal cells and are components that cooperate and produce a favorable microenvironment for progressive tumor formation, have been implicated in numerous processes essential for tumor initiation and growth. Understanding the mechanisms underlying interactions between tumor cells and their adjacent environment holds many promises for the future of cancer-targeted therapies. Herein, we provide a step by-step account of miRNA involvement in tumor-microenvironment interactions as the micromediators of tumor cell and stroma communications. We also focus on the clinical challenges in using miRNAs tof overcome therapy resistance mechanisms and tumor heterogeneity bias in cancer therapy. PMID- 25832737 TI - The chromatin-remodeling factor AtINO80 plays crucial roles in genome stability maintenance and in plant development. AB - INO80 is a conserved chromatin-remodeling factor in eukaryotes. While a previous study reported that the Arabidopsis thaliana INO80 (AtINO80) is required for somatic homologous recombination (HR), the role of AtINO80 in plant growth and development remains obscure. Here, we identified and characterized two independent atino80 mutant alleles, atino80-5 and atino80-6, which display similar and pleiotropic phenotypes, including smaller plant and organ size, and late flowering. Under standard growth conditions, atino80-5 showed decreased HR; however, after genotoxic treatment, HR in the mutant increased, accompanied by more DNA double-strand breaks and stronger cellular responses. Transcription analysis showed that many developmental and environmental responsive genes are overrepresented in the perturbed genes in atino80-5. These genes significantly overlapped with the category of H2A.Z body-enriched genes. AtINO80 also interacts with H2A.Z, and facilitates the enrichment of H2A.Z at the ends of the key flowering repressor genes FLC and MAF4/5. Our characterization of the atino80-5 and atino80-6 mutants confirms and extends the previous AtINO80 study, and provides perspectives for linking studies of epigenetic mechanisms involved in plant chromatin stability with plant response to developmental and environmental cues. PMID- 25832736 TI - Risk Factors for Borderline Personality Disorder in Treatment Seeking Patients with a Substance Use Disorder: An International Multicenter Study. AB - Borderline personality disorder (BPD) and substance use disorders (SUDs) often co occur, partly because they share risk factors. In this international multicenter study, risk factors for BPD were examined for SUD patients. In total, 1,205 patients were comprehensively examined by standardized interviews and questionnaires on psychiatric diagnosis and risk factors, and it was found that 1,033 (85.7%) had SUDs without BPD (SUD) and 172 (14.3%) had SUD with BPD (SUD + BPD). SUD + BPD patients were significantly younger, more often females and more often diagnosed with comorbid adult attention deficit/hyperactivity disorder. SUD + BPD patients did not differ from SUD patients on most risk factors typical for SUD such as maternal use of drugs during pregnancy or parents having any SUD. However, SUD + BPD patients did have a higher risk of having experienced emotional and physical abuse, neglect, or family violence in childhood compared to SUD patients, suggesting that child abuse and family violence are BPD-specific risk factors in patients with SUDs. PMID- 25832738 TI - Stuck in the middle: the use and interpretation of mid-points in items on questionnaires. AB - Likert-type scales are commonly used when assessing attitudes, personality characteristics, and other psychological variables. This study examined the effect of varying the number of response options on the same set of 28 attitudinal items. Participants answered items using either a 4-point scale (forced choice), a 5-point scale that included a "neither" mid-point, or a 4 point scale with an option of "no opinion" presented after the item. The questionnaire also included an item asking participants what they believe the midpoint in a scale indicated. As predicted, participants' interpretations of the midpoint varied widely with the most common responses being: "no opinion," "don't care," "unsure," "neutral," "equal/both," and "neither." The quantitative results showed that participants' levels of item endorsement varied based on the response options offered. For example, "neither" was chosen more often than "no opinion" on all of the items. PMID- 25832739 TI - Mental juggling: when does multitasking impair reading comprehension? AB - The present study investigated the conditions under which multitasking impairs reading comprehension. Participants read prose passages (the primary task), some of which required them to perform a secondary task. In Experiment 1, we compared two different types of secondary tasks (answering trivia questions and solving math problems). Reading comprehension was assessed using a multiple-choice test that measured both factual and conceptual knowledge. The results showed no observable detrimental effects associated with multitasking. In Experiment 2, the secondary task was a cognitive load task that required participants to remember a string of numbers while reading the passages. Performance on the reading comprehension test was lower in the cognitive load conditions relative to the no load condition. The present study delineates the conditions under which multitasking can impair or have no effect on reading comprehension. These results further our understanding of our capacity to multitask and have practical implications in our technologically advanced society in which multitasking has become commonplace. PMID- 25832740 TI - The mediating effects of facial expression on spatial interference between gaze direction and gaze location. AB - Gaze direction is an important social cue that interacts with facial expression. Canadas and Lupianez (2012) reported a reverse-congruency effect such that identification of gaze direction was faster when a face was presented to the left but with the eyes directed to the right, or vice versa. In two experiments, this effect is replicated and then extended to explore the relationship between this effect and facial expression. Results show that the reverse-congruency effect is replicable with speeded gaze-direction identification, and that the effect is mediated by facial expression. The reverse-congruency effect is similar for happy and angry faces, but was not found for fearful faces. Findings are discussed in relation to the similarity of processing of incongruent gaze direction and the processing of direct gaze. PMID- 25832741 TI - Delayed, but not immediate, feedback after multiple-choice questions increases performance on a subsequent short-answer, but not multiple-choice, exam: evidence for the dual-process theory of memory. AB - Three experiments, two performed in the laboratory and one embedded in a college psychology lecture course, investigated the effects of immediate versus delayed feedback following a multiple-choice exam on subsequent short answer and multiple choice exams. Performance on the subsequent multiple-choice exam was not affected by the timing of the feedback on the prior exam; however, performance on the subsequent short answer exam was better following delayed than following immediate feedback. This was true regardless of the order in which immediate versus delayed feedback was given. Furthermore, delayed feedback only had a greater effect than immediate feedback on subsequent short answer performance following correct, confident responses on the prior exam. These results indicate that delayed feedback cues a student's prior response and increases subsequent recollection of that response. The practical implication is that delayed feedback is better than immediate feedback during academic testing. PMID- 25832742 TI - Predicting long-term outcome following traumatic brain injury (TBI). AB - OBJECTIVE: Traumatic brain injury (TBI) is the most common cause of brain damage, resulting in long-term disability. The ever increasing life expectancies among TBI patients necessitate a critical examination of the factors that influence long-term outcome. Our objective was to evaluate the contribution of premorbid factors (which were identified in our previous work) and acute injury indices to long-term functioning following TBI. METHOD: Eighty-nine participants with moderate-to-severe TBI were evaluated at an average of 14.2 years postinjury (range: 1-53 years) with neuropsychological battery, medical examination, clinical interviews, and questionnaires. RESULTS: TBI severity predicted cognitive, social, and daily functioning outcomes. After controlling for injury severity, preinjury intellectual functioning predicted cognitive status, as well as occupational, social, emotional, and daily functioning. Preinjury leisure activity also predicted cognitive, emotional, and daily functioning, whereas socioeconomic status failed to predict any of these variables. CONCLUSION: Findings offer further support for the cognitive reserve construct in explaining significant variance in TBI outcome, over and above the variance explained by injury severity. PMID- 25832746 TI - Genetic effect of the Aegilops caudata plasmon on the manifestation of the Ae. cylindrica genome. AB - In the course of reconstructing Aegilops caudata from its own genome (CC) and its plasmon, which had passed half a century in common wheat (genome AABBDD), we produced alloplasmic Ae. cylindrica (genome CCDD) with the plasmon of Ae. caudata. This line, designated (caudata)-CCDD, was found to express male sterility in its second substitution backcross generation (SB2) of (caudata) AABBCCDD pollinated three times with the Ae. cylindrica pollen. We repeatedly backcrossed these SB2 plants with the Ae. cylindrica pollen until the SB5 generation, and SB5F2 progeny were produced by self-pollination of the SB5 plants. Thirteen morphological and physiological characters, including pollen and seed fertilities, of the (caudata)-CCDD SB5F2 were compared with those of the euplasmic Ae. cylindrica. The results indicated that the male sterility expressed by (caudata)-CCDD was due to genetic incompatibility between the Ae. cylindrica genome and Ae. caudata plasmon that did not affect any other characters of Ae. cylindrica. Also, we report that the genome integrity functions in keeping the univalent transmission rate high. PMID- 25832744 TI - Dysregulation of the Bmi-1/p16(Ink4a) pathway provokes an aging-associated decline of submandibular gland function. AB - Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16(Ink4a) . Therefore, dysregulation of the Bmi-1/p16(Ink4a) pathway is considered key to the loss of tissue homeostasis and development of associated degenerative diseases during aging. However, because Bmi-1 knockout (KO) mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16(Ink4a) pathway occurs during aging in vivo. Using real-time in vivo imaging of p16(Ink4a) expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi 1/p16(Ink4a) pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity. This pathway is dysregulated during aging in vivo, leading to induction of p16(Ink4a) expression and subsequent declined SMG function. These findings will advance our understanding of the molecular mechanisms underlying the aging-related decline of SMG function and associated salivary gland hypofunction, which is particularly problematic among the elderly. PMID- 25832747 TI - Dissection of barley chromosomes 1H and 6H by the gametocidal system. AB - We dissected barley chromosomes 1H and 6H added to common wheat by the gametocidal system and identified structural changes of the chromosomes by fluorescence in situ hybridization and genomic in situ hybridization. We found five aberrations of chromosome 1H, all of which lacked the long arm: one small fragment with the subtelomeric HvT01 sequence, one terminal deletion, and three telocentric chromosomes of the short arm. We established 33 dissection lines carrying single aberrant 6H chromosomes, of which 15 were deletions, 16 were translocations and two were isochromosomes. We conducted PCR analysis of the aberrant barley chromosomes using 75 and 81 EST markers specific to chromosomes 1H and 6H, respectively. This enabled us to construct a cytological map of chromosome 6H and to compare it to the previously reported genetic map and also to the physical map, which were released by the International Barley Genome Sequencing Consortium. The marker orders on the three maps were largely in agreement. The cytological map had better resolution in the proximal region of chromosome 6H than the corresponding genetic map. We discuss some of the discrepancies in marker order between the three maps that might be due to intraspecific polymorphism and gene duplication, as well as to technical problems inherent in the physical mapping process. PMID- 25832748 TI - Changes in genome-wide gene expression during allopolyploidization and genome stabilization in hexaploid wheat. AB - Allopolyploidization is an important evolutionary event in plants, but its genome wide effects are not fully understood. Common wheat, Triticum aestivum (AABBDD), evolved through amphidiploidization between T. turgidum (AABB) and Aegilops tauschii (DD). Here, global gene expression patterns in the seedlings of a synthetic triploid wheat line (ABD), its chromosome-doubled hexaploid (AABBDD) and stable synthetic hexaploid (AABBDD), and the parental lines T. turgidum (AABB) and Ae. tauschii (DD) were compared using an oligo-DNA microarray to identify metabolic pathways affected by the genome conflict that occurs during allopolyploidization and genome stabilization. Characteristic gene expression patterns of non-additively expressed genes were detected in the newly synthesized triploid and hexaploid, and in the stable synthetic hexaploid. Hierarchical clustering of all differentially expressed and non-additively expressed genes revealed that the gene expression patterns of the triploid (ABD) were similar to those of the maternal parent (AABB), and that expression patterns in successive generations arising from self-pollination became closer to that of the pollen parent (DD). The non-additive gene expression profiles markedly differed between the triploid (ABD) and chromosome-doubled hexaploid (AABBDD), as supported by Gene Ontology (GOSlim) analysis. Four hundred and nineteen non-additively expressed genes were commonly detected in all three generations. GOSlim analysis indicated that these non-additively expressed genes were predominantly involved in "biological pathways". Notably, four of 11 genes related to sugar metabolism displayed elevated expression throughout allopolyploidization. These may be useful candidates for promoting heterosis and adaptation in plants. PMID- 25832749 TI - Mitochondrial genetic diversity, phylogeny and population structure of Hydropotes inermis in South Korea. AB - The water deer (Hydropotes inermis) is one of the rarest species of deer in the family Cervidae. Only two subspecies exist in East Asia, and few studies have examined the genetic characteristics of the species. Here, we investigated the genetic diversity, phylogeny and population differentiation of the Korean subspecies (H. inermis argyropus). Seventeen mitochondrial D-loop haplotypes (822 bp) were detected and analyzed from 107 individual samples, together with a Chinese subspecies (H. inermis inermis) haplotype. The genetic diversity of the Korean subspecies is lower (pi = 0.756%, h = 0.867) than that of the Chinese subspecies estimated in a previous study. This low genetic diversity may result from historical anthropogenic disturbances and/or a founder effect during the glacial period. The phylogenetic tree and median-joining network showed no location-specific distribution of D-loop haplotypes, but revealed two major lineages, A and B, of water deer. The A and B lineages were separated from each other at the beginning of the Pleistocene era (2.1-1.3 million years ago), with a genetic divergence of 1.332 +/- 0.340%. The genetic divergence within lineages A and B was 0.525 +/- 0.167% and 0.264 +/- 0.113%, respectively. This suggests that climate change affected the division of the two lineages. Water deer sampled from the three Korean regions (26 locations) were slightly distinct in their genetic structure (AMOVA: F(ST) = 0.28416, P < 0.00001; Phi(ST) = 0.19239, P < 0.00001). Such slight population differentiation may be derived from differential dispersal ability in males and females. The use of genetic markers, such as nuclear microsatellite and Y-linked DNA markers, and samples collected from various localities in East Asia should improve our understanding of the water deer's genetic characteristics. PMID- 25832750 TI - Importance of synonymous substitutions under dense taxon sampling and appropriate modeling in reconstructing the mitogenomic tree of Eutheria. AB - Although molecular phylogenetics is a strong tool for reconstructing the tree of life, many problems persist due to systematic errors caused by model mis specifications. Resolving misconstructed trees should lead us to better understand the processes of molecular evolution. Mammalian mitogenomes provide us with a good opportunity in this respect, because the mammalian tree is well established on the basis of multiple nuclear genes, and mitogenome trees are sometimes in conflict with it, for example concerning the positions of tarsiers and colugos. The utility of mitogenomes as a phylogenetic marker is therefore sometimes questioned, and an important problem is whether any method can overcome the misleading phylogenetic signals of mitogenomes. Here we show that the maximum likelihood tree of 463 eutherian mitogenomes reconstructed from nucleotide sequences of protein-encoding genes gives positions of tarsiers and colugos that are consistent with the well-established nuclear tree; this is the first study to obtain a consistent tree with respect to the positions of tarsiers and colugos using mitogenomes. Furthermore, our mitogenome tree of the 463 eutherians is mostly consistent with the nuclear gene tree. Previous mitogenomic studies have been hampered by sparse taxon sampling, and our analysis demonstrates the importance of dense taxon sampling to relieve the misleading phylogenetic signals of mitogenomes. However, because there are many convergent and parallel substitutions in the amino acid sequences, the effect of dense taxon sampling on the accuracy of tree reconstruction seems to be very limited. We further show the importance of using synonymous substitutions with dense taxon sampling as well as with appropriate modeling in recovering the well-established tree from lower to even higher levels of eutherian phylogeny. PMID- 25832751 TI - Cognitive and behavioural impairment in ALS: What now for the ALS patient perspective? PMID- 25832753 TI - An unusual three-dimensional Dy-Cd2 framework exhibiting single-ion magnet behavior. AB - A framework approach was successfully performed to give a three-dimensional heterometallic compound exhibiting single-ion magnet (SIM) behavior. Enhanced SIM behavior was obtained by continuous application of diamagnetic-ion dilution and an external dc field. PMID- 25832752 TI - Impaired exercise capacity and left ventricular function in long-term adult survivors of childhood acute lymphoblastic leukemia. AB - BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for late cardiotoxic effects of cancer treatment, but conflicting evidence exists on the effects of anthracyclines on left ventricular (LV) diastolic function and exercise capacity. PROCEDURE: We performed a cross-sectional study with comprehensive echocardiography in 138 adult survivors of childhood ALL, median 23.4 years after diagnosis. Pulsed tissue Doppler measurements of early diastolic mitral annular velocities (e') were used for the assessment of diastolic function, and compared to 138 matched controls. Of the survivors, 133 also performed ergospirometry measuring peak oxygen uptake (VO2 max). Associations between cancer treatment, LV function, and VO2 max were analyzed. RESULTS: The survivor group had lower e' values than controls (e' septal 11.0 vs. 12.6 cm/s, P < 0.001), but the difference was confined to the subgroup of anthracycline treated survivors (median cumulative dose 120 mg/m(2) ). Anthracycline exposure was inversely correlated with e' (regression coefficient -1.581, P=0.009). Reduced VO2 max/kg occurred in 47% of the survivors, but more often in anthracycline treated survivors (56%) than anthracycline naive survivors (17%, P<0.001). Anthracycline exposure was inversely correlated with VO2 max/kg (regression coefficient -3.084, P = 0.05 in multivariate analysis). Furthermore, associations were observed between measures of LV function and VO2 max/kg, and e' was the best predictor of VO2 max/kg (standardized coefficient 0.355, P < 0.001 in multivariate analysis). CONCLUSIONS: Adult survivors of childhood ALL have increased risk for impaired LV diastolic function and impaired exercise capacity, both associated with previous anthracycline exposure. Furthermore, there is an association between LV diastolic function and exercise capacity. PMID- 25832754 TI - Ablative fractional laser alters biodistribution of ingenol mebutate in the skin. AB - Topically applied ingenol mebutate (IngMeb) is approved for field-treatment of actinic keratosis and is currently being investigated for treatment of non melanoma skin cancer (NMSC). Ablative fractional lasers (AFXLs) generate microscopic ablation zones (MAZs) in the skin, which may help induce a deep penetration needed for effective treatment of NMSC. Using Franz diffusion cells, uptake and bio-distribution were investigated over 21 h in intact (n = 9) and AFXL-exposed porcine skin (n = 58). A 2940-nm fractional Er:YAG laser generated intraepidermal (11.2 mJ/MAZ; 66 MUm deep, 177 MUm wide) and intradermal (128 mJ/MAZ; 570 MUm deep, 262 wide) MAZ's with 16, 97, and 195 MAZs/cm(2). Surface ablation densities corresponded to 0.5, 2.5, and 5 % for intraepidermal MAZs, and corresponded to 1, 5, and 10.5 % for intradermal MAZs. Liquid-chromatography-mass spectrometry quantified deposition of IngMeb in stratum corneum, epidermis, dermis, and receiver chamber. In intact skin, IngMeb readily penetrated to the epidermal layer (1,314 ng, 41 % of the applied IngMeb), while dermal deposition was limited (508 ng, 16 %). In AFXL-exposed skin, a profound dermal deposition of IngMeb was achieved, while less accumulated in SC and epidermis. Uptake depended entirely on laser density; increasing coverage from 0 % to 0.5 %, 1 %, 2.5 %, 5 %, and 10.5 % enhanced dermal uptake 1.6-, 2.1-, 3.1-, 3.4-, and 3.9-fold, respectively (p < 0.0001). Channel depth did not influence drug uptake; at 5 % density, dermal deposition with intraepidermal and intradermal MAZs was analogous (1801 vs. 1744; p = 0.447). In conclusion, IngMeb readily distributes to superficial layers of intact skin, whereas dermal uptake is limited. Independent of channel depth, AFXL enhances dermal drug deposition, providing for customized topical delivery and potential use of IngMeb for treatment of NMSC. PMID- 25832755 TI - Computed tomography-guided in vivo cardiac orientation and correlation with ECG in individuals without structural heart disease and in age-matched obese and older individuals. AB - The cardiac axis in a structurally normal heart is influenced by a number of factors. We investigated the anatomical and electrical cardiac axes in middle aged individuals without structural heart disease and compared this with age matched obese and older individuals without structural heart disease. A retrospective study of controls included those between 30 and 60 years old with a normal body mass index (BMI), who were then compared with obese individuals between 30 and 60 years old and with individuals more than 60 years old with a normal BMI. The anatomical cardiac axis was determined along the long axis by cardiac computed tomography (CT) and correlated with the electrical cardiac axis on a surface electrocardiogram (ECG) in the frontal plane. A total of 124 patients were included. In the controls (n = 59), the mean CT axis was 38.1 degrees +/- 7.8 degrees whilst the mean ECG axis was 51.8 degrees +/- 26.6 degrees , Pearson r value 0.12 (P = 0.365). In the obese (n = 36), the mean CT axis was 25.1 degrees +/- 6.2 degrees whilst the mean ECG axis was 20.1 degrees +/- 23.9 degrees , Pearson r value 0.05 (P = 0.808). In the older group (n = 29), the mean CT axis was 34.4 degrees +/- 9.1 degrees whilst the mean ECG axis was 34.4 degrees +/- 30.3 degrees , Pearson r value 0.26 (P = 0.209). Obese individuals have a more leftward rotation of both axes than age-matched normals (P <0.0001), which could be secondary to elevation of the diaphragm. Older individuals have a more leftward rotation only of their electrical cardiac axis (P = 0.01), which could be a normal variant or reflect underlying conduction disturbances in this age group. PMID- 25832757 TI - Patient-controlled hospital admission in psychiatry: A systematic review. AB - BACKGROUND: Patient-controlled admission is a concept that invites patients with long-term mental illness to decide for themselves when inpatient treatment is necessary without a clinician serving as gatekeeper. AIM: To review the current knowledge of patient-controlled hospital admission in adult psychiatry. METHOD: A systematic literature search was conducted in PubMed/MEDLINE, EMBASE and the Cochrane Library with the aim of identifying all relevant scientific papers from 1990 onwards. RESULTS: Six articles reporting on four different study sites were identified. Detailed account of the models is given and quantitative and qualitative outcome data is reviewed. Rationales behind the concept include increased patient autonomy, promotion of coping skills, early help-seeking, avoidance of power struggles, establishment of an asylum function, reduced time spent in inpatient care and prevention of coercive measures. Quantitative data points toward a dramatic reduction of total time spent in inpatient care and of involuntary admissions in patients with previously high inpatient care consumption, whereas qualitative data indicates that the concept increases patient autonomy, responsibility and confidence in daily life. CONCLUSION: Patient-controlled admission is a promising novel approach to inpatient care in psychiatry. However, available studies are small and quality of evidence is generally low. PMID- 25832756 TI - Chimeric fusion proteins used for therapy: indications, mechanisms, and safety. AB - Chimeric fusion proteins, produced by genetic engineering, are currently made up of effector peptides, for example, a ligand-binding portion of a cytokine or growth factor, extracellular domains of lymphocyte antigens, or a toxin linked to a suitable fusion partner. This review covers eight fusion proteins that have received regulatory approval for human therapy: etanercept, belatacept, abatacept, alefacept, rilonacept, romiplostim, aflibercept, and denileukin diftitox. Important requirements for an effective fusion protein are effective targeting and binding, cytotoxicity, and a stable molecule with an extended half life. The Fc region of human IgG1 is generally chosen as the fusion partner for the effector molecule(s) because it extends the fusion protein half-life by recycling via the salvage neonatal FcRn receptor and protects the molecule from lysosomal degradation. Each of the fusion proteins has IgG1 Fc as a fusion partner except denileukin-diftitox, which employs a modified diphtheria toxin effector peptide linked to interleukin-2. For six of the Fc fusion proteins, the effector peptide(s) is linked to the N-terminus of the Fc piece but for the thrombopoietin-mimetic romiplostim, linkage is through the C-terminus. Although some clear type I and IV hypersensitivities are known to be induced by fusion protein therapy, the pathomechanisms underlying many adverse hematologic, respiratory, renal, and cutaneous events have generally not been investigated. Assessment of immunogenicity risk is important because a number of immune-based, or influenced, adverse reactions such as anaphylaxis, cutaneous manifestations, infusion, and injection-site reactions, and cytokine release syndrome can occur. Features of many reactions, some autoimmune in nature, suggest type II, III, or IV hypersensitivities. Clinical findings with the anti-arthritis anti-psoriasis biologic etanercept provide the largest body of current knowledge of fusion protein-induced adverse events. For most fusion proteins, little information is available on appropriate diagnostic and desensitization procedures for hypersensitivity and other adverse responses, although skin test concentrations and some successful desensitization protocols have been published for etanercept. PMID- 25832758 TI - The prevalence of personality disorders in psychiatric outpatients with borderline intellectual functioning: Comparison with outpatients from regular mental health care and outpatients with mild intellectual disabilities. AB - BACKGROUND: There is little research on the subject of personality disorder (PD) in individuals with borderline intellectual functioning (BIF). Unlike in most countries, in the Netherlands, patients with BIF are eligible for specialized mental health care. This offers the unique possibility of examining the rates of PDs in patients, who in other countries are treated relatively invisibly in regular mental health care. AIM: To compare, in a naturalistic setting, the frequency of PD diagnoses in outpatients with BIF with outpatients from regular mental health care and outpatients with mild ID. METHODS: We compared the rates of all DSM-IV-TR axis II PDs in outpatients with BIF (BIF group; n = 235) with rates of the same disorders in outpatients from regular mental health care (RMHC group; n = 1026) and outpatients with mild intellectual disability (ID) (mild ID group; n = 152) in a naturalistic cross-sectional anonymized medical chart review. RESULTS: Over half of the patients with BIF (52.8%) were diagnosed with a PD, compared with one in five in the RMHC group (19.3%) and one in three of the mild ID group (33.6%). All PD diagnoses, except for cluster A PDs and histrionic PDs, were most frequently diagnosed in the BIF group. PD NOS and borderline PD were the most frequently diagnosed PDs in BIF. The majority of PD patients had one or more comorbid axis I disorder. CONCLUSION: There is a high frequency of PD diagnoses in BIF outpatients in daily clinical practice. In anticipation of further scientific research, results suggest that PDs should not be overlooked in patients with BIF. PMID- 25832760 TI - A Multidisciplinary Assessment of River Surface Water Quality in Areas Heavily Influenced by Human Activities. AB - The present study could serve as a multidisciplinary approach for the assessment of river surface water quality with the use of chemical and biological methods. Specifically, physicochemical parameters, heavy metals, and pesticides were measured in water samples from three different stations (sampling station S1, S2, and S3) along Asopos River (Greece). In parallel, algal species (primary producers)-such as Scenedesmus rubescens and Chlorococcum sp.; consumer invertebrate species, such as the fairy shrimp Thamnocephalus platyurus and the rotifer Brachionus calyciflorus; as well as human lymphocytes-were exposed to those samples for assessing their toxic and genotoxic/mutagenic effects. According to the results, although the values of almost all of the physicochemical parameters tested, heavy metals (zinc, cadmium, lead, and mercury) and pesticides were lower than or within the respective environmental quality standards, thus offering no clear evidence for their natural or anthropogenic origin. Values recorded for nickel, chromium, hexavalent chromium, and malathion represent a typical case of mixed influence from natural and anthropogenic enrichments. In contrast, the algal growth arrest, the acute toxic effects on the freshwater invertebrates, and the increased micronuclei frequencies observed in human lymphocytes showed the presence of human-derived hazardous substances, which were hardly determinable with the use of conventional chemical methods. Given that the presence of priority pollutants in river surface waters, heavily burdened by anthropogenic activities, could give no clear evidence for their biological risk, the results of the present study showed that chemical and biological assays should be applied in parallel, thus serving as a reliable tool for the assessment of river water quality. PMID- 25832759 TI - Renal function in survivors of nonsyndromic Wilms tumor treated with unilateral radical nephrectomy. AB - BACKGROUND: Partial nephrectomy is considered by some for children with unilateral Wilms tumor (UWT) to avoid the theoretical complication of renal insufficiency. In the current study, the authors evaluated the prevalence of hypertension and impaired renal function in long-term survivors of nonsyndromic UWT who were treated without nephrotoxic chemotherapy or ionizing radiation. METHODS: Eligibility included age <=15 years at the time of diagnosis of nonsyndromic UWT, treatment receipt before 2002, and maintenance of disease remission after unilateral nephrectomy without receipt of abdominal irradiation or nephrotoxic chemotherapy. Renal function was assessed by urinalysis and estimated glomerular filtration rate (eGFR). Patients receiving antihypertensive medication or those with blood pressure readings of >140/90 mm Hg were considered to be hypertensive. RESULTS: A total of 75 patients with a median age at diagnosis of 3.2 years (range, 0.2-12.1 years) met eligibility criteria. The median length of follow-up was 19.6 years (range, 10.0-32.8 years). All but 1 patient had stage I/II disease. Sixty-eight patients (90.7%) patients had WT with favorable histology and 7 patients had anaplastic histology. Sixteen patients (21.3%) had an eGFR <90 mL/minute/1.73m(2), 2 of whom also had proteinuria (12.5%). No patient had an eGFR <60 mL/minute/1.73m(2). Five patients (6.7%) had hypertension, 3 of whom were receiving antihypertensive medications. At the time of last follow-up, no patient had developed end-stage renal disease. CONCLUSIONS: Patients with UWT who were treated with unilateral radical nephrectomy without nephrotoxic chemotherapy or ionizing radiation appear to be at low risk of developing significant long-term renal dysfunction. For this patient population, the routine use of partial nephrectomy does not appear justified. However, monitoring and counseling are important for identifying the rare patient who develops subtle renal insufficiency and therefore might be at an increased risk of adverse cardiovascular sequelae. PMID- 25832762 TI - C-Arm Cone-Beam Volume CT in Transjugular Intrahepatic Portosystemic Shunt: Initial Clinical Experience. AB - PURPOSE: The purpose of this study was to compare two-dimensional digital subtraction angiography (2D-DSA) with C-arm cone-beam volume computed tomography (CACT) in the evaluation of portal vein entry and shunt course during transjugular intrahepatic portosystemic shunt (TIPS) procedure. MATERIALS AND METHODS: Between May 2010 and November 2011, 21 patients who underwent direct portography in anteroposterior and lateral projections and subsequent CACT before stent placement during TIPS creation were reviewed retrospectively. CACT images were examined for evaluation of the portal vein entry and shunt course in comparison to 2D-DSA images by two experienced interventional radiologists. RESULTS: CACT was proven to be better than 2D-DSA in identification of the portal vein entry (P < 0.001) and intra- or extrahepatic puncture (P < 0.001). No significant difference was observed in evaluating the shunt course (P = 0.086). The portal vein entry was considered inappropriate in seven (33%) out of 21 patients; among them, four cases were due to extrahepatic puncture, and three cases were due to peripheral puncture of the portal vein which may result in stent kinking. CONCLUSION: While 2D-DSA remains the standard imaging method to evaluate portal vein entry, shunt course, and portal vein anatomy during TIPS procedure, CACT can effectively identify the portal vein entry and assess shunt course in difficult cases intra-procedurally, hence may reduce the risk of potential life-threatening intra-abdominal hemorrhage and shunt dysfunction. PMID- 25832763 TI - Retrospective Study in 40 Patients of Utility of C-arm FDCT as an Adjunctive Modality in Technically Challenging Image-Guided Percutaneous Drainage Procedures. AB - PURPOSE: To explore the utility of C-arm flat detector computed tomography (FDCT) as an adjunctive modality in technically challenging image-guided percutaneous drainage procedures. METHODS: Clinical and image data were reviewed on 40 consecutive patients who underwent percutaneous drainage of fluid collections in technically challenging anatomic locations that required the use of C-arm FDCT between 2009 and 2013. Percutaneous drainage was performed under ultrasound and fluoroscopic guidance with the use of C-arm FDCT as a problem-solving tool to identify appropriate needle/wire placement prior to drainage catheter placement (n = 33) or to confirm catheter positioning within the fluid collection (n = 8). Technical success and procedural complications were recorded and retrospectively analyzed. RESULTS: Forty one fluid collections were identified in 40 patients. Mean number of C-arm FDCT rotational acquisitions per patient was 1.25. Mean procedure time per patient was 59.3 min. Mean fluoroscopy time was 5.5 min, and mean air kerma was 394.3 mGy. Percutaneous drainage with the use of C-arm FDCT was successful in 35 of 40 patients (87.5%). Technical failure was encountered in 5 of 40 patients due to too narrow window (n = 1), too small or no fluid collection noted on C-arm FDCT images (n = 2), and poor image quality requiring the use of a conventional CT scan (n = 2). Three procedure-related complications occurred (7.5%), which included traversed rectum, traversed spleen, and sepsis. CONCLUSION: C-arm FDCT is useful as an adjunctive modality in the interventional suite for technically challenging percutaneous drainage procedures by providing sufficient anatomic detail. Complications of catheter misplacement can be avoided if C-arm FDCT is used prior to tract dilatation. If C-arm FDCT image quality of needle and/or wire placement is poor, conventional CT guidance is recommended. PMID- 25832764 TI - Transarterial Chemoembolization of Liver Metastases from Uveal Melanoma Using Irinotecan-Loaded Beads: Treatment Response and Complications. AB - PURPOSE: The purpose of this study was to evaluate treatment response and complications of transarterial chemoembolization using drug-eluting beads loaded with irinotecan (DEBIRI) in patients with liver metastases from uveal melanoma (UM). MATERIALS AND METHODS: Patients treated with DEBIRI (n = 14) were retrospectively analyzed regarding overall survival, compared to patients (n = 14) treated with intravenous dacarbazine (DTIC). Median overall survival was calculated from time of diagnosis of metastatic disease (OS1) and start of treatment (OS2). Radiological response for DEBIRI was assessed according to RECIST 1.1 on contrast-enhanced computed tomography (CT), obtained 1.5 months (range 1.2-3.7) post treatment. Major complications of DEBIRI were defined according to the Society of Interventional Radiology classification for complications by outcome. RESULTS: In the DEBIRI group, OS1 was 14.8 months (range 3.9-47.5), and OS2 was 9.4 months (range 1.7-39). Further, 11/13 (84.6%) of these patients had progressive disease on first follow-up CT and new lesions were seen in nine. There were 12 major complications in nine patients, possibly including one case of mortality due to disseminated intravascular coagulation (DIC). CONCLUSION: For patients with liver metastases from UM, the effect on overall survival of DEBIRI alone is questionable. Compared to previous reports, the response rate of DEBIRI was poor, with new liver lesions observed in the majority of patients. Major complications possibly included one case of DIC. PMID- 25832765 TI - Artificial Ascites for Pain Relief During Microwave Ablation of Subcapsular Liver Tumors. AB - PURPOSE: To compare post-procedure pain of subcapsular hepatic metastasis treated with microwave ablation (MWA) with and without artificial ascites. MATERIALS AND METHODS: During a 2-years period, 41 patients underwent MWA of 52 peripheral liver metastases including 20 patients (10 men and 10 women (mean +/- SD age: 62 +/- 9.3 years) who underwent MWA of 27 metastasis without artificial ascites (group 1), and 21 patients (12 men and 9 women (mean age: 63.5 +/- 9.9 years) who underwent MWA of 25 metastasis with artificial ascites (group 2). Patient's pain assessment cores [10-point visual analog scale (VAS)] at 6, 24 h, and 4 days after the MWA procedure were compared among groups, as well as 24 h cumulative morphine dose was also compared among groups. Complications were reported. Statistical significance was evaluated by Fisher's exact test and Student's t test. RESULTS: Pain VAS were 8.6 +/- 2.7, 3.9 +/- 1.4, and 0.6 +/- 1.2 at 6, 24 h, 4 days, respectively, for group-I and 0.8 +/- 1.9, 0.3 +/- 0.9, and 6.6 +/- 3.5 for group II. Pain VAS were significantly different at 6, 24 h, and 4 days between the two groups (p < 0.0001). The average 24 h dose of morphine was 5.8 +/ 2.2 mg in group-I and 0.2 +/- 0.6 mg in group-II (p < 0.0001). Complications occurred in two patients from group-I (10%), including one bilio-pleural fistula and one minor cutaneous burn. One patient (9.5%) in group-II developed a lobar infarction. No bleeding and no procedure-related death were reported. CONCLUSION: Artificial ascites prevents immediate post-procedural pain, which re-appears intensively 4 days later. PMID- 25832766 TI - Development and characterization of an embryonic cell line from endangered endemic cyprinid Honmoroko Gnathopogon caerulescens (Sauvage, 1883). AB - Establishing a cell line from endemic species facilitates the cell biological research of these species in the laboratory. In this study, an epithelium-like cell line RME1 was established from the blastula-stage embryos of the critically endangered cyprinid Honmoroko Gnathopogon caerulescens, which is endemic to ancient Lake Biwa in Japan. To the best of our knowledge, this is the first embryonic cell line from an endangered fish species. This cell line is well adapted to grow at 28 degrees C in the culture medium, which was successfully used for establishing testicular and ovarian cell lines of G. caerulescens, and has displayed stable growth over 60 passages since its initiation in June 2011. Although RME1 did not express the genes detected in blastula-stage embryos, such as oct4, sox2, nanog, and klf4, it showed a high euploidy rate (2n = 50; 67.2%) with normal diploid karyotype morphology, suggesting that RME1 retains the genomic organization of G. caerulescens and can prove to be a useful tool to investigate the unique properties of endangered endemic fishes at cellular level. PMID- 25832767 TI - Prenatal diagnosis of multiple ventriculocoronary connections in pulmonary atresia with an intact ventricular septum: a case report. AB - We report a case of prenatally detected pulmonary atresia with an intact ventricular septum accompanied by multiple ventriculocoronary connections. This lesion was diagnosed by using ultrasonography at 20 weeks' gestation, and this antepartum diagnosis was confirmed with both postnatal echocardiography and chest computed tomography. The neonate underwent a modified Blalock-Taussig shunt on the 15th day of life, and was discharged 8 days after the surgery. PMID- 25832768 TI - Radiation-induced hemorrhagic duodenitis associated with sorafenib treatment. AB - Sorafenib, an oral inhibitor of multiple tyrosine kinase receptors, has been widely used as a standard medical treatment for advanced hepatocellular carcinoma (HCC). Here, we report a 66-year-old male patient who developed gastrointestinal bleeding due to radiation-induced hemorrhagic duodenitis associated with sorafenib treatment. We started oral administration of sorafenib because of the recurrence of HCC with lung metastases. The patient had been treated by radiotherapy for para-aortic lymph node metastases from HCC 4 months before the bleeding. Esophagogastroduodenoscopy (EGD) revealed edematous reddish mucosa with friability and telangiectasia in the second portion of the duodenum. Computed tomography and capsule endoscopy revealed that the hemorrhagic lesions were located in the distal duodenum. After discontinuation of sorafenib, the bleeding disappeared and a follow-up EGD confirmed improvement of duodenitis. Based on these findings, the diagnosis of radiation-induced hemorrhagic duodenitis associated with sorafenib was made. PMID- 25832769 TI - Lack of significant improvements in long-term allograft survival in pediatric solid organ transplantation: A US national registry analysis. AB - Improvements across many facets of transplantation have led to better 1-yr outcomes of transplanted organs. In this study, we assessed whether longer-term attrition rates improved in pediatric kidney (KI), liver (LI), heart (HR) and lung (LU) transplant (TX) survival. We analyzed data between 1989 and 2008 from 5747 KI, 7348 LI, 5103 HR, and 715 LU TXs (under 18 yr of age at transplant, first solitary transplant only), from the National Scientific Registry of Transplant Recipients database in the USA. Kaplan-Meier (K-M) or ordinary least square (OLS) estimates were used to calculate median and projected survival half lives. Attrition rates, defined as percent failing within a given time period, were stratified by year of TX. Median half-lives from 1989 TX year to 2005 TX year have shown a major improvement only in LI TX, remaining unchanged in HR and KI TX, or remaining very low in LU TX. All four organ TX types have shown a dramatic drop in first-year attrition rates from 1989 to 2008. However, longer term attrition rates (1-3, 3-5, 5-10 yr) have remained largely unchanged for all four organ TX types. Further progress in long-term survival will need targeting end-points beyond first-year rejection and survival rates. PMID- 25832770 TI - The effect of beta-amyloid on face processing in young and old adults: A multivariate analysis of the BOLD signal. AB - The recent ability to measure in vivo beta-amyloid (Abeta), a marker of Alzheimer's disease (AD), has led to an increased focus on the significance of Abeta deposition in clinically normal adults. Evidence suggests that healthy adults with elevated cortical Abeta show differences in neural activity associated with memory encoding-specifically encoding of face stimuli. Here, we examined if Abeta deposition in clinically normal adults was related to differences in neural activity in ventral visual cortex during face viewing. Our sample included 23 high-Abeta older adults, 23 demographically matched low-Abeta older adults, and 16 young adults. Participants underwent cognitive testing, Abeta positron emission tomography imaging with (18) F-Florbetapir, and functional magnetic resonance imaging to measure neural activity while participants passively viewed photographs of faces. Using barycentric discriminant analysis-a between-groups classification technique-we found that patterns of neural activity in the left fusiform gyrus, a region highly responsive to faces, distinguished Abeta status of participants. Older adults with elevated Abeta were characterized by decreased activity in left fusiform compared to Abeta-negative older adults. Further, we found that the degree to which older adults expressed decreased fusiform activity was related to worse performance on tasks of processing speed. Our results provide unique evidence that, in addition to previously studied memory and default regions, decreased neural activity in a region important for face perception was associated with elevated Abeta and may be an early manifestation of AD. PMID- 25832771 TI - Refilling the half-empty glass--Investigating the potential role of the Interpretation Modification Paradigm for Depression (IMP-D). AB - BACKGROUND AND OBJECTIVES: Cognitive biases are known to cause and maintain depression. However, little research has been done on techniques targeting interpretation tendencies found in depression, despite the promising findings of anxiety studies. This paper presents two experiments, investigating the suitability of an Interpretation Modification Paradigm for Depression (IMP-D) in healthy individuals, which has already proven its effectiveness in anxiety (Beard & Amir, 2008). Different from other paradigms, the IMP-D aims at modifying an interpretation bias on response- and on a more implicit reaction time-level, making this task less susceptible to demand effects. METHODS: The Word-Sentence Association Paradigm for Depression (Hindash & Amir, 2011) was modified and administered in healthy volunteers (experiment I: N = 81; experiment II: N = 105). To enhance a positive interpretation bias, endorsing benign and rejecting negative interpretations of ambiguous scenarios was reinforced through feedback. This intervention was compared to the opposite training (both experiments) and a control training (experiment II only). RESULTS: Both experiments revealed a significant increase in bias towards benign interpretations on the level of overt decisions, while only in the first experiment a change was found on a reaction time level. These modifications are not reflected in group-differences in emotional vulnerability. LIMITATIONS: Possible limitations regarding the reliability of inter-dependent response and reaction time measures are discussed. CONCLUSIONS: The IMP-D is able to modify interpretation biases, but adaptations are required to maximize its beneficial effects. PMID- 25832772 TI - Monoarthritis in a 28-Year-Old Man With Juvenile Idiopathic Arthritis. PMID- 25832773 TI - Localising oxidant "stress" in the antiphospholipid syndrome. PMID- 25832774 TI - Enhanced epithelial-to-mesenchymal transition associated with lysosome dysfunction in podocytes: role of p62/Sequestosome 1 as a signaling hub. AB - BACKGROUND: Autophagy is of importance in the regulation of cell differentiation and senescence in podocytes. It is possible that derangement of autophagy under different pathological conditions activates or enhances Epithelial-to-Mesenchymal Transition (EMT) in podocytes, resulting in glomerular sclerosis. To test this hypothesis, the present study produced lysosome dysfunction by inhibition of the vacuolar H(+)-ATPase (V-ATPase) to test whether deficiency of autophagic flux leads to enhancement of EMT in podocytes. METHODS AND RESULTS: By Western blot and confocal analysis, lysosome inhibition using a V-ATPase inhibitor or its siRNA was found to markedly decreases the epithelial markers (P-cadherin and ZO 1) and increases the mesenchymal markers (FSP-1 and alpha-SMA). This enhancement was accompanied by deficient autophagic flux, as demonstrated by marked increases in LC3B-II and p62/Sequestosome 1. However, inhibition of autophagosome formation using spaudin-1 significantly attenuated both enhancement of EMT and deficiency of autophagic flux. To explore the mechanisms by which deficient autophagic flux enhances EMT, we tested the role of accumulated p62 as a signal hub in this process. Neither the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear kappa-light-chain-enhancer pathways of p62 contributed to enhanced EMT. However, inhibition of cyclin-dependent kinase 1 (CDK1) activity reduced the phosphorylation of p62 and enhanced EMT in podocytes similar to lysosome dysfunction. CONCLUSION: The lack of phosphorylated p62 leads to a faster exit from cell mitosis, enhanced EMT associated with lysosome dysfunction may be attributed to accumulation of p62 and associated reduction of p62 phosphorylation. PMID- 25832775 TI - Understanding Health Needs and Perspectives of Middle-Aged and Older Women Experiencing Homelessness. AB - OBJECTIVES: Middle-aged and older homeless women have unique health and social service delivery needs; yet, limited research has been conducted in this area. The purpose of this study was to assess perspectives among prefrail and frail, middle-aged and older homeless women. DESIGN AND SAMPLE: Focus group methodology was conducted to assess perspectives among these homeless women (N=20) aged 43 to 62. MEASURES: Sociodemographic and frailty characteristics were assessed by structured instruments, along with mobility, assistive device use and falls. RESULTS: The average age was 53.4; the majority of the sample was African American (70%). In total, 60% reported living in a shelter for the last 30 days, while 20% were unsheltered. The majority of the sample reported walking independently (80%) and not using an assistive device (65%). Over one third (35%) fell in the last 30 days and 70% fell in the last year. Content analysis revealed several themes that included (1) health care needs and challenges experienced; (2) perspectives on sexual decision making; (3) employment difficulties; (4) existing support systems; and (5) development of future program planning. CONCLUSIONS: Future research development and implications are discussed. PMID- 25832776 TI - Charge generation layers for solution processed tandem organic light emitting diodes with regular device architecture. AB - Tandem organic light emitting diodes (OLEDs) utilizing fluorescent polymers in both sub-OLEDs and a regular device architecture were fabricated from solution, and their structure and performance characterized. The charge carrier generation layer comprised a zinc oxide layer, modified by a polyethylenimine interface dipole, for electron injection and either MoO3, WO3, or VOx for hole injection into the adjacent sub-OLEDs. ToF-SIMS investigations and STEM-EDX mapping verified the distinct functional layers throughout the layer stack. At a given device current density, the current efficiencies of both sub-OLEDs add up to a maximum of 25 cd/A, indicating a properly working tandem OLED. PMID- 25832777 TI - Endoplasmic reticulum-resident chaperones modulate the inflammatory and angiogenic responses of endothelial cells. AB - BACKGROUND: Wound healing depends on a well-balanced regulation of inflammation and angiogenesis. In chronic wounds the healing process is disturbed and inflammation persists. Regulation of wound closure is controlled by transmembrane and extracellular proteins, the folding and maturation of which occur in the endoplasmic reticulum (ER) by ER-resident chaperone machinery. OBJECTIVES: To study the role of the ER-resident chaperones BiP/Grp78, its cochaperone Mdg1/ERdJ4, and Grp94 in chronic, nonhealing wounds. METHODS: Immunohistochemical staining of these chaperones in individual human biopsies and investigation of the possible role of BiP and Mdg1 in endothelial cells, focusing on their inflammatory response and angiogenic potential. RESULTS: In all chronic wounds investigated, the levels of these ER-resident chaperones were elevated in endothelial cells and leucocytes. The proangiogenic role of BiP has been shown in tumour growth studies before and was confirmed in this study. Proangiogenic activity of the cochaperone Mdg1 has been postulated before but could not be confirmed in this study. The chemokine tumour necrosis factor (TNF)-alpha was shown to trigger the presentation of proinflammatory adhesion molecules and the release of proinflammatory cytokines. Here we show that TNF-alpha does not affect endogenous chaperone levels, but that the ER-resident chaperones BiP and Mdg1 modulate the cellular TNF-alpha-induced proinflammatory response. CONCLUSIONS: According to the presented data we assume that in chronic wounds upregulated levels of ER-resident chaperones might contribute to persistent inflammation in chronic wounds. Therapies to downregulate chaperone levels might provide a tool that switches the imbalanced chronic wound microenvironment from inflammation to healing. PMID- 25832778 TI - The case for a public forum within the United Nations to listen to those who use armed violence to address their grievances. PMID- 25832779 TI - Modulation of Electron Injection Dynamics of Ru-Based Dye/TiO2 System in the Presence of Three Different Organic Solvents: Role of Solvent Dipole Moment and Donor Number. AB - In the present work, femtosecond transient absorption spectroscopy (fs-TAS) has been employed to investigate the electron injection efficiency (EIE) both from the singlet and triplet excited states of a well-known ruthenium dye (N719) to the conduction band (CB) of nanostructured TiO(2) in presence of three different organic solvents [gamma-butylactone (GBL), 3-methoxypropionitrile (MPN), and dimethylformamide (DMF)] with different donor numbers (DNs) and dipole moments (DMs). The DM and DN of a solvent modulates the CB edge energy of TiO(2), and this effect reflects well in the fs-TAS results, which shows an EIE trend following the order GBL>=MPN?DMF, that is, highest in GBL and lowest in DMF solvent environments. Fs-TAS results indicate a lower contribution of electron injection from both the singlet and triplet states in DMF, for which the dominant adsorption of DMF molecules on the TiO(2) surface seems to play an important role in the mechanism. PMID- 25832781 TI - Erratum to: Up-converted fluorescence from photosynthetic light-harvesting complexes linearly dependent on excitation intensity. PMID- 25832780 TI - Critical assessment of the emission spectra of various photosystem II core complexes. AB - We evaluate low-temperature (low-T) emission spectra of photosystem II core complexes (PSII-cc) previously reported in the literature, which are compared with emission spectra of PSII-cc obtained in this work from spinach and for dissolved PSII crystals from Thermosynechococcus (T.) elongatus. This new spectral dataset is used to interpret data published on membrane PSII (PSII-m) fragments from spinach and Chlamydomonas reinhardtii, as well as PSII-cc from T. vulcanus and intentionally damaged PSII-cc from spinach. This study offers new insight into the assignment of emission spectra reported on PSII-cc from different organisms. Previously reported spectra are also compared with data obtained at different saturation levels of the lowest energy state(s) of spinach and T. elongatus PSII-cc via hole burning in order to provide more insight into emission from bleached and/or photodamaged complexes. We show that typical low-T emission spectra of PSII-cc (with closed RCs), in addition to the 695 nm fluorescence band assigned to the intact CP47 complex (Reppert et al. J Phys Chem B 114:11884-11898, 2010), can be contributed to by several emission bands, depending on sample quality. Possible contributions include (i) a band near 690 691 nm that is largely reversible upon temperature annealing, proving that the band originates from CP47 with a bleached low-energy state near 693 nm (Neupane et al. J Am Chem Soc 132:4214-4229, 2010; Reppert et al. J Phys Chem B 114:11884 11898, 2010); (ii) CP43 emission at 683.3 nm (not at 685 nm, i.e., the F685 band, as reported in the literature) (Dang et al. J Phys Chem B 112:9921-9933, 2008; Reppert et al. J Phys Chem B 112:9934-9947, 2008); (iii) trap emission from destabilized CP47 complexes near 691 nm (FT1) and 685 nm (FT2) (Neupane et al. J Am Chem Soc 132:4214-4229, 2010); and (iv) emission from the RC pigments near 686 687 nm. We suggest that recently reported emission of single PSII-cc complexes from T. elongatus may not represent intact complexes, while those obtained for T. elongatus presented in this work most likely represent intact PSII-cc, since they are nearly indistinguishable from emission spectra obtained for various PSII-m fragments. PMID- 25832782 TI - Quantification of patulin in fruit leathers by ultra-high-performance liquid chromatography-photodiode array (UPLC-PDA). AB - Patulin is a mycotoxin commonly found in certain fruit and fruit products. For this reason many countries have established regulatory limits pertaining to, in particular, apple juice and apple products. Fruit leathers are produced by dehydrating fruit puree, leaving a sweet product that has a leathery texture. A recent report in the literature described the detection of patulin at substantial levels in fruit leathers. To investigate this further, an ultra-high-performance liquid chromatography-photodiode array (UPLC-PDA) method was developed for the sensitive detection of patulin in fruit leathers. Investigations were also made of the suitability of direct analysis in real time-mass spectrometry (DART-MS) for detection of patulin from the surface of fruit leathers. Results indicated DART-MS was insufficiently sensitive for quantification from the surface of home style apple leathers, although patulin spiked onto the surface of leather or peel could be detected. The UPLC-PDA method was used to determine the fate of patulin during the preparation of home-made fruit leathers. Interestingly, when a home style process was used, the patulin was not destroyed, but rather increased in concentration as the puree was dehydrated. The UPLC-PDA method was also used to screen for patulin in commercial fruit leathers. Of the 36 products tested, 14 were above the limit of detection (3.5 MUg kg(-1)) and nine were above the limit of quantification (12 MUg kg(-1)). Positive samples were confirmed by UPLC-MS/MS. Only one sample was found above the US regulatory limit for single-strength apple juice products (50 MUg kg(-1)). These results suggest patulin can be concentrated during preparation and can be found in fruit leathers. The limited survey suggests that patulin is fairly prevalent in such commercial products, but that the levels are usually low. PMID- 25832783 TI - One-pot catalytic asymmetric borylation of unsaturated aldehyde-derived imines; functionalisation to homoallylic boronate carboxylate ester derivatives. AB - The beta-borylation reaction of alpha,beta-unsaturated aldehyde-derived imines, formed in situ, has been studied using a one-pot methodology, as a route to beta boryl aldehydes. The instability of the beta-boryl aldehydes meant that derivatisation was required and routes to both acetal derivatives and homoallylic boronates were examined. beta-Boryl acetals were also found to be unstable, however, the formation of homoallylic boronate derivatives using an in situ imine hydrolysis-Wittig olefination protocol was found to be suitable, resulting in an efficient synthesis with high enantiomeric excesses. PMID- 25832784 TI - Effects of liquid konjac on parameters related to obesity in diet-induced obese mice. AB - Konjac-mannan has been suggested to exert a protective effect against visceral obesity. However, there is little knowledge about the effects of liquid konjac (LK) that is partially alkali gelled. The purpose of the present work was to evaluate the potential beneficial effects of a LK powder on obesity in mice. Male C57BL/6J mice were fed a high-fat diet supplemented with either 2.5 or 5% LK powder for 80 days. Growth parameters, abdominal fat content, serum biochemical markers, and hepatic lipid accumulations were measured. Dietary supplementation with LK resulted in decreased body weight gain and abdominal fat accumulation. Dose-dependent decreases were observed in accumulation of hepatic lipids and serum total cholesterol, leptin, insulin concentrations. The study findings indicated that LK had preventing effect against obesity, including the reduction of abdominal and hepatic lipid accumulation and serum parameters related to obesity. PMID- 25832785 TI - Select microtubule inhibitors increase lysosome acidity and promote lysosomal disruption in acute myeloid leukemia (AML) cells. AB - To identify new biological vulnerabilities in acute myeloid leukemia, we screened a library of natural products for compounds cytotoxic to TEX leukemia cells. This screen identified the novel small molecule Deoxysappanone B 7,4' dimethyl ether (Deox B 7,4), which possessed nanomolar anti-leukemic activity. To determine the anti-leukemic mechanism of action of Deox B 7,4, we conducted a genome-wide screen in Saccharomyces cerevisiae and identified enrichment of genes related to mitotic cell cycle as well as vacuolar acidification, therefore pointing to microtubules and vacuolar (V)-ATPase as potential drug targets. Further investigations into the mechanisms of action of Deox B 7,4 and a related analogue revealed that these compounds were reversible microtubule inhibitors that bound near the colchicine site. In addition, Deox B 7,4 and its analogue increased lysosomal V-ATPase activity and lysosome acidity. The effects on microtubules and lysosomes were functionally important for the anti-leukemic effects of these drugs. The lysosomal effects were characteristic of select microtubule inhibitors as only the Deox compounds and nocodazole, but not colchicine, vinca alkaloids or paclitaxel, altered lysosome acidity and induced lysosomal disruption. Thus, our data highlight a new mechanism of action of select microtubule inhibitors on lysosomal function. PMID- 25832786 TI - Development of an improved RT-PCR for specific detection of spring viraemia of carp virus. AB - Spring viraemia of carp (SVC) is a rhabdovirus infection, which has a significant economic impact in pond cultures of carp in Europe and western Independent States of the former Soviet Union. The causative agent of SVC, spring viraemia of carp virus (SVCV), has been divided into four subgroups, Ia, Ib, Ic and Id, on the basis of glycoprotein (G) protein gene sequences. In this study, a new primer set was designed from a G gene sequence of SVCV to identify the four subtypes of SVCV by reverse transcription polymerase chain reaction (RT-PCR). The specific PCR products of 369 bp were amplified from 15 SVCV isolates of all four subtypes. However, pike fry rhabdovirus (PFRV), which is antigenically related to SVCV, and other viruses antigenically related to SVCV and PFRV were not amplified. The four subtypes of SVCV were specifically amplified by the RT-PCR. Furthermore, the detection limit of the RT-PCR was 7.1 * 10(2) copies/reaction, and it was not influenced by the addition of RNA extracted from fish tissues. The RT-PCR will be applied not only to RNA extracted from viral suspensions, but also from fish tissue. It will contribute to rapid identification of SVCV in fish with clinical signs of SVC. PMID- 25832787 TI - Review: Bioelectrical mechanisms in spinal cord stimulation. AB - OBJECTIVES: The aim of this review is to make specialists in a variety of disciplines familiar with basic aspects of spinal cord stimulation and the role of mathematical modeling in understanding its mechanisms of action and the solution of basic problems. METHODS: The paper is divided into five sections. The content of each section also covers aspects of various disciplines. Most aspects are presented in an unusual way, likely resulting in new viewpoints and further developments in the growing field of neuromodulation. RESULTS: A special, integrating role is the mathematical modeling of spinal cord stimulation and the simulation studies of various aspects, such as the stimulation in axial low-back pain. CONCLUSIONS: In particular the conclusions from several computer simulation studies are relevant and of interest to specialists in many disciplines. PMID- 25832788 TI - Dynamic changes of bacterial community under bioremediation with Sphingobium sp. LY-6 in buprofezin-contaminated soil. AB - Buprofezin is a commonly used chemical with satisfactory biological activity against sucking insect pests, but its disposal can cause serious environmental problems. To study the feasibility of remedying contamination by buprofezin, microcosm experiments were carried out to study the effects of various concentrations of buprofezin and Sphingobium sp. LY-6 on soil bacterial communities in soils collected from vegetable fields. In this experiment, the results showed that buprofezin was effectively degraded by Sphingobium sp. LY-6 in incubation soils. Comparing to non-incubated soils, the cumulative degradation ratio of buprofezin was significantly increased, up to the extent of 85 and 51%, in the initial concentration of 10 and 100 mg kg(-1). The abundance and community structure of the bacterial communities were analysed by real-time PCR (qPCR) and terminal-restriction fragment length polymorphism (T-RFLP). The findings suggest that buprofezin had a negative effect on soil bacterial community, and decreases in bacterial abundance were observed in the later part of the incubation period. The bacterial community structure and diversity shifted significantly at each sampling time. In conclusion, the buprofezin-degrading strain LY-6 played a major role in the bioremediation of the buprofezin-contaminated soil and influenced the dynamics and structure of the bacterial community, demonstrating the great potential of exogenous microorganisms for soil remediation. PMID- 25832789 TI - Enhancing fermentable sugar yield from cassava pulp for bioethanol production: microwave-coupled enzymatic hydrolysis approach. AB - Cassava pulp, a potential biological feedstock for ethanol production has been subjected to microwave-assisted alkali pretreatment and microwave-coupled enzymatic hydrolysis. Microwave pretreatment may be a good alternative as it can reduce the pretreatment time and improve the enzymatic activity during hydrolysis. Liquid to solid ratio for the pretreatment of cassava pulp was found to be 20:1. Cassava pulp was pretreated at various NaOH concentration, microwave temperature and gave maximum yield of reducing sugar with 1.5% NaOH at 90 degrees C in 30 min than conventional alkali pretreatment after enzymatic hydrolysis. The subsequent enzymatic saccharification of pretreated cassava pulp using alpha amylase dosage of 400 IU at microwave temperature of 90 degrees C resulted in highest reducing sugar yield of 723 mg/g pulp. Microwave-assisted alkali pretreatment improved the enzymatic saccharification of cassava pulp by increasing its accessibility to hydrolytic enzymes. Microwave-assisted alkali pretreatment and microwave-coupled enzymatic hydrolysis are found to be efficient for improving the yield of reducing sugar. PMID- 25832790 TI - Cell mass energetic yields of fed-batch culture by Lipomyces starkeyi. AB - Estimation of the energy capacity of a microbial cell mass on the basis of its lipid content and elemental composition can be used for the comparative evaluation of different microbial sources of biodiesel. Lipomyces starkeyi cell mass concentration reached 94.6 g/L with 37.4% of lipids in a fed-batch process using xylose and urea as substrates. The fatty acid composition of the yeast oil was quite similar to that of palm oil. L. starkeyi converted more than 80% of the energy contained in xylose into cell mass energy yield. The approach used in this study makes it possible to determine the energy of a cell mass by its elemental composition. A heat of combustion (Q c) of 25.7 (kJ/g) was obtained for the cell mass after 142 h of fed-batch cultivation, which represents approximately 56% of the energy content of diesel oil (45.4 kJ/g). The Q c of the triacylglycerols produced was 48.9 (kJ/g), indicating the potential of this oleaginous yeast for biodiesel production. Our work developed here provides a simple and efficient tool for characterization of this cell mass to further our understanding of its use as a feedstock for bioenergy production. PMID- 25832793 TI - Gastroenterology team of the year. PMID- 25832794 TI - Merger of visible light induced oxidation and enantioselective alkylation with a chiral iridium catalyst. AB - A single chiral octahedral iridium(III) complex is used for visible light activated asymmetric photoredox catalysis. In the presence of a conventional household lamp and under an atmosphere of air, the oxidative coupling of 2-acyl-1 phenylimidazoles with N,N-diaryl-N-(trimethylsilyl)methylamines provides aminoalkylated products in 61-93 % yields with high enantiomeric excess (90-98 % ee). Notably, the iridium center simultaneously serves three distinct functions: as the exclusive source of chirality, as the catalytically active Lewis acid, and as a central part of the photoredox sensitizer. This conceptionally simple reaction Scheme may provide new avenues for the green synthesis of non-racemic chiral molecules. PMID- 25832795 TI - Au-catalyzed ring-opening reactions of 2-(1-alkynyl-cyclopropyl)pyridines with nucleophiles. AB - A novel method for the C-C bond cleavage of cyclopropanes was developed by gold catalyzed cycloisomerization of 2-(1-alkynyl-cyclopropyl)pyridine with nucleophiles, which provides efficient access to structurally diverse indolizines under mild conditions. A series of N-, C- and O-based nucleophiles were involved in this reaction to afford the corresponding indolizines in modest to excellent yields. PMID- 25832796 TI - Soluble triggering receptor expressed on myeloid cells-1 is a biomarker of anti CCP-positive, early rheumatoid arthritis. AB - OBJECTIVES: To assess serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) levels in disease-modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis (ERA), to investigate the association of sTREM-1 levels with Disease Activity Score in 28 joints (DAS28) and seropositivity for anti-cyclic citrullinated peptide (CCP) antibody and to determine the predictive value of sTREM-1 with respect to clinical response to DMARD therapy. METHODS: Twenty-two consecutive patients with DMARD-naive ERA were prospectively evaluated for serum sTREM-1 by means of ELISA at diagnosis and at the following clinic visit after prednisone and/or DMARD has been administered, and related to DAS28 and serum level of anti-CCP antibody. We compared the sTREM-1 level to that of 31 patients with established RA as well as to 24 controls. RESULTS: Serum sTREM-1 level was significantly higher in the DMARD-naive ERA group (212.9 +/- 388.9 rhog/mL) compared to established RA group (1478.0 +/- 280.0 rhog/mL, P = 0.001) and normal control (34.4 +/- 7.4 rhog/mL, P < 0.001). In the ERA group, elevated basal sTREM-1 level correlated with higher DAS28-CRP score (P = 0.001, HR 3.23, 95% CI 1.4-8.12), DAS28-ESR (P = 0.04, HR 2.34 95% CI 0.1-8.12), as well as predicted higher DAS28 score at the following encounter after DMARD treatment was administered (P = 0.001, HR 3.2 95% CI 1.1-7.2). Higher serum level of sTREM-1 correlated with higher titres of anti-CCP antibody (P < 0.001). CONCLUSIONS: Our results suggest that serum sTREM-1 may provide a novel biomarker for DMARD-naive ERA as well as for seropositivity for anti-CCP antibody and RA activity. PMID- 25832797 TI - Effect of collision energy on the reaction mechanism of C((3)P) + OH(X(2) Pi) -> CO(X(1) Sigma(+)) + H((2)S). AB - Quasiclassical trajectory calculations based on a fully global ab initio potential energy surface of the rotational angular momentum polarisation of the product CO in the title reaction are reported. The alignment and orientation of the rotational angular momentum of the CO fragment in the scattering frame were found to be sensitive to the initial collision energy chosen. Differences in the angular momentum polarization at different collision energies were traced to differences in the microscopic reaction mechanism. The results of this study suggest that the title reaction is mainly dominated by an abstraction reaction mechanism (involving the short-lived and metastable intermediate complex COH) at low collision energies; however, at relatively high energies, an insertion reaction mechanism (involving the long-lived and stable intermediate complex HCO) plays a role. PMID- 25832798 TI - In silico identification of novel kinase inhibitors by targeting B-Raf(v660e) from natural products database. AB - The Ras/Raf/MEK/ERK (MAPK) signaling pathway has gained much attention from scientific community for therapeutic intervention in the past decades, specifically in oncology. Notably, a most prevalent B-Raf(v600e) mutant in Raf kinase family exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, virtual screening is applied to identify its potential inhibitors. Following the 25 ns molecular dynamic (MD) simulations, ZINC38541768, ZINC38541767, and ZINC12496469 are identified as B-Raf(v600e) potential inhibitors in a DFG-in conformation. Furthermore, according to the molecular mechanics/generalized born surface area (MM/GBSA) method, these three small molecules exhibit similar and good binding affinity toward B-Raf(v600e) (-38.76 kcal mol(-1), -42.60 kcal mol(-1), and -39.04 kcal mol(-1)). At the same time, several critical residues, such as I463, V471 in the P-loop, and DFG motif residue D594 within the A-loop, are also well clarified. All these results may not only indicate some future applications of inhibitors targeting B-Raf(v600e), but also benefit B-Raf(v600e) harboring cancer patients. PMID- 25832799 TI - Acquiring a Pet Dog Significantly Reduces Stress of Primary Carers for Children with Autism Spectrum Disorder: A Prospective Case Control Study. AB - This study describes the impact of pet dogs on stress of primary carers of children with Autism Spectrum Disorder (ASD). Stress levels of 38 primary carers acquiring a dog and 24 controls not acquiring a dog were sampled at: Pre intervention (17 weeks before acquiring a dog), post-intervention (3-10 weeks after acquisition) and follow-up (25-40 weeks after acquisition), using the Parenting Stress Index. Analysis revealed significant improvements in the intervention compared to the control group for Total Stress, Parental Distress and Difficult Child. A significant number of parents in the intervention group moved from clinically high to normal levels of Parental Distress. The results highlight the potential of pet dogs to reduce stress in primary carers of children with an ASD. PMID- 25832800 TI - The "Reading the Mind in the Eyes" Test: Investigation of Psychometric Properties and Test-Retest Reliability of the Persian Version. AB - The psychometric properties of the Persian "Reading the Mind in the Eyes" test were investigated, so were the predictions from the Empathizing-Systemizing theory of psychological sex differences. Adults aged 16-69 years old (N = 545, female = 51.7 %) completed the test online. The analysis of items showed them to be generally acceptable. Test-retest reliability, as measured by Intra-class correlation coefficient, was 0.735 with a 95 % CI of (0.514, 0.855). The percentage of agreement for each item in the test-retest was satisfactory and the mean difference between test-retest scores was -0.159 (SD = 3.42). However, the internal consistency of Persian version, calculated by Cronbach's alpha (0.371), was poor. Females scored significantly higher than males but academic degree and field of study had no significant effect. PMID- 25832801 TI - The Autism Diagnostic Observation Schedule, Toddler Module: Standardized Severity Scores. AB - Standardized calibrated severity scores (CSS) have been created for Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) Modules 1-4 as a metric of the relative severity of autism-specific behaviors. Total and domain CSS were created for the Toddler Module to facilitate comparison to other modules. Analyses included 388 children with ASD age 12-30 months and were replicated on 435 repeated assessments from 127 children with ASD. Compared to raw scores, associations between total and domain CSS and participant characteristics were reduced in the original sample. Verbal IQ effects on Social Affect-CSS were not reduced in the replication sample. Toddler Module CSS increases comparability of ADOS-2 scores across modules and allows studies of symptom trajectories to extend to earlier ages. PMID- 25832802 TI - Do oral health conditions adversely impact young adults? AB - This study assessed the extent to which clinically measured oral health conditions, adjusted for sociodemographic and oral health behavior determinants, impact adversely on the oral health-related quality of life (OHRQoL) in a sample of Belgian young adults. The null hypothesis was that, among young adults, the oral health conditions would have no impact on their quality of life. The participants were 611 new patients aged 16-32 years seeking consultation at the Saint-Luc University Hospital in Brussels in 2010-2011. The patients (56.0% female) were examined for their oral health conditions and answered a validated questionnaire about sociodemographic and oral health behavior determinants in addition to questions about their OHRQoL. The abridged Oral Health Impact Profile 14 was used to assess the OHRQoL. Interexaminer reliability for caries was 0.86 (95% CI 0.84-0.89, nonweighted kappa). The outcome was a high score on the OHRQoL (median split). Hierarchical logistic regression analysis showed that young adults with clinical absolute D1MFS scores between 9 and 16 (OR = 2.14, p = 0.031) and between 17 and 24 (OR = 3.10, p = 0.003) were significantly more likely to report a high impact on their quality of life than those with lower scores. Also, periodontal conditions compromised significantly (OR = 1.79, p = 0.011) the quality of life of young adults. In conclusion, this study identified oral health conditions with a significant adverse effect on the OHRQoL of young adults. However, the prevalence of young adults reporting impacts on at least 1 performance affected fairly often or very often was limited to 18.7% of the sample. PMID- 25832804 TI - Orthogonal insertion of lanthanide and transition-metal atoms in metal-organic networks on surfaces. AB - The orthogonal coordinative properties of tetrapyrrole macrocycles and nitrile ligands have been used in a multistep procedure towards interfacial d-f hetero bimetallic nanoarchitectures based on a free-base porphyrin derivative functionalized with meso-cyanobiphenylene substituents. Molecular-level scanning tunneling microscopy studies reveal that the porphyrin module alone self assembles on Ag(111) in a close-packed layer with a square unit cell. Upon co deposition of Gd atoms, a square-planar motif is formed that reflects the fourfold coordination of CN ligands to the rare-earth centers. The resulting nanoporous network morphology is retained following exposure to a beam of Co atoms, which induces selective porphyrin metalation and ultimately yields a gridlike 2D metallosupramolecular architecture. PMID- 25832803 TI - Preference for concentric orientations in the mouse superior colliculus. AB - The superior colliculus is a layered structure important for body- and gaze orienting responses. Its superficial layer is, next to the lateral geniculate nucleus, the second major target of retinal ganglion axons and is retinotopically organized. Here we show that in the mouse there is also a precise organization of orientation preference. In columns perpendicular to the tectal surface, neurons respond to the same visual location and prefer gratings of the same orientation. Calcium imaging and extracellular recording revealed that the preferred grating varies with retinotopic location, and is oriented parallel to the concentric circle around the centre of vision through the receptive field. This implies that not all orientations are equally represented across the visual field. This makes the superior colliculus different from visual cortex and unsuitable for translation-invariant object recognition and suggests that visual stimuli might have different behavioural consequences depending on their retinotopic location. PMID- 25832805 TI - Crystal Engineering with the New Linker Tolanedisulfonic Acid (H2 TDS): Helical Chains in Zn(TDS)(DMA)3 , Linear Chains in Zn(TDS)(NMP)3 , and Complex Anions in [HDMA]2 [Zn(TDS)2 (DMA)3 ](DMA)2. AB - Reaction of 4,4'-tolanedisulfonic acid, H2 TDS, with zinc hydroxide in dimethylacetamide, DMA, under solvothermal conditions led to the coordination polymer Zn(TDS)(DMA)3 (I). In the crystal structure [trigonal, P32 21, Z=3, a=1175.0(1) pm, c=1949.5(1) pm, R1 ; wR2 (Io > 2sigma(Io ))=0.0393; 0.0921] the disulfonate anions linked the Zn(2+) ions into helical chains according to infinity (1) [Zn(DMA)3/1 (TDS)2/2 ] (I) causing the chirality of the compound. By using higher concentrations of H2 TDS in the starting mixture the compound [HDMA]2 [Zn(TDS)2 (DMA)3 ](DMA)2 (II) was formed. The structure [monoclinic, Cc, Z=4, a=1201.5(1) pm, b=1996.0(1) pm, c=2749.2(2) pm, beta=101.897(2) degrees , R1 ; wR2 (Io > 2sigma(Io ))=0.0699; 0.2017] displayed the complex anion [Zn(TDS)2 (DMA)3 ](2-) which was a perfect cut-off of the helical chain in I. Charge compensation was achieved by protonated DMA molecules. If N-methylpyrrolidone, NMP, was chosen as a solvent, the sulfonate Zn(TDS)(NMP)3 (III) [monoclinic, I2/a, Z=4, a=1575.7(1) pm, b=1077.3(1) pm, c=1870.0(1) pm, beta=101.189(9) degrees , R1 ; wR2 (Io > 2sigma(Io ))=0.0563; 0.1320] was obtained. Similarly to the findings for I, the formation of chains according to infinity (1) [Zn(NMP)3/1 (TDS)2/2 ] was observed. However, due to the more bulky NMP molecules these chains were no longer helical but straight instead. PMID- 25832808 TI - Optofluidic holographic microscopy with custom field of view (FoV) using a linear array detector. AB - Simple and effective imaging strategies are of utmost interest for applications on a lab-on-chip scale. In fact, the majority of diagnostic tools for medical as well as biotechnological studies still employ image-based approaches. Having onboard the chip a compact but powerful imaging apparatus with multiple imaging capabilities, such as 3D dynamic focusing along the optical axis, unlimited field of view (FoV) and double outputs, namely, intensity and quantitative phase contrast maps of biological objects, is of extreme importance for the next generation of Lab-on-a-Chip (LoC) devices. Here we present a coherent 3D microscopy approach with a holographic modality that is specifically suitable for studying biological samples while they simply flow along microfluidic paths. The LoC device is equipped with a compact linear array detector to capture and generate a new conceptual type of a digital hologram in the space-time domain, named here as Space-Time Digital Hologram (STDH). The reported results show that the method is a promising diagnostic tool for optofluidic investigations of biological specimens. PMID- 25832807 TI - Meniere's disease treatment: a patient-centered systematic review. AB - Meniere's disease is a disorder of the inner ear affecting hearing and balance to a varying degree. It is characterized by episodes of vertigo, low-pitched tinnitus, and hearing loss. There is currently no gold standard treatment for Meniere's disease. We conducted a systematic search of the Cochrane Database, as a high-quality source of evidence-based therapies, for reviews on the efficacy of etiological therapy or on Meniere's disease or its symptoms. Following recent positive experiences reported by other research teams, we decided to involve a patients' representative in the assessment and analysis of the evidence retrieved in the literature in order to achieve a more patient-centered evaluation of the therapies. Evidence confirms that an effective treatment of Meniere's disease is still missing, but recent discoveries on the microvascular etiology of Meniere's disease may be assimilated by new evidence-based therapeutic approaches. PMID- 25832806 TI - Identification of P-glycoprotein co-fractionating proteins and specific binding partners in rat brain microvessels. AB - Drug delivery to the brain for the treatment of pathologies with a CNS component is a significant clinical challenge. P-glycoprotein (PgP), a drug efflux pump in the endothelial cell membrane, is a major factor in preventing therapeutics from crossing the blood-brain barrier (BBB). Identifying PgP regulatory mechanisms is key to developing agents to modulate PgP activity. Previously, we found that PgP trafficking was altered concomitant with increased PgP activity and disassembly of high molecular weight PgP-containing complexes during acute peripheral inflammatory pain. These data suggest that PgP activity is post-translationally regulated at the BBB. The goal of the current study was to identify proteins that co-localize with PgP in rat brain microvessel endothelial cell membrane microdomains and use the data to suggest potential regulatory mechanisms. Using new density gradients of microvessel homogenates, we identified two unique pools (1,2) of PgP in membrane fractions. Caveolar constituents, caveolin1, cavin1, and cavin2, co-localized with PgP in these fractions indicating the two pools contained caveolae. A chaperone (Hsc71), protein disulfide isomerase and endosomal/lysosomal sorting proteins (Rab5, Rab11a) also co-fractionated with PgP in the gradients. These data suggest signaling pathways with a potential role in post-translational regulation of PgP activity at the BBB. PMID- 25832809 TI - The Contribution of MRI after Fetal Anomalies Have Been Diagnosed by Ultrasound: Correlation with Postnatal Outcomes. AB - OBJECTIVE: The aim of this study was to investigate the additional value of fetal magnetic resonance imaging (MRI) in the assessment and management of fetuses with abnormal findings on ultrasound. METHODS: A total of 257 patients who had fetal MRI following the ultrasound diagnosis of a fetal anomaly, or were at high risk, were included. The patients were grouped by referral category for fetal MRI. Fetal MRI was compared to ultrasound in the detection of anomalies, i.e. whether additional findings were identified and if this changed diagnosis, prognosis and management during pregnancy. RESULTS: Ultrasound findings were confirmed on fetal MRI in 89% of the cases. Additional findings were seen with MRI in 28% of all patients. The diagnosis changed in 21% and the prognosis in 19% of the cases. Perinatal management changed in 8%. The antenatal findings were confirmed in all cases that had a postmortem examination following termination of pregnancy. In all the pregnancies that continued to delivery and for which the postnatal outcome is known, the findings correlated in 97% of the cases. CONCLUSION: Fetal MRI provided additional detection of fetal anomalies, leading to a change in diagnosis and prognosis in 19% of the cases. Neonatal and postmortem findings mostly confirmed the fetal MRI diagnosis, suggesting it to be a useful tool for clinical decision making in perinatal management. PMID- 25832810 TI - Refraction and visual acuity in a national Danish cohort of 4-year-old children of extremely preterm delivery. AB - PURPOSE: A recent threefold increase in laser treatment for advanced retinopathy of prematurity (ROP) triggered a nationwide preschool ophthalmic and developmental status among extremely preterm survivors. Here, we discuss refraction and visual acuity. METHODS: Survivors (n = 178) from a national birth cohort (February 2004 to March 2006) of gestational age <28 weeks (PT) and 56 full-term (FT) controls attended for evaluation at age 4 years. Cycloplegic refraction and keratometry were achieved by Retinomax autokeratorefractor and visual acuities by symbol recognition (HOTV, logMAR). RESULTS: The refractive distribution presented a myopic tail (4.5%) and a hyperopic tail (11.9% >=+2.5 D) as special preterm features, and corneas were more curved. Astigmatism and anisometropia were only marginally increased, and visual acuities were generally good. Best-corrected binocular median logMAR visual acuity was 0.1 in FT and 0.2 in PT, in Snellen equivalents 0.8 and 0.63. Snellen acuity <=0.5 occurred across the ROP subgroups, but mainly in those with at least ROP stage 3. Two children had low vision. CONCLUSIONS: The overall fair outcome for refraction and function is in accordance with other recent northern Europe experience. The results differ in particular from the poorer ophthalmic outcomes reported in the pioneer US treatment studies (cryotherapy for ROP and ETROP). The diode laser ablations (n = 32) appeared effective in our series; except one child, all treated subjects had good or fair social vision at the age of 4 years. PMID- 25832811 TI - Ketogenic diet attenuates NMDA-induced damage to rat's retinal ganglion cells in an age-dependent manner. AB - OBJECTIVE: This study was conducted to investigate neuroprotective effects of a high fat/low carbohydrate and protein diet (ketogenic diet, KD) in a model of N methyl D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage in juvenile and young adult rats. METHODS: Juvenile (30-35 days old) and young adult (56-70 days old) female Brown Norway rats were fed the KD for 21 days; rats exposed to a standard rodent diet (SRD) served as controls. The main constituents of the KD used in the present study were approximately 80% fats, 8% proteins, and less than 1% carbohydrates. On day 14 of exposure to the KD (or the SRD in the control group), each rat received a single intravitreal injection of NMDA; RGCs were then retrogradely labelled by hydroxystilbamidine on day 19 and collected on day 21 to assess the degree of damage induced by NMDA. Blood biomarkers to confirm the expected metabolic response to the KD (i.e. ketosis and hypoglycaemia) were also assessed. RESULTS: Although both the juvenile and young adult rats developed comparable ketosis and hypoglycaemia when fed the KD, NMDA-induced loss in RGCs was significantly attenuated only in juvenile rats exposed to the KD in comparison with those fed the SRD; exposure to the KD had no protective effect in young adult rats. In summary, exposure to the KD had a neuroprotective effect in NMDA-induced RGC damage in juvenile rats, but not in young adult rats. CONCLUSION: These results support further exploration of metabolic interventions to treat optic neuropathies associated with neurodegeneration. PMID- 25832812 TI - Carbon-catalysed reductive hydrogen atom transfer reactions. AB - Generally, transition metal catalysts are essential for the reductive hydrogen atom transfer reaction, which is also known as the transfer hydrogenation reaction or the borrowing-hydrogen reaction. It has been reported that graphene can be an active catalyst in ethylene and nitrobenzene reductions, but no report has described carbon-based materials as catalysts for alcohol amination via the borrowing-hydrogen reaction mechanism. Here we show the results from the preparation, characterization and catalytic performance investigation of carbon catalysts in transition metal-free borrowing-hydrogen reactions using alcohol amination and nitro compound/ketone reduction as model reactions. XPS, XRD, SEM, FT-IR and N2 adsorption-desorption studies revealed that C=O group in the carbon catalysts may be a possible catalytically active site, and high surface area is important for gaining high activity. The activity of the carbon catalyst remained unchanged after reuse. This study provides an attractive and useful methodology for a wider range of applications. PMID- 25832814 TI - Moonlight pollination in the gymnosperm Ephedra (Gnetales). AB - Most gymnosperms are wind-pollinated, but some are insect-pollinated, and in Ephedra (Gnetales), both wind pollination and insect pollination occur. Little is, however, known about mechanisms and evolution of pollination syndromes in gymnosperms. Based on four seasons of field studies, we show an unexpected correlation between pollination and the phases of the moon in one of our studied species, Ephedra foeminea. It is pollinated by dipterans and lepidopterans, most of them nocturnal, and its pollination coincides with the full moon of July. This may be adaptive in two ways. Many nocturnal insects navigate using the moon. Further, the spectacular reflection of the full-moonlight in the pollination drops is the only apparent means of nocturnal attraction of insects in these plants. In the sympatric but wind-pollinated Ephedra distachya, pollination is not correlated to the full moon but occurs at approximately the same dates every year. The lunar correlation has probably been lost in most species of Ephedra subsequent an evolutionary shift to wind pollination in the clade. When the services of insects are no longer needed for successful pollination, the adaptive value of correlating pollination with the full moon is lost, and conceivably also the trait. PMID- 25832815 TI - Transoceanic migration by a 12 g songbird. AB - Many fundamental aspects of migration remain a mystery, largely due to our inability to follow small animals over vast spatial areas. For more than 50 years, it has been hypothesized that, during autumn migration, blackpoll warblers (Setophaga striata) depart northeastern North America and undertake a non-stop flight over the Atlantic Ocean to either the Greater Antilles or the northeastern coast of South America. Using miniaturized light-level geolocators, we provide the first irrefutable evidence that the blackpoll warbler, a 12 g boreal forest songbird, completes an autumn transoceanic migration ranging from 2270 to 2770 km (mean +/- s.d.: 2540 +/- 257) and requiring up to 3 days (62 h +/- 10) of non stop flight. This is one of the longest non-stop overwater flights recorded for a songbird and confirms what has long been believed to be one of the most extraordinary migratory feats on the planet. PMID- 25832816 TI - Acoustic telemetry reveals cryptic residency of whale sharks. AB - Although whale sharks (Rhincodon typus) have been documented to move thousands of kilometres, they are most frequently observed at a few predictable seasonal aggregation sites. The absence of sharks at the surface during visual surveys has led to the assumption that sharks disperse to places unknown during the long 'off seasons' at most of these locations. Here we compare 2 years of R. typus visual sighting records from Mafia Island in Tanzania to concurrent acoustic telemetry of tagged individuals. Sightings revealed a clear seasonal pattern with a peak between October and February and no sharks observed at other times. By contrast, acoustic telemetry demonstrated year-round residency of R. typus. The sharks use a different habitat in the off-season, swimming deeper and further away from shore, presumably in response to prey distributions. This behavioural change reduces the sharks' visibility, giving the false impression that they have left the area. We demonstrate, for the first time to our knowledge, year-round residency of unprovisioned, individual R. typus at an aggregation site, and highlight the importance of using multiple techniques to study the movement ecology of marine megafauna. PMID- 25832818 TI - Integrated copy number and gene expression profiling analysis of Epstein-Barr virus-positive diffuse large B-cell lymphoma. AB - Viral oncogenes and host immunosenescence have been suggested as causes of Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV + DLBCL) of the elderly. To investigate the molecular genetic basis of immune evasion and tumor outgrowth, we analyzed copy number alterations (CNAs) and gene expression profiles in EBV + DLBCL samples compared with EBV - DLBCL. There were relatively few genomic alterations in EBV + DLBCL compared with those detected in EBV negative DLBCL. The most frequent CNAs (>30%) in EBV + DLBCLs were gains at 1q23.2-23.3, 1q23.3, 1q32.1, 5p15.3, 8q22.3, 8q24.1-24.2, and 9p24.1; losses at 6q27, 7q11.2, and 7q36.2-36.3 were also recurrent. A gene expression profile analysis identified the host immune response as a key molecular signature in EBV + DLBCL. Antiviral response genes, proinflammatory cytokines, and chemokines associated with the innate immune response were overexpressed, indicating the presence of a virusinduced inflammatory microenvironment. Genes associated with the B-cell receptor signaling pathway were downregulated. An integrated analysis indicated that SLAMF1 and PDL2 were key targets of the gains detected at 1q23.2 23.3 and 9p24.1. The chromosomal gain at 9p24.1 was associated with poor overall survival. Taken together, our results led to the identification of recurrent copy number alterations and distinct gene expression associated with the host immune response in EBV + DLBCL. We suggest that the upregulation of PDL2 on 9p24.1 promotes immune evasion and is associated with poor prognosis in EBV + DLBCL. PMID- 25832817 TI - Population genetic structure of serotine bats (Eptesicus serotinus) across Europe and implications for the potential spread of bat rabies (European bat lyssavirus EBLV-1). AB - Understanding of the movements of species at multiple scales is essential to appreciate patterns of population connectivity and in some cases, the potential for pathogen transmission. The serotine bat (Eptesicus serotinus) is a common and widely distributed species in Europe where it frequently harbours European bat lyssavirus type 1 (EBLV-1), a virus causing rabies and transmissible to humans. In the United Kingdom, it is rare, with a distribution restricted to south of the country and so far the virus has never been found there. We investigated the genetic structure and gene flow of E. serotinus across the England and continental Europe. Greater genetic structuring was found in England compared with continental Europe. Nuclear data suggest a single population on the continent, although further work with more intensive sampling is required to confirm this, while mitochondrial sequences indicate an east-west substructure. In contrast, three distinct populations were found in England using microsatellite markers, and mitochondrial diversity was very low. Evidence of nuclear admixture indicated strong male-mediated gene flow among populations. Differences in connectivity could contribute to the high viral prevalence on the continent in contrast with the United Kingdom. Although the English Channel was previously thought to restrict gene flow, our data indicate relatively frequent movement from the continent to England highlighting the potential for movement of EBLV-1 into the United Kingdom. PMID- 25832819 TI - Cloning and expression of fumarylacetoacetate hydrolase derived from marine yeast Rhodosporidium diobovatum. AB - Fumarylacetoacetate hydrolase (FAH) catalyzes the hydrolytic cleavage of a carbon carbon bond in fumarylacetoacetate to yield acetoacetate and fumarate as the final step in tyrosine degradation. In this study, the FAH genomic DNA and cDNA of Rhodosporidium. diobovatum were cloned by using the methods of degenerate polymerase chain reaction and RACE method. The results showed that the gene contained six exons, and that the encoded polypeptide held a sequence of 308 amino acid residues, containing a 75 residue N-terminal prosequence, a 216 residue proteinase domain, and a 17 residue C-terminal domain. Then, the expression vectors pET28a-FAH were constructed and expressed in Escherichia coli. The enzymatic activity of FAH protein was determined by monitoring the decrease in optical density at 330 nm of the substrate fumarylacetoacetate. The values for Km and Vmax of the purified enzyme was 1.4 uM and 2.3 umol . min(-1) . mg(-1), respectively. PMID- 25832820 TI - No big data without small data: learning health care systems begin and end with the individual patient. PMID- 25832822 TI - Commentary on Trajectories and predictors of functional decline in hospitalised older patients. Journal of Clinical Nursing, 22, 1322-1331. PMID- 25832824 TI - Considerations in civil commitment of individuals with substance use disorders. AB - Several states currently have enacted laws that allow for civil commitment for individuals diagnosed with severe substance use disorders. Civil commitment or involuntary commitment refers to the legal process by which individuals with mental illness are court-ordered into inpatient and/or outpatient treatment programs. Although initially civil commitment laws were intended for individuals with severe mental illness, these statutes have been extended to cover individuals with severe substance use disorders. Much of the recent legislation allowing for civil commitment of individuals with substance use disorders has come about in response to the heroin epidemic and is designed to provide an alternative to the unrelenting progression of opioid use disorders. Civil commitment also provides an opportunity for individuals with opioid use disorders to make informed decisions regarding ongoing or continued treatment. However, civil commitment also raises concerns regarding the potential violation of 14th Amendment rights, specifically pertaining to abuses of deprivation of liberty or freedom, which are guaranteed under the 14th Amendment to the United States Constitution. This commentary examines these issues while supporting the need for effective brief civil commitment legislation in all states. PMID- 25832823 TI - Neuropsychological sex differences associated with age of initiated use among young adult cannabis users. AB - INTRODUCTION: Earlier initiation of cannabis use is associated with poorer neuropsychological functioning across several domains. Given well-documented sex differences in neuromaturation during adolescence, initiation of cannabis use during this time may affect neuropsychological functioning differently for males and females. METHOD: In the current study, we examined sex differences in the relationship between age of initiated cannabis use and neuropsychological performance after controlling for amount of lifetime cannabis use in 44 male and 25 female young adult cannabis users. RESULTS: We found that an earlier age of initiated use was related to poorer episodic memory, especially immediate recall, in females, but not in males. On the other hand, we found that, surprisingly, an earlier age of initiated use was associated with better decision making overall. However, exploratory analyses found sex-specific factors associated with decision making and age of initiated use, specifically that attention deficit/hyperactivity disorder (ADHD) symptoms in females may drive the relationship between an earlier age of initiated use and better decision making. Further, an earlier age of initiated use was associated with less education, a lower IQ, and fewer years of mother's education for females, but more lifetime cannabis use for males. CONCLUSIONS: Taken together, our findings suggest there are sex differences in the associations between age of initiated cannabis use and neuropsychological functioning. The current study provides preliminary evidence that males and females may have different neuropsychological vulnerabilities that place them at risk for initiating cannabis use and continued cannabis use, highlighting the importance of examining the impact of cannabis on neuropsychological functioning separately for males and females. PMID- 25832825 TI - Measurement of shrinkage and cracking in lyophilized amorphous cakes, part 3: hydrophobic vials and the question of adhesion. AB - The importance of cake adhesion to the inside vial wall during lyophilization of amorphous trehalose cakes was determined by using hydrophobized vials. The degrees of cake shrinkage and cracking were determined independently by photographic imaging of the cake top surface in a dark cell. Additionally, measurements with microcomputed tomography were performed. Adhesion is found to be a determining factor in both cake shrinkage and cracking. The correlation between cake detachment from the vial inner wall and trehalose concentration indicates that adhesion of the frozen solute phase is a determining factor in shrinkage. The hydrophobized vials give reduced cracking at trehalose concentrations of up to 15%. The reduced wetting of the hydrophobized inside vial wall gives a planar cake topography with a uniform distribution of cracks within the cake. PMID- 25832826 TI - Synchronous primary lung cancer presenting with small cell carcinoma and adenocarcinoma. AB - Multiple synchronous primary lung cancers presenting with different histologic types are uncommon. Among reported cases with different histologic findings, only a few had small cell lung cancer (SCLC) and adenocarcinoma. This unusual combination of lung cancers has not been well reported. In this report, we describe two cases of synchronous primary lung cancer presenting with lymph node metastasis of SCLC and early-stage adenocarcinoma. Epidermal growth factor receptor (EGFR) mutation was not detected in either SCLC or adenocarcinoma in the two cases. PMID- 25832827 TI - In reference to "The effect of a rapid response team on resident perceptions of education and autonomy". PMID- 25832829 TI - Improving the Utility of Laryngeal Adductor Reflex Testing: A Translational Tale of Mice and Men. AB - OBJECTIVES: Evaluation of the laryngeal adductor reflex (LAR) entails delivering air through an endoscope positioned 1 to 2 mm from the arytenoid mucosa to elicit bilateral vocal fold (VF) closure. This short working distance limits visualization to only the ipsilateral arytenoid and results in quantification of a single LAR metric: threshold pressure that evokes the LAR. Our goal was to evolve the LAR procedure to optimize its utility in clinical practice and translational research. STUDY DESIGN: Prospective translational experiment. SETTING: Academic institution. SUBJECTS: Young healthy human adults (n = 13) and 3 groups of mice: healthy, primary aging mice (n = 5), a transgenic mouse model of amyotrophic lateral sclerosis (ALS; n = 4), and young healthy controls (n = 10). METHODS: The VFs were visualized bilaterally during supramaximal air stimulation through an endoscope. Responses were analyzed to quantify 4 novel metrics: VF adduction phase duration, complete glottic closure duration, VF abduction phase duration, and total LAR duration. RESULTS: The 4 LAR metrics are remarkably similar between healthy young humans and mice. Compared to control mice, aging mice have shorter glottic closure durations, whereas ALS-affected mice have shorter VF abduction phase durations. CONCLUSIONS: We have established a new LAR protocol that permits quantification of novel LAR metrics that are translatable between mice and humans. Using this protocol, we showed that VF adduction is impaired in primary aging mice, whereas VF abduction is impaired in ALS-affected mice. These preliminary findings highlight the enhanced diagnostic potential of LAR testing. PMID- 25832828 TI - A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement. AB - Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo controlled trial. PMID- 25832830 TI - Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus Immunology: A Pilot Study. AB - OBJECTIVE: To elucidate specific cytokine and chemokine markers in patients diagnosed with pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS). STUDY DESIGN: Prospective cohort study. STUDY SETTING: Academic university hospital. METHODS: Tonsil tissue was collected from 24 patients and organized into 3 groups: experimental PANDAS cohort (12 patients), group A beta hemolytic streptococcus control cohort (6 patients), and obstructive sleep apnea control cohort (6 patients). Each tissue sample was extracted with MSD Tris lysis buffer, and protein lysates were analyzed for human chemokines and cytokines by the Human Cytokine 30-Plex Assay on the Mesoscale System. RESULTS: We identified a significant difference in expression regarding the 8 following cytokines when comparing the experimental PANDAS, group A beta hemolytic streptococcus, and obstructive sleep apnea control cohorts: tumor necrosis factor alpha and eotaxin-3. In addition, our group also identified a significant reduction in the expression of interleukin (IL)-8, interferon inducible protein 10, IL-17a, interferon-gamma, IL-10, and IL-12 across the aforementioned groups. CONCLUSIONS: Patients diagnosed with PANDAS appear to maintain significantly different concentrations of cytokines when compared with patients afflicted by chronic group A beta hemolytic streptococcus infections and obstructive sleep apnea. As a result, one could potentially use the described characterization of immunologic markers as a basis for future mechanistic and epidemiological studies. PMID- 25832832 TI - [New trend in metal-based drug research]. PMID- 25832833 TI - [Iron, aluminum, and lanthanum-based drugs for treatment of hyperphosphatemia]. AB - The control of the serum phosphorus (P) level in chronic kidney disease patients is important because elevated serum P levels are associated with progression of vascular calcification and increased mortality in these patients. In 2014, a novel phosphate binder, ferric citrate hydrate (Riona((r))), became available for the treatment of hyperphosphatemia in Japan, the first country to approve this medication. Ferric citrate hydrate, which relies upon the potent phosphate binding capacity of ferric iron, inhibits P absorption by forming complexes between ferric iron and dietary phosphate in the gut. The active pharmaceutical ingredient in ferric citrate hydrate provides a larger specific surface area and higher water solubility; therefore, it is expected to have greater efficacy in terms of its phosphate-binding capacity. In clinical trials, ferric citrate hydrate significantly reduced the serum phosphate level and effectively maintained serum P concentrations throughout the duration of the trials. Moreover, in one clinical trial, ferric citrate hydrate significantly decreased levels of fibroblast growth factor-23 (FGF-23) in nondialysis patients. FGF-23 is an endocrine hormone that increases urinary phosphate excretion to maintain serum P at the proper level. A portion of the iron from ferric citrate hydrate is absorbed and transported throughout the body as transferrin-bound iron, where it is used for the synthesis of hemoglobin, enzymes, and others. Although safer and more effective phosphate binders are expected in the future, ferric citrate hydrate will become a new approach for the treatment of hyperphosphatemia. PMID- 25832834 TI - [Application of radioisotopes for theranostics, a combination of diagnostics and therapy]. AB - Radioisotopes emit radiation with various characteristics. These characteristics have been used for various applications of radioisotopes in clinical fields. For example, diagnostic nuclear medicine is a technique that uses gamma-emitted radionuclides with high permeability into the body and can visualize changes in physiological and biochemical processes throughout the distributed and interrelated systems of living tissues and organs. Therapeutic nuclear medicine is a technique that uses beta-emitted radionuclides with high radiation damage to the cell and can be used for internal radiation therapy. Therefore, a strategy in which the same ligand is labeled with beta-emitted or gamma-emitted radioisotopes, i.e., a theranostics approach, is useful because an extensive availability of diagnostics and therapeutics is possible. In this presentation, some examples of a theranostics approach for radiolabeled compounds will be reported, including the results of our recent research. PMID- 25832831 TI - Chimeric antigen receptors and bispecific antibodies to retarget T cells in pediatric oncology. AB - Cancer immunotherapy using antigen-specific T cells has broad therapeutic potential. Chimeric antigen receptors and bispecific antibodies can redirect T cells to kill tumors without human leukocyte antigens (HLA) restriction. Key determinants of clinical potential include the choice of target antigen, antibody specificity, antibody affinity, tumor accessibility, T cell persistence, and tumor immune evasion. For pediatric cancers, additional constraints include their propensity for bulky metastatic disease and the concern for late toxicities from treatment. Nonetheless, the recent preclinical and clinical developments of these T cell based therapies are highly encouraging. PMID- 25832835 TI - [Decorporation agents for internal radioactive contamination]. AB - When radionuclides are accidentally ingested or inhaled, blood circulation or tissue/organ deposition of the radionuclides causes systemic or local radiation effects. In such cases, decorporation therapy is used to reduce the health risks due to their intake. Decorporation therapy includes reduction and/or inhibition of absorption from the gastrointestinal tract, isotopic dilution, and the use of diuretics, adsorbents, and chelating agents. For example, penicillamine is recommended as a chelating agent for copper contamination, and diethylene triamine pentaacetic acid is approved for the treatment of internal contamination with plutonium. During chelation therapy, the removal effect of the drugs should be monitored using a whole-body counter and/or bioassay. Some authorities, such as the National Council on Radiation Protection and Measurements and International Atomic Energy Agency, have reported recommended decorporation agents for each radionuclide. However, few drugs are approved by the US Food and Drug Administration, and many are off-label-use agents. Because many decontamination agents are drugs that have been available for a long time and have limited efficacy, the development of new, higher-efficacy drugs has been carried out mainly in the USA and France. In this article, in addition to an outline of decorporation agents for internal radioactive contamination, an outline of our research on decorporation agents for actinide (uranium and plutonium) contamination and for radio-cesium contamination is also presented. PMID- 25832836 TI - [Front-line research of idiosyncratic drug toxicity]. PMID- 25832837 TI - [Recent findings regarding the mechanism of idiosyncratic drug toxicity]. AB - Animal experiments cannot predict the probability of idiosyncratic drug toxicity; consequently, an important goal of the pharmaceutical industry is to develop a new methodology for preventing this form of drug reaction. Although the mechanism remains unclear, immune reactions are likely involved in the toxic processes underlying idiosyncratic drug toxicity: the drug is first activated into a chemically reactive metabolite that binds covalently to proteins and then acts as an immunogen. Therefore, screening tests to detect chemically reactive metabolites are conducted early during drug development and typically involve trapping with glutathione. More quantitative methods are then used in a later stage of drug development and frequently employ (14)Cor (3)H-labeled compounds. It has recently been demonstrated that a zone classification system can be used to separate risky drugs from likely safe drugs: by plotting the amount of each protein-bound reactive metabolite in vitro against the dose levels in vivo, the risk associated with each drug candidate can be assessed. A mechanism for idiosyncratic drug-induced hepatotoxicity was proposed by analogy to virus induced hepatitis, in which cytotoxic T lymphocytes play an important role. This mechanism suggests that polymorphism in human leukocyte antigens is involved in idiosyncrasy, and a strong correlation with a specific genotype of human leukocyte antigens has been found in many cases of idiosyncratic drug toxicity. Therefore, gene biomarkers hold promise for reducing the clinical risk and prolonging the life cycle of otherwise useful drugs. PMID- 25832838 TI - [Establishment of animal models of drug-induced liver injury and analysis of possible mechanisms]. AB - Drug-induced liver injury (DILI) is one of leading causes of attrition during both early and late stages of drug development and postmarketing. DILI is generally classified into the intrinsic and idiosyncratic types. Intrinsic DILI is dose dependent and predictable as exemplified by acetaminophen toxicity. However, the occurrence of idiosyncratic DILI with very low incidence and severe liver damage is difficult to predict because of the complex nature of DILI and poor understanding of its mechanism. In this review, we summarize current knowledge and our accumulated experimental findings on the pathogenic mechanisms of DILI focusing on the reactive metabolites of drugs formed by drug-metabolizing enzymes and immune- and inflammation-related responses. Considering drug metabolism and pharmacokinetics, we have established nonclinical animal models of DILI for 10 types of clinical drug known to cause idiosyncratic DILI in humans. Using animal models, it has been shown that the formation of reactive metabolites and both innate and adaptive immunity are involved in the pathogenesis of drug hepatotoxicity. Based on information on biomarkers obtained from animal models, we developed a cell-based system that predicts the potential DILI risks of drugs. The results of these studies increased our understanding of the mechanisms of DILI and help to predict and prevent idiosyncratic DILI caused by drug candidates. PMID- 25832839 TI - [Predictive genomic markers for severe adverse drug reactions]. AB - Severe adverse drug reactions are an important issue to be considered during proper drug usage in postmarketing period. Most severe adverse reactions are idiosyncratic and unrelated to their pharmacological actions via primary targets. Although these reactions were not predictable, recent developments in the field of genomics have revealed closely associated markers responsible for some severe adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). This review demonstrates genomic biomarkers for SJS/TEN and drug-induced liver injury (DILI) that were found mainly in Japanese patients and reveal ethnic differences. We and other groups have found the following associations of SJS/TEN with susceptible drugs: 1) HLA-B*58:01 for allopurinol related cases; 2) HLA-B*15:11 and HLA-A*31:01 for carbamazepine-related cases; 3) HLA-B*51:01 for phenobarbital-related cases; 4) HLA-A*02:07 for zonisamide related cases; 5) CYP2C9*3 for phenytoin-related cases; and 6) HLA-A*02:06 for cold medicine-related cases. The allele frequencies of these related HLA types vary among Asian populations. In addition, direct (noncovalent) binding of carbamazepine or an allopurinol metabolite, oxypurinol, to the associated HLA type proteins was suggested. Associated genomic biomarkers are also summarized for DILI in Japanese and Caucasian populations. The application of these genomic biomarkers to prevent the onset of a reaction has been utilized in a few countries. However, in Japan, the package inserts only contain precautions that cite the research findings. To overcome this limitation, the following points should be addressed: 1) factors responsible for the development of SJS/TEN should be identified in addition to the above-mentioned HLA alleles; and 2) an inexpensive genotyping strategy and assay methods should be developed to provide a pharmacoeconomical viewpoint. Further research on severe adverse reactions is warranted. PMID- 25832840 TI - [Gene regulation involved in the formation of long-term memory]. AB - My former research focused on silk fibroin gene transcription. The in vivo transcription initiation site of the fibroin gene, which is similar to the site corresponding to the 5'-terminal of mature fibroin mRNA, was determined. By developing a cell-free transcription system prepared from silk glands, it was found that the upstream region of the fibroin gene is responsible for efficient transcription initiation, which has enhancer-like features. More recent research has switched my focus to cellular neurobiology to understand the molecular mechanisms of long-term memory at the level of gene expression in terms of cell differentiation. I first developed an experimental system to analyze promoter activity in primary cultured neuronal cells. Particularly focusing on the transcription regulation of the brain-derived neurotrophic factor (BDNF) gene (Bdnf), I found that the interaction of the cAMP response element-binding protein (CREB) with the CRE sequence is important for the activity-dependent activation of the Bdnf promoter. In addition, this activity-dependent transcriptional regulation occurs in cultured neurons stimulated with excitatory GABAergic inputs, which plays a critical role in promoting the step of neuronal differentiation. Finally, I found that stimulation of the G-protein coupled receptor (GPCR) effectively activates Bdnf promoter IV through selective activation of the calcineurin pathway, irrespective of the type of GPCR if the protein kinase A or C pathway is activated. This induction mechanism appears important to understand intracellular mechanisms evoked via simultaneous neurotransmission of excitatory and modulatory inputs into neurons of the brain. PMID- 25832841 TI - [Clinical pharmacology and pharmacoepidemiology for medication safety in clinical settings]. AB - In this review, optimization of individualized analgesic therapy in cancer-pain patients (1), pharmacoepidemiological studies using a hospital database (DB) (2), and other clinical and practical research studies (3) were summarized. (1) The aim of the analgesic study was to evaluate individual factors in the effects of pain-relief, and ADR of analgesics from the viewpoints of clinical pharmacokinetics and pharmacodynamics. Oxycodone, fentanyl, and gabapentin were used. For the dose escalation and ADR of oxycodone, the plasma disposition of noroxycodone regulated by CYP3A5 polymorphisms and cancer cachexia were found to be individual factors. The ADR and clinical response of fentanyl were affected by polymorphisms of CYP3A5 and ABCB1. In the pharmacokinetics of gabapentin, concomitant magnesium oxide reduced the intestinal absorption of gabapentin. (2) The aim of the DB study was to demonstrate a pharmacoepidemiological advantage using a hospital DB of a million-scale for post-marketing safety management. We tried to detect fluoroquinolone (FQ)-induced tendon disorders, because its risk ratio in Japan has not been clarified. The risk of a tendon disorder in FQ prescribed patients was 0.082% (95%CI: 0.049-0.137%), and significantly higher than that in cephalosporin-prescribed patients. The risk ratio in FQ-prescribed patients in relation to cephalosporin-prescribed patients was 6.29 (95%CI: 2.27 17.46). (3) Individual variation of plasma exposure of free linezolid and its ratio to minimum inhibitory concentration in critically ill patients, as well as three other studies, were described. In conclusion, our achievement in accurately assessing these would contribute to medication safety and the appropriate use of medicines in clinical settings. PMID- 25832842 TI - [Preparation and physicochemical study of the preservation of nanoparticles]. AB - The importance of nanoparticle formulation is increasingly recognized in supporting pharmaceutical development. Thus, maintaining nanoparticles in a constant state is a major issue. A method involving lyophilization with the addition of saccharides can be used to maintain the steady state of nanoparticles. In this study, trisaccharides, tetrasaccharides, and pentasaccharides were added to nanoparticle suspensions, followed by rehydration of the samples, which had been either dried normally or freeze-dried. The particle size after rehydration was measured. In addition, each powder was measured using a powder X-ray diffractometer and thermal analysis device to investigate the correlation between the nanoparticles' aggregation and the crystal form of saccharides. The diameter of the nanoparticles was maintained when it was freeze-dried, while particle aggregation occurred when normally dried samples were used. In addition, crystalline saccharide was not observed in the freeze-dried group, but did appear in the normally dried group. PMID- 25832843 TI - [Analysis of phthalates in aromatic and deodorant aerosol products and evaluation of exposure risk]. AB - We established an analytical method for the detection of seven phthalates, dimethyl phthalate, diethyl phthalate (DEP), benzyl butyl phthalate, di-i-butyl phthalate, dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), and di-n octhyl phthalate, using an ultra high performance liquid chromatograph equipped with a photodiode array detector. This method is quick, with minimal contamination, and was applied to the analysis of aromatic and deodorant aerosol products. Phthalates were detected in 15 of 52 samples purchased from 1999 to 2012 in Yokohama. Three types of phthalate (DEP, DBP, DEHP) were detected, and their concentrations ranged from 0.0085-0.23% DEP in nine samples, 0.012-0.045% DBP in four samples, and 0.012-0.033% DEHP in four samples. No other phthalate esters were detected. Furthermore, we estimated phthalate exposure via breathing in commonly used aromatic and deodorant aerosol products, then evaluated the associated risk. The estimated levels of phthalate exposure were lower than the tolerated daily limit, but the results indicated that aromatic and deodorant aerosol products could be a significant source of phthalate exposure. PMID- 25832844 TI - [Elevated serum lithium concentration due to switch from parenteral nutrition alone to parenteral with enteral nutrition]. AB - We report a patient with elevated serum lithium concentration caused by switching from parenteral nutrition alone to parenteral with enteral nutrition. A 73-year old female inpatient was treated with lithium carbonate 600 mg/d for manic episodes of bipolar disorder. Her serum lithium level was maintained at 0.57-0.79 mEq/L. She was administered total parenteral nutrition owing to difficulty in oral intake. Her diet contained 4.8-5.8 g/d of sodium chloride. After this, parenteral with enteral nutrition was initiated. The total sodium chloride intake decreased from 6.3 to 3.0-4.0 g/d following this change. On day 15 after initiation of parenteral with enteral nutrition, her serum lithium level increased to 1.17 mEq/L, which is closer to the upper therapeutic range limit. Therefore enteral nutrition was stopped immediately, and an electrolyte solution was administered instead of enteral nutrition. An antibiotic agent was also simultaneously administered because of infection. The total amount of sodium chloride administered was increased to 7.0 g/d during this treatment. Four days after treatment, the serum lithium level returned to 0.57 mEq/L. This case suggests that administration of appropriate sodium chloride nutrition is important during treatment with lithium carbonate, because disposition of lithium ion is paralleled to that of sodium. PMID- 25832845 TI - The relationship between bone mineral density and metabolic syndrome in peri- and post-menopausal Thai women. AB - PURPOSES: To compare the bone mineral density (BMD) measured in the lumbar spine and femoral neck in peri- and post-menopausal Thai women with and without metabolic syndrome, and to determine which contributory factors associated with metabolic syndrome influence BMD. METHODS: 427 peri- or post-menopausal Thai women were screened against the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) for Asian populations' criteria for metabolic syndrome. The BMD of those with and without metabolic syndrome was compared, and potential relationships between the factors associated with metabolic syndrome and BMD were sought. RESULTS: There was no difference in lumbar spine or femoral neck BMD between the groups (p = 0.605 and 0.415, respectively), but women with central obesity (waist circumference >=80 cm, p = 0.004 and >88 cm, p = 0.002), low serum high-density lipoprotein cholesterol (HDL C) concentration (p = 0.011) and a greater number of contributory factors to metabolic syndrome (p = 0.007) had significantly higher BMD at the femoral neck. CONCLUSIONS: A diagnosis of metabolic syndrome did not correlate with either lumbar spine or femoral neck BMD. However, higher femoral neck BMD was significantly associated with increased waist circumference, low serum HDL-C concentration and the number of contributory factors to metabolic syndrome. PMID- 25832846 TI - Zuckerkandl's tubercle of the thyroid gland: Its location in the anatomical position, and comparative morphology of the same specimens before and after fixation. AB - The aim of this study was to elucidate the definition of the borders and surface of the thyroid lobe in the anatomical position, and to compare the morphology of Zuckerkandl's tubercle (ZT) in the fresh and fixed states. One hundred thyroid lobes from 50 fresh Korean cadavers were used. The lateral border of the thyroid lobe could be defined as the most lateral margin of its anterior aspect when in the anatomical position. The posteromedial border was the margin that projected toward the trachea or tracheoesophageal groove. The lateral and posteromedial borders, and the posterior surface between these borders, could be identified in most of the fixed cadavers. The posterolateral border could only be identified in the thyroid lobe if there was compression by the internal carotid artery in cross sectioned specimens and CT images. The ZT was identifiable in 85% of both fresh and fixed specimens. It was identified mainly at the posteromedial border of the thyroid lobe when in the anatomical position, and extended to the tracheoesophageal groove or esophagus. In the fresh state, the ZT projected as a rounded cone with a usually semicircular base, but its shape was very variable in the fixed state. In the present study, the ZT was found at the posteromedial border or posterior surface of the thyroid lobe in both the fresh and fixed states, contrary to most previous reports. The location of the ZT should be established in the anatomical position to avoid confusion. PMID- 25832847 TI - Magnetic superexchange interactions: trinuclear bis(oxamidato) versus bis(oxamato) type complexes. AB - The diethyl ester of o-phenylenebis(oxamic acid) (opbaH2Et2) was treated with an excess of RNH2 in MeOH to cause the exclusive formation of the respective o phenylenebis(N(R)-oxamides) (opboH4R2, R = Me , Et , (n)Pr ) in good yields. Treatment of with half an equivalent of [Cu2(AcO)4(H2O)2] or one equivalent of [Ni(AcO)2(H2O)4] followed by the addition of four equivalents of [(n)Bu4N]OH resulted in the formation of mononuclear bis(oxamidato) type complexes [(n)Bu4N]2[M(opboR2)] (M = Ni, R = Me , Et , (n)Pr ; M = Cu, R = Me , Et , (n)Pr ). By addition of two equivalents of [Cu(pmdta)(NO3)2] to MeCN solutions of , novel trinuclear complexes [Cu3(opboR2)(L)2](NO3)2 (L = pmdta, R = Me , Et , (n)Pr ) could be obtained. Compounds have been characterized by elemental analysis and NMR/IR spectroscopy. Furthermore, the solid state structures of and have been determined by single-crystal X-ray diffraction studies. By controlled cocrystallization, diamagnetically diluted and (1%) in the host lattice of and (99%) (@ and @), respectively, in the form of single crystals have been made available, allowing single crystal ESR studies to extract all components of the g factor and the tensors of onsite (Cu)A and transferred (N)A hyperfine (HF) interaction. From these studies, the spin density distribution of the [Cu(opboEt2)](2-) and [Cu(opbo(n)Pr2)](2-) complex fragments of and , respectively, could be determined. Additionally, as a single crystal ENDOR measurement of @ revealed the individual HF tensors of the N donor atoms to be unequal, individual estimates of the spin densities on each N donor atom were made. The magnetic properties of were studied by susceptibility measurements versus temperature to give J values varying from -96 cm(-1) () over -104 cm(-1) () to -132 cm(-1) (). These three trinuclear Cu(II)-containing bis(oxamidato) type complexes exhibit J values which are comparable to and slightly larger in magnitude than those of related bis(oxamato) type complexes. In a summarizing discussion involving experimentally obtained ESR results (spin density distribution) of and , the geometries of the terminal [Cu(pmdta)](2+) fragments of determined by crystallographic studies, together with accompanying quantum chemical calculations, an approach is derived to explain these phenomena and to conclude if the spin density distribution of mononuclear bis(oxamato)/bis(oxamidato) type complexes could be a measure of the J couplings of corresponding trinuclear complexes. PMID- 25832848 TI - Kidney transplant complications from undiagnosed benign prostatic hypertrophy. AB - BACKGROUND: It is estimated that approximately 50% of males over 50 have benign prostatic hypertrophy (BPH). BPH is underappreciated in anuric patients with end stage renal disease, and failure of diagnosis in this population can lead to complications after kidney transplantation. METHODS: A single-center retrospective review of male patients over 50 yr of age transplanted from January 1, 2010, until September 30, 2013, was performed. Outcomes assessed were as follows: graft survival, urinary retention, discharge with Foley catheter, and urinary tract infection (UTI). RESULTS: Of 147 patients, 17.0% were diagnosed with BPH before transplant, 19.0% received a BPH diagnosis after transplant, and 64% did not have BPH. Compared to those without BPH, a post-transplant BPH diagnosis was associated with urinary retention during the transplant admission (0% vs. 46.4%, p < 0.01), discharge with Foley catheter (0% vs. 21.4%, p < 0.01), readmission related to urinary retention (0% vs. 46.4%, p < 0.01), and UTI (18.0% vs. 64.3%, p < 0.01). Patients with prior diagnosis of BPH and on therapy had similar outcomes to those without BPH. CONCLUSIONS: Following kidney transplant, urinary tract complications are more common in patients with BPH; however, being on medical therapy prior to transplantation diminishes the incidence of these complications significantly. PMID- 25832849 TI - Elevated Aortic Augmentation Index in Children Following Fontan Palliation: Evidence of Stiffer Arteries? AB - Children born with a functional single ventricle who undergo Fontan palliation are prone to early pump failure. Whether they develop early arterial stiffness with resultant increase in afterload is not well known. We hypothesized that the aortic stiffness is higher in pediatric Fontan patients when compared to healthy controls. A prospective study was conducted at the Children's Hospital of Michigan. Twenty-two Fontan patients (aged 6-21 years) were compared with 22 healthy controls (aged 9-17 years) selected from children referred to our clinic who had normal cardiac anatomy and function on the echocardiogram. Aortic stiffness was assessed noninvasively by measuring the aortic augmentation index (AAI) using applanation tonometry (Sphygmocor, Atcor, IL). AAI was calculated as AP/PP where augmentation pressure (AP) is the increase in aortic systolic blood pressure (BP) and pulse pressure (PP) is the difference between aortic systolic and diastolic BP. Ten patients (45 %) had hypoplastic left ventricle, and 11 (50 %) had undergone aortic arch surgery. The median AAI was significantly higher in Fontan patients when compared to controls (12.5, IQR 4.8, 17.3 vs 0, IQR -6.3, 5.8; p = 0.0003). History of aortic arch surgery and single ventricle morphology did not have a significant impact on AAI. Pediatric patients who undergo Fontan palliation have significantly higher AAI, a marker of aortic stiffness and increased afterload, compared to healthy controls. Larger longitudinal studies are warranted to elucidate the possible contribution of elevated AAI on pump failure in these patients. PMID- 25832850 TI - Vitamin D, Low-Grade Inflammation and Cardiovascular Risk in Young Children: A Pilot Study. AB - Vitamin D has anti-inflammatory properties, and deficiency is prevalent in children. There is a paucity of data regarding vitamin D status and its correlation with low-grade inflammation and vasculature. We prospectively enrolled 25 children, 9-11 years old (13 male); 21 obese. Eight atherosclerosis promoting risk factors were scored as categorical variables with the following thresholds defining abnormality: body mass index Z score >= 1.5; systolic blood pressure >= 95th percentile (for age, sex, and height); triglyceride >= 100 mg/dL; low-density lipoprotein cholesterol (LDL-C) >= 110 mg/dL; high-density lipoprotein cholesterol <= 45 mg/dL; hemoglobin A1C (HBA1C) >= 5.5; 25 hydroxyvitamin D [25(OH) D] <= 30 ng/mL, and tobacco smoke exposure. High sensitivity C-reactive protein (hsCRP) was measured to assess low-grade inflammation and classified as low- (<1 mg/L), average- (1-3 mg/L), and high-risk (>3 to <10 mg/L) groups. The proportion of children within each hsCRP group who had above threshold risk factors was calculated. Carotid artery ultrasound was performed to measure carotid artery intima-media thickness (CIMT). Median (range) for 25(OH) D was 24 (17-45) ng/mL. Eighteen were either 25 (OH) D deficient (<20 ng/mL) or insufficient (20-30 ng/mL), and seven were sufficient (>30 ng/mL). hsCRP was 1.7 (0.2-9.1) mg/L, with 11 being <1.0 mg/L, 8 between 1.0-3.0 and 6 > 3.0 to < 10.0 mg/L. Risk factor score was 3.9 +/- 1.7 out of eight. 25(OH) D levels did not correlate with hsCRP or CIMT. While vitamin D deficiency, inflammation, and risk factors coexist at a very young age, causative mechanisms remain unclear. PMID- 25832851 TI - Meir Wetzler, MD. PMID- 25832852 TI - A rare case of cerebellar agenesis: a probabilistic Constrained Spherical Deconvolution tractographic study. AB - Aim of this study is to show the potential of probabilistic tractographic techniques, based on the Constrained Spherical Deconvolution (CSD) algorithms, in recognizing white matter fiber bundle anomalies in patients with complex cerebral malformations, such as cerebellar agenesis. The morphological and tractographic study of a 17-year-old male patient affected by cerebellar agenesis was performed by using a 3Tesla MRI scanner. Genetic and neuropsychological tests were carried out. An MRI morphological study showed the absence of both cerebellar hemispheres and the flattening of the anterior side of the pons. Moreover, it showed a severe vermian hypoplasia with a minimal vermian residual. The study recognized two thin cerebellar remnants, medially in contact with the small vermian residual, at the pontine level. The third ventricle, morphologically normal, communicated with a permagna cerebello-medullary cistern. Probabilistic CSD tractography identified some abnormal and aberrant infratentorial tracts, symmetrical on both sides. In particular, the transverse pontine fibers were absent and the following tracts with aberrant trajectories have been identified: "cerebello-thalamic" tracts; "fronto-cerebellar" tracts; and ipsilateral and contralateral "spino-cerebellar" tracts. Abnormal tracts connecting the two thin cerebellar remnants have also been detected. There were no visible alterations in the main supratentorial tracts in either side. Neuropsychiatric evaluation showed moderate cognitive motor impairment with discrete adaptive compensation. Probabilistic CSD tractography is a promising technique that overcome reconstruction biases of other diffusion tensor-based approaches and allowed us to recognize, in a patient with cerebellar agenesis, abnormal tracts and aberrant trajectories of normally existing tracts. PMID- 25832853 TI - Current and future treatment options for polycythemia vera. AB - Patients with polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications and have reduced quality of life due to a substantial symptom burden that includes pruritus, fatigue, constitutional symptoms, microvascular disturbances, and bleeding. Conventional therapeutic options aim at reducing vascular and thrombotic risk, with low-dose aspirin and phlebotomy as first-line recommendations for patients at low risk of thrombotic events and cytoreductive therapy (usually hydroxyurea or interferon alpha) recommended for high-risk patients. However, long-term effective and well-tolerated treatments are still lacking. The discovery of mutations in Janus kinase 2 (JAK2) as the underlying molecular basis of PV has led to the development of several targeted therapies, including JAK inhibitors, and results from the first phase 3 clinical trial with a JAK inhibitor in PV are now available. Here, we review the current treatment landscape in PV, as well as therapies currently in development. PMID- 25832854 TI - Acute presentation of gestational diabetes insipidus with pre-eclampsia complicated by cerebral vasoconstriction: a case report and review of the published work. AB - Gestational diabetes insipidus (GDI) is a rare, self-limited complication of pregnancy. As it is related to excess placental vasopressinase enzyme activity, which is metabolized in the liver, GDI is more common in pregnancies complicated by conditions associated with liver dysfunction. We present a case of a 41-year old woman at 38 weeks' gestation who presented with pre-eclampsia with severe features, including impaired liver function and renal insufficiency. Following cesarean section she was diagnosed with GDI, which was further complicated by cerebral vasoconstriction as demonstrated by magnetic resonance angiography. This case raises the possibility that cerebral vasoconstriction may be related to the cause of GDI. A high index of suspicion of GDI should be maintained in patients who present with typical signs and symptoms, especially in the setting of pregnancy complications associated with liver dysfunction. PMID- 25832857 TI - Insufficient sex description of cells supplied by commercial vendors. PMID- 25832856 TI - Schizophrenia-like topological changes in the structural connectome of individuals with subclinical psychotic experiences. AB - Schizophrenia is often regarded as a "dysconnectivity" disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population-based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion-weighted MRI. Whole-brain structural connectomes were derived and a range of global and local GT-metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair-wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair-wise connections illustrates that, at less severe stages of psychosis, white-matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness. PMID- 25832858 TI - Hypertension. AB - Raised blood pressure is the biggest single contributor to the global burden of disease and to global mortality. The numbers of people affected and the prevalence of high blood pressure worldwide are expected to increase over the next decade. Preventive strategies are therefore urgently needed, especially in less developed countries, and management of hypertension must be optimised. Genetic advances in some rare causes of hypertension have been made lately, but the aggregate effect on blood pressure of all the genetic loci identified to date is small. Hence, intervention on key environmental determinants and effective implementation of trial-based therapies are needed. Three-drug combinations can control hypertension in about 90% of patients but only if resources allow identification of patients and drug delivery is affordable. Furthermore, assessment of optimal drug therapy for each ethnic group is needed. PMID- 25832860 TI - Proposed method for internal electron therapy based on high-intensity laser acceleration. AB - Radiotherapy is one of the main methods to treat cancer. However, due to the propagation pattern of high-energy photons in tissue and their inability to discriminate between healthy and malignant tissues, healthy tissues may also be damaged, causing undesired side effects. A possible method for internal electron therapy, based on laser acceleration of electrons inside the patient's body, is suggested. In this method, an optical waveguide, optimized for high intensities, is used to transmit the laser radiation and accelerate electrons toward the tumor. The radiation profile can be manipulated in order to create a patient specific radiation treatment profile by changing the laser characteristics. The propagation pattern of electrons in tissues minimizes the side effects caused to healthy tissues. A simulation was developed to demonstrate the use of this method, calculating the trajectories of the accelerated electron as a function of laser properties. The simulation was validated by comparison to theory, showing a good fit for laser intensities of up to 2 * 10(20) (W/cm2), and was then used to calculate suggested treatment profiles for two tumor test cases (with and without penetration to the tumor). The results show that treatment profiles can be designed to cover tumor area with minimal damage to adjacent tissues. PMID- 25832859 TI - Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis. AB - OBJECTIVE: To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. METHODS: Patients who had completed 24 weeks of TCZ-SC (162 mg/2 weeks) or TCZ-IV (8 mg/kg/4 weeks) monotherapy in the double-blind period of the MUSASHI study were enrolled in an 84-week open-label extension period. All received TCZ SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). RESULTS: Overall, 319 patients received >=1 dose of TCZ-SC during the open-label extension period; 160 switched from TCZ-IV to TCZ-SC (TCZ IV/SC) and 159 continued TCZ-SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing >=70 kg, the percentage with a sufficient serum TCZ concentration (>=1 MUg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. CONCLUSION: Efficacy is adequately maintained in most patients switching from TCZ-IV (8 mg/kg/4 weeks) to TCZ-SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ-IV can switch to TCZ-SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight. PMID- 25832862 TI - Ionization methods in mass spectrometry. PMID- 25832861 TI - Inhibition of ocular neovascularization by co-inhibition of VEGF-A and PLGF. AB - BACKGROUND/AIMS: Age-related macular degeneration (AMD) appears to be a disease with increasing incidence in Western countries and may develop into acquired blindness. Choroidal neovascularization (CNV) is the most frequent cause for AMD, and is commonly induced by regional inflammation. Past studies have highlighted vascular endothelial growth factor A (VEGF-A) as a major trigger for CNV. However, studies on the associated angiogenic factors other than VEGF-A are lacking. METHODS: Here, we used a well-established laser burn (LB)-induced experimental CNV mouse model to study the molecular mechanisms underlying the development of CNV after ocular injury. We analyzed vessel density by lectin labeling. We isolated macrophages, endothelial cells and other cell types by flow cytometry, and analyzed levels of different angiogenic factors in these populations. We used antisera against VEGF-A (aVEGF) and/or antisera against placental growth factor (PLGF; aPLGF) to antagonize CNV. We used an antibody driven toxin to selectively eliminate macrophages to evaluate the role of macrophages in CNV. We also examined expression of PLGF in macrophage subtypes. RESULTS: The choroidal vessel density increased significantly 7 days after LB. LB increased significantly the levels of VEGF-A and PLGF in mouse eyes. Treatment with aVEGF significantly blunted increases in vessel density by LB. Treatment with aPLGF alone did not significantly reduce increases in vessel density. However, aPLGF significantly increased the inhibitory effects of aVEGF on vessel density increases. While VEGF-A was produced by endothelial cells, macrophages and other types at similar levels, PLGF seemed to be predominantly produced by macrophages. Selective macrophage depletion significantly reduced CNV. M2, but M1 macrophages produced high levels of PLGF. CONCLUSIONS: Together, our data suggest a previously unappreciated role of PLGF in coordination with VEGF-A to regulate CNV during ocular injury. Our study highlights macrophages and their production of PLGF as novel targets for CNV therapy. PMID- 25832863 TI - Identification of potential therapeutic target genes, key miRNAs and mechanisms in acute myeloid leukemia based on bioinformatics analysis. AB - The study was aimed to explore the underlying mechanisms and identify the potential target genes and key miRNAs for acute myeloid leukemia (AML) treatment by bioinformatics analysis. The microarray data of GSE9476 were downloaded from Gene Expression Omnibus database. A total of 64 samples, including 26 AML and 38 normal samples, were used to identify differentially expressed genes (DEGs) between AML and normal samples. The functional enrichment analysis was performed, and protein-protein interaction (PPI) network of the DEGs was constructed by Cytoscape software. Besides, the target miRNAs for DEGs were identified. Totally, 323 DEGs were identified, including 87 up-regulated and 236 down-regulated genes. Not only up-regulated genes but also down-regulated genes were related to hematopoietic-related functions. Besides, down-regulated genes were also enriched in primary immunodeficiency pathway. Tumor necrosis factor (TNF), interleukin 7 receptor (IL7R), lymphocyte-specific protein tyrosine kinase (LCK), CD79a molecule and immunoglobulin-associated alpha (CD79A) were identified in these functions. TNF and LCK were hub nodes in PPI networks. miR-124 and miR-181 were important miRNAs in this study. The hematopoietic-related functions and primary immunodeficiency pathway may be associated with AML development. Genes, such as TNF, IL7R, LCK and CD79A, may be potential therapeutic target genes for AML, and miR-124 and miR-181 may be key miRNAs in AML development. PMID- 25832864 TI - Hydroxyethyl starch 200/0.5 decreases circulating tumor cells of colorectal cancer patients and reduces metastatic potential of colon cancer cell line through inhibiting platelets activation. AB - Platelets play an important role in metastasis of circulating tumor cells (CTCs). It has been demonstrated that hydroxyethyl starch (HES) inhibits platelets function. However, the effect of HES on CTCs in patients with colorectal cancer remains unclear. We compared the effects of HES 200/0.5 and HES 130/0.4 on CTCs and platelets activation of colorectal patients in this study. Additionally, the effects of HES 200/0.5 or HES 130/0.4 on metastasis ability of colon cancer cell line that stimulated by activated platelets have been explored. In vivo, 90 patients undergoing colorectal cancer radical surgery received randomly 15 mL/kg of HES 200/0.5 (n = 45) or HES 130/0.4 (n = 45) infusion before surgery. Platelet glycoprotein IIb/IIIa (GPIIb/IIIa), CD62P and platelets aggregation rate (PAR) were evaluated pre-, intra- and postoperatively. Cytokeratin-20 (CK-20) mRNA was detected by reverse transcriptase polymerase chain reaction before and after surgery. In vitro, colon cancer SW480 cells were incubated with activated platelets in the presence or absence HES 200/0.5 or HES 130/0.4. The metastasis ability of SW480 cells was assessed by Transwell assay. The results showed that CK-20 mRNA positive rate in HES 200/0.5 group after surgery was decreased significantly as compared to group HES 130/0.4 (chi (2) = 6.164, P = 0.013). Simultaneously, a more pronounced inhibition of platelets activation was observed in group HES 200/0.5. A positive correlation between platelets activation marker and CK-20 mRNA positive rate was found. In vitro, HES 200/0.5, but not HES 130/0.4, decreased the invasion and migration ability of SW480 cells that induced by activated platelets. Besides, the expression of GPIIb/IIIa, CD62P and PAR was inhibited more strongly in group HES 200/0.5 than those in group HES 130/0.4. In summary, we found that HES 200/0.5 significantly decreased CTCs of patients undergoing colorectal cancer radical surgery as compared to HES 130/0.4, which might be associated with inhibiting platelets activation of HES 200/0.5. Furthermore, HES 200/0.5, but not HES 130/0.4, reduced the metastatic potential of colon cell line stimulated by activated platelets through depressing platelets activation. Modulation of platelets activity may be a novel strategy to minimize the risk of metastasis during surgery. PMID- 25832865 TI - Identifications of genetic differences between metastatic and non-metastatic osteosarcoma samples based on bioinformatics analysis. AB - To investigate the differences in gene expression level between metastatic and non-metastatic osteosarcoma (OS) samples and the potential mechanism. Gene expression profile data GSE9508 were downloaded from Gene Expression Omnibus database to identify the differentially expressed genes (DEGs) between metastatic, non-metastatic OS samples, and normal control samples via SAM method. Function expression matrix of the DEGs was constructed by calculating the functional node scores based on the genes sets collected from the pathways recorded in MsigDB database. Next, t test was applied to screen the differentially expressed functional nodes between each two kinds of samples. Finally, we compared the significant genes between selected DEGs and genes in differentially expressed functional nodes. There were 79 up-regulated DEGs between non-metastatic OS and normal samples, 380 up-regulated and 134 down regulated DEGs between the metastatic OS and normal samples, and 761 up-regulated plus 186 down-regulated DEGs between metastatic and non-metastatic OS samples. A total of 3846 functional gene sets were collected to form the function expression profile matrix. The numbers of differentially expressed functional nodes between non-metastatic OS and normal samples, metastatic OS and normal samples, and metastatic and non-metastatic OS samples were 8, 39, and 5, respectively. The gene level difference between metastatic and non-metastatic OS samples can be distinguished using bioinformatics analysis. TGFB1, LFT3, KDM1A, and KRAS genes have the potential to be used as biomarkers for OS; however, further analysis is needed to verify the current results. PMID- 25832868 TI - Paradoxical worsening of pemphigus vulgaris following rituximab therapy. PMID- 25832867 TI - Ubiquitin-conjugating enzyme E2C regulates apoptosis-dependent tumor progression of non-small cell lung cancer via ERK pathway. AB - The oncogenic role of ubiquitin-conjugating enzyme E2C (UBE2C) had been identified in some types of human tumors, while the clinical and biological role of UBE2C in non-small cell lung cancer (NSCLC) is still elusive. Here, we have determined the specific role of UBE2C in NSCLC. Western blot and qRT-PCR were used for detecting the mRNA level and protein level of UBE2C in NSCLC samples and cell lines, respectively. Lentivirus product was used to conduct loss of function assay. qRT-PCR array was employed to detect potential downstream genes regulated by UBE2C. As the result, UBE2C mRNA level was approximately threefold overexpression in NSCLC tissues compared with normal tissues, while a sharp change was detected at protein level. Overexpression of UBE2C in lung cancer samples was correlated with advanced pathological stage. UBE2C regulated cell growth in an apoptosis-dependent way. PCR Array analysis revealed that UBE2C regulated the expression of genes associated with tumor growth, apoptosis, and angiogenesis. Furthermore, UBE2C could regulate phospho-ERK1/2 level but not STAT3, YAP, or AKT pathway, which was accompanied with the classic function of ERK pathway in cell growth and apoptosis. In conclusion, our results indicated UBE2C might be a novel therapeutic target in NSCLC. PMID- 25832866 TI - Stromal interaction molecule 1 (STIM1) silencing inhibits tumor growth and promotes cell cycle arrest and apoptosis in hypopharyngeal carcinoma. AB - As an important pathway maintaining the balance of intracellular calcium (Ca(2+)), store-operated Ca(2+) entry (SOCE) is critical for cellular functions. Stromal interaction molecule 1 (STIM1), a key component of SOCE, plays a dual role as an endoplasmic reticulum Ca(2+) receptor and an SOCE exciter. Aberrant expression of STIM1 could be discovered in several human cancer cells. However, the role of STIM1 in regulating human hypopharyngeal carcinoma still remains unclear. Real-time polymerase chain reaction (PCR) was used to detect expression of STIM1 in human hypopharyngeal carcinoma cell line FaDu. STIM1 on FaDu cells was knocked down by lentiviral transduction method. The biological impacts after knocking down of STIM1 on FaDu cells were investigated in vitro and in vivo. The result of real-time PCR showed that STIM1 was expressed in FaDu cells. Lentiviral transduction efficiently downregulated the expression of STIM1 in FaDu cells at both mRNA and protein levels. Significant downregulation of STIM1 on FaDu cells inhibited cell proliferation, induced cell cycle arrest in G0/G1 phase, promoted cell apoptosis, and restrained cell growth rate. The antigrowth effect of STIM1 silencing was also discovered in FaDu hypopharyngeal tumor model. Our findings indicate that STIM1 is likely to become a new therapeutic target for hypopharyngeal carcinoma treatment. PMID- 25832869 TI - Cervical cancer: what is the optimal age for routine testing? PMID- 25832870 TI - Actual benefit of chemo-hormonal therapy in non-castrate metastatic prostate cancer. PMID- 25832871 TI - Monitor cancer progression without surgery, meet the technique's inventor. PMID- 25832872 TI - Targeting leukemic stem cells with multifunctional bioactive polypeptide nanoparticles. PMID- 25832873 TI - The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma. AB - Ixazomib is an investigational, reversible 20S proteasome inhibitor. It is the first oral proteasome inhibitor under clinical investigation in multiple myeloma (MM). Under physiological conditions, the stable citrate ester drug substance, ixazomib citrate (MLN9708), rapidly hydrolyzes to the biologically active boronic acid, ixazomib (MLN2238). Preclinical studies have demonstrated antitumor activity in MM cell lines and xenograft models. In Phase I/II clinical studies ixazomib has had generally manageable toxicities, with limited peripheral neuropathy observed to date. Preliminary data from these studies indicate ixazomib is active as a single agent in relapsed/refractory MM and as part of combination regimens in newly diagnosed patients. Phase III studies in combination with lenalidomide-dexamethasone are ongoing. PMID- 25832874 TI - Pazopanib for the treatment of renal cell carcinoma. AB - The incidence and mortality from renal cell cancer (RCC) is increasing. RCC tumors are particularly vascular in nature as a result of disruption of the VHL gene and/or its upstream pathway leading to upregulation of the hypoxia-inducible factor transcription factor. The hypoxia-inducible factor pathway drives angiogenesis by upregulating VEGF and bFGF, amongst other proangiogenic downstream target genes. Therapies which target angiogenesis have been successful in treating metastatic RCC (mRCC) and the receptor tyrosine kinase inhibitor, pazopanib, is licensed for first line treatment of mRCC. This review details the past, current and future roles of pazopanib in the treatment of mRCC. PMID- 25832875 TI - Adjuvant hormonal therapy and fertility preservation in premenopausal breast cancer: a survey among Italian oncologists. AB - BACKGROUND: Increasing age of first pregnancy among Italian women with premenopausal breast cancer makes adjuvant hormonal therapy a hot topic, justifying a survey on the therapeutic approach of Italian oncologists. MATERIALS & METHODS: From April to July 2012, an 11-item electronic questionnaire was submitted to Italian oncologists and 611 out of 974 invited filled questionnaires were collected from all over Italy. RESULTS: In total, 97.7% of patients aged <40 years needing only hormonal therapy would receive both tamoxifen and luteinizing hormone-releasing hormone agonists (LHRHa); 2.3% tamoxifen or LHRHa alone. For the majority of oncologists LHRHa was also the preferred choice to preserving fertility. CONCLUSION: Results are rather consistent with major guidelines but with a greater use of LHRHa and aromatase inhibitor. PMID- 25832876 TI - Use of gemcitabine-platinum in Indian patients with advanced gall bladder cancer. AB - BACKGROUND: Gemcitabine-platinum (Gem-P) is the current standard for patients with advanced gall bladder cancer. MATERIALS & METHODS: This is retrospective analysis of a prospectively maintained database of 210 patients with advanced gall bladder cancer treated with Gem-P between January 2012 and September 2013. RESULTS: Median age was 53 years, 65.2% females. In total,158 patients had metastatic and 52 had locoregional disease. Median number of cycles was 5 (1-12). At a median follow-up of 10 months, median overall survival/progression-free survival was 10/5 months, respectively. On multivariate analysis, patients who underwent prior surgery for primary and locoregional disease had a significantly better progression-free survival and those with locoregional disease had a significantly better overall survival. A total of 45.7% received second-line chemotherapy. CONCLUSION: Use of Gem-P in Indian patients leads to slightly worse outcomes suggesting an aggressive biology. PMID- 25832877 TI - MGMT promoter methylation status in brain metastases from colorectal cancer and corresponding primary tumors. AB - BACKGROUND: Brain metastases (BM) from colorectal cancer are usually associated with poor prognosis. The aim of this retrospective study is to evaluate MGMT promoter methylation in BM and their corresponding primary colorectal cancer tumors. MATERIALS & METHODS: MGMT promoter methylation status was assessed by pyrosequencing in 53 consecutive patients resected for BM. A concordance analysis between BM and matched primary tumor was performed in 39 cases. RESULTS: MGMT methylation was found in 34 (64.2%) BM and in 25 corresponding primary tumors (64.1%). Median survival after neurosurgery was independent from MGMT promoter methylation (163 days for those with methylated MGMT versus 193 days for the unmethylated). CONCLUSION: Epigenetic MGMT promoter methylation was common and the concordance between primary and secondary lesions was high. PMID- 25832878 TI - Molecular features and clinical outcome of lung malignancies in very young people. AB - INTRODUCTION: We describe the clinical features, outcome and incidence of druggable targets of lung cancers in patients <= 40 years old. MATERIALS & METHODS: Young patients were compared with two other groups (41-64 and >= 65 years). Neuroendocrine tumors, adenocarcinoma and non-adenocarcinoma/unspecified non-small-cell lung cancer were analyzed separately. Molecular characteristics of adenocarcinoma were evaluated in a subset of young patients. RESULTS: Of 2847 patients with lung cancer, 100 were <= 40 years old. The young group contained more women, never-smokers and patients presenting with advanced disease. The commonest tumor in young patients was adenocarcinoma. In total, 19 of 34 young patients with adenocarcinoma had tumors with specific molecular alterations. CONCLUSION: Lung cancers in young patients have distinctive features but outcomes similar to those in older patients. PMID- 25832880 TI - 'Liver-first' approach for metastatic colorectal cancer. AB - The liver-first approach was proposed for the first time in 2006 to obtain resectability of stage IV colorectal cancer patients and complete the therapeutic plan. From then some groups have used this new revolutionary approach reporting promising results. Other alternative strategies have been proposed for metastatic patients. The authors reviewed the literature weighing the pros and cons of each strategy proposed to manage these advanced tumor stages. The therapeutic options are analyzed in the light of oncologic problems and evidence. Also problems, questions and perspectives are given. Even if the 'liver-first' approach seems to be a promising strategy, the ideal diagnostic-therapeutic flowchart for metastatic colorectal cancer is still difficult to standardize. The great heterogeneity of this population of patients is one of the main problems. A 'tailored approach' philosophy is necessary to calibrate, in a multidisciplinary setting, a case-by-case choice of therapeutic options. PMID- 25832879 TI - Targeted therapy for thymic epithelial tumors: a new horizon? Review of the literature and two cases reports. AB - Surgical resection remains the cornerstone of therapy for early-stage thymic epithelial tumors (TETs), while in advanced or recurrent forms, a multimodality approach incorporating radiation and chemotherapy is required. Given the absence of effective treatment options for metastatic/refractory TETs and the poor related prognosis, there is a compelling need to identify promising 'drugable' molecular targets. Initial reports of activity from targeted agents in TETs derived from anecdotal cases have been often associated with specific activating mutations. Only in recent years, several agents have been formally investigated into prospective clinical trials, with varying success rates. We reviewed the literature on targeted therapy in TETs along with two cases of thymoma achieving striking responses to sorafenib in combination with lapatinib. PMID- 25832881 TI - Personalized treatment of early-stage non-small-cell lung cancer: the challenging role of EGFR inhibitors. AB - Adjuvant cisplatin-based chemotherapy significantly improves outcomes of completely resected early-stage non-small-cell lung cancer (NSCLC) patients. However, its effect on overall survival is limited and may be unsuitable for many patients due to toxicity. Targeted therapies and individualization of adjuvant treatment offer the potential to improve curability and extend survival of these patients while decreasing toxicity. Here we review Phase II and III studies examining the role of EGF receptor inhibitors, including tyrosine kinase inhibitors and the monoclonal antibody cetuximab, as adjuvant therapy in resected patients or as part of multimodality treatment for stage III NSCLC. Recent results from genotype-directed adjuvant tyrosine kinase inhibitors trials including early-stage NSCLC patients with EGFR mutations are promising, but more data are needed to support their use in this setting. PMID- 25832882 TI - Temozolomide-based combination for advanced neuroendocrine neoplasms: a systematic review of the literature. AB - BACKGROUND: In this systematic review, we explored the value of using temozolomide (TMZ)-based combinations for advanced neuroendocrine neoplasms (NENs). METHODS: Database search were conducted using the terms 'NENs' and 'TMZ' and 'systemic therapy.' Outcomes of interest included progression-free survival and overall survival, toxicities and tumor response. RESULTS: In total, 16 trials including 348 patients were included. Median progression-free survival ranged from 6 to 31 months. The disease control rate ranged from 65 to 100%. Frequently reported grade 3/4 toxicities were leukopenia, lymphopenia and elevated transaminases. CONCLUSION: The published clinical data suggest that TMZ-based combination with some anticancer agents (especially capecitabine) could be an effective treatment option for advanced low-intermediate grade NENs. PMID- 25832884 TI - Investigation of thermodynamic, dynamic, and structural properties of H2 adsorption on a Ag-Au nanoalloy with a carbon nanotube support. AB - We have performed MD simulations to investigate H(2) adsorption on Ag-Au nanoclusters with the different Au mole fractions supported on the carbon nanotubes with the different diameters. Our thermodynamic results shown that the saturation value of coverage and the enthalpy of adsorption increases as the mole fraction of Au is increased. Our structural results showed that the presence of the H(2) gas exerts a significant effect on the nanocluster surface atoms and tends to stabilize the surface atoms on the nanocluster. Also, the structural changes are irreversible in such a way that by gradually decreasing the pressure to zero, the nanocluster geometry is not reversed to its initial structure in vacuum conditions. We have also shown that the nanoclusters have smaller values of the self-diffusion coefficients in presence of H(2) molecules than those values in the initial state (vacuum), which is due to the increasing of the interface structure between the nanocluster and the nanotube. PMID- 25832883 TI - Genetic Vulnerability to Menthol Cigarette Preference in Women. AB - BACKGROUND: Smokers may prefer menthol cigarettes to mask the bitter taste of nicotine. Variation in the taste receptor gene, TAS2R38, may contribute to preference for menthol cigarettes. AIMS: To determine whether two common haplotypes of TAS2R38 (proline-alanine-valine [PAV] and alanine-valine-isoleucine [AVI]), which have been associated, respectively, with bitter taste or a lack of bitter taste produced by propylthiouracil, are associated with preference for menthol cigarettes. METHODS: Data on smoking and blood for DNA extraction and genotyping were obtained from 323 pregnant non-Hispanic or Hispanic Caucasian smokers. We genotyped three TAS2R38 single nucleotide polymorphisms (rs713598, rs1726866, and rs10246939) and constructed haplotypes. We examined associations between menthol preference and the frequency and distribution of the AVI and PAV haplotypes among study participants. RESULTS: Participants smoked an average of 16 cigarettes per day before pregnancy. The PAV and AVI haplotype frequencies were 48% and 45%, respectively. Non-Hispanic women were less likely than Hispanic women to smoke menthol cigarettes. As hypothesized, the frequency of the PAV haplotype was greater in menthol than non-menthol smokers in both non-Hispanics (54% vs. 30%; chi(2) = 13.04, P < .001) and Hispanics (53% vs. 25%; chi(2) = 5.77, P = .016). This effect persisted after controlling for potential confounders in multivariate logistic regression. Menthol smokers had a greater number of PAV haplotypes/individual than non-menthol smokers [non-Hispanics odds ratio (OR) = 3.02 (1.56-5.85); P = .001; Hispanics OR = 3.60 (1.23-10.56); P = .020]. CONCLUSIONS: These preliminary data support the hypothesis that a genetic propensity to experience heightened bitter taste perception increases the preference for menthol cigarettes. PMID- 25832885 TI - Anticancer properties of novel 4-methylene-1,2-diphenylpyrazolidin-3-ones. AB - The limited success of the currently used antitumor therapies is the driving force for organic chemists to seek new lead structures with anticancer potential. Two alpha-methylene-gamma-lactams with an additional nitrogen atom in the lactam ring, 5-vinyl-1,2-diphenyl-4-methylenepyrazolidin-3-one (2a) and 5-phenyl-1,2 diphenyl-4-methylenepyrazolidin-3-one (2b) have been synthesized. Their anticancer activity was assessed in MCF-7 cells. Both compounds inhibited cell proliferation and induced DNA damage and apoptosis, with 2a being the more potent analog. Synergistic effects of 2a used in combination with known anticancer drugs, 5-fluorouracil, taxol, and oxaliplatin were evaluated. Compound 2a significantly enhanced the antitumor action of oxaliplatin and 5-fluorouracil, but not taxol. PMID- 25832886 TI - Experiences in Disseminating Evidence-Based Prevention Programs in a Real-World Setting. AB - The primary aim of family-based prevention programs is to promote children's health. Unfortunately, it is difficult to reach families with such evidence-based prevention programs (EBP). Therefore, implementing EBP on a population level could be a promising approach to reach more families, including those faced with socioeconomic challenges who are usually less likely to participate in randomized controlled trials (RCT). Is a population rollout appropriate to reach more and different families than those participating in RCT, especially those representative of the target population? We implemented three EBP in a city in an uncontrolled trial. The effects of this population rollout were tracked on the level of the participating families and on the level of all families living in the city. More than 3480 families (30 % of the population) with children up to 12 years of age participated based on practitioner report. Analyses indicate that a greater percentage of low socioeconomic-status families attended a program compared with a randomly surveyed sample from the city's general population. The sizes of the within-subject effect for parental strategies, child behavior problems, and children's quality of life for a subsample of n = 411 families were similar to those of other uncontrolled EBP studies. The study contributes to highly needed type 2 translation research. The population-based dissemination of EBP could be a promising approach to reach families at risk. However, there are considerable barriers to the implementation process, which currently limit the effectiveness of this rollout in a community. PMID- 25832888 TI - Species identification of processed animal proteins (PAPs) in animal feed containing feed materials from animal origin. AB - Since June 2013 the total feed ban of processed animal proteins (PAPs) was partially lifted. Now it is possible to mix fish feed with PAPs from non ruminants (pig and poultry). To guarantee that fish feed, which contains non ruminant PAPs, is free of ruminant PAPs, it has to be analysed with a ruminant PCR assay to comply with the total ban of feeding PAPs from ruminants. However, PCR analysis cannot distinguish between ruminant DNA, which originates from proteins such as muscle and bones, and ruminant DNA, which comes from feed materials of animal origin such as milk products or fat. Thus, there is the risk of obtaining positive ruminant PCR signals based on these materials. The paper describes the development of the combination of two analysis methods, micro dissection and PCR, to eliminate the problem of 'false-positive' PCR signals. With micro-dissection, single particles can be isolated and subsequently analysed with PCR. PMID- 25832887 TI - CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. AB - BACKGROUND: von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/METHODS: In 364 type 1 VWD and 240 type 2 VWD patients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. RESULTS: In type 1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0 IU dL(-1) per allele; 95% confidence interval [CI] -6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3 IU dL(-1) per allele; 95% CI -7.9 to 0.6) and lower VWF:Act (-5.7 IU dL(-1) per allele; 95% CI -10.9 to -0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. CONCLUSIONS: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD. PMID- 25832889 TI - The role of cytoskeleton and adhesion proteins in the resistance to photodynamic therapy. Possible therapeutic interventions. AB - It is known that Photodynamic Therapy (PDT) induces changes in the cytoskeleton, the cell shape, and the adhesion properties of tumour cells. In addition, these targets have also been demonstrated to be involved in the development of PDT resistance. The reversal of PDT resistance by manipulating the cell adhesion process to substrata has been out of reach. Even though the existence of cell adhesion-mediated PDT resistance has not been reported so far, it cannot be ruled out. In addition to its impact on the apoptotic response to photodamage, the cytoskeleton alterations are thought to be associated with the processes of metastasis and invasion after PDT. In this review, we will address the impact of photodamage on the microfilament and microtubule cytoskeleton components and its regulators on PDT-treated cells as well as on cell adhesion. We will also summarise the impact of PDT on the surviving and resistant cells and their metastatic potential. Possible strategies aimed at taking advantage of the changes induced by PDT on actin, tubulin and cell adhesion proteins by targeting these molecules will also be discussed. PMID- 25832890 TI - Development of a multi-epitope antigen of S protein-based ELISA for antibodies detection against infectious bronchitis virus. AB - An indirect enzyme-linked immunosorbent assay (ELISA) method based on a novel multi-epitope antigen of S protein (SE) was developed for antibodies detection against infectious bronchitis virus (IBV). The multi-epitope antigen SE protein was designed by arranging three S gene fragments (166-247 aa, S1 gene; 501-515 aa, S1 gene; 8-30 aa, S2 gene) in tandem. It was identified to be approximately 32 kDa as a His-tagged fusion protein and can bind IBV positive serum by western blot analysis. The conditions of the SE-ELISA method were optimized. The optimal concentration of the coating antigen SE was 3.689 MUg/mL and the dilution of the primary antibodies was identified as 1:1000 using a checkerboard titration. The cut-off OD450 value was established at 0.332. The relative sensitivity and specificity between the SE-ELISA and IDEXX ELISA kit were 92.38 and 89.83%, respectively, with an accuracy of 91.46%. This assay is sensitive and specific for detection of antibodies against IBV. PMID- 25832891 TI - Flavobacterium spartansii induces pathological changes and mortality in experimentally challenged Chinook salmon Oncorhynchus tshawytscha (Walbaum). PMID- 25832893 TI - How to implement quality indicators successfully in palliative care services: perceptions of team members about facilitators of and barriers to implementation. AB - PURPOSE: There is an increasing demand for the use of quality indicators in palliative care. With previous research about implementation in this field lacking, we aimed to evaluate the barriers to and facilitators of implementation. METHODS: Three focus group interviews were organized with 21 caregivers from 18 different specialized palliative care services in Belgium. Four had already worked with the indicators during a pilot study. The focus group discussions were transcribed verbatim and analyzed using the thematic framework approach. RESULTS: The caregivers anticipated that a positive attitude by the team towards quality improvement, the presence of a good leader, and the possible link between quality indicators and reimbursement might facilitate the implementation of quality indicators in specialized palliative care services. Other facilitators concerned the presence of a need to demonstrate quality of care, to perform improvement actions, and to learn from other caregivers and services in the field. A negative attitude by caregivers towards quality measurement and a lack of skills, time, and staff were mentioned as barriers to successful implementation. CONCLUSION: Palliative caregivers anticipate a number of opportunities and problems when implementing quality indicators. These relate to the attitudes of the team regarding quality measurement; the attitudes, knowledge, and skills of the individual caregivers within the team; and the organizational context and the economic and political context. Training in the advantages of quality indicators and how to use them is indispensable, as are structural changes in the policy concerning palliative care, in order to progress towards systematic quality monitoring. PMID- 25832892 TI - Being cool: how body temperature influences ageing and longevity. AB - Temperature is a basic and essential property of any physical system, including living systems. Even modest variations in temperature can have profound effects on organisms, and it has long been thought that as metabolism increases at higher temperatures so should rates of ageing. Here, we review the literature on how temperature affects longevity, ageing and life history traits. From poikilotherms to homeotherms, there is a clear trend for lower temperature being associated with longer lifespans both in wild populations and in laboratory conditions. Many life-extending manipulations in rodents, such as caloric restriction, also decrease core body temperature. Nonetheless, an inverse relationship between temperature and lifespan can be obscured or reversed, especially when the range of body temperatures is small as in homeotherms. An example is observed in humans: women appear to have a slightly higher body temperature and yet live longer than men. The mechanisms involved in the relationship between temperature and longevity also appear to be less direct than once thought with neuroendocrine processes possibly mediating complex physiological responses to temperature changes. Lastly, we discuss species differences in longevity in mammals and how this relates to body temperature and argue that the low temperature of the long lived naked mole-rat possibly contributes to its exceptional longevity. PMID- 25832894 TI - Potential factors associated with perceived cognitive impairment in breast cancer survivors. AB - PURPOSE: This cross-sectional study was designed to explore potential factors associated with perceived cognitive impairment (PCI) in breast cancer survivors compared to controls and gain insight into perceived levels of severity for cognitive complaints. METHODS: Women (N = 363, 317: breast cancer, 46: healthy controls) completed demographic questionnaire, MD Anderson Symptom Inventory, Attentional Function Index, and Functional Assessment for Cancer Therapy Cognition. Group classification included pre-chemotherapy, current chemotherapy, and postchemotherapy (<1, >1- < 2, >2- < 5, >5 years). RESULTS: A significant group effect was seen for PCI (F 6, 355 = 7.01, p < 0.0001). Controls reported less PCI than all other groups. Neuropathy was inversely correlated with PCI (r = -0.23; p < 0.0001) for participants with breast cancer. A significant association was demonstrated between exercise frequency and PCI in women exposed to chemotherapy (F 3, 135 = 3.78, p < 0.05). A multiple linear regression model built using forward selection methods explained 24 % of the variance (adjusted R (2)) for PCI in breast cancer participants and included group, body mass index (BMI), exercise, fatigue, and distress. Exercise frequency moderated the relationship between BMI and PCI for breast cancer participants (F 3, 198 = 2.4, p = 0.07) and reduced the negative effects of high BMI. The moderating effect of exercise was significant (F 3, 133 = 3.1, p = 0.03) when limited to participants exposed to chemotherapy. CONCLUSIONS: PCI decreased for women >5 years postchemotherapy. Overweight survivors who exercised frequently reported less PCI than sedentary survivors. Study results provide support for a relationship between BMI and PCI in breast cancer survivors and exercise as a potential intervention for cognitive complaints. Further investigation of the influence of weight and exercise on cognitive function is warranted. PMID- 25832895 TI - Exercise preferences, levels and quality of life in lung cancer survivors. AB - PURPOSE: Lung cancer poses multiple challenges to adopting an exercise (EX) program, and the ideal timing of an EX program to improve quality of life (QoL) is unknown. This study explored the EX counselling and programming preferences of lung cancer survivors and examined the association of EX before diagnosis, during treatment and after treatment on QoL. METHODS: Cross-sectional, retrospective survey design in a sample of lung cancer survivors. EX preferences were compared between patients who had received radical chest radiation or lung surgery versus those who had not. EX was measured by self-report using the Godin Leisure Time Exercise Questionnaire (GLTEQ). Separate linear regression models, controlling for significant covariates, examined the association of EX at each time point with scores on QoL measures and subscales. RESULTS: Participants (N = 66, M age 66.4 +/- 9.1) were between 4 months and 11.5 years after lung cancer diagnosis (M = 31.7 +/- 22.9 months). Patients who had lung surgery were more likely to prefer to start an EX program during adjuvant treatment than those who did not have surgery (t(33) = 2.43, p = .025). Compared to prediagnosis EX (M = 36.7 +/- 56.0 MET h/week), EX levels declined significantly during (M = 12.4 +/- 25.0 MET h/week) and after (M = 12.3 +/- 17.4 MET h/week) treatment (p < .05). After controlling for disease stage and income, regression models were not significant, but EX after treatment was a significant individual predictor of fatigue (beta = .049, p = .006) and QoL measured by the Chronic Respiratory Disease Questionnaire (beta = .163, p = .025). CONCLUSIONS: Lung cancer patient preferences indicate that EX program timing should take into account whether the patient has undergone surgery. Lung cancer survivors' EX levels declined after diagnosis and engaging in EX after treatment may improve fatigue and QoL. PMID- 25832896 TI - Heart rate recovery and aerobic endurance capacity in cancer survivors: interdependence and exercise-induced improvements. AB - PURPOSE: Whilst evidence supports beneficial effects of exercise on heart rate variability in cancer patients, its impact on heart rate recovery (HRR) and possible associations of exercise capacity and HRR have not yet been investigated. We aimed to evaluate the effects of an exercise intervention on HRR in relation to the baseline aerobic capacity. METHODS: Cancer patients (n = 309, 178 females) performed a cardiopulmonary exercise test at baseline and at a 4 month interval follow-up with home-based and supervised exercise programs in between. VO2 and heart rate were assessed during and HRR at 60 and 120 s after test termination. Based on a median split of the VO2 peak baseline values, participants were dichotomized into two groups: below median (47 female; 57.5 +/- 10 years) and above median (48 female; 54.3 +/- 12 years). RESULTS: In the baseline sample (n = 309), VO2 peak correlated significantly with HRR60 (r = .327, p < .01) and HRR120 (r = .524, p < .01). For the compliers who completed intervention and assessments (n = 158), group comparisons demonstrated differences between below median versus above median group in absolute changes of HRR60 (3.1 +/- 10.5 bpm (95% CI +0.6; +5.4) vs -1.8 +/- 8.7 bpm (95% CI -3.7; +0.5)) and VO2 peak (2.9 +/- 3.5 ml/kg/min (95% CI +2.1; +3.7) vs 0.66 +/- 4 ml/kg/min (95% CI -0.6; +1.5)) (p < .01), but not in HRR120 (3.9 +/- 11.8 bpm (95% CI +1.2; +6.6) vs 0.8 +/- 10.8 bpm (95% CI -1.7; +3.5); p > .05). CONCLUSIONS: These findings point toward a positive linear relationship between aerobic capacity and vagal reactivation in cancer patients. Patients with initial VO2 peak values below median showed improved VO2 peak, HRR60 and HRR120 following the moderate aerobic exercise intervention and differences to patients above median in all outcomes compared. PMID- 25832897 TI - Prevalence of oral mucositis, dry mouth, and dysphagia in advanced cancer patients. AB - BACKGROUND: Oral symptoms can be a sign of an underlying systemic condition and have a significant impact on quality of life, nutrition, and cost of care, while these lesions are often studied in the context of cancer treatment. However, information regarding oral symptoms in advanced cancer patients is poor. The aim of this multicenter study was to determine the prevalence and the characteristics of oral symptoms in a large population of advanced cancer patients. METHODS: A consecutive sample of patients with advanced cancer for a period of 6 months was prospectively assessed for an observational study. At time of admission, the epidemiological characteristics, surgery-radiotherapy of head and neck, and oncologic treatments in the last month were recorded. The presence of mucositis, dry mouth, and dysphagia was assessed by clinical examination and patients' report and their intensity recorded. Patients were also asked whether they had limitation on nutrition of hydration due to the local condition. RESULTS: Six hundred sixty-nine patients were surveyed in the period taken into consideration. The mean age was 72.1 years (SD 12.3), and 342 patients were males. The primary tumors are listed in Table 1. The prevalence of mucositis was 22.3 %. The symptom relevantly reduced the ingestion of food or fluids and was statistically associated with the Karnofsky level and head and neck cancer. The prevalence of dry mouth was 40.4 %, with a mean intensity of 5.4 (SD 2.1). Several drugs were concomitantly given, particularly opioids (78 %), corticosteroids (75.3 %), and diuretics (70.2 %). Various and nonhomogeneous treatments were given for dry mouth, that was statistically associated with current or recent chemotherapy, and hematological tumors. The prevalence of dysphagia was 15.4 % with a mean intensity of 5.34 (SD 3). Dysphagia for liquids was observed in 52.4 % of cases. A high level of limitation for oral nutrition due to dysphagia was found, and in 53.4 % of patients, alternative routes to the oral one were used. Dysphagia was statistically associated with the Karnofsky level and head and neck cancer. A strong relationship between the three oral symptoms was found. CONCLUSION: In advanced cancer patients, a range of oral problems significantly may impact on the physical, social, and psychological well-being of advanced cancer patients to varying degrees. These symptoms should be carefully assessed early but become imperative in the palliative care setting when they produce relevant consequences that may be life-threatening other than limiting the daily activities, particularly eating and drinking. PMID- 25832899 TI - Using rap music to promote adolescent health: pilot study of VoxBox. AB - ISSUE ADDRESSED: Alcohol, tobacco and other drugs (ATODs) usage among adolescents, particularly those living in lower socioeconomic communities, is a population health problem in Australia that requires innovative health promotion strategies. There is a growing recognition of the potential of arts-based approaches to engage youth in health promoting activities. This paper presents the process evaluation of the pilot VoxBox intervention that used rap to build adolescents' awareness of risks associated with ATODs. METHODS: The VoxBox intervention was piloted in Logan, Queensland, at five high schools with 18 adolescents completing the intervention. Data collection methods included observation, focus groups, semi-structured interviews and a survey of adolescent participants. RESULTS: The intervention was well received by participants and stakeholders. Three factors characterising the project's successful engagement of adolescents were: participate - go with the flow, learning from the real deal and resourced to make some noise. CONCLUSION: In VoxBox, the emphasis on engaging adolescents in an activity of real interest that was appropriately resourced and delivered was central to credibility and success. SO WHAT?: The findings highlight the importance of interventions matching the interests of the targeted population group. PMID- 25832898 TI - Novel High-Frequency Peripheral Nerve Stimulator Treatment of Refractory Postherpetic Neuralgia: A Brief Technical Note. AB - OBJECTIVES: The study aims to describe an ultrasound (US)-guided peripheral nerve stimulation implant technique and describe the effect of high-frequency peripheral nerve stimulation on refractory postherpetic neuralgia. MATERIALS AND METHODS: Following a cadaver pilot trial using US and confirmatory fluoroscopic guidance, a 52-year-old man with refractory left supraorbital neuralgia underwent combined US and fluoroscopic-guided supraorbital peripheral nerve stimulator trial. The patient was subsequently implanted with a percutaneous lead over the left supraorbital and supratrochlear nerve utilizing a high-frequency stimulation paradigm. RESULTS: At 9 months follow-up, the pain intensity had declined from a weekly average of 8/10 to 1/10 on the pain visual analog scale (VAS). After implant, both nerve conduction and blink reflex studies were performed, which demonstrated herpetic nerve damage and frequency-specific peripheral nerve stimulation effects. The patient preferred analgesia in the supraorbital nerve distribution accomplished with high-frequency paresthesia-free stimulation (HFS) at an amplitude of 6.2 mA, a frequency of 100-1200 Hz, and a pulse width of 130 MUsec, to paresthesia-mediated pain relief associated with low-frequency stimulation. CONCLUSION: We report the implant of a supraorbital peripheral nerve stimulating electrode that utilizes a high-frequency program resulting in sustained suppression of intractable postherpetic neuralgia. PMID- 25832900 TI - Sulfoxide-Directed Metal-Free ortho-Propargylation of Aromatics and Heteroaromatics. PMID- 25832901 TI - Mild one-pot Horner-Wadsworth-Emmons olefination and intramolecular N-arylation for the syntheses of indoles, all regio-isomeric azaindoles, and thienopyrroles. AB - The syntheses of various N-protected aromatic-ring fused pyrrole-2-carboxylate derivatives have been accomplished using mild one-pot Horner-Wadsworth-Emmons olefination and Cu-catalyzed intramolecular N-arylation reactions. The optimized mild one-pot reaction conditions of various 2-bromo arylcarboxaldehydes with commercially available N-protected phosphonoglycine trimethylesters gave the desired aromatic-ring fused pyrrole-2-carboxylates, such as substituted indole-, all regio-isomeric azaindole-, and thienopyrrole-2-carboxylates, in good to excellent yields. These conditions showed broad substrate compatibility, without the loss of the protecting group. PMID- 25832902 TI - Modulation of platelet and monocyte function by the chemokine fractalkine (CX3 CL1) in cardiovascular disease. AB - BACKGROUND: The chemokine fractalkine, CX3CL1, bears unique features within the chemokine family: it exists in a membrane bound form acting as an adhesion molecule and surface receptor; however, when cleaved by ADAM 10, it functions as a soluble chemokine. Fractalkine and its chemokine receptor CX3CR1 are known to have multiple roles in diverse human diseases, for example inflammatory diseases, rheumatoid arthritis, renal diseases and atherosclerosis. MATERIALS AND METHODS: This review is based on the material obtained via PubMed up to November 2014. The key search terms used were 'fractalkine', 'CX3CL1', 'CX3CR1', 'cardiovascular disease', 'platelets', 'monocytes' and 'platelet-monocyte complexes'. RESULTS: Atherosclerosis is recognized as a highly inflammatory disease, and it has become increasingly evident that the immune system plays an important role in atherogenesis and atheroprogression. Two blood cell populations are crucially involved in the early development of atherosclerotic lesions: monocytes and platelets. They are detected at vascular sites of endothelial dysfunction and are involved in inflammatory immune responses. These cells directly interact with each other, forming platelet-monocyte complexes that are increased in cardiovascular diseases. During the development of atherosclerosis, fractalkine mediates leukocyte recruitment to the inflamed endothelium, which promotes early formation of lesions. This process only effectively works in the presence of activated platelets. It has been suggested that fractalkine and its receptor contribute to platelet-monocyte aggregate formation underlining the two important impacts of this chemokine for platelets as well as monocytes. CONCLUSION: Interesting data hint at a role of fractalkine for platelet activation, adhesion and subsequent monocyte recruitment to activated endothelial cells in cardiovascular diseases. However, the exact mechanisms remain to become unravelled. PMID- 25832904 TI - Corrigendum: Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids. PMID- 25832903 TI - The evolution of vertebrate and invertebrate myelin: a theoretical computational study. AB - Multilayered, lipid-rich myelin increases nerve impulse conduction velocity, contributes to compact nervous systems, and reduces metabolic costs of neural activity. Based on the hypothesis that increased impulse conduction velocity provides a selective advantage that drives the evolution of myelin, we simulated a sequence of plausible intermediate stages of myelin evolution, each of which providing an enhancement of conduction speed. We started with the expansion of insulating glial coverage, which led first to a single layer of myelin surrounding the axon and then to multiple myelin wraps with well-organized nodes. The myelinated fiber was modeled at three levels of complexity as the hypothesized evolutionary progression became more quantitatively exacting: 1) representing the fiber as a mathematically-tractable uniform active cylinder with the effect of myelination approximated by changing its specific capacitance (C(m)); 2) representing it as a chain of simple, cable-model compartments having alternating nodal and internodal parameters subject to optimization, and 3) representing it in a double cable model with the axon and myelin sheath treated separately. Conduction velocity was optimized at each stage. To maintain optimal conduction velocities, increased myelin coverage of axonal surface must be accompanied by an increase in channel density at the evolving nodes, but along with increases in myelin thickness, a reduction in overall average channel density must occur. Leakage under the myelin sheath becomes more of a problem with smaller fiber diameters, which may help explain the tendency for myelin to occur preferentially in larger nerve fibers in both vertebrates and invertebrates. PMID- 25832905 TI - Cerebrolysin in mild-to-moderate Alzheimer's disease: a meta-analysis of randomized controlled clinical trials. AB - OBJECTIVE: The aim of this study was to provide a systematic and quantitative summary of benefit and risk of Cerebrolysin in patients with mild-to-moderate Alzheimer's disease (AD) and to avoid major deficiencies of an earlier meta analysis. DESIGN: This is a meta-analysis of randomized double-blind placebo controlled clinical trials. DATA SOURCES: Trials were identified with the help of PubMed, the Cochrane Dementia Group database, the Center for Collaborative Neurosciences, and references from reviews; no language restrictions were applied. STUDY SELECTION: All randomized double-blind placebo-controlled studies on 30 ml/day of Cerebrolysin in mild-to-moderate AD were included. RESULTS: There were 6 eligible randomized controlled trials comparing Cerebrolysin with placebo. For all studies, either individual patient data and/or published data (aggregate data) were available. Analyses were based on the odds ratio (OR) for dichotomized global clinical change and for safety criteria, on the standardized mean difference (SMD) for pooling of cognitive function, and on the Mann-Whitney statistic (MW) for multivariate analysis of 'global benefit' (combined effect of global clinical change and cognitive function). Cerebrolysin was significantly more effective than placebo at 4 weeks regarding cognitive function (4 weeks: SMD -0.40 points; 95% CI -0.66 to -0.13; p = 0.0031; 6 months: SMD -0.37 points; 95% CI -0.90 to 0.16; p = 0.1710), at 4 weeks and 6 months regarding global clinical change (4 weeks: OR 3.32; 95% CI 1.20-9.21; p = 0.0212; 6 months: OR 4.98; 95% CI 1.37-18.13; p = 0.0150), and at 4 weeks and 6 months regarding 'global benefit' (combined efficacy criteria; 4 weeks: MW 0.57, 95% CI 0.53-0.61; p = 0.0006; 6 months: MW 0.57; 95% CI 0.53-0.61; p = 0.0010). The safety aspects of Cerebrolysin were comparable to placebo. CONCLUSION: This meta-analysis provides evidence that Cerebrolysin has an overall beneficial effect and a favorable benefit-risk ratio in patients with mild-to-moderate AD. Cerebrolysin as a therapeutic agent should be considered by clinicians seeking treatment options for mild-to-moderate AD. PMID- 25832906 TI - Effects of ketone bodies in Alzheimer's disease in relation to neural hypometabolism, beta-amyloid toxicity, and astrocyte function. AB - Diet supplementation with ketone bodies (acetoacetate and beta-hydroxybuturate) or medium-length fatty acids generating ketone bodies has consistently been found to cause modest improvement of mental function in Alzheimer's patients. It was suggested that the therapeutic effect might be more pronounced if treatment was begun at a pre-clinical stage of the disease instead of well after its manifestation. The pre-clinical stage is characterized by decade-long glucose hypometabolism in brain, but ketone body metabolism is intact even initially after disease manifestation. One reason for the impaired glucose metabolism may be early destruction of the noradrenergic brain stem nucleus, locus coeruleus, which stimulates glucose metabolism, at least in astrocytes. These glial cells are essential in Alzheimer pathogenesis. The beta-amyloid peptide Abeta interferes with their cholinergic innervation, which impairs synaptic function because of diminished astrocytic glutamate release. Abeta also reduces glucose metabolism and causes hyperexcitability. Ketone bodies are similarly used against seizures, but the effectively used concentrations are so high that they must interfere with glucose metabolism and de novo synthesis of neurotransmitter glutamate, reducing neuronal glutamatergic signaling. The lower ketone body concentrations used in Alzheimer's disease may owe their effect to support of energy metabolism, but might also inhibit release of gliotransmitter glutamate. Alzheimer's disease is a panglial-neuronal disorder with long-standing brain hypometabolism, aberrations in both neuronal and astrocytic glucose metabolism, inflammation, hyperexcitability, and dementia. Relatively low doses of beta hydroxybutyrate can have an ameliorating effect on cognitive function. This could be because of metabolic supplementation or inhibition of Abeta-induced release of glutamate as gliotransmitter, which is likely to reduce hyperexcitability and inflammation. The therapeutic beta-hydroxybutyrate doses are too low to reduce neuronally released glutamate. PMID- 25832907 TI - Sound source localization by hearing preservation patients with and without symmetrical low-frequency acoustic hearing. AB - The aim of this article was to study sound source localization by cochlear implant (CI) listeners with low-frequency (LF) acoustic hearing in both the operated ear and in the contralateral ear. Eight CI listeners had symmetrical LF acoustic hearing and 4 had asymmetrical LF acoustic hearing. The effects of two variables were assessed: (i) the symmetry of the LF thresholds in the two ears and (ii) the presence/absence of bilateral acoustic amplification. Stimuli consisted of low-pass, high-pass, and wideband noise bursts presented in the frontal horizontal plane. Localization accuracy was 23 degrees of error for the symmetrical listeners and 76 degrees of error for the asymmetrical listeners. The presence of a unilateral CI used in conjunction with bilateral LF acoustic hearing does not impair sound source localization accuracy, but amplification for acoustic hearing can be detrimental to sound source localization accuracy. PMID- 25832908 TI - System responses to chronic cold stress probed via(1)H NMR spectroscopy in plasma and urine matrices. AB - Chronic cold stress can trigger biochemical and physiological changes in living organisms, which leads to a rapid loss of homeostasis. However, the biochemical responses of the organism to chronic cold stress are unclear. In this study, we systematically analysed the metabonomic changes under chronic cold stress by using a (1)H NMR-based metabonomics approach in conjunction with clinical biochemistry assessments. We found that chronic cold exposure caused significant elevation in the levels of lipoproteins (HDL, LDL), lactate, acetoacetate, creatine, creatinine, choline metabolites (GPC, PC and betaine), TMAO and taurine but reduction in the levels of VLDL, glutamine, glycine and glycerol in plasma. Increased levels in urinary TCA cycle intermediates (2-ocoglutarate and citrate), acetoacetate, taurine, TMAO, betaine and hippurate were also found in model rats, together with the reduction of creatinine and tryptophan levels. The results indicated that chronic cold stress caused widespread metabolic changes involved in lipid and energy metabolism, gluconeogenesis, the TCA cycle, and gut microbiota disorders, accompanied with hepatic and renal dysfunction. These findings provide a comprehensive insight into the biochemical consequences and metabolic responses to chronic cold stress in rats. PMID- 25832909 TI - Prospective, Randomized Intervention Study Comparing Retinal Pigment Epithelium Choroid Graft Surgery and Anti-VEGF Therapy in Patients with Exudative Age Related Macular Degeneration. AB - PURPOSE: To investigate whether patients with exudative age-related macular degeneration and a submacular hemorrhage, retinal pigment epithelium (RPE) tear or nonresponders to anti-vascular endothelial growth factor (VEGF) benefit more from a free RPE-choroid graft transplantation surgery than from (continuation of) anti-VEGF treatment. PROCEDURES: A total of 20 patients were included in this prospective, international, multicenter, randomized intervention study. RESULTS: The change in the mean number of Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the graft group 1 year postoperatively was -15 (range -54 to +26), whilst 2 patients experienced a gain of >10 letters. The median preoperative visual acuity (VA) was 0.75 logMAR (range 0.46-2.8), and the mean postoperative VA was 1.48 logMAR (range 0.14-2.8). The change in the mean number of ETDRS letters in the anti-VEGF group was -8 (range -26 to +6); no patients experienced a >10 letter gain. The median preoperative VA was 1.36 logMAR (range 0.58-1.6), and the median postoperative VA was 1.42 logMAR (range 0.44-1.66). CONCLUSIONS: The included patient group is far too small to draw conclusions. However, both gain and loss of VA may be experienced by patients undergoing either treatment method; more gain might be possible for patients with a graft in the absence of complications. PMID- 25832910 TI - Autologous serum and plasma rich in growth factors in ophthalmology: preclinical and clinical studies. AB - The use of blood derivatives represents an alternative therapeutic approach that is gaining interest in regenerative medicine due to its potential to stimulate and accelerate tissue healing. Autologous serum eye drops and platelet-enriched plasma eye drops are being used in the treatment of different ophthalmological disorders. In this review, we summarize the different blood-derived formulations used in the treatment and care of ocular surface disorders. The biological basis and use of autologous serum and plasma rich in growth factors are deeply evaluated as well as the challenges to be addressed in the future in this new generation of blood-derived therapies. PMID- 25832912 TI - Robin Stott: Focused, rebellious, receptive. PMID- 25832911 TI - Impaired light detection of the circadian clock in a zebrafish melanoma model. AB - The circadian clock controls the timing of the cell cycle in healthy tissues and clock disruption is known to increase tumourigenesis. Melanoma is one of the most rapidly increasing forms of cancer and the precise molecular circadian changes that occur in a melanoma tumor are unknown. Using a melanoma zebrafish model, we have explored the molecular changes that occur to the circadian clock within tumors. We have found disruptions in melanoma clock gene expression due to a major impairment to the light input pathway, with a parallel loss of light dependent activation of DNA repair genes. Furthermore, the timing of mitosis in tumors is perturbed, as well as the regulation of certain key cell cycle regulators, such that cells divide arhythmically. The inability to co-ordinate DNA damage repair and cell division is likely to promote further tumourigenesis and accelerate melanoma development. PMID- 25832913 TI - Pseudocapacitance of MXene nanosheets for high-power sodium-ion hybrid capacitors. AB - High-power Na-ion batteries have tremendous potential in various large-scale applications. However, conventional charge storage through ion intercalation or double-layer formation cannot satisfy the requirements of such applications owing to the slow kinetics of ion intercalation and the small capacitance of the double layer. The present work demonstrates that the pseudocapacitance of the nanosheet compound MXene Ti2C achieves a higher specific capacity relative to double-layer capacitor electrodes and a higher rate capability relative to ion intercalation electrodes. By utilizing the pseudocapacitance as a negative electrode, the prototype Na-ion full cell consisting of an alluaudite Na2Fe2(SO4)3 positive electrode and an MXene Ti2C negative electrode operates at a relatively high voltage of 2.4 V and delivers 90 and 40 mAh g(-1) at 1.0 and 5.0 A g(-1) (based on the weight of the negative electrode), respectively, which are not attainable by conventional electrochemical energy storage systems. PMID- 25832914 TI - Risk reduction in dominant temporal lobe epilepsy surgery combining fMRI/DTI maps, neuronavigation and intraoperative 1.5-Tesla MRI. AB - BACKGROUND: In dominant temporal lobe epilepsy surgery, speech, memory and visual systems are at risk. OBJECTIVE: Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging combined with intraoperative neuronavigation and MRI were investigated retrospectively regarding risk reductions for favorable neurological and seizure outcome. METHODS: Functional imaging risk maps were generated for 14 patients suffering from dominant temporal lobe epilepsy [7 with hippocampal sclerosis (HS), 7 with various lesions] and used for neuronavigation guided tailored resection. Postoperative neurological and seizure outcome and complications were evaluated. RESULTS: None of the patients had postoperative speech dysfunction despite 2.3/3.6-cm mean hippocampal/neocortical resection. Verbal memory decline was found in 2 of the 14 (14.3%) patients, correlating with surgical lesions in fMRI memory-activated functional areas in the dominant posterior parahippocampal gyrus. Verbal memory scores did not statistically differ between the HS and the lesional group, neither pre- nor postoperatively. A contralateral visual field defect occurred in 1 patient (7.1%). An Engel class I seizure outcome was found in 12 patients (85.7%), and 11 were completely seizure free (78.6%) at a mean follow-up of 19.5 months. CONCLUSION: This retrospectively investigated protocol led to an excellent neurological and seizure outcome and a low complication rate in dominant temporal lobe epilepsy surgery. PMID- 25832915 TI - Micro-RNAs and their roles in eye disorders. AB - Micro-RNAs (miRNAs) are members of the family of noncoding RNA molecules that regulate gene expression by translational repression and mRNA degradation. Initial identification of miRNAs revealed them only as developmental regulators; later, their radiated roles in various cellular processes have been established. They regulate several pathways, including developmental timing, hematopoiesis, organogenesis, apoptosis, cell differentiation and proliferation. Their roles in eye disorders are being explored by biologists around the world. Eye physiology requires the perfect orchestration of all the regulatory networks; any defect in any of the networks leads to eye disorders. The dysregulation of miRNA expression has been reported in many eye disorders, which paves the way for new therapeutics. This review summarizes the biogenesis of miRNAs and their role in eye disorders. miRNA studies also have implications for the understanding of various complex metabolic pathways leading to disorders of the eye. The ultimate understanding leads to potential opportunities in evaluating miRNAs as molecular biomarkers, prognostic tools, diagnostic tools and therapeutic agents for eye disorders. PMID- 25832916 TI - Become Related: FIAS, an Intensive Early Intervention for Young Children with Autism Spectrum Disorders. AB - BACKGROUND: In autism spectrum disorders (ASDs), impairments in fundamental social abilities and a lack of interest in social stimuli become apparent early in life. These impairments are thought to negatively affect further brain and behavioural development. Early intensive interventions can help to attenuate social-development and other risk factors and, thus, to ameliorate the deficits associated with ASDs. We present FIAS, an intensive early intervention approach for young children with ASD, which aims at developing children's social motivation. During 18 days, therapists work continuously for 6 h a day with the affected child, involving the whole family in a day care setting. Follow-up care at home over 1 year as well as fresh-up interventions and inclusion in kindergarten or a play group should stabilise the effects and help to respond to further challenges. MATERIAL AND METHODS: Here, we present observations from the first 12 patients (25-48 months of age) treated according to the FIAS approach. We evaluated changes in core autistic symptoms and level of functioning after the 18 days of intensive intervention. Beyond standardised assessment, two innovative video-based instruments (Autism Behaviour Coding System and Evaluationsfragebogen) have been developed to assess autistic symptoms and interaction parameters during intervention. RESULTS: Improvements were noted in most core autistic symptom domains, with the highest effect sizes in domains like eye contact, communication, repetitive behaviour, imitation, motivation and reciprocity. In addition, the level of functioning significantly improved. CONCLUSIONS: The first evaluation of the FIAS approach shows promising results, as the FIAS intervention appears to improve core autistic symptom domains as well as the level of everyday functioning. Limitations of this study are the small sample size and the lack of a control group. A more comprehensive and longitudinal evaluation is in progress; this will focus on the stability of the observed effects and will attempt to identify potential predictors of treatment response. (c) 2015 S. Karger AG, Basel. PMID- 25832917 TI - Isolated nocturnal hypertension and subclinical target organ damage: a systematic review of the literature. AB - Isolated nocturnal hypertension (INH) is associated with greater mortality and cardiovascular events. Subclinical target organ damage (TOD) is a prognostic marker for cardiovascular events. Our objective is to systematically summarize evidence on the association between INH and subclinical TOD. Observational population studies were considered. INH was defined as nighttime blood pressure (BP) ?120 and/or 70 mm Hg with daytime BP <135/85 mm Hg. We systematically searched Pubmed, EMBASE and the Cochrane Library. Abstracts were reviewed by two assessors. Potentially eligible articles were compared with inclusion criteria. The search yielded 954 titles, 13 abstracts were selected for review and four articles fulfilled inclusion criteria. INH was associated with higher ambulatory arterial stiffness index (0.4 unit vs. 0.35 unit, P<0.05), pulse wave velocity (16.2 m s(-1) vs. 14.7 m s(-1), P<0.05), central (140.4% vs. 134.0%, P<0.05) and peripheral (82.6% vs. 76.5%, P<0.01) augmentation index in a Chinese study. In the same population there was no association with left ventricular hypertrophy documented by electrocardiogram. INH was not associated with increased arterial stiffness or left venticular mass index in a Swedish study. An American study demonstrated higher left ventricular mass (152.46 g vs. 136.16 g, P=0.01) and greater odds of left ventricular hypertrophy (odds ratio 3.03, 95% confidence interval 1.02-9.05) in unadjusted analysis. There was no association with proteinuria. Evidence is inconclusive regarding the association between INH and subclinical TOD. Future research should focus on trying to elucidate the mechanisms that generate INH and contribute to the higher mortality associated with this BP pattern. PMID- 25832918 TI - Left ventricular layer function in hypertension assessed by myocardial strain rate using novel one-beat real-time three-dimensional speckle tracking echocardiography with high volume rates. AB - We recently developed novel software to measure phasic strain rate (SR) using automated one-beat real-time three-dimensional speckle tracking echocardiography (3D-STE) with high volume rates. We tested the hypothesis that left ventricular (LV) systolic function and relaxation analyzed by SR with the novel 3D-STE in hypertension (HTN) with hypertrophy may be impaired in the endocardium before there is LV systolic dysfunction. We measured LV longitudinal, radial and circumferential SR in patients with HTN (n=80, 69+/-7 years) and age-matched normotensive controls (n= 60, 69+/-10 years) using 3D-STE. HTN patients were divided into four groups according to LV geometry: normal, concentric remodeling, concentric hypertrophy and eccentric hypertrophy. We measured SR during systole as an index of systolic function, SR during isovolumic relaxation (IVR) as an index of relaxation and E/e' as an index of filling pressure. Endocardial SR during systole in HTN with concentric and eccentric hypertrophy decreased compared with that in controls despite no reduction in ejection fraction or epicardial SR. Endocardial radial SR during IVR decreased even in normal geometry, and it was further reduced in concentric remodeling and hypertrophy despite no reduction in epicardial SR. LV phasic SR assessed by 3D-STE with high volume rates is a useful index to detect early decreases in LV systolic function and to predict subclinical LV layer dysfunction in patients with HTN. PMID- 25832919 TI - Combining drugs to optimize the therapy of hypertension: experimental evidence derived from animal models. PMID- 25832921 TI - Awareness of the Japanese Society of Hypertension Guidelines for the Management of Hypertension and their use in clinical practices: 2009 survey results. AB - The objective of this study was to investigate physicians' awareness and use of the Japanese Society of Hypertension (JSH) Guidelines for the Management of Hypertension (JSH2004 and JSH2009), and determine what changes need to be implemented in the future. A questionnaire was used to survey physicians' awareness and their use of JSH2004 and JSH2009. Physicians attending educational seminars on hypertension that were held during the months after the publication of JSH2009 (January-April 2009) were asked to participate in the survey. Of the 5795 respondents, 88% were aware of the JSH2009 publication. Furthermore, physicians were also aware of JSH2004, with about 90% using JSH2004 in their practice. A hypertension blood pressure (BP) reference value of 140/90 mm Hg was used by 55% in office BP, whereas 31% used 135/85 mm Hg for home BP. Target BP levels used by physicians were 130/80 mm Hg for patients with diabetes or kidney disease (52%) and for elderly patients with diabetes or kidney disease (45%), whereas 140/90 mm Hg was used for elderly patients with low cardiovascular disease risk (44%) and for patients with chronic-phase stroke (27%). Answers to the questionnaire varied among physicians according to sex, age, workplace and specialty. The majority of the participating Japanese physicians were familiar with both JSH2004 and JSH2009, with many following the guidelines in their practice. However, some physicians use different reference values for hypertension and target BP levels. Physicians' adherence to and use of the guidelines should be regularly examined and promoted. PMID- 25832920 TI - Activation of the D4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of AT1a receptor expression. AB - Angiotensin (Ang) II has an important role in the vascular smooth muscle cell (VSMC) proliferation and migration and subsequently in the development of vascular diseases, whereas dopamine has the opposite effect. Previous studies have shown an interaction between dopamine and AT(1) receptors in the kidney. The dopamine D(4) receptor is expressed in arteries and has an inhibitory effect on VSMC proliferation. We hypothesized that the D(4) receptor, through its interaction with the AT(1a) receptor, may have an inhibitory effect on Ang II mediated VSMC proliferation and migration, which could have a pivotal role in hypertension-induced vascular remodeling. In the current study, we found that Ang II markedly induced the proliferation and migration of A10 cells, which was inhibited by the D(4) receptor agonist PD168077. The activation of the D(4) receptor by PD168077 inhibited AT(1a) receptor expression in a concentration- and time-dependent manner. These effects were attenuated by silencing the D(4) receptor with a D(4) receptor-targeting small interfering RNA. The D(4) receptor mediated inhibition of AT(1) receptor function involved protein kinase A (PKA). The activation of the D(4) receptor by PD168077 increased PKA activity in A10 cells, and the presence of a PKA inhibitor (PKA inhibitor 14-22, 10(-7) mol l(-1) per 24 h) blocked the inhibitory effect of the D(4) receptor on AT(1) receptor expression and function. The inhibitory effect of the D(4) receptor on AT(1) receptor expression and function was preserved in VSMCs (primary culture) from spontaneously hypertensive rats relative to VSMCs from Wistar-Kyoto rats. In conclusion, our data provide insight into the regulatory role of the D(4) receptor on AT(1a) receptor expression and function in VSMCs and suggest that targeting the action of the D(4) receptor may represent an effective therapeutic approach for the treatment of cardiovascular diseases. PMID- 25832923 TI - Routine outcome monitoring and process quality in mental health care: a descriptive study in daily practice. AB - RATIONALE, AIMS AND OBJECTIVES: Routine outcome monitoring (ROM) is used to improve quality of health care by improving the process of care. ROM was introduced nationwide in mental health care in the Netherlands with the primary goal of enhancing the quality of treatment. This study aims to establish the impact of ROM on the process quality of treatment in the daily practice of secondary mental health care in the Netherlands. METHODS: Two cohorts from the same treatment programme were identified, before and after implementation of ROM. Data on patient characteristics, presence of baseline ROM measurement and indicators of the quality of the treatment process were retrieved from the electronic health care information system. Patient data were collected until 6 months after enrolment in the treatment programme. The magnitude of the effect of ROM on the quality of the treatment process was established. RESULTS: The pre-ROM cohort comprised 271 patients and 231 patients constituted the post-ROM cohort. In the ROM cohort, both indicators for process quality 'presence of treatment plan' and 'presence of cancellations' were significantly higher; the odd ratios were 3,37 [confidence interval (CI) 2.32-4.89] and 1,63 (CI 1.14-2.33), respectively. CONCLUSIONS: Indicators on process quality are important for understanding and establishing the impact of ROM in daily practice of secondary mental health care. Implementing ROM moderately increased the presence of a treatment plan. While this suggests improved treatment agreement, it did not result in better compliance of patients with individual treatment activities, as presence of cancellations was significantly higher after introduction of ROM. PMID- 25832922 TI - Therapeutic effects of udenafil on pressure-overload cardiac hypertrophy. AB - This study was performed to determine whether the newly developed phosphodiesterase type 5 (PDE5) inhibitor udenafil had beneficial effects on pressure-overload cardiac hypertrophy. Pressure overload cardiac hypertrophy was created by using suprarenal aortic constriction (SAC) in male Sprague-Dawley rats. Rats were divided into three groups: sham (n=19), SAC (n=18) and SAC+udenafil (n=14) groups. Three-week periods of SAC provoked significant left ventricular (LV) hypertrophy. Udenafil was administered (20 mg kg(-1) PO, daily) between the 3rd and 20th weeks after SAC in the SAC+udenafil group. Udenafil improved the survival rate (log-rank P=0.012) and exercise capacity (maximal exercise duration at the 20th week after surgery: 448+/-54 s for the SAC+udenafil group versus 317+/-73 s for the SAC group, P<0.05) of the rats with SAC. Serial echocardiographic examinations showed that udenafil attenuated LV remodeling processes following SAC (mean LV end-diastolic dimension at the 20th week after surgery: 9.84+/-0.59 mm for SAC and 9.05+/-0.58 mm for SAC+udenafil group, P<0.05). Invasive hemodynamic studies showed that udenafil improved the LV performance. Udenafil-attenuated myocardial fibrosis and apoptosis. Udenafil also decreased myocardial matrix metalloproteinase-9 expression and augmented serum interleukin-10 concentration. Long-term udenafil use prevented cardiac remodeling and improved exercise capacity and survival in rats exposed to pressure-overload cardiac hypertrophy. PMID- 25832924 TI - Biodegradation of pesticide profenofos by the free and immobilized cells of Pseudoxanthomonas suwonensis strain HNM. AB - Profenofos is an organophosphate pesticide used extensively in agriculture to control pests. A bacterium capable of degrading profenofos was isolated from pesticide-contaminated soil samples and identified as Pseudoxanthomonas suwonensis strain HNM based on its morphological and biochemical characteristics and phylogenetic analysis of 16S rRNA gene sequences. 4-Bromo-2-chlorophenol was identified as a metabolite of profenofos degradation by HPLC and GC-MS analysis. The organism degraded profenofos by hydrolysis to yield 4-bromo-2-chlorophenol which was further utilized as carbon source for growth. The organism utilized various organophosphate pesticides such as temephos, quinalphos, and chloropyrifos as carbon sources. The optimum conditions for degradation of profenofos by P. suwonensis strain HMN were found to be at pH 7 and 30 degrees C. We have investigated the rate of degradation of profenofos by the free and immobilized cells of P. suwonensis strain HNM in various matrices such as sodium alginate (SA), sodium alginate-polyvinyl alcohol (SA-PVA), and SA-bentonite clay. The rate of degradation of 3 and 6 mM profenofos by the freely suspended cells were compared with that by immobilized cells in batches and semi-continuous with shaken cultures. The SA-bentonite clay-immobilized cells showed higher rate of degradation of 3 and 6 mM profenofos then freely suspended cells and cells immobilized in SA and SA-PVA. The SA-bentonite clay-immobilized cells of P. suwonensis strain HNM could be reused for more than 32 cycles without losing their degradation capacity. Thus, the immobilized cells are more efficient than freely suspended cells for the degradation of organophosphate pesticide contaminated water. PMID- 25832925 TI - Validation of the Affective Word List as a measure of verbal learning and memory. AB - INTRODUCTION: This study evaluated the Affective Word List (AWL), a measure designed to assess affective bias, as a measure of verbal learning and memory in the context of baseline concussion evaluations. The AWL was developed to assess affective bias in order to circumvent the tendency of some examinees to minimize self-report of depression symptoms. However, because it is designed as a traditional list-learning task, the cognitive indices of the AWL have the added potential to be used as measures of verbal learning and memory. It would be useful to have a performance-based measure that is sensitive to both the affective and cognitive consequences of concussion. METHOD: Participants from a university-based sports concussion program were used to evaluate the descriptive statistics and distribution of the AWL and its convergent and discriminant validity. A separate sample of undergraduate students, active in intramural or club athletics, served as participants for a delayed alternate-form reliability study. All reliability and validity results were compared with those of the Hopkins Verbal Learning Test-Revised (HVLT-R) and the Immediate Post-Concussion Assessment and Cognitive Testing Verbal Memory Composite (ImPACT-VM). RESULTS: Results of this study showed that the cognitive indices of the AWL have normal distributions, and its four forms are equivalent. The AWL demonstrated moderate delayed alternate-form reliability, moderate convergent validity with other measures of verbal learning and memory, and strong discriminant validity with measures of processing speed and reaction time. CONCLUSIONS: Results of this study suggest that the AWL may have clinical utility as a measure of verbal learning and memory in concussion management and research. PMID- 25832927 TI - Hepatitis B reactivation in multiple myeloma patients with resolved hepatitis B undergoing chemotherapy. AB - BACKGROUND & AIMS: Despite increasing reports of hepatitis B virus (HBV) reactivation in multiple myeloma (MM), HBV reactivation in patients with resolved hepatitis B [hepatitis B surface antigen (HBsAg)-negative/anti-hepatitis B core antigen antibody (anti-HBc)-positive] is still poorly characterized. The aim of this study was to clarify its frequency and risk factors. METHODS: A total of 230 MM patients with resolved hepatitis B were retrospectively reviewed for HBV reactivation and biochemical flare. RESULTS: During a median 2.4 years of follow up, HBV reactivation was diagnosed in 12 patients (5.2%). The cumulative rates of HBV reactivation at 2 years and 5 years were 5% and 8% respectively. A baseline anti-HBs-negative status (P = 0.033) and high-dose therapy/autologous stem-cell transplantation [HDT/ASCT (P = 0.025)] were significant risk factors that were positively associated with HBV reactivation. In subgroup analysis of patients treated with HDT/ASCT (n = 127), a baseline anti-HBs-negative status was the only significant risk factor for HBV reactivation (hazard ratio, 4.64; 95% CI, 1.47 14.7; P = 0.009). DISCUSSION: These data show that evaluation of anti-HBc is needed for MM patients, and suggest that monitoring of HBV DNA should be considered for patients with resolved hepatitis B undergoing HDT/ASCT, especially those who are anti-HBs-negative. PMID- 25832926 TI - The influence of sensory afferent input on local motor cortical excitatory circuitry in humans. AB - In human, sensorimotor integration can be investigated by combining sensory input and transcranial magnetic stimulation (TMS). Short latency afferent inhibition (SAI) refers to motor cortical inhibition 20-25 ms after median nerve stimulation. We investigated the interaction between SAI and short-interval intracortical facilitation (SICF), an excitatory motor cortical circuit. Seven experiments were performed. Contrary to expectations, SICF was facilitated in the presence of SAI (SICF(SAI)). This effect is specific to SICF since there was no effect at SICF trough 1 when SICF was absent. Furthermore, the facilitatory SICF(SAI) interaction increased with stronger SICF or SAI. SAI and SICF correlated between individuals, and this relationship was maintained when SICF was delivered in the presence of SAI, suggesting an intrinsic relationship between SAI and SICF in sensorimotor integration. The interaction was present at rest and during muscle contraction, had a broad degree of somatotopic influence and was present in different interneuronal SICF circuits induced by posterior anterior and anterior-posterior current directions. Our results are compatible with the finding that projections from sensory to motor cortex terminate in both superficial layers where late indirect (I-) waves are thought to originate, as well as deeper layers with more direct effect on pyramidal output. This interaction is likely to be relevant to sensorimotor integration and motor control. PMID- 25832928 TI - Lifestyle factors and efficacy of lifestyle interventions in gastroesophageal reflux disease patients with functional dyspepsia: primary care perspectives from the LEGEND study. AB - OBJECTIVE: Although gastroesophageal reflux disease (GERD), a very common disorder worldwide, is considered to be a lifestyle disease, the pathogenic role of lifestyle factors and consequently the efficacy of lifestyle interventions, remains controversial. Lifestyle factors associated with GERD and the beneficial effect of specific recommended lifestyle interventions in the primary care setting were evaluated as a post-hoc analysis of the LEGEND study which investigated the effect of lansoprazole in patients with GERD who reported dyspeptic symptoms. METHODS: GERD patients with dyspepsia were treated with lansoprazole 15 mg or 30 mg daily for four weeks. Reflux and dyspeptic symptoms were evaluated using patient-reported questionnaires before and four weeks after the administration of lansoprazole. RESULTS: Among 12,653 patients, "feelings of continued stress" was the most common lifestyle factor (45.6% of patients), and >30% of the patients reported "eating sweet foods at least once every two to three days," "eating greasy foods at least once every two to three days" and "drinking coffee almost daily." Introducing lifestyle interventions had a significant effect on both reflux and dyspeptic symptoms. CONCLUSION: Lifestyle interventions are thus considered to be important in GERD patients with dyspepsia who receive a proton pump inhibitor. PMID- 25832929 TI - Meta-analysis of sequential, concomitant and hybrid therapy for Helicobacter pylori eradication. AB - OBJECTIVE: To compare the efficacy of sequential therapy, concomitant therapy and hybrid therapy for the treatment of Helicobacter pylori (H. pylori) infection. METHODS: PubMed, Web of Science, Medline, Embase, the Cochrane Central Register of Controlled Trials and CNKI were searched up to the end of May 10, 2014 in order to identify all randomized controlled trials (RCTs) reporting the effects of sequential therapy, concomitant therapy and hybrid therapy on H. pylori eradication. The relative risk (RR) of eradicating H. pylori infection after sequential therapy compared with concomitant therapy or hybrid therapy was pooled. The eradication rates were considered both on an intention-to-treat (ITT) and per-protocol (PP) basis. RESULTS: A total of 10 RCTs involving 3,501 patients were included. The pooled data suggested that the differences between the three groups were not statistically significant (ITT analysis: sequential therapy vs. concomitant therapy: RR=1.01, 95%confidence interval (CI): 0.97-1.04, sequential therapy vs. hybrid therapy: RR=1.02, 95%CI: 0.85-1.22, concomitant therapy vs. hybrid therapy: RR=1.03, 95%CI: 0.97-1.08; PP analysis: sequential therapy vs. concomitant therapy: RR=1.00, 95%CI: 0.96-1.03, sequential therapy vs. hybrid therapy: RR=0.97, 95%CI: 0.86-1.09, concomitant therapy vs. hybrid therapy: RR=1.01, 95%CI: 0.93-1.10). In the ITT and PP analyses, the overall eradication rates were 84.3% (95%CI: 79.1-89.4) and 86.4% (95%CI: 81.7-91.0) for the sequential therapy group, 86.7% (95%CI: 81.0-92.3) and 89.8% (95%CI: 85.1-94.5) for the concomitant therapy group and 86.6% (95%CI: 82.3-91.0) and 92.7% (95%CI: 90.5-94.9) for the hybrid therapy group, respectively. There were no significant differences among these therapies in terms of the rate of side effects. CONCLUSION: The pooled evidence suggests that sequential therapy, concomitant therapy and hybrid therapy are similar with respect to the treatment of H. pylori infection. PMID- 25832930 TI - Factors associated with mother-to-child transmission of hepatitis B virus despite immunoprophylaxis. AB - OBJECTIVE: This study aimed to assess risk factors for mother-to-child transmission (MTCT) of hepatitis B virus (HBV) after immunoprophylaxis. METHODS: Risk factors for MTCT were assessed using a multivariate logistic regression model. PATIENTS: We enrolled 256 mother-child pairs with positive maternal hepatitis B surface antigens (HBsAg) between January 2010 and June 2013. All children received passive-active immunization after birth. The children were tested for HBsAg at birth and 6-12 months and/or 1-3 years of age. RESULTS: Among 256 children, 10 (3.9%) developed HBV infection, all of whom were born to hepatitis B e antigen (HBeAg)-positive mothers with a high HBV DNA level (median, 7.36; range, 6.75-8.00 log10 IU/mL). A total of 20 mothers received antiviral treatment during pregnancy. The maternal viral load decreased from an average of 7.16 to 3.08 log10 IU/mL (p<0.0001) at delivery. The multivariate logistic regression analysis showed that a high maternal HBV DNA level [odds ratio (OR) for each log10 IU/mL increase, 2.44; 95% confidence interval (CI), 1.13-5.29, p=0.023] and vaginal delivery (OR=6.96, 95% CI, 1.80-26.93, p=0.005) were risk factors for HBV immunoprophylaxis failure. CONCLUSION: Additional treatment strategies should be considered in HBeAg-positive mothers with an HBV DNA level above 6-7 log10 IU/mL. In addition, our study supports the use of Cesarean section for infants born to HBsAg-positive mothers. PMID- 25832931 TI - Utility of 75-g oral glucose tolerance test results and hemoglobin a1c values for predicting the incidence of diabetes mellitus among middle-aged Japanese men -a large-scale retrospective cohort study performed at a single hospital. AB - OBJECTIVE: The aim of this study was to investigate the associations between the incidence of diabetes and the accumulation of markers of impaired glucose metabolism; i.e., pre-diabetes. METHODS: This retrospective cohort study recruited 1,631 men without diabetes at baseline who attended more than two routine health check-ups at our institution between 2006 and 2012. The participants were divided into four groups based on the number of markers of impaired glucose metabolism exhibited at the initial examination. The following markers of impaired glucose metabolism were defined as risk factors for diabetes: a fasting plasma glucose level of >=110 mg/dL, 2-hour plasma glucose level of >=140 mg/dL and glycated hemoglobin (HbA1c) value of >=6.0% (42 mmol/moL). The risk of developing diabetes was assessed using a multivariate analysis. RESULTS: The median examination interval was 1,092 days. The incidence of diabetes rose in association with the number of markers. The subjects with two markers displayed a multivariate-adjusted odds ratio (OR) for diabetes of 19.43 [95% confidence interval (CI): 9.70-38.97] and the subjects with three markers displayed an OR of 48.30 (95% CI: 20.39-115.85) compared with the subjects with one or no markers. CONCLUSION: The present results demonstrate the impact of accumulating markers of impaired glucose metabolism on the risk of developing diabetes. Anti-diabetes intervention strategies should aim to comprehensively assess an individual's risk of developing diabetes at the pre-diabetes stage. PMID- 25832932 TI - Clinical evaluation of Chinese patients with primary distal renal tubular acidosis. AB - OBJECTIVE: Distal renal tubular acidosis (dRTA) is a hyperchloremic metabolic acidosis disorder characterized by a normal anion gap with abnormal urinary hydrogen (H(+)) excretion. At present, there are few available reports regarding the clinical status of primary dRTA. The primary objective of this study was to analyze the clinical features and outcomes of primary dRTA. METHODS: This was a retrospective study performed in patients with primary dRTA who were hospitalized at Ruijin Hospital between March 1996 and July 2009; the clinical features of these patients were analyzed. RESULTS: This study included 95 consecutive inpatients: 40 men (42.11%) and 55 women (57.89%). Among them, 60 had hypokalemia (63.12%), 29 had complete dRTA and 66 had incomplete dRTA. The mean urine calcium levels of the patients with and without urinary lithiasis were 0.10+/-0.04 and 0.07+/-0.05 mmol/24 h?kg, respectively (p=0.04). The blood pH values of the patients with and those without bone disease were 7.37+/-0.06 and 7.32+/-0.06, respectively (p=0.01). A total of 8.33% (8/27) of the patients had tubular proteinuria. CONCLUSION: Hypokalemia is the most common clinical manifestation of primary dRTA. Primary dRTA can also be accompanied by proximal tubular dysfunction. Controlling the urine calcium and citrate levels is crucial for the treatment of nephrocalcinosis and/or nephrolithiasis, while restoring the blood pH to the normal level is essential for controlling bone disease. PMID- 25832933 TI - Safety and efficacy of bronchoalveolar lavage using a laryngeal mask airway in cases of acute hypoxaemic respiratory failure with diffuse lung infiltrates. AB - Objective Fibre-optic bronchoscopy with bronchoalveolar lavage (FOB-BAL) is an important tool for diagnosing and selecting treatment for acutely hypoxaemic patients with diffuse lung infiltrates. However, FOB-BAL carries a risk of significant hypoxaemia and subsequent tracheal intubation during and after the procedure. The application of FOB-BAL using a laryngeal mask airway (LMA) in combination with continuous positive airway pressure (CPAP) may minimize the incidence of hypoxaemia; however, the safety and efficacy of this procedure have not been investigated. Methods A retrospective chart review was performed from April to September 2013. Data regarding the recovered volume of BAL fluid, incidence of tracheal intubation within eight hours after the completion of FOB BAL, respiratory and haemodynamic parameters and treatment modifications were collected for the evaluation. Results Ten trials of FOB-BAL using an LMA and CPAP were performed in nine patients with severe acute hypoxaemia associated with diffuse lung infiltrates. The BAL fluid recovery rate was 56%, and the procedure was completed without subsequent complications. In addition, the percutaneous arterial oxygen saturation decreased to 95.7%+/-3.8%, although it was never lower than 90.0% during the procedure, and no patients required intubation. Furthermore, the arterial blood pressure significantly but transiently decreased due to sedation, and the procedure yielded diagnostic information in all nine patients. Conclusion FOB-BAL using LMA and CPAP appears to be safe and effective in patients who develop severe acute hypoxaemia. PMID- 25832934 TI - Validity of the chemotherapy-induced peripheral neuropathy self-check sheet. AB - Objective Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side effect of some anti-cancer drugs. However, medical staff frequently encounter difficulties in ascertaining the severity of CIPN. We sought to develop a questionnaire in order to accurately assess CIPN. The validity of this questionnaire was compared with that of free-style interviews. Methods We developed the CIPN self-check sheet by analyzing existing self-assessment tools for CIPN and matching the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grades. From August to December 2011, 77 cancer patients participated in this study. In order to evaluate the validity of the CIPN self-check sheet compared with a free-style interview assessment, the cross classification and kappa coefficients between the CTCAE grades from each assessment and those from a comprehensive assessment were analyzed. The comprehensive assessment utilized information obtained from the medical examination, free-style interview and CIPN self-check sheet. Results Upon completion of the study, 248 CIPN self-check sheets were collected (median number of sheets per patient, 3; range, 1-14). The cross-classification analysis illustrated that the CIPN self-check sheet successfully identified all grade 3 cases. The coefficient of the CIPN self-check sheet was significantly higher than that of the free-style interviews [kappa values: 0.988 (p<0.01) and 0.501 (p<0.01) for the self-check sheet and interviews, respectively]. Conclusion The CIPN self-check sheet can be used to assess the severity of CIPN based on the CTCAE grade more accurately than free-style interviews. PMID- 25832935 TI - Non-occlusive mesenteric ischemia after splenic metastasectomy for small-cell lung cancer. AB - A 68-year-old man presented with severe abdominal pain. Seven months earlier, he had received systemic chemotherapy for small-cell lung cancer with solitary metastasis to the spleen, followed by splenectomy. Abdominal computed tomography and abdominal arterial angiography showed diffuse ischemia of the mesenteric artery without apparent occlusion. The patient also suffered from septicemia caused by Enterococcus faecium. Therefore, a diagnosis of non-occlusive mesenteric ischemia (NOMI) induced by septicemia was supposed. Although treatment with antibiotics and papaverine hydrochloride was administered and the necrotic tissue in the intestinal tract was resected, the patient died. Physicians should be aware that patients undergoing splenectomy are likely to be affected by septicemia, which may subsequently induce NOMI. PMID- 25832936 TI - Tracheobronchitis with dyspnea in a patient with ulcerative colitis. AB - We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patient's respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement. PMID- 25832937 TI - Acute pancreatitis with an intramural duodenal hematoma. AB - The patient was a 43-year-old man admitted to the hospital with intermittent epigastric pain and vomiting, without any evidence of trauma. Blood tests showed elevated lipase/amylase levels. Abdominal computed tomography (CT) revealed pancreatitis complicated by an intramural duodenal hematoma (IDH). He was conservatively treated, and one month after admission, follow-up panendoscopy showed normal duodenal mucosa without luminal narrowing. Non-traumatic IDH is typically associated with coagulation abnormalities. Abdominal CT is an excellent tool for diagnosis in cases of acute abdomen. However, the pathogenesis of and relationship between IDH and pancreatitis remain unknown. PMID- 25832938 TI - Familial and multiple gastrointestinal stromal tumors with fair response to a half-dose of imatinib. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Since our first report in 1998, approximately 30 families with multiple GISTs due to a germline gain-of-function mutation of c-kit have been reported. We herein present a case of a family with multiple GISTs that have a germline c-kit mutation in exon 11 (Del-Val560) in two siblings. One of the patients showed a fair response to treatment with a half-dose of imatinib (200 mg/day). There are few reports describing the response to imatinib in familial GISTs and this drug appears to be a promising therapeutic option. PMID- 25832939 TI - Solitary fibrous tumor of the liver from development to resection. AB - A 55-year-old man was annually followed up for a large hepatic cyst. In 2006, a 20-mm nodule was detected in contact with the cyst that gradually grew thereafter. By 2013, the mass had expanded to 90 mm, and a percutaneous biopsy revealed a solitary fibrous tumor (SFT). Surgical resection was subsequently performed, and the patient has since been doing well for 11 months, without recurrence. SFT of the liver is a rare neoplasm; only 44 cases have been reported to date. This is the first report to describe the long-term progression of hepatic SFT from the time of its development. PMID- 25832940 TI - Hepatic inflammatory pseudotumor associated with xanthogranulomatous cholangitis mimicking cholangiocarcinoma. AB - Inflammatory pseudotumor (IPT) is a rare benign condition often misdiagnosed as malignancy. An 80-year-old man was referred to our clinic for an asymptomatic hepatic mass detected on plain abdominal CT. Abdominal ultrasonography identified the lesion as a poorly defined hypoechoic mass. Although a liver biopsy did not provide any evidence of malignancy, imaging modalities suggested a diagnosis of cholangiocarcinoma. The patient underwent left lobectomy, and the pathological findings were consistent with the features of xanthogranulomatous cholangitis. This case is the first report of hepatic IPT originating from xanthogranulomatous cholangitis without symptoms and illustrates the importance of obtaining a preoperative diagnosis in order to avoid a misdiagnosis of malignant tumor. PMID- 25832941 TI - Hepatitis C-associated osteosclerosis: a new case with long-term follow-up and a review of the literature. AB - Hepatitis C-associated osteosclerosis (HCAO) is an uncommon condition characterized by increased bone density, skeletal pain and elevated bone formation markers. Since 1992, only 17 cases have been reported. We herein describe the case of a 61-year-old woman affected by severe pain involving the lower limbs. The laboratory data showed an elevated serum alkaline phosphatase level, and the patient was found to be seropositive for hepatitis C virus infection. In addition, an X-ray skeleton survey showed marked cortical thickening of both femurs and tibias, and a whole-body bone scan revealed an increased cortical radionuclide uptake in the involved bones. These findings were consistent with a diagnosis of HCAO. In this report, we discuss the patient's clinical course over 16 years and, for the first time, show a normalized radioisotope uptake on bone scanning 10 years after the diagnosis. PMID- 25832942 TI - The transformation of a nonfunctioning islet cell tumor of the pancreas into a proinsulinoma under conditions of lung metastasis. AB - We herein report the first case of a nonfunctioning islet cell tumor that transformed into a proinsulinoma during the process of metastasis to the lungs. This phenomenon was confirmed in a 69-year-old woman with an advanced pancreatic islet cell tumor and multiple liver metastases who later developed multiple lung metastases. She underwent pancreatic resection followed by the administration of chemotherapy and survived for seven years. Although the patient initially had hyperglycemia due to diabetes mellitus, she conversely began to manifest hypoglycemic attacks 63 months postoperatively with the concomitant development of multiple lung metastases. An autopsy revealed that only the tumor in the lungs produced proinsulin; no other hormones were detected. PMID- 25832943 TI - Two cases of delayed cardiac tamponade due to pericarditis after pulmonary vein (PV) isolation for atrial fibrillation. AB - Catheter ablation is an established treatment for atrial fibrillation (AF). The incidence of major complications related to the procedure is reported to be 4.5%, and delayed cardiac tamponade (DCT) is a rare, although recently recognized, complication. However, the mechanisms underlying the development of DCT remain unclear. We herein report the cases of two men, both 49 years of age, who developed cardiac tamponade requiring pericardiocentesis a few weeks after undergoing pulmonary vein isolation for persistent AF. Physicians should explain to the patient the potential for DCT as a complication prior to performing catheter ablation and provide careful follow-up for at least a few weeks after the session. PMID- 25832945 TI - Percutaneous coronary intervention for left main compression syndrome due to severe idiopathic pulmonary arterial hypertension: one year follow-up using intravascular imaging. AB - A 60-year-old woman presented with ST-elevation myocardial infarction due to extrinsic compression of the left main coronary artery (LMCA) caused by a dilated pulmonary artery (PA) with idiopathic pulmonary hypertension and was successfully treated with intravascular ultrasound- and optical coherence tomography-guided stenting. Continuous subcutaneous epoprostenol infusion therapy was initiated immediately after the procedure and increased aggressively. Imaging modalities were extremely useful in making the diagnosis and providing follow-up of LMCA compression syndrome in this case. Over the one-year observation period, a sufficient hemodynamic improvement was obtained, without exacerbation of the PA dilatation, resulting in the absence of compression of the LMCA. PMID- 25832944 TI - Right-sided infective endocarditis with a ruptured sinus of Valsalva and multiple septic pulmonary emboli in a patient with atopic dermatitis. AB - We herein report the case of 34-year-old woman with acute tricuspid valve infective endocarditis (IE) associated with a ruptured sinus of Valsalva and multiple septic pulmonary emboli. She had no history of medical problems, except for atopic dermatitis (AD). Blood cultures identified methicillin-sensitive Staphylococcus aureus. Despite the administration of two months of antibiotic therapy, the patient experienced recurrent pulmonary emboli and developed heart failure due to a left-to-right shunt, whereas the area of vegetation did not change in size. She subsequently underwent surgery for shunt closure and tricuspid valve replacement. The AD was thought to be the cause of the patient's bacteremia, which consequently resulted in aggressive right-sided IE. PMID- 25832946 TI - Reappearance of the left ventricular pressure gradient in a patient with hypertrophic obstructive cardiomyopathy. AB - An 84-year-old woman diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) was referred to our hospital due to chest pain associated with an increased level of troponin T. Following the administration of cibenzoline, the left ventricular outflow pressure gradient (LVPG) completely disappeared. Left ventricular pressure pullback tracing subsequently demonstrated the "reappearance" of the LVPG. Left ventriculography showed apical ballooning with excessive contractions at the base of heart, and we therefore made a diagnosis of Takotsubo cardiomyopathy in a patient with HOCM. Hypercontractions of the base of the heart associated with Takotsubo cardiomyopathy may be responsible for the "reappearance" of LVPG in this case. PMID- 25832947 TI - Diffuse thyroid enlargement following metastasis of lung adenocarcinoma. AB - A 55-year-old man presented with a rapidly enlarging thyroid. He had been diagnosed with lung adenocarcinoma nine months earlier. Computed tomography (CT) and ultrasound (US) detected reticular cord-like structures, but no nodules, in the thyroid. A fine-needle aspiration biopsy (FNAB) of the thyroid revealed thyroglobulin-negative adenocarcinoma cells, thus establishing the diagnosis of diffuse thyroid metastases of lung cancer. Moreover, the fluid demonstrated milky chyliform effusion. This case suggests that the presence of reticular cord-like structures on US and CT may be a key imaging finding for the clinical diagnosis of diffuse thyroid metastases and that chyliform effusion may contribute to rapid goiter formation. PMID- 25832948 TI - Hypercalcemic crisis due to primary hyperparathyroidism occurring concomitantly with Graves' disease. AB - We herein describe a case of hypercalcemic crisis in a 52-year-old Japanese woman. She suffered from thirst and fatigue for one month. Her serum calcium (a) levels were 19.0 mg/dL, and she was diagnosed with hypercalcemic crisis. Circulating levels of parathyroid and thyroid hormones were elevated. She was diagnosed with primary hyperparathyroidism accompanied by Graves' disease. Thyroparathyroidectomy was performed after circulating levels of Ca and thyroid hormones were normalized. Both of primary hyperparathyroidism and Graves' disease can contribute and accelerate hypercalcemia, resulting in a state of crisis. The possibility of their coexistence should therefore be taken into consideration in cases of hypercalcemia. PMID- 25832949 TI - The development of fulminant type 1 diabetes during chemotherapy for rectal cancer. AB - A 34-year-old man with a history of rectal cancer was receiving oral chemotherapy [tegafur-uracil (UFT) with leucovorin]. He visited our hospital due to nausea and abdominal pain, and his laboratory data revealed the presence of urinary ketones, hyperglycemia and high anion gap metabolic acidosis, and HbA1c level of 6.8%. Accordingly, we diagnosed fulminant type 1 diabetes. The development of fulminant type 1 diabetes during chemotherapy for malignancy is a rare, but potentially fatal condition. Therefore, clinicians should consider diabetic ketoacidosis in the differential diagnosis when examining chemotherapy patients who present with gastrointestinal symptoms. PMID- 25832950 TI - Minimal change nephrotic syndrome associated with gefitinib and a successful switch to erlotinib. AB - Minimal change nephrotic syndrome (MCNS) is a common form of nephrotic syndrome (NS). We herein present the case of a 57-year-old woman with advanced lung adenocarcinoma treated with the tyrosine kinase inhibitor (TKI) gefitinib who developed NS. A renal biopsy revealed minor glomerular abnormalities, and the patient's symptoms improved exclusively with the discontinuation of gefitinib. Therefore, we diagnosed her with MCNS associated with gefitinib treatment. A few months later, however, she developed recurrent lung tumors. Following the challenging initiation of the TKI erlotinib, she achieved remission without proteinuria. We thus conclude that erlotinib is a potential treatment option in patients with NS associated with gefitinib therapy. PMID- 25832951 TI - Dapsone hypersensitivity syndrome-related lung injury without eosinophilia in the bronchoalveolar lavage fluid. AB - A 73-year-old man was admitted in respiratory failure that had subacutely progressed after five weeks of dapsone treatment for a skin rash. He also presented with fever, systemic erythroderma and liver dysfunction. Chest computed tomography showed diffuse reticular shadows with ground-glass opacity and bilateral mediastinal lymphadenopathy. Lymphocytes, but not eosinophils, were increased in the bronchoalveolar lavage fluid. Moreover, reactivation of human herpes virus-6 was confirmed on a paired serum test. Finally, we diagnosed the patient with dapsone hypersensitivity syndrome (DHS), a rare adverse event of this drug. Lung injury unaccompanied by eosinophilia in the bronchoalveolar lavage fluid is even more rare as a DHS-related lung manifestation. PMID- 25832952 TI - Alveolar hemorrhage associated with pemetrexed administration. AB - We herein describe a 67-year-old man with advanced adenocarcinoma of the lung who developed an alveolar hemorrhage (AH) associated with pemetrexed. He received four courses of pemetrexed therapy with carboplatin and seven courses of pemetrexed maintenance therapy. One week after the last pemetrexed administration, the patient developed hemoptysis with deteriorating dyspnea and anemia. Chest images showed diffuse ground-glass attenuation. The diagnosis of AH was based on findings of bloody bronchoalveolar lavage (BAL) fluid, hemosiderin laden macrophages in the BAL fluid, and a transbronchial lung biopsy sample. This report is the first to describe AH associated with pemetrexed. PMID- 25832953 TI - Cerebral venous thrombosis as a complication of neuropsychiatric systemic lupus erythematosus. AB - A 51-year-old woman undergoing steroid treatment for systemic lupus erythematosus (SLE) was admitted to our hospital after developing a fever, consciousness disturbance and seizures, leading to a diagnosis of SLE-induced meningoencephalitis. Although steroid therapy improved her symptoms, she complained of post-lumbar puncture thunderclap headaches during follow-up, and cerebral venous thrombosis (CVT) was subsequently diagnosed on magnetic resonance venography and cerebral angiography. This is a rare case of neuropsychiatric SLE complicated by CVT during treatment for aseptic meningoencephalitis. The onset of aseptic meningoencephalitis and administration of the lumbar puncture and steroid therapy may have induced the development of the patient's CVT symptoms. PMID- 25832954 TI - Medullary hemorrhage that preceded the onset of multiple cavernous angiomas. AB - Medullary hemorrhage is rare, and the causative role of hypertension still remains controversial. Cavernous angioma and other vascular malformations have been reported to cause medullary hemorrhage. A 53-year-old man was admitted to our hospital for vertigo. Medullary hemorrhage and multiple small hypointense lesions were detected on T2-star weighted magnetic resonance imaging (T2*W MRI). One and four months later, the appearance of new lesions confirmed the diagnosis of cerebral cavernous angioma. Cavernous angioma is often characterized by de novo appearance/progression on MRI. A follow-up MRI is required to diagnose cavernous angioma in patients with medullary hemorrhage. PMID- 25832955 TI - Central nervous system manifestations of tuberculosis-associated immune reconstitution inflammatory syndrome during adalimumab therapy: a case report and review of the literature. AB - A 64-year-old neurologically asymptomatic woman with rheumatoid arthritis who was treated with the tumor necrosis factor (TNF)-alpha antagonist adalimumab developed disseminated tuberculosis (TB). After receiving anti-TB therapy and discontinuing adalimumab, she exhibited paradoxical worsening due to immune reconstitution inflammatory syndrome (IRIS) with the appearance of meningitis and brain tuberculomas. This case indicates that continuing anti-TNF therapy may be necessary to prevent IRIS in patients who develop TB, particularly disseminated TB, during the course of anti-TNF therapy. In addition, careful screening for central nervous system (CNS) TB should be performed prior to the initiation of therapy, as even neurologically asymptomatic patients can develop CNS manifestations of IRIS. PMID- 25832957 TI - Ruptured mycotic aneurysm and microbleeds in a patient with infective endocarditis. PMID- 25832956 TI - Native valve endocarditis caused by Neisseria elongata Subsp. nitroreducens. AB - Neisseria elongata, a normal resident in the human oral cavity, rarely causes invasive infections. We herein report a case of endocarditis caused by Neisseria elongata subsp. nitroreducens that occurred in a patient without any apparent cardiac complications. The patient received aortic valve replacement following the administration of intravenous beta-lactam for five weeks. To our knowledge, this is the first published case in Japan of N. elongata infection in a patient without a prosthetic device. PMID- 25832958 TI - "Hot cross bun" sign associated with SCA1. PMID- 25832959 TI - Rotator cuff tear mimicking cerebral infarction. PMID- 25832960 TI - A case of progressive elephantiasis nostras verrucosa. PMID- 25832961 TI - Acquired hemophilia. PMID- 25832962 TI - Fibrodysplasia ossificans progressiva misdiagnosed as cervical exostosis. PMID- 25832963 TI - ADIPOQ polymorphisms are associated with insulin resistance in Japanese women. AB - Visceral fat accumulation contributes to the development of insulin resistance, leading to metabolic syndrome. Adiponectin provides a link between visceral fat accumulation and insulin resistance. In addition to environmental factors, genetic factors play important roles in visceral fat accumulation and circulating adiponectin levels. Genome-wide association studies (GWASs) have identified genetic variations in the adiponectin, C1Q and collagen domain containing (ADIPOQ) gene that are associated with adiponectin levels. In this study, we investigated whether ADIPOQ single nucleotide polymorphisms (SNPs) were associated with visceral fat accumulation and insulin resistance. We measured the visceral fat area (VFA) by computed tomography (CT) and examined the presence of the insulin resistance-related phenotype (fasting plasma glucose, fasting insulin, and homeostasis model assessment-insulin resistance [HOMA-IR]) in a set of Japanese individuals (731 men and 864 women) who were genotyped for seven ADIPOQ SNPs reported by recent GWASs (namely, rs6810075, rs10937273, rs1648707, rs864265, rs182052, rs17366568, and rs6773957). SNPs associated with the phenotype (P < 0.05) were then evaluated by association analysis using a second set of the study participants (383 men and 510 women). None of the SNPs was associated with body mass index (BMI) or VFA in men or women. However, the adiponectin-decreasing alleles of rs10937273 and rs1648707 were significantly associated with HOMA-IR (P = 0.0030 and P = 0.00074, respectively) in women, independently of BMI. These SNPs were significantly associated with decreased adiponectin levels in women. Our results suggested that rs10937273 and rs1648707 may affect insulin sensitivity by regulating adiponectin production by adipose tissue in women. PMID- 25832964 TI - Validity of activity monitors worn at multiple nontraditional locations under controlled and free-living conditions in young adult women. AB - The purpose of this study was to examine the validity of counting steps and computing indices of moderate-to-vigorous physical activity (MVPA) using miniature activity monitors with 3-D technology worn at various locations under controlled (CON) and free-living conditions (FL). Kenz e-style2, Tanita Calorism Smart, and Omron Calori Scan HJA-306 activity monitors were assessed. Nine and 31 young adult women were assigned to the CON and FL studies, respectively. While walking or jogging on a treadmill at 5 different speeds, the subjects simultaneously carried the 3 different monitors in a pants pocket (PP), a chest shirt pocket, and a shoulder bag (B). Under the FL condition, the 3 monitors were placed only at the PP and B locations for practical reasons. Significant effects of monitor location and walking/jogging speed on the step count measured by the 3 monitors were evaluated under the CON condition. Monitors placed at both PP and B tended to underestimate the number of steps; however, there were no significant differences between the values obtained with the Kenz monitor and those obtained with a criterion accelerometer under the FL condition. Moreover, strong correlations were observed between steps measured by monitors placed at PP and steps measured by the criterion accelerometer. The amount of MVPA for the PP location and the non-carrying duration of the bag for the B location were considered to be important determinants of the accuracy of step counting under the FL condition. In conclusion, monitors placed at the PP location, especially the Kenz monitor, showed acceptable accuracy for young adult women in real-life settings. In contrast, MVPA indices assessed using these monitors showed limited validity. PMID- 25832965 TI - The third hand: low rates of stethoscope hygiene on general medical services. PMID- 25832966 TI - Cost-effectiveness of heat and moisture exchangers compared to usual care for pulmonary rehabilitation after total laryngectomy in Poland. AB - The beneficial physical and psychosocial effects of heat and moisture exchangers (HMEs) for pulmonary rehabilitation of laryngectomy patients are well evidenced. However, cost-effectiveness in terms of costs per additional quality-adjusted life years (QALYs) has not yet been investigated. Therefore, a model-based cost effectiveness analysis of using HMEs versus usual care (UC) (including stoma covers, suction system and/or external humidifier) for patients after laryngectomy was performed. Primary outcomes were costs, QALYs and incremental cost-effectiveness ratio (ICER). Secondary outcomes were pulmonary infections, and sleeping problems. The analysis was performed from a health care perspective of Poland, using a time horizon of 10 years and cycle length of 1 year. Transition probabilities were derived from various sources, amongst others a Polish randomized clinical trial. Quality of life data was derived from an Italian study on similar patients. Data on frequencies and mortality-related tracheobronchitis and/or pneumonia were derived from a Europe-wide survey amongst head and neck cancer experts. Substantial differences in quality-adjusted survival between the use of HMEs (3.63 QALYs) versus UC (2.95 QALYs) were observed. Total health care costs/patient were 39,553 PLN (9465 Euro) for the HME strategy and 4889 PLN (1168 Euro) for the UC strategy. HME use resulted in fewer pulmonary infections, and less sleeping problems. We could conclude that given the Polish threshold of 99,000 PLN/QALY, using HMEs is cost-effective compared to UC, resulting in 51,326 PLN/QALY (12,264 Euro/QALY) gained for patients after total laryngectomy. For the hospital period alone (2 weeks), HMEs were cost saving: less costly and more effective. PMID- 25832967 TI - Effectiveness of various methods of formaldehyde neutralization using monoethanolamine. AB - Formaldehyde is the most commonly used fixative chemical for the preservation of human cadavers used for educational purposes in the United States. Formaldehyde is also a known carcinogenic agent whose exposure level is regulated by guidelines of the Occupational Safety and Health Administration. Various methods for formaldehyde neutralization exist, yet many donations programs do not take any steps to neutralize the formaldehyde in embalmed donor bodies. The effectiveness of monoethanolamine (MEA) in neutralizing formaldehyde is well documented when used as a final injection during embalming. The purpose of this study is to report the effectiveness of several post-embalming techniques of formaldehyde neutralization. Twenty-four donor bodies were assigned to four experimental groups of six. For the three experimental groups, the techniques tested involve delivery of a 20:1 dilution of deionized water:MEA via recannulization and gravity flow infusion, compartment injection, and alternate wetting solution containing four percent MEA. Our results indicated that spray bottle delivery was not effective in neutralization of formaldehyde compared to the control group, but that formaldehyde levels decreased when recannulization or compartment injection were used. The most effective method of formaldehyde neutralization was compartment injection of MEA solution (P < 0.01). The results of this study indicate that, in situations where MEA is not used as a final infusion during embalming, compartment injection of MEA solution is an effective method of formaldehyde neutralization. PMID- 25832968 TI - Clinical practice guideline (update): adult sinusitis. AB - OBJECTIVE: This update of a 2007 guideline from the American Academy of Otolaryngology--Head and Neck Surgery Foundation provides evidence-based recommendations to manage adult rhinosinusitis, defined as symptomatic inflammation of the paranasal sinuses and nasal cavity. Changes from the prior guideline include a consumer added to the update group, evidence from 42 new systematic reviews, enhanced information on patient education and counseling, a new algorithm to clarify action statement relationships, expanded opportunities for watchful waiting (without antibiotic therapy) as initial therapy of acute bacterial rhinosinusitis (ABRS), and 3 new recommendations for managing chronic rhinosinusitis (CRS). PURPOSE: The purpose of this multidisciplinary guideline is to identify quality improvement opportunities in managing adult rhinosinusitis and to create explicit and actionable recommendations to implement these opportunities in clinical practice. Specifically, the goals are to improve diagnostic accuracy for adult rhinosinusitis, promote appropriate use of ancillary tests to confirm diagnosis and guide management, and promote judicious use of systemic and topical therapy, which includes radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia. ACTION STATEMENTS: The update group made strong recommendations that clinicians (1) should distinguish presumed ABRS from acute rhinosinusitis (ARS) caused by viral upper respiratory infections and noninfectious conditions and (2) should confirm a clinical diagnosis of CRS with objective documentation of sinonasal inflammation, which may be accomplished using anterior rhinoscopy, nasal endoscopy, or computed tomography. The update group made recommendations that clinicians (1) should either offer watchful waiting (without antibiotics) or prescribe initial antibiotic therapy for adults with uncomplicated ABRS; (2) should prescribe amoxicillin with or without clavulanate as first-line therapy for 5 to 10 days (if a decision is made to treat ABRS with an antibiotic); (3) should reassess the patient to confirm ABRS, exclude other causes of illness, and detect complications if the patient worsens or fails to improve with the initial management option by 7 days after diagnosis or worsens during the initial management; (4) should distinguish CRS and recurrent ARS from isolated episodes of ABRS and other causes of sinonasal symptoms; (5) should assess the patient with CRS or recurrent ARS for multiple chronic conditions that would modify management, such as asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia; (6) should confirm the presence or absence of nasal polyps in a patient with CRS; and (7) should recommend saline nasal irrigation, topical intranasal corticosteroids, or both for symptom relief of CRS. The update group stated as options that clinicians may (1) recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation for symptomatic relief of viral rhinosinusitis; (2) recommend analgesics, topical intranasal steroids, and/or nasal saline irrigation) for symptomatic relief of ABRS; and (3) obtain testing for allergy and immune function in evaluating a patient with CRS or recurrent ARS. The update group made recommendations that clinicians (1) should not obtain radiographic imaging for patients who meet diagnostic criteria for ARS, unless a complication or alternative diagnosis is suspected, and (2) should not prescribe topical or systemic antifungal therapy for patients with CRS. PMID- 25832969 TI - Antibiotic prescribing in long-term care facilities: a meta-synthesis of qualitative research. AB - OBJECTIVES: The objective of this review was to synthesize the findings of qualitative studies investigating the factors influencing antibiotic prescribing in long-term care facilities (LTCFs). These findings will inform the development of future antimicrobial stewardship strategies (AMS) in this setting. METHODS: We searched Embase, PubMed, PsycInfo, Social Science Citations Index and Google Scholar for all qualitative studies investigating health care professionals' views on antibiotic prescribing in LTCFs. The quality of the papers was assessed using the Critical Appraisal Skills Programme (CASP) assessment tool for qualitative research. Thematic synthesis was used to integrate the emergent themes into an overall analytical theme. RESULTS: The synthesis of eight qualitative studies indicated that health care professionals and administrators have identified factors that influence antibiotic prescribing in LTCFs. These factors include variations in knowledge and practice among health care professionals, and the LTCF context, which is unique given the complex patient population and restricted access to doctors and diagnostic tests. The social factors underpinning the interaction between nurses, residents' families and doctors also influence decision making around antibiotic prescribing. The study also found that there is an acknowledged need for collaborative, evidence-based AMS specific to LTCFs, as antibiotic prescribing is heavily influenced by factors unique to this setting. CONCLUSION: This review highlighted the key contextual challenges for AMS in LTCFs. The findings provide an in-depth insight into the factors--such as the LTCF context, social factors, variability in knowledge and prescribing practices, and antimicrobial resistance--that impact on antibiotic prescribing and AMS strategies. These factors must be considered in order to ensure the feasibility and applicability of future AMS interventions. PMID- 25832971 TI - Long-term Plans for Those Selecting Hospital Medicine as an Initial Career Choice. AB - BACKGROUND: The proportion of the newly graduated pediatric workforce that becomes hospitalists has been increasing slightly over the past decade. However, it is unknown what proportion of those who accept hospitalist positions as their first job intend to remain in the field longer term. This is important to workforce projections regarding the magnitude of those who will function in this role. METHODS: The American Board of Pediatrics incorporated a structured questionnaire within the online application process to the General Pediatrics certification application. Respondents identified as residents or chief residents who selected "hospitalist position" as their immediate postresidency plan were the focus this study. We compared survey responses by gender and location of the medical school attended. RESULTS: Since the initiation of the general pediatrics certification examination application survey, 6335 completed the questionnaire. 79% (n=5001) were either in residency training or were a chief resident. Of those, 8% (n=376) reported they planned to work as a pediatric hospitalist immediately after completing residency. Fewer than half (43%; n=161) reported this to be their long-term career plan. This finding varied by both medical school type and by gender. CONCLUSIONS: The majority of pediatric residents and chief residents who take hospitalist positions immediately after training do not intend for hospital practice to be the long-term focus of their careers. As the field of hospital medicine continues to develop, understanding career trajectories can help inform current and future efforts regarding the potential for different mechanisms for training and certification. PMID- 25832970 TI - Potentially inappropriate anticholinergic medication use in community-dwelling older adults: a national cross-sectional study. AB - BACKGROUND: Inappropriate medications are often used in older adults despite their unfavourable risk-to-benefit profile. Although many of the medications in the American Geriatrics Society (AGS) Beers list are potentially inappropriate because of their anticholinergic properties, little is known regarding the nature and extent of potentially inappropriate anticholinergic medication use in older adults. OBJECTIVES: To determine the prevalence of, and factors associated with, potentially inappropriate anticholinergic medication use in the older population. METHODS: A retrospective, cross-sectional study was conducted, involving older adults (aged 65 years and older), using 2009-2010 Medical Expenditure Panel Survey (MEPS) data. The 2012 AGS Beers Criteria were used to define potentially inappropriate anticholinergic medications on the basis of the list of medications to avoid using in older adults irrespective of the diagnosis. Descriptive analyses were used to examine the nature and extent of potentially inappropriate anticholinergic medication use. Multivariable logistic regression within the conceptual framework of the Andersen Behavioral Model was used to identify the factors associated with potentially inappropriate anticholinergic use in older adults. RESULTS: According to the MEPS, there were 78.60 million older adults in the USA; an estimated 7.51 million (9.56 %) of these older adults used potentially inappropriate anticholinergic medications in 2009-2010. The most frequently used potentially inappropriate anticholinergics were cyclobenzaprine, promethazine, amitriptyline, hydroxyzine and dicyclomine. Multivariable regression analyses revealed that female sex, residing in the South and the presence of anxiety disorder increased the likelihood of receiving potentially inappropriate anticholinergic medications, whereas older adults aged 75-84 or >= 85 years, and those with over 15 years of education, had a decreased likelihood of receiving potentially inappropriate anticholinergic medications. CONCLUSION: The study found that approximately one in ten older adults used potentially inappropriate anticholinergic medications. Several predisposing, enabling and need factors were associated with the use of potentially inappropriate anticholinergic medications. Concerted efforts are needed to optimize potentially inappropriate anticholinergic medication use in older adults. PMID- 25832972 TI - Variability of intensive care management for children with bronchiolitis. AB - OBJECTIVE: To determine the extent of variability in testing and treatment of children with bronchiolitis requiring intensive care. METHODS: This prospective, multicenter observational study included 16 academic children's hospitals across the United States during the 2007 to 2010 fall and winter seasons. The study included children<2 years old hospitalized with bronchiolitis who required admission to the ICU and/or continuous positive airway pressure (CPAP) within 24 hours of admission. Among the 2207 enrolled patients with bronchiolitis, 342 children met inclusion criteria. Clinical data and nasopharyngeal aspirates were collected. RESULTS: Respiratory distress severity scores and intraclass correlation coefficients were calculated. The study patients' median age was 2.6 months, and 59% were male. Across the 16 sites, the median respiratory distress severity score was 5.1 (interquartile range: 4.5-5.4; P<.001). The median value of the percentages for all sites using CPAP was 15% (range: 3%-100%), intubation was 26% (range: 0%-100%), and high-flow nasal cannula (HFNC) was 24% (range: 0% 94%). Adjusting for site-specific random effects (as well as children's demographic characteristics and severity of bronchiolitis), the intraclass correlation coefficient for CPAP and/or intubation was 21% (95% confidence interval: 8-44); for HFNC, it was 44.7% (95% confidence interval: 24-67). CONCLUSIONS: In this multicenter study of children requiring intensive care for bronchiolitis, we identified substantial institutional variability in testing and treatment, including use of CPAP, intubation, and HFNC. These differences were not explained by between-site differences in patient characteristics, including severity of illness. Further research is needed to identify best practices for intensive care interventions for this major cause of pediatric hospitalization. PMID- 25832974 TI - Voluntary implementation of critical congenital heart disease screening in Washington hospitals. AB - OBJECTIVES: To determine the extent of voluntary implementation of pulse oximetry screening for critical congenital heart disease (CCHD) in Washington. At the time of the study, there was no state legislative or regulatory mandate for CCHD screening in Washington. METHODS: A Web-based survey was sent to the nurse manager or nurse educator of the well newborn unit at each of the 64 Washington hospitals with active delivery services in May and June 2013. Telephone follow-up was conducted for incomplete surveys. The survey assessed awareness and implementation of the recommendation, the protocol followed, staffing and equipment issues, pediatric cardiology support services, and the availability of prostaglandin E1 at each birth hospital. A brief follow-up was performed in December 2013 for hospitals not screening at the time of the initial survey. RESULTS: As of December 2013, 89% of Washington birth hospitals (accounting for 91.4% of births) had active CCHD screening programs. The recommended protocol is used in 95% of screening hospitals. Screening programs were instituted in 96% of hospitals using existing staff, but 52% of hospitals purchased new durable equipment to institute screening. CONCLUSIONS: There has been widespread voluntary adoption of pulse oximetry screening for CCHD in Washington birth hospitals. Quality assurance efforts are needed to assess the quality of the screening programs. PMID- 25832975 TI - Effect of early-onset sepsis evaluations on in-hospital breastfeeding practices among asymptomatic term neonates. AB - OBJECTIVE: To examine the effect of separation for early-onset sepsis (EOS) evaluations due to perinatal risk factors on breastfeeding practices among asymptomatic term newborns. METHODS: This observational study included 692 nulliparous women with term, singleton uncomplicated pregnancies who intended to breastfeed and whose infants were well appearing at birth. We examined the rate of early breastfeeding initiation (within 2 hours of birth) and formula supplementation (in the first 24 hours) among this mother-infant cohort. RESULTS: Asymptomatic infants separated for EOS evaluation within 2 hours of birth were more likely to have delayed initiation of breastfeeding (46.5% vs 12.5%; P<.001). This association remained significant when adjusted for potential confounders (adjusted odds ratio [aOR]: 5.5 [95% confidence interval (CI): 3.4-8.9]; P<.001). Among infants separated for EOS evaluation, mother-infant time together of <=0.5 hour in the first 2 hours of life significantly delayed initiation (aOR: 8.9 [95% CI: 1.5-53.7]; P=.02) compared with infants spending >1.5 hours with their mothers. In bivariate analysis, both separation and initiation were associated with formula supplementation. After adjusting for confounders, only delayed initiation remained significantly associated with supplementation (aOR: 1.9 [95% CI: 1.1-3.5]; P=.03). CONCLUSIONS: Early separation of asymptomatic infants from their mothers for EOS evaluation was significantly associated with delayed initiation of breastfeeding, which in turn was associated with increased formula supplementation in the first day of life. This unintended consequence of EOS evaluations among asymptomatic infants may be minimized by delaying early separation for performance of the evaluation, attempting breastfeeding initiation before separation, and/or applying more efficient criteria for identifying infants requiring evaluation. PMID- 25832973 TI - Variation in the use of procedural sedation for incision and drainage of skin and soft tissue infection in pediatric emergency departments. AB - OBJECTIVES: Little is known about procedural sedation use for anxiety and pain associated with skin and soft tissue infections (SSTIs) requiring incision and drainage (I&D). Our objectives were therefore (1) to characterize the use of procedural sedation use for SSTI I&D procedures in pediatric emergency departments (EDs), (2) to compare the frequency of procedural sedation for I&D across hospitals, and (3) to determine factors associated with use of procedural sedation for I&D. METHODS: We performed a retrospective cohort study of pediatric EDs contributing to the Pediatric Health Information Systems database in 2010. Cases were identified by primary International Classification of Diseases, 9th revision, Clinical Modification procedure codes for I&D. We used descriptive statistics to describe procedural sedation use across hospitals and logistic generalized linear mixed models to identify factors associated with use of procedural sedation. RESULTS: There were 6322 I&D procedures, and procedural sedation was used in 24% of cases. Hospital-level use of procedural sedation varied widely, with a range of 2% to 94% (median 17%). Procedural sedation use was positively associated with sensitive body site, female gender, and employer based insurance, and negatively associated with African American race and increasing age. Estimates of hospital-level use of procedural sedation for a referent case eliminating demographic differences exhibit similar variability with a range of 5% to 97% (median 34%). CONCLUSIONS: Use of procedural sedation for SSTI I&D varies widely across pediatric EDs, and the majority of variation is independent of demographic differences. Additional work is needed to understand decision-making and to standardize delivery of procedural sedation in children requiring I&D. PMID- 25832976 TI - Pediatric hospitalist perceptions regarding trainees' effects on cost and quality of care. AB - OBJECTIVE: To determine pediatric hospitalists' perceptions about residents' effects on cost and quality of care and their own ability to provide and teach cost-effective, high-quality care. METHODS: A 15-item survey assessing hospitalist perceptions of resident impact on costs/quality and their role in teaching cost-effectiveness was developed and sent to 180 hospitalists from 113 institutions in the United States. RESULTS: Of 180 hospitalists surveyed, 127 completed surveys (71%). Overall, 76 (60%) and 91 (72%) hospitalists believed that residents increase quality and cost of care, respectively. Respondents who worked with residents all the time were more likely to state that residents increase quality (50 of 70 [71%]) compared with those who worked with residents sometimes (18 of 42 [43%]) or never (8 of 15 [53%]; P=.01). Similarly, academic hospitalists were more likely than community hospitalists to believe that residents increase quality (67 of 103 [65%] vs 9 of 24 [38%]; P=.03). Although only 28 (22%) respondents reported receiving formal cost-effectiveness training, 116 (91%) believed that they provided cost-effective care, and 103 (81%) believed that they were qualified to teach this topic. Most respondents (n=115 [91%]) believed that residents should participate in a cost-effectiveness curriculum. CONCLUSIONS: Most respondents felt trainees increase both the costs and quality of care for hospitalized children. The perception of increased quality was associated with increased resident interaction, whereas cost perceptions were similar across groups. Pediatric hospitalists report a lack of formal cost effectivesness training, but nearly all respondents supported the incorporation of such training into graduate medical education programs. PMID- 25832977 TI - The effectiveness of family-centered transition processes from hospital settings to home: a review of the literature. AB - BACKGROUND AND OBJECTIVES: The quality of care transitions is of growing concern because of a high incidence of postdischarge adverse events, poor communication with patients, and inadequate information transfer between providers. The objective of this study was to conduct a targeted literature review of studies examining the effectiveness of family-centered transition processes from hospital and emergency department (ED)-to-home for improving patient health outcomes and health care utilization. METHODS: We conducted an electronic search (2001-2012) of PubMed, CINAHL, Cochrane, PsycInfo, Embase, and Web of Science databases. Included were experimental studies of hospital and ED-to-home transition interventions in pediatric and adult populations meeting the following inclusion criteria: studies evaluating hospital or ED-to-home transition interventions, study interventions involving patients/families, studies measuring outcomes<=30 days after discharge, and US studies. Transition processes, principal outcome measures (patient health outcomes and health care utilization), and assessment time-frames were extracted for each study. RESULTS: The search yielded 3458 articles, and 16 clinical trials met final inclusion criteria. Four studies evaluated pediatric ED-to-home transitions and indicated family-tailored discharge education was associated with better patient health outcomes. Remaining trials evaluating adult hospital-to-home transitions indicated a transition needs assessment or provision of an individualized transition record was associated with better patient health outcomes and reductions in health care utilization. The effectiveness of postdischarge telephone follow-up and/or home visits on health care utilization showed mixed results. CONCLUSIONS: Patient-tailored discharge education is associated with improved patient health outcomes in pediatric ED patients. Effective transition processes identified in the adult literature may inform future quality improvement research regarding pediatric hospital-to-home transitions. PMID- 25832978 TI - Counting Hospitalists--Does it Matter? PMID- 25832979 TI - Persistent lethargy, hypothermia, and failure to thrive in a neonate. PMID- 25832980 TI - Should we make less fuss about pus? PMID- 25832981 TI - Use of IVIg to identify potential miRNA targets for allograft rejection and GvHD therapy. AB - Allograft rejection (AR) and graft-versus-host disease (GvHD) are serious complications following transplantation. Micro-RNAs (miRNAs) have recently been identified as key players in the regulation of these disorders. Because intravenous immunoglobulin (IVIg) has shown therapeutic potential for the prophylaxis and post-transplant reduction of AR and GvHD, we hypothesized that the effect of IVIg could result from the modulation of specific miRNA expression. To identify such miRNA, we performed mixed lymphocyte reactions (MLRs) as an in vitro model of AR and GvHD, with or without IVIg. We herein show that IVIg strongly inhibits the MLRs. This inhibition is associated with a modulation in the expression of miRNAs implicated in the regulation of pro-inflammatory cytokine (IL-2, IL-6, IFN-gamma) and costimulatory molecule (CD80) expression. We propose that these identified miRNAs could represent potential therapeutic targets for the prevention and therapy of AR and GvHD. PMID- 25832982 TI - Excellent graphitic carbon nitride nanosheets-based photoelectrochemical platform motivated by Schottky barrier and LSPR effect and its sensing application. AB - A visible light responsive photocatalytic hybrid with excellent photoelectrochemical activity was first fabricated via the self-assembly of Au nanorods onto poly(l-cysteine) modified graphitic carbon nitride nanosheets. Herein, layered structural graphitic carbon nitride nanosheets with a proper band gap, high stability, and nontoxicity, as a photoactive material, demonstrate a high photocatalytic activity. Furthermore, the incorporation of multifunctional Au nanorods gave the hybrid a Schottky barrier and localized surface plasmonic resonance, which considerably enhanced the separation of the photo-excited electrons and holes, resulting in increased photoelectrochemical performance. As a proof of concept, mercapto-beta-cyclodextrin as a bionic recognition device was introduced into the hybrid to selectively detect naringin on the basis of the dramatic decreasing of photocurrent. The visible-light driven photoelectrochemical sensor exhibited excellent analytical performance, including high sensitivity, good selectivity and wide linear range from 1 * 10(-4) to 1 * 10(-10) M. PMID- 25832984 TI - Contemporary relevance of TID: Based on the company it keeps. PMID- 25832983 TI - Imaging in patients after cardiac transplantation and in patients with ventricular assist devices. AB - The field of cardiac imaging and the management of patients with severe heart failure have advanced substantially during the past 10 years. Cardiac transplantation offers the best long-term survival with high quality of life for the patients with end stage heart failure. However, acute cardiac rejection and cardiac allograft vasculopathy (CAV) can occur post cardiac transplantation and these problems necessitate regular surveillance. The short-term success of mechanical circulatory support devices (MCSD), such as ventricular assist devices (VADs), in improving survival and quality of life has led to a dramatic growth of the patient population with these devices. The development of optimal imaging techniques and algorithms to evaluate these advanced heart failure patients is evolving and multimodality non-invasive imaging approaches and invasive techniques are commonly employed. Most of the published studies done in the transplant and VAD population are small, and biased based on the strength of the particular program, and there is a relative lack of published protocols to evaluate these patient groups. Moreover, the techniques of echocardiography, computed tomography (CT), magnetic resonance imaging, and nuclear cardiology have all progressed rapidly in recent years. There is thus a knowledge gap for cardiologists, radiologists, and clinicians, especially regarding surveillance for CAV and ideal imaging approaches for patients with VADs. The purpose of this review article is to provide an overview of different noninvasive imaging modalities used to evaluate patients after cardiac transplantation and for patients with VADs. The review focuses on the role of echocardiography, CT, and nuclear imaging in surveillance for CAV and rejection and on the assessment of ventricular structure and function, myocardial remodeling and complications for VAD patients. PMID- 25832985 TI - The Pattern of Adjustments after Laparoscopic Adjustable Gastric Band. AB - BACKGROUND: The success of laparoscopic adjustable gastric band (LAGB) is dependent on gradual adjustments over time. The aim of this study is to describe that pattern of LAGB adjustments that are required after surgery. METHODS: A non randomized observational study of consecutive LAGB from a single practise. Patients were sourced from a prospective database. Details of each LAGB adjustment were recorded along with weight loss and complications. RESULTS: There were 125 consecutive LAGB between March 2009 and September 2011 (mean age 46.6 +/ 11.9 years; 113 female, BMI 42.1 +/- 5.9 kg/m(2)). The mean %EBWL was 41.4 +/- 19.1 % at 2 years. There was a total of 746 band adjustments with mean 7.1 +/- 4.4 per patient. Approximately, a third of patients (34 %) reached optimal volume within 6 months but 49 patients (39 %) still required adjustments beyond a year. Weight loss was maximal prior to the first adjustment (41 % of mean total weight loss). The rate of weight loss decreased down to 1-3 %EBWL between later fills despite repeated increases in band volume. Urgent deflations were required in 63 patients with 24 of these patients having multiple overfills. There were two patients who had gastric prolapse but no other LAGB-related complications occurred in the first 2 years after surgery. CONCLUSIONS: LAGB requires a considerable postoperative commitment that may take several months. Overfills are common and may be the result of a false perception that tightening the band will hasten weight loss. PMID- 25832987 TI - Optimizing fluid management of diabetic ketoacidosis. PMID- 25832986 TI - Bariatric Surgery in Patients with Dialysis-Dependent Renal Failure. AB - BACKGROUND: Laparoscopic procedures for the treatment of morbid obesity are commonly offered to patients with comorbidities previously thought to carry prohibitive operative risk. In this study, we reviewed characteristics and perioperative outcomes of patients with dialysis-dependent renal failure (DDRF) who underwent laparoscopic bariatric procedures. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2006 to 2011 was reviewed. Preoperative characteristics and 30-day outcome data of patients who underwent three common laparoscopic procedures were analyzed using ANOVA and Pearson chi-squared tests. RESULTS: One hundred thirty-eight patients (52.5 % female) with DDRF and a median body mass index (BMI) of 45.5 kg/m(2) were identified; 33.8 % (n = 47) underwent laparoscopic banding (LAGB), 48.9 % (n = 68) laparoscopic Roux-en-Y gastric bypass (RYGB), and 16.5 % (n = 23) laparoscopic sleeve gastrectomy (LSG). No differences were found among groups in age, prevalence of American Society of Anesthesiology IV classification, BMI, weight, gender, prevalence of diabetes, and vascular or neurologic comorbidities. Total operation time and length of hospital stay were significantly different between groups. Mortality was 0.7 %, and overall morbidity was 5.8 %. The case mix reflected a decrease in LAGB procedures from 45.5 to 23.3 % from 2006-2009 to 2010-2011 and an increase in LSG procedures from 9.1 to 24.7 % (p < 0.006). CONCLUSIONS: When performed in selected DDRF patients, bariatric surgery is safe. An increase in LSG with a concurrent decline in LAGB procedures was demonstrated over the period of the study. PMID- 25832988 TI - Neuroimaging experience in pediatric Horner syndrome. AB - BACKGROUND: Horner syndrome in children is rare. The frequency and spectrum of malignancy as the cause of Horner syndrome in children remains unclear. Also unclear is whether the imaging work-up should include the entire oculo sympathetic pathway or should be more targeted. In addition, the value of cross sectional angiographic imaging in Horner syndrome is uncertain. OBJECTIVE: To review imaging pathology in a cohort of children with Horner syndrome at a major academic pediatric medical center. MATERIALS AND METHODS: We reviewed a 22-year period of CT and MR imaging studies in children with a clinical diagnosis of Horner syndrome referred for imaging. RESULTS: We found 38 patients who fulfilled study criteria of Horner syndrome and 6/38 had relevant imaging findings: 2/6 etiologies were neoplastic (congenital neuroblastoma and central astrocytoma), 1/6 had a vascular abnormality (hypoplastic carotid artery), 1/6 had maldevelopment (Chiari I malformation), and 2/6 had inflammatory/traumatic etiology (viral cervical lymphadenopathy, post jugular vein cannulation). There was a similar number of congenital and acquired pathologies. The malignancies were found at any level of the oculosympathetic pathway. CONCLUSION: There are treatable causes, including malignancies, in children presenting with Horner syndrome, which justify imaging work-up of the entire oculosympathetic pathway, unless the lesion level can be determined clinically. PMID- 25832990 TI - Pregnancy outcome at term in low-risk population: study at a tertiary obstetric hospital. AB - AIM: The aim of this study was to evaluate the risk of perinatal death and peripartum morbidity at term amongst the models of care at a single tertiary hospital. MATERIAL AND METHODS: This is a 10-year population study of singleton births at term at the Mercy Hospital for Women comparing the mixed-risk models of care (private obstetrician and a conventional collaborative model of obstetricians and midwives) with the low-risk models (team midwifery and family birth center). Outcome measures included rates of perinatal death, low Apgar scores and obstetric procedures. RESULTS: Data on 44 557 normal term singletons were available for study. Overall, the hospital has a substantially lower term singleton perinatal mortality (1.3/1000) than the reported rate from the state of Victoria over an overlapping period (2.4/1000). The perinatal mortality amongst women selected for low obstetric risk (2.3/1000) was significantly higher than the perinatal mortality in other patients (1.2/1000; P = 0.03). Low Apgar scores at 5 min were also significantly more likely in women selected for low obstetric risk (9.0 vs 6.7/1000; P = 0.03). The differences could not be attributed to socioeconomic status, as this was higher in the low obstetric risk group. Obstetric procedures (induction of labor, cesarean section and instrumental birth) were substantially less common in the low-risk-care patients, as is expected for a low-risk population. CONCLUSION: Women selected for low-risk under midwife-led models of care do not appear to have better outcomes than women with all levels of perinatal risk cared for under traditional obstetrician-led models of care. PMID- 25832991 TI - Facile luminescent tuning of Zn(II)/Hg(II) complexes based on flexible, semi rigid and rigid polydentate Schiff bases from blue to green to red: structural, photophysics, electrochemistry and theoretical calculations studies. AB - The photophysical properties of Zn(II)/Hg(II) Schiff base complexes could be fine and predictably tuned over a wide range of wavelengths by changing the ligand structures. A new series of polydentate Schiff base-type ligands, N,N'-bis(2 pyridinylethylidene)R(3)-1,2-diamine (), which contain a flexible, semi-rigid or rigid group (R(3) = butyl, cyclohexane, tolyl and phenylene), has been designed and employed for synthetizing new mononuclear or binuclear trans Zn(II)/Hg(II) complexes with a general formula of [M()Cl2] ( = N,N'-bis(2 pyridinylethylidene)phenylene-1,2-diamine, M = Zn, ; M = Hg, ), [M()Cl2] ( = N,N' bis(2-pyridinylethylidene)toluene-3,4-diamine, M = Zn, ; M = Hg, ), [M2()Cl4].nCH2Cl2 ( = N,N'-bis(2-pyridinylmethylene)cyclohexane-1,2-diamine, M = Zn, n = 0, ; M = Hg, n = 1, ), [M2()Cl4].nCH3OH ( = N,N'-bis(2 pyridinylethylidene)cyclohexane-1,2-diamine, M = Zn, n = 1, ; M = Hg, n = 0, ), [M2()Cl4] ( = N,N'-bis(3-methoxy-2-pyridinylmethylene)-cyclohexane-1,2-diamine, M = Zn, ; M = Hg, ), [M2()Cl4].nCH3CN ( = N,N'-bis(3-methoxy-2 pyridinylmethylene)butane-1,4-diamine, M = Zn, n = 4, ; M = Hg, n = 0, ). All the ligands and complexes have been characterized by elemental analyses, IR spectra, and (1)H NMR spectra. Twelve structures of , , , , , and crystallized in three different conditions are further determined by single-crystal X-ray diffraction analyses. Their properties are fully characterized by UV-vis and fluorescence spectra both in solution and the solid state at room temperature. The luminescence color of these Zn(II)/Hg(II) Schiff base complexes could be tuned from blue to green to red (429-639 nm for , 434-627 nm for ) in solution by changing the ligand conjugated systems from flexibile () to semi-rigid () to rigid (). The spectra of the free Schiff bases are centered around 402-571 nm, which are perturbed upon the coordination to the Zn(II)/Hg(II) ion. Both the electrochemical data and TD-DFT calculations show that the HOMO-LUMO band gap from the ligand to the complex is reduced by complexation. Meanwhile, the emission efficiencies of Zn(II)-complexes are found to be strongly dependent on the Schiff-base ligands with quantum yields ranging from 14% to 25% for . However, the emission efficiencies dramatically decline in Hg(II)-complexes with quantum yields ranging from 4% to 19%, due to the heavy atom effect. PMID- 25832989 TI - The myths we believed in familial Mediterranean fever: what have we learned in the past years? AB - Familial Mediterranean fever is the most common monogenic periodic fever syndrome over the world especially in the eastern Mediterranean. It presents with recurrent and self-limited inflammatory attacks of fever and polyserositis along with high acute-phase reactants. The disease is associated with mutations in the MEFV gene that encodes pyrin, a component of inflammasome, which leads to exaggerated inflammatory response through uncontrolled production of interleukin 1. With the identification of the gene associated with the disease, we believed that everything was solved and that this was an ordinary monogenic disease with autosomal recessive inheritance. However, through the breathtaking progress in the basic research field as well as the clinical care of these patients, we have understood that the picture for this monogenic disorder was more complicated than we had anticipated. In this review, we have discussed the myths we believed in familial Mediterranean fever and how they have evolved during the past years. PMID- 25832992 TI - Mass Production of an Active Peptide-N-Glycosidase F Using Silkworm-Baculovirus Expression System. AB - The peptide-N (4)-(N-acetyl-beta-D-glucosaminyl) asparagine amidase F (PNGase F) catalyzes the cleavage of N-linked oligosaccharides between the innermost GlcNAc and asparagine residues of high mannose, hybrid and complex oligosaccharides from glycoproteins. The PNGase F has broad substrate specificity and thus is extensively used for the structural and functional studies of the glycoproteins. In this study, we tried to produce active recombinant PNGase F as secreted and intracellular-expressed forms using baculovirus expression vector system (BEVS) through silkworm larvae or cultured cells. PNGase F itself contains potential N linked glycosylation sites and we found that it was N-glycosylated when PNGase F secreted from silkworm cells. Intriguingly, the secreted recombinant PNGase F has the lower catalytic activity and self-digests its N-linked glycans and therefore this secreted form of this enzyme produced from BEVS is not appropriate for carbohydrate chain analysis. Instead, we successfully mass-produced (2.1 mg/20 silkworm larvae) and purified active recombinant PNGase F as an intracellular protein without N-glycosylations. Besides, we confirmed by directed mutagenesis that several amino acid residues are crucial for the function of PNGase F. Our results provide an alternative method for the mass production of active enzymes involved in the study of glycoproteins. PMID- 25832994 TI - An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis. AB - OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. METHODS: We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. RESULTS: HLA-DRB1*09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1*08:03 and DRB1*14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P = 1.9 * 10(-51) ). The association was mainly conferred by alanine residue (P = 4.5 * 10( 51) ). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1*08:03, DRB1*09:01, DRB1*14:06, DRB1*15:01, and DRB1*15:02). CONCLUSION: Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap. PMID- 25832993 TI - Oral contraceptive pill use is associated with localized decreases in cortical thickness. AB - Oral contraceptive pills (OCs), which are used to prevent pregnancy by the majority of women in the United States, contain steroid hormones that may affect the brain's structure and function. In this investigation, we tested the hypothesis that OC use is associated with differences in brain structure using a hypothesis-driven, surface-based approach. In 90 women, (44 OC users, 46 naturally-cycling women), we compared the cortical thickness of brain regions that participate in the salience network and the default mode network, as well as the volume of subcortical regions in these networks. We found that OC use was associated with significantly lower cortical thickness measurements in the lateral orbitofrontal cortex and the posterior cingulate cortex. These regions are believed to be important for responding to rewards and evaluating internal states/incoming stimuli, respectively. Further investigations are needed to determine if cortical thinning in these regions are associated with behavioral changes, and also to identify whether OC use is causally or only indirectly related to these changes in brain morphology. PMID- 25832996 TI - Human recreational exposure to antibiotic resistant bacteria in coastal bathing waters. AB - Infections caused by antibiotic resistant bacteria (ARB) are associated with poor health outcomes and are recognised globally as a serious health problem. Much research has been conducted on the transmission of ARB to humans. Yet the role the natural environment plays in the spread of ARB and antibiotic resistance genes is not well understood. Antibiotic resistant bacteria have been detected in natural aquatic environments, and ingestion of seawater during water sports is one route by which many people could be directly exposed. The aim was to estimate the prevalence of resistance to one clinically important class of antibiotics (third-generation cephalosporins (3GCs)) amongst Escherichia coli in coastal surface waters in England and Wales. Prevalence data was used to quantify ingestion of 3GC-resistant E. coli (3GCREC) by people participating in water sports in designated coastal bathing waters. A further aim was to use this value to derive a population-level estimate of exposure to these bacteria during recreational use of coastal waters in 2012. The prevalence of 3GC-resistance amongst E. coli isolated from coastal surface waters was estimated using culture based methods. This was combined with the density of E. coli reported in designated coastal bathing waters along with estimations of the volumes of water ingested during various water sports reported in the literature to calculate the mean number of 3GCREC ingested during different water sports. 0.12% of E. coli isolated from surface waters were resistant to 3GCs. This value was used to estimate that in England and Wales over 6.3 million water sport sessions occurred in 2012 that resulted in the ingestion of at least one 3GCREC. Despite the low prevalence of resistance to 3GCs amongst E. coli in surface waters, there is an identifiable human exposure risk for water users, which varies with the type of water sport undertaken. The relative importance of this exposure is likely to be greater in areas where a large proportion of the population enjoys water sports. Millions of water sport sessions occurred in 2012 that were likely to have resulted in people ingesting E. coli resistant to a single class of antibiotics (3GCs). However, this is expected to be a significant underestimate of recreational exposure to all ARB in seawater. This is the first study to use volumes of water ingested during different water sports to estimate human exposure to ARB. Further work needs to be done to elucidate the health implications and clinical relevance of exposure to ARB in both marine and fresh waters in order to fully understand the risk to public health. PMID- 25832995 TI - Rationale, design, and progress of the ENhanced Control of Hypertension ANd Thrombolysis strokE stuDy (ENCHANTED) trial: An international multicenter 2 * 2 quasi-factorial randomized controlled trial of low- vs. standard-dose rt-PA and early intensive vs. guideline-recommended blood pressure lowering in patients with acute ischaemic stroke eligible for thrombolysis treatment. AB - RATIONALE: Controversy exists over the optimal dose of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0.6 mg/kg) is more efficacious than standard-dose (0.9 mg/kg) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group. AIMS: The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0.6 mg/kg body weight; maximum 60 mg) i.v. rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0.9 mg/kg body weight; maximum 90 mg) i.v. rt-PA; and (ii) early intensive BP lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg). DESIGN: The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2 * 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. STUDY OUTCOMES: The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. RESULTS: Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. CONCLUSIONS: Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide. PMID- 25832997 TI - Brominated polyunsaturated lipids with protein tyrosine phosphatase-1B inhibitory activity from Chinese marine sponge Xestospongia testudinaria. AB - A new brominated polyunsaturated lipid, methyl (E,E)-14,14-dibromo-4,6,13 tetradecatrienoate (1), along with three known related analogues (2-4), were isolated from the Et2O-soluble portion of the acetone extract of Chinese marine sponge Xestospongia testudinaria treated with diazomethane. The structure of the new compound was elucidated by detailed spectroscopic analysis and by comparison with literature data. Compound 3 exhibited significant inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), a key target for the treatment of type II diabetes and obesity, with an IC50 value of 5.30 +/- 0.61 MUM, when compared to the positive control oleanolic acid (IC50 = 2.39 +/- 0.26 MUM). PMID- 25832998 TI - Overcoming challenges to meaningful informed consent for whole genome sequencing in pediatric cancer research. AB - BACKGROUND: Introducing whole genome sequencing (WGS) into pediatric cancer research at diagnosis poses unique challenges related to informed consent. WGS requires tissue obtained prior to initiating treatment, when families may be overwhelmed with uncertainty and fear. Motivation to participate may be high without fully understanding the range of possible results, including secondary findings. Little is known about parental knowledge, attitudes, and beliefs about this type of research. PROCEDURE: A qualitative study was conducted to investigate parental knowledge about genetic concepts and WGS, thoughts about the informed consent process, and preferences for secondary findings. Focus groups were conducted with parents/guardians of children with cancer and semi-structured interviews were conducted in a control group without cancer. All transcripts were analyzed using content analysis. RESULTS: Four focus groups included 15 participants; eight semi-structured interviews included 10 participants. Basic knowledge about genetics was limited to heredity. Some knowledge of genomic analysis was present in 3/15 focus group participants. Major factors related to participation in WGS research were: (i) hope for their child and future children; (ii) no additional procedures; (iii) and protection of privacy. All favored a two step consent process, first to store extra tissue from a diagnostic biopsy/resection, followed by consenting to WGS research, one-to-two months later. The desire to receive secondary findings was high among both groups, but there were individuals who did not want these results, fearing increased anxiety. CONCLUSIONS: Parents/guardians of children with cancer have limited knowledge about WGS. A two-step consent process may improve their ability to provide meaningful informed consent. PMID- 25832999 TI - A bifactorial solution to the Psychopathy Checklist: Screening Version in a sample of civil psychiatric patients. AB - BACKGROUND: There is considerable debate about the underlying factor structure of the Psychopathy Checklist: Screening Version (PCL: SV). An established view is that it reflects a unitary construct underpinned by two correlated factors. More recent research has, however, undermined this conceptualisation. AIMS: Our aim was to compare 10 competing models of the PCL: SV in a sample of civil psychiatric patients. METHOD: Ten distinct factor models were specified and tested using conventional confirmatory factor analytic techniques, along with confirmatory bifactor modelling. RESULTS: A bifactor model, including two general factors (interpersonal-affective and antisocial-lifestyle), and four subordinate factors (interpersonal, affective, antisocial and lifestyle) provided the best fit to the data. The reliability of the conceptualisation was supported through the use of composite reliability, and the differential relationships exhibited between the general factors and measures of personality, impulsivity and mental health. CONCLUSIONS: Our findings provide further weight to taking the two general psychopathy factors into account when interpreting the PCL: SV for clinical purposes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 25833000 TI - Tumor-suppressing effect of miR-4458 on human hepatocellular carcinoma. AB - BACKGROUND: Besides multiple genetic and epigenetic changes of protein coding genes in hepatocellular carcinoma (HCC), growing evidence indicate that deregulation of miRNAs contribute to HCC development by influencing cell growth, apoptosis, migration, or invasion. IKBKE is amplified and over-expressed in a large percentage of human breast tumors and identified as an oncogene of human breast tumor. Microarray analysis showed that miR-4458 was down-regulated in HCC tissues. METHODS: The level of miR-4458 was up-regulated by miR-4458 mimics transfection, or down-regulated by miR-4458 ASO transfection. Cell proliferation was assayed by MTT analysis. MiRNAs and mRNA expression were assayed by qRT-PCR. These potential targeted genes of miR-4458 were predicted by bioinformatic algorithms. Dual luciferase reporter assay system was used to analyze the interaction between miR-4458 and IKBKE. IKBKE protein level was assayed by Western blot. The role of miR-4458 or IKBKE in the survival of HCC patients were revealed by Kaplan-Meier plot of overall survival. RESULTS: Lower miR-4458 expression level or higher IKBKE level in HCC tissues correlated with worse prognosis of HCC patients. Overexpression of miR-4458 inhibited the HCC cells growth and vice versa. MiR-4458 played its role via targeting 3'UTR of IKBKE. CONCLUSIONS: MiR-4458 or IKBKE may be potential predictors of HCC prognosis. Restoration of miR-4458 or inhibition of IKBKE could be a prospective therapeutic approach for HCC. PMID- 25833001 TI - Electrochemical push-pull probe: from scanning electrochemical microscopy to multimodal altering of cell microenvironment. AB - To understand biological processes at the cellular level, a general approach is to alter the cells' environment and to study their chemical responses. Herein, we present the implementation of an electrochemical push-pull probe, which combines a microfluidic system with a microelectrode, as a tool for locally altering the microenvironment of few adherent living cells by working in two different perturbation modes, namely electrochemical (i.e., electrochemical generation of a chemical effector compound) and microfluidic (i.e., infusion of a chemical effector compound from the pushing microchannel, while simultaneously aspirating it through the pulling channel, thereby focusing the flow between the channels). The effect of several parameters such as flow rate, working distance, and probe inclination angle on the affected area of adherently growing cells was investigated both theoretically and experimentally. As a proof of concept, localized fluorescent labeling and pH changes were purposely introduced to validate the probe as a tool for studying adherent cancer cells through the control over the chemical composition of the extracellular space with high spatiotemporal resolution. A very good agreement between experimental and simulated results showed that the electrochemical perturbation mode enables to affect precisely only a few living cells localized in a high-density cell culture. PMID- 25833002 TI - Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase. AB - Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function. PMID- 25833003 TI - Determination of biogenic amine profiles in conventional and organic cocoa-based products. AB - Cocoa contains many compounds such as biogenic amines (BAs), known to influence consumer health. Spermidine, spermidine, putrescine, histamine, tyramine, beta phenylethylamine, cadaverine and serotonine have been found in several cocoa based products using HPLC with UV detection after derivatisation with dansyl chloride. Once optimised in terms of linearity, percentage recovery, LOD, LOQ and repeatability, this method was applied to real samples. Total concentrations of BAs ranged from 5.7 to 79.0 ug g(-)(1) with wide variations depending on the type of sample. BAs present in all samples were in decreasing order: histamine (1.9 38.1 ug g(-)(1)) and tyramine (1.7-31.7 ug g(-)(1)), while putrescine (0.9-32.7 ug g(-)(1)), spermidine (1.0-9.7 ug g(-)(1)) and spermidine (0.6-9.3 ug g(-)(1)) were present in most of the samples. Cadaverine, serotonine and beta phenylethylamine were present in a few samples at much lower concentrations. Organic samples always contained much lower levels of BAs than their conventional counterparts and, generally speaking, the highest amounts of BAs were found in the most processed products. PMID- 25833004 TI - Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. AB - The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use? PMID- 25833005 TI - White piedra caused by Trichosporon inkin: a report of two cases in a northern climate. PMID- 25833006 TI - Thermal stability of G-rich anti-parallel DNA triplexes upon insertion of LNA and alpha-L-LNA. AB - G-rich anti-parallel DNA triplexes were modified with LNA or alpha-L-LNA in their Watson-Crick and TFO strands. The triplexes were formed by targeting a pyrimidine strand to a putative hairpin formed by Hoogsteen base pairing in order to use the UV melting method to evaluate the stability of the triplexes. Their thermal stability was reduced when the TFO strand was modified with LNA or alpha-L-LNA. The same trend was observed when the TFO strand and the purine Watson-Crick strand both were modified with LNA. When all triad components were modified with alpha-L-LNA and LNA in the middle of the triplex, the thermal melting was increased. When the pyrimidine sequence was modified with a single insertion of LNA or alpha-L-LNA the DeltaTm increased. Moreover, increasing the number of alpha-L-LNA in the pyrimidine target sequence to six insertions, leads to a high increase in the thermal stability. The conformational S-type structure of alpha-L LNA in anti-parallel triplexes is preferable for triplex stability. PMID- 25833007 TI - Enhancement of the binding affinity of methylene blue to site I in human serum albumin by cupric and ferric ions. AB - In this work, the binding characteristics of methylene blue (MB) to human serum albumin (HSA) and the influence of Cu(2+) and Fe(3+) on the binding affinity of MB to HSA were investigated using fluorescence, absorption, circular dichroism (CD) spectroscopy and molecular modelling. The results of competitive binding experiments using the site probes ketoprofen and ibuprofen as specific markers suggested that MB was located in site I within sub-domain IIA of HSA. The molecular modelling results agreed with the results of competitive site marker experiments and the results of CD spectra indicated that the interaction between MB and HSA caused the conformational changes in HSA. The binding affinity of MB to HSA was enhanced but to a different extent in the presence of Cu(2+) and Fe(3+), respectively, which indicated that the influence of different metal ions varied. Enhancement of the binding affinity of MB to HSA in the presence of Cu(2+) is due to the formation of Cu(2+)-HSA complex leading to the conformational changes in HSA, whereas in the presence of Fe(3+), enhancement of the binding affinity is due to the greater stability of the Fe(3+)-HSA-MB complex compared with the MB-HSA complex. PMID- 25833008 TI - Early Use of 60 Hz Frequency Subthalamic Stimulation in Parkinson's Disease: A Case Series and Review. AB - BACKGROUND: Deep brain stimulation (DBS) is effective in treating the segmental symptoms of Parkinson's disease (PD) as well as axial symptoms that are levodopa responsive. PD patients on chronic DBS who develop axial symptoms and gait disturbances several years later oftentimes are refractory to high frequency stimulation (HFS). Several studies report benefit produced by low frequency subthalamic nucleus (STN) stimulation in such patients, though the sustainability of the effects has been mixed. OBJECTIVE: To report the clinical outcomes of a series of patients with Parkinson's disease and levodopa responsive axial and gait disturbances who were switched to 60 Hz stimulation within one year of their DBS surgery. METHODS: A retrospective review of 5 patients, whose severe pre-DBS, levodopa responsive gait disorders worsened on HFS STN-DBS and were subsequently switched to 60 Hz stimulation within 1 year of their surgery. RESULTS: The median age of this cohort was 66 years with median disease duration of 14 years. Four of 5 patients' experienced acute worsening of their axial and gait UPDRS III scores on HFS. All patients' gait disorder improved with 60 Hz along with amelioration of their segmental symptoms and reduction of their levodopa induced dyskinesia. The median time on HFS prior to switching to 60 Hz was two months. Stimulation through the ventral contacts was utilized in all patients with relatively modest changes achieved in levodopa equivalent daily dose. CONCLUSION: This case series demonstrates the clinical efficacy of utilizing low frequency (60 Hz) STN stimulation early in the DBS programming course in more advanced PD patients with levodopa responsive gait disturbance and freezing of gait. Activation of a broader stimulation field likely contributed to both axial and segmental symptom improvement while possibly aiding in the reduction of dyskinesia. PMID- 25833010 TI - Effect of Cu(II) shock loads on shortcut biological nitrogen removal in a hybrid biofilm nitrogen removal reactor. AB - The effect of Cu(II) shock loads on shortcut biological nitrogen removal during a continuous-flow anoxic/aerobic process was investigated using a hybrid biofilm nitrogen removal reactor. The results demonstrated that [Formula: see text]-N removal was not affected by any Cu(II) shock loads, but TN removal was inhibited by Cu(II) of shock loads of 2 and 5 mg/L, and the performance could not be recovered at 5 mg/L. Furthermore, the TN removal pathway also changed in response to Cu(II) concentrations of 2 and 5 mg/L. Denitrification is more sensitive to Cu(II) shock in SBNR processes. Examination of amoA communities using quantitative PCR showed that the abundance of AOB in the aerobic tank decreased after Cu(II) shock with 5 mg/L, which supported the observed changes in [Formula: see text]-N removal efficiency. The abundance of denitrification genes declined obviously at Cu(II) concentrations of 2 and 5 mg/L, which explained the decreased TN removal efficiency at those concentrations. PMID- 25833009 TI - The value of systematic lymph node dissection for intrahepatic cholangiocarcinoma from the viewpoint of liver lymphatics. AB - Lymph node (LN) metastasis from intrahepatic cholangiocarcinoma (IHCC) might be one of the most important indicators of aggressive surgical resection, yet the value of LN dissection is still controversial. To address this clinical problem, we need to better understand the multidirectional lymphatic outflow from the liver. Although most hepatic lymph flows into the hilar LNs along portal triads, there are also several lymphatic outflows directly communicating with distant areas or the general lymphatic system. Moreover, it has been revealed that LN metastasis spreads to more distal LNs through the hepatoduodenal ligament or other multidirectional lymphatic pathways connected to the general lymphatic system. Therefore, systematic LN dissection might merely be LN sampling in IHCC with LN metastasis. A multidisciplinary strategy focusing on adjuvant treatment after surgery is immediately necessary in these cases. In IHCC without LN metastasis, the accuracy of preoperative imaging assessment of LN metastasis is unsatisfactory and useless for detecting metastatic LNs in clinical settings. Therefore, prophylactic systematic LN dissection for IHCC without preoperative LN swelling is recommended for accurate LN status assessment and reduction of local recurrences. However, this procedure might not offer any clinical benefit according to the results of retrospective comparative studies. In this review, we summarize previous reports regarding lymphatic outflow of the liver and discuss LN dissection for IHCC. PMID- 25833011 TI - Evaluation of the pilot phase of the 'Give up smokes for good' social marketing campaign. AB - ISSUE ADDRESSED: The prevalence of tobacco smoking among Aboriginal and Torres Strait Islander people in Australia is comparatively high. To help combat this, an Aboriginal-specific social marketing campaign, 'Give up smokes for good', was piloted in South Australia in 2011. METHODS: To evaluate the campaign, a face-to face survey was conducted with two samples of convenience through Aboriginal Health services in South Australia (city and regional locations; n=190). Surveys assessed the cultural appropriateness of the campaign, campaign awareness and recognition, knowledge of the harms of smoking and smoking/quit smoking behaviours. RESULTS: Campaign awareness was high with 76.3% of participants aware of at least one aspect of the campaign. Participants indicated campaign materials (posters and radio ads) to be culturally appropriate. Knowledge that smoking and passive smoking caused illness was high (85.8% and 86.8%); however, knowledge of specific illnesses was not as high. Large proportions of participants had imposed bans on smoking in homes (73.2%) and in cars (75.9%). CONCLUSIONS: Our findings suggest the 'Give up smokes for good' campaign reached the intended audience with high levels of campaign awareness. Results also suggest the pilot campaign made progress in achieving its communication objectives. SO WHAT?: High quality, culturally targeted anti-tobacco poster and radio campaigns can be effective ways to reach Aboriginal Australians. Future research could explore the impact of this type of social marketing campaign, particularly in regards to the impact on quitting intention and behaviour. PMID- 25833012 TI - Stressor experience negatively affects life satisfaction in adolescents: the positive role of sense of coherence. AB - PURPOSE: The aim of the present study was to investigate the association between different normative stressors, sense of coherence and life satisfaction separately for gender in Norwegian adolescents. The interaction effect of stress by sense of coherence in relation to life satisfaction was also investigated. METHODS: The data are based on a cross-sectional sample of 1239 adolescents (13 18 years) from public elementary and secondary schools in Central Norway. Hierarchical multiple regression analysis was used to evaluate the association between stressors, sense of coherence and life satisfaction, separately for gender. RESULTS: The results showed significant differences between genders, where boys reported higher scores than girls on sense of coherence and life satisfaction, whereas girls scored higher than boys on five of seven stressor domains. All stressors were significantly and inversely associated with life satisfaction in both genders; however, all associations were stronger for girls compared to boys. Sense of coherence showed a significant strong and positive association with life satisfaction, controlled for age and each individual stressor. A significant although weak interaction effect of stress related to romantic relationships by sense of coherence was found in association with life satisfaction for boys; the other interaction effects were nonsignificant in both genders. CONCLUSION: The results give support for a significant unique role of stressor experience and sense of coherence in relation to life satisfaction in both genders during adolescence, where the associations were especially strong in girls. PMID- 25833013 TI - Validity of EQ-5D in general population of Taiwan: results of the 2009 National Health Interview and Drug Abuse Survey of Taiwan. AB - PURPOSE: The aim of this study was to examine the validity of the EuroQOL five dimensions questionnaire (EQ-5D) using a nationally representative data from the National Health Interview Survey (NHIS) through comparison with short-form 36 (SF 36). METHODS: Data for this study came from the 2009 NHIS in Taiwan. The study sample was the 4007 participants aged 20-64 years who completed the survey. We used SUDAAN 10.0 (SAS-Callable) to carry out weighed estimation and statistical inference. The EQ index was estimated using norm values from a Taiwanese study as well as from Japan and the United Kingdom (UK). The SF-36 score was standardized using American norm values. RESULTS: In terms of concurrent validity, the EQ-5D met the five hypotheses. The results did not fulfill hypothesis that women would have lower visual analogue scale (EQ-VAS) scores. In terms of discriminant validity, the EQ-5D fulfilled two hypotheses. Our results approached but did not fulfill hypothesis that there would be a weak association between the physical and psychological dimensions of the EQ-5D and the mental component summary score of the SF-36. Results were comparable regardless of whether the Japanese or UK norm value sets were used. CONCLUSIONS: We were able to fulfill many, not all of our validity hypotheses regardless of whether the established Japanese or UK norm value sets or the Taiwanese norm values were used. The EQ-5D is an effective and simple instrument for assessing health-related quality of life of general population in Taiwan. PMID- 25833014 TI - Resveratrol alleviates vascular inflammatory injury by inhibiting inflammasome activation in rats with hypercholesterolemia and vitamin D2 treatment. AB - OBJECTIVE: Atherosclerosis (AS) is an inflammatory disease involved in vascular inflammatory injury. The inflammasome is an important part of inflammatory diseases and participates in the vascular inflammatory injury. Resveratrol (RSV) possesses anti-inflammatory activities, but its effects on inflammasomes during vascular injury remain unclear. This study focused on the effects and mechanisms of RSV on inflammasomes during vascular injury. METHODS: Male Sprague-Dawley rats were treated with a purified diet or cholesterol-enriched diet combined with vitamin D2 (VD; 1.8 million units/kg/days, Po) and saline or RSV (50 mg/kg/days, Po) daily for 5 weeks. The concentrations and enzyme activities of related indicators were measured by a spectrophotometer or ELISA kit. Their gene and protein expression levels were analyzed by reverse transcription-polymerase chain reaction and Western blot, respectively. RESULTS: Upon administration with RSV, rats with combined hyper cholesterol and VD demonstrated the following changes: the vascular histopathological changes were relieved, and the level of the von Willebrand factor decreased. The level of serum IL-1beta, a marker of inflammasome activation, significantly decreased. The mRNA and protein expression levels of the three components of inflammasomes, namely, NOD-like receptor pyrin domain containing 3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase-1, were downregulated. The effects of RSV were closely related to hypolipidemia (decrease in the levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol combined with the expression of the lectin-like ox-LDL receptor and increase in high-density lipoprotein cholesterol), antioxidation (decrease in MDA levels and increase in SOD and GPx activities), and anti-inflammation (downregulation of the expression of IL-1beta, intracellular adhesion molecule-1, and monocyte chemotactic protein 1). The mechanisms for the downregulation of NF-kappaB p65 and p38 MAPK expression, as well as the upregulation of SIRT1 expression, were analyzed. CONCLUSION: This study proved that RSV inhibited inflammasome activation to protect vascular injury in vivo. RSV exhibited therapeutic potential in the treatment of vascular injury. PMID- 25833015 TI - The importance of animals in advancing research on alcohol use disorders. PMID- 25833016 TI - Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. PMID- 25833017 TI - Challenges and exciting new opportunities to advance personalized treatment for alcohol use disorder. PMID- 25833018 TI - Reinforcement-related subphenotypes as a basis for personalized treatment in alcoholism. PMID- 25833019 TI - A matter of outlook. PMID- 25833020 TI - Opportunities for opening the door to transdiagnostic approaches. PMID- 25833021 TI - Implications of an alcohol addiction RDoC for delivery science research and clinical care. PMID- 25833022 TI - Effects of idazoxan on alcohol pharmacokinetics and intoxication: a preliminary human laboratory study. AB - BACKGROUND: Preliminary basic and human studies suggest that the alpha2 adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence. The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral mechanisms of idazoxan may alter alcohol's effects. METHODS: This was a preliminary double-blind, single-dose, placebo-controlled, crossover, randomized human laboratory study. Ten social drinkers were dosed, in 2 different alcohol challenge studies (ACS), with a single oral dose of idazoxan (40 mg) or placebo, followed by a fixed alcohol dose 60 minutes later. Participants returned after a 1-week washout, and they were crossed over to the opposite medication condition. RESULTS: There were no significant differences in adverse events between idazoxan and placebo. Moreover, during the ACS paradigm, 40 mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (p < 0.01) and time to peak (p < 0.05) compared to placebo. A PK/pharmacodynamic model aligned the biobehavioral effects, demonstrating that the co-administration of 40 mg idazoxan with alcohol decreased alcohol-related stimulation (p < 0.05) and increased alcohol-related sedation (p < 0.05). CONCLUSIONS: This study supports the safety and tolerability of 40 mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients. PMID- 25833024 TI - Relative fluid novelty differentially alters the time course of limited-access ethanol and water intake in selectively bred high-alcohol-preferring mice. AB - BACKGROUND: The influence of previous alcohol (ethanol [EtOH])-drinking experience on increasing the rate and amount of future EtOH consumption might be a genetically regulated phenomenon critical to the development and maintenance of repeated excessive EtOH abuse. We have recently found evidence supporting this view, wherein inbred C57BL/6J (B6) mice develop progressive increases in the rate of binge EtOH consumption over repeated drinking-in-the-dark (DID) EtOH access sessions (i.e., "front loading"). The primary goal of this study was to evaluate identical parameters in high-alcohol-preferring (HAP) mice to determine whether similar temporal alterations in limited-access EtOH drinking develop in a population selected for high EtOH preference/intake under continuous (24-hour) access conditions. METHODS: Using specialized volumetric drinking devices, HAP mice received 14 daily 2-hour DID EtOH or water access sessions. A subset of these mice was then given 1 day access to the opposite assigned fluid on day 15. Home cage locomotor activity was recorded concomitantly on each day of these studies. The possibility of behavioral/metabolic tolerance was evaluated on day 16 using experimenter-administered EtOH. RESULTS: The amount of EtOH consumed within the first 15 minutes of access increased markedly over days. However, in contrast to previous observations in B6 mice, EtOH front loading was also observed on day 15 in mice that only had previous DID experience with water. Furthermore, a decrease in the amount of water consumed within the first 15 minutes of access compared to animals given repeated water access was observed on day 15 in mice with 14 previous days of EtOH access. CONCLUSIONS: These data further illustrate the complexity and importance of the temporal aspects of limited-access EtOH consumption and suggest that previous procedural/fluid experience in HAP mice selectively alters the time course of EtOH and water consumption. PMID- 25833025 TI - Acute alcohol exposure impairs neural representation of visual motion speed in the visual cortex area posteromedial lateral suprasylvian cortex of cats. AB - BACKGROUND: Psychophysical and behavioral studies have demonstrated that perception of motion can be impaired by acute alcohol exposure. The neural activities of posteromedial lateral suprasylvian cortex (PMLS) of cats are directly linked to the perception of visual motion speed. To date, there have been no studies on the effects of acute alcohol exposure in vivo upon the representation of speed in PMLS neurons. METHODS: Alcohol was administered intravenously as a 20% (v/v) saline solution via a syringe at a dose levels of 0.5, 1, or 2 g/kg to generate a series of blood alcohol concentrations. Using extracellular single-unit recording technique, we recorded the speed-tuning properties of PMLS neurons that responded to random-dot patterns before and after alcohol administration, and simultaneously monitored the concentration of ethanol by detecting the breath alcohol concentration using a breath analyzer. RESULTS: After acute alcohol treatment, PMLS cells preferred lower speeds. A broadened speed-tuning bandwidth of PMLS cells was also observed after acute alcohol administration. Additionally, response modulation and discriminative capacity for speed of visual motion in the PMLS cells were significantly impaired after acute alcohol exposure. Concurrently, PMLS cells after acute alcohol exposure showed decreased spontaneous activity, peak responses, and signal-to-noise ratios. CONCLUSIONS: There is a significant functional degradation in the neural representation of visual motion speed in PMLS of cats after acute alcohol exposure. These neural changes may contribute to the alcohol-related deficits in visual motion perception observed in behavioral studies. PMID- 25833023 TI - Quantitative trait locus mapping of acute functional tolerance in the LXS recombinant inbred strains. AB - BACKGROUND: We previously reported that acute functional tolerance (AFT) to the hypnotic effects of alcohol was significantly correlated with drinking in the dark (DID) in the LXS recombinant inbred panel, but only in mice that had been pretreated with alcohol. Here, we have conducted quantitative trait locus (QTL) mapping for AFT. DNA sequencing of the progenitor ILS and ISS strains and microarray analyses were also conducted to identify candidate genes and functional correlates. METHODS: LXS mice were given either saline or alcohol (5 g/kg) on day 1 and then tested for loss of righting reflex AFT on day 2. QTLs were mapped using standard procedures. Two microarray analyses from brain were conducted: (i) naive LXS mice and (ii) an alcohol treatment time course in the ILS and ISS. The full genomes of the ILS and ISS were sequenced to a depth of approximately 30*. RESULTS: A significant QTL for AFT in the alcohol pretreatment group was mapped to distal chromosome 4; numerous suggestive QTLs were also mapped. Preference drinking and DID have previously been mapped to the chromosome 4 locus. The credible interval of the significant chromosome 4 QTL spanned 23 Mb and included 716 annotated genes of which 150 had at least 1 nonsynonymous single nucleotide polymorphism or small indel that differed between the ILS and ISS; expression of 48 of the genes was cis-regulated. Enrichment analysis indicated broad functional categories underlying AFT, including proteolysis, transcription regulation, chromatin modification, protein kinase activity, and apoptosis. CONCLUSIONS: The chromosome 4 QTL is a key region containing possibly pleiotropic genes for AFT and drinking behavior. Given that the region contains many viable candidates and a large number of the genes in the interval fall into 1 or more of the enriched functional categories, we postulate that many genes of varying effect size contribute to the observed QTL effect. PMID- 25833027 TI - The effects of chronic alcohol self-administration in nonhuman primate brain networks. AB - BACKGROUND: Long-term alcohol abuse is associated with change in behavior, brain structure, and brain function. However, the nature of these changes is not well understood. In this study, we used network science to analyze a nonhuman primate model of ethanol self-administration to evaluate functional differences between animals with chronic alcohol use and animals with no exposure to alcohol. Of particular interest was how chronic alcohol exposure may affect the resting state network. METHODS: Baseline resting state functional magnetic resonance imaging was acquired in a cohort of vervet monkeys. Animals underwent an induction period where they were exposed to an isocaloric maltose dextrin solution (control) or ethanol in escalating doses over three 30-day epochs. Following induction, animals were given ad libitum access to water and a maltose dextrin solution (control) or water and ethanol for 22 h/d over 12 months. Cross-sectional analyses examined region of interests in hubs and community structure across animals to determine differences between drinking and nondrinking animals after the 12-month free access period. RESULTS: Animals were classified as lighter (<2.0 g/kg/d) or heavier drinkers (>=2.0 g/kg/d) based on a median split of their intake pattern during the 12-month ethanol free access period. Statistical analysis of hub connectivity showed significant differences in heavier drinkers for hubs in the precuneus, posterior parietal cortices, superior temporal gyrus, subgenual cingulate, and sensorimotor cortex. Heavier drinkers were also shown to have less consistent communities across the brain compared to lighter drinkers. The different level of consumption between the lighter and heavier drinking monkeys suggests that differences in connectivity may be intake dependent. CONCLUSIONS: Animals that consume alcohol show topological differences in brain network organization, particularly in animals that drink heavily. Differences in the resting state network were linked to areas that are associated with spatial association, working memory, and visuomotor processing. PMID- 25833026 TI - Differential response of glial fibrillary acidic protein-positive astrocytes in the rat prefrontal cortex following ethanol self-administration. AB - BACKGROUND: Prefrontal cortex (PFC) dysfunction is believed to contribute to the transition from controlled substance use to abuse. Because astrocytes have been suggested to play a key role in the development and maintenance of drug-seeking behaviors, we sought to determine whether PFC astrocytes are affected by ethanol (EtOH) self-administration. METHODS: EtOH consumption was modeled in rats by 3 self-administration paradigms where EtOH was made concurrently available with water in the home cage either continuously (CEA) or intermittently (IEA). In the third paradigm, EtOH was only available in the operant chamber (OEA). To avoid the potential confound of acute EtOH effects, all rats were sacrificed after either 24-hour or 3-week abstinence. In all groups, the effect of EtOH consumption on PFC astrocytes was measured using unbiased stereological counting of cells expressing the astrocyte marker glial fibrillary acidic protein (GFAP). GFAP immunoreactivity commonly changes in response to pharmacological insult or injury. RESULTS: GFAP-positive astrocyte number increased in the prelimbic and anterior cingulate cortex regions of the PFC after IEA. No change was found in the infralimbic or orbitofrontal cortex after IEA. After 3-week abstinence, there was a reduction of astrocytes in the prelimbic and orbitofrontal cortex of the CEA cohort as well as a reduction in the orbitofrontal cortex of the OEA cohort. CONCLUSIONS: These findings demonstrate that discrete PFC subregions contain GFAP positive astrocyte populations that respond differentially to distinct EtOH consumption paradigms. A better understanding of how specific astrocyte populations uniquely adapt to EtOH consumption could provide insight for targeted therapeutic interventions. PMID- 25833028 TI - Serum concentrations of mast cell tryptase are reduced in heavy drinkers. AB - BACKGROUND: Baseline serum tryptase concentrations are commonly used in clinical practice as a marker of the body's mast cell burden. This study aimed to investigate serum tryptase concentrations in heavy drinkers. METHODS: Serum tryptase concentrations were determined in 126 heavy drinkers (75% males, median age 47 years) who were admitted to the hospital because of alcohol withdrawal syndrome (n = 60), general symptoms with abnormalities on biochemical tests that indicated acute liver disease (n = 19), complications of advanced liver disease (n = 33), and miscellaneous reasons (n = 14). Results were compared with those of 70 healthy controls (66% males, median age 40 years). RESULTS: Serum tryptase concentrations were lower in heavy drinkers than in healthy controls (median 2.23 MUg/l vs. median 3.25 MUg/l, p < 0.001). Ten heavy drinkers (7.9%) had undetectable (<1 MUg/l) serum tryptase levels versus none of the healthy controls (p = 0.01). The association of low tryptase levels with heavy drinking was independent of age, gender, and smoking status. Among heavy drinkers, the lowest tryptase concentrations were observed in patients with alcohol withdrawal syndrome and patients with general symptoms with abnormalities on biochemical tests that indicated acute liver disease. Furthermore, serum tryptase concentrations were negatively correlated with markers of acute liver damage or alcohol consumption (serum aspartate aminotransferase and gamma-glutamyl transferase). Atopy (skin prick test positivity) was not associated with serum tryptase concentrations in heavy drinkers. CONCLUSIONS: Serum concentrations of mast cell tryptase are lower in heavy drinkers than in healthy controls. PMID- 25833029 TI - Co-occurrence of alcohol, drug use, DSM-5 alcohol use disorder, and symptoms of drug use disorder on both sides of the U.S.-Mexico border. AB - BACKGROUND: The U.S.-Mexico border displays elevated rates of hazardous alcohol and drug use. Whether the co-occurrence of alcohol and drug use and disorders is also high in the border area is unknown. METHODS: Data are from the U.S.-Mexico Study on Alcohol and Related Conditions, a cross-sectional survey of randomly selected respondents interviewed from 2011 to 2013. Participants included 1,690 Mexican Americans from Texas (572 in an off-border city and 1,118 from 3 border cities) and 1,293 Mexicans from Nuevo Leon and Tamaulipas (415 in an off-border city and 878 from 3 Mexican cities bordering Texas) who reported drinking in the last 12 months. Participants were interviewed regarding the prevalence of and risk factors for: (i) co-occurring hazardous alcohol use (5+/4+ at least monthly) and drug use (medical and illicit) and (ii) co-occurring presence of a DSM-5 alcohol use disorder (AUD) and 2 symptoms (hazardous use and quit/control) of drug use disorder (DUD symptoms). RESULTS: Co-occurring hazardous alcohol and drug use was more common in the U.S. border cities (14.7%) than off-border (7.2%), but similar for Mexican border (1.2%) and off-border (1.4%) cities. Co occurrence of AUD and DUD symptoms was likewise more common at the U.S. border (6.8%) than off-border (3.3%), as well as at the Mexican border (1.3%), compared to off-border (0.6%), but not statistically significant for Mexico. In models adjusting for demographics, mobility factors and exposure to the U.S. culture, border residence in both countries related to a nearly twofold increase in prevalence ratios (PRs) of co-occurring AUD and DUD symptoms (PR = 1.97, 95% CI = 1.36 to 2.85). CONCLUSIONS: Increased rates of co-occurring AUDs and DUDs suggest an added negative impact on already difficult conditions of the border population. PMID- 25833030 TI - Relationship between craving and ghrelin, adiponectin, and resistin levels in patients with alcoholism. AB - BACKGROUND: Alcoholism is a leading cause of mortality and morbidity. The most widely accepted hypothesis of its etiology is multidimensional and includes biological, psychological, and sociological factors. The biological factors have been the focus of investigation. In recent years, pathways related to nutrition and the relationship between alcohol addiction and craving have been studied. Our aim was to explore the relationship between the appetite hormones (adiponectin, ghrelin, and resistin) and alcohol craving. METHODS: Blood samples were obtained from 107 male patients over a 7-day period. Levels of adiponectin, resistin, and ghrelin, the Obsessive Compulsive Drinking Scale (OCDS) score, and the Penn Alcohol Craving Scale (PACS) score were assessed on days 0 and 7. Adiponectin, resistin, and ghrelin levels were also tested in 83 healthy males in the control group. RESULTS: The sample group consisted of 190 males (107 patients and 83 healthy controls). Comparison of alcohol craving scales with biological markers in the patient group showed a positive correlation between adiponectin levels and the OCDS compulsive subscale scores, and a positive correlation between ghrelin levels and the OCDS total and compulsive subscale scores and the PACS resistance subscale scores. Resistin levels were negatively correlated with the OCDS total, obsessive subscale, and compulsive subscale scores. CONCLUSIONS: Although we did not observe a significant relationship between craving and any of the 3 biomarkers on day 0, craving was positively correlated with the levels of adiponectin and ghrelin and negatively correlated resistin levels on day 7. Our findings support the hypothesis that appetite hormones are trait markers for alcohol craving. Nevertheless, more conclusive results require future studies that evaluate the relationship between these hormones and withdrawal/detoxification period or long-term soberness. PMID- 25833032 TI - Cognitive impairment following consumption of alcohol with and without energy drinks. AB - BACKGROUND: The aim of this study was to assess the relative effects of alcohol mixed with energy drink (AmED) versus alcohol alone on cognitive performance across the ascending and descending breath alcohol concentration (BrAC) limb using doses similar to real-world intake. METHODS: Using a single-blind, placebo controlled, crossover design, 19 participants completed 4 sessions where they received: (i) placebo, (ii) alcohol, (iii) AmED 500 ml energy drink (ED), and (iii) AmED 750 ml ED. Performance on measures of psychomotor function (Compensatory Tracking Task [CTT]), information processing (Digit Symbol Substitution Task [DSST]; Inspection Time Task [ITT]), and response inhibition (Brief Stop-Signal Task [Brief SST]) was assessed at ~0.05% ascending BrAC, ~0.08% peak BrAC, and ~0.05% descending BrAC. RESULTS: The ITT and Brief SST showed no differential effect of AmED versus alcohol (gs < 0.30 and gs < 0.36, respectively). Moderate magnitude improvements in alcohol-induced impairment of CTT and DSST performance were observed after AmED versus alcohol on the descending BrAC limb (gs > 0.45 and gs > 0.37, respectively). A moderate magnitude decrease in DSST errors was also observed after AmED relative to alcohol at 0.050% ascending target BrAC (gs > 0.43). CONCLUSIONS: Changes in cognitive function after AmED administration were dependent on the degree of intoxication, BrAC curve limb, and ED volume. Co-administration of ED doses which matched (500 ml) and exceeded (500 ml) maximum daily intake guidelines with alcohol decreased impairment of psychomotor function and global information processing after alcohol consumption. These results cannot be necessarily interpreted to suggest that people are less impaired after AmED, as behavior is the result of coordination of multiple cognitive functions, and reduced impairment on one aspect of cognition may not translate into global improvements. PMID- 25833031 TI - Verbal learning and memory impairment in children with fetal alcohol spectrum disorders. AB - BACKGROUND: Previous studies using the California Verbal Learning Test-Children's Version (CVLT-C) to examine effects of heavy prenatal alcohol exposure on verbal learning and memory have reported impaired information acquisition (i.e., encoding), rather than retrieval, as the primary mechanism underlying learning and memory impairment. We administered the CVLT-C to 2 independent cohorts to determine whether (i) effects on encoding are also seen at moderate exposure levels, using both categorical (diagnostic/exposure group) and continuous exposure measures; (ii) these deficits are specific or secondary to alcohol related impairment in IQ; (iii) effects on retrieval can be detected over and above effects on initial encoding; and (iv) effects on learning are attributable to less efficient learning strategy use. METHODS: We administered the CVLT-C and Wechsler Intelligence Scale for Children to 151 Cape Town heavy and nonexposed children (M = 10.3 years), and 291 Detroit adolescents recruited to over represent moderate-to-heavy prenatal alcohol exposure (M = 14.4 years). RESULTS: Effects on encoding in the heavily exposed Cape Town cohort and on retrieval in both cohorts were significant after adjustment for IQ. Although effects on retrieval were no longer significant in Cape Town after control for initial encoding, effects on recognition memory continued to be evident in Detroit. Children with full or partial fetal alcohol syndrome were less able to use the semantic cluster encoding strategy implicit in the CVLT-C. CONCLUSIONS: Effects on verbal learning were seen primarily in the more heavily exposed Cape Town cohort; effects on recall and recognition memory were also seen at moderate exposure levels in Detroit. These effects were not attributable to alcohol related impairment in overall intellectual competence. The finding that effects on retention continued to be evident after statistical adjustment for initial encoding in Detroit suggests that a fetal alcohol-related deficit in retrieval is not secondary to a failure to encode the initial information. These data confirm that this impairment in initial learning is mediated, in part, by failure to use the semantic cluster learning strategy. PMID- 25833033 TI - Using contingency management procedures to reduce at-risk drinking in heavy drinkers. AB - BACKGROUND: Treatments for alcohol use disorders typically have been abstinence based, but harm reduction approaches that encourage drinkers to alter their drinking behavior to reduce the probability of alcohol-related consequences, have gained in popularity. This study used a contingency management procedure to determine its effectiveness in reducing alcohol consumption among heavy drinkers. METHODS: Eighty-two nontreatment-seeking heavy drinkers (ages 21 to 54, M = 30.20) who did not meet diagnostic criteria for alcohol dependence participated in the study. The study had 3 phases: (i) an Observation phase (4 weeks) where participants drank normally; (ii) a Contingency Management phase (12 weeks) where participants were paid $50 weekly for not exceeding low levels of alcohol consumption as measured by transdermal alcohol concentrations, <0.03 g/dl; and (iii) a Follow-up phase (12 weeks) where participants (n = 66) returned monthly for 3 months to self-report drinking after the contingencies were removed. Transdermal alcohol monitors were used to verify meeting contingency requirements; all other analyses were conducted on self-reported alcohol use. RESULTS: On average 42.3% of participants met the contingency criteria and were paid an average of $222 during the Contingency Management phase, with an average $1,998 in total compensation throughout the study. Compared to the Observation phase, the percent of any self-reported drinking days significantly decreased from 59.9 to 40.0% in the Contingency Management and 32.0% in the Follow-up phases. The percent of self-reported heavy drinking days reported also significantly decreased from 42.4% in the Observation phase to 19.7% in the Contingency Management phase, which was accompanied by a significant increase in percent days of self-reported no (from 40.1 to 60.0%) and low-level drinking (from 9.9 to 15.4%). Self-reported reductions in drinking either persisted, or became more pronounced, during the Follow-up phase. CONCLUSIONS: Contingency management was associated with a reduction in self-reported episodes of heavy drinking among nontreatment-seeking heavy drinkers. These effects persisted even after incentives were removed, indicating the potential utility of contingency management as a therapeutic intervention to reduce harmful patterns of drinking. PMID- 25833034 TI - Chronic intermittent ethanol exposure in mice leads to an up-regulation of CRH/CRHR1 signaling. AB - BACKGROUND: One of the most commonly used approaches to induce ethanol (EtOH) dependence in rodents is EtOH vapor inhalation. This procedure requires the co administration of pyrazole-an inhibitor of the alcohol dehydrogenase-to obtain stable blood EtOH concentrations (BECs) during the entire induction course. However, pyrazole can produce unwanted side effects. Our goal was to obtain EtOH dependent mice without pyrazole and to study their behavioral and molecular postdependent phenotype. In particular, we were interested in alterations in the corticotrophin-releasing hormone (CRH) and receptor (CRHR1 and CRHR2) system as a prominent role of CRH in driving the postdependent state via actions in the central extended amygdala (CeA) has been demonstrated in rats but not in postdependent mice. METHODS: We established an alternative model of chronic intermittent EtOH (CIE) inhalation without the use of pyrazole in C57BL/6N mice. Our CIE exposure protocol involved 8 cycles. One cycle consisted of 8 hours with EtOH inhalation and 8 hours without EtOH. We then examined withdrawal symptoms. After 2 weeks of abstinence, we studied relapse, reinstatement of EtOH-seeking, and stress-induced EtOH self-administration. We also did transcriptional analysis of components of the CRH system during CIE, protracted abstinence, and after stress-induced EtOH self-administration. RESULTS: CIE exposure without pyrazole resulted in reproducible BECs during the induction procedure. Mice showed strong withdrawal scores during 4 to 12 hours after the last CIE cycle and enhanced stress-induced EtOH self-administration. This postdependent phenotype during abstinence was accompanied by enhanced Crh and Crhr1 transcripts but no change in Crhr2 transcripts in the CeA. Cue-induced EtOH-seeking behavior and relapse (alcohol deprivation effect) were not affected by the inhalation procedure. CONCLUSIONS: We have established a CIE inhalation protocol without pyrazole in mice and showed excessive EtOH self-administration under mild stress and enhanced CRH/CRHR1 signaling in the CeA. PMID- 25833035 TI - Reducing asthma attacks: consider patients' beliefs. PMID- 25833036 TI - Distribution of mitochondrial DNA nucleoids inside the linear tubules vs. bulk parts of mitochondrial network as visualized by 4Pi microscopy. AB - Mitochondrial nucleoids are confined sites of mitochondrial DNA existing in complex clusters with the DNA-compacting mitochondrial (mt) transcription factor A (TFAM) and other accessory proteins and gene expression machinery proteins, such as a mt single-stranded-DNA-binding protein (mtSSB). To visualize nucleoid distribution within the mt reticular network, we have employed three-dimensional (3D) double-color 4Pi microscopy. The mt network was visualized in hepatocellular carcinoma HepG2 cells via mt-matrix-addressed GFP, while 3D immunocytochemistry of mtSSB was performed. Optimization of iso-surface computation threshold for nucleoid 4Pi images to 30 led to an average nucleoid diameter of 219 +/- 110 and 224 +/- 100 nm in glucose- and galactose-cultivated HepG2 cells (the latter with obligatory oxidative phosphorylation). We have positioned mtDNA nucleoids within the mt reticulum network and refined our model for nucleoid redistribution within the fragmented network--clustering of up to ten nucleoids in 2 MUm diameter mitochondrial spheroids of a fragmented mt network, arising from an original 10 MUm mt tubule of a 400 nm diameter. However, the theoretically fragmented bulk parts were observed most frequently as being reintegrated into the continuous mt network in 4Pi images. Since the predicted nucleoid counts within the bulk parts corresponded to the model, we conclude that fragmentation/reintegration cycles are not accompanied by mtDNA degradation or that mtDNA degradation is equally balanced by mtDNA replication. PMID- 25833037 TI - Proposal of a novel evaluation index for the effects of shear stress and exposure time on hepatocyte damage. AB - The purpose of this study was to propose a novel evaluation index for the effects of shear stress level and exposure time on hepatocyte damage. Suspensions of rat hepatocytes (0.5 mL) were subjected to shear stress from 1.2 to 3.1 Pa for 10 min (n = 3) using a rheoscope. We counted living and dead cells in photographs taken at 1-min intervals using a digital camera attached to the microscope. Living and dead cells were distinguished using a Trypan blue exclusion test. Under each level of shear stress, at each 1-min time interval, we measured the viability [living-cell number (t)/countable cell number (t)] and the ratio of living cells [RLC: living-cell number (t)/countable cell number in the initial condition]. The effects of shear stress and exposure time on viability and RLC were assessed by multiple regression analysis. As expected, we observed an increase in the number of dead cells and little change in the number of living cells when shear stress was increased. The coefficient of determination (R (2)) to predict the effectiveness of viability and RLC indicated a low to moderate correlation. Viability correlated with shear stress and exposure time (p < 0.001); however, RLC only correlated with exposure time of shear stress (p < 0.001). In this test condition, viability was strongly related not to living-cell damage but to dead cell damage. Therefore, we propose RLC as a novel and effective index for investigating the effect of shear stress on living hepatocytes. PMID- 25833038 TI - In prostate cancer, low adiponectin levels are not associated with insulin resistance. AB - PURPOSE: Adiponectin, an adipose tissue-derived hormone with insulin-sensitizing effect, has been inversely associated with several hormonally dependent malignancies. Prostate cancer is associated with low levels of adiponectin, which have been proposed as an independent risk factor for this malignancy. Aim of this study was to examine whether hypoadiponectinaemia in prostate is associated with insulin resistance. EXPERIMENTAL DESIGN: Plasma samples and covariate data in the context of a case-control study of 300 Greek men were evaluated including 75 patients with prostate cancer, 75 patients with benign prostatic hyperplasia (BPH) and 150 age-matched healthy controls. RESULTS: Patients with prostate cancer had significantly lower plasma adiponectin levels compared with the other two groups, that is BPH patients and healthy controls (7.4 +/- 5 ng/mL vs. 11.5 +/- 6.4 ng/mL and 12.8 +/- 8 ng/mL, respectively). On the other hand, no statistically significant differences were found between patients with prostate cancer and the other two groups for both HOMA-IR and QUICKI (P-value = 0.551). As expected, in all three groups, the levels of adiponectin correlated negatively with HOMA-IR (rho = -0.214, P-value = 0.006), QUICKI (rho = 0.214, P-value = 0.006) and insulin levels (rho = 0.942, P-value < 0.001). CONCLUSION: In spite of what would have been expected from the relevant literature, our data suggest that the hypoadiponectinaemia in prostatic cancer does not appear to be associated with insulin resistance. PMID- 25833039 TI - A layered P2- and O3-type composite as a high-energy cathode for rechargeable sodium-ion batteries. AB - A layered composite with P2 and O3 integration is proposed toward a sodium-ion battery with high energy density and long cycle life. The integration of P2 and O3 structures in this layered oxide is clearly characterized by XRD refinement, SAED and HAADF and ABF-STEM at atomic resolution. The biphase synergy in this layered P2+O3 composite is well established during the electrochemical reaction. This layered composite can deliver a high reversible capacity with the largest energy density of 640 mAh g(-1), and it also presents good capacity retention over 150 times of sodium extraction and insertion. PMID- 25833040 TI - Systolic cardiac function assessment by feature tracking echocardiography in dogs with myxomatous mitral valve disease. AB - OBJECTIVES: To evaluate endomyocardial and epimyocardial left ventricular circumferential and longitudinal peak systolic strain and strain rate in dogs with myxomatous mitral valve disease using two-dimensional feature tracking imaging echocardiography. MATERIALS AND METHODS: Epimyocardial and endomyocardial global and regional myocardial peak systolic strain and strain rate using two dimensional feature tracking imaging were evaluated in healthy dogs and those in stages B1, B2 and C of myxomatous mitral valve disease. Strain and strain rate in circumferential and longitudinal aspect were evaluated in 48 small- and medium sized dogs. RESULTS: Global endomyocardial circumferential strain and global epimyocardial circumferential strain systolic peak were lower in stage C than in stage B2 (P = 0 . 04 and P = 0 . 02) and similar to healthy dogs. Endomyocardial circumferential strain rate in septal and inferior segments were lower in stage C compared to B2 (P = 0 . 0007 and P = 0 . 0056), but not different from healthy dogs. There were no statistical differences in the epimyocardial circumferential strain rate, longitudinal strain and strain rate between healthy and affected dogs. CLINICAL SIGNIFICANCE: Two-dimensional feature tracking imaging determination of myocardial deformation in epimyocardial and endomyocardial layers allows detection of increased compensatory circumferential left ventricular myocardial systolic performance due to volume overload and absence of this response as disease advances to congestive heart failure. PMID- 25833041 TI - Thick solid electrolyte interphases grown on silicon nanocone anodes during slow cycling and their negative effects on the performance of Li-ion batteries. AB - Thickness, homogeneity and coverage of the surface passivation layer on Si anodes for Li-ion batteries have decisive influences on their cyclic performance and coulombic efficiency, but related information is difficult to obtain, especially during cycling. In this work, a well-defined silicon nanocone (SNC) on silicon wafer sample has been fabricated as a model electrode in lithium ion batteries to investigate the growth of surface species on the SNC electrode during cycling using ex situ scanning electronic microscopy. It is observed that an extra 5 MUm thick layer covers the top of the SNCs after 25 cycles at 0.1 C. This top layer has been proven to be a solid electrolyte interphase (SEI) layer by designing a solid lithium battery. It is noticed that the SEI layer is much thinner at a high rate of 1 C. The cyclic performance of the SNCs at 1 C looks much better than that of the same electrode at 0.1 C in the half cell. Our findings clearly demonstrate that the formation of the thick SEI on the naked nanostructured Si anode during low rate cycling is a serious problem for practical applications. An in depth understanding of this problem may provide valuable guidance in designing Si-based anode materials. PMID- 25833042 TI - Noncapped Alphavirus Genomic RNAs and Their Role during Infection. AB - Alphaviruses are enveloped positive-sense RNA viruses that exhibit a wide host range consisting of vertebrate and invertebrate species. Previously we have reported that the infectivity of Sindbis virus (SINV), the model alphavirus, was largely a function of the cell line producing the viral particles. Mammalian-cell derived SINV particles, on average, exhibit a higher particle-to-PFU ratio than mosquito cell-derived SINV particles. Nevertheless, the outcome of nonproductive infection, the molecular traits that determine particle infectivity and the biological importance of noninfectious particles were, prior to this study, unknown. Here, we report that the incoming genomic RNAs of noninfectious SINV particles undergo rapid degradation following infection. Moreover, these studies have led to the identification of the absence of the 5' cap structure as a primary molecular determinant of particle infectivity. We show that the genomic RNAs of alphaviruses are not universally 5' capped, with a significant number of noncapped genomic RNA produced early in infection. The production of noncapped viral genomic RNAs is important to the establishment and maintenance of alphaviral infection. IMPORTANCE: This report is of importance to the field of virology for three reasons. First, these studies demonstrate that noncapped Sindbis virus particles are produced as a result of viral RNA synthesis. Second, this report is, to our knowledge, the first instance of the direct measurement of the half-life of an incoming genomic RNA from a positive-sense RNA virus. Third, these studies indicate that alphaviral infection is likely a concerted effort of infectious and noninfectious viral particles. PMID- 25833043 TI - Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication Competent Virus: Implications for Cure Research. AB - Simian immunodeficiency virus SIVsab infection is completely controlled in rhesus macaques (RMs) through functional immune responses. We report that in SIVsab infected RMs, (i) viral replication is controlled to <0 to 3 copies/ml, (ii) about one-third of the virus strains in reservoirs are replication incompetent, and (iii) rebounding virus after CD8(+) cell depletion is replication competent and genetically similar to the original virus stock, suggesting early reservoir seeding. This model permits assessment of strategies aimed at depleting the reservoir without multidrug antiretroviral therapy. PMID- 25833044 TI - Determinants of Dengue Virus NS4A Protein Oligomerization. AB - Flavivirus NS4A protein induces host membrane rearrangement and functions as a replication complex component. The molecular details of how flavivirus NS4A exerts these functions remain elusive. Here, we used dengue virus (DENV) as a model to characterize and demonstrate the biological relevance of flavivirus NS4A oligomerization. DENV type 2 (DENV-2) NS4A protein forms oligomers in infected cells or when expressed alone. Deletion mutagenesis mapped amino acids 50 to 76 (spanning the first transmembrane domain [TMD1]) of NS4A as the major determinant for oligomerization, while the N-terminal 50 residues contribute only slightly to the oligomerization. Nuclear magnetic resonance (NMR) analysis of NS4A amino acids 17 to 80 suggests that residues L31, L52, E53, G66, and G67 could participate in oligomerization. Ala substitution for 15 flavivirus conserved NS4A residues revealed that these amino acids are important for viral replication. Among the 15 mutated NS4A residues, 2 amino acids (E50A and G67A) are located within TMD1. Both E50A and G67A attenuated viral replication, decreased NS4A oligomerization, and reduced NS4A protein stability. In contrast, NS4A oligomerization was not affected by the replication-defective mutations (R12A, P49A, and K80A) located outside TMD1. trans complementation experiments showed that expression of wild-type NS4A alone was not sufficient to rescue the replication-lethal NS4A mutants. However, the presence of DENV-2 replicons could partially restore the replication defect of some lethal NS4A mutants (L26A and K80A), but not others (L60A and E122A), suggesting an unidentified mechanism governing the outcome of complementation in a mutant-dependent manner. Collectively, the results have demonstrated the importance of TMD1-mediated NS4A oligomerization in flavivirus replication. IMPORTANCE: We report that DENV NS4A forms oligomers. Such NS4A oligomerization is mediated mainly through amino acids 50 to 76 (spanning the first transmembrane domain [TMD1]). The biological importance of NS4A oligomerization is demonstrated by results showing that mutations of flavivirus conserved residues (E50A and G67A located within TMD1) reduced the oligomerization and stability of the NS4A protein, leading to attenuated viral replication. A systematic mutagenesis analysis demonstrated that flavivirus conserved NS4A residues are important for DENV replication. A successful trans complementation of replication-lethal NS4A mutant virus requires wild-type NS4A in the context of the viral replication complex. The wild-type NS4A protein alone is not sufficient to rescue the replication defect of NS4A mutants. Intriguingly, distinct NS4A mutants yielded different complementation outcomes in the replicon-containing cells. Overall, the study has enhanced our understanding of flavivirus NS4A at the molecular level. The results also suggest that inhibitor blocking of NS4A oligomerization could be explored for antiviral drug discovery. PMID- 25833045 TI - Coronavirus and influenza virus proteolytic priming takes place in tetraspanin enriched membrane microdomains. AB - Coronaviruses (CoVs) and low-pathogenicity influenza A viruses (LP IAVs) depend on target cell proteases to cleave their viral glycoproteins and prime them for virus-cell membrane fusion. Several proteases cluster into tetraspanin-enriched microdomains (TEMs), suggesting that TEMs are preferred virus entry portals. Here we found that several CoV receptors and virus-priming proteases were indeed present in TEMs. Isolated TEMs, when mixed with CoV and LP IAV pseudoparticles, cleaved viral fusion proteins to fusion-primed fragments and potentiated viral transductions. That entering viruses utilize TEMs as a protease source was further confirmed using tetraspanin antibodies and tetraspanin short hairpin RNAs (shRNAs). Tetraspanin antibodies inhibited CoV and LP IAV infections, but their virus-blocking activities were overcome by expressing excess TEM-associated proteases. Similarly, cells with reduced levels of the tetraspanin CD9 resisted CoV pseudoparticle transductions but were made susceptible by overproducing TEM associated proteases. These findings indicated that antibodies and CD9 depletions interfere with viral proteolytic priming in ways that are overcome by surplus proteases. TEMs appear to be exploited by some CoVs and LP IAVs for appropriate coengagement with cell receptors and proteases. IMPORTANCE: Enveloped viruses use their surface glycoproteins to catalyze membrane fusion, an essential cell entry step. Host cell components prime these viral surface glycoproteins to catalyze membrane fusion at specific times and places during virus cell entry. Among these priming components are proteases, which cleave viral surface glycoproteins, unleashing them to refold in ways that catalyze virus-cell membrane fusions. For some enveloped viruses, these proteases are known to reside on target cell surfaces. This research focuses on coronavirus and influenza A virus cell entry and identifies TEMs as sites of viral proteolysis, thereby defining subcellular locations of virus priming with greater precision. Implications of these findings extend to the use of virus entry antagonists, such as protease inhibitors, which might be most effective when localized to these microdomains. PMID- 25833046 TI - Quantification of Hepatitis C Virus Cell-to-Cell Spread Using a Stochastic Modeling Approach. AB - It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread is fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads from cell to cell and has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors. Using a multidisciplinary approach, we performed HCV spread assays and assessed the appropriateness of different stochastic models for describing HCV focus expansion. To evaluate the effect of blocking specific host cell factors on HCV cell-to-cell transmission, assays were performed in the presence of blocking antibodies and/or small-molecule inhibitors targeting different cellular HCV entry factors. In all experiments, HCV-positive cells were identified by immunohistochemical staining and the number of HCV-positive cells per focus was assessed to determine focus size. We found that HCV focus expansion can best be explained by mathematical models assuming focus size-dependent growth. Consistent with previous reports suggesting that some factors impact HCV cell-to-cell spread to different extents, modeling results estimate a hierarchy of efficacies for blocking HCV cell-to-cell spread when targeting different host factors (e.g., CLDN1 > NPC1L1 > TfR1). This approach can be adapted to describe focus expansion dynamics under a variety of experimental conditions as a means to quantify cell-to-cell transmission and assess the impact of cellular factors, viral factors, and antivirals. IMPORTANCE: The ability of viruses to efficiently spread by direct cell-to-cell transmission is thought to play an important role in the establishment and maintenance of viral persistence. As such, elucidating the dynamics of cell-to-cell spread and quantifying the effect of blocking the factors involved has important implications for the design of potent antiviral strategies and controlling viral escape. Mathematical modeling has been widely used to understand HCV infection dynamics and treatment response; however, these models typically assume only cell-free virus infection mechanisms. Here, we used stochastic models describing focus expansion as a means to understand and quantify the dynamics of HCV cell-to-cell spread in vitro and determined the degree to which cell-to-cell spread is reduced when individual HCV entry factors are blocked. The results demonstrate the ability of this approach to recapitulate and quantify cell-to-cell transmission, as well as the impact of specific factors and potential antivirals. PMID- 25833047 TI - Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy. AB - A number of men receiving prolonged suppressive highly active antiretroviral therapy (HAART) still shed human immunodeficiency virus (HIV) in semen. To investigate whether this seminal shedding may be due to poor drug penetration and/or viral production by long-lived cells within male genital tissues, we analyzed semen and reproductive tissues from macaques chronically infected with simian immunodeficiency virus mac251 (SIVmac251) who were treated for 4 months with HAART, which was intensified over the last 7 weeks with an integrase inhibitor. We showed that a subset of treated animals continued shedding SIV in semen despite efficient HAART. This shedding was not associated with low antiretroviral drug concentrations in semen or in testis, epididymis, seminal vesicles, and prostate. HAART had no significant impact on SIV RNA in the urethra, whereas it drastically reduced SIV RNA levels in the prostate and vas deferens and to a lesser extent in the epididymis and seminal vesicle. The only detectable SIV RNA-positive cells within the male genital tract after HAART were urethral macrophages. SIV DNA levels in genital tissues were not decreased by HAART, suggesting the presence throughout the male genital tract of nonproductively infected cells. In conclusion, our results demonstrate that 4 months of HAART induced variable and limited control of viral infection in the male reproductive organs, particularly in the urethra, and suggest that infected long-lived cells in the male genital tract may be involved in persistent seminal shedding during HAART. These results pave the way for further investigations of male genital organ infection in long-term-treated infected individuals. IMPORTANCE: A substantial subset of men receiving prolonged HAART suppressing viral loads in the blood still harbor HIV in semen, and cases of sexual transmission have been reported. To understand the origin of this persistence, we analyzed the semen and male reproductive tissues from SIV-infected macaques treated with HAART. We demonstrated that persistent seminal shedding was not linked to poor drug penetration in semen or semen-producing prostate, seminal vesicle, epididymis, and testis. We revealed that HAART decreased SIV RNA to various extents in all male genital organs, with the exception of the urethra, in which SIV RNA(+) macrophages were observed despite HAART. Importantly, HAART did not impact SIV DNA levels in the male genital organs. These results suggest that infection of male genital organs, and particularly the urethra, could be involved in the release of virus in semen during HAART. PMID- 25833048 TI - Interregional Coevolution Analysis Revealing Functional and Structural Interrelatedness between Different Genomic Regions in Human Mastadenovirus D. AB - Human mastadenovirus D (HAdV-D) is exceptionally rich in type among the seven human adenovirus species. This feature is attributed to frequent intertypic recombination events that have reshuffled orthologous genomic regions between different HAdV-D types. However, this trend appears to be paradoxical, as it has been demonstrated that the replacement of some of the interacting proteins for a specific function with other orthologues causes malfunction, indicating that intertypic recombination events may be deleterious. In order to understand why the paradoxical trend has been possible in HAdV-D evolution, we conducted an interregional coevolution analysis between different genomic regions of 45 different HAdV-D types and found that ca. 70% of the genome has coevolved, even though these are fragmented into several pieces via short intertypic recombination hot spot regions. Since it is statistically and biologically unlikely that all of the coevolving fragments have synchronously recombined between different genomes, it is probable that these regions have stayed in their original genomes during evolution as a platform for frequent intertypic recombination events in limited regions. It is also unlikely that the same genomic regions have remained almost untouched during frequent recombination events, independently, in all different types, by chance. In addition, the coevolving regions contain the coding regions of physically interacting proteins for important functions. Therefore, the coevolution of these regions should be attributed at least in part to natural selection due to common biological constraints operating on all types, including protein-protein interactions for essential functions. Our results predict additional unknown protein interactions. IMPORTANCE: Human mastadenovirus D, an exceptionally type-rich human adenovirus species and causative agent of different diseases in a wide variety of tissues, including that of ocular region and digestive tract, as well as an opportunistic infection in immunocompromised patients, is known to have highly diverged through frequent intertypic recombination events; however, it has also been demonstrated that the replacement of a component protein of a multiprotein system with a homologous protein causes malfunction. The present study solved this apparent paradox by looking at which genomic parts have coevolved using a newly developed method. The results revealed that intertypic recombination events have occurred in limited genomic regions and been avoided in the genomic regions encoding proteins that physically interact for a given function. This approach detects purifying selection against recombination events causing the replacement of partial components of multiprotein systems and therefore predicts physical and functional interactions between different proteins and/or genomic elements. PMID- 25833049 TI - Lymphocytic Choriomeningitis Virus Differentially Affects the Virus-Induced Type I Interferon Response and Mitochondrial Apoptosis Mediated by RIG-I/MAVS. AB - Arenaviruses are important emerging human pathogens maintained by noncytolytic persistent infection in their rodent reservoir hosts. Despite high levels of viral replication, persistently infected carrier hosts show only mildly elevated levels of type I interferon (IFN-I). Accordingly, the arenavirus nucleoprotein (NP) has been identified as a potent IFN-I antagonist capable of blocking activation of interferon regulatory factor 3 (IRF3) via the retinoic acid inducible gene (RIG)-I/mitochondrial antiviral signaling (MAVS) pathway. Another important mechanism of host innate antiviral defense is represented by virus induced mitochondrial apoptosis via RIG-I/MAVS and IRF3. In the present study, we investigated the ability of the prototypic Old World arenavirus lymphocytic choriomeningitis virus (LCMV) to interfere with RIG-I/MAVS-dependent apoptosis. We found that LCMV does not induce apoptosis at any time during infection. While LCMV efficiently blocked induction of IFN-I via RIG-I/MAVS in response to superinfection with cytopathic RNA viruses, virus-induced mitochondrial apoptosis remained fully active in LCMV-infected cells. Notably, in LCMV-infected cells, RIG-I was dispensable for virus-induced apoptosis via MAVS. Our study reveals that LCMV infection efficiently suppresses induction of IFN-I but does not interfere with the cell's ability to undergo virus-induced mitochondrial apoptosis as a strategy of innate antiviral defense. The RIG-I independence of mitochondrial apoptosis in LCMV-infected cells provides the first evidence that arenaviruses can reshape apoptotic signaling according to their needs. IMPORTANCE: Arenaviruses are important emerging human pathogens that are maintained in their rodent hosts by persistent infection. Persistent virus is able to subvert the cellular interferon response, a powerful branch of the innate antiviral defense. Here, we investigated the ability of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) to interfere with the induction of programmed cell death, or apoptosis, in response to superinfection with cytopathic RNA viruses. Upon viral challenge, persistent LCMV efficiently blocked induction of interferons, whereas virus-induced apoptosis remained fully active in LCMV-infected cells. Our studies reveal that the persistent virus is able to reshape innate apoptotic signaling in order to prevent interferon production while maintaining programmed cell death as a strategy for innate defense. The differential effect of persistent virus on the interferon response versus its effect on apoptosis appears as a subtle strategy to guarantee sufficiently high viral loads for efficient transmission while maintaining apoptosis as a mechanism of defense. PMID- 25833050 TI - Crystal Structures of Yeast-Produced Enterovirus 71 and Enterovirus 71/Coxsackievirus A16 Chimeric Virus-Like Particles Provide the Structural Basis for Novel Vaccine Design against Hand-Foot-and-Mouth Disease. AB - Human enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the two major causative agents for hand-foot-and-mouth disease (HFMD). Previously, we demonstrated that a virus-like particle (VLP) for EV71 produced from Saccharomyces cerevisiae is a potential vaccine candidate against EV71 infection, and an EV71/CVA16 chimeric VLP can elicit protective immune responses against both virus infections. Here, we presented the crystal structures of both VLPs, showing that both the linear and conformational neutralization epitopes identified in EV71 are mostly preserved on both VLPs. The replacement of only 4 residues in the VP1 GH loop converted strongly negatively charged surface patches formed by portions of the SP70 epitope in EV71 VLP into a relatively neutral surface in the chimeric VLP, which likely accounted for the additional neutralization capability of the chimeric VLP against CVA16 infection. Such local variations in the amino acid sequences and the surface charge potential are also present in different types of polioviruses. In comparison to EV71 VLP, the chimeric VLP exhibits structural changes at the local site of amino acid replacement and the surface loops of all capsid proteins. This is consistent with the observation that the VP1 GH loop located near the pseudo-3-fold junction is involved in extensive interactions with other capsid regions. Furthermore, portions of VP0 and VP1 in EV71 VLP are at least transiently exposed, revealing the structural flexibility of the VLP. Together, our structural analysis provided insights into the structural basis of enterovirus neutralization and novel vaccine design against HFMD and other enterovirus-associated diseases. IMPORTANCE: Our previous studies demonstrated that the enterovirus 71 (EV71) virus-like particle (VLP) produced from yeast is a vaccine candidate against EV71 infection and that a chimeric EV71/coxsackievirus A16 (CVA16) VLP with the replacement of 4 amino acids in the VP1 GH loop can confer protection against both EV71 and CVA16 infections. This study reported the crystal structures of both the EV71 VLP and the chimeric EV71/CVA16 VLP and revealed that the major neutralization epitopes of EV71 are mostly preserved in both VLPs. In addition, the mutated VP1 GH loop in the chimeric VLP is well exposed on the particle surface and exhibits a surface charge potential different from that contributed by the original VP1 GH loop in EV71 VLP. Together, this study provided insights into the structural basis of enterovirus neutralization and evidence that the yeast-produced VLPs can be developed into novel vaccines against hand-foot-and mouth disease (HFMD) and other enterovirus-associated diseases. PMID- 25833051 TI - Artificial Recruitment of UAF1-USP Complexes by a PHLPP1-E1 Chimeric Helicase Enhances Human Papillomavirus DNA Replication. AB - The E1 helicase from anogenital human papillomavirus (HPV) types interacts with the cellular WD repeat-containing protein UAF1 in complex with the deubiquitinating enzyme USP1, USP12, or USP46. This interaction stimulates viral DNA replication and is required for maintenance of the viral episome in keratinocytes. E1 associates with UAF1 through a short UAF1-binding site (UBS) located within the N-terminal 40 residues of the protein. Here, we investigated if the E1 UBS could be replaced by the analogous domain from an unrelated protein, the pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). We found that PHLPP1 and E1 interact with UAF1 in a mutually exclusive manner and mapped the minimal PHLPP1 UBS (PUBS) to a 100-amino acid region sufficient for assembly into UAF1-USP complexes. Similarly to the E1 UBS, overexpression of PUBS in trans inhibited HPV DNA replication, albeit less efficiently. Characterization of a PHLPP1-E1 chimeric helicase revealed that PUBS could partially substitute for the E1 UBS in enhancing viral DNA replication and that the stimulatory effect of PUBS likely involves recruitment of UAF1-USP complexes, as it was abolished by mutations that weaken UAF1-binding and by overexpression of catalytically inactive USPs. Although functionally similar to the E1 UBS, PUBS is larger in size and requires both the WD repeat region and C terminal ubiquitin-like domain of UAF1 for interaction, in contrast to E1, which does not contact the latter. Overall, this comparison of two heterologous UBSs indicates that these domains function as transferable protein interaction modules and provide further evidence that the association of E1 with UAF1-containing deubiquitinating complexes stimulates HPV DNA replication. IMPORTANCE: The E1 protein from anogenital HPV types interacts with the UAF1-associated deubiquitinating enzymes USP1, USP12, and USP46 to stimulate replication of the viral genome. Little is known about the molecular nature of the E1-UAF1 interaction and, more generally, how UAF1-USP complexes recognize their substrate proteins. To address this question, we characterized the UAF1-binding site (UBS) of PHLPP1, a protein unrelated to E1. Using a PHLPP1-E1 chimeric helicase, we show that the PHLPP1 UBS (PUBS) can partially substitute for the E1 UBS in stimulating HPV DNA replication. This stimulation required conserved sequences in PUBS that meditate its interaction with UAF1, including a motif common to the E1 UBS. These results indicate that UAF1-binding sequences function as transferable protein interaction modules and provide further evidence that UAF1-USP complexes stimulate HPV DNA replication. PMID- 25833052 TI - Continual Reintroduction of Human Pandemic H1N1 Influenza A Viruses into Swine in the United States, 2009 to 2014. AB - The diversity of influenza A viruses in swine (swIAVs) presents an important pandemic threat. Knowledge of the human-swine interface is particularly important for understanding how viruses with pandemic potential evolve in swine hosts. Through phylogenetic analysis of contemporary swIAVs in the United States, we demonstrate that human-to-swine transmission of pandemic H1N1 (pH1N1) viruses has occurred continuously in the years following the 2009 H1N1 pandemic and has been an important contributor to the genetic diversity of U.S. swIAVs. Although pandemic H1 and N1 segments had been largely removed from the U.S. swine population by 2013 via reassortment with other swIAVs, these antigens reemerged following multiple human-to-swine transmission events during the 2013-2014 seasonal epidemic. These findings indicate that the six internal gene segments from pH1N1 viruses are likely to be sustained long term in the U.S. swine population, with periodic reemergence of pandemic hemagglutinin (HA) and neuraminidase (NA) segments in association with seasonal pH1N1 epidemics in humans. Vaccinating U.S. swine workers may reduce infection of both humans and swine and in turn limit the role of humans as sources of influenza virus diversity in pigs. IMPORTANCE: Swine are important hosts in the evolution of influenza A viruses with pandemic potential. Here, we analyze influenza virus sequence data generated by the U.S. Department of Agriculture's national surveillance system to identify the central role of humans in the reemergence of pandemic H1N1 (pH1N1) influenza viruses in U.S. swine herds in 2014. These findings emphasize the important role of humans as continuous sources of influenza virus diversity in swine and indicate that influenza viruses with pandemic HA and NA segments are likely to continue to reemerge in U.S. swine in association with seasonal pH1N1 epidemics in humans. PMID- 25833053 TI - In Vivo Activation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits Acute In Vivo HIV-1 Infection in Humanized Mice. AB - Natural killer (NK) cells with anti-HIV-1 activity may inhibit HIV-1 replication and dissemination during acute HIV-1 infection. We hypothesized that the capacity of NK cells to suppress acute in vivo HIV-1 infection would be augmented by activating them via treatment with an interleukin-15 (IL-15) superagonist, IL-15 bound to soluble IL-15Ralpha, an approach that potentiates human NK cell-mediated killing of tumor cells. In vitro stimulation of human NK cells with a recombinant IL-15 superagonist significantly induced their expression of the cytotoxic effector molecules granzyme B and perforin; their degranulation upon exposure to K562 cells, as indicated by cell surface expression of CD107a; and their capacity to lyse K562 cells and HIV-1-infected T cells. The impact of IL-15 superagonist induced activation of human NK cells on acute in vivo HIV-1 infection was investigated by using hu-spl-PBMC-NSG mice, NOD-SCID-IL2rgamma(-/-) (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMCs) which develop productive in vivo infection after intrasplenic inoculation with HIV-1. IL-15 superagonist treatment potently inhibited acute HIV-1 infection in hu-spl-PBMC-NSG mice even when delayed until 3 days after intrasplenic HIV-1 inoculation. Removal of NK cells from human PBMCs prior to intrasplenic injection into NSG mice completely abrogated IL-15 superagonist-mediated suppression of in vivo HIV-1 infection. Thus, the in vivo activation of NK cells, integral mediators of the innate immune response, by treatment with an IL-15 superagonist increases their anti-HIV activity and enables them to potently suppress acute in vivo HIV-1 infection. These results indicate that in vivo activation of NK cells may represent a new immunotherapeutic approach to suppress acute HIV-1 infection. IMPORTANCE: Epidemiological studies have indicated that NK cells contribute to the control of HIV-1 infection, and in vitro studies have demonstrated that NK cells can selectively kill HIV-1-infected cells. We demonstrated that in vivo activation of NK cells by treatment with an IL-15 superagonist that potently stimulates the antitumor activity of NK cells markedly inhibited acute HIV-1 infection in humanized mice, even when activation of NK cells by IL-15 superagonist treatment is delayed until 3 days after HIV-1 inoculation. NK cell depletion from PBMCs prior to their intrasplenic injection abrogated the suppression of in vivo HIV-1 infection observed in humanized mice treated with the IL-15 superagonist, demonstrating that activated human NK cells were mediating IL-15 superagonist-induced inhibition of acute HIV-1 infection. Thus, in vivo immunostimulation of NK cells, a promising therapeutic approach for cancer therapy, may represent a new treatment modality for HIV-1-infected individuals, particularly in the earliest stages of infection. PMID- 25833054 TI - Us9-Independent Axonal Sorting and Transport of the Pseudorabies Virus Glycoprotein gM. AB - Axonal sorting and transport of fully assembled pseudorabies virus (PRV) virions is dependent on the viral protein Us9. Here we identify a Us9-independent mechanism for axonal localization of viral glycoprotein M (gM). We detected gM mCherry assemblies transporting in the anterograde direction in axons. Furthermore, unlabeled gM, but not glycoprotein B, was detected by Western blotting in isolated axons during Us9-null PRV infection. These results suggest that gM differs from other viral proteins regarding axonal transport properties. PMID- 25833055 TI - Equine Herpesvirus 1 Multiply Inserted Transmembrane Protein pUL43 Cooperates with pUL56 in Downregulation of Cell Surface Major Histocompatibility Complex Class I. AB - Herpesviruses have evolved an array of strategies to counteract antigen presentation by major histocompatibility complex class I (MHC-I). Previously, we identified pUL56 of equine herpesvirus 1 (EHV-1) as one major determinant of the downregulation of cell surface MHC-I (G. Ma, S. Feineis, N. Osterrieder, and G. R. Van de Walle, J. Virol. 86:3554-3563, 2012, http://dx.doi.org/10.1128/JVI.06994-11; T. Huang, M. J. Lehmann, A. Said, G. Ma, and N. Osterrieder, J. Virol. 88:12802-12815, 2014, http://dx.doi.org/10.1128/JVI.02079-14). Since pUL56 was able to exert its function only in the context of virus infection, we hypothesized that pUL56 cooperates with another viral protein. Here, we generated and screened a series of EHV-1 single-gene deletion mutants and found that the pUL43 orthologue was required for downregulation of cell surface MHC-I expression at the same time of infection as when pUL56 exerts its function. We demonstrate that the absence of pUL43 was not deleterious to virus growth and that expression of pUL43 was detectable from 2 h postinfection (p.i.) but decreased after 8 h p.i. due to lysosomal degradation. pUL43 localized within Golgi vesicles and required a unique hydrophilic N-terminal domain to function properly. Finally, coexpression of pUL43 and pUL56 in transfected cells reduced the cell surface expression of MHC-I. This process was dependent on PPxY motifs present in pUL56, suggesting that late domains are required for pUL43- and pUL56-dependent sorting of MHC class I for lysosomal degradation. IMPORTANCE: We describe here that the poorly characterized herpesviral protein pUL43 is involved in downregulation of cell surface MHC-I. pUL43 is an early protein and degraded in lysosomes. pUL43 resides in the Golgi vesicles and needs an intact N terminus to induce MHC-I downregulation in infected cells. Importantly, pUL43 and pUL56 cooperate to reduce MHC-I expression on the surface of transfected cells. Our results suggest a model for MHC-I downregulation in which late domains in pUL56 are required for the rerouting of vesicles containing MHC-I, pUL56, and pUL43 to the lysosomal compartment. PMID- 25833056 TI - Morphogenesis of Endoplasmic Reticulum Membrane-Invaginated Vesicles during Beet Black Scorch Virus Infection: Role of Auxiliary Replication Protein and New Implications of Three-Dimensional Architecture. AB - All well-characterized positive-strand RNA viruses[(+)RNA viruses] induce the formation of host membrane-bound viral replication complexes (VRCs), yet the underlying mechanism and machinery for VRC formation remain elusive. We report here the biogenesis and topology of the Beet black scorch virus (BBSV) replication complex. Distinct cytopathological changes typical of endoplasmic reticulum (ER) aggregation and vesiculation were observed in BBSV-infected Nicotiana benthamiana cells. Immunogold labeling of the auxiliary replication protein p23 and double-stranded RNA (dsRNA) revealed that the ER-derived membranous spherules provide the site for BBSV replication. Further studies indicated that p23 plays a crucial role in mediating the ER rearrangement. Three dimensional electron tomographic analysis revealed the formation of multiple ER originated vesicle packets. Each vesicle packet enclosed a few to hundreds of independent spherules that were invaginations of the ER membranes into the lumen. Strikingly, these vesicle packets were connected to each other via tubules, a rearrangement event that is rare among other virus-induced membrane reorganizations. Fibrillar contents within the spherules were also reconstructed by electron tomography, which showed diverse structures. Our results provide the first, to our knowledge, three-dimensional ultrastructural analysis of membrane bound VRCs of a plant (+)RNA virus and should help to achieve a better mechanistic understanding of the organization and microenvironment of plant (+)RNA virus replication complexes. IMPORTANCE: Assembly of virus replication complexes for all known positive-strand RNA viruses depends on the extensive remodeling of host intracellular membranes. Beet black scorch virus, a necrovirus in the family Tombusviridae, invaginates the endoplasmic reticulum (ER) membranes to form spherules in infected cells. Double-stranded RNAs, the viral replication intermediate, and the viral auxiliary replication protein p23 are all localized within such viral spherules, indicating that these are the sites for generating progeny viral RNAs. Furthermore, the BBSV p23 protein could to some extent reorganize the ER when transiently expressed in N. benthamiana. Electron tomographic analysis resolves the three-dimensional (3D) architecture of such spherules, which are connected to the cytoplasm via a neck-like structure. Strikingly, different numbers of spherules are enclosed in ER-originated vesicle packets that are connected to each other via tubule-like structures. Our results have significant implications for further understanding the mechanisms underlying the replication of positive-strand RNA viruses. PMID- 25833057 TI - Ultrasonic hammer produces hot spots in solids. AB - Mechanical action can produce dramatic physical and mechanochemical effects when the energy is spatially or temporally concentrated. An important example of such phenomena in solids is the mechanical initiation of explosions, which has long been speculated to result from 'hot spot' generation at localized microstructures in the energetic material. Direct experimental evidence of such hot spots, however, is exceptionally limited; mechanisms for their generation are poorly understood and methods to control their locations remain elusive. Here we report the generation of intense, localized microscale hot spots in solid composites during mild ultrasonic irradiation, directly visualized by a thermal imaging microscope. These ultrasonic hot spots, with heating rates reaching ~22,000 K s( 1), nucleate exclusively at interfacial delamination sites in composite solids. Introducing specific delamination sites by surface modification of embedded components provides precise and reliable control of hot spot locations and permits microcontrol of the initiation of reactions in energetic materials including fuel/oxidizer explosives. PMID- 25833058 TI - Advancing equity in healthcare. PMID- 25833059 TI - Carl Friedrich Richard Foerster (1825-1902) - the inventor of perimeter and photometer. AB - Carl Friedrich Richard Foerster (1825-1902) was a German who was born in the Polish city Leszno. He studied medicine at the Medical Faculty of Breslau (now Wroclaw, Poland) University, and later in Heidelberg and Berlin. From 1855, he worked in Breslau, where he established in 1857 the first ophthalmology clinic. Later, he became a professor in ophthalmology, the first director of the Department of Ophthalmology at the University of Breslau, and even the rector of this University. Forster did many pioneering works on visual fields, invented a photometer and the first perimeter, known for many years as the Foerster perimeter. Moreover, he studied night blindness, visual field changes due to different pathologies, and many eye diseases, including glaucoma, cataract, retinal and choroidal diseases. PMID- 25833060 TI - The Diagnosis of Polycystic Ovary Syndrome during Adolescence. AB - BACKGROUND/AIMS: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. METHODS: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. RESULTS AND CONCLUSION: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls. (c) 2015 S. Karger AG, Basel. PMID- 25833061 TI - Identification of Underlying Causes of Spontaneous Submacular Hemorrhage by Indocyanine Green Angiography. AB - PURPOSE: To investigate the causes of acute spontaneous submacular hemorrhage with indocyanine green angiography (ICGA). METHODS: Retrospective observation case series. A total of 51 eyes from 51 patients with newly developed spontaneous submacular hemorrhage were enrolled. Best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, spectral domain optical coherence tomography (OCT), and ICGA at baseline were analyzed. The extent of hemorrhage using fundus photography, height of hemorrhage, and central foveal thickness measured by OCT was analyzed to compare the diagnostic and nondiagnostic groups. RESULTS: The mean logarithm of the minimum angle of resolution (logMAR) BCVA at presentation was 1.21 +/- 0.74 (Snellen equivalent, 20/324); the mean follow-up period was 23.9 +/- 23.9 months. The cause of submacular hemorrhage was diagnosed in 43 of 51 eyes (84.3%) based on ICGA at presentation. The initial diagnoses were correct in 93% of eyes. In 3 cases, the initial diagnosis of age-related macular degeneration (AMD) was changed to polypoidal choroidal vasculopathy (PCV) based on follow-up ICGA. The central foveal thickness was significantly greater in the nondiagnostic group (1,102.4 vs. 666.7 MUm, respectively; p = 0.008). The most common cause of submacular hemorrhage was neovascular AMD (52.9%), followed by PCV (37.3%), macroaneurysm (5.9%), and lacquer crack (3.9%). The mean final visual acuity was generally worse in patients with submacular hemorrhage with typical AMD (visual acuity 20/618) or PCV (visual acuity 20/240) compared to that in patients with retinal macroaneurysm (visual acuity 20/100) or lacquer crack (visual acuity 20/72). CONCLUSIONS: ICGA at initial presentation helps identify causes of submacular hemorrhage, allowing differential treatment approaches that may improve outcomes and safety. PMID- 25833062 TI - TLR4 activation by lipopolysaccharide confers survival advantage to growth factor deprived prostate cancer cells. AB - BACKGROUND: Prostate cancer (PCa) cells express Toll-like receptor-4 (TLR4), a known pro-tumorigenic molecule for different cancer cells. The cancer cells residing in the avascular region of the tumor confront various metabolic stresses and continuously adapt mechanisms to overcome them. We hypothesized that TLR4 activation might provide direct survival advantage to metabolically stressed PCa cells. METHODS: We first investigated the effect of LPS on survival of serum deprived PCa cells. To understand the molecular mechanisms involved in TLR4 mediated PCa survival, we next investigated change in expression of markers for apoptosis, senescence and autophagy. Ultimately, the effect of LPS on established prostate tumors was confirmed in vivo using a syngeneic rat model for PCa. RESULTS: Lipopolysaccharide (LPS)-mediated TLR4 activation significantly enhanced survival of serum deprived (SD) PC3, DU145 and MAT-LyLu PCa cells. TLR4 inhibition by a specific inhibitor resulted in rapid death of SD-PC3 cells, which was significantly suppressed by LPS. Interestingly, LPS treatment suppressed macroautophagy in SD-PC3 cells and increased expression of CCL2 (C-C motif ligand 2), a known autophagy inhibitor and pro-survival factor. Intra-tumor LPS injection resulted in increased tumor mass, induced TLR4 activation, suppressed autophagy, and increased the macrophage population in MAT-LyLu-tumors. CONCLUSIONS: Our study reveals that bacterial LPS enhance survival of PCa cells under conditions of nutrient stress through TLR4 activation. Moreover, LPS induces overexpression of CCL2 involved in the suppression of starvation-induced macroautophagy in PCa cells, and enhanced macrophage population in prostate tumors in vivo. Taken together, the current study suggests the importance of bacterial infection or TLR4-activation in prostate cancer pathogenesis. PMID- 25833063 TI - Anti-inflammatory effect of white wine in CKD patients and healthy volunteers. AB - BACKGROUND: Mediterranean-style diet has been considered for its important beneficial effects on the progression of CV disease. Wine is an important component of the Mediterranean diet, and moderate wine drinkers have lower mortality rates than nondrinkers and heavy drinkers in epidemiologic studies. The beneficial effects of red wine are thought to be dependent on the polyphenol compounds such as resveratrol that exhibit potent antioxidant activity. However, white wine, although lacking polyphenols, contains simple phenols, such as tyrosol (Tyr) and hydroxytyrosol (OH-Tyr), characteristic also of extra-virgin olive oil, which may share similar antioxidant and inflammatory properties. PATIENTS AND METHODS: The effect of white wine and extra-virgin olive oil on inflammatory markers was evaluated in 10 healthy volunteers and in 10 patients with CKD (chronic kidney disease) K-DOQI stage III-IV in a prospective, single blind, randomized, cross-over trial. After two weeks of wash-out from alcoholic beverages, subjects were randomized to a cross-over design A-B or B-A of a 2-week treatment with white wine (4 ml/kg body weight, 0.48 g/kg of alcohol 12%, corresponding to 2-3 glasses/daily) and extra-virgin olive oil (treatment A) or extra-virgin olive oil alone (treatment B). The two study periods were separated by a two-week wash-out period. At baseline and at the end of each treatment, plasma levels of inflammatory markers C-reactive protein (CRP), interleukin-6 (IL 6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8) concentration were determined. Urinary levels of Tyr, OH-Tyr, and their metabolites were measured at the same time. RESULTS: During combined consumption of white wine and extra-virgin olive oil (treatment A), plasma levels of CRP and IL-6 decreased from 4.1 +/- 1.8 to 2.4 +/- 1.9 mg/l (p < 0.05) and from 5.3 +/- 3.2 to 3.4 +/- 2.3 mg/l (p < 0.05) in CKD patients. CRP decreased from 2.6 +/- 1.2 to 1.9 +/- 0.9 mg/l (p < 0.05), and IL-6 decreased from 2.2 +/- 1.8 to 1.7 +/ 1.3 mg/l (p = ns) in healthy volunteers. No significant variation versus baseline was observed during treatment B. A significant increase in urinary Tyr and OH-Tyr was observed during treatment A (white wine and extra-virgin olive oil). CONCLUSIONS: Plasma markers of chronic inflammation were significantly reduced in CKD patients during the combined consumption of white wine and olive oil, suggesting a possible anti-inflammatory effect of this nutritional intervention. PMID- 25833064 TI - Ethical persuasion: the rhetoric of communication in critical care. AB - This article reviews the ethics of rhetoric in critical care. Rational appeals in critical care fail to move patients or surrogates to a better course of action. Appeals to their emotions are considered illegitimate because they may preclude autonomous choice. This article discusses whether it is always unethical to change someone's beliefs, whether persuasive communication is inherently harmful and whether it leaves no space for voluntariness. To answer these questions, the article engages with Aristotle's work, Rhetoric. In considering whether there is a place for emotionally charged messages in a patient-provider relationship, the article intends to delineate the nature of this relationship and describe the duties this relationship implies. The article presents examples of persuasive communication used in critical care and discusses whether providers may have a duty to persuade patients. This duty is supported by the fact that doctors often influence patients' and families' choices by framing presented options. Doctors should assume responsibility in recognizing these personal and contextual influences that may influence the medical choices of their patients. They should attempt to modify these contextual factors and biases in a way that would assist patients and families in reaching the desired outcomes. The opening sections surveyed a number of definitions found in relevant literature and outlined some of the concepts included in the proposed definition. This definition helps to distinguish instances of persuasion from cases of manipulation, coercion and deception. Considering the fact that patients and families often make irrational decisions and the fact that doctors inadvertently influence their choices, the article suggested that persuasion can be a positive tool in medical communication. When patients or families clearly do not understand the risks or make decisions that contradict their long-term goals, persuasion can be used as a positive influence. PMID- 25833065 TI - Treatment of postherpetic neuralgia using DREZotomy guided by spinal cord stimulation. AB - BACKGROUND: Postherpetic neuralgia (PHN) is the most common complication following an episode of acute herpes zoster. The curative effect of current treatments is limited. OBJECTIVES: The purpose of this paper is to report a new treatment for PHN with a combination of dorsal root entry zone lesion (DREZotomy) and spinal cord stimulation (SCS). METHODS: Microsurgical DREZotomy assisted with SCS for target localization was performed in 6 patients with PHN. A visual analog scale (VAS) was used to evaluate the pain pre- and postoperatively. RESULTS: Except for 1 patient, in whom the test SCS was unsatisfactory, all patients finally underwent DREZotomy. These 5 patients experienced apparent symptom relief postoperatively, and the VAS score decreased from a baseline of 8.4 +/- 1.14 to 2.4 +/- 1.14 (p = 0.0020) and did not change significantly during the follow-up of up to 24 months. CONCLUSIONS: Microsurgical DREZotomy assisted with SCS for target localization is an effective remedy for PHN. PMID- 25833066 TI - Bacterial lysate increases the percentage of natural killer T cells in peripheral blood and alleviates asthma in children. AB - AIMS: To assess the efficacy of conventional treatment combined with bacterial lysate [OM-85 Broncho-Vaxom (BV)] in the prevention of asthma in children as well as its influence on the number of natural killer T (NKT) cells and their cytokine production. MATERIALS AND METHODS: Sixty children diagnosed with asthma were divided into either a BV-treated group (with oral OM-85 BV) or a conventional inhaled corticosteroid (ICS) group. The numbers of NKT cells and CD4+ NKT cells were measured in the peripheral blood by flow cytometry. The levels of IFN-gamma, IL-4, and IL-10 after the blood cells had been cultured with an NKT cell agonist were detected by ELISA. RESULTS: After therapy, asthma attacks were significantly decreased compared with before therapy in both groups. However, after therapy, respiratory tract infections were reduced compared with before therapy in the BV treated group only. Additionally, the frequency of asthma attacks and use of antibiotics in the BV-treated group were lower than in the ICS group. With BV treatment, the numbers of peripheral blood NKT cells and CD4+ NKT cells were higher after therapy than before therapy. After therapy, the ratio of IFN gamma/IL-4 and IL-10 levels were increased in the BV-treated group, whereas IL-4 was reduced in the BV-treated group compared with the ICS group. CONCLUSION: BV combined with conventional asthma treatment can prevent recurrent respiratory tract infections and suppress the severity of asthma attacks, possibly by altering the rates and cytokines of NKT cells. PMID- 25833067 TI - Injury response checkpoint and developmental timing in insects. AB - In insects, localized tissue injury often leads to global (organism-wide) delays in development and retarded metamorphosis. In Drosophila, for example, injuries to the larval imaginal discs can retard pupariation and prolong metamorphosis. Injuries induced by treatments such as radiation, mechanical damage and induction of localized cell death can trigger similar delays. In most cases, the duration of the developmental delay appears to be correlated with the extent of damage, but the effect is also sensitive to the developmental stage of the treated animal. The proximate cause of the delays is likely a disruption of the ecdysone signaling pathway, but the intermediate steps leading from tissue injury and/or regeneration to that disruption remain unknown. Here, we review the evidence for injury-induced developmental delays, and for a checkpoint or checkpoints associated with the temporal progression of development and the on-going efforts to define the mechanisms involved. PMID- 25833069 TI - Self-organizing large-scale extracellular-matrix protein networks. PMID- 25833068 TI - Exacerbation of experimental autoimmune encephalomyelitis in ceramide synthase 6 knockout mice is associated with enhanced activation/migration of neutrophils. AB - Ceramides are mediators of inflammatory processes. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that CerS6 mRNA expression was upregulated 15-fold in peripheral blood leukocytes before the onset of EAE symptoms. In peripheral blood leukocytes from MS patients, a 3.9-fold upregulation was found. Total genetic deletion of CerS6 and the selective deletion of CerS6 in peripheral blood leucocytes exacerbated the progression of clinical symptoms in EAE mice. This was associated with enhanced leukocyte, predominantly neutrophil infiltration and enhanced demyelination in the lumbar spinal cord of EAE mice. Interferon-gamma/tumor necrosis factor alpha (IFN-gamma/TNF-alpha) and granulocyte colony-stimulating factor (G-CSF) both drive EAE development and induce expression of the integrin CD11b and the chemokine receptor C-X-C motif chemokine receptor 2 (CXCR2), and we found they also induce CerS6 expression. In vivo, the genetic deletion of CerS6 enhanced the activation/migration of neutrophils, as reflected by an enhanced upregulation of CD11b and CXCR2. In vitro, the genetic deletion of CerS6 enhanced the activation status of IFN-gamma/TNF-alpha-stimulated neutrophils, as shown by increased expression of nitric oxide and CD11b and an increased adhesion capacity. In G-CSF stimulated neutrophils, the migration status was enhanced, as reflected by an elevated level of CXCR2 and an increased migration capacity. These data suggest that CerS6/C16-Cer mediates feedback regulation by inhibiting the formation of CD11b and CXCR2, which are induced either by IFN-gamma/TNF-alpha or by G-CSF, respectively. We conclude that CerS6/C16-Cer mediates anti-inflammatory effects during the development of EAE and MS possibly by suppressing the migration and deactivation of neutrophils. PMID- 25833071 TI - Structure and properties of binder gels formed in the system Mg(OH)2-SiO2-H2O for immobilisation of Magnox sludge. AB - A cementitious system for the immobilisation of magnesium rich Magnox sludge was produced by blending an Mg(OH)2 slurry with silica fume and an inorganic phosphate dispersant. The Mg(OH)2 was fully consumed after 28 days of curing, producing a disordered magnesium silicate hydrate (M-S-H) with cementitious properties. The structural characterisation of this M-S-H phase by (29)Si and (25)Mg MAS NMR showed clearly that it has strong nanostructural similarities to a disordered form of lizardite, and does not take on the talc-like structure as has been proposed in the past for M-S-H gels. The addition of sodium hexametaphosphate (NaPO3)6 as a dispersant enabled the material to be produced at a much lower water/solids ratio, while still maintaining the fluidity which is essential in practical applications, and producing a solid monolith. Significant retardation of M-S-H formation was observed with larger additions of phosphate, however the use of 1 wt% (NaPO3)6 was beneficial in increasing fluidity without a deleterious effect on M-S-H formation. This work has demonstrated the feasibility of using M-S-H as binder to structurally immobilise Magnox sludge, enabling the conversion of a waste into a cementitious binder with potentially very high waste loadings, and providing the first detailed nanostructural description of the material thus formed. PMID- 25833070 TI - Concurrent validity of the differential ability scales, second edition with the Mullen Scales of Early Learning in young children with and without neurodevelopmental disorders. AB - Estimates of intelligence in young children with neurodevelopmental disorders are critical for making diagnoses, in characterizing symptoms of disorders, and in predicting future outcomes. The limitations of standardized testing for children with developmental delay or cognitive impairment are well known: Tests do not exist that provide developmentally appropriate material along with norms that extend to the lower reaches of ability. Two commonly used and interchanged instruments are the Mullen Scales of Early Learning (MSEL), a test of developmental level, and the Differential Ability Scales, second edition (DAS II), a more traditional cognitive test. We evaluated the correspondence of contemporaneous MSEL and the DAS-II scores in a mixed sample of children aged 2 10 years with autism spectrum disorder (ASD), non-ASD developmental delays, and typically developing children across the full spectrum of cognitive ability. Consistent with published data on the original DAS and the MSEL, scores on the DAS-II and MSEL were highly correlated. However, curve estimation revealed large mean differences that varied as a function of the child's cognitive ability level. We conclude that interchanging MSEL and DAS-II scores without regard to the discrepancy in scores may produce misleading results in both cross-sectional and longitudinal studies of children with and without ASD, and, thus, this practice should be implemented with caution. PMID- 25833072 TI - Speech production, intelligibility and oromotor function in seven individuals with Mobius sequence. AB - PURPOSE: Mobius sequence is a rare disease characterized by congenital facial and abducent nerve palsy. Other cranial nerves may be affected. Cleft palate, intellectual disability and neuropsychiatric disorders are associated with the diagnosis. The aim was to explore speech production, intelligibility and oromotor function in a group of individuals with Mobius sequence. METHOD: Three children (5-11 years) and four adults (26-54 years) were recruited to the study via the Swedish Mobius syndrome association. In addition to cranial nerve dysfunction, two had a hearing impairment, one Asperger syndrome and one a cleft palate. Perceptual assessments included an evaluation of intelligibility in single words and spontaneous speech, the percentage of phonemes correct (PPC) and screening of orofacial functions (NOT-S). Objective measurements were used for the evaluation of nasality, lip force and tongue force. RESULT: Three individuals had severely impaired intelligibility, two slightly impaired and two had fully intelligible speech. The PPC varied between 59.3-100%. Five individuals had bilateral facial palsy, two unilateral facial palsy and six tongue impairment. One had a slightly increased nasalance score. Compensatory strategies were being effectively used. CONCLUSION: This case series contributes more in-depth knowledge of speech production, intelligibility and oromotor function in this rare condition. PMID- 25833073 TI - Elizabeth Usher Memorial Lecture: Placing therapy in the context of the self and social connection. AB - BACKGROUND: The concept of self influences the choice of goals and helps to make sense of lives. Essentially, self-concept is a dynamic internal representation of the individual. This representation shapes behaviour and how information about oneself is processed. The self-story is developed and validated through social interactions and shaped continuously through life experiences. METHOD: The focus of this paper is the client's perspective of self and how one can actively use that perspective to plan therapy, particularly in the case of individuals with acquired brain injury (ABI). The paper draws upon the results of a number of research projects constructed around two primary aims: (1) to represent the perspectives of clients and their close others and (2) to maximize social connection through the delivery of effective communication intervention. RESULT: A model of self, derived from in-depth qualitative exploration of the experiences of people with ABI, is presented as a framework to guide collaborative therapy. The model depicts the multidimensional and cyclical nature of self- conceptualization supported by factors that facilitate social connection. CONCLUSION: Communication is crucial to maintaining social ties and communication breakdown is a significant predictor of participation. A new intervention that effectively improves coping with communication breakdown is presented. PMID- 25833074 TI - Developing clinical skills in paediatric dysphagia management using human patient simulation (HPS). AB - PURPOSE: The use of simulated learning environments to develop clinical skills is gaining momentum in speech-language pathology training programs. The aim of the current study was to examine the benefits of adding Human Patient Simulation (HPS) into the university curriculum in the area of paediatric dysphagia. METHOD: University students enrolled in a mandatory dysphagia course (n = 29) completed two, 2-hour HPS scenarios: (a) performing a clinical feeding assessment with a medically complex infant; and (b) conducting a clinical swallow examination (CSE) with a child with a tracheostomy. Scenarios covered technical and non-technical skills in paediatric dysphagia management. Surveys relating to students' perceived knowledge, skills, confidence and levels of anxiety were conducted: (a) pre-lectures; (b) post-lectures, but pre-HPS; and (c) post-HPS. A fourth survey was completed following clinical placements with real clients. RESULT: Results demonstrate significant additive value in knowledge, skills and confidence obtained through HPS. Anxiety about working clinically reduced following HPS. Students rated simulation as very useful in preparing for clinical practice. Post clinic, students indicated that HPS was an important component in their preparation to work as a clinician. CONCLUSION: This trial supports the benefits of incorporating HPS as part of clinical preparation for paediatric dysphagia management. PMID- 25833075 TI - In reference to "Similar outcomes among general medicine patients discharged on weekends". PMID- 25833076 TI - Elevated plasma B-type natriuretic peptide concentration and resistive index, but not decreased aortic distensibility, associate with impaired blood flow at popliteal artery in type 2 diabetic patients. AB - Blood flow in lower extremity arteries is frequently impaired in diabetic patients even though they have a normal ankle-brachial index (ABI 1.0-1.4). Risk factors contributing to this lower extremity arterial disease have not been fully elucidated. We enrolled 52 type 2 diabetic patients with normal ABI and 30 age matched nondiabetic subjects consecutively admitted to our hospital. Plasma B type natriuretic peptide (BNP) concentrations were measured. Distensibility in ascending thoracic and abdominal aortas as well as total flow volume and resistive index at popliteal artery were evaluated by gated magnetic resonance imaging. An automatic device was used to measure ABI and brachial-ankle pulse wave velocity (baPWV). Diabetic patients showed lower distensibility in ascending thoracic aorta (p<0.001) and total flow volume (p<0.001) and higher baPWV (p<0.001) and resistive index (p=0.005) and similar BNP and distensibility in abdominal aorta compared to nondiabetic subjects. Simple linear regression analyses revealed that distensibility in ascending thoracic (p=0.019) and abdominal (p=0.030) aortas positively as well as baPWV (p=0.020), resistive index (p<0.001) and BNP (p<0.001) negatively correlated with total flow volume. Stepwise multiple regression analysis demonstrated that increased BNP and resistive index were independent risk factors for total flow volume in diabetic patients (r(2)=0.639, p<0.001). These results indicate that increased plasma BNP levels and peripheral vascular resistance, but not decreased aortic distensibility, associate with impaired blood flow in lower extremity arteries in diabetic patients. PMID- 25833078 TI - Non-specific and Usual Interstitial Pneumonia, Short-Term Survival After Surgical Biopsy. PMID- 25833077 TI - Miglitol protects against age-dependent weight gain in mice: A potential role of increased UCP1 content in brown adipose tissue. AB - Miglitol is an absorbable alpha-glucosidase inhibitor that is used to control post-prandial hyperglycemia. We previously found that miglitol stimulates brown adipose tissue and prevents diet-induced obesity in mice that are fed a high-fat, high-carbohydrate diet. In this study, we examined whether miglitol can also protect against aging-dependent weight gain in mice that are fed a normal chow diet. Male C57Bl/6J mice were fed normal chow with or without miglitol (800 ppm) for 12 weeks, starting at 12 weeks of age. Food intake and body weight were monitored. After 12 weeks, adiposity, energy expenditure, and locomotor activities were measured. After sacrifice, weight of the epididymal white adipose tissue and adipocyte size were measured. Finally, Ucp1 gene expression and UCP1 protein abundance in brown adipose tissue were quantified by RT-PCR and Western analyses, respectively. Miglitol prevented age-related weight gain without affecting growth of the animals. Miglitol-treated mice showed reduced adiposity and increased oxygen consumption compared to controls, accompanied by higher UCP1 protein abundance in brown adipose tissue. Food intake and locomotor activities were not affected. These results suggest that miglitol can protect against age dependent weight gain. Elucidating the molecular targets of miglitol in brown adipose tissue and optimizing drug delivery and efficacy may provide new strategies to combat obesity. PMID- 25833079 TI - Time to challenge public health guidelines on physical activity. AB - There is striking evidence in support of physical activity (PA) as a very strong factor in health promotion and disease prevention. Since the mid-1990s, public health guidelines on PA have established PA recommendations to promote health and prevent several non-communicable diseases (NCDs). However, it is not clear that there is universal agreement on the validity of all aspects of these recommendations. Indeed, a growing body of evidence has accumulated over the last 20 years showing that less than 150 min/week of moderate PA, i.e. the minimum PA level currently recommended, promotes health and prevents NCDs. Moreover, when determining whether someone achieves the minimum PA recommendations, the quantities of PA undertaken are added together regardless of what domain of PA they represent, i.e. leisure-time, occupational, transport or housework. However, while convincing evidence exists to show that leisure-time and transport PA are important factors for promoting health, the evidence for occupational PA and housework is mixed. Therefore, the purpose of this article is to discuss two major issues relating to public health guidelines on PA for adults and older adults: the minimum volumes of PA required and the importance of PA domains in health promotion. A proposal on how to tackle these issues and ultimately strengthen PA recommendations is also presented. PMID- 25833080 TI - Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. METHODS AND RESULTS: Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1alpha (HIF1alpha), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. CONCLUSIONS: Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1alpha-EPO pathway. PMID- 25833081 TI - Circulating CD14++CD16+ Monocyte Subsets as a Surrogate Marker of the Therapeutic Effect of Corticosteroid Therapy in Patients With Cardiac Sarcoidosis. AB - BACKGROUND: We aimed to evaluate whether specific monocyte subsets could serve as surrogate markers of disease activity in cardiac sarcoidosis (CS) evaluated by 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). METHODS AND RESULTS: We studied 28 patients with CS (8 men; mean age: 61+/-9 years) diagnosed according to consensus criteria. We divided the patients into 2 groups: known CS receiving corticosteroid therapy (Rx(+); n=13) and new-onset CS (Rx(-); n=15), and analyzed 3 distinct monocyte subsets (CD14+CD16-, CD14++CD16+, and CD14+ CD16+). Monocyte subsets were also analyzed in 10 Rx(-) patients before and 12 weeks after starting corticosteroid therapy. Inflammatory activity was quantified by 18F-FDG PET using the coefficient of variation (COV) of the standardized uptake value (SUV). The proportion of CD14++CD16+ monocytes in Rx(+) patients (10.8 [0.2-23.5] %) was significantly lower than in Rx(-) patients (23.0 [11.5 38.4] %, P=0.001). After corticosteroid therapy, the COV of the SUV was significantly improved from 0.32 [0.14-0.62] to 0.17 [0.04-0.43] (P=0.017). The proportion of CD14++16+ monocytes showed a significant decrease from 22.2 [8.8 38.4] % to 8.4 [1.8-16.8] % (P=0.001). The decrease in the proportion of CD14++16+ monocytes significantly correlated with the decrease in the COV of the SUV (r=0.495, P=0.027). CONCLUSIONS: CD14++16+ monocytes are a possible surrogate marker of the therapeutic effect of corticosteroid therapy in CS. PMID- 25833082 TI - Biatrial Myxomas With Various Manifestations--Carney Complex. PMID- 25833083 TI - A smart tailor-made G-clip reporter for sensitive detection of G-triplet containing sequences. AB - Taking advantage of the intrinsic characteristics of G-triplet-containing sequences, a pioneering tailor-made clip-like reporter containing three-fourths of a G-quadruplex is established. The reporter can clip the G triplet in the target sequence through a recognition process to form a complete G-quadruplex structure. PMID- 25833084 TI - Correlating Cerebral (18)FDG PET-CT Patterns with Histological Analysis During Early Brain Injury in a Rat Subarachnoid Hemorrhage Model. AB - Early brain injury (EBI) plays a significant role in poor outcomes for subarachnoid hemorrhage (SAH) patients. Further investigations are required to characterize the cellular metabolic and related histological changes that may contribute to EBI following SAH. We investigated the image patterns of 18 fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET CT) during EBI and correlated histopathological changes utilizing a rat SAH model. SAH was induced in six adult male Sprague-Dawley rats by endovascular perforation, and animals were randomly assigned to receive (18)FDG PET-CT imaging at either 3 or 12 h post-procedure. Mean (18)FDG standard uptake value (SUV) of the brain was calculated. Animals were euthanized 48 h post-procedure, and brain samples were used for heme oxygenase-1 (HO-1) and dopamine- and cAMP-regulated phosphoprotein (DARPP-32) Mr 32 kDa immunohistochemistry. Rats within the SAH group had higher mean whole brain (18)FDG SUV (2.349 +/- 0.376 g/ml in the 3-h group and 2.453 +/- 0.495 g/ml in the 12-h group) compared to that of sham (n = 3; mean SUV = 2.030 +/- 0.247 g/ml; P < 0.05) or control groups (n = 3; mean SUV = 1.800 +/- 0.484 g/ml; P < 0.05). Whole brain (18)FDG SUV did not vary significantly between rats imaged at 3 h vs. those imaged at 12 h post-SAH (P > 0.05). Regions of decreasing SUV in SAH rats correlated with neuronal death and increased expression of HO-1. Higher (18)FDG PET SUV was evident in rats post-SAH compared to sham and control groups. Regions of decreasing SUV in SAH rats correlated with neuronal death and increased HO-1 expression as evaluated by histopathology. PMID- 25833085 TI - When should we change our clinical practice based on the results of a clinical study? Searching for evidence: PICOS and PubMed. PMID- 25833086 TI - Seeing red: over-the-counter chloramphenicol. PMID- 25833087 TI - Let's put our house in order, or have it done for us: the future of RANZCO as a reputable professional organization. PMID- 25833089 TI - Mechanisms of the self-assembly of EAK16-family peptides into fibrillar and globular structures: molecular dynamics simulations from nano- to micro-seconds. AB - The self-assembly of EAK16-family peptides in a bulk solution was studied using a combination of all-atom and coarse-grained molecular dynamics simulations. In addition, specified concentrations of EAK16 peptides were induced to form fibrillary or globular assemblies in vitro. The results show that the combination of all-atom molecular dynamics simulations on the single- and double-chain levels and coarse-grained simulations on the many-chain level predicts the experimental observations reasonably well. At neutral pH conditions, EAK16-I and EAK16-II assemble into fibrillary structures, whereas EAK16-IV aggregates into globular assemblies. Mechanisms of the formation of fibrillar and globular assemblies are described using the simulation results. PMID- 25833090 TI - Left hemisphere EEG coherence in infancy predicts infant declarative pointing and preschool epistemic language. AB - Pointing plays a central role in preverbal communication. While imperative pointing aims at influencing another person's behavior, declarative gestures serve to convey epistemic information and to share interest in an object. Further, the latter are hypothesized to be a precursor ability of epistemic language. So far, little is known about their underlying brain maturation processes. Therefore, the present study investigated the relation between brain maturation processes and the production of imperative and declarative motives as well as epistemic language in N = 32 infants. EEG coherence scores were measured at 14 months, imperative and declarative point production at 15 months and epistemic language at 48 months. Results of correlational analyses suggest distinct behavioral and neural patterns for imperative and declarative pointing, with declarative pointing being associated with the maturation of the left hemisphere. Further, EEG coherence measures of the left hemisphere at 14 months and declarative pointing at 15 months are related to individual differences in epistemic language skills at 48 months, independently of child IQ. In regression analyses, coherence measures of the left hemisphere prove to be the most important predictor of epistemic language skills. Thus, neural processes of the left hemisphere seem particularly relevant to social communication. PMID- 25833091 TI - Citrobacter bitternis sp. nov. isolated from bitterns. AB - In this study, we reported two gram-negative bacteria that were isolated from bitterns, designated as SKKU-TP7(T) and SKKU-TP20, representing a novel species of Citrobacter. Based on the 16S rRNA gene sequences, the two strains were found to be closely related and showed the highest pairwise similarity with Citrobacter farmeri CDC 2992-81(T) (97.1-97.3 %) and other Citrobacter species. Cellular fatty acid analysis revealed that the profiles of strains SKKU-TP7(T) and SKKU TP20 were similar to those of related species of Citrobacter. The major cellular fatty acids were C16:0 (31.5 %), summed feature 3 (C16:1 omega7c, C16:1 omega6c, 19.7 %), summed feature 8 (C18:1 omega7c, C18:1 omega6c, 11.9 %), C17:0 cyclo (10.7 %), and summed feature 2 (C12:0 aldehyde/unknown 10928, 9.5 %). Although the strains could utilize sucrose and raffinose as a carbon source, they did not produce ornithine decarboxylase and urease. The biochemical and genotypic characteristics indicate that strains SKKU-TP7(T) and SKKU-TP20 represent a novel species of Citrobacter, for which the name Citrobacter bitterns sp. nov. is proposed. The type strain is SKKU-TP7(T) (=KCTC 42139(T) = JCM 30009(T)). PMID- 25833092 TI - Psychiatric comorbidity in women with polycystic ovary syndrome. AB - AIM: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that women experience during their reproductive years and is associated with many psychiatric disorders. This study sought to determine the existence of psychiatric disorders in women with untreated PCOS. Another objective of the study was to examine whether an association exists between psychiatric disorders, insulin resistance, and body mass index. MATERIAL AND METHODS: Women who met the Rotterdam criteria for PCOS (n = 88) were included. Structured Clinical Interviews for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edn were conducted. After the psychiatric evaluations, blood samples were obtained from the participants. RESULTS: Prevalence for all comorbid psychiatric disorders was 50% (n = 44). The most common psychiatric disorder was major depression (33%), followed by generalized anxiety disorder (13.6%) and binge-eating disorder (6.8%). No significant difference in body mass index and insulin resistance index scores was found between women with and without psychiatric disorders (P > 0.05 for both comparisons). CONCLUSION: A considerable number of women with PCOS experience a psychiatric disorder during their lifetime. Clinicians should be aware that women with PCOS are at a high risk for major depression, generalized anxiety disorder, and binge-eating disorder. PMID- 25833093 TI - Hydrophilicity/Hydrophobicity reversable and redox-sensitive nanogels for anticancer drug delivery. AB - Long circulation in the blood, efficient cellular internalization, and intracellular drug release in the tumor cells are major challenges in the development of ideal anticancer drug delivery systems. In this paper, hydrophilicity/hydrophobicity reversable and redox-sensitive poly(oligo(ethylene glycol) methacrylates-ss-acrylic acid) (P(OEGMAs-ss-AA)) nanogels were constructed as drug carriers for cancer therapy. The nanogels underwent a pH dependent hydrophilic/hydrophobic change. The nanogels were hydrophilic under physiological conditions (pH 7.4, 37 degrees C), resulting in fewer opsonization of proteins and less phagocytosis by macrophage RAW264.7 cells, while they were hydrophobic in the tumor tissues (pH 6.5, 37 degrees C), resulting in strong internalization by Bel7402 cells. The doxorubicin (DOX) release from DOX-loaded nanogels was increased in intracellular reductive and lysosome acidic environments. DOX-loaded nanogels exhibited higher cellular proliferation inhibition to GSH-OEt-pretreated Bel7402 cells at pH 6.5 than to unpretreated cells at pH 7.4. Further studies showed that the loaded DOX and nanogels were internalized into the cells together via both lipid raft/caveolae- and clathrin mediated endocytic pathways. After internalization, the DOX-loaded nanogels were transported via the specific route in endo/lysosomal system. The loaded DOX was released from the nanogels with the introduction of intracellular GSH and entered the nucleus. This study indicated that the hydrophilicity/hydrophobicity reversable and redox-sensitive nanogels might be used as potential carriers for anticancer drugs, which provided a foundation for designing an effective drug delivery system for cancer therapy. PMID- 25833094 TI - Disposable diapers decrease the incidence of neonatal infections compared to cloth diapers in a level II neonatal intensive care unit. AB - OBJECTIVE: To study whether disposable diapers decrease the incidence of neonatal infections compared with cloth diapers in a level II neonatal intensive care unit (NICU). METHOD AND MATERIAL: All neonates admitted to the NICU and having duration of stay >48 h were enrolled. Those babies with signs and symptoms of infection were screened with septic screen and/or blood culture. RESULTS: The primary outcome of the study was incidence of probable sepsis. Of 253 babies enrolled in the study period, probable sepsis was present in 101 (39.9%) infants in the total study group and was higher in cloth diaper group as compared with disposable diaper group (p = 0.01). For an average NICU stay of 6 days, cloth diapers would cost Rs. 241 vs. Rs. 162 for disposable diaper for any infant. CONCLUSION: Usage of disposable diapers decrease the incidence of probable sepsis in babies admitted to NICU. It is also cost effective to use disposable diapers in the NICU. PMID- 25833095 TI - Blood pressure variation with gestational age and birth weight in Indian newborn. AB - Prospective observational study was conducted in a tertiary care hospital of India over 8 months to measure blood pressure (BP) in healthy term and preterm neonates using oscillometric method and explore the associations with gestational age and birth weight. Consecutive BP measurements were taken by standard oscillometric method on 1617 neonates on day 4, 7 and 14 of life. Mean birth weight was 2.7 +/- 0.46 kg, and mean gestational age was 38.2 +/- 2.12 weeks. The mean arterial pressure (MAP) on day 4, 7 and 14 were 59.3 +/- 7.33, 63.2 +/- 6.55 and 66.4 +/- 6.13 mmHg, respectively. Larger and mature newborns had significantly higher BP than those who were smaller and premature. Birth weight more strongly correlated with MAP than gestational age. Predictive equations linking MAP with gestational age and birth weight were deduced, which can be used for judicious fluid inotrope management. PMID- 25833096 TI - Assessing providers' vaccination behaviors during routine immunization in India. AB - Progress has been made toward improving routine immunization coverage in India, but universal coverage has not been achieved. Little is known about how providers' vaccination behaviors affect coverage rates. The purpose of this study was to identify provider behaviors that served as barriers to vaccination that could lead to missed opportunities to vaccinate. We conducted a study of health care providers' vaccination behaviors during clinic visits for children <3 years of age. Information on provider behaviors was collected through parent report and direct observation. Compared with illness visits, parents were eight times more likely to report vaccination status was verified (p < 0.001) and three times more likely to report receiving counseling on immunization (p = 0.022) during vaccination visits. Training of all vaccination practitioners should focus on behaviors such as the necessity of verifying vaccination status regardless of visit type, stressing the importance of counseling parents on immunization and emphasizing what is a valid contraindication to vaccination. PMID- 25833097 TI - Acinetobacter baumannii infections in a South African paediatric intensive care unit. AB - OBJECTIVES: To describe and compare characteristics and outcomes of patients colonized or infected with Acinetobacter baumannii (cases) to a control group. METHODS: A retrospective case-controlled study of patients admitted to a South African paediatric intensive care unit (PICU) between January and December 2010. RESULTS: Acinetobacter baumannii was isolated in 194 patients. Mortality was similar between cases (9.3%) and controls (9.8%). Median duration of PICU stay and mechanical ventilation in cases vs. controls was 10 vs. 2 (p < 0.0001) and 9 vs. 1 days (p < 0.0001), respectively. Admission diagnosis of traumatic brain injury [adjusted odds ratio (OR): 5.6, 95% CI: 1.2-27.0; p = 0.03] and duration of mechanical ventilation (adjusted OR: 1.4, 95% CI: 1.3-1.5; p < 0.0001) were independently associated with A. baumannii aquisition. CONCLUSION: Acinetobacter baumannii acquisition was common and associated with increased morbidity, but not increased mortality. PMID- 25833099 TI - alpha-Synuclein Over-Expression Induces Increased Iron Accumulation and Redistribution in Iron-Exposed Neurons. AB - Parkinson's disease is the most common alpha-synucleinopathy, and increased levels of iron are found in the substantia nigra of Parkinson's disease patients, but the potential interlink between both molecular changes has not been fully understood. Metal to protein binding assays have shown that alpha-synuclein can bind iron in vitro; therefore, we hypothesized that iron content and iron distribution could be modified in cellulo, in cells over-expressing alpha synuclein. Owing to particle-induced X-ray emission and synchrotron X-ray fluorescence chemical nano-imaging, we were able to quantify and describe the iron distribution at the subcellular level. We show that, in neurons exposed to excess iron, the mere over-expression of human alpha-synuclein results in increased levels of intracellular iron and in iron redistribution from the cytoplasm to the perinuclear region within alpha-synuclein-rich inclusions. Reproducible results were obtained in two distinct recombinant expression systems, in primary rat midbrain neurons and in a rat neuroblastic cell line (PC12), both infected with viral vectors expressing human alpha-synuclein. Our results link two characteristic molecular features found in Parkinson's disease, the accumulation of alpha-synuclein and the increased levels of iron in the substantia nigra. PMID- 25833100 TI - Pseudocatalytic Antiaggregation Activity of Antibodies: Immunoglobulins can Influence alpha-Synuclein Aggregation at Substoichiometric Concentrations. AB - Protein aggregation is involved in a variety of diseases. Alteration of the aggregation pathway, either to produce less toxic structures or to increase aggregate clearance, is a promising therapeutic route. Both active and passive immunization has been used for this purpose. However, the mechanism of action of antibodies on protein aggregates is not completely clear especially given poor ability of antibodies to cross blood-brain barrier. Here, we have shown that antibodies can interfere with protein aggregation at substoichiometric concentrations (as low as 1:1000 antibody to protein ratio). This is an indication that antibodies interact with aggregation intermediates in chaperone like manner altering the aggregation pathways at very low antibody levels. This observation supports earlier suggestions that antibodies can inhibit aggregation by interaction with low abundance aggregation intermediates. PMID- 25833101 TI - Serum CXCL12 Levels as a Novel Predictor of Future Stroke Recurrence in Patients with Acute Ischemic Stroke. AB - Previous studies had shown that CXC chemokine ligand-12 (CXCL12) plays a significant role in animal models of ischemic stroke, but its role in human stroke is unclear. The aim of this study was to test the relationship between elevated serum circulating CXCL12 levels and the 1-year stroke recurrence in Chinese patients with acute ischemic stroke (AIS). All consecutive patients with first-ever acute ischemic stroke from January 2011 to September 2013 were recruited to participate in the study. Serum levels of CXCL12 and National Institute of Health Stroke Scale (NIHSS) were measured at the time of admission. Logistic regression analysis was used to evaluate the stroke recurrence according to serum CXCL12 levels. Receiver operating characteristic (ROC) curve was used to evaluate the accuracy of serum CXCL12 in predicting stroke recurrence. Clinical follow-up was performed at 1 year. In our study, 248 patients finished the 1-year follow-up. At 1-year follow-up, 31 patients had a recurrence ischemic stroke. The median CXCL12 levels were significantly higher in those who sustained a recurrence ischemic stroke compared with those who did not [24.2 ng/mL (IQR 15.4 33.7) vs 6.5 ng/mL (IQR 3.4-10.2); Z = 8.258, P < 0.0001]. In multivariate analysis, there was an increased risk of stroke recurrence associated with serum CXCL12 levels >=12.15 ng/mL (OR 9.122, 95 % CI 6.103-15.104) after adjusting for above possible confounders. The time to recurrence stroke distribution between patients with baseline CXCL12 levels >=12.15 ng/mL and those with baseline CXCL12 levels <12.15 ng/mL were significantly different (P < 0.0001, log-rank test). Elevated circulating CXCL12 levels at admission are strongly associated with the future recurrence of ischemic stroke in Chinese patients with AIS. Further studies are warranted to confirm this association and define the role for CXCL12 as a novel predictor biomarker for stroke recurrence. PMID- 25833098 TI - The Essential Role of Soluble Abeta Oligomers in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaque and neurofibrillary tangles (NFT). With the finding that soluble nonfibrillar Abeta levels actually correlate strongly with the severity of the disease, the initial focus on amyloid plaques shifted to the contemporary concept that AD memory failure is caused by soluble Abeta oligomers. The soluble Abeta are known to be more neurotoxicthan fibrillar Abeta species. In this paper, we summarize the essential role of soluble Abeta oligomers in AD and discuss therapeutic strategies that target soluble Abeta oligomers. PMID- 25833102 TI - Minocycline Attenuates Neonatal Germinal-Matrix-Hemorrhage-Induced Neuroinflammation and Brain Edema by Activating Cannabinoid Receptor 2. AB - Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes. PMID- 25833104 TI - Effects of differently activated rodent macrophages on sensory neurons: implications for arthritis pain. AB - OBJECTIVE: In arthritis, macrophages invade the affected joint. Experimental arthritis models have shown that macrophages also invade the dorsal root ganglia (DRGs) of the inflamed segments in which the perikarya of sensory neurons are located. It is unclear whether this macrophage invasion contributes to arthritis pain and/or furthers neuronal damage. The present study was undertaken to investigate how differently activated macrophages affect DRG neurons. METHODS: We determined the phenotype of macrophages in the DRGs of rats with antigen-induced arthritis (AIA). In a DRG neuron-macrophage coculture system, we investigated whether differently activated macrophages (stimulated with either lipopolysaccharide [LPS]/interferon-gamma [IFNgamma], tumor necrosis factor [TNF], or interleukin-4) damage DRG neurons and/or stimulate them to release the mediator calcitonin gene-related peptide (CGRP), which promotes pain and neurogenic inflammation. RESULTS: Macrophages in the DRGs of rats with AIA showed the phenotype of TNF-stimulated macrophages but did not express inducible nitric oxide synthase, which was found in cultured macrophages only after LPS/IFNgamma activation. In neuron-macrophage cocultures, activation of macrophages stimulated DRG neurons to release CGRP within 1 hour, indicating neuronal activation by macrophages. Only 48-hour activation of macrophages with LPS/IFNgamma increased the neuronal cell death rate in culture, provided that the macrophages were in direct contact with DRG neurons. This effect was dependent on nitric oxide. CONCLUSION: Macrophages have the potential to stimulate sensory neurons in the DRGs, and this may contribute to arthritis pain. If they are classically activated, such as after LPS/IFNgamma stimulation, this may also further neuronal cell death. This is not the case in AIA but may occur in models involving damage of sensory neurons. PMID- 25833103 TI - Age and sex effects on corpus callosum morphology across the lifespan. AB - The corpus callosum (CC) is the largest interhemispheric white matter tract in the human brain, and is characterized by pronounced differences in morphology among individuals. There are limited data, however, regarding typical development, sex differences, and the neuropsychological correlates of individual differences within CC subregions. Magnetic resonance (MR) imaging exams were collected in a large cohort (N = 305) of healthy individuals (ages 8-68). We used a highly reliable program to automatically identify the midsagittal plane and obtain CC subregion measures according to approaches described by Witelson [1989]: Brain 112:799-835 and Hampel et al. [1998]: Arch Neurol 55:193-198 and a measure of whole CC shape (i.e., circularity). CC measurement parameters, including area, perimeter, length, circularity, and CC subregion area values were generally characterized by inverted U-shaped curves across the observed age range. Peak values for CC subregions were observed between ages 32 and 45, and descriptive linear correlations were consistent with sharper area changes in development. We also observed differing age-associated changes across the lifespan between males and females in the CC subregion corresponding to the genu (Witelson's subregion 2), as well as CC circularity. Mediation analysis using path modeling indicated that genu area mediated the relationship between age and processing speed for females, and the relationship between age and visual learning and executive functioning for males. Taken together, our findings implicate sex differences in CC morphology across the lifespan that are localized to the genu, which appear to mediate neuropsychological functions. PMID- 25833106 TI - The heart is lost without the brain - the autonomic perspective. PMID- 25833105 TI - International survey of acute stroke imaging used to make revascularization treatment decisions. AB - BACKGROUND: To assess the differences across continental regions in terms of stroke imaging obtained for making acute revascularization therapy decisions, and to identify obstacles to participating in randomized trials involving multimodal imaging. METHODS: STroke Imaging Repository (STIR) and Virtual International Stroke Trials Archive (VISTA)-Imaging circulated an online survey through its website, through the websites of national professional societies from multiple countries as well as through email distribution lists from STIR and the above mentioned societies. RESULTS: We received responses from 223 centers (2 from Africa, 38 from Asia, 10 from Australia, 101 from Europe, 4 from Middle East, 55 from North America, 13 from South America). In combination, the sites surveyed administered acute revascularization therapy to a total of 25,326 acute stroke patients in 2012. Seventy-three percent of these patients received intravenous (i.v.) tissue plasminogen activator (tPA), and 27%, endovascular therapy. Vascular imaging was routinely obtained in 79% (152/193) of sites for endovascular therapy decisions, and also as part of standard IV tPA treatment decisions at 46% (92/198) of sites. Modality, availability and use of acute vascular and perfusion imaging before revascularization varied substantially between geographical areas. The main obstacles to participate in randomized trials involving multimodal imaging included: mainly insufficient research support and staff (50%, 79/158) and infrequent use of multimodal imaging (27%, 43/158) . CONCLUSION: There were significant variations among sites and geographical areas in terms of stroke imaging work-up used tomake decisions both for intravenous and endovascular revascularization. Clinical trials using advanced imaging as a selection tool for acute revascularization therapy should address the need for additional resources and technical support, and take into consideration the lack of routine use of such techniques in trial planning. PMID- 25833107 TI - The heart's 'little brain' controlling cardiac function in the rabbit. AB - NEW FINDINGS: What is the topic of this review? The topic of the review is the intrinsic cardiac nervous system in the rabbit. What advances does it highlight? The anatomy of rabbit intrinsic ganglia is similar to that of other species, including humans. Immunohistochemistry confirms the presence of cholinergic and adrenergic neurones, with a striking arrangement of neuronal nitric oxide synthase-positive cell bodies. Activation of atrial ganglia produces effects on local and remote regions. Heart disease is a primary cause of mortality in the developed world, and it is well recognized that neural mechanisms play an important role in many cardiac pathologies. The role of extrinsic autonomic nerves has traditionally attracted the most attention. However, there is a rich intrinsic innervation of the heart, including numerous cardiac ganglia (ganglionic plexuses), that has the potential to affect cardiac function independently as well as to influence the actions of the extrinsic nerves. To investigate this, an isolated, perfused, innervated rabbit Langendorff heart preparation was considered the best option. Although ganglionic plexuses have been well described for several species, there was no full description of the anatomy and histochemistry of rabbit hearts. To this end, rabbit intrinsic ganglia were located using acetylcholinesterase histology (n = 33 hearts). This revealed six generalized ganglionic regions, defined as a left neuronal complex above the left pulmonary vein, a right neuronal complex around the base of right cranial vein, three scattered in the dorsal right atrium and a region containing numerous ventricular ganglia located on the conus arteriosus. Using immunohistochemistry, neurons were found to contain choline acetyltransferase or tyrosine hydroxylase and/or neuronal nitric oxide synthase in differing amounts (choline acetyltransferase > tyrosine hydroxylase > neuronal nitric oxide synthase). The function of rabbit intrinsic ganglia was investigated using a bolus application of nicotine or electrical stimulation at each of the above sites whilst measuring heart rate and atrioventricular conduction. Nicotine applied to different ganglionic plexuses caused a bradycardia, a tachycardia or a mixture of the two, with the right atrial plexus producing the largest chronotropic responses. Electrical stimulation at these sites induced only a bradycardia. Atrioventricular conduction was modestly changed by nicotine, the main response being a prolongation. Electrical stimulation produced significant prolongation of atrioventricular conduction, particularly when the right neuronal complex was stimulated. These studies show that the intrinsic plexuses of the heart are important and could be crucial for understanding impairments of cardiac function. Additionally, they provide a strong basis from which to progress using the isolated, innervated rabbit heart preparation. PMID- 25833108 TI - Control of muscle exercise hyperaemia: are the mechanisms found in transition? PMID- 25833109 TI - Response to: control of muscle exercise hyperaemia: are the mechanisms found in transition? PMID- 25833110 TI - Interpreting the confidence intervals of model parameters of breath-by-breath pulmonary O2 uptake. PMID- 25833111 TI - Reply: To PMID 25063837. PMID- 25833113 TI - Secondary histiocytic sarcoma may cause apparent persistence or recurrence of minimal residual disease in childhood acute lymphoblastic leukemia. AB - Histiocytic sarcoma (HS) is a rare disease with poor prognosis which may develop subsequent to acute lymphoblastic leukemia (ALL). Here we report two children treated within the AIEOP-BFM ALL 2009 trial: one patient succumbed to fulminant hemophagocytic lymphohistiocytosis triggered by HS during ALL maintenance therapy, the other patient had a smoldering course of HS for over 2 years, and subsequently died after allogeneic stem cell transplantation. In both cases, HS and ALL were clonally related and apparent return of minimal residual disease (MRD) was detected by qPCR in bone marrow. Thus, HS should be considered in ALL when MRD appears to persist or reappear. PMID- 25833114 TI - Variation of electrocardiogram interpretation: yet another contributor to the Achilles heel of pre-participation electrocardiographic programmes in athletes. PMID- 25833115 TI - Radiofrequency catheter ablation of ventricular tachycardia caused by the tip of a defibrillation lead. PMID- 25833116 TI - Relationship between echocardiographic right-ventricular dimensions and signal averaged electrocardiogram abnormalities in endurance athletes. AB - AIMS: Regular physical exercise results in physiological cardiovascular changes. Athletes may demonstrate electrocardiographic changes that can also be seen in certain cardiomyopathies such as arrhythmogenic right-ventricular cardiomyopathy (ARVC). The aim of this study was to assess the prevalence of one such electrocardiographic characteristic, the abnormal signal-averaged ECG (SAECG), and to assess the correlation between SAECG parameters and echocardiographic parameters in athletes participating in sporting disciplines with combined strength and endurance components. METHODS AND RESULTS: We evaluated 24 elite athletes and 27 amateur athletes participating in combined high dynamic and high static (HDHS) sports, using an ECG, SAECG, and a transthoracic echocardiogram. The SAECG was regarded as positive for late potentials if one out of three parameters was abnormal. Prolongation of the filtered QRS duration (fQRS) was present in all of the elite athletes, compared with 74.1% of the amateur athletes (P = 0.011). There was a low prevalence of abnormalities in the other two SAECG parameters [low-amplitude signal (LAS) duration and root-mean-square (RMS) voltage]. The percentage of elite athletes and amateur athletes with >=2 abnormal SAECG parameters was 8.3 and 7.4% (P = 0.99), respectively. Most of the echocardiographic dimensions were significantly greater in the elite athlete group compared with the amateur athletes. There was a moderate positive correlation between the fQRS and right-ventricular dimensions. CONCLUSION: The majority of elite and amateur athletes participating in HDHS sports reveal a prolonged fQRS duration on the SAECG, and according to the 2010 Task Force criteria for the diagnosis of ARVC, these athletes therefore demonstrate late potentials. The extent of fQRS prolongation is positively correlated with RV dimensions. Therefore SAECG findings should be interpreted with caution in endurance athletes. PMID- 25833117 TI - Improving usual care after sudden death in the young with focus on inherited cardiac diseases (the CAREFUL study): a community-based intervention study. AB - AIMS: Inherited cardiac diseases play an important role in sudden death (SD) in the young. Autopsy and cardiogenetic evaluation of relatives of young SD victims identifies relatives at risk. We studied the usual care after SD in the young aimed at identifying inherited cardiac disease, and assessed the efficacy of two interventions to improve this usual care. METHODS AND RESULTS: We conducted a community-based intervention study to increase autopsy rates of young SD victims aged 1-44 years and referral of their relatives to cardiogenetic clinics. In the Amsterdam study region, a 24/7 central telephone number and a website were available to inform general practitioners and coroners. In the Utrecht study region, they were informed by a letter and educational meetings. In two control regions usual care was monitored. Autopsy was performed in 169 of 390 registered SD cases (43.3%). Cardiogenetic evaluation of relatives was indicated in 296 of 390 cases (75.9%), but only 25 of 296 families (8.4%) attended a cardiogenetics clinic. Autopsy rates were 38.7% in the Amsterdam study region, 45.5% in the Utrecht study region, and 49.0% in the control regions. The proportion of families evaluated at cardiogenetics clinics in the Amsterdam study region, the Utrecht study region, and the control regions was 7.3, 9.9, and 8.8%, respectively. CONCLUSIONS: The autopsy rate in young SD cases in the Netherlands is low and few families undergo cardiogenetic evaluation to detect inherited cardiac diseases. Two different interventions did not improve this suboptimal situation substantially. PMID- 25833118 TI - Endothelial cells regulate cardiac myocyte reorganisation through beta1-integrin signalling. AB - BACKGROUND: In normal hearts, capillaries are densely distributed throughout the myocardial tissue, and the cross-talk between myocytes and capillary endothelial cells plays a pivotal role in regulating cardiac development, maturation and function. Although previous studies have suggested a role for the endothelium in the organisation of nearby cardiomyocytes, the underlying mechanism has yet to be illustrated. METHODS AND RESULTS: Using a transwell coculture system, we studied the paracrine effect of endothelial cells on cardiomyocytes and found that the regulation of cardiomyocyte spatial reorganisation and cytoskeletal dynamics by endothelial cells was coupled with beta1-integrin induction. To determine the role of beta1-integrin in this process, we preincubated myocytes with a beta1 integrin function-blocking antibody before coculture. beta1-integrin blockage abolished myocyte chemotactic activity and inhibited microtubule extension and stress fibre assembly. We further evaluated the therapeutic potential of combined endothelial cell-cardiac myocyte transplantation against ischemic cardiomyopathy in an acute myocardial infarction (AMI) mouse model. The results showed that myocytes and endothelial cells synergistically promoted ischemic myocardial repair, as evidenced by the robust engraftment and migration of implanted cells within the infarcted area, as well as the stimulation of angiogenesis, the attenuation of scar tissue and the improvement of cardiac function. CONCLUSION: Our study demonstrated the necessity of beta1-integrin in the interactions between cardiomyocytes and endothelial cells and presented a novel combined transplantation approach that might hold promise for treating ischemic cardiomyopathy. PMID- 25833120 TI - Vascular management during live donor nephrectomy: an online survey among transplant surgeons. AB - In 2006, a survey from the American Society of Transplant Surgeons disclosed significant and sometimes fatal hemorrhagic events in live donor nephrectomies (LDN) related to failure of clips, leading to the contraindication of the Weck(r) Hem-o-lok(r) clip for control of the renal artery during LDN. A survey regarding vascular control techniques, their perceived safety ratings and their failures was sent to 645 European Society for Organ Transplantation members who profiled their profession as "surgeon" and selected "kidney" as organ type. Two hundred forty-three (41%) members responded, of whom 171 (63.3%) independently perform LDN. Their responses were analyzed. For arterial and venous vascular control, the GIATM and TATMstapler are used most frequently, and were rated the safest. Of the 121 reported hemorrhagic events, slippage and dislodgement of clips occurred at least 58 times, while stapler malfunction occurred at least 40 times. One donor death from hemorrhage related to clip dysfunction was reported. Hemorrhagic complications of LDN with fatal and non-fatal outcomes still occur. Strikingly, many surgeons do not use the vascular closing technique that they consider most safe. Failure of non-transfixion techniques is associated with greater risks for the donor. Control of major vessels in LDN must employ transfixion techniques for optimal donor safety. PMID- 25833119 TI - A blood spot method for detecting fumonisin-induced changes in putative sphingolipid biomarkers in LM/Bc mice and humans. AB - Fumonisins (FB) are mycotoxins found in maize. They are hypothesised risk factors for neural tube defects (NTDs) in humans living where maize is a dietary staple. In LM/Bc mice, FB1-treatment of pregnant dams induces NTDs and results in increased levels of sphingoid base 1-phosphates in blood and tissues. The increased level of sphingoid base 1-phosphates in blood is a putative biomarker for FB1 inhibition of ceramide synthase in humans. Collection of blood spots on paper from finger sticks is a relatively non-invasive way to obtain blood for biomarker analysis. The objective of this study was to develop and validate in an animal model, and ultimately in humans, a method to estimate the volume of blood collected as blood spots on absorbent paper so as to allow quantification of the molar concentration of sphingoid base 1-phosphates in blood. To accomplish this objective, blood was collected from unexposed male LM/Bc and FB1-exposed pregnant LM/Bc mice and humans and applied to two types of absorbent paper. The sphingoid base 1-phosphates, absorbance at 270 nm (A270), and total protein content (Bradford) were determined in the acetonitrile:water 5% formic acid extracts from the dried blood spots. The results show that in both mouse and human the A270, total protein, and blood volume were closely correlated and the volume of blood spotted was accurately estimated using only the A270 of the extracts. In mouse blood spots, as in tissues and embryos, the FB1-induced changes in sphingolipids were correlated with urinary FB1. The half-life of FB1 in the urine was short (<24 h) and the elevation in sphingoid base 1-phosphates in blood was also short, although more persistent than the urinary FB1. PMID- 25833121 TI - Cervical cancer prevented by screening: Long-term incidence trends by morphology in Norway. AB - Both major morphologic types of cervical cancer, squamous cell carcinoma (SCC) and adenocarcinoma (AC), are causally related to persistent infection with high risk human papillomavirus (hrHPV), but screening has primarily been effective at preventing SCC. We analysed incidence trends of cervical cancer in Norway stratified by morphologies over 55 years, and projected SCC incidence in the absence of screening by assessing the changes in the incidence rate of AC. The Cancer Registry of Norway was used to identify all 19,530 malignancies in the cervix diagnosed in the period 1956-2010. The majority of these (82.9%) were classified as SCCs, 10.5% as ACs and the remaining 6.6% were of other or undefined morphology. By joint-point analyses of a period of more than five decades, the average annual percentage change in the age-standardised incidence was -1.0 (95%CI: -2.1-0.1) for cervical SCC, 1.5 (95%CI:1.1-1.9) for cervical AC and -0.9 (95%CI: -1.4 to -0.3) for cervical cancers of other or undefined morphology. The projected age-standardised incidence rate of cervical SCC in Norway, assuming no screening, was 28.6 per 100,000 woman-years in 2010, which compared with the observed SCC rate of 7.3 corresponds to an estimated 74% reduction in SCC or a 68% reduction due to screening in the total cervical cancer burden. Cytology screening has impacted cervical cancer burden more than suggested by the overall observed cervical cancer incidence reduction since its peak in the mid-1970s. The simultaneous substantial increase in cervical adenocarcinoma in Norway is presumably indicative of an increase in exposure to HPV over time. PMID- 25833122 TI - Late corneal decompensation after obstetrical forceps ocular trauma at birth. PMID- 25833123 TI - Formation of adhesion domains in stressed and confined membranes. AB - The adhesion bonds connecting a lipid bilayer to an underlying surface may undergo a condensation transition resulting from an interplay between a short range attractive potential between them, and a long range fluctuation-induced potential of mean force. Here, we use computer simulations of a coarse-grained molecular model of supported lipid bilayers to study this transition in confined membranes, and in membranes subjected to a non-vanishing surface tension. Our results show that confinement may alter significantly the condensation transition of the adhesion bonds, whereas the application of surface tension has a very minor effect on it. We also investigate domain formation in membranes under negative tension which, in free membranes, causes the enhancement of the amplitude of membrane thermal undulations. Our results indicate that in supported membranes, this effect of a negative surface tension on the fluctuation spectrum is largely eliminated by the pressure resulting from the mixing entropy of the adhesion bonds. PMID- 25833124 TI - Assessment of vitiligo severity: patient-reported estimates are not accurate. PMID- 25833125 TI - Case report of achalasia secondary to a lung carcinoma of the mediastinal type. AB - Pseudo- or secondary achalasia may mimic primary achalasia upon radiological examination and may be difficult to diagnose. It is usually due to a cancer or metastases involving the gastroesophageal junction. We present the case of a 53 year-old woman with recent onset of dysphagia, and with typical findings suggesting primary achalasia. We found a 4-cm mediastinal tumor invading the lower esophagus, which was proven to be a metastasis from a lung carcinoma. The patient was treated with surgery, chemotherapy and radiotherapy. In patients with a new onset of achalasia symptoms, keeping in mind the possibility of an underlying cancer is important. PMID- 25833126 TI - In reply: Non-invasive cardiac output monitoring during sinus surgery. PMID- 25833127 TI - CT-based renal volume and graft function after living-donor kidney transplantation: Is there a volume threshold to avoid? AB - PURPOSE: Donated kidney volume influences post-transplant outcomes and graft survival. We evaluated the relationship between living-donor kidney volume and recipient graft function at 12 months post-transplantation, exploring a volume threshold for a suboptimal graft function, and compared two different formulas of volume estimation. METHODS: A retrospective analysis of 82 pairs of living-donor kidney transplants was conducted. Donor renal volumes were estimated from computerized tomography scans using the ellipsoid formula and the voxel counting technique. Linear and restricted cubic regression spline was used to analyze the association of volume with graft function. Additionally, we determined the correlation between the two volume estimation formulas and established a correction factor for the ellipsoid formula. RESULTS: Renal volume (adjusted to recipient BSA) had the strongest independent effect (B = 1.65 per 10 ml/m(2) increase, p value <0.001) on graft function at 12 months. The eGFR at 12 months was 52.5, 63.6 and 67.6 ml/min/1.73 m(2) for the low, medium and high volume ratio terciles, respectively (p value <0.001). The odds of a GFR <50 ml/min became significantly reduced with volumes above 145 cc/1.73 m(2). A strong positive correlation between the two formulas was identified (R(2) = 0.705), but the optimal correction factor for our cohort was 0.566. CONCLUSIONS: In a Caucasian population, higher donor kidney volumes estimated from preoperative CT scans are associated with higher recipient eGFRs at 12 months after live-donor transplantation. Using this criterion, transplant teams can potentially improve selection of living donors if multiple donors are available. However, the need for precise estimation of donor kidney volumes should not be overlooked. PMID- 25833129 TI - Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors. AB - Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects. PMID- 25833131 TI - Pain in aquatic animals. AB - Recent developments in the study of pain in animals have demonstrated the potential for pain perception in a variety of wholly aquatic species such as molluscs, crustaceans and fish. This allows us to gain insight into how the ecological pressures and differential life history of living in a watery medium can yield novel data that inform the comparative physiology and evolution of pain. Nociception is the simple detection of potentially painful stimuli usually accompanied by a reflex withdrawal response, and nociceptors have been found in aquatic invertebrates such as the sea slug Aplysia. It would seem adaptive to have a warning system that allows animals to avoid life-threatening injury, yet debate does still continue over the capacity for non-mammalian species to experience the discomfort or suffering that is a key component of pain rather than a nociceptive reflex. Contemporary studies over the last 10 years have demonstrated that bony fish possess nociceptors that are similar to those in mammals; that they demonstrate pain-related changes in physiology and behaviour that are reduced by painkillers; that they exhibit higher brain activity when painfully stimulated; and that pain is more important than showing fear or anti predator behaviour in bony fish. The neurophysiological basis of nociception or pain in fish is demonstrably similar to that in mammals. Pain perception in invertebrates is more controversial as they lack the vertebrate brain, yet recent research evidence confirms that there are behavioural changes in response to potentially painful events. This review will assess the field of pain perception in aquatic species, focusing on fish and selected invertebrate groups to interpret how research findings can inform our understanding of the physiology and evolution of pain. Further, if we accept these animals may be capable of experiencing the negative experience of pain, then the wider implications of human use of these animals should be considered. PMID- 25833130 TI - Healing indicators after pterygium excision by optical coherence tomography. AB - PURPOSE: To establish the sequence of tomographic changes in the tissue recovery process after pterygium excision and to propose healing indicators. METHODS: Optical coherence tomography (OCT) images were taken at 1 week, 1, 3 and 6 months after lesion excision in 73 eyes of 73 patients (33 male, 40 female; mean age 50, S.D. 5.0, range 40-70 years) with primary nasal pterygium. Biomicroscopy was performed at each visit and at 12 months, to diagnose clinical healing or lesion recurrence. The presence of well demarcated corneal epithelium, conjunctival epithelium, limbal demarcation area, and graft thickening were analysed. Comparisons between tomographic data of both clinical situations were made at each time point using contingency tables. RESULTS: Eleven eyes displayed lesion recurrence (R group) and 62 eyes showed no recurrence (NR group). Normal anatomical structures, corneal and conjunctival epithelium and limbal demarcation area, were identified by OCT images in a higher percentage of NR cases over time, compared to the R group where most of the cases presented without these markers of tissue recovery. In contrast, the variable graft thickening, which analysed a pathological event, revealed similar results in both groups (p > 0.05; Fisher's exact statistic), with a clear decrease of cases which showed graft thickening over time. Differences between groups started at 1 month, when no eye had yet presented clinical recurrence, with greater identification of corneal epithelium in the NR group (p = 0.04; Fisher's exact statistic). At 3 months, corneal and conjunctival epithelium identification tended to be more frequent in the NR than in the R group (in both cases, p = 0.0001; Fisher's exact statistic). Finally, at 6 months these different patterns consolidated, with a significantly higher number of limbal demarcation areas being identified in the NR group (p = 0.001; Fisher's exact statistic). In fact, this landmark of a normally structured limbus was never found in the R group. CONCLUSIONS: The sequence of tissue restoration, according to OCT images, seems to start in the cornea and end in the limbal area, similar to the process of pterygium injury in reverse. Although the visualisation of corneal epithelium could be an early indicator of successful surgery, identification of the limbal demarcation area, as a normal limbal pattern in OCT images, seems to be a better positive predictive value in diagnosing healing. PMID- 25833128 TI - The notochord: structure and functions. AB - The notochord is an embryonic midline structure common to all members of the phylum Chordata, providing both mechanical and signaling cues to the developing embryo. In vertebrates, the notochord arises from the dorsal organizer and it is critical for proper vertebrate development. This evolutionary conserved structure located at the developing midline defines the primitive axis of embryos and represents the structural element essential for locomotion. Besides its primary structural function, the notochord is also a source of developmental signals that patterns surrounding tissues. Among the signals secreted by the notochord, Hedgehog proteins play key roles during embryogenesis. The Hedgehog signaling pathway is a central regulator of embryonic development, controlling the patterning and proliferation of a wide variety of organs. In this review, we summarize the current knowledge on notochord structure and functions, with a particular emphasis on the key developmental events that take place in vertebrates. Moreover, we discuss some genetic studies highlighting the phenotypic consequences of impaired notochord development, which enabled to understand the molecular basis of different human congenital defects and diseases. PMID- 25833132 TI - Effect of temperature on leg kinematics in sprinting tarantulas (Aphonopelma hentzi): high speed may limit hydraulic joint actuation. AB - Tarantulas extend the femur-patella (proximal) and tibia-metatarsal (distal) joints of their legs hydraulically. Because these two hydraulically actuated joints are positioned in series, hemolymph flow within each leg is expected to mechanically couple the movement of the joints. In the current study, we tested two hypotheses: (1) at lower temperatures, movement of the two in-series hydraulic joints within a leg will be less coupled because of increased hemolymph viscosity slowing hemolymph flow; and (2) at higher temperatures, movement of the two in-series hydraulic joints will be less coupled because the higher stride frequencies limit the time available for hemolymph flow. We elicited maximal running speeds at four ecologically relevant temperatures (15, 24, 31 and 40 degrees C) in Texas Brown tarantulas (Aphonopelma hentzi). The spiders increased sprint speed 2.5-fold over the temperature range by changing their stride frequency but not stride length. The coefficient of determination for linear regression (R(2)) of the proximal and distal joint angles was used as the measure of the degree of coupling between the two joints. This coupling coefficient between the proximal and distal joint angles, for both forelegs and hind-legs, was significantly lowest at the highest temperature at which the animals ran the fastest with the highest stride frequencies. The coordination of multiple, in series hydraulically actuated joints may be limited by operating speed. PMID- 25833133 TI - Cheating on the mutualistic contract: nutritional gain through seed predation in the frugivorous bat Chiroderma villosum (Phyllostomidae). AB - Most frugivorous bats are efficient seed dispersers, as they typically do not damage seeds and transport them over long distances. In contrast, bats of the phyllostomid genus Chiroderma cheat fig trees by acting more as seed predators than as seed dispersers. The bats initially separate seeds from fruit pulp in the mouth. After extracting the juice from the fruit pulp, they thoroughly chew the seeds and spit out small seed fragments in a pellet. Consequently, the faeces contain almost no viable seeds. We compared the nutrient content of intact fig seeds with ejecta and faecal samples from both Chiroderma villosum and the 'conventional' frugivorous bat Artibeus watsoni. We show that C. villosum can extract nutrients from the seeds, especially protein and fat. The processing time of figs showed no significant difference between the two bat species. Food-choice experiments showed that C. villosum preferred fig species with more seeds over those with fewer seeds. This preference, in combination with the specialized seed chewing behaviour, leads to an increased nutrient intake per fig. This unique strategy enables C. villosum to satisfy its nutritional requirements with a lower number of figs than other species, which decreases the amount of energy necessary for foraging flights as well as the predation risk during foraging. PMID- 25833134 TI - Magnetic navigation behavior and the oceanic ecology of young loggerhead sea turtles. AB - During long-distance migrations, animals navigate using a variety of sensory cues, mechanisms and strategies. Although guidance mechanisms are usually studied under controlled laboratory conditions, such methods seldom allow for navigation behavior to be examined in an environmental context. Similarly, although realistic environmental models are often used to investigate the ecological implications of animal movement, explicit consideration of navigation mechanisms in such models is rare. Here, we used an interdisciplinary approach in which we first conducted lab-based experiments to determine how hatchling loggerhead sea turtles (Caretta caretta) respond to magnetic fields that exist at five widely separated locations along their migratory route, and then studied the consequences of the observed behavior by simulating it within an ocean circulation model. Magnetic fields associated with two geographic regions that pose risks to young turtles (due to cold wintertime temperatures or potential displacement from the migratory route) elicited oriented swimming, whereas fields from three locations where surface currents and temperature pose no such risk did not. Additionally, at locations with fields that elicited oriented swimming, simulations indicate that the observed behavior greatly increases the likelihood of turtles advancing along the migratory pathway. Our findings suggest that the magnetic navigation behavior of sea turtles is intimately tied to their oceanic ecology and is shaped by a complex interplay between ocean circulation and geomagnetic dynamics. PMID- 25833135 TI - Ocean acidification impacts on sperm mitochondrial membrane potential bring sperm swimming behaviour near its tipping point. AB - Broadcast spawning marine invertebrates are susceptible to environmental stressors such as climate change, as their reproduction depends on the successful meeting and fertilization of gametes in the water column. Under near-future scenarios of ocean acidification, the swimming behaviour of marine invertebrate sperm is altered. We tested whether this was due to changes in sperm mitochondrial activity by investigating the effects of ocean acidification on sperm metabolism and swimming behaviour in the sea urchin Centrostephanus rodgersii. We used a fluorescent molecular probe (JC-1) and flow cytometry to visualize mitochondrial activity (measured as change in mitochondrial membrane potential, MMP). Sperm MMP was significantly reduced in DeltapH -0.3 (35% reduction) and DeltapH -0.5 (48% reduction) treatments, whereas sperm swimming behaviour was less sensitive with only slight changes (up to 11% decrease) observed overall. There was significant inter-individual variability in responses of sperm swimming behaviour and MMP to acidified seawater. We suggest it is likely that sperm exposed to these changes in pH are close to their tipping point in terms of physiological tolerance to acidity. Importantly, substantial inter individual variation in responses of sperm swimming to ocean acidification may increase the scope for selection of resilient phenotypes, which, if heritable, could provide a basis for adaptation to future ocean acidification. PMID- 25833136 TI - Correction. Locomotor benefits of being a slender and slick sand-swimmer. PMID- 25833137 TI - Illness perceptions and coping strategies among individuals diagnosed with HIV. AB - Illness perceptions can influence the coping strategies used in response to HIV related stressors, and ultimately patients' clinical status. With this work, we aimed to: (1) identify illness perception-related profiles of HIV-positive patients; (2) evaluate the association between the profiles, illness-related coping strategies, HIV-progression biomarkers (CD4+ cell counts and viral load) and antiretroviral therapy use. Data about illness perceptions, HIV-related coping strategies and HIV-progression biomarkers (CD4+ and viral load) were collected from 248 Italian HIV-positive patients. Three latent classes ("high," "moderate" and "low" influence perception) that differed on consequences, emotional representation, personal control and identity were identified. A greater perception of illness influence was associated with dysfunctional coping strategies (e.g., passive coping and alcohol use), and greater viral load was observed among patients with high and moderate influence perception. In conclusion, patients with detectable or high viral load may show a greater perception of illness influence (i.e., consequences), which is associated with dysfunctional coping strategies in response to HIV-related stressors. PMID- 25833138 TI - 'For a mere cough, men must just chew Conjex, gain strength, and continue working': the provider construction and tuberculosis care-seeking implications in Blantyre, Malawi. AB - BACKGROUND: Delay by men in seeking healthcare results in their higher mortality while on HIV or tuberculosis (TB) treatment and contributes to ongoing community level disease transmission before going on treatment. OBJECTIVE: To understand masculinity's role in delay in healthcare seeking for men, with a focus on TB suggestive symptoms. DESIGN: Data were collected between March 2011 and March 2012 in low-income suburbs in urban Blantyre using focus group discussions with community members (n=8) and health workers (n=2), in-depth interviews with 20 TB patients (female=14) and 20 uninvestigated chronic coughers (female=8), and a 3 day participatory workshop with 27 health stakeholder representatives. The research process drew to a large extent on grounded theory principles in the manner of Strauss and Corbin (1998) and also Charmaz (1995). RESULTS: Role descriptions by both men and women in the study universally assigned men as primary material providers for their immediate family, that is, the ones earning and bringing livelihood and additional material needs. In a context where collectivism was valued, men were also expected to lead the provision of support to wider kin. Successful role enactment was considered key to achieving recognition as an adequate man; at the same time, job scarcity and insecurity, and low earnings gravely impeded men. Pressures to generate continuing income then meant constantly looking for jobs, or working continuously to retain insecure jobs or to raise money through self-employment. All this led men to relegate their health considerations. CONCLUSIONS: Early engagement with formal healthcare is critical to dealing with TB and HIV. However, role constructions as portrayed for men in this study, along with the opportunity costs of acknowledging illness seem, in conditions of vulnerability, important barriers to care-seeking. There is a need to address hidden care-seeking costs and to consider more complex interventions, including reducing precarity, in efforts to improve men's engagement with their health. PMID- 25833139 TI - Impact of metabolic syndrome on the hospitalization rate of Crohn's disease patients seen at a tertiary care center: a retrospective cohort study. AB - BACKGROUND/AIMS: Recent studies suggest that markers of mesenteric inflammation, such as increased adipose tissue, may be associated with poor outcomes in Crohn's disease (CD). This study's hypothesis is that CD patients with metabolic syndrome (MetS) have more CD-related hospitalizations than CD patients without MetS. METHODS: We conducted a retrospective cohort study of CD patients seen from 2000 to 2012 at our tertiary care center. We analyzed crude and age-, sex- and duration of CD-adjusted incidence rate ratio (IRR) of CD-related hospitalization of those with MetS versus those without MetS. We also investigated possible associations between individual component conditions of MetS and rate of CD related hospitalization. RESULTS: A total of 868 CD patients were included. There were 37 (4%) patients with MetS at initial observation. After multi-variable adjustment, patients with MetS had a CD-related hospitalization rate twice that of those who did not have MetS. High triglycerides (TG), low high density lipoprotein (HDL) cholesterol and diabetes mellitus (DM) were associated with increased risk of CD-related hospitalization. CONCLUSIONS: CD patients with MetS have a higher rate of CD-related hospitalization compared to those without MetS. Hypertriglyceridemia, low HDL cholesterol and DM may be good markers of local and systemic inflammation as seen in CD. PMID- 25833140 TI - Remarriage Beliefs as Predictors of Marital Quality and Positive Interaction in Stepcouples: An Actor-Partner Interdependence Model. AB - Using an Actor-Partner Interdependence Model, we examined remarriage beliefs as predictors of marital quality and positive interaction in a sample of 179 stepcouples. Three beliefs were measured using subscales from the Remarriage Belief Inventory (RMBI) including success is slim, children are the priority, and finances should be pooled. Several significant actor and partner effects were found for both wives' and husbands' beliefs. Wives' marital quality was positively associated with their own beliefs that finances should be pooled and negatively associated with their own beliefs that success is slim. Wives' reports of their own and spouses' positive interaction were both positively associated with their beliefs that finances should be pooled. Their reports of spouses' positive interaction were also negatively associated with husbands' beliefs that success is slim. Husbands' marital quality was positively associated with wives' beliefs that children are the priority, positively associated with their own beliefs that finances should be pooled, and negatively with success is slim. Positive interaction for husbands was positively associated with wives' beliefs that finances should be pooled and negatively associated with their own beliefs that success is slim. Finally, husbands' reports of positive interaction for their spouses were positively associated with wives' beliefs that finances should be pooled. Implications for future research utilizing dyadic data analysis with stepcouples are addressed. PMID- 25833141 TI - The Parkinson's-associated protein DJ-1 regulates the 20S proteasome. AB - The Parkinson's-associated protein, DJ-1, is a highly conserved homodimer, ubiquitously expressed in cells. Here we demonstrate that DJ-1 is a 20S proteasome regulator. We show that DJ-1 physically binds the 20S proteasome and inhibits its activity, rescuing partially unfolded proteins from degradation. Consequently, DJ-1 stabilizes the cellular levels of 20S proteasome substrates, as we show for alpha-synuclein and p53. Furthermore, we demonstrate that following oxidative stress, DJ-1 is involved in the Nrf2-dependent oxidative stress response that leads to the upregulation of both the 20S proteasome and its regulator, NQO1. Overall, our results suggest a regulatory circuit in which DJ-1, under conditions of oxidative stress, both upregulates and inhibits the 20S proteasome, providing a rigorous control mechanism at a time when the 20S proteasome becomes the major proteolytic machinery. Such a tight regulation of the 20S proteasome may sustain the balance between the need to rapidly eliminate oxidatively damaged proteins and maintain the abundance of native, intrinsically unstructured proteins, which coordinate regulatory and signalling events. PMID- 25833142 TI - Formation of tri- and tetranuclear titanacycles through decamethyltitanocene mediated intermolecular C-C coupling of dinitriles. AB - The reactions of [Cp*2 Ti(eta(2) -Me3 SiC2 SiMe3 )] (Cp*=eta(5) pentamethylcyclopentadienyl) with various dicyano compounds were investigated. Nitrile-nitrile C?C couplings result in multinuclear complexes owing to the bifunctionality of the substrates. Applying 1,3- or 1,4-dicyanobenzene led to tri and tetranuclear complexes of the rare 1-metalla-2,5-diaza-cyclopenta-2,4 dienes. These are potential catalysts and were tested in the ring-opening polymerization of epsilon-caprolactone. The reaction with adiponitrile as alkyl dinitrile afforded a trinuclear 1-metalla-2,5-diaza-cyclopent-3-ene through additional protonation of the nitrogen atoms. The structure and bonding of the products were investigated by X-ray crystallography and DFT analysis to understand the molecular organization in the macrocycles. PMID- 25833144 TI - Improvement of large-joint ultrasonographic synovitis is delayed in patients with newly diagnosed rheumatoid arthritis: results of a 12-month clinical and ultrasonographic follow-up study of a local cohort. AB - We analyzed the longitudinal changes in gray-scale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS) parameters and correlated them with clinical, functional, and radiologic outcomes in patients with newly diagnosed rheumatoid arthritis (RA). GSUS and PDUS examinations, 44-joint disease activity score (DAS44) calculations, measurements of erythrocyte sedimentation rate, and C reactive protein levels were performed in 68 RA patients at baseline and after 1, 3, 6, 9, and 12 months. Metacarpophalangeal joints, wrist, elbow, knee, ankle, metatarsophalangeal joints, and wrist and ankle tendons were examined by GSUS and PDUS. The laboratory and clinical findings began to decrease significantly at 1 month (P < 0.05). Improvement of the ultrasonography (US) variables began at 3 months. After 6 months, all of the joint synovitis scores, except those of the knee, elbow, and ankle joints, showed a statistically significant reduction compared to baseline scores (P < 0.001). DAS44 scores were lower in the very early RA group at 12 months compared to those whose symptom duration was greater than 3 months of RA (respectively, 1.53 +/- 0.34; 1.80 +/- 0.38; z = -2501, P = 0.012). The total modified Sharp scores at 12 months correlated with total PDUS synovitis scores at 12 months (r = 0.354, P = 0.003). Regression of US synovitis at large joints such as the knee, elbow, and ankle tended to be delayed compared to that at small joints. PD synovitis that is persistent despite disease modifying anti-rheumatic drug therapy may cause radiographic bone erosions. PMID- 25833143 TI - The protean ocular involvement in monogenic autoinflammatory diseases: state of the art. AB - Ocular involvement is frequent in the monogenic autoinflammatory disorders and generally occurs as spontaneously recurring inflammatory events at different ocular sites caused by the aberrant release of proinflammatory cytokines, mainly IL-1beta. Over the past decade, we witnessed a significant growth of eye abnormalities associated with idiopathic granulomatous disorders, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and cryopyrin-associated periodic syndrome. The pathogenetic mechanisms of these disorders have shown the evidence of disrupted cytokine signaling, but the explanation for the heterogeneous ocular involvement remains to be elucidated. We herein review the monogenic autoinflammatory disorders affecting the eye, describing their main clinical features with specific regard to the ocular involvement, which can lead to decreased visual acuity and even blindness, if the primary disorder is undetected or left untreated. PMID- 25833146 TI - High pressure pyrolyzed non-precious metal oxygen reduction catalysts for alkaline polymer electrolyte membrane fuel cells. AB - Non-precious metal catalysts, such as metal-coordinated to nitrogen doped-carbon, have shown reasonable oxygen reduction reaction (ORR) performances in alkaline fuel cells. In this report, we present the development of a highly active, stable and low-cost non-precious metal ORR catalyst by direct synthesis under autogenic pressure conditions. Transmission electron microscopy studies show highly porous Fe-N-C and Co-N-C structures, which were further confirmed by Brunauer-Emmett Teller surface area measurements. The surface areas of the Fe-N-C and Co-N-C catalysts were found to be 377.5 and 369.3 m(2) g(-1), respectively. XPS results show the possible existence of N-C and M-Nx structures, which are generally proposed to be the active sites in non-precious metal catalysts. The Fe-N-C electrocatalyst exhibits an ORR half-wave potential 20 mV higher than the reference Pt/C catalyst. The cycling durability test for Fe-N-C over 5000 cycles shows that the half-wave potential lost only 4 mV, whereas the half-wave potential of the Pt/C catalyst lost about 50 mV. The Fe-N-C catalyst exhibited an improved activity and stability compared to the reference Pt/C catalyst and it possesses a direct 4-electron transfer pathway for the ORR process. Further, the Fe-N-C catalyst produces extremely low HO2(-) content, as confirmed by the rotating ring-disk electrode measurements. In the alkaline fuel single cell tests, maximum power densities of 75 and 80 mW cm(-2) were observed for the Fe-N C and Pt/C cathodes, respectively. Durability studies (100 h) showed that decay of the fuel cell current was more prominent for the Pt/C cathode catalyst compared to the Fe-N-C cathode catalyst. Therefore, the Fe-N-C catalyst appears to be a promising new class of non-precious metal catalysts prepared by an autogenic synthetic method. PMID- 25833145 TI - Erosive osteoarthritis, psoriatic arthritis and pseudogout; a casual association? AB - According to recent hypothesis, the inflammation has a pivotal role in the onset and progression of erosive hand osteoarthritis (EHOA), psoriatic arthritis (PsA) and chondrocalcinosis (CC)/pseudogout. Albeit, it has been recognised for years as an association between EHOA and radiographic evidence of CC, but there are few reports of coexistence of microcrystalline arthritis and PsA. This is the first report that described a clinical experience concerning two consecutive cases of patients presented with EHOA, PsA and pseudogout. Two Caucasian women of 71 and 85 years old with a history of OA and mild psoriasis are presented with tenderness and swelling of first interphalangeal (IP) and wrist joint, respectively. Arthrocentesis performed at the first IP and wrist joint, respectively, showed an inflammatory synovial fluid with presence of calcium pyrophosphate dehydrate crystals. X-rays of hands, feet and knees showed characteristic features of EHOA, PsA and CC. Furthermore, HLA typing evinces the presence of HLA C*06; DRB*01 07 and HLA C*07; DRB*01 *11 alleles, respectively, predisposing factors of these inflammatory diseases. The relationship between these aggressive rheumatic diseases along with their clinical, radiographic, laboratory and genetic features is discussed. PMID- 25833147 TI - Acoustic radiation force impulse elastography of the spleen in healthy dogs of different ages. AB - OBJECTIVES: To determine the elastographic characteristics of splenic parenchyma in clinically healthy dogs of various ages in order to establish preliminary qualitative and quantitative standards/reference intervals for this technique. MATERIALS AND METHODS: Thirty three healthy dogs categorized as young, adult and elderly were used. Splenic echotexture, echogenicity, size and ages were assessed with B-mode ultrasonography. Using qualitative elastography, the spleen (head, body and tail) was examined for homogeneity and presence of deformities. Shear velocities in different splenic segments were then quantitatively evaluated. RESULTS: All splenic segments visualised with the B-mode ultrasonography appeared normal. Different splenic segments examined with qualitative elastography were free of any detectable malformations and the images appeared as homogeneous dark areas. The mean shear velocity values were 2 . 32 m/s for head, 2 . 16 m/s for body and 2 . 25 m/s for tail of the spleen (P = 0 . 40), and they did not vary between the different age groups (P > 0 . 05). CLINICAL SIGNIFICANCE: Quantitative and qualitative ARFI elastography of the spleen in clinically healthy dogs differing in age could be easily performed, and it may aid in the diagnosis and evaluation of splenic abnormalities routinely assessed in veterinary practice with B-mode ultrasonography. PMID- 25833148 TI - Copper-zinc alloy nanopowder: a robust precious-metal-free catalyst for the conversion of 5-hydroxymethylfurfural. AB - Noble-metal-free copper-zinc nanoalloy (<150 nm) is found to be uniquely suited for the highly selective catalytic conversion of 5-hydroxymethylfurfural (HMF) to potential biofuels or chemical building blocks. Clean mixtures of 2,5 dimethylfuran (DMF) and 2,5-dimethyltetrahydrofuran (DMTHF) with combined product yields up to 97 % were obtained at 200-220 degrees C using 20-30 bar H2 . It is also possible to convert 10 wt % HMF solutions in CPME, with an excellent DMF yield of 90 %. Milder temperatures favor selective (95 %) formation of 2,5 furandimethanol (FDM). The one-pot conversion of fructose to valuable furan ethers was also explored. Recycling experiments for DMF production show remarkable catalyst stability. Transmission electron microscopy (TEM) characterization provides more insight into morphological changes of this intriguing class of materials during catalysis. PMID- 25833149 TI - Mutational Profile and New IASLC/ATS/ERS Classification Provide Additional Prognostic Information about Lung Adenocarcinoma: A Study of 125 Patients from Brazil. AB - AIM: To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatments. METHODS: In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). RESULTS: EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (<72 packs/year), clinical stage I/II, and acinar histologic subtype presented better survival than women aged <= 71 years, with a history of smoking (>72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. CONCLUSIONS: These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC. PMID- 25833150 TI - One hundred-year-old human corneal and transplanted corneal graft endothelium. AB - PURPOSE: To investigate and analyse one hundred-year-old endothelial cells of human transplanted corneal grafts and compare them with intact endothelium of unoperated eyes. SUBJECTS AND METHODS: Specular microscopy was performed on seven individuals (14 eyes) aged >100 years and on seven transplanted corneas with endothelial cells of at least 100 years old. All keratoplasties were performed by the same surgeon (PR) 25-35 years before the time of examination. As controls, 14 unoperated healthy individuals (26 eyes) of 90-100 years, 12 individuals (24 eyes) of 48-52 years, 12 students (24 eyes) of 19-24 years and 11 children (22 eyes) from 10 to 14 years of age were photographed and analysed. RESULTS: The mean cell density in the oldest age group, over 100 years of age (average 102 years), was very good 2365 cells/mm(2) . The mean cell density in the transplanted corneas, the endothelial cells of which were over 100 years old (mean 106 years), was 923 cells/mm(2) (range 585-1800 cells/mm(2) ). CONCLUSION: Corneal endothelial cells may remain viable and capable to perform their function over 100 years. Donor corneas up to 70-75 years of age can be approved for transplantation, provided that the endothelial cells have been thoroughly evaluated with vital staining before the operation. PMID- 25833151 TI - Novel Splice Site Mutation in MAMLD1 in a Patient with Hypospadias. AB - MAMLD1 is a causative gene for disorders of sex development. Several MAMLD1 mutations have been shown to cause hypospadias by generating dysfunctional proteins and/or unstable mRNAs. Here, we identified an intronic mutation of MAMLD1 (g.IVS4-2A>G) in 1 of 180 hypospadias patients. RT-PCR of the patient's skin sample showed normal expression of full-length MAMLD1 and markedly reduced expression of a known splice variant lacking exon 4. A hitherto unreported splice variant that lacks exon 5 was similarly identified in samples of the patient and control individuals. The full-length transcript of the patient contained mutant mRNA lacking the first 10 nucleotides of exon 5 (c.1822_1831delACTCATGTAG, p.K609fsX1070). In vitro assays using cells expressing the full-length wild-type and mutant proteins revealed reduced expression of the mutant. The expression of the wild-type and mutant MAMLD1 showed parallel changes upon treatment with a proteasome inhibitor and a translation inhibitor. The mutant-expressing cells exerted low transactivation activity for the Hes3 promoter, which reflected limited expression of the mutant protein. These results imply that the pathogenic events resulting from MAMLD1 mutations include splice errors. Furthermore, this study raises the possibility of translation failure of MAMLD1 mutants, which deserves further investigation. PMID- 25833152 TI - Adapting the mobile laboratory to the changing needs of the Ebolavirus epidemic. AB - The current Ebolavirus disease (EVD) epidemic in West Africa has now been running for >1 year and has been an international health emergency for >6 months. As the weekly number of new cases falls, the World Health Organization is preparing its response to the final stages of the epidemic. The final totals will exceed 20,000 cases and 8000 deaths. An ability to adapt disease countermeasures including laboratory support to the changing epidemiology of EVD has become a matter of urgency. This article considers the planning, development and modification of a flexible microbiology laboratory response, and describes logistic and operational considerations for clinical and public health microbiologists. PMID- 25833153 TI - Bacillus lycopersici sp. nov., isolated from a tomato plant (Solanum lycopersicum L.). AB - A Gram-stain-positive, rod-shaped, endospore-forming bacterium (designated strain CC-Bw-5(T)) was isolated from chopped tomato stems. The isolate grew at 20-40 degrees C, pH 6.0-8.0 and tolerated 6% (w/v) NaCl. The most closely related strains in terms of 16S rRNA gene sequence similarity were Bacillus isabeliae (95.3%) and Bacillus oleronius (95.3%). The G+C content of the genomic DNA was 37.2 +/- 3.6 mol%. Strain CC-Bw-5(T) was determined to possess C16 : 0, iso-C14 : 0, iso-C15 : 0, anteiso-C15 : 0 and iso-C16 : 0 as predominant fatty acids. The polar lipid profile consisted of predominant amounts of diphosphatidylglycerol, and moderate-to-trace amounts of phosphatidylethanolamine, phosphatidylglycerol, two unidentified glycolipids, an unidentified phospholipid and an unidentified phosphoglycolipid. The cell-wall peptidoglycan contained meso-diaminopimelic acid; menaquinone (MK-7) was the predominant respiratory quinone. According to distinct phylogenetic, phenotypic and chemotaxonomic features, strain CC-Bw-5(T) is proposed to represent a novel species within the genus Bacillus for which the name Bacillus lycopersici sp. nov. is proposed. The type strain is CC-Bw-5(T) ( = BCRC 80623(T) = JCM 19140(T)). PMID- 25833154 TI - Lactococcus hircilactis sp. nov. and Lactococcus laudensis sp. nov., isolated from milk. AB - Two strains of lactic acid bacteria, designated 117(T) and 4195(T), were isolated from goat milk in Valtellina, Italy and from cow milk in Valle Trompia, Italy, respectively, and characterized taxonomically by a polyphasic approach. The strains were Gram-stain-positive, coccoid, non-spore-forming and catalase negative bacteria. Morphological, physiological and phylogenetic data indicated that these isolates belonged to the genus Lactococcus. Strain 117(T) was closely related to Lactococcus fujiensis, Lactococcus lactis subsp. lactis, L. lactis subsp. cremoris, L. lactis subsp. hordniae, L. lactis subsp. tructae and Lactococcus taiwanensis, showing 93-94% and 82-89% 16S rRNA and rpoB gene sequence similarities, respectively. Strain 4195(T) was closely related to Lactococcus chungangensis, Lactococcus raffinolactis, Lactococcus plantarum and Lactococcus piscium, showing 92-98% and 86-99% 16S rRNA and rpoB gene sequence similarities, respectively. Based on this evidence and the data obtained in the present study, the milk isolates represent two novel species of the genus Lactococcus, for which the names Lactococcushircilactis sp. nov., and Lactococcuslaudensis sp. nov. are proposed. The respective type strains are 117(T) ( = LMG 28352(T) = DSM 28960(T)) and 4195(T )( = LMG 28353(T) = DSM 28961(T)). PMID- 25833155 TI - Maribacter spongiicola sp. nov. and Maribacter vaceletii sp. nov., isolated from marine sponges, and emended description of the genus Maribacter. AB - Two Gram-stain-negative, rod-shaped, orange, catalase- and oxidase-positive, non motile bacteria, designated W13M1A(T) and W15M10(T), were isolated from the marine sponges Suberites carnosus and Leucosolenia sp., respectively, which were sampled from Lough Hyne, Co. Cork, Ireland. Analysis of the 16S rRNA gene sequences of these isolates revealed that they are members of the genus Maribacter, in the family Flavobacteriaceae of the phylum Bacteroidetes. The type strain most closely related to strain W13M1A(T) is Maribacter forsetii DSM 18668(T) with a gene sequence similarity of 96.5%. The closest related type strain to strain W15M10(T) is Maribacter orientalis DSM 16471(T) with a gene sequence similarity of 98.3%. Phylogenetic inference and phenotypic data combined indicate that the isolates represent two novel species of the genus Maribacter, for which the names Maribacter spongiicola sp. nov. with type strain W15M10(T) ( = NCIMB 14725(T) = DSM 25233(T)) and Maribacter vaceletii sp. nov. with type strain W13M1A(T) ( = NCIMB 14724(T) = DSM 25230(T)), are proposed. PMID- 25833156 TI - Progesterone receptor expression during prostate cancer progression suggests a role of this receptor in stromal cell differentiation. AB - BACKGROUND: The progesterone receptor, like the androgen receptor, belongs to the steroid receptor superfamily. Our previous studies have reported that the PR is expressed specifically in prostate stroma. PR inhibits proliferation of, and regulates cytokine secretion by stromal cells. However, PR protein expression in cancer-associated stroma during prostate cancer progression has not been profiled. Since the phenotypes of prostate stromal cells change dynamically as tumors progress, whether the PR plays a role in regulating stromal cell differentiation needs to be investigated. METHODS: Immunohistochemistry assays measured PR protein levels on human prostate tissue microarrays containing 367 tissue cores from benign prostate, prostate tumors with different Gleason scores, tumors under various durations of castration therapy, and tumors at the castration-resistant stage. Immunoblotting assays determined whether PR regulated the expression of alpha smooth muscle actin (alpha-SMA), vimentin, and fibroblast specific protein (FSP) in human prostate stromal cells. RESULTS: PR protein levels decreased in cancer-associated stroma when compared with that in benign prostate stroma. This reduction in PR expression was not correlated with Gleason scores. PR protein levels were elevated by castration therapy, but reduced to pre castration levels when tumors progressed to the castration-resistant stage. Enhanced PR expression in human prostate stromal cells increased alpha-SMA, but decreased vimentin and FSP protein levels ligand-independently. CONCLUSION: These results suggest that PR plays an active role in regulating stromal cell phenotypes during prostate cancer progression. PMID- 25833157 TI - Effect of Massachusetts healthcare reform on racial and ethnic disparities in admissions to hospital for ambulatory care sensitive conditions: retrospective analysis of hospital episode statistics. AB - OBJECTIVES: To examine the impact of Massachusetts healthcare reform on changes in rates of admission to hospital for ambulatory care sensitive conditions (ACSCs), which are potentially preventable with good access to outpatient medical care, and racial and ethnic disparities in such rates, using complete inpatient discharge data (hospital episode statistics) from Massachusetts and three control states. DESIGN: Difference in differences analysis to identify the change, overall and according to race/ethnicity, adjusted for secular changes unrelated to reform. SETTING: Hospitals in Massachusetts, New York, New Jersey, and Pennsylvania, United States. PARTICIPANTS: Adults aged 18-64 (those most likely to have been affected by the reform) admitted for any of 12 ACSCs in the 21 months before and after the period during which reform was implemented (July 2006 to December 2007). MAIN OUTCOME MEASURES: Admission rates for a composite of all 12 ACSCs, and subgroup composites of acute and chronic ACSCs. RESULTS: After adjustment for potential confounders, including age, race and ethnicity, sex, and county income, unemployment rate and physician supply, we found no evidence of a change in the admission rate for overall composite ACSC (1.2%, 95% confidence interval -1.6% to 4.1%) or for subgroup composites of acute and chronic ACSCs. Nor did we find a change in disparities in admission rates between black and white people (-1.9%, -8.5% to 5.1%) or white and Hispanic people (2.0%, -7.5% to 12.4%) for overall composite ACSC that existed in Massachusetts before reform. In analyses limited to Massachusetts only, we found no evidence of a change in admission rate for overall composite ACSC between counties with higher and lower rates of uninsurance at baseline (1.4%, -2.3% to 5.3%). CONCLUSIONS: Massachusetts reform was not associated with significantly lower overall or racial and ethnic disparities in rates of admission to hospital for ACSCs. In the US, and Massachusetts in particular, additional efforts might be needed to improve access to outpatient care and reduce preventable admissions. PMID- 25833158 TI - Loss of glycogen synthase kinase 3 isoforms during murine oocyte growth induces offspring cardiac dysfunction. AB - Glycogen synthase kinase-3 (GSK3) is a constitutively active serine threonine kinase with 1) two isoforms (GSK3A and GSK3B) that have unique and overlapping functions, 2) multiple molecular intracellular mechanisms that involve phosphorylation of diverse substrates, and 3) implications in pathogenesis of many diseases. Insulin causes phosphorylation and inactivation of GSK3 and mammalian oocytes have a functional insulin-signaling pathway whereby prolonged elevated insulin during follicle/oocyte development causes GSK3 hyperphosphorylation, reduced GSK3 activity, and altered oocyte chromatin remodeling. Periconceptional diabetes and chronic hyperinsulinemia are associated with congenital malformations and onset of adult diseases of cardiovascular origin. Objectives were to produce transgenic mice with individual or concomitant loss of GSK3A and/or GSK3B and investigate the in vivo role of oocyte GSK3 on fertility, fetal development, and offspring health. Wild-type males bred to females with individual or concomitant loss of oocyte GSK3 isoforms did not have reduced fertility. However, concomitant loss of GSK3A and GSK3B in the oocyte significantly increased neonatal death rate due to congestive heart failure secondary to ventricular hyperplasia. Individual loss of oocyte GSK3A or GSK3B did not induce this lethal phenotype. In conclusion, absence of oocyte GSK3 in the periconceptional period does not alter fertility yet causes offspring cardiac hyperplasia, cardiovascular defects, and significant neonatal death. These results support a developmental mechanism by which periconceptional hyperinsulinemia associated with maternal metabolic syndrome, obesity, and/or diabetes can act on the oocyte and affect offspring cardiovascular development, function, and congenital heart malformation. PMID- 25833159 TI - Tamoxifen prevents apoptosis and follicle loss from cyclophosphamide in cultured rat ovaries. AB - Recent studies documented that the selective estrogen receptor modulator tamoxifen prevents follicle loss and promotes fertility following in vivo exposure of rodents to irradiation or ovotoxic cancer drugs, cyclophosphamide and doxorubicin. In an effort to characterize the ovarian-sparing mechanisms of tamoxifen in preantral follicle classes, cultured neonatal rat ovaries (Day 4, Sprague Dawley) were treated for 1-7 days with active metabolites of cyclophosphamide (i.e., 4-hydroxycyclophosphamide; CTX) (0, 1, and 10 MUM) and tamoxifen (i.e., 4-hydroxytamoxifen; TAM) (0 and 10 MUM) in vitro, and both apoptosis and follicle numbers were measured. CTX caused marked follicular apoptosis and follicular loss. TAM treatment decreased follicular loss and apoptosis from CTX in vitro. TAM alone had no effect on these parameters. IGF-1 and IGF-1 receptor were assessed in ovarian tissue showing no impact of TAM or CTX on these endpoints. Targeted mRNA analysis during follicular rescue by TAM revealed decreased expression of multiple genes related to inflammation, including mediators of lipoxygenase and prostaglandin production and signaling (Alox5, Pla2g1b, Ptgfr), cytokine binding (Il1r1, Il2rg ), apoptosis (Tnfrsf1a), second messenger signaling (Mapk1, Mapk14, Plcg1), as well as tissue remodeling and vasodilation (Bdkrb2, Klk15). The results suggest that TAM protects the ovary from CTX-mediated toxicity through direct ovarian actions that oppose follicular loss. PMID- 25833160 TI - Effects of hemoadsorption with a novel adsorbent on sepsis: in vivo and in vitro study. AB - BACKGROUND/AIMS: Hemoadsorption may improve outcomes for sepsis by removing circulating cytokines. We tested a new sorbent used for hemoadsorption. METHODS: CTR sorbent beads were filled into columns of three sizes: CTR0.5 (0.5 ml), CTR1 (1.0 ml) and CTR2 (2.0 ml) and tested using IL-6 capture in vitro. Next, rats were subjected to cecal ligation and puncture and randomly assigned to hemoadsorption with CTR0.5, CTR1, CTR2 or sham treatment. Plasma biomarkers were measured. RESULTS: In vitro, IL-6 removal was accelerated with increasing bead mass. In vivo, TNF, IL-6, IL-10, high mobility group box1, and cystatin C were significantly lower 24 h after CTR2 treatment. Seven-day survival rate was 50, 64, 63, and 73% for the sham, CTR0.5, CTR1, CTR2, respectively. CONCLUSION: CTR appeared to have a favorable effect on kidney function despite no immediate effects on cytokine removal. However, CTR2 beads did result in a late decrease of cytokines. PMID- 25833161 TI - Risk assessment of magnetic resonance imaging in chronically implanted paddle electrodes for cortical stimulation. AB - BACKGROUND: Cortical epidural stimulation is used for the treatment of different neuropsychiatric disorders such as chronic neuropathic pain, tinnitus, movement disorders, and psychiatric diseases. While preoperative magnetic resonance imaging (MRI) is considered the imaging tool of choice for planning the approach and electrode placement, postoperative MRI is still a contraindication with implanted paddle leads due to the risk of thermal damage or current induction creating seizures or neurological deficits. OBJECTIVES: In this feasibility in vitro study the temperature changes and induction were determined as well as the artifacts caused by 2 parallel paddle leads (Resume II, Model 3587 A; Medtronic, Minneapolis, Minn., USA), commonly used in clinical practice with and without a pulse generator (Prime Advanced, Model 7489; Medtronic). METHODS: An ultrasound gel-filled head phantom with 2 paddle leads mimicking the surgical scenario was used to evaluate temperature changes as well as induced currents in a 1.5- and 3 tesla MR scanner. In addition, 1 patient underwent a 3-tesla MRI with an implanted subdural paddle lead. RESULTS: Negligible temperature changes were detected with turbo spin echo sequences in the 1.5- and 3-tesla scanner using a head and body coil. Induced voltages up to 6 V were measured. The imaging artifacts in the phantom were well tolerable. The patient's imaging was uneventful under the settings which are accepted for deep brain stimulation imaging. CONCLUSION: MRI under the conditions described here seems to be safe with the implants used in this study. In particular, the induced temperature is much lower with paddle compared to conventional leads due to the different electrode design. The induced voltage does not carry any risks. However, these findings cannot automatically be transferred to other implants or other scanning conditions, and further studies are needed. The biomedical companies should be encouraged to develop MR-conditional paddle leads. Also, further research is necessary to study the mechanism of action of cortical stimulation in the future. PMID- 25833162 TI - Effects of methoxychlor and 2,2-bis ( p -hydroxyphenyl)-1,1,1-trichloroethane on cytochrome P450 enzyme activities in human and rat livers. AB - Cytochrome P450 (CYP) enzymes are involved in the metabolism of endogenous and exogenous compounds. Human and rat liver microsomes were used to investigate the inhibitory effects of methoxychlor (MXC) and its metabolite 2,2-bis(p hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on the activities of corresponding human and rat CYPs. Probe drugs were used to test the inhibitory effects of MXC and HPTE on human and rat CYPs. The results showed that MXC and HPTE inhibited both human CYP2C9 and rat liver CYP2C11 activity, with half-maximal inhibitory concentration (IC50) values of 15.47 +/- 0.36 (MXC) and 8.87 +/- 0.53 MUmol/l (HPTE) for human CYP2C9, and of 22.45 +/- 1.48 (MXC) and 24.63 +/- 1.35 MUmol/l (HPTE) for rat CYP2C11. MXC and HPTE had no effects on human CYP2C19 activity but inhibited rat CYP2C6 activity with IC50 values of 14.84 +/- 0.04 (MXC) and 8.72 +/- 0.25 MUmol/l (HPTE). With regard to human CYP2D6 and rat CYP2D2 activity, only HPTE potently inhibited human CYP2D6 activity, with an IC50 value of 16.56 +/- 0.69 MUmol/l. Both chemicals had no effect on human CYP3A4 and rat CYP3A1 activity. In summary, MXC and HPTE are potent inhibitors of some human and rat CYPs. PMID- 25833163 TI - Safety and immunogenocity of a novel combined Haemophilus influenzae type b Neisseria meningitidis serogroups A and C-tetanus-toxoid conjugate vaccine in healthy Chinese children aged 6 months to 5 years old. AB - A novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups A and C-tetanus-toxoid conjugate vaccine (Hib-MenAC vaccine) has been developed to protect children against diseases caused by Hib, MenA, and MenC. This study investigated the safety and immunogenicity of the Hib-MenAC vaccine administered in 2-dose series to children aged 6-23 months and in a single dose to children aged 2-5 y. A randomized, positive-controlled, non-inferiority clinical trial was conducted for 1200 healthy participants in each age group. Within each age group, participants were randomly allocated to the Hib-MenAC group or the control group at a ratio of 1:1. Adverse reactions were recorded within 28 d after each dose. Blood samples were obtained to assess immunogenicity on day 0 and at 28 d after a complete vaccination course. For the investigational vaccine, the incidence of total adverse reactions in vaccinees aged 6-23 months was 46.8% and that in vaccinees aged 2-5 y was 29.8%. Most adverse reactions were mild or moderate. One non-fatal serious adverse event occurred in the Hib-MenAC group, but was unrelated to vaccination. The seroconversion rate to the 3 components reached 94.0%, and the proportion of vaccinees with rSBA titers >= 1:8 and PRP >= 0.15 g/mL reached 97.0% in both age groups. The safety and immunogenicity of the Hib MenAC vaccine were non-inferior when compared to the licensed vaccines. It was concluded that the novel vaccine would be expected to protect children against all of the targeted diseases. PMID- 25833165 TI - Bioactive gyroid scaffolds formed by sacrificial templating of nanocellulose and nanochitin hydrogels as instructive platforms for biomimetic tissue engineering. AB - A sacrificial templating process using lithographically printed minimal surface structures allows complex de novo geo-metries of delicate hydrogel materials. The hydrogel scaffolds based on cellulose and chitin nanofibrils show differences in terms of attachment of human mesenchymal stem cells, and allow their differentiation into osteogenic outcomes. The approach here serves as a first example toward designer hydrogel scaffolds viable for biomimetic tissue engineering. PMID- 25833164 TI - Hypoxic pulmonary vasoconstriction, carotid body function and erythropoietin production in adult rats perinatally exposed to hyperoxia. AB - KEY POINTS: Adult animals that have been perinatally exposed to oxygen-rich atmospheres (hyperoxia), recalling those used for oxygen therapy in infants, exhibit a loss of hypoxic pulmonary vasoconstriction, whereas vasoconstriction elicited by depolarizing agents is maintained. Loss of pulmonary hypoxic vasoconstriction is not linked to alterations in oxygen-sensitive K(+) currents in pulmonary artery smooth muscle cells. Loss of hypoxic vasoconstriction is associated with early postnatal oxidative damage and corrected by an antioxidant diet. Perinatal hyperoxia damages carotid body chemoreceptor cell function and the antioxidant diet does not reverse it. The hypoxia-elicited increase in erythropoietin plasma levels is not affected by perinatal hyperoxia. The potential clinical significance of the findings in clinical situations such as pneumonia, chronic obstructive pulmonary disease or general anaesthesia is considered. ABSTRACT: Adult mammalians possess three cell systems that are activated by acute bodily hypoxia: pulmonary artery smooth muscle cells (PASMC), carotid body chemoreceptor cells (CBCC) and erythropoietin (EPO)-producing cells. In rats, chronic perinatal hyperoxia causes permanent carotid body (CB) atrophy and functional alterations of surviving CBCC. There are no studies on PASMC or EPO-producing cells. Our aim is to define possible long-lasting functional changes in PASMC or EPO-producing cells (measured as EPO plasma levels) and, further, to analyse CBCC functional alterations. We used 3- to 4-month-old rats born and reared in a normal atmosphere or exposed to perinatal hyperoxia (55-60% O2 for the last 5-6 days of pregnancy and 4 weeks after birth). Perinatal hyperoxia causes an almost complete loss of hypoxic pulmonary vasoconstriction (HPV), which was correlated with lung oxidative status in early postnatal life and prevented by antioxidant supplementation in the diet. O2 -sensitivity of K(+) currents in the PASMC of hyperoxic animals is normal, indicating that their inhibition is not sufficient to trigger HPV. Perinatal hyperoxia also abrogated responses elicited by hypoxia on catecholamine and cAMP metabolism in the CB. An increase in EPO plasma levels elicited by hypoxia was identical in hyperoxic and control animals, implying a normal functioning of EPO-producing cells. The loss of HPV observed in adult rats and caused by perinatal hyperoxia, comparable to oxygen therapy in premature infants, might represent a previously unrecognized complication of such a medical intervention capable of aggravating medical conditions such as regional pneumonias, atelectases or general anaesthesia in adult life. PMID- 25833166 TI - Opiorphin-dependent upregulation of CD73 (a key enzyme in the adenosine signaling pathway) in corporal smooth muscle cells exposed to hypoxic conditions and in corporal tissue in pre-priapic sickle cell mice. AB - The precise molecular mechanisms underlying priapism associated with sickle cell disease remain to be defined. However, there is increasing evidence that upregulated activity of the opiorphin and adenosine pathways in corporal tissue, resulting in heighted relaxation of smooth muscle, have an important role in development of priapism. A key enzyme in the adenosine pathway is CD73, an ecto 5'-nucleotidase (5'-ribonucleotide phosphohydrolase; EC 3.1.3.5) which catalyzes the conversion of adenosine mononucleotides to adenosine. In the present study we investigated how sickle cell disease and hypoxia regulate the interplay between opiorphin and CD73. In the corpora of sickle cell mice we observed significantly elevated expression of both the mouse opiorphin homolog mSmr3a (14-fold) and CD73 (2.2-fold) relative to non-sickle cell controls at a life stage before the exhibition of priapism. Sickle cell disease has a pronounced hypoxic component, therefore we determined if CD73 was also modulated in in vitro corporal smooth muscle (CSM) models of hypoxia. Hypoxia significantly increased CD73 protein and mRNA expression by 1.5-fold and 2-fold, respectively. We previously demonstrated that expression of another component of the adenosine signaling pathway, the adensosine 2B receptor, can be regulated by sialorphin (the rat opiorphin homolologue), and we demonstrate that sialorphin also regulates CD73 expression in a dose- and time-dependent fashion. Using siRNA to knockdown sialorphin mRNA expression in CSM cells in vitro, we demonstrate that the hypoxic upregulation of CD73 is dependent on the upregulation of sialorphin. Overall, our data provide further evidence to support a role for opiorphin in CSM in regulating the cellular response to hypoxia or sickle cell disease by activating smooth muscle relaxant pathways. PMID- 25833167 TI - Relations between key executive functions and aggression in childhood. AB - The present study examined relationships between three key executive functions (working memory, inhibition, and mental set-shifting) and multiple types of aggression in a general population sample of 9-year-old children. One hundred and forty-eight children completed a battery of executive function tasks and were rated on aggression by their primary teachers. All executive function (EF) composites were related to a composite measure of aggression. Working memory (WM) was most consistently related to the different types of aggression (overt, relational, reactive, and proactive), whereas inhibition and mental set-shifting only were related to relational and reactive aggression, respectively. Specificity in relations (studied as independent contributions) was generally low with the exception of the relation between WM and relational aggression. Taken together, our results highlight the roles of WM and relational aggression in EF aggression relations in middle childhood. PMID- 25833168 TI - Descriptive analyses of differentially expressed genes during larval development of Calliphora vicina (Diptera: Calliphoridae). AB - The analysis of insect evidence is often used in death investigations as the development of necrophagous insect species can be used to determine a minimum post-mortem interval (PMImin). Usually, the PMImin estimations are based on the age estimation of larvae developed on the corpse. So far, age estimation mostly relies on length or weight measurement of the larvae. These measurements are then compared to species-specific reference growth data obtained from laboratory studies. However, length and weight do not always represent the best developmental markers to provide accurate and precise age estimates for PMImin calculation, especially for post-feeding third-instar larvae which decrease in size. Therefore, more growth markers are required to improve age estimation not only for post-feeding larvae but also for all larval stages. As the analysis of temporally regulated genes proved suitable for age prediction in blow fly pupae, we examined the gene expression patterns of six genes (15_2, 2014192, EcdR, AR, hsp90 and actin) during larval development of Calliphora vicina at three constant temperatures and analysed the effect of a combination of morphological and molecular age markers on statistical models of development. EcdR, AR and 15_2 showed reliable tendencies to classify the post-feeding stage more precisely, and inclusion of gene expression data in models of development improved the statistical fit of the model. Nevertheless, for depicting the first larval stages and for quantifying the onset of the post-feeding stage more accurately, results of this preliminary study should be supported by searching for more informative genes. PMID- 25833169 TI - Differences between male and female cyclists' performances under the acute influence of alcohol. AB - To examine the effects of alcohol regarding the fitness required to ride a bicycle, practical cycling tests, accompanied by medical examinations, were carried out at different blood alcohol concentrations. Seventy-eight persons were included in the trials (41 males, 37 females). Eighty-three evaluable trials were obtained. Men committed less coordinative driving faults with comparable blood alcohol concentrations. Single highly alcoholized men were able to safely ride their bicycle; however, each of the female test persons had at least one severe driving fault at blood alcohol levels above 1.43 g/kg. Women tended to exhibit signs of alcoholization in the medical examination reports earlier than men. PMID- 25833170 TI - A single-tube 27-plex SNP assay for estimating individual ancestry and admixture from three continents. AB - A single-tube multiplex assay of a small set of ancestry-informative markers (AIMs) for effectively estimating individual ancestry and admixture is an ideal forensic tool to trace the population origin of an unknown DNA sample. We present a newly developed 27-plex single nucleotide polymorphism (SNP) panel with highly robust and balanced differential power to perfectly assign individuals to African, European, and East Asian ancestries. Evaluating 968 previously described intercontinental AIMs from three HapMap population genotyping datasets (Yoruban in Ibadan, Nigeria (YRI); Utah residents with Northern and Western European ancestry from the Centre de'Etude du Polymorphism Humain (CEPH) collection (CEU); and Han Chinese in Beijing, China (CHB)), the best set of markers was selected on the basis of Hardy-Weinberg equilibrium (p > 0.00001), population-specific allele frequency (two of three delta values >0.5), according to linkage disequilibrium (r (2) < 0.2), and capable of being multiplexed in one tube and detected by capillary electrophoresis. The 27-SNP panel was first validated by assigning the ancestry of the 11 populations in the HapMap project. Then, we tested the 27-plex SNP assay with 1164 individuals from 17 additional populations. The results demonstrated that the SNP panel was successful for ancestry inference of individuals with African, European, and East Asian ancestry. Furthermore, the system performed well when inferring the admixture of Eurasians (EUR/EAS) after analyzing admixed populations from Xinjiang (Central Asian) as follows: Tajik (68:27), Uyghur (49:46), Kirgiz (40:57), and Kazak (36:60). For individual analyses, we interpreted each sample with a three-ancestry component percentage and a population match probability sequence. This multiplex assay is a convenient and cost-effective tool to assist in criminal investigations, as well as to correct for the effects of population stratification for case-control studies. PMID- 25833175 TI - Editorial retraction. "Probiotics: A Comprehensive Approach toward Health Foods". PMID- 25833171 TI - The effect of banning MDPV on the incidence of MDPV-positive findings among users of illegal drugs and on court decisions in traffic cases in Finland. AB - In this study, we sought to determine what impact the banning of 3, 4- methylenedioxypyrovalerone (MDPV) had on the incidence of MDPV-positive findings and on user profiles in driving under the influence of drugs (DUID) and postmortem (PM) investigations in Finland. All MDPV-positive cases and a selection of corresponding court cases between 2009 and 2012 were examined. The median serum concentration of MDPV in DUID cases was 0.030 mg/L and in PM blood 0.12 mg/L. The number of MDPV-positive cases decreased both in DUID and PM investigations after the drug was banned. The decrease in the mean monthly numbers of MDPV-positive DUID cases was 51.1%. In court cases, MDPV was rarely mentioned until banned and frequently mentioned thereafter. Of the convicted, 37% were without a fixed abode, 98% had other charges besides that of DUID, and 13% appeared in the study material more than once. In MDPV-positive PM cases, the proportion of suicides was very high (24%). Research on new psychoactive substances is required not only to support banning decisions but more importantly to be able to provide a scientific assessment of the risks of these new substances to the public and potential users. PMID- 25833176 TI - Influence of housing characteristics on bacterial and fungal communities in homes of asthmatic children. AB - Variations in home characteristics, such as moisture and occupancy, affect indoor microbial ecology as well as human exposure to microorganisms. Our objective was to determine how indoor bacterial and fungal community structure and diversity are associated with the broader home environment and its occupants. Next generation DNA sequencing was used to describe fungal and bacterial communities in house dust sampled from 198 homes of asthmatic children in southern New England. Housing characteristics included number of people/children, level of urbanization, single/multifamily home, reported mold, reported water leaks, air conditioning (AC) use, and presence of pets. Both fungal and bacterial community structures were non-random and demonstrated species segregation (C-score, P < 0.00001). Increased microbial richness was associated with the presence of pets, water leaks, longer AC use, suburban (vs. urban) homes, and dust composition measures (P < 0.05). The most significant differences in community composition were observed for AC use and occupancy (people, children, and pets) characteristics. Occupant density measures were associated with beneficial bacterial taxa, including Lactobacillus johnsonii as measured by qPCR. A more complete knowledge of indoor microbial communities is useful for linking housing characteristics to human health outcomes. Microbial assemblies in house dust result, in part, from the building's physical and occupant characteristics. PMID- 25833178 TI - Clinical significance of non-vitamin K antagonist oral anticoagulants in the management of atrial fibrillation. AB - Atrial fibrillation (AF) is the most commonly observed rhythm disorder in clinical practice. It is associated with a high risk of thromboembolic stroke and increased cardiovascular mortality. Vitamin K antagonists (VKAs), the only oral anticoagulants used for thromboembolic prophylaxis in AF patients over the past 60 years, have been effective in reducing thromboembolic stroke, compared with placebo and aspirin, in this group of patients. However, VKAs have a very narrow therapeutic window, so regular monitoring of the therapeutic effect is obligatory for their use. The need for regular assessment of blood anticoagulation often causes dissatisfaction and reduces patients' quality of life. Non-VKA oral anticoagulants (NOACs), such as dabigatran, a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban, have been developed in recent years and have increased the armamentarium available to the physician for thromboprophylaxis in non-valvular AF (NVAF) patients. This review describes the characteristics of NOACs, analyzing aspects related to their use in the thromboprophylaxis of NVAF patients. It also discusses how to optimize NOAC therapy in specific clinical conditions, such as renal or liver impairment, and concomitant assumption of drugs potentially interfering with NOACs action. Finally, it focuses on NOAC-related bleeding management in the setting of non cardiac surgery or radiofrequency catheter ablation of NVAF. PMID- 25833180 TI - Oblique venotomy with parallelogram anastomosis in sequential bypass grafting. AB - The proximal vein graft is incised obliquely and anastomosed to the coronary artery to ensure that the proximal rim of the vein incision is adjusted to the lateral side of the coronary artery incision adjacent to the proximal rim. So the vein graft can be placed perpendicular to the coronary artery without kinking, and the anastomosis orifice can be made wider than those made with diamond anastomosis. Oblique venotomy with parallelogram anastomosis provides sufficient anastomotic flow, allows long incisions, and prevents kinking. PMID- 25833179 TI - Lipodystrophies: adipose tissue disorders with severe metabolic implications. AB - Lipodystrophy encompass a group of heterogeneous disorders consisting in marked reduction, absence, and/or the redistribution of adipose tissue. Lipodystrophy is frequently complicated with severe insulin resistance, diabetes, hyperlipidemia, and fatty liver. Anatomically, lipodystrophies can be partial or generalized. Etiologically, they can be congenital or acquired. Lipodystrophy diagnosis can be challenging, and it has been suggested that partial forms can be easily misdiagnosed as common central obesity with associated metabolic syndrome. Conventional insulin-sensitizing approaches usually fail to fully ameliorate insulin resistance in lipodystrophic patients. Leptin replacement is an approved therapy for the metabolic complications of congenital generalized lipodystrophy. Novel nutritional interventions are promising complementary approaches for treating lipodystrophy metabolic complications. PMID- 25833177 TI - Improved Long-Term Prognosis of Dilated Cardiomyopathy With Implementation of Evidenced-Based Medication - Report From the CHART Studies - . AB - BACKGROUND: Recent trends in the clinical characteristics, management and prognosis of dilated cardiomyopathy (DCM) remain to be examined in Japan. METHODS AND RESULTS: We compared 306 and 710 DCM patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 (2000-2005, n=1,278) and the CHART-2 (2006-present, n=10,219) Studies, respectively. Between the 2 groups of DCM patients, there were no significant differences in baseline characteristics. The prevalence of hypertension, dyslipidemia and diabetes mellitus were all significantly increased from the CHART-1 to the CHART-2 Study. The use of beta-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was significantly decreased in the CHART-2 Study. The 3-year mortality rate was significantly improved from 14% in the CHART-1 to 9% in the CHART-2 Study (adjusted HR, 0.60; 95% CI: 0.49-0.81; P=0.001). In particular, 3-year incidence of cardiovascular death was significantly decreased (adjusted HR, 0.26; 95% CI: 0.14-0.50, P<0.001), while that of HF admission was not (adjusted HR, 0.90; 95% CI: 0.59-1.37, P=0.632). The prognostic improvement was noted in patients with BNP <220 pg/ml, LVEF>40%, beta blocker use and aldosterone antagonist use. CONCLUSIONS: Long-term prognosis of DCM patients has been improved, along with the implementation of evidence-based medication in Japan. PMID- 25833182 TI - Generation of Lactococcus lactis capable of coexpressing epidermal growth factor and trefoil factor to enhance in vitro wound healing. AB - Epidermal growth factor (EGF) and trefoil factor 3 (TFF3) are peptides that actively support the restitution and repair of mucosal epithelial barriers. Previous studies have shown that TFF3 enhanced EGF effect in wound healing, suggesting that the combined application of the two factors may be advantageous in clinical tissue repair. Expression of multiple proteins in a single host is a desirable approach in a biotechnological process, allowing to reduce cost and increase production efficiency. The aim of the present study was to study the feasibility of coexpressing EGF and TFF3 in food grade bacteria, Lactococcus lactis (L. lactis). Using an expression construct allowing simultaneous translation of two separate recombinant peptides, we generated a L. lactis that coexpressed and secreted EGF and TFF3 dually (LL-ET). Western blot analysis revealed that LL-ET secreted 45-54 % more total recombinant peptides (EGF+TFF3) per flask fermentation and 21-37 % more total recombinant proteins in bioreactor fermentation compared to their single factor expressing L. lactis counterparts (LL-EGF and LL-TFF3, respectively). The resulted recombinant EGF and TFF3 showed enhancement in wound healing activity in vitro. Our data suggest that the dual expression and secretion of EGF and TFF3 by L. lactis effectively accelerated cell migration, demonstrating potential future oral application of L. lactis fermentation product containing dual factors or a cocktail of factors to potentially treat intestinal damage and inflammation. PMID- 25833181 TI - Bacterial expansins and related proteins from the world of microbes. AB - The discovery of microbial expansins emerged from studies of the mechanism of plant cell growth and the molecular basis of plant cell wall extensibility. Expansins are wall-loosening proteins that are universal in the plant kingdom and are also found in a small set of phylogenetically diverse bacteria, fungi, and other organisms, most of which colonize plant surfaces. They loosen plant cell walls without detectable lytic activity. Bacterial expansins have attracted considerable attention recently for their potential use in cellulosic biomass conversion for biofuel production, as a means to disaggregate cellulosic structures by nonlytic means ("amorphogenesis"). Evolutionary analysis indicates that microbial expansins originated by multiple horizontal gene transfers from plants. Crystallographic analysis of BsEXLX1, the expansin from Bacillus subtilis, shows that microbial expansins consist of two tightly packed domains: the N-terminal domain D1 has a double-psi beta-barrel fold similar to glycosyl hydrolase family-45 enzymes but lacks catalytic residues usually required for hydrolysis; the C-terminal domain D2 has a unique beta-sandwich fold with three co-linear aromatic residues that bind beta-1,4-glucans by hydrophobic interactions. Genetic deletion of expansin in Bacillus and Clavibacter cripples their ability to colonize plant tissues. We assess reports that expansin addition enhances cellulose breakdown by cellulase and compare expansins with distantly related proteins named swollenin, cerato-platanin, and loosenin. We end in a speculative vein about the biological roles of microbial expansins and their potential applications. Advances in this field will be aided by a deeper understanding of how these proteins modify cellulosic structures. PMID- 25833183 TI - Functional analysis of Trichoderma reesei CKIIalpha2, a catalytic subunit of casein kinase II. AB - Trichoderma reesei is the most important industrial cellulase-producing filamentous fungus. Although its molecular physiology has been investigated, the signal transduction pathways are not fully understood. In particular, the role of casein kinase II (CKII) is not yet clear. In this work, we carried out functional investigations on a catalytic subunit of CKII, CKIIalpha2. Comparison of the phenotypic features of T. reesei parent and Deltack2alpha2 strains showed significant changes following ck2alpha2 disruption. T. reesei Deltack2alpha2 form significantly smaller mycelial pellets in glucose-containing liquid minimum media, have shorter and fewer branch hyphae, produce smaller amounts of chitinases, produce more spores, show more robust growth on glucose-containing agar plates, and consume glucose at a significantly higher rate. Suggestions can be made that CKIIalpha2 governs chitinase expression, and the disruption of ck2alpha2 results in lower levels of chitinase production, leading to a weaker cell wall disruption capability, further resulting in weaker hyphal branching, which eventually leads to smaller mycelial pellets in liquid media. Further conclusions can be made that CKIIalpha2 is involved in repression of sporulation and glucose metabolism, which is consistent with the proposal that CKIIalpha2 represses global metabolism. These observations make the deletion of ck2alpha2 a potentially beneficial genetic disruption for T. reesei during industrial applications, as smaller mycelial pellets, more spores and more robust glucose metabolism are all desired traits for industrial fermentation. This work reports novel unique functions of a CKII catalytic subunit and is also the first genetic and physiological investigation on CKII in T. reesei. PMID- 25833184 TI - Modeling the evolution space of breakage fusion bridge cycles with a stochastic folding process. AB - Breakage-fusion-bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then 'unfolds' into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. Here we study the evolution space of breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are [Formula: see text] qualitatively distinct evolutions involving [Formula: see text] breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the process to show these evolutions are not equally likely, and also describe how amplicons become localized. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples. PMID- 25833185 TI - A geometric analysis of fast-slow models for stochastic gene expression. AB - Stochastic models for gene expression frequently exhibit dynamics on several different scales. One potential time-scale separation is caused by significant differences in the lifetimes of mRNA and protein; the ratio of the two degradation rates gives a natural small parameter in the resulting chemical master equation, allowing for the application of perturbation techniques. Here, we develop a framework for the analysis of a family of 'fast-slow' models for gene expression that is based on geometric singular perturbation theory. We illustrate our approach by giving a complete characterisation of a standard two stage model which assumes transcription, translation, and degradation to be first order reactions. In particular, we present a systematic expansion procedure for the probability-generating function that can in principle be taken to any order in the perturbation parameter, allowing for an approximation of the corresponding propagator probabilities to that same order. For illustrative purposes, we perform this expansion explicitly to first order, both on the fast and the slow time-scales; then, we combine the resulting asymptotics into a composite fast slow expansion that is uniformly valid in time. In the process, we extend, and prove rigorously, results previously obtained by Shahrezaei and Swain (Proc Natl Acad Sci USA 105(45):17256-17261, 2008) and Bokes et al. (J Math Biol 64(5):829 854, 2012; J Math Biol 65(3):493-520, 2012). We verify our asymptotics by numerical simulation, and we explore its practical applicability and the effects of a variation in the system parameters and the time-scale separation. Focussing on biologically relevant parameter regimes that induce translational bursting, as well as those in which mRNA is frequently transcribed, we find that the first order correction can significantly improve the steady-state probability distribution. Similarly, in the time-dependent scenario, inclusion of the first order fast asymptotics results in a uniform approximation for the propagator probabilities that is superior to the slow dynamics alone. Finally, we discuss the generalisation of our geometric framework to models for regulated gene expression that involve additional stages. PMID- 25833186 TI - Immuno-epidemiology of a population structured by immune status: a mathematical study of waning immunity and immune system boosting. AB - When the body gets infected by a pathogen the immune system develops pathogen specific immunity. Induced immunity decays in time and years after recovery the host might become susceptible again. Exposure to the pathogen in the environment boosts the immune system thus prolonging the time in which a recovered individual is immune. Such an interplay of within host processes and population dynamics poses significant challenges in rigorous mathematical modeling of immuno epidemiology. We propose a framework to model SIRS dynamics, monitoring the immune status of individuals and including both waning immunity and immune system boosting. Our model is formulated as a system of two ordinary differential equations (ODEs) coupled with a PDE. After showing existence and uniqueness of a classical solution, we investigate the local and the global asymptotic stability of the unique disease-free stationary solution. Under particular assumptions on the general model, we can recover known examples such as large systems of ODEs for SIRWS dynamics, as well as SIRS with constant delay. PMID- 25833187 TI - From invasion to latency: intracellular noise and cell motility as key controls of the competition between resource-limited cellular populations. AB - In this paper we analyse stochastic models of the competition between two resource-limited cell populations which differ in their response to nutrient availability: the resident population exhibits a switch-like response behaviour while the invading population exhibits a bistable response. We investigate how noise in the intracellular regulatory pathways and cell motility influence the fate of the incumbent and invading populations. We focus initially on a spatially homogeneous system and study in detail the role of intracellular noise. We show that in such well-mixed systems, two distinct regimes exist: In the low (intracellular) noise limit, the invader has the ability to invade the resident population, whereas in the high noise regime competition between the two populations is found to be neutral and, in accordance with neutral evolution theory, invasion is a random event. Careful examination of the system dynamics leads us to conclude that (i) even if the invader is unable to invade, the distribution of survival times, PS(t), has a fat-tail behaviour (PS(t) ~ t(-1)) which implies that small colonies of mutants can coexist with the resident population for arbitrarily long times, and (ii) the bistable structure of the invading population increases the stability of the latent population, thus increasing their long-term likelihood of survival, by decreasing the intensity of the noise at the population level. We also examine the effects of spatial inhomogeneity. In the low noise limit we find that cell motility is positively correlated with the aggressiveness of the invader as defined by the time the invader takes to invade the resident population: the faster the invasion, the more aggressive the invader. PMID- 25833188 TI - Should magnesium sulfate be administered to women with mild pre-eclampsia? A systematic review of published reports on eclampsia. AB - AIM: Magnesium sulfate is an evidence-based anticonvulsant drug used to prevent and control eclampsia. Controversy persists on routine administration of magnesium sulfate in cases of pre-eclampsia without severe features. Our objective was to assess the pattern of blood pressure and maternal symptoms preceding eclamptic seizure based on the current published work. MATERIAL AND METHODS: A comprehensive computer-based publication search was conducted in the African Journals Online, Google scholar, HINARI, PubMed, and MEDLINE databases and the Cochrane library to identify descriptive study reports for blood pressure, severity symptoms or stage of pregnancy during convulsion in women with eclampsia. RESULTS: A total of 59 publications were eligible for this review. Overall, 21,149 eclamptic women from 26 countries were included for the interest of one or more of the selected variables. Out of 18,488 eclamptic women, the proportion of antepartum, intrapartum and post-partum eclampsia was 59%, 20% and 21%, respectively. Out of 3443 eclamptic women, 25% were normotensive; 20% had mild-to-moderate hypertension; 32% had severe hypertension; and 21% were hypertensive but unclassified. Out of 2163 eclamptic women, 66% and 27% had a headache and visual disturbance, respectively, preceding the occurrence of convulsion. Out of 2053 eclamptic women, 25% had epigastric area pain, and out of 1092 women with eclampsia, 25% were asymptomatic. CONCLUSION: Although eclampsia is known to result from severe pre-eclampsia with or without organ function derangement, this review has revealed that a significant number of eclamptic women had either normal blood pressure or mild-to-moderate hypertension immediately before seizure. The findings are apparently in support of initiating magnesium sulfate prophylaxis to all women with mild pre-eclampsia. PMID- 25833189 TI - Interactions between default mode and control networks as a function of increasing cognitive reasoning complexity. AB - Successful performance of challenging cognitive tasks depends on a consistent functional segregation of activity within the default-mode network, on the one hand, and control networks encompassing frontoparietal and cingulo-opercular areas on the other. Recent work, however, has suggested that in some cognitive control contexts nodes within the default-mode and control networks may actually cooperate to achieve optimal task performance. Here, we used functional magnetic resonance imaging to examine whether the ability to relate variables while solving a cognitive reasoning problem involves transient increases in connectivity between default-mode and control regions. Participants performed a modified version of the classic Wason selection task, in which the number of variables to be related is systematically varied across trials. As expected, areas within the default-mode network showed a parametric deactivation with increases in relational complexity, compared with neural activity in null trials. Critically, some of these areas also showed enhanced connectivity with task positive control regions. Specifically, task-based connectivity between the striatum and the angular gyri, and between the thalamus and right temporal pole, increased as a function of relational complexity. These findings challenge the notion that functional segregation between regions within default-mode and control networks invariably support cognitive task performance, and reveal previously unknown roles for the striatum and thalamus in managing network dynamics during cognitive reasoning. PMID- 25833191 TI - Expression pattern of key microRNAs in patients with newly diagnosed chronic myeloid leukemia in chronic phase. AB - INTRODUCTION: Chronic myeloid leukemia (CML) is caused by reciprocal translocation in hematopoietic stem cells (HSCs). This translocation forms the BCR-ABL1 oncogene, which alters several signaling pathways that control malignancy. CML has three phases: chronic, accelerated, and blast crisis. The microRNAs (miRNAs or miRs) are noncoding RNAs that downregulate their target gene by targeting 3' UTR of mRNA or through translational inhibition. It has been shown that miRNAs regulate many biological processes, and dysregulation of these regulatory RNAs is involved in disease development, particularly in cancer. The important role of miRNAs as therapeutic agents and biomarkers has been demonstrated in CML patients at different phases of the disease. METHODS: Stem loop reverse transcription polymerase chain reaction was used to characterize differentially expressed miRNAs of leukocytes in the peripheral blood of 50 newly diagnosed CML patients in chronic phase. RESULTS: Some onco-miRNAs were found to be downregulated (miR-155 and miR-106), and some tumor suppressor miRs (miR-16-1, miR-15a, miR-101, miR-568) were upregulated. CONCLUSION: These results show that very few miRNAs alone would be good candidates for CML diagnosis independently of conflicting results, but together could be an additional tool for CML diagnosis. Moreover, miRNAs might be good candidates for prognosis prediction and CML therapy. PMID- 25833190 TI - Disease-Associated Single-Nucleotide Polymorphisms From Noncoding Regions in Juvenile Idiopathic Arthritis Are Located Within or Adjacent to Functional Genomic Elements of Human Neutrophils and CD4+ T Cells. AB - OBJECTIVE: Juvenile idiopathic arthritis (JIA) is considered a complex disease in which the environment interacts with inherited genes to produce a phenotype that shows broad interindividual variability. Twenty-four regions of genetic risk for JIA were identified in a recent genome-wide association study (GWAS); however, as is typical of the results of GWAS, most of the regions of genetic risk (22 of 24) were in noncoding regions of the genome. This study was undertaken to identify functional elements (other than genes) that might be located within the regions of genetic risk. METHODS: We used paired-end RNA sequencing to identify noncoding RNAs (ncRNAs) located within 5 kb of disease-associated single-nucleotide polymorphisms (SNPs). In addition, we used chromatin immunoprecipitation (ChIP) followed by sequencing to identify epigenetic marks associated with enhancer function (H3K4me1 and H3K27ac) in human neutrophils to determine whether enhancer associated histone marks were enriched in the linkage disequilibrium blocks that encompassed the 22 SNPs identified in the GWAS. RESULTS: In human neutrophils, we identified H3K4me1 and/or H3K27ac marks in 15 of the 22 regions previously identified as risk loci for JIA. In CD4+ T cells, 18 regions had H3K4me1 and/or H3K27ac marks. In addition, we identified ncRNA transcripts at the rs4705862 and rs6894249 loci in human neutrophils. CONCLUSION: Much of the genetic risk for JIA lies within or adjacent to regions of neutrophil and CD4+ T cell genomes that carry epigenetic marks associated with enhancer function and/or ncRNA transcripts. These findings are consistent with the hypothesis that JIA is fundamentally a disorder of gene regulation that includes both the innate and the adaptive immune system. Elucidating the specific roles of these noncoding elements within leukocyte genomes will be critical to our understanding of JIA pathogenesis. PMID- 25833192 TI - Prevalence of high-level positivity of anti-parietal cell antibodies in Turkish population. PMID- 25833193 TI - Performance of the Osteoporosis Self-Assessment Tool for Asians (OSTA) in Screening Osteoporosis Among Middle-Aged and Old Women in the Chengdu Region of China. AB - The purpose of this study was to assess the performance of an osteoporosis self assessment tool for Asians (OSTA) for screening middle-aged and old healthy women in the Chengdu region of China. OSTA scores were used to evaluate the effect of age on the development of osteoporosis. A total of 15,752 healthy women older than 40 yr, who reside in the Chengdu region, were assigned to 9 age groups divided by 5-yr intervals. Bone mineral density of the lumbar vertebrae, L1-L4, and the left hip was measured with a GE Lunar Prodigy advance dual-energy X-ray absorptiometry system (GE Healthcare, Cincinnati, OH). All subjects were classified into 3 categories according to OSTA cutoff values. The OSTA values used to define the categories were >=-1, >-4 and <-1, and <=-4. The accuracy of the OSTA index was compared with T-scores measured by dual-energy X-ray absorptiometry at various skeletal sites. All statistical analyses were performed using SPSS, version 17.0 (SPSS, Inc., Chicago, IL). The detection rate of osteoporosis and osteopenia at the lumbar vertebrae and the femur was found to increase with age. Furthermore, the sensitivity of OSTA value for detection of osteoporosis also gradually enhanced with subject age. In contrast, the specificity gradually decreased with age. The sensitivity and negative predictive value of the OSTA index for detecting osteoporosis gradually increased with higher OSTA cutoff values, and the specificity and positive predictive value appeared to gradually decline. It was concluded that the OSTA is a useful screening tool to detect osteoporosis in middle-aged and old women in the Chengdu region of China. Furthermore, specific OSTA cutoff values should be selected for screening individuals who belong to different age groups. PMID- 25833194 TI - Response to the Letter to the Editor on "Appropriate Osteoporosis Treatment by Family Physicians in Response to FRAX vs CAROC Reporting: Results From a Randomized Controlled Trial". PMID- 25833195 TI - Intraperitoneal bleomycin for sarcomatosis-related malignant ascites: Prolonged symptom relief. PMID- 25833196 TI - Cinnamaldehyde derivative (CB-PIC) sensitizes chemo-resistant cancer cells to drug-induced apoptosis via suppression of MDR1 and its upstream STAT3 and AKT signalling. AB - BACKGROUND/AIMS: Our group reported that cinnamaldehyde derivative, (E)-4-((2-(3 oxopop-1-enyl)phenoxy)methyl)pyridinium malonic acid (CB-PIC) induced apoptosis in hypoxic SW620 colorectal cancer cells via activation of AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase (ERK). Herein, sensitizing effect of CB-PIC was investigated in resistant cancer cells such as paclitaxel (PT) resistant lung cancer cells (H460/PT), and Adriamycin (Adr) resistant breast cancer (MCF7/Adr) and colon cancer (HCT15/cos) cells. METHODS: Various drug resistant cell lines were treated with CB-PIC, and the signalling pathway and functional assay were explored by Western blot, Rhodamine assay, FACS, RT-PCR and MTT assay. RESULTS: We found that CB-PIC effectively exerted cytotoxicity, increased sub G1 population and the cleaved form of poly (ADP ribose) polymerase (PARP) and caspase 9 in drug resistant cancer cells. Furthermore, CB-PIC sensitized resistant cancer cells to adriamycin via downregulation of survival proteins such as survivin, Bcl-xL and Bcl-2, along with MDR1 suppression leading to accumulation of drug in the intracellular region. Of note, CB-PIC transcriptionally decreased MDR1 expression via suppression of STAT3 and AKT signalling in three resistant cancer cells with highly expressed P-glycoprotein. Nonetheless, CB-PIC did not affect transport activity of P-glycoprotein in a short time efflux assay, while epigallocatechin gallate (EGCG) accumulated Rhodamine 123 into intracellular region of cell by direct inhibition of MDR1 transport activity. CONCLUSIONS: These data demonstrate that CB-PIC suppresses the P-glycoprotein expression through inhibition of STAT3 and AKT signalling to overcome drug resistance in chemo-resistant cancer cells as a potent chemotherapeutic sensitizer. PMID- 25833197 TI - Immunophenotypic profile and increased risk of hospital admission for infection in infants born to female kidney transplant recipients. AB - Children born to female kidney recipients are exposed to immunosuppressive drugs during gestation. Little is known about their immune system at birth or in the long term. Twenty-eight children born to female kidney recipients and 40 full term children born to healthy mothers were evaluated. T, B, NK, NKT, gammadeltaT cells were assessed by flow cytometry and functional evaluation of T and dendritic cells after in vitro activation was performed at birth and at 8 months of age. At birth, infants born to female kidney recipients showed lower numbers of CD4+ T, NKT and intense reduction of B cells (median cells/mm(3) , transplant: 153.7 X control: 512.4; p < 0.001). There was also a reduced percentage of activated CD8+ T and of CD4+ regulatory T cells. Activated memory and exhausted memory B cells showed higher percentages among children exposed to immunosuppressors when compared to control group. At 8 months, most immune alterations were no longer observed, but four children still had low numbers of some lymphocyte subsets at this age. Children born to female kidney recipients had 4.351 (95% CI: 1.026-15.225; p = 0.046) higher risk of hospital admission in the first months of life-some, with severe clinical manifestations-than those born to healthy women. PMID- 25833200 TI - Self-rolled nanotubes with controlled hollow interiors by patterned grafts. AB - By patterning surface grafts, we propose a simple and systematic method to form tubular structures for which two-dimensional grafted sheets are programmed to self-roll into hollow tubes with a desired size of the internal cavity. The repeating pattern of grafts utilizing defect sites causes anisotropy in the surface-grafted nanosheet, which spontaneously transforms into a curved secondary architecture and, thus, becomes a potential tool with which to form and control the curvature of nanotubes. In fact, the degree and the type of graft defect allow control of the internal cavity size and shape of the resulting nanotubes. By performing dissipative particle dynamics simulations on coarse-grained sheets, we found that the inner cavity size is inversely proportional to the graft-defect density, the difference in the graft densities between the two surface sides of the layer, regardless of whether the defects are patterned or random. While a random distribution of defects gives rise to a non-uniform local curvature and often leads to twisted tubes, regular patterns of graft defects ensure uniform local curvature throughout the sheet, which is important to generate monodisperse nanotubes. At a low graft-defect density, the sheet-to-tube transformation is governed by the layer anisotropy, which induces spontaneous scrolling along the long edge of the sheet, resulting in short tubes. Thus, the curve formation rate and the cavity diameter are independent of the pattern of the graft defects. At a high graft-defect density, however, the scroll direction owing to the graft pattern may conflict with that due to the layer anisotropy. To produce monodisperse nanotubes, two factors are important: (1) a graft-defect pattern parallel to the short edge of the layer, and (2) a graft-defect area wider than half of the graft coil length. PMID- 25833198 TI - Guggulsterone and bexarotene induce secretion of exosome-associated breast cancer resistance protein and reduce doxorubicin resistance in MDA-MB-231 cells. AB - Many breast cancer cells acquire multidrug resistance (MDR) mediated by ABC transporters such as breast cancer resistance protein (BCRP/ABCG2). Here we show that incubation of human breast cancer MDA-MB-231 cells with farnesoid X receptor antagonist guggulsterone (gug) and retinoid X receptor agonist bexarotene (bex) elevated ceramide, a sphingolipid known to induce exosome secretion. The gug+bex combination reduced cellular levels of BCRP to 20% of control cells by inducing its association and secretion with exosomes. Exogenous C6 ceramide also induced secretion of BCRP-associated exosomes, while siRNA-mediated knockdown or GW4869 mediated inhibition of neutral sphingomyelinase 2 (nSMase2), an enzyme generating ceramide, restored cellular BCRP. Immunocytochemistry showed that ceramide elevation and concurrent loss of cellular BCRP was prominent in Aldefluor-labeled breast cancer stem-like cells. These cells no longer excluded the BCRP substrate Hoechst 33342 and showed caspase activation and apoptosis induction. Consistent with reduced BCRP, ABC transporter assays showed that gug+bex increased doxorubicin retention and that the combination of gug+bex with doxorubicin enhanced cell death by more than fivefold. Taken together, our results suggest a novel mechanism by which ceramide induces BCRP secretion and reduces MDR, which may be useful as adjuvant drug treatment for sensitizing breast cancer cells and cancer stem cells to chemotherapy. PMID- 25833199 TI - Improving Human Milk and Breastfeeding Practices in the NICU. AB - OBJECTIVE: To determine if systematic implementation of the Spatz Ten Steps for Promoting and Protecting Breastfeeding for Vulnerable Infants (Ten Steps) would result in an improvement in the percentage of infants receiving mother's own milk (MOM) at initiation of feedings and at hospital discharge. DESIGN: Continuous quality improvement (QI) process. SETTING: Urban, 82-bed, Level-III NICU. PATIENTS: Very- low-birth-weight (VLBW) infants weighing fewer than 1500 grams. INTERVENTION: The Ten Step method was implemented during a 3-year period. MEASUREMENTS: Process measurements included percentage of VLBW infants receiving MOM at initiation of feeds, number of mothers of VLBW infants with hospital-grade electric breast pump at hospital discharge, and number of mothers of VLBW infants initiating pumping within 6 hours of delivery. Outcome measurements included percentage of VLBW infants with any human milk at discharge to home and parent satisfaction with nurses' support of mother's efforts to breastfeed. Balancing measurements included percentage of VLBW infants at less than the third percentile for growth on the Fenton growth chart at discharge and receiving pasteurized donor milk (PDM). RESULTS: Significant improvements were achieved in the percentages of mothers expressing their milk within 6 hours of delivery, infants receiving MOM at initiation of feeds, and mothers with a hospital-grade pump at discharge. Improvements in these processes resulted in increased parent satisfaction with nurses' support of breastfeeding and a 3.1-fold greater odds of the VLBW infant receiving MOM at discharge in 2013 compared to 2010 (odds ratio [OR]= 3.01, 95% confidence interval [CI] [1.75, 5.17], p < .001). Despite an increase in the use of MOM, there was not a significant increase in VLBW infants discharged at less than the third percentile for growth, and initiation of PDM did not negatively affect the percentage of VLBW infants with any human milk at discharge. CONCLUSIONS: Implementation of the Ten Steps method using QI methodology resulted in significantly improved rates of use of MOM at initiation of feeds and at hospital discharge. PMID- 25833201 TI - Epidemiology of keloids in normally pigmented Africans and African people with albinism: population-based cross-sectional survey. PMID- 25833202 TI - Are preoperative platelet-lymphocyte and neutrophil-lymphocyte ratio prognostic factors for patients with esophageal squamous cell cancer? PMID- 25833203 TI - Spino-pelvic alignment influences disc hydration properties after AIS surgery: a prospective MRI-based study. AB - PURPOSE: To analyze the disc hydration and volumetric changes of the intervertebral disc after scoliosis surgery depending on the sagittal spino pelvic organization. METHODS: We conducted a prospective MRI study in 45 patients with surgically treated adolescent idiopathic scoliosis (AIS) with a minimum 2 year follow-up. Fusion ended at L1 (n = 13), L2 (n = 14), L3 (n = 11) or L4 (n = 7). Total disc (Vd) and nucleus volumes (Vn) were extrapolated from 3D reconstruction using a custom-made image processing software (Biomechlab, Toulouse, France). Nucleus and external disc contours were semi-automatically detected on turbo spin echo T2-weighted sequence joined 3-mm sagittal cuts. Disc hydration was extrapolated from the nucleus-disc volume ratio (Vn/Vd). Radiographic sagittal parameters were measured pre- and post-operatively on full spine standing views (pelvic incidence, sacral slope, L1S1 lumbar lordosis). Lumbo-pelvic congruity was calculated by the ratio LL/SS according to Stagnara. RESULTS: Mean PI of the cohort was 55 degrees (34 degrees -85 degrees ). After surgical correction, lumbar lordosis was slightly increased by 3 degrees (p = 0.02) decreasing lumbo-pelvic congruity from 1.37 to 1.27 (p < 0.01). When pelvic incidence was less than 55 degrees (mean PI 46 degrees ), nucleus volumes have increased on average by 30 % compared to the preoperative status in the unfused lumbar discs, while the total disc volumes has remained stable. Five-year follow up (n = 13) confirmed the constant improvement of the disc hydration ratio. When PI was high (mean PI 64 degrees ), volumetric changes were very mild and significant changes in nucleus volumes and disc hydration ratio concerned only the intermediate lumbar levels (L2L3, L3L4 and L4L5). CONCLUSIONS: This prospective MRI study showed a significant and sustainable improvement in T2 hypersignal of the disc, indirectly indicating improvement of disc hydration content after AIS surgery. Analysis of disc volumetric changes according to the pelvic incidence suggests that these changes are under the influence of the sagittal spino-pelvic alignment. PI seems to play a key role in the homeostasis of the discs under fusion and should be taken into account for preoperative planning. The restoration of the lumbo-pelvic congruence may help to limit early degenerative changes in the free-motion segment discs after AIS surgery. Hydration content was less sensitive to surgery when PI was high, suggesting higher shear stress in the lower discs. Longer follow-up is required to confirm this hypothesis. PMID- 25833204 TI - Systematic review of observational studies reveals no association between low back pain and lumbar spondylolysis with or without isthmic spondylolisthesis. AB - PURPOSE: The hypothesis that spondylolysis (SL) and/or isthmic spondylolisthesis (IS) cause low back pain (LBP) is widely accepted representing surgical indication in symptomatic cases. If SL/IS cause LBP, individuals with these conditions should be more prone to LBP than those without SL/IS. Therefore, the goal of the study was to assess whether the published primary data demonstrate an association between SL/IS and LBP in the general adult population. METHODS: Systematic review of published observational studies to identify any association between SL/IS and LBP in adults. The methodological quality of the cohort and case-control studies was evaluated using the Newcastle-Ottawa scale. RESULTS: Fifteen studies met inclusion criteria (one cohort, seven case-control, seven cross-sectional). Neither the cohort study nor the two highest-quality case control studies detected an association between SL/IS and LBP; the same is true for the remaining studies. CONCLUSIONS: There is no strong or consistent association between SL/IS and LBP in epidemiological studies of the general adult population that would support a hypothesis of causation. It is possible that SL/IS coexist with LBP, and observed effects of surgery and other treatment modalities are primarily due to benign natural history and nonspecific treatment effects. We conclude that traditional surgical practice for the adult general population, in which SL/IS is assumed to be the cause of non-radicular LBP whenever the two coexist, should be reconsidered in light of epidemiological data accumulated in recent decades. PMID- 25833206 TI - [Atopic dermatitis in children. New aspects]. AB - Atopic dermatitis in childhood is controlled by adaequate topical treatment in the majority of cases. Severe manifestations, recurrent superinfections, associated food allergy and psychosocial aspects of a chronic disease in childhood need special consideration. Furthermore, prevention is an important issue in this age group. The following article focuses on new aspects with repercussions on the management of childhood atopic dermatitis and possible implications for the future. PMID- 25833205 TI - Molecular detection of hepatitis E virus in sheep from southern Xinjiang, China. AB - Hepatitis E virus (HEV) is a causative agent of infectious hepatitis in animals and humans both in developing and developed countries. Here, we collected 500 sheep sera and 75 raw sheep liver samples from a slaughterhouse in the southern part of the Xinjiang region, China, along with 26 sera of butchers from the same slaughterhouse. All serum samples were tested for anti-HEV antibody by enzyme linked immunosorbent assay. Both serum and liver samples were evaluated for the presence of HEV RNA by nested polymerase chain reaction targeting partial nucleotide sequences of open reading frame 2 (ORF2). The results indicate that sheep seroprevalence was 35.20 % (176/500) and that four of the 75 (5.3 %) sheep livers showed detectable amounts of HEV RNA. The seroprevalence of the butchers was 57.7 % (15/26). The four amplicons shared 97.8-100 % nucleotide sequence identity and had pairwise sequence identities of 81.6-85.3 %, 84.2-85.3 %, 82.1 85.3 % and 84.7-97.9 % with the corresponding regions of genotypes 1, 2, 3 and 4 of HEV, respectively. A phylogenetic tree was constructed based on alignments of an amplified 186-bp ORF2 sequence and corresponding reference strains. The analysis showed that the four sheep strains detected in our study formed a lineage within a genotype 4 cluster that contains hb-3, bjsw1, T1, swCH189 and swCH25, all of which belong to genotype 4, subtype 4d. The results indicated a high level of seroconversion in sheep and suggested that sheep liver may be a source of foodborne HEV infection in humans. PMID- 25833207 TI - Developing preceptorship through action research: part 2. AB - Clinical preception in practice plays a significant role in the education of both Registered Nurses and practical nurses. This study presents the evaluation of an interprofessional research and development project (2009-2103) on clinical preceptorship between two universities of applied sciences, two vocational institutes and four healthcare organisations in western Finland. The research question was as follows: How did the participants evaluate the process and outcomes of developing preceptorship through an action-research approach? The primary target group consisted of professionals within the healthcare sector and nursing teachers at the universities of applied sciences and the vocational institutes. The five units represented in the healthcare organisations functioned as clinical practice placements for both nursing and practical nursing students, with Registered Nurses and practical nurses acting as their preceptors. Each unit developed a unique preceptorship model to answer their specific needs. The models were implemented and tested during one academic year followed by a quantitative (a 4-point scale) and qualitative evaluation of the process. The models are presented in another article, and the evaluation results are presented in this article. The evaluation showed that preceptorship has become an important and accepted part of work, including the practice of starting any preception at a unit with a thorough introduction. The project's emphasis on critical thinking, reflection and focus on ethics were valued by the staff. Pedagogical further education should be arranged on a regular basis to strengthen the knowledge base of the preceptors. Furthermore, enough time for preceptorship should be allocated, as it is a pedagogical duty. The implication of this project is that more cooperation between different stake holders is needed, in order to narrow the gap between theory and praxis. PMID- 25833208 TI - CRLX101, an investigational camptothecin-containing nanoparticle-drug conjugate, targets cancer stem cells and impedes resistance to antiangiogenic therapy in mouse models of breast cancer. AB - Antiangiogenic therapies inhibit the development of new tumor blood vessels, thereby blocking tumor growth. Despite the advances in developing antiangiogenic agents, clinical data indicate that these drugs have limited efficacy in breast cancer patients. Tumors inevitably develop resistance to antiangiogenics, which is attributed in part to the induction of intra-tumoral hypoxia and stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha), a transcription factor that promotes tumor angiogenesis, invasion, metastasis, and cancer stem cell (CSC) self-renewal. Here, we tested whether inhibiting HIF-1alpha can reverse the stimulatory effects of antiangiogenic-induced hypoxia on breast CSCs. Breast cancer cells grown under hypoxic conditions were treated with the dual topoisomerase-1 (TOPO-1) and HIF-1alpha inhibitor camptothecin and assessed for their CSC content. In a preclinical model of breast cancer, treatment with bevacizumab was compared to the combination treatment of bevacizumab with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload or CRLX101 monotherapy. While exposure to hypoxia increased the number of breast CSCs, treatment with CPT blocked this effect. In preclinical mouse models, concurrent administration of CRLX101 impeded the induction of both HIF-1alpha and CSCs in breast tumors induced by bevacizumab treatment. Greater tumor regression and delayed tumor recurrence were observed with the combination of these agents compared to bevacizumab alone. Tumor reimplantation experiments demonstrated that the combination therapy effectively targets the CSC populations. The results from these studies support the combined administration of dual TOPO-1- and HIF-1alpha targeted agents like CRLX101 with antiangiogenic agents to increase the efficacy of these treatments. PMID- 25833209 TI - Prognostic associations of 25 hydroxy vitamin D in NCIC CTG MA.21, a phase III adjuvant randomized clinical trial of three chemotherapy regimens in high-risk breast cancer. AB - Low vitamin D levels have been associated with poor breast cancer outcomes in observational studies. We examined the association of vitamin D blood levels with relapse-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) in the MA.21 randomized clinical trial. Fasting blood was collected pre-chemotherapy in 934/2104 (44.4 %) of subjects; 25 hydroxy vitamin D was measured (radioimmunoassay, Diasorin) in one batch. Vitamin D was assessed as a transformed continuous factor, and categorically (quartiles and clinical classifications). Univariate and multivariate prognostic analyses (adjusted for treatment, stratification factors, and baseline imbalances) were performed using Cox models. Most patients were young (median 47.8 years), white (91.6 %) and premenopausal (69.4 %) with grade III (52 %), HER2 negative or missing (89.5 %), ER positive (61.9 %), T1-2 (89.4 %), N + (72.7 %) breast cancer. Compared to the full population, those with vitamin D levels were more likely to be white, PS 1 or 2, to have undergone mastectomy, and to have an ER + tumor. Mean vitamin D was 69.7 nmol/L (27.9 ng/ml) and did not vary by tumor subtype. The majority (80.5 %) had levels >50 nmol/L (20 ng/ml), considered adequate by Institute of Medicine. Continuous vitamin D was not multivariately associated with RFS, BCSS, or OS (p = 0.36, 0.26, 0.33, respectively); categorical vitamin D was also not associated with outcome. Vitamin D associations with RFS did not differ within ER/HER2 subgroups. There was no evidence that vitamin D blood level was associated with RFS, BCSS, and OS in MA.21; the majority of subjects had adequate vitamin D levels at study entry. PMID- 25833210 TI - Two PALB2 germline mutations found in both BRCA1+ and BRCAx familial breast cancer. AB - Partner and localizer of BRCA2 (PALB2), plays an important functional role in DNA damage repair. Recent studies indicate that germline mutations in PALB2 predispose individuals to a high risk of developing familial breast cancer. Therefore, comprehensive identification of PALB2 germline mutations is potentially important for understanding their roles in tumorigenesis and for testing their potential utility as clinical targets. Most of the previous studies of PALB2 have focused on familial breast cancer cases with normal/wild-type BRCA1 and BRCA2 (BRCAx). We hypothesize that PALB2 genetic mutations also exist in individuals with BRCA mutations (BRCA+). To test this hypothesis, PALB2 germline mutations were screened in 107 exome data sets collected from familial breast cancer families who were either BRCA1+ or BRCAx. Two novel heterozygous mutations predicted to alter the function of PALB2 were identified (c.2014G>C, p.E672Q and c.2993G>A, p.G998E). Notably, both of these mutations co-existed in BRCA1+ and BRCA1x families. These studies show that mutations in PALB2 can occur independent of the status of BRCA1 mutations, and they highlight the importance to include BRCA1+ families in PALB2 mutation screens. PMID- 25833212 TI - Erratum to: recurrent mutation testing of BRCA1 and BRCA2 in Asian breast cancer patients identify carriers in those with presumed low risk by family history. PMID- 25833211 TI - PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers. AB - Previous studies have shown that basal breast cancers, which may have an inherent "BRCAness" phenotype and sensitivity to inhibitors of poly (ADP-Ribose) polymerase (PARP), express elevated levels of PARP1. Our lab recently reported that HER2+ breast cancers also exhibit sensitivity to PARP inhibitors (PARPi) by attenuating the NF-kappaB pathway. In this study, we assessed PARP1 and phospho p65, a marker of activated NF-kappaB levels in human breast cancer tissues. PARP1 and PARP2 copy number, mRNA, and protein expression was assessed by interrogating the PAM-50 defined breast cancer patient set from the TCGA using cBioPortal. PARP1 and phospho-p65 immunohistochemistry and correlation to clinical parameters was conducted using 307 primary breast cancer specimens (132 basal, 82 luminal, 93 HER2+) through univariate and multivariate analyses. In the PAM50 breast cancer data set, PARP1 and 2 expression was altered in 24/58 (41 %) HER2+, 32/81 (40 %) basal, and 75/324 (23 %) luminal A/B breast cancer patients. This correlated with a statistically significant increase in PARP1 protein levels in HER2+ and basal but not luminal breast cancers (p = 0.003, p = 0.027, p = 0.289, respectively). No change in PARP2 protein level was observed. Interestingly, using breast cancer specimens from 307 patients, HER2 positivity correlated with elevated PARP1 expression (p < 0.0001) and was three times more likely than HER2 negative breast cancers to exhibit high PARP1 levels. No significant differences were noted between race, ER status, or PR status for PARP1 expression. Additionally, we found a significant correlation between HER2 status and phospho p65 expression (p < 0.0001). Lastly, a direct correlation between PARP1 and phospho-p65 (p < 0.0001) was noted. These results indicate a potential connection between HER2, PARP1, and phospho-p65. Furthermore, these data suggest that the PARPi sensitivity we previously observed in HER2+ breast cancer cells may be due to elevated PARP1 expression. PMID- 25833214 TI - Immunotherapy: A triple blow for cancer. PMID- 25833213 TI - Quantum dots-based tissue and in vivo imaging in breast cancer researches: current status and future perspectives. AB - As the most common malignant tumor for females, breast cancer (BC) is a highly heterogeneous disease regarding biological behaviors. Precisely targeted imaging on BC masses and biomarkers is critical to BC detection, treatment, monitoring, and prognostic evaluation. As an important imaging technique, quantum dots (QDs) based imaging has emerged as a promising tool in BC researches owe to its outstanding optical properties. However, few reviews have been specifically devoted to discussing applications of QDs-based imaging in BC researches. This review summarized recent promising works in QDs-based tissue and in vivo imaging for BC studies. Physicochemical and optical properties of QDs and its potential applications were briefly described first. Then QDs-based imaging studies in BC were systematically reviewed, including tissue imaging for studying biomarkers interactions, and evaluating prognostic biomarkers, in vivo imaging for mapping axillary lymphatic system, showing BC xenograft tumor, and detecting BC metastases. At last, the future perspectives with special emphasis on the potential clinical applications have also been discussed. Potential applications of QDs-based imaging on clinical BC in the future are mainly focused on tissue study, especially in BC molecular pathology due to its optimal optical properties and quantitative information capabilities on multiple biomarkers. PMID- 25833215 TI - Immunotherapy: Primed for a response. PMID- 25833216 TI - Alkaloid venom weaponry of three Megalomyrmex thief ants and the behavioral response of Cyphomyrmex costatus host ants. AB - Social parasites exploit other societies by invading and stealing resources. Some enter protected nests using offensive chemical weaponry made from alkaloid-based venom. We characterized the venoms of three Megalomyrmex thief ant species (M. mondabora, M. mondaboroides, and M. silvestrii) that parasitize the fungus growing ants, and developed an ethogram to describe host ant reactions to raiding M. mondaboroides and M. silvestrii parasites. We compared piperidine, pyrrolidine, and pyrolizidine venom alkaloid structures with synthetic samples from previous studies, and describe the novel stereochemistry of trans 2-hexyl-5 [8-oxononyl]-pyrrolidine (3) from M. mondabora. We showed that workers of Cyphomyrmex costatus, the host of M. mondaboroides and M. silvestrii, react to a sting by Megalomyrmex parasites mainly with submissive behavior, playing dead or retreating. Host submission also followed brief antennal contact. The behavior of C. costatus ants observed in this study was similar to that of Cyphomyrmex cornutus, host of M. mondabora, suggesting that the alkaloidal venoms with pyrrolidines from M. mondabora, piperidines from M. mondaboroides, and pyrolizidines from M. silvestrii may function similarly as appeasement and repellent allomones against host ants, despite their different chemical structure. With the use of these chemical weapons, the Megalomyrmex thief ants are met with little host resistance and easily exploit host colony resources. PMID- 25833217 TI - Floral volatiles in a sapromyiophilous plant and their importance in attracting house fly pollinators. AB - Floral scent in sapromyiophilous plants often consists of complex blends with not only fetid (e.g., sulfides) but also sweet (e.g., terpenoids) volatile organic compounds, and a recent study suggests that both groups of compounds are involved in pollinator attraction. However, little is known about the number and identity of compounds involved in pollinator attraction in these deceptive plants that mimic breeding sites of fly pollinators. In the present paper, we studied flower volatiles of sapromyiophilous Periploca laevigata and their capability to elicit biological responses in one of the pollinator species, Musca domestica. Floral volatiles were collected by dynamic headspace and analyzed by gas chromatography/mass spectrometry (GC/MS), and electrophysiological (GC/EAD) and behavioral assays (two choice olfactometer) were conducted. In the floral scent of P. laevigata, we detected 44 compounds, of which indole, beta-caryophyllene, and germacrene D, as well as dimethyl trisulfide, which was present in trace amounts, were electrophysiologically active in the antennae of M. domestica. However, when we evaluated in behavioral experiments the attractiveness of the electrophysiologically active compounds (complete mixture against partial mixtures or against single compounds), we found that indole was the only attractive compound for the flies. PMID- 25833218 TI - Flattened tumor requires a more careful attention for residual distal cancer spread in locally advanced lower rectal carcinoma after chemoradiotherapy. AB - BACKGROUND/AIMS: Limited data are available on distal resection margin (DRM) for lower rectal cancer (LRC) after preoperative chemoradiotherapy (pre-CRT); thus, we aimed to establish the criteria for DRMs as estimated by the macroscopic tumor appearance. METHODS: This was a pathological study using whole-mount sections that included the entire circumference of tumor. Residual cancer spread located most distally from the macroscopic tumor border was mainly evaluated. RESULTS: A retrospective cohort of 42 consecutive patients with locally advanced LRC after pre-CRT was enrolled, and 38 patients were eligible for this study. According to the macroscopic tumor appearance, 18 patients had raised-type and 20 had flattened-type tumors. Patients with flattened-type tumors were closely associated with histopathological regression grade. Residual distal cancer spread (RDCS) was located <=4.0 mm (median, 0.1 mm) in the raised-type tumors and <=17.1 mm (median, 4.2 mm) in the flattened-type tumors. RDCS in flattened-type tumors was distributed diffusely and distally from the tumor border (p = 0.022). CONCLUSION: Even in patients evaluated as pre-CRT responders, flattened tumors often accompanied distally located residual cancer that had spread from the tumor border and require more careful attention in order to ensure cancer clearance. PMID- 25833220 TI - Glutathione Depletion Induces Spermatogonial Cell Autophagy. AB - The development and survival of male germ cells depend on the antioxidant capacity of the seminiferous tubule. Glutathione (GSH) plays an important role in the antioxidant defenses of the spermatogenic epithelium. Autophagy can act as a pro-survival response during oxidative stress or nutrient deficiency. In this work, we evaluated whether autophagy is involved in spermatogonia-type germ cell survival during severe GSH deficiency. We showed that the disruption of GSH metabolism with l-buthionine-(S,R)-sulfoximine (BSO) decreased reduced (GSH), oxidized (GSSG) glutathione content, and GSH/GSSG ratio in germ cells, without altering reactive oxygen species production and cell viability, evaluated by 2',7'-dichlorodihydrofluorescein (DCF) fluorescence and exclusion of propidium iodide assays, respectively. Autophagy was assessed by processing the endogenous protein LC3I and observing its sub-cellular distribution. Immunoblot and immunofluorescence analysis showed a consistent increase in LC3II and accumulation of autophagic vesicles under GSH-depletion conditions. This condition did not show changes in the level of phosphorylation of AMP-activated protein kinase (AMPK) or the ATP content. A loss in S-glutathionylated protein pattern was also observed. However, inhibition of autophagy resulted in decreased ATP content and increased caspase-3/7 activity in GSH-depleted germ cells. These findings suggest that GSH deficiency triggers an AMPK-independent induction of autophagy in germ cells as an adaptive stress response. PMID- 25833221 TI - Corrigendum: Size and frequency of natural forest disturbances and the Amazon forest carbon balance. PMID- 25833222 TI - Microscale Crystals of Cytochrome c and Calixarene on Electrodes: Interprotein Electron Transfer between Defined Sites. AB - The assembly of redox proteins on electrodes is an important step in biosensor development. Recently, p-sulfonato-calix[4]arene was shown to act as "molecular glue" for the assembly and crystallization of cytochrome c (cyt c). Electrochemical data are presented for microscale cyt c-calixarene crystals grown on self-assembled monolayers (SAM)-modified Au electrodes. The crystals were characterized by cyclic voltammetry and exceptionally high concentrations of electroactive cyt c were obtained. The peak currents were found to increase linearly with the square root of the scan rate, thus allowing an evaluation of the rate constant for electron self-exchange. This study revealed high electroactivity accompanied by fast interprotein electron transfer in crystals, which may have implications for the construction of novel bioelectronic devices. PMID- 25833223 TI - Wild chacma baboons (Papio ursinus) remember single foraging episodes. AB - Understanding animal episodic-like memory is important for tracing the evolution of the human mind. However, our knowledge about the existence and nature of episodic-like memory in non-human primates is minimal. We observed the behaviour of a wild male chacma baboon faced with a trade-off between protecting his stationary group from aggressive extra-group males and foraging among five out-of sight platforms. These contained high-priority food at a time of natural food shortage. In 10 morning and eight evening trials, the male spontaneously visited the platforms in five and four different sequences, respectively. In addition, he interrupted foraging sequences at virtually any point on eight occasions, returning to the group for up to 2 h. He then visited some or all of the remaining platforms and prevented revisits to already depleted ones, apparently based on his memory for the previous foraging episode about food value, location, and time. Efficient use of memory allowed him to keep minimal time absent from his group while keeping food intake high. These findings support the idea that episodic-like memory offers an all-purpose solution to a wide variety of problems that require flexible, quick, yet precise decisions in situations arising from competition for food and mates in wild primates. PMID- 25833219 TI - Opioid-induced central immune signaling: implications for opioid analgesia. AB - Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by Toll-like receptor 4, purinergic, ceramide, and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted. PMID- 25833225 TI - Dynamic effects in friction and adhesion through cooperative rupture and formation of supramolecular bonds. AB - We introduce a molecular toolkit for studying the dynamics in friction and adhesion from the single molecule level to effects of multivalency. As experimental model system we use supramolecular bonds established by the inclusion of ditopic adamantane connector molecules into two surface-bound cyclodextrin molecules, attached to a tip of an atomic force microscope (AFM) and to a flat silicon surface. The rupture force of a single bond does not depend on the pulling rate, indicating that the fast complexation kinetics of adamantane and cyclodextrin are probed in thermal equilibrium. In contrast, the pull-off force for a group of supramolecular bonds depends on the unloading rate revealing a non-equilibrium situation, an effect discussed as the combined action of multivalency and cantilever inertia effects. Friction forces exhibit a stick-slip characteristic which is explained by the cooperative rupture of groups of host guest bonds and their rebinding. No dependence of friction on the sliding velocity has been observed in the accessible range of velocities due to fast rebinding and the negligible delay of cantilever response in AFM lateral force measurements. PMID- 25833224 TI - Simplified protocol for flow cytometry analysis of fluorescently labeled exosomes and microvesicles using dedicated flow cytometer. AB - Flow cytometry is a powerful method, which is widely used for high-throughput quantitative and qualitative analysis of cells. However, its straightforward applicability for extracellular vesicles (EVs) and mainly exosomes is hampered by several challenges, reflecting mostly the small size of these vesicles (exosomes: ~80-200 nm, microvesicles: ~200-1,000 nm), their polydispersity, and low refractive index. The current best and most widely used protocol for beads-free flow cytometry of exosomes uses ultracentrifugation (UC) coupled with floatation in sucrose gradient for their isolation, labeling with lipophilic dye PKH67 and antibodies, and an optimized version of commercial high-end cytometer for analysis. However, this approach requires an experienced flow cytometer operator capable of manual hardware adjustments and calibration of the cytometer. Here, we provide a novel and fast approach for quantification and characterization of both exosomes and microvesicles isolated from cell culture media as well as from more complex human samples (ascites of ovarian cancer patients) suitable for multiuser labs by using a flow cytometer especially designed for small particles, which can be used without adjustments prior to data acquisition. EVs can be fluorescently labeled with protein-(Carboxyfluoresceinsuccinimidyl ester, CFSE) and/or lipid- (FM) specific dyes, without the necessity of removing the unbound fluorescent dye by UC, which further facilitates and speeds up the characterization of microvesicles and exosomes using flow cytometry. In addition, double labeling with protein- and lipid-specific dyes enables separation of EVs from common contaminants of EV preparations, such as protein aggregates or micelles formed by unbound lipophilic styryl dyes, thus not leading to overestimation of EV numbers. Moreover, our protocol is compatible with antibody labeling using fluorescently conjugated primary antibodies. The presented methodology opens the possibility for routine quantification and characterization of EVs from various sources. Finally, it has the potential to bring a desired level of control into routine experiments and non-specialized labs, thanks to its simple bead-based standardization. PMID- 25833226 TI - Going mainstream: Online sharing of health data and test results with patients. PMID- 25833227 TI - Influence of dyadic matching of affect on infant self-regulation. AB - BACKGROUND/AIMS: Affective behavioural matching during face-to-face interaction fosters the transition from mutual regulation to infant self-regulation. Optimum midrange models of mother-infant interaction hold that moderate degrees of dyadic matching facilitate infant socio-emotional development. The aim of this study was to examine which degree of dyadic matching is most beneficial for infant self regulation. METHODS: To evaluate this model, 3 groups of highly, midrange and poorly matched dyads were created from a mixed sample of 68 dyads with healthy and post-partum depressed mothers and their infants (age range = 1-8 months, mean age = 3.9 months). Mother-infant interactions were videotaped in the face-to-face still-face paradigm (FFSF) and micro-analytically coded. Specifically, the relation between affective behavioural matching in FFSF play and infant positive and negative affect in FFSF still face and FFSF reunion was explored. RESULTS: Contrary to our expectation, we found a monotonous trend for all groups: the more matching in FFSF play, the more positive and less negative affect the infant showed in FFSF still face and FFSF reunion, respectively. CONCLUSION: The present findings further illuminate the association between different degrees of dyadic matching in early mother-infant interaction and infant self-regulation. Further research should focus on the integration and replication of findings and conceptual approaches to further evaluate and refine the concept of midrange matching and make it applicable to therapeutic work with mothers and their infants. PMID- 25833228 TI - Correlation between measurement of IL-10 and IL-6 in paired aqueous humour and vitreous fluid in primary vitreoretinal lymphoma. PMID- 25833229 TI - Short Stature in KBG Syndrome: First Responses to Growth Hormone Treatment. AB - BACKGROUND: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. METHODS: We summarized the height data of 14 adults and 18 children (age range 2 16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. RESULTS: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. CONCLUSION: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising. PMID- 25833230 TI - Randomized clinical trial of adjuvant chemotherapy with S-1 versus gemcitabine after pancreatic cancer resection. AB - BACKGROUND: Randomized studies of adjuvant chemotherapy using gemcitabine suggest a survival benefit after resection of pancreatic cancer. S-1 has also been shown to prolong survival in patients with unresectable pancreatic cancer. This study compared the effects of adjuvant chemotherapy with S-1 or gemcitabine after resection of pancreatic cancer in a randomized trial. METHODS: Patients who had undergone resection of pancreatic cancer were registered in this randomized clinical trial. The primary endpoint was disease-free survival (DFS). Expression levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) mRNAs in cancer tissues were measured as indicators of fluoropyrimidine sensitivity. RESULTS: Of 57 patients registered, 29 were allocated to the S-1 group and 28 to gemcitabine. DFS tended to be better with S-1 (median 14.6 (90 per cent c.i. 8.8 to 28.4) months versus 10.5 (7.0 to 28.4) months in the gemcitabine group; P = 0.188), with a similar pattern for overall survival: 21.5 (95 per cent c.i. 14.4 to 42.3) and 18.0 (13.3 to 42.8) months respectively (P = 0.293). When patients were divided into subgroups based on high or low DPD and TS expression, those with a DPD level below the median of 0.88 or a TS level of at least 2.00 had a significant prolongation of DFS after S-1 treatment compared with gemcitabine (P = 0.008 and P = 0.035 respectively). CONCLUSION: Overall, S-1 did not improve DFS compared with gemcitabine after pancreatic cancer resection, but there seemed to be a DFS advantage in patients with low expression of DPD or high expression of TS. Reference number: UMIN000009118 (http://www.umin.ac.jp/ctr/). PMID- 25833232 TI - High IFN-gamma/IL-10 expression ratio and increased frequency of persistent human T-cell lymphotropic virus type 1-infected clones are associated with human T-cell lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis development. AB - BACKGROUND/AIMS: Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes a persistent infection, and only 0.5-5% of infected individuals will develop HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Therefore, we investigated parameters to discriminate HTLV-1 asymptomatic carriers (ACs) with an increased chance to develop HAM/TSP. METHODS: We evaluated integration patterns of HTLV-1 provirus, the relative expression of HTLV-1 tax and HBZ mRNAs and of IFN-gamma and IL-10 mRNAs, in addition to proviral load (PVL) levels. RESULTS: HAM/TSP patients presented a higher number of large persistent HTLV-1-carrying clones compared to ACs, and the expression of the HTLV 1 tax and HBZ genes by infected cells was detected at low levels and correlated positively with PVL. In addition, HAM/TSP patients and ACs with high PVL expressed higher levels of IFN-gamma mRNA in comparison to IL-10, while ACs with low PVL presented an equilibrate IFN-gamma/IL-10 ratio. CONCLUSIONS: The presence of large persistent HTLV-1-infected clones in association with viral gene expression, even at small levels, could stimulate the intense inflammatory response in HTLV-1-infected individuals. This was supported by a high ratio of IFN-gamma/IL-10 relative expression in HAM/TSP patients and ACs with high PVL, indicating that these parameters could aid the identification of ACs with a high risk to develop HAM/TSP. PMID- 25833231 TI - Nonequilibrium Conditions Explain Spatial Variability in Genetic Structuring of Little Penguin (Eudyptula minor). AB - Factors responsible for spatial structuring of population genetic variation are varied, and in many instances there may be no obvious explanations for genetic structuring observed, or those invoked may reflect spurious correlations. A study of little penguins (Eudyptula minor) in southeast Australia documented low spatial structuring of genetic variation with the exception of colonies at the western limit of sampling, and this distinction was attributed to an intervening oceanographic feature (Bonney Upwelling), differences in breeding phenology, or sea level change. Here, we conducted sampling across the entire Australian range, employing additional markers (12 microsatellites and mitochondrial DNA, 697 individuals, 17 colonies). The zone of elevated genetic structuring previously observed actually represents the eastern half of a genetic cline, within which structuring exists over much shorter spatial scales than elsewhere. Colonies separated by as little as 27 km in the zone are genetically distinguishable, while outside the zone, homogeneity cannot be rejected at scales of up to 1400 km. Given a lack of additional physical or environmental barriers to gene flow, the zone of elevated genetic structuring may reflect secondary contact of lineages (with or without selection against interbreeding), or recent colonization and expansion from this region. This study highlights the importance of sampling scale to reveal the cause of genetic structuring. PMID- 25833233 TI - Metformin does not improve survival of cholangiocarcinoma patients with diabetes. PMID- 25833234 TI - Repertoires of autophagy in the pathogenesis of ocular diseases. AB - Autophagy is an important intracellular degradative process that delivers cytoplasmic proteins to lysosome for degradation. Dysfunction of autophagy is implicated in several human diseases, such as neurodegenerative diseases, infectious diseases, and cancers. Autophagy-related proteins are constitutively expressed in the eye. Increasing studies have revealed that abnormal autophagy is an important pathological feature of several ocular diseases. Pharmacological manipulation of autophagy may provide an alternative therapeutic target for some ocular diseases. In this manuscript, we reviewed the relevant progress about the role of autophagy in the pathogenesis of ocular diseases. PMID- 25833235 TI - Successful use of high-frequency spinal cord stimulation following traditional treatment failure. AB - INTRODUCTION: High-frequency spinal cord stimulation (HFSCS) offers an alternative treatment for chronic refractory pain syndromes nonresponsive to traditional spinal cord stimulation (SCS). Following the conflicting findings of preliminary HFSCS clinical studies performed at 5-10 kHz, this study is the first to report successful clinical usage of 1-kHz frequency SCS with a standard generator. PATIENTS: We used HFSCS in 2 patients who had inadequate relief with traditional SCS. Patient 1 was initially programmed at 40 Hz and a pulse width of 330 MUs with bipolar stimulation. After multiple setting adjustments with inadequate pain relief, the patient was reprogrammed to HFSCS at settings of 1.15 kHz, 120 MUs, and 5 V. Patient 2 was initially programmed at a frequency of 1.2 kHz and a pulse width of 120 MUs, which she favored over the standard setting of 40 Hz and 390 MUs pulse width. HFSCS provided optimal pain alleviation and increased quality of life for both patients. CONCLUSIONS: HFSCS at the frequency of 1 kHz offers a new tool for treatment of chronic pain in patients with traditional stimulation settings. Furthermore, most standard SCS batteries are capable of delivering stimulation in this frequency range. PMID- 25833236 TI - Irinotecan induces cell cycle arrest, but not apoptosis or necrosis, in Caco-2 and CW2 colorectal cancer cell lines. AB - Irinotecan, a topoisomerase I inhibitor, is clinically used as an anticancer drug. The present study investigated the anticancer effect of irinotecan on p53 negative Caco-2 and p53-positive CW2 human colorectal cancer cell lines. Cell viability for both Caco-2 and CW2 cells was little affected by treatment with irinotecan at concentrations ranging from 0.3 to 30 MUmol/l for 24-48 h. Irinotecan did not increase the number of TUNEL-positive cells and did not affect the population of propidium iodide (PI)-positive and annexin V-negative cells, corresponding to primary necrosis, or that of PI-positive and annexin-positive cells, corresponding to late apoptosis/secondary necrosis, in either of the two cell lines. In the cell cycle analysis, irinotecan significantly increased the proportions at the S and G2/M phases of cell cycling in parallel with a decreased population at the G1 phase in both cell lines. Irinotecan significantly inhibited tumor growth in mice inoculated with CW2 cells. Taken together, these results indicate that irinotecan induces cell cycle arrest, but not apoptosis or necrosis, both in Caco-2 and CW2 cells, leading to suppression of cell proliferation. PMID- 25833237 TI - Towards causally cohesive genotype-phenotype modelling for characterization of the soft-tissue mechanics of the heart in normal and pathological geometries. AB - A scientific understanding of individual variation is key to personalized medicine, integrating genotypic and phenotypic information via computational physiology. Genetic effects are often context-dependent, differing between genetic backgrounds or physiological states such as disease. Here, we analyse in silico genotype-phenotype maps (GP map) for a soft-tissue mechanics model of the passive inflation phase of the heartbeat, contrasting the effects of microstructural and other low-level parameters assumed to be genetically influenced, under normal, concentrically hypertrophic and eccentrically hypertrophic geometries. For a large number of parameter scenarios, representing mock genetic variation in low-level parameters, we computed phenotypes describing the deformation of the heart during inflation. The GP map was characterized by variance decompositions for each phenotype with respect to each parameter. As hypothesized, the concentric geometry allowed more low-level parameters to contribute to variation in shape phenotypes. In addition, the relative importance of overall stiffness and fibre stiffness differed between geometries. Otherwise, the GP map was largely similar for the different heart geometries, with little genetic interaction between the parameters included in this study. We argue that personalized medicine can benefit from a combination of causally cohesive genotype-phenotype modelling, and strategic phenotyping that captures effect modifiers not explicitly included in the mechanistic model. PMID- 25833238 TI - A wrinkle in flight: the role of elastin fibres in the mechanical behaviour of bat wing membranes. AB - Bats fly using a thin wing membrane composed of compliant, anisotropic skin. Wing membrane skin deforms dramatically as bats fly, and its three-dimensional configurations depend, in large part, on the mechanical behaviour of the tissue. Large, macroscopic elastin fibres are an unusual mechanical element found in the skin of bat wings. We characterize the fibre orientation and demonstrate that elastin fibres are responsible for the distinctive wrinkles in the surrounding membrane matrix. Uniaxial mechanical testing of the wing membrane, both parallel and perpendicular to elastin fibres, is used to distinguish the contribution of elastin and the surrounding matrix to the overall membrane mechanical behaviour. We find that the matrix is isotropic within the plane of the membrane and responsible for bearing load at high stress; elastin fibres are responsible for membrane anisotropy and only contribute substantially to load bearing at very low stress. The architecture of elastin fibres provides the extreme extensibility and self-folding/self-packing of the wing membrane skin. We relate these findings to flight with membrane wings and discuss the aeromechanical significance of elastin fibre pre-stress, membrane excess length, and how these parameters may aid bats in resisting gusts and preventing membrane flutter. PMID- 25833239 TI - Optimal control strategies of eradicating invisible glioblastoma cells after conventional surgery. AB - Glioblastoma, the most aggressive type of brain cancer, has median survival time of 1 year after diagnosis. It is characterized by alternating modes of rapid proliferation and aggressive invasion in response to metabolic stress in the microenvironment. A particular microRNA, miR-451, and its downstream signalling molecules, AMPK complex, are known to be key determinants in switching cell fate. These components form a core control system determining a balance between cell growth and migration which is regulated by fluctuating glucose levels in the microenvironment. An important factor from the treatment point of view is that low levels of glucose affect metabolism and activate cell migration through the miR-451-AMPK control system, creating 'invisible' migratory cells and making them inaccessible by conventional surgery. In this work, we apply optimal control theory to deal with the problem of maintaining upregulated miR-451 levels that prevent cell infiltration to surrounding brain tissue and thus induce localization of these cancer cells at the surgical site. The model also considers the effect of a drug that blocks inhibitive pathways of miR-451 from AMPK complex. Glucose infusion control and drug infusion control are chosen to represent dose rates of glucose and drug intravenous administrations, respectively. The characteristics of optimal control lead us to investigate the structure of optimal intravenous infusion regimen under various circumstances and predict best clinical outcomes with minimum expense possible. PMID- 25833240 TI - Accuracy of the Michaelis-Menten approximation when analysing effects of molecular noise. AB - Quantitative biology relies on the construction of accurate mathematical models, yet the effectiveness of these models is often predicated on making simplifying approximations that allow for direct comparisons with available experimental data. The Michaelis-Menten (MM) approximation is widely used in both deterministic and discrete stochastic models of intracellular reaction networks, owing to the ubiquity of enzymatic activity in cellular processes and the clear biochemical interpretation of its parameters. However, it is not well understood how the approximation applies to the discrete stochastic case or how it extends to spatially inhomogeneous systems. We study the behaviour of the discrete stochastic MM approximation as a function of system size and show that significant errors can occur for small volumes, in comparison with a corresponding mass-action system. We then explore some consequences of these results for quantitative modelling. One consequence is that fluctuation-induced sensitivity, or stochastic focusing, can become highly exaggerated in models that make use of MM kinetics even if the approximations are excellent in a deterministic model. Another consequence is that spatial stochastic simulations based on the reaction-diffusion master equation can become highly inaccurate if the model contains MM terms. PMID- 25833241 TI - Experimental evolution gone wild. AB - Because of their large population sizes and rapid cell division rates, marine microbes have, or can generate, ample variation to fuel evolution over a few weeks or months, and subsequently have the potential to evolve in response to global change. Here we measure evolution in the marine diatom Skeletonema marinoi evolved in a natural plankton community in CO2-enriched mesocosms deployed in situ. Mesocosm enclosures are typically used to study how the species composition and biogeochemistry of marine communities respond to environmental shifts, but have not been used for experimental evolution to date. Using this approach, we detect a large evolutionary response to CO2 enrichment in a focal marine diatom, where population growth rate increased by 1.3-fold in high CO2-evolved lineages. This study opens an exciting new possibility of carrying out in situ evolution experiments to understand how marine microbial communities evolve in response to environmental change. PMID- 25833242 TI - Coastal foredune evolution: the relative influence of vegetation and sand supply in the US Pacific Northwest. AB - Biophysical feedbacks between vegetation and sediment are important for forming and modifying landscape features and their ecosystem services. These feedbacks are especially important where landscape features differ in their provision of ecosystem services. For example, the shape of coastal foredunes, a product of both physical and biological forces, determines their ability to protect communities from rising seas and changing patterns of storminess. Here we assessed how sand supply and changes in vegetation over interannual (3 year) and decadal (21 year) scales influenced foredune shape along 100 km of coastline in the US Pacific Northwest. Across 21 years, vegetation switched from one congeneric non-native beachgrass to another (Ammophila arenaria to A. breviligulata) while sand supply rates were positive. At interannual timescales, sand supply rates explained the majority of change in foredune height (64-69%) and width (56-80%). However, at decadal scales, change in vegetation explained the majority of the change in foredune width (62-68%), whereas sand supply rates explained most of the change in foredune height (88-90%). In areas with lower shoreline change rates (+/-2 m yr(-1)), the change in vegetation explained the majority of decadal changes in foredune width (56-57%) and height (59-76%). Foredune shape directly impacts coastal protection, thus our findings are pertinent to coastal management given pressures of development and climate change. PMID- 25833243 TI - The entropic basis of collective behaviour. AB - We identify a unique viewpoint on the collective behaviour of intelligent agents. We first develop a highly general abstract model for the possible future lives these agents may encounter as a result of their decisions. In the context of these possibilities, we show that the causal entropic principle, whereby agents follow behavioural rules that maximize their entropy over all paths through the future, predicts many of the observed features of social interactions among both human and animal groups. Our results indicate that agents are often able to maximize their future path entropy by remaining cohesive as a group and that this cohesion leads to collectively intelligent outcomes that depend strongly on the distribution of the number of possible future paths. We derive social interaction rules that are consistent with maximum entropy group behaviour for both discrete and continuous decision spaces. Our analysis further predicts that social interactions are likely to be fundamentally based on Weber's law of response to proportional stimuli, supporting many studies that find a neurological basis for this stimulus-response mechanism and providing a novel basis for the common assumption of linearly additive 'social forces' in simulation studies of collective behaviour. PMID- 25833245 TI - Obstacle avoidance in social groups: new insights from asynchronous models. AB - For moving animals, the successful avoidance of hazardous obstacles is an important capability. Despite this, few models of collective motion have addressed the relationship between behavioural and social features and obstacle avoidance. We develop an asynchronous individual-based model for social movement which allows social structure within groups to be included. We assess the dynamics of group navigation and resulting collision risk in the context of information transfer through the system. In agreement with previous work, we find that group size has a nonlinear effect on collision risk. We implement examples of possible network structures to explore the impact social preferences have on collision risk. We show that any social heterogeneity induces greater obstacle avoidance with further improvements corresponding to groups containing fewer influential individuals. The model provides a platform for both further theoretical investigation and practical application. In particular, we argue that the role of social structures within bird flocks may have an important role to play in assessing the risk of collisions with wind turbines, but that new methods of data analysis are needed to identify these social structures. PMID- 25833244 TI - A century of transitions in New York City's measles dynamics. AB - Infectious diseases spreading in a human population occasionally exhibit sudden transitions in their qualitative dynamics. Previous work has successfully predicted such transitions in New York City's historical measles incidence using the seasonally forced susceptible-infectious-recovered (SIR) model. This work relied on a dataset spanning 45 years (1928-1973), which we have extended to 93 years (1891-1984). We identify additional dynamical transitions in the longer dataset and successfully explain them by analysing attractors and transients of the same mechanistic epidemiological model. PMID- 25833246 TI - Chloroform alters interleaflet coupling in lipid bilayers: an entropic mechanism. AB - The interaction of the two leaflets of the plasmatic cell membrane is conjectured to play an important role in many cell processes. Experimental and computational studies have investigated the mechanisms that modulate the interaction between the two membrane leaflets. Here, by means of coarse-grained molecular dynamics simulations, we show that the addition of a small and polar compound such as chloroform alters interleaflet coupling by promoting domain registration. This is interpreted in terms of an entropic gain that would favour frequent chloroform commuting between the two leaflets. The implication of this effect is discussed in relation to the general anaesthetic action. PMID- 25833247 TI - The mortality of companies. AB - The firm is a fundamental economic unit of contemporary human societies. Studies on the general quantitative and statistical character of firms have produced mixed results regarding their lifespans and mortality. We examine a comprehensive database of more than 25 000 publicly traded North American companies, from 1950 to 2009, to derive the statistics of firm lifespans. Based on detailed survival analysis, we show that the mortality of publicly traded companies manifests an approximately constant hazard rate over long periods of observation. This regularity indicates that mortality rates are independent of a company's age. We show that the typical half-life of a publicly traded company is about a decade, regardless of business sector. Our results shed new light on the dynamics of births and deaths of publicly traded companies and identify some of the necessary ingredients of a general theory of firms. PMID- 25833248 TI - Analysis of unstable modes distinguishes mathematical models of flagellar motion. AB - The mechanisms underlying the coordinated beating of cilia and flagella remain incompletely understood despite the fundamental importance of these organelles. The axoneme (the cytoskeletal structure of cilia and flagella) consists of microtubule doublets connected by passive and active elements. The motor protein dynein is known to drive active bending, but dynein activity must be regulated to generate oscillatory, propulsive waveforms. Mathematical models of flagellar motion generate quantitative predictions that can be analysed to test hypotheses concerning dynein regulation. One approach has been to seek periodic solutions to the linearized equations of motion. However, models may simultaneously exhibit both periodic and unstable modes. Here, we investigate the emergence and coexistence of unstable and periodic modes in three mathematical models of flagellar motion, each based on a different dynein regulation hypothesis: (i) sliding control; (ii) curvature control and (iii) control by interdoublet separation (the 'geometric clutch' (GC)). The unstable modes predicted by each model are used to critically evaluate the underlying hypothesis. In particular, models of flagella with 'sliding-controlled' dynein activity admit unstable modes with non-propulsive, retrograde (tip-to-base) propagation, sometimes at the same parameter values that lead to periodic, propulsive modes. In the presence of these retrograde unstable modes, stable or periodic modes have little influence. In contrast, unstable modes of the GC model exhibit switching at the base and propulsive base-to-tip propagation. PMID- 25833249 TI - Regional ejection fraction and regional area strain for left ventricular function assessment in male patients after first-time myocardial infarction. PMID- 25833250 TI - Overexpression of HIF-2alpha in pancreatic beta cells does not alter glucose homeostasis. AB - Both type 1 and type 2 diabetes are associated with insufficient functional beta cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions. Activation of this pathway increases expression of numerous genes involved in multiple cellular processes and has been shown to impact the regulation of beta-cell function. Previously, deletion of HIF-1alpha or HIF-1beta in pancreatic beta-cells, as well as constitutive activation of the HIF pathway in beta-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2alpha overexpression in pancreatic beta cells in vivo. We overexpressed HIF-2alpha in pancreatic beta-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2alpha overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or beta-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2alpha in the pancreatic beta-cells does not play a significant role in beta-cell function and glucose homeostasis. PMID- 25833251 TI - Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors. AB - Emerging evidence suggests that activin with its associated receptors, second messengers, and antagonists would be excellent targets for therapeutic drug development in the treatment of diabetes. We undertook the current study to investigate the ability to extrapolate findings from rodent studies to human islets in which data thus far has been scarce. We tested the hypothesis that human islets synthesize activin and that activin participates in the regulation of islet beta-cells. Human islets from 33 separate isolations were categorized based on functional status, culture status and diabetic status. Statistical comparisons were made by ANOVA with Tukey post-hoc adjustment for multiple comparisons. Experiments investigating activin utilized qPCR, FACS cell sorting, immunofluorescent antibody staining, functionality assays, viability assays and protein secretion assays. We have defined the transcript expression patterns of activin and the TGFbeta superfamily in human islets. We found INHBA (the gene encoding activin A) to be the most highly expressed of the superfamily in normal, cultured islets. We elucidated a link between the islet microenvironment and activin A. We found differential ligand expression based on diabetic, culture and functional status. Further, this is also the first report that links direct effects of activin A with the ability to restore glucose-stimulated insulin secretion in human islets from type 2 diabetic donors thereby establishing the relevance of targeting activin for therapeutic drug development. PMID- 25833253 TI - Magneto-optical studies on spin-dependent charge recombination and dissociation in perovskite solar cells. PMID- 25833252 TI - Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats. AB - WNIN/GR-Ob mutant rat is a novel animal model to study metabolic syndrome (obesity, insulin resistance, hyperinsulinemia, impaired glucose tolerance and cardiovascular diseases). We have investigated the islet characteristics of obese mutants at different age groups (1, 6 and 12 months) to assess the islet changes in response to early and chronic metabolic stress. Our data demonstrates altered islet cell morphology and function (hypertrophy, fibrotic lesions, vacuolation, decreased stimulation index, increased TNFalpha, ROS and TBARS levels) in mutants as compared to controls. Furthermore, network analysis (gene-gene interaction) studied in pancreas demonstrated increased inflammation as a key factor underlying obesity/metabolic syndrome in mutants. These observations pave way to explore this model to understand islet adaptation in response to metabolic syndrome. PMID- 25833256 TI - Application of the enabling occupation II guidelines in a non-Canadian context. AB - BACKGROUND: The Canadian Enabling Occupation II guidelines contain theory and examples of how to apply client-centredness in occupation-based practice. Little information is available about the feasibility of the guidelines in other contexts. For 18 months, nine Dutch occupational therapists participated in a community of practice to explore, together with three researchers, their experiences with the application of the Enabling Occupation II guidelines. PURPOSE: To understand the experiences of Dutch occupational therapists with the application of the Enabling Occupation II guidelines. METHOD: A qualitative study using four focus group discussions and content analysis. FINDINGS: Four themes emerged: (1) an indication that the guidelines of Enabling Occupation II are in line with values and norms of Dutch occupational therapists, (2) the meaningfulness of an intensive process of studying, discussing, applying and reflecting, (3) the struggles faced by the occupational therapists with translating English and getting a grip on concepts and (4) the challenges to implementing the guidelines in practice. IMPLICATIONS: Findings indicate that Enabling Occupation II embody values and norms of Dutch occupational therapists. They experience many benefits in their doing, thinking and being when applying the guidelines in practice. Struggles with reading English, getting a grip on concepts and theories, and difficulties in handling obstacles indicate that the application of the guidelines takes effort. An understanding of the philosophy, application, and reflection on professional identity may be prerequisites for appraising the feasibility of adoption of client-centred guidelines cross culturally. PMID- 25833255 TI - Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity. AB - BACKGROUND: Maternal obesity is a major problem in obstetrics, and the placenta is involved in obesity-related complications via its roles at the maternal-fetal interface. We have recently shown a causative role for micro(mi)RNA-210, a so called 'hypoxamir' regulated by HIF-1alpha, in mitochondrial dysfunction in placentas from women with preeclampsia. We also reported mitochondrial dysfunction in placentas with maternal obesity. Here we hypothesized that expression of miR-210 is dysregulated in the placentas with obesity. METHODS: Placentas from uncomplicated pregnancies were collected at term from healthy weight or control (CTRL, pre-pregnancy body mass index (BMI)<25), overweight (OW, BMI=25-24.9) and obese (OB, BMI>30) women following C-section with no labor. Expression of miRNA-210 and its target genes was measured by reverse transcription-PCR and Western Blot, respectively. Mitochondrial respiration was assessed by Seahorse Analyzer in syncytiotrophoblast (ST) 72 h after cytotrophoblast isolation. RESULTS: Expression of miR-210 was significantly increased in placentas of OB and OW women with female but not male fetuses compared with CTRL placentas of females. However, expression of HIF-1alpha in these placentas remained unchanged. Levels of tumor-necrosis factor-alpha (TNFalpha) were increased in OW and OB placentas of females but not males, and in silico analysis suggested that activation of miR-210 expression in these placentas might be activated by NFkappaB1 (p50) signaling. Indeed, chromatin Immunoprecipitation assay showed that NFkB1 binds to placental miR-210 promoter in a fetal sex-dependent manner. Female but not male STs treated with TNFalpha showed overexpression of miR-210, reduction of mitochondrial target genes and decreased mitochondrial respiration. Pre-treatment of these STs with small interfering RNA to NFkB1 or antagomiR-210 prevented the TNFalpha-mediated inhibition of mitochondrial respiration. CONCLUSIONS: Our data suggest that the inflammatory intrauterine environment associated with maternal obesity induces an NFkappaB1-mediated increase in miR-210 in a fetal sex-dependent manner, leading to inhibition of mitochondrial respiration and placental dysfunction in the placentas of female fetuses. PMID- 25833254 TI - Channel function reconstitution and re-animation: a single-channel strategy in the postcrystal age. AB - The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the potassium channel is primordial and the most ubiquitous in the biological world, and knowledge of this channel underlies the understanding of features of other ion channels. The strategy applied to studying channels changed dramatically after the crystal structure of the potassium channel was resolved. Given the abundant structural information available, we exploited the bacterial KcsA potassium channel as a simple model channel. In the postcrystal age, there are two effective frameworks with which to decipher the functional codes present in the channel structure, namely reconstitution and re-animation. Complex channel proteins are decomposed into essential functional components, and well-examined parts are rebuilt for integrating channel function in the membrane (reconstitution). Permeation and gating are dynamic operations, and one imagines the active channel by breathing life into the 'frozen' crystal (re-animation). Capturing the motion of channels at the single-molecule level is necessary to characterize the behaviour of functioning channels. Advanced techniques, including diffracted X-ray tracking, lipid bilayer methods and high-speed atomic force microscopy, have been used. Here, I present dynamic pictures of the KcsA potassium channel from the submolecular conformational changes to the supramolecular collective behaviour of channels in the membrane. These results form an integrated picture of the active channel and offer insights into the processes underlying the physiological function of the channel in the cell membrane. PMID- 25833257 TI - MtrA, an essential response regulator of the MtrAB two-component system, regulates the transcription of resuscitation-promoting factor B of Mycobacterium tuberculosis. AB - The resuscitation-promoting factors of Mycobacterium tuberculosis are hydrolytic enzymes, which are required for resuscitation of dormant cells. RpfB, a peptidoglycan remodelling enzyme similar to the lytic transglycosylase of Escherichia coli, is required for reactivation of M. tuberculosis from chronic infection in vivo, underscoring the need to understand its transcriptional regulation. Here, we identified the transcriptional and translational start points of rpfB, and suggested from rpf promoter-driven GFP expression and in vitro transcription assays that its transcription possibly occurs in a SigB dependent manner. We further demonstrated that rpfB transcription is regulated by MtrA - the response regulator of the essential two-component system MtrAB. Association of MtrA with the rpfB promoter region in vivo was confirmed by chromatin immunoprecipitation analysis. Electrophoretic mobility shift assays (EMSAs) revealed a loose direct repeat sequence associated with MtrA binding. Binding of MtrA was enhanced upon phosphorylation. MtrA could be pulled down from lysates of M. tuberculosis using a biotinylated DNA fragment encompassing the MtrA-binding site on the rpfB promoter, confirming that MtrA binds to the rpfB promoter. Enhanced GFP fluorescence driven by the rpfB promoter, upon deletion of the MtrA-binding site, and repression of rpfB expression, upon overexpression of MtrA, suggested that MtrA functions as a repressor of rpfB transcription. This was corroborated by EMSAs showing diminished association of RNA polymerase (RNAP) with the rpfB promoter in the presence of MtrA. In vitro transcription assays confirmed that MtrA inhibits RNAP-driven rpfB transcription. PMID- 25833258 TI - Investigating the fall-injury reducing effect of impact absorbing flooring among female nursing home residents: initial results. AB - BACKGROUND: Fall-related injuries affect the lives of elderly to a substantial degree. This quasi-experimental study investigates the fall-injury reducing effect of impact absorbing flooring among female nursing home residents. METHODS: The intervention site is a nursing home in Sweden where impact absorbing flooring was installed in parts of one of six wards (six out of 10 apartments (excluding bathrooms), the communal dining-room and parts of the corridor). The impact absorbing flooring is a 12 mm thick closed cell flexible polyurethane/polyurea composite tile (500*500 mm) with an exterior surface of polyurethane/polyurea. A generalised linear model (log-binomial) was used to calculate the RR of injury from falls on impact absorbing flooring compared to falls on regular flooring, adjusted for age, body mass index, visual and cognitive impairments. RESULTS: During the study period (1 October 2011 to 31 March 2014), 254 falls occurred on regular flooring and 77 falls on impact absorbing flooring. The injury/fall rate was 30.3% for falls on regular flooring and 16.9% for falls on impact absorbing flooring. Adjusted for covariates, the impact absorbing flooring significantly reduced the RR of injury in the event of a fall by 59% (RR 0.41 (95% Cl 0.20 to 0.80)). CONCLUSIONS: This is, to our knowledge, the first study evaluating the injury-reducing effect of impact absorbing flooring in a nursing home showing statistically significant effect. The results from this study are promising, indicating the considerable potential of impact absorbing flooring as a fall related injury intervention among frail elderly. PMID- 25833260 TI - Anyone linked with trafficking human organs will be punishable under new convention. PMID- 25833259 TI - Validation of the OMRON M3500 Blood Pressure Measuring Device Using Normal- and High-Speed Modes in Adult and Specific Populations (Obese and Children) According to AAMI Protocol. AB - The present study aimed to validate the accuracy of blood pressure (BP) measurements of the OMRON M3500 automatic oscillometric BP device by using normal and high-speed modes in adult and specific populations (obese and children) according to American National Standards Institute/Association for the Advancement of Medical Instrumentation (AAMI)/International Organization for Standardization/81060-2:2009 protocol. The validation was performed in 135 patients: 100 adults and 35 children (aged 3-12 years). The results showed a mean error of the individual paired determinations of the OMRON device and mercury sphygmomanometers within values of criterion 1 (5+/-8 mm Hg). Analysis of the averaged paired determinations per subject of the OMRON device and standard mercury sphygmomanometer fit within the acceptable ranges of criterion 2 (<6.71 systolic BP and <5.77 diastolic BP). Readings of the OMRON M3500 BP device fulfill criteria 1 and 2 of the AAMI protocol in both speed modes. PMID- 25833261 TI - Steroid psychosis caused by perioperative steroid replacement for pituitary adenoma: a case report. AB - Steroid psychosis is a frequent complication of steroid treatment. Although perioperative steroid replacement therapy is generally administered in patients undergoing pituitary surgery, there are no previous reports concerning the development of steroid psychosis after perioperative steroid replacement therapy following pituitary surgery. We herein report a case of steroid psychosis induced by perioperative steroid replacement therapy for pituitary surgery. A 35-year-old man presented with a visual disturbance that had persisted for 1 year. A magnetic resonance imaging scan showed a large pituitary tumor, and a laboratory study revealed slight dysfunction of the hypothalamo-pituitary-adrenal axis. The patient was diagnosed with a non-functioning pituitary tumor and underwent tumor resection via the endoscopic endonasal approach. The initial dose of perioperative steroid replacement therapy was 200 mg of hydrocortisone administered immediately before the operation. The replacement dose was gradually tapered and discontinued over a 7-day period. On postoperative day 4, the patient exhibited an elated mood, grandiose delusions, anxiety, and agitation. We diagnosed these psychiatric symptoms as steroid psychosis induced by steroid replacement and we prescribed risperidone as a treatment. The symptoms gradually improved and did not recur. This case highlights the risk of steroid psychosis following treatment with perioperative steroid replacement therapy for pituitary adenoma and raises questions regarding the appropriateness of perioperative steroid replacement for pituitary adenoma. PMID- 25833263 TI - Surgical management of petroclival meningiomas: Factors affecting early post operative outcome. AB - INTRODUCTION: Petroclival meningiomas pose a major challenge to the treating neurosurgeon. The philosophy of treatment has changed over the decades from a nihilistic attitude to that of aggressive total excision to now a more tempered, maximal safe excision preventing morbidity followed by adjuvant treatment. Despite the advances in neurosurgery, surgical management of these tumours is still associated with sizable morbidity and mortality. MATERIAL AND METHODS: This is a retrospective study of surgically managed petroclival meningiomas at our institute. Clinical status, radiological features and surgical outcome were analysed. RESULTS: Between January 2003 and August 2013, we have operated on 30 patients. The most common presenting complaints were varying degrees of cranial nerve involvement and cerebellar dysfunction. Surgery was done using one of the skull base approaches with the retrosigmoid approach being used maximally (22 cases). Total or near-total excision was possible in 11 cases. There was a post operative deterioration in cranial nerve functions in all patients and deterioration in Karnofsky Performance Score in seven patients at discharge. Three improved to independent status on follow-up. There was mortality in two cases. Overall 23 of the 30 patients (76.6%) had favourable outcomes. CONCLUSIONS: These are challenging tumours to treat and are associated with sizable morbidity and mortality. On statistical analysis, we found that if the tumour has a size of 3-5 cm and petroclival in location with no sphenoid extension and the lesion is homogenous on T2-weighted images, then there was a trend towards gross total resection and favourable outcome. PMID- 25833262 TI - Association mapping in Populus reveals the interaction between Pto-miR530a and its target Pto-KNAT1. AB - MAIN CONCLUSION: We used transcript profiling and multi-SNP association to investigate the genetic regulatory relationship between miRNA Pto-miR530a and its target Pto-KNAT1, identifying additive, dominant, and epistatic effects. MicroRNAs (miRNAs) play crucial roles in the post-transcriptional regulation of plant growth and development; indeed, many studies have described the importance of miRNA-target interactions in herbaceous species. However, elucidation of the miRNA-target interactions in trees may require novel strategies. In the present study, we describe a strategy combining expression profiling by reverse transcription quantitative PCR (RT-qPCR) and association mapping with multiple single nucleotide polymorphisms (SNPs) to evaluate the interaction between Pto miR530a and its target Pto-KNAT1 in Populus tomentosa. RT-qPCR analysis showed a negative correlation (r = -0.62, P < 0.05) between expression levels of Pto miR530a and Pto-KNAT1 in eight tissues. We used a Bayesian hierarchical model to identify allelic variants of Pto-miR530a and Pto-KNAT1 that associated with eight traits related to growth and wood properties, in a population of 460 unrelated individuals of P. tomentosa. This analysis identified 27 associations, with the proportions of phenotypic variance (R (2)) contributed by each SNP ranging of 0.82-15.81 %, the additive effects of each SNP ranging of 0.16-18.09, and the dominant effects ranging from -14.09 to 19.00. Epistatic interaction models showed a strong interaction among SNPs in the miRNA target with R (2) of 0.1-3.56 %, and information gain of significant SNP pairs of -3.09 to 0.93 %, representing the regulatory interactions between the miRNA and the mRNA. Thus, we used a new strategy that combines association genetics and expression profiling based on SNPs to study the regulatory relationship between this miRNA and its target mRNA, thereby providing novel advances in our understanding of the genetic architecture of important traits. PMID- 25833264 TI - Brain abscess due to Trueperella bernardiae. AB - We present the case of a brain abscess caused by a combination of rare organisms (Trueperella bernardiae and Peptoniphilus harei) in a patient with chronic suppurative otitis media that had been complicated by the presence of a cholesteatoma. The authors believe this is the first report published in the literature. PMID- 25833265 TI - Advanced air distribution: improving health and comfort while reducing energy use. AB - Indoor environment affects the health, comfort, and performance of building occupants. The energy used for heating, cooling, ventilating, and air conditioning of buildings is substantial. Ventilation based on total volume air distribution in spaces is not always an efficient way to provide high-quality indoor environments at the same time as low-energy consumption. Advanced air distribution, designed to supply clean air where, when, and as much as needed, makes it possible to efficiently achieve thermal comfort, control exposure to contaminants, provide high-quality air for breathing and minimizing the risk of airborne cross-infection while reducing energy use. This study justifies the need for improving the present air distribution design in occupied spaces, and in general the need for a paradigm shift from the design of collective environments to the design of individually controlled environments. The focus is on advanced air distribution in spaces, its guiding principles and its advantages and disadvantages. Examples of advanced air distribution solutions in spaces for different use, such as offices, hospital rooms, vehicle compartments, are presented. The potential of advanced air distribution, and individually controlled macro-environment in general, for achieving shared values, that is, improved health, comfort, and performance, energy saving, reduction of healthcare costs and improved well-being is demonstrated. Performance criteria are defined and further research in the field is outlined. PMID- 25833266 TI - Ratio of Vestibular Endolymph in Patients with Isolated Lateral Semicircular Canal Dysplasia. AB - PURPOSE: Isolated vestibular-lateral semicircular canal dysplasia (LSCCD) is one of the most common anomalies of the inner ear. However, endolymphatic size in LSCCD is unknown. We measured the size of the endolymph in the vestibule of patients with LSCCD and compared it with that measured in patients without LSCCD. METHODS: We extracted 1102 magnetic resonance (MR) studies for the evaluation of endolymphatic hydrops (EH) from our database of radiology reports. Among these, we found 15 ears from 11 patients with LSCCD; 4 patients had bilateral abnormalities. Seven of the 15 ears demonstrated aplasia and 8 ears, hypoplasia of the lateral semicircular canal (LSCC). The control group consisted of 26 ears from 13 randomly selected patients without LSCCD. We measured the area of endolymph in the vestibule (ELA), total area of vestibular lymph fluid (TLA), and area of the central bony island (CBI) of the LSCC from axial MR images obtained after intratympanic or intravenous administration of gadolinium-based contrast material. The ratio of endolymphatic area to total lymphatic area (%EL) was defined as %EL = ELA/TLA * 100.We evaluated the correlation between %EL and the area of the CBI and compared age, %EL, degree of cochlear EH, hearing level, and presence of rotating vertigo among the 3 groups (aplasia, hypoplasia, control). RESULTS: The mean %EL was 76.7% in the aplasia group, 50.0% in the hypoplasia group, and 27.8% in the control group (P < 0.001). There was a relatively strong linear correlation between the area of the CBI and %EL (r = -0.767). Patient age, mean hearing level, degree of cochlear EH, or presence of vertigo attacks did not differ significantly among the groups (P > 0.05). CONCLUSION: The size of vestibular endolymph was larger in the groups with aplasia or hypoplasia than the control group. Thus, the current diagnostic cut-off value for significant vestibular EH (>50%) might not be appropriate for ears with LSCCD. PMID- 25833267 TI - Volume Quantification of Endolymph after Intravenous Administration of a Single Dose of Gadolinium Contrast Agent: Comparison of 18- versus 8-minute Imaging Protocols. AB - PURPOSE: We measured the volume of the endolymphatic space by extending a previously proposed less observer-dependent method of area quantification and compared volume measurements obtained using long (18 min, Image A) and short (8 min, Image B) scan times. METHODS: We performed MR imaging of 40 ears in 20 patients with clinically suspected endolymphatic hydrops 4 hours after intravenous administration of single-dose gadolinium-based contrast material (IV SD-GBCM). Two observers separately measured the ratio of the volume of the endolymph to that of total lymph in the cochlea and vestibule by extending the area ratio measurement method previously reported (Image A and B). The correlation between the values by Image A and B was calculated. RESULTS: We observed a strong linear correlation between Images A and B in the cochlear images; the Pearson's correlation coefficient (r) was 0.928 for Observer A and 0.926 for Observer B (P < 0.001, for all). A strong linear correlation was also observed in the vestibular images; the Pearson's correlation coefficient (r) was 0.962 for Observer A and 0.968 for Observer B (P < 0.001, for all). CONCLUSION: Measurement of endolymphatic volume after IV-SD-GBCM may be feasible using an MR imaging protocol with a reduced scan time of 8 min. This method might facilitate greater use of endolymphatic hydrops imaging in clinical applications. PMID- 25833268 TI - Changes to Muscle T2after Single-finger Exercise Measured with 0.2T MR Imaging. AB - We constructed an arm holder for muscle exercise from a forearm-shaped plastic shell and magnetic resonance (MR) imaging position markers and determined the echo time (39 ms) for T2-weighted spin-echo MR imaging from T2values of the exercised (50 ms) and resting (32 ms) muscle at 0.2 tesla. The smallest detectable muscle was the extensor digiti minimi muscle (cross-sectional area 25 mm2). This combination could be useful to monitor finger exercise in patients undergoing physical therapy. PMID- 25833269 TI - The Impact of Flip Angle and TR on the Enhancement Ratio of Dynamic Gadobutrol enhanced MR Imaging: In Vivo VX2 Tumor Model and Computer Simulation. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used to diagnose cancer and monitor therapy. The maximum enhancement ratio (ERmax) obtained from the curve of signal intensity over time could be a biomarker to distinguish cancer from normal tissue or benign tumors. We evaluated the impact of flip angle (FA) and repetition time (TR) on the ERmax values of dynamic gadobutrol-enhanced MR imaging, obtaining T1-weighted (T1W) MR imaging of VX2 tumors using 2-dimensional fast spoiled gradient echo (2D FSPGR) with various FAs (30 degrees , 60 degrees and 90 degrees ) at 1.5 tesla before and after injection of 0.1 mmol/kg gadobutrol. In vivo study indicated significant differences between ERmax values and area under the ER-time curve (AUC100) of VX2 tumors and muscle tissue, with the highest ERmax and AUC100 at FA 90 degrees . Computer simulation also demonstrated the ER as a strictly increasing monotonic function in the closed interval [0 degrees , 90 degrees ] for a given TR when using T1W FSPGR, and the highest ER value always occurred at FA 90 degrees . The FA for the highest ER differed from that for the highest signal-to-noise or contrast-to-noise ratio. For long TR, the ER value increases gradually. However, for short TR, the ER value increases rapidly and plateaus so that the ER value changes little beyond a certain FA value. Therefore, we suggest use of a higher FA, near 90 degrees , to obtain a higher ERmax for long TR in 2D SPGR or FSPGR and a smaller FA, much less than 90 degrees , to reach an appropriate ERmax for short TR in 3D SPGR or FSPGR. This information could be helpful in setting the optimal parameters for DCE-MRI. PMID- 25833270 TI - See-through Brains and Diffusion Tensor MRI Clarified Fiber Connections: A Preliminary Microstructural Study in a Mouse with Callosal Agenesis. AB - Clearing methods that render the brain optically transparent allow high resolution three-dimensional (3D) imaging of neural networks. We used diffusion tensor imaging (DTI) and two-photon imaging of cleared brains to analyze white matter in BTBR mice. We confirmed corpus callosum agenesis and identified an abnormal commissure close to the third ventricle. DTI and cleared-brain two photon imaging revealed that these commissural fibers constituted a frontal clustering of the ventral hippocampal commissure and provided a detailed assessment of white matter structure in mice. PMID- 25833272 TI - Noise Power Spectrum in PROPELLER MR Imaging. AB - The noise power spectrum (NPS), an index for noise evaluation, represents the frequency characteristics of image noise. We measured the NPS in PROPELLER (Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction) magnetic resonance (MR) imaging, a nonuniform data sampling technique, as an initial study for practical MR image evaluation using the NPS. The 2-dimensional (2D) NPS reflected the k-space sampling density and showed agreement with the shape of the k-space trajectory as expected theoretically. Additionally, the 2D NPS allowed visualization of a part of the image reconstruction process, such as filtering and motion correction. PMID- 25833273 TI - Hemodynamic-based Mapping of Neural Activity in Medetomidine-sedated Rats using a 1.5T Compact Magnetic Resonance Imaging System: A Preliminary Study. AB - The use of compact magnetic resonance (MR) systems for the neuroimaging of small animals is spreading. We investigated the potential of such systems in functional MR imaging (fMRI) of somatosensory cortex activity elicited by forepaw stimulation in medetomidine-sedated rats. Using a 1.5-tesla compact imager, we detected maximum activity with an electrophysiologically optimized frequency of 9 Hz in 3 appropriately sedated rats. With this compact system, we successfully mapped neural activity by combining optimum stimulation for a large hemodynamic response with appropriate anesthesia, thus demonstrating the utility of such systems in hemodynamic-based fMRI in preclinical and translational research. PMID- 25833274 TI - Optimization of Inversion Time for Postmortem Fluid-attenuated Inversion Recovery (FLAIR) MR Imaging at 1.5T: Temperature-based Suppression of Cerebrospinal Fluid. AB - PURPOSE: Signal intensity (SI) and image contrast on postmortem magnetic resonance (MR) imaging are different from those of imaging of living bodies. We sought to suppress the SI of cerebrospinal fluid (CSF) sufficiently for fluid attenuated inversion recovery (FLAIR) sequence in postmortem MR (PMMR) imaging by optimizing inversion time (TI). MATERIALS AND METHODS: We subject 28 deceased patients to PMMR imaging 3 to 113 hours after confirmation of death (mean, 27.4 hrs.). PMMR imaging was performed at 1.5 tesla, and T1 values of CSF were measured with maps of relaxation time. Rectal temperatures (RT) measured immediately after PMMR imaging ranged from 6 to 32 degrees C (mean, 15.4 degrees C). We analyzed the relationship between T1 and RT statistically using Pearson's correlation coefficient. We obtained FLAIR images from one cadaver using both a TI routinely used for living bodies and an optimized TI calculated from the RT. RESULTS: T1 values of CSF ranged from 2159 to 4063 ms (mean 2962.4), and there was a significantly positive correlation between T1 and RT (r = 0.96, P < 0.0001). The regression expression for the relationship was T1 = 74.4 * RT + 1813 for a magnetic field strength of 1.5T. The SI of CSF was effectively suppressed with the optimized TI (0.693 * T1), namely, TI = 0.693 * (77.4 * RT + 1813). CONCLUSION: Use of the TI calculated from the linear regression of the T1 and RT optimizes the FLAIR sequence of PMMR imaging. PMID- 25833275 TI - The Technical and Clinical Features of 3D-FLAIR in Neuroimaging. AB - In clinical MR neuroimaging, 3D fluid-attenuated inversion recovery (3D-FLAIR) with a variable-flip-angle turbo spin echo sequence is becoming popular. There are more than 100 reports regarding 3D-FLAIR in the PubMed database. In this article, the technical and clinical features of 3D-FLAIR for neuroimaging are reviewed and summarized. 3D-FLAIR allows thinner slices with multi-planar reformation capability, a higher flow sensitivity, high sensitivity to subtle T1 changes in fluid, images without cerebrospinal fluid (CSF) inflow artifacts, and a 3D dataset compatible with computer-aided analysis. In addition, 3D-FLAIR can be obtained within a clinically reasonable scan time. It is important for radiologists to be familiar with the features of 3D-FLAIR and to provide useful information for patients. PMID- 25833276 TI - Improvement of diagnostic confidence for detection of multiple myeloma involvement of the ribs by a new CT software generating rib unfolded images: Comparison with 5- and 1-mm axial images. AB - OBJECTIVE: To investigate the performance of a new CT software generating rib unfolded images for improved detection of rib osteolyses in patients with multiple myeloma. MATERIALS AND METHODS: One hundred sixteen patients who underwent whole-body reduced-dose multidetector computed tomography (WBRD-MDCT) for multiple myeloma diagnosis and during follow-up were retrospectively evaluated. Nonenhanced CT scans with 5- and 1-mm slice thickness were interpreted by two readers with focus on detection of rib involvement (location, number, fracture). Image analysis of "unfolded," 1-mm-based CT rib images was subsequently undertaken. We classified the number of lytic bone lesions into 0, 1, 2, <5, <10 and >=10. For all three data sets the reading time was registered. RESULTS: An approximated sum of 6,727 myeloma-related rib lesions was found. On a patient-based analysis, CT (5 mm), CT (1 mm) and CT (1 mm "unfolded rib") yielded a sensitivity, specificity and accuracy of 79.7/94.7/87.1, 88.1/93/90.5 and 98.3/96.5/97.4, respectively. In a lesion-based analysis, the sensitivity, specificity and accuracy of the three evaluations were 69.7/87.2/70.5, 79.8/55.9/78 and 96.5/89.7/96.1. Mean reading time for 5 mm/1 mm axial images and unfolded images was 178.7/215.1/90.8 s, respectively. CONCLUSION: The generation of "unfolded rib" images improves detection of rib involvement in patients with multiple myeloma and significantly reduces reading time. PMID- 25833277 TI - Surface primary bone tumors: Systematic approach and differential diagnosis. AB - Surface primary bone tumors may appear similar to their intramedullary counterpart, but because they are rare, they may pose diagnostic challenges when showing different characteristics compared to their intramedullary counterpart. It is important for radiologists to recognize the imaging findings for various uncommon surface primary bone tumors, which may help to reduce the differential diagnosis or to lead to a specific diagnosis. Radiography is typically used for first-line imaging. If necessary, it is followed by CT or MRI for evaluation and characterization of surface bone tumors. The aim of this article is to review the imaging findings and differential diagnosis for surface primary bone tumors. PMID- 25833278 TI - Giant cell tumor of soft tissue: a case report with emphasis on MR imaging. AB - Giant cell tumor of soft tissue is a rare neoplasm, histologically resembling giant cell tumor of bone. In this report, we describe a deep and solid giant cell tumor of soft tissue interpreted as a benign soft tissue tumor based on magnetic resonance (MR) findings with hypointense to intermediate signals on T2-weighted images and impeded diffusivity (water movement) on diffusion-weighted imaging (DWI), which could suggest a giant-cell-containing benign soft tissue tumor, despite the malignancy suggested by 18F-fluorodeoxyglucose positron emission tomography-computed tomography in a 35-year-old male. To our knowledge, this report introduces the first deep, solid giant cell tumor of soft tissue with MR features of a giant-cell-containing benign soft tissue tumor, despite the malignancy-mimicking findings on 18F-FDG PET-CT. PMID- 25833279 TI - Rare case of giant cystic adenomyoma mimicking a uterine malformation, diagnosed and treated by hysteroscopy. AB - We describe a case of giant cystic uterine adenomyoma that was diagnosed and treated by hysteroscopy. In a 27-year-old woman with menometrorrhagia, severe dysmenorrhea, and chronic pelvic pain, pelvic ultrasonography revealed an enlarged uterine cavity filled with homogeneous low echogenic fluid content. A large cornual hematometra of 8.0 cm in diameter in a bicornuate uterus was suspected, and this hypothesis was also supported by magnetic resonance imaging findings. On the contrary, hysteroscopy revealed a bilocular huge cystic lesion of the posterior uterine wall that was removed by means of monopolar loop resection. The operative finding and the histopathologic examination confirmed the diagnosis of cystic adenomyoma of the uterus. Hysteroscopy may represent a valid tool for diagnosis and minimally invasive treatment of cystic adenomyoma, including those of large volume. Its use is helpful in differential diagnosis between cystic adenomyoma and uterine malformations as a possible cause of pelvic pain. PMID- 25833281 TI - Serotonin transporter gene polymorphism (5-HTTLPR) influences trait anxiety by modulating the functional connectivity between the amygdala and insula in Han Chinese males. AB - A functional polymorphism (5-hydroxytryptamine transporter linked polymorphic region [5-HTTLPR]) in the promoter region of human serotonin transporter gene has been found to be associated with several dimensions of neuroticism and psychopathology, especially anxiety. However, the neural basis underlying the association between 5-HTTLPR and anxiety is less clear. Here, we explored how 5 HTTLPR influenced anxiety by modulating the spontaneous brain activities in Han Chinese. First, we found an association between 5-HTTLPR and anxiety only in the male and not in the female population, where male S/S homozygotes had a significantly higher level of anxiety than male L allele carriers. Then, we examined how 5-HTTLPR influenced anxiety at both regional and network levels in the brain at rest. At the regional level, we found a significantly higher fractional amplitude of low-frequency fluctuations in the amygdala in male S/S homozygotes relative to male L allele carriers. At the network level, male S/S homozygotes showed a weaker resting-state functional connectivity (RSFC) between the amygdala and various regions, including the insula, Heschl's gyrus, lateral occipital cortex, superior temporal gyrus, and hippocampus, and a stronger RSFC between the amygdala and various regions, including the supramariginal gyrus and middle frontal gyrus. However, at both levels, only was the amygdala-insula RSFC correlated with anxiety. Mediation analyses further revealed that the amygdala insula RSFC mediated the association between 5-HTTLPR and anxiety. In short, our study provided the first empirical evidence that the amygdala-insula RSFC served as the neural basis underlying the association between 5-HTTLPR and anxiety, suggesting a potential neurogenetic susceptibility mechanism for anxiety. PMID- 25833280 TI - Evidence of pulpotomy in primary teeth comparing MTA, calcium hydroxide, ferric sulphate, and electrosurgery with formocresol. AB - AIM: The aim of this study was to evaluate the scientific evidence of pulpotomy in primary teeth comparing mineral troxide aggregate (MTA), calcium hydroxide, ferric sulphate, and electrosurgery with formocresol. METHODS: A systematic search using key words was conducted using seven databases up to December 10, 2013. Clinical articles in English, Portuguese and Spanish were selected, which were in accordance with the inclusion and exclusion criteria and the research objective of comparing whether pulpotomy performed with formocresol in primary teeth is more effective than other medicaments or techniques. RESULTS: Out of the 12,515 publication initially identified, 30 clinical articles were included in the systematic review and analysed by four meta-analyses. The success rate of MTA (94.6 %) was higher than that of formocresol (87.4 %), with a statistically significant difference (OR = 0.39; 95 % CI = 0.25-0.62). Formocresol pulpotomy success was not statistically different from ferric sulphate or electrosurgery. CONCLUSION: MTA was clinically and radiographically superior to formocresol for pulpotomy of primary teeth. The other alternatives to formocresol such as electrosurgery and ferric sulphate can be used instead of formocresol since they showed success similar to formocresol. In addition, there is no evidence to support calcium hydroxide for pulpotomies in primary teeth. PMID- 25833283 TI - Is thoracic aortic disease a growing problem in Japan? AB - An article by Okita was recently published in General Thoracic and Cardiovascular Surgery. The paper thoroughly reviewed the surgical treatments for thoracic aortic disease in Japan. Valve-sparing aortic root operation, cerebral protection during aortic arch aneurysmectomy, and spinal cord protection during thoracoabdominal aneurysm repair are discussed in the present editorial. PMID- 25833284 TI - Abstracts of the australasian college of dermatologists 48th annual scientific meeting, 16 may 2015, adelaide, australia. PMID- 25833286 TI - Information Needs of Men with Localized Prostate Cancer During Radiation Therapy. AB - The purpose of this study was to describe how patient information needs change over the course of receiving radiation therapy for prostate cancer. Convenience sampling was utilized to recruit men with stage I-III prostate cancer. A longitudinal repeated measures design was implemented for this pilot study. Patients were presented with 36 paired comparisons, each asking the participant to choose the most important information topic(s) for today. Following completion of the survey instruments, the clinic nurse delivered the four top-ranked information topic handouts to each patient with brief instruction on how to use the handouts. Over the course of 6 months, we were able to recruit 35 men. The four highest priority topics across all four sessions were prognosis, stage of disease, treatment options, and side effects. Our results suggest trends in the information priorities that men hold over the course of radiation treatment. The information priorities do appear to shift over time, notably prognosis concerns and risk for family members continued to rise over time, while side effect information declined. These findings will extend an already strong foundation of evidence for preparatory information in radiation therapy. Furthermore, these findings will strengthen current evidence that computerized assessment of patient self-report information is feasible and an important adjunct to clinical practice. PMID- 25833287 TI - Introduction to the special issue: attachment-based treatments for adolescents. AB - During the past decade, new attachment-based treatments (ABTs) for adolescents have been developed and tested in both field and randomized control trials. The papers in this special issue represent important contributions to defining a more general model of ABTs for adolescents. Our discussion of these papers is organized by a series of challenges to developing and evaluating these treatments. We first consider how disturbances in the caregiver-adolescent attachment bond are implicated in adolescent psychopathology and family distress. We then describe different potential targets for attachment-based interventions for adolescents and their caregivers. Finally we review the different interventions and change mechanisms that have been used to increase security in the caregiver-adolescent bond. A general model of ABTs for adolescents can be useful in guiding future efforts to measure change in attachment constructs, evaluate the dynamic process of change in attachment bonds, and test the effectiveness of specific treatment elements in reducing adolescents' symptoms and increasing attachment security. PMID- 25833288 TI - Of goats and men: rethinking anaplasmoses as zoonotic infections. PMID- 25833289 TI - Human infection with a novel tick-borne Anaplasma species in China: a surveillance study. AB - BACKGROUND: Anaplasma phagocytophilum and Anaplasma ovis cause human infections. We investigated the potential for human pathogenicity of a newly discovered Anaplasma species infecting goats in China. METHODS: We collected blood samples from patients with a history of tick bite in the preceding 2 months at Mudanjiang Forestry Central Hospital of Heilongjiang Province from May 1, to June 10, 2014, to detect the novel Anaplasma species by PCR. We inoculated positive samples into cell cultures. We characterised the isolated pathogen by morphological and phylogenetic analyses. We tested serum antibodies by indirect immunofluorescence assay. FINDINGS: 28 (6%) of 477 patients assessed were infected with the novel Anaplasma species according to PCR and sequencing. We isolated the pathogen in vitro from three patients. Phylogenetic analyses of rrs, gltA, groEL, msp2, and msp4 showed that the pathogen was distinct from all known Anaplasma species. We provisionally nominate it "Anaplasma capra". 22 (92%) of 24 patients with data available had seroconversion or a four-fold increase in antibody titres. All 28 patients developed non-specific febrile manifestations, including fever in 23 (82%), headache in 14 (50%), malaise in 13 (46%), dizziness in nine (32%), myalgia in four (14%), and chills in four (14%). Additionally, ten (36%) of 28 patients had rash or eschar, eight (29%) had lymphadenopathy, eight (29%) had gastrointestinal symptoms, and three (11%) had stiff neck. Five patients were admitted to hospital because of severe disease. Six (35%) of 17 patients with data available had high hepatic aminotransferase concentrations. INTERPRETATION: The emergence of "A capra" as a cause of human disease suggests that individuals living in or travelling to endemic regions in northern China should take precautions to reduce their risk of exposure to this novel tick-borne pathogen. FUNDING: Natural Science Foundation of China and the US National Institutes of Health. PMID- 25833290 TI - Role of (64)CuCl 2 PET/CT in staging of prostate cancer. AB - AIM: The presence of an elevated copper concentration in cancer cells may be potentially used to differentiate healthy from transformed cells. In this study, we aimed to look at the possible role of (64)CuCl2 PET/CT in staging of patients with prostate cancer (PC). METHODS: Seven patients affected by histologically confirmed PC have been prospectively enrolled. Three patients underwent adrenal deprivation therapy (ADT) at time of imaging. The remaining four patients had no ADT, surgery, or external beam radiation therapy (EBRT). In all patients, up to three (64)CuCl2 PET/CT scans 10 min, 1 h and 3 h (and an additional scan 24 h in 2 patients) after administration of mean 339 MBq (64)CuCl2 were performed and analyzed for presence of disease. Additionally, dosimetric calculations were performed. All patients underwent a multiparametric magnetic resonance imaging (mMRI) for confirmation of disease. RESULTS: Lesions specifically in the pelvic area could be easily delineated, which was due to the absence of urinary excretion of the tracer. (64)CuCl2 uptake was higher in primary tumors of patients without ADT than in patients under bicalutamide therapy. In two patients with suspected lymphadenopathy at MRI (>10 mm diameter), there was no enhanced (64)CuCl2 uptake. In other two patients, there was focal enhanced uptake in involved pelvic lymph nodes, one of which with a normal size of <10 mm. CONCLUSIONS: The preliminary results of this study show a high uptake of (64)CuCl2 in PC and involved regional lymph nodes indicating to a great potential of (64)CuCl2 PET/CT for primary staging of patients with prostate cancer. PMID- 25833291 TI - Pulmonary solid tumor with coexisting pulmonary aspergillosis: case reports and literature review. AB - BACKGROUND AND AIMS: The association of noncavitary untreated lung cancer with coexisting pulmonary Aspergillosis in immunocompetent patients is an extremely rare occurrence. The present paper aims to summarize the clinical data, and gives an overview of the current knowledge on the etiology, diagnosis and treatment of this condition. METHODS: We report four cases and review seven cases in the literature. RESULTS: The four cases describe pulmonary solid tumor with coexisting pulmonary Aspergillosis condition. All cases underwent complicated procession for the terminal diagnosis. CONCLUSION: Clinicians should be alert to underlying malignant disease if airway Aspergillus infection is suspicious in a patient without strong risk factors for invasive fungal disease. On the other hand, when lung cancer is coexisting with airway necrotizing Aspergillosis, clinicians should properly manage these two diseases simultaneously. PMID- 25833293 TI - Acute Changes in Peripheral Vascular Tonus and Systemic Circulation during Static Stretching. AB - This study aimed to investigate the acute effect of static stretching (SS) on peripheral vascular tonus and to clarify the effect of SS on systemic circulation. Twenty healthy young male volunteers performed a 1-min SS motion of the right triceps surae muscle, repeated five times. The peripheral vascular tonus (|d/a| ratio) was obtained using second derivatives of the photoplethysmogram readings before, during, and after SS. Heart rate and blood pressure (BP) were also measured. The |d/a| ratio and BP were transiently, but significantly, elevated during SS and returned to baseline immediately after SS. Furthermore, we observed a significant correlation between the amount of change in the |d/a| ratio and the ankle range of motion during SS (r = 0.793 to 0.832, P = 0.01). These responses may be caused by mechanical stress during SS. PMID- 25833294 TI - Stochastic protein interactions monitored by hundreds of single-molecule plasmonic biosensors. AB - We present a plasmonic biosensor based on hundreds of individual gold nanorods with single-molecule sensitivity that are simultaneously monitored in real-time within a dark-field microscopy setup. The approach allows for the statistical analysis of single-molecule interactions without requiring any labeling of the analyte. We study an antibody-antigen interaction and find that the waiting-time distribution is concentration-dependent and obeys Poisson statistics. The ability to probe hundreds of nanoparticles simultaneously will provide a sensor with a dynamic range of 7 decades in concentration and will enable the study of heterogeneity in molecular interactions. PMID- 25833292 TI - Brief Report: Autocrine Cytokine-Mediated Deficiency of TRAIL-Induced Monocyte Apoptosis in Rheumatoid Arthritis. AB - OBJECTIVE: Dysregulated apoptosis of monocytes is a pathogenic feature of rheumatoid arthritis (RA). The aim of this study was to investigate the role of TRAIL and TRAIL-induced apoptosis in patients with RA. METHODS: Cell surface expression and serum concentrations of TRAIL were determined in 63 patients with RA, and TRAIL-induced monocyte apoptosis was quantified. Surface expression of TRAILR-1, TRAILR-2, TRAILR-3, TRAILR-4, CXCR1, and CXCR2 was determined, and intracellular signal transduction was investigated. In 8 patients with RA, clinical and laboratory parameters of disease activity were investigated longitudinally, before and after initiation of treatment with tumor necrosis factor (TNF) inhibitors. RESULTS: Serum concentrations of both TRAIL and interleukin-8 (IL-8) were increased in patients with RA, while cell surface expression of the TRAIL receptors TRAILR-1, TRAILR-2, TRAILR-3, and TRAILR-4 was diminished. TRAIL-induced monocyte apoptosis was significantly decreased in RA due to increased TRAIL-induced IL-8 secretion by RA monocytes. The combined effect of TRAIL and IL-8 on monocytes resulted in activation of antiapoptotic pathways, including p42/44 MAPK and p38. Susceptibility to TRAIL-induced apoptosis was restored in RA monocytes after 3 months of TNF inhibition. CONCLUSION: In RA, circulating monocytes with the potential to produce proinflammatory cytokines appear to have defects in several pathways of apoptosis induction, among which is a deficiency in TRAIL-induced apoptosis. Although this resistance to apoptosis might contribute to perpetuation of the disease, it remains to be determined whether specific induction of apoptosis could be therapeutically beneficial. PMID- 25833295 TI - Structural origin of the anisotropic and isotropic thermal expansion of K2NiF4 Type LaSrAlO4 and Sr2TiO4. AB - K2NiF4-type LaSrAlO4 and Sr2TiO4 exhibit anisotropic and isotropic thermal expansion, respectively; however, their structural origin is unknown. To address this unresolved issue, the crystal structure and thermal expansion of LaSrAlO4 and Sr2TiO4 have been investigated through high-temperature neutron and synchrotron X-ray powder diffraction experiments and ab initio electronic calculations. The thermal expansion coefficient (TEC) along the c-axis (alphac) being higher than that along the a-axis (alphaa) of LaSrAlO4 [alphac = 1.882(4)alphaa] is mainly ascribed to the TEC of the interatomic distance between Al and apical oxygen O2 alpha(Al-O2) being higher than that between Al and equatorial oxygen O1 alpha(Al-O1) [alpha(Al-O2) = 2.41(18)alpha(Al-O1)]. The higher alpha(Al-O2) is attributed to the Al-O2 bond being longer and weaker than the Al-O1 bond. Thus, the minimum electron density and bond valence of the Al-O2 bond are lower than those of the Al-O1 bond. For Sr2TiO4, the Ti-O2 interatomic distance, d(Ti-O2), is equal to that of Ti-O1, d(Ti-O1) [d(Ti-O2) = 1.0194(15)d(Ti-O1)], relative to LaSrAlO4 [d(Al-O2) = 1.0932(9)d(Al-O1)]. Therefore, the bond valence and minimum electron density of the Ti-O2 bond are nearly equal to those of the Ti-O1 bond, leading to isotropic thermal expansion of Sr2TiO4 than LaSrAlO4. These results indicate that the anisotropic thermal expansion of K2NiF4-type oxides, A2BO4, is strongly influenced by the anisotropy of B-O chemical bonds. The present study suggests that due to the higher ratio of interatomic distance d(B-O2)/d(B-O1) of A2(2.5+)B(3+)O4 compared with A2(2+)B(4+)O4, A2(2.5+)B(3+)O4 compounds have higher alpha(B-O2), and A2(2+)B(4+)O4 materials exhibit smaller alpha(B-O2), leading to the anisotropic thermal expansion of A2(2.5+)B(3+)O4 and isotropic thermal expansion of A2(2+)B(4+)O4. The "true" thermal expansion without the chemical expansion of A2BO4 is higher than that of ABO3 with a similar composition. PMID- 25833296 TI - Antibodies to BK virus in children prior to allogeneic hematopoietic cell transplant. AB - BK virus (BKV) is associated with kidney and bladder disease after hematopoietic cell transplantation (HCT) but less is known about the seroprevalence of pre transplant antibodies to BKV in children. We measured BKV IgG antibody titers in 36 children before HCT. BKV IgG antibodies were detected in all 36 patients, with 28/36 (77.8%) developing BK viremia in the first 100 days. Pre-HCT BKV IgG antibody titers >1:40,960 were protective against later BK viremia >=10,000 copies/ml. The seroprevalence of antibodies to BKV is high in children undergoing HCT and post-transplant BK viremia, which is associated with bladder and kidney injury, is common. PMID- 25833297 TI - CTGF positively regulates BMP12 induced tenogenic differentiation of tendon stem cells and signaling. AB - BACKGROUND/AIMS: Disordered differentiation of tendon stem cells (TSCs) during repair of injured tendon can result in the pathogenesis of chronic tendinopathy. Understanding tenocyte differentiation may provide new therapeutic insights for the prevention and treatment of chronic tendinopathy. The aim of our study was to determine if CTGF exerts a similar effect on BMP12-driven differentiation of rat TSCs. METHODS: In overexpressing and RNA interference CTGF TSCs, tenogenic differentitation and the expression of related genes were determined by immunofluorescence staining, quantitative PCR, and western blotting, with or without BMP12 treatment. The interaction in vitro between CTGF and BMP12 was detected by Chemical crosslinking assay. RESULTS: Our results showed that BMP12 effectively increased the expression of the tenocyte lineage markers scleraxis (Scx) and tenomodulin (Tnmd) at both mRNA and protein levels. Over-expression of CTGF from a lentiviral vector increased the expression of Scx and Tnmd as well as tendon proteins type I collagen (ColI) and tenascin-C (Tn-C) in TSCs compared to non-treated control cells with or without simultaneous BMP12 stimulation. Knockdown of CTGF expression decreased the expression of Scx, Tnmd, ColI and Tn-C compared to control cells. Chemical crosslinking experiments demonstrated a direct interaction between CTGF and BMP12. CONCLUSION: In conclusion, BMP12 plays a crucial role in tenogenesis via the Smad1/5/8 pathway, and CTGF positively promotes this effect. PMID- 25833298 TI - Hcmv-miR-UL22A-5p: A Biomarker in Transplantation With Broad Impact on Host Gene Expression and Potential Immunological Implications. AB - Cytomegalovirus (CMV) encodes multiple microRNAs. While these have been partially characterized in vitro, their relevance to clinical CMV infection has not been evaluated. We analyzed samples from a cohort of solid organ transplant patients with CMV disease (n = 245) for viral microRNA expression. Several CMV microRNAs were readily detectable in patients with CMV disease in variable relative abundance. Expression level generally correlated with DNA viral load and the absence of viral microRNA was associated with faster viral clearance. Detection of hcmv-miR-UL22A-5p at baseline independently predicted the recurrence of CMV viremia upon discontinuation of antiviral therapy (OR 3.024, 95% CI: 1.35-6.8; p = 0.007). A combination of direct mRNA targeting by the microRNA and indirect modulation of gene expression involving isoforms of the transcriptional regulator C-MYC may be responsible for the broad effects seen in the association of gene transcripts with the RNA-induced silencing complex and in global protein expression upon hcmv-miR-UL22A-5p transfection. This novel study of in vivo viral microRNA expression profiles provides unique insight into the complexity of clinical CMV infection following transplantation. We provide evidence that viral microRNAs may have complex effects on gene expression and be associated with specific virologic and clinical outcomes, and thus could be further evaluated as biomarkers. PMID- 25833300 TI - A dynamic and self-crosslinked polysaccharide hydrogel with autonomous self healing ability. AB - Natural polymeric hydrogels with self-healing capability that can recover the functionalities and structures of gels after damage are extremely attractive due to their emerging applications in the biomedical field. Here we report a self healable polymeric hydrogel by self-crosslinking two natural polymers acrylamide modified chitin (AMC) containing amino groups and oxidized alginate containing dialdehyde groups. The generation of the self-crosslinked hydrogel relies on the dynamic covalent linkage through Schiff base between the polysaccharide chains. The self-healing capability of the crosslinked hydrogel depends on the molar ratio of AMC and oxidized alginate and the surrounding pH. Under certain circumstances, the damaged hydrogel shows a complete recovery and can be stretched to a favorable extent, which is seldom observed for polysaccharide self healing hydrogel. Notably, we find that the self-healing ability can be "stored" by freeze-drying and "activated" by rehydration. In addition, we demonstrate that the hydrogel can be used as a soft template to guide the repair of inorganic materials like hydroxyapatite. We anticipate that this self-healable hydrogel consisting of biocompatible and biodegradable polysaccharides can be applied to various biomedical fields. PMID- 25833299 TI - Increased linear bone growth by GH in the absence of SOCS2 is independent of IGF 1. AB - Growth hormone (GH) signaling is essential for postnatal linear bone growth, but the relative importance of GHs actions on the liver and/or growth plate cartilage remains unclear. The importance of liver derived insulin like-growth factor-1 (IGF-1) for endochondral growth has recently been challenged. Here, we investigate linear growth in Suppressor of Cytokine Signaling-2 (SOCS2) knockout mice, which have enhanced growth despite normal systemic GH/IGF-1 levels. Wild type embryonic ex vivo metatarsals failed to exhibit increased linear growth in response to GH, but displayed increased Socs2 transcript levels (P < 0.01). In the absence of SOCS2, GH treatment enhanced metatarsal linear growth over a 12 day period. Despite this increase, IGF-1 transcript and protein levels were not increased in response to GH. In accordance with these data, IGF-1 levels were unchanged in GH-challenged postnatal Socs2(-/-) conditioned medium despite metatarsals showing enhanced linear growth. Growth-plate Igf1 mRNA levels were not elevated in juvenile Socs2(-/-) mice. GH did however elevate IGF-binding protein 3 levels in conditioned medium from GH challenged metatarsals and this was more apparent in Socs2(-/-) metatarsals. GH did not enhance the growth of Socs2(-/-) metatarsals when the IGF receptor was inhibited, suggesting that IGF receptor mediated mechanisms are required. IGF-2 may be responsible as IGF-2 promoted metatarsal growth and Igf2 expression was elevated in Socs2(-/-) (but not WT) metatarsals in response to GH. These studies emphasise the critical importance of SOCS2 in regulating GHs ability to promote bone growth. Also, GH appears to act directly on the metatarsals of Socs2(-/-) mice, promoting growth via a mechanism that is independent of IGF-1. PMID- 25833302 TI - Acid suppressing therapy as a risk factor for Candida esophagitis. AB - Studies were reviewed from PubMed for risk factors for the development, recurrence, prevention and therapy of Candida esophagitis, and for mechanisms induced by acid-suppressing therapy potentially influencing these factors. Documented observations included greatly increased Candida populations in the mouth, esophagus, stomach, and upper small intestine induced by acid-suppressing therapy. Among patients without HIV disease, PPI consumers more frequently had developed Candida esophagitis than did non-consumers and had also developed its recurrences more frequently. Similar phenomena associated with H2 -blocker use were less intense, and the possibility of similar phenomena in patients with HIV disease apparently had not yet been examined in spite of their high frequency of this disorder. PPI-induced elimination of the gastric acid barrier is a major mechanism leading to oro-pharyngeal and esophageal candida colonization, while PPI-induced impairment of absorption of most orally administered antifungal agents may limit the prophylactic and therapeutic success of these agents. These observations suggest potential value in limiting PPI use in populations of patients with Candida infections including esophagitis, as well as in patients at risk for their development, and also suggest that post-PPI rebound acid hypersecretion may provide additional anti-Candida benefit. Studies designed to develop the risk-benefit ratios of PPI use in these patients deserve investigation with high priority appropriate for studies in patients with HIV disease. PMID- 25833301 TI - Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. AB - Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy proven EMD was identified, comprising 8.3% of the total study population. EMD was present at the time of diagnosis in 14.5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4.1 years (95% CI: 3.1, 5.1) and the median overall survival from time of EMD diagnosis was 1.3 years (95% CI: 0.8, 2.3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation. PMID- 25833303 TI - The phrenic nerve as a donor for brachial plexus injuries: is it safe and effective? Case series and literature analysis. AB - BACKGROUND: Controversy exists surrounding the use of the phrenic nerve for transfer in severe brachial plexus injuries. The objectives of this study are: (1) to present the experience of the authors using the phrenic nerve in a single institution; and (2) to thoroughly review the existing literature to date. METHODS: Adult patients with C5-D1 and C5-C8 lesions and a phrenic nerve transfer were retrospectively included. Patients with follow-up shorter than 18 months were excluded. The MRC muscle strength grading system was used to rate the outcome. Clinical repercussions relating to sectioning of the phrenic nerve were studied. An intense rehabilitation program was started after surgery, and compliance to this program was monitored using a previously described scale. Statistical analysis was performed with the obtained data. RESULTS: Fifty-one patients were included. The mean time between trauma and surgery was 5.7 months. Three-quarters of the patients had C5-D1, with the remainder C5-C8. Mean post operative follow-up was 32.5 months A MRC of M4 was achieved in 62.7% patients, M3 21.6%, M2 in 3.9%, and M1 in 11.8%. The only significant differences between the two groups were in graft length (9.8 vs. 15.1 cm, p = 0.01); and in the rehabilitation compliance score (2.86 vs. 2.00, p = 0.01). CONCLUSIONS: Results of phrenic nerve transfer are predictable and good, especially if the grafts are short and the rehabilitation is adequate. It may adversely affect respiratory function tests, but this rarely correlates clinically. Contraindications to the use of the phrenic nerve exist and should be respected. PMID- 25833304 TI - Subsidence as of 12 months after single-level anterior cervical inter-body fusion. Is it related to clinical outcomes? AB - BACKGROUND: Subsidence is a frequent phenomenon in the interbody fusion process in patients with anterior cervical discectomy and fusion (ACDF). There is little evidence of whether subsidence in the cervical spine has any impact on clinical outcomes. OBJECTIVES: The purpose of this study is to investigate the correlation of subsidence and clinical outcomes after ACDF and to consider reasons subsidence might not cause unfavorable clinical outcomes. METHODS: A total of 158 consecutive patients who underwent single-level ACDF were included. The patients were divided into a subsidence group (S-group) and a no subsidence group (N group), with subsidence defined as a decrease by >=3 mm in total intervertebral height (TIH). We analyzed outcomes resulting from subsidence, particularly focusing on clinical outcomes and subsequent global and segmental kyphosis using a repeated measure analysis of variance (RM-ANOVA). RESULTS: Subsidence occurred in 74 patients (46.8%) as of a 12-month follow-up. The S-group included 58.6% with a stand-alone cage for interbody fusion (p = 0.002). Clinical outcomes improved significantly over time (neck pain, RM-ANOVA: F(1.3, 205) = 125.1, p < 0.001; arm pain, RM-ANOVA: F(1.3, 203) = 290.8, p < 0.001). There was no significant difference in interaction with subsidence and clinical outcomes between the S- and N-group (neck pain, RM-ANOVA: F(2,153) = 1.04, p = 0.356, partial eta(2) = 0.229; arm pain, RM-ANOVA: F(2,153) = 0.56, p = 0.571, partial eta(2) = 0.142). Segmental angle increased in both groups over time and showed a statistically significant difference between the S- and N-groups (RM-ANOVA: F(3,143) = 6.148, p = 0.001, partial eta(2) = 0.959). Although, global cervical angle decreased generally and displayed no statically significant difference between the S- and N-group (RM-ANOVA: F(3,119) = 2.361, p = 0.075, partial eta(2) = 0.056). CONCLUSIONS: Radiographic subsidence after ACDF occurred in 46.8% patients as of 12 months after the single-level ACDF. The lack of correlation between bad clinical outcome and radiographic subsidence may be due to segmental kyphosis, preserved posterior height, and maintaining the global cervical angle. PMID- 25833305 TI - Nanophotonic control of circular dipole emission. AB - Controlling photon emission by single emitters with nanostructures is crucial for scalable on-chip information processing. Nowadays, nanoresonators can affect the lifetime of linear dipole emitters, while nanoantennas can steer the emission direction. Expanding this control to the emission of orbital angular momentum changing transitions would enable a future coupling between solid state and photonic qubits. As these transitions are associated with circular dipoles, such control requires knowledge of the interaction of a complex dipole with optical eigenstates containing local helicity. We experimentally map the coupling of classical, circular dipoles to photonic modes in a photonic crystal waveguide. We show that, depending on the combination of the local helicity of the mode and the dipole helicity, circular dipoles can couple to left- or rightwards propagating modes with a near-unity directionality. The experimental maps are in excellent agreement with calculations. Our measurements, therefore, demonstrate the possibility of coupling the spin to photonic pathway. PMID- 25833307 TI - CCR 20th Anniversary commentary: in search of cetuximab's first indication combination therapy with irinotecan in colorectal cancer. AB - The research article by Prewett and colleagues, published in the May 1, 2002, issue of Clinical Cancer Research, provided important translational data that extended earlier preclinical and clinical studies with the human-murine chimeric anti-EGFR monoclonal antibody C225. Subsequent clinical trials with C225 led to the demonstration of its efficacy in combination with irinotecan and regulatory approval for the treatment of metastatic colorectal cancer. PMID- 25833308 TI - Conditional Survival: A Useful Concept to Provide Information on How Prognosis Evolves over Time. AB - Conditional survival (CS) is defined as the probability of surviving further t years, given that a patient has already survived s years after the diagnosis of a chronic disease. It is the simplest form of a dynamic prediction in which other events in the course of the disease or biomarker values measured up to time s can be incorporated. CS has attracted attention in recent years either in an absolute or relative form where the latter is based on a comparison with an age-adjusted normal population being highly relevant from a public health perspective. In its absolute form, CS constitutes the quantity of major interest in a clinical context. Given a clinical cohort of patients with a particular type of cancer, absolute CS can be estimated by conditional Kaplan-Meier estimates in strata defined, for example, by age and disease stage or by a conditional version of the Cox and other regression models for time-to-event data. CS can be displayed as a function of the prediction time s in parametric as well as nonparametric fashion. We illustrate the use of absolute CS in a large clinical cohort of patients with multiple myeloma. For investigating CS, it is necessary to ensure almost complete long-term follow-up of the patients enrolled in the clinical cohort and to consider potential age-stage migration as well as changing treatment modalities over time. CS provides valuable and relevant information on how prognosis develops over time. It also serves as a starting point for identifying factors related to long-term survival. PMID- 25833309 TI - Correction: Molecular Pathways: Targeting the Kinase Effectors of RHO-Family GTPases. PMID- 25833310 TI - Correction: TRAIL and Doxorubicin Combination Induces Proapoptotic and Antiangiogenic Effects in Soft Tissue Sarcoma In Vivo. PMID- 25833311 TI - Correction: Combining PCI-24781, a Novel Histone Deacetylase Inhibitor, with Chemotherapy for the Treatment of Soft Tissue Sarcoma. PMID- 25833313 TI - Substantial production of drosophilin A methyl ether (tetrachloro-1,4 dimethoxybenzene) by the lignicolous basidiomycete Phellinus badius in the heartwood of mesquite (Prosopis juliflora) trees. AB - Toxic organohalogen pollutants produced as by-products of industrial processes, such as chloroform and polychlorinated dibenzo-p-dioxins, also have significant natural sources. A substantial terrestrial source of halogenated organics originates from fungal decay of wood and leaf litter. Here we show that the lignicolous basidiomycete Phellinus badius deposits up to 30,000 mg of the halogenated metabolite drosophilin A methyl ether (DAME, tetrachloro-1,4 dimethoxybenzene) per kilogram of decayed heartwood in the mesquite Prosopis juliflora. DAME occurs as clusters of glassy crystals up to 1 mm long within the decayed heartwood. In addition, the Phellinus badius basidiocarps contain an average of 24,000 mg DAME/kg dried fruiting body, testifying to the significant translocation and accumulation of Cl accompanied by DAME biosynthesis. The high DAME concentrations attest to the substantial Cl content of the heartwood, which averages near 5,000 ppm, with Cl/K near 1:1, consistent with an inorganic chloride precursor. Phellinus badius has a circumglobal distribution in the tropics and subtropics, where it is widely distributed on hardwoods and commonly associated with decay of mesquite. There is the potential for extensive DAME formation within decayed heartwood worldwide given the extensive range of Phellinus badius and its propensity to form DAME within mesquites. Further, DAME production is not limited to Phellinus badius but occurs in a range of lignicolous basidiomycetes, suggesting a significant natural reservoir for this chloroaromatic with potential environmental implications. PMID- 25833312 TI - Synergism of ursolic acid derivative US597 with 2-deoxy-D-glucose to preferentially induce tumor cell death by dual-targeting of apoptosis and glycolysis. AB - Ursolic acid (UA) is a naturally bioactive product that exhibits potential anticancer effects. The relatively safe and effective molecule intrigued us to explore a way to further improve its anti-cancer activity and tumor-targeting specificity. In the present study, a series of structural modifications of UA was achieved, which resulted in significant increase in growth inhibition on various cancer cell lines with minimal effects on normal cells. The leading molecule US597 (UA-4) caused depolarization of mitochondrial membrane potential, cell arrest in G0/G1 phase and apoptosis/necrosis in a dose-dependent manner. Structural docking suggested that the carbon chains of the modified UA derivatives compete strongly with glucose for binding to glucokinase, the key glycolysis enzyme presumably active in cancer cells. The combination of 2-deoxy-D glucose (2-DG) and UA-4 induced cell cycle arrest in G2/M phase, promoted caspase dependent cell death, reduced hexokinase activity, aggravated depletion of intracellular ATP, decreased lactate production and synergistically inhibited cancer cell growth in vitro (HepG2) and in vivo (H22). Collectively, our findings suggest that the structural modification enhances efficacy and selectivity of UA, and the combination of UA-4 with 2-DG produces synergistic inhibition on hepatoma cell proliferation by dual targeting of apoptosis and glycolysis. PMID- 25833315 TI - Electronic transport in benzodifuran single-molecule transistors. AB - Benzodifuran (BDF) single-molecule transistors have been fabricated in electromigration break junctions for electronic measurements. The inelastic electron tunneling spectrum validates that the BDF molecule is the pathway of charge transport. The gating effect is analyzed in the framework of a single level tunneling model combined with transition voltage spectroscopy (TVS). The analysis reveals that the highest occupied molecular orbital (HOMO) of the thiol terminated BDF molecule dominates the charge transport through Au-BDF-Au junctions. Moreover, the energy shift of the HOMO caused by the gate voltage is the main reason for conductance modulation. In contrast, the electronic coupling between the BDF molecule and the gold electrodes, which significantly affects the low-bias junction conductance, is only influenced slightly by the applied gate voltage. These findings will help in the design of future molecular electronic devices. PMID- 25833314 TI - Chlamydia pneumoniae and Chlamydia Trachomatis Infection Differentially Modulates Human Dendritic Cell Line (MUTZ) Differentiation and Activation. AB - Chlamydia trachomatis and Chlamydia pneumoniae are important human pathogens that infect the urogenital/anorectal and respiratory tracts, respectively. Whilst the ability of these bacteria to infect epithelia is well defined, there is also considerable evidence of infection of leucocytes, including dendritic cells (DCs). Using a human dendritic cell line (MUTZ), we demonstrate that the infection and replication of chlamydiae inside DCs is species and serovar specific and that live infection with C. pneumoniae is required to upregulate costimulatory markers CD80, CD83 and human leucocyte antigen (HLA)-DR on MUTZ cells, as well as induce secretion of interleukin (IL)-2, IL-6, IL-8, IL-12 (p70), interferon-gamma and tumour necrosis factor-alpha Conversely, C. trachomatis serovar D failed to upregulate DC costimulatory markers, but did induce secretion of high concentrations of IL-8. Interestingly, we also observed that infection of MUTZ cells with C. pneumoniae or C. trachomatis serovar L2, whilst not replicative, remained infectious and upregulated lymph node migratory marker CCR7 mRNA. Taken together, these data confirm the findings of other groups using primary DCs and demonstrate the utility of MUTZ cells for further studies of chlamydial infection. PMID- 25833316 TI - Genetic Approaches To Identifying Novel Osteoporosis Drug Targets. AB - During the past two decades effective drugs for treating osteoporosis have been developed, including anti-resorptives inhibiting bone resorption (estrogens, the SERM raloxifene, four bisphosphonates, RANKL inhibitor denosumab) and the anabolic bone forming daily injectable peptide teriparatide. Two potential drugs (odanacatib and romosozumab) are in late stage clinical development. The most pressing unmet need is for orally active anabolic drugs. This review describes the basic biological studies involved in developing these drugs, including the animal models employed for osteoporosis drug development. The genomics revolution continues to identify potential novel osteoporosis drug targets. Studies include human GWAS studies and identification of mutant genes in subjects having abnormal bone mass, mouse QTL and gene knockouts, and gene expression studies. Multiple lines of evidence indicate that Wnt signaling plays a major role in regulating bone formation and continued study of this complex pathway is likely to lead to key discoveries. In addition to the classic Wnt signaling targets DKK1 and sclerostin, LRP4, LRP5/LRP6, SFRP4, WNT16, and NOTUM can potentially be targeted to modulate Wnt signaling. Next-generation whole genome and exome sequencing, RNA sequencing and CRISPR/CAS9 gene editing are new experimental techniques contributing to understanding the genome. The International Knockout Mouse Consortium efforts to knockout and phenotype all mouse genes are poised to accelerate. Accumulating knowledge will focus attention on readily accessible databases (Big Data). Efforts are underway by the International Bone and Mineral Society to develop an annotated Skeletome database providing information on all genes directly influencing bone mass, architecture, mineralization or strength. PMID- 25833317 TI - Further evidence for a pain pathway involving the cingulate gyrus: a case of chronic cluster headache cured by glioblastoma. AB - The authors report a case of a 49-year-old man with long-standing, chronic cluster headache (CH) refractory to medical therapy and occipital nerve stimulation that resolved a few weeks prior to the diagnosis of glioblastoma involving primarily the right cingulate gyrus. An attempt to explore the underlying role of the cingulate cortex in pain modulation by appraising the current literature is presented. This report suggests that the cingulate gyri could be a potential target for neuromodulation in patients with medically refractory chronic CH. PMID- 25833318 TI - Efficacy of a vaporization-resection of the prostate median lobe enlargement and vaporization of the prostate lateral lobe for benign prostatic hyperplasia using a 120-W GreenLight high-performance system laser: the effect on storage symptoms. AB - GreenLight laser photoselective vaporization of the prostate (PVP) was established as a minimally invasive procedure to treat patients with benign prostatic hyperplasia (BPH). However, it may be difficult to achieve adequate tissue removal from a large prostate, particularly those with an enlarged median lobe. The purpose of this study was to investigate the feasibility and clinical effect of a 120-W GreenLight high-performance system laser vaporization-resection for an enlarged prostate median lobe compared with those of only vaporization. A total of 126 patients from January 2010 to January 2014 had an enlarged prostate median lobe and were included in this study. Ninety-six patients underwent vaporization only (VP group), and 30 patients underwent vaporization-resection for an enlarged median lobe (VR group). The clinical outcomes were International Prostate Symptoms Score (IPSS), quality of life (QOL), maximum flow rate (Q max), and post-void residual urine volume (PVR) assessed at 1, 3, 6, and 12 months postoperatively between the two groups. The parameters were not significantly different preoperatively between the two groups, except for PVR. Operative time and laser time were shorter in the VR group than those in the VP group. (74.1 vs. 61.9 min and 46.7 vs. 37.8 min; P = 0.020 and 0.013, respectively) and used less energy (218.2 vs. 171.8 kJ, P = 0.025). Improved IPSS values, increased Q max, and a reduced PVR were seen in the two groups. In particular, improved storage IPSS values were higher at 1 and 3 months in the VR group than those in the VP group (P = 0.030 and 0.022, respectively). No significant complications were detected in either group. Median lobe tissue vaporization-resection was complete, and good voiding results were achieved. Although changes in urinary symptoms were similar between patients who received the two techniques, shorter operating time and lower energy were superior with the vaporization-resection technique. In addition, vaporization-resection may have a beneficial effect on storage symptoms. PMID- 25833319 TI - Knowledge and Attitudes of Cervical Cancer Screening Among Caribbean Women: A Qualitative Interview Study From Barbados. AB - The purpose of this study was to explore Barbadian women's attitudes toward and knowledge of routine cervical cancer screening (Pap tests). We conducted semi structured individual interviews with fourteen female patients between the ages of 20 and 60 years who attended a selected public clinic in Barbados in May and June 2013. Interviews were audio-recorded with participants' consent. The interviews were then transcribed verbatim and, using thematic content analysis, indexed and coded inductively for emerging similar themes. We identified four themes: (1) women had poor knowledge of the purpose of Pap tests. The most frequently occurring misconception was that the test was for the detection of sexually transmitted infections. (2) The women displayed limited cervical cancer awareness. (3) Health professionals were identified by the women as the main driving force behind women taking up screening. (4) The screening procedure was perceived as painful, but women's overriding attitude was that screening was necessary. These findings suggest that Barbadian women would benefit from focused health education efforts surrounding cervical cancer screening to eradicate the misconception that the purpose of the Pap test is the detection of sexually transmitted diseases. PMID- 25833320 TI - Cytomegalovirus glycoprotein B genotypes in Mexican children and women. AB - OBJECTIVE: Cytomegalovirus (CMV) is widely distributed and constitutes the main cause of congenital infections worldwide. CMV transmission during pregnancy represents one of the major impacts of this virus on public health. This study aimed at assessing glycoprotein B (gB) CMV genotypes in Mexican children and pregnant women, since there is limited information regarding CMV genomic diversity in Mexico. METHODS: We analyzed CMV strains detected in Mexican children (n = 38) and women (n = 38) between 2001 and 2012. A fragment of the gB gene was amplified and sequenced, and genotypes were defined based on prototype sequences. RESULTS: The gB1 genotype was detected more frequently in children (68.4%) compared to women (31.6%; p = 0.0028), while genotype 2 was more common in women (65.8%) compared to children (26.3%, p = 0.0012). Genotype 3 was uncommon in both groups (5.3 and 2.6%). Nucleotide sequences exhibited a high degree of similarity to prototype strains. However, we identified 17 distinct sequences that resulted in changes in the encoded amino acid sequence in four strains. CONCLUSIONS: gB1 and gB2 are the most common strains associated with CMV infection in Mexican children and women. In addition, we found that the frequency for each genotype differed amongst them, possibly due to variability in transmission or reactivation dynamics. PMID- 25833321 TI - The empirical status of psychodynamic psychotherapy - an update: Bambi's alive and kicking. AB - BACKGROUND: The Task Force on Promotion and Dissemination of Psychological Procedures proposed rigorous criteria to define empirically supported psychotherapies. According to these criteria, 2 randomized controlled trials (RCTs) showing efficacy are required for a treatment to be designated as 'efficacious' and 1 RCT for a designation as 'possibly efficacious'. Applying these criteria modified by Chambless and Hollon, this article presents an update on the evidence for psychodynamic therapy (PDT) in specific mental disorders. METHODS: A systematic search was performed using the criteria by Chambless and Hollon for study selection, as follows: (1) RCT of PDT in adults, (2) use of reliable and valid measures for diagnosis and outcome, (3) use of treatment manuals or manual-like guidelines, (4) adult population treated for specific problems and (5) PDT superior to no treatment, placebo or alternative treatment or equivalent to an established treatment. RESULTS: A total of 39 RCTs were included. Following Chambless and Hollon, PDT can presently be designated as efficacious in major depressive disorder (MDD), social anxiety disorder, borderline and heterogeneous personality disorders, somatoform pain disorder, and anorexia nervosa. For MDD, this also applies to the combination with pharmacotherapy. PDT can be considered as possibly efficacious in dysthymia, complicated grief, panic disorder, generalized anxiety disorder, and substance abuse/dependence. Evidence is lacking for obsessive-compulsive, posttraumatic stress, bipolar and schizophrenia spectrum disorder(s). CONCLUSIONS: Evidence has emerged that PDT is efficacious or possibly efficacious in a wide range of common mental disorders. Further research is required for those disorders for which sufficient evidence does not yet exist. PMID- 25833322 TI - Highly Efficient Solid-Phase Labeling of Saccharides within Boronic Acid Functionalized Mesoporous Silica Nanoparticles. AB - Labeling is critical for the detection, quantitation, and structural identification of saccharides. However, conventional liquid-phase labeling suffers from apparent disadvantages, such as time-consuming, the presence of excessive labeling reagent, and high applicable saccharide concentration. A solid phase approach is presented for highly efficient labeling of saccharides, using boronic acid functionalized mesoporous silica nanoparticles (MSNs) as a selective extraction sorbent and nanoscale reactor. The solid-phase labeling approach exhibited several significant advantages, including: much faster reaction speed (taking only 2 min), high product purity, and much lower applicable saccharide concentration (four orders of magnitude lower than that of liquid-phase labeling). Thus, this labeling approach opens up new avenues to the facile and efficient labeling of saccharides. PMID- 25833323 TI - Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) patients suffer from a poor survival rate and a high incidence of postoperative recurrence. The hepatic microenvironment plays a significant role in the initiation, progression, and recurrence of HCC; however, the causal mechanisms of these phenomena are unclear. Given the predominant underlying fibrotic and cirrhotic conditions of the liver prone to HCC and its recurrence, alterations of components of the inflammatory milieu have been suggested as factors that promote HCC development. In particular, activated hepatic stellate cells (A-HSCs), which play a key role in liver fibrosis and cirrhosis, have been suggested as contributors to the HCC-prone microenvironment. Here, we have identified and validated an A-HSC-specific gene expression signature among nontumor tissues of 319 HCC patients that is significantly and independently associated with HCC recurrence and survival. Peritumoral, rather than tumor tissue-related, A-HSC-specific gene expression is associated with recurrence and poor survival. Analyses of A-HSC-specific gene signatures and further immunohistochemical validation in an additional 143 HCC patients have revealed that A-HSCs preferentially affect monocyte populations, shifting their gene expression from an inflammatory to an immunosuppressive signature. In addition, the interaction between A-HSCs and monocytes induces protumorigenic and progressive features of HCC cells by enhancing cell migration and tumor sphere formation. CONCLUSION: A-HSCs play a significant role in promoting HCC progression through interaction with and alteration of monocyte activities within the liver microenvironment; thus, disrupting the interactions and signaling events between the inflammatory milieu and components of the microenvironment may be useful therapeutic strategies for preventing HCC tumor relapse. PMID- 25833325 TI - Identification of amino acid residues involved in hemin binding in Porphyromonas gingivalis hemagglutinin 2. AB - Porphyromonas gingivalis (P. gingivalis) is a major etiological agent in the development and progression of chronic periodontitis. It produces cysteine proteases (gingipains), including a lysine-specific gingipain and two arginine specific gingipains. Heme binding and uptake are fundamental to the growth and virulence of P. gingivalis. The recombinant hemagglutinin 2 domain (rHA2) of gingipain binds hemin with high affinity. The aim of the present work was to identify the key residues involved in its hemin-binding activity. A functional rHA2 was expressed and bound to hemin-agarose, and then digested with endopeptidases. The peptides bound to hemin-agarose were identified by mass spectrometry and the amino acids were assessed by mutation and peptide binding inhibition analysis. The DHYAVMISK sequence was identified in peptides derived from both Asp-N and Lys-C endopeptidase digestions of rHA2. A monoclonal antibody, mAb QB, was produced and its epitope was associated with the DGFPGDHYAVMISK peptide within the HA2 domain. Hemin was shown to competitively inhibit the immunoreactivity of rHA2 or the peptide to mAb QB. The peptide DHYAVMISK inhibited hemin-binding activity; although, this inhibition was not seen when the peptide contained the H1001E mutation (DEYAVMISK). Based on these results, we propose that residue His1001 is involved in the hemin-binding mechanism of the P. gingivalis rHA2 and the peptide containing this residue, DHYAVMISK, may be an inhibitor of hemin binding. PMID- 25833326 TI - An apple a day does not keep the doctor away, US study finds. PMID- 25833327 TI - Primary and secondary stabbing headache. AB - Eight out of the 33 cases of primary stabbing headache seen in a general neurology clinic (40% have headache as their chief complaint) in the last 3.5 years are presented. The epidemiology, association with other primary headache disorders, secondary associations, testing, and treatment of primary stabbing headache are reviewed. PMID- 25833329 TI - Respiratory-gated (4D) FDG-PET detects tumour and normal lung response after stereotactic radiotherapy for pulmonary metastases. AB - BACKGROUND: Response assessment after stereotactic ablative body radiotherapy (SABR) in lung can be confounded by radiation-induced inflammation, fibrosis and subsequent alteration of tumour motion. The purpose of this prospective pilot study was to evaluate the utility of four-dimensional (4D) FDG-PET/CT for post SABR tumour and normal lung response assessment in pulmonary oligometastases. MATERIAL AND METHODS: Patients enrolled from February 2010 to December 2011 in this prospective ethics approved study had 1-2 pulmonary metastases on staging FDG-PET. Serial contemporaneous 3D and 4D FDG-PET/CT scans were performed at baseline, 14 days and 70 days after a single fraction of 26 Gy SABR. Tumour response was evaluated in 3D and 4D using SUVmax, RECIST and PERCIST criteria. Normal lung radiotoxicity was evaluated using SUVmean within 0-2 Gy, 2-5 Gy, 5-10 Gy, 10-20 Gy and 20 + Gy isodose volumes. RESULTS: In total, 17 patients were enrolled of which seven were ineligible due to interval progression from staging PET to baseline 4D-PET. The mean time between scans was 62 days. At a median follow-up of 16 months, 10 patients with 13 metastases received SABR, with no patient having local progression. The vector of tumour motion was larger in patients with discordant 3D and 4D PET PERCIST response (p < 0.01), with a mean (+/- SEM) motion of 10.5 mm (+/- 0.96 mm) versus 6.14 mm (+/- 0.81 mm) in those patients with concordant 3D and 4D response. Surrounding normal lung FDG uptake at 70 days was strongly correlated to delivered radiation dose (r(2) = 0.99, p < 0.01), with significant elevations across all dose levels (p <= 0.05), except the < 2 Gy volume (p = 0.30). CONCLUSIONS: We demonstrate high rates of interval progression between staging PET scans in patients with oligometastases. We found that tumour response on conventional 3D PET is not concordant with 4D PET for tumours with large motion. Normal lung metabolic uptake is strongly dose dependent after SABR, a novel finding that should be further validated. PMID- 25833328 TI - Sick leave and disability pension among Swedish testicular cancer survivors according to clinical stage and treatment. AB - PURPOSE: To investigate if testicular cancer survivors (TCSs) have a higher incidence of work loss compared with the population, accounting for stage, treatment and relapse. MATERIAL AND METHODS: A cohort of 2146 Swedish TCSs diagnosed 1995-2007 (seminoma n = 926, non-seminoma n = 1220) was identified in the SWENOTECA (Swedish-Norwegian Testicular Cancer Group) register, and matched 1:4 to population comparators. Prospectively recorded work loss data (both before and after diagnosis) were obtained from national registers through September 2013. Adjusted relative risks (RR) and 95% confidence intervals (CI) of sick leave and/or disability pension were calculated annually and overall with Poisson and Cox regression, censoring at relapse. The mean number of annual work days lost was also estimated. RESULTS: TCSs were at a modestly increased annual risk of work loss up to the third year of follow-up (RR3rd year 1.25, 95% CI 1.08, 1.43), attributed to a more pronounced risk among extensively treated patients (4 chemotherapy courses: RR3rd year 1.60, 95% CI 1.19, 2.15; > 4 courses: RR3rd year 3.70, 95% CI 2.25, 6.11). Patients on surveillance or limited treatment (radiotherapy, 1-3 chemotherapy courses) did not have an increased risk of work loss beyond the first year. TCSs receiving > 4 chemotherapy courses had higher mean number of annual days of work loss up to the 10th year post-diagnosis, and a five-fold risk of disability pension (RR 5.16, 95% CI 2.00, 10.3). CONCLUSION: Extensively treated TCSs, but not those on surveillance or limited treatment, are at increased risk of work loss long-term, not explained by relapse. These patients may benefit from early rehabilitation initiatives. PMID- 25833330 TI - Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial. AB - PURPOSE: Detection of bone metastases in breast and prostate cancer patients remains a major clinical challenge. The aim of the current trial was to compare the diagnostic accuracy of (99m)Tc-hydroxymethane diphosphonate ((99m)Tc-HDP) planar bone scintigraphy (BS), (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and whole body 1.5 Tesla magnetic resonance imaging (MRI), including diffusion weighted imaging, (wbMRI+DWI) for the detection of bone metastases in high risk breast and prostate cancer patients. MATERIAL AND METHODS: Twenty-six breast and 27 prostate cancer patients at high risk of bone metastases underwent (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI. Five independent reviewers interpreted each individual modality without the knowledge of other imaging findings. The final metastatic status was based on the consensus reading, clinical and imaging follow-up (minimal and maximal follow-up time was 6, and 32 months, respectively). The bone findings were compared on patient-, region-, and lesion-level. RESULTS: (99m)Tc-HDP BS was false negative in four patients. In the region-based analysis, sensitivity values for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT, and wbMRI+DWI were 62%, 74%, 85%, 93%, and 91%, respectively. The number of equivocal findings for (99m)Tc-HDP BS, (99m)Tc-HDP SPECT, (99m)Tc-HDP SPECT/CT, (18)F-NaF PET/CT and wbMRI+DWI was 50, 44, 5, 6, and 4, respectively. CONCLUSION: wbMRI+DWI showed similar diagnostic accuracy to (18)F-NaF PET/CT and outperformed (99m)Tc-HDP SPECT/CT, and (99m)Tc-HDP BS. PMID- 25833331 TI - CXCR7 Mediates Neural Progenitor Cells Migration to CXCL12 Independent of CXCR4. AB - Neural progenitor cell (NPC) migration is an essential process for brain development, adult neurogenesis, and neuroregeneration after brain injury. Stromal cell-derived factor-1 (SDF-1, CXCL12) and its traditional receptor CXCR4 are well known to regulate NPC migration. However, the discovery of CXCR7, a newly identified CXCL12 receptor, adds to the dynamics of the existing CXCL12/CXCR4 pair. Antagonists for either CXCR4 or CXCR7 blocked CXCL12-mediated NPC migration in a transwell chemotaxis assay, suggesting that both receptors are required for CXCL12 action. We derived NPC cultures from Cxcr4 knockout (KO) mice and used transwell and stripe assays to determine the cell migration. NPCs derived from Cxcr4 KO mice polarized and migrated in response to CXCL12 gradient, suggesting that CXCR7 could serve as an independent migration receptor. Furthermore, Cxcr4 KO NPCs transplanted into the adult mouse striatum migrated in response to the adjacent injection of CXCL12, an effect that was blocked by a CXCR7 antagonist, suggesting that CXCR7 also mediates NPC migration in vivo. Molecular mechanism studies revealed that CXCR7 interact with Rac1 in the leading edge of the polarized NPCs in the absence of CXCR4. Both CXCR7 and Rac1 are required for extracellular signal-regulated kinases (ERK) 1/2 activation and subsequent NPC migration, indicating that CXCR7 could serve as a functional receptor in CXCL12-mediated NPC migration independent of CXCR4. Together these results reveal an essential role of CXCR7 for CXCL12-mediated NPC migration that will be important to understand neurogenesis during development and in adulthood. PMID- 25833332 TI - Cost analysis of early versus delayed loop ileostomy closure: a case-matched study. AB - BACKGROUND/AIMS: The optimal timing for the closure of loop ileostomies remains controversial. The aim of the current study was to investigate whether early ileostomy closure (EC) (<2 weeks post-formation) results in significant healthcare savings as against late closure (LC). METHODS: Patients with available cost data that underwent EC between January 2008 and December 2012 were compared against matched patients undergoing LC during the same period. Direct hospital costs for the two groups were compared. RESULTS: There were 42 EC patients and 61 LC patients. EC patients had significantly less ileostomy-related complications (p < 0.001) and hospital readmissions (p < 0.001). Operative time (p < 0.001) and operative cost (p = 0.002) were also both significantly less in the EC group. Community nursing costs favoured the LC group (p = 0.047). The EC group had an increased post-closure wound infection rate (p = 0.02). The mean total direct cost per patient was NZD 13,724 (SD NZD 3,736) for EC and NZD 16,728 (SD NZD 8,028) for LC. Representing an average costs saving of NZD 3,004 per patient favouring EC (p = 0.012). CONCLUSION: Although EC increases the post-closure wound infection rate, EC reduces ileostomy complications, hospital readmissions and operative costs resulting in significant healthcare savings. In order to improve patient outcomes and make EC even more cost effective, efforts should be taken to reduce wound infections. PMID- 25833334 TI - Is Cancer a Risk Factor for Cognitive Decline in Late Life? AB - With advances in screening and early detection, coupled with improved treatment and care, the number of cancer survivors has risen exponentially over the past several decades. Moreover, because age is the most significant risk factor for cancer, the majority of cancer survivors are over 65 years of age. Finally, cancer survivors often experience significant health issues for many years after the treatment has subsided. In the current article, we describe select research that has focused on changes to cognitive performance associated with cancer and its treatment, i.e., alterations that have been colloquially referred to as chemobrain. Although understanding changes in cognitive performance following cancer treatment is an active area of inquiry, the experience of older adult cancer survivors has been somewhat neglected. For example, evidence is mixed as to whether changes in cognitive performance associated with normal aging are exacerbated by cancer survivorship status. It is also unclear whether a history of cancer makes it more or less likely that a person will be diagnosed with dementia or Alzheimer's disease in the future. Finally, we identify a number of areas where existing cognitive aging research can inform studies on cognitive performance following cancer treatment. Future efforts should be directed towards designing studies that focus on the experience of older adult cancer survivors and are informed by the clinical oncology and cognitive aging literature. PMID- 25833324 TI - Regulation of bacterial virulence by Csr (Rsm) systems. AB - Most bacterial pathogens have the remarkable ability to flourish in the external environment and in specialized host niches. This ability requires their metabolism, physiology, and virulence factors to be responsive to changes in their surroundings. It is no surprise that the underlying genetic circuitry that supports this adaptability is multilayered and exceedingly complex. Studies over the past 2 decades have established that the CsrA/RsmA proteins, global regulators of posttranscriptional gene expression, play important roles in the expression of virulence factors of numerous proteobacterial pathogens. To accomplish these tasks, CsrA binds to the 5' untranslated and/or early coding regions of mRNAs and alters translation, mRNA turnover, and/or transcript elongation. CsrA activity is regulated by noncoding small RNAs (sRNAs) that contain multiple CsrA binding sites, which permit them to sequester multiple CsrA homodimers away from mRNA targets. Environmental cues sensed by two-component signal transduction systems and other regulatory factors govern the expression of the CsrA-binding sRNAs and, ultimately, the effects of CsrA on secretion systems, surface molecules and biofilm formation, quorum sensing, motility, pigmentation, siderophore production, and phagocytic avoidance. This review presents the workings of the Csr system, the paradigm shift that it generated for understanding posttranscriptional regulation, and its roles in virulence networks of animal and plant pathogens. PMID- 25833333 TI - Meta-analysis of reconstruction techniques after low anterior resection for rectal cancer. AB - BACKGROUND: Options for reconstruction after low anterior resection (LAR) for rectal cancer include straight or side-to-end coloanal anastomosis (CAA), colonic J pouch and transverse coloplasty. This systematic review compared these techniques in terms of function, surgical outcomes and quality of life. METHODS: A systematic literature search (MEDLINE, Embase and the Cochrane Library, from inception of the databases until November 2014) was conducted to identify randomized clinical trials comparing reconstructive techniques after LAR. Random effects meta-analyses were carried out, and results presented as weighted odds ratios or mean differences with corresponding 95 per cent c.i. A network meta analysis was conducted for the outcome anastomotic leakage. RESULTS: The search yielded 965 results; 21 trials comprising data from 1636 patients were included. Colonic J pouch was associated with lower stool frequency and antidiarrhoeal medication use for up to 1 year after surgery compared with straight CAA. Transverse coloplasty and side-to-end CAA had similar functional outcomes to the colonic J pouch. No superiority was found for any of the techniques in terms of anastomotic leak rate. CONCLUSION: Colonic J pouch and side-to-end CAA or transverse coloplasty lead to a better functional outcome than straight CAA for the first year after surgery. PMID- 25833335 TI - Randomized Trial of Telegenetics vs. In-Person Cancer Genetic Counseling: Cost, Patient Satisfaction and Attendance. AB - Telegenetics-genetic counseling via live videoconferencing-can improve access to cancer genetic counseling (CGC) in underserved areas, but studies on cancer telegenetics have not applied randomized methodology or assessed cost. We report cost, patient satisfaction and CGC attendance from a randomized trial comparing telegenetics with in-person CGC among individuals referred to CGC in four rural oncology clinics. Participants (n = 162) were randomized to receive CGC at their local oncology clinic in-person or via telegenetics. Cost analyses included telegenetics system; mileage; and personnel costs for genetic counselor, IT specialist, and clinic personnel. CGC attendance was tracked via study database. Patient satisfaction was assessed 1 week post-CGC via telephone survey using validated scales. Total costs were $106 per telegenetics patient and $244 per in person patient. Patient satisfaction did not differ by group on either satisfaction scale. In-person patients were significantly more likely to attend CGC than telegenetics patients (89 vs. 79 %, p = 0.03), with bivariate analyses showing an association between lesser computer comfort and lower attendance rate (Chi-square = 5.49, p = 0.02). Our randomized trial of telegenetics vs. in-person counseling found that telegenetics cost less than in-person counseling, with high satisfaction among those who attended. This study provides support for future randomized trials comparing multiple service delivery models on longer-term psychosocial and behavioral outcomes. PMID- 25833337 TI - Redox proteomic analysis of mytilus edulis gills: effects of the pharmaceutical diclofenac on a non-target organism. AB - Veterinary and human pharmaceuticals are an emerging category of chemical pollutants with potential to cause serious toxicity to non-target organisms. Filter-feeding aquatic organisms such as mussels are especially threatened. In this study, the blue mussel, Mytilus edulis, was exposed to two doses (0.2 mg/L and 1 mg/L) of the anti-inflammatory diclofenac. Effects on the gill, the principal feeding organ of mussels, were investigated. It was noted that, while no effect was evident on gill glutathione transferase or catalase activities, there was a tissue-specific increase in glutathione reductase activity and reduction in total protein thiol groups. Two dimensional electrophoresis was performed and some affected proteins identified by in-gel tryptic digestion and peptide mass fingerprinting. Of these, four unique proteins (caspase 3/7-4, heat shock cognate protein 70, a predicted enolase-like protein, arginine kinase) were found to be oxidized whilst eight unique proteins (beta-tubulin, actin, isocitrate dehydrogenase, arginine kinase, heavy metal-binding HIP, cytosolic malate dehydrogenase, proteasome subunit alpha type 2, Mg: bb02e05 (glyceraldehyde-3-phosphate dehydrogenase) and superoxide dismutase) were found to have altered abundance. In addition, bioinformatic analysis suggested putative identities for six hypothetical proteins which either were oxidized or decreased in abundance. These were; 78 kDa glucose-regulated protein precursor, alpha enolase, calreticulin, mitochondrial H + -ATPase, palmitoyl protein thioesterase 1 and initiation factor 5a. It is concluded that diclofenac causes significant oxidative stress to gills and that this affects key structural, metabolic and stress-response proteins. PMID- 25833338 TI - Quantitative proteomic analysis of the metastasis-inhibitory mechanism of miR 193a-3p in non-small cell lung cancer. AB - BACKGROUND: microRNAs can repress the expression of target genes by destabilizing their mRNAs or by inhibiting their translation. Our previous findings suggested that miR-193a-3p inhibited the progression of NSCLC both in vitro and in vivo. However, the biological processes and molecular pathways through which this miRNA exerts its positive effects are unknown. METHODS: To explore the molecular mechanisms by which miR-193a-3p inhibited NSCLC metastasis, we investigated the changes in the protein profile of SPC-A-1sci (highly metastatic) cells in response to the up-regulation of miR-193a-3p expression using a proteomics approach (iTRAQ combined with NanoLC-MS/MS). Changes in the profiles of the expressed proteins were verified using western blotting and were analyzed using the DAVID and STRING programs. RESULTS: In the two replicated experiments, 4962/4946 proteins were identified, and the levels of expression of 4923/4902 proteins were quantified. In total, 112 of these proteins were differentially expressed. Among them, the up-regulated levels of expression of two of the 62 proteins with up-regulated expression (PPP2R2A and GSN) and the down-regulated levels of expression four of the 50 proteins with down-regulated expression (LMNB2, UHRF1, G3BP1, and HNRNPU) were verified using western blotting. The bioinformatics analysis revealed the interactions and signaling networks of these differentially expressed proteins. CONCLUSION: miR-193a-3p inhibited the metastasis of lung cancer cells by deregulating the expression of tumor-related proteins. These findings may improve the understanding of the molecular mechanisms underlying the metastatic-inhibitory effect of miR-193a-3p on lung cancer cells. PMID- 25833336 TI - Four-leaf clover qRT-PCR: A convenient method for selective quantification of mature tRNA. AB - Transfer RNAs (tRNAs) play a central role in translation and also recently appear to have a variety of other functions in biological processes beyond translation. Here we report the development of Four-Leaf clover qRT-PCR (FL-PCR), a convenient PCR-based method, which can specifically quantify individual mature tRNA species. In FL-PCR, T4 RNA ligase 2 specifically ligates a stem-loop adapter to mature tRNAs but not to precursor tRNAs or tRNA fragments. Subsequent TaqMan qRT-PCR amplifies only unmodified regions of the tRNA-adapter ligation products; therefore, FL-PCR quantification is not influenced by tRNA post-transcriptional modifications. FL-PCR has broad applicability for the quantification of various tRNAs in different cell types, and thus provides a much-needed simple method for analyzing tRNA abundance and heterogeneity. PMID- 25833339 TI - Switching from Endoscopic Extraperitoneal Radical Prostatectomy to Robot-Assisted Laparoscopic Prostatectomy: Comparing Outcomes and Complications. AB - OBJECTIVE: Endoscopic extraperitoneal radical prostatectomy (EERPE) and robot assisted laparoscopic prostatectomy (RALP) are minimally invasive surgical techniques to treat localized prostate cancer. We report the outcome and complications of these two techniques conducted by one individual surgeon. PATIENTS AND METHODS: 86 patients underwent EERPE between January 2008 and June 2011, and 100 patients underwent RALP between August 2011 and October 2012. All surgeries were performed by one single surgeon. RESULTS: The patients of the EERPE and RALP groups had similar clinical characteristics in PSA, prostate volume and D'Amico classification, and were significantly different in their age and BMI as well as in the number of prior surgeries. RALP surgeries were significantly slower (183 vs. 157 min) but also involved lower blood loss (147 vs. 245 ml). Pathological stages and positive surgical margins were similar in both groups. Complications were assessed by the Clavien-Dindo classification. 6 patients in the EERPE group and 3 patients of the RALP group suffered major complications (IIIb-IV). CONCLUSION: Altogether our results indicate that the learning curve for RALP was short after experience with EERPE. We hypothesize that this is more a result of the surgical experience of the surgeon with the EERPE than on the robotic technique. PMID- 25833340 TI - Mechanisms underlying presynaptic Ca2+ transient and vesicular glutamate release at a CNS nerve terminal during in vitro ischaemia. AB - KEY POINTS: Here we demonstrate presynaptic responses and mechanisms of increased vesicular glutamate release during in vitro ischaemia in the calyx of Held terminal, an experimentally accessible presynaptic terminal in the CNS. The ischaemia-induced increase in presynaptic Ca(2+) was mediated by both Ca(2+) influx and Ca(2+) -induced Ca(2+) release from intracellular stores. The reverse operation of the plasma membrane Na(+) /Ca(2+) exchanger (NCX) plays a key role in Ca(2+) influx for triggering Ca(2+) release from intracellular stores at presynaptic terminals during in vitro ischaemia. Ca(2+) uptake via NCX underlies the ischaemia-induced Ca(2+) rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia. ABSTRACT: An early consequence of brain ischaemia is an increase in vesicular glutamate release from presynaptic terminals. However, the mechanisms of this increased glutamate release are not fully understood. Here we studied presynaptic responses and mechanisms of increased glutamate release during in vitro ischaemia, using pre- and postsynaptic whole-cell recordings and presynaptic Ca(2+) imaging at the calyx of Held synapse in rat brainstem slices. Consistent with results from other brain regions, in vitro ischaemia significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) without affecting their amplitude, suggesting that ischaemia enhances vesicular glutamate release from presynaptic terminals. We found that ischaemia-induced vesicular glutamate release was dependent on a rise in basal Ca(2+) at presynaptic terminals, which resulted from extracellular Ca(2+) influx and Ca(2+) release from intracellular stores. During early ischaemia, increased Ca(2+) influx into presynaptic terminals was due to reverse operation of the plasma membrane Na(+) /Ca(2+) exchanger (NCX) rather than presynaptic depolarization or voltage-activated Ca(2+) currents. KB-R7943, an inhibitor of NCX, prevented the ischaemia-induced increases in presynaptic Ca(2+) and vesicular glutamate release. In addition, the removal of extracellular Na(+) completely inhibited the ischaemia-induced Ca(2+) rise. It therefore appears that a link between Na(+) accumulation and Ca(2+) uptake via NCX underlies the ischaemia-induced Ca(2+) rise and the consequent increase in vesicular glutamate release from presynaptic terminals in the early phase of brain ischaemia. PMID- 25833341 TI - High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence. AB - Exercise is a uniquely effective and pluripotent medicine against several noncommunicable diseases of westernised lifestyles, including protection against neurodegenerative disorders. High-intensity interval exercise training (HIT) is emerging as an effective alternative to current health-related exercise guidelines. Compared with traditional moderate-intensity continuous exercise training, HIT confers equivalent if not indeed superior metabolic, cardiac, and systemic vascular adaptation. Consequently, HIT is being promoted as a more time efficient and practical approach to optimize health thereby reducing the burden of disease associated with physical inactivity. However, no studies to date have examined the impact of HIT on the cerebrovasculature and corresponding implications for cognitive function. This review critiques the implications of HIT for cerebrovascular function, with a focus on the mechanisms and translational impact for patient health and well-being. It also introduces similarly novel interventions currently under investigation as alternative means of accelerating exercise-induced cerebrovascular adaptation. We highlight a need for studies of the mechanisms and thereby also the optimal dose-response strategies to guide exercise prescription, and for studies to explore alternative approaches to optimize exercise outcomes in brain-related health and disease prevention. From a clinical perspective, interventions that selectively target the aging brain have the potential to prevent stroke and associated neurovascular diseases. PMID- 25833343 TI - Optical measurement of mouse strain differences in cerebral blood flow using indocyanine green. AB - C57BL/6 mice have more cerebral arterial branches and collaterals than BALB/c mice. We measured and compared blood flow dynamics of the middle cerebral artery (MCA) in these two strains, using noninvasive optical imaging with indocyanine green (ICG). Relative maximum fluorescence intensity (Imax) and the time needed for ICG to reach Imax in the MCA of C57BL/c were lower than that in BALB/c mice. Moreover, the mean transit time was significantly lower in C57BL/6 than in BALB/c mice. These data suggest that the higher number of arterial branches and collaterals in C57BL/6 mice yields a lower blood flow per cerebral artery. PMID- 25833342 TI - [11C]PBR28 PET imaging is sensitive to neuroinflammation in the aged rat. AB - Neuroinflammation in the aging rat brain was investigated using [(11)C]PBR28 microPET (positron emission tomography) imaging. Normal rats were studied alongside LRRK2 p.G2019S transgenic rats; this mutation increases the risk of Parkinson's disease in humans. Seventy [(11)C]PBR28 PET scans were acquired. Arterial blood sampling enabled tracer kinetic modeling and estimation of VT. In vitro autoradiography was also performed. PBR28 uptake increased with age, without differences between nontransgenic and transgenic rats. In 12 months of aging (4 to 16 months), standard uptake value (SUV) increased by 56% from 0.44 to 0.69 g/mL, whereas VT increased by 91% from 30 to 57 mL/cm(3). Standard uptake value and VT were strongly correlated (r = 0.52, 95% confidence interval (CI) = 0.31 to 0.69, n = 37). The plasma free fraction, fp, was 0.21 +/- 0.03 (mean +/- standard deviation, n = 53). In vitro binding increased by 19% in 16 months of aging (4 to 20 months). The SUV was less variable across rats than VT; coefficients of variation were 13% (n = 27) and 29% (n = 12). The intraclass correlation coefficient for SUV was 0.53, but was effectively zero for VT. These data show that [(11)C]PBR28 brain uptake increases with age, implying increased microglial activation in the aged brain. PMID- 25833344 TI - The neuroprotective agent CNTF decreases neuronal metabolites in the rat striatum: an in vivo multimodal magnetic resonance imaging study. AB - Ciliary neurotrophic factor (CNTF) is neuroprotective against multiple pathologic conditions including metabolic impairment, but the mechanisms are still unclear. To delineate CNTF effects on brain energy homeostasis, we performed a multimodal imaging study, combining in vivo proton magnetic resonance spectroscopy, high performance liquid chromatography analysis, and in situ glutamate imaging by chemical exchange saturation transfer. Unexpectedly, we found that CNTF expression through lentiviral gene transfer in the rat striatum significantly decreased the levels of neuronal metabolites (N-acetyl-aspartate, N-acetyl aspartyl-glutamate, and glutamate). This preclinical study shows that CNTF remodels brain metabolism, and suggests that decreased levels of neuronal metabolites may occur in the absence of neuronal dysfunction. PMID- 25833346 TI - A sweet polydopamine nanoplatform for synergistic combination of targeted chemo photothermal therapy. AB - Inspired by sweet or sugar-coated bullets that are used for medications in clinics and the structure and function of biological melanin, a novel kind of sweet polydopamine nanoparticles and their anticancer drug doxorubicin loaded counterparts are prepared, which integrate an active targeting function, photothermal therapy, and chemotherapy into one polymeric nanocarrier. The oxidative polymerization of lactosylated dopamine and/or with dopamine are performed under mild conditions and the resulting sweet nanoparticles are thoroughly characterized. When exposed to an 808 nm continuous-wave diode laser, the magnitude of temperature elevation not only increases with the concentration of nanoparticles, but can also be tuned by the laser power density. The nanoparticles possess strong near infrared light absorption, high photothermal conversion efficiency, and good photostability. The nanoparticles present tunable binding with RCA120 lectin and a targeting effect to HepG2 cells, confirmed by dynamic light scattering, turbidity analysis, MTT assay, and flow cytometry. Importantly, the sweet nanoparticles give the lowest IC50 value of 11.67 MUg mL( 1) for chemo-photothermal therapy compared with 43.19 MUg mL(-1) for single chemotherapy and 67.38 MUg mL(-1) for photothermal therapy alone, demonstrating a good synergistic effect for the combination therapy. PMID- 25833345 TI - Imaging the cannabinoid CB1 receptor in humans with [11C]OMAR: assessment of kinetic analysis methods, test-retest reproducibility, and gender differences. AB - The Radiotracer [(11)C]OMAR was developed for positron emission tomography (PET) imaging of cannabinoid type-1 receptors (CB1R). The objectives of the present study were to evaluate kinetic analysis methods, determine test-retest reliability, and assess gender differences in receptor availability. Dynamic PET data were acquired in 10 human subjects, and analyzed with one-tissue (1T) and two-tissue (2T) compartment models and by the Logan and multilinear analysis (MA1) methods to estimate regional volume of distribution (VT). The 2T model inclusive of a vascular component (2TV) and MA1 were the preferred techniques. Test-retest reliability of VT was good (mean absolute deviation ~9%; intraclass correlation coefficient ~0.7). Tracer parent fraction in plasma was lower in women (P<0.0001). Cerebral uptake normalized by body weight and injected dose was higher in men by 17% (P<0.0001), but VT was significantly greater in women by 23% (P<0.0001). These findings show that [(11)C]OMAR binding can be reliably quantified by the 2T model or MA1 method and demonstrate the utility of this tracer for in vivo imaging of CB1R. In addition, results from the present study indicate that gender difference in receptor binding should be taken into consideration when [(11)C]OMAR is used to quantify CB1R availability in neuropsychiatric disorders. PMID- 25833347 TI - Luminescent chromism of boron diketonate crystals: distinct responses to different stresses. PMID- 25833348 TI - Exploratory study of pre-surgical medications with dienogest or leuprorelin in laparoscopic cystectomy of endometrial cysts. AB - AIM: The aim of this study was to compare the effects of pre-surgical medication with dienogest or leuprorelin on post-surgical ovarian function. MATERIAL AND METHODS: We conducted an exploratory study in two centers in Japan that comprised 30 patients with ovarian endometrial cysts for whom surgical excision was planned. Patients were enrolled and divided into pre-surgical medication groups with dienogest or leuprorelin for 12 weeks. Thereafter, patients were treated by laparoscopic cystectomy. The primary outcome was ovarian function post-surgery, as assessed by serum anti-Mullerian hormone (AMH) level, antral follicle count (AFC) and resumption of menses. Secondary outcome was the effect of pre-surgical medication, as assessed by the size of endometrial cysts and visual analog scale (VAS) score. Serum AMH, AFC, size of endometrial cysts, and VAS scores were measured at baseline (before medication), after medication (1 day before surgery), and at 4 and 12 weeks post-surgery. RESULTS: Serum AMH levels did not change after pre-surgical medication with either dienogest or leuprorelin. Although AMH decreased after surgery, it recovered by 12 weeks post-surgery in both groups with no statistically significant difference. Mean AFC did not change after surgery in either group. Menses returned by 12 weeks post-surgery in all patients except for those who were pregnant. The rate of reduction of endometrial cyst volume did not differ between the groups. Both dienogest and leuprorelin were associated with substantial reductions in VAS scores. CONCLUSION: There were no statistically significant differences between pre-surgical medication with dienogest and leuprorelin in post-surgical ovarian function. Both medications were effective in reducing endometrial cyst volume and VAS score. PMID- 25833349 TI - Low-Dose Aspirin for Preventing Preeclampsia and Its Complications: A Meta Analysis. AB - Low-dose aspirin (LDA) is thought to prevent preeclampsia in high-risk pregnancy, but it is not universally used out of concern for its efficacy and safety. The authors meta-analyzed 29 randomized controlled trials (RCTs) to evaluate LDA for preventing preeclampsia and its complications. LDA can reduce the incidence of preeclampsia (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.57-0.87), severe preeclampsia (OR, 0.37; 95% CI, 0.23-0.61), preterm birth (OR, 0.81; 95% CI, 0.75-0.88), and intrauterine growth restriction (IUGR) (OR, 0.80; 95% CI, 0.71-0.90). LDA is more effective in reducing incidence of preeclampsia or IUGR if used before 16 gestational weeks than if used later. LDA increases the incidence of placental abruption (OR, 1.35; 95% CI, 1.05-1.73) but not other major complications. The available evidence suggests that LDA is effective in preventing preeclampsia, preterm birth, and IUGR in high-risk pregnancies without posing a major safety risk to mothers or fetuses. PMID- 25833350 TI - The Dixon technique and the frequency-selective fat suppression technique in three-dimensional T1 weighted MRI of the liver: a comparison of contrast-to-noise ratios of hepatocellular carcinomas-to-liver. AB - OBJECTIVE: The use of three-dimensional T1 weighted gradient echo sequences such as the Dixon technique and the frequency-selective fat suppression (FS) technique is currently widely accepted method in MRI examinations of the liver. To assess the image qualities of the Dixon technique and the frequency-selective FS technique, the contrast-to-noise ratios (CNRs) of hepatocellular carcinoma (HCC) to-liver and fat-to-liver were compared between the two techniques in the hepatobiliary phase (HBP) following administration of gadolinium-ethoxybenzyl diethylenetriamine penta-acetic acid. METHODS: MR images of 59 patients with a total of 86 HCCs were retrospectively evaluated. Images were consecutively obtained with the Dixon and frequency-selective FS methods in the HBP and their CNRs of HCC-to-liver and fat-to-liver were compared. CNRs and contrast ratios were calculated by the mean value of the liver parenchyma, HCC, fat and standard deviation of the liver parenchyma. The Wilcoxon signed-ranks test was used for statistical analysis. RESULTS: The median CNRs for the frequency-selective FS and Dixon techniques of HCC-to-liver were 4.3 and 5.4 (p < 0.01), mesenteric fat-to liver were 9.9 and 12.8 (p < 0.01) and subcutaneous fat-to-liver were 9.9 and 13.2 (p < 0.01), respectively. CONCLUSION: The Dixon technique yielded higher CNRs of HCC-to-liver than that of the frequency-selective FS technique. ADVANCES IN KNOWLEDGE: There are a limited number of reports on quantitative analysis of the image qualities of the Dixon technique and the frequency-selective FS technique, particularly within the same patient and examination. PMID- 25833351 TI - Preoperative risk stratification using metabolic parameters of (18)F-FDG PET/CT in patients with endometrial cancer. AB - PURPOSE: To evaluate the usefulness of metabolic parameters obtained by (18)F-FDG PET/CT for preoperative stratification of high-risk and low-risk endometrial carcinomas. METHODS: Preoperative (18)F-FDG PET/CT was performed in 56 women with endometrial cancer. Maximum standardized uptake values (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of primary tumours were compared with clinicopathological features of surgical specimens. Diagnostic performance in terms of differentiation of low-risk disease (endometrioid histology, histological grade 1 or 2, invasion of less than half of the myometrium, and FIGO stage I) from high-risk disease was assessed. RESULTS: MTV and TLG were significantly higher in patients with higher histological grade (p = 0.0026 and p = 0.034), larger tumour size (p = 0.002 and p = 0.0017), lymphovascular space involvement (LVSI; p = 0.012 and p = 0.0051), myometrial invasion (p = 0.027 and p = 0.031), cervical stromal invasion (p = 0.023 and p = 0.014), ovarian metastasis (p = 0.00022 and p = 0.00034), lymph node metastasis (p < 0.0001 and p < 0.0001), and higher FIGO stage (p = 0.0011 and p = 0.00048). SUVmax was significantly higher in patients with larger tumour size (p = 0.0025), LVSI (p = 0.00023) and myometrial invasion (p < 0.0001). The areas under the ROC curves (AUCs) for distinguishing high-risk from low-risk carcinoma were 0.625, 0.829 and 0.797 for SUVmax, MTV and TLG, respectively. AUCs for both MTV and TLG were significantly larger than that for SUVmax (p = 0.0049 and p = 0.021). The optimal TLG cut-off value of 70.2, determined by ROC analysis, was found to have 72.0% sensitivity and 74.2% specificity for risk stratification. CONCLUSION: MTV and TLG of primary endometrial cancer show better correlations with clinicopathological features and are more useful for differentiating high-risk from low-risk carcinoma than SUVmax. PMID- 25833352 TI - (11)C-PBR28 imaging in multiple sclerosis patients and healthy controls: test retest reproducibility and focal visualization of active white matter areas. AB - PURPOSE: Activated microglia play a key role in inflammatory demyelinating injury in multiple sclerosis (MS). Microglial activation can be measured in vivo using a positron emission tomography (PET) ligand (11)C-PBR28. We evaluated the test retest variability (TRV) and lesion detectability of (11)C-PBR28 binding in MS subjects and healthy controls (HCs) with high-resolution PET. METHODS: Four clinically and radiologically stable relapsing-remitting MS subjects (age 41 +/- 7 years, two men/two women) and four HCs (age 42 +/- 8 years, 2 two men/two women), matched for translocator protein genotype [two high- and two medium affinity binders according to DNA polymorphism (rs6971) in each group], were studied for TRV. Another MS subject (age 41 years, male) with clinical and radiological activity was studied for lesion detectability. Dynamic data were acquired over 120 min after injection of 634 +/- 101 MBq (11)C-PBR28. For the TRV study, subjects were scanned twice, on average 1.4 weeks apart. Volume of distribution (V T) derived from multilinear analysis (MA1) modeling (t* = 30 min, using arterial input data) was the main outcome measure. RESULTS: Mean test V T values (ml cm(-3)) were 3.9 +/- 1.4 in the whole brain gray matter (GM), 3.6 +/- 1.2 in the whole brain white matter (WM) or normal-appearing white matter (NAWM), and 3.3 +/- 0.6 in MS WM lesions; mean retest V T values were 3.7 +/- 1.0 in GM, 3.3 +/- 0.9 in WM/NAWM, and 3.3 +/- 0.7 in MS lesions. Test-retest results showed a mean absolute TRV ranging from 7 to 9 % across GM, WM/NAWM, and MS lesions. High-affinity binders demonstrated 30 % higher V T than medium-affinity binders in GM. Focal (11)C-PBR28 uptake was detected in two enhancing lesions of the active MS patient. CONCLUSION: High-resolution (11)C-PBR28 PET can visualize focal areas where microglial activation is known to be present and has good test retest reproducibility in the human brain. (11)C-PBR28 PET is likely to be valuable for monitoring both MS disease evolution and response to therapeutic strategies that target microglial activation. PMID- 25833353 TI - Stromal cell-derived factor-1 (SDF1)-dependent recruitment of bone marrow-derived renal endothelium-like cells in a mouse model of acute kidney injury. AB - Ischemic acute kidney injury (AKI) is the most key pathological event for accelerating progression to chronic kidney disease through vascular endothelial injury or dysfunction. Thus, it is critical to elucidate the molecular mechanism of endothelial protection and regeneration. Emerging evidence indicates that bone marrow-derived cells (BMCs) contribute to tissue reconstitution in several types of organs post-injury, but little is known whether and how BMCs contribute to renal endothelial reconstitution, especially in an early-stage of AKI. Using a mouse model of ischemic AKI, we provide evidence that incorporation of BMCs in vascular components (such as endothelial and smooth muscle cells) becomes evident within four days after renal ischemia and reperfusion, associated with an increase in stromal cell-derived factor-1 (SDF1) in endothelium and that in CXCR4/SDF1-receptor in BMCs. Notably, anti-CXCR4 antibody decreased the numbers of infiltrated BMCs and BMC-derived endothelium-like cells, but not of BMC derived smooth muscle cell-like cells. These results suggest that reconstitution of renal endothelium post-ischemia partially depends on a paracrine loop of SDF1 CXCR4 between resident endothelium and BMCs. Such a chemokine ligand-receptor system may be attributable for selecting a cellular lineage (s), required for renal vascular protection, repair and homeostasis, even in an earlier phase of AKI. PMID- 25833354 TI - Asylum Doctor Extraordinaire: Dr. Thomas Drapes (1847-1919). AB - Dr. Thomas Drapes (1847-1919) was resident medical superintendent of Enniscorthy District Asylum in County Wexford, Ireland from 1883 to 1919, and one of the leading figures in Irish asylum medicine for several decades. Drapes' career was as complex as it was remarkable. Drapes was elected president of the Medico Psychological Association for the term 1911-12 but had to decline on health grounds. In 1912, however, he was unanimously elected as co-editor of the Journal of Mental Science, to which he devoted his considerable energies and intellect. Drapes published widely, opposing Emil Kraepelin's proposed division of "functional" psychosis into manic-depressive illness and dementia praecox; openly examining the use of "punitive measures" in asylums (Enniscorthy had notably low rates of restraint and seclusion); and publicly bemoaning the folly of "psychophysical parallelism", or the spurious division between mental and physical symptoms in medicine. Although not immune to passing trends in medical thought (e.g. regarding sterilisation of the mentally ill to prevent further mental disorder), Drapes was generally independent-minded, insightful and incisive, and his legacy was to help shape Irish mental health care for many decades. PMID- 25833355 TI - Evaluation of function and structure of arterial wall in girls and young women with Turner syndrome. AB - PURPOSE: Patients with Turner syndrome (TS) are frequently affected by congenital as well as acquired cardiovascular diseases. The aim of the study was to evaluate the blood pressure, the endothelial function (FMD) and the intima media thickness (IMT) at the level of the common carotid arteries in a group of girls and young women with TS in comparison to healthy controls. METHODS: We evaluated 40 unselected TS patients, with a mean age of 18.6 +/- 0.9 years and 103 age matched healthy subjects. MAIN OUTCOME MEASURES: blood pressure, FMD and IMT. RESULTS: No differences were found in systolic and diastolic blood pressure between TS patients and controls. FMD was higher in TS than in controls (14.2 +/- 1.4 vs 11.4 +/- 0.3%, p = 0.005) whereas IMT was not statistically different in the two study groups (0.54 +/- 0.04 vs 0.57 +/- 0.01 mm). However, in TS patients an inverse correlation was found between FMD and both age (-0.03 +/- 0.01, p = 0.003) and years of estrogen therapy (-0.72 +/- 0.31, p < 0.03), whereas a positive correlation was found between IMT and age (R 2 = 0.35, p < 0.0001) and estrogen therapy duration (R 2 = 0.65, p < 0.0001), suggesting a clear tendency toward a premature decrease in FMD and premature increase in IMT compared to controls. CONCLUSIONS: Young TS patients show an arterial wall which is functionally and structurally comparable or better than controls. They show, however, a premature derangement of the arterial function and structure, which seems to be partly influenced by age and duration of oestrogen treatment. PMID- 25833356 TI - Methodological limitations of an etiological framing of Ariarathes' goitre: response to Tekiner et al. PMID- 25833357 TI - Endocrinology and art. Man with enormous trilobar goiter. PMID- 25833358 TI - Analysis of renal functions and proteinuria in young obese adults. AB - OBJECTIVE: To investigate the prevalence of obesity in young adults and to analyze the influencing factors on renal functions and proteinuria in this population. METHODS: This study comprised civil servants between 20 and 39 years old, who received physical examinations at the First Affiliated Hospital of Fujian Medical University. The subjects were categorized into four groups based on age (20-24, 25-29, 30-34 and 35-39 years) and the number of risk factors they had (hypertension, dyslipidemia, hyperglycemia and hyperuricemia). The relationships between obesity and the prevalence of proteinuria, between obesity and risk factors and between estimated glomerular filtration rate (eGFR) and proteinuria were analyzed. RESULTS: Among the 2293 young civil servants, in men the prevalence of obesity was 33.3 % and proteinuria was 2.5 %. However in women the prevalence of obesity and proteinuria was 7.5 % and 1.7 %, respectively. The levels of blood pressure, serum uric acid (UA), cholesterol (TC), triglyceride (TG), fasting glucose (FBG) and low-density lipoprotein cholesterol (LDL-C) were lower and the level of serum high-density lipoprotein cholesterol (HDL-C) was higher in nonobese groups compared with obese groups. There were no significant differences in eGFR between the two groups. The eGFR in male subjects was associated with age, UA, body mass index (BMI), FBG, TC, TG, LDL and HDL, and in female subjects associated with UA, age, BMI, diastolic blood pressure, FBG and LDL. BMI in both males and females increased with the higher number of risk factors. Multiple regression analysis revealed that hypertension, dyslipidemia, hyperglycemia and hyperuricemia were independently associated with obesity. eGFR decreased with a higher number of risk factors. Obesity, blood pressure, dyslipidemia, hyperglycemia and hyperuricemia were independently associated with proteinuria. CONCLUSION: Obesity can pose an independent risk factor for proteinuria in young adults. Hypertension, dyslipidemia, hyperglycemia and hyperuricemia were independently associated with obesity. eGFR decreased with a higher number of risk factors. PMID- 25833359 TI - Knowledge, attitudes and behaviors of physicians towards thyroid disorders and iodine requirements in pregnancy. AB - PURPOSE: Thyroid disorders including iodine deficiency during pregnancy are important health problems worldwide. However, considering real life, assessment of knowledge, attitudes, and practice of physicians is lacking. We aim to evaluate knowledge, attitudes and behaviors of physicians towards thyroid disorders and requirements of iodine during pregnancy on a nationwide basis. METHODS: Clinicians from different medical disciplines most likely to encounter pregnant women in daily practice (i.e., obstetricians, endocrinologists, and family physicians) were included. Family physicians were selected from primary care centers; endocrinologists and gynecologists were selected from state hospitals. Randomly selected 322 physicians from seven geographical regions of Turkey were included. Subjects filled a questionnaire which consisted of three sections about knowledge, attitudes and behaviors towards thyroid disorders and iodine requirements during pregnancy. RESULTS: Physicians had insufficient and/or erroneous knowledge about thyroid disorders during pregnancy. 73.1 % of endocrinologists, 32.7 % of family physicians, and 17.8 % of obstetricians knew the correct level of TSH during pregnancy (p < 0.001). 67.1 % of physicians thought it is unnecessary to offer iodine supplementation to pregnant women. Endocrinologists achieved the highest scores in each section, and also had the highest total scores (p < 0.001). Family physicians achieved higher scores than obstetricians. CONCLUSIONS: Physicians who encounter pregnant women in Turkey do not have sufficient information about management of thyroid disorders and providing iodine support during pregnancy and lactation. PMID- 25833360 TI - Serum nesfatin-1 and leptin levels in non-obese girls with premature thelarche. AB - AIM: We aimed to investigate serum nesfatin-1 level in girls with premature thelarche (PT) and its relationship with anthropometric parameters and leptin, which are involved in the initiation of pubertal process. SUBJECTS-METHODS: Non obese girls who presented with the complaint of early (2-8 years) and isolated breast development were included in the study. The control group consisted of age matched healthy prepubertal girls. Auxological measurements were performed in all subjects. Gonadotropin-releasing hormone (GnRH) stimulation test and bone age assessment were conducted in subjects with early breast development. Girls with a bone age/chronologic age ratio <1.2 and a peak luteinizing hormone (LH) response to GnRH stimulation <5 mIU/L were included in the PT group. RESULTS: The study included 22 non-obese girls with PT and 24 healthy prepubertal controls. Body mass index (BMI), BMI-standard deviation score (SDS) and height SDS were similar between the groups (p > 0.05). Serum leptin and nesfatin-1 levels were found significantly higher in the PT group compared to controls (p < 0.05). No correlation was detected between nesfatin-1 and basal LH, basal follicle stimulating hormone (FSH), stimulated peak LH, peak FSH, leptin levels and anthropometric parameters in the PT group (p > 0.05). CONCLUSION: Results of the present study showed that serum nesfatin-1 and leptin levels are significantly higher in girls with PT than in prepubertal controls. This finding suggests that similar to leptin, nesfatin-1 may also have a central or peripheral role in the initiation of pubertal process and may be related to PT pathogenesis. PMID- 25833366 TI - Osseoinductive elements for promoting osseointegration around immediate implants: a pilot study in the foxhound dog. AB - OBJECTIVE: The aim of this study was to evaluate the effects of topical applications of melatonin over implant surfaces placed immediately after extraction by means of histological and histomorphometric analysis of peri implant tissues. MATERIAL AND METHODS: Six American foxhound dogs were used in the study; mandibular premolar distal roots were extracted. Thirty-six immediate conical implants were randomly assigned to the distal site on each site of the mandible in three groups: (Group CI) 12 titanium implants alone; (Group MI) 12 titanium implants supplemented with melatonin; and (Group DI) 12 titanium implants supplemented with vitamin D (DI). Prior to implanting test, implants (MI) were submerged in melatonin 5% solution, and implants from (DI) group were submerged in vitamin D 10% solution. No treatment was applied at control implants. After 12 weeks, animals were sacrificed. Block sections were obtained and processed for mineralized ground sectioning. Bone-to-implant contact (total BIC), new bone formation (NBF), inter-thread bone (ITB) and histological linear measurements (HLM) were analyzed. RESULTS: At 12 weeks, all implants were clinically stable and histologically osseointegrated. Total BIC values were 48.36 +/- 7.45* for the MI group and 44.82 +/- 10.98 for the CI group (P = 0.035) with statistically significant difference between groups. BIC% were 41.36 +/- 3.93 for MI and 41.34 +/- 9.26 for CI (P > 0.05). Inter-thread bone formation values were MI 15.99 +/- 2.43* and CI 14.79 +/- 3.62 (P = 0.03), MI showing significantly better results. No statistically significant differences in peri-implant new bone formation could be found between the two groups: MI 25.37 +/- 2.32, CI 26.55 +/- 7.75 (P > 0.05). Linear measurements showed that the MI group showed significantly less lingual crestal bone loss (CBL) (MI 0.52 +/- 0.74*, CI 0.92 +/ 1.98) (P = 0.045) and less lingual peri-implant mucosa (PIM) (MI 3.13 +/- 1.41*, CI 3.71 +/- 1.81) (P = 0.042). No significant differences were observed in the buccal aspect. CONCLUSIONS: Within the limitations of this animal study, the topical application of melatonin improved bone formation around immediate implants and reduced lingual bone and lingual peri-implant mucosa, after 12 weeks of osseointegration. PMID- 25833367 TI - Reply: To PMID 25369761. PMID- 25833368 TI - Re: Diagnosis of fetal submicroscopic chromosomal abnormalities in failed array CGH samples: copy number by sequencing as an alternative to microarrays for invasive fetal testing. K. Cohen, A. Tzika, H. Wood, S. Berri, P. Roberts, G. Mason and E. Sheridan. Ultrasound Obstet Gynecol 2015; 45: 394-401. PMID- 25833369 TI - Re: Maternal venous Doppler characteristics are abnormal in pre-eclampsia but not in gestational hypertension. W. Gyselaers, A. Staelens, T. Mesens, K. Tomsin, J. Oben, S. Vonck, L. Verresen and G. Molenberghs. Ultrasound Obstet Gynecol 2015; 45: 421-426. PMID- 25833370 TI - Re: Fetal intervention for severe lower urinary tract obstruction: a multicenter case-control study comparing fetal cystoscopy with vesicoamniotic shunting. R. Ruano, N. Sananes, H. Sangi-Haghpeykar, S. Hernandez-Ruano, R. Moog, F. Becmeur, A. Zaloszyc, A. M. Giron, B. Morin and R. Favre. Ultrasound Obstet Gynecol 2015; 45: 452-458. PMID- 25833371 TI - Postmortem high-resolution episcopic microscopy (HREM) of small human fetal hearts. PMID- 25833372 TI - Ruthenium-catalyzed ortho-C-H mono- and di-imidation of arenes with N tosyloxyphthalimide. AB - The Ru(II)-catalyzed imidation of the o-C-H bond in arenes with N tosyloxyphthalimide is realized with the assistance of a methyl phenylsulfoximine (MPS) directing group. This method is applicable to access the hitherto difficult o-C-H di-imidation products. The sequential C-N and C-C bond formation of o-C-H arenes creates peripherally decorated benzoic acid derivatives. The readily removable MPS-DG and easily modifiable phthaloyl moiety make this strategy synthetically viable for constructing highly functionalized C-N bearing arenes and heteroarenes. PMID- 25833373 TI - Solvent dependent ordering of poly(3-dodecylthiophene) in thin films. AB - The strong influence of solvents on the ordering of poly(3-dodecylthiophene) (P3DDT) due to edge-on oriented stacking, in the spin-coated thin film on the Si substrate, both near the substrate and away from it, depending upon the substrate surface nature, is observed from the X-ray reflectivity study. The absence of any appreciable amount of coil-like P3DDT chains (i.e. charge localized states) and formation of pi-stacked aggregates (i.e. charge delocalized states) in the spin coated thin films, with slightly better uniformity for the film prepared from toluene (TL) compared to that prepared from chloroform (CF) and chlorobenzene (CB), are well evident from the optical absorption study. No ordering near the weakly hydrophobic H-Si substrate is found in the films prepared from TL, probably due to less diffusion of P3DDT in TL and the appreciable pinning (film substrate interaction) effect, while appreciable ordering near the film-air interface, overcoming the pinning effect, is likely to be related to the moderate values of the viscosity and the evaporation rate of the solvent. A better ordered Form-I-like relaxed structure near the film-substrate interface and a less ordered interpenetrating Form-II-like structure toward the film-air interface are found in the films prepared from CF, probably related to the low viscosity and high evaporation rate, respectively, of the solvent. Less ordered and mixed but more toward Form-II-like structures are formed throughout the film prepared from CB, probably due to the high viscosity of the solvent, even though its evaporation rate is low. The high evaporation rate of CF and high viscosity of CB probably create hindrance in the formation of continuous films on the weakly hydrophilic O-Si substrate at low speed, while the moderate values of both the parameters for TL, help to form continuous films on the O-Si substrate even at low speed. Such moderate values also help to form less variable (and more toward Form-I-like) structures and better ordering in the latter film. The relative fluctuation between aggregates along the film-thickness is, however, found slightly more in the film prepared from TL compared to that prepared from CF. PMID- 25833374 TI - Do you really represent my task? Sequential adaptation effects to unexpected events support referential coding for the joint Simon effect. AB - Recent findings suggest that a Simon effect (SE) can be induced in Individual go/nogo tasks when responding next to an event-producing object salient enough to provide a reference for the spatial coding of one's own action. However, there is skepticism against referential coding for the joint Simon effect (JSE) by proponents of task co-representation. In the present study, we tested assumptions of task co-representation and referential coding by introducing unexpected double response events in a joint go/nogo and a joint independent go/nogo task. In Experiment 1b, we tested if task representations are functionally similar in joint and standard Simon tasks. In Experiment 2, we tested sequential updating of task co-representation after unexpected single response events in the joint independent go/nogo task. Results showed increased JSEs following unexpected events in the joint go/nogo and joint independent go/nogo task (Experiment 1a). While the former finding is in line with the assumptions made by both accounts (task co-representation and referential coding), the latter finding supports referential coding. In contrast to Experiment 1a, we found a decreased SE after unexpected events in the standard Simon task (Experiment 1b), providing evidence against the functional equivalence assumption between joint and two-choice Simon tasks of the task co-representation account. Finally, we found an increased JSE also following unexpected single response events (Experiment 2), ruling out that the findings of the joint independent go/nogo task in Experiment 1a were due to a re-conceptualization of the task situation. In conclusion, our findings support referential coding also for the joint Simon effect. PMID- 25833375 TI - Hemidiaphragm Paralysis after Robotic Prostatectomy: Medical Malpractice or Unforeseeable Event? AB - The authors present a case of suspected malpractice linked to the onset of hemidiaphragm paralysis after robot-assisted radical prostatectomy (RARP). The approach to the case is shown from a medico-legal point of view. It is demonstrated how, after a thorough review of the literature, this was not a case of medical malpractice but an unforeseeable event. This paper aims at contributing to the very few reports dealing with the onset of hemidiaphragm paralysis after RARP, thus fostering clinical knowledge of these rare events and meanwhile providing useful data for the medico-legal handling in case of alleged negligence of surgeons. PMID- 25833376 TI - 'My body is mine': Qualitatively exploring agency among internally displaced women participants in a small-group intervention in Leogane, Haiti. AB - The 2010 earthquake resulted in the breakdown of Haiti's social, economic and health infrastructure. Over one-quarter of a million people remain internally displaced (ID). ID women experience heightened vulnerability to intimate partner violence (IPV) due to increased poverty and reduced community networks. Scant research has examined experiences of IPV among ID women in post-earthquake Haiti. We conducted a qualitative study to explore the impact of participating in Famn an Aksyon Pou Sante Yo (FASY), a small-group HIV prevention intervention, on ID women's agency in Leogane, Haiti. We conducted four focus groups with ID women, FASY participants (n = 40) and in-depth individual interviews with peer health workers (n = 7). Our study was guided by critical ethnography and paid particular attention to power relations. Findings highlighted multiple forms of IPV (e.g., physical, sexual). Participants discussed processes of intrapersonal (confidence), interpersonal (communication), relational (support) and collective (women's rights) agency. Yet structural factors, including patriarchal gender norms and poverty, silenced IPV discussions and constrained women's agency. Findings suggest that agency among ID women is a multi-level, non-linear and incremental process. To effectively address IPV among ID women in Haiti, interventions should address structural contexts of gender inequity and poverty and concurrently facilitate multi-level processes of agency. PMID- 25833377 TI - Rare presentation of pseudosequestration in childhood: CT and CT angiography findings. AB - Anomalous systemic arterial supply to the lungs with normal bronchial branching and pulmonary arterial supply is an unusual variant of the sequestration spectrum. Pseudosequestration is referred as the combination of systemic arterial supply to lung with normal bronchial connection. Thorax computed tomography (CT) and CT angiography are non-invasive and useful techniques in making the definitive diagnosis. Herein, we report two paediatric patients with anomalous systemic arterial supply to normal basal segments of the lower lobes. PMID- 25833378 TI - Increased efficiency of Campylobacter jejuni N-oligosaccharyltransferase PglB by structure-guided engineering. AB - Conjugate vaccines belong to the most efficient preventive measures against life threatening bacterial infections. Functional expression of N oligosaccharyltransferase (N-OST) PglB of Campylobacter jejuni in Escherichia coli enables a simplified production of glycoconjugate vaccines in prokaryotic cells. Polysaccharide antigens of pathogenic bacteria can be covalently coupled to immunogenic acceptor proteins bearing engineered glycosylation sites. Transfer efficiency of PglBCj is low for certain heterologous polysaccharide substrates. In this study, we increased glycosylation rates for Salmonella enterica sv. Typhimurium LT2 O antigen (which lacks N-acetyl sugars) and Staphylococcus aureus CP5 polysaccharides by structure-guided engineering of PglB. A three-dimensional homology model of membrane-associated PglBCj, docked to the natural C. jejuni N glycan attached to the acceptor peptide, was used to identify potential sugar interacting residues as targets for mutagenesis. Saturation mutagenesis of an active site residue yielded the enhancing mutation N311V, which facilitated fivefold to 11-fold increased in vivo glycosylation rates as determined by glycoprotein-specific ELISA. Further rounds of in vitro evolution led to a triple mutant S80R-Q287P-N311V enabling a yield improvement of S. enterica LT2 glycoconjugates by a factor of 16. Our results demonstrate that bacterial N-OST can be tailored to specific polysaccharide substrates by structure-guided protein engineering. PMID- 25833380 TI - Reflections on Cellular Physiology as a Catalytic Framework for Medicine. AB - These are the reflections of a retired physician who was introduced to cellular physiology in 1947 at the University of Pennsylvania. I majored in Zoology. I took the required major courses, which were interesting but not exciting. I was a premedical student at the time. Fortunately I was introduced to cellular physiology in 1947. The teacher was Professor Louis Heilbrunn, an amazing man dedicated to teaching and the love of his students. He had a number of graduate students at the time. The undergraduates were well integrated with these advanced students. We used his textbook of physiology and we were all proud of being his students. He gave us a new way of thinking about biology. It was exciting and we were treated as mature students. PMID- 25833381 TI - Living and deceased organ donation should be financially neutral acts. AB - The supply of organs-particularly kidneys-donated by living and deceased donors falls short of the number of patients added annually to transplant waiting lists in the United States. To remedy this problem, a number of prominent physicians, ethicists, economists and others have mounted a campaign to suspend the prohibitions in the National Organ Transplant Act of 1984 (NOTA) on the buying and selling of organs. The argument that providing financial benefits would incentivize enough people to part with a kidney (or a portion of a liver) to clear the waiting lists is flawed. This commentary marshals arguments against the claim that the shortage of donor organs would best be overcome by providing financial incentives for donation. We can increase the number of organs available for transplantation by removing all financial disincentives that deter unpaid living or deceased kidney donation. These disincentives include a range of burdens, such as the costs of travel and lodging for medical evaluation and surgery, lost wages, and the expense of dependent care during the period of organ removal and recuperation. Organ donation should remain an act that is financially neutral for donors, neither imposing financial burdens nor enriching them monetarily. PMID- 25833382 TI - miR-429 determines poor outcome and inhibits pancreatic ductal adenocarcinoma growth by targeting TBK1. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) ranks fourth on the list of cancer-related causes of death and its prognosis has not improved significantly over the past decades. Deregulation or dysfunction of miRNAs contribute to cancer development. Previous data indicates that miR-429 is involved in the pathogenesis of PDAC. However, the role of miR-429 in PDAC remained unknown. METHODS: MiR-429 levels in sample tissues of 78 patients and in PANC1 and SW1990 cell lines were quantified by real-time PCR. MiR-429 expression was modulated using specific pre- and anti-miRNAs and cell growth was assayed by MTT analysis. Bioinformatics prediction of the miR-429 putative target genes was performed and luciferase assays confirmed TBK1 as a direct target gene. TBK1 levels in PDAC tissues were analyzed by immunohistochemistry. RESULTS: MiR-429 was remarkably decreased in PDAC tissues and cell lines. Lower miR-429 expression in PDAC tissues significantly correlated with shorter survival of PDAC patients. Overexpression of miR-429 inhibited PDAC cell lines growth in vitro and vice versa. TBK1 was found to be the direct target gene of miR-429. Higher TBK1 protein level in PDAC tissues correlated with shorter survival of PDAC patients. Overexpression of TBK1 partly restored cell proliferation. CONCLUSIONS: Low level of miR-429 and high level of TBK1 in PDAC promoted PDAC cells growth which might be related to the low survival rate of PDAC patients. MiR-429 play its role in PDAC by targeting TBK1. PMID- 25833383 TI - Patient experiences and outcomes following facial skin cancer surgery: A qualitative study. AB - Early melanoma and non-melanoma skin cancer of the facial area are primarily treated with surgery. Little is known about the outcomes of treatment for facial skin cancer patients. The objective of the study was to identify concerns about aesthetics, procedures and health from the patients' perspective after facial skin surgery. Semi-structured in-depth interviews were conducted with 15 participants. Line-by-line coding was used to establish categories and develop themes. We identified five major themes on the impact of skin cancer surgery: appearance-related concerns; psychological (e.g., fear of new cancers or recurrence); social (e.g. impact on social activities and interaction); physical (e.g. pain and swelling) concerns and satisfaction with the experience of care (e.g., satisfaction with surgeon). The priority of participants was the removal of the facial skin cancer, as this reduced their overall worry. The aesthetic outcome was secondary but important, as it had important implications on the participants' social and psychological functioning. The participants' experience with the care provided by the surgeon and staff also contributed to their satisfaction with their treatment. This conceptual framework provides the basis for the development of a new patient-reported outcome instrument. PMID- 25833384 TI - Utility of biological sensor tags in animal conservation. AB - Electronic tags (both biotelemetry and biologging platforms) have informed conservation and resource management policy and practice by providing vital information on the spatial ecology of animals and their environments. However, the extent of the contribution of biological sensors (within electronic tags) that measure an animal's state (e.g., heart rate, body temperature, and details of locomotion and energetics) is less clear. A literature review revealed that, despite a growing number of commercially available state sensor tags and enormous application potential for such devices in animal biology, there are relatively few examples of their application to conservation. Existing applications fell under 4 main themes: quantifying disturbance (e.g., ecotourism, vehicular and aircraft traffic), examining the effects of environmental change (e.g., climate change), understanding the consequences of habitat use and selection, and estimating energy expenditure. We also identified several other ways in which sensor tags could benefit conservation, such as determining the potential efficacy of management interventions. With increasing sensor diversity of commercially available platforms, less invasive attachment techniques, smaller device sizes, and more researchers embracing such technology, we suggest that biological sensor tags be considered a part of the necessary toolbox for conservation. This approach can measure (in real time) the state of free-ranging animals and thus provide managers with objective, timely, relevant, and accurate data to inform policy and decision making. PMID- 25833385 TI - Phylogenomics of non-model ciliates based on transcriptomic analyses. AB - Ciliates are one of the oldest living eukaryotic unicellular organisms, widely distributed in the waters around the world. As a typical marine oligotrich ciliate, Strombidium sulcatum plays an important role in marine food webs and energy flow. Here we report the first deep sequencing and analyses of RNA-Seq data from Strombidium sulcatum. We generated 42,640 unigenes with an N50 of 1,451 bp after de novo assembly and removing rRNA, mitochondrial and bacteria contaminants. We employed SPOCS to detect orthologs from S. sulcatum and 17 other ciliates, and then carried out the phylogenomic reconstruction using 127 single copy orthologs. In phylogenomic analyses, concatenated trees have similar topological structures with concordance tree on the class level. Together with phylogenetic networks analysis, it aroused more doubts about the placement of Protocruzia, Mesodinium and Myrionecta. While epiplasmic proteins are known to be related to morphological characteristics, we found the potential relationship between gene expression of epiplasmic proteins and morphological characteristics. This work supports the use of high throughput approaches for phylogenomic analysis as well as correlation analysis between expression level of target genes and morphological characteristics. PMID- 25833386 TI - Process Evaluation of a Quality Improvement Project to Decrease Hospital Readmissions From Skilled Nursing Facilities. AB - OBJECTIVE: To describe and evaluate the impact of quality improvement (QI) support provided to skilled nursing facilities (SNFs) by a Quality Improvement Organization (QIO). DESIGN: Retrospective, mixed-method, process evaluation of a QI project intended to decrease preventable hospital readmissions from SNFs. SETTING: Five SNFs in Connecticut. PARTICIPANTS: SNF Administrators, Directors of Nursing, Assistant Directors of Nursing, Admissions Coordinators, Registered Nurses, Certified Nursing Assistants, Receptionists, QIO Quality Improvement Consultant. INTERVENTION: QIO staff provided training and technical assistance to SNF administrative and clinical staff to establish or enhance QI infrastructure and implement an established set of QI tools [Interventions to Reduce Acute Care Transfers (INTERACT) tools]. MEASUREMENTS: Baseline SNF demographic, staffing, and hospital readmission data; baseline and follow-up SNF QI structure (QI Committee), processes (general and use of INTERACT tools), and outcome (30-day all-cause hospital readmission rates); details of QIO-provided training and technical assistance; QIO-perceived barriers to quality improvement; SNF leadership-perceived barriers, accomplishments, and suggestions for improvement of QIO support. RESULTS: Success occurred in establishing QI Committees and targeting preventable hospital readmissions, as well as implementing INTERACT tools in all SNFs; however, hospital readmission rates decreased in only 2 facilities. QIO staff and SNF leaders noted the ongoing challenge of engaging already busy SNF staff and leadership in QI activities. SNF leaders reported that they appreciated the training and technical assistance that their institutions received, although most noted that additional support was needed to bring about improvement in readmission rates. CONCLUSION: This process evaluation documented mixed clinical results but successfully identified opportunities to improve recruitment of and provision of technical support to participating SNFs. Recommendations are offered for others who wish to conduct similar projects. PMID- 25833388 TI - Quality of handover in a pediatric postanesthesia care unit. AB - BACKGROUND: The quality of anesthetic handovers to postanesthesia care units (PACU) is known to be poor in adults, and only very limited reports are available regarding the quality of handovers in pediatric anesthesia. In particular, it is not known which and in what quality information is communicated. This current study investigated, therefore, the presence of any handover component as well as its consistency in a pediatric postanesthesia care unit. METHODS: This prospective observational study evaluated postoperative anesthetic handovers to a pediatric PACU using a detailed checklist, comprising 55 possible items. The main outcome measure was the proportion of information verbally transmitted in relation to the written documentation within the anesthesia record. RESULTS: Four hundred and forty-three handovers were observed with two handovers excluded due to missing data. Type of surgery (93% [95% CI 91-95]) and any intra-operative regional anesthesia (89% [95% CI 85-94]) were most frequently communicated. Items such as ASA-PS (3% [95% CI 2-5]) and fluid management (4% of cases [95% CI 2-6]) were rarely handed over. Eleven of the 55 items contained within the checklist were communicated in more than 70% of patients. CONCLUSIONS: The observed handovers to PACU staff were incomplete and missing important information. However, omission of essential information potentially compromises patient safety. A standardized universal mandatory handover protocol following pediatric anesthesia is required. PMID- 25833379 TI - Ubiquitylation, neddylation and the DNA damage response. AB - Failure of accurate DNA damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA damage detection and repair, collectively termed the DNA damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair. PMID- 25833389 TI - Biological potential of nanomaterials strongly depends on the suspension media: experimental data on the effects of fullerene C60 on membranes. AB - Fullerenes (C60) are some of the most promising carbon nanomaterials to be used for medical applications as drug delivery agents. Computational and experimental studies have proposed their ability to enter cells by penetrating lipid bilayers. The aim of our study was to provide experimental evidence on whether pristine C60 in physiological media could penetrate cell membranes. The effect was tested on phospholipid vesicles (liposomes) composed of 1,2-dipalmitoyl-sn-glycero-3 phosphocholine, and validated on isolated human red blood cells (RBCs). We incubated the liposomes in an aqueous suspension of C60 and dissolved the lipids and C60 together in chloroform and subsequently formatted the liposomes. By differential scanning calorimetry measurements, we assessed the effect of C60 on the phospholipid thermal profile. The latter was not affected after the incubation of liposomes in the C60 suspension; also, a shape transformation of RBCs did not occur. Differently, by dispersing both C60 and the phospholipids in chloroform, we confirmed the possible interaction of C60 with the bilayer. We provide experimental data suggesting that the suspension medium is an important factor in determining the C60-membrane interaction, which is not always included in computational studies. Since the primary particle size is not the only crucial parameter in C60-membrane interactions, it is important to determine the most relevant characteristics of their effects on membranes. PMID- 25833392 TI - Commentary. PMID- 25833390 TI - A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study. AB - A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0.32). Although not statistically different, results suggest IVB may be a promising combination. PMID- 25833391 TI - Encoding and decoding spatio-temporal information for super-resolution microscopy. AB - The challenge of increasing the spatial resolution of an optical microscope beyond the diffraction limit can be reduced to a spectroscopy task by proper manipulation of the molecular states. The nanoscale spatial distribution of the molecules inside the detection volume of a scanning microscope can be encoded within the fluorescence dynamics and decoded by resolving the signal into its dynamics components. Here we present a robust and general method to decode this information using phasor analysis. As an example of the application of this method, we optically generate spatially controlled gradients in the fluorescence lifetime by stimulated emission. Spatial resolution can be increased indefinitely by increasing the number of resolved dynamics components up to a maximum determined by the amount of noise. We demonstrate that the proposed method provides nanoscale imaging of subcellular structures, opening new routes in super resolution microscopy based on the encoding/decoding of spatial information through manipulation of molecular dynamics. PMID- 25833393 TI - Integrating ontologies of rare diseases and radiological diagnosis. AB - PURPOSE: The author sought to integrate an ontology of rare diseases with a large ontological model of radiological diagnosis. MATERIALS AND METHODS: The Orphanet Rare Disease Ontology (ORDO) comprised 6794 rare diseases. The Radiology Gamuts Ontology (RGO) incorporated 16 197 terms and 53,425 causal relations linking disorders to imaging manifestations. Semi-automated string-matching was used to match ORDO terms to RGO terms. RESULTS: Of 6794 ORDO terms, 1587 (23.3%) were matched to RGO terms. An additional 700 ORDO terms whose names were hyphenated lists of phenotypic features were added to RGO with causal links from the disease name to the various features. Matched terms were more likely to have higher disease prevalence. CONCLUSIONS: Integrating these ontologies expanded the set of terms and scope of knowledge available for radiological differential diagnosis, and can support translational rare-disease research by linking knowledge of genetics and imaging phenotypes. PMID- 25833394 TI - Implications for informatics given expanding access to care for Veterans and other populations. AB - Recent investigations into appointment scheduling within facilities operated by the US Department of Veterans Affairs (VA) illuminate systemic challenges in meeting its goal of providing timely access to care for all Veterans. In the wake of these investigations, new policies have been enacted to expand access to care at VA facilities as well as non-VA facilities if the VA is unable to provide access within a reasonable timeframe or a Veteran lives more than 40 miles from a VA medical facility. These policies are similar to broader health reform efforts that seek to expand access to care for other vulnerable populations. In this perspective, we discuss the informatics implications of expanded access within the VA and its wider applicability across the US health system. Health systems will require robust health information exchange, to maintain coordination while access to care is expanded. Existing informatics research can guide short-term implementation; furthermore, new research is needed to generate evidence about how best to achieve the long-term aim of expanded access to care. PMID- 25833395 TI - bFGF Protects Pre-oligodendrocytes from Oxygen/Glucose Deprivation Injury to Ameliorate Demyelination. AB - One of the pathological hallmarks of periventricular white matter injury is the vulnerability of pre-oligodendrocytes (preOLs) to hypoxia-ischemia (HI). There is increasing evidence that basic fibroblast growth factor (bFGF) is an important signaling molecule for neurogenesis and neuroprotection in the central nervous system. However, it is unknown whether bFGF protects preOLs from oxygen/glucose deprivation (OGD) damage in vitro and promotes remyelination in HI-induced rats. In this present study, bFGF exerted a protective effect on myelin by increasing the myelin thickness, the number of myelinated axons, and myelin basic protein expression in the HI-induced demyelinated neonatal rat corpus callosum. In vitro, bFGF ameliorated the impaired mitochondria and cell processes induced by OGD to promote the survival of isolated O4-positive preOLs. Additionally, the expression of fibroblast growth factor receptor 3 (FGFR3) was dramatically up-regulated in the preOLs after bFGF administration in vivo and in vitro. Thus, bFGF-stimulated remyelination in HI-induced rats by protecting the preOLs from hypoxic injury, and the mechanism involved may be mediated by FGFR3. PMID- 25833396 TI - Survival of effector CD8+ T cells during influenza infection is dependent on autophagy. AB - The activation and expansion of effector CD8(+) T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known. In this study, we generated a novel inducible autophagy knockout mouse to study T cell effector responses during the course of a virus infection. In response to influenza infection, Atg5(-/-) CD8(+) T cells had a decreased capacity to reach the peak effector response and were unable to maintain cell viability during the effector phase. As a consequence of Atg5 deletion and the impairment in effector-to-memory cell survival, mice fail to mount a memory response following a secondary challenge. We found that Atg5(-/-) effector CD8(+) T cells upregulated p53, a transcriptional state that was concomitant with widespread hypoxia in lymphoid tissues of infected mice. The onset of p53 activation was concurrent with higher levels of reactive oxygen species (ROS) that resulted in ROS-dependent apoptotic cell death, a fate that could be rescued by treating with the ROS scavenger N-acetylcysteine. Collectively, these results demonstrate that effector CD8(+) T cells require autophagy to suppress cell death and maintain survival in response to a viral infection. PMID- 25833397 TI - CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif. AB - In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28's prosurvival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte-induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte-induced maturation protein-1 transcriptional nexus involved in long-term survival and function. PMID- 25833399 TI - Placental melatonin system is present throughout pregnancy and regulates villous trophoblast differentiation. AB - Melatonin is highly produced in the placenta where it protects against molecular damage and cellular dysfunction arising from hypoxia/re-oxygenation-induced oxidative stress as observed in primary cultures of syncytiotrophoblast. However, little is known about melatonin and its receptors in the human placenta throughout pregnancy and their role in villous trophoblast development. The purpose of this study was to determine melatonin-synthesizing enzymes, arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT), and melatonin receptors (MT1 and MT2) expression throughout pregnancy as well as the role of melatonin and its receptors in villous trophoblast syncytialization. Our data show that the melatonin generating system is expressed throughout pregnancy (from week 7 to term) in placental tissues. AANAT and HIOMT show maximal expression at the 3rd trimester of pregnancy. MT1 receptor expression is maximal at the 1st trimester compared to the 2nd and 3rd trimesters, while MT2 receptor expression does not change significantly during pregnancy. Moreover, during primary villous cytotrophoblast syncytialization, MT1 receptor expression increases, while MT2 receptor expression decreases. Treatment of primary villous cytotrophoblast with an increasing concentration of melatonin (10 pM-1 mM) increases the fusion index (syncytium formation; 21% augmentation at 1 mM melatonin vs. vehicle) and beta-hCG secretion (121% augmentation at 1 mM melatonin vs. vehicle). This effect of melatonin appears to be mediated via its MT1 and MT2 receptors. In sum, melatonin machinery (synthetizing enzymes and receptors) is expressed in human placenta throughout pregnancy and promotes syncytium formation, suggesting an essential role of this indolamine in placental function and pregnancy well-being. PMID- 25833398 TI - PLZF regulates CCR6 and is critical for the acquisition and maintenance of the Th17 phenotype in human cells. AB - Th17 cells, which express the chemokine receptor CCR6, are implicated in many immune-mediated disorders, such as psoriasis and multiple sclerosis. We found that expression levels of CCR6 on human effector/memory CD4(+) T cells reflect a continuum of Th17 differentiation. By evaluating the transcriptome in cells with increasing CCR6, we detected progressive upregulation of ZBTB16, which encodes the broad complex, tramtrack, bric-a-brac-zinc finger transcription factor promyelocytic leukemia zinc finger protein (PLZF). Using chromatin immunoprecipitation for modified histones, p300, and PLZF, we identified enhancer like sites at -9/-10 and -13/-14 kb from the upstream transcription start site of CCR6 that bind PLZF in CCR6(+) cells. For Th cells from adult blood, both in the CCR6(+) memory population and in naive cells activated ex vivo, knockdown of ZBTB16 downregulated CCR6 and other Th17-associated genes. ZBTB16 and RORC (which encodes the "master regulator" RORgammat) cross-regulate each other, and PLZF binds at the RORC promoter in CCR6(+) cells. In naive Th cells from cord blood, ZBTB16 expression was confined to CD161(+) cells, which are Th17 cell precursors. ZBTB16 was not expressed in mouse Th17 cells, and Th17 cells could be made from luxoid mice, which harbor an inactivating mutation in Zbtb16. These studies demonstrate a role for PLZF as an activator of transcription important both for Th17 differentiation and the maintenance of the Th17 phenotype in human cells, expand the role of PLZF as a critical regulator in the human adaptive immune system, and identify a novel, essential element in a regulatory network that is of significant therapeutic interest. PMID- 25833400 TI - [Age-related changes in swallowing. Physiology and pathophysiology]. AB - The term presbyphagia refers to all changes of swallowing physiology that are manifested with increasing age. Alterations in the pattern of deglutition that are part of healthy aging are called primary presbyphagia. Primary presbyphagia is not an illness in itself but contributes to a more pervasive naturally diminished functional reserve, making older adults more susceptible to dysphagia. If disorders in swallowing occur in the elderly as a comorbidity of a specific disease, for example stroke or neurodegenerative disorders, this is called secondary presbyphagia. Increasing age has an impact on each stage of deglutition. In the oral preparatory phase a diminished input for smell and taste as well as a usually multifactorial cause of dry mouth are the most important influencing factors. Sarcopenia, the degenerative loss of skeletal muscle mass, strength and quality associated with aging, interferes in particular with the oropharyngeal phase. A decreased sensory feedback from the oropharyngeal mucosa leads to a delayed triggering of the swallowing reflex. Finally, a reduction in connective tissue elasticity and changes of the axial skeleton lead to various modifications of the swallowing pattern with advanced age. PMID- 25833402 TI - An effective approach to reduce inflammation and stenosis in carotid artery: polypyrrole nanoparticle-based photothermal therapy. AB - Photothermal therapy (PTT), as a promising treatment for tumours, has rarely been reported for application in artery restenosis, which is a common complication of endovascular management due to enduring chronic inflammation and abnormal cell proliferation. In our study, biodegradable polypyrrole nanoparticles (PPy-NPs) were synthesized and characterized, including their size distribution, UV-vis-NIR absorbance, molar extinction coefficients, and photothermal properties. We then verified that PPy-NP incubation followed by 915 nm near-infrared (NIR) laser irradiation could effectively ablate inflammatory macrophages in vitro, leading to significant cell apoptosis and cell death. Further, it was found that a combination of local PPy-NP injection with 915 nm NIR laser irradiation could significantly alleviate arterial inflammation by eliminating infiltrating macrophages and further ameliorating artery stenosis in an ApoE(-/-) mouse model, without showing any obvious toxic side effects. Thus, we propose that PTT based on PPy-NPs as photothermal agents and a 915 nm NIR laser as a power source can serve as a new effective treatment for reducing inflammation and stenosis formation in inflamed arteries after endovascular management. PMID- 25833401 TI - [Pegylated interferon beta 1a. A new therapy option for treatment of relapsing remitting multiple sclerosis]. AB - Pegylation of pharmacological substances was developed in the 1970s as a way of improving their efficacy and elimination and hence reducing the dosage frequency. A prominent example is pegylation of IFNalpha, which revolutionized the treatment of virus hepatitis in the late 1990s. Efforts have now succeeded in producing a pegylated interferon beta (PEG-IFN-beta1a) to treat multiple sclerosis (MS) and the efficacy and safety have been investigated in a phase III trial called the ADVANCE study. The 1-year results of this randomized, double blind, multicenter, placebo-controlled study in more than 1500 MS patients show that administration of subcutaneous PEG-IFN-beta1a significantly reduces the annual relapse rate and disability progression. The safety and tolerability profile of PEG-IFN-beta1a was found to be similar to that of conventional IFN-beta drugs. The most common adverse events were flu-like symptoms and redness at the injection site. The results of this study underscore that PEG-IFN-beta1a is an interesting new therapeutic option in the treatment of relapsing-remitting MS that combines highly effective interferon with the established tolerability and safety profile of IFN-beta at a reduced dosage frequency. PMID- 25833403 TI - Efficacy of Cell Wall-Deficient Spheroplasts Against Experimental Murine Listeriosis. AB - Various strategies adapted to develop an efficient vaccine against foodborne pathogen, Listeria monocytogenes, have met with little success. Spheroplasts (bacterial cell devoid of cell wall) are likely to undergo membrane-membrane fusion, leading to the delivery of their content to the cytosol of antigen presenting cells, thus facilitating MHC class I antigen processing and presentation. In this study, we evaluated the prophylactic potential of Listeria spheroplast-based vaccine against experimental murine listeriosis in comparison with heat-killed Listeria (HKL) and archaeosome-entrapped Listeria whole-cell protein (LWCP). Compared with HKL, the spheroplast-based vaccine was found to evoke better Th1 response as exhibited by the presence of type 1 cytokines in the host (interferon-gamma and IL-12) and a high IgG2a /IgG1 ratio. Robust lympho proliferative efficacy was apparent in both spheroplast-immunized and archaeosome entrapped LWCP-immunized groups. The upregulation of costimulatory and effector memory markers upon immunization with spheroplasts was found to be at par with that evoked by archaeosome-entrapped LWCP-immunized group. Central memory response in gated CD8(+) T cell was much higher in spheroplast-immunized animals when compared with archaeosome-entrapped LWCP group. The data presented here clearly demonstrate that spheroplasts evoked a robust immune response and offer better prophylactic potential against L. monocytogenes. PMID- 25833404 TI - Computational Modelling of Dapsone Interaction With Dihydropteroate Synthase in Mycobacterium leprae; Insights Into Molecular Basis of Dapsone Resistance in Leprosy. AB - The molecular basis for determination of resistance to anti-leprosy drugs is the presence of point mutations within the genes of Mycobacterium leprae (M. leprae) that encode active drug targets. The downstream structural and functional implications of these point mutations on drug targets were scarcely studied. In this study, we utilized computational tools to develop native and mutant protein models for 5 point mutations at codon positions 53 and 55 in 6-hydroxymethyl-7, 8 dihydropteroate synthase (DHPS) of M. leprae, an active target for dapsone encoded by folp1 gene, that confer resistance to dapsone. Molecular docking was performed to identify variations in dapsone interaction with mutant DHPS in terms of hydrogen bonding, hydrophobic interactions, and energy changes. Schrodinger Suite 2014-3 was used to build homology models and in performing molecular docking. An increase in volume of the binding cavities of mutant structures was noted when compared to native form indicating a weakening in interaction (60.7 A(3) in native vs. 233.6 A(3) in Thr53Ala, 659.9 A(3) in Thr53Ile, 400 A(3) for Thr53Val, 385 A(3) for Pro55Arg, and 210 A(3) for Pro55Leu). This was also reflected by changes in hydrogen bonds and decrease in hydrophobic interactions in the mutant models. The total binding energy (DeltaG) decreased significantly in mutant forms when compared to the native form (-51.92 Kcal/mol for native vs. 35.64, -35.24, -46.47, -47.69, and -41.36 Kcal/mol for mutations Thr53Ala, Thr53Ile, Thr53Val, Pro55Arg, and Pro55Leu, respectively. In brief, this analysis provided structural and mechanistic insights to the degree of dapsone resistance contributed by each of these DHPS mutants in leprosy. PMID- 25833405 TI - Statins and Cardiovascular Primary Prevention in CKD: A Meta-Analysis. AB - BACKGROUND AND OBJECTIVES: Multiple meta-analyses of lipid-lowering therapies for cardiovascular primary prevention in the general population have been performed. Other meta-analyses of lipid-lowering therapies in CKD have also been performed, but not for primary prevention. This meta-analysis assesses lipid-lowering therapies for cardiovascular primary prevention in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic review and meta-analysis using a random-effects model was performed. MEDLINE was searched between January 2012 and September 2013 for new studies using predefined search criteria without language restrictions. A number of other sources including previously published meta analyses were also reviewed. Inclusion criteria were randomized control trials of primary prevention with lipid-lowering therapy in non-end stage CKD. RESULTS: Six trials were identified, five including patients with stage 3 CKD only. These studies included 8834 participants and 32,846 person-years of follow-up. All trials were post hoc subgroup analyses of statins in the general population. Statins reduced the risk of cardiovascular disease (the prespecified primary outcome) by 41% in stages 1-3 CKD compared with placebo (pooled risk ratio, 0.59; 95% confidence interval [95% CI], 0.48 to 0.72). For the secondary outcomes, the risk ratios were 0.66 (95% CI, 0.49 to 0.88) for total mortality, 0.55 (95% CI, 0.42 to 0.72) for coronary heart disease events, and 0.56 (95% CI, 0.28 to 1.13) for stroke. In study participants with stage 3 CKD specifically, the results were similar. CONCLUSIONS: This meta-analysis suggests that the use of statins in CKD for primary prevention of cardiovascular disease is effective. These findings are consistent with recent guidance for the use of statins in all patients with CKD. PMID- 25833407 TI - The Association Between Household Consumer Durable Assets and Maternal Health Seeking Behavior in Ghana. AB - This article examined the association between household consumer durable assets and maternal health-seeking behavior. Several studies have suggested a relationship between households' socioeconomic status (SES) and health outcomes. However, SES is a multidimensional concept that encompasses variables, such as wealth, education, and income. By grouping these variables together as one construct, prior studies have not provided enough insight into possible independent associations with health outcomes. This study used data from the 2008 Ghana Demographic and Health Survey of 2,065 women aged between 15 and 49 years to examine the association between household consumer durables (a component of SES) and maternal health-seeking behavior in Ghana. Results from a set of generalized linear models indicated that household consumer durable assets were positively associated with four measures of maternal health-seeking behaviors, namely, seeking prenatal care from skilled health personnel, delivery by skilled birth attendant, place of delivery, and the number of antenatal visits. Also, households with more assets whose residents lived in urban areas were more likely to use skilled health personnel before and during delivery, and at an approved health facility, compared those who lived in rural areas. Implications for health interventions and policies that focus on the most vulnerable households are discussed. PMID- 25833406 TI - Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension? AB - We examined the impacts of aspirin and metformin on the life history of the cricket Acheta domesticus (growth rate, maturation time, mature body size, survivorship, and maximal longevity). Both drugs significantly increased survivorship and maximal life span. Maximal longevity was 136 days for controls, 188 days (138 % of controls) for metformin, and 194 days (143 % of controls) for aspirin. Metformin and aspirin in combination extended longevity to a lesser degree (163 days, 120 % of controls). Increases in general survivorship were even more pronounced, with low-dose aspirin yielding mean longevity 234 % of controls (i.e., health span). Metformin strongly reduced growth rates of both genders (<60 % of controls), whereas aspirin only slightly reduced the growth rate of females and slightly increased that of males. Both drugs delayed maturation age relative to controls, but metformin had a much greater impact (>140 % of controls) than aspirin (~118 % of controls). Crickets maturing on low aspirin showed no evidence of a trade-off between maturation mass and life extension. Remarkably, by 100 days of age, aspirin-treated females were significantly larger than controls (largely reflecting egg complement). Unlike the reigning dietary restriction paradigm, low aspirin conformed to a paradigm of "eat more, live longer." In contrast, metformin-treated females were only ~67 % of the mass of controls. Our results suggest that hormetic agents like metformin may derive significant trade offs with life extension, whereas health and longevity benefits may be obtained with less cost by agents like aspirin that regulate geroprotective pathways. PMID- 25833408 TI - Increased cerebral cannabinoid-1 receptor availability is a stable feature of functional dyspepsia: a [F]MK-9470 PET study. AB - BACKGROUND: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). METHODS: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [(18)F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 +/- 9.6 months (range: 25.2-50.4 months). RESULTS: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 +/- 9.6 months. CONCLUSIONS: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs. PMID- 25833409 TI - Potent Antifouling Marine Dihydroquinolin-2(1H)-one-Containing Alkaloids from the Gorgonian Coral-Derived Fungus Scopulariopsis sp. AB - Marine biofouling has a major economic impact, especially when it occurs on ship hulls or aquaculture facilities. Since the International Maritime Organization (IMO) treaty to ban the application of organotin-based paints to ships went into effect in 2008, there is an urgent demand for the development of efficient and environmentally friendly antifouling agents. Marine microorganisms have proved to be a potential source of antifouling natural compounds. In this study, six dihydroquinolin-2-one-containing alkaloids, three monoterpenoids combined with a 4-phenyl-3,4-dihydroquinolin-2(1H)-one (1-3) and three 4-phenyl-3,4 dihydroquinolin-2(1H)-one alkaloids (4-6), were isolated from the gorgonian coral derived fungus Scopulariopsis sp. collected in the South China Sea. These dihydroquinolin-2-one-containing alkaloids were evaluated against the larval settlement of barnacle Balanus amphitrite, and antifouling activity was detected for the first time for this class of metabolites. All of them except 6 showed strong antifouling activity. Compounds 1 and 2 were discovered to be the most promising non-toxic antilarval settlement candidates. Especially, compound 1 is the strongest antifouling compound in nature until now which showed highly potent activity with picomolar level (EC50 17.5 pM) and a very safety and high therapeutic ratio (LC50/EC50 1200). This represents an effective non-toxic, anti larval settlement structural class of promising antifouling lead compound. PMID- 25833410 TI - Elastin organization in pig and cardiovascular disease patients' pericardial resistance arteries. AB - Peripheral vascular resistance is increased in essential hypertension. This involves structural changes of resistance arteries and stiffening of the arterial wall, including remodeling of the extracellular matrix. We hypothesized that biopsies of the human parietal pericardium, obtained during coronary artery bypass grafting or cardiac valve replacement surgeries, can serve as a source of resistance arteries for structural research in cardiovascular disease patients. We applied two-photon excitation fluorescence microscopy to study the parietal pericardium and isolated pericardial resistance arteries with a focus on the collagen and elastin components of the extracellular matrix. Initial findings in pig tissue were confirmed in patient biopsies. The microarchitecture of the internal elastic lamina in both the pig and patient pericardial resistance arteries (studied at a transmural pressure of 100 mm Hg) is fiber like, and no prominent external elastic lamina could be observed. This microarchitecture is very different from that in rat mesenteric arteries frequently used for resistance artery research. In conclusion, we add three-dimensional information on the structure of the extracellular matrix in resistance arteries from cardiovascular disease patients and propose further use of patient pericardial resistance arteries for studies of the human microvasculature. PMID- 25833411 TI - An Unusually Small Singlet-Triplet Gap in a Quinoidal 1,6-Methano[10]annulene Resulting from Baird's 4n pi-Electron Triplet Stabilization. AB - Within the continuum of pi-extended quinoidal electronic structures exist molecules that by design can support open-shell diradical structures. The prevailing molecular design criteria for such structures involve proaromatic nature that evolves aromaticity in open-shell diradical resonance structures. A new diradical species built upon a quinoidal methano[10]annulene unit is synthesized and spectroscopically evaluated. The requisite intersystem crossing in the open-shell structure is accompanied by structural reorganization from a contorted Mobius aromatic-like shape in S0 to a more planar shape in the Huckel aromatic-like T1. This stability was attributed to Baird's Rule which dictates the aromaticity of 4n pi-electron triplet excited states. PMID- 25833412 TI - Parent stress across molecular subtypes of children with Angelman syndrome. AB - BACKGROUND: Parenting stress has been consistently reported among parents of children with developmental disabilities. However, to date, no studies have investigated the impact of a molecular subtype of Angelman syndrome (AS) on parent stress, despite distinct phenotypic differences among subtypes. METHOD: Data for 124 families of children with three subtypes of AS: class I and II deletions (n = 99), imprinting centre defects (IC defects; n = 11) and paternal uniparental disomy (UPD; n = 14) were drawn from the AS Rare Diseases Clinical Research Network (RDCRN) database and collected from five research sites across the Unites States. The AS study at the RDCRN gathered health information to understand how the syndrome develops and how to treat it. Parents completed questionnaires on their perceived psychological stress, the severity of children's aberrant behaviour and children's sleep patterns. Children's adaptive functioning and developmental levels were clinically evaluated. RESULTS: Child related stress reached clinical levels for 40% of parents of children with deletions, 100% for IC defects and 64.3% for UPD. Sleep difficulties were similar and elevated across subtypes. There were no differences between molecular subtypes for overall child and parent-related stress. However, results showed greater isolation and lack of perceived parenting skills for parents of children with UPD compared with deletions. Better overall cognition for children with deletions was significantly related to more child-related stress while their poorer adaptive functioning was associated with more child-related stress. For all three groups, the severity of children's inappropriate behaviour was positively related to different aspects of stress. CONCLUSIONS: How parents react to stress depends, in part, on children's AS molecular subtype. Despite falling under the larger umbrella term of AS, it is important to acknowledge the unique aspects associated with children's molecular subtype. Identifying these factors can lead to tailored interventions that fit the particular needs of families of children with different AS subtypes. PMID- 25833413 TI - Global DNA methylation and hydroxymethylation differ in hepatocellular carcinoma and cholangiocarcinoma and relate to survival rate. AB - In addition to DNA methylation, hydroxymethylation of DNA is recognized as a novel epigenetic mark. Primary liver cancers, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), are highly prevalent but epigenetically poorly characterized, so far. In the present study we measured global methylcytosine (mCyt) and hydroxymethylcytosine (hmCyt) in HCC and CC tissues and in peripheral blood mononuclear cell (PBMC) DNA to define mCyt and hmCyt status and, accordingly, the survival rate. Both mCyt and hmCyt were measured by a liquid chromatography/tandem mass spectrometry method in neoplastic and homologous nonneoplastic tissues, i.e., liver and gallbladder, and in PBMCs of 31 HCC and 16 CC patients. Content of mCyt was notably lower in HCC than in CC tissues (3.97% versus 5.26%, respectively; P < 0.0001). Significantly reduced mCyt was also detected in HCC compared to nonneoplastic tissue (3.97% versus 4.82% mCyt, respectively; P < 0.0001), but no such difference was found for CC versus homologous nonneoplastic tissue. Hydroxymethylation was significantly decreased in HCC versus nonneoplastic liver tissue (0.044 versus 0.128, respectively; P < 0.0001) and in CC versus both liver and gallbladder nonneoplastic tissue (0.030 versus 0.124, P = 0.026, and 0.030 versus 0.123, P = 0.006, respectively). When the survival rate was evaluated according to mCyt PBMC content by Kaplan-Meier analysis, patients with mCyt >=5.59% had a significantly higher life expectancy than those with mCyt <5.59% (P = 0.034) at a follow-up period up to 48 months. CONCLUSION: A significant DNA hypomethylation distinguishes HCC from CC, while DNA hypo-hydroxymethylation characterizes both HCC and CC, and a PBMC DNA mCyt content >=5.59% relates to a favorable outcome in primary liver cancers. PMID- 25833414 TI - Costs in different states of prostate cancer. AB - OBJECTIVES: This cross-sectional study assesses resource use and costs in different states of prostate cancer (PCa) in a real-life setting. Costs were estimated as incremental costs due to cancer for a six-month period and they included direct medical costs, productivity costs and costs of informal care. METHODS: Resource use and cost data, irrespective of who the payer was, were retrieved from the registries for 611 PCa patients in the Helsinki area in Finland. In addition, patients answered background questions concerning informal care, work capacity and educational status. Patients were divided into four mutually exclusive groups based on disease state and time from diagnosis: primary (local disease, first six months after diagnosis; n = 47), rehabilitation (local disease, 0.5-1.5 years after diagnosis or recurrence; n = 158), remission (local disease, more than 1.5 years after diagnosis; n = 317) and metastatic (after detection of metastases; n = 89). RESULTS: Costs differed markedly between the states of disease. Mean direct health care costs for the six-month periods were: primary treatment state ? 2750, rehabilitation state ? 1143, remission state ? 760 and metastatic state ? 7423. Productivity costs were also highest (? 4277) in the metastatic state. Overall, the average share of indirect costs was around one third of the total costs. However, when including informal care, their combined share of the total costs increased to around half or more. CONCLUSIONS: The results provided state-specific estimates of the direct health care and indirect costs of PCa in Finland. The treatment of metastatic disease is significantly more costly than treatment of early stage PCa. Although direct medical costs were higher compared to productivity costs, they should be taken into consideration when evaluating the costs of PCa. PMID- 25833415 TI - Validity of three rating scales for measuring pain intensity in youths with physical disabilities. AB - BACKGROUND: There is growing evidence confirming that youths with physical disabilities are at risk for chronic pain. Although many scales for assessing pain intensity exist, it is unclear whether they are all equally suitable for youths. The aim of this study was to address this knowledge gap by comparing the validity of the Numerical Rating Scale (NRS-11), the Wong Baker FACES Pain Rating Scale (FACES), and a 6-point categorical Verbal Rating Scale (VRS-6) for assessing pain intensity among youths (aged 8-20) with physical disabilities. METHODS: One hundred and thirteen youths (mean age = 14.19 years; SD = 2.9) were interviewed and asked to rate their current pain intensity and recalled (in the past week) worst, least, and average pain with the NRS-11 and the FACES. Participants were also asked to rate their average pain intensity during the past 4 weeks using a VRS-6, and were administered measures assessing pain interference, disability and psychological functioning. RESULTS: Analyses showed that all of the pain intensity measures were associated positively with each other. Nevertheless, the NRS-11 appeared to out-perform both the VRS-6 and in particular the FACES scale with respect to: (1) the associations with the validity criterion (i.e. pain interference, disability and psychological functioning) and (2) a lack of any moderating effect of age on the association between the measure and the criterion variables. CONCLUSIONS: The findings support the validity of the NRS-11 for assessing pain intensity in youths with physical disabilities between the ages of 8 and 20 years. PMID- 25833417 TI - Systematic review of compression following treatment for varicose veins. AB - BACKGROUND: Consensus regarding compression following treatment of varicose veins has yet to be reached. This systematic review aims to establish the optimal compression regimen after venous treatment. METHODS: A systematic review of MEDLINE, Embase and CENTRAL was performed to identify randomized clinical trials (RCTs) investigating different compression strategies following treatment for superficial venous insufficiency. RESULTS: Seven RCTs comparing different durations and methods of compression fulfilled the inclusion criteria. The treatment modality was open surgery in three trials, foam sclerotherapy in two and endovenous laser ablation (EVLA) in two trials. The quality of the studies was variable, and significant sources of potential bias were present. Both the studies and compression regimens used were heterogeneous. Ten products were used in six general regimens for a duration of 0-42 days. One study suggested that 7 days rather than 2 days of stockings following EVLA was associated with superior quality of life and less pain at 1 week. Another study reported that, following surgery, application of a compression stocking after 3 days of bandaging was associated with a slightly longer recovery than no compression after 3 days. One study recorded compliance clearly, finding it to be only 40 per cent. The quality and heterogeneity of the studies precluded meta-analysis. CONCLUSION: There is currently little quality evidence upon which to base any recommendations concerning compression following treatment for varicose veins. PMID- 25833416 TI - Administration of antithrombin III attenuates posthepatectomy liver failure in hepatocellular carcinoma. AB - BACKGROUND/AIMS: Coagulopathy can cause disseminated intravascular coagulation and posthepatectomy liver failure. Posthepatectomy liver failure predicts a poor prognosis after hepatectomy for hepatocellular carcinoma. Although antithrombin III reduces hypercoagulation, the impact of postoperative antithrombin III administration remains unknown. The aim of this study was to determine whether postoperative antithrombin III administration protects against the development of coagulation disorders. METHODS: Data from 164 patients who received antithrombin III and 169 who did following curative hepatectomy for hepatocellular carcinoma were retrospectively collected and analyzed. To overcome bias due to different distributions of covariates for the two groups, a one-to-one match was created using propensity score analysis. After matching, patient outcomes were analyzed. RESULTS: A multivariate analysis of the whole group revealed that antithrombin III activity of <50% on postoperative day 1 was an independent risk factor for posthepatectomy liver failure. After one-to-one matching, the rate of posthepatectomy liver failure was significantly lower in the AT-III-treated group than in the non-AT-III-treated group (16.3% (7/43) vs. 44.2% (19/43), p < 0.01). CONCLUSIONS: Antithrombin III may attenuate posthepatectomy liver failure in hepatocellular carcinoma, possibly by suppressing coagulopathy. PMID- 25833418 TI - MicroRNA-20a is essential for normal embryogenesis by targeting vsx1 mRNA in fish. AB - MicroRNAs are major post-transcriptional regulators of gene expression and have essential roles in diverse developmental processes. In vertebrates, some regulatory genes play different roles at different developmental stages. These genes are initially transcribed in a wide embryonic region but restricted within distinct cell types at subsequent stages during development. Therefore, post transcriptional regulation is required for the transition from one developmental stage to the next and the establishment of different cell identities. However, the regulation of many multiple functional genes at post-transcription level during development remains unknown. Here we show that miR-20a can target the mRNA of vsx1, a multiple functional gene, at the 3'-UTR and inhibit protein expression in both goldfish and zebrafish. The expression of miR-20a is initiated ubiquitously at late gastrula stage and exhibits a tissue-specific pattern in the developing retina. Inhibition of vsx1 3'-UTR mediated protein expression occurs when and where miR-20a is expressed. Decoying miR-20a resulted in severely impaired head, eye and trunk formation in association with excessive generation of vsx1 marked neurons in the spinal cord and defects of somites in the mesoderm region. These results demonstrate that miR-20a is essential for normal embryogenesis by restricting Vsx1 expression in goldfish and zebrafish, and that post-transcriptional regulation is an essential mechanism for Vsx1 playing different roles in diverse developmental processes. PMID- 25833419 TI - Modifiable Risk Factors for Major Non-communicable Diseases Among Medical Students in Nepal. AB - The objective of this study was to assess the prevalence of modifiable risk factors of the major non-communicable diseases (NCDs) among medical students. A cross sectional study was conducted at three randomly selected medical colleges in the Kathmandu Valley in Nepal. All third-year medical students (n = 191) participated in the study. A total of 62.3% of the respondents were male, and 37.7% were female. The mean age of the respondents was 21.5 +/- 1.0 (SD) years. A total of 20.4% (n = 39) of the medical students were current tobacco users and 50.8% (n = 97) have ever consumed alcohol. The majority (85.6%) of the medical students did not consume the daily recommended amount of fruits and vegetables. A total of 30.9% (n = 59) of the medical students were involved in low level of physical activity and 42.9% (n = 82) were involved in moderate level of physical activity. This study showed a high prevalence of risk factors of major NCDs among medical students and interventions are needed to change the unhealthy behaviour of medical students being role models in society. PMID- 25833420 TI - The Association Between Maternal Depression During Pregnancy and Adverse Birth Outcomes: A Retrospective Cohort Study of PRAMS Participants. AB - Women of reproductive age are at higher risk for depression than men; and depressive behaviors and endocrine imbalances could lead to adverse birth outcomes. The purpose of this study was to investigate whether maternal depression during pregnancy affected adverse birth outcomes, specifically preterm birth and small for gestational age (SGA). This study included 4123 women who participated in the 2009-2011 Utah Pregnancy Risk Assessment Monitoring System, an ongoing surveillance project that investigates maternal behaviors in women who have recently had a live birth. Women self-reported information on depression and outcome data were obtained from birth certificates. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Women who self reported a diagnosis of depression during pregnancy had statistically significant increased odds of preterm birth as compared to women who had not been diagnosed with depression (OR 1.51; 95% CI 1.07, 2.12); there was no association between depression and SGA (OR 0.92; 95% CI 0.63, 1.34). After adjustment for prenatal care visits, the depression-preterm birth association was attenuated and no longer statistically significant (OR 1.29; 95% CI 0.90, 1.85). After adjustment for smoking, there continued to be no strong association between depression and SGA (OR 0.80; 95% CI 0.54, 1.20). The findings of this study do not support a maternal depression-adverse birth outcomes relationship among a predominantly healthy population of non-Hispanic White, well educated women. Future studies should focus on other diverse populations of women to determine if there is an association for these subgroups. PMID- 25833422 TI - Asymmetric asynchrony of financial time series based on asymmetric multiscale cross-sample entropy. AB - The paper proposes the asymmetric multiscale cross-sample entropy (AMCSE) method and applies it to analyze the financial time series of US, Chinese, and European stock markets. The asynchronies of these time series in USA, China, and Europe all decrease (the correlations increase) with the increase in scale which declares that taking into account bigger time scale to study these financial time series is capable of revealing the intrinsic relations between these stock markets. Meanwhile, we find that there is a crossover between the upwards and the downwards in these AMCSE results, which indicates that when the scale reach a certain value, the asynchronies of the upwards and the downwards for these stock markets are equal and symmetric. But for the other scales, the asynchronies of the upwards and the downwards are different from each other indicating the necessity and importance of multiscale analysis for revealing the most comprehensive information of stock markets. The series with a positive trend have a higher decreasing pace on asynchrony than those with a negative trend, while the asynchrony between the series with a positive or negative trend is lower than that between the original series. Moreover, it is noticeable that there are some small abnormal rises at some abnormal scales. We find that the asynchronies are the highest at scales smaller than 2 when investigating the time series of stock markets with a negative trend. The existences of asymmetries declare the inaccuracy and weakness of multiscale cross-sample entropy, while by comparing the asymmetries of US, Chinese, and European markets, similar conclusions can be drawn and we acquire that the asymmetries of Chinese markets are the smallest and the asymmetries of European markets are the biggest. Thus, it is of great value and benefit to investigate the series with different trends using AMCSE method. PMID- 25833423 TI - Bifurcation behaviors of synchronized regions in logistic map networks with coupling delay. AB - Network synchronized regions play an extremely important role in network synchronization according to the master stability function framework. This paper focuses on network synchronous state stability via studying the effects of nodal dynamics, coupling delay, and coupling way on synchronized regions in Logistic map networks. Theoretical and numerical investigations show that (1) network synchronization is closely associated with its nodal dynamics. Particularly, the synchronized region bifurcation points through which the synchronized region switches from one type to another are in good agreement with those of the uncoupled node system, and chaotic nodal dynamics can greatly impede network synchronization. (2) The coupling delay generally impairs the synchronizability of Logistic map networks, which is also dominated by the parity of delay for some nodal parameters. (3) A simple nonlinear coupling facilitates network synchronization more than the linear one does. The results found in this paper will help to intensify our understanding for the synchronous state stability in discrete-time networks with coupling delay. PMID- 25833424 TI - Is the Henon attractor chaotic? AB - By performing a systematic study of the Henon map, we find low-period sinks for parameter values extremely close to the classical ones. This raises the question whether or not the well-known Henon attractor-the attractor of the Henon map existing for the classical parameter values-is a strange attractor, or simply a stable periodic orbit. Using results from our study, we conclude that even if the latter were true, it would be practically impossible to establish this by computing trajectories of the map. PMID- 25833425 TI - Chaotic dynamics and diffusion in a piecewise linear equation. AB - Genetic interactions are often modeled by logical networks in which time is discrete and all gene activity states update simultaneously. However, there is no synchronizing clock in organisms. An alternative model assumes that the logical network is preserved and plays a key role in driving the dynamics in piecewise nonlinear differential equations. We examine dynamics in a particular 4 dimensional equation of this class. In the equation, two of the variables form a negative feedback loop that drives a second negative feedback loop. By modifying the original equations by eliminating exponential decay, we generate a modified system that is amenable to detailed analysis. In the modified system, we can determine in detail the Poincare (return) map on a cross section to the flow. By analyzing the eigenvalues of the map for the different trajectories, we are able to show that except for a set of measure 0, the flow must necessarily have an eigenvalue greater than 1 and hence there is sensitive dependence on initial conditions. Further, there is an irregular oscillation whose amplitude is described by a diffusive process that is well-modeled by the Irwin-Hall distribution. There is a large class of other piecewise-linear networks that might be analyzed using similar methods. The analysis gives insight into possible origins of chaotic dynamics in periodically forced dynamical systems. PMID- 25833426 TI - Parameter estimation, nonlinearity, and Occam's razor. AB - Nonlinear systems are capable of displaying complex behavior even if this is the result of a small number of interacting time scales. A widely studied case is when complex dynamics emerges out of a nonlinear system being forced by a simple harmonic function. In order to identify if a recorded time series is the result of a nonlinear system responding to a simpler forcing, we develop a discrete nonlinear transformation for time series based on synchronization techniques. This allows a parameter estimation procedure which simultaneously searches for a good fit of the recorded data, and small complexity of a fluctuating driving parameter. We illustrate this procedure using data from respiratory patterns during birdsong production. PMID- 25833427 TI - Assessing the direction of climate interactions by means of complex networks and information theoretic tools. AB - An estimate of the net direction of climate interactions in different geographical regions is made by constructing a directed climate network from a regular latitude-longitude grid of nodes, using a directionality index (DI) based on conditional mutual information (CMI). Two datasets of surface air temperature anomalies-one monthly averaged and another daily averaged-are analyzed and compared. The network links are interpreted in terms of known atmospheric tropical and extra-tropical variability patterns. Specific and relevant geographical regions are selected, the net direction of propagation of the atmospheric patterns is analyzed, and the direction of the inferred links is validated by recovering some well-known climate variability structures. These patterns are found to be acting at various time-scales, such as atmospheric waves in the extratropics or longer range events in the tropics. This analysis demonstrates the capability of the DI measure to infer the net direction of climate interactions and may contribute to improve the present understanding of climate phenomena and climate predictability. The work presented here also stands out as an application of advanced tools to the analysis of empirical, real-world data. PMID- 25833428 TI - A new method for observing the running states of a single-variable nonlinear system. AB - In order to timely grasp a single variable nonlinear system running states, a new method called Scatter Point method is put forward in this paper. It can be used to observe or monitor the running states of a single variable nonlinear system in real-time. In this paper, the definition of the method is given at first, and then its working principle is expounded theoretically, after this, some physical experiments based on Chua's nonlinear system are conducted. At the same time, many scatter point graphs are measured by a general analog oscilloscope. The motion, number, and distribution of these scatter points shown on the oscilloscope screen can directly reflect the current states of the tested system. The experimental results further confirm that the method is effective and practical, in which the system running states are not easily lost. In addition, this method is not only suitable for single variable systems but also for multivariable systems. PMID- 25833430 TI - Exact coherent structures and chaotic dynamics in a model of cardiac tissue. AB - Unstable nonchaotic solutions embedded in the chaotic attractor can provide significant new insight into chaotic dynamics of both low- and high-dimensional systems. In particular, in turbulent fluid flows, such unstable solutions are referred to as exact coherent structures (ECS) and play an important role in both initiating and sustaining turbulence. The nature of ECS and their role in organizing spatiotemporally chaotic dynamics, however, is reasonably well understood only for systems on relatively small spatial domains lacking continuous Euclidean symmetries. Construction of ECS on large domains and in the presence of continuous translational and/or rotational symmetries remains a challenge. This is especially true for models of excitable media which display spiral turbulence and for which the standard approach to computing ECS completely breaks down. This paper uses the Karma model of cardiac tissue to illustrate a potential approach that could allow computing a new class of ECS on large domains of arbitrary shape by decomposing them into a patchwork of solutions on smaller domains, or tiles, which retain Euclidean symmetries locally. PMID- 25833429 TI - Synchronization, non-linear dynamics and low-frequency fluctuations: analogy between spontaneous brain activity and networked single-transistor chaotic oscillators. AB - In this paper, the topographical relationship between functional connectivity (intended as inter-regional synchronization), spectral and non-linear dynamical properties across cortical areas of the healthy human brain is considered. Based upon functional MRI acquisitions of spontaneous activity during wakeful idleness, node degree maps are determined by thresholding the temporal correlation coefficient among all voxel pairs. In addition, for individual voxel time-series, the relative amplitude of low-frequency fluctuations and the correlation dimension (D2), determined with respect to Fourier amplitude and value distribution matched surrogate data, are measured. Across cortical areas, high node degree is associated with a shift towards lower frequency activity and, compared to surrogate data, clearer saturation to a lower correlation dimension, suggesting presence of non-linear structure. An attempt to recapitulate this relationship in a network of single-transistor oscillators is made, based on a diffusive ring (n = 90) with added long-distance links defining four extended hub regions. Similarly to the brain data, it is found that oscillators in the hub regions generate signals with larger low-frequency cycle amplitude fluctuations and clearer saturation to a lower correlation dimension compared to surrogates. The effect emerges more markedly close to criticality. The homology observed between the two systems despite profound differences in scale, coupling mechanism and dynamics appears noteworthy. These experimental results motivate further investigation into the heterogeneity of cortical non-linear dynamics in relation to connectivity and underline the ability for small networks of single-transistor oscillators to recreate collective phenomena arising in much more complex biological systems, potentially representing a future platform for modelling disease-related changes. PMID- 25833431 TI - Dynamics of classical particles in oval or elliptic billiards with a dispersing mechanism. AB - Some dynamical properties for an oval billiard with a scatterer in its interior are studied. The dynamics consists of a classical particle colliding between an inner circle and an external boundary given by an oval, elliptical, or circle shapes, exploring for the first time some natural generalizations. The billiard is indeed a generalization of the annular billiard, which is of strong interest for understanding marginally unstable periodic orbits and their role in the boundary between regular and chaotic regions in both classical and quantum (including experimental) systems. For the oval billiard, which has a mixed phase space, the presence of an obstacle is an interesting addition. We demonstrate, with details, how to obtain the equations of the mapping, and the changes in the phase space are discussed. We study the linear stability of some fixed points and show both analytically and numerically the occurrence of direct and inverse parabolic bifurcations. Lyapunov exponents and generalized bifurcation diagrams are obtained. Moreover, histograms of the number of successive iterations for orbits that stay in a cusp are studied. These histograms are shown to be scaling invariant when changing the radius of the scatterer, and they have a power law slope around -3. The results here can be generalized to other kinds of external boundaries. PMID- 25833432 TI - The influence of a phase shift between the top and bottom walls on the Brownian transport of self-propelled particles. AB - Transport of noninteracting self-propelled particles is numerically investigated in a two-dimensional horizontally asymmetrical channel with nonstraight midline which can be controlled by the phase shift between the top and bottom walls. From numerical simulations, we found that self-propelled particles can be rectified by the self-propelled velocity. The direction of the average velocity is determined by the horizontally asymmetrical parameter of the channel. The average velocity is very sensitive to the phase shift and its behaviors can be manipulated by changing the phase shift. As the phase shift is increased, the average velocity decreases and its peak position moves (to right or left). Remarkably, the average velocity is zero when the phase shift is in the interval [ 3pi/5, 4pi/5]. The small phase shift may facilitate the rectification process for the large horizontal asymmetry of the channel. PMID- 25833433 TI - Time-delayed feedback control of coherence resonance near subcritical Hopf bifurcation: theory versus experiment. AB - Using the model of a generalized Van der Pol oscillator in the regime of subcritical Hopf bifurcation, we investigate the influence of time delay on noise induced oscillations. It is shown that for appropriate choices of time delay, either suppression or enhancement of coherence resonance can be achieved. Analytical calculations are combined with numerical simulations and experiments on an electronic circuit. PMID- 25833434 TI - A new closeness centrality measure via effective distance in complex networks. AB - Closeness centrality (CC) measure, as a well-known global measure, is widely applied in many complex networks. However, the classical CC presents many problems for flow networks since these networks are directed and weighted. To address these issues, we propose an effective distance based closeness centrality (EDCC), which uses effective distance to replace conventional geographic distance and binary distance obtained by Dijkstra's shortest path algorithm. The proposed EDCC considers not only the global structure of the network but also the local information of nodes. And it can be well applied in directed or undirected, weighted or unweighted networks. Susceptible-Infected model is utilized to evaluate the performance by using the spreading rate and the number of infected nodes. Numerical examples simulated on four real networks are given to show the effectiveness of the proposed EDCC. PMID- 25833435 TI - Amplitude equations for collective spatio-temporal dynamics in arrays of coupled systems. AB - We study the coupling induced destabilization in an array of identical oscillators coupled in a ring structure where the number of oscillators in the ring is large. The coupling structure includes different types of interactions with several next neighbors. We derive an amplitude equation of Ginzburg-Landau type, which describes the destabilization of a uniform stationary state and close by solutions in the limit of a large number of nodes. Studying numerically an example of unidirectionally coupled Duffing oscillators, we observe a coupling induced transition to collective spatio-temporal chaos, which can be understood using the derived amplitude equations. PMID- 25833436 TI - Measuring political polarization: Twitter shows the two sides of Venezuela. AB - We say that a population is perfectly polarized when divided in two groups of the same size and opposite opinions. In this paper, we propose a methodology to study and measure the emergence of polarization from social interactions. We begin by proposing a model to estimate opinions in which a minority of influential individuals propagate their opinions through a social network. The result of the model is an opinion probability density function. Next, we propose an index to quantify the extent to which the resulting distribution is polarized. Finally, we apply the proposed methodology to a Twitter conversation about the late Venezuelan president, Hugo Chavez, finding a good agreement between our results and offline data. Hence, we show that our methodology can detect different degrees of polarization, depending on the structure of the network. PMID- 25833437 TI - A fixed mass method for the Kramers-Moyal expansion--application to time series with outliers. AB - Extraction of stochastic and deterministic components from empirical data necessary for the reconstruction of the dynamics of the system-is discussed. We determine both components using the Kramers-Moyal expansion. In our earlier papers, we obtained large fluctuations in the magnitude of both terms for rare or extreme valued events in the data. Calculations for such events are burdened by an unsatisfactory quality of the statistics. In general, the method is sensitive to the binning procedure applied for the construction of histograms. Instead of the commonly used constant width of bins, we use here a constant number of counts for each bin. This approach-the fixed mass method-allows to include in the calculation events, which do not yield satisfactory statistics in the fixed bin width method. The method developed is general. To demonstrate its properties, here, we present the modified Kramers-Moyal expansion method and discuss its properties by the application of the fixed mass method to four representative heart rate variability recordings with different numbers of ectopic beats. These beats may be rare events as well as outlying, i.e., very small or very large heart cycle lengths. The properties of ectopic beats are important not only for medical diagnostic purposes but the occurrence of ectopic beats is a general example of the kind of variability that occurs in a signal with outliers. To show that the method is general, we also present results for two examples of data from very different areas of science: daily temperatures at a large European city and recordings of traffics on a highway. Using the fixed mass method, to assess the dynamics leading to the outlying events we studied the occurrence of higher order terms of the Kramers-Moyal expansion in the recordings. We found that the higher order terms of the Kramers-Moyal expansion are negligible for heart rate variability. This finding opens the possibility of the application of the Langevin equation to the whole range of empirical signals containing rare or outlying events. Note, however, that the higher order terms are non-negligible for the other data studied here and for it the Langevin equation is not applicable as a model. PMID- 25833438 TI - Introduction to focus issue: Nonlinear dynamics for planet Earth. PMID- 25833439 TI - A dynamical systems analysis of the data assimilation linked ecosystem carbon (DALEC) models. AB - Changes in our climate and environment make it ever more important to understand the processes involved in Earth systems, such as the carbon cycle. There are many models that attempt to describe and predict the behaviour of carbon stocks and stores but, despite their complexity, significant uncertainties remain. We consider the qualitative behaviour of one of the simplest carbon cycle models, the Data Assimilation Linked Ecosystem Carbon (DALEC) model, which is a simple vegetation model of processes involved in the carbon cycle of forests, and consider in detail the dynamical structure of the model. Our analysis shows that the dynamics of both evergreen and deciduous forests in DALEC are dependent on a few key parameters and it is possible to find a limit point where there is stable sustainable behaviour on one side but unsustainable conditions on the other side. The fact that typical parameter values reside close to this limit point highlights the difficulty of predicting even the correct trend without sufficient data and has implications for the use of data assimilation methods. PMID- 25833440 TI - How robust is dispersal-induced spatial synchrony? AB - Many biological populations fluctuate in synchrony over large geographic regions. This behavior may increase the chance of extinction. The combination of time scale separation between interacting species and weak spatial linear diffusive coupling is one mechanism that can generate synchrony; however, accounting for travel time between habitat patches may destabilize this synchrony. Here, we show that ubiquitous behavioral aspects of dispersal (e.g., predator avoidance), implemented as nonlinear diffusive coupling, may also destabilize synchrony. In addition, these aspects interact with travel-time delays and amplify mechanisms that destroy synchrony. Our work suggests that dispersal-induced synchrony is more rare than typically assumed. PMID- 25833442 TI - Flow networks: a characterization of geophysical fluid transport. AB - We represent transport between different regions of a fluid domain by flow networks, constructed from the discrete representation of the Perron-Frobenius or transfer operator associated to the fluid advection dynamics. The procedure is useful to analyze fluid dynamics in geophysical contexts, as illustrated by the construction of a flow network associated to the surface circulation in the Mediterranean sea. We use network-theory tools to analyze the flow network and gain insights into transport processes. In particular, we quantitatively relate dispersion and mixing characteristics, classically quantified by Lyapunov exponents, to the degree of the network nodes. A family of network entropies is defined from the network adjacency matrix and related to the statistics of stretching in the fluid, in particular, to the Lyapunov exponent field. Finally, we use a network community detection algorithm, Infomap, to partition the Mediterranean network into coherent regions, i.e., areas internally well mixed, but with little fluid interchange between them. PMID- 25833441 TI - Tipping point analysis of atmospheric oxygen concentration. AB - We apply tipping point analysis to nine observational oxygen concentration records around the globe, analyse their dynamics and perform projections under possible future scenarios, leading to oxygen deficiency in the atmosphere. The analysis is based on statistical physics framework with stochastic modelling, where we represent the observed data as a composition of deterministic and stochastic components estimated from the observed data using Bayesian and wavelet techniques. PMID- 25833443 TI - The temporal patterns of disease severity and prevalence in schistosomiasis. AB - Schistosomiasis is one of the most widespread public health problems in the world. In this work, we introduce an eco-epidemiological model for its transmission and dynamics with the purpose of explaining both intra- and inter annual fluctuations of disease severity and prevalence. The model takes the form of a system of nonlinear differential equations that incorporate biological complexity associated with schistosome's life cycle, including a prepatent period in snails (i.e., the time between initial infection and onset of infectiousness). Nonlinear analysis is used to explore the parametric conditions that produce different temporal patterns (stationary, endemic, periodic, and chaotic). For the time-invariant model, we identify a transcritical and a Hopf bifurcation in the space of the human and snail infection parameters. The first corresponds to the occurrence of an endemic equilibrium, while the latter marks the transition to interannual periodic oscillations. We then investigate a more realistic time varying model in which fertility of the intermediate host population is assumed to seasonally vary. We show that seasonality can give rise to a cascade of period doubling bifurcations leading to chaos for larger, though realistic, values of the amplitude of the seasonal variation of fertility. PMID- 25833444 TI - An early warning indicator for atmospheric blocking events using transfer operators. AB - The existence of persistent midlatitude atmospheric flow regimes with time-scales larger than 5-10 days and indications of preferred transitions between them motivates to develop early warning indicators for such regime transitions. In this paper, we use a hemispheric barotropic model together with estimates of transfer operators on a reduced phase space to develop an early warning indicator of the zonal to blocked flow transition in this model. It is shown that the spectrum of the transfer operators can be used to study the slow dynamics of the flow as well as the non-Markovian character of the reduction. The slowest motions are thereby found to have time scales of three to six weeks and to be associated with meta-stable regimes (and their transitions) which can be detected as almost invariant sets of the transfer operator. From the energy budget of the model, we are able to explain the meta-stability of the regimes and the existence of preferred transition paths. Even though the model is highly simplified, the skill of the early warning indicator is promising, suggesting that the transfer operator approach can be used in parallel to an operational deterministic model for stochastic prediction or to assess forecast uncertainty. PMID- 25833445 TI - Detection of bifurcations in noisy coupled systems from multiple time series. AB - We generalize a method of detecting an approaching bifurcation in a time series of a noisy system from the special case of one dynamical variable to multiple dynamical variables. For a system described by a stochastic differential equation consisting of an autonomous deterministic part with one dynamical variable and an additive white noise term, small perturbations away from the system's fixed point will decay slower the closer the system is to a bifurcation. This phenomenon is known as critical slowing down and all such systems exhibit this decay-type behaviour. However, when the deterministic part has multiple coupled dynamical variables, the possible dynamics can be much richer, exhibiting oscillatory and chaotic behaviour. In our generalization to the multi-variable case, we find additional indicators to decay rate, such as frequency of oscillation. In the case of approaching a homoclinic bifurcation, there is no change in decay rate but there is a decrease in frequency of oscillations. The expanded method therefore adds extra tools to help detect and classify approaching bifurcations given multiple time series, where the underlying dynamics are not fully known. Our generalisation also allows bifurcation detection to be applied spatially if one treats each spatial location as a new dynamical variable. One may then determine the unstable spatial mode(s). This is also something that has not been possible with the single variable method. The method is applicable to any set of time series regardless of its origin, but may be particularly useful when anticipating abrupt changes in the multi-dimensional climate system. PMID- 25833446 TI - The effect of slow spatial processes on emerging spatiotemporal patterns. AB - We consider a two-component system of evolutionary partial differential equations posed on a bounded domain. Our system is pattern forming, with a small stationary pattern bifurcating from the background state. It is also equipped with a multiscale structure, manifesting itself through the presence of spectrum close to the origin. Spatial processes are associated with long time scales and affect the nonlinear pattern dynamics strongly. To track these dynamics past the bifurcation, we develop an asymptotics-based method complementing and extending rigorous center manifold reduction. Using it, we obtain a complete analytic description of the pattern stability problem in terms of the linear stability of the background state. Through this procedure, we portray with precision how slow spatial processes can destabilize small patterns close to onset. We further illustrate our results on a model describing phytoplankton whose growth is co limited by nutrient and light. Localized colonies forming at intermediate depths are found to be subject to oscillatory destabilization shortly after emergence, whereas boundary-layer type colonies at the bottom persist. These analytic results are in agreement with numerical simulations for the full model, which we also present. PMID- 25833447 TI - Nonlinear response in runoff magnitude to fluctuating rain patterns. AB - The runoff coefficient of a hillslope is a reliable measure for changes in the streamflow response at the river link outlet. A high runoff coefficient is a good indicator of the possibility of flash floods. Although the relationship between runoff coefficient and streamflow has been the subject of much study, the physical mechanisms affecting runoff coefficient including the dependence on precipitation pattern remain open topics for investigation. In this paper, we analyze a rainfall-runoff model at the hillslope scale as that hillslope is forced with different rain patterns: constant rain and fluctuating rain with different frequencies and amplitudes. When an oscillatory precipitation pattern is applied, although the same amount of water may enter the system, its response (measured by the runoff coefficient) will be maximum for a certain frequency of precipitation. The significant increase in runoff coefficient after a certain pattern of rainfall can be a potential explanation for the conditions preceding flash-floods. PMID- 25833448 TI - Understanding the distinctively skewed and heavy tailed character of atmospheric and oceanic probability distributions. AB - The probability distributions of large-scale atmospheric and oceanic variables are generally skewed and heavy-tailed. We argue that their distinctive departures from Gaussianity arise fundamentally from the fact that in a quadratically nonlinear system with a quadratic invariant, the coupling coefficients between system components are not constant but depend linearly on the system state in a distinctive way. In particular, the skewness arises from a tendency of the system trajectory to linger near states of weak coupling. We show that the salient features of the observed non-Gaussianity can be captured in the simplest such nonlinear 2-component system. If the system is stochastically forced and linearly damped, with one component damped much more strongly than the other, then the strongly damped fast component becomes effectively decoupled from the weakly damped slow component, and its impact on the slow component can be approximated as a stochastic noise forcing plus an augmented nonlinear damping. In the limit of large time-scale separation, the nonlinear augmentation of the damping becomes small, and the noise forcing can be approximated as an additive noise plus a correlated additive and multiplicative noise (CAM noise) forcing. Much of the diversity of observed large-scale atmospheric and oceanic probability distributions can be interpreted in this minimal framework. PMID- 25833449 TI - Striped pattern selection by advective reaction-diffusion systems: resilience of banded vegetation on slopes. AB - For water-limited arid ecosystems, where water distribution and infiltration play a vital role, various models have been set up to explain vegetation patterning. On sloped terrains, vegetation aligned in bands has been observed ubiquitously. In this paper, we consider the appearance, stability, and bifurcations of 2D striped or banded patterns in an arid ecosystem model. We numerically show that the resilience of the vegetation bands is larger on steeper slopes by computing the stability regions (Busse balloons) of striped patterns with respect to 1D and transverse 2D perturbations. This is corroborated by numerical simulations with a slowly decreasing water input parameter. Here, long wavelength striped patterns are unstable against transverse perturbations, which we also rigorously prove on flat ground through an Evans function approach. In addition, we prove a "Squire theorem" for a class of two-component reaction-advection-diffusion systems that includes our model, showing that the onset of pattern formation in 2D is due to 1D instabilities in the direction of advection, which naturally leads to striped patterns. PMID- 25833450 TI - A bimodality trap in model projections. AB - We expose a phenomenon that can occur in the process of joint state and parameter estimation. Such estimation is crucial in tuning parameters for climate models and offline parameterizations used in the models. We show how a bimodal distribution can temporarily appear during this process and that a scheme relying on linear and Gaussian approximations may cause it to get trapped in the wrong mode and hence lead to faulty estimation. We propose a practical and effective resolution using a two-stage filtering process. PMID- 25833451 TI - Effect of agricultural sites on differentiation between Chemlali and Neb Jmel olive oils. AB - The chemical composition, oxidative stability, aroma and sensory profiles of virgin olive oils from two Tunisian cultivars, Chemlali and Neb Jmel, grown in two different locations, the center and south of Tunisia, have been evaluated. There were significant differences between the oils from both cultivars when grown in the two different environments. At higher altitude, the oils showed a greater amount of oleic acid, phenols and a higher oxidative stability, while at lower altitude, the oils had higher saturated and linoleic acid contents. The aroma profiles in Chemlali and Neb Jmel cultivars were also influenced by the pedoclimatic conditions, as shown by the difference in volatiles as a function of the geographical area. The volatile compounds of the monovarietal virgin olive oils were identified and compared using headspace solid-phase microextraction (HS SPME) technique coupled with GC-MS and GC-FID. The proportions of different classes of volatiles of the oils have shown significant differences throughout the obtained oils. These results suggest that besides the genetic factor, the agronomic conditions affect the volatile formation and, therefore, the organoleptic properties of VOO, and can be used to discriminate and characterize the Chemlali and Neb Jmel olive oils from each region. PMID- 25833452 TI - Fabrication and characterization of core-shell magnetic chitosan nanoparticles as a novel carrier for immobilization of Burkholderia cepacia lipase. AB - In this study, the chitosan magnetic core-shell nanoparticles (CMNPs) was synthesized and then used as a support for immobilization of lipase. The characteristics of CMNPs, including morphology, topography and spectra type before and after immobilization were determined. The scanning electron micrographs of the CMNPs showed that they were approximately uniform spheres and the distribution chart indicated that the particles have the mean diameter of 100 nm. Kinetic parameters of Km and Vm were calculated as 1.07 mM and 29.43 U/mg for free B. cepacia lipase and 1.29 mM and 25.82 U/mg for immobilized lipase on CMNPs, respectively. The activity of immobilized lipase was 32 U/mg under optimum temperature and pH. CMNP's were used in trasesterification reaction in order to evaluate the activity of the immobilized enzyme compared to the free enzyme. Immobilization of lipase on CMNPs improved stability and total relative activity of the enzyme. It could be concluded that CMNPs be considered as a suitable carrier for enzyme immobilization. PMID- 25833454 TI - Asymmetric synthesis of Ampelomin A and ent-Epiampelomin A. AB - We synthesized the naturally occurring carbasugar ampelomin A and its epimer from a common starting material. The enantiomerically pure starting material was obtained by base-catalyzed asymmetric Diels-Alder reaction of 3-hydroxy-2-pyrone and chiral acrylate. The total yield of ampelomin A was 14% in seven synthetic steps. The key step of the synthesis of ampelomin A was inversion of the stereochemistry at the C-6 position, which was achieved by stereoselective catalytic hydrogenation of the corresponding methylidene group. Further synthesis of the epimer was straightforward, because all stereogenic centers had already been introduced on the starting material; the total yield was 44% in four synthetic steps. Both the final products were obtained in pure form without contamination with undesired isomers. The reported (1)H NMR chemical shift of the C-7 methyl protons and the H-5axial coupling pattern of natural ampelomin A were inconsistent with those of our synthetic product. After careful comparison of the spectra and examination of the stable conformation obtained through MM2 calculations, we present revised NMR data for ampelomin A. PMID- 25833453 TI - Kinetic study for the ethanolysis of fish oil catalyzed by lipozyme((r)) 435 in different reaction media. AB - The ethanolysis of fish oil in various reaction medium (tert-pentanol, n-hexane and solvent free system) catalyzed by the immobilized commercial lipase Lipozyme((r)) 435 (Candida Antarctica) at atmospheric pressure has been studied in this work. The effect of some kinetic parameters, such as the amount of lipase, temperature and the initial reactant molar ratio ethanol:oil on monoacyglyceride and ethyl ester yield has been analyzed. Experimental data were successfully correlated by a simple kinetic model based on the elementary reactions proposed in this work. At high initial reactant molar ratio the three elementary steps can be considered as irreversible. However the reaction rate constants ratio for the deacylation of monoglyceride to glycerol decreased by decreasing the molar ratio ethanol:oil. The reaction rates are slower in n-hexane as reaction medium compared to tert-pentanol and a solvent-free system, at the experimental conditions essayed in this work. In this last case, ethanol acts as solvent for reaction and as reactant. PMID- 25833455 TI - Capillary rarefaction as an index for the microvascular assessment of hypertensive patients. AB - Arterial hypertension represents a leading cause of cardiovascular mortality and morbidity worldwide through its detrimental effects on target organs. Therefore, the early identification and appropriate management of high-risk patients emerges as extremely important. Given that the microvasculature is subject to a series of morphological and functional changes under the continuous effect of high blood pressure, research over the last years has gradually moved toward the identification of specific microcirculatory alterations that may serve as early prognostic markers of cardiovascular risk. Dermal capillaries represent an "open window" for the in vivo study of human microcirculation that has been long used mainly for the study of rheumatic diseases. However, capillaroscopy has been relatively understudied and only recently applied in the field of hypertension. Capillaroscopy represents a forthcoming promising estimate of the microvascular status in hypertensive patients, with capillary rarefaction representing the most typical finding. The present review aims at summarizing available evidence and the main findings, as well as the premises and promises, of capillary rarefaction as a tool for evaluating patients with hypertension. PMID- 25833456 TI - Cardiovascular and renal effects of weight reduction in obesity and the metabolic syndrome. AB - Obesity is a critical public health issue worldwide. Patients with obesity have markedly increased morbidity and mortality compared to the general population. The increased health risks of obesity in part are due to its close association with each of the other components of the metabolic syndrome, including hypertension, dyslipidemia, and insulin resistance. Accordingly, obese individuals are at particularly increased risk of cardiovascular disease and chronic kidney disease. Modest weight loss results in improvements in serum cholesterol levels, blood pressure, and glycemic profiles. Lifestyle interventions for weight loss have long been the mainstay of treatment in obesity. However, the existing literature demonstrates limited weight loss sustainability and inconsistent cardiovascular and renal benefits using these modalities. In addition to improvements in intermediate risk factors, surgical interventions provide a more lasting impact on long-term cardiovascular and renal outcomes, though carry higher short-term risks due to perioperative complications. PMID- 25833457 TI - Hypertension in pregnancy: natural history and treatment options. AB - Hypertensive disorders of pregnancy affect approximately 5-10% of all maternities and are major contributors of maternal and neonatal morbidity and mortality worldwide. This group of disorders encompasses chronic hypertension, as well as conditions that arise de novo in pregnancy: gestational hypertension and pre eclampsia. The latter group is thought to be part of the same continuum but with arbitrary division. Research into the aetiology of hypertension in pregnancy have largely been focused on pre-eclampsia, with a majority of studies exploring either pregnancy-associated factors such as placental-derived or immunologic responses to pregnancy tissue, or maternal constitutional factors such as cardiovascular health and endothelial dysfunction. The evidence base for the pathophysiology and progression of hypertensive disorders in pregnancy, particularly pre-eclampsia, is reviewed. Clinical algorithms and pharmacological agents for the management of hypertension in pregnancy are summarised, with a brief focus on post-partum considerations and long-term health implications. Novel therapeutic options for the management of pre-eclampsia are also explored. PMID- 25833458 TI - Assessment of right ventricular function in pulmonary hypertension. AB - Right ventricular function is a major determinant of symptomatology and prognosis in severe pulmonary hypertension. The diagnosis of right heart failure rests on a clinical approach with invasive and noninvasive measurements. Magnetic resonance and echocardiographic imaging of the right ventricle is of prognostic relevance. The gold standard of right ventricular function is the ratio of end-systolic to arterial elastances determined from synchronized volume and pressure measurements. Pressure measurements can be obtained during a right heart catheterization and volume measurements by integration of Doppler pulmonary flow velocity, magnetic resonance imaging, or, more recently, three-dimensional echocardiography. Imaging also informs about regional function and derived estimates of dyssynchrony and asynchrony. Modern imaging with 3D echocardiography and magnetic resonance aims at improved assessment of regional function and right ventriculo-arterial coupling to assist in the evaluation and prognostication of severe pulmonary hypertension. PMID- 25833460 TI - LCZ696: the next step in improving RAS inhibition? AB - LCZ696 is a single molecule which combines the angiotensin receptor blocker valsartan with the neprilysn inhibitor sacubitril (AHU377). In the recently published PARADIGM-HF trial, LCZ696 proved superior to enalapril in reducing overall mortality, heart failure hospitalizations, and other endpoints in patients with systolic dysfunction heart failure. Increases in counter-regulatory natriuretic peptides which oppose sodium retention, vasoconstriction, and the deleterious structural changes which follow neurohormonal activation are thought to account for these improved outcomes. In two large hypertension studies, LCZ696 has proved to be a potent, effective antihypertensive agent with tolerability similar to valsartan and placebo and potency comparable to amlodipine. Although several have occurred in the heart failure population, there have been no cases of angioedema noted in the hypertension trials, although few black patients-a group at high risk for its occurrence-have been studied. Whether LCZ696 will displace angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) as preferred renin-angiotensin system (RAS) blocking agents in hypertension will require demonstration of improved long-term outcomes compared with currently preferred first-line drugs. In this regard, experience has shown that it is difficult to extrapolate results achieved in heart failure to the treatment of hypertension, a condition in which neurohormonal activation is less critical in determining long-term prognosis. It will be particularly important to demonstrate renal protection with LCZ696 in patients with diabetes, proteinuria, and hypertension-the only therapeutic area other than heart failure in which RAS blockade has proved essential for optimal endpoint reduction. Superiority over available RAS blockers in terms of 'vascular protection' in high-risk populations represents another path to acceptance of LCZ696 as a preferred agent in cardiovascular medicine. PMID- 25833459 TI - Management of pulmonary hypertension and right heart failure in the intensive care unit. AB - Management of acute right ventricular failure, both with and without coexisting pulmonary hypertension, is a common challenge encountered in the intensive care setting. Both right ventricular dysfunction and pulmonary hypertension portend a poor prognosis, regardless of the underlying cause and are associated with significant morbidity and mortality. The right ventricle is embryologically distinct from the left ventricle and has unique morphologic and functional properties. Management of right ventricular failure and pulmonary hypertension in the intensive care setting requires tailored hemodynamic management, pharmacotherapy, and often mechanical circulatory support. Unfortunately, our understanding of the management of right ventricular failure lags behind that of the left ventricle. In this review, we will explore the underlying pathophysiology of the failing right ventricle and pulmonary vasculature in patients with and without pulmonary hypertension and discuss management strategies based on evidence-based studies as well as our current understanding of the underlying physiology. PMID- 25833462 TI - Roundabout4 suppresses glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated PI3K/AKT and FAK signaling pathways. AB - BACKGROUND AND AIMS: Endothelial cell (EC) proliferation, migration, and tube formation are the critical steps for tumor angiogenesis, which is involved in the formation of new tumor blood vessels. Roundabout4 (Robo4), a new member of Robo proteins family, is specifically expressed in endothelial cells. This study aimed to investigate the effects of Robo4 on glioma-induced endothelial cell proliferation, migration and tube formation in vitro. METHODS AND RESULTS: We found that Robo4 was endogenously expressed in Human Brain Microvascular Endothelial Cells (HBMECs), while Robo4 was significantly down-regulated in endothelial cells cultured in glioma conditioned medium. Robo4 over-expression remarkably suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro. In addition, Robo4 influenced the glioma-induced angiogenesis via binding to its ligand Slit2. Further studies demonstrated that the knockdown of Robo4 up-regulated the phosphorylation of VEGFR2, PI3K, AKT and FAK in EC cultured in glioma conditioned medium. VEGFR2 inhibitor SU-1498, AKT inhibitor LY294002 and FAK inhibitor 14 (FAK inhibitor) blocked the Robo4 knockdown-mediated alteration in glioma angiogenesis in vitro. CONCLUSION: Our results proved that Robo4 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated activation of PI3K/AKT and FAK signaling pathways. PMID- 25833461 TI - Control of energy balance by the brain renin-angiotensin system. AB - The renin-angiotensin system (RAS) exists as a circulating hormone system but it is also used by various tissues of the body, including the brain, as a paracrine signaling mechanism. The local brain version of the RAS is mechanistically involved in fluid balance and blood pressure control, and there is growing appreciation for a role of the brain RAS in the control of energy balance. Here, we review major evidence for the control of energy balance by the brain RAS; outline the current understanding of the RAS components, targets, and mechanisms involved; and highlight some major questions that currently face the field. PMID- 25833463 TI - A unified method for estimating pressure losses at vascular junctions. AB - In reduced-order (0D/1D) blood or respiratory flow models, pressure losses at junctions are usually neglected. However, these may become important where velocities are high and significant flow redirection occurs. Current methods for estimating losses rely on relatively complex empirical equations that are only valid for specific junction geometries and flow regimes. In pulsatile multi directional flows, switching between empirical equations upon reversing flow may introduce unrealistic discontinuities in simulated haemodynamic waveforms. Drawing from work by Bassett et al. (SAE Trans 112:565-583, 2003), we therefore developed a unified method (Unified0D) for estimating loss coefficients that can be applied to any junction (i.e. any number of branches at any angle) and any flow regime. Discontinuities in simulated waveforms were avoided by extending Bassett et al.'s control volume-based method to incorporate a 'pseudodatum' supplier branch, an imaginary effective vessel containing all inflow to the junction. Energy exchange between diverging flow streams was also accounted for empirically. The formulation was validated using high resolution computational fluid dynamics in a wide range flow conditions and junction configurations. In a pulsatile 1D simulation exhibiting transitions between four different flow regimes, the new formulation produced smooth transitions in calculated pressure losses. PMID- 25833464 TI - Thawed and liquid plasma--what do we know? AB - There is increasing interest in the use of liquid or frozen plasma thawed and stored for extended periods (>24 h) to reduce wastage and to improve rapid availability of plasma in massive transfusion protocols advocating the early use of plasma in trauma by some centres. There is now a body of studies that have assessed individual coagulation factors during storage of thawed plasma. These show that factor VIII (FVIII) is the worst affected factor and that its activity is mainly lost during the first 24 h following thawing. However, for most factors studied, there is a continual decline during further storage. The few studies that have assessed thrombin generation in thawed plasma have shown variable results. Extended storage of plasma is associated with an increase in levels of DEHP in the component and could theoretically increase the risk of bacterial contamination, although the latter does not appear to have been an issue in countries that have adopted the use of thawed plasma. There are no clinical studies relating to the efficacy of extended-thawed plasma, and therefore, the potential reduction in its efficacy must be balanced with the clinical need for the component. PMID- 25833465 TI - Single-junction organic solar cells based on a novel wide-bandgap polymer with efficiency of 9.7%. PMID- 25833466 TI - Sex Differences of >= pT1 Bladder Cancer Survival in Austria: A Descriptive, Long Term, Nation-Wide Analysis Based on 27,773 Patients. AB - INTRODUCTION: In recent days, the relationship between gender, tumour stage and survival of bladder cancer has attracted interest. MATERIALS AND METHODS: The Austrian cancer registry was linked to the national death statistics. All patients with urothelial cancer of the urinary bladder with stages pT1, pT2, pT3 and pT4 diagnosed between 1983 until 2012 were followed for up to 15 years. Overall and cancer-specific mortality were estimated by cumulative incidence. RESULTS: A total of 27,773 patients were analysed. The male:female ratio declined from 3:1 for stage pT1-tumours (n = 16,416) to 2.6:1 for pT2 (n = 6,548), 2.1:1 for pT3 (n = 3,111) and 1.9:1 for pT4 (n = 1,698). The 5 years cumulative overall death rate for pT1 tumours was slightly lower for women (0.31 vs. 0.32; p = 0.016). The opposite was observed for more advanced tumour stages: pT2: women 0.66, men: 0.60 (p = 0.0001); pT3: women 0.76, men 0.72 (p = 0.0004) and for pT4: women 0.90, men 0.85 (p = 0.0001). Cancer-specific survival was identical for pT1 tumours in both sexes, while women had a worse cancer-specific survival in both age cohorts (<70 years and >=70 years) with higher tumour stages. CONCLUSIONS: This population-based study demonstrates that (1) a rise of advanced bladder cancer stages in women and (2) that women with tumour stages >pT1 have a shorter cancer-specific and overall survival. PMID- 25833467 TI - Breast size and asymmetry during pregnancy in dependence of a fetus's sex. AB - OBJECTIVES: Breast size and fluctuating asymmetry (FA) are related to women's biological condition, as size correlates positively with fecundity, whereas FA correlates negatively with biological quality. We tested if breast volume, FA, and their changes during pregnancy are related to a fetus's sex. Women with bigger, symmetrical breasts, with a greater increase in size during pregnancy, should be more likely to carry a more ecologically sensitive and energetically demanding male fetus. METHODS: Ninety-three women participated in a 3-stage longitudinal study. 3D breast scans were performed in the first, second, and third trimester of pregnancy. As there was a small variation in pregnancy week at each research stage between the participants, the expected breast volume and FA values for the 12th, 22nd, and 32nd pregnancy week were calculated, basing on the obtained measurements. Those values were compared between mothers who carried a boy and mothers who carried a girl. RESULTS: Although women who carried a boy had somewhat larger breasts at each trimester than women who carried a girl, the difference was not significant. ANOVA for repeated measurements revealed a greater breast size increase in women carrying a boy (P = 0.039). FA decreased during pregnancy, but was not related to a fetus's sex. CONCLUSION: Pregnancy induced breast volume increase is a better cue of a fetus's sex than breast asymmetry or breast size per se, i.e., the traits that are supposed to indicate a woman's biological condition. Women with a larger increase in breast size during pregnancy are more likely to carry to term a more ecologically vulnerable male fetus. PMID- 25833470 TI - Y chromosome of Aisin Gioro, the imperial house of the Qing dynasty. AB - The House of Aisin Gioro is the imperial family of the last dynasty in Chinese history-Qing dynasty (1644-1911). The Aisin Gioro family originated from Jurchen tribes and founded the Manchu people before they conquered China. By investigating the Y chromosomal short tandem repeats (STRs) of seven modern male individuals who claim to belong to the Aisin Gioro family (three of which have full records of pedigree), we found that three of them (two of which having full pedigree, whose most recent common ancestor is Nurgaci) showed very close relationship (1-2 steps of differences in 17 STRs) and possessed a rare haplotype. We therefore conclude that this haplotype is the Y chromosome of the House of Aisin Gioro. Further tests of single-nucleotide polymorphisms indicate that they belong to haplogroup C3b2b1*-M401(xF5483), although their Y-STR results indicate that they are not a part of the 'star cluster' (once linked to Genghis Khan), which belongs to the same haplogroup. This study forms the base for the pedigree research of the imperial family of Qing dynasty by means of genetics. PMID- 25833468 TI - Patterns and functional roles of LINE-1 and Alu methylation in the keratinocyte from patients with psoriasis vulgaris. AB - Alterations in LINE-1 methylation are related to many diseases. The levels and patterns of LINE-1 hypomethylation were associated with a higher risk in developing several cancers, having a poorer prognosis and more aggressiveness. To evaluate the LINE-methylated status in psoriasis, LINE-1 methylation in various cells from patients with psoriasis, squamous cell carcinoma and normal controls were assessed by combined bisulfite restriction analysis of LINE-1. The results of the epigenetic changes for intragenic LINE-1 gene expression were also tested on two known expression microarrays. In patients with psoriasis, hypomethylation of LINE-1 and increase in %(u)C(u)C were prominent in the keratinocytes when compared with normal controls (P=0.014 and P=0.020, respectively). Alternatively, %(u)C(m)C was significantly lower in patients with severe psoriasis compared with mild psoriasis (P=0.022). The receiver-operating characteristic curve analysis indicated the high specificity and sensitivity of (u)C(u)C and (u)C(m)C in detecting psoriasis and severity of psoriasis. From expression array analysis, genes with LINE-1 were downregulated more than those genes without LINE-1 (P=3.84 * 10(-27) and P=2.14 * 10(-21), respectively). Modification in LINE-1 methylation may alter the gene expression resulting in a phenotypic change of the psoriatic skin. %(u)C(u)C and %(u)C(m)C may be used as biomarkers for psoriasis. PMID- 25833469 TI - Tissue- and case-specific retention of intron 40 in mature dystrophin mRNA. AB - The dystrophin gene, which is mutated in Duchenne muscular dystrophy (DMD), comprises 79 exons that show multiple alternative splicing events. Intron retention, a type of alternative splicing, may control gene expression. We examined intron retention in dystrophin introns by reverse-transcription PCR from skeletal muscle, focusing on the nine shortest (all <1000 bp), because these are more likely to be retained. Only one, intron 40, was retained in mRNA; sequencing revealed insertion of a complete intron 40 (851 nt) between exons 40 and 41. The intron 40 retention product accounted for 1.2% of the total product but had a premature stop codon at the fifth intronic codon. Intron 40 retention was most strongly observed in the kidney (36.6%) and was not obtained from the fetal liver, lung, spleen or placenta. This indicated that intron retention is a tissue specific event whose level varies among tissues. In two DMD patients, intron 40 retention was observed in one patient but not in the other. Examination of splicing regulatory factors revealed that intron 40 had the highest guanine cytosine content of all examined introns in a 30-nt segment at its 3' end. Further studies are needed to clarify the biological role of intron 40-retained dystrophin mRNA. PMID- 25833471 TI - Genetic and linguistic correlation of the Kra-Dai-speaking groups in Thailand. AB - The Kra-Dai linguistic family includes Thai and Lao as well as a great number of languages spoken by ethnic minorities in Southeast Asia. In Thailand, a dozen of other Kra-Dai languages are spoken in addition to Thai, the national language. The genetic structure of the Kra-Dai-speaking populations in Thailand has been studied extensively using uniparentally inherited markers. To extend this line of genetic investigation, this study used 15 autosomal microsatellites of 500 individuals from 11 populations, belonging to nine Kra-Dai ethnicities, namely, the Kaleung, Phu Thai, Saek, Nyo, Lao Isan, Yuan, Black Tai, Phuan and Lue. These ethnolinguistic groups are dispersed in three different geographic regions of Thailand, that is, Northern, Northeastern and Central. The results show a very low average of pairwised F(st) (0.0099), as well as no population substructure based on STRUCTURE analysis, indicating genetic homogeneity within the Kra-Dai speaking group, possibly owing to shared linguistic ancestry. The Mantel test, an analysis of molecular variance, and the approximate Bayesian computation procedure employed to evaluate potential factors for driving genetic diversity revealed that language is the predominant factor affecting genetic variations, whereas geography is not. The result of distance-based clustering analyses and spatial analysis of molecular variance revealed genetic distinctions of some populations, reflecting the effects of genetic drift and gene flow on allele frequency within populations, in concordance with the result of R-matrix regression. The genetic and linguistic affiliations of the contemporary Kra-Dai speaking groups are consistent with each other despite certain deviation due to various evolutionary factors that may have occurred during their migrations and resettlements. PMID- 25833473 TI - Opioids and lactation: insufficient evidence of safety. PMID- 25833472 TI - Prognostic factors in patients with penile carcinoma and inguinal lymph node metastasis. AB - OBJECTIVES: To identify prognostic factors in patients with penile carcinoma and confirmed lymph node metastasis. METHODS: Patients were selected from a historical series of patients with penile carcinoma. An experienced pathologist reviewed all cases. Information regarding the total number of lymph nodes excised, the number of positive lymph nodes and the presence of extranodal extension were used. Lymph node ratio was categorized as <0.15 and >0.15. RESULTS: The 5-year recurrence-free survival and disease-specific survival rates were 55.3% and 64.1%, respectively. Lymphovascular invasion, lymph node ratio and pN status influenced survival rates in univariate analysis. Lymphovascular invasion and lymph node ratio remained as independent predictors of disease specific survival and recurrence-free survival in the multivariate analysis. A risk stratification of death and tumor recurrence was observed when patients were grouped into three categories: absence of risk factors; the presence of one risk factor; and the presence of two or more risk factors. CONCLUSIONS: The presence of one or more of the following parameters is correlated with a significantly higher risk of death and tumor recurrence in patients with penile carcinoma and inguinal lymph node metastasis: extranodal extension, lymph node ratio >0.15 and lymphovascular invasion. PMID- 25833474 TI - The rise of on-demand research and specific applications: optogenetics in urology. PMID- 25833475 TI - Emerging neural stimulation technologies for bladder dysfunctions. AB - In the neural engineering field, physiological dysfunctions are approached by identifying the target nerves and providing artificial stimulation to restore the function. Neural stimulation and recording technologies play a central role in this approach, and various engineering devices and stimulation techniques have become available to the medical community. For bladder control problems, electrical stimulation has been used as one of the treatments, while only a few emerging neurotechnologies have been used to tackle these problems. In this review, we introduce some recent developments in neural stimulation technologies including microelectrode array, closed-loop neural stimulation, optical stimulation, and ultrasound stimulation. PMID- 25833476 TI - Role of Nicotinic Acetylcholine Receptor alpha3 and alpha7 Subunits in Detrusor Overactivity Induced by Partial Bladder Outlet Obstruction in Rats. AB - PURPOSE: To investigate the role of alpha3 and alpha7 nicotinic acetylcholine receptor subunits (nAChRs) in the bladder, using a rat model with detrusor overactivity induced by partial bladder outlet obstruction (BOO). METHODS: Forty Sprague-Dawley rats were used: 10 were sham-operated (control group) and 30 were observed for 3 weeks after partial BOO. BOO-induced rats were further divided into 3 groups: Two groups of 10 rats each received intravesicular infusions with hexamethonium (HM group; n=10) or methyllycaconitine (MLC group; n=10), which are antagonists for alpha3 and alpha7 nAChRs, respectively. The remaining BOO-induced rats received only saline infusion (BOO group; n=10). Based on the contraction interval measurements using cystometrogram, the contraction pressure and nonvoiding bladder contractions were compared between the control and the three BOO-induced groups. Immunofluorescent staining and Western blotting were used to analyze alpha3 and alpha7 nAChRs levels. RESULTS: The contraction interval of the MLC group was higher than that of the BOO group (P<0.05). Nonvoiding bladder contraction almost disappeared in the HM and MLC groups. Contraction pressure increased in the BOO group (P<0.05) compared with the control group and decreased in the HM and MLC groups compared with the BOO group (P<0.05). Immunofluorescence staining showed that the alpha3 nAChR signals increased in the urothelium, and the alpha7 nAChR signals increased in the urothelium and detrusor muscle of the BOO group compared with the control group. Western blot analysis showed that both alpha3 and alpha7 nAChR levels increased in the BOO group (P<0.05). CONCLUSIONS: Alpha3 and alpha7 nAChRs are associated with detrusor overactivity induced by BOO. Furthermore, nAChR antagonists could help in clinically improving detrusor overactivity. PMID- 25833477 TI - Mirodenafil prevents bladder dysfunction induced by chronic bladder ischemia in rats. AB - PURPOSE: To investigate the protective effect of mirodenafil on bladder function in a rat model of chronic bladder ischemia (CBI). METHODS: Twenty-four Sprague Dawley rats were randomized to three groups: untreated, sham-operated rats (control group); untreated, CBI model rats (CBI group); and CBI rats treated daily with 4 mg/kg mirodenafil (CBI+mirodenafil group). The CBI and CBI+mirodenafil groups underwent endothelial injury to the iliac arteries and were fed a 2% cholesterol diet after injury. Four weeks after surgery, the CBI+mirodenafil group started daily treatment with mirodenafil for four weeks. Eight weeks after surgery, continuous in vivo cystometry and in vivo organ bath studies of detrusor muscle strips were performed. RESULTS: in vivo cystometry revealed that the rats in the CBI group had a significantly higher micturition frequency, lower bladder capacity, and lower compliance than the rats in the control and CBI+mirodenafil groups. The detrusor muscle strip study showed that the magnitude of the carbachol-induced contractile response was significantly lower in the CBI group compared to either the control or CBI+mirodenafil group. Addition of daily mirodenafil after induction of CBI decreased the contractile response, compared to untreated CBI rats. CBI induced submucosal fibrosis and degenerative changes in bladder walls, which was reversed by the addition of mirodenafil. CONCLUSIONS: Daily treatment with mirodenafil showed protective effects against bladder dysfunction resulting from CBI in rats. PMID- 25833478 TI - Stress-Induced Depression Is Alleviated by Aerobic Exercise Through Up-Regulation of 5-Hydroxytryptamine 1A Receptors in Rats. AB - PURPOSE: Stress is associated with depression, which induces many psychiatric disorders. Serotonin, also known as 5-hydroxy-tryptamine (5-HT), acts as a biochemical messenger and regulator in the brain. It also mediates several important physiological functions. Depression is closely associated with an overactive bladder. In the present study, we investigated the effect of treadmill exercise on stress-induced depression while focusing on the expression of 5-HT 1A (5-H1A) receptors in the dorsal raphe. METHODS: Stress was induced by applying a 0.2-mA electric foot shock to rats. Each set of electric foot shocks comprised a 6-second shock duration that was repeated 10 times with a 30-second interval. Three sets of electric foot shocks were applied each day for 7 days. For the confirmation of depressive state, a forced swimming test was performed. To visualize the expression of 5-HT and tryptophan hydroxylase (TPH), immunohistochemistry for 5-HT and TPH in the dorsal raphe was performed. Expression of 5-H1A receptors was determined by western blot analysis. RESULTS: A depressive state was induced by stress, and treadmill exercise alleviated the depression symptoms in the stress-induced rats. Expressions of 5-HT, TPH, and HT 1A in the dorsal raphe were reduced by the induction of stress. Treadmill exercise increased 5-HT, TPH, and HT 1A expressions in the stress-induced rats. CONCLUSIONS: Treadmill exercise enhanced 5-HT synthesis through the up-regulation of 5-HT1A receptors, and improved the stress-induced depression. In the present study, treadmill exercise improved depression symptoms by enhancing 5-HT1A receptor expression. The present results suggest that treadmill exercise might be helpful for the alleviation of overactive bladder and improve sexual function. PMID- 25833480 TI - Population-based survey on disease insight, quality of life, and health-seeking behavior associated with female urinary incontinence. AB - PURPOSE: To evaluate disease insight, personal distress, and healthcare-seeking behavior of women with urinary incontinence (UI) to improve women's health in Korea. METHODS: In October 2012, 500 Korean women residing around Seoul, Incheon, and Gyeonggi-do were selected by random sampling for a population-based cross sectional survey conducted by computer-aided telephone interview. Sixteen questions, which included information on demographic characteristics, information sources, disease insights, and general health-seeking behavior, were used for data collection. RESULTS: Among the responders, 23.8% experienced UI, the prevalence of which increased with increasing age; 83.3% knew about UI through the mass media out of 98.2% apprehended people. Regarding general awareness of UI, 77.2% understood that UI is caused by aging. A total of 48.7% of subjects experienced societal restrictions because of UI. Most women in in their 30s (25.6%) in the acquired UI information from the Internet, while those in their 50s and 60s (50-59 years, 51.1%; 60-64 years, 42.4%) learned about UI through friends. Among subjects who did not have UI, 89.37% intended to see a doctor or consult a professional if they developed UI (83.2%). Among those with UI, however, only 59.0% had talked about UI; 79.7% had talked with friends or associates, whereas only 23.2% had consulted a professional. CONCLUSIONS: Most respondents tended to obtain information on UI through the mass media. Subjects who did not have UI expressed their intention to consult a professional if they developed UI, while the percentage of subjects with UI who had consulted a professional was very low. Many women are ashamed of UI in Korea, which may be changed by providing efficient advertising with the right information and establishing a new perception of UI. PMID- 25833479 TI - Loss of Caveolin 1 is Associated With the Expression of Aquaporin 1 and Bladder Dysfunction in Mice. AB - PURPOSE: It is suggested that caveolin and aquaporin might be closely associated with bladder signal activity. We investigated the effect of the deletion of caveolin 1, using caveolin 1 knockout mice, on the expression of aquaporin 1 in order to identify their relation in the urothelium of the urinary bladder. METHODS: The cellular localization and expressions of aquaporin 1 and caveolin 1, in the wild type and caveolin 1 knockout mice urinary bladder, were examined by Western blot and immunofluorescence techniques. RESULTS: Aquaporin 1 and caveolin 1 were coexpressed in the arterioles, venules, and capillaries of the suburothelial layer in the wild type controls. Aquaporin 1 protein expression was significantly higher in the caveolin 1 knockout mice than in the wild type controls (P <0.05). CONCLUSIONS: The results imply that aquaporin 1 and caveolin 1 may share a distinct relation with the bladder signal activity. This might play a specific role in bladder dysfunction. PMID- 25833481 TI - Postoperative ureteral leak treated using a silicone-covered nitinol stent. AB - Ureteral fistula is a serious complication of abdomino-pelvic surgeries, often resulting in poor outcomes owing to lack of proper treatment. We report the case of a 49-year-old woman who underwent placement of a silicone-covered ureteral occlusion stent in her right ureter for the management of ureteral leakage after pelvic surgery. A ureterogram obtained 18 months following the stent placement confirmed that there was no stent migration or additional urine leakage. We propose that the silicone-covered ureteral occlusion stent is practical, fast, and safe for the management of ureteral leakage. PMID- 25833482 TI - Urogynecology and Reconstructive Pelvic Surgery. 4th ed. PMID- 25833483 TI - A novel cysteine sulfinic Acid decarboxylase knock-out mouse: comparison between newborn and weanling mice. PMID- 25833484 TI - A novel cysteine sulfinic Acid decarboxylase knock-out mouse: pathology of the kidney and lung in newborn pups. PMID- 25833485 TI - Insights into Taurine Synthesis and Function Based on Studies with Cysteine Dioxygenase (CDO1) Knockout Mice. PMID- 25833486 TI - Oxidation of Hypotaurine and Cysteine Sulfinic Acid by Peroxidase-generated Reactive Species. PMID- 25833487 TI - Increased N-acetyltaurine in serum and urine after endurance exercise in human. PMID- 25833488 TI - Effects of taurine depletion on human placental syncytiotrophoblast renewal and susceptibility to oxidative stress. PMID- 25833489 TI - In Vitro Analysis of Taurine as Anti-stress Agent in Tomato (Solanum Lycopersicum)-Preliminary Study. PMID- 25833490 TI - A novel cysteine sulfinic Acid decarboxylase knock-out mouse: immune function. PMID- 25833491 TI - Taurine Chloramine, a Taurine Metabolite from Activated Neutrophils, Inhibits Osteoclastogenesis by Suppressing NFATc1 Expression. PMID- 25833492 TI - Impact of Taurine on Innate and Adaptive Immunity as the Result of HOCl Neutralization. PMID- 25833493 TI - Taurine Haloamines and Biofilm. Part I: Antimicrobial Activity of Taurine Bromamine and Chlorhexidine Against Biofilm Forming Pseudomonas aeruginosa. PMID- 25833494 TI - Taurine Haloamines and Biofilm: II. Efficacy of Taurine Bromamine and Chlorhexidine Against Selected Microorganisms of Oral Biofilm. PMID- 25833495 TI - Thiotaurine modulates human neutrophil activation. PMID- 25833496 TI - Perinatal taurine exposure alters hematological and chemical properties of blood in adult male rats. PMID- 25833497 TI - Effect of Taurine on Viability and Proliferation of Murine Melanoma B16F10 Cells. PMID- 25833498 TI - Investigation of antioxidant and anticancer potential of taurine by means of multiple chemical and biological assays. PMID- 25833499 TI - Effect of Taurine on In Vitro Migration of MCF-7 and MDA-MB-231 Human Breast Carcinoma Cells. PMID- 25833500 TI - Effect of taurine on prostate-specific antigen level and migration in human prostate cancer cells. PMID- 25833501 TI - The quest for an animal model of diabetic nephropathy and the role of taurine deficiency. PMID- 25833502 TI - Taurine can enhance the protective actions of metformin against diabetes-induced alterations adversely affecting renal function. PMID- 25833503 TI - Evaluation of the actions of metformin and taurine, singly and in combination, on metabolic and oxidative alterations caused by diabetes in rat erythrocytes and plasma. PMID- 25833505 TI - Impact of light ethanol intake and of taurine, separately and together, on pathways of glucose metabolism in the kidney of diabetic rats. PMID- 25833504 TI - Taurine ameliorates hypercholesterolemia but not obesity in rats fed a lard based, high-fat diet. PMID- 25833506 TI - Hypoglycemia is one possible mechanism in the combined toxicity of ethanol and taurine. PMID- 25833507 TI - Role of taurine on the actions of alcohol against systemic and cardiac biochemical changes in the diabetic rat. PMID- 25833508 TI - Long-term taurine supplementation leads to enhanced hepatic steatosis, renal dysfunction and hyperglycemia in mice fed on a high-fat diet. PMID- 25833509 TI - Taurine Supplementation Enhances Insulin Secretion Without Altering Islet Morphology in Non-obese Diabetic Mice. PMID- 25833510 TI - Taurine supplementation regulates pancreatic islet function in response to potentiating agents in leptin-deficient obese mice. PMID- 25833511 TI - Effects of a high fat diet and taurine supplementation on metabolic parameters and skeletal muscle mitochondrial function in rats. PMID- 25833512 TI - Taurine and regulation of mitochondrial metabolism. PMID- 25833513 TI - Open questions concerning taurine with emphasis on the brain. PMID- 25833514 TI - Taurine supplementation induces hyperinsulinemia and neuronal hyperexcitability. PMID- 25833515 TI - Taurine recovers mice emotional learning and memory disruptions associated with fragile x syndrome in context fear and auditory cued-conditioning. PMID- 25833516 TI - Contribution of taurine signatures in the detached cat retina. PMID- 25833517 TI - Effect of taurine on reproductive hormone secretion in female rats. PMID- 25833518 TI - Taurine enhances proliferation and promotes neuronal specification of murine and human neural stem/progenitor cells. PMID- 25833519 TI - Effects of chronic taurine administration on gene expression, protein translation and phosphorylation in the rat hippocampus. PMID- 25833520 TI - Potential Anti-aging Role of Taurine via Proper Protein Folding: A Study from Taurine Transporter Knockout Mouse. PMID- 25833521 TI - Analysis of Taurine as Modulator of Neurotransmitter in Caenorhabditis elegans. PMID- 25833522 TI - The Changes by Hypoxia Inducible Factor-1alpha (HIF-1alpha) on Taurine Uptake in Brain Capillary Endothelial Cells at High Glucose Conditions. PMID- 25833523 TI - Thiotaurine protects mouse cerebellar granule neurons from potassium deprivation induced apoptosis by inhibiting the activation of caspase-3. PMID- 25833525 TI - Taurine Targets the GluN2b-Containing NMDA Receptor Subtype. PMID- 25833524 TI - Experimental study of taurine on the cerebral dehydrogenase activity in the model of unilateral cerebral ischemia. PMID- 25833526 TI - Experimental study of taurine antitoxic activity in the model of chronic epinephrine intoxication. PMID- 25833527 TI - Does taurine prolong lifespan by improving heart function? PMID- 25833528 TI - Taurine Depletion Decreases GRP78 Expression and Downregulates Perk-Dependent Activation of the Unfolded Protein Response. PMID- 25833529 TI - Role of ROS Production and Turnover in the Antioxidant Activity of Taurine. PMID- 25833530 TI - Taurine supplementation prevents the adverse effect of high sugar intake on arterial pressure control after cardiac ischemia/reperfusion in female rats. PMID- 25833531 TI - Effects of Taurine on Blood Index of Hypothalamic Pituitary Adrenal (HPA) Axis of Stress-Induced Hypertensive Rat. PMID- 25833532 TI - Taurine in 24-h Urine Samples Is Inversely Related to Cardiovascular Risks of Middle Aged Subjects in 50 Populations of the World. PMID- 25833533 TI - Use of taurine during rehabilitation after cardiac surgery. PMID- 25833534 TI - Newer insights into the taurinuria of vitamin D deficiency: a review. PMID- 25833536 TI - Perinatal taurine depletion alters the renal excretory effect of the Renin Angiotensin system in adult female rats. PMID- 25833535 TI - The Effect of Perinatal Taurine on Adult Renal Function Does Not Appear to Be Mediated by Taurine's Inhibition of the Renin-Angiotensin System. PMID- 25833537 TI - Fructose feeding changes taurine homeostasis in wistar rats. PMID- 25833538 TI - Effects of taurine supplementation on adipose tissue of obese trained rats. PMID- 25833539 TI - The effect of taurine supplementation on glucose homeostasis: the role of insulin degrading enzyme. PMID- 25833540 TI - The association among dietary taurine intake, obesity and quality of sleep in korean women. PMID- 25833541 TI - Taurine supplementation leads to a disruption in energy homeostasis in menopausal obese mice. PMID- 25833542 TI - Effects of paternal hypothalamic obesity and taurine supplementation on adiposity and vascular reactivity in rat offspring. PMID- 25833543 TI - Taurine supplementation reduces eccentric exercise-induced delayed onset muscle soreness in young men. PMID- 25833544 TI - The effects of taurine administration against inflammation in heavily exercised skeletal muscle of rats. PMID- 25833545 TI - Needs assessment for development of health functional taurine-containing food for korean college students. PMID- 25833546 TI - Taurine accelerates alcohol and fat metabolism of rats with alcoholic Fatty liver disease. PMID- 25833547 TI - Protective Effect of Mussel (Mytilus Coruscus) Extract Containing Taurine Against AAPH-Induced Oxidative Stress in Zebrafish Model. PMID- 25833548 TI - Anti-inflammatory Effect of Short Neck Clam (Tapes philippinarum) Water Extract Containing Taurine in Zebrafish Model. PMID- 25833549 TI - In Vitro and In Vivo Antioxidant and Anti-inflammatory Activities of Abalone (Haliotis discus) Water Extract. PMID- 25833550 TI - Effect of N-(D-Ribopyranosyl)taurine Sodium Salt Supplementation on the Hepatic Antioxidant System in Rat Models of Diet-Induced Obesity and Taurine Deficiency. PMID- 25833551 TI - Evaluation of the Toxicity of a Single Oral Dose of N-(D-Ribopyranosyl)taurine Sodium Salt in Mice. PMID- 25833552 TI - N-(beta- D-Xylopyranosyl)taurine Sodium Salt Supplementation Has Beneficial Effect on the Hepatic Antioxidant System of Rats Fed a High-Fat Diet and beta Alanine. PMID- 25833553 TI - A Safety Assessment of N-(beta-D-Xylopyranosyl)Taurine Sodium Salt in Male and Female ICR Mice. PMID- 25833554 TI - Anti-obesity and Hypolipidemic Effects of N-(beta-D-Xylopyranosyl) Taurine Sodium Salt Supplementation in Rats Fed a High-Fat Diet and beta-Alanine. PMID- 25833555 TI - N-(D-Ribopyranosyl)Taurine Sodium Salt Has Anti-obesity Effect in Diet-Induced Obesity and Taurine Deficiency Rat Model. PMID- 25833556 TI - Catalytic thermal treatment (catalytic thermolysis) of a rice grain-based biodigester effluent of an alcohol distillery plant. AB - The catalytic thermolysis (CT) process is an effective and novel approach to treat rice grain-based biodigester effluent (BDE) of the distillery plant. CT treatment of rice grain-based distillery wastewater was carried out in a 0.5 dm(3) thermolytic batch reactor using different catalysts such as CuO, copper sulphate and ferrous sulphate. With the CuO catalyst, a temperature of 95 degrees C, catalyst loading of 4 g/dm(3) and pH 5 were found to be optimal, obtaining a maximum chemical oxygen demand (COD) and colour removal of 80.4% and 72%, respectively. The initial pH (pHi) was an important parameter to remove COD and colour from BDE. At higher pHi (pH 9.5), less COD and colour reduction were observed. The settling characteristics of CT-treated sludge were also analysed at different temperatures. It was noted that the treated slurry at a temperature of 80 degrees C gave best settling characteristics. Characteristics of residues are also analysed at different pH. PMID- 25833557 TI - Communication: Unusual structure and transport in ionic liquid-hexane mixtures. AB - Ionic liquids having a sufficiently amphiphilic cation can dissolve large volume fractions of alkanes, leading to mixtures with intriguing properties on molecular length scales. The trihexyl(tetradecyl)phosphonium cation paired with the bis(trifluoromethylsulfonyl)amide anion provides an ionic liquid that can dissolve large mole fractions of hexane. We present experimental results on mixtures of n-C6D14 with this ionic liquid. High-energy X-ray scattering studies reveal a persistence of the characteristic features of ionic liquid structure even for 80% dilution with n-C6D14. Nuclear magnetic resonance self-diffusion results reveal decidedly non-hydrodynamic behavior where the self-diffusion of the neutral, non-polar n-C6D14 is on average a factor of 21 times faster than for the cation. Exploitation of the unique structural and transport properties of these mixtures may lead to new opportunities for designer solvents for enhanced chemical reactivity and interface science. PMID- 25833558 TI - Communication: Improved pair approximations in local coupled-cluster methods. AB - In local coupled cluster treatments the electron pairs can be classified according to the magnitude of their energy contributions or distances into strong, close, weak, and distant pairs. Different approximations are introduced for the latter three classes. In this communication, an improved simplified treatment of close and weak pairs is proposed, which is based on long-range cancellations of individually slowly decaying contributions in the amplitude equations. Benchmark calculations for correlation, reaction, and activation energies demonstrate that these approximations work extremely well, while pair approximations based on local second-order Moller-Plesset theory can lead to errors that are 1-2 orders of magnitude larger. PMID- 25833559 TI - Analytic second derivative of the energy for density functional theory based on the three-body fragment molecular orbital method. AB - Analytic second derivatives of the energy with respect to nuclear coordinates have been developed for spin restricted density functional theory (DFT) based on the fragment molecular orbital method (FMO). The derivations were carried out for the three-body expansion (FMO3), and the two-body expressions can be obtained by neglecting the three-body corrections. Also, the restricted Hartree-Fock (RHF) Hessian for FMO3 can be obtained by neglecting the density-functional related terms. In both the FMO-RHF and FMO-DFT Hessians, certain terms with small magnitudes are neglected for computational efficiency. The accuracy of the FMO DFT Hessian in terms of the Gibbs free energy is evaluated for a set of polypeptides and water clusters and found to be within 1 kcal/mol of the corresponding full (non-fragmented) ab initio calculation. The FMO-DFT method is also applied to transition states in SN2 reactions and for the computation of the IR and Raman spectra of a small Trp-cage protein (PDB: 1L2Y). Some computational timing analysis is also presented. PMID- 25833560 TI - Calculation of the molecular integrals with the range-separated correlation factor. AB - Explicitly correlated quantum chemical calculations require calculations of five types of two-electron integrals beyond the standard electron repulsion integrals. We present a novel scheme, which utilises general ideas of the McMurchie-Davidson technique, to compute these integrals when the so-called "range-separated" correlation factor is used. This correlation factor combines the well-known short range behaviour resulting from the electronic cusp condition, with the exact long range asymptotics derived for the helium atom [Lesiuk, Jeziorski, and Moszynski, J. Chem. Phys. 139, 134102 (2013)]. Almost all steps of the presented procedure are formulated recursively, so that an efficient implementation and control of the precision are possible. Additionally, the present formulation is very flexible and general, and it allows for use of an arbitrary correlation factor in the electronic structure calculations with minor or no changes. PMID- 25833561 TI - Time-dependent projected Hartree-Fock. AB - Projected Hartree-Fock (PHF) has recently emerged as an alternative approach to describing degenerate systems where static correlation is abundant, when the spin symmetry is projected. Here, we derive a set of linearized time-dependent equations for PHF in order to be able to access excited states. The close connection of such linear-response time-dependent PHF (TDPHF) to the stability condition of a PHF wave function is discussed. Expanding this analysis also makes it possible to give analytical expressions for the projected coupling terms of Hamiltonian and overlaps between excited Slater determinants. TDPHF with spin projection (TDSUHF) and its Tamm-Dancoff approximation are benchmarked for several electronically degenerate molecules including the dissociating H2, F2 and O3 at equilibrium, and the distorted ethylene. It is shown that they give consistently better descriptions of excited states than does time-dependent HF (TDHF). Furthermore, we demonstrate that they offer not only singly but also doubly excited states, which naturally arise upon spin-projection. We also address the thermodynamic limit of TDSUHF, using non-interacting He gas. While TDPHF singly excited states tend to converge to those of HF with the size of the system due to the lack of size-extensivity of PHF, doubly excited states remain reasonable even at the thermodynamic limit. We find that the overall performance of our method is systematically better than the regular TDHF in many cases at the same computational scaling. PMID- 25833562 TI - Benchmarking DFT and semiempirical methods on structures and lattice energies for ten ice polymorphs. AB - Water in different phases under various external conditions is very important in bio-chemical systems and for material science at surfaces. Density functional theory methods and approximations thereof have to be tested system specifically to benchmark their accuracy regarding computed structures and interaction energies. In this study, we present and test a set of ten ice polymorphs in comparison to experimental data with mass densities ranging from 0.9 to 1.5 g/cm(3) and including explicit corrections for zero-point vibrational and thermal effects. London dispersion inclusive density functionals at the generalized gradient approximation (GGA), meta-GGA, and hybrid level as well as alternative low-cost molecular orbital methods are considered. The widely used functional of Perdew, Burke and Ernzerhof (PBE) systematically overbinds and overall provides inconsistent results. All other tested methods yield reasonable to very good accuracy. BLYP-D3(atm) gives excellent results with mean absolute errors for the lattice energy below 1 kcal/mol (7% relative deviation). The corresponding optimized structures are very accurate with mean absolute relative deviations (MARDs) from the reference unit cell volume below 1%. The impact of Axilrod Teller-Muto (atm) type three-body dispersion and of non-local Fock exchange is small but on average their inclusion improves the results. While the density functional tight-binding model DFTB3-D3 performs well for low density phases, it does not yield good high density structures. As low-cost alternative for structure related problems, we recommend the recently introduced minimal basis Hartree-Fock method HF-3c with a MARD of about 3%. PMID- 25833564 TI - Next generation of the self-consistent and environment-dependent Hamiltonian: Applications to various boron allotropes from zero- to three-dimensional structures. AB - An upgrade of the previous self-consistent and environment-dependent linear combination of atomic orbitals Hamiltonian (referred as SCED-LCAO) has been developed. This improved version of the semi-empirical SCED-LCAO Hamiltonian, in addition to the inclusion of self-consistent determination of charge redistribution, multi-center interactions, and modeling of electron-electron correlation, has taken into account the effect excited on the orbitals due to the atomic aggregation. This important upgrade has been subjected to a stringent test, the construction of the SCED-LCAO Hamiltonian for boron. It was shown that the Hamiltonian for boron has successfully characterized the electron deficiency of boron and captured the complex chemical bonding in various boron allotropes, including the planar and quasi-planar, the convex, the ring, the icosahedral, and the fullerene-like clusters, the two-dimensional monolayer sheets, and the bulk alpha boron, demonstrating its transferability, robustness, reliability, and predictive power. The molecular dynamics simulation scheme based on the Hamiltonian has been applied to explore the existence and the energetics of ~230 compact boron clusters BN with N in the range from ~100 to 768, including the random, the rhombohedral, and the spherical icosahedral structures. It was found that, energetically, clusters containing whole icosahedral B12 units are more stable for boron clusters of larger size (N > 200). The ease with which the simulations both at 0 K and finite temperatures were completed is a demonstration of the efficiency of the SCED-LCAO Hamiltonian. PMID- 25833563 TI - Variational cross-validation of slow dynamical modes in molecular kinetics. AB - Markov state models are a widely used method for approximating the eigenspectrum of the molecular dynamics propagator, yielding insight into the long-timescale statistical kinetics and slow dynamical modes of biomolecular systems. However, the lack of a unified theoretical framework for choosing between alternative models has hampered progress, especially for non-experts applying these methods to novel biological systems. Here, we consider cross-validation with a new objective function for estimators of these slow dynamical modes, a generalized matrix Rayleigh quotient (GMRQ), which measures the ability of a rank-m projection operator to capture the slow subspace of the system. It is shown that a variational theorem bounds the GMRQ from above by the sum of the first m eigenvalues of the system's propagator, but that this bound can be violated when the requisite matrix elements are estimated subject to statistical uncertainty. This overfitting can be detected and avoided through cross-validation. These result make it possible to construct Markov state models for protein dynamics in a way that appropriately captures the tradeoff between systematic and statistical errors. PMID- 25833565 TI - A transformed framework for dynamic correlation in multireference problems. AB - We describe how multireference dynamic correlation theories can be naturally obtained as single-reference correlation theories in a canonically transformed frame. Such canonically transformed correlation theories are very simple and involve identical expressions to their single-reference counterparts. The corresponding excitations involve quasiparticles rather than the bare particles of the system. High-order density matrices (or their approximations) and the numerical metric instabilities common to multireference correlation theories do not appear. As an example, we formulate the Bogoliubov canonically transformed version of second-order Moller-Plesset perturbation theory and demonstrate its performance in H2, H2O, N2, and BeH2 bond dissociation. PMID- 25833566 TI - Soft-spring wall based non-periodic boundary conditions for non-equilibrium molecular dynamics of dense fluids. AB - Non-equilibrium molecular dynamics (MD) simulations require imposition of non periodic boundary conditions (NPBCs) that seamlessly account for the effect of the truncated bulk region on the simulated MD region. Standard implementation of specular boundary conditions in such simulations results in spurious density and force fluctuations near the domain boundary and is therefore inappropriate for coupled atomistic-continuum calculations. In this work, we present a novel NPBC model that relies on boundary atoms attached to a simple cubic lattice with soft springs to account for interactions from particles which would have been present in an untruncated full domain treatment. We show that the proposed model suppresses the unphysical fluctuations in the density to less than 1% of the mean while simultaneously eliminating spurious oscillations in both mean and boundary forces. The model allows for an effective coupling of atomistic and continuum solvers as demonstrated through multiscale simulation of boundary driven singular flow in a cavity. The geometric flexibility of the model enables straightforward extension to nonplanar complex domains without any adverse effects on dynamic properties such as the diffusion coefficient. PMID- 25833567 TI - Thermal transport properties of halide solid solutions: Experiments vs equilibrium molecular dynamics. AB - The composition dependence of thermal transport properties of the (Na,K)Cl rocksalt solid solution is investigated through equilibrium molecular dynamics (EMD) simulations in the entire range of composition and the results are compared with experiments published in recent work [Gheribi et al., J. Chem. phys. 141, 104508 (2014)]. The thermal diffusivity of the (Na,K)Cl solid solution has been measured from 473 K to 823 K using the laser flash technique, and the thermal conductivity was deduced from critically assessed data of heat capacity and density. The thermal conductivity was also predicted at 900 K in the entire range of composition by a series of EMD simulations in both NPT and NVT statistical ensembles using the Green-Kubo theory. The aim of the present paper is to provide an objective analysis of the capability of EMD simulations in predicting the composition dependence of the thermal transport properties of halide solid solutions. According to the Klemens-Callaway [P. G. Klemens, Phys. Rev. 119, 507 (1960) and J. Callaway and H. C. von Bayer, Phys. Rev. 120, 1149 (1960)] theory, the thermal conductivity degradation of the solid solution is explained by mass and strain field fluctuations upon the phonon scattering cross section. A rigorous analysis of the consistency between the theoretical approach and the EMD simulations is discussed in detail. PMID- 25833568 TI - Natural scaling of size distributions in homogeneous and heterogeneous rate equations with size-linear capture rates. AB - We obtain exact solutions of the rate equations for homogeneous and heterogeneous irreversible growth models with linear size dependences of the capture rates. In the limit of high ratios of diffusion constant over deposition rate, both solutions yield simple analytical scaling functions with the correct normalizations. These are given by the cumulative distribution function and the probability density function of the gamma-distribution in homogeneous and heterogeneous cases, respectively. Our size distributions depend on the value of the capture rate a in the reaction of joining two mobile monomers A1 (A1 + A1 -> A2) or the monomer attachment to the reactive defect B (A1 + B -> AB). In homogeneous cases, the size distribution is monotonically decreasing regardless of a. In heterogeneous growth, the distribution is monotonically decreasing when a <= 1 and monomodal when a > 1. The obtained solutions describe fairly well the experimental data on the length distributions of Al, Ga, In, and Mn adatom chains on Si(100)-2 * 1 surfaces. PMID- 25833569 TI - Effective binary theory of multi-component nucleation. AB - Classical theory of multi-component nucleation [O. Hirschfelder, J. Chem. Phys. 61, 2690 (1974)] belongs to the class of the so-called intractable problems: it requires computational time which is an exponential function of the number of components N. For a number of systems of practical interest with N > 10, the brute-force use of the classical theory becomes virtually impossible and one has to resort to an effective medium approach. We present an effective binary model which captures important physics of multi-component nucleation. The distinction between two effective species is based on the observation that while all N components contribute to the cluster thermodynamic properties, there is only a part of them which trigger the nucleation process. The proposed 2D-theory takes into account adsorption by means of the Gibbs dividing surface formalism and uses statistical mechanical considerations for the treatment of small clusters. Theoretical predictions for binary-, ternary-, and 14-component mixtures are compared with available experimental data and other models. PMID- 25833570 TI - Surveying the free energy landscapes of continuum models: Application to soft matter systems. AB - A variety of methods are developed for characterising the free energy landscapes of continuum, Landau-type free energy models. Using morphologies of lipid vesicles and a multistable liquid crystal device as examples, I show that the methods allow systematic study of not only the most relevant minimum energy configurations, but also the transition pathways between any two minima, as well as their corresponding energy barriers and transition state configurations. A global view of the free energy landscapes can then be visualized using either a disconnectivity graph or a network representation. Different forms of free energy functionals and boundary conditions can be readily implemented, thus allowing these tools to be utilised for a broad range of problems. PMID- 25833571 TI - Functional differentiability in time-dependent quantum mechanics. AB - In this work, we investigate the functional differentiability of the time dependent many-body wave function and of derived quantities with respect to time dependent potentials. For properly chosen Banach spaces of potentials and wave functions, Frechet differentiability is proven. From this follows an estimate for the difference of two solutions to the time-dependent Schrodinger equation that evolve under the influence of different potentials. Such results can be applied directly to the one-particle density and to bounded operators, and present a rigorous formulation of non-equilibrium linear-response theory where the usual Lehmann representation of the linear-response kernel is not valid. Further, the Frechet differentiability of the wave function provides a new route towards proving basic properties of time-dependent density-functional theory. PMID- 25833572 TI - Solid-state EPR strategies for the structural characterization of paramagnetic NO adducts of frustrated Lewis pairs (FLPs). AB - Anisotropic interactions present in three new nitroxide radicals prepared by N,N addition of NO to various borane-phosphane frustrated Lewis pairs (FLPs) have been characterized by continuous-wave (cw) and pulsed X-band EPR spectroscopies in solid FLP-hydroxylamine matrices at 100 K. Anisotropic g-tensor values and (11)B, (14)N, and (31)P hyperfine coupling tensor components have been extracted from continuous-wave lineshape analyses, electron spin echo envelope modulation (ESEEM), and hyperfine sublevel correlation spectroscopy (HYSCORE) experiments with the help of computer simulation techniques. Suitable fitting constraints are developed on the basis of density functional theory (DFT) calculations. These calculations reveal that different from the situation in standard nitroxide radicals (TEMPO), the g-tensors are non-coincident with any of the nuclear hyperfine interaction tensors. The determination of these interaction parameters turns out to be successful, as the cw- and pulse EPR experiments are highly complementary in informational content. While the continuous-wave lineshape is largely influenced by the anisotropic hyperfine coupling to (14)N and (31)P, the ESEEM and HYSCORE spectra contain important information about the (11)B hyperfine coupling and nuclear electric quadrupolar interaction. The set of cw- and pulsed EPR experiments, with fitting constraints developed by DFT calculations, defines an efficient strategy for the structural analysis of paramagnetic FLP adducts. PMID- 25833573 TI - Applied quantum chemistry: Spectroscopic detection and characterization of the F2BS and Cl2BS free radicals in the gas phase. AB - In this and previous work [D. J. Clouthier, J. Chem. Phys. 141, 244309 (2014)], the spectroscopic signatures of the X2BY (X = H, halogen, Y = O, S) free radicals have been predicted using high level ab initio theory. The theoretical results have been used to calculate the electronic absorption and single vibronic level (SVL) emission spectra of the radicals under typical jet-cooled conditions. Using these diagnostic predictions, the previously unknown F2BS and Cl2BS free radicals have been identified and characterized. The radicals were prepared in a free jet expansion by subjecting precursor mixtures of BF3 or BCl3 and CS2 vapor to an electric discharge at the exit of a pulsed molecular beam valve. The B(2)A1 X(2)B2 laser-induced fluorescence spectra were found within 150 cm(-1) of their theoretically predicted positions with vibronic structure consistent with our Franck-Condon simulations. The B(2)A1 state emits down to the ground state and to the low-lying A(2)B1 excited state and the correspondence between the observed and theoretically derived SVL emission Franck-Condon profiles was used to positively identify the radicals and make assignments. Excited state Coriolis coupling effects complicate the emission spectra of both radicals. In addition, a forbidden component of the electronically allowed B-X band system of Cl2BS is evident, as signaled by the activity in the b2 modes in the spectrum. Symmetry arguments indicate that this component gains intensity due to a vibronic interaction of the B(2)A1 state with a nearby electronic state of (2)B2 symmetry. PMID- 25833574 TI - Accurate high level ab initio-based global potential energy surface and dynamics calculations for ground state of CH2(+). AB - A global many-body expansion potential energy surface is reported for the electronic ground state of CH2 (+) by fitting high level ab initio energies calculated at the multireference configuration interaction level with the aug-cc pV6Z basis set. The topographical features of the new global potential energy surface are examined in detail and found to be in good agreement with those calculated directly from the raw ab initio energies, as well as previous calculations available in the literature. In turn, in order to validate the potential energy surface, a test theoretical study of the reaction CH(+)(X(1)Sigma(+))+H((2)S)->C(+)((2)P)+H2(X(1)Sigmag (+)) has been carried out with the method of time dependent wavepacket on the title potential energy surface. The total integral cross sections and the rate coefficients have been calculated; the results determined that the new potential energy surface can both be recommended for dynamics studies of any type and as building blocks for constructing the potential energy surfaces of larger C(+)/H containing systems. PMID- 25833575 TI - Three-body fragmentation of CO2 driven by intense laser pulses. AB - Dissociative ionization dynamics were studied experimentally for CO2 driven by intense laser pulses. Three-dimensional momentum vectors of correlated atomic ions were obtained for each three-body fragmentation event using triple ion coincidence measurement. Newton diagram demonstrated that three-body fragmentation of CO2 (n+) (n = 3-6) can occur through Coulomb explosion process and sequential fragmentation process depending on the fragmentation channels. The experimental data from these two processes were disentangled by using correlation diagram of correlated ions. Based on the accurate Coulomb explosion data, we reconstructed the bond angle distributions of CO2 (n+) at the moment of fragmentation, which are close to that of neutral CO2 before laser irradiation. PMID- 25833576 TI - The vibrational dynamics of 3D HOCl above dissociation. AB - We explore the classical vibrational dynamics of the HOCl molecule for energies above the dissociation energy of the molecule. Above dissociation, we find that the classical dynamics is dominated by an invariant manifold which appears to stabilize two periodic orbits at energies significantly above the dissociation energy. These stable periodic orbits can hold a large number of quantum states and likely can support a significant quasibound state of the molecule, well above the dissociation energy. The classical dynamics and the lifetime of quantum states on the invariant manifold are determined. PMID- 25833577 TI - Photoelectron imaging and photodissociation of ozonide in O3(-)?(O2)n (n = 1-4) clusters. AB - The photoelectron images of O3 (-) and O3 (-) ? (O2)n (n = 1-4) have been measured using 3.49 eV photon energy. The spectra exhibit several processes, including direct photodetachment and photodissociation with photodetachment of O( ) photofragments. Several spectra also exhibit autodetachment of vibrationally excited O2 (-) photofragments. Comparison of the bare O3 (-) photoelectron spectra to that of the complexes shows that the O3 (-) core is preserved upon clustering with several O2 molecules, though subtle changes in the Franck-Condon profile of the ground state photodetachment transition suggest some charge transfer from O3 (-) to the O2 molecules. The electron affinities of the complexes increase by less than 0.1 eV with each additional O2 molecule, which is comparable to the corresponding binding energy [K. Hiraoka, Chem. Phys. 125, 439 444 (1988)]. The relative intensity of the photofragment O(-) detachment signal to the O3 (-) ? (O2)n direct detachment signal increases with cluster size. O2 ( ) autodetachment signal is only observed in the O3 (-), O3 (-) ? (O2)3, and O3 ( ) ? (O2)4 spectra, suggesting that the energy of the dissociative state also varies with the number of O2 molecules present in the cluster. PMID- 25833578 TI - Differential cross sections for electron-impact vibrational-excitation of tetrahydrofuran at intermediate impact energies. AB - We report differential cross sections (DCSs) for electron-impact vibrational excitation of tetrahydrofuran, at intermediate incident electron energies (15-50 eV) and over the 10 degrees -90 degrees scattered electron angular range. These measurements extend the available DCS data for vibrational excitation for this species, which have previously been obtained at lower incident electron energies (<=20 eV). Where possible, our data are compared to the earlier measurements in the overlapping energy ranges. Here, quite good agreement was generally observed where the measurements overlapped. PMID- 25833579 TI - The role of electron-impact vibrational excitation in electron transport through gaseous tetrahydrofuran. AB - In this paper, we report newly derived integral cross sections (ICSs) for electron impact vibrational excitation of tetrahydrofuran (THF) at intermediate impact energies. These cross sections extend the currently available data from 20 to 50 eV. Further, they indicate that the previously recommended THF ICS set [Garland et al., Phys. Rev. A 88, 062712 (2013)] underestimated the strength of the electron-impact vibrational excitation processes. Thus, that recommended vibrational cross section set is revised to address those deficiencies. Electron swarm transport properties were calculated with the amended vibrational cross section set, to quantify the role of electron-driven vibrational excitation in describing the macroscopic swarm phenomena. Here, significant differences of up to 17% in the transport coefficients were observed between the calculations performed using the original and revised cross section sets for vibrational excitation. PMID- 25833581 TI - Vibrational state-selective autodetachment photoelectron spectroscopy from dipole bound states of cold 2-hydroxyphenoxide: o-HO(C6H4)O(-). AB - We report a photodetachment and high-resolution photoelectron imaging study of cold 2-hydroxyphenoxide anion, o - HO(C6H4)O(-), cooled in a cryogenic ion trap. Photodetachment spectroscopy revealed a dipole-bound state (DBS) of the anion, 25 +/- 5 cm(-1), below the detachment threshold of 18 784 +/- 5 cm-1 (2.3289 +/- 0.0006 eV), i.e., the electron affinity of the 2-hydroxyphenoxy radical o - HO(C6H4)O(?). Twenty-two vibrational levels of the DBS are observed as resonances in the photodetachment spectrum. By tuning the detachment laser to these DBS vibrational levels, we obtain 22 high-resolution resonant photoelectron spectra, which are highly non-Franck-Condon due to mode-selective autodetachment and the Deltav = - 1 propensity rule. Numerous Franck-Condon inactive vibrational modes are observed in the resonant photoelectron spectra, significantly expanding the vibrational information that is available in traditional high-resolution photoelectron spectroscopy. A total of 15 fundamental vibrational frequencies are obtained for the o - HO(C6H4)O(?) radical from both the photodetachment spectrum and the resonant photoelectron spectra, including six symmetry-forbidden out-of plane modes as a result of resonant enhancement. PMID- 25833580 TI - The hyperfine structure in the rotational spectra of D2(17)O and HD(17)O: Confirmation of the absolute nuclear magnetic shielding scale for oxygen. AB - Guided by theoretical predictions, the hyperfine structures of the rotational spectra of mono- and bideuterated-water containing (17)O have been experimentally investigated. To reach sub-Doppler resolution, required to resolve the hyperfine structure due to deuterium quadrupole coupling as well as to spin-rotation (SR) and dipolar spin-spin couplings, the Lamb-dip technique has been employed. The experimental investigation and in particular, the spectral analysis have been supported by high-level quantum-chemical computations employing coupled-cluster techniques and, for the first time, a complete experimental determination of the hyperfine parameters involved was possible. The experimentally determined (17)O spin-rotation constants of D2 (17)O and HD(17)O were used to derive the paramagnetic part of the corresponding nuclear magnetic shielding constants. Together with the computed diamagnetic contributions as well as the vibrational and temperature corrections, the latter constants have been employed to confirm the oxygen nuclear magnetic shielding scale, recently established on the basis of spin-rotation data for H2 (17)O [Puzzarini et al., J. Chem. Phys. 131, 234304 (2009)]. PMID- 25833582 TI - Low energy elastic electron scattering from CF3Br molecules. AB - CF3Br is a potentially valuable precursor molecule for generating beams of gas phase Br radicals suitable for electron collisions studies. However, the utility of CF3Br for this purpose depends critically on the availability of sound scattering cross sections to allow the contribution of the precursor to be isolated within the total scattering signal. To this end, here we present elastic differential cross section (DCS) measurements for CF3Br at incident energies between 15 and 50 eV. Comparison of these DCSs to those from the only other available experimental study [Sunohara et al., J. Phys. B: At., Mol. Opt. Phys. 36, 1843 (2003)] and a Schwinger multichannel with pseudo potentials (SMCPPs) calculation [Bettega et al., J. Phys. B: At., Mol. Opt. Phys. 36, 1263 (2003)] shows generally a very good accord. Integral elastic and momentum transfer cross sections, derived from our DCSs, are also found to be in quite good agreement with the SMCPP results. PMID- 25833583 TI - Adsorption of carbon monoxide on small aluminum oxide clusters: Role of the local atomic environment and charge state on the oxidation of the CO molecule. AB - We present extensive density functional theory (DFT) calculations dedicated to analyze the adsorption behavior of CO molecules on small AlxOy (+/-) clusters. Following the experimental results of Johnson et al. [J. Phys. Chem. A 112, 4732 (2008)], we consider structures having the bulk composition Al2O3, as well as smaller Al2O2 and Al2O units. Our electron affinity and total energy calculations are consistent with aluminum oxide clusters having two-dimensional rhombus-like structures. In addition, interconversion energy barriers between two- and one dimensional atomic arrays are of the order of 1 eV, thus clearly defining the preferred isomers. Single CO adsorption on our charged AlxOy (+/-) clusters exhibits, in general, spontaneous oxygen transfer events leading to the production of CO2 in line with the experimental data. However, CO can also bind to both Al and O atoms of the clusters forming aluminum oxide complexes with a CO2 subunit. The vibrational spectra of AlxOy + CO2 provides well defined finger prints that may allow the identification of specific isomers. The AlxOy (+) clusters are more reactive than the anionic species and the final Al2O(+) + CO reaction can result in the production of atomic Al and carbon dioxide as observed from experiments. We underline the crucial role played by the local atomic environment, charge density distribution, and spin-multiplicity on the oxidation behavior of CO molecules. Finally, we analyze the importance of coadsorption and finite temperature effects by performing DFT Born-Oppenheimer molecular dynamics. Our calculations show that CO oxidation on AlxOy (+) clusters can be also promoted by the binding of additional CO species at 300 K, revealing the existence of fragmentation processes in line with the ones experimentally inferred. PMID- 25833584 TI - A novel and facile decay path of Criegee intermediates by intramolecular insertion reactions via roaming transition states. AB - We have discovered a new and highly competitive product channel in the unimolecular decay process for small Criegee intermediates, CH2OO and anti/syn CH3C(H)OO, occurring by intramolecular insertion reactions via a roaming-like transition state (TS) based on quantum-chemical calculations. Our results show that in the decomposition of CH2OO and anti-CH3C(H)OO, the predominant paths directly produce cis-HC(O)OH and syn-CH3C(O)OH acids with >110 kcal/mol exothermicities via loose roaming-like insertion TSs involving the terminal O atom and the neighboring C-H bonds. For syn-CH3C(H)OO, the major decomposition channel occurs by abstraction of a H atom from the CH3 group by the terminal O atom producing CH2C(H)O-OH. At 298 K, the intramolecular insertion process in CH2OO was found to be 600 times faster than the commonly assumed ring-closing reaction. PMID- 25833585 TI - Circular and linear magnetic birefringences in xenon at lambda = 1064 nm. AB - The circular and linear magnetic birefringences corresponding to the Faraday and the Cotton-Mouton effects, respectively, have been measured in xenon at lambda = 1064 nm. The experimental setup is based on time dependent magnetic fields and a high finesse Fabry-Perot cavity. Our value of the Faraday effect is the first measurement at this wavelength. It is compared to theoretical predictions. Our uncertainty of a few percent yields an agreement at better than 1sigma with the computational estimate when relativistic effects are taken into account. Concerning the Cotton-Mouton effect, our measurement, the second ever published at lambda = 1064 nm, agrees at better than 1sigma with theoretical predictions. We also compare our error budget with that established for other experimental published values. PMID- 25833586 TI - Identification of four rotamers of m-methoxystyrene by resonant two-photon ionization and mass analyzed threshold ionization spectroscopy. AB - We report the vibronic and cation spectra of four rotamers of m-methoxystyrene, recorded by using the two-color resonant two-photon ionization and mass-analyzed threshold ionization techniques. The excitation energies of the S1<- S0 electronic transition are found to be 32 767, 32 907, 33 222, and 33 281 cm(-1), and the corresponding adiabatic ionization energies are 65 391, 64 977, 65 114, and 64 525 cm(-1) for these isomeric species. Most of the observed active vibrations in the electronically excited S1 and cationic ground D0 states involve in-plane ring deformation and substituent-sensitive bending motions. It is found that the relative orientation of the methoxyl with respect to the vinyl group does not influence the vibrational frequencies of the ring-substituent bending modes. The two dimensional potential energy surface calculations support our experimental finding that the isomerization is restricted in the S1 and D0 states. PMID- 25833587 TI - Initial mechanisms for the decomposition of electronically excited energetic materials: 1,5'-BT, 5,5'-BT, and AzTT. AB - Decomposition of nitrogen-rich energetic materials 1,5'-BT, 5,5'-BT, and AzTT (1,5'-Bistetrazole, 5,5'-Bistetrazole, and 5-(5-azido-(1 or 4)H-1,2,4-triazol-3 yl)tetrazole, respectively), following electronic state excitation, is investigated both experimentally and theoretically. The N2 molecule is observed as an initial decomposition product from the three materials, subsequent to UV excitation, with a cold rotational temperature (<30 K). Initial decomposition mechanisms for these three electronically excited materials are explored at the complete active space self-consistent field (CASSCF) level. Potential energy surface calculations at the CASSCF(12,8)/6-31G(d) level illustrate that conical intersections play an essential role in the decomposition mechanism. Electronically excited S1 molecules can non-adiabatically relax to their ground electronic states through (S1/S0)CI conical intersections. 1,5'-BT and 5,5'-BT materials have several (S1/S0)CI conical intersections between S1 and S0 states, related to different tetrazole ring opening positions, all of which lead to N2 product formation. The N2 product for AzTT is formed primarily by N-N bond rupture of the -N3 group. The observed rotational energy distributions for the N2 products are consistent with the final structures of the respective transition states for each molecule on its S0 potential energy surface. The theoretically derived vibrational temperature of the N2 product is high, which is similar to that found for energetic salts and molecules studied previously. PMID- 25833588 TI - Density functional theory and chromium: Insights from the dimers. AB - The binding in small Cr clusters is re-investigated, where the correct description of the dimer in three charge states is used as criterion to assign the most suitable density functional theory approximation. The difficulty in chromium arises from the subtle interplay between energy gain from hybridization and energetic cost due to exchange between s and d based molecular orbitals. Variations in published bond lengths and binding energies are shown to arise from insufficient numerical representation of electron density and Kohn-Sham wave functions. The best functional performance is found for gradient corrected (GGA) functionals and meta-GGAs, where we find severe differences between functionals from the same family due to the importance of exchange. Only the "best fit" from Bayesian error estimation is able to predict the correct energetics for all three charge states unambiguously. With this knowledge, we predict small bond-lengths to be exclusively present in Cr2 and Cr2 (-). Already for the dimer cation, solely long bond-lengths appear, similar to what is found in the trimer and in chromium bulk. PMID- 25833589 TI - Signatures of non-adiabatic dynamics in the fine-structure state distributions of the OH(X/A) products in the B-band photodissociation of H2O. AB - A detailed quantum mechanical characterization of the photodissociation dynamics of H2O at 121.6 nm is presented. The calculations were performed using a full dimensional wave packet method on coupled potential energy surfaces of all relevant electronic states. Our state-to-state model permits a detailed analysis of the OH(X/A) product fine-structure populations as a probe of the non-adiabatic dissociation dynamics. The calculated rotational state distributions of the two Lambda-doublet levels of OH(X, v = 0) exhibit very different characteristics. The A' states, produced mostly via the B->X conical intersection pathway, have significantly higher populations than the A" counterparts, which are primarily from the B->A Renner-Teller pathway. The former features a highly inverted and oscillatory rotational state distribution, while the latter has a smooth distribution with much less rotational excitation. In good agreement with experiment, the calculated total OH(X) rotational state distribution and anisotropy parameters show clear even-odd oscillations, which can be attributed to a quantum mechanical interference between waves emanating from the HOH and HHO conical intersections in the B->X non-adiabatic pathway. On the other hand, the experiment-theory agreement for the OH(A) fragment is also satisfactory, although some small quantitative differences suggest remaining imperfections of the ab initio based potential energy surfaces. PMID- 25833590 TI - Tuning structure and mobility of solvation shells surrounding tracer additives. AB - Molecular dynamics simulations and a stochastic Fokker-Planck equation based approach are used to illuminate how position-dependent solvent mobility near one or more tracer particle(s) is affected when tracer-solvent interactions are rationally modified to affect corresponding solvation structure. For tracers in a dense hard-sphere fluid, we compare two types of tracer-solvent interactions: (1) a hard-sphere-like interaction, and (2) a soft repulsion extending beyond the hard core designed via statistical mechanical theory to enhance tracer mobility at infinite dilution by suppressing coordination-shell structure [Carmer et al., Soft Matter 8, 4083-4089 (2012)]. For the latter case, we show that the mobility of surrounding solvent particles is also increased by addition of the soft repulsive interaction, which helps to rationalize the mechanism underlying the tracer's enhanced diffusivity. However, if multiple tracer surfaces are in closer proximity (as at higher tracer concentrations), similar interactions that disrupt local solvation structure instead suppress the position-dependent solvent dynamics. PMID- 25833591 TI - Mode coupling theory analysis of electrolyte solutions: Time dependent diffusion, intermediate scattering function, and ion solvation dynamics. AB - A self-consistent mode coupling theory (MCT) with microscopic inputs of equilibrium pair correlation functions is developed to analyze electrolyte dynamics. We apply the theory to calculate concentration dependence of (i) time dependent ion diffusion, (ii) intermediate scattering function of the constituent ions, and (iii) ion solvation dynamics in electrolyte solution. Brownian dynamics with implicit water molecules and molecular dynamics method with explicit water are used to check the theoretical predictions. The time dependence of ionic self diffusion coefficient and the corresponding intermediate scattering function evaluated from our MCT approach show quantitative agreement with early experimental and present Brownian dynamic simulation results. With increasing concentration, the dispersion of electrolyte friction is found to occur at increasingly higher frequency, due to the faster relaxation of the ion atmosphere. The wave number dependence of intermediate scattering function, F(k, t), exhibits markedly different relaxation dynamics at different length scales. At small wave numbers, we find the emergence of a step-like relaxation, indicating the presence of both fast and slow time scales in the system. Such behavior allows an intriguing analogy with temperature dependent relaxation dynamics of supercooled liquids. We find that solvation dynamics of a tagged ion exhibits a power law decay at long times-the decay can also be fitted to a stretched exponential form. The emergence of the power law in solvation dynamics has been tested by carrying out long Brownian dynamics simulations with varying ionic concentrations. The solvation time correlation and ion-ion intermediate scattering function indeed exhibit highly interesting, non-trivial dynamical behavior at intermediate to longer times that require further experimental and theoretical studies. PMID- 25833592 TI - Urea and deuterium mixtures at high pressures. AB - Urea, like many network forming compounds, has long been known to form inclusion (guest-host) compounds. Unlike other network formers like water, urea is not known to form such inclusion compounds with simple molecules like hydrogen. Such compounds if they existed would be of interest both for the fundamental insight they provide into molecular bonding and as potential gas storage systems. Urea has been proposed as a potential hydrogen storage material [T. A. Strobel et al., Chem. Phys. Lett. 478, 97 (2009)]. Here, we report the results of high-pressure neutron diffraction studies of urea and D2 mixtures that indicate no inclusion compound forms up to 3.7 GPa. PMID- 25833593 TI - Weak links between fast mobility and local structure in molecular and atomic liquids. AB - We investigate by molecular-dynamics simulations, the fast mobility-the rattling amplitude of the particles temporarily trapped by the cage of the neighbors-in mildly supercooled states of dense molecular (linear trimers) and atomic (binary mixtures) liquids. The mixture particles interact by the Lennard-Jones potential. The non-bonded particles of the molecular system are coupled by the more general Mie potential with variable repulsive and attractive exponents in a range which is a characteristic of small n-alkanes and n-alcohols. Possible links between the fast mobility and the geometry of the cage (size and shape) are searched. The correlations on a per-particle basis are rather weak. Instead, if one groups either the particles in fast-mobility subsets or the cages in geometric subsets, the increase of the fast mobility with both the size and the asphericity of the cage is revealed. The observed correlations are weak and differ in states with equal relaxation time. Local forces between a tagged particle and the first neighbour shell do not correlate with the fast mobility in the molecular liquid. It is concluded that the cage geometry alone is unable to provide a microscopic interpretation of the known, universal link between the fast mobility and the slow structural relaxation. We suggest that the particle fast dynamics is affected by regions beyond the first neighbours, thus supporting the presence of collective, extended fast modes. PMID- 25833594 TI - Molecular dynamics simulation of CO2 hydrates: Prediction of three phase coexistence line. AB - The three phase equilibrium line (hydrate-liquid water-liquid carbon dioxide) has been estimated for the water + carbon dioxide binary mixture using molecular dynamics simulation and the direct coexistence technique. Both molecules have been represented using rigid nonpolarizable models. TIP4P/2005 and TIP4P/Ice were used for the case of water, while carbon dioxide was considered as a three center linear molecule with the parameterizations of MSM, EPM2, TraPPE, and ZD. The influence of the initial guest occupancy fraction on the hydrate stability has been analyzed first in order to determine the optimal starting configuration for the simulations, paying attention to the influence of the two different cells existing in the sI hydrate structure. The three phase coexistence temperature was then determined for a pressure range from 2 to 500 MPa. The qualitative shape of the equilibrium curve estimated is correct, including the high pressure temperature maximum that determines the hydrate re-entrant behaviour. However, in order to obtain quantitative agreement with experimental results, a positive deviation from the classical Lorentz-Berthelot combining rules must be considered. PMID- 25833595 TI - Crystallization of Lennard-Jones nanodroplets: From near melting to deeply supercooled. AB - We carry out molecular dynamics (MD) and Monte Carlo (MC) simulations to characterize nucleation in liquid clusters of 600 Lennard-Jones particles over a broad range of temperatures. We use the formalism of mean first-passage times to determine the rate and find that Classical Nucleation Theory (CNT) predicts the rate quite well, even when employing simple modelling of crystallite shape, chemical potential, surface tension, and particle attachment rate, down to the temperature where the droplet loses metastability and crystallization proceeds through growth-limited nucleation in an unequilibrated liquid. Below this crossover temperature, the nucleation rate is still predicted when MC simulations are used to directly calculate quantities required by CNT. Discrepancy in critical embryo sizes obtained from MD and MC arises when twinned structures with five-fold symmetry provide a competing free energy pathway out of the critical region. We find that crystallization begins with hcp-fcc stacked precritical nuclei and differentiation to various end structures occurs when these embryos become critical. We confirm that using the largest embryo in the system as a reaction coordinate is useful in determining the onset of growth-limited nucleation and show that it gives the same free energy barriers as the full cluster size distribution once the proper reference state is identified. We find that the bulk melting temperature controls the rate, even though the solid-liquid coexistence temperature for the droplet is significantly lower. The value of surface tension that renders close agreement between CNT and direct rate determination is significantly lower than what is expected for the bulk system. PMID- 25833596 TI - Decoupling of relaxation and diffusion in random pinning glass-forming liquids. AB - We investigate numerically the relaxation and diffusion dynamics in three dimensional Kob-Andersen glass-forming liquids in which part of the particles are randomly chosen and pinned permanently. We find that both the relaxation dynamics and diffusion dynamics slow down as increasing the pinning concentration (cpin) at fixed temperatures that we study. For higher temperature and lower cpin, the alpha relaxation time tau and the diffusion coefficient D have the scaling relationship D ~ tau(-1). However, this coupling behavior breaks down if cpin is further increased, and the scaling relationship is replaced by D ~ tau(-nu) with nu < 1. At temperatures around the onset temperature of the bulk system, a transition from nu ~ 0.75 to nu ~ 0.61 with increasing cpin is found. However, at lower temperatures, nu ~ 0.67 holds in the whole studied cpin range. By fitting the relaxation time as a function of cpin with Vogel-Fulcher-Tamman equation, we find that the change of scaling exponent nu is accompanied with the change of fragility parameter K at higher temperatures. However, at lower temperatures, pinning particles have little effect on the system's qualitative properties. Moreover, we investigate three measures of heterogeneity of dynamics and find that the relaxation and the diffusion motion of particles show different responses to the pinned particles, which may lead to the slower relaxation than diffusion and the decoupling of relaxation and diffusion. The string-like motion is found to saturate at the mode-coupling theory (MCT) crossover point, which indicates that other relaxation modes may exist below the MCT transition point. PMID- 25833597 TI - Structures of water molecules in carbon nanotubes under electric fields. AB - Carbon nanotubes (CNTs) are promising for water transport through membranes and for use as nano-pumps. The development of CNT-based nanofluidic devices, however, requires a better understanding of the properties of water molecules in CNTs because they can be very different from those in the bulk. Using all-atom molecular dynamics simulations, we investigate the effect of axial electric fields on the structure of water molecules in CNTs having diameters ranging from (7,7) to (10,10). The water dipole moments were aligned parallel to the electric field, which increases the density of water inside the CNTs and forms ordered ice like structures. The electric field induces the transition from liquid to ice nanotubes in a wide range of CNT diameters. Moreover, we found an increase in the lifetime of hydrogen bonds for water structures in the CNTs. Fast librational motion breaks some hydrogen bonds, but the molecular pairs do not separate and the hydrogen bonds reform. Thus, hydrogen bonds maintain the water structure in the CNTs, and the water molecules move collectively, decreasing the axial diffusion coefficient and permeation rate. PMID- 25833598 TI - Characterization of adsorbed water in MIL-53(Al) by FTIR spectroscopy and ab initio calculations. AB - Here, we report ab-initio calculations developed with a twofold purpose: understand how adsorbed water molecules alter the infrared spectrum of the metal organic framework MIL-53(Al) and to investigate which are the associated physico chemical processes. The analyzed structures are the two anhydrous narrow (np?) and large (lp?) pore forms and the hydrated narrow pore form (np-H2O) of the MIL 53(Al). For these structures, we determined their corresponding infrared spectra (FTIR) and we identified the vibrational modes associated to the dominant spectral lines. We show that wagging and scissoring modes of CO2 give flexibility to the structure for facilitating the lp?- np? transition. In our studies, this transition is identified by eight vibrational modes including the deltaCH(18a) vibrational mode currently used to identify the mentioned transition. We report an exhaustive band identification of the infrared spectra associated to the analyzed structures. Moreover, the FTIR for the np-H2O structure allowed us to identify four types of water molecules linked to the host structure by one to three hydrogen bonds. PMID- 25833599 TI - Opening gates to oxygen reduction reactions on Cu(111) surface. AB - Electrocatalytic reduction of oxygen is composed of multiple steps, including the diffusion-adsorption-dissociation of molecular oxygen. This study explores the role of electrical double layer in aqueous medium in quantifying the rate of these coupled electrochemical processes at the electrode interface during oxygen reduction. The electronic, energetic, and configurational aspects of molecular oxygen diffusion and adsorption onto Cu(111) in water are identified through density functional theory based computations. The liquid phase on Cu(111) is modeled with hexagonal-ordered water bilayers, at two slightly different structures, with O-H bonds either facing the vacuum or the metal surface. The results indicate that the energetically preferred structure of water bilayers and adsorption configuration of O2 are different in cathodic and anodic potentials. The diffusion of O2 is found to be heavily hindered at the water/metal interface because of the ordering of water molecules in bilayers as compared to the bulk liquid. The unique correlations of diffusion and adsorption kinetics with water structure identified in this work can provide clues for improving oxygen reduction efficiency. PMID- 25833600 TI - A first-principles study of Pt thin films on SrTiO3(100): Support effects on CO adsorption. AB - Density functional theory was used to study CO adsorption on thin Pt metal films supported on SrO- and TiO2-terminated SrTiO3(100) surfaces. Regardless of substrate-termination, significant enhancement in CO binding occurred on the Pt monolayer compared to the bulk Pt(100) surface. We also observed CO-coverage dependent shifting of Pt atoms, influenced by the nature of underlying oxide atoms. These oxide-induced effects become negligible after depositing more than 2 monolayers of Pt. Evaluating the electronic structures of oxide-supported Pt showed that the interaction of filled Pt dxz+yz and empty Pt dz(2) states with CO molecular orbitals can be directly related to CO adsorption on the Pt/SrTiO3(100) surface. A hybrid d-band model is able to capture the CO adsorption trends for systems that do not show large lateral distortion except for the case of Pt adsorbed above the Sr atom on the SrO-termination. For this case, charge transfer from adjacent Pt atoms leads to a large filled dz(2) peak below the Fermi level that weakens the Pt-CO sigma bonding due to Pauli repulsion. PMID- 25833601 TI - Electrolyte pore/solution partitioning by expanded grand canonical ensemble Monte Carlo simulation. AB - Using a newly developed grand canonical Monte Carlo approach based on fractional exchanges of dissolved ions and water molecules, we studied equilibrium partitioning of both components between laterally extended apolar confinements and surrounding electrolyte solution. Accurate calculations of the Hamiltonian and tensorial pressure components at anisotropic conditions in the pore required the development of a novel algorithm for a self-consistent correction of nonelectrostatic cut-off effects. At pore widths above the kinetic threshold to capillary evaporation, the molality of the salt inside the confinement grows in parallel with that of the bulk phase, but presents a nonuniform width-dependence, being depleted at some and elevated at other separations. The presence of the salt enhances the layered structure in the slit and lengthens the range of inter wall pressure exerted by the metastable liquid. Solvation pressure becomes increasingly repulsive with growing salt molality in the surrounding bath. Depending on the sign of the excess molality in the pore, the wetting free energy of pore walls is either increased or decreased by the presence of the salt. Because of simultaneous rise in the solution surface tension, which increases the free-energy cost of vapor nucleation, the rise in the apparent hydrophobicity of the walls has not been shown to enhance the volatility of the metastable liquid in the pores. PMID- 25833602 TI - Structure and dynamics of POPC bilayers in water solutions of room temperature ionic liquids. AB - Molecular dynamics simulations in the NPT ensemble have been carried out to investigate the effect of two room temperature ionic liquids (RTILs), on stacks of phospholipid bilayers in water. We consider RTIL compounds consisting of chloride ([bmim][Cl]) and hexafluorophosphate ([bmim][PF6]) salts of the 1-buthyl 3-methylimidazolium ([bmim](+)) cation, while the phospholipid bilayer is made of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Our investigations focus on structural and dynamical properties of phospholipid and water molecules that could be probed by inelastic and quasi-elastic neutron scattering measurements. The results confirm the fast incorporation of [bmim](+) into the lipid phase already observed in previous simulations, driven by the Coulomb attraction of the cation for the most electronegative oxygens in the POPC head group and by sizeable dispersion forces binding the neutral hydrocarbon tails of [bmim](+) and of POPC. The [bmim](+) absorption into the bilayer favours the penetration of water into POPC, causes a slight but systematic thinning of the bilayer, and further stabilises hydrogen bonds at the lipid/water interface that already in pure samples (no RTIL) display a lifetime much longer than in bulk water. On the other hand, the effect of RTILs on the diffusion constant of POPC (DPOPC) does not reveal a clearly identifiable trend, since DPOPC increases upon addition of [bmim][Cl] and decreases in the [bmim][PF6] case. Moreover, because of screening, the electrostatic signature of each bilayer is only moderately affected by the addition of RTIL ions in solution. The analysis of long wavelength fluctuations of the bilayers shows that RTIL sorption causes a general decrease of the lipid/water interfacial tension and bending rigidity, pointing to the destabilizing effect of RTILs on lipid bilayers. PMID- 25833603 TI - Effects of the internal friction and the solvent quality on the dynamics of a polymer chain closure. AB - Using 3D Langevin dynamics simulations, we investigate the effects of the internal friction and the solvent quality on the dynamics of a polymer chain closure. We show that the chain closure in good solvents is a purely diffusive process. By extrapolation to zero solvent viscosity, we find that the internal friction of a chain plays a non-ignorable role in the dynamics of the chain closure. When the solvent quality changes from good to poor, the mean closure time tauc decreases by about 1 order of magnitude for the chain length 20 <= N <= 100. Furthermore, tauc has a minimum as a function of the solvent quality. With increasing the chain length N, the minimum of tauc occurs at a better solvent. Finally, the single exponential distributions of the closure time in poor solvents suggest that the negative excluded volume of segments does not alter the nearly Poisson statistical characteristics of the process of the chain closure. PMID- 25833604 TI - Small membranes under negative surface tension. AB - We use computer simulations and a simple free energy model to study the response of a bilayer membrane to the application of a negative (compressive) mechanical tension. Such a tension destabilizes the long wavelength undulation modes of giant vesicles, but it can be sustained when small membranes and vesicles are considered. Our negative tension simulation results reveal two regimes-(i) a weak negative tension regime characterized by stretching-dominated elasticity and (ii) a strong negative tension regime featuring bending-dominated elastic behavior. This resembles the findings of the classic Evans and Rawicz micropipette aspiration experiment in giant unilamellar vesicles (GUVs) [E. Evans and W. Rawicz, Phys, Rev. Lett. 64, 2094 (1990)]. However, in GUVs the crossover between the two elasticity regimes occurs at a small positive surface tension, while in smaller membranes it takes place at a moderate negative tension. Another interesting observation concerning the response of a small membrane to negative surface tension is related to the relationship between the mechanical and fluctuation tensions, which are equal to each other for non-negative values. When the tension decreases to negative values, the fluctuation tension gamma drops somewhat faster than the mechanical tension tau in the small negative tension regime, before it saturates (and becomes larger than tau) for large negative tensions. The bending modulus exhibits an "opposite" trend. It remains almost unchanged in the stretching-dominated elastic regime, and decreases in the bending-dominated regime. Both the amplitudes of the thermal height undulations and the projected area variations diverge at the onset of mechanical instability. PMID- 25833605 TI - Regulating block copolymer phases via selective homopolymers. AB - The phase behavior of strongly segregated AB diblock copolymer and selective C homopolymer blends is examined theoretically using a combination of strong stretching theory (SST) and self-consistent field theory (SCFT). The C homopolymer is immiscible with the B-blocks but strongly attractive with the A blocks. The effect of homopolymer content on the order-order phase transitions is analyzed. It is observed that, for AB diblock copolymers with majority A-blocks, the addition of the C-homopolymers results in lamellar to cylindrical to spherical phase transitions because of the A/C complexation. For diblock copolymers with minor A-blocks, adding C-homopolymers leads to transitions from spherical or cylindrical morphology with A-rich core to lamellae to inverted cylindrical and spherical morphologies with B-rich core. The results from analytical SST and numerical SCFT are in good agreement within most regions of the phase diagram. But the deviation becomes more obvious when the composition of A-blocks is too small and the content of added C-homopolymers is large enough, where the SCFT predicts a narrow co-existence region between different ordered phases. Furthermore, it is found that the phase behavior of the system is insensitive to the molecular weight of C-homopolymer. PMID- 25833606 TI - Excluded volume effects in compressed polymer brushes: A density functional theory. AB - A classical density functional theory (DFT) is applied to investigate the behavior of compressed polymer brushes composed of hard-sphere chains. The excluded volume interactions among the chain segments are explicitly treated. Two compression systems are used to study the behavior of brush-wall and brush-brush interactions. For the brush-brush systems, an obvious interpenetration zone has been observed. The extent of the interpenetration depends strongly on the grafting density. Furthermore, the repulsive force between the brush and wall or between the two brushes has been obtained as a function of the compression distance. Compared to the prediction of the analytic self-consistent field theory, such force increases more rapidly in the brush-wall compression with high polymer grafting densities or at higher compressions. In the brush-brush compression system, the interpenetration between the two compressed brushes creates a "softer" interaction. The influence of hard-sphere solvents on the behavior of compressed brushes is also discussed. PMID- 25833607 TI - How does a flexible chain of active particles swell? AB - We study the swelling of a flexible linear chain composed of active particles by analytical theory and computer simulation. Three different situations are considered: a free chain, a chain confined to an external harmonic trap, and a chain dragged at one end. First, we consider an ideal chain with harmonic springs and no excluded volume between the monomers. The Rouse model of polymers is generalized to the case of self-propelled monomers and solved analytically. The swelling, as characterized by the spatial extension of the chain, scales with the monomer number defining a Flory exponent nu which is nu = 1/2, 0, 1 in the three different situations. As a result, we find that activity does not change the Flory exponent but affects the prefactor of the scaling law. This can be quantitatively understood by mapping the system onto an equilibrium chain with a higher effective temperature such that the chain swells under an increase of the self-propulsion strength. We then use computer simulations to study the effect of self-avoidance on active polymer swelling. In the three different situations, the Flory exponent is now nu = 3/4, 1/4, 1 and again unchanged under self-propulsion. However, the chain extension behaves non-monotonic in the self-propulsion strength. PMID- 25833608 TI - DNA-binding protein searches for its target: Non-monotonic dependence of the search time on the density of roadblocks bound on the DNA chain. AB - The search of DNA-binding proteins for their target sites positioned on DNA plays a very important role in many cellular processes, and this search process combines 3D excursions in the bulk solution with one-dimensional sliding along the DNA chain. In living cells, there exist roadblocks along DNA chain formed by other proteins; however, the role of the roadblock in search rate is poorly understood. Based on 3D Langevin dynamics simulations, we have investigated the effect of the blocker on the search dynamics. For a pair of symmetrically placed blockers with respect to the target, we find that, with increasing the distance between the blocker and the target, the search time, tau, rapidly decreases and then saturates. For randomly placed blockers with density phi, tau may initially increase to its maximum and then unexpectedly decreases with increasing phi, or always increase with phi, depending on the nonspecific interaction strength and the volume fraction of DNA in the system. The previous contradicted results on the role of the blocker in search time are reconciled by these findings. Particularly, the nonmonotonic behavior of tau with phi indicates that blockers may facilitate the search after a critical phi. PMID- 25833609 TI - Dependence of FRET efficiency on distance in single donor-acceptor pairs. AB - Possibility to create single donor-acceptor (D-A) pairs by attaching dye molecules to various sites of DNA strands with control of the inter-dye distance R enables one to measure average Forster resonance energy transfer (FRET) efficiency E as a function of R. Triplet states of the dyes influence the dependence E(R) considerably. Two types of FRET efficiency are considered: E = EA and E = ED. The efficiency EA(R) = JA(R)/[JA(R) + JD(R)] depends on the donor and the acceptor average intensities JD(R) and JA(R) measured in D- and A fluorescence, whereas the efficiency ED(R) = 1 - JD(R)/JD(infinity) depends only on the intensity of D-fluorescence, so-called the donor quenching method. The shape of the functions ED (R) and EA (R) depends strongly on whether the dyes have blinking fluorescence. FRET efficiencies ED (R) and EA (R) undergo the influence of many experimental factors and therefore, differ considerably from pure FRET efficiencies ED (s) (R) and EA (s) (R). Pure FRET efficiencies ED,A (s) (R) are calculated with the help of rate equations for D-A pairs, whose molecules have triplet states. It is shown how the calculated efficiencies ED,A (s) (R) can be compared to FRET efficiencies measured with the help of the intensities ID,A(R) corrected by cross talk and background light. PMID- 25833610 TI - Flexibility of short DNA helices with finite-length effect: From base pairs to tens of base pairs. AB - Flexibility of short DNA helices is important for the biological functions such as nucleosome formation and DNA-protein recognition. Recent experiments suggest that short DNAs of tens of base pairs (bps) may have apparently higher flexibility than those of kilo bps, while there is still the debate on such high flexibility. In the present work, we have studied the flexibility of short DNAs with finite-length of 5-50 bps by the all-atomistic molecular dynamics simulations and Monte Carlo simulations with the worm-like chain model. Our microscopic analyses reveal that short DNAs have apparently high flexibility which is attributed to the significantly strong bending and stretching flexibilities of ~6 bps at each helix end. Correspondingly, the apparent persistence length lp of short DNAs increases gradually from ~29 nm to ~45 nm as DNA length increases from 10 to 50 bps, in accordance with the available experimental data. Our further analyses show that the short DNAs with excluding ~6 bps at each helix end have the similar flexibility with those of kilo bps and can be described by the worm-like chain model with lp ~ 50 nm. PMID- 25833611 TI - Isotope-enriched protein standards for computational amide I spectroscopy. AB - We present a systematic isotope labeling study of the protein G mutant NuG2b as a step toward the production of reliable, structurally stable, experimental standards for amide I infrared spectroscopic simulations. By introducing isotope enriched amino acids into a minimal growth medium during bacterial expression, we induce uniform labeling of the amide bonds following specific amino acids, avoiding the need for chemical peptide synthesis. We use experimental data to test several common amide I frequency maps and explore the influence of various factors on map performance. Comparison of the predicted absorption frequencies for the four maps tested with empirical assignments to our experimental spectra yields a root-mean-square error of 6-12 cm(-1), with outliers of at least 12 cm( 1) in all models. This means that the predictions may be useful for predicting general trends such as changes in hydrogen bonding configuration; however, for finer structural constraints or absolute frequency assignments, the models are unreliable. The results indicate the need for careful testing of existing literature maps and shed light on possible next steps for the development of quantitative spectral maps. PMID- 25833612 TI - Increasing the sampling efficiency of protein conformational transition using velocity-scaling optimized hybrid explicit/implicit solvent REMD simulation. AB - The application of temperature replica exchange molecular dynamics (REMD) simulation on protein motion is limited by its huge requirement of computational resource, particularly when explicit solvent model is implemented. In the previous study, we developed a velocity-scaling optimized hybrid explicit/implicit solvent REMD method with the hope to reduce the temperature (replica) number on the premise of maintaining high sampling efficiency. In this study, we utilized this method to characterize and energetically identify the conformational transition pathway of a protein model, the N-terminal domain of calmodulin. In comparison to the standard explicit solvent REMD simulation, the hybrid REMD is much less computationally expensive but, meanwhile, gives accurate evaluation of the structural and thermodynamic properties of the conformational transition which are in well agreement with the standard REMD simulation. Therefore, the hybrid REMD could highly increase the computational efficiency and thus expand the application of REMD simulation to larger-size protein systems. PMID- 25833613 TI - Publisher's Note: "Unusual behavior in magnesium-copper cluster matter produced by helium droplet mediated deposition" [J. Chem. Phys. 142, 084307 (2015)]. PMID- 25833614 TI - Publisher's Note: "The total position-spread tensor: Spin partition" [J. Chem. Phys. 142, 094113 (2015)]. PMID- 25833615 TI - Erratum: "Electron impact excitation of the low-lying 3s[3/2]1 and 3s'[1/2]1 levels in neon for incident energies between 20 and 300 eV" [J. Chem. Phys. 139, 184301 (2013)]. PMID- 25833616 TI - Erratum: "The PtAl(-) and PtAl2 (-) anions: Theoretical and photoelectron spectroscopic characterization" [J. Chem. Phys. 140, 164316 (2014)]. PMID- 25833617 TI - Erratum: "Electronic couplings for molecular charge transfer: Benchmarking CDFT, FODFT, and FODFTB against high-level ab initio calculations" [J. Chem. Phys. 140, 104105 (2014)]. PMID- 25833618 TI - The cultural heritage of tattooing: a brief history. AB - For millennia, peoples around the world have tattooed human skin to communicate various ontological, psychosocial, and sociocultural concepts encompassing beauty, cultural identity, status and position, medicine, and supernatural protection. As a system of knowledge transmission, tattooing has been and continues to be a visual language of the skin whereby culture is inscribed, experienced, and preserved in a myriad of specific ways. If we are to fully comprehend the meanings that tattoos have carried across human history and into the present, then it would be useful to explore some of the ways tattoos, as instruments that transmit culture, have been deployed cross-culturally through time. PMID- 25833620 TI - Tattoo machines, needles and utilities. AB - Starting out as a professional tattooist back in 1977 in Copenhagen, Denmark, Frank Rosenkilde has personally experienced the remarkable development of tattoo machines, needles and utilities: all the way from home-made equipment to industrial products of substantially improved quality. Machines can be constructed like the traditional dual-coil and single-coil machines or can be e coil, rotary and hybrid machines, with the more convenient and precise rotary machines being the recent trend. This development has resulted in disposable needles and utilities. Newer machines are more easily kept clean and protected with foil to prevent crosscontaminations and infections. The machines and the tattooists' knowledge and awareness about prevention of infection have developed hand-in-hand. For decades, Frank Rosenkilde has been collecting tattoo machines. Part of his collection is presented here, supplemented by his personal notes. PMID- 25833619 TI - Epidemiology of tattoos in industrialized countries. AB - In 1974, the first professional French tattooist C. Bruno wrote a book, entitled 'Tatoues, qui etes-vous?', depicting his experience as a tattooist in the picturesque Pigalle tourist district of Paris. However, we have come a long way since then. Tattooing has gained tremendous visibility, notoriety and popularity in Western countries. In Germany, 8.5% of the population (aged between 14 and 90 years) has a tattoo. Similar trends have been found in France, Finland and Australia, where approximately 10% of the populations have at least one tattoo. However, the overall tattoo prevalences overseas and in Europe are even higher, especially among the youth, for whom it is up to 15-25% according to the country. Much has been written about the tattooed and tattooists. However, who are they currently? What motivates them to get tattooed and give tattoos? How do they see themselves? Why do some individuals remove their tattoos? Is there a 'profile' of the tattooed? Are they really 'risk takers'? And how do the nontattooed perceive them? Through a critical review of the literature, we will reconsider tattooing from an epidemiological aspect, challenge current beliefs and explore new insights into the motivations and fears of tattoo artists and their clients. PMID- 25833621 TI - The technique and craftsmanship of tattooing in the professional tattoo parlour. AB - This chapter will briefly explain the tools and techniques behind a good tattoo. Beside the fact that the professional tattoo artist needs to have talent for composing and drawing motives - the artistic part of his or her profession - the technical side of the process must also be mastered to make great tattoos. The craftsmanship behind the art. PMID- 25833622 TI - Tattoo as art, the drivers behind the fascination and the decision to become tattooed. AB - For many people, getting a tattoo is like purchasing art, and many professional and famous tattooists are artists who are acknowledged by colleagues and authorities. The history of tattooing goes back for thousands of years, and the reasons for getting tattooed are many. These permanent markings are always personal, they can be plain or elaborate, and they serve as amulets, healing and status symbols, declarations of love, signs of religion, adornments and even forms of punishment. Drivers behind the fascination of acquiring a tattoo may fall into four main groups, namely healing, affiliation, art and fashion. PMID- 25833623 TI - Personal records from my tattoo parlour: deep emotions drawn as life-long pictures on the skin's canvas. AB - The author, who has been a professional tattooist for years, reports four individuals whose tragic life events led to decisions to be tattooed with illustrations of their life stories. The authors' personal experiences with tattooist-client interactions and clients' expectations and demands are reviewed. During the last decade, tattooing has moved in the direction of becoming more individualized and is often very personal. The working process and the intimacy between the client and tattooist create a comfort zone of trust and loyalty. PMID- 25833624 TI - Tattooist-customer relationships in a diversified environment of professional tattooists and 'scratchers'. AB - The world of tattooing and body art has never been like it is today. This chapter seeks to investigate this situation through the lens of tattooing. One of the areas in which tattooing has changed is the relationship between the tattoo artist and his or her clients. Whereas being a tattoo artist used to be impersonal and very much just a job like any other, it has transformed tremendously today. The cause of this and, even more so, what exactly has changed are what this chapter will seek to shed light on. First of all, the format of the shops and how the art is done have changed, which allows for much greater flexibility from the perspective of the artist. Second, from the perspective of the client/customer, a transformation has also occurred, in some part thanks to developments such as the internet and other social/communication media, which give the client much more room and opportunity to discover and research tattoos. However, most importantly, this chapter seeks to map out a change in discourse when it comes to the relationship between the client and the tattoo artist and to explain how it has changed into a relationship based on mutual and reciprocated communication as well as focussed on making a product/piece of art that both can be satisfied with. PMID- 25833625 TI - Tattoo complaints and complications: diagnosis and clinical spectrum. AB - Tattoos cause a broad range of clinical problems. Mild complaints, especially sensitivity to sun, are very common and seen in 1/5 of cases. Medical complications are dominated by allergy to tattoo pigment haptens or haptens generated in the skin, especially in red tattoos but also in blue and green tattoos. Symptoms are major and can be compared to cumbersome pruritic skin diseases. Tattoo allergies and local reactions show distinct clinical manifestations, with plaque-like, excessive hyperkeratotic, ulcero-necrotic, lymphopathic, neuro-sensory, and scar patterns. Reactions in black tattoos are papulo-nodular and non-allergic and associated with the agglomeration of nanoparticulate carbon black. Tattoo complications include effects on general health conditions and complications in the psycho-social sphere. Tattoo infections with bacteria, especially staphylococci, which may be resistant to multiple antibiotics, may be prominent and may progress into life-threatening sepsis. Contaminated tattoo ink is an open-window risk vector that can lead to epidemic tattoo infections across national borders due to contaminated bulk production. Hepatitis B and C and human immunodeficiency virus (HIV) transferred by tattooing remain a significant risk needing active prevention. It is noteworthy that cancer arising in tattoos, in regional lymph nodes, and in other organs due to tattoo pigments and ingredients has not been detected or noted as a significant clinical problem hitherto, despite millions of people being tattooed for decennia. Clinical observation and epidemiology disagree with register data, which indicate an increased risk of cancer due to chemical carcinogens present in some inks. Registers rely on chronic dosaging of cell lines and animals. However, tattooing in humans is essentially a single-dose exposure, which might explain the observed discrepancy. PMID- 25833626 TI - Complications of cosmetic tattoos. AB - Cosmetic tattoos, which are better known as permanent make-up, have become popular in the last decades. This same procedure can be used to camouflage pathological skin conditions, to mask scars and to complete the aesthetic results of plastic and reconstructive surgeries. The risks and complications of tattooing procedures include infections and allergic reactions. Scarring can occur. Fanning and fading of the colorants and dissatisfaction with colour and shape are not unusual. Different lasers can offer solutions for the removal of unwanted cosmetic tattoos, but complications due to the laser treatment, such as paradoxical darkening and scarring, can arise. PMID- 25833627 TI - Chronic tattoo reactions cause reduced quality of life equaling cumbersome skin diseases. AB - Tattoos are often associated with mild complaints, but some people develop complications that may require medical treatment, and the burden of these events has hitherto been neglected. To understand the dimensions and the psychological symptomatology of adverse events both the sensory and affective impacts, including the effect on quality of life, should be studied. Itch severity and influence on quality of life can be measured objectively. The Itch Severity Scale and Dermatology Life Quality Index scoring systems have been applied to different dermatological diseases. When ISS and DLQI scores were applied to patients with chronic tattoo reactions, tattoo complaints and impact on quality of life that were comparable to patients presenting cumbersome dermatological disease such as psoriasis, eczema and pruritus, which often show widespread effects to the skin, were uncovered. In conclusion, chronic tattoo reactions should be ranked as a cumbersome dermatological disease and, accordingly, given priority attention and qualified treatment by the public health care system. PMID- 25833628 TI - Contraindications for tattooing. AB - Tattooing is getting increasingly popular among the young. However, not everyone is suited to getting tattooed. Indeed, it is not rare for patients with a chronic skin disease or another systemic condition to be eager to get a tattoo. They perceive tattooing as a harmless, risk-free procedure. Therefore, some patients may not seek medical advice before the procedure. Some also fear a judgmental approach by their physician, who may try to discourage them. Lastly, the tattooist does not have either the training or the education to properly advise a customer about his/her condition. Therefore, it is important that any physician be able to provide adequate counselling regarding the possibility of getting tattooed and under which conditions. Even though an exhaustive list is impossible to address, the main issues include chronic skin disorders, pigmented lesions of the skin, (congenital) heart disease, immunosuppressive diseases and treatments, blood clotting disorders, and pregnancy/breastfeeding. PMID- 25833629 TI - Laser tattoo removal, precautions, and unwanted effects. AB - Laser tattoo removal uses the physical properties of photoselective thermolysis in order to remove tattoo pigment. The technique has gradually improved over the years with the development of Q-switched lasers, with overall good results and a relatively low degree of adverse effects. However, lasers cannot always erase the unwanted tattoo completely, and there are still risks of unwanted effects such as scarring, pigment changes, ink darkening, and potential aggravation of latent skin conditions. This chapter will discuss the precautions that have to be taken and what pitfalls to avoid before starting the procedure of laser tattoo removal. PMID- 25833630 TI - Nano-scale observations of tattoo pigments in skin by atomic force microscopy. AB - In this study, we have shown how particles in carbon black tattoo ink accumulate in the human skin dermis using fine-resolution atomic force microscopy, with which a single ink particle in the collagenous network can be imaged. This information further demonstrates that tattoo inks are nano-particles. Further, we have deposited a commercially available tattoo ink on a glass slide and calculated a range of volumes for single ink particles. PMID- 25833631 TI - Manufacturing of tattoo ink products today and in future: Europe. AB - The article describes the European market situation and the legal framework in Europe. It shows the state-of-the-art production under ISO 9001:2008 quality management and describes the future of tattoo ink production based on good manufacturing practice guidelines for tattoo inks. PMID- 25833632 TI - The realistic variables underlying true safety in tattoo pigment manufacturing. AB - The regulation of the manufacture of tattoo ink products in the USA and the rest of the world is the focus of this article, which outlines the historical relationships between official and unofficial manufacturing and associated regulations, self-regulating movements within the industry and the impacts of over-regulation on the economics of ink manufacturing markets. The author, Mario Barth, highlights that changes in industry standards of production that are too rapid can cause the system to deteriorate, leading to an essentially negative shift to the underground markets. In addition, these regulations would not lead to a healthier end product because the currently considered health problems associated with tattoos (affecting 6% of tattoos performed in Germany) could be caused by multiple additional factors, such as the tattooing technique and aftercare. The pigment itself (which causes health issues in only 0.6% of tattoos) could in this equation not be optimized within an overregulated market. Further, aspects of price and revenue are analyzed in detail, showing that high quality suppliers are spending most of their efforts on passing regulations and that these regulations are not decreasing the amount of low-quality products in the general market. Finally, the notion of tattooing as 'an adult decision' is explained as another variable that has to be considered in creating regulations because the decision-making process for a tattoo (considering the price, quality and definitely the permanency) has and will have a self-regulating impact driven by the clients. PMID- 25833633 TI - Making innovative tattoo ink products with improved safety: possible and impossible ingredients in practical usage. AB - Today's tattoo inks are no longer just simple solids in liquid suspension. Nowadays, these inks are high-tech dispersions made from finely spread pigments in a binder-solvent mixture. These so-called colour dispersions must follow the modern standards of tattooing, which are increasing every year. They must be rich in chromophoric pigments and yet fluid, they must not dry rapidly, and there should be no occurrence of any sedimentation, even during longer tattoo seasons. An innovative tattoo ink should enable long-lasting, brilliant tattoos without a negative impact on the artist's workflow and of course without endangering the consumer. The high standard in tattoos, regarding the motives and techniques, that is witnessed today could not be achieved by the artists without quality tools and modern tattoo ink. This article will give the reader a brief overview of the different ingredients of tattoo ink and of the function of binding agents and solvents in modern tattoo ink as well as describe what additives are used to achieve the desired behaviour during application. Furthermore, the article will take a look into the pigments that are used in tattoo ink and show why certain pigments are not suited for tattoo ink. The differences, advantages and disadvantages of organic and inorganic pigments will be explained. PMID- 25833634 TI - Tailored surface engineering of pigments by layer-by-layer coating. AB - We have evaluated the feasibility of layer-by-layer encapsulation technology for the improvement of dye pigments used for tattoos or permanent make-up. The formation of core-shell structures is possible by coating pigments with thin films of several different polyelectrolytes using this technology. The physicochemical surface properties, such as charge density and chemical functionality, can be reproducibly varied in a wide range. Tailoring the surface properties independently from the pigment core allows one to control the rheological behaviour of pigment suspensions, to prevent aggregation between different pigments, to reduce the cytotoxicity, and to influence the response of phagocytes in order to have similar or the same uptake and bioclearance for all pigments. These properties determine the durability and colour tone stability of tattoos and permanent make-up. PMID- 25833635 TI - Chemical purity and toxicology of pigments used in tattoo inks. AB - The safety of tattoo inks has obviously increased in Europe since the existence of European Union Resolution ResAP(2008)1, which resulted in the improved quality control of pigment raw materials due to the definition of impurity limits that manufacturers can refer to. High-performance pigments are mostly used in tattoo inks, and these pigments are supposed to be chemically inert and offer high light fastness and low migration in solvents. However, these pigments were not developed or produced for applications involving long-term stay in the dermis or contact with bodily fluids. Therefore, these pigments often do not comply with the purity limits of the resolution; however, it is required that every distributed tattoo ink does not contain aromatic amines and not exceed the limits of heavy metals or polycyclic aromatic hydrocarbons. Current toxicity studies of pigments underline that no ecotoxicological threat to human health or to the environment should be expected. However, the pigment as well as its impurities and coating materials must be considered. In order to evaluate the safety of pigments according to their impurities, two different validated sample preparation methods are necessary: (1) simulation of their long-term stay in the bodily fluid of the dermis and (2) simulation of cleavage due to laser removal or ultraviolet exposure. The development of standardized, validated and well-adapted methods for this application has to be part of prospective efforts. Concerning legislation, it might be appropriate that the first regulative approaches be based on those of cosmetics. PMID- 25833636 TI - Survey on European studies of the chemical characterisation of tattoo ink products and the measurement of potentially harmful ingredients. AB - The results of the detection of carcinogenic aromatic amines in about 300 ink samples are discussed. All analysed inks contained at least one or more azo compound pigments, and the presence of aromatic amines could only have originated from these compounds through a chemical process named 'reductive cleavage'. Sometimes, aromatic amines were also present as impurities derived from the processing of the pigments. A systematic surveillance programme in Italy, promoted by the Italian Ministry of Health with the involvement of Italian regions, local public health authorities and Agenzia Regionale per la Protezione Ambiente del Piemonte (Environmental Protection Agency), has shown that about 40% of the monitored inks are not regular according to European Resolution ResAP(2008):1. The method utilised for the detection of aromatic amines has allowed the identification of other substances that are not carcinogenic but are toxic or have sensitisation properties that are derived from reductive cleavage or that are present as impurities. PMID- 25833637 TI - Tattoo inks: legislation, pigments, metals and chemical analysis. AB - Legal limits for chemical substances require that they are linked to clearly defined analytical methods. Present limits for certain chemicals in tattoo and permanent make-up inks do not mention analytical methods for the detection of metals, polycyclic aromatic hydrocarbons or forbidden colourants. There is, therefore, no established method for the determination of the quantities of these chemicals in tattoo and permanent make-up inks. Failing to provide an appropriate method may lead to unqualified and questionable results which often cause legal disputes that are ultimately resolved by a judge with regard to the method that should have been applied. Analytical methods are tuned to exactly what is to be found and what causes the health problems. They are extremely specific. Irrespective of which is the correct method for detecting metals in tattoo inks, the focus should be on the actual amounts of ink in the skin. CTL(r) has conducted experiments to determine these amounts and these experiments are crucial for toxicological evaluations and for setting legal limits. When setting legal limits, it is essential to also incorporate factors such as daily consumption, total uptake and frequency of use. A tattoo lasts for several decades; therefore, the limits that have been established for heavy metals used in drinking water or soap are not relevant. Drinking water is consumed on a daily basis and soap is used several times per week, while tattooing only occurs once. PMID- 25833638 TI - The challenges and limitations of chemical analysis of particulate pigments of very low solubility. AB - When performing a chemical analysis of colorants in tattoo products, specific degradation products as well as impurity patterns can be predicted. Mislabeling or false declarations can also be avoided using this test. It is notable that pigment identification in tattoo products may serve as a precursory technique to recognize the colorants contained in a patient's tattoo prior to laser removal therapy. In contrast to the analysis of banned pigments, positive identification of pigments will normally require few reference substances. Given the fact that tattoo pigments are nearly insoluble in water and many organic solvents, different chemical pigment analyses are outlined and evaluated. Related publications from the study of art are also mentioned. It is recommended that access to comprehensive pigment standards and spectroscopic databanks should be offered to laboratories dealing with tattoo product analysis in the future. PMID- 25833639 TI - Photostability and breakdown products of pigments currently used in tattoo inks. AB - Tattoos fade with time. Part of this fading can be attributed to the photodegradation of pigments. When people get tired of their tattoos, removal by laser irradiation is the method of choice. In vivo laser irradiation of tattoos on mice has shown that the degradation of pigments can result in toxic compounds. Various in vitro studies on photodegradation by sunlight or laser have shown similar degradation products for both irradiations. Even visible light was shown to be able to decompose some pigments to toxic degradation products in vitro. Whereas the investigated phthalocyanins (C.I. 74160, 74260), quinacridones (C.I. 73915) or dioxazines (C.I. 51319) were fairly photostable in vitro, all azo pigments exposed to sunlight or laser were degraded into a variety of products, some of which were toxic or even carcinogenic, such as 2-amino-4-nitrotoluene, 3,3'-dichlorobenzidine and o-toluidine. Up to now, the absence of specific toxicological data is the reason why legal restrictions for tattoo inks are derived from those for cosmetics, toys and textiles. Photodegradation has not been considered. In light of the present analytical findings, even with their possible shortcomings, the evidence weighs heavily enough to consider banning azo pigments containing carcinogenic aromatic amines or allergens in their structure from use in tattoo inks. PMID- 25833640 TI - Carbon black nanoparticles and other problematic constituents of black ink and their potential to harm tattooed humans. AB - Black is the most common tattoo color, but only a few studies have shed light on the multitude of functional and contaminating chemicals present in black inks. These studies have generally shown that black inks are a diverse group, containing anything from 5 to 50+ organic components. Little is known about the possible effects on humans of internalizing these chemicals. Analysis has shown that the production of the main component, carbon black, can lead to the formation of pigments with polycyclic aromatic hydrocarbon (PAH) contents that range from very high to almost completely absent. Similar variations in PAH concentrations are observed in black inks. PAHs are known carcinogens and thus, low recommended levels have been suggested by the Council of Europe. Reactive oxygen species (ROS) have recently been a topic in scientific literature related to tattoo ink. Again, it has been shown that some inks produce deleterious ROS (e.g. singlet oxygen or peroxyl radicals), presumably via either adhered organic compounds or particle surface defects. It has been shown that black tattoo inks may contain a multitude of chemicals, including carcinogens and allergens, and some have unknown toxicologies. However, it has additionally been demonstrated that some black inks already on the market do not produce ROS and also contain PAHs at levels that are below those recommended by the Council of Europe and very few additional contaminants. PMID- 25833641 TI - Absorption, distribution, metabolism and excretion of tattoo colorants and ingredients in mouse and man: the known and the unknown. AB - During tattooing, high amounts of tattoo colorants, which usually contain various substances, are injected into skin. The major ingredient in tattoo colorants is the coloring component, which can be assigned to two different groups. First, amorphous carbon particles (Carbon Black) are found almost exclusively in black tattoos. Second, tattooists use azo and polycyclic pigments to create nearly all colors of the visible spectrum. Due to their different chemistries, those tattoo colorants usually contain various compounds, such as by-products and impurities. Professional tattooists inject the colorant mixture into skin using the solid needles of tattoo machines, and studies have shown that about 2.5 mg of tattoo pigment is injected to stain about 1 cm(2) of skin. Animal experiments revealed that about one-third of that amount disappeared from skin within weeks after tattooing, and this finding was confirmed by pigment extraction from long existing tattoos. It is assumed that some of the tattoo colorants stay in the skin because the pigment particles are insoluble and too large to be transported. The other part of the tattoo colorants shows up at least in the lymph nodes located next to the tattoo. To date, no investigations determining whether and to what extent tattoo colorants can be found in any other organs of the human body have been performed. Thus, tattooing of colorants into skin entails a complex reaction of the skin that triggers the immune system and launches manifold transport processes, which might pose additional health risks not only to skin but also to other organs of humans. PMID- 25833642 TI - Towards the limiting of health risks associated with tattooing: whitelists for tattoo pigments and preservatives. AB - The number of pigments that could potentially be used in tattoo inks is vast. However, pigments are generally not manufactured for the purpose of being injected into subepidermal layers of the skin. Assuming 100% bioavailability after injection means that pigments can be imminently hazardous to human health. Given the ever-increasing number of pigments being circulated on the market or through the internet, a 'negative list' ('black' list) containing pigments with known adverse effects will never be finalised. If incriminated, substances could easily be replaced by structurally similar pigments that might be even more deleterious to human health. Therefore, we and others suggest the establishment of a whitelist ('positive list') that would only contain pigments that had undergone a risk assessment specifically for their application into the dermis. Some of the problems associated with such a 'positive list' are discussed. Another important issue with regard to tattoo safety is related to the preservatives used in ink preparations. Notwithstanding the demand for sterile tattoo inks, a whitelist for these compounds would be beneficial. At present, many technical preservatives are being used, despite their known detrimental effects to human health. Criteria for the inclusion of preservatives in a 'positive list' are also discussed. PMID- 25833643 TI - Survey of studies on microbial contamination of marketed tattoo inks. AB - Tattooing became a popular phenomenon during the late twentieth century. Because the act of tattooing involves repeated injection of ink through the skin, a risk of contracting infections from contaminated tattooing equipment and ink and the surrounding environment exists. Progress has been made in infection control strategies; however, contraction of bacterial and viral infections from tattooing continues to occur. The risk of acquiring a tattoo-related infection largely depends on the hygiene conditions under which the tattoo is applied. Nevertheless, even when adequate hygiene and sanitation measures are taken, the inks themselves may contain infectious microorganisms that are able to survive under hostile conditions, such as in inks. The results of the few studies on the microbiological quality of unopened and opened tattoo inks are reported. Some authors' conclusions demonstrated that the current ink sterilisation systems show a low capability to inactivate microbial contamination in tattoo inks. At the moment, European Resolution ResAP2008-1 recommends that the ink be sterile and supplied in containers that maintain the sterility of the product until application. In light of the outcomes of published studies, at the moment, preservation of the microbial quality and safety of ink seems challenging and still difficult to reach. PMID- 25833644 TI - The European landscape of national regulations of tattoo inks and businesses. AB - A rising number of tattooed people in all parts of society and increasing concerns regarding potential health effects triggered the development of specific regulatory measures at the beginning of the 21st century. The first principles considering chemical safety and hygienic aspects were laid down by two resolutions of the Council of Europe, in 2003 and 2008. The applied principle of 'negative lists' of substances that should not be used in tattoo inks has subsequently been transferred to national regulations. However, surveillance data show that in particular, the chemical quality of tattoo inks is still insufficient. The reasons are, amongst others, the lack of analytical methods, the implementation of different thresholds, and the lack of awareness of distributors and producers when it comes to potential health hazards. PMID- 25833645 TI - Implementation of European Council resolution ResAP(2008)1 in Italy. National and regional regulation of tattoo practices: diversity and challenges. AB - In Italy, tattoos and permanent make-up have become increasingly popular in recent years. The number of tattoo parlours has increased from 257 in 2009 to 2,055 in 2014, wich is a eight-fold increase over the last 6 years. Although there is no specific legislation, the Italian Ministry of Health issued a document containing the 'Guidelines for the implementation of procedures for tattooing and piercing in safe conditions'. This document has not been adopted by all Italian regions, principally regarding training course requirements for tattoo professionals, creating a highly fragmented situation that resembles the European scene in miniature. ResAP(2008)1, which is not mandatory in Italy but was made binding by Italian Decree n. 206/2005, has been applied uniformly throughout the country. Thus, as far as the safety of inks is concerned, the surveillance system appears to be working well. However, surveillance has highlighted the presence of non-compliant inks and potentially unsafe preparations for tattoo removal in the market. Updating and rebalancing the situation will be the goal in order to face the challenge of combining well-being with the on-going social demand of looking after and beautifying the body. This would include the growing fashion of tattoos, provided that the products that are used are safe and that tattooing is performed in controlled hygienic conditions that fully guarantee the health of consumers. PMID- 25833646 TI - EU actions to ensure the safety of tattoos and the protection of consumers. AB - The number of tattooed persons has been continuously increasing in the last few years, particularly in the younger population. At the same time, the possibility of purchasing tattoo inks online is easier than ever worldwide. Consumers are not always sufficiently aware of the possible health problems associated with this 'cool fashion' if hygiene conditions are not respected and/or if the injected mixtures contain dangerous chemicals. Concerns about the possible health risks associated with such practices arise from the absence of a clear legislative framework, the lack of proper risk assessment of the chemicals used, and non harmonised or missing hygiene and purity requirements, among other factors. There is a general consensus among all active stakeholders that EU harmonised rules would help to ensure a consistent high level of protection of consumers across the EU. PMID- 25833647 TI - Surveillance of tattoo-related adverse events by the EU RAPEX system and by national monitoring. AB - A resolution of the Council of Europe in 2008 (ResAP (2008)1) helped to define requirements and criteria for the safety of tattoos and permanent make-up in order to increase the level of consumer health protection for these products. Tattoo product usage is not without risk. These products are injected into the skin and may represent a risk to human health due to possible microbiological contamination and/or contamination by the presence of hazardous substances in the products. ResAP (2008) laid the foundation for the safety of tattoo products in Europe. This has generated awareness by European Member States and has encouraged them to adapt this resolution in their own law or to use it as a model to define their own regulation on tattoos. In order, to communicate on the hazard associated with these products between Member States and the European Commission, the European RAPEX system was created; this system will be further explained in this article. Finally, some Member States have created a specific vigilance system related to the adverse effects of tattoos. In this respect, a European national example will be presented. PMID- 25833648 TI - The Amsterdam model for control of tattoo parlours and businesses. AB - In the early 1980s, an outbreak of hepatitis B in Amsterdam stood at the start of the development of the first hygiene guidelines for tattooists in The Netherlands. Ever since, infection control in tattoo practice has continued to prove its importance as tattoo-related outbreaks of infectious diseases have continued to be reported in Europe. Furthermore, the act of tattooing includes breaking the skin barrier but is performed by professionals who are not medically trained. The Ministry of Health has now implemented uniform regulations that apply to professionals who perform tattooing and apply permanent make-up. These regulations include hygiene guidelines that were developed by the National Institute for Public Health and the Environment in cooperation with representatives of the tattooing associations. The guidelines contain a list of requirements, including for the studio interior, the cleanness of the studio, the safe use of permitted equipment and products, sterilization methods, and the information provided to the customer. A permit may be granted after an inspection by the local health service, during which the act of tattooing has to be performed. It is now estimated that over 95% of all tattoos in The Netherlands were obtained at one of the almost 900 licensed studios. Reports of complications are generally low in number. We suggest that uniform European hygiene guidelines would further contribute to the safety of tattooing. PMID- 25833649 TI - Hygiene standards for tattooists. AB - The following excerpt is taken from the hygiene guidelines written by Deutsche Organisierte Tatowierer (DOT e.V. Germany; German Association of Professional Tattoo Artists) and United European Tattoo Artists e.V. (UETA). It has been published with the intention of creating a standard that is understandable and accomplishable in practice, focusing on a minimum standard level that guarantees the highest possible safety for tattooists and customers at the same time. The DOT and UETA consistently strive to participate in the research of tattoo hygiene and tattoo colours because important insider information can be provided by professional tattoo artists with many years of work experience. PMID- 25833650 TI - Hygiene standards in the tattoo parlour and practices for prevention of infection. AB - The tattoo studio and the procedures and operations of practicing tattooing may help to reduce the risk of infections associated with tattooing or, if improper, increase the risk. Thus, as a preventive measure, the tattoo studio should be optimized. All procedures should be carefully chosen to eliminate microbial contamination from the environment (from needles, machines, and other utilities) and also from persons. This chapter provides a detailed generic description of the organization of a safe tattoo procedure, i.e. guidance for professional tattooists on how to set up or reorganize their studio with the aim of the highest standard possible, which may satisfy customers' needs and make the procedure safe for the end consumer as well as the practitioner. These practices are necessary to meet upcoming official requirements in the future. PMID- 25833651 TI - Seamless prevention of adverse events from tattooing: integrated strategy emphasising the customer-tattooist interaction. AB - The boom in tattooing has been paralleled by more frequent adverse events, which may be localised in the skin or systemic and manifested clinically or latent. Infections, allergic reactions from red-coloured tattoos and papulo-nodular reactions from black tattoos dominate. Mild complaints are very common, with 1/5 of all tattooed individuals having acquired sensitivity to sunlight in the tattooed skin. The potential risk of cancer due to potential carcinogens in some tattoo inks has hitherto not manifested in clinical reports, despite the millions of people who have been tattooed over many decades. A risk of death from tattooing remains associated with severe infection, i.e. sepsis. Preventive strategies may rely on focused preventions, and sterility and preservation of ink is essential, rational and knowledge-based. The chemical and particle contents of ink nanoparticles cannot be unrestricted; however, focused control of ink is facing many uncertainties, including analytical problems, lack of identification of allergens in ink and discrepancies between the content of potential carcinogens and manifestation of cancer in the clinic. The concept of seamless prevention is introduced as a pragmatic strategy that emphasises the customer tattooist interaction, which is the 'engine' of tattoo safety. This strategy amalgamates the range of narrow-scope preventive instruments and shall ensure that any relevant instrument is used actively and without deficiency or drop out, thus resulting in a complete orchestration of a multi-targeted strategy. High priority elements of this strategy shall facilitate a qualified 'go' or 'no go' decision by the customer before the tattoo is made and should involve informed consent, qualification of the tattooist and the parlour, including supplies of inks etc., and attention to hygienic security. Records and documentation of tattoo cases with complications and the culprit inks as well as the establishment of national or European-based surveillance systems that are properly equipped to deliver efficient clarification and handling of adverse events and hazards of tattooing and inks, which needs attention and timely action to prevent additional cases and epidemic outbreaks, are part of this seamless strategy, along with optimised medical therapy and research. PMID- 25833652 TI - Regulation of tattoo ink production and the tattoo business in the US. AB - The production of tattoo ink and pigments in the US is unregulated. There are no guidelines or standards issued by national agencies. However, the practice of tattooing is regulated at the state and local levels but varies widely. Adverse events are addressed when a problem is reported. PMID- 25833653 TI - AST/ASTS workshop on increasing organ donation in the United States: creating an "arc of change" from removing disincentives to testing incentives. AB - The American Society of Transplantation (AST) and American Society of Transplant Surgeons (ASTS) convened a workshop on June 2-3, 2014, to explore increasing both living and deceased organ donation in the United States. Recent articles in the lay press on illegal organ sales and transplant tourism highlight the impact of the current black market in kidneys that accompanies the growing global organ shortage. We believe it important not to conflate the illegal market for organs, which we reject in the strongest possible terms, with the potential in the United States for concerted action to remove all remaining financial disincentives for donors and critically consider testing the impact and acceptability of incentives to increase organ availability in the United States. However, we do not support any trials of direct payments or valuable considerations to donors or families based on a process of market-assigned values of organs. This White Paper represents a summary by the authors of the deliberations of the Incentives Workshop Group and has been approved by both AST and ASTS Boards. PMID- 25833654 TI - Conducting an audit to improve the facilitation of emergency maternal and newborn referral in northern Ghana. AB - Ghana Health Service conducted an audit to strengthen the referral system for pregnant or recently pregnant women and newborns in northern Ghana. The audit took place in 16 facilities with two 3-month cycles of data collection in 2011. Midwife-led teams tracked 446 referred women until they received definitive treatment. Between the two audit cycles, teams identified and implemented interventions to address gaps in referral services. During this time period, we observed important increases in facilitating referral mechanisms, including a decrease in the dependence on taxis in favour of national or facility ambulances/vehicles; an increase in health workers escorting referrals to the appropriate receiving facility; greater use of referral slips and calling ahead to alert receiving facilities and higher feedback rates. As referral systems require attention from multiple levels of engagement, on the provider end we found that regional managers increasingly resolved staffing shortages; district management addressed the costliness and lack of transport and increased midwives' ability to communicate with pregnant women and drivers; and that facility staff increasingly adhered to guidelines and facilitating mechanisms. By conducting an audit of maternal and newborn referrals, the Ghana Health Service identified areas for improvement that service providers and management at multiple levels addressed, demonstrating a platform for problem solving that could be a model elsewhere. PMID- 25833655 TI - An Evaluation of Patient Safety Event Report Categories Using Unsupervised Topic Modeling. AB - OBJECTIVE: Patient safety event data repositories have the potential to dramatically improve safety if analyzed and leveraged appropriately. These safety event reports often consist of both structured data, such as general event type categories, and unstructured data, such as free text descriptions of the event. Analyzing these data, particularly the rich free text narratives, can be challenging, especially with tens of thousands of reports. To overcome the resource intensive manual review process of the free text descriptions, we demonstrate the effectiveness of using an unsupervised natural language processing approach. METHODS: An unsupervised natural language processing technique, called topic modeling, was applied to a large repository of patient safety event data to identify topics, or themes, from the free text descriptions of the data. Entropy measures were used to evaluate and compare these topics to the general event type categories that were originally assigned by the event reporter. RESULTS: Measures of entropy demonstrated that some topics generated from the unsupervised modeling approach aligned with the clinical general event type categories that were originally selected by the individual entering the report. Importantly, several new latent topics emerged that were not originally identified. The new topics provide additional insights into the patient safety event data that would not otherwise easily be detected. CONCLUSION: The topic modeling approach provides a method to identify topics or themes that may not be immediately apparent and has the potential to allow for automatic reclassification of events that are ambiguously classified by the event re- porter. PMID- 25833656 TI - Sandwiched Electrochemiluminescent Peptide Biosensor for the Detection of Prognostic Indicator in Early-Stage Cancer Based on Hollow, Magnetic, and Self Enhanced Nanosheets. AB - Currently, peptide-based protein-recognition has been recognized as an effective and promising approach for protein assays. However, sandwiched peptide-based biosensor with high sensitivity and low background has not been proposed before. Herein, a sandwiched electrochemiluminescence (ECL) peptide-based biosensor is constructed for Cyclin A(2) (CA2), a prognostic indicator in early stage of multiple cancers, based on nanosheets with hollow, magnetic, and ECL self enhanced properties. First, hollow and magnetic manganese oxide nanocrystals (H Mn(3)O(4)) are synthesized using triblock copolymeric micelles with core-shell corona architecture as templates. Then, polyethyleneimine (PEI) and the composite of platinum nanoparticles and tris (4,4'-dicarboxylicacid-2,2'-bipyridyl) ruthenium (II) (PtNPs-Ru) are immobilized on H-Mn(3)O(4) to form H-Mn(3)O(4) -PEI PtNPs-Ru nanocomposite, in which PEI as coreactant can effectively enhance the luminous efficiency and PtNPs as nanochannels can greatly accelerate the electron transfer. Finally, due to the coordination between Eu(3+) and carboxyl, the obtained H-Mn(3)O(4) -PEI-PtNPs-Ru aggregates locally to form sheet-like nanostructures ((H-Mn(3)O(4) -PEI-PtNPs-Ru)(n) -Eu(3+)), by which the luminous efficiency is further increased. Based on the nanosheets and two designed peptides, a sandwiched ECL biosensor, using palladium nanocages synthesized through galvanic replacement reaction as substrate, is proposed for CA2 with a linear range from 0.001 to 100 ng mL(-1) and a detection limit of 0.3 pg mL(-1). PMID- 25833657 TI - Age Neutrality of Categorically and Dimensionally Measured DSM-5 Section II Personality Disorder Symptoms. AB - Studies on the face validity of DSM-5 Section II categorical personality disorder (PD) symptoms indicate a bias against older adults. To extend these results, this article explores whether categorically and dimensionally scored PD symptoms of DSM-5 Section II, as measured in the Assessment of DSM-IV Personality Disorders (ADP-IV; Schotte & de Doncker, 1994), corroborate potential age bias across younger (aged 18-34), middle-aged (35-59 years), and older adults (aged 60-75). Differential item functioning (DIF) analyses, following a classical test theory approach, showed that 2 of the 79 symptoms were measured differently across 3 age groups when categorically assessed, and 4 when dimensionally measured. Nevertheless, subsequent differential test functioning analyses supported a low aggregated impact of DIF on the dimensional scales, justifying mean-level comparisons across age groups. Generalizability of the results is discussed in light of methodological issues concerning the research of age neutrality of PD symptoms, including the employed measurement instrument, PD symptom measurement approach, and sample and age range used to describe older adults. PMID- 25833658 TI - Are 'asymptomatic' chronic infections truly asymptomatic? PMID- 25833659 TI - Is Quality of Life Related to Cardiorespiratory Fitness in Overweight and Obese Breast Cancer Survivors? AB - This study assessed changes in quality of life (QoL) and cardiorespiratory fitness (CRF) during a diet and physical activity (PA) intervention in breast cancer (BC) survivors and investigated the relation between these changes. The intervention of this single-arm pre-post study involved supervised, 1-hour weekly, diet sessions and 75-minute bi-weekly PA sessions of moderate-to-high intensity. This 12-week intervention targeted overweight/obese women who had recently completed BC treatment. Pre- and post-CRF and QoL measurements were compared using paired t-tests. Linear regression models, including baseline participants' characteristics and weight change, were used to assess the association between changes in CRF and QoL. The 37 BC survivors who completed the intervention between May 7, 2012 and July 27, 2012 showed significant increases in CRF and QoL. Peak oxygen uptake (mL/kg/min) increased from 19.0 +/- 2.8 to 24.0 +/- 4.1 while peak workload (watts/kg) increased from 1.3 +/- 0.3 to 1.7 +/- 0.3. Although statistical significance was not reached, the increase in workload seemed associated with increases in physical, mental, and general health and with a decrease in fatigue. This lifestyle intervention improved BC survivors' QoL and CRF and suggested possible relationships between CRF and QoL. More research needs to confirm these associations and promote lifestyle interventions aiming at improving BC survivors' QoL. PMID- 25833660 TI - The vacuum cleaner effect in minimally invasive percutaneous nephrolitholapaxy. AB - INTRODUCTION: Percutaneous stone removal increasingly plays an important role among the different approaches of interventional stone therapy, particularly since the development of miniaturized instruments is resulting in lower morbidity for the patients. One major drawback of smaller instruments is the increased difficulty of stone retrieval after disintegration due to the reduced tract diameter. This results in longer operation time and the need of additional tools such as disposable retrieval baskets. One of the key factors in the development of minimally invasive percutaneous nephrolitholapaxy (MIP) was the design of an Amplatz sheath which provides a built-in vacuum cleaner effect for stone retrieval. METHODS: A series of flow analyses with the gauges and shapes of the most commonly used nephroscopes and sheaths in percutaneous nephrolitholapaxy was performed by computational fluid dynamics. Flow velocity and direction in front of the nephroscope were computed and visualized by the software. RESULTS: In our study, the vacuum cleaner effect developed exclusively when a round-shaped nephroscope was used (Nagele Miniature Nephroscope System, Karl Storz GmbH & Co. KG) and depended on the relation between nephroscope diameter and inner sheath diameter. The strongest effect was observed with a 12 F nephroscope and an inner sheath diameter of 15 F. It did not develop when an oval- or crescent-shaped nephroscope was used. In front of the distal end of the round-shaped nephroscope, a slipstream develops, induced by the excursive change of width of the fluid flow on the outlet of the flushing canal. This allows the adhesion of a stone fragment in the eddy while the fluid flow is circulating around the stone. CONCLUSION: This study illustrates and explains the vacuum cleaner effect which has been detected in the development of the Nagele Miniature Nephroscope System used in MIP. It combines the reduced morbidity of smaller kidney puncture diameters with the benefit of quick and complete stone removal. PMID- 25833661 TI - Impact of 2004 ISUP/WHO classification on bladder cancer grading. AB - PURPOSE: To determine whether implementation of the 2004 WHO/ISUP bladder cancer (BCa) grading system caused a grade migration, i.e., more tumors being graded as high grade (HG). METHODS: Data on 1040 BCa cases from 668 patients treated at our institution between 2000 and 2013 and reviewed by six pathologists were evaluated: low grade (LG): 249; HG: 791; Ta: 389; T1: 214; CIS: 95; >=T2: 342. Differences in LG or HG cases (expressed as %BCa cases/year) were analyzed by Mann-Whitney test. Correlation between the year of diagnosis and clinical/pathological parameters was evaluated by logistic regression analyses. RESULTS: During the study period, BCa cases diagnosed as LG significantly decreased with a corresponding increase in HG cases. Nonlinear regression analysis indicated that ~2008 was the crossover point for grade migration; %LG: 31.8 +/- 4.8 (2000-2007); 14.1 +/- 7.0 (2008-2013); %HG: 68.2 +/- 4.8 (2000 2007); 85.9 +/- 6.9 (2008-2013), P = 0.004. The grade migration was confined to Ta cases with %LG Ta cases diagnosed decreasing by 3.6-fold from 2000-2007 to 2008-2013 (P = 0.004). Univariate and multivariate analyses confirmed the grade migration following the adoption of the 2004 system (P < 0.0001). Kaplan-Meier curves showed no significant differences between the two time intervals in terms of disease progression (P > 0.05). CONCLUSIONS: Implementation of the 2004 WHO/ISUP system caused a significant increase in pathologists grading Ta cases as HG; however, this increase did not seem to correlate with disease progression. Since LG and HG Ta tumors are treated differently, grade migration may impact the clinical management of BCa patients. PMID- 25833662 TI - Minimally invasive treatment of renal transplant nephrolithiasis. AB - PURPOSE: Urolithiasis is a rare complication of renal transplantation, and there is limited evidence to guide treatment. Management of stones in the transplanted kidney can be challenging. We present our experience in treating upper urinary tract (UUT) allograft lithiasis using minimally invasive procedures, with the aim of demonstrating their efficacy and safety in renal transplant recipients. METHODS: The records of 1615 patients undergoing kidney transplantation and follow-up in our center between August 2000 and July 2014 were reviewed. The mode of presentation, donor type, onset time, immunosuppression protocol, stone character, therapeutic intervention and outcomes of those with UUT allograft lithiasis were recorded. Extracorporeal shock wave lithotripsy (SWL), flexible ureteroscopy (F-URS) and percutaneous nephrolithotomy (PCNL) were used in the management of these calculi. Stone composition was analyzed after the procedure. RESULTS: Nineteen renal transplant recipients (1.2 %, nine males and ten females) were found to have UUT allograft calculi. Of these, five underwent SWL (26.3 %), four had F-URS combined with lithotomy forceps extraction or holmium laser disruption (21.1 %), six had PNCL (31.6 %), one submitted to F-URS after two failed sessions of SWL (5.3 %), one combined PCNL and F-URS (5.3 %), and two spontaneously of stones (10.5 %). All patients were rendered stone-free with a combination of treatments, and none required a blood transfusion. CONCLUSIONS: The incidence of calculi in the transplanted kidney is low. Minimally invasive procedures are safe and effective means of removing allograft calculi. PMID- 25833663 TI - Governing the UN sustainable development goals: interactions, infrastructures, and institutions. PMID- 25833664 TI - Were the Effects of Glucosamine and Chondroitin on Knee Osteoarthritis Underestimated? Comment on the Article by Yang et al. PMID- 25833665 TI - Social support and the incidence and persistence of depression between antenatal and postnatal examinations in Turkey: a cohort study. AB - OBJECTIVES: This study aims to measure incidence and persistence of depression and to investigate the influence of self-reported antenatal social support and traditional/nuclear family structure on incidence and persistence of depression between the third trimester of pregnancy and following childbirth. We hypothesised that lower antenatal social support would be associated with incidence and persistence of case-level depressive symptoms and the family structure would have an effect on the incidence and persistence of depressive symptoms. SETTINGS: The cohort study described here was carried out in and around Ankara the capital of Turkey, because of the considerable heterogeneity of the population in terms of traditional Middle Eastern and 'modern' Western lifestyle and social environment. Samples were drawn from 20 urban and rural antenatal clinics (mainly primary care settings) within the geographic catchment. PARTICIPANTS: Of 730 women recruited in their third trimester, 578 (79.2%) were re-examined between 2 and 6 months after childbirth. Exclusion criteria were as follows: aged younger than 18 years, illiteracy, significant health problems and refusal to participate. PRIMARY AND SECONDARY OUTCOME MEASURES: Close Persons Questionnaire items enquired about relationships with the husband, mother and mother-in-law and depression was ascertained using the Edinburgh Postnatal Depression Scale at the each assessments. RESULTS: In those followed, onset of postnatal depression occurred in 13.9% and persistence of antenatal depression in 49.7%. After adjustment, worse emotional support from the mother-in-law was significantly associated with postnatal depression incidence (OR=0.93, 95% CI 0.87 to 0.99) and worse emotional support from the husband with postnatal persistence (OR=0.89, 95% CI 0.83 to 0.96) of antenatal depression. Family structure was not a risk or modifying factor. CONCLUSIONS: The incidence and persistence of postnatal depression in this Middle Eastern cohort were comparable to international findings. Certain family relationships predicted incidence and persistence of postnatal depression but no role of traditional/nuclear family structure was found. PMID- 25833666 TI - Pharmacist-led management of chronic pain in primary care: costs and benefits in a pilot randomised controlled trial. AB - OBJECTIVES: To explore differences in mean costs (from a UK National Health Service perspective) and effects of pharmacist-led management of chronic pain in primary care evaluated in a pilot randomised controlled trial (RCT), and to estimate optimal sample size for a definitive RCT. DESIGN: Regression analysis of costs and effects, using intention-to-treat and expected value of sample information analysis (EVSI). SETTING: Six general practices: Grampian (3); East Anglia (3). PARTICIPANTS: 125 patients with complete resource use and short form six-dimension questionnaire (SF-6D) data at baseline, 3 months and 6 months. INTERVENTIONS: Patients were randomised to either pharmacist medication review with face-to-face pharmacist prescribing or pharmacist medication review with feedback to general practitioner or treatment as usual (TAU). MAIN OUTCOME MEASURES: Differences in mean total costs and effects measured as quality adjusted life years (QALYs) at 6 months and EVSI for sample size calculation. RESULTS: Unadjusted total mean costs per patient were L452 for prescribing (SD: L466), L570 for review (SD: L527) and L668 for TAU (SD: L1333). After controlling for baseline costs, the adjusted mean cost differences per patient relative to TAU were L77 for prescribing (95% CI -82 to 237) and L54 for review (95% CI -103 to 212). Unadjusted mean QALYs were 0.3213 for prescribing (SD: 0.0659), 0.3161 for review (SD: 0.0684) and 0.3079 for TAU (SD: 0.0606). Relative to TAU, the adjusted mean differences were 0.0069 for prescribing (95% CI -0.0091 to 0.0229) and 0.0097 for review (95% CI -0.0054 to 0.0248). The EVSI suggested the optimal future trial size was between 460 and 690, and between 540 and 780 patients per arm using a threshold of L30,000 and L20,000 per QALY gained, respectively. CONCLUSIONS: Compared with TAU, pharmacist-led interventions for chronic pain appear more costly and provide similar QALYs. However, these estimates are imprecise due to the small size of the pilot trial. The EVSI indicates that a larger trial is necessary to obtain more precise estimates of differences in mean effects and costs between treatment groups. TRIAL REGISTRATION NUMBER: ISRCTN06131530. PMID- 25833667 TI - Risk communication with Arab patients with cancer: a qualitative study of nurses and pharmacists. AB - OBJECTIVES: To explore pharmacist and nurse views and experiences in educating patients regarding their treatment safety and tolerability as well as the roles of other professions in this regard. DESIGN: In this qualitative study, six focus group discussions were conducted. SETTING: The National Center for Cancer Care and Research in Qatar. PARTICIPANTS: Eleven pharmacists and 22 nurses providing direct patient care. RESULTS: Concepts related to three key themes were drawn from the seeding questions and included factors for determining the level of risk they communicated: the specific treatment regimen in question; the patient; and their assessment of the patient. Patient-related considerations arose from additional subthemes; both nurses and pharmacists described aspects related to the perceived psychological health status of the patient, as well as anticipated comprehension, as ascertained by demonstrated education and language abilities. In all discussions, it was noted that physician and family non-disclosure of cancer diagnosis to the patient profoundly influenced the nature of information they provided. While a high level of cohesion in safety communication prioritisation among these two health disciplines was found, a number of pharmacists asserted a more formal role compared to informal and repeated teaching by nurses. CONCLUSIONS: Nurses and pharmacists in this Middle East healthcare environment were not reluctant to discuss treatment side effects with patients and draw on similar professional judgements in prioritising treatment risk information. We found that they did not always recognise each other's informal educational encounters and that there are opportunities to explore increased collaboration in this regard to enhance the patient care experience. PMID- 25833668 TI - Community-based physical activity interventions among women: a systematic review. AB - OBJECTIVE: Review and assess the effectiveness of community-based physical activity interventions among women aged 18-65 years. DESIGN: Systematic review METHODS: To find relevant articles, the researcher selected reports published in English between 1 January 2000 and 31 March 2013. Systematic search was to find controlled-trial studies that were conducted to uncover the effect of community based interventions to promote physical activity among women 18-65 years of age, in which physical activity was reported as one of the measured outcomes. The methodological quality assessment was performed using a critical appraisal sheet. Also, the levels of evidence were assessed for the types of interventions. RESULTS: The literature search identified nine articles. Four of the studies were randomised and the others studies had high methodological quality. There was no evidence, on the basis of effectiveness, for social cognitive theory-based interventions and inconclusive evidence of effectiveness for the rest of interventions. CONCLUSIONS: There is insufficient evidence to assess the effectiveness of community-based interventions for enhancing physical activity among women. There is a need for high-quality randomised clinical trials with adequate statistical power to determine whether multicomponent and community based intervention programmes increase physical activity among women, as well as to determine what type of interventions have a more effective and sustainable impact on women's physical activity. PMID- 25833669 TI - Prevention of oxaliplatin-induced peripheral neuropathy by a polyamine-reduced diet-NEUROXAPOL: protocol of a prospective, randomised, controlled, single-blind and monocentric trial. AB - INTRODUCTION: Oxaliplatin remains the most widely used chemotherapeutic agent for treating advanced colorectal cancer but its efficacy is hampered by dose-limiting neurotoxicity manifested by a painful polyneuropathy. Oxaliplatin-induced peripheral neuropathy (OIPN) is characterised by acute and transient cold hyperaesthesia in the hours and days following oxaliplatin infusion (>90% of patients), but also by retarded chronic neuropathy due to the repetition of chemotherapy cycles (30-50% of patients). OIPN impairs the health-related quality of life (HRQOL) of patients and no preventive or curative strategies have as yet proven effective. A polyamine-reduced diet (PRD) has recently demonstrated its efficacy to prevent OIPN in animals without adverse effects. METHODS AND ANALYSIS: The NEUROXAPOL trial is a prospective, randomised, controlled, single blind, monocentric and interventional study. This trial is aimed at evaluating the efficacy and feasibility of a PRD compared to a normal polyamine containing diet to prevent OIPN in patients treated by oxaliplatin-based chemotherapy. Patients (n=40 per group) will be randomly assigned to receive either a PRD or a normal diet before and during the chemotherapy regimen. The main objectives are to improve the cold pain thresholds, neuropathic pain symptoms, comorbidities (anxiety and depression) and HRQOL of patients. The primary end point is the assessment of cold pain thresholds 2 weeks after the third cycle of chemotherapy. The secondary end points are the evaluation of thermal pain thresholds, the grade of neuropathy, neuropathic pain, symptoms of anxiety and depression and HRQOL, until the 12th cycle of chemotherapy. ETHICS AND DISSEMINATION: The study was approved by an independent medical ethics committee 1 (CPP Sud Est 1, Saint Etienne, France) and registered by the competent French authority (ANSM, Saint Denis, France). The results will be disseminated in a peer-reviewed journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT01775449. PMID- 25833670 TI - Investigating the effect of hypoxic culture on the endothelial differentiation of human amniotic fluid-derived stem cells. AB - Amniotic fluid-derived stem cells (AFSCs) are a unique stem cell source that may have great potential for use in tissue engineering (TE) due to their pluripotentiality. AFSCs have previously shown angiogenic potential and may present an alternative cell source for endothelial-like cells that could be used in range of applications, including the pre-vascularisation of TE constructs and the treatment of ischaemic diseases. This study investigated the ability of these cells to differentiate down an endothelial lineage with the aim of producing an endothelial-like cell suitable for use in pre-vascularisation. As hypoxia and the associated HIF-1 pathway have been implicated in the induction of angiogenesis in a number of biological processes, it was hypothesised that culture in hypoxic conditions could enhance the endothelial differentiation of AFSCs. The cells were cultured in endothelial cell media supplemented with 50 ng mL(-1) of VEGF, maintained in normoxia, intermittent hypoxia or continuous hypoxia and assessed for markers of endothelial differentiation at day 7 and 14. The results demonstrated that AFSCs subjected to these culture conditions display an endothelial gene expression profile and adopted functional endothelial cell characteristics indicative of early endothelial differentiation. Culture in continuous hypoxia enhanced endothelial gene expression but did not enhance functional endothelial cell characteristics. Overall, AFSCs subjected to endothelial stimuli demonstrated a less mature endothelial gene expression profile and phenotype when compared with HUVECs, the endothelial cell control. However, this study is the first time that the positive effect of an extended period of continuous hypoxic culture on endothelial differentiation in AFSCs has been demonstrated. PMID- 25833671 TI - A study of IgG antibodies to the ApoB protein in non-ST segment elevation acute coronary syndrome. AB - OBJECTIVES: It has long been noted that there is an association of antibodies against oxidized low-density lipoprotein (oxLDL) with cardiovascular disease, but the anti-oxLDL antibody has not been confirmed as a biomarker for prediction of acute coronary syndrome (ACS). Apolipoprotein B (ApoB) may carry the epitopes for the immune response to oxLDL. The present work was thus undertaken to detect circulating antibodies to ApoB in non-ST segment elevation ACS (NSTE-ACS). DESIGN: A total of 130 patients with NSTE-ACS and 201 control subjects were recruited. Six ApoB-derived peptipe antigens (Ag1-Ag6) were used to develop an in house enzyme-linked immunosorbent assay to examine circulating anti-ApoB IgG levels. RESULTS: The anti-Ag1 IgG level was significantly higher in the patient group than the control group (P < 0.001) and the non-ST segment elevation myocardial infarction appeared to be the main form of NSTE-ACS contributing to the increased levels of anti-Ag1 IgG (P < 0.001); there was no significant alteration in the levels of IgG to the other 5 antigens in NSTE-ACS. CONCLUSIONS: Circulating anti-ApoB IgG test may be useful for prediction of NSTE-ACS although further confirmation is needed in large-scale clinical studies. PMID- 25833672 TI - Tuberculosis management continues to utilize a large amount of hospital resources in the United States. AB - BACKGROUND AND AIMS: The objective of this study is to examine longitudinal trends in hospital admissions attributed to tuberculosis and resulting hospitalization outcomes in the United States for the years 2000-2010. METHODS: We used the Nationwide Inpatient Sample, which is the largest all-payer and nationally representative in-hospital dataset in the United States. All hospitalizations that had a primary diagnosis for tuberculosis were selected for analysis. Patient characteristics and outcomes including discharge status following hospitalization, length of stay in hospital and hospitalization charges were examined. RESULTS: During the study period, a total of 96 431 hospitalizations occurred due to tuberculosis. The mean age of hospitalizations was 48.6 years. Males comprised 64.2% of all hospitalizations; 24.8% were Whites, 25.5% Blacks, 26.5% Hispanics, 14.3% Asians/Pacific Islanders, 1% Native Americans, and 7.9% other/mixed races. Following hospitalization, 72.1% were discharged routinely, 3.4% were transferred to another acute-care hospital, 10.7% to long-term care facilities including skilled nursing facilities, 7.6% to home health care, and 2.1% were discharged against medical advice. There were 3815 patients who died (4% of hospitalizations). The total hospitalization charge for this cohort of patients admitted due to tuberculosis across the United States was $6.96 billion and the total hospitalization days over study period was 1 419 605 days. CONCLUSION: High-risk cohorts who are likely to be hospitalized due to tuberculosis included Blacks and Hispanics. Majority of hospitalization comprised of males. Even though the annual number of hospitalizations reduced over the study period, substantial amounts of resources are used in hospital settings to manage tuberculosis. PMID- 25833673 TI - What is the acceptable rate of negative appendectomy? Comment on "Prospective evaluation of the added value of imaging within the Dutch National Diagnostic Appendicitis Guideline--do we forget our clinical eye"? PMID- 25833674 TI - Indole-3-acetic acid production by newly isolated red yeast Rhodosporidium paludigenum. AB - Indole 3-acetic acid (IAA) is the principal hormone which regulates various developmental and physiological processes in plants. IAA production is considered as a key trait for supporting plant growth. Hence, in this study, production of indole-3-acetic acid (IAA) by a basidiomycetous red yeast Rhodosporidium paludigenum DMKU-RP301 (AB920314) was investigated and improved by the optimization of the culture medium and culture conditions using one factor at a time (OFAT) and response surface methodology (RSM). The study considered the effects of incubation time, carbon and nitrogen sources, growth factor, tryptophan, temperature, shaking speed, NaCl and pH, on the production of IAA. The results showed that all the factors studied, except NaCl, affected IAA production by R. paludigenum DMKU-RP301. Maximum IAA production of 1,623.9 mg/l was obtained as a result of the studies using RSM. The optimal medium and growth conditions observed in this study resulted in an increase of IAA production by a factor of up to 5.0 compared to the unoptimized condition, i.e. when yeast extract peptone dextrose (YPD) broth supplemented with 0.1% l-tryptophan was used as the production medium. The production of IAA was then scaled up in a 2-l stirred tank fermenter, and the maximum IAA of 1,627.1 mg/l was obtained. This experiment indicated that the obtained optimal medium and condition (pH and temperature) from shaking flask production can be used for the production of IAA in a larger size production. In addition, the present research is the first to report on the optimization of IAA production by the yeast Rhodosporidium. PMID- 25833675 TI - Nar is the dominant dissimilatory nitrate reductase under high pressure conditions in the deep-sea denitrifier Pseudomonas sp. MT-1. AB - The deep-sea denitrifier Pseudomonas sp. MT-1 has two gene clusters encoding dissimilatory nitrate reductases, periplasmic nitrate reductase (Nap) and membrane-bound nitrate reductase (Nar). In order to investigate the physiological role of these enzymes, we constructed the disrupted mutants of napA, narG, and narK (encoding the catalytic subunits of Nap and Nar, as well as the nitrate transporter, respectively). The napA mutant showed almost the same growth rate as the wild-type under both atmospheric and high pressure of 30 MPa. On the other hand, the narG and narK mutants showed growth deficiencies under atmospheric pressure which were more pronounced at a pressure of 30 MPa. Thus, Nar was shown to be the dominant dissimilatory nitrate reductase in MT-1, especially under high pressure, whereas Nap can support the growth with denitrification to some extent. Further, nitrate reductase activity of the soluble and membrane fractions of MT-1 was measured under high pressure. Both activities were highly piezotolerant even under a pressure of 150 MPa. Therefore, the stability of nitrate reductases under high pressure is not a limiting step for the growth of MT-1 under these conditions. Although the reason why Nar rather than Nap is dominant and the physiological role of Nap in MT-1 are still unclear, we have demonstrated the mechanisms of the denitrification system in the environment of the deep-sea. PMID- 25833676 TI - Purification, biochemical characterization, and genetic cloning of the phytase produced by Burkholderia sp. strain a13. AB - A phytase-producing bacterium, Burkholderia sp. a13 (JCM 30421), was isolated from Lake Kasumigaura by enrichment cultivation using minimum medium containing phytic acid as the sole phosphorus source. The phytase production by strain a13 was induced by the presence of phytic acid and repressed by the addition of glucose. The purified enzyme had a molecular weight of 44 kDa and a phytase activity of 174 MUmol min(-1) mg(-1). The enzyme showed broad substrate specificity, but the highest activity was observed with phytic acid. The enzyme activity was strongly inhibited by Cu(2+), Zn(2+), Hg(2+), and iodoacetic acid, indicating the requirement of a thiol group for the activity. Genetic cloning reveals that the mature portion of this enzyme consists of 428 amino acids with a calculated molecular weight of 46 kDa. The amino acid sequence showed the highest similarity to the phytase produced by Hafnia alvei with 48% identity; it also contained histidine acid phosphatase (HAP) motifs (RHGXRXP and HD), indicating the classification of this enzyme in the HAP phytase family. We have successfully expressed the cloned gene in Escherichia coli from its putative initiation codon, showing that the gene actually encodes the phytase. PMID- 25833677 TI - Relationship between chromosomal GC content and isoelectric points of histones in fungi. PMID- 25833678 TI - Acceleration effect of sodium selenite on yeast growth and fermentative capability. PMID- 25833679 TI - Anaerobic degradation of tannins in Acacia nilotica pods by Enterococcus faecalis in co-culture with ruminal microbiota. PMID- 25833680 TI - Quantitating and dating recent gene flow between European and East Asian populations. AB - Historical records indicate that extensive cultural, commercial and technological interaction occurred between European and Asian populations. What have been the biological consequences of these contacts in terms of gene flow? We systematically estimated gene flow between Eurasian groups using genome-wide polymorphisms from 34 populations representing Europeans, East Asians, and Central/South Asians. We identified recent gene flow between Europeans and Asians in most populations we studied, including East Asians and Northwestern Europeans, which are normally considered to be non-admixed populations. In addition we quantitatively estimated the extent of this gene flow using two statistical approaches, and dated admixture events based on admixture linkage disequilibrium. Our results indicate that most genetic admixtures occurred between 2,400 and 310 years ago and show the admixture proportions to be highly correlated with geographic locations, with the highest admixture proportions observed in Central Asia and the lowest in East Asia and Northwestern Europe. Interestingly, we observed a North-to-South decline of European gene flow in East Asians, suggesting a northern path of European gene flow diffusing into East Asian populations. Our findings contribute to an improved understanding of the history of human migration and the evolutionary mechanisms that have shaped the genetic structure of populations in Eurasia. PMID- 25833681 TI - Immortalized Mouse Floxed Fam20c Dental Papillar Mesenchymal and Osteoblast Cell Lines Retain Their Primary Characteristics. AB - Fam20c is essential for the normal mineralization of dentin and bone. The generation of odontoblast and osteoblast cell lines carrying floxed Fam20c allele can offer valuable tools for the study of the roles of Fam20c in the mineralization of dentin and bone. The limited capability of the primary odontoblasts and osteoblasts to proliferate necessitates the development of odontoblast and osteoblast cell lines serving as substitutes for the study of differentiation and mineralization of the odontoblasts and osteoblasts. In this study, we established and characterized immortalized mouse floxed Fam20c dental papilla mesenchymal and osteoblast cell lines. The isolated primary mouse floxed Fam20c dental papilla mesenchymal cells and osteoblasts were immortalized by the infection of lentivirus containing Simian Virus 40 T-antigen (SV40 T-Ag). The immortalization of floxed Fam20c dental papilla mesenchymal cells and osteoblasts was verified by the long-term passages and genomic integration of SV40 T-Ag. The immortalized floxed Fam20c dental papilla mesenchymal and osteoblast cell lines not only proliferated at a high rate and retained the morphology of their primary counterparts, but also preserved the dentin and bone specific gene expression as the primary dental papilla mesenchymal cells and osteoblasts did. Consistently, the capability of the primary floxed Fam20c dental papilla mesenchymal cells and osteoblasts to mineralize was also inherited by the immortalized dental papilla mesenchymal and osteoblast cell lines. Thus, we have successfully generated the immortalized mouse floxed Fam20c dental papilla mesenchymal and osteoblast cell lines. PMID- 25833682 TI - Evolutionary stasis despite selection on a heritable trait in an invasive zooplankton. AB - Invasive species are one of the greatest threats to ecosystems, and there is evidence that evolution plays an important role in the success or failure of invasions. Yet, few studies have measured natural selection and evolutionary responses to selection in invasive species, particularly invasive animals. We quantified the strength of natural selection on the defensive morphology (distal spine) of an invasive zooplankton, Bythotrephes longimanus, in Lake Michigan across multiple months during three growing seasons. We used multiple lines of evidence, including historic and contemporary wild-captured individuals and palaeoecology of retrieved spines, to assess phenotypic change in distal spine length since invasion. We found evidence of temporally variable selection, with selection for decreased distal spine length early in the growing season and selection for increased distal spine length later in the season. This trend in natural selection is consistent with seasonal changes in the relative strength of non-gape-limited and gape-limited fish predation. Yet, despite net selection for increased distal spine length and a known genetic basis for distal spine length, we observed little evidence of an evolutionary response to selection. Multiple factors likely limit an evolutionary response to selection, including genetic correlations, trade-offs between components of fitness, and phenotypic plasticity. PMID- 25833683 TI - Resveratrol Regulates the Quiescence-Like Induction of Activated Stellate Cells by Modulating the PPARgamma/SIRT1 Ratio. AB - The activation of hepatic stellate cell (HSC), from a quiescent cell featuring cytoplasmic lipid droplets to a proliferative myofibroblast, plays an important role in liver fibrosis development. The GRX line is an activated HSC model that can be induced by all-trans-retinol to accumulate lipid droplets. Resveratrol is known for activating Sirtuin1 (SIRT1), a NAD(+)-dependent deacetylase that suppresses the activity of peroxisome proliferator-activated receptor gamma (PPARgamma), an important adipogenic transcription factor involved in the quiescence maintenance of HSC. We evaluated the effects of 0.1 MUM of resveratrol in retinol-induced GRX quiescence by investigating the interference of SIRT1 and PPARgamma on cell lipogenesis. GRX lipid accumulation was evaluated through Oil red O staining, triacylglycerides quantification, and [(14)C] acetate incorporation into lipids. mRNA expression and protein content of SIRT1 and PPARgamma were measured by RT-PCR and immunoblotting, respectively. Resveratrol mediated SIRT1 stimuli did not induce lipogenesis and reduced the retinol mediated fat-storing capacity in GRX. In order to support our results, we established a cell culture model of transgenic super expression of PPARgamma in GRX cells (GRXPgamma). Resveratrol reduced lipid droplets accumulation in GRXPgamma cells. These results suggest that the PPARgamma/SIRT1 ratio plays an important role in the fate of HSC. Thus, whenever the PPARgamma activity is greater than SIRT1 activity the lipogenesis is enabled. PMID- 25833684 TI - Immunomodulatory adjunctive treatment options for Ebola virus disease patients. PMID- 25833685 TI - Association of white matter hyperintensities and gray matter volume with cognition in older individuals without cognitive impairment. AB - Both presence of white matter hyperintensities (WMH) and smaller total gray matter volume on brain magnetic resonance imaging (MRI) are common findings in old age, and contribute to impaired cognition. We tested whether total WMH volume and gray matter volume had independent associations with cognition in community dwelling individuals without dementia or mild cognitive impairment (MCI). We used data from participants of the Rush Memory and Aging Project. Brain MRI was available in 209 subjects without dementia or MCI (mean age 80; education = 15 years; 74 % women). WMH and gray matter were automatically segmented, and the total WMH and gray matter volumes were measured. Both MRI-derived measures were normalized by the intracranial volume. Cognitive data included composite measures of five different cognitive domains, based on 19 individual tests. Linear regression analyses, adjusted for age, sex, and education, were used to examine the relationship of logarithmically-transformed total WMH volume and of total gray matter volume to cognition. Larger total WMH volumes were associated with lower levels of perceptual speed (p < 0.001), but not with episodic memory, semantic memory, working memory, or visuospatial abilities (all p > 0.10). Smaller total gray matter volumes were associated with lower levels of perceptual speed (p = 0.013) and episodic memory (p = 0.001), but not with the other three cognitive domains (all p > 0.14). Larger total WMH volume was correlated with smaller total gray matter volume (p < 0.001). In a model with both MRI-derived measures included, the relation of WMH to perceptual speed remained significant (p < 0.001), while gray matter volumes were no longer related (p = 0.14). This study of older community-dwelling individuals without overt cognitive impairment suggests that the association of larger total WMH volume with lower perceptual speed is independent of total gray matter volume. These results help elucidate the pathological processes leading to lower cognitive function in aging. PMID- 25833686 TI - Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL 17A. AB - Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2-12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-alpha, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells "foamy DCs" and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A. PMID- 25833687 TI - Accurate and reliable quantification of 25-hydroxy-vitamin D species by liquid chromatography high-resolution tandem mass spectrometry. AB - In general, mass spectrometric quantification of small molecules in routine laboratory testing utilizes liquid chromatography coupled to low mass resolution triple-quadrupole mass spectrometers (QQQs). Here we introduce high-resolution tandem mass spectrometry (quadrupole-Orbitrap) for the quantification of 25 hydroxy-vitamin D [25(OH)D], a marker of the vitamin D status, because the specificity of 25(OH)D immunoassays is still questionable and mass spectrometric quantification is becoming increasingly important. Liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/HR-MS) was used to quantify 25 hydroxy-cholecalciferol [25(OH)D3], 25-hydroxy-ergocalciferol [25(OH)D2], and their C3-epimers 3-epi-25(OH)D3 and 3-epi-25(OH)D2. The method has a run time of 5 min and was validated according to the US Food and Drug Administration and the European Medicines Agency guidelines. High mass resolution was advantageously applied to separate a quasi-isobaric interference of the internal standard D6 25(OH)D2 with 3-epi-25(OH)D3. All analytes showed an imprecision of below 10% coefficient of variation (CV), trueness between 90% and 110%, and limits of quantification below 10 nM. Concentrations measured by LC-MS/HR-MS are in good agreement with those of the National Institute of Standards and Technology reference methods using LC-MS/MS (QQQ). In conclusion, quantification of 25(OH)D by LC-MS/HR-MS is applicable for routine testing and also holds promise for highly specific quantification of other small molecules. PMID- 25833689 TI - Facile Synthesis of Quasi-One-Dimensional Au/PtAu Heterojunction Nanotubes and Their Application as Catalysts in an Oxygen-Reduction Reaction. AB - An intermediate-template-directed method has been developed for the synthesis of quasi-one-dimensional Au/PtAu heterojunction nanotubes by the heterogeneous nucleation and growth of Au on Te/Pt core-shell nanostructures in aqueous solution. The synthesized porous Au/PtAu bimetallic nanotubes (PABNTs) consist of porous tubular framework and attached Au nanoparticles (AuNPs). The reaction intermediates played an important role in the preparation, which fabricated the framework and provided a localized reducing agent for the reduction of the Au and Pt precursors. The Pt7 Au PABNTs showed higher electrocatalytic activity and durability in the oxygen-reduction reaction (ORR) in 0.1 M HClO4 than porous Pt nanotubes (PtNTs) and commercially available Pt/C. The mass activity of PABNTs was 218 % that of commercial Pt/C after an accelerated durability test. This study demonstrates the potential of PABNTs as highly efficient electrocatalysts. In addition, this method provides a facile strategy for the synthesis of desirable hetero-nanostructures with controlled size and shape by utilizing an intermediate template. PMID- 25833688 TI - Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops. AB - Scavenger receptors (SRs) like cluster determinant 36 (CD36) and SR class B type I (SR-BI) play a debated role in lipid transport across the intestinal brush border membrane. We used surface plasmon resonance to analyze real-time interactions between the extracellular protein loops and various ligands ranging from single lipid molecules to mixed micelles. Micelles mimicking physiological structures were necessary for optimal binding to both the extracellular loop of CD36 (lCD36) and the extracellular loop of SR-BI (lSR-BI). Cholesterol, phospholipid, and fatty acid micellar content significantly modulated micelle binding to and dissociation from the transporters. In particular, high phospholipid micellar concentrations inhibited micelle binding to both receptors (-53.8 and -74.4% binding at 0.32 mM compared with 0.04 mM for lCD36 and lSR-BI, respectively, P < 0.05). The presence of fatty acids was crucial for micelle interactions with both proteins (94.4 and 81.3% binding with oleic acid for lCD36 and lSR-BI, respectively, P < 0.05) and fatty acid type substitution within the micelles was the component that most impacted micelle binding to the transporters. These effects were partly due to subsequent modifications in micellar size and surface electric charge, and could be correlated to micellar vitamin D uptake by Caco-2 cells. Our findings show for the first time that micellar lipid composition and micellar properties are key factors governing micelle interactions with SRs. PMID- 25833690 TI - Gemcitabine impacts differentially on bladder and kidney cancer cells: distinct modulations in the expression patterns of apoptosis-related microRNAs and BCL2 family genes. AB - Bladder and renal cancer are two representative cases of tumors that respond differentially to gemcitabine. Previous studies have shown that gemcitabine can trigger apoptosis in various cancer cells. Herein, we sought to investigate the impact of gemcitabine on the expression levels of the BCL2 family members BCL2, BAX, and BCL2L12 and the apoptosis-related microRNAs miR-182, miR-96, miR-145, and miR-16 in the human bladder and kidney cancer cell lines T24 and Caki-1, respectively. Cancer cells' viability as well as the IC50 doses of gemcitabine were estimated by the MTT assay, while the detection of cleaved PARP via Western blotting was used as an indicator of apoptosis. Furthermore, T24 and Caki-1 cells' ability to recover from treatment was also monitored. Two different highly sensitive quantitative real-time RT-PCR methodologies were developed in order to assess the expression levels of BCL2 family genes and microRNAs. Exposure of cancer cells to gemcitabine produced the IC50 values of 30 and 3 nM for Caki-1 and T24 cells, correspondingly, while cleaved PARP was detected only in Caki-1 cells. T24 cells demonstrated the ability to recover from gemcitabine treatment, whereas Caki-1 cells' recovery capability was dependent on the initial time of exposure. BCL2 and BAX were significantly modulated in treated Caki-1 cells. Instead, T24 cells exhibited alterations only in the latter, as well as in all studied microRNAs. Therefore, according to our data, bladder and renal cancer cells' response to gemcitabine is accompanied by distinct alterations in the expression levels of their apoptosis-related genes and microRNAs. PMID- 25833691 TI - The influence of SRPK1 on glioma apoptosis, metastasis, and angiogenesis through the PI3K/Akt signaling pathway under normoxia. AB - Gliomas, the most common primary brain tumors, have low survival rates and poorly defined molecular mechanisms to target for treatment. Serine/arginine SR protein kinases 1 (SRPK1) can highly and specifically phosphorylate the SR protein found in many tumors, which can influence cell proliferation and angiogenesis. However, the roles and regulatory mechanisms of SRPK1 in gliomas are not understood. The aim of this study was to determine the functions and regulation of SRPK1 in gliomas. We found that SRPK1 inhibition induces early apoptosis and significantly inhibits xenograft tumor growth. Our results indicate that SRPK1 affects Akt and eIF4E phosphorylation, Bax and Bcl-2 activation, and HIF-1 and VEGF production in glioma cells. Moreover, transfection of SRPK1 siRNA strongly reduced cell invasion and migration by regulating the expression of MMP2 and MMP9 and significantly decreased the volume of tumors and angiogenesis. We show here that a strong link exists among SRPK1, Akt, eIF4E, HIF-1, and VEGF activity that is functionally involved in apoptosis, metastasis, and angiogenesis of gliomas under normoxic conditions. Thus, SRPK1 may be a potential anticancer target to inhibit glioma progression. PMID- 25833693 TI - Leucine-rich repeat-containing protein 59 mediates nuclear import of cancerous inhibitor of PP2A in prostate cancer cells. AB - Using yeast two-hybrid analysis, we identified several novel protein interactions for the oncoprotein Cancerous Inhibitor of PP2A (CIP2A) and confirmed a subset of these interactions in human cancer cell lines. Analysis of the interaction in prostate carcinoma cells between CIP2A and leucine-rich repeat-containing protein 59 (LRRC59) suggests that CIP2A is translocated into the nucleus at G2/M through its association with LRRC59. Recent work by others has demonstrated that nuclear CIP2A disrupts mitotic checkpoints, which promotes deregulation of the cell cycle and increases cancerous phenotypes. Thus, we provide a novel therapeutic mechanism for inhibiting CIP2A function in cancerous cells via targeting the CIP2A-LRRC59 interaction. PMID- 25833692 TI - Vascular invasion in hepatitis B virus-related hepatocellular carcinoma with underlying cirrhosis: possible associations with ascites and hepatitis B viral factors? AB - Vascular invasion is one of the most important prognostic factors for patients with hepatocellular carcinoma (HCC). The objective of the current, retrospective study was to determine the associations of ascites and hepatitis B viral factors (HBeAg and anti-HBe status and HBV DNA levels), as well as tumor-related factors (size, tumor number, grade, and location) with micro- or macroscopic vascular invasion in patients with HCC that developed as a result of hepatitis B virus (HBV)-related cirrhosis. A total of 336 consecutive patients were included. Potential factors associated with micro- or macroscopic vascular invasion were analyzed by logistic regression. Ascites were more commonly detected in patients with micro- or macroscopic vascular invasion, and the presence of ascites was independently associated with vascular invasion. Among patients with mild-to moderate or severe ascites, the odds ratio for macroscopic vascular invasion was 4.83 (95 % confidence interval [CI] 2.29-10.16) and 11.87 (95 % CI 4.53-31.07), respectively. Similarly, the presence of ascites was associated with microscopic vascular invasion (OR 5.00; 95 % CI 1.23-20.31). In contrast, hepatitis B viral factors were not significantly associated with vascular invasion. The presence of ascites was associated with vascular invasion in patients with HBV-related cirrhotic HCC. Thus, patients with ascites, vascular invasion should be considered and more frequent surveillance should be performed after curative treatment. PMID- 25833694 TI - Down-regulation of miR-489 contributes into NSCLC cell invasion through targeting SUZ12. AB - microRNAs are small, non-coding RNAs that contribute into various biological processes during cancer progression. However, the potential role of miR-489 in the development of Non-Small Cell Lung Cancer (NSCLC) is not demonstrated. In present study, miR-489 was down-regulated both in tumor tissues and cells. Inhibition of miR-489 promoted cells invasion by using an invasion assay. Furthermore, miR-489 could regulate SUZ12 as shown by luciferase reporter and Western blot assays. Aberrant miR-489 expression could regulate the molecular changes (E-cadherin, N-cadherin, and Vimentin) of epithelial mesenchymal transition (EMT). In conclusion, our study revealed that miR-489 may play an essential role in the progression of NSCLC. PMID- 25833695 TI - MiR-197 induces Taxol resistance in human ovarian cancer cells by regulating NLK. AB - Chemotherapy is the preferred therapeutic approach for the therapy of advanced ovarian cancer, but 5-year survival rate remains low due to the development of drug resistance. Increasing evidence has documented that microRNAs (miRNAs) act important roles in drug resistance in a variety types of cancer. However, the roles of miRNA in regulating Taxol resistance in ovarian cancer and the detailed mechanism are less reported. We used Taqman probe stem loop real-time PCR to accurately measure the levels of miR-197 in normal ovarian cells, ovarian cancer cells, and Taxol-resistant ovarian cancer cells and found that miR-197 was significantly increased in Taxol-resistant ovarian cancer cells. Enforced expression of miR-197 can promote Taxol resistance, cell proliferation, and invasion of ovarian cancer cells. Meanwhile, repression of miR-197 in ovarian cancer cells can sensitize its response to Taxol and also induced attenuated cell proliferation and invasion ability. Furthermore, investigation of the detailed mechanism showed that the promotion of miR-197 on drug resistance in ovarian cancer cells was partially mediated by downregulating NLK, a negative regulator of WNT signaling pathway. Taken together, our work first demonstrated that miR 197 can confer drug resistance to Taxol, by regulating tumor suppressor, NLK expression in ovarian cancer cells. PMID- 25833696 TI - Decreased expression of RPS15A suppresses proliferation of lung cancer cells. AB - Lung cancer is the leading cause of cancer-related death in the world. Previous report has identified ribosomal protein s15a (RPS15A) as a TGF-beta-responsible gene in the lung adenocarcinoma cell line A549. In this study, we used specific si-RNA to downregulate RPS15A expression in A549 cells and found that decreased RPS15A expression significantly inhibited cell proliferation and survival, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Moreover, A549 cells were obviously accumulated in the G0/G1 phase in response to RPS15A knockdown, suggesting that RPS15A inhibition could induce a diminution of proliferation through cell cycle arrest. In addition, immunohistochemistry analysis further revealed that RPS15A was overexpressed in surgically resected lung cancer tissues. In conclusion, we identify RPS15A as a novel potential oncogenic gene involved in lung carcinogenesis. This study may provide a preliminary experimental basis for a gene therapy approach for treating lung cancer. PMID- 25833697 TI - miR-139-5p suppresses cancer cell migration and invasion through targeting ZEB1 and ZEB2 in GBM. AB - Invasion and migration of glioblastoma multiforme (GBM) is a multistep process and an important phenotype that causes this disease to invade surrounding tissues in the brain. Recent studies have highlighted that miRNAs play a pivotal role in controlling GBM cell plasticity. In this report, we used wound healing and transwell assays to identify a novel role of miR-139-5p in inhibition of GBM cell migration and invasion. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-139-5p inhibited expression of ZEB1 and ZEB2, which are master regulators of tumor metastasis. MiR-139-5p specifically interacts with the 3'-UTR regions of ZEB1 and ZEB2, attenuating their expression in GBM cells. To corroborate this finding, we rescued ZEB1 and ZEB2 expression and found partial but significant increases in miR-139-5p-suppressed invasion of GBM cells. The biological relevance of our study was validated by analyzing levels of miR 139-5p in GBM tissue. We found that its expression significantly downregulated compared to normal tissue and shorter overall survival rates in patients with lower miR-139-5p expression. These results confirm that miR-139-5p suppresses GBM migration and invasion and highlight its potential as a biomarker and therapeutic target for treating GBM. PMID- 25833698 TI - Downscaled projections of Caribbean coral bleaching that can inform conservation planning. AB - Projections of climate change impacts on coral reefs produced at the coarse resolution (~1 degrees ) of Global Climate Models (GCMs) have informed debate but have not helped target local management actions. Here, projections of the onset of annual coral bleaching conditions in the Caribbean under Representative Concentration Pathway (RCP) 8.5 are produced using an ensemble of 33 Coupled Model Intercomparison Project phase-5 models and via dynamical and statistical downscaling. A high-resolution (~11 km) regional ocean model (MOM4.1) is used for the dynamical downscaling. For statistical downscaling, sea surface temperature (SST) means and annual cycles in all the GCMs are replaced with observed data from the ~4-km NOAA Pathfinder SST dataset. Spatial patterns in all three projections are broadly similar; the average year for the onset of annual severe bleaching is 2040-2043 for all projections. However, downscaled projections show many locations where the onset of annual severe bleaching (ASB) varies 10 or more years within a single GCM grid cell. Managers in locations where this applies (e.g., Florida, Turks and Caicos, Puerto Rico, and the Dominican Republic, among others) can identify locations that represent relative albeit temporary refugia. Both downscaled projections are different for the Bahamas compared to the GCM projections. The dynamically downscaled projections suggest an earlier onset of ASB linked to projected changes in regional currents, a feature not resolved in GCMs. This result demonstrates the value of dynamical downscaling for this application and means statistically downscaled projections have to be interpreted with caution. However, aside from west of Andros Island, the projections for the two types of downscaling are mostly aligned; projected onset of ASB is within +/ 10 years for 72% of the reef locations. PMID- 25833699 TI - Conflict of Interest and Ethics at IFAR. PMID- 25833700 TI - Chronic rhinosinusitis (CRS) and CRS with nasal polyposis (CRSwNP). PMID- 25833701 TI - Predictive markers of chemoradiotherapy for rectal cancer: comparison of biopsy specimens taken before and about 1 week after the start of chemoradiotherapy. AB - BACKGROUND: Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in patients with rectal cancer. Although various biomarkers in biopsy specimens obtained before starting CRT have been examined, reliable prognostic factors have yet to be established. We tested the hypothesis that biopsy specimens obtained soon after the start of CRT can be used as prognostic factors. METHODS: Preoperative CRT was given to 70 consecutive patients with rectal cancer. Biopsies were taken before and about 7 days after starting CRT. The specimens were stained with hematoxylin and eosin (HE), and the expressions of Ki67, p53, and p21 and apoptosis were evaluated immunohistochemically. RESULTS: The expressions of Ki67, p53, and p21 and apoptosis before treatment were not significantly related to histologic response or tumor shrinkage. In specimens obtained about 7 days after CRT began, marked histologic regression was significantly higher in p21-positive, apoptosis-positive cases, and in cases with moderate changes on HE specimens (p = 0.017, p = 0.010, and p = 0.004, respectively). The tumor shrinkage was significantly higher in apoptosis-positive cases and cases with moderate changes on HE specimens (p = 0.002 and p < 0.001, respectively). Disease-free survival (DFS) was significantly higher in patients who had marked regression than in those who did not (p = 0.019). DFS was also significantly higher in patients with moderate changes on HE specimens than in those with mild changes (p = 0.016). CONCLUSIONS: Changes on HE-stained biopsy specimens obtained about 1 week after starting CRT are a reliable prognostic factor, similar to histologic marked regression in resected specimens; a major advantage is that the former results are available at an early phase. PMID- 25833702 TI - Studies using Australia's Pharmaceutical Benefits Scheme data for pharmacoepidemiological research: a systematic review of the published literature (1987-2013). AB - PURPOSE: Research using dispensing claims is used increasingly to study post market medicines use and outcomes. The purpose of this review is to catalogue more than 25 years of published literature using Australia's Pharmaceutical Benefits Scheme (PBS) dispensing records. METHODS: We searched MEDLINE, PreMEDLINE and Embase and conducted author searches for studies published from 1987 to 2013. Independent reviewers screened abstracts of 3209 articles and reviewed 264 full-text manuscripts. Included studies used PBS dispensing data to measure patterns and/or outcomes of prescribed medicines use or dispensing claims to derive a proxy for a specific disease cohort or health outcome. RESULTS: Of the 228 studies identified, 106 used PBS claims only (56 using claims-level data and 50 using individual-level data) and 63 studies linked individual-level PBS claims to other health data. Most commonly, studies examined trends in drug utilisation (33%), clinician and patient practices (26%), drug use and outcomes (18%) and evaluations of intervention impacts (17%). Sixty-two percent of studies using individual-level data were based on a subset of elderly Australians. Most studies focused on drug classes acting on the nervous system (36%), cardiovascular system (15%) and alimentary tract (11%). Few studies examined prescribed medicines use in children and pregnant women. CONCLUSIONS: Pharmaceutical Benefits Scheme claims represent a significant resource to examine Australia's billion-dollar annual investment in prescribed medicines. The body of research is growing and has increased in complexity over time. Australia has great potential to undertake world-class, whole-of-population pharmacoepidemiological studies. Recent investment in data linkage infrastructure will significantly enhance these opportunities. PMID- 25833703 TI - Combination antihypertensive therapy in clinical practice. The analysis of 1254 consecutive patients with uncontrolled hypertension. AB - The aim of the study was to analyze the clinical use of different types of combination therapy in a large sample of consecutive patients with uncontrolled hypertension referred to Hypertension Centre. We performed a retrospective analysis of combination antihypertensive therapy in 1254 consecutive patients with uncontrolled hypertension receiving at least triple-combination antihypertensive therapy. Among the most prescribed antihypertensive classes were renin-angiotensin blockers (96.8%), calcium channel blockers (82.5%), diuretics (82.0%), beta-blockers (73.0%), centrally acting drugs (56.0%) and urapidil (24.1%). Least prescribed were spironolactone (22.2%) and alpha-1-blockers (17.1%). Thiazide/thiazide-like diuretics were underdosed in more than two-thirds of patients. Furosemide was prescribed in 14.3% of patients treated with diuretics, while only indicated in 3.9%. Inappropriate combination therapy was found in 40.4% of patients. Controversial dual and higher blockade of renin angiotensin system occurred in 25.2%. Incorrect use of a combination of two antihypertensive drugs with the similar mechanism of action was found in 28.1%, most commonly a combination of two drugs with central mechanism (13.5%). In conclusion, use of controversial or incorrect combinations of drugs in uncontrolled hypertension is common. Diuretics are frequently underdosed and spironolactone remains neglected in general practice. The improper combination of antihypertensive drugs may contribute to uncontrolled hypertension. PMID- 25833704 TI - Factors associated with hypertension prevalence, awareness, treatment and control among participants in the International Mobility in Aging Study (IMIAS). AB - The aim of this study is to assess the factors associated with hypertension prevalence, awareness, treatment, and control, in the elderly populations of the International Mobility in Aging Study (IMIAS). Approximately 200 men and 200 women aged 65-74 years were recruited at each site (n=1995) during IMIAS' 2012 baseline survey at five cities: Kingston (Canada), Saint-Hyacinthe (Canada), Tirana (Albania), Manizales (Colombia) and Natal (Brazil). Blood pressure and anthropometric measurements were taken at participants' homes. Hypertension prevalence ranged from 53.4% in Saint-Hyacinthe to 83.5% in Tirana. Diabetes and obesity were identified as risk factors in all cities. More than two-thirds of hypertensive participants were aware of their condition (from 67.3% in Saint Hyacinthe to 85.4% in Tirana); women were more aware than men. Awareness was positively associated with diabetes in Kingston, Manizales and Natal. Though most of those aware of their hypertensive condition were being treated pharmacologically, associations between awareness and physical activity and refraining from smoking were weak. Control among treated hypertensive participants was low, especially in Tirana and Natal. Diabetes and physical inactivity were associated with poor hypertension control. Hypertension is common in the older populations of IMIAS. Diabetes is strongly associated with hypertension prevalence, awareness and lack of control of hypertension. The fact that awareness is not strongly associated with healthy behaviours suggests that antihypertensive medication is not accompanied by non-pharmacological therapies. Improved health behaviours could strengthen hypertension control. Efforts should be made to increase men's awareness of hypertension. Hypertension control in diabetic patients is a challenge. PMID- 25833705 TI - Differences in the management of hypertension, diabetes mellitus and dyslipidemia between obesity classes. AB - We did not find any paper that assessed clinical inertia in obese patients. Therefore, no paper has compared the clinical inertia rates between morbidly and nonmorbidly obese patients. A cross-sectional observational study was carried out. We analysed 8687 obese patients ?40 years of age who attended their health care center for a checkup as part of a preventive program. The outcome was morbid obesity. Secondary variables were as follows: failure in the management of high blood pressure (HBP), high blood cholesterol (HBC) and high fasting blood glucose (HFBG); gender; personal history of hypertension, dyslipidemia, diabetes, smoking and cardiovascular disease; and age (years). We analysed the association between failures and morbid obesity by calculating the adjusted odds ratio (OR). Of 8687 obese patients, 421 had morbid obesity (4.8%, 95% confidence interval (CI): 4.4 5.3%). The prevalence rates for failures were as follows: HBP, 34.7%; HBC, 35.2%; and HFBG, 12.4%. Associated factors with morbid obesity related with failures were as follows: failure in the management of HBP (OR=1.42, 95% CI: 1.15-1.74, P=0.001); failure in the management of HBC (OR=0.73, 95% CI: 0.58-0.91, P=0.004); and failure in the management of HFBG (OR=2.24, 95% CI: 1.66-3.03, P<0.001). Morbidly obese patients faced worse management for HBP and HFBG, and better management for HBC. It would be interesting to integrate alarm systems to avoid this problem. PMID- 25833706 TI - Medication adherence and visit-to-visit variability of systolic blood pressure in African Americans with chronic kidney disease in the AASK trial. AB - Lower adherence to antihypertensive medications may increase visit-to-visit variability of blood pressure (VVV of BP), a risk factor for cardiovascular events and death. We used data from the African American Study of Kidney Disease and Hypertension (AASK) trial to examine whether lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive chronic kidney disease (CKD). Determinants of VVV of BP were also explored. AASK participants (n=988) were categorized by self-report or pill count as having perfect (100%), moderately high (75-99%), moderately low (50-74%) or low (<50%) proportion of study visits with high medication adherence over a 1-year follow-up period. We used multinomial logistic regression to examine determinants of medication adherence, and multivariable-adjusted linear regression to examine the association between medication adherence and systolic VVV of BP, defined as the coefficient of variation or the average real variability (ARV). Participants with lower self-reported adherence were generally younger and had a higher prevalence of comorbid conditions. Compared with perfect adherence, moderately high, moderately low and low adherence was associated with 0.65% (+/-0.31%), 0.99% (+/ 0.31%) and 1.29% (+/-0.32%) higher systolic VVV of BP (defined as the coefficient of variation) in fully adjusted models. Results were qualitatively similar when using ARV or when using pill counts as the measure of adherence. Lower medication adherence is associated with higher systolic VVV of BP in African Americans with hypertensive CKD; efforts to improve medication adherence in this population may reduce systolic VVV of BP. PMID- 25833707 TI - Elephant conservation and corruption beyond the ivory trade. PMID- 25833708 TI - Glycogen synthase kinase-3 (Gsk-3) plays a fundamental role in maintaining DNA methylation at imprinted loci in mouse embryonic stem cells. AB - Glycogen synthase kinase-3 (Gsk-3) is a key regulator of multiple signal transduction pathways. Recently we described a novel role for Gsk-3 in the regulation of DNA methylation at imprinted loci in mouse embryonic stem cells (ESCs), suggesting that epigenetic changes regulated by Gsk-3 are likely an unrecognized facet of Gsk-3 signaling. Here we extend our initial observation to the entire mouse genome by enriching for methylated DNA with the MethylMiner kit and performing next-generation sequencing (MBD-Seq) in wild-type and Gsk-3alpha( /-);Gsk-3beta(-/-) ESCs. Consistent with our previous data, we found that 77% of known imprinted loci have reduced DNA methylation in Gsk-3-deficient ESCs. More specifically, we unambiguously identified changes in DNA methylation within regions that have been confirmed to function as imprinting control regions. In many cases, the reduced DNA methylation at imprinted loci in Gsk-3alpha(-/-);Gsk 3beta(-/-) ESCs was accompanied by changes in gene expression as well. Furthermore, many of the Gsk-3-dependent, differentially methylated regions (DMRs) are identical to the DMRs recently identified in uniparental ESCs. Our data demonstrate the importance of Gsk-3 activity in the maintenance of DNA methylation at a majority of the imprinted loci in ESCs and emphasize the importance of Gsk-3-mediated signal transduction in the epigenome. PMID- 25833709 TI - Pat1 protects centromere-specific histone H3 variant Cse4 from Psh1-mediated ubiquitination. AB - Evolutionarily conserved histone H3 variant Cse4 and its homologues are essential components of specialized centromere (CEN)-specific nucleosomes and serve as an epigenetic mark for CEN identity and propagation. Cse4 is a critical determinant for the structure and function of the kinetochore and is required to ensure faithful chromosome segregation. The kinetochore protein Pat1 regulates the levels and spatial distribution of Cse4 at centromeres. Deletion of PAT1 results in altered structure of CEN chromatin and chromosome segregation errors. In this study, we show that Pat1 protects CEN-associated Cse4 from ubiquitination in order to maintain proper structure and function of the kinetochore in budding yeast. PAT1-deletion strains exhibit increased ubiquitination of Cse4 and faster turnover of Cse4 at kinetochores. Psh1, a Cse4-specific E3-ubiquitin ligase, interacts with Pat1 in vivo and contributes to the increased ubiquitination of Cse4 in pat1? strains. Consistent with a role of Psh1 in ubiquitination of Cse4, transient induction of PSH1 in a wild-type strain resulted in phenotypes similar to a pat1? strain, including a reduction in CEN-associated Cse4, increased Cse4 ubiquitination, defects in spatial distribution of Cse4 at kinetochores, and altered structure of CEN chromatin. Pat1 interacts with Scm3 and is required for its maintenance at kinetochores. In conclusion, our studies provide novel insights into mechanisms by which Pat1 affects the structure of CEN chromatin and protects Cse4 from Psh1-mediated ubiquitination for faithful chromosome segregation. PMID- 25833710 TI - The Arp2/3 complex has essential roles in vesicle trafficking and transcytosis in the mammalian small intestine. AB - The Arp2/3 complex is the only known nucleator of branched F-actin filaments. Work in cultured cells has established a wide array of functions for this complex in controlling cell migration, shape, and adhesion. However, loss of Arp2/3 complex function in tissues has yielded cell type-specific phenotypes. Here we report essential functions of the Arp2/3 complex in the intestinal epithelium. The Arp2/3 complex was dispensable for intestinal development, generation of cortical F-actin, and cell polarity. However, it played essential roles in vesicle trafficking. We found that in the absence of ArpC3, enterocytes had defects in the organization of the endolysosomal system. These defects were physiologically relevant, as transcytosis of IgG was disrupted, lipid absorption was perturbed, and neonatal mice died within days of birth. These data highlight the important roles of the Arp2/3 complex in vesicle trafficking in enterocytes and suggest that defects in cytoplasmic F-actin assembly by the Arp2/3 complex, rather than cortical pools, underlie many of the phenotypes seen in the mutant small intestine. PMID- 25833711 TI - Chromatids segregate without centrosomes during Caenorhabditis elegans mitosis in a Ran- and CLASP-dependent manner. AB - During mitosis, chromosomes are connected to a microtubule-based spindle. Current models propose that displacement of the spindle poles and/or the activity of kinetochore microtubules generate mechanical forces that segregate sister chromatids. Using laser destruction of the centrosomes during Caenorhabditis elegans mitosis, we show that neither of these mechanisms is necessary to achieve proper chromatid segregation. Our results strongly suggest that an outward force generated by the spindle midzone, independently of centrosomes, is sufficient to segregate chromosomes in mitotic cells. Using mutant and RNAi analysis, we show that the microtubule-bundling protein SPD-1/MAP-65 and BMK-1/kinesin-5 act as a brake opposing the force generated by the spindle midzone. Conversely, we identify a novel role for two microtubule-growth and nucleation agents, Ran and CLASP, in the establishment of the centrosome-independent force during anaphase. Their involvement raises the interesting possibility that microtubule polymerization of midzone microtubules is continuously required to sustain chromosome segregation during mitosis. PMID- 25833712 TI - Centriolar satellite- and hMsd1/SSX2IP-dependent microtubule anchoring is critical for centriole assembly. AB - Centriolar satellites are numerous electron-dense granules dispersed around the centrosome. Mutations in their components are linked to various human diseases, but their molecular roles remain elusive. In particular, the significance of spatial communication between centriolar satellites and the centrosome is unknown. hMsd1/SSX2IP localizes to both the centrosome and centriolar satellites and is required for tethering microtubules to the centrosome. Here we show that hMsd1/SSX2IP-mediated microtubule anchoring is essential for proper centriole assembly and duplication. On hMsd1/SSX2IP knockdown, the centriolar satellites become stuck at the microtubule minus end near the centrosome. Intriguingly, these satellites contain many proteins that normally localize to the centrosome. Of importance, microtubule structures, albeit not being anchored properly, are still required for the emergence of abnormal satellites, as complete microtubule depolymerization results in the disappearance of these aggregates from the vicinity of the centrosome. We highlighted, using superresolution and electron microscopy, that under these conditions, centriole structures are faulty. Remarkably, these cells are insensitive to Plk4 overproduction-induced ectopic centriole formation, yet they accelerate centrosome reduplication upon hydroxyurea arrest. Finally, the appearance of satellite aggregates is cancer cell specific. Together our findings provide novel insights into the mechanism of centriole assembly and microtubule anchoring. PMID- 25833713 TI - Misfolding of mutant adenine nucleotide translocase in yeast supports a novel mechanism of Ant1-induced muscle diseases. AB - Approximately one-third of proteins in the cell reside in the membrane. Mutations in membrane proteins can induce conformational changes and expose nonnative polar domains/residues to the lipid environment. The molecular effect of the resulting membrane stress is poorly defined. Adenine nucleotide translocase 1 (Ant1) is a mitochondrial inner membrane protein involved in ATP/ADP exchange. Missense mutations in the Ant1 isoform cause autosomal dominant progressive external ophthalmoplegia (adPEO), cardiomyopathy, and myopathy. The mechanism of the Ant1 induced pathologies is highly debated. Here we show that equivalent mutations in the yeast Aac2 protein cause protein misfolding. Misfolded Aac2 drastically affects the assembly and stability of multiple protein complexes in the membrane, which ultimately inhibits cell growth. Despite causing similar proteostatic damages, the adPEO- but not the cardiomyopathy/myopathy-type Aac2 proteins form large aggregates. The data suggest that the Ant1-induced diseases belong to protein misfolding disorders. Protein homeostasis is subtly maintained on the mitochondrial inner membrane and can be derailed by the misfolding of one single protein with or without aggregate formation. This finding could have broad implications for understanding other dominant diseases (e.g., retinitis pigmentosa) caused by missense mutations in membrane proteins. PMID- 25833715 TI - Unveiling the optimal parameters for cellulolytic characteristics of Talaromyces verruculosus SGMNPf3 and its secretory enzymes. AB - AIMS: Elucidation of different physico-chemical parameters and the secretory enzymes released by Talaromyces verruculosus SGMNPf3 during cellulosic biomass degradation. METHODS AND RESULTS: We determined the optimal pH, temperature and time course parameters for the efficient degradation of different natural and commercial cellulosic substrates by T. verruculosus SGMNPf3, previously isolated from a forest soil. The optimal growth of the fungus and production of its cellulases were obtained when the culture condition was maintained at pH 3.3 and temperature 30 degrees C. Activity of the crude cellulases was maximum at 60 degrees C. Activity of cellulase enzymes produced on natural cellulose substrates was higher than that on commercial cellulose substrates. A continuous increase in cellulase activity at different time points indicated no apparent end product inhibition. This might be attributed to the high individual cellulases, notably beta-glucosidase (316.1 MUmol g(-1) ) production. Zymogram of extracellular crude proteins showed two dominant extracellular protein bands of molecular weight 72.3 and 61.4 kDa, indicating their cellulolytic nature. MALDI-TOF and LC-MS/MS analysis of the 2DE spots also identified several enzymes including beta glucosidase involved in the process of cellulose degradation. CONCLUSIONS: Based on its optimal parameters for cellulolytic activities, we suggest that the fungus is acido-mesophilic. There was apparently no end-product inhibition of the cellulase activity and this is attributed to the ability of the fungus to produce sufficient beta-glucosidase. The dominant proteins secreted by the fungus were confirmed to be cellulases. SIGNIFICANCE AND IMPACT OF THE STUDY: The high individual cellulase activities, better cellulase production on natural substrates and apparent absence of end-product inhibition are characteristics of T. verruculosus SGMNPf3 for use in harvesting naturally endowed energy in cellulosic biomass. PMID- 25833714 TI - Generating evidence to narrow the treatment gap for mental disorders in sub Saharan Africa: rationale, overview and methods of AFFIRM. AB - There is limited evidence on the acceptability, feasibility and cost effectiveness of task-sharing interventions to narrow the treatment gap for mental disorders in sub-Saharan Africa. The purpose of this article is to describe the rationale, aims and methods of the Africa Focus on Intervention Research for Mental health (AFFIRM) collaborative research hub. AFFIRM is investigating strategies for narrowing the treatment gap for mental disorders in sub-Saharan Africa in four areas. First, it is assessing the feasibility, acceptability and cost-effectiveness of task-sharing interventions by conducting randomised controlled trials in Ethiopia and South Africa. The AFFIRM Task sharing for the Care of Severe mental disorders (TaSCS) trial in Ethiopia aims to determine the acceptability, affordability, effectiveness and sustainability of mental health care for people with severe mental disorder delivered by trained and supervised non-specialist, primary health care workers compared with an existing psychiatric nurse-led service. The AFFIRM trial in South Africa aims to determine the cost-effectiveness of a task-sharing counselling intervention for maternal depression, delivered by non-specialist community health workers, and to examine factors influencing the implementation of the intervention and future scale up. Second, AFFIRM is building individual and institutional capacity for intervention research in sub-Saharan Africa by providing fellowship and mentorship programmes for candidates in Ethiopia, Ghana, Malawi, Uganda and Zimbabwe. Each year five Fellowships are awarded (one to each country) to attend the MPhil in Public Mental Health, a joint postgraduate programme at the University of Cape Town and Stellenbosch University. AFFIRM also offers short courses in intervention research, and supports PhD students attached to the trials in Ethiopia and South Africa. Third, AFFIRM is collaborating with other regional National Institute of Mental Health funded hubs in Latin America, sub Saharan Africa and south Asia, by designing and executing shared research projects related to task-sharing and narrowing the treatment gap. Finally, it is establishing a network of collaboration between researchers, non-governmental organisations and government agencies that facilitates the translation of research knowledge into policy and practice. This article describes the developmental process of this multi-site approach, and provides a narrative of challenges and opportunities that have arisen during the early phases. Crucial to the long-term sustainability of this work is the nurturing and sustaining of partnerships between African mental health researchers, policy makers, practitioners and international collaborators. PMID- 25833717 TI - Environmental microbes and uveitis: is microbial exposure always bad? AB - The eye generally is considered to be an immune-privileged organ, but this notion is being increasingly challenged as ocular antigens can be expressed in the generative lymphoid organs, resulting in attainment of self-tolerance. What triggers a break in this tolerant state is a fundamental question in autoimmunity research. The general belief is that exposure to environmental microbes can break self-tolerance in genetically susceptible individuals, leading to the induction of autoimmune responses. The molecular mimicry hypothesis has been proposed as one major mechanistic, pathway through which microbes, by generating cross reactive immune responses, can induce ocular damage of the kind that might occur in uveitis. However, our recent data suggest that exposure to microbial products containing mimicry epitopes for retinal antigens can potentially be beneficial to the host. In this review, we discuss the immune mechanisms with particular reference to the molecular mimicry hypothesis as it relates to immune-mediated uveitis. PMID- 25833716 TI - Enantioselective palladium(0)-catalyzed Nazarov-type cyclization. AB - A Pd(0)-catalyzed asymmetric Nazarov-type cyclization is described. The optimized ligand for the reaction incorporates a weakly coordinating pyridine ring into a TADDOL-derived phosphoramidite (TADDOL=alpha,alpha,alpha,alpha-tetraaryl-1,3 dioxolane-4,5-dimethanol). The reaction leads to the formation of cyclopentenones as single diastereoisomers that incorporate two contiguous asymmetric centers, one tertiary and one an all-carbon-atom quaternary stereocenter, in high yield and optical purity. It is noteworthy that the reaction does not require that substrates should be activated by aryl substituents. PMID- 25833718 TI - Enhancing the mechanical and biological performance of a metallic biomaterial for orthopedic applications through changes in the surface oxide layer by nanocrystalline surface modification. AB - Nanostructured metals are a promising class of biomaterials for application in orthopedics to improve the mechanical performance and biological response for increasing the life of biomedical implants. Surface mechanical attrition treatment (SMAT) is an efficient way of engineering nanocrystalline surfaces on metal substrates. In this work, 316L stainless steel (SS), a widely used orthopedic biomaterial, was subjected to SMAT to generate a nanocrystalline surface. Surface nanocrystallization modified the nature of the oxide layer present on the surface. It increased the corrosion-fatigue strength in saline by 50%. This increase in strength is attributed to a thicker oxide layer, residual compressive stresses, high strength of the surface layer, and lower propensity for intergranular corrosion in the nanocrystalline layer. Nanocrystallization also enhanced osteoblast attachment and proliferation. Intriguingly, wettability and surface roughness, the key parameters widely acknowledged for controlling the cellular response remained unchanged after nanocrystallization. The observed cellular behavior is explained in terms of the changes in electronic properties of the semiconducting passive oxide film present on the surface of 316L SS. Nanocrystallization increased the charge carrier density of the n-type oxide film likely preventing denaturation of the adsorbed cell-adhesive proteins such as fibronectin. In addition, a net positive charge developed on the otherwise neutral oxide layer, which is known to facilitate cellular adhesion. The role of changes in the electronic properties of the oxide films on metal substrates is thus highlighted in this work. This study demonstrates the advantages of nanocrystalline surface modification by SMAT for processing metallic biomaterials used in orthopedic implants. PMID- 25833719 TI - The contribution of germinal mosaicism to human aneuploidy. AB - Germinal mosaicism in a parent is considered to be a rare cause of aneuploidy in the offspring. The aim of this study was to assess the incidence of pre-meiotic errors, indicative of germinal mosaicism, leading to aneuploidy compared with those that occur at meiosis I. The material consisted of 126 oocytes, unexposed to sperm, donated by 57 women with an average maternal age of 35. The oocytes were at various stages of maturity and were analysed by array comparative genomic hybridisation. Of these, 102 gave conclusive results, comprising 47 that were immature, at the germinal vesicle (GV) or metaphase I stage (MI); 34 complete metaphase II-first polar body (MII-PB) complexes together with 21 incomplete complexes. Oocytes at the GV or MI stage provide direct evidence of pre-meiotic aneuploidy. Complete MII-PB complexes with the expected reciprocal gains/losses provide information on MI errors; those with non-reciprocal gains have pre meiotic errors. Overall, 29 oocytes were aneuploid, and the source of the error was known for 21. In 8 (from 7 women) the error was pre-meiotic consisting of 4 MI oocytes and 4 MII-PB complexes with non-reciprocal gains. The remaining 13 were the result of errors at meiosis I. Although pre-meiotic errors occurred in only 10% of informative oocytes, most notable was the fact that for those oocytes where the source of the error was known, 38% were caused by germinal mosaicism compared with 62% that were the outcome of a meiosis I error. None of the women with germinal mosaicism were infertile. PMID- 25833720 TI - Enhancement of cysteine catabolism into taurine impacts glutathione homeostasis in rats challenged with ethanol. AB - We determined the alterations in metabolic conversion of cysteine into glutathione and taurine in liver of rats treated with ethanol acutely. Ethanol treatment reduced cysteine as well as glutathione levels in liver for 24 h. However, cysteine dioxygenase was up-regulated rapidly, and hypotaurine/taurine levels were significantly higher than those found in the saline-treated rats. It is therefore suggested that enhancement of cysteine catabolism into taurine contributes to the depletion of hepatic glutathione, which could exacerbate the ethanol-induced oxidative liver injury. PMID- 25833721 TI - Recent topics in graft-versus-host disease: from the perspectives of pathogenesis and treatment. PMID- 25833722 TI - Increased number of peripheral CD8+ T cells but not eosinophils is associated with late-onset skin reactions caused by bendamustine. AB - Bendamustine is a chemotherapeutic drug that has recently come to be used frequently in the treatment of indolent B cell lymphomas. Skin toxicity is recognized as one of its characteristic side effects, but detailed information on such reactions has not yet been obtained. To clarify the clinical features of skin toxicity associated with bendamustine, we retrospectively analyzed skin reactions that developed in patients treated with bendamustine and rituximab (BR). Of 34 patients treated with 3-6 cycles of BR, 11 developed late-onset, persistent skin eruptions. These patients demonstrated increases in CD8(+) T cell number and CD8(+):CD4(+) cell ratio at the end of chemotherapy. In contrast, peripheral eosinophil count was not associated with such adverse events, whereas eosinophil infiltration was frequently observed in the skin. Patients with skin reactions tended to have higher seropositivity of hepatitis B core antibody, and multiplex viral screening PCR of the frozen sera demonstrated cytomegalovirus-DNA in some of the eruption-positive patients. It is speculated that inappropriate activation of CD8(+) T cells by latently infected pathogens may be one of the triggers of late-onset skin reactions caused by bendamustine. PMID- 25833723 TI - Myelodysplastic syndrome with t(9;22)(p24;q11.2), a BCR-JAK2 fusion: case report and review of the literature. AB - The human JAK2 gene is mainly targeted by two types of genetic lesions that play roles in the pathogenesis of hematologic malignancies: intragenic mutations and chromosomal translocations. Chromosomal translocations of JAK2 are typically associated with myeloid or lymphoid malignancies with an aggressive course and poor outcome. Here we report a t(9;22)(p24;q11.2) translocation, in a MDS patient and review results associated with BCR-JAK2 fusion reported in the literature. PMID- 25833725 TI - Factors Influencing Suicidal Ideation Among Korean Adults by Age: Results of the 2010-2011 Korean Health and Nutrition Examination Survey. AB - Suicidal ideation increases the risk of suicide. This study investigated the age specific contributions of sociodemographic factors, health status, and health behaviors to suicidal ideation using nationally representative data. The factors associated with suicidal ideation differ by age. Perceived bad health, stress, and depression had a significant influence on suicidal ideation in all age groups, but their specific effects differed in different age groups. The influence of perceived bad health increased with age, and the effect of stress was strongest among those aged 45-64 years. Moreover, the effect of being depressed decreased by age and was strongest among those 20-44 years of age. Disease and marital status did not have a significant effect on suicidal ideation among those 45-64 years old, and education had no effect among those 65 years or older. PMID- 25833724 TI - Sustained remission of chronic immune thrombocytopenia after discontinuation of treatment with thrombopoietin-receptor agonists in adults. AB - Thrombopoietin-receptor agonists (TPO-RAs) are highly effective in immune thrombocytopenia (ITP). Recently, reports of sustained remission after TPO-RA discontinuation in adult ITP have been reported. We aimed to describe the subset of patients in whom TPO-RA therapy may induce a durable response. We retrospectively analyzed all of our adult ITP patients treated with TPO-RAs, and focused on patients with discontinued TPO-RA therapy due to treatment response. Forty-six relapsed or refractory ITP patients were treated with TPO-RAs. In 11 of these cases, TPO-RA therapy (seven romiplostim; four eltrombopag) was stopped after achieving treatment response. No side effects of TPO-RAs were observed. These patients were pretreated with 1-3 therapy lines plus splenectomy in six patients prior to TPO-RA administration. None of these patients experienced disease relapse after therapy discontinuation over a median follow-up of 33 months (16-54). Substantial proportion of ITP patients receiving TPO-RAs can maintain a durable response after treatment discontinuation. Sustained ITP remission probably does not depend on previous treatment, splenectomy, or disease duration. PMID- 25833726 TI - Treatment Satisfaction Among Patients Taking Antidepressant Medication. AB - This study sought to assess treatment satisfaction among patients on antidepressants, ascertaining whether there might be an association with depressive symptomatology and other variables. Cross-sectional study conducted on 564 adult patients taking antidepressant medication. Satisfaction with antidepressant treatment was assessed using the Assessment of Satisfaction with Antidepressant Treatment Questionnaire (ESTA/Evaluacion de la Satisfaccion con el Tratamiento Antidepresivo). A moderate negative correlation was observed between satisfaction and intensity of depressive symptoms, as assessed with the Montgomery-Asberg scale. A weak negative correlation was observed between greater satisfaction and less favourable views about taking medication. Satisfaction scale scores were higher among those who took antidepressant medication for 1 year or more versus shorter periods. Most patients reported being satisfied with the antidepressant treatment but the level of satisfaction was higher among those who presented with less marked depressive symptoms, received longer-term treatment and viewed drug treatments favourably. Treatment satisfaction is one of the patient-reported outcome measures that can serve to complement clinical evaluation of depressive disorders. PMID- 25833727 TI - A pilot randomized trial of red blood cell transfusion for acute treatment of vaso-occlusive pain episodes in sickle cell anaemia. PMID- 25833728 TI - Between Scylla and Charybdis: charting an ethical course for research into financial incentives for living kidney donation. AB - New approaches to address the kidney scarcity in the United States are urgently needed. The greatest potential source of kidneys is from living donors. Proposals to offer financial incentives to increase living kidney donation rates remain highly controversial. Despite repeated calls for a pilot study to assess the impact of financial compensation on living kidney donation rates, many fear that financial incentives will exploit vulnerable individuals and cast the field of transplantation in a negative public light, ultimately reducing donation rates. This paper provides an ethical justification for conducting a pilot study of a federally regulated approach to providing financial incentives to living kidney donors, with the goal of assessing donors' perceptions. PMID- 25833729 TI - Digit ratio (2D:4D) does not correlate with daily 17beta-estradiol and progesterone concentrations in healthy women of reproductive age. AB - OBJECTIVES: Second-to-fourth digit ratio (2D:4D) is proposed as a proxy for the prenatal balance of sex hormones, is related to hormone-dependent characteristics in adult life, and is a possible predictor of disease later in life. Here, we studied the relationship between 2D:4D and ovarian steroid hormones (17beta estradiol and progesterone) among women of reproductive age. METHODS: From 186 healthy premenopausal women, aged 24-37 years, we collected saliva samples daily during the entire menstrual cycle. Data on reproductive and lifestyle characteristics were collected via questionnaires, and anthropometric measurements were performed. RESULTS: No statistically significant relationships were detected between adult women's sex hormone concentrations (17beta-estradiol and progesterone) during the menstrual cycle and 2D:4D, in either left or right hand, when controlling for size at birth, body mass index, and physical activity. CONCLUSIONS: This study shows, for the first time in a large sample of women of reproductive age, that 2D:4D is not a predictor of adult women's sex hormone concentration. The lack of relationship may be because 2D:4D might be genetically determined and is not related to maternal nutritional environment during fetal development. These results support the hypothesis that, in contrast to the nutritional quality of the fetal environment, the fetal hormonal environment (reflected by 2D:4D) does not determine reproductive physiology in later life. PMID- 25833730 TI - Complications of Flexible Ureteroscopic Treatment for Renal and Ureteral Calculi during the Learning Curve. AB - BACKGROUND: The flexible ureterorenoscope (URS) and associated devices have developed rapidly. However, despite its therapeutic benefits, URS may be associated with some complications. To the best of our knowledge, there are no studies discussing the complications of flexURS during the learning curve. METHODS: A retrospective review of the records of patients who underwent flexURS from January 2005 to June 2013 was performed. To compare the complications after the introduction of flexURS, patients were divided into four groups based on the surgeon's training experience, that is, based on the number of cases performed by the surgeon. A total of 219 cases underwent flexURS. Groups 1, 2, 3, and 4 included 35, 50, 50, and 84 cases, respectively. The complications were classified using the Clavien system (I-IV). RESULTS: The mean operation time and stone-free rate were significantly different (p < 0.001, p = 0.013, respectively). The total complication rates were 13.6, 10, 8.3, and 3.2%, respectively (p = 0.068). The more the surgeon's experience, the less was the complication rate. Despite our best efforts, the incidence of urosepsis was not reduced (p = 0.902). CONCLUSIONS: To reduce severe complications, it is necessary to have performed about 100 cases. Increased surgeon experience tended to decrease the risk of severe complications, but the incidence of urosepsis was not reduced. PMID- 25833732 TI - Latent change score modeling as a method for analyzing the antidepressant effect of a psychosocial intervention in Alzheimer's disease. AB - BACKGROUND: Developing and evaluating interventions for patients with age associated disorders is a rising field in psychotherapy research. Its methodological challenges include the high between-subject variability and the wealth of influencing factors associated with longer lifetime. Latent change score modeling (LCSM), a technique based on structural equation modeling, may be well suited to analyzing longitudinal data sets obtained in clinical trials. Here, we used LCSM to evaluate the antidepressant effect of a combined cognitive behavioral/cognitive rehabilitation (CB/CR) intervention in Alzheimer's disease (AD). METHODS: LCSM was applied to predict the change in depressive symptoms from baseline as an outcome of the CORDIAL study, a randomized controlled trial involving 201 patients with mild AD. The participants underwent either the CORDIAL CB/CR program or standard treatment. Using LCSM, the model best predicting changes in Geriatric Depression Scale scores was determined based on this data set. RESULTS: The best fit was achieved by a model predicting a decline in depressive symptoms between before and after testing. Assignment to the intervention group as well as female gender revealed significant effects in model fit indices, which remained stable at 6- and 12-month follow-up examinations. The pre-post effect was pronounced for patients with clinically relevant depressive symptoms at baseline. CONCLUSIONS: LCSM confirmed the antidepressant effect of the CORDIAL therapy program, which was limited to women. The effect was pronounced in patients with clinically relevant depressive symptoms at baseline. Methodologically, LCSM appears well suited to analyzing longitudinal data from clinical trials in aged populations, by accounting for the high between-subject variability and providing information on the differential indication of the probed intervention. PMID- 25833731 TI - Hinesol, a compound isolated from the essential oils of Atractylodes lancea rhizome, inhibits cell growth and induces apoptosis in human leukemia HL-60 cells. AB - Hinesol is a unique sesquiterpenoid isolated from the Chinese traditional medicine, Atractylodes lancea rhizome. In a previous study, we screened various natural products in human leukemia HL-60 cells and identified an essential oil fraction from A. lancea rhizome that exhibited apoptosis-inducing activity in these cells; hinesol was subsequently shown to be the compound responsible for this apoptosis-inducing activity. In this study, we describe the cytotoxic effects and molecular mechanisms of hinesol in HL-60 cells. The antitumor effect of hinesol was associated with apoptosis. When HL-60 cells were treated with hinesol, characteristic features of apoptosis, such as nuclear fragmentation and DNA fragmentation, were observed. These growth-inhibitory and apoptosis-inducing activities of hinesol in leukemia cells were much stronger than those of beta eudesmol, another compound isolated from the essential oil fraction. Furthermore, hinesol induced activation of c-Jun N-terminal kinase (JNK), but not p38, prior to the onset of apoptosis. These results suggested that hinesol induced apoptosis through the JNK signaling pathway in HL-60 cells. Therefore, hinesol may represent a novel medicinal drug having indications in the treatment of various cancers, including leukemia. PMID- 25833733 TI - Phytochemical characterization and evaluation of anticataract potential of seabuckthorn leaf extract. AB - OBJECTIVE: This study was undertaken to carry out phytochemical characterization of aqueous extract of Seabuckthorn (SBT, Hippophae rhamnoides L.) leaves and evaluation of its therapeutic role in oxidative stress-induced cataract in isolated goat lenses using Vit. E as reference compound. ANIMAL STUDIED: A total of 42 goat eye lenses were used in the present study. PROCEDURE: Seabuckthorn leaf extract was characterized by total phenol content estimation and HPLC analysis of quercetin and catechin. Further, cataract was induced in goat lenses using hydrogen peroxide (H2O2) and anticataract activity was evaluated using the extract in the dose range of 100, 200, 500, and 1000 MUg/mL concentrations through estimation of biochemical markers such as superoxide dismutase (SOD), reduced glutathione (GSH), and malonaldehyde (MDA). RESULTS: The results of the phytochemical characterization showed the total phenol content of the extract to be 365 mg/g in terms of gallic acid equivalents. Quercetin and catechin were estimated to be 0.01 and 0.12% w/w, respectively. In biochemical analysis, H2O2 introduction resulted in a decrease in SOD (approximately 85%) and GSH (approximately 63%) contents and an increase in MDA content (approximately 300%). The decreased levels of SOD and GSH were significantly restored in experimental groups receiving 500 and 1000 1g/mL of SBT extract. All the experimental groups showed significantly reduced MDA level in all the doses. CONCLUSION: Aqueous extract of SBT leaves showed the potential to delay onset and/or progression of cataract, at least during in vitro conditions. Results indicate the possibilities of evaluating this extract for its use as anticataract agent during in vivo conditions. PMID- 25833734 TI - Grapheme-color synesthesia subtypes: Stable individual differences reflected in posterior alpha-band oscillations. AB - Grapheme-color synesthesia is a condition in which seeing letters and numbers produces sensations of colors (e.g., the letter R may elicit a sky-blue percept). Recent evidence implicates posterior parietal areas, in addition to lower-level sensory processing regions, in the neurobiological mechanisms involved in synesthesia. Furthermore, these mechanisms seem to differ for "projectors" (synesthetes who report seeing the color "out there in the real world") versus "associators" (synesthetes who report the color to be only an internal experience). Relatively little is known about possible electrophysiological characteristics of grapheme-color synesthesia. Here we used EEG to investigate functional oscillatory differences among associators, projectors, and non synesthetes. Projectors had stronger stimulus-related alpha-band (~10 Hz) power over posterior parietal electrodes, compared to both associators and non synesthetes. Posterior alpha activity was not statistically significantly different between associators from non-synesthetes. We also performed a test retest assessment of the projector-associator score and found strong retest reliability, as evidenced by a correlation coefficient of .85. These findings demonstrate that the projector-associator distinction is highly reliable over time and is related to neural oscillations in the alpha band. PMID- 25833736 TI - Congratulations on the 20 years anniversary of Pathology International. PMID- 25833738 TI - Sulphate control by ettringite precipitation in textile industry wastewaters. AB - In the present study, ettringite precipitation was theoretically and experimentally evaluated as a means of sulphate removal. The results showed that ettringite precipitation is an effective and reliable method for sulphate removal. Synthetically prepared samples which were simulated to total wastewaters originating from the textile industry (sulphate concentration of 0.06 M) and to dye bath effluent (sulphate concentration of 0.22 M) were subjected to ettringite precipitation using the systems with Na2SO4-AlCl3-Ca(OH)2-NaOH, Na2SO4-AlCl3 Ca(OH)2, and Na2CO3-Na2SO4-AlCl3-Na(OH)2. An equilibrium model involving precipitation more than one solid phase and with ionic strength correction was used to predict the sulphate removal efficiency as well as solution composition. The optimum pH for ettringite precipitation in all systems was found to be around 12.0. By the application of the method, 0.06 M initial sulphate concentration was reduced down to 60 mg/L for synthetically prepared samples and 325 mg/L for real wastewater. For the concentrated samples of 0.22 M initial sulphate, remaining sulphate levels varying between 230 and 280 mg/L were obtained for both synthetic and real wastewater samples. PMID- 25833739 TI - Clinical practice of platelet transfusions in haemato-oncology. AB - Platelets are prophylactically transfused to patients receiving myeloablative chemotherapy. The trigger can be adapted if a patient has risk factors for bleeding. We performed an international survey to quantify differences in transfusion policies. While platelet counts are most important, bleeding, fever, use of anticoagulants and invasive procedures also determine transfusion strategies. The largest variation of triggers was observed for lumbar punctures and removal of central venous catheters. PMID- 25833740 TI - Magnetic Resonance Imaging-Confirmed Pleuritis in Systemic Lupus Erythematosus Associated Shrinking Lung Syndrome. PMID- 25833741 TI - Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms. AB - In the vertebrate neural tube, the morphogen Sonic Hedgehog (Shh) establishes a characteristic pattern of gene expression. Here we quantify the Shh gradient in the developing mouse neural tube and show that while the amplitude of the gradient increases over time, the activity of the pathway transcriptional effectors, Gli proteins, initially increases but later decreases. Computational analysis of the pathway suggests three mechanisms that could contribute to this adaptation: transcriptional upregulation of the inhibitory receptor Ptch1, transcriptional downregulation of Gli and the differential stability of active and inactive Gli isoforms. Consistent with this, Gli2 protein expression is downregulated during neural tube patterning and adaptation continues when the pathway is stimulated downstream of Ptch1. Moreover, the Shh-induced upregulation of Gli2 transcription prevents Gli activity levels from adapting in a different cell type, NIH3T3 fibroblasts, despite the upregulation of Ptch1. Multiple mechanisms therefore contribute to the intracellular dynamics of Shh signalling, resulting in different signalling dynamics in different cell types. PMID- 25833742 TI - Beneficial bacteria affect Danio rerio development by the modulation of maternal factors involved in autophagic, apoptotic and dorsalizing processes. AB - BACKGROUND/AIMS: Probiotic strains have been recognized to exert important roles in many biological systems, including immune response, growth, development and reproduction. However, to date, no studies have focused either on the relation among probiotics and maternal factors or on probiotics' ability to qualitatively and/or quantitatively modulate maternal transcripts. METHODS: In this study, the effects of Lactobacillus rhamnosus administered to parental fish on the control of maternal factors involved in autophagic, apoptotic and dorsalizing processes during zebrafish embryo development were assessed through q-PCRs, WMISH and TUNEL assay. RESULTS: The results we obtained show that probiotic induced significant changes in both maternal and zygotic mRNA levels involved in embryo development. The maternal autophagy-regulating genes herein investigated--ambra1a, ambra1b, beclin, lc3-, as well as those involved in the apoptotic process--caspase3, bcl2, bax--were modulated in disfavor and favor of the treated group, respectively. Also, the key transcripts ruling the dorsalizing process--goosecoid and chordin- were subject to a significant regulation of their gene expression. CONCLUSION: The results we acquired demonstrated that parentally administered Lactobacillus rhamnosus is able to modulate important physiological processes involved in zebrafish embryo development. PMID- 25833743 TI - Indoxyl sulfate, not P-cresyl sulfate, is associated with advanced glycation end products in patients on long-term hemodialysis. AB - BACKGROUND/AIMS: Advanced glycation end products (AGEs) are pro-inflammatory and pro-oxidative compounds that play a critical role in endothelial dysfunction and atherosclerosis. Protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), inhibit endothelial function. We explored the association of IS and PCS with AGEs in a hemodialysis (HD) cohort. METHODS: This study was a cross sectional study that recruited 129 stable patients on maintenance HD in a single medical center from July 1 to July 15, 2011. Serum levels of total and free IS, PCS and AGEs were measured concurrently. General laboratory results and patient background were also investigated. RESULTS: Serum levels of AGEs were associated with total IS (r = 2.7, p < 0.01) but not total PCS (r = 0.01, NS), free IS (r = 0.11, NS) or free PCS (r = 0.04, NS) using Pearson's analysis. Multiple linear regression analysis showed that total IS was significantly related to AGEs (beta = 0.296, p < 0.01), free IS (beta = 0.502, p < 0.01) and creatinine (beta = 0.294, p < 0.01). Serum AGEs levels were also independently correlated with diabetes status (beta = 0.250, p = 0.01) and total IS (beta = 0.341, p < 0.01) concentrations after adjusting for other confounding variables. Moreover, patients with diabetes had higher serum AGEs levels than patients without diabetes (p < 0.01). CONCLUSIONS: These findings suggest that serum levels of total IS were associated with AGEs levels, which may participate in the process of atherosclerosis. PMID- 25833744 TI - When nurses are also patients: Intimate partner violence and the health system as an enabler of women's health and agency in Johannesburg. AB - While violence against women is a recognised global health problem, women's agency in marginalised settings is poorly understood, particularly in relation to health systems. We explored agency as a practical and theoretical construct through qualitative research among 20 nurses with direct or indirect experiences of intimate partner violence (IPV) in Johannesburg. Interviews conducted from August 2013 to March 2014 generated rich descriptions from respondents in five health facilities. Nurses' self-reported IPV matched national prevalence of 24 31%. Findings revealed the way in which agency is enacted by nurses, allowing them the economic means to leave abusive partnerships, yet disabling them from agency and health promotion in their workplace. At the same time, nurses expanded agentic possibilities for patients by enabling a national response to IPV within South African health clinics - one that is largely undocumented. We posit that nurses can serve as important agentic actors in public health systems in low- and middle-income country settings by assisting patients to address IPV, even in the absence of targeted training and guidelines. To ensure the health and well-being of women experiencing IPV, nurses should be supported by the health sector to respond skilfully to patients and to safely process their own experiences of violence. PMID- 25833745 TI - Gene, environment and cognitive function: a Chinese twin ageing study. AB - BACKGROUND: the genetic and environmental contributions to cognitive function in the old people have been well addressed for the Western populations using twin modelling showing moderate to high heritability. No similar study has been conducted in the world largest and rapidly ageing Chinese population living under distinct environmental condition as the Western populations. OBJECTIVE: this study aims to explore the genetic and environmental impact on normal cognitive ageing in the Chinese twins. DESIGN/SETTING: cognitive function was measured on 384 complete twin pairs with median age of 50 years for seven cognitive measurements including visuospatial, linguistic skills, naming, memory, attention, abstraction and orientation abilities. Data were analysed by fitting univariate and bivariate twin models to estimate the genetic and environmental components in the variance and co-variance of the cognitive assessments. RESULTS: intra-pair correlation on cognitive measurements was low to moderate in monozygotic twins (0.23-0.41, overall 0.42) and low in dizygotic twins (0.05 0.30, overall 0.31) with the former higher than the latter for each item. Estimate for heritability was moderate for overall cognitive function (0.44, 95% CI: 0.34-0.53) and low to moderate for visuospatial, naming, attention and orientation abilities ranging from 0.28 to 0.38. No genetic contribution was estimated to linguistic skill, abstraction and memory which instead were under low to moderate control by shared environmental factors accounting for 23-33% of the total variances. In contrast, all cognitive performances showed moderate to high influences by the unique environmental factors. CONCLUSIONS: genetic factor and common family environment have a limited contribution to cognitive function in the Chinese adults. Individual unique environment is likely to play a major role in determining the levels of cognitive performance. PMID- 25833746 TI - Inhibition of immune tolerance unmasks drug-induced allergic hepatitis. PMID- 25833747 TI - CT for evaluation of urolithiasis: image quality of ultralow-dose (Sub mSv) CT with knowledge-based iterative reconstruction and diagnostic performance of low dose CT with statistical iterative reconstruction. AB - PURPOSE: To compare radiation dose and image quality in regular, low, and ultralow-dose CT protocols, and to evaluate diagnostic performance of low-dose CT for urolithiasis. MATERIALS AND METHODS: Sixty-five patients with suspected urolithiasis underwent three different scans under the regular, low, and ultralow dose protocols. The regular dose scans were reconstructed using filtered back projection and the low-dose scans were reconstructed using a statistical iterative reconstruction. The ultralow-dose scans were reconstructed using both techniques in addition to a knowledge-based IR. Effective radiation doses were compared. Objective image noise was assessed by measuring standard deviation of HU and subjective image assessment was performed with a 3- or 5-point scale. Diagnostic performance of the low-dose image was evaluated, using the regular dose image as a standard reference and the interobserver agreement between two reviewers with different levels of experience was calculated. RESULTS: The effective radiation dose was significantly different in each protocol (p < 0.001) and estimated dose reduction of the low-dose and ultralow-dose protocols was 76.4% and 89.8%, respectively. The knowledge-based iterative reconstruction algorithm showed poorer subjective image quality than the regular and low-dose protocols, but it also had the least objective image noise. Overall, the low-dose image set showed a greater than 84% concordance rate and 100% in ureter stones larger than 3 mm. Interobserver agreement was substantial (kappa value = 0.61). CONCLUSIONS: The knowledge-based IR can provide a better quality image while reducing radiation exposure under the same protocol. Furthermore, the diagnostic performance of the low-dose CT protocol is comparable to the regular dose scan. PMID- 25833748 TI - Anisotropy of local stress tensor leads to line tension. AB - Line tension of three-phase contact lines is an important physical quantity in understanding many physical processes such as heterogeneous nucleation, soft lithography and behaviours in biomembrane, such as budding, fission and fusion. Although the concept of line tension was proposed as the excess free energy in three-phase coexistence regions a century ago, its microscopic origin is subtle and achieves long-term concerns. In this paper, we correlate line tension with anisotropy of diagonal components of stress tensor and give a general formula of line tension. By performing molecular dynamic simulations, we illustrate the formula proposed in Lennard-Jones gas/liquid/liquid and gas/liquid/solid systems, and find that the spatial distribution of line tension can be well revealed when the local distribution of stress tensor is considered. PMID- 25833749 TI - Muscular dystrophy-related hospitalizations among male pediatric patients in the United States. AB - OBJECTIVE: While the economic burden of muscular dystrophy (MD) has been well documented, little is known of specific costs associated with Duchenne muscular dystrophy (DMD), the most prevalent form of MD. This study assessed trends in MD related hospitalizations and costs among young males, which may reflect utilization of the DMD population in the United States. STUDY DESIGN: A retrospective observational study of hospitalizations of males aged 0-20 years with a primary diagnosis code for MD was conducted using data from a weighted, nationally representative database of pediatric hospitalizations in the US. Rates, characteristics and cost of MD-related hospitalizations were compared to hospitalizations not related to MD. RESULTS: The rate of MD-related hospitalizations increased by 9% between 2000 and 2006 and then decreased by 13% in 2009. The mean length of stay for discharges related to MD was approximately 9 days during each study year. The most frequent observed diagnoses (other than MD) and procedures were for respiratory-related complications. The mean total costs for MD-related discharges increased across the study period from $26,785 in 2000 to $42,751 in 2009. CONCLUSION: This study provides baseline and trend data describing hospitalizations of male pediatric patients with MD that may be used as baseline measurements for assessment of the impact of new strategies for managing the disease. Further assessment of the burden and the clinical, economic, and humanistic impacts of DMD is warranted. PMID- 25833750 TI - Liver transplantation and the Rubicon. PMID- 25833751 TI - The sRNA SorY confers resistance during photooxidative stress by affecting a metabolite transporter in Rhodobacter sphaeroides. AB - Exposure to oxygen and light generates photooxidative stress by the bacteriochlorophyll a mediated formation of singlet oxygen ((1)O2) in the facultative photosynthetic bacterium Rhodobacter sphaeroides. We have identified SorY as an sRNA, which is induced under several stress conditions and confers increased resistance against (1)O2. SorY by direct interaction affects the takP mRNA, encoding a TRAP-T transporter. We present a model in which SorY reduces the metabolite flux into the tricarboxylic acid cycle (TCA cycle) by reducing malate import through TakP. It was previously shown that oxidative stress in bacteria leads to switch from glycolysis to the pentose phosphate pathway and to reduced activity of the TCA cycle. As a consequence the production of the prooxidant NADH is reduced and production of the protective NADPH is enhanced. In R. sphaeroides enzymes for glycolysis, pentose phosphate pathway, Entner-Doudoroff pathway and gluconeogenesis are induced in response to (1)O2 by the alternative sigma factor RpoHII. The same is true for the sRNA SorY. By limiting malate import SorY thus contributes to the balance of the metabolic fluxes under photooxidative stress conditions. This assigns a so far unknown function to an sRNA in oxidative stress response. PMID- 25833752 TI - A novel authentication scheme using self-certified public keys for telecare medical information systems. AB - Telecare medical information systems (TMIS), with the explosive growth of communication technology and physiological monitoring devices, are applied increasingly to enable and support healthcare delivery services. In order to safeguard patients' privacy and tackle the illegal access, authentication schemes for TMIS have been investigated and designed by many researchers. Many of them are promising for adoption in practice, nevertheless, they still have security flaws. In this paper, we propose a novel remote authentication scheme for TMIS using self-certified public keys, which is formally secure in the ID-mBJM model. Besides, the proposed scheme has better computational efficiency. Compared to the related schemes, our protocol is more practical for telemedicine system. PMID- 25833753 TI - [Channelography and mechanism of action in canaloplasty]. AB - BACKGROUND: Canaloplasty lowers the intraocular pressure (IOP) by restoring the natural outflow system. The success of canaloplasty depends on the function of this system. OBJECTIVES: To evaluate the natural outflow system regarding canaloplasty by two clinical tests, provocative gonioscopy and channelography and to describe the mechanism of action of canaloplasty. MATERIAL AND METHODS: Provocative gonioscopy evaluates the pattern of blood reflux which is induced by ocular hypotension as the result of a reversed pressure gradient between the episcleral venous pressure and IOP following paracentesis. In channelography the transtrabecular diffusion and the filling properties of the episcleral venous system are assessed by a microcatheter and a fluorescein tracer. RESULTS: Blood reflux varied greatly in glaucomatous eyes and showed an inverse correlation with the preoperative IOP. The higher the IOP, the poorer the blood reflux. The filling qualities of the episcleral venous system and diffusion through the trabecular meshwork were different. Poor trabecular passage and good episcleral fluorescein outflow indicates patent distal outflow pathways, poor trabecular passage and poor episcleral fluorescein outflow indicates obstructed trabecular meshwork and closed collector channels and good trabecular passage together with poor episcleral fluorescein outflow suggests that the site of impairment is mainly in the distal outflow system. CONCLUSIONS: The quality of blood reflux and the characteristics of the episcleral filling and the transtrabecular diffusion by fluorescein represent the clinical state of the outflow pathway and help in the prediction of the surgical outcome in canaloplasty. The mechanism for canaloplasty is not yet completely clarified; currently under discussion are circumferential viscodilation, permanent distension of the inner wall of Schlemm's canal using a suture and a Stegmann canal expander. PMID- 25833754 TI - [The German Acanthamoeba keratitis register: Initial results of a multicenter study]. AB - BACKGROUND AND PURPOSE: In September 2011 the cornea section of the German Ophthalmological Society (DOG) established the first German Acanthamoeba keratitis registry. The data of this multicenter survey are being collected, compiled and evaluated at the Department of Ophthalmology at the Saarland University. The aim of this article is to present an intermediate report. PATIENTS AND METHODS: Data from 172 eyes with Acanthamoeba keratitis were collected during the last 10 years. For this interim report we actually evaluated 121 eyes (60.2 % female patients, average age 41.3 years) and collected the following data: date of onset of symptoms, date and method of diagnosis, initial diagnosis, anamnestic data, clinical symptoms and signs at diagnosis and during follow-up, conservative and surgical therapy. Criteria for inclusion in the Acanthamoeba registry was the established diagnosis of an Acanthamoeba keratitis with at least one of the methods described in this article. RESULTS: Acanthamoeba keratitis could be histologically proven in 55.3 % of the cases, via PCR in 25.6 %, with confocal microscopy in 20.4 % and using in vitro cultivation in 15.5 %. Clinical symptoms and signs in Acanthamoeba keratitis were pain in 67.0 %, ring infiltrates in 53.4 %, pseudodendritiform epitheliopathy in 11.7 % and keratoneuritis in 5.8 %. In 47.6 % of the cases the initial diagnosis was herpes simplex virus keratitis followed by bacterial keratitis in 25.2 % and fungal keratitis in 3.9 %. Acanthamoeba keratitis was the correct initial diagnosis in only 23.2 % of cases. The average time period between first symptoms and diagnosis was 2.8 +/- 4.0 months (range 0-23 months). A triple therapy with Brolene(r) Lavasept(r) and antibiotic eye drops at least 5 */day was used in 54.5 % of eyes (n = 66). Penetrating keratoplasty was performed in 40.4 %, in 18 cases in combination with cryotherapy of the cornea. The mean graft diameter was 7.9 +/ 1.1 mm (range 3.5-11.0 mm). The final visual acuity (Snellen visual acuity chart at 5 m) was comparable in the two groups of eyes with (5/40 +/- 5/25) and without (5/32 +/- 5/25) keratoplasty. CONCLUSION: Acanthamoeba keratitis is a rare and often very late diagnosed disease and two thirds of the cases were initially misdiagnosed. The early recognition of the typical symptoms is crucial for the prognosis of the disease. All ophthalmological departments in Germany are invited to submit further data of all confirmed cases (berthold.seitz@uks.eu), whether retrospectively or prospectively in order to generate an adequate standardized diagnostic and therapeutic approach for this potentially devastating disease. PMID- 25833755 TI - Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity. AB - Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 % cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF) 1alpha and nuclear factor-kappa B (NF-kappaB) p65 were immunohistochemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1alpha and NF-kappaB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-kappaB. In human coronary plaques, the number of HIF-1alpha-immunopositive nuclei was positively correlated with that of NF-kappaB-immunopositive nuclei and TF-immunopositive and PAI-1 immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation. PMID- 25833756 TI - Attachment style, representations of psychotherapy, and clinical interventions with insecurely attached clients. AB - The primary aim of this article was to demonstrate the clinical utility of an empirically grounded perspective on the complex interplay between patients' attachment style and their ability to create, remember, and use benignly influential representations of their experiences with their therapists. We focused on 2 interrelated questions: Are there significant attachment-related differences in the thematic content of the remembrances and fantasies that patients have about therapy? And, if so, what are the implications for practice? Results of a study of individuals currently in therapy (N = 176) indicated that although all the patients with different insecure attachment styles struggled to evoke positively valenced therapist representations, the specific nature of their representational patterns varied as a function of specific attachment styles. We offer several clinical strategies that may increase insecure patients' abilities to form adaptive representations of their therapist and therapy. We illustrate our recommendations by presenting case material from the psychotherapy of a compulsively self-reliant man. PMID- 25833757 TI - Clinical audit as a framework for the consultation on the future of Libyan Health Services. PMID- 25833758 TI - 'The white blood cell always eat the red': how Jamaicans with sickle cell disease understand their illness. AB - OBJECTIVE: To explore lay understandings of sickle cell disease (SCD) among Jamaicans living with the illness. There is no qualitative research on this subject in Jamaica, where SCD is the most common genetic disorder. DESIGN: Thirty in-depth semi-structured interviews (50% males, 50% urban residence) were conducted with adult patients attending the Sickle Cell Unit in Jamaica. Transcribed data were analysed using thematic analysis. RESULTS: Patients' narratives focused on two main themes: lay understandings of how SCD works (using ideas of attack and fortification, and blockage and flow); and what causes the illness (lay ideas of inheritance). The most common description of SCD was that their white blood cells were 'eating/sucking out/feeding on' their red blood cells. Hence, treatment required 'building up' their blood, while a key to good health was ensuring an unimpeded flow of blood. Most participants believed SCD was hereditary, but there were various understandings of the mechanism and probability of its transmission. Belief in the possibility of transmitting SCD was not always a barrier to reproduction, nor did participants always insist on their partner or child being tested. CONCLUSIONS: Participants engaged in medical pluralism, a dynamic combination of folk and biomedical beliefs. Their concerns, experiences and interpretations were powerful motivators of reproductive and screening behaviour. Their narratives of SCD transcend the individual to express social, societal and cultural realities. Health care professionals and policy makers should communicate clearly to ensure understanding, and recognize and engage with their patients' sociocultural context. PMID- 25833759 TI - Akt Activation and Inhibition of Cytochrome C Release: Mechanistic Insights into Leptin-promoted Survival of Type II Alveolar Epithelial Cells. AB - Fetal growth restriction (FGR) increases the risk of perinatal death, partly due to defects in lung development. Leptin, a polypeptide hormone, is involved in fetal lung development. We previously demonstrated that treatment with exogenous leptin during gestation significantly promotes fetal lung maturity in the rat model of FGR. In this study, to delineate the molecular pathways through which leptin may enhance fetal lung development, we investigated the impact of leptin treatment on the survival of type II alveolar epithelial cells (AECs), essential leptin-responsive cells involved in lung development, in a rat model of FGR. The rat model of FGR was induced in pregnant Sprague-Dawley rats by partial uterine artery and vein ligation. In vivo and in vitro analyses of fetal lung tissues and freshly-isolated cultured AECs, respectively, showed that leptin protects type II AECs from hypoxia-induced apoptosis. Further molecular studies revealed the role of Akt activation in the leptin-mediated promotion of survival of type II AECs. The data also showed that the anti-apoptotic effects of leptin are dependent on phosphoinositol 3-kinase (PI3K) activation, and involve the down-regulation of caspases 3 and 9, upregulation of pro-survival proteins Bcl-2, and p-Bad, and inhibition of the release of cytochrome c from mitochondria. Taken together, our data suggested that leptin enhances the maturity of fetal lungs by mediating the regulation of caspase-3 and -9 during hypoxia-induced apoptosis of type II AECs and provide support for the potential of leptin as a therapeutic agent for promoting lung development in FGR. PMID- 25833760 TI - Gender differences of chronic obstructive pulmonary disease associated with manifestations on HRCT. AB - BACKGROUND AND AIMS: Patients with chronic obstructive pulmonary disease (COPD) have been shown to have significant gender differences in terms of susceptibility, severity and response to therapy. We hypothesized that this was due to differences in functional and pathologic changes in the airway, which can be revealed by high-resolution computed tomography (HRCT) in addition to pulmonary function test (PFT). METHODS: A total of 84 patients with COPD were enrolled in the study. Within 1 week of enrollment, a history of each patient's current illness was obtained. PFT and chest HRCT scan were performed. RESULTS: The patients were classified as phenotype A, E and M based on the chest HRCT presentations. No significant gender differences were found in COPD severity (chi2 = 4.993, P = 0.172). Male patients have more smoking history and smaller average age compared with female patients. Female patients showed a significantly higher FEV1 /FVC, lower inspiratory capacity and milder residual volume/total lung capacity than that of male patients. Based on the HRCT results, more males were classified as phenotype M, whereas females tended to be phenotype A. Males had a greater grade of low attenuation areas and were more likely to show evidence of emphysema on a HRCT scan than females (chi2 = 15.373, P = 0.001), whereas females had less airway wall thickening than males, although this change had no statistical significance. (chi2 = 0.163, P = 0.922). CONCLUSION: Gender differences of COPD patients were seen in ages of onset, smoking history, and PFT and HRCT presentations. The use of HRCT imaging indicates that there are significant gender differences in the clinical manifestations of COPD. PMID- 25833761 TI - A Zr metal-organic framework based on tetrakis(4-carboxyphenyl) silane and factors affecting the hydrothermal stability of Zr-MOFs. AB - A new (4,8)-connected Zr-MOF porous zirconium metal-organic framework (Zr-MOF) with flu topology, Zr6(MU3-O)4(MU3-OH)4(TCPS)2(H2O)4(OH)4 (, TCPS = tetrakis(4 carboxyphenyl) silane) with a BET specific area of 1402 m(2) g(-1) has been constructed and fully characterized. is stable in air and acid media but unstable in water and basic media, and thermally stable up to 200 degrees C. The new MOF is a wide band gap semiconductor with Eg = 3.95 eV. The excitation of at 260 nm gives a ligand-based emission peak at 435 nm. After solvent exchange processes and activation at 200 degrees C, this MOF exhibits high storage capacities for H2, CH4 and CO2. We summarized the hydrothermal stability data of Zr-MOFs, calculated the NBO (natural bond orbital) charges of the coordinating oxygen atoms of the corresponding carboxylate ligands and analyzed the influencing factors. Besides the known reasons of hydrothermal stabilities of Zr-MOFs, we demonstrated that NBO charges of coordinating atoms of the ligands can be used to explain the hydrothermal stabilities of Zr-MOFs. PMID- 25833762 TI - Vitamin D in childhood and adolescence: an expert position statement. AB - Vitamin D is a key hormone in the regulation of calcium and phosphorus metabolism and plays a pivotal role in bone health, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Great interest has been placed in recent years on vitamin D's extraskeletal actions. However, while recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious and autoimmune diseases, the actual impact of vitamin D status on the global health of children and adolescents, other than bone, remains a subject of debate. In the meantime, pediatricians still need to evaluate the determinants of vitamin D status and consider vitamin D supplementation in children and adolescents at risk of deficiency. This review is the result of an expert meeting that was held during the congress "Update on vitamin D and bone disease in childhood" convened in Pisa, Italy, in May 2013. CONCLUSION: The collaboration of the international group of experts produced this "state of the art" review on vitamin D in childhood and adolescence. After dealing with vitamin D status and its determinants, the review outlines the current debate on vitamin D's health benefits, concluding with a practical approach to vitamin D supplementation during childhood and adolescence. WHAT IS KNOWN: * Vitamin D deficiency is a worldwide health problem. * Vitamin D deficiency affects not only musculoskeletal health but also a potentially wide range of acute and chronic diseases. What is New: * We reviewed the literature focusing on randomized controlled trials of vitamin D supplementation during childhood and adolescence. * This review will help pediatricians to appreciate the clinical relevance of an adequate vitamin D status and it will provide a practical approach to vitamin D supplementation. PMID- 25833764 TI - Risk factors for and reproductive outcomes of phantom cows on New Zealand dairy farms. AB - AIMS: To determine some of the risk factors for cows not observed in oestrus within 35-42 days of an unsuccessful artificial insemination (AI; phantom cows), and the reproductive outcomes and effect of treatment of phantom cows. MATERIALS AND METHODS: Over 2 years, in dairy herds from the Waikato (n=10) and Canterbury (n=4) regions of New Zealand, pregnancy diagnosis was carried out 35-42 days after AI on cows that had been inseminated in the first 3 weeks after the start of mating (PSM) but had not been seen returning to oestrus. Risk factors for phantom cows were analysed using a generalised linear mixed effect model. In Year 1, all phantom cows were left untreated. In Year 2, phantom cows were categorised as having a corpus luteum (CL) (CL+ n=120), or having ovarian follicles>=10 (n=101) or <10 (n=40) mm in diameter. Cows with a CL were treated with cloprostenol or untreated and placed with bulls. Cows with no CL received intravaginal progesterone (P4) for 7 days, with injection of gonadotrophin releasing hormone (GnRH) on Days 0 and 9, and cloprostenol on Day 7 followed by AI. Pregnancy diagnosis of all cows took place 100-120 days after PSM and interval to conception and final pregnancy rate determined. RESULTS: Overall, of cows inseminated in the first 3 weeks after PSM that did not return to oestrus, 610/6,734 (9.1%) were phantom cows. From the final multivariable analysis, treatment for anoestrus, BCS<=4.0 at mating, being 2 or >6 years of age, and pure bred, and decreasing interval between calving and mating, until 98 days post calving, were associated with increased odds of being a phantom cow. Compared to all other groups of cows, phantom cows had a longer interval to conception (p<0.001) and a lower final pregnancy rate (p<0.001). Treatment of CL+ cows or cows with follicles>=10 mm did not affect reproductive outcomes (p>0.3). For cows with follicles<10 mm treatment decreased the final percentage not pregnant (3/27; 11%; p=0.01) and interval to conception (21 days; p=0.02) compared with controls (7/13; 54% and 37 days, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Risk factors for phantom cows were identified that could be manipulated to reduce the number of phantom cows in a herd, in particular increasing BCS. Treatment of the majority of phantom cows did not improve reproductive performance. PMID- 25833763 TI - Different antibiotic strategies in transient tachypnea of the newborn: an ambispective cohort study. AB - The purpose of this study is to determine the outcome and infection-related events in neonates with transient tachypnea of the newborn (TTN) managed with an antibiotic initiation strategy. An ambispective cohort study was carried out to compare two different antibiotic strategies in of TTN patients. The first strategy is based on clinical risk evaluation, in which antibiotics are initiated according to clinical signs, while the other is a combined strategy that integrates information regarding clinical signs, perinatal risk factors, and lab based surveillance of infectious indicators. The antibiotic use in the combined strategy group (n = 716) was lower than that of the control group (n = 769) (35.06 vs 54.75 %, P < 0.01). Outcomes including total duration of antibiotic therapy (5.45 +/- 4.17 vs 5.18 +/- 3.45 days, P = 0.36), mortality (0 vs 0), length of hospital stay (7.78 +/- 4.20 vs 8.14 +/- 3.62 days, P = 0.07), and hospital readmission (4.89 vs 4.94 %, P = 0.94) did not differ; nor did infection related events such as nosocomial infection (2.93 vs 2.99 %, P = 0.95), infectious pneumonia (18.30 vs 19.90 %, P = 0.43), septicemia (1.96 vs 1.95 %, P = 0.99), and necrotizing enterocolitis (0.14 vs 0.26 %). CONCLUSION: The combined strategy effectively reduces antibiotic usage during incidences of TTN with no negative impact on the clinical outcome. WHAT IS KNOWN: * TTN is easy to be confused with infection only based on clinical signs. * Many TTN patients had been treated with unnecessary antibiotics. WHAT IS NEW: * Our combined strategy for TTN can reduce antibiotics usage. * New strategy did not increase the incidence of infection and adverse outcomes. PMID- 25833765 TI - Multiple-stimulus-responsive supramolecular gels and regulation of chiral twists: the effect of spacer length. AB - A new class of homologous gelators, LG12 -(CH2 )n -BSA, composed of bipyridinyl groups, L-glutamic moieties having double dodecyl chains, and linked alkyl spacers with different lengths were synthesized. It was found that these gelators could immobilize medium-polarity solvents readily and the behaviors of these gels showed a dependence on the spacer length. Of all the gels, the LG12 -(CH2 )11 BSA gels exhibited self-healing property and multiple-stimulus responsibility, such as heating, shaking, and sonication. The investigation of CD spectra indicated that the supramolecular chirality, which was attributed to the chiral transfer from the chiral center to the assemblies, was also closely related to the length of methylene spacers. The longer the alkyl spacers, the weaker the transmitted supramolecular chirality. Only LG12 -(CH2 )1 -BSA gelators, which had the shortest spacers, formed right-handed nanoscale chiral twists owing to crowded hydrogen bonding interactions. Moreover, the high-polarity solvent DMF was found to be able to regulate the chiral twist as well as its pitch length readily. PMID- 25833766 TI - Genomic instability in the PARK2 locus is associated with Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder affecting mostly elderly people, although there is a group of patients developing so-called early onset PD (EOPD). Mutations in the PARK2 gene are a common cause of autosomal recessive EOPD. PARK2 belongs to the family of extremely large human genes which are often localised in genomic common fragile sites (CFSs) and exhibit gross instability. PARK2 is located in the centre of FRA6E, the third most mutation susceptible CFS of the human genome. The gene encompasses a region of 1.3 Mbp and, among its mutations, large rearrangements of single or multiple exons account for around 50%. We performed an analysis of the PARK2 gene in a group of 344 PD patients with EOPD and classical form of the disease. Copy number changes were first identified using multiplex ligation probe amplification (MLPA), with their ranges characterised by array comparative genomic hybridisation (aCGH). Exact breakpoints were mapped using direct sequencing. Rearrangements were found in eight subjects, including five deletions and three duplications. Rearrangements were mostly non-recurrent and no repetitive sequences or extended homologies were identified in the regions flanking breakpoint junctions. However, in most cases, 1-3 bp microhomologies were present, strongly suggesting that microhomology-mediated mechanisms, specifically non-homologous end joining (NHEJ) and fork stalling and template switching (FoSTeS)/microhomology-mediated break induced replication (MMBIR), are predominantly involved in the rearrangement processes in this genomic region. PMID- 25833767 TI - Strategies for medical data extraction and presentation part 2: creating a customizable context and user-specific patient reference database. AB - One of the greatest challenges facing healthcare professionals is the ability to directly and efficiently access relevant data from the patient's healthcare record at the point of care; specific to both the context of the task being performed and the specific needs and preferences of the individual end-user. In radiology practice, the relative inefficiency of imaging data organization and manual workflow requirements serves as an impediment to historical imaging data review. At the same time, clinical data retrieval is even more problematic due to the quality and quantity of data recorded at the time of order entry, along with the relative lack of information system integration. One approach to address these data deficiencies is to create a multi-disciplinary patient referenceable database which consists of high-priority, actionable data within the cumulative patient healthcare record; in which predefined criteria are used to categorize and classify imaging and clinical data in accordance with anatomy, technology, pathology, and time. The population of this referenceable database can be performed through a combination of manual and automated methods, with an additional step of data verification introduced for data quality control. Once created, these referenceable databases can be filtered at the point of care to provide context and user-specific data specific to the task being performed and individual end-user requirements. PMID- 25833768 TI - Strategies for Medical Data Extraction and Presentation Part 3: Automated Context and User-Specific Data Extraction. AB - In current medical practice, data extraction is limited by a number of factors including lack of information system integration, manual workflow, excessive workloads, and lack of standardized databases. The combined limitations result in clinically important data often being overlooked, which can adversely affect clinical outcomes through the introduction of medical error, diminished diagnostic confidence, excessive utilization of medical services, and delays in diagnosis and treatment planning. Current technology development is largely inflexible and static in nature, which adversely affects functionality and usage among the diverse and heterogeneous population of end users. In order to address existing limitations in medical data extraction, alternative technology development strategies need to be considered which incorporate the creation of end user profile groups (to account for occupational differences among end users), customization options (accounting for individual end user needs and preferences), and context specificity of data (taking into account both the task being performed and data subject matter). Creation of the proposed context- and user-specific data extraction and presentation templates offers a number of theoretical benefits including automation and improved workflow, completeness in data search, ability to track and verify data sources, creation of computerized decision support and learning tools, and establishment of data-driven best practice guidelines. PMID- 25833769 TI - Development of a mother-child database for drug exposure and adverse event detection in the Military Health System. AB - PURPOSE: The aim of this study was to develop a mother-child linked database consisting of all eligible active duty military personnel, retirees, and their dependents in order to conduct medication-related analyses to improve the safety and quality of care in the Military Health System (MHS). METHODS: Eligible women of reproductive age with at least one pregnancy-related encounter between January 2005 and December 2013 receiving care in the MHS were included in the study population. Building on previously published algorithms, we used pregnancy related diagnostic and procedure codes, parameterized temporal constraints, and data elements unique to the MHS to identify pregnancies ending in live births, stillbirth, spontaneous abortion, or ectopic pregnancy. Pregnancies ending in live births were matched to presumptive offspring using birth dates and family based sponsorship identification. Antidepressant and antiepileptic use during pregnancy was evaluated using electronic pharmacy data. RESULTS: Algorithms identified 755,232 women who experienced 1,099,648 complete pregnancies with both pregnancy care encounter and pregnancy outcome. Of the 924,320 live birth pregnancies, 827,753 (90.0%) were matched to offspring. Algorithms also identified 5,663 stillbirths, 11,358 ectopic pregnancies, and 169,665 spontaneous abortions. Among the matched singleton live birth pregnancies, 7.1% of mothers were dispensed an antidepressant at any point during pregnancy, usually a selective serotonin reuptake inhibitor, (75.3%), whereas 1.3% of mothers were dispensed an antiepileptic drug. PMID- 25833770 TI - Mapping and determinism of soil microbial community distribution across an agricultural landscape. AB - Despite the relevance of landscape, regarding the spatial patterning of microbial communities and the relative influence of environmental parameters versus human activities, few investigations have been conducted at this scale. Here, we used a systematic grid to characterize the distribution of soil microbial communities at 278 sites across a monitored agricultural landscape of 13 km2. Molecular microbial biomass was estimated by soil DNA recovery and bacterial diversity by 16S rRNA gene pyrosequencing. Geostatistics provided the first maps of microbial community at this scale and revealed a heterogeneous but spatially structured distribution of microbial biomass and diversity with patches of several hundreds of meters. Variance partitioning revealed that both microbial abundance and bacterial diversity distribution were highly dependent of soil properties and land use (total variance explained ranged between 55% and 78%). Microbial biomass and bacterial richness distributions were mainly explained by soil pH and texture whereas bacterial evenness distribution was mainly related to land management. Bacterial diversity (richness, evenness, and Shannon index) was positively influenced by cropping intensity and especially by soil tillage, resulting in spots of low microbial diversity in soils under forest management. Spatial descriptors also explained a small but significant portion of the microbial distribution suggesting that landscape configuration also shapes microbial biomass and bacterial diversity. PMID- 25833771 TI - Glucagon-like peptide 1 interacts with ghrelin and leptin to regulate glucose metabolism and food intake through vagal afferent neuron signaling. AB - Emerging evidence has suggested a possible physiologic role for peripheral glucagon-like peptide 1 (GLP-1) in regulating glucose metabolism and food intake. The likely site of action of GLP-1 is on vagal afferent neurons (VANs). The vagal afferent pathway is the major neural pathway by which information about ingested nutrients reaches the central nervous system and influences feeding behavior. Peripheral GLP-1 acts on VANs to inhibit food intake. The mechanism of the GLP-1 receptor (GLP-1R) is unlike other gut-derived receptors; GLP-1Rs change their cellular localization according to feeding status rather than their protein concentrations. It is possible that several gut peptides are involved in mediating GLP-1R translocation. The mechanism of peripheral GLP-1R translocation still needs to be elucidated. We review data supporting the role of peripheral GLP-1 acting on VANs in influencing glucose homeostasis and feeding behavior. We highlight evidence demonstrating that GLP-1 interacts with ghrelin and leptin to induce satiation. Our aim was to understand the mechanism of peripheral GLP-1 in the development of noninvasive antiobesity treatments. PMID- 25833772 TI - Habitual physical activity and plasma metabolomic patterns distinguish individuals with low vs. high weight loss during controlled energy restriction. AB - BACKGROUND: Total weight loss induced by energy restriction is highly variable even under tightly controlled conditions. Identifying weight-loss discriminants would provide a valuable weight management tool and insights into body weight regulation. OBJECTIVE: This study characterized responsiveness to energy restriction in adults from variables including the plasma metabolome, endocrine and inflammatory markers, clinical indices, body composition, diet, and physical activity. METHODS: Data were derived from a controlled feeding trial investigating the effect of 3-4 dairy product servings in an energy-restricted diet (2092 kJ/d reduction) over 12 wk. Partial least squares regression was used to identify weight-loss discriminants in 67 overweight and obese adults. Linear mixed models were developed to identify discriminant variable differences in high vs. low-weight-loss responders. RESULTS: Both pre- and postintervention variables (n = 127) were identified as weight-loss discriminants (root mean squared error of prediction = 1.85 kg; Q(2) = 0.43). Compared with low-responders (LR), high-responders (HR) had greater decreases in body weight (LR: 2.7 +/- 1.6 kg; HR: 9.4 +/- 1.8 kg, P < 0.01), BMI (in kg/m(2); LR: 1.0 +/- 0.6; HR: 3.3 +/- 0.5, P < 0.01), and total fat (LR: 2.2 +/- 1.1 kg; HR: 8.0 +/- 2.1 kg, P < 0.01). Significant group effects unaffected by the intervention were determined for the respiratory exchange ratio (LR: 0.86 +/- 0.05; HR: 0.82 +/- 0.03, P < 0.01), moderate physical activity (LR: 127 +/- 52 min; HR: 167 +/- 68 min, P = 0.02), sedentary activity (LR: 1090 +/- 99 min; HR: 1017 +/- 110 min, P = 0.02), and plasma stearate [LR: 102,000 +/- 21,000 quantifier ion peak height (QIPH); HR: 116,000 +/- 24,000 QIPH, P = 0.01]. CONCLUSIONS: Overweight and obese individuals highly responsive to energy restriction had accelerated reductions in adiposity, likely supported in part by higher lipid mobilization and combustion. A novel observation was that person-to-person differences in habitual physical activity and magnitude of weight loss were accompanied by unique blood metabolite signatures. This trial was registered at clinicaltrials.gov as NCT00858312. PMID- 25833773 TI - Whey protein supplementation does not alter plasma branched-chained amino acid profiles but results in unique metabolomics patterns in obese women enrolled in an 8-week weight loss trial. AB - BACKGROUND: It has been suggested that perturbations in branched-chain amino acid (BCAA) catabolism are associated with insulin resistance and contribute to elevated systemic BCAAs. Evidence in rodents suggests dietary protein rich in BCAAs can increase BCAA catabolism, but there is limited evidence in humans. OBJECTIVE: We hypothesize that a diet rich in BCAAs will increase BCAA catabolism, which will manifest in a reduction of fasting plasma BCAA concentrations. METHODS: The metabolome of 27 obese women with metabolic syndrome before and after weight loss was investigated to identify changes in BCAA metabolism using GC-time-of-flight mass spectrometry. Subjects were enrolled in an 8-wk weight-loss study including either a 20-g/d whey (whey group, n = 16) or gelatin (gelatin group, n = 11) protein supplement. When matched for total protein by weight, whey protein has 3 times the amount of BCAAs compared with gelatin protein. RESULTS: Postintervention plasma abundances of Ile (gelatin group: 637 +/- 18, quantifier ion peak height / 100; whey group: 744 +/- 65), Leu (gelatin group: 1210 +/- 33; whey group: 1380 +/- 79), and Val (gelatin group: 2080 +/- 59; whey group: 2510 +/- 230) did not differ between treatment groups. BCAAs were significantly correlated with homeostasis model assessment of insulin resistance at baseline (r = 0.52, 0.43, and 0.49 for Leu, Ile, and Val, respectively; all, P < 0.05), but correlations were no longer significant at postintervention. Pro- and Cys-related pathways were found discriminant of whey protein vs. gelatin protein supplementation in multivariate statistical analyses. CONCLUSIONS: These findings suggest that BCAA metabolism is, at best, only modestly affected at a whey protein supplementation dose of 20 g/d. Furthermore, the loss of an association between postintervention BCAA and homeostasis model assessment suggests that factors associated with calorie restriction or protein intake affect how plasma BCAAs relate to insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT00739479. PMID- 25833774 TI - Tryptophan catabolism and vitamin B-6 status are affected by gender and lifestyle factors in healthy young adults. AB - BACKGROUND: Abnormalities of tryptophan (Trp) metabolism through the kynurenine (Kyn) pathway have been reported in various diseases; however, nutritional and lifestyle factors that affect this pathway in healthy individuals are not well documented. OBJECTIVE: Our aim was to examine the effect of vitamin B-6 status and lifestyle factors including the use of vitamin B-6 supplements, alcohol, smoking, and oral contraceptives on Trp and its Kyn metabolites in a cohort of 2436 healthy young adults aged 18-28 y. METHODS: Anthropometric and lifestyle data were collected by questionnaire. Participants provided blood samples for analysis of Trp, Kyn, anthranilic acid, kynurenic acid (KA), 3-hydroxykynurenine (HK), 3-hydroxyanthranilic acid (HAA), and xanthurenic acid (XA). Vitamin B-6 species were also measured. RESULTS: Serum Trp metabolites were 10-15% higher among men (n = 993) compared with women (n = 1443; P < 0.0001), except for HK and XA. In all participants, serum Trp was positively associated with plasma pyridoxal 5'-phosphate (PLP; r = 0.28, P < 0.0001), reaching a plateau at PLP concentrations of ~83 nmol/L. HK was inversely associated with PLP (r = -0.14, P < 0.01). Users of vitamin B-6 supplements (n = 671) had 6% lower concentrations of HK than nonusers (n = 1765; P = 0.0006). Oral contraceptive users (n = 385) had lower concentrations of KA (20.7%) but higher XA (24.1%) and HAA (9.0%) than did nonusers (n = 1058; P < 0.0001). After adjustment for gender and other lifestyle variables, XA concentrations were 16% higher in heavy drinkers (n = 713) than in never or occasional drinkers (n = 975; P = 0.0007). Concentrations of 2 other essential amino acids, methionine and arginine, also were positively associated with serum Trp (r = 0.65 and 0.33, respectively; P < 0.0001). CONCLUSIONS: In this population of healthy young adults, gender has the largest influence on serum Kyn metabolite concentrations. The significant covariance of Trp with unrelated amino acids suggests that protein intake may be an important consideration in evaluating Kyn metabolism. PMID- 25833775 TI - Dietary intakes of glutamic acid and glycine are associated with stroke mortality in Japanese adults. AB - BACKGROUND: Dietary intakes of glutamic acid and glycine have been reported to be associated with blood pressure. However, the link between intakes of these amino acids and stroke has not been studied. OBJECTIVE: We aimed to examine the association between glutamic acid and glycine intakes and the risk of mortality from stroke in a population-based cohort study in Japan. METHODS: The analyses included 29,079 residents (13,355 men and 15,724 women) of Takayama City, Japan, who were aged 35-101 y and enrolled in 1992. Their body mass index ranged from 9.9 to 57.4 kg/m(2). Their diets were assessed by a validated food frequency questionnaire. Deaths from stroke were ascertained over 16 y. RESULTS: During follow-up, 677 deaths from stroke (328 men and 349 women) were identified. A high intake of glutamic acid in terms of a percentage of total protein was significantly associated with a decreased risk of mortality from total stroke in women after controlling for covariates; the HR (95% CI) for the highest vs. lowest quartile was 0.72 (0.53, 0.98; P-trend: 0.03). Glycine intake was significantly associated with an increased risk of mortality from total and ischemic stroke in men without history of hypertension at baseline; the HRs (95% CIs) for the highest vs. lowest tertile were 1.60 (0.97, 2.51; P-trend: 0.03) and 1.88 (1.01, 3.52; P-trend: 0.02), respectively. There was no association between animal or vegetable protein intake and mortality from total and any subtype of stroke. CONCLUSION: The data suggest that glutamic acid and glycine intakes may be associated with risk of stroke mortality. Given that this is an initial observation, our results need to be confirmed. PMID- 25833776 TI - A proinflammatory diet is associated with systemic inflammation and reduced kidney function in elderly adults. AB - BACKGROUND: Diet can affect kidney health through its effects on inflammation. OBJECTIVE: We tested whether the Adapted Dietary Inflammatory Index (ADII) is associated with kidney function and whether effects of diet on chronic low-grade inflammation explain this association. METHODS: This was an observational analysis in 1942 elderly community-dwelling participants aged 70-71 y from 2 independent cohorts: the Uppsala Longitudinal Study of Adult Men (n = 1097 men) and the Prospective Investigation of Vasculature in Uppsala Seniors (n = 845 men and women). The ADII was calculated from 7-d food records, combining putatively proinflammatory and anti-inflammatory effects of nutrients, vitamins, and trace elements. The ADII was validated against serum C-reactive protein (CRP) concentrations. The estimated glomerular filtration rate (eGFR) was assessed from serum cystatin C (cys) and creatinine (crea). Associations between the ADII and eGFR were investigated, and CRP was considered to be a mediator. RESULTS: In adjusted analysis, a 1-SD higher ADII was associated with higher CRP (beta: 6%; 95% CI: 1%, 10%; P = 0.01) and lower eGFR [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)cys: -2.1%; 95% CI: -3.2%, -1.1%; CKD-EPIcys+crea: -1.8%; 95% CI: -2.7%, -0.9%; both P < 0.001]. CRP was also inversely associated with eGFR. Mediation analyses showed that of the total effect of the ADII on kidney function, 15% and 17% (for CKD-EPIcys+crea and CKD-EPIcys equations, respectively) were explained/mediated by serum CRP. Findings were similar when each cohort was analyzed separately. CONCLUSIONS: A proinflammatory diet was associated with systemic inflammation as well as with reduced kidney function in a combined analysis of 2 community-based cohorts of elderly individuals. Our results also suggest systemic inflammation to be one potential pathway through which this dietary pattern is linked to kidney function. PMID- 25833777 TI - A high-glycemic index, low-fiber breakfast affects the postprandial plasma glucose, insulin, and ghrelin responses of patients with type 2 diabetes in a randomized clinical trial. AB - BACKGROUND: Meals with a low glycemic index (GI) and rich in fiber could be beneficial with regard to postprandial metabolic profile and satiety. OBJECTIVE: The aim of this study was to investigate the effect of 4 breakfasts with a different GI and amount of fiber on postprandial plasma glucose, insulin, and appetite in patients with type 2 diabetes. METHODS: This randomized 4 intervention crossover trial included 14 patients [7 men; ages 65.8 +/- 5.2 y; glycated hemoglobin: 6.6 +/- 0.9%; BMI (in kg/m(2)): 27.2 +/- 3.1]. Dietary interventions were as follows: breakfasts with a high GI (60.4 +/- 0.1%) and high fiber (6.0 +/- 0.3 g) (HGI-HF), a high GI (60.9 +/- 1.7%) and low fiber (2.5 +/- 0.4 g) (HGI-LF), a low GI (37.7 +/- 0.1%) and high fiber (6.2 +/- 0.3 g) (LGI HF), and a low GI (39.8 +/- 1.3%) and low fiber (2.0 +/- 0.1 g) (LGI-LF). Plasma glucose, insulin, and total ghrelin were evaluated postprandially (0-180 min). A visual analog scale was used to assess appetite. Data were analyzed by generalized estimating equations and post hoc least significant difference (LSD) tests. Data are reported as means +/- SDs. RESULTS: The area under the curve (AUC) [mean (95% CI); P for LSD tests] for plasma glucose (mmol/L * min) was higher after patients consumed the HGI-LF breakfast [9.62 (8.39, 10.84)] than after the LGI-HF breakfast [8.95 (7.71, 10.18)] (P <= 0.05). Insulin AUC (MUIU/mL * min) after patients consumed the HGI-LF meal [65.72 (38.24, 93.19)] was higher than after the HGI-HF meal [57.24 (32.44, 82.04)] (P <= 0.05). The other observed difference was higher insulin AUC after the consumption of the LGI-LF breakfast [61.54 (36.61, 86.48)] compared with the AUC after the LGI-HF breakfast [54.16 (31.43, 76.88)] (P <= 0.05). Plasma ghrelin decreased in comparison with baseline only after patients consumed the LGI-HF and LGI-LF breakfasts (P <= 0.05). Subjective satiety did not differ between breakfasts. CONCLUSIONS: Plasma glucose, insulin, and ghrelin responses were least favorable when patients with type 2 diabetes consumed a breakfast with a high GI and low fiber, which suggests that reducing the GI or increasing the fiber content or both of breakfasts may be a useful strategy to improve the postprandial metabolic profile of these patients. This trial was registered at clinicaltrials.gov as NCT01410292. PMID- 25833778 TI - Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients. AB - BACKGROUND: Oxidative stress plays an essential role in the pathogenesis of type 2 diabetes. Anthocyanin, a natural antioxidant, has been reported to reduce oxidative stress and to attenuate insulin resistance and diabetes in animal models; however, the translation of these observations to humans has not been fully tested. OBJECTIVE: This study was designed to investigate the effects of purified anthocyanins on dyslipidemia, oxidative status, and insulin sensitivity in patients with type 2 diabetes. METHODS: A total of 58 diabetic patients were given 160 mg of anthocyanins twice daily or placebo (n = 29/group) for 24 wk in a randomized, placebo-controlled, double-blind trial. Participants and investigators were masked to treatment allocation. RESULTS: Anthocyanin supplementation significantly decreased serum LDL cholesterol (by 7.9%; P < 0.05), triglycerides (by 23.0%; P < 0.01), apolipoprotein (apo) B-48 (by 16.5%; P < 0.05), and apo C-III (by 11.0%; P < 0.01) and increased HDL cholesterol (by 19.4%; P < 0.05) compared with placebo after the 24-wk intervention. In addition, patients in the anthocyanin group showed higher total radical-trapping antioxidant parameter and ferric ion reducing antioxidant power values than did patients in the placebo group (both P < 0.05). Serum concentrations of 8-iso prostaglandin F2alpha, 13-hydroxyoctadecadienoic acid, and carbonylated proteins in patients in the anthocyanin group were significantly less than in patients in the placebo group (23.4%, 25.8%; P < 0.01 and 20%; P = 0.022, respectively). Furthermore, supplementation with anthocyanin lowered fasting plasma glucose (by 8.5%; P < 0.05) and homeostasis model assessment for insulin resistance index (by 13%; P < 0.05), and elevated serum adiponectin (by 23.4%; P < 0.01) and beta hydroxybutyrate (by 42.4%; P = 0.01) concentrations compared with placebo supplementation. CONCLUSION: These findings demonstrate that anthocyanin supplementation exerts beneficial metabolic effects in subjects with type 2 diabetes by improving dyslipidemia, enhancing antioxidant capacity, and preventing insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT02317211. PMID- 25833779 TI - Urine excretion of caffeine and select caffeine metabolites is common in the U.S. population and associated with caffeine intake. AB - BACKGROUND: Caffeine is a widely consumed psychoactive stimulant and is of epidemiologic interest. Major sources of caffeine are challenging to standardize, and the use of biomarkers is proposed as an alternative means of assessing intake. OBJECTIVE: We described urine caffeine and caffeine metabolite concentrations (n = 2466) and excretion rates (n = 2261) in the US population >=6 y by age, sex, race-ethnicity, and caffeine intake (from foods, beverages, and dietary supplements). METHODS: We measured caffeine and 14 of its metabolites in spot urine samples from the cross-sectional NHANES 2009-2010 by use of LC-tandem mass spectrometry. RESULTS: Caffeine and its metabolites were detectable in the urine of most persons, generally at concentrations >=1 MUmol/L. Median concentrations (95% CI) ranged from 0.560 (0.497, 0.620) MUmol/L to 58.6 (48.6, 67.2) MUmol/L; median excretion rates from 0.423 (0.385, 0.468) nmol/min to 46.0 (40.7, 50.2) nmol/min. Urine concentrations and excretion rates for 9 analytes (caffeine, theophylline, paraxanthine, 1-methylxanthine, 1-methyluric acid, 1,3 dimethyluric acid, 1,7-dimethyluric acid, 1,3,7-trimethyluric acid, and 5 acetylamino-6-amino-3-methyluracil) had moderate correlations with caffeine intake (Spearman rho = 0.55-0.68, P < 0.0001); the remaining analytes had low correlations (rho = 0.15-0.33, P < 0.0001). We observed larger differences in geometric mean concentrations and excretion rates between the highest vs. lowest quartiles of caffeine intake for these 9 compounds than the rest. Consistent with dietary caffeine intake, we observed that urine concentrations and excretion rates for most compounds were significantly (P < 0.05) higher in men than women, non-Hispanic whites than Hispanics and non-Hispanic blacks, and highest in persons aged 40-59 y. CONCLUSION: Excretion of caffeine and its metabolites in urine is common in the US population. According to the observed associations between spot urine concentrations or excretion rates with caffeine intake, several of these compounds show promise as potential biomarkers of caffeine intake. PMID- 25833780 TI - Dietary patterns track from infancy to preschool age: cross-sectional and longitudinal perspectives. AB - BACKGROUND: Although it has been suggested that dietary patterns emerge early in life, less is known about the extent to which they track through the toddler and preschool ages. OBJECTIVES: The objectives of this study were to derive cross sectional dietary patterns at 2, 3, and 5 y of age and assess their correlations and to derive multi-time point dietary patterns from ages 2-5 y and assess their associations with sociodemographic factors and infant feeding patterns. METHODS: Depending on the age considered, analyses included 989-1422 children from the EDEN (Etude des Determinants pre- et postnatals precoces du developpement et de la sante de l'ENfant) mother-child cohort. Dietary intake was collected with the use of food-frequency questionnaires at 2, 3, and 5 y of age. Principal component analyses were applied to these data, first cross-sectionally at each age, then longitudinally accounting for the data collected at all 3 ages. Tracking between patterns was estimated by Spearman correlation coefficients and associations with either the infant feeding patterns or the demographic and socioeconomic factors were assessed with the use of multivariable linear regression analyses. RESULTS: Overall, we derived 2 main cross-sectional patterns labeled "Processed and fast foods" and "Guidelines," the latter being characterized by intakes approximating age-specific dietary guidelines; and 2 multi-time point dietary patterns that corresponded to consistent exposures to similar foods across the 3 ages. The first, labeled "Processed and fast foods at 2, 3, and 5 y," was inversely associated with maternal education and age, and positively associated with the presence of older siblings. The second, called "Guidelines at 2, 3, and 5 y," was predicted by maternal education. Moderate tracking was observed between similar patterns assessed at different ages. CONCLUSIONS: Our findings confirmed the emergence of dietary profiles socially differentiated early in life as well as a moderate tracking of the diet. The promotion of healthy dietary trajectories should be encouraged as early as infancy, in particular in the presence of older siblings and among the most socially disadvantaged population groups. PMID- 25833782 TI - Vitamin D deficiency in school-age children is associated with sociodemographic and lifestyle factors. AB - BACKGROUND: There is concern about a reemergence of vitamin D deficiency in children in developed countries. OBJECTIVES: The aims of this study were to describe vitamin D status in the Generation R study, a large multiethnic cohort of 6-y-old children in The Netherlands, and to examine sociodemographic, lifestyle, and dietary determinants of vitamin D deficiency. METHODS: We measured serum 25-hydroxyvitamin D [25(OH)D] concentrations in 4167 children aged 6 y and defined deficiency following recommended cutoffs. We examined the associations between subject characteristics and vitamin D deficiency with the use of multivariable logistic regression analyses. RESULTS: Serum 25(OH)D concentrations ranged from 4 to 211 nmol/L (median: 64 nmol/L), with 6.2% of the children having severely deficient (<25 nmol/L), 23.6% deficient (25 to <50 nmol/L), 36.5% sufficient (50 to <75 nmol/L), and 33.7% optimal (>=75 nmol/L) 25(OH)D concentrations. The prevalence of vitamin D deficiency [25(OH)D <50 nmol/L] was higher in winter (51.3%) than in summer (10.3%); and higher in African, Asian, Turkish, and Moroccan children (54.5%) than in those with a Dutch or other Western ethnic background (17.6%). In multivariable models, several factors were associated with vitamin D deficiency, including household income (OR: 1.74; 95% CI: 1.34, 2.27 for low vs. high income), child age (OR: 1.39; 95% CI: 1.20, 1.62 per year), child television watching (OR: 1.32; 95% CI: 1.06, 1.64 for >=2 vs. <2 h/d), and playing outside (OR: 0.71; 95% CI: 0.57, 0.89 for >=1 vs. <1 h/d). In a subgroup with dietary data (n = 1915), vitamin D deficiency was associated with a lower diet quality, but not with vitamin D intake or supplement use in early childhood. CONCLUSIONS: Suboptimal vitamin D status is common among 6-y-old children in The Netherlands, especially among non-Western children and in winter and spring. Important modifiable factors associated with vitamin D deficiency were overall diet quality, sedentary behavior, and playing outside. PMID- 25833781 TI - Dietary modifications, weight loss, and changes in metabolic markers affect global DNA methylation in Hispanic, African American, and Afro-Caribbean breast cancer survivors. AB - BACKGROUND: Lower levels of global DNA methylation in tissue and blood have been associated with increased cancer risk. Conversely, cross-sectional analyses of healthier lifestyle patterns have been associated with higher levels of global DNA methylation. OBJECTIVE: In this trial, we explored the associations between changes in lifestyle modifications (diet, weight loss), metabolic markers, and global epigenetic biomarkers in white blood cells. METHODS: Study participants were Hispanic, African American, and Afro-Caribbean overweight and sedentary female breast cancer survivors (n = 24) who participated in a larger randomized, crossover, pilot study of a 6-mo weight loss intervention and who had available blood specimens. Anthropometric measures, a food-frequency questionnaire, and peripheral blood were collected at baseline, 6 mo, and 12 mo. Plasma samples were analyzed for metabolic markers (insulin, glucose). We measured DNA methylation of long interspersed nucleotide element 1 (LINE-1) and satellite 2 by pyrosequencing and MethyLight, respectively, and global DNA methylation by the luminometric methylation assay (LUMA). RESULTS: DNA methylation of LINE-1 was statistically significantly elevated at 6 mo [75.5% vs. 78.5% (P < 0.0001)] and 12 mo [75.5% vs. 77.7% (P < 0.0001)], compared to baseline. Over a 12-mo period, changes in percentage body fat and plasma glucose concentrations were positively associated with LINE-1 DNA methylation (beta = 0.19, P = 0.001) and LUMA DNA methylation levels (beta = 0.24, P = 0.02), respectively. Similarly, 12-mo changes in dietary measures such as vegetable (beta = 0.009, P = 0.048), protein (beta = 0.04, P = 0.001), and total caloric (beta = 0.05, P = 0.01) intake were positively associated with changes in LUMA DNA methylation, as was intake of fruit positively associated with changes in LINE-1 DNA methylation (beta = 0.004, P = 0.02). CONCLUSIONS: Our hypothesis-generating results suggest that lifestyle modifications may be associated with changes in global DNA methylation detectable at 6 and 12 mo. These biomarkers may be useful intermediate biomarkers to use in future intervention trials. This trial was registered at clinicaltrials.gov as NCT00811824. PMID- 25833783 TI - Mothers' child-feeding practices are associated with children's sugar-sweetened beverage intake. AB - BACKGROUND: Sugar-sweetened beverage (SSB) intake is a substantial source of energy in the diet of US children. OBJECTIVE: We examined the associations between mothers' child-feeding practices and SSB intake among 6-y-old children. METHODS: We analyzed data from the Year 6 Follow-up of the Infant Feeding Practices Study II in 1350 US children aged 6 y. The outcome variable was child's SSB intake. The exposure variables were 4 child-feeding practices of mothers: setting limits on sweets or junk foods, regulating their child's favorite food intake to prevent overconsumption, pressuring their child to eat enough, and pressuring their child to "clean the plate." We used multinomial logistic regression and controlled for child and maternal characteristics. Analyses were stratified on child weight status. RESULTS: The consumption of SSBs >=1 time/d was observed among 17.1% of underweight/normal-weight children and in 23.2% of overweight/obese children. Adjusted ORs (aORs) of consuming SSBs >=1 time/d (vs. no SSB consumption) were significantly lower in children whose mothers reported setting limits on sweets/junk foods (aOR: 0.29; 95% CI: 0.15, 0.58 for underweight/normal-weight children; aOR: 0.16; 95% CI: 0.03, 0.79 for overweight/obese children). SSB intake was higher among underweight/normal-weight children whose mothers reported trying to keep the child from eating too much of their favorite foods (aOR: 2.03; 95% CI: 1.25, 3.29). Mothers' tendency to pressure their children to consume more food or to "clean the plate" was not associated with child's SSB intake. CONCLUSIONS: SSBs were commonly consumed by young children. The odds of daily SSB intake were lower among children whose mothers set limits on sweets/junk foods regardless of child's weight but were higher among underweight/normal-weight children whose mothers restricted the child's favorite food intake. Future studies can investigate the impact of alternatives to restrictive feeding practices that could reduce children's SSB intake. PMID- 25833784 TI - Ready-to-use supplementary food increases fat mass and BMI in Haitian school-aged children. AB - BACKGROUND: In Haiti and other countries, large-scale investments in school feeding programs have been made with marginal evidence of nutrition outcomes. OBJECTIVE: We aimed to examine the effectiveness of a fortified ready-to-use supplementary food (RUSF), Mamba, on reduced anemia and improved body composition in school-aged children compared to an unfortified cereal bar, Tablet Yo, and control groups. METHODS: A cluster, randomized trial with children ages 3-13 y (n = 1167) was conducted in the north of Haiti. Six schools were matched and randomized to the control group, Tablet Yo group (42 g, 165 kcal), or Mamba group (50 g, 260 kcal, and >75% of the RDA for critical micronutrients). Children in the supplementation groups received the snack daily for 100 d, and all were followed longitudinally for hemoglobin concentrations, anthropometry, and bioelectrical impedance measures: baseline (December 2012), midline (March 2013), and endline (June 2013). Parent surveys were conducted at baseline and endline to examine secondary outcomes of morbidities and dietary intakes. Longitudinal regression modeling using generalized least squares and logit with random effects tested the main effects. RESULTS: At baseline,14.0% of children were stunted, 14.5% underweight, 9.1% thin, and 73% anemic. Fat mass percentage (mean +/- SD) was 8.1% +/- 4.3% for boys and 12.5% +/- 4.4% for girls. In longitudinal modeling, Mamba supplementation increased body mass index z score (regression coefficient +/- SEE) 0.25 +/- 0.06, fat mass 0.45 +/- 0.14 kg, and percentage fat mass 1.28% +/- 0.27% compared with control at each time point (P < 0.001). Among boys, Mamba increased fat mass (regression coefficient +/- SEE) 0.73 +/- 0.19 kg and fat-free mass 0.62 +/- 0.34 kg compared with control (P < 0.001). Mamba reduced the odds of developing anemia by 28% compared to control (adjusted OR: 0.72; 95% CI: 0.57, 0.91; P < 0.001). No treatment effect was found for hemoglobin concentration. CONCLUSION: To our knowledge, this is the first study to give evidence of body composition effects from an RUSF in school-aged children. PMID- 25833785 TI - Early childhood stunting is associated with lower developmental levels in the subsequent generation of children. AB - BACKGROUND: Linear growth retardation (stunting) is associated with lower adult cognition, educational attainment, and income. These effects, together with possible effects of stunting on birth weight and subsequent growth of offspring, suggest that stunting could be associated with poor development in the next generation of children. OBJECTIVE: The objective was to compare developmental levels in children born to parents who were stunted or nonstunted in early childhood. METHODS: This is a prospective cohort study of the children of participants in the Jamaica supplementation and stimulation study. The analysis compared children born to a parent who was stunted at age 9-24 mo, and did not receive the stimulation intervention, with children born to a parent in the nonstunted group. Developmental levels were measured with the Griffiths mental development scales between ages 12 and 72 mo. Mixed model regression analyses were conducted to allow for clustering of children within families and child (repeat assessments). The analyses included 89 children with a total of 156 assessments. Caregiver and home characteristics associated with the developmental quotient (DQ) or any of the subscales were included in the regressions. RESULTS: Children born to a stunted parent had lower DQs (-5.29 points; 95% CI: -9.06, 1.52 points; P = 0.01) and lower scores on the cognitive subscale (-5.77 points; 95% CI: -10.68, -0.87 points; P = 0.022). The offspring of stunted parents had lower height-for-age (-0.61 z scores; 95% CI: -1.13, -0.10 z scores; P = 0.021). In analyses, adjusting for child height-for-age or birth weight, the developmental differences remained significant. CONCLUSIONS: To our knowledge, this is the first report comparing the development of offspring of persons stunted in early childhood to the development of offspring of nonstunted parents. The findings suggest that the impact of stunting on development continues in the next generation of children. If replicated, these findings have important implications for estimation of the cost of stunting to social and economic development. PMID- 25833786 TI - Fish-oil-derived n-3 PUFAs reduce inflammatory and chemotactic adipokine-mediated cross-talk between co-cultured murine splenic CD8+ T cells and adipocytes. AB - BACKGROUND: Obese adipose tissue (AT) inflammation is characterized by dysregulated adipokine production and immune cell accumulation. Cluster of differentiation (CD) 8+ T cell AT infiltration represents a critical step that precedes macrophage infiltration. n-3 (omega-3) Polyunsaturated fatty acids (PUFAs) exert anti-inflammatory effects in obese AT, thereby disrupting AT inflammatory paracrine signaling. OBJECTIVE: We assessed the effect of n-3 PUFAs on paracrine interactions between adipocytes and primary CD8+ T cells co-cultured at the cellular ratio observed in obese AT. METHODS: C57BL/6 mice were fed either a 3% menhaden fish-oil + 7% safflower oil (FO) diet (wt:wt) or an isocaloric 10% safflower oil (wt:wt) control (CON) for 3 wk, and splenic CD8+ T cells were isolated by positive selection (via magnetic microbeads) and co-cultured with 3T3 L1 adipocytes. Co-cultures were unstimulated (cells alone), T cell receptor stimulated, or lipopolysaccharide (LPS) stimulated for 24 h. RESULTS: In LPS stimulated co-cultures, FO reduced secreted protein concentrations of interleukin (IL)-6 (-42.6%), tumor necrosis factor alpha (-67%), macrophage inflammatory protein (MIP) 1alpha (-52%), MIP-1beta (-62%), monocyte chemotactic protein (MCP) 1 (-23%), and MCP-3 (-19%) vs. CON, which coincided with a 74% reduction in macrophage chemotaxis toward secreted chemotaxins in LPS-stimulated FO-enriched co-culture-conditioned media. FO increased mRNA expression of the inflammatory signaling negative regulators monocyte chemoattractant 1-induced protein (Mcpip; +9.3-fold) and suppressor of cytokine signaling 3 (Socs3; +1.7-fold), whereas FO reduced activation of inflammatory transcription factors nuclear transcription factor kappaB (NF-kappaB) p65 and signal transducer and activator of transcription 3 (STAT3) by 27% and 33%, respectively. Finally, mRNA expression of the inflammasome components Caspase1 (-36.4%), Nod-like receptor family pyrin domain containing 3 (Nlrp3; -99%), and Il1b (-68.8%) were decreased by FO compared with CON (P <= 0.05). CONCLUSION: FO exerted an anti-inflammatory and antichemotactic effect on the cross-talk between CD8+ T cells and adipocytes and has implications in mitigating macrophage-centered AT-driven components of the obese phenotype. PMID- 25833788 TI - Erratum for Ferrario et al. Modulation of fecal Clostridiales bacteria and butyrate by probiotic intervention with Lactobacillus paracasei DG varies among healthy adults. J Nutr 2014;144:1787-1796. PMID- 25833787 TI - Erratum for Marini. Protein requirements: are we ready for new recommendations? J Nutr 2015;145:5-6. PMID- 25833790 TI - Prognostic value of complete remission status at end-of-treatment FDG-PET in R CHOP-treated diffuse large B-cell lymphoma: systematic review and meta-analysis. AB - This study systematically reviewed and meta-analysed the prognostic value of complete remission status at end-of-treatment (18) F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). The systematic PubMed/MEDLINE search yielded seven suitable studies comprising a total of 737 R-CHOP-treated DLBCL patients who were in complete remission at end-of-treatment FDG-PET. Overall, the methodological quality of included studies was reasonable. The disease relapse rate among all patients with complete remission status according to end-of-treatment FDG-PET ranged from 7.0% to 20.0%, with a weighted summary proportion of 13.7%. Five of seven studies reported progression-free survival (PFS) of these patients at various specific time points, i.e., 2-year PFS (n = 1), estimated 3-year PFS (n = 3) and 5-year PFS (n = 1), which was 83%, 85-86.4% and 75%, respectively. Three of seven studies reported overall survival (OS) of these patients at various specific time points, i.e., estimated 3-year OS (n = 2) and estimated 5-year OS (n = 1), which were 90%, 93.6% and 83%, respectively. In conclusion, a non negligible proportion of R-CHOP-treated DLBCL patients who achieve complete remission according to end-of-treatment FDG-PET experiences disease relapse during follow-up. PMID- 25833791 TI - Sol processing of conjugated carbon nitride powders for thin-film fabrication. AB - The chemical protonation of graphitic carbon nitride (CN) solids with strong oxidizing acids, for example HNO3, is demonstrated as an efficient pathway for the sol processing of a stable CN colloidal suspension, which can be translated into thin films by dip/disperse-coating techniques. The unique features of CN colloids, such as the polymeric matrix and the reversible hydrogen bonding, result in the thin-film electrodes derived from the sol solution exhibiting a high mechanical stability with improved conductivity for charge transport, and thus show a remarkably enhanced photo-electrochemical performance. The polymer system can in principle be broadly tuned by hybridization with desired functionalities, thus paving the way for the application of CN for specific tasks, as exemplified here by coupling with carbon nanotubes. PMID- 25833792 TI - Four-dimensional layer-stacking carbon-ion beam dose distribution by use of a lung numeric phantom. AB - To extend layer-stacking irradiation to accommodate intrafractional organ motion, we evaluated the carbon-ion layer-stacking dose distribution using a numeric lung phantom. We designed several types of range compensators. The planning target volume was calculated from the respective respiratory phases for consideration of intrafractional beam range variation. The accumulated dose distribution was calculated by registering of the dose distributions at respective phases to that at the reference phase. We evaluated the dose distribution based on the following six parameters: motion displacement, direction, gating window, respiratory cycle, range-shifter change time, and prescribed dose. All parameters affected the dose conformation to the moving target. By shortening of the gating window, dose metrics for superior-inferior (SI) and anterior-posterior (AP) motions were decreased from a D95 of 94 %, Dmax of 108 %, and homogeneity index (HI) of 23 % at T00-T90, to a D95 of 93 %, Dmax of 102 %, and HI of 20 % at T40-T60. In contrast, all dose metrics except the HI were independent of respiratory cycle. All dose metrics in SI motion were almost the same in respective motion displacement, with a D95 of 94 %, Dmax of 108 %, Dmin of 89 %, and HI of 23 % for the ungated phase, and D95 of 93 %, Dmax of 102 %, Dmin of 85 %, and HI of 20 % for the gated phase. The dose conformation to a moving target was improved by the gating strategy and by an increase in the prescribed dose. A combination of these approaches is a practical means of adding them to existing treatment protocols without modifications. PMID- 25833793 TI - Effect of biogeographic history on population vulnerability in European amphibians. AB - The genetic diversity of populations, which contributes greatly to their adaptive potential, is negatively affected by anthropogenic habitat fragmentation and destruction. However, continental-scale losses of genetic diversity also resulted from the population expansions that followed the end of the last glaciation, an element that is rarely considered in a conservation context. We addressed this issue in a meta-analysis in which we compared the spatial patterns of vulnerability of 18 widespread European amphibians in light of phylogeographic histories (glacial refugia and postglacial routes) and anthropogenic disturbances. Conservation statuses significantly worsened with distances from refugia, particularly in the context of industrial agriculture; human population density also had a negative effect. These findings suggest that features associated with the loss of genetic diversity in post-glacial amphibian populations (such as enhanced fixation load or depressed adaptive potential) may increase their susceptibility to current threats (e.g., habitat fragmentation and pesticide use). We propose that the phylogeographic status of populations (i.e., refugial vs. post-glacial) should be considered in conservation assessments for regional and national red lists. PMID- 25833794 TI - Computational chemistry for graphene-based energy applications: progress and challenges. AB - Research in graphene-based energy materials is a rapidly growing area. Many graphene-based energy applications involve interfacial processes. To enable advances in the design of these energy materials, such that their operation, economy, efficiency and durability is at least comparable with fossil-fuel based alternatives, connections between the molecular-scale structure and function of these interfaces are needed. While it is experimentally challenging to resolve this interfacial structure, molecular simulation and computational chemistry can help bridge these gaps. In this Review, we summarise recent progress in the application of computational chemistry to graphene-based materials for fuel cells, batteries, photovoltaics and supercapacitors. We also outline both the bright prospects and emerging challenges these techniques face for application to graphene-based energy materials in future. PMID- 25833795 TI - Vitamin D status in Well-Controlled Caucasian HIV Patients in Relation to Inflammatory and Metabolic Markers--A Cross-Sectional Cohort Study in Sweden. AB - To study vitamin D (25OH D3 ) in relation to (i) microbial translocation (ii) systemic inflammation and (iii) blood lipid markers, in Caucasian, well controlled HIV patients and healthy controls, plasma and serum samples from n = 97 male, HIV patients on HAART with immeasurable viral load (<20 copies/ml) since median 6.5 years and no concurrent inflammatory or infectious disease and n = 30 healthy controls were analysed for (i) LPS; (ii) sCD14, hsCRP, IL-4, IL-6, IL-10, IL-17, MCP-1 and IFN-gamma; as well as (iii) blood lipids. Vitamin D levels were similarly distributed and equally low in both HIV patients and controls. There was no association between vitamin D levels and markers of microbial translocation, systemic inflammation or dyslipidemia. LPS levels were similar in both groups but HIV patients expressed higher levels of sCD14 and hsCRP, with HIV as an independent risk factor. HIV patients had higher cholesterol and Apo B levels. Notably, more HIV patients smoked and smoking was associated with lower vitamin D levels. In conclusion; these well-treated Caucasian HIV patients had similar vitamin D levels as healthy controls. However, despite perfect virological control, they exhibited slightly increased inflammatory markers and disturbed blood lipids. However, neither of these parameters were associated with low vitamin D levels but appeared to be linked to the HIV-disease per se. Thus, the rationale for vitamin D substitution as a way to improve microbial translocation and systemic inflammation is not fully supported in this HIV population. PMID- 25833796 TI - Wandering anatomists and itinerant anthropologists: the antipodean sciences of race in Britain between the wars. AB - While the British Empire conventionally is recognized as a source of research subjects and objects in anthropology, and a site where anthropological expertise might inform public administration, the settler-colonial affiliations and experiences of many leading physical anthropologists could also directly shape theories of human variation, both physical and cultural. Antipodean anthropologists like Grafton Elliot Smith were pre-adapted to diffusionist models that explained cultural achievement in terms of the migration, contact and mixing of peoples. Trained in comparative methods, these fractious cosmopolitans also favoured a dynamic human biology, often emphasizing the heterogeneity and environmental plasticity of body form and function, and viewing fixed, static racial typologies and hierarchies sceptically. By following leading representatives of empire anatomy and physical anthropology, such as Elliot Smith and Frederic Wood Jones, around the globe, it is possible to recover the colonial entanglements and biases of interwar British anthropology, moving beyond a simple inventory of imperial sources, and crediting human biology and social anthropology not just as colonial sciences but as the sciences of itinerant colonials. PMID- 25833797 TI - John Flamsteed and the turn of the screw: mechanical uncertainty, the skilful astronomer and the burden of seeing correctly at the Royal Observatory, Greenwich. AB - Centring on John Flamsteed (1646-1719), the first Astronomer Royal, this paper investigates the ways in which astronomers of the late seventeenth century worked to build and maintain their reputations by demonstrating, for their peers and for posterity, their proficiency in managing visual technologies. By looking at his correspondence and by offering a graphic and textual analysis of the preface to his posthumous Historia Coelestis Britannica (1725), I argue that Flamsteed based the legitimacy of his life's work on his capacity to serve as a skilful astronomer who could coordinate the production and proper use of astronomical sighting instruments. Technological advances in astrometry were, for Flamsteed, a necessary but not a sufficient condition for the advancement of astronomy. Technological resources needed to be used by the right person. The work of the skilful astronomer was a necessary precondition for the mobilization and proper management of astronomical technologies. Flamsteed's understanding of the astronomer as a skilled actor importantly shifted the emphasis in precision astronomical work away from the individual observer's ability to see well and toward the astronomer's ability to ensure that instruments guaranteed accurate vision. PMID- 25833798 TI - 'Most rare workmen': optical practitioners in early seventeenth-century Delft. AB - A special interest in optics among various seventeenth-century painters living in the Dutch city of Delft has intrigued historians, including art historians, for a long time. Equally, the impressive career of the Delft microscopist Antoni van Leeuwenhoek has been studied by many historians of science. However, it has never been investigated who, at that time, had access to the mathematical and optical knowledge necessary for the impressive achievements of these Delft practitioners. We have tried to gain insight into Delft as a 'node' of optical knowledge by following the careers of three minor local figures in early seventeenth-century Delft. We argue that through their work, products, discussions in the vernacular and exchange of skills, rather than via learned publications, these practitioners constituted a foundation on which the later scientific and artistic achievements of other Delft citizens were built. Our Delft case demonstrates that these practitioners were not simple and isolated craftsmen; rather they were crucial components in a network of scholars, savants, painters and rich virtuosi. Decades before Vermeer made his masterworks, or Van Leeuwenhoek started his famous microscopic investigations, the intellectual atmosphere and artisanal knowledge in this city centred on optical topics. PMID- 25833799 TI - 'The televising of science is a process of television': establishing Horizon, 1962-1967. AB - BBC Television's Horizon series, fifty years old on 2 May 2014, despite its significance to the history of the public culture of science, has been little studied. This microhistorical account follows the gestation and early years of the programme, demonstrating how it established a social and cultural account of science. This was a result of televisual factors, notably the determination to follow the format of the successful arts television programme Monitor. It illuminates how the processes of television production, with a handful of key participants - Aubrey Singer, Gerald Leach, Philip Daly, Gordon Rattray Taylor, Ramsay Short, Michael Peacock and Robert Reid - established the format of the programme. This occurred over seventeen months of prior preparation followed by three troubled years of seeking to establish a stable form. This was finally achieved in 1967 when the programme adopted a film documentary approach after extended attempts at making it as a studio-based magazine programme. The story has implications for understanding the social accounts of science that were circulating in the key decade of the 1960s. PMID- 25833800 TI - Reinventing machines: the transmission history of the Leibniz calculator. AB - This paper argues that we should take into account the process of historical transmission to enrich our understanding of material culture. More specifically, I want to show how the rewriting of history and the invention of tradition impact material objects and our beliefs about them. I focus here on the transmission history of the mechanical calculator invented by the German savant Gottfried Wilhelm Leibniz. Leibniz repeatedly described his machine as functional and wonderfully useful, but in reality it was never finished and didn't fully work. Its internal structure also remained unknown. In 1879, however, the machine re emerged and was reinvented as the origin of all later calculating machines based on the stepped drum, to protect the priority of the German Leibniz against the Frenchman Thomas de Colmar as the father of mechanical calculation. The calculator was later replicated to demonstrate that it could function 'after all', in an effort to deepen this narrative and further enhance Leibniz's computing acumen. PMID- 25833801 TI - A history of the Allais paradox. AB - This article documents the history of the Allais paradox, and shows that underneath the many discussions of the various protagonists lay different, irreconcilable epistemological positions. Savage, like his mentor von Neumann and similar to economist Friedman, worked from an epistemology of generalized characterizations. Allais, on the other hand, like economists Samuelson and Baumol, started from an epistemology of exact descriptions in which every axiom was an empirical claim that could be refuted directly by observations. As a result, the two sides failed to find a common ground. Only a few decades later was the now so-called Allais paradox rediscovered as an important precursor when a new behavioural economic subdiscipline started to adopt the epistemology of exact descriptions and its accompanying falsifications of rational choice theory. PMID- 25833802 TI - Far from depleted.... PMID- 25833803 TI - Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular angiogenesis. AB - Due to its essential roles in angiogenesis, Notch pathway has emerged as an attractive target for the treatment of pathologic angiogenesis. Although both activation and blockage of Notch signal can impede angiogenesis, activation of Notch signal may be more promising because it was shown that long-term Notch signal blockage resulted in vessel neoplasm. However, an in vivo deliverable Notch ligand with highly efficient Notch-activating capacity has not been developed. Among all the Notch ligands, Delta-like4 (Dll4) is specifically involved in angiogenesis. In this study, we generated a novel soluble Notch ligand hD4R, which consists of the Delta-Serrate-Lag-2 fragment of human Dll4 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We demonstrated that hD4R could bind to ECs through its RGD motif and effectively triggered Notch signaling in ECs. Further, we confirmed that hD4R could suppress angiogenesis in vitro as manifested by network formation assay and sprouting assay. More importantly, hD4R efficiently repressed neonatal retinal angiogenesis and laser-induced choroidal neovascularization (CNV) as well in vivo. In conclusion, we have developed an in vivo deliverable Notch ligand hD4R, which suppresses angiogenesis both in vitro and in vivo, thus providing a new approach to tackle excessive angiogenesis relevant disease such as CNV. PMID- 25833804 TI - Chemical composition and antifungal activity of the volatile oil from Epichloe gansuensis, endophyte-infected and non-infected Achnatherum inebrians. PMID- 25833805 TI - Isolation and characterization of mesenchymal stem-like cells from human nucleus pulposus tissue. PMID- 25833806 TI - The diversity of coral associated bacteria and the environmental factors affect their community variation. AB - Coral associated bacterial community potentially has functions relating to coral health, nutrition and disease. Culture-free, 16S rRNA based techniques were used to compare the bacterial community of coral tissue, mucus and seawater around coral, and to investigate the relationship between the coral-associated bacterial communities and environmental variables. The diversity of coral associated bacterial communities was very high, and their composition different from seawater. Coral tissue and mucus had a coral associated bacterial community with higher abundances of Gammaproteobacteria. However, bacterial community in seawater had a higher abundance of Cyanobacteria. Different populations were also found in mucus and tissue from the same coral fragment, and the abundant bacterial species associated with coral tissue was very different from those found in coral mucus. The microbial diversity and OTUs of coral tissue were much higher than those of coral mucus. Bacterial communities of corals from more human activities site have higher diversity and evenness; and the structure of bacterial communities were significantly different from the corals collected from other sites. The composition of bacterial communities associated with same coral species varied with season's changes, geographic differences, and coastal pollution. Unique bacterial groups found in the coral samples from more human activities location were significant positively correlated to chemical oxygen demand. These coral specific bacteria lead to coral disease or adjust to form new function structure for the adaption of different surrounding needs further research. PMID- 25833807 TI - The impact of postpartum depression and anxiety disorders on children's processing of facial emotional expressions at pre-school age. AB - To enhance understanding of impaired socio-emotional development in children of postpartum depressed or anxious mothers, this longitudinal study addressed the question of whether maternal postpartum depression and anxiety disorders result in deficits in children's processing of facial emotional expressions (FEEs) at pre-school age. Thirty-two mothers who had fulfilled Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for postpartum depression and/or anxiety disorder and their pre-school aged children were tested for FEE processing abilities and compared to a healthy control group (n = 29). Child assessments included separate tasks for emotion recognition and emotion labelling. Mothers completed an emotion recognition test as well as the Structured Clinical Interview for DSM-IV Axis I Disorders I (SCID-I). Children of postpartum depressed and/or anxious mothers performed significantly worse than control children at labelling, but not at recognizing facial expressions of basic emotions. Emotion labelling at pre-school age was predicted by child age and maternal postpartum mental health, but neither current maternal mental health nor current maternal emotion recognition was associated with child FEE processing. Results point to a specific importance of early social experiences for the development of FEE labelling skills. However, further studies involving sensitive measures of emotion recognition are needed to determine if there might also exist subtle effects on FEE recognition. PMID- 25833809 TI - Decision management in transoral robotic surgery: Indications, individual patient selection, and role in the multidisciplinary treatment for head and neck cancer from a European perspective. AB - BACKGROUND: Transoral robotic surgery (TORS) has become an accepted first-line treatment for T1 and T2 head and neck squamous cell carcinoma (HNSCC). The growing popularity of this procedure is the result of mounting skepticism as to the survival and quality of life (QOL) benefits of primary chemoradiation over definitive surgery, the rising incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) in progressively younger patients, and the advantages of TORS over transoral laser microsurgery (TOLM) and open surgery. METHODS: The authors use their experience and data gained from the TORS based management of >100 patients to establish a systematic approach to the use of TORS in HNSCC. RESULTS: This approach is constructed on a framework which goal is to select the primary treatment option that is most likely to reduce morbidity while preserving function and maintaining oncologic safety. CONCLUSION: A consensus regarding the indications of TORS and its role in the multidisciplinary management of HNSCC is to be established. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2190-E2196, 2016. PMID- 25833808 TI - Avoidance as an obstacle to preventing depression among urban women at high risk for violent trauma. AB - The impact of depression interventions is often attenuated in women who have experienced trauma. We explored whether psychological avoidance could explain this phenomenon. We synthesized two pilot randomized trials of problem-solving education (PSE) among a total of 93 urban mothers. Outcomes included depressive symptoms and perceived stress. Mothers with avoidant coping styles experienced an average 1.25 episodes of moderately severe depressive symptoms over 3 months of follow-up, compared to 0.40 episodes among those with non-avoidant coping (adjusted incident rate ratio [aIRR] 2.18; 95 % CI 1.06, 4.48). PSE tended to perform better among mothers with non-avoidant coping. Among mothers with non avoidant coping, PSE mothers experienced an average 0.24 episodes, compared to 0.58 episodes among non-avoidant controls (aIRR 0.27; 95 % CI 0.05, 1.34). Among mothers with avoidant coping, PSE mothers experienced an average 1.26 episodes, compared to 1.20 episodes among avoidant controls (aIRR 0.76; 95 % CI 0.44, 1.33). This trend toward differential impact persisted when avoidance was measured as a problem-solving style and among traumatized mothers with and without avoidant PTSD symptoms. Further research is warranted to explore the hypothesis that psychological avoidance could explain why certain depression treatment and prevention strategies break down in the presence of trauma. PMID- 25833810 TI - Activation of KIT modulates the function of tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) in mast cells. AB - BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) associated with activating mutations of KIT. Tumor necrosis factor-related apoptosis-inducing ligand receptors (TRAIL-Rs) are preferentially expressed on neoplastic cells and induce the extrinsic apoptotic pathway. Recent studies reported on the expression of TRAIL-Rs and TRAIL-induced apoptosis in cultured human MCs, which depend on stem cell factor (SCF)-induced or constitutive KIT activation. MATERIAL AND METHODS: We sought to further define the impact of TRAIL Rs on MCs in vivo and in vitro. Using Cre/loxP recombination, we generated mice with MC-specific and ubiquitous knockout of TRAIL-R. In these mice, anaphylaxis and numbers of MCs were investigated. We also explored the expression and function of TRAIL-Rs in cultured murine and human MCs upon activation of KIT. By conducting immunofluorescence staining, we analyzed the expression of TRAIL-Rs in MCs infiltrating the bone marrow of patients with mastocytosis. RESULTS: MC specific deletion of TRAIL-R was associated with a slight, but significant increase in anaphylaxis. Numbers of MCs in MC-specific knockouts of TRAIL-R were comparable to controls. Whereas cultured IL-3-dependent murine MCs from wild-type mice were resistant to TRAIL-induced apoptosis, SCF-stimulated MCs underwent apoptosis in response to TRAIL. Interestingly, activating KIT mutations also promoted sensitivity to TRAIL-mediated apoptosis in human MCs. In line with these findings, MCs infiltrating the bone marrow of patients with mastocytosis expressed TRAIL-R1. CONCLUSIONS: Activation of KIT regulates the function of TRAIL-Rs in MCs. TRAIL-R1 may represent an attractive diagnostic and therapeutic target in diseases associated with KIT mutations, such as mastocytosis. PMID- 25833811 TI - Linguistic Markers of Inference Generation While Reading. AB - Words can be informative linguistic markers of psychological constructs. The purpose of this study is to examine associations between word use and the process of making meaningful connections to a text while reading (i.e., inference generation). To achieve this purpose, think-aloud data from third-fifth grade students ([Formula: see text]) reading narrative texts were hand-coded for inferences. These data were also processed with a computer text analysis tool, Linguistic Inquiry and Word Count, for percentages of word use in the following categories: cognitive mechanism words, nonfluencies, and nine types of function words. Findings indicate that cognitive mechanisms were an independent, positive predictor of connections to background knowledge (i.e., elaborative inference generation) and nonfluencies were an independent, negative predictor of connections within the text (i.e., bridging inference generation). Function words did not provide unique variance towards predicting inference generation. These findings are discussed in the context of a cognitive reflection model and the differences between bridging and elaborative inference generation. In addition, potential practical implications for intelligent tutoring systems and computer based methods of inference identification are presented. PMID- 25833812 TI - Reversal of Arthritis by Human Monomeric IgA Through the Receptor-Mediated SH2 Domain-Containing Phosphatase 1 Inhibitory Pathway. AB - OBJECTIVE: Rheumatoid arthritis (RA), one of the most frequent chronic inflammatory rheumatic disorders, is characterized by the presence of autoantibodies and joint infiltration by activated immune cells, leading to cartilage and bone destruction. IgA occurs predominantly as monomers (mIgA) in plasma and regulates many cell responses through interaction with the Fcalpha receptor type I (FcalphaRI). FcalphaRI targeting by anti-FcalphaRI Fab inhibits activating receptors by inducing an inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) configuration through SH2 domain-containing phosphatase 1 (SHP-1) recruitment. The aim of this study was to investigate the potential utility of mIgA for the treatment of arthritis by acting as an inducer of ITAMi signaling. METHODS: The effect of plasma-derived human mIgA on inhibition of multiple heterologous receptors was evaluated on FcalphaRI+ cell transfectants, blood phagocytes from healthy individuals, and synovial cells from RA patients. FcalphaRI-transgenic mice and wild-type mice treated with mIgA were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The mice were assessed for development of arthritis using an arthritis score, and joint tissue samples were evaluated for the extent of leukocyte infiltration and expression of phosphatase. RESULTS: Treatment with mIgA impaired cell activation in an FcalphaRI-FcRgamma-dependent manner, involving ITAMi signaling. Human mIgA or anti-FcalphaRI Fab were strongly effective in either preventing or attenuating CAIA or CIA in FcalphaRI-transgenic mice. Administration of mIgA markedly inhibited the recruitment of leukocytes to the inflamed joints of mice, which was associated with induction of SHP-1 phosphorylation in joint tissue cells. Moreover, mIgA reversed the state of inflammation in the synovial fluid of RA patients by inducing an ITAMi configuration. CONCLUSION: These results demonstrate a therapeutic potential of human mIgA in experimental arthritis. The findings support future clinical exploration of mIgA for the treatment of RA. PMID- 25833813 TI - Enhanced liver fibrosis score predicts transplant-free survival in primary sclerosing cholangitis. AB - There is a need to determine biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC). We evaluated the prognostic utility of the enhanced liver fibrosis (ELF) score in Norwegian PSC patients. Serum samples were available from 305 well-characterized large-duct PSC patients, 96 ulcerative colitis patients, and 100 healthy controls. The PSC patients constituted a derivation panel (recruited 1992-2006 [n = 167]; median age 41 years, 74% male) and a validation panel (recruited 2008-2012 [n = 138]; median age 40 years, 78% male). We used commercial kits to analyze serum levels of hyaluronic acid, tissue inhibitor of metalloproteinases-1, and propeptide of type III procollagen and calculated ELF scores by the previously published algorithm. Results were also validated by analysis of ELF tests using the ADVIA Centaur XP system and its commercially available reagents. We found that PSC patients stratified by ELF score tertiles exhibited significantly different transplant-free survival in both panels (P < 0.001), with higher scores associated with shorter survival, which was confirmed in the validation panel stratified by ELF test tertiles (P = 0.003). The ELF test distinguished between mild and severe disease defined by clinical outcome (transplantation or death) with an area under the curve of 0.81 (95% confidence interval [CI] 0.73-0.87) and optimal cutoff of 10.6 (sensitivity 70.2%, specificity 79.1%). In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively). The ELF test correlated with ultrasound elastography in separate assessments. CONCLUSION: The ELF score is a potent prognostic marker in PSC, independent of the Mayo risk score. PMID- 25833814 TI - Selective enhancement of topologically induced interface states in a dielectric resonator chain. AB - The recent realization of topological phases in insulators and superconductors has advanced the search for robust quantum technologies. The prospect to implement the underlying topological features controllably has given incentive to explore optical platforms for analogous realizations. Here we realize a topologically induced defect state in a chain of dielectric microwave resonators and show that the functionality of the system can be enhanced by supplementing topological protection with non-hermitian symmetries that do not have an electronic counterpart. We draw on a characteristic topological feature of the defect state, namely, that it breaks a sublattice symmetry. This isolates the state from losses that respect parity-time symmetry, which enhances its visibility relative to all other states both in the frequency and in the time domain. This mode selection mechanism naturally carries over to a wide range of topological and parity-time symmetric optical platforms, including couplers, rectifiers and lasers. PMID- 25833815 TI - A novel tunable blue-green-emitting CaGdGaAl2O7:Ce(3+),Tb(3+) phosphor via energy transfer for UV-excited white LEDs. AB - CaGdGaAl2O7 and CaGdGaAl2O7:Ce(3+),Tb(3+) have been synthesized by a traditional solid state reaction for the first time. The Rietveld refinement confirmed that CaGdGaAl2O7 has a tetragonal crystal system with the space group P4[combining macron]21m. The photoluminescence properties show that the obtained phosphors can be efficiently excited in the range from 330 to 400 nm, which matches perfectly with commercial UV LED chips. A tunable blue-green emitting CaGdGaAl2O7:Ce(3+),Tb(3+) phosphor has been obtained, by codoping Ce(3+) and Tb(3+) ions into the host and varying their relative ratios, and may be a good candidate for blue-green components in UV white LEDs. The luminescence properties and lifetimes reveal an efficient energy transfer from the Ce(3+) to Tb(3+) ions. The energy transfer is demonstrated to be a dipole-quadrupole mechanism, and the critical distance for Ce(3+) to Tb(3+) calculated by the concentration quenching is 12.25 A. PMID- 25833816 TI - Association between pressure pain sensitivity and autonomic function as assessed by a tilt table test. AB - BACKGROUND: We tested the hypothesis that pressure sensitivity of the sternum (PPS) is associated with autonomic nervous system (ANS) function as assessed by tilt table test (TTT). in patients with stable ischemic heart disease. OBJECTIVES: (1) To evaluate an association between PPS and systolic blood pressure (SBP) and heart rate (HR) responses to TTT; and (2) to test the hypothesis that a reduction of resting PPS raises the PPS, SBP and HR responses to TTT response and lowers risk factors for ANS dysfunction (ANSD). METHODS: Cross-sectional study: In 361 patients with stable ischemic heart disease we measured PPS, SBP, and HR during TTT. Intervention study: We reassessed subjects with persistent stress who concluded a stress intervention trial by a second TTT. RESULTS: Cross-sectional study: Resting PPS and the PPS response to TTT were correlated (r = - 0.37). The PPS response to TTT was correlated with that of SBP (r = 0.44) and HR (r = 0.49), and with the number of risk factors for ANSD (r = - 0.21) (all p < 0.0001). Intervention study: A reduction in resting PPS was associated with an increment in PPS response to TTT (r = - 0.52, p < 0.0001). The greater this increment, the greater was the reduction in ANSD risk factors (r = - 0.23; p = 0.003). CONCLUSION: The results are consistent with the hypothesis that PPS at rest and in response to TTT reflects ANS function. PMID- 25833817 TI - Hughlings Jackson on joking. PMID- 25833818 TI - Mutation analysis of CHCHD10 in different neurodegenerative diseases. PMID- 25833820 TI - Reply: Differential functions of ventral and dorsal striatum. PMID- 25833819 TI - Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. AB - Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret(r)) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain. PMID- 25833821 TI - Differential functions of ventral and dorsal striatum. PMID- 25833822 TI - Using toxicokinetic-toxicodynamic modeling as an acute risk assessment refinement approach in vertebrate ecological risk assessment. AB - Recent guidance identified toxicokinetic-toxicodynamic (TK-TD) modeling as a relevant approach for risk assessment refinement. Yet, its added value compared to other refinement options is not detailed, and how to conduct the modeling appropriately is not explained. This case study addresses these issues through 2 examples of individual-level risk assessment for 2 hypothetical plant protection products: 1) evaluating the risk for small granivorous birds and small omnivorous mammals of a single application, as a seed treatment in winter cereals, and 2) evaluating the risk for fish after a pulsed treatment in the edge-of-field zone. Using acute test data, we conducted the first tier risk assessment as defined in the European Food Safety Authority (EFSA) guidance. When first tier risk assessment highlighted a concern, refinement options were discussed. Cases where the use of models should be preferred over other existing refinement approaches were highlighted. We then practically conducted the risk assessment refinement by using 2 different models as examples. In example 1, a TK model accounting for toxicokinetics and relevant feeding patterns in the skylark and in the wood mouse was used to predict internal doses of the hypothetical active ingredient in individuals, based on relevant feeding patterns in an in-crop situation, and identify the residue levels leading to mortality. In example 2, a TK-TD model accounting for toxicokinetics, toxicodynamics, and relevant exposure patterns in the fathead minnow was used to predict the time-course of fish survival for relevant FOCUS SW exposure scenarios and identify which scenarios might lead to mortality. Models were calibrated using available standard data and implemented to simulate the time-course of internal dose of active ingredient or survival for different exposure scenarios. Simulation results were discussed and used to derive the risk assessment refinement endpoints used for decision. Finally, we compared the "classical" risk assessment approach with the model-based approach. These comparisons showed that TK and TK-TD models can bring more realism to the risk assessment through the possibility to study realistic exposure scenarios and to simulate relevant mechanisms of effects (including delayed toxicity and recovery). Noticeably, using TK-TD models is currently the most relevant way to directly connect realistic exposure patterns to effects. We conclude with recommendations on how to properly use TK and TK-TD model in acute risk assessment for vertebrates. PMID- 25833823 TI - STAT3 and HIF1alpha Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors. AB - Therapeutic options are limited for neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNST) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoral molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signaling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1, and S1507.2) were used. The data demonstrate that small-molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration, and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion, and tumor formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3 functions as a common driver of tumorigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of hypoxia-inducible factor (HIF)1alpha, HIF2alpha, and VEGF-A in all four MPNST lines. Finally, the data demonstrate that wound healing, cell migration, invasion, and tumor formation through STAT3 are highly dependent on HIF signaling, where knockdown of HIF1alpha ablated these oncogenic facets of STAT3. IMPLICATIONS: This research reveals that aberrant STAT3 and HIF1a activity drives tumor progression in MPNSTs, indicating that inhibition of the STAT3/HIF1alpha/VEGF-A signaling axis is a viable treatment strategy. PMID- 25833824 TI - Medical student web-based formative assessment tool for renal pathology. AB - BACKGROUND: Web-based formative assessment tools have become widely recognized in medical education as valuable resources for self-directed learning. OBJECTIVES: To explore the educational value of formative assessment using online quizzes for kidney pathology learning in our renal pathophysiology course. METHODS: Students were given unrestricted and optional access to quizzes. Performance on quizzed and non-quizzed materials of those who used ('quizzers') and did not use the tool ('non-quizzers') was compared. Frequency of tool usage was analyzed and satisfaction surveys were utilized at the end of the course. RESULTS: In total, 82.6% of the students used quizzes. The greatest usage was observed on the day before the final exam. Students repeated interactive and more challenging quizzes more often. Average means between final exam scores for quizzed and unrelated materials were almost equal for 'quizzers' and 'non-quizzers', but 'quizzers' performed statistically better than 'non-quizzers' on both, quizzed (p=0.001) and non-quizzed (p=0.024) topics. In total, 89% of surveyed students thought quizzes improved their learning experience in this course. CONCLUSIONS: Our new computer assisted learning tool is popular, and although its use can predict the final exam outcome, it does not provide strong evidence for direct improvement in academic performance. Students who chose to use quizzes did well on all aspects of the final exam and most commonly used quizzes to practice for final exam. Our efforts to revitalize the course material and promote learning by adding interactive online formative assessments improved students' learning experience overall. PMID- 25833825 TI - Mentoring in general surgery in Switzerland. AB - BACKGROUND: Mentorship has been found as a key factor for a successful and satisfying career in academic medicine and surgery. The present study was conducted to describe the current situation of mentoring in the surgical community in Switzerland and to evaluate sex differences regarding the impact of mentoring on career success and professional satisfaction. METHODS: The study was designed as an anonymous national survey to all members of the Swiss Surgical Society in 2011 (820 ordinary and 49 junior members). It was a 25-item questionnaire addressing mentor-mentee relationships and their impact on the professional front. RESULTS: Of the 869 mailed surveys, 512 responses were received (response rate: 58.9%). Mentor-mentee relationships were reported by 344 respondents (68.1%) and structured mentoring programs were noted in 23 respondents (6.7%). Compared to individuals without mentors, male mentees exhibited significantly higher subjective career advancement (5.4+/-1.2 vs. 5.0+/ 1.3; p=0.03) and career development (3.3+/-1.9 vs. 2.5+/-1.7; p<0.01) scores, but the differences for female mentees were not statistically significant (4.7+/-1.1 vs. 4.3+/-1.2, p=0.16; 2.5+/-1.6 vs. 1.9+/-1.4, p=0.26; respectively). The pursuit of an academic career was not influenced by the presence of a mentor mentee relationship for female (p=0.14) or male participants (p=0.22). CONCLUSIONS: Mentor-mentee relationships are important for the career advancement of male surgeons. The reason for the lack of an impact on the careers of female surgeons is difficult to ascertain. However, mentoring also provides lifelong learning and personal development. Thus, specific attention should be paid to the development of more structured mentoring programs for both sexes. PMID- 25833826 TI - Low zinc and selenium concentrations in sepsis are associated with oxidative damage and inflammation. AB - BACKGROUND: Oxidative stress with dysregulated inflammation are hallmarks of sepsis. Zinc and selenium have important antioxidant functions, such that they could be important in patients with sepsis. We used an in vitro approach to assess the effect of zinc and selenium on oxidative stress, mitochondrial function, and inflammatory responses in conditions mimicking sepsis and related the findings to plasma concentrations and biomarkers in patients with and without sepsis. METHODS: Human endothelial cells were exposed to a range of zinc and selenium concentrations in conditions mimicking sepsis. Zinc, selenium, and a series of biomarkers of oxidative stress and inflammation were measured in plasma from critically ill patients with and without sepsis. RESULTS: Culturing cells with different concentrations of zinc caused altered zinc transporter protein expression and cellular zinc content, and selenium affected glutathione peroxidase 3 activity. Although zinc or selenium at physiological concentrations had no effect on interleukin-6 release in vitro, higher concentrations of the trace elements were associated with improved mitochondrial function. Plasma zinc and selenium concentrations were low in patients [zinc: median (range) 4.6 (2.1 6.5) MUM in control patients without sepsis and 3.1 (1.5-5.4) MUM in patients with sepsis, P=0.002; and selenium: 0.78 (0.19-1.32) MUM in control patients and 0.42 (0.22-0.91) MUM in sepsis patients, P=0.0009]. Plasma concentrations of interleukin-6, other biomarkers of inflammation, and markers of oxidative damage to proteins and lipids were elevated, particularly in patients with sepsis, and were inversely related to plasma zinc and selenium concentrations. CONCLUSIONS: Zinc and selenium concentrations were reduced in critically ill patients, with increased oxidative stress and inflammatory biomarkers, particularly in patients with sepsis. Oxidative stress as a result of suboptimal selenium and zinc concentrations might contribute to damage of key proteins. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: registration number NCT01328509. PMID- 25833827 TI - "It is a thin line to walk on": challenges of staff working at Swedish immigration detention centres. AB - Detention of irregular migrants awaiting deportation is widely practiced in many countries and has been shown to have profound negative impact on health and well being of detainees. Detention staff, an integral part of the detention environment, affect and are affected by detainees' health and well-being. The objective of the study was to explore experiences of staff working at Swedish immigration detention centres. Fifteen semi-structured interviews were conducted with staff in three Swedish detention centres and were analysed using thematic analysis. The results indicate that the main challenge for the staff was to manage the emotional dilemma entailed in working as migration officers and simultaneously fellow human beings whose task was to implement deportation decisions while being expected to provide humane service to detainees. They tried to manage their dilemma by balancing the two roles, but still found it challenging. Among the staff, there was a high perception of fear of physical threat from detainees that made detention a stressful environment. Limited interaction between the staff and detainees was a reason for this. There is thus a need to support detention staff to improve their interaction with detainees in order to decrease their fear, manage their emotional dilemma, and provide better service to detainees. It is important to address staff challenges in order to ensure better health and well-being for both staff and detainees. PMID- 25833829 TI - PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion. AB - Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis. PMID- 25833830 TI - Loss of TGFbeta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance. AB - One third of the patients with estrogen receptor alpha (ERalpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ERalpha and TGFbeta signaling, such that tamoxifen nonresponsiveness or resistance in breast cancer might involve aberrant TGFbeta signaling. In this study, we analyzed TGFbeta receptor type 2 (TGFBR2) expression and correlated it with ERalpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ERalpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ERalpha phosphorylation, tamoxifen-induced transcriptional activation of TGFbeta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGFbeta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ERalpha positive forms of this disease. PMID- 25833831 TI - Correction: Resveratrol inhibits drug-induced apoptosis in human leukemia cells by creating an intracellular milieu nonpermissive for death execution. PMID- 25833832 TI - Correction: Genetic Polymorphisms and Protein Expression of NRF2 and Sulfiredoxin Predict Survival Outcomes in Breast Cancer. PMID- 25833833 TI - Letter to the editor: The effect of autonomic nervous system on the association between epicardial adipose tissue and cognitive function. PMID- 25833834 TI - Reply to "Letter to the editor: The effect of autonomic nervous system on the association between epicardial adipose tissue and cognitive function". PMID- 25833835 TI - PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer. AB - PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAK(Y397) in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAK(Y397) expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAK(Y397) expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAK(Y397) expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. PMID- 25833836 TI - Chemotherapy-Regulated microRNA-125-HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer. AB - Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. HER2 is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2 targeted therapy for SCLC remains unclear. Here, we first identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR-125b bound to the 3'-untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay, we demonstrated a significantly enhanced cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the enhanced antitumor effect of these agents in an orthotopic lung cancer model in vivo. Our results offer a novel therapeutic strategy for HER2-positive SCLCs by using trastuzumab combined with cytotoxic drugs. PMID- 25833837 TI - Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer. AB - There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)-based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC 1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8(+) T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8(+) T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by alphaSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials. PMID- 25833838 TI - TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression. AB - The testicular nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily that mediates various biologic functions with key impacts on metabolic disorders and tumor progression. Here, we demonstrate that TR4 may play a positive role in prostate cancer CD133(+) stem/progenitor (S/P) cell invasion. Targeting TR4 with lentiviral silencing RNA significantly suppressed prostate cancer CD133(+) S/P cell invasion both in vitro and in vivo. Mechanism dissection found that TR4 transcriptionally regulates the oncogene EZH2 via binding to its 5' promoter region. The consequences of targeting TR4 to suppress EZH2 expression may then suppress the expression of its downstream key metastasis-related genes, including NOTCH1, TGFbeta1, SLUG, and MMP9. Rescue approaches via adding the EZH2 reversed the TR4-mediated prostate cancer S/P cell invasion. Together, these results suggest that the TR4->EZH2 signaling may play a critical role in the prostate cancer S/P cell invasion and may allow us to develop a better therapy to battle the prostate cancer metastasis. PMID- 25833840 TI - Chromosomal meiotic segregation, embryonic developmental kinetics and DNA (hydroxy)methylation analysis consolidate the safety of human oocyte vitrification. AB - Oocyte vitrification has been introduced into clinical settings without extensive pre-clinical safety testing. In this study, we analysed major safety aspects of human oocyte vitrification in a high security closed system: (i) chromosomal meiotic segregation, (ii) embryonic developmental kinetics and (iii) DNA (hydroxy)methylation status. Fresh and vitrified sibling oocytes from young donors after intracytoplasmic sperm injection (ICSI) were compared in three different assays. Firstly, the chromosomal constitution of the fertilized zygotes was deduced from array comparative genomic hybridization results obtained from both polar bodies biopsied at Day 1. Secondly, embryo development up to Day 3 was analysed by time-lapse imaging. Ten specific time points, six morphokinetic time intervals and the average cell number on Day 3 were recorded. Thirdly, global DNA methylation and hydroxymethylation patterns were analysed by immunostaining on Day 3 embryos. The nuclear fluorescence intensity was measured by Volocity imaging software. Comprehensive chromosomal screening of the polar bodies demonstrated that at least half of the zygotes obtained after ICSI of fresh and vitrified oocytes were euploid. Time-lapse analysis showed that there was no significant difference in cleavage timings, the predictive morphokinetic time intervals nor the average cell number between embryos developed from fresh and vitrified oocytes. Finally, global DNA (hydroxy)methylation patterns were not significantly different between Day 3 embryos obtained from fresh and from vitrified oocytes. Our data further consolidate the safety of the oocyte vitrification technique. Nevertheless, additional testing in young and older sub fertile/infertile patients and sound follow-up studies of children born after oocyte cryopreservation remain mandatory. PMID- 25833839 TI - Awake vs. anesthetized: layer-specific sensory processing in visual cortex and functional connectivity between cortical areas. AB - During general anesthesia, global brain activity and behavioral state are profoundly altered. Yet it remains mostly unknown how anesthetics alter sensory processing across cortical layers and modulate functional cortico-cortical connectivity. To address this gap in knowledge of the micro- and mesoscale effects of anesthetics on sensory processing in the cortical microcircuit, we recorded multiunit activity and local field potential in awake and anesthetized ferrets (Mustela putoris furo) during sensory stimulation. To understand how anesthetics alter sensory processing in a primary sensory area and the representation of sensory input in higher-order association areas, we studied the local sensory responses and long-range functional connectivity of primary visual cortex (V1) and prefrontal cortex (PFC). Isoflurane combined with xylazine provided general anesthesia for all anesthetized recordings. We found that anesthetics altered the duration of sensory-evoked responses, disrupted the response dynamics across cortical layers, suppressed both multimodal interactions in V1 and sensory responses in PFC, and reduced functional cortico-cortical connectivity between V1 and PFC. Together, the present findings demonstrate altered sensory responses and impaired functional network connectivity during anesthesia at the level of multiunit activity and local field potential across cortical layers. PMID- 25833841 TI - Salt Accelerates Allograft Rejection through Serum- and Glucocorticoid-Regulated Kinase-1-Dependent Inhibition of Regulatory T Cells. AB - A high-salt diet (HSD) in humans is linked to a number of complications, including hypertension and cardiovascular events. Whether a HSD affects the immune response in transplantation is unknown. Using a murine transplantation model, we investigated the effect of NaCl on the alloimmune response in vitro and in vivo. Incremental NaCl concentrations in vitro augmented T cell proliferation in the settings of both polyclonal and allospecific stimulation. Feeding a HSD to C57BL/6 wild-type recipients of bm12 allografts led to accelerated cardiac allograft rejection, despite similar mean BP and serum sodium levels in HSD and normal salt diet (NSD) groups. The accelerated rejection was associated with a reduction in the proportion of CD4(+)Foxp3(+) regulatory T cells (Tregs) and a significant decrease in Treg proliferation, leading to an increased ratio of antigen-experienced CD4(+) T cells to Tregs in mice recipients of a HSD compared with mice recipients of a NSD. Because serum- and glucocorticoid-regulated kinase 1 (SGK1) has been proposed as a potential target of salt in immune cells, we fed a HSD to CD4(Cre)SGK1(fl/fl) B6-transplanted recipients and observed abrogation of the deleterious effect of a HSD in the absence of SGK1 on CD4(+) cells. In summary, we show that NaCl negatively affects the regulatory balance of T cells in transplantation and precipitates rejection in an SGK1-dependent manner. PMID- 25833842 TI - Signaling networks: information flow, computation, and decision making. AB - Signaling pathways come together to form networks that connect receptors to many different cellular machines. Such networks not only receive and transmit signals but also process information. The complexity of these networks requires the use of computational models to understand how information is processed and how input output relationships are determined. Two major computational approaches used to study signaling networks are graph theory and dynamical modeling. Both approaches are useful; network analysis (application of graph theory) helps us understand how the signaling network is organized and what its information-processing capabilities are, whereas dynamical modeling helps us determine how the system changes in time and space upon receiving stimuli. Computational models have helped us identify a number of emergent properties that signaling networks possess. Such properties include ultrasensitivity, bistability, robustness, and noise-filtering capabilities. These properties endow cell-signaling networks with the ability to ignore small or transient signals and/or amplify signals to drive cellular machines that spawn numerous physiological functions associated with different cell states. PMID- 25833846 TI - The PI3K-PKB/Akt pathway. PMID- 25833844 TI - Meiosis and maternal aging: insights from aneuploid oocytes and trisomy births. AB - In most organisms, genome haploidization requires reciprocal DNA exchanges (crossovers) between replicated parental homologs to form bivalent chromosomes. These are resolved to their four constituent chromatids during two meiotic divisions. In female mammals, bivalents are formed during fetal life and remain intact until shortly before ovulation. Extending this period beyond ~35 years greatly increases the risk of aneuploidy in human oocytes, resulting in a dramatic increase in infertility, miscarriage, and birth defects, most notably trisomy 21. Bivalent chromosomes are stabilized by cohesion between sister chromatids, which is mediated by the cohesin complex. In mouse oocytes, cohesin becomes depleted from chromosomes during female aging. Consistent with this, premature loss of centromeric cohesion is a major source of aneuploidy in oocytes from older women. Here, we propose a mechanistic framework to reconcile data from genetic studies on human trisomy and oocytes with recent advances in our understanding of the molecular mechanisms of chromosome segregation during meiosis in model organisms. PMID- 25833845 TI - Adult neurogenesis in neurodegenerative diseases. AB - Adult neurogenesis is limited to specific brain regions in the mammalian brain, such as the hippocampal dentate gyrus and the subventricular zone/olfactory bulb system. Alterations in adult neurogenesis appear to be a common hallmark in different neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This is remarkable, because the distinct pathological proteins responsible for the different diseases induce the loss of different neural populations. Impaired adult neurogenesis was shown in numerous animal models of neurodegenerative diseases; however, only few postmortem studies have been performed. We will review concepts related to the interplay between cellular plasticity in regions of adult neurogenesis with a specific focus on cell-autonomous and non-cell-autonomous factors. Furthermore, various strategies aimed to stimulate neuronal plasticity will be discussed within the context of a potential translation into therapeutic approaches for neuropsychiatric symptoms associated with PD, HD, and AD. PMID- 25833843 TI - Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. AB - Homologous recombination (HR) is a major pathway for the repair of DNA double strand breaks in mammalian cells, the defining step of which is homologous strand exchange directed by the RAD51 protein. The physiological importance of HR is underscored by the observation of genomic instability in HR-deficient cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HR genes. The tumor suppressors BRCA1 and BRCA2, key players at different stages of HR, are frequently mutated in familial breast and ovarian cancers. Other HR proteins, including PALB2 and RAD51 paralogs, have also been identified as tumor suppressors. This review summarizes recent findings on BRCA1, BRCA2, and associated proteins involved in human disease with an emphasis on their molecular roles and interactions. PMID- 25833847 TI - Caspase functions in cell death and disease. PMID- 25833849 TI - The nature of nurture in a wild mammal's fitness. AB - Genetic variation in fitness is required for the adaptive evolution of any trait but natural selection is thought to erode genetic variance in fitness. This paradox has motivated the search for mechanisms that might maintain a population's adaptive potential. Mothers make many contributions to the attributes of their developing offspring and these maternal effects can influence responses to natural selection if maternal effects are themselves heritable. Maternal genetic effects (MGEs) on fitness might, therefore, represent an underappreciated source of adaptive potential in wild populations. Here we used two decades of data from a pedigreed wild population of North American red squirrels to show that MGEs on offspring fitness increased the population's evolvability by over two orders of magnitude relative to expectations from direct genetic effects alone. MGEs are predicted to maintain more variation than direct genetic effects in the face of selection, but we also found evidence of maternal effect trade-offs. Mothers that raised high-fitness offspring in one environment raised low-fitness offspring in another environment. Such a fitness trade-off is expected to maintain maternal genetic variation in fitness, which provided additional capacity for adaptive evolution beyond that provided by direct genetic effects on fitness. PMID- 25833848 TI - Early-late life trade-offs and the evolution of ageing in the wild. AB - Empirical evidence for declines in fitness components (survival and reproductive performance) with age has recently accumulated in wild populations, highlighting that the process of senescence is nearly ubiquitous in the living world. Senescence patterns are highly variable among species and current evolutionary theories of ageing propose that such variation can be accounted for by differences in allocation to growth and reproduction during early life. Here, we compiled 26 studies of free-ranging vertebrate populations that explicitly tested for a trade-off between performance in early and late life. Our review brings overall support for the presence of early-late life trade-offs, suggesting that the limitation of available resources leads individuals to trade somatic maintenance later in life for high allocation to reproduction early in life. We discuss our results in the light of two closely related theories of ageing-the disposable soma and the antagonistic pleiotropy theories-and propose that the principle of energy allocation roots the ageing process in the evolution of life history strategies. Finally, we outline research topics that should be investigated in future studies, including the importance of natal environmental conditions in the study of trade-offs between early- and late-life performance and the evolution of sex-differences in ageing patterns. PMID- 25833850 TI - Stable isotopes reveal links between human food inputs and urban ant diets. AB - The amount of energy consumed within an average city block is an order of magnitude higher than that consumed in any other ecosystem over a similar area. This is driven by human food inputs, but the consequence of these resources for urban animal populations is poorly understood. We investigated the role of human foods in ant diets across an urbanization gradient in Manhattan using carbon and nitrogen stable isotopes. We found that some-but not all-ant species living in Manhattan's most urbanized habitats had delta(13)C signatures associated with processed human foods. In particular, pavement ants (Tetramorium sp. E) had increased levels of delta(13)C similar to delta(13)C levels in human fast foods. The magnitude of this effect was positively correlated with urbanization. By contrast, we detected no differences in delta(15)N, suggesting Tetramorium feeds at the same trophic level despite shifting to human foods. This pattern persisted across the broader ant community; species in traffic islands used human resources more than park species. Our results demonstrate that the degree urban ants exploit human resources changes across the city and among species, and this variation could play a key role in community structure and ecosystem processes where human and animal food webs intersect. PMID- 25833851 TI - Ancient collagen reveals evolutionary history of the endemic South American 'ungulates'. AB - Since the late eighteenth century, fossils of bizarre extinct creatures have been described from the Americas, revealing a previously unimagined chapter in the history of mammals. The most bizarre of these are the 'native' South American ungulates thought to represent a group of mammals that evolved in relative isolation on South America, but with an uncertain affinity to any particular placental lineage. Many authors have considered them descended from Laurasian 'condylarths', which also includes the probable ancestors of perissodactyls and artiodactyls, whereas others have placed them either closer to the uniquely South American xenarthrans (anteaters, armadillos and sloths) or the basal afrotherians (e.g. elephants and hyraxes). These hypotheses have been debated owing to conflicting morphological characteristics and the hitherto inability to retrieve molecular information. Of the 'native' South American mammals, only the toxodonts and litopterns persisted until the Late Pleistocene-Early Holocene. Owing to known difficulties in retrieving ancient DNA (aDNA) from specimens from warm climates, this research presents a molecular phylogeny for both Macrauchenia patachonica (Litopterna) and Toxodon platensis (Notoungulata) recovered using proteomics-based (liquid chromatography-tandem mass spectrometry) sequencing analyses of bone collagen. The results place both taxa in a clade that is monophyletic with the perissodactyls, which today are represented by horses, rhinoceroses and tapirs. PMID- 25833852 TI - Sex-chromosome differentiation and 'sex races' in the common frog (Rana temporaria). AB - Sex-chromosome differentiation was recently shown to vary among common frog populations in Fennoscandia, suggesting a trend of increased differentiation with latitude. By rearing families from two contrasted populations (respectively, from northern and southern Sweden), we show this disparity to stem from differences in sex-determination mechanisms rather than in XY-recombination patterns. Offspring from the northern population display equal sex ratios at metamorphosis, with phenotypic sexes that correlate strongly with paternal LG2 haplotypes (the sex chromosome); accordingly, Y haplotypes are markedly differentiated, with male specific alleles and depressed diversity testifying to their smaller effective population size. In the southern population, by contrast, a majority of juveniles present ovaries at metamorphosis; only later in development do sex ratios return to equilibrium. Even at these later stages, phenotypic sexes correlate only mildly with paternal LG2 haplotypes; accordingly, there are no recognizable Y haplotypes. These distinct patterns of gonadal development fit the concept of 'sex races' proposed in the 1930s, with our two populations assigned to the 'differentiated' and 'semi-differentiated' races, respectively. Our results support the suggestion that 'sex races' differ in the genetic versus epigenetic components of sex determination. Analysing populations from the 'undifferentiated race' with high-density genetic maps should help to further test this hypothesis. PMID- 25833853 TI - Distributed nestmate recognition in ants. AB - We propose a distributed model of nestmate recognition, analogous to the one used by the vertebrate immune system, in which colony response results from the diverse reactions of many ants. The model describes how individual behaviour produces colony response to non-nestmates. No single ant knows the odour identity of the colony. Instead, colony identity is defined collectively by all the ants in the colony. Each ant responds to the odour of other ants by reference to its own unique decision boundary, which is a result of its experience of encounters with other ants. Each ant thus recognizes a particular set of chemical profiles as being those of non-nestmates. This model predicts, as experimental results have shown, that the outcome of behavioural assays is likely to be variable, that it depends on the number of ants tested, that response to non-nestmates changes over time and that it changes in response to the experience of individual ants. A distributed system allows a colony to identify non-nestmates without requiring that all individuals have the same complete information and helps to facilitate the tracking of changes in cuticular hydrocarbon profiles, because only a subset of ants must respond to provide an adequate response. PMID- 25833854 TI - Bacterial adaptation to sublethal antibiotic gradients can change the ecological properties of multitrophic microbial communities. AB - Antibiotics leak constantly into environments due to widespread use in agriculture and human therapy. Although sublethal concentrations are well known to select for antibiotic-resistant bacteria, little is known about how bacterial evolution cascades through food webs, having indirect effect on species not directly affected by antibiotics (e.g. via population dynamics or pleiotropic effects). Here, we used an experimental evolution approach to test how temporal patterns of antibiotic stress, as well as migration within metapopulations, affect the evolution and ecology of microcosms containing one prey bacterium, one phage and two protist predators. We found that environmental variability, autocorrelation and migration had only subtle effects for population and evolutionary dynamics. However, unexpectedly, bacteria evolved greatest fitness increases to both antibiotics and enemies when the sublethal levels of antibiotics were highest, indicating positive pleiotropy. Crucially, bacterial adaptation cascaded through the food web leading to reduced predator-to-prey abundance ratio, lowered predator community diversity and increased instability of populations. Our results show that the presence of natural enemies can modify and even reverse the effects of antibiotics on bacteria, and that antibiotic selection can change the ecological properties of multitrophic microbial communities by having indirect effects on species not directly affected by antibiotics. PMID- 25833855 TI - Biogeography of worm lizards (Amphisbaenia) driven by end-Cretaceous mass extinction. AB - Worm lizards (Amphisbaenia) are burrowing squamates that live as subterranean predators. Their underground existence should limit dispersal, yet they are widespread throughout the Americas, Europe and Africa. This pattern was traditionally explained by continental drift, but molecular clocks suggest a Cenozoic diversification, long after the break-up of Pangaea, implying dispersal. Here, we describe primitive amphisbaenians from the North American Palaeocene, including the oldest known amphisbaenian, and provide new and older molecular divergence estimates for the clade, showing that worm lizards originated in North America, then radiated and dispersed in the Palaeogene following the Cretaceous Palaeogene (K-Pg) extinction. This scenario implies at least three trans-oceanic dispersals: from North America to Europe, from North America to Africa and from Africa to South America. Amphisbaenians provide a striking case study in biogeography, suggesting that the role of continental drift in biogeography may be overstated. Instead, these patterns support Darwin and Wallace's hypothesis that the geographical ranges of modern clades result from dispersal, including oceanic rafting. Mass extinctions may facilitate dispersal events by eliminating competitors and predators that would otherwise hinder establishment of dispersing populations, removing biotic barriers to dispersal. PMID- 25833856 TI - Biotic interactions govern genetic adaptation to toxicants. AB - The genetic recovery of resistant populations released from pesticide exposure is accelerated by the presence of environmental stressors. By contrast, the relevance of environmental stressors for the spread of resistance during pesticide exposure has not been studied. Moreover, the consequences of interactions between different stressors have not been considered. Here we show that stress through intraspecific competition accelerates microevolution, because it enhances fitness differences between adapted and non-adapted individuals. By contrast, stress through interspecific competition or predation reduces intraspecific competition and thereby delays microevolution. This was demonstrated in mosquito populations (Culex quinquefasciatus) that were exposed to the pesticide chlorpyrifos. Non-selective predation through harvesting and interspecific competition with Daphnia magna delayed the selection for individuals carrying the ace-1(R) resistance allele. Under non-toxic conditions, susceptible individuals without ace-1(R) prevailed. Likewise, predation delayed the reverse adaptation of the populations to a non-toxic environment, while the effect of interspecific competition was not significant. Applying a simulation model, we further identified how microevolution is generally determined by the type and degree of competition and predation. We infer that interactions with other species-especially strong in ecosystems with high biodiversity-can delay the development of pesticide resistance. PMID- 25833857 TI - Genome-wide association mapping in a wild avian population identifies a link between genetic and phenotypic variation in a life-history trait. AB - Understanding the genetic basis of traits involved in adaptation is a major challenge in evolutionary biology but remains poorly understood. Here, we use genome-wide association mapping using a custom 50 k single nucleotide polymorphism (SNP) array in a natural population of collared flycatchers to examine the genetic basis of clutch size, an important life-history trait in many animal species. We found evidence for an association on chromosome 18 where one SNP significant at the genome-wide level explained 3.9% of the phenotypic variance. We also detected two suggestive quantitative trait loci (QTLs) on chromosomes 9 and 26. Fitness differences among genotypes were generally weak and not significant, although there was some indication of a sex-by-genotype interaction for lifetime reproductive success at the suggestive QTL on chromosome 26. This implies that sexual antagonism may play a role in maintaining genetic variation at this QTL. Our findings provide candidate regions for a classic avian life-history trait that will be useful for future studies examining the molecular and cellular function of, as well as evolutionary mechanisms operating at, these loci. PMID- 25833858 TI - The effects of connectivity on metapopulation persistence: network symmetry and degree correlations. AB - A spatial metapopulation is a mosaic of interconnected patch populations. The complex routes of colonization between the patches are governed by the metapopulation's dispersal network. Over the past two decades, there has been considerable interest in uncovering the effects of dispersal network topology and its symmetry on metapopulation persistence. While most studies find that the level of symmetry in dispersal pattern enhances persistence, some have reached the conclusion that symmetry has at most a minor effect. In this work, we present a new perspective on the debate. We study properties of the in- and out-degree distribution of patches in the metapopulation which define the number of dispersal routes into and out of a particular patch, respectively. By analysing the spectral radius of the dispersal matrices, we confirm that a higher level of symmetry has only a marginal impact on persistence. We continue to analyse different properties of the in-out degree distribution, namely the 'in-out degree correlation' (IODC) and degree heterogeneity, and find their relationship to metapopulation persistence. Our analysis shows that, in contrast to symmetry, the in-out degree distribution and particularly, the IODC are dominant factors controlling persistence. PMID- 25833859 TI - Fertility decline and the changing dynamics of wealth, status and inequality. AB - In the course of demographic transitions (DTs), two large-scale trends become apparent: (i) the broadly positive association between wealth, status and fertility tends to reverse, and (ii) wealth inequalities increase and then temporarily decrease. We argue that these two broad patterns are linked, through a diversification of reproductive strategies that subsequently converge as populations consume more, become less self-sufficient and increasingly depend on education as a route to socio-economic status. We examine these links using data from 22 mid-transition communities in rural Poland. We identify changing relationships between fertility and multiple measures of wealth, status and inequality. Wealth and status generally have opposing effects on fertility, but these associations vary by community. Where farming remains a viable livelihood, reproductive strategies typical of both pre- and post-DT populations coexist. Fertility is lower and less variable in communities with lower wealth inequality, and macro-level patterns in inequality are generally reproduced at the community level. Our results provide a detailed insight into the changing dynamics of wealth, status and inequality that accompany DTs at the community level where peoples' social and economic interactions typically take place. We find no evidence to suggest that women with the most educational capital gain wealth advantages from reducing fertility, nor that higher educational capital delays the onset of childbearing in this population. Rather, these patterns reflect changing reproductive preferences during a period of profound economic and social change, with implications for our understanding of reproductive and socio economic inequalities in transitioning populations. PMID- 25833861 TI - The impact of over 80 years of land cover changes on bee and wasp pollinator communities in England. AB - Change in land cover is thought to be one of the key drivers of pollinator declines, and yet there is a dearth of studies exploring the relationships between historical changes in land cover and shifts in pollinator communities. Here, we explore, for the first time, land cover changes in England over more than 80 years, and relate them to concurrent shifts in bee and wasp species richness and community composition. Using historical data from 14 sites across four counties, we quantify the key land cover changes within and around these sites and estimate the changes in richness and composition of pollinators. Land cover changes within sites, as well as changes within a 1 km radius outside the sites, have significant effects on richness and composition of bee and wasp species, with changes in edge habitats between major land classes also having a key influence. Our results highlight not just the land cover changes that may be detrimental to pollinator communities, but also provide an insight into how increases in habitat diversity may benefit species diversity, and could thus help inform policy and practice for future land management. PMID- 25833860 TI - Insect antimicrobial peptides show potentiating functional interactions against Gram-negative bacteria. AB - Antimicrobial peptides (AMPs) and proteins are important components of innate immunity against pathogens in insects. The production of AMPs is costly owing to resource-based trade-offs, and strategies maximizing the efficacy of AMPs at low concentrations are therefore likely to be advantageous. Here, we show the potentiating functional interaction of co-occurring insect AMPs (the bumblebee linear peptides hymenoptaecin and abaecin) resulting in more potent antimicrobial effects at low concentrations. Abaecin displayed no detectable activity against Escherichia coli when tested alone at concentrations of up to 200 MUM, whereas hymenoptaecin affected bacterial cell growth and viability but only at concentrations greater than 2 MUM. In combination, as little as 1.25 MUM abaecin enhanced the bactericidal effects of hymenoptaecin. To understand these potentiating functional interactions, we investigated their mechanisms of action using atomic force microscopy and fluorescence resonance energy transfer-based quenching assays. Abaecin was found to reduce the minimal inhibitory concentration of hymenoptaecin and to interact with the bacterial chaperone DnaK (an evolutionarily conserved central organizer of the bacterial chaperone network) when the membrane was compromised by hymenoptaecin. These naturally occurring potentiating interactions suggest that combinations of AMPs could be used therapeutically against Gram-negative bacterial pathogens that have acquired resistance to common antibiotics. PMID- 25833862 TI - A simple model for the influence of habitat resource availability on lateral clonal spread. AB - Plant clonal spread is ubiquitous and of great interest, owing both to its key role in plant community assembly and its suitability for plant behaviour research. However, mechanisms that govern spreading distance are not well known. Here we link spacer costs and below-ground competition in a simple model of growth in a homogeneous below-ground environment, in which optimal distance between ramets is based on minimizing the sum of these costs. Using this model, we predict a high prevalence of clonal growth that does not employ spacers in resource-poor environments and a nonlinear increase in spreading distance in response to increasing below-ground resource availability. Analysis of database data on clonal growth in relationship to below-ground resource availability revealed that patterns of the spread based on stolons is compatible with the model's predictions. As expected, model prediction failed for rhizomatous species, where spacer sizes are likely to be selected mainly to play roles other than spread. The model's simplicity makes it useful as a null model in testing hypotheses about the effects of environmental heterogeneity on clonal spread. PMID- 25833863 TI - Avoidable errors in the modelling of outbreaks of emerging pathogens, with special reference to Ebola. AB - As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely used modelling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far overestimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola virus disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modelling response to future infectious disease outbreaks. PMID- 25833864 TI - Correction to 'Sex-specific, counteracting responses to inbreeding in a bird'. PMID- 25833865 TI - Technological innovations in mental healthcare: harnessing the digital revolution. AB - Digital technology has the potential to transform mental healthcare by connecting patients, services and health data in new ways. Digital online and mobile applications can offer patients greater access to information and services and enhance clinical management and early intervention through access to real-time patient data. However, substantial gaps exist in the evidence base underlying these technologies. Greater patient and clinician involvement is needed to evaluate digital technologies and ensure they target unmet needs, maintain public trust and improve clinical outcomes. PMID- 25833866 TI - Lawfulness of preventive recall from a community treatment order. AB - Preventive recall to hospital of a patient on a community treatment order can be lawful when it is based on a convincing prediction that relapse in illness would otherwise occur. The legislation for England and Wales provides several indications that authorising preventive recall in those circumstances is a purpose of the community treatment order regime. PMID- 25833867 TI - Interventions to improve the experience of caring for people with severe mental illness: systematic review and meta-analysis. AB - BACKGROUND: Informal caregiving is an integral part of the care of people with severe mental illness, but the support needs of those providing such care are not often met. AIMS: To determine whether interventions provided to people caring for those with severe mental illness improve the experience of caring and reduce caregiver burden. METHOD: We conducted a systematic review and meta-analyses of randomised controlled trials (RCTs) of interventions delivered by health and social care services to informal carers (i.e. family or friends who provide support to someone with severe mental illness). RESULTS: Twenty-one RCTs with 1589 carers were included in the review. There was evidence suggesting that the carers' experience of care was improved at the end of the intervention by psychoeducation (standardised mean difference -1.03, 95% CI -1.69 to -0.36) and support groups (SMD = -1.16, 95% CI -1.96 to -0.36). Psychoeducation had a benefit on psychological distress more than 6 months later (SMD = -1.79, 95% CI 3.01 to -0.56) but not immediately post-intervention. Support interventions had a beneficial effect on psychological distress at the end of the intervention (SMD = -0.99, 95% CI -1.48 to -0.49) as did problem-solving bibliotherapy (SMD = -1.57, 95% CI -1.79 to -1.35); these effects were maintained at follow-up. The quality of the evidence was mainly low and very low. Evidence for combining these interventions and for self-help and self-management was inconclusive. CONCLUSIONS: Carer-focused interventions appear to improve the experience of caring and quality of life and reduce psychological distress of those caring for people with severe mental illness, and these benefits may be gained in first episode psychosis. Interventions for carers should be considered as part of integrated services for people with severe mental health problems. PMID- 25833872 TI - Intergenerational transmission of psychopathy. PMID- 25833873 TI - Authors' reply. PMID- 25833874 TI - Influences of schizophrenia risk variant rs7914558 at CNNM2 on brain structure. PMID- 25833875 TI - Authors' reply. PMID- 25833877 TI - From the Editor's desk: matters of the heart and mind. PMID- 25833876 TI - Kaleidoscope. PMID- 25833879 TI - Optimizing stroke prevention in atrial fibrillation: better adherence and compliance from patients and physicians leads to better outcomes. PMID- 25833880 TI - Corrigendum to: European Cardiac Resynchronization Therapy Survey II: rationale and design. PMID- 25833881 TI - Radiofrequency ablation on veno-arterial extracorporeal life support in treatment of very sick infants with incessant tachymyopathy. AB - AIMS: To evaluate the use of extracorporeal membrane oxygenation (ECMO) in supporting infants who require radiofrequency ablation (RFA) for incessant tachyarrhythmias, with particular emphasis on modifications required to standard ablation techniques. METHODS AND RESULTS: Three cases of RFA carried out in infancy on ECMO support were reviewed retrospectively. Two infants with permanent junctional reciprocating tachycardia (PJRT) and one with ventricular tachycardia (VT) presented in a low cardiac output state, owing to cardiomyopathy caused by incessant tachycardia. In each case antiarrhythmic drug therapy caused haemodynamic collapse, requiring emergency ECMO support. Drug therapy on ECMO was not successful. In one patient, the tachycardia was controlled on ECMO with antiarrhythmic drugs, but recurred following ECMO decannulation. Each patient had a successful RFA on ECMO support. Power delivery was low during ablation lesions. In the PJRT cases power as low as 3-5 Watts was effective. In the VT ablation, an irrigated tip RFA catheter was required when cooling remained poor even after temporarily stopping ECMO flow. CONCLUSION: Extracorporeal membrane oxygenation provides a haemodynamically stable and safe platform for antiarrhythmic drug therapy and RFA in infants with incessant tachyarrhythmias. Once ECMO has been commenced, if the tachyarrhythmia remains difficult to control with antiarrhythmic drugs, RFA should be strongly considered, to avoid the risk of tachycardia recurrence following ECMO decannulation. Power delivery during ablation lesions may be low because of inadequate cooling of the catheter tip. Reducing or stopping flow in the ECMO circuit may not provide adequate cooling and an irrigated tip catheter may be required. PMID- 25833882 TI - Usefulness of exercise test in the diagnosis of short QT syndrome. AB - AIMS: Short QT syndrome (SQTS) is a rare arrhythmogenic inherited heart disease. Diagnosis can be challenging in subjects with slightly shortened QT interval at electrocardiogram. In this study we compared the QT interval behaviour during exercise in a cohort of SQTS patients with a control group, to evaluate the usefulness of exercise test in the diagnosis of SQTS. METHODS AND RESULTS: Twenty one SQTS patients and 20 matched control subjects underwent an exercise test. QT interval was measured at different heart rates (HRs), at rest and during effort. The relation between QT interval and HR was evaluated by linear regression analysis according to the formula: QT = beta *HR + alpha, where beta is the slope of the linear relation, and alpha is the intercept. Rest and peak exercise HRs were not different in the two groups. Short QT syndrome patients showed lower QT intervals as compared with controls both at rest (276 +/- 27 ms vs. 364 +/- 25 ms, P < 0.0001) and at peak exercise (228 +/- 27 ms vs. 245 +/- 26 ms, P = 0.05), with a mean variation from rest to peak effort of 48 +/- 14 ms vs. 120 +/- 20 ms (P < 0.0001). Regression analysis of QT/HR relationship revealed a less steep slope for SQTS patients compared with the control group, never exceeding the value of -0.90 ms/beat/min (mean value -0.53 +/- 0.15 ms/beat/min vs. -1.29 +/- 0.30 ms/beat/min, P < 0.0001). CONCLUSION: Short QT syndrome patients show a reduced adaptation of the QT interval to HR. Exercise test can be a useful tool in the diagnosis of SQTS. PMID- 25833883 TI - Left atrial appendage closure-indications, techniques, and outcomes: results of the European Heart Rhythm Association Survey. AB - The purpose of this EP Wire was to assess the indications, techniques, and outcomes of left atrial appendage occlusion (LAAO) in Europe. Thirty-three European centres, all members of the European Heart Rhythm Association electrophysiology (EP) research network, responded to this survey by completing the questionnaire. The major indication for LAAO (94%) was the prevention of stroke in patients at high thrombo-embolic risk (CHA2DS2-VASc >= 2) and contraindications to oral anticoagulants (OACs). Twenty-one (64%) of the responding centres perform LAAO in their own institution and 80% implanted 30 or less LAAO devices in 2014. Two-dimensional transoesophageal echocardiography was the preferred imaging technique to visualize LAA before, during, and after LAAO in 79, 58, and 62% of the participating centres, respectively. Following LAAO, 49% of the centres prescribe vitamin K antagonists or novel OACs. Twenty-five per cent of the centres combine LAAO with pulmonary vein isolation. The periprocedural complications included death (range, 0-3%), ischaemic or haemorrhagic stroke (0-25%), tamponade (0-25%), and device embolization (0-20%). In conclusion, this EP Wire has demonstrated that LAAO is most commonly employed in patients at high thrombo-embolic risk in whom OAC is contraindicated. The technique is not yet very widespread and the complication rates remain significant. PMID- 25833884 TI - Catheter ablation via the brachial artery of ventricular arrhythmia originating from the right coronary cusp. PMID- 25833885 TI - Estimating the population distribution of usual 24-hour sodium excretion from timed urine void specimens using a statistical approach accounting for correlated measurement errors. AB - BACKGROUND: High US sodium intake and national reduction efforts necessitate developing a feasible and valid monitoring method across the distribution of low to-high sodium intake. OBJECTIVE: We examined a statistical approach using timed urine voids to estimate the population distribution of usual 24-h sodium excretion. METHODS: A sample of 407 adults, aged 18-39 y (54% female, 48% black), collected each void in a separate container for 24 h; 133 repeated the procedure 4-11 d later. Four timed voids (morning, afternoon, evening, overnight) were selected from each 24-h collection. We developed gender-specific equations to calibrate total sodium excreted in each of the one-void (e.g., morning) and combined two-void (e.g., morning + afternoon) urines to 24-h sodium excretion. The calibrated sodium excretions were used to estimate the population distribution of usual 24-h sodium excretion. Participants were then randomly assigned to modeling (n = 160) or validation (n = 247) groups to examine the bias in estimated population percentiles. RESULTS: Median bias in predicting selected percentiles (5th, 25th, 50th, 75th, 95th) of usual 24-h sodium excretion with one void urines ranged from -367 to 284 mg (-7.7 to 12.2% of the observed usual excretions) for men and -604 to 486 mg (-14.6 to 23.7%) for women, and with two void urines from -338 to 263 mg (-6.9 to 10.4%) and -166 to 153 mg (-4.1 to 8.1%), respectively. Four of the 6 two-void urine combinations produced no significant bias in predicting selected percentiles. CONCLUSIONS: Our approach to estimate the population usual 24-h sodium excretion, which uses calibrated timed void sodium to account for day-to-day variation and covariance between measurement errors, produced percentile estimates with relatively low biases across low-to-high sodium excretions. This may provide a low-burden, low-cost alternative to 24-h collections in monitoring population sodium intake among healthy young adults and merits further investigation in other population subgroups. PMID- 25833886 TI - Progress and challenges in developing metabolic footprints from diet in human gut microbial cometabolism. AB - Homo sapiens harbor trillions of microbes, whose microbial metagenome (collective genome of a microbial community) using omic validation interrogation tools is estimated to be at least 100-fold that of human cells, which comprise 23,000 genes. This article highlights some of the current progress and open questions in nutrition-related areas of microbiome research. It also underscores the metabolic capabilities of microbial fermentation on nutritional substrates that require further mechanistic understanding and systems biology approaches of studying functional interactions between diet composition, gut microbiota, and host metabolism. Questions surrounding bacterial fermentation and degradation of dietary constituents (particularly by Firmicutes and Bacteroidetes) and deciphering how microbial encoding of enzymes and derived metabolites affect recovery of dietary energy by the host are more complex than previously thought. Moreover, it is essential to understand to what extent the intestinal microbiota is subject to dietary control and to integrate these data with functional metabolic signatures and biomarkers. Many lines of research have demonstrated the significant role of the gut microbiota in human physiology and disease. Probiotic and prebiotic products are proliferating in the market in response to consumer demand, and the science and technology around these products are progressing rapidly. With high-throughput molecular technologies driving the science, studying the bidirectional interactions of host-microbial cometabolism, epithelial cell maturation, shaping of innate immune development, normal vs. dysfunctional nutrient absorption and processing, and the complex signaling pathways involved is now possible. Substantiating the safety and mechanisms of action of probiotic/prebiotic formulations is critical. Beneficial modulation of the human microbiota by using these nutritional and biotherapeutic strategies holds considerable promise as next-generation drugs, vaccinomics, and metabolic agents and in novel food discovery. PMID- 25833887 TI - Epigenetics of inflammation, maternal infection, and nutrition. AB - Studies have demonstrated that epigenetic changes such as DNA methylation, histone modification, and chromatin remodeling are linked to an increased inflammatory response as well as increased risk of chronic disease development. A few studies have begun to investigate whether dietary nutrients play a beneficial role by modifying or reversing epigenetically induced inflammation. Results of these studies show that nutrients modify epigenetic pathways. However, little is known about how nutrients modulate inflammation by regulating immune cell function and/or immune cell differentiation via epigenetic pathways. This overview will provide information about the current understanding of the role of nutrients in the epigenetic control mechanisms of immune function. PMID- 25833888 TI - Current issues and priorities in childhood nutrition, growth, and infections. AB - Forty-five percent of the 6.6 million under-5 deaths in 2012 were attributable to infectious disease, of which pneumonia and diarrhea were the leading causes. Despite the close interrelation between these infections and nutrition conditions, key nutrition interventions for prevention of childhood diarrhea and pneumonia have not received deserved attention, especially in low- and middle income countries. Several interventions and strategies can effectively address these issues but are not available to those in need. This article discusses in detail the burden and trends of global under-5 mortality, infections, and nutrition conditions; etiology and associated risk factors; biological plausibility and the interrelation between infections, nutrition, and growth; and existing interventions and strategies to reduce major childhood infections and improve nutrition and growth and implications. PMID- 25833889 TI - Supplementation of Mice with Specific Nondigestible Oligosaccharides during Pregnancy or Lactation Leads to Diminished Sensitization and Allergy in the Female Offspring. AB - BACKGROUND: The maternal environment and early life exposure affect immune development in offspring. OBJECTIVE: We investigated whether development of food allergy in offspring is affected by supplementing pregnant or lactating sensitized or nonsensitized mice with a mixture of nondigestible oligosaccharides. METHODS: Dams were sensitized intragastrically with ovalbumin before mating, with use of cholera toxin (CT) as an adjuvant. Nonsensitized dams received CT only. Dams were fed a control diet or a diet supplemented with short chain galacto oligosaccharides (scGOSs), long-chain fructo oligosaccharides (lcFOSs), and pectin-derived acidic oligosaccharides (pAOSs) in a ratio of 9:1:2 at a dose of 2% during pregnancy or lactation, resulting in 7 experimental groups. After weaning, offspring were fed a control diet and ovalbumin-CT sensitized. Acute allergic skin responses (ASRs), shock symptoms, body temperature, and specific plasma immunoglobulins were measured upon intradermal ovalbumin challenge. Th2/Th1- and regulatory T cells were analyzed with use of quantitative polymerase chain reaction and flow cytometric analysis in spleen, mesenteric lymph nodes, and blood. RESULTS: Supplementing sensitized pregnant or lactating dams with scGOS/lcFOS/pAOS resulted in lower ASRs in the offspring [offspring of sensitized female mice fed experimental diet during pregnancy (S Preg): 48 +/- 2.1 MUm; offspring of sensitized female mice fed experimental diet during lactation (S-Lact): 60 +/- 6.2 MUm] compared with the sensitized control group (119 +/- 13.9 MUm). In the S-Lact group, this coincided with an absence of shock symptoms compared with the offspring of sensitized female mice fed control food during pregnancy and lactation (S-Con) and S-Preg groups, and lower ovalbumin-IgG1 [S-Con: 3.8 +/- 0.1 arbitrary units (AUs); S-Preg: 3.3 +/- 0.1 AUs; S-Lact: 2.4 +/- 0.1 AUs] and higher ovalbumin-IgG2a concentrations (S-Con: 1.1 +/- 0.1 AUs; S-Preg: 0.8 +/- 0.1 AUs; S-Lact: 2.0 +/- 0.1 AUs). Supplementing nonsensitized pregnant or lactating dams with scGOS/lcFOS/pAOS resulted in lower plasma ovalbumin-IgE [offspring of nonsensitized female mice fed experimental diet during pregnancy (NS-Preg): 1.6 +/- 0.4 AUs; offspring of nonsensitized female mice fed experimental diet during lactation (NS-Lact): 0.3 +/- 0.1 AUs vs. offspring of nonsensitized female mice fed control food during pregnancy and lactation (NS-Con): 3.1 +/- 0.6 AUs] and ovalbumin-IgG1 (NS-Lact: 2.3 +/- 0.3 AUs vs. NS-Con: 3.4 +/- 0.3 AUs) concentrations in offspring. Ovalbumin-IgG2a plasma concentrations were higher in offspring of scGOS/lcFOS/pAOS-supplemented dams (NS Preg: 1.1 +/- 0.1 AUs; NS-Lact: 1.1 +/- 0.1 AUs) than in those of unsupplemented, nonsensitized controls (0.4 +/- 0.0 AUs). CONCLUSIONS: These data show impaired sensitization in offspring of scGOS/lcFOS/pAOS-supplemented mice. A number of the analyzed variables are differentially affected by whether supplementation occurs during pregnancy or lactation, and the outcome of dietary supplementation is affected by whether the mother has been sensitized to ovalbumin and CT. PMID- 25833890 TI - The use of adjustment factors to address the impact of inflammation on vitamin A and iron status in humans. AB - Many nutrient biomarkers are altered by inflammation. We calculated adjustment factors for retinol and ferritin by using meta-analyses of studies containing the respective biomarker and 2 acute phase proteins in serum, C-reactive protein (CRP), and alpha1-acid glycoprotein (AGP). With the use of CRP and AGP we identified 4 groups in each study: reference (CRP <=5 mg/L, AGP <=1 g/L), incubation (CRP >5 mg/L, AGP <=1 g/L), early convalescence (CRP >5 mg/L, AGP >1 g/L), and late convalescence (CRP <=5 mg/L, AGP >1 g/L). For each biomarker, ratios of the geometric means of the reference to each inflammation group concentration were used to calculate adjustment factors for retinol (1.13, 1.24, and 1.11) and ferritin (0.77, 0.53, and 0.75) for the incubation, early, and late convalescent groups, respectively. The application of the meta-analysis factors in more recent studies compares well with study-specific factors. The same method was used to calculate adjustment factors for soluble transferrin receptor (sTfR) and body iron stores (BISs) in Lao children. We found no advantage in adjusting sTfR for inflammation; in fact, adjustment decreased iron deficiency. Neither adjusted (10% <0 mg/kg) nor nonadjusted (12% <0 mg/kg) BISs detected as much iron deficiency as did ferritin (18% <12 MUg/L) and adjusted ferritin (21% <12 MUg/L) unless the cutoff for BISs was increased from 0 to <3 mg/kg. However, we could find no evidence that the larger number of children identified as having BISs <3 mg/kg had risks of anemia comparable to those identified by using ferritin <12 MUg/L. In conclusion, both corrected and uncorrected ferritin concentrations <12 MUg/L are associated with more iron deficiency and anemia than either sTfR >8.3 mg/L or BISs <0 mg/kg in Lao children. PMID- 25833891 TI - Nutrition and metabolic correlates of obesity and inflammation: clinical considerations. AB - Since 1980, the global prevalence of obesity has doubled; in the United States, it has almost tripled. Billions of people are overweight and obese; the WHO reports that >65% of the world's population die of diseases related to overweight rather than underweight. Obesity is a complex disease that can be studied from "metropolis to metabolite"-that is, beginning at the policy and the population level through epidemiology and intervention studies; to bench work including preclinical models, tissue, and cell culture studies; to biochemical assays; and to metabolomics. Metabolomics is the next research frontier because it provides a real-time snapshot of biochemical building blocks and products of cellular processes. This report comments on practical considerations when conducting metabolomics research. The pros and cons and important study design concerns are addressed to aid in increasing metabolomics research in the United States. The link between metabolism and inflammation is an understudied phenomenon that has great potential to transform our understanding of immunometabolism in obesity, diabetes, cancer, and other diseases; metabolomics promises to be an important tool in understanding the complex relations between factors contributing to such diseases. PMID- 25833892 TI - Indian women of childbearing age do not metabolically conserve arginine as do American and Jamaican women. AB - BACKGROUND: In a previous study in pregnant American women, we reported that arginine flux and nitric oxide synthesis increased in trimester 2. More recently, we reported that Indian women do not increase arginine flux during pregnancy as their American or Jamaican counterparts do. OBJECTIVE: The purpose of this study was to determine whether Indian women of childbearing age are producing less arginine and/or catabolizing more arginine and therefore have less available for anabolic pathways than do Jamaican and American women. METHODS: Thirty healthy women aged 28.3 +/- 0.8 y from the United States, India, and Jamaica (n = 10/group) were given 6 h primed, constant intravenous infusions of guanidino-15N2 arginine, 5,5-2H2-citrulline, 15N2-ornithine, and ring-2H5-phenylalanine, in addition to primed, oral doses of U-13C6-arginine in both the fasting and postprandial states. An oral dose of deuterium oxide was also given to determine fat-free mass (FFM). RESULTS: Compared with American women, Indian and Jamaican women had greater ornithine fluxes (MUmol . kg fat FFM-1 . h-1) in the fasting and postprandial states (27.3 +/- 2.5 vs. 39.6 +/- 3.7 and 37.2 +/- 2.0, respectively, P = 0.01), indicating greater arginine catabolism. However, Jamaican women had a higher endogenous arginine flux than did Indian and American women in the fasting (66.1 +/- 3.1 vs. 54.2 +/- 3.1 and 56.1 +/- 2.1, respectively, P = 0.01) and postprandial (53.8 +/- 2.2 vs. 43.7 +/- 4.9 and 42.8 +/- 3.1, respectively, P = 0.06) states. As a consequence, Indian women had lower arginine bioavailability (MUmol . kg FFM-1 . h-1) in the fasting state (42.0 +/- 2.6) than did American (49.9 +/- 1.3, P = 0.045) and Jamaican (55.5 +/- 3.5, P = 0.004) women, as well as in the postprandial state (40.7 +/- 3.5 vs. 51.8 +/- 1.2 and 57.5 +/- 3.2, respectively, P = 0.001). CONCLUSION: Compared with American and Jamaican women, Indian women of childbearing age have a decreased arginine supply because of increased arginine catabolism without an increase in arginine flux. PMID- 25833894 TI - Possible association of single nucleotide polymorphisms in the 3' untranslated region of HOXB9 with acetabular overcoverage. AB - OBJECTIVES: Excessive acetabular coverage is the most common cause of pincer-type femoroacetabular impingement. To date, an association between acetabular over coverage and genetic variations has not been studied. In this study we investigated the association between single nucleotide polymorphisms (SNPs) of paralogous Homeobox (HOX)9 genes and acetabular coverage in Japanese individuals to identify a possible genetic variation associated with acetabular over coverage. METHODS: We investigated 19 total SNPs in the four HOX9 paralogs, then focused in detail on seven of those located in the 3' untranslated region of HOXB9 (rs8844, rs3826541, rs3826540, rs7405887, rs2303485, rs2303486, rs79931349) using a case-control association study. The seven HOXB9 SNPs were genotyped in 316 subjects who had all undergone radiological examination. The association study was performed by both single-locus and haplotype-based analyses. RESULTS: The genotype and allele frequencies of the five HOXB9 SNPs showed significant association with acetabular over-coverage compared with controls (rs7405887 OR = 3.16, p = 5.29E-6, 95% CI 1.91 to 5.25). A significant difference was also detected when haplotypes were evaluated (OR = 2.59, p = 2.61E-5, 95% CI 1.65 to 4.08). The two HOXB9 SNPs (rs2303485, rs2303486) were associated with decreased acetabular coverage (rs2303485 OR = 0.524, p = 0.0091, 95% CI 0.322 to 0.855; rs2303486 OR = 0.519, p = 0.011, 95% CI 0.312 to 0.865). CONCLUSIONS: The five HOXB9 SNPs (rs8844, rs3826541, rs3826540, rs7405887, rs79931349) were associated with acetabular over-coverage. On the other hand, the two SNPs (rs2303485 and rs2303486) were associated with the lower acetabular coverage. The association of rs2303486 would be consistent with the previous study. Therefore, the HOXB9 SNPs might be involved in the morphogenesis of acetabular coverage, and could be an independent risk factor for developing pincer-type femoroacetabular impingement. Cite this article: Bone Joint Res 2015;4:50-5. PMID- 25833895 TI - Four days a week or less on appropriate anti-HIV drug combinations provided long term optimal maintenance in 94 patients: the ICCARRE project. AB - Short, intraweekly cycles of anti-HIV combinations have provided intermittent, effective therapy (on 48 patients) (1). The concept is now extended to 94 patients on treatment, 4 days per week or less, over a median of 2.7 discontinuous treatment years per patient. On suppressive combinations, 94 patients volunteered to treatment, 5 and 4 days per week, or reduced stepwise to 4, 3, 2, and 1 days per week in 94, 84, 66, and 12 patients, respectively, on various triple, standard, antiviral combinations, or nonregistered, quadruple, antiviral combinations. Ninety-four patients on treatment 4 days per week aggregated 165 intermittent treatment years; no viral breakthrough was observed over 87 average treatment weeks per patient, 63 of 94 having passed 2.5 intermittent treatment years on any of the antiviral combinations prescribed. On the hyperintermittent treatment of 3, 2, and 1 days per week, HIV RNA surged >50 copies, 4 weeks apart, in 18 instances (6.8 viral escapes/100 hyperdiscontinuous maintenance years). Viral escapes could have been a result of erratic adherence (EA) to regimen or follow-up (3 patients)--drug taken at half of the daily recommended dosage (8 patients) and/or overlooked archival-resistant HIVs from antecedent treatment failures (6 patients). Aside from the above circumstances, HIV unexpectedly rebounded in 3 patients on 2 days per week treatment and 1 patient on 1 day per week treatment, posting 2.2 intrinsic viral escapes/100 highly discontinuous treatment years. All 18 escapes were eventually reversed by 7 days per week salvage combinations, and 11 of 18 patients have been back for a second course of intermittent therapy, 4 days per week or less. Both cell activation markers on the surface of T lymphocytes and cell-bound HIV DNA levels remained stable or declined. CD4/CD8 ratios rose to >=1 in 35% of patients, whereas CD4 counts went >=500/ul in 75%. These values were previously 7 and 40%, respectively, on 7 days per week therapy. In our aging, long, HIV-enduring, multitreated patient cohort, treatment 4 days per week and less over 421 intermittent treatment years reduced prescription medicines by 60%--equivalent to 3 drug-free/3 virus-free remission year per patient--actually sparing ?3 million on just 94 patients at the cost of 2.2 intrinsic viral failure/100 hyperintermittent treatment years. At no risk of viral escape, maintenance therapy, 4 days per week, would quasiuniversally offer 40% cuts off of current overprescriptions. PMID- 25833896 TI - Mean glandular dose in six digital mammography services in Santiago, Chile: preliminary reference levels. AB - The purpose of this paper was to estimate mean glandular dose levels (DG) in six digital mammography systems in Santiago, Chile, and to propose preliminary reference levels to execute mammography in Chile. The study was carried out assessing two direct digital systems and four computer-based radiography (CR) systems. Estimates of DG were calculated for different thicknesses of polymethyl methacrylate according to the quality control protocol in digital mammography of the Spanish Society of Medical Physics and NHSBSP Equipment Report 0604 Version 3. DG values ranged between 0.64 and 7.26 mGy for a range of 20- to 70-mm thickness, respectively. Thirty-six per cent of DG was higher than the acceptable dose level and 100 % of DG was higher than the desirable level. It is therefore necessary to optimise doses. The initial proposal to establish dose reference levels for DG would range between 0.90 and 6.40 mGy for a thickness range of 20 to 70 mm. PMID- 25833897 TI - Follow-up of children exposed to ionising radiation from cardiac catheterisation: the Coccinelle study. AB - Cardiac catheterisation has become an essential tool in the diagnosis and treatment of children with a wide variety of congenital and acquired forms of cardiovascular disease. Despite the clear clinical benefit to the patient, radiation exposure from paediatric cardiac catheterisation procedures (CCPs) may be substantial. Given children's greater sensitivity to radiation and the longer life span during which radiation health effects can develop, an epidemiological cohort study, named Coccinelle or 'Ladybird' (French acronym for 'Cohorte sur le risque de cancer apres cardiologie interventionnelle pediatrique'), is carried out in France to evaluate the risks of leukaemia and solid cancers in this population. A total number of 8000 included children are expected. Individual CCP related doses will be assessed for each child included in the cohort. For each CCP performed, dosimetric parameters (dose-area product, fluoroscopy time and total number of cine frames) are retrieved retrospectively. Organ doses, especially to the lung, the oesophagus and the thyroid, are calculated with PCXMC software. The cohort will be followed up through linkage with French paediatric cancer registries. PMID- 25833898 TI - Indication-based national diagnostic reference levels for paediatric CT: a new approach with proposed values. AB - Indication-based national diagnostic reference levels (DRLs) for a few most common paediatric computed tomography (CT) examinations are proposed. Patient dose data (CTDI vol and dose length product) were collected for over 1000 patients in 4 university hospitals with best experiences in paediatric CT. Four indications for chest CT and two for abdomen (abdomen + pelvis), chest + abdomen and head CT were considered. The DRLs for the body examinations are proposed as exponential DRL-curves, where CTDI vol and dose length product are presented as a function of patient weight. The same DRL curve applies to all the indications studied. The basic 75 % level curve is supplemented by 50 % level curve to enable considerations on varying levels of technology. For head CT, DRLs are proposed for a few age groups (1, 1-5, 5-10 and 10-15 y), separately for routine CT and CT for ventricular size. The proposed DRLs are generally lower than the few published DRLs in other countries. PMID- 25833899 TI - Simultaneous Quantitation of 78 Drugs and Metabolites in Urine with a Dilute-And Shoot LC-MS-MS Assay. AB - A novel LC-MS-MS assay that simultaneously detects and quantitates 78 drugs and metabolites was developed and validated for chronic pain management. Urine specimen was diluted and mixed with internal standards (ISs) before injected into LC-MS-MS. Seventy-two analytes were detected with positive electrospray ionization mode and the remaining six analytes with negative mode. Two separate gradient elution chromatographic programs were established with the same mobile phases on the same bi-phenyl HPLC column. The assay was linear for all analytes with linear regression coefficient ranging 0.994-1.000. The intra-assay precision was between 1.7 and 8.8% and inter-assay precision between 1.9 and 12.2%, with bias <20% for all but six analytes. All analytes in urine specimens were stable for 7 days at 4 degrees C, and no significant matrix effect or carryover was observed. A suboptimal recovery rate (60.0-156.8%) was observed for six analytes, potentially due to the lack of available deuterated ISs, requiring comparison to a chemically different IS. Method comparison using patient and proficiency testing samples demonstrated that this assay was sensitive and accurate. The assay improves on currently existing assays by including glucuronide conjugates, allowing direct detection of metabolites that might otherwise be missed by existing methods. PMID- 25833900 TI - A novel antidoping and medical care delivery model at the 2nd Summer Youth Olympic Games (2014), Nanjing China. AB - BACKGROUND: Antidoping and medical care delivery programmes are required at all large international multisport events. OBJECTIVE: To document and critique the novel antidoping and medical care delivery models implemented at the 2nd Summer Youth Olympic Games, Nanjing 2014. METHODS: The International Olympic Committee implemented two new models of delivery of antidoping and medical care at the YOG. A review of these models as well as the public health programme and two health educational initiatives in the Cultural and Educational Program was undertaken by the International Olympic Committee. RESULTS: The implementation of the new antidoping model was feasible in the setting of the YOG. The antidoping rules and regulations of the International Olympic Committee were respected. This model enhanced the educational initiative and provided financial as well as human resource savings. The execution of the hospital-based venue model of medical care delivery at the YOG was also feasible in this setting. This model provided a practical infrastructure for the delivery of medical care at multisport events with the goal of providing optimum athlete healthcare. A public health prevention programme was implemented and no public health risks were encountered by the participants or the Nanjing citizens during the YOG. Finally, the implementation of the athlete health educational programmes within the Cultural and Educational Program provided athletes with an opportunity to improve their health and performance. CONCLUSIONS: To achieve the goal of protecting athlete health, and of employing effective doping control and education, new alternate models of antidoping and medical care delivery can be implemented. PMID- 25833901 TI - The epidemiology of groin injury in senior football: a systematic review of prospective studies. AB - BACKGROUND: Groin injuries are troublesome in men's and women's football. AIM: To review the literature on the epidemiology of groin injury in senior football and compare injury occurrence between sexes. METHODS: Studies were identified through a search of PubMed, EMBASE, CINAHL and Web of Science, in the reference lists of the selected articles and the authors' bibliographies. The number of injuries, percentage of groin injury from all injuries and rate of groin injury per 1000 h were extracted. Exposure and injury data were aggregated across included studies and the absolute differences in groin injury proportion and rate of groin injury were compared between sexes. Risk of bias was assessed using a 5-item checklist. RESULTS: 34 articles met the study criteria and were included. The proportion of groin injury in club-seasonal football was 4-19% in men and 2-14% in women. Aggregated data analysis (29 studies) showed a higher relative proportion of groin injury in men than in women (12.8% vs 6.9%, absolute difference 5.9%, 95% CI 4.6% to 7.1%). The rate of groin injury varied from 0.2 to 2.1/1000 h in men and 0.1 to 0.6/1000 h in women's club football, and aggregated analysis (23 studies) showed a more than two-fold higher rate in men (0.83/1000 h vs 0.35/1000 h, rate ratio 2.4, 95% CI 2.0 to 2.9). High risk of bias was identified for participant selection (18 studies), exposure (17 studies) and precision estimate (16 studies). CONCLUSIONS: Groin injuries are frequent in senior football and are more common in men than women. Future research needs to be of higher quality. PMID- 25833902 TI - 15 years of tracking physiotherapy evidence on PEDro, where are we now? PMID- 25833903 TI - Risk factors for groin injury in sport: an updated systematic review. AB - BACKGROUND: The identification of risk factors for groin injury in sport is important to develop and implement injury prevention strategies. OBJECTIVE: To identify and evaluate the evidence examining risk factors for groin injury in sport. MATERIAL AND METHODS: Nine electronic databases were systematically searched to June 2014. Studies selected met the following criteria: original data; analytic design; investigated a risk factor(s); included outcomes for groin injury sustained during sport participation. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed and two independent authors assessed the quality and level of evidence with the Downs and Black (DB) criteria and Oxford Centre of Evidence-Based Medicine model, respectively. RESULTS: Of 2521 potentially relevant studies, 29 were included and scored. Heterogeneity in methodology and injury definition precluded meta analyses. The most common risk factors investigated included age, hip range of motion, hip adductor strength and height. The median DB score across studies was 11/33 (range 6-20). The majority of studies represented level 2 evidence (cohort studies) however few considered the inter-relationships between risk factors. There is level 1 and 2 evidence that previous groin injury, higher-level of play, reduced hip adductor (absolute and relative to the hip abductors) strength and lower levels of sport-specific training are associated with increased risk of groin injury in sport. CONCLUSIONS: We recommended that investigators focus on developing and evaluating preparticipation screening and groin injury prevention programmes through high-quality randomised controlled trials targeting athletes at greater risk of injury. PMID- 25833904 TI - Monotherapy with stenting in subarachnoid hemorrhage (SAH) after middle cerebral artery dissection. AB - Isolated middle cerebral artery dissection is a rare clinical entity, with descriptions limited to a few case reports and case series. Symptomatic dissection in the anterior circulation can present as an ischemic stroke in a young population; however, it is rarely associated with subarachnoid hemorrhage. We describe a young patient who presented with acute headache from a subarachnoid hemorrhage that was ultimately determined to be due to a vascular dissection in the middle cerebral artery. The initial angiogram showed vascular irregularities in this area with stenosis. Repeat imaging 4 days after presentation identified a pseudoaneurysm proximal to the stenosis. The patient was successfully treated with a self-expanding nitinol stent and followed up with serial angiography during postoperative recovery in the hospital; additional angiograms were performed approximately 1 and 6 months after treatment. Serial angiograms demonstrated incremental healing of the dissection. The patient was discharged and remains neurologically intact at the 6-month follow-up. PMID- 25833905 TI - Residual vasomotor activity assessed by heart rate variability in a brain-dead case. AB - A patient assessed by heart rate variability (HRV) methodology, beginning just after the completion of brain death (BD) diagnosis, showed remaining very low frequency (VLF) waves for approximately 10 min. A time-varying spectral analysis showed that during the first 550 s, a significant power spectral density remained in the high-frequency (HF), low-frequency (LF) and VLF bands. From 550 to 675 s, the HF oscillations totally vanished, and a marked progressive decay of the LF and VLF power density occurred. After 700 s the VLF undulations stopped and remaining small amplitude oscillations at 0.2 Hz coincided with the ventilator frequency. The VLF oscillations recorded in our case might be related to residual sympathetic vasomotor activity that progressively disappeared due to the extension of necrosis affecting the nervous centres of the lower part of the medulla and the first 2-3 cervical spine segments. PMID- 25833906 TI - Paravaginal aggressive angiomyxoma. AB - A 34-year-old nulliparous woman with a long-standing history of uterine fibroids and infertility had undergone prior open myomectomy, then uterine artery embolisation in treatment of an apparent large fibroid. Imaging on referral revealed an atypical 12*11*10 cm pelvic mass with the appearance of a fibroid. At laparotomy, the lesion was encapsulated but softer than a fibroid and located deep in the paravaginal space. The histopathological outcome was an aggressive angiomyxoma. PMID- 25833907 TI - Treatment of tachycardia: bradycardia syndrome in a patient with obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSAS) affects 4% of men and 2% of women aged 30-65 years. It is diagnosed in the presence of excessive daytime sleepiness and an apnoea-hypopnoea index (AHI) of >=5 on polysomnography. Rhythm disturbances are common in OSAS and continuous positive airway pressure (CPAP) has been shown to be beneficial. We present a case of a patient with obesity, atrial fibrillation with fast ventricular response, significant nocturnal pauses (3.9 s) and tachycardiomyopathy. A polysomnography confirmed severe OSAS (AHI=64.25). CPAP improved bradycardia and allowed for the introduction of beta-blockers. Subsequent Holter monitoring revealed better rate control with the longest pause of 2 s and the patient's left ventricular systolic function improved. CPAP prevented our patient from invasive treatment, allowed for rate control and improvement of tachycardiomyopathy. With such a high prevalence of OSAS, clinicians should be aware that CPAP may aid arrhythmia control. PMID- 25833908 TI - A prominent 'A' notch in the pulmonary valve M mode-one more cause of the same. AB - The M mode echocardiogram is not the main priority, during routine echocardiographic evaluation now-a-days. However, there are still a few classical conditions where this remains instructive and educative. One such situation is the presence of an 'a' wave in the pulmonary valve M mode tracing in normals and it's absence in pulmonary hypertension. In valvular pulmonary stenosis we expect a deeper 'a' wave. We describe one more cause of a prominent 'a' wave in the pulmonary valve M mode. We describe this in a common tropical disease, endemic to Kerala. PMID- 25833909 TI - Ruptured hepatic artery aneurysm: an unusual presentation of polyarteritis nodosa. AB - A 52-year-old woman presented with severe acute right upper quadrant abdominal pain and signs of intra-abdominal haemorrhage. CT and selective angiography revealed a ruptured right hepatic artery aneurysm and diffuse aneurysmatic disease involving most intra-abdominal organs, suggestive of polyarteritis nodosa. Although treatment with high-dose steroids was initiated, the patient died of progressive bowel ischaemia. PMID- 25833910 TI - Mycotic pseudoaneurysm by vancomycin-intermediate Staphylococcus aureus: a rare cause of persistent bacteraemia. AB - Pseudoaneurysms are vessel wall ruptures, that are often mistaken for deep vein thrombosis (DVT). A middle-aged man presented with right leg pain, swelling and erythema. His history was significant for persistent Staphylococcus aureus bacteraemia. Ultrasound revealed subacute DVT and laboratory parameters were suggestive of sepsis. He was started on intravenous heparin and antimicrobials. Owing to persistent anaemia despite blood transfusion, MRI of the right thigh was obtained. It revealed a 13*17 cm superficial femoral artery infected mycotic pseudoaneurysm (MPA) with a fresh haematoma. The patient underwent arterial ligation and extensive debridement. Intraoperative cultures revealed daptomycin resistant vancomycin-intermediate S. aureus (VISA) and he was managed with 6 weeks of intravenous ceftaroline. MPAs are most common in the femoral artery and form <1% of aneurysms. Therapy involves surgical debridement and prolonged antimicrobials. VISA causing MPA is associated with worse outcomes. We report the first time use of ceftaroline in the management of a VISA MPA. PMID- 25833911 TI - Burning mouth syndrome due to herpes simplex virus type 1. AB - Burning mouth syndrome is characterised by chronic orofacial burning pain. No dental or medical cause has been found. We present a case of burning mouth syndrome of 6 months duration in a healthy 65-year-old woman, which was associated with high copy numbers of herpes simplex virus type 1 (HSV-1) DNA in the saliva. Her pain resolved completely after antiviral treatment with a corresponding absence of salivary HSV-1 DNA 4 weeks and 6 months later. PMID- 25833912 TI - Primary cutaneous rhinosporidiosis: an unusual lesion with an unusual presentation. PMID- 25833913 TI - Primary failure of eruption (PFE). PMID- 25833914 TI - What goes around, comes around. PMID- 25833893 TI - Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE). AB - An increasing recognition has emerged of the complexities of the global health agenda-specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations. PMID- 25833915 TI - Comparison of male versus female responses in the Pig-a mutation assay. AB - Validation of the Pig-a gene mutation assay has been based mainly on studies in male rodents. To determine if the mutagen-induced responses of the X-linked Pig-a gene differ in females compared to males, 7- or 14-week old male and female Sprague Dawley rats were exposed to N-ethyl-N-nitrosourea (ENU). In the study with the 7-week old rats, exposure was to 0, 1, 5 or 25mg ENU/kg/day for three consecutive days (study Days 1-3). Pig-a mutant phenotype reticulocyte (RET(CD59 )) and mutant phenotype erythrocyte (RBC(CD59-)) frequencies were determined on study Days -4, 15, 29 and 46 using immunomagnetic separation in conjunction with flow cytometric analysis (In Vivo MutaFlow(r)). Additionally, blood samples collected on Day 4 were analysed for micronucleated reticulocyte (MN-RET) frequency (In Vivo MicroFlow(r)). The percentage of reticulocytes (%RET) was markedly higher in the 7-week old males compared to females through Day 15 (2.39 fold higher on Day -4). At 25mg/kg/day, ENU reduced Day 4 RET frequencies in both sexes, and the two highest dose levels resulted in elevated MN-RET frequencies, with no sex or treatment * sex interaction. The two highest dose levels significantly elevated the frequencies of mean RET(CD59-) and RBC(CD59-) in both sexes from Day 15 onward. RET(CD59-) and RBC(CD59-) frequencies were somewhat lower for females compared to males at the highest dose level studied, and differences in RET(CD59-) resulted in a statistically significant interaction effect of treatment * sex. In the study with 14-week old rats, treatment was for 3 days with 0 or 25mg ENU/kg/day. RET frequencies differed to a lesser degree between the sexes, and in this case there was no evidence of a treatment * sex interaction. These results suggest that the slightly higher response in younger males than in the younger females may be related to differences in erythropoiesis function at that age. In conclusion, while some quantitative differences were noted, there were no qualitative differences in how males and females responded to a prototypical mutagen, and support the contention that both sexes are equally acceptable for Pig-a gene mutation studies. PMID- 25833918 TI - A remembrance of Roger Boles, MD. PMID- 25833917 TI - Corrigendum. Human airway smooth muscle maintain in situ cell orientation and phenotype when cultured on aligned electrospun scaffolds. PMID- 25833916 TI - Rat Pig-a mutation assay responds to the genotoxic carcinogen ethyl carbamate but not the non-genotoxic carcinogen methyl carbamate. AB - Determination of the mode of action of carcinogenic agents is an important factor in risk assessment and regulatory practice. To assess the ability of the erythrocyte-based Pig-a mutation assay to discriminate between genotoxic and non genotoxic modes of action, the mutagenic response of Sprague Dawley rats exposed to methyl carbamate (MC) or ethyl carbamate (EC) was investigated. EC, a potent carcinogen, is believed to induce DNA damage through the formation of a DNA reactive epoxide group, whereas the closely structurally related compound, MC, cannot form this epoxide and its weaker carcinogenic activity is thought to be secondary to inflammation and promotion of cell proliferation. The frequency of Pig-a mutant phenotype cells was monitored before, during, and after 28 consecutive days of oral gavage exposure to either MC (doses ranging from 125 to 500 mg/kg/day) or EC (250 mg/kg/day). Significant increases in the frequency of mutant reticulocytes were observed from Days 15 through 43, with a peak mean frequency of 19.9*10(-6) on Day 29 (i.e. 24.9-fold increase relative to mean vehicle control across all four sampling times). As expected, mutant erythrocyte responses lagged behind mutant reticulocyte responses, with a maximal mean frequency of 8.2*10(-6) on Day 43 (i.e. 16.4-fold increase). No mutagenic effects were observed with MC. A second indicator of in vivo genotoxicity, peripheral blood micronucleated reticulocytes, was also studied. This endpoint was responsive to EC (3.3-fold mean increase), but not to MC. These results support the hypothesis that genotoxicity contributes to the carcinogenicity of EC but not of MC, and illustrates the value of the Pig-a assay for discriminating between genotoxic and non-genotoxic modes of action. PMID- 25833919 TI - Highlights from the current issue: April 2015. PMID- 25833920 TI - Balancing evidence, innovation, and regulation. PMID- 25833921 TI - Gizmo is a mean word! AB - The editorial titled "Gizmos" in the April issue of Otolaryngology-Head and Neck Surgery was unfortunate. Intracapsular tonsillectomy is a rational surgical option for managing tonsillar hypertrophy causing obstructive sleep apnea in selected children. It is performed routinely by surgeons across the globe and has become the standard of care across northern Europe due to the high safety profile of the operation. The semirigid, dartlike design of the sinuplasty devices suggested the idea for an airway-specific set of high-pressure balloons. We began working on these in 2007 and had FDA approval in 2009. They are in wide use by many airway surgeons. Lingual tonsils are a frequent cause of obstructive sleep apnea, and there is no tool that manages this as effectively as endoscopic plasma ablation. We are all engaged in an honorable effort to improve care; surgical and creative skills are as important as analytical skills. Both are necessary for the continuous improvement of our work. Both are worthy of respect. PMID- 25833922 TI - Gizmos revisited (response to Koltai commentary). PMID- 25833923 TI - Where is Consumer Reports when we need it? A clinician's view of surgical innovation. PMID- 25833924 TI - The ABCDEs of technology adoption. PMID- 25833925 TI - Evidence and innovation in private practice: an evolving paradigm. PMID- 25833926 TI - Expanded pediatric cochlear implant candidacy. PMID- 25833927 TI - Clinical practice guideline (update): Adult Sinusitis Executive Summary. AB - The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue featuring the updated "Clinical Practice Guideline: Adult Sinusitis" as a supplement to Otolaryngology-Head and Neck Surgery. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 developed recommendations address diagnostic accuracy for adult rhinosinusitis, the appropriate use of ancillary tests to confirm diagnosis and guide management (including radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function), and the judicious use of systemic and topical therapy. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia. An updated guideline is needed as a result of new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group. PMID- 25833928 TI - Online tracheostomy care resources--there's more out there. PMID- 25833929 TI - Letter in reply: Online tracheostomy care resources--there's more out there. PMID- 25833930 TI - 2-year sleep surgery and medicine fellowships for otolaryngologists. PMID- 25833931 TI - Response to "2-year sleep surgery and medicine fellowships for otolaryngologists": the array of sleep fellowship formats. PMID- 25833932 TI - The misleading meta-analysis. PMID- 25833933 TI - Re: Early versus late tracheostomy: a systematic review and meta-analysis. PMID- 25833934 TI - Ibuprofen and acetaminophen for posttonsillectomy pain. PMID- 25833935 TI - Ibuprofen with acetaminophen for tonsillectomy pain. PMID- 25833936 TI - Activation state of the hyperpolarization-activated current modulates temperature sensitivity of firing in locus coeruleus neurons from bullfrogs. AB - Locus coeruleus neurons of anuran amphibians contribute to breathing control and have spontaneous firing frequencies that, paradoxically, increase with cooling. We previously showed that cooling inhibits a depolarizing membrane current, the hyperpolarization-activated current (I h) in locus coeruleus neurons from bullfrogs, Lithobates catesbeianus (Santin JM, Watters KC, Putnam RW, Hartzler LK. Am J Physiol Regul Integr Comp Physiol 305: R1451-R1464, 2013). This suggests an unlikely role for I h in generating cold activation, but led us to hypothesize that inhibition of I h by cooling functions as a physiological brake to limit the cold-activated response. Using whole cell electrophysiology in brain slices, we employed 2 mM Cs(+) (an I h antagonist) to isolate the role of I h in spontaneous firing and cold activation in neurons recorded with either control or I h agonist (cyclic AMP)-containing artificial intracellular fluid. I h did not contribute to the membrane potential (V m) and spontaneous firing at 20 degrees C. Although voltage-clamp analysis confirmed that cooling inhibits I h, its lack of involvement in setting baseline firing and V m precluded its ability to regulate cold activation as hypothesized. In contrast, neurons dialyzed with cAMP exhibited greater baseline firing frequencies at 20 degrees C due to I h activation. Our hypothesis was supported when the starting level of I h was enhanced by elevating cAMP because cold activation was converted to more ordinary cold inhibition. These findings indicate that situations leading to enhancement of I h facilitate firing at 20 degrees C, yet the hyperpolarization associated with inhibiting a depolarizing cation current by cooling blunts the net V m response to cooling to oppose normal cold-depolarizing factors. This suggests that the influence of I h activation state on neuronal firing varies in the poikilothermic neuronal environment. PMID- 25833937 TI - The role of spinal GABAergic circuits in the control of phrenic nerve motor output. AB - While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed. PMID- 25833938 TI - Age-related changes in thirst, salt appetite, and arterial blood pressure in response to aldosterone-dexamethasone combination in rats. AB - This work examined the effects of age on daily water and sodium ingestion and cardiovascular responses to chronic administration of the mineralocorticoid, aldosterone (ALDO) either alone or together with the glucocorticoid, dexamethasone (DEX). Young (4 mo), adult (12 mo), and aged (30 mo) male Brown Norway rats were prepared for continuous telemetry recording of blood pressure (BP) and heart rate (HR). Baseline water and sodium (i.e., 0.3 M NaCl) intake, BP, and HR were established for 10 days. Then ALDO (60 MUg/day sc) was infused alone, or together with DEX (2.5 or 20 MUg/day sc), for another 10 days. Compared with baseline levels, ALDO stimulated comparable increases in daily saline intake at all ages. ALDO together with the higher dose of DEX (i.e., ALDO/DEX20) increased daily saline intake more than did ALDO, but less so in aged rats. Infusion of ALDO/DEX20 increased mean arterial pressure (MAP), and decreased HR, more than did infusion of ALDO. The changes in MAP in response to both treatments depended on age. For all ages, MAP and saline intake increased simultaneously during ALDO, while MAP always increased before saline intake did during ALDO/DEX20. Contrary to our predictions, MAP did not increase more in old rats in response to either treatment. We speculate that age-related declines in cardiovascular responses to glucocorticoids contributed to the attenuated increases in sodium intake in response to glucocorticoids that were observed in older animals. PMID- 25833939 TI - Evaluation d'impact sur la sante et evaluation d'impact sur l'equite en sante : eventail de pratiques et questions de recherche. AB - L'Evaluation d'Impact sur la Sante (EIS) se developpe au niveau international et est encore au stade emergent en France. Elle vise a evaluer les effets positifs et negatifs potentiels d'un projet, d'un programme ou d'une politique sur la sante. L'objectif est de produire des recommandations en direction des decideurs, afin d'en maximiser les effets positifs et d'en diminuer les effets negatifs. L'EIS est un moyen particulierement interessant d'action sur les determinants de la sante au-dela des comportements individuels et du systeme de sante. Les politiques de logement, de transport, de solidarite, economiques, etc. ont, en effet, des impacts souvent non prevus sur la sante. Au-dela des effets sur la sante, l'EIS doit aussi permettre d'apprecier la distribution de ces effets dans la population.Si la preoccupation pour l'equite en sante est centrale dans l'EIS, elle reste cependant difficilement traduite en pratique. Face a cette difficulte, des demarches d'evaluation d'impact ont ete developpees pour renforcer la prise en compte de l'equite a chaque etape de l'EIS ou " Equity Focused Health Impact Assessment ", ou prendre en compte les impacts sur les inegalites de sante de facon specifique. Ainsi, l'Evaluation de l'Impact sur l'Equite en Sante (EIES) semble, par exemple, particulierement interessante pour evaluer l'impact sur les inegalites de projets dans le champ sanitaire.L'EIS et l'EIES posent de nombreuses questions de recherche, notamment autour de la reunion, dans une meme demarche, du politique, du citoyen et de l'expert. La participation des populations vulnerables potentiellement affectees par la politique evaluee est une valeur centrale de l'EIS, mais pose des questions d'acceptabilite sociale. La collaboration avec les decideurs politiques est egalement un enjeu majeur. Les difficultes methodologiques, notamment de quantification des impacts, peuvent constituer des freins a la promotion de la demarche aupres des decideurs. PMID- 25833940 TI - Signal transduction in cancer. AB - Cancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells. PMID- 25833941 TI - Animal models and the molecular biology of hepadnavirus infection. AB - Australian antigen, the envelope protein of hepatitis B virus (HBV), was discovered in 1967 as a prevalent serum antigen in hepatitis B patients. Early electron microscopy (EM) studies showed that this antigen was present in 22-nm particles in patient sera, which were believed to be incomplete virus. Complete virus, much less abundant than the 22-nm particles, was finally visualized in 1970. HBV was soon found to infect chimpanzees, gorillas, orangutans, gibbon apes, and, more recently, tree shrews (Tupaia belangeri) and cynomolgus macaques (Macaca fascicularis). This restricted host range placed limits on the kinds of studies that might be performed to better understand the biology and molecular biology of HBV and to develop antiviral therapies to treat chronic infections. About 10 years after the discovery of HBV, this problem was bypassed with the discovery of viruses related to HBV in woodchucks, ground squirrels, and ducks. Although unlikely animal models, their use revealed the key steps in hepadnavirus replication and in the host response to infection, including the fact that the viral nuclear episome is the ultimate target for immune clearance of transient infections and antiviral therapy of chronic infections. Studies with these and other animal models have also suggested interesting clues into the link between chronic HBV infection and hepatocellular carcinoma. PMID- 25833942 TI - Antiviral therapies and prospects for a cure of chronic hepatitis B. AB - Current therapies of chronic hepatitis B (CHB) remain limited to either pegylated interferon-alpha (Peg-IFN-alpha), or one of the five approved nucleoside analog (NA) treatments. Although viral suppression can be achieved in the majority of patients with high-barrier-to-resistance new-generation NAs (i.e., entecavir and tenofovir), HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5 years. Attempts to improve the response by administering two different NAs or a combination of NA and Peg-IFN-alpha have been unsuccessful. Therefore, there is a renewed interest to investigate a number of steps in the hepatitis B virus (HBV) replication cycle and specific virus-host cell interactions as potential targets for new antivirals. Novel targets and compounds could readily be evaluated using both relevant in vitro and newly developed in vivo models of HBV infection. The addition of one or several new drugs to current regimens should offer the prospect of markedly improving the response to therapy, thus reducing the burden of drug resistance, as well as the incidence of cirrhosis and hepatocellular carcinoma (HCC). PMID- 25833943 TI - mTOR signaling in epilepsy: insights from malformations of cortical development. AB - Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as "mTORopathies." Mutations in mTOR regulatory genes (e.g., TSC1, TSC2, AKT3, DEPDC5) have been associated with several focal MCD highly associated with epilepsy such as tuberous sclerosis complex (TSC), hemimegalencephaly (HME; brain malformation associated with dramatic enlargement of one brain hemisphere), and cortical dysplasia. mTOR plays important roles in the regulation of cell division, growth, and survival, and, thus, aberrant activation of the cascade during cortical development can cause dramatic alterations in cell size, cortical lamination, and axon and dendrite outgrowth often observed in focal MCD. Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability. Clinical trials with mTOR inhibitors have shown efficacy in the treatment of seizures associated with focal MCD. PMID- 25833944 TI - The N-terminal Set-beta Protein Isoform Induces Neuronal Death. AB - Set-beta protein plays different roles in neurons, but the diversity of Set-beta neuronal isoforms and their functions have not been characterized. The expression and subcellular localization of Set-beta are altered in Alzheimer disease, cleavage of Set-beta leads to neuronal death after stroke, and the full-length Set-beta regulates retinal ganglion cell (RGC) and hippocampal neuron axon growth and regeneration in a subcellular localization-dependent manner. Here we used various biochemical approaches to investigate Set-beta isoforms and their role in the CNS, using the same type of neurons, RGCs, across studies. We found multiple alternatively spliced isoforms expressed from the Set locus in purified RGCs. Set transcripts containing the Set-beta-specific exon were the most highly expressed isoforms. We also identified a novel, alternatively spliced Set-beta transcript lacking the nuclear localization signal and demonstrated that the full-length (~39-kDa) Set-beta is localized predominantly in the nucleus, whereas a shorter (~25-kDa) Set-beta isoform is localized predominantly in the cytoplasm. Finally, we show that an N-terminal Set-beta cleavage product can induce neuronal death. PMID- 25833945 TI - 14-3-3 proteins restrain the Exo1 nuclease to prevent overresection. AB - The DNA end resection process dictates the cellular response to DNA double strand break damage and is essential for genome maintenance. Although insufficient DNA resection hinders homology-directed repair and ATR (ataxia telangiectasia and Rad3 related)-dependent checkpoint activation, overresection produces excessive single-stranded DNA that could lead to genomic instability. However, the mechanisms controlling DNA end resection are poorly understood. Here we show that the major resection nuclease Exo1 is regulated both positively and negatively by protein-protein interactions to ensure a proper level of DNA resection. We have shown previously that the sliding DNA clamp proliferating cell nuclear antigen (PCNA) associates with the C-terminal domain of Exo1 and promotes Exo1 damage association and DNA resection. In this report, we show that 14-3-3 proteins interact with a central region of Exo1 and negatively regulate Exo1 damage recruitment and subsequent resection. 14-3-3s limit Exo1 damage association, at least in part, by suppressing its association with PCNA. Disruption of the Exo1 interaction with 14-3-3 proteins results in elevated sensitivity of cells to DNA damage. Unlike Exo1, the Dna2 resection pathway is apparently not regulated by PCNA and 14-3-3s. Our results provide critical insights into the mechanism and regulation of the DNA end resection process and may have implications for cancer treatment. PMID- 25833946 TI - Binding of Substrates to the Central Pore of the Vps4 ATPase Is Autoinhibited by the Microtubule Interacting and Trafficking (MIT) Domain and Activated by MIT Interacting Motifs (MIMs). AB - The endosomal sorting complexes required for transport (ESCRT) pathway drives reverse topology membrane fission events within multiple cellular pathways, including cytokinesis, multivesicular body biogenesis, repair of the plasma membrane, nuclear membrane vesicle formation, and HIV budding. The AAA ATPase Vps4 is recruited to membrane necks shortly before fission, where it catalyzes disassembly of the ESCRT-III lattice. The N-terminal Vps4 microtubule-interacting and trafficking (MIT) domains initially bind the C-terminal MIT-interacting motifs (MIMs) of ESCRT-III subunits, but it is unclear how the enzyme then remodels these substrates in response to ATP hydrolysis. Here, we report quantitative binding studies that demonstrate that residues from helix 5 of the Vps2p subunit of ESCRT-III bind to the central pore of an asymmetric Vps4p hexamer in a manner that is dependent upon the presence of flexible nucleotide analogs that can mimic multiple states in the ATP hydrolysis cycle. We also find that substrate engagement is autoinhibited by the Vps4p MIT domain and that this inhibition is relieved by binding of either Type 1 or Type 2 MIM elements, which bind the Vps4p MIT domain through different interfaces. These observations support the model that Vps4 substrates are initially recruited by an MIM-MIT interaction that activates the Vps4 central pore to engage substrates and generate force, thereby triggering ESCRT-III disassembly. PMID- 25833947 TI - Crucial roles of single residues in binding affinity, specificity, and promiscuity in the cellulosomal cohesin-dockerin interface. AB - Interactions between cohesin and dockerin modules play a crucial role in the assembly of multienzyme cellulosome complexes. Although intraspecies cohesin and dockerin modules bind in general with high affinity but indiscriminately, cross species binding is rare. Here, we combined ELISA-based experiments with Rosetta based computational design to evaluate the contribution of distinct residues at the Clostridium thermocellum cohesin-dockerin interface to binding affinity, specificity, and promiscuity. We found that single mutations can show distinct and significant effects on binding affinity and specificity. In particular, mutations at cohesin position Asn(37) show dramatic variability in their effect on dockerin binding affinity and specificity: the N37A mutant binds promiscuously both to cognate (C. thermocellum) as well as to non-cognate Clostridium cellulolyticum dockerin. N37L in turn switches binding specificity: compared with the wild-type C. thermocellum cohesin, this mutant shows significantly increased preference for C. cellulolyticum dockerin combined with strongly reduced binding to its cognate C. thermocellum dockerin. The observation that a single mutation can overcome the naturally observed specificity barrier provides insights into the evolutionary dynamics of this system that allows rapid modulation of binding specificity within a high affinity background. PMID- 25833948 TI - Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy. AB - Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components. Cancer cells are thought to take advantage of autophagy to help them to cope with the stress of tumorigenesis; thus targeting autophagy is an attractive therapeutic approach. However, there are currently no specific inhibitors of autophagy. ULK1, a serine/threonine protein kinase, is essential for the initial stages of autophagy, and here we report that two compounds, MRT67307 and MRT68921, potently inhibit ULK1 and ULK2 in vitro and block autophagy in cells. Using a drug-resistant ULK1 mutant, we show that the autophagy-inhibiting capacity of the compounds is specifically through ULK1. ULK1 inhibition results in accumulation of stalled early autophagosomal structures, indicating a role for ULK1 in the maturation of autophagosomes as well as initiation. PMID- 25833949 TI - EDD, a ubiquitin-protein ligase of the N-end rule pathway, associates with spindle assembly checkpoint components and regulates the mitotic response to nocodazole. AB - In this work, we identify physical and genetic interactions that implicate E3 identified by differential display (EDD) in promoting spindle assembly checkpoint (SAC) function. During mitosis, the SAC initiates a mitotic checkpoint in response to chromosomes with kinetochores unattached to spindle pole microtubules. Similar to Budding uninhibited by benzimidazoles-related 1 (BUBR1) siRNA, a bona fide SAC component, EDD siRNA abrogated G2/M accumulation in response to the mitotic destabilizing agent nocodazole. Furthermore, EDD siRNA reduced mitotic cell viability and, in nocodazole-treated cells, increased expression of the promitotic progression protein cell division cycle 20 (CDC20). Copurification studies also identified physical interactions with CDC20, BUBR1, and other components of the SAC. Taken together, these observations highlight the potential role of EDD in regulating mitotic progression and the cellular response to perturbed mitosis. PMID- 25833950 TI - In Vitro Studies Reveal a Sequential Mode of Chain Processing by the Yeast SUMO (Small Ubiquitin-related Modifier)-specific Protease Ulp2. AB - Sumoylation is a post-translational modification essential in most eukaryotes that regulates stability, localization, activity, or interaction of a multitude of proteins. It is a reversible process wherein counteracting ligases and proteases, respectively, mediate the conjugation and deconjugation of SUMO molecules to/from target proteins. Apart from attachment of single SUMO moieties to targets, formation of poly-SUMO chains occurs by the attachment of additional SUMO molecules to lysine residues in the N-terminal extensions of SUMO. In Saccharomyces cerevisiae there are apparently only two SUMO(Smt3)-specific proteases: Ulp1 and Ulp2. Ulp2 has been shown to be important for the control of poly-SUMO conjugates in cells and to dismantle SUMO chains in vitro, but the mechanism by which it acts remains to be elucidated. Applying an in vitro approach, we found that Ulp2 acts sequentially rather than stochastically, processing substrate-linked poly-SUMO chains from their distal ends down to two linked SUMO moieties. Furthermore, three linked SUMO units turned out to be the minimum length of a substrate-linked chain required for efficient binding to and processing by Ulp2. Our data suggest that Ulp2 disassembles SUMO chains by removing one SUMO moiety at a time from their ends (exo mechanism). Apparently, Ulp2 recognizes surfaces at or near the N terminus of the distal SUMO moiety, as attachments to this end significantly reduce cleavage efficiency. Our studies suggest that Ulp2 controls the dynamic range of SUMO chain lengths by trimming them from the distal ends. PMID- 25833951 TI - Chloroplast SRP54 Was Recruited for Posttranslational Protein Transport via Complex Formation with Chloroplast SRP43 during Land Plant Evolution. AB - In bacteria, membrane proteins are targeted cotranslationally via a signal recognition particle (SRP). During the evolution of higher plant chloroplasts from cyanobacteria, the SRP pathway underwent striking adaptations that enable the posttranslational transport of the abundant light-harvesting chlorophyll-a/b binding proteins (LHCPs). The conserved 54-kDa SRP subunit in higher plant chloroplasts (cpSRP54) is not bound to an SRP RNA, an essential SRP component in bacteria, but forms a stable heterodimer with the chloroplast-specific cpSRP43. This heterodimeric cpSRP recognizes LHCP and delivers it to the thylakoid membrane whereby cpSRP43 plays a central role. This study shows that the cpSRP system in the green alga Chlamydomonas reinhardtii differs significantly from that of higher plants as cpSRP43 is not complexed to cpSRP54 in Chlamydomonas and cpSRP54 is not involved in LHCP recognition. This divergence is attributed to altered residues within the cpSRP54 tail and the second chromodomain of cpSRP43 that are crucial for the formation of the binding interface in Arabidopsis. These changes are highly conserved among chlorophytes, whereas all land plants contain cpSRP proteins with typical interaction motifs. These data demonstrate that the coevolution of LHCPs and cpSRP43 occurred independently of complex formation with cpSRP54 and that the interaction between cpSRP54 and cpSRP43 evolved later during the transition from chlorophytes to land plants. Furthermore, our data show that in higher plants a heterodimeric form of cpSRP is required for the formation of a low molecular weight transit complex with LHCP. PMID- 25833953 TI - Construction of phosphorylation interaction networks by text mining of full length articles using the eFIP system. AB - Protein phosphorylation is a reversible post-translational modification where a protein kinase adds a phosphate group to a protein, potentially regulating its function, localization and/or activity. Phosphorylation can affect protein protein interactions (PPIs), abolishing interaction with previous binding partners or enabling new interactions. Extracting phosphorylation information coupled with PPI information from the scientific literature will facilitate the creation of phosphorylation interaction networks of kinases, substrates and interacting partners, toward knowledge discovery of functional outcomes of protein phosphorylation. Increasingly, PPI databases are interested in capturing the phosphorylation state of interacting partners. We have previously developed the eFIP (Extracting Functional Impact of Phosphorylation) text mining system, which identifies phosphorylated proteins and phosphorylation-dependent PPIs. In this work, we present several enhancements for the eFIP system: (i) text mining for full-length articles from the PubMed Central open-access collection; (ii) the integration of the RLIMS-P 2.0 system for the extraction of phosphorylation events with kinase, substrate and site information; (iii) the extension of the PPI module with new trigger words/phrases describing interactions and (iv) the addition of the iSimp tool for sentence simplification to aid in the matching of syntactic patterns. We enhance the website functionality to: (i) support searches based on protein roles (kinases, substrates, interacting partners) or using keywords; (ii) link protein entities to their corresponding UniProt identifiers if mapped and (iii) support visual exploration of phosphorylation interaction networks using Cytoscape. The evaluation of eFIP on full-length articles achieved 92.4% precision, 76.5% recall and 83.7% F-measure on 100 article sections. To demonstrate eFIP for knowledge extraction and discovery, we constructed phosphorylation-dependent interaction networks involving 14-3-3 proteins identified from cancer-related versus diabetes-related articles. Comparison of the phosphorylation interaction network of kinases, phosphoproteins and interactants obtained from eFIP searches, along with enrichment analysis of the protein set, revealed several shared interactions, highlighting common pathways discussed in the context of both diseases. PMID- 25833952 TI - Cysteine Cathepsins Activate ELR Chemokines and Inactivate Non-ELR Chemokines. AB - Cysteine cathepsins are primarily lysosomal proteases involved in general protein turnover, but they also have specific proteolytic functions in antigen presentation and bone remodeling. Cathepsins are most stable at acidic pH, although growing evidence indicates that they have physiologically relevant activity also at neutral pH. Post-translational proteolytic processing of mature chemokines is a key, yet underappreciated, level of chemokine regulation. Although the role of selected serine proteases and matrix metalloproteases in chemokine processing has long been known, little has been reported about the role of cysteine cathepsins. Here we evaluated cleavage of CXC ELR (CXCL1, -2, -3, -5, and -8) and non-ELR (CXCL9-12) chemokines by cysteine cathepsins B, K, L, and S at neutral pH by high resolution Tris-Tricine SDS-PAGE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Whereas cathepsin B cleaved chemokines especially in the C-terminal region, cathepsins K, L, and S cleaved chemokines at the N terminus with glycosaminoglycans modulating cathepsin processing of chemokines. The functional consequences of the cleavages were determined by Ca(2+) mobilization and chemotaxis assays. We show that cysteine cathepsins inactivate and in some cases degrade non-ELR CXC chemokines CXCL9-12. In contrast, cathepsins specifically process ELR CXC chemokines CXCL1, -2, -3, 5, and -8 N-terminally to the ELR motif, thereby generating agonist forms. This study suggests that cysteine cathepsins regulate chemokine activity and thereby leukocyte recruitment during protective or pathological inflammation. PMID- 25833954 TI - CHOPIN: a web resource for the structural and functional proteome of Mycobacterium tuberculosis. AB - Tuberculosis kills more than a million people annually and presents increasingly high levels of resistance against current first line drugs. Structural information about Mycobacterium tuberculosis (Mtb) proteins is a valuable asset for the development of novel drugs and for understanding the biology of the bacterium; however, only about 10% of the ~4000 proteins have had their structures determined experimentally. The CHOPIN database assigns structural domains and generates homology models for 2911 sequences, corresponding to ~73% of the proteome. A sophisticated pipeline allows multiple models to be created using conformational states characteristic of different oligomeric states and ligand binding, such that the models reflect various functional states of the proteins. Additionally, CHOPIN includes structural analyses of mutations potentially associated with drug resistance. Results are made available at the web interface, which also serves as an automatically updated repository of all published Mtb experimental structures. Its RESTful interface allows direct and flexible access to structures and metadata via intuitive URLs, enabling easy programmatic use of the models. PMID- 25833955 TI - BioSurfDB: knowledge and algorithms to support biosurfactants and biodegradation studies. AB - Crude oil extraction, transportation and use provoke the contamination of countless ecosystems. Therefore, bioremediation through surfactants mobilization or biodegradation is an important subject, both economically and environmentally. Bioremediation research had a great boost with the recent advances in Metagenomics, as it enabled the sequencing of uncultured microorganisms providing new insights on surfactant-producing and/or oil-degrading bacteria. Many research studies are making available genomic data from unknown organisms obtained from metagenomics analysis of oil-contaminated environmental samples. These new datasets are presently demanding the development of new tools and data repositories tailored for the biological analysis in a context of bioremediation data analysis. This work presents BioSurfDB, www.biosurfdb.org, a curated relational information system integrating data from: (i) metagenomes; (ii) organisms; (iii) biodegradation relevant genes; proteins and their metabolic pathways; (iv) bioremediation experiments results, with specific pollutants treatment efficiencies by surfactant producing organisms; and (v) a biosurfactant curated list, grouped by producing organism, surfactant name, class and reference. The main goal of this repository is to gather information on the characterization of biological compounds and mechanisms involved in biosurfactant production and/or biodegradation and make it available in a curated way and associated with a number of computational tools to support studies of genomic and metagenomic data. PMID- 25833956 TI - Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. AB - Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, beta2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F1+2 and d-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973. PMID- 25833957 TI - A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. AB - Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been recommended as a standard of care. However, 60 mg/m(2) is widely used and has never been directly compared with 90 mg/m(2). As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m(2) or 60 mg/m(2) on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m(2) on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m(2) arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2 year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535. PMID- 25833958 TI - Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell dependent induction of CD4+CD25+FoxP3+ Treg. AB - CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) are critical elements for maintaining immune tolerance, for instance to exogenous antigens that are introduced during therapeutic interventions such as cell/organ transplant or gene/protein replacement therapy. Coadministration of antigen with rapamycin simultaneously promotes deletion of conventional CD4(+) T cells and induction of Treg. Here, we report that the cytokine FMS-like receptor tyrosine kinase ligand (Flt3L) enhances the in vivo effect of rapamycin. This occurs via selective expansion of plasmacytoid dendritic cells (pDCs), which further augments the number of Treg. Whereas in conventional DCs, rapamycin effectively blocks mammalian target of rapamycin (mTOR) 1 signaling induced by Flt3L, increased mTOR1 activity renders pDCs more resistant to inhibition by rapamycin. Consequently, Flt3L and rapamycin synergistically promote induction of antigen specific Treg via selective expansion of pDCs. This concept is supported by the finding that Treg induction is abrogated upon pDC depletion. The combination with pDCs and rapamycin is requisite for Flt3L/antigen-induced Treg induction because Flt3L/antigen by itself fails to induce Treg. As co-administering Flt3L, rapamycin, and antigen blocked CD8(+) T-cell and antibody responses in models of gene and protein therapy, we conclude that the differential effect of rapamycin on DC subsets can be exploited for improved tolerance induction. PMID- 25833959 TI - Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling. AB - Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by alpha-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes alpha-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile. PMID- 25833961 TI - Immune checkpoint blockade in hematologic malignancies. AB - Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, we may begin to envision its morning. PMID- 25833960 TI - Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach. AB - Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes. PMID- 25833962 TI - TGF-beta signaling in the control of hematopoietic stem cells. AB - Blood is a tissue with high cellular turnover, and its production is a tightly orchestrated process that requires constant replenishment. All mature blood cells are generated from hematopoietic stem cells (HSCs), which are the self-renewing units that sustain lifelong hematopoiesis. HSC behavior, such as self-renewal and quiescence, is regulated by a wide array of factors, including external signaling cues present in the bone marrow. The transforming growth factor-beta (TGF-beta) family of cytokines constitutes a multifunctional signaling circuitry, which regulates pivotal functions related to cell fate and behavior in virtually all tissues of the body. In the hematopoietic system, TGF-beta signaling controls a wide spectrum of biological processes, from homeostasis of the immune system to quiescence and self-renewal of HSCs. Here, we review key features and emerging concepts pertaining to TGF-beta and downstream signaling pathways in normal HSC biology, featuring aspects of aging, hematologic disease, and how this circuitry may be exploited for clinical purposes in the future. PMID- 25833963 TI - The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-kappaB positive feedback loop in peripheral T-cell lymphoma. AB - Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor kappaB (NF-kappaB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-kappaB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-kappaB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-kappaB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. PMID- 25833965 TI - Sensitivity to verb bias in American sign language-English bilinguals. AB - Native speakers of English are sensitive to the likelihood that a verb will appear in a specific subcategorization frame, known as verb bias. Readers rely on verb bias to help them resolve temporary ambiguity in sentence comprehension. We investigate whether deaf sign-print bilinguals who have acquired English syntactic knowledge primarily through print exposure show sensitivity to English verb biases in both production and comprehension. We first elicited sentence continuations for 100 English verbs as an offline production measure of sensitivity to verb bias. We then collected eye movement records to examine whether deaf bilinguals' online parsing decisions are influenced by English verb bias. The results indicate that exposure to a second language primarily via print is sufficient to influence use of implicit frequency-based characteristics of a language in production and also to inform parsing decisions in comprehension for some, but not all, verbs. PMID- 25833964 TI - Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3. AB - Mice reconstituted with a human immune system provide a tractable in vivo model to assess human immune cell function. To date, reconstitution of murine strains with human hematopoietic stem cells (HSCs) from patients with monogenic immune disorders have not been reported. One obstacle precluding the development of immune-disease specific "humanized" mice is that optimal adaptive immune responses in current strains have required implantation of autologous human thymic tissue. To address this issue, we developed a mouse strain that lacks murine major histocompatibility complex class II (MHC II) and instead expresses human leukocyte antigen DR1 (HLA-DR1). These mice displayed improved adaptive immune responses when reconstituted with human HSCs including enhanced T-cell reconstitution, delayed-type hypersensitivity responses, and class-switch recombination. Following immune reconstitution of this novel strain with HSCs from a patient with immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome, associated with aberrant FOXP3 function, mice developed a lethal inflammatory disorder with multiorgan involvement and autoantibody production mimicking the pathology seen in affected humans. This humanized mouse model permits in vivo evaluation of immune responses associated with genetically altered HSCs, including primary immunodeficiencies, and should facilitate the study of human immune pathobiology and the development of targeted therapeutics. PMID- 25833966 TI - Minimally invasive decompression versus open laminectomy for central stenosis of the lumbar spine: pragmatic comparative effectiveness study. AB - OBJECTIVE: To test the equivalence for clinical effectiveness between microdecompression and laminectomy in patients with central lumbar spinal stenosis. DESIGN: Multicentre observational study. SETTING: Prospective data from the Norwegian Registry for Spine Surgery. PARTICIPANTS: 885 patients with central stenosis of the lumbar spine who underwent surgery at 34 Norwegian orthopaedic or neurosurgical departments. Patients were treated from October 2006 to December 2011. INTERVENTIONS: Laminectomy and microdecompression. MAIN OUTCOME MEASURES: The primary outcome was change in Oswestry disability index score one year after surgery. Secondary endpoints were quality of life (EuroQol EQ-5D), perioperative complications, and duration of surgical procedures and hospital stays. A blinded biostatistician performed predefined statistical analyses in unmatched and propensity matched cohorts. RESULTS: The study was powered to detect a difference between the groups of eight points on the Oswestry disability index at one year. 721 patients (81%) completed the one year follow-up. Equivalence between microdecompression and laminectomy was shown for the Oswestry disability index (difference 1.3 points, 95% confidence interval -1.36 to 3.92, P<0.001 for equivalence). Equivalence was confirmed in the propensity matched cohort and full information regression analyses. No difference was found between groups in quality of life (EQ-5D) one year after surgery. The number of patients with complications was higher in the laminectomy group (15.0% v 9.8%, P=0.018), but after propensity matching for complications the groups did not differ (P=0.23). The duration of surgery for single level decompression was shorter in the microdecompression group (difference 11.2 minutes, 95% confidence interval 4.9 to 17.5, P<0.001), but after propensity matching the groups did not differ (P=0.15). Patients in the microdecompression group had shorter hospital stays, both for single level decompression (difference 1.5 days, 95% confidence interval 1.7 to 2.6, P<0.001) and two level decompression (0.8 days, 1.0 to 2.2, P=0.003). CONCLUSION: At one year the effectiveness of microdecompression is equivalent to laminectomy in the surgical treatment of central stenosis of the lumbar spine. Favourable outcomes were observed at one year in both treatment groups.Trial registration ClinicalTrials.gov NCT02006901. PMID- 25833967 TI - Does dietary cholesterol influence cardiovascular disease risk in people with type 2 diabetes? PMID- 25833968 TI - Satiation attenuates BOLD activity in brain regions involved in reward and increases activity in dorsolateral prefrontal cortex: an fMRI study in healthy volunteers. AB - BACKGROUND: Neural responses to rewarding food cues are significantly different in the fed vs. fasted (>8 h food-deprived) state. However, the effect of eating to satiety after a shorter (more natural) intermeal interval on neural responses to both rewarding and aversive cues has not been examined. OBJECTIVE: With the use of a novel functional magnetic resonance imaging (fMRI) task, we investigated the effect of satiation on neural responses to both rewarding and aversive food tastes and pictures. DESIGN: Sixteen healthy participants (8 men, 8 women) were scanned on 2 separate test days, before and after eating a meal to satiation or after not eating for 4 h (satiated vs. premeal). fMRI blood oxygen level dependent (BOLD) signals to the sight and/or taste of the stimuli were recorded. RESULTS: A whole-brain cluster-corrected analysis (P < 0.05) showed that satiation attenuated the BOLD response to both stimulus types in the ventromedial prefrontal cortex (vmPFC), orbitofrontal cortex, nucleus accumbens, hypothalamus, and insula but increased BOLD activity in the dorsolateral prefrontal cortex (dlPFC; local maxima corrected to P <= 0.001). A psychophysiological interaction analysis showed that the vmPFC was more highly connected to the dlPFC when individuals were exposed to food stimuli when satiated than when not satiated. CONCLUSIONS: These results suggest that natural satiation attenuates activity in reward-related brain regions and increases activity in the dlPFC, which may reflect a "top down" cognitive influence on satiation. This trial was registered at clinicaltrials.gov as NCT02298049. PMID- 25833969 TI - The effect of a high-egg diet on cardiovascular risk factors in people with type 2 diabetes: the Diabetes and Egg (DIABEGG) study-a 3-mo randomized controlled trial. AB - BACKGROUND: Previously published research that examined the effects of high egg consumption in people with type 2 diabetes (T2D) produced conflicting results leading to recommendations to limit egg intake. However, people with T2D may benefit from egg consumption because eggs are a nutritious and convenient way of improving protein and micronutrient contents of the diet, which have importance for satiety and weight management. OBJECTIVE: In this randomized controlled study, we aimed to determine whether a high-egg diet (2 eggs/d for 6 d/wk) compared with a low-egg diet (<2 eggs/wk) affected circulating lipid profiles, in particular high-density lipoprotein (HDL) cholesterol, in overweight or obese people with prediabetes or T2D. DESIGN: A total of 140 participants were randomly assigned to one of the 2 diets as part of a 3-mo weight maintenance study. Participants attended the clinic monthly and were instructed on the specific types of foods and quantities to be consumed. RESULTS: There was no significant difference in the change in HDL cholesterol from screening to 3 mo between groups; the mean difference (95% CI) between high- and low-egg groups was +0.02 mmol/L (-0.03, 0.08 mmol/L; P = 0.38). No between-group differences were shown for total cholesterol, low-density lipoprotein cholesterol, triglycerides, or glycemic control. Both groups were matched for protein intake, but the high-egg group reported less hunger and greater satiety postbreakfast. Polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) intakes significantly increased from baseline in both groups. CONCLUSIONS: High egg consumption did not have an adverse effect on the lipid profile of people with T2D in the context of increased MUFA and PUFA consumption. This study suggests that a high-egg diet can be included safely as part of the dietary management of T2D, and it may provide greater satiety. This trial was registered at the Australia New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12612001266853. PMID- 25833970 TI - Imaging gastric structuring of lipid emulsions and its effect on gastrointestinal function: a randomized trial in healthy subjects. AB - BACKGROUND: Efficient fat digestion requires fat processing within the stomach and fat sensing in the intestine. Both processes also control gastric emptying and gastrointestinal secretions. OBJECTIVE: We aimed to visualize the influence of the intragastric stability of fat emulsions on their dynamics of gastric processing and structuring and to assess the effect this has on gastrointestinal motor and secretory functions. DESIGN: Eighteen healthy subjects with normal body mass index (BMI) were studied on 4 separate occasions in a double-blind, randomized, crossover design. Magnetic resonance imaging (MRI) data of the gastrointestinal tract and blood triglycerides were recorded before and for 240 min after the consumption of the following 4 different fat emulsions: lipid emulsion 1 (LE1; acid stable, 0.33 MUm), lipid emulsion 2 (LE2; acid stable, 52 MUm), lipid emulsion 3 (LE3; acid unstable, solid fat, 0.32 MUm), and lipid emulsion 4 (LE4; acid unstable, liquid fat, 0.38 MUm). RESULTS: Intragastric emulsion instability was associated with a change in gastric emptying. Acid unstable emulsions exhibited biphasic and faster emptying profiles than did the 2 acid-stable emulsions (P <= 0.0001). When combined with solid fat (LE3), different dynamics of postprandial gallbladder volume were induced (P <= 0.001). For acid-stable emulsions, a reduction of droplet size by 2 orders of magnitude [LE1 (0.33 MUm) compared with LE2 (52 MUm)] delayed gastric emptying by 38 min. Although acid-stable (LE1 and LE2) and redispersible (LE4) emulsions caused a constant increase in blood triglycerides, no increase was detectable for LE3 (P < 0.0001). For LE3, MRI confirmed the generation of large fat particles during gastric processing, which emptied into and progressed through the small intestine. CONCLUSIONS: MRI allows the detailed characterization of the in vivo fate of lipid emulsions. The acute effects of lipid emulsions on gastric emptying, gallbladder volume, and triglyceride absorption are dependent on microstructural changes undergone during consumption. Gastric peristalsis and secretion were effective at redispersing pools of liquid fat in the stomach. This trial was registered at clinicaltrials.gov as NCT01253005. PMID- 25833972 TI - Effects of animal source food and micronutrient fortification in complementary food products on body composition, iron status, and linear growth: a randomized trial in Cambodia. AB - BACKGROUND: Poor nutritional quality of complementary foods often limits growth. Animal source foods, such as milk or meat, are often unaffordable. Local affordable alternatives are needed. OBJECTIVE: We evaluate the efficacy of 2 newly developed, rice-based complementary food products: WinFood (WF) with small fish and edible spiders and WinFood-Lite (WF-L) fortified with small fish, against 2 existing fortified corn-soy blend products, CSB+ (purely plant based) and CSB++ (8% dried skimmed milk). DESIGN: In total, 419 infants aged 6 mo were enrolled in this randomized, single-blinded study for 9 mo, designed primarily to assess increments in fat-free mass by a deuterium dilution technique and change in plasma ferritin and soluble transferrin receptor. Secondary endpoints were changes in anthropometric variables, including knee-heel length. Data were analyzed by the intention-to-treat approach. RESULTS: There was no difference in fat-free mass increment in WF or WF-L compared with CSB+ [WF: +0.04 kg (95% CI: 0.20, 0.28 kg); WF-L: +0.14 kg (95% CI: -0.10, 0.38 kg)] or CSB++ [WF: -0.03 kg (95% CI: -0.27, 0.21 kg); WF-L: +0.07 kg (95% CI: -0.18, 0.31 kg)] and no effect on iron status. The 1.7-mm (95% CI: -0.1, 3.5 mm) greater increase in knee-heel length in WF-L than in CSB+ was not significant. CONCLUSIONS: No difference was found between the locally produced products (WF and WF-L) and the CSBs. Micronutrient fortification may be necessary, and small fish may be an affordable alternative to milk to improve complementary foods. The dietary role of edible spiders needs to be further explored. This trial was registered at controlled trials.com as ISRCTN19918531. PMID- 25833971 TI - Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: the Viva La Familia Study. AB - BACKGROUND: Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children. OBJECTIVE: The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study. DESIGN: We conducted a genomewide association study with 1.1 million genetic markers in 815 children. RESULTS: We found serum uric acid to be significantly heritable [h(2) +/- SD = 0.45 +/- 0.08, P = 5.8 * 10(-11)] and associated with SLC2A9 variants (P values between 10(-16) and 10(-7)). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (rhoG = 0.45, P = 0.002), percentage of body fat (rhoG = 0.28, P = 0.04), fat mass (rhoG = 0.34, P = 0.02), waist circumference (rhoG = 0.42, P = 0.003), and waist-to-height ratio (rhoG = 0.46, P = 0.001). CONCLUSIONS: Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children. PMID- 25833973 TI - Body composition and all-cause mortality in subjects older than 65 y. AB - BACKGROUND: A low or high body mass index (BMI) has been associated with increased mortality risk in older subjects without taking fat mass index (FMI) and fat-free mass index (FFMI) into account. This information is essential because FMI is modulated through different healthcare strategies than is FFMI. OBJECTIVE: We aimed to determine the relation between body composition and mortality in older subjects. DESIGN: We included all adults >=65 y old who were living in Switzerland and had a body-composition measurement by bioelectrical impedance analysis at the Geneva University Hospitals between 1990 and 2011. FMI and FFMI were divided into sex-specific quartiles. Quartile 1 (i.e., the reference category) corresponded to the lowest FMI or FFMI quartile. Mortality data were retrieved from the hospital database, the Geneva death register, and the Swiss National Cohort until December 2012. Comorbidities were assessed by using the Cumulative Illness Rating Scale. RESULTS: Of 3181 subjects included, 766 women and 1007 men died at a mean age of 82.8 and 78.5 y, respectively. Sex specific Cox regression models, which were used to adjust for age, BMI, smoking, ambulatory or hospitalized state, and calendar time, showed that body composition did not predict mortality in women irrespective of whether comorbidities were taken into account. In men, risk of mortality was lower with FFMI in quartiles 3 and 4 [HR: 0.78 (95% CI: 0.62, 0.98) and 0.64 (95% CI: 0.49, 0.85), respectively] but was not affected by FMI. When comorbidities were adjusted for, FFMI in quartile 4 (>19.5 kg/m(2)) still predicted a lower risk of mortality (HR: 0.72; 95% CI: 0.54, 0.96). CONCLUSIONS: Low FFMI is a stronger predictor of mortality than is BMI in older men but not older women. FMI had no impact on mortality. These results suggest potential benefits of preventive interventions with the aim of maintaining muscle mass in older men. This trial was registered at clinicaltrials.gov as NCT01472679. PMID- 25833974 TI - Factors affecting food choices of older adults from high and low socioeconomic groups: a discrete choice experiment. AB - BACKGROUND: Healthiness, price, and convenience are typically indicated as important motives for food choices; however, it is largely unknown to what extent older adults from high and low socioeconomic groups differ in these underlying motives. A discrete choice experiment (DCE) is an innovative way to elicit implicit motives for food choices. OBJECTIVE: The aim was to investigate differences in food motives between socioeconomic groups by means of a DCE. DESIGN: A DCE was carried out during a face-to-face interview among older adults as part of the Health and Living Conditions in Eindhoven and surrounding cities (GLOBE) cohort study, The Netherlands. Participants (n = 399; mean age: 63.3 y) were offered a series of choice sets about a usual dinner at home and were asked to choose in each choice set between 2 meals and an opt-out choice, with different combinations of attribute levels. We included 5 meal attributes (taste, healthiness, preparation time, travel time to shops, and price) and 3 or 4 levels for each attribute. Data were analyzed by multinomial logit models. RESULTS: Healthiness, taste, price, and travel time to the grocery store proved to significantly influence older adults' meal decisions; preparation time was not significant. Healthiness was the most important attribute for all of the participants. More highly educated participants rated a healthy and less expensive meal to be more important than did less educated participants. Those with a high income rated a meal that was healthy and very tasteful to be more important than did those with a lower income. CONCLUSIONS: Healthiness, taste, price, and travel time to grocery shops influenced older adults' meal decisions. Higher socioeconomic groups valued health more than did lower socioeconomic groups. DCEs represent a promising method to gain insight into the relative importance of motives for food choices. This trial was registered at www.isrctn.com as ISRCTN60293770. PMID- 25833975 TI - Associations of dairy intake with glycemia and insulinemia, independent of obesity, in Brazilian adults: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: Inverse associations between dairy intake and the risk of type 2 diabetes have been shown, but more studies are needed, especially from low- and middle-income countries. OBJECTIVE: The objective was to describe the association between dairy products and direct measures of glycemic status in adults without known diabetes. DESIGN: The Brazilian Longitudinal Study of Adult Health (ELSA Brasil) includes 15,105 adults, aged 35-74 y, enrolled from universities and research institutions in 6 Brazilian capital cities. We excluded participants with a known diabetes diagnosis, cardiovascular diseases, and cancer. Dairy consumption was assessed by a food-frequency questionnaire, and we computed servings per day for total and subgroups of dairy. Associations with fasting blood glucose (FG) and fasting insulin, 2-h postload glucose (PG), 2-h postload insulin (PI), glycated hemoglobin (Hb A1c), and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed through multivariable linear regression analysis with adjustment for demographic characteristics, behavioral risk factors, other dietary factors, and anthropometric measurements. RESULTS: The sample size after exclusions was 10,010. The intake of total dairy was inversely associated with FG (linear beta for dairy servings/d = -0.46 +/- 0.2 mg/dL), PG (-1.25 +/- 0.5 mg/dL), PI (-1.52 +/- 0.6 mg/dL), Hb A1c (-0.02 +/- 0.0%), and HOMA-IR (-0.04 +/- 0.0) after adjustment for all covariates (P < 0.05 for all). The findings were consistent across categories of sex, race, obesity status, and dairy fat amount (reduced-fat vs. full-fat dairy). Fermented dairy products showed particularly strong inverse associations with the outcomes, with adjusted differences for a 1-serving/d increment of -0.24 (95% CI: -0.46, -0.02) mg/dL for FG, -0.86 (-1.42, -0.30) mg/dL for PG, and -0.01% (-0.02%, 0.00%) for Hb A1c. Myristic acid was the only nutrient that appeared to mediate the association between dairy intake and glycemia. CONCLUSION: Dairy intake, especially fermented dairy, was inversely associated with measures of glycemia and insulinemia in Brazilian adults without diagnosed diabetes. This trial was registered at clinicaltrials.com as NCT02320461. PMID- 25833976 TI - Nut consumption on all-cause, cardiovascular, and cancer mortality risk: a systematic review and meta-analysis of epidemiologic studies. AB - BACKGROUND: Recent pooled analyses supported a beneficial impact of nut consumption on health, but to our knowledge, whether nuts are associated with overall decreased mortality has not been previously reviewed. OBJECTIVES: We aimed to systematically review prospective studies that explored the effects of nut consumption on all-cause, cardiovascular disease (CVD), and cancer mortality and quantify the size effect through a meta-analysis. We also reviewed confounding factors associated with nut consumption to assess potential clustering with other covariates. DESIGN: We searched PubMed and EMBASE for studies published up to June 2014. Study characteristics, HRs, and 95% CIs were generated on the basis of quantitative analyses. A dose-response analysis was performed when data were available. RESULTS: Seven studies for all-cause mortality, 6 studies for CVD mortality, and 2 studies for cancer mortality were included in the meta-analysis with a total of 354,933 participants, 44,636 cumulative incident deaths, and 3,746,534 cumulative person-years. Nut consumption was associated with some baseline characteristics such as lower body mass index and smoking status as well as increased intakes of fruit, vegetables, and alcohol. One-serving of nuts per week and per day resulted in 4% (RR: 0.96; 95% CI: 0.93, 0.98) and 27% (RR: 0.73; 95% CI: 0.60, 0.88) decreased risk of all cause mortality, respectively, and decreased risk of CVD mortality [RR: 0.93 (95% CI: 0.88, 0.99) and 0.61 (95% CI: 0.42, 0.91), respectively]. Effects were primarily driven by decreased coronary artery disease deaths rather than stroke deaths. Nut consumption was also associated with decreased risk of cancer deaths when highest compared with lowest categories of intake were compared (RR: 0.86; 95% CI: 0.75, 0.98), but no dose-effect was shown. CONCLUSION: Nut consumption is associated with lower risk of all-cause, CVD, and cancer mortality, but the presence of confounding factors should be taken into account when considering such findings. PMID- 25833977 TI - MRI-determined total volumes of visceral and subcutaneous abdominal and trunk adipose tissue are differentially and sex-dependently associated with patterns of estimated usual nutrient intake in a northern German population. AB - BACKGROUND: Visceral (VAT) and subcutaneous abdominal (SAAT) and trunk (STRAT) adipose tissue (AT) have been suggested to be differentially influenced by diet. OBJECTIVE: We investigated whether and to what extent usual patterns of nutrient intake are associated with VAT, SAAT, and STRAT compared with nondietary predictors in northern German adults (n = 583). DESIGN: AT volumes were quantified by magnetic resonance imaging. Nutrient intake was estimated by a 112 item food-frequency questionnaire linked to the German Food Code and Nutrient Database. Exploratory nutrient patterns were derived by principal components analysis (PCA) and partial least-squares regression (PLS) of 87 nutrients. Cross sectional associations between nutrient patterns, single nutrients, or total energy intake and AT compartments were analyzed by multiple linear regression. RESULTS: Next to sex and age, respectively, which were important nondietary predictors and accounted for more of the variation in VAT (~13% and ~4%) than in SAAT or STRAT (both 4-7% and <1%), variation in VAT (16.8% or 17.6%) was explained to a greater extent by 9 or 2 nutrient patterns derived by principal components analysis or partial least-squares regression, respectively, than was variation in SAAT (10.6% or 8.2%) or STRAT (11.5% or 8.6%). Whereas VAT (16.6%) was primarily explained by nutrient quality, SAAT (6.9%) and STRAT (7.4%) were mainly explained by total energy intake. VAT was positively associated with nutrients characteristic of animal (except for dairy) products, including arachidonic acid (standardized beta: 0.25; 95% CI: 0.15, 0.34; P < 0.0001), but negatively with dietary fiber, including polypentoses (standardized beta: -0.17; 95% CI: -0.24, -0.09; P < 0.0001), and nutrients found in milk. The direction and strength of many associations, however, depended strongly on sex and adjustment for BMI. CONCLUSION: VAT may be particularly associated with sex-specific interplays of nutrients found in animal products and fiber, whereas SAAT and STRAT are associated with total energy intake. PMID- 25833978 TI - Price promotions on healthier compared with less healthy foods: a hierarchical regression analysis of the impact on sales and social patterning of responses to promotions in Great Britain. AB - BACKGROUND: There is a growing concern, but limited evidence, that price promotions contribute to a poor diet and the social patterning of diet-related disease. OBJECTIVE: We examined the following questions: 1) Are less-healthy foods more likely to be promoted than healthier foods? 2) Are consumers more responsive to promotions on less-healthy products? 3) Are there socioeconomic differences in food purchases in response to price promotions? DESIGN: With the use of hierarchical regression, we analyzed data on purchases of 11,323 products within 135 food and beverage categories from 26,986 households in Great Britain during 2010. Major supermarkets operated the same price promotions in all branches. The number of stores that offered price promotions on each product for each week was used to measure the frequency of price promotions. We assessed the healthiness of each product by using a nutrient profiling (NP) model. RESULTS: A total of 6788 products (60%) were in healthier categories and 4535 products (40%) were in less-healthy categories. There was no significant gap in the frequency of promotion by the healthiness of products neither within nor between categories. However, after we controlled for the reference price, price discount rate, and brand-specific effects, the sales uplift arising from price promotions was larger in less-healthy than in healthier categories; a 1-SD point increase in the category mean NP score, implying the category becomes less healthy, was associated with an additional 7.7-percentage point increase in sales (from 27.3% to 35.0%; P < 0.01). The magnitude of the sales uplift from promotions was larger for higher-socioeconomic status (SES) groups than for lower ones (34.6% for the high-SES group, 28.1% for the middle-SES group, and 23.1% for the low-SES group). Finally, there was no significant SES gap in the absolute volume of purchases of less-healthy foods made on promotion. CONCLUSION: Attempts to limit promotions on less-healthy foods could improve the population diet but would be unlikely to reduce health inequalities arising from poorer diets in low-socioeconomic groups. PMID- 25833979 TI - Dietary patterns and breast cancer risk: a study in 2 cohorts. AB - BACKGROUND: Evidence for a role of dietary risk factors in the cause of breast cancer has been inconsistent. The evaluation of overall dietary patterns instead of foods in isolation may better reflect the nature of true dietary exposure in a population. OBJECTIVE: We used 2 cohort studies to identify and confirm associations between dietary patterns and breast cancer risk. DESIGN: Dietary patterns were derived by using a principal components factor analysis in 1097 breast cancer cases and an age-stratified subcohort of 3320 women sampled from 39,532 female participants in the Canadian Study of Diet, Lifestyle and Health (CSDLH). We conducted a confirmatory factor analysis in 49,410 subjects in the National Breast Screening Study (NBSS) in whom 3659 cases of incident breast cancer developed. Cox regression models were used to estimate HRs for the association between derived dietary factors and risk of breast cancer in both cohorts. RESULTS: The following 3 dietary factors were identified from the CSDLH: healthy, ethnic, and meat and potatoes. In the CSDLH, the healthy dietary pattern was associated with reduced risk of breast cancer (HR for high compared with low quintiles: 0.73; 95% CI: 0.58, 0.91; P-trend = 0.001), and the meat and potatoes dietary pattern was associated with increased risk in postmenopausal women only (HR for high compared with low quintiles: 1.26; 95% CI: 0.92, 1.73; P-trend = 0.043). In the NBSS, the association between the meat and potatoes pattern and postmenopausal breast cancer risk was confirmed (HR: 1.31; 95% CI: 0.98, 1.76; P trend = 0.043), but there was no association between the healthy pattern and risk of breast cancer. CONCLUSION: Adherence to a plant-based diet that limits red meat intake may be associated with reduced risk of breast cancer, particularly in postmenopausal women. PMID- 25833980 TI - Lipid-based nutrient supplement increases the birth size of infants of primiparous women in Ghana. AB - BACKGROUND: The International Lipid-Based Nutrient Supplements Project developed a small-quantity (20 g/d) lipid-based nutrient supplement (LNS) for pregnant and lactating women. OBJECTIVE: We evaluated the effects of prenatal LNS supplementation on fetal growth. DESIGN: In a community-based, partially double blind, individually randomized controlled trial, 1320 women <=20 wk pregnant received 60 mg Fe/400 MUg folic acid (IFA), or 1-2 Recommended Dietary Allowances of 18 micronutrients, including 20 mg Fe (MMN), or LNS with the same micronutrients as the MMN group, plus 4 minerals and macronutrients contributing 118 kcal (LNS) daily until delivery. Fetal growth was compared across groups by using intention-to-treat analysis. The primary outcome was birth length. RESULTS: This analysis included 1057 women (IFA = 349, MMN = 354, LNS = 354). Groups did not differ significantly in mean birth length, length-for-age z score (LAZ), head circumference, or percentage low birth length but differed in mean birth weight (P = 0.044), weight-for-age z score (WAZ; P = 0.046), and BMI-for-age z score (BMIZ; P = 0.040), with a trend toward differences in low birth weight (P = 0.069). In pairwise comparisons, the LNS group had greater mean birth weight (+85 g; P = 0.040), WAZ (+0.19; P = 0.045), and BMIZ (+0.21; P = 0.035) and a lower risk of low birth weight (RR: 0.61, 95% CI: 0.39, 0.96; P = 0.032) than did the IFA group. The other group differences were not significant. The effect of intervention was modified by mother's parity, age, height, baseline hemoglobin, household food insecurity, and child sex, with parity being the most consistent modifier. Among primiparous women (IFA = 131; MMN = 110; LNS = 128), the LNS group had greater mean birth length (+0.91 cm; P = 0.001), LAZ (+0.47; P = 0.001), weight (+237 g; P < 0.001), WAZ (+0.56; P < 0.001), BMIZ (+0.52; P < 0.001), head circumference (0.50 cm; P = 0.017), and head circumference-for-age z score (+0.40; P = 0.022) than did the IFA group; similar differences were found when comparing the LNS and MMN groups among primiparous women, and no group differences were found among multiparous women. CONCLUSION: Prenatal LNS supplementation can improve fetal growth among vulnerable women in Ghana, particularly primiparous women. This trial was registered at clinicaltrials.gov as NCT00970866. PMID- 25833981 TI - Community-based management of severe acute malnutrition in India: new evidence from Bihar. AB - BACKGROUND: An estimated one-third of the world's children who are wasted live in India. In Bihar state, of children <5 y old, 27.1% are wasted and 8.3% have severe acute malnutrition (SAM). In 2009, Medecins Sans Frontieres (MSF) initiated a community-based management of acute malnutrition (CMAM) program for children aged 6-59 mo with SAM. OBJECTIVE: In this report, we describe the characteristics and outcomes of 8274 children treated between February 2009 and September 2011. DESIGN: Between February 2009 and June 2010, the program admitted children with a weight-for-height z score (WHZ) <-3 SD and/or midupper arm circumference (MUAC) <110 mm and discharged those who reached a WHZ >-2 SDs and MUAC >110 mm. These variables changed in July 2010 to admission on the basis of an MUAC <115 mm and discharge at an MUAC >=120 mm. Uncomplicated SAM cases were treated as outpatients in the community by using a WHO-standard, ready-to-use, therapeutic lipid-based paste produced in India; complicated cases were treated as inpatients by using F75/F100 WHO-standard milk until they could complete treatment in the community. RESULTS: A total of 8274 children were admitted including 5149 girls (62.2%), 6613 children aged 6-23 mo (79.9%), and 87.3% children who belonged to Scheduled Caste, Scheduled Tribe, or Other Backward Caste families or households. Of 3873 children admitted under the old criteria, 41 children (1.1%) died, 2069 children (53.4%) were discharged as cured, and 1485 children (38.3%) defaulted. Of 4401 children admitted under the new criteria, 36 children (0.8%) died, 2526 children (57.4%) were discharged as cured, and 1591 children (36.2%) defaulted. For children discharged as cured, the mean (+/-SD) weight gain and length of stay were 4.7 +/- 3.1 and 5.1 +/- 3.7 g . kg(-1) . d( 1) and 8.7 +/- 6.1 and 7.3 +/- 5.6 wk under the old and new criteria, respectively (P < 0.01). After adjustment, significant risk factors for default were as follows: no community referral for admission, more severe wasting on admission, younger age, and a long commute for treatment. CONCLUSIONS: To our knowledge, this is the first conventional CMAM program in India and has achieved low mortality and high cure rates in nondefaulting children. The new admission criteria lower the threshold for severity with the result that more children are included who are at lower risk of death and have a smaller WHZ deficit to correct than do children identified by the old criteria. This study was registered as a retrospective observational analysis of routine program data at http://www.isrctn.com as ISRCTN13980582. PMID- 25833982 TI - Maternal dietary uridine causes, and deoxyuridine prevents, neural tube closure defects in a mouse model of folate-responsive neural tube defects. AB - BACKGROUND: Folic acid prevents neural tube closure defects (NTDs), but the causal metabolic pathways have not been established. Serine hydroxymethyltransferase 1 (SHMT1) is an essential scaffold protein in folate dependent de novo thymidylate synthesis in the nucleus. SHMT1-deficient mice provide a model to investigate folic acid-responsive NTDs wherein disruption of de novo thymidylate synthesis impairs neural tube closure. OBJECTIVE: We examined the effects of maternal supplementation with the pyrimidine nucleosides uridine, thymidine, or deoxyuridine with and without folate deficiency on NTD incidence in the Shmt1 mouse model. DESIGN: Shmt1(+/+) and Shmt1(-/-) female mice fed folate replete or folate-deficient diets and supplemented with uridine, thymidine, or deoxyuridine were bred, and litters (n = 10-23 per group) were examined for the presence of NTDs. Biomarkers of impaired folate status and metabolism were measured, including plasma nucleosides, hepatic uracil content, maternal plasma folate concentrations, and incorporation of nucleoside precursors into DNA. RESULTS: Shmt1(+/-) and Shmt1(-/-) embryos from dams fed the folate-deficient diet were susceptible to NTDs. No NTDs were observed in litters from dams fed the folate-deficient diet supplemented with deoxyuridine. Surprisingly, uridine supplementation increased NTD incidence, independent of embryo genotype and dietary folic acid. These dietary nucleosides did not affect maternal hepatic uracil accumulation in DNA but did affect plasma folate concentrations. CONCLUSIONS: Maternal deoxyuridine supplementation prevented NTDs in dams fed the folate-deficient diet, whereas maternal uridine supplementation increased NTD incidence, independent of folate and embryo genotype. These findings provide new insights into the metabolic impairments and mechanisms of folate-responsive NTDs resulting from decreased Shmt1 expression. PMID- 25833983 TI - Dairy proteins, dairy lipids, and postprandial lipemia in persons with abdominal obesity (DairyHealth): a 12-wk, randomized, parallel-controlled, double-blinded, diet intervention study. AB - BACKGROUND: Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovascular disease (CVD) and mortality, and both are affected by dietary behavior. OBJECTIVE: We investigated whether dietary supplementation with whey protein and medium-chain saturated fatty acids (MC SFAs) improved postprandial lipid metabolism in humans with abdominal obesity. DESIGN: We conducted a 12-wk, randomized, double-blinded, diet intervention study. Sixty-three adults were randomly allocated to one of 4 diets in a 2 * 2 factorial design. Participants consumed 60 g milk protein (whey or casein) and 63 g milk fat (with high or low MC-SFA content) daily. Before and after the intervention, a high-fat meal test was performed. We measured changes from baseline in fasting and postprandial triacylglycerol, apolipoprotein B-48 (apoB 48; reflecting chylomicrons of intestinal origin), free fatty acids (FFAs), insulin, glucose, glucagon, glucagon-like peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP). Furthermore, changes in the expression of adipose tissue genes involved in lipid metabolism were investigated. Two-factor ANOVA was used to examine the difference between protein types and fatty acid compositions, as well as any interaction between the two. RESULTS: Fifty-two participants completed the study. We found that the postprandial apoB-48 response decreased significantly after whey compared with casein (P = 0.025) independently of fatty acid composition. Furthermore, supplementation with casein resulted in a significant increase in the postprandial GLP-1 response compared with whey (P = 0.003). We found no difference in postprandial triacylglycerol, FFA, insulin, glucose, glucagon, or GIP related to protein type or MC-SFA content. We observed no interaction between milk protein and milk fat on postprandial lipemia. CONCLUSION: We found that a whey protein supplement decreased the postprandial chylomicron response compared with casein in persons with abdominal obesity, thereby indicating a beneficial impact on CVD risk. This trial was registered at clinicaltrials.gov as NCT01472666. PMID- 25833984 TI - Dietary omega-3 polyunsaturated fatty acids decrease retinal neovascularization by adipose-endoplasmic reticulum stress reduction to increase adiponectin. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a vision-threatening disease in premature infants. Serum adiponectin (APN) concentrations positively correlate with postnatal growth and gestational age, important risk factors for ROP development. Dietary omega-3 (n-3) long-chain polyunsaturated fatty acids (omega 3 LCPUFAs) suppress ROP and oxygen-induced retinopathy (OIR) in a mouse model of human ROP, but the mechanism is not fully understood. OBJECTIVE: We examined the role of APN in ROP development and whether circulating APN concentrations are increased by dietary omega-3 LCPUFAs to mediate the protective effect in ROP. DESIGN: Serum APN concentrations were correlated with ROP development and serum omega-3 LCPUFA concentrations in preterm infants. Mouse OIR was then used to determine whether omega-3 LCPUFA supplementation increases serum APN concentrations, which then suppress retinopathy. RESULTS: We found that in preterm infants, low serum APN concentrations positively correlate with ROP, and serum APN concentrations positively correlate with serum omega-3 LCPUFA concentrations. In mouse OIR, serum total APN and bioactive high-molecular-weight APN concentrations are increased by omega-3 LCPUFA feed. White adipose tissue, where APN is produced and assembled in the endoplasmic reticulum, is the major source of serum APN. In mouse OIR, adipose endoplasmic reticulum stress is increased, and APN production is suppressed. omega-3 LCPUFA feed in mice increases APN production by reducing adipose endoplasmic reticulum stress markers. Dietary omega-3 LCPUFA suppression of neovascularization is reduced from 70% to 10% with APN deficiency. APN receptors localize in the retina, particularly to pathologic neovessels. CONCLUSION: Our findings suggest that increasing APN by omega-3 LCPUFA supplementation in total parental nutrition for preterm infants may suppress ROP. PMID- 25833985 TI - A critical appraisal on the association and effects of magnesium and bone density on physical performance in elderly women. PMID- 25833986 TI - Reply to CP Unocc et al. PMID- 25833987 TI - Glutamine supplementation, citrulline production, and de novo arginine synthesis: is there a relation? PMID- 25833988 TI - Reply to GC Ligthart-Melis et al. PMID- 25833989 TI - Erratum for Lichtenstein et al. Food-intake patterns assessed by using front-of pack labeling program criteria associated with better diet quality and lower cardiometabolic risk. Am J Clin Nutr 2014;99:454-62. PMID- 25833990 TI - Erratum for Cercamondi et al. Afebrile Plasmodium falciparum parasitemia decreases absorption of fortification iron but does not affect systemic iron utilization: a double stable-isotope study in young Beninese women. Am J Clin Nutr 2010;92:1385-92. PMID- 25833992 TI - Health professionals call for urgent halt to fracking because of public health concerns. PMID- 25833993 TI - No increase in Australia's illicit tobacco trade is seen after plain packs are introduced. PMID- 25833994 TI - Wear of PEEK-OPTIMA(r) and PEEK-OPTIMA(r)-Wear Performance articulating against highly cross-linked polyethylene. AB - The idea of all polymer artificial joints, particularly for the knee and finger, has been raised several times in the past 20 years. This is partly because of weight but also to reduce stress shielding in the bone when stiffer materials such as metals or ceramics are used. With this in mind, pin-on-plate studies of various polyetheretherketone preparations against highly cross-linked polyethylene were conducted to investigate the possibility of using such a combination in the design of a new generation of artificial joints. PEEK OPTIMA((r)) (no fibre) against highly cross-linked polyethylene gave very low wear factors of 0.0384 * 10(-6) mm(3)/N m for the polyetheretherketone pins and 0.025 * 10(-6) mm(3)/N m for the highly cross-linked polyethylene plates. The carbon-fibre-reinforced polyetheretherketone (PEEK-OPTIMA((r))-Wear Performance) also produced very low wear rates in the polyetheretherketone pins but produced very high wear in the highly cross-linked polyethylene, as might have been predicted since the carbon fibres are quite abrasive. When the fibres were predominantly tangential to the sliding plane, the mean wear factor was 0.052 * 10(-6) mm(3)/N m for the pins and 49.3 * 10(-6) mm(3)/N m for the highly cross linked polyethylene plates; a half of that when the fibres ran axially in the pins (0.138 * 10(-6) mm(3)/N m for the pins and 97.5 * 10(-6) mm/ N m for the cross-linked polyethylene plates). PEEK-OPTIMA((r)) against highly cross-linked polyethylene merits further investigation. PMID- 25833995 TI - Design and development of a device to measure the deformities of clubfoot. AB - Clubfoot describes a range of foot abnormalities usually present at birth, in which the foot of a baby is twisted out of shape or position. In order to develop an effective treatment plan for clubfoot and/or assess the extent to which existing interventions are successful, medical practitioners need to be able to accurately measure the nature and extent of the deformity. This is typically performed using a goniometer. However, this device is only able to measure one dimension at a time. As such, a complete assessment of the condition of a foot can be extremely burdensome and time-consuming. This article describes a new device that can quickly and efficiently take several measurements on feet of various sizes and shapes. The use of this device was verified by measuring the deformities of real clubfeet. A silicone rubber clubfoot model was also used in this study to clearly illustrate the effectiveness with which the proposed device can measure the various deformities of clubfoot. It is envisaged that the use of this device will significantly reduce the time and effort orthopedists require to measure clubfoot deformities and develop and assess treatment plans. PMID- 25833996 TI - Mechanics of pericardial effusion: a simulation study. AB - Pericardial effusion is a pathological accumulation of fluid within pericardial cavity, which may compress heart chambers with hemodynamic impairment. We sought to determine the mechanics underlying the physiology of the hemodynamic impairment due to pericardial effusion using patient-specific computational modeling. Computational models of left ventricle and right ventricle were based on magnetic resonance images obtained from patients with pericardial effusion and controls. Myocardial material parameters were adjusted, so that volumes of ventricular chambers and pericardial effusion agreed with magnetic resonance imaging data. End-diastolic and end-systolic pressure-volume relationships as well as stroke volume were determined to evaluate impaired cardiac function of biventricular model. Distributions of myocardial fiber stresses and their regional variation along left ventricular wall were compared between patient groups. Both end-diastolic and end-systolic pressure-volume relationships shifted to the left for patients with pericardial effusion, with right ventricle diastolic filling particularly restricted. Left ventricle function as estimated by Starling curve was reduced by pericardial effusion. End-systolic fiber stress of left ventricle was significantly reduced as compared to that found for healthy patients. Myocardial stress was found increased at interventricular septum when compared to that exerted at lateral wall of left ventricle. Right ventricular myocardial stress was reduced as a consequence of the pressure equalization between right ventricle and pericardial effusion. Diastolic right ventricle collapse in patients with pericardial effusion is related to higher myocardial fiber stress on interventricular septum and to an extensible pericardium reducing motion of ventricular chambers, with right ventricle particularly restrained. These findings likely portend progression of pericardial effusion to cardiac tamponade. PMID- 25833998 TI - Comparative study for surface topography of bone drilling using conventional drilling and loose abrasive machining. AB - Drilling through the bone is a complicated process in orthopaedic surgery. It involves human as a part of the work so it needs better perfection and quality which leads to the sustainability. Different studies were carried out on this curious topic and some interesting results were obtained, which help the orthopaedic surgeon on the operation table. Major problems faced during bone drilling were crack initiation, thermal necrosis and burr formation. The surface topography of the bone is an indirect indication for the sustainability of bone joint. In this study, a comparison is made between conventional and a loose abrasive unconventional drilling technique for the surface characterization of the bone. The attempt has been made to show the feasibility of bone drilling with non-conventional technique and its aftereffect on the bone structure. The burr formation during conventional bone drilling was found to be more which leads to problems such as crack initiation and thermal necrosis. Scanning electrode microscope and surface roughness tester were used to characterize the surface of the fine drilled bone specimen and the results testified quite better surface finish and least crack formation while drilling with loose abrasive unconventional technique. PMID- 25833997 TI - A low-cost, high-field-strength magnetic resonance imaging-compatible actuator. AB - To perform minimally invasive surgical interventions with the aid of robotic systems within a magnetic resonance imaging scanner offers significant advantages compared to conventional surgery. However, despite the numerous exciting potential applications of this technology, the introduction of magnetic resonance imaging-compatible robotics has been hampered by safety, reliability and cost concerns: the robots should not be attracted by the strong magnetic field of the scanner and should operate reliably in the field without causing distortion to the scan data. Development of non-conventional sensors and/or actuators is thus required to meet these strict operational and safety requirements. These demands commonly result in expensive actuators, which mean that cost effectiveness remains a major challenge for such robotic systems. This work presents a low cost, high-field-strength magnetic resonance imaging-compatible actuator: a pneumatic stepper motor which is controllable in open loop or closed loop, along with a rotary encoder, both fully manufactured in plastic, which are shown to perform reliably via a set of in vitro trials while generating negligible artifacts when imaged within a standard clinical scanner. PMID- 25833999 TI - A novel computational model for the hemodynamics of bileaflet mechanical valves in the opening phase. AB - A powerful alternative means to study the hemodynamics of bileaflet mechanical heart valves is the computational fluid dynamics method. It is well recognized that computational fluid dynamics allows reliable physiological blood flow simulation and measurements of flow parameters. To date, in almost all of the modeling studies on the hemodynamics of bileaflet mechanical heart valves, a velocity (mass flow)-based boundary condition and an axisymmetric geometry for the aortic root have been assigned, which, to some extent, are erroneous. Also, there have been contradictory reports of the profile of velocity in downstream of leaflets, that is, in some studies, it is suggested that the maximum blood velocity occurs in the lateral orifice, and in some other studies, it is postulated that the maximum velocities in the main and lateral orifices are identical. The reported values for the peak velocities range from 1 to 3 m/s, which highly depend on the model assumptions. The objective of this study is to demonstrate the importance of the exact anatomical model of the aortic root and the realistic boundary conditions in the hemodynamics of the bileaflet mechanical heart valves. The model considered in this study is based on the St Jude Medical valve in a novel modeling platform. Through a more realistic geometrical model for the aortic root and the St Jude Medical valve, we have developed a new set of boundary conditions in order to be used for the assessment of the hemodynamics of aortic bileaflet mechanical heart valves. The results of this study are significant for the design improvement of conventional bileaflet mechanical heart valves and for the design of the next generation of prosthetic valves. PMID- 25834000 TI - Assessment of non-contacting optical methods to measure wear and surface roughness in ceramic total disc replacements. AB - This study presents a method for measuring the low volumetric wear expected in ceramic total disc replacements, which can be used to replace intervertebral discs in the spine, using non-contacting optical methods. Alumina-on-alumina ball on-disc tests were conducted with test conditions approximating those of cervical (neck region of the spine) total disc replacement wear tests. The samples were then scanned using a three-dimensional non-contacting optical profilometer and the data used to measure surface roughness and develop a method for measuring the wear volume. The results showed that the magnification of the optical lens affected the accuracy of both the surface roughness and wear volume measurements. The method was able to successfully measure wear volumes of 0.0001 mm(3), which corresponds to a mass of 0.0001 mg, which would have been undetectable using the gravimetric method. A further advantage of this method is that with one scan the user can measure changes in surface topography, volumetric wear and the location of the wear on the implant surface. This method could also be applied to more severe wear, other types of orthopaedic implants and different materials. PMID- 25834001 TI - Shape memory alloy-based biopsy device for active locomotive intestinal capsule endoscope. AB - Recently, capsule endoscopes have been used for diagnosis in digestive organs. However, because a capsule endoscope does not have a locomotive function, its use has been limited to small tubular digestive organs, such as small intestine and esophagus. To address this problem, researchers have begun studying an active locomotive intestine capsule endoscope as a medical instrument for the whole gastrointestinal tract. We have developed a capsule endoscope with a small permanent magnet that is actuated by an electromagnetic actuation system, allowing active and flexible movement in the patient's gut environment. In addition, researchers have noted the need for a biopsy function in capsule endoscope for the definitive diagnosis of digestive diseases. Therefore, this paper proposes a novel robotic biopsy device for active locomotive intestine capsule endoscope. The proposed biopsy device has a sharp blade connected with a shape memory alloy actuator. The biopsy device measuring 12 mm in diameter and 3 mm in length was integrated into our capsule endoscope prototype, where the device's sharp blade was activated and exposed by the shape memory alloy actuator. Then the electromagnetic actuation system generated a specific motion of the capsule endoscope to extract the tissue sample from the intestines. The final biopsy sample tissue had a volume of about 6 mm(3), which is a sufficient amount for a histological analysis. Consequently, we proposed the working principle of the biopsy device and conducted an in-vitro biopsy test to verify the feasibility of the biopsy device integrated into the capsule endoscope prototype using the electro-magnetic actuation system. PMID- 25834002 TI - Wear of the Charite(r) lumbar intervertebral disc replacement investigated using an electro-mechanical spine simulator. AB - The Charite((r)) lumbar intervertebral disc replacement was subjected to wear testing in an electro-mechanical spine simulator. Sinusoidally varying compression (0.6-2 kN, frequency 2 Hz), rotation (+/-2 degrees , frequency 1 Hz), flexion-extension (6 degrees to -3 degrees , frequency 1 Hz) and lateral bending (+/-2 degrees , frequency 1 Hz) were applied out of phase to specimens immersed in diluted calf serum at 37 degrees C. The mass of the ultra-high-molecular weight polyethylene component of the device was measured at intervals of 0.5, 1, 2, 3, 4 and 5 million cycles; its volume was also measured by micro-computed tomography. Total mass and volume losses were 60.3 +/- 4.6 mg (mean +/- standard deviation) and 64.6 +/- 6.0 mm(3). Corresponding wear rates were 12.0 +/- 1.4 mg per million cycles and 12.8 +/- 1.2 mm(3) per million cycles; the rate of loss of volume corresponds to a mass loss of 11.9 +/- 1.1 mg per million cycles, that is, the two sets of measurements of wear agree closely. Wear rates also agree closely with measurements made in another laboratory using the same protocol but using a conventional mechanical spine simulator. PMID- 25834004 TI - Revisiting a familiar but lethal cardiovascular risk factor: sedentary lifestyle. PMID- 25834005 TI - Biventricular pacemakers in patients with heart failure. AB - Patients with heart failure may benefit from implantation of a biventricular pacemaker. This article discusses the indications for biventricular pacemaker implantation and the assessment of patients with biventricular pacemakers. Biventricular pacemakers require more assessments than do traditional single- or dual-chamber pacemakers. PMID- 25834006 TI - Standards for resuscitation after cardiac surgery. AB - Of the 250 000 patients who undergo major cardiac operations in the United States annually, 0.7% to 2.9% will experience a postoperative cardiac arrest. Although Advanced Cardiac Life Support (ACLS) is the standard approach to management of cardiac arrest in the United States, it has significant limitations in these patients. The European Resuscitation Council (ERC) has endorsed a new guideline specific to resuscitation after cardiac surgery that advises important, evidence based deviations from ACLS and is under consideration in the United States. The ACLS and ERC recommendations for resuscitation of these patients are contrasted on the basis of the essential components of care. Key to this approach is the rapid elimination of reversible causes of arrest, followed by either defibrillation or pacing (as appropriate) before external cardiac compressions that can damage the sternotomy, cautious use of epinephrine owing to potential rebound hypertension, and prompt resternotomy (within 5 minutes) to promote optimal cerebral perfusion with internal massage, if prior interventions are unsuccessful. These techniques are relatively simple, reproducible, and easily mastered in Cardiac Surgical Unit-Advanced Life Support courses. Resuscitation of patients after heart surgery presents a unique opportunity to achieve high survival rates with key modifications to ACLS that warrant adoption in the United States. PMID- 25834007 TI - Continuing to challenge practice to be evidence based. AB - Practice habits continue in clinical practice despite the availability of research and other forms of evidence that should be used to guide critical care practice interventions. This article is based on a presentation at the 2014 National Teaching Institute of the American Association of Critical-Care Nurses. The article is part of a series of articles that challenge critical care nurses to examine the evidence guiding nursing practice interventions. Four common practice interventions are reviewed: (1) weight-based medication administration, (2) chest tube patency maintenance, (3) daily interruption of sedation, and (4) use of chest physiotherapy in children. For weight-based administration of medication, the patient's actual weight should be measured, rather than using an estimate. The therapeutic effectiveness and dosages of medications used in obese patients must be critically evaluated. Maintaining patency of chest tubes does not require stripping and milking, which probably do more harm than good. Daily interruption of sedation and judicious use of sedatives are appropriate in most patients receiving mechanical ventilation. Traditional chest physiotherapy does not help children with pneumonia, bronchiolitis, or asthma and does not prevent atelectasis after extubation. Critical care nurses are challenged to evaluate their individual practice and to adopt current evidence-based practice interventions into their daily practice. PMID- 25834008 TI - Fecal microbiota transplant to treat recurrent Clostridium difficile infections. AB - The prevalence of recurrent or refractory Clostridium difficile infection has been steadily increasing since 2000. Consequently, alternative treatments to the standard antibiotic therapies are now being considered. One alternative treatment is fecal microbiota transplant. Although fecal microbiota transplant is relatively new--and not appealing to most people--it has been around for many years and has great promise as an inexpensive, safe, and efficient treatment of refractory and recurrent C difficile infection. With a better understanding of the intricacies of the colonic microbiome and its role in colonic physiology and pathophysiology, critical care nurses will recognize that fecal microbiota transplant has the potential to become the standard of care for treatment of recurrent or refractory C difficile infection. The American College of Gastroenterology and the Infectious Diseases Society of America provide the latest treatment guidelines for care of patients with these clostridial infections. PMID- 25834009 TI - Nurse-physician collaboration and hospital-acquired infections in critical care. AB - BACKGROUND: Nurse-physician collaboration may be related to outcomes in health care-associated infections. OBJECTIVE To examine the relationship between nurse physician collaboration and health care-associated infections in critically ill adults. METHODS: A secondary analysis was done of 5 years of nurses' perception data from 671 surveys from 4 intensive care units. Ventilator-associated pneumonia and central catheter-associated bloodstream infections were examined. Multilevel modeling was used to examine relationships between nurse-physician collaboration and the 2 infections. RESULTS: Nurse-physician collaboration was significantly related to both infections. For every 0.5 unit increase in collaboration, the rate of the bloodstream infections decreased by 2.98 (P= .005) and that of pneumonia by 1.13 (P= .005). Intensive care units with a higher proportion of certified nurses were associated with a 0.43 lower incidence of bloodstream infections (P= .02) and a 0.17 lower rate of the pneumonia (P= .01). With nursing hours per patient day as a covariate, units with more nursing hours per patient day were associated with a 0.42 decrease in the rate of bloodstream infections (P= .05). CONCLUSION: Nurse-physician collaboration was significantly related to health care-associated infections. PMID- 25834010 TI - R-E-L-A-X. PMID- 25834011 TI - Discontinuing the indwelling catheter for a critically ill patient with spinal cord injury. PMID- 25834012 TI - Permissive hypoxemia versus normoxemia for critically ill patients receiving mechanical ventilation. PMID- 25834013 TI - Bedside nurses leading the way for falls prevention: an evidence-based approach. AB - Incidence and characteristics of patient falls and fall prevention programs have been a topic of interest in the literature; however, few articles on fall reduction strategies written by staff nurses have been published. Falls in hospitalized patients are serious threats to patient safety. According to Morse, sequelae of falls are the second leading cause of death in the United States. Costs resulting from falls alone have been reported at between 0.85% and 1.5% of the total health care expenses within the United States, Australia, the European Union, and the United Kingdom. A fall is the most reported safety incident in inpatients and occurs in all adult clinical areas. Accidental falls are among the most common incidents reported in hospitals and occur in approximately 2% of all hospital stays. Growing evidence indicates that falls occurring in the hospital can be reduced with planning and intervention techniques PMID- 25834015 TI - I am a critical care nurse. PMID- 25834016 TI - Training forward surgical teams for deployment: the US Army Trauma Training Center. AB - Since the late 1980s, the US Army has been deploying forward surgical teams to the most intense areas of conflict to care for personnel injured in combat. The forward surgical team is a 20-person medical team that is highly mobile, extremely agile, and has relatively little need of outside support to perform its surgical mission. In order to perform this mission, however, team training and trauma training are required. The large majority of these teams do not routinely train together to provide patient care, and that training currently takes place at the US Army Trauma Training Center (ATTC). The training staff of the ATTC is a specially selected 10-person team made up of active duty personnel from the Army Medical Department assigned to the University of Miami/Jackson Memorial Hospital Ryder Trauma Center in Miami, Florida. The ATTC team of instructors trains as many as 11 forward surgical teams in 2-week rotations per year so that the teams are ready to perform their mission in a deployed setting. Since the first forward surgical team was trained at the ATTC in January 2002, more than 112 forward surgical teams and other similar-sized Department of Defense forward resuscitative and surgical units have rotated through trauma training at the Ryder Trauma Center in preparation for deployment overseas. PMID- 25834018 TI - Clonal analysis reveals granule cell behaviors and compartmentalization that determine the folded morphology of the cerebellum. AB - The mammalian cerebellum consists of folds of different sizes and shapes that house distinct neural circuits. A crucial factor underlying foliation is the generation of granule cells (gcs), the most numerous neuron type in the brain. We used clonal analysis to uncover global as well as folium size-specific cellular behaviors that underlie cerebellar morphogenesis. Unlike most neural precursors, gc precursors divide symmetrically, accounting for their massive expansion. We found that oriented cell divisions underlie an overall anteroposteriorly polarized growth of the cerebellum and gc clone geometry. Clone geometry is further refined by mediolateral oriented migration and passive dispersion of differentiating gcs. Most strikingly, the base of each fissure acts as a boundary for gc precursor dispersion, which we propose allows each folium to be regulated as a developmental unit. Indeed, the geometry and size of clones in long and short folia are distinct. Moreover, in engrailed 1/2 mutants with shorter folia, clone cell number and geometry are most similar to clones in short folia of wild type mice. Thus, the cerebellum has a modular mode of development that allows the plane of cell division and number of divisions to be differentially regulated to ensure that the appropriate number of cells are partitioned into each folium. PMID- 25834017 TI - Protective Efficacy of the Conserved NP, PB1, and M1 Proteins as Immunogens in DNA- and Vaccinia Virus-Based Universal Influenza A Virus Vaccines in Mice. AB - The conventional hemagglutinin (HA)- and neuraminidase (NA)-based influenza vaccines need to be updated most years and are ineffective if the glycoprotein HA of the vaccine strains is a mismatch with that of the epidemic strain. Universal vaccines targeting conserved viral components might provide cross-protection and thus complement and improve conventional vaccines. In this study, we generated DNA plasmids and recombinant vaccinia viruses expressing the conserved proteins nucleoprotein (NP), polymerase basic 1 (PB1), and matrix 1 (M1) from influenza virus strain A/Beijing/30/95 (H3N2). BALB/c mice were immunized intramuscularly with a single vaccine based on NP, PB1, or M1 alone or a combination vaccine based on all three antigens and were then challenged with lethal doses of the heterologous influenza virus strain A/PR/8/34 (H1N1). Vaccines based on NP, PB1, and M1 provided complete or partial protection against challenge with 1.7 50% lethal dose (LD50) of PR8 in mice. Of the three antigens, NP-based vaccines induced protection against 5 LD50 and 10 LD50 and thus exhibited the greatest protective effect. Universal influenza vaccines based on the combination of NP, PB1, and M1 induced a strong immune response and thus might be an alternative approach to addressing future influenza virus pandemics. PMID- 25834019 TI - Temporal ordering and registration of images in studies of developmental dynamics. AB - Progress of development is commonly reconstructed from imaging snapshots of chemical or mechanical processes in fixed tissues. As a first step in these reconstructions, snapshots must be spatially registered and ordered in time. Currently, image registration and ordering are often done manually, requiring a significant amount of expertise with a specific system. However, as the sizes of imaging data sets grow, these tasks become increasingly difficult, especially when the images are noisy and the developmental changes being examined are subtle. To address these challenges, we present an automated approach to simultaneously register and temporally order imaging data sets. The approach is based on vector diffusion maps, a manifold learning technique that does not require a priori knowledge of image features or a parametric model of the developmental dynamics. We illustrate this approach by registering and ordering data from imaging studies of pattern formation and morphogenesis in three model systems. We also provide software to aid in the application of our methodology to other experimental data sets. PMID- 25834020 TI - Regulation by a TGFbeta-ROCK-actomyosin axis secures a non-linear lumen expansion that is essential for tubulogenesis. AB - Regulation of lumen growth is crucial to ensure the correct morphology, dimensions and function of a tubular structure. How this is controlled is still poorly understood. During Ciona intestinalis notochord tubulogenesis, single extracellular lumen pockets grow between pairs of cells and eventually fuse into a continuous tube. Here, we show that lumen growth exhibits a lag phase, during which the luminal membranes continue to grow but the expansion of the apical/lateral junction pauses for ~30 min. Inhibition of non-muscle myosin II activity abolishes this lag phase and accelerates expansion of the junction, resulting in the formation of narrower lumen pockets partially fusing into a tube of reduced size. Disruption of actin dynamics, conversely, causes a reversal of apical/lateral junction expansion, leading to a dramatic conversion of extracellular lumen pockets to intracellular vacuoles and a tubulogenesis arrest. The onset of the lag phase is correlated with a de novo accumulation of actin that forms a contractile ring at the apical/lateral junctions. This actin ring actively restricts the opening of the lumen in the transverse plane, allowing sufficient time for lumen growth via an osmotic process along the longitudinal dimension. The dynamics of lumen formation is controlled by the TGFbeta pathway and ROCK activity. Our findings reveal a TGFbeta-ROCK-actomyosin contractility axis that coordinates lumen growth, which is powered by the dynamics of luminal osmolarity. The regulatory system may function like a sensor/checkpoint that responds to the change of luminal pressure and fine-tunes actomyosin contractility to effect proper tubulogenesis. PMID- 25834021 TI - Sox7 controls arterial specification in conjunction with hey2 and efnb2 function. AB - SoxF family members have been linked to arterio-venous specification events and human pathological conditions, but in contrast to Sox17 and Sox18, a detailed in vivo analysis of a Sox7 mutant model is still lacking. In this study we generated zebrafish sox7 mutants to understand the role of Sox7 during vascular development. By in vivo imaging of transgenic zebrafish lines we show that sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV). In situ hybridization and live observations in flt4:mCitrine transgenic embryos revealed increased expression levels of flt4 in arterial endothelial cells at the exact location of the aberrant vascular connections in sox7 mutants. An identical circulatory short loop could also be observed in newly generated mutants for hey2 and efnb2. By genetically modulating levels of sox7, hey2 and efnb2 we demonstrate a genetic interaction of sox7 with hey2 and efnb2. The specific spatially confined effect of loss of Sox7 function can be rescued by overexpressing the Notch intracellular domain (NICD) in arterial cells of sox7 mutants, placing Sox7 upstream of Notch in this aspect of arterial development. Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block. PMID- 25834022 TI - The loss of Hh responsiveness by a non-ciliary Gli2 variant. AB - Hedgehog signaling is crucial for vertebrate development and physiology. Gli2, the primary effector of Hedgehog signaling, localizes to the tip of the primary cilium, but the importance of its ciliary localization remains unclear. We address the roles of Gli2 ciliary localization by replacing endogenous Gli2 with Gli2(DeltaCLR), a Gli2 variant not localizing to the cilium. The resulting Gli2(DeltaCLRKI) and Gli2(DeltaCLRKI);Gli3 double mutants resemble Gli2-null and Gli2;Gli3 double mutants, respectively, suggesting the lack of Gli2(DeltaCLR) activation in development. Significantly, Gli2(DeltaCLR) cannot be activated either by pharmacochemical activation of Smo in vitro or by loss of Ptch1 in vivo. Finally, Gli2(DeltaCLR) exhibits strong transcriptional activator activity in the absence of Sufu, suggesting that the lack of its activation in vivo results from a specific failure in relieving the inhibitory function of Sufu. Our results provide strong evidence that the ciliary localization of Gli2 is crucial for cilium-dependent activation of Hedgehog signaling. PMID- 25834023 TI - Avastin and Lucentis: a guide through the legal maze. PMID- 25834024 TI - Why have UK doctors been deterred from prescribing Avastin? PMID- 25834025 TI - Attacks on publicly funded trials: what happens when industry does not want to know the answer. PMID- 25834026 TI - A licence to cure. PMID- 25834027 TI - Splitting blood and blood product packaging reduces donor exposure for patients undergoing cardiopulmonary bypass. AB - BACKGROUND: Cardiopulmonary bypass for congenital heart surgery requires packed red cells (PRBC) and fresh frozen plasma (FFP) to be available, both for priming of the circuit as well as to replace blood loss. This study examines the hypothesis that splitting one unit of packed red blood cells and one unit of fresh frozen plasma into two half units reduces blood product exposure and wastage in the Operating Room. METHODS: Beginning August 2013, the blood bank at Children's National Medical Center began splitting one unit of packed red blood cells (PRBC) and one unit of fresh frozen plasma (FFP) for patients undergoing cardiopulmonary bypass (CPB). The 283 patients who utilized CPB during calendar year 2013 were divided into 2 study groups: before the split and after the split. The principal endpoints were blood product usage and donor exposure intra operatively and within 72 hours post-operatively. RESULTS: There was a significant decrease in median total donor exposures for FFP and cryoprecipitate from 5 to 4 per case (p = 0.007, Mann-Whitney U-test). However, there was no difference in the volume of blood and blood products used; in fact, there was a significant increase in the amount of FFP that was wasted with the switch to splitting the unit of FFP. CONCLUSIONS: We found that modification of blood product packaging can decrease donor exposure. Future investigation is needed as to how to modify packaging to minimize wastage. PMID- 25834029 TI - Color is processed less efficiently than orientation in change detection but more efficiently in visual search. AB - Basic visual features (e.g., color, orientation) are assumed to be processed in the same general way across different visual tasks. Here, a significant deviation from this assumption was predicted on the basis of the analysis of stimulus spatial structure, as characterized by the Boolean-map notion. If a task requires memorizing the orientations of a set of bars, then the map consisting of those bars can be readily used to hold the overall structure in memory and will thus be especially useful. If the task requires visual search for a target, then the map, which contains only an overall structure, will be of little use. Supporting these predictions, the present study demonstrated that in comparison to stimulus colors, bar orientations were processed more efficiently in change-detection tasks but less efficiently in visual search tasks (Cohen's d = 4.24). In addition to offering support for the role of the Boolean map in conscious access, the present work also throws doubts on the generality of processing visual features. PMID- 25834028 TI - Probing the Dynamic Updating of Value in Schizophrenia Using a Sensory-Specific Satiety Paradigm. AB - It has been proposed that both positive and negative symptoms in schizophrenia (SZ) may derive, at least in part, from a disrupted ability to accurately and flexibly represent the value of stimuli and actions. To assess relationships between dimensions of psychopathology in SZ, and the tendency to devalue food stimuli, on which subjects were fed to satiety, we administered a sensory specific satiety (SSS) paradigm to 42 SZ patients and 44 controls. In each of 2 sessions, subjects received 16 0.7-ml squirts of each of 2 rewarding foods and 32 squirts of a control solution, using syringes. In between the 2 sessions, each subject was instructed to drink one of the foods until he/she felt "full, but not uncomfortable." At 10 regular intervals, interspersed throughout the 2 sessions, subjects rated each liquid for pleasantness, using a Likert-type scale. Mann Whitney U-tests revealed group differences in SSS effects. Within-group tests revealed that, while controls showed an effect of satiety that was sensory specific, patients showed an effect of satiety that was not, devaluing the sated and unsated foods similarly. In SZ patients, we observed correlations between the magnitude of SSS effects and measures of both positive and negative symptoms. We argue that the ability to flexibly and rapidly update representations of the value of stimuli and actions figures critically in the ability of patients with psychotic illness to process salient events and adaptively engage in goal directed behavior. PMID- 25834030 TI - Targeted screen for human UDP-glucuronosyltransferases inhibitors and the evaluation of potential drug-drug interactions with zafirlukast. AB - Inhibition of drug metabolizing enzymes is a major mechanism in drug-drug interactions (DDIs). A number of cases of DDIs via inhibition of UDP glucuronosyltranseferases (UGTs) have been reported, although the changes in pharmacokinetics are relatively small in comparison with drugs that are metabolized by cytochrome P450s. Most of the past studies have investigated hepatic UGTs, although recent studies have revealed a significant contribution of UGTs in the small intestine to drug clearance. To evaluate potential DDIs caused by inhibition of intestinal UGTs, we assessed inhibitory effects of 578 compounds, including drugs, xenobiotics, and endobiotics, on human UGT1A8 and UGT1A10, which are major contributors to intestinal glucuronidation. We identified 29 inhibitors by monitoring raloxifene glucuronidation with recombinant UGTs. All of the inhibitors potently inhibited UGT1A1 activity, as well. We found that zafirlukast is a potent general inhibitor of UGT1As and a moderate inhibitor of UGT2Bs because it monitors 4-methylumbelliferone glucuronidation by recombinant UGTs. However, zafirlukast did not potently inhibit diclofenac glucuronidation, suggesting that the inhibitory effects might be substrate specific. Inhibitory effects of zafirlukast on some UGT substrates were further investigated in human liver and human small intestine microsomes in order to evaluate potential DDIs. The R values (the ratios of intrinsic clearance with and without an inhibitor) revealed that zafirlukast has potential to cause clinical DDIs in the small intestine. Although we could not identify specific UGT1A8 and UGT1A10 inhibitors, zafirlukast was identified as a general inhibitor for UGTs in vitro. The present study suggests that the inhibition of UGT in the small intestine would be an underlying mechanism for DDIs. PMID- 25834031 TI - Biodistribution of etanercept to tissues and sites of inflammation in arthritic rats. AB - Many monoclonal antibodies (mAbs) and other protein drugs have targets usually residing within tissues, making tissue concentrations of mAbs relevant to their pharmacologic effects. Therefore, knowledge of tissue distribution kinetics is important to better understand their pharmacokinetics and pharmacodynamics. The tissue distribution of mAbs is affected by many physiologic factors that may be altered in disease status. In the present work, we studied the tissue distribution kinetics of the fusion protein etanercept in inflamed joint tissues and examined the impact of inflammation on the tissue distribution of etanercept. Etanercept concentration profiles in plasma, blister fluid, and different tissues were obtained from healthy and collagen-induced arthritic (CIA) rats by use of a fluorescence quantification method via IRDye800CW labeling. Stepwise minimal and full physiologically based pharmacokinetic (PBPK) approaches were applied to characterize the distribution kinetics of etanercept in tissues in healthy and diseased animals. Etanercept exhibited modest tissue access (tissue/plasma area under the concentration curve [AUC] ratios 0.03-0.15 and estimated tissue reflection coefficients [sigma] of 0.6-1.0), but with good penetration into arthritic paws (tissue/plasma AUC ratio 0.23 and sigma 0.36). Etanercept exposure in the inflamed paws of CIA rats was approximately 3-fold higher than in normal paws taken from either CIA or healthy rats (tissue/plasma AUC ratios 0.23 versus 0.07 and sigma 0.36 versus 0.71). The tissue distribution kinetics of etanercept in arthritic paws were well characterized with PBPK modeling approaches. Etanercept shows good penetration to arthritic paws in CIA rats. Our study indicates that inflammation produced increased tissue distribution of etanercept in CIA rats. PMID- 25834032 TI - Adhesive intestinal obstruction caused by extragastrointestinal anisakiasis. PMID- 25834033 TI - Spinal epidural hematoma and gnathostomiasis. PMID- 25834034 TI - Erratum. PMID- 25834035 TI - Dorsolateral-ventromedial prefrontal cortex interactions during value-guided choice: a function of context or difficulty? PMID- 25834036 TI - Advances in the diagnosis and treatment of vestibular disorders: psychophysics and prosthetics. AB - Although vestibular disorders are common and often disabling, they remain difficult to diagnose and treat. For these reasons, considerable interest has been focused on developing new ways to identify peripheral and central vestibular abnormalities and on new therapeutic options that could benefit the numerous patients who remain symptomatic despite optimal therapy. In this review, I focus on the potential utility of psychophysical vestibular testing and vestibular prosthetics. The former offers a new diagnostic approach that may prove to be superior to the current tests in some circumstances; the latter may be a way to provide the brain with information about head motion that restores some elements of the information normally provided by the vestibular labyrinth. PMID- 25834038 TI - The influence of movement preparation time on the expression of visuomotor learning and savings. AB - Following a change in the environment or motor apparatus, human subjects are able to rapidly compensate their movements to recover accurate performance. This ability to adapt is thought to be achieved through multiple, qualitatively distinct learning processes acting in parallel. It is unclear, however, what the relative contributions of these multiple processes are during learning. In particular, long-term memories in such paradigms have been extensively studied through the phenomenon of savings-faster adaptation to a given perturbation the second time it is experienced-but it is unclear which components of learning contribute to this effect. Here we show that distinct components of learning in an adaptation task can be dissociated based on the amount of preparation time they require. During adaptation, we occasionally forced subjects to generate movements at very low preparation times. Early in learning, subjects expressed only a limited amount of their prior learning in these trials, though performance improved gradually with further practice. Following washout, subjects exhibited a strong and persistent aftereffect in trials in which preparation time was limited. When subjects were exposed to the same perturbation twice in successive days, they adapted faster the second time. This savings effect was, however, not seen in movements generated at low preparation times. These results demonstrate that preparation time plays a critical role in the expression of some components of learning but not others. Savings is restricted to those components that require prolonged preparation to be expressed and might therefore reflect a declarative rather than procedural form of memory. PMID- 25834037 TI - Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory. AB - Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion. PMID- 25834039 TI - The knockdown of alphakap alters the postsynaptic apparatus of neuromuscular junctions in living mice. AB - A muscle-specific nonkinase anchoring protein (alphakap), encoded within the calcium/calmodulin kinase II (camk2) alpha gene, was recently found to control the stability of acetylcholine receptor (AChR) clusters on the surface of cultured myotubes. However, it remains unknown whether this protein has any effect on receptor stability and the maintenance of the structural integrity of neuromuscular synapses in vivo. By knocking down the endogenous expression of alphakap in mouse sternomastoid muscles with shRNA, we found that the postsynaptic receptor density was dramatically reduced, the turnover rate of receptors at synaptic sites was significantly increased, and the insertion rates of both newly synthesized and recycled receptors into the postsynaptic membrane were depressed. Moreover, we found that alphakap shRNA knockdown impaired synaptic structure as postsynaptic AChR clusters and their associated postsynaptic scaffold proteins within the neuromuscular junction were completely eliminated. These results provide new mechanistic insight into the role of alphakap in regulating the stability of the postsynaptic apparatus of neuromuscular synapses. PMID- 25834040 TI - Delayed inhibition of VEGF signaling after stroke attenuates blood-brain barrier breakdown and improves functional recovery in a comorbidity-dependent manner. AB - Diabetes is a common comorbidity in stroke patients and a strong predictor of poor functional outcome. To provide a more mechanistic understanding of this clinically relevant problem, we focused on how diabetes affects blood-brain barrier (BBB) function after stroke. Because the BBB can be compromised for days after stroke and thus further exacerbate ischemic injury, manipulating its function presents a unique opportunity for enhancing stroke recovery long after the window for thrombolytics has passed. Using a mouse model of Type 1 diabetes, we discovered that ischemic stroke leads to an abnormal and persistent increase in vascular endothelial growth factor receptor 2 (VEGF-R2) expression in peri infarct vascular networks. Correlating with this, BBB permeability was markedly increased in diabetic mice, which could not be prevented with insulin treatment after stroke. Imaging of capillary ultrastructure revealed that BBB permeability was associated with an increase in endothelial transcytosis rather than a loss of tight junctions. Pharmacological inhibition (initiated 2.5 d after stroke) or vascular-specific knockdown of VEGF-R2 after stroke attenuated BBB permeability, loss of synaptic structure in peri-infarct regions, and improved recovery of forepaw function. However, the beneficial effects of VEGF-R2 inhibition on stroke recovery were restricted to diabetic mice and appeared to worsen BBB permeability in nondiabetic mice. Collectively, these results suggest that aberrant VEGF signaling and BBB dysfunction after stroke plays a crucial role in limiting functional recovery in an experimental model of diabetes. Furthermore, our data highlight the need to develop more personalized stroke treatments for a heterogeneous clinical population. PMID- 25834042 TI - Regulation of patterned dynamics of local exocytosis in growth cones by netrin-1. AB - Axonal guidance and synaptic specification depends on specific signaling mechanisms that occur in growth cones. While several signaling pathways implicated in cone navigation have been identified, membrane dynamics in growth cones remains largely unknown. We took advantage of SynaptopHluorin and high speed optical recordings to monitor the patterns of membrane dynamics in rat hippocampal growth cones. We show that exocytosis occurs both at the peripheral and central domains, including filopodia, and that SynaptopHluorin signals occur as spontaneous patterned peaks. Such transients average approximately two per minute and last ~30 s. We also demonstrate that the chemoattractant Netrin-1 elicits increases in the frequency and slopes of these transients, with peaks averaging up to six per minute in the peripheral domain. Netrin-1-dependent regulation of exocytotic events requires the activation of the Erk1/2 and SFK pathways. Furthermore, we show that domains with high SynaptopHluorin signals correlate with high local calcium concentrations and that local, spontaneous calcium increases are associated with higher SynaptopHluorin signals. These findings demonstrate highly stereotyped, spontaneous transients of local exocytosis in growth cones and that these transients are positively regulated by chemoattractant molecules such as Netrin-1. PMID- 25834041 TI - Osmoregulation requires brain expression of the renal Na-K-2Cl cotransporter NKCC2. AB - The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABA-mediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats. PMID- 25834043 TI - A proteomic analysis reveals the interaction of GluK1 ionotropic kainate receptor subunits with Go proteins. AB - Kainate receptors (KARs) are found ubiquitously in the CNS and are present presynaptically and postsynaptically regulating synaptic transmission and excitability. Functional studies have proven that KARs act as ion channels as well as potentially activating G-proteins, thus indicating the existance of a dual signaling system for KARs. Nevertheless, it is not clear how these ion channels activate G-proteins and which of the KAR subunits is involved. Here we performed a proteomic analysis to define proteins that interact with the C terminal domain of GluK1 and we identified a variety of proteins with many different functions, including a Go alpha subunit. These interactions were verified through distinct in vitro and in vivo assays, and the activation of the Go protein by GluK1 was validated in bioluminescence resonance energy transfer experiments, while the specificity of this association was confirmed in GluK1 deficient mice. These data reveal components of the KAR interactome, and they show that GluK1 and Go proteins are natural partners, accounting for the metabotropic effects of KARs. PMID- 25834044 TI - Distributed representation of visual objects by single neurons in the human brain. AB - It remains unclear how single neurons in the human brain represent whole-object visual stimuli. While recordings in both human and nonhuman primates have shown distributed representations of objects (many neurons encoding multiple objects), recordings of single neurons in the human medial temporal lobe, taken as subjects' discriminated objects during multiple presentations, have shown gnostic representations (single neurons encoding one object). Because some studies suggest that repeated viewing may enhance neural selectivity for objects, we had human subjects discriminate objects in a single, more naturalistic viewing session. We found that, across 432 well isolated neurons recorded in the hippocampus and amygdala, the average fraction of objects encoded was 26%. We also found that more neurons encoded several objects versus only one object in the hippocampus (28 vs 18%, p < 0.001) and in the amygdala (30 vs 19%, p < 0.001). Thus, during realistic viewing experiences, typical neurons in the human medial temporal lobe code for a considerable range of objects, across multiple semantic categories. PMID- 25834046 TI - Mechanisms underlying encoding of short-lived versus durable episodic memories. AB - We continuously encounter and process novel events in the surrounding world, but only some episodes will leave detailed memory traces that can be recollected after weeks and months. Here, our aim was to monitor brain activity during encoding of events that eventually transforms into long-term stable memories. Previous functional magnetic resonance imaging (fMRI) studies have shown that the degree of activation of different brain regions during encoding is predictive of later recollection success. However, most of these studies tested participants' memories the same day as encoding occurred, whereas several lines of research suggest that extended post-encoding processing is of crucial importance for long term consolidation. Using fMRI, we tested whether the same encoding mechanisms are predictive of recollection success after hours as after a retention interval of several weeks. Seventy-eight participants were scanned during an associative encoding task and given a source memory test the same day or after ~6 weeks. We found a strong link between regional activity levels during encoding and recollection success over short time intervals. However, results further showed that durable source memories, i.e., events recollected after several weeks, were not simply the events associated with the highest activity levels at encoding. Rather, strong levels of connectivity between the right hippocampus and perceptual areas, as well as with parts of the self-referential default-mode network, seemed instrumental in establishing durable source memories. Thus, we argue that an initial intensity-based encoding is necessary for short-term encoding of events, whereas additional processes involving hippocampal-cortical communication aid transformation into stable long-term memories. PMID- 25834045 TI - Conditional deletion of the glutamate transporter GLT-1 reveals that astrocytic GLT-1 protects against fatal epilepsy while neuronal GLT-1 contributes significantly to glutamate uptake into synaptosomes. AB - GLT-1 (EAAT2; slc1a2) is the major glutamate transporter in the brain, and is predominantly expressed in astrocytes, but at lower levels also in excitatory terminals. We generated a conditional GLT-1 knock-out mouse to uncover cell-type specific functional roles of GLT-1. Inactivation of the GLT-1 gene was achieved in either neurons or astrocytes by expression of synapsin-Cre or inducible human GFAP-CreERT2. Elimination of GLT-1 from astrocytes resulted in loss of ~80% of GLT-1 protein and of glutamate uptake activity that could be solubilized and reconstituted in liposomes. This loss was accompanied by excess mortality, lower body weight, and seizures suggesting that astrocytic GLT-1 is of major importance. However, there was only a small (15%) reduction that did not reach significance of glutamate uptake into crude forebrain synaptosomes. In contrast, when GLT-1 was deleted in neurons, both the GLT-1 protein and glutamate uptake activity that could be solubilized and reconstituted in liposomes were virtually unaffected. These mice showed normal survival, weight gain, and no seizures. However, the synaptosomal glutamate uptake capacity (Vmax) was reduced significantly (40%). In conclusion, astrocytic GLT-1 performs critical functions required for normal weight gain, resistance to epilepsy, and survival. However, the contribution of astrocytic GLT-1 to glutamate uptake into synaptosomes is less than expected, and the contribution of neuronal GLT-1 to synaptosomal glutamate uptake is greater than expected based on their relative protein expression. These results have important implications for the interpretation of the many previous studies assessing glutamate uptake capacity by measuring synaptosomal uptake. PMID- 25834047 TI - Relative unisensory strength and timing predict their multisensory product. AB - Understanding the principles by which the brain combines information from different senses provides us with insight into the computational strategies used to maximize their utility. Prior studies of the superior colliculus (SC) neuron as a model suggest that the relative timing with which sensory cues appear is an important factor in this context. Cross-modal cues that are near-simultaneous are likely to be derived from the same event, and the neural inputs they generate are integrated more strongly than those from cues that are temporally displaced from one another. However, the present results from studies of cat SC neurons show that this "temporal principle" of multisensory integration is more nuanced than previously thought and reveal that the integration of temporally displaced sensory responses is also highly dependent on the relative efficacies with which they drive their common target neuron. Larger multisensory responses were achieved when stronger responses were advanced in time relative to weaker responses. This new temporal principle of integration suggests an inhibitory mechanism that better accounts for the sensitivity of the multisensory product to differences in the timing of cross-modal cues than do earlier mechanistic hypotheses based on response onset alignment or response overlap. PMID- 25834048 TI - Definition of a molecular pathway mediating alpha-synuclein neurotoxicity. AB - alpha-Synuclein physiologically chaperones SNARE-complex assembly at the synapse but pathologically misfolds into neurotoxic aggregates that are characteristic for neurodegenerative disorders, such as Parkinson's disease, and that may spread from one neuron to the next throughout the brain during Parkinson's disease pathogenesis. In normal nerve terminals, alpha-synuclein is present in an equilibrium between a cytosolic form that is natively unfolded and monomeric and a membrane-bound form that is composed of an alpha-helical multimeric species that chaperones SNARE-complex assembly. Although the neurotoxicity of alpha synuclein is well established, the relationship between the native conformations of alpha-synuclein and its pathological aggregation remain incompletely understood; most importantly, it is unclear whether alpha-synuclein aggregation originates from its monomeric cytosolic or oligomeric membrane-bound form. Here, we address this question by introducing into alpha-synuclein point mutations that block membrane binding and by then assessing the effect of blocking membrane binding on alpha-synuclein aggregation and neurotoxicity. We show that membrane binding inhibits alpha-synuclein aggregation; conversely, blocking membrane binding enhances alpha-synuclein aggregation. Stereotactic viral expression of wild-type and mutant alpha-synuclein in the substantia nigra of mice demonstrated that blocking alpha-synuclein membrane binding significantly enhanced its neurotoxicity in vivo. Our data delineate a folding pathway for alpha-synuclein that ranges from a physiological multimeric, alpha-helical, and membrane-bound species that acts as a SNARE-complex chaperone over a monomeric, natively unfolded form to an amyloid-like aggregate that is neurotoxic in vivo. PMID- 25834049 TI - Hoxb8 intersection defines a role for Lmx1b in excitatory dorsal horn neuron development, spinofugal connectivity, and nociception. AB - Spinal cord neurons respond to peripheral noxious stimuli and relay this information to higher brain centers, but the molecules controlling the assembly of such pathways are poorly known. In this study, we use the intersection of Lmx1b and Hoxb8::Cre expression in the spinal cord to genetically define nociceptive circuits. Specifically, we show that Lmx1b, previously shown to be expressed in glutamatergic dorsal horn neurons and critical for dorsal horn development, is expressed in nociceptive dorsal horn neurons and that its deletion results in the specific loss of excitatory dorsal horn neurons by apoptosis, without any effect on inhibitory neuron numbers. To assess the behavioral consequences of Lmx1b deletion in the spinal cord, we used the brain sparing driver Hoxb8::Cre. We show that such a deletion of Lmxb1 leads to a robust reduction in sensitivity to mechanical and thermal noxious stimulation. Furthermore, such conditional mutant mice show a loss of a subpopulation of glutamatergic dorsal horn neurons, abnormal sensory afferent innervations, and reduced spinofugal innervation of the parabrachial nucleus and the periaqueductal gray, important nociceptive structures. Together, our results demonstrate an important role for the intersection of Lmx1b and Hoxb8::cre expression in the development of nociceptive dorsal horn circuits critical for mechanical and thermal pain processing. PMID- 25834050 TI - Activation of corticostriatal circuitry relieves chronic neuropathic pain. AB - Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID- 25834051 TI - Differential regulation of two isoforms of the glial glutamate transporter EAAT2 by DLG1 and CaMKII. AB - The gene for EAAT2, the major astrocytic glutamate transporter, generates two carrier isoforms (EAAT2a and EAAT2b) that vary at their C termini as a consequence of alternative RNA splicing. The EAAT2b cytoplasmic C terminus contains a postsynaptic density-95/Discs large/zona occludens-1 (PDZ) ligand, which is absent in EAAT2a. To understand how the distinct C termini might affect transporter trafficking and surface localization, we generated Madin-Darby canine kidney (MDCK) cells that stably express EGFP-EAAT2a or EGFP-EAAT2b and found robust basolateral membrane expression of the EAAT2b isoform. In contrast, EAAT2a displayed a predominant distribution within intracellular vesicle compartments, constitutively cycling to and from the membrane. Addition of the PDZ ligand to EAAT2a as well as its deletion from EAAT2b confirmed the importance of the motif for cell-surface localization. Using EAAT2 constructs with an extracellular biotin acceptor tag to directly assess surface proteins, we observed significant PDZ ligand-dependent EAAT2b surface expression in cultured astrocytes, consistent with observations in cell lines. Discs large homolog 1 (DLG1; SAP97), a PDZ protein prominent in both astrocytes and MDCK cells, colocalized and coimmunoprecipitated with EAAT2b. shRNA knockdown of DLG1 expression decreased surface EAAT2b in both MDCK cells and cultured astrocytes, suggesting that the DLG scaffolding protein stabilizes EAAT2b at the surface. DLG1 can be phosphorylated by Ca(2+)/calmodulin-dependent protein kinase (CaMKII), resulting in disruption of its PDZ-mediated interaction. In murine astrocytes and acute brain slices, activation of CaMKII decreases EAAT2b surface expression but does not alter the distribution of EAAT2a. These data indicate that the surface expression and function of EAAT2b can be rapidly modulated through the disruption of its interaction with DLG1 by CaMKII activation. PMID- 25834052 TI - Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders. AB - Leucine-rich repeat kinase 2 (LRRK2) is the single most common genetic cause of both familial and sporadic Parkinson's disease (PD), both of which share pathogenetic and neurologic similarities with human immunodeficiency virus 1 (HIV 1)-associated neurocognitive disorders (HAND). Pathologic LRRK2 activity may also contribute to neuroinflammation, because microglia lacking LRRK2 exposed to proinflammatory stimuli have attenuated responses. Because microglial activation is a hallmark of HIV-1 neuropathology, we have investigated the role of LRRK2 activation using in vitro and in vivo models of HAND. We hypothesize that LRRK2 is a key modulator of microglial inflammatory responses, which play a pathogenic role in both HAND and PD, and that these responses may cause or exacerbate neuronal damage in these diseases. The HIV-1 Tat protein is a potent neurotoxin produced during HAND that induces activation of primary microglia in culture and long-lasting neuroinflammation and neurotoxicity when injected into the CNS of mice. We found that LRRK2 inhibition attenuates Tat-induced pS935-LRRK2 expression, proinflammatory cytokine and chemokine expression, and phosphorylated p38 and Jun N-terminal kinase signaling in primary microglia. In our murine model, cortical Tat injection in LRRK2 knock-out (KO) mice results in significantly diminished neuronal damage, as assessed by microtubule-associated protein 2 (MAP2), class III beta-tubulin TUJ1, synapsin-1, VGluT, and cleaved caspase-3 immunostaining. Furthermore, Tat-injected LRRK2 KO animals have decreased infiltration of peripheral neutrophils, and the morphology of microglia from these mice were similar to that of vehicle-injected controls. We conclude that pathologic activation of LRRK2 regulates a significant component of the neuroinflammation associated with HAND. PMID- 25834053 TI - A critical role for purinergic signalling in the mechanisms underlying generation of BOLD fMRI responses. AB - The mechanisms of neurovascular coupling underlying generation of BOLD fMRI signals remain incompletely understood. It has been proposed that release of vasoactive substances by astrocytes couples neuronal activity to changes in cerebrovascular blood flow. However, the role of astrocytes in fMRI responses remains controversial. Astrocytes communicate via release of ATP, and here we tested the hypothesis that purinergic signaling plays a role in the mechanisms underlying fMRI. An established fMRI paradigm was used to trigger BOLD responses in the forepaw region of the somatosensory cortex (SSFP) of an anesthetized rat. Forepaw stimulation induced release of ATP in the SSFP region. To interfere with purinergic signaling by promoting rapid breakdown of the vesicular and/or released ATP, a lentiviral vector was used to express a potent ectonucleotidase, transmembrane prostatic acid phosphatase (TMPAP), in the SSFP region. TMPAP expression had no effect on resting cerebral blood flow, cerebrovascular reactivity, and neuronal responses to sensory stimulation. However, TMPAP catalytic activity markedly reduced the magnitude of BOLD fMRI responses triggered in the SSFP region by forepaw stimulation. Facilitated ATP breakdown could result in accumulation of adenosine. However, blockade of A1 receptors had no effect on BOLD responses and did not reverse the effect of TMPAP. These results suggest that purinergic signaling plays a significant role in generation of BOLD fMRI signals. We hypothesize that astrocytes activated during periods of enhanced neuronal activity release ATP, which propagates astrocytic activation, stimulates release of vasoactive substances and dilation of cerebral vasculature. PMID- 25834055 TI - Contribution of the potassium-chloride cotransporter KCC2 to the strength of inhibition in the neonatal rodent spinal cord in vitro. AB - In healthy mature motoneurons (MNs), KCC2 cotransporters maintain the intracellular chloride concentration at low levels, a prerequisite for postsynaptic inhibition mediated by GABA and glycine. KCC2 expression in lumbar MNs is reduced after spinal cord injury (SCI) resulting in a depolarizing shift of the chloride equilibrium potential. Despite modeling studies indicating that such a downregulation of KCC2 function would reduce the strength of postsynaptic inhibition, physiological evidence is still lacking. The present study aimed at investigating the functional impact of a modification of KCC2 function. We focused on a well characterized disynaptic inhibitory pathway responsible for reciprocal inhibition between antagonistic muscles. We performed in vitro extracellular recordings on spinal cords isolated from rodents at the end of the first postnatal week. Genetic reduction of KCC2 expression, pharmacological blockade of KCC2, as well as SCI-induced downregulation of KCC2 all resulted in a reduction of the strength of reciprocal inhibition. We then tried to restore endogenous inhibition after SCI by means of zinc ions that have been shown to boost KCC2 function in other models. Zinc chloride indeed hyperpolarized the chloride equilibrium potential in MNs and increased reciprocal inhibition after neonatal SCI. This study demonstrates that the level of KCC2 function sets the strength of postsynaptic inhibition and suggests that the downregulation of KCC2 after SCI likely contributes to the high occurrence of flexor-extensor cocontractions in SCI patients. PMID- 25834054 TI - Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive MS. AB - The demyelinating disease multiple sclerosis (MS) has an early inflammatory phase followed by an incurable progressive phase with subdued inflammation and poorly understood neurodegenerative mechanism. In this study, we identified various parallelisms between progressive MS and the dysmyelinating mouse model Shiverer and then genetically deleted a major neuron-specific mitochondrial anchoring protein Syntaphilin (SNPH) from the mouse. Prevailing evidence suggests that deletion of SNPH is harmful in demyelination. Surprisingly, SNPH deletion produces striking benefits in the Shiverer by prolonging survival, reducing cerebellar damage, suppressing oxidative stress, and improving mitochondrial health. In contrast, SNPH deletion does not benefit clinical symptoms in experimental autoimmune encephalomyelitis (EAE), a model for early-phase MS. We propose that deleting mitochondrial anchoring is a novel, specific treatment for progressive MS. PMID- 25834056 TI - Incoherent feed-forward regulatory loops control segregation of C mechanoreceptors, nociceptors, and pruriceptors. AB - Mammalian skin is innervated by diverse, unmyelinated C fibers that are associated with senses of pain, itch, temperature, or touch. A key developmental question is how this neuronal cell diversity is generated during development. We reported previously that the runt domain transcription factor Runx1 is required to coordinate the development of these unmyelinated cutaneous sensory neurons, including VGLUT3(+) low-threshold c-mechanoreceptors (CLTMs), MrgprD(+) polymodal nociceptors, MrgprA3(+) pruriceptors, MrgprB4(+) c-mechanoreceptors, and others. However, how these Runx1-dependent cutaneous sensory neurons are further segregated is poorly illustrated. Here, we find that the Runx1-dependent transcription factor gene Zfp521 is expressed in, and required for establishing molecular features that define, VGLUT3(+) CLTMs. Furthermore, Runx1 and Zfp521 form a classic incoherent feedforward loop (I-FFL) in controlling molecular identities that normally belong to MrgprD(+) neurons, with Runx1 and Zfp51 playing activator and repressor roles, respectively (in genetic terms). A knock out of Zfp521 allows prospective VGLUT3 lineage neurons to acquire MrgprD(+) neuron identities. Furthermore, Runx1 might form other I-FFLs to regulate the expression of MrgprA3 and MrgprB4, a mechanism preventing these genes from being expressed in Runx1-persistent VGLUT3(+) and MrgprD(+) neurons. The evolvement of these I-FFLs provides an explanation for how modality-selective sensory subtypes are formed during development and may also have intriguing implications for sensory neuron evolution and sensory coding. PMID- 25834058 TI - The role of relational binding in item memory: evidence from face recognition in a case of developmental amnesia. AB - Current theories state that the hippocampus is responsible for the formation of memory representations regarding relations, whereas extrahippocampal cortical regions support representations for single items. However, findings of impaired item memory in hippocampal amnesics suggest a more nuanced role for the hippocampus in item memory. The hippocampus may be necessary when the item elements need to be bound within and across episodes to form a lasting representation that can be used flexibly. The current investigation was designed to test this hypothesis in face recognition. H.C., an individual who developed with a compromised hippocampal system, and control participants incidentally studied individual faces that either varied in presentation viewpoint across study repetitions or remained in a fixed viewpoint across the study repetitions. Eye movements were recorded during encoding and participants then completed a surprise recognition memory test. H.C. demonstrated altered face viewing during encoding. Although the overall number of fixations made by H.C. was not significantly different from that of controls, the distribution of her viewing was primarily directed to the eye region. Critically, H.C. was significantly impaired in her ability to subsequently recognize faces studied from variable viewpoints, but demonstrated spared performance in recognizing faces she encoded from a fixed viewpoint, implicating a relationship between eye movement behavior in the service of a hippocampal binding function. These findings suggest that a compromised hippocampal system disrupts the ability to bind item features within and across study repetitions, ultimately disrupting recognition when it requires access to flexible relational representations. PMID- 25834057 TI - Neuronal-derived nitric oxide and somatodendritically released vasopressin regulate neurovascular coupling in the rat hypothalamic supraoptic nucleus. AB - The classical model of neurovascular coupling (NVC) implies that activity dependent axonal glutamate release at synapses evokes the production and release of vasoactive signals from both neurons and astrocytes, which dilate arterioles, increasing in turn cerebral blood flow (CBF) to areas with increased metabolic needs. However, whether this model is applicable to brain areas that also use less conventional neurotransmitters, such as neuropeptides, is currently unknown. To this end, we studied NVC in the rat hypothalamic magnocellular neurosecretory system (MNS) of the supraoptic nucleus (SON), in which dendritic release of neuropeptides, including vasopressin (VP), constitutes a key signaling modality influencing neuronal and network activity. Using a multidisciplinary approach, we investigated vasopressin-mediated vascular responses in SON arterioles of hypothalamic brain slices of Wistar or VP-eGFP Wistar rats. Bath-applied VP significantly constricted SON arterioles (Delta-41 +/- 7%) via activation of the V1a receptor subtype. Vasoconstrictions were also observed in response to single VP neuronal stimulation (Delta-18 +/- 2%), an effect prevented by V1a receptor blockade (V2255), supporting local dendritic VP release as the key signal mediating activity-dependent vasoconstrictions. Conversely, osmotically driven magnocellular neurosecretory neuronal population activity leads to a predominant nitric oxide-mediated vasodilation (Delta19 +/- 2%). Activity-dependent vasodilations were followed by a VP-mediated vasoconstriction, which acted to limit the magnitude of the vasodilation and served to reset vascular tone following activity-dependent vasodilation. Together, our results unveiled a unique and complex form of NVC in the MNS, supporting a competitive balance between nitric oxide and activity-dependent dendritic released VP, in the generation of proper NVC responses. PMID- 25834059 TI - Improvement in visual search with practice: mapping learning-related changes in neurocognitive stages of processing. AB - Practice can improve performance on visual search tasks; the neural mechanisms underlying such improvements, however, are not clear. Response time typically shortens with practice, but which components of the stimulus-response processing chain facilitate this behavioral change? Improved search performance could result from enhancements in various cognitive processing stages, including (1) sensory processing, (2) attentional allocation, (3) target discrimination, (4) motor response preparation, and/or (5) response execution. We measured event-related potentials (ERPs) as human participants completed a five-day visual-search protocol in which they reported the orientation of a color popout target within an array of ellipses. We assessed changes in behavioral performance and in ERP components associated with various stages of processing. After practice, response time decreased in all participants (while accuracy remained consistent), and electrophysiological measures revealed modulation of several ERP components. First, amplitudes of the early sensory-evoked N1 component at 150 ms increased bilaterally, indicating enhanced visual sensory processing of the array. Second, the negative-polarity posterior-contralateral component (N2pc, 170-250 ms) was earlier and larger, demonstrating enhanced attentional orienting. Third, the amplitude of the sustained posterior contralateral negativity component (SPCN, 300-400 ms) decreased, indicating facilitated target discrimination. Finally, faster motor-response preparation and execution were observed after practice, as indicated by latency changes in both the stimulus-locked and response-locked lateralized readiness potentials (LRPs). These electrophysiological results delineate the functional plasticity in key mechanisms underlying visual search with high temporal resolution and illustrate how practice influences various cognitive and neural processing stages leading to enhanced behavioral performance. PMID- 25834060 TI - Auditory distance coding in rabbit midbrain neurons and human perception: monaural amplitude modulation depth as a cue. AB - Mechanisms underlying sound source distance localization are not well understood. Here we tested the hypothesis that a novel mechanism can create monaural distance sensitivity: a combination of auditory midbrain neurons' sensitivity to amplitude modulation (AM) depth and distance-dependent loss of AM in reverberation. We used virtual auditory space (VAS) methods for sounds at various distances in anechoic and reverberant environments. Stimulus level was constant across distance. With increasing modulation depth, some rabbit inferior colliculus neurons increased firing rates whereas others decreased. These neurons exhibited monotonic relationships between firing rates and distance for monaurally presented noise when two conditions were met: (1) the sound had AM, and (2) the environment was reverberant. The firing rates as a function of distance remained approximately constant without AM in either environment and, in an anechoic condition, even with AM. We corroborated this finding by reproducing the distance sensitivity using a neural model. We also conducted a human psychophysical study using similar methods. Normal-hearing listeners reported perceived distance in response to monaural 1 octave 4 kHz noise source sounds presented at distances of 35-200 cm. We found parallels between the rabbit neural and human responses. In both, sound distance could be discriminated only if the monaural sound in reverberation had AM. These observations support the hypothesis. When other cues are available (e.g., in binaural hearing), how much the auditory system actually uses the AM as a distance cue remains to be determined. PMID- 25834061 TI - Temporal-pattern similarity analysis reveals the beneficial and detrimental effects of context reinstatement on human memory. AB - A powerful force in human memory is the context in which memories are encoded (Tulving and Thomson, 1973). Several studies suggest that the reinstatement of neural encoding patterns is beneficial for memory retrieval (Manning et al., 2011; Staresina et al., 2012; Jafarpour et al., 2014). However, reinstatement of the original encoding context is not always helpful, for instance, when retrieving a memory in a different contextual situation (Smith and Vela, 2001). It is an open question whether such context-dependent memory effects can be captured by the reinstatement of neural patterns. We investigated this question by applying temporal and spatial pattern similarity analysis in MEG and intracranial EEG in a context-match paradigm. Items (words) were tagged by individual dynamic context stimuli (movies). The results show that beta oscillatory phase in visual regions and the parahippocampal cortex tracks the incidental reinstatement of individual context trajectories on a single-trial level. Crucially, memory benefitted from reinstatement when the encoding and retrieval contexts matched but suffered from reinstatement when the contexts did not match. PMID- 25834062 TI - Relationship of fast- and slow-timescale neuronal dynamics in human MEG and SEEG. AB - A growing body of evidence suggests that the neuronal dynamics are poised at criticality. Neuronal avalanches and long-range temporal correlations (LRTCs) are hallmarks of such critical dynamics in neuronal activity and occur at fast (subsecond) and slow (seconds to hours) timescales, respectively. The critical dynamics at different timescales can be characterized by their power-law scaling exponents. However, insight into the avalanche dynamics and LRTCs in the human brain has been largely obtained with sensor-level MEG and EEG recordings, which yield only limited anatomical insight and results confounded by signal mixing. We investigated here the relationship between the human neuronal dynamics at fast and slow timescales using both source-reconstructed MEG and intracranial stereotactical electroencephalography (SEEG). Both MEG and SEEG revealed avalanche dynamics that were characterized parameter-dependently by power-law or truncated-power-law size distributions. Both methods also revealed robust LRTCs throughout the neocortex with distinct scaling exponents in different functional brain systems and frequency bands. The exponents of power-law regimen neuronal avalanches and LRTCs were strongly correlated across subjects. Qualitatively similar power-law correlations were also observed in surrogate data without spatial correlations but with scaling exponents distinct from those of original data. Furthermore, we found that LRTCs in the autonomous nervous system, as indexed by heart-rate variability, were correlated in a complex manner with cortical neuronal avalanches and LRTCs in MEG but not SEEG. These scalp and intracranial data hence show that power-law scaling behavior is a pervasive but neuroanatomically inhomogeneous property of neuronal dynamics in central and autonomous nervous systems. PMID- 25834063 TI - Broad thorny ganglion cells: a candidate for visual pursuit error signaling in the primate retina. AB - Functional analyses exist only for a few of the morphologically described primate ganglion cell types, and their correlates in other mammalian species remain elusive. Here, we recorded light responses of broad thorny cells in the whole mounted macaque retina. They showed ON-OFF-center light responses that were strongly suppressed by stimulation of the receptive field surround. Spike responses were delayed compared with parasol ganglion cells and other ON-OFF cells, including recursive bistratified ganglion cells and A1 amacrine cells. The receptive field structure was shaped by direct excitatory synaptic input and strong presynaptic and postsynaptic inhibition in both ON and OFF pathways. The cells responded strongly to dark or bright stimuli moving either in or out of the receptive field, independent of the direction of motion. However, they did not show a maintained spike response either to a uniform background or to a drifting plaid pattern. These properties could be ideally suited for guiding movements involved in visual pursuit. The functional characteristics reported here permit the first direct cross-species comparison of putative homologous ganglion cell types. Based on morphological similarities, broad thorny ganglion cells have been proposed to be homologs of rabbit local edge detector ganglion cells, but we now show that the two cells have quite distinct physiological properties. Thus, our data argue against broad thorny cells as the homologs of local edge detector cells. PMID- 25834064 TI - GluA2 trafficking is involved in apoptosis of retinal ganglion cells induced by activation of EphB/EphrinB reverse signaling in a rat chronic ocular hypertension model. AB - EphB1, expressed in Muller cells, and ephrinB2, expressed in both Muller cells and retinal ganglion cells (RGCs), constitute an EphB/ephrinB reverse signaling in RGCs. Whether and how this reverse signaling is involved in RGC apoptosis in a rat chronic ocular hypertension (COH) model was investigated. In the COH model, both EphB1 and ephrinB2 were significantly increased and the reverse signaling was activated, which was accompanied by increased protein levels of phosphorylated (p) src, GluA2, and p-GluA2. Intravitreal injection of EphB2-Fc, an activator of ephrinB2, induced an increase in TUNEL-positive signals in normal retinae. A coimmunoprecipitation assay demonstrated direct interactions among ephrinB2, p-src, and GluA2. Moreover, in COH rats the expression of GluA2 proteins on the surface of retinal cells was decreased. Such GluA2 endocytosis could be prevented by preoperational intravitreal injection of 4-amino-3-(4 chlorophenyl)-1-(t-butyl)-1H-pyrazolo [3,4-d] pyrimidine (PP2), an inhibitor of src family tyrosine kinases, and possibly involved the protein interacting with C kinase 1 and phosphorylation of GluA2. In normal rats, intravitreal injection of EphB2-Fc caused changes in these protein levels similar to those observed in COH rats, which all could be avoided by preinjection of PP2. Patch-clamp experiments further showed that the current-voltage relationship of AMPA receptor-mediated EPSCs of RGCs exhibited stronger inward rectification in EphB2-Fc-injected rats. Furthermore, preinjection of PP2 or N-[3-[[4-[(3 aminopropyl)amino]butyl]amino]propyl]-1-naphthaleneacetamide trihydrochloride) (Naspm), a Ca(2+)-permeable GluA2-lacking AMPA receptor inhibitor, remarkably inhibited RGC apoptosis in either EphB2-Fc-injected or COH rats. Together, elevated GluA2 trafficking induced by activated EphB2/ephrinB2 reverse signaling likely contributes to RGC apoptosis in COH rats. PMID- 25834065 TI - Disruption of a neural microcircuit in the rod pathway of the mammalian retina by diabetes mellitus. AB - Diabetes leads to dysfunction of the neural retina before and independent of classical microvascular diabetic retinopathy, but previous studies have failed to demonstrate which neurons and circuits are affected at the earliest stages. Here, using patch-clamp recording and two-photon Ca(2+) imaging in rat retinal slices, we investigated diabetes-evoked changes in a microcircuit consisting of rod bipolar cells and their dyad postsynaptic targets, AII and A17 amacrine cells, which play an essential role in processing scotopic visual signals. AII amacrines forward their signals to ON- and OFF-cone bipolar cells and A17 amacrines provide GABAergic feedback inhibition to rod bipolar cells. Whereas Ca(2+)-permeable AMPA receptors mediate input from rod bipolar cells to both AII and A17 amacrines, diabetes changes the synaptic receptors on A17, but not AII amacrine cells. This was expressed as a change in pharmacological properties and single-channel conductance of the synaptic receptors, consistent with an upregulation of the AMPA receptor GluA2 subunit and reduced Ca(2+) permeability. In addition, two photon imaging revealed reduced agonist-evoked influx of Ca(2+) in dendritic varicosities of A17 amacrine cells from diabetic compared with normal animals. Because Ca(2+)-permeable receptors in A17 amacrine cells mediate synaptic release of GABA, the reduced Ca(2+) permeability of these receptors in diabetic animals leads to reduced release of GABA, followed by disinhibition and increased release of glutamate from rod bipolar cells. This perturbation of neuron and microcircuit dynamics can explain the decreased dynamic range and sensitivity of scotopic vision that has been observed in diabetes. PMID- 25834066 TI - 12-year trends in occupational class differences in short sickness absence among young women. AB - AIMS: Socioeconomic differences in sickness absence are well established among middle-aged employees but poorly known among younger employees, in particular for shorter spells. We examined trends in occupational class differences in short sickness absence among young women. METHODS: The data were obtained from the registers of the City of Helsinki, Finland, and included female employees aged 18 34 years from 2002 to 2013. Self-certified (1-3 days) sickness absence spells were examined. Occupational class was classified into four hierarchical categories. Joinpoint regression models were used to identify major changes in sickness absence trends. RESULTS: Short sickness absence increased until 2008, after which it decreased in all occupational classes except manual workers. Differences in sickness absence between occupational classes remained over time. Routine non-manuals had the highest amount of short sickness absence, while managers and professionals had the smallest amount. Manual workers had somewhat less short sickness absence than routine non-manuals and semi-professionals. CONCLUSIONS: The socioeconomic differences in short sickness absence were clear among young women but not fully consistent as routine non-manuals tended to have more sickness absence than manual workers. Preventive measures are needed to narrow socioeconomic differences in young women's sickness absence especially among routine non-manuals. PMID- 25834067 TI - Experiences of and attitudes towards HIV/STI prevention among holidaymaking men who have sex with men living in Sweden: a cross-sectional Internet survey. AB - AIM: Foreign travellers and men who have sex with men (MSM) are prioritised groups for human immunodeficiency virus/sexually transmitted infection (HIV/STI) prevention efforts in Sweden because of high prevalence of sexual risk-taking. This study aims to describe experiences of and attitudes towards HIV/STI prevention efforts, prior to travelling abroad, among MSM, and to investigate the kinds of prevention efforts that are desirable. METHODS: The study is based on survey responses from 656 MSM who had travelled abroad. Recruitment took place through a Nordic website, and had a cross-sectional design. The analysis has mainly been descriptive, but bivariate analyses were performed using the chi square test. The level of significance was p <.05. RESULTS: Only a few of the participants had encountered HIV/STI prevention efforts in Sweden (5%) and abroad (23%), and a majority (58%) felt that it should be more prevalent. Having free access to condoms and lubricants was preferred among 68% of the men. Furthermore, having written information, as opposed to oral, was also preferred (68% vs. 26%). MSM felt that it was easy to find out information (79%) and claimed they would use the Internet to do so (87%). CONCLUSIONS: Service providers who offer their services to travellers are encouraged to provide helpful links to information about sexual health. Information that is geared towards risk groups such as young adults should be presented with awareness that MSM are also part of that group. It is important for information to be conveyed respectfully to everyone, but perhaps MSM in particular, since they may have experienced feelings of being stigmatised or discriminated against previously. PMID- 25834068 TI - Leaving Sweden behind: Gains in life expectancy in Canada. AB - AIMS: Sweden and Canada are known for quality of living and exceedingly high life expectancy, but recent data on how these countries compare are lacking. We measured life expectancy in Canada and Sweden during the past decade, and identified factors responsible for changes over time. METHODS: We calculated life expectancy at birth for Canada and Sweden annually from 2000 to 2010, and determined the ages and causes of death responsible for the gap between the two countries using Arriaga's method. We determined how population growth, ageing, and mortality influenced the number of deaths over time. RESULTS: During 2000 2010, life expectancy in Canada caught up with Sweden for men, and surpassed Sweden by 0.4 years for women. Sweden lost ground owing to a slower reduction in circulatory and tumour mortality after age 65 years compared with Canada. Nonetheless, population ageing increased the number of deaths in Canada, especially for mental and nervous system disorders. In Sweden, the number of deaths decreased. CONCLUSIONS: In only one decade, life expectancy in Canada caught up and surpassed Sweden due to rapid improvements in circulatory and tumour mortality. Population ageing increased the number of deaths in Canada, potentially stressing the health care system more than in Sweden. PMID- 25834069 TI - Antenatal glucocorticoid treatment alters Na+ uptake in renal proximal tubule cells from adult offspring in a sex-specific manner. AB - We have shown a sex-specific effect of fetal programming on Na(+) excretion in adult sheep. The site of this effect in the kidney is unknown. Therefore, we tested the hypothesis that renal proximal tubule cells (RPTCs) from adult male sheep exposed to betamethasone (Beta) before birth have greater Na(+) uptake than do RPTCs from vehicle-exposed male sheep and that RPTCs from female sheep similarly exposed are not influenced by antenatal Beta. In isolated RPTCs from 1- to 1.5-yr-old male and female sheep, we measured Na(+) uptake under basal conditions and after stimulation with ANG II. To gain insight into the mechanisms involved, we also measured nitric oxide (NO) levels, ANG II receptor mRNA levels, and expression of Na(+)/H(+) exchanger 3. Basal Na(+) uptake increased more in cells from Beta-exposed male sheep than in cells from vehicle-exposed male sheep (400% vs. 300%, P < 0.00001). ANG II-stimulated Na(+) uptake was also greater in cells from Beta-exposed males. Beta exposure did not increase Na(+) uptake by RPTCs from female sheep. NO production was suppressed more by ANG II in RPTCs from Beta-exposed males than in RPTCs from either vehicle-exposed male or female sheep. Our data suggest that one site of the sex-specific effect of Beta-induced fetal programming in the kidney is the RPTC and that the enhanced Na(+) uptake induced by antenatal Beta in male RPTCs may be related to the suppression of NO in these cells. PMID- 25834070 TI - Kidney adysplasia and variable hydronephrosis, a new mutation affecting the odd skipped related 1 gene in the mouse, causes variable defects in kidney development and hydronephrosis. AB - Many genes, including odd-skipped related 1 (Osr1), are involved in regulation of mammalian kidney development. We describe here a new recessive mutation (kidney adysplasia and variable hydronephrosis, kavh) in the mouse that leads to downregulation of Osr1 transcript, causing several kidney defects: agenesis, hypoplasia, and hydronephrosis with variable age of onset. The mutation is closely associated with a reciprocal translocation, T(12;17)4Rk, whose Chromosome 12 breakpoint is upstream from Osr1. The kavh/kavh mutant provides a model to study kidney development and test therapies for hydronephrosis. PMID- 25834071 TI - Platelets are relevant mediators of renal injury induced by primary endothelial lesions. AB - Several studies have suggested a prominent (pro)inflammatory and harmful role of platelets in renal disease, and newer work has also demonstrated platelet release of proangiogenic factors. In the present study, we investigated the role of platelets in a mouse model of selective endothelial cell injury using either platelet depletion or the pharmacological P2Y12 receptor blocker clopidogrel as an interventional strategy. The concanavalin A/anti-concanavalin A model was induced in left kidneys of C57bl/6J wild-type mice after initial platelet depletion or platelet-inhibiting therapy using clopidogrel. FACS analysis of glycoprotein IIb/IIIa/P-selectin double-positive platelets and platelet-derived microparticles demonstrated relevant platelet activation after the induction of selective endothelial injury in mice. Enhanced platelet activation persisted for 5 days after disease induction and was accompanied by increased amounts of circulating platelet-derived microparticles as potential mediators of a prolonged procoagulant state. By immunohistochemistry, we detected significantly reduced glomerular injury in platelet-depleted mice compared with control mice. In parallel, we also saw reduced endothelial loss and a consequently reduced repair response as indicated by diminished proliferative activity. The P2Y12 receptor blocker clopidogrel demonstrated efficacy in limiting platelet activation and subsequent endothelial injury in this mouse model of renal microvascular injury. In conclusion, platelets are relevant mediators of renal injury induced by primary endothelial lesions early on, as demonstrated by platelet depletion as well as platelet inhibition via the P2Y12 receptor. While strategies to prevent platelet-endothelial interactions have shown protective effects, the contribution of platelets during renal regeneration remains unknown. PMID- 25834072 TI - Activation of nuclear factor of activated T cells 5 in the peritoneal membrane of uremic patients. AB - Peritoneal inflammation and fibrosis are responses to the uremic milieu and exposure to hyperosmolar dialysis fluids in patients on peritoneal dialysis. Cells respond to high osmolarity via the transcription factor nuclear factor of activated T cells (NFAT5). In the present study, the response of human peritoneal fibroblasts to glucose was analyzed in vitro. Expression levels of NFAT5 and chemokine (C-C motif) ligand (CCL2) mRNA were quantified in peritoneal biopsies of five nonuremic control patients, five uremic patients before PD (pPD), and eight patients on PD (oPD) using real-time PCR. Biopsies from 5 control patients, 25 pPD patients, and 25 oPD patients were investigated using immunohistochemistry to detect the expression of NFAT5, CCL2, NF-kappaB p50, NF-kappaB p65, and CD68. High glucose concentrations led to an early, dose-dependent induction of NFAT5 mRNA in human peritoneal fibroblasts. CCL2 mRNA expression was upregulated by high concentrations of glucose after 6 h, but, most notably, a concentration dependent induction of CCL2 was present after 96 h. In human peritoneal biopsies, NFAT5 mRNA levels were increased in uremic patients compared with nonuremic control patients. No significant difference was found between the pPD group and oPD group. CCL2 mRNA expression was higher in the oPD group. Immunohistochemistry analysis was consistent with the results of mRNA analysis. CD68-positive cells were significantly increased in the oPD group. In conclusion, uremia results in NFAT5 induction, which might promote early changes of the peritoneum. Upregulation of NFAT5 in PD patients is associated with NFkappaB induction, potentially resulting in the recruitment of macrophages. PMID- 25834073 TI - Memories that last in hypertension. AB - In recent years, it has become clear that the immune system contributes to the genesis of hypertension. Hypertensive stimuli, such as angiotensin II, DOCA-salt, and norepinephrine, cause T cells and monocytes/macrophages to accumulate in the kidney and vasculature. These cells release inflammatory cytokines, such as IL-6, interferon-gamma, and IL-17, that promote renal and vascular dysfunction. These cytokines also promote angiotensinogen production in the proximal tubule and Na(+) retention in the distal nephron and contribute to renal fibrosis and glomerular damage. For several years, we have observed accumulation of memory T cells in the kidney and vasculature. Given the propensity for memory cells to produce cytokines such as interferon-gamma and IL-17, interventions to prevent the formation or renal accumulation of specific memory T cell subsets could prevent end-organ damage and blood pressure elevation in response to hypertensive stimuli. PMID- 25834075 TI - Clinical indicators of occult musculoskeletal pain in aggressive dogs. PMID- 25834074 TI - KCNJ10 (Kir4.1) is expressed in the basolateral membrane of the cortical thick ascending limb. AB - The aim of the present study is to examine the role of Kcnj10 (Kir.4.1) in contributing to the basolateral K conductance in the cortical thick ascending limb (cTAL) using Kcnj10(+/+) wild-type (WT) and Kcnj10(-/-) knockout (KO) mice. The patch-clamp experiments detected a 40- and an 80-pS K channel in the basolateral membrane of the cTAL. Moreover, the probability of finding the 40-pS K was significantly higher in the late part of the cTAL close to the distal convoluted tubule than those in the initial part. Immunostaining showed that Kcnj10 staining was detected in the basolateral membrane of the cTAL but the expression was not uniformly distributed. The disruption of Kcnj10 completely eliminated the 40-pS K channel but not the 80-pS K channel, suggesting the role of Kcnj10 in forming the 40-pS K channel of the cTAL. Also, the disruption of Kcnj10 increased the probability of finding the 80-pS K channel in the cTAL, especially in the late part of the cTAL. Because the channel open probability of the 80-pS K channel in KO was similar to those of WT mice, the increase in the 80 pS K channel may be achieved by increasing K channel number. The whole cell recording further showed that K reversal potential measured with 5 mM K in the bath and 140 mM K in the pipette was the same in the WT and KO mice. Moreover, Western blot and immunostaining showed that the disruption of Kcnj10 did not affect the expression of Na-K-Cl cotransporter 2 (NKCC2). We conclude that Kir.4.1 is expressed in the basolateral membrane of cTAL and that the disruption of Kir.4.1 has no significant effect on the membrane potential of the cTAL and NKCC2 expression. PMID- 25834076 TI - Tendon transfer surgery in upper-extremity cerebral palsy is more effective than botulinum toxin injections or regular, ongoing therapy. AB - BACKGROUND: For children with upper-extremity cerebral palsy (CP) who meet standard indications for tendon transfer surgery, we hypothesized that surgical treatment would result in greater functional improvement than treatment with botulinum toxin injections or regular, ongoing therapy. METHODS: Thirty-nine children with upper-extremity CP, who were four to sixteen years of age and surgical candidates for the transfer of the flexor carpi ulnaris to the extensor carpi radialis brevis, pronator teres release, and extensor pollicis longus rerouting with adductor pollicis release, were prospectively assigned, either randomly (twenty-nine patients) or by patient/family preference (ten patients), to one of three treatment groups: surgical treatment (Group 1); botulinum toxin injections (Group 2); or regular, ongoing therapy (Group 3). Seven centers participated. Assessment measurements included active range of motion, pinch and grip strength, stereognosis, and scores as measured with eight additional functional or patient-oriented outcome instruments. Thirty-four patients (twenty five randomized and nine from the patient-preference arm) were evaluated twelve months post-treatment as the study cohort. RESULTS: For the primary outcome of the Shriners Hospital Upper Extremity Evaluation (SHUEE) dynamic positional analysis (DPA), significantly greater improvement was seen in Group 1 than in the other two groups (p < 0.001). Improvements in SHUEE DPA reflected improved supination and wrist extension during functional activities after surgical treatment. Group 1 showed more improvement in the Pediatric Quality of Life Inventory (PedsQL) CP module domain of movement and in the Canadian Occupational Performance Measure (COPM) score for satisfaction than Groups 2 and 3. Both Groups 1 and 3 showed more improvement in pinch strength than did Group 2. CONCLUSIONS: For children with upper-extremity CP who were candidates for standard tendon transfer, surgical treatment was demonstrated to provide greater improvement, of modest magnitude, than botulinum toxin injections or regular, ongoing therapy at twelve months of follow-up for the SHUEE DPA, the PedsQL CP module domain of movement, and COPM satisfaction. PMID- 25834077 TI - The effect of femoral and acetabular version on clinical outcomes after arthroscopic femoroacetabular impingement surgery. AB - BACKGROUND: The impact of proximal femoral and combined femoral and acetabular version on patient-reported outcomes after arthroscopic surgery for femoroacetabular impingement (FAI) remains undefined. The purpose of this study was to identify associations of proximal femoral version as well as combined version (McKibbin index) with disease-specific, validated, patient-reported outcomes following arthroscopic correction of symptomatic FAI. METHODS: A prospective hip arthroscopy registry was utilized to evaluate 243 patients who underwent arthroscopic surgery to correct FAI. Femoral version and the McKibbin index were measured prospectively on preoperative computed tomography scans. Disease-specific, patient-reported outcomes included the modified Harris hip score (mHHS) and the Hip Outcome Score (HOS) ADL (Activities of Daily Living) and Sports subscales. Disease impact on quality of life was determined with use of the International Hip Outcome Tool (iHOT-33). Comparative analyses were used to evaluate the impact of femoral version on changes in patient-reported outcome scores; multiple regression was used to adjust for potential confounders. RESULTS: The patient cohort contained 243 patients (123 female and 120 male) with a mean age of 29.2 years and a mean postoperative follow-up of twenty-one months (range, twelve to forty-two months). The cohort experienced significant improvements (p < 0.001) in all patient-reported outcome measures, with most patients improving by at least the minimal clinically important difference for all of these measures. The mean improvement was 20 points for the mHHS, 15 for the HOS ADL, 23 for the HOS Sports, and 23 for the iHOT-33. When stratified by femoral version, the postoperative improvements in patients with relative femoral retroversion (<5 degrees anteversion) were clinically important but of significantly smaller magnitude than those in the other version groups. We did not find any associations between the McKibbin index and any patient-reported outcomes. CONCLUSIONS: Although clinically important improvements can be expected after arthroscopic FAI surgery in all femoral version groups, patients with relative femoral retroversion (<5 degrees femoral anteversion) may experience less improvement than those with normal or increased version. PMID- 25834078 TI - Does periacetabular osteotomy for hip dysplasia modulate cartilage biochemistry? AB - BACKGROUND: The aim of periacetabular osteotomy is to improve joint mechanics in patients with developmental dysplasia of the hip. In our study, we tried to determine whether the proteoglycan content, as measured with delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), can be modulated with the alteration of the hip joint biomechanics. METHODS: In this prospective cohort study, thirty-seven patients (thirty-seven hips) with no or minimal osteoarthritis were treated with periacetabular osteotomy for symptomatic acetabular dysplasia. All patients had preoperative and one-year follow-up dGEMRIC scans. Twenty-eight of the thirty-seven also had two-year scans. The changes in dGEMRIC findings and hip morphology between the preoperative visit and the examinations at one and two years following the periacetabular osteotomy were assessed. RESULTS: The mean preoperative dGEMRIC index (and standard deviation) was 561.6 +/- 117.6 ms; this decreased to 515.2 +/- 118.4 ms at one year after periacetabular osteotomy but subsequently recovered to 529.2 +/- 99.1 ms at two years postoperatively. The decrease in the dGEMRIC index of the acetabular cartilage after surgery appears to be most pronounced at the superior aspect of the acetabulum, where the decrease in mechanical loading after periacetabular osteotomy would be most pronounced. All domains of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) demonstrated significant improvement from the preoperative to the postoperative visits (all p < 0.001). CONCLUSIONS: Periacetabular osteotomy for developmental dysplasia of the hip appears to alter the mechanical loading of articular cartilage in the hip, which in turn alters the cartilage matrix composition, as demonstrated by dGEMRIC. PMID- 25834079 TI - Baseline predictors of health-related quality of life after anterior cruciate ligament reconstruction: a longitudinal analysis of a multicenter cohort at two and six years. AB - BACKGROUND: Limited information exists regarding predictors of general quality of life following anterior cruciate ligament (ACL) reconstruction with up to six year follow-up. We hypothesized that certain variables evaluated at the time of ACL reconstruction will predict the general quality of life as measured by the Short Form-36 (SF-36). METHODS: All unilateral ACL reconstructions from 2002 to 2004 in patients currently enrolled in a prospective multicenter cohort were evaluated. Patients preoperatively completed the SF-36 validated outcome instrument. Surgeons documented intra-articular pathological conditions and treatment, as well as the ACL reconstruction surgical technique. At baseline and at a minimum of two and six years postoperatively, patients completed the SF-36. Longitudinal analysis was performed for the two-year and six-year end points. RESULTS: Of the initial 1512 subjects, at least one follow-up questionnaire was obtained from 1411 subjects (93%). The cohort was 44% female, and the median patient age at enrollment was twenty-three years. The mean scores were 41.9 points for the Physical Component Summary (PCS) and 51.7 points for the Mental Component Summary (MCS) at baseline, 53.6 points for the PCS and 52.0 points for the MCS at two years, and 54.0 points for the PCS and 52.4 points for the MCS at six years. Significant predictors of a higher PCS score were a higher baseline PCS score, younger age, lower baseline body mass index, having >50% of the lateral meniscus excised, or having no treatment done on a lateral meniscal tear. In contrast, significant predictors of a lower PCS score were a shorter follow-up time since surgery, revision ACL reconstruction, smoking at baseline, fewer years of education, and chondromalacia of the lateral tibial plateau. The mean utility gained at six years after ACL reconstruction was 5.3 quality-adjusted life years (QALYs). CONCLUSIONS: Large improvements in the PCS (with an effect size of 1.2) were noted at two years and were maintained at six years after ACL reconstruction. Lower education and smoking were significant predictors of lower PCS and MCS scores. ACL reconstruction resulted in a relatively high gain of QALYs. PMID- 25834080 TI - Risk factors for failure of a single surgical debridement in adults with acute septic arthritis. AB - BACKGROUND: Acute septic arthritis in a native joint may require more than one surgical debridement to eradicate the infection. Our objectives were to determine the prevalence of failure of a single surgical debridement for acute septic arthritis, to identify risk factors for failure of a single debridement, and to develop a prognostic probability algorithm to predict failure of a single surgical debridement for acute septic arthritis in adults. METHODS: We collected initial laboratory and medical comorbidity data of 128 adults (132 native joints) with acute septic arthritis who underwent at least one surgical debridement at our institution between 2000 and 2011. Univariate and logistic regression analyses were used to identify potential risk factors for failure of a single surgical debridement. Stepwise variable selection was used to develop a prediction model and identify probabilities of failure of a single surgical debridement. RESULTS: Of the 128 patients (132 affected joints) who underwent surgical debridement for acute septic arthritis, forty-nine (38%) of the patients (fifty joints) experienced failure of a single debridement and required at least two debridements (range, two to four debridements). Staphylococcus aureus was the most common bacterial isolate (in sixty, or 45%, of the 132 joints). Logistic regression analysis identified five independent clinical predictors for failure of a single surgical debridement: a history of inflammatory arthropathy (odds ratio [OR], 7.3; 95% confidence interval [CI], 2.4 to 22.6; p < 0.001), the involvement of a large joint (knee, shoulder, or hip) (OR, 7.0; 95% CI, 1.2 to 37.5; p = 0.02), a synovial-fluid nucleated cell count of >85.0 x 10(9) cells/L (OR, 4.7; 95% CI, 1.8 to 17.7; p = 0.002), S. aureus as the bacterial isolate (OR, 4.6; 95% CI, 1.8 to 11.9; p = 0.002), and a history of diabetes (OR, 2.6; 95% CI, 1.1 to 6.2; p = 0.04). CONCLUSIONS: Most (62%) of the septic joints were managed effectively with a single surgical debridement. Adults with a history of inflammatory arthropathy, involvement of a large joint, a synovial-fluid nucleated cell count of >85.0 x 10(9) cells/L, an infection with S. aureus, or a history of diabetes had a higher risk of failure of a single surgical debridement for acute septic arthritis and requiring additional surgical debridement(s). PMID- 25834081 TI - Architectural and biochemical adaptations in skeletal muscle and bone following rotator cuff injury in a rat model. AB - BACKGROUND: Injury to the rotator cuff can cause irreversible changes to the structure and function of the associated muscles and bones. The temporal progression and pathomechanisms associated with these adaptations are unclear. The purpose of this study was to investigate the time course of structural muscle and osseous changes in a rat model of a massive rotator cuff tear. METHODS: Supraspinatus and infraspinatus muscle architecture and biochemistry and humeral and scapular morphological parameters were measured three days, eight weeks, and sixteen weeks after dual tenotomy with and without chemical paralysis via botulinum toxin A (BTX). RESULTS: Muscle mass and physiological cross-sectional area increased over time in the age-matched control animals, decreased over time in the tenotomy+BTX group, and remained nearly the same in the tenotomy-alone group. Tenotomy+BTX led to increased extracellular collagen in the muscle. Changes in scapular bone morphology were observed in both experimental groups, consistent with reductions in load transmission across the joint. CONCLUSIONS: These data suggest that tenotomy alone interferes with normal age-related muscle growth. The addition of chemical paralysis yielded profound structural changes to the muscle and bone, potentially leading to impaired muscle function, increased muscle stiffness, and decreased bone strength. CLINICAL RELEVANCE: Structural musculoskeletal changes occur after tendon injury, and these changes are severely exacerbated with the addition of neuromuscular compromise. PMID- 25834082 TI - Osteocartilaginous transfer of the proximal part of the fibula for osseous overgrowth in children with congenital or acquired tibial amputation: surgical technique and results. AB - BACKGROUND: Osseous overgrowth is a common problem in children after tibial transcortical amputation. We present the results of forty-seven children (fifty tibiae) treated for tibial osseous overgrowth with an autologous osteocartilaginous cap from the proximal part of the ipsilateral fibula. METHODS: We reviewed the records of all patients who underwent amputation at a single pediatric hospital from 1990 to 2011. All patients who had been followed for a minimum of two years after undergoing osteocartilaginous capping with the proximal part of the ipsilateral fibula to treat established tibial overgrowth were included. Patients with acquired and congenital amputations were compared. RESULTS: Fifty tibiae in forty-seven patients met our inclusion criteria. There were thirty-one acquired and nineteen congenital amputations. The mean age at surgery was 7.6 years (range, 2.1 to 15.6 years), and the mean duration of follow up was 7.2 years (range, 2.2 to 15.4 years). Five tibiae (10%) in four patients had recurrence of the overgrowth at a mean of 5.4 years (range, 2.8 to 7.6 years) after the osteocartilaginous transfer. There was no significant difference in the results between children with an acquired amputation and those with a congenital amputation. CONCLUSIONS: At a mean of 7.2 years after autologous osteocartilaginous capping with the proximal part of the fibula, 90% of the limbs had not had recurrent overgrowth. This is a safe and effective treatment of long bone overgrowth following either congenital or acquired amputation in children. PMID- 25834085 TI - Unplanned excision of soft-tissue sarcomas: current concepts for management and prognosis. AB - ? Biopsy, staging, preoperative imaging and planning, as well as surgical treatment of soft-tissue sarcomas, are best carried out in specialized sarcoma centers, with the support of a multidisciplinary tumor board.? Tumor bed excision is recommended after most unplanned excisions, with a goal of obtaining complete tumor removal with an appropriately wide margin of resection.? The surgical resection area tends to be more extensive during tumor bed excision than during primary resection because of the need to resect potential areas of contamination, resulting in the need for more reconstructive procedures (flaps and skin grafts) and wider radiation fields.? Unplanned excisions are associated with an increased rate of local recurrence related to residual disease and positive margins after tumor bed excision, a deep location, and certain histologic subtypes, such as malignant peripheral nerve sheath tumor, myxofibrosarcoma, and dermatofibrosarcoma protuberans.? While adjuvant radiation therapy has not been found to mitigate the risk of local recurrence in unplanned excisions, it is generally utilized in the treatment of unplanned excisions as it is in the treatment of primary soft-tissue sarcomas.? Given the surgical and oncologic sequelae of unplanned excisions, prevention through the diffusion of concepts by means of provider education on how to approach soft-tissue masses, which can be potential soft-tissue sarcomas, is the best strategy. PMID- 25834083 TI - Preliminary validation of the Review of Musculoskeletal System (ROMS) questionnaire. AB - BACKGROUND: Measurement of clinical outcomes is necessary to define best practice. It requires a validated tool that can be easily applied as part of clinical practice. We present the preliminary validation of a brief self-reported Review of Musculoskeletal System (ROMS) questionnaire that captures functional limitations due to musculoskeletal problems and other medical and emotional conditions. METHODS: Data were derived from a clinical outcomes database (Orthopaedic Minimal Data Set [OrthoMiDaS]) that combines patient-reported data collected as part of routine care and secondary data extracted from electronic medical records. The study utilized 82,873 encounters collected from 24,116 consecutive patients with problems in the upper and lower extremities. In addition to the ROMS, the study used version 2 of the Short Form-12 (SF-12v2), the Penn Shoulder Score (PSS), the Hip disability and Osteoarthritis Outcome Score (HOOS), and the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaires. Fifteen cross-sectional samples were used to evaluate the floor and ceiling effects as well as the construct and content validity. Five longitudinal cohorts were used to measure test-retest reliability and responsiveness. Standard statistical tests were applied. RESULTS: The floor and ceiling effects of the ROMS questionnaire in patients with shoulder, hip, and knee problems ranged from 1.3% to 8.5%. Construct-validity tests confirmed convergent and divergent validity of the ROMS. The tests also justified its additional value when the ROMS was used with joint-specific tools. When measuring test-retest reliability of the ROMS scales, intraclass correlation ranged from 0.80 to 0.90 at approximately one week and from 0.71 to 0.87 at approximately four weeks. Responsiveness of the ROMS was greater than that of the SF-12 and less than that of the joint-specific questionnaires. CONCLUSIONS: The ROMS is compatible with routine clinical process and has good psychometric properties in patients with shoulder, hip, and knee disorders. It can be used as a primary outcome tool for large observational studies and can supplement more specific tools in controlled studies. CLINICAL RELEVANCE: The ROMS was developed as a tool to measure and monitor the clinical status of the musculoskeletal system in a population of patients during and after treatment as well as over time. PMID- 25834086 TI - A cadaver study revisiting the original methodology of Lauge-Hansen and a commentary on modern usage. AB - BACKGROUND: The study by Lauge-Hansen published in the Archives of Surgery in 1950 still stands as the seminal work for our understanding of the pathomechanics of ankle fractures. The purpose of the present study was to recreate Lauge Hansen's experiments for the supination-external rotation (SER) fracture mechanism and to determine whether the predicted sequence of osseous and soft tissue injury is reproducible on the basis of his originally described methodology. METHODS: Ten fresh-frozen cadaver specimens amputated above the knee were utilized. The foot was axially loaded in a position of neutral dorsiflexion and supination. External rotation was applied manually in accordance with Lauge Hansen's description until osseous and/or soft-tissue injury occurred. Fluoroscopic images were made and anatomic dissection was performed. RESULTS: Although several specimens exhibited findings consistent with certain stages of the SER injury pattern, no specimen demonstrated the complete sequence of predicted osseous and soft-tissue injury. CONCLUSIONS: Loading cadaver specimens with an SER mechanism utilizing a methodology similar to that in the original experiments by Lauge-Hansen does not reliably produce the sequence of osseous and soft-tissue injury predicted by Lauge-Hansen. PMID- 25834084 TI - Intermediate-term follow-up after ankle distraction for treatment of end-stage osteoarthritis. AB - BACKGROUND: Treatment of end-stage ankle osteoarthritis remains challenging, especially in young patients. Initial reports have shown early benefits of joint distraction for the treatment of ankle osteoarthritis. We report the five to ten year results of a previously described patient cohort following ankle distraction surgery. METHODS: All thirty-six patients who had undergone ankle distraction surgery between December 2002 and October 2006 were contacted. Patients were evaluated by a clinical investigator and completed the Ankle Osteoarthritis Scale (AOS) and Short Form-36 (SF-36) surveys. Radiographs as well as computed tomography and magnetic resonance imaging scans of the ankles were obtained at the follow-up visits. RESULTS: Twenty-nine patients (81%) were followed for a minimum of five years (mean and standard deviation, 8.3 +/- 2.2 years). Sixteen (55%) of the twenty-nine patients still had the native ankle joint whereas thirteen patients (45%) had undergone either ankle arthrodesis or total ankle arthroplasty. Positive predictors of ankle survival included a better AOS score at two years (hazard ratio [HR] = 0.048, 95% confidence interval [CI] = 0.0028 to 0.84, p = 0.04), older age at surgery (HR = 0.91, 95% CI = 0.83 to 0.99, p = 0.04), and fixed distraction (HR = 0.094, 95% CI = 0.017 to 0.525, p < 0.01). Radiographs and advanced imaging revealed progression of ankle osteoarthritis at the time of final follow-up. CONCLUSIONS: Ankle function following joint distraction declines over time. Patients should be well informed of the commitment that they must make during the treatment period as well as the long term results after surgery. PMID- 25834087 TI - Demonstrating the value of orthopaedic surgery through multicenter trials: AOA critical issues. AB - Orthopaedic surgery is expensive and will be carefully scrutinized in the U.S. under health-care reform. Unfortunately, although the orthopaedic literature is replete with clinical outcomes studies, there is still a paucity of meaningful clinical outcomes data that are free from bias. It is possible that orthopaedic procedures may be among the most cost-effective medical treatments for the aging population. However, it is only through the collection of patient-generated outcomes data in prospective randomized and observational studies that orthopaedic surgery can be shown to provide high value (defined as high-quality outcomes at a relatively low cost) to society.The burden of musculoskeletal disease in the U.S. is high; nearly half of all adults describe themselves as having a chronic musculoskeletal condition, and approximately one-quarter of all health-care dollars are spent treating musculoskeletal disease. For this reason, treatment for osteoarthritis, the costliest condition in the elderly population, has drawn great scrutiny from insurers and the government. In the absence of clinical outcomes data that prove the value of orthopaedic interventions, there will be pressure to reduce payments or even deny treatments for these conditions if they are perceived to be too expensive or lack outcomes data supporting their use.Multicenter trials are expensive; this paper analyzes challenges to, and opportunities for, funding. Although National Institutes of Health (NIH) funding has dropped nearly 20% over the past ten years in inflation-adjusted dollars, it has begun a gradual reorientation toward clinical research, which comprised almost 50% of its budget in 2013. The Patient Protection and Affordable Care Act focused more attention on clinical outcomes research, with the establishment of the Patient-Centered Outcomes Research Institute (PCORI), which will ultimately fund $750 million of comparative effectiveness research annually. Another new funding source within the Centers for Medicare & Medicaid Services (CMS) is the Center for Medicare & Medicaid Innovation (CMMI), which recently funded several major initiatives, including a $1 billion health-care innovations grant program in 2012.The purpose of this article is to promote increased participation in prospective orthopaedic multicenter trials, which can answer clinical questions that affect the care of millions of patients. Some have enrolled large numbers of patients and have demonstrated the cost-effectiveness of surgery, provided subgroup analyses to define the optimal timing of surgery, and identified which patients are most and least helped by surgery. These studies have the power to establish new standards of care and prove the value of orthopaedic surgery. PMID- 25834088 TI - The inadequacy of musculoskeletal knowledge in graduating medical students in the United Kingdom. AB - BACKGROUND: Musculoskeletal symptoms are common reasons for patients seeking medical attention. Basic competency in musculoskeletal medicine is therefore essential for all clinicians. To our knowledge, this is the first assessment of the competency in musculoskeletal medicine of medical students in the United Kingdom. METHODS: Medical students were enrolled after passing final university examinations and being awarded degrees of Bachelor of Medicine, Bachelor of Surgery (MBBS) or Medicinae Baccalaureus, Baccalaureus Chirurgiae (MBChB) in 2013 and were assessed with use of the Freedman and Bernstein musculoskeletal cognitive examination tool. RESULTS: Two hundred and thirty students were recruited, of whom 210 were suitable for inclusion. Only 21% (forty-four students) passed the assessment. Mandatory exposure to musculoskeletal medicine during medical school consisted of orthopaedics for 100% of participants for a mean duration of 2.65 weeks, rheumatology for 96% of participants for a mean duration of 2.5 weeks, and sports medicine for 1% of participants for a mean duration of two weeks. There was a significant difference (p = 0.002) in scores between those with career interests in musculoskeletal specialties (69.3%) and the rest of the cohort (54.9%). There was also a significant difference (p = 0.001) in scores between participants with career interests in general practice (42%) and the rest of the cohort (56%). Only 40% of participants considered themselves competent in musculoskeletal medicine. Fifty-five percent thought that musculoskeletal conditions would be an important component of their future practice. CONCLUSIONS: Our findings suggest that medical schools may be currently failing to ensure that medical students have a basic competence in musculoskeletal medicine. Further investigation is warranted to fully assess the current training provided by U.K. medical schools in musculoskeletal medicine, and appropriate steps must be taken to improve the quantity and quality of training in musculoskeletal medicine in the United Kingdom. PMID- 25834089 TI - Should version concern us? Commentary on an article by Peter D. Fabricant, MD, MPH, et al.: "The effect of femoral and acetabular version on clinical outcomes after arthroscopic femoroacetabular impingement surgery". PMID- 25834090 TI - A comparative review of methods for comparing means using partially paired data. AB - In medical experiments with the objective of testing the equality of two means, data are often partially paired by design or because of missing data. The partially paired data represent a combination of paired and unpaired observations. In this article, we review and compare nine methods for analyzing partially paired data, including the two-sample t-test, paired t-test, corrected z-test, weighted t-test, pooled t-test, optimal pooled t-test, multiple imputation method, mixed model approach, and the test based on a modified maximum likelihood estimate. We compare the performance of these methods through extensive simulation studies that cover a wide range of scenarios with different effect sizes, sample sizes, and correlations between the paired variables, as well as true underlying distributions. The simulation results suggest that when the sample size is moderate, the test based on the modified maximum likelihood estimator is generally superior to the other approaches when the data is normally distributed and the optimal pooled t-test performs the best when the data is not normally distributed, with well-controlled type I error rates and high statistical power; when the sample size is small, the optimal pooled t-test is to be recommended when both variables have missing data and the paired t-test is to be recommended when only one variable has missing data. PMID- 25834091 TI - Characterisation of subpopulations of myeloid cells in infantile haemangioma. AB - AIMS: Cells expressing markers of mast cells, macrophages and dendritic cells have previously been demonstrated within the interstitium of infantile haemangioma (IH). This study characterised these myeloid cellular subpopulations within IH. METHODS: Immunohistochemical staining was performed on proliferating and involuted IHs for the expression of Nanog, tryptase, CD163, DC-SIGN and CD45. The presence of mRNA corresponding to Nanog, tryptase alpha/beta-1, tryptase beta 2, CD163 and DC-SIGN was confirmed by NanoString and RT-PCR in snap-frozen IH tissues. RESULTS: Immunohistochemical staining showed expression of Nanog by interstitial phenotypical mast cells within proliferating IH, which were separate from the interstitial M2-polarised macrophages that also expressed DC-SIGN, a dendritic cell marker. These two myeloid cellular subpopulations in IH did not express the pan-haematopoietic marker, CD45. CONCLUSIONS: There are two interstitial subpopulations of myeloid cells within IH: phenotypical mast cells which also express Nanog, indicating a primitive phenotype; and M2-polarised macrophages which also express DC-SIGN. PMID- 25834092 TI - SAS doctors career progression survey 2013. AB - We conducted a national survey of Staff, Associate Specialists and Specialty (SAS) doctors working in sexual health clinics in the UK in 2013 in order to explore their career progression. The aim of the survey was to assess SAS doctors' experience in passing through the thresholds and to gather information about the adherence by SAS doctors and employers to the terms and conditions of service laid out by the new 2008 contract. Out of 185 responders, whom the authors estimate comprise 34% of the total workforce, 159 were on the new contract. Of those, most SAS doctors were women (84%), the majority (67%) worked less than nine programmed activities per week; only a few had intentions to join the consultant grade (15%), and a considerable minority (26%) were older than 54 years of age and likely to retire in the next ten years. The survey showed that most participating SAS doctors had undergone appraisal in the previous 15 months (90%), most had a job planning discussion (83%) with their employer and most had some allocated time for supporting professional activities (86%). However, a significant minority had no appraisal (10%), no job planning discussion (17%) and had no allocated supporting professional activities (14%), which allows time for career development in the specialty. Most SAS doctors, who had the opportunity, had progressed through the thresholds automatically (88%); some experienced difficulties in passing (8%) and only a few did not pass (4%). SAS doctors must ensure that they work together with their employer in order to improve adherence to the terms and conditions of service of the contract, which allow for career progression and benefit both the individual doctors and ultimately service provision. PMID- 25834094 TI - Bombyx mori nucleopolyhedrovirus nucleic acid binding proteins BRO-B and BRO-E associate with host T-cell intracellular antigen 1 homologue BmTRN-1 to influence protein synthesis during infection. AB - Previous reports have indicated that the Bombyx mori nucleopolyhedrovirus (BmNPV) nucleic acid binding proteins BRO-B and BRO-E are expressed during the early stage of infection and that the BRO family likely supports the regulation of mRNA; however, no study has directly examined the function of BRO family proteins in virus-permissive cells. Here, we show that BRO-B and BRO-E associate with cellular T-cell intracellular antigen 1 homologue (BmTRN-1), a translational regulator, and other cellular translation-related proteins in silkworm cells during viral infection. We created BM-N cells that expressed BRO-B/E to study molecular interactions between BmTRN-1 and BRO-B/E and how they influenced protein synthesis. Fluorescent microscopy revealed that BmTRN-1 was localized in cytoplasmic foci during BmNPV infection. Immunofluorescence studies confirmed that BmTRN-1 and BRO-B/E were colocalized in the amorphous conspicuous cytoplasmic foci. Reporter gene studies revealed that co-expression of BRO-B/E synergistically led to a significant decrease in protein synthesis from a designed transcript carrying the 5'untranslated region of a cellular mRNA with no significant change of transcript abundance. Additionally, RNA interference mediated knockdown of BmTRN-1 resulted in a marked inhibition of the ability of BRO-B/E to regulate the transcript. These results suggested that the association of BmTRN-1 with BRO-B/E is responsible for the inhibitory regulation of certain mRNAs at the post-transcriptional level and add an additional mechanism for how baculoviruses control protein synthesis during infection. PMID- 25834093 TI - Live attenuated simian immunodeficiency virus vaccination confers superinfection resistance against macrophage-tropic and neurovirulent wild-type SIV challenge. AB - Vaccination with live attenuated simian immunodeficiency virus (SIV) in non-human primate species provides a means of characterizing the protective processes of retroviral superinfection and may lead to novel advances of human immunodeficiency virus (HIV)/AIDS vaccine design. The minimally attenuated SIVmacC8 vaccine has been demonstrated to elicit early potent protection against pathogenic rechallenge with genetically diverse viral isolates in cynomolgus macaques (Macaca fascicularis). In this study, we have characterized further the biological breadth of this vaccine protection by assessing the ability of both the nef-disrupted SIVmacC8 and its nef-intact counterpart SIVmacJ5 viruses to prevent superinfection with the macrophage/neurotropic SIVmac239/17E-Fr (SIVmac17E-Fr) isolate. Inoculation with either SIVmacC8 or SIVmacJ5 and subsequent detailed characterization of the viral replication kinetics revealed a wide range of virus-host outcomes. Both nef-disrupted and nef-intact immunizing viruses were able to prevent establishment of SIVmac17E-Fr in peripheral blood and secondary lymphoid tissues. Differences in virus kinetics, indicative of an active process, identified uncontrolled replication in one macaque which although able to prevent SIVmac17E-Fr superinfection led to extensive neuropathological complications. The ability to prevent a biologically heterologous, CD4 independent/CCR5+ viral isolate and the macrophage-tropic SIVmac316 strain from establishing infection supports the hypothesis that direct target cell blocking is unlikely to be a central feature of live lentivirus vaccination. These data provide further evidence to demonstrate that inoculation of a live retroviral vaccine can deliver broad spectrum protection against both macrophage-tropic as well as lymphocytotropic viruses. These data add to our knowledge of live attenuated SIV vaccines but further highlight potential safety concerns of vaccinating with a live retrovirus. PMID- 25834095 TI - Egg yolk proteins and peptides with biological activity. AB - Many proteins of food reveal biological activity. In the sequence of these proteins also numerous biologically active peptides are encrypted. These peptides are released during proteolysis naturally occurring in the gastrointestinal tract, food fermentation or during designed enzymatic hydrolysis in vitro. Biopeptides may exert multiple activities, affecting the cardiovascular, endocrine, nervous and immune systems. An especially rich source of bioactive proteins and biopeptides is egg. Bioactive peptides released from egg white proteins have been well described, whereas egg yolk proteins as precursors of biopeptides are less well characterized. This manuscript describes biologically active proteins and peptides originating from egg yolk and presents their potential therapeutic role. PMID- 25834096 TI - [The hematological malignancies related to primary hypereosinophilia and their diagnostics]. AB - Published in 2008, by experts of the World Health Organization, the new classification of hematological malignancies forced a change of look at chromosomal aberrations and gene mutations, which are important in establishing the diagnosis and prognosis for patients with these malignancies. The new classification includes a new category of neoplasms - hematological malignancies with hypereosinophilia. Due to the high diversity of causes of hypereosinophilia and underlying genetic changes, their differential diagnosis is based on classical cytogenetics, fluorescence in situ hybridization (FISH) and genetic molecular techniques. Cytogenetic analysis of bone marrow cells showed that the majority of hypereosinophilia cases can be characterized by the presence of normal karyotype. Therefore, routine cytogenetic diagnostics should be complemented by FISH with break-apart probes for potentially rearranged genes (e.g., CBFB, ETV6) and unique probes for fusion genes (e.g., FIP1L1-PDGFRA), specific for hypereosinophilia-associated diseases. In differential diagnosis of hypereosinophilia, the analysis of characteristic gene mutations (e.g., cKIT) and gene fusions (e.g., ETV6-PDGFRB) is also applied, using molecular genetic methods. PMID- 25834097 TI - History-taking still the best diagnostic modality? The case of a threatening mass in the right ventricle. PMID- 25834098 TI - Large protruding thrombus over left atrial appendage occlusion device successfully treated with apixaban. PMID- 25834099 TI - Isolated venous thrombosis of inferior vena cava presenting Budd-Chiari syndrome associated with Behcet's disease. PMID- 25834100 TI - A large mass inside the left atrium? PMID- 25834101 TI - Watch out for the WATCHMAN. PMID- 25834102 TI - PIM1 regulates glycolysis and promotes tumor progression in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is characteristically one of the most rapidly proliferating tumors which outgrows functional blood supply and results in regional oxygen deprivation. Overexpression of PIM1, a serine/threonine kinase, has been identified recently in human cancers. Knowledge on PIM1 in HCC is however, scarce. By immunohistochemical analysis on 56 human primary HCC samples, we observed overexpression of PIM1 in 39% of the cases. In two independent cohorts of paired primary and extra-hepatic metastatic HCC tissues, PIM1 expression was higher (p=0.002) in the extra-hepatic metastatic HCC tissues as compared with the corresponding primary HCCs. PIM1 was markedly up-regulated in multiple HCC cell lines in hypoxic condition (1% O2) versus normoxia (20% O2). Silencing of PIM1 suppressed HCC cell invasion in vitro as compared to non-target control, and decreased HCC cell proliferation in vitro and tumor growth and metastatic potential in vivo. Knockdown of PIM1 significantly reduced glucose uptake by HCC cells and was associated with decreased levels of p-AKT and key molecules in the glycolytic pathway. Taken together, PIM1 is up-regulated by hypoxia in HCC and promotes tumor growth and metastasis through facilitating cancer cell glycolysis. Targeting PIM1 may have potential role in the management of HCC. PMID- 25834104 TI - EEG artifact removal-state-of-the-art and guidelines. AB - This paper presents an extensive review on the artifact removal algorithms used to remove the main sources of interference encountered in the electroencephalogram (EEG), specifically ocular, muscular and cardiac artifacts. We first introduce background knowledge on the characteristics of EEG activity, of the artifacts and of the EEG measurement model. Then, we present algorithms commonly employed in the literature and describe their key features. Lastly, principally on the basis of the results provided by various researchers, but also supported by our own experience, we compare the state-of-the-art methods in terms of reported performance, and provide guidelines on how to choose a suitable artifact removal algorithm for a given scenario. With this review we have concluded that, without prior knowledge of the recorded EEG signal or the contaminants, the safest approach is to correct the measured EEG using independent component analysis-to be precise, an algorithm based on second-order statistics such as second-order blind identification (SOBI). Other effective alternatives include extended information maximization (InfoMax) and an adaptive mixture of independent component analyzers (AMICA), based on higher order statistics. All of these algorithms have proved particularly effective with simulations and, more importantly, with data collected in controlled recording conditions. Moreover, whenever prior knowledge is available, then a constrained form of the chosen method should be used in order to incorporate such additional information. Finally, since which algorithm is the best performing is highly dependent on the type of the EEG signal, the artifacts and the signal to contaminant ratio, we believe that the optimal method for removing artifacts from the EEG consists in combining more than one algorithm to correct the signal using multiple processing stages, even though this is an option largely unexplored by researchers in the area. PMID- 25834103 TI - Lipin-1 regulates cancer cell phenotype and is a potential target to potentiate rapamycin treatment. AB - Lipogenesis inhibition was reported to induce apoptosis and repress proliferation of cancer cells while barely affecting normal cells. Lipins exhibit dual function as enzymes catalyzing the dephosphorylation of phosphatidic acid to diacylglycerol and as co-transcriptional regulators. Thus, they are able to regulate lipid homeostasis at several nodal points. Here, we show that lipin-1 is up-regulated in several cancer cell lines and overexpressed in 50 % of high grade prostate cancers. The proliferation of prostate and breast cancer cells, but not of non-tumorigenic cells, was repressed upon lipin-1 knock-down. Lipin-1 depletion also decreased cancer cell migration through RhoA activation. Lipin-1 silencing did not significantly affect global lipid synthesis but enhanced the cellular concentration of phosphatidic acid. In parallel, autophagy was induced while AKT and ribosomal protein S6 phosphorylation were repressed. We also observed a compensatory regulation between lipin-1 and lipin-2 and demonstrated that their co-silencing aggravates the phenotype induced by lipin-1 silencing alone. Most interestingly, lipin-1 depletion or lipins inhibition with propranolol sensitized cancer cells to rapamycin. These data indicate that lipin 1 controls main cellular processes involved in cancer progression and that its targeting, alone or in combination with other treatments, could open new avenues in anticancer therapy. PMID- 25834106 TI - Engineering as a new frontier for translational medicine. AB - The inclusion of engineering ideas and approaches makes medicine a quantitative and systems-based discipline that facilitates precision diagnostics and therapeutics to improve health care delivery for all. PMID- 25834105 TI - Compliant intracortical implants reduce strains and strain rates in brain tissue in vivo. AB - OBJECTIVE: The objective of this research is to characterize the mechanical interactions of (1) soft, compliant and (2) non-compliant implants with the surrounding brain tissue in a rodent brain. Understanding such interactions will enable the engineering of novel materials that will improve stability and reliability of brain implants. APPROACH: Acute force measurements were made using a load cell in n = 3 live rats, each with 4 craniotomies. Using an indentation method, brain tissue was tested for changes in force using established protocols. A total of 4 non-compliant, bare silicon microshanks, 3 non-compliant polyvinyl acetate (PVAc)-coated silicon microshanks, and 6 compliant, nanocomposite microshanks were tested. Stress values were calculated by dividing the force by surface area and strain was estimated using a linear stress-strain relationship. Micromotion effects from breathing and vascular pulsatility on tissue stress were estimated from a 5 s interval of steady-state measurements. Viscoelastic properties were estimated using a second-order Prony series expansion of stress displacement curves for each shank. MAIN RESULTS: The distribution of strain values imposed on brain tissue for both compliant nanocomposite microshanks and PVAc-coated, non-compliant silicon microshanks were significantly lower compared to non-compliant bare silicon shanks. Interestingly, step-indentation experiments also showed that compliant, nanocomposite materials significantly decreased stress relaxation rates in the brain tissue at the interface (p < 0.05) compared to non-compliant silicon and PVAc-coated silicon materials. Furthermore, both PVAc-coated non-compliant silicon and compliant nanocomposite shanks showed significantly reduced (by 4-5 fold) stresses due to tissue micromotion at the interface. SIGNIFICANCE: The results of this study showed that soft, adaptive materials reduce strains and strain rates and micromotion induced stresses in the surrounding brain tissue. Understanding the material behavior at the site of tissue contact will help to improve neural implant design. PMID- 25834107 TI - Developing vaccines for an aging population. AB - The demographics of the world's population are changing, with many adults now surviving into their 80s. With this change comes the need to protect the aging and other underserved populations not only against infectious diseases but also against cancer and other chronic conditions. New technologies derived from recent advances in the fields of immunology, structural biology, synthetic biology, and genomics have brought a revolution in the vaccine field. Among them, vaccine adjuvants have the potential to harness the immune system to provide protection against new types of diseases, improve protection in young children, and expand this protection to adults and the elderly. However, in order to do so we need also to overcome the nontechnical challenges that could limit the implementation of innovative vaccines, including controversies regarding the safety of adjuvants, increasing regulatory complexity, the inadequate methods used to assess the value of novel vaccines, and the resulting industry alienation from future investment. This Perspective summarizes the outcome of a recent multidisciplinary symposium entitled "Enhancing Vaccine Immunity and Value," held in Siena, Italy, in July 2014, that addressed two related questions: how to improve vaccine efficacy by using breakthrough technologies and how to capture the full potential of novel vaccines. PMID- 25834108 TI - G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease. AB - Granulocyte colony-stimulating factor (G-CSF) is routinely used to collect peripheral blood stem cells (PBSCs) from healthy donors for allogeneic hematopoietic stem cell transplantation (allo-HSCT). We show that, in both humans and mice, G-CSF mobilizes a subset of CD34(+) cells with mature monocyte features. These cells, which are phenotypically and functionally conserved in mice and humans, are transcriptionally distinct from myeloid and monocytic precursors but similar to mature monocytes and endowed with immunosuppressive properties. In response to interferon-gamma released by activated T cells, these cells produce nitric oxide, which induces allogeneic T cell death both in vitro and in vivo. These apoptotic T cells are engulfed by macrophages that release transforming growth factor-beta and promote regulatory T cell expansion. Indeed, the fraction of CD34(+) monocytes in peripheral blood CD34(+) cells inversely correlates with the incidence of acute graft-versus-host disease (GVHD) in humans. Therefore, G-CSF-mobilized cells are an attractive candidate population to be expanded ex vivo for cellular therapy against GVHD. PMID- 25834110 TI - An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth. AB - EphB receptors regulate the proliferation and positioning of intestinal stem and progenitor cells. In addition, they can act as tumor promoters for adenoma development but suppress progression to invasive carcinoma. We used imatinib to abrogate Abl kinase activity in Apc(Min/+) mice and in mice with LGR5(+) stem cells that were genetically engineered to develop adenomatous polyposis coli. Imatinib treatment inhibited the tumor-promoting effects of EphB signaling without attenuating EphB-mediated tumor suppression, demonstrating a role for EphB signaling in the initiation of intestinal tumors. The imatinib treatment regimen extended the life span of Apc(Min/+) mice and reduced cell proliferation in cultured slices of adenomas from patients with familial adenomatous polyposis. These findings connect the EphB signaling pathway to the regulation of intestinal adenoma initiation via Abl kinase. Our findings may have clinical implications for pharmacological therapy against adenoma formation and cancer progression in patients predisposed to develop colorectal cancer. PMID- 25834109 TI - Cytomegalovirus infection enhances the immune response to influenza. AB - Cytomegalovirus (CMV) is a beta-herpesvirus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli, and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down regulation of immune components in aged individuals regardless of CMV status. In contrast, CMV-seropositive young adults exhibited enhanced antibody responses to influenza vaccination, increased CD8(+) T cell sensitivity, and elevated levels of circulating interferon-gamma compared to seronegative individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the ubiquity of CMV infection in humans and many other species. PMID- 25834114 TI - Endovascular medicine certification 2005-2014: report from the American Board of Vascular Medicine. AB - This report describes the methods used to develop and maintain the endovascular medicine certification examination, which has been offered by the American Board of Vascular Medicine (ABVM) to practicing physicians since 2005. The report covers the methods and findings used to develop examination specifications which ensure the content and construct validity of the examination assessment such that the examination is reflective of the job tasks associated with the endovascular medicine specialty, as well as being a meaningful indicator of whether a candidate possesses the knowledge and skills necessary for competent practice. Further, this report covers the procedures used to develop, maintain, and administer the examination, including a summary of the content review process and the use of statistical information. Based on psychometric evaluation of the examination's performance, the ABVM's endovascular medicine examination appears to be a valid assessment of professional competency in the specialty area; a finding that supports the inference that candidates who pass the examination are qualified to practice in a manner that protects patients. PMID- 25834113 TI - Evaluation of focused multipolar stimulation for cochlear implants in long-term deafened cats. AB - OBJECTIVE: Focused multipolar (FMP) stimulation has been shown to produce restricted neural activation using intracochlear stimulation in animals with a normal population of spiral ganglion neurons (SGNs). However, in a clinical setting, the widespread loss of SGNs and peripheral fibres following deafness is expected to influence the effectiveness of FMP. APPROACH: We compared the efficacy of FMP stimulation to both monopolar (MP) and tripolar (TP) stimulation in long-term deafened cat cochleae (n = 8). Unlike our previous study, these cochleae contained <10% of the normal SGN population adjacent to the electrode array. We also evaluated the effect of electrode position on stimulation modes by using either modiolar facing or lateral wall facing half-band electrodes. The spread of neural activity across the inferior colliculus, a major nucleus within the central auditory pathway, was used as a measure of spatial selectivity. MAIN RESULTS: In cochleae with significant SGN degeneration, we observed that FMP and TP stimulation resulted in greater spatial selectivity than MP stimulation (p < 0.001). However, thresholds were significantly higher for FMP and TP stimulation compared to MP stimulation (p < 0.001). No difference between FMP and TP stimulation was found in any measures. The high threshold levels for FMP stimulation was significantly reduced without compromising spatial selectivity by varying the degree of current focusing (referred as 'partial-FMP' stimulation). Spatial selectivity of all stimulation modes was unaffected by the electrode position. Finally, spatial selectivity in long-term deafened cochleae was significantly less than that of cochleae with normal SGN population (George S S et al 2014 J. Neural Eng. 11 065003). SIGNIFICANCE: The present results indicate that the greater spatial selectivity of FMP and TP stimulation over MP stimulation is maintained in cochleae with significant neural degeneration and is not adversely affected by electrode position. The greater spatial selectivity of FMP and TP stimulation would be expected to result in improved clinical performance. PMID- 25834116 TI - Images in vascular medicine. Abdominal aorta mycotic pseudoaneurysm with rapid growth. PMID- 25834115 TI - The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data. AB - The purpose of this study was to evaluate the accuracy of using a combination of International Classification of Diseases (ICD) diagnostic codes and imaging procedure codes for identifying deep vein thrombosis (DVT) and pulmonary embolism (PE) within administrative databases. Information from the Alberta Health (AH) inpatients and ambulatory care administrative databases in Alberta, Canada was obtained for subjects with a documented imaging study result performed at a large teaching hospital in Alberta to exclude venous thromboembolism (VTE) between 2000 and 2010. In 1361 randomly-selected patients, the proportion of patients correctly classified by AH administrative data, using both ICD diagnostic codes and procedure codes, was determined for DVT and PE using diagnoses documented in patient charts as the gold standard. Of the 1361 patients, 712 had suspected PE and 649 had suspected DVT. The sensitivities for identifying patients with PE or DVT using administrative data were 74.83% (95% confidence interval [CI]: 67.01 81.62) and 75.24% (95% CI: 65.86-83.14), respectively. The specificities for PE or DVT were 91.86% (95% CI: 89.29-93.98) and 95.77% (95% CI: 93.72-97.30), respectively. In conclusion, when coupled with relevant imaging codes, VTE diagnostic codes obtained from administrative data provide a relatively sensitive and very specific method to ascertain acute VTE. PMID- 25834117 TI - The Notch pathway is a critical regulator of angiogenesis in a skin model of ischemia. AB - The Notch pathway is definitely required for normal vascular development. Although the contribution of Notch in postnatal angiogenesis is the focus of intense investigation, the implication of Notch in reparative neovascularization in the skin remains unexplored. In this study, we investigated Notch changes using a skin model of ischemia. Thirty Sprague-Dawley rats were divided into two groups. In the surgery group (n = 24), a caudally based dorsal skin flap was raised and sutured back into its initial position. In the control group, no surgical procedure was performed. Tissue biopsies were obtained at different time intervals. Tissue specimens were assessed for Delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF) gene expression by real-time polymerase chain reaction (PCR). Immunohistochemical staining was used for detection of DLL4 in tissue materials. Quantitative assessment of skin flap microvasculature was made. Compared with normoperfused tissue, VEGF and DLL4 expressions increased significantly (p < 0.01). Immunohistochemical analysis revealed weak and patchy expression of DLL4 in microvascular endothelial cells of normoperfused tissues. Conversely, DLL4 expression was upregulated in capillary endothelial cells after ischemia. In conclusion, in this study we have shown that the Notch ligand DLL4 is upregulated in skin tissue after ischemia. A deeper understanding of these fundamental principles will aid in the development of new avenues for the treatment of blood vessel-related skin pathologies. PMID- 25834112 TI - Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. AB - Clonal evolution in cancer-the selection for and emergence of increasingly malignant clones during progression and therapy, resulting in cancer metastasis and relapse-has been highlighted as an important phenomenon in the biology of leukemia and other cancers. Tracking mutant alleles to determine clonality from diagnosis to relapse or from primary site to metastases in a sensitive and quantitative manner is most often performed using next-generation sequencing. Such methods determine clonal frequencies by extrapolation of allele frequencies in sequencing data of DNA from the metagenome of bulk tumor samples using a set of assumptions. The computational framework that is usually used assumes specific patterns in the order of acquisition of unique mutational events and heterozygosity of mutations in single cells. However, these assumptions are not accurate for all mutant loci in acute myeloid leukemia (AML) samples. To assess whether current models of clonal diversity within individual AML samples are appropriate for common mutations, we developed protocols to directly genotype AML single cells. Single-cell analysis demonstrates that mutations of FLT3 and NPM1 occur in both homozygous and heterozygous states, distributed among at least nine distinct clonal populations in all samples analyzed. There appears to be convergent evolution and differential evolutionary trajectories for cells containing mutations at different loci. This work suggests an underlying tumor heterogeneity beyond what is currently understood in AML, which may be important in the development of therapeutic approaches to eliminate leukemic cell burden and control clonal evolution-induced relapse. PMID- 25834111 TI - Neuregulin stimulation of cardiomyocyte regeneration in mice and human myocardium reveals a therapeutic window. AB - Therapies developed for adult patients with heart failure have been shown to be ineffective in pediatric clinical trials, leading to the recognition that new pediatric-specific therapies for heart failure must be developed. Administration of the recombinant growth factor neuregulin-1 (rNRG1) stimulates regeneration of heart muscle cells (cardiomyocytes) in adult mice. Because proliferation competent cardiomyocytes are more abundant in growing mammals, we hypothesized that administration of rNRG1 during the neonatal period might be more effective than in adulthood. If so, neonatal rNRG1 delivery could be a new therapeutic strategy for treating heart failure in pediatric patients. To evaluate the effectiveness of rNRG1 administration in cardiac regeneration, newborn mice were subjected to cryoinjury, which induced myocardial dysfunction and scar formation and decreased cardiomyocyte cell cycle activity. Early administration of rNRG1 to mice from birth to 34 days of age improved myocardial function and reduced the prevalence of transmural scars. In contrast, administration of rNRG1 from 4 to 34 days of age only transiently improved myocardial function. The mechanisms of early administration involved cardiomyocyte protection (38%) and proliferation (62%). We also assessed the ability of rNRG1 to stimulate cardiomyocyte proliferation in intact cultured myocardium from pediatric patients. rNRG1 induced cardiomyocyte proliferation in myocardium from infants with heart disease who were less than 6 months of age. Our results identify an effective time period within which to execute rNRG1 clinical trials in pediatric patients for the stimulation of cardiomyocyte regeneration. PMID- 25834118 TI - A hybrid BCI based on EEG and fNIRS signals improves the performance of decoding motor imagery of both force and speed of hand clenching. AB - OBJECTIVE: In order to increase the number of states classified by a brain computer interface (BCI), we utilized a motor imagery task where subjects imagined both force and speed of hand clenching. APPROACH: The BCI utilized simultaneously recorded electroencephalographic (EEG) and functional near infrared spectroscopy (fNIRS) signals. The time-phase-frequency feature was extracted from EEG, whereas the HbD [the difference of oxy-hemoglobin (HbO) and deoxy-hemoglobin (Hb)] feature was used to improve the classification accuracy of fNIRS. The EEG and fNIRS features were combined and optimized using the joint mutual information (JMI) feature selection criterion; then the extracted features were classified with the extreme learning machines (ELMs). MAIN RESULTS: In this study, the averaged classification accuracy of EEG signals achieved by the time phase-frequency feature improved by 7%, to 18%, more than the single-type feature, and improved by 15% more than common spatial pattern (CSP) feature. The HbD feature of fNIRS signals improved the accuracy by 1%, to 4%, more than Hb, HbO, or HbT (total hemoglobin). The EEG-fNIRS feature for decoding motor imagery of both force and speed of hand clenching achieved an accuracy of 89% +/- 2%, and improved the accuracy by 1% to 5% more than the sole EEG or fNIRS feature. SIGNIFICANCE: Our novel motor imagery paradigm improves BCI performance by increasing the number of extracted commands. Both the time-phase-frequency and the HbD feature improve the classification accuracy of EEG and fNIRS signals, respectively, and the hybrid EEG-fNIRS technique achieves a higher decoding accuracy for two-class motor imagery, which may provide the framework for future multi-modal online BCI systems. PMID- 25834120 TI - Human pluripotent stem cell-derived radial glia recapitulate developmental events and provide real-time access to cortical neurons and astrocytes. AB - Studies of human cerebral cortex development are limited by difficulties in accessing and manipulating human neural tissue at specific development stages. We have derived human radial glia (hRG), which are responsible for most cerebral cortex neurogenesis, from human pluripotent stem cells. These hRG display the hallmark morphological, cellular, and molecular features of radial glia in vitro. They can be passaged and generate layer-specific subtypes of cortical neurons in a temporal and passage-dependent fashion. In later passages, they adopt a distinct progenitor phenotype that gives rise to cortical astrocytes and GABAergic interneurons. These hRG are also capable of following developmental cues to engraft, differentiate, migrate, and integrate into the embryonic mouse cortex when injected into E14 lateral ventricles. Moreover, hRG-derived cells can be cryopreserved at specific stages and retain their stage-specific phenotypes and competence when revived. Our study demonstrates that cultured hRG maintain a cell-intrinsic clock that regulates the progressive generation of stage-specific neuronal and glial subtypes. It also describes an easily accessible cell source for studying hRG lineage specification and progression and an on-demand supply of specific cortical neuron subtypes and astrocytes. PMID- 25834119 TI - Inhibition of an NAD+ salvage pathway provides efficient and selective toxicity to human pluripotent stem cells. AB - The tumorigenic potential of human pluripotent stem cells (hPSCs) is a major limitation to the widespread use of hPSC derivatives in the clinic. Here, we demonstrate that the small molecule STF-31 is effective at eliminating undifferentiated hPSCs across a broad range of cell culture conditions with important advantages over previously described methods that target metabolic processes. Although STF-31 was originally described as an inhibitor of glucose transporter 1, these data support the reclassification of STF-31 as a specific NAD+ salvage pathway inhibitor through the inhibition of nicotinamide phosphoribosyltransferase (NAMPT). These findings demonstrate the importance of an NAD+ salvage pathway in hPSC biology and describe how inhibition of NAMPT can effectively eliminate hPSCs from culture. These results will advance and accelerate the development of safe, clinically relevant hPSC-derived cell-based therapies. PMID- 25834121 TI - Delayed minimally invasive injection of allogenic bone marrow stromal cell sheets regenerates large bone defects in an ovine preclinical animal model. AB - Cell-based tissue engineering approaches are promising strategies in the field of regenerative medicine. However, the mode of cell delivery is still a concern and needs to be significantly improved. Scaffolds and/or matrices loaded with cells are often transplanted into a bone defect immediately after the defect has been created. At this point, the nutrient and oxygen supply is low and the inflammatory cascade is incited, thus creating a highly unfavorable microenvironment for transplanted cells to survive and participate in the regeneration process. We therefore developed a unique treatment concept using the delayed injection of allogenic bone marrow stromal cell (BMSC) sheets to regenerate a critical-sized tibial defect in sheep to study the effect of the cells' regeneration potential when introduced at a postinflammatory stage. Minimally invasive percutaneous injection of allogenic BMSCs into biodegradable composite scaffolds 4 weeks after the defect surgery led to significantly improved bone regeneration compared with preseeded scaffold/cell constructs and scaffold-only groups. Biomechanical testing and microcomputed tomography showed comparable results to the clinical reference standard (i.e., an autologous bone graft). To our knowledge, we are the first to show in a validated preclinical large animal model that delayed allogenic cell transplantation can provide applicable clinical treatment alternatives for challenging bone defects in the future. PMID- 25834123 TI - Susceptibility-weighted imaging in parenchymal neurosyphilis: identification of a new MRI finding. AB - BACKGROUND: General paresis (GP) is a late form of parenchymal neurosyphilis causing dementia and neuropsychiatric disorders. The diagnosis is often difficult since the clinical signs are protean. So far, neuroimaging has played a minor role as radiological findings are not specific. METHODS: We studied three immunocompetent patients, admitted to hospital for cognitive impairment. The diagnosis of neurosyphilis was formulated on the basis of serological texts and cerebrospinal fluid analysis. The patients underwent a 3 T MR examination including susceptibility-weighted imaging (SWI) sequence before and after the initiation of penicillin therapy. RESULTS: In all patients, SWI revealed cortical hypointensity, mostly distributed in frontal and temporal lobes. In drug-naive patients, the hypointensity extended over the whole cortical thickness, from the cortical/subcortical junction to the pial surface. After starting the penicillin therapy, the cortical hypointensity partially reversed, involving only the deep cortical layers. CONCLUSIONS: The MRI pattern at SWI observed in patients with GP was not reported in other infectious or inflammatory disease of the central nervous system, thus we suggest it could be a peculiar radiological finding of the disease. On the basis of previous pathological data, we hypothesise that cortical SWI hypointensity could be expression of iron deposits within activated microglia. PMID- 25834122 TI - High prevalence of sexually transmitted infections in pregnant adolescent girls in Tanzania: a multi-community cross-sectional study. AB - BACKGROUND: Limited data document sexually transmitted infections (STIs) among pregnant adolescents in sub-Saharan Africa, where prenatal screening typically includes only HIV and syphilis. Given that HIV incidence in this population is among the world's highest, we sought to assess the prevalence and factors associated with STIs in a population of rural pregnant adolescents in Tanzania. METHODS: We enrolled 403 pregnant adolescent girls from 10 antenatal clinics near Mwanza, Tanzania. Girls answered structured interviews about sexual health and risk factors and were tested for six common STIs. RESULTS: 199 girls (49.4%) had at least one STI. Herpes Simplex Virus- Type 2 was most prevalent (139 girls, 34.5%), followed by trichomoniasis (54 girls, 13.4%), chlamydia (46 girls, 11.4%), gonorrhoea (27 girls, 6.7%), syphilis (21 girls, 5.2%) and HIV (30 girls, 4.7%). Of note, 53/199 (26.6%) of girls with laboratory-proven STIs were asymptomatic. On multivariable analysis, the presence of any STI was associated with being in a long-term (as opposed to short-term) relationship (OR=2.6 (1.4 to 4.9) p=0.004), younger age at first sexual debut (OR=0.9 per year (0.8 to 0.99), p=0.034), increasing age difference between the girl and her partner (OR=1.1 (1.0 to 1.1) per year, p=0.03) and history of prior pregnancy (OR=1.6 (1.0 to 2.6), p=0.04). CONCLUSIONS: STIs affected half of rural pregnant adolescents in Tanzania. Our work demonstrates the urgent need to incorporate routine STI testing into antenatal care in Tanzania to prevent morbidity and mortality in young girls and their babies. We also identify behavioural and demographic risk factors that can be used to target interventions to those at highest risk. PMID- 25834124 TI - Utility of the transcervical approach in bilateral synchronous lung cancer. AB - Bilateral pulmonary nodules represent a challenge in distinguishing between synchronous bronchogenic carcinomas and metastatic disease. In the case of potentially curable synchronous lung cancer, it is recommended to treat each lesion with curative intent if there is no evidence of mediastinal involvement or extrathoracic disease. In this situation, surgical staging of the mediastinum is recommended. This case shows the utility of a transcervical approach to perform precise mediastinal staging and lymphadenectomy, and to access the pleural cavity to resect a pulmonary nodule. Moreover, video-assisted mediastinoscopic lymphadenectomy combined with video-assisted lobectomy could be a good option for a radical lymphadenectomy. PMID- 25834125 TI - Dealing with a left ventricular pseudoaneurysm during assist device implant. AB - Despite increasing use of left ventricular devices for the surgical treatment of heart failure, there is limited experience with implantation of devices in the setting of challenging left apical anatomy. We report the case of a 68-year-old man with a chronic post-infarction calcified apical pseudoaneurysm, who underwent pseudoaneurysmectomy, ventricular myoplasty, and left ventricular assist device implantation. A review of the literature and operative strategies are presented. PMID- 25834126 TI - Multiple pulmonary arteriovenous malformations. PMID- 25834127 TI - A malpositioned chest tube within the liver. PMID- 25834128 TI - Brains and brawn in academe: we ain't come to play SCHOOL! PMID- 25834129 TI - Retinoids are back. PMID- 25834130 TI - Corrigendum. PMID- 25834131 TI - Mechanisms of disease: paracine effects of adipose tissue, progenitor cell function, and epigenetics of diabetic vascular disease. PMID- 25834132 TI - Hotlines in the European Heart Journal: new and novel features. PMID- 25834133 TI - Trichotillomania: Impulsive, compulsive or both? PMID- 25834134 TI - Manic illness associated with right temporo-thalamic arteriovenous malformation: A rare presentation. PMID- 25834135 TI - New-onset trichotillomania in a 50-year-old patient. PMID- 25834136 TI - The bupropion-related subcortical changes in a depression patient. PMID- 25834137 TI - Re: "Coffee Consumption and Mortality From all Causes, Cardiovascular Disease, and Cancer: A Dose-Response Meta-Analysis". PMID- 25834139 TI - A dynamic panel model of the associations of sweetened beverage purchases with dietary quality and food-purchasing patterns. AB - Investigating the association between consumption of sweetened beverages and dietary quality is challenging because issues such as reverse causality and unmeasured confounding might result in biased and inconsistent estimates. Using a dynamic panel model with instrumental variables to address those issues, we examined the independent associations of beverages sweetened with caloric and low calorie sweeteners with dietary quality and food-purchasing patterns. We analyzed purchase data from the Homescan survey, an ongoing, longitudinal, nationally representative US survey, from 2000 to 2010 (n = 34,294). Our model included lagged measures of dietary quality and beverage purchases (servings/day in the previous year) as exposures to predict the outcomes (macronutrient (kilocalories per capita per day; %), total energy, and food purchases) in the next year after adjustment for other sociodemographic covariates. Despite secular declines in purchases (kilocalories per capita per day) from all sources, each 1-serving/day increase in consumption of either beverage type resulted in higher purchases of total daily kilocalories and kilocalories from food, carbohydrates, total sugar, and total fat. Each 1-serving/day increase in consumption of either beverage was associated with more purchases of caloric-sweetened desserts or sweeteners, which accounted for a substantial proportion of the increase in total kilocalories. We concluded that consumers of both beverages sweetened with low-calorie sweeteners and beverages sweetened with caloric sweeteners had poorer dietary quality, exhibited higher energy from all purchases, sugar, and fat, and purchased more caloric-sweetened desserts/caloric sweeteners compared with nonconsumers. PMID- 25834138 TI - Violent Victimization, Mental Health, and Service Utilization Outcomes in a Cohort of Homeless and Unstably Housed Women Living With or at Risk of Becoming Infected With HIV. AB - Most studies about the association between exposure to violence and higher psychological vulnerability have been cross-sectional in nature. Using longitudinal data from the Shelter, Health, and Drug Outcomes Among Women Study on 300 homeless or unstably housed women infected with or at risk of becoming infected with human immunodeficiency virus who were living in San Francisco, California, in 2008-2012, we examined the relationship between recent violent victimization and mental health status, mental health-related emergency department visits, and psychiatric hospitalization. We used generalized estimating equations to account for potentially confounding time-invariant and time-varying variables, including comorbid psychiatric conditions and lifetime history of child abuse. A total of 207 (69%) women experienced childhood abuse. The median number of psychiatric diagnoses per woman at baseline was 8 (interquartile range, 5-11). Recent exposure to violence was associated with lower mental health status (b = -1.85, 95% confidence interval: -3.02, -0.68) and higher risks of mental health-related emergency department visits (adjusted risk ratio = 2.96, 95% confidence interval: 1.51, 5.78) and psychiatric hospitalizations (adjusted risk ratio = 2.32, 95% confidence interval: 1.10, 4.91). We did not find strong evidence of a reciprocal relationship. Among homeless or unstably housed women with severe preexisting comorbid psychiatric conditions, recent violence has adverse mental health consequences. Reducing ongoing violence may improve mental health in this population. PMID- 25834140 TI - Two-Year Outcomes After Arthroscopic Rotator Cuff Repair in Recreational Athletes Older Than 70 Years. AB - BACKGROUND: Outcomes after arthroscopic rotator cuff repair in recreational athletes older than 70 years are not widely reported. PURPOSE: To evaluate clinical outcomes after arthroscopic repair of full-thickness rotator cuff tears in recreational athletes aged 70 years or older. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Institutional review board approval was obtained before initiation of this study. Data were collected prospectively and were retrospectively reviewed. From December 2005 to August 2012, patients who were at least 70 years of age, who described themselves as recreational athletes, and who underwent a primary or revision arthroscopic repair of full-thickness supraspinatus tears by a single surgeon were identified from a surgical registry. Demographic data, surgical data, and the following pre- and postoperative clinical outcomes scores were collected: American Shoulder and Elbow Surgeons (ASES), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), Short Form 12 Physical Component Summary (SF-12 PCS), and Single Assessment Numeric Evaluation (SANE). Acromiohumeral distance and Goutallier classifications were recorded. Patient satisfaction (range, 1-10, 10 = best) and reasons for activity modification were collected at final follow-up. RESULTS: Forty-nine shoulders (44 patients) were included. The mean age was 73 years (range, 70-82 years). There were 33 men and 11 women (5 bilateral). The mean preoperative acromiohumeral distance was 9.2 mm (range, 3.0-15.9 mm). All patients had Goutallier classifications of 0, 1, or 2. Mean follow-up was 3.6 years (range, 2.0-6.9 years) in 43 of 49 (88%) shoulders. No rotator cuff repairs were revised, however, 1 patient had surgical treatment for stiffness. All postoperative outcomes measures demonstrated significant improvements when compared with their preoperative baselines. The mean ASES score was 90.3 (range, 60-100), the mean SANE score was 85.1 (range, 29-100), the mean QuickDASH score was 11.3 (0-50), and the mean SF-12 PCS score was 51.6 (range, 38-58) with a median patient satisfaction of 10 (range, 1-10). Patients who modified their recreational activities due to postoperative weakness were significantly less satisfied (P = .018). In this study, 24 of 31 (77%) who responded were able to return to their sport at a similar level of intensity. CONCLUSION: Arthroscopic rotator cuff repair was highly effective at reducing pain, improving function, and returning patients to sport in recreational athletes 70 years of age and older. PMID- 25834141 TI - Response to: 'Concerns about report suggesting glucosamine and chondroitin protect against cartilage loss' by Felson. PMID- 25834142 TI - Ultrasound-detected inflammation predicts radiographic progression in hand osteoarthritis after 5 years. AB - OBJECTIVE: To examine whether ultrasound predicts radiographic hand osteoarthritis (OA) progression after 5 years. METHODS: We included 78 participants (71 women, mean (SD) age 67.8 (5.2) years) from the Oslo Hand OA cohort with ultrasound examination (gray-scale (GS) synovitis and power Doppler (PD) signals) at baseline and conventional radiographs and clinical examination at baseline and 5-year follow-up. Radiographic progression was defined as an increase in global OA according to the Kellgren-Lawrence (KL) scale or progression of individual radiographic OA features. We examined whether baseline ultrasound features and clinical examination predicted radiographic progression using generalised estimating equations, adjusted for age, sex, body mass index and follow-up time. RESULTS: Radiographic progression occurred in 17.9% joints for KL, 12.1% for joint space narrowing, 11.7% for osteophytes and 4.5% for erosions. Ultrasound-detected inflammation predicted KL progression, and dose response associations were observed for GS synovitis grade 1 (OR=2.8, 95% CI 1.8 to 4.2), grade 2 (OR=3.6, 95% CI 2.2 to 5.8) and grade 3 (OR=15.2, 95% CI 6.9 to 33.6), and for PD signal grade 1 (OR=2.9, 95% CI 1.2 to 6.8) and grades 2-3 (OR=12.0, 95% CI 3.5 to 41.0). Significant associations were also observed between ultrasound inflammation and progression of all individual radiographic features, and between clinical soft tissue swelling at baseline and radiographic progression. CONCLUSIONS: Ultrasound-detected GS synovitis and PD signals were significantly associated with radiographic progression after 5 years. This study supports the use of ultrasound as a tool to detect patients with hand OA who are likely to progress. PMID- 25834143 TI - Helicobacter pylori induces IL-1beta and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway. AB - This study investigated whether Helicobacter pylori could activate the nucleotide binding oligomerization domain-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome in human macrophages and the involvement of reactive oxygen species (ROS) in inflammasome activation. Phorbol-12-myristate-13 acetate (PMA)-differentiated human acute monocytic leukemia cell line THP-1 was infected with H. pylori. The levels of pro-inflammatory cytokines interleukin (IL)-1beta and IL-18 in supernatant were measured by ELISA. Intracellular ROS level was analyzed by flow cytometry. Quantitative real-time PCR and western blot analysis were employed to determine the mRNA and protein expression levels of NLRP3 and caspase-1 in THP-1 cells, respectively. Our results showed that H. pylori infection could induce IL-1beta and IL-18 production in PMA-differentiated THP-1 cells in a dose- and time-dependent manner. Moreover, secretion of IL-1beta and IL-18 in THP-1 cells following H. pylori infection was remarkably reduced by NLRP3-specific small interfering RNA treatment. In addition, the intracellular ROS level was elevated by H. pylori infection, which could be eliminated by the ROS scavenger N-acetylcysteine (NAC). Furthermore, NAC treatment could inhibit NLRP3 inflammasome formation and caspase-1 activation and suppress the release of IL-1beta and IL-18 from H. pylori-infected THP-1 cells. These findings provide novel insights into the innate immune response against H. pylori infection, which could potentially be used for the prevention and treatment of H. pylori-related diseases. PMID- 25834144 TI - Leptospira interrogans reduces fibrin clot formation by modulating human thrombin activity via exosite I. AB - Pathogenic bacteria of the genus Leptospira are the etiological agents of leptospirosis, a disease that affects humans and animals worldwide. Although there are an increasing number of studies on the biology of Leptospira, the mechanisms of pathogenesis are not yet understood. We report in this work that Leptospira interrogans FIOCRUZ L1-130 virulent, M20 culture attenuated and the saprophyte L. biflexa Patoc 1 strains do not bind prothrombin. Leptospiral binding to thrombin was detected with the virulent, followed by culture attenuated M20, and practically none was observed with the saprophyte strain. The interaction of Leptospira with thrombin mostly occurs via exosite I, with a minor participation of catalytic site, as determined by employing the thrombin inhibitors hirugen, hirudin and argatroban. Leptospira interrogans binding to thrombin inhibits its catalytic activity reducing fibrin clot formation in thrombin-catalyzed reaction of fibrinogen. This inhibition was more efficient with the virulent FIOCRUZ L1-130 than with the M20 culture attenuated, while none was seen with the saprophyte strain, suggesting that this binding might be important for bacterial virulence. This is the first study reporting the binding of pathogenic Leptospira to thrombin promoting a decrease in fibrin clotting that could lead to hemorrhage, helping bacteria dissemination. PMID- 25834147 TI - Prevalence of major risk factors and use of screening tests for cancer in the United States. AB - Much of the suffering and death from cancer could be prevented by more systematic efforts to reduce tobacco use, improve diet, increase physical activity, reduce obesity, and expand the use of established screening tests. Monitoring the prevalence of cancer risk factors and screening is important to measure progress and strengthen cancer prevention and early detection efforts. In this review article, we provide recent prevalence estimates for several cancer risk factors, including tobacco, obesity, physical activity, nutrition, ultraviolet radiation exposure as well as human papillomavirus and hepatitis B vaccination coverage and cancer screening prevalence in the United States. In 2013, cigarette smoking prevalence was 17.8% among adults nationally, but ranged from 10.3% in Utah to 27.3% in West Virginia. In addition, 15.7% of U.S. high school students were current smokers. In 2011-2012, obesity prevalence was high among both adults (34.9%) and adolescents (20.5%), but has leveled off since 2002. About 20.2% of high school girls were users of indoor tanning devices, compared with 5.3% of boys. In 2013, cancer screening prevalence ranged from 58.6% for colorectal cancer to 80.8% for cervical cancer and remains low among the uninsured, particularly for colorectal cancer screening where only 21.9% of eligible adults received recommended colorectal cancer screening. PMID- 25834145 TI - Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer associated fibroblasts abrogates pancreatic tumour chemoresistance. AB - Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of alpha-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential. PMID- 25834148 TI - Survivors of childhood cancer in the United States: prevalence and burden of morbidity. AB - BACKGROUND: No studies have estimated the population-level burden of morbidity in individuals diagnosed with cancer as children (ages 0-19 years). We updated prevalence estimates of childhood cancer survivors as of 2011 and burden of morbidity in this population reflected by chronic conditions, neurocognitive dysfunction, compromised health-related quality of life, and health status (general health, mental health, functional impairment, functional limitations, pain, and fear/anxiety). METHODS: Surveillance, Epidemiology, and End Results (SEER) Program data from 1975 to 2011 were used to update the prevalence of survivors of childhood cancers in the United States. Childhood Cancer Survivor Study data were used to obtain estimates of morbidity burden indicators, which were then extrapolated to SEER data to obtain population-level estimates. RESULTS: There were an estimated 388,501 survivors of childhood cancer in the United States as of January 1, 2011, of whom 83.5% are >=5 years after diagnosis. The prevalence of any chronic condition among >=5-year survivors ranged from 66% (ages 5-19) to 88% (ages 40-49). Estimates for specific morbidities ranged from 12% (pain) to 35% (neurocognitive dysfunction). Generally, morbidities increased by age. However, mental health and anxiety remained fairly stable, and neurocognitive dysfunction exhibited initial decline and then remained stable by time since diagnosis. CONCLUSIONS: The estimated prevalence of survivors of childhood cancer is increasing, as is the estimated prevalence of morbidity in those >=5 years after diagnosis. IMPACT: Efforts to understand how to effectively decrease morbidity burden and incorporate effective care coordination and rehabilitation models to optimize longevity and well-being in this population should be a priority. PMID- 25834169 TI - Neonatal outcomes and delivery of care for infants born late preterm or moderately preterm: a prospective population-based study. AB - OBJECTIVE: To describe neonatal outcomes and explore variation in delivery of care for infants born late (34-36 weeks) and moderately (32-33 weeks) preterm (LMPT). DESIGN/SETTING: Prospective population-based study comprising births in four major maternity centres, one midwifery-led unit and at home between September 2009 and December 2010. Data were obtained from maternal and neonatal records. PARTICIPANTS: All LMPT infants were eligible. A random sample of term born infants (>=37 weeks) acted as controls. OUTCOME MEASURES: Neonatal unit (NNU) admission, respiratory and nutritional support, neonatal morbidities, investigations, length of stay and postnatal ward care were measured. Differences between centres were explored. RESULTS: 1146 (83%) LMPT and 1258 (79% of eligible) term-born infants were recruited. LMPT infants were significantly more likely to receive resuscitation at birth (17.5% vs 7.4%), respiratory (11.8% vs 0.9%) and nutritional support (3.5% vs 0.3%) and were less likely to be fed breast milk (64.2% vs 72.2%) than term infants. For all interventions and morbidities, a gradient of increasing risk with decreasing gestation was evident. Although 60% of late preterm infants were never admitted to a NNU, 83% required medical input on postnatal wards. Clinical management differed significantly between services. CONCLUSIONS: LMPT infants place high demands on specialist neonatal services. A substantial amount of previously unreported specialist input is provided in postnatal wards, beyond normal newborn care. Appropriate expertise and planning of early care are essential if such infants are managed away from specialised neonatal settings. Further research is required to clarify optimal and cost-effective postnatal management for LMPT babies. PMID- 25834170 TI - Neurodevelopmental outcomes following late and moderate prematurity: a population based cohort study. AB - OBJECTIVE: There is a paucity of data relating to neurodevelopmental outcomes in infants born late and moderately preterm (LMPT; 32(+0)-36(+6) weeks). This paper present the results of a prospective, population-based study of 2-year outcomes following LMPT birth. DESIGN: 1130 LMPT and 1255 term-born children were recruited at birth. At 2 years corrected age, parents completed a questionnaire to assess neurosensory (vision, hearing, motor) impairments and the Parent Report of Children's Abilities-Revised to identify cognitive impairment. Relative risks for adverse outcomes were adjusted for sex, socio-economic status and small for gestational age, and weighted to account for over-sampling of term-born multiples. Risk factors for cognitive impairment were explored using multivariable analyses. RESULTS: Parents of 638 (57%) LMPT infants and 765 (62%) controls completed questionnaires. Among LMPT infants, 1.6% had neurosensory impairment compared with 0.3% of controls (RR 4.89, 95% CI 1.07 to 22.25). Cognitive impairments were the most common adverse outcome: LMPT 6.3%; controls 2.4% (RR 2.09, 95% CI 1.19 to 3.64). LMPT infants were at twice the risk for neurodevelopmental disability (RR 2.19, 95% CI 1.27 to 3.75). Independent risk factors for cognitive impairment in LMPT infants were male sex, socio-economic disadvantage, non-white ethnicity, preeclampsia and not receiving breast milk at discharge. CONCLUSIONS: Compared with term-born peers, LMPT infants are at double the risk for neurodevelopmental disability at 2 years of age, with the majority of impairments observed in the cognitive domain. Male sex, socio-economic disadvantage and preeclampsia are independent predictors of low cognitive scores following LMPT birth. PMID- 25834171 TI - Simultaneous Determination of 10 Active Components in Hulisan Tablets by a High Performance Liquid Chromatographic-Diode Array Detector. AB - Hulisan tablets (HLST), a famous classic traditional Chinese prescriptions consisting of four medicinal herbs, have been applied for treating fractures, rheumatoid arthritis, mechanical phlebitis and traumatic bleeding extensively. In this study, a simple and reliable method using high-performance liquid chromatography with diode array detector (HPLC-DAD) was established for the simultaneous determination of 10 active compounds in HLST. The chromatographic analysis was performed on a Symmetry((r))-C18 column (4.6 * 250 mm, i.d., 5 um; Waters, Wexford, Leinster, Ireland) at 30 degrees C with a gradient elution of 0.1 mol/L ammonium acetate (containing 0.5 mL glacial acetic acid per 1,000 mL) and acetonitrile at a flow rate of 1.0 mL/min. The detection UV wavelengths were set at 232, 254 and 280 nm. The method was validated by linearity, precision, stability and recovery. Calibration curves for the 10 compounds showed good linear regressions (R(2) > 0.9992). The limits of detection and quantification fell in the ranges of 0.03-0.36 and 0.11-1.01 ug/mL, respectively. The results of the recovery test were 97.19-102.04% with a RSD value of 0.65-2.47%. The developed method was subsequently applied to evaluate five batches of HLST and testified to be suitable for the quality control. PMID- 25834172 TI - An Eco-Friendly Direct Injection HPLC Method for Methyldopa Determination in Serum by Mixed-Mode Chromatography Using a Single Protein-Coated Column. AB - A simple, rapid and environment-friendly direct injection HPLC method for the determination of methyldopa (MTD) in human serum has been developed and validated. The method was based on cleanup and separation of MTD from serum by mixed-mode liquid chromatography using a single protein-coated TSK gel ODS-80 TM analytical column (50 * 4.0 mm i.d., 5 um). The protein-coated column exhibited excellent resolution, selectivity and functioned in two chromatographic modes: size-exclusion chromatography [i.e., solid-phase extraction (SPE) for serum proteins] and reversed-phase chromatography for the final separation of MTD. SPE and HPLC separation were carried out simultaneously with a green mobile phase consisting of acetate buffer (0.1 M, pH 2.4) at a flow rate of 1 mL/min and at room temperature (23 +/- 1 degrees C). The eluent was monitored at emission and excitation wavelengths of 320 and 270 nm, respectively. A calibration curve was linear over the range of 0.1-30 ug/mL with a detection limit of 0.027 ug/mL. This online SPE method was successfully applied to real samples obtained from patients receiving MTD therapy. PMID- 25834173 TI - NIH partnership launches big data portal for AD drug discovery. PMID- 25834174 TI - History Corner: from the new SNMMI historian. PMID- 25834175 TI - AMA, 99 other groups call for ICD-10 transition contingencies. PMID- 25834176 TI - Lenvatinib receives approval in DTC. PMID- 25834177 TI - SNMMI leadership update: SNMMI annual meeting heads to Baltimore. PMID- 25834180 TI - Canadian NRU extended; medical isotope partnership announced. PMID- 25834181 TI - Long-Term Placement Trajectories of Children Who Were Maltreated and Entered the Child Welfare System at an Early Age: Consequences for Physical and Behavioral Well-Being. AB - OBJECTIVE: This study aimed to identify children's long-term placement trajectories following early child welfare involvement and the association of these trajectories with subsequent physical and behavioral well-being. METHOD: Participants were 330 children who entered out-of-home care following a substantiated report of child abuse or neglect during infancy/early childhood and their caregivers. Participants were interviewed at child ages 4 and 12 years to assess children's physical and behavioral well-being and every 2 years in between to determine child placements. RESULTS: Latent Class Analyses identified four stable placement trajectories (i.e., adopted [32%], kinship care [15%], stable reunified [27%], and stable foster care [9%]), and two unstable trajectories (i.e., disrupted reunified [12%] and unstable foster care [5%]). Logistic regressions revealed that children in the unstable trajectories had significantly poorer physical and behavioral well-being than children in stable trajectories. CONCLUSIONS AND RELEVANCE: Maltreated children placed in out-of-home care are at risk for long-term placement instability and poorer physical and behavioral well being. PMID- 25834182 TI - Forward problem of electrocardiography: is it solved? AB - BACKGROUND: The relationship between epicardial and body surface potentials defines the forward problem of electrocardiography. A robust formulation of the forward problem is instrumental to solving the inverse problem, in which epicardial potentials are computed from known body surface potentials. Here, the accuracy of different forward models has been evaluated experimentally. METHODS AND RESULTS: Body surface and epicardial potentials were recorded simultaneously in anesthetized closed-chest pigs (n=5) during sinus rhythm, and epicardial and endocardial ventricular pacing (65 records in total). Body surface potentials were simulated from epicardial recordings using experiment-specific volume conductor models constructed from magnetic resonance imaging. Results for homogeneous (isotropic electric properties) and inhomogeneous (incorporating lungs, anisotropic skeletal muscle, and subcutaneous fat) forward models were compared with measured body surface potentials. Correlation coefficients were 0.85+/-0.08 across all animals and activation sequences with no significant difference between homogeneous and inhomogeneous solutions (P=0.85). Despite this, there was considerable variance between simulated and measured body surface potential distributions. Differences between the body surface potential extrema predicted with homogeneous forward models were 55% to 78% greater than observed (P<0.05) and attenuation of potentials adjacent to extrema were 10% to 171% greater (P<0.03). The length and orientation of the vector between potential extrema were also significantly different. Inclusion of inhomogeneous electric properties in the forward model reduced, but did not eliminate these differences. CONCLUSIONS: These results demonstrate that homogeneous volume conductor models introduce substantial spatial inaccuracies in forward problem solutions. This probably affects the precision of inverse reconstructions of cardiac potentials, in which this assumption is made. PMID- 25834183 TI - Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation. AB - BACKGROUND: Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. METHODS AND RESULTS: Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10 minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2*10(8) IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (P<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; P<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (P<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. CONCLUSIONS: Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase. PMID- 25834184 TI - Care in the last year of life for community patients with heart failure. AB - BACKGROUND: Healthcare utilization peaks at the end of life (EOL) in patients with heart failure. However, it is unclear what factors affect end of life utilization in patients with heart failure and if utilization has changed over time. METHODS AND RESULTS: Southeastern Minnesota residents with heart failure were prospectively enrolled into a longitudinal cohort study from 2003 to 2011. Patients who died before December 31, 2012, were included in the analysis. Information on hospitalizations and outpatient visits in the last year of life was obtained using administrative sources. Negative binomial regression was used to assess the association between patient characteristics and utilization. The 698 decedents (47.3% men; 53.4% preserved ejection fraction) experienced 1528 hospitalizations (median 2 per person; range, 0-12; 37.6% because of cardiovascular causes) and 12 927 outpatient visits (median 14 per person; range, 0-119) in their last year of life. Most patients (81.5%) were hospitalized at least once and 28.4% died in the hospital. Patients who were older and those with dementia had lower utilization. Patients who were married, resided in a skilled nursing facility, and had more comorbidities had higher utilization. Patients with preserved ejection fraction had higher rates of noncardiovascular hospitalizations although other utilization was similar. Over time, rates of hospitalizations and outpatient visits decreased, whereas palliative care consults and enrollment in hospice increased. CONCLUSIONS: Although patient factors remain associated with differential healthcare utilization at the end of life, utilization declined over time and use of palliative care services increased. These results are encouraging given the high resource use in patients with heart failure. PMID- 25834185 TI - Endothelial plasticity drives arterial remodeling within the endocardium after myocardial infarction. AB - RATIONALE: Revascularization of injured, ischemic, and regenerating organs is essential to restore organ function. In the postinfarct heart, however, the mechanisms underlying the formation of new coronary arteries are poorly understood. OBJECTIVE: To study vascular remodeling of coronary arteries after infarction. METHODS AND RESULTS: We performed permanent left coronary ligation on Connexin40-GFP mice expressing green fluorescent protein (GFP) in endothelial cells of coronary arteries but not veins, capillaries, or endocardium. GFP(+) endothelial foci were identified within the endocardium in the infarct zone. These previously undescribed structures, termed endocardial flowers, have a distinct endothelial phenotype (Cx40(+), VEGFR2(+), and endoglin(-)) to the surrounding endocardium (Cx40(-), VEGFR2(-), and endoglin(+)). Endocardial flowers are contiguous with coronary vessels and associated with subendocardial smooth muscle cell accumulation. Genetic lineage tracing reveals extensive endothelial plasticity in the postinfarct heart, showing that endocardial flowers develop by arteriogenesis of Cx40(-) cells and by outgrowth of pre-existing coronary arteries. Finally, endocardial flowers exhibit angiogenic features, including early VEGFR2 expression and active proliferation of adjacent endocardial and smooth muscle cells. CONCLUSIONS: Arterial endothelial foci within the endocardium reveal extensive endothelial cell plasticity in the infarct zone and identify the endocardium as a site of endogenous arteriogenesis and source of endothelial cells to promote vascularization in regenerative strategies. PMID- 25834186 TI - Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles. PMID- 25834187 TI - BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. PMID- 25834188 TI - Erratum. Aronson et al. Variation in care of the febrile young infant <90 days in US pediatric emergency departments. Pediatrics. 2014;134(4):667-677. PMID- 25834189 TI - Erratum. Klaiman et al. Longitudinal profiles of adaptive behavior in fragile X syndrome. Pediatrics. 2014;134(2):315-324. PMID- 25834190 TI - Erratum. Jacob et al. Etiologies of NICU deaths. Pediatrics. 2015;135(1):e59-e65. PMID- 25834192 TI - Lessons for the United States from the Chinese pediatricians' experience. PMID- 25834193 TI - Chinese pediatricians face a crisis: reform is coming. PMID- 25834194 TI - Predictors of 1-Year Mortality in a Prospective Cohort of Elderly Patients With Cancer. AB - BACKGROUND: Mortality prediction is crucial to select the optimal treatment in elderly cancer patients. Our objective was to identify cancer-related factors and Comprehensive Geriatric Assessment (CGA) findings associated with 1-year mortality in elderly inpatients and outpatients with cancer. METHODS: We prospectively included patients aged >=70 years who had solid or hematologic malignancies and in whom the CGA was performed by geriatricians in two French teaching hospitals. We identified independent predictors of 1-year mortality after study inclusion, using multivariate Cox models stratified on inpatient/outpatient status. We built three multivariate Cox models, since strong correlations linked activities of daily living (ADL), Eastern Cooperative Oncology Group Performance Status (ECOG-PS), and timed get-up-and-go test (GUG) results; and since physicians' preferences for these three assessments vary. A sensitivity analysis was performed using multiple imputation. RESULTS: Of the 993 patients (mean age, 80.2 years; 51.2% men), 58.2% were outpatients and 46% had metastatic disease. Colorectal cancer was the most common malignancy (21.4%). Mortality rates after 6 and 12 months were 30.1% and 41.2%, respectively. In all models, tumor site and metastatic status (p < .001), age >80 years (p < .05), higher number of severe comorbidities (p < .05), and malnutrition (p < .001) were associated with death independently from impaired ECOG-PS (p < .001), ADL (p < .001), and GUG (p < .001). The adverse effect of metastatic status differed significantly across tumor sites, being greatest for breast and prostate cancer (p < .001). Multiple imputation produced similar results. CONCLUSION: The predictors of 1-year mortality identified in our study may help physicians select the optimal cancer-treatment strategy in elderly patients. PMID- 25834195 TI - Weaker Seniors Exhibit Motor Cortex Hypoexcitability and Impairments in Voluntary Activation. AB - BACKGROUND: Weakness predisposes seniors to a fourfold increase in functional limitations. The potential for age-related degradation in nervous system function to contribute to weakness and physical disability has garnered much interest of late. In this study, we tested the hypothesis that weaker seniors have impairments in voluntary (neural) activation and increased indices of GABAergic inhibition of the motor cortex, assessed using transcranial magnetic stimulation. METHODS: Young adults (N = 46; 21.2+/-0.5 years) and seniors (N = 42; 70.7+/-0.9 years) had their wrist flexion strength quantified along with voluntary activation capacity (by comparing voluntary and electrically evoked forces). Single-pulse transcranial magnetic stimulation was used to measure motor-evoked potential amplitude and silent period duration during isometric contractions at 15% and 30% of maximum strength. Paired-pulse transcranial magnetic stimulation was used to measure intracortical facilitation and short-interval and long interval intracortical inhibition. The primary analysis compared seniors to young adults. The secondary analysis compared stronger seniors (top two tertiles) to weaker seniors (bottom tertile) based on strength relative to body weight. RESULTS: The most novel findings were that weaker seniors exhibited: (i) a 20% deficit in voluntary activation; (ii) ~20% smaller motor-evoked potentials during the 30% contraction task; and (iii) nearly twofold higher levels of long-interval intracortical inhibition under resting conditions. CONCLUSIONS: These findings indicate that weaker seniors exhibit significant impairments in voluntary activation, and that this impairment may be mechanistically associated with increased GABAergic inhibition of the motor cortex. PMID- 25834196 TI - Unmet Need for ADL Assistance Is Associated With Mortality Among Older Adults With Mild Disability. AB - BACKGROUND: Unmet need for assistance with activities of daily living (ADLs) disability is associated with increased risk for future hospitalization. To further explore the association between unmet ADL need and future health outcomes, we examined the association between unmet need for ADL assistance and 1 year mortality. METHODS: A prospective study of 6,730 community-living Medicare recipients was conducted among respondents to the 1994, 1999, and/or 2004 National Long Term Care Survey. Only those who reported having one or more ADL disabilities were included. Time to death within 1 year after the community survey was determined from Centers for Medicare and Medicaid Services vital statistics records. The community interviews provided demographic, health, and ADL information. RESULTS: Unadjusted 1-year death rates were 8.7%, 10.6%, 11.4%, 19.2%, and 27.3%, respectively, for respondents with disabilities in 1, 2, 3, 4, and 5 ADLs. Overall, 21.3% reported unmet need for assistance for one or more ADL disabilities. After controlling for demographic and health characteristics, we found a significant interaction between unmet ADL need and level of ADL disability (p = .018). Post hoc analyses revealed that unmet ADL need was associated with increased risk for mortality only for those with one (hazard ratio = 1.96; 95% CI = 1.29-2.87) or two ADL disabilities (hazard ratio = 1.37; 95% CI = 1.07-1.75), but not for those with three or more ADL disabilities. CONCLUSION: Future studies are needed to determine whether these findings are replicable and, if so, whether physiologic or process of care variables explain why ADL is associated with mortality only for those with mild disability. PMID- 25834197 TI - Reply: To PMID 25738953. PMID- 25834198 TI - Validation of the Toronto Psoriatic Arthritis Screen Version 2 (ToPAS 2). AB - OBJECTIVE: We previously developed and performed an initial validation of a screening questionnaire, the Toronto Psoriatic Arthritis Screen (ToPAS), for psoriatic arthritis (PsA). In our original analysis, we found that the index constructed appeared to discriminate well between those with a confirmed diagnosis of PsA and those without PsA in various clinical settings. However, it was suggested that ToPAS would benefit from additional refinement to the questions and the scoring system, because items pertaining to axial involvement were not included in our original index. Subsequently, a second version of ToPAS was developed, ToPAS 2, which incorporated the suggested refinements. We aimed to validate ToPAS 2 as a screening instrument for PsA. METHODS: ToPAS 2 was administered to 3 "diagnostic" groups of individuals - patients with PsA, patients with psoriasis, and healthy controls, and the data collected were analyzed. RESULTS: It was found that the new version of ToPAS, ToPAS 2, again performed well, with the axial domain now featuring in the new scoring system. The constructed index, ToPAS2_cap, had an overall area under the receiver operation curve of 0.910, with overall values of sensitivity and specificity, at a cutpoint of 8 (or 7), of 87.2% (92.0%) and 82.7% (77.2%), respectively. CONCLUSION: ToPAS 2 shows much promise as a screening instrument for identifying PsA both in people with psoriasis and in individuals from the general population. Its performance against other proposed screening instruments for PsA should be evaluated in other clinics and for other study designs. PMID- 25834199 TI - Low levels of serum uric Acid increase the risk of low bone mineral density in young male patients with ankylosing spondylitis. AB - OBJECTIVE: Uric acid (UA) has antiosteoporotic effects in postmenopausal women. This study investigated the association between serum UA levels and bone mineral density (BMD) in young male patients with ankylosing spondylitis (AS). METHODS: One hundred fifty patients who fulfilled the modified New York criteria for the classification of AS were analyzed. All patients were male and under 50 years of age. BMD, serum UA concentrations, clinical variables, and radiographic progression were assessed. The associations between UA and BMD at the lumbar spine and hip were evaluated using multiple linear regression analysis. Multivariate logistic regression analyses were performed to identify risk factors associated with low BMD. RESULTS: Mean serum UA concentration in the 150 patients with AS was 5.5 +/- 1.3 mg/dl. BMD at the lumbar spine, but not at the total hip and femoral neck, increased with increasing serum UA tertiles (p = 0.033). The significant positive association between serum UA and BMD at the lumbar spine remained after adjustment for confounding factors (beta = 0.185, p = 0.014, adjusted R(2) = 0.310). Multiple logistic regression analyses showed that lower UA concentrations (OR 4.02, 95% CI 1.34-12.3) and body mass index and increased erythrocyte sedimentation rate were independently associated with the risk of low BMD. CONCLUSION: Lower serum UA levels are associated with lower BMD in young male patients with AS. UA may be a novel predictive marker or therapeutic target in patients with AS. PMID- 25834200 TI - The Effect of Disease Severity and Comorbidity on Length of Stay for Orthopedic Surgery in Rheumatoid Arthritis: Results from 2 UK Inception Cohorts, 1986-2012. AB - OBJECTIVE: To examine factors predicting length of stay (LoS) for orthopedic intervention in rheumatoid arthritis (RA). METHODS: LoS for orthopedic intervention was examined in 2 consecutive, multicenter inception cohorts: the Early RA Study (n = 1465, 9 centers) and the Early RA Network (n = 1236, 23 centers). Date, type of orthopedic procedure, and LoS were recorded and validated against national data, the UK National Joint Registry, and the UK Hospital Episode Statistics database. Clinical, laboratory, and radiographic measures and comorbidity recorded at baseline and annually were examined for their predictive power on LoS using regression analysis. RESULTS: A total of 770 of 2701 patients (28.5%) had 1602 orthopedic interventions: 40% major (mainly total hip/knee replacements), 24% intermediate (mainly hand/wrist and ankle/foot surgery), and 16% minor (mainly soft tissue surgery). Median (interquartile range) LoS was 8 (5 13), 3 (1-5), and 1 (0-2) days for major, intermediate, and minor interventions, respectively. Older age predicted longer LoS (p < 0.001) whereas a more recent operation year predicted shorter LoS (p < 0.001). Markers of active disease, namely low hemoglobin, high Health Assessment Questionnaire, and high Disease Activity Scores in the first year all predicted longer LoS for all types of surgery (p = 0.001, p < 0.001, p = 0.05, respectively). Presence of 1 or more major comorbidities predicted longer LoS (p < 0.001). CONCLUSION: Comorbidity and standard clinical and laboratory markers of disease activity affect the LoS for orthopedic surgery in RA, which has important clinical and economic implications, providing a target for improving patient outcomes. PMID- 25834201 TI - Alcohol intake and risk of incident psoriatic arthritis in women. AB - OBJECTIVE: Alcohol intake has been associated with an increased risk of psoriasis. However, the association between alcohol intake and risk of psoriatic arthritis (PsA) has been unclear. We evaluated the association between alcohol intake and risk of incident PsA in a large cohort of US women. METHODS: Our present study included a total of 82,672 US women who provided repeated data on alcohol intake over the followup period (1991-2005). Self-reported PsA was validated using the Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire. Cox proportional hazards models were used to estimate the age adjusted and multivariate-adjusted HR and 95% CI for the PsA in association with alcohol intake. RESULTS: We documented 141 incident PsA cases during 14 years (1,137,763 person-yrs) of followup. Compared to non-drinkers, the multivariate HR for PsA were 0.70 (95% CI 0.48-1.01) for 0.1-14.9 g/day, 1.43 (95% CI 0.67-3.08) for 15.0-29.9 g/day, and 4.45 (95% CI 2.07-9.59) for >= 30.0 g/day of cumulative average alcohol intake. Risk estimates were generally consistent when using updated alcohol intake and baseline alcohol intake in 1991 as the exposures, and when the analysis was restricted to those who developed psoriasis during the followup. CONCLUSION: Excessive alcohol intake was associated with an increased risk of incident PsA in a cohort of US women. PMID- 25834202 TI - Direct health costs of inflammatory polyarthritis 10 years after disease onset: results from the Norfolk Arthritis Register. AB - OBJECTIVES: To explore the change in direct medical costs associated with inflammatory polyarthritis (IP) 10 to 15 years after its onset. METHODS: Patients from the Norfolk Arthritis Register who had previously participated in a health economic study in 1999 were traced 10 years later and invited to participate in a further prospective questionnaire-based study. The study was designed to identify direct medical costs and changes in health status over a 6-month period using previously validated questionnaires as the primary source of data. RESULTS: A representative sample of 101 patients with IP from the 1999 cohort provided complete data over the 6-month period. The mean disease duration was 14 years (SD 2.1, median 13.6, interquartile range 12.6-15.4). The mean direct medical cost per patient over the 6-month period was L1496 for IP (inflated for 2013 prices). This compared with L582 (95% CI L355-L964) inflated to 2013 prices per patient with IP 10 years earlier in their disease. The increased cost was largely associated with the use of biologics in the rheumatoid arthritis subgroup of patients (51% of total costs incurred). Other direct cost components included primary care costs (11%), hospital outpatient (19%), day care (12%), and inpatient stay (4%). CONCLUSION: The direct healthcare costs associated with IP have more than doubled with increasing disease duration, largely as a result of the use of biologics. The results showed a shift in the direct health costs from inpatient to outpatient service use. PMID- 25834204 TI - Longterm efficacy and safety of abatacept in patients with rheumatoid arthritis treated in routine clinical practice: effect of concomitant methotrexate after 24 weeks. AB - OBJECTIVE: Our study aimed to evaluate the longterm efficacy and safety of abatacept (ABA), and to explore factors that increase its longterm efficacy in patients with rheumatoid arthritis (RA) treated in routine clinical practice. METHODS: There were 231 participants with RA treated with ABA who were prospectively registered in a Japanese multicenter registry. They were followed up for at least 52 weeks. RESULTS: Mean age of the patients was 64.3 years, mean disease duration was 12.1 years, mean 28-joint Disease Activity Score (DAS28)-C reactive protein was 4.49, and 48.5% of patients were concomitantly treated with methotrexate (MTX). Overall retention rate of ABA was 77.1% at 52 weeks; 14.8% of patients discontinued because of inadequate response and 3.5% because of adverse events. The proportion of patients achieving DAS28-defined low disease activity (LDA) significantly increased from baseline to 52 weeks (7.3% to 43.8%, p < 0.01); 40.9% of patients who did not achieve LDA at 24 weeks had more than 1 categorical improvement in DAS28-defined disease activity at 52 weeks. Multivariate logistic regression revealed concomitant MTX use to be an independent predictor of the categorical improvement in DAS28-defined disease activity from 24 to 52 weeks (adjusted OR 3.124, p = 0.010). CONCLUSION: In routine clinical practice, ABA demonstrated satisfactory clinical efficacy and safety in patients with established RA for 52 weeks. The clinical efficacy of ABA increased with time even after 24 weeks, and this was strongly influenced by concomitant MTX use. Our study provides valuable real-world findings on the longterm management of RA with ABA. PMID- 25834205 TI - Patient Information about Gout: An International Review of Existing Educational Resources. AB - OBJECTIVE: Inadequate patient information about gout may contribute to poor disease outcomes. We reviewed existing educational resources for gout to identify strengths and weaknesses and compare resources cross-nationally. METHODS: Content, readability, and dietary recommendations were reviewed using a sample of 30 resources (print and Web-based) from 6 countries. RESULTS: More than half of the resources were written at a highly complex level. Some content areas were lacking coverage, including comorbidity risks, uric acid target levels, and continuing allopurinol during acute attacks. CONCLUSION: Our findings suggest significant room for improvement in gout patient educational resources, particularly regarding self-management. PMID- 25834203 TI - Longterm Safety and Efficacy of Subcutaneous Tocilizumab Monotherapy: Results from the 2-year Open-label Extension of the MUSASHI Study. AB - OBJECTIVE: To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA). METHODS: Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI 101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks. RESULTS: The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) <= 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy. CONCLUSION: TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ IV, TCZ-SC could provide an additional treatment option for patients with RA. PMID- 25834207 TI - Risk of Overall and Site-specific Cancers in Behcet Disease: A Nationwide Population-based Study in Taiwan. AB - OBJECTIVE: The relationship between autoimmune disease and cancer is complex while large-scale epidemiological studies of cancer risk in Behcet disease (BD) have not been reported. Therefore, we conducted a nationwide population-based cohort study. METHODS: By using the National Health Insurance Research Database of 23 million people in Taiwan, we identified 1314 new patients with BD without previous cancer from 2000-2009 as a cohort. Standardized incidence ratios (SIR) of overall and site-specific cancers in patients with BD in comparison with the general population were calculated from 2000-2011. RESULTS: Among the 1314 patients with BD, 30 developed cancers (9 men and 21 women). In overall cancer risk analysis, patients with BD had a higher risk (SIR 1.5, 95% CI 1.03-2.11). Among them, female patients with BD (SIR 1.8, 95% CI 1.14-2.7), but not male patients with BD (SIR 1.08, 95% CI 0.53-1.98), have a higher risk of overall cancer. In site-specific cancer risk analysis, patients with BD had a higher risk of non-Hodgkin lymphoma (SIR 8.3, 95% CI 2.1-22.7), hematological malignancy (SIR 4.2, 95% CI 1.3-10.2), and female breast cancer (SIR 2.2, 95% CI 1.004-4.1). The cancer risk was highest within the first-year followup (SIR 2.7, 95% CI 1.3-5.1), with 75% of the hematological malignancies found within the first year. CONCLUSION: This nationwide cohort study of cancer risk in patients with BD provides important information about the relationship between BD and malignancies. The results can be useful for cancer surveys in the future. PMID- 25834206 TI - Yoga in Sedentary Adults with Arthritis: Effects of a Randomized Controlled Pragmatic Trial. AB - OBJECTIVE: To evaluate the effect of Integral-based hatha yoga in sedentary people with arthritis. METHODS: There were 75 sedentary adults aged 18+ years with rheumatoid arthritis (RA) or knee osteoarthritis randomly assigned to 8 weeks of yoga (two 60-min classes and 1 home practice/wk) or waitlist. Poses were modified for individual needs. The primary endpoint was physical health [Medical Outcomes Study Short Form-36 (SF-36) physical component summary (PCS)] adjusted for baseline; exploratory adjusted outcomes included fitness, mood, stress, self efficacy, SF-36 health-related quality of life (HRQOL), and RA disease activity. In everyone completing yoga, we explored longterm effects at 9 months. RESULTS: Participants were mostly female (96%), white (55%), and college-educated (51%), with a mean (SD) age of 52 years (12 yrs). Average disease duration was 9 years and 49% had RA. At 8 weeks, yoga was associated with significantly higher PCS (6.5, 95% CI 2.0-10.7), walking capacity (125 m, 95% CI 15-235), positive affect (5.2, 95% CI 1.4-8.9), and lower Center for Epidemiologic Studies Depression Scale (-3.0, 95% CI -4.8 - -1.3). Significant improvements (p < 0.05) were evident in SF-36 role physical, pain, general health, vitality, and mental health scales. Balance, grip strength, and flexibility were similar between groups. Twenty-two out of 28 in the waitlist group completed yoga. Among all yoga participants, significant (p < 0.05) improvements were observed in mean PCS, flexibility, 6-min walk, and all psychological and most HRQOL domains at 8 weeks with most still evident 9 months later. Of 7 adverse events, none were associated with yoga. CONCLUSION: Preliminary evidence suggests yoga may help sedentary individuals with arthritis safely increase physical activity, and improve physical and psychological health and HRQOL. Clinical Trials NCT00349869. PMID- 25834208 TI - Outcome Domains and Measures in Total Joint Replacement Clinical Trials: Can We Harmonize Them? An OMERACT Collaborative Initiative. AB - OBJECTIVE: To develop a plan for harmonizing outcomes for people undergoing total joint replacement (TJR), to achieve consensus regarding TJR outcome research. METHODS: The TJR working group met during the 2014 Outcome Measures in Rheumatology (OMERACT) 12 meeting in Budapest, Hungary. Multiple conference calls preceded the face-to-face meeting. Brief presentations were made during a 1.5-h meeting, which included an overview of published systematic reviews of TJR trials and the results of a recent systematic review of TJR clinical trial outcome domains and measures. This was followed by discussion of potential core set areas/domains for TJR clinical trials (as per OMERACT Filter 2.0) as well as the challenges associated with the measurement of these domains. RESULTS: Working group participants discussed which TJR clinical trial outcome domains/areas map to the inner versus outer core for core domain set. Several challenges were identified with TJR outcomes including how to best measure function after TJR, elucidating the source of the pre- and post-TJR joint pain being measured, joint specific versus generic quality of life instruments and the importance of patient satisfaction and revision surgery as outcomes. A preliminary core domain set for TJR clinical trials was proposed and included pain, function, patient satisfaction, revision, adverse events, and death. This core domain set will be further vetted with a broader audience. CONCLUSION: An international effort with active collaboration with the orthopedic community to standardize key outcome domains and measures is under way with the TJR working group. This effort will be further developed with new collaborations. PMID- 25834209 TI - Clinical trials perception in rheumatology patients: experience from a single rheumatology tertiary center. AB - OBJECTIVE: To investigate the perception and willingness of rheumatology patients to participate in clinical trials. No previous similar studies are available. METHODS: We conducted a cross-sectional survey of rheumatology patients using a questionnaire, which comprised 2 demographic questions, two 5-point Likert opinion questions, 19 true/false/unsure knowledge questions, and 1 open question addressing what would help the participant to gain a better understanding about clinical trials. RESULTS: Eighty-five patients returned the questionnaires (response rate 84.1%). The mean number of correct answers to the 19 knowledge questions was 10.5 +/- 2.87. Patients with higher versus lower levels of education had significantly higher knowledge scores (mean correct answers 59.4 +/ 13.1 vs 39.8 +/- 20.4, p = 0.013). They also expressed greater willingness to take part in research (87.5% vs 48.2%, p < 0.001). The patients who agreed to participate in research provided significantly more correct answers (59.4 +/- 15.3% vs 47.7 +/- 27.2%, p = 0.032). Poor disease control as the main reason to join a clinical trial correlated well with patients' previous participation in research (r = 0.71; p < 0.05) and the lack of understanding of research principles (defined as less than 50% correct answers to the knowledge questions) correlated with the lack of willingness to participate in clinical trials (r = 0.72; p < 0.05). CONCLUSION: The results of our study revealed that patients lack information about clinical trials (the correct response rate was only slightly above 50%), and that they had a moderate willingness to take part in clinical trials. The need for educational programs about clinical research was highlighted by the participants to the survey. PMID- 25834210 TI - Predictors of longterm changes in body mass index in rheumatoid arthritis. AB - OBJECTIVE: Low body mass index (BMI) is a risk factor for poor longterm outcomes in rheumatoid arthritis (RA). The purpose of this study was to identify factors associated with longterm changes in BMI. METHODS: Subjects with RA from the Veterans Affairs (VA) Rheumatoid Arthritis (VARA) Registry (n = 1474) were studied. Information on inflammatory markers, presence of erosions, and smoking status were extracted from the VARA database. BMI was extracted from VA electronic medical records within 14 days of each visit date. VA pharmacy records were queried to identify prescriptions for specific RA therapies within 1 month of the visit date. We used robust generalized estimating equations marginal regression models to calculate independent associations between clinical variables and BMI over time. Similar models determined predictors of change in weight and risk of weight loss over the subsequent study observation period. RESULTS: Increasing age, active smoking, and the presence of erosions at baseline were associated with lower BMI. Weight decreased over time among older adults. Factors associated with greater reductions in BMI over time and a greater risk of weight loss were higher inflammatory markers, smoking, older age, higher BMI, and less subsequent improvement in inflammation. Methotrexate use was associated with a lower risk of weight loss. The use of prednisone or anti-tumor necrosis factor therapies was not associated with change in BMI or the risk of weight loss independent of other factors. CONCLUSION: Greater age, greater inflammatory activity, and active smoking are associated with greater weight loss in RA over time. PMID- 25834211 TI - Myeloperoxidase-antineutrophil Cytoplasmic Antibodies (MPO-ANCA) and Proteinase 3 ANCA without Immunofluorescent ANCA Found by Routine Clinical Testing. AB - OBJECTIVE: Concurrent testing for serum antineutrophil cytoplasmic antibodies (ANCA) by indirect immunofluorescence (IF) and by antiproteinase 3 (PR3)/antimyeloperoxidase (MPO) antibody assays may identify patients with PR3 ANCA or MPO-ANCA despite a negative IF (IF-negative MPO/PR3-positive); however, the significance of this result is not clear. We sought to determine whether IF negative, MPO/PR3-positive results identified any cases of clinically meaningful systemic vasculitis at our institution. METHODS: We conducted a retrospective chart review of all IF-negative, MPO/PR3-positive patients identified at our institution over a 2-year period. RESULTS: Of the 2345 samples tested over 2 years, 1998 were IF-negative. Among these IF-negative samples, 49 samples (2.5%) derived from 38 patients tested positive for MPO-ANCA or PR3-ANCA. Only 1 IF negative, MPO/PR3-positive patient was subsequently diagnosed with ANCA associated vasculitis (AAV). Eleven IF-negative, MPO/PR3-positive patients (29%) had been previously diagnosed and treated for AAV, all with positive IF and antibody tests prior to treatment. Four patients had evidence of cutaneous vasculitis not attributed to AAV, while several of the remaining IF-negative, MPO/PR3-positive patients had other immunologic disorders, including systemic lupus erythematosus (5 patients) and inflammatory bowel disease (3 patients). CONCLUSION: In this real-life cohort assayed simultaneously by IF and multiplexed bead assays, the detection of MPO-ANCA or PR3-ANCA without a positive IF rarely led to a new diagnosis of systemic vasculitis, and was more likely to occur in the context of a non-vasculitic inflammatory condition. Our results suggest that concurrent IF and MPO/PR3 testing may be of limited use in preventing a missed diagnosis of new-onset AAV. PMID- 25834212 TI - Clinical remission in patients with active psoriatic arthritis treated with adalimumab and correlations in joint and skin manifestations. AB - OBJECTIVE: Adalimumab (ADA) was evaluated for its efficacy in patients with moderate to severely active psoriatic arthritis (PsA) and for the presence of correlations in disease change variables. METHODS: Patients with inadequate response to standard PsA therapy were given 40 mg of ADA every other week for up to 12 weeks or 20 weeks. Outcome variables encompassed tender joint count (TJC), swollen joint count (SJC), physician's global assessment (PGA) of psoriasis, Health Assessment Questionnaire (HAQ), patient's global assessment (PtGA) of disease activity and pain, C-reactive protein, as well as composite measures of disease activity. Patients with inactive skin disease symptoms at baseline were excluded from the remission analyses. RESULTS: Of 268 patients with active baseline joint and skin disease and data available at Week 12 following open label ADA therapy, 73 achieved joint remission (27.2%, TJC <= 1 + SJC <= 1) and 144 achieved skin remission criteria (53.7%, PGA = clear/almost clear). Simultaneous joint and skin remission criteria were achieved in 16.0% and 24.8% of patients at weeks 12 and 20, respectively. In patients who did not achieve skin and/or joint remission, 12-week ADA treatment improved mean clinical and functional scores. Joint remission was more frequently associated with achieving clinically relevant outcomes including HAQ, PtGA disease activity, and PtGA pain compared to skin remission. No correlation between improvement in skin and joint disease was observed. CONCLUSION: ADA was effective in achieving strict criteria for remission in joint or skin disease in many patients with active PsA within 12 weeks and sustained through 20 weeks. (NCT00235885). PMID- 25834213 TI - Counting Costs under Severe Financial Constraints: A Cost-of-Illness Analysis of Spondyloarthropathies in a Tertiary Hospital in Greece. AB - OBJECTIVE: To investigate the total annual direct cost of patients with spondyloarthritis (SpA) in Greece. METHODS: Retrospective study with 156 patients diagnosed and followed up in the rheumatology clinic of the University Hospital of Ioannina. Sixty-four had ankylosing spondylitis (AS) and 92 had psoriatic arthritis (PsA). Health resource use for each patient was elicited through a retrospective chart review that documented the use of monitoring visits, medications, laboratory/diagnostic tests, and inpatient stays for the previous year from the date that the review took place. Costs were calculated from a third party payer perspective and are reported in 2014 euros. RESULTS: The mean +/- SD annual direct cost for the patients with SpA reached ?8680 +/- 6627. For the patients with PsA and AS, the cost was estimated to be ?8097 +/- 6802 and ?9531 +/- 6322, respectively. The major cost was medication, which represented 88.9%, 88.2%, and 89.3% of the mean total direct cost for SpA, AS, and PsA, respectively. The annual amount of the scheduled tests for all patients corresponded to 7.5%, and for those performed on an emergency basis, 1.1%. Further, the cost for scheduled and emergency hospitalization, as well as the cost of scheduled visits to an outpatient clinic, corresponded to 2.5% of the mean total annual direct cost for the patients with SpA. CONCLUSION: SpA carries substantial financial cost, especially in the era of new treatment options. Adequate access and treatment for patients with SpA remains a necessity, even in times of fiscal constraint. Thus, the recommendations of the international scientific organizations should be considered when administering high-cost drugs such as biological treatments. PMID- 25834214 TI - Response of Polygenic Traits Under Stabilizing Selection and Mutation When Loci Have Unequal Effects. AB - We consider an infinitely large population under stabilizing selection and mutation in which the allelic effects determining a polygenic trait vary between loci. We obtain analytical expressions for the stationary genetic variance as a function of the distribution of effects, mutation rate, and selection coefficient. We also study the dynamics of the allele frequencies, focusing on short-term evolution of the phenotypic mean as it approaches the optimum after an environmental change. We find that when most effects are small, the genetic variance does not change appreciably during adaptation, and the time until the phenotypic mean reaches the optimum is short if the number of loci is large. However, when most effects are large, the change of the variance during the adaptive process cannot be neglected. In this case, the short-term dynamics may be described by those of a few loci of large effect. Our results may be used to understand polygenic selection driving rapid adaptation. PMID- 25834215 TI - Analysis of RNA Interference Lines Identifies New Functions of Maternally Expressed Genes Involved in Embryonic Patterning in Drosophila melanogaster. AB - Embryonic patterning in Drosophila melanogaster is initially established through the activity of a number of maternally expressed genes that are expressed during oogenesis. mRNAs from some of these genes accumulate in the posterior pole plasm of the oocyte and early embryo and localize further into RNA islands, which are transient ring-like structures that form around the nuclei of future primordial germ cells (pole cells) at stage 3 of embryogenesis. As mRNAs from several genes with known functions in anterior-posterior patterning and/or germ cell specification accumulate in RNA islands, we hypothesized that some other mRNAs that localize in this manner might also function in these developmental processes. To test this, we investigated the developmental functions of 51 genes whose mRNAs accumulate in RNA islands by abrogating their activity in the female germline using RNA interference. This analysis revealed requirements for ttk, pbl, Hip14, eIF5, eIF4G, and CG9977 for progression through early oogenesis. We observed dorsal appendage defects in a proportion of eggs produced by females expressing double-stranded RNA targeting Mkrn1 or jvl, implicating these two genes in dorsal-ventral patterning. In addition, posterior patterning defects and a reduction in pole cell number were seen in the progeny of Mkrn1 females. Because the mammalian ortholog of Mkrn1 acts as an E3 ubiquitin ligase, these results suggest an additional link between protein ubiquitination and pole plasm activity. PMID- 25834217 TI - Measles: vaccinate, close loopholes. PMID- 25834216 TI - Comparative Genetics of Seed Size Traits in Divergent Cereal Lineages Represented by Sorghum (Panicoidae) and Rice (Oryzoidae). AB - Seed size is closely related to fitness of wild plants, and its modification has been a key recurring element in domestication of seed/grain crops. In sorghum, a genomic and morphological model for panicoid cereals, a rich history of research into the genetics of seed size is reflected by a total of 13 likelihood intervals determined by conventional QTL (linkage) mapping in 11 nonoverlapping regions of the genome. To complement QTL data and investigate whether the discovery of seed size QTL is approaching "saturation," we compared QTL data to GWAS for seed mass, seed length, and seed width studied in 354 accessions from a sorghum association panel (SAP) that have been genotyped at 265,487 SNPs. We identified nine independent GWAS-based "hotspots" for seed size associations. Targeted resequencing near four association peaks with the most notable linkage disequilibrium provides further support of the role(s) of these regions in the genetic control of sorghum seed size and identifies two candidate causal variants with nonsynonymous mutations. Of nine GWAS hotspots in sorghum, seven have significant correspondence with rice QTL intervals and known genes for components of seed size on orthologous chromosomes. Identifying intersections between positional and association genetic data are a potentially powerful means to mitigate constraints associated with each approach, and nonrandom correspondence of sorghum (panicoid) GWAS signals to rice (oryzoid) QTL adds a new dimension to the ability to leverage genetic data about this important trait across divergent plants. PMID- 25834218 TI - Body fluid composition. AB - Body fluid composition is maintained in a normal physiologic range by regulatory mechanisms that control sodium and water metabolism. A detailed knowledge of the homeostatic mechanisms will help in understanding the pathogenesis and management of disorders of sodium and water balance. OBJECTIVES: After completing this article, readers should be able to: 1. Understand the distribution of fluid and solute in different body compartments. 2. Demonstrate the homeostatic mechanisms involved in maintaining sodium and water metabolism. 3. Calculate osmolality and recognize the clinical importance of maintaining osmotic equilibrium. 4. Recognize common disorders of hypernatremia or hyperosmolality and evaluate and understand the role of calculating free water deficit in the treatment of these disorders. 5. Recognize common disorders of hyponatremia or hypo-osmolality, appreciate the role of urine sodium and urine osmolality in evaluation,and understand the importance of slow correction of these disorders. PMID- 25834219 TI - Urinary tract infections in children: knowledge updates and a salute to the future. AB - 1. Evaluating and treating bladder and bowel dysfunction are critical in reducing the risk of urinary tract infections (UTIs). 2. The pathogenesis of Escherichia coli infections reveals that quiescent intracellular reservoirs may be antibiotic protected sources of recurrent infections. OBJECTIVES: 1. Review the documentation of UTI and the importance of the urine culture. 2. Understand the controversy over imaging and management of febrile UTIs in children. 3. Recognize the risk factors for recurrent UTIs and strategies for intervention. 4. Update information on the pathogenesis of E coli UTIs. PMID- 25834220 TI - Escherichia coli Infections. AB - Virulent strains of Escherichia coli are responsible for most diarrheal infections, meningitis, septicemia, and urinary tract infections in children worldwide. Clinicians must learn to recognize, treat, and prevent these infections. OBJECTIVES: After completing this article, readers should be able to: 1. Describe the epidemiology of E coli infections. 2. Recognize the clinical features of E coli infections, including the O157: H7 strain. 3. Appropriately treat children with various types of E coli infections. 4. Understand ways to prevent E coli infections. PMID- 25834221 TI - Case 1: failure to thrive, microcephaly, and intracranial calcifications in a 6 week-old girl. PMID- 25834222 TI - Case 2: fatigue and abnormal behavior in a 17-year-old boy. PMID- 25834223 TI - Case 3: anterior neck swelling, fever, and hypertension in a 3-year-old boy. PMID- 25834224 TI - Addendum: Mood and affect disorders. PMID- 25834225 TI - Correction. AB - An error appeared in the December 2014 Index of Suspicion column (Pediatrics in Review. 2014;35(12):531-537, doi: 10.1542/pir.35-12-531). On page 533, in the Case 2 Presentation, paragraph 2, the sentence should read: " ...head circumference is 46.5 cm (>97th percentile)." The online version of the article was corrected. The journal regrets the error. PMID- 25834226 TI - Coccidioidomycosis. PMID- 25834227 TI - Visual diagnosis: 8-year-old boy with recurrent rash. PMID- 25834228 TI - The physiology of protein S-acylation. AB - Protein S-acylation, the only fully reversible posttranslational lipid modification of proteins, is emerging as a ubiquitous mechanism to control the properties and function of a diverse array of proteins and consequently physiological processes. S-acylation results from the enzymatic addition of long chain lipids, most typically palmitate, onto intracellular cysteine residues of soluble and transmembrane proteins via a labile thioester linkage. Addition of lipid results in increases in protein hydrophobicity that can impact on protein structure, assembly, maturation, trafficking, and function. The recent explosion in global S-acylation (palmitoyl) proteomic profiling as a result of improved biochemical tools to assay S-acylation, in conjunction with the recent identification of enzymes that control protein S-acylation and de-acylation, has opened a new vista into the physiological function of S-acylation. This review introduces key features of S-acylation and tools to interrogate this process, and highlights the eclectic array of proteins regulated including membrane receptors, ion channels and transporters, enzymes and kinases, signaling adapters and chaperones, cell adhesion, and structural proteins. We highlight recent findings correlating disruption of S-acylation to pathophysiology and disease and discuss some of the major challenges and opportunities in this rapidly expanding field. PMID- 25834229 TI - The evolving impact of g protein-coupled receptor kinases in cardiac health and disease. AB - G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent beta-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure. PMID- 25834231 TI - Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. AB - The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L cells) of the intestinal mucosa, pancreatic islet alpha-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis. PMID- 25834233 TI - Metabolic methanol: molecular pathways and physiological roles. AB - Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amounts of methanol and formaldehyde, the content of these molecules increases sharply after receiving even methanol-free ethanol, indicating an endogenous source of the metabolic methanol present at low levels in the blood regulated by a cluster of genes. Recent studies of the pathogenesis of neurological disorders indicate metabolic formaldehyde as a putative causative agent. The detection of increased formaldehyde content in the blood of both neurological patients and the elderly indicates the important role of genetic and biochemical mechanisms of maintaining low levels of methanol and formaldehyde. PMID- 25834235 TI - Concerning the validity of gastrointestinal extracellular recordings. PMID- 25834236 TI - Reply to O'Grady et al. PMID- 25834237 TI - Does a positive HLA-B27 test increase your risk of mortality? PMID- 25834238 TI - Analysis of bone samples from patients with spondyloarthritides-identifying causes of new bone formation in axial spondyloarthritis. PMID- 25834239 TI - Osseous sarcoid. PMID- 25834232 TI - Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. AB - This review focuses on how blood flow to contracting skeletal muscles is regulated during exercise in humans. The idea is that blood flow to the contracting muscles links oxygen in the atmosphere with the contracting muscles where it is consumed. In this context, we take a top down approach and review the basics of oxygen consumption at rest and during exercise in humans, how these values change with training, and the systemic hemodynamic adaptations that support them. We highlight the very high muscle blood flow responses to exercise discovered in the 1980s. We also discuss the vasodilating factors in the contracting muscles responsible for these very high flows. Finally, the competition between demand for blood flow by contracting muscles and maximum systemic cardiac output is discussed as a potential challenge to blood pressure regulation during heavy large muscle mass or whole body exercise in humans. At this time, no one dominant dilator mechanism accounts for exercise hyperemia. Additionally, complex interactions between the sympathetic nervous system and the microcirculation facilitate high levels of systemic oxygen extraction and permit just enough sympathetic control of blood flow to contracting muscles to regulate blood pressure during large muscle mass exercise in humans. PMID- 25834240 TI - "Mutilans-type" Jaccoud Arthropathy. PMID- 25834241 TI - Evaluation of leptin with atherosclerosis in rheumatoid arthritis. PMID- 25834243 TI - Monoclonal antibodies, systemic lupus erythematosus, and pregnancy: insights from an open-label study. PMID- 25834242 TI - Dr. Dessein, et al reply. PMID- 25834244 TI - Inclusion body myositis in a patient with RNA polymerase III antibody-positive systemic sclerosis. PMID- 25834234 TI - Transient receptor potential channels in the vasculature. AB - The mammalian genome encodes 28 distinct members of the transient receptor potential (TRP) superfamily of cation channels, which exhibit varying degrees of selectivity for different ionic species. Multiple TRP channels are present in all cells and are involved in diverse aspects of cellular function, including sensory perception and signal transduction. Notably, TRP channels are involved in regulating vascular function and pathophysiology, the focus of this review. TRP channels in vascular smooth muscle cells participate in regulating contractility and proliferation, whereas endothelial TRP channel activity is an important contributor to endothelium-dependent vasodilation, vascular wall permeability, and angiogenesis. TRP channels are also present in perivascular sensory neurons and astrocytic endfeet proximal to cerebral arterioles, where they participate in the regulation of vascular tone. Almost all of these functions are mediated by changes in global intracellular Ca(2+) levels or subcellular Ca(2+) signaling events. In addition to directly mediating Ca(2+) entry, TRP channels influence intracellular Ca(2+) dynamics through membrane depolarization associated with the influx of cations or through receptor- or store-operated mechanisms. Dysregulation of TRP channels is associated with vascular-related pathologies, including hypertension, neointimal injury, ischemia-reperfusion injury, pulmonary edema, and neurogenic inflammation. In this review, we briefly consider general aspects of TRP channel biology and provide an in-depth discussion of the functions of TRP channels in vascular smooth muscle cells, endothelial cells, and perivascular cells under normal and pathophysiological conditions. PMID- 25834245 TI - Combined physical and chemical methods to control lesser mealworm beetles under laboratory conditions. AB - The lesser mealworm beetle, Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae), is an important insect pest. The insect acts as a disease vector and reservoir, negatively affecting the health of birds and humans, and harming poultry husbandry. Controlling the lesser mealworm is generally based on using synthetic chemical insecticides, which are sometimes ineffective, and is limited due to market concerns regarding the toxicity of chemical residues in food products. In this context, the present study aimed to evaluate the potential for the combination of physical and chemical methods to control A. diaperinus. Bioassays were conducted using poultry bedding and known populations of beetle adults and larvae. The treatments consisted of the isolated application of 400 g/m2 hydrated lime; 20% added moisture (distilled water); temperature increase to 45 degrees C; an insecticide composed of cypermethrin, chlorpyrifos, and citronellal; and a combination of these factors. Beetle mortality was measured at 7 and 10 d of treatment. The hydrated lime and moisture treatments alone did not control A. diaperinus. Raising the temperature of the poultry bedding to 45 degrees C effectively controlled both larvae (90+/-6%) and adults (90+/-4%). The use of insecticide provided adequate control of A. diaperinus in the conditions of the bioassay (93+/-2% and 68+/-5% for adults and larvae, respectively). The combination of the studied factors led to the total control of larvae and adults after 7 d of treatment. PMID- 25834246 TI - Effects of feed supplemented with fermented pine needles (Pinus ponderosa) on growth performance and antioxidant status in broilers. AB - The objective of this study was to compare the effects of Aspergillus niger fermented pine needles and nonfermented pine needles on growth performance and antioxidant capacity in broiler chicks. In total, 300 1-day-old broiler chicks were randomly allocated to 5 dietary treatments, which were then denoted as the control treatment (basal diet); the nonfermented treatment (containing 0.3% and 0.6% nonfermented treatment, respectively, in the starter and grower phase); or the fermented 1, fermented 2, or fermented 3 treatments. The fermented 1, fermented 2, and fermented 3 treatments contained 0.1, 0.3, and 0.5% fermented treatment, respectively, in the starter phase and 0.2, 0.6, and 1.0% fermented treatment, respectively, in the growth phase for 42 d. The results showed that fermentation treated supplementation had no adverse effect on the growth performance of broilers at 42 d of age. The activity of total nitric oxide synthase was significantly (P<0.05) decreased in the fermented treatment compared with the control and nonfermented treatments in broilers at 21 d of age. Compared with the control, broilers had higher (P<0.05) total superoxide dismutase activities and total antioxidant capacity when they were provided with either the fermented 2 or fermented 3 diet. The malondialdehyde content was significantly (P<0.05) decreased in the fermented 2 and fermented 3 treatments compared with the control and nonfermented treatments. It was concluded that the addition of fermented treatment to the diet could improve antioxidant capacity in broilers, as evidenced by the decrease in malondialdehyde and the increase in total superoxide dismutase activities; however, the effect of fermentation treatment on growth performance was negligible. PMID- 25834247 TI - The response of meat ducks from 15 to 35 d of age to gossypol from cottonseed meal. AB - The objective of this study was to investigate the responses of meat ducks of 15 to 35 d of age to free gossypol (FG) from cottonseed meal (CSM) and to establish the maximum limits of dietary FG concentration based on growth performance, blood parameters, and tissue residues of gossypol. Nine hundred 15-d-old ducks were randomly allocated to 5 treatments with 10 cages/treatment and 18 ducks/cage on the basis of BW. Five isonitrogenous and isocaloric experimental diets were formulated on a digestible amino acid basis to produce diets in which 0% (without FG), 25% (36 mg FG/kg), 50% (75 mg FG/kg), 75% (111 mg FG/kg), and 100% (153 mg FG/kg) of protein from soybean meal were replaced by that from CSM. Increasing dietary FG content, BW, and ADG decreased (linearly, P<0.05, except for ADG of days 29 to 35), and F/G linearly increased (P<0.05). At 35 d, blood hemoglobin, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration linearly decreased (P<0.05), while serum total protein, albumin, and globulin content linearly decreased (P<0.05), and the residue of gossypol in liver, kidney, heart, breast, and leg muscle linearly increased (P<0.001) with increases in dietary FG concentration. Ducks fed 36 mg FG/kg (5.83% CSM of diet) diet had a normal histological structure of liver, and muscle (breast and leg) had no residue of gossypol. The maximum limit of dietary FG concentration was estimated to range from a low of 36 mg/kg to maximize serum globulin concentration to a high of 124 mg/kg to minimize feed intake for 22 to 28 d on the basis of a quadratic broken-line model. PMID- 25834248 TI - Higher rates of internal ovulations occur in broiler breeder hens treated with testosterone. AB - Maximal profit in both the commercial egg and meat industries requires that the quantity of oviposited eggs closely matches the quantity of large yellow follicles maturing in the ovary. While laying hens are genetically selected for maximal egg production and strategies for management of broiler breeders have been constructed to achieve a similar outcome, a percentage of ovarian follicles that are selected into the ovulatory hierarchy in these hens still never make it to oviposition possibly due to atresia of large yellow follicles or internal ovulation of the oocyte into the peritoneal cavity rather than the oviduct. The causes and mechanisms responsible for these processes remain unclear, however, evidence in wild birds suggests that stressful and/or territorial challenges may stimulate oocyte losses. Since testosterone and corticosterone are central to the responses to territorial intrusions and stress, respectively, and since both large yellow follicles and the oviduct that will engulf them are sensitive to hormonal cues, one or both hormones may play a role in the loss of large yellow follicles via atresia and/or internal ovulation in laying hens. To test this, broiler breeder hens were treated with corticosterone or testosterone 5 h prior to ovulation and observed to see whether these treatments influenced the likelihood that a hen would lay an egg 24 h after the predicted ovulation time. A subset of hens that did not lay an egg were killed and dissected to look for evidence of follicle atresia and internal ovulation. Testosterone treatment resulted in significantly more oocyte losses, and 60% of these occurred due to internal ovulations, as was indicated by the presence of yolk in the peritoneal cavity. Corticosterone did not influence the rate of oocyte losses, follicle atresia, or internal ovulation. These results suggest that testosterone can cause disruptions that ultimately prevent the oviduct from capturing the oocyte after ovulation. PMID- 25834249 TI - Absolute quantification of a very virulent Marek's disease virus dynamic quantity and distributions in different tissues. AB - Chickens infected with Marek's disease virus (MDV) carry the virus consistently for a long time, which increases the incidence and rate of virus-induced multi organ tumors and increases its potential for horizontal transmission. There is a positive correlation between very virulent (vv) MDV quantity and the pathology. The purpose of this study was to determine the vvMDV loads dynamics in different phases, and the correlation between the viral quantity and tumor development. We used a SYBR Green duplex real-time quantitative PCR (q-PCR) assay to detect and quantify MDV loads and distributions in different tissues, targeting the Eco-Q protein gene (meq) of the virus and the house-keeping ovotransferrin (ovo) gene of chickens. The q-PCR was performed using different tissue DNA preparations derived from chickens which were infected with 1,000 pfu of the SDWJ1302 strain and tissue samples were collected from control and MDV-infected birds on 7, 10, 15, 21, 28, 40, 60, and 90 d post-infection (DPI). The data indicated that the MDV genome was almost quantifiable in immune organs of infected chickens as early as 7 DPI, and the number of MDV genome copies in the blood and different organs peaked by 28 DPI, but then gradually decreased by 40 DPI. The levels of viral quantity in the lymphocytes, liver, and spleen were all higher than those in other organs, and that in the feather follicles was the highest among different phases of MDV infection. The vvMDV could still be detected in peripheral blood and tissues by 90 DPI, and the vast existence of virus will stimulate tissue destruction. The data provided further evidence of viral infection involving multi-organ distribution and mainly involving immune organ proliferation, resulting in immunosuppression. PMID- 25834250 TI - Sensory quality of broiler breast meat influenced by low atmospheric pressure stunning, deboning time and cooking methods. AB - Stunning method (low atmospheric pressure stunning, LAPS and electrical stunning, ES), deboning time (0.75 h and 4 h), and cooking method (baking, frying, and sous vide) were evaluated for their impact on the descriptive sensory characteristics and consumer acceptability of breast meat (n=576, 144 birds per stunning * deboning time combination). Sensory evaluation was conducted by trained descriptive (n=8) and consumer (n=185) panels. On average, no differences (P>0.05) existed in the sensory acceptability of fried and sous vide cooked broiler breast treatment combinations. However, for oven-baking, the LAPS treatment that was deboned at 4 h was more acceptable (P<0.05) than other treatments and the ES and LAPS 4 h samples had greater (P<0.05) acceptability for texture than their ES and LAPS 0.75 h counterparts. Since consumers were highly variable in their liking of chicken breast treatments, consumers were grouped into clusters for each cooking method based on liking and preference. Cluster analysis data revealed that the largest groups of consumers liked (score>=6.0) all chicken breast treatments, but a larger proportion of consumers liked the 4 h LAPS and ES treatments when compared to the 0.75 h LAPS and ES treatments for all cooking methods. In addition, the consumers who indicated that baked chicken breast was highly acceptable preferred (P<0.05) 4 h LAPS over the 4 h ES samples. Based on sensory results, chicken breast meat from all stunning and deboning method combinations was highly acceptable to the majority of consumers, but the LAPS 4 h treatment had enhanced sensory characteristics when baked. PMID- 25834251 TI - Partition of metabolizable energy, and prediction of growth performance and lipid deposition in broiler chickens. AB - The study presented here consisted of the calculation of cross relationships between growth performance parameters, body growth composition, and feed characteristics, using data from an experiment reported in 2 previous publications. In the previous experiment, 30 pelleted diets were given to broiler chickens (8/diet) (21 to 35 d) for in vivo measurement and prediction of AMEn and net energy (NE) values of diets, using 3 trials with 10 diets/trial. In the course of NE determination, individual values for growth, feed intake, and deposition of lipid and protein were measured. Average energy deposited as lipid and protein represented 25.4 and 19.1% AME intake, respectively. Using a multiple regression predicting AME intake, the partial efficiencies of AME for energy deposition as lipid and protein were calculated to be 91.6 and 67.3%, respectively, and the daily amount of AME required for maintenance was evaluated at 0.683 MJ/kg BW0.7. The mean diet NE/AMEn ratios were predicted by an equation combining the lipid content of body growth (positive coefficient) and the apparent digestible protein (ADP) to AMEn ratio (ADP/AMEn), with a quadratic expression for the latter variable. This quadratic response expressed a positive asymptotic relationship, with a plateau for ADP/AMEn values above 1.45 [%/(MJ/kg)]. The equations predicting growth always included either the dietary percentage of water-insoluble cell wall or the AMEn value. The other major parameters predicting growth were either the lipid content of body growth or the CP/AMEn ratio. In many cases, quadratic responses were observed in growth prediction equations. Regressions predicting feed efficiency showed only linear responses. Feed efficiency was predicted precisely by multiple linear regressions based only on AMEn and a dietary protein parameter. According to these regressions, 1% CP was equivalent to 0.247 MJ/kg AMEn in terms of feed efficiency. The most efficient regression predicting the individual lipid content of body growth combined the protein efficiency value (negative coefficient), the CP/AMEn ratio (negative coefficient), AMEn (positive coefficient), and the feather content of body growth (positive coefficient). PMID- 25834252 TI - Modulation of small intestinal phosphate transporter by dietary supplements of mineral phosphorus and phytase in broilers. AB - Dietary phosphorus (P) is known as a main modulator of phosphate (Pi) transporter expression. The effect of supplemented mineral P with or without phytase on protein expression of two sodium-dependent Pi (NaPi) transporters and a calcium channel was studied in the small intestine of broilers. Thirty-six broilers were randomly assigned to six different diets at 15 days of age. Two levels of total P (tP, adjusted by monocalcium phosphate (MCP) supplementation), 0.39% (BD-) and 0.47% (BD+) were fed until day 25; and at each tP level, three levels of phytase were used with 0, 500, and 12,500 FTU/kg of an E. coli phytase. Mucosa samples from jejunum and ileum were taken and apical membranes were isolated by MgCl2 precipitation. Protein expression of NaPi IIb, NaPi type III (PiT1) and the calcium channel TRPV6 were semiquantitatively measured by Western blotting and jejunal mucosal phytase activity by measurement of Pi release. The jejunal NaPi IIb transporter was expressed with two distinct bands, which were modulated differently by diet. NaPi IIb Band1 increased (P < 0.05) and Band2 decreased (P < 0.05) with phytase supplementation but was not affected by MCP supplementation. This inverse modulation of Band1 and Band2 was significantly related to the amount of net absorbed P with higher expression of Band1 at higher amounts of net absorbed P. In addition, a second Pi transporter, PiT1, was detected in which ileal expression decreased (P < 0.05) in response to higher phytase supplementation. The expression of the calcium channel TRPV6 was increased in BD+ groups. A trend for an interaction between MCP and phytase supplementation on mucosal phytase activity was observed (P = 0.079) with a decrease in activity when BD+ with 12,500 FTU/kg phytase was fed. Chicken intestinal epithelial cells responded to dietary supplemented phytase and MCP by changing the Pi transporter expression in apical membranes. In conclusion, availability of Pi is most likely the key modulator of transporter protein expression. However, a contribution of lower inositol phosphates generated by phytases and other phosphatases may also be relevant. PMID- 25834253 TI - Chromatin immunoprecipitation with fixed animal tissues and preparation for high throughput sequencing. PMID- 25834254 TI - Rabies viral vectors for monosynaptic tracing and targeted transgene expression in neurons. AB - Deletion-mutant rabies viral (RV) vectors are powerful tools for neuroscience, allowing monosynaptic tracing of inputs to defined populations and rapid, high level transgene expression in neurons targeted by multiple routes. High titers and high purity are critical for the successful use of RV vectors in vivo. Here we present a protocol for producing high-quality viral stocks that can be concentrated by ultracentrifugation for final titers in excess of 10(10) infectious units per milliliter. PMID- 25834255 TI - Lentiviral vectors for retrograde delivery of recombinases and transactivators. AB - Lentiviral vectors pseudotyped with the rabies virus (RV) envelope glycoprotein efficiently infect via axon terminals to stably deliver transgenes to distant neurons projecting to an injection site, but the resulting expression levels are too low and variable for most neuroscientific applications. If used to deliver recombinases or transactivators, however, lentiviral vectors are excellent means of targeting projection neurons when used in reporter mice or in combination with a second virus to express "payload" transgenes at high levels. For retrograde infection of significant numbers of neurons, high virus titers are critical. Here we present reagents and a protocol for generating high-titer supernatants that can be concentrated 1000-fold for final titers in excess of 10(10) infectious units per milliliter. We demonstrate the usefulness of these vectors by selectively targeting corticothalamic and corticotectal neurons for high-level expression of a fluorophore in knock-in reporter mice. PMID- 25834256 TI - Concentration and purification of rabies viral and lentiviral vectors. AB - Rabies viral and lentiviral vectors are very useful tools for neuroscientists, but high titer and purity are critical for in vivo applications. Here we present a protocol for concentration and purification of viral stocks by ultracentrifugation on a sucrose step gradient to remove impurities of both higher and lower densities than the virus itself, with sucrose removed by a subsequent pelleting step. The final stocks are concentrated in volume by a factor of up to 1000, with higher expected purity than is obtained following previously published protocols for preparing G-deleted rabies viral vectors. PMID- 25834257 TI - Basic methods for monitoring intracellular Ca2+ in cardiac myocytes using Fluo-3. AB - In cardiac myocytes, the physiological increase of intracellular calcium, the [Ca(2+)]i transient, elicited during excitation-contraction coupling typically reaches a peak amplitude of up to 1 um, from a resting value of ~100 nm, within 50-100 msec, depending on the species. Various conditions will affect the amplitude and rise time of the [Ca(2+)]i transient and, depending on the nature of the Ca(2+) signals under study, a variety of different probes are available for monitoring changes in intracellular Ca(2+). In this protocol, we focus on Fluo-3, which exists in the cytosol in its salt form K5Fluo-3. This form is practically nonfluorescent in the absence of Ca(2+), but the fluorescence increases dramatically on Ca(2+) binding. Although Fluo-3 is a single excitation emission dye, it has a number of advantages for investigators, including an ideal dissociation constant (Kd) value and high quantum yield, meaning that it can be used at low concentrations that introduce minimal buffering. Here, we describe the basic setup and methodology for recording the global cytosolic [Ca(2+)]i transient with this probe during simultaneous patch-clamp and whole-cell recording of membrane voltage or of ionic currents under voltage clamp. PMID- 25834258 TI - Characterizing the trigger for sarcoplasmic reticulum Ca2+ release in cardiac myocytes. AB - Here, we describe a method for characterizing the L-type Ca(2+) current, ICaL, which is a major trigger for Ca(2+) release from the sarcoplasmic reticulum (SR). The protocol includes measuring ICaL amplitude and voltage dependence and the elicited SR Ca(2+) release. The procedure for measuring ICaL activity is performed using solutions (internal and external) and voltage control such that other ionic currents are eliminated. The resultant relationship between the Ca(2+) current and the associated internal [Ca(2+)]i transient is a first approach for evaluating coupling gain. We discuss which parameters are most appropriate for this analysis and how an evaluation of gain needs to be further explored by measuring the SR Ca(2+) content. PMID- 25834259 TI - Measuring sarcoplasmic reticulum Ca2+ content, fractional release, and Ca2+ buffering in cardiac myocytes. AB - Here, we describe a protocol for the reliable measurement of the amount of Ca(2+) in the sarcoplasmic reticulum (SR) Ca(2+) store of cardiac myocytes. The whole cell patch-clamp method is used to provide controlled loading of the SR during conditioning depolarizing pulses, followed by rapid application of a high dose of caffeine to release all SR Ca(2+) and to prevent Ca(2+) reuptake by the SR. Simultaneous measurement of membrane currents records Ca(2+) extruded through the Na(+)-Ca(2+) exchanger. The integral of the caffeine-induced Na(+)-Ca(2+) exchange current is then used as a measure of the SR Ca(2+). Derived measurements include the Ca(2+) buffering capacity and measurement of fractional release as an indicator of coupling gain. Caveats, advantages, and disadvantages of this method and alternative methods are discussed. PMID- 25834260 TI - Culturing adult stem cells from mouse small intestinal crypts. AB - In recent years, the study of primary cells in culture has evolved from an extraphysiological, two-dimensional platform to novel, three-dimensional platforms in which the addition of matrix components and/or supporting cells provide an ex vivo niche. Such studies have provided the basis on which to study more advanced physiological processes in detail, including multilayered, long term cultures, epithelial-stromal interactions, and stem cell behaviors that more closely recapitulate normal morphology than two-dimensional culture. Various techniques for three-dimensional organotypic culture and crypt culture of primary cells from mouse and human small intestine and colon have been described. These methods have allowed for the study of specific stem cell characteristics, including survival, self-renewal, and long-term growth in culture, as well as the ability to propagate all the appropriate progenitor and postmitotic lineages. These assays have become a widely accepted functional measure of "stemness" and, in combination with lineage-tracing experiments in various genetically engineered mouse models, have been critical in the identification of specific markers of intestinal stem cells. In this protocol we draw upon recently described methods for the isolation and culture of mouse small intestinal enterospheres/enteroids from isolated crypts and/or single cells. Cultures of murine colon epithelium, as well as human small intestine and colon, require additional growth factors not discussed here. The description provided here represents current knowledge, and it is possible, if not likely, that modifications in the future will emerge. PMID- 25834261 TI - Three-dimensional organotypic culture of stratified epithelia. AB - One of the limitations of conventional tissue culture on flat two-dimensional surfaces is the loss of complex interactions between the epithelium and stroma. We have devised a culture system that recreates the salient features of the stratified epithelium using primary cell cultures from mouse models. The protocol described here is applicable to the esophageal epithelium, but stratified epithelial cells from other organs (e.g., skin) can be grown. Once established, the system can be used to interrogate the effect of various pharmacologic and genetic manipulations on epithelial homeostasis and invasion. PMID- 25834262 TI - Quantification of cell, actin, and nuclear DNA morphology with high-throughput microscopy and CalMorph. AB - Automated image acquisition and processing systems have been developed to quantitatively describe yeast cell morphology. These systems are superior to the preceding qualitative methods in terms of reproducibility, as they completely avoid subjective recognition of images. Because high-throughput microscopy has enabled rapid production of numerous cellular images, reinforcement of high performance and high-throughput automated image-processing techniques has been in increasing demand in the field of biology. This protocol describes how to use a high-throughput microscope in conjunction with the image-processing software CalMorph, which outputs more than 500 morphological parameters, for quantification of cell, actin, and nuclear DNA morphology. PMID- 25834263 TI - Measuring the length of poly(A) tails. AB - Adenylation status has an important role in the regulation of mRNA metabolism: mRNAs are deadenylated before degradation, microRNAs (miRNAs) can cause deadenylation, and the poly(A) length of certain mRNAs is regulated during development. This protocol describes methods that can be used to measure the poly(A) tail length of specific mRNAs. These include, in the order of increasing sensitivity, (1) northern blotting of intact and experimentally deadenylated mRNAs and (2) northern blotting of intact and experimentally deadenylated mRNA fragments that have been cleaved near the 3' end with RNase H. Highly sensitive polymerase chain reaction (PCR)-based approaches are also discussed. PMID- 25834264 TI - Isolation of ribosomes by chromatography. AB - Mixed-mode chromatography on cysteine-SulfoLink resin efficiently separates ribosomes from cell lysates and is particularly effective at rapidly removing endogenous proteases and nucleases, resulting in ribosomes of improved purity, integrity, and activity. Binding occurs partly by anion exchange of the RNA of the ribosomes, so that cells must be lysed in a buffer of moderate ionic strength (conductivity no more than 20 mS for chromatography of bacterial ribosomes) without any highly charged additives (e.g., heparin, which is used to inhibit RNases in yeast). A robust protocol for Escherichia coli is given here as an example. PMID- 25834265 TI - Dissociation of ribosomes into large and small subunits. AB - Structural and functional studies of ribosomal subunits require the dissociation of intact ribosomes into individual small and large ribosomal subunits. The dissociation of the prokaryotic 70S ribosomes into the 50S and 30S subunits is achieved by dialysis against a buffer containing a lower Mg(2+) concentration. Eukaryotic 80S ribosomes are dissociated into 60S and 40S subunits by incubation in a buffer containing puromycin and higher KCl and Mg(2+) concentrations. PMID- 25834266 TI - Strategies for isolation of exosomes. AB - Exosomes are tiny vesicles (diameter 30-150 nm) secreted by cells in culture and found in all body fluids. These vesicles, loaded with unique RNA and protein cargos, have many biological functions, of which only a small fraction is currently understood-for example, they participate in cell-to-cell communication and signaling within the human body. The spectrum of current scientific interest in exosomes is wide and ranges from understanding their functions and pathways to using them in diagnostics, as biomarkers, and in the development of therapeutics. Here we provide an overview of different strategies for isolation of exosomes from cell-culture media and body fluids. PMID- 25834267 TI - Image correlation spectroscopy: principles and applications. AB - Image correlation spectroscopy (ICS) was developed as the imaging analog of fluorescence correlation spectroscopy. Using standard fluorescence microscopy image series as input, different versions of ICS can be used to extract parameters on the molecular transport properties (diffusion and flow) and oligomerization state for fluorescently labeled species in cells. This review introduces the various forms of spatial and temporal ICS and discusses application of these methods to reveal properties of the biomolecules that can be measured from standard fluorescence image time series sampled from cells and neurons. PMID- 25834268 TI - Progress in public health in the Year of the Goat. PMID- 25834269 TI - Health promotion financing with Mongolia's social health insurance. AB - Health promotion is receiving more attention in Mongolia. A survey is undertaken to examine health promotion in terms of health-related information, education, counseling, screening, preventive and medical checkups. Almost all (97.5%) of the subjects feel that access to reliable and systematically organized health-related information is important. About 60% of the subjects expressed that the amount of currently available information is inadequate. There are several factors that limit the implementation of public health programs. These include inadequate focus on promoting health at individual level, lack of funds, and limited incentives to promote health. This article examined social health insurance as an option to address these issues. Three hypothetical benefits package options expanded to health promotion were developed and simulated by a computerized tool. The simulations show that all 3 options are financially sustainable at the existing level of contribution if Mongolia will gain near universal health insurance coverage and improve revenue collection practices. PMID- 25834270 TI - Factors influencing the hospitalization costs of patients with type 2 diabetes. AB - This study aims to research the factors influencing the hospitalization costs of patients with type 2 diabetes, so as to provide some references for reducing their economic burden. Based on the Hospital Information System of a 3A grade hospital in China, we analyzed 2970 cases with type 2 diabetes during 2005-2012. Both the number of inpatients and the hospitalization costs had increased in the study period. Using multiple linear regression analysis, we found that patients in Urban Employee Basic Medical Insurance had higher costs than those in New Rural Cooperative Medical Scheme. We also found hospitalization costs to be higher in male patients and older patients, patients who stayed more days at hospital and who had surgeries, patients who had at least 1 complication, and patients whose admission status was emergency. After standardizing the regression coefficients, we found that the hospital stay, the forms of payment, and presence of complications were the first 3 factors influencing hospitalization costs in our study. In conclusion, the hospitalization costs of patients with type 2 diabetes could be influenced by age, gender, forms of payment, hospital stay, admission status, complications, and surgery. Medical workers in the studied region should take actions to reduce the duration of hospital stay for diabetic patients and prevent relevant complications. What is more, medical insurance needs further improvement. PMID- 25834271 TI - Neck and shoulder muscle strength in patients with tension-type headache: A case control study. AB - INTRODUCTION: Tension-type headache (TTH) is highly prevalent in the general population, and it is characterized by increased muscle tenderness with increasing headache frequency and intensity. AIM: The aim of this case-control study was to compare muscle strength in neck and shoulder muscles in TTH patients and healthy controls by examining maximal voluntary isometric contraction (MVC) during shoulder abduction, neck flexion and extension as well as the extension/flexion strength ratio of the neck. METHODS: Sixty TTH patients and 30 sex- and age-matched healthy controls were included. Patients were included if they had TTH >=8 days per month. The MVC neck extensor and flexor muscles were tested with the participant seated upright. MVC shoulder abduction was tested with the individual lying supine. RESULTS: Compared to controls TTH patients had significantly weaker muscle strength in neck extension (p = 0.02), resulting in a significantly lower extension/flexion moment ratio (p = 0.03). TTH patients also showed a tendency toward significantly lower muscle strength in shoulder abduction (p = 0.05). Among the 60 TTH patients, 25 had frequent episodic TTH (FETTH), and 35 had chronic TTH (CTTH). CONCLUSION: Patients with TTH exhibited decreased muscle strength in the neck extensor muscles, inducing a reduced cervical extension/flexion ratio compared to healthy people. PMID- 25834272 TI - Effective occipital nerve stimulation during pregnancy in a cluster headache patient. PMID- 25834273 TI - Dysplastic Nevus: Management by Canadian Dermatologists. AB - BACKGROUND: The management of dysplastic nevi is controversial. No studies have collected data regarding management of the lesion amongst Canadian dermatologists. OBJECTIVE: To provide a comprehensive review of what the prevailing opinions are, regarding treatment and terminology of dysplastic nevi, amongst Canadian dermatologists. METHODS: An online survey of 25 questions was e mailed to 613 members of the Canadian Dermatology Association, in French and English. RESULTS: A total of 179 responses were received. Varying numbers of participants completed each question. The majority of participants think that the term dysplastic nevus should not be abandoned, and they indicated that they never reexcise lesions with mild to moderate atypia even when the margins are positive. CONCLUSIONS: The majority of Canadian dermatologists retain the use of the term dysplastic nevus and do not reexcise lesions with mild to moderate atypia even when the margins are positive. PMID- 25834274 TI - Lack of evidence and standardization in care pathway documents for patients with ST-elevated myocardial infarction. AB - BACKGROUND: Clinical practice variation and the subsequent burden on health care quality has been documented for patients with ST-elevated myocardial infarction (STEMI). Reduction of clinical practice variation is possible by increasing guideline adherence. Care pathway documents can increase guideline adherence by implementing evidence-based key interventions and quality indicators in daily practice. AIMS: This study aims to examine guideline adherence of care pathway documents for patients with STEMI. METHODS: Lay-out, size and timeframe of submitted care pathways documents were analysed. Two independent reviewers used a checklist to systematically assess the guideline adherence of care pathway documents. The checklist comprised a set of key interventions and quality indicators extracted from evidence and international guidelines. The checklist distinguished the evidence level for each item and was validated by expert consensus. Results were verified by inviting participating hospitals to provide feedback. RESULTS: Fifteen out of 25 invited hospitals submitted care pathway documents for STEMI. The care pathway documents differed in timeframe, lay-out and size. Analysis of the care pathway documents showed important variation in formalizing adherence to evidence: between hospitals, inclusion of 24 key interventions in care pathway documents varied from 13 to 97%. Inclusion of 11 essential quality indicators varied from 0 to 40%. CONCLUSION: Care pathway documents for patients with STEMI differ considerably in lay-out, timeframe and size. This study showed variation in, and suboptimal inclusion of, evidence-based key interventions and quality indicators in care pathway documents. The use of these care pathway documents might result in suboptimal quality of care for STEMI patients. PMID- 25834275 TI - Do lifestyle restrictions and precautions prevent dislocation after total hip arthroplasty? A systematic review and meta-analysis of the literature. AB - OBJECTIVE: A systematic literature review and meta-analysis on the effectiveness of lifestyle restrictions and precautions to prevent dislocation after total hip arthroplasty. DATA SOURCES: MEDLINE and the Cochrane Library were searched in February 2015, with additional hand searching of systematic reviews and reference lists. REVIEW METHODS: This review was conducted in accordance with the PRISMA statement for reporting systematic reviews and meta-analysis. PubMed and the Cochrane Library were searched from their start date through to February 2015. Randomized controlled trials and comparative case series in English, Dutch or German language were included. Only primary total hip arthroplasty procedures managed with different postoperative restrictions and precautions protocols were included. Primary outcome was the total hip arthroplasty dislocation rate, secondary outcomes were patient functioning, return to activities of daily living and patient satisfaction. RESULTS: A total of 119 eligible articles were identified, six were included: three randomized controlled trials, one retrospective matched cohort study, one retrospective and one prospective cohort study, describing 1122 procedures (restrictions group: n = 528; no restrictions group: n = 594). Both the standard posterior and anterolateral surgical approaches were included. There were eight dislocations (1.5%) in the restricted group, vs. six dislocations (1.0%) in the unrestricted group. Patients in the unrestricted group resumed activities significantly faster and were more satisfied with their pace of recovery. CONCLUSION: A more liberal lifestyle restrictions and precautions protocol will not lead to worse dislocation rates after total hip arthroplasty, but will lead to earlier and better resumption of activities and higher patient satisfaction. These results appear to hold up for various surgical approaches. PMID- 25834230 TI - Renal autoregulation in health and disease. AB - Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study. PMID- 25834276 TI - Efficacy of the Alexander Technique in treating chronic non-specific neck pain: a randomized controlled trial. AB - OBJECTIVE: To test the efficacy of the Alexander Technique, local heat and guided imagery on pain and quality of life in patients with chronic non-specific neck pain. DESIGN: A randomized controlled trial with 3 parallel groups was conducted. SETTING: Outpatient clinic, Department of Internal and Integrative Medicine. SUBJECTS: A total of 72 patients (65 females, 40.7+/-7.9 years) with chronic non specific neck pain. INTERVENTIONS: Patients received 5 sessions of the Alexander Technique--an educational method which aims to modify dysfunctional posture, movement and thinking patterns associated with musculoskeletal disorders. Control groups were treated with local heat application or guided imagery. All interventions were conducted once a week for 45 minutes each. MAIN MEASURES: The primary outcome measure at week 5 was neck pain intensity on a 100-mm visual analogue scale; secondary outcomes included neck disability, quality of life, satisfaction and safety. STATISTICS: Analyses of covariance were applied; testing ordered hypotheses. RESULTS: No group difference was found for pain intensity for the Alexander Technique compared to local heat (difference 4.5mm; 95% CI: 8.1;17.1; p=0.48), but exploratory analysis revealed the superiority of the Alexander Technique over guided imagery (difference -12.9 mm; 95% CI:-22.6;-3.1, p=0.01). Significant group differences in favor of the Alexander Technique were also found for physical quality of life (P<0.05). Adverse events mainly included slightly increased pain and muscle soreness. CONCLUSION: The Alexander Technique was not superior to local heat application in treating chronic non-specific neck pain. It cannot be recommended as routine intervention at this time. Further trials are warranted for conclusive judgment. PMID- 25834277 TI - The longitudinal effect of drug use on productivity status of nonmetropolitan african american young adults. AB - The purpose of this study was to investigate the longitudinal effect of marijuana and heavy alcohol use on the productivity status of nonmetropolitan African American young adults. This analysis was based on secondary data from the Family and Community Health Study. For alcohol, the study evaluated the effects on productivity status for individuals with heavy alcohol use trajectories from adolescence into young adulthood while marijuana effects were evaluated during the period when adolescents are more likely to have initiated usage (14-16 years of age). Productivity status was measured when study participants were between 18 and 21 years, for both alcohol and marijuana. Multivariate logistic regression models were used to test the association between subjects' drug use and productivity. Bivariate analysis of the effects of marijuana use indicate that marijuana users by age 16 are 35% less likely to be productive at age 21 than those who have not initiated marijuana use (p < .005). After controlling for individual, community, and family factors, the multivariate logistic models for alcohol and marijuana use suggest that early adolescence drug use (marijuana and heavy alcohol use) do not have an impact on productivity status during early adulthood. Analyzing and understanding the different drug use trajectories in relation to a productivity outcome is important for policies and research geared to preventing drug use and in identifying its relation with micro- and macro level labor market outcomes. PMID- 25834278 TI - Temporary Internal Fixation for Ligamentous and Osseous Lisfranc Injuries: Outcome and Technical Tip. AB - BACKGROUND: Open rather than closed reduction and internal fixation as well as primary definitive arthrodesis are well accepted for ligamentous and osseous Lisfranc injuries. For ligamentous injuries, a better outcome after primary definitive partial arthrodesis has been published. METHODS: Of 135 Lisfranc injuries that were treated from 1998 to 2012 with open reduction, temporary internal fixation by screws and plates, and restricted weight bearing in a lower leg cast for 3 months followed by an arch support for another 4 to 6 weeks, 29 ligamentous Lisfranc injuries were available for follow-up. They were compared with 29 osseous Lisfranc injuries matched in age and gender. RESULTS: Between the groups, there were no significant differences in average age (39.9 vs 38 years) or in average follow-up time (8.3 vs 9.1 years). Also, no significant differences were seen in the AOFAS midfoot score (84 vs 85.3 points), the FFI pain scale (9.9 vs 14.9 points), SF 36 physical component (56.2 vs 53.9 points), SF 36 mental component (57 vs 56.4 points), or VAS for pain (1.6 vs 1.5 points). The FFI function scale was significantly lower in the ligamentous group (11.6 vs 19.5 points). Radiographically, loss of reduction was recorded 3 times in the ligamentous injuries and 4 times in the osseous injuries. Arthritis was mild/moderate/severe in 5/3/0 ligamentous injuries and in 7/2/1 osseous injuries, requiring 1 definitive secondary Lisfranc arthrodesis in each group. CONCLUSION: With longer and conservative postoperative management, open reduction and temporary internal fixation in ligamentous and osseous Lisfranc injuries led to equal medium-term outcome. Inferior outcome in ligamentous injuries was not found. LEVEL OF EVIDENCE: Level III, retrospective comparative cohort study. PMID- 25834279 TI - Defining the quality of acupuncture: the case of acupuncture for cancer-related fatigue. AB - BACKGROUND: The quality and dose of acupuncture used in a clinical trial affects the outcome, as with the quality and dose of any intervention. The dose of acupuncture treatment may be characterized by the frequency of treatment, needle type and depth, length of needle retention, point selection, and combination. The dose in trials of acupuncture has at times been described as low or inappropriate but is seldom assessed in systematic reviews of acupuncture trials. This article examines the research evaluating acupuncture for cancer-related fatigue to determine what characteristics of treatment may contribute to a quality acupuncture intervention. METHODOLOGY: English and Chinese language databases were searched from inception to December 2013 for randomized controlled trials of acupuncture for the treatment of cancer-related fatigue. Assessment of the quality of the acupuncture intervention was undertaken using the domains and items from the NICMAN framework. RESULTS: Seven studies with a total of 690 patients were included. Four of the studies were designed as feasibility or pilot studies, and the other 3 studies were described as "effectiveness" trials. The treatment paradigm for the active intervention was based on traditional Chinese medicine in all studies, yet few of the studies were explicit as to how the active intervention was justified within a traditional Chinese medicine paradigm. Acupuncture point prescriptions were developed by a small consensus panel or based on typical points and/or "clinical experience." No discussion of traditional Chinese medicine theory or literature review was reported in any studies. Acupuncture point location was adequately described in 4 of the 7 studies. Frequency of treatment was twice per week in 2 studies; all others were once per week. Two studies did not apply needle manipulation or stimulation, and no justification was given. CONCLUSION: The 7 trials reviewed meet some criteria for a quality acupuncture intervention. However, frequently elements of the intervention were not addressed, and it is possible that the dosage trialed was suboptimal. Systematic reviews of acupuncture are likely to continue to be inconclusive while comparisons are conducted of heterogeneous interventions without providing. PMID- 25834281 TI - Communication of a schizophrenia diagnosis: A qualitative study of patients' perspectives. AB - BACKGROUND: Transparent diagnostic communication is considered best practice for clinicians. However, while patients expect to receive a schizophrenia diagnosis from their psychiatrist, research suggests mental health clinicians are often reluctant to provide this information to patients. AIM: This study examines the perceptions of people with schizophrenia surrounding the communication of this diagnosis. METHODS: A generic qualitative methodological approach was used. A total of 14 patients with schizophrenia were recruited through community mental health services (n = 10) and the Australia Schizophrenia Research Bank (ASRB; n = 4) in New South Wales (NSW), Australia. Semi-structured interviews were used to explore the experiences and perceptions of people with schizophrenia about the way a schizophrenia diagnosis was communicated by mental health clinicians. Interviews were recorded, transcribed, codes generated and thematic analysis undertaken aided by NVivo. RESULTS: The majority of participants felt it was beneficial to receive a diagnosis despite acknowledging the distress this information sometimes caused, with many reporting this knowledge gave a sense of relief. It helped to understand their experiences and behaviours, improved their trust in the psychiatric system and increased treatment adherence. However, many reported difficulty in obtaining information about their condition, its treatment and prognosis, and expressed dissatisfaction with the way a diagnosis of schizophrenia was communicated. DISCUSSION: Insight into the perceptions and experiences of patients with schizophrenia about how a diagnosis of schizophrenia is communicated is a key outcome of this research. This knowledge will inform the development of future training programmes for mental health clinicians, and influence the clinical practice of health professionals treating patients with schizophrenia. PMID- 25834280 TI - Biological effects and mechanisms of action of mesenchymal stem cell therapy in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is the most frequent chronic respiratory disease and a leading cause of morbidity and mortality, worldwide. Given that the foremost risk factor leading to the development of COPD is cigarette smoke, the initial treatment for COPD is smoking cessation. Even after smoking cessation, inflammation, apoptosis and oxidative stress can persist and continue to contribute to COPD. Although current therapies for COPD (which are primarily based on anti-inflammatory drugs such as corticosteroids, theophylline and bronchodilators) reduce airway obstruction, limit COPD exacerbation and improve the patient's health-related quality-of-life, none can prevent disease progression or reduce mortality. Recent advances in stem cell research have provided novel insight into the potential of bone marrow mesenchymal stem cells (MSCs) in the treatment of several pulmonary diseases. This review article discusses the biological effects and mechanisms of action of MSC transplantation in COPD, and highlights the foundation that MSCs provide for novel therapeutic approaches in COPD. PMID- 25834282 TI - The Acute Management of Sport Concussion in Pediatric Athletes. AB - During the past two decades the focus on sport concussion has increased significantly. Young athletes represent the most vulnerable population to sustain a sport concussion yet receive the least amount of attention. Specifically, young athletes who sustain a sport concussion can go unrecognized and continue to participate in sport putting them at an increased risk for a more significant injury. The purpose of this review is to provide a clinical framework for the evaluation and management of sport concussion. In addition, this review provides considerations for health care professionals in regard to clinical measures and follow-up strategies during the acute phase following concussion in young concussed athletes following injury. PMID- 25834283 TI - The hierarchical stability of the seven known large size ratio triple asteroids using the empirical stability parameters. AB - In this study, the hierarchical stability of the seven known large size ratio triple asteroids is investigated. The effect of the solar gravity and primary's J2 are considered. The force function is expanded in terms of mass ratios based on the Hill's approximation and the large size ratio property. The empirical stability parameters are used to examine the hierarchical stability of the triple asteroids. It is found that the all the known large size ratio triple asteroid systems are hierarchically stable. This study provides useful information for future evolutions of the triple asteroids. PMID- 25834284 TI - High-order space-time finite element schemes for acoustic and viscodynamic wave equations with temporal decoupling. AB - We revisit a method originally introduced by Werder et al. (in Comput. Methods Appl. Mech. Engrg., 190:6685-6708, 2001) for temporally discontinuous Galerkin FEMs applied to a parabolic partial differential equation. In that approach, block systems arise because of the coupling of the spatial systems through inner products of the temporal basis functions. If the spatial finite element space is of dimension D and polynomials of degree r are used in time, the block system has dimension (r + 1)D and is usually regarded as being too large when r > 1. Werder et al. found that the space-time coupling matrices are diagonalizable over [Formula: see text] for r ?100, and this means that the time-coupled computations within a time step can actually be decoupled. By using either continuous Galerkin or spectral element methods in space, we apply this DG-in-time methodology, for the first time, to second-order wave equations including elastodynamics with and without Kelvin-Voigt and Maxwell-Zener viscoelasticity. An example set of numerical results is given to demonstrate the favourable effect on error and computational work of the moderately high-order (up to degree 7) temporal and spatio-temporal approximations, and we also touch on an application of this method to an ambitious problem related to the diagnosis of coronary artery disease. Copyright (c) 2014 The Authors. International Journal for Numerical Methods in Engineering published by John Wiley & Sons Ltd. PMID- 25834285 TI - Greater accumulation of litter in spruce (Picea abies) compared to beech (Fagus sylvatica) stands is not a consequence of the inherent recalcitrance of needles. AB - BACKGROUND AND AIMS: Replacement of beech by spruce is associated with changes in soil acidity, soil structure and humus form, which are commonly ascribed to the recalcitrance of spruce needles. It is of practical relevance to know how much beech must be admixed to pure spruce stands in order to increase litter decomposition and associated nutrient cycling. We addressed the impact of tree species mixture within forest stands and within litter on mass loss and nutritional release from litter. METHODS: Litter decomposition was measured in three adjacent stands of pure spruce (Picea abies), mixed beech-spruce and pure beech (Fagus sylvatica) on three nutrient-rich sites and three nutrient-poor sites over a three-year period using the litterbag method (single species and mixed species bags). RESULTS: Mass loss of beech litter was not higher than mass loss of spruce litter. Mass loss and nutrient release were not affected by litter mixing. Litter decay indicated non-additive patterns, since similar remaining masses under pure beech (47%) and mixed beech-spruce (48%) were significantly lower than under pure spruce stands (67%). Release of the main components of the organic substance (Corg, Ntot, P, S, lignin) and associated K were related to mass loss, while release of other nutrients was not related to mass loss. CONCLUSIONS: In contradiction to the widely held assumption of slow decomposition of spruce needles, we conclude that accumulation of litter in spruce stands is not caused by recalcitrance of spruce needles to decay; rather adverse environmental conditions in spruce stands retard decomposition. Mixed beech spruce stands appear to be as effective as pure beech stands in counteracting these adverse conditions. PMID- 25834286 TI - Soil CO2 efflux in a bioenergy plantation with fast-growing Populus trees - influence of former land use, inter-row spacing and genotype. AB - AIMS: In this study we quantified the annual soil CO2 efflux (annual SCE) of a short rotation coppice plantation in its establishment phase. We aimed to examine the effect of former (agricultural) land use type, inter-row spacing and genotype. METHODS: Annual SCE was quantified during the second growth year of the establishment rotation in a large scale poplar plantation in Flanders. Automated chambers were distributed over the two former land use types, the two different inter-row spacings and under two poplar genotypes. Additional measurements of C, N, P, K, Mg, Ca and Na concentrations of the soil, pH, bulk density, fine root biomass, microbial biomass C, soil mineralization rate, distance to trees and tree diameters were performed at the end of the second growth year. RESULTS: Total carbon loss from soil CO2 efflux was valued at 589 g m-2 yr-1. Annual SCE was higher in former pasture as compared to cropland, higher in the narrow than in the wider inter-row spacings, but no effect of genotype was found. CONCLUSIONS: Spatial differences in site characteristics are of great importance for understanding the effect of ecosystem management and land use change on soil respiration processes and need to be taken into account in modeling efforts of the carbon balance. PMID- 25834287 TI - A closeup study of early beech litter decomposition: potential drivers and microbial interactions on a changing substrate. AB - AIMS: Litter decomposition and subsequent nutrient release play a major role in forest carbon and nutrient cycling. To elucidate how soluble or bulk nutrient ratios affect the decomposition process of beech (Fagus sylvatica L.) litter, we conducted a microcosm experiment over an 8 week period. Specifically, we investigated leaf-litter from four Austrian forested sites, which varied in elemental composition (C:N:P ratio). Our aim was to gain a mechanistic understanding of early decomposition processes and to determine microbial community changes. METHODS: We measured initial litter chemistry, microbial activity in terms of respiration (CO2), litter mass loss, microbial biomass C and N (Cmic and Nmic), non purgeable organic carbon (NPOC), total dissolved nitrogen (TDN), NH4+, NO3- and microbial community composition (phospholipid fatty acids - PLFAs). RESULTS: At the beginning of the experiment microbial biomass increased and pools of inorganic nitrogen (N) decreased, followed by an increase in fungal PLFAs. Sites higher in NPOC:TDN (C:N of non purgeable organic C and total dissolved N), K and Mn showed higher respiration. CONCLUSIONS: The C:N ratio of the dissolved pool, rather than the quantity of N, was the major driver of decomposition rates. We saw dynamic changes in the microbial community from the beginning through the termination of the experiment. PMID- 25834288 TI - Fine root biomass and turnover of two fast-growing poplar genotypes in a short rotation coppice culture. AB - BACKGROUND AND AIMS: The quantification of root dynamics remains a major challenge in ecological research because root sampling is laborious and prone to error due to unavoidable disturbance of the delicate soil-root interface. The objective of the present study was to quantify the distribution of the biomass and turnover of roots of poplars (Populus) and associated understory vegetation during the second growing season of a high-density short rotation coppice culture. METHODS: Roots were manually picked from soil samples collected with a soil core from narrow (75 cm apart) and wide rows (150 cm apart) of the double row planting system from two genetically contrasting poplar genotypes. Several methods of estimating root production and turnover were compared. RESULTS: Poplar fine root biomass was higher in the narrow rows than in the wide rows. In spite of genetic differences in above-ground biomass, annual fine root productivity was similar for both genotypes (ca. 44 g DM m-2 year-1). Weed root biomass was equally distributed over the ground surface, and root productivity was more than two times higher compared to poplar fine roots (ca. 109 g DM m-2 year-1). CONCLUSIONS: Early in SRC plantation development, weeds result in significant root competition to the crop tree poplars, but may confer certain ecosystem services such as carbon input to soil and retention of available soil N until the trees fully occupy the site. PMID- 25834289 TI - Coarse and fine root plants affect pore size distributions differently. AB - AIMS: Small scale root-pore interactions require validation of their impact on effective hydraulic processes at the field scale. Our objective was to develop an interpretative framework linking root effects on macroscopic pore parameters with knowledge at the rhizosphere scale. METHODS: A field experiment with twelve species from different families was conducted. Parameters of Kosugi's pore size distribution (PSD) model were determined inversely from tension infiltrometer data. Measured root traits were related to pore variables by regression analysis. A pore evolution model was used to analyze if observed pore dynamics followed a diffusion like process. RESULTS: Roots essentially conditioned soil properties at the field scale. Rooting densities higher than 0.5 % of pore space stabilized soil structure against pore loss. Coarse root systems increased macroporosity by 30 %. Species with dense fine root systems induced heterogenization of the pore space and higher micropore volume. We suggested particle re-orientation and aggregate coalescence as main underlying processes. The diffusion type pore evolution model could only partially capture the observed PSD dynamics. CONCLUSIONS: Root systems differing in axes morphology induced distinctive pore dynamics. Scaling between these effective hydraulic impacts and processes at the root-pore interface is essential for plant based management of soil structure. PMID- 25834290 TI - Root induced changes of effective 1D hydraulic properties in a soil column. AB - AIMS: Roots are essential drivers of soil structure and pore formation. This study aimed at quantifying root induced changes of the pore size distribution (PSD). The focus was on the extent of clogging vs. formation of pores during active root growth. METHODS: Parameters of Kosugi's lognormal PSD model were determined by inverse estimation in a column experiment with two cover crops (mustard, rye) and an unplanted control. Pore dynamics were described using a convection-dispersion like pore evolution model. RESULTS: Rooted treatments showed a wider range of pore radii with increasing volumes of large macropores >500 MUm and micropores <2.5 MUm, while fine macropores, mesopores and larger micropores decreased. The non-rooted control showed narrowing of the PSD and reduced porosity over all radius classes. The pore evolution model accurately described root induced changes, while structure degradation in the non-rooted control was not captured properly. Our study demonstrated significant short term root effects with heterogenization of the pore system as dominant process of root induced structure formation. CONCLUSIONS: Pore clogging is suggested as a partial cause for reduced pore volume. The important change in micro- and large macropores however indicates that multiple mechanic and biochemical processes are involved in root-pore interactions. PMID- 25834291 TI - Metal mobilization from soils by phytosiderophores - experiment and equilibrium modeling. AB - AIMS: To test if multi-surface models can provide a soil-specific prediction of metal mobilization by phytosiderophores (PS) based on the characteristics of individual soils. METHODS: Mechanistic multi-surface chemical equilibrium modeling was applied for obtaining soil-specific predictions of metal and PS speciation upon interaction of the PS 2'-deoxymugineic acid (DMA) with 6 soils differing in availability of Fe and other metals. Results from multi-surface modeling were compared with empirical data from soil interaction experiments. RESULTS: For soils in which equilibrium was reached during the interaction experiment, multi-surface models could well predict PS equilibrium speciation. However, in uncontaminated calcareous soils, equilibrium was not reached within a week, and experimental and modeled DMA speciation differed considerably. In soils with circum-neutral pH, on which Fe deficiency is likely to occur, no substantial Fe mobilization by DMA was predicted. However, in all but the contaminated soils, Fe mobilization by DMA was observed experimentally. Cu and Ni were the quantitatively most important metals competing with Fe for complexation and mobilization by DMA. CONCLUSION: Thermodynamics are unable to explain the role of PS as Fe carrier in calcareous soils, and the kinetic aspects of metal mobilization by PS need to be closer examined in order to understand the mechanisms underlying strategy II Fe acquisition. PMID- 25834292 TI - Environmental and vegetation controls on the spatial variability of CH4 emission from wet-sedge and tussock tundra ecosystems in the Arctic. AB - AIMS: Despite multiple studies investigating the environmental controls on CH4 fluxes from arctic tundra ecosystems, the high spatial variability of CH4 emissions is not fully understood. This makes the upscaling of CH4 fluxes from plot to regional scale, particularly challenging. The goal of this study is to refine our knowledge of the spatial variability and controls on CH4 emission from tundra ecosystems. METHODS: CH4 fluxes were measured in four sites across a variety of wet-sedge and tussock tundra ecosystems in Alaska using chambers and a Los Gatos CO2 and CH4 gas analyser. RESULTS: All sites were found to be sources of CH4, with northern sites (in Barrow) showing similar CH4 emission rates to the southernmost site (ca. 300 km south, Ivotuk). Gross primary productivity (GPP), water level and soil temperature were the most important environmental controls on CH4 emission. Greater vascular plant cover was linked with higher CH4 emission, but this increased emission with increased vascular plant cover was much higher (86 %) in the drier sites, than the wettest sites (30 %), suggesting that transport and/or substrate availability were crucial limiting factors for CH4 emission in these tundra ecosystems. CONCLUSIONS: Overall, this study provides an increased understanding of the fine scale spatial controls on CH4 flux, in particular the key role that plant cover and GPP play in enhancing CH4 emissions from tundra soils. PMID- 25834293 TI - Light affects in vitro organogenesis of Linum usitatissimum L. and its cyanogenic potential. AB - The relationships between organogenesis of oil flax (Linum usitatissimum L., cv. 'Szafir') in vitro, cyanogenic potential (HCN-p) of these tissues and light were investigated. Shoot multiplication obtained on Murashige and Skoog medium containing 0.05 mg L-1 2,4-dichloro-phenoxyacetic acid and 1 mg L-1 6 benzyladenine (BA), was about twice higher in light-grown cultures than those in darkness. Light-grown explants showed also higher rate of roots regeneration (in medium containing 1 mg L-1 alpha-naphtaleneacetic acid and 0.05 mg L-1 BA) than dark-grown ones. The cyanogenic potential (expressed both as linamarin and lotaustralin content and linamarase activity) of flax cultured in vitro was tissue-specific and generally was higher under light conditions than in darkness. The highest concentration of linamarin and lotaustralin was detected in light regenerated shoots, and its amount was twice as high as in roots, and about threefold higher than in callus tissue. The activities of linamarase and beta cyanoalanine synthase in light-regenerated organs were also higher than those in darkness. Thus, higher frequency of regeneration of light-grown cultures than dark-grown ones seems to be correlated with higher HCN-p of these tissues. We suggest that free HCN, released from cyanoglucosides potentially at higher level under light conditions, may be involved in some organogenetic processes which improve regeneration efficiency. PMID- 25834294 TI - Lupine embryo axes under salinity stress. II. Mitochondrial proteome response. AB - Germination is the first step of plant growth in plant life cycle. An embryonic radicle protruding the seed coat is the first part of plant which has direct contact with external environment including salt-affected soil. In embryo axes, mitochondria are the main energy producer. To understand better salinity impact on mitochondria functioning, this study was focused on the effect of NaCl stress onto mitochondria proteome. Mitochondria were isolated from yellow lupine (Lupine luteus L. 'Mister') embryo axes cultured in vitro for 12 h with 250 and 500 mM NaCl. Two-dimensional gel electrophoresis of mitochondrial proteins isolated from NaCl-treated axes demonstrated significant changes in proteins abundances as a response to salinity treatment. Twenty-one spots showing significant changes in protein expression profiles both under 250 and 500 mM NaCl treatment were selected for tandem mass spectrometry identification. This approach revealed proteins associated with different metabolic processes that represent enzymes of tricarboxylic acid cycle, mitochondrial electron transport chain, enzymes and proteins involved in mitochondria biogenesis and stresses response. Among proteins involved in mitochondria biogenesis, mitochondrial import inner membrane translocase, subunit Tim17/22, mitochondrial-processing peptidase subunit alpha 1, mitochondrial elongation factor Tu and chaperonins CPN60 were revealed. Finally, formate dehydrogenase 1 was found to accumulate in lupine embryo axes mitochondria under salinity. The functions of identified proteins are discussed in relation to salinity stress response, including salinity-induced PCD. PMID- 25834295 TI - Towards a Relational Phenomenology of Violence. AB - This article elaborates a relational phenomenology of violence. Firstly, it explores the constitution of all sense in its intrinsic relation with our embodiment and intercorporality. Secondly, it shows how this relational conception of sense and constitution paves the path for an integrative understanding of the bodily and symbolic constituents of violence. Thirdly, the author addresses the overall consequences of these reflections, thereby identifying the main characteristics of a relational phenomenology of violence. In the final part, the paper provides an exemplification of the outlined conception with regard to a concrete phenomenon of violence, i.e., slapping, and a concluding reflection upon its overall significance for research on violence. PMID- 25834296 TI - Climate change and impacts in the Eastern Mediterranean and the Middle East. AB - The Eastern Mediterranean and the Middle East (EMME) are likely to be greatly affected by climate change, associated with increases in the frequency and intensity of droughts and hot weather conditions. Since the region is diverse and extreme climate conditions already common, the impacts will be disproportional. We have analyzed long-term meteorological datasets along with regional climate model projections for the 21st century, based on the intermediate IPCC SRES scenario A1B. This suggests a continual, gradual and relatively strong warming of about 3.5-7 degrees C between the 1961-1990 reference period and the period 2070 2099. Daytime maximum temperatures appear to increase most rapidly in the northern part of the region, i.e. the Balkan Peninsula and Turkey. Hot summer conditions that rarely occurred in the reference period may become the norm by the middle and the end of the 21st century. Projected precipitation changes are quite variable. Annual precipitation is expected to decrease in the southern Europe - Turkey region and the Levant, whereas in the Arabian Gulf area it may increase. In the former region rainfall is actually expected to increase in winter, while decreasing in spring and summer, with a substantial increase of the number of days without rainfall. Anticipated regional impacts of climate change include heat stress, associated with poor air quality in the urban environment, and increasing scarcity of fresh water in the Levant. PMID- 25834297 TI - The importance of health co-benefits in macroeconomic assessments of UK Greenhouse Gas emission reduction strategies. AB - We employ a single-country dynamically-recursive Computable General Equilibrium model to make health-focussed macroeconomic assessments of three contingent UK Greenhouse Gas (GHG) mitigation strategies, designed to achieve 2030 emission targets as suggested by the UK Committee on Climate Change. In contrast to previous assessment studies, our main focus is on health co-benefits additional to those from reduced local air pollution. We employ a conservative cost effectiveness methodology with a zero net cost threshold. Our urban transport strategy (with cleaner vehicles and increased active travel) brings important health co-benefits and is likely to be strongly cost-effective; our food and agriculture strategy (based on abatement technologies and reduction in livestock production) brings worthwhile health co-benefits, but is unlikely to eliminate net costs unless new technological measures are included; our household energy efficiency strategy is likely to breakeven only over the long term after the investment programme has ceased (beyond our 20 year time horizon). We conclude that UK policy makers will, most likely, have to adopt elements which involve initial net societal costs in order to achieve future emission targets and longer term benefits from GHG reduction. Cost-effectiveness of GHG strategies is likely to require technological mitigation interventions and/or demand-constraining interventions with important health co-benefits and other efficiency-enhancing policies that promote internalization of externalities. Health co-benefits can play a crucial role in bringing down net costs, but our results also suggest the need for adopting holistic assessment methodologies which give proper consideration to welfare-improving health co-benefits with potentially negative economic repercussions (such as increased longevity). PMID- 25834298 TI - Dietary greenhouse gas emissions of meat-eaters, fish-eaters, vegetarians and vegans in the UK. AB - The production of animal-based foods is associated with higher greenhouse gas (GHG) emissions than plant-based foods. The objective of this study was to estimate the difference in dietary GHG emissions between self-selected meat eaters, fish-eaters, vegetarians and vegans in the UK. Subjects were participants in the EPIC-Oxford cohort study. The diets of 2,041 vegans, 15,751 vegetarians, 8,123 fish-eaters and 29,589 meat-eaters aged 20-79 were assessed using a validated food frequency questionnaire. Comparable GHG emissions parameters were developed for the underlying food codes using a dataset of GHG emissions for 94 food commodities in the UK, with a weighting for the global warming potential of each component gas. The average GHG emissions associated with a standard 2,000 kcal diet were estimated for all subjects. ANOVA was used to estimate average dietary GHG emissions by diet group adjusted for sex and age. The age-and-sex adjusted mean (95 % confidence interval) GHG emissions in kilograms of carbon dioxide equivalents per day (kgCO2e/day) were 7.19 (7.16, 7.22) for high meat eaters ( > = 100 g/d), 5.63 (5.61, 5.65) for medium meat-eaters (50-99 g/d), 4.67 (4.65, 4.70) for low meat-eaters ( < 50 g/d), 3.91 (3.88, 3.94) for fish-eaters, 3.81 (3.79, 3.83) for vegetarians and 2.89 (2.83, 2.94) for vegans. In conclusion, dietary GHG emissions in self-selected meat-eaters are approximately twice as high as those in vegans. It is likely that reductions in meat consumption would lead to reductions in dietary GHG emissions. PMID- 25834299 TI - What do we know about UK household adaptation to climate change? A systematic review. AB - The UK Government's first National Adaptation Programme seeks to create a 'climate-ready society' capable of making well-informed and far-sighted decisions to address risks and opportunities posed by a changing climate, where individual households are expected to adapt when it is in their interest to do so. How, and to what extent, households are able to do this remains unclear. Like other developed countries, research on UK adaptation has focused predominately on public and private organisations. To fill that gap, a systematic literature review was conducted to understand what actions UK households have taken in response to, or in anticipation of, a changing climate; what drives or impedes these actions; and whether households will act autonomously. We found that UK households struggle to build long-term adaptive capacity and are reliant upon traditional reactive coping responses. Of concern is that these coping responses are less effective for some climate risks (e.g. flooding); cost more over the long-term; and fail to create household capacity to adapt to other stresses. While low-cost, low-skill coping responses were already being implemented, the adoption of more permanent physical measures, behavioural changes, and acceptance of new responsibilities are unlikely to happen autonomously without further financial or government support. If public policy on household adaptation to climate change is to be better informed than more high-quality empirical research is urgently needed. PMID- 25834300 TI - Difference in the prognostic significance of N-terminal pro-B-type natriuretic peptide between cardioembolic and noncardioembolic ischemic strokes. AB - BACKGROUND AND AIM: Because B-type natriuretic peptide is a powerful predictor of heart failure, its capability to predict a fatal outcome in stroke might be limited to the cardioembolic stroke subtype. In this study, we attempt to ascertain the difference in the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) between cardioembolic and noncardioembolic stroke subgroups. METHODS: 410 acute stroke patients were included. According to the presence of a cardioembolic source (CES), there were 221 patients with CES and 189 patients without CES. Logistic regression analysis was performed to ascertain the association between NT-proBNP and 6-month mortality/functional outcome in each group. RESULTS: The mean age of our patients was 67.2 years (range, 18-97 years). NT-proBNP was a multivariate independent predictor of mortality in the CES group alone, whereas it was only a univariate predictor of 6-month mortality in the total patient and non-CES groups with its association disappearing in the multivariate model. In addition, it was only a univariate predictor of good functional outcome in all of the groups. CONCLUSIONS: Our data suggest that NT proBNP can more reliably predict 6-month mortality in patients with cardioembolic stroke than in patients with other stroke subtypes. PMID- 25834302 TI - Rebamipide protects small intestinal mucosal injuries caused by indomethacin by modulating intestinal microbiota and the gene expression in intestinal mucosa in a rat model. AB - The effect of rebamipide, a mucosal protective drug, on small intestinal mucosal injury caused by indomethacin was examined using a rat model. Indomethacin administration (10 mg/kg, p.o.) induced intestinal mucosal injury was accompanied by an increase in the numbers of intestinal bacteria particularly Enterobacteriaceae in the jejunum and ileum. Rebamipide (30 and 100 mg/kg, p.o., given 5 times) was shown to inhibit the indomethacin-induced small intestinal mucosal injury and decreased the number of Enterococcaceae and Enterobacteriaceae in the jejunal mucosa to normal levels. It was also shown that the detection rate of segmented filamentous bacteria was increased by rebamipide. PCR array analysis of genes related to inflammation, oxidative stress and wound healing showed that indomethacin induced upregulation and downregulation of 14 and 3 genes, respectively in the rat jejunal mucosa by more than 5-fold compared to that of normal rats. Rebamipide suppressed the upregulated gene expression of TNFalpha and Duox2 in a dose-dependent manner. In conclusion, our study confirmed that disturbance of intestinal microbiota plays a crucial role in indomethacin-induced small intestinal mucosal injury, and suggests that rebamipide could be used as prophylaxis against non-steroidal anti-inflammatory drugs -induced gastrointestinal mucosal injury, by modulating microbiota and suppressing mucosal inflammation in the small intestine. PMID- 25834301 TI - A mitochondrial superoxide theory for oxidative stress diseases and aging. AB - Fridovich identified CuZnSOD in 1969 and manganese superoxide dismutase (MnSOD) in 1973, and proposed "the Superoxide Theory," which postulates that superoxide (O2 (*-)) is the origin of most reactive oxygen species (ROS) and that it undergoes a chain reaction in a cell, playing a central role in the ROS producing system. Increased oxidative stress on an organism causes damage to cells, the smallest constituent unit of an organism, which can lead to the onset of a variety of chronic diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and other neurological diseases caused by abnormalities in biological defenses or increased intracellular reactive oxygen levels. Oxidative stress also plays a role in aging. Antioxidant systems, including non-enzyme low molecular-weight antioxidants (such as, vitamins A, C and E, polyphenols, glutathione, and coenzyme Q10) and antioxidant enzymes, fight against oxidants in cells. Superoxide is considered to be a major factor in oxidant toxicity, and mitochondrial MnSOD enzymes constitute an essential defense against superoxide. Mitochondria are the major source of superoxide. The reaction of superoxide generated from mitochondria with nitric oxide is faster than SOD catalyzed reaction, and produces peroxynitrite. Thus, based on research conducted after Fridovich's seminal studies, we now propose a modified superoxide theory; i.e., superoxide is the origin of reactive oxygen and nitrogen species (RONS) and, as such, causes various redox related diseases and aging. PMID- 25834303 TI - Pre-germinated brown rice prevents high-fat diet induced hyperglycemia through elevated insulin secretion and glucose metabolism pathway in C57BL/6J strain mice. AB - This study investigated the effect and mechanism of pre-germinated brown rice (PGBR) prevented hyperglycemia in C57BL/6J mice fed high-fat-diet (HFD). Normal six-week-old mice were randomly divided into three groups. Group 1 was fed standard-regular-diet (SRD) and group 2 was fed HFD for 16 weeks. In group 3, the mice were fed a HFD with its carbohydrate replaced with PGBR for 16 weeks. Comparing the SRD and HFD groups, we found the HFD group had higher blood pressure, higher concentrations of blood glucose and HbA1c. The HFD group had less protein expression of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3K), glucose transporter-4 (GLUT-4) and glucokinase (GCK) and greater expression of glucogen synthase kinase (GSK) in skeletal muscle. The HFD group also had less expression of IR, serine/threonine kinase PI3K-linked protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), GCK and peroxisome proliferator-activated receptor gamma (PPARgamma) in liver. In the HFD + PGBR group, the PGBR could reverse the disorders of blood pressure, blood glucose, HbA1c and increase insulin concentration. PGBR increased the IR, IRS-1, PI3K, Akt, GLUT-1 and GLUT-4 proteins, and ameliorated AMPK, GCK, GSK and PPARgamma proteins. Together, PGBR prevented HFD-induced hyperglycemia through improving insulin levels, insulin receptor, glucose transporters and enhancing glucose metabolism. PMID- 25834304 TI - Ingestion of hyaluronans (molecular weights 800 k and 300 k) improves dry skin conditions: a randomized, double blind, controlled study. AB - Hyaluronan (HA) has been increasingly used as a dietary supplement to improve the skin. However, the effect of ingested HA may depend on its molecular weight (MW) because its physiological activities in the body vary with its MW. In this study, we examined the effects of ingested HA with varying MW on the skin. In this randomized, double blind, placebo controlled study, 61 subjects with dry skin received oral HA (120 mg/day), of MWs 800 k and 300 k or placebo, for 6 weeks. The skin moisture contents of the first two groups increased more than those of the placebo group during the ingestion period. In addition, group HA 300 k exhibited significant improvements in skin moisture content 2 weeks after ingestion ended compared with the placebo group. A questionnaire survey about subjective facial aging symptoms showed that the HA treated groups exhibited significantly improved the skin condition compared with the placebo treated group. Furthermore, dermatologists objectively evaluated the clinical symptoms of the facial and whole body skin, showing that no adverse events were related to daily ingestion of HA. This study shows that both of ingesting HAs (MWs 800 k and 300 k) improved the skin condition by increasing the moisture content. PMID- 25834305 TI - Co-localization of iron binding on silica with p62/sequestosome1 (SQSTM1) in lung granulomas of mice with acute silicosis. AB - The cellular mechanisms involved in the development of silicosis have not been fully elucidated. This study aimed to examine influence of silica-induced lung injury on autophagy. Suspensions of crystalline silica particles were administered transnasally to C57BL/6j mice. Immunohistochemical examination for Fas and p62 protein expression was performed using lung tissue specimens. Two dimensional and quantitative analysis of silica deposits in the lungs were performed in situ using lung tissue sections by an in-air microparticle induced X ray emission (in-air micro-PIXE) analysis system, which was based on irrradiation of specimens with a proton ion microbeam. Quantitative analysis showed a significant increase of iron levels on silica particles (assessed as the ratio of Fe relative to Si) on day 56 compared with day 7 (p<0.05). Fas and p62 were expressed by histiocytes in granulomas on day 7, and the expressions persisted for day 56. Fas- and p62-expressing histiocytes were co-localized in granulomas with silica particles that showed an increase of iron levels on silica particles in mouse lungs. Iron complexed with silica induces apoptosis, and may lead to dysregulations of autophagy in histiocytes of granulomas, and these mechanisms may contribute to granuloma development and progression in silicosis. PMID- 25834306 TI - Continuous-wave broadly tunable high-power Cr:CdS laser. AB - We report spectroscopic characteristics and laser properties of the mid-infrared active laser medium Cr2+:CdS. Temperature-dependent absorption, luminescence and lifetime measurements of the 5E exited state allow determination of peak emission cross section value of 1.35 * 10-18 cm2 in sigma-polarization at room temperature. Lifetime values vary from 7.6 us at 8 K to 0.48 us at 320 K, corresponding to 22 % quantum yield at 285 K. Under Tm-fiber laser pumping, the continuous-wave output reached 1.8 W at 2.5 MUm with 35.5 % slope efficiency. With a single CaF2 prism, the CW Cr2+:CdS laser could be tuned from 2.240 to 3.285 um. PMID- 25834307 TI - Effect of crossing C57BL/6 and FVB mouse strains on basal cytokine expression. AB - C57BL/6 is the most often used laboratory mouse strain. However, sometimes it is beneficial to cross the transgenic mice on the C57BL/6 background to the other strain, such as FVB. Although this is a common strategy, the influence of crossing these different strains on homeostatic expression of cytokines is not known. Here we have investigated the differences in the expression of selected cytokines between C57BL/6J and C57BL/6JxFVB mice in serum and skeletal muscle. We have found that only few cytokines were altered by crossing of the strains. Concentrations of IL5, IL7, LIF, MIP-2, and IP-10 were higher in serum of C57BL/6J mice than in C57BL/6JxFVB mice, whereas concentration of G-CSF was lower in C57BL/6J. In the skeletal muscle only the concentration of VEGF was higher in C57BL/6J mice than in C57BL/6JxFVB mice. Concluding, the differences in cytokine expression upon crossing C57BL/6 and FVB strain in basal conditions are not profound. PMID- 25834308 TI - Cytokines in the cerebrospinal fluids of patients with chronic fatigue syndrome/myalgic encephalomyelitis. AB - OBJECTIVES: Previous research has provided evidence for dysregulation in peripheral cytokines in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To date only one study has examined cytokines in cerebrospinal fluid (CSF) samples of CFS/ME patients. The purpose of this pilot study was to examine the role of cytokines in CSF of CFS/ME patients. METHODS: CSF was collected from 18 CFS/ME patients and 5 healthy controls. The CSF samples were examined for the expression of 27 cytokines (interleukin- (IL-) 1beta, IL 1ra, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-gamma, IP-10, MCP-1 (MCAF), MIP-1alpha, MIP-1beta, PDGF-BB, RANTES, TNF-alpha, and VEGF) using the Bio-Plex Human Cytokine 27-plex Assay. RESULTS: Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls. CONCLUSIONS: This preliminary investigation suggests that perturbations in inflammatory cytokines in the CSF of CFS/ME patients may contribute to the neurological discrepancies observed in CFS/ME. PMID- 25834309 TI - Genome-based nutrition: an intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis. AB - Obesity and nonalcoholic steatohepatitis are increasing in westernized countries, regardless of their geographic location. In Latin America, most countries, including Mexico, have a heterogeneous admixture genome with Amerindian, European and African ancestries. However, certain high allelic frequencies of several nutrient-related polymorphisms may have been achieved by past gene-nutrient interactions. Such interactions may have promoted the positive selection of variants adapted to regional food sources. At present, the unbalanced diet composition of the Mexicans has led the country to a 70% prevalence rate of overweightness and obesity due to substantial changes in food habits, among other factors. International guidelines and intervention strategies may not be adequate for all populations worldwide because they do not consider disparities in genetic and environmental factors, and thus there is a need for differential prevention and management strategies. Here, we provide the rationale for an intervention strategy for the prevention and management of obesity-related diseases such as non-alcoholic steatohepatitis based on a regionalized genome-based diet. The components required to design such a diet should focus on the specific ancestry of each population around the world and the convenience of consuming traditional ethnic food. PMID- 25834310 TI - Management of hepatocellular carcinoma with portal vein thrombosis. AB - Management of hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) is complex and requires an understanding of multiple therapeutic options. PVT is present in 10%-40% of HCC at the time of diagnosis, and is an adverse prognostic factor. Management options are limited, as transplantation is generally contraindicated, and surgical resection is only rarely performed in select centers. Systemic medical therapy with sorafenib has been shown to modestly prolong survival. Transarterial chemoembolization has been performed in select cases but has shown a high incidence of complications. Emerging data on treatment of PVT with Y-90 radioembolization suggest that this modality is well-tolerated and associated with favorable overall survival. Current society guidelines do not yet specifically recommend radioembolization for patients with PVT, but this may change with the development of newer staging systems and treatment algorithms. In this comprehensive literature review, we present current and available management options with the relative advantages, disadvantages and contraindications of these treatment options with summarized data on overall survival. PMID- 25834311 TI - Lessons from rare tumors: hepatic lymphoepithelioma-like carcinomas. AB - In this review we focus on lymphoepithelioma-like hepatocellular carcinomas (LEL HCC) and lymphoepithelioma-like cholangiocarcinomas (LEL-ICC). Despite their rarity, these tumors are of general interest because of their epidemiological and clinical features, and because they represent a distinct model of interaction between the immune system and neoplastic cells. Approximately half of LEL-HCC arise in the context of chronic hepatitis C virus (HCV) infection and have been described both in Eastern and Western patients. By contrast, LEL-ICC is associated in almost all cases with Epstein-Barr virus (EBV) infection and exhibits the same epidemiological features of EBV related malignancies. Compared with classical hepatocellular carcinoma and intrahepatic cholangiocarcinoma of corresponding stage, both LEL-HCC and LEL-ICC are characterized by lower rates of recurrence after surgery and better overall survival. How this behavior is related to distinct genetic alterations and tumor microenvironment is unclear. The pathophysiological mechanisms of lymphoid infiltrations seem to be different among the two groups of tumors. In fact, LEL-HCC frequently arises in the context of inflammatory changes driven by HCV infection, and has been recognized as a variant of classical hepatocellular carcinoma. At variance, lymphocyte recruitment of LEL-ICC is similar to that described in nasopharyngeal carcinoma and gastric LEL, and possibly depends on the expression pattern of latent EBV infection. PMID- 25834312 TI - Hepatitis C virus-specific cytotoxic T cell response restoration after treatment induced hepatitis C virus control. AB - Hepatitis C virus (HCV)-specific cytotoxic T cell (CTL) response plays a major role in viral control during spontaneous infection resolution. These cells develop an exhausted and pro-apoptotic status during chronic onset, being unable to get rid of HCV. The role of this response in contributing to sustained viral response (SVR) after anti-HCV is controversial. Recent studies show that after successful interferon-based anti-HCV treatment, HCV traces are still detectable and this correlates with a peak of HCV-specific CTL response activation, probably responsible for maintaining SVR by subsequent complete HCV clearing. Moreover, SVR patients' serum is still able to induce HCV infection in naive chimpanzees, suggesting that the infection could be under the control of the immune system after a successful treatment, being transmissible in absence of this adaptive response. At least theoretically, treatment-induced viral load decrease could allow an effective HCV-specific CTL response reestablishment. This effect has been recently described with anti-HCV interferon-free regimes, based on direct acting antivirals. Nevertheless, this is to some extent controversial with interferon-based therapies, due to the detrimental immunoregulatory alpha interferon effect on T cells. Moreover, HCV-specific CTL response features during anti-HCV treatment could be a predictive factor of SVR that could have clinical implications in patient management. In this review, the recent knowledge about the role of HCV-specific CTL response in the development of SVR after anti-HCV treatment is discussed. PMID- 25834313 TI - Long-chain acyl-CoA synthetase in fatty acid metabolism involved in liver and other diseases: an update. AB - Long-chain acyl-CoA synthetase (ACSL) family members include five different ACSL isoforms, each encoded by a separate gene and have multiple spliced variants. ACSLs on endoplasmic reticulum and mitochondrial outer membrance catalyze fatty acids with chain lengths from 12 to 20 carbon atoms to form acyl-CoAs, which are lipid metabolic intermediates and involved in fatty acid metabolism, membrane modifications and various physiological processes. Gain- or loss-of-function studies have shown that the expression of individual ACSL isoforms can alter the distribution and amount of intracellular fatty acids. Changes in the types and amounts of fatty acids, in turn, can alter the expression of intracellular ACSLs. ACSL family members affect not only the proliferation of normal cells, but the proliferation of malignant tumor cells. They also regulate cell apoptosis through different signaling pathways and molecular mechanisms. ACSL members have individual functions in fatty acid metabolism in different types of cells depending on substrate preferences, subcellular location and tissue specificity, thus contributing to liver diseases and metabolic diseases, such as fatty liver disease, obesity, atherosclerosis and diabetes. They are also linked to neurological disorders and other diseases. However, the mechanisms are unclear. This review addresses new findings in the classification and properties of ACSLs and the fatty acid metabolism-associated effects of ACSLs in diseases. PMID- 25834314 TI - Degradation of intestinal mRNA: a matter of treatment. AB - AIM: To characterize the influence of location, species and treatment upon RNA degradation in tissue samples from the gastrointestinal tract. METHODS: The intestinal samples were stored in different medium for different times under varying conditions: different species (human and rat), varying temperature (storage on crushed ice or room temperature), time point of dissection of the submucous-mucous layer from the smooth muscle (before or after storage), different rinsing methods (rinsing with Medium, PBS, RNALater or without rinsing at all) and different regions of the gut (proximal and distal small intestine, caecum, colon and rectum). The total RNA from different parts of the gut (rat: proximal and distal small intestine, caecum, colon and rectum, human: colon and rectum) and individual gut layers (muscle and submucosal/mucosal) was extracted. The quality of the RNA was assessed by micro capillary electrophoresis. The RNA quality was expressed by the RNA integrity number which is calculated from the relative height and area of the 18 S and 28 S RNA peaks. From rat distal small intestine qPCR was performed for neuronal and glial markers. RESULTS: RNA obtained from smooth muscle tissue is much longer stable than those from submucosal/mucosal tissue. At RT muscle RNA degrades after one day, on ice it is stable at least three days. Cleaning and separation of gut layers before storage and use of RNALater, maintains the stability of muscle RNA at RT for much longer periods. Different parts of the gut show varying degradation periods. RNA obtained from the submucosal/mucosal layer always showed a much worse amplification rate than RNA from muscle tissue. In general RNA harvested from rat tissue, either smooth muscle layer or submucosal/mucosal layer is much longer stable than RNA from human gut tissue, and RNA obtained from smooth muscle tissue shows an increased stability compared to RNA from submucosal/mucosal tissue. At RT muscle RNA degrades after one day, while the stability on ice lasts at least three days. Cleaning and separation of gut layers before storage and use of RNALater, maintains the stability of muscle RNA at RT for much longer periods. Different parts of the gut show varying degradation periods. The RNA from muscle and submucosal/mucosal tissue of the proximal small intestine degrades much faster than the RNA of distal small intestine, caecum or colon with rectum. RNA obtained from the submucosal/mucosal layer always showed a much more reduced amplification rate than RNA from muscle tissue [beta-Tubulin III for muscle quantification cycle (Cp): 22.07 +/- 0.25, for beta-Tubulin III submucosal/mucosal Cp: 27.42 +/- 0.19]. CONCLUSION: Degradation of intestinal mRNA depends on preparation and storage conditions of the tissue. Cooling, rinsing and separating of intestinal tissue reduce the degradation of mRNA. PMID- 25834315 TI - Effect of entacapone on colon motility and ion transport in a rat model of Parkinson's disease. AB - AIM: To study the effects of entacapone, a catechol-O-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson's disease (PD) rats. METHODS: Distribution and expression of catechol-O-methyltransferase (COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitro by means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current (ISC ) technique and scanning ion selective electrode technique (SIET). Intracellular detection of cAMP and cGMP was accomplished by radioimmunoassay testing. RESULTS: COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The beta2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67% (P < 0.01). Entacapone increased mucosal ISC in the colon of rats with PD. This induction was significantly inhibited by apical application of Cl(-) channel blocker diphenylamine-2, 2'-dicarboxylic acid, basolateral application of Na(+)-K(+)-2Cl( )co-transporter antagonist bumetanide, elimination of Cl(-) from the extracellular fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacapone-induced ISC by 45% (P < 0.01). When SIET was applied to measure Cl(-) flux changes, this provided similar results. Entacapone significantly increased intracellular cAMP content in the colonic mucosa, which was greatly inhibited by indomethacin. CONCLUSION: COMT expression exists in rat colons. The beta2 adrenoceptor is involved in the entacapone-induced inhibition of colon motility. Entacapone induces cAMP-dependent Cl(-) secretion in the PD rat. PMID- 25834316 TI - Primary analysis and screening of microRNAs in gastric cancer side population cells. AB - AIM: To explore the microRNA (miRNA) profiles and to determine the key miRNAs within the side population (SP) cells of the gastric cancer cell line MKN-45. METHODS: We used fluorescence-activated cell sorting and Hoechst 33342 labeling to obtain SP cells from the human gastric carcinoma cell line MKN-45. The miRNA expression profiles of the SP and major population (MP) cells were examined using a miRNA gene chip, and key miRNAs were obtained according to aberrant expression and the miRNAs' possible targets as predicted by bioinformatics. RESULTS: Using a significance criterion of a 1.5-fold or greater difference in expression level, we observed an increase in the expression of 34 miRNAs and a decrease in the expression of 34 miRNAs when comparing SP to MP cells. Using quantitative real time reverse transcription-polymerase chain reaction to test for differentially expressed miRNAs combined with bioinformatics results, we found that the downregulated miRNAs, such as hsa-miR-3175 and hsa-miR-203, and the upregulated miRNAs, including hsa-miR-130a, hsa-miR-324-5p, hsa-miR-34a, and hsa-miR-25-star, may be important in maintaining and regulating the characteristics of SP cells. CONCLUSION: There are key miRNAs expressed within the SP cells of the gastric cancer cell line MKN-45, and include hsa-miR-3175, hsa-miR-203, hsa-miR-130a, hsa miR-324-5p, hsa-miR-34a, and hsa-miR-25-star. PMID- 25834317 TI - High persistence rate of hepatitis B virus in a hydrodynamic injection-based transfection model in C3H/HeN mice. AB - AIM: To optimize the viral persistence rate in a hydrodynamic injection (HI) based hepatitis B virus (HBV) transfection mouse model. METHODS: (1) 5-6-wk-old male C3H/HeN and C57BL/6 mice were hydrodynamically injected with 10 MUg endotoxin-free pAAV/HBV1.2 plasmid DNA via the tail vein. Hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and HBV DNA, both in the serum and liver, were detected at different time points post HI by ELISA, immunohistochemical staining or quantitative polymerase chain reaction (PCR); (2) male C3H/HeN and C57BL/6 mice, either hydrodynamically injected mice at 10 wk post HI or naive mice, were all immunized subcutaneously with 5 MUg HBsAg formulated in complete Freund's adjuvant three times at a 2-wk interval. Two weeks after the final immunization, splenocytes were isolated for T cell function analysis by ELISPOT assay; and (3) five weeks post HI, C3H/HeN mice were intragastrically administered 0.1 mg/kg entecavir once a day for 14 d, or were intraperitoneally injected with 1 mg/kg interferon (IFN)-alpha twice a week for 2 wk, or were treated with PBS as controls. The sera were collected and assayed for HBV DNA on days 0, 7 and 14 after drug treatment. RESULTS: (1) Approximately 90% (22/25) of the injected C3H/HeN mice were still HBsAg-positive at 46 wk post HI, whereas HBsAg in C57BL/6 mice were completely cleared at 24 wk. Serum levels of HBeAg in C3H/HeN mice were higher than those in C57BL/6 mice from 4 wk to 46 wk. HBV DNA levels in the hydrodynamically injected C3H/HeN mice were higher than those in the C57BL/6 mice, both in the serum (from 4 wk to 46 wk) and in the liver (detected at 8 wk and 46 wk post HI). Histology showed that hepatitis B core antigen and HBsAg were expressed longer in the liver of C3H/HeN mice than in C57BL/6; (2) HBsAg specific T cell responses after HBsAg vaccination in hydrodynamically injected C3H/HeN and C57BL/6 mice, or naive control mice were detected by ELISPOT assay. After stimulation with HBsAg, the frequencies of IFN gamma producing splenocytes in the hydrodynamically injected C3H/HeN mice were significantly lower than those in hydrodynamically injected C57BL/6 mice, control C3H/HeN and control C57BL/6 mice, which were 0, 17 +/- 7, 18 +/- 10, and 41 +/- 10 SFCs/10(6) splenocytes, respectively, and the mean spot sizes showed the same pattern. Even just stimulated with PMA and ionomysin, T-cell responses elicited in the vaccinated control C3H/HeN were much higher than those in hydrodynamically injected C3H/HeN mice; and (3) For drug treatment experiments on the hydrodynamically injected C3H/HeN mice, serum HBV DNA levels in the entecavir treatment group declined (131.2 folds, P < 0.01) on day 7 after treatment and kept going down. In the group of IFN-alpha treatment, serum HBV DNA levels declined to a lowest point (6.42 folds, P < 0.05) on 7 d after treatment and then rebounded. CONCLUSION: We have developed a novel HI-based HBV transfection model using C3H/HeN mice, which had a higher HBV persistence rate than the classic C57BL/6 mouse model. PMID- 25834318 TI - Therapeutic effect of Qingyi decoction in severe acute pancreatitis-induced intestinal barrier injury. AB - AIM: To investigate the effect of Qingyi decoction on the expression of secreted phospholipase A2 (sPLA2) in intestinal barrier injury. METHODS: Fifty healthy Sprague-Dawley rats were randomly divided into control, severe acute pancreatitis (SAP), Qingyi decoction-treated (QYT), dexamethasone-treated (DEX), and verapamil treated (VER) groups. The SAP model was induced by retrograde infusion of 1.5% sodium deoxycholate into the biliopancreatic duct of the rats. All rats were sacrificed 24 h post-SAP induction. Arterial blood, intestine, and pancreas from each rat were harvested for investigations. The levels of serum amylase (AMY) and diamine oxidase (DAO) were determined using biochemical methods, and serum tumor necrosis factor (TNF)-alpha level was measured by an enzyme linked immunosorbent assay. Pathologic changes in the harvested tissues were investigated by microscopic examination of hematoxylin and eosin-stained tissue sections. The expressions of sPLA2 at mRNA and protein levels were detected by reverse transcriptase PCR and Western blot, respectively. A terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was used to investigate apoptosis of epithelial cells in the intestinal tissues. RESULTS: Compared to the control group, the expression of sPLA2 at both the mRNA and protein levels increased significantly in the SAP group (0.36 +/- 0.13 vs 0.90 +/- 0.38, and 0.16 +/- 0.05 vs 0.64 +/- 0.05, respectively; Ps < 0.01). The levels of AMY, TNF alpha and DAO in serum were also significantly increased (917 +/- 62 U/L vs 6870 +/- 810 U/L, 59.7 +/- 14.3 ng/L vs 180.5 +/- 20.1 ng/L, and 10.37 +/- 2.44 U/L vs 37.89 +/- 5.86 U/L, respectively; Ps < 0.01). The apoptosis index of intestinal epithelial cells also differed significantly between the SAP and control rats (0.05 +/- 0.02 vs 0.26 +/- 0.06; P < 0.01). The serum levels of DAO and TNF alpha, and the intestinal apoptosis index significantly correlated with sPLA2 expression in the intestine (r = 0.895, 0.893 and 0.926, respectively; Ps < 0.05). The levels of sPLA2, AMY, TNF-alpha, and DAO in the QYT, VER, and DEX groups were all decreased compared with the SAP group, but not the control group. Qingyi decoction intervention, however, gave the most therapeutic effect against intestinal barrier damage, although the onset of its therapeutic effect was slower. CONCLUSION: Qingyi decoction ameliorates acute pancreatitis-induced intestinal barrier injury by inhibiting the overexpression of intestinal sPLA2. This mechanism may be similar to that of verapamil. PMID- 25834319 TI - Surgical outcomes of Korean ulcerative colitis patients with and without colitis associated cancer. AB - AIM: To determine the clinicopathologic characteristics of surgically treated ulcerative colitis (UC) patients, and to compare the characteristics of UC patients with colitis-associated cancer (CAC) to those without CAC. METHODS: Clinical data on UC patients who underwent abdominal surgery from 1980 to 2013 were collected from 11 medical institutions. Data were analyzed to compare the clinical features of patients with CAC and those of patients without CAC. RESULTS: Among 415 UC patients, 383 (92.2%) underwent total proctocolectomy, and of these, 342 (89%) were subjected to ileal pouch-anal anastomosis. CAC was found in 47 patients (11.3%). Adenocarcinoma was found in 45 patients, and the others had either neuroendocrine carcinoma or lymphoma. Comparing the UC patients with and without CAC, the UC patients with CAC were characteristically older at the time of diagnosis, had longer disease duration, underwent frequent laparoscopic surgery, and were infrequently given preoperative steroid therapy (P < 0.001 0.035). During the 37 mo mean follow-up period, the 3-year overall survival rate was 82.2%. CONCLUSION: Most Korean UC patients experience early disease exacerbation or complications. Approximately 10% of UC patients had CAC, and UC patients with CAC had a later diagnosis, a longer disease duration, and less steroid treatment than UC patients without CAC. PMID- 25834320 TI - Primary biliary cirrhosis-associated hepatocellular carcinoma in Chinese patients: incidence and risk factors. AB - AIM: To investigate the incidence, characteristics, and risk factors for hepatocellular carcinoma (HCC) in Chinese patients with primary biliary cirrhosis (PBC). METHODS: We reviewed the data of 52 PBC-associated HCC patients treated at Beijing 302 Hospital from January 2002 to December 2013 and analyzed its incidence and characteristics between the two genders. The risk factors for PBC associated HCC were analyzed via a case-control study comprising 20 PBC patients with HCC and 77 matched controls without HCC. The matched factors included gender, age, follow-up period and Child-Pugh scores. Conditional logistic regression was used to evaluate the odds ratios of potential risk factors for HCC development. A P < 0.05 was considered statistically significant. RESULTS: The incidence of HCC in Chinese PBC patients was 4.13% (52/1255) and was significantly higher in the males (9.52%) than in the females (3.31%). Among the 52 PBC patients with HCC, 55.76% (29/52) were diagnosed with HCC and PBC simultaneously, and 5.76% (3/52) were diagnosed with HCC before PBC. The males with PBC-associated HCC were more likely than the females to have undergone blood transfusion (18.75% vs 8.33%, P = 0.043), consumed alcohol (31.25% vs 8.33%, P = 0.010), smoked (31.25% vs 8.33%, P = 0.010), had a family history of malignancy (25% vs 5.56%, P = 0.012), and had serious liver inflammation, as indicated by the elevated levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase (P < 0.05). Conditional logistic regression analysis revealed that body mass index (BMI) >= 25 [adjusted odds ratio (AOR) = 1.116, 95%CI: 1.002-1.244, P = 0.045] and history of alcohol intake (AOR = 10.294, 95%CI: 1.108-95.680, P = 0.040) were significantly associated with increased odds of HCC development in PBC patients. CONCLUSION: HCC is not rare in Chinese PBC patients. Risk factors for PBC-associated HCC include BMI >= 25 and a history of alcohol intake. In addition to regular monitoring, PBC patients may benefit from abstinence from alcohol and body weight control. PMID- 25834321 TI - Hepatectomy with primary closure of common bile duct for hepatolithiasis combined with choledocholithiasis. AB - AIM: To evaluate the feasibility of hepatectomy and primary closure of common bile duct for intrahepatic and extrahepatic calculi. METHODS: From January 2008 to May 2013, anatomic hepatectomy followed by biliary tract exploration without biliary drainage (non-drainage group) was performed in 43 patients with intrahepatic and extrahepatic calculi. After hepatectomy, flexible choledochoscopy was used to extract residual stones and observe the intrahepatic bile duct and common bile duct (CBD) for determination of biliary stricture and dilatation. Function of the sphincter of Oddi was determined by manometry of the CBD. Primary closure of the CBD without T-tube drainage or bilioenteric anastomosis was performed when there was no biliary stricture or sphincter of Oddi dysfunction. Dexamethasone and anisodamine were intravenously injected 2-3 d after surgery to prevent postoperative retrograde infection due to intraoperative bile duct irrigation, and to maintain relaxation of the sphincter of Oddi, respectively. During the same period, anatomic hepatectomy followed by biliary tract exploration with biliary drainage (drainage group) was performed in 48 patients as the control group. Postoperative complications and hospital stay were compared between the two groups. RESULTS: There was no operative mortality in either group of patients. Compared to intrahepatic and extrabiliary drainage, hepatectomy with primary closure of the CBD (non-drainage) did not increase the incidence of complications, including residual stones, bile leakage, pancreatitis and cholangitis (P > 0.05). Postoperative hospital stay and costs were nevertheless significantly less in the non-drainage group than in the drainage group. The median postoperative hospital stay was shorter in the non-drainage group than in the drainage group (11.2 +/- 2.8 d vs 15.4 +/- 2.1 d, P = 0.000). The average postoperative cost of treatment was lower in the non-drainage group than in the drainage group (29325.6 +/- 5668.2 yuan vs 32933.3 +/- 6235.1 yuan, P = 0.005). CONCLUSION: Hepatectomy followed by choledochoendoscopic stone extraction without biliary drainage is a safe and effective treatment of hepatolithiasis combined with choledocholithiasis. PMID- 25834322 TI - Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease: effect of N-acetyl transferase polymorphisms. AB - AIM: To evaluate variation of the concentration of thiopurine metabolites after 5 aminosalicylate (5-ASA) interruption and the role of genetic polymorphisms of N acetyl transferase (NAT) 1 and 2. METHODS: Concentrations of thioguanine nucleotides (TGN) and methymercaptopurine nucleotides (MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients (3 females and 9 males, median age 16 years) with inflammatory bowel disease (6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines (7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase (ITPA) and thiopurine methyl transferase (TPMT) genes was performed using PCR assays. RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 10(8) erythrocytes (range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations (absolute mean reduction 109 pmol/8 * 10(8) erythrocytes) was observed (median 221 pmol/8 * 10(8) erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration (P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study. CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study. PMID- 25834323 TI - Computed tomography-guided percutaneous core needle biopsy in pancreatic tumor diagnosis. AB - AIM: To evaluate the techniques, results, and complications related to computed tomography (CT)-guided percutaneous core needle biopsies of solid pancreatic lesions. METHODS: CT-guided percutaneous biopsies of solid pancreatic lesions performed at a cancer reference center between January 2012 and September 2013 were retrospectively analyzed. Biopsy material was collected with a 16-20 G Tru Core needle (10-15 cm; Angiotech, Vancouver, CA) using a coaxial system and automatic biopsy gun. When direct access to the lesion was not possible, indirect (transgastric or transhepatic) access or hydrodissection and/or pneumodissection maneuvers were used. Characteristics of the patients, lesions, procedures, and histologic results were recorded using a standardized form. RESULTS: A total of 103 procedures included in the study were performed on patients with a mean age of 64.8 year (range: 39-94 year). The mean size of the pancreatic lesions was 45.5 mm (range: 15-195 mm). Most (75/103, 72.8%) procedures were performed via direct access, though hydrodissection and/or pneumodissection were used in 22.2% (23/103) of cases and indirect transhepatic or transgastric access was used in 4.8% (5/103) of cases. Histologic analysis was performed on all biopsies, and diagnoses were conclusive in 98.1% (101/103) of cases, confirming 3.9% (4/103) of tumors were benign and 94.2% (97/103) were malignant; results were atypical in 1.9% (2/103) of cases, requiring a repeat biopsy to diagnose a neuroendocrine tumor, and surgical resection to confirm a primary adenocarcinoma. Only mild/moderate complications were observed in 9/103 patients (8.7%), and they were more commonly associated with biopsies of lesions located in the head/uncinate process (n = 8), than of those located in the body/tail (n = 1) of the pancreas, but this difference was not significant. CONCLUSION: CT-guided biopsy of a pancreatic lesion is a safe procedure with a high success rate, and is an excellent option for minimally invasive diagnosis. PMID- 25834324 TI - Appropriate empirical antibiotic use and 30-d mortality in cirrhotic patients with bacteremia. AB - AIM: To analyze whether prompt and appropriate empirical antibiotic (AEA) use is associated with mortality in cirrhotic patients with bacteremia. METHODS: A total of 102 episodes of bacteremia in 72 patients with cirrhosis were analyzed. AEA was defined as a using or starting an antibiotic appropriate to the isolated pathogen at the time of bacteremia. The primary endpoint was 30-d mortality. RESULTS: The mortality rate at 30 d was 30.4% (31/102 episodes). Use of AEA was associated with better survival at 30 d (76.5% vs 46.9%, P = 0.05), and inappropriate empirical antibiotic (IEA) use was an independent factor associated with increased mortality (OR = 3.24; 95%CI: 1.50-7.00; P = 0.003, adjusted for age, sex, Child-Pugh Class, gastrointestinal bleeding, presence of septic shock). IEA use was more frequent when the isolated pathogen was a multiresistant pathogen, and when infection was healthcare-related or hospital-acquired. CONCLUSION: AEA use was associated with increased survival of cirrhotic patients who developed bacteremia. Strategies for AEA use, tailored according to the local epidemiological patterns, are needed to improve survival of cirrhotic patients with bacteremia. PMID- 25834325 TI - Formalin irrigation for hemorrhagic chronic radiation proctitis. AB - AIM: To assess the efficacy and safety of a modified topical formalin irrigation method in refractory hemorrhagic chronic radiation proctitis (CRP). METHODS: Patients with CRP who did not respond to previous medical treatments and presented with grade II-III rectal bleeding according to the Common Terminology Criteria for Adverse Events were enrolled. Patients with anorectal strictures, deep ulcerations, and fistulas were excluded. All patients underwent flexible endoscopic evaluation before treatment. Patient demographics and clinical data, including primary tumor, radiotherapy and previous treatment options, were collected. Patients received topical 4% formalin irrigation in a clasp-knife position under spinal epidural anesthesia in the operating room. Remission of rectal bleeding and related complications were recorded. Defecation, remission of bleeding, and other symptoms were investigated at follow-up. Endoscopic findings in patients with rectovaginal fistulas were analyzed. RESULTS: Twenty-four patients (19 female, 5 male) with a mean age of 61.5 +/- 9.5 years were enrolled. The mean time from the end of radiotherapy to the onset of bleeding was 11.1 +/- 9.0 mo (range: 2-24 mo). Six patients (25.0%) were blood transfusion dependent. The median preoperative Vienna Rectoscopy Score (VRS) was 3 points. Nineteen patients (79.2%) received only one course of topical formalin irrigation, and five (20.8%) required a second course. No side effects were observed. One month after treatment, bleeding cessation was complete in five patients and obvious in 14; the effectiveness rate was 79.1% (19/24). For long-term efficacy, 5/16, 1/9 and 0/6 patients complained of persistent bleeding at 1, 2 and 5 years after treatment, respectively. Three rectovaginal fistulas were found at 1 mo, 3 mo and 2 years after treatment. Univariate analysis showed associations of higher endoscopic VRS and ulceration score with risk of developing rectovaginal fistula. CONCLUSION: Modified formalin irrigation is an effective and safe method for hemorrhagic CRP, but should be performed cautiously in patients with a high endoscopic VRS. PMID- 25834326 TI - Poor prognosis for hepatocellular carcinoma with transarterial chemoembolization pre-transplantation: retrospective analysis. AB - AIM: To investigate whether transarterial chemoembolization (TACE) before liver transplantation (LT) improves long-term survival in hepatocellular carcinoma (HCC) patients. METHODS: A retrospective study was conducted among 204 patients with HCC who received LT from January 2002 to December 2010 in PLA General Hospital. Among them, 88 patients received TACE before LT. Prognostic factors of serum alpha-fetoprotein (AFP), intraoperative blood loss, intraoperative blood transfusion, disease-free survival time, survival time with tumor, number of tumor nodules, tumor size, tumor number, presence of blood vessels and bile duct invasion, lymph node metastasis, degree of tumor differentiation, and preoperative liver function were determined in accordance with the Child-Turcotte Pugh (Child) classification and model for end-stage liver disease. We also determined time of TACE before transplant surgery and tumor recurrence and metastasis according to different organs. Cumulative survival rate and disease free survival rate curves were prepared using the Kaplan-Meier method, and the log-rank and chi(2) tests were used for comparisons. RESULTS: In patients with and without TACE before LT, the 1, 3 and 5-year cumulative survival rate was 70.5% +/- 4.9% vs 91.4% +/- 2.6%, 53.3% +/- 6.0% vs 83.1% +/- 3.9%, and 46.2% +/- 7.0% vs 80.8% +/- 4.5%, respectively. The median survival time of patients with and without TACE was 51.857 +/- 5.042 mo vs 80.930 +/- 3.308 mo (chi(2) = 22.547, P < 0.001, P < 0.05). The 1, 3 and 5-year disease-free survival rates for patients with and without TACE before LT were 62.3% +/- 5.2% vs 98.9% +/- 3.0%, 48.7% +/- 6.7% vs 82.1% +/- 4.1%, and 48.7% +/- 6.7% vs 82.1% +/- 4.1%, respectively. The median survival time of patients with and without TACE before LT was 50.386 +/- 4.901 mo vs 80.281 +/- 3.216 mo (chi(2) = 22.063, P < 0.001, P < 0.05). TACE before LT can easily lead to pulmonary or distant metastasis of the primary tumor. Although there was no significant difference between the two groups, the chance of metastasis of the primary tumor in the group with TACE was significantly higher than that of the group without TACE. CONCLUSION: TACE pre-LT for HCC patients increased the chances of pulmonary or distant metastasis of the primary tumor, thus reducing the long-term survival rate. PMID- 25834327 TI - Endoscopic ultrasound-guided deep and large biopsy for diagnosis of gastric infiltrating tumors with negative malignant endoscopy biopsies. AB - AIM: To assess the diagnostic yield and safety of a deep and large biopsy technique under the guidance of endoscopic ultrasound (EUS) for diagnosis of gastric infiltrating tumors with negative malignant endoscopy biopsies. METHODS: From January 2009 to March 2014, 36 patients in whom gastric infiltrating tumors had been diagnosed by EUS received negative results for malignancy after endoscopic biopsies. The deep and large biopsy technique combined bite-on-bite technique with or without endoscopic mucosal resection (EMR) to obtain submucosal tissue from lesions. EUS was used to select the appropriate biopsy sites. If the lesion protruded into the cavity, EMR was performed for removal of the overlying mucosa and then bite-on-bite technique was conducted in the resected area to obtain submucosal tissue. If the lesion appeared to be flat or was difficult to lift by injection, the bite-on-bite technique was directly used. RESULTS: Twenty eight of the 36 patients were treated by EMR followed by bite-on-bite technique, while 8 patients only underwent bite-on-bite technique. Histological results showed 23 of the 36 lesions were poorly differentiated adenocarcinomas, 2 diffuse large B cell lymphomas, 4 mucosa-associated lymphoid tissue-type lymphomas, and 7 undiagnosed. The deep and large biopsy technique provided a definitive and conclusive diagnosis in 29 (80.6%) of the 36 patients. The 12 gastric linitis plastica and 6 lymphoma patients received chemotherapy and avoided surgery. Minor oozing of blood in 2 mucosal resection wounds was managed by argon plasma coagulation and in 5 cases after deep biopsies by epinephrine (0.001%). Neither severe hemorrhage nor perforation occurred in any patient. CONCLUSION: The deep and large biopsy technique is superior to ordinary endoscopic biopsy for achieving an accurate diagnosis of gastric infiltrating tumors. This procedure guided by EUS is an effective and safe diagnostic method for gastric infiltrating tumors in which endoscopic biopsy results were negative for malignancy. PMID- 25834328 TI - Cholecystectomy does not significantly increase the risk of fatty liver disease. AB - AIM: To investigate the relationship between cholecystectomy and fatty liver disease (FLD) in a Chinese population. METHODS: A total of 32428 subjects who had voluntarily undergone annual health checkups in the Second Affiliated Hospital of Nanjing Medical University from January 2011 to May 2013 were included in this study. Basic data collection, physical examination, laboratory examination, and abdominal ultrasound examination were performed. RESULTS: Subjects undergoing cholecystectomy were associated with greater age, female sex, higher body mass index, and higher levels of systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol, and triglycerides. However, no significant differences were found in high-density lipoprotein cholesterol, low density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, albumin, and serum uric acid. The overall prevalence of FLD diagnosed by ultrasonography was high at 38.4%. The prevalence of FLD was significantly higher for subjects who had undergone cholecystectomy (46.9%) than those who had not undergone cholecystectomy (38.1%; chi(2) test, P < 0.001). Cholecystectomy was positively associated with FLD (OR = 1.433, 95%CI: 1.259-1.631). However, after adjusting for possible factors associated with FLD, multivariate regression analysis showed that the association between cholecystectomy and FLD was not statistically significant (OR = 1.096; 95%CI: 0.939-1.279). CONCLUSION: According to our study results, cholecystectomy may not be a significant risk factor for FLD. PMID- 25834330 TI - Prevalence and factors associated with irritable bowel syndrome among university students in Lebanon: findings from a cross-sectional study. AB - AIM: To describe the bowel habits and the prevalence of irritable bowel syndrome (IBS) and to investigate the influence of health behavior and social factors on IBS prevalence in university students. METHODS: This cross-sectional study was conducted at five major universities in Greater Beirut and its suburbs, between February and June 2014. Using a convenience sample, a total of 813 students aged 18 years old and above participated in this study. Participants were asked to complete a comprehensive anonymous questionnaire which detailed characteristics on socio-demographic, health-related, and lifestyle factors, as well as IBS. The ROME III criteria were used as a tool to ascertain IBS. A chi(2) test was used to determine differences between categorical variables; stepwise logistic regression was used to measure the association between IBS and its risk factors. RESULTS: An overall prevalence of IBS of 20% was recorded among university students. The bivariate analysis showed that females were significantly more likely to report having IBS than males (29.1% vs 18.2%, P < 0.01). Those living at the school dormitory or in a private residence (39.5%) were more likely to have IBS than those living with their families (16.3%) (P < 0.01). The multivariate analysis showed that those who had a relatively high family income level (US$ > 2000) were almost 6 times more likely to report having IBS than their counterparts. CONCLUSION: This is the first study to describe the nature of IBS among young adults in Lebanon. The prevalence of IBS among university students in our sample was higher than that reported in the West. PMID- 25834329 TI - Scintigraphy in laryngopharyngeal and gastroesophageal reflux disease: a definitive diagnostic test? AB - AIM: To investigate the utility of scintigraphic studies in predicting response to laparoscopic fundoplication (LF) for chronic laryngopharyngeal reflux symptoms. METHODS: Patients with upper aero-digestive symptoms that remained undiagnosed after a period of 2 mo were studied with conventional pH and manometric studies. Patients mainly complained of cough, sore throat, dysphonia and globus. These patients were imaged after ingestion of 99m-technetium diethylene triamine pentaacetic acid. Studies were quantified with time activity curves over the pharynx, upper and lower oesophagus and background. Late studies of the lungs were obtained for aspiration. Patients underwent LF with post operative review at 3 mo after surgery. RESULTS: Thirty four patients (20 F, 14 M) with an average age of 57 years and average duration of symptoms of 4.8 years were studied. Twenty four hour pH and manometry studies were abnormal in all patients. On scintigraphy, 27/34 patients demonstrated pharyngeal contamination and a rising or flat pharyngeal curve. Lung aspiration was evident in 50% of patients. There was evidence of pulmonary aspiration in 17 of 34 patients in the delayed study (50%). Pharyngeal contamination was found in 27 patients. All patients with aspiration showed pharyngeal contamination. In the 17 patients with aspiration, graphical time activity curve showed rising activity in the pharynx in 9 patients and a flat curve in 8 patients. In those 17 patients without pulmonary aspiration, 29% (5 patients) had either a rising or flat pharyngeal graph. A rising or flat curve predicted aspiration with a positive predictive value of 77% and a negative predictive value of 100%. Over 90% of patients reported a satisfactory symptomatic response to LF with an acceptable side-effect profile. CONCLUSION: Scintigraphic reflux studies offer a good screening tool for pharyngeal contamination and aspiration in patients with gastroesophageal reflux disease. PMID- 25834331 TI - Helicobacter pylori and serum kynurenine-tryptophan ratio in patients with colorectal cancer. AB - AIM: To evaluate how Helicobacter pylori (H. pylori) is able to evade the immune response and whether it enhances systemic immune tolerance against colorectal cancer. METHODS: This prospective randomized study involved 97 consecutive colorectal cancer patients and 108 cancer-free patients with extra-digestive diseases. Colorectal cancer and cancer-free patients were assigned into subgroups according to H. pylori IgG seropositivity. Exposure to H. pylori was determined by IgG seropositivity which was detected by enzyme linked immunoassay (ELISA). Serum neopterin levels were measured by ELISA. Serum tryptophan, kynurenine, and urinary biopterin concentrations were measured by high performance liquid chromatography. Serum nitrite levels were detected spectrophotometrically. Serum indoleamine 2,3-dioxygenase activity was estimated by the kynurenine to tryptophan ratio and by assessing the correlation between serum neopterin concentrations and the kynurenine to tryptophan ratio. The frequencies of increased serum kynurenine to tryptophan ratio of H. pylori seronegative and seropositive colorectal cancer subgroups were estimated by comparing them with the average kynurenine to tryptophan ratio of H. pylori seronegative tumor-free patients. RESULTS: Compared with respective controls, in both H. pylori seronegative and seropositive colorectal cancer patients, while serum tryptophan levels were decreased (controls vs patients; seronegative: 20.37 +/- 0.89 MUmol/L vs 15.71 +/- 1.16 MUmol/L, P < 0.05; seropositive: 20.71 +/- 0.81 MUmol/L vs 14.97 +/- 0.79 MUmol/L, P < 0.01) the kynurenine to tryptophan ratio was significantly increased (controls vs patients; seronegative: 52.85 +/- 11.85 MUmol/mmol vs 78.91 +/- 8.68 MUmol/mmol, P < 0.01, seropositive: 47.31 +/- 5.93 MUmol/mmol vs 109.65 +/- 11.50 MUmol/mmol, P < 0.01). Neopterin concentrations in cancer patients were significantly elevated compared with controls (P < 0.05). There was a significant correlation between serum neopterin levels and kynurenine/tryptophan in control and colorectal cancer patients groups (rs = 0.494, P = 0.0001 and rs = 0.293, P = 0.004, respectively). Serum nitrite levels of H. pylori seropositive cancer cases were significantly decreased compared with seropositive controls (controls vs patients; 26.04 +/- 2.39 MUmol/L vs 20.41 +/- 1.48 MUmol/L, P < 0.05) The decrease in the nitrite levels of H. pylori seropositive cancer patients may be attributed to excessive formation of peroxynitrite and other reactive nitrogen species. CONCLUSION: A significantly high kynurenine/tryptophan suggested that H. pylori may support the immune tolerance leading to cancer development, even without an apparent upper gastrointestinal tract disease. PMID- 25834332 TI - Colorectal cancers in ulcerative colitis from a low-prevalence area for colon cancer. AB - AIM: To determine the incidence and risk factors for colorectal cancer (CRC) in patients with ulcerative colitis from a low prevalence region for CRC. METHODS: Our prospective database yielded a cohort of 430 patients [age: 44 +/- 14.6 years; 248 men (57.7%)] with ulcerative colitis (median disease duration 6, range: 1-39 years) for analysis. Of these, 131 (30.5%) had left-sided colitis and 159 (37%) extensive colitis. Patients with histologically confirmed CRC within the segment with colitis were compared with those without CRC, to determine the risk factors for the development of CRC. RESULTS: Twelve patients (2.8%) developed CRC. The overall incidence density was 3.56/1000 patient-years of disease - 3/1000 in the first 10 years, 3.3/1000 at 10 to 20 years, and 7/1000 at > 20 years. Three of our 12 patients developed CRC within 8 years of disease onset. On univariate analysis, extensive colitis, longer duration of disease, and poor control of disease were associated with development of CRC. On multivariate analysis, duration of disease and extent of colitis remained significant. CONCLUSION: CRC occurred in 2.8% of patients with ulcerative colitis in our population - an incidence density similar to that in Western countries in spite of a low overall prevalence of colon cancer in our population. The risk increased with extent and duration of disease. PMID- 25834333 TI - Differences in clinical features of Crohn's disease and intestinal tuberculosis. AB - AIM: To investigate the clinical features of Crohn's disease (CD) and intestinal tuberculosis (ITB) with a scoring system that we have developed. METHODS: A total of 25 CD and 40 ITB patients were prospectively enrolled from August 2011 to July 2012. Their characteristics and clinical features were recorded. Laboratory, endoscopic, histologic and radiographic features were determined. The features with a high specificity were selected to establish a scoring system. The features supporting CD scored +1, and those supporting ITB scored -1; each patient received a final total score. A receiver operating characteristic (ROC) curve was used to determine the best cut-off value for distinguishing CD from ITB. RESULTS: Based on a high specificity of differentiating between CD and ITB, 12 features, including longitudinal ulcers, nodular hyperplasia, cobblestone-like mucosa, intestinal diseases, intestinal fistula, the target sign, the comb sign, night sweats, the purified protein derivative test, the interferon-gamma release assay (T-SPOT.TB), ring ulcers and ulcer scars, were selected for the scoring system. The results showed that the average total score of the CD group was 3.12 +/- 1.740, the average total score of the ITB group was -2.58 +/- 0.984, the best cutoff value for the ROC curve was -0.5, and the diagnostic area under the curve was 0.997, which was statistically significant (P < 0.001). The patients whose total scores were higher than -0.5 were diagnosed with CD; otherwise, patients were diagnosed with ITB. Overall, the diagnostic accuracy rate and misdiagnosis rate of this scoring system were 97% and 3%, respectively. CONCLUSION: Some clinical features are valuable for CD and ITB diagnosis. The described scoring system is key to differentiating between CD and ITB. PMID- 25834334 TI - Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B. AB - AIM: To evaluate urine beta2-microglobulin (beta2-M), retinol-binding protein (RBP) excretion, and renal impairment with adefovir dipivoxil (ADV) for chronic hepatitis B. METHODS: We enrolled 165 patients with chronic hepatitis B infection who were treated with ADV monotherapy (n = 90) or ADV plus lamivudine combination therapy (n = 75). An additional 165 chronic hepatitis B patients treated with entecavir were recruited as controls. We detected serum creatinine, urine beta2 M, and RBP levels, and estimated the glomerular filtration rate (eGFR) at the initiation of antiviral therapy and every 6 mo for a period of five years. RESULTS: Urine beta2-M abnormalities were observed in patients during the first (n = 3), second (n = 7), third (n = 11), fourth (n = 16), and fifth (n = 21) year of ADV treatment. Urinary RBP abnormalities were observed in patients during the first (n = 2), second (n = 8), third (n = 12), fourth (n = 15), and fifth (n = 22) year of ADV treatment. eGFR decreased 20%-30% from baseline in 20 patients, 30%-50% in 12 patients, and > 50% in 3 patients during the five years of treatment. Further analysis indicated that decreases in eGFR of >= 30% relative to the baseline level correlated significantly with urine RBP and beta2-M abnormalities. In contrast, both serum creatinine and eGFR remained stable in patients treated with entecavir, and only one of these patients developed a urine beta2-M abnormality, and two developed urine RBP abnormalities during the five years of treatment. CONCLUSION: Urine RBP and beta2-M are biomarkers of renal injury during long-term ADV treatment for chronic hepatitis B, and indicate when treatment should be switched to entecavir. PMID- 25834335 TI - Doctor communication quality and Friends' attitudes influence complementary medicine use in inflammatory bowel disease. AB - AIM: To examine the frequency of regular complementary and alternative therapy (CAM) use in three Australian cohorts of contrasting care setting and geography, and identify independent attitudinal and psychological predictors of CAM use across all cohorts. METHODS: A cross sectional questionnaire was administered to inflammatory bowel disease (IBD) patients in 3 separate cohorts which differed by geographical region and care setting. Demographics and frequency of regular CAM use were assessed, along with attitudes towards IBD medication and psychological parameters such as anxiety, depression, personality traits and quality of life (QOL), and compared across cohorts. Independent attitudinal and psychological predictors of CAM use were determined using binary logistic regression analysis. RESULTS: In 473 respondents (mean age 50.3 years, 60.2% female) regular CAM use was reported by 45.4%, and did not vary between cohorts. Only 54.1% of users disclosed CAM use to their doctor. Independent predictors of CAM use which confirm those reported previously were: covert conventional medication dose reduction (P < 0.001), seeking psychological treatment (P < 0.001), adverse effects of conventional medication (P = 0.043), and higher QOL (P < 0.001). Newly identified predictors were CAM use by family or friends (P < 0.001), dissatisfaction with patient-doctor communication (P < 0.001), and lower depression scores (P < 0.001). CONCLUSION: In addition to previously identified predictors of CAM use, these data show that physician attention to communication and the patient-doctor relationship is important as these factors influence CAM use. Patient reluctance to discuss CAM with physicians may promote greater reliance on social contacts to influence CAM decisions. PMID- 25834336 TI - Comparison of the efficacy and safety of sedation between dexmedetomidine remifentanil and propofol-remifentanil during endoscopic submucosal dissection. AB - AIM: To compare the efficacy and safety of sedation protocols for endoscopic submucosal dissection (ESD) between dexmedetomidine-remifentanil and propofol remifentanil. METHODS: Fifty-nine patients scheduled for ESD were randomly allocated into a dexmedetomidine-remifentanil (DR) group or a propofol remifentanil (PR) group. To control patient anxiety, dexmedetomidine or propofol was infused to maintain a score of 4-5 on the Modified Observer's Assessment of Alertness/Sedation scale. Remifentanil was infused continuously at a rate of 6 MUg/kg per hour in both groups. The ease of advancing the scope into the throat, gastric motility grading, and satisfaction of the endoscopist and patient were assessed. Hemodynamic variables and hypoxemic events were compared to evaluate patient safety. RESULTS: Demographic data were comparable between the groups. The hemodynamic variables and pulse oximetry values were stable during the procedure in both groups despite a lower heart rate in the DR group. No oxygen desaturation events occurred in either group. Although advancing the scope into the throat was easier in the PR group ("very easy" 24.1% vs 56.7%, P = 0.010), gastric motility was more suppressed in the DR group ("no + mild" 96.6% vs 73.3%, P = 0.013). The endoscopists felt that the procedure was more favorable in the DR group ("very good + good" 100% vs 86.7%, P = 0.042), whereas patient satisfaction scores were comparable between the groups. En bloc resection was performed 100% of the time in both groups, and the complete resection rate was 94.4% in the DR group and 100% in the PR group (P = 0.477). CONCLUSION: The efficacy and safety of dexmedetomidine and remifentanil were comparable to propofol and remifentanil during ESD. However, the endoscopists favored dexmedetomidine perhaps due to lower gastric motility. PMID- 25834338 TI - Association between cadherin-17 expression and pathological characteristics of gastric cancer: a meta-analysis. AB - AIM: To construct a meta-analysis in order to examine the relationship between cadherin-17 (CDH17) and gastric cancer (GC). METHODS: Related articles were selected by searching the following English or Chinese electronic databases: CINAHL, MEDLINE, Science Citation Index, the Chinese Journal Full-Text, and the Weipu Journal. Newcastle-Ottawa Scale (NOS) criteria were used to ensure consistency in reviewing and reporting results. Statistical analyses were conducted with Version 12.0 STATA statistical software. RESULTS: Ultimately, 11 articles, with a total of 2,120 GC patients, were found to be eligible for study inclusion. In comparisons of GC patients by TNM stage (III-IV vs I-II: OR = 2.35, 95%CI: 1.15-4.825, P = 0.019), histologic grade (3-4 vs 1-2: OR = 3.48, 95%CI: 1.36-8.92, P = 0.009), invasion grade (T3-4 vs T1-2: OR = 2.86; 95%CI: 1.69-4.83; P = 0.000), and lymph node metastasis (positive vs negative: OR = 2.64; 95%CI: 1.33-5.27; P = 0.006), it was found that CDH17 showed more positive expressions in each of the more severe cases. Country-stratified analyses from all four experimental subgroups showed that high CDH17 expression levels may be related to GC among Chinese and Korean populations (all P < 0.05), with the exception of the invasion grade T3-4 vs T1-2 comparison, where the relation only held among the Chinese population (OR = 2.86, 95%CI: 1.69-4.83, P = 0.000). CONCLUSION: Collectively, the data reflects the capacity of CDH17 in tumor proliferation and metastasis among GC patients. PMID- 25834339 TI - Prognostic value of c-Met in colorectal cancer: a meta-analysis. AB - AIM: To assess the prognostic value of c-Met status in colorectal cancer. METHODS: We conducted a search in PubMed, Web of Science, and the Cochrane Library covering all published papers up to July 2014. Only studies assessing survival in colorectal cancer by c-Met status were included. This meta-analysis was performed by using STATA11.0. RESULTS: Ultimately, 11 studies were included in this analysis. Meta-analysis of the hazard ratios (HR) indicated that patients with high c-Met expression have a significantly poorer overall survival (OR) (HR = 1.33, 95%CI: 1.06-1.59) and progression-free survival (PFS) (HR = 1.47, 95%CI: 1.03-1.91). Subgroup analysis showed a significant association between high c-Met expression and poorer overall survival in the hazard ratio reported (HR = 1.41, 95%CI: 1.08-1.74). CONCLUSION: The present meta-analysis indicated that high c Met expression was associated with poor prognosis in patients with colorectal cancer. PMID- 25834337 TI - Cholecystectomy and the risk of alimentary tract cancers: a systematic review. AB - AIM: To investigate the association between cholecystectomy and gastro-intestinal tract (GIT) cancers. METHODS: We conducted a systematic review according to the PRISMA guidelines. A MEDLINE search was performed with predefined search criteria for English Language articles on the association between cholecystectomy and GIT cancers. Additional articles were retrieved by manual search of references. All relevant articles were accessed in full text. Data on study type; cases; controls; country; effect estimate; adjustments for confounders and quality of publication were extracted. The quality of the publications were scored by adherence to the STROBE checklist. The data for each part of the GIT were presented in separate tables. RESULTS: Seventy-five studies and 5 meta-analyses satisfied the predefined criteria for inclusion and were included in this review. There were inconsistent reports and no strong evidence of an association between cholecystectomy and cancers of the oesophagus (Adenocarcinoma), pancreas, small bowel and right-sided colon cancers. In squamous cancer of the oesophagus, cancers of the stomach, liver, bile ducts, small bowel and left sided colon cancers, good quality studies suggested a lack of association with cholecystectomy. Equally, distal colon and rectal cancers were found not to be associated with cholecystectomy. Several mechanisms for carcinogenesis/promotion of carcinogensis have been proposed. These have focused on a role for bile salts in carcinogenesis with several potential mutagenic molecular events and gut metabolic hormones signaling cell proliferation or initiation of carcinogenesis. CONCLUSION: This is a comprehensive review of the association between GIT cancers and cholecystectomy. This review found no clear association between cholecystectomy and GIT cancers. PMID- 25834340 TI - Association of cholesterol with risk of pancreatic cancer: a meta-analysis. AB - AIM: To evaluate the effect of dietary cholesterol and serum total cholesterol (TC) on the risk of pancreatic cancer. METHODS: A literature search was performed up to June 2014 in PubMed, EMBASE, China National Knowledge Infrastructure and China Biology Medical literature database for relevant articles published in English or Chinese. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. RESULTS: We included 14 published articles with 439355 participants for dietary cholesterol, and 6 published articles with 1805697 participants for serum TC. For the highest vs lowest category of dietary cholesterol, the pooled RR (95%CI) of pancreatic cancer was 1.308 (1.097-1.559). After excluding two studies (RR > 3.0), the pooled RR (95%CI) was 1.204 (1.050-1.380). In subgroup analysis stratified by study design, the pooled RRs (95%CIs) were 1.523 (1.226-1.893) for case-control studies and 1.023 (0.871-1.200) for cohort studies. The association of dietary cholesterol with the risk of pancreatic cancer was significant for studies conducted in North America [1.275 (1.058-1.537)] and others [2.495 (1.565 3.977)], but not in Europe [1.149 (0.863-1.531)]. No significant association [1.003 (0.859-1.171)] was found between the risk of pancreatic cancer and serum TC. CONCLUSION: Dietary cholesterol may be associated with an increased risk of pancreatic cancer in worldwide populations, except for Europeans. The results need to be confirmed further. PMID- 25834341 TI - Effects of neutrophil elastase inhibitor in patients undergoing esophagectomy: a systematic review and meta-analysis. AB - AIM: To evaluate the benefit and safety of sivelestat (a neutrophil elastase inhibitor) administration in patients undergoing esophagectomy. METHODS: Online databases including PubMed, EMBASE, the Cochrane Library, Web of Knowledge, and Chinese databases (Wanfang database, VIP and CNKI) were searched systematically up to November 2013. Randomized controlled trials and high-quality comparative studies were considered eligible for inclusion. Three reviewers evaluated the methodological quality of the included studies, and Stata 12.0 software was used to analyze the extracted data. The risk ratio (RR) was used to express the effect size of dichotomous outcomes, and mean difference (MD) or standardized mean difference was used to express the effect size of continuous outcomes. RESULTS: Thirteen studies were included in this systematic review and nine studies were included in the meta-analysis. The duration of mechanical ventilation was significantly decreased in the sivelestat group on postoperative day 5 [I (2) = 76.3%, SMD = -1.41, 95%CI: -2.63-(-0.19)]. Sivelestat greatly lowered the incidence of acute lung injury in patients after surgery (I (2) = 0%, RR = 0.27, 95%CI: 0.08-0.93). However, it did not decrease the incidence of pneumonia, intensive care unit stay or postoperative hospital stay, and did not increase the incidence of complications such as anastomotic leakage, recurrent nerve palsy, wound infection, sepsis and catheter-related fever. CONCLUSION: A neutrophil elastase inhibitor is beneficial in patients undergoing esophagectomy. More high quality, large sample, multi-center and randomized controlled trials are needed to validate this effect. PMID- 25834342 TI - Pyogenic liver abscess caused by Fusobacterium in a 21-year-old immunocompetent male. AB - A 21-year-old male with no significant past medical history, presented with right upper quadrant (RUQ) abdominal pain along with fevers and chills. Lab work revealed leukocytosis, anemia, and slightly elevated alkaline phosphatase. Viral serology for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus were negative and he was immunocompetent. Computed tomography imaging revealed hepatic abscesses, the largest measuring 9.5 cm. Empiric antibiotics were started and percutaneous drains were placed in the abscesses. Anaerobic cultures from the abscesses grew Fusobacterium nucleatum. This is a gram negative anaerobic bacteria; a normal flora of the oral cavity. Fusobacterium is most commonly seen in Lemiere's disease, which is translocation of oral bacteria to the internal jugular vein causing a thrombophlebitis and subsequent spread of abscesses. Our patient did not have Lemiere's, and is the first case described of fusobacterium pyogenic liver abscess in a young immunocompetent male with good oral hygiene. This case was complicated by sepsis, empyema, and subsequent abscesses located outside the liver. These abscesses' have the propensity to flare abruptly and can be fatal. This case not only illustrates fusobacterium as a rare entity for pyogenic liver abscess, but also the need for urgent diagnosis and treatment. It is incumbent on physicians to diagnose and drain any suspicious hepatic lesions. While uncommon, such infections may develop without any overt source and can progress rapidly. Prompt drainage with antibiotic therapy remains the cornerstone of therapy. PMID- 25834343 TI - Complicated fecal microbiota transplantation in a tetraplegic patient with severe Clostridium difficile infection. AB - A 65-year-old male suffering from acute spinal cord injury leading to incomplete tetraplegia presented with severe recurrent Clostridium difficile (C. difficile) infection subsequent to antibiotic treatment for pneumonia. After a history of ineffective antimicrobial therapies, including metronidazole, vancomycin, fidaxomicin, rifaximin and tigecycline, leading to several relapses, the patient underwent colonoscopic fecal microbiota transplantation from his healthy son. Four days subsequent to the procedure, the patient showed a systemic inflammation response syndrome. Without detecting an infectious cause, the patient received antimicrobial treatment, including tigecycline, metronidazole, vancomycin via polyethylene glycol and an additional enema for a period of seven days, leading to a prompt recovery and no reported C. difficile infection relapse during a 12 wk follow up. PMID- 25834344 TI - Fulminant phlegmonitis of the esophagus, stomach, and duodenum due to Bacillus thuringiensis. AB - We report a case of phlegmonitis of the esophagus, stomach, and duodenum in patient in an immunocompromised state. Culture of gastric juice and blood yielded Bacillus thuringiensis. This case showed that even low-virulence bacilli can cause lethal gastrointestinal phlegmonous gastritis in conditions of immunodeficiency. PMID- 25834345 TI - Cetuximab and panitumumab in a patient with colon cancer and concomitant chronic skin disease: a potential beneficial effect on psoriasis vulgaris. AB - Monoclonal antibodies against epidermal growth factor receptor (EGFR) are used in the treatment of advanced colorectal cancer. However, these agents can induce severe dermatological side effects that discourage their administration in patients with chronic dermatological disease. EGFR plays a key role in normal skin development and immunological function, and is expressed in various tissues and organs, although contrarily, it is overexpressed in psoriasis-related skin lesions. Thus, discussion is ongoing regarding the putative pathological role and therapeutic potential of this protein. We herein report on a patient with advanced colon cancer and concomitant long-standing psoriasis vulgaris who received anti-EGFR antibody monotherapy as a third-line treatment for metastatic disease. One week after the initiation of treatment, the patient's skin lesions dramatically subsided and the improvement was sustained during therapy. Based on this case, we propose that anti-EGFR antibody therapy is not necessarily contraindicated in patients with psoriasis vulgaris. Moreover, the findings reaffirmed that EGFR is an important molecule in the pathology of psoriasis. PMID- 25834346 TI - Cytomegalovirus colitis followed by ischemic colitis in a non-immunocompromised adult: a case report. AB - We report a rare case of cytomegalovirus (CMV) colitis followed by severe ischemic colitis in a non-immunocompromised patient. An 86-year-old woman was admitted after experiencing episodes of vomiting and diarrhea. The next day, hematochezia was detected without abdominal pain. The initial diagnosis of ischemic colitis was based on colonoscopy and histological findings. The follow up colonoscopy revealed a prolonged colitis. Immunohistochemical staining detected CMV-positive cells following conservative therapy. Intravenous ganciclovir therapy led to successful healing of ulcers and disappearance of CMV positive cells. The prevalence of CMV infection is common in adults. CMV colitis is relatively common in immunocompromised patients; however, it is rare in immunocompetent patients. In our case, CMV infection was allowed to be established due to the disruption of the colonic mucosa by the prior severe ischemic colitis. Our experience suggests that biopsies may be necessary to detect CMV and the prompt management of CMV colitis should be instituted when intractable ischemic colitis is observed. PMID- 25834347 TI - Liver transplantation for recurrent posthepatectomy malignant hepatic angiomyolipoma: a case report. AB - Hepatic angiomyolipomas (AMLs) are typically benign tumors containing varying amounts of smooth muscle cells, adipose tissue, and vessels, and are commonly found in the kidney and occasionally in the liver. The preoperative diagnosis of hepatic AML is primarily made from imaging and fine-needle aspiration biopsy results, though limited experience for such diagnoses can result in misdiagnosis. Some uncommon features of hepatic AML have been reported in the literature without an objective or qualitative consensus. As the majority of cases are benign, conservative treatment of AMLs is recommended. However, in rare cases, liver transplantation has been implemented. Only five cases of malignant hepatic AML have been reported. We report a rare case of recurrent posthepatectomy malignant hepatic AML that was misdiagnosed as liver cancer in a 37-year-old woman, which was treated by liver transplantation. The imaging and pathologic findings are presented in order to provide a more concise description to aid in future diagnoses. PMID- 25834348 TI - Gastritis cystica profunda in a previously unoperated stomach: a case report. AB - Gastritis cystica profunda is a relatively rare disease, usually observed at anastomotic sites in stomachs of patients that have undergone gastric procedures. We present the rare case of an elevated lesion in the anterior wall of the gastric antrum of a 43-year-old Chinese woman who had never undergone gastric surgery and had no gastrointestinal tract symptoms. Although the physical examination and laboratory data showed no abnormalities, endoscopic ultrasonography revealed an anechoic cystic structure. Abdominal computed tomography and magnetic resonance imaging showed the gastric wall of the greater curvature of the antrum was markedly and irregularly thickened, and mild to moderate enhancement was observed around the lesion with no enhancement in the central portion, suggestive of a gastrointestinal stromal tumor. The patient underwent a distal gastric resection of the 2.5 cm * 1.5 cm lesion. A postoperative pathologic examination showed dilated cystic glands in the muscularis mucosa and submucosal layers and erosion of the mucosal surface of the tumor, confirming the diagnosis of gastritis cystica profunda without malignancy. PMID- 25834349 TI - Retinoic Acid promotes interleukin-4 plasmid-dimethylsulfoxide topical transdermal delivery for treatment of psoriasis. AB - BACKGROUND: Psoriasis is an autoimmune disease that is caused by a shift in the Th1/Th2 balance toward Th1-dominant immunity. It has been established as an effective treatment to counteract psoriasis by subcutaneous injection of recombinant interleukin (IL)-4, and IL-4 gene therapy by topical transdermal penetration has shown its antipsoriatic effect in mice. Retinoic acid (RA) and dimethylsulfoxide can increase the efficiency of gene transfection in the topical transdermal delivery system. OBJECTIVE: We investigated whether RA could improve anti-psoriasis efficiency using IL-4 expression plasmid pORF-mIL-4 (pIL-4) via transdermal delivery system in K14-vascular endothelial growth (K14-VEGF) factor transgenic mice. METHODS: After pretreatment with RA, plasmid pIL-4 in 10% dimethylsulfoxide was applied to the ear skin by topical transdermal penetration. Hematoxylin- eosin staining and immunohistochemistry were performed with ear samples to evaluate anti-psoriasis efficiency in mice. RESULTS: The psoriasis pathological features were relieved and psoriasis-associated factors were significantly reduced. CONCLUSION: Our results reveal that topical application of pIL-4 in dimethylsulfoxide by transdermal delivery with RA pretreatment can improve psoriasis significantly. PMID- 25834350 TI - TNF, IL12B, and IFNG Gene Polymorphisms in Serbian Patients with Psoriasis. AB - BACKGROUND: Psoriasis is a common chronic inflammatory skin disease with a strong genetic basis. Cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukins (ILs) such are IL-12 and IL-23, and interferon gamma (IFN-gamma) are released from various inflammatory and resident cells, and have been implicated in the initiation/maintenance of inflammation. Certain alleles of the aforementioned cytokines may be associated with disease susceptibility/severity. OBJECTIVE: To investigate the association of three common functional gene polymorphisms, namely TNF -308 G/A (rs1800629), IL12B (encoding the p40 subunit of IL-12/23) +1188 A/C (rs3212227), and IFNG +874 T/A (rs2430561) with psoriasis development and severity in Serbian patients. METHODS: We genotyped 130 patients with psoriasis (26 of whom also had psoriatic arthritis) and 259 controls; rs1800629 and rs3212227, and rs2430561, by real-time PCR assay. RESULTS: The TNF GG genotype was detected at a higher frequency in patients with psoriasis compared to control subjects (OR, 1.420; 95% CI, 0.870~2.403) without statistical significance (p=0.191). Lack of the TNF G allele was associated with lower psoriasis severity (p=0.007). The IL12B AC genotype was underrepresented in the patients with psoriatic arthritis compared to healthy subjects (OR, 0.308; 95% CI, 0.090~1.057; p=0.049). The distribution of the rs2430561 allele and genotype frequencies was similar between patients with psoriasis and controls. CONCLUSION: Our study demonstrates an effect of the rs1800629 on psoriasis severity, and a marginal impact of the rs3212227 on susceptibility to psoriatic arthritis. Collectively, our results obtained in a Serbian cohort expand current knowledge regarding individual predisposition to psoriatic disease. PMID- 25834351 TI - Periadnexal mucin as an additional histopathologic feature of chronic eczematous dermatitis. AB - BACKGROUND: Cutaneous mucinoses are a heterogeneous group of disorders characterized by an abnormal amount of mucin in the skin. However, the pathomechanism of an excessive mucin deposition in the skin is still unknown. Eczematous dermatitis is sub-classified histologically into acute, subacute, and chronic variants. The characteristic histopathologic findings for chronic eczema are variable. However, periadnexal mucin deposition is not known as a feature of chronic eczema. OBJECTIVE: To evaluate the presence of periadnexal mucin deposition in chronic eczematous dermatitis. METHODS: We analyzed the skin biopsy specimens from 36 patients who were pathologically diagnosed with chronic eczematous dermatitis. Alcian blue, colloidal iron, and periodic acid-Schiff stains were used to evaluate the mucin deposition in histologic sections. Two dermatologists and two dermatopathologists evaluated the degree of mucin deposition using a 4-point scale. RESULTS: Various amounts of mucin deposition were observed in the periadnexal area of patients who were diagnosed with chronic eczema. Mucin deposition was more visible after staining with mucin-specific stains. Evaluation of the staining analysis scores revealed that the staining intensities were significantly higher in patients with chronic eczema than age- and site-matched controls (normal, acute to subacute eczema, and psoriasis vulgaris). CONCLUSION: Periadnexal mucin (secondary mucinoses) may be an additional finding of chronic eczematous dermatitis. PMID- 25834352 TI - Ethanol Extract of Peanut Sprout Exhibits a Potent Anti-Inflammatory Activity in Both an Oxazolone-Induced Contact Dermatitis Mouse Model and Compound 48/80 Treated HaCaT Cells. AB - BACKGROUND: We developed an ethanol extract of peanut sprouts (EPS), a peanut sprout-derived natural product, which contains a high level of trans-resveratrol (176.75 ug/ml) and was shown to have potent antioxidant activity. OBJECTIVE: We evaluated the potential anti-inflammatory activity of EPS by measuring its antioxidant potential in skin. METHODS: The anti-inflammatory activity of EPS was tested using two models of skin inflammation: oxazolone (OX)-induced contact dermatitis in mice and compound 48/80-treated HaCaT cells. As biomarkers of skin inflammation, cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) levels were measured. RESULTS: OX-induced contact dermatitis was suppressed markedly in mice that were treated with an ointment containing 5% EPS as evidenced by a decrease in the extent of scaling and thickening (p<0.05) and supported by a histological study. COX-2 (messenger RNA [mRNA] and protein) and NGF (mRNA) levels, which were upregulated in the skin of OX-treated mice, were suppressed markedly in the skin of OX+EPS-treated mice. Consistent with this, compound 48/80-induced expression of COX-2 (mRNA and protein) and NGF (mRNA) in HaCaT cells were suppressed by EPS treatment in a dose-dependent manner. As an inhibitor of NF-kappaB, IkappaB protein levels were dose-dependently upregulated by EPS. Fluorescence-activated cell sorting (FACS) analysis revealed that EPS scavenged compound 48/80-induced reactive oxygen species (ROS) in HaCaT cells. CONCLUSION: EPS exerts a potent anti-inflammatory activity via its anti-oxidant activity in both mouse skin and compound 48/80-treated HaCaT cells in vitro. Compound 48/80-treated HaCaT cells are a useful new in vitro model of skin inflammation. PMID- 25834353 TI - Mechanism of Macrophage-Derived Chemokine/CCL22 Production by HaCaT Keratinocytes. AB - BACKGROUND: CC chemokine ligand 17 (CCL17) and CCL22 are the functional ligands for CCR4. We previously reported that inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase (p38 MAPK), but not of extracellular signal related kinase (ERK), inhibited tumor necrosis factor (TNF)-alpha- and interferon (IFN)-gamma-induced production of CCL17 by the human keratinocyte cell line, HaCaT. Further, an inhibitor of epidermal growth factor receptor (EGFR) enhanced the CCL17 production by these keratinocytes. OBJECTIVE: To identify the mechanism underlying CCL22 production by HaCaT cells. METHODS: We investigated the signal transduction pathways by which TNF-alpha and IFN-gamma stimulate HaCaT cells to produce CCL22 by adding various inhibitors. RESULTS: TNF-alpha- and IFN-gamma induced CCL22 production was inhibited by PD98059, PD153035, Bay 11-7085, SB202190, c-Jun N-terminal kinase (JNK) inhibitor II, and Janus kinase (JAK) inhibitor 1. CONCLUSION: Our results indicate that CCL22 production in HaCaT cells is dependent on ERK, EGFR, p38 MAPK, JNK, and JAK and is mediated by different signal pathways from those regulating CCL17 production. Altogether, our previous and present results suggest that EGFR activation represses CCL17 but enhances CCL22 production by these cells. PMID- 25834354 TI - Identification of leukocyte-specific protein 1-positive cells: a clue to the cell of origin and a marker for the diagnosis of dermatofibroma. AB - BACKGROUND: Dermatofibroma (DF) comprises a heterogeneous group of mesenchymal tumors, with fibroblastic and histiocytic elements present in varying proportions. The cell of origin of DF has been investigated, but remains unclear. OBJECTIVE: The present study attempted to investigate the expression of leukocyte specific protein 1 (LSP1), a marker of fibrocytes, in DF. Additionally, we evaluated the effectiveness of LSP1 in the differential diagnosis of DF from dermatofibrosarcoma protuberans (DFSP). METHODS: Immunohistochemical staining was performed on 20 cases of DF using antibodies against LSP1, CD68, and factor XIIIa (FXIIIa). In addition, the expression of LSP1 and FXIIIa was evaluated in 20 cases of DFSP. RESULTS: Eighteen of 20 cases (90%) of DF stained positive for LSP1, with variation in the intensity of expression. CD68 was positive in 10 cases (50%), and FXIIIa was expressed in all cases of DF. There were differences between the regional expression patterns of the three markers in individual tumors. In contrast, only 2 of 20 cases of DFSP expressed LSP1, and none of DFSP cases stained positive for FXIIIa. CONCLUSION: The LSP1-positive cells in DF could potentially be fibrocyte-like cells. FXIIIa and CD68 expression suggests that dermal dendritic cells and histiocytes are constituent cells of DF. It is known that fibrocytes, dermal dendritic cells and histiocytes are all derived from CD14+ monocytes. Therefore, we suggest that DF may originate from CD14+ monocytes. Additionally, the LSP1 immunohistochemical stain could be useful in distinguishing between DF and DFSP. PMID- 25834355 TI - Inflammatory Cytokine Expression and Sebum Production after Exposure of Cultured Human Sebocytes to Ultraviolet A Radiation and Light at Wavelengths of 650 nm and 830 nm. AB - BACKGROUND: The effectiveness of ultraviolet (UV) radiation, visible light, or infrared light therapy for the treatment of acne is the subject of ongoing scientific debate. OBJECTIVE: This study was conducted to investigate changes in sebum production and the expression of inflammatory cytokines, matrix metalloproteinases (MMPs), and antimicrobial peptides (AMPs), following exposure of cultured human sebocytes to UVA radiation and light at wavelengths of 650 nm and 830 nm. METHODS: Reverse transcription polymerase chain reaction assays were performed to measure the gene expression levels of inflammatory cytokines (interleukin [IL]-1beta, IL-6, IL-8, and tumor necrosis factor-alpha), MMPs (MMP 1, MMP-3, and MMP-9), and AMPs (psoriasin, hBD-2, hBD-3, and LL-37) in cultured sebocytes after exposure to UVA radiation (2 J/cm(2), 3 J/cm(2), and 5 J/cm(2)) and light at wavelengths of 650 nm (14 J/cm(2), 29 J/cm(2), and 87 J/cm(2)) and 830 nm (5 J/cm(2), 10 J/cm(2), and 30 J/cm(2)). Expression of inflammatory cytokine proteins and sebum production were measured using enzyme-linked immunoassays and a lipid analysis kit, respectively. RESULTS: Exposure of cultured sebocytes to UVA radiation and light at wavelengths of 650 nm and 830 nm did not show a significant increase in the expression of inflammatory cytokines, MMPs, or AMPs. Sebum production was not significantly decreased after exposure to UVA radiation and light at both wavelengths. CONCLUSION: We propose that UVA radiation, visible light, and infrared light can be used to target Propionibacterium acnes for the treatment of acne, without an increase in the expression of inflammatory biomarkers and sebum production. PMID- 25834356 TI - Analysis of the Results from the Patch Test to Para-Phenylenediamine in the TRUE Test in Patients with a Hair Dye Contact Allergy. AB - BACKGROUND: Para-phenylenediamine (PPD) is the primary patch test screening agent for hair dye contact allergy (HDCA). However, no recent studies have been published that describe the results of reactions to patch tests using PPD and hair dyes in Korea. OBJECTIVE: To analyze the results of the patch tests to PPD using the thin-layer rapid use epicutaneous (TRUE) Test system in patients with HDCA and to investigate patients' awareness that hair dyes contains allergens, which cause the development of HDCA. METHODS: Eighty-four patients with suspected HDCA (32 men and 52 women) underwent patch testing using the TRUE Test system and their own hair dyes. The patients' demographic data, behavior associated with hair dyeing, and clinical manifestations of HDCA were examined retrospectively. RESULTS: Positive patch-test reactions to hair dyes occurred in 53.6% of patients who used hair dyes, and they were diagnosed with HDCA. Although there was a significant correlation between HDCA and PPD sensitization (p=0.001), only 40% of the patients with HDCA showed positive reactions to PPD. Of the 45 patients diagnosed with HDCA, only 7 (15.6%) were aware that their hair dyes contained allergens that caused HDCA. CONCLUSION: This study's findings show that PPD is an effective HDCA marker. However, we propose that investigations on hair dye components other than PPD should be conducted to develop and validate additional predictive HDCA markers. PMID- 25834357 TI - Evaluation of advanced oxidation protein products, prooxidant-antioxidant balance, and total antioxidant capacity in untreated vitiligo patients. AB - BACKGROUND: Vitiligo is a chronic, common disease of unknown etiology, and oxidative stress is suggested to have a role in its etiopathogenesis. OBJECTIVE: Advanced oxidation protein products (AOPPs), prooxidant-antioxidant balance (PAB), and ferric-reducing antioxidant power (FRAP) were evaluated regarding their role in the pathogenesis of vitiligo as well as their relationship with clinical presentation and disease severity, and these parameters were compared with those of healthy controls. METHODS: The study included 53 patients with vitiligo and 20 healthy volunteers as the control group. AOPP level, PAB, and FRAP were determined by colorimetric methods. RESULTS: PAB and FRAP level were significantly higher in patients with vitiligo than in healthy controls (p<0.001). The AOPP levels in vitiligo patients were not statistically significantly higher than those in healthy controls. The Vitiligo Area Scoring Index positively correlated with disease duration (rs: 0.531, p<0.001). CONCLUSION: To the best of our knowledge, this is the first report of AOPP and PAB status in vitiligo. PAB may be used as an indicator for oxidative stress in the etiopathogenesis of vitiligo. Our results show that these parameters may play a major role in the melanocyte damage observed in vitiligo. Further studies are required to confirm the mechanisms underlying this effect. PMID- 25834358 TI - Comparison of Treatment Goals for Moderate-to-Severe Psoriasis between Korean Dermatologists and the European Consensus Report. AB - BACKGROUND: The development of therapies for psoriasis has led to the need for a new strategy to the treatment of patients with moderate-to-severe psoriasis. New consensus guidelines for psoriasis treatment have been developed in some countries, some of which have introduced treatment goals to determine the timing of therapeutic regimens for psoriasis. OBJECTIVE: To investigate the opinions held by Korean dermatologists who specialize in psoriasis about treatment goals, and to compare these with the European consensus. METHODS: Korean dermatologists who specialize in psoriasis were asked 11 questions about defining the treatment goals for psoriasis. The questionnaire included questions about the factors used to classify the severity of psoriasis, defining the induction and maintenance phases of psoriasis treatment, defining treatment responses during the induction phase, and defining treatment responses during the maintenance phase. RESULTS: The Korean consensus showed responses that were almost similar to the European consensus, even without using the Delphi technique, which uses repeated rounds of questions to reach a consensus. Only one response that related to psoriasis severity in the context of the quality of patients' lives differed from the European consensus. CONCLUSION: The concept of using treatment goals in the treatment of moderate-to-severe psoriasis can be applied to Korean psoriasis patients. Since a tool for assessing the quality of patients' lives is not commonly used in Korea, the development of a simple, rapidly completed, and region-specific health-related quality of life assessment tool would enable treatment goals to be used in routine clinical practice. PMID- 25834359 TI - Hypersensitivity reaction as a harbinger of acute myeloid leukemia: a case report and review of the literature. AB - Cutaneous paraneoplastic syndromes comprise a broad spectrum of cutaneous reactions to an underlying malignancy. These dermatoses are not the result of metastatic spread to the skin, but rather a reaction to the presence of malignancy. Cutaneous paraneoplastic syndromes often precede the identification of a malignancy. We describe the case of a 79-year-old man with a six-month history of recalcitrant treatment- resistant dermatitis. A complete blood count test performed at the time of initial presentation was normal. The patient ultimately presented with erythroderma and was diagnosed with acute myeloid leukemia (AML). The evolution of the dermatitis to erythroderma coincided with the clinical presentation of AML, and was therefore considered to be a paraneoplastic syndrome. The patient decided against therapy and died seven weeks after diagnosis. Physicians should consider a cutaneous paraneoplastic syndrome when faced with dynamic recalcitrant dermatoses that are difficult to treat and decide on laboratory testing accordingly. Patients should be evaluated regularly for two to three years after initial diagnosis with a physical exam and review of systems to monitor for signs and symptoms of malignancy. PMID- 25834360 TI - Multiple nuchal-type fibromas on the scalp: a case report. AB - Nuchal-type fibroma is a rare, benign, fibrous, tumor-like proliferation characterized by dense hypocellular bundles of collagen, with sparsely scattered fibroblasts, interspersed fat tissue, and entrapped nerve fibers. It usually develops in the posterior neck as a solitary, firm, poorly circumscribed, subcutaneous mass. Herein, we report about a 32-year-old man who presented with a 6-year history of multiple nodules on the scalp. Histopathological features were consistent with those of nuchal-type fibroma. The tumors were surgically excised. PMID- 25834361 TI - Poikiloderma vasculare atrophicans showing features of ashy dermatosis in the beginning. AB - Poikiloderma vasculare atrophicans (PVA) is a rare poikilodermatous variant of early-stage mycosis fungoides characterized by generalized poikiloderma, atrophy, mottled dyspigmentation, and telangiectasia. In 2001, a 14-year-old male presented with asymptomatic brownish-gray polymorphic macules throughout the body with flexural accentuation. A skin biopsy showed increased melanophages with focal hydropic changes. Ashy dermatosis was considered a possible diagnosis. In 2005, the lesions began to show darkening and lichenification in the lower part of the trunk. In 2011, his skin showed definite poikilodermatous changes, and a biopsy showed band-like inflammatory infiltrations of atypical lymphocytes, epidermal atrophy, and epidermotropism of predominantly CD4(-)CD8(+) atypical T cells. In addition, results of T-cell receptor gene rearrangement analysis were positive. Based on the aforementioned findings, he was diagnosed with PVA. If a patient shows long-standing and progressive hyperpigmentary skin changes, periodic follow-up and repeated skin biopsies are recommended to determine the underlying condition. PMID- 25834362 TI - Amelanotic Acral Melanoma Associated with KIT Mutation and Vitiligo. AB - Amelanotic acral melanoma is rare and difficult to diagnose, both clinically and pathologically. KIT mutations are frequently found in acral melanomas and are considered a risk factor for poor prognosis. The presence of vitiligo in melanoma has been reported, and KIT is thought to be partly responsible for the dysfunction and loss of melanocytes observed in vitiligo. We report a case of amelanotic subungual melanoma with multiple metastases that was associated with KIT mutation and vitiligo. An 85-year-old man presented with a 3-year history of a tender erythematous ulcerated tumor on the left third fingertip and developed hypopigmented patches on the face and trunk. Histopathological examination of the ulcerative tumor showed aggregates of tumor cells that were pleomorphic epithelioid cells. Immunohistochemical staining of the tumor cells was positive for S100, HMB45, and c-Kit. Histopathological findings from the hypopigmented patch on the face were consistent with vitiligo. Mutation analysis showed a KIT mutation in exon 17 (Y823D). The patient had metastasis to the brain, liver, bone, and both lungs. The patient refused chemotherapy, and died 3 months after the first visit. PMID- 25834363 TI - A case of spitzoid melanoma. AB - Spitzoid melanoma is a subtype of melanoma that, clinically and histologically, resembles a Spitz nevus. Clinically, spitzoid melanomas usually evolve from amelanotic nodular lesions, growing to 1 cm or more in diameter. They often remain clinically undiagnosed because of their wide variety of clinical appearances and a lack of pigmentation. Distinguishing a Spitz nevus from a spitzoid melanoma can be extremely difficult. Features that favor the diagnosis of a spitzoid melanoma are asymmetrical shape, diameter greater than 1 cm, a lesion with a deep invasive component, and a high degree of cytologic atypia. There have been only rare reports in the literature of the presence of giant cells in malignant melanoma, and the presence of these cells may result in its misdiagnosis as a histiocytic tumor. We present a case of spitzoid melanoma on the right ankle of a 22-year-old-woman. PMID- 25834364 TI - Frequency of antinuclear antibody positivity in patients with pattern hair loss. PMID- 25834365 TI - Basal cell carcinoma presenting as a perianal ulcer and treated with radiotherapy. PMID- 25834366 TI - Actinic granuloma arising from the pulsed dye laser-treated skin in a patient with capillary malformation. PMID- 25834367 TI - Twisted and rolled body hairs: a new report in asians. PMID- 25834368 TI - Segmentally arranged hyperpigmented basaloid follicular hamartoma. PMID- 25834369 TI - A case of cutaneous metastatic cholangiocarcinoma on the percutaneous transhepatic biliary drainage catheter insertion site. PMID- 25834370 TI - Successful treatment of hailey-hailey disease with aminolevulinic Acid photodynamic therapy. PMID- 25834371 TI - Foreign body reaction to injectable hyaluronic Acid: late granuloma formation. PMID- 25834372 TI - Preoperative evaluation of a subungual glomus tumor case using multidetector computed tomography angiography. PMID- 25834373 TI - Oral and cutaneous lichenoid eruption with nail changes due to imatinib treatment in a chinese patient with chronic myeloid leukemia. PMID- 25834374 TI - Influence of Pulse Type on Subcellular Selective Photothermolysis of Melanosomes in Adult Zebrafish Skin Following 1,064-nm, Q-switched, Nd:YAG Laser Irradiation: A Pilot Study. PMID- 25834375 TI - A case of solitary porokeratosis mimicking circumscribed palmar hypokeratosis. PMID- 25834376 TI - Degos Disease Associated with Behcet's Disease. PMID- 25834377 TI - A case of keratoacanthoma associated with Basal cell carcinoma. PMID- 25834378 TI - Preliminary study of intralesional bleomycin injection for the treatment of genital warts. PMID- 25834379 TI - Textures and traction: how tube-dwelling polychaetes get a leg up. AB - By controlling the traction between its body and the tube wall, a tube-dwelling polychaete can move efficiently from one end of its tube to the other, brace its body during normal functions (e.g., ventilation and feeding), and anchor within its tube avoiding removal by predators. To examine the potential physical interaction between worms and the tubes they live in, scanning electron microscopy was used to reveal and quantify the morphology of worm bodies and the tubes they produce for species representing 13 families of tube-dwelling polychaetes. In the tubes of most species there were macroscopic or nearly macroscopic (~10 MUm-1 mm) bumps or ridges that protruded slightly into the lumen of the tube; these could provide purchase as a worm moves or anchors. At this scale (~10 MUm-1 mm), the surfaces of the chaetal heads that interact with the tube wall were typically small enough to fit within spaces between these bumps (created by the inward projection of exogenous materials incorporated into the tube wall) or ridges (made by secretions on the interior surface of the tube). At a finer scale (0.01-10 MUm), there was a second overlap in size, usually between the dentition on the surfaces of chaetae that interact with the tube walls and the texture provided by the secreted strands or microscopic inclusions of the inner linings. These linings had a surprising diversity of micro-textures. The most common micro-texture was a "fabric" of secreted threads, but there were also orderly micro-ridges, wrinkles, and rugose surfaces provided by microorganisms incorporated into the inner tube lining. Understanding the fine structures of tubes in conjunction with the morphologies of the worms that build them gives insight into how tubes are constructed and how worms live within them. PMID- 25834381 TI - Erratum: The efficacy and safety of add-on 0.1% brimonidine tartrate preserved with sodium chlorite in on-treatment Japanese normal-tension glaucoma patients [Corrigendum]. AB - [This corrects the article on p. 1681 in vol. 8, PMID: 25214761.]. PMID- 25834380 TI - The Technology of the Gibbet. AB - The practice of "hanging in chains" or gibbeting had been part of the punitive repertoire of the English and Welsh judicial system for centuries before the 1751 52 Murder Act specified it as one of two mandatory post-mortem punishments for murderers. The practice was not abolished until 1834. This article considers the technical and design features of the gibbet cage, through an exhaustive survey and catalogue of their surviving remains. It notes that, given the comparative rarity of hanging in chains, no chronological or regional traditions of design are evident in this kind of artifact, since blacksmiths were individually solving the problem of fulfilling the necessary functions of a gibbet cage without knowledge of previous examples and under great time pressure. The technology of the gibbet shows how state directives intersected with geographical discretion in the creation of idiosyncratic local solutions. PMID- 25834382 TI - Bevacizumab for the treatment of a complicated posterior melanocytoma. AB - PURPOSE: To present a case of a complicated posterior melanocytoma that was successfully treated with intravitreal bevacizumab. CASE REPORT: A 50-year-old Caucasian man was referred with sudden-onset metamorphopsia and decreased vision in his right eye over the course of the last 2 months. His best-corrected visual acuity was 20/80 and poorer than Jaeger 14 in the right eye, and 20/20 and Jaeger 1 in his left eye. In the right fundus, there was a melanocytic lesion occupying the inferotemporal quadrant of the optic disk, extending to the adjacent choroid inferiorly; optic nerve edema, superotemporal retinal vein dilatation, and subretinal fluid under the macula and nasal half of the posterior pole were observed, and a subretinal choroidal neovascularization complex was observed adjacent to the superotemporal margin of the optic disk, confirmed by fluorescein angiography, surrounded by a dense subretinal hemorrhage. Optical coherence tomography showed retinal edema and detachment of neurosensory retina. The patient was treated with three consecutive doses on a monthly basis of intravitreal 1.25 mg/0.05 mL bevacizumab. Visual acuity recovered rapidly, and at 4 months after treatment, it was 20/20 and Jaeger 1, with complete resolution of macular edema and subretinal fluid and hemorrhage. After 3 years of follow-up, best-corrected visual acuity remained stable, macular area was normal, and there was no evident optic nerve edema, retinal vein caliber and aspect were normal, and there was no significant change of the tumor. Fluorescein angiography only evidenced late staining of choroidal neovascularization scar, and optical coherence tomography showed a normal macular anatomy. CONCLUSION: Intravitreal bevacizumab was effective in the treatment of choroidal neovascularization, optic nerve edema, venous dilatation, and local capillary telangiectasia, complicating an optic disk melanocytoma. PMID- 25834383 TI - Difference in ocular surface temperature by infrared thermography in phakic and pseudophakic patients. AB - PURPOSE: To assess the change in ocular surface temperature between healthy phakic and pseudophakic patients. METHODS: We included patients with no history of ocular disease other than cataract. Patients were divided into three groups: clear lens, cataract, and pseudophakic. All patients had two ocular surface digital thermal scans. An average of five surface points was used as the mean ocular surface temperature. Results were analyzed with a one-way analysis of variance and a Tukey's least significance difference test. The patients were further divided into phakic and pseudophakic groups. Correlation coefficients between several variables were done in order to assess dependencies. RESULTS: Fifty-six eyes (28 cataracts, 12 clear lenses, 16 pseudophakic) were enrolled. The mean ocular surface temperature in the cataract group was 34.14 degrees C+/ 1.51 degrees C; clear lens: 34.43 degrees C+/-2.27 degrees C; and pseudophakic: 34.97 degrees C+/-1.57 degrees C. There were no statistical differences among the study groups (P=0.3). There was a nonsignificant negative correlation trend between age and surface temperature in the phakic group. The trend inverted in the pseudophakic group but without statistical significance. CONCLUSION: Although cataract extraction and intraocular lens implantation seem to induce a mild increase in ocular surface temperature, the effect is not clear and not significant. PMID- 25834384 TI - Toxic anterior segment syndrome after uncomplicated cataract surgery possibly associated with intracamaral use of cefuroxime. AB - PURPOSE: To report toxic anterior segment syndrome (TASS) after cataract surgery possibly associated with intracameral use of cefuroxime. METHODS: We conducted a retrospective chart review and analysis on the pre- and postoperative conditions of the subjects who had developed TASS. RESULTS: The patient group consisted of 17 patients. Tyndallization and fibrin fibers were positive in all eyes. In four eyes, hypopyon formation developed. These reactions diminished on the third day and fully resolved 1 week after the operations with the use of intensive topical steroid and mydriatic therapy. To determine the etiology of TASS, infusion fluid, viscoelastics, and intracameral antibiotic agent were changed respectively. After changing intracameral antibiotic agent from cefuroxime axetile to moxifloxacin no new cases of TASS were diagnosed. CONCLUSION: All agents injected into the anterior chamber can cause TASS. Ophthalmologists and operating room staff need to pay careful attention to all drugs and irrigating solutions. PMID- 25834385 TI - Corneal decompensation following filtering surgery with the Ex-PRESS((r)) mini glaucoma shunt device. AB - PURPOSE: To report a case of corneal decompensation due to the Ex-PRESS((r)) mini glaucoma shunt device (Ex-PRESS). PATIENT AND METHODS: A 75-year-old man had pseudoexfoliation glaucoma in his right eye. He underwent filtration surgery with Ex-PRESS. His intraocular pressure was 7 mmHg after 9 months. RESULTS: We observed partial decompensation of the corneal endothelium adjacent to the filtering bleb. Specular microscopy revealed a marked decrease in the endothelial cell density at the center of the cornea. CONCLUSION: Anterior segment optical coherence tomography is very useful for evaluating corneal edema and the position of Ex-PRESS. It is important to follow up with an examination of the corneal endothelial cells. PMID- 25834386 TI - Standard versus trans-epithelial collagen cross-linking in keratoconus patients suitable for standard collagen cross-linking. AB - PURPOSE: Evaluating the clinical results of trans-epithelial collagen cross linking (CXL) and standard CXL in patients with progressive keratoconus. METHODS: This prospective study comprised 20 eyes of 20 patients with progressive keratoconus. Ten eyes were treated by standard CXL and ten by trans-epithelial cross-linking (TE-CXL, epithelium on) with 1 year of follow-up. All patients underwent complete ophthalmologic testing that included pre- and postoperative uncorrected visual acuity, corrected visual acuity, spherical error, spherical equivalent, corneal astigmatism, simulated maximum, minimum, and average keratometry, coma and spherical aberration, optical pachymetry, and endothelial cell density. Intra-and postoperative complications were recorded. The solution used for standard CXL comprised riboflavin 0.1% and dextran 20.0% (Ricrolin), while the solution for TE-CXL (Ricrolin, TE) comprised riboflavin 0.1%, dextran 15.0%, trometamol (Tris), and ethylenediaminetetraacetic acid. Ultraviolet-A treatment was performed with UV-X System at 3 mW/cm(2). RESULTS: In both the standard CXL group (ten patients, ten eyes; mean age, 30.4+/-7.3 years) and the TE-CXL group (ten patients, ten eyes; mean age, 28+/-3.8 years), uncorrected visual acuity and corrected visual acuity improved significantly after treatment. Furthermore, a significant improvement in topographic outcomes, spherical error, and spherical equivalent was observed in both groups at month 12 posttreatment. No significant variations were recorded in other parameters. No complications were noted. CONCLUSION: A 1-year follow-up showed stability of clinical and refractive outcomes after standard CXL and TE-CXL. PMID- 25834387 TI - Optical coherence tomography classification of indirect choroidal ruptures: conclusive or misleading? PMID- 25834388 TI - Lead time for appointment and the no-show rate in an ophthalmology clinic. AB - PURPOSE: The purpose of this study was to determine if there is a correlation between the time in advance an appointment is scheduled and the no-show rate. METHODS: This was a cross-sectional study conducted in an outpatient ophthalmology clinic. Appointment data were analyzed for 51,529 ophthalmology appointments in the computerized scheduling database during a 12-month period. RESULTS: The average no-show rate was 21.7% and 6.6% for resident- and faculty clinic, respectively (P<0.001). The no-show rate increased, and the likelihood an appointment would be kept decreased as the time in advance an appointment was scheduled increased. With a lead time for appointment of 0-2 weeks, the average no-show rate was 9.1% and 2.4% for the resident- and faculty-clinic, respectively. With a lead time for appointment of 6 months, the average no-show rate increased to 38.3% (P<0.001) and 6.9% (P<0.001) for the resident-and faculty clinic, respectively. A predicted no-show rate model showed approximately 2% reduction of the no-show rate for 10% increase of the proportion of patients scheduled within 2 weeks, potentially reducing the no-show rate by nearly 60% with all appointments scheduled 0-2 weeks in advance. CONCLUSION: Clinic no-show rate increased as appointment lead time increased. Predictive models suggest that the implementation of a short-term appointment scheduling strategy may reduce the overall clinic no-show rate, particularly in clinic populations with a high no show rate. PMID- 25834389 TI - Spontaneous resolution of subfoveal perfluorocarbon. AB - Perfluorocarbon liquids (PFCL) have transformed the surgical approach to complex retinal detachments, but their use can be complicated by subretinal retention. Migration of peripherally located subretinal PFCL towards the fovea is well established, but spontaneous resolution of subfoveal PFCL without surgical evacuation or displacement has rarely been described. We present a case of a large single retained subfoveal PFCL droplet following vitrectomy with membrane peeling, inferior relaxing retinectomy, and silicone oil tamponade that demonstrated spontaneous resolution 3 weeks postoperatively, with subsequent anatomic and visual improvement. No residual subretinal PFCL was noted, and we hypothesize that the PFCL droplet spontaneously extruded through a transient hole created in the thinned retina overlying the droplet, which subsequently closed spontaneously. Further understanding of the mechanisms of PFCL migration and resolution may facilitate improved treatments for this complication. PMID- 25834390 TI - Near-infrared reflectance bull's eye maculopathy as an early indication of hydroxychloroquine toxicity. AB - IMPORTANCE: In some patients, hydroxychloroquine ocular toxicity may progress even following cessation of therapy. Any leverage the clinician may use to allow earlier detection may avert significant vision loss. OBSERVATION: We report three cases suggesting that bull's eye maculopathy seen on near-infrared reflectance with a confocal scanning laser ophthalmoscope could be an early, objective manifestation of hydroxychloroquine ocular toxicity, and with progression of the disease this near-infrared "bull's eye" change may disappear. CONCLUSION AND RELEVANCE: Alerting clinicians to this observation may allow a larger case series to corroborate the hypothesis that bull's eye maculopathy detected by near infrared reflectance may represent an early sign of hydroxychloroquine toxicity. PMID- 25834392 TI - The effect of ethanol sclerotherapy of 5 minutes duration on cyst diameter and rat ovarian tissue in simple ovarian cysts. AB - OBJECTIVES: To examine the effect of 95% ethanol sclerotherapy (EST) administered over 5 minutes on cyst diameter and ovarian tissue in experimentally induced simple ovarian cysts in a rat model. MATERIALS AND METHODS: In order to induce ovarian cysts, unilateral total salpingectomy was performed in regularly menstruating adult female Wistar albino rats (n=20) between 12 and 14 weeks of age and weighing between 200 and 220 g. One month after the procedure, the abdominal cavity was opened and 14 rats (70%) were found to have developed macroscopic cysts. Rats with macroscopic cysts (n=14) were assigned into two groups in a prospective and single-blinded manner: group 1 (G1) (n=7), control rats; and group 2 (G2) (n=7), 5-minute EST 95% group. Cyst diameter was measured and recorded for each rat. In G2, after whole cyst fluid was aspirated the cystic cavity was irrigated with 95% ethanol, approximately equal to half of the aspirated cyst volume, after which an interval of 5 minutes was allowed and same amount was re-aspirated and the abdominal cavity was closed. One month after this procedure, abdominal cavities were reopened and intra-abdominal adhesion scoring was performed in both groups. Cyst diameter was measured for each rat, and the right ovary was removed, fixed in 10% formaldehyde, and transported to the laboratory. A histologic assessment of the ovarian tissues was performed under light microscopy following staining with hematoxylin and eosin. Mann-Whitney U test was used for statistical analysis. A P-level less than 0.05 was considered significant. RESULTS: In comparison with G1, there was a statistically significant reduction in the mean ovarian cyst dimensions in G2, while there were no significant differences between the two groups with respect to total number of follicles. Again, a significant increase in apoptotic activity and germinal epithelial degeneration was observed in G2 as compared to G1. The two groups were similar in terms of adhesion formation. CONCLUSION: Although 95% EST results in a reduction in the size of simple ovarian cysts, this effect seems to be achieved at the expense of ovarian tissue injury. PMID- 25834391 TI - Profile of atacicept and its potential in the treatment of systemic lupus erythematosus. AB - The importance of B cell activating factors in the generation of autoantibodies in patients with systemic lupus erythematosus (SLE) is now recognized. The two key factors, known as BAFF and APRIL, produced by a variety of cells including monocytes, dendritic cells and T cells, also help to regulate B cell maturation, function and survival. Biologic agents that block these factors have now been developed and tried out in large scale clinical trials in SLE patients. Benlysta which blocks BAFF has met some of its end points in clinical trials and is approved for use in patients with skin and joint disease who have failed conventional drugs. In contrast, clinical trials using atacicept which blocks both BAFF and APRIL have been more challenging to interpret. An early study in lupus nephritis was, mistakenly, abandoned due to serious infections thought to be linked to the biologic when in fact the dramatic fall in the immunoglobulin levels took place when the patients were given mycophenolate, prior to the introduction of the atacicept. Likewise the higher dose arm (150 mgm) of a flare prevention study was terminated prematurely when 2 deaths occurred. However, the mortality rate in this study was identical to that seen in the Benlysta studies and a post hoc analysis found a highly significant benefit for the 150mgm arm compared to the lower dose (75 mgm) and placebo arms. Other trials with both Benlysta and atacicept are on-going. PMID- 25834393 TI - Clinicopathological significance of CXCR4 in non-small cell lung cancer. AB - BACKGROUND: Emerging evidence indicates that C-X-C chemokine receptor type 4 (CXCR4) is a candidate oncogene in several types of human tumors including non small cell lung cancer (NSCLC). However, the correlation between CXCR4 expression and clinicopathological characteristics of NSCLC remains unclear. Here, we conducted a meta-analysis to quantitatively evaluate the association of CXCR4 expression with the incidence of NSCLC and clinicopatho-logical characteristics. METHODS: A detailed literature search was made from Medline and Web of Science for related research publications written in English and Chinese. The methodological quality of the studies was also evaluated. Analyses of pooled data were performed. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized. RESULTS: The final analysis of 1,446 NSCLC patients from 13 eligible studies was performed. We observed that CXCR4 expression was significantly higher in NSCLC than in normal lung tissue from the pooled OR from five studies including 380 NSCLC and 118 normal lung tissue (OR=12.86, 95% confidence interval =3.63-45.59, P<0.0001). CXCR4 expression was not associated with smoking status and type of pathology. However, CXCR4 expression was significantly associated with clinical stages, metastatic status, and overall survival in NSCLC patients. CONCLUSION: The results of this meta-analysis suggest that CXCR4 expression is associated with an increased risk and worse survival in NSCLC patients. The aberrant CXCR4 expression plays an important role in the carcinogenesis and metastasis of NSCLC. PMID- 25834394 TI - Development and in vitro characterization of drug delivery system of rifapentine for osteoarticular tuberculosis. AB - The study was to develop and evaluate the rifapentine-loaded poly(lactic acid-co glycolic acid) (PLGA) microspheres (RPMs) for the treatment of osteoarticular tuberculosis to avoid critical side effects caused by oral regimens of antibiotics or intravenous antibiotics. The RPMs were spherical with rough surfaces, and elevated amounts of rifapentine in the formulation markedly increased the particle size and drug loading, while decreased the size distribution and entrapment efficiency. The highest drug loading and encapsulation efficiency of RPMs were 23.93%+/-3.93% and 88.49%+/-8.49%, respectively. After the initial rapid drug release, the release rate gradually decreased, and approximately 80% of the encapsulated rifapentine was released after 30 days of incubation. Moreover, RPMs could effectively inhibit the growth of Staphylococcus aureus. With increasing rifapentine content, the inhibition zones were continuously enlarged while the minimal inhibitory concentration values decreased. These results suggested that RPMs were bioactive and controlled release delivery systems for the treatment of osteoarticular tuberculosis. PMID- 25834395 TI - Evaluation of cationic polyamidoamine dendrimers' dermal toxicity in the rat skin model. AB - Polyamidoamine (PAMAM) dendrimers are multi-branched, three-dimensional polymers with unique architecture, which makes these molecules attractive for medical and pharmaceutical applications. Using PAMAM as drug carriers for topical delivery might be beneficial as they only produce a transient effect without skin irritation. To evaluate the dermal toxicity of cationic PAMAM dendrimers generation 2 and generation 3, skin irritation studies were performed in vivo in the rat skin model. After 10 days topical application of various concentrations of PAMAM-NH2 (0.3 mg/mL, 3 mg/mL, 6 mg/mL, 30 mg/mL, 300 mg/mL), skin irritation was evaluated by visual, histopathological, and immunohistochemical examination. Microscopic assessment after hematoxylin-eosin staining revealed significant morphological changes of epidermal cells after application of PAMAM-NH2 at a concentration of >=6 mg/mL. Morphological alterations of epidermal cells included cytoplasmic vacuolization of keratinocytes in the basal and spinous layers. Cytomorphological changes in keratinocytes, overall picture of the epidermis, and histopathological changes in the dermis were dose dependent. Detected alterations concerned hyperplasia of connective tissue fibers and leukocyte infiltration. Visible granulocyte infiltration in the upper dermis and sockets formed by necrotic, cornified cells in the hyperplastic foci of epithelium were also noted. Immunohistochemical analyses revealed that increased nuclear immunoreactivity to PCNA correlated with the concentration of PAMAM-NH2, but no significant differences in the cell proliferation activity in skin treated with PAMAM-NH2 generation 2 or generation 3 were observed. Significantly higher expression of PCNA extended throughout the skin layers might suggest abnormal cell proliferation, which, as a consequence, might even lead to neoplastic changes. PMID- 25834396 TI - Development and optimization of carvedilol orodispersible tablets: enhancement of pharmacokinetic parameters in rabbits. AB - BACKGROUND: Carvedilol (CVD) is used for the treatment of essential hypertension, heart failure, and systolic dysfunction after myocardial infarction. Due to its lower aqueous solubility and extensive first-pass metabolism, the absolute bioavailability of CVD does not exceed 30%. To overcome these drawbacks, the objective of this work was to improve the solubility and onset of action of CVD through complexation with hydroxypropyl-beta-cyclodextrin and formulation of the prepared complex as orodispersible tablets (ODTs). METHODS: Compatibility among CVD and all tablet excipients using differential scanning calorimetry and Fourier transform infrared spectroscopy, complexation of CVD with different polymers, and determination of the solubility of CVD in the prepared complexes were first determined. A Box-Behnken design (BBD) was used to study the effect of tablet formulation variables on the characteristics of the prepared tablets and to optimize preparation conditions. According to BBD design, 15 formulations of CVD ODTs were prepared by direct compression and then evaluated for their quality attributes. The relative pharmacokinetic parameters of the optimized CVD-ODTs were compared with those of the marketed CVD tablet. A single dose, equivalent to 2.5 mg/kg CVD, was administered orally to New Zealand white rabbits using a double-blind, randomized, crossover design. RESULTS: The solubility of CVD was improved from 7.32 to 22.92 mg/mL after complexation with hydroxypropyl-beta cyclodextrin at a molar ratio of 1:2 (CVD to cyclodextrin). The formulated CVD ODTs showed satisfactory results concerning tablet hardness (5.35 kg/cm(2)), disintegration time (18 seconds), and maximum amount of CVD released (99.72%). The pharmacokinetic data for the optimized CVD-ODT showed a significant (P<0.05) increase in maximum plasma concentration from 363.667 to 496.4 ng/mL, and a shortening of the time taken to reach maximum plasma concentration to 2 hours in comparison with the marketed tablet. CONCLUSION: The optimized CVD-ODTs showed improved oral absorption of CVD and a subsequent acceleration of clinical effect, which is favored for hypertensive and cardiac patients. PMID- 25834397 TI - Steroids as an adjunct for reducing the incidence of proliferative vitreoretinopathy after rhegmatogenous retinal detachment surgery: a systematic review and meta-analysis. AB - BACKGROUND: This meta-analysis was performed to determine the effectiveness of steroids as an adjunct following rhegmatogenous retinal detachment (RRD) surgery. METHODS: RRD patients with or without proliferative vitreoretinopathy (PVR) were included. The treatment group included patients in whom steroids were used as an adjunct and a control group in which placebo was used. Only randomized controlled trials were included. We searched the main electronic databases and included studies published until July 2014. PVR odds ratio, visual acuity, retinal reattachment rate, and complications were evaluated in three trials. RESULTS: Three randomized controlled trials were included in the meta-analysis. There was no significant difference in the incidence of postoperative PVR between groups (heterogeneity I (2)=48%, P=0.14). However, the incidence of postoperative PVR was lower in the treatment group (I (2)=0%, P<0.0001) than in the control group when a PVR grade C study was excluded. There was no statistically significant difference in postoperative visual acuity between the treatment and control groups (odds ratio -0.18; 95% confidence interval -0.38, 0.02; P=0.08). The two groups had similar results for primary/final retinal reattachment and reoperation rate. There was no significant difference in postoperative intraocular pressure. CONCLUSION: This systematic review demonstrates that steroids may significantly reduce the incidence of postoperative PVR grade B or lower following RRD surgery. PMID- 25834398 TI - In vivo antitumor and antimetastatic effects of flavokawain B in 4T1 breast cancer cell-challenged mice. AB - Flavokawain B (FKB) is a naturally occurring chalcone that can be isolated through the root extracts of the kava-kava plant (Piper methysticum). It can also be synthesized chemically to increase the yield. This compound is a promising candidate as a biological agent, as it is reported to be involved in a wide range of biological activities. Furthermore, FKB was reported to have antitumorigenic effects in several cancer cell lines in vitro. However, the in vivo antitumor effects of FKB have not been reported on yet. Breast cancer is one of the major causes of cancer-related deaths in the world today. Any potential treatment should not only impede the growth of the tumor, but also modulate the immune system efficiently and inhibit the formation of secondary tumors. As presented in our study, FKB induced apoptosis in 4T1 tumors in vivo, as evidenced by the terminal deoxynucleotidyl transferase dUTP nick end labeling and hematoxylin and eosin staining of the tumor. FKB also regulated the immune system by increasing both helper and cytolytic T-cell and natural killer cell populations. In addition, FKB also enhanced the levels of interleukin 2 and interferon gamma but suppressed interleukin 1B. Apart from that, FKB was also found to inhibit metastasis, as evaluated by clonogenic assay, bone marrow smearing assay, real time polymerase chain reaction, Western blot, and proteome profiler analysis. All in all, FKB may serve as a promising anticancer agent, especially in treating breast cancer. PMID- 25834399 TI - Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. AB - Plumbagin (PLB) has been shown to have anticancer activities in animal models, but the role of PLB in prostate cancer treatment is unclear. This study aimed to investigate the effects of PLB on apoptosis and autophagy and the underlying mechanisms in human prostate cancer cell lines PC-3 and DU145. Our study has shown that PLB had potent pro-apoptotic and pro-autophagic effects on PC-3 and DU145 cells. PLB induced mitochondria-mediated apoptosis and autophagy in concentration- and time-dependent manners in both PC-3 and DU145 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways and activation of 5'-AMP-dependent kinase (AMPK) as indicated by their altered phosphorylation, contributing to the pro-autophagic activity of PLB. Modulation of autophagy altered basal and PLB-induced apoptosis in both cell lines. Furthermore, PLB downregulated sirtuin 1 (Sirt1), and inhibition of Sirt1 enhanced autophagy, whereas the induction of Sirt1 abolished PLB-induced autophagy in PC-3 and DU145 cells. In addition, PLB downregulated pre B cell colony-enhancing factor/visfatin, and the inhibition of pre-B cell colony enhancing factor/visfatin significantly enhanced basal and PLB-induced apoptosis and autophagy in both cell lines. Moreover, reduction of intracellular reactive oxygen species (ROS) level attenuated the apoptosis- and autophagy-inducing effects of PLB on both PC-3 and DU145 cells. These findings indicate that PLB promotes apoptosis and autophagy in prostate cancer cells via Sirt1- and PI3K/Akt/mTOR-mediated pathways with contribution from AMPK-, p38 MAPK-, visfatin , and ROS-associated pathways. PMID- 25834400 TI - Plumbagin induces G2/M arrest, apoptosis, and autophagy via p38 MAPK- and PI3K/Akt/mTOR-mediated pathways in human tongue squamous cell carcinoma cells. AB - Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone; PLB), a naturally occurring naphthoquinone isolated from the roots of Plumbaginaceae plants, has been reported to possess anticancer activities in both in vitro and in vivo studies, but the effect of PLB on tongue squamous cell carcinoma (TSCC) is not fully understood. This study aimed to investigate the effects of PLB on cell cycle distribution, apoptosis, and autophagy, and the underlying mechanisms in the human TSCC cell line SCC25. The results have revealed that PLB exerted potent inducing effects on cell cycle arrest, apoptosis, and autophagy in SCC25 cells. PLB arrested SCC25 cells at the G2/M phase in a concentration- and time-dependent manner with a decrease in the expression level of cell division cycle protein 2 homolog (Cdc2) and cyclin B1 and increase in the expression level of p21 Waf1/Cip1, p27 Kip1, and p53 in SCC25 cells. PLB markedly induced apoptosis and autophagy in SCC25 cells. PLB decreased the expression of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl) while increasing the expression level of the pro-apoptotic protein Bcl-2-associated X protein (Bax) in SCC25 cells. Furthermore, PLB inhibited phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3beta (GSK3beta), and p38 mitogen-activated protein kinase (p38 MAPK) pathways as indicated by the alteration in the ratio of phosphorylation level over total protein expression level, contributing to the autophagy inducing effect. In addition, we found that wortmannin (a PI3K inhibitor) and SB202190 (a selective inhibitor of p38 MAPK) strikingly enhanced PLB-induced autophagy in SCC25 cells, suggesting the involvement of PI3K- and p38 MAPK-mediated signaling pathways. Moreover, PLB induced intracellular reactive oxygen species (ROS) generation and this effect was attenuated by l-glutathione (GSH) and n-acetyl-l-cysteine (NAC). Taken together, these results indicate that PLB promotes cellular apoptosis and autophagy in TSCC cells involving p38 MAPK- and PI3K/Akt/mTOR-mediated pathways with contribution from the GSK3beta and ROS mediated pathways. PMID- 25834401 TI - The investigational Aurora kinase A inhibitor alisertib (MLN8237) induces cell cycle G2/M arrest, apoptosis, and autophagy via p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells. AB - Alisertib (ALS) is an investigational potent Aurora A kinase inhibitor currently undergoing clinical trials for the treatment of hematological and non hematological malignancies. However, its antitumor activity has not been tested in human breast cancer. This study aimed to investigate the effect of ALS on the growth, apoptosis, and autophagy, and the underlying mechanisms in human breast cancer MCF7 and MDA-MB-231 cells. In the current study, we identified that ALS had potent growth-inhibitory, pro-apoptotic, and pro-autophagic effects in MCF7 and MDA-MB-231 cells. ALS arrested the cells in G2/M phase in MCF7 and MDA-MB-231 cells which was accompanied by the downregulation of cyclin-dependent kinase (CDK)1/cell division cycle (CDC) 2, CDK2, and cyclin B1 and upregulation of p21 Waf1/Cip1, p27 Kip1, and p53, suggesting that ALS induces G2/M arrest through modulation of p53/p21/CDC2/cyclin B1 pathways. ALS induced mitochondria-mediated apoptosis in MCF7 and MDA-MB-231 cells; ALS significantly decreased the expression of B-cell lymphoma 2 (Bcl-2), but increased the expression of B-cell lymphoma 2-associated X protein (Bax) and p53-upregulated modulator of apoptosis (PUMA), and increased the expression of cleaved caspases 3 and 9. ALS significantly increased the expression level of membrane-bound microtubule associated protein 1 light chain 3 (LC3)-II and beclin 1 and induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways in MCF7 and MDA-MB-231 cells as indicated by their altered phosphorylation, contributing to the pro-autophagic activities of ALS. Furthermore, treatment with wortmannin markedly downregulated ALS-induced p38 MAPK activation and LC3 conversion. In addition, knockdown of the p38 MAPK gene by ribonucleic acid interference upregulated Akt activation and resulted in LC3-II accumulation. These findings indicate that ALS promotes cellular apoptosis and autophagy in breast cancer cells via modulation of p38 MAPK/Akt/mTOR pathways. Further studies are warranted to further explore the molecular targets of ALS in the treatment of breast cancer. PMID- 25834402 TI - A phase I/II study of biweekly capecitabine and irinotecan plus bevacizumab as second-line chemotherapy in patients with metastatic colorectal cancer. AB - BACKGROUND: Triweekly capecitabine plus irinotecan (XELIRI) is not completely regarded as a valid substitute for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in metastatic colorectal cancer (mCRC) because of the potential for greater toxicity. We conducted a phase I/II study to assess the efficacy and safety of biweekly XELIRI plus bevacizumab (BV) as second-line chemotherapy for mCRC. METHODS: Patients with mCRC who had received prior chemotherapy including oxaliplatin and BV and had a UGT1A1 genotype of wild-type or heterozygous for UGT1A1*6 or *28 were eligible for this study. Treatment comprised capecitabine 1,000 mg/m(2) twice daily from the evening of day 1 to the morning of day 8, intravenous irinotecan on day 1, and BV 5 mg/kg on day 1 every 2 weeks. The phase I study consisted of two steps (irinotecan 150 and 180 mg/m(2)), and dose limiting toxicity was assessed during the first treatment cycle. The primary endpoint of the phase II study was progression-free survival (PFS). RESULTS: The recommended dose of irinotecan was determined to be 180 mg/m(2) in the phase I study. Between November 2010 and August 2013, 44 patients were enrolled in phase II. The patients' characteristics were as follows (N=44): median age, 60 years (range 32-80); male/female, 21/23; and UGT1A1 wild-type/heterozygous, 29/15. The median PFS was 6.8 months (95% confidence interval, 5.3-8.2 months), and the primary endpoint was met. Median overall survival was 18.3 months. The response rate was 22.7%. There was no significant difference in PFS or overall survival according to UGT1A1 status. Grade 3 or higher adverse events were mainly neutropenia in six patients and diarrhea in five patients. There were no other severe adverse events or treatment-related deaths. CONCLUSION: In mCRC patients with wild-type or heterozygous UGT1A1*6 or *28 genotype, biweekly XELIRI + BV is effective and feasible as second-line chemotherapy. Biweekly XELIRI + BV is considered a valid substitute for FOLFIRI + BV in mCRC. PMID- 25834403 TI - Synthesis and biological evaluation of a novel class of curcumin analogs as anti inflammatory agents for prevention and treatment of sepsis in mouse model. AB - A novel class of asymmetric mono-carbonyl analogs of curcumin (AMACs) were synthesized and screened for anti-inflammatory activity. These analogs are chemically stable as characterized by UV absorption spectra. In vitro, compounds 3f, 3m, 4b, and 4d markedly inhibited lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in a dose-dependent manner, with IC50 values in low micromolar range. In vivo, compound 3f demonstrated potent preventive and therapeutic effects on LPS-induced sepsis in mouse model. Compound 3f downregulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 MAPK and suppressed IkappaBalpha degradation, which suggests that the possible anti-inflammatory mechanism of compound 3f may be through downregulating nuclear factor kappa binding (NF kappaB) and ERK pathways. Also, we solved the crystal structure of compound 3e to confirm the asymmetrical structure. The quantitative structure-activity relationship analysis reveals that the electron-withdrawing substituents on aromatic ring of lead structures could improve activity. These active AMACs represent a new class of anti-inflammatory agents with improved stability, bioavailability, and potency compared to curcumin. Our results suggest that 3f may be further developed as a potential agent for prevention and treatment of sepsis or other inflammation-related diseases. PMID- 25834404 TI - Human colon carcinogenesis is associated with increased interleukin-17-driven inflammatory responses. AB - Inflammation is known to contribute to carcinogenesis in human colorectal cancer. Proinflammatory cytokine interleukin-17 (IL-17 or IL-17A) has been shown to play a critical role in colon carcinogenesis in mouse models. However, few studies have investigated IL-17A in human colon tissues. In the present study, we assessed IL-17-driven inflammatory responses in 17 cases of human colon adenocarcinomas, 16 cases of human normal colon tissues adjacent to the resected colon adenocarcinomas, ten cases of human ulcerative colitis tissues from biopsies, and eight cases of human colon polyps diagnosed as benign adenomas. We found that human colon adenocarcinomas contained the highest levels of IL-17A cytokine, which was significantly higher than the IL-17A levels in the adenomas, ulcerative colitis, and normal colon tissues (P<0.01). The levels of IL-17 receptor A (IL-17RA) were also the highest in human colon adenocarcinomas, followed by adenomas and ulcerative colitis. The increased levels of IL-17A and IL-17RA were accompanied with increased IL-17-driven inflammatory responses, including activation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK) pathways, increase in expression of matrix metalloproteinase (MMP)9, MMP7, MMP2, B-cell lymphoma (Bcl-2), and cyclin D1, decrease in Bcl-2-associated X protein (BAX) expression, and increase in vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) expression that were associated with increased angiogenesis. These findings suggest that IL-17 and its signaling pathways appear as promising new targets in the design and development of drugs for cancer prevention and treatment, particularly in colorectal cancer. PMID- 25834406 TI - Solifenacin/tamsulosin fixed-dose combination therapy to treat lower urinary tract symptoms in patients with benign prostatic hyperplasia. AB - Treatment of male lower urinary tract symptoms (LUTS) has traditionally focused on the management of benign prostatic obstruction, but the contribution of bladder dysfunction has been recently recognized. Therefore, it is well understood that LUTS have multifactorial etiology and often occur in clusters and not in isolation. Voiding LUTS are highly prevalent in men, but storage LUTS have been proved to be more bothersome. alpha1-Blockers are the most widely used pharmacologic agents for the treatment of symptoms relating to benign prostatic enlargement due to benign prostatic hyperplasia (BPH), while antimuscarinics are the drug class of choice for overactive bladder symptoms. A combination of the two drug classes would be a reasonable approach to treat men with both storage and voiding symptoms, and several short-term studies have proved the efficacy and safety of different combinations with an alpha1-blocker and an antimuscarinic. Following previous studies on the separate administration of solifenacin and tamsulosin, a fixed-dose combination tablet of tamsulosin oral controlled absorption system (OCAS) 0.4 mg and solifenacin succinate 6 mg has been recently introduced, and the current review evaluates the available data on the use of this fixed-dose combination in the treatment of LUTS in men with BPH. PMID- 25834407 TI - Patient preferences and willingness to pay for innovations in intermittent self catheters. AB - BACKGROUND: Intermittent catheterization is the gold standard for bladder management in Europe in people with spinal cord injuries. The aim of the present study was to identify and investigate individuals' preferences regarding intermittent self-catheterization (ISC) devices and furthermore investigate the willingness to pay for attributes in ISC devices in the UK, France, and the Netherlands. METHODS: A discrete choice experiment survey was conducted to evaluate the patients' perceived value of catheter features. Attributes were selected based upon a literature review of the most important characteristics of catheters and the survey was developed and validated with input from patients and medical experts. Data were analyzed using the conditional logit model whereby the coefficients obtained from the model provided an estimate of the (log) odds ratios of preference for attributes. Willingness to pay was estimated for all levels of the attributes. RESULTS: Two-hundred and eighty-three participants completed the questionnaire and were included in data analysis. Risk of infection had the highest odds ratios as preferred important attribute for all three countries followed by ease of insertion. "Pre-coated catheters" was found to be valued as the most preferred coating technology across all countries. Out of pocket cost was a significant influence on patients' choice. CONCLUSION: Users of ISC perceive the value of convenience (size of catheter), ease of insertion, and reduced risk of infection as the most important features attached to an intermittent catheter. These results are applicable both for the "classic" ISC user as well as for another broad group of catheter dependent individuals. PMID- 25834405 TI - Complete genome-wide screening and subtractive genomic approach revealed new virulence factors, potential drug targets against bio-war pathogen Brucella melitensis 16M. AB - Brucella melitensis 16M is a Gram-negative coccobacillus that infects both animals and humans. It causes a disease known as brucellosis, which is characterized by acute febrile illness in humans and causes abortions in livestock. To prevent and control brucellosis, identification of putative drug targets is crucial. The present study aimed to identify drug targets in B. melitensis 16M by using a subtractive genomic approach. We used available database repositories (Database of Essential Genes, Kyoto Encyclopedia of Genes and Genomes Automatic Annotation Server, and Kyoto Encyclopedia of Genes and Genomes) to identify putative genes that are nonhomologous to humans and essential for pathogen B. melitensis 16M. The results revealed that among 3 Mb genome size of pathogen, 53 putative characterized and 13 uncharacterized hypothetical genes were identified; further, from Basic Local Alignment Search Tool protein analysis, one hypothetical protein showed a close resemblance (50%) to Silicibacter pomeroyi DUF1285 family protein (2RE3). A further homology model of the target was constructed using MODELLER 9.12 and optimized through variable target function method by molecular dynamics optimization with simulating annealing. The stereochemical quality of the restrained model was evaluated by PROCHECK, VERIFY-3D, ERRAT, and WHATIF servers. Furthermore, structure-based virtual screening was carried out against the predicted active site of the respective protein using the glycerol structural analogs from the PubChem database. We identified five best inhibitors with strong affinities, stable interactions, and also with reliable drug-like properties. Hence, these leads might be used as the most effective inhibitors of modeled protein. The outcome of the present work of virtual screening of putative gene targets might facilitate design of potential drugs for better treatment against brucellosis. PMID- 25834408 TI - Impact of recipient-related factors on structural dysfunction of xenoaortic bioprosthetic heart valves. AB - OBJECTIVE: To analyze the influence of recipient-related metabolic factors on the rate of structural dysfunction caused by the calcification of xenoaortic bioprostheses. MATERIALS AND METHODS: We retrospectively analyzed clinical status, calcium-phosphorus metabolism, and nonspecific markers of inflammatory response in bioprosthetic mitral valve recipients with calcific degeneration confirmed by histological and electron microscopic studies (group 1, n=22), and in those without degeneration (group 2, n=48). RESULTS: Patients with confirmed calcification of bioprostheses were more likely to have a severe clinical state (functional class IV in 36% in group 1 versus 15% in group 2, P=0.03) and a longer cardiopulmonary bypass period (112.8+/-18.8 minutes in group 1 versus 97.2+/-23.6 minutes in group 2, P=0.02) during primary surgery. Patients in group 1 demonstrated moderate hypovitaminosis D (median 34.0, interquartile range [21.0; 49.4] vs 40 [27.2; 54.0] pmol/L, P>0.05), osteoprotegerin deficiency (82.5 [44.2; 115.4] vs 113.5 [65.7; 191.3] pg/mL, P>0.05) and osteopontin deficiency (4.5 [3.3; 7.7] vs 5.2 [4.1; 7.2] ng/mL, P>0.05), and significantly reduced bone specific alkaline phosphatase isoenzyme (17.1 [12.2; 21.4] vs 22.3 [15.5; 30.5] U/L, P=0.01) and interleukin-8 levels (9.74 [9.19; 10.09] pg/mL vs 13.17 [9.72; 23.1] pg/mL, P=0.045) compared with group 2, with an overall increase in serum levels of proinflammatory markers. CONCLUSION: Possible predictors of the rate of calcific degeneration of bioprostheses include the degree of decompensated heart failure, the duration and invasiveness of surgery, and the characteristics of calcium-phosphorus homeostasis in the recipient, defined by bone resorption and local and systemic inflammation. The results confirm the hypothesis that cell mediated regulation of pathological calcification is caused by dysregulation of metabolic processes, which are in turn controlled by proinflammatory signals. PMID- 25834409 TI - Needs of family caregivers of stroke patients: a longitudinal study of caregivers' perspectives. AB - BACKGROUND: After a stroke, patients often suffer from varying degrees of disability that require acute inpatient treatment and extended care at home. Therefore, the caregivers assume multiple responsibilities that can result in stress, particularly when their own needs are inadequately addressed during the patient's recovery. OBJECTIVES: This study aimed to explore the changing needs of family caregivers of stroke patients and factors related to the needs in four stages, before the transfer from intensive care unit to neurological unit, before discharge, 2 weeks post-hospitalization, and 3 months post-hospitalization. METHODS: The design of this study was based on longitudinal research, and the participants were family caregivers of stroke patients. Sixty family caregivers were recruited in this study. Data were collected at four time points by questionnaire. RESULTS: We found that the total number of needs of family caregivers decreased as the illness duration increased and that needs differed significantly between the four time points (P<0.01). Although the needs were different in each stage, health information, professional support, and community networks were the leading need domains in all four stages. The major factors affecting the care needs of family caregivers were the National Institutes of Health Stroke Scale scores of patients on admission, length of hospital stay, and physical dependence of patients. CONCLUSION: Family caregivers expected to obtain assistance and related care information from professionals during the course of the disease. Assessing the needs of family caregivers is important for health care workers in understanding problems from the caregivers' perspectives. Relevant information and counseling should be provided to family caregivers to help them access support when needed. PMID- 25834410 TI - Evaluation of reliability and validity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, Albanian version) among breast cancer patients from Kosovo. AB - PATIENTS AND METHODS: A sample of breast cancer patients (n=62 women) were interviewed for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in Albanian. Reliability of the questionnaire was considered acceptable if Cronbach's alpha was >=0.70. Item convergent-discriminant validity was tested through multitrait scaling analysis. Construct validity was tested under the hypotheses that QLQ-C30 interscale correlations would have an acceptable value of >=0.40 and as well as by known group comparisons assessing differences of patient subgroups with reference to disease stage and education level. RESULTS: The mean age of the patients was 50 years (standard deviation: 10.9 years). Cronbach's alpha ranged from 0.54 for the cognitive functioning scale to 0.96 for the global health quality of life (GH/QoL) scale. In multitrait scaling analysis, the strength of Spearman's correlations between an item and its own subscale was >=0.40, with the exception of item 5 (rho=0.22); results for item discriminant validity were satisfactory, with the exception of item 5, which showed higher correlation with other subscales than with its own physical functioning. The Spearman's interscale coefficients generally were correlated with each other. Results of known group comparisons did not show significant differences in terms of disease stage. Regarding education level, patients with high school/university education had better functional scales scores only in certain subscales compared to other subgroups; furthermore, patients with secondary school education had better GH/QoL compared to other subgroups of patients. CONCLUSION: The EORTC QLQ-C30 (v3.0) in Albanian was found to be valid and reliable for women with breast cancer and could be considered as a starting point for further evaluation study. PMID- 25834411 TI - Health care consumers' perspectives on pharmacist integration into private general practitioner clinics in Malaysia: a qualitative study. AB - BACKGROUND: Pharmacists are considered medication experts but are underutilized and exist mainly at the periphery of the Malaysian primary health care team. Private general practitioners (GPs) in Malaysia are granted rights under the Poison Act 1952 to prescribe and dispense medications at their primary care clinics. As most consumers obtain their medications from their GPs, community pharmacists' involvement in ensuring safe use of medicines is limited. The integration of a pharmacist into private GP clinics has the potential to contribute to quality use of medicines. This study aims to explore health care consumers' views on the integration of pharmacists within private GP clinics in Malaysia. METHODS: A purposive sample of health care consumers in Selangor and Kuala Lumpur, Malaysia, were invited to participate in focus groups and semi structured interviews. Sessions were audio recorded and transcribed verbatim and thematically analyzed using NVivo 10. RESULTS: A total of 24 health care consumers participated in two focus groups and six semi-structured interviews. Four major themes were identified: 1) pharmacists' role viewed mainly as supplying medications, 2) readiness to accept pharmacists in private GP clinics, 3) willingness to pay for pharmacy services, and 4) concerns about GPs' resistance to pharmacist integration. Consumers felt that a pharmacist integrated into a private GP clinic could offer potential benefits such as to provide trustworthy information on the use and potential side effects of medications and screening for medication misadventure. The potential increase in costs passed on to consumers and GPs' reluctance were perceived as barriers to integration. CONCLUSION: This study provides insights into consumers' perspectives on the roles of pharmacists within private GP clinics in Malaysia. Consumers generally supported pharmacist integration into private primary health care clinics. However, for pharmacists to expand their capacity in providing integrated and collaborative primary care services to consumers, barriers to pharmacist integration need to be addressed. PMID- 25834412 TI - Electromagnetic field versus circuit weight training on bone mineral density in elderly women. AB - BACKGROUND AND PURPOSE: Osteoporosis is a common skeletal disorder with costly complications and a global health problem and one of the leading causes of morbidity and mortality worldwide. Magnetic field therapy and physical activity have been proven as beneficial interventions for prevention and treatment of osteoporosis. The purpose of this study was to compare the response of bone mineral content and bone mineral density (BMD) in elderly women to either low frequency low-intensity pulsed magnetic field (LFLIPMF) or circuit weight training (CWT) on short-run basis (after 12 weeks). PATIENTS AND METHODS: Thirty elderly women, aged 60-70 years, were randomly assigned into two groups (magnetic field and CWT) (n=15 each group). The session was performed three times per week for magnetic field and CWT groups, for 12 weeks. BMD and bone mineral content of lumbar spine (L2-L4) and femoral neck, trochanter, and Ward's triangle were evaluated before and after 12 weeks of treatment. RESULTS: Both magnetic field and CWT for 12 weeks in elderly women seem to yield beneficial and statistically significant increasing effect on BMD and bone mineral content (P<0.05). But magnetic field seems to have more beneficially and statistically significant effect than does CWT. CONCLUSION: It is possible to conclude that LFLIPMF and CWT programs are effective modalities in increasing BMD but LFLIPMF is more effective in elderly women. PMID- 25834413 TI - Pulsed radiofrequency treatment of articular branches of femoral and obturator nerves for chronic hip pain. AB - PURPOSE: Chronic hip pain is a common symptom experienced by many people. Often, surgery is not an option for patients with multiple comorbidities, and conventional drugs either have many side effects or are ineffective. Pulsed radiofrequency (PRF) is a new method in the treatment of pain. We attempt to compare the efficacy of PRF relative to conservative management for chronic hip pain. PATIENTS AND METHODS: Between August 2011 and July 2013, 29 patients with chronic hip pain were divided into two groups (PRF and conservative treatment) according to consent or refusal to undergo PRF procedure. Fifteen patients received PRF of the articular branches of the femoral and obturator nerves, and 14 patients received conservative treatment. Visual analog scale (VAS), Oxford hip scores (OHS), and pain medications were used for outcome measurement before treatment and at 1 week, 4 weeks, and 12 weeks after treatment. RESULTS: At 1 week, 4 weeks, and 12 weeks after treatment initiation, improvements in VAS were significantly greater with PRF. Improvements in OHS were significantly greater in the PRF group at 1 week, 4 weeks, and 12 weeks. Patients in the PRF group also used less pain medications. Eight subjects in the conservative treatment group switched to the PRF group after 12 weeks, and six of them had >50% improvement. CONCLUSION: When compared with conservative treatment, PRF of the articular branches of the femoral and obturator nerves offers greater pain relief for chronic hip pain and can augment physical functioning. PMID- 25834414 TI - Sleep cognitions associated with anxiety and depression in the elderly. AB - PURPOSE: The objective of this study was to identify the maladaptive sleep related cognitions most often maintained by the elderly, according to the presence or absence of anxiety and mood disorders. The presence of dysfunctional sleep-related beliefs and attitudes at bedtime in asymptomatic, depressive, and anxious seniors was thus compared. The second objective was to verify the relationships between various dysfunctional cognitions and mental disorders. METHOD: The sample in this study consisted of 2,759 participants aged 65 years and over, with a mean age of 73.8 years. They were recruited through a method of random generation of telephone numbers according to a sampling strategy based on geographic location. After the goal of the study was explained to them, the participants agreed to have health professionals visit their home and to answer questions in a 1.5-hour-long structured interview (after signing a consent form). RESULTS: Depressive and anxious seniors adopt dysfunctional sleep-related cognitions in higher proportions than asymptomatic older persons. Once we had controlled for the other factors, we were able to specifically link two sleep related beliefs and all the sleep-related attitudes studied to the probability of being anxious or depressive. CONCLUSION: The clarifications obtained will make it possible to improve detection, assessment, and intervention processes regarding anxiety or mood disorders, by pinpointing the most direct link between each of the dysfunctional cognitions and the two types of mental disorders, and not just the link to sleep problems. PMID- 25834415 TI - Evaluation of the psychometric properties of the Nighttime Symptoms of COPD Instrument. AB - BACKGROUND: Nighttime symptoms can negatively impact the quality of life of patients with chronic obstructive pulmonary disease (COPD). The Nighttime Symptoms of COPD Instrument (NiSCI) was designed to measure the occurrence and severity of nighttime symptoms in patients with COPD, the impact of symptoms on nighttime awakenings, and rescue medication use. The objective of this study was to explore item reduction, inform scoring recommendations, and evaluate the psychometric properties of the NiSCI. METHODS: COPD patients participating in a Phase III clinical trial completed the NiSCI daily. Item analyses were conducted using weekly mean and single day scores. Descriptive statistics (including percentage of respondents at floor/ceiling and inter-item correlations), factor analyses, and Rasch model analyses were conducted to examine item performance and scoring. Test-retest reliability was assessed for the final instrument using the intraclass correlation coefficient (ICC). Correlations with assessments conducted during study visits were used to evaluate convergent and known-groups validity. RESULTS: Data from 1,663 COPD patients aged 40-93 years were analyzed. Item analyses supported the generation of four scores. A one-factor structure was confirmed with factor analysis and Rasch analysis for the symptom severity score. Test-retest reliability was confirmed for the six-item symptom severity (ICC, 0.85), number of nighttime awakenings (ICC, 0.82), and rescue medication (ICC, 0.68) scores. Convergent validity was supported by significant correlations between the NiSCI, St George's Respiratory Questionnaire, and Exacerbations of Chronic Obstructive Pulmonary Disease Tool-Respiratory Symptoms scores. CONCLUSION: The results suggest that the NiSCI can be used to determine the severity of nighttime COPD symptoms, the number of nighttime awakenings due to COPD symptoms, and the nighttime use of rescue medication. The NiSCI is a reliable and valid instrument to evaluate these concepts in COPD patients in clinical trials and clinical practice. Scoring recommendations and steps for further research are discussed. PMID- 25834416 TI - Comorbidities of patients in tiotropium clinical trials: comparison with observational studies of patients with chronic obstructive pulmonary disease. AB - BACKGROUND: There is an ongoing debate on whether patients with chronic obstructive pulmonary disease (COPD) seen in real-life clinical settings are represented in randomized controlled trials (RCTs) of COPD. It is thought that the stringent inclusion and exclusion criteria of RCTs may prevent the participation of patients with specific characteristics or risk factors. METHODS: We surveyed a database of patients recruited into 35 placebo-controlled tiotropium RCTs and also conducted a systematic literature review of large-scale observational studies conducted in patients with a documented diagnosis of COPD between 1990 and 2013. Patient demographics and comorbidities with a high prevalence in patients with COPD were compared between the two patient populations at baseline. Using the Medical Dictionary for Regulatory Activities (MedDRA; v 14.0), patient comorbidities in the pooled tiotropium RCTs were classified according to system organ class, pharmacovigilance (PV) endpoints, and Standardised MedDRA Queries to enable comparison with the observational studies. RESULTS: We identified 24,555 patients in the pooled tiotropium RCTs and 61,361 patients among the 13 observational studies that met our search criteria. The Global initiative for chronic Obstructive Lung Disease (GOLD) staging of patients in the RCTs differed from that in observational studies: the proportion of patients with GOLD stages I+II disease ranged from 40.0% to 51.5% in the RCTs but 24.5% to 44.1% in the observational studies; for GOLD stage III or IV disease these ranges were 7.2%-45.8% (RCTs) and 13.7-42.1% (observational studies). The comorbidities with the highest prevalence reported in the RCTs and observational studies were: hypertension (39.4%-40.0% vs 40.1%-60.6%), other ischemic heart disease (12.3%-14.2% vs 12.5%-41.0%), diabetes (10.3%-10.9% vs 4.0%-38.9%), depression (8.5%-9.5% vs 17.0%-20.6%), and cardiac arrhythmia (7.8%-11.4% vs 11.3%-15.8%). CONCLUSION: The clinical profile of COPD patients treated in the tiotropium trial program appears to be largely in the range of clinical characteristics, including cardiovascular comorbidities, reported for "real-life patients." The tiotropium RCTs tended to include patients with more severe disease than the observational studies. PMID- 25834417 TI - Impact of roflumilast on exacerbations of COPD, health care utilization, and costs in a predominantly elderly Medicare Advantage population. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with declining lung function and health-related quality of life, and increased hospitalization and mortality. Clinical trials often poorly represent the elderly and thus have only partial applicability to their clinical care. OBJECTIVE: To compare exacerbations, COPD-related health care utilization (HCU), and costs in a predominantly elderly Medicare COPD population initiated on roflumilast versus those not initiated on roflumilast. METHODS: Deidentified administrative claims data from a large, national payer were utilized. Medicare patients aged 40-89 years with at least one COPD diagnosis from May 1, 2010 to December 31, 2012 were included. Members with at least one roflumilast pharmacy claim (index) were assigned to the roflumilast group and those without were assigned to the non-roflumilast group. Proxy index dates for the non-roflumilast group were randomly assigned for similar distribution of all patients' time at risk. Subjects with at least one pre-index COPD exacerbation had to be continuously enrolled for >=365 days pre-index and post-index. Unadjusted and adjusted difference-in-difference (DID) analyses contrasted pre-index with post index changes in exacerbations, HCU, and costs of roflumilast treatment compared with non-roflumilast treatment. RESULTS: A total of 500 roflumilast and 60,145 non-roflumilast patients were included (mean age 69.7 and 72.3 years, respectively; P<0.0001). Unadjusted DID favored roflumilast for all exacerbations, with greater pre-index to post-index reductions in mean per 30-day COPD-related hospitalizations (-0.0182 versus -0.0013, P=0.009), outpatient visits (-0.2500 versus -0.0606, P<0.0001), and COPD-related inpatient costs ( US$141 versus -US$11, P=0.0346) and outpatient costs (-US$31 versus -US$4, P<0.0001). Multivariate analyses identified significantly improved pre-index to post-index COPD-related total costs (P=0.0005) and total exacerbations (P<0.0001) for the roflumilast group versus non-roflumilast group. CONCLUSION: In a predominantly elderly Medicare COPD population, newly initiated roflumilast patients displayed similar or significantly better unadjusted reductions in all exacerbation-related, COPD-related HCU-related, and COPD-related costs outcomes compared with non-roflumilast patients. These analyses also suggest better adjusted COPD-related costs and total exacerbations for roflumilast-initiated patients. PMID- 25834418 TI - Causes of death in patients with asthma and asthma-chronic obstructive pulmonary disease overlap syndrome. AB - BACKGROUND: The administration of inhaled corticosteroids and worldwide usage of several asthma guidelines have improved asthma mortality. Elderly patients with asthma show high mortality rates, and may have several comorbidities, including overlap with chronic obstructive pulmonary disease (COPD). Among patients showing asthma overlapped with COPD (asthma-COPD overlap syndrome; ACOS), mortality is worse than for asthma alone. Therefore, we investigated comorbidities, malignancies, and causes of death in patients with asthma and ACOS. METHODS: This was a retrospective study. From January 2000 to March 2012, 650 patients were followed up at Tottori University Hospital. Medical records were reviewed to collect data regarding patient characteristics and comorbidities, and causes of death were recorded for patients who died during the study period. RESULTS: Eighty-seven patients died during the study period. The most frequent cause of death was malignancy. The proportion of malignant disease was 21.7% in all patients, 19.4% in patients with asthma alone, and 32.4% in patients with ACOS. One patient died from an asthma attack during this period. CONCLUSION: The most frequent cause of death in patients with asthma and ACOS was malignant disease. It is necessary to control not only asthma but also comorbidities in patients with asthma, especially in those with ACOS. PMID- 25834419 TI - Length of stay of COPD hospital admissions between 2006 and 2010: a retrospective longitudinal study. AB - BACKGROUND: Hospitalizations for COPD are associated with poor patient prognosis. Length of stay (LOS) of COPD admissions in a large urban area and patient and hospital factors associated with it are described. METHODS: Retrospective longitudinal study. All COPD patients registered with London general practitioners and admitted as an emergency with COPD (2006-2010), not having been admitted with COPD in the preceding 12 months were included. Association of patient and hospital characteristics with mean LOS of COPD admissions was assessed. Association between hospital and LOS was determined by negative binomial regression. RESULTS: The total number of admissions was 38,504, from 22,462 patients. The mean LOS for first admissions fell by 0.8 days (95% confidence interval [CI]: 0.7-1.5) from 8.2 to 7.0 days between 2006 and 2010. Seventy-nine percent of first admissions were <=10 days, with a mean LOS of 3.7 days (2009-2010). The mean LOS of successive COPD admissions of the same patients was the same or less throughout the study period. The interval between successive admissions fell from a mean of 357 days between the first and second admission to a mean of 19 days after eight admissions. Age accounted for 2.3% of the variance in LOS. Socioeconomic deprivation did not predict LOS. Fewer discharges happened at the weekend (1,893/day) than on weekdays (5,218/day). The mean LOS varied between hospitals, from 4.9 days (95% CI: 3.8-5.9) to 9.5 days (95% CI: 8.6-10.3) when adjusting for clustering, age, sex, and socioeconomic deprivation. CONCLUSION: The fall in LOS of the first COPD admission between 2006 and 2010 reflects international trends. The stability of LOS in successive admissions suggests that increasing severity of disease does not affect recovery time from an exacerbation. Variations between hospitals of nearly 5 days in LOS for COPD admissions suggests that significant improvements in patient outcomes and in savings in health care utilization could be made in hospitals with longer LOS. PMID- 25834420 TI - Early impact of treatment with tiotropium, long-acting anticholinergic preparation, in patients with COPD - real-life experience from an observational study. AB - BACKGROUND: Long-acting inhaled bronchodilators, including anticholinergic tiotropium, are recommended for the maintenance therapy of chronic obstructive pulmonary disease (COPD). It has been shown in a number of studies that treatment with tiotropium alleviates symptoms, improves exercise tolerance, health status, and reduces exacerbations in patients with moderate to very severe stage COPD. AIM: The aim of this noninterventional study was to observe the early effects of the maintenance treatment with tiotropium in patients with COPD of different severities, who had been previously treated on a regular basis, or as required, with at least one short-acting bronchodilator, in a real-life setting in Poland. The effect of the treatment was assessed through the collection of COPD Assessment Test (CAT) data. PATIENTS AND METHODS: The MATHS clinical study was an observational, noninterventional, open-label, prospective, uncontrolled, single arm, postmarketing, surveillance, real-life study conducted with the involvement of 236 pulmonology clinics based in Poland. The tiotropium observational period was 3 months. The health and COPD status was measured with the CAT questionnaire. The primary efficacy endpoint was the mean change from the baseline in the total CAT score at the end of the 3-month observational period. RESULTS: Patients treated with 18 MUg of tiotropium once daily for 3 months showed a statistically significant result, with a clinically meaningful mean reduction (improvement) of 7.0 points in the total CAT score. The improvement was slightly greater in patients with more severe COPD; the mean change in the total CAT score was 7.6 in the subgroup of patients with more severe COPD and 6.7 points in the subgroup of patients with moderate COPD. CONCLUSION: Results of this real-life study provide further support for the use of tiotropium as a first-line maintenance treatment for patients with COPD of different severities in Poland. PMID- 25834421 TI - Comparison of laboratory- and field-based exercise tests for COPD: a systematic review. AB - Exercise tests are often used to evaluate the functional status of patients with COPD. However, to the best of our knowledge, a comprehensive systematic comparison of these tests has not been performed. We systematically reviewed studies reporting the repeatability and/or reproducibility of these tests, and studies comparing their sensitivity to therapeutic intervention. A systematic review identified primary manuscripts in English reporting relevant data on the following exercise tests: 6-minute walk test (6MWT) and 12-minute walk test, incremental and endurance shuttle walk tests (ISWT and ESWT, respectively), incremental and endurance cycle ergometer tests, and incremental and endurance treadmill tests. We identified 71 relevant studies. Good repeatability (for the 6MWT and ESWT) and reproducibility (for the 6MWT, 12-minute walk test, ISWT, ESWT, and incremental cycle ergometer test) were reported by most studies assessing these tests, providing patients were familiarized with them beforehand. The 6MWT, ISWT, and particularly the ESWT were reported to be sensitive to therapeutic intervention. Protocol variations (eg, track layout or supplemental oxygen use) affected performance significantly in several studies. This review shows that while the validity of several tests has been established, for others further study is required. Future work will assess the link between these tests, physiological mechanisms, and patient-reported measures. PMID- 25834422 TI - Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents. AB - Magnetic resonance imaging (MRI) has become one of the most widely used and powerful tools for noninvasive clinical diagnosis owing to its high degree of soft tissue contrast, spatial resolution, and depth of penetration. MRI signal intensity is related to the relaxation times (T 1, spin-lattice relaxation and T 2, spin-spin relaxation) of in vivo water protons. To increase contrast, various inorganic nanoparticles and complexes (the so-called contrast agents) are administered prior to the scanning. Shortening T 1 and T 2 increases the corresponding relaxation rates, 1/T 1 and 1/T 2, producing hyperintense and hypointense signals respectively in shorter times. Moreover, the signal-to-noise ratio can be improved with the acquisition of a large number of measurements. The contrast agents used are generally based on either iron oxide nanoparticles or ferrites, providing negative contrast in T 2-weighted images; or complexes of lanthanide metals (mostly containing gadolinium ions), providing positive contrast in T 1-weighted images. Recently, lanthanide complexes have been immobilized in nanostructured materials in order to develop a new class of contrast agents with functions including blood-pool and organ (or tumor) targeting. Meanwhile, to overcome the limitations of individual imaging modalities, multimodal imaging techniques have been developed. An important challenge is to design all-in-one contrast agents that can be detected by multimodal techniques. Magnetoliposomes are efficient multimodal contrast agents. They can simultaneously bear both kinds of contrast and can, furthermore, incorporate targeting ligands and chains of polyethylene glycol to enhance the accumulation of nanoparticles at the site of interest and the bioavailability, respectively. Here, we review the most important characteristics of the nanoparticles or complexes used as MRI contrast agents. PMID- 25834423 TI - SERS-based quantitative detection of ovarian cancer prognostic factor haptoglobin. AB - Surface-enhanced Raman spectroscopy (SERS) is increasingly being used for biosensing because of its high sensitivity and low detection limit, which are made possible by the unique Raman 'fingerprint' spectra from the biomolecules. Here we propose a novel SERS method for the fast, sensitive, and reliable quantitative analysis of haptoglobin (Hp), an acute phase plasma glycoprotein that is widely gaining application as a prognostic ovarian cancer biomarker. We exploited the peroxidase activity of the hemoglobin-haptoglobin (Hb-Hp) complex formed by the selective and specific binding of Hp to free Hb to catalyze the reaction of 3,3',5,5'-tetramethylbenzidine (TMB) substrate and hydrogen peroxide to result in the final product of strongly SERS-active TMB(2+). We observed a linear increase in the SERS signal of TMB(2+) with increasing concentrations of Hb-Hp complex from 50 nM to 34 MUM. Based on this concentration-dependent SERS spectrum, we quantified Hp in clinical samples. We observed that our inference about the prognosis of the disease coincided with the histology data and that our method was much more sensitive than the enzyme-linked immunosorbent assay method. PMID- 25834424 TI - Peptide-enhanced mRNA transfection in cultured mouse cardiac fibroblasts and direct reprogramming towards cardiomyocyte-like cells. AB - The treatment of myocardial infarction is a major challenge in medicine due to the inability of heart tissue to regenerate. Direct reprogramming of endogenous cardiac fibroblasts into functional cardiomyocytes via the delivery of transcription factor mRNAs has the potential to regenerate cardiac tissue and to treat heart failure. Even though mRNA delivery to cardiac fibroblasts has the therapeutic potential, mRNA transfection in cardiac fibroblasts has been challenging. Herein, we develop an efficient mRNA transfection in cultured mouse cardiac fibroblasts via a polyarginine-fused heart-targeting peptide and lipofectamine complex, termed C-Lipo and demonstrate the partial direct reprogramming of cardiac fibroblasts towards cardiomyocyte cells. C-Lipo enabled the mRNA-induced direct cardiac reprogramming due to its efficient transfection with low toxicity, which allowed for multiple transfections of Gata4, Mef2c, and Tbx5 (GMT) mRNAs for a period of 2 weeks. The induced cardiomyocyte-like cells had alpha-MHC promoter-driven GFP expression and striated cardiac muscle structure from alpha-actinin immunohistochemistry. GMT mRNA transfection of cultured mouse cardiac fibroblasts via C-Lipo significantly increased expression of the cardiomyocyte marker genes, Actc1, Actn2, Gja1, Hand2, and Tnnt2, after 2 weeks of transfection. Moreover, this study provides the first direct evidence that the stoichiometry of the GMT reprogramming factors influence the expression of cardiomyocyte marker genes. Our results demonstrate that mRNA delivery is a potential approach for cardiomyocyte generation. PMID- 25834425 TI - Single peptide ligand-functionalized uniform hollow mesoporous silica nanoparticles achieving dual-targeting drug delivery to tumor cells and angiogenic blood vessel cells. AB - BACKGROUND: The purpose of this study was to construct hollow mesoporous silica nanoparticles (HMSN) decorated with tLyp-1 peptide (tHMSN) for dual-targeting drug delivery to tumor cells and angiogenic blood vessel cells. METHODS: HMSN were synthesized de novo using a novel cationic surfactant-assisted selective etching strategy and were then modified with tLyp-1. Multiple methods, including transmission electron microscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis, bicinchoninic acid assay, and nitrogen adsorption and desorption isotherms, were used to characterize the tHMSN. Doxorubicin were chosen as the model cargo, and the uptake of doxorubicin-loaded tHMSN into MDA-MB 231 cells and human umbilical vein endothelial cells (HUVECs), as models of tumor cells and tumor neovascular endothelial cells, respectively, were observed and detected by confocal laser scanning microscopy and flow cytometry. An in vitro pharmacodynamic study and a study of the mechanism via which the nanoparticles were endocytosed were also performed. RESULTS: HMSN with a highly uniform size and well oriented mesopores were synthesized. After tHMSN were characterized, enhanced uptake of the cargo carried by tHMSN into MDA-MB-231 cells and HUVECs compared with that of their unmodified counterparts was validated by confocal laser scanning microscopy and flow cytometry at the qualitative and quantitative levels, respectively. Further, the pharmacodynamic study suggested that, compared with their unmodified counterparts, doxorubicin-loaded tHMSN had an enhanced inhibitory effect on MDA-MB-231 cells and HUVECs in vitro. Finally, a preliminary study on the mechanism by which the nanoparticles were endocytosed indicated that the clathrin-mediated endocytosis pathway has a primary role in the transport of tHMSN into the cytoplasm. CONCLUSION: tHMSN might serve as an effective active targeting nanocarrier strategy for anti-mammary cancer drug delivery. PMID- 25834427 TI - Photothermal killing of Staphylococcus aureus using antibody-targeted gold nanoparticles. AB - PURPOSE: The continued emergence of multidrug resistant bacterial infections and the decline in discovery of new antibiotics are major challenges for health care throughout the world. This situation has heightened the need for novel antimicrobial therapies as alternatives to traditional antibiotics. The combination of metallic nanoparticles and laser exposure has been proposed as a strategy to induce physical damage to bacteria, regardless of antibiotic sensitivity. The purpose of this study was to test the antibacterial effect of antibody-targeted gold nanoparticles combined with pulsed laser irradiation. METHODS: Gold nanoparticles conjugated to antibodies specific to Staphylococcus aureus peptidoglycan were incubated with suspensions of methicillin-resistant and methicillin-sensitive S. aureus (MRSA and MSSA). Bacterial suspensions were then exposed to 8 ns pulsed laser irradiation at a wavelength of 532 nm and fluences ranging from 1 to 5 J/cm(2). Viability of the bacteria following laser exposure was determined using colony forming unit assays. Scanning electron microscopy was used to confirm the binding of nanoparticles to bacteria and the presence of cellular damage. RESULTS: The laser-activated nanoparticle treatment reduced the surviving population to 31% of control in the MSSA population, while the survival in the MRSA population was reduced to 58% of control. Significant decreases in bacterial viability occurred when the laser fluence exceeded 1 J/cm(2), and this effect was linear from 0 to 5 J/cm(2) (r (2)=0.97). Significantly less bactericidal effect was observed for nonfunctionalized nanoparticles or functionalized nanoparticles without laser activation. CONCLUSION: Laser activated nanoparticles targeted to S. aureus surface antigens significantly reduced the percentage of viable organisms and represents a promising new treatment modality that could be used either alone or as an adjunct to existing, conventional antibiotic therapy. PMID- 25834426 TI - Accessing to the minor proteome of red blood cells through the influence of the nanoparticle surface properties on the corona composition. AB - Nanoparticle (NP)-protein interactions in complex samples have not yet been clearly understood. Nevertheless, several studies demonstrated that NP's physicochemical features significantly impact on the protein corona composition. Taking advantage of the NP potential to harvest different subsets of proteins, we assessed for the first time the capacity of three kinds of superparamagnetic NPs to highlight the erythrocyte minor proteome. Using both qualitative and quantitative proteomics approaches, nano-liquid chromatography-tandem mass spectrometry allowed the identification of 893 different proteins, confirming the reproducible capacity of NPs to increase the number of identified proteins, through a reduction of the sample concentration range and the capture of specific proteins on the three different surfaces. These NP-specific protein signatures revealed significant differences in their isoelectric point and molecular weight. Moreover, this NP strategy offered a deeper access to the erythrocyte proteome highlighting several signaling pathways implicated in important erythrocyte functions. The automated potentiality, the reproducibility, and the low-consuming sample demonstrate the strong compatibility of our strategy for large-scale clinical studies and may become a standardized sample preparation in future erythrocyte-associated proteomics studies. PMID- 25834428 TI - Electrospun gelatin/polycaprolactone nanofibrous membranes combined with a coculture of bone marrow stromal cells and chondrocytes for cartilage engineering. AB - Electrospinning has recently received considerable attention, showing notable potential as a novel method of scaffold fabrication for cartilage engineering. The aim of this study was to use a coculture strategy of chondrocytes combined with electrospun gelatin/polycaprolactone (GT/PCL) membranes, instead of pure chondrocytes, to evaluate the formation of cartilaginous tissue. We prepared the GT/PCL membranes, seeded bone marrow stromal cell (BMSC)/chondrocyte cocultures (75% BMSCs and 25% chondrocytes) in a sandwich model in vitro, and then implanted the constructs subcutaneously into nude mice for 12 weeks. Gross observation, histological and immunohistological evaluation, glycosaminoglycan analyses, Young's modulus measurement, and immunofluorescence staining were performed postimplantation. We found that the coculture group formed mature cartilage-like tissue, with no statistically significant difference from the chondrocyte group, and labeled BMSCs could differentiate into chondrocyte-like cells under the chondrogenic niche of chondrocytes. This entire strategy indicates that GT/PCL membranes are also a suitable scaffold for stem cell-based cartilage engineering and may provide a potentially clinically feasible approach for cartilage repairs. PMID- 25834429 TI - A new strategy for specific imaging of neural cells based on peptide-conjugated gold nanoclusters. AB - Despite the significant progress in molecular imaging technologies that has been made in recent years, the specific detection of neural cells still remains challenging. Here, we suggest the use of gold nanoclusters (AuNCs) modified with a brain-targeting peptide as a potential imaging candidate for detecting neural cells in vitro and in mice. AuNCs of less than 10 nm (dynamic light scattering analysis) were first prepared using the "green" synthetic approach, and then a targeting peptide, rabies virus glycoprotein derived peptide (RDP), was conjugated to the AuNCs for improving the efficiency and specificity of neural cell penetration. The conjugate's mechanism of cellular attachment and entry into neural cells was suggested to be receptor-mediated endocytosis through clathrin coated pits. Also, noninvasive imaging analysis and animal studies indicated that the RDP-modified nanoclusters could concentrate in the brain and locate in neural cells. This study suggests the feasibility of using targeting peptide-modified nanoclusters for noninvasive imaging brain cells in vivo. PMID- 25834431 TI - Facile biofunctionalization of silver nanoparticles for enhanced antibacterial properties, endotoxin removal, and biofilm control. AB - Infectious diseases cause a huge burden on healthcare systems worldwide. Pathogenic bacteria establish infection by developing antibiotic resistance and modulating the host's immune system, whereas opportunistic pathogens like Pseudomonas aeruginosa adapt to adverse conditions owing to their ability to form biofilms. In the present study, silver nanoparticles were biofunctionalized with polymyxin B, an antibacterial peptide using a facile method. The biofunctionalized nanoparticles (polymyxin B-capped silver nanoparticles, PBSNPs) were assessed for antibacterial activity against multiple drug-resistant clinical strain Vibrio fluvialis and nosocomial pathogen P. aeruginosa. The results of antibacterial assay revealed that PBSNPs had an approximately 3-fold higher effect than the citrate-capped nanoparticles (CSNPs). Morphological damage to the cell membrane was followed by scanning electron microscopy, testifying PBSNPs to be more potent in controlling the bacterial growth as compared with CSNPs. The bactericidal effect of PBSNPs was further confirmed by Live/Dead staining assays. Apart from the antibacterial activity, the biofunctionalized nanoparticles were found to resist biofilm formation. Electroplating of PBSNPs onto stainless steel surgical blades retained the antibacterial activity against P. aeruginosa. Further, the affinity of polymyxin for endotoxin was exploited for its removal using PBSNPs. It was found that the prepared nanoparticles removed 97% of the endotoxin from the solution. Such multifarious uses of metal nanoparticles are an attractive means of enhancing the potency of antimicrobial agents to control infections. PMID- 25834430 TI - Non-chemotoxic induction of cancer cell death using magnetic nanowires. AB - In this paper, we show that magnetic nanowires with weak magnetic fields and low frequencies can induce cell death via a mechanism that does not involve heat production. We incubated colon cancer cells with two concentrations (2.4 and 12 MUg/mL) of nickel nanowires that were 35 nm in diameter and exposed the cells and nanowires to an alternating magnetic field (0.5 mT and 1 Hz or 1 kHz) for 10 or 30 minutes. This low-power field exerted a force on the magnetic nanowires, causing a mechanical disturbance to the cells. Transmission electron microscopy images showed that the nanostructures were internalized into the cells within 1 hour of incubation. Cell viability studies showed that the magnetic field and the nanowires separately had minor deleterious effects on the cells; however, when combined, the magnetic field and nanowires caused the cell viability values to drop by up to 39%, depending on the strength of the magnetic field and the concentration of the nanowires. Cell membrane leakage experiments indicated membrane leakage of 20%, suggesting that cell death mechanisms induced by the nanowires and magnetic field involve some cell membrane rupture. Results suggest that magnetic nanowires can kill cancer cells. The proposed process requires simple and low-cost equipment with exposure to only very weak magnetic fields for short time periods. PMID- 25834432 TI - Targeted delivery of polyamidoamine-paclitaxel conjugate functionalized with anti human epidermal growth factor receptor 2 trastuzumab. AB - BACKGROUND: Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2. METHODS: TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. RESULTS: Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM. CONCLUSION: TMAB can serve as an effective targeting agent, and the TMAB-conjugated PAMAM can be exploited as a potential targeted chemotherapeutic drug delivery system for tumors that overexpress HER2. PMID- 25834434 TI - Sensitive electrochemical immunosensor based on three-dimensional nanostructure gold electrode. AB - A sensitive electrochemical immunosensor was developed for detection of alpha fetoprotein (AFP) based on a three-dimensional nanostructure gold electrode using a facile, rapid, "green" square-wave oxidation-reduction cycle technique. The resulting three-dimensional gold nanocomposites were characterized by scanning electron microscopy and cyclic voltammetry. A "sandwich-type" detection strategy using an electrochemical immunosensor was employed. Under optimal conditions, a good linear relationship between the current response signal and the AFP concentrations was observed in the range of 10-50 ng/mL with a detection limit of 3 pg/mL. This new immunosensor showed a fast amperometric response and high sensitivity and selectivity. It was successfully used to determine AFP in a human serum sample with a relative standard deviation of <5% (n=5). The proposed immunosensor represents a significant step toward practical application in clinical diagnosis and monitoring of prognosis. PMID- 25834435 TI - The antitumor activity of tumor-homing peptide-modified thermosensitive liposomes containing doxorubicin on MCF-7/ADR: in vitro and in vivo. AB - Clotted plasma proteins are present on the walls of tumor vessels and in tumor stroma. Tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA) could recognize the clotted plasma proteins in tumor vessels. Thermosensitive liposomes could immediately release the encapsulated drug in the vasculature of the heated tumor. In this study, we designed a novel form of targeted thermosensitive liposomes, CREKA-modified lysolipid-containing thermosensitive liposomes (LTSLs), containing doxorubicin (DOX) (DOX-LTSL-CREKA), to investigate the hypothesis that DOX-LTSL CREKA might target the clotted plasma proteins in tumor vessels as well as tumor stroma and then exhibit burst release of the encapsulated DOX at the heated tumor site. We also hypothesized that the high local drug concentration produced by these thermosensitive liposomes after local hyperthermia treatment will be useful for treatment of multidrug resistance. The multidrug-resistant human breast adenocarcinoma (MCF-7/ADR) cell line was chosen as a tumor cell model, and the targeting and immediate release characteristics of DOX-LTSL-CREKA were investigated in vitro and in vivo. Furthermore, the antitumor activity of DOX LTSL-CREKA was evaluated in MCF-7/ADR tumor-bearing nude mice in vivo. The targeting effect of the CREKA-modified thermosensitive liposomes on the clotted plasma proteins was confirmed in our in vivo imaging and immunohistochemistry experiments. The burst release of this delivery system was observed in our in vitro temperature-triggered DOX release and flow cytometry analysis and also by confocal microscopy experiments. The antitumor activity of the DOX-LTSL-CREKA was confirmed in tumor-bearing nude mice in vivo. Our findings suggest that the combination of targeting the clotted plasma proteins in the tumor vessel wall as well as tumor stroma by using CREKA peptide and temperature-triggered drug release from liposomes by using thermosensitive liposomes offers an attractive strategy for chemotherapeutic drug delivery to tumors. PMID- 25834433 TI - Parameters and characteristics governing cellular internalization and trans barrier trafficking of nanostructures. AB - Cellular internalization and trans-barrier transport of nanoparticles can be manipulated on the basis of the physicochemical and mechanical characteristics of nanoparticles. Research has shown that these factors significantly influence the uptake of nanoparticles. Dictating these characteristics allows for the control of the rate and extent of cellular uptake, as well as delivering the drug-loaded nanosystem intra-cellularly, which is imperative for drugs that require a specific cellular level to exert their effects. Additionally, physicochemical characteristics of the nanoparticles should be optimal for the nanosystem to bypass the natural restricting phenomena of the body and act therapeutically at the targeted site. The factors at the focal point of emerging smart nanomedicines include nanoparticle size, surface charge, shape, hydrophobicity, surface chemistry, and even protein and ligand conjugates. Hence, this review discusses the mechanism of internalization of nanoparticles and ideal nanoparticle characteristics that allow them to evade the biological barriers in order to achieve optimal cellular uptake in different organ systems. Identifying these parameters assists with the progression of nanomedicine as an outstanding vector of pharmaceuticals. PMID- 25834436 TI - Rescuing compound bioactivity in a secondary cell-based screening by using gamma cyclodextrin as a molecular carrier. AB - In vitro primary screening for identifying bioactive compounds (inhibitors, activators or pharmacological chaperones) against a protein target results in the discovery of lead compounds that must be tested in cell-based efficacy secondary screenings. Very often lead compounds do not succeed because of an apparent low potency in cell assays, despite an excellent performance in primary screening. Primary and secondary screenings differ significantly according to the conditions and challenges the compounds must overcome in order to interact with their intended target. Cellular internalization and intracellular metabolism are some of the difficulties the compounds must confront and different strategies can be envisaged for minimizing that problem. Using a novel screening procedure we have identified 15 compounds inhibiting the hepatitis C NS3 protease in an allosteric fashion. After characterizing biophysically the interaction with the target, some of the compounds were not able to inhibit viral replication in cell assays. In order to overcome this obstacle and potentially improve cellular internalization three of these compounds were complexed with gamma-cyclodextrin. Two of them showed a five- and 16-fold activity increase, compared to their activity when delivered as free compounds in solution (while gamma-cyclodextrin did not show antiviral activity by itself). The most remarkable result came from a third compound that showed no antiviral activity in cell assays when delivered free in solution, but its gamma-cyclodextrin complex exhibited a 50% effective concentration of 5 MUM. Thus, the antiviral activity of these compounds can be significantly improved, even completely rescued, using gamma-cyclodextrin as carrier molecule. PMID- 25834437 TI - Is it possible to use highly realistic virtual reality in the elderly? A feasibility study with image-based rendering. AB - BACKGROUND: Virtual reality (VR) opens up a vast number of possibilities in many domains of therapy. The primary objective of the present study was to evaluate the acceptability for elderly subjects of a VR experience using the image-based rendering virtual environment (IBVE) approach and secondly to test the hypothesis that visual cues using VR may enhance the generation of autobiographical memories. METHODS: Eighteen healthy volunteers (mean age 68.2 years) presenting memory complaints with a Mini-Mental State Examination score higher than 27 and no history of neuropsychiatric disease were included. Participants were asked to perform an autobiographical fluency task in four conditions. The first condition was a baseline grey screen, the second was a photograph of a well-known location in the participant's home city (FamPhoto), and the last two conditions displayed VR, ie, a familiar image-based virtual environment (FamIBVE) consisting of an image-based representation of a known landmark square in the center of the city of experimentation (Nice) and an unknown image-based virtual environment (UnknoIBVE), which was captured in a public housing neighborhood containing unrecognizable building fronts. After each of the four experimental conditions, participants filled in self-report questionnaires to assess the task acceptability (levels of emotion, motivation, security, fatigue, and familiarity). CyberSickness and Presence questionnaires were also assessed after the two VR conditions. Autobiographical memory was assessed using a verbal fluency task and quality of the recollection was assessed using the "remember/know" procedure. RESULTS: All subjects completed the experiment. Sense of security and fatigue were not significantly different between the conditions with and without VR. The FamPhoto condition yielded a higher emotion score than the other conditions (P<0.05). The CyberSickness questionnaire showed that participants did not experience sickness during the experiment across the VR conditions. VR stimulates autobiographical memory, as demonstrated by the increased total number of responses on the autobiographical fluency task and the increased number of conscious recollections of memories for familiar versus unknown scenes (P<0.01). CONCLUSION: The study indicates that VR using the FamIBVE system is well tolerated by the elderly. VR can also stimulate recollections of autobiographical memory and convey familiarity of a given scene, which is an essential requirement for use of VR during reminiscence therapy. PMID- 25834438 TI - Changes in proinflammatory cytokines and white matter in chronically stressed rats. AB - Although the pathogenesis of depression, an incapacitating psychiatric ailment, remains largely unknown, previous human and animal studies have suggested that both proinflammatory cytokines and altered oligodendrocytes play important roles in the condition. This study examined these two factors in the brains of rats following unpredictable chronic mild stress for 4 weeks, with the hypothesis that chronic stress may affect oligodendrocytes and elevate proinflammatory cytokines in the brain. After suffering unpredictable stressors for 4 weeks, the rats showed depression-like behaviors, including decreased locomotion in the open field, increased immobility time in the forced swim test, and decreased sucrose consumption and less sucrose preference when compared with controls. Immunohistochemical staining of brain sections showed higher immunoreactivity of proinflammatory cytokines in certain brain regions of stressed rats compared with controls; lower immunoreactivity of myelin basic protein and fewer mature oligodendrocytes were seen in the prefrontal cortex, but no demyelination was detected. These results are interpreted and discussed in the context of recent findings from human and animal studies. PMID- 25834440 TI - Anti-NMDA receptor antibodies in patients with a first episode of schizophrenia. AB - BACKGROUND: Encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDA-R) is classified as an autoimmune disorder with psychotic symptoms, which are frequently dominant. However, it remains unclear how frequently NMDA-R antibodies lead to a condition that mimics psychosis and first-episode schizophrenia. In our work, we investigated the presence of antibodies against NMDA-R in patients with first-episode psychosis (FEP) in comparison with healthy volunteers. METHODS: This study included 50 antipsychotic-naive patients with FEP (including 21 women) and 50 healthy volunteers (including 21 women). The mean age of the patients was 27.4 (+/-7.4) years and that of the healthy controls was 27.0 (+/-7.3) years. Antibodies against NMDA-R in the serum were detected by immunofluorescence. RESULTS: None of the investigated patients with an FEP and none of the healthy controls showed positive antibodies against NMDA-Rs. CONCLUSION: According to results of studies, a small proportion of patients with an FEP possess antibodies against NMDA-R. However, the extent to which this finding contributes to the etiopathogenesis of the response to antipsychotic medication and whether immunomodulatory therapy is indicated in these cases remains uncertain. PMID- 25834439 TI - Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats. AB - Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light-dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders. PMID- 25834441 TI - Rosa damascena oil improves SSRI-induced sexual dysfunction in male patients suffering from major depressive disorders: results from a double-blind, randomized, and placebo-controlled clinical trial. AB - BACKGROUND: A substantial disadvantage of psychopharmacological treatment of major depressive disorder (MDD) with selective serotonin-reuptake inhibitors (SSRIs) is the impact on sexual dysfunction. The aim of the present study was to investigate whether the oil of Rosa damascena can have a positive influence on SSRI-induced sexual dysfunction (SSRI-I SD) of male patients who are suffering from MDD and are being treated with SSRIs. METHOD: In a double-blind, randomized, and placebo-controlled clinical trial, a total of 60 male patients treated with an SSRI and suffering from MDD (mean age =32 years) and SSRI-I SD were randomly assigned to take either verum (R. damascena oil) or a placebo. Patients completed self-ratings of depression and sexual function at baseline, at 4 weeks later, and at the end of the study, 8 weeks after it started. RESULTS: Over time, sexual dysfunction improved more in the verum group than in the control group. Improvements were observed in the verum group from week 4 to week 8. Self-rated symptoms of depression reduced over time in both groups, but did so more so in the verum group than in the control group. CONCLUSION: This double-blind, randomized, and placebo-controlled clinical trial showed that the administration of R. damascena oil ameliorates sexual dysfunction in male patients suffering from both MDD and SSRI-I SD. Further, the symptoms of depression reduced as sexual dysfunction improved. PMID- 25834442 TI - Global and regional brain volumes normalization in weight-recovered adolescents with anorexia nervosa: preliminary findings of a longitudinal voxel-based morphometry study. AB - The recent literature on anorexia nervosa (AN) suggests that functional and structural abnormalities of cortico-limbic areas might play a role in the evolution of the disease. We explored global and regional brain volumes in a cross-sectional and follow-up study on adolescents affected by AN. Eleven adolescents with AN underwent a voxel-based morphometry study at time of diagnosis and immediately after weight recovery. Data were compared to volumes carried out in eight healthy, age and sex matched controls. Subjects with AN showed increased cerebrospinal fluid volumes and decreased white and gray matter volumes, when compared to controls. Moreover, significant regional gray matter decrease in insular cortex and cerebellum was found at time of diagnosis. No regional white matter decrease was found between samples and controls. Correlations between psychological evaluation and insular volumes were explored. After weight recovery gray matter volumes normalized while reduced global white matter volumes persisted. PMID- 25834443 TI - A retrospective study to assess resource utilization in patients with cervical dystonia in the United Kingdom. AB - PURPOSE: Cervical dystonia (CD) is a hypertonic condition caused by damage to the central nervous system. Very few studies have assessed the overall economic burden of the disease. The objective of this study was to describe the utilization of health care resources of patients with CD in the UK primary care setting, using a large population-based database. PATIENTS AND METHODS: Adults with a first diagnosis of CD between January 1, 2007 and January 31, 2011, who were registered to a general practitioner (GP) practice contributing to The Health Improvement Network (THIN), were included. Sociodemographic and clinical characteristics were assessed at the time of diagnosis. Health care resource utilization and pharmacological treatment were investigated at the end of the first and second year after diagnosis. RESULTS: Overall, 4,024 newly diagnosed patients with CD were identified, with average age at diagnosis of 45 years old; 65.3% were female. Depression in the year prior to diagnosis was the most common comorbidity. Primary care utilization was high in the first year, with 99.2% of patients visiting their GP (on average 6.2 times), and 43% visiting a nurse (on average 2.5 times). Patients were most commonly referred to an orthopedic surgeon, and 15.9% reported at least one physiotherapy visit. In the second year, utilization was similar. Prescriptions of at least one of the investigated treatments were found in 82.0% and 45.3%, in the first and second year, respectively. CONCLUSION: Findings suggest a high number of new CD cases are being identified in primary care, but not all will be referred to secondary care. Health care resource utilization was compared with that of all patients registered in THIN, which is representative of the UK, and the adjusted usage of primary care resources was found to be similar to that of the THIN population. PMID- 25834444 TI - Do physical exercise and reading reduce the risk of Parkinson's disease? a cross sectional study on factors associated with Parkinson's disease in elderly Chinese veterans. AB - BACKGROUND: The purpose of this study was to investigate risk factors for and factors protecting against Parkinson's disease (PD) in elderly Chinese veterans. METHODS: Using a database containing detailed information on the health status of the nervous system in elderly Chinese veterans, univariate and multivariate analyses of factors that may be associated with PD were performed. Univariate analysis of qualitative data was done using the Pearson Chi-square and Fisher's exact tests, and the Mann-Whitney U nonparametric test was used for univariate analysis of quantitative data. Multivariate logistic regression analysis was used to identify independent risk factors for and factors protecting against PD in elderly Chinese veterans. RESULTS: A total of 9,676 elderly Chinese veterans were enrolled, including 228 cases with PD and 183 cases with Parkinson's syndrome, with 9,265 non-PD subjects serving as controls. Age (odds ratio [OR] 1.343, 95% confidence interval [CI] 1.028-1.755) and medical history of essential tremor (OR 1.228, 95% CI 1.081-1.396) were identified as independent risk factors for PD, with age being the most important risk factor. Physical exercise (OR 0.478, 95% CI 0.355-0.643) and reading (OR 0.513, 95% CI 0.357-0.735) were identified as independent factors protecting against PD, and physical exercise showed better protection against PD relative to reading. Smoking, alcohol use, anemia, cerebral trauma, education level, and electromagnetic field exposure showed no association with PD. CONCLUSION: Physical exercise and reading may be independent factors that protect against PD among elderly Chinese veterans, while advancing age and medical history of essential tremor may be independent risk factors for PD. This study was cross-sectional, so further research is needed to confirm its results. PMID- 25834445 TI - Augmentation with antidepressants in schizophrenia treatment: benefit or risk. AB - We focused on the application of antidepressants in schizophrenia treatment in this review. Augmentation of antidepressants with antipsychotics is a common clinical practice to treat resistant symptoms in schizophrenia, including depressive symptoms, negative symptoms, comorbid obsessive-compulsive symptoms, and other psychotic manifestations. However, recent systematic review of the clinical effects of antidepressants is lacking. In this review, we have selected and summarized current literature on the use of antidepressants in patients with schizophrenia; the patterns of use and effectiveness, as well as risks and drug drug interactions of this clinical practice are discussed in detail, with particular emphasis on the treatment of depressive symptoms in schizophrenia. PMID- 25834446 TI - Psychobiotics and the gut-brain axis: in the pursuit of happiness. AB - The human intestine houses an astounding number and species of microorganisms, estimated at more than 10(14) gut microbiota and composed of over a thousand species. An individual's profile of microbiota is continually influenced by a variety of factors including but not limited to genetics, age, sex, diet, and lifestyle. Although each person's microbial profile is distinct, the relative abundance and distribution of bacterial species is similar among healthy individuals, aiding in the maintenance of one's overall health. Consequently, the ability of gut microbiota to bidirectionally communicate with the brain, known as the gut-brain axis, in the modulation of human health is at the forefront of current research. At a basic level, the gut microbiota interacts with the human host in a mutualistic relationship - the host intestine provides the bacteria with an environment to grow and the bacterium aids in governing homeostasis within the host. Therefore, it is reasonable to think that the lack of healthy gut microbiota may also lead to a deterioration of these relationships and ultimately disease. Indeed, a dysfunction in the gut-brain axis has been elucidated by a multitude of studies linked to neuropsychological, metabolic, and gastrointestinal disorders. For instance, altered microbiota has been linked to neuropsychological disorders including depression and autism spectrum disorder, metabolic disorders such as obesity, and gastrointestinal disorders including inflammatory bowel disease and irritable bowel syndrome. Fortunately, studies have also indicated that gut microbiota may be modulated with the use of probiotics, antibiotics, and fecal microbiota transplants as a prospect for therapy in microbiota-associated diseases. This modulation of gut microbiota is currently a growing area of research as it just might hold the key to treatment. PMID- 25834447 TI - The influence of comorbid personality disorders on recovery from depression. AB - PURPOSE: The impact of personality disorders on the treatment of and recovery from depression is still a controversial topic. The aim of this paper is to provide more information on what has led to this disagreement. MATERIALS AND METHODS: Clinician-rated Hamilton Depression Rating Scale (HAMD) scores were assessed among 82 depressed outpatients who were receiving a routine treatment combination of antidepressant medication and psychosocial intervention. The participants were followed up over five visits at 3-month intervals: at the baseline, at 3, 6, 9 and 12 months. Personality disorders were assessed after the last visit in accordance with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. These repeated measures were used to explore the impact of personality disorders on HAMD scores by using a linear mixed model. RESULTS: Among the four personality clusters that were used (A, B, C, and mixed), only those in cluster B and in the mixed cluster were found to take significantly longer than those without personality disorders, for reduction in HAMD scores over the course of treatment. CONCLUSION: In this study, the impact of personality disorders on treatment outcomes varied with the way that the personality disorder variables were described and used as independent predictors. This is because the outcomes were influenced by the impact weight of each personality disorder, even within the same cluster. PMID- 25834448 TI - Red cell distribution width and neurological scoring systems in acute stroke patients. AB - OBJECTIVES: The purpose of the present study was to evaluate the association between the red blood cell distribution width (RDW) and the Glasgow Coma Scale (GCS), Canadian Neurological Scale (CNS), and National Institutes of Health Stroke Scale (NIHSS) scores in patients who had acute ischemic stroke. METHODS: This prospective observational cohort study included 88 patients who have had acute ischemic stroke and a control group of 40 patients who were evaluated in the Emergency Department for disorders other than acute ischemic stroke. All subjects had RDW determined, and stroke patients had scoring with the GCS, CNS, and NIHSS scores. The GCS, CNS, and NIHSS scores of the patients were rated as mild, moderate, or severe and compared with RDW. RESULTS: Stroke patients had significantly higher median RDW than control subjects. The median RDW values were significantly elevated in patients who had more severe rather than milder strokes rated with all three scoring systems (GCS, CNS, and NIHSS). The median RDW values were significantly elevated for patients who had moderate rather than mild strokes rated by GCS and CNS and for patients who had severe rather than mild strokes rated by NIHSS. The area under the receiver operating characteristic curve was 0.760 (95% confidence interval, 0.676-0.844). Separation of stroke patients and control groups was optimal with RDW 14% (sensitivity, 71.6%; specificity, 67.5%; accuracy, 70.3%). CONCLUSION: In stroke patients who have symptoms <24 hours, the RDW may be useful in predicting the severity and functional outcomes of the stroke. PMID- 25834449 TI - Effects of a selective educational system on fatigue, sleep problems, daytime sleepiness, and depression among senior high school adolescents in Taiwan. AB - OBJECTIVE: The aim of the study reported here was to clarify the effects of academic pressure on fatigue, sleep problems, daytime sleepiness, and depression among senior high school adolescents in Taiwan. METHODS: This cross-sectional study enrolled 757 senior high school adolescents who were classified into four groups: Grade 1 (n=261), Grade 2 (n=228), Grade 3T (n=199; Grade 3 students who had another college entrance test to take), and Grade 3S (n=69; Grade 3 students who had succeeded in their college application). Fatigue, sleep quality, daytime sleepiness, and depression were assessed using the Chinese version of the Multidimensional Fatigue Symptom Inventory - Short Form, Pittsburgh Sleep Quality Index-Taiwan Form, the Chinese version of the Epworth Sleepiness Scale, and the Chinese version of the Beck Depression Inventory((r))-II (BDI-II), respectively. RESULTS: Physical, emotional, and mental fatigue scores were all higher in higher grade groups. The Grade 3T (test) students had the worst fatigue severity, and the Grade 3S (success) students had the least fatigue severity. More than half of the students (60.9%) went to bed after 12 am, and they had on average 6.0 hours of sleep per night. More than 30% of the students in Grade 2 (37.3%) and Grades 3T/S (30.2%/30.4%) possibly had daily sleepiness problems. The students in Grade 3T had the worst BDI-II score (13.27+/-9.24), and the Grade 3S students had a much lower BDI-II score (7.91+/-6.13). CONCLUSION: Relatively high proportions of fatigue, sleep problems, daytime sleepiness, and depression among senior high school adolescents were found in our study. The severities of fatigue, sleep problems, and depression were significantly diminished in the group under less academic stress (Grade 3S). Our findings may increase the understanding of the mental health of senior high school students under academic pressure in Taiwan. Further large sample size and population-based study should be done for better understanding about this topic. PMID- 25834450 TI - Optimal management of night eating syndrome: challenges and solutions. AB - Night Eating Syndrome (NES) is a unique disorder characterized by a delayed pattern of food intake in which recurrent episodes of nocturnal eating and/or excessive food consumption occur after the evening meal. NES is a clinically important disorder due to its relationship to obesity, its association with other psychiatric disorders, and problems concerning sleep. However, NES often goes unrecognized by both health professionals and patients. The lack of knowledge regarding NES in clinical settings may lead to inadequate diagnoses and inappropriate treatment approaches. Therefore, the proper diagnosis of NES is the most important issue when identifying NES and providing treatment for this disorder. Clinical assessment tools such as the Night Eating Questionnaire may help health professionals working with populations vulnerable to NES. Although NES treatment studies are still in their infancy, antidepressant treatments and psychological therapies can be used for optimal management of patients with NES. Other treatment options such as melatonergic medications, light therapy, and the anticonvulsant topiramate also hold promise as future treatment options. The purpose of this review is to provide a summary of NES, including its diagnosis, comorbidities, and treatment approaches. Possible challenges addressing patients with NES and management options are also discussed. PMID- 25834452 TI - Neuroinflammatory responses to traumatic brain injury. PMID- 25834451 TI - Long-term total sleep deprivation decreases the default spontaneous activity and connectivity pattern in healthy male subjects: a resting-state fMRI study. AB - OBJECTIVE: The aim of this study is to use resting-state functional connectivity (rsFC) and amplitude of low-frequency fluctuation (ALFF) methods to explore intrinsic default-mode network (DMN) impairment after sleep deprivation (SD) and its relationships with clinical features. METHODS: Twelve healthy male subjects underwent resting-state functional magnetic resonance imaging twice: once following rested wakefulness (RW) and the other following 72 hours of total SD. Before the scans, all subjects underwent the attention network test (ANT). The independent component analysis (ICA), rsFC, and ALFF methods were used to examine intrinsic DMN impairment. Receiver operating characteristic (ROC) curve was used to distinguish SD status from RW status. RESULTS: Compared with RW subjects, SD subjects showed a lower accuracy rate (RW =96.83%, SD =77.67%; P<0.001), a slower reaction time (RW =695.92 ms; SD =799.18 ms; P=0.003), a higher lapse rate (RW =0.69%, SD =19.29%; P<0.001), and a higher intraindividual coefficient of variability in reaction time (RW =0.26, SD =0.33; P=0.021). The ICA method showed that, compared with RW subjects, SD subjects had decreased rsFC in the right inferior parietal lobule (IPL, BA40) and in the left precuneus (PrC)/posterior cingulate cortex (PCC) (BA30, 31). The two different areas were selected as regions of interest (ROIs) for future rsFC analysis. Compared with the same in RW subjects, in SD subjects, the right IPL showed decreased rsFC with the left PrC (BA7) and increased rsFC with the left fusiform gyrus (BA37) and the left cluster of middle temporal gyrus and inferior temporal gyrus (BA37). However, the left PrC/PCC did not show any connectivity differences. Compared with RW subjects, SD subjects showed lower ALFF area in the left IPL (BA39, 40). The left IPL, as an ROI, showed decreased rsFC with the right cluster of IPL and superior temporal gyrus (BA39, 40). ROC curve analysis showed that the area under the curve (AUC) value of the left IPL was 0.75, with a cutoff point of 0.834 (mean ALFF signal value). Further diagnostic analysis exhibited that the AUC alone discriminated SD status from RW status, with 75% sensitivity and 91.7% specificity. CONCLUSION: Long-term SD disturbed the spontaneous activity and connectivity pattern of DMN. PMID- 25834454 TI - Clinical use of pasireotide for Cushing's disease in adults. AB - CUSHING'S DISEASE: Excessive corticotroph hormone levels sustained by an adrenocorticotropic hormone-secreting pituitary adenoma lead to a severe clinical condition caused by excess cortisol secretion, called Cushing's disease (CD). Neurosurgery and radiotherapy are used to treat the pituitary adenoma directly, but new medical treatments targeting the corticotroph cells have recently become available. PASIREOTIDE: This is a novel multireceptor ligand somatostatin (SST) analog with a high binding affinity for SST receptor 5, the predominant receptor in human corticotroph adenomas that is not downregulated by high cortisol levels (as SST receptor 2 is). Pasireotide has been recently approved by the European Medical Agency and the US Food and Drug Administration for treating adults with CD with recurrent hypercortisolism after surgery, or for whom surgery is not an option. A dose of 600-1,200 MUg twice a day can normalize urinary free cortisol levels after 3 months of treatment in up to 28% of patients, reducing their blood pressure and improving their weight, lipid profile, and quality of life. Combining pasireotide with cabergoline to achieve a greater hormone response can normalize cortisol secretion in 50% of patients, and adding ketoconazole induces biochemical control in most patients with CD. SAFETY AND HYPERGLYCEMIA: The adverse effects of pasireotide are similar to those of other SST analogs, including diarrhea, nausea, and biliary sludge or gallstones. Hyperglycemia is common during pasireotide treatment, which affects the secretion of pancreatic insulin and intestinal glucagon-like peptide 1. Self-monitoring is essential to achieve good metabolic control, and endocrinologists should first administer metformin if insulin resistance is evident and then add dipeptidyl peptidase 4 inhibitors/glucagon-like peptide 1 receptor agonists or insulin. CONCLUSION: In recent years, medical treatment with pasireotide has been proposed as monotherapy for adults with CD characterized by mild to moderate hypercortisolemia, as well as in combination with other available therapies. It is generally well-tolerated, but endocrinologists need to monitor glucose levels to ensure prompt treatment. PMID- 25834453 TI - Risk factors for osteoporosis in Japan: is it associated with Helicobacter pylori? AB - BACKGROUND: A number of diseases and drugs may influence bone mineral density; however, there are few reports concerning the relationship between lifestyle related diseases and osteoporosis in Japan as determined by multivariate analysis. The aim of this study was to investigate the risk factors for osteoporosis and whether infection by or eradication of Helicobacter pylori is associated with osteoporosis. METHODS: Between February 2008 and November 2014, using a cross-sectional study design, we investigated patient profile (age, sex, BMI, alcohol, smoking), H. pylori infection status, comorbidities, internal medicine therapeutic agents (calcium channel blocker, HMG-CoA reductase inhibitors, proton pump inhibitor), serum parameters (Hb, calcium, gammaGTP), bone turn over markers (bone-specific alkaline phosphatase (BAP) and collagen type I cross-linked N telopeptide (NTX), findings on dual-energy x-ray absorptiometry (DEXA) and upper gastrointestinal endoscopy, and Frequency Scale for the Symptoms of GERD score in consecutive outpatients aged >=50 years at our hospital. We divided the subjects into an osteoporosis group and a non osteoporosis group and investigated risk factors for osteoporosis between the two groups by bivariate and multivariate analyses. RESULTS: Of the 255 eligible study subjects, 43 (16.9%) had osteoporosis. Bivariate analysis showed that advanced age, female sex, lower body mass index, lower cumulative alcohol intake, lower Brinkman index, H. pylori positivity, lower hemoglobin, bone-specific alkaline phosphatase, lower prevalence of hiatal hernia, and endoscopic gastric mucosal atrophy were related to osteoporosis. Multivariate analysis showed that advanced age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.07-1.19, P<0.001), female sex (OR 6.27, 95% CI 2.26-17.39, P<0.001), low BMI (OR 0.82, 95% CI 0.72 0.94, P=0.005), H. pylori positivity (OR 3.00, 95% CI 1.31-6.88, P=0.009), and BAP (OR 1.07, 95% CI 1.01-1.14, P=0.035) were related to osteoporosis. CONCLUSION: Advanced age, low BMI, BAP, and H. pylori positivity were risk factors for osteoporosis; however, the success of H. pylori eradication was not a risk factor for osteoporosis in Japan. PMID- 25834455 TI - Experiences of using the Theoretical Domains Framework across diverse clinical environments: a qualitative study. AB - BACKGROUND: The Theoretical Domains Framework (TDF) is an integrative framework developed from a synthesis of psychological theories as a vehicle to help apply theoretical approaches to interventions aimed at behavior change. PURPOSE: This study explores experiences of TDF use by professionals from multiple disciplines across diverse clinical settings. METHODS: Mixed methods were used to examine experiences, attitudes, and perspectives of health professionals in using the TDF in health care implementation projects. Individual interviews were conducted with ten health care professionals from six disciplines who used the TDF in implementation projects. Deductive content and thematic analysis were used. RESULTS: Three main themes and associated subthemes were identified including: 1) reasons for use of the TDF (increased confidence, broader perspective, and theoretical underpinnings); 2) challenges using the TDF (time and resources, operationalization of the TDF) and; 3) future use of the TDF. CONCLUSION: The TDF provided a useful, flexible framework for a diverse group of health professionals working across different clinical settings for the assessment of barriers and targeting resources to influence behavior change for implementation projects. The development of practical tools and training or support is likely to aid the utility of TDF. PMID- 25834456 TI - Association between the ERCC1 rs11615 polymorphism and clinical outcomes of oxaliplatin-based chemotherapies in gastrointestinal cancer: a meta-analysis. AB - PURPOSE: The relationship between the excision repair cross-complementing 1 (ERCC1) rs11615 polymorphism (C/T) and responses to oxaliplatin-based chemotherapy for gastric cancer (GC) and colorectal cancer (CRC) patients is controversial. Therefore, we performed a meta-analysis to assess this relationship. METHOD: Relevant studies were retrieved by searching the PubMed database. A systematic review and meta-analysis was performed to evaluate the predictive value of the ERCC1 rs11615 polymorphism for the clinical outcomes of GC and CRC patients receiving oxaliplatin-based chemotherapy. Therapeutic response to chemotherapy, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: A total of 22 studies were included in this meta analysis, including 1,242 cases of GC and 1,772 cases of CRC. For the ERCC1 rs11615 polymorphism, the T allele was associated with a reduced response to chemotherapy in Asians and GC patients (P<0.05). On the other hand, the T allele was associated with a significant increase in the risk for shorter PFS and OS in all patients (PFS: hazard ratio [HR] =1.22, P<0.001, 95% confidence interval [CI] =0.93-1.51 and OS: HR =1.12, P<0.001, 95% CI =0.85-1.40). CONCLUSION: The ERCC1 rs11615 polymorphism was closely associated with the clinical outcomes of GC and CRC patients treated with oxaliplatin-based chemotherapy. PMID- 25834457 TI - A major step forward for sublingual immunotherapy: the quality of 5-grass pollen tablet is recognized also in Italy. PMID- 25834458 TI - Costs of illness analysis in Italian patients with chronic obstructive pulmonary disease (COPD): an update. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide, and its epidemiological, clinical, and socioeconomic impact is progressively increasing. A first estimate of the economic burden of COPD in Italy was conducted in 2008 (the SIRIO [Social Impact of Respiratory Integrated Outcomes] study). The aim of the present study is to provide an updated picture of the COPD economic burden in Italy. METHODS: Sequential patients presenting at the specialist center for the first time during the period 2008-2012 and with record file complete (demographic, clinical, lung function, and therapeutic data; health care resources consumed in the 12 months before the enrollment and for the 3 subsequent years) were selected from the institutional database. RESULTS: Two hundred and seventy-five COPD patients fitting the inclusion criteria were selected (226 males; mean age: 70.9 years [standard deviation: +/-8.4 years]; 45.8% were from the north, 25.1% from central Italy, and 29.1% from south Italy). COPD-related average costs per patient in the 12 months before enrollment were as follows: hospitalization: ?1,970; outpatient care: ?463; pharmaceutical: ?499; and indirect costs: ?358. Average direct costs and total societal costs were ?2,932 and ?3,291, respectively. Direct cost was ?2,461 (hospitalization: ?1,570; outpatient: ?344; and pharmaceutical: ?547) in the first year of follow-up, while total societal cost was ?2,707. No significant difference was reported in any cost category between sexes. CONCLUSION: The therapeutic approach followed in a specialist center, based on the application of clinical guidelines, has been shown to be a highly effective investment for the long-term management of COPD. A small increase of pharmaceutical costs per year allowed a substantial saving in terms of hospitalizations, costs related to outpatient services, and indirect costs. PMID- 25834459 TI - Erratum: Annual biologic treatment cost for new and existing patients with moderate to severe plaque psoriasis in Greece [Corrigendum]. AB - [This corrects the article on p. 73 in vol. 7, PMID: 25609988.]. PMID- 25834460 TI - Daily intake of rosehip extract decreases abdominal visceral fat in preobese subjects: a randomized, double-blind, placebo-controlled clinical trial. AB - BACKGROUND: Obesity has become a great problem all over the world. We repeatedly screened to find an effective food to treat obesity and discovered that rosehip extract shows potent anti-obesity effects. Investigations in mice have demonstrated that rosehip extract inhibits body weight gain and decreases visceral fat. Thus, the present study examined the effect of rosehip extract on human body fat in preobese subjects. METHODS: We conducted a 12-week, single center, double-blind, randomized, placebo-controlled study of 32 subjects who had a body mass index of >=25 but <30. The subjects were assigned to two random groups, and they received one tablet of placebo or rosehip that contained 100 mg of rosehip extract once each day for 12 weeks with no dietary intervention. Abdominal fat area and body fat percent were measured as primary outcomes. The other outcomes were body weight and body mass index. RESULTS: Abdominal total fat area, abdominal visceral fat area, body weight, and body mass index decreased significantly in the rosehip group at week 12 compared with their baseline levels (P<0.01) after receiving the rosehip tablet intake, and the decreases in these parameters were significantly higher when compared with those in the placebo group. Additionally, body fat percent tended to decrease compared with the placebo group and their baseline level. Moreover, the abdominal subcutaneous fat area was significantly lower in the rosehip group than in the placebo group at week 12 after the initiation of intake (P<0.05). In addition, there were no abnormalities, subjective symptoms, and findings that may indicate clinical problems during the study period. CONCLUSION: These results suggest that rosehip extract may be a good candidate food material for preventing obesity. PMID- 25834461 TI - Anagliptin in the treatment of type 2 diabetes: safety, efficacy, and patient acceptability. AB - Anagliptin is a novel dipeptidyl peptidase-4 inhibitor that has been available in Japan since 2012. Because anagliptin is not generally used in countries other than Japan, there are only a small number of reports investigating the effects of anagliptin. In the present article, we review the safety and efficacy of anagliptin according to data obtained from preclinical trials and postmarketing studies. The usual dose of anagliptin is 200 mg daily, and increases in the dose up to 400 mg daily have been approved in cases in which the blood glucose lowering effect is insufficient. In a Phase II trial, the reduction in the HbA1c values from baseline after 12 weeks monotherapy with 200 mg and 400 mg of daily anagliptin was 0.75%+/-0.50% and 0.82%+/-0.46%, respectively, and more than 40% of the subjects receiving anagliptin at a dose of 200 mg or 400 mg daily achieved an HbA1c level below 6.9%. Furthermore, the levels of HbA1c, fasting blood glucose, and postprandial blood glucose were significantly decreased at 52 weeks compared with the baseline values in a Phase III trial investigating the effects of anagliptin included in combination therapy with other oral antidiabetic agents. In a pooled analysis of Phase II and Phase II/III trials, the goal achievement rates for an HbA1c level below 7.0% at 12 weeks were 40.3%, 39.4%, 30.0%, and 34.8% in the patients treated with anagliptin combined with alpha glucosidase inhibitors, thiazolidinediones, sulfonylureas, and biguanides, respectively. Meanwhile, the serum lipid concentrations significantly improved after the administration of anagliptin in a pooled analysis of Phase III trials, and no serious adverse effects have been reported in preclinical trials. Therefore, the use of anagliptin in patients with type 2 diabetes is considered to be safe and effective for both monotherapy and combination therapy. PMID- 25834462 TI - Spectrum of dermatophyte infections in Botswana. AB - BACKGROUND: Dermatophyte infections are a common cause of superficial fungal infection in different geographical locations of the world. Usually, it involves superficial invasion of keratinized tissue, eg, skin, nails, and hair, but in immunosuppressed individuals, it may cause atypical, extensive and deep lesions, which may pose serious diagnostic and therapeutic challenges. AIM: To find out the causative dermatophyte species responsible for the various clinical types of dermatophyte infection. RESULTS: Trichophyton violaceum was found to be the predominant species, being the causative organism responsible for all the clinical types. CONCLUSION: T. violaceum was found to be the most common species responsible for most of the clinical forms of dermatophytosis (96; 80%). Tinea unguium was found to be the most frequent clinical type of dermatophytosis (33; 27.50%). PMID- 25834463 TI - IncobotulinumtoxinA use in aesthetic indications in daily practice: a European multicenter, noninterventional, retrospective study. AB - PURPOSE: To characterize utilization patterns and treatment satisfaction with incobotulinumtoxinA for aesthetic indications and assess adherence to the Summary of Product Characteristics. PATIENTS AND METHODS: Data were collected retrospectively from physicians in Germany, France, and the UK regarding patients (n=638) treated with incobotulinumtoxinA for aesthetic indications. Data on indication, treatment interval, dose injected, physician and patient satisfaction, and adverse drug reactions were recorded according to routine daily practice. RESULTS: Most patients (76.0%) received incobotulinumtoxinA for glabellar frown lines (GFL) and were given doses of <=20 U. The majority of treatment intervals were 5 months or longer. Overall, 64.1% of patients were treated for off-label indications, sometimes in combination with treatment for GFL. The most frequently treated off-label indications were horizontal forehead lines (38.6%) and/or crow's feet (CF; 31.7%); for CF, >95% of injected doses were <=24 U. In Germany, a smaller proportion of patients were given incobotulinumtoxinA treatment for CF (27.6%), compared with France (40.4%) and the UK (33.2%), although country-specific differences were less prominent when treatment cycle data for CF were examined. Treatment satisfaction among physicians and patients (overall, and for GFL specifically) was very high, with excellent tolerability and only one mild adverse drug reaction reported. CONCLUSION: In daily practice, incobotulinumtoxinA is mainly used for GFL; however, its use for CF and horizontal forehead lines (often in combination with GFL) is relatively common. Treatment satisfaction across aesthetic indications is high, and incobotulinumtoxinA is well tolerated, with time intervals of 5 months or longer between injections in the majority of cases. When considering factors such as dose and treatment interval, adherence to the Summary of Product Characteristics when treating GFL in daily practice is good. These results support previous reports that incobotulinumtoxinA is an effective treatment for GFL, with an excellent safety profile. Furthermore, incobotulinumtoxinA may display efficacy and tolerability in other indications. PMID- 25834464 TI - Comparison of acceptance and distraction strategies in coping with experimentally induced pain. AB - BACKGROUND: This study compared an acceptance-based strategy with a control-based strategy (distraction) in terms of the ability of participants to tolerate a painful stimulus, across two experiments. In addition, participants were either actively encouraged, or not, to link pain tolerance with pursuit of valued goals to examine the impact of pursuing a personally meaningful goal or value on the extent to which pain will be tolerated. METHODS: Participants in experiment 1 (n=41) and experiment 2 (n=52) were equally assigned to acceptance or distraction protocols. Further, half the participants in each group generated examples from their own lives in which they had pursued a valued objective, while the other half did not. In experiment 2, the values focus was enhanced to examine the impact on pain tolerance. RESULTS: There were no significant differences overall between the acceptance and distraction groups on pain tolerance in either experiment. However, in experiment 2, individuals classified as accepting in terms of general coping style and who were assigned to the acceptance strategy showed significantly better pain tolerance than accepting individuals who were in the distraction condition. Across both experiments, those with strong goal-driven values in both protocols were more tolerant of pain. Participants appeared to have more difficulty adhering to acceptance than to distraction as a strategy. CONCLUSION: Acceptance may be associated with better tolerance of pain, but may also be more difficult to operationalize than distraction in experimental studies. Matching coping style and coping strategy may be most effective, and enhancement of goal-driven values may assist in pain coping. PMID- 25834465 TI - The health insurance industry: perpetuating the opioid crisis through policies of cost-containment and profitability. PMID- 25834466 TI - Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials. AB - BACKGROUND: Despite advances with new therapies, a significant proportion of patients (>30%) suffer delayed-onset chemotherapy-induced nausea and vomiting (CINV) despite use of antiemetics. APF530 is a sustained-release subcutaneous (SC) formulation of granisetron for preventing CINV. APF530 pharmacokinetics, safety, and efficacy were studied in two open-label, single-dose Phase II trials (C2005-01 and C2007-01, respectively) in patients receiving moderately emetogenic chemotherapy or highly emetogenic chemotherapy. METHODS: In C2005-01, 45 patients received APF530 250, 500, or 750 mg SC (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg SC. Injections were given 30 to 60 minutes before single-day moderately emetogenic chemotherapy or highly emetogenic chemotherapy. Plasma granisetron was measured from predose to 168 hours after study drug administration. Safety and efficacy were also evaluated. RESULTS: APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single SC dose. Median time to maximum plasma concentration and half-life were similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving moderately and highly emetogenic chemotherapy. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (eg, erythema and induration) were predominantly mild and seen in <=20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in >=80% and >=75% of patients in both trials with the 250 and 500 mg doses, respectively. CONCLUSION: After a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and maintained therapeutic granisetron levels for >=5 days. PMID- 25834467 TI - Survey on appropriateness of use of nimesulide in nine European countries. AB - BACKGROUND: Appropriateness of use is a key factor in safeguarding patient's health as well as a product's therapeutic properties. This paper presents the results of a survey conducted in nine European countries to verify the appropriateness of use of nimesulide in patients with inflammatory pain. METHODS: Computer-aided telephone interviews were administered to 1,277 nimesulide prescribing general practitioners in Bulgaria, Czech Republic, Greece, Hungary, Italy, Poland, Portugal, Romania, and Slovakia, covering an estimated 31,719 patients. The interview questionnaire collected information on nimesulide prescriptions with respect to daily dose, treatment duration, and indication. RESULTS: In the majority of cases, prescriptions of nimesulide did not exceed the recommended daily dose of 200 mg (given as 100 mg twice a day), with a range from 161 mg (Greece) to 190 mg (Slovakia). An adherence to the 15-day treatment limit was observed in over 90% of cases. The average number of treatment days was always less than 15, with a range from 5.4 (Italy) to 13.6 (Czech Republic). Nimesulide was primarily used for the treatment of acute pain and short-term painful episodes in chronic conditions. The presence of gastrointestinal diseases/ulcers was the most frequent reason for not prescribing nimesulide. CONCLUSION: The results of this survey demonstrate that nimesulide is generally prescribed in compliance with the information reported in the summary of product characteristics (SmPC) with regard to daily dose and treatment duration, and suggest that it is mainly used for the management of episodes of acute pain in patients with a chronic disorder. These findings indicate the appropriateness of use of nimesulide in the European countries considered in this survey. PMID- 25834468 TI - Lack of facilities rather than sociocultural factors as the primary barrier to physical activity among female Saudi university students. AB - PURPOSE: The Kingdom of Saudi Arabia is experiencing a dramatic increase in physical inactivity, with women having higher levels of inactivity than men among all age groups. It is assumed that factors such as dress codes, restrictions on going outdoors, and conservative norms are the main reasons for women's low physical activity. Our aim was to explore the different parameters related to physical activity, including self-efficacy, as well as the perceived barriers to and benefits of physical activity in young Saudi females. PATIENTS AND METHODS: Ninety-four first-year female Saudi university students in Riyadh, Kingdom of Saudi Arabia, participated in the present study in 2014. The students were from eight bachelor's programs in health and well-being, and each completed a questionnaire with questions divided into five parts as follows: 1) socioeconomic status, 2) physical activity, 3) self-efficacy 4) social factors, and 5) barriers and facilitators related to physical activity. RESULTS: The students exercised at home and alone, and there was low self-efficacy for physical activity (mean score =42+/-14). Among social factors, attending university was the only factor that hindered physical activity (32%). Physical activity was positively perceived overall (mean score =131+/-10). Students showed awareness of the benefits of physical activity for health and well-being. The most important barrier was the lack of designated areas available for physical activity. Students disagreed that family or the Islamic community were barriers to physical activity. CONCLUSION: The lack of facilities and lack of encouragement from the university, but not a lack of knowledge (a high level of knowledge is to be expected given their health and well-being studies backgrounds) and/or restrictions from families and society, seem to hinder female students' physical activity, at least young Saudi students. PMID- 25834469 TI - Teacher Stress Inventory: validation of the Greek version and perceived stress levels among 3,447 educators. AB - BACKGROUND: The Teacher Stress Inventory (TSI) is an instrument for measuring occupational stress in teachers. This study aimed to translate and adapt it for use in Greece, and then assess its reliability and validity. METHODS: The Greek versions of the TSI and the 14-item Perceived Stress Scale (PSS-14) were posted on all Greek educators' official sites during May 2012. A nationwide sample of 3,447 teachers of all levels and specialties completed the questionnaires via the Internet. Reliability was determined by the calculation of Cronbach's alpha coefficient. Confirmatory factor analysis was conducted and validity was further examined by investigating the correlation of the TSI with the PSS-14 and their association with demographics and work-related factors. RESULTS: Satisfactory Cronbach's alpha values (above 0.70) were found for all TSI dimensions. Confirmatory factor analysis confirmed the two-factor construct of TSI (root mean square error of approximation, comparative fit index, and goodness-of-fit index values were 0.079, 0.956, and 0.951, respectively), confirming the pre established theory for the two latent variables, Stress Sources and Stress Manifestations. Significant correlations were found between TSI subscales, PSS-14 sex, age, lack of support, and students' difficulties. CONCLUSION: The Greek version of the TSI was found to have satisfactory psychometric properties, and its use for assessing stress in Greek teachers is warranted. PMID- 25834470 TI - The relationship between spiritual intelligence and personality traits among Jordanian university students. AB - This study was aimed at identifying the level of spiritual intelligence and its correlation with personality traits among a group of Jordanian undergraduate students. A purposive sample of 716 male and female students was chosen from different faculties at the Hashemite University. Two questionnaires on spiritual intelligence and personality traits were distributed to members of the sample during the academic year 2013-2014. Results illustrated a medium level of spiritual intelligence in students, and indicated a positive and statistically significant relationship between spiritual intelligence dimensions (critical existential thinking, personal meaning production, transcendental awareness, and conscious state expansion) and personality traits (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness), but no significant correlation between personal meaning production and transcendental awareness dimensions and neuroticism personality traits. Finally, regression analysis results indicate that critical existential thinking is the first predictor dimension of spiritual intelligence in terms of neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness. In the light of the results of this study, many recommendations were written by the researchers. PMID- 25834471 TI - Achieving optimal delivery of follow-up care for prostate cancer survivors: improving patient outcomes. AB - BACKGROUND: Prostate cancer is the most commonly diagnosed cancer in men in the US, and the second most prevalent cancer in men worldwide. High incidence and survival rates for prostate cancer have resulted in a large and growing population of long-term prostate cancer survivors. Long-term follow-up guidelines have only recently been developed to inform approaches to this phase of care for the prostate cancer population. METHODS: A PubMed search of English literature through August 2014 was performed. Articles were retrieved and reviewed to confirm their relevance. Patient-reported measures that were used in studies of long-term prostate cancer survivors (ie, at least 2 years posttreatment) were reviewed and included in the review. RESULTS: A total of 343 abstracts were initially identified from the database search. After abstract review, 105 full text articles were reviewed of which seven met inclusion criteria. An additional 22 articles were identified from the references of the included articles, and 29 were retained. From the 29 articles, 68 patient-reported outcome measures were identified. The majority (75%) were multi-item scales that had been previously validated in existing literature. We identified four main areas of assessment: 1) physical health; 2) quality of life - general, physical, and psychosocial; 3) health promotion - physical activity, diet, and tobacco cessation; and 4) care quality outcomes. CONCLUSION: There are a number of well-validated measures that assess patient-reported outcomes that document key aspects of long-term follow-up with respect to patient symptoms and quality of life. However, there are fewer patient-reported outcomes related to health promotion and care quality within the prevention, surveillance, and care coordination components of cancer survivorship. Future research should focus on development of additional patient centered and patient-related outcomes that enlarge the assessment portfolio. PMID- 25834472 TI - Exposing medical students to expanding populations. AB - Physicians are required to advocate for and counsel patients based on the best science and the interests of the individual while avoiding discrimination, ensuring equal access to health and mental services. Nonetheless, the communication gap between physician and patients has long been observed. To this end, the Institute for the Public Understanding of Health and Medicine of the Rutgers University New Jersey Medical School has expanded its efforts. This report describes two new programs: a legacy lecture series for medical students and an international "experience", in Huancayo, Peru, for medical students and faculty. The MiniMed outreach program, now in its ninth year and first described in this journal in 2012, was designed to empower the powerless to communicate more effectively with clinicians, thus improving both the effectiveness of the physician-patient relationship and health care outcomes. The approach of the two new programs and their effects on patients, particularly the underserved, and medical students and faculty, are outlined in the following article. PMID- 25834473 TI - Procedural skills practice and training needs of doctors, nurses, midwives and paramedics in rural Victoria. AB - INTRODUCTION: Procedural skills are a significant component of clinical practice. Doctors, nurses, midwives and paramedics are trained to use a variety of procedural skills. Rural clinicians in particular are often required to maintain competence in some procedural skills that are used infrequently, and which may require regular and repeated rehearsal. This paper reports on a research project conducted in Gippsland, Victoria, to ascertain the frequency of use, and relevance to clinical practice, of a range of skills in the fields of medicine, nursing, midwifery, and paramedic practice. The project also gathered data on the attitudes of clinicians regarding how frequently and by what means they thought they needed to practice these skills with a particular focus on the use of simulation as an educational method. METHODS: The research was conducted following identification of a specific set of procedural skills for each professional group. Skills were identified by an expert steering committee. We developed online questionnaires that consisted of two parts: 1) demographic and professional characteristics, and 2) experience of procedural skills and perceived training needs. We sought to invite all practicing clinicians (doctors, nurses, midwives, paramedics) working in Gippsland. Online surveys were distributed between November 2011 and April 2012 with three follow-up attempts. The Monash University Human Research Ethics Committee approved the study. RESULTS: Valid responses were received from 58 doctors, 94 nurses, 46 midwives, and 30 paramedics, whom we estimate to represent not more than 20% of current clinicians within these professions. This response rate reflected some of the difficulties experienced in the conduct of the research. Results were tabulated for each professional group across the range of skills. There was significant correlation between the frequency of certain skills and confidence with maintenance of these skills. This did not necessarily correlate with perceptions of respondents as to how often they need to practice each skill to maintain mastery. The more complex the skill, the more likely the respondents were to report a need for frequent rehearsal of the skill. There was variation between the professional groups as to how to retain mastery; for some skills, professional groups reported skill maintenance through clinical observation and clinical practice; for other skills, simulation was seen to be more appropriate. CONCLUSION: This project provided insight into the clinical application of procedural skills for clinicians comprising a relatively large professional population within a defined geographical region in rural Victoria, as well as attitudes to skills maintenance and competency. Although not the focus of the study, an unexpected outcome was the design of questionnaires on procedural skills. We believe that the questionnaires may have value in other rural settings. We acknowledge the limitations of the study in the text. The project provides some information on which to base planning for procedural skills education, including simulation-based training, and directions for further research. PMID- 25834474 TI - A new species of Lathrolestes Forster (Hymenoptera: Ichneumonidae) from Peruvian Amazonia. AB - Lathrolestesfiedleri sp. n. is described from Peru. This is the first record of the tribe and the genus for the country. PMID- 25834475 TI - Nine genera of Eucnemidae (Coleoptera) new to Peru, with a key to Peruvian genera. AB - Thirteen genera of Eucnemidae containing forty species were collected from the Iquitos region in Peru. Nine of the genera are new to the country: Rhagomicrus Fleutiaux, 1902, Adelorhagus Horn, 1890, Adelothyreus Chevrolat, 1867, Microrhagus Dejean, 1833, Dyscharachthis Blackburn, 1900, Heterotaxis Bonvouloir, 1871, Spinifornax Fleutiaux, 1926, Serrifornax Fleutiaux, 1926 and Maelodrus Fleutiaux, 1928. The previous eucnemid record from Peru contained eleven species in ten genera. Only one of the forty species caught, Entomophthalmusamericanus Bonvouloir, was previously known and described from the country. Dyscharachthis, Maelodrus and Adelorhagus are recorded from South America for the first time. Many of the collected species seem to favor white-sand forest as their habitat. Possible reasons for this are discussed. A list of eucnemids from Peru is included, containing taxa already recorded from the country and also taxa that are likely to occur there. A key to the Peruvian genera is included. PMID- 25834476 TI - Higgs decay into two photons in a warped extra dimension. AB - A detailed five-dimensional calculation of the Higgs-boson decay into two photons is performed in both the minimal and the custodially protected Randall-Sundrum (RS) model, where the Standard Model (SM) fields propagate in the bulk and the scalar sector lives on or near the IR brane. It is explicitly shown that the [Formula: see text] gauge invariance of the sum of diagrams involving bosonic fields in the SM also applies to the case of these RS scenarios. An exact expression for the [Formula: see text] amplitude in terms of the five-dimensional (5D) gauge-boson and fermion propagators is presented, which includes the full dependence on the Higgs-boson mass. Closed expressions for the 5D [Formula: see text]-boson propagators in the minimal and the custodial RS model are derived, which are valid to all orders in [Formula: see text]. In contrast to the fermion case, the result for the bosonic contributions to the [Formula: see text] amplitude is insensitive to the details of the localization of the Higgs profile on or near the IR brane. The various RS predictions for the rate of the [Formula: see text] process are compared with the latest LHC data, and exclusion regions for the RS model parameters are derived. PMID- 25834477 TI - Field sources in a Lorentz-symmetry breaking scenario with a single background vector. AB - This paper is devoted to an investigation of the interactions between stationary sources of the electromagnetic field, in a model which exhibits explicit Lorentz symmetry breaking due to the presence of a single background vector. We focus on physical phenomena that emerge from this kind of breaking and which have no counterpart in Maxwell electrodynamics. PMID- 25834478 TI - Registered nurses' descriptions of caring: a phenomenographic interview study. AB - BACKGROUND: Nursing has come a long way since the days of Florence Nightingale and even though no consensus exists it would seem reasonable to assume that caring still remains the inner core, the essence of nursing. In the light of the societal, contextual and political changes that have taken place during the 21st century, it is important to explore whether these might have influenced the essence of nursing. The aim of this study was to describe registered nurses' conceptions of caring. METHODS: A qualitative design with a phenomenographic approach was used. The interviews with twenty-one nurses took place between March and May 2013 and the transcripts were analysed inspired by Marton and Booth's description of phenomenography. RESULTS: The analysis mirrored four qualitatively different ways of understanding caring from the nurses' perspective: caring as person-centredness, caring as safeguarding the patient's best interests, caring as nursing interventions and caring as contextually intertwined. CONCLUSION: The most comprehensive feature of the nurses' collective understanding of caring was their recognition and acknowledgment of the person behind the patient, i.e. person-centredness. However, caring was described as being part of an intricate interplay in the care context, which has impacted on all the described conceptions of caring. Greater emphasis on the care context, i.e. the environment in which caring takes place, are warranted as this could mitigate the possibility that essential care is left unaddressed, thus contributing to better quality of care and safer patient care. PMID- 25834481 TI - Nanoscale Analysis of a Hierarchical Hybrid Solar Cell in 3D. AB - A quantitative method for the characterization of nanoscale 3D morphology is applied to the investigation of a hybrid solar cell based on a novel hierarchical nanostructured photoanode. A cross section of the solar cell device is prepared by focused ion beam milling in a micropillar geometry, which allows a detailed 3D reconstruction of the titania photoanode by electron tomography. It is found that the hierarchical titania nanostructure facilitates polymer infiltration, thus favoring intermixing of the two semiconducting phases, essential for charge separation. The 3D nanoparticle network is analyzed with tools from stochastic geometry to extract information related to the charge transport in the hierarchical solar cell. In particular, the experimental dataset allows direct visualization of the percolation pathways that contribute to the photocurrent. PMID- 25834480 TI - Tracheal and bronchial involvement in colitis ulcerosa - a colo-bronchitic syndrome? A case report and some additional considerations. AB - Systemic involvement is well known in patients with inflammatory bowel diseases (IBD), but there are only few data looking to Crohn's disease (CD) and ulcerative colitis (UC) separately instead of lumping together both entities to IBD. The frequency of bronchial involvement in UC is not yet exactly analysed but reported to be rare. We asked 100 patients with UC for bronchial complaints, and found in 13 patients a bronchial affection. From reports in the literature it is known that sometimes a bronchial involvement in patients with UC can affect the whole bronchial tree including small bronchi. The involvement of bronchial system in UC is obviously more prominent than previously thought and may fulfil the criteria for a separate syndrome. These relations may have consequences for pathogenetic understanding of UC as well as bronchitis and also consequences for treatment regimes. PMID- 25834482 TI - Examining the impact of changes in school tobacco control policies and programs on current smoking and susceptibility to future smoking among youth in the first two years of the COMPASS study: looking back to move forward. AB - BACKGROUND: School-based prevention activities continue to be an important tobacco control resource, however there is little guidance for school-based tobacco control programming within Ontario. The objective of this study is to identify real-world changes in school-based tobacco control programs or policies in the COMPASS study and examine of those interventions (natural experiments) had any impact on the school-level prevalence of smoking susceptibility and current smoking over time. METHODS: This paper uses longitudinal school-level smoking behaviour data from Year 1 (Y1: 2012-13) and Year 2 (Y2: 2013-14) of the COMPASS study. Changes to school-level tobacco control programs and policies were measured using the COMPASS School Programs and Policies Questionnaire and knowledge broker follow-up interviews. Quasi-experimental tests of proportion and difference-in-difference models were used to evaluate the impact of the interventions identified between Y1 and Y2 on school-level prevalence of smoking susceptibility among never smokers and current smoking. RESULTS: Between Y1 and Y2, 17 schools reported a change in their tobacco control programming or policies. In four of the intervention schools, the increase in the within-school prevalence of susceptible never smokers between Y1 and Y2 was significantly greater than the natural change observed in the control schools. In five of the intervention schools, the decrease in the within-school prevalence of current smokers between Y1 and Y2 was significantly greater than the natural change observed in the control schools. Only two of the new interventions evaluated (both focused on policies of progressive punishment for students caught smoking on school property), were associated with significant desirable changes in both smoking susceptibility and current smoking between Y1 and Y2. DISCUSSION: Interventions specific to effective and enforced tobacco control were the most common and consistently had the desired impact on the school-level prevalence of smoking susceptibility and current smoking. Due to the variation in the types of interventions implemented and their effectiveness, additional evaluation evidence is necessary to determine the most successful activities and contexts among individual students. The results presented here highlight which of these real world promising interventions should be further evaluated using the longitudinal individual-level data in COMPASS over time. PMID- 25834483 TI - Sero-prevalence of herpes simplex type 2 virus (HSV-2) and HIV infection in Kampala, Uganda. AB - BACKGROUND: Prevalence of herpes simplex type 2 virus (HSV-2) is high worldwide. Previous studies in Uganda were rural or in women. We estimated age and sex specific sero-prevalence of HSV-2 in Kampala, Uganda. METHODS: Using two-stage random sampling stratified on population density, a survey of persons 15-65 years was conducted. Type-specific serological tests for HSV-2, HSV-1(HerpeSelect2 and 1 ELISA), HIV (Rapid tests and ELISA), syphilis (RPR and TPHA) were done. Additional prevalence analysis included post-stratification weighting on the Uganda 2002 Census gender distribution. RESULTS: Among 1124 persons, HSV-2 prevalence was 58% (95% CI: 55, 60), HSV-1; 98% (95% CI: 97.6, 99.1), HIV; 17.7% (95% CI: 14.8, 19.2) and syphilis; 1.7% (95% CI: 1.4, 1.9). Weighted HSV-2 prevalence was 53.8% (Women; 63.8%, men; 43.2%), similar to unweighted data. Weighted HIV prevalence was 20.7% in women, 8.6% in men. Of 165 HIV infected persons, 85.4% had HSV-2. Risk factors for HSV-2 were being a woman (OR 2.0; 95% CI: 1.42, 2.78), age (OR 3.3; 95% CI: 2.43, 4.53), education (OR 1.70; 95% CI: 1.34, 2.34) and HIV (OR 4.5; 95% CI: 2.70, 7.50). CONCLUSION: Prevalence of HSV-2 and HIV was high especially in women. Syphilis was rare. Awareness of herpes was low. Interventions in young people are needed. PMID- 25834484 TI - Brucella sero-prevalence and modifiable risk factors among predisposed cattle keepers and consumers of un-pasteurized milk in Mbarara and Kampala districts, Uganda. AB - BACKGROUND: Brucellosis is an important zoonotic disease in developing countries yet it is often not recognized, goes unreported and does not attract public health action by these governments including Uganda. OBJECTIVE: To estimate the sero-prevalence and assess modifiable risk factors associated with Brucella seropositivity in cattle keepers and consumers of unpasteurized milk in Uganda. METHODS: One group comprised of 161 individuals randomly selected from households living on farms that had Brucella sero-positive cattle and/or goats in Mbarara District from an earlier survey; the second group comprised of 168 randomly selected individuals attending an HIV voluntary counseling and testing clinic in Kampala District. Sera samples were tested using Rapid Plate Agglutination Test, Standard Tube Agglutination Test and cELISA. RESULTS: The sero-prevalence of brucellosis among exposed cattle keepers in Mbarara and consumers of unpasteurised milk in Kampala Districts was 5.8% (95%CI: 3.3%, 8.3%) and 9% (95%CI: 13.3%, 4.7%), respectively. Consumption of unboiled milk was significantly (p=0.004) associated with seropositivity in Mbarara District. There was no association between sero-positivity with age, sex and awareness of human brucellosis. CONCLUSION: Human brucellosis is prevalent among livestock rearing communities and consumers of unpasteurised milk. The continued consumption of unboiled milk is a major health risk. PMID- 25834485 TI - Mean platelet volume in brucellosis: correlation between brucella standard serum agglutination test results, platelet count, and C-reactive protein. AB - BACKGROUND: Brucellosis, a zoonotic infection, was most widely diagnosed by the Brucella standard serum agglutination test (SAT). No previous publication has demonstrated a correlation between the degree of Brucella SAT agglutination positivity and the severity of brucellosis infection. OBJECTIVE: To contribute to the clarification of the relationship between patelets and brucellosis. It is also aimed at evaluating the usefulness of the SAT titer as a measure of brucellosis severity. MATERIAL AND METHODS: We compared the control (n=60) and patients (n=96) groups in terms of mean platelet volume (MPV), C-reactive protein (CRP) and platelet values. Patients were grouped according to their degree of agglutination positivity titers and compared by means of CRP, MPV and platelet values. We also investigated the relationship among logarithmic values of MPV, platelet and CRP parameters for each group. RESULTS: Although statistically meaningful difference was observed between control and patients group in terms of MPV and platelet value, there were no statistically significant differences observed among patients groups. The physiological negative correlation between MPV and platelet count was not encountered in group 2 and 3. Logarithmic values of CRP were not correlated with logarithmic values of MPV and platelet counts. CONCLUSION: The MPV could be a new parameter to evaluate hematologic abnormalities in patients with brucellosis. The SAT titer was not a useful measure for evaluation of the severity of brucellosis. PMID- 25834486 TI - Pattern of pathogens from surgical wound infections in a Nigerian hospital and their antimicrobial susceptibility profiles. AB - BACKGROUND: In surgical patients, infection is an important cause of morbidity and mortality. A prospective study to find the pattern of microorganisms responsible for post operative wound infections and their antibiotic susceptibility profile was therefore conducted. SETTING AND METHODS: Surgical wards in Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria. Isolation, identification and antimicrobial susceptibility screening of organisms were done employing standard microbiological techniques. RESULTS: Bacterial pathogens were isolated from all the specimens while the yeast Candida species (spp) was isolated from 12.4%. Staphylococcus aureus was the most frequent organism isolated accounting for 23 (18.3%) of a total of 126 isolates. Other organisms were Pseudomonas aeruginosa and Bacillus spp 11.1% each; Escherichia coli 10.3%; Candida spp 8.7%; Coagulase negative staphylococci 8.7%; Pseudomonas spp 6.3%; Serratia odorifera 4.7%; Bacteroides 4.0%; Enterococcus spp 3.2%; the remaining isolates were other enterobacteria. Sensitivity of the bacterial isolates to antibiotics varied. In general, resistance to the beta-lactam antibiotics was above 98%, whilst more than 70% of isolates were resistant to erythromycin, fusidic acid and tobramycin. CONCLUSIONS: The infections were polymicrobic and multidrug resistant. The quinolones, ciprofloxacin and ofloxacin, should be used as frontline drugs in the management of surgical wound infections at the hospital. PMID- 25834487 TI - Epidemiology of hepatitis C viral infection in Faisalabad, Pakistan: a retrospective study (2010-2012). AB - BACKGROUND: Hepatitis viral infections are major health challenge leading to high morbidity and mortality worldwide. OBJECTIVES: Although the magnitude of hepatitis in Pakistan has been well documented, information regarding the prevalence of hepatitis C virus (HCV) infection in Faisalabad, Pakistan is scarce. The present retrospective study was undertaken to determine the epidemiology of HCV in Faisalabad, Pakistan. METHODS: Between May, 2010 and December, 2012, medical records of 39780 subjects visiting sexually transmitted infections (STIs) clinic, district headquarter (DHQ) hospital, Faisalabad, Pakistan were reviewed. Regression analysis was used to determine independent risk factors. RESULTS: HCV prevalence was 21.99%. With mean age of 49.5 +/- 2.7 years (range 27-63 years), majority (67.15%) of the individuals were male. Marital status and low literacy rates were associated with HCV (P<0.05). Reference to the potential risk factors, the injection drug use was the major mode (72.77%) of infection transmission. Age (OR 1.5, 95% CI 1.2-1.9), male gender (OR 1.2, 95% CI 0.9-1.6) and injection use (OR 1.9, 95% CI 1.0-2.7) were significantly associated with HCV. CONCLUSIONS: Most important finding was higher HCV prevalence in Faisalabad region as compared to the previous assessments that demands an urgent need for preventive intervention strategies. PMID- 25834488 TI - Comparison of HCV core antigen and anti-HCV with HCV RNA results. AB - BACKGROUND: The measurement of anti-HCV antibodies using immunological methods and the confirmation of viral nuclear acid based on molecular methods is important in diagnosis and follow-up of the HCV infection. OBJECTIVES: In this study, we aimed to analyse HCV core Antigen positivity among anti-HCV antibody positive sera to determine the significance of testing of HCV core Ag for the laboratory diagnosis of HCV infection, by considering the correlation between serum HCV core Ag and HCV RNA levels. METHODS: 115 patients suspected of having hepatitis C and who were positive for anti-HCV antibody were investigated using chemiluminescent and molecular methods. Anti-HCV antibody, HCV core Ag and HCV RNA levels were detected by the Vitros ECiQ immunodiagnostic system, Architect i2000 system and RT-PCR, respectively. RESULTS: The sensitivity, specificity, positive and negative predictive values and accuracy rate of HCV core Antigen assay were detected as 86.5%(83/96), 100%(19/19), 100%(83/83), 59.4%(19/32), 88.7%(102/115) respectively. CONCLUSION: HCV core Ag assay could be used for diagnosis of HCV infection as it is easy to perform, cost-effective, has high specificity and positive predictive value. However, it should be kept in mind that it may have lack of sensitivity and negative predictive value. PMID- 25834489 TI - Resistant plasmid profile analysis of multidrug resistant Escherichia coli isolated from urinary tract infections in Abeokuta, Nigeria. AB - BACKGROUND: Multi-drug resistant Escherichia coli has become a major threat and cause of many urinary tract infections (UTIs) in Abeokuta, Nigeria. OBJECTIVES: This study was carried out to determine the resistant plasmids of multidrug resistant Escherichia coli isolated from (Urinary tract infections)UTIs in Abeokuta. METHODS: A total of 120 Escherichia coli isolates were obtained from urine samples collected from patients attending inpatient and outpatient clinics presenting UTI; with their biodata. Antibiotics susceptibility was performed and multi-drug resistant isolates were selected for plasmid profiling. Plasmids were extracted by the alkaline lysis method, electrophoresed on 0.8% agarose gel and profiled using a gel-photo documentation system gel. RESULTS: Escherichia coli isolates obtained shows high resistance to cloxacillin (92.5%), amoxicillin (90.8%), ampicillin (90.8%), erythromycin (75.8%), cotrimoxazole (70.0%), streptomycin (70.0%) and tetracycline (68.3%) while 85.8% and 84.2% were susceptible to gentamycin and ceftazidime respectively. Sixteen Escherichia coli strains were observed to be resistant to more than two classes of antibiotics. The resistant plasmid DNA was detectable in 6(37.5%) of the 16 multidrug resistant Escherichia coli having single sized plasmids of the same weight 854bp and were all resistant to erythromycin, cefuroxime, cloxacillin, amoxicillin, ampicillin and cotrimoxazole. CONCLUSION: This study has highlighted the emergence of multidrug resistant R-plasmids among Escherichia coli causing urinary tract infections in Abeokuta, Nigeria. There is a high level of resistance to many antimicrobials that are frequently used in Abeokuta, Nigeria. PMID- 25834490 TI - The utility of the Helicobacter pylori stool antigen test in managing dyspepsia: an experience from a low resource setting. AB - BACKGROUND: Dyspepsia is defined as a chronic or recurrent pain or discomfort centered in the upper abdomen. Endoscopy is the best strategy for confirming the cause of dyspepsia. Non- invasive strategies would be more appropriate in low resource countries where endoscopy is not readily available. However, there is concern that these strategies may miss serious disease like gastric cancer. One test that needs to be assessed in this regard is the Helicobacter pylori stool antigen test (HPSAT). OBJECTIVE: To determine the validity of the stool antigen test in predicting H. pylori associated disease among patients with dyspepsia. METHODS: In this prospective study patients with dyspepsia attending Mulago Hospital were recruited consecutively. Helicobacter pylori was determined using the Rapid Strip HpSA (r), endoscopy and gastric mucosal biopsy were done. RESULTS: 167 patients with dyspepsia were recruited into the study. There were ninety six (57.5%) females and seventy one (42.5%) males with an average age of 48.1(+/-18.1) years. Patients presenting with dyspepsia in Mulago hospital were more likely to come from the Central 60 (36%) and western tribes 55 (33%). The commonest endoscopic finding was oesophagitis 25 (15%). Peptic ulcer disease was found in 32 (19.2%) and 54 (32.3%) had normal endoscopy findings. H pylori was found in 33.5% and 32.5% using the HPSAT and histology respectively. The validity of the HPSAT in predicting H.pylori associated diseases was generally low with an overall sensitivity of 55.8%, and specificity of 74.2%. However, the validity was higher in predicting the diagnosis of peptic ulcer disease with a sensitivity 59.4% and specificity 72.6%. CONCLUSION AND RECOMMENDATIONS: The HPSAT may be used in the test and treat strategy for young patients with dyspepsia without alarm signs and symptoms in low resource settings. However, because of its low validity in predicting H.pylori associated disease, it is important to follow up patients so that if symptoms persist or recur endoscopy is performed. PMID- 25834491 TI - Risk factors for candida infection of the genital tract in the tropics. AB - OBJECTIVE: To investigate the risk factors associated with candida infection of the genital tract in the tropics. METHODS: We performed questionnaire survey and experiments at the Hainan branch of General Hospital of People's Liberation Army, Hainan General Hospital and Sanya Maternity and Child Health Care Hospital in 2013. Controls were without Candida infection of genital tract, and cases had from Candida infection. RESULTS: We recruited 689 cases and 652 controls. The average age of cases with Candida infection of the genital tract was higher than that of controls. In the multivariate modeling, marriage (adjusted odds ratio: 2.49, 95% confidential interval: 1.09-5.67) and vaginal lavage (adjusted odds ratio: 4.41, 95% confidential interval: 1.13-5.14) were significantly associated with Candida infection of genital tract in tropics. CONCLUSION: Candida infection was related with age. Marriage and Vaginal lavage were significant risk factors. Attention should be paid to health education for the prevention of these infections. PMID- 25834492 TI - Assessment of antibacterial activity of crude leaf and root extracts of Cassia alata against Neisseria gonorrhea. AB - BACKGROUND: Gonorrhea is a major sexually transmitted disease worldwide and for its control, effective treatment is essential. However as more strains of Neisseria gonorrhoeae continuously develop resistance to several drugs, this strategy obliges scientists to discover newer effective drugs. OBJECTIVES: To ascertain whether crude leaf and root extracts of Cassia alata (Caesalpiniaceae) have antimicrobial activity against clinically resistant Neisseria gonorrhoeae bacteria. To determine and compare the MICs of their ether and methanol extracts. MATERIALS AND METHODS: Ether and methanol extracts were prepared from the plant parts. 12-375mg/ml of serially diluted ether extracts in DMSO and methanol extracts in water were tested using agar-well diffusion method against Neisseria gonorrhea clinical isolate cultured on MTM agar. MICs were determined from corresponding concentration-response curves. Ceftriaxone was used as positive control, whereas DMSO and water as negative controls. RESULTS: All the crude extracts showed concentration-dependent Neisseria gonorrhea inhibition. Ether extracts for both leaves and roots gave lower MICs compared to those of methanol. Ether root extract showed the highest potency. CONCLUSIONS: Both the leaf and the root of Cassia alata plant have activity against clinically resistant Neisseria gonorrhoeae; the root having the higher activity. Lipophilic solvent, ether, give more potent antigonorrhoeal extracts. As expected Cassia alata plant in Central Uganda also has antibacterial activity. PMID- 25834493 TI - Mortality associated with tuberculosis/HIV co-infection among patients on TB treatment in the Limpopo province, South Africa. AB - BACKGROUND: South Africa has a high tuberculosis burden, and Limpopo Province experienced higher than national average TB mortality rates between 1997 and 2008. OBJECTIVE: To establish factors associated with TB mortality in Limpopo Province in 2008. DESIGN: Retrospective study using provincial data for patients who died after commencing TB treatment between 01 January 2008 and 31 December 2008. RESULTS: In 2008, some 18074 patients started treatment: 15995 (88.5%) had pulmonsry TB (PTB), while 2079 (11.5%) had Extra pulmonary TB (EPTB). Overall, 2242 (12.4%) patients died, mainly PTB patients (n=1906; 85%), more males (n=1159, 51.7%), mainly those aged 25 to 54 years (n=1749, 78.0%), and new cases (1914; 85.4%). TB mortality was significantly higher among smear negative than smear positive patients (17% vs 13.8%; P<0.001), among those with EPTB compared to PTB patients (P<0.001), and among re-treatment cases (P<0.001). Only 4237 (23.4%) patients had HIV status known, with higher mortality found among HIV positive than the HIV negative patients (P<0.0001); but HIV status was not known for the majority who died (n=1685, 75.2%). CONCLUSION: Higher mortality was associated with age 22-55 years; smear negativity, EPTB, HIV infection, and re treatment. The findings call for greater integration of TB control efforts and HIV services, especially among the 22-55 year age group. PMID- 25834494 TI - Socio-demographic factors affecting knowledge level of Tuberculosis patients in Rajshahi City, Bangladesh. AB - BACKGROUND: The Tuberculosis (TB) control program in Bangladesh is still unsatisfactory due to insufficient knowledge and stigma about TB. Patients with low knowledge may be at higher risk of experiencing delays in diagnosis and appropriate treatment. OBJECTIVES: The aims of this study were to identify the knowledge levels of TB and investigate the factors associated with knowledge level among the TB patients in Bangladesh. METHODS: A cross-sectional study was conducted at Rajshahi City, Bangladesh. A total of 384 TB patients were interviewed through a pretested, structured questionnaire using purposive sampling techniques. Logistic regression analysis was used to evaluate the effects of selected socio-demographic factors on TB knowledge level. RESULTS: The results revealed that pulmonary TB patients had greater knowledge than that of extra-pulmonary patients, and that sex, age, educational status and TB type were significantly associated with knowledge level. CONCLUSIONS: In general, males and young adults, ages 21-35, had greater awareness about transmission and prevention of TB than females and adults over 35. Individuals with higher education and urban area patients were comparatively better informed about TB infection. Patients with greater knowledge about TB were also less likely to experience delays in seeking treatment. PMID- 25834495 TI - Effectiveness of a home-based pulmonary rehabilitation programme in pulmonary function and health related quality of life for patients with pulmonary tuberculosis: a pilot study. AB - BACKGROUND: Patients with Pulmonary Tuberculosis (PTB) often develop impairment in pulmonary function due to anatomical changes secondary to the illness. Physiotherapy in the form of pulmonary rehabilitation has been advocated. OBJECTIVE: The aim of the study was to determine whether adherence to a six-week home-based pulmonary rehabilitation programme (PRP) improved the baseline measurements of lung function, exercise tolerance and health-related quality of life (HRQoL) in patients receiving out-patient treatment for PTB. METHOD: A single blinded randomized control study design was used to assess the effects of a six-week home- based PRP in patients receiving treatment for PTB at a local clinic in Khayelitsha, Western Cape. We evaluated lung function by spirometry (MINATO AUTOSPIRO-model no. AZ-505), exercise tolerance using the 6-min-walk test (6MWT), the Borg exercise exertion scale and HRQoL using the EQ-5 D questionnaire in an intervention group (n=34) and a control group (n=33). The trend of the effects of the PRP on lung function was towards increases, but there was no statistical difference between the intervention and control groups at the end of the sixth week in the values of FVC (p=0.2; 95% CI -0.9 to 0.51) as well as FEV1 (p=0.1; 95% CI -0.07 to 0.51). Similar trend was observed for exercise tolerance, and there was no significant difference in HRQoL (p=0.789). CONCLUSION: The outcome of the study provides motivation for further consideration and implementation of a pulmonary rehabilitation programme for patients with PTB. PMID- 25834496 TI - Evaluation of cases with a preliminary diagnosis of Crimean- Congo hemorrhagic fever and comparison of characteristics in patients admitted to a secondary care hospital in Kastamonu, Turkey. AB - BACKGROUND: Crimean-Congo hemorrhagic fever (CCHF) is an endemic disease in Turkey. The clinical presentation and laboratory findings are not specific especially in cases without hemorrhagic findings. OBJECTIVE: We aimed to evaluate CCHF cases and compare them with non-CCHF cases in terms of their characteristics during admission. METHODS: Cases with a preliminary diagnosis of CCHF at a secondary care hospital in Kastamonu in 2013 were evaluated, retrospectively. Cases testing RNA/IgM positive were considered as CCHF. Cases testing both RNA and IgM negative were considered as non-CCHF. The two groups were then compared in terms of their clinical, laboratory and epidemiological characteristics during admission. RESULTS: A total of 41 cases were tested and CCHF was found in 46.3% of cases. Fatality was 5.3% in CCHF cases. The frequency of tick bites and CK elevation in CCHF cases was significantly higher than non-CCHF cases (p<0.05). There were no significant differences between the two groups regarding other characteristics (p>0.05). CONCLUSIONS: In cases with a preliminary diagnosis of CCHF, especially in cases without a history of tick bite and with normal CK levels during admission, performing tests for the differential diagnosis may be advisable without waiting for the results of tests for CCHF. PMID- 25834497 TI - Tackling malaria, village by village: a report on a concerted information intervention by medical students and the community in Mifumi, Eastern Uganda. AB - BACKGROUND: Can an information intervention facilitated by information technology and carried out by an interdisciplinary team comprising medical students, technical experts, and the community itself make a positive contribution in reducing the burden of malaria at the village level? In Mifumi village in Eastern Uganda, MIFUMI Project, Makerere University College of Health Sciences Community Based Education and Service program (COBES), and the U.S. National Library of Medicine carried out a series of activities between 2007 and 2010. METHODS: The team surveyed the community's knowledge of malaria prevention and treatment; implemented a health information intervention using tutorials in a variety of media; and observed the community's use of previously distributed insecticide treated nets (ITNs) using a digital pen application. RESULTS: As a result of concerted education and outreach, the village residents have a good understanding of malaria prevention and treatment seeking behaviors. Leveraging the power of information technology and interdisciplinary teamwork, medical students and the denizens of a rural community were able to engage in an interactive experience of health education and promotion. CONCLUSION: Preliminary observations suggest that a health information intervention in concert with a collaborative community effort of education and prevention can build capacity within a community to take control of its own health. PMID- 25834498 TI - Does the national program of prevention of mother to child transmission of HIV (PMTCT) reach its target in Ouagadougou, Burkina Faso? AB - BACKGROUND: In the context of universal access to prevention, treatment, care and support, each country has to ensure that 80% of women and children in need have access to PMTCT interventions. OBJECTIVE: To assess the PMTCT program achievement in Ouagadougou, the capital city of Burkina Faso. METHODS: Between August and October 2008, a cross sectional study was carried out in the five health districts of the Centre Health Region. We reviewed weekly statistics from all health care centres (HCC) to compute the coverage of PMTCT program. In 38 HCC with functional PMTCT program, we extracted data of interest from HCC registers and made direct observations of PMTCT services. RESULTS: The PMTCT program was implemented in 49% of HCC (target for the national program: 70%). Fifteen to 31% of these centers were often in shortage for PMTCT consumables. Patients' privacy was not observed in 67% of Voluntary Counselling & HIV Testing wards. Care providers were not qualified enough to deliver PMTCT services. Vitamin A supplementation was not implemented. None of the facilities offered the whole package of PMTCT program interventions. HCC providing HIV testing in labour or in postnatal ward were consistently lacking. Only 86% of antenatal care new attendants benefited from pre-test counselling; 2.4% of pretested women were HIV positive and 39% of positive mothers received antiretroviral prophylaxis. CONCLUSION: Coverage and quality of PMTCT programme in the Centre Health Region in Burkina Faso are still limited. Particular support is needed for training, supervision and infrastructures upgrading. PMID- 25834499 TI - Vancomycin-resistant enterococci colonization in patients with hematological malignancies: screening and its cost-effectiveness. AB - BACKGROUND AND OBJECTIVE: We evaluated the rates of vancomycin-resistant enterococci (VRE) colonization and VRE-related bacteremia in patients with hematological malignancies in terms of routine screening culture and its cost effectiveness. MATERIALS AND METHODS: All patients of the hematology department who were older than 14 years of age and who developed at least one febrile neutropenia episode during chemotherapy for hematological cancers between November 2010 and November 2012 were evaluated retrospectively. RESULTS: We retrospectively analyzed 282 febrile episodes in 126 neutropenic patients during a two-year study period. The study included 65 cases in the first study-year and 78 cases in the second study-year. The numbers of colonization days and colonized patient were748 days of colonization in 29 patients (44%) in the first study-year and 547 colonization days in 21 patients (26%) in the second study-year, respectively. Routine screening culture for VRE cost $4516,4 (427 cultures) in the first study-year, $5082,7 (504 cultures) in the second study-year depending on the number of patients and their length of stay. CONCLUSION: In line with our study results, routine screening of hematological patients for VRE colonization is not costeffective. Routine surveillance culture for VRE should be considered with respect to the conditions of health care setting. PMID- 25834500 TI - Blood pressure and heart rate adjustment following acute Frenkel's ambulatory exercise in chronic hemiparetics stroke survivors: a comparative study. AB - BACKGROUND: Frenkel's ambulatory activity has been routinely employed by physiotherapists for rehabilitation of gait coordination, however, its immediate influence on blood pressure and heart rate has not been investigated. OBJECTIVE: To investigate the acute effect of Frenkel's ambulatory activity on blood pressure and heart rate of chronic hemiparetic stroke survivors. METHOD: Using a comparative study design, 60 chronic hemiparetic stroke survivors of varying onset of stroke, <=6, >6-11 and >=12 months were subjected to a 2-minute Frenkel's ambulatory activity on marked footsteps (from standard adult described footsteps). Participants were assessed for both blood pressure and heart rate before and after the Frenkel's ambulatory activity. RESULTS: Blood pressure and heart rate significantly increased (p<0.05) following Frenkel's ambulatory activity in all the 3 categories of stroke onset above baseline. However, there was no significant difference (p>0.05) across the onsets in both blood pressure and heart rate responses. CONCLUSION: The outcome of this study indicated that Frenkel's ambulatory activity has the propensity to increase blood pressure and heart rate of hemiparetic stroke survivors irrespective of the onset of stroke. We recommend a pre, within and post-activity monitoring of stroke survivors while subjecting them to Frenkel's ambulatory activity. PMID- 25834501 TI - Serum HE4 is more suitable as a biomarker than CA125 in Chinese women with benign gynecologic disorders. AB - OBJECTIVE: This study measured the human epididymis protein 4 (HE4) and CA125 levels in Chinese women with benign gynecological disorders. MATERIAL AND METHODS: Sera were obtained from Chinese women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with HE4 and CA125 levels were compared. RESULTS: There were 68 Chinese women with benign diseases. HE4 levels were less elevated than CA125 (1% V.S. 29%, P<0.001). The significant difference was observed in patients with endometriosis/endometriomas in which HE4 was not elevated patients and CA125 was elevated in 53% (P<0.001). Serum HE4 level was not elevated in patients with cystadenoma (0% V.S. 23%, P<0.001) and in patients with germ cell tumors (0% V.S. 5%, P<0.001). CONCLUSION: HE4 was less elevated and more suitable as a biomarker than CA125 in chinese women with benign disease. PMID- 25834502 TI - Association between mean platelet volume levels and inflammation in SLE patients presented with arthritis. AB - BACKGROUND: Systemic lupus erythematosus (SLE) may be characterized by periods of remissions and chronic or acute relapses. The complexity of clinical presentation of the SLE patients leads to incorrect evaluation of disease activity. Mean platelet volume (MPV) has been studied as a simple inflammatory marker in several diseases. There is no study in the literature about MPV levels in adult SLE patients with arthritis. OBJECTIVES: We aimed to investigate the MPV levels in the SLE population with arthritis during and between activations. METHODS: The study consisted of 44 SLE patients with arthritis in activation period (Group 1), the same 44 SLE patients with arthritis in remission period (Group 2) and 44 healthy controls (Group 3). Erythrocyte sedimentation rate (ESR), creactive protein (CRP), white blood cell count, platelet count, and mean platelet volume (MPV) levels were retrospectively recorded from patient files. RESULTS: The mean ages of the SLE subjects were 42 +/- 16 years, while the mean ages of controls was 41 +/- 17 years. MPV was significantly lower in Group 1(7.66+/-0.89fL) than in Group 2 (8.61+/-1.06 fL) and Group 3(8.62+/-1.11fL) (p<0.0001). The differences between groups reached statistical significance. CONCLUSIONS: We suggest that MPV levels decrease in patients with arthritis of SLE activation when compared to the same patients in remission and healthy controls. PMID- 25834503 TI - Explanation of colon cancer pathophysiology through analyzing the disrupted homeostasis of bile acids. AB - BACKGROUND: The colon plays a key role in regulating the homeostasis of bile acids. AIM: The present study aims to evaluate the influence of colon cancer towards the homeostasis of bile acids. METHODS: The free and conjugated bile acids were determined using ultraperformance LC (UPLC) coupled with ABI 4000 QTRAP triple quadrupole instruments. RESULTS: The results showed that the free bile acids in serum of patients with colon cancers tend to increase, and the conjugated bile acids tended to decrease, especially for taurolithocholate (TLCA) (p<0.001). CONCLUSION: The alteration of bile acids balance in colon cancers indicated the possibility of complicated diseases due to the disrupted balance of bile acids. PMID- 25834504 TI - The association between dyslipidemia and anthropometric indicators in black and white adolescents residing in Tlokwe Municipality, North-West Province, South Africa: the PAHL study. AB - BACKGROUND: The dyslipidemia associated with excess weight is a risk for cardiovascular disease. Worldwide and in South Africa adolescent obesity has been reported. OBJECTIVES: To determine the association between dyslipidemia and anthropometric indices in black and white adolescents. METHODS: The study involved 129 black and 69 white adolescents aged 12 to 16 years. Data collected included height, weight, waist circumference (WC) and skinfolds, blood pressure and blood for glucose, insulin, total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides (Trig) and C - reactive protein (CRP). RESULTS: WC correlated negatively with HDL in both blacks (p=0.042) and whites (p=0.008) and in whites it correlated positively with LDL (p=0.006); TC/HDL (p=<0.001) and LDL/HDL ratio (p<0.0001). WC/Hgt correlated negatively with HDL (p=0.028) and positively with LDL/HDL (p=0.026 and p<0.0001) in both races. In whites positive correlations were between WC/Hgt and TC (p=0.049); LDL (p=0.003) and TC/HDL (p<0.0001). BAZ correlated positively with TC/HDL ratio (p=0.004) and LDL/HDL ratio (p=0.002). The most common abnormalities were HDL and LDL. CONCLUSION: Whites exhibited more associations between dyslipidemia and anthropometric indicators as compared to Blacks, suggesting that there might be differences in the lipid metabolism or even susceptibility to risk factors in adolescents. PMID- 25834505 TI - Demographic profile of patients diagnosed with intracranial meningiomas in two academic hospitals in Johannesburg, South Africa: a 12-month prospective study. AB - BACKGROUND: Meningiomas are common brain tumours and display gender, racial and ethnic differences in their demographic profile. The demographic profile of our patients diagnosed with intracranial meningiomas is presented and compared with the literature. OBJECTIVES: To determine the age, gender, racial and ethnic distribution of our patients diagnosed with intracranial meningiomas. METHODS: Consecutive patients (48 in number) seen at Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) and Chris Hani Baragwanath Academic Hospital (CHBAH), Johannesburg, with histologically proven meningiomas over a 12 month period were recruited for the study. RESULTS: Meningiomas accounted for 33.8% of all primary brain tumours. The mean age of patients was 45.7 +/- 10.5 years with a female-to male ratio of 3.8:1. The mean age for male patients was 39.3 +/- 13.5 years while that of female patients was 47.4 +/- 9.0 years. The peak age range at presentation was in the fifth (41.7%) decade. The highest frequency was among Black Africans (75%) and Sotho ethnic nationality (27.1%). CONCLUSION: The study showed a female preponderance for intracranial meningiomas among our patients. Although intracranial meningiomas were more in frequency among Black Africans, the racial distribution mirrored our population distribution while the highest frequency was among Sotho ethnic nationality. PMID- 25834506 TI - Outcome of patients undergoing open heart surgery at the Uganda heart institute, Mulago hospital complex. AB - BACKGROUND: Heart disease is a disabling condition and necessary surgical intervention is often lacking in many developing countries. Training of the superspecialties abroad is largely limited to observation with little or no opportunity for hands on experience. An approach in which open heart surgeries are conducted locally by visiting teams enabling skills transfer to the local team and helps build to build capacity has been adopted at the Uganda Heart Institute (UHI). OBJECTIVES: We reviewed the progress of open heart surgery at the UHI and evaluated the postoperative outcomes and challenges faced in conducting open heart surgery in a developing country. METHODS: Medical records of patients undergoing open heart surgery at the UHI from October 2007 to June 2012 were reviewed. RESULTS: A total of 124 patients underwent open heart surgery during the study period. The commonest conditions were: venticular septal defects (VSDs) 34.7% (43/124), Atrial septal defects (ASDs) 34.7% (43/124) and tetralogy of fallot (TOF) in 10.5% (13/124). Non governmental organizations (NGOs) funded 96.8% (120/124) of the operations, and in only 4 patients (3.2%) families paid for the surgeries. There was increasing complexity in cases operated upon from predominantly ASDs and VSDs at the beginning to more complex cases like TOFs and TAPVR. The local team independently operated 19 patients (15.3%). Postoperative morbidity was low with arrhythmias, left ventricular dysfunction and re operations being the commonest seen. Post operative sepsis occurred in only 2 cases (1.6%). The overall mortality rate was 3.2. CONCLUSION: Open heart surgery though expensive is feasible in a developing country. With increased direct funding from governments and local charities to support open heart surgeries, more cardiac patients access surgical treatment locally. PMID- 25834507 TI - Mucin as possible cause of early adhesional intestinal obstruction. AB - OBJECTIVES: To report the case of a 24 year old female undergraduate who presented with bowel obstruction, three weeks following the excision of a mucinous ovarian cyst. PATIENT AND METHODS: The records of the patients past and recent medical history laboratory and imaging studies were reviewed. RESULTS: Clinical findings of a distended and a plain abdominal radiogram showing distended loops of bowel(Figure 2) were in keeping with acute bowel obstruction. This was confirmed by the intraoperative finding of fibrous encasement of small bowel. This was excised ,and 12months thereafter, patient has remain in good health. Figure 2Preoperative A-P abdominal X-ray in erect position showing small distension. CONCLUSION: Early and absolute adhesional bowel obstruction from abdominal surgery is failing conservative management rate. We attributed this to the ruptured mucinous cyst in our earlier operation. We therefore suggest that should a rupture cyst of this type occurs during a surgical procedure, any of the preventive methods discussed should be tried as a prophylactic measure. PMID- 25834508 TI - Unmet social needs and teenage pregnancy in Ogbomosho, South-western Nigeria. AB - BACKGROUND: Consistent high teenage pregnancy rates in South-western Nigeria are characteristically underpinned by the unmet social needs of the teenagers. OBJECTIVE: To elicit intergenerational views on the influence of unmet social needs on teenage pregnancy. METHODS: Through a descriptive and cross-sectional design, a total of 174 respondents who were either pregnant teenagers, teenage mothers during the survey or had been pregnant as teenagers, were interviewed, using questionnaire supplemented with 12 key informant interviews. RESULTS: With the mean age of 16.5 years, and educational status range of between primary and below (25.8%) and tertiary (9.8%) levels, only 39.7% respondents were married, about half (47.7%) remained single while others were separated (12.6%). Less than half (44.9%) of the respondents were engaged in occupational activities. The unmet material and financial supports expected from parents (43.1%), the lack of free education from government up till secondary school level (51.2%), the lack of sex education and knowledge needs for signs of maturity (53.4%) and discouragement from friends not to have boyfriend (66.1%) prone teenagers to unplanned pregnancy. CONCLUSION: Promotion of sexual education and parental care is encouraged as strategy against unplanned pregnancy among teenagers. PMID- 25834509 TI - Hypercholesterolaemia in pregnancy as a predictor of adverse pregnancy outcome. AB - BACKGROUND: Prevention of viable spontaneous preterm birth and low birth weight through screening is one of the key aims of antenatal care as these have implications for the child, mother and society. If women can be identified to be at high risk of these adverse birth outcomes in early pregnancy, they can be targeted for more intensive antenatal surveillance and prophylactic interventions. OBJECTIVES: This study is therefore aimed to determine the association between elevated maternal serum cholesterol level in pregnancy and adverse pregnancy outcome. METHODS: It was a prospective observational cohort study in which eligible participants were enrolled at gestational age of 14 to 20 weeks. Blood samples were obtained to measure total serum cholesterol concentrations and the sera were then analyzed enzymatically by the cholesterol oxidase: p-aminophenazone (CHOD PAP) method. Pregnancy outcomes were obtained by extraction from medical records and the labour ward register. RESULTS: The incidences of the two adverse pregnancy outcomes examined in the study (preterm births and low birth weight (LBW) in term neonates) were 8.0% and 14.4% respectively. Preterm birth was 6.89-times more common in mothers with high cholesterol than in control mothers with normal total cholesterol level (38.5% versus 5.4%, P=0.029) while LBW was 7.99-times more common in mothers with high total maternal cholesterol than in mothers with normal cholesterol (87.5% versus 10.5%, P=0.019). CONCLUSION: We can infer that the high maternal serum cholesterol (hypercholesterolaemia) is associated with preterm delivery/ low birth weight (LBW) in term infants. However, further validation of these findings with more robust prospective and longitudinal characterization of maternal serum cholesterol profiles is required in subsequent investigations. PMID- 25834510 TI - Skilled delivery care service utilization in Ethiopia: analysis of rural-urban differentials based on national demographic and health survey (DHS) data. AB - BACKGROUND: Despite the slight progress made on Antenatal Care (ANC) utilization, skilled delivery care service utilization in Ethiopia is still far-below any acceptable standards. Only 10% of women receive assistance from skilled birth attendants either at home or at health institutions, and as a result the country is recording a high maternal mortality ratio (MMR) of 676 per 100,000 live births (EDHS, 2011). Hence, this study aimed at identifying the rural-urban differentials in the predictors of skilled delivery care service utilization in Ethiopia. METHODS: The study used the recent Ethiopian Demographic and Health Survey (EDHS 2011) data. Women who had at least one birth in the five years preceding the survey were included in this study. The data were analyzed using univariate (percentage), bivariate (chi-square) and multivariate (Bayesian logistic regression). RESULTS: The results showed that of the total 6,641 women, only 15.6% received skilled delivery care services either at home or at health institution. Rural women were at greater disadvantage to receive the service. Only 4.5% women in rural areas received assistance from skilled birth attendants (SBAs) compared to 64.1 % of their urban counter parts. Through Bayesian logistic regression analysis, place of residence, ANC utilization, women's education, age and birth order were identified as key predictors of service utilization. CONCLUSION: The findings highlight the need for coordinated effort from government and stakeholders to improve women's education, as well as strengthen community participation. Furthermore, the study recommended the need to scale up the quality of ANC and family planning services backed by improved and equitable access, availability and quality of skilled delivery care services. PMID- 25834511 TI - Neonatal mortality in a referral hospital in Cameroon over a seven year period: trends, associated factors and causes. AB - BACKGROUND: The fourth Millennium Development Goals targets reduction by 2/3 the mortality rate of under-fives by 2015. This reduction starts with that of neonatal mortality representing 40% of childhood mortality. In Cameroon neonatal mortality was 310/00 in 2011. OBJECTIVES: We assessed the trends, associated factors and causes of neonatal deaths at the Yaounde Gynaeco-Obstetric and Pediatric Hospital. METHODS: The study was a retrospective chart review. Data was collected from the hospital records, and included both maternal and neonatal variables from 1st January 2004 to 31st December 2010. RESULTS: The neonatal mortality was 10%. Out-borns represented 49.3% of the deceased neonates with 11.3% born at home. The neonatal mortality rate followed a downward trend dropping from 12.4% in 2004 to 7.2% in 2010. The major causes of deaths were: neonatal sepsis (37.85%), prematurity (31.26%), birth asphyxia (16%), and congenital malformations (10.54%). Most (74.2%) of the deaths occurred within the first week with 35% occurring within 24hours of life. Mortality was higher in neonates with birth weight less than 2500g and a gestational age of less than 37 weeks. In the mothers, it was high in single parenthood , primiparous and in housewives and students. CONCLUSION: There has been a steady decline of neonatal mortality since 2004. Neonatal sepsis, prematurity, birth asphyxia and congenital malformations were the major causes of neonatal deaths. Neonatal sepsis remained constant although at lower rates over the study period. PMID- 25834512 TI - Pneumonia among children under five in Uganda: symptom recognition and actions taken by caretakers. AB - BACKGROUND: Pneumonia is a leading cause of death among children under five years of age. Pneumonia deaths could be averted if caretakers recognized the danger signs and sought appropriate treatment promptly. METHODS: We interviewed 278 caretakers in Mukono district Uganda, whose under-five children had suffered from probable pneumonia two weeks prior to the evaluation. Through structured questionnaires we assessed caretaker's knowledge about danger signs among under five children with pneumonia and the actions taken to manage probable pneumonia using descriptive statistics. We also conducted in-depth interviews with caretakers and community health workers. RESULTS: Lower chest wall in drawing (a pneumonia specific danger sign) was mentioned by only 9.4% of the caretakers. Among the Integrated Management of Childhood Illnesses (IMCI) standard general danger signs, inability to feed was the most commonly cited danger sign (37.8%) followed by incessant vomiting (10.1%). No caretaker mentioned all the four standard general danger signs. In terms of actions taken, most caretakers offered drinks (49.6%) and traditional herbs (45.3%) while, 31.7% gave antibiotics. CONCLUSIONS: Caretaker's knowledge about danger signs was inadequate in relation to the IMCI guidelines. Caretakers used both modern and traditional forms of treatment to manage pneumonia. Comprehensive interventions geared at increasing symptom recognition and improving health-seeking behavior are needed to reverse this trend. PMID- 25834513 TI - Hygiene and sanitation risk factors of diarrhoeal disease among under-five children in Ibadan, Nigeria. AB - BACKGROUND: Diarrhoea diseases are among the leading causes of morbidity and mortality in under-five-children (U-5C) in Nigeria. Inadequate safe water, sanitation, and hygiene account for the disease burden. Cases of diarrhoea still occur in high proportion in the study area despite government-oriented interventions. OBJECTIVE: To determine the hygiene and sanitation risk factors predisposing U-5C to diarrhoea in Ibadan, Nigeria. METHODS: Two hundred and twenty pairs of children, matched on age, were recruited as cases and controls over a period of 5 months in Ibadan. Questionnaire and observation checklist were used to obtain information on hygiene practices from caregivers/mothers and sanitation conditions in the households of 30% of the consenting mothers/caregivers. Data were analysed using descriptive and inferential statistics. RESULTS: Caregivers/mothers' mean ages were 31.3 +/-7.5 (cases) and 30.6 +/-6.0(controls) years. The risk of diarrhoea was significantly higher among children whose mothers did not wash hands with soap before food preparation (OR=3.0, p<0.05), before feeding their children (OR=3.0, p<0.05) and after leaving the toilet (OR=4.7, p<0.05). Factors significantly associated with diarrhoea were: poor water handling (OR=2.0,CI=1.2-3.5), presence of clogged drainage near the house (OR=2.1,CI=1.2-3.7) and breeding places for flies (OR=2.7,CI=1.6-4.7). The mean risk score among cases and controls from the sanitary inspection of drinking water sources were 5.4 +/- 2.2 and 3.2 +/- 1.9 (p<0.05) and household storage containers were 2.4 +/- 1.8 and 1.2 +/- 0.7 (p<0.05) respectively. CONCLUSION: Hygiene and sanitation conditions within households were risk factors for diarrhoea. This study revealed the feasibility of developing and implementing an adequate model to establish intervention priorities in sanitation in Ibadan, Nigeria. PMID- 25834514 TI - Toxicological evaluation of methanol leaves extract of Vernonia bipontini Vatke in blood, liver and kidney tissues of mice. AB - BACKGROUND: Various medicinal plants have been studied using modern scientific approaches. These plants have a variety of properties and various biological components that can be used to treat various diseases. However, harmful effects of plants are common clinical occurrence. OBJECTIVE: This study was designed to investigate toxicological assessment of acute and chronic methanol leaf extract of Vernonia bipontini Vatke (V.bipontini V) on blood, liver and kidney tissues of mice. METHODS: Lethal dose (LD) at which 50% of experimental mice died and long term toxicity of methanolic leaf extract of V. bipontini V were determined. Some hematological and biochemical parameters were evaluated. Then, liver and kidney tissues of each animal were taken and processed for light microscopy. RESULTS: Almost all mice treated with 800mg/kg methanol leaf extract of V. bipontini V showed swellings on the left part of abdominal region related to location of spleen, mild diarrhea and enlargement of spleen. The LD50 of the methanol leaf extract of V. bipontini V was 2130.6+/-1.5mg/kg. Treatment with 800mg/kg body weight of methanol leaf extract significantly decreased body, liver and kidney weights, red blood cells (RBC), haemoglobin (Hgb), mean cell haemoglobin (Mch), Mchc, platelet and significantly increased serum aspartate transferance (AST), vatanine tranferance(ALT) and alkaline phosphate (ALP) levels while 400mg/kg dose had no effect on these parameters. The reduced organ weights did not correlate with loss of body weight at 800mg/kg of methanol leaf extract of the plant. Light microscope observations of liver tissue of mice treated with 800mg/kg of the methanol leaf extract revealed dilated sinusoids, nuclear enlargement, lots of bi nucleation of hepatocytes, peripheral cramped chromatin, shrinkages (single cell death) of hepatocytes, fragmentation of hepatocytes while no histopathological changes were observed in liver and kidney of mice treated at 400mg/kg. Kidney tissue sections of mice did not show significant histopathological changes at 400mg/kg. However, at 800mg/kg kidney sections showed increased cellularity of glomerulus, urinary space obliteration and enlarged macula densa. CONCLUSION: This study suggests that the methanol leaf extract may have been phytotoxic to liver that resulted in a rise in serum AST, ALT and ALP levels. PMID- 25834515 TI - A meta-analysis on diagnostic value of serum cystatin C and creatinine for the evaluation of glomerular filtration function in renal transplant patients. AB - OBJECTIVES: This meta-analysis aimed to perform a systematic review on comparing the diagnostic value of serum cystatin C and creatinine for glomerular filtration rate in renal transplant patients. METHODS: The data was extracted into 2*2 table after the articles were assessed by the tool of QUADAS and heterogeneity analysis. The SROC curve and meta-analysis were performed by MetaDisc1.4. RESULTS: Meta-analysis showed that the serum cystatin C had no heterogeneity (P=0.418, I2=2.2%, DOR=25.03), while creatinine heterogeneity was high (P=0.109, I2=37.5%, DOR=9.11). The values of SEN, SPE and SAUC were calculated as 0.86, 0.70 and 0.9015 for cystatin C, and 0.78, 0.73 and 0.8285 for creatinine individually. This study utilized GFR detection and subgroups analysis by cutoff. The PLR was 6.13 and the NLR was 0.12 for cystatin C, compared to SCr (3.72, 0.32). There was homogeneity among these studies using PENIA testing for cystatin C (chi2=2.61, P=0.4560, I2=0.0%. CONCLUSIONS: There were significant correlations among cystatin C , creatinine and glomerular filtration rate (GFR). Cystatin C had more sensitivity but less specificity than creatinine for evaluation of GFR. Cystatin C had strong ability in diagnosing renal function after renal transplant and ruling out diagnostic efficacy. PMID- 25834516 TI - Health seeking behaviour and challenges in utilising health facilities in Wakiso district, Uganda. AB - BACKGROUND: The health seeking behaviour of a community determines how they use health services. Utilisation of health facilities can be influenced by the cost of services, distance to health facilities, cultural beliefs, level of education and health facility inadequacies such as stock-out of drugs. OBJECTIVES: To assess the health seeking practices and challenges in utilising health facilities in a rural community in Wakiso district, Uganda. METHODS: The study was a cross sectional survey that used a structured questionnaire to collect quantitative data among 234 participants. The sample size was obtained using the formula by Leslie Kish. RESULTS: While 89% of the participants were aware that mobile clinics existed in their community, only 28% had received such services in the past month. The majority of participants (84%) did not know whether community health workers existed in their community. The participants' health seeking behaviour the last time they were sick was associated with age (p = 0.028) and occupation (p = 0.009). The most significant challenges in utilising health services were regular stock-out of drugs, high cost of services and long distance to health facilities. CONCLUSIONS: There is potential to increase access to health care in rural areas by increasing the frequency of mobile clinic services and strengthening the community health worker strategy. PMID- 25834517 TI - Virtual medical plant modeling based on L-system. AB - BACKGROUND: Searching the drug molecules from the medicinal plants become more and more popular given that herbal components have been widely considered to be safe. In medical virtual plant studies, development rules are difficult to be extracted, the construction of plant organs is highly dependent on equipment and the process is complicated. AIM: To establish three-dimensional structural virtual plant growth model. METHODS: The quasi-binary tree structure and its properties were obtained through the research of theory on binary tree, then the relationship between quasi-binary tree structure and plant three-dimensional branching structure model was analyzed, and the three-dimensional morphology of plants was described. RESULTS: A three-dimensional plant branch structure pattern extracting algorithm based on quasi-binary tree structure. By using 3-D L-system method, the extracted rules were systematized, and standardized. Further more, we built a comprehensive L-model system. With the aid of graphics and PlantVR, we implemented the plant shape and 3-D structure's reconstruction. CONCLUSION: Three dimensional structure virtual plant growth model based on time-controlled L system has been successfully established. PMID- 25834518 TI - Fournier's ganrene in the HIV era. AB - BACKGROUND: Fournier's gangrene is a devastating condition that affects mostly patients whose immunity has been reduced. There is increasing evidence for increasing incidence of the disease in those with HIV disease. OBJECTIVE: To evaluate the presentation, bacteriology and outcome of Fournier's gangrene in our area in recent times in view of the high prevalence in Nairobi and its environs. RESULTS: One hundred and forty six patients were treated for Fournier's gangrene during the study period; all were male. They had a mean age of 38.6 years (range 2 months - 86 years). HIV infection was the most common associated underlying illness (16.4 %), followed by diabetes mellitus and alcoholism (11%). CONCLUSIONS: HIV infection is emerging as leading predisposing factor and has overtaken diabetes in predisposing for Fournier's gangrene in Kenyatta National Hospital. PMID- 25834519 TI - Splanchnic venous thrombosis driven by a constitutively activated JAK2 V617F philadelphia-negative myeloproliferative neoplasm: a case report. AB - INTRODUCTION: Splanchnic venous thrombosis (SVT) has varied etiology with Philadelphia-negative myeloproliferative neoplasms (MPNs) being the most frequent underlying prothrombotic factor. Hematological indices often remain within normal range because of portal hypertension and its sequelae, causing diagnostic challenges. The high frequency of JAK2 mutation among patients with SVT reinforces the diagnostic utility of JAK2V617F testing. CASE REPORT: We report a case of a 62-year-old black man with progressive abdominal swelling and features of decompensated chronic liver disease found to have SVT-portal vein thrombosis and how JAK2 V617F was useful in unmasking an underlying myeloproliferative neoplasm. CONCLUSION: A high index of suspicion for an underlying prothrombotic factor is critical for patients presenting with thrombosis in unusual sites. This is useful in prognostic stratification and patient outcomes. JAK2 mutation screening is now part of the standard diagnostic workup in SVT. PMID- 25834520 TI - Lassa fever - full recovery without ribavarin treatment: a case report. AB - BACKGROUND: Lassa fever is a rodent-borne zoonosis that clinically manifests as an acute hemorrhagic fever. It is treated using ribavarin. Surviving Lassa fever without receiving the antiviral drug ribavarin is rare. Only few cases have been documented to date. CASE PRESENTATION: We report a case of a 59-year old female with fever who was initially thought to have acute pyelonephritis and sepsis syndrome with background malaria. Further changes in her clinical state and laboratory tests led to a suspicion of Lassa fever. However at the time her laboratory confirmatory test for Lassa fever returned, her clinical state had improved and she made full recovery without receiving ribavarin. Her close contacts showed no evidence of Lassa virus infection. CONCLUSION: This report adds to the literature on the natural history of Lassa fever; and that individuals may survive Lassa fever with conservative management of symptoms of the disease and its complications. PMID- 25834521 TI - Mapping Rwanda public health research (1975-2014). AB - BACKGROUND: Since the genocide occurred in 1994, Rwanda has faced up to the challenge of rebuilding. Public health is a main field to understand this rebuilding. OBJECTIVES: In this paper, the aim was to map the scientific research on public health in Rwanda after the genocide and to present the links between different financing systems. METHODS: We used bibliographic analyses with Web of Science of papers published during the period 1975-2014. We performed analyses on journals, most cited articles, authors, publication years, organizations, funding companies, countries, and keywords. RESULTS: We obtained 86 articles between 1975 and 2014. Most articles were published after 2007. The main countries of research laboratories were the United States of America, Rwanda, England and Belgium and represented the main network collaboration. The relevant keywords were: HIV, woman, child, program, rural and violence. CONCLUSIONS: Public health research on Rwanda appeared 14 years after the genocide. A main field was emerging: the spread of HIV with mother-child transmission, and the policies to take this subject into account in rural zones. The network of institutions developing these studies was USA-Rwanda. PMID- 25834522 TI - Ebola outbreak in west Africa. PMID- 25834523 TI - Editorial. PMID- 25834524 TI - High seropositivity of IgG and IgM antibodies against cytomegalovirus (CMV) among HIV-1 seropositive patients in Ilorin, Nigeria. AB - BACKGROUND: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is a major public health problem in sub-saharan Africa. Cytomegalovirus (CMV) has been reported to enhance HIV replication and accelerate the progression of HIV infection to AIDS. OBJECTIVE: This study reports on the high seropositivity of immunoglobulin (Ig) G and M antibodies against CMV and the risk factors for CMV infection among HIV/AIDS patients in Ilorin, Nigeria. METHOD: A total of 180 consented HIV-1 seropositive patients (age-range 16-56 years; 108 females and 72 males) were consecutively recruited. Socio demographic/behavioral data and 5 ml blood samples were collected from each patient. Plasma of each sample was assayed for anti-CMV IgG/IgM using a CMV IgG and IgM Enzyme Linked ImmunoSorbent Assay (ELISA) kit. RESULTS: Twenty (11.1%) of the 180 HIV-1 seropositive subjects were positive for anti-CMV IgM antibody while 169(93.9%) were positive for anti-CMV IgG antibody. Age, marital status, number of sexual partners, CD4 cells counts and previous history of blood transfusion were the main correlates of CMV seropositivity among these patients. However, occupation, sex, highly active antiretroviral therapy (HAART) were not statistically associated with CMV seropositivity in this study. CONCLUSION: This study has shown that greater percentages of HIV-1 seropositive patients had active CMV infection. It has further shown that CMV is hyperendemic in HIV-1 seropositive patients in Ilorin, Nigeria. PMID- 25834525 TI - Types and predictors of partner reactions to HIV status disclosure among HIV infected adult Nigerians in a tertiary hospital in the Niger Delta. AB - BACKGROUND AND OBJECTIVE: Our aim was to describe the types and determinants of partner reactions to HIV-status disclosure among adults attending an antiretroviral therapy-(ART) clinic in the Bayelsa State, Nigeria. METHODS: A cross-sectional study was undertaken between January and March 2013 among consecutive adult patients who had disclosed their HIV-status to their current sexual partner. Sociodemograhic data and types of initial and subsequent partner reactions to disclosure were obtained using interviewer-administered standardized questionnaire. Independent determinants of reactions to disclosure were ascertained by unconditional logistic regression. RESULTS: Out of 123 study participants, 57.7% were females, 92% were receiving ART and 86.1% were currently married. Majority of the participants reported predominant positive or supportive initial (72.4%) and subsequent (89.5%) partner reactions to disclosure, with significant increase in positive reactions over time. Positive initial partner reactions were independently associated with prior post-test counselling-(Odds ratio [OR]-6.5, 95% Confidence interval [CI]-1.3-31.6-p=0.02), age>35 years-(OR 5.8, 95% CI-1.6-20.9-p=0.008) and being healthy at time of disclosure-(OR-7.8, 95% CI-1.7-35.4-p=0.008). Subsequent positive partner reactions were significantly associated with receiving antiretroviral therapy and having only one lifetime sexual partner. CONCLUSION: Our results indicate that partner reactions to HIV-status disclosure are predominantly supportive. Disclosure counselling and early initiation of ART may be effective in improving HIV-status disclosure in Nigeria. PMID- 25834526 TI - Seroprevalence of transfusion transmissible infections (TTI), in first time blood donors in Abeokuta, Nigeria. AB - BACKGROUND: Transfusion transmissible infections, such as HIV, HBV, HCV and syphilis are on the rise and pose a threat to blood safety. OBJECTIVE: To determine prevalence and demographic profiles of TTI's among first time blood donors in Abeokuta, Nigeria. METHODS: The study was conducted between February to November 2013; 130 first time blood donors were tested for the presence of HIV, HBsAg, HCV antibodies and Treponema palidium antibodies using EIA based rapid immunochromatographic kits. Data analysis was done using SPSS with a level of significance of p<0.05. RESULTS: Prevalence rates to HIV, HBsAg, HCV antibody, were 6.2% (n=8), 10% (n=13) and 1.5% (n=2), there was 0% prevalence to Treponema palidium antibodies. Group specific prevalence rates revealed that educational status was associated with HBsAg positivity (p = 0.028), donors with a history of previous blood transfusion was also statistically associated with HIV sero reactivity (p = 0.013). CONCLUSIONS: High levels of HBsAg and HIV were observed, there is need to revise the donor testing algorithm in Nigeria in line with the prevalence of TTI's. We also advocate that a National surveillance system for TTI's be established through our National blood transfusion service (NBTS) program, a second serological test is also suggested to reduce the risk of occult HBV infection in Nigeria. PMID- 25834527 TI - Does parents' socio-economic status matter in intentions of vaccinating against human papillomavirus for adolescent daughters? AB - BACKGROUND: The Human Papilloma Virus (HPV) vaccination provides substantial protection, and it is best to be taken before the age of twelve. Taiwan approved HPV vaccines since 2006. However, very few female adolescent have been vaccinated until now. OBJECTIVES: To examine whether the parents' socio-economic status matters in deciding to purchase HPV vaccination for their daughters based on the theory of planned behavior. METHOD: A structured questionnaire to collect 394 responses from parents of adolescent girls in Taiwan. Data was coded to categorize relevant socio-economic classes, and was analyzed with SPSS. RESULTS: The behavior intentions of parents with low (mean= 5.28) and high (5.01) socio economic status are significantly stronger than the moderate (4.56) in deciding to purchase the HPV vaccination. Socio-economic factor has a slightly negative impact (B= -0.08), and attitude (0.68), subjective norms (0.16), and behavior control (0.32) have positive impacts on the parents' intention. CONCLUSION: Major impacts on the decision to purchase an HPV vaccination for their adolescent was not due to the parents' socio-economic status but the parent's attitude. As the major predictor of a less complicated decision, attitudes toward the HPV vaccination should be reinforced through continuous communications between service providers and patient-advocate groups. PMID- 25834528 TI - Feasibility of delivering HPV vaccine to girls aged 10 to 15 years in Uganda. AB - BACKGROUND: Cervical cancer is a leading cause of mortality among women in Uganda. The availability of the human papillomavirus (HPV) vaccine presents an opportunity to prevent cervical cancer. The Government of Uganda conducted a demonstration project exploring the feasibility of two delivery strategies. OBJECTIVE: To explore the feasibility of two HPV vaccine delivery strategies: 1) a stand-alone school-based strategy that selected girls based on their enrolment in grade 5 (known as the "grade-based" strategy; and 2) an age-based strategy that delivered the HPV vaccine based on the girls' age (10-year-olds). This strategy combined the delivery of the vaccine with the distribution of deworming medication and vitamin A through an existing Child Days Plus program. METHODS: A qualitative study that explored the feasibility of the two delivery strategies from the perspective of health workers, district leaders, and staff of the Uganda National Expanded Programme on Immunization, utilizing in-depth interviews and focus group discussions. RESULTS: Coverage data showed that more girls (88%) were vaccinated using the grade-based strategy and completed all three doses compared to those (73%) vaccinated using the age-based strategy. Health workers and teachers indicated that determining vaccination eligibility was easier by grade than by age and there were minor disruptions to health services and school programs during vaccinations, as reported by health workers and teachers using the grade-based strategy. CONCLUSION: HPV vaccine delivery at schools using grade eligibility was more feasible than selecting girls by age. Lessons learned in Uganda could be relevant for countries considering implementing HPV vaccinations. PMID- 25834529 TI - Investigating payment coping mechanisms used for the treatment of uncomplicated malaria to different socio-economic groups in Nigeria. AB - BACKGROUND: Given the enormous economic burden of malaria in Nigeria and in sub Saharan Africa, it is important to determine how different population groups cope with payment for malaria treatment. This paper provides new information about the differences in household coping mechanisms for expenditures on malaria treatment. METHODS: The study was undertaken in two communities in Southeast Nigeria. A total of 200 exit interviews were conducted with patients and their care givers after consultation and treatment for malaria. The methods that were used to cope with payments for malaria treatment expenditures were determined. The coping mechanisms were disaggregated by socio-economic status (SES). RESULTS: The average expenditure to treat malaria was $22.9, which was all incurred through out-of- pocket payments. Some households used more than one coping method but none reported using health insurance. It was found that use of household savings (79.5%) followed by reduction in other household expenses (22.5%) were the most common coping methods. The reduction of other household expenses was significantly more prevalent with the average (Q4) SES group (p<0.05). . CONCLUSION: People used different coping strategies to take care of their malaria expenditures, which are mostly paid out-of-pocket. The average socio-economic household had to forego other basic household expenditures in order to cope with malaria illness; otherwise there were no other significant differences in the coping mechanisms across the different SES groups. This could be indicative of the catastrophic nature of malaria treatment expenditures. Interventions that will reduce the burden of malaria expenditures on all households, within the context of Universal Health Coverage are needed so as to decrease the economic burden of malaria on households. PMID- 25834530 TI - Level of understanding of co-trimoxazole use among HIV infected, recurrent pulmonary tuberculosis suspects at a national referral tuberculosis clinic in Kampala, Uganda: a qualitative analysis. AB - BACKGROUND: Co-trimoxazole use is the standard of care for preventing Pneumocystis jirovecii pneumonia in sub-Saharan Africa but implementation remains slow. Co-trimoxazole is self- administered with uncertain adherence. Knowledge of co-trimoxazole use among HIV infected persons is unknown. OBJECTIVES: To assess knowledge, attitudes and practices of co-trimoxazole use among HIV infected adults evaluated for recurrent PTB in Kampala, Uganda. METHODS: A qualitative study utilizing 5 focus group discussions among 30 HIV infected PTB suspects at the national referral tuberculosis treatment centre in Kampala. RESULTS: Males and females had similar median ages. 80% were currently on co-trimoxazole and 50% of participants were on HAART. Majority of participants defined co-trimoxazole as an analgesic. Few noted co-trimoxazole was a drug to treat cough and chest pain. However, few responses revealed that co-trimoxazole prevents opportunistic diseases among PLHIV. Most of participants believed HAART and anti-TB drugs work as co-trimoxazole thus it should not be taken together with them. This belief may lead to increased risk of opportunistic infections, morbidity and mortality. CONCLUSIONS: We revealed gaps in understanding of co-trimoxazole use among study participants. We therefore recommend that more facts about co-trimoxazle as prophylaxis against P. jirovecii, bacterial and diarrheal pathogens should be incorporated in VCT fact sheets. PMID- 25834531 TI - Taenia solium metacestode preparation in rural areas of sub-Saharan Africa: a source for diagnosis and research on cysticercosis. AB - BACKGROUND: Taenia solium metacestodes/cysts obtained from pig carcasses constitute a primary source for diagnostic tools used for the detection of human cysticercosis. Data on T. solium cyst preparation in Africa is still scarce but required to establish independent reference laboratories. OBJECTIVES: The aim of the present study is a) to present the likely yield of T. solium cyst material by the use of two different preparation methods in the field and b) to investigate its suitability for immunodiagnosis of human cysticercosis. METHODS: In Zambia, Uganda and Tanzania 670 pigs were screened for T. solium infection. Cysts were prepared by 'shaking method' and 'washing method'. Generated crude antigens were applied in a standard western blot assay. RESULTS: 46 out of 670 pigs (6.9%) were found positive for T. solium (Zambia: 12/367, 3.3%; Uganda: 11/217, 5.1%; Tanzania 23/86, 26.7%). Mean values of 77.7 ml whole cysts, 61.8 ml scolices/membranes and 10.9 ml cyst fluid were obtained per pig. Suitability of collected material for the use as crude antigen and molecular diagnostic techniques was demonstrated. CONCLUSION: This study clearly shows that T. solium cyst preparation in African settings by simple field methods constitutes an effective way to obtain high quality material as source for diagnostic tools and research purposes. PMID- 25834532 TI - Stroke subtypes and factors associated with ischemic stroke in Kinshasa, Central Africa. AB - BACKGROUND AND PURPOSE: Ischemic stroke causes death and disability worldwide. Better understanding and controlling factors associated will improve the prevention of the disease. This study reviews records of patients with ischemic stroke in Central Africa. MATERIAL AND METHODS: Patients of Bantu ethnicity with clinical diagnosis of stroke and lesion on computed tomography scan from January 2011 to December 2012 were selected. Computed tomographic subtypes of ischemic stroke and factors associated were considered with tropical seasonal variation. RESULTS: Of the 303 first-ever stroke patients (average age 53 years old, range 3 84 years old; 62% male) were included in the study. The prevalence of computed tomography stroke subtypes was: lacunar infarct (63%) and non lacunar infarct lesion (37%). Silent brain infarct was seen in 9 % of patients. Prevalence of factors associated with ischemic stroke was: age>=60 years old (55%); male gender (63%), chronic and uncontrolled hypertension (54%) and type 2 Diabetes mellitus (11%). A seasonal high prevalence was observed in warmer season (p < 0.05). CONCLUSIONS: This study shows a high prevalence of lacunar infarct than non lacunar in Bantu of Central Africa. PMID- 25834533 TI - Stroke mortality and its predictors in a Nigerian teaching hospital. AB - BACKGROUND: Stroke is the third leading cause of death worldwide. Stroke mortality has been noted to be higher in blacks in biracial studies. There have been few studies on stroke mortality and its predictors in Nigeria. This study examines mortality of stroke and its predictors in a Northern Nigerian teaching hospital. METHODS: This was a prospective study that was carried out at Jos University Teaching Hospital in Nigeria. One hundred and twenty stroke patients admitted into the medical wards within one year were assessed. Demographic data was recorded. Patients were examined and ancillary investigations were carried out. The deaths and predictors were recorded. Multivariate logistic regression was used to identify independent predictors of mortality. RESULTS: There were one hundred and twenty participants. Forty two (35%), patients died. Most (76.2%) deaths occurred within the first week. Predictors of mortality on univariate analysis were age >= 60 years, male sex, loss of consciousness, high NIHSS score (>=16), the presence of co-morbid conditions and presence of complications. On multivariate analysis, the predictors of mortality were the presence of co-morbid conditions, GCS<10 and high NIHSS score. CONCLUSION: Stroke mortality was quite high in this study. Predictors of mortality were the indices of severity and the presence of co-morbid conditions. PMID- 25834534 TI - The visibility of non-communicable diseases in Northern Uganda. AB - BACKGROUND: WHO and Uganda's Ministry of Health emphasize the need to address the growing burden of non-communicable diseases (NCDs). Treatment for these conditions is urgent in northern Uganda where war has negatively affected both health and the public health care system. OBJECTIVES: We aimed to explore the recognized presence of selected chronic conditions in the out-patient population and to relate this 'visibility' to the ability of health units to diagnose and treat them. METHODS: At six health facilities we reviewed patient registers for one month to determine the frequency of hypertension, diabetes, depression, and post traumatic stress disorder (PTSD). We checked the availability of diagnostic instruments and medicines, and interviewed health workers. RESULTS: The four conditions were rarely diagnosed in the outpatient population. Hypertension was the most common, but still constituted under 1% of diagnoses. Patterns of diagnosis were uneven, with higher frequency of particular diagnoses at some health facilities. Diagnostic equipment was not sufficient and screening was irregular. Medicine was mostly available although stockouts of some relevant drugs were reported. CONCLUSIONS: The four conditions are relatively invisible in the outpatient population. Greater visibility would be facilitated by regular clinic days for hypertension and diabetes, availability and regular use of diagnostic instruments, and a more reliable supply of the relevant medicines. PMID- 25834535 TI - Bone turnover biomarkers in obese postmenopausal Saudi women with type-II diabetes mellitus. AB - BACKGROUND: There is a high prevalence of diabetes mellitus type-2 (T2DM) and osteoporosis are problems worldwide. In this study, we evaluated the correlation between T2DM and bone turnover in diabetic obese postmenopausal Saudi women. SUBJECTS AND METHODS: The present study included total of 65 T2-DM obese postmenopausal Saudi women, (36 uncontrolled, 29 controlled). The following serum biochemical parameters were evaluated [fasting blood glucose (FBG), total calcium (Ca), phosphorus (Pi), parathyroid hormone (PTH), 1,25-(OH)2 Vitamin D3, osteocalcin (OC), procollagen (PICP) and cathepsin k (Cath K)]. RESULTS: Serum OC levels were significantly decreased in diabetic obese postmenopausal group compared to their respective healthy group (P < 0.004). PICP and Cath K were significantly elevated in diabetic postmenopausal group compared to the healthy group (P < 0.024 & 0.001). A significant elevation in 1,25(OH)2 Vitamin D3, Ca and Pi levels in diabetic obese postmenopausal patients group compared to the healthy group. However, a non-significant changes was observed in serum PTH level between different groups. CONCLUSION: In this study, the changes in the biochemical parameters and bone turnover markers in obese women are strong risk factors for diabetes development that may contribute to osteopenia and osteoporosis. The study showed the strong effect of T2DM on biochemical markers of bone turnover in obese postmenopausal Saudi women. PMID- 25834536 TI - Inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism. AB - BACKGROUND: Da Huang (Radix et Rhizoma Rhei) is the dried root or rhizome of Rheum palmatum L., Rheum tanguticum Maxim ex Balf. or Rheum officinale Braill of family Polygonaceae. It has heat clearing, damp drying, fire purging and toxin removing effects. Because of its definite curative efficacy, it has been widely applied in clinical settings. OBJECTIVE: To study the inhibitory effect of emodin on human hepatoma cell line SMMC-7721 and its mechanism. METHODS: MTT assay, flow cytometry and electron microscopy were used to investigate the inhibitory effect of different concentrations of emodin on human hepatoma cell line SMMC-7721. RESULTS: 12 h, 24 h and 48 h after the action of 20, 40 and 80 umol/L emodin on SMMC-7721 cells, the proliferation of human hepatoma SMMC-7721 cells was inhibited; the inhibitory effects showed time-and concentration-dependence. 48 h after the action of different concentrations of emodin on SMMC-7721 cells, cells in G2/M phase increased significantly, while the proportion of S phase cells gradually declined. CONCLUSION: Emodin can inhibit human hepatoma cell line SMMC 7721. PMID- 25834537 TI - Optimization of processing technology of Rhizoma Pinelliae Praeparatum and its anti-tumor effect. AB - BACKGROUND: Rhizoma Pinelliae is the dried tuber of Pinellia ternata (Thunb.) Breit. Modern pharmacological studies have shown that Rhizoma Pinelliae has antitussive, antiemetic, glandular secretion inhibiting and antitumor effects. OBJECTIVES: To optimize the processing technology of Rhizoma Pinelliae Praeparatum, and to study its anti-tumor effect. METHODS: Orthogonal design method was applied to analyze the effects of factors such as licorice concentration volume, soaking time and processing temperature on processing technology of Rhizoma Pinelliae Praeparatum; MTT assay and flow cytometry were used to determine the inhibitory effect of Rhizoma Pinelliae Praeparatum on Bel 7402 cells. RESULTS: During the processing of Rhizoma Pinelliae Praeparatum, the size of influence of licorice concentration volume, soaking time and processing temperature on processing results of Rhizoma Pinelliae was: B>C>A in descending order, i.e. soaking time>processing temperature>licorice concentration volume, different concentrations of Rhizoma Pinelliae Praeparatum ethanol extracts could all exert inhibitory effect on the growth and proliferation of Bel-7402 cells, and with the increase of drug concentration and the extension of culture time, the cell proliferation inhibitory effect of Rhizoma Pinelliae Praeparatum ethanol extract became more and more evident. Apoptotic rate of 1.5 mg/ml Rhizoma Pinelliae Praeparatum ethanol extract group reached 13.53%, the difference was extremely significant compared with the control group. In conclusion the factor most influential to the processing technology of Rhizoma Pinelliae Praeparatum was soaking time, followed by processing temperature, the factor least influential was licorice concentration volume. CONCLUSION: Rhizoma Pinelliae Praeparatum has inhibitory effect on growth and proliferation of Bel-7402 cells. PMID- 25834538 TI - Diagnostic accuracy of fine needle aspiration cytology in providing a diagnosis of cervical lymphadenopathy among HIV-infected patients. AB - BACKGROUND: Opportunistic infections and malignancies cause lymphadenopathy in HIV-infected patients. The use and accuracy of fine needle aspiration cytology in diagnosing of cervical lymphadenopathy among HIV-infected patients is not well studied in Uganda. OBJECTIVE: The aim of this study was to determine the diagnostic accuracy of fine needle aspiration cytology in providing a diagnosis of cervical lymphadenopathy among HIV-infected patients in Uganda. METHODS: We consecutively recruited adult HIV-infected patients with cervical lymphadenopathy admitted to Mulago Hospital medical wards. Clinical examination, fine needle aspiration and lymph node biopsy were performed. We estimated the sensitivity, specificity; negative and positive predictive values using histology as the gold standard. RESULTS: We enrolled 108 patients with a mean age of 33 years (range, 18-60), 59% were men and mean CD4 was 83(range, 22-375) cells/mm(3). The major causes of cervical lymphadenopathy were: tuberculosis (69.4%), Kaposi's sarcoma KS (10.2%) and reactive adenitis (7.4%). Overall fine needle aspiration cytology accurately predicted the histological findings in 65 out of 73 cases (89%) and missed 7 cases (9.5%). With a sensitivity of 93.1%, specificity of 100%, positive predictive value of 100% and negative predictive value of 78.7% for tuberculosis and 80%; 98.4%;88.9% and 98.9% for KS respectively. No fine needle aspiration complications were noted. CONCLUSIONS: Fine needle aspiration cytology is safe and accurate in the diagnosis of tuberculosis and KS cervical lymphadenopathy among HIV-positive patients. PMID- 25834539 TI - The association of XRCC3 Thr241Met genetic variant with risk of prostate cancer: a meta-analysis. AB - BACKGROUND: Previous studies suggest that the X-ray repair cross-complementing group 3 gene (XRCC3) Thr241Met genetic variant could be potentially associated with the risk of prostate cancer. However, results from these published studies were conflicting rather than conclusive. OBJECTIVES: his meta-analysis aimed to conduct a better understanding of the effects of XRCC3 Thr241Met genetic variant on prostate cancer risk. METHODS: We identified three eligible studies, 499 prostate cancer cases and 571 controls. RESULTS: Overall, significant associations were detected in the heterozygote comparison genetic model (CT versus (vs.) CC: OR = 0.71, 95% CI 0.53-0.94, Z =2.38, p= 0.017), and the dominant genetic model (TT/CT vs. CC: OR = 0.74, 95% CI 0.57-0.98, Z = 2.11, p =0.035). In the subgroup analysis by ethnicities, we found that this genetic variant was significantly associated with the decrease risk of prostate cancer in Caucasians for heterozygote comparison genetic model (CT vs. CC: OR = 0.66, 95% CI 0.44-0.98, Z = 2.04, p = 0.042). No publication bias was found in this study. CONCLUSIONS: Results from this meta-analysis indicate that the XRCC3 Thr241Met genetic variant is associated with prostate cancer risk. PMID- 25834540 TI - Diagnostic utility of clinical and biochemical parameters in pancreatic head malignancy patients with normal carbohydrate antigen 19-9 levels. AB - BACKGROUND: Carbohydrate antigen (CA)19-9 that is the most widely used biomarker for pancreatic cancer has certain limitations in diagnosis, which results in a tough job to distinguish pancreatic cancer from benign tumors with normal CA19-9. The aim of this study was to investigate the diagnostic utility of clinical parameters and serum markers in patients with pancreatic head masses but without elevated CA19-9. METHODS: Retrospectively, 106 (69 malignant, 37 benign) of 487 patients admitted for pancreatic head masses were enrolled with CA19-9 level of <37u/ml. Clinical parameters and serum biomarkers were assessed. Among the patients with pancreatic head mass, male individuals (p=0.025) and elder individuals (p<0.001) were more likely to have cancer; and cancer patients were more likely to present with abdominal-pain (p=0.023), weight-loss (p=0.013) and jaundice (p<0.001). Serum bilirubin levels among malignancies, including total bilirubin (p<0.001), direct bilirubin (p<0.001) and indirect bilirubin (p<0.001), were considerably higher than those of benign ones. Logistic regression further concluded that age-distribution, abdominal-pain and direct-bilirubin were three independent factors correlating with final diagnosis. However, CEA (p=0.156) was not sufficient enough to exclude pancreatic cancer. CONCLUSIONS: In patients with pancreatic head masses and CA19-9 of <37u/ml, age-distribution, abdominal-pain and direct bilirubin might be helpful in differential diagnosis. CEA was insufficient for exclusion of malignancy. PMID- 25834541 TI - The relationship between serum cortisol, adrenaline, blood glucose and lipid profile of undergraduate students under examination stress. AB - BACKGROUND: Stress is an extremely adaptive phenomenon in human beings and cortisol is a known stress hormone. Examination has been described as a naturalistic stressor capable of affecting human health. OBJECTIVES: To estimate the relationship between serum cortisol, adrenaline, fasting blood glucose (FBG) and lipid profile during examination stress. METHODS: Two hundred and eight (208) apparently-healthy undergraduate students (aged, 24 +/- 6 years) were involved in the study. Exactly 5 mls of venous blood was collected from each subject 1-3 hours before a major examination. A second assessment was done on the same students 3-4 weeks before any examination (control samples). Cortisol and adrenaline were assayed using ELISA techniques, FBG was assayed using enzymatic method while lipid parameters were assayed using standard enzymatic spectrophotometric methods. RESULTS: There was statistically significant increase in serum cortisol, adrenaline, Total cholesterol, HDL-cholesterol and LDL cholesterol levels in students under examination stress compared to the non examination period (p=0.001, 0.013, 0.0001, 0.0001 and 0.0001, respectively). FBG showed no significant increase. There was also significant positive correlation (r=0.297, p=0.032) between serum cortisol and TC/HDL ratio (cardiac risk factor) before examination stress but not during the stress period. CONCLUSIONS: Significant positive correlation was observed between cortisol and TC/HDL ratio before examination stress. PMID- 25834542 TI - Co-morbid anxiety disorders in patients with schizophrenia in a tertiary institution in South East Nigeria: prevalence and correlates. AB - BACKGROUND: Anxiety disorders occur commonly in schizophrenia but are often overlooked by psychiatrists. Their presence may compound the challenges faced by these patients and may contribute to poor outcome. OBJECTIVES: The purpose of this study was to determine the prevalence of anxiety disorders among the participants with schizophrenia, and the association between this co-morbidity and disability. METHOD: A total of 367 participants were recruited from the out patient department of Federal neuropsychiatric hospital Enugu, Nigeria. Socio demographic questionnaire, schedules for clinical assessment in neuropsychiatry, positive and negative syndrome scale and the 12-item version of the World Health Organization disability assessment schedule were administered. RESULTS: A total of 189 females (51.5%) and 178 (48.5%) males were studied. A lifetime prevalence of 12.3% was reported for anxiety disorder. Anxiety disorder was more likely in females (kappa(2)=4.93, p<0.03). Specific prevalence for anxiety disorder in schizophrenia was generalized anxiety disorder 6.3%, obsessive compulsive disorder 3.3%, and phobic anxiety disorder 2.7%. Anxiety disorder was associated with increased disability (t=3.50, p<0.001) and psychopathology (t=3.40, p<0.001) among the participants studied. Phobias were associated with prescription of low doses of antipsychotics (kappa(2)=4.08, p<0.04). There was a low rate of identification of anxiety disorder in routine clinical practice (k=0.08, p<0.001). CONCLUSION: Co-morbid anxiety disorders are common in schizophrenia and they are associated with increased disability and psychopathology. The results emphasize the need to screen for anxiety disorders in patients with schizophrenia. PMID- 25834543 TI - Ganoderic acid B's influence towards the therapeutic window of trifluoperazine (TFP). AB - BACKGROUND: Ganoderic acid B is an important bioactive ingredient isolated from Ganoderma lucidum, and exhibits various pharmacological activities. AIMS: To investigate the influence of Ganoderic acid B towards the therapeutic window of trifluoperazine (TFP). METHODS: In vitro human liver microsomes (HLMs) incubation system was used to determine the inhibition of Ganoderic acid B towards the glucuronidation of trifluoperazine (TFP). RESULTS: Ganoderic acid B exerted concentration-dependent inhibition towards the glucuronidation of TFP. Furthermore, Dixon plot was used to determine the inhibition type. The intersection point was located in the second quadrant in Dixon plot, indicating the competitive inhibition of Ganoderic acid B towards TFP glucuronidation. Through fitting the data using competitive nonlinear fitting equation, the inhibition kinetic parameter was calculated to be 56.7 uM. CONCLUSION: All this data indicated the potential influence of Ganoderic acid B-containing herbs towards therapeutic window of TFP. Given that the glucuronidation reaction of TFP is the probe reaction of UGT1A4, the data obtained from the present study also indicated the potential influence of Ganoderic acid-containing herbs towards the therapeutic window of drugs mainly undergoing UGT1A4-mediated metabolism. PMID- 25834544 TI - Influence of gender preference and sex composition of surviving children on childbearing intention among high fertility married women in stable union in Malawi. AB - BACKGROUND: Child's gender preference (GP) frequently leads to high fertility which has adverse effect on family health. The link between women's fertility intention, GP and Living Children's Sex Composition (LCSC) as found in this study is less explored in Malawi. OBJECTIVES: We examined the relationship between GP, LCSC and fertility intention. METHODS: This study utilized 2010 MDHS dataset and focused on married women aged 15-49 years (n=1739) in stable unions who currently have at least 5 living children. Data was analyzed at bivariate and multivariate levels (alpha=0.05). RESULTS: About 39.7% of the women have GP and higher proportion (23.3%) has preference for females. Age, region, wealth-quintile, religion, residence and family planning programmes were significantly associated with fertility intention. Women who have GP and same LCSC were 1.35 and 2.4 times significantly more likely to have intention to bear more children than those who have no GP and different sexes composition respectively. These odd ratios changed to 1.38 for GP and 2.44 for LCSC after adjusting for other socio-demographic variables. CONCLUSIONS: We find that GP and LCSC significantly influence women's intention to bear more children. Women should stop childbearing after attaining their desired number irrespective of the LCSC. PMID- 25834545 TI - Women's attitudes towards receiving family planning services from community health workers in rural Western Kenya. AB - BACKGROUND: Kenya ranks among the countries in Africa with high fertility rates. In order to reverse the trends in high fertility rates, there is need to increase uptake of family planning services particularly by use of community health workers (CHWs) in providing these services in rural areas. OBJECTIVE: To describe the perceptions of women towards family planning service provision by CHWs in four rural districts of Western Kenya. It is based on baseline survey data from a three-year, rural community-based family planning project funded by The David and Lucile Packard Foundation. METHODS: A cross-sectional baseline survey was conducted in Western Kenya. The data presented is part of a broader the broader survey . A survey questionnaire was administered to 1,997 women (15-49 years) but only 963 cases were valid for our analyses. RESULTS: The findings revealed that only a third of the respondents exhibited high approval for Family Planning services from CHWs. Only four out of the thirteen variables explored showed significance on attitudes towards family planning services from CHWs. These are age, level of education, knowledge about family planning benefits and districts. CONCLUSION: Women's perception towards family planning services delivered by CHWs in Western region in Kenya is quite low. To improve the demand and supply for family planning services in this region, there is need to invest a substantial amount of effort into sensitization of women on the relevance of CHWs in providing family planning services. PMID- 25834546 TI - Obstructive sleep apnea syndrome and erectile dysfunction: does long term continuous positive airway pressure therapy improve erections? AB - OBJECTIVES: The aim of this age-matched, controlled, prospective clinical study was to investigate frequency and degree of erectile dysfunction (ED) in patients with obstructive sleep apnea syndrome (OSAS) and to evaluate the results of only continuous positive airway pressure (CPAP) therapy on ED in patients with OSAS. MATERIALS AND METHODS: A total of 90 patients were evaluated for potential OSAS. They were given an International Index of Erectile Function questionnaire (IIEF) and Beck Depression Inventory. Sixty-two patients with the diagnosis of OSAS were regarded as study group. Twenty-eight patients in whom the OSAS was excluded, were regarded as the control group. Biochemical and hormonal laboratory evaluation were performed. Then all patients underwent a full-night in laboratory polysomnography examination. The degree of OSAS were evaluated by an expert from chest diseases department. RESULTS: When compared to the control group, a decrease in IIEF-5 scores was found in patients with OSAS. However, this decrease was not statistically significant. After 3 months of CPAP usage in patients with mild to moderate and severe degree OSAS, improvement in IIEF-5 scores was statistically significant. Mean value of IIEF-5 score was 16.63+/-5.91 before CPAP and were improved up to 20.92+/-6.79 (P=0.001). CONCLUSION: It is not certainly possible to say that OSAS is clearly associated with ED. However, after 3 months of regular CPAP usage, ED complaints in patients with OSAS might improve positively. Trials with larger series may give more conclusive data. PMID- 25834547 TI - Knowledge of birth defects among nursing mothers in a developing country. AB - BACKGROUND: In the absence of established guidelines, where formal screening is unavailable for birth defects, a lot of responsibility is placed on parents in the recognition of these defects. OBJECTIVES: The aim of the study was to determine the awareness of mothers about birth effects in a developing country and assess what they know about the prevention, detection and treatment of children with birth defects. METHODS: This was a descriptive cross-sectional study of 714 mothers consecutively selected at two major hospitals in Nigeria between May and December, 2012. Data were collected with interviewer administered questionnaires. Descriptive and inferential statistics were performed using SPSS and statistical significance set at p <0.05. RESULTS: The participants were aged 17 to 42 years. Only 183 (25.6%) were aware of birth defects. Factors associated with awareness of birth defects were older age, religious belief, better education, higher socioeconomic class, early age at booking and registering at a tertiary care facility. Education, socioeconomic class as well as month and location of booking were found to be independent predictors of awareness of birth defects. CONCLUSION: Mothers in Ibadan, Nigeria, a country without a formal newborn screening programme, have a poor level of awareness about birth defects. PMID- 25834548 TI - Developmental screening in South Africa: comparing the national developmental checklist to a standardized tool. AB - BACKGROUND: Worldwide, more than 200 million children in low- and middle-income countries have developmental delays and/or disabilities. In South Africa the only nationally implemented developmental 'screening' tool is integrated as part of 'The Road to Health Booklet (RTHB). METHOD: The study employed a comparative cross-sectional within-subject design to evaluate the accuracy of the RTHB developmental checklist against a standardized international tool i.e. the PEDS tools, consisting of the PEDS and PEDS:DM. A total of 201 participants were included through convenience sampling at primary health care facilities in Tshwane, South Africa. RESULTS: Sensitivity of the RTHB developmental checklist is low, but specificity is high. The RTHB developmental checklist failed to identify more than half the infants at risk of delays or disorders. The nationally implemented developmental checklist is ineffective to identify at-risk infants. It should be adapted and validated or replaced in order to improve identification of at-risk infants. PMID- 25834549 TI - Prevalence and immediate outcome of candida colonized preterm neonates admitted to Special Care Unit of Mulago Hospital, Kampala Uganda. AB - BACKGROUND: Candida species is the third commonest cause of sepsis among neonates. Colonization by Candida is a predictor for candidemia among preterm neonates. OBJECTIVES: To determine prevalence of early Candida colonization and early outcome among colonized preterm neonates admitted to Mulago hospital Special Care Unit. METHODS: A prospective observational cohort was conducted between December 2008 and April 2009. Preterm neonates aged >72 hours and less than one week were screened for Candida colonization of the groin, oral pharynx and rectum using CHROMagar. Colonized neonates were followed up for 14 days. Blood cultures were done for those with signs of septicaemia. The Fisher's exact tests and logistic regression were conducted for factors associated with colonization and mortality among colonized neonates. P values of < 0.05 were considered significant and confidence interval of 95% was used. RESULTS: Candida colonization occurred in 50/213 (23.5%) neonates. Gestational age <= 30 weeks was the only factor independently associated with colonization (p = 0.005). Of the colonized 14/46 (30.4%) died and 13/46 (28.3%) developed mucocutaneous candidiasis. No candidemia was identified. Multiple site colonization was independently associated with mortality (p=0.035). CONCLUSION: The consequence of high colonization observed in this study needs to be further elucidated in Uganda. PMID- 25834550 TI - Validity of common ultrasound methods of fetal weight estimation in late pregnancy among women in Kwale, Niger Delta region, Nigeria. AB - BACKGROUND: Accuracy of some ultrasound equations used in our locality for fetal weight estimation is doubtful. OBJECTIVE: To assess the accuracy of common ultrasound equations used for fetal weight estimation. SUBJECTS AND METHODS: A longitudinal study was conducted on selected Nigerian obstetric population at Central Hospital, Kwale between March, 2009 and January, 2011. Sonography was performed on 412 women with advanced singleton cyesis and measurements of BPD, HC, AC, and FL were obtained and figured into 12 common ultrasound equations for the estimation of fetal weight. The actual birth weight at delivery was recorded. RESULTS: The highest intraclass correlation coefficient was generated by the Hadlock 5 and Hsieh 2 equations. The least mean absolute percent error was obtained with Hsieh 2 equation, followed by Woo 3, and Hadlock 5. These equations also had the least percentage error and the least range of limits of agreement in the same order with no significant difference between their mean fetal weight estimates and that of the actual birth weight (p > 0.05). All twelve equations had strong positive correlation with the actual birth weight with Nzeh 2 equation the least. CONCLUSION: Hsieh 2 equation has the best accuracy in fetal weight estimation studied. PMID- 25834551 TI - Women's status within the household as a determinant of maternal health care use in Nigeria. AB - BACKGROUND: Although gender inequality is often cited as a barrier to improving maternal health in sub-saharan Africa, there is lack of empirical data on how women's socio-cultural characteristics may influence use of health services in Nigeria. OBJECTIVE: To describe how women's position in the household affects receipt of maternity care services. METHODS: Secondary data analysis of 10,052 and 4,590 currently married women aged 15 to 49 years from the 2008 Nigerian DHS who receive skilled antenatal and delivery care at least till pregnancy was done. RESULTS: Receipt of skilled delivery care was by 37.9% while, natal care was by 98.4%. Education, residence and wealth index all significantly influenced receipt of maternal health care. Women who were involved in decision making on their own health (aOR=1.97; 95%CI=1.88-2.06) and were employed throughout the year (aOR=1.11; 95%CI=1.01-1.23) were more likely to receive skilled antenatal care, while those who justified physical intimate partner violence were less likely to receive both skilled antenatal care (aOR=0.92; 95%CI=0.85-0.98) and delivery services (aOR 0.54; 95% CI 0.33-0.87). CONCLUSION: Interventions aimed at improving maternal care should promote women empowerment (decision making, self worth, educational and economic) and should involve partners. PMID- 25834552 TI - Prevalence of artificially created maxillary midline diastema and its complications in a selected nigerian population. AB - BACKGROUND: Maxillary midline diastema (MMD) is generally regarded as a symbol of beauty in Nigeria. The desperation to look beautiful has caused many individuals to seek the creation of artificial midline diastema and that comes often with undesirable side effects. AIM: To determine the prevalence of artificially created maxillary midline diastema (MMD) and its complications in a selected Nigerian population. METHOD: A cross-sectional study using a semi-structured questionnaire as the instrument for data collection was done among patients attending a private clinic in Owerri the capital of Imo state in Nigeria over a period of 18 months. The data were retrieved from the questionnaires and analyzed using the SPSS version 20. RESULTS: There were 141 respondents comprising 58(41.1%) males and 83(58.9%) females, giving a male to female ratio of 1:1.4. The prevalence of artificially created MMD was 34.0% with increased frequency in: the 21-30 years age group; among the females and in respondents with tertiary level of education. Majority of the respondents (69.5%) desire MMD and 20.8% of those without it wanted it created through cosmetic dentistry. Twenty of the 48 respondents with artificial MMD had it done to enhance personal beauty and aesthetics. The commonest complication was tooth sensitivity (44.8%), followed by toothache (41.4%). CONCLUSION: The prevalence of artificially created MMD was 34.0% in this study; and it is commoner in females and younger age group .The commonest complication was tooth sensitivity. Enhancement of personal beauty and aesthetic was the major reason for having it done. PMID- 25834553 TI - Factors influencing awareness and attendance of traditional oral health care practices by residents of a peri-urban community in Ibadan, Nigeria. AB - BACKGROUND: In order to institute preventive programmes against harmful traditional oral health practices there is a need to identify targets. OBJECTIVES: To investigate factors influencing awareness and attendance of traditional oral health practices by residents of a peri-urban community in Ibadan, Nigeria. METHODS: A cross-sectional study of adult residents selected by simple random sampling in a peri-urban community in Ibadan, Nigeria, was conducted over a period of six months. Information was obtained with interviewer administered questionnaires. Data were recorded using SPSS version 16 software. RESULTS: A total of 172 (44.1%) respondents were aware of the existence of traditional healers for dental problems. Only 34 (8.7%) participants had been to traditional healers on account of toothache. About 76.5% reported having relief after treatment with relapse occurring in 12 cases (46.2%). Twenty (58.8%) of these (34) participants said they would not choose this option of treating dental problems in future. Significant associations existed between knowing that traditional healers provided dental treatment and gender (p = 0.001) or history of dental problems (p =0.008). CONCLUSION: The study showed moderate awareness of traditional oral care practices in Ibadan, Nigeria as influenced by gender and previous dental problems. PMID- 25834554 TI - Spectrum of neurosurgical complications following medical tourism: challenges of patients without borders. AB - BACKGROUND AND OBJECTIVES: The cost of medical care and availability of resources (human and facilities) which differs from nation to nation are amongst others, factors driving medical tourism (MT) despite its potential drawbacks. The aim of the study was to analyse all patients that presented with neurosurgical complications following MT. METHODS: A single institution prospective study was carried out. Data which included patients' demographics, diagnosis, Glasgow coma scale score at admission, type of complication, and outcome were collected over a 3 year period and analysed. RESULTS: A total of 23 neurosurgical cases were seen during the study period with a median age of 42 years (17-70 years). India is the most common country visited by Nigerian patients. Nine patients died from various complications on arrival in Nigeria. There was no significant statistical difference between the outcome and patients clinical status prior to travel (p=0.107), country where the surgery was done (p=0.776), admission GCS in Nigeria (p=0.169), and redo surgery in Nigeria (0.181). CONCLUSION: Government in different nations should have legislations to ensure that medical tourists' receive appropriate care abroad, proper follow-up care upon their return, and also promulgate laws to regulate quasi and organised MT agencies that are operating in a regulatory vacuum. PMID- 25834555 TI - Prevalence of cholelithiasis among persons undergoing abdominal ultrasound at the Komfo Anokye Teaching Hospital, Kumasi, Ghana. AB - BACKGROUND: The prevalence of gallstones among Ghanaians is unknown. We aimed to determine the prevalence of gallstones among persons undergoing abdominal ultrasound at the Komfo Anokye Teaching Hospital (KATH). METHODS: We performed a cross-sectional study of patients aged >=14years presenting to KATH for abdominal ultrasound between 2009 and 2012. Patient demographics were recorded. The gallbladder was assessed by ultrasonography. Cholelithiasis was defined as presence of gallstones or absence of gallbladder. Data was expressed as descriptive and inferential statistics. RESULTS: There were 2824 participants. 55% were females. Mean age was 47+/-18 years. Mean body mass index (BMI) was 24.0+/-5.5. Mean parity among females was 3+/-3. Prevalence of cholelithiasis was 5.9 (95%C.I:5.0,6.8). Females had a high prevalence compared to males (6.8 vs 4.7). Prevalence increased steadily by age. Prevalence was 6.6, 5.1 and 8.8 for patients with BMI <18.5, 18.5-24.9 and >=30 respectively. Prevalence among women with parity of 0,1-5 and >5 was 3.1, 6.7 and 6.4 respectively.On multivariate regression analysis, female sex (AOR=1.55;p<0.05), age>=40 years (AOR=2.05;p<0.01), BMI<18.5 (AOR=1.25;p>0.05) or BMI>=30 (AOR=1.39;p>0.05) and family history of gallstones (AOR=11.9;p<0.01) increased the odds of cholelithiasis. CONCLUSIONS: Prevalence of cholelithiasis among patients undergoing ultrasonography at KATH was 5.9. Patient age, sex and family history significantly influenced the prevalence. PMID- 25834556 TI - Anemia in patients on chronic hemodialysis in Cameroon: prevalence, characteristics and management in low resources setting. AB - BACKGROUND: Anemia is a common complication of chronic kidney disease. We investigated the prevalence, characteristics and management of anemia in patients on chronic hemodialysis and assessed the response to blood-transfusion based management in Cameroon. METHODS: This was a cohort study of five months' duration (August-December 2008) conducted at the Yaounde General Hospital's hemodialysis center, involving 95 patients (67 men, 70.5%) on chronic hemodialysis by a native arteriovenous fistula. A monthly evaluation included full blood counts, number of pints of red cell concentrates transfused, and vital status. RESULTS: At baseline, 75 (79%) patients had anemia which was microcytic and hypochromic in 32 (43%). Anemia was corrected in 67 (70.5%) patients using blood transfusion only, while 28 (29.5%) patients were receiving erythropoietin (11 regularly, 39%). Only 77.2% of 342 pints (median 3.0, range 0-17 per patients) of red cell concentrates prescribed were effectively received during the follow-up at an unacceptably high cost to patients and families. Mean hemoglobin and mean corpuscular hemoglobin levels remained stable during follow-up, while mean corpuscular volume increased. Erythropoietin treatment was the main determinant of favorable trajectories of hematological markers. CONCLUSIONS: Patients on chronic hemodialysis have predominantly microcytic hypochromic anemia, with limited capacity for correction using blood transfusion. PMID- 25834557 TI - Problem based learning: tutors' views 5 years after implementation at a sub Saharan University. AB - BACKGROUND: Curriculum evaluation is key to continuous assurance of quality of education. OBJECTIVES: To assess the teachers' perceptions on how well student teaching and learning activities were conducted at an institution that had practiced PBL for five years. METHODS: A cross sectional descriptive study. 150 teachers from 23 departments at the College of Health Sciences participated in the study. A 25 item self-administered questionnaire was used to collect data. Activities evaluated included; students assessment, self-directed learning, feedback and clinical exposure. Data were entered in epi data and analysed using SPSS. Ethical approval was obtained. RESULTS: The participants' average teaching experience was eight years. The PBL/COBES approach mostly achieved the aim of producing self-directed and lifelong learners. Half of the teaching staff actively provided regular feedback about the learning and teaching activities they were involved in. Early clinical exposure was widely accepted as a highly rewarding appropriate teaching and learning strategy. COBES activities were well organized although involvement of College staff was low. CONCLUSION: PBL/COBES program was successfully executed and had high acceptance among Faculty. The biggest challenge was getting all staff to provide regular feedback. Self institutional curriculum review can be done cheaply and quickly to provide feedback for continual curriculum improvement. PMID- 25834558 TI - Use of simulators in operative dental education: experience in southern Nigeria. AB - BACKGROUND: Though the use of simulators in operative dentistry is not new, the teaching and learning practices that take place during clinical sessions in skills laboratories are rarely reported. This study was designed to determine the current practices relating to teaching and learning of dental clinical skills in southern Nigeria. METHODS: A cross-sectional study was conducted among the final year dental students in southern Nigeria using anonymous structured questionnaire as instrument for data collection. The questionnaire items included statements relating to existing teaching and learning practices. A five-point Likert scale response option was provided and descriptive summary statistics was computed. RESULTS: There were 56 (34.8%) females and 105 (65.2%) males. Most of the students (41.0%) agreed that the theoretical concept behind clinical skills is taught prior to clinical sessions and most agreed that the objectives of each clinical session are stated and that the procedures are usually demonstrated. Most of the respondents (39.8%) agreed that feedback was sometimes embarrassing and given at the end of clinical sessions (76.6%). Equipment breakdown was a major challenge to learning. CONCLUSION: Dental education in the skills labs within the region appeared standard. However, feedback should be continuous and constructive. Equipment breakdown was the major constraint to learning. PMID- 25834559 TI - Exploring the scope of community-based rehabilitation in ensuring the holistic development of differently-abled people. AB - BACKGROUND: Globally, it has been estimated that almost 15% of world's population live with some form of disability, of which the majority are from developing nations. OBJECTIVES: To explore the role of community-based rehabilitation (CBR) in the health sector, identify the prevalent challenges, and to suggest measures to facilitate its smooth implementation in community. METHODS: An extensive search of all materials related to the topic was made using library sources including Pubmed, Medline and World Health Organization. Keywords used in the search included community, community-based rehabilitation, disabled, and public health. RESULTS: The notion of community-based rehabilitation (CBR) emerged in 1978 with an aim to improve the accessibility of disabled people to rehabilitation services, especially in developing countries, by ensuring optimal use of locally available resources. CBR programs support people with disabilities by providing health services at their doorsteps, and thus estalish a strong linkage between people with disabilities and the health-care system. CONCLUSION: CBR encompasses a set of interventions that are implemented for a diverse and complex group of disabled people, and thus necessitates careful planning and systematic execution for ensuring welfare of these vulnerable people. PMID- 25834560 TI - South African patient's acceptance of generic drugs. PMID- 25834561 TI - Dangerous to mix: culture and politics in a traditional circumcision in South Africa. AB - BACKGROUND: Traditional circumcision (initiation) is an integral part of the Xhosa speaking communities. Circumcision is the first step towards manhood. It involves a number of cultural, religious, legal and ethical issues, which in terms of the constitution of the Republic of South Africa, are rights that must be protected. OBJECTIVE: To highlight the problem of circumcision related death in South Africa. CASE REPORT: This case report examines a 16- year boy who had died as result of botched circumcision by an unqualified traditional surgeon. He kept the boy in his custody despite his serious illness. He applied a tight bandage to control the bleeding, resulting in gangrene of the penis followed by septicemia. The histories, postmortem findings, cause of death and medico- legal and social aspects have been discussed in this manuscript. CONCLUSION: There are unacceptable deaths related with circumcision in South Africa. The right to life cannot be sacrificed at the altar of culture and politics. PMID- 25834562 TI - Resolution of dilated cardiomyopathy in an adolescent with change of a failing highly active antiretroviral drug therapy. AB - BACKGROUND: Cardiovascular dysfunction is a recognized complication of HIV infection in children. Cardiac complications of HIV usually occur late in the course of the disease; they may be associated with drug therapy, and hence become more common as therapy and survival improve. Left ventricular (LV) dysfunction at baseline is a risk factor for death independent of the CD4 cell count, HIV viral load, and neurological disease. CLINICAL CASE: We present the case of a 15 year old girl with HIV who developed left ventricular dysfunction while non-compliant on highly active antiretroviral therapy (HAART). She presented with features of heart failure over a course of two months. Her laboratory evaluation was significant for leucopenia with a low CD4 count, high viral load, elevated ESR and CRP. The ECG showed a sinus tachycardia with diffuse ST-T segment changes and LVH with strain. Initial echo revealed dilated left heart chambers with poor LV systolic function and a small pericardial effusion with the development of an LV thrombus on follow up echo evaluation. She was started on heart failure medicines and had anticoagulation for the LV thrombus. She received adherence counseling and her HAART regimen was changed. Six months after presentation she became asymptomatic with higher CD4 counts and a normal LV size and function on echo. CONCLUSION: Immunological recovery following a switch of a failing or potentially cardiotoxic HAART in addition to improved HAART adherence may result in resolution of left ventricular dysfunction. Early and regular cardiology evaluation may improve outcomes in these patients. PMID- 25834563 TI - Giant simple hepatic cyst: a case report and review of relevant literature. AB - BACKGROUND: Giant cysts of the liver are uncommon. Symptoms are related primarily to the mass effect of the enlarging cyst. OBJECTIVE: To highlight the challenges of management of giant simple hepatic cyst in a resource limited setting. CASE REPORT: Presented is a 58-year-old seamstress with a 5-year history of an enlarging abdominal mass with easy satiety. Surgery revealed an exophytic giant simple hepatic cyst arising from liver segment IV that drained 4.6 litres of serous fluid. CONCLUSION: Simple hepatic cyst can attain giant dimensions and should be considered in the differential diagnosis of intraabdominal masses. PMID- 25834564 TI - Hypogammaglobulinemia in sub-Saharan Africa: a case report and review of the literature. AB - Patients with hypogammaglobulinemia are susceptible to recurrent bacterial, viral, fungal, and parasitic infections. The most common clinical manifestation includes recurrent severe infections caused by encapsulated bacteria, in which antibody opsonization is the primary defense mechanism. To our knowledge, this is the first case report of hypogammaglobulinemia in a Ugandan child in Sub-Saharan Africa. The case emphasizes the importance of including hypogammaglobulinemia in the differential diagnosis for children presenting with a history of recurrent infections. AIM: To raise the index of clinical suspicion of hypogammaglobulinemia in an African child and allow for prompt recognition and management of hypogammaglobulinemia. PMID- 25834565 TI - Idiopathic hypertrophic pachymeningitis presenting with occipital neuralgia. AB - BACKGROUND: Although occipital neuralgia is usually caused by degenerative arthropathy, nearly 20 other aetiologies may lead to this condition. METHODS: We present the first case report of hypertrophic pachymeningitis revealed by isolated occipital neuralgia. RESULTS AND CONCLUSIONS: Idiopathic hypertrophic pachymeningitis is a plausible cause of occipital neuralgia and may present without cranial-nerve palsy. There is no consensus on the treatment for idiopathic hypertrophic pachymeningitis, but the usual approach is to start corticotherapy and then to add immunosuppressants. When occipital neuralgia is not clinically isolated or when a first-line treatment fails, another disease diagnosis should be considered. However, the cost effectiveness of extended investigations needs to be considered. PMID- 25834566 TI - Bystander cardiopulmonary resuscitation in out of hospital cardiac arrest: need of the hour. PMID- 25834567 TI - Platelet indices evaluation in patients with liver cirrhosis: methodological drawbacks. PMID- 25834568 TI - Managing Ebola from rural to urban slum settings: experiences from Uganda. AB - BACKGROUND: Five outbreaks of ebola occurred in Uganda between 2000-2012. The outbreaks were quickly contained in rural areas. However, the Gulu outbreak in 2000 was the largest and complex due to insurgency. It invaded Gulu municipality and the slum- like camps of the internally displaced persons (IDPs). The Bundigugyo district outbreak followed but was detected late as a new virus. The subsequent outbreaks in the districts of Luwero district (2011, 2012) and Kibaale (2012) were limited to rural areas. METHODS: Detailed records of the outbreak presentation, cases, and outcomes were reviewed and analyzed. Each outbreak was described and the outcomes examined for the different scenarios. RESULTS: Early detection and action provided the best outcomes and results. The ideal scenario occurred in the Luwero outbreak during which only a single case was observed. Rural outbreaks were easier to contain. The community imposed quarantine prevented the spread of ebola following introduction into Masindi district. The outbreak was confined to the extended family of the index case and only one case developed in the general population. However, the outbreak invasion of the town slum areas escalated the spread of infection in Gulu municipality. Community mobilization and leadership was vital in supporting early case detection and isolations well as contact tracing and public education. CONCLUSION: Palliative care improved survival. Focusing on treatment and not just quarantine should be emphasized as it also enhanced public trust and health seeking behavior. Early detection and action provided the best scenario for outbreak containment. Community mobilization and leadership was vital in supporting outbreak control. International collaboration was essential in supporting and augmenting the national efforts. PMID- 25834569 TI - From Ebola in the slums of East and West Africa to NCDs, mental, child and reproductive health. PMID- 25834570 TI - Immune centroids oversampling method for binary classification. AB - To improve the classification performance of imbalanced learning, a novel oversampling method, immune centroids oversampling technique (ICOTE) based on an immune network, is proposed. ICOTE generates a set of immune centroids to broaden the decision regions of the minority class space. The representative immune centroids are regarded as synthetic examples in order to resolve the imbalance problem. We utilize an artificial immune network to generate synthetic examples on clusters with high data densities, which can address the problem of synthetic minority oversampling technique (SMOTE), which lacks reflection on groups of training examples. Meanwhile, we further improve the performance of ICOTE via integrating ENN with ICOTE, that is, ICOTE + ENN. ENN disposes the majority class examples that invade the minority class space, so ICOTE + ENN favors the separation of both classes. Our comprehensive experimental results show that two proposed oversampling methods can achieve better performance than the renowned resampling methods. PMID- 25834571 TI - Gremlin, a bone morphogenetic protein antagonist, is a crucial angiogenic factor in pituitary adenoma. AB - Gremlin is an antagonist of bone morphogenetic protein (BMP) and a major driving force in skeletal modeling in the fetal stage. Several recent reports have shown that Gremlin is also involved in angiogenesis of lung cancer and diabetic retinopathy. The purpose of this study was to investigate the role of Gremlin in tumor angiogenesis in pituitary adenoma. Double fluorescence immunohistochemistry of Gremlin and CD34 was performed in pituitary adenoma tissues obtained during transsphenoidal surgery in 45 cases (7 PRLoma, 17 GHoma, 2 ACTHoma, and 2 TSHoma). Gremlin and microvascular density (MVD) were detected by double immunofluorescence microscopy in CD34-positive vessels from tissue microarray analysis of 60 cases of pituitary adenomas (6 PRLoma, 23 GHoma, 22 NFoma, 5 ACTHoma, and 4 TSHoma). In tissue microarray analysis, MVD was significantly correlated with an increased Gremlin level (linear regression: P < 0.005, r (2) = 0.4958). In contrast, Gremlin expression showed no correlation with tumor subtype or Knosp score. The high level of expression of Gremlin in pituitary adenoma tissue with many CD34-positive vessels and the strong coherence of these regions indicate that Gremlin is associated with angiogenesis in pituitary adenoma cells. PMID- 25834573 TI - Lacrimal Gland Fistula following Severe Head Trauma. AB - We aim to present a unique case with discharging lacrimal gland fistula secondary to severe head trauma by an animal. A 9-year-old girl presented with serous fluid discharge from a cutaneous fistula in the left orbital region. The patient had history of surgery for traumatic frontal bone fracture and skin laceration in the superior orbital rim three weeks earlier. She underwent a complete ophthalmological examination and there was no anterior segment or fundus pathology. The orifice of the fistula was detected in mediolateral part of the left superior orbital rim and fluid secretion was increasing with irritation of the left eye. Neurosurgical complications were excluded and radiological assessment was nonremarkable. The patient's legal representatives were informed and lacrimal gland fistulectomy was planned. However, the fistula was self-closed one week after initial ophthalmological examination, and the patient had no symptoms. In conclusion, traumatic injuries of superior orbital region should be carefully evaluated and wounds should be well closed to prevent consecutive lacrimal gland fistula. PMID- 25834572 TI - Overexpression of Activation-Induced Cytidine Deaminase in MTX- and Age-Related Epstein-Barr Virus-Associated B-Cell Lymphoproliferative Disorders of the Head and Neck. AB - Recent research has shown that activation-induced cytidine deaminase (AID) triggers somatic hypermutation and recombination, in turn contributing to lymphomagenesis. Such aberrant AID expression is seen in B-cell leukemia/lymphomas, including Burkitt lymphoma which is associated with c-myc translocation. Moreover, Epstein-Barr virus (EBV) latent membrane protein-1 (LMP 1) increases genomic instability through early growth transcription response-1 (Egr-1) mediated upregulation of AID in B-cell lymphoma. However, few clinicopathological studies have focused on AID expression in lymphoproliferative disorders (LPDs). Therefore, we conducted an immunohistochemical study to investigate the relationship between AID and LMP-1 expression in LPDs (MTX-/Age related EBV-associated), including diffuse large B-cell lymphomas (DLBCLs). More intense AID expression was detected in LPDs (89.5%) than in DLBCLs (20.0%), and the expression of LMP-1 and EBER was more intense in LPDs (68.4% and 94.7%) than in DLBCLs (10.0% and 20.0%). Furthermore, stronger Egr-1 expression was found in MTX/Age-EBV-LPDs (83.3%) than in DLBCLs (30.0%). AID expression was significantly constitutively overexpressed in LPDs as compared with DLBCLs. These results suggest that increased AID expression in LPDs may be one of the processes involved in lymphomagenesis, thereby further increasing the survival of genetically destabilized B-cells. AID expression may be a useful indicator for differentiation between LPDs and DLBCLs. PMID- 25834574 TI - Diabetic ketoacidosis as first presentation of latent autoimmune diabetes in adult. AB - A 54-year-old white female with hypothyroidism presented with abdominal pain, nausea, vomiting, and diarrhea. She was found to have diabetic ketoacidosis (DKA) and admitted to our hospital for treatment. Laboratory workup revealed positive antiglutamic acid decarboxylase antibodies and subsequently she was diagnosed with latent onset autoimmune diabetes in adult (LADA). She was successfully treated with insulin with clinical and laboratory improvement. Diagnosis of LADA has been based on three criteria as given by The Immunology of Diabetes Society: (1) adult age of onset (>30 years of age); (2) presence of at least one circulating autoantibody (GADA/ICA/IAA/IA-2); and (3) initial insulin independence for the first six months. The importance of this case is the unlikely presentation of LADA. We believe that more research is needed to determine the exact proportion of LADA patients who first present with DKA, since similar cases have only been seen in case reports. Adult patients who are obese and have high blood sugar may deserve screening for LADA, especially in the presence of other autoimmune diseases. Those patients once diagnosed with LADA need extensive diabetic education including potentially serious events such as diabetic ketoacidosis. PMID- 25834575 TI - Comparative investigation of human amniotic epithelial cells and mesenchymal stem cells for application in bone tissue engineering. AB - Emerging evidence suggests amniotic epithelial cells (AECs) as a promising source of progenitor cells in regenerative medicine and bone tissue engineering. However, investigations comparing the regenerative properties of AECs with other sources of stem cells are particularly needed before the feasibility of AECs in bone tissue engineering can be determined. This study aimed to compare human amniotic epithelial cells (hAECs), human bone marrow mesenchymal stem cells (hBMSCs), and human amniotic fluid derived mesenchymal stem cells (hAFMSCs) in terms of their morphology, proliferation, immunophenotype profile, and osteogenic capacity in vitro and in vivo. Not only greatly distinguished by cell morphology and proliferation, hAECs, hAFMSCs, and hBMSCs exhibited remarkably different signature regarding immunophenotypical profile. Microarray analysis revealed a different expression profile of genes involved in ossification along the three cell sources, highlighting the impact of different anatomical origin and molecular response to osteogenic induction on the final tissue-forming potential. Furthermore, our data indicated a potential role of FOXC2 in early osteogenic commitment. PMID- 25834576 TI - Improved dosimetry in prostate brachytherapy using high resolution contrast enhanced magnetic resonance imaging: a feasibility study. AB - PURPOSE: To assess detailed dosimetry data for prostate and clinical relevant intra- and peri-prostatic structures including neurovascular bundles (NVB), urethra, and penile bulb (PB) from postbrachytherapy computed tomography (CT) versus high resolution contrast enhanced magnetic resonance imaging (HR-CEMRI). MATERIAL AND METHODS: Eleven postbrachytherapy prostate cancer patients underwent HR-CEMRI and CT imaging. Computed tomography and HR-CEMRI images were randomized and 2 independent expert readers created contours of prostate, intra- and peri prostatic structures on each CT and HR-CEMRI scan for all 11 patients. Dosimetry data including V100, D90, and D100 was calculated from these contours. RESULTS: Mean V100 values from CT and HR-CEMRI contours were as follows: prostate (98.5% and 96.2%, p = 0.003), urethra (81.0% and 88.7%, p = 0.027), anterior rectal wall (ARW) (8.9% and 2.8%, p < 0.001), left NVB (77.9% and 51.5%, p = 0.002), right NVB (69.2% and 43.1%, p = 0.001), and PB (0.09% and 11.4%, p = 0.005). Mean D90 (Gy) derived from CT and HR-CEMRI contours were: prostate (167.6 and 150.3, p = 0.012), urethra (81.6 and 109.4, p = 0.041), ARW (2.5 and 0.11, p = 0.003), left NVB (98.2 and 58.6, p = 0.001), right NVB (87.5 and 55.5, p = 0.001), and PB (11.2 and 12.4, p = 0.554). CONCLUSIONS: Findings of this study suggest that HR CEMRI facilitates accurate and meaningful dosimetric assessment of prostate and clinically relevant structures, which is not possible with CT. Significant differences were seen between CT and HR-CEMRI, with volume overestimation of CT derived contours compared to HR-CEMRI. PMID- 25834577 TI - Prostate brachytherapy in New South Wales: patterns of care study and impact of caseload on treatment quality. AB - PURPOSE: We performed the first comprehensive, population-based brachytherapy (BT) Patterns of Care Study in the Australian setting. Herein we report on prostate BT and assess the technical quality of BT practice, focusing on whether a caseload effect could be identified in New South Wales (NSW). MATERIAL AND METHODS: Site visits were made to all radiation oncology departments in NSW that delivered prostate BT, collecting relevant data on NSW residents treated with prostate BT in 2003. Overall quality of NSW prostate BT treatment was assessed using benchmarks including treatment of appropriate prostate cancer disease risk category, absence of (relative) physical contraindications, optimal planned and treated dosimetry, and pre-/post-implant planning/CT. Quality was compared between higher and lower caseload departments. RESULTS: One hundred and fifty seven (67%) patients underwent temporary BT and 79 (33%) permanent seed BT. Prostate BT was concentrated in five departments, with three of four departments with active programmes treating greater than the recommended 25 cases. Rates of concordance with quality benchmarks were high (85-99%) with no consistent caseload effect identified. CONCLUSIONS: Prostate BT in NSW in 2003 was generally of high quality and a caseload effect on quality could not be identified. This may be because the number of departments was insufficient to determine a caseload effect, or because the prostate BT was largely concentrated in a small number of high caseload departments. PMID- 25834578 TI - Postoperative interstitial brachytherapy in eyelid cancer: long term results and assessment of Cosmesis After Interstitial Brachytherapy scale. AB - PURPOSE: To analyse feasibility and safety of postoperative interstitial brachytherapy (IBRT) in patients of eyelid cancer treated primarily by surgical excision. MATERIAL AND METHODS: In this series, 8 patients with eyelid cancer were treated using postoperative interstitial brachytherapy. Patients were followed up for local control, cosmetic outcome, and acute and late toxicities. Cosmetic outcome was measured using a 6 point indigenous Cosmesis After Interstitial Brachytherapy (CAIB) scale. RESULTS: The patients were between 23-82 years (median: 71 years). There were 3 females and 5 males, and 3 patients had lesions in upper eyelid. Postoperative high-dose-rate brachytherapy was used in all with 2 catheters implanted in most of them (6 out of 8). Local control was calculated from end of treatment to last follow-up. At last follow-up, all patients remained locally controlled. Two patients had nodal recurrence 6 months after interstitial brachytherapy and were salvaged effectively by external beam radiotherapy. At last follow-up, 7 patients were loco-regionally controlled and one was lost to follow up. All patients had Radiation Therapy Oncology Group (RTOG) grade 1 acute toxicity and 2 had grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version.3 late toxicities. The cosmesis score for the whole group ranged between 0-1 indicating excellent to very good cosmesis. CONCLUSIONS: Postoperative high-dose-rate brachytherapy resulted in excellent disease control and cosmesis without significant acute or late toxicities. It is an effective modality for treatment of eyelid cancers in selected patients. Future prospective studies with the validation of CAIB scale would give us more insight to this effective yet often ignored modality of IBRT. PMID- 25834579 TI - Depth determination of skin cancers treated with superficial brachytherapy: ultrasound vs. histopathology. AB - PURPOSE: The purpose of this study is to compare high frequency ultrasonography (HFUS) and histpathologic assessment done by punch biopsy in order to determine depth of basal cell carcinoma (BCC), in both superficial and nodular BCCs prior to brachytherapy treatment. MATERIAL AND METHODS: This study includes 20 patients with 10 superficial and 10 nodular BCCs. First, punch biopsy was done to confirm the diagnosis and to measure tumour depth (Breslow rate). Subsequently, HFUS was done to measure tumour depth to search for correlation of these two techniques. RESULTS: Neither clear tendency nor significance of the punch biopsy vs. HFUS depth determination is observed. Depth value differences with both modalities resulted patient dependent and then consequence of its uncertainty. Conceptually, HFUS should determine the macroscopic lesion (gross tumour volume - GTV), while punch biopsy is able to detect the microscopic extension (clinical target volume CTV). Uncertainties of HFUS are difficult to address, while punch biopsy is done just on a small lesion section, not necessarily the deepest one. CONCLUSIONS: According to the results, HFUS is less accurate at very shallow depths. Nodular cases present higher depth determination differences than superficial ones. In our clinical practice, we decided to prescribe at 3 mm depth when HFUS measurements give depth lesion values smaller than this value. PMID- 25834580 TI - Single versus multichannel applicator in high-dose-rate vaginal brachytherapy optimized by inverse treatment planning. AB - PURPOSE: To retrospectively compare the potential dosimetric advantages of a multichannel vaginal applicator vs. a single channel one in intracavitary vaginal high-dose-rate (HDR) brachytherapy after hysterectomy, and evaluate the dosimetric advantage of fractional re-planning. MATERIAL AND METHODS: We randomly selected 12 patients with endometrial carcinoma, who received adjuvant vaginal cuff HDR brachytherapy using a multichannel applicator. For each brachytherapy fraction, two inverse treatment plans (for central channel and multichannel loadings) were performed and compared. The advantage of fractional re-planning was also investigated. RESULTS: Dose-volume-histogram (DVH) analysis showed limited, but statistically significant difference (p = 0.007) regarding clinical target-volume dose coverage between single and multichannel approaches. For the organs-at-risk rectum and bladder, the use of multichannel applicator demonstrated a noticeable dose reduction, when compared to single channel, but statistically significant for rectum only (p = 0.0001). For D2cc of rectum, an average fractional dose of 6.1 +/- 0.7 Gy resulted for single channel vs. 5.1 +/- 0.6 Gy for multichannel. For D2cc of bladder, an average fractional dose of 5 +/- 0.9 Gy occurred for single channel vs. 4.9 +/- 0.8 Gy for multichannel. The dosimetric benefit of fractional re-planning was demonstrated: DVH analysis showed large, but not statistically significant differences between first fraction plan and fractional re-planning, due to large inter-fraction variations for rectum and bladder positioning and filling. CONCLUSIONS: Vaginal HDR brachytherapy using a multichannel vaginal applicator and inverse planning provides dosimetric advantages over single channel cylinder, by reducing the dose to organs at risk without compromising the target volume coverage, but at the expense of an increased vaginal mucosa dose. Due to large inter-fraction dose variations, we recommend individual fraction treatment plan optimization. PMID- 25834581 TI - Effects of bladder distension on dose distribution of vaginal vault brachytherapy in patients with endometrial cancer. AB - PURPOSE: To investigate dosimetric effects of bladder distention on organs at risk (OARs) during treatment of endometrial cancer using 3D image-based planning of postoperative vaginal vault brachytherapy (BRT). MATERIAL AND METHODS: Fifteen patients with early-stage endometrial cancer were studied, each undergoing adjuvant BRT of vaginal vault via 3.5 cm diameter cylinder. As treatment, 25 Gy in 5 fractions were delivered to 5 mm depth of the vaginal mucosa. Dose-volume histograms of OARs were generated individually with bladder empty and with bladder inflated by sterile saline (180 ml), to compare doses received. RESULTS: Bladder distention appreciably impacted dosimetry of bladder, sigmoid colon, and small bowel, but dosimetry of rectum was unaffected. With bladder inflated, mean cylinder-to-bowel distance increased significantly (1.69 cm vs. 1.20 cm; p = 0.006). Mean minimum dose to most exposed 2 cc (D2cc) volume also rose significantly at bladder (5.40 Gy vs. 4.55 Gy [18.7%]; p < 0.001), as opposed to near-significant reductions in D2cc at sigmoid colon (15.1%; p = 0.11) and at small bowel (10.5%; p = 0.14). A full bladder had no effect on dose to 50% volume (D50%) of bladder or rectum, and declines seen in mean D50% values of sigmoid colon (22.7%; p = 0.12) and small bowel (19.0%; p = 0.13) again fell short of statistical significance. CONCLUSIONS: The combination of a full bladder and an empty rectum may cause significant unwanted increases in BRT dosing of bladder, without significantly impacting sigmoid colon and small bowel exposures. These findings should be validated through further clinical studies. PMID- 25834582 TI - Effect of diameter of nanoparticles and capture cross-section library on macroscopic dose enhancement in boron neutron capture therapy. AB - PURPOSE: The aim of this study is evaluation of the effect of diameter of (10)B nanoparticles and various neutron capture cross-section libraries on macroscopic dose enhancement in boron neutron capture therapy (BNCT). MATERIAL AND METHODS: MCNPX Monte Carlo code was used for simulation of a (252)Cf source, a soft tissue phantom and a tumor containing (10)B nanoparticles. Using (252)Cf as a neutron source, macroscopic dose enhancement factor (MDEF) and total dose rate in tumor in the presence of 100, 200, and 500 ppm of (10)B nanoparticles with 25 nm, 50 nm, and 100 nm diameters were calculated. Additionally, the effect of ENDF, JEFF, JENDL, and CENDL neutron capture cross-section libraries on MDEF was evaluated. RESULTS: There is not a linear relationship between the average MDEF value and nanoparticles' diameter but the average MDEF grows with increased concentration of (10)B nanoparticles. There is an increasing trend for average MDEF with the tumor distance. The average MDEF values were obtained the same for various neutron capture cross-section libraries. The maximum and minimum doses that effect on the total dose in tumor were neutron and secondary photon doses, respectively. Furthermore, the boron capture related dose component reduced in some extent with increase of diameter of (10)B nanoparticles. CONCLUSIONS: Based on the results of this study, it can be concluded that from physical point of view, various nanoparticle diameters have no dominant effect on average MDEF value in tumor. Furthermore, it is concluded that various neutron capture cross section libraries are resulted to the same macroscopic dose enhancements. However, it is predicted that taking into account the biological effects for various nanoparticle diameters will result in different dose enhancements. PMID- 25834583 TI - Perineal recurrence of prostate cancer six years after trans-perineal brachytherapy. AB - We report a case of perineal recurrence of prostate cancer 6 years after low-dose rate (LDR) brachytherapy for localized prostate cancer. The most common approach to treat such perineal masses, including those occurring after prior biopsy or surgery, is local excision. We report the use of stereotactic radiotherapy with volumetric modulated arc therapy (VMAT) as a novel non-invasive, potentially curative, and patient-friendly alternative to local excision. PMID- 25834584 TI - Recurrent Bowen's disease of scalp treated with high dose rate surface mold brachytherapy: a case report and review of the literature. AB - Our case is a 46-year-old female presenting to us with Bowen's disease of scalp since 5 years. Patient had failed topical therapy with 5% 5-florouracil, 0.1% tacrolimus and was intolerant to topical imiquimod. At presentation, she had 15 cm * 10 cm erythematous, hyperpigmented, crusted plaque with irregular border in the superior and lateral aspect of left side of scalp with extension in to forehead. Patient was treated with computed tomography based customized surface mold high dose rate brachytherapy with Iridium-192 to a dose of 35 Gy in 10 fractions (twice daily, 6 hours apart) over 5 days. Patient tolerated the treatment well and showed regression of the lesion with mild dermatitis at the end of treatment. Though dermatitis increased at 2 weeks, at 4 weeks post treatment there was near complete resolution of the lesion with adjacent alopecia. At 8 weeks after completion of the treatment, there was complete resolution of the lesion and patient was asymptomatic. Alopecia in the adjacent area has resolved and the skin pigmentation has begun. Patient is satisfied with both the disease control and the cosmetic outcome of the procedure. Our case report demonstrates successful application of surface mold high dose rate brachytherapy in the treatment of recurrent Bowen's disease of the scalp. Brachytherapy can play an important role in the management of recurrent malignant and premalignant diseases of the complex treatment sites like scalp and it's non hesitant use should be encouraged in appropriately selected patients at the earliest. PMID- 25834585 TI - The use of an interstitial boost in the conservative treatment of breast cancer: how to perform it routinely in a radiotherapy department. AB - PURPOSE: To demonstrate the utility of a boost with interstitial brachytherapy (BT) in breast-conserving therapy (BCT) by doing a thorough review of the literature and describing in detail our technique for delivering this boost. MATERIAL AND METHODS: Our department has been delivering the boost with interstitial BT since 1989, in most cases with rigid needles and a theoretical dosimetry. In the early years, we used low-dose-rate (LDR) with iridium-192 wires. The dose administered was 15 Gy if there were no risk factors for local relapse or 20-25 Gy in the presence of risk factors. The risk factors considered were the presence of a close margin (less than 10 mm) and an extensive intraductal component (more than 25%). After 2002, we switched to high-dose-rate (HDR); using the linear quadratic model we changed the low dose to 3 fractions of 4.5 Gy in the case of no risk factors for local relapse or to 3 fractions of 5 Gy in the presence of risk factors. RESULTS: In 79 consecutive boost patients treated in our department between 2010 and 2011, with a median follow-up of 46 months, the local control rate was 97.47%. With respect to cosmesis, fibrosis occurred in 17 cases (21.5%) and hyperpigmentation in 26 cases (32.9%). Our hospital's results are comparable in terms of local control and cosmesis to those of other authors. CONCLUSIONS: This educational article describes our department's boost technique with rigid needles and comments briefly on our results using this technique in a group of consecutively treated patients in our department. A review of the literature and the published results on local control and cosmesis is also described. PMID- 25834586 TI - Modern head and neck brachytherapy: from radium towards intensity modulated interventional brachytherapy. AB - Intensity modulated brachytherapy (IMBT) is a modern development of classical interventional radiation therapy (brachytherapy), which allows the application of a high radiation dose sparing severe adverse events, thereby further improving the treatment outcome. Classical indications in head and neck (H&N) cancers are the face, the oral cavity, the naso- and oropharynx, the paranasal sinuses including base of skull, incomplete resections on important structures, and palliation. The application type can be curative, adjuvant or perioperative, as a boost to external beam radiation as well as without external beam radiation and with palliative intention. Due to the frequently used perioperative application method (intraoperative implantation of inactive applicators and postoperative performance of radiation), close interdisciplinary cooperation between surgical specialists (ENT-, dento-maxillary-facial-, neuro- and orbital surgeons), as well interventional radiotherapy (brachytherapy) experts are obligatory. Published results encourage the integration of IMBT into H&N therapy, thereby improving the prognosis and quality of life of patients. PMID- 25834587 TI - Clinical implementation of a new electronic brachytherapy system for skin brachytherapy. AB - Although surgery is usually the first-line treatment for nonmelanoma skin cancers, radiotherapy (RT) may be indicated in selected cases. Radiation therapy as primary therapy can result in excellent control rates, cosmetics, and quality of life. Brachytherapy is a radiation treatment modality that offers the most conformal option to patients. A new modality for skin brachytherapy is electronic brachytherapy. This involves the placement of a high dose rate X-ray source directly in a skin applicator close to the skin surface, and therefore combines the benefits of brachytherapy with those of low energy X-ray radiotherapy. The Esteya electronic brachytherapy system is specifically designed for skin surface brachytherapy procedures. The purpose of this manuscript is to describe the clinical implementation of the new Esteya electronic brachytherapy system, which may provide guidance for users of this system. The information covered includes patient selection, treatment planning (depth evaluation and margin determination), patient marking, and setup. The justification for the hypofractionated regimen is described and compared with others protocols in the literature. Quality assurance (QA) aspects including daily testing are also included. We emphasize that these are guidelines, and clinical judgment and experience must always prevail in the care of patients, as with any medical treatment. We conclude that clinical implementation of the Esteya brachytherapy system is simple for patients and providers, and should allow for precise and safe treatment of nonmelanoma skin cancers. PMID- 25834588 TI - An index to predict ribavirin-induced anemia in asian patients with chronic genotype 1 hepatitis C. AB - BACKGROUND: Single-nucleotide polymorphisms (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene correlate with ribavirin (RBV)-induced anemia in patients with chronic hepatitis C (CHC) receiving combination therapy. Managing anemia is an early priority in the treatment process. OBJECTIVES: The aim was to develop a predictive index based on ITPA SNP status to identify CHC patients at risk of anemia. PATIENTS AND METHODS: A total of 418 eligible East Asian patients diagnosed with CHC genotype 1 (G1) received combination therapy in this study. Participant DNA was genotyped for a functional ITPA SNP (C/C, A/A or C/A) on chromosome 20 at rs1127354. A predictive index was constructed by incorporating independent factors identified for severe anemia events (hemoglobin < 10 g/dL). Areas under the receiver-operating characteristic curves (AUCs) represented the diagnostic accuracies of the predictive index in randomly assigned development and validation cohorts. RESULTS: Multiple logistic regressions identified age (>= 50 y: OR = 9.7, 95% CI = 5.0 - 18.6), ITPA rs1127354 (C/C: OR = 3.3, 95% CI = 1.8 - 5.8) and baseline hemoglobin (< 14.0 g/dL: OR 6.4, 95% CI = 3.3 - 12.1; 14.0 - 14.9: OR = 2.4, 95% CI = 1.2 - 4.6) as predictors of severe anemia throughout the treatment. For severe anemia, the predictive index incorporating age, ITPA SNP status and baseline hemoglobin yielded diagnostic accuracies (AUCs) of 0.830 (95% CI = 0.783 - 0.871) in the development (n = 324) and 0.902 (0.826 - 0.925) in the validation (n = 81) cohorts. CONCLUSIONS: In patients with CHC G1 and receiving combination therapy, ITPA SNP-based index was an accurate and practical solution for prediction of severe anemia. PMID- 25834589 TI - Histological Evaluation of Single and Double-visit Direct Pulp Capping with Different Materials on Sound Human Premolars: A Randomized Controlled Clinical Trial. AB - INTRODUCTION: The aim of this study was to evaluate the clinical and histological status of the pulp in sound human premolars after direct pulp capping (DPC) with four different DPC methods/materials. METHODS AND MATERIALS: This study was conducted on eight volunteers who had to extract four first premolars due to orthodontic treatment. Subsequent to tooth isolation, standardized class I occlusal cavities were prepared and the buccal pulp horns were exposed. Then four different protocols of DPC were applied randomly: group A (control); calcium hydroxide lining paste (Dycal), group B; ProRoot MTA (standard double-visit method), group C; ProRoot MTA (single-visit method) and group D; calcium hydroxide injectable paste (Multi-Cal). The cavities were then restored and the patients were put on a six-week clinical follow-up and by the end of this period the teeth were extracted for histological evaluation. Data were analyzed with the Kruskal Wallis test and the level of significance was set at 0.05. RESULTS: In terms of clinical symptoms and formation of hard tissue bridge (HTB), no significant differences were found between groups A, B and C (P>0.05); however, group D's results were significantly different as they exhibited minimal HTB formation and excessive sensitivity (P<0.05). Inflammation was significantly lower in group B (P>0.05). CONCLUSION: Application of MTA during a single-visit protocol of DPC was clinically and histologically as successful as the standard double-visit method but the routine use of Multi-Cal as pulp capping material is questionable and should be reconsidered. PMID- 25834590 TI - Cytotoxicity of two resin-based sealers and a fluoride varnish on human gingival fibroblasts. AB - INTRODUCTION: Assessment of cellular cytotoxicity is a regular method for evaluating the biocompatibility of novel materials. In a recent study, 5% fluoride varnish (Duraflur) has shown reasonable sealing ability and coverage of root canal walls when used as a sealer. The aim of the present study was to compare the cytotoxicity of Duraflur varnish with two popular commonly used root canal sealers (AH-Plus and AH-26) on human gingival fibroblasts (HGF). METHODS AND MATERIALS: The HGFs were incubated with different concentrations (1/2, 1/4, and 1/8) of AH-plus, AH-26, and Duraflur varnish for 24 h. The percentage of cell viability was assessed with methyl-thiazol-tetrazolium (MTT) assay. The data was analyzed using the one-way ANOVA followed by Student-Newman-Keuls test. The level of significance was set at 0.001. RESULTS: MTT assay showed that higher concentrations of the tested materials resulted in lower viability of HGFs. AH Plus showed significantly greater cell viability compared to AH-26 at all dilutions (P<0.001); however, no significant difference was found between Duraflur and AH-Plus in terms of cell viability at 1/8 dilution (P>0.001). Duraflur showed significantly higher cell viability compared to AH-26 except at 1/2 dilution (P<0.001). CONCLUSION: Although Duraflur varnish had better biocompatibility compared to AH-26, it should still be evaluated with further biocompatibility tests such as intraosseous and subcutaneous implantation. PMID- 25834591 TI - Retreatability of Root Canals Obturated Using Gutta-Percha with Bioceramic, MTA and Resin-Based Sealers. AB - INTRODUCTION: The aim of this study was to evaluate the retreatability of root canals obturated with gutta-percha (GP) and three different endodontic sealers [iRoot SP (bioceramic sealer), MTA Fillapex (MTA-based sealer) and AH-26 (epoxy resin-based sealer)] using the ProTaper Universal Retreatment (PTR) system. METHODS AND MATERIALS: Forty extracted single-rooted human teeth were prepared with universal ProTaper files up to F4 (40/0.06). Specimens were randomly divided into four groups according to obturation technique/material: single-cone GP/AH 26, lateral compaction of GP/AH-26, single-cone GP/iRoot SP, and single-cone GP/MTA Fillapex. Root fillings were removed with PTR. The time taken to reach the working-length (TWL) was recorded. Roots were longitudinally sectioned and each half was evaluated using a stereomicroscope. Three observers scored each third of all specimen. Obtained data were analyzed using the Kruskal-Wallis, Mann-Whitney U, Welch and Games-Howell tests. The level of significance was set at 0.05. RESULTS: In single-cone GP/MTA Fillapex group the TWL was significantly shorter. The remnant of filling material in the apical and middle thirds of groups was similar and higher than the coronal thirds. CONCLUSION: None of the tested sealers were completely removed from the root canal system. PMID- 25834592 TI - Apical sealing ability of bioceramic paste and mineral trioxide aggregate retrofillings: a dye leakage study. PMID- 25834593 TI - Effect of different mixing and placement methods on the compressive strength of calcium-enriched mixture. AB - INTRODUCTION: The aim of this experimental laboratory study was to evaluate the effect of different mixing and placement techniques on compressive strength (CS) of calcium-enriched mixture (CEM) cement. METHODS AND MATERIALS: CEM powder was mixed with its liquid either by hand mixing or amalgamator mixing. The mixture was loaded to cylindrical acrylic molds with 6.0+/-0.1 mm height and 4.0+/-1 mm diameter. Half of the specimens in each group were selected randomly and ultrasonic energy was applied to them for 30 sec. All samples were incubated for 7 days at 37( degrees )C. The CS test was performed by means of a universal testing machine. The data were analyzed by the two-way analysis of variance (ANOVA) and Tukey's post hoc tests. The level of significance was set at 0.05. RESULTS: The maximum CS was seen in the amalgamator-mixed samples that did not receive ultrasonic agitation. The CS value of amalgamator-mixed samples was significantly higher than manually-mixed ones (P=0.003). Ultrasonic vibration did not change the CS of specimens. CONCLUSION: According to the results, mixing with amalgamator increases the CS of CEM cement, while ultrasonic vibration had no positive effect. PMID- 25834594 TI - Nano-hydroxyapatite and calcium-enriched mixture for pulp capping of sound primary teeth: a randomized clinical trial. AB - INTRODUCTION: Nano-hydroxyapatite (NHA) has been used for regeneration of osseous defects. Calcium-enriched mixture (CEM) cement is also used for various dental treatments. This trial compared the efficacy of NHA and CEM cement for direct pulp capping (DPC) of sound primary teeth. METHODS AND MATERIALS: In this randomized clinical trial with split-mouth design, after attaining informed consent, 20 sound primary canines scheduled for orthodontic extraction, were selected. After mechanical pulp exposure, the exposed site was capped with either NHA or CEM cement and then immediately restored with glass-ionomer and resin composite. The teeth were extracted after two months and examined histologically. Parameters of hard tissue bridge (HTB) formation, its type and quality as well as pulpal inflammation scores were compared between the two experimental groups. The data were analyzed using the Mann Whitney U and Fisher's exact test. The level of significance was set at 0.001. RESULTS: All CEM specimens showed inflammation score of 0 (less than 10%). However, in NHA group, inflammation scores of 0 (less than 10%), 1 (10%-30%) and 2 (30%-50%) were observed in 2 (20%), 4 (40%) and 4 (40%) specimens, respectively (P<0.001). HTB was formed in all CEM specimens while it was developed in 2 specimens of NHA (20%; P<0.001). All CEM specimens showed normal pulp; only two cases in NHA group (20%) demonstrated uninflamed normal pulp. CONCLUSION: CEM cement was superior to NHA as a DPC agent in terms of HTB formation and pulp inflammation scores. It is a suitable material for the DPC of primary teeth. PMID- 25834595 TI - Preferred materials and methods employed for endodontic treatment by Iranian general practitioners. AB - INTRODUCTION: The aim of this study was to gather information on the materials and methods employed in root canal treatment (RCT) by general dental practitioners (GDPs) in Iran. METHODS AND MATERIALS: A questionnaire was distributed among 450 dentists who attended the 53(th) Iranian Dental Association congress. Participants were asked to consider demographic variables and answer the questions regarding the materials and methods commonly used in RCT. Descriptive statistics were given as absolute frequencies and valid percentages. The chi-square test was used to investigate the influence of gender and the years of professional activity for the employed materials and techniques. RESULTS: The response rate was 84.88%. The results showed that 61.5% of the participants did not perform pulp sensitivity tests prior to RCT. Less than half of the general dental practitioners (47.4%) said that they would trace a sinus tract before starting the treatment. Nearly 16% of practitioners preferred the rubber dam isolation method. Over 36% of the practitioners reported using formocresol for pulpotomy. The combined approach of working length (WL) radiographs and electronic apex locators was used by 35.2% of the practitioners. Most of the respondents used K-file hand instruments for canal preparation and the technique of choice was step-back (43.5%), while 40.1% of respondents used NiTi rotary files, mostly ProTaper and RaCe. The most widely used irrigant was normal saline (61.8%). Calcium hydroxide was the most commonly used inter appointment medicament (84.6%). The most popular obturation technique was cold lateral condensation (81.7%) with 51% using zinc oxide-eugenol-based sealers. CONCLUSIONS: The majority of Iranian GDPs who participated in the present survey do not comply with quality guidelines of endodontic treatment. PMID- 25834596 TI - Location of Mental Foramen in a Selected Iranian Population: A CBCT Assessment. AB - INTRODUCTION: Mental foramen (MF) is an important anatomic landmark in dentistry and knowledge about its variable locations (L) and type of emergence (TE), has an effect on the sufficiency of local anesthesia and safety of surgical procedures. The aim of this study was to evaluate the L and TE of this radiographic landmark as well as the presence of accessory MF, by means of cone-beam computed tomography (CBCT). METHODS AND MATERIALS: In this cross sectional study, a total of 156 CBCT images were retrieved from the archive of a private radiology clinic and were then evaluated for the position of MF and its TE and the existence of accessory foramina in the body of mandible. The extracted information was compared in both genders, in both sides of mandible and among three different age groups (20-29, 30-44 and 45-59 years). The Pearson chi-square and Fisher's Exact tests were used for statistical analysis. The level of significance was set at 0.05. RESULTS: Second premolar was the most common anterolateral L of MF; in general, 48.7% of right and 51.9% of left MFs were located at the apex of second premolar. Anterior and straight ET were more common in right and left side, respectively. Accessory MF was present in only 8 (5.1%) of cases. CONCLUSION: The possible presence of accessory MF should not be overlooked for avoiding the occurrence of a neurosensory disturbance during surgery and implant insertion. PMID- 25834597 TI - Diagnostic value of cone-beam computed tomography and periapical radiography in detection of vertical root fracture. AB - INTRODUCTION: Vertical root fracture (VRF) is the longitudinal fracture of the root in endodontically treated teeth. Considering the limitations of two dimensional radiographic images in detection of VRF and introduction of cone-beam computed tomography (CBCT), this study was designed to find the sensitivity, specificity and accuracy of CBCT and periapical (PA) radiography in detection of VRFs. METHODS AND MATERIALS: This was a cross-sectional in vitro study on 80 extracted human single canal teeth including 40 maxillary and 40 mandibular teeth. After standardized endodontic treatment of the roots, VRF was induced in half of the teeth in each group, and other half were left without fracture. Teeth were inserted in dry maxillary and mandibular alveoli. PA radiographs and CBCT images were taken from the specimens. Data were analyzed with SPSS software. The McNemar test was used to evaluate the sensitivity, specificity and accuracy of images, and kappa coefficient was used to assess the degree of agreement between the observers. The level of significance was set at 0.05. RESULTS: Sensitivity and specificity values of CBCT were 97.5% and 95%, respectively. However, for PA radiography the sensitivity and specificity were 67.5% and 92.5%, in order of appearance. Accuracy of CBCT (96.25%) and PA radiography (80%) in both jaws were significantly different (P=0.022). Two methods were not significantly different when testing specificity (P=0.298). CONCLUSION: This study showed that the sensitivity and accuracy of CBCT in detection of vertical root fracture are higher than periapical radiography. CBCT can be recommended to be used in detection of vertical root fractures. PMID- 25834598 TI - Radiographic evaluation of root canal fillings accomplished by undergraduate dental students. AB - INTRODUCTION: The purpose of this study was to evaluate the radiographic quality of root canal fillings by fourth-, fifth-, and sixth-year undergraduate students at Tabriz Faculty of Dentistry between 2006 and 2012. METHODS AND MATERIALS: A total of 1183 root canal fillings in 620 teeth were evaluated by two investigators (and in case of disagreement by a third investigator) regarding the presence or absence of under-fillings, over-fillings and perforations. For each tooth, preoperative, working and postoperative radiographs were checked. The Pearson's chi-square test was used for statistical evaluation of the data. Inter examiner agreement was measured by Cohen's kappa (k) values. The level of significance was set at 0.05. RESULTS: Total frequencies of over-filling, under filling and perforation were 5.6%, 20.4% and 1.9%, respectively. There were significant differences between frequencies of over- and under-fillings (P<0.05). Unacceptable quality, under- and over-fillings were detected in 27.9% of 1183 evaluated canals. CONCLUSION: The technical quality of root canal therapies performed by undergraduate dental students using step-back preparation and lateral compaction techniques was unacceptable in almost one-fourth of the cases. PMID- 25834599 TI - Evaluation of apical leakage in root canals obturated with three different sealers in presence or absence of smear layer. AB - INTRODUCTION: Microleakage can result in failure of endodontic treatment. An important characteristic of endodontic sealer is sealing ability. The aim of this experimental study was to compare the apical leakage of teeth obturated with gutta-percha and three different sealers (resin- and zinc oxide eugenol-based) with/without smear layer (SL). MATERIALS AND METHODS: In this study, 100 single rooted teeth were used after cutting off their crowns. Cleaning and shaping was carried out with step-back technique and the samples were randomly divided into three groups (n=30) which were then divided into two subgroups (n=15) according to the presence/absence of SL. Two negative and positive control groups (n=5) were also prepared. In the various groups, the canals were obturated with gutta percha and either of the test sealers (AH-26, Adseal or Endofill). The samples were submerged in India ink for 72 h. Then they were longitudinally sectioned and observed under a stereomicroscope at 20* magnification. Data were analyzed with descriptive statistical methods and one-way ANOVA. The significance level was set at 0.05. RESULTS: The mean penetration length of dye in AH-26, Adseal and Endofill samples were 2.53, 2.76 and 3.03 mm, respectively. The differences between three groups were not significant (P>0.05); also, the mean dye penetration in AH-26, Adseal and Endofill samples in presence or absence of the SL was not significantly different. CONCLUSION: AH-26, Adseal and Endofill were similarly effective in prevention of apical microleakage. Differences in the mean dye penetration between the groups with/without the SL were not statistically significant. PMID- 25834601 TI - The Effect of Different Mixing Methods on the pH and Solubility of Mineral Trioxide Aggregate and Calcium-Enriched Mixture. AB - INTRODUCTION: The aim of this study was to evaluate the effect of different mixing techniques on the pH and solubility of mineral trioxide aggregate (MTA) and calcium-enriched mixture (CEM). METHODS AND MATERIALS: Five samples were prepared from each biomaterial with different mixing techniques including hand-, amalgamator- or ultrasonic-mixing and were then placed in pre-weighted plastic tubes to determine their pH values. Each tube was then incubated in 10 mL deionized distilled water for 1 h at 37(o)C. An electrode was placed in the fluid in each flask at 24(o)C and the pH was recorded. In the next stage, six samples from each mixing technique/material were separately placed in glass bottles containing 50 mL of distilled water at 37(o)C for 1 h and were let dry for 1 h at 37(o)C. The samples' weights were measured and recorded twice. The procedure was repeated at 1-, 7- and 21-day intervals. Data were analyzed with the repeated measures ANOVA (for solubility) and two-way ANOVA (for pH) and then the post-hoc Tukey's test was done. RESULTS: The pH of the materials was not significantly affected by mixing methods. (P=0.8 for CEM and P=0.1 for MTA). The solubility of all test groups was within the acceptable range (=3%). However, the solubility of CEM at 1- and 21-day intervals was significantly different (P=0.03 for 1 day and P=0.001 for 21 days). Different mixing techniques had significant effects on the solubility of MTA at the three time points (P=0.004, 0.003 and 0.002 for 1-, 7- and 21-day intervals, respectively). CONCLUSION: The pH of biomaterials was not influenced by the mixing technique and their solubility was within the acceptable range. PMID- 25834600 TI - Root canal shaping by single-file systems and rotary instruments: a laboratory study. AB - INTRODUCTION: The aim of this study was to compare the shaping ability of two single-file systems and conventional rotary instruments in severely curved root canals of extracted human molars. METHODS AND MATERIALS: Mesiobuccal canals of 120 mandibular molars with angles of curvature ranging between 25( degrees ) and 35( degrees ) and radii of curvature from 5 to 9 mm, were divided into three groups (n=40). In each group the canals were instrumented with either WaveOne (W), Reciproc (R) or ProTaper (P). The time required for canal shaping and the frequency of broken instruments were recorded. The standardized pre and post instrumentation radiographs were taken to determine changes in working length (WL) and straightening of canal curvature. The presence of blockage or perforation was also evaluated. Data were analyzed using the one-way analysis of variance (ANOVA) and post-hoc Tukey's test. The level of significance was set at 0.05. RESULTS: Both single-instrument systems reduced the canal preparation time by approximately 50% (P<0.05). No incidence of broken instruments from single file systems was reported; however, two F2 instruments in the P group were broken (P<0.05). Reduction in WL and straightening of canal curvature was observed in all three systems with the highest scores belonging to P system (P<0.05). No case of blockage or perforation was found during shaping in any group. CONCLUSION: Single-file systems shaped curved canals with substantial saving in time and a significant decrease in incidence of instrument separation, change in WL, and straightening of canal curvature. PMID- 25834603 TI - Surgical Treatment of an Immature Short-Rooted Traumatized Incisor with an Extensive Apical Lesion Using CEM Cement. AB - Severe traumatic injuries to immature teeth often cause damage to periodontal ligament as well as dental pulp; pulp necrosis, root resorption and subsequent apical lesion are common consequences. This article reports the surgical management of an infected immature maxillary central incisor associated with a gigantic periradicular lesion and severe root resorption. The tooth had a history of trauma and the patient suffered from purulent sinus tract and tooth mobility. After unsuccessful multi-session disinfection with calcium hydroxide, root end surgery was planned. During flap surgery and lesion enucleation, the root end was cleaned and filled with calcium-enriched mixture (CEM) cement. After one year, the radiographic examination revealed that the lesion was almost completely replaced with newly formed bone. In addition, clinical examination showed favorable outcomes; the tooth was symptom-free and in function. Due to chemical, physical and biological properties of CEM cement, this biomaterial might be considered as the root-end filling material of choice. PMID- 25834602 TI - A comparative study of antifungal activity of endodontic irrigants. AB - INTRODUCTION: The purpose of this in vitro study was to assess the antifungal activity of final canal rinse with either three concentrations of sodium hypochlorite (NaOCl) (0.5, 2.6 and 6%), two concentrations of chlorhexidine (CHX) (2% and 0.2%), MTAD, Tetraclean, Hypoclean and Chlor-Xtra on Candida albicans (C. albicans) in a human tooth model. METHODS AND MATERIALS: Two hundred and thirty five extracted human maxillary central and lateral incisors were used in this study. Teeth were randomly divided into nine test groups (n=25) and positive and a negative control groups (n=5). After cleaning and shaping, teeth were contaminated with C. albicans and incubated for 72 h. The irrigation solution in nine experimental groups included: 6% NaOCl, 2.6% NaOCl, 0.5% NaOCl, 2% CHX, 0.2% CHX, MTAD, Tetraclean, Hypoclean and Chlor-Xtra. After culturing on Sabouraud 4% dextrose agar, colony-forming units (CFU) were counted. RESULTS: 6% NaOCl, 2% CHX and Chlor-Xtra were equally effective (P>0.05) and significantly superior to MTAD and Tetraclean (P<0.05). In addition, the effectiveness of Tetraclean and MTAD was significantly less than Hypoclean, NaOCl at all concentrations (6% 2.6% and 0.5%), MTAD and 0.2% CHX (P<0.05). Furthermore, Tetraclean was significantly more effective than MTAD (P<0.05). CONCLUSION: Antifungal activity of 6% NaOCl, Chlor Xtra and 2% CHX was significantly greater than 2.6% NaOCl, 0.5% NaOCl, MTAD, 0.2% CHX and Tetraclean. PMID- 25834604 TI - Clinicopathological significance of dual-specificity protein phosphatase 4 expression in invasive ductal carcinoma of the breast. AB - PURPOSE: Dual-specificity protein phosphatase 4 (DUSP4), also known as mitogen activated protein kinase phosphatase (MKP) 2 is a member of the inducible nuclear MKP group. The role of DUSP4 in cancer development and progression appears to vary with the type of malignancy. The purpose of this study was to investigate DUSP4 expression in a case series of invasive ductal carcinoma of the breast. METHODS: We constructed tissue microarrays consisting of 16, 14, 47, and 266 cases of normal breast tissue, usual ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma, respectively. DUSP4 expression was investigated by immunohistochemistry. RESULTS: Cytoplasmic DUSP4 expression was observed. DUSP4 was more frequently expressed in malignant than in benign cases (p=0.024). The mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (p=0.019). DUSP4 expression was significantly correlated with a larger tumor size (>2 cm, p=0.015). There was no significant correlation between overall survival or disease-free survival and DUSP4 expression in all 266 patients. We evaluated the impact of DUSP4 expression on the survival of 120 patients with T1-stage tumors. Interestingly, Kaplan-Meier survival curves revealed that DUSP4 expression had a significant effect on both overall patient survival (p=0.034, log-rank test) and disease-free survival (p=0.045, log-rank test). In early T-stage breast cancer, DUSP4 expression was associated with a worse prognosis. CONCLUSION: DUSP4 is frequently upregulated in breast malignancy, and may play an important role in cancer development and progression. In addition, it may be a marker of adverse prognosis, especially in patients with early T1-stage cancer. PMID- 25834605 TI - Survival Improvement in Korean Breast Cancer Patients Due to Increases in Early Stage Cancers and Hormone Receptor Positive/HER2 Negative Subtypes: A Nationwide Registry-Based Study. AB - PURPOSE: The aim of this study was to investigate whether the observed changes over time in the survival rates vary according to the intrinsic subtypes of breast cancer diagnosed. METHODS: Data from 46,320 breast cancer patients in the Korean Breast Cancer Registry who underwent surgery between 1999 and 2006 were reviewed. Among them, results from 25,887 patients with available data about the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were analyzed. Patients were classified into two cohorts according to the year in which they underwent surgery: 1999-2002 and 2003-2006. RESULTS: The patients treated in the latter time period showed significantly better overall survival (OS) compared with those in the former period when adjusted for follow-up duration. The proportion of hormone receptor+/HER2-subtype and stage I breast cancer were significantly higher in the latter period (47.4% vs. 54.6%, p<0.001; 31.0% vs. 39.6%, p<0.001, respectively). Improvement in OS between the former and latter periods was seen in all subtypes of breast cancer, including triple-negative cancers (all p-values <0.001 in univariate and multivariate analyses). CONCLUSION: Improvement in survival in Korean breast cancer patients over the study years is being observed in all subtypes of breast cancer, implying that increases in both early-stage detection and the proportion of less aggressive cancers contribute to this improvement. PMID- 25834606 TI - Predictive Significance of p53, Ki-67, and Bcl-2 Expression for Pathologic Complete Response after Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer. AB - PURPOSE: Patients with triple-negative breast cancer (TNBC) with pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) have superior survival outcomes compared to those with residual disease after NAC. This study investigated the value of three biomarkers, p53, Ki-67, and Bcl-2 for predicting pCR in NAC-treated patients with TNBC. METHODS: Between 2003 and 2012, 198 patients with pathologically confirmed primary TNBC were treated with two different taxane-based chemotherapeutic regimens prior to surgery. Before NAC, expression of p53 (cutoff 25%), Ki-67 (cutoff 10%), and Bcl-2 (cutoff 10%) was assessed immunohistochemically in core biopsy specimens. The incidence of pCR was correlated with the expression of these biomarkers. RESULTS: Overall, pCR occurred in 37 of the 198 patients (18.7%). A significant association was observed between the pCR rate and overexpression of the p53 and Ki-67 biomarkers. Multivariate analysis showed that only p53 expression was independently associated with pCR to NAC (odds ratio, 3.961; p=0.003). The sensitivity, specificity, positive predictive value, and negative predictive value of p53 expression for predicting pCR were 77.8%, 50.3%, 26.2%, and 90.9%, respectively. The pCR rate was the lowest (5.2%) in patients with low expression of both p53 and Ki-67, and it was the highest (25.8%) when both biomarkers showed high expression. CONCLUSION: Expression of p53 was significantly associated with pCR after NAC in patients with TNBC, suggesting that this biomarker might be particularly valuable in identifying TNBC patients prone to have residual disease after NAC. PMID- 25834607 TI - Sentinel lymph node biopsy alone after neoadjuvant chemotherapy in patients with initial cytology-proven axillary node metastasis. AB - PURPOSE: Neoadjuvant chemotherapy (NAC) has been recently used to downstage breast cancer. However, in patients with initial axillary lymph node (ALN) metastasis, ALN dissection regardless of the NAC response remains the standard treatment. The purpose of this study was to identify the feasibility and accuracy of sentinel lymph node biopsy (SLNB) after NAC in patients with ALN metastasis at diagnosis. METHODS: From January 2007 to August 2013, data of patients who were diagnosed with invasive breast cancer and ALN metastasis and treated with NAC followed by definitive surgery in two centers were collected retrospectively. A total of 386 patients were enrolled and classified into five groups according to surgical procedure for the ALNs and pathologic results. RESULTS: At SLNB after NAC, sentinel lymph nodes (SLNs) that stained blue or were hot, including suspicious nodes, were identified; the SLN identification and false-negative rates was 96% and 10%, respectively. There was no difference in the overall survival among the groups. For patients who revealed a pathologic complete node response, there was a significant difference in the disease-free survival rate between the SLNB only and complete ALN dissection groups (p=0.031). However, the rate of axillary recurrence demonstrated no significant differences among the groups (p>0.050). CONCLUSION: SLNB after NAC in breast cancer patients with initial ALN metastasis may help identify downstaging to negative nodal status and thereby reduce the surgical morbidity by avoiding standard ALN dissection. PMID- 25834608 TI - Local control of brain metastasis: treatment outcome of focal brain treatments in relation to subtypes. AB - PURPOSE: To investigate treatment options for local control of metastasis in the brain, we compared focal brain treatment (FBT) with or without whole brain radiotherapy (WBRT) vs. WBRT alone, for breast cancer patients with tumor relapse in the brain. We also evaluated treatment outcomes according to the subtypes. METHODS: We conducted a retrospective review of breast cancer patients with brain metastasis after primary surgery. All patients received at least one local treatment for brain metastasis. Surgery or stereotactic radiosurgery was categorized as FBT. Patients were divided into two groups: the FBT group received FBT+/-WBRT, whereas the non-FBT group received WBRT alone. Subtypes were defined as follows: hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, HR-positive/HER2-positive, HR-negative/HER2-positive, and triple-negative (TN). We examined the overall survival after brain metastasis (OSBM), brain metastasis-specific survival (BMSS), and brain metastasis-specific progression-free survival (BMPFS). RESULTS: A total of 116 patients were identified. After a median follow-up of 50.9 months, the median OSBM was 11.5 months (95% confidence interval, 9.0-14.1 months). The FBT group showed significantly superior OSBM and BMSS. However, FBT was not an independent prognostic factor for OSBM and BMSS on multivariate analyses. In contrast, multivariate analyses showed that patients who underwent surgery had improved BMPFS, indicating local control of metastasis in the brain. FBT resulted in better BMPFS in patients with HR-negative/HER2-positive cancer or the TN subtype. CONCLUSION: We found that patients who underwent surgery experienced improved local control of brain metastasis, regardless of its extent. Furthermore, FBT showed positive results and could be considered for better local control of brain metastasis in patients with aggressive subtypes such as HER2-positive and TN. PMID- 25834609 TI - Operable breast cancer of the inner hemisphere is associated with poor survival. AB - PURPOSE: This study investigated the clinicopathological features of operable breast cancer lesions located in different hemispheres of the breast and determined related survival outcomes. METHODS: Data from 5,330 patients with invasive ductal carcinoma were retrospectively analyzed based on tumor location. RESULTS: The median follow-up time was 68 months (range, 18-176 months). Patients with breast cancer located in the outer hemisphere of the breast had lesions with more advanced nodal stages and more frequently received adjuvant chemotherapy than patients with breast cancer in the inner hemisphere. The 5-year disease-free survival (DFS) rates of patients with tumors located in outer versus inner hemispheres were 81.5% and 77.0%, respectively (p=0.004); the overall survival (OS) rates were 90.7% and 88.8%, respectively (p<0.001). The association between tumor location and the 5-year DFS rate was most apparent in node-positive patients (73.1% vs. 65.8% for outer vs. inner hemisphere lesions, p<0.001) and in patients with primary tumors greater than 2 cm in diameter (78.2% vs. 72.3%, p=0.002). Multivariate analysis showed that tumor location was an independent predictor of DFS (hazard ratio [HR], 1.23; p=0.002) and OS (HR, 1.28; p=0.006). There were no significant differences in 5-year DFS or OS rates between patients with outer versus inner hemisphere tumors when internal mammary node irradiation was performed. CONCLUSION: This study demonstrated that tumor location was an independent prognostic factor for operable breast cancer. Internal mammary node irradiation is recommended for patients with breast cancer of the inner hemisphere and positive axillary lymph nodes or large primary tumors. PMID- 25834610 TI - Ultrasonography-guided surgical clip placement for tumor localization in patients undergoing neoadjuvant chemotherapy for breast cancer. AB - PURPOSE: We investigated the feasibility of using surgical clips as markers for tumor localization and their effect on the imaging evaluation of treatment responses after neoadjuvant chemotherapy (NAC). METHODS: A total of 16 breast cancers confirmed by needle biopsy in 15 patients were included in this study from October 2012 to June 2014. Under ultrasonography (US)-guidance, the surgical clips were placed prior to NAC. Additional mammography, breast US, and breast magnetic resonance examinations were performed within 10 days before surgery. The time period from marker insertion to operation date was documented. Images acquired via the three modalities were evalu-ated for the following parameters: location of clip, clip migration (>1 cm), the presence of complications from clip placement, and the effect of clips on the assessment of treatment. RESULTS: The mean time period was 128.6+/-34.4 days (median, 132.0 days) from the date of clip insertion to the date of surgery. The mean number of inserted clips was 2.3+/-0.7 (median, 2.0). Clip migration was not visualized by imaging in any patient, and there were no complications reported. Surgical clips did not negatively affect the assessment of treatment responses to NAC. CONCLUSION: Surgical clips may replace commercial tissue markers for tumor localization in breast cancer patients undergoing NAC without migration. Surgical clips are well tolerated and safe for the patient, easily visualized on imaging, do not interfere with treatment response, and are cost-effective. PMID- 25834611 TI - Proportion and clinical outcomes of postoperative radiotherapy omission after breast-conserving surgery in women with breast cancer. AB - PURPOSE: The present study was conducted to investigate the proportion and clinical outcomes of breast cancer patients who did not receive postoperative radiotherapy (PORT) after breast-conserving surgery (BCS). METHODS: This retrospective study included all breast cancer patients received curative BCS without PORT between 2003 and 2013. In the PORT omission group, characteristics and local recurrence differences were compared between the recommended group and the refused group. To compare the local recurrence-free survival (LRFS) of the PORT omission group and the control group who received PORT, subjects were selected by using the pooled data of patients treated between 1994 and 2007. RESULTS: During the study period, 96 patients did not receive PORT among a total of 6,680 patients who underwent BCS. Therefore, the overall rate of PORT omission was 1.4%. Among the 96 patients, 20 were recommended for PORT omission (recommended group) and 76 refused PORT (refused group). The median follow-up period of all study participants was 19.3 months (range, 0.3-115.1 months). Patients in the recommended group were older (p=0.004), were more likely to be postmenopausal (p=0.013), and had more number of positive prognostic factors compared with the refused group. Overall, 12 cases of disease recurrence, including 11 cases of local recurrence, developed in the PORT-refused group. The LRFS of the PORT-omission group was significantly inferior to that of patients who received PORT after BCS (p<0.001). In the PORT-omission group, significant favorable prognostic factors for LRFS were having histologic grade 1 or 2 disease (p=0.023), having no axillary lymph node metastasis (p=0.039), receiving adjuvant endocrine therapy (p=0.046), and being in the recommended group (p=0.026). CONCLUSION: The rate of PORT omission in the present study is very low among women who underwent surgery compared to that of other studies worldwide. PORT omission is significantly related to a high local recurrence rate. PMID- 25834612 TI - A Dosimetric Comparative Analysis of TomoDirect and Three-Dimensional Conformal Radiotherapy in Early Breast Cancer. AB - PURPOSE: The purpose of this study is to compare dosimetric parameters of intensity-modulated mode of TomoDirect and three-dimensional conformal radiotherapy (3D-CRT) in patients with early breast cancer. METHODS: TomoDirect and 3D-CRT planning were carried out for 26 patients with early breast cancer who had received breast-conserving surgery. A total of 50.4 Gy in 28 fractions were prescribed to the planning target volume. The organs at risk (OAR) such as lung and heart were contoured. Planning target volume (PTV) dose coverage, radiation conformity index (RCI), radical dose homogeneity index (rDHI), and irradiation dose of organs at risk were compared between TomoDirect and 3D-CRT planning. RESULTS: The mean PTV dose (51.65+/-0.37 Gy) and V47.8 (100%) in TomoDirect were significantly higher than the mean PTV dose (50.88+/-0.65 Gy) and V47.8 (89.23%+/ 0.06%) in 3D-CRT (all, p<0.001). The RCI value in TomoDirect was significantly better than that in 3D-CRT (1.00 vs. 1.13, p<0.001). However, the rDHI value in TomoDirect was not significantly better than that in 3D-CRT (0.72 vs. 0.67, p=0.056). The mean lung dose and V10, V20, V30, and V40 values of ipsilateral lung in TomoDirect were significantly lower than those in 3D-CRT (all, p<0.05). There is no significant difference in the V10, V20, V30, and V40 values of heart between TomoDirect and 3D-CRT. And the mean dose for heart in TomoDirect was marginally lower than that in 3D-CRT (1.05 Gy vs. 1.62 Gy, p=0.085). The mean dose for left anterior descending coronary artery in left breast cancer was significantly lower in TomoDirect than in 3D-CRT (7.2 Gy vs. 12.1 Gy, p<0.001). CONCLUSION: Compared to 3D-CRT, TomoDirect could result in favorable target coverage while reducing the irradiation dose of the ipsilateral lung for patients with early breast cancer. PMID- 25834613 TI - Effectiveness of Breast MRI and (18)F-FDG PET/CT for the Preoperative Staging of Invasive Lobular Carcinoma versus Ductal Carcinoma. AB - PURPOSE: We evaluated the utility of magnetic resonance imaging (MRI) and (18)F fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) for the preoperative staging of invasive lobular carcinoma (ILC) of the breast and compared the results with those of invasive ductal carcinoma (IDC). METHODS: The study included pathologically proven 32 ILCs and 73 IDCs. We compared clinical and histopathological characteristics and the diagnostic performances of MRI and (18)F-FDG PET/CT for the primary mass, additional ipsilateral and/or contralateral lesion(s), and axillary lymph node metastasis between the ILC and IDC groups. RESULTS: Primary ILCs were greater in size, but demonstrated lower maximum standardized uptake values than IDCs. All primary masses were detected on MRI. The detection rate for ILCs (75.0%) was lower than that for IDCs (83.6%) on (18)F-FDG PET/CT, but the difference was not significant. For additional ipsilateral lesion(s), the sensitivities and specificities of MRI were 87.5% and 58.3% for ILC and 100.0% and 66.7% for IDC, respectively; whereas the sensitivities and specificities of (18)F-FDG PET/CT were 0% and 91.7% for ILC and 37.5% and 94.7% for IDC, respectively. The sensitivity of (18)F-FDG PET/CT for ipsilateral lesion(s) was significantly lower in the ILC group than the IDC group. The sensitivity for ipsilateral lesion(s) was significantly higher with MRI; however, specificity was higher with (18)F-FDG PET/CT in both tumor groups. There was no significant difference in the diagnostic performance for additional contralateral lesion(s) or axillary lymph node metastasis on MRI or (18)F-FDG PET/CT for ILC versus IDC. CONCLUSION: The MRI and (18)F-FDG PET/CT detection rates for the primary cancer do not differ between the ILC and IDC groups. Although (18)F-FDG PET/CT demonstrates lower sensitivity for primary and additional ipsilateral lesions, it shows higher specificity for additional ipsilateral lesions, and could play a complementary role in the staging of ILC as well as IDC. PMID- 25834614 TI - Incidental Breast Lesions Identified by (18)F-FDG PET/CT: Which Clinical Variables Differentiate between Benign and Malignant Breast Lesions? AB - PURPOSE: The aim of our study was to evaluate the risk of malignancy and to determine which clinical variables differentiate between benign and malignant focal breast lesions found incidentally on (18)F-flourodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT). METHODS: From March 2005 to October 2011, 21,224 women with no history of breast cancer underwent FDG PET/CT at three university-affiliated hospitals. We retrospectively identified 214 patients with incidental focal hypermetabolic breast lesions and grouped them into benign and malignant lesion groups. Of the 214 patients, 82 patients with 91 lesions were included in this study. All lesions were confirmed histologically or were assessed by follow-up imaging for greater than 2 years. The patient age, maximum standardized uptake value (SUVmax), lesion size on ultrasonography (US), and Breast Imaging-Reporting and Data System (BI-RADS) category on US in conjunction with mammography were compared between the groups. Multivariate logistic regression analysis was used to identify independent factors associated with malignancy. RESULTS: The risk of malignancy was 29.7% (27/91) in breast incidentalomas detected by FDG PET/CT. The univariate analysis showed that the patient age, SUVmax, tumor size, and BI-RADS category differed significantly between the malignant and benign groups. The multivariate analysis showed that the BI-RADS category was the only significant factor differentiating benign from malignant lesions (p=0.002). CONCLUSION: BIRADS category based on US in conjunction with mammography was the only useful tool to differentiate between malignant and benign lesions in breast incidentalomas on FDG PET/CT. PMID- 25834615 TI - Cosmetic evaluation methods adapted to asian patients after breast-conserving surgery and examination of the necessarily elements for cosmetic evaluation. AB - PURPOSE: Although various strategies have been reported, there are no defined criteria for cosmetic evaluation methods after breast-conserving surgery (BCS). Since Asians tend to have smaller breasts, indistinct inframammary folds, and conspicuous scars, differences in the cosmetic results are expected. So we examined two subjective methods and one objective method to determine the differences, and elements necessary for a cosmetic evaluation after BCS. METHODS: Frontal photographs of 190 Japanese were evaluated using the Harris scale (Harris) and the evaluation method proposed by the Japanese Breast Cancer Society Sawai group (Sawai group) as the subjective methods, and the Breast Cancer Conservation Treatment cosmetic results (BCCT.core) as the objective method, respectively. In order to examine the necessary elements for developing a new ideal method, 100 out of 190 were selected and assessed separately by six raters using both the Harris and modified Sawai group methods in the observer assessment. The correlation between the two methods was examined using the Spearman rank-correlation coefficient. RESULTS: The results of the BCCT.core and the other two methods were clearly different. In the observer assessment, the consensuses of the six raters were evaluated as follows: 27, 27, 26, and 20 cases were evaluated as "excellent," "good," "fair," and "poor," respectively. For the Spearman rank-correlation coefficient, values higher than 0.7 indicated a strong correlation, as seen by the values of 0.909 for the breast shape and 0.345 for the scar. The breast shape accounted for the most significant part of the evaluation, and the scar had very little correlation. CONCLUSION: In this study, we recognized a clear difference between the subjective and objective evaluation methods, and identified the necessary elements for cosmetic evaluation. We would like to continue developing an ideal cosmetic evaluation that is similar to subjective one and is independent from raters. PMID- 25834616 TI - Effects of a 4-week multimodal rehabilitation program on quality of life, cardiopulmonary function, and fatigue in breast cancer patients. AB - PURPOSE: This study examines the effects of a rehabilitation program on quality of life (QoL), cardiopulmonary function, and fatigue in breast cancer patients. The program included aerobic exercises as well as stretching and strengthening exercises. METHODS: Breast cancer patients (n=62) who had completed chemotherapy were randomly assigned to an early exercise group (EEG; n=32) or a delayed exercise group (DEG; n=30). The EEG underwent 4 weeks of a multimodal rehabilitation program for 80 min/day, 5 times/wk for 4 weeks. The DEG completed the same program during the next 4 weeks. The European Organization for Research and Treatment of Cancer-Core Quality of Life Questionnaire (EORTC QLQ-C30), EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23), predicted maximal volume of oxygen consumption (VO2max), and fatigue severity scale (FSS) were used for assessment at baseline, and at 2, 4, 6, and 8 weeks. RESULTS: After 8 weeks, statistically significant differences were apparent in global health, physical, role, and emotional functions, and cancer-related symptoms such as fatigue and pain, nausea, and dyspnea on the EORTC QLQ-C30; cancer-related symptoms involving the arm and breast on the EORTC QLQ-BR23; the predicted VO2max; muscular strength; and FSS (p<0.050), according to time, between the two groups. CONCLUSION: The results of our study suggest that a supervised multimodal rehabilitation program may improve the physical symptoms, QoL, and fatigue in patients with breast cancer. PMID- 25834617 TI - Early-Onset Breast Cancer in a Family with Neurofibromatosis Type 1 Associated with a Germline Mutation in BRCA1. AB - Neurofibromatosis type 1 (NF1), which may occur as an autosom-al dominant disorder, is caused by the absence of neurofibromin protein due to somatic mutations in the NF1 gene, and it has been associated with an increased risk of breast cancer. Herein we describe a family with two women affected by both NF1 and early-onset breast cancer. We evaluated whether the concomitance of NF1 and early-onset breast cancer could be due to disease-causing mutations in both NF1 and BRCA1 gene in a Korean family with clinical features of both NF1 and hereditary breast cancer. Mutation analyses identified nonsense mutations in NF1 and BRCA1 genes. Our findings indicate that an awareness of the possible concomitance of NF1 and BRCA1 gene mutations is important for identifying the genetic origin of early-onset breast cancer in patients with NF1 to achieve early detection of cancers and decrease breast cancer-associated morbidity and mortality in these patients. PMID- 25834618 TI - Retraction note to: "Clinical Significance of the Axillary Arch in Sentinel Lymph Node Biopsy". AB - [This retracts the article on p. 244 in vol. 17, PMID: 25320622.]. PMID- 25834619 TI - Clinical factors, including All Patient Refined Diagnosis Related Group severity, as predictors of early rehospitalization after COPD exacerbation. AB - BACKGROUND: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations carry a high risk for early rehospitalization. We wished to identify the basic clinical factors associated with a high risk of rehospitalization, and to see how well the standardized All Patient Refined Diagnosis Related Group (APR-DRG) severity of illness (SOI) subclassification predicted rehospitalization if combined with other simple clinical measures. METHODS: We identified adult patients aged >=40 years discharged from a major hospital in the Southwestern USA with a COPD discharge diagnosis during the study index period (1 October 2009 to 30 September 2010). Patients readmitted within 30 days ("early rehospitalization") and 90 days ("any rehospitalization") were each compared with those not rehospitalized. Clinical parameters (including demographics, comorbidities) and recent healthcare utilization were examined for their association with rehospitalization. Factors independently associated with rehospitalization were then combined with the index admission APR-DRG SOI assessment using conditional linear regression to find the best models in terms of the highest C-statistic. RESULTS: Among 306 patients hospitalized for COPD, 62 (20.3%) had a rehospitalization within 90 days and 28 (9.2%), an early readmission. An APR-DRG SOI subclassification >=3 was a modest independent predictor of early or any readmission, with adjusted odds ratios ranging from 2.09 to 3.33. Models that combined the APR-DRG SOI subclassification with clinical factors present before the index hospitalization had strong C-statistics of >=0.80. Good models without the APR-DRG SOI subclassification but including a history of recent hospitalizations before the index hospitalization were also identified. CONCLUSIONS: An APR-DRG SOI subclassification of >=3 for the index COPD admission is associated with an increased risk of early rehospitalizations, and can be combined with a few historical clinical factors to create strong predictive models for rehospitalization. This study demonstrates that hospitals can use commonly collected clinical information to help identify COPD patients at a high risk of failure after discharge. PMID- 25834621 TI - Reduction in inpatient resource utilization and costs associated with long-acting injectable antipsychotics across different age groups of Medicaid-insured schizophrenia patients. AB - OBJECTIVE: Evaluate utilization of inpatient healthcare resources and associated costs after 12 months of treatment using long-acting injectable (LAI) antipsychotic medications among a large sample of Medicaid-insured patients categorized by different age groups. METHOD: Adult patients with schizophrenia were identified from the Thomson Reuters MarketScan Research database (1/1/2006 12/31/2010) before initiation of treatment using LAI antipsychotic agents. Utilization of inpatient healthcare resources and associated direct medical costs were compared for 12-month baseline and 12-month follow-up periods. RESULTS: Among 3,094 Medicaid-insured patients with schizophrenia initiating treatment with LAIs, the mean number of all-cause hospitalizations and hospitalization days were reduced by 24% and 31% (p<0.0001) compared with baseline, respectively, with similar significant reductions among all age groups (18-30, 31-40, 41-50, and 51 60 years). During 12-month follow-up with LAIs, mean reductions in all-cause costs were $4,369 (18-30 years, p<0.0001), $3,681 (31-40 years, p<0.0001), $2,051 (41-50 years, p=0.1332), and $4,492 (51-60 years, p=0.0107). Subanalyses separating first-generation and second-generation medication groups resulted in mean reduction in all-cause costs of $3,561 and $3,645, respectively. CONCLUSIONS: Results from this large cohort study provide naturalistic real-world evidence of the utility of LAIs in patients with schizophrenia and suggest that these agents may help to reduce the risk of relapse across all age groups (especially among younger patients). Given that relapse prevention is the ultimate goal of antipsychotic treatment, results from this large Medicaid patient population establish the value of LAIs for the management of schizophrenia. PMID- 25834620 TI - Glioblastoma treatment patterns, survival, and healthcare resource use in real world clinical practice in the USA. AB - BACKGROUND: Glioblastoma (GB) treatment remains challenging because of recurrence and poorly defined treatment options after first-line therapy. To better understand real-world application of treatment paradigms and their impact on outcomes, we describe patterns of treatment, outcomes, and use of cancer-related healthcare resource for glioblastoma in the USA. METHODS: A retrospective, online chart-abstraction study was conducted; each participating oncologist contributed <=5 charts. Patients were >=18 years with biopsy-confirmed primary or secondary newly diagnosed GB on or after 1 January 2010, had received first- and second line therapies, and had information collected for >=3 months after initiation of second-line therapy or until death. Assessments were descriptive and included Kaplan- Meier analyses from initiation to end of second-line therapy, disease progression, or death. RESULTS: One hundred sixty physicians contributed information on 503 patient charts. During first-line therapy, patients most commonly underwent temozolomide monotherapy (76.5%). During second-line therapy, patients most commonly underwent bevacizumab monotherapy (58.1%). Median duration of second-line therapy was 130 days; median time to disease progression was 113 days. Median survival was 153 days. Use of supportive care was observed to be numerically higher in first- compared with second-line therapy except for anti depressants, growth factors, and stimulants. Frequently used resources included corticosteroids (78.8% of patients in first-line and 62.6% in second-line therapies), anti-epileptics (45.8% and 41.5%) and narcotic opioids (45.3% and 41.4%). CONCLUSIONS: Most GB patients received temozolomide during first-line therapy and bevacizumab monotherapy or combination therapy during second-line therapy. Use of supportive care appeared to be higher in first- compared with second-line therapy for some agents. PMID- 25834622 TI - Metabolomic analysis of clinical plasma from cerebral infarction patients presenting with blood stasis. AB - Blood stasis (BS) is characterized as a disorder of blood circulation. In traditional Korean medicine (TKM), it is viewed as a cause factor of diseases such as multiple sclerosis and stroke. This study investigated differences in the plasma metabolites profiles of subjects displaying BS or non-BS patterns. Thirty one patients with cerebral infarction diagnosed with BS and an equal number of sex- and age-matched non-BS patients were enrolled. Metabolic profiling was performed using UPLC-MS. The ratio of subjects with a rough pulse and purple coloration of the tongue was higher in patients presenting with BS pattern. Through metabolomics analysis, 82 metabolites that differed significantly between the BS and non-BS pattern were identified, and the two groups were significantly separated using an orthogonal partial least square-discriminant analysis model (P < 0.001). Of these 82 metabolites, acetyl carnitine, leucine, kynurenine, phosphocholine, hexanoyl carnitine, and decanoyl carnitine were present in significantly higher levels in patients with a BS pattern than those with a non BS pattern. Our results also demonstrated that seven plasma metabolites, including acyl-carnitines and kynurenine, were associated with a BS pattern, suggesting that variant plasma metabolic profiles may serve as a biomarker for diagnosis of BS in patients with cerebral infarction. PMID- 25834623 TI - Exploratory clinical trial to evaluate the efficacy of a topical traditional chinese herbal medicine in psoriasis vulgaris. AB - Objective. To evaluate the efficacy and safety of herbal ointment, Shi Du Ruan Gao, in patients with plaque-type psoriasis. Design. Single-center, randomized, investigator-blinded, parallel group, placebo-controlled study. Participants. One hundred outpatients with mild to moderate chronic plaque-type psoriasis were enrolled. Intervention. The patients applied either Shi Du Ruan Gao ointment or vehicle ointment topically to for 8 weeks. Main Outcome Measures. The outcomes were assessed using the following criteria: Total Severity Score (TSS, sum of erythema, scaling, and plaque elevation/induration, on a 0 to 4 scale), Investigator Global Assessment (IGA) evaluated on a 0 (Clear) to 4 (s to very severe) scale, and Global Subjects' Assessment of treatment response on a 7-point scale from -1 (worse) to 5 (Cleared). Results. Significant reductions in the Total Severity Score (P < 0.001) (mean score: 2.7 after Shi Du Ruan Gao treatment versus 5.1 in control subjects). Both Investigator Global Assessment (IGA) and Global Subjects' Assessment of treatment are better in the Shi Du Ruan Gao group than the control group (P < 0.001). Conclusion. Shi Du Ruan Gao ointment was a safe, and effective therapy for plaque-type psoriasis. PMID- 25834624 TI - Integrative Gynecology and Women's Healthcare. PMID- 25834625 TI - An Overview of International Literature on School Interventions to Promote Mental Health and Well-being in Children and Adolescents. AB - INTRODUCTION: Mental disorders are the largest cause of the burden of disease in the world. Most of the burden affecting adult life has its onset during childhood and adolescence. The European Pact for Mental Health and Wellbeing calls for immediate action and investments in the mental health of children and adolescents. Schools may be the ideal location for promoting health and delivering healthcare services, since schools are a location where young people usually spend their daytime and socialize, schools are easily accessible to families, can provide non-stigmatizing health actions, and form links with the community. Aims and Goals of this Special Issue: This issue is developed within the framework of the Joint Action on Mental Health promoted by the European Commission. This special issue presents a set of systematic reviews on the evidence of the international literature on school interventions for the promotion of the mental health and wellbeing of children and adolescents. It is focused on five topical main areas: promoting general health and wellbeing; programs targeting specific mental disorders and conditions and integration of adolescents with mental health problems; Bullying; Sport; Alcohol and Drugs. An additional paper on the results of the largest epidemiological study conducted in some European countries on the prevalence and relative risk factors of mental disorders in school-age completes the issue. CONCLUSION: These reviews are a first contribution to address future European research and interventions, in particular about the multiple ways through which European policies could support the schooling and wellbeing of children and adolescents. PMID- 25834626 TI - Enhancing the Emotional and Social Skills of the Youth to Promote their Wellbeing and Positive Development: A Systematic Review of Universal School-based Randomized Controlled Trials. AB - BACKGROUND: The acquisition of social and emotional skills is associated with positive youth development, character education, healthy lifestyle behaviours, reduction in depression and anxiety, conduct disorders, violence, bullying, conflict, and anger. School-based interventions aimed to enhance these skills go beyond a problem-focused approach to embrace a more positive view of health; they could also improve the youth's wellbeing. AIM: To describe the main features and to establish the effectiveness of universal school-based RCTs for children and the youth, aimed to promote their psychosocial wellbeing, positive development, healthy lifestyle behaviours and/or academic performance by improving their emotional and social skills. METHODS: Systematic review by searching for relevant papers in PubMed/Medline with the following key words: "mental health" OR "wellbeing" OR "health promotion" OR "emotional learning" OR "social learning" OR "emotional and social learning" OR "positive youth development" OR "life skills" OR "life skills training" AND "school". Interval was set from January 2000 to April 2014. RESULTS: 1,984 papers were identified through the search. Out of them 22 RCTs were included. While most interventions were characterized by a whole school approach and SAFE practices, few studies only used standardized measures to assess outcomes, or had collected follow-up data after >= 6 months. The results of all these trials were examined and discussed. CONCLUSION: Universal school-based RCTs to enhance emotional and social skills showed controversial findings, due to some methodological issues mainly. Nevertheless they show promising outcomes that are relatively far-reaching for children and youth wellbeing and therefore are important in the real world. PMID- 25834627 TI - Integrating children with psychiatric disorders in the classroom: a systematic review. AB - BACKGROUND: The school setting may be the optimal context for early screening of and intervention on child mental health problems, because of its large reach and intertwinement with various participants (child, teacher, parent, other community services). But this setting also exposes children to the risk of stigma, peer rejection and social exclusion. This systematic literature review investigates the efficacy of mental health interventions addressed to children and adolescents in school settings, and it evaluates which programs explicitly take into account social inclusion indicators. METHOD: Only randomized controlled trials conducted on clinical populations of students and carried out in school settings were selected: 27 studies overall. Most studies applied group Cognitive Behavioural Therapy or Interpersonal Psychotherapy. RESULTS: Findings were suggestive of the effectiveness of school-based intervention programs in reducing symptoms of most mental disorders. Some evidence was found about the idea that effective studies on clinical populations may promote the social inclusion of children with an ongoing mental disorder and avoid the risk of being highly stigmatized. CONCLUSION: School programs are still needed that implement standardized models with verifiable and evidence-based practices involving the whole school community. PMID- 25834628 TI - Interventions on bullying and cyberbullying in schools: a systematic review. AB - Background : bullying (and cyberbullying) is a widespread phenomenon among young people and it is used to describe interpersonal relationships characterized by an imbalance of power. In this relationships often show aggressive behavior and intentional "harm doing" repeated over time. The prevalence of bullying among youth has been reported to vary widely among countries (5.1%-41.4%) and this behavior seems generally higher among student boys than girls. Several school interventions have been developed to reduce bullying, but reported inconsistent results possibly related to limitations in the study design or to other methodological shortcomings. Aims : evaluating randomized-controlled trials (RTCs) conducted between 2000 and 2013 to assess the effectiveness of school interventions on bullying and cyberbullying. Methods : a systematic search of the scientific literature was conducted on Pubmed/Medline and Ebsco online databases. We also contacted experts in the field of preventive bullying research. Results : 17 studies met the inclusion criteria. The majority of studies did not show positive effects in the long term; the interventions focused on the whole school were more effective in reducing bullying than interventions delivered through classroom curricula or social skills training alone. Conclusion : while there is evidence that programs aimed at reducing bullying can be effective in the short term, their long-term effectiveness has not been established, and there are important differences in the results based on gender, age and socio-economic status of participants. Internal inconsistency in the findings of some studies, together with the wide variability of experimental designs and lack of common standardized measures in outcome evaluation, are important limitations in this field of research. PMID- 25834629 TI - Physical activity interventions in schools for improving lifestyle in European countries. AB - BACKGROUND: In the last decades, children's and adolescents' obesity and overweight have increased in European Countries. Unhealthy eating habits and sedentary lifestyle have been recognized to determine such an epidemic. Schools represent an ideal setting to modify harmful behaviors, and physical activity could be regarded as a potential way to avoid the metabolic risks related to obesity. Methods : A systematic review of the literature was carried out to summarize the evidence of school-based interventions aimed to promote, enhance and implement physical activity in European schools. Only randomized controlled trials were included, carried out in Europe from January 2000 to April 2014, universally delivered and targeting pupils aged between 3 and 18 years old. Results : Forty-seven studies were retrieved based either on multicomponent interventions or solely physical activity programs. Most aimed to prevent obesity and cardiovascular risks among youths. While few studies showed a decrease in BMI, positive results were achieved on other outcomes, such as metabolic parameters and physical fitness. Conclusion : Physical activity in schools should be regarded as a simple, non-expensive and enjoyable way to reach all the children and adolescents with adequate doses of moderate to vigorous physical activity. PMID- 25834632 TI - Concluding remarks. PMID- 25834630 TI - A Systematic Review of School-Based Alcohol and other Drug Prevention Programs. AB - BACKGROUND: Alcohol use in adolescents constitutes a major public health concern. Europe is the heaviest drinking region of the world. Several school-based alcohol prevention programs have been developed but it is not clear whether they are really effective. The present study was aimed at identifying the typology with the best evidence of effectiveness in European studies. METHODS: A systematic search of meta-analyses and/or randomized controlled trials (RCTs) on interventions school-based prevention programs aimed at preventing alcohol consumption or changing the attitudes to consume alcohol. RESULTS: A meta analysis published in 2011 and 12 RCTs more recently published were identified. The meta-analysis evaluated 53 RCTs but only 11.3% of them were conducted in Europe. Globally, 23 RCTs (43.4%) showed some evidence of effectiveness, and 30 RCTs (56.6%) did not find significant difference between the groups. According to the conclusions of the meta-analysis, the Unplugged program should be considered as a practice option in Europe. Among the other 12 RCTs, 42% were conducted in Europe. Globally, 7 studies (58.3%) achieved positive results, and 5 studies (41.7%) did not find significant differences or produced a mixed pattern of results. Three of the 5 European trials (60%) used the Unplugged program with positive results. CONCLUSION: Even if further studies should be conducted to confirm these results, Unplugged appears to be the prevention project with the best evidence of effectiveness in European studies. PMID- 25834631 TI - The School Children Mental Health in Europe (SCMHE) Project: Design and First Results. AB - Background : The School Children Mental Health in Europe (SCMHE) project aims to build up a set of indicators to collect and monitor children's mental health in an efficient and comparable methodology across the EU countries. It concerns primary schools children aged 6 to 11 years a range where few data are available whereas school interventions are promising. Methods : Three informants were used: parents, teachers and children. In selecting instruments language, instruments were selected according to the easiness to translate them: SDQ (Strengths and Difficulties Questionnaire) for parents and teachers and DI (Dominic Interactive). A two-step procedure was used: schools randomization then six children by class in each grade. Results : 9084 children from seven countries (Italy, Netherlands, Germany, Romania, Bulgaria, Lithuania, and Turkey) completed the Dominic Interactive in their own language. 6563 teachers and 6031 parents completed their questionnaire, and a total of 5574 interviews have been completed by the 3 informants. The participation rate of the children with parents in the participating schools was about 66.4%. As expected teachers report more externalised problems and less internalised problems than parents. Children report more internalised problems than parents and teachers. Boys have consistently more externalised problems than girls and this is the reverse for internalised problems. Combining the diverse informants and impairment levels children with problems requiring some sort of mental health care were about 9.9%: 76% did not see any mental health professional: 78.7% In Eastern countries 63.1% in Western Europe. PMID- 25834633 TI - Computational intelligence techniques in medicine. PMID- 25834634 TI - Equilibrium analysis of a yellow Fever dynamical model with vaccination. AB - We propose an equilibrium analysis of a dynamical model of yellow fever transmission in the presence of a vaccine. The model considers both human and vector populations. We found thresholds parameters that affect the development of the disease and the infectious status of the human population in the presence of a vaccine whose protection may wane over time. In particular, we derived a threshold vaccination rate, above which the disease would be eradicated from the human population. We show that if the mortality rate of the mosquitoes is greater than a given threshold, then the disease is naturally (without intervention) eradicated from the population. In contrast, if the mortality rate of the mosquitoes is less than that threshold, then the disease is eradicated from the populations only when the growing rate of humans is less than another threshold; otherwise, the disease is eradicated only if the reproduction number of the infection after vaccination is less than 1. When this reproduction number is greater than 1, the disease will be eradicated from the human population if the vaccination rate is greater than a given threshold; otherwise, the disease will establish itself among humans, reaching a stable endemic equilibrium. The analysis presented in this paper can be useful, both to the better understanding of the disease dynamics and also for the planning of vaccination strategies. PMID- 25834635 TI - Towards multidimensional radiotherapy: key challenges for treatment individualisation. AB - Functional and molecular imaging of tumours have offered the possibility of redefining the target in cancer therapy and individualising the treatment with a multidimensional approach that aims to target the adverse processes known to impact negatively upon treatment result. Following the first theoretical attempts to include imaging information into treatment planning, it became clear that the biological features of interest for targeting exhibit considerable heterogeneity with respect to magnitude, spatial, and temporal distribution, both within one patient and between patients, which require more advanced solutions for the way the treatment is planned and adapted. Combining multiparameter information from imaging with predictive information from biopsies and molecular analyses as well as in treatment monitoring of tumour responsiveness appears to be the key approach to maximise the individualisation of treatment. This review paper aims to discuss some of the key challenges for incorporating into treatment planning and optimisation the radiobiological features of the tumour derived from pretreatment PET imaging of tumour metabolism, proliferation, and hypoxia and combining them with intreatment monitoring of responsiveness and other predictive factors with the ultimate aim of individualising the treatment towards the maximisation of response. PMID- 25834636 TI - Stakeholder views on a recovery-oriented psychiatric rehabilitation art therapy program in a rural Australian mental health service: a qualitative description. AB - BACKGROUND: Recovery-oriented care is a guiding principle for mental health services in Australia, and internationally. Recovery-oriented psychiatric rehabilitation supports people experiencing mental illness to pursue a meaningful life. In Australia, people with unremitting mental illness and psychosocial disability are often detained for months or years in secure extended care facilities. Psychiatric services have struggled to provide rehabilitation options for residents of these facilities. Researchers have argued that art participation can support recovery in inpatient populations. This study addressed the research question: Is there a role for the creative arts in the delivery of recovery oriented psychiatric rehabilitation for people with enduring mental illness and significant psychosocial disability detained in a secure extended care unit? METHODS: The study had two major aims: to explore the experiences of consumers detained in a rural Australian secure extended care unit of an art therapy project, and to examine the views of nurse managers and an art therapist on recovery-oriented rehabilitation programs with regard to the art therapy project. A qualitative descriptive design guided the study, and a thematic network approach guided data analysis. Ethics approval was granted from the local ethics committee (AU/1/9E5D07). Data were collected from three stakeholders groups. Five consumers participated in a focus group; six managers and the art therapist from the project participated in individual interviews. RESULTS: The findings indicate that consumer participants benefitted from art participation and wanted more access to rehabilitation-focussed programs. Consumer participants identified that art making provided a forum for sharing, self-expression, and relationships that built confidence, absent in the regular rehabilitation program. Nurse manager and the art therapist participants agreed that art participation was a recovery oriented rehabilitation tool, however, systemic barriers thwarted its provision. CONCLUSIONS: The transformation of mental health services towards a recovery orientation requires commitment from service leaders to provide evidence-based programs. Psychiatric rehabilitation programs based on local need should be included in public mental health services. This study supports the use of art based rehabilitation programs for people detained in rural secure extended care facilities. Introducing these programs into clinical practice settings can improve the consumer experience and support organisational culture change towards a recovery orientation. PMID- 25834637 TI - Transcriptomic analysis revealed the mechanism of oil dynamic accumulation during developing Siberian apricot (Prunus sibirica L.) seed kernels for the development of woody biodiesel. AB - BACKGROUND: Siberian apricot (Prunus sibirica L.) has emerged as a novel potential source of biodiesel in China, but the molecular regulatory mechanism of oil accumulation in Siberian apricot seed kernels (SASK) is still unknown at present. To better develop SASK oil as woody biodiesel, it is essential to profile transcriptome and to identify the full repertoire of potential unigenes involved in the formation and accumulation of oil SASK during the different developing stages. RESULTS: We firstly detected the temporal patterns for oil content and fatty acid (FA) compositions of SASK in 7 different developing stages. The best time for obtaining the high quality and quantity of SASK oil was characterized at 60 days after flowering (DAF), and the representative periods (10, 30, 50, 60, and 70 DAF) were selected for transcriptomic analysis. By Illumina/Solexa sequencings, approximately 65 million short reads (average length = 96 bp) were obtained, and then assembled into 124,070 unigenes by Trinity strategy (mean size = 829.62 bp). A total of 3,000, 2,781, 2,620, and 2,675 differentially expressed unigenes were identified at 30, 50, 60, and 70 DAF (10 DAF as the control) by DESeq method, respectively. The relationship between the unigene transcriptional profiles and the oil dynamic patterns in developing SASK was comparatively analyzed, and the specific unigenes encoding some known enzymes and transcription factors involved in acetyl-coenzyme A (acetyl-CoA) formation and oil accumulation were determined. Additionally, 5 key metabolic genes implicated in SASK oil accumulation were experimentally validated by quantitative real-time PCR (qRT-PCR). Our findings could help to construction of oil accumulated pathway and to elucidate the molecular regulatory mechanism of increased oil production in developing SASK. CONCLUSIONS: This is the first study of oil temporal patterns, transcriptome sequencings, and differential profiles in developing SASK. All our results will serve as the important foundation to further deeply explore the regulatory mechanism of SASK high-quality oil accumulation, and may also provide some reference for researching the woody biodiesel plants. PMID- 25834638 TI - Rapid analysis of composition and reactivity in cellulosic biomass feedstocks with near-infrared spectroscopy. AB - BACKGROUND: Obtaining accurate chemical composition and reactivity (measures of carbohydrate release and yield) information for biomass feedstocks in a timely manner is necessary for the commercialization of biofuels. Our objective was to use near-infrared (NIR) spectroscopy and partial least squares (PLS) multivariate analysis to develop calibration models to predict the feedstock composition and the release and yield of soluble carbohydrates generated by a bench-scale dilute acid pretreatment and enzymatic hydrolysis assay. Major feedstocks included in the calibration models are corn stover, sorghum, switchgrass, perennial cool season grasses, rice straw, and miscanthus. RESULTS: We present individual model statistics to demonstrate model performance and validation samples to more accurately measure predictive quality of the models. The PLS-2 model for composition predicts glucan, xylan, lignin, and ash (wt%) with uncertainties similar to primary measurement methods. A PLS-2 model was developed to predict glucose and xylose release following pretreatment and enzymatic hydrolysis. An additional PLS-2 model was developed to predict glucan and xylan yield. PLS-1 models were developed to predict the sum of glucose/glucan and xylose/xylan for release and yield (grams per gram). The release and yield models have higher uncertainties than the primary methods used to develop the models. CONCLUSION: It is possible to build effective multispecies feedstock models for composition, as well as carbohydrate release and yield. The model for composition is useful for predicting glucan, xylan, lignin, and ash with good uncertainties. The release and yield models have higher uncertainties; however, these models are useful for rapidly screening sample populations to identify unusual samples. PMID- 25834640 TI - Improving a recombinant Zymomonas mobilis strain 8b through continuous adaptation on dilute acid pretreated corn stover hydrolysate. AB - BACKGROUND: Complete conversion of the major sugars of biomass including both the C5 and C6 sugars is critical for biofuel production processes. Several inhibitory compounds like acetate, hydroxymethylfurfural (HMF), and furfural are produced from the biomass pretreatment process leading to 'hydrolysate toxicity,' a major problem for microorganisms to achieve complete sugar utilization. Therefore, development of more robust microorganisms to utilize the sugars released from biomass under toxic environment is critical. In this study, we use continuous culture methodologies to evolve and adapt the ethanologenic bacterium Zymomonas mobilis to improve its ethanol productivity using corn stover hydrolysate. RESULTS: A turbidostat was used to adapt the Z. mobilis strain 8b in the pretreated corn stover liquor. The adaptation was initiated using pure sugar (glucose and xylose) followed by feeding neutralized liquor at different dilution rates. Once the turbidostat reached 60% liquor content, the cells began washing out and the adaptation was stopped. Several 'sub-strains' were isolated, and one of them, SS3 (sub-strain 3), had 59% higher xylose utilization than the parent strain 8b when evaluated on 55% neutralized PCS (pretreated corn stover) liquor. Using saccharified PCS slurry generated by enzymatic hydrolysis from 25% solids loading, SS3 generated an ethanol yield of 75.5% compared to 64% for parent strain 8b. Furthermore, the total xylose utilization was 57.7% for SS3 versus 27.4% for strain 8b. To determine the underlying genotypes in these new sub strains, we conducted genomic resequencing and identified numerous single nucleotide mutations (SNPs) that had arisen in SS3. We further performed quantitative reverse transcription PCR (qRT-PCR) on genes potentially affected by these SNPs and identified significant down-regulation of two genes, ZMO0153 and ZMO0776, in SS3 suggesting potential genetic mechanisms behind SS3's improved performance. CONCLUSION: We have adapted/evolved Z. mobilis strain 8b for enhanced tolerance to the toxic compounds present in corn stover hydrolysates. The adapted strain SS3 has higher xylose utilization rate and produce more ethanol than the parent strain. We have identified transcriptional changes which may be responsible for these phenotypes, providing foundations for future research directions in improving Z. mobilis as biocatalysts for the production of ethanol or other fuel precursors. PMID- 25834639 TI - Genetic basis of the highly efficient yeast Kluyveromyces marxianus: complete genome sequence and transcriptome analyses. AB - BACKGROUND: High-temperature fermentation technology with thermotolerant microbes has been expected to reduce the cost of bioconversion of cellulosic biomass to fuels or chemicals. Thermotolerant Kluyveromyces marxianus possesses intrinsic abilities to ferment and assimilate a wide variety of substrates including xylose and to efficiently produce proteins. These capabilities have been found to exceed those of the traditional ethanol producer Saccharomyces cerevisiae or lignocellulose-bioconvertible ethanologenic Scheffersomyces stipitis. RESULTS: The complete genome sequence of K. marxianus DMKU 3-1042 as one of the most thermotolerant strains in the same species has been determined. A comparison of its genomic information with those of other yeasts and transcriptome analysis revealed that the yeast bears beneficial properties of temperature resistance, wide-range bioconversion ability, and production of recombinant proteins. The transcriptome analysis clarified distinctive metabolic pathways under three different growth conditions, static culture, high temperature, and xylose medium, in comparison to the control condition of glucose medium under a shaking condition at 30 degrees C. Interestingly, the yeast appears to overcome the issue of reactive oxygen species, which tend to accumulate under all three conditions. CONCLUSIONS: This study reveals many gene resources for the ability to assimilate various sugars in addition to species-specific genes in K. marxianus, and the molecular basis of its attractive traits for industrial applications including high-temperature fermentation. Especially, the thermotolerance trait may be achieved by an integrated mechanism consisting of various strategies. Gene resources and transcriptome data of the yeast are particularly useful for fundamental and applied researches for innovative applications. PMID- 25834641 TI - Reduced Slc2a4/GLUT4 expression in subcutaneous adipose tissue of monosodium glutamate obese mice is recovered after atorvastatin treatment. AB - BACKGROUND: Decreased expression of glucose transporter protein GLUT4, encoded by the solute carrier 2A4 (Slc2a4) gene, is involved in obesity-induced insulin resistance. Local tissue inflammation, by nuclear factor-kappaB (NFkappaB) mediated pathway, has been related to Slc2a4 repression; a mechanism that could be modulated by statins. Using a model of obesity with insulin resistance, this study investigated whether (1) inflammatory markers and Slc2a4 expression are altered; (2) atorvastatin has beneficial effects on inflammation and Slc2a4 expression; and (3) inhibitor of NFkappaB (IKK)/NFkappaB pathway is involved in subcutaneous adipose tissue (SAT). FINDINGS: Obese mice showed insulin resistance, decreased expression of Slc2a4 mRNA (66%, P < 0.01) and GLUT4 protein (30%, P < 0.05), and increased expression of interleukin 6 (Il6) mRNA (44%, P < 0.05) in SAT. Obese mice treated with atorvastatin had enhanced in vivo insulin sensitivity, besides increased Slc2a4/GLUT4 expression and reduced Il6 expression in SAT. No alterations of tumor necrosis factor-alpha, interleukin 1beta and adiponectin expression or IKKalpha/beta activity in SAT of obese mice or obese mice treated with atorvastatin were observed. CONCLUSIONS: Atorvastatin has beneficial effect upon glycemic homeostasis, which may be related to its positive impact on Il6 and Slc2a4/GLUT4 expression in SAT. PMID- 25834643 TI - Linking a research register to clinical records in older adults' mental health services: a mixed-methods study. AB - INTRODUCTION: Patients can provide consent to have their clinical records linked to a research register, a process known as consent for contact (C4C). There is evidence about how to engage people with mental illness in C4C, but nothing specific to older adults. This is a priority area for research (for example, dementia trials), although sign-up rates to C4C are lower than for younger populations. Through this study we seek to understand these disparities. METHODS: This was a two-stage cross-sectional observational study. In phase one, focus groups with service users, carers and clinicians informed a framework for clinicians to explain C4C to those on their caseload. In phase two, clinicians explained C4C to 26 service users (and carers where applicable). These conversations were recorded, and their content was analysed. Service users and carers were then interviewed to provide further feedback on their conversations with clinicians. A total of 31 service users, 24 carers and 13 clinical staff took part across the two phases. RESULTS: In phase one, service users and carers sought assurance of the right to refuse participation in further studies (after joining C4C). Clinicians expressed concerns over legal and practical implications of ascertaining mental capacity and best interest. In phase two, clinicians' explanations were less thorough than similar explanations given to younger adults with psychosis. Clinicians omitted details of service users' right to stipulate contact arrangements, which was significantly associated with whether service users/carers agreed to join. Common reasons for joining C4C included altruism and the chance to speak to new people. Few participants refused to join, but reasons included avoidance of stress (potentially alleviated through the presence of a carer). CONCLUSIONS: Implementing C4C in older adults' services requires clinicians to deliver concise, simple explanations to individuals and their carers where applicable. Older adults can be suspicious of unsolicited contact; thus, explanations must emphasise freedom to negotiate suitable contact arrangements. Hearing about research opportunities can be in the best interests of older adults, but communicating these opportunities requires a tailored approach. PMID- 25834644 TI - Cyclic growth of hierarchical structures in the aluminum-silicate system. AB - BACKGROUND: Biological structures grow spontaneously from a seed, using materials supplied by the environment. These structures are hierarchical, with the 'building blocks' on each level constructed from those on the lower level. To understand and model the processes that occur on many levels, and later construct them, is a difficult task. However interest in this subject is growing. It is now possible to study the spontaneous growth of hierarchical structures in simple, two component chemical systems. RESULTS: Aluminum-silicate systems have been observed to grow into structures that are approximately conical. These structures are composed of multiple smaller cones with several hierarchical levels of complexity. On the highest level the system resembles a metropolis, with a horizontal resource distribution network connecting vertical, conical structures. The cones are made from many smaller cones that are connected together forming a whole with unusual behavior. The growth is observed to switch periodically between the vertical and horizontal directions. CONCLUSION: A structure grown in a dish is observed to have many similarities to other hierarchical systems such as biological organisms or cities. This system may provide a simple model system to search for universal laws governing the growth of complex hierarchical structures. Graphical AbstractSide view of the chemical structure made from many vertical cones to form a chemical metropolis. The tallest structure is 17 cm high. PMID- 25834645 TI - Transposable elements in a clade of three tetraploids and a diploid relative, focusing on Gypsy amplification. AB - BACKGROUND: Polyploidization can activate specific transposable elements, leading to their accumulation. At the same time, the preferential loss of repetitive elements in polyploids may be central to diploidization. The paucity of studies of transposable element (TE) dynamics in closely related diploid and polyploid species, however, prevents generalizations about these patterns. Here, we use low coverage Illumina sequencing data for a clade of three tetraploid Orobanche species and a diploid relative to quantify the abundance and relative frequencies of different types of TEs. We confirmed tetraploidy in the sequenced individuals using standard cytogenetic methods and inferred the time of origin of the tetraploid clade with a rate-calibrated molecular clock. FINDINGS: The sequenced individuals of Orobanche austrohispanica, Orobanche densiflora, and Orobanche gracilis have 2n = 76 chromosomes, are tetraploid, and shared a most recent common ancestor some 6.7 Ma ago. Comparison of TE classifications from the Illumina data with classification from 454 data for one of the species revealed strong effects of sequencing technology on the detection of certain types of repetitive DNA. The three tetraploids show repeat enrichment especially of Gypsy TE families compared to eight previously analyzed Orobanchaceae. However, the diploid Orobanche rapum-genistae genome also has a very high proportion (30%) of Gypsy elements. CONCLUSIONS: We had earlier suggested that tetraploidization might have contributed to an amplification of Gypsy elements, particularly of the Tekay clade, and that O. gracilis underwent genome downsizing following polyploidization. The new data reveal that Gypsy amplification in Orobanchaceae does not consistently relate to tetraploidy and that more species sampling is required to generalize about Tekay accumulation patterns. PMID- 25834646 TI - Association of Information Sources and Knowledge on HIV/AIDS in Rural China. AB - OBJECTIVE: To investigate the association between the number of available information sources on HIV/AIDS and HIV/AIDS-related knowledge in a rural population in China. DESIGN: We performed a cross-sectional survey on the number and types of sources of HIV/AIDS information available to rural residents of China and assessed HIV/AIDS-related knowledge in this population. We collected information from 5,355 Chinese rural residents and then correlated the results of the scores on knowledge to the numbers of information sources, and adjusted for age, sex, education and occupation. RESULTS: The sources of HIV/AIDs information reported by subjects included television, radio, newspapers, periodicals, discussions with neighbors and friends. There were significant differences in sources of information based on gender, occupation, educational level and age. The average number of information sources was 3.01 +/- 1.74. The average score on the AIDS related knowledge questionnaire was 8.21 +/- 4.23. Subjects who reported 6 sources of HIV/AIDS information had an average score of 11.67 +/- 3.0 on the HIV/AIDS knowledge questionnaire. Subjects who reported between 3-7 sources of HIV/AIDS information had significantly higher scores than those who had 1,2 or 8 sources of information. CONCLUSIONS: There is an association between HIV/AIDS knowledge and the number of available information sources. By increasing the sources, one could not always make more people curious or interested in HIV/AIDS knowledge. PMID- 25834647 TI - Exponential synchronization of discontinuous neural networks with time-varying mixed delays via state feedback and impulsive control. AB - This paper investigates drive-response synchronization for a class of neural networks with time-varying discrete and distributed delays (mixed delays) as well as discontinuous activations. Strict mathematical proof shows the global existence of Filippov solutions to neural networks with discontinuous activation functions and the mixed delays. State feedback controller and impulsive controller are designed respectively to guarantee global exponential synchronization of the neural networks. By using Lyapunov function and new analysis techniques, several new synchronization criteria are obtained. Moreover, lower bound on the convergence rate is explicitly estimated when state feedback controller is utilized. Results of this paper are new and some existing ones are extended and improved. Finally, numerical simulations are given to verify the effectiveness of the theoretical results. PMID- 25834642 TI - The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms. AB - Modern lifestyle has profoundly modified human sleep habits. Sleep duration has shortened over recent decades from 8 to 6.5 hours resulting in chronic sleep deprivation. Additionally, irregular sleep, shift work and travelling across time zones lead to disruption of circadian rhythms and asynchrony between the master hypothalamic clock and pacemakers in peripheral tissues. Furthermore, obstructive sleep apnea syndrome (OSA), which affects 4 - 15% of the population, is not only characterized by impaired sleep architecture but also by repetitive hemoglobin desaturations during sleep. Epidemiological studies have identified impaired sleep as an independent risk factor for all cause of-, as well as for cardiovascular, mortality/morbidity. More recently, sleep abnormalities were causally linked to impairments in glucose homeostasis, metabolic syndrome and Type 2 Diabetes Mellitus (T2DM). This review summarized current knowledge on the metabolic alterations associated with the most prevalent sleep disturbances, i.e. short sleep duration, shift work and OSA. We have focused on various endocrine and molecular mechanisms underlying the associations between inadequate sleep quality, quantity and timing with impaired glucose tolerance, insulin resistance and pancreatic beta-cell dysfunction. Of these mechanisms, the role of the hypothalamic-pituitary-adrenal axis, circadian pacemakers in peripheral tissues, adipose tissue metabolism, sympathetic nervous system activation, oxidative stress and whole-body inflammation are discussed. Additionally, the impact of intermittent hypoxia and sleep fragmentation (key components of OSA) on intracellular signaling and metabolism in muscle, liver, fat and pancreas are also examined. In summary, this review provides endocrine and molecular explanations for the associations between common sleep disturbances and the pathogenesis of T2DM. PMID- 25834648 TI - Noise-induced burst and spike synchronizations in an inhibitory small-world network of subthreshold bursting neurons. AB - We are interested in noise-induced firings of subthreshold neurons which may be used for encoding environmental stimuli. Noise-induced population synchronization was previously studied only for the case of global coupling, unlike the case of subthreshold spiking neurons. Hence, we investigate the effect of complex network architecture on noise-induced synchronization in an inhibitory population of subthreshold bursting Hindmarsh-Rose neurons. For modeling complex synaptic connectivity, we consider the Watts-Strogatz small-world network which interpolates between regular lattice and random network via rewiring, and investigate the effect of small-world connectivity on emergence of noise-induced population synchronization. Thus, noise-induced burst synchronization (synchrony on the slow bursting time scale) and spike synchronization (synchrony on the fast spike time scale) are found to appear in a synchronized region of the [Formula: see text]-[Formula: see text] plane ([Formula: see text]: synaptic inhibition strength and [Formula: see text]: noise intensity). As the rewiring probability [Formula: see text] is decreased from 1 (random network) to 0 (regular lattice), the region of spike synchronization shrinks rapidly in the [Formula: see text] [Formula: see text] plane, while the region of the burst synchronization decreases slowly. We separate the slow bursting and the fast spiking time scales via frequency filtering, and characterize the noise-induced burst and spike synchronizations by employing realistic order parameters and statistical mechanical measures introduced in our recent work. Thus, the bursting and spiking thresholds for the burst and spike synchronization transitions are determined in terms of the bursting and spiking order parameters, respectively. Furthermore, we also measure the degrees of burst and spike synchronizations in terms of the statistical-mechanical bursting and spiking measures, respectively. PMID- 25834649 TI - The stability of impulsive stochastic Cohen-Grossberg neural networks with mixed delays and reaction-diffusion terms. AB - The global asymptotic stability of impulsive stochastic Cohen-Grossberg neural networks with mixed delays and reaction-diffusion terms is investigated. Under some suitable assumptions and using Lyapunov-Krasovskii functional method, we apply the linear matrix inequality technique to propose some new sufficient conditions for the global asymptotic stability of the addressed model in the stochastic sense. The mixed time delays comprise both the time-varying and continuously distributed delays. The effectiveness of the theoretical result is illustrated by a numerical example. PMID- 25834650 TI - Brain electrical activities of dancers and fast ball sports athletes are different. AB - Exercise training has been shown not only to influence physical fitness positively but also cognition in healthy and impaired populations. However, some particular exercise types, even though comparable based on physical efforts, have distinct cognitive and sensorimotor features. In this study, the effects of different types of exercise, such as fast ball sports and dance training, on brain electrical activity were investigated. Electroencephalography (EEG) scans were recorded in professional dancer, professional fast ball sports athlete (FBSA) and healthy control volunteer groups consisting of twelve subjects each. In FBSA, power of delta and theta frequency activities of EEG was significantly higher than those of the dancers and the controls. Conversely, dancers had significantly higher amplitudes in alpha and beta bands compared to FBSA and significantly higher amplitudes in the alpha band in comparison with controls. The results suggest that cognitive features of physical training can be reflected in resting brain electrical oscillations. The differences in resting brain electrical oscillations between the dancers and the FBSA can be the result of innate network differences determining the talents and/or plastic changes induced by physical training. PMID- 25834652 TI - Local use of ankaferd blood clotter in emergent beating heart coronary artery bypass grafting. AB - BACKGROUND: Severe beeding which requiring massive blood transfusion after emergent beating heart surgery is shown to be 1-3%. Therefore, complications and side effects of transfusion can be seen. The aim of this study was to investigate the effectiveness of Ankaferd blood clotter (ABC) as a new topical herbal blood clotter to decrease mediastinal bleeding in emergent beating heart CABG patients who medicated with clopidogrel and acetyl salisilic acite (ASA) prior to CABG surgery. MATERIALS AND METHODS: 25 CABG patients received a high dose clopidogrel (600 mgr) and 300 mgr ASA have been included into the study (ABC group). 25 patients have also been included into the study for comparison (placebo group, PG). After the administration of protamine sulphate, a 10 ml of ABC solution has been sprayed to the surgical area including mediastinum and epicardial sac. We compared mediastinal drenaige, reoperation due to tamponade, and required blood and blood products in both groups. RESULTS: The mean amount of bleeding after operation was 230 ml in ABC group, and 490 ml in CG (P=0.001). In ICU, bleeding in ABC group and CG was 410ml and 680ml, respectively (P=0.0022). The mean total bleeding from mediastinum was 530+/-280 mL and 990+/-440 mL In ABC and CG group, respectively (P=0.001). The amount of autotransfusion was as follows: 175 mL in ABC group, and 290 mL in CG (P=0.002). No patient needed the surgical revision in ABC group, but four patients (16%) from CG group because of cardiac tamponade. Seventeen patients from CG required blood transfusion due to low hematocrite level postoperatively. In CG, the mean hematocrite level was 17+/-2,3. Transfusion of fresh frozen plasma and platelets in ABC group and CG were as follows: 0.2 and 0 in ABC group, and 0.3and 0.4 in CG. CONCLUSION: Our study showed that the local use of 10 mL ABC reduces bleeding significantly. Therefore, transfusion requirements of PRBC, platelets, and total blood units in patients on clopidogrel and ASA undergoing emergent beating heart CABG. To provide cardiac tamponade because of excessive mediastinal bleeding and requirement of blood transfusion after emergent CABG patients who previously administered clopidogrel and ASA, we propose local use of ABC solution as a potent coagulant agent. PMID- 25834651 TI - Association of high blood pressure with body mass index, smoking and physical activity in healthy young adults. AB - INTRODUCTION: The purpose of this study was to examine the associations between resting blood pressure (BP), smoking, physical activity (PA) and body mass index (BMI) in Greek young adults. MATERIALS AND METHODOLOGY: A standardised questionnaire and the Greek version of IPAQ-short were given to 1500 randomly selected health science students, in order to record smoking behaviour, PA status, BMI and resting BP. All healthy young adults aged 19-30 years old were eligible. The final size of the study cohort was 1249 students (522 men). RESULTS: Males' BP was 129.2/77.0 mmHg, significantly higher than the females' values of 119.9/73.4 mmHg. Approximately 17% of the total population were classified as overweight and 3% as obese. In the overall population, smoking prevalence was 35.2%, with 15.3% being heavy smokers (>=21 cigs/d). Smoking prevalence did not differ significantly between sexes. The prevalence of health enhancing PA (high PAclass) was only 14.0%, while 42.8% of the study population were classified as insufficiently active (low PAclass). Of the three lifestyle risk factors examined, only BMI was significantly and directly associated with systolic and diastolic BP levels. The prevalence of hypertension (>=140/90 mmHg) was significantly higher in men compared to women, and in obese and overweight participants compared to normal-weight subjects. Smoking and categorical PA (PAclass) were not correlated with BP. Continuous vigorous PAscore was significantly and directly associated with systolic BP, but only in males. CONCLUSION: BMI was significantly and directly associated with resting BP in both sexes. Smoking prevalence and PA status were not associated with BP in this sample of Greek young adults. PMID- 25834653 TI - Body Surface Mapping of T-wave Alternans Depends on the Distribution of Myocardial Scarring. AB - T-Wave alternans (TWA) testing using 12-lead electrocardiogram/Frank leads is emerging as an important non-invasive biomarker to identify patients at high risk of Sudden Cardiac Death (SCD). Cardiac scarring is very common among cardiomyopathy patients; however, its influence on the body surface distribution of TWA has not yet been defined. Our objective was to perform a simulation study in order to determine whether cardiac scarring affects the distribution of TWA on thorax such that the standard leads fail to detect TWA in some of cardiomyopathy patients; thereby producing a false-negative test. Developing such a novel lead configuration could improve TWA quantification and potentially optimize electrocardiogram (ECG) lead configuration and risk stratification of SCD in cardiomyopathy patients. The simulation was performed in a 1500-node heart model using ECGSIM. TWA was mimicked by simulating action potential duration alternans in the ventricles. Cardiac scarring with different sizes were simulated by manipulating the apparent velocity, transmembrane potential and transition zone at varied locations along the left ventricular posterior wall. Our simulation study showed that the location of maximum TWA depends on the location and size of the myocardium scarring in patients with cardiomyopathy, which can give rise to false-negative TWA signal detection using standard clinical leads. The TWA amplitude generally increased with the increment of scar size (P<0.00001). We found one specific location (a non-standard lead) that consistently appeared as the top five maximum TWA leads and could be considered as an additional lead to improve the outcome of the TWA testing in cardiomyopathy patients. PMID- 25834654 TI - Cardiovascular Risk Assessment and Effects on Behavior in Switzerland The Swiss Heart Foundation HerzCheck((r))/Cardio-Test((r)). AB - BACKGROUND: "CardioTest ((r)) " is a tool for cardiovascular risk assessment. The aim of this study was to evaluate if this test used in Swiss pharmacies provides risk stratification and if it had impact on individual behaviour. METHODS: Individuals were evaluated (blood pressure, body waist circumference, random blood samples and coronary artery disease risk factors). The cardiovascular risk was calculated (AGLA Risk Score (ARS) a modified PROCAM Score) and participants were informed about their result. One year after the initial testing individuals were followed up by questionnaire with respect to the action they had taken based upon the ARS results. The relation between ARS results and events during follow up were assessed. Events were defined as cardiovascular events due to chest pain, myocardial infarction or stroke. RESULT: A total of 1415 individuals were contacted for follow-up, 746 (53%) with a mean age of 62.7 (+/-12.8) years (60% were male) returned their questionnaire. The cardiovascular risk throughout the study-population turned out to be low: 73.9% had a low ARS <10%, 21.7% an intermediate ARS 10-20% and 4.4% had a high ARS >20%. Significantly more participants with ARS >20% consulted their family doctor (46.2%) than those with ARS 10-20% (25.2%) and ARS <10% (10.4%), respectively (p<0,01 for both comparisons). Sixty-four individuals (9%) suffered a cardiovascular event. The event rates increased as a function of ARS. CONCLUSION: The overall cardiovascular risk of individuals participating in a pharmacy based risk assessment program seems to be low. CardioTest ((r)) provided risk stratification with respect to future cardio-vascular events. CardioTest ((r)) seems to have impact on individual behavior and lifestyle modification. Other settings and locations for screening might be considered to reach higher risk individuals at an earlier stage. PMID- 25834655 TI - Reduction in dental hypersensitivity with nano-hydroxyapatite, potassium nitrate, sodium monoflurophosphate and antioxidants. AB - OBJECTIVE: This clinical study aimed to evaluate effectiveness of a commercially available toothpaste containing potassium nitrate, sodium monoflurophosphate, and nano-hydroxyapatite as well as antioxidants phloretin, ferulic acid and silymarin in reducing dental hypersensitivity in adults. METHODS: The clinical trial enrolled patients with a history of dentin hypersensitivity. A test toothpaste was introduced into the daily routine, which included initial instruction on usage. Patients completed a five-question visual analog scale (VAS) at the inception/baseline, after two days and after two weeks of using the toothpaste to determine their level of tooth sensitivity at baseline with the use of the toothpaste over time. RESULTS: Patients that had significant sensitivity at baseline had a range of 52% to 76 % improvement after 48 hours and a range of 70% to 84% improvement after two weeks. CONCLUSION: A toothpaste containing potassium nitrate, sodium monoflurophosphate, and nano-hydroxyapatite plus antioxidants phloretin, ferulic acid and silymarin applied daily significantly decreased tooth pain of dentin hypersensitivity within a two-day and two-week time period. CLINICAL SIGNIFICANCE: Based on the clinical study results, a daily application of a toothpaste containing potassium nitrate, sodium monofluorophosphate, and nano-hydroxyapatite plus antioxidants phloretin, ferulic acid and silymarin can significantly and quickly reduce tooth pain of dentin hypersensitivity. PMID- 25834656 TI - The Validity and Reliability of an Arabic Version of the STOP-Bang Questionnaire for Identifying Obstructive Sleep Apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common, serious, under-recognized and under-diagnosed medical disorder. Polysomnography (PSG) is the gold standard diagnostic test for OSA; however, the cost of testing and the shortage of sleep disorders laboratories limit access to this tool. Therefore, there is a need for a simple and reliable diagnostic tool to screen patients at risk of OSA. OBJECTIVE: This study was conducted to evaluate the validity and reliability of an Arabic version of the STOP-Bang questionnaire (SBQ) as a screening tool for OSA. METHODS: This study was conducted in three steps, as follows: Step 1: the SBQ was translated from English to Arabic (examining both forward and backward translations); Step 2: the test-retest reliability of the questionnaire was investigated; and Step 3: the questionnaire was validated against PSG data prospectively on 100 patients attending a sleep disorders clinic who were subjected to a full-night PSG study after completing the translated version of the SBQ. The validity of the test was tested against the apnea-hypopnea index (AHI). RESULTS: The study group had a mean age of 46.6 +/- 14.0 years and a mean AHI of 50.0 +/- 37.0/hour. The study demonstrated a high degree of internal consistency and stability over time for the translated SBQ. The Cronbach's alpha coefficient for the 8-item tool was 0.7. Validation of the SBQ against the AHI at a cut-off of 5 revealed a sensitivity of 98% and positive and negative predictive values of 86% and 67%, respectively. CONCLUSION: The Arabic version of the SBQ is an easy-to-administer, simple, reliable and valid tool for the identification of OSA in the sleep disorders clinic setting. PMID- 25834657 TI - Bilateral papilledema as the first sign of ventriculoperitoneal shunt dysfunctionS. AB - A 12 year-old girl patient with a history of ventriculoperitoneal shunt placement at the age of 6 months presented with progressive bilateral decrease in visual acuity. Ophthalmologic examination was consistent with bilateral papilledema. No other systemic manifestations of increased intracranial pressure were evident and laboratory work-up excluded other inflammatory or infectious processes. We present here an interesting case of a patient with ophthalmologic manifestations as the initial finding of ventriculoperitoneal shunt dysfunction. PMID- 25834658 TI - Calculating Optical Absorption Spectra of Thin Polycrystalline Organic Films: Structural Disorder and Site-Dependent van der Waals Interaction. AB - We propose a new approach for calculating the change of the absorption spectrum of a molecule when moved from the gas phase to a crystalline morphology. The so called gas-to-crystal shift Delta[Formula: see text] m is mainly caused by dispersion effects and depends sensitively on the molecule's specific position in the nanoscopic setting. Using an extended dipole approximation, we are able to divide Delta[Formula: see text] m = -QWm in two factors, where Q depends only on the molecular species and accounts for all nonresonant electronic transitions contributing to the dispersion while Wm is a geometry factor expressing the site dependence of the shift in a given molecular structure. The ability of our approach to predict absorption spectra is demonstrated using the example of polycrystalline films of 3,4,9,10-perylenetetracarboxylic diimide (PTCDI). PMID- 25834659 TI - Identify-isolate-inform: a tool for initial detection and management of measles patients in the emergency department. AB - Measles (rubeola) is a highly contagious airborne disease that was declared eliminated in the U.S. in the year 2000. Only sporadic U.S. cases and minor outbreaks occurred until the larger outbreak beginning in 2014 that has become a public health emergency. The "Identify-Isolate-Inform" tool will assist emergency physicians to be better prepared to detect and manage measles patients presenting to the emergency department. Measles typically presents with a prodrome of high fever, and cough/coryza/conjunctivitis, sometimes accompanied by the pathognomonic Koplik spots. Two to four days later, an erythematous maculopapular rash begins on the face and spreads down the body. Suspect patients must be immediately isolated with airborne precautions while awaiting laboratory confirmation of disease. Emergency physicians must rapidly inform the local public health department and hospital infection control personnel of suspected measles cases. PMID- 25834660 TI - Kiosk versus in-person screening for alcohol and drug use in the emergency department: patient preferences and disclosure. AB - INTRODUCTION: Annually eight million emergency department (ED) visits are attributable to alcohol use. Screening ED patients for at-risk alcohol and substance use is an integral component of screening, brief intervention, and referral to treatment programs, shown to be effective at reducing substance use. The objective is to evaluate ED patients' acceptance of and willingness to disclose alcohol/substance use via a computer kiosk versus an in-person interview. METHODS: This was a cross-sectional, survey-based study. Eligible participants included those who presented to walk-in triage, were English speaking, >=18 years, were clinically stable and able to consent. Patients had the opportunity to access the kiosk in the ED waiting room, and were approached for an in-person survey by a research assistant (9am-5pm weekdays). Both surveys used validated assessment tools to assess drug and alcohol use. Disclosure statistics and preferences were calculated using chi-square tests and McNemar's test. RESULTS: A total of 1,207 patients were screened: 229 in person only, 824 by kiosk, and 154 by both in person and kiosk. Single-modality participants were more likely to disclose hazardous drinking (p=0.003) and high-risk drug use (OR=22.3 [12.3-42.2]; p<0.0001) via kiosk. Participants who had participated in screening via both modalities were more likely to reveal high-risk drug use on the kiosk (p=0.003). When asked about screening preferences, 73.6% reported a preference for an in-person survey, which patients rated higher on privacy and comfort. CONCLUSION: ED patients were significantly more likely to disclose at risk alcohol and substance use to a computer kiosk than an interviewer. Paradoxically patients stated a preference for in-person screening, despite reduced disclosure to a human screener. PMID- 25834661 TI - Patients who use multiple EDs: quantifying the degree of overlap between ED populations. AB - INTRODUCTION: The degree to which individual patients use multiple emergency departments (EDs) is not well-characterized. We determined the degree of overlap in ED population between three geographically proximate hospitals. METHODS: This retrospective cohort study reviewed administrative hospital records from 2003 to 2007 for patients registered to receive ED services at an urban academic, urban community, and suburban community ED located within 10 miles of one another. We determined the proportion who sought care at multiple EDs and secondarily characterized patterns of repeat encounters. RESULTS: There were 795,176 encounters involving 282,903 patients. There were 89,776 (31%) patients with multiple encounters to a single ED and 39,920 (14%) patients who sought care from multiple EDs. The 39,920 patients who sought care from multiple EDs generated 185,629 (23%) of all encounters. Patients with repeat encounters involving multiple EDs were more likely to be frequent or highly frequent users (30%) than patients with multiple encounters to a single ED (14%). CONCLUSION: While only 14% of patients received care from more than one ED, they were responsible for a quarter of ED encounters. Patients who use multiple EDs are more often frequent or highly frequent users than are repeat ED visitors to the same ED. Overlap between ED populations is sufficient to warrant consideration by multiple domains of research, practice, and policy. PMID- 25834662 TI - Do emergency physicians and medical students find it unethical to 'look up' their patients on facebook or Google? AB - INTRODUCTION: The use of search engines and online social media (OSM) websites by healthcare providers is increasing and may even be used to search for patient information. This raises several ethical issues. The objective of this study is to evaluate the prevalence of OSM and web-searching for patient information and to explore attitudes towards the ethical appropriateness of these practices by physicians and trainees in the emergency department (ED). METHODS: We conducted an online survey study of Canadian emergency physicians and trainees listed under then Canadian Association of Emergency Physicians (CAEP) and senior medical students at the University of Toronto. RESULTS: We received 530 responses (response rate 49.1%): 34.9% medical students, 15.5% residents, 49.6% staff physicians. Most had an active Facebook account (74%). Sixty-four participants (13.5%) had used Google to research a patient and 10 (2.1%) had searched for patients on Facebook. There were no differences in these results based on level of training, and 25% of physicians considered using Facebook to learn about a patient "very unethical." The most frequent ethical concerns were with violation of patient confidentiality, dignity, and consent. The practice was usually not disclosed to patients (14%), but often disclosed to senior colleagues (83%). CONCLUSION: This is the first study examining the prevalence of and attitudes towards online searching for obtaining patient information in the ED. This practice occurs among staff physicians and trainees despite ethical concerns. Future work should explore the utility and desirability of searching for patient information online. PMID- 25834663 TI - Inferior vena cava filter fracture: potential liability for emergency physicians. PMID- 25834664 TI - The social media index: measuring the impact of emergency medicine and critical care websites. AB - INTRODUCTION: The number of educational resources created for emergency medicine and critical care (EMCC) that incorporate social media has increased dramatically. With no way to assess their impact or quality, it is challenging for educators to receive scholarly credit and for learners to identify respected resources. The Social Media index (SMi) was developed to help address this. METHODS: We used data from social media platforms (Google PageRanks, Alexa Ranks, Facebook Likes, Twitter Followers, and Google+ Followers) for EMCC blogs and podcasts to derive three normalized (ordinal, logarithmic, and raw) formulas. The most statistically robust formula was assessed for 1) temporal stability using repeated measures and website age, and 2) correlation with impact by applying it to EMCC journals and measuring the correlation with known journal impact metrics. RESULTS: The logarithmic version of the SMi containing four metrics was the most statistically robust. It correlated significantly with website age (Spearman r=0.372; p<0.001) and repeated measures through seven months (r=0.929; p<0.001). When applied to EMCC journals, it correlated significantly with all impact metrics except number of articles published. The strongest correlations were seen with the Immediacy Index (r=0.609; p<0.001) and Article Influence Score (r=0.608; p<0.001). CONCLUSION: The SMi's temporal stability and correlation with journal impact factors suggests that it may be a stable indicator of impact for medical education websites. Further study is needed to determine whether impact correlates with quality and how learners and educators can best utilize this tool. PMID- 25834665 TI - Non-thrombotic abnormalities on lower extremity venous duplex ultrasound examinations. AB - INTRODUCTION: Emergency physician-performed compression ultrasonography focuses primarily on the evaluation of the proximal veins of the lower extremity in patients with suspected deep venous thrombosis (DVT). A detailed sonographic evaluation of lower extremity is not performed. The objective of this study was to determine the prevalence of non-thrombotic findings on comprehensive lower extremity venous duplex ultrasound (US) examinations performed on emergency department (ED) patients. METHODS: We performed a retrospective six-year review of an academic ED's records of adult patients who underwent a comprehensive lower extremity duplex venous US examination for the evaluation of DVT. The entire US report was thoroughly reviewed for non-thrombotic findings. RESULTS: We detected non-thrombotic findings in 263 (11%, 95% CI [9.5-11.9%]) patients. Among the non thrombotic findings, venous valvular incompetence (81, 30%) was the most frequent, followed by cyst/mass (41, 15%), lymphadenopathy (33, 12%), phlebitis (12, 4.5%), hematoma (8, 3%), cellulitis (1, 0.3%) and other (6, 2.2%). CONCLUSION: In our study, we detected a variety of non-thrombotic abnormalities on comprehensive lower extremity venous duplex US examinations performed on ED patients. Some of these abnormalities could be clinically significant and potentially be detected with point-of-care lower extremity US examinations if the symptomatic region is evaluated. In addition to assessment of the proximal veins for DVT, we recommend sonographic evaluation of the symptomatic area in the lower extremity when performing point-of-care ultrasound examinations to identify non thrombotic abnormalities that may require immediate intervention or close follow up. PMID- 25834666 TI - Can emergency physicians perform common carotid Doppler flow measurements to assess volume responsiveness? AB - INTRODUCTION: Common carotid flow measurements may be clinically useful to determine volume responsiveness. The objective of this study was to assess the ability of emergency physicians (EP) to obtain sonographic images and measurements of the common carotid artery velocity time integral (VTi) for potential use in assessing volume responsiveness in the clinical setting. METHODS: In this prospective observational study, we showed a five-minute instructional video demonstrating a technique to obtain common carotid ultrasound images and measure the common carotid VTi to emergency medicine (EM) residents. Participants were then asked to image the common carotid artery and obtain VTi measurements. Expert sonographers observed participants imaging in real time and recorded their performance on nine performance measures. An expert sonographer graded image quality. Participants were timed and answered questions regarding ease of examination and their confidence in obtaining the images. RESULTS: A total of 30 EM residents participated in this study and each performed the examination twice. Average time required to complete one examination was 2.9 minutes (95% CI [2.4-3.4 min]). Participants successfully completed all performance measures greater than 75% of the time, with the exception of obtaining measurements during systole, which was completed in 65% of examinations. Median resident overall confidence in accurately performing carotid VTi measurements was 3 (on a scale of 1 [not confident] to 5 [confident]). CONCLUSION: EM residents at our institution learned the technique for obtaining common carotid artery Doppler flow measurements after viewing a brief instructional video. When assessed at performing this examination, they completed several performance measures with greater than 75% success. No differences were found between novice and experienced groups. PMID- 25834667 TI - Bedside ultrasound identification of infectious flexor tenosynovitis in the emergency department. AB - Infectious flexor tenosynovitis (FTS) is a serious infection of the hand and wrist that can lead to necrosis and amputation without prompt diagnosis and surgical debridement. Despite the growing use of point-of-care ultrasound (POCUS) by emergency physicians there is only one reported case of the use of POCUS for the diagnosis of infectious FTS in the emergency department setting. We present a case of a 58 year-old man where POCUS identified tissue necrosis and fluid along the flexor tendon sheath of the hand. Subsequent surgical pathology confirmed the diagnosis of infectious FTS. PMID- 25834668 TI - Change in intraocular pressure during point-of-care ultrasound. AB - INTRODUCTION: Point-of-care ocular ultrasound (US) is a valuable tool for the evaluation of traumatic ocular injuries. Conventionally, any maneuver that may increase intraocular pressure (IOP) is relatively contraindicated in the setting of globe rupture. Some authors have cautioned against the use of US in these scenarios because of a theoretical concern that an US examination may cause or exacerbate the extrusion of intraocular contents. This study set out to investigate whether ocular US affects IOP. The secondary objective was to validate the intraocular pressure measurements obtained with the Diaton(r) as compared with standard applanation techniques (the Tono-Pen(r)). METHODS: We enrolled a convenience sample of healthy adult volunteers. We obtained the baseline IOP for each patient by using a transpalpebral tonometer. Ocular US was then performed on each subject using a high-frequency linear array transducer, and a second IOP was obtained during the US examination. A third IOP measurement was obtained following the completion of the US examination. To validate transpalpebral measurement, a subset of subjects also underwent traditional transcorneal applanation tonometry prior to the US examination as a baseline measurement. In a subset of 10 patients, we obtained baseline pre-ultrasound IOP measurements with the Diaton(r) and Tono-Pen(r), and then compared them. RESULTS: The study included 40 subjects. IOP values during ocular US examination were slightly greater than baseline (average +1.8mmHg, p=0.01). Post-US examination IOP values were not significantly different than baseline (average -0.15mmHg, p=0.42). In a subset of 10 subjects, IOP values were not significantly different between transpalpebral and transcorneal tonometry (average +0.03mmHg, p=0.07). CONCLUSION: In healthy volunteer subjects, point-of-care ocular US causes a small and transient increase in IOP. We also showed no difference between the Diaton(r) and Tono-Pen(r) methods of IOP measurement. Overall, the resulting change in IOP with US transducer placement is considerably less than the mean diurnal variation in healthy subjects, or pressure generated by physical examination, and is therefore unlikely to be clinically significant. However, it is important to take caution when performing ocular ultrasound, since it is unclear what the change in IOP would be in patients with ocular trauma. PMID- 25834669 TI - Young patients with suspected uncomplicated renal colic are unlikely to have dangerous alternative diagnoses or need emergent intervention. AB - INTRODUCTION: In the United States there is debate regarding the appropriate first test for new-onset renal colic, with non-contrast helical computed tomography (CT) receiving the highest ratings from both Agency for Healthcare Research and Quality and the American Urological Association. This is based not only on its accuracy for the diagnosis of renal colic, but also its ability to diagnose other surgical emergencies, which have been thought to occur in 10-15% of patients with suspected renal colic, based on previous studies. In younger patients, it may be reasonable to attempt to avoid immediate CT if concern for dangerous alternative diagnosis is low, based on the risks of radiation from CTs, and particularly in light of evidence that patients with renal colic have a very high likelihood of having multiple CTs in their lifetimes. The objective is to determine the proportion of patients with a dangerous alternative diagnosis in adult patients age 50 and under presenting with uncomplicated (non-infected) suspected renal colic, and also to determine what proportion of these patients undergo emergent urologic intervention. METHODS: Retrospective chart review of 12 months of patients age 18-50 presenting with "flank pain," excluding patients with end stage renal disease, urinary tract infection, pregnancy and trauma. Dangerous alternative diagnosis was determined by CT. RESULTS: Two hundred and ninety-one patients met inclusion criteria. One hundred and fifteen patients had renal protocol CTs, and zero alternative emergent or urgent diagnoses were identified (one-sided 95% CI [0-2.7%]). Of the 291 encounters, there were 7 urologic procedures performed upon first admission (2.4%, 95% CI [1.0-4.9%]). The prevalence of kidney stone by final diagnosis was 58.8%. CONCLUSION: This small sample suggests that in younger patients with uncomplicated renal colic, the benefit of immediate CT for suspected renal colic should be questioned. Further studies are needed to determine which patients benefit from immediate CT for suspected renal colic, and which patients could undergo alternate imaging such as ultrasound. PMID- 25834670 TI - Characteristics of patients that do not initially respond to intravenous antihypertensives in the emergency department: subanalysis of the CLUE trial. AB - INTRODUCTION: Hypertensive emergency has a high mortality risk and the treatment goal is to quickly lower blood pressure with intravenous (IV) medications. Characteristics that are associated with non-response to IV antihypertensives have not been identified. The objective is to identify patient characteristics associated with resistance to IV antihypertensives. METHODS: This was a subanalysis of patients enrolled in the previously described comparative effectiveness trial of IV nicardipine vs. labetalol use in the emergency department (CLUE) study, a randomized trial of nicardipine vs. labetalol. Non responders were defined as those patients who did not achieve target systolic blood pressure (SBP), as set by the treating physician, within thirty minutes of IV antihypertensive medication, +/- 20mmHg. Stepwise logistic regression was used to identify covariates associated with the measurement outcomes. RESULTS: CLUE enrolled 226 patients, 52.7% female, 76.4% black, mean age of 52.6+/-14.6 years, of whom 110 were treated with nicardipine and 116 with labetalol. The median (IQR) initial systolic blood pressure was 211mmHg (198, 226), 210 (200, 230), and 211mmHg (198, 226), for the total, non-responder, and responder cohorts, respectively (p-value=0.65, 95% CI [-5.8-11.3]). Twenty-nine were non-responders, 9 in the nicardipine and 20 in the labetalol group. In univariate analysis, several symptoms suggestive of end organ damage were associated with non response. After multiple variable logistic regression (AUC = 0.72), treatment with labetalol (OR 2.7, 95% CI [1.1-6.7]), history of stroke (OR 5.4, 95% CI [1.6 18.5]), and being male (OR 3.3, 95% CI [1.4-8.1]) were associated with failure to achieve target blood pressure. CONCLUSION: Male gender and history of previous stroke are associated with difficult to control blood pressure. PMID- 25834671 TI - Long-term neurological outcomes in adults with traumatic intracranial hemorrhage admitted to ICU versus floor. AB - INTRODUCTION: The objective of this study was to compare long-term neurological outcomes in low-risk patients with traumatic intracranial hemorrhage (tICH) admitted to the ICU (intensive care unit) versus patients admitted to the floor. METHODS: This retrospective study was conducted at a Level 1 trauma center from October 1, 2008, to February 1, 2013. We defined low-risk patients as age less than 65 years, isolated head injury, normal admission mental status, and no shift or swelling on initial head CT (computed tomography). Clinical data were abstracted from a trauma registry and linked to a brain injury database. We compared the Extended Glasgow Outcome Scale (GOS-E) score at six months between patients admitted to the ICU and patients admitted to the floor. We did a risk adjusted analysis of the influence of floor admission on a normal GOS-E. RESULTS: We identified 151 patients; 45 (30%) were admitted to the floor and 106 (70%) to the ICU. Twenty-three (51%; 95% CI [36-66%]) patients admitted to the floor and 55 (52%; 95% CI [42-62%]) patients admitted to the ICU had a normal GOS-E. On adjusted analysis; the odds ratio for floor admission was 0.77 (95% CI [0.36 1.64]) for a normal GOS-E at six months. CONCLUSION: Long-term neurological outcomes in low-risk patients with tICH were not markedly different between patients admitted to the ICU and those admitted to the floor. However, we were unable to demonstrate non-inferiority on adjusted analysis. Future work aimed at a larger, prospective cohort may better evaluate the relative impacts of admission type on outcomes. PMID- 25834672 TI - Headache in pregnancy: an approach to emergency department evaluation and management. AB - Headache is a common presenting complaint in the emergency department. The differential diagnosis is broad and includes benign primary causes as well as ominous secondary causes. The diagnosis and management of headache in the pregnant patient presents several challenges. There are important unique considerations regarding the differential diagnosis, imaging options, and medical management. Physiologic changes induced by pregnancy increase the risk of cerebral venous thrombosis, dissection, and pituitary apoplexy. Preeclampsia, a serious condition unique to pregnancy, must also be considered. A high index of suspicion for carbon monoxide toxicity should be maintained. Primary headaches should be a diagnosis of exclusion. When advanced imaging is indicated, magnetic resonance imaging (MRI) should be used, if available, to reduce radiation exposure. Contrast agents should be avoided unless absolutely necessary. Medical therapy should be selected with careful consideration of adverse fetal effects. Herein, we present a review of the literature and discuss an approach to the evaluation and management of headache in pregnancy. PMID- 25834673 TI - Diagnosis of pneumoperitoneum with bedside ultrasound. PMID- 25834674 TI - Jaguar attack on a child: case report and literature review. AB - Jaguar attacks on humans rarely occur in the wild. When they do, they are often fatal. We describe a jaguar attack on a three-year-old girl near her home deep in a remote area of the Guyanese jungle. The patient had a complex but, relatively, rapid transport to a medical treatment facility for her life-threatening injuries. The child, who suffered typical jaguar-inflicted injury patterns and survived, is highlighted. We review jaguar anatomy, environmental status, hunting and killing behaviors, and discuss optimal medical management, given the resource limited treatment environment of this international emergency medicine case. PMID- 25834675 TI - Die another day. PMID- 25834676 TI - Descending necrotizing mediastinitis in an infant. PMID- 25834677 TI - Left flank pain. PMID- 25834678 TI - Cecal diverticulitis: a diagnostic conundrum. PMID- 25834679 TI - Silent killer: case report of acute gastrostomy tube erosion. PMID- 25834680 TI - Penile foreskin avulsion from parrot fish bite. PMID- 25834681 TI - Spontaneous pneumomediastinum on bedside ultrasound: case report and review of the literature. AB - Spontaneous pneumomediastinum is a rare disease process with no clear etiology, although it is thought to be related to changes in intrathoracic pressure causing chest pain and dyspnea. We present a case of a 17-year-old male with acute chest pain evaluated initially by bedside ultrasound, which showed normal lung sliding but poor visualization of the parasternal and apical cardiac views due to significant air artifact, representing air in the thoracic cavity. The diagnosis was later verified by chest radiograph. We present a case report on ultrasound diagnosed pneumomediastinum, and we review the diagnostic modalities to date. PMID- 25834682 TI - Disaster response team FAST skills training with a portable ultrasound simulator compared to traditional training: pilot study. AB - INTRODUCTION: Pre-hospital focused assessment with sonography in trauma (FAST) has been effectively used to improve patient care in multiple mass casualty events throughout the world. Although requisite FAST knowledge may now be learned remotely by disaster response team members, traditional live instructor and model hands-on FAST skills training remains logistically challenging. The objective of this pilot study was to compare the effectiveness of a novel portable ultrasound (US) simulator with traditional FAST skills training for a deployed mixed provider disaster response team. METHODS: We randomized participants into one of three training groups stratified by provider role: Group A. Traditional Skills Training, Group B. US Simulator Skills Training, and Group C. Traditional Skills Training Plus US Simulator Skills Training. After skills training, we measured participants' FAST image acquisition and interpretation skills using a standardized direct observation tool (SDOT) with healthy models and review of FAST patient images. Pre- and post-course US and FAST knowledge were also assessed using a previously validated multiple-choice evaluation. We used the ANOVA procedure to determine the statistical significance of differences between the means of each group's skills scores. Paired sample t-tests were used to determine the statistical significance of pre- and post-course mean knowledge scores within groups. RESULTS: We enrolled 36 participants, 12 randomized to each training group. Randomization resulted in similar distribution of participants between training groups with respect to provider role, age, sex, and prior US training. For the FAST SDOT image acquisition and interpretation mean skills scores, there was no statistically significant difference between training groups. For US and FAST mean knowledge scores, there was a statistically significant improvement between pre- and post-course scores within each group, but again there was not a statistically significant difference between training groups. CONCLUSION: This pilot study of a deployed mixed-provider disaster response team suggests that a novel portable US simulator may provide equivalent skills training in comparison to traditional live instructor and model training. Further studies with a larger sample size and other measures of short- and long term clinical performance are warranted. PMID- 25834683 TI - Asking for a commitment: violations during the 2007 match and the effect on applicant rank lists. AB - INTRODUCTION: Applicants to residency face a number of difficult questions during the interview process, one of which is when a program asks for a commitment to rank the program highly. The regulations governing the National Resident Matching Program (NRMP) match explicitly forbid any residency programs asking for a commitment. METHODS: We conducted a cross-sectional survey of applicants from U.S. medical schools to five specialties during the 2006-2007 interview season using the Electronic Residency Application Service of the Association of American Medical Colleges. Applicants were asked to recall being asked to provide any sort of commitment (verbal or otherwise) to rank a program highly. Surveys were sent after rank lists were submitted, but before match day. We analyzed data using descriptive statistics and logistic regression. RESULTS: There were 7,028 unique responses out of 11,983 surveys sent for a response rate of 58.6%. Of those who identified their specialty (emergency medicine, internal medicine, obstetrics and gynecology [OBGYN], general surgery and orthopedics), there were 6,303 unique responders. Overall 19.6% (1380/7028) of all respondents were asked to commit to a program. Orthopedics had the highest overall prevalence at 28.9% (372/474), followed by OBGYN (23.7%; 180/759), general surgery (21.7%; 190/876), internal medicine (18.3%; 601/3278), and finally, emergency medicine (15.4%; 141/916). Of those responding, 38.4% stated such questions made them less likely to rank the program. CONCLUSION: Applicants to residencies are being asked questions expressly forbidden by the NRMP. Among the five specialties surveyed, orthopedics and OBGYN had the highest incidence of this violation. Asking for a commitment makes applicants less likely to rank a program highly. PMID- 25834684 TI - Virtual alternative to the oral examination for emergency medicine residents. AB - INTRODUCTION: The oral examination is a traditional method for assessing the developing physician's medical knowledge, clinical reasoning and interpersonal skills. The typical oral examination is a face-to-face encounter in which examiners quiz examinees on how they would confront a patient case. The advantage of the oral exam is that the examiner can adapt questions to the examinee's response. The disadvantage is the potential for examiner bias and intimidation. Computer-based virtual simulation technology has been widely used in the gaming industry. We wondered whether virtual simulation could serve as a practical format for delivery of an oral examination. For this project, we compared the attitudes and performance of emergency medicine (EM) residents who took our traditional oral exam to those who took the exam using virtual simulation. METHODS: EM residents (n=35) were randomized to a traditional oral examination format (n=17) or a simulated virtual examination format (n=18) conducted within an immersive learning environment, Second Life (SL). Proctors scored residents using the American Board of Emergency Medicine oral examination assessment instruments, which included execution of critical actions and ratings on eight competency categories (1-8 scale). Study participants were also surveyed about their oral examination experience. RESULTS: We observed no differences between virtual and traditional groups on critical action scores or scores on eight competency categories. However, we noted moderate effect sizes favoring the Second Life group on the clinical competence score. Examinees from both groups thought that their assessment was realistic, fair, objective, and efficient. Examinees from the virtual group reported a preference for the virtual format and felt that the format was less intimidating. CONCLUSION: The virtual simulated oral examination was shown to be a feasible alternative to the traditional oral examination format for assessing EM residents. Virtual environments for oral examinations should continue to be explored, particularly since they offer an inexpensive, more comfortable, yet equally rigorous alternative. PMID- 25834686 TI - Residency applicants prefer online system for scheduling interviews. AB - INTRODUCTION: Residency coordinators may be overwhelmed when scheduling residency interviews. Applicants often have to coordinate interviews with multiple programs at once, and relying on verbal or email confirmation may delay the process. Our objective was to determine applicant mean time to schedule and satisfaction using online scheduling. METHODS: This pilot study is a retrospective analysis performed on a sample of applicants offered interviews at an urban county emergency medicine residency. Applicants were asked their estimated time to schedule with the online system compared to their average time using other methods. In addition, they were asked on a five-point anchored scale to rate their satisfaction. RESULTS: Of 171 applicants, 121 completed the survey (70.8%). Applicants were scheduling an average of 13.3 interviews. Applicants reported scheduling interviews using the online system in mean of 46.2 minutes (median 10, range 1-1800) from the interview offer as compared with a mean of 320.2 minutes (median 60, range 3-2880) for other programs not using this system. This difference was statistically significant. In addition, applicants were more likely to rate their satisfaction using the online system as "satisfied" (83.5% vs 16.5%). Applicants were also more likely to state that they preferred scheduling their interviews using the online system rather than the way other programs scheduled interviews (74.2% vs 4.1%) and that the online system aided them coordinating travel arrangements (52.1% vs 4.1%). CONCLUSION: An online interview scheduling system is associated with higher satisfaction among applicants both in coordinating travel arrangements and in overall satisfaction. PMID- 25834685 TI - Structured communication: teaching delivery of difficult news with simulated resuscitations in an emergency medicine clerkship. AB - INTRODUCTION: The objective is to describe the implementation and outcomes of a structured communication module used to supplement case-based simulated resuscitation training in an emergency medicine (EM) clerkship. METHODS: We supplemented two case-based simulated resuscitation scenarios (cardiac arrest and blunt trauma) with role-play in order to teach medical students how to deliver news of death and poor prognosis to family of the critically ill or injured simulated patient. Quantitative outcomes were assessed with pre and post clerkship surveys. Secondarily, students completed a written self-reflection (things that went well and why; things that did not go well and why) to further explore learner experiences with communication around resuscitation. Qualitative analysis identified themes from written self-reflections. RESULTS: A total of 120 medical students completed the pre and post-clerkship surveys. Majority of respondents reported that they had witnessed or role-played the delivery of difficult news, but only few had real-life experience of delivering news of death (20/120, 17%) and poor prognosis (34/120, 29%). This communication module led to statistically significant increased scores for comfort, confidence, and knowledge with communicating difficult news of death and poor prognosis. Pre-post scores increased for those agreeing with statements (somewhat/very much) for delivery of news of poor prognosis: comfort 69% to 81%, confidence 66% to 81% and knowledge 76% to 90% as well as for statements regarding delivery of news of death: comfort 52% to 68%, confidence 57% to 76% and knowledge 76% to 90%. Respondents report that patient resuscitations (simulated and/or real) generated a variety of strong emotional responses such as anxiety, stress, grief and feelings of loss and failure. CONCLUSION: A structured communication module supplements simulated resuscitation training in an EM clerkship and leads to a self-reported increase in knowledge, comfort, and competence in communicating difficult news of death and poor prognosis to family. Educators may need to seek ways to address the strong emotions generated in learners with real and simulated patient resuscitations. PMID- 25834687 TI - Emergency medicine residency boot Camp curriculum: a pilot study. AB - INTRODUCTION: Establishing a boot camp curriculum is pertinent for emergency medicine (EM) residents in order to develop proficiency in a large scope of procedures and leadership skills. In this article, we describe our program's EM boot camp curriculum as well as measure the confidence levels of resident physicians through a pre- and post-boot camp survey. METHODS: We designed a one month boot camp curriculum with the intention of improving the confidence, procedural performance, leadership, communication and resource management of EM interns. Our curriculum consisted of 12 hours of initial training and culminated in a two-day boot camp. The initial day consisted of clinical skill training and the second day included code drill scenarios followed by interprofessional debriefing. RESULTS: Twelve EM interns entered residency with an overall confidence score of 3.2 (1-5 scale) across all surveyed skills. Interns reported the highest pre-survey confidence scores in suturing (4.3) and genitourinary exams (3.9). The lowest pre-survey confidence score was in thoracostomy (2.4). Following the capstone experience, overall confidence scores increased to 4.0. Confidence increased the most in defibrillation and thoracostomy. Additionally, all interns reported post-survey confidence scores of at least 3.0 in all skills, representing an internal anchor of "moderately confident/need guidance at times to perform procedure." CONCLUSION: At the completion of the boot camp curriculum, EM interns had improvement in self-reported confidence across all surveyed skills and procedures. The described EM boot camp curriculum was effective, feasible and provided a foundation to our trainees during their first month of residency. PMID- 25834688 TI - Erratum: this article corrects: "correlation of the NBME advanced clinical examination in EM and the national EM M4 exams". AB - [This corrects the article on p. 138 in vol. 16, PMID: 25671023.]. PMID- 25834689 TI - Hair Regeneration Treatment Using Adipose-Derived Stem Cell Conditioned Medium: Follow-up With Trichograms. AB - OBJECTIVE: Adipose-derived stem cells secrete various growth factors that promote hair growth. This study examined the effects of adipose-derived stem cell conditioned medium on alopecia. METHODS: Adipose-derived stem cell-conditioned medium was intradermally injected in 22 patients (11 men and 11 women) with alopecia. Patients received treatment every 3 to 5 weeks for a total of 6 sessions. Hair numbers were counted using trichograms before and after treatment. A half-side comparison study was also performed in 10 patients (8 men and 2 women). RESULTS: Hair numbers were significantly increased after treatment in both male (including those without finasteride administration) and female patients. In the half-side comparison study, the increase in hair numbers was significantly higher on the treatment side than on the placebo side. CONCLUSION: Treatment using adipose-derived stem cell-conditioned medium appears highly effective for alopecia and may represent a new therapy for hair regeneration. PMID- 25834690 TI - A novel use of integraTM bilayer matrix wound dressing on a pediatric scalp avulsion: a case report. AB - OBJECTIVE: Soft tissue injuries with full-thickness skin involvement not amenable to local flaps may be treated with dermal matrices and subsequent skin grafting. METHODS: A pediatric patient presented with a 50-cm(2) scalp avulsion down to periosteum and outer cranial table post-vehicular trauma. After cultivating healthy cranial neodermis with Integra Bilayer Matrix Wound Dressing, a novel modification of treatment protocol was attempted by removal of the silastic layer. RESULTS: Neodermis transformation to granulation tissue followed by contraction of the wound reduced alopecia while also eliminating the need for a split-thickness skin graft to the area. CONCLUSION: A novel modification of treatment protocols utilizing acellular dermal matrices improved aesthetic outcomes and may present a cost-, time-, and procedure-sparing treatment option for avulsion injuries. PMID- 25834691 TI - Klippel-feil syndrome and unilateral diaphragmatic paralysis. PMID- 25834692 TI - Calciphylaxis. PMID- 25834693 TI - Mobius syndrome and poland syndrome presenting together in a single patient. PMID- 25834694 TI - Surgical management of morel-lavallee lesion. PMID- 25834695 TI - A phosphorus burn. PMID- 25834696 TI - An Important Differential: Extramammary Paget's Disease. PMID- 25834697 TI - Submuscular lipoma of the forehead. PMID- 25834698 TI - Traumatic thumb amputation: case and review. PMID- 25834700 TI - A nitric oxide-donor furoxan moiety improves the efficacy of edaravone against early renal dysfunction and injury evoked by ischemia/reperfusion. AB - Edaravone (5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, EDV) is a free-radical scavenger reduces organ ischemic injury. Here we investigated whether the protective effects of EDV in renal ischemia/reperfusion (I/R) injury may be enhanced by an EDV derivative bearing a nitric oxide- (NO-) donor furoxan moiety (NO-EDV). Male Wistar rats were subjected to renal ischemia (45 minutes), followed by reperfusion (6 hours). Administration of either EDV (1.2-6-30 umol/kg, i.v.) or NO-EDV (0.3-1.2-6 umol/kg, i.v.) dose-dependently attenuated markers of renal dysfunction (serum urea and creatinine, creatinine clearance, urine flow, urinary N-acetyl-beta-D-glucosaminidase, and neutrophil gelatinase associated lipocalin/lipocalin-2). NO-EDV exerted protective effects in the dose range 1.2-6 umol/kg, while a higher dose (30 umol/kg) was needed to obtain protection by EDV. Both EDV and NO-EDV modulated tissue markers of oxidative stress and lipid peroxidation. NO-EDV, but not EDV, activated endothelial NO synthase (NOS) and blunted I/R-induced upregulation of inducible NOS, secondary to modulation of Akt and NF-kappaB activation, respectively. Besides NO-EDV administration inhibited I/R-induced IL-1beta, IL-18, IL-6, and TNF-alpha overproduction. Overall, these findings demonstrate that the NO-donor moiety contributes to the protection against early renal I/R injury and suggest that NO donor EDV codrugs are worthy of additional study as innovative pharmacological tools. PMID- 25834699 TI - Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. AB - Neuroinflammation and mitochondrial dysfunction are common features of chronic neurodegenerative diseases of the central nervous system. Both conditions can lead to increased oxidative stress by excessive release of harmful reactive oxygen and nitrogen species (ROS and RNS), which further promote neuronal damage and subsequent inflammation resulting in a feed-forward loop of neurodegeneration. The cytokine tumor necrosis factor (TNF), a master regulator of the immune system, plays an important role in the propagation of inflammation due to the activation and recruitment of immune cells via its receptor TNF receptor 1 (TNFR1). Moreover, TNFR1 can directly induce oxidative stress by the activation of ROS and RNS producing enzymes. Both TNF-induced oxidative stress and inflammation interact and cooperate to promote neurodegeneration. However, TNF plays a dual role in neurodegenerative disease, since stimulation via its second receptor, TNFR2, is neuroprotective and promotes tissue regeneration. Here we review the interrelation of oxidative stress and inflammation in the two major chronic neurodegenerative diseases, Alzheimer's and Parkinson's disease, and discuss the dual role of TNF in promoting neurodegeneration and tissue regeneration via its two receptors. PMID- 25834702 TI - Studying the Balance of the Coper and Non-Coper ACL-Deficient Knee Subjects. AB - PURPOSE: It seems that there is an association between the anterior cruciate ligament (ACL) and stability of the knee. This study aimed to evaluate the balance condition of the injured and non-injured sides of the coper and non-coper ACL-D (deficient) subjects during single and bilateral standing conditions. METHODS: This case-control study was carried out on 10 coper and 5 non-coper ACL D knee subjects and 15 sex-age matched healthy subjects. A Zebris platform pedobarograph tool was used in this study. The subjects were tested barefoot during single and bilateral leg stance conditions. The outcome measurements included measurement of the center of pressure (COP) path line length, confidence ellipse area and sway velocity. RESULTS: In double leg stance, data analysis revealed that the COP path line length, confidence ellipse area and sway velocity all showed a significant increase in the injured leg of the non-coper ACL-D subjects when compared to the injured leg of the coper ACL-D and healthy subjects (P=0.002). During single leg stance, all of the parameters showed significant increase in the injured leg of both coper and non-copers of the ACL-D subjects relative to the healthy subjects (P<0.05). CONCLUSION: This study confirmed a balance deficiency in the injured and apparently healthy leg of the non-coper and coper ACL-D knee subjects. Increased COP path line length, sway velocity and the coinfidence ellipse area clearly showed an impaired body balance. The reduced postural control of the non-coper ACL-D knee subjects in bilateral standing could be more evidence of their poor knee stability status. PMID- 25834703 TI - Effects of recovery type after a kickboxing match on blood lactate and performance in anaerobic tests. AB - PURPOSE: To verify whether active recovery (AR) applied after a kickboxing match resulted in better performance in anaerobic tests when compared to passive recovery (PR). METHODS: Eighteen kickboxers volunteered to participate on a Kickboxing match preceded and followed by anaerobic tests: squat jump (SJ), the counter movement jump (CMJ) and the upper-body Wingate test. Blood lactate (BL), heart rate (HR) and rate of perceived exertion (RPE) were analyzed before and after rounds. The recovery sessions consisted of 10min at 50% of maximal aerobic speed or PR. BL was measured at 3, 5 and 10 min after the match, while HR, RPE and anaerobic power were assessed after the recovery period. RESULTS: BL, HR and RPE increased significantly (P<0.001) during the match. BL was lower (P<0.001) after AR compared to PR at 5 min and 10 min (e.g. AR: 8.94 +/- 0.31 mmol.l(-1), PR: 10.98 +/- 0.33 mmol.l(-1)). However, PR resulted in higher (P<0.05) upper body mean power (4.65 +/- 0.5 W.kg(-1)) compared to AR (4.09 +/- 0.5 W.kg(-1)), while SJ and CMJ were not affected by the recovery type. CONCLUSION: The lactate removal was improved with AR when compared with PR, but AR did not improve subsequent performance. PMID- 25834701 TI - Relationship of anthropometric and training characteristics with race performance in endurance and ultra-endurance athletes. AB - A variety of anthropometric and training characteristics have been identified as predictor variables for race performance in endurance and ultra-endurance athletes. Anthropometric characteristics such as skin-fold thicknesses, body fat, circumferences and length of limbs, body mass, body height, and body mass index were bi-variately related to race performance in endurance athletes such as swimmers in pools and in open water, in road and mountain bike cyclists, and in runners and triathletes over different distances. Additionally, training variables such as volume and speed were also bi-variately associated with race performance. Multi-variate regression analyses including anthropometric and training characteristics reduced the predictor variables mainly to body fat and speed during training units. Further multi-variate regression analyses including additionally the aspects of previous experience such as personal best times showed that mainly previous best time in shorter races were the most important predictors for ultra-endurance race times. Ultra-endurance athletes seemed to prepare differently for their races compared to endurance athletes where ultra endurance athletes invested more time in training and completed more training kilometers at lower speed compared to endurance athletes. In conclusion, the most important predictor variables for ultra-endurance athletes were a fast personal best time in shorter races, a low body fat and a high speed during training units. PMID- 25834704 TI - Effects of Resistance versus Endurance Training on Plasma Lipocalin-2 in Young Men. AB - PURPOSE: Lipocalin-2 (Lcn2) has been recognized as an adipocyte-derived acute phase protein that is positively correlated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. The effects of resistance and endurance training (RT vs. ET) on plasma lipocalin-2 are still unclear. Therefore, the purpose of this study was to examine the effects of RT vs. ET on plasma lipocalin-2 in young men. METHODS: Twenty nine healthy and sedentary young men (age, 21-29 years) participated in this study. The subjects were randomly assigned to RT group (n=9), ET group (n=10) or control group (n=10). The experimental groups performed either RT or ET, 3 days a week for 8 weeks. The endurance training program included continuous running at an intensity corresponding to 65-80% of maximal heart rate, while resistance training consisted of 2-4 sets of circuit weight training for 8 stations and at an intensity corresponding to 65-80% of 1-RM in each station. RESULTS: No significant changes in the body mass, BMI, body fat percentage and WHR were found after the RT and ET. The results showed that Lcn2 decreased after RT and ET compared with the control group (P<0.05). High sensitivity C-reactive protein (hs CRP) and insulin resistance determined by HOMA-IR, did not change in the RT and ET compared with the control group. CONCLUSION: Lcn2 decreases after 8 weeks RT and ET, but this improvement was not accompanied by decreased hs-CRP and insulin resistance in healthy and sedentary young men. PMID- 25834705 TI - Assessment of Correlation between Electrogoniometer Measurements and Sports Specific Movement in Karate Elites. AB - PURPOSE: To examine the intra-rater reliability of knee movement data in sagital plane obtained from electrogoniometer (EGM) in a basic, sport-specific task of karate. METHODS: A total of 23 elite karate athletes (13 females and 10 males; mean age of 16.10+/-1.26 yrs) participated in this study. The task was defined as performing three consecutive Zenkutsu-dachi in two sessions. The used EGM was a twin axis of Biometrics company. EGM curves were plotted in MATLAB software separately. The indices of three points in the plots corresponding to extremes of flexion and extension of knee in the first dachi were determined. There was also another (forth) point which was not in extremes of movement. As it was repeated in all curves, it was perceived as a biomechanical event and was assessed. The phases of movement between the points were scaled between 0 to 100% of activity. RESULTS: Repeatability of the forth point index was assessed by intraclass correlation method. Intraclass correlation of the ratio in the first testing session was 0.666 and in second was 0.448. The interval between points were considered as phases of movement. After determining three phases of dachi, it was shown that these phases pertained a specific ratio of the total plot which were 48%, 36% and 16% of total respectively. CONCLUSION: Dachi could be divided into three distinct phases; each of them should constitute a specific percent of the total in an elite athlete. PMID- 25834706 TI - The effect of two-week L-carnitine supplementation on exercise -induced oxidative stress and muscle damage. AB - PURPOSE: This study was conducted to assess the effect of Two-week L-carnitine supplementation on known markers of oxidative stress and muscle damage following acute bouts of exercise in active healthy young men. METHODS: Twenty-one active healthy men volunteered for this study. Participants were randomized in a double blind placebo-controlled fashion into two groups: L-carnitine (C group; n=10) and placebo group (P group; n=11). They arrived at the laboratory after overnight fasting. A baseline blood sample was taken. Afterwards, subjects consumed either L-carnitine (2 capsules containing totally 2000 mg L-carnitine) or placebo (2 capsules containing totally 2000 mg lactose) daily for 14 days. On the day of the test, participants attended the athletics arena after overnight fasting. Then, participants were asked to run 14 km on the track at their highest ability. Blood samples were taken immediately, 2, and 24 hours after exercise. Plasma total antioxidant capacity (TAC), malondialdehyde (MDA) as thiobarbituric acid-reactive substance (TBARS) as a marker of lipid peroxidation, creatine kinase (CK) and lactate dehydrogenase (LDH) as markers of muscle damage were measured. RESULTS: TAC increased significantly 14 days after supplementation and 24h after exercise in C group compared with P group (P<0.05). Serum MDA-TBARS, CK, and LDH were significantly lower 24h after exercise in C group compared with P group (P<0.05). CONCLUSION: These results suggest that two-week daily oral supplementation of L carnitine has alleviating effects on lipid peroxidation and muscle damage markers following an acute bout of exercise in active healthy young men. PMID- 25834707 TI - Surgical treatment of pectoralis major tendon rupture (outcome assessment). AB - PURPOSE: Rupture of pectoralis major (PM) occurs most commonly as a result of an indirect mechanism associated with extensive tension on a maximally contracted muscle. Patients with PM tendon ruptures, classically present a history of sudden severe pain in arm and shoulder at the time of injury. Treatment options vary from conservative to operative. In cases with total or near-total injuries, surgical treatment by anatomic repair is generally advised, since conservative treatment may lead to poor results. The present paper reports 24 cases of surgically-treated ruptured PM while assessing the results. METHODS: Between 2005 and 2010, 32 cases of unilaterally distal ruptured PM were surgically treated by the same surgeon and same technique, in two teaching hospitals of Tehran University of Medical Sciences. All cases were followed postoperatively by physical examination and functional criteria. RESULTS: Since eight of the cases were lost from follow up, 24 cases were followed for at least one year. According to modified Kakwani system, 6 of our patients (25%) rated as excellent, 15 cases(62.5%) rated as good, 2 cases (8.33%) rated as fair and 1 case (4.1%) rated as poor. CONCLUSION: In conclusion, we see that 87.5% of the patients had good to excellent results, according to modified Kakwani classification, after one year of follow up. So it seems that surgical repair of the pectoralis major ruptures will help the patients to return to their previous activities more frequently and we believe, to achieve better functional outcome. Meticulous surgical technique and attention to rehabilitation program are more important than delay in surgery. PMID- 25834708 TI - Late care in marathon runs leading to exertional heat stroke with multiple organ failure. AB - BACKGROUND: Exertional heat stroke (EHS) is still a main cause of death in sport. Many of EHS complications could have been prevented if EHS had been recognized and treated early and properly. CASE PRESENTATION: We report an unusual case of multiple organ failure caused by EHS due to intensive sportive activities in a hot environment with lack of primary care. A 35-year-old healthy sportive man was admitted in our hospital because of muscle aches and weakness as well as dark urine three days after a six hour marathon run (Agadir Semi-Marathon) in a very sunny day. Patient developed rhabdomyolysis, acute renal failure (ARF) requiring hemodialysis because of hyperkaliemia, azotemia and severe metabolic acidosis, disseminated intravascular coagulation and acute liver failure. Unfortunately, after eight days of intensive care, the patient died from septic shock and multiple organ failure. CONCLUSION: This case reminds us that, despite the advancements of knowledge in the area of EHS prevention, recognition, and treatment, knowledge has not been translated into practice. PMID- 25834709 TI - Emergency Management of Dental Trauma among Physical Education Teachers of 2 Districts in Karnataka, India. PMID- 25834710 TI - Cloning and Expression of Poly 3-Hydroxybutyrate Operon Into Escherichia coli. AB - BACKGROUND: Poly 3-Hydroxybutyrate (PHB), a class of Poly Hydroxyalkanoates (PHAs), is a group of bacterial storage polymers, produced by various microorganisms in response to nutrient limitation. PHAs are biodegradable polymers which could be a good substitute for current petrochemical plastics. PHB has been synthesized during three enzymatic steps including three genes. OBJECTIVES: Our aim was PHB production from recombinant bacteria. MATERIALS AND METHODS: Ralstonia eutropha was cultured and its genomic DNA was extracted. The phbCAB operon was amplified using designed primers. The fragment was cloned into pET-28a expression vector and then transformed into Escherichia coli BL21. Sudan black staining was used to show the production of PHB. RESULTS: The extracted recombinant plasmid was digested with restriction enzymes. Separation of the desired fragment from the vector was performed to prove the correct insertion of the PCR products into the vector. The colony PCR and sequencing results confirmed the successful transformation. The production of PHB was confirmed by Sudan Black B staining under a light microscope. CONCLUSIONS: Various metabolic and fermentation methods have been used in some bacterial strains for PHB production. The use of a recombinant system harboring PHB synthesis genes can produce PHB in higher concentrations compare to natural PHA-producing bacteria. The present study was one of the most important and basic steps of designing a recombinant E. coli that can produce PHB. PMID- 25834711 TI - Diagnosing of herpes simplex virus infections in suspected patients using real time PCR. AB - BACKGROUND: Herpes simplex virus infections are very common worldwide. The virus can cause infection in various body parts, especially eyes and the nervous system. Therefore, an early diagnosis and highly sensitive method is very helpful. OBJECTIVES: The present study sought to investigate the efficiency of Real-time TaqMan probe PCR in the diagnosis of HSV infection in suspected patients. PATIENTS AND METHODS: In this study, 1566 patients with suspected HSV infections were enrolled. They aged 17 days to 96 years. The collected specimens were classified into four groups; cerebrospinal fluid (CSF) from HSE suspected individuals, samples from eye epithelial scraping, tear fluid or aqueous humor from herpes simplex keratitis (HSK) suspected patients, plasma of immune compromised patients and mucocutaneous collected samples from different body parts. The samples were analyzed by Real-time PCR assays. RESULTS: In total, 44 (5.6%), 118 (26.8%), 23 (11.7%), 13 (44.8%) and 65 (45.5%) of 791 HSE, 407 HSK, 29 skin HSV, 143 oropharyngeal suspected patients and 196 patients with systemic HSV infection HSV had positive results by Real-time PCR assays, respectively. CONCLUSIONS: Real-time PCR assay, due to its high sensitivity and specificity, can help in early diagnosis and more effective treatment for patients. Also, it requires shorter hospital stay and promotes patients' survival. PMID- 25834712 TI - Effective Phages as Green Antimicrobial Agents Against Antibiotic-Resistant Hospital Escherichia coli. AB - BACKGROUND: Bacteriophages are viruses that attack bacteria and lead to their lysis in an efficient and highly specific manner. These natural enemies of bacteria were used as therapeutic agents before the advent of antibiotics. Currently, with the rapid spread of multi-drug resistant bacteria, phage therapy can be an effective alternative treatment for antibiotic resistant bacteria. OBJECTIVES: This study evaluated the effectiveness of bacteriophages in removing antibiotic-resistant clinical Escherichia coli strains in vitro and in vivo. PATIENTS AND METHODS: Different samples were taken from bed sore and foot ulcers of patients with diabetes. E. coli strains were isolated and identified by standard methods. The antibiogram was ascertained using the Kirby Bauer disc diffusion method for ten antibiotics. The bacteriophages were isolated from environmental water samples. They were exposed to the host bacteria by the double layer agar technique (DLA) to observe plaques. Cross reaction of the phages on test E. coli strains was performed to determine broader-spectrum phages. Phage TPR7 was selected for animal trials. Five groups of mice including a control group, bacterial group, phage group, antibiotic therapy group and phage therapy group, were examined. RESULTS: Ten E. coli strains were isolated from hospital samples. They showed high resistance to the used antibiotics. An effective bacteriophage was isolated for each strain. The cross-reaction showed phages which affect more than six E. coli strains. They can be a good choice for clinical therapeutic use. In animal trials the group challenged with phages after being infected showed similar results as the group treated with gentamicin after being infected. In both groups infection was removed after 48 hours. CONCLUSIONS: According to the results, six strains were resistant to six or seven antibiotics and all strains were at least resistant to two antibiotics. However, for each of these resistant bacteria one bacteriophage was isolated from environmental samples, which showed the effectiveness of bacteriophages to remove clinically resistant E. coli strains. Effective phages in vitro showed effective results in vivo as well. PMID- 25834713 TI - Oncogenic Virus Infections in the General Population and End-stage Renal Disease Patients With Special Emphasis on Kaposi's Sarcoma Associated Herpes Virus (KSHV) in Northeast of Iran. AB - BACKGROUND: Globally, almost 20% of cancers are related to infectious agents that can be prevented. Oncogenicity refers to viruses that may cause cancers, more importantly in immunocompromised subjects such as transplant and hemodialysis patients. Therefore, epidemiological studies are the first line for understanding the importance of these agents in public health, particularly, in mobile populations, tourism and pilgrimage regions. OBJECTIVES: Oncogenic viral infections, such as hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein barr virus (EBV) are the most common viral agents in immunocompromised patients. Furthermore, human T lymphocyte virus type I (HTLV-I), due to endemicity in Khorasan Razavi province located northeast of Iran as a pilgrimage region, and Kaposi's sarcoma associated herpes virus (KSHV), as an oncogenic herpesvirus in immunocompromised subjects have been investigated among the general population and those with end-stage renal diseases (ESRD). PATIENTS AND METHODS: A cross sectional study was carried out among 1227 randomly selected individuals; 25 donors and 195 patients with ESRD, including 60 kidney transplant recipients and 135 dialysis patients from the Khorasan Razavi province, Iran. Serological tests were carried out using commercial enzyme-immunoassay kits. To confirm positive serology tests, the extracted viral DNA or RNA was examined for the presence of KSHV, HTLV-I and HCV by conventional PCR. RESULTS: The prevalence of KSHV infection in the general population was 1.71% (21/1227); 2.60% (10/384) males and 1.30% (11/843) females. In kidney transplants, viral infections occurred in 23.3% of subjects; including EBV, HTLV-I and HBV-HCV co-infection in 8.3%, 3.3% and 1.7%, respectively. In patients on hemodialysis, viral infections were present in 29.6% including EBV, HTLV-I and HBV-HCV co-infection in 2.2%, 5.9% and 16.3%, respectively. Seroprevalence of KSHV in patients with kidney transplants was 1.7% and in patients on dialysis was 3.0%. Furthermore, KSHV and HTLV-I genome was detected in 25% and 100% of seropositive subjects, respectively. CONCLUSIONS: In conclusion, this study demonstrated that these tumor virus infections including HTLV-I, KSHV and particularly hepatitis viruses (HBV plus HCV) are prevalent in the general population and in patients on hemodialysis, which might be an important health concern in this region due to the mobile population. PMID- 25834714 TI - Seroprevalence of Toxoplasma gondii and Neospora spp. Infections in Arab Horses, Southwest of Iran. AB - BACKGROUND: Because of the economic importance of the Arab race horses and also the role of Toxoplasma gondii and Neospora spp. in abortion and reproductive failure of these animals, we decided to perform this study. OBJECTIVES: We designed this study to investigate the seroprevalence of anti-Toxoplasma gondii and anti-Neospora spp. antibodies in Arab horses from 12 cities of Khuzestan province in southwest of Iran. MATERIALS AND METHODS: From October 2009 to March 2011, a total of 235 blood samples were collected from jugular veins of Arab horses of different ages and genders from 12 cities of Khuzestan province. All the sera were tested for anti-Toxoplasma antibodies using the modified agglutination test (MAT) and the existence of anti-Neospora antibodies were tested using N-MAT for Neospora spp. RESULTS: According to the MAT results, antibodies to T. gondii were found in 114 (48.5%) of 235 sera with titers of 1:20 in 84, 1:40 in 19, 1:80 in four, 1:160 in four, and 1:320 in three horses. According to the N-MAT results, antibodies to Neospora spp. were found in 47 (20%) of 235 sera with titers of 1:40 in 39, 1:80 in five, and 1:160 in three horses. We did not observe any statistically significant differences regarding age groups and genders between seropositive and seronegative horses for Neospora spp. using chi-square (chi(2)) test, but it seemed that anti-Toxoplasma antibodies were more prevalent in older horses (>= 10 years old). CONCLUSIONS: The results indicated that Arab horses are exposed to these parasites in southwest of Iran. Further research is required to determine the genomic structures of these parasites in Arab horses in southwest of Iran. PMID- 25834716 TI - Rapid quantitative estimation of chlorinated methane utilizing bacteria in drinking water and the effect of nanosilver on biodegradation of the trichloromethane in the environment. AB - BACKGROUND: Halomethanes are toxic and carcinogenic chemicals, which are widely used in industry. Also they can be formed during water disinfection by chlorine. Biodegradation by methylotrophs is the most important way to remove these pollutants from the environment. OBJECTIVES: This study aimed to represent a simple and rapid method for quantitative study of halomethanes utilizing bacteria in drinking water and also a method to facilitate the biodegradation of these compounds in the environment compared to cometabolism. MATERIALS AND METHODS: Enumeration of chlorinated methane utilizing bacteria in drinking water was carried out by most probable number (MPN) method in two steps. First, the presence and the number of methylotroph bacteria were confirmed on methanol containing medium. Then, utilization of dichloromethane was determined by measuring the released chloride after the addition of 0.04 mol/L of it to the growth medium. Also, the effect of nanosilver particles on biodegradation of multiple chlorinated methanes was studied by bacterial growth on Bushnell-Haas Broth containing chloroform (trichloromethane) that was treated with 0.2 ppm nanosilver. RESULTS: Most probable number of methylotrophs and chlorinated methane utilizing bacteria in tested drinking water were 10 and 4 MPN Index/L, respectively. Chloroform treatment by nanosilver leads to dechlorination and the production of formaldehyde. The highest growth of bacteria and formic acid production were observed in the tubes containing 1% chloroform treated with nanosilver. CONCLUSIONS: By combining the two tests, a rapid approach to estimation of most probable number of chlorinated methane utilizing bacteria is introduced. Treatment by nanosilver particles was resulted in the easier and faster biodegradation of chloroform by bacteria. Thus, degradation of these chlorinated compounds is more efficient compared to cometabolism. PMID- 25834715 TI - Isolation and Identification of Two Novel Escherichia coli Bacteriophages and Their Application in Wastewater Treatment and Coliform's Phage Therapy. AB - BACKGROUND: Phage therapy or use of lytic bacteriophages for eliminating bacterial populations has been developed for several aspects of human affairs such as medicine, agriculture and food industries. OBJECTIVES: The high load of coliforms of treated wastewater effluents that are discharged into the rivers or agricultural lands is a serious concern of the Iran Department of Environment and the reduction of coliforms using phages to overcome this problem is an asset. This research aimed to isolate and identify specific lytic coliphages and investigate their effects on native and standard Escherichia coli strains as well as coliform populations in municipal wastewater. MATERIALS AND METHODS: The wastewater sample was cultured on selective culture media to isolate a native coliform strain and characterized using molecular methods. River water was centrifuged and passed through a 0.45 MUm filter and its lytic coliphages were enriched and purified against a native E. coli as well as a standard E. coli strain. Municipal wastewater was treated with isolated lytic coliphages and most probable number (MPN) reduction was examined. RESULTS: E. coli SBSWF27, which is a native strain of E. coli from Isfahan municipal wastewater treatment plant, was isolated and characterized. Also two novel bacteriophages related to Myoviridae and Podoviridae families of bacteriophages from Zayandehrood River (Isfahan, Iran) were isolated. These coliphages had lytic effects on E. coli PTCC1399 and E. coli SBSWF27 as coliform's index. The myovirus had a hexagonal head measuring 27.28 nm and a noncontractile tail measuring 204.5 * 13.63 nm. The podovirus had an oval head measuring 98 * 35 nm and a tail, 14 nm in diameter. The treatment of municipal sewage with the coliphage mixture resulted in a 22-fold decrease of the coliform's MPN from 2400 to 110 after two hours of incubation. CONCLUSIONS: This is the first report on isolation and identification of two novel lytic myovirus and podovirus from Zayandehrood River in Isfahan that had lytic effects on E. coli PTCC1399 and E. coli SBSWF27 strains as well as coliform's population of Isfahan municipal wastewater. We suggest that the use of these lytic coliphages for reduction of coliform's population in sewage could be considered as an effective and simple alternative for costly replacement of instruments and establishments of the old wastewater treatment plants. PMID- 25834717 TI - Identification of Legionella Pneumophila in Intubated Patients With TaqMan Real Time PCR. AB - BACKGROUND: Legionellaceae contains Legionella genus with over 52 species and 64 serogroups. It is one of the most important causes of respiratory disease in human. More than 30% of hospital-acquired pneumonia is caused by Legionella. Ventilator-associated pneumonia (VAP) is an infection acquired in hospital wards, particularly in intensive care unit (ICU). This disease approximately affects 9% to 20% of intubated patients. Mortality in these patients varies between 8% and 76%. Legionella is one of the important factors for infection in intubated patients. OBJECTIVES: The present study was aimed to investigate the use of molecular methods in diagnosis of infection caused by Legionella pneumophila. MATERIALS AND METHODS: In this study, 109 samples of lung secretions collected from intubated patients admitted to ICU wards of four university hospitals in a three-month period were examined. Cultivation and Real time Polymerase Chain Reaction (PCR) methods were used to assess L. pneumophila colonization in these samples. RESULTS: Eleven samples had positive results using real time PCR analysis of 16s rRNA gene fragments specific for L. pneumophila, but according to culture method on specific buffered charcoal-yeast extract medium (BCYE), no positive cases were detected. Of the total positive cases, six were males, one female and four infants. The seven adults aged 40-65 years. CONCLUSIONS: Using molecular methods in diagnosis of infection caused by L. pneumophila has a great value because of its high specificity and rapid diagnosis potency. PMID- 25834718 TI - Frequency of adenoviruses, rotaviruses and noroviruses among diarrhea samples collected from infants of zabol, southeastern iran. AB - BACKGROUND: Viruses are one of the major reasons of gastrointestinal disease worldwide, and commonly infect children less than five years of age in developing countries. OBJECTIVES: The current study aimed to determine the frequency of adenoviruses, rotaviruses and noroviruses among diarrhea samples collected from infants of Zabol, south-east of Iran. This study is the first investigation of adenoviruses, rotaviruses and noroviruses among diarrhea samples in Zabol. PATIENTS AND METHODS: In this study, eighty-two diarrhea stool samples were collected from infants aged < 1 to 12 months admitted to the hospital, internal laboratory and central laboratory of Zabol, Iran. All samples were subjected to the rapid immunochromatography assay. RESULTS: The results showed that the frequency of rotaviruses, adenoviruses and noroviruses among infants with diarrhea were 70.20%, 20.30% and 9.50%, respectively. There were 50 subjects aged one to five months and 2 subjects aged nine to twelve months. The results of geographical distribution showed that the number of infants living in rural and urban areas with these viruses were 50 and 32, respectively. Rotaviruses were most common in rural and urban infants with 42 and 10 cases, respectively. Regarding the feeding patterns of infants with diarrhea, mixed feeding and breast feeding were found in 51 and 31 cases, respectively. CONCLUSIONS: In conclusion, the results of our study showed that the major viral pathogens that caused infantile diarrhea in Zabol city were rotaviruses followed by adenoviruses and noroviruses. The results of our study can useful for prosperous control of infantile diarrhea. PMID- 25834719 TI - Cytomegalovirus infection and atherosclerosis in candidate of coronary artery bypass graft. AB - BACKGROUND: Although there is enough evidence that infectious agents such as Chlamydia pneumonia and Helicobacter pylori may play a pathogenic role in atherosclerosis, this role for cytomegalovirus (CMV) is yet controversial. OBJECTIVES: The aim of the present study was to detect CMV-DNA in atherosclerotic plaques in patients who underwent coronary artery bypass graft (CABG). PATIENTS AND METHODS: In this case-control study, candidates for CABG (cases) and patients with valvular or congenital malformation but without atherosclerotic plaques (controls) were studied from 2012 to 2013 at Golestan hospital, Ahvaz, IR Iran. Demographic and laboratory data were collected. Atherosclerotic and histological samples were obtained from visible plaques and from aorta by the surgeon. All the samples were examined for the presence of CMV-DNA by polymerase chain reaction (PCR) method using a commercial kit (SinaClon, Tehran, IR Iran). RESULTS: The mean ages in case and control groups were 60.8 +/- 6.8 and 57.5 +/- 11.5 years, respectively, with no significant difference (P = 0.09). Thirty patients (54.5%) in case and 32 (58.2%) in control groups were male with no significant difference (P = 0.7). CMV-DNA was present in 8 (14.5%) of the cases and 2 (4%) of the controls. CMV-DNA was associated with higher risk of atherosclerosis (OR: 7.7, 95% CI = 1.1-51.4, P = 0.03). Of the total normal aortic samples (55 in cases and 55 in controls), there was no individual with simultaneous positive CMV-DNA among aortic atherosclerotic and normal tissue samples. CONCLUSIONS: The presence of CMV-DNA in aortic plaques is associated with increased risk of atherosclerosis. CMV infection may be considered as an independent risk factor for this event. PMID- 25834720 TI - RNA Polymerase II Second Largest Subunit Molecular Identification of Boletus griseipurpureus Corner From Thailand and Antibacterial Activity of Basidiocarp Extracts. AB - BACKGROUND: Boletus griseipurpureus Corner, an edible mushroom, is a putative ectomycorrhizal fungus. Currently, the taxonomic boundary of this mushroom is unclear and its bitter taste makes it interesting for evaluating its antibacterial properties. OBJECTIVES: The purpose of this study was to identify the genetic variation of this mushroom and also to evaluate any antibacterial activities. MATERIALS AND METHODS: Basidiocarps were collected from 2 north eastern provinces, Roi Et and Ubon Ratchathani, and from 2 southern provinces, Songkhla and Surat Thani, in Thailand. Genomic DNA was extracted and molecular structure was examined using the RNA polymerase II (RPB2) analysis. Antibacterial activities of basidiocarp extracts were conducted with Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 29523 and methicillin-resistant Staphylococcus aureus (MRSA) 189 using the agar-well diffusion method. RESULTS: All the samples collected for this study constituted a monophyletic clade, which was closely related with the Boletus group of polypore fungi. For the antibacterial study, it was found that the crude methanol extract of basidiomes inhibited the growth of all bacteria in vitro more than the crude ethyl acetate extract. CONCLUSIONS: Basidomes collected from four locations in Thailand had low genetic variation and their extracts inhibited the growth of all tested bacteria. The health benefits of this edible species should be evaluated further. PMID- 25834721 TI - Predicting local and non-local effects of resources on animal space use using a mechanistic step selection model. AB - Predicting space use patterns of animals from their interactions with the environment is fundamental for understanding the effect of habitat changes on ecosystem functioning. Recent attempts to address this problem have sought to unify resource selection analysis, where animal space use is derived from available habitat quality, and mechanistic movement models, where detailed movement processes of an animal are used to predict its emergent utilization distribution. Such models bias the animal's movement towards patches that are easily available and resource-rich, and the result is a predicted probability density at a given position being a function of the habitat quality at that position. However, in reality, the probability that an animal will use a patch of the terrain tends to be a function of the resource quality in both that patch and the surrounding habitat.We propose a mechanistic model where this non-local effect of resources naturally emerges from the local movement processes, by taking into account the relative utility of both the habitat where the animal currently resides and that of where it is moving. We give statistical techniques to parametrize the model from location data and demonstrate application of these techniques to GPS location data of caribou (Rangifer tarandus) in Newfoundland.Steady-state animal probability distributions arising from the model have complex patterns that cannot be expressed simply as a function of the local quality of the habitat. In particular, large areas of good habitat are used more intensively than smaller patches of equal quality habitat, whereas isolated patches are used less frequently. Both of these are real aspects of animal space use missing from previous mechanistic resource selection models.Whilst we focus on habitats in this study, our modelling framework can be readily used with any environmental covariates and therefore represents a unification of mechanistic modelling and step selection approaches to understanding animal space use. PMID- 25834722 TI - Measuring telomere length and telomere dynamics in evolutionary biology and ecology. AB - Telomeres play a fundamental role in the protection of chromosomal DNA and in the regulation of cellular senescence. Recent work in human epidemiology and evolutionary ecology suggests adult telomere length (TL) may reflect past physiological stress and predict subsequent morbidity and mortality, independent of chronological age.Several different methods have been developed to measure TL, each offering its own technical challenges. The aim of this review is to provide an overview of the advantages and drawbacks of each method for researchers, with a particular focus on issues that are likely to face ecologists and evolutionary biologists collecting samples in the field or in organisms that may never have been studied in this context before.We discuss the key issues to consider and wherever possible try to provide current consensus view regarding best practice with regard to sample collection and storage, DNA extraction and storage, and the five main methods currently available to measure TL.Decisions regarding which tissues to sample, how to store them, how to extract DNA, and which TL measurement method to use cannot be prescribed, and are dependent on the biological question addressed and the constraints imposed by the study system. What is essential for future studies of telomere dynamics in evolution and ecology is that researchers publish full details of their methods and the quality control thresholds they employ. PMID- 25834723 TI - Inferring positive selection in humans from genomic data. AB - Adaptation can be described as an evolutionary process that leads to an adjustment of the phenotypes of a population to their environment. In the classical view, new mutations can introduce novel phenotypic features into a population that leave footprints in the genome after fixation, such as selective sweeps. Alternatively, existing genetic variants may become beneficial after an environmental change and increase in frequency. Although they may not reach fixation, they may cause a shift of the optimum of a phenotypic trait controlled by multiple loci. With the availability of polymorphism data from various organisms, including humans and chimpanzees, it has become possible to detect molecular evidence of adaptation and to estimate the strength and target of positive selection. In this review, we discuss the two competing models of adaptation and suitable approaches for detecting the footprints of positive selection on the molecular level. PMID- 25834724 TI - Genome-wide insights into the genetic history of human populations. AB - Although mtDNA and the non-recombining Y chromosome (NRY) studies continue to provide valuable insights into the genetic history of human populations, recent technical, methodological and computational advances and the increasing availability of large-scale, genome-wide data from contemporary human populations around the world promise to reveal new aspects, resolve finer points, and provide a more detailed look at our past demographic history. Genome-wide data are particularly useful for inferring migrations, admixture, and fine structure, as well as for estimating population divergence and admixture times and fluctuations in effective population sizes. In this review, we highlight some of the stories that have emerged from the analyses of genome-wide SNP genotyping data concerning the human history of Southern Africa, India, Oceania, Island South East Asia, Europe and the Americas and comment on possible future study directions. We also discuss advantages and drawbacks of using SNP-arrays, with a particular focus on the ascertainment bias, and ways to circumvent it. PMID- 25834725 TI - Clinical decision support systems for improving diagnostic accuracy and achieving precision medicine. AB - As research laboratories and clinics collaborate to achieve precision medicine, both communities are required to understand mandated electronic health/medical record (EHR/EMR) initiatives that will be fully implemented in all clinics in the United States by 2015. Stakeholders will need to evaluate current record keeping practices and optimize and standardize methodologies to capture nearly all information in digital format. Collaborative efforts from academic and industry sectors are crucial to achieving higher efficacy in patient care while minimizing costs. Currently existing digitized data and information are present in multiple formats and are largely unstructured. In the absence of a universally accepted management system, departments and institutions continue to generate silos of information. As a result, invaluable and newly discovered knowledge is difficult to access. To accelerate biomedical research and reduce healthcare costs, clinical and bioinformatics systems must employ common data elements to create structured annotation forms enabling laboratories and clinics to capture sharable data in real time. Conversion of these datasets to knowable information should be a routine institutionalized process. New scientific knowledge and clinical discoveries can be shared via integrated knowledge environments defined by flexible data models and extensive use of standards, ontologies, vocabularies, and thesauri. In the clinical setting, aggregated knowledge must be displayed in user-friendly formats so that physicians, non-technical laboratory personnel, nurses, data/research coordinators, and end-users can enter data, access information, and understand the output. The effort to connect astronomical numbers of data points, including '-omics'-based molecular data, individual genome sequences, experimental data, patient clinical phenotypes, and follow-up data is a monumental task. Roadblocks to this vision of integration and interoperability include ethical, legal, and logistical concerns. Ensuring data security and protection of patient rights while simultaneously facilitating standardization is paramount to maintaining public support. The capabilities of supercomputing need to be applied strategically. A standardized, methodological implementation must be applied to developed artificial intelligence systems with the ability to integrate data and information into clinically relevant knowledge. Ultimately, the integration of bioinformatics and clinical data in a clinical decision support system promises precision medicine and cost effective and personalized patient care. PMID- 25834726 TI - PGC-1alpha modulates denervation-induced mitophagy in skeletal muscle. AB - BACKGROUND: Alterations in skeletal muscle contractile activity necessitate an efficient remodeling mechanism. In particular, mitochondrial turnover is essential for tissue homeostasis during muscle adaptations to chronic use and disuse. While mitochondrial biogenesis appears to be largely governed by the transcriptional co-activator peroxisome proliferator co-activator 1 alpha (PGC 1alpha), selective mitochondrial autophagy (mitophagy) is thought to mediate organelle degradation. However, whether PGC-1alpha plays a direct role in autophagy is currently unclear. METHODS: To investigate the role of the co activator in autophagy and mitophagy during skeletal muscle remodeling, PGC 1alpha knockout (KO) and overexpressing (Tg) animals were unilaterally denervated, a common model of chronic muscle disuse. RESULTS: Animals lacking PGC 1alpha exhibited diminished mitochondrial density alongside myopathic characteristics reminiscent of autophagy-deficient muscle. Denervation promoted an induction in autophagy and lysosomal protein expression in wild-type (WT) animals, which was partially attenuated in KO animals, resulting in reduced autophagy and mitophagy flux. PGC-1alpha overexpression led to an increase in lysosomal capacity as well as indicators of autophagy flux but exhibited reduced localization of LC3II and p62 to mitochondria, compared to WT animals. A correlation was observed between the levels of the autophagy-lysosome master regulator transcription factor EB (TFEB) and PGC-1alpha in muscle, supporting their coordinated regulation. CONCLUSIONS: Our investigation has uncovered a regulatory role for PGC-1alpha in mitochondrial turnover, not only through biogenesis but also via degradation using the autophagy-lysosome machinery. This implies a PGC-1alpha-mediated cross-talk between these two opposing processes, working to ensure mitochondrial homeostasis during muscle adaptation to chronic disuse. PMID- 25834727 TI - Helping address the national research and research capacity needs of Australian chiropractic: introducing the Australian Chiropractic Research Network (ACORN) project. AB - Chiropractic is a popular health care choice in Australia and yet major gaps in our empirical understanding of this area of practice remain. Furthermore, while some research excellence exists, a largely uncoordinated approach to research activity and development has in effect led to silos of interest and a lack of strategic 'big-picture' planning essential to producing a sustainable research culture and capacity for the profession. This commentary identifies the significance of a number of key features - including a national, coordinated focus, and a rich engagement with the practitioner and patient base amongst others - arguably important to the future development of research and research capacity within Australian chiropractic. The design features and phases of the Australian Chiropractic Research Network (ACORN) project are also outlined. ACORN is one contemporary initiative specifically developed to address chiropractic's research and research capacity building needs and help grow a broad evidence-base to inform safe, effective patient care. PMID- 25834728 TI - Emergence of Escherichia coli producing OXA-48 beta-lactamase in the community in Switzerland. AB - BACKGROUND: The emergence and worldwide spread of carbapenemase-producing Enterobacteriaceae is of great concern to public health services. The aim of this study was to investigate the occurrence of carbapenemase-producing Enterobacteriaceae in the community in Switzerland. FINDINGS: One thousand and eighty-six stool samples of healthy humans (staff members of a food-processing company which were screened for the occurrence of salmonellae) were collected in September 2014. After an initial enrichment-step, carbapenemase-producing Enterobacteriaceae were isolated from the carbapenem-containing selective medium SUPERCARBA II. Grown colonies from 11 samples were screened by PCR for the presence of bla KPC, bla NDM, bla OXA-48 and bla VIM. A single OXA-48-producing Escherichia coli was detected. Phylogenetic grouping and multi-locus sequence typing (MLST) revealed that this strain belonged to D:ST38, a type which had been previously reported in the UK, France, Lebanon and Egypt. CONCLUSIONS: The results of this study show that OXA-48-producing Enterobacteriaceae have started to spread into the community in Switzerland, and a continuous monitoring is necessary to better understand their dissemination in the human population as well as in animals and the environment. PMID- 25834729 TI - Mini review: linkage between alpha-Synuclein protein and cognition. AB - alpha-synuclein is a protein that plays important roles in cognitive function in the normal brain, although its exact role is not fully understood. However, current studies reveal that defects in alpha-synuclein function could contribute to various neurodegenerative disorders, such as Parkinson's disease (PD), a disease with symptomatic progression of deterioration in motor and cognitive function. Recent studies show that the level of alpha -synuclein in cerebrospinal fluid (CSF) is highly correlated with speed of cognitive decline, suggesting a potential role of alpha-synuclein in cognitive function. In this mini review, we will be focus on literatures of alpha-synuclein in cognitive function in the non diseased brain, as well as the impact that defective alpha-synuclein has on cognition in disease brain. This will be accomplished by assessing the effects of soluble alpha-synuclein, alpha-synuclein oligomers, and extracellular alpha synuclein transport, on neurodegeneration. PMID- 25834730 TI - Voxel-based meta-analysis of grey matter changes in Alzheimer's disease. AB - BACKGROUND: Voxel-based morphometry (VBM) using structural brain MRI has been widely used for the assessment of impairment in Alzheimer's disease (AD), but previous studies in VBM studies on AD remain inconsistent. OBJECTIVE: We conducted meta-analyses to integrate the reported studies to determine the consistent grey matter alterations in AD based on VBM method. METHODS: The PubMed, ISI Web of Science, EMBASE and Medline database were searched for articles between 1995 and June 2014. Manual searches were also conducted, and authors of studies were contacted for additional data. Coordinates were extracted from clusters with significant grey matter difference between AD patients and healthy controls (HC). Meta-analysis was performed using a new improved voxel based meta-analytic method, Effect Size Signed Differential Mapping (ES-SDM). RESULTS: Thirty data-sets comprising 960 subjects with AD and 1195 HC met inclusion criteria. Grey matter volume (GMV) reduction at 334 coordinates in AD and no GMV increase were found in the current meta-analysis. Significant reductions in GMV were robustly localized in the limbic regions (left parahippocampl gyrus and left posterior cingulate gyrus). In addition, there were GM decreases in right fusiform gyrus and right superior frontal gyrus. The findings remain largely unchanged in the jackknife sensitivity analyses. CONCLUSIONS: Our meta-analysis clearly identified GMV atrophy in AD. These findings confirm that the most prominent and replicable structural abnormalities in AD are in the limbic regions and contributes to the understanding of pathophysiology underlying AD. PMID- 25834731 TI - Endovascular recanalisation of an acute superior mesenteric artery occlusion. A case report and review of the literature. AB - INTRODUCTION: Acute mesenteric ischaemia (AMI) continues to have a high mortality, ranging from 60 to 80%. PRESENTATION OF CASE: A 78-year-old male presented with a 20-hour history of abdominal pain, secondary to a superior mesenteric artery (SMA) thromboembolic occlusion diagnosed on computed tomography (CT) angiography. Following confirmation of bowel viability at laparotomy, endovascular intervention using combined thrombolysis, angioplasty and thromboaspiration was performed. Despite successful recanalisation of the occlusion, his condition continued to deteriorate fatally due to progressive sepsis. DISCUSSION: We discuss the role of biphasic CT in diagnosis of AMI, and review the evidence for endovascular interventions now increasingly used in the emergent management of thromboembolic AMI. CONCLUSION: Early diagnosis using CT angiography is essential, as it is highly sensitive in detecting a visceral arterial occlusion. However, laparotomy is often required to accurately determine bowel viability and the need for resection. Endovascular interventions appear to be effective alternatives to open surgery with appropriate patient selection. PMID- 25834732 TI - Pre-operative thrombotic complications of neoadjuvant chemotherapy for breast cancer: Implications for immediate breast reconstruction. AB - Thrombotic complications arising during the treatment of breast cancer can impact the breast reconstruction pathway. We set out to review the details of cases of thromboembolism occurring during neoadjuvant chemotherapy and peri-operatively to study the impact of the event and its management on subsequent breast reconstruction. METHODS: We retrospectively reviewed the medical records of seven patients who had experienced a thrombotic event during their treatment of breast cancer between 2008 and 2012, who then proceeded to breast reconstruction. We recorded size and grade of tumour, neoadjuvant chemotherapeutic regimen, details of port insertion, planned reconstruction, thrombotic event and its management and the surgery performed and outcome. RESULTS: All patients received chemotherapy via central venous access and went on to present with local symptomatic thrombosis. They were managed with anticoagulant regimens at the time of mastectomy and reconstruction, which were unique for each patient. The results revealed delays to surgery and modifications to planned reconstruction. DISCUSSION: The majority of patients developing thrombotic complications go on to achieve successful reconstruction. There is significant variation in the anticoagulation management in this patient group. Identification of optimal anticoagulant regimes and the possibilities for prophylaxis may prove key in informing surgeons when planning the reconstructive process. CONCLUSION: An awareness of the effects of thrombotic events in this patient group is important in terms of developing an understanding of its impact on the performance of reconstruction, on the management of anticoagulation peri-operatively and on monitoring for post-operative complications. PMID- 25834733 TI - The daily dynamics of cystic fibrosis airway microbiota during clinical stability and at exacerbation. AB - BACKGROUND: Recent work indicates that the airways of persons with cystic fibrosis (CF) typically harbor complex bacterial communities. However, the day-to day stability of these communities is unknown. Further, airway community dynamics during the days corresponding to the onset of symptoms of respiratory exacerbation have not been studied. RESULTS: Using 16S rRNA amplicon sequencing of 95 daily sputum specimens collected from four adults with CF, we observed varying degrees of day-to-day stability in airway bacterial community structures during periods of clinical stability. Differences were observed between study subjects with respect to the degree of community changes at the onset of exacerbation. Decreases in the relative abundance of dominant taxa were observed in three subjects at exacerbation. We observed no relationship between total bacterial load and clinical status and detected no viruses by multiplex PCR. CONCLUSION: CF airway microbial communities are relatively stable during periods of clinical stability. Changes in microbial community structure are associated with some, but not all, pulmonary exacerbations, supporting previous observations suggesting that distinct types of exacerbations occur in CF. Decreased abundance of species that are dominant at baseline suggests a role for less abundant taxa in some exacerbations. Daily sampling revealed patterns of change in microbial community structures that may prove useful in the prediction and management of CF pulmonary exacerbations. PMID- 25834734 TI - Being me and being us - adolescents' experiences of treatment for eating disorders. AB - BACKGROUND: This qualitative study addresses adolescents' perception of treatment for eating disorders. The importance of involving parents in treatment of young people with eating disorders, especially young people with Anorexia Nervosa, is emphasized in a number of studies. Even so, this form of treatment does not work for everybody, not even within a limited diagnostic group. Previous research has revealed that many young people are not entirely satisfied with their treatment. However, there is a lack of knowledge concerning the perspectives of adolescents in outpatient treatment, whose treatment often involves family. The aim of the present study was to investigate how young people with experience from adolescent outpatient treatment for eating disorders, involving family-based and individual based interventions, perceive their time in treatment. METHODS: This study was conducted using a hermeneutic phenomenological approach. Fifteen participants were recruited in collaboration with four specialized eating disorder units and interviewed with the purpose to gather narratives. RESULTS: The analysis revealed that the adolescents sometimes felt more or less forced into treatment, and strong ambivalent feelings about if and how to participate in treatment permeated the adolescents' narratives. The common factors which emerged in the narratives were assembled under the two major themes: Having to involve family in treatment in one way or another and Making progress in treatment - a matter of trust. CONCLUSIONS: It is of great importance to involve family in treatment in order to understand the problems of the adolescents in their context and be able to take advantage of the resource that parents constitute. However, in certain situations, it is necessary to prioritise individual treatment interventions so that instead of sorting out difficult family situations the therapist focuses on enhancing the young people's resilience, thus enabling them to tackle problematic situations in life. PMID- 25834736 TI - Enzootic plague foci, Algeria. AB - In Algeria, PCR sequencing of pla, glpD and rpoB genes found Yersinia pestis in 18/237 (8%) rodents of five species, including Apodemus sylvaticus, previously undescribed as pestiferous; and disclosed three new plague foci. Multiple spacer typing confirmed a new Orientalis variant. Rodent survey should be reinforced in this country hosting reemerging plague. PMID- 25834735 TI - Anorexia nervosa - medical complications. AB - In contrast to other mental health disorders, eating disorders have a high prevalence of concomitant medical complications. Specifically, patients suffering from anorexia nervosa (AN) have a litany of medical complications which are commonly present as part of their eating disorders. Almost every body system can be adversely, affected by this state of progressive malnutrition. Moreover, some of the complications can have permanent adverse effects even after there is a successful program of nutritional rehabilitation and weight restoration. Within this article we will review all body systems affected by AN. There is also salient information about both, how to diagnose these medical complications and which are the likely ones to result in permanent sequelae if not diagnosed and addressed early in the course of AN. In a subsequent article, the definitive medical treatment for these complications will be presented in a clinically practical manner. PMID- 25834737 TI - Associations of the major international high-risk resistant clones and virulent clones with specific ompK36 allele groups in Klebsiella pneumoniae in Taiwan. AB - This study was conducted to investigate the association between ompK36 variants and international high-risk clones in Klebsiella pneumoniae. Fifty-nine sequence types (STs) divided into four ompK36 allele groups (groups A to D) were identified among 185 K. pneumoniae isolates. The major high-risk clones (29 ST11, 13 ST15, 7 ST37 and 1 ST147 isolates) were assigned to group A, while 6 STs (15 ST23, 2 ST65, 3 ST86, 1 ST163, 1 ST373 and 2 ST375 isolates) associated with pyogenic liver abscess were assigned to group C. The genotyping assay developed in this study may be useful for screening of epidemic STs. PMID- 25834738 TI - Experimental design approach to the optimization of PAHs bioremediation from artificially contaminated soil: application of variables screening development. AB - BACKGROUND: The effectiveness of bioremediation systems for PAH-contaminated soil may be constrained by physicochemical properties of contaminants and environmental factors. Information on what is the most effective factor in bioremediation process is essential in the decision of what stimulations can be taken to assist the biodegradation efficacy. METHODS: In this study, four factors of surfactant (Tween 80), humic acid (HA), salinity and nutrients in a 2(4) full factorial design were screened in bioremediation of phenanthrene contaminated soil by using a consortium of bacteria. RESULTS: Between the employed levels of the factors only salinity had not significant effect. Optimal concentrations of surfactant, HA and nutrient were obtained by a response surface design. For phenanthrene biodegradation, a central composite face centred design (CCFD) showed that nutrient, surfactant and HA concentrations had highly significant, significant and insignificant effects, respectively. The best conditions with 87.1% phenanthrene biodegradation were 150 mg HA/Kg soil, 12.68 MUg/L surfactant, and nutrients as K2HPO4, 0.8; KH2PO4, 0.2 and KNO3, 1 g/L. A high similarity was between the model prediction and experimental results. CONCLUSIONS: This study showed that nutrient with 81.27% efficiency could be considered as the most effective factor for practical implications of bioremediation process for PAHs contaminated soil cleanup strategies. PMID- 25834739 TI - Randomized, clinical trial on diathermy and scalpel incisions in elective general surgery. AB - BACKGROUND: Since a long time skin incisions have routinely been made with scalpels. Now a day there is a shift in trend from this method to electrosurgical skin incisions. However, fear of bad scars and improper wound healing has prevented its wide spread use. This Study aimed to compare both methods of skin incisions for different variables. OBJECTIVES: The aim of this study was to examine incisional time, blood loss during incision and postoperative wound complications and pain with both methods of skin incision. PATIENTS AND METHODS: A prospective, comparative and randomized study was conducted at different hospitals of Hyderabad and Nawabshah, Pakistan from 1(st) of December 2009 to 30(th) of November 2011. The study included patients of either sex above the age of five years with general surgical pathology who were to undergo surgery. these candidates were randomly put into two groups. In Group A patients incision was made with a scalpel and in group B with diathermy. Data was analyzed for age, sex, comorbid illness, incisional time, blood loss during incision making and postoperative pain and wound complications. RESULTS: A total of 283 patients completed the follow-up and were included in the final analysis. Group A comprised of 143 (50.53%) patients; 83 (58%) males and 60 (42%) females with a mean age of 36.03 years. Amongst the 140 patients of group B, there were 85 (60.7%) males and 55 (39.3%) females with a mean age of 36.52 years. Twenty-five (17.48%) patients of group A and 27 (19.28%) of group B had comorbid illnesses. Mean incision time was 8.9025-sec/cm(2) for group A and 7.3057 sec/cm(2) for group B patients. Mean blood loss during incision making was 1.8262 mL/cm(2) and 1.1346 mL/cm(2) for group A and B patients, respectively. Pain was 5.2957 for group A patients on day one and 3.1181 for group B patients. Pain score was 2.1049 and 1.6206 on day two and 0.8191 and 0.7192 on day five, for group A and B patients, respectively. Postoperative wound complications were noticed in 26 (18.18%) patients of group A and 22 (15.71%) patients of group B. CONCLUSIONS: Diathermy incision is a safe and expedient technique. It takes less time than scalpel incision and loss of blood is also lower during incision. Diathermy is associated with lesser post-operative pain and complications than the scalpel incision. Diathermy should be method of choice in general elective surgery. PMID- 25834740 TI - Expectations of multiple sclerosis patients and their families: a qualitative study in iran. AB - BACKGROUND: Multiple Sclerosis (MS) is a neurological disease that is most commonly observed among young people. Drug and non-drug treatments are used to prevent the progression of the disease and to control illness-related disorders. Patients with MS often have multiple and complicated needs that require a broad spectrum of health services. OBJECTIVES: This study was conducted to identify the expectations of individuals with MS and their families for healthcare services. PATIENTS AND METHODS: This article is part of a qualitative case study. The participants were selected by a purposive sampling method. In this study, semi structured interviews of 20 individuals with MS and 8 family members were conducted to identify the expectations of MS patients and their families. In addition to the interviews, the documents related to the aim of the study, including weblogs, MS magazines, special websites of individuals with MS, and news agencies were gathered. Analysis of data was performed by a conventional content analysis method. RESULTS: The age of the participants ranged from 22-63 years. The data obtained from this study was classified into 5 main categories as follows: being cured, need for comfort, promoting knowledge, economic welfare, and social security. CONCLUSIONS: Individuals with MS and their families had different expectations pertaining to all dimensions of life, such that not meeting the needs related to any dimension could have affect the other dimensions. Therefore, it is necessary for healthcare providers to have a holistic assessment as well as try to meet all needs and expectations. PMID- 25834741 TI - Combination of Angiotensin Converting Enzyme Insertion/Deletion (I/D) (rs4646994) and VEGF Polymorphism (+405G/C; rs2010963) Synergistically Associated With the Development, of Albuminuria in Iranian Patients With Type 2 Diabetes. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) and vascular endothelial growth factor (VEGF) polymorphisms have been shown to associate with diabetic nephropathy (DN). OBJECTIVES: We examined the hypothesis that ACE-D and VEGF-G alleles act synergistically in association with DN, in patients with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: The VEGF (rs2010963) and ACE (rs4646994) genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 490 T2DM patients. Diabetic patients were classified as T2DM patients with and without albuminuria (control). The PCR and RFLP were used to detect the VEGF and ACE alleles. RESULTS: A total of 255 consecutive patients with T2DM and microalbuminuria (Group A) and 235 patients with T2DM and normoalbuminuria (Group B) were included in the study. In univariate analysis, the groups were statistically similar for all variables, except for glycated hemoglobin (HbA1c) (P = 0.034), and the frequency of ACE (P = 0.015) and VEGF (P = 0.006) genotypes. Our study showed that the VEGF-G and ACE-D alleles are independently associated with the development of nephropathy. According to our data, the combination of these two risk factors had a significant synergistic effect on the risk of microalbuminuria development. CONCLUSIONS: Our study indicated that ACE-D and VEGF-G alleles can be an independent risk factor for microalbominuria in T2DM patients. PMID- 25834742 TI - Stability of renal function in spite of low glomerular filtration rate: a case report. AB - INTRODUCTION: Chronic renal dysfunction is a progressive and irreversible process in kidney function, which often resulted in chronic kidney disease (CKD) or chronic renal failure (CRF). Range of CKD is varying from proteinuria and renal failure to CRF. CASE PRESENTATION: A 78-year-old man presented with stage 4 CKD for 7 years; the glomerular filtration rate (GFR) and creatinine levels remained constant despite no change in his weight. CONCLUSIONS: Although our patient had CKD stage 4, but his condition has not deteriorated and remained constant and stable for several years only by control of blood pressure and usual treatment which prescribed for patients at this stage. PMID- 25834743 TI - Iranian Women's Experiences of Health Information Seeking Barriers: A Qualitative Study in Kerman. AB - BACKGROUND: Women as active health information seekers play a key role in determining lifestyle and possible implementation of preventive measures, thereby improving the health of individuals, families and society. Although studies indicate that equipping people with adequate health information leads to optimal health outcomes, sometimes the complexity of human behavior and presence of barriers and limitations expose them to challenges. OBJECTIVES: This study was designed to explore women's experiences of health information seeking barriers. PATIENTS AND METHODS: In this qualitative content analysis study, data collection was conducted regarding inclusion criteria, through purposive sampling and semi structured interviews with 17 women and using documentation and field notes until data saturation. Qualitative data analysis was performed constantly and simultaneously with data collection. RESULTS: Five central themes were emerged to explain women's experiences of barriers to health information seeking as inadequate support from health care system, shame and embarrassment, costs, wrong ideas and beliefs and inadequate health literacy. CONCLUSIONS: It seems the accurate and evidence-based review of the current health system is crucial to support the health informative requirements in a community-based approach, respecting the community cultural-religious beliefs and client participation in health care and according to local resources. PMID- 25834744 TI - Synthesis and biological activity of arylspiroborate salts derived from caffeic Acid phenethyl ester. AB - Two novel boron compounds containing caffeic acid phenethyl ester (CAPE) derivatives have been prepared and characterized fully. These new compounds and CAPE have been investigated for potential antioxidant and antimicrobial properties and their ability to inhibit 5-lipoxygenase and whether chelation to boron improves their biological activity. Sodium salt 4 was generally more active than ammonium salt 5 in the biological assays and surpassed the radical scavenging ability of CAPE. Compounds 4 and 5 were more active than CAPE and Zileuton in human polymorphonuclear leukocytes. These results clearly show the effectiveness of the synthesized salts as transporter of CAPE. PMID- 25834745 TI - Similar and additive effects of ovariectomy and diabetes on insulin resistance and lipid metabolism. AB - Type 2 diabetes mellitus (T2DM) is among the leading causes of death in postmenopausal women. The disruption of ovarian function may contribute to the incidence of T2DM. The purpose of this study was to investigate the effects of ovariectomy and T2DM on glucose and lipid homeostasis, perilipin levels in adipose tissues, as a lipolytic regulator, and levels of certain adipokines. Ovariectomized (OVX) rats were used as a model for postmenopausal women. The study was performed on sham, OVX, sham diabetic, and OVX diabetic female rats. The results indicated that ovariectomy alters adipose tissue metabolism through reducing perilipin content in white adipose tissue (WAT); however it has no effect on perilipin level in brown adipose tissue (BAT). OVX diabetic females suffer from serious metabolic disturbances, suggested by exacerbation of insulin resistance in terms of disrupted lipid profile, higher HOMA-IR, hyperinsulinemia, higher leptin, and lower adiponectin concentrations. These metabolic derangements may underlie the predisposition for cardiovascular disease in women after menopause. Therefore, for efficient treatment, the menopausal status of diabetic female should be addressed, and the order of events is of great importance because ovariectomy following development of diabetes has more serious complications compared to development of diabetes as result of menopause. PMID- 25834746 TI - If hunters end up in the emergency room: a retrospective analysis of hunting injuries in a swiss emergency department. AB - Aim. to characterize the mechanisms, patterns, and outcomes of nonfatal hunting related injuries in patients presenting to Bern University Hospital, Switzerland, and compare these to reports of hunting injuries worldwide. Methods. patients presenting with hunting-related injuries to the Emergency Department at Bern University hospital from 2000 to 2014 were identified by retrospectively searching the department database using the keyword "hunt." Each case was analyzed in terms of the patient age and gender, the mechanism and pattern of injury, and management and patient follow-up. Results. 19 patients were identified. 16 were male with a mean age of 50 years (range: 16-74). Mechanisms of injury included firearm-related injuries, falls, and knife wounds. The most common patterns of injury were head injuries (7), followed by injuries to the upper (5) or lower limb (5) and trunk (2). Over half of the patients were admitted, and nine required emergency surgery. Conclusion. Nonfatal hunting accidents in Bern, Switzerland, are largely caused by firearms and falls and tend to occur in male hunters with a mean age of 50 years. The most common patterns of injury are orthopedic and head injuries, often requiring surgery. These findings are consistent with international studies of nonfatal hunting accidents. PMID- 25834747 TI - Erratum to "Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies". AB - [This corrects the article DOI: 10.1155/2014/946010.]. PMID- 25834748 TI - A CADASIL-Like Case with a Novel Noncysteine Mutation of the NOTCH3 Gene and Granular Deposits in the Renal Arterioles. AB - We herein report the finding of a 62-year-old male, who developed dysarthria and dysphagia, with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy- (CADASIL-) like cerebral lesions. He also suffered from slowly progressive renal failure with the findings of granular deposits similar to electron-dense granular osmiophilic material in the renal arterioles. We found a novel heterozygous missense mutation of the NOTCH3 gene, c.4039G>C in exon 24, resulting in a p.Gly1347Arg substitution in its extracellular domain. The noncysteine substitution may underlie the pathogenesis of white matter lesions in the brain and of the chronic renal failure in the present case. PMID- 25834749 TI - Round ligament of uterus leiomyoma: an unusual cause of dyspareunia. AB - Round ligament of uterus leiomyoma is a rare, benign tumor of the vulva. Its incidence is not known exactly, and the mean age ranges from 13 to 70. Although clinical properties of benign and malignant diseases in the vulvar area are frequently similar, early diagnosis and treatment are essential. Local excision is recommended as definitive therapy. We present an 28-year-old female without any birth with a mass in anterior vaginal wall diagnosed as vulvar leiomyoma. In conclusion, a brief review of relevant literature emphasizes that leiomyomas are quite rare outside of the uterus but they might occur in any tissue or organ containing smooth muscle, spontaneously or parasitically after the spreading effect of an accident or surgical trauma. Clinicians should be alert especially for the diagnosis in a tissue with smooth muscle content. PMID- 25834750 TI - Carbon Monoxide Poisoning during Pregnancy: Presentation of a Rare Severe Case with Fetal Bladder Complications. AB - Carbon monoxide poisoning during pregnancy is a rare and potentially serious condition. Fetal complications are uncommon, related to anoxic lesions. The severity of these complications does not depend on the level of maternal COHb. We report the case of a 22-year-old pregnant woman who at 30 weeks of gestation had carbon monoxide poisoning secondary to a fire in her home, complicated by cardiac arrest and severe fetal damage. The child had not brain damage, but presented bladder lesions not previously described, with urinary ascites complicating megacystis. PMID- 25834751 TI - Validation of an RPHPTLC-Densitometric Method Using Silica Gel 60 RP18WF254 for Simultaneous Determination of Nicotinamide in Selected Pharmaceutical Formulations. AB - This research study describes the applicability of silica gel 60 RPW18F254 plates for the development and validation of new, simple, economic, accurate, and precise RPHPTLC-densitometric method suitable for the quantification of nicotinamide (as Vitamin PP) in three marketed preparations. The mobile phase used was methanol-water in volume composition 3 : 7. Detection wavelength was 200 nm. The proposed method was validated according to ICH guidelines and also based on Ferenczi-Fodor and Konieczka reports. Results were found to be linear over a range of 1.00 to 2.00 MUg/spot. Limit of detection (LOD) and limit of quantification (LOQ) were 0.15 MUg/spot and 0.45 MUg/spot, respectively. The percent content of nicotinamide in the investigated preparations was found to be 99.2% (Product 1), 99.3% (Product 2), and 99.4% (Product 3). Developed method is accurate and precise (CV < 3%) and may be successfully applied for the quality control of pharmaceutical formulations containing nicotinamide in the presence of its derivatives, such as N,N-diethylnicotinamide, N-methylnicotinamide, and nicotinic acid. PMID- 25834752 TI - An on-line solid phase extraction-liquid chromatography-tandem mass spectrometry method for the determination of perfluoroalkyl acids in drinking and surface waters. AB - An UHPLC-MS/MS multiresidue method based on an on-line solid phase extraction (SPE) procedure was developed for the simultaneous determination of 9 perfluorinated carboxylates (from 4 to 12 carbon atoms) and 3 perfluorinated sulphonates (from 4 to 8 carbon atoms). This work proposes using an on-line solid phase extraction before chromatographic separation and analysis to replace traditional methods of off-line SPE before direct injection to LC-MS/MS. Manual sample preparation was reduced to sample centrifugation and acidification, thus eliminating several procedural errors and significantly reducing time-consuming and costs. Ionization suppression between target perfluorinated analytes and their coeluting SIL-IS were detected for homologues with a number of carbon atoms less than 9, but the quantitation was not affected. Total matrix effect corrected by SIL-IS, inclusive of extraction efficacy, and of ionization efficiency, ranged between -34 and +39%. The percentage of recoveries, between 76 and 134%, calculated in different matrices (tap water and rivers impacted by different pollutions) was generally satisfactory. LODs and LOQs of this on-line SPE method, which also incorporate recovery losses, ranged from 0.2 to 5.0 ng/L and from 1 to 20 ng/L, respectively. Validated on-line SPE-LC/MS/MS method has been applied in a wide survey for the determination of perfluoroalkyl acids in Italian surface and ground waters. PMID- 25834753 TI - Resolution of Suicidal Ideation With Corticosteroids in a Patient With Concurrent Addison's Disease and Depression. PMID- 25834754 TI - Assessing capacity in psychiatric patients with acute medical illness who refuse care. AB - Three cases are presented that demonstrate the difficulty of assessing medical decision-making capacity in patients with psychiatric illness who are refusing care. Health professionals often assess capacity differently in practice. Provided their patients have some understanding of their illness and have some plans for meeting basic needs, psychiatrists are often inclined to give patients the freedom to refuse care even if they do not exhibit a full understanding of the medical facts of their case and why they are refusing it. Adult medicine physicians, in contrast, are inclined to require patients to state a more complete understanding of the benefits and burdens of evaluation and treatment before allowing them to refuse care when their refusals might result in adverse medical outcomes. The 3 cases exemplify the tension between these approaches and highlight the role of hospital ethics consultation in addressing this conflict. PMID- 25834756 TI - Live until you die. PMID- 25834757 TI - Fludrocortisone in posttraumatic stress disorder: effective for symptoms and prazosin-induced hypotension. PMID- 25834755 TI - Sadness: diagnosis, evaluation, and treatment. PMID- 25834758 TI - Alcohol and prescription drug abuse and borderline personality disorder symptomatology among male and female perpetrators of partner violence. PMID- 25834759 TI - A case of glioblastoma masquerading as an affective disorder. PMID- 25834760 TI - A case report of clozapine-induced severe gastrointestinal hypomotility. PMID- 25834761 TI - Outpatient metformin management of obese individuals with schizophrenia. PMID- 25834762 TI - Clozapine-induced euphoria: a case report. PMID- 25834763 TI - Impact of the creation and implementation of a clinical management guideline for personality disorders in reducing use of mechanical restraints in a psychiatric inpatient unit. AB - OBJECTIVE: To evaluate the impact of the implementation of a guideline for the management of personality disorders on reducing the frequency of use of mechanical restraints in a psychiatric inpatient unit. METHOD: This retrospective study was conducted in a psychiatric inpatient unit with 42 beds, which serves an urban area of 330,000 inhabitants. The sample consisted of all patients with a clinical diagnosis of personality disorder (DSM-IV-TR criteria) who were admitted to the unit from January 2010 to December 2010 and from January 2011 to December 2011 (ie, before and after, respectively, the implementation of the guideline). The guideline focused on cluster B disorders and follows a psychodynamic perspective. RESULTS: Restraint use was reduced from 38 of 87 patients with personality disorders (43.7%) to 3 of 112 (2.7%), for a relative risk of 0.06 (95% CI, 0.02-0.19) and an absolute risk reduction of 41% (95% CI, 29.9%-51.6%). The risk of being discharged against medical advice increased after the intervention, with a relative risk of 1.84 (95% CI, 0.96-3.51). Restraint use in patients with other diagnoses was also reduced to a similar extent. CONCLUSIONS: The use of mechanical restraints was dramatically reduced after the implementation of a clinical practice guideline on personality disorders, suggesting that these coercive measures might be decreased in psychiatric inpatient units. PMID- 25834764 TI - Illness progression as a function of independent and accumulating poor prognosis factors in outpatients with bipolar disorder in the United States. AB - OBJECTIVE: Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression. METHOD: From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann Whitney) test, chi(2), and logistical regression. RESULTS: All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course. CONCLUSIONS: Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder. PMID- 25834765 TI - Nonpsychiatric medication interventions initiated by a postgraduate year 2 psychiatric pharmacy resident in a patient-centered medical home. AB - OBJECTIVE: Studies have demonstrated the benefits of incorporating comprehensive medication management into primary care, but no study describes the types of nonpsychiatric medication-related interventions provided by a psychiatric pharmacist while providing comprehensive medication management. METHOD: A chart review of Center for Community Health patients enrolled in the University of Southern California Psychiatric Pharmacy Clinic, Los Angeles, between July 1, 2013, and January 10, 2014, was conducted. Progress notes were reviewed to collect medication recommendations and interventions. The number and types of interventions were compared between groups based on substance abuse history, comorbid medical conditions, number of psychiatric diagnoses, and number of medications. An anonymous survey was distributed to primary care providers (PCPs) regarding perceptions and attitudes toward a postgraduate year 2 psychiatric pharmacy resident's interventions pertaining to nonpsychiatric medications. RESULTS: 177 nonpsychiatric medication interventions were documented. Fifty interventions required PCP approval, and 45% of those were accepted. Having a diagnosis of diabetes (P < .0001), hypertension (P < .0001), gastroesophageal reflux disease (P < .0001), >= 9 medications (P < .0001), or >= 5 medical diagnoses (P < .0001) were all associated with an increased mean number of interventions. Of the PCPs, 66% viewed the psychiatric pharmacist as a resource for addressing medical interventions by providing drug information. The PCPs were agreeable to having a psychiatric pharmacist provide drug information and monitor the patient but reported mixed opinions on whether a psychiatric pharmacist should comanage nonpsychiatric conditions. CONCLUSIONS: Psychiatric pharmacists can successfully collaborate with PCPs in primary care clinics to provide comprehensive medication management that optimizes pharmacotherapy for patients with medical and psychiatric conditions. Continued efforts are needed to promote interdisciplinary approaches to provide comprehensive medication management services for patients with both psychiatric and medical disorders. PMID- 25834766 TI - Promoting medication adherence in older adults through early diagnosis of neurocognitive disorders. AB - OBJECTIVE: Community-dwelling older adults with neurocognitive disorders experience high risk of and often suffer severe consequences from medication nonadherence. Due to the important role of informal caregivers in the care of patients with neurocognitive disorders, medication management involves both patients and families. A formal diagnosis of a neurocognitive disorder may improve both provider-patient and provider-family communications and resulting regimen adherence, yet many with signs of neurocognitive disorders remain undiagnosed. The goal of this study was to examine the differences in medication management behaviors for family caregivers of mildly impaired older adults with or without a formal neurocognitive disorder diagnosis. METHOD: The study included 112 women who provided at least 2 forms of medication assistance for a mildly cognitively impaired older adult with (n = 38, 34%) or without (n = 75, 66%) a reported neurocognitive disorder diagnosis and who completed online self assessments of medication adherence and self-efficacy for medication management from May 2012 to May 2013. Cases were selected for analyses based on analog Clinical Dementia Rating scores between 0.5 and 1, indicating mild cognitive impairment in the older adult. RESULTS: Compared to families unaware of a neurocognitive disorder diagnosis, caregivers reporting knowledge of a neurocognitive disorder diagnosis in their older family member endorsed higher medication management self-efficacy and increased levels of adherence-related behaviors. Step-wise logistic regression analyses demonstrated statistical significance in using these adherence and self-efficacy variables to differentiate between the presence or absence of a known neurocognitive disorder diagnosis (N = 112, chi (2) 6 = 22.84, P < .05). CONCLUSIONS: A formally charted and communicated neurocognitive disorder diagnosis is associated with improved medication management behaviors and medication-related self-efficacy in neurocognitive disorder family caregivers. PMID- 25834767 TI - A cross-sectional survey of childhood trauma and compliance with general health care among adult primary care outpatients. AB - OBJECTIVE: Beyond the examination of medication compliance among individuals with substance abuse or human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), few studies have examined relationships between childhood trauma and health care compliance in adulthood-the focus of the present study. METHOD: Using a cross-sectional approach and a self-report survey methodology, we examined 5 types of childhood trauma (ie, witnessing violence, physical neglect, emotional abuse, physical abuse, sexual abuse) in relationship to 4 measures of general health care compliance (ie, self-rated general conscientiousness with medical treatment; 5 items pertaining to general health care compliance such as scheduling regular dental checkups, timely arrival for doctor's appointments, and timely completion of laboratory work; 2 medication compliance items; and the Medical Outcomes Study general adherence score) among a sample of adult primary care outpatients (N = 272). Data were collected in March 2014. RESULTS: According to findings, some health care adherence variables demonstrated relationships with the summed childhood trauma score, whereas others did not. It could be interpreted that the more subjective health care compliance variables (eg, self rated conscientiousness with regard to medical treatment) demonstrated no relationship with a summed childhood trauma score, whereas the more objective health care compliance variables (eg, frequency of regular dental checkups, ability to remember to take all medications, Medical Outcomes Study general adherence score) did demonstrate statistically significant relationships with a summed childhood trauma score (most at P < .01). CONCLUSIONS: Patients with histories of childhood trauma demonstrate some deficits with health care compliance in comparison to those without childhood trauma. One interpretation is that the mistreated appear to believe that they are fairly compliant with health care treatment, but objective variables appear to suggest otherwise. PMID- 25834768 TI - Diagnosis and management of sleep disorders in posttraumatic stress disorder:a review of the literature. AB - OBJECTIVE: International and societal conflicts and natural disasters can leave physical and mental scars in people who are directly affected by these traumatic experiences. Posttraumatic stress disorder (PTSD) is the clinical manifestation of these experiences in the form of re-experiencing the trauma, avoidance of trauma-related stimuli, and persistent symptoms of hyperarousal. There is growing evidence that sleep disruption that occurs following trauma exposure may in fact contribute to the pathophysiology of PTSD and poor clinical outcomes. The purpose of this review is to highlight the importance of recognition and management of sleep disorders in patients with PTSD. DATA SOURCES: English-language, adult research studies published between 1985 and April 2014 were identified via the PubMed database. The search terms used were PTSD AND sleep disorders. STUDY SELECTION: The search identified 792 original and review articles. Of these, 53 articles that discussed or researched sleep disorders in PTSD were selected. Fourteen randomized controlled trials of therapy for PTSD are included in this review. RESULTS: Impaired sleep is a common complaint mainly in the form of nightmares and insomnia among people with PTSD. Sleep apnea and periodic limb movement disorder are particularly prevalent in patients with PTSD and, yet, remain unrecognized. Although selective serotonin reuptake inhibitors are effective in improving PTSD global symptoms, they have a variable and modest effect on sleep disorder symptoms. Cognitive-behavioral treatment targeted to sleep and/or the use of the centrally acting selective alpha1 antagonist prazosin have been more successful in treating insomnia and nightmares in PTSD than other classes of medications. In view of the high occurrence of sleep apnea and periodic leg movement disorder, a thorough sleep evaluation and treatment are warranted. CONCLUSIONS: Patients with PTSD have a high prevalence of sleep disorders and should be queried for insomnia, nightmares, periodic limb movement disorder, and sleep-disordered breathing. PMID- 25834769 TI - Classifying acoustic signals into phoneme categories: average and dyslexic readers make use of complex dynamical patterns and multifractal scaling properties of the speech signal. AB - Several competing aetiologies of developmental dyslexia suggest that the problems with acquiring literacy skills are causally entailed by low-level auditory and/or speech perception processes. The purpose of this study is to evaluate the diverging claims about the specific deficient peceptual processes under conditions of strong inference. Theoretically relevant acoustic features were extracted from a set of artificial speech stimuli that lie on a /bAk/-/dAk/ continuum. The features were tested on their ability to enable a simple classifier (Quadratic Discriminant Analysis) to reproduce the observed classification performance of average and dyslexic readers in a speech perception experiment. The 'classical' features examined were based on component process accounts of developmental dyslexia such as the supposed deficit in Envelope Rise Time detection and the deficit in the detection of rapid changes in the distribution of energy in the frequency spectrum (formant transitions). Studies examining these temporal processing deficit hypotheses do not employ measures that quantify the temporal dynamics of stimuli. It is shown that measures based on quantification of the dynamics of complex, interaction-dominant systems (Recurrence Quantification Analysis and the multifractal spectrum) enable QDA to classify the stimuli almost identically as observed in dyslexic and average reading participants. It seems unlikely that participants used any of the features that are traditionally associated with accounts of (impaired) speech perception. The nature of the variables quantifying the temporal dynamics of the speech stimuli imply that the classification of speech stimuli cannot be regarded as a linear aggregate of component processes that each parse the acoustic signal independent of one another, as is assumed by the 'classical' aetiologies of developmental dyslexia. It is suggested that the results imply that the differences in speech perception performance between average and dyslexic readers represent a scaled continuum rather than being caused by a specific deficient component. PMID- 25834770 TI - A predictive model for canine dilated cardiomyopathy-a meta-analysis of Doberman Pinscher data. AB - Dilated cardiomyopathy is a prevalent and often fatal disease in humans and dogs. Indeed dilated cardiomyopathy is the third most common form of cardiac disease in humans, reported to affect approximately 36 individuals per 100,000 individuals. In dogs, dilated cardiomyopathy is the second most common cardiac disease and is most prevalent in the Irish Wolfhound, Doberman Pinscher and Newfoundland breeds. Dilated cardiomyopathy is characterised by ventricular chamber enlargement and systolic dysfunction which often leads to congestive heart failure. Although multiple human loci have been implicated in the pathogenesis of dilated cardiomyopathy, the identified variants are typically associated with rare monogenic forms of dilated cardiomyopathy. The potential for multigenic interactions contributing to human dilated cardiomyopathy remains poorly understood. Consistent with this, several known human dilated cardiomyopathy loci have been excluded as common causes of canine dilated cardiomyopathy, although canine dilated cardiomyopathy resembles the human disease functionally. This suggests additional genetic factors contribute to the dilated cardiomyopathy phenotype.This study represents a meta-analysis of available canine dilated cardiomyopathy genetic datasets with the goal of determining potential multigenic interactions relating the sex chromosome genotype (XX vs. XY) with known dilated cardiomyopathy associated loci on chromosome 5 and the PDK4 gene in the incidence and progression of dilated cardiomyopathy. The results show an interaction between known canine dilated cardiomyopathy loci and an unknown X-linked locus. Our study is the first to test a multigenic contribution to dilated cardiomyopathy and suggest a genetic basis for the known sex-disparity in dilated cardiomyopathy outcomes. PMID- 25834771 TI - Autonomous Sensory Meridian Response (ASMR): a flow-like mental state. AB - Autonomous Sensory Meridian Response (ASMR) is a previously unstudied sensory phenomenon, in which individuals experience a tingling, static-like sensation across the scalp, back of the neck and at times further areas in response to specific triggering audio and visual stimuli. This sensation is widely reported to be accompanied by feelings of relaxation and well-being. The current study identifies several common triggers used to achieve ASMR, including whispering, personal attention, crisp sounds and slow movements. Data obtained also illustrates temporary improvements in symptoms of depression and chronic pain in those who engage in ASMR. A high prevalence of synaesthesia (5.9%) within the sample suggests a possible link between ASMR and synaesthesia, similar to that of misophonia. Links between number of effective triggers and heightened flow state suggest that flow may be necessary to achieve sensations associated with ASMR. PMID- 25834772 TI - Capsules of the diatom Achnanthidium minutissimum arise from fibrillar precursors and foster attachment of bacteria. AB - Achnanthidium minutissimum is a benthic freshwater diatom that forms biofilms on submerged surfaces in aquatic environments. Within these biofilms, A. minutissimum cells produce extracellular structures which facilitate substrate adhesion, such as stalks and capsules. Both consist of extracellular polymeric substance (EPS), but the microstructure and development stages of the capsules are so far unknown, despite a number of hypotheses about their function, including attachment and protection. We coupled scanning electron microscopy (SEM) to bright-field microscopy (BFM) and found that A. minutissimum capsules mostly possess an unstructured surface. However, capsule material that was mechanically stressed by being stretched between or around cells displayed fibrillar substructures. Fibrils were also found on the frustules of non encapsulated cells, implicating that A. minutissimum capsules may develop from fibrillar precursors. Energy-dispersive X-ray (EDX) spectroscopy revealed that the capsule material do not contain silicon, distinguishing it from the frustule material. We furthermore show that bacteria preferentially attach to capsules, instead of non-encapsulated A. minutissimum cells, which supports the idea that capsules mediate diatom-bacteria interactions. PMID- 25834773 TI - Disentangling the impacts of heat wave magnitude, duration and timing on the structure and diversity of sessile marine assemblages. AB - Extreme climatic events, including heat waves (HWs) and severe storms, influence the structure of marine and terrestrial ecosystems. Despite growing consensus that anthropogenic climate change will increase the frequency, duration and magnitude of extreme events, current understanding of their impact on communities and ecosystems is limited. Here, we used sessile invertebrates on settlement panels as model assemblages to examine the influence of HW magnitude, duration and timing on marine biodiversity patterns. Settlement panels were deployed in a marina in southwest UK for >=5 weeks, to allow sufficient time for colonisation and development of sessile fauna, before being subjected to simulated HWs in a mesocosm facility. Replicate panel assemblages were held at ambient sea temperature (~17 degrees C), or +3 degrees C or +5 degrees C for a period of 1 or 2 weeks, before being returned to the marina for a recovery phase of 2-3 weeks. The 10-week experiment was repeated 3 times, staggered throughout summer, to examine the influence of HW timing on community impacts. Contrary to our expectations, the warming events had no clear, consistent impacts on the abundance of species or the structure of sessile assemblages. With the exception of 1 high-magnitude long-duration HW event, warming did not alter not assemblage structure, favour non-native species, nor lead to changes in richness, abundance or biomass of sessile faunal assemblages. The observed lack of effect may have been caused by a combination of (1) the use of relatively low magnitude, realistic heat wave treatments compared to previous studies (2), the greater resilience of mature adult sessile fauna compared to recruits and juveniles, and (3) the high thermal tolerance of the model organisms (i.e., temperate fouling species, principally bryozoans and ascidians). Our study demonstrates the importance of using realistic treatments when manipulating climate change variables, and also suggests that biogeographical context may influence community level responses to short-term warming events, which are predicted to increase in severity in the future. PMID- 25834774 TI - A specimen of Paralycoptera Chang & Chou 1977 (Teleostei: Osteoglossoidei) from Hong Kong (China) with a potential Late Jurassic age that extends the temporal and geographical range of the genus. AB - We describe a Mesozoic fish Paralycoptera sp. (Teleostei: Osteoglossoidei), on the basis of a postcranial skeleton collected from the volcaniclastic mudstones of the Lai Chi Chong Formation of Hong Kong, China. The new finding-representing the city's first Mesozoic fish-extends the geographical distribution of Paralycoptera from eastern mainland China into Hong Kong, demonstrating a wider distribution than previously appreciated for this genus. A radiometric age for the Lai Chi Chong Formation of 146.6 +/- 0.2 Ma implies a temporal range expansion for Paralycoptera of approximately 40 million years back from the Early Cretaceous (~110 Ma). However, spores found in the Formation suggest an Early Cretaceous age that is consistent with the existing age assignment to Paralycoptera. We argue that the proposed temporal range extension is genuine because it is based on recent high precision radiometric age data, but given the discrepancies with the biostratigraphic ages further investigation is needed to confirm this. This study provides an important step towards revealing Hong Kong's Mesozoic vertebrate fauna and understanding its relationship to well-studied mainland Chinese ones. PMID- 25834775 TI - Low-cost, low-input RNA-seq protocols perform nearly as well as high-input protocols. AB - Recently, a number of protocols extending RNA-sequencing to the single-cell regime have been published. However, we were concerned that the additional steps to deal with such minute quantities of input sample would introduce serious biases that would make analysis of the data using existing approaches invalid. In this study, we performed a critical evaluation of several of these low-volume RNA seq protocols, and found that they performed slightly less well in per-gene linearity of response, but with at least two orders of magnitude less sample required. We also explored a simple modification to one of these protocols that, for many samples, reduced the cost of library preparation to approximately $20/sample. PMID- 25834776 TI - Effects of preservation methods of muscle tissue from upper-trophic level reef fishes on stable isotope values (delta (13)C and delta (15)N). AB - Research that uses stable isotope analysis often involves a delay between sample collection in the field and laboratory processing, therefore requiring preservation to prevent or reduce tissue degradation and associated isotopic compositions. Although there is a growing literature describing the effects of various preservation techniques, the results are often contextual, unpredictable and vary among taxa, suggesting the need to treat each species individually. We conducted a controlled experiment to test the effects of four preservation methods of muscle tissue from four species of upper trophic-level reef fish collected from the eastern Gulf of Mexico (Red Grouper Epinephelus morio, Gag Mycteroperca microlepis, Scamp Mycteroperca phenax, and Red Snapper Lutjanus campechanus). We used a paired design to measure the effects on isotopic values for carbon and nitrogen after storage using ice, 95% ethanol, and sodium chloride (table salt), against that in a liquid nitrogen control. Mean offsets for both delta (13)C and delta (15)N values from controls were lowest for samples preserved on ice, intermediate for those preserved with salt, and highest with ethanol. Within species, both salt and ethanol significantly enriched the delta (15)N values in nearly all comparisons. Ethanol also had strong effects on the delta (13)C values in all three groupers. Conversely, for samples preserved on ice, we did not detect a significant offset in either isotopic ratio for any of the focal species. Previous studies have addressed preservation-induced offsets in isotope values using a mass balance correction that accounts for changes in the isotope value to that in the C/N ratio. We tested the application of standard mass balance corrections for isotope values that were significantly affected by the preservation methods and found generally poor agreement between corrected and control values. The poor performance by the correction may have been due to preferential loss of lighter isotopes and corresponding low levels of mass loss with a substantial change in the isotope value of the sample. Regardless of mechanism, it was evident that accounting for offsets caused by different preservation methods was not possible using the standard correction. Caution is warranted when interpreting the results from specimens stored in either ethanol or salt, especially when using those from multiple preservation techniques. We suggest the use of ice as the preferred preservation technique for muscle tissue when conducting stable isotope analysis as it is widely available, inexpensive, easy to transport and did not impart a significant offset in measured isotopic values. Our results provide additional evidence that preservation effects on stable isotope analysis can be highly contextual, thus requiring their effects to be measured and understood for each species and isotopic ratio of interest before addressing research questions. PMID- 25834777 TI - Measuring spinal canal size in lumbar spinal stenosis: description of method and preliminary results. AB - BACKGROUND: Lumbar spinal stenosis is a pathological condition of the spinal channel with its concentric narrowing with presence of specific clinical syndrome. Absence of the clear unified radiological signs is the one of the basic problems of the lumbar spinal stenosis. PURPOSE: The authors seek to create method of assessment of the spinal canal narrowing degree, based on anatomical aspects of lumbar spinal stenosis. STUDY DESIGN: Development of diagnostic criteria based on analysis of a consecutive patients group and a control group. METHODS: Thirty seven patients (73 stenotic segments) with mean age 62,4 years old were involved in the study. Severity of clinical symptoms has been estimated by the measuring scales: Oswestry Disability Index (ODI) and Swiss Spinal Stenosis Questionnaire (SSQ). Mean number of the stenotic segments was 1.97. For all patients 8 radiological criteria have been measured. In the control group have been included 37 randomly selected patients (volunteers) in mean age of 53,4 years old without stenosis signs and narrowing of the spinal canal on the MRI imaging (73 segments total). Measurements were performed at the middle of intervertebral disc and facet joints level. RESULTS: For description of the state of spinal canal we offer the coefficient: ratio of the lateral canals total area to the cross-sectional area of the dural sac ("coefficient of stenosis"). Comparison of mean values of "coefficient of stenosis" for main and control groups showed statistically significant differences (t = -12,5; p < 0.0001). Strong statistically significant correlation with the ODI and SSS scales was revealed for the obtained coefficient (p <0.05). CONCLUSIONS: In our study new method of assessment of the spinal canal narrowing degree has been applied. Promising results have been obtained in a small group of patients. It is necessary to check the data on a large sample of recommendations for its clinical application. PMID- 25834778 TI - Structure-based identification of functional residues in the nucleoside-2'-O methylase domain of Bluetongue virus VP4 capping enzyme. AB - Bluetongue virus (BTV) encodes a single capping protein, VP4, which catalyzes all reactions required to generate cap1 structures on nascent viral transcripts. Further, structural analysis by X-ray crystallography indicated each catalytic reaction is arranged as a discrete domain, including a nucleoside-2'-O methyltransferase (2'-O MTase). In this study, we have exploited the structural information to identify the residues that are important for the catalytic activity of 2'-O MTase of VP4 and their influence on BTV replication. The effect of these mutations on GMP binding, guanylyltransferase (GTase) and methylase activities were analysed by a series of in vitro biochemical assays using recombinant mutant proteins; subsequently their effects on virus replication were assessed by introducing the same mutations in replicating viral genome using a reverse genetics system. Our data showed that single substitution mutations in the catalytic tetrad K-D-K-E were sufficient to abolish 2'-O MTase activity in vitro and to completely abrogate BTV replication in cells; although these mutants retained the upstream GMP binding, GTase and guanine-N7-methyltransferase activities. Mutations of the surrounding substrate-binding pocket (predicted to recruit cap0) had variable effects on in vitro VP4 capping activity. Only triple but not single substitution mutations of these residues in genome resulted in reduced virus replication kinetics. This is the first report investigating the importance of 2'-O MTase function for any member of the Reoviridae and highlights the significance of K-D-K-E tetrad and surrounding residues for the efficiency of 2'-O MTase activity and in turn, for virus fitness. PMID- 25834779 TI - Kruppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells. AB - Kruppel-like factor 4 (KLF4) functions as either a tumor suppressor or an oncogene in different tissues by regulating the expression of various genes. The aim of this study was to reveal the functions of KLF4 in regulating breast cancer apoptosis, proliferation, and tumorigenic progression. KLF4 expression levels in breast cancer tissues and breast cancer cell lines were found to be much lower than those in nontumorous tissues and a nontransformed mammary epithelial cell line. KLF4 was upregulated in the tumor necrosis factor-alpha-induced SK-BR-3 breast cancer cell apoptotic process. Overexpression of KLF4 promoted SK-BR-3 breast cancer cell apoptosis and suppressed SK-BR-3 cell tumorigenicity in vivo. PMID- 25834781 TI - A novel FBN2 mutation in a Chinese family with congenital contractural arachnodactyly. AB - Congenital contractural arachnodactyly (CCA, OMIM: 121050) is an autosomal dominant condition that shares skeletal features with Marfan syndrome (MFS, OMIM: 154700), including contractures, arachnodactyly, dolichostenomelia, scoliosis, crumpled ears and pectus deformities but excluding the ocular and cardiovascular complications that characterize MFS. These two similar syndromes result from mutations in two genes belonging to the fibrillin family, FBN1 and FBN2, respectively. We successfully identified a novel FBN2 mutation (C1406R) in a Chinese family with CCA for over five generations. This mutation was detected in the patients of this family but not in the seven unaffected family members or 100 normal individuals. SIFT and PolyPhen analyses suggested that the mutation was pathogenic. We identified a missense mutation in the calcium binding-epidermal growth factor (cbEGF)-like domain. Our study extends the mutation spectrum of CCA and confirms a relationship between mutations in the FBN2 gene and the clinical findings of CCA. PMID- 25834780 TI - Oligomer-dependent and -independent chaperone activity of sHsps in different stressed conditions. AB - A great number of studies have proven that sHsps protect cells by inhibiting protein aggregation under heat stress, while little is known about their function to protect cells under acid stress. In this work, we show that Hsp20.1 and Hsp14.1 oligomers dissociated to smaller oligomeric species or even dimer/monomer at low pH (pH 4.0 and pH 2.0), whereas no prominent quaternary structural changes were seen at 50 degrees C. Both oligomers and smaller oligomeric species exhibited abilities to suppress client aggregation at low pH and at 50 degrees C. These results suggest that sHsps may function in different modes in different stressed conditions. PMID- 25834782 TI - Analysis of a temperature-sensitive mutation in Uba1: Effects of the click reaction on subsequent immunolabeling of proteins involved in DNA replication. AB - In our previous study, a Met-to-Ile substitution at amino acid 256 in the catalytic domain of Uba1 was determined in temperature-sensitive CHO-K1 mutant tsTM3 cells, which exhibited chromosomal instability and cell-cycle arrest in the S to G2 phases with decreased DNA synthesis at the nonpermissive temperature, 39 degrees C. Mutant cells were also characterized by a significant decrease of Uba1 in the nucleus with decreased ubiquitination activity at 39 degrees C. Defects of ubiquitination activity in the nucleus resulted in an inappropriate balance between Cdt1 and geminin, a licensing factor of DNA replication and its inhibitor. In the present study, we found that the Cu(I)-catalyzed [3 + 2] cycloaddition (click) reaction inhibits the subsequent indirect immunolabeling of Cdt1 but allows for the detection of PCNA with nascent DNA. Using a procedure without the click reaction, we also demonstrated that Cdt1 remained close to active replication sites in tsTM3 cells at the nonpermissive temperature. Analysis of genome replication by DNA fiber spreading revealed that DNA synthesis continues for at least 10 h after incubation at 39 degrees C, suggesting that impaired ubiquitination in the nucleus, caused by the defect of Uba1, affected DNA replication only after a long delay. PMID- 25834783 TI - Functional characterization of a BCL10 isoform in the rainbow trout Oncorhynchus mykiss. AB - The complexes formed by BCL10, MALT1 and members of the family of CARMA proteins have recently been the focus of much attention because they represent a key mechanism for regulating activation of the transcription factor NF-kappaB. Here, we report the functional characterization of a novel isoform of BCL10 in the trout Oncorhynchus mykiss, which we named tBCL10. tBCL10 dimerizes, binds to components of the CBM complex and forms cytoplasmic filaments. Functionally, tBCL10 activates NF-kappaB transcription factor and is inhibited by the deubiquitinating enzyme A20. Finally, depletion experiments indicate that tBCL10 can functionally replace the human protein. This work demonstrates the evolutionary conservation of the mechanism of NF-kappaB activation through the CBM complex, and indicates that the rainbow trout O . mykiss can serve as a model organism to study this pathway. PMID- 25834784 TI - Characterization of G protein coupling mediated by the conserved D134(3.49) of DRY motif, M241(6.34), and F251(6.44) residues on human CXCR1. AB - CXCR1, a receptor for interleukin-8 (IL-8), plays an important role in defending against pathogen invasion during neutrophil-mediated innate immune response. Human CXCR1 is a G protein-coupled receptor (GPCR) with its characteristic seven transmembrane domains (TMs). Functional and structural analyses of several GPCRs have revealed that conserved residues on TM3 (including the highly conserved Asp Arg-Tyr (DRY) motif) and TM6 near intracellular loops contain domains critical for G protein coupling as well as GPCR activation. The objective of this study was to elucidate the role of critical amino acid residues on TM3 near intracellular loop 2 (i2) and TM6 near intracellular loop 3 (i3), including S132(3.47) (Baldwin location), D134(3.49), M241(6.34), and F251(6.44), in G protein coupling and CXCR1 activation. The results demonstrate that mutations of D134(3.49) at DRY motif of CXCR1 (D134N and D134V) completely abolished the ligand binding and functional response of the receptor. Additionally, point mutations at positions 241 and 251 between TM6 and i3 loop generated mutant receptors with modest constitutive activity via Galpha15 signaling activation. Our results show that D134(3.49) on the highly conserved DRY motif has a distinct role for CXCR1 compared to its homologues (CXCR2 and KSHV-GPCR) in G protein coupling and receptor activation. In addition, M241(6.34) and F251(6.44) along with our previously identified V247(6.40) on TM6 are spatially located in a "hot spot" likely essential for CXCR1 activation. Identification of these amino acid residues may be useful for elucidating mechanism of CXCR1 activation and designing specific antagonists for the treatment of CXCR1-mediated diseases. PMID- 25834785 TI - Insertion of sequences at the original provirus integration site of mouse ROSA26 locus using the CRISPR/Cas9 system. AB - Targeted transgenic mouse models, where an exogenous gene is inserted into a specified genomic locus to achieve its stable and reliable expression, have been widely used in biomedical research. However, the available methodologies for targeted insertion of sequences require many laborious steps that involve the use of embryonic stem (ES) cells. We recently developed Pronuclear Injection-based Targeted Transgenesis (PITT), a method that uses a recombinase-mediated cassette exchange (RMCE) to enable insertion of sequences at a predetermined genomic locus, such as ROSA26. The PITT technique uses fertilized eggs (instead of ES cells) collected from 'seed mice' that contain the RMCE landing pad. The PITT method can rapidly generate reliable targeted transgenic mice; it requires a seed mouse, which in our previous study was generated using ES cell targeting approaches. Here, we demonstrate that seed mice containing the RMCE landing pad can be developed rapidly by using the CRISPR/Cas9 system. One of the CRISPR targets tested in this study enabled the insertion of sequences precisely at the original ROSA26 provirus integration site. We anticipate that using a similar approach, PITT landing pad sequences can be rapidly and precisely inserted at other genomic loci to develop an array of PITT tools. This two-step strategy combines the best features of the two newer technologies-rapid creation of PITT landing pads using the CRISPR/Cas9 system and efficient and precise insertion of larger cassettes at the landing pads using PITT. This study also revealed that anomalous and mosaic sequence insertions can occur with the CRISPR/Cas9 system. PMID- 25834786 TI - How should we manage a patient with invasive mucoromycosis who develops life threatening reaction to amphotericin B? Report of two cases and literature review. AB - This report presents two cases of invasive rhino-orbital mucormycosis who had life-threatening reactions to amphotericin B. Both cases were treated with a combination of posaconazole-caspofungin favorably with no evidence of recurrence upon long-term follow-up. To our knowledge, this is the first report of successful treatment of invasive mucormycosis with azole-echinocandin combination. It may suggest that caspofungin exerts additional or even synergistic antimucoral effects to posaconazole. PMID- 25834787 TI - Calcium oxalate in the sputum may aid in the diagnosis of pulmonary aspergillosis: A report of two cases. AB - We present two cases of pulmonary aspergillosis in which calcium oxalate crystals in the sputum proved to be a useful diagnostic clue. In case 1, Aspergillus hyphae was not identified; however, calcium oxalate crystals were present, and chronic necrotizing pulmonary aspergillosis was diagnosed. In case 2, calcium oxalate was detected and Aspergillus fumigatus was identified later. Thus, the presence of calcium oxalate in the sputum may be an important indicator for an A. fumigatus infection. PMID- 25834788 TI - Elevation and vegetation determine Cryptosporidium oocyst shedding by yellow bellied marmots (Marmota flaviventris) in the Sierra Nevada Mountains. AB - Wildlife are increasingly recognized as important biological reservoirs of zoonotic species of Cryptosporidium that might contaminate water and cause human exposure to this protozoal parasite. The habitat range of the yellow-bellied marmot (Marmota flaviventris) overlaps extensively with the watershed boundaries of municipal water supplies for California communities along the foothills of the Sierra Nevada. We conducted a cross-sectional epidemiological study to estimate the fecal shedding of Cryptosporidium oocysts by yellow-bellied marmots and to quantify the environmental loading rate and determine risk factors for Cryptosporidium fecal shedding in this montane wildlife species. The observed proportion of Cryptosporidium positive fecal samples was 14.7% (33/224, positive number relative to total number samples) and the environmental loading rate was estimated to be 10,693 oocysts animal(-1) day(-1). Fecal shedding was associated with the elevation and vegetation status of their habitat. Based on a portion of the 18s rRNA gene sequence of 2 isolates, the Cryptosporidium found in Marmota flaviventris were 99.88%-100% match to multiple isolates of C. parvum in the GenBank. PMID- 25834789 TI - Diversity of Cryptosporidium in brush-tailed rock-wallabies (Petrogale penicillata) managed within a species recovery programme. AB - Host-parasite relationships are likely to be impacted by conservation management practices, potentially increasing the susceptibility of wildlife to emerging disease. Cryptosporidium, a parasitic protozoan genus comprising host-adapted and host-specific species, was used as an indicator of parasite movement between populations of a threatened marsupial, the brush-tailed rock-wallaby (Petrogale penicillata). PCR screening of faecal samples (n = 324) from seven wallaby populations across New South Wales, identified Cryptosporidium in 7.1% of samples. The sampled populations were characterised as captive, supplemented and wild populations. No significant difference was found in Cryptosporidium detection between each of the three population categories. The positive samples, detected using 18S rRNA screening, were amplified using the actin and gp60 loci. Multi-locus sequence analysis revealed the presence of Cryptosporidium fayeri, a marsupial-specific species, and C. meleagridis, which has a broad host range, in samples from the three population categories. Cryptosporidium meleagridis has not been previously reported in marsupials and hence the pathogenicity of this species to brush-tailed rock-wallabies is unknown. Based on these findings, we recommend further study into Cryptosporidium in animals undergoing conservation management, as well as surveying wild animals in release areas, to further understand the diversity and epidemiology of this parasite in threatened wildlife. PMID- 25834790 TI - Zonisamide-induced acute kidney injury. PMID- 25834791 TI - The economic burden of traumatic brain injury due to fatal traffic accidents in shahid rajaei trauma hospital, shiraz, iran. AB - BACKGROUND: Traumatic Brain Injuries (TBIs) as a result of traffic accidents are one of the major causes of deaths, which lead to the loss of individuals' productive and working years of life. OBJECTIVES: This study aimed to calculate the economic burden of traumatic brain injuries in fatal crashes at Shahid Rajaei Trauma Hospital, Shiraz, Iran for a period of five years. PATIENTS AND METHODS: In this descriptive, cross-sectional study the population included people who had died as a result of TBIs during 2009 to 2013 in Shiraz Shahid Rajaei Trauma Hospital. Cost and demographic data were obtained from the participants' medical records using data gathering forms, and some other information was also collected via telephone calls to the victims' families. Economic burden of TBIs due to traffic accidents, which led to death, was estimated using the human capital as direct costs of treatment, and the number of potential years of life lost and lost productivity as indirect costs. RESULTS: Deaths resulting from TBIs due to traffic accidents in Shiraz imposed 6.2 billion Rials (511000 USD) of hospital costs, 6390 potential years of life lost, and 506 billion Rials (20 million USD) of productivity lost. In the present study, the mean age of the individuals who died was 38.4 +/- 19.41 and the productivity lost per capita was 1.8 billion Rials (73000 USD). CONCLUSIONS: The findings of this study indicated that the economic burden of TBIs was high in fatal accidents in Fars Province so that it was equivalent to 0.00011% of Iran's Gross Domestic Product (GDP) in 2013. Therefore, more attention has to be paid to the rules to prevent the fatal accidents. PMID- 25834792 TI - Bilateral symptomatic discoid medial meniscus of the knee: a case report and review of literature. AB - INTRODUCTION: A discoid medial meniscus is a rare pathology of the knee joint, and is even rarer when it presents bilaterally with clinical symptoms. CASE PRESENTATION: We present the case of a 38-year-old female with symptomatic bilateral discoid medial meniscus. Magnetic Resonance Imaging (MRI) showed complete discoid meniscus in one knee and incomplete, on the other side. The MRI findings were confirmed on arthroscopy, with horizontal cleavage tear in both knees. Arthroscopic partial meniscectomies of both menisci were performed. CONCLUSIONS: The patient had an excellent functional outcome at the most recent follow-up, with no recurrence of symptoms and full range of movements. PMID- 25834793 TI - Establishing an integrated trauma system in iran: the time of translating information into action. PMID- 25834794 TI - Retracted: epidemiological pattern of bullying among school children in mazandaran province, iran. AB - [This retracts the article DOI: 10.5812/atr.22551.]. PMID- 25834795 TI - Personalized treatment of hepatitis B. AB - There are seven approved drugs for treatment of hepatitis B. Professional guidelines provide a framework for managing patients but these guidelines should be interpreted in the context of the individual patient's clinical and social circumstances. Personalized management of hepatitis B can be applied based on prediction of the individual patient's risk of cirrhosis and hepatocellular carcinoma to guide the frequency and intensity of monitoring and urgency of treatment. It can also be applied to decisions regarding when to start treatment, which drug to use, and when to stop based on the individual patient's disease characteristics, preference, comorbidities and other mitigating circumstances. PMID- 25834796 TI - Clinical implications of advances in liver regeneration. AB - Remarkable advances have been made recently in the area of liver regeneration. Even though liver regeneration after liver resection has been widely researched, new clinical applications have provided a better understanding of the process. Hepatic damage induces a process of regeneration that rarely occurs in normal undamaged liver. Many studies have concentrated on the mechanism of hepatocyte regeneration following liver damage. High mortality is usual in patients with terminal liver failure. Patients die when the regenerative process is unable to balance loss due to liver damage. During disease progression, cellular adaptations take place and the organ microenvironment changes. Portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy are relatively recent techniques exploiting the remarkable progress in understanding liver regeneration. Living donor liver transplantation is one of the most significant clinical outcomes of research on liver regeneration. Another major clinical field involving liver regeneration is cell therapy using adult stem cells. The aim of this article is to provide an outline of the clinical approaches being undertaken to examine regeneration in liver diseases. PMID- 25834797 TI - The cost of liver disease in Korea: methodology, data, and evidence. AB - BACKGROUND/AIMS: This study introduces methods for estimating the cost of liver disease and presents useful and reliable sources of data. The available evidence on the costs associated with liver disease is also discussed. METHODS: Costing methodology can be used to identify, measure, and value relevant resources incurred during the care of patients with liver diseases. It adjusts for discounting, skewed distribution, and missing or censored cost data. The human capital approach for productivity cost assumes that deceased patients would have lived to a normal expected life expectancy, and have earned a salary in line with the current age profile of wages, in order to measure potential earnings lost due to premature death or job loss. EVIDENCE: The number of deaths due to liver cancer (C22) increased from 6,384 in 1983 to 11,405 in 2013, while deaths due to other liver diseases (K70-K76) increased from 12,563 in 1983 to 13,458 in 1995, and then declined to 6,665 in 2013. According to the Global Burden of Disease study conducted by the World Health Organization, liver cancer caused 325,815 disability-adjusted life years (DALYs), and cirrhosis of the liver caused 206,917 DALYs in 2012. The total cost of liver disease was estimated at 1,941 billion Korean won in 2001 and 5,689 billion Korean won in 2008. Much of this cost is attributable to productivity cost, and especially that of economically active men. CONCLUSIONS: The economic burden of liver disease is immense because of the associated high mortality and morbidity, especially among the economically active population. This indicates the need to prioritize the development of appropriate health interventions. PMID- 25834798 TI - Regression of liver cirrhosis: orthodoxy or paradigm shift? PMID- 25834799 TI - Efficacy of prolonged entecavir monotherapy in treatment-naive chronic hepatitis B patients exhibiting a partial virologic response to entecavir. AB - BACKGROUND/AIMS: The optimal management of patients exhibiting a partial virologic response (PVR) to entecavir (ETV) has not been determined. The aim of this study was to determine the long-term efficacy of prolonged ETV monotherapy in treatment-naive chronic hepatitis B (CHB) patients exhibiting a PVR to ETV therapy. METHODS: This study included 364 treatment-naive CHB patients treated with ETV for >=48 weeks and who received continuous ETV monotherapy for >=96 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log(10) IU/mL from baseline but with detectable HBV DNA by real-time PCR assay at week 48. RESULTS: Fifty-two of the 364 patients (14.3%) showed a PVR. Among them, 41 patients received continuous ETV monotherapy for >=96 weeks (median duration 144 weeks, range 96-312 weeks), and 40 of these patients (95%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged ETV monotherapy (median duration 78 weeks, range 60-288 weeks). The cumulative probabilities of a VR at weeks 96, 144, and 192 from treatment initiation were 78.0%, 92.7%, and 95.1%, respectively. The VR rate was 97.2% (35/36) in HBeAg positive patients and 100% (5/5) in HBeAg-negative patients. In multivariate analysis, HBeAg positivity (odds ratio [OR], 9.231; 95% confidence interval [CI], 1.03-82.91; P=0.047) and a high baseline HBV DNA level (OR, 0.170; 95% CI, 0.08 0.37; P=0.000) were independently associated with a delayed virologic response. No patient developed genotypic resistance to ETV during follow-up. CONCLUSIONS: Long-term ETV monotherapy is effective for achieving a VR in treatment-naive CHB patients exhibiting a PVR to ETV. HBeAg positivity and high baseline HBV DNA level were independently associated with a delayed virologic response. PMID- 25834800 TI - The factors associated with longitudinal changes in liver stiffness in patients with chronic hepatitis B. AB - BACKGROUND/AIMS: Liver stiffness (LS) as assessed by transient elastography (TE) can change longitudinally in patients with chronic hepatitis B (CHB). The aim of this study was to identify the factors that improve LS. METHODS: Between April 2007 and December 2012, 151 patients with CHB who underwent two TE procedures with an interval of about 2 years were enrolled. Ninety-six of the 151 patients were treated with nucleos(t)ide analogues [the antiviral therapy (+) group], while the remaining 55 patients were not [the antiviral therapy (-) group]. The two groups of patients were stratified according to whether they exhibited an improvement or a deterioration in LS during the study period (defined as an LS change of <=0 or >0 kPa, respectively, over a 1-year period), and their data were compared. RESULTS: No differences were observed between the antiviral therapy (+) and (-) groups with respect to either their clinical characteristics or their initial LS. The observed LS improvement was significantly greater in the antiviral therapy (+) group than in the antiviral therapy (-) group (-3.0 vs. 0.98 kPa, P=0.011). In the antiviral therapy (+) group, the initial LS was higher in the LS improvement group (n=63) than in the LS deterioration group (n=33; 7.9 vs. 4.8 kPa, P<0.001). However, there were no differences in any other clinical characteristic. In the antiviral therapy (-) group, the initial LS was also higher in the LS improvement group (n=29) than in the LS deterioration group (n=26; 8.3 vs. 6.5 kPa, P=0.021), with no differences in any other clinical characteristic. CONCLUSIONS: A higher initial LS was the only factor associated with LS improvement in patients with CHB in this study. PMID- 25834801 TI - Tenofovir disoproxil fumarate monotherapy for nucleos(t)ide analogue-naive and nucleos(t)ide analogue-experienced chronic hepatitis B patients. AB - BACKGROUND/AIMS: This study investigated the antiviral effects of tenofovir disoproxil fumarate (TDF) monotherapy in nucleos(t)ide analogue (NA)-naive and NA experienced chronic hepatitis B (CHB) patients. METHODS: CHB patients treated with TDF monotherapy (300 mg/day) for >=12 weeks between December 2012 and July 2014 at a single center were retrospectively enrolled. Clinical, biochemical, and virological parameters were assessed every 12 weeks. RESULTS: In total, 136 patients (median age 49 years, 96 males, 94 HBeAg positive, and 51 with liver cirrhosis) were included. Sixty-two patients were nucleos(t)ide (NA)-naive, and 74 patients had prior NA therapy (NA-exp group), and 31 patients in the NA-exp group had lamivudine (LAM)-resistance (LAM-R group). The baseline serum hepatitis B virus (HBV) DNA level was 4.9+/-2.3 log IU/mL (mean+/-SD), and was higher in the NA-naive group than in the NA-exp and LAM-R groups (5.9+/-2.0 log IU/mL vs 3.9+/-2.0 log IU/mL vs 4.2+/-1.7 log IU/mL, P<0.01). The complete virological response (CVR) rate at week 48 in the NA-naive group (71.4%) did not differ significantly from those in the NA-exp (71.3%) and LAM-R (66.1%) groups. In multivariate analysis, baseline serum HBV DNA was the only predictive factor for a CVR at week 48 (hazard ratio, 0.809; 95% confidence interval, 0.729-0.898), while the CVR rate did not differ with the NA experience. CONCLUSIONS: TDF monotherapy was effective for CHB treatment irrespective of prior NA treatment or LAM resistance. Baseline serum HBV DNA was the independent predictive factor for a CVR. PMID- 25834802 TI - Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. AB - BACKGROUND/AIMS: Silibinin, the main component of silymarin, is used as a hepatoprotectant and exhibits anticancer effects against various cancer cells. This study evaluated the effects of a combination of silibinin with either gefitinib or sorafenib on hepatocellular carcinoma (HCC) cells. METHODS: Several different human HCC cell lines were used to test the growth-inhibiting effects and cell toxicity of silibinin both alone and in combination with either gefitinib or sorafenib. The cell viability and growth inhibition were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and a colony-forming assay. Furthermore, changes in epidermal growth factor receptor (EGFR)-related signals were evaluated by Western blot analysis. RESULTS: Gefitinib, sorafenib, and silibinin individually exhibited dose-dependent antiproliferative effects on HCC cells. Combined treatment with silibinin enhanced the gefitinib-induced growth-inhibiting effects in some HCC cell lines. The combination effect of gefitinib and silibinin was synergistic in the SNU761 cell line, but was only additive in the Huh-BAT cell line. The combination effect may be attributable to inhibition of EGFR-dependent Akt signaling. Enhanced growth-inhibiting effects were also observed in HCC cells treated with a combination of sorafenib and silibinin. CONCLUSIONS: Combined treatment with silibinin enhanced the growth-inhibiting effects of both gefitinib and sorafenib. Therefore, the combination of silibinin with either sorafenib or gefitinib could be a useful treatment approach for HCC in the future. PMID- 25834803 TI - Fibroblast growth factor receptor isotype expression and its association with overall survival in patients with hepatocellular carcinoma. AB - BACKGROUND/AIMS: Fibroblast growth factor signaling is involved in hepatocarcinogenesis. The aim of this study was to determine the fibroblast growth factor receptor (FGFR) isotype expression in hepatocellular carcinoma (HCC) and neighboring nonneoplastic liver tissue, and elucidate its prognostic implications. METHODS: Immunohistochemical staining of FGFR1, -2, -3, and -4 was performed in the HCCs and paired neighboring nonneoplastic liver tissue of 870 HCC patients who underwent hepatic resection. Of these, clinical data for 153 patients who underwent curative resection as a primary therapy were reviewed, and the relationship between FGFR isotype expression and overall survival was evaluated (development set). This association was also validated in 73 independent samples (validation set) by Western blot analysis. RESULTS: FGFR1, 2, -3, and -4 were expressed in 5.3%, 11.1%, 3.8%, and 52.7% of HCCs, respectively. Among the development set of 153 patients, FGFR2 positivity in HCC was associated with a significantly shorter overall survival (5-year survival rate, 35.3% vs. 61.8%; P=0.02). FGFR2 expression in HCC was an independent predictor of a poor postsurgical prognosis (hazard ratio, 2.10; P=0.02) in the development set. However, the corresponding findings were not statistically significant in the validation set. CONCLUSIONS: FGFR2 expression in HCC could be a prognostic indicator of postsurgical survival. PMID- 25834804 TI - Alteration of laboratory findings after radiofrequency ablation of hepatocellular carcinoma: relationship to severity of the underlying liver disease and the ablation volume. AB - BACKGROUND/AIMS: To investigate sequential changes in laboratory markers after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) and the relationship of these changes to the severity of the underlying liver disease. METHODS: This retrospective analysis included 65 patients (44 males, 21 females) who underwent RFA of HCC. Hematologic and biochemical markers were assessed at the pre-RFA period and 1 day, 2-3 days, and 1-2 weeks after RFA. We classified the subjects into two groups: Child-Pugh A (n=41) and Child-Pugh B (n=24). The ablative margin volume (AMV) of each patient was measured. We analyzed the changes in laboratory profiles from the baseline, and investigated whether these laboratory changes were correlated with the AMV and the Child-Pugh classification. RESULTS: Most of the laboratory values peaked at 2-3 days after RFA. AMV was significantly correlated with changes in WBC count, hemoglobin level, and serum total bilirubin level (Pearson's correlation coefficient, 0.324 0.453; P<0.05). The alanine aminotransferase (ALT) level varied significantly over time (P=0.023). CONCLUSIONS: Most of the measured laboratory markers changed from baseline, peaking at 2-3 days. The ALT level was the only parameter for which there was a significant difference after RFA between Child-Pugh A and B patients: it increased significantly more in the Child-Pugh A patients. PMID- 25834805 TI - A case of primary hepatic actinomycosis: an enigmatic inflammatory lesion of the liver. AB - Primary hepatic actinomycosis is one of the chronic abscess-forming infections of the liver. Accurate diagnosis is frequently delayed due to its indolent course and nonspecific clinical and radiological manifestations. We report a case of a 57-year-old man presenting with asymptomatic multiple hepatic masses on follow-up abdominal computed tomography performed 1 year after stomach cancer surgery. Although a percutaneous liver biopsy procedure was conducted twice in order to obtain confirmative pathology, only a nonspecific organizing abscess with plasma cell infiltration was revealed, without identification of any organism in the tissue cultures. Ultimately, actinomycosis was diagnosed following the detection of sulfur granules on open surgical biopsied tissue. This case suggests that primary hepatic actinomycosis should be considered as one of the possible causes for enigmatic inflammatory lesions of the liver. PMID- 25834806 TI - Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient. AB - Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC. PMID- 25834807 TI - Budd-Chiari syndrome with multiple large regenerative nodules. PMID- 25834809 TI - Erratum. AB - [This corrects the article on p. 355 in vol. 20, PMID: 25548741.][This corrects the article on p. 368 in vol. 20, PMID: 25548743.]. PMID- 25834808 TI - Recent advances in the imaging of hepatocellular carcinoma. AB - The role of imaging is crucial for the surveillance, diagnosis, staging and treatment monitoring of hepatocellular carcinoma (HCC). Over the past few years, considerable technical advances were made in imaging of HCCs. New imaging technology, however, has introduced new challenges in our clinical practice. In this article, the current status of clinical imaging techniques for HCC is addressed. The diagnostic performance of imaging techniques in the context of recent clinical guidelines is also presented. PMID- 25834810 TI - Comprehensive Analysis of Transcriptome Sequencing Data in the Lung Tissues of COPD Subjects. AB - Background and Objectives. Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airflow limitation. Although airway inflammation and oxidative stress are known to be important in the pathogenesis of COPD, the mechanism underlying airflow obstruction is not fully understood. Gene expression profiling of lung tissue was performed to define the molecular pathways that are dysregulated in COPD. Methods. RNA was isolated from lung tissues obtained from 98 subjects with COPD and 91 control subjects with normal spirometry. The RNA samples were processed with RNA-seq using the HiSeq 2000 system. Genes expressed differentially between the two groups were identified using Student's t-test. Results. After filtering for genes with zero counts and noncoding genes, 16,676 genes were evaluated. A total of 2312 genes were differentially expressed between the lung tissues of COPD and control subjects (false discovery rate corrected q < 0.01). The expression of genes related to oxidative phosphorylation and protein catabolism was reduced and genes related to chromatin modification were dysregulated in lung tissues of COPD subjects. Conclusions. Oxidative phosphorylation, protein degradation, and chromatin modification were the most dysregulated pathways in the lung tissues of COPD subjects. These findings may have clinical and mechanistic implications in COPD. PMID- 25834811 TI - Genetic vectors as a tool in association studies: definitions and application for study of rheumatoid arthritis. AB - To identify putative relations between different genetic factors in the human genome in the development of common complex disease, we mapped the genetic data to an ensemble of spin chains and analysed the data as a quantum system. Each SNP is considered as a spin with three states corresponding to possible genotypes. The combined genotype represents a multispin state, described by the product of individual-spin states. Each person is characterized by a single genetic vector (GV) and individuals with identical GVs comprise the GV group. This consolidation of genotypes into GVs provides integration of multiple genetic variants for a single statistical test and excludes ambiguity of biological interpretation known for allele and haplotype associations. We analyzed two independent cohorts, with 2633 rheumatoid arthritis cases and 2108 healthy controls, and data for 6 SNPs from the HTR2A locus plus shared epitope allele. We found that GVs based on selected markers are highly informative and overlap for 98.3% of the healthy population between two cohorts. Interestingly, some of the GV groups contain either only controls or only cases, thus demonstrating extreme susceptibility or protection features. By using this new approach we confirmed previously detected univariate associations and demonstrated the most efficient selection of SNPs for combined analyses for functional studies. PMID- 25834812 TI - Own experience in treatment of patients with penile cancer using photodynamic therapy. AB - Penile cancer is a rare pathology. For penile cancer surgical treatment, radiotherapy, chemotherapy, and combined modality treatment are available. Because of great importance of this organ for mental condition of patient, the development of organ-preserving methods allowing to minimize impact on patient's quality of life without compromising of oncological results is desirable. In the Center of Laser and Photodynamic diagnosis and treatment of tumors in P.A. Herzen Moscow Cancer Research Institute the methods of photodynamic therapy in patients with penile cancer have been developed. From 2011 to 2013 the treatment was conducted in 11 patients with precancer and cancer of penile. The average age was 56.6. According to morphological diagnosis photodynamic therapy (PDT) was performed using two methods. One method included topical application of agent for PDT and the second intravenous administration of photosensitizer. For topical application alasens was used and for intravenous injection we applied radachlorine. All patients had no complications. Complete regression was achieved in 9 patients, and partial regression in 2. Thus, the results showed that photodynamic therapy for penile cancer stage Tis-1N0M0 permits performing organ preserving treatment with satisfactory oncological results and no impairment of patient's quality of life. PMID- 25834813 TI - Technological advances in instrumental assessment in rehabilitation. PMID- 25834814 TI - Incidence and diversity of antimicrobial multidrug resistance profiles of uropathogenic bacteria. AB - The aim of this study was to assess the most frequent multidrug resistant (MDR) profiles of the main bacteria implicated in community-acquired urinary tract infections (UTI). Only the MDR profiles observed in, at least, 5% of the MDR isolates were considered. A quarter of the bacteria were MDR and the most common MDR profile, including resistance to penicillins, quinolones, and sulfonamides (antibiotics with different mechanisms of action, all mainly recommended by the European Association of Urology for empirical therapy of uncomplicated UTI), was observed, alone or in association with resistance to other antimicrobial classes, in the main bacteria implicated in UTI. The penicillin class was included in all the frequent MDR profiles observed in the ten main bacteria and was the antibiotic with the highest prescription during the study period. The sulfonamides class, included in five of the six more frequent MDR profiles, was avoided between 2000 and 2009. The results suggest that the high MDR percentage and the high diversity of MDR profiles result from a high prescription of antibiotics but also from antibiotic-resistant genes transmitted with other resistance determinants on mobile genetic elements and that the UTI standard treatment guidelines must be adjusted for the community of Aveiro District. PMID- 25834815 TI - Antimicrobial peptides: current and potential applications in biomedical therapies. PMID- 25834816 TI - A functional variant at miR-520a binding site in PIK3CA alters susceptibility to colorectal cancer in a Chinese Han population. AB - An increasing body of evidence has indicated that polymorphisms in the miRNA binding site of target gene can alter the ability of miRNAs to bind their target genes and modulate the risk of cancer. We aimed to investigate the association between a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3'-UTR and the risk of colorectal cancer (CRC) in a Chinese Han population. The polymorphism rs141178472 was analyzed in a case-control study, including 386 CRC patients and 394 age- and sex-matched controls; the relationship between the polymorphism and the risk of colorectal cancer was examined. Individuals carrying the rs141178472 CC genotype or C allele had an increased risk of developing CRC (CC versus TT, OR (95% CI): 1.716 (1.084-2.716), P = 0.022; C versus T, OR (95% CI): 1.258 (1.021 1.551), P = 0.033). Furthermore, the expression of PIK3CA was detected in the peripheral blood mononucleated cell of CRC patients, suggesting that mRNA levels of PIK3CA might be associated with SNP rs141178472. These findings provide evidence that a miR-520a binding site polymorphism rs141178472 in the PIK3CA 3' UTR may play a role in the etiology of CRC. PMID- 25834817 TI - TNF-related apoptosis inducing ligand in ocular cancers and ocular diabetic complications. AB - TNF-related apoptosis inducing ligand (TRAIL) is an intensively studied cytokine, in particular for its anticancer activity. The discovery that conjunctival sac fluid contains extremely high levels of soluble TRAIL as compared to other body fluids suggested important implications in the context of the immunological surveillance of the eye, in particular of the anterior surface. In this review, we discuss the potential physiopathologic and therapeutic role of the TRAIL/TRAIL receptor system in a variety of ocular cancers. Moreover, since an increasing amount of data has indicated the important biological activities of the TRAIL/TRAIL receptor systems also in a completely different pathologic context such as diabetes mellitus, in the second part of this review we summarize the currently available data on the involvement of TRAIL in the ocular complications of diabetes mellitus as modulator of the inflammatory and angiogenic response in the eye. PMID- 25834818 TI - The effect of iloprost and N-acetylcysteine on skeletal muscle injury in an acute aortic ischemia-reperfusion model: an experimental study. AB - OBJECTIVE: The objective of this study was to examine the effects of iloprost and N-acetylcysteine (NAC) on ischemia-reperfusion (IR) injuries to the gastrocnemius muscle, following the occlusion-reperfusion period in the abdominal aorta of rats. MATERIALS AND METHODS: Forty male Sprague-Dawley rats were randomly divided into four equal groups. Group 1: control group. Group 2 (IR): aorta was occluded. The clamp was removed after 1 hour of ischemia. Blood samples and muscle tissue specimens were collected following a 2-hour reperfusion period. Group 3 (IR + iloprost): during a 1-hour ischemia period, iloprost infusion was initiated from the jugular catheter. During a 2-hour reperfusion period, the iloprost infusion continued. Group 4 (IR + NAC): similar to the iloprost group. FINDINGS: The mean total oxidant status, CK, and LDH levels were highest in Group 2 and lowest in Group 1. The levels of these parameters in Group 3 and Group 4 were lower compared to Group 2 and higher compared to Group 1 (P < 0.05). The histopathological examination showed that Group 3 and Group 4, compared to Group 2, had preserved appearance with respect to hemorrhage, necrosis, loss of nuclei, infiltration, and similar parameters. CONCLUSION: Iloprost and NAC are effective against ischemia-reperfusion injury and decrease ischemia-related tissue injury. PMID- 25834820 TI - Incidence of alpha-globin gene defect in the Lebanese population: a pilot study. AB - BACKGROUND: It is well established that the Mediterranean and Arab populations are at high risk for thalassemias in general and for alpha-thalassemia in particular. Yet, reports on alpha-thalassemia in Lebanon are still lacking. In this study, we aim at assessing the incidence of alpha-thalassemia in the Lebanese population. METHODS: 230 newborns' dried blood cards remaining from routine neonatal screening at the American University of Beirut Medical Center were collected for DNA extraction. Samples were screened for the 21 most common alpha-globin deletions and point mutations reported worldwide, through multiplex Polymerase Chain Reaction (PCR) and Reverse-Hybridization technique. RESULTS: Upon analyses, the carrier rate of alpha-thalassemia was found to be 8%. Two mutations detected the -alpha(3,7) single gene deletion found in 75% of cases and the nongene deletion alpha2 IVS1 [-5nt] in the remaining samples. CONCLUSION: This study is the first dedicated to investigate alpha-thalassemia trait incidence in Lebanon. Data obtained demonstrates a high carrier rate in a relatively, highly consanguineous population; it also highlighted the presence of two common mutations. These results may be of an important impact on premarital and newborn screening policies in our country. PMID- 25834819 TI - TRAF1/C5 but not PTPRC variants are potential predictors of rheumatoid arthritis response to anti-tumor necrosis factor therapy. AB - BACKGROUND: The aim of our work was to replicate, in a Southern European population, the association reported in Northern populations between PTPRC locus and response to anti-tumor necrosis factor (anti-TNF) treatment in rheumatoid arthritis (RA). We also looked at associations between five RA risk alleles and treatment response. METHODS: We evaluated associations between anti-TNF treatment responses assessed by DAS28 change and by EULAR response at six months in 383 Portuguese patients. Univariate and multivariate linear and logistic regression analyses were performed. In a second step to confirm our findings, we pooled our population with 265 Spanish patients. RESULTS: No association was found between PTPRC rs10919563 allele and anti-TNF treatment response, neither in Portuguese modeling for several clinical variables nor in the overall population combining Portuguese and Spanish patients. The minor allele for RA susceptibility, rs3761847 SNP in TRAF1/C5 region, was associated with a poor response in linear and logistic univariate and multivariate regression analyses. No association was observed with the other allellic variants. Results were confirmed in the pooled analysis. CONCLUSION: This study did not replicate the association between PTPRC and the response to anti-TNF treatment in our Southern European population. We found that TRAF1/C5 risk RA variants potentially influence anti-TNF treatment response. PMID- 25834821 TI - Soluble c-Met is a reliable and sensitive marker to detect c-Met expression level in lung cancer. AB - c-Met has been demonstrated as an attractive target in lung cancer therapy. Current studies showed that detection of c-Met status in tumor is critical in Met targeted therapy. However not all patients are suitable for tissue sample collection. It is important to discover novel surrogate markers to detect c-Met status. In the study, soluble c-Met (s-Met) in plasma from 146 Chinese lung cancer patients and 40 disease-free volunteers was measured by enzyme-linked immunosorbent. In parallel, expression of c-Met in those tumors was also assessed by immunohistochemistry. Results showed that, in 146 lung cancer patients, 93 were c-Met expression positive and 74 of 93 were overexpressed. In c-Met overexpressed patients, plasma s-Met was significantly increased. And further studies showed that plasma s-Met linearly correlated with c-Met expression in tumor. After tumor was removed in Met-overexpressed patients via resection, plasma s-Met significantly decreased to basal level. In addition, plasma s-Met showed to be poorly correlated with tumor size in Met-overexpressed patients. These results demonstrated that plasma s-Met is a sensitive and reliable marker to detect c-Met overexpression in lung cancers, and it is independent of tumor volume. PMID- 25834822 TI - Comparative analysis of classifiers for developing an adaptive computer-assisted EEG analysis system for diagnosing epilepsy. AB - Computer-assisted analysis of electroencephalogram (EEG) has a tremendous potential to assist clinicians during the diagnosis of epilepsy. These systems are trained to classify the EEG based on the ground truth provided by the neurologists. So, there should be a mechanism in these systems, using which a system's incorrect markings can be mentioned and the system should improve its classification by learning from them. We have developed a simple mechanism for neurologists to improve classification rate while encountering any false classification. This system is based on taking discrete wavelet transform (DWT) of the signals epochs which are then reduced using principal component analysis, and then they are fed into a classifier. After discussing our approach, we have shown the classification performance of three types of classifiers: support vector machine (SVM), quadratic discriminant analysis, and artificial neural network. We found SVM to be the best working classifier. Our work exhibits the importance and viability of a self-improving and user adapting computer-assisted EEG analysis system for diagnosing epilepsy which processes each channel exclusive to each other, along with the performance comparison of different machine learning techniques in the suggested system. PMID- 25834823 TI - Inhibition of osteoclast activation by phloretin through disturbing alphavbeta3 integrin-c-Src pathway. AB - This study was to explore the sequential signaling of disorganization of the actin cytoskeletal architecture by phloretin. RAW 264.7 macrophages were incubated with 1-20 MUM phloretin for 5 days in the presence of RANKL. C57BL/6 mice were ovariectomized (OVX) and orally treated with 10 mg/kg phloretin once a day for 8 weeks. Phloretin allayed RANKL stimulated formation of actin podosomes with the concomitant retardation of the vinculin activation. Oral administration of phloretin suppressed the induction of femoral gelsolin and vinculin in OVX mice. The RANK-RANKL interaction resulted in the alphavbeta3 integrin induction, which was demoted by phloretin. The RANKL induction of actin rings and vacuolar type H(+)-ATPase entailed Pyk2 phosphorylation and c-Src and c-Cbl induction, all of which were blunted by phloretin. Similar inhibition was also observed in phloretin-exposed OVX mouse femoral bone tissues with decreased trabecular collagen formation. Phloretin suppressed the paxillin induction in RANKL activated osteoclasts and in OVX epiphyseal bone tissues. Also, phloretin attenuated the Syk phosphorylation and phospholipase Cgamma induction by RANKL in osteoclasts. These results suggest that phloretin was an inhibitor of actin podosomes and sealing zone, disrupting alphavbeta3 integrin-c-Src-Pyk2/Syk signaling pathway for the regulation of actin cytoskeletal organization in osteoclasts. PMID- 25834824 TI - Novel mutations in the transcriptional activator domain of the human TBX20 in patients with atrial septal defect. AB - BACKGROUND: The relevance of TBX20 gene in heart development has been demonstrated in many animal models, but there are few works that try to elucidate the effect of TBX20 mutations in human congenital heart diseases. In these studies, all missense mutations associated with atrial septal defect (ASD) were found in the DNA-binding T-box domain, none in the transcriptional activator domain. METHODS: We search for TBX20 mutations in a group of patients with ASD or ventricular septal defect (VSD) using the High Resolution Melting (HRM) method and DNA sequencing. RESULTS: We report three missense mutations (Y309D, T370O, and M395R) within the transcriptional activator domain of human TBX20 that were associated with ASD. CONCLUSIONS: This is the first association of TBX20 transcriptional activator domain missense mutations with ASD. These findings could have implications for diagnosis, genetic screening, and patient follow-up. PMID- 25834826 TI - Gold nanotheranostics: photothermal therapy and imaging of Mucin 7 conjugated antibody nanoparticles for urothelial cancer. AB - OBJECTIVE: To kill urothelial cancer cells while preserving healthy cells, this study used photothermal therapy (PTT). PTT techniques target urothelial cancer cells using gold nanoparticles (GNPs) and a green light laser. MATERIALS AND METHODS: The GNPs were conjugated with anti-Mucin 7 antibodies, which acted as a probe for targeting tumor cells. Conjugated GNPs were exposed to a green light laser (532 nm) with sufficient thermal energy to kill the transitional cell carcinomas (TCCs). RESULTS: According to our results, nanoparticles conjugated with Mucin 7 antibodies damaged all types of cancer cells (MBT2, T24, 9202, and 8301) at relatively low energy levels (i.e., 500 laser shots at 10 W/cm(2) in power, 1.6 Hz in frequency, and 300 ms in duration). Nonconjugated nanoparticles required 30 W/cm(2) or more to achieve the same effect. Cell damage was directly related to irradiation time and applied laser energy. CONCLUSIONS: The minimally invasive PTT procedure combined with Mucin 7 targeted GNPs is able to kill cancer cells and preserve healthy cells. The success of this treatment technique can likely be attributed to the lower amount of energy required to kill targeted cancer cells compared with that required to kill nontargeted cancer cells. Our in vitro pilot study yielded promising results; however, additional animal studies are required to confirm these findings. PMID- 25834825 TI - Endocrine and bone complications in beta-thalassemia intermedia: current understanding and treatment. AB - Thalassemia intermedia (TI), also known as nontransfusion dependent thalassemia (NTDT), is a type of thalassemia where affected patients do not require lifelong regular transfusions for survival but may require occasional or even frequent transfusions in certain clinical settings and for defined periods of time. NTDT encompasses three distinct clinical forms: beta-thalassemia intermedia (beta-TI), Hb E/beta-thalassemia, and alpha-thalassemia intermedia (Hb H disease). Over the past decade, our understanding of the molecular features, pathophysiology, and complications of NTDT particularly beta-TI has increased tremendously but data on optimal treatment of disease and its various complications are still lacking. In this paper, we shall review a group of commonly encountered complications in beta TI, mainly endocrine and bone complications. PMID- 25834827 TI - Mosaicism of mitochondrial genetic variation in atherosclerotic lesions of the human aorta. AB - OBJECTIVE: The aim of the present study was an analysis of heteroplasmy level in mitochondrial mutations 652delG, A1555G, C3256T, T3336C, 652insG, C5178A, G12315A, G13513A, G14459A, G14846A, and G15059A in normal and affected by atherosclerosis segments of morphologically mapped aortic walls. METHODS: We investigated the 265 normal and atherosclerotic tissue sections of 5 human aortas. Intima of every aorta was divided according to morphological characteristics into segments with different types of atherosclerotic lesions: fibrous plaque, lipofibrous plaque, primary atherosclerotic lesion (fatty streak and fatty infiltration), and normal intima from human aorta. PCR-fragments were analyzed by a new original method developed in our laboratory on the basis of pyrosequence technology. RESULTS: According to the obtained data, mutations G12315A and G14459A are significantly associated with total and primary atherosclerotic lesions of intimal segments and lipofibrous plaques (P <= 0.01 and P <= 0.05, accordingly). Mutation C5178A is significantly associated with fibrous plaques and total atherosclerotic lesions (P <= 0.01). A1555G mutation shows an antiatherosclerotic effect in primary lesion in lipofibrous plaques (P <= 0.05). Meanwhile, G14846A mutation is antiatherogenic for lipofibrous plaques (P <= 0.05). CONCLUSION: Therefore, mutations C5178A, G14459A, G12315A, A1555G, and G14846A were found to be associated with atherosclerotic lesions. PMID- 25834828 TI - Sepsis: pathogenesis, biomarkers, and treatment. PMID- 25834829 TI - A versatile orthotopic nude mouse model for study of esophageal squamous cell carcinoma. AB - Increasing evidence indicates tumor-stromal interactions play a crucial role in cancer. An in vivo esophageal squamous cell carcinoma (ESCC) orthotopic animal model was developed with bioluminescence imaging established with a real-time monitoring platform for functional and signaling investigation of tumor-stromal interactions. The model was produced by injection of luciferase-labelled ESCC cells into the intraesophageal wall of nude mice. Histological examination indicates this orthotopic model is highly reproducible with 100% tumorigenesis among the four ESCC cell lines tested. This new model recapitulates many clinical and pathological properties of human ESCC, including esophageal luminal stricture by squamous cell carcinoma with nodular tumor growth, adventitia invasion, lymphovascular invasion, and perineural infiltration. It was tested using an AKT shRNA knockdown of ESCC cell lines and the in vivo tumor suppressive effects of AKT knockdown were observed. In conclusion, this ESCC orthotopic mouse model allows investigation of gene functions of cancer cells in a more natural tumor microenvironment and has advantages over previous established models. It provides a versatile platform with potential application for metastasis and therapeutic regimen testing. PMID- 25834830 TI - The use of infrared thermography as a rapid, quantitative, and noninvasive method for evaluation of inflammation response in different anatomical regions of rats. AB - PURPOSE: Thermographic assessment of temperature distribution within the examined tissues allows a quick, noncontact, noninvasive measurement of their temperature. The aim of the study was to evaluate the usefulness of digital infrared imaging in monitoring experimental inflammation of pleura (PL), lower lip (LL), and left paw (LP) and right paw (RP) of lower limbs in rats. MATERIALS AND METHODS: The inflammatory reaction was induced by injection of 1% carrageenin solution into pleural cavity, lip, or paws. With the use of digital infrared imaging temperature measurement was conducted at 0 to 72 hours of the inflammatory reaction. RESULTS: The temperature decrease was observed at the site of injection directly afterwards. Next, it was gradually increasing and it reached the maximum on the third day of the inflammatory reaction. Statistically significant changes were observed after 48-hour period in PL and LL regions, as well as after 72-hour period in LP and RP regions (P < 0.005). CONCLUSION: It was found that thermographic examination allows for indicating the presence of inflammatory reaction within examined tissues and determining the dynamics of this process. This method could be used as alternative procedure that allows using fewer animals for experiments. PMID- 25834831 TI - Regulation of hyaluronan synthesis in vascular diseases and diabetes. AB - Cell microenvironment has a critical role determining cell fate and modulating cell responses to injuries. Hyaluronan (HA) is a ubiquitous extracellular matrix glycosaminoglycan that can be considered a signaling molecule. In fact, interacting with several cell surface receptors can deeply shape cell behavior. In vascular biology, HA triggers smooth muscle cells (SMCs) dedifferentiation which contributes to vessel wall thickening. Furthermore, HA is able to modulate inflammation by altering the adhesive properties of endothelial cells. In hyperglycemic conditions, HA accumulates in vessels and can contribute to the diabetic complications at micro- and macrovasculature. Due to the pivotal role in favoring atherogenesis and neointima formation after injuries, HA could be a new target for cardiovascular pathologies. This review will focus on the recent findings regarding the regulation of HA synthesis in human vascular SMCs. In particular, the effects of the intracellular HA substrates availability, adenosine monophosphate-activated protein kinase (AMPK), and protein O GlcNAcylation on the main HA synthetic enzyme (i.e., HAS2) will be discussed. PMID- 25834832 TI - NADPH oxidase-induced NALP3 inflammasome activation is driven by thioredoxin interacting protein which contributes to podocyte injury in hyperglycemia. AB - Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and previously we demonstrated that NALP3 inflammasome was involved in the pathogenesis of DN. Here we investigated the mechanisms of NALP3 inflammasome activation in podocyte injury during DN. We found that, besides the activation of NALP3 inflammasome and upregulated thioredoxin-interacting protein (TXNIP), the glomerular expression of gp91 (phox) , a subunit of NADPH oxidase, was enhanced in DN mice simultaneously. Inhibiting NADPH oxidase abrogated NALP3 inflammasome activation, and IL-1beta production and eventually protected podocytes from high glucose- (HG-) induced injury. TXNIP, an inhibitor of thioredoxin, acts as a suppressor for antioxidant defense system. Our observation indicated that in HG exposed podocytes genetic deletion of TXNIP by shRNA reversed gp91 (phox) overexpression and alleviated the injury of podocyte. Collectively, our findings proposed that HG-induced NADPH oxidase activation was driven by TXNIP which subsequently triggered NALP3 inflammasome activation in podocytes and ultimately led to podocyte injury, and blocking TXNIP/NADPH oxidase signaling may be a promising treatment for DN. PMID- 25834834 TI - Safety evaluation of local weight-gain formulas in the Saudi Arabian markets. AB - BACKGROUND: The utilization of herbal formulas is continuously increasing on the global level. However, assessment of contamination and impurities is the leading challenge in the use of herbal medicines. OBJECTIVE: Assessment of therapeutic application in relation to herbal formulas usage for reducing weight is the objective for this investigation. RESULTS: Reduced dietary fibers and fats are common outcomes of herbal usage. 9.8% of the mixtures were contaminated because of lead. However, investigation has indicated <10 microbial counts in herbal products. Increased levels of calcium, minerals, fibers, and lead traces have been identified in the herbals; however, products lacked nicotinamide, riboflavin, and vitamin C. CONCLUSION: It was concluded that majority of herbal products were pure and uncontaminated in order to reduce the complications of obesity efficiently. PMID- 25834835 TI - On some transverse geometrical structures of lifted foliation to its conormal bundle. AB - We consider the lift of a foliation to its conormal bundle and some transverse geometrical structures associated with this foliation are studied. We introduce a good vertical connection on the conormal bundle and, moreover, if the conormal bundle is endowed with a transversal Cartan metric, we obtain that the lifted foliation to its conormal bundle is a Riemannian one. Also, some transversally framed f(3, epsilon)-structures of corank 2 on the normal bundle of lifted foliation to its conormal bundle are introduced and an almost (para)contact structure on a transverse Liouville distribution is obtained. PMID- 25834833 TI - The story of CD4+ CD28- T cells revisited: solved or still ongoing? AB - CD4(+)CD28(-) T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4(+) T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4(+)CD28(-) T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4(+)CD28(-) T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-alpha blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4(+)CD28(-) T cell level. The clinical relevance of targeting CD4(+)CD28(-) T cells as a therapeutic option has not been examined so far. PMID- 25834836 TI - Abstract computation in schizophrenia detection through artificial neural network based systems. AB - Schizophrenia stands for a long-lasting state of mental uncertainty that may bring to an end the relation among behavior, thought, and emotion; that is, it may lead to unreliable perception, not suitable actions and feelings, and a sense of mental fragmentation. Indeed, its diagnosis is done over a large period of time; continuos signs of the disturbance persist for at least 6 (six) months. Once detected, the psychiatrist diagnosis is made through the clinical interview and a series of psychic tests, addressed mainly to avoid the diagnosis of other mental states or diseases. Undeniably, the main problem with identifying schizophrenia is the difficulty to distinguish its symptoms from those associated to different untidiness or roles. Therefore, this work will focus on the development of a diagnostic support system, in terms of its knowledge representation and reasoning procedures, based on a blended of Logic Programming and Artificial Neural Networks approaches to computing, taking advantage of a novel approach to knowledge representation and reasoning, which aims to solve the problems associated in the handling (i.e., to stand for and reason) of defective information. PMID- 25834837 TI - Virtual goods recommendations in virtual worlds. AB - Virtual worlds (VWs) are computer-simulated environments which allow users to create their own virtual character as an avatar. With the rapidly growing user volume in VWs, platform providers launch virtual goods in haste and stampede users to increase sales revenue. However, the rapidity of development incurs virtual unrelated items which will be difficult to remarket. It not only wastes virtual global companies' intelligence resources, but also makes it difficult for users to find suitable virtual goods fit for their virtual home in daily virtual life. In the VWs, users decorate their houses, visit others' homes, create families, host parties, and so forth. Users establish their social life circles through these activities. This research proposes a novel virtual goods recommendation method based on these social interactions. The contact strength and contact influence result from interactions with social neighbors and influence users' buying intention. Our research highlights the importance of social interactions in virtual goods recommendation. The experiment's data were retrieved from an online VW platform, and the results show that the proposed method, considering social interactions and social life circle, has better performance than existing recommendation methods. PMID- 25834838 TI - Mobility based key management technique for multicast security in mobile ad hoc networks. AB - In MANET multicasting, forward and backward secrecy result in increased packet drop rate owing to mobility. Frequent rekeying causes large message overhead which increases energy consumption and end-to-end delay. Particularly, the prevailing group key management techniques cause frequent mobility and disconnections. So there is a need to design a multicast key management technique to overcome these problems. In this paper, we propose the mobility based key management technique for multicast security in MANET. Initially, the nodes are categorized according to their stability index which is estimated based on the link availability and mobility. A multicast tree is constructed such that for every weak node, there is a strong parent node. A session key-based encryption technique is utilized to transmit a multicast data. The rekeying process is performed periodically by the initiator node. The rekeying interval is fixed depending on the node category so that this technique greatly minimizes the rekeying overhead. By simulation results, we show that our proposed approach reduces the packet drop rate and improves the data confidentiality. PMID- 25834839 TI - A simulated annealing methodology to multiproduct capacitated facility location with stochastic demand. AB - A stochastic multiproduct capacitated facility location problem involving a single supplier and multiple customers is investigated. Due to the stochastic demands, a reasonable amount of safety stock must be kept in the facilities to achieve suitable service levels, which results in increased inventory cost. Based on the assumption of normal distributed for all the stochastic demands, a nonlinear mixed-integer programming model is proposed, whose objective is to minimize the total cost, including transportation cost, inventory cost, operation cost, and setup cost. A combined simulated annealing (CSA) algorithm is presented to solve the model, in which the outer layer subalgorithm optimizes the facility location decision and the inner layer subalgorithm optimizes the demand allocation based on the determined facility location decision. The results obtained with this approach shown that the CSA is a robust and practical approach for solving a multiple product problem, which generates the suboptimal facility location decision and inventory policies. Meanwhile, we also found that the transportation cost and the demand deviation have the strongest influence on the optimal decision compared to the others. PMID- 25834840 TI - Mathematical modeling of uniaxial mechanical properties of collagen gel scaffolds for vascular tissue engineering. AB - Small diameter tissue-engineered arteries improve their mechanical and functional properties when they are mechanically stimulated. Applying a suitable stress and/or strain with or without a cycle to the scaffolds and cells during the culturing process resides in our ability to generate a suitable mechanical model. Collagen gel is one of the most used scaffolds in vascular tissue engineering, mainly because it is the principal constituent of the extracellular matrix for vascular cells in human. The mechanical modeling of such a material is not a trivial task, mainly for its viscoelastic nature. Computational and experimental methods for developing a suitable model for collagen gels are of primary importance for the field. In this research, we focused on mechanical properties of collagen gels under unconfined compression. First, mechanical viscoelastic models are discussed and framed in the control system theory. Second, models are fitted using system identification. Several models are evaluated and two nonlinear models are proposed: Mooney-Rivlin inspired and Hammerstein models. The results suggest that Mooney-Rivlin and Hammerstein models succeed in describing the mechanical behavior of collagen gels for cyclic tests on scaffolds (with best fitting parameters 58.3% and 75.8%, resp.). When Akaike criterion is used, the best is the Mooney-Rivlin inspired model. PMID- 25834841 TI - Similar Outcomes for Two Anemia Treatment Strategies among Elderly Hemodialysis Patients with Diabetes. AB - BACKGROUND/AIMS: To compare mortality and cardiovascular risk in elderly dialysis patients with diabetes under two clinical strategies of anemia correction: maintaining hematocrit (Hct) between 34.5 and < 39.0% (high Hct strategy), and between 30.0 and <34.5% (low Hct strategy) using intravenous alpha epoetin. METHODS: Observational data were used to emulate a randomized trial in which diabetic patients who initiated hemodialysis in 2006-2008 were assigned to each anemia correction strategy. Inverse-probability weighting was used to adjust for measured time-dependent confounding. RESULTS: Comparing high with low hematocrit strategy, the hazard ratio (95% confidence interval) was 1.07 (0.83, 1.38) for all-cause mortality and 1.00 (0.81, 1.24) for a composite mortality and cardiovascular endpoint. CONCLUSIONS: Among a cohort of elderly hemodialysis patients with diabetes, no differences were found between the low and high hematocrit strategies. A lower target hematocrit - per current Food and Drug Administration (FDA) guidelines - appears to be as safe as higher targets among this population. PMID- 25834842 TI - Test-retest reliability of postural stability on two different foam pads. AB - OBJECTIVE: Foam pads are commonly used devices in the clinics and laboratories to assess postural control. However, no reliability data are presently available to support the use of one type of foam over another. The purpose of this study was to evaluate the test-rest reliability of postural sway parameters while using two different types of foam that are commonly used and to determine which type of foam is optimal for providing a consistent and effective perturbation. DESIGN: Test-retest reliability. SETTING: Clinical setting. PARTICIPANTS: Ten healthy young subjects were recruited. MAIN OUTCOME MEASURES: The Balance Accelerometry Measure device was used to collect postural sway for 90 seconds with eyes open and closed on three different surface conditions (firm, Airex foam and Neurocom foam). Intraclass correlation coefficients were used to determine test-retest reliability. RESULTS: Eyes open and eyes closed on a firm surface showed fair to good reliability for the path length value (ICC (3,1) = 0.61-0.64, p <0.05). Eyes open and eyes closed on the Airex pad showed fair to excellent reliability for the path length value (ICC (3,1) = 0.41-0.81, p >0.05 with eyes open and eyes closed). Eyes open and eyes closed on the Neurocom foam showed fair to good reliability for the path length value (ICC (3,1)= 0.29-0.45, p >0.05). CONCLUSIONS: The Airex and Neurocom foam pads both provide fair to good reliability. The Airex foam had higher reliability scores with eyes closed than the Neurocom foam pad. Both foam pads appear to produce repeatable findings. PMID- 25834843 TI - Antibiotic translocation through porins studied in planar lipid bilayers using parallel platforms. AB - In general, the method of choice to characterize the conductance properties of channel-forming bacterial porins is electrophysiology. Here, the classical method is to reconstitute single porins into planar lipid bilayers to derive functional information from the observed channel conductance. In addition to an estimated pore size, ion selectivity or transport properties in general are of importance. For the latter, measuring the ion current fluctuation can provide some information about the mode of transport of charged molecules penetrating the proteins. For instance, increasing the external voltage modifies the residence time in the channel: charged molecules with the ability to permeate through channels will travel faster whereas non-permeating molecules get pushed to the constriction zone with enhanced residence time. Here, we are interested in the ability of antibiotics to permeate channels and compare different techniques to reveal fast events. PMID- 25834844 TI - 3D elemental sensitive imaging by full-field XFCT. AB - X-ray fluorescence computed tomography (XFCT) is a stimulated emission tomography modality that maps the three-dimensional (3D) distribution of elements. Generally, XFCT is done by scanning a pencil-beam across the sample. This paper presents a feasibility study of full-field XFCT (FF-XFCT) for 3D elemental imaging. The FF-XFCT consists of a pinhole collimator and X-ray imaging detector with no energy resolution. A prototype imaging system was set up at the Shanghai Synchrotron Radiation Facility (SSRF) for imaging the phantom. The first FF-XFCT experimental results are presented. The cadmium (Cd) and iodine (I) distributions were reconstructed. The results demonstrate FF-XFCT is fit for 3D elemental imaging and the sensitivity of FF-XFCT is higher than a conventional CT system. PMID- 25834846 TI - Proceedings of the 20th Annual Think Tank: "Exfoliation Syndrome: What We Know and Where We Need To Go" September 19-21, 2013 New York, NY. PMID- 25834847 TI - Proceedings of The 12th OESO World Conference: Cancers of the Esophagus, August 27-30, 2013, Paris, France. PMID- 25834845 TI - Er(3+)/Yb(3+) upconverters for InGaP solar cells under concentrated broadband illumination. AB - The inability of solar cell materials to convert all incident photon energy into electrical current, provides a fundamental limit to the solar cell efficiency; the so called Shockley-Queisser (SQ) limit. A process termed upconversion provides a pathway to convert otherwise unabsorbed low energy photons passing through the solar cell into higher energy photons, which subsequently can be redirected back to the solar cell. The combination of a semi-transparent InGaP solar cell with lanthanide upconverters, consisting of ytterbium and erbium ions doped in three different host materials (Gd2O2S, Y2O3 and NaYF4) is investigated. Using sub-band gap light of wavelength range 890 nm to 1045 nm with a total accumulated power density of 2.7 kW m(-2), a distinct photocurrent was measured in the solar cell when the upconverters were applied whereas a zero current was measured without upconverter. Furthermore, a time delay between excitation and emission was observed for all upconverter systems which can be explained by energy transfer upconversion. Also, a quadratic dependence on the illumination intensity was observed for the NaYF4 and Y2O3 host material upconverters. The Gd2O2S host material upconverter deviated from the quadratic illumination intensity dependence towards linear behaviour, which can be attributed to saturation effects occurring at higher illumination power densities. PMID- 25834848 TI - Proceedings of the Thirteenth International Conference, September 8-11, 2013, Tokyo, Japan. PMID- 25834849 TI - Proceedings of the 60th International Congress of Meat Science and Technology, August 17th-22nd, 2014, Punta Del Este, Uruguay. PMID- 25834851 TI - Proceedings of The 13th International Conference on Trichinellosis, August 1-6, 2011, Changchun, China. PMID- 25834850 TI - Author's reply. PMID- 25834852 TI - Author's reply. PMID- 25834853 TI - "The man in the red hoodie": thoughts on a provoking letter to the editor. PMID- 25834854 TI - Author's response: Prosthetic rehabilitation after orbital exenteration: a case series. PMID- 25834855 TI - Author's response Comments on Repeat gas insufflation for successful closure of idiopathic macular hole following failed primary surgery. PMID- 25834857 TI - Abstracts from the 2014 Advances in Inflammatory Bowel Diseases Crohn's & Colitis Foundation's National Clinical & Research Conference, December 4-6, 2014, Orlando, Florida, USA. PMID- 25834856 TI - Author's response: Maximizing the visual outcome in traumatic cataract cases: the value of a primary posterior capsulotomy and anterior vitrectomy. PMID- 25834858 TI - EJO talks to Stefan Seregard, President of the European Society of Ophthalmology, about the SOE 2015 congress and what makes the SOE congress so unique. PMID- 25834859 TI - Adult congenital heart disease: a substrate for infective endocarditis. PMID- 25834860 TI - [Comment on "The relationship of left ventricular trabeculation to ventricular function and structure over a 9.5 year follow-up. The MESA study"]. PMID- 25834912 TI - [Current and future trend of chemotherapy for ovarian cancer]. PMID- 25834861 TI - Heroin use in Indonesia is associated with higher expression of CCR5 on CD4+ cells and lower ex-vivo production of CCR5 ligands. AB - Opioid use may affect HIV infection through altered expression of HIV co receptors. This was examined in Indonesia among antiretroviral therapy-naive HIV patients, many of whom use drugs. C-C chemokine receptor type 5 (CCR5) expression on CD4+ cells was higher in heroin (P = 0.007), methadone (P = 0.024) and former opioid users (P = 0.003) compared to nonusers, whereas production of RANTES and other CCR5 ligands was similar or lower. This suggests that opioids can affect HIV susceptibility through up-regulation of CCR5 or down-regulation of its ligands. PMID- 25834913 TI - [Impact of molecular classification on clinical management of ovarian cancer]. PMID- 25834914 TI - [Recent process of molecular target therapies in ovarian serous and endometrioid carcinomas on basis of intergrated genomic characterization]. PMID- 25834915 TI - [Treatment of ovarian clear cell carcinoma]. PMID- 25834916 TI - [Low-grade serous, mucinous carcinoma]. PMID- 25834917 TI - Individual Phosphatidylcholine Species Analysis by RP-HPLC-ELSD for Determination of Polyenylphosphatidylcholine in Lecithins. AB - Polyenylphosphatidylcholine (PPC), a subgroup of the bioactive agents in phosphatidylcholine (PC), has been indicated to possess liver-protective effects. This study aimed to investigate a promising and feasible method to determine PC molecular species with a reverse phase (RP) high-performance liquid chromatograph (HPLC) equipped with an evaporative light scattering detector (ELSD). Chromatography was achieved using a C30 column and an isocratic mobile phase consisting of acetonitrile/methanol/triethylamine (40/58/2, v/v/v) at a flow rate of 1 mL/min, and ELSD detection was performed using 80 degrees C for the drift tube and an air flow rate of 1.8 L/min. To identify individual peaks on the chromatogram, MALDI-TOF-MS was employed for initial detection, and then the results were used to investigate the relationship between the retention time and fatty acyl chains of each PC molecule. A linear correlation was observed between the retention time and theoretical carbon number (TCN) of individual PC species. The compositions of PC molecular species in soybean and sunflower lecithins were similar to each other, and the major PC molecular species were 1,2-dilinoleoyl-sn glycero-3-phosphocholine (LLPC), 1-oleoyl-2-linoleoyl-sn-glycero-3-phosphocholine (OLPC), and 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC). The contents of LLPC in soybean PC and sunflower PC were 40.6% and 64.3%, respectively. PMID- 25834918 TI - A method of cryoprotection for protein crystallography by using a microfluidic chip and its application for in situ X-ray diffraction measurements. AB - We demonstrate a seamless and contactless method from protein crystallization to X-ray analysis using a microfluidic chip with the aim of obtaining a complete crystallographic data set of a protein crystal under cryogenic conditions. Our microfluidics-based approach did not require direct manipulation of the protein crystal. Therefore, the microfluidic chip approach is suitable for novices of X ray analysis of protein crystals. We also investigated the effect of stepwise cryoprotection on the quality of protein crystals. Protein crystals with cryoprotection via on-chip manipulation did not show deterioration of crystallographic quality of the protein crystal. The complete diffraction data set of a protein crystal, which is required for determining the 3D structure of the target protein, is obtainable by a simple manipulation. PMID- 25834919 TI - Integrated plant nutrient system - with special emphasis on mineral nutriton and biofertilizers for Black pepper and cardamom - A review. AB - Integrated Plant Nutrition System (IPNS) as a concept and farm management strategy embraces and transcends from single season crop fertilization efforts to planning and management of plant nutrients in crop rotations and farming systems on a long-term basis for enhanced productivity, profitability and sustainability. It is estimated that about two-thirds of the required increase in crop production in developing countries will have to come from yield increases from lands already under cultivation. IPNS enhances soil productivity through a balanced use of soil nutrients, chemical fertilizers, combined with organic sources of plant nutrients, including bio-inoculants and nutrient transfer through agro-forestry systems and has adaptation to farming systems in both irrigated and rainfed agriculture. Horticultural crops, mainly plantation crops, management practices include application of fertilizers and pesticides which become inevitable due to the depletion of soil organic matter and incidence of pests and diseases. The extensive use of chemical fertilizers in these crops deteriorated soil health that in turn affected the productivity. To revitalize soil health and to enhance productivity, it is inexorable to enrich the soil using microorganisms. The lacunae observed here is the lack of exploitation of indigenous microbes having the potential to fix atmospheric nitrogen (N) and to solubilize Phosphorus (P) and Potassium (K). The concept of biofertilizer application appears to be technically simple and financially feasible, but the task of developing biofertilizers with efficient strains in appropriate combinations in a consortia mode is not easier. More than developing consortia, a suitable delivery system to discharge the microbial inoculants warranted much effort. This review focuses on the integrated plant nutrition system incorporating biofertilizer with special emphasis on developing and formulating biofertilizer consortium. PMID- 25834920 TI - Normal flora and bacterial vaginosis in pregnancy: an overview. AB - The female genital tract is an intricate, yet balanced ecosystem that hosts a variety of different residential microflora. The physiological changes that occur during pregnancy may disrupt this balanced ecosystem and predispose women to a potentially pathogenic microbiota. Bacteria that are associated with bacterial vaginosis (BV) are opportunistic pathogens that frequently form part of this microbiota. The overgrowth of and infections with these bacteria are linked to poor obstetric outcomes and increased transmission of other reproductive tract infections (RTIs). These infections increase women's susceptibility of acquiring HIV, the rates of HIV shedding and the development of acquired immune deficiency syndrome (AIDS) in HIV-infected patients. It is unknown how the plethora of bacterial species associated with BV contributes to the dynamics of this condition. The use of high-throughput methods have led to the in-depth investigation of different BV-related bacterial species and the functional capabilities of these species. However, the pathogenesis of BV is still poorly defined and the role of individual BV-related bacterial species in specific pregnancy complications is unclear and controversial. The majority of BV infections are asymptomatic and successful diagnosis is complicated by the lack of reliable and standardized diagnostic tests. PMID- 25834921 TI - Effects of notoginsenoside R1 on CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2 activities in rats by cocktail probe drugs. AB - CONTEXT: Notoginsenoside R1 (NGR1) is the main component with cardiovascular activity in Panax notoginseng (Burk.) F. H. Chen, an herbal medicine that is widely used to enhance blood circulation and dissipate blood stasis. OBJECTIVE: The objective of this study is to investigate NGR1's effects on CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2 activities in rats in vivo through the use of the Cytochrome P450 (CYP450) probe drugs. MATERIALS AND METHODS: After pretreatment with NGR1 or physiological saline, the rats were administered intraperitoneally with a mixture solution of cocktail probe drugs containing caffeine (10 mg/kg), tolbutamide (15 mg/kg), metoprolol (20 mg/kg), and dapsone (10 mg/kg). The bloods were then collected at a set of time-points for the ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis. RESULTS: NGR1 was shown to exhibit an inhibitory effect on CYP1A2 by increased caffeine Cmax (43.13%, p < 0.01) and AUC0 - infinity (40.57%, p < 0.01), and decreased CL/F (62.16%, p < 0.01) in the NGR1-treated group compared with those of the control group, but no significant changes in pharmacokinetic parameters of tolbutamide, metoprolol, and dapsone were observed between the two groups, indicating that NGR1 had no effects on rat CYP2C11, CYP2D1, and CYP3A1/2. DISCUSSION AND CONCLUSION: When NGR1 is co-administered with drugs that are metabolized by CYP1A2, the pertinent potential herb-drug interactions should be monitored. PMID- 25834922 TI - A national incident reporting and learning system in England and Wales, but at what cost? AB - Recent high-profile failures in healthcare highlight the ongoing need for improvements in patient safety. Moreover, the fiscal challenge facing many health systems has brought the costs and economic efficiencies associated with improving quality (and safety) to bear. Currently, there is a lack of economic evidence underpinning resource allocation decisions in patient safety. Incident reporting systems are considered an important means of addressing these challenges by monitoring incident rates over time, identifying new threats to patient care and ultimately preventing repetition of costly adverse events. Uniquely, for more than a decade, the UK has been developing a National Reporting and Learning System to provide these functions for the English and Welsh health system(s), in addition to pre-existing local systems. The need to evaluate the impact of national incident reporting, and learning systems in terms of effectiveness and efficiency is argued and the methodological challenges that must be considered in an economic analysis are outlined. PMID- 25834923 TI - Preparation of Pickering double emulsions using block copolymer worms. AB - The rational formulation of Pickering double emulsions is described using a judicious combination of hydrophilic and hydrophobic block copolymer worms as highly anisotropic emulsifiers. More specifically, RAFT dispersion polymerization was utilized to prepare poly(lauryl methacrylate)-poly(benzyl methacrylate) worms at 20% w/w solids in n-dodecane and poly(glycerol monomethacrylate)-poly(2 hydroxypropyl methacrylate)-poly(benzyl methacrylate) worms at 13% w/w solids in water by polymerization-induced self-assembly (PISA). Water-in-oil-in-water (w/o/w) double emulsions can be readily prepared with mean droplet diameters ranging from 30 to 80 MUm using a two-stage approach. First, a w/o precursor emulsion comprising 25 MUm aqueous droplets is prepared using the hydrophobic worms, followed by encapsulation within oil droplets stabilized by the hydrophilic worms. The double emulsion droplet diameter and number of encapsulated water droplets can be readily varied by adjusting the stirring rate employed during the second stage. For each stage, the droplet volume fraction is relatively high at 0.50. The double emulsion nature of the final formulation was confirmed by optical and fluorescence microscopy studies. Such double emulsions are highly stable to coalescence, with little or no change in droplet diameter being detected over storage at 20 degrees C for 10 weeks as judged by laser diffraction. Preliminary experiments indicate that the complementary o/w/o emulsions can also be prepared using the same pair of worms by changing the order of homogenization, although somewhat lower droplet volume fractions were required in this case. Finally, we demonstrate that triple and even quadruple emulsions can be formulated using these new highly anisotropic Pickering emulsifiers. PMID- 25834924 TI - Beneficial effects of omega-3 PUFA in children on cardiovascular risk factors during childhood and adolescence. AB - Omega-3 polyunsatured fatty acids (omega-3 PUFA) are essential nutrients mainly derived from fish and seafood but present also in vegetables such as nuts and seed-oils. Some epidemiological and clinical studies indicate a protection of omega-3 FA against cardiovascular disease and a favourable effect on cardiovascular risk factors control in adults. The evidences of their effects in children and adolescents are scanty but a possible beneficial role, especially for insulin sensitivity and blood pressure control, has been proposed. In this review we want to focus especially on the evidences, which could justify the assumption of omega-3 in children and adolescents, and to underline the aspects which need further investigation. Mechanisms through which omega-3 FA act are manifolds and still a matter of investigation: beside their interaction with ion channel and their influence on plasma membrane fluidity, probably the main effect is acting as competitor for cytochrome P-450 (CYP) with respect to omega-6 FA. Thus, they can modulate the biosynthesis of eicosanoids and other lipid mediators, which likely exert a protective action. Another suggestive hypothesis is that their beneficial effect is not dependent only on the intake of omega-3 FA, but also on the complex interaction between different nutrients including omega-3 and other FAs with polymorphisms in genes involved in omega-3 FA modulation. This complex interaction has seldom been explored in children and adolescents. Further studies are needed to investigate all these points in order to find a better collocation of omega-3 FA on the available armamentarium for preventive, possibly individualized, medicine. PMID- 25834925 TI - Au133(SPh-tBu)52 nanomolecules: X-ray crystallography, optical, electrochemical, and theoretical analysis. AB - Crystal structure determination has revolutionized modern science in biology, chemistry, and physics. However, the difficulty in obtaining periodic crystal lattices which are needed for X-ray crystal analysis has hindered the determination of atomic structure in nanomaterials, known as the "nanostructure problem". Here, by using rigid and bulky ligands, we have overcome this limitation and successfully solved the X-ray crystallographic structure of the largest reported thiolated gold nanomolecule, Au133S52. The total composition, Au133(SPh-tBu)52, was verified using high resolution electrospray ionization mass spectrometry (ESI-MS). The experimental and simulated optical spectra show an emergent surface plasmon resonance that is more pronounced than in the slightly larger Au144(SCH2CH2Ph)60. Theoretical analysis indicates that the presence of rigid and bulky ligands is the key to the successful crystal formation. PMID- 25834926 TI - Antioxidant and antitumor activities in vitro of polysaccharides from E. sipunculoides. AB - Three polysaccharides (SAP30, SAP60 and SAP80) were separated from the body of Edwardsia sipunculoides by tissue homogenate and papain hydrolysis. Total soluble sugar contents, monosaccharide compositions, antioxidant and antitumor activities in vitro of those polysaccharides were investigated, respectively. Results showed that the total soluble sugar contents of SAP composed of Man, GlcN, Rha, GalN, GlcUA, Glc, Gal, Xyl and Fuc were more than 85% estimated by the phenol-sulfuric acid assay. In addition, SAP had potential antioxidant and antitumor activities. SAP30 has the most significant antitumor effect. This study suggested that SAP could be a potential natural antioxidants and antitumor agents. PMID- 25834927 TI - Does it matter? Discounting and its role in the cost-effectiveness of preventative interventions. The case of HPV vaccination. PMID- 25834928 TI - Occupational vaccination of health care workers: uptake, attitudes and potential solutions. AB - OBJECTIVES: Occupational vaccination of health care workers is strongly recommended to prevent health care associated transmission but coverage in general remains suboptimal. The aim of this survey was to: 1. Estimate levels vaccination coverage for annual flu and MMR vaccines among hospital-based health care workers; 2. Explore the reasons behind low vaccination rates; and 3. Identify potential practical and policy solutions. STUDY DESIGN: A cross sectional study. METHODS: An opportunistic survey was used to estimate MMR and flu vaccination coverage, and review attitudes and explore solutions. Staff from eight randomly selected wards, stratified by ward-level patient susceptibility, were invited to participate. RESULTS: In total 133 staff responded, an approximate response rate of 68%. Seventy one percent had ever received an MMR and 42% had received the most recent flu vaccination. Actively declining vaccination was more common for flu than MMR (29% and 7% respectively). Side effects, insufficient knowledge and vaccine ineffectiveness were popular justifications for declining flu vaccination but not MMR. Not seeing vaccination as a professional responsibility was associated with declining flu vaccination (P < 0.001). Improving vaccination coverage with booster vaccines for new staff and immunity testing received strong support from staff working with vulnerable groups (82% and 74% respectively); 70% of this staff group also supported compulsory vaccination. CONCLUSIONS: Improving staff education may increase coverage. Clarification of the benefits of vaccination in specific staff groups may also improve uptake. Routine booster vaccinations and immunity testing were generally acceptable and compulsory vaccination of certain staff groups warrants further investigation. PMID- 25834929 TI - Getting food policy on the Mayoral table: a comparison of two election cycles in New York and London. AB - Cities and Mayors are increasingly being recognized as important in shaping social policy and improving social well-being. And municipal food policies are increasingly important as a tool to reduce food insecurity and prevent diet related chronic diseases. Thus city governments have a unique ability to improve local food environments. To realize this potential for improving urban food environments, nutrition advocates will need to find innovative approaches for influencing municipal food policy. This paper examines Mayoral elections as a vehicle to advance food policy. To explore this strategy, Mayoral elections in two cities, New York City (NYC) and London, during two recent cycles were compared. To gather evidence multiple sources were used including campaign documents, media and opinion polls as well as the authors' own observations as food policy observers and participants in the two cities. Mayoral governance differs between NYC and London, with the Mayor in NYC having greater powers of management and administration, whilst the London Mayor has a more strategic role and may need to also use 'influence'. Food policy and related issues did not feature strongly in the first election cycles in either city. However by the 2012 and 2013 elections food issues were definitely 'on the table' and featured in main candidates' campaign literature. These latter elections also saw the importance of food advocates coming together to form common alliances and place food issues higher on the municipal agenda. In this way, food policy has become part of the election dialogue in both cities and candidates are expected to consider food policy issues. This analysis leads to make observations which could guide advocates as to how to use Mayoral elections to raise policy objectives for the benefit of public health. PMID- 25834930 TI - Cost-utility analysis of a 12-week whole-body vibration based treatment for people with type 2 diabetes: reanalysis of a RCT in a primary care context. PMID- 25834931 TI - Predicting storage-lipid water partitioning of organic solutes from molecular structure. AB - Partitioning to storage fat is the major process for bioaccumulation of many neutral organic chemicals. In this work, we evaluated the performance of four predictive models, ABSOLV, COSMOtherm, KOWWIN, and SPARC to calculate storage lipid-water partition coefficients. In a first step of the validation, we used over 300 literature data for chemicals with relatively simple molecular structures. For these compounds the overall performance was similar for all models with a root-mean-square error (rmse) between 0.45 and 0.61 log units. Clear differences became visible in the second validation step where a subset with only H-bond-donor compounds was used. Here, COSMOtherm and SPARC performed clearly better with an rmse of 0.35 and 0.42 log units, respectively, compared to ABSOLV and KOWWIN with an rmse of 0.91 and 0.85 log units, respectively. The last step in our validation was a comparison with experimental values for 22 complex, multifunctional chemicals (including pesticides, hormones, mycotoxins) that we measured specifically for this validation purpose. For these chemicals, predictions by all models were less accurate than those for simpler chemicals. COSMOtherm performed the best (rmse 0.71 log units) while the other methods showed considerably poorer results (rmse 1.29 (ABSOLV), 1.25 (SPARC), and 1.62 (KOWWIN) log units). PMID- 25834933 TI - Facile one-pot synthesis of highly porous carbon foams for high-performance supercapacitors using template-free direct pyrolysis. AB - Foam-like porous carbons with specific surface area (SSA) up to 2340 m(2)/g were synthesized using direct pyrolysis of sugar and zinc nitrate mixtures without any hard templates. The role of the ZnO nanoparticles formed from the decomposition of zinc nitrate, and the effects of high-temperature annealing on the formation of the high-SSA carbon foams were systematically studied. Due to the facile and quick reaction conditions, these carbon foams could be easily synthesized on a large scale. When used as supercapacitor electrode materials, a specific capacitance up to 280 F/g was achieved at current density of 0.1 A/g and remained as high as 207 F/g, even at a high current density of 10 A/g. PMID- 25834934 TI - The on-road experiences and awareness of sleepiness in a sample of Australian highway drivers: A roadside driver sleepiness study. AB - OBJECTIVE: Driver sleepiness contributes substantially to road crash incidents. Simulator and on-road studies clearly reveal an impairing effect from sleepiness on driving ability. However, the degree to which drivers appreciate the dangerousness of driving while sleepy is somewhat unclear. This study sought to determine drivers' on-road experiences of sleepiness, their prior sleep habits, and personal awareness of the signs of sleepiness. METHODS: Participants were a random selection of 92 drivers traveling on a major highway in the state of Queensland, Australia, who were stopped by police as part of routine drink driving operations. Participants completed a brief questionnaire that included demographic information, sleepy driving experiences (signs of sleepiness and on road experiences of sleepiness), and prior sleep habits. A modified version of the Karolinska Sleepiness Scale (KSS) was used to assess subjective sleepiness in the 15 min prior to being stopped by police. RESULTS: Participants' ratings of subjective sleepiness were quite low, with 90% reporting being alert to extremely alert on the KSS. Participants were reasonably aware of the signs of sleepiness, with many signs of sleepiness associated with on-road experiences of sleepiness. Additionally, the number of hours spent driving was positively correlated with the drivers' level of sleep debt. CONCLUSIONS: The results suggest that participants had moderate experiences of driving while sleepy and many were aware of the signs of sleepiness. The relationship between driving long distances and increased sleep debt is a concern for road safety. Increased education regarding the dangers of sleepy driving seems warranted. PMID- 25834935 TI - A phonology-free mobile communication app. AB - PURPOSE: Aphasia - loss of comprehension or expression of language - is a devastating functional sequela of stroke. There are as yet no effective methods for rehabilitation of aphasia. An assistive device that allows aphasia patients to communicate and interact at speeds approaching real time is urgently needed. METHODS: Behavioral and linguistic studies of aphasia patients show that they retain normal thinking processes and most aspects of language. They lack only phonology: the ability to translate (input) and/or output sounds (or written words) such as "ta-ble" into the image of a four-legged object with a top at which one works or eats. RESULTS: We have made a phonology-free communication mobile app that may be useful for patients with aphasia and other communication disorders. Particular innovations of our app include calling Google Images as a "subroutine" to allow a near-infinite number of choices (e.g. food or clothing items) for patients without having to make countless images, and by the use of animation for words, phrases or concepts that cannot be represented by a single image. We have tested our app successfully in one patient. CONCLUSIONS: The app may be of great benefit to patients with aphasia and other communication disorders. Implications for Rehabilitation We have made a phonology-free mobile communication app. This app may facilitate communication for patients with aphasia and other communication disorders. PMID- 25834932 TI - The American Geriatrics Society/National Institute on Aging Bedside-to-Bench Conference: Research Agenda on Delirium in Older Adults. PMID- 25834936 TI - Cathelicidin related antimicrobial peptide, laminin, Toll-like receptors and chemokines levels in experimental hypersensitivity pneumonitis in mice. AB - INTRODUCTION: Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by unresolved inflammation and tissue repair pathologies triggered by repeated organic dust exposure. The aim of the study was to investigate changes in levels of the cathelicidin related antimicrobial peptide (CRAMP), laminin (LAM A1), selected Toll-like receptors (TLR) and chemokines in experimental HP in mice. MATERIALS AND METHODS: Three and 18-month-old female C57BL/6J mice underwent inhalations of the saline extract of Pantoea agglomerans cells, Gram negative bacterium common in organic dust and known for its pathogenic impact. The inhalations were repeated daily (28 days). ELISA was used for measuring in lung tissue homogenates concentration of CRAMP, LAM-A1, TLR2, TLR4, TLR8, CXCL9 (chemokine [C-X-C motif] ligand) and CXCL10. RESULTS: Levels of TLR2, TLR4 and CXCL9 were significantly higher in both young and old mice lungs already after 7 days of inhalations, while significant increase of LAM-A1 and CXCL10 was noted after 28 days, compared to untreated samples. TLR8 level was significantly augmented only in young mice. Only CRAMP level significantly declined. Significantly higher TLR8 and CXCL9 concentration in untreated samples were noted in old animals compared to young ones. CONCLUSION: Significant alterations of the examined factors levels indicate their role in HP pathogenesis. PMID- 25834937 TI - The effects of long-term stress exposure on aging cognition: a behavioral and EEG investigation. AB - A large field of research seeks to explore and understand the factors that may cause different rates of age-related cognitive decline within the general population. However, the impact of experienced stress on the human aging process has remained an under-researched possibility. This study explored the association between cumulative stressful experiences and cognitive aging, addressing whether higher levels of experienced stress correlate with impaired performance on 2 working memory tasks. Behavioral performance was paired with electroencephalographic recordings to enable insight into the underlying neural processes impacted on by cumulative stress. Thus, the electroencephalogram was recorded while both young and elderly performed 2 different working memory tasks (a Sternberg and N-back paradigm), and cortical oscillatory activity in the theta, alpha, and gamma bandwidths was measured. Behavioral data indicated that a higher stress score among elderly participants related to impaired performance on both tasks. Electrophysiological findings revealed a reduction in alpha and gamma event-related synchronization among high-stress-group elderly participants, indicating that higher levels of experienced stress may impact on their ability to actively maintain a stimulus in working memory and inhibit extraneous information interfering with successful maintenance. Findings provide evidence that cumulative experienced stress adversely affects cognitive aging. PMID- 25834938 TI - Superficial white matter as a novel substrate of age-related cognitive decline. AB - Studies of diffusion tensor imaging have focused mainly on the role of deep white matter tract microstructural abnormalities associated with aging and age-related cognitive decline. However, the potential role of superficial white matter (SWM) in aging and, by extension, cognitive-aging, is less clear. Healthy individuals (n = 141; F/M: 66/75 years) across the adult lifespan (18-86 years) underwent diffusion tensor imaging and a battery of cognitive testing. SWM was assessed via a combination of probabilistic tractography and tract-based spatial statistics (TBSS). A widespread inverse relationship of fractional anisotropy (FA) values in SWM with age was observed. SWM-FA adjacent to the precentral gyri was associated with fine-motor-speed, whereas performance in visuomotor-attention/processing speed correlated with SWM-FA in all 4 lobes of the left-hemisphere and in right parieto-occipital SWM-FA (family-wise error corrected p < 0.05). Independent of deep white matter-FA, right frontal and right occipital SWM-FA-mediated age effects on motor-speed and visuomotor-attention/processing speed, respectively. Altogether, our results indicate that SWM-FA contributes uniquely to age-related cognitive performance, and should be considered as a novel biomarker of cognitive aging. PMID- 25834939 TI - Goldmann versus Disposable Applanation Tonometer Tips in Glaucoma Patients and Normal Subjects. AB - PURPOSE: To assess agreement of intraocular pressure (IOP) measured with Goldmann applanation and disposable Luneau SA applanation prisms in glaucoma patients compared with normal subjects. METHODS: In a prospective comparative study, one eye per primary open-angle glaucoma (POAG) patient was measured for IOP using Goldmann and disposable Luneau SA (Tonojet) applanation tonometry prisms. Glaucoma patients found with IOP < 21 mmHg were compared to an age-matched group of normal subjects. The main outcomes measured were IOP and the difference in IOP between either prism. Bland-Altman plots were used to study the agreement between measurements. Regression analysis was applied to either group. RESULTS: One hundred and four POAG patients (eyes) were enrolled into this study. Seventy-one of them were found with IOPs < 21 mmHg, and were compared to 71 normal subjects (eyes). The mean difference between either prism was almost similar, 2.0 +/- 2.0 and 2.1 +/- 1.7 mmHg in the glaucoma and normal eye groups, respectively. Bias of two SD from the mean ranged from -1.8 to 5.8 mmHg in glaucoma group and -1.2 to 5.4 mmHg with normal subjects (p < 0.0001 in either group). The inaccuracy was non-systematic with glaucoma patients while was systematic with normal subjects. CONCLUSIONS: The disagreement between disposables and standard Goldmann tips followed different patterns in glaucoma patients when compared with normal subjects. The use of the Goldmann tip is advised with glaucoma patients. PMID- 25834940 TI - Aspects of abuse: consequences of childhood victimization. AB - Childhood maltreatment is unfortunately a common occurrence in the United States, affecting 1 in 8 children annually.(1) The consequences of maltreatment can be considerable, and exact a heavy toll on the individual, family, and society. Child abuse and neglect can cause permanent, heritable changes in the body's response to stress, which in turn inflicts profound changes in the developing brain. While these changes allow a child to contend with a neglectful, chaotic, or possibly violent environment, they strongly influence an individual's behavioral, educational, physical, and mental functioning and well-being throughout his/her lifetime, long after the maltreatment has ended. As the adverse childhood experiences (ACE) studies clearly demonstrate, adult survivors of maltreatment experience significant health harms that can cause significant morbidity and contribute to early death. Further, the lifetime economic cost to society of childhood maltreatment is estimated to be $124 billion dollars.(2) The study of resilient individuals who appear to suffer fewer negative consequences of their maltreatment offers insights into possible interventions for clinical practice as well as advocacy and public policy opportunities that would begin to lessen the significant burdens of childhood maltreatment. PMID- 25834941 TI - The Affordable Care Act: how can we know whether the intended consequences are occurring and the unintended ones are being avoided? AB - When the Affordable Care Act (ACA) was signed into law on March 23, 2010, policymakers intended that it would improve access to care by lowering the uninsured rate, improve health care quality, and lower costs. Now, 4 years later, researchers and policymakers need to ask whether those intentions have been realized or whether the ACA has produced unintended consequences that affect patient care. This article raises the importance of assessing what changes in patient access and clinical care have occurred, points out how challenging those assessments may be to conduct, and concludes with a call to action about how those challenges might be addressed. PMID- 25834943 TI - Fracture mechanics of monolayer molybdenum disulfide. AB - Molecular dynamics (MD) modeling is used to study the fracture toughness and crack propagation path of monolayer molybdenum disulfide (MoS(2)) sheets under mixed modes I and II loading. Sheets with both initial armchair and zigzag cracks are studied. The MD simulations predict that crack edge chirality, tip configuration and the loading phase angle influence the fracture toughness and crack propagation path of monolayer MoS(2) sheets. Furthermore, under all loading conditions, both armchair and zigzag cracks prefer to extend along a zigzag path, which is in agreement with the crack propagation path in graphene. A remarkable out-of-plane buckling can occur during mixed mode loading which can lead to the development of buckling cracks in addition to the propagation of the initial cracks. PMID- 25834942 TI - A phase 1 trial of preoperative partial breast radiation therapy: Patient selection, target delineation, and dose delivery. AB - PURPOSE: Diffusion of accelerated partial breast irradiation into clinical practice is limited by the need for specialized equipment and training. The accessible external beam technique yields unacceptable complication rates, likely from large postoperative target volumes. We designed a phase 1 trial evaluating preoperative radiation therapy to the intact tumor using widely available technology. METHODS AND MATERIALS: Patients received 15, 18, or 21 Gy in a single fraction to the breast tumor plus margin. Magnetic resonance imaging (MRI) was used in conjunction with standard computed tomography (CT)-based planning to identify contrast enhancing tumor. Skin markers and an intratumor biopsy marker were used for verification during treatment. RESULTS: MRI imaging was critical for target delineation because not all breast tumors were reliably identified on CT scan. Breast shape differences were consistently seen between CT and MRI but did not impede image registration or tumor identification. Target volumes were markedly smaller than historical postoperative volumes, and normal tissue constraints were easily met. A biopsy marker within the breast proved sufficient for setup localization. CONCLUSIONS: This single fraction linear accelerator based partial breast irradiation approach can be easily incorporated at most treatment centers. In vivo targeting may improve accuracy and can reduce the dose to normal tissues. PMID- 25834944 TI - Energy flows in graphene: hot carrier dynamics and cooling. AB - Long lifetimes of hot carriers can lead to qualitatively new types of responses in materials. The magnitude and time scales for these responses reflect the mechanisms governing energy flows. We examine the microscopics of two processes which are key for energy transport, focusing on the unusual behavior arising due to graphene's unique combination of material properties. One is hot carrier generation in its photoexcitation dynamics, where hot carriers multiply through an Auger type carrier-carrier scattering cascade. The hot-carrier generation manifests itself through elevated electronic temperatures which can be accessed in a variety of ways, in particular optical conductivity measurements. Another process of high interest is electron-lattice cooling. We survey different cooling pathways and discuss the cooling bottleneck arising for the momentum-conserving electron-phonon scattering pathway. We show how this bottleneck can be relieved by higher-order collisions-supercollisions-and examine the variety of supercollision processes that can occur in graphene. PMID- 25834945 TI - Interactive multimedia consent for biobanking: a randomized trial. AB - PURPOSE: The potential of interactive multimedia to improve biobank informed consent has yet to be investigated. The aim of this study was to test the separate effectiveness of interactivity and multimedia at improving participant understanding and confidence in understanding of informed consent compared with a standard, face-to-face (F2F) biobank consent process. METHODS: A 2 (face-to-face versus multimedia) * 2 (standard versus enhanced interactivity) experimental design was used with 200 patients randomly assigned to receive informed consent. All patients received the same information provided in the biobank's nine-page consent document. RESULTS: Interactivity (F(1,196) = 7.56, P = 0.007, partial eta(2) = 0.037) and media (F(1,196) = 4.27, P = 0.04, partial eta(2) = 0.021) independently improved participants' understanding of the biobank consent. Interactivity (F(1,196) = 6.793, P = 0.01, partial eta(2) = 0.033), but not media (F(1,196) = 0.455, not significant), resulted in increased participant confidence in their understanding of the biobank's consent materials. Patients took more time to complete the multimedia condition (mean = 18.2 min) than the face-to-face condition (mean = 12.6 min). CONCLUSION: This study demonstrated that interactivity and multimedia each can be effective at promoting an individual's understanding and confidence in their understanding of a biobank consent, albeit with additional time investment. Researchers should not assume that multimedia is inherently interactive, but rather should separate the two constructs when studying electronic consent. PMID- 25834946 TI - Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann-Pick disease type B (acid sphingomyelinase deficiency). AB - PURPOSE: Enzyme replacement therapy with olipudase alfa (recombinant human acid sphingomyelinase) is being developed for Niemann-Pick disease type B (NPD B). METHODS: A single-center, open-label, nonrandomized, single-ascending-dose trial evaluated the safety of intravenous olipudase alfa (0.03-1.0 mg/kg) in 11 adults with NPD B. Patients were monitored in the hospital for 72 h after infusion and had follow-up visits on days 14 and 28. RESULTS: Plasma ceramide, a product of sphingomyelin catabolism by olipudase alfa, showed dose-dependent elevations by 6 h postdose, or postinfusion. No serious adverse drug reactions (ADRs) occurred during the study. Acute phase reaction-type ADRs, as evidenced by elevated inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-8, and calcitonin) and constitutional symptoms (fever, pain, nausea, and/or vomiting) emerged 12-24 h following doses >=0.3 mg/kg olipudase alfa. Three patients experienced hyperbilirubinemia. The study was terminated after a patient dosed at 1 mg/kg exhibited severe hyperbilirubinemia; he was subsequently diagnosed with Gilbert syndrome. CONCLUSION: The maximum tolerated dose of olipudase alfa in adults with NPD B was 0.6 mg/kg. First-dose ADRs were likely induced by elevated concentrations of ceramide (or its downstream derivatives) generated by the catabolism of accumulated sphingomyelin. Within-patient dose escalation to slowly catabolize sphingomyelin stores may be a strategy to mitigate first-dose ADRs in patients with NPD B.Genet Med 18 1, 34-40. PMID- 25834947 TI - The challenge of comprehensive and consistent sequence variant interpretation between clinical laboratories. AB - PURPOSE: Genetic testing has shifted from academic laboratories with expertise in specific genes to commercial laboratories that offer tests of a diverse array of genes. The purpose of this comparative study was to determine whether one academic laboratory's model of variant interpretation is similar to that of several commercial laboratories. METHODS: The Collagen Diagnostic Laboratory (CDL) received, over a 14-month period, 38 requests to interpret variants originally identified by an outside laboratory (OL). The interpretations by the OL and CDL were compared and discrepancies were assessed. RESULTS: Interpretations from the OL and CDL were concordant in 11 inquiries (29%); discrepancies were moderate in 11 instances (29%) and significant in 16 (42%). Factors that caused discrepancies included the following: (i) private data were not shared in a public database (n = 9); (ii) publicly available allele frequency data were not referenced and used as evidence (n = 5); and (iii) important aspects of protein structure and function were not taken into account (n = 13). CONCLUSION: Comprehensive interpretation of sequence variants depends on good functional tests and well-curated variant databases. Provision of clinical information to the clinical laboratory, mandatory submission of identified variants with phenotype data to common resources, and collaboration between clinical laboratories and recognized experts is likely to improve consistency in variant interpretation among clinical laboratories.Genet Med 18 1, 20-24. PMID- 25834948 TI - A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II. AB - PURPOSE: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid. METHODS: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for >=6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly. RESULTS: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10 mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months. CONCLUSIONS: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81. PMID- 25834949 TI - Fatty acid oxidation flux predicts the clinical severity of VLCAD deficiency. AB - PURPOSE: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid beta-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity. METHODS: We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading. RESULTS: The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6 6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05). CONCLUSION: Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms. PMID- 25834950 TI - Patient feedback and early outcome data with a novel tiered-binned model for multiplex breast cancer susceptibility testing. AB - PURPOSE: The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing. METHODS: BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing. RESULTS: Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P < 0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing. CONCLUSION: Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.Genet Med 18 1, 25-33. PMID- 25834951 TI - Risk of new tumors in von Hippel-Lindau patients depends on age and genotype. AB - PURPOSE: The von Hippel-Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype. METHODS: In a national cohort study, we included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Manifestation rates were analyzed using Poisson regression and compared in groups of different ages, tumor sites, and genotypes. RESULTS: The rate of new tumor development varied significantly with age and was highest at 30-34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval: 1.06-3.24, P value = 0.031). CONCLUSION: The rate of new manifestation development is not constant throughout the life span of vHL patients; instead, it varies significantly with age and genotype and depends on anatomical location. Retinal surveillance is crucial during the teenage years, whereas cerebellar surveillance is especially important in adulthood.Genet Med 18 1, 89-97. PMID- 25834952 TI - Is maternal plasma DNA testing impacting serum-based screening for aneuploidy in the United States? AB - PURPOSE: We sought to determine whether tests for fetal aneuploidy based on next generation sequencing of cell-free DNA in maternal circulation have had an impact on routine serum-based screening in the general pregnant population. METHODS: We compared results from laboratory surveys in 2011 and 2014 that reported types of prenatal serum screening tests and numbers of tests performed. Testing records from two prenatal serum screening laboratories examined temporal trends in the proportion of screened women 35 years of age and older from 2008 (or 2009) to 2014. RESULTS: The 82 laboratory survey results available for comparison showed that 1.7 million women were screened in 2014, a 5% increase over 2011. In the two screening laboratories, the proportion of screened women age 35 and older increased for several years but then experienced reductions of 8 and 18% by mid 2014 when compared with the highest rates observed. CONCLUSION: As of 2014, maternal plasma DNA testing appears to have had only a minor impact on serum screening rates in the United States. Ongoing surveillance has the potential to determine if, and when, DNA testing begins to replace serum testing as a primary screen for Down syndrome in the United States. PMID- 25834954 TI - Whole-exome sequencing revealed two novel mutations in Usher syndrome. AB - Usher syndrome is a clinically and genetically heterogeneous autosomal recessive inherited disorder accompanied by hearing loss and retinitis pigmentosa (RP). Since the associated genes are various and quite large, we utilized whole-exome sequencing (WES) as a diagnostic tool to identify the molecular basis of Usher syndrome. DNA from a 12-year-old male diagnosed with Usher syndrome was analyzed by WES. Mutations detected were confirmed by Sanger sequencing. The pathogenicity of these mutations was determined by in silico analysis. A maternally inherited deleterious frameshift mutation, c.14439_14454del in exon 66 and a paternally inherited non-sense c.10830G>A stop-gain SNV in exon 55 of USH2A were found as two novel compound heterozygous mutations. Both of these mutations disrupt the C terminal of USH2A protein. As a result, WES revealed two novel compound heterozygous mutations in a Turkish USH2A patient. This approach gave us an opportunity to have an appropriate diagnosis and provide genetic counseling to the family within a reasonable time. PMID- 25834955 TI - Graphene-modified Pd/C cathode and Pd/GAC particles for enhanced electrocatalytic removal of bromate in a continuous three-dimensional electrochemical reactor. AB - Bromate (BrO3(-)) is a carcinogenic and genotoxic contaminant commonly generated during ozonation of bromide-containing water. In this work, the reductive removal of BrO3(-) in a continuous three-dimensional electrochemical reactor with palladium-reduced graphene oxide modified carbon paper (Pd-rGO/C) cathode and Pd rGO modified granular activated carbon (Pd-rGO/GAC) particles was investigated. The results indicated that the rGO sheets significantly promoted the electrochemical reduction of BrO3(-). With the enhanced electron transfer by rGO sheets, the electroreduction of H2O to atomic H* on the polarized Pd particles could be significantly accelerated, leading to a faster reaction rate of BrO3(-) with atomic H*. The synergistic effect of the Pd-rGO/C cathode and Pd-rGO/GAC particles were also exhibited. The atomic H* involved in various electroreduction processes was detected by electron spin resonance spectroscopy and its role for BrO3(-) reduction was determined. The performance of the reactor was evaluated in terms of the removal of BrO3(-) and the yield of Br(-) as a function of the GO concentration, Pd loading amount, current density, hydraulic residence time (HRT), and initial BrO3(-) concentration. Under the current density of 0.9 mA/cm(2), BrO3(-) with the initial concentration of 20 MUg/L was reduced to be less than 6.6 MUg/L at the HRT of 20 min. The BrO3(-) reduction was inhibited in the presence of dissolved organic matter. Although the precipitates generated from Ca(2+) and Mg(2+) in the tap water would cover the Pd catalysts, a long lasting electrocatalytic activity could be maintained for the 30 d treatment. SEM and XPS analysis demonstrated that the precipitates were predominantly deposited onto the Pd-rGO/C cathode rather than the Pd-rGO/GAC particles. PMID- 25834953 TI - Signaling and sensory adaptation in Escherichia coli chemoreceptors: 2015 update. AB - Motile Escherichia coli cells track gradients of attractant and repellent chemicals in their environment with transmembrane chemoreceptor proteins. These receptors operate in cooperative arrays to produce large changes in the activity of a signaling kinase, CheA, in response to small changes in chemoeffector concentration. Recent research has provided a much deeper understanding of the structure and function of core receptor signaling complexes and the architecture of higher-order receptor arrays, which, in turn, has led to new insights into the molecular signaling mechanisms of chemoreceptor networks. Current evidence supports a new view of receptor signaling in which stimulus information travels within receptor molecules through shifts in the dynamic properties of adjoining structural elements rather than through a few discrete conformational states. PMID- 25834956 TI - Effects of Rapid Intravenous Rehydration in Children With Mild-to-Moderate Dehydration. AB - BACKGROUND: New guidelines for "rapid or ultrarapid" intravenous rehydration are being developed in different emergency departments. These new guidelines propose a faster administration of fluids and electrolytes than in traditional protocols. However, there is still insufficient evidence to establish a standard protocol. OBJECTIVE: Our objective was to determine the effects of an outpatient rapid intravenous rehydration regimen based on the administration of 0.9% saline + 2.5% dextrose, at a rate of 20 mL/kg per hour for 2 hours, in children with mild-to moderate isonatremic dehydration resulting from acute gastroenteritis. METHODS: We performed a 2-institution, prospective, observational, descriptive study. Eighty-three patients were included in the study. All patients underwent a first evaluation, including physical examination, laboratory tests, and assessment of clinical degree of dehydration. After this initial evaluation, all children received our intravenous rehydration regimen. A second evaluation including the same items as in the first one was made after in all the children. RESULTS: Intravenous rehydration was successful in 69 patients (83.1%). It failed in 14 patients (16.8%), who required hospitalization because of persistent vomiting in 9 patients and poor general appearance in 5 patients. After intravenous rehydration, we observed a statistically significant decrease in the levels of ketonemia and uremia and in the Gorelick scale score. However, no significant changes were observed in sodium, chloride, potassium, and osmolarity values. CONCLUSIONS: We conclude that, in children with mild-to-moderate dehydration, the administration of 20 mL/kg per hour for 2 hours of 0.9% saline solution + 2.5% glucose improved clinical scores and may be used as an alternative and safe way for intravenous rehydration. PMID- 25834957 TI - Mental Health Utilization in a Pediatric Emergency Department. AB - OBJECTIVE: Mental health complaints are frequent in the pediatric emergency department (PED). The objective of this study was to describe trends over time in PED utilization for mental health care at in a single pediatric tertiary care hospital. It is our hypothesis that the resources used by this patient population are high and that mental health-related visits have increased over the most recent decade. METHODS: This was a retrospective study of all pediatric mental health presentations to the PED from January 2009 to July 2013 at a single pediatric hospital. All patients aged 1 to 19 years with an International Classification of Diseases, Ninth Revision code of 291, 292, 295 to 309, and 311 to 314 were included. Data collected included demographic data, medications received, restraint use, suicidality, length of stay (LOS), charges incurred, final disposition, and daily PED operation variables. Trends over time in presentation, charges, and LOS were analyzed using multiple mixed effects regression models after adjusting for potential patient and PED level confounding variables and clustering of multiple visits within patients. RESULTS: A total of 732 PED visits from 2009 to 2013 were identified representing 646 unique patients. The average age was 13.8 years, and 53% were male. Approximately 25% of the patients expressed suicidal ideation, and 44% of those had attempted suicide before arrival. Behavioral or chemical restraints were used in 33% of patients during their PED visit. There were statistically significant increases in annual visits, LOS, and charges over this period (P < 0.05). Increased charges were significantly associated with longer LOS (P = 0.0062). Charges (P = 0.46) and LOS (P = 0.62) were not significantly different between suicidal and nonsuicidal patients. Approximately 21% of patients were admitted or transferred to another facility. CONCLUSIONS: In this single-center study, we found evidence that the resources required to care for pediatric patients with mental health complaints have increased significantly over time both by increased number of annual visits and an increasing LOS. Further research is necessary to determine if our data are consistent with national trends to further our understanding of the problem and improve resource allocation. PMID- 25834958 TI - Concussion Among Youth Skiers and Snowboarders: A Review of the National Trauma Data Bank From 2009 to 2010. AB - OBJECTIVE: There are limited data regarding concussion among youth skiers and snowboarders. The objective of this study was to examine the frequency of concussion among helmeted and unhelmeted youth skiers and snowboarders presenting to trauma centers. METHODS: Subjects 18 years or younger with a ski- or snowboard related injury were studied using data from the National Trauma Data Bank from 2009 to 2010. We further selected those with head/neck injuries and stratified based on helmet status. Concussive injuries were identified from International Classification of Diseases, 9th Revision codes. Severity analysis was based on the Glasgow Coma Scale and Injury Severity Score. RESULTS: A total of 1001 subjects met inclusion criteria with 678 subjects having documented helmet status. Subjects 12 years or younger were more likely to use helmets compared to 13-18 year-olds (odds ratio, 2.21; 95% confidence interval [95% CI], 1.52-3.21). Skiers were more likely to use helmets compared to snowboarders (odds ratios, 1.60; 95% CI, 1.16-2.19). Snowboarders had a greater likelihood of concussion (estimated-beta, 2.1; 95% CI, 1.48-2.85) after adjusting for helmet status and age. There was no significant difference in the frequency of concussion among helmeted compared to unhelmeted subjects. Imputing missing values for helmets status had no effect on outcome for concussion. We found no difference in injury severity among helmeted compared to unhelmeted subjects. CONCLUSIONS: Among youth skiers and snowboarders who present to trauma centers with a head injury, the likelihood of that injury involving a concussion was not associated with helmet use. PMID- 25834959 TI - Improving Quality of Care for Sickle Cell Patients in the Pediatric Emergency Department. AB - OBJECTIVE: The aim of this study was to identify the factors associated with delays in treatment of sickle pain crisis in the pediatric emergency department with the goal of discerning whether earlier pain management is correlated with better clinical outcome. METHODS: This retrospective study examined data collected from clinical records of patients, aged 21 years or younger, who was treated for sickle cell pain crisis between January and June 2012. Demographic and clinical characteristics were extracted from electronic records, as well as time of registration, triage, initial pain assessment, analgesic administration, and pain reassessment. RESULT: A total of 160 sickle cell pain crises visits by 67 unique patients were identified. Opiates were the most common initial pain medication prescribed and administered. The mean time to initial analgesic administration and pain reassessment was 89 and 60 minutes, respectively. Patients with orders for imaging studies experienced significant delays in time to initial analgesic medication and pain reassessment. In addition, higher triage pain score correlated with shorter time to first dose of pain medication. However, age, sex, and final disposition did not affect time to administration of analgesic medications.Earlier pain management resulted in shorter ED length of stay for all patients regardless of disposition. However, earlier pain management did not affect the total length of hospitalization for patients admitted to the inpatient services. CONCLUSIONS: Pediatric patients with sickle cell pain crises experienced significant delays to initial analgesic medication. A standardized approach to pain management may improve ED management of SCD crises. PMID- 25834960 TI - Pediatricians Support Initiation of Asthma Controller Medications in the Emergency Department: A National Survey. AB - OBJECTIVES: Although National Asthma Guidelines recommend that emergency department (ED) physicians consider initiating controller medications, research suggests that this practice occurs infrequently. The goal of this study was to assess primary care pediatricians' (PCP) beliefs and attitudes regarding ED initiation of controller medications for children with persistent asthma symptoms. METHODS: This was a cross-sectional mail survey of a randomly selected national sample of pediatricians from the American Academy of Pediatrics. The survey posed questions regarding beliefs, barriers, and support for national guideline recommendations. RESULTS: Eight hundred eighty-six (44.3%) of 2000 subjects responded. Five hundred seventy-two (64.5%) respondents met eligibility for analysis. When presented with a vignette of a child with persistent asthma, 476 (83%) of PCPs felt it was appropriate for the ED physician to initiate controller medications. Most (80%) PCPs supported the national guideline recommendation, although a similar proportion reported they have never or rarely experienced this practice before. Only 11% opposed the practice in all circumstances. Beliefs supporting this practice included the following: opportunity to capture patients lost to follow-up (85%), reinforcement of daily use of controller medications (83%), and controller medication may shorten an acute exacerbation (53%). Barriers included lack of time for education in ED (65%), reinforcement of ED use for primary care (64%), lack of PCP communication (62%), and inability to assess severity appropriately (41%). Most (90%) PCPs expect communication from the ED provider. CONCLUSIONS: A majority of pediatricians support the practice of ED physicians initiating controller medication during an acute visit for asthma. Communication with the PCP, appropriate screening of severity, and education about controller medications were important considerations expressed by these providers. PMID- 25834961 TI - Assessing the Utility of Urine Testing in Febrile Infants Aged 2 to 12 Months With Bronchiolitis. AB - OBJECTIVES: The aims of the study were to investigate whether the prevalence of urinary tract infections (UTIs) in febrile infants aged 2 to 12 months with bronchiolitis is higher than the presumed prevalence of asymptomatic bacteriuria (1%) in similarly aged patients and thus to determine whether UTI testing is necessary for these patients. METHODS: This was a prospective cohort study in which we enrolled a convenience sample of febrile infants aged 2 to 12 months with a clinical diagnosis of bronchiolitis. All patients were seen in the emergency department at a large children's hospital between November 1, 2011 and April 15, 2012, had reported or documented fever higher than 38 degrees C, and had urine collected for determination of the presence of UTI. After the conclusion of enrollment, a chart review was conducted to assess missed cases. RESULTS: Positive urine cultures were found in 6/90 (6.7%) patients (confidence interval, 2.5%-13.9%). The positive urine cultures and urinalysis results were found in 4/90 (4.5%) patients (confidence interval, 1.2%-11%). CONCLUSIONS: In our patient population, a significant proportion of infants aged 2 to 12 months who present with bronchiolitis and fever have a concurrent UTI. Obtaining a urine specimen for UTI testing should be considered in infants aged 2 to 12 months with bronchiolitis and fever. A larger multicenter study is needed to further assess the risk factors for UTIs in this patient population. PMID- 25834962 TI - Pediatric Endotracheal Tube Cuff Pressures During Aeromedical Transport. AB - OBJECTIVES: Cuffed endotracheal tubes (ETTs) are frequently used in children, allowing fewer air leaks and helping prevent ventilator-associated pneumonia. Tracheal mucosal perfusion is compromised at an ETT cuff pressure (ETTCP) of 30 cm H2O with blood flow completely absent above 50 cm H2O. Our objective was to compare multiple pediatric-sized ETTCPs at ground level and various altitudes during aeromedical transport. METHODS: Simulating the transport environment, 4 pediatric-sized mannequin heads were intubated with appropriately sized cuffed ETTs (3.0, 4.0, 5.0, 6.0) and transported by helicopter or nonpressurized fixed wing aircraft 20 times each. The ETTCP was set to 10 cm H2O before transport, and the pressure was measured with a standard manometer at 1000-ft intervals until reaching peak altitude or CP greater than 60 cm H2O. Ground elevation ranged from 400-650 ft mean sea level (MSL) and peak altitude from 3500 to 5000 ft MSL. RESULTS: Increased altitude caused a significant increase in ETTCP of all ETT sizes (P < 0.001). However, there is no statistical difference in pressures between ETT sizes (P = 0.28). On average, ETTCP in 3.0, 4.0, and 6.0 ETTs surpassed 30 cm H2O at approximately 1500 ft MSL and 50 cm H2O at approximately 2800 ft MSL. In the 5.0 ETT, the CP reached 30 cm H2O at 2000 ft MSL and 50 cm H2O at 3700 ft MSL. CONCLUSIONS: The ETTCP in pediatric-sized ETTs regularly exceed recommended pressure limits at relatively low altitudes. There is no additional pressure increase related to ETT size. This has the potential to decrease mucosal blood flow, possibly increasing risk of subsequent tracheal stenosis, rupture, and other complications. PMID- 25834963 TI - Teaching Splinting Techniques Using a Just-in-Time Training Instructional Video. AB - OBJECTIVE: Splinting is a multistep procedure that is seldom performed by primary care physicians. Just-in-time training (JITT) is an emerging teaching modality and can be an invaluable asset for infrequently performed procedures or in locations where teaching resources and trained professionals are limited. Our objective was to determine the utility of JITT for teaching medical students the short-arm (SA) volar splinting technique. METHODS: This was a prospective randomized controlled pilot study. An instructional video on SA volar splinting was produced. Students viewed the video or had access to standard medical textbooks (control group) immediately before applying an SA volar splint. The students were assessed for the quality of the splint via a standard 6-point skills checklist. The times required for presplinting preparation and for completion of the splint were also measured. RESULTS: Just-in-time training group students scored higher on the splint checklist (mean [SD], 5.45 [1.06]; 95% confidence interval [CI], 4.99-5.92 vs mean [SD], 1.58 [1.12]; 95% CI, 1.04-2.12; P < 0.0001), had higher pass rates (73%; 95% CI, 53%-93% vs 0%; P < 0.0001), and required less time (minutes) for presplinting preparation (mean [SD], 7.86 [2.45]; 95% CI, 6.78-8.94 vs mean [SD], 9.89 [0.46]; 95% CI, 9.67-10.12; P < 0.0001) compared with the control group. No difference was seen in the time required to complete a splint, successful or not. CONCLUSIONS: In comparison with reading standard textbooks, watching a brief JITT instructional video before splinting yielded faster learning times combined with more successful procedural skills. The use of a JITT instructional video may have potential applications, including globally, as an alternative resource for teaching and disseminating procedural skills, such as SA volar splinting. PMID- 25834964 TI - Etomidate Versus Ketamine: Effective Use in Emergency Procedural Sedation for Pediatric Orthopedic Injuries. AB - OBJECTIVES: The aim of this study was to compare the induction and recovery times, postsedation observation durations, and adverse effects of etomidate and ketamine in pediatric patients with fractures and/or dislocations requiring closed reduction in the emergency department. METHODS: Forty-four healthy children aged 7 to 18 years were included. The patients were randomly divided into 2 groups. Group 1 (24 patients) received etomidate and fentanyl, and group 2 (20 patients) received ketamine intravenously. The Ramsay Sedation Scale and American Pediatric Association discharge criteria were used to evaluate the patients. RESULTS: There were 70 fractured bones and 3 joint dislocations. Except in 1 case (2.3%), all of the injuries were reducted successfully. The mean amount of drugs used to provide adequate sedation and analgesia were 0.25 mg/kg of etomidate and 1.30 MUg/kg of fentanyl in group 1 and 1.25 mg/kg of ketamine in group 2. Fourteen patients (31.8%) reported adverse effects, and none required hospitalization. There was no difference between the groups in the recovery times, occurrence of adverse effects, and postsedation observation durations (P > 0.05). The mean (SD) induction time for the patients in group 1 was 4.3 (1.0) minutes, whereas it was 2.2 (1.6) minutes in group 2 (P < 0.001). CONCLUSIONS: Etomidate induces effective and adequate sedation in the pediatric emergency department for painful orthopedic procedures. Ketamine, which has longer action times, might be preferred for reductions because orthopedic procedures could be lengthy. PMID- 25834965 TI - Practices, Beliefs, and Perceived Barriers to Adolescent Human Immunodeficiency Virus Screening in the Emergency Department. AB - OBJECTIVE: Limited data exist regarding knowledge of and compliance to the Centers for Disease Control and Prevention's universal adolescent human immunodeficiency virus (HIV) screening recommendations. Our objective was to assess current guideline knowledge, practice, and perceived barriers to emergency department (ED)-based adolescent HIV screening. METHODS: We administered an anonymous Web-based cross-sectional survey from May 1, 2012, to June 30, 2012, to 1073 physicians from the American Academy of Pediatrics Section on Emergency Medicine LISTSERV. Survey participants were included if they (1) practiced as attending-level physicians, (2) practiced primarily in pediatric emergency medicine or general emergency medicine, and (3) provided clinical care for patients younger than the age of 21 years. The survey examined respondent demographics, knowledge, attitudes, beliefs, practices, and barriers to ED-based HIV screening. Standard descriptive statistics and comparative analyses were performed. RESULTS: A total of 220 responses were obtained; 29 responses were excluded and 191 responses were included in the study. Most of the participants were from urban, free-standing children's hospitals and had an annual ED volume of more than 61,000 patient visits. Respondent knowledge of the Centers for Disease Control and Prevention guidelines was low; less than 40% of the respondents identified correct consent requirements. Only 15.4% of the respondents reported screening for HIV more than 10 times for the prior 6 months. Most frequently cited barriers included concerns for privacy (67.4%), follow-up (67%), and cost-effectiveness (65.4%). Human immunodeficiency virus screening facilitators included availability of health educators (83%), established follow up (74.7%), and rapid HIV tests (65.2%). CONCLUSIONS: Emergency department clinicians exhibit poor knowledge of adolescent HIV screening recommendations. Current universal screening practices remain low; barriers to screening are numerous. Future efforts should disseminate guideline knowledge, increase rapid HIV testing and health educator availability, as well as reduce adolescent specific barriers. PMID- 25834966 TI - Laboratory Errors in a Pediatric Emergency Department Network: An Analysis of Incident Reports. AB - OBJECTIVES: To describe the types and severity of reported laboratory errors in pediatric emergency departments. METHODS: Retrospective review of incident reports classified as laboratory errors from July 2007 to June 2008 within the Pediatric Emergency Care Applied Research Network. Laboratory testing errors recorded included: delayed results or lost specimen, unlabeled specimens, wrong patient, failure to label specimen correctly, and other. The severity of laboratory-related incidents was characterized using the National Coordinating Council for Medication Error Reporting and Prevention severity classification system. Contributing factors were classified as environmental, equipment, human (employee), information technology systems, parent or guardian, or systems-based. RESULTS: A total of 335 (42.2%) laboratory reports were related to events in the preanalytic phase. Involved staff personnel were identified in 345 of the reports (43.5%). Nurses were identified in 179 (22.6%) and physicians in 38 (4.8%). The majority of laboratory errors [408 (51.5%)] were not associated with harm; 138 (17.4%) patients were harmed by the error; 136 (98.6%) patients were temporarily harmed and required treatment, and 1 (0.7%) patient was hospitalized or had their hospitalization prolonged with the event. Human factors 657 (82.8%) were the most common contributing factor. CONCLUSIONS: Laboratory errors are a common cause of safety events in the pediatric ED. Most events are preanalytic and involve problems with specimens that are improperly collected, mislabeled, or lost. Although most events were not associated with harm, there is potential for significant injury. PMID- 25834967 TI - Minimally invasive surgical approach to treat posterior urethral diverticulum. AB - Urethral diverticulum is a localized saccular or fusiform out-pouching of the urethra. It may occur at any point along the urethra in both male and females. Male urethral diverticulum is rare, and could be either congenital or acquired, anterior or posterior. The mainstay treatment of posterior urethral diverticulum (PUD) is the open surgical approach. Here we discuss our minimally invasive surgical approach (MIS) in managing posterior urethral diverticulum. PMID- 25834968 TI - The role of implantable hemodynamic monitors to manage heart failure. AB - Heart failure is associated with high rates of hospitalization and rehospitalization, resulting in substantial clinical and economic burden. Current approaches to monitoring patients with heart failure have done little to reduce these high rates of heart failure hospitalization. Implantable hemodynamic monitors have been developed to remotely provide direct measurement of intracardiac and pulmonary artery pressures in ambulatory patients with heart failure. These devices have the potential to direct day-to-day management of patients with heart failure to reduce hospitalization rates. The use of a pulmonary artery pressure measurement system has been shown to reduce the risk of heart failure hospitalization in patients with systolic and diastolic heart failure. PMID- 25834969 TI - Nonhemodynamic parameters from implantable devices for heart failure risk stratification. AB - "Implantable devices are well suited to monitor and record several parameters that carry prognostic information. Specifically, the primary function of implantable cardioverter defibrillators (ICDs) is to monitor for changes in heart rhythm and treat both tachyarrhythmias and bradyarrhythmias. They are efficient in monitoring the heart rate, incidence of arrhythmias, and patient activity level, which provide prognostic information. Parameters such as thoracic impedance, heart sounds, and respiratory rate and patterns may further refine prognostic information available from ICDs. Combining parameters may provide a better way to interpret and use the available information." PMID- 25834970 TI - Role of revascularization to improve left ventricular function. AB - Coronary revascularization to improve left ventricular (LV) function and improve mortality in patients with ischemic cardiomyopathy remains controversial, especially in the absence of angina or ischemia. A large body of observational evidence suggests that patients with dysfunctional but viable myocardium may experience improvement in mortality and LV function after revascularization. However, results of randomized trials conducted in the last decade dispute the value of viability testing or coronary revascularization in improving outcomes of patients with ischemic cardiomyopathy. However, because of the numerous methodological limitations of these studies, clinical equipoise persists regarding the role of coronary revascularization in certain patients. PMID- 25834971 TI - Hemodynamic support with percutaneous devices in patients with heart failure. AB - The use of surgically implanted durable mechanical circulatory support (MCS) in high-risk patients with heart failure is declining and short-term, nondurable MCS device use is growing. Percutaneously delivered MCS options for advanced heart failure include the intra-aortic balloon pump, Impella axial flow catheter, TandemHeart centrifugal pump, and venoarterial extracorporeal membrane oxygenation. Nondurable MCS devices have unique implantation characteristics and hemodynamic effects. Algorithms and guidelines for optimal nondurable MCS device selection do not exist. Emerging technologies and applications will address the need for improved left ventricular unloading using lower-profile devices, longer term ambulatory support, and the potential for myocardial recovery. PMID- 25834972 TI - Transcatheter aortic valve replacement for patients with heart failure. AB - Older patients suffering severe heart failure related to aortic stenosis (AS) undergo transcatheter aortic valve replacement (TAVR), owing to their high surgical risk. The diagnosis is made based on echocardiographic examination, but may require a multimodality imaging approach in patients with low gradients. In severely decompensated heart failure or cardiogenic shock, rescue percutaneous balloon aortic valvuloplasty as a bridge to TAVR seems reasonable. Emergent TAVR has been reported. Efforts should be made to avoid late diagnosis or referring patients with severe AS to offer them timely interventions, reduce the risk of TAVR, and predict whether left ventricular function will improve. PMID- 25834973 TI - Percutaneous intervention for mitral regurgitation. AB - Percutaneous treatment of mitral regurgitation (MR) is a promising alternative for patients with functional MR (FMR) who are not appropriate for surgery and are not responding to optimal medical therapy and cardiac resynchronization therapy. Unlike degenerative MR, where repair therapy is clearly preferred, the optimal approach for FMR has not been defined. Challenges for novel mitral repair devices are to demonstrate safety and superior efficacy to medical management in higher risk patients. Transcatheter mitral valve replacement is emerging as a feasible therapy, but requires significant additional clinical trials to define its place in treating heart failure related to MR. PMID- 25834974 TI - Percutaneous left ventricular restoration. AB - The ventricular partitioning device known as Parachute is the first and only percutaneously implantable device aimed at restoration of normal left ventricular geometry in humans. Since its conception, this technology has undergone extensive animal and human testing, with proved feasibility and safety, and is currently being studied in a pivotal randomized clinical trial. This article discusses ventricular remodeling and therapies attempted in the past, details the components of the ventricular partitioning device, describes the implanting technique, and reviews the most current experience of this device in humans. PMID- 25834975 TI - Stem cell therapy for heart failure. AB - "During the past decade, studies in animals and humans have suggested that cell therapy has positive effects for the treatment of heart failure. This clinical effect may be mediated by angiogenesis and reduction in fibrosis rather than by regeneration of myocytes. Increased microvasculature and decreased scar also likely lead to improved cardiac function in the failing heart. The effects of cell therapy are not limited to one type of cell or delivery technique. Well designed, large-scale, randomized clinical trials with objective end points will help to fully realize the therapeutic potential of cell-based therapy for treating heart failure." PMID- 25834976 TI - Cardiac resynchronization therapy: past, present, and future. AB - Cardiac resynchronization therapy (CRT), or biventricular pacing, has become a standard therapeutic modality for patients with symptomatic heart failure (HF), depressed left ventricular (LV) function, and electrical dyssynchrony. Despite the overall success of CRT in improving morbidity and mortality in selected patients with HF, a significant minority demonstrates nonresponse. This review describes the electrical and physiologic rationale for biventricular pacing therapy, summarizes landmark clinical trials assessing CRT efficacy, highlights strategies to optimize the response to CRT, and frames future challenges in the use, delivery, and care of patients undergoing CRT. PMID- 25834977 TI - Ablation of atrial arrhythmias in heart failure. AB - HF and AF are on the rise and often coexist. Pharmacologic rhythm control has not been shown to improve outcomes compared with pharmacologic rate control. It is possible that the benefits of maintaining SR are offset by the adverse effects of AADs. Catheter ablation of AF offers an opportunity to achieve SR without the downside of AADs. Several studies have shown that AF ablation improves prognostic markers, including ventricular function, exercise tolerance, and perceived quality of life in HF patients. Studies addressing the impact of this treatment strategy on cardiovascular outcomes and cost-effectiveness are ongoing. PMID- 25834978 TI - Ablation of ventricular arrhythmia in patients with heart failure. AB - Ventricular arrhythmias (VAs) in patients with cardiomyopathy and advanced symptom class heart failure (HF) are associated with significant morbidity and mortality. VAs are typically managed with antiarrhythmic drug therapy and implantable cardiac defibrillators (ICD). Although ICDs are highly effective in reducing sudden cardiac death by termination of VA, they do not prevent arrhythmia recurrences. Recurrent shocks are not only associated with poor quality of life but also progressive HF and increased mortality and morbidity. Radiofrequency catheter ablation has emerged as an important therapeutic option for patients with drug-refractory ventricular tachycardia to reduce or prevent ICD shocks. PMID- 25834979 TI - Interventional and device-based autonomic modulation in heart failure. AB - "Heart failure is an increasingly prevalent disease with high mortality and public health burden. It is associated with autonomic imbalance characterized by sympathetic hyperactivity and parasympathetic hypoactivity. Evolving novel interventional and device-based therapies have sought to restore autonomic balance by neuromodulation. Results of preclinical animal studies and early clinical trials have demonstrated the safety and efficacy of these therapies in heart failure. This article discusses specific neuromodulatory treatment modalities individually-spinal cord stimulation, vagus nerve stimulation, baroreceptor activation therapy, and renal sympathetic nerve denervation." PMID- 25834980 TI - The hi-tech age of heart failure management. PMID- 25834981 TI - Expanding the boundaries of heart failure care with interventional and device therapy. PMID- 25834982 TI - Laparoscopic management of recurrent ureteropelvic junction obstruction following pyeloplasty. AB - OBJECTIVE: The aim was to analyze the operative, postoperative and functional outcome of laparoscopic management of previously failed pyeloplasty and to compare operative and postoperative outcome with laparoscopic pyeloplasty for primary ureteropelvic junction obstruction (UPJO). MATERIALS AND METHODS: All patients who underwent laparoscopic management for previously failed dismembered pyeloplasty were analyzed in this study. Detailed clinical and imaging evaluation was performed. Transperitoneal approach was followed to repair the recurrent UPJO. Operative, postoperative, and follow-up functional details were recorded. Operative and postoperative outcomes of laparoscopic redo pyeloplasty were compared with that of laparoscopic primary pyeloplasty. RESULTS: A total of 16 patients were managed with laparoscopic approach for previously failed pyeloplasty. Primary surgical approach for dismembered pyeloplasty was open in 11, laparoscopy in four patients and robotic assisted in one patient. Fifteen were treated with redo pyeloplasty and one with ureterocalicostomy. Mean operative time was 191.25 +/- 24.99 min, mean duration of hospital stay was 3.2 +/- 0.45 days and mean follow-up duration was 29.9 +/- 18.5 months with success rate of 93.3%. Operative time was significantly prolonged with redo pyeloplasty group compared with primary pyeloplasty group (191.25 +/- 24.99 vs. 145 +/- 22.89, P = 0.0001). CONCLUSION: Laparoscopic redo pyeloplasty is a viable option with a satisfactory outcome and less morbidity. PMID- 25834983 TI - Performance of the Osteoporosis Self-Assessment Tool for Asians in Screening Osteoporosis Among Middle-Aged and Old Women in the Chengdu Region of China: Commentary. PMID- 25834984 TI - Video game experience and its influence on visual attention parameters: an investigation using the framework of the Theory of Visual Attention (TVA). AB - Experts with video game experience, in contrast to non-experienced persons, are superior in multiple domains of visual attention. However, it is an open question which basic aspects of attention underlie this superiority. We approached this question using the framework of Theory of Visual Attention (TVA) with tools that allowed us to assess various parameters that are related to different visual attention aspects (e.g., perception threshold, processing speed, visual short term memory storage capacity, top-down control, spatial distribution of attention) and that are measurable on the same experimental basis. In Experiment 1, we found advantages of video game experts in perception threshold and visual processing speed; the latter being restricted to the lower positions of the used computer display. The observed advantages were not significantly moderated by general person-related characteristics such as personality traits, sensation seeking, intelligence, social anxiety, or health status. Experiment 2 tested a potential causal link between the expert advantages and video game practice with an intervention protocol. It found no effects of action video gaming on perception threshold, visual short-term memory storage capacity, iconic memory storage, top-down control, and spatial distribution of attention after 15 days of training. However, observations of a selected improvement of processing speed at the lower positions of the computer screen after video game training and of retest effects are suggestive for limited possibilities to improve basic aspects of visual attention (TVA) with practice. PMID- 25834985 TI - Probing the interaction of anthraquinone with DNA by spectroscopy, molecular modeling and cancer cell imaging technique. AB - A new anthraquinone derivative, (E)-2-(1-(4,5-dihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yloxyimino)ethyl)-1,4-dihydroxyanthracene-9,10-dione (AODGlc), was synthesized and its binding properties towards DNA were explored under physiological conditions by fluorescence spectroscopy, DNA melting as well as docking techniques. The experimental results revealed that AODGlc could bind to calf thymus DNA (ctDNA) through intercalation between DNA base pairs. The values of thermodynamic parameters at different temperatures including DeltaG, DeltaH, and DeltaS and the molecular modeling study implied that hydrophobic interactions and hydrogen bonds were the main interactions in the AODGlc-ctDNA system. Cervical cancer cells (HepG2 cells) were used in cell viability assay and cell imaging experiment. AODGlc could interact with HepG2 cells and kill HepG2 cells under high concentration with nice curative effect, indicating its potential bioapplication in the future. PMID- 25834986 TI - NMR study of the O-specific polysaccharide and the core oligosaccharide from the lipopolysaccharide produced by Plesiomonas shigelloides O24:H8 (strain CNCTC 92/89). AB - The structures of the O-specific polysacccharide and core oligosaccharide of the lipopolysaccharide from Plesiomonas shigelloides O24:H8, strain CNCTC 92/89, have been investigated by NMR spectroscopy and ESI mass spectrometry. The O-specific polysaccharide was found to be composed of a tetrasaccharide repeating unit consisting of [->3)-alpha-FucpNAc-(1->3)-alpha-GalpNAcA-(1->3)-alpha-QuipNAc-(1 >] and of alpha-RhapNAc (1->4) linked to the GalpNAcA residue. An identical structure has been reported for the capsular polysaccharide of the clinical isolate of Vibrio vulnificus strain BO62316 [1]. The core oligosaccharide was composed of a decasaccharide which structure is identical with these in P. shigelloides serotype O54 [2] and serotype O37 [3]. PMID- 25834987 TI - Antileishmanial and cytotoxic compounds from Valeriana wallichii and identification of a novel nepetolactone derivative. AB - The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2-3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6-7) and two known valtrates (compounds 8-9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, beta-bisabolol (10), alpha-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated. PMID- 25834988 TI - Synthesis and QSAR study of novel 6-chloro-3-(2-Arylmethylene-1-methylhydrazino) 1,4,2-benzodithiazine 1,1-dioxide derivatives with anticancer activity. AB - A series of new 6-chloro-3-(2-arylmethylene-1-methylhydrazino)-1,4,2 benzodithiazine 1,1-dioxide derivatives were effectively synthesized from N methyl-N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazines. The intermediate compounds as well as the products, were evaluated for their cytotoxic effects toward three human cancer cell lines. All compounds shown moderate or weak cytotoxic effects against the tested cancer cell lines, but selective cytotoxic effects were observed. Compound 16 exhibited the most potent cytotoxic activity against the HeLa cell line, with an IC50 value of 10 uM, while 14 was the most active against the MCF-7 and HCT-116 cell lines, affording IC50 values of 15 uM and 16 uM, respectively. The structure-activity relationship was evaluated based on QSAR methodology. The QSAR MCF-7 model indicated that natural charge on carbon atom C13 and energy of highest occupied molecular orbital (HOMO) are highly involved in cytotoxic activity against MCF-7 cell line. The cytotoxic activity of compounds against HCT-116 cell line is dependent on natural charge on carbon atom C13 and electrostatic charge on nitrogen atom N10. The obtained QSAR models could provide guidelines for further development of novel anticancer agents. PMID- 25834989 TI - Fibulin1C peptide induces cell attachment and extracellular matrix deposition in lung fibroblasts. AB - Fibulin-1 is an extracellular matrix (ECM) protein, levels of which are elevated in serum and lung tissue from patients with idiopathic pulmonary fibrosis compared to healthy volunteers. Inhibition of fibulin-1C, one of four fibulin-1 isoforms, reduced proliferation and wound healing in human airway smooth muscle (ASM) cells. This study identified the bioactive region/s of fibulin-1C which promotes fibrosis. Seven fibulin-1C peptides were synthesized and used to pre coat tissue culture plates before lung derived ASM cells and fibroblasts from patients with pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD) or neither disease (Control) were plated. Peptide effects on in vitro measures of fibrosis: cell attachment, proliferation and viability, and ECM deposition, were examined. Among these peptides, peptide 1C1 (FBLN1C1) enhanced ASM cell and fibroblast attachment. FBLN1C1 increased mitochondrial activity and proliferation in fibroblasts. In addition, FBLN1C1 stimulated fibulin1 deposition in PF and COPD fibroblasts, and augmented fibronectin and perlecan deposition in all three groups. Peptides FBLN1C2 to FBLN1C7 had no activity. The active fibulin 1C peptide identified in this study describes a useful tool for future studies. Ongoing investigation of the role of fibulin-1 may reveal the mechanisms underlying the pathphysiology of chronic lung diseases. PMID- 25834990 TI - IgG4-related disease mimicking chalazion in the upper eyelid with skin manifestations on the trunk. AB - IgG4-related disease is a recently defined inflammatory process characterized by IgG4-bearing plasma cells in the involved tissues. The most common sites of involvement are the pancreas, hepatobiliary tract, salivary glands, lymph nodes, retroperitoneum and orbit, especially the lacrimal glands. Other ocular or ocular adnexal sites are rare. To our knowledge, there is one reported case of a conjunctival involvement. We describe a patient, who had an IgG4-RD mimicking chalazion in the upper eyelid, confined to the tarsus, with multiple skin lesions on the trunk. This is a case report of a 55-year-old female. A 55-year-old female presented with an upper eyelid lesion, which was clinically diagnosed as chalazion and drained three times. Histopathological diagnoses were chalazion and inflammation with mixed cells, respectively. Additionally, the patient had had skin nodules on the trunk for several years. Finally, after a third recurrence, the tarsal eyelid lesion was completely excised. The tarsal pathology specimen showed 85 IgG4 positive plasma cells per HPF and the IgG4/IgG ratio was 0.64, suggesting a probable IgG4-related disease. The re-examined skin lesions resembled histologically the eyelid lesion. It is essential to be aware of IgG4 related disease, including in recurrent chalazia. PMID- 25834991 TI - Transoral robotic surgery alone for oropharyngeal cancer: quality-of-life outcomes. AB - IMPORTANCE: Few studies have examined quality-of-life (QOL) outcomes in patients who undergo transoral robotic surgery (TORS) alone (ie, without adjuvant radiotherapy or chemoradiotherapy). OBJECTIVE: To report QOL outcomes of patients with oropharyngeal squamous cell carcinoma who receive only TORS. DESIGN, SETTING, AND PARTICIPANTS: Medical records for all patients undergoing TORS for treatment of primary oropharyngeal squamous cell carcinoma from May 1, 2010, to March 31, 2014, at a tertiary care academic cancer center were examined from June through September 2014. Thirty-four patients who did not receive adjuvant therapy after TORS were included in the study. INTERVENTION: Primary surgical resection via TORS. MAIN OUTCOMES AND MEASURES: The University of Washington Quality of Life, version 4, questionnaire was completed by patients preoperatively and at 1 , 6-, 12-, and 24-month intervals after TORS. Demographic, clinicopathologic, and follow-up data were collected. RESULTS: Mean follow-up time was 14 months (May 1, 2010, to April 30, 2014). Most patients had T1 (20 [59%]) or T2 (13 [38%]) and N0 (13 [38%]) or N1 (16 [47%]) disease. Statistically significant improvement in QOL outcomes was noted in the following postoperative domains: chewing from 1 month (median, 50 [IQR, 50-100]) to 12 months (100 [IQR, 100-100]; P = .048), swallowing from 1 month (70 [IQR, 30-85]) to 6 months (100 [IQR, 70-100]; P = .047) and 1 to 24 months (100 [IQR, 70-100]; P = .048), pain from 1 month (38 [IQR, 25-75]) to 6 months (88 [IQR, 75-100]; P = .006) and 1 to 12 months after surgery (100 [IQR, 75-100]; P = .01), and activity from 1 month (63 [IQR, 50-88]) to 24 months (100 [IQR, 75-100]; P = .03). Two participants (6%) died during the follow-up period: 1 because of disease and 1 because of a myocardial infarction. Two patients (6%) required temporary gastrostomy tube placement, but none required tracheostomy. CONCLUSIONS AND RELEVANCE: Appropriately selected patients who undergo TORS alone for oropharyngeal squamous cell carcinoma experience acceptable short- and long-term QOL outcomes. PMID- 25834992 TI - The impact of regional economic reliance on the tobacco industry on current smoking in China. AB - The purpose of this study was to conduct a preliminary assessment of province of residence and other contextual factors on the likelihood of being a current smoker in China. A cross-sectional, multistage sampling process was used to recruit participants, and their smoking status and sociodemographic characteristics were obtained through face-to-face interviews. The contextual variables were retrieved from a national database. Multilevel logistic regression analysis was performed to assess the impact of provincial economic reliance on the tobacco industry, as well as individual-level characteristics, on the likelihood of being a current smoker. Participants totaled 20,601 from 27 cities located in 26 of the 31 municipalities/provinces in China. Overall smoking prevalence was 31.3% (95% CI: 19.3-33.2%), with rates being highest in Yinchuan City in Ningxia Province (49.8%) and lowest in Shanghai (21.6%). The multilevel analysis showed an excess likelihood of being a current smoker for individuals living in provinces with the highest rate of cigarette production relative to those with the smallest (p<0.001). Findings underscore the importance of restricting cigarette production and regulating the marketing of tobacco products in China. PMID- 25834993 TI - Sentinel Lymph Node Biopsy Use Among Melanoma Patients 75 Years of Age and Older. AB - INTRODUCTION: While SLN biopsy is recommended for melanoma >=1 mm in depth, its use among the elderly population is more controversial. We reviewed our experience at the University of Michigan with melanoma patients >=75 years of age. METHODS: A total of 952 melanoma patients >=75 years of age from 1996 to 2011 were identified from our institutional review board-approved database. In addition to clinicopathologic features and outcome data, comorbidity data were collected to calculate the Charlson comorbidity index (CCI). Univariate and multivariate Cox regression analysis was performed to characterize predictors of outcome. Kaplan-Meier analysis was used to generate survival curves. RESULTS: Among 553 clinically node-negative patients with melanoma >=1 mm in Breslow thickness, 213 had wide excision alone, whereas 340 had excision and SLN biopsy, with 83 (24 %) having a positive SLN. SLN biopsy was less likely with older age (p < 0.0001) and H&N location (p = 0.007), but not CCI. SLN involvement was associated with female gender [odds ratio (OR) 2.15, p = 0.009], Breslow thickness [OR 1.23/mm increase, p = 0.004], and satellitosis (OR 4.43, p = 0.004). Distant disease-specific survival was negatively associated with male gender (OR 1.5, p = 0.007), increasing age (OR 1.05/year, p < 0.001), increasing Breslow thickness (OR 1.07/year, p = 0.013), ulceration (OR 1.51, p = 0.004), a positive SLN (OR 2.61, p < 0.001), and not having a SLN biopsy (OR 1.72, p < 0.001). CCI did not predict worse disease-free or melanoma-specific survival. CONCLUSIONS: WLE and SLN biopsy was not only strongly prognostic, but compared with WLE alone was associated with improved outcome, even after factoring for age and comorbidities. If otherwise healthy, SLN biopsy should be strongly considered for this population. PMID- 25834995 TI - Consumption of sucrose from infancy increases the visceral fat accumulation, concentration of triglycerides, insulin and leptin, and generates abnormalities in the adrenal gland. AB - Consumption of sugar-sweetened beverages promotes the development of metabolic syndrome (MetS) and type 2 diabetes mellitus in humans. One factor related to the appearance of MetS components is the dysfunction of the adrenal gland. In fact, the experimental generation of hyperglycemia has been associated with morphological and microvascular changes in the adrenal glands of rats. We hypothesized that high sucrose consumption from infancy promotes histological disruption of the adrenal glands associated with the appearance of metabolic syndrome indicators. Male Wistar rats were separated at weaning (21 days old) into two groups: free access to tap water (control group, C) or 30 % sucrose diluted in water (sugar-fed group). After 12 weeks, high sucrose consumption promoted an increase in visceral fat accumulation, adipose cell number, and insulin resistance. Also, a rise in the concentration of triglycerides, very low density lipoprotein, insulin and leptin was observed. In control rats, a histomorphometric asymmetry between the right and left adrenal glands was found. In the sugar-fed group, sucrose consumption produced a major change in adrenal gland asymmetry. No changes in corticosterone serum level were observed in either group. Our results suggest that a high sucrose liquid-diet from early life alters the morphology of adrenocortical zones, leading to MetS indicators. PMID- 25834996 TI - Twist grain boundary (TGB) states of chiral liquid crystalline bent-core mesogens. AB - 4-Cyanoresorcinol derived bent-core molecules with a chiral (S)-2-methylbutoxy chain form liquid crystalline phases with TGBA- and TGBC-like structures at the transition from cybotactic nematic via SmA to SmC phases. PMID- 25834998 TI - The Use of Wearable Microsensors to Quantify Sport-Specific Movements. AB - BACKGROUND: Microtechnology has allowed sport scientists to understand the locomotor demands of various sports. While wearable global positioning technology has been used to quantify the locomotor demands of sporting activities, microsensors (i.e. accelerometers, gyroscopes and magnetometers) embedded within the units also have the capability to detect sport-specific movements. OBJECTIVE: The objective of this study was to determine the extent to which microsensors (also referred to as inertial measurement units and microelectromechanical sensors) have been utilised in quantifying sport-specific movements. METHODS: A systematic review of the use of microsensors and associated terms to evaluate sport-specific movements was conducted; permutations of the terms used included alternate names of the various technologies used, their applications and different applied environments. Studies for this review were published between 2008 and 2014 and were identified through a systematic search of six electronic databases: Academic Search Complete, CINAHL, PsycINFO, PubMed, SPORTDiscus, and Web of Science. Articles were required to have used athlete-mounted sensors to detect sport-specific movements (e.g. rugby union tackle) rather than sensors mounted to equipment and monitoring generic movement patterns. RESULTS: A total of 2395 studies were initially retrieved from the six databases and 737 results were removed as they were duplicates, review articles or conference abstracts. After screening titles and abstracts of the remaining papers, the full text of 47 papers was reviewed, resulting in the inclusion of 28 articles that met the set criteria around the application of microsensors for detecting sport-specific movements. Eight articles addressed the use of microsensors within individual sports, team sports provided seven results, water sports provided eight articles, and five articles addressed the use of microsensors in snow sports. All articles provided evidence of the ability of microsensors to detect sport-specific movements. Results demonstrated varying purposes for the use of microsensors, encompassing the detection of movement and movement frequency, the identification of movement errors and the assessment of forces during collisions. CONCLUSION: This systematic review has highlighted the use of microsensors to detect sport specific movements across a wide range of individual and team sports. The ability of microsensors to capture sport-specific movements emphasises the capability of this technology to provide further detail on athlete demands and performance. However, there was mixed evidence on the ability of microsensors to quantify some movements (e.g. tackling within rugby union, rugby league and Australian rules football). Given these contrasting results, further research is required to validate the ability of wearable microsensors containing accelerometers, gyroscopes and magnetometers to detect tackles in collision sports, as well as other contact events such as the ruck, maul and scrum in rugby union. PMID- 25834997 TI - Chronotropic Incompetence During Exercise in Type 2 Diabetes: Aetiology, Assessment Methodology, Prognostic Impact and Therapy. AB - During incremental exercise tests, chronotropic incompetence (CI), which is the inability of the heart rate (HR) to rise in proportion to an increase in metabolic demand, is often observed in patients with type 2 diabetes mellitus (T2DM). Despite the fact that CI is associated with exercise intolerance and elevated risks of development of cardiovascular disease and premature death, this clinical anomaly is often ignored or overlooked by clinicians and physiologists. CI is, however, a significant clinical abnormality that deserves further attention, examination and treatment. The aetiology of CI in T2DM remains poorly understood and is complex. Certain T2DM-related co-morbidities or physiological anomalies may contribute to development of CI, such as altered blood catecholamine and/or potassium levels during exercise, structural myocardial abnormalities, ventricular and/or arterial stiffness, impaired baroreflex sensitivity and cardiovascular autonomic neuropathy. Clinicians should thus be aware of the potential presence of yet undetected anomalies or diseases in T2DM patients who experience CI during exercise testing. However, an effective treatment for CI in T2DM is yet to be developed. Exercise training programmes seem to be the only potentially effective and feasible interventions for partial restoration of the chronotropic response in T2DM, but it remains poorly understood how these interventions lead to restoration of the chronotropic response. Studies are thus warranted to elucidate the aetiology of CI and develop an effective treatment for CI in T2DM. In particular, the impact of (different) exercise interventions on CI in T2DM deserves greater attention in future studies. PMID- 25834999 TI - Morph-specific genetic and environmental variation in innate and acquired immune response in a color polymorphic raptor. AB - Genetic color polymorphism is widespread in nature. There is an increasing interest in understanding the adaptive value of heritable color variation and trade-off resolution by differently colored individuals. Melanin-based pigmentation is often associated with variation in many different life history traits. These associations have recently been suggested to be the outcome of pleiotropic effects of the melanocortin system. Although pharmacological research supports that MC1R, a gene with a major role in vertebrate pigmentation, has important immunomodulatory effects, evidence regarding pleiotropy at MC1R in natural populations is still under debate. We experimentally assessed whether MC1R-based pigmentation covaries with both inflammatory and humoral immune responses in the color polymorphic Eleonora's falcon. By means of a cross fostering experiment, we disentangled potential genetic effects from environmental effects on the covariation between coloration and immunity. Variation in both immune responses was primarily due to genetic factors via the nestlings' MC1R-related color genotype/phenotype, although environmental effects via the color morph of the foster father also had an influence. Overall, dark nestlings had lower immune responses than pale ones. The effect of the color morph of the foster father was also high, but in the opposite direction, and nestlings raised by dark eumelanic foster fathers had higher immune responses than those raised by pale foster fathers. Although we cannot completely discard alternative explanations, our results suggest that MC1R might influence immunity in this species. Morph-specific variation in immunity as well as pathogen pressure may therefore contribute to the long-term maintenance of genetic color polymorphism in natural populations. PMID- 25835001 TI - cocor: a comprehensive solution for the statistical comparison of correlations. AB - A valid comparison of the magnitude of two correlations requires researchers to directly contrast the correlations using an appropriate statistical test. In many popular statistics packages, however, tests for the significance of the difference between correlations are missing. To close this gap, we introduce cocor, a free software package for the R programming language. The cocor package covers a broad range of tests including the comparisons of independent and dependent correlations with either overlapping or nonoverlapping variables. The package also includes an implementation of Zou's confidence interval for all of these comparisons. The platform independent cocor package enhances the R statistical computing environment and is available for scripting. Two different graphical user interfaces-a plugin for RKWard and a web interface-make cocor a convenient and user-friendly tool. PMID- 25835000 TI - Lipid-induced epigenomic changes in human macrophages identify a coronary artery disease-associated variant that regulates PPAP2B Expression through Altered C/EBP beta binding. AB - Genome-wide association studies (GWAS) have identified over 40 loci that affect risk of coronary artery disease (CAD) and the causal mechanisms at the majority of loci are unknown. Recent studies have suggested that many causal GWAS variants influence disease through altered transcriptional regulation in disease-relevant cell types. We explored changes in transcriptional regulation during a key pathophysiological event in CAD, the environmental lipid-induced transformation of macrophages to lipid-laden foam cells. We used a combination of open chromatin mapping with formaldehyde-assisted isolation of regulatory elements (FAIRE-seq) and enhancer and transcription factor mapping using chromatin immuno precipitation (ChIP-seq) in primary human macrophages before and after exposure to atherogenic oxidized low-density lipoprotein (oxLDL), with resultant foam cell formation. OxLDL-induced foam cell formation was associated with changes in a subset of open chromatin and active enhancer sites that strongly correlated with expression changes of nearby genes. OxLDL-regulated enhancers were enriched for several transcription factors including C/EBP-beta, which has no previously documented role in foam cell formation. OxLDL exposure up-regulated C/EBP-beta expression and increased genomic binding events, most prominently around genes involved in inflammatory response pathways. Variants at CAD-associated loci were significantly and specifically enriched in the subset of chromatin sites altered by oxLDL exposure, including rs72664324 in an oxLDL-induced enhancer at the PPAP2B locus. OxLDL increased C/EBP beta binding to this site and C/EBP beta binding and enhancer activity were stronger with the protective A allele of rs72664324. In addition, expression of the PPAP2B protein product LPP3 was present in foam cells in human atherosclerotic plaques and oxLDL exposure up regulated LPP3 in macrophages resulting in increased degradation of pro inflammatory mediators. Our results demonstrate a genetic mechanism contributing to CAD risk at the PPAP2B locus and highlight the value of studying epigenetic changes in disease processes involving pathogenic environmental stimuli. PMID- 25835003 TI - The impact of forest thinning on the reliability of water supply in central Arizona. AB - Economic growth in Central Arizona, as in other semiarid systems characterized by low and variable rainfall, has historically depended on the effectiveness of strategies to manage water supply risks. Traditionally, the management of supply risks includes three elements: hard infrastructures, landscape management within the watershed, and a supporting set of institutions of which water markets are frequently the most important. In this paper we model the interactions between these elements. A forest restoration initiative in Central Arizona (the Four Forest Restoration Initiative, or 4FRI) will result in thinning of ponderosa pine forests in the upper watershed, with potential implications for both sedimentation rates and water delivery to reservoirs. Specifically, we model the net effect of ponderosa pine forest thinning across the Salt and Verde River watersheds on the reliability and cost of water supply to the Phoenix metropolitan area. We conclude that the sediment impacts of forest thinning (up to 50% of canopy cover) are unlikely to compromise the reliability of the reservoir system while thinning has the potential to increase annual water supply by 8%. This represents an estimated net present value of surface water storage of $104 million, considering both water consumption and hydropower generation. PMID- 25835004 TI - Thriving through transformation. PMID- 25835002 TI - Effects of verapamil SR and atenolol on 24-hour blood pressure and heart rate in hypertension patients with coronary artery disease: an international verapamil SR trandolapril ambulatory monitoring substudy. AB - Elevated nighttime blood pressure (BP) and heart rate (HR), increased BP and HR variability, and altered diurnal variations of BP and HR (nighttime dipping and morning surge) in patients with systemic hypertension are each associated with increased adverse cardiovascular events. However, there are no reports on the effect of hypertension treatment on these important hemodynamic parameters in the growing population of hypertensive patients with atherosclerotic coronary artery disease (CAD). This was a pre-specified subgroup analysis of the INternational VErapamil SR-Trandolapril STudy (INVEST), which involved 22,576 clinically stable patients aged >= 50 years with hypertension and CAD randomized to either verapamil SR- or atenolol-based hypertension treatment strategies. The subgroup consisted of 117 patients undergoing 24-hour ambulatory monitoring at baseline and after 1 year of treatment. Hourly systolic and diastolic BP (SBP and DBP) decreased after 1 year for both verapamil SR- and atenolol-based treatment strategies compared with baseline (P<0.0001). Atenolol also decreased hourly HR (P<0.0001). Both treatment strategies decreased SBP variability (weighted standard deviation: P = 0.012 and 0.021, respectively). Compared with verapamil SR, atenolol also increased the prevalence of BP and HR nighttime dipping among prior non-dippers (BP: OR = 3.37; 95% CI: 1.26-8.97 P = 0.015; HR: OR = 4.06; 95% CI: 1.35-12.17; P = 0.012) and blunted HR morning surge (+2.8 vs. +4.5 beats/min/hr; P = 0.019). Both verapamil SR- and especially atenolol-based strategies resulted in favorable changes in ambulatory monitoring parameters that have been previously associated with increased adverse cardiovascular events. PMID- 25835005 TI - Getting buzzed on innovative leadership. PMID- 25835006 TI - Safety culture and care: a program to prevent surgical errors. AB - Surgical errors are under scrutiny in health care as part of ensuring a culture of safety in which patients receive quality care. Hospitals use safety measures to compare their performance against industry benchmarks. To understand patient safety issues, health care providers must have processes in place to analyze and evaluate the quality of the care they provide. At one facility, efforts made to improve its quality and safety led to the development of a robust safety program with resources devoted to enhancing the culture of safety in the Perioperative Services department. Improvement initiatives included changing processes for safety reporting and performance improvement plans, adding resources and nurse roles, and creating communication strategies around adverse safety events and how to improve care. One key outcome included a 54% increase in the percentage of personnel who indicated in a survey that they would speak up if they saw something negatively affecting patient care. PMID- 25835007 TI - I can't read that! Improving perioperative literacy for ambulatory surgical patients. AB - Low literacy and low health literacy are surprisingly rampant problems facing health care providers. Patient educators in all settings should consider the need for improved patient education materials that are easy to read and understand for the majority of patients. In the ambulatory surgery setting, patients often have time to prepare for scheduled outpatient surgery, yet education is provided primarily in the postoperative period. This article highlights the need for incorporating education into all phases of the perioperative process, beginning in the preoperative period. Perioperative educators should address all learning styles that provide education in a simple and cost-effective way to appeal to all patients and help to reduce postoperative complications and increase patient satisfaction in the ambulatory surgery setting. PMID- 25835008 TI - The nature and hazards of diathermy plumes: a review. AB - Perioperative nurses in the OR may experience more extensive and sustained exposure to surgical plumes than other surgical personnel. Compared with laser plumes, less policy attention has been given to mitigating the risks associated with exposure to diathermy plumes. Diathermy can produce ultrafine particles and volatile chemical and biological substances, of which a number are teratogenic or carcinogenic. Evidence suggests diathermy plumes contain more biohazards than laser plumes, although protective smoke evacuation equipment is less likely to be used with diathermy. Although there is no direct evidence of harm to OR personnel, further research is required to conclusively establish actual risks and appropriate standards for safe exposure. Interventional strategies should address staff attitudes toward diathermy plume exposure and protective measures. This structured review of the literature describes the nature and risks associated with exposure to diathermy plumes and clarifies the implications for protective techniques and nursing practices. PMID- 25835009 TI - Special needs population: Care of the geriatric patient population in the perioperative setting. AB - The geriatric population, defined as people 65 years of age and older, undergoing surgical procedures is a vulnerable population. Age, once considered a contraindication for a surgical procedure, is no longer a constraint for individuals requiring surgical intervention. However, older adult patients are at increased risk for developing a variety of complications. This article reviews age-related physiological changes and discusses the special needs of the geriatric population across the perioperative continuum of care. PMID- 25835010 TI - Stepping up teamwork via TeamSTEPPS. PMID- 25835011 TI - Crisis management of air embolism in the or. AB - An air embolism in the OR is a life-threatening emergency that demands prompt coordinated interventions by all perioperative team members. Specific applications of protocols and guidelines, such as the flowchart provided in this article, provide key components of traditional and effective responses to surgical crises. Successful management of an air embolism event requires critical skills of perioperative nurses who must consider both the risks for VAE or AAE and preventive actions, be aware of the resources available during an air embolism in the OR, and collaborate with their team members through precise and accurate communication. PMID- 25835012 TI - Safe instrument reprocessing: the perioperative role. PMID- 25835014 TI - DRESSed for failure. PMID- 25835015 TI - Regime shift by an exotic nitrogen-fixing shrub mediates plant facilitation in primary succession. AB - Ecosystem invasion by non-native, nitrogen-fixing species is a global phenomenon with serious ecological consequences. However, in the Mediterranean basin few studies addressed the impact of invasion by nitrogen-fixing shrubs on soil quality and hydrological properties at local scale, and the possible effects on succession dynamics and ecosystem invasibility by further species. In this multidisciplinary study we investigated the impact of Genista aetnensis (Biv.) DC., an exotic nitrogen-fixing shrub, on the Vesuvius Grand Cone (Southern Italy). Specifically, we tested the hypotheses that the invasion of G. aetnensis has a significant impact on soil quality, soil hydrological regime, local microclimate and plant community structure, and that its impact increases during the plant ontogenetic cycle. We showed that G. aetnensis, in a relatively short time-span (i.e. ~ 40 years), has been able to build-up an island of fertility under its canopy, by accumulating considerable stocks of C, N, and P in the soil, and by also improving the soil hydrological properties. Moreover, G. aetnensis mitigates the daily range of soil temperature, reducing the exposure of coexisting plants to extremely high temperatures and water loss by soil evaporation, particularly during the growing season. Such amelioration of soil quality, coupled with the mitigation of below-canopy microclimatic conditions, has enhanced plant colonization of the barren Grand Cone slopes, by both herbaceous and woody species. These results suggest that the invasion of G. aetnensis could eventually drive to the spread of other, more resource-demanding exotic species, promoting alternative successional trajectories that may dramatically affect the local landscape. Our study is the first record of the invasion of G. aetnensis, an additional example of the regime shifts driven by N fixing shrubs in Mediterranean region. Further studies are needed to identity specific management practices that can limit the spread and impacts of this species. PMID- 25835016 TI - Correction: effects of the magnetic resonance imaging contrast agent Gd-DTPA on plant growth and root imaging in rice. PMID- 25835017 TI - Detoxification of 1,1,2-trichloroethane to ethene by desulfitobacterium and identification of its functional reductase gene. AB - 1,1,2-trichloroethane (1,1,2-TCA) has become a common groundwater pollutant due to historically extensive utilization, improper disposal, as well as from incomplete dechlorination of 1,1,2,2-tetrachloroethane. Currently, limited information is available on microbial detoxification of 1,1,2-TCA. Desulfitobacterium sp. strain PR, which was isolated from an anaerobic bioreactor maintained to dechlorinate chloroethenes/ethanes, exhibited the capacity to dechlorinate 1,1,1-trichloroethane and chloroform. In this study, the dechlorinating ability of strain PR was further explored. Strain PR showed the capability to dechlorinate 1,1,2-TCA (~1.12 mM) predominantly to 1,2 dichloroethane (1,2-DCA) and chloroethane, and to trace amounts of vinyl chloride and ethene within 20 days. Strain PR coupled growth with dechlorination of 1,1,2 TCA to 1,2-DCA, while no cell growth was observed with dechlorination of 1,2-DCA to chloroethane. Later, through transcriptomic and enzymatic analysis, the reductive dehalogenase CtrA, which was previously reported to be responsible for 1,1,1-trichloroethane and chloroform dechlorination, was identified as the 1,1,2 TCA reductive dehalogenase. Since trichloroethene (TCE) is usually co contaminated with 1,1,2-TCA, a co-culture containing Dehalococcoides mccartyi strain 11a capable of detoxifying TCE and 1,2-DCA and strain PR was established. Interestingly, this co-culture dechlorinated 1,1,2-TCA and TCE to the non-toxic end-product ethene within 48 days without chloroethane production. This novel pathway avoids production of the carcinogenic intermediate dechlorination product vinyl chloride, providing a more environmentally friendly strategy to treat 1,1,2 TCA. PMID- 25835018 TI - Incidence of carbapenem-resistant gram negatives in Italian transplant recipients: a nationwide surveillance study. AB - BACKGROUND: Bacterial infections remain a challenge to solid organ transplantation. Due to the alarming spread of carbapenem-resistant gram negative bacteria, these organisms have been frequently recognized as cause of severe infections in solid organ transplant recipients. METHODS AND FINDINGS: Between 15 May and 30 September 2012 we enrolled 887 solid organ transplant recipients in Italy with the aim to describe the epidemiology of gram negative bacteria spreading, to explore potential risk factors and to assess the effect of early isolation of gram negative bacteria on recipients' mortality during the first 90 days after transplantation. During the study period 185 clinical isolates of gram negative bacteria were reported, for an incidence of 2.39 per 1000 recipient days. Positive cultures for gram negative bacteria occurred early after transplantation (median time 26 days; incidence rate 4.33, 1.67 and 1.14 per 1,000 recipient-days in the first, second and third month after SOT, respectively). Forty-nine of these clinical isolates were due to carbapenem resistant gram negative bacteria (26.5%; incidence 0.63 per 1000 recipient-days). Carbapenems resistance was particularly frequent among Klebsiella spp. isolates (49.1%). Recipients with longer hospital stay and those who received either heart or lung graft were at the highest risk of testing positive for any gram negative bacteria. Moreover recipients with longer hospital stay, lung recipients and those admitted to hospital for more than 48h before transplantation had the highest probability to have culture(s) positive for carbapenem-resistant gram negative bacteria. Forty-four organ recipients died (0.57 per 1000 recipient days) during the study period. Recipients with at least one positive culture for carbapenem-resistant gram negative bacteria had a 10.23-fold higher mortality rate than those who did not. CONCLUSION: The isolation of gram-negative bacteria is most frequent among recipient with hospital stays >48 hours prior to transplant and in those receiving either heart or lung transplants. Carbapenem resistant gram negative isolates are associated with significant mortality. PMID- 25835020 TI - Pegylated-interferon alpha therapy for treatment-experienced chronic hepatitis B patients. AB - BACKGROUND: Studies are limited on pegylated interferon (Peg-IFN) therapy for chronic hepatitis B (CHB) patients who failed or relapsed on previous antiviral therapy. OBJECTIVES: We aimed to investigate the effect of Peg-IFN therapy in treatment-experienced CHB patients. STUDY DESIGN: A total of 57 treatment experienced CHB patients at two medical centers were enrolled. All of the patients were treated with Peg-IFN alpha-2a at 180 MUg weekly for 24 or 48 weeks. The hepatitis B serological markers and viral loads were tested every 3 months until 1 year after stopping Peg-IFN therapy. The endpoints were HBV DNA <2000IU/mL, hepatitis B e antigen (HBeAg) seroconversion, and a hepatitis B surface antigen (HBsAg) loss at 12 months post-treatment. RESULTS: In HBeAg positive patients, 25.0%, 29.2%, and 12.5% of the patients achieved HBeAg seroconversion, HBV DNA <2000 IU/mL and a combined response, respectively, at 12 months post-treatment. Prior IFN therapy, a high baseline ALT level, a low creatinine level, undetectable HBV DNA at 12 weeks and a decline in HBV DNA >2 log10 IU/mL at 12 weeks of therapy were factors associated with treatment response. In HBeAg-negative patients, 9.1%, 15.2%, and 6.1% of the patients achieved undetectable HBV DNA, HBV DNA <2000 IU/mL, and an HBsAg loss, respectively, at 12 months post-treatment. No factor was significantly associated with the treatment response in the HBeAg-negative patients. The median HBsAg level declined from 3.4 to 2.6 log10 IU/mL in all the patients, and the 5-year cumulative rate of the HBsAg loss was 9.8% in the HBeAg-negative patients. Overall, none of the patients prematurely discontinued the Peg-IFN therapy. CONCLUSIONS: Peg-IFN re-treatment is effective for a proportion of HBeAg-positive treatment-experienced patients; it has limited efficacy for HBeAg-negative treatment-experienced patients. Peg-IFN might facilitate HBsAg loss in HBeAg negative treatment-experienced patients. PMID- 25835021 TI - The Standardization Approach in End-of-Life Withdrawal of Life-Sustaining Treatment: Sacrificing Patient's Safety and the Quality of Care. PMID- 25835022 TI - Milk bioactives may manipulate microbes to mediate parent-offspring conflict. AB - Among mammals, milk constituents directly influence the ecology of the infant's commensal microbiota. The immunological and nutritional impacts of breast milk and microbiota are increasingly well understood; less clear are the consequences for infant behavior. Here, we propose that interactions among bioactives in mother's milk and microbes in the infant gut contribute to infant behavioral phenotype and, in part, have the potential to mediate parent-offspring conflict. We hypothesize that infant behavior likely varies as a function of their mother's milk composition interacting with the infant's neurobiology directly and indirectly through the commensal gut bacteria. In this article, we will explore our hypothesis of a milk-microbiota-brain-behavior dynamic in the context of the coevolution between human milk oligosaccharides, bacteria, the gut-brain axis and behavior. Integrating established features of these systems allows us to generate novel hypotheses to motivate future research and consider potential implications of current and emerging clinical treatments. PMID- 25835023 TI - Should Age Limit the Use of Catheter-Directed Thrombolysis: Results of National Survey. AB - OBJECTIVE: To determine whether advanced age should be a contraindication to catheter-directed thrombolysis (CDT) based on hemorrhagic complication rate. METHODS: A survey was generated via Survey Monkey and sent out to vascular surgeons who were members of the society of vascular surgery (SVS). RESULTS: Of the responders, 32.7% state they do not have an age limit for tissue plasminogen activator (TPA) infusion, and the remaining 29.2% of the responders use 80 years of age as their limitation. When asked why place limits on age for TPA infusion, 56.6% stated concern for intracranial hemorrhage. Major complications were access site hemorrhage (58.4%) and intracranial hemorrhage (41.6%). Chi-square analysis did not show age as a limiting factor to thrombolysis. Furthermore, when asked in which age-group complications occurred most commonly, 72.4% were less than 80. CONCLUSION: Among vascular specialist, there seems to be no consensus on age limitations for TPA infusion. Serious complications do not seem to be age related and thus age alone should not be a contraindication for catheter-directed thrombolysis. PMID- 25835024 TI - Block of postjunctional muscle-type acetylcholine receptors in vivo causes train of-four fade in mice. AB - BACKGROUND: Train-of-four (TOF) fade during nerve-mediated muscle contraction is postulated to be attributable to inhibition of prejunctional nicotinic alpha3beta2 acetylcholine receptors (nAChRs), while decrease of twitch tension is attributable to block of postjunctional muscle nAChRs. The validity of these presumptions was tested using specific prejunctional and postjunctional nAChR antagonists, testing the hypothesis that fade is not always a prejunctional phenomenon. METHODS: Pentobarbital anaesthetized mice had TOF fade measured after administration of: either 0.9% saline; the prejunctional alpha3beta2 nAChR antagonist, dihydro-beta-erythroidine (DHbetaE); the postjunctional nAChR antagonists, alpha-bungarotoxin (alpha-BTX) or alpha-conotoxin GI; and a combination of alpha-BTX and DHbetaE; or a combination of alpha-conotoxin GI and DHbetaE. RESULTS: Saline caused no neuromuscular changes. Administration of muscle nAChR antagonists, alpha-BTX or alpha-conotoxin GI caused significant decrease of twitch tension and TOF fade compared with baseline (P<0.01). DHbetaE alone caused no change of twitch tension or fade even after 90 min, but its coadministration with alpha-BTX or alpha-conotoxin GI significantly accelerated the onset of paralysis and degree of fade compared with alpha-BTX or alpha conotoxin GI alone (P<0.01). CONCLUSIONS: Occupation of postjunctional nAChRs alone by alpha-BTX or alpha-conotoxin GI causes fade. As the prejunctional effects of DHbetaE on fade became manifest only when co-administered with alpha BTX or alpha-conotoxin GI, specific inhibition of prejunctional nAChR alone is not necessary and sufficient to cause fade. Fade observed during repetitive nerve stimulation can be because of block of either postjunctional nAChRs alone, or block of prejunctional and postjunctional nAChRs together. PMID- 25835025 TI - Intrajugular balloon catheter reduces air embolism in vitro and in vivo. AB - BACKGROUND: Neurosurgical procedures requiring a sitting position may put the patient at risk of a potentially life-threatening air embolism. Transient manual jugular venous compression limits further air entry in this situation. This study presents an alternative technique aimed at reducing the risk of air embolism. METHODS: In an in vitro model, an intrajugular balloon catheter was inserted to demonstrate that this device prevents air embolism. In an in vivo study, this device was bilaterally placed into jugular vessels in pigs. Using an ultrasound technique, blood flow was monitored and jugular venous pressure was recorded before and during cuff inflation. Air was applied proximally to the inflated cuffs to test the hypothesis that this novel device blocks air passage. RESULTS: In vitro, the intrajugular balloon catheter reliably prevented further air entry (n=10). Additionally, accumulated air could be aspirated from an orifice of the catheter (n=10). In vivo, inflation of the catheter balloon completely obstructed venous blood flow (n=8). Bilateral inflation of the cuff significantly increased the proximal jugular venous pressure from 9.8 (2.4) mm Hg to 14.5 (2.5) mm Hg (n=8, P<0.05). Under conditions mimicking an air embolism, air passage across the inflated cuffs was prevented and 78 (20%) (n=6) of the air dose could be aspirated by the proximal orifice of the catheter. CONCLUSIONS: These findings may serve as a starting point for the development of intrajugular balloon catheters designed to reduce the risk of air embolism in patients undergoing neurosurgery in a sitting position. PMID- 25835026 TI - Marinobacter nitratireducens sp. nov., a halophilic and lipolytic bacterium isolated from coastal surface sea water. AB - A novel Gram-stain-negative, rod-shaped, motile bacterium, designated strain AK21(T), was isolated from coastal surface sea water at Visakhapatnam, India. The strain was positive for oxidase, catalase, lipase, L-proline arylamidase and tyrosine arylamidase activities. The predominant fatty acids were C12:0, C12:0 3 OH, C16:0, C16:1omega9c, C18:1omega9c and summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH). The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unidentified aminophospholipid, two unidentified phospholipids and one unidentified lipid. Q 10 was the predominant respiratory quinone. The DNA G+C content of the strain was 54.6 mol%. 16S rRNA gene sequence analysis indicated that strain AK21(T) was a member of the genus Marinobacter and was closely related to Marinobacter xestospongiae, with pairwise sequence similarity of 97.2% to the type strain, with similarity to other members of the genus of 94.0-96.8%. The mean DNA-DNA relatedness of strain AK21(T) with M. xestospongiae JCM 17469(T) was 34.5%, and relatedness with Marinobacter mobilis JCM 15154(T) was 40.5%. Phylogenetic analysis showed that strain AK21(T) clustered with the type strains of M. xestospongiae and M. mobilis at distances of 2.9 and 2.8% (97.1 and 97.2% similarity), respectively. Based on the phenotypic characteristics and on phylogenetic inference, it appears that strain AK21(T) represents a novel species of the genus Marinobacter, for which the name Marinobacter nitratireducens sp. nov. is proposed. The type strain of Marinobacter nitratireducens is AK21(T) ( = MTCC 11704(T ) = JCM 18428(T)). PMID- 25835027 TI - Phylogenomic analysis shows that Bacillus amyloliquefaciens subsp. plantarum is a later heterotypic synonym of Bacillus methylotrophicus. AB - The rhizosphere-isolated bacteria belonging to the Bacillus amyloliquefaciens subsp. plantarum and Bacillus methylotrophicus clades are an important group of strains that are used as plant growth promoters and antagonists of plant pathogens. These properties have made these strains the focus of commercial interest. Here, we present the draft genome sequence of B. methylotrophicus KACC 13105(T) ( = CBMB205(T)). Comparative genomic analysis showed only minor differences between this strain and the genome of the B. amyloliquefaciens subsp. plantarum type strain, with the genomes sharing approximately 95% of the same genes. The results of morphological, physiological, chemotaxonomic and phylogenetic analyses indicate that the type strains of these two taxa are highly similar. In fact, our results show that the type strain of B. amyloliquefaciens subsp. plantarum FZB42(T) ( = DSM 23117(T) = BGSC 10A6(T)) does not cluster with other members of the B. amyloliquefaciens taxon. Instead, it clusters well within a clade of strains that are assigned to B. methylotrophicus, including the type strain of that species. Therefore, we propose that the subspecies B. amyloliquefaciens subsp. plantarum should be reclassified as a later heterotypic synonym of B. methylotrophicus. PMID- 25835028 TI - Differentiating Milk and Non-milk Proteins by UPLC Amino Acid Fingerprints Combined with Chemometric Data Analysis Techniques. AB - Amino acid fingerprinting combined with chemometric data analysis was used to differentiate milk and non-milk proteins in this study. Microwave-assisted hydrolysis and ultraperformance liquid chromatography (UPLC) were used to obtain the amino acid fingerprints. Both univariate and multivariate chemometrics methods were applied for differentiation. The confidence boundary of amino acid concentration, principal component analysis (PCA), and partial least-squares discriminant analysis (PLS-DA) of the amino acid fingerprints demonstrated that there were significant differences between milk proteins and inexpensive non-milk protein powders from other biological sources including whey, peanut, corn, soy, fish, egg yolk, beef extract, collagen, and cattle bone. The results indicate that the amino acid compositions with the chemometric techniques could be applied for the detection of potential protein adulterants in milk. PMID- 25835029 TI - Hot carrier relaxation of Dirac fermions in bilayer epitaxial graphene. AB - Energy relaxation of hot Dirac fermions in bilayer epitaxial graphene is experimentally investigated by magnetotransport measurements on Shubnikov-de Haas oscillations and weak localization. The hot-electron energy loss rate is found to follow the predicted Bloch-Gruneisen power-law behaviour of T(4) at carrier temperatures from 1.4 K up to ~100 K, due to electron-acoustic phonon interactions with a deformation potential coupling constant of 22 eV. A carrier density dependence n(e)(-1.5) in the scaling of the T(4) power law is observed in bilayer graphene, in contrast to the n(e)(-0.5) dependence in monolayer graphene, leading to a crossover in the energy loss rate as a function of carrier density between these two systems. The electron-phonon relaxation time in bilayer graphene is also shown to be strongly carrier density dependent, while it remains constant for a wide range of carrier densities in monolayer graphene. Our results and comparisons between the bilayer and monolayer exhibit a more comprehensive picture of hot carrier dynamics in graphene systems. PMID- 25835030 TI - Hydrogen adsorption study. Formation of quantum dots on graphene nanoribbons within tight-binding approach. AB - Based on the tight-binding model, we investigate the formation process of quantum dots onto graphene nanoribbons (GNRs) by the sequential adsorption of hydrogen atoms onto the ribbon's surface. We define the difference between hydrogenation processes onto the surface of zigzag (ZGNR) and armchair graphene nanoribbons (AGNR) by calculating the binding energies with respect to the energy of isolated hydrogen atoms for all considered structures. PMID- 25835031 TI - Growth Behavior, Geometrical Shape, and Second CMC of Micelles Formed by Cationic Gemini Esterquat Surfactants. AB - Micelles formed by novel gemini esterquat surfactants have been investigated with small-angle neutron scattering (SANS). The growth behavior of the micelles is found to differ conspicuously depending on the length of the gemini surfactant spacer group. The gemini surfactant with a long spacer form rather small triaxial ellipsoidal tablet-shaped micelles that grow weakly with surfactant concentration in the entire range of measured concentrations. Geminis with a short spacer, on the other hand, form weakly growing oblates or tablets at low concentrations that start to grow much more strongly into polydisperse rodlike or wormlike micelles at higher concentrations. The latter behavior is consistent with the presence of a second CMC that marks the transition from the weakly to the strongly growing regime. It is found that the growth behavior in terms of aggregation number as a function of surfactant concentration always appear concave in weakly growing regimes, while switching to convex behavior in strongly growing regimes. As a result, we are able to determine the second CMC of the geminis with short spacer by means of suggesting a rather precise definition of it, located at the point of inflection of the growth curve that corresponds to the transition from concave to convex growth behavior. Our SANS results are rationalized by comparison with the recently developed general micelle model. In particular, this theory is able to explain and reproduce the characteristic appearances of the experimental growth curves, including the presence of a second CMC and the convex strongly growing regime beyond. By means of optimizing the agreement between predictions from the general micelle model and results from SANS experiments, we are able to determine the three bending elasticity constants spontaneous curvature, bending rigidity, and saddle-splay constant for each surfactant. PMID- 25835032 TI - Realization of Cu-Doped p-Type ZnO Thin Films by Molecular Beam Epitaxy. AB - Cu-doped p-type ZnO films are grown on c-sapphire substrates by plasma-assisted molecular beam epitaxy. Photoluminescence (PL) experiments reveal a shallow acceptor state at 0.15 eV above the valence band edge. Hall effect results indicate that a growth condition window is found for the formation of p-type ZnO thin films, and the best conductivity is achieved with a high hole concentration of 1.54 * 10(18) cm(-3), a low resistivity of 0.6 Omega cm, and a moderate mobility of 6.65 cm(2) V(-1) s(-1) at room temperature. Metal oxide semiconductor capacitor devices have been fabricated on the Cu-doped ZnO films, and the characteristics of capacitance-voltage measurements demonstrate that the Cu-doped ZnO thin films under proper growth conditions are p-type. Seebeck measurements on these Cu-doped ZnO samples lead to positive Seebeck coefficients and further confirm the p-type conductivity. Other measurements such as X-ray diffraction, X ray photoelectron, Raman, and absorption spectroscopies are also performed to elucidate the structural and optical characteristics of the Cu-doped p-type ZnO films. The p-type conductivity is explained to originate from Cu substitution of Zn with a valency of +1 state. However, all p-type samples are converted to n type over time, which is mostly due to the carrier compensation from extrinsic defects of ZnO. PMID- 25835033 TI - Direct night-time ejection of particle-phase reduced biogenic sulfur compounds from the ocean to the atmosphere. AB - The influence of oceanic biological activity on sea spray aerosol composition, clouds, and climate remains poorly understood. The emission of organic material and gaseous dimethyl sulfide (DMS) from the ocean represents well-documented biogenic processes that influence particle chemistry in marine environments. However, the direct emission of particle-phase biogenic sulfur from the ocean remains largely unexplored. Here we present measurements of ocean-derived particles containing reduced sulfur, detected as elemental sulfur ions (e.g., (32)S(+), (64)S2(+)), in seven different marine environments using real-time, single particle mass spectrometry; these particles have not been detected outside of the marine environment. These reduced sulfur compounds were associated with primary marine particle types and wind speeds typically between 5 and 10 m/s suggesting that these particles themselves are a primary emission. In studies with measurements of seawater properties, chlorophyll-a and atmospheric DMS concentrations were typically elevated in these same locations suggesting a biogenic source for these sulfur-containing particles. Interestingly, these sulfur-containing particles only appeared at night, likely due to rapid photochemical destruction during the daytime, and comprised up to ~67% of the aerosol number fraction, particularly in the supermicrometer size range. These sulfur-containing particles were detected along the California coast, across the Pacific Ocean, and in the southern Indian Ocean suggesting that these particles represent a globally significant biogenic contribution to the marine aerosol burden. PMID- 25835034 TI - Fibroepithelial vaginal polyp in a newborn. AB - A fibroepithelial polyp of the vagina (FEPV) is a mucosal polypoid lesion with a connective tissue core covered by a benign squamous epithelium. A vaginal polyp must be considered in the evaluation of interlabial masses in prepubertal girls. This article describes a newborn girl with an interlabial mass that the histological analysis revealed to be an FEPV. Surgical excision of the mass was performed, and the patient has not experienced recurrence after 1-year of follow up. A review of the literature revealed that our case was the third reported case of a fibroepithelial polyp in a neonate. PMID- 25835035 TI - Role of steroidal anti-inflammatory agent prior to intracorporeal lithotripsy under local anesthesia for ureterovesical junction calculus: A prospective randomized controlled study. AB - OBJECTIVE: The objective of the following study is to assess the effect of steroidal anti-inflammatory agent on the outcome of ureterorenoscopic lithotripsy (URSL) for ureterovesical junction (UVJ) calculus. SETTINGS AND DESIGN: This was a prospective randomized controlled study conducted at the Department of Urology, Regional Institute of Medical Sciences, Imphal. SUBJECTS AND METHODS: One hundred and twenty-six patients requiring ureteroscopic lithotripsy for UVJ calculus were randomly assigned into two groups. The study group received tablet deflazacort 30 mg once a day for 10 days prior to the procedure, whereas the control group did not receive such treatment. Parameters with respect to the outcome of the procedure were recorded for all patients in both groups. STATISTICAL ANALYSIS USED: Fisher's exact and independent t-test was used to compare the outcome between the groups where P < 0.05 was considered to be statistically significant. RESULTS: There was significant statistical difference (P - 0.016) on the endoscopic appearance of the region of ureteric orifice in patients receiving steroidal anti-inflammatory agent compared with control. Severe procedure related pain and mean operative time was less in the study group compared to control (P - 0.020 and 0.031, respectively). Re-treatment rates in the study group were lower than the control group (4.76% vs. 17.46%) and found to be statistically significant (P - 0.044). It is found that computed tomography (CT) appearance (r 0.399) and stone size (r - 0.410) strongly correlate with the endoscopic findings of the region of UVJ (P - 0.001). CONCLUSIONS: Inflamed and or obliterated ureteric orifice is the major constraints for stone clearance at ureterovesical junction. The present study showed the administration of tablet deflazacort (a steroidal anti-inflammatory agent) significantly improves the outcome of URSL under local anesthesia. We strongly recommend its use prior to URSL for UVJ calculus, especially for stone size >=10.24 mm and on CT evidence of prominent soft tissue swelling at the UVJ. PMID- 25835036 TI - Ventricular tachycardia on chronic fingolimod treatment for multiple sclerosis. PMID- 25835037 TI - Psychosis associated with expansions in the C9orf72 gene: the influence of a 10 base pair gene deletion. PMID- 25835039 TI - Mitochondrial transfer RNA variants and primary congenital glaucoma. AB - Variants in mitochondrial DNA (mtDNA) are the most important causes for vision loss, the mt-tRNA variants being the largest group among them. In this study, we report the molecular characterization of 15 mt-tRNA variants with primary congenital glaucoma (PCG). Based on phylogenetic approach, we found that only half of them were definitely pathogenic with PCG, other mutations were single nucleotide polymorphisms (SNP) in human population. Thus, our study provided novel insight into the pathogenesis of PCG. PMID- 25835038 TI - Candidate-gene analysis of white matter hyperintensities on neuroimaging. AB - BACKGROUND: White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR). METHODS: Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR. RESULTS: We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixed-effects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(-344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90-3.41; observed OR=1.68; 95% CI, 0.97 2.94). Neither CYP11B2 T(-344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH. CONCLUSIONS: There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest. PMID- 25835040 TI - Extent and divergence of heteroplasmy of the DNA barcoding region in Anapodisma miramae (Orthoptera: Acrididae). AB - A partial sequence of the mitochondrial cytochrome oxidase subunit I (COI) gene is widely used as a molecular marker for species identification in animals, also termed a DNA barcode. However, the presence of more than one sequence type in a single individual, also known as heteroplasmy, is one of the shortcomings of barcode identification. In this study, we examined the extent and divergence of COI heteroplasmy, including nuclear-encoded mitochondrial pseudogenes (NUMTs), at the genomic-DNA level from 13 insect species including orthopteran Anapodisma miramae, and a long fragment of mitochondrial DNA and cDNA from A. miramae as templates. When multiple numbers of clones originated from genomic DNA were sequenced, heteroplasmy was prevalent in all species and NUMTs were observed in five species. Long fragment DNA (~13.5 kb) also is a source of heteroplasmic amplification, but the divergent haplotypes and NUMTs obtained from genomic DNA were not detected in A. miramae. On the other hand, cDNA was relatively heteroplasmy-free. Consistently, one dominant haplotype was always obtained from the genomic DNA-origin clones in all species and also from the long fragment- and cDNA-origin clones in the two tested individuals of A. miramae. Furthermore, the dominant haplotype was identical in sequence, regardless of the DNA source in A. miramae. Thus, one possible solution to avoid the barcoding problem in relationship to heteroplasmy could be the acquisition of multiple numbers of barcoding sequences to determine a dominant haplotype that can be assigned as barcoding sequence for a given species. PMID- 25835041 TI - A new method for fast chitin extraction from shells of crab, crayfish and shrimp. AB - A new method for quick chitin isolation from the shells of crab, crayfish and shrimp is described. The main difference between the new method and the conventional method is two sodium hypochlorite (NaClO) treatments for 10 min each before the processes of demineralisation and deproteinisation. After the NaClO treatment, only 15 min is adequate for the demineralisation and 20 min for the deproteinisation processes. Newly extracted chitin from crab, crayfish and shrimp shells and commercial chitin were characterised using FT-IR, TGA, X-ray diffractometry and elemental analysis. From the results, it was observed that the chitins isolated with the new method and the commercial chitin had almost the same physicochemical properties. The advantage of the new method compared to traditional methods is the relatively rapid chitin extraction. When compared to the traditional chitin extraction method, the proposed method appears to be promising regarding its time and energy saving nature. PMID- 25835042 TI - Novel natural food colourant G8000 benefits LDL- and HDL-cholesterol in humans. AB - The aim of this study was to investigate the phenolic composition of a natural food colourant (G8000TM) as well as its effects on plasma markers after 28-day consumption by healthy individuals at a dietary dose (70 g). Parameters of total cholesterol and its fractions, triglycerides and plasma enzymes biomarkers of muscle injury were measured. Major compounds identified in G8000TM by ESI-MS showed the presence of anthocyanins, organic acids, phenolic acids as well as monosaccharides. HDL levels significantly increased from 43 +/- 10.2 mg/dL to 95 +/- 16.9 mg/dL. LDL levels significantly decreased from 110 +/- 40.9 mg/dL to 69 +/- 39 mg/dL (p < 0.001). No significant statistical differences (p > 0.05) were observed for total cholesterol, triglycerides and VLDL. After the intake, plasma enzyme CK-MB decreased from 20 +/- 12.1 U/L to 10 +/- 1.9 U/L while LDH levels increased from 275 +/- 124.4 U/L to 317 +/- 114.7 U/L (p < 0.005). No significant differences were observed for CK levels. Taken together, dietary intake of natural colourant G8000TM was able to exert beneficial effects on atherosclerosis biomarkers. PMID- 25835043 TI - Evaluation of the risk of post-operative bleeding complications in skin cancer surgery without interruption of anticoagulant/antithrombotic medication: A prospective cohort study. AB - BACKGROUND: Previous reports showed lack of consensus concerning interruption of anticoagulant/antithrombotic (AC/AT) treatment before skin cancer surgery. AIM: The aim of this study was to evaluate the risk of postoperative bleeding in patients on AC/AT treatment undergoing skin cancer surgery without interruption of this treatment. METHOD: This prospective cohort study included 271 consecutive patients divided into two groups - patients without and patients with AC/AT therapy. Inclusion criteria were skin cancer (basal-cell carcinoma, squamous-cell carcinoma, or malignant melanoma). Exclusion criteria were patients undergoing regional lymph node dissection or sentinel lymph node biopsy. Postoperative bleeding complications taken into consideration were those evaluated as moderate or severe and requiring some form of surgical or non-surgical hemostasis on an outpatient or inpatient basis. RESULTS: There were 47 patients in the AC/AT group and 224 in the control group (mean age = 76.6 and 68 years, respectively), with almost equal distribution of tumours in both groups. There were 34.1% of patients on AT, 55% on AC treatment, and 10.6% on mixed treatment (AC+AT or AT+AT). Postoperative bleeding complications did not show a statistically significant difference between the two groups (p = 0.063). CONCLUSION: Skin cancer surgery can be safely performed without discontinuation of AC/AT treatment, since the risk of postoperative bleeding is statistically insignificant. PMID- 25835044 TI - Protection motivation theory and social distancing behaviour in response to a simulated infectious disease epidemic. AB - Epidemics of respiratory infectious disease remain one of the most serious health risks facing the population. Non-pharmaceutical interventions (e.g. hand-washing or wearing face masks) can have a significant impact on the course of an infectious disease epidemic. The current study investigated whether protection motivation theory (PMT) is a useful framework for understanding social distancing behaviour (i.e. the tendency to reduce social contacts) in response to a simulated infectious disease epidemic. There were 230 participants (109 males, 121 females, mean age 32.4 years) from the general population who completed self report measures assessing the components of PMT. In addition, participants completed a computer game which simulated an infectious disease epidemic in order to provide a measure of social distancing behaviour. The regression analyses revealed that none of the PMT variables were significant predictors of social distancing behaviour during the simulation task. However, fear (beta = .218, p < .001), response efficacy (beta = .175, p < .01) and self-efficacy (beta = .251, p < .001) were all significant predictors of intention to engage in social distancing behaviour. Overall, the PMT variables (and demographic factors) explain 21.2% of the variance in intention. The findings demonstrated that PMT was a useful framework for understanding intention to engage in social distancing behaviour, but not actual behaviour during the simulated epidemic. These findings may reflect an intention-behaviour gap in relation to social distancing behaviour. PMID- 25835045 TI - Discrete-choice experiments versus rating scale exercises to evaluate the importance of attributes. AB - AIM: To examine the difference between discrete-choice experiments (DCE) and rating scale exercises (RSE) in determining the most important attributes using a case study. METHODS: Undergraduate health sciences students were asked to complete a DCE and a RSE. Six potentially important attributes were identified in focus groups. Fourteen unlabelled choice tasks were constructed using a statistically efficient design. Mixed multinomial logistic regression analysis was used for DCE data analysis. RESULTS: In total, 254 undergraduate students filled out the questionnaire. In the DCE, only four attributes were statistically significant, whereas in the RSE, all attributes except one were rated four or higher. CONCLUSION: Attribute importance differs between DCE and RSE. The DCE had a differentiating effect on the relative importance of the attributes; however, determining relative importance using DCE should be done with caution as a lack of statistically significant difference between levels does not necessarily imply that the attribute is not important. PMID- 25835046 TI - Biomarkers of selenium status. AB - The essential trace element, selenium (Se), has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 MUg/day and for animals <20 MUg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites. PMID- 25835047 TI - The infant gut microbiome: evidence for obesity risk and dietary intervention. AB - Increasing globally, particularly in children, obesity is a serious public health issue and risk factor for overweight and metabolic disease in later life. Both in experimental animal and human studies, advances in gene sequencing technologies have yielded intriguing possibilities for the role of the gut microbiome in later development of overweight status. Before translating study findings into practice, we must first reconcile inconsistencies between animal experimentation, and human adult and infant studies. Recent evidence for associations with gut microbiota and infant weight gain or child weight status, implicate Bacteroides and Lactobacillus species. Dietary manipulation with human milk and pre/probiotic formulations holds promise for preventing obesity. PMID- 25835048 TI - The role of omega-3 fatty acids in acute pancreatitis: a meta-analysis of randomized controlled trials. AB - To determine whether treatment with omega-3 fatty acids (omega-3 FA) provides benefits to patients with acute pancreatitis (AP). The Cochrane Library, PubMed, Embase, Web of Science, and Chinese Biomedical Literature Database were searched. Data analysis was performed using Revman 5.2 software. A total of eight randomized controlled trials (RCTs) were included. Overall, omega-3 FA treatment resulted in a significantly reduced risk of mortality (RR 0.35; 95% CI 0.16 to 0.75, p < 0.05), infectious complications (RR 0.54; 95% CI 0.34 to 0.85, p < 0.05) and length of hospital stay (MD -6.50; 95% CI -9.54 to -3.46, p < 0.05), but not length of ICU stay (MD -1.98; 95% CI -6.92 to 2.96, p > 0.05). In subgroup analysis, only patients who received omega-3 FA parenterally had some statistically significant benefits in terms of mortality (risk ratio (RR) 0.37; 95% confidence interval (CI) 0.16 to 0.86, p < 0.05), infectious complications (RR 0.5; 95% CI 0.28 to 0.9, p < 0.05) and length of hospital stay (mean difference (MD) -8.13; 95% CI -10.39 to -5.87, p < 0.001). The administration of omega-3 FA may be beneficial for decreasing mortality, infectious complications, and length of hospital stay in AP, especially when used parenterally. Large and rigorously designed RCTs are required to elucidate the efficacy of parenteral or enteral omega-3 FA treatment in AP. PMID- 25835051 TI - Surgical Treatment of Dysthyroid Optic Neuropathy: Long-Term Visual Outcomes with Comparison of 2-Wall versus 3-Wall Orbital Decompression. AB - PURPOSE: To compare the long-term visual outcomes after 2-wall (medial-lateral) versus 3-wall (medial-lateral-inferior) orbital decompression combined with fat removal in patients with dysthyroid optic neuropathy (DON). METHODS: Records of 68 eyes of 42 patients were retrospectively reviewed. Two-and 3-wall decompression was performed in 41 and 27 eyes, respectively. Transcaruncular approach was used for medial wall decompression. Lateral canthotomy combined with upper eyelid crease incision was used for lateral wall removal, and combined with transconjunctival lower eyelid incision if floor decompression performed. Outcome measures were visual acuity (VA), color vision, Hertel measures, visual field mean deviation (MD) and pattern standard deviation (PSD) Result: The mean follow up time was 39.3 months (range, 12-72 months). All indicators of visual function significantly improved after 2-and 3-wall decompression. The improvement in VA and color vision was similar between groups. (logMAR VA: 2-wall: 0.52 +/- 0.68 versus 3-wall: 0.71 +/- 0.86, p = 0.335); (color vision on Ishihara plates: 2 wall: 10.1 +/- 8.1 versus 3-wall: 11.6 +/- 7.8, p = 0.447). The improvement in MD and PSD were higher after 3-wall decompression (MD: 2-wall: 10.0 +/- 5.5 versus 3 wall: 14.3 +/- 7.5 dB, p = 0.020); (PSD: 2-wall: 3.5 +/- 1.9 versus 3-wall: 4.8 +/- 3.0 dB, p = 0.045). Proptosis reduction was higher after 3-wall decompression (2-wall: 5.1 +/- 1.3 versus 3-wall: 7.2 +/- 1.9 mm, p = 0.0001). New onset diplopia was seen 20% and 28.5% of cases in 2-and 3-wall decompression, respectively. No adnexal/orbital complications were seen in 2-wall group, however orbital hematoma (1 case) and persisting eyelid edema (1 case) were encountered in 3-wall group. CONCLUSION: Both 2-and 3-wall orbital decompressions are safe and effective for management of visual dysfunction in DON. Although 3-wall decompression provide better improvement in the parameters of visual field analysis and Hertel measures, new onset diplopia, adnexal/orbital complications are more common with this technique. PMID- 25835050 TI - c-Myc modulation: a key role in melanoma drug response. AB - Understanding molecular mechanisms involved in melanoma resistance to drugs is a big challenge. Experimental evidences suggested a correlation between mutational status in B-RAF and melanoma cell susceptibility to drugs, such as paclitaxel, doxorubicin and temozolomide, which generate an accumulation of hydrogen peroxide (H2O2) in the cells. We investigated the survival phenotype and the protein level of c-myc, a B-RAF target molecule, in melanoma cells, carrying a different mutational status in B-RAF, upon paclitaxel, doxorubicin and H2O2 treatment. For the first time, we reported c-myc modulation is critical for melanoma drug response. It appeared drug-specific and post-transcriptionally driven through PP2A; in correlation, cell pre-treatment with okadaic acid (OA), a specific PP2A inhibitor, as well as PP2A silencing of melanoma cells, was able to increase melanoma cell drug-sensitivity and c-myc protein level. This is relevant for designing efficacious therapeutic strategies in melanoma. PMID- 25835052 TI - Functional flexibility in women's commitment-skepticism bias. AB - If a woman overestimates her romantic partner's commitment, the cost to her fitness-reproduction without an investing partner-can be considerable. Error Management Theory predicts that women have an evolved bias to be skeptical of men's commitment in a relationship, which reduces the likelihood of making a costly false positive error. However, because error probabilities are inversely related, this commitment-skepticism bias simultaneously increases the likelihood of missed opportunities, or false negatives. False positives when gauging a partner's commitment are the more costly error for women, but missing an opportunity to secure a genuinely high-quality mate can also be quite costly. We predicted and found that women's mating cognitions are functionally flexible, such that women do not exhibit the commitment-skepticism bias when faced with behavioral evidence that a male partner is willing to commit (Study 1). This suggests that relationship-enhancing behaviors are one contextual cue that may lessen the bias. However, not all relationship-enhancing behaviors are equally diagnostic of a person's true commitment intent. When comparing men and women's commitment thresholds, we found that women require more behavioral evidence than men do to feel certain of their partner's commitment to them (Study 2). PMID- 25835049 TI - Duodenal cytochrome b (DCYTB) in iron metabolism: an update on function and regulation. AB - Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally; both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake; rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut; ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities; intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes; namely those of the cytochrome b561 class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron) on the opposite side of the membrane. One member of this family; duodenal cytochrome b (DCYTB); may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis; the emergent "IRP1-HIF2alpha axis"; DCYTB and ascorbate in relation to iron metabolism. PMID- 25835054 TI - Is ring breaking feasible in relative binding free energy calculations? AB - Our interest is relative binding free energy (RBFE) calculations based on molecular simulations. These are promising tools for lead optimization in drug discovery, computing changes in binding free energy due to modifications of a lead compound. However, in the "alchemical" framework for RBFE calculations, some types of mutations have the potential to introduce error into the computed binding free energies. Here we explore the magnitude of this error in several different model binding calculations. We find that some of the calculations involving ring breaking have significant errors, and these errors are especially large in bridged ring systems. Since the error is a function of ligand strain, which is unpredictable in advance, we believe that ring breaking should be avoided when possible. PMID- 25835053 TI - Psychosocial interventions for pregnant women in outpatient illicit drug treatment programs compared to other interventions. AB - BACKGROUND: Illicit drug use in pregnancy is a complex social and public health problem. The consequences of drug use in pregnancy are high for both the woman and her child. Therefore, it is important to develop and evaluate effective treatments. There is evidence for the effectiveness of psychosocial interventions in drug treatment but it is unclear whether they are effective in pregnant women. This is an update of a Cochrane review originally published in 2007. OBJECTIVES: To evaluate the effectiveness of psychosocial interventions in pregnant women enrolled in illicit drug treatment programmes on birth and neonatal outcomes, on attendance and retention in treatment, as well as on maternal and neonatal drug abstinence. In short, do psychosocial interventions translate into less illicit drug use, greater abstinence, better birth outcomes, or greater clinic attendance? SEARCH METHODS: We conducted the original literature search in May 2006 and performed the search update up to January 2015. For both review stages (original and update), we searched the Cochrane Drugs and Alcohol Group Trial's register (May 2006 and January 2015); the Cochrane Central Register of Trials (CENTRAL; the Cochrane Library 2015, Issue 1); PubMed (1996 to January 2015); EMBASE (1996 to January 2015); and CINAHL (1982 to January 2015). SELECTION CRITERIA: We included randomized controlled trials comparing any psychosocial intervention vs. a control intervention that could include pharmacological treatment, such as methadone maintenance, a different psychosocial intervention, counselling, prenatal care, STD counselling and testing, transportation, or childcare. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. We performed analyses based on three comparisons: any psychosocial intervention vs. control, contingency management (CM) interventions vs. control, and motivational interviewing based (MIB) interventions vs. MAIN RESULTS: In total, we included 14 studies with 1298 participants: nine studies (704 participants) compared CM vs. control, and five studies (594 participants) compared MIB interventions vs. CONTROL: We did not find any studies that assessed other types of psychosocial interventions. For the most part, it was unclear if included studies adequately controlled for biases within their studies as such information was not often reported. We assessed risk of bias in the included studies relating to participant selection, allocation concealment, personnel and outcome assessor blinding, and attrition.The included trials rarely captured maternal and neonatal outcomes. For studies that did measure such outcomes, no difference was observed in pre-term birth rates (RR 0.71, 95% confidence interval (CI) 0.34 to 1.51; three trials, 264 participants, moderate quality evidence), maternal toxicity at delivery (RR 1.18, 95% CI 0.52 to 2.65; two trials, 217 participants, moderate quality evidence), or low birth weight (RR 0.72, 95% CI 0.36 to 1.43; one trial, 160 participants, moderate quality evidence). However, the results did show that neonates remained in hospital for fewer days after delivery in CM intervention groups (RR -1.27, 95% CI -2.52 to -0.03; two trials, 103 participants, moderate quality evidence). There were no differences observed at the end of studies in retention or abstinence (as assessed by positive drug test at the end of treatment) in any psychosocial intervention group compared to control (Retention: RR 0.99, 95% CI 0.93 to 1.06, nine trials, 743 participants, low quality evidence; and Abstinence: RR 1.14, 95% CI 0.75 to 1.73, three trials, 367 participants, low quality evidence). These results held for both CM and MIB combined. Overall, the quality of the evidence was low to moderate. AUTHORS' CONCLUSIONS: The present evidence suggests that there is no difference in treatment outcomes to address drug use in pregnant women with use of psychosocial interventions, when taken in the presence of other comprehensive care options. However, few studies evaluated obstetrical or neonatal outcomes and rarely did so in a systematic way, making it difficult to assess the effect of psychosocial interventions on these clinically important outcomes. It is important to develop a better evidence base to evaluate psychosocial modalities of treatment in this important population. PMID- 25835055 TI - Breast cancer in women in their thirties (2007-2013): a retrospective review. AB - Due to an increasing number of breast cancer diagnoses in younger women anecdotally noted at our institution, we conceived of this study %was to retrospectively review the records of women diagnosed with breast cancer under the age of 40 for potentially alterable versus unalterable risk factors in their history. Between 2007 and 2013, there were 52 patients less than 40 years of age with breast cancer at our institution: 79% (41/52) presented with a clinical abnormality (palpable mass, nipple discharge or inversion) and 21% (11/52) were asymptomatic but diagnosed on early screening mammograms. Seventy-five percent (39/52) of the cancers had an invasive component and 87% (45/52) were intermediate to high grade. Sixty percent (31/52) of subjects had stage 0 or I disease, but 40% (21/52) had later stage disease (stage II or greater). The vast majority of the cancers were ER+ (82%) and PR+ (78%). Fifty-six percent (28/50; 2 unknown) of the subjects had a documented history of hormonal contraception. Fifty-three percent (27/51; 1 unknown) of had no family history of breast cancer whatsoever, and 80% (41/51) had no family history of breast cancer in a first degree relative. Six were positive for BRCA 1, 2, or a variant (6/52 = 12%). PMID- 25835056 TI - Ultrasensitive graphene far-infrared power detectors. AB - We describe the properties of ultrasensitive graphene photon detectors for use in the far-infrared/terahertz spectral region and present theoretical predictions for their power detection sensitivity. These predictions are based on two graphene contacting schemes with superconducting contacts: contacts with a thin insulating barrier, and direct superconducting contacts. To quantitatively assess these predictions, we perform thermal measurements of graphene at low temperatures and analyse them to extract information on electron-phonon cooling in graphene. These new results for the electron-phonon cooling channel allow reliable prediction of the noise equivalent power (NEP) that can be expected from an optimized graphene detector, using measurement of the Johnson noise emission as the thermometry method. We find that an NEP of 2 * 10(-19) W Hz(-1/2) should be achievable under certain biasing conditions with an ideal device. PMID- 25835057 TI - Stick-jump mode in surface droplet dissolution. AB - The analogy between evaporating surface droplets in air to dissolving long-chain alcohol droplets in water is worked out. We show that next to the three known modi for surface droplet evaporation or dissolution (constant contact angle mode, constant contact radius mode, and stick-slide mode), a fourth mode exists for small droplets on supposedly smooth substrates, the stick-jump mode: intermittent contact line pinning causes the droplet to switch between sticking and jumping during the dissolution. We present experimental data and compare them to theory to predict the dissolution time in this stick-jump mode. We also explain why these jumps were easily observed for microscale droplets but not for larger droplets. PMID- 25835058 TI - Disulfide-Mediated beta-Strand Dimers: Hyperstable beta-Sheets Lacking Tertiary Interactions and Turns. AB - Disulfide bonds between cysteine residues are essential to the structure and folding of many proteins. Yet their role in the design of structured peptides and proteins has frequently been limited to use as intrachain covalent staples that reinforce existing structure or induce knot-like conformations. In beta-hairpins, their placement at non-H-bonding positions across antiparallel strands has proven useful for achieving fully folded positive controls. Here we report a new class of designed beta-sheet peptide dimers with strand-central disulfides as a key element. We have found that the mere presence of a disulfide bond near the middle of a short peptide chain is sufficient to nucleate some antiparallel beta-sheet structure; addition of beta-capping units and other favorable cross-strand interactions yield hyperstable sheets. Strand-central cystines were found to be superior to the best designed reversing turns in terms of nucleating beta-sheet structure formation. We have explored the limitations and possibilities of this technique (the use of disulfides as sheet nucleators), and we provide a set of rules and rationales for the application and further design of disulfide-tethered "turnless" beta-sheets. PMID- 25835059 TI - Antibiotics prophylaxis before prostate biopsy in practice: Review of online clinical guidelines. PMID- 25835061 TI - In vitro assessment of endocrine disrupting potential of naphthenic Acid fractions derived from oil sands-influenced water. AB - Oil sands-influenced process waters have been observed to cause reproductive effects and to induced CYP1A activity in fishes; however, little progress has been made in determining causative agents. Naphthenic acids (NAs) are the predominant organic compounds in process-affected waters, but due to the complexity of the mixture, it has been difficult to examine causal linkages in fishes. The aim of this study was to use in vitro assays specific to reproductive and CYP1A mechanisms to determine if specific acid extractable fractions of NAs obtained from oil sands-influenced water are active toward reproductive processes or interact with the Ah receptor responsible for CYP1A activity. NAs were extracted from aged oil sands-influenced waters by use of acid precipitation, and the mixture was fractionated into three acidic and one neutral fraction. The four fractions were examined for Ah receptor-mediated potency by use of the H4IIE-luc bioassay, effects on production of steroid hormones by use of the H295R steroidogenesis assay, and sex steroid receptor binding activity using the yeast estrogen screen and yeast androgen screen. The mixtures were characterized by high resolution mass spectrometry, (1)H nuclear magnetic resonance, and attenuated total reflectance infrared spectroscopy. The neutral fraction elicited Ah-receptor mediated activity after 24 h but not after 48 or 72 h. None of the fractions contained measurable levels of estrogen or androgen receptor agonists nor did they cause reductions in steroidogenesis. A number of fractions showed antiestrogenic or antiandrogenicity potency, with the neutral and main acidic fractions being the most potent. Neutral aromatic compounds are likely responsible for the CYP1A activity observed. Direct estrogenic, androgenic, or steroidogenic mechanisms are unlikely for NAs based on these results, but NAs act as potent antiandrogen or antiestrogens. PMID- 25835062 TI - Plasmonic three-dimensional transparent conductor based on Al-doped zinc oxide coated nanostructured glass using atomic layer deposition. AB - Transparent nanostructured glass coatings, fabricated on glass substrates, with a unique three-dimensional (3D) architecture were utilized as the foundation for designing plasmonic 3D transparent conductors. Transformation of the nonconducting 3D structure to a conducting porous surface network was accomplished through atomic layer deposition of aluminum-doped zinc oxide (AZO). After AZO growth, gold nanoparticles (AuNPs) were deposited by electron-beam evaporation to enhance light trapping and decrease the overall sheet resistance. Field emission scanning electron microscopy and atomic force microcopy images revealed the highly porous, nanostructured morphology of the AZO-coated glass surface along with the in-plane dimensions of the deposited AuNPs. Sheet resistance measurements conducted on the coated samples verified that the electrical properties of the 3D network are comparable to those of untextured two dimensional AZO-coated glass substrates. In addition, transmittance measurements of the glass samples coated at various AZO thicknesses showed preservation of the transparent nature of each sample, and the AuNPs demonstrated enhanced light scattering as well as light-trapping capabilities. PMID- 25835063 TI - A narrowing range of bone scan in newly diagnosed prostate cancer patients: A retrospective comparative study. AB - OBJECTIVES: The objective of the following study is to clarify a suitable group whereby a bone scan could be spared at the initial staging of prostate cancer, we wished to identify the possible relationship between bone metastasis and clinical and pathological parameters including serum total prostate specific antigen (PSA) concentration, alkaline phosphatase (ALP), biopsy Gleason Score (GS), and percentage of pathological cores. MATERIALS AND METHODS: We reviewed the results of 220 bone scintigraphies, which were done between January 1, 2011 and June 30, 2013 in patients with newly diagnosed prostate cancer. These parameters were evaluated together with standard clinicopathological data to determine the prediction ability of the bone scan by univariate and multivariate analyses. RESULTS: Bone metastases were seen in 44 patients of all 220 patients (20%, 95% confidence interval, 17-24%). In univariate analysis, PSA and biopsy GS were useful in predicting the bone scan result, but ALP and percentage of pathological cores was not. In multivariate analysis, the single most useful parameter in predicting the bone scan result was PSA (P < 0.001). CONCLUSIONS: A bone scan seems to be impractical in newly diagnosed prostate cancer patients with serum PSA level <20 ng/ml and GS up to seven and pre-treatment PSA is the best predictor of the need for the bone scan according to results of this study. PMID- 25835064 TI - Large Syncytia in Lymph Nodes Induced by CCR5-Tropic HIV-1. PMID- 25835065 TI - Hydrodynamic modelling of free water-surface constructed storm water wetlands using a finite volume technique. AB - One of the key factors in designing free water-surface constructed wetlands (FWS CW) is the hydraulic efficiency (lambda), which depends primarily on the retention time of the polluted storm water. Increasing the hydraulic retention time (HRT) at various flow levels will increase lambda of the overall constructed wetland (CW). The effects of characteristic geometric features that increase HRT were explored through the use of a two-dimensional depth-average hydrodynamic model. This numerical model was developed to solve the equations of continuity and motions on an unstructured triangular mesh using the Galerkin finite volume formulation and equations of the k-epsilon turbulence model. Eighty-nine diverse forms of artificial FWS CW with 11 different aspect ratios were numerically simulated and subsequently analysed for four scenarios: rectangular CW, modified rectangular CW with rounded edges, different inlet/outlet configurations of CW, and surface and submerged obstructions in front of the inlet part of the CW. Results from the simulations showed that increasing the aspect ratio has a direct influence on the enhancement of lambda in all cases. However, the aspect ratio should be at least 9 in order to achieve an appropriate rate for lambda in rectangular CW. Modified rounded rectangular CW improved lambda by up to 23%, which allowed for the selection of a reduced aspect ratio. Simulation results showed that CW with low aspect ratios benefited from obstructions and optimized inlet/outlet configurations in terms of improved HRT. PMID- 25835066 TI - Complete mitochondrial genome of the spotted scat Scatophagus argus (Teleostei, Scatophagidae). AB - The complete mitochondrial sequence of the spotted scat Scatophagus argus has been determined using long amplification polymerase chain reaction (LA-PCR). The total length of sequence is 16,778 bp, and includes 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 control region. The base composition of H-strand is 27.23% (A), 27.54% (T), 16.22% (G) and 28.81% (C), with an AT content of 55.08%. The arrangement of genes in S. argus is identical to that of other fish species. All genes are encoded on the heavy strand with the exception of ND6 and eight tRNA genes. The mitochondrial genome of S. argus presented here will contribute to resolve phylogenetic relationships within the family Scatophagidae and the Perciformes. PMID- 25835067 TI - New metastable form of glibenclamide prepared by redispersion from ternary solid dispersions containing polyvinylpyrrolidone-K30 and sodium lauryl sulfate. AB - Modification of polymorphic forms of poorly water-soluble drugs is one way to achieve the desirable properties. In this study, glibenclamide (GBM) particles with different polymorphic forms, including a new metastable form, were obtained from redispersion of ternary solid dispersion systems. The ternary solid dispersion systems, consisting of GBM, polyvinylpyrrolidone-K30 (PVP-K30) and sodium lauryl sulfate (SLS), were prepared by solvent evaporation method and subsequently redispersed in deionized water. The precipitated drug particles were then collected at a given time period. The drug particles with different polymorphic forms could be achieved depending on the polymer/surfactant ratio. Amorphous drug nanoparticles could be obtained by using a high polymer/surfactant ratio, whereas two different crystalline forms were obtained from the systems containing low polymer/surfactant ratios. Interestingly, a new metastable form IV of GBM with improved dissolution behavior could be obtained from the system of GBM:PVP-K30:SLS with the weight ratio of 2:2:4. This new polymorphic form IV of GBM was confirmed by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD) and solid state 13C nuclear magnetic resonance (NMR) spectroscopy. The molecular arrangement of the new polymorphic form IV of GBM was proposed. The GBM particles with polymorphic form IV also showed an improved dissolution behavior. In addition, it was found that the formation of the new polymorphic form IV of GBM by this process was reproducible. PMID- 25835068 TI - Influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions. AB - The purpose of this paper was to study the influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions. Four drug nanosuspensions were produced by high-pressure homogenization technique, which were the same in stabilizer and similar in particle size. Differential scanning calorimetry and powder X-ray diffraction analysis showed that the crystalline state of the nanocrystals did not change. In vitro permeation study demonstrated that the drug nanosuspensions have a higher rate of permeation that ranged from 1.69- to 3.74-fold compared to drug microsuspensions. Correlation analysis between drug physicochemical properties and Jss revealed that log P and pKa were factors that influenced the in vitro transdermal absorption of hydrophobic drug nanosuspensions, and drugs with a log P value around 3 and a higher pKa value (when pKa < pH+2) would gain higher Jss in this paper. PMID- 25835069 TI - Giotto's applications of embodied perception: Lateral and vertical dimensions of space. AB - Giotto's Arena Chapel frescoes, dating from the early fourteenth century, provide salient illustrations of two types of embodied perceptions. One is universal, a consequence of biology and the physical laws of nature, linked to the vertical dimension of space, and impacting on affect and moral judgement. The other is culturally determined, acquired from the direction of reading script and affecting perceptions of directions of movement, time and causality. Giotto's intuitive use of embodiments, the result of a newly evolving realism in painting, may have prompted late mediaeval chapel-visitors to empathize with the storied biblical characters, so that figures that were once only the object of religious veneration and awe were now made into living beings with a shared humanity, resulting in an awakening of a personal agency that fueled the Renaissance and Modernism. PMID- 25835070 TI - Emerging therapeutic targets for the treatment of human acute myeloid leukemia (part 1) - gene transcription, cell cycle regulation, metabolism and intercellular communication. AB - Human acute myeloid leukemia is a heterogeneous disease and the effect of therapeutic targeting of specific molecular mechanisms will probably vary between patient subsets. Cell cycle regulators are among the emerging targets (e.g., aurora and polo-like kinases, cyclin-dependent kinases). Inhibition of communication between acute myeloid leukemia and stromal cells is also considered; among the most promising of these strategies are inhibition of hedgehog-initiated, CXCR4-CXCL12 and Axl-Gas6 signaling. Finally, targeting of energy and protein metabolism is considered, the most promising strategy being inhibition of isocitrate dehydrogenase in patients with IDH mutations. Thus, several strategies are now considered, and a major common challenge for all of them is to clarify how they should be combined with each other or with conventional chemotherapy, and whether their use should be limited to certain subsets of patients. PMID- 25835071 TI - Development of an HPLC post-column antioxidant assay for Solidago canadensis radical scavengers. AB - The aim of this work was to modify and validate the post-column high-performance liquid chromatography (HPLC)-ABTS and DPPH methods for evaluating the antioxidant activity of the methanolic extracts of Solidago canadensis (Canadian goldenrod) leaves and flowers. Separation of the analytes was performed via the HPLC-PDA method on a YMC analytical column using a gradient elution program. Three compounds with antioxidant properties - chlorogenic acid, rutin and isoquercitrin - and two unidentified antioxidants were established. The research showed that the coil temperature regimes and loop length combinations influence the optimised post-column assay method for detecting the antioxidant activity of goldenrod radical scavengers. Investigations established that the temperature in the reaction coil was a substantial factor contributing to the signal strength of the analytes after reacting with the DPPH and ABTS radicals. PMID- 25835072 TI - KDM4D crosstalks with PARP1 and RNA at DNA DSBs. PMID- 25835073 TI - Target fortification of breast milk: how often should milk analysis be done? AB - Target fortification (TFO) reduces natural macronutrient variation in breast milk (BM). Daily BM analysis for TFO increases neonatal intensive care unit work load by 10-15 min/patient/day and may not be feasible in all nurseries. The variation of macronutrient intake when BM analysis is done for various schedules was studied. In an observational study, we analyzed 21 subsequent samples of native 24-h BM batches, which had been prepared for 10 healthy infants (gestational age 26.1 +/- 1.3 weeks, birth weight: 890 +/- 210 g). Levels of protein and fat (validated near-infrared milk analyzer), as well as lactose (UPLC-MS/MS) generated the database for modelling TFO to meet recommendations of European Society for Paediatric Gastroenterology Hepatology and Nutrition. Intake of macronutrients and energy were calculated for different schedules of BM measurements for TFO (n = 1/week; n = 2/week; n = 3/week; n = 5/week; n = 7/week) and compared to native and fixed dose fortified BM. Day-to-day variation of macronutrients (protein 20%, carbohydrate 13%, fat 17%, energy 10%) decreased as the frequency of milk analysis increased and was almost zero for protein and carbohydrate with daily measurements. Measurements two/week led to mean macronutrient intake within a range of +/- 5% of targeted levels. A reduced schedule for macronutrient measurement may increase the practical use of TFO. To what extent the day-to-day variation affects growth while mean intake is stable needs to be studied. PMID- 25835074 TI - Moderate amounts of vitamin D3 in supplements are effective in raising serum 25 hydroxyvitamin D from low baseline levels in adults: a systematic review. AB - There is controversy surrounding the designation of vitamin D adequacy as defined by circulating levels of the metabolite 25-hydroxyvitamin D (25(OH)D). Depending on the cutoff level chosen, dietary intakes of vitamin D may or may not provide sufficient impact upon vitamin D status measured as improvement in serum levels of 25(OH)D. We sought to examine whether modest daily doses (5-20 MUg) as found in fortified foods or multivitamin supplements had a measureable impact on vitamin D status, defined as moving from below to above 50 nmol/L, or from less than 30 nmol/L to above 30 nmol/L. Published literature was searched for relevant articles describing randomized controlled trials. Exclusion criteria were: studies not involving humans; review articles; studies lacking blood level data pre- and post-treatment; no control group; bolus treatments (weekly, monthly, yearly); vitamin D < 5 MUg or > 20 MUg; baseline 25(OH)D >= 75 nmol/L; subjects not defined as healthy; studies < 8 weeks; and age < 19 years. Of the 127 studies retrieved, 18 publications with 25 separate comparisons met criteria. The mean rate constant, defined as change in 25(OH)D in nmol/L per MUg vitamin D administered, was calculated as 2.19 +/- 0.97 nmol/L per MUg. There was a significant negative correlation (r = -0.65, p = 0.0004) between rate constant and administered dose. To determine impact of the dose reflecting the Estimated Average Requirement (EAR) of 10 MUg administered in nine studies (10 comparisons), in every case mean 25(OH)D status rose either from "insufficient" (30-50 nmol/L) to "sufficient" (> 50 nmol/L) or from "deficient" (< 30 nmol/L) to "insufficient" (> 30 but < 50 nmol/L). Our study shows that when baseline levels of groups were < 75 nmol/L, for every microgram of vitamin D provided, 25(OH)D levels can be raised by 2 nmol/L; and further, when groups were deficient or insufficient in vitamin D, there was significant value in providing additional 10 MUg per day of vitamin D. PMID- 25835075 TI - Endoscopical Orbital Fat Decompression with Medial Orbital Wall Decompression for Dysthyroid Optic Neuropathy. AB - OBJECTIVE: To describe a novel approach to orbital decompression for dysthyroid optic neuropathy (DON). METHODS: An augmented endoscopic transethmoid medial orbital wall decompression (ETMOWD) was performed on 43 consecutive patients (72 eyes) with DON in order to access the orbital apex adequately. Concurrently, endoscopic transethmoid fat decompression (ETFD) using a novel aspiration/cutting instrument to remove orbital fat was performed for further reduction of proptosis. All patients were followed up periodically for at least 6 months. Outcomes such as improvement of visual acuity (VA), color vision, degree of proptosis reduction as well as the incidence of surgical induced diplopia were analyzed at the final review. RESULTS: Sixty-nine out of 72 eyes (95.8%) had a statistically significant improvement in VA from -0.65 +/- 0.30 to -0.25 +/- 0.22 postoperatively, with a mean improvement of 0.55 +/- 0.17 (p < 0.001). Thirty four out of 45 eyes had an improvement in color vision (p < 0.001). The range of proptosis reduction was 4 to 9 mm (mean 6.2 +/- 1.2 mm). Postoperative symmetry was achieved to within 2 mm using an exophthalmometer in 39 of 43 patients (90.7%). Five patients developed diplopia in the postoperative phase, but had complete resolution within 3 months. Two patients had further deterioration in their diplopia following surgery. CONCLUSION: Our technique of a combined ETFD with ETMOWD appears to be effective in managing patients with DON, with minimal morbidities and a low incidence of postoperative diplopia. PMID- 25835076 TI - Percutaneous treatment of a duodenocutaneous high-flow fistula using a new biological plug. AB - Enterocutaneous fistula is a challenging entity and a gold-standard treatment is not settled so far. Here, we describe the successful closure of a duodenocutaneous fistula with the use of the Biodesign enterocutaneous fistula plug (Cook Medical), which is derived from a biological plug that has been used in recent years in order to close anorectal fistula tracts. PMID- 25835077 TI - Microstructural effects of Ramadan fasting on the brain: a diffusion tensor imaging study. AB - PURPOSE: We aimed to examine whether the brain displays any microstructural changes after a three-week Ramadan fasting period using diffusion tenson imaging. METHODS: This study included a study and a control group of 25 volunteers each. In the study group, we examined and compared apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of the participants during (phase 1) and after (phase 2) a period of fasting. The control group included individuals who did not fast. ADC and FA values obtained in phase 1 and phase 2 were compared between the study and control groups. RESULTS: In the study group, ADC values of hypothalamus and, to a lesser extent, of insula were lower in phase 1 compared with phase 2 and the control group. The FA values of amygdala, middle temporal cortex, thalamus and, to a lesser extent, of medial prefrontal cortex were lower in phase 1 compared with phase 2 and the control group. Phase 2 ADC and FA values of the study group were not significantly different compared with the control group at any brain location. CONCLUSION: A three-week Ramadan fasting period can cause microstructural changes in the brain, and diffusion tensor imaging enables the visualization of these changes. The identification of brain locations where changes occurred in ADC and FA values during fasting can be helpful in diagnostic imaging and understanding the pathophysiology of eating disorders. PMID- 25835078 TI - Pharmacokinetic study of conventional sorafenib chemoembolization in a rabbit VX2 liver tumor model. AB - PURPOSE: Use of oral sorafenib, an antiangiogenic chemotherapeutic agent for hepatocellular carcinoma (HCC), is limited by an unfavorable side effect profile. Transarterial chemoembolization (TACE) employs targeted intravascular drug administration, and has potential as a novel sorafenib delivery method to increase tumoral concentrations and reduce systemic levels. This study aimed to discern the pharmacokinetics of sorafenib TACE in a rabbit VX2 liver tumor model. METHODS: A 3 mg/kg dose of sorafenib ethiodized oil emulsion was delivered via an arterial catheter to VX2 liver tumors in seven New Zealand white rabbits. Following TACE, serum sorafenib levels were measured at days 0, 1, 2, 3, 7, 10, and 14 until the time of sacrifice, after which rabbit livers were harvested for analysis of sorafenib concentrations within treated tumors and normal liver. Liquid chromatography tandem mass spectrometry was used for drug quantification. RESULTS: Sorafenib uptake within liver tumor and nontumorous liver tissue peaked at mean 3.53 and 0.75 MUg/mL, respectively, immediately post-procedure (5:1 tumor to normal tissue drug uptake ratio), before decreasing with a 10-18 hour half life. Serum sorafenib levels peaked immediately after TACE at a mean value of 58.58 MUg/mL before normalizing with a 5.2-hour half-life, suggesting early drug washout from liver into the systemic circulation. Hepatic lab parameters showed transient increase 24 hours post-TACE with subsequent resolution. CONCLUSION: While targeted transarterial delivery of sorafenib ethiodized oil emulsion shows preferential tumor uptake compared to normal liver, systemic washout occurs with a short half-life, resulting in high circulating drug levels. PMID- 25835079 TI - Nonpalpable BI-RADS 4 breast lesions: sonographic findings and pathology correlation. AB - PURPOSE: We aimed to evaluate ultrasonography (US) findings for Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions using BI-RADS US lexicon and determine the positive and negative predictive values (PPV and NPV) of US with respect to biopsy results. METHODS: Sonograms of 186 BI-RADS 4 nonpalpable breast lesions with a known diagnosis were reviewed retrospectively. The morphologic features of all lesions were described using BI-RADS lexicon and the lesions were subcategorized into 4A, 4B, and 4C on the basis of the physician's level of suspicion. Lesion descriptors and biopsy results were correlated. Pathologic results were compared with US features. PPVs of BI-RADS subcategories 4A, 4B, and 4C were calculated. RESULTS: Of 186 lesions, 38.7% were malignant and 61.2% were benign. PPVs according to subcategories 4A, 4B, and 4C were 19.5%, 41.5%, and 74.3%, respectively. Microlobulated, indistinct, and angular margins, posterior acoustic features, and echo pattern were nonspecific signs for nonpalpable BI-RADS 4 lesions. Typical signs of malignancy were irregular shape (PPV, 66%), spiculated margin (PPV, 80%) and nonparallel orientation (PPV, 58.9%). Typical signs of benign lesions were oval shape (NPV, 77.1%), circumscribed margin (NPV, 67.5%), parallel orientation (NPV, 70%), and abrupt interface (NPV, 67.6%). CONCLUSION: BI-RADS criteria are not sufficient for discriminating between malignant and benign lesions, and biopsy is required. Subcategories 4A, 4B, and 4C are useful in predicting the likelihood of malignancy. However, objective and clear subclassification rules are needed. PMID- 25835080 TI - Endovascular management of iatrogenic renal arterial lesions and clinical outcomes. AB - PURPOSE: We aimed to evaluate iatrogenic renal arterial lesions, including pseudoaneurysm, arteriovenous fistula, and arteriocaliceal fistula, their management by endovascular embolization, and the clinical results. METHODS: Fifty five patients (forty males, fifteen females) with a median age of 40 years (range, 8-85 years), who underwent endovascular embolization of iatrogenic renal arterial lesions between March 2003 and December 2013 were included in this retrospective study. Types of iatrogenic lesions and details of embolization procedures were reported. Estimated glomerular filtration rate (eGFR), renal function tests, hemoglobin, and hematocrit levels before and after embolization were recorded and compared. RESULTS: Median follow-up was 24 months. We identified 53 pseudoaneurysms, 30 arteriovenous fistulas, and 11 arteriocaliceal fistulas in 55 patients, after percutaneous nephrolithotomy (n=26), renal biopsy (n=21), nephrostomy (n=3), renal surgery (n=3), and extracorporeal shock wave lithotripsy (n=2). Median number of pseudoaneurysms was 1 (range, 1-4) with a median size of 7 mm (range, 1.5-35 mm). Fifty-one patients underwent coil embolization. Median number of coils was 5 (range, 2-21) and median renal parenchymal loss was 5% (range, 1%-50%). There were no significant differences between pre- and postoperative eGFR and serum parameters. CONCLUSION: Iatrogenic renal arterial lesion can be a life threatening condition. Superselective coil embolization is a safe, minimally invasive treatment option with minimal renal parenchymal loss and without significant change in renal function. PMID- 25835081 TI - Can unenhanced breast MRI be used to decrease negative biopsy rates? AB - PURPOSE: We aimed to determine whether low-risk breast masses can be effectively managed with unenhanced magnetic resonance imaging (MRI) combining T2-weighted sequences with diffusion-weighted imaging (DWI) instead of immediate biopsy to decrease negative biopsy rates. METHODS: After institutional review board and patient approvals, 141 consecutive women with 156 low-risk breast masses, who underwent unenhanced MRI and later on received a final diagnosis, were included in the study. There were 72 BI-RADS 3 masses in women with relative risk factors and 84 BI-RADS 4A masses, all referred for biopsy. Apparent diffusion coefficient (ADC) cutoff was 0.90*10-3 mm2/s. According to ADC values and T2-weighted imaging characteristics, masses were classified as either malignant or benign. Unenhanced MRI results were compared with final diagnoses obtained by histopathology or imaging surveillance, and diagnostic values were calculated. RESULTS: Of 156 masses, 112 underwent biopsy. Four malignancies were diagnosed, three of which having ADC values lower than the cutoff. In women who rejected the biopsy, masses were stable during a follow-up of at least two years (n=44). MRI revealed 91% specificity and 99% negative predictive value (NPV) for detection of breast cancer. CONCLUSION: Combination of T2-weighted imaging with DWI is a feasible method to further characterize breast masses with a low probability of malignancy. With the use of unenhanced MRI instead of immediate biopsy, it might be possible to decrease negative biopsy rates of low-risk breast masses. PMID- 25835082 TI - PockDrug: A Model for Predicting Pocket Druggability That Overcomes Pocket Estimation Uncertainties. AB - Predicting protein druggability is a key interest in the target identification phase of drug discovery. Here, we assess the pocket estimation methods' influence on druggability predictions by comparing statistical models constructed from pockets estimated using different pocket estimation methods: a proximity of either 4 or 5.5 A to a cocrystallized ligand or DoGSite and fpocket estimation methods. We developed PockDrug, a robust pocket druggability model that copes with uncertainties in pocket boundaries. It is based on a linear discriminant analysis from a pool of 52 descriptors combined with a selection of the most stable and efficient models using different pocket estimation methods. PockDrug retains the best combinations of three pocket properties which impact druggability: geometry, hydrophobicity, and aromaticity. It results in an average accuracy of 87.9% +/- 4.7% using a test set and exhibits higher accuracy (~5-10%) than previous studies that used an identical apo set. In conclusion, this study confirms the influence of pocket estimation on pocket druggability prediction and proposes PockDrug as a new model that overcomes pocket estimation variability. PMID- 25835083 TI - Population inversion in monolayer and bilayer graphene. AB - The recent demonstration of saturable absorption and negative optical conductivity in the Terahertz range in graphene has opened up new opportunities for optoelectronic applications based on this and other low dimensional materials. Recently, population inversion across the Dirac point has been observed directly by time- and angle-resolved photoemission spectroscopy (tr ARPES), revealing a relaxation time of only ~130 femtoseconds. This severely limits the applicability of single layer graphene to, for example, Terahertz light amplification. Here we use tr-ARPES to demonstrate long-lived population inversion in bilayer graphene. The effect is attributed to the small band gap found in this compound. We propose a microscopic model for these observations and speculate that an enhancement of both the pump photon energy and the pump fluence may further increase this lifetime. PMID- 25835084 TI - Reconstruction of Colloidal Spheres by Targeted Etching: A Generalized Self Template Route to Porous Amphoteric Metal Oxide Hollow Spheres. AB - Despite the significant progress in developing various synthetic strategies for metal oxide hollow spheres (h-MO), the so-far explored materials are mostly chemically inert metal oxides. Very few attempts have been made for amphoteric metal oxides such as Al2O3 and ZnO due to the difficulties in the control of the dissolution and recrystallization process. Herein, a facile self-template route to the synthesis of amphoteric h-MO with tunable size and shell thickness is developed by targeted etching via an acid-base reaction. With the protection of polyvinylpyrrolidone (PVP) on the surface, the interior of metal oxide solid colloidal spheres (c-MOs) that possess radially divergent structures could be selectively etched with acid/alkali as an etchant, forming h-MO of Al2O3 and ZnO. Our results also show that a wide variety of metal oxide colloidal spheres can be potential self-templates for targeted etching, which paves the way for developing a generalized strategy for the synthesis of various metal oxide hollow spheres. PMID- 25835085 TI - Grain-boundary-dependent CO2 electroreduction activity. AB - Uncovering new structure-activity relationships for metal nanoparticle (NP) electrocatalysts is crucial for advancing many energy conversion technologies. Grain boundaries (GBs) could be used to stabilize unique active surfaces, but a quantitative correlation between GBs and catalytic activity has not been established. Here we use vapor deposition to prepare Au NPs on carbon nanotubes (Au/CNT). As deposited, the Au NPs have a relatively high density of GBs that are readily imaged by transmission electron microscopy (TEM); thermal annealing lowers the density in a controlled manner. We show that the surface-area normalized activity for CO2 reduction is linearly correlated with GB surface density on Au/CNT, demonstrating that GB engineering is a powerful approach to improving the catalytic activity of metal NPs. PMID- 25835086 TI - Author reply on: Relationship between development of urethral stricture after transurethral resection of prostate and glycemic control. PMID- 25835087 TI - Comparison of dynamic contrast-enhanced and diffusion weighted magnetic resonance image in staging and grading of carcinoma bladder with histopathological correlation. AB - BACKGROUND: Bladder cancer is the second most common neoplasm of the urinary tract worldwide. Dynamic contrast-enhanced and diffusion-weighted MRI has been introduced in clinical MRI protocols of bladder cancer because of its accuracy in staging and grading. AIM: To evaluate and compare accuracy of Dynamic contrast enhanced (DCE) and Diffusion weighted (DW) MRI for preoperative T staging of urinary bladder cancer and find correlation between apparent diffusion coefficient (ADC) and maximum enhancement with histological grade. MATERIALS AND METHODS: Sixty patients with bladder cancer were included in study. All patients underwent Magnetic Resonance Imaging (MRI) on a 1.5-T scanner with a phased-array pelvic coil. MR images were evaluated and assigned a stage which was compared with the histolopathological staging. ADC value and maximum enhancement curve were used based on previous studies. Subsequently histological grade was compared with MR characteristics. RESULTS: The extent of agreement between the radiologic staging and histopathological staging was relatively greater with the DW-MRI (kappa=0.669) than DCE-MRI (kappa=0.619). The sensitivity, specificity, and accuracy are maximum and similar for stage T4 tumors in both DCEMRI (100.0, 96.2 and 96.7) and DW-MRI (100.0, 96.2 and 96.7) while minimum for stage T2 tumors - DCEMRI (83.3, 72.2, and 76.7) and DWI-MRI (91.7, 72.2, and 80). CONCLUSION: MRI is an effective tool for determining T stage and histological grade of urinary bladder cancers. Stage T2a and T2b can be differentiated only by DCE-MRI. Results were more accurate when both ADC and DCE-MRI were used together and hence a combined approach is suggested. PMID- 25835088 TI - A Slow-Release Substrate Stimulates Groundwater Microbial Communities for Long Term in Situ Cr(VI) Reduction. AB - Cr(VI) is a widespread environmental contaminant that is highly toxic and soluble. Previous work indicated that a one-time amendment of polylactate hydrogen-release compound (HRC) reduced groundwater Cr(VI) concentrations for >3.5 years at a contaminated aquifer; however, microbial communities responsible for Cr(VI) reduction are poorly understood. In this study, we hypothesized that HRC amendment would significantly change the composition and structure of groundwater microbial communities, and that the abundance of key functional genes involved in HRC degradation and electron acceptor reduction would increase long term in response to this slowly degrading, complex substrate. To test these hypotheses, groundwater microbial communities were monitored after HRC amendment for >1 year using a comprehensive functional gene microarray. The results showed that the overall functional composition and structure of groundwater microbial communities underwent sequential shifts after HRC amendment. Particularly, the abundance of functional genes involved in acetate oxidation, denitrification, dissimilatory nitrate reduction, metal reduction, and sulfate reduction significantly increased. The overall community dynamics was significantly correlated with changes in groundwater concentrations of microbial biomass, acetate, NO3-, Cr(VI), Fe(II) and SO4(2-). Our results suggest that HRC amendment primarily stimulated key functional processes associated with HRC degradation and reduction of multiple electron acceptors in the aquifer toward long-term Cr(VI) reduction. PMID- 25835089 TI - Graphene-Diatom Silica Aerogels for Efficient Removal of Mercury Ions from Water. AB - A simple synthetic approach for the preparation of graphene-diatom silica composites in the form of self-assembled aerogels with three-dimensional networks from natural graphite and diatomite rocks is demonstrated for the first time. Their adsorption performance for the removal of mercury from water was studied as a function of contact time, solution pH, and mercury concentration to optimize the reaction conditions. The adsorption isotherm of mercury fitted well with the Langmuir model, representing a very high adsorption capacity of >500 mg of mercury/g of adsorbent. The prepared aerogels exhibited outstanding adsorption performance for the removal of mercury from water, which is significant for environmental applications. PMID- 25835090 TI - Comparison of Clinical Features, Virulence, and Relapse among Mycobacterium avium Complex Species. AB - RATIONALE: Traditionally, Mycobacterium avium complex (MAC) has been composed of M. avium and M. intracellulare; however, advances in genetic sequencing have allowed discovery of several novel species. With these discoveries, investigation of differences in risk factors, virulence, and clinical outcomes have emerged. OBJECTIVES: We conducted a retrospective cohort study evaluating all MAC isolates obtained from pulmonary specimens at our institution from 2000 to 2012 and investigated the clinical courses associated with distinct MAC species. METHODS: To classify isolates into distinct species, a multilocus sequence analysis using rpoB and internal transcribed spacer (ITS) as targets was performed. We reviewed patient medical records to analyze clinical characteristics and outcomes for the cohort. MEASUREMENTS AND MAIN RESULTS: Of the isolates from the 448 included patients, 54% were M. avium, 18% were M. intracellulare, and 28% were M. chimaera. Using American Thoracic Society/Infectious Diseases Society of America criteria, patients whose isolates were identified as M. avium (adjusted odds ratio [AOR], 2.14; 95% confidence interval [CI], 1.33-3.44) or M. intracellulare (AOR, 3.12; 95% CI, 1.62-5.99) were more likely to meet criteria for infection than patients with M. chimaera. Patients infected with M. chimaera were more likely to be prescribed an immunosuppressant compared with all other patients (AOR, 2.75; 95% CI, 1.17-6.40). Patients treated for infections with M. avium (AOR, 5.64; 95% CI, 1.51-21.10) and M. chimaera (AOR, 4.47; 95% CI, 1.08-18.53) were more likely to have a clinical relapse/reinfection than those with M. intracellulare. CONCLUSIONS: Our findings suggest that specific MAC species have varying degrees of virulence and classifying MAC isolates into distinct species aids in identifying which patients are at higher risk of clinical relapse/reinfection. PMID- 25835091 TI - Liposomal conjugates for drug delivery to the central nervous system. AB - Treatments of central nervous system (CNS) diseases often fail due to the blood brain barrier. Circumvention of this obstacle is crucial for any systemic treatment of such diseases to be effective. One approach to transfer drugs into the brain is the use of colloidal carrier systems-amongst others, liposomes. A prerequisite for successful drug delivery by colloidal carriers to the brain is the modification of their surface, making them invisible to the reticuloendothelial system (RES) and to target them to specific surface epitopes at the blood-brain barrier. This study characterizes liposomes conjugated with cationized bovine serum albumin (cBSA) as transport vectors in vitro in porcine brain capillary endothelial cells (PBCEC) and in vivo in rats using fluorescently labelled liposomes. Experiments with PBCEC showed that sterically stabilized (PEGylated) liposomes without protein as well as liposomes conjugated to native bovine serum albumin (BSA) were not taken up. In contrast, cBSA-liposomes were taken up and appeared to be concentrated in intracellular vesicles. Uptake occurred in a concentration and time dependent manner. Free BSA and free cBSA inhibited uptake. After intravenous application of cBSA-liposomes, confocal fluorescence microscopy of brain cryosections from male Wistar rats showed fluorescence associated with liposomes in brain capillary surrounding tissue after 3, 6 and 24 h, for liposomes with a diameter between 120 and 150 nm, suggesting successful brain delivery of cationized-albumin coupled liposomes. PMID- 25835092 TI - Spinal cord toxoplasmosis in human immunodeficiency virus infection/acquired immunodeficiency syndrome. AB - Neurological complications in patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) are still common, even in the era of highly active antiretroviral therapy. Opportunistic infections, immune reconstitution, the virus itself, antiretroviral drugs and neurocognitive disorders have to be considered when establishing the differential diagnosis. Toxoplasmic encephalitis remains the major cause of space-occupying lesions in the brain of patients with HIV/AIDS; however, spinal cord involvement has been reported infrequently. Here, we review spinal cord toxoplasmosis in HIV infection and illustrate the condition with a recent case from our hospital. We suggest that most patients with HIV/AIDS and myelitis with enhanced spine lesions, multiple brain lesions and positive serology for Toxoplasma gondii should receive immediate empirical treatment for toxoplasmosis, and a biopsy should be performed in those cases without clinical improvement or with deterioration. PMID- 25835093 TI - Robot-integrated intraoperative ultrasound: Initial experience with hepatic malignancies. AB - PURPOSE: A new robotic surgery tool allows intraoperative ultrasound to be performed using a fully robotic technique. Herein, we evaluate the feasibility and reliability of robotically integrated ultrasound to guide resection of malignant hepatic tumors. MATERIAL AND METHODS: A consecutive series of ultrasound-guided robotic resections of primary and secondary hepatic malignancies was analyzed in terms of perioperative data and specimen evaluation, focusing on the reliability of the new robot-integrated ultrasound probe. RESULTS: Ten consecutive patients underwent 15 robotic liver resections. Two patients were resected to excise primary hepatocellular cancers and eight underwent resections of liver metastases. R0 resections were achieved for all lesions. The median operative time was 247 min, and blood loss was limited. No mortality occurred. CONCLUSIONS: Our present analysis confirmed the reliability of fully robotic liver resection guided via robotically integrated ultrasonic assessment. Robotic surgery, particularly hepatic resection, may benefit greatly from better manageability, and the fact that the surgeon can directly manage both the operative and the diagnostic parts of the procedure. PMID- 25835094 TI - PCB 77 action in ovary cells--toxic effects, apoptosis induction and cell cycle analysis. AB - CONTEXT: PCB 77 (3,3',4,4'-tetrachlorobiphenyl), a non-ortho congener with planar configuration, has been identified as potential endocrine disrupter capable to increase the risk of reproductive and developmental failure. OBJECTIVE: In the present study, in vitro PCB 77 toxic potential, apoptosis induction and cell cycle alterations were investigated to reveal direct toxic effects on ovarian cells. METHODS: Chinese Hamster Ovary (CHO-K1) cell line was selected as a model system and decreased cell viability was confirmed by application of four bioassays. Cellular morphology and quantitative analysis of apoptotic, necrotic and viable cells were determined with fluorescent microscopy and cell cycle phase distributions by measuring DNA content using flow cytometry. RESULTS: We have indicated Trypan blue exclusion assay as the most sensitive for quantifying cytotoxicity of PCB 77 in terms of IC50 values, while the results obtained by other methods pointed to a possible localized effect on the lysosomes/endosomes (Neutral red), compromised intracellular metabolic processes (MTT) and possible interferation with the rate of protein synthesis (Kenacid blue). The loss of cell viability, as a consequence of treatment with 10-100 MUM PCB 77, fundamentally was due to induction of apoptosis with observed common series of specific morphological changes characteristic to apoptotic phenomenon. The level of alterations of normal cell cycle progression was low without significant changes at analyzed time intervals. CONCLUSION: These results indicate toxic outcomes of PCB 77 at ovarian cellular level with regard to potential direct adverse effects to female reproductive system. PMID- 25835095 TI - Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. AB - ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1, nuclear receptors and WTIP. Here, functional proteomics of the ASXL family members are reviewed with emphasis on mutation spectra, the ASXM2 domain and the plant homeodomain (PHD) finger. Copy number gains of ASXL1 occur in chromosome 20q11.2 duplication syndrome and cervical cancer. Truncation mutations of ASXLs occur in autism, Bohring-Opitz and related syndromes, hematological malignancies and solid tumors, such as prostate cancer, breast cancer and high-grade glioma, which are gain- or loss-of-function mutations. The ASXM2 domain is a binding module for androgen receptor and estrogen receptor alpha, while the PHD finger is a ligand of WTIP LIM domains and a putative chromatin-binding module. Phylogenetic analyses of 139 human PHD fingers revealed that ASXL PHD fingers cluster with those of BPTF, DIDO, ING1, KDM5A (JARID1A), KMT2E (MLL5), PHF2, PHF8 and PHF23. The cell context-dependent epigenetic code of ASXLs should be deciphered to develop therapeutics for human diseases. PMID- 25835097 TI - [A breakthrough for the treatment of spasticity in multiple sclerosis]. PMID- 25835096 TI - Pros and cons of fatty acids in bone biology. AB - Despite the growing interest in deciphering the causes and consequences of obesity-related disorders, the mechanisms linking fat intake to bone behaviour remain unclear. Since bone fractures are widely associated with increased morbidity and mortality, most notably in elderly and obese people, bone health has become a major social and economic issue. Consistently, public health system guidelines have encouraged low-fat diets in order to reduce associated complications. However, from a bone point of view, mechanisms linking fat intake to bone alteration remain quite controversial. Thus, after more than a decade of dedicated studies, this timely review offers a comprehensive overview of the relationships between bone and fatty acids. Using clinical evidences as a starting-point to more complex molecular elucidation, this work highlights the complexity of the system and reveals that bone alteration that cannot be solved simply by taking omega-3 pills. Fatty acid effects on bone metabolism can be both direct and indirect and require integrated investigations. Furthermore, even at the level of a single cell, one fatty acid is able to trigger several different independent pathways (receptors, metabolites...) which may all have a say in the final cellular metabolic response. PMID- 25835098 TI - Food, the immune system, and the gastrointestinal tract. PMID- 25835099 TI - Identification of MMP-1 and MMP-9 inhibitors from the roots of Eleutherococcus divaricatus, and the PAMPA test. AB - The purpose of this study was the isolation of metalloproteinases MMP-1 and MMP-9 inhibitors from the chloroform extract of the Eleutherococcus divaricatus roots. Using GC-MS, (1)H and (13)C NMR, HMQC, HMBC, COSY and DEPT, (+)-sesamin has been identified as a new anti-MMP inhibitor. We report for the first time that (+) sesamin inhibited MMP-1 and MMP-9 activity in 40% and 17%, respectively. The high inhibitory potential has been shown by ursolic acid (90.9% and 89.8% for MMP-1 and MMP-9). In the PAMPA test, the Pe value for sesamin was established as 17.4 * 10(-6) cm/s, that for ursolic acid as 30.0 * 10(- 6) cm/s. Verapamil and theophylline were used as a positive and negative control (Pe 42.1 and 2.9 * 10( 6) cm/s). To our best knowledge, no information was available on this activity of sesamin and other compounds. These studies provide a biochemical basis for the regulation of MMP-1 and MMP-9 by E. divaricatus compounds. PMID- 25835100 TI - The efficacy and nephrotoxicity associated with colistin use in an intensive care unit in Vietnam: Use of colistin in a population of lower body weight. AB - BACKGROUND: There has been a growing need for colistin as a key drug for the treatment of MDR-GNB infection. Information on colistin use in Asian population is limited. METHODS: A retrospective observational study was conducted to assess the efficacy and nephrotoxicity in critically ill adult patients who received intravenous colistin for MDR-GNB infection in the intensive care unit (ICU) at Bach Mai Hospital in Hanoi, Vietnam. Colistin was administered according to the dosing guideline that was based on pharmacokinetic, pharmacodynamic and toxicodynamic principles, adjusted by body weight and creatinine clearance. RESULTS: Twenty-eight eligible patients were included. The mean patient age was 60+/-20.4 years. The mean body weight was 53+/-8.6kg. The mean daily dose of colistin was 4.1+/-1.6 MIU, and the mean cumulative dose of colistin was 48.2+/ 22.8 MIU. Colistin therapies were classified as clinically effective in 19 (67.9%) cases. Six (21.4%) patients developed nephrotoxicity during the study period according to RIFLE criteria. CONCLUSION: A personalized dosing protocol of colistin was effective, with low nephrotoxicity, among critically ill Vietnamese patients with low body weight. Further studies are warranted for assessing the efficacy and toxicity in a larger cohort. PMID- 25835101 TI - Spontaneous ascitic fluid infection and bacteremia due to Yersinia pseudotuberculosis in a liver transplant patient. AB - We report herein a case of bacteremic ascitic fluid infection in a liver transplant patient caused by a strain of Yersinia pseudotuberculosis serogroup I that lost the yersiniabactin core. The patient's outcome was favorable after a combined therapy with a third-generation cephalosporin and gentamicin. PMID- 25835102 TI - Klebsiella oxytoca with reduced sensitivity to chlorhexidine isolated from a diabetic foot ulcer. AB - In most hospitals, chlorhexidine is used as skin antiseptic prior to clinical procedures, in dressings and when bathing patients. We hereby report, for the first time, the isolation of a clinical Klebsiella oxytoca isolate with reduced sensitivity to chlorhexidine from a foot ulcer of a diabetic patient, which is a common and serious complication associated with diabetes. The Minimum Inhibitory Concentration of the K. oxytoca isolate to chlorhexidine was found to be 30 mg/L and the Minimum Bactericidal Concentration was 60 mg/L. An increased resistance to ethidium bromide (MIC 200 mg/ L) was also observed. Molecular tests revealed that the isolate contained blaCTXM15, blaT(EM-1) and bla(SHV). The other resistant genes detected were qnrB1 and aac(6')-Ib-cr. The resistant determinants were located on a class I integron integrase (intI1) containing qacE gene. DNA sequencing showed homology to K. oxytoca plasmid pACM1. Identification of K. oxytoca with reduced sensitivity to chlorhexidine raises concern regarding dilution standards in hospitals. Adherence to the hospitals' infection control policies should be strictly monitored to avoid continuous low level exposure of bacteria to biocides, specifically in developing countries. PMID- 25835103 TI - Leptospirosis presenting as honeymoon fever. AB - An increasing number of travelers from western countries visit tropical regions, questioning western physicians on the prophylaxis, the diagnosis and the therapeutic management of patients with travel-associated infection. In July 2014, a French couple stayed for an adventure-travel in Columbia without malaria prophylaxis. A week after their return the woman presented with fever, myalgia, and retro-orbital pain. Three days later, her husband presented similar symptoms. In both patients, testing for malaria, arboviruses and blood cultures remained negative. An empirical treatment with doxycycline and ceftriaxone was initiated for both patients. Serum collected from the female patient yielded positive IgM for leptospirosis but was negative for her husband. Positive Real-Time PCR were observed in blood and urine from both patients, confirming leptospirosis. Three lessons are noteworthy from this case report. First, after exclusion of malaria, as enteric fever, leptospirosis and rickettsial infection are the most prevalent travel-associated infections, empirical treatment with doxycycline and third generation cephalosporin should be considered. In addition, the diagnosis of leptospirosis requires both serology and PCR performed in both urine and blood samples. Finally, prophylaxis using doxycycline, also effective against leptospirosis, rickettsial infections or travellers' diarrhea should be recommended for adventure travelers in malaria endemic areas. PMID- 25835104 TI - Variant achalasia, the hole of the original classification. AB - BACKGROUND/AIMS: High-resolution manometry (HRM) is a useful tool for classifying esophageal motility disorders. However, there remain findings that cannot be classified in clinical fields. Recently, an updated classification system was announced. The purpose of this study was to evaluate whether originally unclassifiable groups can now be classified according to the updated Chicago Classification system. MATERIALS AND METHODS: We reviewed the results of HRM studies performed from January 2008 to December 2010 on 150 consecutive patients (75 men, age 17-76) referred to the Gospel Hospital manometry laboratory for evaluation. We found originally unclassified results and re-categorized them according to the updated Chicago Classification system. RESULTS: Thirty-seven of 150 patients were originally unclassified cases. Patients from the unclassified and classified groups had similar distributions of age and sex. All unclassified patients were re-diagnosed as having variant achalasia according to the updated Chicago Classification system. CONCLUSION: The updated Chicago Classification can categorize originally unclassified groups of esophageal motility disorder. PMID- 25835105 TI - A functional study of the esophagus in patients with non-cardiac chest pain and dysphagia. AB - BACKGROUND/AIMS: Nutcracker esophagus and non-specific motility disorders are the main causes of non-cardiac chest pain (NCCP), with gastroesophageal reflux in 60% of cases. Achalasia and diffuse esophageal spasm are the most frequent anomalies described in patients with dysphagia. The goal of this study was to evaluate the occurrence of esophageal body and lower esophageal sphincter motor abnormalities in patients with dysphagia, NCCP, or both. MATERIALS AND METHODS: This study is a retrospective analysis of 716 patients with NCCP and/or dysphagia tested between January 1994 and December 2010. 1023 functional studies were performed, 707 of which were esophageal manometries, 225 esophageal pH-meters, and 44 bilimetries. We divided the patients into three groups: group 1 was composed of patients affected with dysphagia, group 2 with NCCP and group 3 with NCCP and dysphagia. RESULTS: Manometric anomalies were detected in 84.4% of cases (p<0.001). The most frequent esophageal motility alteration was achalasia (36%). The lower esophageal sphincter was normal in 45.9% of patients (p<0.001). In all 3 groups, 80.9%, 98.8%, and 93.8, respectively, of patients showed normal upper esophageal sphincter (p=0.005). CONCLUSION: Our data differs from those of other studies because they were collected from and analyzed by a single tertiary level referral center by a single examiner. This could have eliminated the variability found in different hands and different experiences. The high percentage of symptomatic patients with non-pathologic esophageal motility pattern suggests an unclear origin of the disease, with possible neuromuscular involvement. As a result, these patients may need more-detailed diagnostic studies. PMID- 25835106 TI - P53, KI-67, CD117 expression in gastrointestinal and pancreatic neuroendocrine tumours and evaluation of their correlation with clinicopathological and prognostic parameters. AB - BACKGROUND/AIMS: Gastrointestinal and pancreatic neuroendocrine tumors (GEPNETs) originate from the cells of the endocrine system. Their molecular genetic mechanism of development and progression is complex and remains largely unknown. The purpose of this study was to review the gastrointestinal and pancreatic neuroendocrine tumors and to evaluate p53, Ki-67 and CD 117 expressions with their clinicopathological correlations. MATERIALS AND METHODS: Twenty-one patients were reviewed and classified as having well-differentiated neuroendocrine neoplasm (WDET, Grade I), well-differentiated neuroendocrine carcinoma (WDEC, Grade II) and poorly differentiated neuroendocrine carcinoma (PDEC, Grade III). We performed immunohistochemical tests to characterize the expession of the immunoreactivity for synaptophysin, chromogranin, p53, Ki67 and CD 117. RESULTS: Median age of 21 patients was 43 years. Thirteen (61.9%) patients were male and eight (38.1%) patients were female. Tumors were located in the stomach (38.1%), appendix (38.1%), duodenum (4.8%), ileum (4.8%), colon (9.5%), and pancreas (4.8%). CONCLUSION: There was a statistically significant difference between well-differentiated endocrine neoplasm (Grade I), and well differentiated endocrine carcinoma (WDEC, Grade II) and PDEC for Ki-67 >20% (p<0.001) (Pearson chi-square test). There was a statistically significant difference between WDET (Grade I), WDEC (Grade II) and PDEC (Grade III) for p53 positivity (p<0.05) (Pearson chi-square test). PMID- 25835107 TI - The diagnostic value of endoscopic narrow band imaging in helicobacter pylori gastritis in children. AB - BACKGROUND/AIMS: In this study we aimed to investigate the sensitivity and specificity of Narrow Band Imaging (NBI) in H. pylori gastritis and compare them with those of rapid urease test and urea breath test. MATERIALS AND METHODS: A hundred sixty-five children who admitted to Uludag University Pediatric Gastroenterology Unit between October 2009-March 2011 with upper gastrointestinal symptoms were consecutively enrolled. During the endoscopy procedure gastric corporeal, antral and fundal images were obtained, afterwards the same areas were visualized with narrow band imaging and images were recorded again. RESULTS: The study included 68 (41.2%) boys and 97(58.8%) girls. The mean age of the patients were 11.88+/-4.55. Tissue culture positivity and/or histopathological staining for H. pylori was determined in 56 (33.9%) patients (Group 1) and the other patients (n:109, 43.6%) didn't have an evidence of H. pylori infection (Group 2). Narrow band images have supported H. pylori infection in 56.4%. The sensitivity of narrow band images for determining H. pylori infection was 92.86% (95% CI 82.7 98), specificity was 62.39% (95% CI 52.6-71.5). CONCLUSION: Our study is the first to show the role of NBI in diagnosing H. pylori infection in children, as well as determining the sensitivity and specificity of the technique. The specificity is low; however, we suggest that the specific mucosal view of H. pylori gastritis provided by NBI is useful for identifying the areas from which the biopsies should be taken. Moreover, by using this technique, treatment of H. pylori infection may be initiated immediately without performing rapid urease test and without waiting for histopathology report and tissue culture. PMID- 25835108 TI - Gastric polyps and polypoid lesions: Retrospective analysis of 36650 endoscopic procedures in 29940 patients. AB - BACKGROUND/AIMS: The frequency of gastric polyps increases with the widespread use of endoscopy for diagnosis and treatment. As gastric polyps can be malignant or premalignant, histopathological evaluation is needed. The aim of this study is to determine the prevalence and characteristics of gastric polyps in patients undergoing endoscopy. MATERIALS AND METHODS: This study consisted of a retrospective analysis of 36650 consecutive endoscopy and associated pathology reports of 29940 patients between December 2005 and February 2012 in a tertiary referral center. RESULTS: Gastric polypoid lesions were detected in 666 (2.22%) patients. Hyperplastic polyps were the most common type of polyps (36.2%), followed by fundic gland polyps (8.3%), inflammatory fibroid polyps (2.4%) and adenomatous polyps (1.9%). Foveolar hyperplasia, neuroendocrine tumor, xanthoma, gastrointestinal stromal tumor, adenocarcinoma and lymphoma were less commonly seen. Malignant transformation was seen in 0.42% of hyperplastic polyps and in 23.1% of adenomatous polyps. CONCLUSION: Endoscopic appearance of gastric polyps can be variable, distinguishing macroscopically can be misleading. Because of their malignant potential histopathological evaluation is mandatory and polypectomy should be performed whenever possible. PMID- 25835109 TI - Low-dose ramosetron accelerates gastric emptying in the early phase: A crossover study in healthy volunteers using a continuous real-time 13C breath test (BreathID System). AB - BACKGROUND/AIMS: The aim of this study was to determine the correlation between low-dose ramosetron pre-treatment and gastric emptying using a novel, non invasive technique for measuring gastric emptying, namely, the continuous real time 13C breath test (BreathID system: Exalenz Bioscience Ltd., Israel). MATERIALS AND METHODS: Twelve healthy male volunteers participated in this randomized two-way crossover study. The subjects fasted overnight and were randomly assigned to receive the test meal (200 kcal per 200 mL) after an hour pre-treatment with 5 ug ramosetron or the test meal alone. Gastric emptying was monitored for 4 hours after administration of the test meal with the 13C-acetic acid breath test performed continuously using the BreathID system. Using Oridion Research Software (beta version), T 1/2, T lag, GEC and the regression-estimated constants (beta and kappa) were calculated. The differences in the parameters measured at two time-points were analyzed using Wilcoxon's signed-rank test. RESULTS: There was a significant difference in the calculated parameter beta. No significant differences in the calculated parameters T 1/2, T lag, GEC or kappa were observed between the test meal with ramosetron group and the test meal alone group. CONCLUSION: This study showed that ramosetron pre-treatment enhances the early gastric emptying of liquid nutrients. PMID- 25835110 TI - Assessment of 35 children with abdominal tuberculosis. AB - BACKGROUND/AIMS: To contribute to the diagnosis and treatment of pediatric abdominal tuberculosis cases by assessing the clinical, laboratory, and radiological features of patients who presented at our clinic and were diagnosed with abdominal tuberculosis. MATERIALS AND METHODS: Clinical, laboratory, and radiological features were reviewed retrospectively for 35 patients diagnosed with abdominal tuberculosis and followed up at the Pediatric Infectious Diseases Clinic between January 1987 and August 2012. RESULTS: The study group included 16 female (45.7%) and 19 male (54.3%) patients with an age range of 6 months to 16 years (mean: 9.77+/-4.36 years). Twenty-nine patients were diagnosed with tuberculosis peritonitis, five patients with intestinal tuberculosis, and one patient with pelvic tuberculosis. The most common signs and symptoms were ascites, abdominal pain, abdominal distention, weight loss, and fever. Mean duration of the complaints was 109 days (range: 10 days to 3 years). CONCLUSION: Abdominal tuberculosis is a disease with an insidious course without disease specific clinical and laboratory signs. When the disease is suspected, laparoscopy or laparotomy could be helpful in diagnosis. Employing ultrasound and computed tomography signs, abdominal tuberculosis should be included in differential diagnoses in regions with a high incidence of tuberculosis when there is abdominal pain, weight loss, ascites, history of contact with individuals with tuberculosis, and positive tuberculin skin test when patients have not been Bacillus Calmette Guerin BCG vaccinated. PMID- 25835111 TI - Different effect of smoking on genders in Crohn's disease. AB - BACKGROUND/AIMS: Smoking is a well-established environmental risk factor in Crohn's disease (CD). The study was aimed to investigate possible gender differences in the effect of smoking on the course of CD, with a special focus on selected immune parameters such as Th1/Th2/Th17 cytokines and regulatory T cells (Tregs). MATERIALS AND METHODS: A group of 55 adults with CD was enrolled to the study. The analysis of clinical, demographic and immunological characteristics of patients was performed according to their smoking status and gender. Values were considered significant when p<=0.05. RESULTS: Patients who smoked, particularly females, more frequently suffered from a moderate-to-severe form of the disease, requiring glucocorticoid and immunosuppressive therapies. Smokers, particularly females, were also hospitalized and underwent surgeries more frequently than non smokers. Cytometric analysis showed higher levels of serum proinflammatory cytokines and lower levels of peripheral Tregs in female smokers and former smokers, comparing to males from these subgroups. CONCLUSION: Presented results demonstrate that in all investigated subgroups, particularly however among current smokers and former smokers, female patients seemed to be more affected by CD. Females developed more severe form of the disease and experienced the onset earlier than men. The imbalance between pro- and anti-inflammatory factors observed in CD patients was also more distinct in female smokers and former smokers, comparing to males, and could substantially contribute to the severity of the disease. Exposure to smoking seems to be one of the environmental factors contributing to the gender differences in CD. PMID- 25835112 TI - The impact of anorectal biofeedback therapy on the quality of life of patients with dyssynergic defecation. AB - BACKGROUND/AIMS: Dyssynergic defecation is a common health problem affecting the quality of life of patients adversely. We aimed to evaluate the impact of biofeedback therapy on the quality of life of constipated patients due to dyssynergic defecation. MATERIALS AND METHODS: Constipated patients due to dyssynergic defecation were enrolled to the study. Patients having secondary causes of constipation and who didn't fulfill the eligible criteria were excluded. All the patients underwent three to ten sessions each of which was thirty minutes biofeedback therapy under the supervision of a trained nurse. After one month the patients were assessed for the control. The impact of biofeedback therapy on the quality of life of patients having dyssynergic defecation was assessed using the validated Medical Outcomes Study Short Form-36 (SF-36) questionnaire before and one month after therapy. RESULTS: Thirty-two patients (20 female 62.5%, 12 male 37.5% and mean age 48 (18-72) underwent three to ten sessions biofeedback therapy. Post-therapy improvements of subscores of SF 36 consists of eight domains were all statistically significant when we compared with the pre-therapy values. CONCLUSION: This study showed not only the effectiveness of biofeedback as a therapy modality for constipation but also its impact on the improvement of QOL of constipated patients due to dyssynergic defecation. Patients with chronic constipation not improved by dietary fiber and laxatives should be referred to specialized centers that have facilities for further anorectal physiological assessments. PMID- 25835113 TI - Epidemiology of colorectal cancer in Turkey: A cross-sectional disease registry study (A Turkish Oncology Group trial). AB - BACKGROUND/AIMS: This study aimed to determine the epidemiological characteristics of colorectal cancer in Turkey. MATERIALS AND METHODS: In this multicenter, prospective, and cross-sectional registry study, data for 968 patients with colorectal cancer from 21 centers in 7 geographic regions were analyzed. RESULTS: Diagnosis was colon cancer in 662 (68.4%) and rectum cancer in 306 (31.6%) patients. In total, 60.9% of patients was male; mean age was 58.9+/ 12.6 years. Among patients, 15.0% was drinking alcohol, 17.5% was smoking, 1.5% had familial history of polyposis, 15.0% had diabetes mellitus, 1.0% had inflammatory bowel disease. Fruit and vegetable consumption was low (<3 times/week) in 35.5% and red meat consumption was high (>=3 times/week) in 47.4% of the patients. Median time-to diagnosis was 3.0 months and 4.0 months for patients with colon and rectum cancer, respectively. Mean body mass index was >25 in all group of patients. Distal rectum (61.3%) and sigmoid colon (36.8%) were the most common locations of cancer, for rectum and colon respectively. In total, 85.6% of patients were operated; 25.8% had emergency surgery. Low anterior resection rate was 64.2% in rectum cancer. In majority (89.8%) of the patients with rectum cancer who received preoperative treatment, conventional chemo radiotherapy regimen was given. pTNM staging at diagnosis showed that stage III and IV patients were in majority (35.9% and 29.7%, respectively). CONCLUSION: Colon cancer is more frequent than rectum cancer in Turkey. Colorectal cancer patients are diagnosed at later stages. Most of the cases were operated. Interregional differences for risk factors are worthwhile for evaluation in future trials. PMID- 25835114 TI - Cyclooxygenase-2 (COX2) gene polymorphisms and the risk of sporadic colorectal cancer and polyps among Jordanian population. AB - BACKGROUND/AIMS: Cyclooxygenase-2 (COX2) is a crucial enzyme involved in the metabolism of Prostaglandins and it has been implicated in several processes. This study was done to investigate the associations of polymorphisms in COX2 gene with the risk of colorectal cancer or polyps development among Jordanian population and to correlate with other ethnicities. MATERIALS AND METHODS: One hundred and thirty five cases (135) of colorectal carcinoma were studied for COX2 -A1195G polymorphisms employing PCR-RFLP technique, in addition to 104 cases of adenomatous polyps and 115 matched controls taken from the general population. RESULTS: Sixty eight colorectal cancer patients were males and 67 of patients were females with a median age of (58.0+/-13.9 year). Sixty six (66) of polyp cases were males and 38 were females with a median age of (58.1+/-14.16). The A 1195G AA carriers were 3.1 times less likely to develop CRC (95% CI: 1.8-5.3, p<0.0001), and 1.8 times less likely to develop polyps (95% CI: 0.99-3.2, p=0.056).The A-1195G AG carriers were at higher risk to develop cancer in a dose dependent manner. The AG carriers were 2.9 time more likely to develop CRC and two times more likely to develop polyps when compared to controls. The A allele was more predominant in controls than in polyps or CRC cases. Carriers of the A allele were 1.6 times less likely to develop polyps and 2.6 times less likely to develop CRC. CONCLUSION: The presence of the COX-2 -1195AA genotype may protect against risk of developing colorectal cancer. PMID- 25835115 TI - The long-term mortality of spontaneous bacterial peritonitis in cirrhotic patients: A 3-year nationwide cohort study. AB - BACKGROUND/AIMS: There is no nationwide population-based study for the long-term mortality after single episode of spontaneous bacterial peritonitis (SBP) in cirrhotic patients. Our study showed the short-term and long-term mortalities, and identified the mortality risk of SBP. MATERIALS AND METHODS: The National Health Insurance Database, derived from the Taiwan National Health Insurance program, was used to collect data from 16,992 cirrhotic patients. These cirrhotic patients were classified into three groups: SBP group (n=451, 2.7%), ascites without SBP group (n=2,564, 15.1%), and non-ascites (n=13,977, 82.3%) group. Each patient was followed up to 3 years after the initial hospitalization. RESULTS: The 30-day mortalities in SBP, ascites without SBP, and non-ascites groups were 24.2%, 14.1%, and 8.1%, respectively. The 3-year mortalities in SBP, ascites without SBP, and non-ascites groups were 66.5%, 61.1%, and 41.5%. After Cox's regression analysis adjusted by the patients' age, gender, and underlying medical disorders, the SBP patients (hazard ratio=2.52) and ascites without SBP patients (hazard ratio=1.91) have higher risk for 3-year mortality than those without ascites. CONCLUSION: Cirrhotic patients with SBP have a 2.5-fold increase of 3 year mortality, compared to those without ascites. PMID- 25835116 TI - The efficacy and the immunomodulatory effect of rifaximin in prophylaxis of spontaneous bacterial peritonitis in cirrhotic Egyptian patients. AB - BACKGROUND/AIMS: This study aimed to evaluate the efficacy and the immunomodulatory effect of rifaximin as another promising prophylactic therapy against spontaneous bacterial peritonitis (SBP) in cirrhotics. MATERIALS AND METHODS: Seventy cirrhotic patients with ascites were included in the study. Patients were divided into two groups in a randomized single-blind fashion. Group one (n=40) received rifaximin and group two (n=30) received norfloxacin (control group). The treatment duration was 6 months. Serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 ( IL-6), and interleukin-10 (IL-10) were the primary inflammatory markers of the study to evaluate the effect of the medications used. RESULTS: Three months after treatment, five cases on norfloxacin therapy showed SBP, whereas all cases on rifaxmine therapy were free from SBP. In addition, there was no significant difference between patients on rifaximin and norfloxacin therapy with respect to TNF-alpha, IL-6, and IL-10 serum levels (p>0.05). Furthermore, patients on both rifaximin and norfloxacin therapies showed a statistically significant decrease in TNF-alpha and IL-6 serum levels compared with their baseline levels (p=0.000 and p=0.000, respectively). In contrast, serum IL-10 showed a statistically significant increase in both groups in comparison with its baseline level (p>0.00). Six-month after treatment, patients on rifaximin therapy showed more effective remission from SBP than those on norfloxacin therapy. CONCLUSION: In conclusion, the use of rifaximin not only prevents bacterial translocation but also modulates the immune response of the inflammatory and the anti-inflammatory cytokines in SBP patients. However, the efficacy and the immunomodulatory effect of rifaximin in the prophylaxis of SBP in cirrhotics needs further prospective large-scale, double-blind studies. PMID- 25835117 TI - 18F-FDG activitiy PET/CT and CA-19.9 levels for the prediction of histopathological features and localization of peri- ampullary tumors. AB - BACKGROUND/AIMS: We sought to investigate the roles of maximum standardized uptake value (SUVmax) and serum carbohydrate antigen 19-9 (CA 19-9) in predicting the histopathological features of periampullary tumors. MATERIALS AND METHODS: Thirty-four patients with histologically confirmed periampullary tumors were classified into two groups, according to the localizations of their tumors (ampulla Vateri or pancreas). SUVmax was obtained from [(18)F]-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT). SUVmax and CA 19-9 levels were measured and compared with histopathological features of the tumors. Logistic regression was used to assess the significance and independence of predictive factors. RESULTS: 18F-FDG PET/CT SUVmax (<2.5 vs. >=2.5; p=0.031) and CA 19-9 level (normal vs. elevated; p=0.045) were significantly and independently predictive of the histopathological origin of the tumors (ampulla Vateri vs. pancreas). The ratio of CA 19-9 levels and SUVmax were found to be higher in cases of poorly differentiated tumors and tumors greater than 2 cm in diameter. CONCLUSION: A surgical approach to treatment may be considered for patients who have both i) an established or suspected diagnosis of periampullary tumors and ii) low SUVmax and CA 19-9 levels. PMID- 25835118 TI - Mutation analysis of PRSS1, SPINK1 and CFTR gene in patients with alcoholic and idiopathic chronic pancreatitis: A single center study. AB - BACKGROUND/AIMS: A relation between some genetic mutations and chronic pancreatitis (CP) has been reported. However, the relation of genetic mutation to alcoholic CP (ACP) and idiopathic CP (ICP) still remains controversial. In this study, we investigated the prevalence of protease serine 1 (PRSS1), serine protease inhibitor, Kazal type 1 (SPINK1) SPINK1 and cystic fibrosis transmembrane conductance regulator (CFTR) mutations in ACP and ICP patients in Turkey. MATERIALS AND METHODS: Forty-one patients with ACP and 38 patients with ICP were enrolled, and 35 healthy individuals served as controls. The PRSS1 and SPINK1 mutations were investigated by the polymerase chain reaction (PCR) restriction fragment-length polymorphism (RFLP) technique. The CFTR mutation was examined with PCR direct sequencing. RESULTS: The mean ages of the ACP, ICP and healthy control groups were 53.2, 40.4 and 46.3 years, respectively. A CFTR F508 mutation was detected as a heterozygote in one (2.4%) patient with ACP. In the ICP and control populations, PRSS1, SPINK1 and CFTR mutations were not detected. CONCLUSION: This study shows that PRSS1, SPINK1 and CFTR mutations do not play a role in ACP and ICP patients. PMID- 25835119 TI - Effects of preoperative and postoperative enteral nutrition on postoperative nutritional status and immune function of gastric cancer patients. AB - BACKGROUND/AIMS: Effects of preoperative one week enteral nutrition (EN) support on the postoperative nutritional status, immune function and inflammatory response of gastric cancer patients were investigated. MATERIALS AND METHODS: 106 cases of gastric cancer patients were randomly divided into preoperative one week EN group (trial group) and early postoperative EN group (control group), which were continuously treated with EN support until the postoperative 9th day according to different treatment protocols. All the patients were checked for their body weight, skinfold thickness, upper arm circumference, white blood cell count (WBC), albumin (ALB), prealbumin (PA), C-reactive protein (CRP), humoral immunity (IgA, IgG), T cell subsets (CD4, CD8 and CD4/CD8), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), etc. on the preoperative and the postoperative 1st and 10th day, respectively. RESULTS: PA and IgG levels of the experimental group were higher than those of the control group on the postoperative 10th day, whereas IL-6 level of the experimental group was lower than that of the control group. CONCLUSION: EN support for preoperative gastric cancer patients will improve the postoperative nutritional status and immune function, alleviate inflammatory response, and facilitate the recovery of patients. PMID- 25835120 TI - Megabulbus in endoscopy; suspect for superior mesenteric artery syndrome in children. AB - Rarity of Superior Mesenteric Artery Syndrome (SMAS) and necessity of invasive tests to verify the diagnosis leads to patients receiving symptom-oriented drugs for a long period without any definite diagnosis. Diagnostic tests such as barium series, abdominal CT scan, abdominal angiography or magnetic resonance arteriography are used in patients with suspected SMAS. In pediatric patients, a non-invasive SMAS diagnosis may be considered easily with abdominal ultrasound performed by experienced hands. Megabulbus is used as a radiological term; however, reviewing the literature an endoscopic definition for megabulbus was not found. We decided to mention severely dilated pyloric ring and bulb as megabulbus. Megabulbus might be an indicator for SMAS. This is the first case of SMAS in adult and pediatric age groups presenting with megabulbus. PMID- 25835121 TI - Face skin hyperpigmentation during pegylated interferon and ribavirin therapy. PMID- 25835122 TI - A case of upper extremity thrombosis in patient with ulcerative colitis. PMID- 25835123 TI - Idiopathic abdominal cocoon syndrome: Preoperative diagnosis with computed tomography. PMID- 25835124 TI - Subcutaneous and muscular metastasis of the colorectal cancer on F-18 FDG PET/CT. PMID- 25835125 TI - Verneuil's disease: A case report and literature review. PMID- 25835126 TI - Self-Assembly and Collagen-Stimulating Activity of a Peptide Amphiphile Incorporating a Peptide Sequence from Lumican. AB - The self-assembly and bioactivity of a peptide amphiphile (PA) incorporating a 13 residue sequence derived from the last 13 amino acids of the C-terminus of lumican, C16-YEALRVANEVTLN, attached to a hexadecyl (C16) lipid chain have been examined. Lumican is a proteoglycan found in many types of tissue and is involved in collagen fibril organization. A critical aggregation concentration (cac) for the PA was determined through pyrene fluorescence measurements. The structure of the aggregates was imaged using electron microscopy, and twisted and curved nanotapes were observed. In situ small-angle X-ray scattering and fiber X-ray diffraction reveal that these tapes contain interdigitated bilayers of the PA molecules. FTIR and circular dichroism spectroscopy and fiber X-ray diffraction indicate that the lumican sequence in the PA adopts a beta-sheet secondary structure. Cell assays using human dermal fibroblasts show that below the cac the PA displays good biocompatibility and also stimulates collagen production over a period of 3 weeks, exceeding a 2-fold enhancement for several concentrations. Thus, this PA has promise in future biological applications, in particular, in tissue engineering. PMID- 25835127 TI - Pianists exhibit enhanced memory for vocal melodies but not piano melodies. AB - Nonmusicians remember vocal melodies (i.e., sung to la la) better than instrumental melodies. If greater exposure to the voice contributes to those effects, then long-term experience with instrumental timbres should elicit instrument-specific advantages. Here we evaluate this hypothesis by comparing pianists with other musicians and nonmusicians. We also evaluate the possibility that absolute pitch (AP), which involves exceptional memory for isolated pitches, influences melodic memory. Participants heard 24 melodies played in four timbres (voice, piano, banjo, marimba) and were subsequently required to distinguish the melodies heard previously from 24 novel melodies presented in the same timbres. Musicians performed better than nonmusicians, but both groups showed a comparable memory advantage for vocal melodies. Moreover, pianists performed no better on melodies played on piano than on other instruments, and AP musicians performed no differently than non-AP musicians. The findings confirm the robust nature of the voice advantage and rule out explanations based on familiarity, practice, and motor representations. PMID- 25835128 TI - High-field transport in graphene: the impact of Zener tunneling. AB - We study, theoretically, the impact of Zener tunneling (the generation of electron-hole pairs by the electric field) on the charge-transport properties of graphene in the high-field regime. We model Zener tunneling in a rigorous way, using the quantum master equation for the density matrix. In the presence of Zener tunneling, a steady-state can be reached only by further including an efficient mechanism for the electron thermalization such as electron-electron scattering. We treat the effects of electron-electron relaxation within a simplified model, that assumes an instantaneous separate thermalization of the electrons in the conduction band and of the holes in the valence band. The inclusion of both Zener tunneling and electron-electron relaxation improves the agreement with measurements performed in graphene in the high-field regime at low doping. PMID- 25835129 TI - Segregating phototransduction from morphogenesis in photoreceptor outer segments. PMID- 25835131 TI - Latex urinary catheters for the short-time drainage. PMID- 25835130 TI - Incomplete Blinking May Attribute to the Development of Meibomian Gland Dysfunction. AB - PURPOSE: To investigate the relationship between meibomian gland dysfunction (MGD) and incomplete blinking caused by cranial nerve seven (CN VII) palsy. METHODS: A prospective case series of 60 consecutive patients with unilateral CN VII palsy was evaluated for MGD. According to the House-Brackmann scale, patients were divided into complete or incomplete blinking group, with the incomplete group further subdivided to early, middle or late stage according to the paralysis duration. Schirmer's I test, tear break-up time (BUT), superficial punctate keratopathy, eyelid abnormality, ability and quality of meibum expression were evaluated. Unaffected contralateral eyes were used as control for comparison. RESULTS: A paired sample t-test between affected and unaffected eyes demonstrated a significant difference for BUT, superficial punctate keratopathy, eyelid abnormality, ability and quality of meibum expression in the incomplete blinking group. However, only BUT showed significant difference between affected and unaffected eyes in complete blinking group. Furthermore, we showed that paralysis duration was related to the incidence of MGD. Significant difference was demonstrated between the affected and unaffected eyes for superficial punctate keratopathy, eyelid abnormality, ability and quality of meibum expression in the middle and late stage, but not early stage. CONCLUSIONS: These findings suggest that the inability to blink completely induced by CN VII palsy for more than one week might contribute to the development of MGD. Clinical optimization of blinking may ameliorate MGD symptom and benefit CN VII palsy patients. PMID- 25835132 TI - A randomized, double-blind, placebo-controlled, crossover trial of "on-demand" tramadol for treatment of premature ejaculation. AB - OBJECTIVES: The objective of this study is to assess the dose-related effects of tramadol on a group of patients with premature ejaculation (PE). SUBJECTS AND METHODS: During the period of months between June 2010 and July 2012, 180 PE patients presented to outpatient clinic of our hospital. Patients were randomized in a 1:1:1 fashion to receive different sequences of the three medications: placebo, 50 mg of tramadol and 100 mg of tramadol. Every patient received 10 doses of each medication for 2 months. Intra-vaginal ejaculatory latency time (IELT) was recorded in seconds initially and for each arm. Successful treatment of PE is defined if IELT exceeded 120 s. Side-effects of medications were reported. RESULTS: Of patients enrolled, 125 (69.4%) continued the study. Patients' age range was 20-55 years with PE complaint of 1 to 10 years duration. Mean IELT was 72 at presentation, 82 for placebo, 150 for tramadol 50 mg, and 272 for tramadol 100 mg (P < 0.001 for all comparisons). PE was successfully treated in only 2.4% of patients with placebo, in contrast to 53.6% and 85.6% with 50 and 100 mg tramadol, respectively (P < 0.001 for all comparisons). On multivariate logistic regression analysis, baseline IELT was the only predictor of successful treatment of PE with both tramadol 50 mg (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03-1.07, P < 0.001) and tramadol 100 mg (OR: 1.07, 95% CI: 1.04 1.11, P < 0.001). Postmicturition dribble annoyed 12.8% of those who received 50 mg tramadol and 33.6% of those who received 100 mg tramadol (P < 0.001). Weak scanty ejaculation was the main complaint in 7.2% versus 21.6% of those using 50 and 100 mg tramadol, respectively (P = 0.002). Two patients discontinued tramadol 100 mg due to side-effects. CONCLUSION: Tramadol hydrochloride exhibits a significant dose-related efficacy and side-effects over placebo for treatment of PE. PMID- 25835133 TI - [Not to do]. PMID- 25835134 TI - [Certainties and doubts about the management of acute pharyngitis]. PMID- 25835135 TI - [Childhood obesity prevention from a community view]. AB - The percentage of failure and relapse in the treatment of obesity is high. Where possible, the preferred strategy for preventing obesity is to modify eating habits and lifestyles. This article aims to provide a framework for evidence on the most effective interventions for addressing childhood obesity, both from a prevention point of view, as well as reducing it, when it is already established. After a review of the scientific literature, the issues that must be considered both in the universal and selective prevention of childhood obesity are presented. Also, in light of the controversy over the tools for measuring and controlling the problem, some clarification is provided on the criteria. Finally, the approach to the prevention of overweight and obesity with a community perspective is separated, with two short protocols being offered with diagrams of the basic procedure to follow. PMID- 25835136 TI - The observation of an ipsilateral carotid canal hypoplasia cannot be used to ascertain the congenital nature of a carotid artery occlusion. PMID- 25835137 TI - Commentary: Consistency and collapsibility: are they crucial for instrumental variable analysis with a survival outcome in mendelian randomization? PMID- 25835138 TI - In utero SSRI exposure and risk of clubfoot. PMID- 25835139 TI - The authors respond. PMID- 25835141 TI - Alternative splicing in plants: directing traffic at the crossroads of adaptation and environmental stress. AB - In recent years, high-throughput sequencing-based analysis of plant transcriptomes has suggested that up to ~60% of plant gene loci encode alternatively spliced mature transcripts. These studies have also revealed that alternative splicing in plants can be regulated by cell type, developmental stage, the environment, and the circadian clock. Alternative splicing is coupled to RNA surveillance and processing mechanisms, including nonsense mediated decay. Recently, non-protein-coding transcripts have also been shown to undergo alternative splicing. These discoveries collectively describe a robust system of post-transcriptional regulatory feedback loops which influence RNA abundance. In this review, we summarize recent studies describing the specific roles alternative splicing and RNA surveillance play in plant adaptation to environmental stresses and the regulation of the circadian clock. PMID- 25835142 TI - Radial head arthroplasty, 11 years experience: A series of 82 patients. AB - OBJECTIVES: The indications for radial head arthroplasty are essentially complex fractures with ligament damage (medial, lateral or Essex-Lopresti), and/or associated with bone damage (coronoids or olecranon). The aim of this study is to review our experience with the use of a radial head prosthesis in the context of a trauma. MATERIAL AND METHOD: An observational, descriptive and retrospective study, with a follow-up of 1- 11 years, was performed on a study group of 82 patients with a mean age of 41.6 (+/- 9.2) years. The inclusion criteria were: patients of working age (25-64 years) with complex radial head fractures (Mason II, III, IV), with soft tissue and bone injuries that caused instability, non reconstructable by osteosynthesis and treated using arthroplasty. The primary variables analysed were social demographics, Mason classification, or surgical aspects such as delay, surgical time, type of prosthesis (where the bipolar prosthesis was most used, 88.6%), need of fixation or further surgery. Rehabilitation time, causes of prosthesis failure, radiological findings (according to Van-Riet), areas of loosening (according to Popovic), as well as the Mayo Elbow Performance Score (MEPS) and the Cassebaum scale. Various associated injuries were observed, such as injuries in the lateral collateral ligament of the elbow in 39% of cases, coronoid fractures in 25.6%, and an olecranon fracture in 15.9% of the series. There was one case of an Essex- Lopresti injury. The tests used for the statistical analysis were Chi squared and Fisher test for categorical variables and contingency tables. The Mann Whitney U or Kruskall Wallis tests were used for the numerical variables. Evidence level: IV. RESULTS: The mean surgical time was 100 (+/- 56.8) minutes. The prosthesis was fixed in 53.8% of cases. The mean score on the MEPS scale was 80.4 (+/- 19.3) points, being good-excellent in 71.6%. The elbow was stable in 93.7% of cases. There was moderate instability, with 10 degrees or more in varus or valgus, and in 1.3% in the rest of the series. The rehabilitation time was lower in the fixed cases (P=.03), and there was greater rigidity (P=.03) and more sequelae (limitations in mobility, residual pain), (P<0.05) in the cases where the LCL had to be repaired (given that there were other serious injuries in these cases). When the surgical delay was less than one week, better results were obtained on the Cassebaum scale (P=.02), as well as more excellent results on the MEPS scale MEPS (P=.02). The prosthesis was removed in 11 cases (13.4%), with the main cause for removal being pain in pronosupination in 5 cases, and capitellar injuries in 4 cases, one dislocation, and one infections. The most frequent complication was rigidity (30.5%). There were 3 infections (3.7%). Popovic areas 1 and 7 had greater osteolysis. CONCLUSIONS: The presence of concomitant bone and ligament injuries determined a longer surgical time and more sequelae. Early surgery would achieve better clinical results. PMID- 25835143 TI - Recurrent seizures, mental retardation and extensive brain calcinosis related to delayed diagnosis of hypoparathyroidism in an adolescent boy. AB - Reports of adolescent patients presenting with intractable seizures and mental retardation secondary to idiopathic hypothyroidism are uncommon in the literature. In this case, we report a 17-year-old boy who developed recurrent seizures, mental retardation and extensive brain calcinosis related to delayed diagnosis of hypoparathyroidism. Hypoparathyroidism can be easily missed in children and adolescents, and may lead to irreversible neurologic sequelae. This case highlights the need to consider hypocalcemia in any patient with uncontrolled seizures. PMID- 25835144 TI - Osteoblastic cells trigger gate currents on nanocrystalline diamond transistor. AB - We show the influence of osteoblastic SAOS-2 cells on the transfer characteristics of nanocrystalline diamond solution-gated field-effect transistors (SGFET) prepared on glass substrates. Channels of these fully transparent SGFETs are realized by hydrogen termination of undoped diamond film. After cell cultivation, the transistors exhibit about 100* increased leakage currents (up to 10nA). During and after the cell delamination, the transistors return to original gate currents. We propose a mechanism where this triggering effect is attributed to ions released from adhered cells, which depends on the cell adhesion morphology, and could be used for cell culture monitoring. PMID- 25835145 TI - Hybridization of different antisense oligonucleotides on the surface of gold nanoparticles to silence zinc metalloproteinase gene after uptake by Leishmania major. AB - The use of antisense oligonucleotides is a novel strategy to treat infectious diseases. In this approach, vital mRNAs are targeted by antisense oligonucleotides. The aim of this study was to evaluate the effects of gold nanoparticles hybridized with different antisense oligonucleotides on Leishmania (L) major. In this project, gold nanoparticles were first synthesized, and then conjugated with primary oligonucleotides, 3'-AAA-5'. Next, conjugated gold nanoparticles (NP1) were separately hybridized with three types of antisense oligonucleotide from coding reign of GP63 gene (NP2), non-coding reign of GP63 gene (NP3), and both coding and non-coding reigns of GP63 (NP4). Then, 1mL of L. major suspension was separately added to 1mL of different hybridized gold nanoparticles at serial concentrations (1-200MUg/mL), and incubated for 24, 48, and 72h at 37 degrees C. Next, the uptake of each nanoparticle was separately measured by atomic absorption spectroscopy. After incubation, the cell viability was separately evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay. Also, the expression of GP63 gene was read out by quantitative real-time PCR. This study showed that NP2 and NP3 had higher (5-fold) uptake than NP1 and NP4. Moreover, NP2 and NP3 led to less cell viability and gene expression, compared with NP1 and NP4. It could be concluded that both sequence and size of antisense oligonucleotide were important for transfection of L. major. Importantly, these antisense oligonucleotides can be obtained from both coding and non-coding reign of GP63 gene. Moreover, hybridized gold nanoparticles not only could silence GP63 gene, but also could kill L. major. PMID- 25835146 TI - Dynamic surface properties of lysozyme solutions. Impact of urea and guanidine hydrochloride. AB - Urea and guanidine hydrochloride (GuHCl) have different influence on surface properties of lysozyme solutions. The increase of GuHCl concentration leads to noticeable changes of kinetic dependencies of the dynamic surface elasticity and ellipsometric angles while the main effect of urea reduces to a strong drop of the static surface tension. The difference between the effects of these two denaturants on the surface properties of other investigated globular proteins is significantly weaker and is mainly a consequence of a different extent of the globule unfolding in the surface layer at equal concentrations of the denaturants. The obtained results for lysozyme solutions are connected with the strongly different denaturation mechanisms under the influence of urea and GuHCl. In the former case the protein preserves its globular structure in the adsorption layer at high urea concentrations (up to 9M) but without tightly packed interior of the globule and with a dynamic tertiary structure (molten globule state). On the contrary, the increase of GuHCl concentration leads to partial destruction of the protein tertiary structure in the surface layer, although this effect is not as strong as in the case of previously studied bovine serum albumin and beta lactoglobulin. PMID- 25835147 TI - Decompression induced bubble dynamics on ex vivo fat and muscle tissue surfaces with a new experimental set up. AB - Vascular gas bubbles are routinely observed after scuba dives using ultrasound imaging, however the precise formation mechanism and site of these bubbles are still debated and growth from decompression in vivo has not been extensively studied, due in part to imaging difficulties. An experimental set-up was developed for optical recording of bubble growth and density on tissue surface area during hyperbaric decompression. Muscle and fat tissues (rabbits, ex vivo) were covered with nitrogen saturated distilled water and decompression experiments performed, from 3 to 0bar, at a rate of 1bar/min. Pictures were automatically acquired every 5s from the start of the decompression for 1h with a resolution of 1.75MUm. A custom MatLab analysis code implementing a circular Hough transform was written and shown to be able to track bubble growth sequences including bubble center, radius, contact line and contact angles over time. Bubble density, nucleation threshold and detachment size, as well as coalescence behavior, were shown significantly different for muscle and fat tissues surfaces, whereas growth rates after a critical size were governed by diffusion as expected. Heterogeneous nucleation was observed from preferential sites on the tissue substrate, where the bubbles grow, detach and new bubbles form in turn. No new nucleation sites were observed after the first 10min post decompression start so bubble density did not vary after this point in the experiment. In addition, a competition for dissolved gas between adjacent multiple bubbles was demonstrated in increased delay times as well as slower growth rates for non-isolated bubbles. PMID- 25835148 TI - Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin. AB - Nuclear receptor humanized mice models have been developed to predict regulation of drug metabolizing enzyme by xenobiotics. However, limited information is available concerning xenobiotic-induced regulation of drug metabolizing enzymes in multiple nuclear receptor humanized mice. The present study investigated the hepatic regulation of cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) in the pregnane X receptor (PXR) and the constitutive androstane receptor double humanized mice treated with rifampicin (RIF; 10mg/kg) for 4 days. RIF increased hepatic microsomal protein and total CYP contents, and CYP reductase activity in the humanized mice, but not in normal mice. Moreover, hepatic induction of Cyp2b10, Cyp2c, and Cyp3a11 were observed only in the RIF-treated humanized mice, suggesting that the humanized mice are sensitive to RIF with respect to the regulation of the hepatic CYP system. Hepatic UGT activities using estradiol, serotonin, and mefenamic acid, but not chenodeoxycholic acid as substrates, increased in the RIF-treated humanized mice, and the glucuronidation activities of estradiol and chenodeoxycholic acid increased in RIF-treated normal mice. These results raise the possibility that a PXR-independent mechanism may be involved in hepatic regulation of UGTs by RIF. PMID- 25835149 TI - Temporal variation and interaction of full size spectrum Alcian blue stainable materials and water quality parameters in a reservoir. AB - This paper reports on the fate of different fractions of Alcian blue (AB) stainable material in Pao-Shan reservoir, Taiwan, in a one-year study (2013-2014) and an intensive study during phytoplankton bloom (2014). The interactions between the fractions, including AB stained particles, particle and colloidal transparent exopolymer particles (pTEP and cTEP), dissolved acid polysaccharide (dAPS), and their relationship to other water quality parameters were analyzed. The Flow Cytometer and Microscope (FlowCAM) was for first time used to characterize AB stained particles. The results of the one-year study likely showed relationships of pTEP concentration to phytoplankton count and chlorophyll a, while in the intensive study, AB stained particles abundance and pTEP concentration were correlated neither phytoplankton count nor chlorophyll a, but strongly positively correlated with some phytoplankton species' abundance. The difference indicates that sampling frequency and phytoplankton composition should be addressed for studying the links between AB stained fractions and phytoplankton. The interaction between different AB stained fractions further suggests that the majority of AB stained particles and pTEP would be directly generated by some phytoplankton species, whereas their abiotic generation by cTEP or dAPS may only have contributed partly to their formation. This differs from previous studies which generally posited that pTEP are mainly formed abiotically from dissolved precursors. Successful application of FlowCAM for visualization of AB stained particles recommends this technique by which particle morphologies can be conserved and morphological features of particle can be simultaneously elucidated. PMID- 25835151 TI - Determination of iohexol in human serum by a semi-automated liquid chromatography tandem mass spectrometry method. AB - OBJECTIVES: Measured glomerular filtration rate (mGFR) is the best indicator of renal function in children and adolescents. GFR determination using iohexol clearance has been increasingly accepted and applied in clinical practice because it is accurate, readily available, non-radioactive, safe and is used intravenously even in the presence of renal disease. This study describes the development and evaluation of a semi-automated method for determination of iohexol in human serum using liquid chromatography coupled with electrospray ionization (ESI) tandem mass spectrometry (LC-MS/MS). DESIGN AND METHODS: Iohexol was extracted from serum using a MICROLAB(r) NIMBUS4 automation robot and supernatant was dried under nitrogen gas and reconstituted in mobile phase. Ioversol was used as the internal standard. Chromatography was performed using a C-8 analytical column (Phenomenex, 3 MUm, 50 * 3.0 mm I.D.) at room temperature and a gradient LC method on a Waters 2795 Alliance HT HPLC system. The flow rate was 0.5 mL/min and the retention times were 2.36 min and 2.14 min for iohexol and ioversol, respectively. Detection by MS/MS was achieved using a (Micromass Quattro Micro) tandem mass spectrometer operated in the ESI-positive mode. The multiple-reaction monitoring (MRM) method used ion transitions m/z 821.9 to 803.7 for iohexol and m/z 807.9 to 588.7 for ioversol. Method validation studies were conducted to determine the linearity, accuracy, precision, matrix effects and stability. A method comparison of blinded, residual patient samples was conducted with a well-established method. RESULTS: The method was linear from 7.7 MUg/mL to 2000.0 MUg/mL. The low limit of quantification and the detection limit were established at 7.7 and 3.0 MUg/mL, respectively. Within-run and between-run precisions were found to be <6% CV and measured values deviated no more than 5% from target concentrations. Carryover and matrix effects were not significant. Comparison to a well-established method showed very good agreement with correlation coefficient of 0.996 for iohexol and 0.993 for GFR/1.73 m(2). CONCLUSIONS: This method accurately and precisely quantifies iohexol in 50 MUL of serum, enabling determination of mGFR by iohexol clearance. The method is highly correlated to a reference method. Use of an automated liquid handler reduces labor-intensive, manual sample preparation steps. The stability of this analyte and the robustness of this assay fit well within our clinical workflow and we have successfully applied this method to determine mGFR in pediatric patients. PMID- 25835152 TI - Evaluation of a HbA1c point-of-care analyzer. AB - OBJECTIVES: A better glycemic monitoring of diabetic patients and avoiding complications of poorly controlled diabetes could be possible with point-of-care testing technology (POCT) for HbA1c determination. B-Analyst(r) was studied to check whether it complied with the quality requirements for this purpose. DESIGN AND METHODS: We evaluated the B-Analyst(r) (Menarini Diagnostics), which is based in the principle of latex agglutination immunoturbidimetry, to assess the validity of the technique of HbA1c. We carried out the method comparison with the HA-8180(r) (Menarini Diagnostics) as a reference method [High Performance Liquid Chromatography (HPLC)]. We assessed the analytical quality of the B-Analyst(r) studying the accuracy: inter-assay variability and intra-assay study. Furthermore, possible interferences by hemoglobinopathies were studied. RESULTS: Regression analysis of the data for the method comparison between HA-8180(r) and B-Analyst(r) showed a slope of 1.0085 and an intercept of 0.1208. The Pearson's correlation coefficient was 0.9958 (p<0.0001). Bias study showed a mean difference from B-Analyst(r) with respect to HA-8180(r) of 0.1872 with a 95% confidence interval. The standard error of the estimate (Syx) was 0.2091. The concordance correlation coefficient to assess accuracy was 0.9922 (0.9891 0.9945). The CV for the inter-assay study was 1.4%. For the intra-assay study we analyzed 3 samples with different HbA1c % whose CV were 1.03% [4.7% HbA1c (28 mmol/mol)], 0.46% [6.4% HbA1c (46 mmol/mol)] and 0.78% [8.1% HbA1c (65 mmol/mol)]. CONCLUSION: The B-Analyst(r) evaluated not only showed good correlation with HA-8180(r), but also it presented a great accuracy both in the inter-assay and in the intra-assay studies. The B-Analyst(r) complies with quality specifications required for monitoring of diabetic patients. PMID- 25835153 TI - The advent of genome-wide association studies for bacteria. AB - Significant advances in sequencing technologies and genome-wide association studies (GWAS) have revealed substantial insight into the genetic architecture of human phenotypes. In recent years, the application of this approach in bacteria has begun to reveal the genetic basis of bacterial host preference, antibiotic resistance, and virulence. Here, we consider relevant differences between bacterial and human genome dynamics, apply GWAS to a global sample of Mycobacterium tuberculosis genomes to highlight the impacts of linkage disequilibrium, population stratification, and natural selection, and finally compare the traditional GWAS against phyC, a contrasting method of mapping genotype to phenotype based upon evolutionary convergence. We discuss strengths and weaknesses of both methods, and make suggestions for factors to be considered in future bacterial GWAS. PMID- 25835154 TI - Guiding bioprocess design by microbial ecology. AB - Industrial bioprocess development is driven by profitability and eco-efficiency. It profits from an early stage definition of process and biocatalyst design objectives. Microbial bioprocess environments can be considered as synthetic technical microbial ecosystems. Natural systems follow Darwinian evolution principles aiming at survival and reproduction. Technical systems objectives are eco-efficiency, productivity, and profitable production. Deciphering technical microbial ecology reveals differences and similarities of natural and technical systems objectives, which are discussed in this review in view of biocatalyst and process design and engineering strategies. Strategies for handling opposing objectives of natural and technical systems and for exploiting and engineering natural properties of microorganisms for technical systems are reviewed based on examples. This illustrates the relevance of considering microbial ecology for bioprocess design and the potential for exploitation by synthetic biology strategies. PMID- 25835155 TI - Label-free surface-enhanced Raman spectroscopy detection of DNA with single-base sensitivity. AB - Direct, label-free detection of unmodified DNA is a great challenge for DNA analyses. Surface-enhanced Raman spectroscopy (SERS) is a promising tool for DNA analyses by providing intrinsic chemical information with a high sensitivity. To address the irreproducibility in SERS analysis that hampers reliable DNA detection, we used iodide-modified Ag nanoparticles to obtain highly reproducible SERS signals of single- and double-strand DNA in aqueous solutions close to physiological conditions. The phosphate backbone signal was used as an internal standard to calibrate the absolute signal of each base for a more reliable determination of the DNA structure, which has not been achieved before. Clear identification of DNA with single-base sensitivity and the observation of a hybridization event have been demonstrated. PMID- 25835156 TI - [Tinea pedis due to Fusarium solani in Dakar]. AB - A patient presented with intertrigo at the second, third and fourth interdigitals spaces lasting for four years in which Fusarium solani was highlighted. The search for contributing factors revealed a concept of foot washing with water at least five times a day for ablutions, associated with wearing closed shoes all day and the absence of immunosuppression and diabetes. The diagnosis of Fusarium was made on the basis of direct examination and culture. Combined treatment with griseofulvin oral and topical ciclopirox was introduced and allowed healing after 45 days at which an antifungal powder was prescribed for relay. This case adds to the rare cases of intertrigo Fusarium sp. and confirms the frequent practice of ablutions as favoring factor. PMID- 25835157 TI - Updating the epidemiology of dermatophyte infections in Palestine with special reference to concomitant dermatophytosis. AB - OBJECTIVE: To determine the epidemiology of dermatophytosis in Palestinian patients, detect changes in the etiological agents during the last three decades, and to correlate between concomitant tinea pedis infections, and other cutaneous lesions. MATERIALS AND METHODS: 220 suspected dermatophytosis patients were involved in this study. In an additional 38 cases, where consultation was prompted by tinea pedis, the presence of other lesions of concomitant dermatophytosis was studied, to further investigate the diagnosis. Clinical specimens were collected and identification of dermatophyte species was based on gross and microscopic morphology. RESULTS: Epidemiology of tinea capitis has gone the most radical changes in Palestine in the last three decades, with the zoophilic dermatophyte Microsporum canis replacing Trichophyton violaceum, becoming the predominant causative agent. During this study, 21.6% (38/176) patients with tinea pedis and concomitant lesions caused by the same dermatophytes at sites distant from the primary lesions in the foot were prospectively identified. About 63.2% of patients with tinea pedis have a concomitant toenail onychomycosis infection. CONCLUSIONS: The epidemiology of dermatophytosis, especially tinea capitis, has gone the most radical changes in Palestine in the last three decades, with M. canis replacing T. violaceum, and becoming the predominant causative agent of all cases of infections. The coexistence of tinea pedis with other types of fungal skin infections is a frequent phenomenon; we believe that the infected foot may be a site of primary infection. Thus, the effective therapy for tinea pedis is essential to prevent spreading the infection to other sites of the skin. PMID- 25835158 TI - Sinus balloon catheter dilation in pediatric chronic rhinosinusitis resistant to medical therapy. AB - IMPORTANCE: Sinus balloon catheter dilation (SBCD) has been used for chronic rhinosinusitis (CRS). It is necessary to evaluate its effect on children with CRS. OBJECTIVE: To evaluate the efficacy of SBCD on pediatric CRS in China. DESIGN, SETTING, AND PARTICIPANTS: A prospective case-control study was conducted from October 1, 2012, to May 31, 2013, in an academic tertiary referral hospital. Participants included a total of 79 patients, aged 7 to 12 years, with CRS resistant to medical therapy. INTERVENTIONS: Medical or SBCD treatment of pediatric CRS. MAIN OUTCOMES AND MEASURES: Age, sex, and results of computed tomographic scan, SBCD (case group) or conservative treatment (control group), sinonasal-5 questionnaire (SN-5), and visual analog scale (VAS) were analyzed and compared. RESULTS: Data from 79 of 96 patients who had complete follow-up documents were statistically analyzed (42 boys; 37 girls; mean [SD] age, 9.3 [1.7] years). Compared with the preoperative scores, the SN-5 and VAS scores in children with CRS who underwent SBCD with or without adenoidectomy were significantly lower at 3 months (2.5 vs 4.3 for SN-5; P < .001; 3.1 vs 5.2 for VAS; P < .001) and at 1 year (2.9 vs 4.3 for SN-5; P = .001; 3.1 vs 5.2 for VAS; P < .001). Both SN-5 and VAS scores in the control group were significantly decreased at 3 months (3.1 vs 4.2 for SN-5; P = .001; 3.9 vs 5.1 for VAS; P < .001) but not significantly changed at 12 months (3.8 vs 4.2 for SN-5; P = .01; 4.9 vs 5.1 for VAS; P = .54). The SN-5 and VAS scores in the SBCD group were significantly lower than those for controls at 3 months (2.5 vs 3.1 for SN-5; P = .003; 3.1 vs 3.9 for VAS; P = .01) and at 1 year after surgery (2.9 vs 3.8 for SN 5; P < .001; 3.1 vs 4.9 for VAS; P < .001). By the 12-month SN-5 score evaluation, the rates of marked, moderate, and mild improvement were significantly better in the SBCD group (52% [22 of 42], 26% [11 of 42], and 14% [6 of 42], respectively) than in the control group (14% [5 of 37], 19% [7 of 37], and 11% [4 of 37], respectively) (P < .05 for all comparisons). CONCLUSIONS AND RELEVANCE: The SBCD procedure is a safe and effective technique for pediatric CRS resistant to medical therapy. PMID- 25835159 TI - Solid-State Solvation and Enhanced Exciton Diffusion in Doped Organic Thin Films under Mechanical Pressure. AB - Direct modification of exciton energy has been previously used to optimize the operation of organic optoelectronic devices. One demonstrated method for exciton energy modification is through the use of the solvent dielectric effects in doped molecular films. To gain a deeper appreciation of the underlying physical mechanisms, in this work we test the solid-state solvation effect in molecular thin films under applied external pressure. We observe that external mechanical pressure increases dipole-dipole interactions, leading to shifts in the Frenkel exciton energy and enhancement of the time-resolved spectral red shift associated with the energy-transfer-mediated exciton diffusion. Measurements are performed on host:dopant molecular thin films, which show bathochromic shifts in photoluminescence (PL) under increasing pressure. This is in agreement with a simple solvation theory model of exciton energetics with a fitting parameter based on the mechanical properties of the host matrix material. We measure no significant change in exciton lifetime with increasing pressure, consistent with unchanged aggregation in molecular films under compression. However, we do observe an increase in exciton spectral thermalization rate for compressed molecular films, indicating enhanced exciton diffusion for increased dipole dipole interactions under pressure. The results highlight the contrast between molecular energy landscapes obtained when dipole-dipole interactions are increased by the pressure technique versus the conventional dopant concentration variation methods, which can lead to extraneous effects such as aggregation at higher doping concentrations. The present work demonstrates the use of pressure probing techniques in studying energy disorder and exciton dynamics in amorphous molecular thin films. PMID- 25835160 TI - Budesonide/Formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. AB - RATIONALE: Systemic steroids are the standard treatment for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) despite their poor efficacy and disabling side effects. OBJECTIVES: To evaluate the effectiveness and tolerance of budesonide/formoterol as an alternative treatment for BOS after HSCT. METHODS: In this randomized, double-blind, placebo-controlled study, we randomly assigned 32 HSCT recipients with mild/severe BOS to receive budesonide/formoterol or placebo for 6 months. The primary outcome was the change in the FEV1 after 1 month of treatment (M1) compared with the baseline value. Patients were unblinded at M1 if there was no improvement in the FEV1. Those who had initially received placebo were switched to budesonide/formoterol. Intention-to-treat analysis was performed to assess the primary outcome. Additional analyses took scheduled treatment contamination into account. MEASUREMENTS AND MAIN RESULTS: At M1, the median FEV1 increased by 260 ml in the budesonide/formoterol arm compared with 5 ml in the placebo arm (P = 0.012). The median increases in the FEV1 at M1 relative to the baseline value for the treated and placebo groups were 13 and 0%, respectively (P = 0.019). Twenty five patients received budesonide/formoterol during the study. The median difference in the FEV1 between the baseline and after 1 month of treatment for these patients was +240 ml (P = 0.0001). The effect of budesonide/formoterol on the FEV1 was maintained in the 13 patients who completed 6 months of treatment. CONCLUSIONS: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754). PMID- 25835162 TI - Report sheds new light on veterinary employment. AB - Findings range from wage implications of internships to veterinarians' wish to work fewer hours PMID- 25835163 TI - Ideas for research into feral cat management. PMID- 25835164 TI - What is your diagnosis? Seminal vesicle disease. PMID- 25835165 TI - ECG of the Month. Third-degree AV block with sick sinus syndrome. PMID- 25835166 TI - Theriogenology question of the month. Lymphangioma of the spermatic cord. PMID- 25835167 TI - Correction: Comparison of anamnestic responses to rabies vaccination in dogs and cats with current and out-of-date vaccination status. PMID- 25835168 TI - Pathology in practice. Parvoviral myocarditis in a dog. PMID- 25835169 TI - Pathology in practice. Chylous ascites with secondary neutrophilic inflammation in a foal. PMID- 25835170 TI - Urine protein-to-creatinine concentration ratio in samples collected by means of cystocentesis versus manual compression in cats. AB - Objective-To compare urine protein-to-creatinine concentration (UPC) ratios in samples collected by means of cystocentesis versus manual compression in cats. Design-Evaluation study. Animals-43 client-owned cats requiring urinalysis. Procedures-In all cats, 5 mL of urine from the midstream phase of micturition was collected by means of manual compression and, subsequently, an additional 5 mL of urine was obtained by means of ultrasound-guided cystocentesis. A complete urinalysis was performed on all samples, and UPC ratios were determined. Results Cats were classified on the basis of the International Renal Interest Society substaging system as being free from proteinuria (UPC ratio, < 0.2; n = 19) or as having borderline proteinuria (UPC ratio, 0.2 to 0.4; 7) or proteinuria (UPC ratio, > 0.4; 17). None of the cats had postrenal proteinuria. A significant linear correlation was identified between UPC ratios in urine samples obtained by means of manual compression and ratios in samples obtained by means of cystocentesis. For all cats, UPC ratios for samples obtained by the 2 collection methods resulted in classification in the same IRIS substage. Conclusions and Clinical Relevance-Results suggested that collection of a urine sample from the midstream phase of micturition by manual compression would be a reliable alternative to cystocentesis for the determination of UPC ratio in cats, provided that postrenal proteinuria was excluded by means of urine sediment analysis. Once postrenal proteinuria was ruled out, the method used to collect urine samples did not appear to influence the quantification of urine protein concentration. PMID- 25835171 TI - Ultrasonographic anatomy of bearded dragons (Pogona vitticeps). AB - OBJECTIVE: To determine which organs can be reliably visualized ultrasonographically in bearded dragons (Pogona vitticeps), describe their normal ultrasonographic appearance, and describe an ultrasonographic technique for use with this species. DESIGN: Cross-sectional study. ANIMALS: 14 healthy bearded dragons (6 females and 8 males). PROCEDURES: Bearded dragons were manually restrained in dorsal and sternal recumbency, and coelomic organs were evaluated by use of linear 7- to 15-MHz and microconvex 5- to 8-MHz transducers. Visibility, size, echogenicity, and ultrasound transducer position were assessed for each organ. RESULTS: Coelomic ultrasonography with both microconvex and linear ultrasound transducers allowed for visualization of the heart, pleural surface of the lungs, liver, caudal vena cava, aorta, ventral abdominal vein, gallbladder, fat bodies, gastric fundus, cecum, colon, cloaca, kidneys, and testes or ovaries in all animals. The pylorus was visualized in 12 of 14 animals. The small intestinal loops were visualized in 12 of 14 animals with the linear transducer, but could not be reliably identified with the microconvex transducer. The hemipenes were visualized in 7 of 8 males. The adrenal glands and spleen were not identified in any animal. Anechoic free coelomic fluid was present in 11 of 14 animals. Heart width, heart length, ventricular wall thickness, gastric fundus wall thickness, and height of the caudal poles of the kidneys were positively associated with body weight. Testis width was negatively associated with body weight in males. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated coelomic ultrasonography is a potentially valuable imaging modality for assessment of most organs in bearded dragons and can be performed in unsedated animals. PMID- 25835173 TI - Comparison of laparoscopic versus conventional open cryptorchidectomies on intraoperative and postoperative complications and duration of surgery, anesthesia, and hospital stay in horses. AB - Objective-To compare surgical preparation time, surgery and anesthesia times, hospitalization duration, and intra- and postoperative complications between laparoscopic and conventional open cryptorchidectomy in horses. Design Retrospective cohort study. Animals-60 horses that underwent cryptorchidectomy. Procedures-Medical records were reviewed to identify horses that had undergone cryptorchidectomy from 1991 to 2012. Thirty horses that underwent laparoscopic cryptorchidectomy (case horses) were matched with 30 control horses that had undergone open cryptorchidectomy (ie, inguinal and parainguinal surgical approaches). Horses were matched according to history of previous surgery, testicle location, and type of closure following removal of an undescended unilateral testicle. Duration of surgery, surgical preparation and anesthesia times, hospitalization duration, and number of intra- and postoperative complications were compared between horses that underwent laparoscopic cryptorchidectomy versus open cryptorchidectomy. Comparisons were also made between horses in terms of whether there was a history of previous failed cryptorchidectomy or unknown location of testicle prior to surgery. Results Horses that underwent laparoscopic cryptorchidectomy had significantly longer surgery and anesthesia times overall, compared with horses that underwent open cryptorchidectomy. No difference in surgery time was found between case and control horses that had a previous surgical attempt to remove an undescended testicle or in which the testicle location was unknown prior to surgery. Overall, horses undergoing laparoscopy had a nonsignificant increase in intraoperative complications, compared with control horses, and had significantly more postoperative complications. Conclusions and Clinical Relevance-Horses undergoing laparoscopic cryptorchidectomy had increased surgical preparation time, increased surgery and anesthesia times, and more postoperative complications, compared with horses undergoing open cryptorchictomy. Laparoscopy may be advantageous for a second attempt at cryptorchidectomy or if the testicle location is unknown prior to surgery. PMID- 25835172 TI - Surgical excision of anal sac apocrine gland adenocarcinomas with and without adjunctive chemotherapy in dogs: 42 cases (2005-2011). AB - Objective-To identify variables associated with prognosis in dogs undergoing surgical excision of anal sac apocrine gland adenocarcinomas (ASACs) with and without adjunctive chemotherapy. Design-Retrospective case series. Animals-42 dogs with ASACs. Procedures-Information on signalment, clinical signs, diagnostic procedures, surgical procedures, adjunctive therapies, survival time, and disease free interval was obtained from the medical records. Results-Survival time was significantly associated with the presence of sublumbar lymphadenopathy and sublumbar lymph node extirpation, with median survival time significantly shorter for dogs with sublumbar lymphadenopathy (hazard ratio, 2.31) than for those without and for dogs that underwent lymph node extirpation (hazard ratio, 2.31) than for those that did not. Disease-free interval was significantly associated with the presence of sublumbar lymphadenopathy, lymph node extirpation, and administration of platinum-containing chemotherapeutic agents, with median disease-free interval significantly shorter for dogs with sublumbar lymphadenopathy (hazard ratio, 2.47) than for those without, for dogs that underwent lymph node extirpation (hazard ratio, 2.47) than for those that did not, and for dogs that received platinum-containing chemotherapeutic agents (hazard ratio, 2.69) than for those that did not. Survival time and disease-free interval did not differ among groups when dogs were grouped on the basis of histopathologic margins (complete vs marginal vs incomplete excision). Conclusions and Clinical Relevance-Results suggested that in dogs with ASAC undergoing surgical excision, the presence of sublumbar lymphadenopathy and lymph node extirpation were both negative prognostic factors. However, completeness of surgical excision was not associated with survival time or disease-free interval. PMID- 25835174 TI - Evaluation of annual survival and mortality rates and longevity of bottlenose dolphins (Tursiops truncatus) at the United States Navy Marine Mammal Program from 2004 through 2013. AB - Objective-To evaluate annual survival and mortality rates and the longevity of a managed population of bottlenose dolphins (Tursiops truncatus). Design Retrospective cohort study. Animals-103 bottlenose dolphins at the US Navy Marine Mammal Program (MMP). Procedures-Population age structures, annual survival and crude mortality rates, and median age at death for dolphins > 30 days old were determined from 2004 through 2013. Results-During 2004 through 2013, the annual survival rates for MMP dolphins ranged from 0.98 to 1.0, and the annual crude mortality rates ranged from 0% to 5%, with a mean of 2.7%. The median age at death was 30.1 years from 2004 through 2008 and increased to 32 years from 2009 through 2013. The maximum age for a dolphin in the study was 52 years. Conclusions and Clinical Relevance-Results indicated that the annual mortality rates were low and survival rates were high for dolphins in the MMP from 2004 through 2013 and that the median age at death for MMP dolphins during that time was over 10 years greater than that reported in free-ranging dolphins. These findings were likely attributable to the continually improving care and husbandry of managed dolphin populations. PMID- 25835175 TI - Multi-susceptibile single-phased ceramics with both considerable magnetic and dielectric properties by selectively doping. AB - Multiferroic ceramics with extraordinary susceptibilities coexisting are vitally important for the multi-functionality and integration of electronic devices. However, multiferroic composites, as the most potential candidates, will introduce inevitable interface deficiencies and thus dielectric loss from dissimilar phases. In this study, single-phased ferrite ceramics with considerable magnetic and dielectric performances appearing simultaneously were fabricated by doping target ions in higher valence than that of Fe(3+), such as Ti(4+), Nb(5+) and Zr(4+), into BaFe12O19. In terms of charge balance, Fe(3+)/Fe(2+) pair dipoles are produced through the substitution of Fe(3+) by high-valenced ions. The electron hopping between Fe(3+) and Fe(2+) ions results in colossal permittivity. Whilst the single-phased ceramics doped by target ions exhibit low dielectric loss naturally due to the diminishment of interfacial polarization and still maintain typical magnetic properties. This study provides a convenient method to attain practicable materials with both outstanding magnetic and dielectric properties, which may be of interest to integration and multi-functionality of electronic devices. PMID- 25835176 TI - Expression of aberrant CD markers in acute leukemia: a study of 100 cases with immunophenotyping by multiparameter flowcytometry. AB - BACKGROUND: Acute leukemia is a heterogenous disease having diverse phenotypes. Immunophenotyping by flowcytometry is essential for diagnosis of myeloid and lymphoid subtypes. Aberrant phenotype incidence is controversial and dissimilar results have been reported by different groups. OBJECTIVES: Purpose of the study was to determine the incidence of aberrant phenotypes in North East Indian patients with acute leukemia. METHODS: We analysed a total of 100 cases (AML = 36, ALL = 61, MPAL = 3) by multiparametric flow cytometry using an acute panel of monoclonal antibodies (MoAbs). The MoAbs were selected to identify differentiation-associated antigens of both myeloid and lymphoid lineages. RESULTS: Aberrant phenotypes were found in 21 (58.3%) cases of AML, 36 (59.2%) cases of B-ALL and 6 (66.7%) cases of T-ALL. CD7 was the most frequent lymphoid associated antigen found in 33% of AML cases while CD117 was the myeloid antigen most frequently detected in ALL (54%) cases. Aberrant expression of CD 117 is highly significant by Fischer's exact test (P< 0.0001). CONCLUSION: We conclude that aberrant phenotypes are present in a great majority of acute leukemia patients of North East India. Future studies will be directed to correlate of these markers with prognosis and therapeutic response. PMID- 25835177 TI - MMP-9/ANC score as a predictive biomarker for efficacy of bevacizumab plus platinum doublet chemotherapy in patients with advanced or recurrent non-squamous non-small cell lung cancer. AB - BACKGROUND: Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), which is a key regulator of tumor angiogenesis. OBJECTIVE: To evaluate biomarkers to predict the benefit of paclitaxel and carboplatin plus bevacizumab (PCB) therapy in patients with advanced or recurrent non-squamous non-small cell lung cancer. METHODS: Among 21 patients treated with PCB, 10 were included in the good responder group and 11 in the non-responder group. Serum VEGF, MMP-2 and MMP-9 were measured using ELISA. RESULTS: There were no significant differences in these markers levels between groups. However, the good responder group showed a significantly higher pre treatment MMP-9/ absolute neutrophil count (ANC) score than the non-responder group before the treatment (p= 0.014), and there was a positive correlation between the score and the tumor reduction rate (r= 0.57, p= 0.016). Furthermore, by dividing patients into a high scoring group (MMP-9/ANC >= median, n= 11) and a low scoring group (MMP-9/ANC < median, n= 10), former group showed a significant improvement in the median progression-free survival compared with latter group (636 vs. 196 days, p = 0.032). CONCLUSIONS: MMP-9/ANC score before PCB treatment may be a suitable biomarker to assess the anti-tumor effects of PCB therapy. PMID- 25835178 TI - Cyst fluid iron-related compounds as useful markers to distinguish malignant transformation from benign endometriotic cysts. AB - OBJECTIVE: The purpose of this study was to investigate cyst fluid levels of total iron, heme iron and free iron in benign endometriotic cysts and endometriosis-associated ovarian cancer (EAOC) and to demonstrate the significance of these biomarkers in differential diagnosis between EAOC and endometriotic cysts. METHODS: Cyst fluid samples were obtained from eleven patients with EAOC and thirty-six women with benign endometriotic cysts at the time of surgery. RESULTS: The median (+/- SD) total iron levels for endometriotic cysts and EAOC cysts were 244.4 +/- 204.9 mg/L and 14.2 +/- 36.6 mg/L, respectively. EAOC patients had much lower levels of iron-related compounds compared with endometriotic cyst samples (p< 0.001). When the total iron results were analyzed using the receiver operating characteristics (ROC) curve method, the optimum diagnostic cut-off point was 64.8 mg/L, sensitivity was 90.9%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 97.3%. Patient demographic characteristics such as tumor size, age at operation, parity and menopause were not correlated with cyst fluid iron levels. CONCLUSIONS: We conclude for the first time that iron-related compounds are important biomarkers that can predict malignant transformation with high sensitivity and specificity for women with endometriosis. PMID- 25835179 TI - Significant association of TP53 Arg72Pro polymorphism in susceptibility to differentiated thyroid cancer. AB - BACKGROUND: Among various polymorphic variants of TP53 gene, codon 72 polymorphism (Arg72Pro) has been found to be associated with cancer susceptibility, but only few studies have investigated their effect on thyroid cancer risk. OBJECTIVE: A case control study was conducted to elucidate the possible role of this SNP as risk factor in thyroid cancer development and to examine its correlation with various clinicopathological variables. METHODS: In this study, we tested the genotype distribution by PCR-RFLP in 140 thyroid cancer patients and 200 cancer-free controls from Kashmir Valley. RESULTS: Genotype frequencies of Arg/Arg (GG), Arg/Pro (GC), and Pro/Pro (CC) genotypes among cases were 0.286, 0.343 and 0.371 while in controls 0.45, 0.37 and 0.18 respectively. Proline allele frequency was significantly higher than arginine frequency in patient group (OR = 2.06, 95% C.I = 1.5-2.8). Significant association was found between variant genotype of codon 72 of TP53 gene and young age group, female gender, urban dwellers, non-smokers and patients with elevated TSH levels (P < 0.05). CONCLUSION: It is evident from our study that Arg72Pro SNP of TP53 gene is connected with higher susceptibility to thyroid cancer especially in young age group, female gender, non-smokers and patients with elevated TSH levels, hence, implicated in thyroid carcinogenesis. PMID- 25835180 TI - L-amino acid transporter 1 may be a prognostic marker for local progression of prostatic cancer under expectant management. AB - BACKGROUND: Oncocytic L-amino acid transporter (LAT) 1 could be a target of new molecular therapy against malignancies. OBJECTIVE: To assess the correlation between overexpression of LAT1 and local progression (LP) in prostatic carcinoma (PC) patients under expectant management (EM). METHODS: This retrospective study analyzed 109 patients with PC who received EM from 1991 to 2006. The expression of LAT1, LAT2, and CD98, as well as Ki-67 labeling indices (LI), was analyzed immunohistochemically in first biopsy or TUR samples diagnosed as adenocarcinomas. RESULTS: Of the 109 patients, 44 (40%) showed LP on clinical examinations, whereas 65 showed stable disease (SD). LAT1 score and intensity were significantly higher in the LP than in the SD group, as well as among Gleason score (GS)-low (GS < 7) patients who were associated with low-risk. When the LP group was subdivided by D'Amico risk category (low-, intermediate- and high-risk groups), each showed higher LAT1 expression than the SD group. LAT1 expression did not correlate with GS or Ki-67 LI. CONCLUSIONS: Independently of GS, aberrant overexpression of LAT1 in prostatic adenocarcinoma could predict LP under EM. Although prostate biopsy samples are small, LAT1 may be a novel prognostic biomarker of LP. PMID- 25835181 TI - Polymorphic GT dinucleotide repeat in the PIK3CA gene and risk of colorectal cancer. AB - BACKGROUND: Activated PI3K generate PIP3 to trigger different signaling pathways which regulate a number of cellular functions including cell survival, apoptosis, proliferation and motility. Mutations in many cancers were discovered in the gene encoding the PI3K catalytic subunit, PIK3CA. OBJECTIVE: To date, there has been no report on the association between polymorphism of PIK3CA gene microsatellites and risk of colorectal cancer. In this study, we investigate the relation between the GT dinucleotide repeat in intron 1 of the PIK3CA gene and colorectal cancer risk. METHODS: A case-control study of 103 colorectal cancer patients and 150 controls was conducted in Iranian people. RESULTS: The results of our study demonstrate that PIK3CA gene allele distribution in Iranian population varies between 13 and 20 repeats. Here we demonstrate that individuals who carry alleles shorter than 17 GT repeat are at higher risk of developing colorectal cancer (OR = 4.0, p= 0), by contrast, those individuals with two alleles longer than 16 GT repeats are at a significantly lower risk of developing colorectal cancer (OR = 0.12, p= 0). CONCLUSION: This result suggests polymorphic GT repeat of PIK3CA gene may be a potential predictive marker of colorectal cancer risk in Iranian population. PMID- 25835182 TI - An association of selected ERCC2 and ERCC5 genes polymorphisms, the level of oxidative DNA damage and its repair efficiency with a risk of colorectal cancer in Polish population. AB - Aim of this study was to analyze the correlation between polymorphisms of ERCC2 and ERCC5 genes and efficiency of repair of oxidative DNA damage with the risk of colorectal cancer (CRC). Experimental material was peripheral blood and tumor slices from CRC collected from 235 patients, 240 people without any cancer were control group. Distribution of polymorphisms of ERCC2 and ERCC5 genes in patients with CRC and healthy subjects, as well as level of oxidative DNA damage in patients and in healthy controls was performed. It has been found that the genotype 751Gln/Gln and allele Gln of ERCC2 gene and allele Asp of 312Asn/Asp polymorphism of ERCC2 gene may be associated with an increased risk of colorectal cancer. Reduced DNA repair efficiency was also demonstrated, which can confirm the important role of oxidative damage and polymorphisms of ERCC2 and ERCC5 genes in the pathogenesis of CRC. In summary, it is critical to establish a link between gene polymorphisms in repair of oxidative DNA damage with the risk of cancer. This in future will allow for diagnostic tests which will let to identify persons with high risk of developing cancer and thus effectively implement prophylactic treatment. PMID- 25835185 TI - Congestion based mechanism for route discovery in a V2I-V2V system applying smart devices and IoT. AB - The Internet of Things is a new paradigm in which objects in a specific context can be integrated into traditional communication networks to actively participate in solving a determined problem. The Vehicle-to-Vehicle (V2V) and Vehicle-to Infrastructure (V2I) technologies are specific cases of IoT and key enablers for Intelligent Transportation Systems (ITS). V2V and V2I have been widely used to solve different problems associated with transportation in cities, in which the most important is traffic congestion. A high percentage of congestion is usually presented by the inappropriate use of resources in vehicular infrastructure. In addition, the integration of traffic congestion in decision making for vehicular traffic is a challenge due to its high dynamic behavior. In this paper, an optimization model over the load balancing in the congestion percentage of the streets is formulated. Later, we explore a fully congestion-oriented route discovery mechanism and we make a proposal on the communication infrastructure that should support it based on V2I and V2V communication. The mechanism is also compared with a modified Dijkstra's approach that reacts at congestion states. Finally, we compare the results of the efficiency of the vehicle's trip with the efficiency in the use of the capacity of the vehicular network. PMID- 25835183 TI - Accessing Ni(III)-thiolate versus Ni(II)-thiyl bonding in a family of Ni-N2S2 synthetic models of NiSOD. AB - Superoxide dismutase (SOD) catalyzes the disproportionation of superoxide (O2(* )) into H2O2 and O2(g) by toggling through different oxidation states of a first row transition metal ion at its active site. Ni-containing SODs (NiSODs) are a distinct class of this family of metalloenzymes due to the unusual coordination sphere that is comprised of mixed N/S-ligands from peptide-N and cysteine-S donor atoms. A central goal of our research is to understand the factors that govern reactive oxygen species (ROS) stability of the Ni-S(Cys) bond in NiSOD utilizing a synthetic model approach. In light of the reactivity of metal-coordinated thiolates to ROS, several hypotheses have been proffered and include the coordination of His1-Ndelta to the Ni(II) and Ni(III) forms of NiSOD, as well as hydrogen bonding or full protonation of a coordinated S(Cys). In this work, we present NiSOD analogues of the general formula [Ni(N2S)(SR')](-), providing a variable location (SR' = aryl thiolate) in the N2S2 basal plane coordination sphere where we have introduced o-amino and/or electron-withdrawing groups to intercept an oxidized Ni species. The synthesis, structure, and properties of the NiSOD model complexes (Et4N)[Ni(nmp)(SPh-o-NH2)] (2), (Et4N)[Ni(nmp)(SPh-o-NH2-p CF3)] (3), (Et4N)[Ni(nmp)(SPh-p-NH2)] (4), and (Et4N)[Ni(nmp)(SPh-p-CF3)] (5) (nmp(2-) = dianion of N-(2-mercaptoethyl)picolinamide) are reported. NiSOD model complexes with amino groups positioned ortho to the aryl-S in SR' (2 and 3) afford oxidized species (2(ox) and 3(ox)) that are best described as a resonance hybrid between Ni(III)-SR and Ni(II)-(*)SR based on ultraviolet-visible (UV-vis), magnetic circular dichroism (MCD), and electron paramagnetic resonance (EPR) spectroscopies, as well as density functional theory (DFT) calculations. The results presented here, demonstrating the high percentage of S(3p) character in the highest occupied molecular orbital (HOMO) of the four-coordinate reduced form of NiSOD (NiSODred), suggest that the transition from NiSODred to the five coordinate oxidized form of NiSOD (NiSODox) may go through a four-coordinate Ni (*)S(Cys) (NiSODox-Hisoff) that is stabilized by coordination to Ni(II). PMID- 25835184 TI - Rationally designing aptamer sequences with reduced affinity for controlled sensor performance. AB - The relative ease of predicting the secondary structure of nucleic acid sequences lends itself to the design of sequences to perform desired functions. Here, we combine the utility of nucleic acid aptamers with predictable control over the secondary structure to rationally design sequences with controlled affinity towards a target analyte when employed as the recognition element in an electrochemical sensor. Specifically, we present a method to modify an existing high-gain aptamer sequence to create sequences that, when employed in an electrochemical, aptamer-based sensor, exhibit reduced affinity towards a small molecule analyte tobramycin. Sensors fabricated with the high-gain parent sequence saturate at concentrations much below the therapeutic window for tobramycin (7-18 uM). Accordingly, the rationale behind modifying this high-gain sequence to reduce binding affinity was to tune sensor performance for optimal sensitivity in the therapeutic window. Using secondary structure predictions and analysis of the NMR structure of an aminoglycoside RNA aptamer bound to tobramycin, we are able to successfully modify the aptamer sequence to tune the dissociation constants of electrochemical aptamer-based sensors between 0.17 and 3 uM. The guidelines we present represent a general strategy to lessening binding affinity of sensors employing aptamer-modified electrodes. PMID- 25835186 TI - A support vector machine approach for truncated fingerprint image detection from sweeping fingerprint sensors. AB - A sweeping fingerprint sensor converts fingerprints on a row by row basis through image reconstruction techniques. However, a built fingerprint image might appear to be truncated and distorted when the finger was swept across a fingerprint sensor at a non-linear speed. If the truncated fingerprint images were enrolled as reference targets and collected by any automated fingerprint identification system (AFIS), successful prediction rates for fingerprint matching applications would be decreased significantly. In this paper, a novel and effective methodology with low time computational complexity was developed for detecting truncated fingerprints in a real time manner. Several filtering rules were implemented to validate existences of truncated fingerprints. In addition, a machine learning method of supported vector machine (SVM), based on the principle of structural risk minimization, was applied to reject pseudo truncated fingerprints containing similar characteristics of truncated ones. The experimental result has shown that an accuracy rate of 90.7% was achieved by successfully identifying truncated fingerprint images from testing images before AFIS enrollment procedures. The proposed effective and efficient methodology can be extensively applied to all existing fingerprint matching systems as a preliminary quality control prior to construction of fingerprint templates. PMID- 25835187 TI - A novel multi-digital camera system based on tilt-shift photography technology. AB - Multi-digital camera systems (MDCS) are constantly being improved to meet the increasing requirement of high-resolution spatial data. This study identifies the insufficiencies of traditional MDCSs and proposes a new category MDCS based on tilt-shift photography to improve ability of the MDCS to acquire high-accuracy spatial data. A prototype system, including two or four tilt-shift cameras (TSC, camera model: Nikon D90), is developed to validate the feasibility and correctness of proposed MDCS. Similar to the cameras of traditional MDCSs, calibration is also essential for TSC of new MDCS. The study constructs indoor control fields and proposes appropriate calibration methods for TSC, including digital distortion model (DDM) approach and two-step calibrated strategy. The characteristics of TSC are analyzed in detail via a calibration experiment; for example, the edge distortion of TSC. Finally, the ability of the new MDCS to acquire high-accuracy spatial data is verified through flight experiments. The results of flight experiments illustrate that geo-position accuracy of prototype system achieves 0.3 m at a flight height of 800 m, and spatial resolution of 0.15 m. In addition, results of the comparison between the traditional (MADC II) and proposed MDCS demonstrate that the latter (0.3 m) provides spatial data with higher accuracy than the former (only 0.6 m) under the same conditions. We also take the attitude that using higher accuracy TSC in the new MDCS should further improve the accuracy of the photogrammetry senior product. PMID- 25835188 TI - Dielectric sensors based on electromagnetic energy tunneling. AB - We show that metallic wires embedded in narrow waveguide bends and channels demonstrate resonance behavior at specific frequencies. The electromagnetic energy at these resonances tunnels through the narrow waveguide channels with almost no propagation losses. Under the tunneling behavior, high-intensity electromagnetic fields are produced in the vicinity of the metallic wires. These intense field resonances can be exploited to build highly sensitive dielectric sensors. The sensor operation is explained with the help of full-wave simulations. A practical setup consisting of a 3D waveguide bend is presented to experimentally observe the tunneling phenomenon. The tunneling frequency is predicted by determining the input impedance minima through a variational formula based on the Green function of a probe-excited parallel plate waveguide. PMID- 25835189 TI - Using multiple barometers to detect the floor location of smart phones with built in barometric sensors for indoor positioning. AB - Following the popularity of smart phones and the development of mobile Internet, the demands for accurate indoor positioning have grown rapidly in recent years. Previous indoor positioning methods focused on plane locations on a floor and did not provide accurate floor positioning. In this paper, we propose a method that uses multiple barometers as references for the floor positioning of smart phones with built-in barometric sensors. Some related studies used barometric formula to investigate the altitude of mobile devices and compared the altitude with the height of the floors in a building to obtain the floor number. These studies assume that the accurate height of each floor is known, which is not always the case. They also did not consider the difference in the barometric-pressure pattern at different floors, which may lead to errors in the altitude computation. Our method does not require knowledge of the accurate heights of buildings and stories. It is robust and less sensitive to factors such as temperature and humidity and considers the difference in the barometric-pressure change trends at different floors. We performed a series of experiments to validate the effectiveness of this method. The results are encouraging. PMID- 25835190 TI - Interfacing liquid metals with stretchable metal conductors. AB - Highly stretchable conductors are essential components in deformable electronics. Owing to their high stretchability and conductivity, liquid metals have attracted significant attention for use as circuits and interconnections. However, their poor wettability to stretchable metal electrodes prevents the formation of stable electrical connections. This study examined two approaches for creating a stable interface between a liquid metal (EGaIn) and stretchable metal electrodes via: (i) the use of honeycomb-structured stretchable metal electrodes and (ii) the addition of a conducting polymer interlayer. The line width of the honeycomb had a significant influence on the formation of a stable interface. The liquid metal formed a stable film layer on honeycomb metal electrodes, which have line widths of less than 50 MUm. Coating PEDOT: PSS with a nonionic surfactant lowered the interfacial energy of EGaIn with flat stretchable metal surfaces; hence EGaIn was coated uniformly on the stretchable metal surfaces. Strain sensors were fabricated as a demonstrative example of an application that utilizes the stable interface. PMID- 25835193 TI - Is there a link between COQ6 and schwannomatosis? PMID- 25835194 TI - Response to Trevisson et al. PMID- 25835195 TI - Key emerging themes for assessing the cost-effectiveness of reporting incidental findings. PMID- 25835196 TI - Response to Phillips et al. PMID- 25835197 TI - CORRIGENDUM: Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. AB - Genet Med advance online publication, January 22, 2015; doi:10.1038/gim.2014.205. In the Advance Online Publication version, of this article, there is a mistake on page 2 in the first paragraph of the Materials and Methods section. The sentence beginning "Among 3,459 probands initially referred for HCM genetic testing ..." the correct number of probands is 3,473 not 3,459. The authors regret the error. PMID- 25835198 TI - Contamination of freshly slaughtered pig carcasses with enteropathogenic Yersinia spp.: Distribution, quantification and identification of risk factors. AB - A cross-sectional survey was undertaken to determine the overall prevalence of enteropathogenic Yersinia spp. in the tonsils, feces and on carcasses of pigs at slaughter. Moreover, factors associated with Yersinia contamination of freshly eviscerated pig carcasses were studied. Yersinia enterocolitica serotype O:3 was isolated from the tonsils and feces of 55.3% and 25.6% of pigs, and Y. pseudotuberculosis from 1.4% and 0.6%, respectively. The pathogens were also recovered from 39.7% of carcass surfaces post-evisceration. The highest prevalence was found at the mandibular region (28.9%), followed by the sternal region (16.4%), pelvic duct (7.8%), and split surface near the sacral vertebrae (6.9%). Regarding the quantification of the pathogen, the median concentration of pathogenic Y. enterocolitica was 4.14l og10 CFU/g in tonsils with countable numbers (n=143) and 2.80 log10 CFU/g for fecal samples with countable numbers (n=26). The quantitative load on the carcass surface was generally low as the majority of the carcass samples (97.0%) had Yersinia concentrations below the detection limit of enumeration (<1.30 log10 CFU/100 cm(2)). The initial presence of Y. enterocolitica in the tonsils and/or feces was significantly associated with carcass contamination at all sampled areas. Other risk factors for carcass contamination are the splitting of the head together with the carcass, and incision of the tonsils during removal of the pluck. Small adaptations in slaughter practices and the training of slaughterhouse personnel to respect basic hygienic instructions may diminish carcass contamination with enteropathogenic Yersinia. PMID- 25835199 TI - Take the monkey and run. AB - BACKGROUND: The common marmoset (Callithrix jacchus) is a small, New World primate that is used extensively in biomedical and behavioral research. This short-lived primate, with its small body size, ease of handling, and docile temperament, has emerged as a valuable model for aging and neurodegenerative research. A growing body of research has indicated exercise, aerobic exercise especially, imparts beneficial effects to normal aging. Understanding the mechanisms underlying these positive effects of exercise, and the degree to which exercise has neurotherapeutic effects, is an important research focus. Thus, developing techniques to engage marmosets in aerobic exercise would have great advantages. NEW METHOD: Here we describe the marmoset exercise ball (MEB) paradigm: a safe (for both experimenter and subjects), novel and effective means to engage marmosets in aerobic exercise. We trained young adult male marmosets to run on treadmills for 30 min a day, 3 days a week. RESULTS: Our training procedures allowed us to engage male marmosets in this aerobic exercise within 4 weeks, and subjects maintained this frequency of exercise for 3 months. COMPARISON WITH EXISTING METHODS: To our knowledge, this is the first described method to engage marmosets in aerobic exercise. A major advantage of this exercise paradigm is that while it was technically forced exercise, it did not appear to induce stress in the marmosets. CONCLUSIONS: These techniques should be useful to researchers wishing to address physiological responses of exercise in a marmoset model. PMID- 25835200 TI - Synthesis of beta-Carboline-Based N-Heterocyclic Carbenes and Their Antiproliferative and Antimetastatic Activities against Human Breast Cancer Cells. AB - A series of novel beta-carboline-based N-heterocyclic carbenes was prepared via Mannich reaction between methyl 1-(dimethoxymethyl)-9H-pyrido[3,4-b]indole-3 carboxylate, formaldehyde, and primary amines. All compounds were evaluated for their antiproliferative activity using human breast cancer and lung cancer cell lines. Three compounds, 3c, 3j, and 3h, were discovered to display IC50 less than 10 MUM against human breast cancer MDA-MB-231 cells at 24 h of treatment. Pharmacologically these compounds lead to G2/M phase cell cycle arrest and induction of cellular apoptosis by triggering intrinsic apoptotic pathway through depolarization of mitochondrial membrane potential and activation of caspases. At lower concentrations, these compounds also showed antimigratory and antiinvasive effects against highly metastatic human breast cancer MDA-MB-231 cells via aberration of MAP-kinase signaling and by the inhibition of matrix metalloproteinases. However, these analogues lack in vivo effect in mouse model which may be attributed to their strong affinity to HSA that was investigated spectroscopically with compound 3h. PMID- 25835201 TI - Preliminary Assessment of Tricuspid Valve Annular Velocity Parameters by Cardiac Magnetic Resonance Imaging in Adults with a Volume-Overloaded Right Ventricle: Comparison of Unrepaired Atrial Septal Defect and Repaired Tetralogy of Fallot. AB - The aim is to compare tricuspid valve (TV) atrioventricular junction (AVJ) annular motion parameters in unrepaired atrial septal defect (ASD) and repaired Tetralogy of Fallot (TOF) by cardiac magnetic resonance (CMR) imaging. We retrospectively reviewed CMR studies performed between November 2007 and November 2013 in patients 16-45 years of age with unrepaired ASD (with or without partial anomalous pulmonary venous return) and with repaired TOF, who had previous infundibulotomy, but have not undergone pulmonary valve replacement. Longitudinal motion of lateral TV in four-chamber view cine image was tracked through the cardiac cycle with custom software. Twenty TOF patients and 12 ASD patients were included, and values were compared with 80 controls. Right ventricular end diastolic volume index and right ventricular end-systolic volume index were similar in the ASD and TOF groups and were significantly higher in both groups than in controls. Maximum displacement of the TV in systole, velocity at half maximal displacement during systole, and velocity at half-maximal displacement during early diastole were all significantly lower in the TOF group than the ASD group [1.39 +/- 0.47 vs. 2.21 +/- 0.46 (cm, p < 0.01), 5.9 +/- 2.1 vs. 10.1 +/- 2.3 (cm/s, p < 0.01), and 7.7 +/- 2.6 vs. 10.9 +/- 3.1 (cm/s, p < 0.05)]. TOF patients have diminished early diastolic TV AVJ velocity compared to patients with an unrepaired ASD, despite similar RV volumes. This observation could suggest diastolic dysfunction or cardiac mechanics unique to the postoperative, volume-overloaded right ventricle in patients with repaired TOF. PMID- 25835202 TI - A Short History of Cardiac Inspection: A Quest "To See with a Better Eye". AB - Cardiac examination has evolved over centuries. The goal of cardiac evaluation, regardless the era, is to "see" inside the heart to diagnose congenital and acquired intra-cardiac structural and functional abnormalities. This article briefly reviews the history of cardiac examination and discusses contemporary best, evidence-based methods of cardiac inspection. PMID- 25835203 TI - Repair of Tetralogy of Fallot in Children Less Than 4 kg Body Weight. AB - We reviewed our experience of surgical repair of Tetralogy of Fallot (TOF) in children weighing less than or equal to 4 kg to compare outcome of early palliation versus complete repair as the initial surgical approach. Seventy-six patients, weighing <= 4 kg, with TOF surgery between January 2005 and September 2013 were included in this single-center retrospective study. Twenty-five patients who underwent initial shunt procedure followed by later full repair were compared to 51 patients who had primary full repair for differences in baseline characteristics and outcomes. Shunt group patients had lower body weight, 2.76 +/ 0.69 versus 3.11 +/- 0.65 (kg), p = 0.03, and lower preoperative oxygen saturations, 82 +/- 7 versus 90 +/- 6 (%), p = 0.0001, than full repair group. A higher number of surgical procedures per patient was recorded in shunt patients, 2.29 +/- 0.59 versus 1.27 +/- 0.49, p = 0.00002. Thirteen of 51 patients in the full repair group required a repeat surgery. Catheterization procedures were performed in 12 patients in shunt and in 15 patients in full repair group, with interventional angioplasty in three and 11, respectively, p >= 0.05. Two patients, both in the shunt group, died after the surgery. Early full repair had longer hospital stay but significantly less hospitalizations 1.95 +/- 1.3 versus 2.5 +/- 1.4, p = 0.03. Initial complete repair of TOF in small children yielded favorable outcome with significantly less surgical procedures and subsequent hospitalizations. Cath laboratory re-interventions for residual defects were similar after both surgical approaches, and type of initial surgery does not predict freedom from re-intervention. PMID- 25835204 TI - Systemic Embolic Complications of Pulmonary Vein Angioplasty in Children. AB - Pulmonary vein stenosis (PVS) carries significant morbidity and mortality for affected children, and its management often requires multiple angioplasty procedures. PVS angioplasty can be complicated by systemic embolic events such as stroke, but incidence and risk factors are poorly understood. We reviewed pediatric catheterizations involving PVS angioplasty and/or stent placement performed at Boston Children's Hospital between July 2005 and February 2014. A total of 406 cases were performed in 144 distinct patients. Patients underwent a median of two catheterizations, at median age 1 year and weight 6.9 kg. Eleven (2.7 %) catheterizations were complicated by clinically apparent systemic embolic events, comprising 10 strokes (one with associated hepatic embolism) and 1 renal infarct. Prevalence of clinically evident stroke among this cohort was 7.6 %. Using a prior (uncomplicated) catheterization to allow each patient to serve as their own control, we sought to identify potentially modifiable risk factors for systemic embolic events. Although this analysis was limited by low power, complicated and uncomplicated angioplasties did not appear to differ in case time, contrast dose, anticoagulation management, use of cutting balloons, number of catheter exchanges, or size of long sheath used. Significant non-embolic adverse events were common, occurring in 25 % of catheterizations. Systemic embolism appears to complicate PVS angioplasty at a rate much higher than that described for other congenital catheterizations. This risk may be inherent to the procedure rather than related to any modifiable or operator-dependent factors. PMID- 25835205 TI - [Suprapatellar approach to tibial medullary nailing with electromagnetic field guided distal locking]. AB - Closed tibial shaft fractures are the domain of intramedullary nailing. With the introduction of new nail designs and technologies, even small, dislocated distal fragments can be anatomically aligned and safely fixed. Unsolved or to a lesser degree controlled are the problems of distal locking in the freehand technique, which can still be difficult and can lead to a significant radiation exposure, and how to control very short proximal tibial fragments in metaphyseal tibial fractures or tibial segmental fractures, where the proximal fracture line also runs through the metaphysis.By using a suprapatellar approach, i.e. a skin incision proximal to the patella with an entry point into the tibial bone from within the knee at the same site as for a standard infrapatellar approach, and then nailing the tibia in a semi-extended position, i.e. the knee is only flexed 10-20 degrees , the intraoperative dislocation of a short proximal fragment can be avoided. The main indications for semi-extended tibial nailing are a short diaphyseal fragment in an isolated tibial shaft fracture, a segmental fracture where the proximal fracture line is metaphyseal and in patients where infrapatellar soft tissues are compromised.The use of the electromagnetic guidance system SureShot(r) generates reliable and reproducible results, reduces the operating time and is independent from radiation for distal locking. PMID- 25835206 TI - [Intramedullary nailing of the distal tibia. Does angular stable locking make a difference?]. AB - BACKGROUND: Osteosynthesis of distal tibia fractures relies on stable fixation of the distal fragment. Modern intramedullary implants provide various fixation options for locking screws. These implants expand the indications for intramedullary nailing of tibia fractures towards more distally located fractures. MATERIAL AND METHODS: The most essential options which improve the fixation of the distal fragment include an increase in number, in size and in spacing of the distal locking screws. Further options for nailing of distal tibia fractures include interfragmentary compression and angular stability. Interfragmentary compression considerably increases mechanical stability in axially stable fracture situations. Angular stable fixation of the locking screws has recently become a popular feature in intramedullary nailing; however, the effect of angular stability on the mechanical properties of distal tibia osteosynthesis has been found to be limited. CONCLUSION: The initial stability to provide sufficient load bearing capacity appears to be provided by the available locking options. With at least two screws, preferably in crossed configuration and spaced over the largest available distance of the distal fragment, secure and stable fixation can be achieved. Insertion of the locking screws in a free hand technique typically results in jamming of the locking screw with the nail and with cortical bone, providing inherent angular stability of the construct. Angular stable locking features of the nail itself do not appear to improve mechanical stability or to affect healing of distal tibia fractures. PMID- 25835207 TI - [Plantar approach to hindfoot arthrodesis with compressed angle stable locking option]. AB - BACKGROUND: Tibiotalocalcaneal arthrodesis is indicated in severe combined arthritis of the upper and lower ankle joints and otherwise untreatable malpositioning of the hindfoot. CONCLUSION: Currently available arthrodesis nails have a hindfoot valgus bend which allows the anatomy to be more faithfully reproduced and respected. Anatomical investigations show the endangered structures during retrograde arthrodesis nailing. The valgus bend of the arthrodesis nail necessitates a corresponding correctly placed opening in the calcaneus and talus as the entry point for the nail. A locking screw in the calcaneus running from posterior to anterior increases the stability and is now taken into consideration for nearly all designs of arthrodesis medullary nails. The compression mechanism can be used for apposition and pressing the arthrodesis surfaces together and locking in the hindfoot should be carried out in an angle stable fashion. Augmentation of the locking screws in the calcaneus with bone cement can be an option as a salvage procedure in revision cases. PMID- 25835208 TI - [Surgical treatment of skeletal metastases]. AB - The prevalence of cancerous diseases in Germany is rising. The skeletal system represents the third most common localization for metastases. Nearly two thirds of metastases are found in the region of the spine. Due to longer survival times of tumor patients in the metastasis stage, an increase in the number of patients with bone metastases is to be expected. The treatment of patients with osseus metastases is nowadays an integral component of orthopedic trauma surgery practices. This article presents the principles of the diagnostics, provides aids for estimation of the prognosis and danger of fractures and discusses the various surgical treatment procedures for skeletal metastases with the accompanying advantages and disadvantages. PMID- 25835209 TI - [Dynamic intraligamentary stabilization of the anterior cruciate ligament. Operative technique and short-term clinical results]. AB - BACKGROUND: Reconstruction of tears in the anterior cruciate ligament with a tendon graft is the current gold standard. OBJECTIVES: Dynamic intraligamentary stabilization is a new technique for preservation of the anterior cruciate ligament. METHODS: This article describes the indications, operative technique, rehabilitation and preliminary results after dynamic intraligamentary stabilization for acute anterior cruciate ligament ruptures. RESULTS: A total of 24 women and 31 men with an acute anterior cruciate ligament tear were included in a prospective clinical trial. Of the patients 26 had already been followed-up for 12 months and satisfying values for the Lysholm, Tegner and International Knee Documentation Committee (IKDC) outcome scores were achieved. High subjective patient satisfaction was also achieved. The Lachman test showed a mean anterior translation difference to the healthy side of 1.7 mm. CONCLUSION: Dynamic intraligamentary stabilization in combination with microfracturing of the notch can provide biomechanical and biological conditions for self-healing of the anterior cruciate ligament. Further clinical and biomechanical research is needed to identify appropriate patients and rupture types suitable for this new technique. PMID- 25835210 TI - Stability and Change in the Cognitive and Adaptive Behaviour Scores of Preschoolers with Autism Spectrum Disorder. AB - We examined the stability of cognitive and adaptive behaviour standard scores in children with autism spectrum disorder (ASD) between diagnosis and school entry approximately age 6. IQ increased 18 points in 2-year-olds, 12 points in 3-year olds, and 9 points in 4-year-olds (N = 281). Adaptive behaviour scores increased 4 points across age groups (N = 289). At school entry, 24 % of children met criteria for intellectual disability (cognitive and adaptive behaviour scores <70). No children with both scores >=70 at diagnosis later met criteria for intellectual disability. Outcomes were more variable for children with initial delays in both areas (in 57 %, both scores remained <70). Findings are relevant to clinical decision-making, including specification of intellectual disability in young children with ASD. PMID- 25835211 TI - Influence of Autism Traits and Executive Functioning on Quality of Life in Children with an Autism Spectrum Disorder. AB - Children with Autism Spectrum Disorders (ASDs) often experience a low Quality of Life (QoL). We studied if IQ, early language development, current autism traits, and daily Executive Functions (EFs) are related to QoL in children (aged 8-12 years) with ASD (N = 120) and typically developing (TD) children (N = 76). Children with ASD showed a lower QoL than TD children. This lower QoL was related to higher levels of autism traits and EF deficits. Moreover, specific autism traits and EFs were related to specific QoL subdomains. The low QoL and the aggravating effects of autism traits and EF deficits indicate a potential to identify and target such factors in treatment to improve QoL. PMID- 25835212 TI - Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System. AB - In extended ocular drug delivery applications, it is necessary to exert control over the release characteristics of the drug. Design considerations must be made to limit the initial burst (IB) and ensure complete release of drug from the drug delivery system (DDS). In this study, ovalbumin was used as a model protein to explore the effects on release of polymer formulation and fabrication technique in poly(lactic-co-glycolic acid) (PLGA) microspheres. Furthermore, the effect on release of suspending these microspheres in an injectable, thermo-responsive poly(N-isopropylacrylamide)-based hydrogel was determined. To characterize release, ovalbumin was radiolabeled with iodine-125. Regardless of polymer formulation or fabrication technique, pulsatile release was achieved with a second burst occurring after ~70 days for microspheres alone. Suspending PLGA 75:25 microspheres within hydrogel reduced the IB by ~75%, delayed the second burst by 28 days, and extended release out to ~200 days with steadier, consistent release throughout compared to microspheres alone. The combined microsphere hydrogel DDS remains injectable through small-gauge needles and may have many applications, namely ocular drug delivery to the posterior segment. PMID- 25835213 TI - Structural biology response of a collagen hydrogel synthetic extracellular matrix with embedded human fibroblast: computational and experimental analysis. AB - Adherent cells exert contractile forces which play an important role in the spatial organization of the extracellular matrix (ECM). Due to these forces, the substrate experiments a volume reduction leading to a characteristic shape. ECM contraction is a key process in many biological processes such as embryogenesis, morphogenesis and wound healing. However, little is known about the specific parameters that control this process. With this aim, we present a 3D computational model able to predict the contraction process of a hydrogel matrix due to cell-substrate mechanical interaction. It considers cell-generated forces, substrate deformation, ECM density, cellular migration and proliferation. The model also predicts the cellular spatial distribution and concentration needed to reproduce the contraction process and confirms the minimum value of cellular concentration necessary to initiate the process observed experimentally. The obtained continuum formulation has been implemented in a finite element framework. In parallel, in vitro experiments have been performed to obtain the main model parameters and to validate it. The results demonstrate that cellular forces, migration and proliferation are acting simultaneously to display the ECM contraction. PMID- 25835214 TI - A computational study to evaluate the activation pattern of nerve fibers in response to interferential currents stimulation. AB - Interferential current (IFC) is one of the most popular electrical currents used in electrotherapy. However, there have been limited studies investigating how this stimulation affects the nerve fibers. The aim of this computational study was to evaluate the temporal and spatial patterns of fiber activation in IFC therapy for different modulation and carrier frequencies. The interferential currents were applied by two pairs of point electrodes perpendicular to each other in an infinite homogeneous medium, and a model of myelinated nerve fibers was implemented in NEURON to study the neural response. The activation thresholds for different positions of the fiber and the resultant firing patterns were evaluated. The results suggest that the fibers may fire continuously or in bursts, with frequencies equal or higher than the modulation frequency, or may be blocked, based on their position relative to the electrodes, the modulation frequency and the stimulus strength. The results confirm traditional belief about the role of the modulation frequency in firing frequency of nerve fibers and describe a possible mechanism for less sensation of pain, due to blockage of the fibers by the high-frequency nature of the interferential currents. PMID- 25835215 TI - Perinatal asphyxia leads to PARP-1 overactivity, p65 translocation, IL-1beta and TNF-alpha overexpression, and apoptotic-like cell death in mesencephalon of neonatal rats: prevention by systemic neonatal nicotinamide administration. AB - Perinatal asphyxia (PA) is a leading cause of neuronal damage in newborns, resulting in long-term neurological and cognitive deficits, in part due to impairment of mesostriatal and mesolimbic neurocircuitries. The insult can be as severe as to menace the integrity of the genome, triggering the overactivation of sentinel proteins, including poly (ADP-ribose) polymerase-1 (PARP-1). PARP-1 overactivation implies increased energy demands, worsening the metabolic failure and depleting further NAD(+) availability. Using a global PA rat model, we report here evidence that hypoxia increases PARP-1 activity, triggering a signalling cascade leading to nuclear translocation of the NF-kappaB subunit p65, modulating the expression of IL-1beta and TNF-alpha, pro-inflammatory molecules, increasing apoptotic-like cell death in mesencephalon of neonate rats, monitored with Western blots, qPCR, TUNEL and ELISA. PARP-1 activity increased immediately after PA, reaching a maximum 1-8 h after the insult, while activation of the NF-kappaB signalling pathway was observed 8 h after the insult, with a >twofold increase of p65 nuclear translocation. IL-1beta and TNF-alpha mRNA levels were increased 24 h after the insult, together with a >twofold increase in apoptotic-like cell death. A single dose of the PARP-1 inhibitor nicotinamide (0.8 mmol/kg, i.p.), 1 h post delivery, prevented the effect of PA on PARP-1 activity, p65 translocation, pro inflammatory cytokine expression and apoptotic-like cell death. The present study demonstrates that PA leads to PARP-1 overactivation, increasing the expression of pro-inflammatory cytokines and cell death in mesencephalon, effects prevented by systemic neonatal nicotinamide administration, supporting the idea that PARP-1 inhibition represents a therapeutic target against the effects of PA. PMID- 25835216 TI - The impact of laparoscopic versus open colorectal cancer surgery on subsequent laparoscopic resection of liver metastases: A multicenter study. AB - BACKGROUND: Laparoscopic liver surgery is expanding. Most laparoscopic liver resections for colorectal carcinoma metastases are performed subsequent to the resection of the colorectal primary, raising concerns about the feasibility and safety of advanced laparoscopic liver surgery in the context of an abdomen with possible postoperative adhesions. The aim was to compare the outcome of laparoscopic hepatectomy for colorectal metastases after open versus laparoscopic colorectal surgery. METHODS: This observational, multicenter study reviewed 394 patients undergoing laparoscopic minor and major liver resection for colorectal carcinoma metastases. Main outcome measures were intraoperative unfavorable incidents and short-term results in patients who had previous open versus laparoscopic colorectal cancer surgery. RESULTS: Three hundred six patients (78%) had prior open and 88 (22%) had prior laparoscopic colorectal resection. Laparoscopic major hepatectomies were undertaken in 63 (16%). Intraoperative unfavorable incidents during laparoscopic liver surgery were significantly higher among patients who had prior open colorectal surgery (26%) compared with the laparoscopic group (14%; P = .017). Positive resection margins and postoperative complications were not associated with the approach adopted for the resection of the primary cancer. On multivariate logistic regression analysis, intraoperative unfavorable incidents were associated significantly only with prior open colorectal surgery (odds ratio, 2.8; P = .006) and laparoscopic major hepatectomy (odds ratio, 2.4; P = .009). CONCLUSION: Laparoscopic minor hepatectomy can be performed safely in patients who have undergone previous open colorectal surgery. Laparoscopic major hepatectomy after open colorectal surgery may be challenging. Careful risk assessment in the decision-making process is required not to compromise patient safety and to guarantee the expected benefits from the minimally invasive approach. PMID- 25835217 TI - A new poly(1,3-trimethylene carbonate) film provides effective adhesion reduction after major abdominal surgery in a rat model. AB - BACKGROUND: Postoperative adhesions remain a major clinical problem after abdominal surgery. We evaluated the efficacy of a new poly(trimethylene carbonate) (PTMC) film as an antiadhesive material. In many abdominal operations, there is an increased risk of fecal contamination; the risk of (increased) infection in presence of PTMC film was studied in 2 additional animal models. METHODS: A validated rat adhesion model with peritoneal ischemic buttons was used to compare the new PTMC film with a hyaluronate carboxymethylcellulose (HA-CMC) sheet, icodextrin solution, and a control group. Primary endpoint was occurrence of adhesions at the ischemic buttons after 14 days in 44 rats (n = 11 per group). To evaluate potential risks associated with the film, both an anastomotic leakage model and a cecal ligation and puncture model were used. Kruskal-Wallis tests with subsequent Mann-Whitney tests were used to detect differences between groups. RESULTS: PTMC film showed a significant reduction in the amount of adhesions (median, 0.5 buttons) compared with control group (median, 4 buttons; P < .001) and icodextrin group (median, 4.5; P < .001). The amount of adhesions was similar to the HA-CMC group (median, 2; P = .04). The presence of the film did not increase the risk of anastomotic leakage or bacterial growth in a contaminated environment. CONCLUSION: The presence of a PTMC film leads to a significant reduction in the amount of adhesions after 14 days in an ischemic button rat model. Furthermore, this film was found to be safe in an animal model, even in complex abdominal operations with an increased risk of fecal contamination. PMID- 25835218 TI - Nontechnical skills training for the operating room: A prospective study using simulation and didactic workshop. AB - BACKGROUND: The best surgeons demonstrate skills beyond those required for the performance of technically competent surgery. These skills are described under the term nontechnical skills. Failure in these domains has been associated with adverse events inside the operating room. These nontechnical skills are not learned commonly in a structured manner during surgery training. The main purpose of this study was to explore the effects of participation in simulation-based training, either as a sole strategy or as part of a combined approach on surgeons and surgical trainees nontechnical skills performance in simulation environment. METHODS: The study consisted of a single-blinded, prospective comparative trial. Forty participants were enrolled, all participating in 2 simulation sessions challenging nontechnical skills comprising 3 surgical scenarios. Seventeen participants attended a 1-day, nontechnical skills workshop between simulation sessions. Scenarios were video-recorded for assessment and debriefing purposes. Assessment was made by 2 observers using the Non-Technical Skills for Surgeons (NOTSS) scoring system. RESULTS: There was a significant improvement in nontechnical skills performance of both groups from the first to the second simulation session, for 2 of the 3 scenarios. No difference in performance between the simulation and the simulation plus workshop groups was noted. CONCLUSION: This study provides evidence that formal training in nontechnical skills is feasible and can impact positively participants' nontechnical performance in a simulated environment. The addition of a 1-day didactic workshop does not seem to provide additional benefit over simulation-based training as a sole strategy for nontechnical skills training. PMID- 25835220 TI - Aging-related changes in oxidative stress response of human endothelial cells. AB - BACKGROUND: Oxidative stress is strongly associated with aging and age-related diseases and plays a crucial role in endothelial dysfunction development. AIM: To better understand the molecular mechanisms of aging and stress response in humans, we examined changes to young and older human endothelial cells over time (72, 96 and 120 h), before and after H2O2-induced stress. METHODS: We measured the expression of the deacetylase Sirtuin 1 (Sirt1) and its transcriptional target Forkhead box O3a (Foxo3a); TBARS, a well-known marker of overall oxidative stress, and catalase activity as index of antioxidation. Moreover, we quantified levels of cellular senescence by senescence-associated beta galactosidase (SA betagal) assay. RESULTS: Under oxidative stress induction older cells showed a progressive decrease of Sirt1 and Foxo3a expression, persistently high TBARS levels with high, but ineffective Cat activity to counteract such levels. In addition cellular senescence drastically increased in older cells compared with Young cells both in presence and in the absence of oxidative stress. DISCUSSION: By following the cell behavior during the time course, we can hypothesize that while in young cells an oxidative stress induction stimulated an adequate response through activation of molecular factor crucial to counteract oxidative stress, the older cells are not able to adequately adapt themselves to external stress stimuli. CONCLUSIONS: During their life, endothelial cells impair the ability to defend themselves from oxidative stress stimuli. This dysfunction involves the pathway of Sirt1 a critical regulator of oxidative stress response and cellular lifespan, underlining its crucial role in endothelial homeostasis control during aging and age-associated diseases. PMID- 25835219 TI - Predictive factors for early unplanned rehospitalization of older adults after an ED visit: role of the caregiver burden. AB - BACKGROUND AND AIMS: For older adults, an Emergency Department (ED) visit represents a period of vulnerability that extends beyond the visit itself. This study aimed to determine the impact of the role of caregiver, and geriatric conditions of patients on early unplanned rehospitalization (EUR) within 3 months after an ED visit. METHODS: This prospective longitudinal experimental study included consecutively 173 patients aged 75 and older admitted in an ED over a 2 week period (18.7% of the total visits). Only older patients having a caregiver were analyzed (78.0%, n = 135). Medical conditions and a comprehensive geriatric assessment were recorded for each patient. All caregivers were interviewed about their tasks and emotional impact using the short Zarit Burden Inventory. Three months after, patients or their caregivers were called about the vital status, and EUR of patients. RESULTS: Among the patients included, 64.2% had an EUR and 28.9% of their caregivers reported a high level of burden. EUR was strongly associated with a high caregiver burden (OR 8.7, 95% CI 1.5-49.8). No association was found for patient's medical or geriatric status. Caregivers reported a significantly high burden when patients were malnourished, or were at risk of adverse health outcomes based on the ISAR scale, and when they had greater disabilities in IADLs and ADLs, or cognitive impairments. CONCLUSIONS: Many hospital readmissions after an ED visit may be preventable by identifying caregiver's high burden. Reasons that lead to this high burden should be checked at the first visit. PMID- 25835221 TI - Co-delivery of honokiol, a constituent of Magnolia species, in a self microemulsifying drug delivery system for improved oral transport of lipophilic sirolimus. AB - Sirolimus is recognized as a P-glycoprotein (P-gp) substrate with poor water solubility. To improve its solubility and bioabsorption, self-microemulsifying drug delivery systems (SMEDDS) containing a novel P-gp inhibitor, honokiol, were prepared. The aim of this work was to evaluate the enhanced transport of sirolimus SMEDDS as well as the roles of honokiol. In situ single-pass intestinal perfusion and in vitro human colon adenocarcinoma (Caco-2) cell models were applied to study the effects of honokiol within SMEDDS on the transport of sirolimus. The results indicated that a combination of honokiol with sirolimus in SMEDDS did not significantly alter the particle size, polydispersity index and release of drugs. In addition, the absorption rate constant (Ka) as well as the effective permeability coefficients (Peff) of sirolimus in situ intestinal absorption, and the apparent permeability coefficients (Papp) of sirolimus in caco-2 cells were significantly enhanced by cremophor EL-based SMEDDS with honokiol as compared with those of SMEDDS without honokiol. Rhodamine123 uptake rate in caco-2 cells and in vitro cytotoxicity of sirolimus were enhanced by honokiol in SMEDDS indicating a substantial P-gp inhibition of honokiol. In conclusion, coadministration of honokiol with poor soluble P-gp substrate in SMEDDS, could serve as a favorable approach for oral delivery. PMID- 25835222 TI - Computational analysis of drug transport in tumor microenvironment as a critical compartment for nanotherapeutic pharmacokinetics. AB - Over the last decade, nanotherapeutics gained increasingly important role in drug delivery because of their frequently beneficial pharmacokinetics (PK) and lower toxicity when compared to classical systemic drug delivery. In view of therapeutic payload delivery, convective transport is crucial for systemic distribution via circulatory system, but the target domain is tissue outside vessels where transport is governed by diffusion. Here, we have computationally investigated the understudied interplay of physical transports to characterize PK of payload of nanotherapeutics. The analysis of human vasculature tree showed that convective transport is still 5 times more efficient than diffusion suggesting that circulating and payload releasing drug vectors can contribute mostly to systemic delivery. By comparing payload delivery using systemic circulation and drug vectors to microenvironment, internalized vectors were the most efficient and showed Area under the Curve almost 100 higher than in systemic delivery. The newly introduced zone of influence parameter indicated that vectors, especially internalized, lead to the largest tissue fraction covered with therapeutically significant payload concentration. The internalization to microenvironment minimizes effects of plasma domain on payload extravasation from nanotherapeutics. The computed results showed that classical PK, which mostly relies on concentration profiles in plasma, sometimes might be inadequate or not sufficient in explaining therapeutic efficacy of nanotherapeutics. These results provide a deeper look into PK of drug vectors and can help in the design of better drug delivery strategies. PMID- 25835223 TI - In vitro/in vivo evaluation of agar nanospheres for pulmonary delivery of bupropion HCl. AB - Bupropion HCl is an atypical antidepressant drug with rapid and high first-pass metabolism. Sustained release dosage form of this drug is suggested for reducing its side effects which are mainly seizures. The aim of the present study was to design pulmonary agar nanospheres of bupropion HCl with effective systemic absorption and extended release properties. Bupropion HCl was encapsulated in agar nanospheres by ionic gelation, and characterized for physical and release properties. Pharmacokinetic studies on nanospheres were performed on rats by intratracheal spraying of 5 mg/kg of drug in form of nanospheres compared to intravenous and pulmonary delivery of the same dose as simple solution of the drug. The optimized nanoparticles showed particle size of 320 +/- 90 nm with polydispersity index of 0.85, the zeta potential of -29.6 mV, drug loading efficiency of 43.1 +/- 0.28% and release efficiency of 66.7 +/- 2%. The area under the serum concentration-time profile for the pulmonary nanospheres versus simple solution was 10 237.84 versus 28.8 ug/ml min, Tmax of 360 versus 60 min and the Cmax of 1927.93 versus9.93 ng/ml, respectively. The absolute bioavailability of the drug was 86.69% for nanospheres and 0.25% for pulmonary simple solution. Our results indicate that pulmonary delivery of bupropion loaded agar nanospheres achieves systemic exposure and extends serum levels of the drug. PMID- 25835224 TI - Melanoma therapy with transdermal mitoxantrone cubic phases. AB - CONTEXT: Melanoma therapy absorbs attention because of the high morbidity and mortality. However, currently systematic administrations could take little therapeutic efficiency and severe side effects. OBJECTIVE: An effective transdermal formulation for the convenient melanoma therapy was found and evaluated. MATERIALS AND METHODS: A mitoxantrone (MTO) cubic phase was prepared with glyceryl monooleate, ethanol and water. The permeation, cytotoxicity, in vivo anti-melanoma effect of the MTO cubic phases were evaluated. The anti-cancer mechanism of the MTO cubic phases was explored according to the immunohistochemistry and flow cytometry. RESULTS AND DISCUSSION: The isotropic structure of MTO cubic phases was identified. The transdermal permeability of MTO was greatly improved by the cubic phase compared to that of the MTO solution. The MTO cubic phases showed the high cytotoxicity in B16 melanoma cells evidenced by a modified electrical cell-substrate impedance sensing system. High anti-melanoma effect of the MTO cubic phases was confirmed according to the tumor volume changes and tumor weight. The tumor inhibitory rate of the MTO cubic phases was 68.44%. The calreticulin expression of B16 cells was improved by the MTO cubic phases, and the improved cell uptake of MTO was confirmed by the flow cytometry. CONCLUSION: The MTO cubic phase is a promising topical delivery system for melanoma therapy with the advantages of non-invasion and no severe side effects. PMID- 25835225 TI - Versicorin, a new lovastatin analogue from the fungus Aspergillus versicolor SC0156. AB - A new lovastatin analogue versicorin (1), together with three related compounds, decumbenones A (2) and B (3) and versiol (4), were isolated from mycelial solid cultures of Aspergillus versicolor SC0156. Their structures were elucidated on the basis of MS data and NMR spectroscopic analysis. The new compound versicorin (1) possesses a hexahydro-2H-naphtho[1,8-bc]furan moiety, which is a rare type of the lovastatin-analogous compounds. A hypothetical biosynthetic pathway for compounds 1-4 was proposed. PMID- 25835226 TI - There is no better time than the present: nanotechnology as a disruptive innovation for drug development. PMID- 25835227 TI - Molecular dynamics studies of modular polyketide synthase ketoreductase stereospecificity. AB - Ketoreductases (KRs) from modular polyketide synthases (PKSs) can perform stereospecific catalysis, selecting a polyketide with a D- or L-alpha-methyl substituent for NADPH-mediated reduction. In this report, molecular dynamics (MD) simulations were performed to investigate the interactions that control stereospecificity. We studied the A1-type KR from the second module of the amphotericin PKS (A1), which is known to be stereospecific for a D-alpha-methyl substituted diketide substrate (dkD). MD simulations of two ternary complexes comprised of the enzyme, NADPH, and either the correct substrate, dkD, or its enantiomer (dkL) were performed. The coordinates for the A1/NADPH binary complex were obtained from a crystal structure (PDB entry 3MJS), and substrates were modeled in the binding pocket in conformations appropriate for reduction. Simulations were intended to reproduce the initial weak binding of the polyketide substrate to the enzyme. Long (tens of nanoseconds) MD simulations show that the correct substrate is retained in a conformation closer to the reactive configuration. Many short (up to a nanosecond) MD runs starting from the initial structures display evidence that Q364, three residues N-terminal to the catalytic tyrosine, forms a hydrogen bond to the incorrect dkL substrate to yield an unreactive conformation that is more favorable than the reactive configuration. This interaction is not as strong for dkD, as the D-alpha-methyl substituent is positioned between the glutamine and the reactive site. This result correlates with experimental findings [Zheng, J., et al. (2010) Structure 18, 913-922] in which a Q364H mutant was observed to lose stereospecificity. PMID- 25835228 TI - The growth of oleaginous Rhodotorula glutinis in an airlift bioreactor on crude glycerol through a non-sterile fermentation process. AB - While the use of oleaginous Rhodotorula glutinis as a feedstock for biodiesel production is an attractive idea, as it can avoid the pollutions associated with over-consumption of fossil fuels. Nevertheless, the related costs, including the energy required for sterilization, remain a barrier to commercialization. This study thus used a low-pH non-sterile medium, instead of a completely sterilized one, to grow R. glutinis in a 5-L airlift bioreactor. The results show that R. glutinis can grow well at a low pH level of 4.0 and without sterilization of the medium, producing a final biomass of 11.7 g/L. Nevertheless, such a low pH will lead to fewer total lipids accumulation, and so a two-stage process of pH control in a non-sterile batch was proposed. Even this two-stage pH operation was also able to produce a similar final biomass of 11.7 g/L. However, the batch with two stage pH control had a far higher lipid content of 55 +/- 4% as compared to that of 21 +/- 3% in the batch grown at pH 4.0. This study shows the potential of the proposed non-sterile process with two-stage pH control applied to the growth of R. glutinis to enhance the total lipid accumulation. PMID- 25835230 TI - L-ascorbic acid addition to chitosan reduces body weight in overweight women. AB - Previously, we have found that the addition of L-ascorbic acid to chitosan enhanced the reduction in body weight gain in guinea pigs fed a high-fat diet. We hypothesized that the addition of L-ascorbic acid to chitosan would accelerate the reduction of body weight in humans, similar to the animal model. Overweight subjects administered chitosan with or without L-ascorbic acid for 8 weeks, were assigned to three groups: Control group (N=26, placebo, vehicle only), Chito group (N=27, 3 g/day chitosan), and Chito-vita group (N=27, 3 g/day chitosan plus 2 g/day L-ascorbic acid). The body weights and body mass index (BMI) of the Chito and Chito-vita groups decreased significantly (p<0.05) compared to the Control group. The BMI of the Chito-vita group decreased significantly compared to the Chito group (Chito: -1.0 kg/m2 vs. Chito-vita: -1.6 kg/m2, p<0.05). The results showed that the chitosan enhanced reduction of body weight and BMI was accentuated by the addition of L-ascorbic acid. The fat mass, percentage body fat, body circumference, and skinfold thickness in the Chito and Chito-vita groups decreased more than the Control group; however, these parameters were not significantly different between the three groups. Chitosan combined with L ascorbic acid may be useful for controlling body weight. PMID- 25835229 TI - Does comparing alcohol use along a single dimension obscure within-group differences? Investigating men's hazardous drinking by sexual orientation and race/ethnicity. AB - BACKGROUND: Some studies have found that gay, bisexual, and other men who have sex with men (MSM) have higher odds of alcohol abuse and dependence than heterosexual men, but others have found no differences. We investigated whether the association between sexual orientation and hazardous drinking varied by race/ethnicity. METHODS: We estimated the odds of past-year heavy daily, heavy weekly, and binge drinking by sexual orientation and race/ethnicity among non Latino White, non-Latino Black, and Latino (any race) men (n = 9689) who reported current alcohol use in the 2004-2005 National Epidemiological Survey of Alcohol and Related Conditions (NESARC). Interaction terms were included in multivariable logistic regression models to evaluate possible effect modification. RESULTS: In most comparisons, sexual minority men reported equivalent or lower levels of hazardous drinking than heterosexual peers. There was no association between sexual orientation and heavy daily drinking. Sexual minority Black men had lower odds of heavy weekly drinking and binge drinking than both heterosexual White men and heterosexual Black men. Among Latinos, the odds of heavy weekly drinking were higher for sexual minority men than heterosexuals; there was no difference by sexual orientation for binge drinking among Latinos. CONCLUSIONS: With one exception, sexual minority men were at equivalent or lower risk of hazardous drinking than heterosexual men. The Black-White advantage observed in other alcohol studies was observed in our study and was heightened among sexual minority men, suggesting the presence of protective factors that curb hazardous drinking. Additional research is necessary to identify the mechanisms responsible for these patterns. PMID- 25835231 TI - Poor vitamin C status is associated with increased depression symptoms following acute illness in older people. AB - BACKGROUND: Vitamin C has important physical and mental health benefits and plasma concentrations reflect recent intakes. Inflammation associated with any acute illness can lead to poor appetite and low food intake in older people. The aims of this report were to assess the prevalence and clinical significance of vitamin C deficiency among hospitalized acutely-ill older patients. METHODS: Three hundred and twenty two patients (152 [47%] female), aged 65 yrs. and over who took part in a randomized, double blind, placebo-controlled trial had their nutritional status assessed from anthropometric, hematological and biochemical data at baseline, and after 6 weeks and 6 months. Vitamin C was measured using a fluorimetric technique and logistic regression analysis was performed to determine the influence of a number of clinical indicators, including tissue inflammation measured using C-reactive protein on vitamin C concentrations. Clinical outcome measures including symptoms of depression were also compared between patients with vitamin C deficiency and those with normal levels. RESULTS: At baseline, 116 (36%) patients had a vitamin C concentration below 11 umol/L indicating biochemical depletion. The figures at 6 weeks and 6 months were 28 (22%) and 44 (28%) patients, respectively. Older age, male gender, smoking, increased dependency and tissue inflammation were associated with lower vitamin C concentrations. Patients with vitamin C biochemical depletion had significantly increased symptoms of depression compared with those with higher concentrations at baseline (p=0.035) and at 6 weeks (p=0.028). CONCLUSIONS: A high proportion of older patients had sub-optimal vitamin C status and this was associated with increased symptoms of depression. PMID- 25835232 TI - Fish oil supplementation, resting blood flow and markers of cellular metabolism during incremental exercise. AB - Dietary supplementation of fish oils (n-3 PUFA) have been observed to affect insulin action and hence metabolism, affecting the ability to carry out work. Here we examine the effects of fish oil supplementation in conjunction with a glucose load during exertion, on markers of substrate utilization. A pre-test, post-test design was performed on ten healthy young males to assess the effects of 4 weeks fish oil supplementation on muscle metabolism during incremental exertion. Breath-by-breath analysis for respiratory exchange ratio (RER) along with blood lactate and blood glucose were determined at baseline, during exercise following an acute glucose bolus (10% solution at 4 mL/kg/bw), and again following supplementation of 4.2 g.day(-1) (2.2 g EPA, 1.4 g DHA). To examine the effect of fish oil on blood flow, Doppler ultrasound was used to assess femoral blood flow at rest. Following consumption of fish oils, exercising blood glucose and RER were seen to change significantly (4.66+/-0.44 vs. 4.58+/-0.31 mmol.L(-1) and 0.97+/-0.03 vs. 0.99+/-0.04; p<0.05). Resting femoral arterial blood flow was seen to increase significantly (p<0.05) pre- to post- test; 0.26+/-0.02-0.30+/ 0.03 L.min(-1). Specific population groups such as those undertaking high intensity exercise, and clinical groups such as intermittent claudicants, may benefit from the effects of fish oil supplementation. PMID- 25835233 TI - Vitamin D supplementation and serum levels of magnesium and selenium in type 2 diabetes mellitus patients: gender dimorphic changes. AB - The aim of our study was to evaluate the effects of vitamin D supplementation on circulating levels of magnesium and selenium in patients with type 2 diabetes mellitus (T2DM). A total of 126 adult Saudi patients (55 men and 71 women, mean age 53.6+/-10.7 years) with controlled T2DM were randomly recruited for the study. All subjects were given vitamin D3 tablets (2000 IU/day) for six months. Follow-up mean concentrations of serum 25-hydroxyvitamin D [25-(OH) vitamin D] significantly increased in both men (34.1+/-12.4 to 57.8+/-17.0 nmol/L) and women (35.7+/-13.5 to 60.1+/-18.5 nmol/L, p<0.001), while levels of parathyroid hormone (PTH) decreased significantly in both men (1.6+/-0.17 to 0.96+/-0.10 pmol/L, p=0.003) and women (1.6+/-0.17 to 1.0+/-0.14 pmol/L, p=0.02). In addition, there was a significant increase in serum levels of selenium and magnesium in men and women (p-values<0.001 and 0.04, respectively) after follow-up. In women, a significant correlation was observed between delta change (variables at six months-variable at baseline) of serum magnesium versus high-density lipoprotein (HDL)-cholesterol (r=0.36, p=0.006) and fasting glucose (r=-0.33, p=0.01). In men, there was a significant correlation between serum selenium and triglycerides (r=0.32, p=0.04). Vitamin D supplementation improves serum concentrations of magnesium and selenium in a gender-dependent manner, which in turn could affect several cardiometabolic parameters such as glucose and lipids. PMID- 25835234 TI - Homocysteine but not serum amyloid A, vitamin A and E related to increased risk of metabolic syndrome in post-menopausal Thai women. AB - This study aims to investigate serum amyloid A, homocysteine, and biochemical anthropometric measurements in post-menopausal women with and without metabolic syndrome (MS), and determine whether serum amyloid A and homocysteine are linked to MS among this group. This study was performed with 405 post-menopausal Thai volunteers with a mean age of 57.95+/-5.90 years (135 subjects with MS and 270 subjects without MS). The levels of serum amyloid A, homocysteine, vitamins, glucose, and lipids were measured. Homocysteine levels were significantly higher in the group with MS than in that without MS (p<0.001), whereas for serum amyloid A, vitamin A, vitamin E and vitamin B12, there were no significant differences. There were significant differences between the groups in folate, HDL-C, and anthropometric measurements (p<0.001). Thirty seven percent of the group with MS and 14.1% of the group without MS were classified as having hyperhomocysteinemia (p<0.001). Furthermore, logistic regression analysis revealed that hyperhomocysteinemia (odds ratio (OR): 2.67, 95% confidence interval (95%CI): 1.57-4.58), low folate (OR: 1.79, 95%CI: 1.11-2.89), and BMI (OR: 1.25, 95%CI: 1.16-1.33) were significantly related to MS. These findings suggest that increased homocysteine levels and decreased folate concentrations may influence susceptibility to MS and this effect may be an early event in the development of cardiovascular diseases among post-menopausal women. Therefore, there is a need to evaluate homocysteine levels, especially among post-menopausal Thai women. PMID- 25835235 TI - The effect of oral loading doses of cholecalciferol on the serum concentration of 25-OH-vitamin-D. AB - BACKGROUND/OBJECTIVES: Severe vitamin D deficiency can be treated with oral loading doses of cholecalciferol. Our objective was to develop an algorithm to accurately calculate the amount of cholecalciferol needed for a loading dose, and what factors should be taken into account. METHODS: Two studies were conducted on subjects with Vitamin D deficiency. Study 1 was observational, retrospective and included 88 subjects treated with a daily supplementation of cholecalciferol. 60 of these furthermore received a loading dose, calculated by an algorithm.Study 2 was prospective and included 29 subjects treated with a cholecalciferol loading dose, calculated by an algorithm developed based on data from study 1, which included BMI. RESULTS: Baseline 25OH-vit.D was below 25 nmol/L (study 1) and 23 nmol/L (study 2). Subjects were given a single loading dose of cholecalciferol, averaging 172,000 IU (study 1) and 212,000 IU (study 2), based on their baseline 25OH-vit.D level.25OH-vit.D increased by 35 nmol/L (study 1) and 56 nmol/L (study 2)(range 113.0, SD 29.79) respectively. In study 2 the increase lead to an end 25OH-vit.D of 79 nmol/L--not significantly different from the target value of 80 nmol/L (P=0.46). The increase in 25OH-vit.D in study 1 was significantly lower than in study 2 (P<0.001). CONCLUSION: When calculating loading doses of cholecalciferol, taking subject BMI into account gives a better estimate of the loading dose of vitamin D3 needed to treat vitamin D deficiency. It does not, however, remove the large interindividual variation in dose-response. PMID- 25835236 TI - Combination of vitamin E and folic acid ameliorate oxidative stress and apoptosis in diabetic rat uterus. AB - This study was designed to assess oxidative damage and cell apoptosis in the uterus of rats with streptozotocin (STZ)-induced diabetes. The role of vitamin E (VE) and/or folic acid (FA) in the protection from such damage was also evaluated. The treatments were performed for 4 weeks on six groups of rats: 1) normal control 2) diabetic control 3) diabetic rats receiving olive oil as a vehicle (without VE) 4) diabetic rats treated with VE (200 mg/kg) in olive oil 5) diabetic rats treated with FA (25 mg/kg) and 6) diabetic rats treated with VE+FA (200 and 25 mg/kg, respectively). We measured the malondialdehyde level (MDA), glutathione content (GSH) and the activity of GSH peroxidase (GPx), GSH reductase (GR) and catalase. Changes in caspase-3 activity were quantified in uterine tissue to assess the rate of apoptosis. In the rat uterine tissues, MDA content and caspase-3 activity were significantly elevated, while GPx, GR and CAT activities and the GSH level were significantly decreased in the diabetic control compared with those in normal rats (p<0.05). The combination of the vitamins (VE+FA) restored uterine GSH content and enzymatic activities of GPx, GR and CAT and reduced the MDA level (p<0.05). A prominent reduction in apoptosis of uterine cells was detected in diabetic rats treated with two vitamins (p<0.05). Overall, VE alone, not FA, produced results similar to those of the VE+FA combination. Thus, in the uterine tissue of diabetic rats, diabetes complications (that are caused by oxidative damage and apoptosis induction) can be prevented by the systemic administration of VE and FA. PMID- 25835237 TI - The potential of orange-fleshed sweet potato to prevent vitamin A deficiency in Africa. AB - PURPOSE: Vitamin A deficiency is among major health problems worldwide that leads to blindness, retarded growth and death, particularly in developing countries. In these countries, vitamin A deficiency largely affects pre-school children, pregnant and lactating mothers, and the rural poor. For instance, the predicted prevalence of vitamin A deficiency for 36 sub-Saharan African countries is 19.1%. METHODS: Different strategies, including vitamin A supplementation, food fortification and dietary diversification, have been used to combat this problem. However, these strategies are not sustainable due to their high costs. RESULTS: Orange-fleshed sweet potato (Ipomoea batatas L. Lam) is a low priced crop, which is part of staple foods in most of sub-Saharan Africa that can be a year-round source of vitamin A. Most of the orange-fleshed sweet potato varieties contain 3000-16000 MUg 100 g(-1) of beta-carotene and this contributes to 250 to 1300 MUg 100 g(-1) Retinol Activity Equivalents (RAE). Therefore, by using orange-fleshed sweet potato, it is possible to improve vitamin A status, increase the bio availability of different micro-nutrients such as Fe, Zn, Ca and Mg, reduce vitamin A deficiency and hence reduce child mortality rates by 23 to 30%. CONCLUSION: The article highlights the significance of vitamin A for human nutrition, the effect of vitamin A deficiency, the different prevention methods and the potential of orange- fleshed sweet potato as a food crop to prevent vitamin A deficiency. PMID- 25835238 TI - The anti-atherogenic properties of sesamin are mediated via improved macrophage cholesterol efflux through PPARgamma1-LXRalpha and MAPK signaling. AB - BACKGROUND: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARgamma1 and LXRalpha, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. AIM: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 MUM) on PPARgamma1 and LXRalpha expression and transcriptional activity as well as macrophage cholesterol efflux. METHODS: PPARgamma1 and LXRalpha expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. RESULTS: The 50 MUM, 75 MUM, and 100 MUM concentrations of sesamin up-regulated the expression of PPARgamma1 (p<0.001, p<0.001, p<0.001, respectively) and LXRalpha (p=0.002, p<0.001, p<0.001, respectively) in a concentration-dependent manner. Moreover, 75 MUM and 100 MUM concentrations of sesamin led to 5.2-fold (p<0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p<0.001) and 4.2-fold (p<0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time dependent manner via MAPK signaling. Consistently, 50 MUM, 75 MUM, and 100 MUM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p<0.001), 4.2-fold (p<0.001), and 4.2-fold (p<0.001), respectively, via MAPK signaling. CONCLUSION: Our findings shed light on the molecular mechanism(s) underlying sesamin?s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARgamma1 and LXRalpha expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis. PMID- 25835239 TI - Serum vitamin B12 levels during the first trimester of pregnancy correlate with newborn screening markers of vitamin B12 deficiency. AB - INTRODUCTION: Low maternal vitamin B12 status is a risk factor for various adverse pregnancy outcomes. Although vitamin B12 deficiency is not a primary target of newborn screening (NBS) programs, measurements of propionylcarnitine (C3) and its ratios with acetylcarnitine (C3/C2) and palmitoylcarnitine (C3/C16) may incidentally identify vitamin B12-deficient newborns. The objective of this study was to measure vitamin B12 levels in women during the first trimester of pregnancy, evaluate predictors of these concentrations, and study their relationship with newborn screening results. DESIGN: Vitamin B12 concentrations were evaluated in 204 women during the first trimester of pregnancy and possible confounding factors were analyzed. After giving birth, data of their newborns (189) were collected (sex, gestational age, birthweight) and the acylcarnitine profile obtained by tandem mass spectrometry during NBS was analyzed. To assess the effects of the variables on vitamin B12 serum concentrations and newborn screening markers, stepwise multiple linear regression models were used. RESULTS: The mean serum concentration of vitamin B12 was 370.8 pmol/L (502.4 pg/mL) (SD 142.81). Vitamin B12 concentrations were significantly lower in smokers (p=0.027), and in women with low meat consumption (p=0.040). There was a significant inverse correlation between mothers'? vitamin B12 concentrations and their children?'s C3 (r=-0.24; p=0.001), C3/C2 (r=-0.23; p=0.002) and C3/C16 levels (r=-0.20; p=0.006). CONCLUSIONS: Newborn screening markers (C3, C3/C2, and C3/C16) present an inverse correlation with maternal vitamin B12 status in the first trimester of pregnancy. Regarding factors that may influence maternal serum vitamin B12 levels during the first trimester, smoking seems to have a negative effect, and meat consumption a positive effect. PMID- 25835240 TI - Moderate vitamin D deficiency and inflammation related markers in overweight/obese schoolchildren. AB - OBJECTIVE: Obesity has been associated with vitamin D deficiency and increased oxidative stress, which can lead to the dysregulation of adipokines and inflammation. The aim of the present work was to examine the association of vitamin D status [25(OH)D] on inflammatory related markers in overweight/obese children. SUBJECTS/METHODS: A total of 137 Spanish schoolchildren between 9 and 12 years of age (31.4% with overweight/obesity) were studied. Being overweight was defined as BMI>=85th percentile and obesity as BMI>=97th percentile using the reference tables of Hernandez. Serum 25(OH)D concentrations were measured by chemiluminescent assay. Plasma tumor necrosis factor (TNF-alpha) and interleukin 6 (IL-6) were measured by immunoenzyme assay. Serum adiponectin was determined using an ELISA kit. Serum high-sensitivity C-reactive protein (hs-PCR) was tested by immunonephelometry. RESULTS: IL-6 concentrations were higher in the overweight/obese children with deficient serum 25(OH)D (<20 ng/mL) than in those in this group but whose serum 25(OH)D concentrations were adequate (>=20 ng/mL). Serum 25(OH)D was inversely associated with IL-6 concentrations in the overweight/obese subjects taking into account different covariates; thus, for every 1 ng/mL rise in the former, the latter fell by 0.160 pg/mL (beta=-0.160+/ 0.068; R2=0.131; p=0.023). The obese subjects with concentrations of >=25 ng/mL had lower hs-CRP values compared to those with concentrations of <25 ng/mL (0.053+/-0.035 vs. 0.356+/-0.613 mg/dL; p=0.035). CONCLUSION: Low serum 25(OH)D was significantly associated high serum IL-6 in overweight/obese children, and with increased hs-CRP in obese children. PMID- 25835241 TI - Correlations between psychometric schizotypy, scan path length, fixations on the eyes and face recognition. AB - Psychometric schizotypy in the general population correlates negatively with face recognition accuracy, potentially due to deficits in inhibition, social withdrawal, or eye-movement abnormalities. We report an eye-tracking face recognition study in which participants were required to match one of two faces (target and distractor) to a cue face presented immediately before. All faces could be presented with or without paraphernalia (e.g., hats, glasses, facial hair). Results showed that paraphernalia distracted participants, and that the most distracting condition was when the cue and the distractor face had paraphernalia but the target face did not, while there was no correlation between distractibility and participants' scores on the Schizotypal Personality Questionnaire (SPQ). Schizotypy was negatively correlated with proportion of time fixating on the eyes and positively correlated with not fixating on a feature. It was negatively correlated with scan path length and this variable correlated with face recognition accuracy. These results are interpreted as schizotypal traits being associated with a restricted scan path leading to face recognition deficits. PMID- 25835242 TI - Bio-inspired CO2 conversion by iron sulfide catalysts under sustainable conditions. AB - The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents. PMID- 25835244 TI - Spinal accessory nerve transfer outperforms cervical root grafting for suprascapular nerve reconstruction in neonatal brachial plexus palsy. AB - BACKGROUND: The authors evaluated long-term shoulder function in patients with neonatal brachial plexus palsy undergoing suprascapular nerve reconstruction with cervical root grafting or spinal accessory nerve transfer. METHODS: A retrospective review was performed on all infants presenting with neonatal brachial plexus palsy between 1994 and 2010. Functional outcomes were compared by type of suprascapular nerve reconstruction. RESULTS: Seventy-four patients met the inclusion criteria (46 transfers, 28 grafts). Both groups presented with an active movement scale score of 2.0 for shoulder abduction and 0.0 for external rotation. Postoperative follow-up was 9.0 years for the graft group and 6.7 years for the transfer group. Both groups achieved an active movement scale score of 5.0 for shoulder abduction at 12, 24, and 36 months postoperatively. Active movement scale scores for shoulder external rotation were 1.0, 2.0, and 2.5 for the graft group versus 2.0, 2.0, and 3.0 for the transfer group at 12, 24, and 36 months postoperatively. None of these differences reached statistical significance. Composite Mallet scores were 13.0 for the graft group versus 15.0 for the transfer group at 3 years (p = 0.06) and 13.0 for the graft group versus 16.0 for the transfer group at 5 years postoperatively (p = 0.07). Secondary shoulder surgery was performed on 57.1 percent (16 of 28) of patients with grafts compared with 26.1 percent (12 of 46) of patients with transfers (OR, 3.17; p = 0.02). CONCLUSION: Suprascapular nerve reconstruction by cervical root grafting results in poorer shoulder function and a two-fold increase in secondary shoulder surgery compared with spinal accessory nerve transfer. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25835245 TI - Three-dimensional surface imaging in plastic surgery: foundation, practical applications, and beyond. AB - Three-dimensional surface imaging has gained clinical acceptance in plastic and reconstructive surgery. In contrast to computed tomography/magnetic resonance imaging, three-dimensional surface imaging relies on triangulation in stereophotography to measure surface x, y, and z coordinates. This study reviews the past, present, and future directions of three-dimensional topographic imaging in plastic surgery. Historically, three-dimensional imaging technology was first used in a clinical setting in 1944 to diagnose orthodontologic conditions. Karlan established its use in the field of plastic surgery in 1979, analyzing contours and documenting facial asymmetries. Present use of three-dimensional surface imaging has focused on standardizing patient topographic measurements to enhance preoperative planning and to improve postoperative outcomes. Various measurements (e.g., volume, surface area, vector distance, curvature) have been applied to breast, body, and facial topography to augment patient analysis. Despite the rapid progression of the clinical applications of three-dimensional imaging, current use of this technology is focused on the surgeon's perspective and secondarily the patient's perspective. Advancements in patient simulation may improve patient-physician communication, education, and satisfaction. However, a communal database of three-dimensional surface images integrated with emerging three-dimensional printing and portable information technology will validate measurements and strengthen preoperative planning and postoperative outcomes. Three-dimensional surface imaging is a useful adjunct to plastic and reconstructive surgery practices and standardizes measurements to create objectivity in a subjective field. Key improvements in three-dimensional imaging technology may significantly enhance the quality of plastic and reconstructive surgery in the near future. PMID- 25835246 TI - Enhancement of the repair of dog alveolar cleft by an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture. AB - BACKGROUND: Autologous bone graft has been regarded as the criterion standard for the repair of alveolar cleft. However, the most prominent issue in alveolar cleft treatment is the high absorption rate of the bone graft. The authors' objective was to investigate the effects of an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture on the repair of dog alveolar cleft. METHODS: Twenty beagle dogs with unilateral alveolar clefts created by surgery were divided randomly into four groups: group A underwent repair with an autologous iliac bone, bone marrow-derived mesenchymal stem cell, and platelet-rich fibrin mixture; group B underwent repair with autologous iliac bone and bone marrow-derived mesenchymal stem cells; group C underwent repair with autologous iliac bone and platelet-rich fibrin; and group D underwent repair with autologous iliac bone as the control. One day and 6 months after transplantation, the transplant volumes and bone mineral density were assessed by quantitative computed tomography. All of the transplants were harvested for hematoxylin and eosin staining 6 months later. RESULTS: Bone marrow-derived mesenchymal stem cells and platelet-rich fibrin transplants formed the greatest amounts of new bone among the four groups. The new bone formed an extensive union with the underlying maxilla in groups A, B, and C. Transplants with the bone marrow-derived mesenchymal stem cells, platelet-rich fibrin, and their mixture retained the majority of their initial volume, whereas the transplants in the control group showed the highest absorption rate. Bone mineral density of transplants with the bone marrow-derived mesenchymal stem cells, platelet-rich fibrin, and their mixture 6 months later was significantly higher than in the control group (p < 0.05), and was the highest in bone marrow-derived mesenchymal stem cells and platelet-rich fibrin mixed transplants. Hematoxylin and eosin staining showed that the structure of new bones formed the best in group A. CONCLUSION: Both bone marrow-derived mesenchymal stem cells and platelet-rich fibrin are capable of improving the repair of dog alveolar cleft, and the mixture of them is more potent than each one of them used singly for enhancing new bone regeneration. PMID- 25835247 TI - The impact of plastic and reconstructive surgery: by the numbers. PMID- 25835248 TI - Algorithmic approach to anterolateral thigh flaps lacking suitable perforators in lower extremity reconstruction. AB - BACKGROUND: The anterolateral thigh flap is preferred at the authors' institution for lower extremity reconstruction. When variations in vascular anatomy preclude flap harvest, the authors follow an algorithm for contingency planning. The authors compared outcomes of contingency strategies to anterolateral thigh flaps that go as planned. METHODS: Between January of 2001 and February of 2012, 548 free anterolateral thigh flaps were planned for lower extremity reconstruction at Chang Gung Memorial Hospital. In 30 cases, the flap could not be used because perforators were not identified (n = 12), unreliably small (n = 14), or injured (n = 4). Using the authors' algorithm, the flap was converted to an ipsilateral tensor fasciae latae (n = 21), anteromedial thigh (n = 5), or contralateral vastus lateralis myocutaneous flap (n = 4). Outcomes, including flap failure, necrosis, and re-exploration rate, were compared in successful cases and those that required conversion. RESULTS: The incidence of unreliably small or absent perforators was 4.8 percent. Adding cases of iatrogenic perforator injury, the incidence was 5.5 percent. There was no difference in flap survival, flap loss, or need for re-exploration regardless of whether or not the anterolateral thigh flap was used. In 70 percent of cases, the authors favored the tensor fasciae latae flap; partial flap necrosis occurred in six of 21 cases, and total flap loss occurred in one. CONCLUSIONS: Without preoperative imaging, dilemmas may be encountered in roughly one of 20 anterolateral thigh flaps raised. Using the authors' algorithm, alternative options can reliably confer results comparable to those of planned anterolateral thigh flaps. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25835249 TI - Ultrafast electron dynamics in epitaxial graphene investigated with time- and angle-resolved photoemission spectroscopy. AB - In order to exploit the intriguing optical properties of graphene it is essential to gain a better understanding of the light-matter interaction in the material on ultrashort timescales. Exciting the Dirac fermions with intense ultrafast laser pulses triggers a series of processes involving interactions between electrons, phonons and impurities. Here we study these interactions in epitaxial graphene supported on silicon carbide (semiconducting) and iridium (metallic) substrates using ultrafast time- and angle-resolved photoemission spectroscopy (TR-ARPES) based on high harmonic generation. For the semiconducting substrate we reveal a complex hot carrier dynamics that manifests itself in an elevated electronic temperature and an increase in linewidth of the pi band. By analyzing these effects we are able to disentangle electron relaxation channels in graphene. On the metal substrate this hot carrier dynamics is found to be severely perturbed by the presence of the metal, and we find that the electronic system is much harder to heat up than on the semiconductor due to screening of the laser field by the metal. PMID- 25835250 TI - Transient neonatal radial nerve palsy. A case series and review of the literature. AB - Transient neonatal radial nerve palsy manifests at birth by wrist drop and intact elbow and shoulder function. Spontaneous resolution is universal. We present a case series, including two bilateral cases, and a review of the cases found in the English literature, hypothesizing how this condition is probably misdiagnosed as brachial plexus injury. PMID- 25835251 TI - Characterization and intervention for upper extremity exploration & reaching behaviors in infancy. AB - This article aims to: 1) highlight general exploration, reaching, and object exploration behaviors as key activities of daily living in infancy, 2) describe how knowledge of early warning signs for these behaviors may improve early assessment, and 3) discuss interventions that may advance performance of these behaviors. Early intervention should focus on improving performance of these behaviors because: a) these early, interrelated upper extremity behaviors serve an integral role in global learning and development in infancy, b) among at-risk populations, differences have been observed in the quantity and quality of performance of these behaviors and, in many cases, these differences are associated with related perceptual-motor and cognitive delays. This article highlights how early assessment and intervention can target these key early behaviors in populations at risk for upper extremity disabilities, such as those born preterm, with Down syndrome, brachial plexus palsy, or arthrogryposis multiplex congentia. PMID- 25835252 TI - Long term functional outcomes after early childhood pollicization. AB - STUDY DESIGN: Retrospective Cohort INTRODUCTION: Important outcomes of polliciation to treat thumb hypoplasia/aplasia include strength, function, dexterity, and quality of life. PURPOSE OF THE STUDY: To evaluate outcomes and examine predictors of outcome after early childhood pollicization. METHODS: 8 children (10 hands) were evaluated 3-15 years after surgery. Physical examination, questionnaires, grip and pinch strength, Box and Blocks, 9-hole pegboard, and strength-dexterity (S-D) tests were performed. RESULTS: Pollicized hands had poor strength and performance on functional tests. Six of 10 pollicized hands had normal dexterity scores but less stability in maintaining a steady state force. Predictors of poorer outcomes included older age at surgery, reduced metacarpophalangeal and interphalangeal range of motion, and radial absence. DISCUSSION: Pollicization resulted in poor strength and overall function, but normal dexterity was often achieved using altered control strategies. CONCLUSIONS: Most children should obtain adequate dexterity despite weakness after pollicization except older or severely involved children. LEVEL OF EVIDENCE: IV. PMID- 25835253 TI - Perspectives on glenohumeral joint contractures and shoulder dysfunction in children with perinatal brachial plexus palsy. AB - Shoulder joint deformities continue to be a challenging aspect of treating upper plexus lesions in children with perinatal brachial plexus palsy (PBPP). It is increasingly recognized that PBPP affects the glenohumeral joint specifically, and that abnormal scapulothoracic movements are a compensatory development. The pathophysiology and assessment of glenohumeral joint contractures, the progression of scapular dyskinesia and skeletal dysplasia, and current shoulder imaging techniques are reviewed. PMID- 25835254 TI - Current and emerging strategies for treatment of childhood dystonia. AB - Childhood dystonia is a movement disorder characterized by involuntary sustained or intermittent muscle contractions causing twisting and repetitive movements, abnormal postures, or both (Sanger et al, 2003). Dystonia is a devastating neurological condition that prevents the acquisition of normal motor skills during critical periods of development in children. Moreover, it is particularly debilitating in children when dystonia affects the upper extremities such that learning and consolidation of common daily motor actions are impeded. Thus, the treatment and rehabilitation of dystonia is a challenge that continuously requires exploration of novel interventions. This review will initially describe the underlying neurophysiological mechanisms of the motor impairments found in childhood dystonia followed by the clinical measurement tools that are available to document the presence and severity of symptoms. Finally, we will discuss the state-of-the-art of therapeutic options for childhood dystonia, with particular emphasis on emergent and innovative strategies. PMID- 25835256 TI - The implications of injury in the developing nervous system on upper extremity function. AB - STUDY DESIGN: Literature review. PURPOSE: The corticospinal system (CS) and peripheral nervous system (PNS) are common sites of damage during the early stages of life. The prenatal or immediately prenatal period is the most common time for damage to occur. Here we briefly review the basic features of the development of the CS and the PNS and the clinical consequences of injury to or improper development of these systems on upper extremity (UE) function. RESULTS: The proper development of both the CS and PNS is necessary to achieve adequate function of the (UE). Injury or improper development of these systems can lead to upper extremity dysfunction and limit participation in activities of daily living. CONCLUSIONS: Both the PNS and CS play major roles in the proper functioning of the UE. A better understanding of their roles and common developmental disorders is needed to move rehabilitation of motor impairments forward. PMID- 25835255 TI - Innovative evaluation of dexterity in pediatrics. AB - STUDY DESIGN: Review paper. INTRODUCTION: Hand dexterity is multifaceted and essential to the performance of daily tasks. Timed performance and precision demands are the most common features of quantitative dexterity testing. Measurement concepts such as rate of completion, in-hand manipulation and dynamic force control of instabilities are being integrated into assessment tools for the pediatric population. PURPOSE: To review measurement concepts inherent in pediatric dexterity testing and introduce concepts that are infrequently measured or novel as exemplified with two assessment tools. METHODS: Measurement concepts included in common assessment tools are introduced first. We then describe seldom measured and novel concepts embedded in two instruments; the Functional Dexterity Test (FDT) and the Strength-Dexterity (SD) Test. DISCUSSION: The inclusion of novel yet informative tools and measurement concepts in our assessments could aid our understanding of atypical dexterity, and potentially contribute to the design of targeted therapy programs. PMID- 25835257 TI - Fundamental Study of Emulsions Stabilized by Soft and Rigid Particles. AB - Two distinct uniform hybrid particles, with similar hydrodynamic diameters and comparable zeta potentials, were prepared by copolymerizing N-isopropylacrylamide (NIPAM) and styrene. These particles differed in their styrene to NIPAM (S/N) mass ratios of 1 and 8 and are referred to as S/N 1 and S/N 8, respectively. Particle S/N 1 exhibited a typical behavior of soft particles; that is, the particles shrank in bulk aqueous solutions when the temperature was increased. As a result, S/N 1 particles were interfacially active. In contrast, particle S/N 8 appeared to be rigid in response to temperature changes. In this case, the particles showed a negligible interfacial activity. Interfacial shear rheology tests revealed the increased rigidity of the particle-stabilized film formed at the heptane-water interface by S/N 1 than S/N 8 particles. As a result, S/N 1 particles were shown to be better emulsion stabilizers and emulsify a larger amount of heptane, as compared with S/N 8 particles. The current investigation confirmed a better performance of emulsion stabilization by soft particles (S/N 1) than by rigid particles (S/N 8), reinforcing the importance of controlling softness or deformability of particles for the purpose of stabilizing emulsions. PMID- 25835259 TI - Increased O-GlcNAcylation of NF-kappaB Enhances Retinal Ganglion Cell Death in Streptozotocin-induced Diabetic Retinopathy. AB - PURPOSE: Hyperglycemia results in increased flux through the hexoxamine biosynthetic pathway. We examined whether hyperglycemia increases O-GlcNAcylation in the diabetic retina and whether elevated O-GlcNAcylation of nuclear factor (NF)-kappaB increases apoptosis of retinal ganglion cells (RGCs) in diabetic retinopathy (DR). MATERIALS AND METHODS: Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin. All mice were killed 2 months after injections and expression levels of O-GlcNAcylated proteins, O-linked N-acetylglucosamine transferase (OGT), beta-d-N acetylglucosaminidase and NF-kappaB, and the extent of RGC death were examined. Immunoprecipitations were performed to investigate whether O-GlcNAcylation of NF kappaB led to its activation and RGC death in DR. RESULTS: The expression levels of O-GlcNAcylated proteins and OGT were markedly higher in diabetic retinas than in control retinas. OGT colocalized with NeuN, a RGC-specific marker, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in the ganglion cell layer of diabetic retinas. The p65 subunit of NF kappaB was O-GlcNAcylated and the level of O-GlcNAcylated p65 was higher in diabetic retinas than in control retinas. CONCLUSION: The present data suggest that hyperglycemia increases O-GlcNAcylation in DR and that O-GlcNAcylation of the p65 subunit of NF-kappaB is involved in hyperglycemia-induced NF-kappaB activation and RGC death in DR. PMID- 25835258 TI - Local electrostatic interactions determine the diameter of fusion pores. AB - In regulated exocytosis vesicular and plasma membranes merge to form a fusion pore in response to stimulation. The nonselective cation HCN channels are involved in the regulation of unitary exocytotic events by at least 2 mechanisms. They can affect SNARE-dependent exocytotic activity indirectly, via the modulation of free intracellular calcium; and/or directly, by altering local cation concentration, which affects fusion pore geometry likely via electrostatic interactions. By monitoring membrane capacitance, we investigated how extracellular cation concentration affects fusion pore diameter in pituitary cells and astrocytes. At low extracellular divalent cation levels predominantly transient fusion events with widely open fusion pores were detected. However, fusion events with predominately narrow fusion pores were present at elevated levels of extracellular trivalent cations. These results show that electrostatic interactions likely help determine the stability of discrete fusion pore states by affecting fusion pore membrane composition. PMID- 25835260 TI - [Budd-Chiari syndrome as clinical expression of POEMS syndrome]. PMID- 25835261 TI - [Severe bone marrow aplasia due to triple therapy for hepatitis C virus infection: Apropos of a case]. PMID- 25835262 TI - Attitude and perception of urology by medical students at the end of their medical school: An appraisal from Saudi Arabia. AB - OBJECTIVES: To evaluate the attitude and perception of the graduates of King Saud University (KSU) College of Medicine regarding the quality of their urology rotation, urology exposure during this rotation, confidence about managing common conditions, and career prospects. MATERIALS AND METHODS: In 2013, a questionnaire regarding the students' perceptions of urology rotation was developed and E mailed to all final (5(th)) year medical students and interns of KSU College of Medicine, Riyadh, Saudi Arabia. Individual responses were recorded, tabulated and compared using descriptive statistics. RESULTS: The overall response rate was 67.7%. Respondents included 101 (49.8%) males and 102 (50.2%) females. All the respondents but 18 (8.9%) were enrolled in a urology rotation during undergraduate years. Only 27 (13.3%) were willing to choose urology specialty as a future career. Significant gender differences were found regarding choice of urology as a future career (P = 0.002) and the need for more urology exposure during surgical rotation (P = 0.002). CONCLUSIONS: Knowledge of medical school graduates is insufficient in many urologic subjects, and there is a need for more urology exposure. Social reasons and lack of knowledge about urology hinder the choice of urology specialty as a future career. Clearance of learning objectives, immediate and prompt feedback on performance and adequate emphasis of common problems and ambulatory care are some aspects that should be taken into account by curriculum planners as they consider improvements to urology rotation program. PMID- 25835263 TI - Association between Smoking and Uveitis: Results from the Pacific Ocular Inflammation Study. AB - PURPOSE: To assess whether cigarette smoking is associated with the development of uveitis in a population-based setting. DESIGN: Retrospective, population based, case-control study. PARTICIPANTS: Patients aged >= 18 years who were seen at a Kaiser Permanente Hawaii clinic between January 1, 2006, and December 31, 2007. Analysis included 100 confirmed incident uveitis cases, 522 randomly selected controls from the general Kaiser Hawaii population, and 528 randomly selected controls from the Kaiser Hawaii ophthalmology clinic. METHODS: International Classification of Diseases, 9th revision (ICD-9), diagnosis codes were used to identify possible uveitis cases. A uveitis fellowship-trained ophthalmologist then conducted individual chart review to confirm case status. Multivariate logistic regression models were used to evaluate the association between smoking and uveitis, adjusting for age, sex, race, and socioeconomic status. MAIN OUTCOME MEASURES: Development of uveitis. RESULTS: Current smokers had a 1.63 (95% confidence interval [CI], 0.88-3.00; P = 0.12) and 2.33 (95% CI, 1.22-4.45; P = 0.01) times greater odds of developing uveitis compared with those who never smoked using the general and ophthalmology control groups, respectively. The association was even stronger with noninfectious uveitis, which yielded odds ratios of 2.10 (95% CI, 1.10-3.99; P = 0.02) and 2.96 (95% CI, 1.52 5.77; P = 0.001) using the general and ophthalmology control groups, respectively. CONCLUSIONS: Cigarette smoking is significantly associated with new onset uveitis within a population-based setting. The association was stronger for noninfectious uveitis. Given the well-established risks of smoking with regard to other inflammatory disorders, these results reaffirm the importance of encouraging patients to avoid or cease smoking. PMID- 25835264 TI - Using linkage to electronic primary care records to evaluate recruitment and nonresponse bias in the Avon Longitudinal Study of Parents and Children. PMID- 25835265 TI - In vivo kinematic effects of ball and socket third condyle as a post-cam mechanism in tri-condylar knee implants. AB - BACKGROUND: Tri-condylar implants containing a ball and socket third condyle as a post-cam mechanism were developed to accommodate a lifestyle requiring frequent deep flexion activities. The purpose of the current study was to examine the kinematic effects of the ball and socket third condyle during a deep knee bend activity, and to confirm the contact status of the ball and socket joint. METHODS: Seventeen knees implanted with tri-condylar implants were analyzed using a 3D to 2D registration approach. A distance of less than 1mm denoted ball and socket contact. Medial and lateral contact positions and axial rotation were compared before and after contact. Moreover, the contact position at the third condyle and the center of the ball joint were analyzed. RESULTS: After the third condyle contact, posterior translation of the medial and lateral contact positions increased considerably. Meanwhile, the angular rotation remained still. The center of the third condyle did not move after contact, and the contact position at the third condyle remained low. CONCLUSIONS: The third condyle induced intensive posterior translation of both condyles, and did not prevent axial rotation, which was proved to work properly as a posterior stabilizing post cam mechanism. PMID- 25835266 TI - An in-vitro-in-vivo model for the transdermal delivery of cholecalciferol for the purposes of rodent management. AB - The natural selection of anticoagulant resistant rats has resulted in a need for an alternative to anticoagulant rodenticides which differs in both active ingredient and in the method of dosing. Cholecalciferol toxicity to rodents using the dermal route is demonstrated using a variety of penetration enhancing formulations in two in-vitro models and finally in-vivo. A 1 ml dose of 50/50 (v/v) DMSO/ethanol containing 15% (v/v) PEG 200 and 20% (w/v) cholecalciferol was judged as 'sufficiently effective' in line with the European Union's Biocidal Products Regulation (No. 528/2012) during in-vivo studies. This dose was found to cause 100% mortality in a rat population in 64.4h (+/- 22h). PMID- 25835267 TI - Product and process understanding to relate the effect of freezing method on glycation and aggregation of lyophilized monoclonal antibody formulations. AB - The objective of the study was to analyze the effect of controlled and uncontrolled freezing step of a lyophilization process on the extent of non enzymatic glycation and aggregation of an IgG1 formulation at two concentrations (1mg/ml and 20mg/ml). The degree of glycation (%) was determined through boronate affinity chromatography and its effect on the formation of soluble aggregates and higher molecular weight species was studied using dynamic light scattering (DLS) and size exclusion chromatography with multi-angle light scattering (SEC-MALS). The effect of non-enzymatic glycation on the secondary structure of the formulations was also studied using circular dichroism (CD) spectroscopy and Fourier transform infrared (FT-IR) spectroscopy. Results indicated that controlled nucleation yielded higher residual moisture contents and significantly lower specific surface areas for the two monoclonal antibody concentrations compared with uncontrolled nucleation cycle (p<0.05). For the two concentrations, uncontrolled nucleation resulted in significantly higher levels of glycation compared with controlled nucleation samples (p<0.05). Further, it was observed that higher storage temperatures (25 degrees C/60% RH) versus 5 degrees C resulted in higher glycation. Even though SEC-MALS analyses of the low concentrated formulations did not reveal the formation of higher molecular weight species, DLS analyses at two storage conditions revealed increases in the hydrodynamic radii and polydispersity index of the reconstituted formulations, suggesting the onset of formation of smaller species in the formulations. CD spectroscopy did not reveal any differences in the secondary structure of the mAb for the two concentrations after lyophilization. In conclusion, the freezing step method impacted the extent of glycation in lyophilized samples and the hydrolyzed component of sucrose was critical for increasing glycation. Even though some level of glycation was observed in lyophilized samples, the native structure of the protein was not affected. Further, it was demonstrated that storage of both lyophilized cakes and reconstituted formulations at higher temperatures could increase the extent of glycation in monoclonal antibody formulations. PMID- 25835268 TI - Predicting the dissolution behavior of pharmaceutical tablets with NIR chemical imaging. AB - Near infrared chemical imaging (NIRCI) is a common analytical non-destructive technique for the analysis of pharmaceutical tablets. This powerful process analytical technology provides opportunity to chemically understand the sample, and also to determine spatial distribution and size of ingredients in a tablet. NIRCI has been used to link disintegrant, excipients and active pharmaceutical ingredient (API) to tablet dissolution, as disintegrants play an important role in tablet disintegration, resulting in API dissolution. This article describes a specific methodology to predict API dissolution based on disintegrant chemical information obtained with NIRCI. First, several tablet batches with different disintegrant characteristics were produced. Then, NIRCI was successfully used to provide chemical images of pharmaceutical tablets. A PLS regression model successfully predicted dissolution profiles. These results show that NIRCI is a robust and versatile technique for measuring disintegrant properties in tablet formulations and predicting their effects on dissolution profiles. Thus, NIRCI could routinely complement and eventually replace dissolution testing by monitoring a critical material attribute: disintegrant content. PMID- 25835269 TI - Superficial venous disease and combined hormonal contraceptives: a systematic review. AB - BACKGROUND: Superficial venous disease, which includes superficial venous thrombosis (SVT) and varicose veins, may be associated with a higher risk of venous thromboembolism (VTE). Use of combined hormonal contraceptives (CHCs) has been associated with an increased risk of VTE compared with nonuse. Little is known about whether use of CHCs by women with superficial venous disease may further elevate the risk of VTE. OBJECTIVES: To investigate evidence regarding risk of VTE in women with SVT or varicose veins who use CHCs compared with non CHC users. METHODS: We searched the PubMed database for all English-language articles published from database inception through September 2014. We included primary research studies that examined women with SVT or varicose veins who used CHCs compared to women with these conditions who did not use CHCs. Outcomes of interest included VTE (among women with SVT or varicose veins) and SVT (for those with varicose veins). RESULTS: Two studies were identified that met inclusion criteria. One fair-quality case-control study reported an odds ratio (OR) for VTE of 43.0 (95% confidence interval [CI] 15.5-119.3) among women with SVT using oral contraceptives (OCs) compared with nonusers without SVT. The OR for VTE was also increased for women with SVT not using OCs (OR 5.1; 95% CI 2.8-9.5) and for women without SVT using OCs (OR 4.0; 95% CI 3.3-4.7), compared with nonusers without SVT. One fair-quality cohort study demonstrated that women with varicose veins had an increased rate of VTE with use of OCs (1.85 per 1000 women-years [WY]), compared with users without varicose veins (0.84 per 1000 WY), nonusers with varicose veins (0.31 per 1000 WY) and nonusers without varicose veins (0.19 per 1000 WY). This study also demonstrated that women with varicose veins had an increased rate of SVT with use of OCs (10.63 per 1000 WY), compared with nonusers with varicose veins (7.59 per 1000 WY), users without varicose veins (1.89 per 1000 WY) and nonusers without varicose veins (0.77 per 1000 WY). CONCLUSION: Two studies suggest increased risk of VTE among OC users with superficial venous disease; however, no definitive conclusions can be made due to the limited number of studies and limitations in study quality. Theoretical concerns need to be clarified with further research on whether the risk of significant sequelae from superficial venous disease among CHC users is related to clinical severity of disease and underlying factors. PMID- 25835270 TI - Blocking the entrance of AMP pocket results in hormetic stimulation of imidazolium-based ionic liquids to firefly luciferase. AB - The hormesis characterized by low-concentration stimulation and high concentration inhibition has gained significant interest over the past decades. Some organic solvents and ionic liquids (ILs) have hormetic concentration responses (HCR) to bioluminescence such as firefly luciferase and Vibrio qinghaiensis sp.-Q67. In this study, we determine the effects of 1-alkyl-3 methylimidazolium chlorine ILs ([Cnmim]Cl, n=2, 4, 6, 8, 10 and 12) to firefly luciferase in order to verify the mechanism of hormesis. The luminescence inhibition toxicity tests show that the stimulation effects of [C8mim]Cl and [C10mim]Cl are obvious, [C6mim]Cl and [C12mim]Cl are minor, and [C2mim]Cl and [C4mim]Cl are rare. The enzyme kinetics show that [C8mim]Cl and [C10mim]Cl are the competitive inhibitors with ATP while [C2mim]Cl and [C4mim]Cl are the noncompetitive ones. Molecular dynamics simulation results reveal that imidazolium rings of [C8mim] and [C10mim] locate at the entrance of luciferin pocket which is adjacent to AMP pocket, while alkyl-chains insert into the bottom of the luciferin pocket. Combining the results from inhibition test, kinetics assay and molecular simulation, we can deduce that occupying AMP pocket by imidazolium ring is responsible for hormetic stimulation. PMID- 25835271 TI - Biochemical and physiological responses of Carcinus maenas to temperature and the fungicide azoxystrobin. AB - Research on the effects of thermal stress is currently pertinent as climate change is expected to cause more severe climate-driven events. Carcinus maenas, a recognised estuarine model organism, was selected to test temperature-dependence of azoxystrobin toxicity, a widely applied fungicide. Crabs' responses were assessed after a 10-d acclimation at different temperatures (5 degrees C, 22 degrees C, and 27 degrees C) of which the last 72h were of exposure to an environmental concentration of azoxystrobin. SOD and GST activities, mitochondrial oxygen consumption rates and protein content, as well as the Coupling Index were determined. The hypothesis proposed that extreme temperatures (5 degrees C and 27 degrees C) and azoxystrobin would affect crabs' responses. Results showed statistically significant different effects of SOD and all oxygen rates measured promoted by temperature, and that neither 30.3MUgL(-1) of azoxystrobin nor the combined effect were crab-responsive. Protein content at 5 degrees C was statistically higher when compared with the control temperature (22 degrees C). The Coupling Index revealed both a slight and a drastic decrease of this index promoted by 5 degrees C and 27 degrees C, respectively. Regarding azoxystrobin effects, at 22 degrees C, this index only decreased slightly. However, at extreme temperatures it fell 47% at 5 degrees C and slightly increased at 27 degrees C. Results provided evidence that crabs' responses to cope with low temperatures were more effective than their responses to cope with high temperatures, which are expected in future climate projections. Moreover, crabs are capable of handling environmental concentrations of azoxystrobin. However, the Coupling Index showed that combined stress factors unbalance crabs' natural capability to handle a single stressor. PMID- 25835272 TI - Overview of current multiparametric magnetic resonance imaging approach in the diagnosis and staging of prostate cancer. AB - This article is primarily based on the utility and validity of multiparametric magnetic resonance imaging in the diagnosis and staging of prostate gland tumors. Multiparametric magnetic resonance imaging is an emerging, useful approach for evaluating and detecting prostate cancers. It also aids in the management of a tumor and improve the care and follow-up of patients. PMID- 25835273 TI - Aberrant brain activation of error processing among adults with attention deficit and hyperactivity disorder. AB - Individuals with adult attention deficit/hyperactivity disorder (ADHD) have a deficit in their cognitive control. The aim of this study was to reveal the brain correlates of the deficits in response inhibition or error processing in adult ADHD. A total of 29 adults with ADHD and 25 control individuals were recruited. They completed an event-related-design Go/No-go task under functional magnetic resonance imaging scanning. Both the ADHD group and the control group exhibited activation of the frontostriatal network when processing response inhibition. They also exhibited activation of the frontoinsula cortex and anterior cingulate in error processing. Adults with ADHD have a lower brain activation of error processing over the right inferior frontal lobe adjacent to the insula than control individuals. The altered frontoinsula cortex activation may represent the mechanism of error processing deficit among adults with ADHD. PMID- 25835274 TI - Comparison of the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 test v1.0 with v2.0 in HIV-1 viral load quantification. AB - Roche modified the COBAS AmpliPrep/COBAS TaqMan human immunodeficiency virus type 1 (HIV-1) test version 1.0 (CAP/CTM v1.0), resulting in the COBAS AmpliPrep/COBAS TaqMan HIV-1 test version 2.0 (CAP/CTM v2.0). The aim of this study was to evaluate the performance of the CAP/CTM v2.0 and to compare this performance with that of the CAP/CTM v1.0. The study was conducted in a small local study group in Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. A total of 86 plasma samples from HIV-1-seropositive patients were tested using the two assays. The correlation and concordance of results between the two assays were calculated. The CAP/CTM v2.0 generated higher values than did the CAP/CTM v1.0, and five samples (5.8%) yielded a difference of > 1 log10 copies/mL. In addition, our data show that CAP/CTM v1.0 and CAP/CTM v2.0 yielded relatively consistent values for 23 samples with low viral loads (< 200 copies/mL). Furthermore, when viral loads were in a medium range (2-5 log10 copies/mL), the results of the two assays were more compatible. This study shows a good correlation between CAP/CTM v1.0 and v2.0 in HIV-1 viral load measurement. Further attention must be paid to those cases in which measured viral loads present larger differences between the two assays. PMID- 25835275 TI - Association between prostatic resistive index and cardiovascular risk factors in patients with benign prostatic hyperplasia. AB - We evaluated the relationship between prostatic resistive index (RI) and cardiovascular system (CVS) risk factors in patients with benign prostatic hyperplasia. The study included 120 patients who were attending our outpatient clinic with lower urinary tract symptoms related to benign prostatic hyperplasia. The clinical, laboratory, anthropometric data, and CVS risk factors (hypertension, diabetes mellitus, metabolic syndrome, history of CVS events, and smoking) of the patients were evaluated regarding the association between prostate RI level by regression analyses. The prostatic RI levels of the patients were measured using power Doppler imaging. In univariate regression analysis, there were statistically significant relationships between prostatic RI levels and the patients' age, International Prostate Symptom Score, hip circumference, fasting blood glucose, prostate specific antigen, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total prostate volume, uroflowmetric maximal flow rate, and all investigated CVS risk factors (p < 0.05). The prostatic RI levels were found to be associated with fasting blood glucose and total prostate volume, and also with CVS risk factors including only metabolic syndrome and cigarette smoking in the multivariate regression analysis. Our results showed that prostatic RI level is significantly related to metabolic syndrome and smoking among the investigated CVS risk factors. PMID- 25835276 TI - Increased carotid artery intima-media thickness in patients with tympanosclerosis: Common risk factors with atherosclerosis? AB - We investigated the relationship between tympanosclerosis, known atherosclerotic risk factors, and the intima-media thickness of bilateral carotid arteries using ultrasonography. A total of 122 patients admitted to our clinic with chronic otitis media between 2005 and 2010 were included in the study. The study group consisted of 61 patients with tympanosclerosis; the control group comprised 61 patients without tympanosclerosis. Internal carotid artery intima-media thickness (CAIMT), total cholesterol, triglyceride, low- and high-density lipoprotein cholesterol, C-reactive protein, and homocysteine levels were measured in all patients. Homocysteine, low-density lipoprotein, total cholesterol, and triglyceride levels in the study group were higher compared with those of the control group (p < 0.05). Right and left CAIMT was greater in the study group versus the control group (p <= 0.001). In conclusion, atherosclerosis and tympanosclerosis were associated with identical risk factors; in the tympanosclerosis group, CAIMT was increased significantly. PMID- 25835277 TI - Modified Mitchell osteotomy alone does not have higher rate of residual metatarsalgia than combined first and lesser metatarsal osteotomy. AB - Transfer metatarsalgia (TM) is a common forefoot disorder secondary to hallux valgus (HV). Some authors suggest that a combined lesser metatarsal osteotomy while undergoing HV surgery improves metatarsalgia, whereas others concluded that isolated HV corrective osteotomy can improve symptomatic metatarsalgia. The main purpose of this retrospective study was to compare clinical outcomes in patients with and without combined lesser metatarsal osteotomy while receiving HV correction surgery. We retrospectively reviewed the patients who underwent osteotomy for HV correction between January 2000 and December 2010. All patients underwent HV correction with modified Mitchell osteotomy. Clinical evaluations including the American Orthopaedic Foot and Ankle Society score and residual metatarsalgia were assessed, and radiographic measurements were carried out. Sixty-five patients (83 feet) meeting the selection criteria were enrolled. Thirty feet receiving a combined lesser metatarsal osteotomy were classified as the combined surgery (CS) group, and the others were classified as the control (CN) group (53 feet). The overall rate of persistent symptomatic metatarsalgia was 19.28% after operative treatment. There were six feet with residual metatarsalgia in the CS group, and 10 feet in the CN group. There was no significant difference in the rate of persistent symptoms between the two groups (p = 0.9). According to this result, modified Mitchell osteotomy alone did not have a higher rate of residual metatarsalgia than CS. We also found that the average recovery rate of TM was about 80.7% and those patients whose preoperative HV angle was > 30 degrees had the higher risk of residual metatarsalgia after surgery. PMID- 25835278 TI - The psychosocial indicators related to neuroticism in both sexes: A study of incoming university students. AB - Neuroticism may have great impact on mental and physical health in both sexes. The aims of this study were to explore whether relationships between neuroticism scores and psychosocial indicators as well as metabolic syndrome in a population of incoming university students existed in the different sexes. In total, 4266 incoming students were included in this study. The test battery comprised a self administered structured questionnaire, including the neuroticism subscale of the Maudsley Personality Inventory, the 12-item Chinese Health Questionnaire, the Chinese Internet Addiction Scale-Revision, the measurement of support functions, and the Pittsburgh Sleep Quality Index. Multivariate logistic regression showed that higher Pittsburgh Sleep Quality Index scores, higher Chinese Internet Addiction Scale-Revision scores, and higher 12-item Chinese Health Questionnaire scores were significantly correlated with neuroticism in both sexes, but lower perceived routine support: measurement of support functions scores were associated only with the male participants. No significant differences were found in terms of body mass index or other metabolic profiles. Individuals with poorer mental health and a poorer personal lifestyle had higher neuroticism scores, and sex effects may influence the scale of perceived social support in the neuroticism group. However, the lack of an association between neuroticism score and metabolic syndrome may be due to the recruitment of younger participants in this study. PMID- 25835279 TI - Establish a perioperative check forum for peripheral intravenous access to prevent the occurrence of phlebitis. AB - The prevalence of intravenous (IV) catheter-related infections is 0.5 per 1000 device days, and these infections cause tenderness, erythema, swelling and phlebitis. Catheter-related bloodstream infections (CRBSI) may independently increase hospital costs and length of stay; the aim of the study was to set up a standard operating procedure (SOP) for the maintenance of peripheral vein catheter patency and the prevention of IV catheter-related complications. This is a retrospective study, enrolling patients who received anesthesia between April 2010 and January 2011. The study included 1 month of pretest phase, and 3 months each of "notification" phase, "observation" phase and "end" phase, respectively. The cannulations were set up by surgical ward nurses following the SOP on establishing peripheral intravenous catheter in our hospital. The cannulation sites were then examined before surgery and postoperatively by registered nurse anesthetists using the Baxter Scale. We also tried to set up a feedback circuit to let ward nurses know about the IV patency rate. As a result, 14,682 patients were enrolled in the study. The incidence of IV therapy-related adverse events was 0.78% in the notification phase, 0.43% in the observation phase, and 0.13% in the end phase. Overall IV therapy-related events declined significantly (p < 0.01), and the presence of phlebitis was associated with age (p < 0.05). An SOP established to assess IV patency through a checklist can reduce phlebitis and improve quality. The checklist increases ward nurses' and nurse anesthetists' awareness of IV patency, and the feedback circuit substantially reduces IV event rate. PMID- 25835280 TI - Enantioselective A(3) reactions of secondary amines with a Cu(I)/acid-thiourea catalyst combination. AB - Pyrrolidine and related amines undergo asymmetric A(3) reactions in the presence of copper iodide and an easily accessible cocatalyst possessing both a carboxylic acid and a thiourea moiety. Propargylamines are obtained with up to 96% ee, and catalyst loadings can be as low as 1 mol %. Pyrrolidine-derived propargylamines, in the absence of directing groups, can be transformed to the corresponding allenes without loss of enantiopurity. PMID- 25835281 TI - Perinatal overnutrition exacerbates adipose tissue inflammation caused by high fat feeding in C57BL/6J mice. AB - Obesity causes white adipose tissue (WAT) inflammation and insulin resistance in some, but not all individuals. Here, we used a mouse model of early postnatal overfeeding to determine the role of neonatal nutrition in lifelong WAT inflammation and metabolic dysfunction. C57BL/6J mice were reared in small litters of 3 (SL) or normal litters of 7 pups (NL) and fed either regular chow or a 60% high fat diet (HFD) from 5 to 17 weeks. At weaning, SL mice did not develop WAT inflammation despite increased fat mass, although there was an up-regulation of WAT Arg1 and Tlr4 expression. On HFD, adult SL mice had greater inguinal fat mass compared to NL mice, however both groups showed similar increases in visceral fat depots and adipocyte hypertrophy. Despite the similar levels of visceral adiposity, SL-HFD mice displayed greater impairments in glucose homeostasis and more pronounced hepatic steatosis compared to NL-HFD mice. In addition, WAT from SL mice fed a HFD displayed greater crown-like structure formation, increased M1 macrophages, and higher cytokine gene expression. Together, these data suggest that early postnatal overnutrition may be a critical determinant of fatty liver and insulin resistance in obese adults by programming the inflammatory capacity of adipose tissue. PMID- 25835283 TI - Revision rates and speech outcomes following pharyngeal flap surgery for velopharyngeal insufficiency. AB - IMPORTANCE: Velopharyngeal insufficiency in children with cleft palate (and other causes) contributes to difficulty with communication and quality of life. The pharyngeal flap is a workhorse to address hypernasality and nasal air escape. However, there is a paucity of literature on the characteristics of cases that require revision. OBJECTIVE: To measure the revision rate of pharyngeal flaps, compare the preperceptual and postperceptual speech scores, and identify the characteristics of those patients who required revision. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical record review was completed for patients who underwent pharyngeal flap surgery from June 1, 2008, through January 31, 2013, at a tertiary academic center. MAIN OUTCOMES AND MEASURES: Perceptual speech analyses and surgical revision rates. Perceptual speech patterns before and after surgery were compared using nasal air emission and resonance scores. The association between requiring revision surgery and covariates was analyzed using multivariable mixed-effects logistic regression. RESULTS: Sixty-one patients were identified, including 24 boys (39%) and 37 girls (61%). The mean (SD) patient age at the time of pharyngeal flap surgery was 8.2 (6.8) years (range, 3-55 years). Velopharyngeal insufficiency was associated with cleft palate in 51 patients (84%), and 17 patients (28%) had a syndrome. The mean (SD) time to surgery after the speech evaluation was 225 (229) days (range, 14-1341 days). The mean (SD) nasal air emission scores decreased by -1.1 (2.0 [1.1] preoperatively to 0.8 [1.1] postoperatively). The mean (SD) resonance score decreased by -1.5 (2.4 [1.1] preoperatively to 0.9 [1.1] postoperatively; P < .001). Flaps were revised in 12 patients (20%), including port revision in 9, complete flap revision in 2, and flap takedown in 1. The only covariate that was significantly associated with revision rates was increased age at surgery, which was associated with a higher probability of revision surgery (odds ratio, 1.31; 95% CI, 1.03-1.66; P = .04). CONCLUSIONS AND RELEVANCE: Pharyngeal flap surgery, when appropriately selected, was effective at improving speech with a revision rate of 20%, which is comparable to previously published studies. Increased age at the time of the pharyngeal flap surgery was associated with an increased need for revision surgery, supporting evidence that cleft centers should encourage early childhood speech evaluations with consistent documentation and prompt treatment. LEVEL OF EVIDENCE: 3. PMID- 25835282 TI - Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents. AB - RATIONALE: Structural risk factors for obstructive sleep apnea syndrome (OSAS) in adolescents have not been well characterized. Because many adolescents with OSAS are obese, we hypothesized that the anatomic OSAS risk factors would be more similar to those in adults than those in children. OBJECTIVES: To investigate the anatomic risk factors in adolescents with OSAS compared with obese and lean control subjects using magnetic resonance imaging (MRI). METHODS: Three groups of adolescents (age range: 12-16 yr) underwent MRI: obese individuals with OSAS (n = 49), obese control subjects (n = 38), and lean control subjects (n = 50). MEASUREMENTS AND MAIN RESULTS: We studied 137 subjects and found that (1) obese adolescents with OSAS had increased adenotonsillar tissue compared with obese and lean control subjects; (2) obese OSAS adolescents had a smaller nasopharyngeal airway than control subjects; (3) the size of other upper airway soft tissue structures (volume of the tongue, parapharyngeal fat pads, lateral walls, and soft palate) was similar between subjects with OSAS and obese control subjects; (4) although there were no major craniofacial abnormalities in most of the adolescents with OSAS, the ratio of soft tissue to craniofacial space surrounding the airway was increased; and (5) there were sex differences in the pattern of lymphoid proliferation. CONCLUSIONS: Increased size of the pharyngeal lymphoid tissue, rather than enlargement of the upper airway soft tissue structures, is the primary anatomic risk factor for OSAS in obese adolescents. These results are important for clinical decision making and suggest that adenotonsillectomy should be considered as the initial treatment for OSAS in obese adolescents, a group that has poor continuous positive airway pressure adherence and difficulty in achieving weight loss. PMID- 25835284 TI - Spin transition in arrays of gold nanoparticles and spin crossover molecules. AB - We investigate if the functionality of spin crossover molecules is preserved when they are assembled into an interfacial device structure. Specifically, we prepare and investigate gold nanoparticle arrays, into which room-temperature spin crossover molecules are introduced, more precisely, [Fe(AcS-BPP)2](ClO4)2, where AcS-BPP = (S)-(4-{[2,6-(dipyrazol-1-yl)pyrid-4-yl]ethynyl}phenyl)ethanethioate (in short, Fe(S-BPP)2). We combine three complementary experiments to characterize the molecule-nanoparticle structure in detail. Temperature-dependent Raman measurements provide direct evidence for a (partial) spin transition in the Fe(S-BPP)2-based arrays. This transition is qualitatively confirmed by magnetization measurements. Finally, charge transport measurements on the Fe(S BPP)2-gold nanoparticle devices reveal a minimum in device resistance versus temperature, R(T), curves around 260-290 K. This is in contrast to similar networks containing passive molecules only that show monotonically decreasing R(T) characteristics. Backed by density functional theory calculations on single molecular conductance values for both spin states, we propose to relate the resistance minimum in R(T) to a spin transition under the hypothesis that (1) the molecular resistance of the high spin state is larger than that of the low spin state and (2) transport in the array is governed by a percolation model. PMID- 25835285 TI - Spreading pathologies precede cognitive decline in Alzheimer's disease. PMID- 25835286 TI - Alzheimer's disease: distinct stages in neurogenic decline? PMID- 25835287 TI - Reducing beta-amyloid by inhibition of BACE1: how low should you go? PMID- 25835288 TI - Association Between Vitamin K and the Metabolic Syndrome: A 10-Year Follow-Up Study in Adults. AB - CONTEXT: The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with increased risk of diabetes and cardiovascular diseases. Phylloquinone, menaquinones, and vitamin K status are associated with several components of MetS, but the association with MetS has hardly been studied to date. OBJECTIVE: This study aimed to examine whether the intake and/or status of vitamin K is associated with MetS and its components. DESIGN: This study comprised two cohorts, one of 402 women and one of 400 men (age 40-80 y). At followup 625 participants were still alive and willing to participate. Data were analyzed both cross sectionally and longitudinally with Poisson and linear regression adjusted for multiple confounders. Baseline phylloquinone/menaquinone intakes were measured with a validated food frequency questionnaire and vitamin K status with serum desphospho-uncarborxylated matrix-Gla protein level. RESULTS: At baseline 270 (34.5%) participants had MetS and 171 (35.7%) at followup. Cross sectionally, high menaquinones intakes were associated (P(trend) = .08) with a lower prevalence of MetS with a prevalence ratio (PR) of 0.74 (95% confidence interval [CI], 0.54-1.03) for the highest vs the lowest tertile. At followup, the highest tertiles of menaquinones intake (PR = 0.62; 95% CI, 0.40-0.95) and vitamin K status (PR = 0.57; 95% CI, 0.38-0.87) were associated (P(trend) = .01) with a lower occurrence of MetS. These associations were mainly driven by relations with lower triacylglycerol concentrations for menaquinones and lower waist circumference for vitamin K status. Phylloquinone intake was not associated with MetS prevalence. CONCLUSIONS: This study shows that a high intake of menaquinones and high vitamin K status are associated with a lower occurrence of MetS. PMID- 25835289 TI - Genetic and Epigenetic Modulation of Growth Hormone Sensitivity Studied With the IGF-1 Generation Test. AB - CONTEXT: Like all hormones, GH has variable physiological effects across people. Many of these effects initiated by the binding of GH to its receptor (GHR) in target tissues are mediated by the expression of the IGF1 gene. Genetic as well as epigenetic variation is known to contribute to the individual diversity of GH dependent phenotypes through two mechanisms. The first one is the genetic polymorphism of the GHR gene due to the common deletion of exon 3. The second, more recently reported, is the epigenetic variation in the methylation of a cluster of CGs dinucleotides located within the proximal part of the P2 promoter of the IGF-1 (IGF1) gene, notably CG-137. OBJECTIVE: The current study evaluates the relative contribution of these two factors controlling individual GH sensitivity by measuring the response of serum IGF-1 to a GH injection (IGF-1 generation test) in a sample of 72 children with idiopathic short stature. RESULTS: Although the d3 polymorphism of the GHR contributed 19% to the variance of the IGF-1 response, CG-137 methylation in the IGF-1 promoter contributed 30%, the combined contribution of the two factors totaling 43%. CONCLUSION: Our observation indicates that genetic and epigenetic variation at the GHR and IGF-1 loci play a major role as independent modulators of individual GH sensitivity. PMID- 25835290 TI - Spermine alleviates drought stress in white clover with different resistance by influencing carbohydrate metabolism and dehydrins synthesis. AB - The objective of this research was to analyse whether ameliorating drought stress through exogenously applied spermine (Spm) was related to carbohydrate metabolism, dehydrins accumulation and the transcription of genes encoding dehydrins in two white clovers (drought-susceptible cv. 'Ladino' and drought resistant cv. 'Haifa') under controlled drying conditions for 10 days. The results show that the application of Spm effectively alleviates negative effects caused by drought stress in both cultivars. Exogenous Spm led to accumulation of more water-soluble carbohydrates (WSC), sucrose, fructose and sorbitol in both cultivars under drought stress, and also significantly elevated glucose content in leaves of drought-resistant cv. 'Haifa', but had no effect on drought susceptible cv. 'Ladino'. Accordingly, the key enzyme activities of sucrose and sorbitol metabolism changed along with the application of Spm under drought stress. Spm induced a significant increase in sucrose phosphate synthase (SPS) or sorbitol dehydrogenase (SDH) activity, but decrease in sucrose synthetase (SS) activity when two cultivars were subjected to drought. In addition, the improved accumulation of dehydrins induced by exogenous Spm coincided with three genes expression which was responsible for dehydrins synthesis. But Spm-induced transcript level of dehydrin genes increased earlier in cv. 'Ladino' than that in cv. 'Haifa'. Thus, these results suggest that ameliorating drought stress through exogenously applied Spm may be associated with increased carbohydrate accumulation and dehydrins synthesis. There are differences between drought susceptible and -resistant white clover cultivars related to Spm regulation of WSC metabolism and dehydrins expression. PMID- 25835292 TI - Delivering an Automated and Integrated Approach to Combination Screening Using Acoustic-Droplet Technology. AB - Drug combination testing in the pharmaceutical industry has typically been driven by late-stage opportunistic strategies rather than by early testing to identify drug combinations for clinical investigation that may deliver improved efficacy. A rationale for combinations exists across a number of diseases in which pathway redundancy or resistance to therapeutics are evident. However, early assays are complicated by the absence of both assay formats representative of disease biology and robust infrastructure to screen drug combinations in a medium throughput capacity. When applying drug combination testing studies, it may be difficult to translate a study design into the required well contents for assay plates because of the number of compounds and concentrations involved. Dispensing these plates increases in difficulty as the number of compounds and concentration points increase and compounds are subsequently rolled onto additional labware. We describe the development of a software tool, in conjunction with the use of acoustic droplet technology, as part of a compound management platform, which allows the design of an assay incorporating combinations of compounds. These enhancements to infrastructure facilitate the design and ordering of assay-ready compound combination plates and the processing of combinations data from high content organotypic assays. PMID- 25835291 TI - Leptin levels are negatively correlated with 2-arachidonoylglycerol in the cerebrospinal fluid of patients with osteoarthritis. AB - BACKGROUND: There is compelling evidence in humans that peripheral endocannabinoid signaling is disrupted in obesity. However, little is known about the corresponding central signaling. Here, we have investigated the relationship between gender, leptin, body mass index (BMI) and levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the serum and cerebrospinal fluid (CSF) of primarily overweight to obese patients with osteoarthritis. METHODOLOGY/PRINCIPAL FINDINGS: Patients (20 females, 15 males, age range 44-78 years, BMI range 24-42) undergoing total knee arthroplasty for end-stage osteoarthritis were recruited for the study. Endocannabinoids were quantified by liquid chromatography - mass spectrometry. AEA and 2-AG levels in the serum and CSF did not correlate with either age or BMI. However, 2-AG levels in the CSF, but not serum, correlated negatively with CSF leptin levels (Spearman's rho 0.48, P=0.0076, n=30). No such correlations were observed for AEA and leptin. CONCLUSIONS/SIGNIFICANCE: In the patient sample investigated, there is a negative association between 2-AG and leptin levels in the CSF. This is consistent with pre-clinical studies in animals, demonstrating that leptin controls the levels of hypothalamic endocannabinoids that regulate feeding behavior. PMID- 25835293 TI - Dissemination of Methicillin-Susceptible CC398 Staphylococcus aureus strains in a rural Greek area. AB - A large collection of Staphylococcus aureus including a. 745 clinically significant isolates that were consecutively recovered from human infections during 2012-2013, b. 19 methicillin-susceptible (MSSA), randomly selected between 2006-2011 from our Staphylococcal Collection, c. 16 human colonizing isolates, and d. 10 strains from colonized animals was investigated for the presence and the molecular characteristics of CC398. The study was conducted in Thessaly, a rural region in Greece. The differentiation of livestock-associated clade from the human clade was based on canSNPs combined with the presence of the phi3 bacteriophage and the tetM, scn, sak, and chp genes. Among the 745 isolates, two MRSA (0.8% of total MRSA) and thirteen MSSA (2.65% of total MSSA) were found to belong to CC398, while, between MSSA of our Staphylococcal Collection, one CC398, isolated in 2010, was detected. One human individual, without prior contact with animals, was found to be colonized by a MSSA CC398. No CC398 was identified among the 10 S. aureus isolated from animals. Based on the molecular markers, the 17 CC398 strains were equally placed in the livestock-associated and in the human clades. This is the first report for the dissemination of S. aureus CC398 among humans in Greece. PMID- 25835294 TI - Ratiometric analysis of fura red by flow cytometry: a technique for monitoring intracellular calcium flux in primary cell subsets. AB - Calcium flux is a rapid and sensitive measure of cell activation whose utility could be enhanced with better techniques for data extraction. We describe a technique to monitor calcium flux by flow cytometry, measuring Fura Red calcium dye by ratiometric analysis. This technique has several advantages: 1) using a single calcium dye provides an additional channel for surface marker characterization, 2) allows robust detection of calcium flux by minority cell populations within a heterogeneous population of primary T cells and monocytes 3) can measure total calcium flux and additionally, the proportion of responding cells, 4) can be applied to studying the effects of drug treatment, simultaneously stimulating and monitoring untreated and drug treated cells. Using chemokine receptor activation as an example, we highlight the utility of this assay, demonstrating that only cells expressing a specific chemokine receptor are activated by cognate chemokine ligand. Furthermore, we describe a technique for simultaneously stimulating and monitoring calcium flux in vehicle and drug treated cells, demonstrating the effects of the Galphai inhibitor, pertussis toxin (PTX), on chemokine stimulated calcium flux. The described real time calcium flux assay provides a robust platform for characterizing cell activation within primary cells, and offers a more accurate technique for studying the effect of drug treatment on receptor activation in a heterogeneous population of primary cells. PMID- 25835295 TI - Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. AB - Homozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we generated GBA nonsense mutant (GBA-/-) medaka that are completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death in humans and mice lacking GCase activity, GBA-/- medaka survived for months, enabling analysis of the pathological progression. GBA-/- medaka displayed the pathological phenotypes resembling human neuronopathic GD including infiltration of Gaucher cell-like cells into the brains, progressive neuronal loss, and microgliosis. Detailed pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein (alpha-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of alpha-syn did not improve the life span, formation of axonal swellings, neuronal loss, or neuroinflammation in GBA-/- medaka. Taken together, the present study revealed GBA-/- medaka as a novel neuronopathic GD model, the pahological mechanisms of alpha-syn accumulation caused by GCase deficiency, and the minimal contribution of alpha syn to the pathogenesis of neuronopathic GD. PMID- 25835296 TI - The influence of mitigation on sage-grouse habitat selection within an energy development field. AB - Growing global energy demands ensure the continued growth of energy development. Energy development in wildlife areas can significantly impact wildlife populations. Efforts to mitigate development impacts to wildlife are on-going, but the effectiveness of such efforts is seldom monitored or assessed. Greater sage-grouse (Centrocercus urophasianus) are sensitive to energy development and likely serve as an effective umbrella species for other sagebrush-steppe obligate wildlife. We assessed the response of birds within an energy development area before and after the implementation of mitigation action. Additionally, we quantified changes in habitat distribution and abundance in pre- and post mitigation landscapes. Sage-grouse avoidance of energy development at large spatial scales is well documented. We limited our research to directly within an energy development field in order to assess the influence of mitigation in close proximity to energy infrastructure. We used nest-location data (n = 488) within an energy development field to develop habitat selection models using logistic regression on data from 4 years of research prior to mitigation and for 4 years following the implementation of extensive mitigation efforts (e.g., decreased activity, buried powerlines). The post-mitigation habitat selection models indicated less avoidance of wells (well density beta = 0.18 +/- 0.08) than the pre-mitigation models (well density beta = -0.09 +/- 0.11). However, birds still avoided areas of high well density and nests were not found in areas with greater than 4 wells per km2 and the majority of nests (63%) were located in areas with <= 1 well per km2. Several other model coefficients differed between the two time periods and indicated stronger selection for sagebrush (pre-mitigation beta = 0.30 +/- 0.09; post-mitigation beta = 0.82 +/- 0.08) and less avoidance of rugged terrain (pre-mitigation beta = -0.35 +/- 0.12; post-mitigation beta = -0.05 +/- 0.09). Mitigation efforts implemented may be responsible for the measurable improvement in sage-grouse nesting habitats within the development area. However, we cannot reject alternative hypotheses concerning the influence of population density and intraspecific competition. Additionally, we were unable to assess the actual fitness consequences of mitigation or the source-sink dynamics of the habitats. We compared the pre-mitigation and post-mitigation models predicted as maps with habitats ranked from low to high relative probability of use (equal area bins: 1 - 5). We found more improvement in habitat rank between the two time periods around mitigated wells compared to non-mitigated wells. Informed mitigation within energy development fields could help improve habitats within the field. We recommend that any mitigation effort include well-informed plans to monitor the effectiveness of the implemented mitigation actions that assess both habitat use and relevant fitness parameters. PMID- 25835298 TI - Correction: Sugarcane giant borer transcriptome analysis and identification of genes related to digestion. PMID- 25835299 TI - Coarse initial orbit determination for a geostationary satellite using single epoch GPS measurements. AB - A practical algorithm is proposed for determining the orbit of a geostationary orbit (GEO) satellite using single-epoch measurements from a Global Positioning System (GPS) receiver under the sparse visibility of the GPS satellites. The algorithm uses three components of a state vector to determine the satellite's state, even when it is impossible to apply the classical single-point solutions (SPS). Through consideration of the characteristics of the GEO orbital elements and GPS measurements, the components of the state vector are reduced to three. However, the algorithm remains sufficiently accurate for a GEO satellite. The developed algorithm was tested on simulated measurements from two or three GPS satellites, and the calculated maximum position error was found to be less than approximately 40 km or even several kilometers within the geometric range, even when the classical SPS solution was unattainable. In addition, extended Kalman filter (EKF) tests of a GEO satellite with the estimated initial state were performed to validate the algorithm. In the EKF, a reliable dynamic model was adapted to reduce the probability of divergence that can be caused by large errors in the initial state. PMID- 25835297 TI - Function and regulation domains of a newly isolated putative beta-actin promoter from pacific white shrimp. AB - Current development of transgenic shrimp research has been hampered due to the lack of the suitable promoters and efficient transfection methods for crustaceans. A 1642 bp sequence, containing 5'-upstream sequence, exon 1, intron 1 and partial exon 2, which is responsible for transcriptional initiation of the newly reported shrimp beta-actin (actinT1), has been isolated from the Pacific white shrimp (Litopenaeus vannamei) and named as SbaP. To determine its function and potential application in marine biotechnology, the sequence and functional domains were examined by constitutive expression of the luciferase reporter gene. We have identified 5' regions that play a central role in the expression of the beta-actin gene. The proximal promoter (-1642/-1325) contains two highly conserved transcriptional sites, CCAAT box and CArG motif. Two negative (-1140/ 924, -222/-21) and one positive (-810/-425) regulatory elements have been identified in intron1. Transient transfection assay with a construct containing proximal promoter and enhancer (SbaPDelta-222/+1Delta-1325/-924) regions of the shrimp beta-actin coupled with luciferase and EGFP (enhanced green fluorescent protein) showed that the promoter was not only functional in sf21 cells, but promoter activity was more than 8-fold higher than a viral-origin promoter (ie1, white spot syndrome virus immediate early gene promoter). Furthermore, SbaPDelta 222/+1Delta-1325/-924 drove a successful expression of luciferase injection assay in vivo injection and also showed higher promoter activity than the ie1 promoter, suggesting that the expression vectors constructed with SbaPDelta-222/+1Delta 1325/-924 have important potential in gene transfer studies for shrimp and other crustacean species. PMID- 25835300 TI - A simple method for decreasing the liquid junction potential in a flow-through type differential pH sensor probe consisting of pH-FETs by exerting spatiotemporal control of the liquid junction. AB - The liquid junction potential (LJP), the phenomenon that occurs when two electrolyte solutions of different composition come into contact, prevents accurate measurements in potentiometry. The effect of the LJP is usually remarkable in measurements of diluted solutions with low buffering capacities or low ion concentrations. Our group has constructed a simple method to eliminate the LJP by exerting spatiotemporal control of a liquid junction (LJ) formed between two solutions, a sample solution and a baseline solution (BLS), in a flow through-type differential pH sensor probe. The method was contrived based on microfluidics. The sensor probe is a differential measurement system composed of two ion-sensitive field-effect transistors (ISFETs) and one Ag/AgCl electrode. With our new method, the border region of the sample solution and BLS is vibrated in order to mix solutions and suppress the overshoot after the sample solution is suctioned into the sensor probe. Compared to the conventional method without vibration, our method shortened the settling time from over two min to 15 s and reduced the measurement error by 86% to within 0.060 pH. This new method will be useful for improving the response characteristics and decreasing the measurement error of many apparatuses that use LJs. PMID- 25835302 TI - Highly luminescent Sm(III) complexes with intraligand charge-transfer sensitization and the effect of solvent polarity on their luminescent properties. AB - Samarium complexes with the highest quantum yields to date have been synthesized, and their luminescence properties were studied in 12 solvents. Sensitization via a nontriplet intraligand charge-transfer pathway was also successfully demonstrated in solution states with good quantum yields. PMID- 25835301 TI - Brain process for perception of the "out of the body" tactile illusion for virtual object interaction. AB - "Out of the body" tactile illusion refers to the phenomenon in which one can perceive tactility as if emanating from a location external to the body without any stimulator present there. Taking advantage of such a tactile illusion is one way to provide and realize richer interaction feedback without employing and placing actuators directly at all stimulation target points. However, to further explore its potential, it is important to better understand the underlying physiological and neural mechanism. As such, we measured the brain wave patterns during such tactile illusion and mapped out the corresponding brain activation areas. Participants were given stimulations at different levels with the intention to create veridical (i.e., non-illusory) and phantom sensations at different locations along an external hand-held virtual ruler. The experimental data and analysis indicate that both veridical and illusory sensations involve, among others, the parietal lobe, one of the most important components in the tactile information pathway. In addition, we found that as for the illusory sensation, there is an additional processing resulting in the delay for the ERP (event-related potential) and involvement by the limbic lobe. These point to regarding illusion as a memory and recognition task as a possible explanation. The present study demonstrated some basic understanding; how humans process "virtual" objects and the way associated tactile illusion is generated will be valuable for HCI (Human-Computer Interaction). PMID- 25835303 TI - Eu3+-based bridged silsesquioxanes for transparent luminescent solar concentrators. AB - The sol-gel preparation of a bridged silsesquioxane containing europium(III) salts and 2-thenoyltrifluoroacetone has been achieved from a new ethane tetracarboxamide-based organosilane. Free-standing films with thicknesses up to 440 MUm and maximum absolute quantum yield (q) of 0.34 +/- 0.03 (excitation at 320 nm) were prepared by the drop cast method, while thin films (~200-400 nm) spin-coated on glass substrates led to highly luminescent coatings with q = 0.60 +/- 0.02 (excitation at 345 nm). The thin films were tested as planar luminescent solar concentrators and the optimized device displays an optical conversion efficiency of 12.3% in the absorbing spectral region of the active layer (300-380 nm). PMID- 25835304 TI - Database improvements for motor vehicle/bicycle crash analysis. AB - BACKGROUND: Bicycling is healthy but needs to be safer for more to bike. Police crash templates are designed for reporting crashes between motor vehicles, but not between vehicles/bicycles. If written/drawn bicycle-crash-scene details exist, these are not entered into spreadsheets. OBJECTIVE: To assess which bicycle-crash-scene data might be added to spreadsheets for analysis. METHODS: Police crash templates from 50 states were analysed. Reports for 3350 motor vehicle/bicycle crashes (2011) were obtained for the New York City area and 300 cases selected (with drawings and on roads with sharrows, bike lanes, cycle tracks and no bike provisions). Crashes were redrawn and new bicycle-crash-scene details were coded and entered into the existing spreadsheet. The association between severity of injuries and bicycle-crash-scene codes was evaluated using multiple logistic regression. RESULTS: Police templates only consistently include pedal-cyclist and helmet. Bicycle-crash-scene coded variables for templates could include: 4 bicycle environments, 18 vehicle impact-points (opened-doors and mirrors), 4 bicycle impact-points, motor vehicle/bicycle crash patterns, in/out of the bicycle environment and bike/relevant motor vehicle categories. A test of including these variables suggested that, with bicyclists who had minor injuries as the control group, bicyclists on roads with bike lanes riding outside the lane had lower likelihood of severe injuries (OR, 0.40, 95% CI 0.16 to 0.98) compared with bicyclists riding on roads without bicycle facilities. CONCLUSIONS: Police templates should include additional bicycle-crash-scene codes for entry into spreadsheets. Crash analysis, including with big data, could then be conducted on bicycle environments, motor vehicle potential impact points/doors/mirrors, bicycle potential impact points, motor vehicle characteristics, location and injury. PMID- 25835305 TI - WITHDRAWN: Psychosocial interventions for cocaine and psychostimulant amphetamines related disorders. PMID- 25835306 TI - Letter to the editor. PMID- 25835307 TI - Comparing aflibercept, bevacizumab, and ranibizumab for DME: analysis of DRCR Protocol T. PMID- 25835308 TI - Paraneoplastic retinopathy associated with systemic follicular cell lymphoma. AB - The authors describe two rare cases of autoimmune retinopathy associated with follicular cell lymphoma, including a 54-year-old man who experienced nyctalopia for 1 year (patient 1) and a 59-year-old man who had bilateral loss of central vision for 6 months (patient 2). Visual field testing of patient 1 revealed nonspecific defects, and multifocal electroretinogram (ERG) testing showed mildly subnormal amplitudes more pronounced in the left than the right eye. Serologic testing detected antibodies against a 47-kD protein, presumed to be alpha enolase. Goldmann perimetry of patient 2 showed dense central scotomas, and a full-field ERG revealed reduced amplitudes of bright scotopic responses. Serological testing yielded anti-bipolar cell antibodies. A variable presentation of autoimmune retinopathy can occur in the setting of follicular cell lymphoma. Disparate serum autoantibodies may have mediated the pathogenesis of retinal degeneration in these two patients and could explain the difference in course and severity of retinopathy. PMID- 25835309 TI - Localized choroidal thickness variation and pigment epithelial detachment in dome shaped macula with subretinal fluid. AB - The objective of this report is to demonstrate that individuals with dome-shaped macula can develop persistent subretinal fluid due to abrupt changes in the thickness of the choroid, making it unlikely to be reported. Additionally, these patients often have pigment epithelial detachments, suggestive of possible choroidal neo-vascularization. These two qualities can often lead to persistent subretinal fluid that is refractory to treatment. PMID- 25835310 TI - 8 Questions with Dr. Puliafito. PMID- 25835311 TI - Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge. AB - Influenza virus (IV) infection is a major public health problem, causing millions of cases of severe illness and as many as 500 000 deaths each year worldwide. Given the limitations of current prevention or treatment of acute influenza, novel therapies are needed. RNA interference (RNAi) through microRNAs (miRNA) is an emerging technology that can suppress virus replication in vitro and in vivo. Here, we describe a novel strategy for the treatment of infuenza based on RNAi delivered by a replication-defective adenovirus (Ad) vector, derived from chimpanzee serotype 68 (AdC68). Our results showed that artificial miRNAs (amiRNAs) specifically targeting conserved regions of the IV genome could effectively inhibit virus replication in human embryonic kidney 293 cells. Moreover, our results demonstrated that prophylactic treatment with AdC68 expressing amiRNAs directed against M1, M2 or nucleoprotein genes of IV completely protected mice from homologous A/PR8 virus challenge and partially protected the mice from heterologous influenza A virus strains such as H9N2 and H5N1. Collectively, our data demonstrate that amiRNAs targeting the conserved regions of influenza A virus delivered by Ad vectors should be pursued as a novel strategy for prophylaxis of IV infection in humans and animals. PMID- 25835312 TI - North American paragonimiasis: epidemiology and diagnostic strategies. AB - Paragonimiasis is a zoonotic, food-borne trematode infection that affects around 23 million people in Asia, Africa and the Americas. North American paragonimiasis, caused by Paragonimus kellicotti, is a common infection of crustacean-feeding mammals in parts of the USA and Canada. Although infection rates in crayfish are very high in some areas, human infections are rare and depend on the consumption of raw or undercooked crayfish. Human infections can be easily prevented and treated, but proper diagnosis of paragonimiasis is a problem. Paragonimus lung flukes often cause serious disease symptoms before they produce eggs that may be detectable in sputum, bronchoalveolar lavage, stool or histological sections by microscopy or PCR. Antibodies against selected Paragonimus proteins are detectable as early as 2-3 weeks after infection. Therefore, antibody serology is the most promising diagnostic approach for paragonimiasis in North America and elsewhere. PMID- 25835314 TI - Upregulation of BMP-2 expression in peripheral blood mononuclear cells by proinflammatory cytokines and radiographic progression in ankylosing spondylitis. AB - OBJECTIVES: To investigate the effect of inflammation on expressions of bone morphogenetic proteins (BMPs) in peripheral blood mononuclear cells (PBMCs) and its association with individual radiographic changes in patients with ankylosing spondylitis (AS). METHODS: The changes in BMP-2, -4, and -7 gene expressions in PBMCs were measured after stimulation by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The correlation of increase in gene expression with clinical and radiographic findings in patients with AS were analyzed. RESULTS: Both TNF-alpha and IL-1beta could enhance BMP-2 expression in PBMCs from AS patients. Increases in BMP-2, -4, and -7 expressions in PBMCs positively correlated with total modified Stoke Ankylosing Spondylitis Spinal Score (all p < 0.05). Moreover, increases in BMP-2, -4, and -7 gene expressions after TNF-alpha and IL-1beta stimulation were greater among AS patients with versus without severe sacroiliitis (all p < 0.05). Increases in BMP-2 and -7 expressions were greater in PBMCs from 4 patients with total (cervical, thoracic, and lumbar) spinal ankylosis than in the 8 patients who did not have total spinal ankylosis (all p < 0.05). CONCLUSIONS: In AS, inflammation upregulates the expression of BMPs in PBMCs which may lead to the radiographic progression with new bone formation. PMID- 25835315 TI - Therapeutic drug monitoring of cyclosporine microemulsion in patients with corticosteroid-resistant systemic lupus erythematosus. AB - OBJECTIVES: We retrospectively examined how the cyclosporine-A (CSA) microemulsion administration mode affected blood CSA levels, as well as how the dose and blood levels of CSA affected its therapeutic effect against systemic lupus erythematosus (SLE). METHODS: We calculated the area under the blood concentration time curve (AUC) of CSA in 16 patients with corticosteroid resistant SLE, and analyzed its correlation with CSA levels at the blood sampling time points to investigate the optimum monitoring and dosing regimen. RESULTS: The blood CSA level peaked at 2 h after administration (C2) in all patients. AUC0 6, which most markedly reflects the immunosuppressive effect, significantly correlated with C2 (R2 = 0.905), but not with the trough (C0). In concentration/dose ratio (C/D) of CSA, C2/D level was significantly higher when administered once daily before breakfast than when administered in the divided dose after meals (R2 = 0.355, P = 0.015), but not C0/D. During the 6-month follow up, the CSA C2 tended to correlate with improvement in SLE disease activity index 2000 (R2 = 0.633, P = 0.067). CONCLUSIONS: The treatment with a single dose of CSA before breakfast, followed by monitoring of C2, may be useful for improving the therapeutic effect in patients with corticosteroid-resistant SLE. PMID- 25835316 TI - [Distal clavicle and acromioclavicular joint]. PMID- 25835317 TI - Design, Synthesis, and Structure-Activity Relationship Studies of 3 (Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as a New Class of Src Inhibitors with Potent Activities in Models of Triple Negative Breast Cancer. AB - A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 MUM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues. PMID- 25835318 TI - Vitamin D3 improves decline in cognitive function and cholinergic transmission in prefrontal cortex of streptozotocin-induced diabetic rats. AB - Complications of diabetes mellitus include cognitive impairments and functional changes in the brain. The present study aimed to investigate the possible beneficial effect of vitamin D3 on episodic memory and cholinergic transmission in the prefrontal cortex of streptozotocin-induced diabetic rats. Thirty male Wistar rats (150-200 g) were included into control, diabetic and diabetic supplemented with vitamin D3 groups. Diabetes was induced by single intraperitoneal injection of streptozotocin 45 mg/kg in citrate buffer. Vitamin D3 was administered orally in a dose of 500 IU/kg/day in corn oil for 10 weeks. Then rats were subjected to novel object recognition test to examine for episodic memory. Animals were sacrificed under diethyl ether anesthesia and prefrontal cortices were dissected to measure the activity of choline acetyl transferase (CAT) and acetyle choline esterase (ACE) enzymes to assess for cholinergic transmission. Diabetic rats spent significantly less time exploring the novel object compared to control animals. Vitamin D3 significantly attenuated the diabetes-induced impairment so that animals again spent significantly more time exploring the novel object. The CAT activity was significantly decreased in diabetic animals while the ACE activity was significantly increased compared to control non-diabetic animals. Diabetes-induced alterations in enzyme activity in the prefrontal cortex were mitigated by vitamin D3 supplementation. The present findings demonstrate the potential effect of vitamin D3 supplementation on cognitive function in diabetic animals. It is possible that this effect is mediated through enhancing the prefrontal cortex cholinergic transmission. PMID- 25835319 TI - Motor cortex guides selection of predictable movement targets. AB - The present paper asks whether the motor cortex contributes to prediction-based guidance of target selection. This question was inspired by recent evidence that suggests (i) recurrent connections from the motor system into the attentional system may extract movement-relevant perceptual information and (ii) that the motor cortex cannot only generate predictions of the sensory consequences of movements but may also operate as predictor of perceptual events in general. To test this idea we employed a choice reaching task requiring participants to rapidly reach and touch a predictable or unpredictable colour target. Motor cortex activity was modulated via transcranial direct current stimulation (tDCS). In Experiment 1 target colour repetitions were predictable. Under such conditions anodal tDCS facilitated selection versus sham and cathodal tDCS. This improvement was apparent for trajectory curvature but not movement initiation. Conversely, where no predictability of colour was embedded reach performance was unaffected by tDCS. Finally, the results of a key-press experiment suggested that motor cortex involvement is restricted to tasks where the predictable target colour is movement-relevant. The outcomes are interpreted as evidence that the motor system contributes to the top-down guidance of selective attention to movement targets. PMID- 25835320 TI - Cocaine counteracts LPS-induced hypolocomotion and triggers locomotor sensitization expression. AB - Neuroimmune signalling underlies addiction and comorbid depression. Clinical observations indicate that infections and chronic lesions are more frequent in drug users and elevated inflammatory states are evident in cocaine dependents. Therefore, lipopolysaccharide (LPS) and inflammatory cytokines represent an important tool for the investigation of sickness, depressive illness and addiction behaviour. A major component of addiction is the progressive and persistent increase in locomotor activity after repeated drug administration and even prolonged periods of abstinence. The aim of this study was to investigate the response of locomotor sensitization when a non-sensitizing dose of cocaine is paired with a systemic inflammatory stimulus. LPS and cocaine were administered intraperitonealy in young-adult male C57bl/6 mice during a 5-day acquisition phase. After a 48-h withdrawal period all groups were challenged with cocaine to evaluate locomotor expression. During the acquisition phase, the LPS-treated groups displayed characteristic hypolocomotion related to sickness behaviour. The low dose of cocaine did not increase the distance travelled, characterizing a non sensitization dose. Groups that received both LPS and cocaine did not display hypolocomotion, indicating that cocaine might counteract hypolocomotion sickness behaviour. Moreover, during challenge, only these animals expressed locomotor sensitization. Our results indicate that LPS could facilitate the expression of locomotor sensitization in mice and that the immune system may modulate cocaine induced sensitization. PMID- 25835321 TI - Role of dopamine D1-like receptor within the nucleus accumbens in acute food deprivation- and drug priming-induced reinstatement of morphine seeking in rats. AB - Dopamine is a predominant neurotransmitter in the nervous system, which plays an important role in both drug priming- and cue-induced reinstatement of cocaine and heroin seeking. Therefore, in the present study, the conditioned place preference (CPP) paradigm was used to evaluate the effects of intra-accumbal administration of SCH23390 as a dopamine D1-like receptor antagonist on food deprivation (FD) and drug priming-induced reinstatement. Sixty-eight adult male albino Wistar rats weighing 200-280 g were bilaterally implanted by cannulae into the nucleus accumbens (NAc). For induction of the CPP, subcutaneous (sc) administration of morphine (5mg/kg) was used daily during a three-day conditioning phase. The conditioning score and locomotor activity were recorded by using the Ethovision software. Under extinction conditions, rats were given an 'off' period and were tested for FD-induced reinstatement following the 24-h or 48-h FD condition, and for drug priming-induced reinstatement under the sated condition following an injection of 0.5 and 1mg/kg (sc) morphine. In the next experiments, animals received different doses of intra-accumbal SCH23390 (0.25, 1 and 4 MUg/0.5 MUl saline) bilaterally and were subsequently tested for FD- and morphine priming induced reinstatement. Our findings indicated that only a dose of 1mg/kg and not 0.5mg/kg of morphine induced the reinstatement of morphine. 24-h FD similar to 48 h FD induced the reinstatement of seeking behaviors facilitated by an ineffective dose of morphine (0.5mg/kg). Furthermore, the D1-like receptor antagonist attenuated FD- and drug priming-induced reinstatement dose-dependently. It is concluded that FD- and drug priming-induced reinstatement may be mediated, at least in some way, by activation of dopamine D1-like receptors in the NAc. PMID- 25835322 TI - Sclerosteosis (craniotubular hyperostosis-syndactyly) with complex hyperphalangy of the index finger. AB - We report a 4-year-old boy with sclerosteosis associated with severe digital dysostosis. The initial medical consultation was prompted by bilateral, asymmetrical syndactyly of the index and middle fingers. The left index finger had complicated phalangeal anomalies: hyperphalangy (supernumerary phalanx distal to the middle phalanx) and hypoplasia with bracket epiphyses of the proximal and middle phalanges. Development of facial nerve palsy, hearing impairment and generalized osteosclerosis had occurred between 3 years and 4 years of age, with the subsequent identification of a homozygous SOST mutation. Bilateral second and third fingers syndactyly associated with abnormal patterning of the same fingers should be considered prodromal signs of sclerosteosis. PMID- 25835323 TI - Differential effects of conductances on the phase resetting curve of a bursting neuronal oscillator. AB - The intrinsically oscillating neurons in the crustacean pyloric circuit have membrane conductances that influence their spontaneous activity patterns and responses to synaptic activity. The relationship between the magnitudes of these membrane conductances and the response of the oscillating neurons to synaptic input has not yet been fully or systematically explored. We examined this relationship using the phase resetting curve (PRC), which summarizes the change in the cycle period of a neuronal oscillator as a function of the input's timing within the oscillation. We first utilized a large database of single-compartment model neurons to determine the effect of individual membrane conductances on PRC shape; we found that the effects vary across conductance space, but on average, the hyperpolarization-activated and leak conductances advance the PRC. We next investigated how membrane conductances affect PRCs of the isolated pacemaker kernel in the pyloric circuit of Cancer borealis by: (1) tabulating PRCs while using dynamic clamp to artificially add varying levels of specific conductances, and (2) tabulating PRCs before and after blocking the endogenous hyperpolarization-activated current. We additionally used a previously described four-compartment model to determine how the location of the hyperpolarization activated conductance influences that current's effect on the PRC. We report that while dynamic-clamp-injected leak current has much smaller effects on the PRC than suggested by the single-compartment model, an increase in the hyperpolarization-activated conductance both advances and reduces the noisiness of the PRC in the pacemaker kernel of the pyloric circuit in both modeling and experimental studies. PMID- 25835324 TI - Association between Pregnancy and Active Injection Drug Use and Sex Work among Women Injection Drug Users in Saint Petersburg, Russia. AB - Widespread use of unsafe sexual practices among women injecting drugs both practicing and not practicing sex work leads to high levels of unplanned pregnancies in this population. The goal of this study was to investigate the association between pregnancy and active drug use and sex work. Data were collected using a convenience sample of 500 women in Saint Petersburg, Russia, in 2013. All women had recent experience of drug use, of which 200 were pregnant at the time of the study. The study consisted of a structured interview followed by a rapid HIV test. Pregnancy was protective against both active drug use and sex work. For HIV-positive women, these associations were stronger than for HIV negative women: drug use prevalence ratio (PR) was 0.59 vs 0.85; for sex work, the PRs were 0.36 vs 0.64. Higher levels of education were associated with a lower prevalence ratio for active drug use and sex work in all models. Having children was not associated with active drug use or sex work. Pregnancy might be an optimal time for conducting interventions aimed at cessation of drug use and sex work among women injecting drugs. PMID- 25835325 TI - Replacing stressful challenges with positive coping strategies: a resilience program for clinical placement learning. AB - Clinical education is foundational to health professional training. However, it is also a time of increased stress for students. A student's perception of stressors and their capacity to effectively manage them is a legitimate concern for educators, because anxiety and decreased coping strategies can interfere with effective learning, clinical performance and capacity to care for patients. Resilience is emerging as a valuable construct to underpin positive coping strategies for learning and professional practice. We report the development and evaluation of a psycho-education resilience program designed to build practical skills-based resilience capacities in health science (physiotherapy) students. Six final year undergraduate physiotherapy students attended four action research sessions led by a clinical health psychologist. Resilience strategies drawn from cognitive behavioural therapy, and positive and performance psychology were introduced. Students identified personal learning stressors and their beliefs and responses. They chose specific resilience-based strategies to address them, and then reported their impact on learning performance and experiences. Thematic analysis of the audio-recorded and transcribed action research sessions, and students' de identified notes was conducted. Students' initial descriptions of stressors as 'problems' outside their control resulting in poor thinking and communication, low confidence and frustration, changed to a focus on how they managed and recognized learning challenges as normal or at least expected elements of the clinical learning environment. The research suggests that replacing stressful challenges with positive coping strategies offers a potentially powerful tool to build self-efficacy and cognitive control as well as greater self-awareness as a learner and future health practitioner. PMID- 25835326 TI - Activation of p38 in C2C12 myotubes following ATP depletion depends on extracellular glucose. AB - Muscle cells adjust their glucose metabolism in response to myriad stimuli, and particular attention has been paid to glucose metabolism after contraction, ATP depletion, and insulin stimulation. Each of these requires translocation of GLUT4 to the cell membrane, and may require activation of glucose transporters by p38. In contrast, AICAR stimulates glucose transport without activation of p38, suggesting that p38 activation may be an indirect consequence of accelerated glucose transport or metabolism. This study was designed to investigate the contribution of AMPK and p38 to ATP homeostasis and glucose metabolism to test the hypothesis that p38 reflects glycolytic activity rather than controls glucose uptake. Treating mature myotubes with rotenone caused transient ATP depletion in 15 min with recovery by 120 min, associated with increased lactate production. Both ACC and p38 were rapidly phosphorylated, but ACC remained phosphorylated while p38 phosphorylation declined as ATP recovered. AMPK inhibition blocked ATP recovery, lactate production, and phosphorylation of p38 and ACC. Inhibition of p38 had little effect. AICAR induced ACC phosphorylation, but not lactate production or p38 phosphorylation. Finally, removing extracellular glucose potentiated rotenone-induced AMPK activation, but reduced lactate generation, ATP recovery and p38 activation. Thus, glucose metabolism is highly sensitive to ATP homeostasis via AMPK activity, but p38 activity is dispensable. Although p38 is strongly phosphorylated during ATP depletion, this appears to be an indirect consequence of accelerated glycolysis. PMID- 25835328 TI - Caprine herpesvirus 1 (CpHV-1) vaginal infection of goats: clinical efficacy of fig latex. AB - The latex of Ficus carica Linn. (Moraceae) has been shown to interfere with the replication of caprine herpesvirus (CpHV)-1 in vitro. The present study was undertaken to determine the efficacy of vaginal administration of fig latex in goats experimentally infected with CpHV-1. The fig latex reduced the clinical signs of the herpetic disease although it slightly influenced the titres of CpHV 1 shed. Thus, the fig latex maintained a partial efficacy in vivo. PMID- 25835327 TI - Secondary use of empirical research data in medical ethics papers on gamete donation: forms of use and pitfalls. AB - This paper aims to provide a description of how authors publishing in medical ethics journals have made use of empirical research data in papers on the topic of gamete or embryo donation by means of references to studies conducted by others (secondary use). Rather than making a direct contribution to the theoretical methodological literature about the role empirical research data could play or should play in ethics studies, the focus is on the particular uses of these data and the problems that can be encountered with this use. In the selection of papers examined, apart from being used to describe the context, empirical evidence was mainly used to recount problems that needed solving. Few of the authors looked critically at the quality of the studies they quoted, and several instances were found of empirical data being used poorly or inappropriately. This study provides some initial baseline evidence that shows empirical data, in the form of references to studies, are sometimes being used in inappropriate ways. This suggests that medical ethicists should be more concerned about the quality of the empirical data selected, the appropriateness of the choice for a particular type of data (from a particular type of study) and the correct integration of this evidence in sound argumentation. Given that empirical data can be misused also when merely cited instead of reported, it may be worthwhile to explore good practice requirements for this type of use of empirical data in medical ethics. PMID- 25835329 TI - Mutants of metal binding site M1 in APP E2 show metal specific differences in binding of heparin but not of sorLA. AB - The amyloid precursor protein (APP) and its neurotoxic cleavage product Abeta are key players in the development of Alzheimer's disease (AD) and appear to be essential for neuronal development and cell homeostasis. Proteolytic processing of APP and its physiological function depend on its interaction with heparin and are influenced by the binding of metal ions and sorLA. We created various mutations of metal binding site M1 residing within the extracellular E2 domain of APP. Using isothermal titration calorimetry and circular dichroism spectroscopy, we analyzed the binding of Cu(2+) and Zn(2+) to APP E2 and identified two mutations that are most suited for functional studies to dissect ion specific effects of metal binding. The H313A mutation abrogates only copper-based effects, whereas the H382A mutation weakens any metal binding at M1 of APP E2. Subsequently, we tested the effect of Cu(2+) and Zn(2+) on the binding of heparin and sorLA to APP E2 using a chromatographic technique and surface plasmon resonance. We show that Zn(2+) and to a larger degree also Cu(2+) enhance the binding of heparin to APP E2, consistent with an extracellular regulation of the function of APP by both metal ions. In contrast, neither ion seemed to affect the interaction between APP E2 and sorLA. This supports an intracellular interaction between the latter two partners that would not sense extracellular variations of metal ions upon synaptic activity. PMID- 25835330 TI - Associations between socio-demographic factors, encounters with healthcare professionals and perceived ability to return to work in people sick-listed due to heart failure in Sweden: a cross-sectional study. AB - PURPOSE: The aim of this study was to investigate associations between socio demographic factors, experiences of positive/negative encounters with healthcare professionals, and the encounters' impact on the ability to return to work in a population of people on sick leave due to heart failure. METHODS: This was a cross-sectional study. Data were collected from two official registries in Sweden and from a postal questionnaire. In all, 590 people with heart failure responded to the questionnaire. Associations between variables were calculated with bivariate correlation analyses and logistic regression analyses. RESULTS: For people on sick leave due to heart failure, positive encounters with healthcare professionals are associated with being Swedish-born, female gender, and high income. People with high income are more likely to be supported back to work by positive encounters with healthcare professionals. To perceive that healthcare professionals believe in person's ability to return to work can be facilitating. CONCLUSIONS: Women, people who are not foreign-born, and people with high income are more likely to perceive encounters with healthcare professionals as positive. Healthcare professionals who work with rehabilitation for people with heart failure need to be aware of social inequalities and that being on sick leave is a process of change. IMPLICATIONS FOR REHABILITATION: A failing heart limits everyday life implying risk for long-term sick leave. Even though there are rehabilitation programs for people with heart failure, vocational rehabilitation is often over-looked. The knowledge about factors associated with sick leave due to heart failure is scarce. Experiences of positive encounters with healthcare professionals were associated with being Swedish-born, female gender, and high income. People with high income were more likely to be supported back to work by positive encounters with healthcare professionals. Healthcare professionals who work with rehabilitation for people with heart failure can support patients with heart failure by showing them confidence and trust. However, they need to be aware that sick leave implies a process of change. PMID- 25835331 TI - Esophageal Adenocarcinoma: The Influence of Medications Used to Treat Comorbidities on Cancer Prognosis. AB - Esophageal adenocarcinoma has undergone a continuous rise in incidence since the early 1970s and is the fastest rising cancer among white men in the United States. Epidemiologic studies have demonstrated that medications commonly used to treat multiple chronic conditions (for example, aspirin, non-aspirin nonsteroidal anti-inflammatory drugs, and statins) as well as powerful acid suppressants such as proton pump inhibitors are associated with a reduced risk of esophageal adenocarcinoma. The chemopreventive potential of these classes of medications appears to be especially applicable to persons with Barrett's esophagus, the only known premalignant condition for esophageal adenocarcinoma. However, it is not known whether these medications also influence cancer recurrence and cancer specific mortality in persons diagnosed with esophageal adenocarcinoma. This is an important question because most patients with esophageal adenocarcinoma have 1 or more comorbid conditions at the time of their cancer diagnosis and are receiving medication to treat these conditions. This article summarizes the evidence on the associations between 4 commonly used classes of medications and (1) risk of developing esophageal adenocarcinoma and Barrett's esophagus and (2) risk of cancer recurrence and cancer-specific mortality in patients with esophageal adenocarcinoma. PMID- 25835332 TI - Food for Thought: Complications of Acute Gastric Distension in Prader-Willi Syndrome. PMID- 25835333 TI - Medical information on the internet: a tool for measuring consumer perception of quality aspects. AB - BACKGROUND: Most of adult Internet users have searched for health information on the Internet. The Internet has become one of the most important sources for health information and treatment advice. In most cases, the information found is not verified with a medical doctor, but judged by the "online-diagnosers" independently. Facing this situation, public health authorities raise concern over the quality of medical information laypersons can find on the Internet. OBJECTIVE: The objective of the study was aimed at developing a measure to evaluate the credibility of websites that offer medical advice and information. The measure was tested in a quasi-experimental study on two sleeping-disorder websites of different quality. METHODS: There were 45 survey items for rating the credibility of websites that were tested in a quasi-experimental study with a random assignment of 454 participants to either a high- or a low-quality website exposure. Using principal component analysis, the original items were reduced to 13 and sorted into the factors: trustworthiness, textual deficits of the content, interferences (external links on the Web site), and advertisements. The first two factors focus more on the provided content itself, while the other two describe the embedding of the content into the website. The 45 survey items had been designed previously using exploratory observations and literature research. RESULTS: The final scale showed adequate power and reliability for all factors. The loadings of the principal component analysis ranged satisfactorily (.644 to .854). Significant differences at P<.001 were found between the low- and high quality groups. Advertisements on the website were rated as disturbing in both experimental conditions, meaning that they do not differentiate between good and bad information. CONCLUSIONS: The scale reliably distinguished high- and low quality of medical advice given on websites. PMID- 25835334 TI - Analysis of Hyoid-Larynx Complex Using 3D Geometric Morphometrics. AB - The aim of this study was to obtain a quantitative anatomical description of the hyoid bone-larynx complex using modern 3D reconstruction tools. The study was conducted on 104 bones from CT scan images of living adult subjects. Three dimensional reconstructions were created from CT scan images using AVIZO 6.2 software package. A study of this complex was carried out using metric and morphological analyses. Characteristics of the hyoid bone and larynx were highly heterogeneous and were closely linked with the sex, height, and weight of the individuals. Height and width of larynx were significantly greater in men than in women (24.99 vs. 17.3 mm, p <= 0.05 and 46.75 vs. 41.07, p <= 0.05), whereas the thyroid angle was larger in females (81.12 degrees vs. 74.48 degrees , p <= 0.05). There was a significant correlation between the height and weight of subjects and different measurements of the hyoid-larynx complex. (Pearson's coefficient correlation r = 0.42, p <= 0.05 between the height of thyroid ala and the height of subjects and r = 0.1, p <= 0.05 between the height of thyroid ala and the weight of subjects). Shape and size analysis of the hyoid-larynx complex showed the existence of a significant sexual dimorphism and high interindividual heterogeneity depending to patient morphology. These results encourage us to go further with functional and imaging correlations. PMID- 25835336 TI - The electronic, optical and magnetic consequences of delocalization in multifunctional donor-acceptor organic polymers. AB - Two organic polymers containing alternating electron donating triarylamine and electron accepting thiazolo[5,4-d]thiazole (TzTz) moieties have been synthesized and their redox states investigated. When donor and acceptor units are proximal (polymer )1, electron density is delocalized, leading to a small electrical and optical band gap; these are larger with the inclusion of an adjoining alkynyl phenyl bridge (polymer 2), where electron density is more localized due to the rotation of the monomer units. As a result, 1 and 2 display different optical and fluorescence properties in their neutral states. Upon chemical and electrochemical redox reactions, radicals form in both 1 and 2, yielding magnetic materials that display temperature-independent paramagnetism, attributable to delocalization of radical spins along the polymeric backbones. The ability to convert between diamagnetic and paramagnetic states upon chemical oxidation and/or reduction allows for the materials to display switchable magnetism and fluorescence, imparting multifunctionality to these solid-state purely organic materials. PMID- 25835337 TI - Erratum. PMID- 25835338 TI - Hot-carrier photocurrent effects at graphene-metal interfaces. AB - Photoexcitation of graphene leads to an interesting sequence of phenomena, some of which can be exploited in optoelectronic devices based on graphene. In particular, the efficient and ultrafast generation of an electron distribution with an elevated electron temperature and the concomitant generation of a photo thermoelectric voltage at symmetry-breaking interfaces is of interest for photosensing and light harvesting. Here, we experimentally study the generated photocurrent at the graphene-metal interface, focusing on the time-resolved photocurrent, the effects of photon energy, Fermi energy and light polarization. We show that a single framework based on photo-thermoelectric photocurrent generation explains all experimental results. PMID- 25835339 TI - Si microstructures laminated with a nanolayer of TiO2 as long-term stable and effective photocathodes in PEC devices. AB - Photoelectrochemical (PEC) water splitting is one of the most emerging fields for green energy generation and storage. Here we show a study of microstructured Si covered by a TiO2 nano-layer. The microstructures are prepared by galvanostatic selective etching of Si. The TiO2 nano-layer was deposited by atomic layer deposition (ALD) to protect the microstructured photocathode against corrosion. The obtained microstructured photocathode showed a shift in the onset potential of 400 mV towards the anodic direction compared to bare Si. The Si microstructures laminated with a nano-layer of TiO2 show stability over 60 hours of measurement. PMID- 25835340 TI - Myocardial Damage Detected by Two-Dimensional Speckle-Tracking Echocardiography in Patients with Extracardiac Sarcoidosis: Comparison with Magnetic Resonance Imaging. AB - BACKGROUND: The aim of this study was to determine whether two-dimensional speckle-tracking echocardiography can identify the myocardial damage detected by delayed enhancement (DE) magnetic resonance imaging via the differences in myocardial deformation in patients with extracardiac sarcoidosis who showed no structural and functional abnormalities in the heart. METHODS: Forty-five patients with biopsy-proven extracardiac sarcoidosis were analyzed retrospectively. Patients with abnormal electrocardiographic and echocardiographic findings, including ventricular arrhythmias, heart block, regional wall motion abnormalities, valvular heart disease, and cardiomyopathy, were excluded. Ten age-matched healthy control subjects were recruited as a control group. Comprehensive echocardiography and DE magnetic resonance imaging were performed, and circumferential, longitudinal, and radial strain were consecutively assessed using two-dimensional speckle-tracking echocardiographic software in a 16-segment model of the left ventricle in accordance to the presence (DE+) or absence (DE-) of DE. RESULTS: Among the 45 patients, 36 segments in 13 patients showed DE. DE+ segments had lower peak circumferential strain than DE- and control segments (-14 +/- 5% vs -28 +/- 7% vs -30 +/- 7%, P < .0001). Peak longitudinal strain in DE+ segments was significantly decreased compared with control segments (-19 +/- 4% vs -23 +/- 5%, P = .005). However, peak radial strain was similar among the three groups: 41 +/- 17% in DE+ segments, 45 +/- 23% in DE- segments, and 46 +/- 18% in control segments (P = .50). CONCLUSIONS: Circumferential and longitudinal strain via two-dimensional speckle-tracking echocardiography can identify the myocardial damage detected by DE magnetic resonance imaging in patients with extracardiac sarcoidosis. PMID- 25835341 TI - Mitral Annular Dynamics in Mitral Annular Calcification: A Three-Dimensional Imaging Study. AB - BACKGROUND: The mitral annulus displays complex conformational changes during the cardiac cycle that can now be quantified by three-dimensional echocardiography. Mitral annular calcification (MAC) is increasingly encountered, but its structural and dynamic consequences are largely unexplored. The objective of this study was to describe alterations in mitral annular dimensions and dynamics in patients with MAC. METHODS: Transthoracic three-dimensional echocardiography was performed in 43 subjects with MAC and 36 age- and sex-matched normal control subjects. Mitral annular dimensions were quantified, using dedicated software, at six time points (three diastolic, three systolic) during the cardiac cycle. RESULTS: In diastole, the calcified annulus was larger and flatter than normal, with increased anteroposterior diameter (29.4 +/- 0.6 vs 27.8 +/- 0.6 mm, P = .046), reduced height (2.8 +/- 0.2 vs 3.6 +/- 0.2 mm, P = .006), and decreased saddle shape (8.9 +/- 0.6% vs 11.4 +/- 0.6%, P = .005). In systole, patients with MAC had greater annular area at all time points (P < .05 for each) compared with control subjects, because of reduced contraction along the anteroposterior diameter (P < .001). Saddle shape increased in early systole (from 10.5% to 13.5%, P = .04) in control subjects but not in those with MAC (P = NS). Valvular alterations were also noted; although mitral valve tent length decreased during systole in both groups, decreases were less in patients with MAC (P < .05 for mid and late systole). For certain parameters (e.g., annular area), changes were confined largely to those patients with moderate to severe MAC (P = .006 vs control subjects, but nonsignificant for patients with mild MAC). CONCLUSIONS: Quantitative three-dimensional echocardiography provides new insights into the dynamic consequences of MAC. This imaging technique demonstrates that the mitral annulus is not made smaller by calcification. However, there is loss of annular contraction, particularly along the anteroposterior diameter, and loss of early systolic folding along the intercommissural diameter. Associated valvular alterations include smaller than usual declines in tenting during systole. These quantitative three-dimensional echocardiographic data provide new insights into the dynamic physiology of the calcified mitral annulus. PMID- 25835342 TI - Self-Assembled Monolayers Get Their Final Finish via a Quasi-Langmuir-Blodgett Transfer. AB - The growth of self-assembled monolayers (SAMs) of octadecylphosphonic acid (ODPA) molecules on alpha-Al2O3(0001) and subsequent dewetting of the SAMs were studied with a combination of in situ sum-frequency generation (SFG) and molecular dynamics (MD) simulations. Although SAM growth after deposition times >8 h reduces to nearly negligible values, the resultant ODPA SAMs in solution are still not in a well-ordered state with the alkyl chains in all-trans configurations. In fact, in situ SFG spectroscopy revealed a comparatively high concentration of gauche defects of the SAM in the ODPA 2-propanol solution even after a growth time of 16 h. Here, results of the MD simulations strongly suggest that defects can be caused by ODPA molecules which are not attached to the substrate but are incorporated into the SAM layer with the polar headgroup oriented into the 2-propanol solvent. This inverted adsorption geometry of additional ODPA molecules blocks adsorption sites and thus stabilizes the SAM without improving ordering to an extent that all molecules are in the all-trans configuration. While persistent in solution, the observed defects can be healed out when the SAMs are transferred from the solvent to a gas phase. During this process, a quasi-Langmuir-Blodgett transfer of molecules takes place which drives the SAM into a higher conformational state and significantly improves its quality. PMID- 25835343 TI - Autism spectrum disorders and intestinal microbiota. AB - Through extensive microbial-mammalian co-metabolism, the intestinal microbiota have evolved to exert a marked influence on health and disease via gut-brain microbiota interactions. In this addendum, we summarize the findings of our recent study on the fecal microbiota and metabolomes of children with pervasive developmental disorder-not otherwise specified (PDD-NOS) or autism (AD) compared with healthy children (HC). Children with PDD-NOS or AD have altered fecal microbiota and metabolomes (including neurotransmitter molecules). We hypothesize that the degree of microbial alteration correlates with the severity of the disease since fecal microbiota and metabolomes alterations were higher in children with PDD-NOS and, especially, AD compared to HC. Our study indicates that the levels of free amino acids (FAA) and volatile organic compounds (VOC) differ in AD subjects compared to children with PDD-NOS, who are more similar to HC. Finally, we propose a new perspective on the implications for the interaction between intestinal microbiota and AD. PMID- 25835344 TI - [Are health district prevalence studies useful in family practice? Report of a case: chronic obstructive pulmonary disease]. AB - OBJECTIVE: To determine the prevalence of COPD and smoking in a Health District, to correlate real, registered, and extrapolated morbidity. To determine personal, family and social profiles. To determine the validity of the lung function questionnaire. DESIGN: Prevalence study. LOCATION: Urban District Health. PARTICIPANTS: Random selection of 233 people aged 40-75years. MAIN MEASUREMENTS: Age, sex, pack/years, spirometry, pulse-oximetry, medication, income. TESTS: Fagerstrom, Richmond, MOS, APGAR, and lung function. RESULTS: Mean age was 53.7+7.6years, with 57.9% women. Registered morbidity for COPD 1.2% (0.5-3.9%). Prevalence 4.7% (1.5% female, 9.2% male), extrapolated prevalence: 10.2%. Registered morbidity for Smoking 10.7% (1-19.4%); prevalence: 18.5% (20% female, 16.3% male), extrapolated prevalence 23.95%. Lung function questionnaire: positive likelihood ratio 3.18; negative 0.1. High probability of COPD (59.5%) in >30 packs/year smokers. Smokers consume a mean of 20.8 packs/year. Women showed higher physical dependence (36% versus 21%). More probability of achieving successful smoking cessation in men (57.1% versus 44%). There was 14.7% perceived family dysfunction; 6.9% have a low global index of social support, and 9.1% in COPD subjects. More than two-thirds (70%) of COPD patients had never been hospitalized. There were 10% polymedicated patients compared to 60% in identified COPDs. CONCLUSIONS: Prevalence of COPD and smoking (indicator of avoidable morbidity attributable to primary care) are substantially lower than the reference data. The lung function questionnaire is valid. There was evidence of inter-professional variability. Women smoke more, are more dependent and are less motivated to quit. Their family and social perception is worse. These investigations are essentials for community intervention and operational planning. PMID- 25835345 TI - Ratio of anogenital warts between different anatomical sites in homosexual and heterosexual individuals in Australia, 2002-2013: implications for susceptibility of different anatomical sites to genital warts. AB - There is little known regarding the transmissibility of human papillomavirus (HPV) between different sites in men who have sex with men (MSM) and heterosexual individuals. We conducted a retrospective analysis investigating all new patients attending the Melbourne Sexual Health Centre in Australia between 2002 and 2013. We describe the prevalence and ratio of the first episode of anogenital warts in MSM and heterosexual males and females. The proportion of new MSM clients with anal and penile warts was 4.0% (362/8978) and 1.6% (141/8978), respectively; which gave an anal-to-penile wart ratio of 1:2.6. About 13.7% (1656/12112) of heterosexual males had penile warts and 10.0% (1121/11166) of females had vulval warts, which yielded a penile-to-vulval wart ratio of 1:0.7. Penile-anal transmission has a higher ratio than penile-vulval transmission, suggesting that the anal epithelium may be more susceptible to HPV infection than the vulval epithelium in females; these ratios are important in modelling the control of HPV in MSM. PMID- 25835346 TI - Lactoferrin Reduces Chorioretinal Damage in the Murine Laser Model of Choroidal Neovascularization. AB - PURPOSE: To determine whether lactoferrin, specifically endogenous mouse lactoferrin and exogenous intraperitoneal lactoferrin treatment, plays a role in reducing the chorioretinal damage in the laser-induced model of choroidal neovascularization. MATERIALS AND METHODS: Four 532-nm argon laser spots were placed between the retinal vessels of each eye. At Day 7, Fluorescein Angiography was performed to grade the lesions. The mice were perfused with fluorescein labeled tomato lectin and sacrificed. The retinal pigment epithelium-choroid sclera complex was flat-mounted and analyzed with a confocal microscope to measure the volume of the lesions. The effect of endogenous lactoferrin was studied by comparing lactoferrin knockout and wild-type (WT) mice. The effect of exogenous lactoferrin treatment was studied by comparing lactoferrin knockout and WT mice treated with lactoferrin for seven days to their respective controls. RESULTS: Lactoferrin knockout mice demonstrated 47% larger lesion volumes than WT mice (p < 0.001). Intraperitoneal treatment with Lactoferrin reduced the lesion volume in Lactoferrin knockout mice by 26% (p < 0.04). Regarding the fluorescein angiography, lesions indicating the greatest damage (grade 2B) occurred more frequently in control lactoferrin knockout mice compared with control WT mice (16% versus 5%). Intraperitoneal treatment with Lactoferrin reduced the grade 2B lesions from 16% to 2% in Lactoferrin knockout mice. CONCLUSION: The endogenous lactoferrin present in WT mice appears to reduce the choroidal neovascularization in the laser-induced choroidal neovascularization model in mice. Treatment with exogenous lactoferrin is capable of reducing the choroidal neovascularization in lactoferrin knockout mice but does not add a significant protective effect to WT. PMID- 25835347 TI - Postpartum reversible cerebral vasoconstriction syndrome: review and analysis of the current data. AB - Postpartum reversible cerebral vasoconstriction syndrome (PPRCVS) is a rare but serious cause of headache that occurs in the early postpartum period. The rarity of this disorder has limited the current literature to single case reports and small, observational case series. The lack of familiarity with PPRCVS may contribute to mismanagement of these unique patients and lead to poor outcomes. To address current gaps in the understanding of PPRCVS, this review and data analysis characterizes the demographics, presentation, clinical course, management and prognosis of PPRCVS and provides a general review of the epidemiology, pathophysiology and diagnosis to assist clinicians who may care for patients with this rare disorder. PMID- 25835348 TI - Proton pump inhibitors and vascular function: A prospective cross-over pilot study. AB - Proton pump inhibitors (PPIs) are commonly used drugs for the treatment of gastric reflux. Recent retrospective cohorts and large database studies have raised concern that the use of PPIs is associated with increased cardiovascular (CV) risk. However, there is no prospective clinical study evaluating whether the use of PPIs directly causes CV harm. We conducted a controlled, open-label, cross over pilot study among 21 adults aged 18 and older who are healthy (n=11) or have established clinical cardiovascular disease (n=10). Study subjects were assigned to receive a PPI (Prevacid; 30 mg) or a placebo pill once daily for 4 weeks. After a 2-week washout period, participants were crossed over to receive the alternate treatment for the ensuing 4 weeks. Subjects underwent evaluation of vascular function (by the EndoPAT technique) and had plasma levels of asymmetric dimethylarginine (ADMA, an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk) measured prior to and after each treatment interval. We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA (r = -0.364). Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo, and this trend was more pronounced amongst those subjects with a history of vascular disease. However, these trends did not reach statistical significance, and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study. In conclusion, in this open-label, cross-over pilot study conducted among healthy subjects and coronary disease patients, PPI use did not significantly influence vascular endothelial function. Larger, long term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes, which has recently been reported in retrospective cohort studies. PMID- 25835349 TI - Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is associated with reduced major adverse cardiovascular events among patients with critical limb ischemia. AB - Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are recommended for secondary prevention in peripheral artery disease, but their effectiveness in patients with critical limb ischemia (CLI) is uncertain. We reviewed 464 patients with CLI who underwent diagnostic angiography or endovascular intervention from 2006-2013 at a multidisciplinary vascular center. ACEI or ARB use was assessed at the time of angiography. Major adverse cardiovascular events (MACE), mortality, and major adverse limb events (MALE) were assessed during three-year follow-up. Propensity weighting was used to adjust for baseline differences between patients taking and not taking ACEIs or ARBs. ACEIs or ARBs were prescribed to 269 (58%) patients. Patients prescribed ACEIs or ARBs had more baseline comorbidities including diabetes and hypertension (p<0.05). Patients prescribed ACEIs or ARBs had lower three-year unadjusted rates of MACE (40% versus 47%) and mortality (33% versus 43%). After propensity weighting, ACEI or ARB use was associated with significantly lower rates of MACE (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.58-0.99, p=0.04) and overall mortality (HR 0.71, 95% CI 0.53-0.95, p=0.02). There was no significant association between ACEI or ARB use and MALE (HR 0.97, 95% CI 0.69-1.35, p=0.2) or major amputation (HR 0.74, 95% CI 0.47-1.18, p=0.1). ACEI/ARB use is associated with lower MACE and mortality in patients with CLI, but there was no effect on limb-related outcomes. PMID- 25835350 TI - Viscum album (mistletoe) for pancreatic cancer, electromagnetic field therapy for osteoarthritis, homeopathy for multidrug-resistant tuberculosis, vitamin D for depression, acupuncture for insomnia. PMID- 25835351 TI - Three Polymorphisms of Vascular Endothelial Growth Factor (+936C > T, -460C > T, and -2578C > A) and Their Susceptibility to Ovarian Cancer: A Meta-Analysis. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen that plays a vital role in angiogenesis, tumor growth, and metastasis. The associations between 3 polymorphisms of VEGF (+936 C > T, -2578 C > A, and 460 C > T) and ovarian cancer (OC) risk have been extensively investigated, but the currently available results are inconsistent. To obtain a more accurate estimation of the association, a meta-analysis was conducted in this study. METHODS: PubMed, Cochrane Library, Embase, and Chinese National Knowledge Infrastructure were searched for all relevant studies published before November 30, 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the VEGF polymorphisms to assess the strength of the association. RESULTS: With regard to the +936 C > T polymorphism, 5 articles were available for analysis (882 cases and 1155 controls), whereas for -2578 C > A (559 cases and 632 controls) and -460 C > T (350 cases and 409 controls), only 2 articles were eligible for analysis, respectively. A significant association between the VEGF +936 C/T polymorphism and OC was demonstrated in white populations (CT vs CC: OR, 0.638 [95% CI, 0.437-0.932; P = 0.020]; TT + CT vs CC: OR, 0.694 [95% CI, 0.483 0.995; P = 0.047]). No relationship was found between -2578 C > A and -460 C > T and susceptibility to develop OC. CONCLUSIONS: This meta-analysis provides supportive evidence that the VEGF +936 C/T polymorphism may influence the risk for the development of OC in a protective model among whites. PMID- 25835352 TI - Assessment of lower urinary tract symptoms in Saudi men using the International Prostate Symptoms Score. AB - BACKGROUND: Benign prostatic hyperplasia-related lower urinary tract symptoms (LUTS) are common among older men, the incidence and prevalence are increasing rapidly, and they are associated with diminished health-related quality-of-life (QOL). OBJECTIVE: The aim was to describe the prevalence of LUTS in Saudi population and its relation to some other parameters. SUBJECTS AND METHODS: Saudi men over the age of 40 were invited to participate in the study; in Riyadh city from August 2012 through March 2013. All participants were assessed for the serum level of prostate-specific antigen (PSA) and digital rectal examination. Participants were given a linguistically validated Arabic version of the International Prostate Symptom Score (IPSS). Demographic and other medical comorbidities were assessed. RESULTS: Based on the IPSS, a subdivision of men into three symptoms classes has been proposed, resulting in groups with mild (1265, 58.3%), moderate (505, 27.3%), and severe symptoms (81, 4.4%) and the prevalence of moderate to severe was 31.7%. There was a weak, but significant correlation between the total IPSS and age, total prostate volume, and PSA. Severity of symptoms is increasing with increased age. Multiple regression analysis reported that prostate volume and all individual items of IPSS except straining were significant predictors of QOL and patient satisfaction, where frequency and incomplete emptying had the heaviest impact on patient's QOL. CONCLUSION: LUTS were common among men in Saudi population over 40, the prevalence increases with age and most of them were unpleased because of their urinary symptoms, poor QOL was mainly determined by individual symptoms; mainly frequency and incomplete emptying. PMID- 25835353 TI - Insight into the 3D-trabecular architecture of the human patella. AB - The subchondral bone plate (SBP), a dynamic component of the osteochondral unit, shows functional adaptation to long-term loading by distribution of the mineral content in a manner best serving the mechanical demands. Since the received joint load is transmitted into the trabecular system, the spongy bone also exhibits differences in strain energy density which models it for optimal support. To evaluate the regional variations in trabecular architecture, in accordance with the density distribution of the SBP revealing its long-term load intake, CT- and MUCT-datasets of ten physiologic patellae were analysed for defined parameters of bony structure. For the SBP, the density distributions as well as area measurements were used. The trabecular architecture was described using parameters of bone morphology comprising the first 5mm (examined in 1mm steps) below the SBP. The obtained measurements are: Bone volume fraction (BV/TV); Bone surface density (BS/TV); Trabecular number (Tb.N); Trabecular separation (Tb.Sp); Trabecular thickness (Tb.Th); structure model index (SMI); and the Degree of anisotropy (DA). The evaluated architectural parameters varied within the trabecular system and showed an inhomogeneous distribution pattern. It proved to be distinctive with maxima of material and stability situated below areas of the highest long-term load intake. With increasing depth, the pattern of distribution was persistent but lessened in intensity. The parameters significantly correlated with the density distribution of the SBP within the first and second millimetres. With increasing depth down to the fifth millimetre, the coefficients of correlation decreased for all values. The trabecular network adapts to its mechanical needs and is therefore not homogenously built. Dependent upon the long term load intake, the trabecular model optimizes the support with significant correlation to the density distribution of the SBP. PMID- 25835355 TI - Tyrosine phosphorylation of cytochrome c as a signaling event in frozen thawed buffalo spermatozoa at the cross-roads of capacitation and apoptosis. AB - Considering the importance of cytochrome c in both life and death, it was of significant interest to investigate the expression of cytochrome c, its tyrosine phosphorylation status and immunolocalization patterns in a frozen-thawed buffalo sperm cell in comparison to in vitro capacitated [heparin (10 MUg/ml) induced, for 4h] and stress [apoptotic (10 MUM staurosporine), oxidative (25 MUM H2O2) and osmotic (180 mM NaCl) for 4h] induced conditions. Proteins were subjected to immunoblotting and probed by using monoclonal anti-phosphotyrosine antibodies. A significant (p<0.05) increase in expression of tyrosine phosphorylated cytochrome c was observed in capacitated buffalo sperm in comparison to frozen-thawed samples. cAMP protein kinase-A dependent and extracellular signal-regulated kinase independent tyrosine phosphorylation of cytochrome c was found during in vitro capacitation of buffalo spermatozoa. Localized increase in cytochrome c and tyrosine phosphorylated proteins were observed in frozen thawed and capacitated sperm. The information generated in this study can be used to understand the molecular mechanism of regulation of an apoptotic protein (cytochrome c) by tyrosine phosphorylation (a capacitation marker) in a frozen thawed sperm cell which could be a good target to combat apoptosis. PMID- 25835354 TI - Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release. AB - BACKGROUND: Medial forebrain bundle (MFB) deep brain stimulation (DBS) is currently being investigated in patients with treatment-resistant depression. Striking features of this therapy are the large number of patients who respond to treatment and the rapid nature of the antidepressant response. OBJECTIVE: To study antidepressant-like behavioral responses, changes in regional brain activity, and monoamine release in rats receiving MFB DBS. METHODS: Antidepressant-like effects of MFB stimulation at 100 MUA, 90 MUs and either 130 Hz or 20 Hz were characterized in the forced swim test (FST). Changes in the expression of the immediate early gene (IEG) zif268 were measured with in situ hybridization and used as an index of regional brain activity. Microdialysis was used to measure DBS-induced dopamine and serotonin release in the nucleus accumbens. RESULTS: Stimulation at parameters that approximated those used in clinical practice, but not at lower frequencies, induced a significant antidepressant-like response in the FST. In animals receiving MFB DBS at high frequency, increases in zif268 expression were observed in the piriform cortex, prelimbic cortex, nucleus accumbens shell, anterior regions of the caudate/putamen and the ventral tegmental area. These structures are involved in the neurocircuitry of reward and are also connected to other brain areas via the MFB. At settings used during behavioral tests, stimulation did not induce either dopamine or serotonin release in the nucleus accumbens. CONCLUSIONS: These results suggest that MFB DBS induces an antidepressant-like effect in rats and recruits structures involved in the neurocircuitry of reward without affecting dopamine release in the nucleus accumbens. PMID- 25835356 TI - New heterocyclic compounds: Synthesis and antitrypanosomal properties. AB - Three new series of quinoline, quinolone, and benzimidazole derivatives were synthesized and evaluated in vitro against Trypanosoma brucei gambiense. In the quinoline series, the metallo antimalarial drug candidate (ferroquine, FQ) and its ruthenium analogue (ruthenoquine, RQ, compound 13) showed the highest in vitro activities with IC50 values around 0.1 MUM. Unfortunately, both compounds failed to cure Trypanosoma brucei brucei infected mice in vivo. The other heterocyclic compounds were active in vitro with IC50 values varying from 0.8 to 34 MUM. One of the most interesting results was a fluoroquinolone derivative (compound 2) that was able to offer a survival time of 8 days after a treatment at the single dose of 100 MUmol/kg by intraperitoneal route. Although no clear cut structure-activity relationships emerged, further pharmacomodulations are worth to be developed in this series. PMID- 25835357 TI - Novel arylazopyrazole inhibitors of cyclin-dependent kinases. AB - Here, we describe new 4-arylazo-3,5-diamino-1H-pyrazole derivatives developed from CAN508, one of the first inhibitors to show preference for transcriptional regulator cyclin-dependent kinase 9. By substituting nitrogen in the pyrazole ring and employing a heteroatom in the 4-aryl ring, we obtained more potent derivatives differing in their CDK-selectivity profiles. The antiproliferative and anti-CDK kinase activities of the novel arylazopyrazoles were examined. The cellular effect of compound IVc was studied on MCF-7 cells synchronized by various methods and compared with other selective CDK inhibitors. The results demonstrated that IVc shows a preference for CDK4 and CDK1. In contrast to cytostatic effects induced by IVc in MCF-7 and K562 cells, we observed apoptotic activities in the RPMI-8226 cell line, which were confirmed by detecting active caspases by different biochemical assays. PMID- 25835358 TI - Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives. AB - An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3 and 13-substituted derivatives 1b-q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure-activity relationship study indicates that an electron-rich aryl moiety as the 13 substituent is key to increasing the inhibitory activity. PMID- 25835359 TI - Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents. AB - Fifteen novel homocamptothecin derivatives with alpha-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted. PMID- 25835360 TI - Editorial: Cutting-edge publications impacting sciences: beyond natural medicines. PMID- 25835361 TI - Salvia miltiorrhiza: Traditional medicinal uses, chemistry, and pharmacology. AB - Salvia miltiorrhiza Bunge (SM) is a very popular medicinal plant that has been extensively applied for many years to treat various diseases, especially coronary heart diseases and cerebrovascular diseases, either alone or in combination with other Chinese plant-based medicines. Although a large number of studies on SM have been performed, they are scattered across a variety of publications. The present review is an up-to-date summary of the published scientific information about the traditional uses, chemical constituents, pharmacological effects, side effects, and drug interactions with SM, in order to lay the foundation for further investigations and better utilization of SM. SM contains diverse chemical components including diterpenoid quinones, hydrophilic phenolic acids, and essential oils. Many pharmacological studies have been done on SM during the last 30 years, focusing on the cardiovascular and cerebrovascular effects, and the antioxidative, neuroprotective, antifibrotic, anti-inflammatory, and antineoplastic activities. The research results strongly support the notion that SM has beneficial therapeutic properties and has a potential of being an effective adaptogenic remedy. PMID- 25835362 TI - Flavonoid-rich fraction of the Monodora tenuifolia seed extract attenuates behavioural alterations and oxidative damage in forced-swim stressed rats. AB - The antidepressant effects of the flavonoid-rich fraction of Monodora tenuifolia seed extract were examined by assessing the extent of attenuation of behavioural alterations and oxidative damage in the rats that were stressed by forced swim test. Compared with the model control group, the altered behavioural parameters were attenuated significantly (P < 0.05) in the group treated with the flavonoid rich fraction (100 and 200 mg.kg(-1)), comparable to the group treated with the standard drug, fluoxetine (10 mg.kg(-1)). The flavonoid-rich fraction and fluoxetine improved significantly (P < 0.05) the activities of the antioxidant enzymes such as superoxide dismutase and catalase as well as other biochemical parameters such as reduced glutathione, protein, and nitrite in the brain of the stressed rats. These results suggested that the flavonoid-rich fraction of Monodora tenuifolia seed extract exerted the antidepressant-like effects which could be useful in the management of stress induced disease. PMID- 25835363 TI - Antipyretic and anti-inflammatory activities of Thais luteostoma extracts and underlying mechanisms. AB - Thais luteostoma has been utilized as a crude drug whose shell and soft tissue have been widely used for the treatment of heat syndrome in China for thousands of years. The present study was designed to investigate the antipyretic and anti inflammatory activities of T. luteostoma. T. luteostoma was divided into shell (TLSH) and soft tissue (TLST) samples in the present study. The rat model of yeast-induced fever was used to investigate their antipyretic effects; and the rat model of hind paw edema induced by carrageenan was utilized to study their anti-inflammatory activities, and at the same time, the concentration variations of the central neurotransmitter [prostaglandin E2 (PGE2) and cyclic adenosine monophosphate (cAMP)], inflammatory mediators [tumor necrosis factor (TNFalpha), interleukin-1beta (IL-1), interleukin-2 (IL-2) and interleukin-6 (IL-6)] and ion (Na(+) and Ca(2+)) were also tested. The results showed that TLSH and TLST extracts significantly inhibited yeast-induced pyrexia in rats (P < 0.05), and exhibited more lasting effects as compared to aspirin, and TLSH had the better antipyretic activity than TLST, and that TLSH and TLST could significantly prevent against carrageenan induced paw edema in rats (P < 0.05); and markedly reduced levels of PGE2, cAMP, TNFalpha, IL-1beta, IL-2, IL-6, and Na(+)/Ca(2+). In fever model, TLST could significantly reduce the levels of PGE2 (P < 0.01) in rats' homogenate and TNFalpha (P < 0.05), IL-1beta (P < 0.01) in the plasma than TLSH, whereas TLSH could reduce the content of IL-2 (P < 0.01) and IL-6 (P < 0.01) in plasma and increase the content of Ca(2+) (P < 0.01) in plasma and homogenate more significantly than TLST. In conclusion, T. luteostoma extract has antipyretic and anti-inflammatory activities, which may be mediated through the suppression of production of PGE2, cAMP, Na(+)/Ca(2+), TNFalpha, IL-1beta, IL-2, and IL-6. PMID- 25835364 TI - Characterization of pumpkin polysaccharides and protective effects on streptozotocin-damaged islet cells. AB - The polysaccharides from pumpkin fruit (PP) were obtained and purified by hot water extraction, anion-exchange chromatography, and gel column chromatography. The physicochemical properties of PP were determined by gel filtration chromatography, gas chromatography, fourier transform infrared (FTIR) spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. Results indicated that the molecular weight of PP was about 23 kDa and PP was composed of D-Arabinose, D-Mannose, D-Glucose, and D-Galactose with a molar ratio of 1 : 7.79 : 70.32 : 7.05. FTIR and NMR spectra indicated that PP was the polysaccharide containing pyranose ring. Additionally, PP protected islets cells from streptozotocin (STZ) injury in vitro via increasing the levels of super-oxide dismutase (SOD) and malondialdehyde (MDA) and reducing the production of NO. The experiment of reverse transcriptase-polymerase chain reaction further proved that PP inhibited apoptosis via modulating the expression of Bax/Bcl-2 in STZ-damaged islet cells. In conclusion, PP could be explored as a novel agent for the treatment of diabetes mellitus. PMID- 25835366 TI - UPLC/Q-TOF-MS analysis of iridoid glycosides and metabolites in rat plasma after oral administration of Paederia scandens extracts. AB - A rapid and validated UPLC-MS method was developed for investigating the absorbed components of Paederia scandens (Lour.) Merrill (P. scandensy) in rat plasma. The bioactive constituents in plasma samples from rats administrated orally with P. scandens extract were analyzed by Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Four prototype compounds were identified in rat serum as potential bioactive components of P. scandens by comparing their retention times and mass spectrometry data or by mass spectrometry analysis and retrieving the reference literatures. Glucuronidation after deglycosylation was the major metabolic pathway for the iridoid glycosides in P. scandens. These results showed that the methods had high sensitivity and resolution and were suitable for identifying the bioactive constituents in plasma after oral administration of P. scandens. providing helpful chemical information for further pharmacological and mechanistic researched on the P. scandens. PMID- 25835365 TI - Determination of alpha-glucosidase inhibitors from Scutellaria baicalensis using liquid chromatography with quadrupole time of flight tandem mass spectrometry coupled with centrifugal ultrafiltration. AB - The present study aimed at identifying potential lead compounds for diabetes mellitus drug discovery. We developed a novel method involving centrifugal ultrafiltration separation subsequent liquid chromatography with quadrupole time of flight tandem mass spectrometry (LC-Q/TOF-MS/MS) determination to screen alpha glucosidase inhibitors in complex Scutellaria baicalensis Georgi (SBG) extract. By adding a second filter to the screening process, the level of non-specific binding of Compounds 1, 3, 10 and 11 was significantly decreased, and the level of non-specific binding of Compounds 5 and 15 also was reduced. As a result, five flavonoids identified as baicalein, baicalein, wogonin, chrysin, and oroxylin A, were rapidly found to interact with alpha-glucosidase and possess potent anti alpha-glucosidase activity in vitro. Specific binding of ligands to alpha glucosidase was demonstrated though the proposed method and the ligands could be ranked in order of affinity for alpha-glucosidase, which were corresponded to the order of inhibitory activity in vitro. In conclusion, our results indicated that the developed method is a rapid and effective screening method for rat intestinal alpha-glucosidase inhibitors from complex herbal medicines such as SBG. PMID- 25835367 TI - Optimization of the processing technology of Fructus Arctii by response surface methodology. AB - The present study was designed to optimize the processing of Fructus Arctii by response surface methodology (RSM). Based on single factor studies, a three variable, three-level Box-Behnken design (BBD) was used to monitor the effects of independent variables, including processing temperature and time, on the dependent variables. Response surfaces and contour plots of the contents of total lignans, chlorogenic acid, arctiin, and arctigenin were obtained through ultraviolet and visible (UV-Vis) monitoring and high performance liquid chromatography (HPLC). Fructus Arctii should be processed under heating in a pot at 311 degrees C, medicine at 119 degrees C for 123s with flipping frequently. The experimental values under the optimized processing technology were consistent with the predicted values. In conclusion, RSM is an effective method to optimize the processing of traditional Chinese medicine (TCM). PMID- 25835368 TI - Simultaneous determination and assignment of 13 major flavonoids and glycyrrhizic acid in licorices by HPLC-DAD and Orbirap mass spectrometry analyses. AB - To determine 13 flavonoids and glycyrrhizic acid in licorice (Glycyrrhiza spp.), several samples from different areas were examined by HPLC-DAD analysis. The analysis was performed on a Zorbax Extend-C18 (250 mm * 4.6 mm, 5 MUm) column connected with a Zorbax Extend guard column (20 mm * 4.6 mm, 5 MUm). The mobile phase consisted of (A) acetonitrile and (B) 0.026% aqueous H3PO4 (VV) using a gradient elution of 20%-25% A at 0-20 min, 25%-33% A at 20-30 min, 33%-50% A at 30-55 min, 50%-60% A at 55-65 min, and 60% A between 65 min and 80 min, and peaks were detected at 280 nm. The fourteen compounds were assigned by HPLC-Orbitrap MS methods. The regression coefficient for the linear equations for the 14 compounds ranged between 0.9998 and 1. The limits of detection and quantification lay in the range of 0.032-2.461 and 0.154-8.202 MUg.mL(1), respectively. The relative recovery rates for the 14 compounds were in the range of 93.90%-106.73% with RSDs being less than 5%. Coefficient variations for intra-day and inter-day precisions were in the range of 0.27%-2.38% and 0.31%-3.51%, respectively. In summary, the validated method was applied to the simultaneous determination of the 14 components in 29 different licorice samples and was proven to be suitable for quality evaluation of licorices and their active fractions. PMID- 25835369 TI - Akebia quinata extract exerts anti-obesity and hypolipidemic effects in high-fat diet-fed mice and 3T3-L1 adipocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dry ripe fruit of the Akebia quinata (A. quinata) plant is used as an analgesic, an antiphlogistic, and a diuretic in traditional medicine. A. quinata has also been used in Korea as a crude drug for treating obesity. The aim of the study was to determine the anti-obesity and hypolipidemic effects of A. quinata extract (AQE) in mice consuming a high-fat diet and in 3T3-L1 adipocytes. MATERIALS AND METHODS: We measured obesity-related physiological parameters, gene expression, and protein phosphorylation in mice consuming a high-fat diet supplemented with AQE (400mg/kg/day) for 6.5 weeks. RESULTS: AQE reduced gain in body weight, adipose tissue weight, and serum lipid levels in mice consuming a high-fat diet. AQE supplementation reduced expression of genes related to adipogenesis and increased expression of PPARalpha, acetyl CoA oxidase, and adiponectin in the epididymal adipose tissue. Furthermore, AQE increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase, both of which are related to fatty acid oxidation, in vivo. HPLC analysis revealed that AQE contained chlorogenic acid, isochlorogenic acid A, and isochlorogenic acid C. AQE and all of these constituents inhibited differentiation of 3T3-L1 cells and enhanced AMPK phosphorylation. CONCLUSIONS: These results suggest the AQE exerted anti-obesity and hypolipidemic effects in mice consuming a high-fat diet by regulating adipogenesis and fatty acid oxidation via AMPK activation. PMID- 25835370 TI - Anti-inflammatory activity and phenolic profile of propolis from two locations in Region Metropolitana de Santiago, Chile. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has long been used as a popular folk medicine due to its wide spectrum of alleged biological and pharmaceutical properties. In Chile, propolis is widely used by folklore medicine as an anti inflammatory agent; however, this property has not been demonstrated by scientific methods. AIM OF THE STUDY: The objective of this study was to determine the anti-inflammatory activity in vivo and in vitro and to establish the phenolic profile of propolis collected in two localities in Region Metropolitana de Santiago (RM), Chile. MATERIALS AND METHODS: Propolis was collected in the areas of Caleu and Buin, RM Chile. Following that, the samples were unwaxed to obtain the global ethanolic extracts of propolis (EEPs) and, from these, the serial extracts of dichloromethane (EEP-DCMs) and ethanol (EEP-EtOHs). The topic anti-inflammatory effect was evaluated through mice ear edema induced by arachidonic acid (AA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) at a dose of 3 mg/ear. Nitric oxide (NO) measurements were determined spectrophotometrically (Greiss reagent) by the accumulation of nitrite in the medium of macrophages RAW 264.7 stimulated with the lipopolysaccharide (LPS, 1 MUg/mL) for 20 h at different concentrations of the EEPs, EEP-DCMs and EEP-EtOHs (6.25-50.00 MUg/mL). The content of total phenols and flavonoids were determined through the methods of Folin-Ciocalteau and AlCl3, respectively. The profile of phenolic compounds was determined by HPLC-UV-ESI-MS/MS. RESULTS: The EEP-EtOH (64%) and EEP (59%) of Buin were the most active in the inflammation induced by TPA and AA respectively, being the anti-inflammatory effect stronger than the same Caleu extracts. Regarding the release of NO, all the extracts from the Buin propolis inhibited significantly its release in a concentration-dependent manner, this inhibition was stronger than the extracts from Caleu propolis. CONCLUSIONS: Our research shows for the first time a comparative study of the topical in vivo activity of two Chilean propolis. Both propolis showed in vivo topical anti inflammatory activity against AA and TPA, the most active was Buin propolis and this difference is due in part to the variations in total phenols and flavonoids content and the phenolic profile. The phenols and flavonoids content of Buin propolis was higher than Caleu propolis. The extracts from Buin propolis result in a lower release of NO. PMID- 25835371 TI - Anti-platelet aggregation activities of different fractions in leaves of Apocynum venetum L. AB - Ethnopharmacological relevance Apocynum venetum: is widely used in Uygur and traditional Chinese medicine. Modern pharmaceutical studies have shown that leaves of A. venetum have effects of liver protection, antidepressant and regulation of blood pressure. However, it is unclear that which components have pharmacological activities. AIM OF THE STUDY: The aim was to study chemical constituents of A. venetum and its anti-platelet aggregation activity. MATERIALS AND METHODS: Nephelometery was applied to evaluate anti-platelet aggregation activity of multi-components of A. venetum. Systematic separation components were characterized by HPLC analysis method, and in vitro screening active components by anti-platelet aggregation study. RESULTS: Ethyl acetate fraction (L-III) and L III-4 have better anti-platelet aggregation activity than other fractions. The results indicated that isoquercitrin, hyperoside and other flavonoids have anti platelet aggregation activity in A. venetum. CONCLUSION: Our studies provide basis on the endeavors of screening chemicals with that anti-platelet aggregation activity in leaves of A. venetum. PMID- 25835372 TI - Intramolecular Insertions into Unactivated C(sp3)-H Bonds by Oxidatively Generated beta-Diketone-alpha-Gold Carbenes: Synthesis of Cyclopentanones. AB - Generation of reactive alpha-oxo gold carbene intermediates via gold-catalyzed oxidation of alkynes has become an increasing versatile strategy of replacing hazardous diazo carbonyl compounds with benign and readily available alkynes in the development of efficient synthetic methods. However, one of the hallmarks of metal carbene/carbenoid chemistry, i.e., insertion into an unactivated C(sp(3))-H bond, has not be realized. This study reveals for the first time that this highly valuable transformation can be readily realized intramolecularly by oxidatively generated beta-diketone-alpha-gold carbenes using ynones as substrates. Substrate conformation control via the Thorpe-Ingold effect is the key design feature that enables generally good to excellent efficiencies, and synthetically versatile cyclopentanones including spiro-, bridged, and fused bicyclic ones can be readily accessed. PMID- 25835374 TI - Volumetric modulated arc therapy for hippocampal-sparing radiotherapy in transformed low-grade glioma: A treatment planning case report. AB - Timing of radiotherapy for low-grade gliomas is still controversial due to concerns of possible adverse late effects. Prevention of possible late cognitive sequelae by hippocampal avoidance has shown promise in phase II trials. A patient with progressive low-grade glioma with gradual dedifferentiation into anaplastic astrocytoma is presented along with description of radiotherapy planning process attempting to spare the hippocampus. To our knowledge, this is the first described case using volumetric modulated arc technique to spare hippocampus during transformed low-grade glioma radiotherapy. Using modern intensity modulated radiotherapy systems it is possible to selectively spare hippocampus together with other standard organs at risk. For selected patients, an attempt to spare hippocampus can be considered as long as other dose characteristics are not significantly compromised compared to standard treatment plan created without any effort to avoid hippocampus. PMID- 25835375 TI - Identification of traffic-related metals and the effects of different environments on their enrichment in roadside soils along the Qinghai-Tibet highway. AB - The road transportation could affect roadside soils environment detrimentally, including heavy metal enrichment. In order to identify and evaluate the enrichment of heavy metals resulted from road transportation on the Tibetan Plateau, the 11 heavy metals (V, Cr, Co, Ni, Cu, Zn, As, Cd, Rb, Pb and Tl) in the topsoil (0-10 cm depth) from four sites along the Qinghai-Tibet highway were discussed in this study. Our results indicate that heavy metals such as Cr, Cu, Zn, As, Cd and Pb are related to road transportation. The content of most of these heavy metals in roadside soils decreased exponentially with the distance from the road, as did some of the Nemero Synthesis Indexes (PN values). The contamination factor for the traffic-related metals ranged from 0.56 (no pollution) to 5.67 (considerable pollution) and the Nemero Synthesis Indexes of these heavy metals ranged from 0.80 (no pollution) to 4.49 (severe pollution). Cd was of priority concern as it had the highest contamination factor. The highest PN value for these traffic-related heavy metals was found in soils at site TTH (alpine steppe). Although transportation contributed to the high contents of these traffic-related metals in roadside environments, regional differences such as wind and the terrain also had significant relationship with their enrichment in these roadside soils. The roadside distance at which there is a potential risk to livestock and wildlife from the contamination of soils by heavy metals should be determined scientifically along the Qinghai-Tibet highway, based on the different natural environments found in the region. PMID- 25835376 TI - Effects of water quality parameters on agglomeration and dissolution of copper oxide nanoparticles (CuO-NPs) using a central composite circumscribed design. AB - Once released into the aquatic environment, nanoparticles (NPs) are expected to interact (e.g., dissolve, agglomerate, settle), with important consequences for particle fate and toxicity. However, a clear understanding of how environmental factors influence the toxicity and fate of NPs in the environment is still in its infancy. In this study, a second order central composite circumscribed design (CCCD) was employed to systematically explore how different combinations of pH, hardness, and natural organic matter (NOM) in receiving water affect the hydrodynamic diameter, surface charge (zeta potential), and release of free Cu(2+) from CuO-NPs under a range of environmentally realistic conditions. The results clearly showed that all three CuO-NP properties varied markedly as functions of pH, hardness and dissolved NOM, confirming that agglomeration and the extent of release of free Cu(2+) largely depend on the surrounding environmental conditions. The response of hydrodynamic diameter, but not zeta potential, to water quality parameters was highly time dependent, showing very different patterns on day 2 and day 10. The approach used in this study can contribute to improving understanding of how, and to what extent, environmental factors affect the physicochemical properties of CuO-NPs once they enter aquatic environments. This understanding can help to predict the conditions under which CuO-NPs are likely to become problematic, which can inform management and mitigation actions. PMID- 25835377 TI - DFT study and crystal structure analysis of a new nano-structure five coordinated Hg(II) complex involving C-H?O, N?O and pi?pi interactions in a supra-molecular structure. AB - In this research, template synthesis and crystal structure of a new HgLI2 complex are presented (L=N(1)-(4-nitrobenzylidene)-N(2)-(2-((E)-(4 nitrobenzylidene)amino)ethyl)ethane-1,2-diamine). The mercury complex crystallizes in the triclinic system with space group of P1-. The crystal structure of the complex shows a distorted trigonal bipyramidal geometry around the mercury(II) center; including two I and an N atoms of Schiff base ligand in equatorial plane and two iminic N atoms in axial positions. Two five membered mercury containing rings [Hg(-N-C-C-N-)] are found in the structure. Some C-H?O, N?O and pi?pi intermolecular interactions causes a supra-molecular network in the solid-state. In addition to crystal structure analysis, density functional theory (DFT) study at the B3LYP/LanL2DZ level of theory has been also performed on the structure. Thereafter some theoretical structural and spectral data were compared with experimental results. Furthermore, total energy levels of HOMO and LUMO orbitals, molecular electrostatic potential, Mullikan atomic charges, thermodynamic and polarizability properties of the complex were calculated. Finally the mercury complex was prepared in nano-structure size confirmed by SEM and XRD analyses. The particles size of the titled complex was evaluated under 40 nm based on Sherrer's formula. PMID- 25835378 TI - A simple spectrophotometric method for the determination of trace levels of molybdenum using N,N'-bis(2-hydroxy-5-bromo-benzyl)1,2 diaminopropane. AB - The present work describes a selective, rapid and economical spectrophotometric method for the determination of molybdenum using N,N'-bis(2-hydroxy-5-bromo benzyl)1,2 diaminopropane. Molybdenum(VI) reacts with N,N'-bis(2-hydroxy-5-bromo benzyl)1,2 diaminopropane to form a stable 1:1 yellow complex with an absorption maximum at 342 nm. The reaction is completed within 10 min and the absorbance of the molybdenum complex remains stable for at least 1 week at room temperature. The effective molar absorption coefficient at 342 nm was 9.6 * 10(3)L mol(-1)cm( 1). Under optimal conditions, the complex obeys Beer's law from 0 to 9.9 MUg mL( 1). The relative standard deviation was 0.08% (for 11 samples, each containing 6 MUg mL(-1) molybdenum). Under the optimum conditions, the detection limit (3sigma) was 17.7 MUg L(-1) for molybdenum without any preconcentration. The precision was determined from 30 results obtained for 4.80 MUg mL(-1) Mo(VI); the mean value of a molybdenum(VI) was 4.83 MUg ml(-1) with a standard derivation of 0.002 MUg ml(-1) molybdenum(VI). PMID- 25835380 TI - Erratum. PMID- 25835379 TI - In situ investigation of the effect of TiF4 and CO2 laser irradiation on the permeability of eroded enamel. AB - OBJECTIVE: Interest in erosion and its role in tooth wear has increased considerably. Due to the limited contribution of patients in modifying their dietary habits, therapeutic resources aiming to reduce the progression of erosion like lesions have been discussed. This study sought to evaluate the effect of TiF4 and CO2 laser in controlling the permeability of in situ eroded enamel. DESIGN: Ten volunteers wore an intraoral palatal device containing two enamel slabs, treated with TiF4 gel and TiF4 gel + CO2 or placebo gel and placebo gel + CO2. After the washout period, volunteers were crossed over to the other treatment. During both phases, specimens were submitted to erosive challenges and then evaluated for permeability measured as the percentage of copper ion penetration over the total enamel thickness. RESULTS: Two-way analysis of variance (ANOVA) revealed that there was a significant interaction between the factors under study (p = 0.0002). Tukey's test showed that TiF4 significantly reduced the enamel permeability of eroded enamel specimens, regardless of whether CO2 laser irradiation was performed. CONCLUSIONS: It may be concluded that when the placebo gel was applied, CO2 laser was able to reduce enamel permeability; however, when TiF4 was applied, laser irradiation did not imply a reduction in permeability. TiF4 provided a lower permeability of eroded enamel, regardless of whether the CO2 laser was used. PMID- 25835381 TI - Maternal risk factors associated with lead, mercury and cadmium levels in umbilical cord blood, breast milk and newborn hair. AB - OBJECTIVE: Lead (Pb), mercury (Hg) and cadmium (Cd) are environmental pollutants that are wide spread throughout the world. The present study aimed to investigate the level of exposure to Pb, Hg and Cd during the prenatal period, and the possible routes of maternal exposure to these toxic heavy metals. PARTICIPANTS: The study included 123 mothers and their newborns. Umbilical cord blood samples were collected immediately after delivery, and breast milk and newborn hair samples were collected between postpartum d 3 and 10. RESULTS: Among the 121 cord blood samples that were analyzed, Pb was present in 120 (99.2%) and the mean level was 1.66 +/- 1.60 ug dL(-1) (range: =2 ug dL(-1) in 29% of the samples. Pb, Hg and Cd were detectable in all the newborn hair samples. DISCUSSION: Among the 107 breast milk samples analyzed, 89 (83.2%) had a detectable level of Pb and the mean level was 14.56 +/- 12.13 ugL(-1). Detection rate of Cd in breast milk was higher in women who resided near to city waste disposal site. Detection rate of Cd in cord blood was significantly higher in the women who consumed >=2 servings of fish weekly. Maternal exposure to environmental tobacco smoke (ETS) resulted in elevated levels of Pb and Cd in newborn hair samples. CONCLUSION: Most of the study samples had detectable levels of Pb, Hg and Cd, indicating that there was long term maternal exposure prior to and during pregnancy, and a considerable number of the cord and breast milk samples had levels that exceeded the present accepted safety level. PMID- 25835382 TI - In situ changes of tropical crustose coralline algae along carbon dioxide gradients. AB - Crustose coralline algae (CCA) fulfill important ecosystem functions in coral reefs, including reef framework stabilization and induction of larval settlement. To investigate in situ the effects of high carbon dioxide on CCA communities, we deployed settlement tiles at three tropical volcanic CO2 seeps in Papua New Guinea along gradients spanning from 8.1 to 7.4 pH. After 5 and 13 months deployment, there was a steep transition from CCA presence to absence around pH 7.8 (660 MUatm pCO2): 98% of tiles had CCA at pH > 7.8, whereas only 20% of tiles had CCA at pH <= 7.8. As pH declined from 8.0 to 7.8, the least and most sensitive CCA species lost 43% and 85% of cover, respectively. Communities on upward facing surfaces exposed to high light and high grazing pressure showed less steep losses than those on shaded surfaces with low grazing. Direct CO2 effects on early life stages were the main mechanisms determining CCA cover, rather than competitive interactions with other benthic groups. Importantly, declines were steepest at near-ambient pH, suggesting that CCA may have already declined in abundance due to the recent seawater pH decline of 0.1 units, and that future severe losses are likely with increasing ocean acidification. PMID- 25835383 TI - Increased autoimmune diabetes in pIgR-deficient NOD mice is due to a "Hitchhiking" interval that refines the genetic effect of Idd5.4. AB - Selective breeding to introduce a gene mutation from one mouse strain onto the genetic background of another strain invariably produces "hitchhiking" (i.e. flanking) genomic intervals, which may independently affect a disease trait of interest. To investigate a role for the polymeric Ig receptor in autoimmune diabetes, a congenic nonobese diabetic (NOD) mouse strain was generated that harbors a Pigr null allele derived from C57BL/6 (B6) mice. These pIgR-deficient NOD mice exhibited increased serum IgA along with an increased diabetes incidence. However, the Pigr null allele was encompassed by a relatively large "hitchhiking" genomic interval that was derived from B6 mice and overlaps Idd5.4, a susceptibility locus for autoimmune diabetes. Additional congenic NOD mouse strains, harboring smaller B6-derived intervals, confirmed Idd5.4 independently of the other three known susceptibility loci on chromosome 1, and further localized Idd5.4 to an interval proximal to Pigr. Moreover, these congenic NOD mice showed that B6 mice harbor a more diabetogenic allele than NOD mice for this locus. The smallest B6-derived interval encompassing the Pigr null allele may, however, confer a small degree of protection against diabetes, but this protection appears to be dependent on the absence of the diabetogenic B6 allele for Idd5.4. This study provides another example of the potential hidden effects of "hitchhiking" genomic intervals and how such intervals can be used to localize disease susceptibility loci. PMID- 25835384 TI - Clostridium perfringens enterotoxin (CPE) and CPE-binding domain (c-CPE) for the detection and treatment of gynecologic cancers. AB - Clostridium perfringens enterotoxin (CPE) is a three-domain polypeptide, which binds to Claudin-3 and Claudin-4 with high affinity. Because these receptors are highly differentially expressed in many human tumors, claudin-3 and claudin-4 may provide an efficient molecular tool to specifically identify and target biologically aggressive human cancer cells for CPE-specific binding and cytolysis. In this review we will discuss these surface proteins as targets for the detection and treatment of chemotherapy-resistant gynecologic malignancies overexpressing claudin-3 and -4 using CPE-based theranostic agents. We will also discuss the use of fluorescent c-CPE peptide in the operative setting for real time detection of micro-metastatic tumors during surgery and review the potential role of CPE in other medical applications. PMID- 25835386 TI - Bio-inspired wooden actuators for large scale applications. AB - Implementing programmable actuation into materials and structures is a major topic in the field of smart materials. In particular the bilayer principle has been employed to develop actuators that respond to various kinds of stimuli. A multitude of small scale applications down to micrometer size have been developed, but up-scaling remains challenging due to either limitations in mechanical stiffness of the material or in the manufacturing processes. Here, we demonstrate the actuation of wooden bilayers in response to changes in relative humidity, making use of the high material stiffness and a good machinability to reach large scale actuation and application. Amplitude and response time of the actuation were measured and can be predicted and controlled by adapting the geometry and the constitution of the bilayers. Field tests in full weathering conditions revealed long-term stability of the actuation. The potential of the concept is shown by a first demonstrator. With the sensor and actuator intrinsically incorporated in the wooden bilayers, the daily change in relative humidity is exploited for an autonomous and solar powered movement of a tracker for solar modules. PMID- 25835387 TI - Cs(TaO2)3(SeO3)2 and Cs(TiOF)3(SeO3)2: structural and second harmonic generation changes induced by the different d(0)-TM coordination octahedra. AB - Two new cesium selenites containing TaO6 or TiO4F2 octahedra, namely, Cs(TaO2)3(SeO3)2 (1) and Cs(TiOF)3(SeO3)2 (2), have been prepared using standard high temperature solid-state method and hydrothermal reaction, respectively. Compound 1 crystallizes in P3m1 and features an unusual [(TaO2)3(SeO3)2](-) sandwich-like double layer in which two [Ta(1)O3(SeO3)](3-) layers are bridged by central Ta(2)O6 octahedra via corner-sharing, whereas Cs(TiOF)3(SeO3)2 with a polar space group P63mc features an interesting hexagonal tungsten oxide (HTO) layered topology and presents a strong second harmonic generation (SHG) of about 5 * KDP (KH2PO4), which is much larger than those of A(VO2)3(QO3)2 (A = K, Tl, Rb, Cs, or NH4; Q = Se, Te) with a similar HTO layered structure. Cs(TiOF)3(SeO3)2 is also type-I phase matching. The SHG of above-mentioned HTO materials can be enhanced greatly with the replacement of VO6 octahedra by TiO4F2 octahedra. Furthermore, thermal stabilities, UV-vis diffuse reflectance spectra, infrared spectra, relationship between crystal structure and SHG, and theoretical calculations were also reported. PMID- 25835385 TI - Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: melittin, apamin and mastoparan. AB - While knowledge of the composition and mode of action of bee and wasp venoms dates back 50 years, the therapeutic value of these toxins remains relatively unexploded. The properties of these venoms are now being studied with the aim to design and develop new therapeutic drugs. Far from evaluating the extensive number of monographs, journals and books related to bee and wasp venoms and the therapeutic effect of these toxins in numerous diseases, the following review focuses on the three most characterized peptides, namely melittin, apamin, and mastoparan. Here, we update information related to these compounds from the perspective of applied science and discuss their potential therapeutic and biotechnological applications in biomedicine. PMID- 25835389 TI - Erratum: In vitro and in vivo anti-schistosomal activity of the alkylphospholipid analog edelfosine. PMID- 25835388 TI - Chromosome replacement and deletion lead to clonal polymorphism of berry color in grapevine. AB - Clonal polymorphism mainly results from somatic mutations that occur naturally during plant growth. In grapevine, arrays of clones have been selected within varieties as a valuable source of diversity, among them clones showing berry color polymorphism. To identify mutations responsible for this color polymorphism, we studied a collection of 33 clones of Pinot noir, Pinot gris, and Pinot blanc. Haplotypes of the L2 cell layer of nine clones were resolved by genotyping self-progenies with molecular markers along a 10.07 Mb region of chromosome 2, including the color locus. We demonstrated that at least six haplotypes could account for the loss of anthocyanin biosynthesis. Four of them resulted from the replacement of sections of the 'colored' haplotype, sized from 31 kb to 4.4 Mb, by the homologous sections of the 'white' haplotype mutated at the color locus. This transfer of information between the two homologous sequences resulted in the partial homozygosity of chromosome 2, associated in one case with a large deletion of 108 kb-long. Moreover, we showed that, in most cases, somatic mutations do not affect the whole plant; instead, they affect only one cell layer, leading to periclinal chimeras associating two genotypes. Analysis of bud sports of Pinot gris support the hypothesis that cell layer rearrangements in the chimera lead to the homogenization of the genotype in the whole plant. Our findings shed new light on the way molecular and cellular mechanisms shape the grapevine genotypes during vegetative propagation, and enable us to propose a scheme of evolutionary mechanism of the Pinot clones. PMID- 25835390 TI - Early successional microhabitats allow the persistence of endangered plants in coastal sand dunes. AB - Many species are adapted to disturbance and occur within dynamic, mosaic landscapes that contain early and late successional microhabitats. Human modification of disturbance regimes alters the availability of microhabitats and may affect the viability of species in these ecosystems. Because restoring historical disturbance regimes is typically expensive and requires action at large spatial scales, such restoration projects must be justified by linking the persistence of species with successional microhabitats. Coastal sand dune ecosystems worldwide are characterized by their endemic biodiversity and frequent disturbance. Dune-stabilizing invasive plants alter successional dynamics and may threaten species in these ecosystems. We examined the distribution and population dynamics of two federally endangered plant species, the annual Layia carnosa and the perennial Lupinus tidestromii, within a dune ecosystem in northern California, USA. We parameterized a matrix population model for L. tidestromii and examined the magnitude by which the successional stage of the habitat (early or late) influenced population dynamics. Both species had higher frequencies and L. tidestromii had higher frequency of seedlings in early successional habitats. Lupinus tidestromii plants in early successional microhabitats had higher projected rates of population growth than those associated with stabilized, late successional habitats, due primarily to higher rates of recruitment in early successional microhabitats. These results support the idea that restoration of disturbance is critical in historically dynamic landscapes. Our results suggest that large-scale restorations are necessary to allow persistence of the endemic plant species that characterize these ecosystems. PMID- 25835391 TI - Ternary Ag/epoxy adhesive with excellent overall performance. AB - Excellent electrical conductivity (EC) generally conflicts with high lap shear strength (LSS) for electrically conductive adhesives (ECAs) since EC increases while LSS decreases with increasing conductive filler content. In this work, the ECAs with the excellent overall performance are developed based on the ternary hybrid of Ag microflakes (Ag-MFs), Ag nanospheres (Ag-NSs), and Ag nanowires (Ag NWs). First, a low silver content adhesive system is determined. Then, the effects of the relative contents of Ag fillers on the EC and the LSS are studied. It is shown that a small amount of Ag-NSs or Ag-NWs can dramatically improve the EC for the Ag-MF/epoxy adhesives. The Ag-NSs and Ag-NWs with appropriate contents have a synergistic effect in improving the EC. Meanwhile, the LSS of the as prepared adhesive with the appropriate Ag contents reaches an optimal value. Both the EC and the LSS of the as-prepared ternary hybrid ECA with a low content of 40 wt % Ag are higher than those of the commercial ECAs filled with the Ag-MF content over 60 wt %. Finally, the ternary hybrid ECA with the optimal formulation is shown to be promising for printing the radio frequency identification tag antennas as an immediate application example. PMID- 25835392 TI - Hydrogen peroxide-inducible clone-5 regulates mesangial cell proliferation in proliferative glomerulonephritis in mice. AB - Hydrogen peroxide-inducible clone-5 (Hic-5) is a transforming growth factor (TGF) beta1-inducible focal adhesion protein. We previously demonstrated that Hic-5 was localized in mesangial cells and its expression was associated with glomerular cell proliferation and matrix expansion in human and rat glomerulonephritis (GN). In the present study, we first assessed the role of Hic-5 in mesangioproliferative GN by injecting Habu venom into heminephrectomized wild type (Hic-5+/+) and Hic-5-deficient (Hic-5-/-) mice. Hic-5+/+ GN mice exhibited glomerular cell proliferation on day 7. Surprisingly, glomerular cell number and Ki-67-positive cells in Hic-5-/- GN mice were significantly greater than those in Hic-5+/+ GN mice on day 7, although the number of glomerular apoptotic cells and the expression of growth factors (platelet-derived growth factor-BB and TGF beta1) and their receptors were similarly increased in both Hic-5+/+ and Hic-5-/- GN mice. In culture experiments, proliferation assays showed that platelet derived growth factor-BB and TGF-beta1 enhanced the proliferation of Hic-5-/- mesangial cells compared with Hic-5+/+ mesangial cells. In addition, mitogenic regulation by Hic-5 was associated with altered and coordinated expression of cell cycle-related proteins including cyclin D1 and p21. The present results suggest that Hic-5 might regulate mesangial cell proliferation in proliferative GN in mice. In conclusion, modulation of Hic-5 expression might have a potential to prevent mesangial cell proliferation in the acute mitogenic phase of glomerulonephritis. PMID- 25835393 TI - Childhood- versus adolescent-onset antisocial youth with conduct disorder: psychiatric illness, neuropsychological and psychosocial function. AB - OBJECTIVE: The present study investigates whether youths with childhood-onset antisocial behavior have higher rates of psychiatric illness, neuropsychological and psychosocial dysfunction than youths who engage in antisocial behavior for the first time in adolescence. Prior studies have generally focused on single domains of function in heterogeneous samples. The present study also examined the extent to which adolescent-onset antisocial behavior can be considered normative, an assumption of Moffitt's dual taxonomy model. METHOD: Forty-three subjects (34 males, 9 females, mean age = 15.31, age range 12-21) with a diagnosis of conduct disorder (CD) were recruited through Headspace Services and the Juvenile Justice Community Centre. We compared childhood-onset antisocial youths (n = 23) with adolescent-onset antisocial youths (n = 20) with a conduct disorder, across a battery of psychiatric, neuropsychological and psychosocial measures. Neuropsychological function of both groups was also compared with normative scores from control samples. RESULTS: The childhood-onset group displayed deficits in verbal learning and memory, higher rates of psychosis, childhood maltreatment and more serious violent behavior, all effects associated with a large effect size. Both groups had impaired executive function, falling within the extremely low range (severely impaired). CONCLUSIONS: Childhood-onset CD displayed greater cognitive impairment, more psychiatric symptoms and committed more serious violent offences. The finding of severe executive impairment in both childhood- and adolescent-onset groupings challenges the assumption that adolescent-onset antisocial behavior is a normative process. PMID- 25835395 TI - Correction: Retinol improves in vitro differentiation of pre-pubertal mouse spermatogonial stem cells into sperm during the first wave of spermatogenesis. PMID- 25835398 TI - JNK2 Regulates Stress-Induced Mitophagy. PMID- 25835394 TI - Heme oxygenase-1 protects corexit 9500A-induced respiratory epithelial injury across species. AB - The effects of Corexit 9500A (CE) on respiratory epithelial surfaces of terrestrial mammals and marine animals are largely unknown. This study investigated the role of CE-induced heme oxygenase-1 (HO-1), a cytoprotective enzyme with anti-apoptotic and antioxidant activity, in human bronchial airway epithelium and the gills of exposed aquatic animals. We evaluated CE-mediated alterations in human airway epithelial cells, mice lungs and gills from zebrafish and blue crabs. Our results demonstrated that CE induced an increase in gill epithelial edema and human epithelial monolayer permeability, suggesting an acute injury caused by CE exposure. CE induced the expression of HO-1 as well as C reactive protein (CRP) and NADPH oxidase 4 (NOX4), which are associated with ROS production. Importantly, CE induced caspase-3 activation and subsequent apoptosis of epithelial cells. The expression of the intercellular junctional proteins, such as tight junction proteins occludin, zonula occludens (ZO-1), ZO-2 and adherens junctional proteins E-cadherin and Focal Adhesion Kinase (FAK), were remarkably inhibited by CE, suggesting that these proteins are involved in CE induced increased permeability and subsequent apoptosis. The cytoskeletal protein F-actin was also disrupted by CE. Treatment with carbon monoxide releasing molecule-2 (CORM-2) significantly inhibited CE-induced ROS production, while the addition of HO-1 inhibitor, significantly increased CE-induced ROS production and apoptosis, suggesting a protective role of HO-1 or its reaction product, CO, in CE-induced apoptosis. Using HO-1 knockout mice, we further demonstrated that HO-1 protected against CE-induced inflammation and cellular apoptosis and corrected CE mediated inhibition of E-cadherin and FAK. These observations suggest that CE activates CRP and NOX4-mediated ROS production, alters permeability by inhibition of junctional proteins, and leads to caspase-3 dependent apoptosis of epithelial cells, while HO-1 and its reaction products protect against oxidative stress and apoptosis. PMID- 25835399 TI - A targeted therapy-driven tumor secretome underlies drug resistance. PMID- 25835401 TI - Nivolumab approved for lung cancer. PMID- 25835402 TI - Mediated learning in the workplace: student perspectives on knowledge resources. AB - PURPOSE: In contemporary clinical practice, student radiographers can use many types of knowledge resources to support their learning. These include workplace experts, digital and nondigital information sources (eg, journals, textbooks, and the Internet), and electronic communication tools such as e-mail and social media. Despite the range of knowledge tools available, there is little available data about radiography students' use of these resources during clinical placement. METHODS: A 68-item questionnaire was distributed to 62 students enrolled in an Australian university undergraduate radiography program after they completed a clinical placement. Researchers used descriptive statistics to analyze student access to workplace experts and their use of digital and nondigital information sources and electronic communication tools. A 5-point Likert scale (1 = very important; 5 = not important) was used to assess the present importance and perceived future value of knowledge tools for workplace learning. RESULTS: Of the 53 students who completed and returned the questionnaire anonymously, most rely on the knowledge of practicing technologists and on print and electronic information sources to support their learning; some students also use electronic communication tools. Students perceive that these knowledge resources also will be important tools for their future learning as qualified health professionals. DISCUSSION: The findings from this study present baseline data regarding the value students attribute to multiple knowledge tools and regarding student access to and use of these tools during clinical placement. In addition, most students have access to multiple knowledge tools in the workplace and incorporate these tools simultaneously into their overall learning practice during clinical placement. CONCLUSION: Although a range of knowledge tools is used in the workplace to support learning among student radiographers, the quality of each tool should be critically analyzed before it is adopted in practice. Integrating practice-based learning with learning mediated by information sources provides a more complete paradigm of learning during clinical placement. PMID- 25835403 TI - A comparison of sequential and spiral scanning techniques in brain CT. AB - PURPOSE: To evaluate and compare image quality and radiation dose of sequential computed tomography (CT) examinations of the brain and spiral CT examinations of the brain imaged on a GE HiSpeed NX/I Dual Slice 2CT scanner. METHODS: A random sample of 40 patients referred for CT examination of the brain was selected and divided into 2 groups. Half of the patients were scanned using the sequential technique; the other half were scanned using the spiral technique. Radiation dose data-both the computed tomography dose index (CTDI) and the dose length product (DLP)-were recorded on a checklist at the end of each examination. Using the European Guidelines on Quality Criteria for Computed Tomography, 4 radiologists conducted a visual grading analysis and rated the level of visibility of 6 anatomical structures considered necessary to produce images of high quality. RESULTS: The mean CTDI(vol) and DLP values were statistically significantly higher (P <.05) with the sequential scans (CTDI(vol): 22.06 mGy; DLP: 304.60 mGy * cm) than with the spiral scans (CTDI(vol): 14.94 mGy; DLP: 229.10 mGy * cm). The mean image quality rating scores for all criteria of the sequential scanning technique were statistically significantly higher (P <.05) in the visual grading analysis than those of the spiral scanning technique. DISCUSSION: In this local study, the sequential technique was preferred over the spiral technique for both overall image quality and differentiation between gray and white matter in brain CT scans. Other similar studies counter this finding. CONCLUSION: The radiation dose seen with the sequential CT scanning technique was significantly higher than that seen with the spiral CT scanning technique. However, image quality with the sequential technique was statistically significantly superior (P <.05). PMID- 25835404 TI - Light beam diaphragm collimation errors and their effects on radiation dose for pelvic radiography. AB - PURPOSE: To investigate the range of collimation errors in x-ray rooms and to calculate their possible effects on the radiation dose for anteroposterior pelvic examinations. METHODS: A collimator test tool was suspended at 3 heights (14, 21, and 28 cm) above the table Bucky in 9 x-ray rooms. Heights corresponded to the typical patient thickness (mean, +/- 2 SD) of 67 patients undergoing anteroposterior pelvic radiography. The x-ray beam was visually collimated to the inner boundary of the test tool and exposed to radiation. Differences between the visualized field size and the resultant x-ray field size (corrected for magnification) indicated a collimation error. Next, using a pelvic phantom, minimum textbook collimation was set and then changed and verified to simulate a range of possible collimation errors. Phantom examinations used a standard anteroposterior technique with exposure termination using outer automatic exposure control chambers. Dose area product (DAP) was recorded. RESULTS: All but 1 of the 9 x-ray machines had a smaller irradiated area than was visually set. Errors ranged from a 16% reduction in irradiated field size to a slight overirradiation by 0.4%. Assuming that these errors could be larger in other institutions, additional errors with a range of -27% to 18% were simulated. Increases in field size by 1 cm (superiorly/inferiorly) increased the DAP by 5%. Laterally, a 1-cm increase caused a 4% rise in DAP. Increases of 1 cm in both planes raised DAP by 4%. DISCUSSION: Within a single clinical department, minimal collimation errors were demonstrated. Further evidence from multiple centers would be beneficial; however, such low incidences might reflect strict legislative requirements governing the use of ionizing radiation. Understanding the magnitude of any error is important, but it is also important to ascertain an error's influence on the effective radiation dose for any given examination. CONCLUSION: Overall, collimation errors were minimal and favored underirradiation. Small collimation errors can affect DAP and are more dose significant in the superior/inferior plane. PMID- 25835405 TI - Techniques, benefits, and challenges of PET-MR. AB - Positron emission tomography (PET) scans can now be acquired in unison with magnetic resonance (MR) scans as a single resource. This hybrid PET-MR solution combines the anatomic detail and functional data of MR scans with the biologic or physiological information offered by PET scans. This article describes aspects of implementing a PET-MR imaging program, including various technical and operational challenges, scheduling and workflow solutions, room construction and equipment, and finally clinical applications of this novel modality. The Directed Reading also discusses the possible future role of PET-MR in the clinical setting. PMID- 25835406 TI - Acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is a life-threatening condition with multiple causes and a high mortality rate. Approximately 150,000 cases are reported in the United States annually, making ARDS a public health concern. Management of the condition is complex because of its severity, and medical imaging is essential for both the diagnosis and management of ARDS. This article introduces common signs, symptoms, risk factors, and causes of ARDS. Diagnostic criteria, histopathology, treatment strategies, and prognostic information also are discussed. The article explains the value of medical imaging studies of ARDS, especially radiography, computed tomography, and ultrasonography. PMID- 25835407 TI - Signal equalization processing artifacts. PMID- 25835408 TI - Competency-based education: a brief overview. PMID- 25835409 TI - A generational assessment of volunteerism among radiation science professionals. PMID- 25835410 TI - Mammography training at home and abroad. PMID- 25835411 TI - A modified Danelius-Miller method solution. PMID- 25835412 TI - Writing for publication: enhancing your scientific writing skills. PMID- 25835413 TI - Positioning challenges. PMID- 25835414 TI - Bullies are common. PMID- 25835416 TI - The "lumpy" chest. PMID- 25835415 TI - Quo vadis: where are we going? PMID- 25835417 TI - Breast disorders in pregnant and lactating women. AB - The breast undergoes extensive changes during pregnancy and lactation that can create diagnostic challenges. This article reviews the anatomy of the breast, breast changes associated with pregnancy and lactation, and breast imaging techniques for pregnant and lactating women. Various benign breast conditions in this patient population also are discussed, such as lactating adenomas, galactoceles, and granulomatous mastitis. Finally, pregnancy-associated breast cancer is presented, including its epidemiology, diagnosis, staging, treatment, and prognosis. PMID- 25835418 TI - Variants in Antiviral Genes are Risk Factors for Cognitive Decline and Dementia. AB - A gene association study of factors regulating antiviral response such as interferon (IFN)-lambda3, also known as IL-28B, mediator complex (Med) 23, and interferon regulatory factor (IRF) 7 with cognitive deterioration and Alzheimer's disease (AD) was performed. Differences in the TT genotype distribution of IL-28B single nucleotide polymorphism (SNP) between AD patients and controls were found. The GG genotype of Med23 gene appeared to influence the progression of the disease, being more frequent in the APOE E4 negative elderly that developed AD during the five year follow-up. Leukocyte positivity for Epstein Barr virus (EBV) and human herpes virus (HHV)-6 DNA was analyzed. Med23 GG genotype correlated with the positivity to HHV-6 DNA. EBV and HHV-6 plasma IgG levels were also investigated and EBV IgG levels were increased in AD with the IRF7 GG genotype. A differential genetic background in genes regulating anti-virus responses was associated with an increased risk of cognitive decline and AD. EBV and HHV-6 appeared to be risk factors for AD in genetically susceptible elderly. PMID- 25835419 TI - Altered Neural Activity during Semantic Object Memory Retrieval in Amnestic Mild Cognitive Impairment as Measured by Event-Related Potentials. AB - Deficits in semantic memory in individuals with amnestic mild cognitive impairment (aMCI) have been previously reported, but the underlying neurobiological mechanisms remain to be clarified. We examined event-related potentials (ERPs) associated with semantic memory retrieval in 16 individuals with aMCI as compared to 17 normal controls using the Semantic Object Retrieval Task (EEG SORT). In this task, subjects judged whether pairs of words (object features) elicited retrieval of an object (retrieval trials) or not (non retrieval trials). Behavioral findings revealed that aMCI subjects had lower accuracy scores and marginally longer reaction time compared to controls. We used a multivariate analytical technique (STAT-PCA) to investigate similarities and differences in ERPs between aMCI and control groups. STAT-PCA revealed a left fronto-temporal component starting at around 750 ms post-stimulus in both groups. However, unlike controls, aMCI subjects showed an increase in the frontal parietal scalp potential that distinguished retrieval from non-retrieval trials between 950 and 1050 ms post-stimulus negatively correlated with the performance on the logical memory subtest of the Wechsler Memory Scale-III. Thus, individuals with aMCI were not only impaired in their behavioral performance on SORT relative to controls, but also displayed alteration in the corresponding ERPs. The altered neural activity in aMCI compared to controls suggests a more sustained and effortful search during object memory retrieval, which may be a potential marker indicating disease processes at the pre-dementia stage. PMID- 25835420 TI - Zinc and Copper in Alzheimer's Disease. AB - In a recent meta-analysis by Ventriglia and colleagues studying the association of zinc levels with Alzheimer's disease (AD), serum zinc has been found significantly decreased in AD patients compared with healthy controls. However, such a finding does not necessarily propose the causal role of low zinc in the pathophysiology of this neurodegenerative disease. On the basis of available evidence, free copper toxicosis may play a causal role in age-related AD, and zinc therapy can be a rational causal treatment. Nevertheless, a randomized controlled clinical trial testing a definite hypothesis is needed before conclusions can be drawn about the value of zinc supplements in the treatment of AD. PMID- 25835421 TI - The Synergistic Relationship between Alzheimer's Disease and Sleep Disorders: An Update. AB - Sleep disorders are frequently reported in Alzheimer's disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Although changes in sleep organization are a hallmark of the normal aging processes, sleep macro- and micro-architectural alterations are more evident in patients affected by AD. Degeneration of neural pathways regulating sleep-wake patterns and sleep architecture may contribute to sleep alterations. In return, several recent studies suggested that common sleep disorders may precede clinical symptoms of dementia and represent risk factors for cognitive decline, through impairment of sleep-dependent memory consolidation processes. Thus, a close relationship between sleep disorders and AD has been largely hypothesized. Here, sleep alterations in AD and its pre-dementia stage, mild cognitive impairment, and their complex interactions are reviewed. PMID- 25835422 TI - False Positives, Outliers, and Other Considerations in Decisional Capacity Screening for Research Consent. PMID- 25835423 TI - Gender-Specific Differences in Cognitive Profiles of Patients with Alzheimer's Disease: Results of the Prospective Dementia Registry Austria (PRODEM-Austria). AB - BACKGROUND: Alzheimer's disease (AD) is one of the most common age-related diseases in the western world. Gender differences in neuropsychological functions are seldom evaluated in AD. OBJECTIVE: Recent investigations suggested that gender may be an important modifying factor in the development and progression of AD. We examined gender-specific differences in the pattern of cognitive dysfunction of patients with mild to moderate AD. METHODS: We examined 113 males (mean age 78) and 173 females (mean age 80) of the prospective registry on dementia in Austria (PRODEM). We analyzed differences in the cognitive profile between male and female AD patients on the CERAD-Plus test battery. RESULTS: We found gender-related differences in the neuropsychological domains of verbal learning; the women tended to perform worse than men. Controlling for depression, stage and duration of dementia, and the level of education, there was still a significant effect of gender on verbal episodic memory. CONCLUSION: There is an interaction between gender and cognitive function, most notable in verbal episodic memory; female patients in the early stage of AD performed worse on verbal episodic memory than men. This indicates that the gender-specificities of neuropsychological functions should be given careful consideration in clinical diagnosis of dementia. PMID- 25835424 TI - Metabolic Modifications in Human Biofluids Suggest the Involvement of Sphingolipid, Antioxidant, and Glutamate Metabolism in Alzheimer's Disease Pathogenesis. AB - Alzheimer's disease (AD) is the most common neurodegenerative dementia, with the accumulation of extracellular amyloid-beta and formation of neurofibrillary tau tangles as leading explanations of pathology. With the difficulties of studying the brain directly, it is hoped that identifying the effect of AD on the metabolite composition of biofluids will provide insights into underlying mechanisms of pathology. The present review identified 705 distinct metabolite reports representing 448 structurally distinct metabolites in six human biofluids, with 147 metabolites increased and 214 metabolites decreased with AD, while 80 metabolites showed inconsistent shifts. Sphingolipid, antioxidant, and glutamate metabolism were found to be strongly associated with AD and were selected for detailed investigation of their role in pathogenesis. In plasma, two ceramides increased and eight sphingomyelins decreased with AD, with total ceramides shown to increase in both serum and cerebrospinal fluid. In general antioxidants were shown to be depleted, with oxidative stress markers elevated in a range of biofluids in patients suggesting AD produces a pro-oxidative environment. Shifts in glutamate and glutamine and elevation of 4-hydroxy-2 nonenal suggests peroxidation of the astrocyte lipid bilayer resulting in reduced glutamate clearance from the synaptic cleft, suggesting a excitotoxicity component to AD pathology; however, due to inconsistencies in literature reports, reliable interpretation is difficult. The present review has shown that metabolite shifts in biofluids can provide valuable insights into potential pathological mechanisms in the brain, with sphingolipid, antioxidant, and glutamate metabolism being implicated in AD pathology. PMID- 25835425 TI - Genetics of Vascular Dementia: Systematic Review and Meta-Analysis. AB - BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia. So far, little is known about the contribution of genetic polymorphisms to the risk of VaD. Many candidate genetic polymorphisms have been examined in a large number of studies. However, due to the conflicting results, the genetics of VaD is still behind the shadow. OBJECTIVE: We conducted a comprehensive meta-analysis on associations between genetic polymorphisms of any gene and VaD to investigate the genetics of VaD. METHOD: We sought the published studies of associations between any genetic polymorphism and VaD and critically appraised them. We assessed the effects of genetic models by calculating pooled odds ratios (ORs), investigating the origin of heterogeneity by subgroup analysis, and testing the robustness by random effect model and sensitivity analysis. RESULTS: 69 studies with 4,462 cases and 11,583 controls were included. We identified APOE E2/E3/E4 and additional four genetic polymorphisms including MTHFR C677T, PON1 L55M, TGF beta1 +29C/T, and TNF-alpha -850C/T associated with VaD. Tested by random effect model and sensitivity analysis, the pooled results show nice robustness. CONCLUSIONS: Our comprehensive meta-analysis highlighted the genetic contribution to sporadic VaD. Because of the small amount of data on associations between genetic polymorphisms, except for APOE, and VaD, more studies are needed to test the existing genetic polymorphisms and detect other related genetic variants. PMID- 25835426 TI - Characterizing Sexual Behavior in Frontotemporal Dementia. AB - BACKGROUND: Frontotemporal dementia (FTD) is characterized by a number of prominent behavioral changes. While FTD has been associated with the presence of aberrant or unusual sexual behaviors in a proportion of patients, few studies have formally investigated changes in sexual function in this disease. OBJECTIVE: We aimed to systematically quantify changes in sexual behavior, including current symptoms and changes from prior diagnoses, in behavioral-variant (bvFTD) and semantic dementia (SD), compared to Alzheimer's disease (AD). METHODS: Carers of 49 dementia patients (21 bvFTD, 11 SD, 17 AD) were interviewed using the Sexual Behavior and Intimacy Questionnaire (SIQ), a survey designed to assess changes in sexual function across multiple domains including initiating, level of affection, and aberrant or unusual sexual behavior. RESULTS: BvFTD patients show prominent hyposexual behavior including decreased affection, initiation, and response to advances by partners, and decreased frequency of sexual relations, compared to AD and to SD patients. The greatest changes in sexual behavior compared to pre diagnoses were found in the bvFTD group with a 90-100% decrease in initiation, response, and frequency of sexual relations. Notably, aberrant or unusual sexual behavior was reported in a minority of bvFTD and SD patients and occurred in patients who also showed hyposexual behavior toward their partner. CONCLUSION: Overall loss of affection, reduced initiation of sexual activity, and responsiveness is an overwhelming feature of bvFTD. In contrast, aberrant or unusual sexual behavior is observed in the minority of bvFTD patients. The underlying pathophysiology of these changes likely reflects structural and functional changes in frontoinsular and limbic regions including the hypothalamus. PMID- 25835427 TI - Effects of Aerobic Training on Cognition and Brain Glucose Metabolism in Subjects with Mild Cognitive Impairment. AB - BACKGROUND: Aerobic training (AT) is a promising intervention for mild cognitive impairment (MCI). OBJECTIVE: To evaluate the effects of AT on cognition and regional brain glucose metabolism (rBGM) in MCI patients. METHODS: Subjects performed a twice-a-week, moderate intensity, AT program for 24 weeks. Assessment with ADAS-cog, a comprehensive neuropsychological battery, and evaluation of rBGM with positron emission tomography with 18F-fluorodeoxyglucose ([18F]FDG-PET) were performed before and after the intervention. Aerobic capacity was compared using the maximal oxygen consumption VO2max (mL/Kg/min). [18F]FDG-PET data were analyzed on a voxel-by-voxel basis with SPM8 software. RESULTS: Forty subjects were included, with a mean (M) age of 70.3 (5.4) years and an initial Mini-Mental State Exam score of 27.4 (1.7). Comparisons using paired t-tests revealed improvements in the ADAS-cog (M difference: -2.7 (3.7), p < 0.001) and VO2max scores (M difference: 1.8 (2.0) mL/kg/min, p < 0.001). Brain metabolic analysis revealed a bilateral decrease in the rBGM of the dorsal anterior cingulate cortex, pFWE = 0.04. This rBGM decrease was negatively correlated with improvement in a visuospatial function/attentional test (rho =-0.31, p = 0.04). Several other brain areas also showed increases or decreases in rBGM. Of note, there was an increase in the retrosplenial cortex, an important node of the default mode network, that was negatively correlated with the metabolic decrease in the dorsal anterior cingulate cortex (r =-0.51, p = 0.001). CONCLUSION: AT improved cognition and changed rBGM in areas related to cognition in subjects with MCI. PMID- 25835430 TI - The MS4A family: counting past 1, 2 and 3. AB - The MS4A (membrane-spanning 4-domain family, subfamily A) family of proteins contains some well-known members including MS4A1 (CD20), MS4A2 (FcERIbeta) and MS4A3 (HTm4). These three MS4A family members are expressed on the cell surface of specific leukocyte subsets and have been well characterized as having key roles in regulating cell activation, growth and development. However, beyond MS4A1-3 there are a large number of related molecules (18 to date in humans) where our understanding of their biological roles is at a relatively nascent stage. This review examines the larger MS4A family focusing on their structure, expression, regulation and characterized and/or emerging biological roles. Our own work on one family member MS4A8B, and its possible role in epithelial cell regulation, is also highlighted. PMID- 25835431 TI - Introduction of a community water supply in rural western Kenya: impact on community wellbeing and child health. AB - BACKGROUND: This study aimed to examine water availability and community health before and after tube wells were introduced in a rural western Kenyan community. Differences in impact among income quintile groups were quantified, and users' perceptions of their water supply measured. METHODS: We conducted a two-part pre- (2009) and post-intervention (2011), cross-sectional study using structured questionnaires for mothers. RESULTS: In total, 1391 (576 in 2009 and 815 in 2011) mothers participated. Well introduction changed the households' drinking-water source from river to ground water. The median distance to the water source was reduced by 40% (500 to 300 metres) and median collection time was reduced by 50% (30 to 15 minutes). Water consumption per household increased by approximately 20% (from 82.6 to 99.0 L) and drinking of untreated water decreased by approximately 10%. Regression analyses revealed mothers with higher monthly incomes had the highest satisfaction levels (beta=0.167, p<0.001). Positive impacts were strongest among wealthier groups. CONCLUSIONS: The small-scale community water supply dramatically affected user hygiene behaviours and daily life. Water supply access improved from 'no access' to 'basic access'. Household connections to a water supply and hygiene education are important steps to enhance community health. PMID- 25835432 TI - Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. AB - BACKGROUND: Pneumocystis jiroveci pneumonia (PCP) remains the most common opportunistic infection in patients infected with the human immunodeficiency virus (HIV). Among patients with HIV infection and PCP the mortality rate is 10% to 20% during the initial infection and this increases substantially with the need for mechanical ventilation. It has been suggested that corticosteroids adjunctive to standard treatment for PCP could prevent the need for mechanical ventilation and decrease mortality in these patients. OBJECTIVES: To assess the effects of adjunctive corticosteroids on overall mortality and the need for mechanical ventilation in HIV-infected patients with PCP and substantial hypoxaemia (arterial oxygen partial pressure < 70 mmHg or alveolar-arterial gradient > 35 mmHg on room air). SEARCH METHODS: For the original review we searched The Cochrane Library (2004, Issue 4), MEDLINE (January 1980 to December 2004) and EMBASE (January 1985 to December 2004) without language restrictions. We further reviewed the reference lists from previously published overviews, searched UptoDate version 2005 and Clinical Evidence Concise (Issue 12, 2004), contacted experts in the field and searched the reference lists of identified publications for citations of additional relevant articles.In this update of our review, we searched the above-mentioned databases in September 2010 and April 2014 for trials published since our original review. We also searched for ongoing trials in ClinicalTrials.gov and the World Health Organization International Clinical Trial Registry Platform (ICTRP). We searched for conference abstracts via AEGIS. SELECTION CRITERIA: Randomised controlled trials that compared corticosteroids to placebo or usual care in HIV-infected patients with PCP in addition to baseline treatment with trimethoprim-sulfamethoxazole, pentamidine or dapsone-trimethoprim, and reported mortality data. We excluded trials in patients with no or mild hypoxaemia (arterial oxygen partial pressure > 70 mmHg or an alveolar-arterial gradient < 35 mmHg on room air) and trials with a follow-up of less than 30 days. DATA COLLECTION AND ANALYSIS: Two teams of review authors independently evaluated the methodology and extracted data from each primary study. We pooled treatment effects across studies and calculated a weighted average risk ratio of overall mortality in the treatment and control groups using a random-effects model.In this update of our review, we used the GRADE methodology to assess evidence quality. MAIN RESULTS: Of 2029 screened records, we included seven studies in the review and six in the meta-analysis. Risk of bias varied: the randomisation and allocation process was often not clearly described, five of seven studies were double-blind and there was almost no missing data. The quality of the evidence for mortality was high. Risk ratios for overall mortality for adjunctive corticosteroids were 0.56 (95% confidence interval (CI) 0.32 to 0.98) at one month and 0.59 (95% CI 0.41 to 0.85) at three to four months of follow-up. In adults, to prevent one death, numbers needed to treat are nine patients in a setting without highly active antiretroviral therapy (HAART) available, and 23 patients with HAART available. The three largest trials provided moderate quality data on the need for mechanical ventilation, with a risk ratio of 0.38 (95% CI 0.20 to 0.73) in favour of adjunctive corticosteroids. One study was conducted in infants, suggesting a risk ratio for death in hospital of 0.81 (95% CI 0.51 to 1.29; moderate quality evidence). AUTHORS' CONCLUSIONS: The number and size of trials investigating adjunctive corticosteroids for HIV infected patients with PCP is small, but the evidence from this review suggests a beneficial effect for adult patients with substantial hypoxaemia. There is insufficient evidence on the effect of adjunctive corticosteroids on survival in infants. PMID- 25835433 TI - Antiviral treatment of influenza in South Korea. AB - Antiviral therapy has an important role in the treatment and chemoprophylaxis of influenza. At present, two classes of antiviral agents, adamantanes and neuraminidase inhibitors, are available for the treatment and chemoprophylaxis of influenza in Korea. Because of the widespread resistance against adamantanes, neuraminidase inhibitors are mainly used. Because each country has a unique epidemiology of influenza, the proper use of antiviral agents should be determined based on local data. Decisions on the clinical practice in the treatment of influenza in South Korea are guided by the local surveillance data, practice guidelines, health insurance system and the resistance patterns of the circulating influenza viruses. This review highlights the role of antiviral agents in the treatment and outcome of influenza in Korea by providing comprehensive information of their clinical usage in Korea. PMID- 25835434 TI - In vivo biocompatibility of boron nitride nanotubes: effects on stem cell biology and tissue regeneration in planarians. AB - AIM: Boron nitride nanotubes (BNNTs) represent an extremely interesting class of nanomaterials, and recent findings have suggested a number of applications in the biomedical field. Anyhow, extensive biocompatibility investigations are mandatory before any further advancement toward preclinical testing. MATERIALS & METHODS: Here, we report on the effects of multiwalled BNNTs in freshwater planarians, one of the best-characterized in vivo models for developmental biology and regeneration research. RESULTS & DISCUSSION: Obtained results indicate that BNNTs are biocompatible in the investigated model, since they do not induce oxidative DNA damage and apoptosis, and do not show adverse effects on planarian stem cell biology and on de novo tissue regeneration. In summary, collected findings represent another important step toward BNNT realistic applications in nanomedicine. PMID- 25835435 TI - Medication adherence in people dually treated for HIV infection and mental health conditions: test of the medications beliefs framework. AB - Beliefs about medication necessity and concerns predict treatment adherence in people with a wide-array of medical conditions, including HIV infection. However, medication beliefs have not been examined in people dually treated with psychotropic medications and antiretroviral therapy. In the current study, we used a prospective design to investigate the factors associated with adherence to psychotropic medications and antiretrovirals among 123 dually treated persons living with HIV. We used unannounced phone-based pill counts to monitor adherence to psychiatric and antiretroviral medications over a 6-week period. Hierarchical regression models included demographic, health and psychosocial characteristics as predictors of adherence followed by medication necessity and concerns beliefs. Results showed that medication necessity beliefs predicted both antiretroviral and psychiatric medication adherence over and above established predictors of adherence. Medication concerns also predicted psychotropic adherence, but not antiretroviral adherence. These models accounted for 31 and 22 % of the variance in antiretroviral and psychotropic adherence, respectively. Findings suggest that the necessity-concerns medication beliefs framework has utility in understanding adherence to multiple medications and addressing these beliefs should be integrated into adherence interventions. PMID- 25835437 TI - Stability analysis of neutral type neural networks with mixed time-varying delays using triple-integral and delay-partitioning methods. AB - This paper investigates the asymptotical stability problem for a class of neutral type neural networks with mixed time-varying delays. The system not only has time varying discrete delay, but also distributed delay, which has never been discussed in the previous literature. Firstly, improved stability criteria are derived by employing the more general delay partitioning approach and generalizing the famous Jensen inequality. Secondly, by constructing a newly augmented Lyapunov-Krasovskii functionals, some less conservative stability criteria are established in terms of linear matrix inequalities (LMIs). Finally, four numerical examples are given to illustrate the effectiveness and the advantage of the proposed main results. PMID- 25835436 TI - The role of inflammatory markers in explaining the association between depression and cardiovascular hospitalisations. AB - This study investigated whether inflammation may explain the relationship between depression and incident cardiovascular hospitalisations. Participants (55-85 years) completed baseline depression and physical assessment. Those without self reported cardiovascular events were followed prospectively for hospital admissions for angina, myocardial infarction and cerebral infarction (median 937 days). Across 5140 person-years of risk (N = 1692), there were 47 incident cardiovascular hospitalisations (2.8 %). Controlling for age and gender, interleukin (IL)-6, C-reactive protein (CRP), body mass index (BMI) and waist-to hip ratio were associated with future cardiovascular events. Mediation analysis showed that CRP accounted for 8.1 % and IL-6 10.9 % of the effect of depression on cardiovascular events, and including the indirect effect in the model substantially reduced the direct relationship between depression and cardiovascular hospitalisations. BMI and waist-to-hip ratio accounted for indirect effects of 7.7 and 10.4 %, respectively. Inflammatory markers partly explain the association between depression and cardiovascular events, although other shared factors also likely contribute. PMID- 25835438 TI - Impact of statins on serial coronary calcification during atheroma progression and regression. AB - BACKGROUND: Statins can regress coronary atheroma and lower clinical events. Although pre-clinical studies suggest procalcific effects of statins in vitro, it remains unclear if statins can modulate coronary atheroma calcification in vivo. OBJECTIVES: This study compared changes in coronary atheroma volume and calcium indices (CaI) in patients receiving high-intensity statin therapy (HIST), low intensity statin therapy (LIST), and no-statin therapy. METHODS: In a post-hoc patient-level analysis of 8 prospective randomized trials using serial coronary intravascular ultrasound, serial changes in coronary percent atheroma volume (PAV) and CaI were measured across matched coronary segments in patients with coronary artery disease. RESULTS: Following propensity-weighted adjustment for differences in baseline and changes in clinical, laboratory, and ultrasonic characteristics, HIST (n = 1,545) associated with PAV regression from baseline ( 0.6 +/- 0.1%; p < 0.001), whereas both LIST (n = 1,726) and no-statin therapy (n = 224) associated with PAV progression (+0.8 +/- 0.1% and +1.0 +/- 0.1%; p < 0.001, respectively; p < 0.001 for both HIST vs. LIST and HIST vs. no-statin; p = 0.35 for LIST vs. no-statin). Significant increases in CaI from baseline were noted across all groups (median [interquartile range] HIST, +0.044 [0.0-0.12]; LIST, +0.038 [0.0-0.11]; no-statin, +0.020 [0.0-0.10]; p < 0.001 for all), which could relate to statin intensity (p = 0.03 for LIST vs. no-statin; p = 0.007 for HIST vs. no-statin; p = 0.18 for HIST vs. LIST). No correlations were found between changes in CaI and on-treatment levels of atherogenic and antiatherogenic lipoproteins, and C-reactive protein, in either of the HIST groups or the no statin group. CONCLUSIONS: Independent of their plaque-regressive effects, statins promote coronary atheroma calcification. These findings provide insight as to how statins may stabilize plaque beyond their effects on plaque regression. PMID- 25835439 TI - The never-ending story on coronary calcium: is it predictive, punitive, or protective? PMID- 25835441 TI - Lipid biomarkers and cardiovascular risk: which path to take at the fork in the road? PMID- 25835440 TI - Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial. AB - BACKGROUND: Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown. OBJECTIVES: This study sought to examine the relationship between these oxidative biomarkers and cardiovascular outcomes in patients with established CHD. METHODS: In a random sample from the TNT (Treating to New Targets) trial, OxPL-apoB levels were measured in 1,503 patients at randomization (after an 8-week run-in period taking atorvastatin 10 mg) and 1 year after being randomized to atorvastatin 10 or 80 mg. We examined the association between baseline levels of OxPL-apoB and MACE, defined as death from CHD, nonfatal myocardial infarction, resuscitation after cardiac arrest, and fatal/nonfatal stroke, as well as the effect of statin therapy on OxPL-apoB levels and MACE. RESULTS: Patients with events (n = 156) had higher randomization levels of OxPL apoB than those without events (p = 0.025). For the overall cohort, randomization levels of OxPL-apoB predicted subsequent MACE (hazard ratio [HR]: 1.21; 95% confidence interval: 1.04 to 1.41; p = 0.018) per doubling and tertile 3 versus tertile 1 (hazard ratio: 1.69; 95% confidence interval [CI]: 1.14 to 2.49; p = 0.01) after multivariate adjustment for age, sex, body mass index, among others, and treatment assignment. In the atorvastatin 10-mg group, tertile 3 was associated with a higher risk of MACE compared to the first tertile (HR: 2.08; 95% CI: 1.20 to 3.61; p = 0.01) but this was not significant in the atorvastatin 80-mg group (HR: 1.40; 95% CI: 0.80 to 2.46; p = 0.24). CONCLUSIONS: Elevated OxPL-apoB levels predict secondary MACE in patients with stable CHD, a risk that is mitigated by atorvastatin 80 mg. (A Study to Determine the Degree of Additional Reduction in CV Risk in Lowering LDL Below Minimum Target Levels [TNT]; NCT00327691). PMID- 25835442 TI - The optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: chasing a mirage. PMID- 25835443 TI - 12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial. AB - BACKGROUND: Results of the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial confirmed the safety but not the efficacy of renal denervation for treatment-resistant hypertension at 6 months post procedure. OBJECTIVES: This study sought to analyze the 12-month SYMPLICITY HTN-3 results for the original denervation group, the sham subjects who underwent denervation after the 6-month endpoint (crossover group), and the sham subjects who did not undergo denervation after 6 months (non-crossover group). METHODS: Eligible subjects were randomized 2:1 to denervation or sham procedure. Subjects were unblinded to their treatment group after the 6-month primary endpoint was ascertained; subjects in the sham group meeting eligibility requirements could undergo denervation. Change in blood pressure (BP) at 12 months post randomization (6 months for crossover subjects) was analyzed. RESULTS: The 12 month follow-up was available for 319 of 361 denervation subjects and 48 of 101 non-crossover subjects; 6-month denervation follow-up was available for 93 of 101 crossover subjects. In denervation subjects, the 12-month office systolic BP (SBP) change was greater than that observed at 6 months (-15.5 +/- 24.1 mm Hg vs. -18.9 +/- 25.4 mm Hg, respectively; p = 0.025), but the 24-h SBP change was not significantly different at 12 months (p = 0.229). The non-crossover group office SBP decreased by -32.9 +/- 28.1 mm Hg at 6 months, but this response regressed to -21.4 +/- 19.9 mm Hg (p = 0.01) at 12 months, increasing to 11.5 +/- 29.8 mm Hg. CONCLUSIONS: These data support no further reduction in office or ambulatory BP after 1-year follow-up. Loss of BP reduction in the non-crossover group may reflect decreased medication adherence or other related factors. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261). PMID- 25835444 TI - The setback of renal denervation should not backfire on sympathetic overactivity in hypertension. PMID- 25835446 TI - Heritable thoracic aortic aneurysm disease: recognizing phenotypes, exploring genotypes. PMID- 25835445 TI - Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections. AB - BACKGROUND: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-beta signaling. OBJECTIVES: This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS: We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS: Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-beta signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up regulation of both canonical and noncanonical TGF-beta signaling in association with up-regulation of the expression of TGF-beta ligands. CONCLUSIONS: Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk. PMID- 25835447 TI - Practical management of anticoagulation in patients with atrial fibrillation. AB - Anticoagulation for atrial fibrillation has become more complex due to the introduction of new anticoagulant agents, the number and kinds of patients requiring therapy, and the interactions of those patients in the matrix of care. The management of anticoagulation has become a "team sport" involving multiple specialties in multiple sites of care. The American College of Cardiology, through the College's Anticoagulation Initiative, convened a roundtable of experts from multiple specialties to discuss topics important to the management of patients requiring anticoagulation and to make expert recommendations on issues such as the initiation and interruption of anticoagulation, quality of anticoagulation care, management of major and minor bleeding, and treatment of special populations. The attendees continued to work toward consensus on these topics, and present the key findings of this roundtable in a state-of- the-art review focusing on the practical aspects of anticoagulation care for the patient with atrial fibrillation. PMID- 25835448 TI - Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA Guidelines. AB - Successful implementation of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines hinges on a clear understanding of the clinician-patient risk discussion (CPRD). This is a dialogue between the clinician and patient about potential for atherosclerotic cardiovascular disease risk reduction benefits, adverse effects, drug-drug interactions, and patient preferences. Designed especially for primary prevention patients, this process of shared decision making establishes the appropriateness of a statin for a specific patient. CPRD respects the autonomy of an individual striving to make an informed choice aligned with personal values and preferences. Dedicating sufficient time to high-quality CPRD offers an opportunity to strengthen clinician-patient relationships, patient engagement, and medication adherence. We review the guideline-recommended CPRD, the general concept of shared decision making and decision aids, the American College of Cardiology/American Heart Association Risk Estimator application as an implementation tool, and address potential barriers to implementation. PMID- 25835449 TI - The American College of Cardiology Board of Governors: an idea incubator and instrument for action. PMID- 25835450 TI - Global cardiovascular research training for implementation science, health systems research, and health policy research. PMID- 25835451 TI - The art of presentation: a valuable skill in a contemporary era. PMID- 25835452 TI - Global survey of esophageal and gastric injury in atrial fibrillation ablation: incidence, time to presentation, and outcomes. PMID- 25835453 TI - Blunted cardiomyocyte remodeling response in exercise-resistant rats. PMID- 25835454 TI - Cardiovascular function and exercise capacity in patients with colorectal cancer: does anticancer therapy matter? PMID- 25835455 TI - Reply: Cardiovascular function and exercise capacity in patients with colorectal cancer: does anticancer therapy matter? PMID- 25835456 TI - The importance of the cardiac cycle in the imaging criteria for left ventricular noncompaction. PMID- 25835457 TI - Reply: The importance of cardiac cycle in the imaging criteria for left ventricular noncompaction. PMID- 25835458 TI - What can a brief narrative exercise reveal about medical students' development as patient-centered physicians and their attitudes toward patients with mental illness? PMID- 25835460 TI - Diffusion tensor imaging change in crus cerebri in striatocapsular infarction and correlation with upper extremity motor dysfunction. AB - PURPOSE: There is limited information about the secondary changes in the pyramidal tract after some specific types of deep brain infarction including striatocapsular infarction. The aims of the current study were to investigate diffusion changes in the crus cerebri in patients with striatocapsular infarction using diffusion tensor imaging (DTI), and analyze the relationship between such changes and upper extremity motor dysfunction. MATERIALS AND METHODS: Fifteen patients with acute onset of striatocapsular infarction and unilateral upper extremity motor dysfunction for the first time were studied prospectively. DTI was performed 2 weeks after disease onset, fractional anisotropy and mean diffusivity values of the bilateral crus cerebri were measured, the asymmetry indices of bilateral fractional anisotropy were calculated, and the relationship between the asymmetry index value and the Fugl-Meyer assessment score for the affected upper extremity function was evaluated. RESULTS: Two weeks after disease onset, the fractional anisotropy value of the affected crus cerebri was reduced significantly compared with that of the unaffected crus cerebri (0.69 vs. 0.77; p < 0.001); there was no significant difference between bilateral mean diffusivity values. After correction for infarct size (448.93 +/- 227.67 mm(2)) there was a negative correlation between the asymmetry index value and the Fugl-Meyer assessment score of the affected upper extremity (r = -0.78, p = 0.001). CONCLUSIONS: DTI can detect the diffusion change in the crus cerebri in patients with striatocapsular infarction during the early stage of the disease and the integrity of the pyramidal tract in the crus cerebri is closely related to the motor function of the affected upper extremity. PMID- 25835461 TI - An Electronic Daily Diary Study of Anal Intercourse in Drug-Using Women. AB - Women (N = 138) with histories of illicit drug use were recruited into an electronic diary study that used Android smartphones for data collection. The diary was to be completed each day for 12 weeks using an "app" created in HTML5 and accessed over the Internet via smartphone. Data collection included information on sexual behaviors with up to 10 partners per day and contextual factors surrounding sexual behavior such as drug use before/after, type of sexual behavior (oral, vaginal, anal), and other activities such as using condoms for vaginal and anal intercourse and use of sexual lubricants. The sample was predominantly African American (58 %); 20 % Latina, 20 % White and 2 % reported as Other. Most women reported either less than a high school education (33 %) or having a high school diploma (33 %). The mean age was 39 years (SD = 11.78). Anal intercourse occurred on days when women also reported using illicit drugs, specifically methamphetamine and cocaine. Anal intercourse was not an isolated sexual activity, but took place on days when vaginal intercourse and giving and receiving oral sex also occurred along with illicit drug use. Anal intercourse also occurred on days when women reported they wanted sex. HIV prevention interventions must address the risks of anal intercourse for women, taking into account concurrent drug use and sexual pleasure that may reduce individual harm reduction behaviors. PMID- 25835464 TI - Editorial Comment. PMID- 25835463 TI - Sexual Behavior, Risk Compensation, and HIV Prevention Strategies Among Participants in the San Francisco PrEP Demonstration Project: A Qualitative Analysis of Counseling Notes. AB - Pre-exposure prophylaxis (PrEP) is a viable HIV prevention strategy but risk compensation could undermine potential benefits. There are limited data that examine this phenomenon outside of clinical trials. We conducted a qualitative analysis of counseling notes from the San Francisco site of the US PrEP demonstration project to assess how men who have sex with men used PrEP as a prevention strategy and its impact on their sexual practices. Four major themes emerged from our analysis of 130 distinct notes associated with 26 participants. Prevention strategy decision-making was dynamic, often influenced by the context and perceived risk of a sexual encounter. Counselors noted that participants used PrEP in conjunction with other health promotion strategies like condoms, asking about HIV status of their sex partners, and seroadaptation. With few exceptions, existing risk reduction strategies were not abandoned upon initiation of PrEP. Risk-taking behavior was 'seasonal' and fluctuations were influenced by various personal, psychosocial, and health-related factors. PrEP also helped relieve anxiety regarding sex and HIV, particularly among serodiscordant partners. Understanding sexual decision-making and how PrEP is incorporated into existing prevention strategies can help inform future PrEP implementation efforts. PMID- 25835462 TI - Behavioral intervention improves treatment outcomes among HIV-infected individuals who have delayed, declined, or discontinued antiretroviral therapy: a randomized controlled trial of a novel intervention. AB - Nationally up to 60 % of persons living with HIV are neither taking antiretroviral therapy (ART) nor well engaged in HIV care, mainly racial/ethnic minorities. This study examined a new culturally targeted multi-component intervention to address emotional, attitudinal, and social/structural barriers to ART initiation and HIV care. Participants (N = 95) were African American/Black and Latino adults with CD4 < 500 cells/mm(3) not taking ART, randomized 1:1 to intervention or control arms, the latter receiving treatment as usual. Primary endpoints were adherence, evaluated via ART concentrations in hair samples, and HIV viral load suppression. The intervention was feasible and acceptable. Eight months post-baseline, intervention participants tended to be more likely to evidence "good" (that is, 7 days/week) adherence (60 vs. 26.7 %; p = 0.087; OR = 3.95), and had lower viral load levels than controls (t(22) = 2.29, p = 0.032; OR = 5.20), both large effect sizes. This highly promising intervention merits further study. PMID- 25835465 TI - Method for fluorescent marker swapping and its application in Steinernema nematode colonization studies. AB - An allelic exchange vector was constructed to replace gfp by mCherry in bacteria previously tagged with mini-Tn5 derivatives. The method was successfully applied to a gfp-labeled Yersinia pseudotuberculosis strain and the re-engineered bacterium was used to study the colonization of Steinernema nematodes hosting their Xenorhabdus symbiont using dual-color confocal microscopy. PMID- 25835466 TI - Reply to the Editor--Re: Extraction of nonfunctional leads at the time of device upgrade: Still unproven benefit compared to abandoning leads. PMID- 25835467 TI - Endoscopic electrocautery dilation of benign anastomotic colonic strictures: a single-center experience. AB - BACKGROUND: Benign anastomotic colonic stenosis sometimes occur after surgery and usually require surgical or endoscopic dilation. Endoscopic dilation of anastomotic colonic strictures by using balloon or bougie-type dilators has been demonstrated to be safe and effective in multiple uncontrolled series. However, few data are available on safety and efficacy of endoscopic electrocautery dilation. The aim of our study was to retrospectively investigate safety and efficacy of endoscopic electrocautery dilation of postsurgical benign anastomotic colonic strictures. METHODS: Sixty patients (37 women; median age 63.6 years, range 22.6-81.7) with benign anastomotic colonic or rectal strictures treated with endoscopic electrocautery dilation between June 2001 and February 2013 were included in the study. Anastomotic stricture was defined as a narrowed anastomosis through which a standard colonoscope could not be passed. Only annular anastomotic strictures were considered suitable for electrocautery dilation which consisted of radial incisions performed with a precut sphincterotome. Treatment was considered successful if the colonic anastomosis could be passed by a standard colonoscope immediately after dilation. Recurrence was defined as anastomotic stricture reappearance during follow-up. RESULTS: The time interval between colorectal surgery and the first endoscopic evaluation or symptoms development was 7.3 months (1.3-60.7). Electrocautery dilation was successful in all the patients. There were no procedure-related complications. Median follow-up was 35.5 months (2.0-144.0). Anastomotic stricture recurrence was observed in three patients who were successfully treated with electrocautery dilation and Savary dilation. CONCLUSIONS: Endoscopic electrocautery dilation is a safe and effective treatment for annular benign anastomotic postsurgical colonic strictures. PMID- 25835468 TI - Quantification and antioxidant and anti-HCV activities of the constituents from the inflorescences of Scabiosa comosa and S. tschilliensis. AB - To investigate the bioactive constituents of the inflorescences of Scabiosa comosa and S. tschilliensis, which are used traditionally for liver diseases, we tested the antioxidant activity using 2,2'-diphenyl-1-picrylhydrazyl (DPPH), 2,2' azinobis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), ferric reducing antioxidant potential (FRAP), and DPPH-ultra high performance liquid chromatography-mass spectrometer (UPLC-MS) assay. In addition, cell-based anti HCV activity of the major compounds were evaluated. The plant extracts showed strong antioxidant activity. For the first time, 3,4-dicaffeoylquinic acid (DCQA), 3,5-DCQA and 4,5-DCQA were identified from genus Scabiosa. A UPLC-MS method in multiple reaction monitoring (MRM) mode was established to quantify 18 constituents in the inflorescences of Scabiosa. The 3,5-DCQA, chlorogenic acid and some glycosides of luteolin or apigenin were found to be the most abundant constituents. Chlorogenic acid and 3,5-DCQA showed excellent radical scavenging activity and demonstrated anti-HCV activity. These findings provided scientific evidences for the clinic use of this herbal medicine for liver diseases. PMID- 25835469 TI - Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor. AB - Brain tumor is one of the most challenging diseases to treat. The major obstacle in the specific drug delivery to brain is blood-brain barrier (BBB). Mostly available anti-cancer drugs are large hydrophobic molecules which have limited permeability via BBB. Therefore, it is clear that the protective barriers confining the passage of the foreign particles into the brain are the main impediment for the brain drug delivery. Hence, the major challenge in drug development and delivery for the neurological diseases is to design non-invasive nanocarrier systems that can assist controlled and targeted drug delivery to the specific regions of the brain. In this review article, our major focus to treat brain tumor by study numerous strategies includes intracerebral implants, BBB disruption, intraventricular infusion, convection-enhanced delivery, intra arterial drug delivery, intrathecal drug delivery, injection, catheters, pumps, microdialysis, RNA interference, antisense therapy, gene therapy, monoclonal/cationic antibodies conjugate, endogenous transporters, lipophilic analogues, prodrugs, efflux transporters, direct conjugation of antitumor drugs, direct targeting of liposomes, nanoparticles, solid-lipid nanoparticles, polymeric micelles, dendrimers and albumin-based drug carriers. PMID- 25835470 TI - Phenotypic features and phylogenetic background of extraintestinal hemolytic Escherichia coli responsible of mortality in puppies. AB - A 10-day-old litter of five puppies of Bracco Italiano dog breed showed weakness and diarrhea and, 2 days later, four of them died. At the same time, the bitch showed high hyperthermia (40 degrees C) and endometritis. The necropsy of a puppy revealed a severe lobar pneumonia accompanied with a bilateral nephrosis. No gross lesions were detected in other organs. Histopathology of the lung revealed severe multifocal fibrino-suppurative necrotizing bronchiolar-alveolitis associated with rod-shaped bacterial aggregates and diffuse interstitial lymphocytic infiltration. The kidney showed severe multifocal necrosis of the tubular epithelium and diffuse severe congestion of the parenchyma. A pure culture of hemolytic Escherichia coli carrying the Cnf-1 gene was identified, from both the puppy organs and bitch's milk. Moreover, phylo-typing assigned them to the phylogroup B2. Two weeks later, fecal samples from the bitch and the survived puppy were collected for a second microbiological analysis, identifying two hemolytic E. coli strains, Cnf positive and Cdt negative and Cnf and Cdt negative, respectively. Some E. coli pathogenic strains may cause enteric or extraintestinal disease. In dogs and cats, strains of extraintestinal pathogenic E. coli (ExPEC) produce specific virulent factors such as hemolysis and cytotoxin necrotizing factors (Cnf). In this episode, we hypothesize that the bitch's milk could be the main source of ExPEC infection causing high puppies mortality. The role of the bitch as a carrier could not be excluded: stressful conditions, such as pregnancy and delivery, would change the host-pathogen dynamics possibly increasing the release of the infectious burden. PMID- 25835472 TI - Efficacy of a Web-based, crowdsourced peer-to-peer cognitive reappraisal platform for depression: randomized controlled trial. AB - BACKGROUND: Self-guided, Web-based interventions for depression show promising results but suffer from high attrition and low user engagement. Online peer support networks can be highly engaging, but they show mixed results and lack evidence-based content. OBJECTIVE: Our aim was to introduce and evaluate a novel Web-based, peer-to-peer cognitive reappraisal platform designed to promote evidence-based techniques, with the hypotheses that (1) repeated use of the platform increases reappraisal and reduces depression and (2) that the social, crowdsourced interactions enhance engagement. METHODS: Participants aged 18-35 were recruited online and were randomly assigned to the treatment group, "Panoply" (n=84), or an active control group, online expressive writing (n=82). Both are fully automated Web-based platforms. Participants were asked to use their assigned platform for a minimum of 25 minutes per week for 3 weeks. Both platforms involved posting descriptions of stressful thoughts and situations. Participants on the Panoply platform additionally received crowdsourced reappraisal support immediately after submitting a post (median response time=9 minutes). Panoply participants could also practice reappraising stressful situations submitted by other users. Online questionnaires administered at baseline and 3 weeks assessed depression symptoms, reappraisal, and perseverative thinking. Engagement was assessed through self-report measures, session data, and activity levels. RESULTS: The Panoply platform produced significant improvements from pre to post for depression (P=.001), reappraisal (P<.001), and perseverative thinking (P<.001). The expressive writing platform yielded significant pre to post improvements for depression (P=.02) and perseverative thinking (P<.001), but not reappraisal (P=.45). The two groups did not diverge significantly at post test on measures of depression or perseverative thinking, though Panoply users had significantly higher reappraisal scores (P=.02) than expressive writing. We also found significant group by treatment interactions. Individuals with elevated depression symptoms showed greater comparative benefit from Panoply for depression (P=.02) and perseverative thinking (P=.008). Individuals with baseline reappraisal deficits showed greater comparative benefit from Panoply for depression (P=.002) and perseverative thinking (P=.002). Changes in reappraisal mediated the effects of Panoply, but not the expressive writing platform, for both outcomes of depression (ab=-1.04, SE 0.58, 95% CI -2.67 to -.12) and perseverative thinking (ab=-1.02, SE 0.61, 95% CI -2.88 to -.20). Dropout rates were similar for the two platforms; however, Panoply yielded significantly more usage activity (P<.001) and significantly greater user experience scores (P<.001). CONCLUSIONS: Panoply engaged its users and was especially helpful for depressed individuals and for those who might ordinarily underutilize reappraisal techniques. Further investigation is needed to examine the long-term effects of such a platform and whether the benefits generalize to a more diverse population of users. TRIAL REGISTRATION: ClinicalTrials.gov NCT02302248; https://clinicaltrials.gov/ct2/show/NCT02302248 (Archived by WebCite at http://www.webcitation.org/6Wtkj6CXU). PMID- 25835474 TI - Hope for regenerative treatments: toward safe transplantation of human pluripotent stem-cell-based therapies. PMID- 25835473 TI - The effects of radio-frequency electromagnetic fields on T cell function during development. AB - With the widespread use of radio-frequency devices, it is increasingly important to understand the biological effects of the associated electromagnetic fields. Thus, we investigated the effects of radio-frequency electromagnetic fields (RF EMF) on T cell responses during development due to the lack of science-based evidence for RF-EMF effects on developmental immune systems. Sprague Dawley (SD) rats were exposed to 2.14-GHz wideband code division multiple-access (W-CDMA) RF signals at a whole-body specific absorption rate (SAR) of 0.2 W/kg. Exposures were performed for a total of 9 weeks spanning in utero development, lactation and the juvenile period. Rats were continuously exposed to RF-EMF for 20 h/day, 7 days/week. Comparisons of control and exposed rats using flow cytometry revealed no changes in the numbers of CD4/CD8 T cells, activated T cells or regulatory T cells among peripheral blood cells, splenocytes and thymocytes. Expression levels of 16 genes that regulate the immunological Th1/Th2 paradigm were analyzed using real-time PCR in the spleen and thymus tissues of control and RF-EMF-exposed rats. Although only the Il5 gene was significantly regulated in spleen tissues, Il4, Il5 and Il23a genes were significantly upregulated in thymus tissues following exposure to RF-EMF. However, ELISAs showed no changes in serum IL-4 protein concentrations. These data indicate no adverse effects of long-term RF EMF exposure on immune-like T cell populations, T cell activation, or Th1/Th2 balance in developing rats, although significant transcriptional effects were observed. PMID- 25835475 TI - Ink4a/Arf locus role in neuronal transdifferentiation. PMID- 25835476 TI - Fifth Congress of Industrial Cell Technology 2014. AB - The highly specialized and informative Fifth Congress of Industrial Cell Technology took place in Luebeck, close to Hamburg, on 11-12 September 2014. It was organized by the Fraunhofer Institution for Marine Biotechnology (EMB), Luebeck and supported by the cluster agency Life Science Nord Management GmbH as well as the Luebeck Chamber of Industry and Commerce. The central aim of the congress was to promote the name-giving platform applications of industrial cell technologies, in other words, the development of complex cell culture systems, analyzing technologies, innovative instruments and materials, etc. This year's sessions were: smart cell culture, bioreactor systems and cell goods including 3D bioprinting. This article highlights selected presentations of the congress. PMID- 25835477 TI - BMP2 repression and optimized culture conditions promote human bone marrow derived mesenchymal stem cell isolation. AB - AIM: Human mesenchymal stem cells (hMSC) are multipotent progenitor cells. We propose the optimization of hMSC isolation and recovery using the application of a controlled hypoxic environment. MATERIALS & METHODS: We evaluated oxygen, glucose and serum in the recovery of hMSC from bone marrow (BMhMSC). Colony forming units-fibroblastic, cell numbers, tri-lineage differentiation, immunofluorescence and microarray were used to confirm and characterize BMhMSC. RESULTS: In an optimized (2% O(2), 4.5 g/l glucose and 5% serum) environment both colony forming units-fibroblastic (p = 0.01) and cell numbers (p = 0.0001) were enhanced over standard conditions. Transcriptional analysis identified differential expression of bone morphogenetic protein 2 (BMP2) and, putatively, chemokine (C-X-C motif) receptor 2 (CXCR2) signaling pathways. CONCLUSION: We have detailed a potential milestone in the process of refinement of the BMhMSC isolation process. PMID- 25835478 TI - Association of mesenchymal stem cells and osteoblasts for bone repair. AB - AIM: We tested the hypothesis that the association of bone marrow mesenchymal stem cells (MSCs) and osteoblasts (OBs) optimize bone repair. MATERIALS & METHODS: MSCs were cultured in growth or osteogenic medium and seeded into gelatin sponge prior to implantation. Defects were created into rat calvariae and implanted with gelatin sponge without cells, with MSCs, with OBs and with association of MSCs and OBs. Histological analysis and micro-CT-based histomorphometry were carried out after 4 weeks. RESULTS: Increased bone formation was observed in defects treated with cells and bone volume was greater in defects treated with either OBs or MSCs/OBs. CONCLUSION: Association of MSCs and OBs did not increase the process of bone repair compared with cell-based therapy using either MSCs or OBs alone. PMID- 25835479 TI - Repair of osteochondral defects in the minipig model by OPF hydrogel loaded with adipose-derived mesenchymal stem cells. AB - AIM: Critical knee osteochondral defects in seven adult minipigs were treated with oligo(polyethylene glycol)fumarate (OPF) hydrogel combined with autologous or human adipose-derived stem cells (ASCs), and evaluated after 6 months. METHODS: Four defects were made on the peripheral part of right trochleas (n = 28), and treated with OPF scaffold alone or pre-seeded with ASCs. RESULTS: A better quality cartilage tissue characterized by improved biomechanical properties and higher collagen type II expression was observed in the defects treated by autologous or human ASC-loaded OPF; similarly this approach induced the regeneration of more mature bone with upregulation of collagen type I expression. CONCLUSION: This study provides the evidence that both porcine and human adipose-derived stem cells associated to OPF hydrogel allow improving osteochondral defect regeneration in a minipig model. PMID- 25835480 TI - Fibrin hydrogels to deliver dental stem cells of the apical papilla for regenerative medicine. AB - AIM: Evaluation of survival, proliferation and neurodifferentiation of dental stem cells from the apical papilla (SCAP) in fibrin hydrogels. We hypothesized that fibrin composition will influence cell behavior. METHODS: Modulus, pore and fiber size were measured. SCAP in vitro viability, proliferation and neural differentiation, as well as in vivo proliferation and angiogenesis were studied. RESULTS: Hydrogel moduli were influenced by fibrin formulation but not hydrogel morphology, SCAP in vitro viability and proliferation. In total 60% of SCAP expressed PanNeurofilament in vitro without induction in Fibrinogen50-Thrombin10. SCAP proliferated when implanted in vivo and stimulated host endothelial cell infiltration. CONCLUSION: Fibrinogen30-Thrombin10 or Thrombin50 would be more favorable to in vitro SCAP viability and in vivo proliferation, while Fibrinogen 50-Thrombin50 would be more adapted to neurodifferentiation. PMID- 25835481 TI - Landscape of current and emerging cell therapy clinical trials in the UK: current status, comparison to global trends and future perspectives. AB - Cell Therapy Clinical Trial and Preclinical Research databases have been established by the Cell Therapy Catapult to document current and future cell therapy clinical trials in the UK. We identified 41 ongoing trials in April 2014, an increase of seven trials from April 2013. In addition, we identified 45 late stage preclinical research projects. The majority of the clinical trials are early phase, primarily led by academic groups. The leading therapeutic areas are cancer, cardiology and neurology. The trends in the UK are also seen globally. As the field matures, more later phase and commercial studies will emerge and the challenges will likely evolve into how to manufacture sufficient cell quantities, manage complex logistics for multi-center trials and control cost. PMID- 25835482 TI - Cell therapy worldwide: an incipient revolution. AB - The regenerative medicine field is large, diverse and active worldwide. A variety of different organizational and product models have been successful, and pioneering entrepreneurs have shown both what can work and, critically, what does not. Evolving regulations, novel funding mechanisms combined with new technological breakthroughs are keeping the field in a state of flux. The field struggles to cope with the lack of infrastructure and investment, it nevertheless has evolved from its roots in human stem cell therapy and tissue and organ transplants to a field composed of a variety of products from multiple cell sources with approval for use in numerous countries. Currently, tens of thousands of patients have been treated with some kind of cell therapy. PMID- 25835483 TI - Vascularization strategies for tissue engineers. AB - All tissue-engineered substitutes (with the exception of cornea and cartilage) require a vascular network to provide the nutrient and oxygen supply needed for their survival in vivo. Unfortunately the process of vascular ingrowth into an engineered tissue can take weeks to occur naturally and during this time the tissues become starved of essential nutrients, leading to tissue death. This review initially gives a brief overview of the processes and factors involved in the formation of new vasculature. It then summarizes the different approaches that are being applied or developed to overcome the issue of slow neovascularization in a range of tissue-engineered substitutes. Some potential future strategies are then discussed. PMID- 25835484 TI - Posterior hemivertebra resection and short segment fusion with pedicle screw fixation for congenital scoliosis in children younger than 10 years: greater than 7-year follow-up. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate the surgical outcomes of posterior hemivertebra resection and short segment fusion with segmental pedicle screw fixation in congenital scoliosis in children younger than 10 years. SUMMARY OF BACKGROUND DATA: This is the first long-term follow-up on surgical outcomes of posterior hemivertebra resection and short segment fusion using segmental pedicle screw fixation in children younger than 10 years with congenital scoliosis. METHODS: Patients with congenital scoliosis (n = 18) younger than 10 years at the time of the surgery were treated by posterior hemivertebra resection and bilateral pedicle screw fixation. The mean age at the time of surgery was 6.6 years (range, 2.6-9.8 yr). They were retrospectively studied with a mean follow-up of 11.4 years (range, 7.1-17.3 yr). RESULTS: The mean Cobb angle of the main curve was 34.4 degrees before surgery, 8.6 degrees after surgery, and 12.9 degrees at last follow-up. In the compensatory cranial curve, the preoperative Cobb angle of 14.5 degrees was corrected to 5.9 degrees postoperatively and was 8.4 degrees at last follow-up. In the compensatory caudal curve, the preoperative Cobb angle of 17.4 degrees improved to 4 degrees postoperatively and 6.6 degrees at last follow-up. There were no crankshaft phenomena and no clinical and radiographical features suggestive of spinal stenosis during follow-up. There were no major vascular or neurological complications related to the pedicle screws. CONCLUSION: Posterior hemivertebra resection after pedicle screw fixation in congenital scoliosis is a safe and effective procedure that can achieve rigid fixation and deformity correction and restore spinal balance. This study showed that early posterior hemivertebra resection of congenital scoliosis before structural changes occur above or below can reduce fusion length, prevent curve progression, and effectively achieve a more satisfactory correction without hazardous iatrogenic spinal stenosis, crankshaft phenomena, or neurological complications. LEVEL OF EVIDENCE: 3. PMID- 25835485 TI - Spin transport properties in lower n-acene-graphene nanojunctions. AB - A series of n-acene-graphene (n = 3, 4, 5, 6) devices, in which n-acene molecules are sandwiched between two zigzag graphene nanoribbon (ZGNR) electrodes, are modeled through the spin polarized density functional theory combined with the non-equilibrium Green's function technique. Our theoretical results show that for n-acene molecules ranging from anthracene to hexacene, the spin-polarized electronic states near the Fermi level can be induced by the spin-polarized ZGNR electrodes, which strengthen gradually to facilitate the electronic transport. A nearly 100% spin filtering ratio and a dual-orientation spin-rectifying effect are observed in a wide range of bias voltage. Importantly, an over 8000% giant magnetoresistance is obtained in the low bias range from -0.1 V to +0.1 V. Moreover, negative differential resistance behaviors are detected in these devices. The potential mechanisms of these intriguing phenomena are proposed and these findings would be instructive for the design and synthesis of high performance graphene-based spin-related devices. PMID- 25835486 TI - Onset of optical-phonon cooling in multilayer graphene revealed by RF noise and black-body radiation thermometries. AB - We report on electron cooling power measurements in few-layer graphene excited by Joule heating by means of a new setup combining electrical and optical probes of the electron and phonon baths temperatures. At low bias, noise thermometry allows us to retrieve the well known acoustic phonon cooling regimes below and above the Bloch-Gruneisen temperature, with additional control over the phonon bath temperature. At high electrical bias, we show the relevance of direct optical investigation of the electronic temperature by means of black-body radiation measurements. In this regime, the onset of new efficient relaxation pathways involving optical modes is observed. PMID- 25835487 TI - Animal Models of Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is one of today's main causes of blindness in numerous developed countries worldwide. The underlying pathogenesis of DR is complex and not well understood, thus impeding development of specific, effective treatment modalities. Consequently, the use of animal models of DR is of critical importance for investigating the pathogenesis of and treatment for DR. While rats and mice are the most commonly used animal models of DR, the zebrafish now appears to be a promising model. Nonhuman primates and humans have similar eye structures, and both can develop spontaneous diabetes mellitus (DM). Although various traditionally used animal models of DR undergo a number of pathological changes similar to those of human DR, several human variations, e.g. retinal neovascularization, cannot yet be fully mimicked in any existing animal model of DM. Since both the animal models and the methods chosen for inducing DR have great influence on experimental results, a clear understanding of available animal models is vital for planning an experimental design. In this review, we summarize the mechanisms, methodologies and pros and cons of the most commonly used animal models of DR. PMID- 25835488 TI - Lorentz microscopy sheds light on the role of dipolar interactions in magnetic hyperthermia. AB - Monodispersed Fe3O4 nanoparticles with comparable size distributions have been synthesized by two different synthesis routes, co-precipitation and thermal decomposition. Thanks to the different steric stabilizations, the described samples can be considered as a model system to investigate the effects of magnetic dipolar interactions on the aggregation states of the nanoparticles. Moreover, the presence of magnetic dipolar interactions can strongly affect the nanoparticle efficiency as a hyperthermic mediator. In this paper, we present a novel way to visualize and map the magnetic dipolar interactions in different kinds of nanoparticle aggregates by the use of Lorentz microscopy, an easy and reliable in-line electron holographic technique. By exploiting Lorentz microscopy, which is complementary to the magnetic measurements, it is possible to correlate the interaction degrees of magnetic nanoparticles with their magnetic behaviors. In particular, we demonstrate that Lorentz microscopy is successful in visualizing the magnetic configurations stabilized by dipolar interactions, thus paving the way to the comprehension of the power loss mechanisms for different nanoparticle aggregates. PMID- 25835489 TI - Off-clamp robotic partial nephrectomy: Technique and outcome. AB - INTRODUCTION: Robotic partial nephrectomy (RPN) is a technically challenging procedure. Advanced skills are needed to accomplish tumor resection, hemostasis, and renorrhaphy within short ischemia time in RPN. Off-clamp RPN with zero ischemia may decrease the risk of ischemic reperfusion injury to the kidney. However, the off-clamp technique has been associated with an increased risk of blood loss. The purpose of this study was to evaluate the outcome of our modified off-clamp technique utilized in certain RPN cases. PATIENTS AND METHODS: A total of 81 patients underwent RPN between September 2009 and July 2013 for renal masses. We studied a subgroup of patients who underwent off-clamp RPN with zero ischemia time. The off-clamp technique was utilized for exophytic, nonhilar tumors that have a base of 2 cm or less. We developed a novel technique to avoid ischemia reperfusion renal injury while minimizing blood loss in certain cases of RPN. RESULTS: Of the 81 cases of RPN, we reviewed and adopted the off-clamp technique in 34 patients (41.98%). Utilizing off-clamp RPN resulted in an average blood loss of 96.29 ml and 1.56 days (range: 1-3 days) of hospital stay and minimal change in serum creatinine. CONCLUSIONS: Off-clamp RPN is safe and feasible approach to excise certain kidney tumors. It carries the benefits of RPN and prevents ischemia reperfusion renal injury. PMID- 25835491 TI - Health administrative data can be used to define a shared care typology for people with HIV. AB - OBJECTIVES: Building on an existing theoretical shared primary care/specialist care framework to (1) develop a unique typology of care for people living with human immunodeficiency virus (HIV) in Ontario, (2) assess sensitivity of the typology by varying typology definitions, and (3) describe characteristics of typology categories. STUDY DESIGN AND SETTING: Retrospective population-based observational study from April 1, 2009, to March 31, 2012. A total of 13,480 eligible patients with HIV and receiving publicly funded health care in Ontario. We derived a typology of care by linking patients to usual family physicians and to HIV specialists with five possible patterns of care. Patient and physician characteristics and outpatient visits for HIV-related and non-HIV-related care were used to assess the robustness and characteristics of the typology. RESULTS: Five possible patterns of care were described as low engagement (8.6%), exclusively primary care (52.7%), family physician-dominated comanagement (10.0%), specialist-dominated comanagement (30.5%), and exclusively specialist care (5.2%). Sensitivity analyses demonstrated robustness of typology assignments. Visit patterns varied in ways that conform to typology assignments. CONCLUSION: We anticipate this typology can be used to assess the impact of care patterns on the quality of primary care for people living with HIV. PMID- 25835490 TI - Inadequate use and regulation of interventions against publication bias decreases their effectiveness: a systematic review. AB - OBJECTIVES: To determine the effectiveness of interventions designed to prevent or reduce publication and related biases. STUDY DESIGN AND SETTING: We searched multiple databases and performed manual searches using terms related to publication bias and known interventions against publication bias. We dually reviewed citations and assessed risk of bias. We synthesized results by intervention and outcomes measured and graded the quality of the evidence (QoE). RESULTS: We located 38 eligible studies. The use of prospective trial registries (PTR) has increased since 2005 (seven studies, moderate QoE); however, positive outcome-reporting bias is prevalent (14 studies, low QoE), and information in nonmandatory fields is vague (10 studies, low QoE). Disclosure of financial conflict of interest (CoI) is inadequate (five studies, low QoE). Blinding peer reviewers may reduce geographical bias (two studies, very low QoE), and open access publishing does not discriminate against authors from low-income countries (two studies, very low QoE). CONCLUSION: The use of PTR and CoI disclosures is increasing; however, the adequacy of their use requires improvement. The effect of open-access publication and blinding of peer reviewers on publication bias is unclear, as is the effect of other interventions such as electronic publication and authors' rights to publish their results. PMID- 25835492 TI - No impact of vitamin D on the CYP3A biomarker 4beta-hydroxycholesterol in patients with abnormal glucose regulation. AB - PURPOSE: To investigate the effect of vitamin D3 on hepatic Cytochrome P450 enzyme (CYP) 3A4 in patients with abnormal glucose regulation using the endogenous marker 4beta-hydroxycholesterol (4beta-OHC):cholesterol ratio. METHODS: The present study took advantage of a trial primarily aiming to investigate the effect of vitamin D3 on beta cell function and insulin sensitivity in patients with abnormal glucose regulation. 44 subjects were randomized to receive vitamin D3, 30000 IU given orally once weekly or placebo for 8 weeks. The two sample t-test was used to test the means of the intra individual differences of 4beta-OHC:cholesterol ratio between the two groups. RESULTS: Mean (SD) 4beta-OHC in the whole group of patients before and after the intervention was 26 (11) ng/ml and 26 (12). Mean (SD) 4beta-OHC:cholesterol ratio in the whole group of patients before and after the intervention was 0.12 (0.046) and 0.13 (0.047). In the Vitamin D group mean (SD) serum 25-OH-vitamin D3 increased from 46 (16) to 85nM (13) during the corresponding time period. To investigate the impact of vitamin D3 on hepatic CYP3A4 we calculated the mean intra-individual differences in 4beta-OHC:cholesterol ratio (delta 4beta OHC:cholesterol ratio) before versus after the intervention in the two treatment groups. The difference (95% CI) between delta 4beta-OHC:cholesterol ratio in the control group and intervention group was -0.0010 (-0.0093, 0.0072), a difference being not statistically significant (p = 0.80). CONCLUSIONS: We provide further evidence that vitamin D3 may not substantially affect hepatic CYP3A4. This does not exclude the possibility of an impact of intestinal first-pass metabolism of orally administered drugs which should be investigated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01497132. PMID- 25835493 TI - Sustained virologic response and other potential genotype-specific roles of statins among patients with hepatitis C-related chronic liver diseases. AB - BACKGROUND: While statins have shown antiviral effects in different studies, few data are available about their effect among different HCV genotypes. AIM: To evaluate the effect of concomitant statin use on sustained virologic response (SVR) and other treatment outcomes among patients with HCV genotypes 1-3. METHOD: Using US Department of Veterans Affairs database, multivariate (MV), propensity score matched (PSM) and repeated measures mixed model analyses were performed on patients who received combination therapy with Peg-IFN and Ribavirin for treatment of HCV genotypes 1-3 between October 2001-December 2011. Concomitant statin users were matched with non-users in each genotype and SVR rates were compared. Changes in serum ALT during treatment was assessed. RESULTS: Of 37,611 treated patients, 236 genotype 1 (GT1), 78 genotype 2 (GT2) and 23 genotype 3 (GT3) statin users and non-users were used for PSM. SVR among GT1 patients was 22.8% (overall), significantly higher among statin users (26.3% vs. 19.5% P<0.01 from PSM; OR=1.49 CI 1.06-2.08 P=0.02 from MV). No significant impact of statin use was observed among GT2 (overall SVR - 55.8%, statin users vs. non-users - 53.9% vs. 57.7%, P=0.32), and GT3 (overall SVR - 58.7%, statin users vs. non users - 60.9% vs. 56.2%, P=0.39) patients. Higher baseline LDL was positively associated with SVR while statin use reduced ALT during treatment in GT1 patients. CONCLUSION: In view of additional benefits of statins, and the prohibitive cost of newer HCV therapies, statins could be a potential assist for hard-to-treat GT1 patients especially in resource-poor settings. PMID- 25835494 TI - Correction: Drosophila tribbles antagonizes insulin signaling-mediated growth and metabolism via interactions with Akt kinase. PMID- 25835495 TI - Thymosin beta 4 may translocate from the cytoplasm in to the nucleus in HepG2 cells following serum starvation. An ultrastructural study. AB - Due to its actin-sequestering properties, thymosin beta-4 (Tbeta4) is considered to play a significant role in the cellular metabolism. Several physiological properties of Tbeta4 have been reported;, however, many questions concerning its cellular function remain to be ascertained. To better understand the role of this small peptide we have analyzed by means of transmission immunoelectron microscopy techniques the ultrastructural localization of Tbeta4 in HepG2 cells. Samples of HepG2 cells were fixed in a mixture of 3% formaldehyde and 0.1% glutaraldehyde in 0.1 M cacodylate buffer and processed for standard electron microscopic techniques. The samples were dehydrated in a cold graded methanol series and embedded in LR gold resin. Ultrathin sections were labeled with rabbit antibodies to Tbeta4, followed by gold-labeled goat anti-rabbit, stained with uranyl acetate and bismuth subnitrate, observed and photographed in a JEOL 100S transmission electron microscope. High-resolution electron microscopy showed that Tbeta4 was mainly restricted to the cytoplasm of HepG2 growing in complete medium. A strong Tbeta4 reactivity was detected in the perinuclear region of the cytoplasmic compartment where gold particles appeared strictly associated to the nuclear membrane. In the nucleus specific Tbeta4 labeling was observed in the nucleolus. The above electron microscopic results confirm and extend previous observations at light microscopic level, highlighting the subcellular distribution of Tbeta4 in both cytoplasmic and nuclear compartments of HepG2 cells. The meaning of Tbeta4 presence in the nucleolus is not on the best of our knowledge clarified yet. It could account for the interaction of Tbeta4 with nucleolar actin and according with this hypothesis, Tbeta4 could contribute together with the other nucleolar acting binding proteins to modulate the transcription activity of the RNA polymerases. PMID- 25835496 TI - Dual-specificity anti-sigma factor reinforces control of cell-type specific gene expression in Bacillus subtilis. AB - Gene expression during spore development in Bacillus subtilis is controlled by cell type-specific RNA polymerase sigma factors. sigmaFand sigmaE control early stages of development in the forespore and the mother cell, respectively. When, at an intermediate stage in development, the mother cell engulfs the forespore, sigmaF is replaced by sigmaG and sigmaE is replaced by sigmaK. The anti-sigma factor CsfB is produced under the control of sigmaF and binds to and inhibits the auto-regulatory sigmaG, but not sigmaF. A position in region 2.1, occupied by an asparagine in sigmaG and by a glutamate in omicronF, is sufficient for CsfB discrimination of the two sigmas, and allows it to delay the early to late switch in forespore gene expression. We now show that following engulfment completion, csfB is switched on in the mother cell under the control of sigmaK and that CsfB binds to and inhibits sigmaE but not sigmaK, possibly to facilitate the switch from early to late gene expression. We show that a position in region 2.3 occupied by a conserved asparagine in sigmaE and by a conserved glutamate in sigmaK suffices for discrimination by CsfB. We also show that CsfB prevents activation of sigmaG in the mother cell and the premature sigmaG-dependent activation of sigmaK. Thus, CsfB establishes negative feedback loops that curtail the activity of sigmaE and prevent the ectopic activation of sigmaG in the mother cell. The capacity of CsfB to directly block sigmaE activity may also explain how CsfB plays a role as one of the several mechanisms that prevent sigmaE activation in the forespore. Thus the capacity of CsfB to differentiate between the highly similar sigmaF/sigmaG and sigmaE/sigmaK pairs allows it to rinforce the cell-type specificity of these sigma factors and the transition from early to late development in B. subtilis, and possibly in all sporeformers that encode a CsfB orthologue. PMID- 25835497 TI - Optimal ligand descriptor for pocket recognition based on the Beta-shape. AB - Structure-based virtual screening is one of the most important and common computational methods for the identification of predicted hit at the beginning of drug discovery. Pocket recognition and definition is frequently a prerequisite of structure-based virtual screening, reducing the search space of the predicted protein-ligand complex. In this paper, we present an optimal ligand shape descriptor for a pocket recognition algorithm based on the beta-shape, which is a derivative structure of the Voronoi diagram of atoms. We investigate six candidates for a shape descriptor for a ligand using statistical analysis: the minimum enclosing sphere, three measures from the principal component analysis of atoms, the van der Waals volume, and the beta-shape volume. Among them, the van der Waals volume of a ligand is the optimal shape descriptor for pocket recognition and best tunes the pocket recognition algorithm based on the beta shape for efficient virtual screening. The performance of the proposed algorithm is verified by a benchmark test. PMID- 25835499 TI - Spirituality and religion in older adults: building knowledge in an emerging discipline. PMID- 25835498 TI - Association between P16INK4a promoter methylation and HNSCC: a meta-analysis of 21 published studies. AB - BACKGROUND: The p16INK4a is an important tumor suppressor gene (TSG) and aberrant methylation of promoter is known to be a major inactivation mechanism of the tumor suppressor and tumor-related genes. Aberrant TSG methylation was considered an important epigenetic silencing mechanism in the progression of head and neck squamous cell carcinoma (HNSCC). However, some studies have reported differences in the methylation frequencies of P16INK4a promoter between cancer and the corresponding control group. Therefore, we conducted a meta-analysis to better identify the association. METHODS: PubMed, Ovid, ISI Web of Science, and EMBASE were searched to identify eligible studies to evaluate the association of p16INK4a promoter methylation and HNSCC. Odds ratio (ORs) and 95% confidence intervals (95%CI) were calculated to evaluate the strength of association between p16INK4a promoter methylation and HNSCC. RESULTS: A total of twenty-one studies with 1155 cases and 1017 controls were included in the meta-analysis. The frequencies of p16INK4a promoter methylation in the cancer group were significantly higher than those in the control group (cancer group: median: 46.67%, range = 7.84%-95.12%; control group: median: 18.37%, range = 0-83.33%; respectively). The pooled odds ratio was 3.37 (95%CI = 2.32-4.90) in the cancer group versus the corresponding control group under the random-effects model. CONCLUSION: This meta-analysis of 21 published studies identified that aberrant methylation of p16INK4a promoter was found to be significantly associated with HNSCC. PMID- 25835500 TI - Commentary on "Disability but not social support predicts cognitive deterioration in late-life depression". PMID- 25835501 TI - Prevalence of mental disorders in non-demented elderly people in primary care- erratum. PMID- 25835502 TI - Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration. AB - The Notch signaling pathway regulates intestinal epithelial cell homeostasis, including stem cell maintenance, progenitor cell proliferation and differentiation. Notch1 and Notch2 receptors are expressed in the epithelium, but individual contributions to these functions are unclear. We used genetic deletion to define receptor roles on stem cell function, cell proliferation/differentiation, and repair after injury. Loss of Notch1 induced a transient secretory cell hyperplasia that spontaneously resolved over time. In contrast, deletion of Notch2 had no secretory cell effect. Compound deletions of Notch1 and Notch2 resulted in a more severe secretory cell hyperplasia than deletion of Notch1 alone. Furthermore, only double deletion of Notch1 and Notch2 decreased cell proliferation, suggesting a low threshold for maintenance of proliferation compared to differentiation. Stem cells were affected by deletion of Notch1, with reduced expression of Olfm4 and fewer LGR5(+) stem cells. Deletion of Notch2 had no apparent affect on stem cell homeostasis. However, we observed impaired crypt regeneration after radiation in both Notch1- and Notch2 deleted intestine, suggesting that higher Notch activity is required post-injury. These findings suggest that Notch1 is the primary receptor regulating intestinal stem cell function and that Notch1 and Notch2 together regulate epithelial cell proliferation, cell fate determination, and post-injury regeneration. PMID- 25835503 TI - Differential alterations in the expression of neurotransmitter receptors in inner retina following loss of photoreceptors in rd1 mouse. AB - Loss of photoreceptors leads to significant remodeling in inner retina of rd1 mouse, a widely used model of retinal degeneration. Several morphological and physiological alterations occur in the second- and third-order retinal neurons. Synaptic activity in the excitatory bipolar cells and the predominantly inhibitory amacrine cells is enhanced. Retinal ganglion cells (RGCs) exhibit hyperactivity and aberrant spiking pattern, which adversely affects the quality of signals they can carry to the brain. To further understand the pathophysiology of retinal degeneration, and how it may lead to aberrant spiking in RGCs, we asked how loss of photoreceptors affects some of the neurotransmitter receptors in rd1 mouse. Using Western blotting, we measured the levels of several neurotransmitter receptors in adult rd1 mouse retina. We found significantly higher levels of AMPA, glycine and GABAa receptors, but lower levels of GABAc receptors in rd1 mouse than in wild-type. Since GABAa receptor is expressed in several retinal layers, we employed quantitative immunohistochemistry to measure GABAa receptor levels in specific retinal layers. We found that the levels of GABAa receptors in inner plexiform layer of wild-type and rd1 mice were similar, whereas those in outer plexiform layer and inner nuclear layer combined were higher in rd1 mouse. Specifically, we found that the number of GABAa immunoreactive somas in the inner nuclear layer of rd1 mouse retina was significantly higher than in wild-type. These findings provide further insights into neurochemical remodeling in the inner retina of rd1 mouse, and how it might lead to oscillatory activity in RGCs. PMID- 25835504 TI - Small scale trial of photodynamic treatment of onychomycosis in Sao Paulo. AB - The use of methylene blue and toluidine blue in the photodynamic treatment of onychomycosis at an ambulatory clinic in Sao Paulo, Brazil is reported. Local application and illumination of infected nails produced a response in 53 of 62 patients, without any pain or burning associated with the therapy. PMID- 25835506 TI - Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause. AB - Polycystic ovary syndrome (PCOS) is a multifactorial disorder that arises from interactions between genetic, environmental and intra-uterine factors. Small-for gestational-age (SGA) babies and the daughters of mothers with PCOS represent possible postnatal clinical targets for developmental programming by steroid excess. The presence of excess glucocorticoids and/or androgens during foetal organogenesis and growth might promote changes in gene expression, and these changes might be related to an increase in the risk of PCOS-like reproductive and metabolic disorders in postnatal life, such as rapid growth and weight gain during the first 2 years of life (only in SGA babies), hyperinsulinaemia, adipocyte dysfunction and childhood visceral obesity, premature pubarche and adrenarche (only in SGA babies) and PCOS. In the fourth decade of life, women who have PCOS may be at higher risk for type 2 diabetes mellitus, dyslipidaemia and systemic arterial hypertension, which suggests that these women are also at higher risk for cardiovascular disease during menopause. However, PCOS can also occur in women who were born at appropriate weight for GA or in newborns of women without PCOS, which suggests that genetic variation and environmental factors play important roles in the development and maintenance of PCOS in a population. Genome-wide association studies based on adequate population samples have shown a higher frequency of genetic polymorphisms of the LHCGR, THADA and DENND1A genes in women with PCOS. Genetic studies of PCOS have also included analyses of structural changes in the chromosome based on an assessment of telomere length in single, cross-sectional evaluations, and these studies have produced controversial results. The present narrative review assesses the multifactorial origins of PCOS (including environmental, genetic and intra-uterine factors) and the development of conditions associated with this disorder. It is concluded that although PCOS might originate in the intra-uterine environment through developmental programming by steroid excess, the interaction between genetic and environmental factors is crucial for its appearance. Follow-up studies should be conducted to assess the same populations over their entire lifespans while taking into account different aspects of the pathogenesis of PCOS. PMID- 25835505 TI - Melatonin prevents myeloperoxidase heme destruction and the generation of free iron mediated by self-generated hypochlorous acid. AB - Myeloperoxidase (MPO) generated hypochlorous acid (HOCl) formed during catalysis is able to destroy the MPO heme moiety through a feedback mechanism, resulting in the accumulation of free iron. Here we show that the presence of melatonin (MLT) can prevent HOCl-mediated MPO heme destruction using a combination of UV-visible photometry, hydrogen peroxide (H2O2)-specific electrode, and ferrozine assay techniques. High performance liquid chromatography (HPLC) analysis showed that MPO heme protection was at the expense of MLT oxidation. The full protection of the MPO heme requires the presence of a 1:2 MLT to H2O2 ratio. Melatonin prevents HOCl-mediated MPO heme destruction through multiple pathways. These include competition with chloride, the natural co-substrate; switching the MPO activity from a two electron oxidation to a one electron pathway causing the buildup of the inactive Compound II, and its subsequent decay to MPO-Fe(III) instead of generating HOCl; binding to MPO above the heme iron, thereby preventing the access of H2O2 to the catalytic site of the enzyme; and direct scavenging of HOCl. Collectively, in addition to acting as an antioxidant and MPO inhibitor, MLT can exert its protective effect by preventing the release of free iron mediated by self-generated HOCl. Our work may establish a direct mechanistic link by which MLT exerts its antioxidant protective effect in chronic inflammatory diseases with MPO elevation. PMID- 25835507 TI - Tuberculosis transmission from healthcare workers to patients and co-workers: a systematic literature review and meta-analysis. AB - Healthcare workers (HCWs) are at risk of becoming infected with tuberculosis (TB), and potentially of being infectious themselves when they are ill. To assess the magnitude of healthcare-associated TB (HCA-TB) transmission from HCWs to patients and colleagues, we searched three electronic databases up to February 2014 to select primary studies on HCA-TB incidents in which a HCW was the index case and possibly exposed patients and co-workers were screened.We identified 34 studies out of 2,714 citations. In 29 individual investigations, active TB was diagnosed in 3/6,080 (0.05%) infants, 18/3,167 (0.57%) children, 1/3,600 (0.03%) adult patients and 0/2,407 HCWs. The quantitative analysis of 28 individual reports showed that combined proportions of active TB among exposed individuals were: 0.11% (95% CI 0.04-0.21) for infants, 0.38% (95% CI 0.01-1.60) for children, 0.09% (95% CI 0.02-0.22) for adults and 0.00% (95% CI 0.00-0.38) for HCWs. Combined proportions of individuals who acquired TB infection were: 0.57% (95% CI 7.28E-03 - 2.02) for infants, 0.9% (95% CI 0.40-1.60) for children, 4.32% (95% CI 1.43-8.67) for adults and 2.62% (95% CI 1.05-4.88) for HCWs. The risk of TB transmission from HCWs appears to be lower than that recorded in other settings or in the healthcare setting when the index case is not a HCW. To provide a firm evidence base for the screening strategies, more and better information is needed on the infectivity of the source cases, the actual exposure level of screened contacts, and the environmental characteristics of the healthcare setting. PMID- 25835508 TI - Do depressed newly diagnosed cancer patients differentially benefit from nurse navigation? AB - OBJECTIVE: To examine whether the effects of a nurse navigator intervention for cancer vary with baseline depressive symptoms. METHOD: Participants were enrolled in a randomized controlled trial of a nurse navigation intervention for patients newly diagnosed with lung, breast or colorectal cancer (N=251). This exploratory analysis used linear regression models to estimate the effect of a nurse navigator intervention on patient experience of care. Models estimated differential effects by including interactions between randomization group and baseline depressive symptoms. Baseline scores on the 9-item Patient Health Questionnaire (PHQ) were categorized into 3 groups: no depression (PHQ=0-4, N=138), mild symptoms of depression (PHQ=5-9, N=76) and moderate to severe symptoms (PHQ=10 or greater, N=34). Patient experience outcomes were measured by subscales of the Patient Assessment of Chronic Illness Care (PACIC) and subscales from an adaptation of the Picker Institute's patient experience survey at 4-month follow-up. RESULTS: With the exception of the PACIC subscale of delivery system/practice design, interaction terms between randomization group and PHQ-9 scores were not statistically significant. CONCLUSIONS: The intervention was broadly useful; we found that it was equally beneficial for both depressed patients and patients who were not significantly depressed in the first 4 months postdiagnosis. However, because of the small sample size, we cannot conclude with certainty that patients with depressive symptoms did not differentially benefit from the intervention. PMID- 25835509 TI - Neuromyelitis optica presenting with psychiatric symptoms and catatonia: a case report. AB - Neuromyelitis optica (NMO) is an aggressive disease characteristically affecting the spinal cord and optic nerves that has recently been differentiated from multiple sclerosis. We present a case of a 16-year-old Antiguan female previously diagnosed with NMO who presented with a 1-week history of confusion and agitation. She had symptoms of psychosis, including delusional thinking and auditory and visual hallucinations, and scored 11/23 on the Bush-Francis Catatonia Scale. This case demonstrates an NMO exacerbation that presented with psychotic symptoms and catatonia. PMID- 25835510 TI - Improvement of dumping syndrome and oversecretion of glucose-dependent insulinotropic polypeptide following a switch from olanzapine to quetiapine in a patient with schizophrenia. AB - Among the most important adverse effects of antipsychotics is abnormal glucose metabolism, which includes not only hyperglycemia but hyperinsulinemia and hypoglycemia. We have previously described five patients who experienced hypoglycemia during treatment with antipsychotics. Thus, an anamnesis of gastric surgery, which often causes dumping syndrome, and treatment with antipsychotics may synergistically induce hypoglycemia. We describe here a patient with schizophrenia under treatment of olanzapine and an anamnesis of gastric surgery, who experienced late dumping syndrome, hyperinsulinemia and overactivation of glucose-dependent insulinotropic polypeptide. Dumping syndrome, however, was improved after the patient was switched from olanzapine to quetiapine. PMID- 25835511 TI - What's on Your Mind? Conversation Topics Chosen by People With Degenerative Cognitive-Linguistic Disorders for Communication Boards. AB - PURPOSE: Conversational topics chosen by a group of adults with degenerative cognitive-linguistic disorders for personalized communication board development were examined. The patient-generated themes commonly selected are presented to guide treatment planning and communication board development. METHOD: Communication boards were created for 109 adults as part of a larger research project. One autobiographical topic that each participant would enjoy discussing multiple times was represented on each communication board with 16 pictures and word labels. For this review, topics were collapsed into general themes through a consensus process and examined by gender and age. RESULTS: Sixty unique conversational topics were identified from 109 participants and collapsed into 9 general themes: Hobbies, Family, Travel, Work, Home/Places I've Lived, Sports/Fitness, Religion, Animals, and World War II. Age and gender produced variations in themes chosen, though no significance in rank orders was found across groups. CONCLUSIONS: Topics selected by adults with degenerative cognitive linguistic disorders for communication boards resemble common conversational adult themes and do not center around basic needs or medical issues. Differences in gender and age for topic selection tend to be based on traditional roles. These general themes should be used when creating personalized communication boards for those who benefit from conversational aids. PMID- 25835512 TI - Pilot study on the bioactivity of vitamin d in the skin after oral supplementation. AB - Laboratory studies suggest that vitamin D (VD) supplementation inhibits skin carcinogenesis. However, epidemiologic studies report mixed findings in the association between circulating VD levels and skin cancer risk. We conducted a clinical study to determine whether oral cholecalciferol supplementation would exert direct bioactivity in human skin through modulation of the VD receptor (VDR). We enrolled 25 individuals with serum 25-hydroxyvitamin-D levels <30 ng/mL and with skin photodamage to take 50,000 IU of cholecalciferol biweekly for 8 to 9 weeks. Then, we obtained baseline and end-of-study skin biopsies from photodamaged (PD) and photoprotected (PP) skin, and from benign nevi (BN) and tested for mRNA expression of VDR and cytochrome P450-24 (CYP24), and markers of keratinocytic differentiation. High-dose cholecalciferol supplementation significantly elevated circulating levels of 25-hydroxyvitamin-D (P < 0.0001) and 1,25-dihydroxyvitamin-D (P < 0.0001). VDR expression in PD- and PP-skin showed minimum changes after supplementation. CYP24 expression in PD- and PP-skin was increased after supplementation by 186%, P = 0.08, and 134%, P = 0.07, respectively. In BNs from 11 participants, a trend for higher VDR and CYP24 expression was observed (average of 20%, P = 0.08, and 544%, P = 0.09, respectively). Caspase-14 expression at the basal layer in PD skin samples was the only epidermal differentiation marker that was significantly increased (49%, P < 0.0001). High-dose cholecalciferol supplementation raised serum VD metabolite levels concurrently with CYP24 mRNA and caspase-14 levels in the skin. Our findings of significant variability in the range of VDR and CYP24 expression across study samples represent an important consideration in studies evaluating the role of VD as a skin cancer chemopreventive agent. PMID- 25835514 TI - Plaque score change as an indicator for periimplant health in periodontal patients with immediately restored dental implants. AB - BACKGROUND: Patients with a history of periodontitis might have a higher risk for implant failure as compared with periodontally healthy subjects. The aim of the present study was to look into this risk factor by examining the association between plaque scores, probing depths (PD), and bleeding on probing (BOP) around teeth and immediately restored dental implants up to 1 year after implant surgery. METHODS: Patients with partial edentulism, diagnosed with and previously treated for generalized chronic periodontitis, received dental implants, abutments, and cemented provisional prostheses up to 72 hours after implant surgery. Plaque scores, PD, and BOP were recorded and evaluated 6 and 12 months postsurgery. RESULTS: Plaque scores deteriorated slightly around teeth and improved around implants. No significant change was observed in the distribution of PD around teeth. The proportion of shallow pockets increased around implants. Improvement in plaque scores was associated with a stable/reduced PD, whereas deterioration in plaque scores was associated with increased PD around implants and teeth. CONCLUSIONS: A direct relationship was found between plaque score improvement and stable/reduced PD. Therefore, partially edentulous patients with a history of periodontitis should be encouraged to improve their plaque scores to maintain shallower pockets around implants. PMID- 25835513 TI - Profiles of influenza A/H1N1 vaccine response using hemagglutination-inhibition titers. AB - To identify distinct antibody profiles among adults 50-to-74 years old using influenza A/H1N1 HI titers up to 75 days after vaccination. Healthy subjects 50 to 74 years old received the 2010-2011 trivalent inactivated influenza vaccine. We measured venous samples from Days 0, 28, and 75 for HI and VNA and B-cell ELISPOTs. Of 106 subjects, HI titers demonstrated a ceiling effect for 11 or 10% for those with a pre-vaccination HI titer of 1:640 where no subject post vaccination had an increase in titer. Of the remaining 95 subjects, only 37 or 35% overall had at least a 4-fold increase by Day 28. Of these 37, 3 waned at least 4-fold, and 13 others 2-fold. Thus 15% of the subjects showed waning antibody titers by Day 75. More than half failed to respond at all. The profiles populated by these subjects as defined by HI did not vary with age or gender. The VNA results mimicked the HI profiles, but the profiles for B-cell ELISPOT did not. HI titers at Days 0, 28, and 75 populate 4 biologically plausible profiles. Limitations include lack of consensus for operationally defining waning as well as for the apparent ceiling. Furthermore, though well accepted as a marker for vaccine response, assigning thresholds with HI has limitations. However, VNA closely matches HI in populating these profiles. Thus, we hold that these profiles, having face- and content-validity, may provide a basis for understanding variation in genomic and transcriptomic response to influenza vaccination in this age group. PMID- 25835515 TI - The effect of the European traditional use directive on the register of herbal medicinal products in Spain. AB - BACKGROUND: Directive 2004/24/EC, which came into force in 2011, created new regulatory requirements for traditional herbal medicines (THM). This study compared the Spanish THM registry before and after the Directive came fully into force in 2011. METHODS: We consulted the herbal medicinal plant and drug catalogues (General Council of the Official Colleges of Pharmacists), the website of the European Medicines Agency (EMA), and retail web sites. RESULTS: Of 315 THM (from 39 companies) licensed in Spain in 2010, only 48 (10 companies) remained licensed in 2013, mainly due to their withdrawal: the EMA had received just 123 applications from Spain and at least 34% formerly licensed THM had shifted to the less strictly regulated food sector, while up to 54% might have disappeared from the market. However, there is still a significant presence of retail websites making illegal health claims. CONCLUSION: In Spain, the public health benefits of the Directive 2004/24/EC might be less than expected. PMID- 25835517 TI - Impact of methylmercury exposure on mitochondrial energetics in AC16 and H9C2 cardiomyocytes. AB - It has been reported that chronic low dose exposures of methylmercury (MeHg) is associated with cardiovascular diseases in many populations worldwide. The toxic mechanisms through which these adverse effects occur are currently unknown. The objective of this study was to determine the bioenergetic and cytotoxic effects of MeHg on AC16 and H9C2 cardiomyocyte cell lines. Both cell lines exhibit significantly decreased mitochondrial function, cell viability and increased reactive oxygen species (ROS) production. Decreases in maximal respiration and reserve capacity was observed in both cell lines at 1MUM. Bioenergetic profile experiments were also performed in tandem with cells exposed to diamide or menadione, compounds which accumulate in mitochondria and disrupt oxidative phosphorylation. AC16 cells show MeHg dose dependant sensitivities with Stateapparent and ATP production values, but H9C2 cells do not show these trends. H9C2 cells may be more resistant to MeHg toxicity than AC16 cells as reflected in the increases of proton leak and Stateapparent. No changes in expression of respiratory complexes were observed. Results suggest that MeHg has the potential to induce cytotoxicity. Furthermore, MeHg may have differential effects on AC16 and H9C2 cells, derived from human and rat cardiac tissue respectively, suggesting that differences in MeHg toxicity may be species-dependent. PMID- 25835516 TI - Impact of the Baltimore Experience Corps Trial on cortical and hippocampal volumes. AB - INTRODUCTION: There is a substantial interest in identifying interventions that can protect and buffer older adults from atrophy in the cortex and particularly, the hippocampus, a region important to memory. We report the 2-year effects of a randomized controlled trial of an intergenerational social health promotion program on older men's and women's brain volumes. METHODS: The Brain Health Study simultaneously enrolled, evaluated, and randomized 111 men and women (58 interventions; 53 controls) within the Baltimore Experience Corps Trial to evaluate the intervention impact on biomarkers of brain health at baseline and annual follow-ups during the 2-year trial exposure. RESULTS: Intention-to-treat analyses on cortical and hippocampal volumes for full and sex-stratified samples revealed program-specific increases in volumes that reached significance in men only (P's <= .04). Although men in the control arm exhibited age-related declines for 2 years, men in the Experience Corps arm showed a 0.7% to 1.6% increase in brain volumes. Women also exhibited modest intervention-specific gains of 0.3% to 0.54% by the second year of exposure that contrasted with declines of about 1% among women in the control group. DISCUSSION: These findings showed that purposeful activity embedded within a social health promotion program halted and, in men, reversed declines in brain volume in regions vulnerable to dementia. CLINICAL TRIAL REGISTRATION: NCT0038. PMID- 25835518 TI - Detection of CMY-2 AmpC beta-lactamase-producing enterohemorrhagic Escherichia coli O157:H7 from outbreak strains in a nursery school in Japan. AB - In 2013, an outbreak of enterohemorrhagic Escherichia coli (EHEC) O157:H7 occurred in a nursery school in Japan. The outbreak affected 12 school children and five members of their families. All 17 isolates obtained from these individuals were found to be clonal, as determined by pulsed-field gel electrophoresis analysis and multilocus variable number tandem repeat analysis. The antimicrobial susceptibility profiles of the isolates to 20 drugs were examined, with three isolates showing resistance to the extended-spectrum cephalosporins (ESC) and cephamycin, including cefotaxime, ceftazidime, and cefminox. The resistant isolates carried the blaCMY-2 AmpC beta-lactamase gene. It is proposed that the ESC-resistant EHEC O157:H7 isolates might have acquired the resistance plasmid encoding the blaCMY-2 gene during human to human infection in the nursery school. PMID- 25835519 TI - Electrochemiluminescence biosensor for ultrasensitive determination of ochratoxin A in corn samples based on aptamer and hyperbranched rolling circle amplification. AB - Determination of ochratoxin A (OTA) is highly important for food safety control. In this study, a signal-on electrochemiluminescence (ECL) biosensor which combined the characteristics of high efficiency of hyperbranched rolling circle amplification (HRCA) and high selectivity of aptamer was developed for OTA determination. The capture probe DNA (CDNA) was firstly immobilized on the gold electrode surface through Au-S interaction, then the OTA aptamer was modified on the electrode surface through hybridization with CDNA. Since OTA can competitively bind with the aptamer due to their high affinity, which would induce the releasing of aptamer from the electrode surface. Subsequently, the free CDNA on the electrode surface can hybridize with the padlock probe and induce HRCA reaction subsequently. Thus, the HRCA products which contained large amount of double-stranded DNA (dsDNA) fragments can be accumulated on the electrode surface. Since Ru(phen)3(2+) can intercalate into the groove of dsDNA and acts as ECL indicator, high ECL intensity can be detected from the electrode surface. The enhanced ECL intensity has a linear relationship with OTA in the range of 0.05-500 pg/mL with a correlation coefficient of 0.9957, and the limit of detection (LOD) was 0.02 pg/mL. The developed biosensor has been applied to determine OTA concentration in the corn samples with satisfied results. PMID- 25835520 TI - Enzymatic electrochemical detection of epidemic-causing Vibrio cholerae with a disposable oligonucleotide-modified screen-printed bisensor coupled to a dry reagent-based nucleic acid amplification assay. AB - In this study, we developed a nucleic acid-sensing platform in which a simple, dry-reagent-based nucleic acid amplification assay is combined with a portable multiplex electrochemical genosensor. Preparation of an amplification reaction mix targeting multiple DNA regions of interest is greatly simplified because the lyophilized reagents need only be reconstituted with ultrapure water before the DNA sample is added. The presence of single or multiple target DNAs causes the corresponding single-stranded DNA (ssDNA) amplicons to be generated and tagged with a fluorescein label. The fluorescein-labeled ssDNA amplicons are then analyzed using capture probe-modified screen-printed gold electrode bisensors. Enzymatic amplification of the hybridization event is achieved through the catalytic production of electroactive alpha-naphthol by anti-fluorescein conjugated alkaline phosphatase. The applicability of this platform as a diagnostic tool is demonstrated with the detection of toxigenic Vibrio cholerae serogroups O1 and O139, which are associated with cholera epidemics and pandemics. The platform showed excellent diagnostic sensitivity and specificity (100%) when challenged with 168 spiked stool samples. The limit of detection was low (10 colony-forming units/ml) for both toxigenic V. cholerae serogroups. A heat stability assay revealed that the dry-reagent amplification reaction mix was stable at temperatures of 4-56 degrees C, with an estimated shelf life of seven months. The findings of this study highlight the potential of combining a dry reagent-based nucleic acid amplification assay with an electrochemical genosensor in a more convenient, sensitive, and sequence-specific detection strategy for multiple target nucleic acids. PMID- 25835521 TI - Therapeutic utility of antibacterial peptides in wound healing. AB - Cationic antimicrobial peptides were first thought to fight infection in animal models by disintegrating bacterial peptides and later by inhibiting bacteria specific intracellular processes. However, ever increasing evidences indicate that cationic peptides accumulate around and modulate the immune system both systemically and in cutaneous and mucosal surfaces where injuries and infections occur. Native and designer antibacterial peptides as well as cationic peptides, never considered as antibiotics, promote wound healing at every step of cutaneous tissue regeneration. This article provides an introductory list of examples of how cationic peptides are involved in immunostimulation and epithelial tissue repair, eliminating wound infections and promoting wound healing in potential therapeutic utility in sight. Although a few antimicrobial peptides reached the Phase II clinical trial stage, toxicity concerns limit the potential administration routes. Resistance induction to both microbiology actions and the integrity of the innate immune system has to be carefully monitored. PMID- 25835522 TI - Virtual lesion of right posterior superior temporal sulcus modulates conscious visual perception of fearful expressions in faces and bodies. AB - The posterior Superior Temporal Suclus (pSTS) represents a central hub in the complex cerebral network for person perception and emotion recognition as also suggested by its heavy connections with face- and body-specific cortical (e.g., the fusiform face area, FFA and the extrastriate body area, EBA) and subcortical structures (e.g., amygdala). Information on whether pSTS is causatively involved in sustaining conscious visual perception of emotions expressed by faces and bodies is lacking. We explored this issue by combining a binocular rivalry procedure (where emotional and neutral face and body postures rivaled with house images) with off-line, 1-Hz repetitive transcranial magnetic stimulation (rTMS). We found that temporary inhibition of the right pSTS reduced perceptual dominance of fearful faces and increased perceptual dominance of fearful bodies, while leaving unaffected the perception of neutral face and body images. Inhibition of the vertex had no effect on conscious visual perception of neutral or emotional face or body stimuli. Thus, the right pSTS plays a causal role in shortening conscious vision of fearful faces and in prolonging conscious vision of fearful bodies. These results suggest that pSTS selectively modulates the activity of segregated networks involved in the conscious visual perception of emotional faces or bodies. We speculate that the opposite role of the right pSTS for conscious perception of fearful face and body may be explained by the different connections that this region entertains with face- and body-selective visual areas as well as with amygdalae and premotor regions. PMID- 25835523 TI - Seeing fearful body language rapidly freezes the observer's motor cortex. AB - Fearful body language is a salient signal alerting the observer to the presence of a potential threat in the surrounding environment. Although detecting potential threats may trigger an immediate reduction of motor output in animals (i.e., freezing behavior), it is unclear at what point in time similar reductions occur in the human motor cortex and whether they originate from excitatory or inhibitory processes. Using single-pulse and paired-pulse transcranial magnetic stimulation (TMS), here we tested the hypothesis that the observer's motor cortex implements extremely fast suppression of motor readiness when seeing emotional bodies - and fearful body expressions in particular. Participants observed pictures of body postures and categorized them as happy, fearful or neutral while receiving TMS over the right or left motor cortex at 100-125 msec after picture onset. In three different sessions, we assessed corticospinal excitability, short intracortical inhibition (SICI) and intracortical facilitation (ICF). Independently of the stimulated hemisphere and the time of the stimulation, watching fearful bodies suppressed ICF relative to happy and neutral body expressions. Moreover, happy expressions reduced ICF relative to neutral actions. No changes in corticospinal excitability or SICI were found during the task. These findings show extremely rapid bilateral modulation of the motor cortices when seeing emotional bodies, with stronger suppression of motor readiness when seeing fearful bodies. Our results provide neurophysiological support for the evolutionary notions that emotion perception is inherently linked to action systems and that fear-related cues induce an urgent mobilization of motor reactions. PMID- 25835524 TI - The diversity of karyotypes and genomes within section Syllinum of the Genus Linum (Linaceae) revealed by molecular cytogenetic markers and RAPD analysis. AB - The wide variation in chromosome number found in species of the genus Linum (2n = 16, 18, 20, 26, 28, 30, 32, 36, 42, 72, 84) indicates that chromosomal mutations have played an important role in the speciation of this taxon. To contribute to a better understanding of the genetic diversity and species relationships in this genus, comparative studies of karyotypes and genomes of species within section Syllinum Griseb. (2n = 26, 28) were carried out. Elongated with 9-aminoacridine chromosomes of 10 species of section Syllinum were investigated by C- and DAPI/S banding, CMA and Ag-NOR-staining, FISH with probes of rDNA and of telomere repeats. RAPD analysis was also performed. All the chromosome pairs in karyotypes of the studied species were identified. Chromosome DAPI/C-banding patterns of 28 chromosomal species were highly similar. Two of the species differed from the others in chromosomal location of rDNA sites. B chromosomes were revealed in all the 28-chromosomal species. Chromosomes of Linum nodiflorum L. (2n = 26) and the 28-chromosomal species were similar in DAPI/C-banding pattern and localization of several rDNA sites, but they differed in chromosomal size and number. The karyotype of L. nodiflorum was characterized by an intercalary site of telomere repeat, one additional 26S rDNA site and also by the absence of B chromosomes. Structural similarities between different chromosome pairs in karyotypes of the studied species were found indicating their tetraploid origin. RAPD analysis did not distinguish the species except L. nodiflorum. The species of section Syllinum probably originated from a common tetraploid ancestor. The 28-chromosomal species were closely related, but L. nodiflorum diverged significantly from the rest of the species probably due to chromosomal rearrangements occurring during evolution. PMID- 25835525 TI - Impact of Yangtze river water transfer on the water quality of the Lixia river watershed, China. AB - To improve water quality and reduce the negative impacts of sudden inputs of water pollution in the Lixia River watershed, China, a series of experimental water transfers from the Yangtze River to the Lixia River were conducted from 2 December 2006 to 7 January 2007. Water samples were collected every six days at 55 monitoring sites during this period. Eight water parameters (water temperature, pH, dissolved oxygen (DO), chemical oxygen demand (COD), potassium permanganate index (CODMn), ammonia nitrogen (NH4+-N), electrical conductivity (EC), and water transparency (WT)) were analyzed to determine changes in nutrient concentrations during water transfers. The comprehensive pollution index (Pi) and single-factor (Si) evaluation methods were applied to evaluate spatio-temporal patterns of water quality during water transfers. Water quality parameters displayed different spatial and temporal distribution patterns within the watershed. Water quality was improved significantly by the water transfers, especially for sites closer to water intake points. The degree of improvement is positively related to rates of transfer inflow and drainage outflow. The effects differed for different water quality parameters at each site and at different water transfer times. There were notable decreases in NH4+-N, DO, COD, and CODMn across the entire watershed. However, positive effects on EC and pH were not observed. It is concluded that freshwater transfers from the Yangtze River can be used as an emergency measure to flush pollutants from the Lixia River watershed. Improved understanding of the effects of water transfers on water quality can help the development and implementation of effective strategies to improve water quality within this watershed. PMID- 25835526 TI - Effects of Biotin Supplementation in the Diet on Adipose Tissue cGMP Concentrations, AMPK Activation, Lipolysis, and Serum-Free Fatty Acid Levels. AB - Several studies have shown that pharmacological concentrations of biotin decrease hyperlipidemia. The molecular mechanisms by which pharmacological concentrations of biotin modify lipid metabolism are largely unknown. Adipose tissue plays a central role in lipid homeostasis. In the present study, we analyzed the effects of biotin supplementation in adipose tissue on signaling pathways and critical proteins that regulate lipid metabolism, as well as on lipolysis. In addition, we assessed serum fatty acid concentrations. Male BALB/cAnN Hsd mice were fed a control or a biotin-supplemented diet (control: 1.76 mg biotin/kg; supplemented: 97.7 mg biotin/kg diet) over 8 weeks postweaning. Compared with the control group, biotin-supplemented mice showed an increase in the levels of adipose guanosine 3',5'-cyclic monophosphate (cGMP) (control: 30.3+/-3.27 pmol/g wet tissue; supplemented: 49.5+/-3.44 pmol/g wet tissue) and of phosphorylated forms of adenosine 5'-monophosphate-activated protein kinase (AMPK; 65.2%+/-1.06%), acetyl-coenzyme A (CoA), carboxylase-1 (196%+/-68%), and acetyl-CoA carboxylase-2 (78.1%+/-18%). Serum fatty acid concentrations were decreased (control: 1.12+/ 0.04 mM; supplemented: 0.91+/-0.03 mM), and no change in lipolysis was found (control: 0.29+/-0.05 MUmol/mL; supplemented: 0.33+/-0.08 MUmol/mL). In conclusion, 8 weeks of dietary biotin supplementation increased adipose tissue cGMP content and protein expression of the active form of AMPK and of the inactive forms of acetyl-CoA carboxylase-1 and acetyl-CoA carboxylase-2. Serum fatty acid levels fell, and no change in lipolysis was observed. These findings provide insight into the effects of biotin supplementation on adipose tissue and support its use in the treatment of dyslipidemia. PMID- 25835527 TI - Accurate Measurements of Dielectric and Optical Functions of Liquid Water and Liquid Benzene in the VUV Region (1-100 eV) Using Small-Angle Inelastic X-ray Scattering. AB - Using a third-generation synchrotron source (the BL12XU beamline at SPring-8), inelastic X-ray scattering (IXS) spectra of liquid water and liquid benzene were measured at energy losses of 1-100 eV with 0.24 eV resolution for small momentum transfers (q) of 0.23 and 0.32 au with +/-0.06 au uncertainty for q. For both liquids, the IXS profiles at these values of q converged well after we corrected for multiple scattering, and these results confirmed the dipole approximation for q <= ~0.3 au. Several dielectric and optical functions [including the optical oscillator strength distribution (OOS), the optical energy-loss function (OLF), the complex dielectric function, the complex index of refraction, and the reflectance] in the vacuum ultraviolet region were derived and tabulated from these small-angle (small q) IXS spectra. These new data were compared with previously obtained results, and this comparison demonstrated the strong reproducibility and accuracy of IXS spectroscopy. For both water and benzene, there was a notable similarity between the OOSs of the liquids and amorphous solids, and there was no evidence of plasmon excitation in the OLF. The static structure factor [S(q)] for q <= ~0.3 au was also deduced and suggests that molecular models that include electron correlation effects can serve as a good approximation for the liquid S(q) values over the full range of q. PMID- 25835528 TI - Enhanced care team response to incidents involving major trauma at night: are helicopters the answer? AB - INTRODUCTION: Challenges exist in how to deliver enhanced care to patients suffering severe injury in geographically remote areas within regionalised trauma networks at night. The physician led Enhanced Care Teams (ECTs) in the West Midlands region of England do not currently utilise helicopters to respond to incidents at night. This study describes this remote trauma workload at night within the regional network in terms of incident location; injury profile and patient care needs and discusses various solutions to the delivery of ECTs to such incidents, including the need for helicopter based platforms. METHODS: We present a retrospective analysis of incidents involving Major Trauma occurring in the West Midlands Regional Trauma Network in England over a one year period (1st April 2012 until the 31st March 2013). Anonymised patient records from the Trauma Audit and Research Network (TARN) for patients that had been conveyed to hospital by ambulance/air ambulance were cross-referenced with the West Midlands Ambulance Service NHS Foundation Trust (WMAS) Computer Assisted Dispatch (CAD) archive for the same period. Data were abstracted from the combined dataset relating to injury severity (ISS/ICU admission/death at scene or as inpatient); ECT resource activations/scene attendances; incident location and the need for enhanced level care. RESULTS: A total of 603 incidents involving Major Trauma were identified during night time hours. Enhanced Care Team resources attended scene in 167 cases (27.7%). Of the incidents not attended by an ECT 179 (41.1%) were due to falls and 91 (20.9%) involved a 'Road Traffic Collision'. A total of 36 incidents (6.0% of total at night) occurred in locations identified as being greater than 45min by road from the nearest major trauma centre. In these cases 13 patients had enhanced care needs that could not be addressed at scene by the attending ambulance service personnel. CONCLUSIONS: There is limited evidence to support the need for night HEMS operations in the West Midlands regional trauma network. The potential role of night HEMS in other regional trauma networks in England requires further evaluation with specific reference to the incidence of Major Trauma and efficiency of existing road based systems. PMID- 25835529 TI - Cadaveric analysis of capsular attachments of the distal femur related to pin and wire placement. AB - OBJECTIVES: Septic arthritis following intra-capsular penetration of the knee by external fixation devices is a complication of traction/fixation devices inserted in the lower extremity [1,2]. The authors were unable to find reference to or exact measurements of the capsular attachments relating to the distal femur documented in the current literature. This study aimed to demonstrate the capsular attachments and reflections of the distal femur to determine safe placements of wires or traction devices. METHODS: The attachments of the capsule to the distal femur were measured in 10 unembalmed cadaveric knees. Capsular attachments were measured anteriorly at the maximal extension of the supra patella pouch. Medially and laterally measurements were expressed as percentages related to the maximal AP diameter of the distal femur. RESULTS: Mean distance from the centre of the anterior part of the notch to the superior fold was 79.5mm (Range 48.1-120.7 mm). The medial capsular reflections measured in a plane from the adductor tubercle to the anterior edge of the medial femoral condyle demonstrated the capsular reflection was attached an average of 57% back from the anterior edge (Range 41-74%). Laterally the capsular reflections on a line drawn from the maximal diameter in the sagittal plane were attached an average of 48% from the anterior reference point (Range 33-57%). Measuring the reflections at 45 degrees to the long axis of the femur in the sagittal plane the attachment was an average of 51% from the anterior reference point. CONCLUSIONS: Capsular reflections varied among specimens. Medially the capsule attachment was up to 74% of diameter of distal femur at the level of the adductor tubercle. Therefore, the insertion of distal femoral traction pins or similar should be placed proximal to the adductor tubercle and no further than 25% of the distance to the anterior cortex. Care is also needed to ensure pins do not travel to exit too anteriorly on the lateral side as capsular attachments were found to be up to a distance 48% of the diameter of the femur from anterior reference point. Distal condylar extra articular fixation with Schanz screws is feasible if orientated in the oblique plane. PMID- 25835531 TI - Development of a recombination system for the generation of occlusion positive genetically modified Anticarsia gemmatalis multiple nucleopolyhedrovirus. AB - Anticarsia gemmatalis is an important pest in legume crops in South America and it has been successfully controlled using Anticarsia gemmatalis Multiple Nucleopolyhedrovirus (AgMNPV) in subtropical climate zones. Nevertheless, in temperate climates its speed of kill is too slow. Taking this into account, genetic modification of AgMNPV could lead to improvements of its biopesticidal properties. Here we report the generation of a two-component system that allows the production of recombinant AgMNPV. This system is based on a parental AgMNPV in which the polyhedrin gene (polh) was replaced by a bacterial beta galactosidase (lacZ) gene flanked by two target sites for the homing endonuclease I-PpoI. Co-transfection of insect cells with linearized (I-PpoI-digested) parental genome and a transfer vector allowed the restitution of polh and the expression of a heterologous gene upon homologous recombination, with a low background of non-recombinant AgMNPV. The system was validated by constructing a recombinant occlusion-positive (polh+) AgMNPV expressing the green fluorescent protein gene (gfp). This recombinant virus infected larvae normally per os and led to the expression of GFP in cell culture as well as in A. gemmatalis larvae. These results demonstrate that the system is an efficient method for the generation of recombinant AgMNPV expressing heterologous genes, which can be used for manifold purposes, including biotechnological and pharmaceutical applications and the production of orally infectious recombinants with improved biopesticidal properties. PMID- 25835530 TI - Eradication of HIV-1 from the macrophage reservoir: an uncertain goal? AB - Human immunodeficiency virus type 1 (HIV-1) establishes latency in resting memory CD4+ T cells and cells of myeloid lineage. In contrast to the T cells, cells of myeloid lineage are resistant to the HIV-1 induced cytopathic effect. Cells of myeloid lineage including macrophages are present in anatomical sanctuaries making them a difficult drug target. In addition, the long life span of macrophages as compared to the CD4+ T cells make them important viral reservoirs in infected individuals especially in the late stage of viral infection where CD4+ T cells are largely depleted. In the past decade, HIV-1 persistence in resting CD4+ T cells has gained considerable attention. It is currently believed that rebound viremia following cessation of combination anti-retroviral therapy (cART) originates from this source. However, the clinical relevance of this reservoir has been questioned. It is suggested that the resting CD4+ T cells are only one source of residual viremia and other viral reservoirs such as tissue macrophages should be seriously considered. In the present review we will discuss how macrophages contribute to the development of long-lived latent reservoirs and how macrophages can be used as a therapeutic target in eradicating latent reservoir. PMID- 25835532 TI - Apigenin restricts FMDV infection and inhibits viral IRES driven translational activity. AB - Foot-and-mouth disease (FMD) is a highly contagious disease of domestic and wild ruminants that is caused by FMD virus (FMDV). FMD outbreaks have occurred in livestock-containing regions worldwide. Apigenin, which is a flavonoid naturally existing in plant, possesses various pharmacological effects, including anti inflammatory, anticancer, antioxidant and antiviral activities. Results show that apigenin can inhibit FMDV-mediated cytopathogenic effect and FMDV replication in vitro. Further studies demonstrate the following: (i) apigenin inhibits FMDV infection at the viral post-entry stage; (ii) apigenin does not exhibit direct extracellular virucidal activity; and (iii) apigenin interferes with the translational activity of FMDV driven by internal ribosome entry site. Studies on applying apigein in vivo are required for drug development and further identification of potential drug targets against FDMV infection. PMID- 25835533 TI - Glycosylation of KSHV encoded vGPCR functions in its signaling and tumorigenicity. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a tumor virus and the etiologic agent of Kaposi's Sarcoma (KS). KSHV G protein-coupled receptor (vGPCR) is an oncogene that is implicated in malignancies associated with KHSV infection. In this study, we show that vGPCR undergoes extensive N-linked glycosylation within the extracellular domains, specifically asparagines 18, 22, 31 and 202. An immunofluorescence assay demonstrates that N-linked glycosylation are necessary for vGPCR trafficking to the cellular membrane. Employing vGPCR mutants whose glycosylation sites were ablated, we show that these vGPCR mutants failed to activate downstream signaling in cultured cells and were severely impaired to induce tumor formation in the xenograph nude mouse model. These findings support the conclusion that glycosylation is critical for vGPCR tumorigenesis and imply that chemokine regulation at the plasma membrane is crucial for vGPCR mediated signaling. PMID- 25835534 TI - Presence of poly(A) tails at the 3'-termini of some mRNAs of a double-stranded RNA virus, southern rice black-streaked dwarf virus. AB - Southern rice black-streaked dwarf virus (SRBSDV), a new member of the genus Fijivirus, is a double-stranded RNA virus known to lack poly(A) tails. We now showed that some of SRBSDV mRNAs were indeed polyadenylated at the 3' terminus in plant hosts, and investigated the nature of 3' poly(A) tails. The non-abundant presence of SRBSDV mRNAs bearing polyadenylate tails suggested that these viral RNA were subjected to polyadenylation-stimulated degradation. The discovery of poly(A) tails in different families of viruses implies potentially a wide occurrence of the polyadenylation-assisted RNA degradation in viruses. PMID- 25835536 TI - Addendum: Kazmierczak, Z.; Gorski, A.; Dabrowska, K. Facing antibiotic resistance: Staphylococcus aureus phages as a medical tool. Viruses 2014, 6, 2551 2570. PMID- 25835535 TI - Tenth International Foamy Virus Conference 2014--achievements and perspectives. AB - For the past two decades, scientists from around the world, working on different aspects of foamy virus (FV) research, have gathered in different research institutions almost every two years to present their recent results in formal talks, to discuss their ongoing studies informally, and to initiate fruitful collaborations. In this report we review the 2014 anniversary conference to share the meeting summary with the virology community and hope to arouse interest by other researchers to join this exciting field. The topics covered included epidemiology, virus molecular biology, and immunology of FV infection in non human primates, cattle, and humans with zoonotic FV infections, as well as recent findings on endogenous FVs. Several topics focused on virus replication and interactions between viral and cellular proteins. Use of FV in biomedical research was highlighted with presentations on using FV vectors for gene therapy and FV proteins as scaffold for vaccine antigen presentation. On behalf of the FV community, this report also includes a short tribute to commemorate Prof. Axel Rethwilm, one of the leading experts in the field of retrovirology and foamy viruses, who passed away 29 July 2014. PMID- 25835537 TI - Steroidal Alkaloids from Veratrum nigrum Enhance Glucose Uptake in Skeletal Muscle Cells. AB - Veratrum nigrum is recognized as a medicinal plant used for the treatment of hypertension, stroke, and excessive phlegm. Chemical investigation of the roots and rhizomes led to the isolation of five new steroidal alkaloids, jervine-3-yl formate (1), veramarine-3-yl formate (2), jerv-5,11-diene-3beta,13beta-diol (3), (1beta,3beta,5beta)-1,3-dihydroxyjervanin-12(13)-en-11-one (4), and veratramine-3 yl acetate (5). Compounds 1 and 5 exhibited potent inhibitory activity (11.3 and 4.7 MUM, respectively) against protein tyrosine phosphatase 1B (PTP1B), which has emerged as a viable target for treatment of type 2 diabetes mellitus. On the basis of their PTP1B inhibitory activity, the compounds were evaluated for their potential to enhance glucose uptake in C2C12 skeletal muscle cells. The insulin stimulated glucose uptake was enhanced upon treatment with compounds 1 and 5 (10 MUM) by 49.9 +/- 6.5% and 56.0 +/- 9.7%, respectively, in a more potent manner than that with the positive control rosiglitazone (47.3 +/- 3.4% at 30 MUM). These results suggest that steroidal alkaloids serve as practical antidiabetes mellitus leads capable of enhancing glucose uptake. PMID- 25835538 TI - Estimating influenza attack rates in the United States using a participatory cohort. AB - We considered how participatory syndromic surveillance data can be used to estimate influenza attack rates during the 2012-2013 and 2013-2014 seasons in the United States. Our inference is based on assessing the difference in the rates of self-reported influenza-like illness (ILI, defined as presence of fever and cough/sore throat) among the survey participants during periods of active vs. low influenza circulation as well as estimating the probability of self-reported ILI for influenza cases. Here, we combined Flu Near You data with additional sources (Hong Kong household studies of symptoms of influenza cases and the U.S. Centers for Disease Control and Prevention estimates of vaccine coverage and effectiveness) to estimate influenza attack rates. The estimated influenza attack rate for the early vaccinated Flu Near You members (vaccination reported by week 45) aged 20-64 between calendar weeks 47-12 was 14.7%(95% CI(5.9%,24.1%)) for the 2012-2013 season and 3.6%(-3.3%,10.3%) for the 2013-2014 season. The corresponding rates for the US population aged 20-64 were 30.5% (4.4%, 49.3%) in 2012-2013 and 7.1%(-5.1%, 32.5%) in 2013-2014. The attack rates in women and men were similar each season. Our findings demonstrate that participatory syndromic surveillance data can be used to gauge influenza attack rates during future influenza seasons. PMID- 25835539 TI - Fourier power spectrum characteristics of face photographs: attractiveness perception depends on low-level image properties. AB - We investigated whether low-level processed image properties that are shared by natural scenes and artworks - but not veridical face photographs - affect the perception of facial attractiveness and age. Specifically, we considered the slope of the radially averaged Fourier power spectrum in a log-log plot. This slope is a measure of the distribution of special frequency power in an image. Images of natural scenes and artworks possess - compared to face images - a relatively shallow slope (i.e., increased high spatial frequency power). Since aesthetic perception might be based on the efficient processing of images with natural scene statistics, we assumed that the perception of facial attractiveness might also be affected by these properties. We calculated Fourier slope and other beauty-associated measurements in face images and correlated them with ratings of attractiveness and age of the depicted persons (Study 1). We found that Fourier slope - in contrast to the other tested image properties - did not predict attractiveness ratings when we controlled for age. In Study 2A, we overlaid face images with random-phase patterns with different statistics. Patterns with a slope similar to those in natural scenes and artworks resulted in lower attractiveness and higher age ratings. In Studies 2B and 2C, we directly manipulated the Fourier slope of face images and found that images with shallower slopes were rated as more attractive. Additionally, attractiveness of unaltered faces was affected by the Fourier slope of a random-phase background (Study 3). Faces in front of backgrounds with statistics similar to natural scenes and faces were rated as more attractive. We conclude that facial attractiveness ratings are affected by specific image properties. An explanation might be the efficient coding hypothesis. PMID- 25835540 TI - Association of household and community socioeconomic position and urbanicity with underweight and overweight among women in Pakistan. AB - BACKGROUND: Similar to other developing countries, Pakistan is going through a rapid nutrition transition where shift from underweight to overweight and obesity is occurring. In this paper, we report on the relationship of household socioeconomic position (SEP), community SEP and urbanicity with under- and over weight categories of BMI among Pakistani women. METHODS: We analyzed data on 4,767 women ages 15-49 years enrolled in a nationally representative Pakistan Demographic Health Survey (PDHS) conducted in 2012-13 that employed a multistage, stratified cluster sampling design. We assessed the association of urbanicity, household and community SEP derived from household assets and utilities, with categories of body mass index (BMI) using multinomial regression analysis where normal weight (BMI 18.6-22.5) was the reference category. RESULTS: Thirteen percent of women were underweight (BMI <18.5), 15% pre-overweight (BMI: 22.6 24.9), 25% overweight (BMI: 25.0-29.9) and 14% were obese (BMI>=30). Pre overweight, overweight and obesity among women increased across household wealth quintiles (HWQs) in a graded fashion whereas there was no significant difference in underweight by household wealth. Women in urban areas were more likely to be obese. There was a pronounced increase in adjusted odds ratios (aORs) for overweight/obesity across HWQs within urban areas compared to rural areas. There was a steeper gradient in aORs for obesity from 1st to 5th HWQs in high income communities compared to the middle- and low income communities. In community level analyses, communities in urban areas were more likely to have higher levels of obesity while in rural areas, especially in Sindh, more communities were more likely to have a higher level of underweight. CONCLUSION: A shift to higher overweight and obesity than underweight in Pakistan is associated with high household and community wealth as well as living in urban areas. Clustering of obesity and underweight in distinct communities afford opportunity for tailored intervention programs. PMID- 25835541 TI - Reiki for depression and anxiety. AB - BACKGROUND: Anxiety and depression affect many people. Treatments do not have complete success and often require people to take drugs for long periods of time. Many people look for other treatments that may help. One of those is Reiki, a 2500 year old treatment described as a vibrational or subtle energy therapy, and is most commonly facilitated by light touch on or above the body. There have been reports of Reiki alleviating anxiety and depression, but no specific systematic review. OBJECTIVES: To assess the effectiveness of Reiki for treating anxiety and depression in people aged 16 and over. SEARCH METHODS: Search of the Cochrane Register of Controlled Trials (CENTRAL - all years), the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR - all years), EMBASE, (1974 to November 2014), MEDLINE (1950 to November 2014), PsycINFO (1967 to November 2014) and AMED (1985 to November 2014). Additional searches were carried out on the World Health Organization Trials Portal (ICTRP) together with ClinicalTrials.gov to identify any ongoing or unpublished studies. All searches were up to date as of 4 November 2014. SELECTION CRITERIA: Randomised trials in adults with anxiety or depression or both, with at least one arm treated with Reiki delivered by a trained Reiki practitioner. DATA COLLECTION AND ANALYSIS: The two authors independently decided on inclusion/exclusion of studies and extracted data. A prior analysis plan had been specified but was not needed as the data were too sparse. MAIN RESULTS: We found three studies for inclusion in the review. One recruited males with a biopsy-proven diagnosis of non-metastatic prostate cancer who were not receiving chemotherapy and had elected to receive external-beam radiation therapy; the second study recruited community-living participants who were aged 55 years and older; the third study recruited university students.These studies included subgroups with anxiety and depression as defined by symptom scores and provided data separately for those subgroups. As this included only 25 people with anxiety and 17 with depression and 20 more with either anxiety or depression, but which was not specified, the results could only be reported narratively. They show no evidence that Reiki is either beneficial or harmful in this population. The risk of bias for the included studies was generally rated as unclear or high for most domains, which reduces the certainty of the evidence. AUTHORS' CONCLUSIONS: There is insufficient evidence to say whether or not Reiki is useful for people over 16 years of age with anxiety or depression or both. PMID- 25835543 TI - Correction: Cryoprotectants and extreme freeze tolerance in a subarctic population of the wood frog. PMID- 25835542 TI - Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1) specific cytotoxic T lymphocytes in acute myeloid leukemia patients. AB - Wilms' tumor gene 1 (WT1) protein is a promising tumor-associated antigen for cancer immunotherapy. We have been performing WT1 peptide vaccination with good clinical responses in over 750 patients with leukemia or solid cancers. In this study, we generated single-cell gene-expression profiles of the effector memory (EM) subset of WT1-specific cytotoxic T lymphocytes (CTLs) in peripheral blood of nine acute myeloid leukemia patients treated with WT1 peptide vaccine, in order to discriminate responders (WT1 mRNA levels in peripheral blood decreased to undetectable levels, decreased but stayed at abnormal levels, were stable at undetectable levels, or remained unchanged from the initial abnormal levels more than 6 months after WT1 vaccination) from non-responders (leukemic blast cells and/or WT1 mRNA levels increased relative to the initial state within 6 months of WT1 vaccination) prior to WT1 vaccination. Cluster and principal component analyses performed using 83 genes did not discriminate between responders and non responders prior to WT1 vaccination. However, these analyses revealed that EM subset of WT1-specific CTLs could be divided into two groups: the "activated" and "quiescent" states; in responders, EM subset of the CTLs shifted to the "quiescent" state, whereas in non-responders, those shifted to the "activated" state following WT1 vaccination. These results demonstrate for the first time the existence of two distinct EM states, each of which was characteristic of responders or non-responders, of WT1-specific CTLs in AML patients, and raises the possibility of using advanced gene-expression profile analysis to clearly discriminate between responders and non-responders prior to WT1 vaccination. PMID- 25835544 TI - Fate of the antibiotic sulfadiazine in natural soils: Experimental and numerical investigations. AB - Based on small-scale laboratory and field-scale lysimeter experiments, the sorption and biodegradation of sulfonamide sulfadiazine (SDZ) were investigated in unsaturated sandy and silty-clay soils. Sorption and biodegradation were low in the laboratory, while the highest leaching rates were observed when SDZ was mixed with manure. The leaching rate decreased when SDZ was mixed with pure water, and was smallest with the highest SDZ concentrations. In the laboratory, three transformation products (TPs) developed after an initial lag phase. However, the amount of TPs was different for different mixing-scenarios. The TP 2 aminopyrimidine was not observed in the laboratory, but was the most prevalent TP at the field scale. Sorption was within the same range at the laboratory and field scales. However, distinctive differences occurred with respect to biodegradation, which was higher in the field lysimeters than at the laboratory scale. While the silty-clay soil favored sorption of SDZ, the sandy, and thus highly permeable, soil was characterized by short half-lives and thus a quick biodegradation of SDZ. For 2-aminopyrimidine, half-lives of only a few days were observed. Increased field-scale biodegradation in the sandy soil resulted from a higher water and air permeability that enhanced oxygen transport and limited oxygen depletion. Furthermore, low pH was more important than the organic matter and clay content for increasing the biodegradation of SDZ. A numerical analysis of breakthrough curves of bromide, SDZ, and its TPs showed that preferential flow pathways strongly affected the solute transport within shallow parts of the soil profile at the field scale. However, this effect was reduced in deeper parts of the soil profile. Due to high field-scale biodegradation in several layers of both soils, neither SDZ nor 2-aminopyrimidine was detected in the discharge of the lysimeter at a depth of 1m. Synthetic 50 year long simulations, which considered the application of manure with SDZ for general agricultural practices in Germany and humid climate conditions, showed that the concentration of SDZ decreased below 0.1 MUg/L in both soils below the depth of 50 cm. PMID- 25835545 TI - Using vapor phase tomography to measure the spatial distribution of vapor concentrations and flux for vadose-zone VOC sources. AB - A test was conducted at a chlorinated-solvent contaminated site in Tucson, AZ, to evaluate the effectiveness of vapor-phase tomography (VPT) for characterizing the distribution of volatile organic contaminants (VOC) in the vadose zone. A soil vapor extraction (SVE) system has been in operation at the site since 2007. Vapor concentration and vacuum pressure were measured at four different depths in each of the four monitoring wells surrounding the extraction well. The test provided a 3D characterization of local vapor concentrations under induced-gradient conditions. Permeability data obtained from analysis of borehole logs were used along with pressure and the vapor-concentration data to determine VOC mass flux within the test domain. A region of higher mass flux was identified in the deepest interval of the S-SW section of the domain, indicating the possible location of a zone with greater contaminant mass. These results are consistent with the TCE-concentration distribution obtained from sediment coring conducted at the site. In contrast, the results of a standard soil gas survey did not indicate the presence of a zone with greater contaminant mass. These results indicate that the VPT test provided a robust characterization of VOC concentration and flux distribution at the site. PMID- 25835546 TI - Using dual isotopes to evaluate sources and transformations of nitrate in the West Lake watershed, eastern China. AB - The West Lake is a World Heritage site in the West Lake watershed in eastern China. In this study, the hydrogeological and dual isotopic approaches were integrated to evaluate the seasonal and spatial variations of nitrate (NO3(-)) in the West Lake watershed, and to characterize NO3(-) sources and transformations. The results revealed that the geochemical facies of the water samples were dominated by Ca(2+)+Na(+)-HCO3(-)+SO4(2)(-) in the surface water and transfer water, Ca(2+)+Na(+)-HCO3(-) and Ca(2+)+Na(+)-SO4(2-) in the groundwater, which most likely reflect natural reactions and anthropogenic inputs. About 13% of the groundwater samples containing NO3(-) exceeded the World Health Organization (WHO) standard of 10 mg N L(-1). NO3(-) was the dominant form of total nitrogen (TN) and was the main surface water contaminant in the West Lake watershed. The delta(15)NNO3 and delta(18)ONO3 values indicated that the dominant NO3(-) sources in surface water were soil nitrogen (soil N) and chemical fertilizers, while the main NO3(-) sources in groundwater were soil N from the forest, chemical fertilizers and manure in the tea garden, domestic sewage from the small, old residential area in the forest as well as urban areas. The distribution of NO3(-) in groundwater was strongly influenced by land use. Results also suggest that there was significant nitrification in surface water and groundwater in the West Lake watershed, and that there were also denitrification processes in groundwater. The annual net fluxes of TN, NO3(-), and NH4(+) into the West Lake were 2.0*10(4), 4.0*10(3), and 1.31*10(4) kg as N, respectively. PMID- 25835548 TI - Persistent decrease in alpha current density in fully remitted subjects with major depressive disorder treated with fluoxetine: A prospective electric tomography study. AB - Major depressive disorder (MDD) is recurrent, and its pathophysiology is not fully understood. Studies using electric tomography (ET) have identified abnormalities in the current density (CD) of MDD subjects in regions associated with the neurobiology of MDD, such as the anterior cingulate cortex (ACC) and medial orbitofrontal cortex (mOFC). However, little is known regarding the long term CD changes in MDD subjects who respond to antidepressants. The aim of this study was to compare CD between healthy and MDD subjects who received 1-year open label treatment with fluoxetine. Thirty-two-channel electroencephalograms (EEGs) were collected from 70 healthy controls and 74 MDD subjects at baseline (pre treatment), 1 and 2weeks and 1, 2, 6, 9 and 12months. Variable-resolution ET (VARETA) was used to assess the CD between subject groups at each time point. The MDD group exhibited decreased alpha CD (alphaCD) in the occipital and parietal cortices, ACC, mOFC, thalamus and caudate nucleus at each time point. The alphaCD abnormalities persisted in the MDD subjects despite their achieving full remission. The low sub-alpha band was different between the healthy and MDD subjects. Differences in the amount of alphaCD between sexes and treatment outcomes were observed. Lack of a placebo arm and the loss of depressed patients to follow-up were significant limitations. The persistence of the decrease in alphaCD might suggest that the underlying pathophysiologic mechanisms of MDD are not corrected despite the asymptomatic state of MDD subjects, which could be significant in understanding the highly recurrent nature of MDD. PMID- 25835547 TI - Impaired T cell responsiveness to interleukin-6 in hematological patients with invasive aspergillosis. AB - Invasive mold infections (IMI) are among the most devastating complications following chemotherapy and hematopoietic stem cell transplantation (HSCT), with high mortality rates. Yet, the molecular basis for human susceptibility to invasive aspergillosis (IA) and mucormycosis remain poorly understood. Herein, we aimed to characterize the immune profile of individuals with hematological malignancies (n = 18) who developed IMI during the course of chemotherapy or HSCT, and compared it to that of hematological patients who had no evidence of invasive fungal infection (n = 16). First, we measured the expression of the pattern recognition receptors pentraxin 3, dectin-1, and Toll-like receptors (TLR) 2 and 4 in peripheral blood of chemotherapy and HSCT recipients with IMI. Compared to hematological controls, individuals with IA and mucormycosis had defective expression of dectin-1; in addition, patients with mucormycosis had decreased TLR2 and increased TLR4 expression. Since fungal recognition via dectin 1 favors T helper 17 responses and the latter are highly dependent on activation of the signal transducer and activator of transcription (STAT) 3, we next used phospho-flow cytometry to measure the phosphorylation of the transcription factors STAT1 and STAT3 in response to interferon-gamma (IFN-gamma) and interleukin (IL)-6, respectively. While IFN-gamma/STAT1 signaling was similar between groups, naive T cells from patients with IA, but not those with mucormycosis, exhibited reduced responsiveness to IL-6 as measured by STAT3 phosphorylation. Furthermore, IL-6 increased Aspergillus-induced IL-17 production in culture supernatants from healthy and hematological controls but not in patients with IA. Altogether, these observations suggest an important role for dectin-1 and the IL-6/STAT3 pathway in protective immunity against Aspergillus. PMID- 25835549 TI - An odor identification approach based on event-related pupil dilation and gaze focus. AB - Olfactory disorders constitute a potential marker of many diseases and are considered valuable clues to the diagnosis and evaluation of progression for many disorders. The most commonly used test for the evaluation of impairments of olfactory identification requires the active participation of the subject, who must select the correct name of the perceived odor from a list. An alternative method is required because speech may be impaired or not yet learned in many patients. As odor identification is known to be facilitated by searching for visual clues, we aimed to develop an objective, vision-based approach for the evaluation of odor identification. We used an eye tracking method to quantify pupillary and ocular responses during the simultaneous presentation of olfactory and visual stimuli, in 39 healthy participants aged from 19 to 77years. Odor presentation triggered an increase in pupil dilation and gaze focus on the picture corresponding to the odor presented. These results suggest that odorant stimuli increase recruitment of the sympathetic system (as demonstrated by the reactivity of the pupil) and draw attention to the visual clue. These results validate the objectivity of this method. PMID- 25835550 TI - Mitochondrial vulnerability and increased susceptibility to nutrient-induced cytotoxicity in fibroblasts from leigh syndrome French canadian patients. AB - Mutations in LRPPRC are responsible for the French Canadian variant of Leigh Syndrome (LSFC), a severe disorder characterized biochemically by a tissue specific deficiency of cytochrome c oxidase (COX) and clinically by the occurrence of severe and deadly acidotic crises. Factors that precipitate these crises remain unclear. To better understand the physiopathology and identify potential treatments, we performed a comprehensive analysis of mitochondrial function in LSFC and control fibroblasts. Furthermore, we have used this cell based model to screen for conditions that promote premature cell death in LSFC cells and test the protective effect of ten interventions targeting well-defined aspects of mitochondrial function. We show that, despite maintaining normal ATP levels, LSFC fibroblasts present several mitochondrial functional abnormalities under normal baseline conditions, which likely impair their capacity to respond to stress. This includes mitochondrial network fragmentation, impaired oxidative phosphorylation capacity, lower membrane potential, increased sensitivity to Ca2+ induced permeability transition, but no changes in reactive oxygen species production. We also show that LSFC fibroblasts display enhanced susceptibility to cell death when exposed to palmitate, an effect that is potentiated by high lactate, while high glucose or acidosis alone or in combination were neutral. Furthermore, we demonstrate that compounds that are known to promote flux through the electron transport chain independent of phosphorylation (methylene blue, dinitrophenol), or modulate fatty acid (L-carnitine) or Krebs cycle metabolism (propionate) are protective, while antioxidants (idebenone, N-acetyl cysteine, resveratrol) exacerbate palmitate plus lactate-induced cell death. Collectively, beyond highlighting multiple alterations in mitochondrial function and increased susceptibility to nutrient-induced cytotoxicity in LSFC fibroblasts, these results raise questions about the nature of the diets, particularly excess fat intake, as well as on the use of antioxidants in patients with LSFC and, possibly, other COX defects. PMID- 25835551 TI - Genome sequencing of the perciform fish Larimichthys crocea provides insights into molecular and genetic mechanisms of stress adaptation. AB - The large yellow croaker Larimichthys crocea (L. crocea) is one of the most economically important marine fish in China and East Asian countries. It also exhibits peculiar behavioral and physiological characteristics, especially sensitive to various environmental stresses, such as hypoxia and air exposure. These traits may render L. crocea a good model for investigating the response mechanisms to environmental stress. To understand the molecular and genetic mechanisms underlying the adaptation and response of L. crocea to environmental stress, we sequenced and assembled the genome of L. crocea using a bacterial artificial chromosome and whole-genome shotgun hierarchical strategy. The final genome assembly was 679 Mb, with a contig N50 of 63.11 kb and a scaffold N50 of 1.03 Mb, containing 25,401 protein-coding genes. Gene families underlying adaptive behaviours, such as vision-related crystallins, olfactory receptors, and auditory sense-related genes, were significantly expanded in the genome of L. crocea relative to those of other vertebrates. Transcriptome analyses of the hypoxia-exposed L. crocea brain revealed new aspects of neuro-endocrine immune/metabolism regulatory networks that may help the fish to avoid cerebral inflammatory injury and maintain energy balance under hypoxia. Proteomics data demonstrate that skin mucus of the air-exposed L. crocea had a complex composition, with an unexpectedly high number of proteins (3,209), suggesting its multiple protective mechanisms involved in antioxidant functions, oxygen transport, immune defence, and osmotic and ionic regulation. Our results reveal the molecular and genetic basis of fish adaptation and response to hypoxia and air exposure. The data generated by this study will provide valuable resources for the genetic improvement of stress resistance and yield potential in L. crocea. PMID- 25835553 TI - Reply to Vikrant and Verma about "Monitor Lizard Envenoming". PMID- 25835552 TI - Diversification, evolution and sub-functionalization of 70kDa heat-shock proteins in two sister species of antarctic krill: differences in thermal habitats, responses and implications under climate change. AB - BACKGROUND: A comparative thermal tolerance study was undertaken on two sister species of Euphausiids (Antarctic krills) Euphausia superba and Euphausia crystallorophias. Both are essential components of the Southern Ocean ecosystem, but occupy distinct environmental geographical locations with slightly different temperature regimes. They therefore provide a useful model system for the investigation of adaptations to thermal tolerance. METHODOLOGY/PRINCIPAL FINDING: Initial CTmax studies showed that E. superba was slightly more thermotolerant than E. crystallorophias. Five Hsp70 mRNAs were characterized from the RNAseq data of both species and subsequent expression kinetics studies revealed notable differences in induction of each of the 5 orthologues between the two species, with E. crystallorophias reacting more rapidly than E. superba. Furthermore, analyses conducted to estimate the evolutionary rates and selection strengths acting on each gene tended to support the hypothesis that diversifying selection has contributed to the diversification of this gene family, and led to the selective relaxation on the inducible C form with its possible loss of function in the two krill species. CONCLUSIONS: The sensitivity of the epipelagic species E. crystallorophias to temperature variations and/or its adaptation to cold is enhanced when compared with its sister species, E. superba. These results indicate that ice krill could be the first of the two species to be impacted by the warming of coastal waters of the Austral ocean in the coming years due to climate change. PMID- 25835554 TI - Heme oxygenase-1 gene promoter polymorphism and the risk of pediatric nonalcoholic fatty liver disease. AB - BACKGROUND AND OBJECTIVES: Oxidative stress and the insulin-resistant state are thought to be key components in the pathogenesis of pediatric nonalcoholic fatty liver disease (NAFLD). Heme oxygenase (HO) is important in the defense against oxidative stress. This study aimed to assess the association of HO-1 gene promoter polymorphism and insulin resistance with NAFLD among obese children. METHODS: A total of 101 obese children aged 6-17 years were recruited. Anthropometric, serum biochemical variables and biomarkers for glucose and insulin metabolism were measured. We screened the allelic frequencies of (GT)n repeats in the HO-1 gene promoter among these obese children. NAFLD was determined through liver ultrasonography. Because the distribution of numbers of (GT)n repeats was bimodal, we divided the alleles into two classes: class S included shorter (27) repeats, and class L included longer (?27) repeats. We assessed the effects of the length of (GT)n repeats in HO-1 gene promoter on pediatric NAFLD. RESULTS: Of the 101 obese subjects, 27 (26.7%) had NAFLD. The alanine aminotransferase level was higher in patients carrying L alleles (L/L and L/S) than patients with S alleles (S/S) (46.2+/-49.3 IU|(-1) versus 30.2+/-20.1 IU|(-1); P=0.027). The significant risk factors for pediatric NAFLD were patients carrying L alleles (L/L and L/S) (odds ratio (OR)=18.84; 95% confidence interval (CI): 1.45-245.22; P=0.025), homeostasis model assessment of insulin resistance (OR=1.40; 95% CI: 1.07-1.83; P=0.014) and age (OR=1.24; 95% CI: 1.03-1.50; P=0.025). CONCLUSION: In this hospital-based study, the obese children with longer GT repeats in the HO-1 gene promoter and insulin resistance were susceptible to NAFLD. PMID- 25835556 TI - Cognitive rehabilitation of working memory in juvenile multiple sclerosis-effects on cognitive functioning, functional MRI and network related connectivity. AB - PURPOSE: To assess possible effects of working memory (WM) training on cognitive functionality, functional MRI and brain connectivity in patients with juvenile MS. METHODS: Cognitive status, fMRI and inter-network connectivity were assessed in 5 cases with juvenile MS aged between 12 and 18 years. Afterwards they received a computerized WM training for four weeks. Primary cognitive outcome measures were WM (visual and verbal) and alertness. Activation patterns related to WM were assessed during fMRI using an N-Back task with increasing difficulty. Inter-network connectivity analyses were focused on fronto-parietal (left and right), default-mode (dorsal and ventral) and the anterior salience network. Cognitive functioning, fMRI and inter-network connectivity were reassessed directly after the training and again nine months following training. RESULTS: Response to treatment was seen in two patients. These patients showed increased performance in WM and alertness after the training. These behavioural changes were accompanied by increased WM network activation and systematic changes in inter-network connectivity. The remaining participants were non-responders to treatment. Effects on cognitive performance were maintained up to nine months after training, whereas effects observed by fMRI disappeared. CONCLUSIONS: Responders revealed training effects on all applied outcome measures. Disease activity and general intelligence may be factors associated with response to treatment. PMID- 25835555 TI - A new technique for modeling neuronal connectivity using human pluripotent stem cells. AB - PURPOSE: We describe a technique for independently differentiating neocortical and mesencephalic dopaminergic (mDA) neurons from a single human pluripotent stem cell (hPSC) line, and subsequently allowing the two cell types to interact and form connections. METHODS: Dopaminergic and neocortical progenitors were differentiated in separate vessels, then separately seeded into the inner and outer compartments of specialized cell culture vessels designed for in vitro studies of wound healing. Cells were further differentiated using dopamine specific and neocortex-specific trophic factors, respectively. The barrier was then removed, and differentiation was continued for three weeks in the presence of BDNF. RESULTS: After three weeks of differentiation, neocortical and mDA cell bodies largely remained in the areas into which they had been seeded, and the gap between the mDA and neocortical neuron populations could still be discerned. Abundant tyrosine hydroxylase (TH)-positive projections had extended from the area of the inner chamber to the outer chamber neocortical area. CONCLUSIONS: We have developed a hPSC-based system for producing connections between neurons from two brain regions, neocortex and midbrain. Future experiments could employ modifications of this method to examine connections between any two brain regions or neuronal subtypes that can be produced from hPSCs in vitro. PMID- 25835557 TI - Impact of left versus right hemisphere subcortical stroke on the neural processing of action observation and imagery. AB - PURPOSE: Mental training appears to be an attractive tool in stroke rehabilitation. The objective of this study was to investigate whether any differences in the processing of action observation and imagery might exist between patients with left and right hemisphere subcortical strokes. METHODS: Eighteen patients with strictly subcortical stroke (nine right-hemispheric) underwent a functional magnetic resonance imaging (fMRI) study with an experimental paradigm in which motor acts had to be observed and/or imagined from a first person perspective. Changes in hemodynamic activity were measured using fMRI. RESULTS: The activity level was found to be higher in the non-lesioned compared to the lesioned hemisphere. Patients with lesions in the left hemisphere had a higher activation level in visual (fusiform and lingual gyri), superior temporal areas and dorsal premotor regions across all performed comparisons than those with right hemisphere lesions. Furthermore they had more vivid imagery experiences and lower scores on the Stroke Impact Scale. CONCLUSIONS: Patients with left hemisphere subcortical lesions recruit more cortical regions in the processing of action pictures and videos. This recruitment was further enhanced during imagery. This is most likely related to the fact that the lesion touched the dominant hemisphere. PMID- 25835558 TI - Polyanionic carbosilane dendrimer-conjugated antiviral drugs as efficient microbicides: Recent trends and developments in HIV treatment/therapy. AB - Polyanionic carbosilane dendrimers (PCDs) are potential candidates for the development of new microbicides for the prevention of HIV transmission. Tenofovir (TFV), which has dual antiviral activity (anti-HIV/HSV-2), and maraviroc (MRV) are the most studied antiretrovirals as microbicides. Here, we introduce developments in the design of innovative dendrimer-based microbicides. We also review and discuss the combination of various PCDs with TFV and/or MRV for their anti-HIV-1 activity and synergistic combinatory potential. Well-defined combinations blocking HIV-1 infection in early steps of HIV-1 replication provide greater efficacy than monotherapy, as reflected by the decrease in concentration and increase in HIV-1 inhibition. These combinations are characterized by lower doses, which minimize toxic side-effects and the emergence of multi-drug resistant mutants. The above facts suggest that the combination of first- and second-generation PCDs with TFV and/or MRV represents a promising candidate microbicide for preventing HIV-1 sexual transmission and simultaneously suppressing HSV-2. FROM THE CLINICAL EDITOR: HIV infection remains a significant and unresolved problem for humankind, despite the development of combination antiretroviral therapy. It has been found that polyanionic carbosilane dendrimers have efficacy in preventing HIV transmission. In this comprehensive review article, the authors discuss the current status and latest development of the use of dendrimers in combination with other antiretroviral drugs as microbicides, which should stimulate others into further research in the fight against HIV. PMID- 25835559 TI - How to manage the reproductive issues of PCOS: a 2015 integrated endocrinological and gynecological consensus statement of the Italian Society of Endocrinology. PMID- 25835560 TI - Intersubgeneric hybridization between Glycine max and G. tomentella: production of F1, amphidiploid, BC1, BC2, BC3, and fertile soybean plants. AB - KEY MESSAGE: This paper describes methods for unlocking genetic treasure from wild perennial Glycine species of Australia for soybean improvement. The genetic resources of the ca. 26 species of the genus Glycine subgenus Glycine have not been exploited to broaden the genetic base of soybean (Glycine max; 2n = 40). The objectives of this study were to develop methods for producing F1, amphidiploid, BC1, BC2, BC3, and fertile soybean plants from crosses of soybean and the genus Glycine subgenus Glycine species, in order to utilize the subgenus Glycine germplasm in soybean breeding. Soybean cultivars were hybridized with six accessions of 78-chromosome G. tomentella as well as one accession each of 40 chromosome G. tomentella, G. argyrea and G. latifolia. They were chosen because they exhibit resistance to soybean rust. We were successful in producing fertile soybean from soybean cv. 'Dwight' and 78-chromosome G. tomentella accession PI 441001, while other hybrids were discontinued either at F1 or amphidiploid stage. The F1 seeds aborted prior to reaching maturity, so developing seeds from 19 to 21 day old pods were cultured aseptically in various media formulations. Seed maturation and multiple embryo generation media were developed. F1 plants with shoots and roots (2n = 59) were transplanted to pots in greenhouse. Amphidiploid (2n = 118) plants were backcrossed to 'Dwight'. BC1 (2n = 79) plants were propagated through in vitro and 43 mature BC2F1 seeds were harvested. Fifteen surviving BC2F1 plants were morphologically distinct, sterile, and had chromosome numbers ranging 2n = 56-59. Chromosome numbers of the BC3F1 plants ranged 2n = 40 49. Derived fertile soybeans were first planted in the field in 2008 and are being evaluated for yield, resistance to pathogens and pests and tolerance to salt through material transfer agreement. PMID- 25835562 TI - Letter by Spence regarding article, "differential effect of B-vitamin therapy by antiplatelet use on risk of recurrent vascular events after stroke". PMID- 25835563 TI - Insular cortex lesions, cardiac troponin, and detection of previously unknown atrial fibrillation in acute ischemic stroke: insights from the troponin elevation in acute ischemic stroke study. AB - BACKGROUND AND PURPOSE: Detection rates of paroxysmal atrial fibrillation (AF) after acute ischemic stroke increase with duration of ECG monitoring. To date, it is unknown which patient group may benefit most from intensive monitoring strategies. Therefore, we aimed to identify predictors of previously unknown AF during in-hospital ECG monitoring. METHODS: All consecutive patients with imaging confirmed ischemic stroke admitted to our tertiary care hospital from February 2011 to December 2013 were registered prospectively. Patients received continuous bedside ECG monitoring for at least 24 hours. Detection of previously unknown AF during in-hospital ECG monitoring was obtained from medical records. Patients with AF on admission ECG or known history of AF were excluded from analysis. RESULTS: Among 1228 patients (median age, 73 years; median National Institutes of Health Stroke Scale, 4; 43.4% women), previously unknown AF was detected in 114 (9.3%) during a median time of continuous ECG monitoring of 3 days (interquartile range, 2-4 days). Duration of monitoring (P<0.01), older age (P<0.01), history of hypertension (P=0.03), insular cortex involvement (P<0.01), and higher high sensitivity cardiac troponin T (P=0.04) on admission were independently associated with subsequent detection of AF in a multiple regression analysis. Addition of high-sensitivity cardiac troponin T, insular cortex stroke, or both to the CHADS2 score (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke [2P]) significantly improved c-statistics from 0.63 to 0.68 (P=0.01), 0.70 (P<0.01), and 0.72 (P<0.001), respectively. CONCLUSIONS: Insular cortex involvement, higher admission high-sensitivity cardiac troponin T, older age, hypertension, and longer monitoring are associated with new detection of AF during in-hospital ECG monitoring. Patients with higher high-sensitivity cardiac troponin T or insular cortex involvement may be candidates for prolonged ECG monitoring. PMID- 25835564 TI - The use of behavior change theory in Internet-based asthma self-management interventions: a systematic review. AB - BACKGROUND: The high prevalence rate of asthma represents a major societal burden. Advancements in information technology continue to affect the delivery of patient care in all areas of medicine. Internet-based solutions, social media, and mobile technology could address some of the problems associated with increasing asthma prevalence. OBJECTIVE: This review evaluates Internet-based asthma interventions that were published between 2004 and October 2014 with respect to the use of behavioral change theoretical frameworks, applied clinical guidelines, and assessment tools. METHODS: The search term (Asthma AND [Online or Internet or Mobile or Application or eHealth or App]) was applied to six bibliographic databases (Ovid MEDLINE, PubMed, BioMed Central, ProQuest Computing, Web of Knowledge, and ACM Digital Library) including only English language articles published between 2004 and October 2014. In total, 3932 articles matched the priori search terms and were reviewed by the primary reviewer based on their titles, index terms, and abstracts. The matching articles were then screened by the primary reviewer for inclusion or exclusion based on their abstract, study type, and intervention objectives with respect to the full set of priori inclusion and exclusion criteria; 331 duplicates were identified and removed. A total of 85 articles were included for in-depth review and the remaining 3516 articles were excluded. The primary and secondary reviewer independently reviewed the complete content of the 85 included articles to identify the applied behavioral change theories, clinical guidelines, and assessment tools. Findings and any disagreement between reviewers were resolved by in-depth discussion and through a consolidation process for each of the included articles. RESULTS: The reviewers identified 17 out of 85 interventions (20%) where at least one model, framework, and/or construct of a behavioral change theory were applied. The review identified six clinical guidelines that were applied across 30 of the 85 interventions (35%) as well as a total of 21 assessment tools that were applied across 32 of the 85 interventions (38%). CONCLUSIONS: The findings of this literature review indicate that the majority of published Internet-based interventions do not use any documented behavioral change theory, clinical guidelines, and/or assessment tools to inform their design. Further, it was found that the application of clinical guidelines and assessment tools were more salient across the reviewed interventions. A consequence, as such, is that many Internet-based asthma interventions are designed in an ad hoc manner, without the use of any notable evidence-based theoretical frameworks, clinical guidelines, and/or assessment tools. PMID- 25835565 TI - Nuclear quantum tunnelling in enzymatic reactions--an enzymologist's perspective. AB - Enzyme-catalysed H-transfer reactions are ubiquitous, yet fundamental details of these reactions remain unresolved. In this perspective, we discuss the roles of nuclear quantum tunnelling and (compressive) dynamics during these reactions. Evidence for the coupling of specific substrate and/or protein vibrations to the chemical coordinate is considered and a case is made for the combination of multiple experimental and computational/theoretical approaches when studying these reactions. PMID- 25835566 TI - Role of laparoscopic partial splenectomy for tumorous lesions of the spleen. AB - BACKGROUND: Laparoscopic partial splenectomy (LPS) is a surgical option for splenic masses, with the goal of reducing postoperative complications while preserving splenic function. METHODS: Thirty-seven patients who underwent laparoscopic splenectomy for tumorous lesions of the spleen at two affiliated hospitals were enrolled. Among them, 22 patients underwent laparoscopic total splenectomy (LTS) and 15 patients underwent LPS. RESULTS: The tumorous lesions of the spleen in both groups, in order of decreasing frequency, consisted of epithelial cysts, hemangiomas, lymphangiomas, abscesses, metastatic tumors, and hamartomas. All procedures were completed by laparoscopy, and the pathologic lesions in the spleen were completely removed in both groups. There were no significant differences between the groups in terms of the operative time (LTS 151.5 +/- 98.5 min, LPS 168.6 +/- 46.8 min, p = 0.483), intraoperative blood loss (LTS 337.3 +/- 188.4 ml, LPS 422.6 +/- 187.4 ml, p = 0.185), and transfusion rate (LTS 3/22 [13.6 %], LPS 3/15 [20.0 %], p = 0.606). However, there were significant differences in postoperative complications such as pleural effusion (LTS 9/22 [40.9 %], LPS 0/15 [0 %], p = 0.005), splenic vein thrombosis (LTS 10/22 [45.5 %], LPS 0/15 [0 %], p = 0.002), and postoperative hospital stay (LTS 5.4 +/- 1.8 days, LPS 4.2 +/- 0.8 days, p = 0.027). CONCLUSIONS: LPS is a feasible, safe surgical procedure in patients with tumorous lesions of the spleen, and it represents an effective approach to reduce postoperative hospital stay and complications. PMID- 25835568 TI - First-principles molecular dynamics study of water dissociation on the gamma-U(1 0 0) surface. AB - Based on first-principles molecular dynamics simulations at finite temperatures, we systematically study the adsorption and dissociation of water molecules on the gamma-U(1 0 0) surface. We predict that water molecules spontaneously dissociate upon approaching the native gamma-U(1 0 0) surface. The dissociation results from electronic interactions between surface uranium 6d states and 1b2, 3a1, and 1b1 molecular orbitals of water. With segregated Nb atoms existing on the surface, adsorbing water molecules also dissociate spontaneously because Nb 3d electronic states can also interact with the molecular orbitals similarly. After dissociation, the isolated hydrogen atoms are found to diffuse fast on both the gamma-U surface and that with a surface substitutional Nb atom, which is very similar to the 'Hot-Atom' dissociation of oxygen molecules on the Al(1 1 1) surface. From a series of consecutive molecular dynamics simulations, we further reveal that on both the gamma-U surface and that with a surface substitutional Nb atom, one surface U atom will be pulled out to form the U-O-U structure after dissociative adsorption of 0.44 ML water molecules. This result indicates that oxide nucleus can form at low coverage of water adsorption on the two surfaces. PMID- 25835567 TI - Chemistry and Biology of Resveratrol-Derived Natural Products. PMID- 25835569 TI - Mechanism of protection of catalysts supported in redox hydrogel films. AB - The use of synthetic inorganic complexes as supported catalysts is a key route in energy production and in industrial synthesis. However, their intrinsic oxygen sensitivity is sometimes an issue. Some of us have recently demonstrated that hydrogenases, the fragile but very efficient biological catalysts of H2 oxidation, can be protected from O2 damage upon integration into a film of a specifically designed redox polymer. Catalytic oxidation of H2 produces electrons which reduce oxygen near the film/solution interface, thus providing a self activated protection from oxygen [Plumere et al., Nat Chem. 2014, 6, 822-827]. Here, we rationalize this protection mechanism by examining the time-dependent distribution of species in the hydrogenase/polymer film, using measured or estimated values of all relevant parameters and the numerical and analytical solutions of a realistic reaction-diffusion scheme. Our investigation sets the stage for optimizing the design of hydrogenase-polymer films, and for expanding this strategy to other fragile catalysts. PMID- 25835570 TI - Semen-Like Floral Scents and Pollination Biology of a Sapromyophilous Plant Stemona japonica (Stemonaceae). AB - By emitting scent resembling that of organic material suitable for oviposition and/or consumption by flies, sapromyophilous flowers use these flies as pollinators. To date, intensive scent analyses of such flowers have been restricted to Apocynaceae, Annonaceae, and Araceae. Recent studies have suggested that the wide range of volatile organic compounds (VOCs) from sapromyophilous flowers play an important role in attracting saprophagous flies by mimicking different types of decomposing substrates (herbivore and carnivore feces, carrion, and the fruiting bodies of fungi, etc.). In this study, we report the flower visitors and the floral VOCs of Stemona japonica (Blume) Miquel, a species native to China. The flowers do not produce rewards, and pollinators were not observed consuming pollen, thus suggesting a deceptive pollination system. Headspace samples of the floral scent were collected via solid-phase micro extraction and analysed by gas chromatography coupled with mass spectrometry. Main floral scent compounds were 1-pyrroline (59.2%), 2-methyl-1-butanol (27.2%), and 3-methyl-1-butanol (8.8%), and resulted in a semen-like odor of blooming flowers. The floral constituents of S. japonica were significantly different from those found in previous sapromyophilous plants. An olfaction test indicated that 1-pyrroline is responsible for the semen-like odor in S. japonica flowers. Main flower visitors were shoot flies of the genus Atherigona (Muscidae). Bioassays using a mixture of all identified floral volatiles revealed that the synthetic volatiles can attract Atherigona flies in natural habitats. Our results suggest that the foul-smelling flowers of S. japonica may represent a new type of sapromyophily through scent mimicry. PMID- 25835571 TI - Sperm population structure in high and low field fertility rams. AB - The aim of the present study was to investigate whether differences in field fertility of rams are reflected in differences in sperm morphometric and kinematic population structures. The association between sperm morphometric and kinematic subpopulations was also investigated. Ejaculates from 8 adult rams, 4 with high and 4 with low field fertility, were collected weekly using an artificial vagina over 6 consecutive weeks. Analyses of sperm motility using computer-assisted sperm analysis (CASA) and sperm nuclear morphometry using computer-assisted sperm morphometry-fluorescence were performed. Clustering procedures using the kinematic and morphometric data from high and low field fertility rams resulted in the classification of spermatozoa in three kinematic and three morphometric sperm subpopulations. The distribution of subpopulations between rams of high and low field fertility was significantly different (P<0.05), with higher percentages of spermatozoa exhibiting fast and linear movements and those with large and long nuclei in the high fertility group. However, these subpopulations were not correlated. Logistic regression analyses were also performed to evaluate the relative utility of sperm subpopulations to classify rams in high and low field fertility. Total progressive sperm motility and the proportion of large and long spermatozoa were identified as the most consistent indicators of fertility. It was concluded that high and low fertility rams had clear differences in morphometric and kinematic sperm subpopulations, and that the most consistent indicators of fertility were the total progressive motility and the proportion of spermatozoa with large and long head present in the ejaculate. PMID- 25835572 TI - Non-mosaic monosomy 59,X in cattle: a case report. AB - A 3-year-old Longhorn heifer was referred to the Veterinary Medical Teaching Hospital of Texas A&M University for inability to get pregnant. Physical examination revealed a small-sized female for age and breed with a normal vulva, vaginal length, and external cervical os. Further assessment by per rectum palpation and trans-rectal ultrasonography revealed a small uterine cervix and cord-like uterine horns with no identifiable ovaries. Additional evaluation including laparoscopy, hormonal evaluation, and genetic analysis allowed ruling out conditions commonly associated with a phenotypic female with infantile or underdeveloped reproductive organs such as freemartin, XY gonadal dysgenesis, testicular feminization, and bilateral ovarian agenesis. Laparoscopy confirmed the presence of a small cervix with small uterine horns and absence of ovaries. Testosterone, progesterone, and 17-beta estradiol concentrations were 200.0pg/mL, 1.48ng/mL, and undetectable, respectively. Genetic evaluation determined that the karyotype was 59,X non-mosaic. Evaluation of phenotypically female cattle with infertility and infantile genital organs and absence of ovaries should include cytogenetic analysis to test for possible X monosomy. The 59,X condition should be considered in the differential diagnoses together with freemartin, dysgenesis XY, testicular feminization, and bilateral ovarian agenesis. PMID- 25835574 TI - Influenza vaccination in children with neurologic or neurodevelopmental disorders. AB - BACKGROUND: Children with neurologic or neurodevelopmental disorders (NNDDs) are at increased risk of complications from influenza. Although the Advisory Committee on Immunization Practices (ACIP) has recognized NNDDs as high-risk conditions for influenza complications since 2005, little is known about influenza vaccination practices in this population. METHODS: CDC collaborated with Family Voices, a national advocacy group for children with special healthcare needs, to recruit parents of children with chronic medical conditions. Parents were surveyed about their knowledge, attitudes, and practices surrounding influenza vaccination. The primary outcome of interest was parental report of vaccination, or intent to vaccinate, at the time of survey participation. CDC also collaborated with the American Academy of Pediatrics to recruit primary care and specialty physicians who provide care for high-risk children, specifically those with neurologic conditions. The primary outcome was physician recognition of ACIP high-risk influenza conditions. RESULTS: 2138 surveys were completed by parents of children with high-risk conditions, including 1143 with at least one NNDD. Overall, 50% of children with an NNDD were vaccinated, or their parents planned to have them vaccinated against influenza. Among all 2138 children, in multivariable analysis, the presence of a respiratory condition and prior seasonal influenza vaccination was significantly associated with receipt or planned current season influenza vaccination, but the presence of an NNDD was not. 412 pediatricians completed the provider survey. Cerebral palsy was recognized as a high-risk influenza condition by 74% of physician respondents, but epilepsy (51%) and intellectual disability (46%) were less commonly identified. CONCLUSIONS: Our estimates of influenza vaccination in children with NNDDs are comparable to published reports of vaccination in healthy children, which continue to be suboptimal. Education of parents of children with NNDDs and healthcare providers about influenza and the benefit of annual influenza vaccination is needed. PMID- 25835575 TI - Vaccines against influenza A viruses in poultry and swine: Status and future developments. AB - Influenza A viruses are important pathogens with a very broad host spectrum including domestic poultry and swine. For preventing clinical disease and controlling the spread, vaccination is one of the most efficient tools. Classical influenza vaccines for domestic poultry and swine are conventional inactivated preparations. However, a very broad range of novel vaccine types ranging from (i) nucleic acid-based vaccines, (ii) replicon particles, (iii) subunits and virus like particles, (iv) vectored vaccines, or (v) live-attenuated vaccines has been described, and some of them are now also used in the field. The different novel approaches for vaccines against avian and swine influenza virus infections are reviewed, and additional features like universal vaccines, novel application approaches and the "differentiating infected from vaccinated animals" (DIVA) strategy are summarized. PMID- 25835573 TI - The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. AB - INTRODUCTION: The molecular mechanics energies combined with the Poisson Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches to estimate the free energy of the binding of small ligands to biological macromolecules. They are typically based on molecular dynamics simulations of the receptor-ligand complex and are therefore intermediate in both accuracy and computational effort between empirical scoring and strict alchemical perturbation methods. They have been applied to a large number of systems with varying success. AREAS COVERED: The authors review the use of MM/PBSA and MM/GBSA methods to calculate ligand-binding affinities, with an emphasis on calibration, testing and validation, as well as attempts to improve the methods, rather than on specific applications. EXPERT OPINION: MM/PBSA and MM/GBSA are attractive approaches owing to their modular nature and that they do not require calculations on a training set. They have been used successfully to reproduce and rationalize experimental findings and to improve the results of virtual screening and docking. However, they contain several crude and questionable approximations, for example, the lack of conformational entropy and information about the number and free energy of water molecules in the binding site. Moreover, there are many variants of the method and their performance varies strongly with the tested system. Likewise, most attempts to ameliorate the methods with more accurate approaches, for example, quantum-mechanical calculations, polarizable force fields or improved solvation have deteriorated the results. PMID- 25835576 TI - Phased introduction of a universal childhood influenza vaccination programme in England: population-level factors predicting variation in national uptake during the first year, 2013/14. AB - INTRODUCTION: Through a phased rollout, the UK is implementing annual influenza vaccination for all healthy children aged 2-16 years old. In the first year of the programme in England in 2013/14, all 2-3 year olds were offered influenza vaccine through primary care and a primary school age programme was piloted, mainly through schools, in geographically distinct areas. Equitable delivery is a key aim of the programme; it is unclear if concerns by some religious groups over influenza vaccine content have impacted on uptake. METHODS: At the end of the 2013/14 season, variations in uptake for 2-3 year olds and 4-11 year olds were assessed and stratified by population-level predictors: deprivation, ethnicity, religious beliefs and rurality. GP practice or school level uptake was linearly regressed against these variables to determine potential predictors and changes in uptake, adjusting for significant factors. RESULTS: Uptake varied considerably by geographic locality for both 2-3 year olds and 4-11 year olds. Lower uptake was seen in increasingly deprived areas, with an adjusted uptake in the most deprived quintile 12% and 8% lower than the least deprived areas by age-group respectively. By ethnicity, the highest non-white population quartile had an adjusted uptake 9% and 14% lower than the lowest non-white quartile by age-group respectively. Uptake also varied according to religious beliefs, with adjusted uptake in 4-11 year olds in the highest Muslim population tertile 8% lower than the lowest Muslim population tertile. CONCLUSION: In the first season of the childhood influenza vaccination programme, uptake was not uniform across the country, with deprivation and ethnicity both predictors of low uptake in pre school and primary school age children, and religious beliefs also an important factor, particularly the latter group. With the continued rollout of the programme, these population-level factors should be addressed to achieve sustained successful uptake, along with assessment of contribution of individual and household-level factors. PMID- 25835578 TI - Predicting stability constants for uranyl complexes using density functional theory. AB - The ability to predict the equilibrium constants for the formation of 1:1 uranyl/ligand complexes (log K1 values) provides the essential foundation for the rational design of ligands with enhanced uranyl affinity and selectivity. We use density functional theory (B3LYP) and the integral equation formalism polarizable continuum model (IEF-PCM) to compute aqueous stability constants for UO2(2+) complexes with 18 donor ligands. Theoretical calculations permit reasonably good estimates of relative binding strengths, while the absolute log K1 values are significantly overestimated. Accurate predictions of the absolute log K1 values (root-mean-square deviation from experiment <1.0 for log K1 values ranging from 0 to 16.8) can be obtained by fitting the experimental data for two groups of mono- and divalent negative oxygen donor ligands. The utility of correlations is demonstrated for amidoxime and imide dioxime ligands, providing a useful means of screening for new ligands with strong chelating capability to uranyl. PMID- 25835577 TI - A retrospective study of administration of vaccination for hepatitis B among newborn infants prior to hospital discharge at a midwestern tertiary care center. AB - OBJECTIVES: Infants are at high risk of developing chronic, life-threatening disease as a result of hepatitis B virus infection. Universal vaccination of infants against hepatitis B virus, before discharge from the hospital after delivery is recommended as a measure to eradicate infection and associated mortality and morbidity. The purpose of this study was to determine rates of perinatal hepatitis B vaccine (Hep B) administration at a tertiary care center in Iowa and to assess the impact of maternal factors on Hep B uptake. METHODS: Data concerning mother-infant pairs that received care at one institution from 1/2009 to 4/1/2013 were extracted from the system's electronic medical record. Characteristics of study participants were compared using chi-square tests. Multivariate logistic regression was used to assess the association between each factor and vaccination status, controlling for other characteristics. RESULTS: Of 5663 mother-infant pairs, 5175 (91.4%) infants received Hep B within 7 days after delivery. The majority of those not vaccinated had a medical indication to delay vaccination. Single women were significantly more likely to have an infant not vaccinated, after adjustment for all other factors. Women of minority groups were significantly less likely to have an infant who lacked Hep B at hospital discharge than Caucasian women. CONCLUSIONS: Significant improvements have occurred in Hep B rates in the state and region. Infants of single mothers may be at the greatest risk for lacking vaccination at hospital discharge. PMID- 25835579 TI - Argumentation and persuasion in patient-centred communication. PMID- 25835580 TI - The difficulty of staying awake during alpha/theta neurofeedback training. AB - Alpha/theta neurofeedback training is supposed to enhance cognitive performance as well as alleviate psychiatric disorders. Sleep during this training is regarded a confounding factor, although it is usually not controlled. Here, the amount of sleep, the impact of sleep on frequency results and the validity of subjective judgments of having fallen asleep were investigated. 40 healthy young subjects participated in 31 training units of real or mock feedback. It turned out that stage 2 sleep occurred in 10-14 % of training time, in 95 % of the subjects and in 1/3 of all training units. Sleep significantly influenced the theta/alpha ratio and theta but not alpha amplitudes. Only about 2/3 of the subjective judgements were correct and no more than 13 % of the participants could reliably identify sleep. These data demonstrate that sleep can easily occur during alpha/theta neurofeedback training and should be controlled by objective means. PMID- 25835581 TI - Efficient synthesis of (R)-harmonine--the toxic principle of the multicolored Asian lady beetle (Harmonia axyridis). AB - A flexible synthetic route to (R)-harmonine ((R)-1), the toxic principle of the Asian lady beetle Harmonia axyridis (H. axyridis), via reductive olefination of the macrocyclic lactone (S)-5, is reported. High enantiomeric purity is achieved by enantioselective saponification of the lactone rac-5 with horse liver esterase. Minor modifications in the synthetic route give access to racemic and chiral harmonine ()1, analogs and putative biosynthetic precursors. In addition, the antimicrobial activity of harmonine against Leishmania major (L. major) is demonstrated and provides the rationale for harmonine-based drug development against parasitic diseases. PMID- 25835582 TI - The shoulder. PMID- 25835583 TI - MRI of the hand and fingers. AB - Injuries of the hand and fingers occur commonly in professional athletes as well as weekend warriors. Magnetic resonance imaging plays a vital role in the evaluation of these injuries for accurate diagnosis, preoperative planning, potential complication, and follow-up during rehabilitation. A detailed analysis of these smaller structures necessitates optimal imaging quality coupled with comprehensive knowledge of the imaging anatomy. In this article, we discuss technical aspects and normal anatomy of hand and fingers imaging on magnetic resonance imaging. This section is followed by discussion of soft tissue and osseous injuries including mechanism of injury, clinical presentation, and imaging findings. PMID- 25835584 TI - Overuse injuries in children. AB - There has been a substantial increase in the number of children participating in organized competitive sports, which has led to a surge in the number of both acute and overuse injuries. To prevent further complications such as limb deformity and disability, radiologists must be familiar with typical overuse injury patterns in children. Traction apophysitis, chronic physeal injury, and stress fractures are the principal overuse injuries. This article reviews overuse injuries in children with an emphasis on the role of magnetic resonance imaging in diagnosis, prognosis, and treatment. PMID- 25835585 TI - Elbow magnetic resonance imaging: imaging anatomy and evaluation. AB - The elbow is a complex joint. Magnetic resonance imaging (MRI) is often the imaging modality of choice in the workup of elbow pain, especially in sports injuries and younger patients who often have either a history of a chronic repetitive strain such as the throwing athlete or a distinct traumatic injury. Traumatic injuries and alternative musculoskeletal pathologies can affect the ligaments, musculotendinous, cartilaginous, and osseous structures of the elbow as well as the 3 main nerves to the upper limb, and these structures are best assessed with MRI.Knowledge of the complex anatomy of the elbow joint as well as patterns of injury and disease is important for the radiologist to make an accurate diagnosis in the setting of elbow pain. This chapter will outline elbow anatomy, basic imaging parameters, compartmental pathology, and finally applications of some novel MRI techniques. PMID- 25835586 TI - WITHDRAWN: Iodinated contrast media and its influence in emphysema CT measurements. PMID- 25835587 TI - WITHDRAWN: Meetings and courses. PMID- 25835588 TI - Photopolymerized Network Polysiloxane Films with Dangling Hydrophilic/Hydrophobic Chains for the Biofouling Release of Invasive Marine Serpulid Ficopomatus enigmaticus. AB - Novel photopolymerized network films based on a polysiloxane matrix containing varied amounts of polyoxyethylene (P3) or perfluorohexylethyl (F) dangling side chains were investigated. For films containing less than 10 wt % P3 and F, the wettability and elastic modulus were similar to those of the photopolymerized network matrix. However, angle-resolved X-ray photoelectron spectroscopy measurements proved that the surface of films with F dangling chains was highly enriched in fluorine depending on both the amount of P3 and F and their relative ratio in the films. The biological performance of the films was evaluated against a new widespread and invasive marine biofoulant, the serpulid Ficopomatus enigmaticus. The diatom Navicula salinicola was also assayed as a conventional model organism for comparison. Films richer in P3 better resisted the settlement and promoted the release of calcified tubeworms of F. enigmaticus. PMID- 25835589 TI - Occurrence of selected pharmaceuticals at drinking water purification plants in Japan and implications for human health. AB - The present study was performed to determine the occurrence of 64 pharmaceuticals and metabolites in source water and finished water at 6 drinking water purification plants and 2 industrial water purification plants across Japan. The analytical methods employed were sample concentration using solid-phase extraction cartridges and instrumental analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS), liquid chromatography with mass spectrometry (LC/MS), or trimethylsilyl derivatization followed by gas chromatography with mass spectrometry (GC/MS). Thirty-seven of the 64 target substances were detected in the source water samples. The maximum concentrations in the source water were mostly below 50 ng/L except for 13 substances. In particular, residual concentrations of iopamidol (contrast agent) exceeded 1000 ng/L at most facilities. Most of the residual pharmaceuticals and metabolites in the source water samples were removed in the course of conventional and/or advanced drinking water treatments, except for 7 pharmaceuticals and 1 metabolite, i.e., amantadine, carbamazepine, diclofenac, epinastine, fenofibrate, ibuprofen, iopamidol, and oseltamivir acid. The removal ratios of the advanced water treatment processes including ozonation and granular activated carbon filtration were typically much higher than those of the conventional treatment processes. The margins of exposure estimated by the ratio of daily minimum therapeutic dose to daily intake via drinking water were substantial, and therefore the pharmacological and physiological impacts of ingesting those residual substances via drinking water would be negligible. PMID- 25835590 TI - Analysis of the persistence of enteric markers in sewage polluted water on a solid matrix and in liquid suspension. AB - Addressing the persistence of bacterial indicators using qPCR and their respective DNA targets under various conditions is a critical part of risk assessment for water quality monitoring. The goal of this study was to examine the persistence of fecal indicator bacteria (FIB) via Escherichia coli uidA, enterococci 23S rDNA and Bacteroides thetataiotaomicron 1,6 alpha mannanase from cells attached to a solid matrix and in suspension. Raw sewage (10% vol/vol) was seeded into autoclaved river water with half of the sample volume in suspension and the other half was filtered onto membranes and stored at 4 degrees , 27 degrees and 37 degrees C for up to 28 days. At various time points, DNA from cells was extracted, markers were quantified, and were fit to linear and non linear models (first order exponential, biphasic (double) exponential, two staged, log-logistic, and Gompertz 3-parameter). First order and biphasic exponential models fit 73% of the experimental data. Persistence increased significantly when the cells were stored in an attached state (p < 0.001). Increasing temperature had an inverse effect on persistence for the cells in suspension. Bacterial cells could be stored on a solid matrix at 4 degrees , 27 degrees and 37 degrees C for up to 27, 18, and 3 days, respectively, with <90% decay. The least stable indicator at 4 degrees , 27 degrees and 37 degrees C was B. thetataiotaomicron in suspension with T90 = 9.6, 1.8, and 1.1 days, respectively. The most persistent indicator was enterococci, with T90 > 28 days in an attached state at all temperatures. PMID- 25835591 TI - High-frequency oscillatory ventilation combined with partial liquid ventilation in experimental lung injury: effects on lung cell apoptosis. AB - OBJECTIVE: To investigate the effects of high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV) on apoptosis of lung tissue induced by steam inhalation injury in rabbit. DESIGN: A prospective, randomized, controlled, multiple-group study. SETTING: An animal research laboratory centre in a university burns centre. SUBJECTS: New Zealand rabbits (n = 32; 2.25 +/- 0.25 kg) of either sex. INTERVENTIONS: The animals were ventilated by HFOV with a mean airway pressure of 10 cm H2O, a frequency of 10 Hz, an amplitude of 20 cm H2O, an inspiratory:expiratory ratio of 1:1, and an FiO2 of 1.0. After the induction of acute lung injury (ALI) by steam inhalation, the animals were randomly divided into four groups: CMV, HFOV, CMV + PLV, HFOV + PLV group. Then they were ventilated for 4 h by CMV, HFOV, CMV + PLV and HFOV + PLV, respectively. After the experimental period, cell apoptosis and apoptosis indexes in the lung tissue were assessed with TUNEL FragELTM (Fragment End Labeling). RESULTS: Lung tissue apoptosis indexes in HFOV group and HFOV + PLV group were lower than that of in CMV group and CMV + PLV group; between-group comparison had significant difference (P < 0.01). HFOV + PLV group showed lowest apoptosis indexes. CONCLUSION: HFOV combined with PLV can suppress lung tissue apoptosis induced by steam inhalation. PMID- 25835592 TI - Exocrine pancreatic insufficiency is not a cause of abdominal complaints in patients with Fabry disease. AB - BACKGROUND: Fabry disease (FD), also called Anderson-Fabry disease, is the second most prevalent lysosomal storage disorder after Gaucher disease. Gastrointestinal (GI) symptoms are very common among male and female individuals, although the age of onset is later among female patients. To our best knowledge, exocrine pancreatic insufficiency (EPI) has not yet been studied in patients with FD as a possible cause of abdominal complaints. The aim of our study was to determine whether exocrine pancreatic function is impaired in patients with FD. PATIENTS AND METHODS: We analysed medical records of patients with FD treated in Fabry Center in Slovenj Gradec General Hospital (Slovenian referral centre for FD) by the evaluation of the following features: gender, age, first symptoms before confirmation of FD diagnosis, time interval between first symptoms and diagnosis, therapy and current abdominal complaints. Diagnosis of FD was established by genetic analysis and confirmation of mutation in the alpha-galactosidase A gene. Faecal elastase-1 (FE-1) measurements were performed using enzyme-linked immunosorbent assay and the commercial kit ScheBo Biotech, Giessen, Germany. RESULTS: There were 28 adult patients (Slovene, Caucasians) with known FD included in the study: 12 male and 16 female; mean age, 45.6 +/- 14.3 (range, 19 75) years. Seventeen patients (63%) were on enzyme replacement therapy (ERT). In seven (25.9%) patients, abdominal complaints (diarrhoea, bloating and feeling of satiety) were present before introduction of ERT. In three out of these seven patients, abdominal complaints resolved after ERT, and in four patients, they were still occasionally present. FE-1 was normal in all patients (547.9 +/- 104.5 ug/g). CONCLUSIONS: Our results show that exocrine pancreatic function is normal in all patients with FD and is most likely not a cause of abdominal complaints in this group of patients. Nevertheless, EPI still could not be completely excluded as an aetiology factor for GI problems in patients with FD because all our patients with GI problems were treated with ERT. Therefore, a potential effect of ERT on EPI cannot be excluded. Further studies are necessary to determine the aetiology, especially in the group of naive male patients. PMID- 25835593 TI - Real-time shear wave elastography may predict autoimmune thyroid disease. AB - OBJECTIVE: To evaluate and compare the values of the elasticity index as measured by shear wave elastography in healthy subjects and in patients with autoimmune thyroid disease, in order to establish if this investigation can predict the occurrence of autoimmune thyroid disease. METHODS: A total of 104 cases were included in the study group: 91 women (87.5%), out of which 52 (50%) with autoimmune thyroid disease diagnosed by specific tests and 52 (50%) healthy volunteers, matched for age and gender. For all the subjects, three measurements were performed on each thyroid lobe and a mean value was calculated. The data were expressed in kPa. The investigation was performed with an Aixplorer system (SuperSonic Imagine, France), using a linear high-resolution 15-4 MHz transducer. RESULTS: The mean value for the elasticity index was similar in the right and the left thyroid lobes, both in normal subjects and in patients with autoimmune thyroid disease: 19.6 +/- 6.6 vs. 19.5 +/- 6.8 kPa, p = 0.92, and 26.6 +/- 10.0 vs. 25.8 +/- 11.7 kPa, p = 0.71, respectively. This parameter was significantly higher in patients with autoimmune thyroid disease than in controls (p < 0.001). For a cut-off value of 22.3 kPa, which resulted in the highest sum of sensitivity and specificity, the elasticity index assessed by shear wave elastography had a sensitivity of 59.6% and a specificity of 76.9% (AUROC = 0.71; p < 0.001) for predicting the presence of autoimmune thyroid disease. CONCLUSION: Quantitative elasticity index measured by shear wave elastography was significantly higher in autoimmune thyroid disease than in normal thyroid parenchyma and may predict the presence of autoimmune thyroid disease. PMID- 25835594 TI - [Guidelines for outpatient pulmonary rehabilitation in Austria]. AB - Pulmonary rehabilitation has become a standard of care for patients with chronic lung disease. It has been clearly demonstrated that pulmonary rehabilitation improves exercise capacity and quality of life in patients with chronic lung disease and reduces the number of hospital days and other measures of health-care utilization in patients with chronic obstructive pulmonary disease (COPD). This is an update of the guidelines in outpatient pulmonary rehabilitation in Austria, closely related to the official American Thoracic Society and European Respiratory Society Statement published in 2013.The guidelines represent standards of quality for requirements of structural and personal qualifications. PMID- 25835595 TI - Featuring the nucleosome surface as a therapeutic target. AB - Chromatin is the major regulator of gene expression and genome maintenance. Proteins that bind the nucleosome, the repetitive unit of chromatin, and the histone H4 tail are critical to establishing chromatin architecture and phenotypic outcomes. Intriguingly, nucleosome-binding proteins (NBPs) and the H4 tail peptide compete for the same binding site at an acidic region on the nucleosome surface. Although the essential facts about the nucleosome were revealed 17 years ago, new insights into its atomic structure and molecular mechanisms are still emerging. Several complex nucleosome:NBP structures were recently revealed, characterizing the NBP-binding sites on the nucleosome surface. Here we discuss the potential of the nucleosome surface as a therapeutic target and the impact and development of exogenous nucleosome-binding molecules (eNBMs). PMID- 25835596 TI - A new minor diketopiperazine from the sponge-derived fungus Simplicillium sp. YZ 11. AB - Chemical investigation of the cultures of a sponge-derived fungus Simplicillium sp. YZ-11 led to the isolation of a new minor diketopiperazine alkaloid cyclo-(2 hydroxy-Pro-Gly) (1) and a natural lactone (S)-dihydro-5-[(S)- hydroxyphenylmethyl]-2(3H)-furanone (2), together with five known ergostane-type sterols (3-7). Their structures were established based on extensive spectroscopic methods ((1)H and (13)C NMR, (1)H-(1)H COSY, HSQC and HMBC) and optical rotation analysis. PMID- 25835597 TI - CHEK2 c.1100delC allele is rarely identified in Greek breast cancer cases. AB - The CHEK2 gene encodes a protein kinase that plays a crucial role in maintenance of genomic integrity and the DNA repair mechanism. CHEK2 germline mutations are associated with increased risk of breast cancer and other malignancies. From a clinical perspective, the most significant mutation identified is the c.1100delC mutation, which is associated with an approximately 25% lifetime breast cancer risk. The distribution of this mutation shows wide geographical variation; it is more prevalent in the Northern European countries and less common, or even absent, in Southern Europe. In order to estimate the frequency of the CHEK2 c.1100delC mutation in Greek breast cancer patients, we genotyped 2,449 patients (2,408 females and 41 males), which was the largest series ever tested for c.1100delC. The mean age of female and male breast cancer diagnosis was 49 and 59 years, respectively. All patients had previously tested negative for the Greek BRCA1 founder and recurrent mutations. The CHEK2 c.1100delC mutation was detected in 0.16% (4 of 2,408) of females, all of whom were diagnosed with breast cancer before the age of 50 years. Only one c.1100delC carrier was reported with breast cancer family history. The present study indicates that the CHEK2 c.1100delC mutation does not contribute substantially to hereditary breast cancer in patients of Greek descent. PMID- 25835598 TI - Editorial retraction. PMID- 25835599 TI - Decoding skills in children with language impairment: contributions of phonological processing and classroom experiences. AB - PURPOSE: Children with language impairment (LI) often demonstrate difficulties with word decoding. Research suggests that child-level (i.e., phonological processing) and environmental-level (i.e., classroom quality) factors both contribute to decoding skills in typically developing children. The present study examined the extent to which these same factors influence the decoding skills of children with LI, and the extent to which classroom quality moderates the relationship between phonological processing and decoding. METHOD: Kindergarten and first-grade children with LI (n = 198) were assessed on measures of phonological processing and decoding twice throughout the academic year. Live classroom observations were conducted to assess classroom quality with respect to emotional support and instructional support. RESULTS: Hierarchical regression analyses revealed that of the 3 phonological processing variables included, only phonological awareness significantly predicted spring decoding outcomes when controlling for children's age and previous decoding ability. One aspect of classroom quality (emotional support) was also predictive of decoding, but there was no significant interaction between classroom quality and phonological processing. CONCLUSIONS: This study provides further evidence that phonological awareness is an important skill to assess in children with LI and that high quality classroom environments can be positively associated with children's decoding outcomes. PMID- 25835600 TI - Liberating Levy walk research from the shackles of optimal foraging. AB - There is now compelling evidence that many organisms have movement patterns that can be described as Levy walks, or Levy flights. Levy movement patterns have been identified in cells, microorganisms, molluscs, insects, reptiles, fish, birds and even human hunter-gatherers. Most research into Levy walks as models of organism movement patterns has been shaped by the 'Levy flight foraging hypothesis'. This states that, since Levy walks can optimize search efficiencies, natural selection should lead to adaptations that select for Levy walk foraging. However, a growing body of research on generative mechanisms suggests that Levy walks can arise freely as by-products of otherwise innocuous behaviours; consequently their advantageous properties are purely coincidental. This suggests that the Levy flight foraging hypothesis should be amended, or even replaced, by a simpler and more general hypothesis. This new hypothesis would state that 'Levy walks emerge spontaneously and naturally from innate behaviours and innocuous responses to the environment but, if advantageous, then there could be selection against losing them'. The new hypothesis has the virtue of making fewer assumptions and being broader than the original hypothesis; it also encompasses the many examples of suboptimal Levy patterns that challenge the prevailing paradigm. This does not detract from the Levy flight foraging hypothesis, in fact, it adds to the theory by providing a stronger and more compelling case for the occurrence of Levy walks. It dispenses with concerns about the theoretical arguments in support of the Levy flight foraging hypothesis and so may lead to a wider acceptance of Levy walks as models of movement pattern data. Furthermore, organisms can approximate Levy walks by adapting intrinsic behaviour in simple ways; this occurs when Levy movement patterns are advantageous, but come with an associated cost. These new developments represent a major change in perspective and provide the broadest picture yet of Levy movement patterns. However, the process of understanding and identifying Levy movement patterns still has a long way to go, and further reinterpretations and shifts in understanding will occur. In conclusion, Levy walk research remains exciting precisely because so much remains to be understood, and because, even relatively small studies, are interesting discoveries in their own right. PMID- 25835601 TI - A comparative study of open, laparoscopic and robotic partial nephrectomy in obese patients. AB - OBJECTIVES: Partial nephrectomy is a standard intervention for the treatment of small renal tumors. Our study compares the outcomes of three different partial nephrectomy methods (open, laparoscopic and robotic assisted) in obese (>=30 Kg/m(2)) patients with renal tumors. MATERIALS AND METHODS: Between 2005-2011, 66 obese patients had partial nephrectomy. Patients were divided into three groups according to intervention received: Open (n = 21), laparoscopic (n = 31) and robotic (n = 14). The outcome variables of blood loss, length of hospital stay, and complications were assessed. RESULTS: Mean blood loss in the laparoscopic group (100 mls) was significantly less than open group (300 mls) and no difference between laparoscopic and robotic groups (150 mls). We observed a shorter median hospital stay in the laparoscopic group (two days) than open group (four days) and no difference between laparoscopic and robotic groups (three days). Three patients in the laparoscopic group had complications: Two grade II and one with grade III (based on Clavien-Dindo classification). Tumor location, pathology, grade, stage, patient gender, age, preoperative creatinine and postoperative creatinine were not different among the groups (P > 0.05). The mean tumor size in the laparoscopic group (2.70 cms) was significantly smaller than that of the open group (4.22 cm) (P < 0.05), but not statistically different from that of the robotic group (2.99 cm). CONCLUSIONS: Our study demonstrates that in obese patients, both laparoscopic and robotic partial nephrectomy are associated with less blood loss than open partial nephrectomy. Second, the length of the hospital stay was not related to the type of utilized intervention. PMID- 25835603 TI - HIV Care Continuum Applied to the US Department of Veterans Affairs: HIV Virologic Outcomes in an Integrated Health Care System. AB - BACKGROUND: The Department of Veterans Affairs (VA), the largest integrated HIV care provider in the United States (US), used the HIV Care Continuum to compare clinical care within the VA HIV population with the general US HIV population and to identify areas for improvement. METHODS: National data from the VA's HIV Clinical Case Registry were used to construct measures along the Continuum for Veterans in VA care diagnosed with HIV by June 2013 and alive by December 31, 2013. Comparisons were made to recent estimates for the same measures for the US HIV population. Additional comparisons were performed for demographic subgroups of sex, race/ethnicity, and age. RESULTS: Of 25,480 Veterans diagnosed with HIV, 77.4% were engaged in care compared with 46.3% in the US population diagnosed with HIV (P < 0.001). Seventy-three percent of Veterans diagnosed with HIV received antiretroviral therapy compared with 43% of the US population diagnosed with HIV (P < 0.001). Nearly two-thirds (65.3%) of HIV-diagnosed Veterans had suppressed HIV viral loads compared with 35.0% of the US population diagnosed with HIV (P < 0.001). CONCLUSIONS: The VA health care system performed better at every stage of the HIV Care Continuum compared with the general US estimates. Comparable high rates with some variation were noted among the demographic groups in the VA cohort. The high viral suppression rate in VA, which was almost double the estimate for the HIV-diagnosed US population, demonstrates that improved outcomes along the HIV Care Continuum can be achieved in a comprehensive integrated health care system. PMID- 25835602 TI - Termination of DNA replication forks: "Breaking up is hard to do". AB - To ensure duplication of the entire genome, eukaryotic DNA replication initiates from thousands of replication origins. The replication forks move through the chromatin until they encounter forks from neighboring origins. During replication fork termination forks converge, the replisomes disassemble and topoisomerase II resolves the daughter DNA molecules. If not resolved efficiently, terminating forks result in genomic instability through the formation of pathogenic structures. Our recent findings shed light onto the mechanism of replisome disassembly upon replication fork termination. We have shown that termination specific polyubiquitylation of the replicative helicase component - Mcm7, leads to dissolution of the active helicase in a process dependent on the p97/VCP/Cdc48 segregase. The inhibition of terminating helicase disassembly resulted in a replication termination defect. In this extended view we present hypothetical models of replication fork termination and discuss remaining and emerging questions in the DNA replication termination field. PMID- 25835604 TI - Critical Review: Building on the HIV Cascade: A Complementary "HIV States and Transitions" Framework for Describing HIV Diagnosis, Care, and Treatment at the Population Level. AB - The HIV cascade--often referred to as "the HIV continuum"--provides a valuable framework for population-level representations of engagement with the HIV healthcare system. The importance and appeal of this framework are evidenced by a large body of scientific literature, as well as by the adoption of cascade related indicators by medical and public health organizations worldwide. Despite its centrality in the fields of HIV treatment and prevention, however, the traditional cascade provides limited description of the processes affecting the numbers it represents. Representations that describe these processes and capture the dynamic nature of HIV-infected persons' pathways through the healthcare system are essential for monitoring and predicting intervention effects and epidemic trends. We propose here a complementary schema--termed the "HIV States and Transitions" framework--designed to maintain key strengths of the traditional cascade while addressing key limitations and more fully describing the dynamic aspects of HIV testing, care, and treatment at the population level. PMID- 25835605 TI - Impact of Availability and Use of ART/PMTCT Services on Fertility Desires of Previously Pregnant Women in Rakai, Uganda: A Retrospective Cohort Study. AB - OBJECTIVE: To assess fertility desires by availability and use of antiretroviral therapy and prevention of mother-to-child transmission (ART/PMTCT) services in Rakai, Uganda. DESIGN: Retrospective analyses of longitudinal data from the Rakai Community Cohort Study. METHODS: Study participants were retrospectively identified and categorized by HIV status. Availability of ART/PMTCT services in Rakai was defined in three periods: (1) pre-ART/PMTCT (<2005), (2) ART/PMTCT rollout (2005-2006), and (3) universal ART/PMTCT (>2006); and use of ART/PMTCT was coded as yes if the woman received services. Trends in fertility desires were assessed by chi. "Modified" Poisson regression was performed using generalized linear models with a log link and Poisson family to estimate prevalence rate ratios (PRRs) and 95% confidence intervals (CIs) of desire for another child among previously and currently pregnant women; PRRs were adjusted for demographic and behavioral factors. RESULTS: A total of 4227 sexually active women in Rakai, including 436 HIV+ women, contributed 13,970 observations over 5 survey rounds. Fertility desires increased in the population in the ART/PMTCT rollout [adjusted (adj.) PRR: 1.08, 95% CI: 1.04 to 1.13] and the universal availability periods (adj. PRR: 1.11, 95% CI: 1.08 to 1.14) compared with pre-ART/PMTCT period. A total of 862 woman observations used ART/PMTCT services. Fertility desires were similar among ART/PMTCT service users and nonusers in cross-sectional analysis (adj. PRR: 0.84, 95% CI: 0.62 to 1.14) and 1 year after ART/PMTCT use (adj. PRR: 1.27, 95% CI: 0.83 to 1.94). CONCLUSIONS: Availability of ART/PMTCT may increase fertility desires of previously pregnant women in Rakai, Uganda. Use of ART/PMTCT services was not correlated with fertility desires of previously or current pregnant women. PMID- 25835606 TI - Transmission Networks of HIV-1 Among Men Who Have Sex With Men in East and Southeast Asia. PMID- 25835608 TI - "Seek, Test, Treat" Lessons From Australia: A Study of HIV Testing Patterns From a Cohort of Men Who Have Sex With Men. AB - OBJECTIVE: HIV diagnoses are increasing in Australia, mostly among men who have sex with men (MSM). Similar to many countries, Australia's HIV prevention strategies emphasize a "seek, test, treat" approach including enhancing HIV testing frequency. We describe HIV testing among MSM and correlates of returning for testing within 12 months in the context of new HIV prevention paradigms. METHODS: Testing and behavioral data (2007-2013) contributed by MSM aged >= 16 years were included. Total HIV tests by calendar year and repeat tests within 12 months were described, alongside negative binomial regression for trend. A 2 level mixed-effects logistic regression model examined correlates of testing within 12 months. Median (days) between HIV tests was compared between MSM diagnosed with HIV and persistently HIV-negative MSM. RESULTS: The study included 46,060 tests from 17,904 MSM. There was an increase in annual tests (P < 0.01), repeat tests within 12 months (P < 0.01), and the proportion of tests within 12 months of an index test (P < 0.01), although only to 53.3% in 2013. Return rates were higher in MSM aged 16-29 years (adjusted odds ratio 1.30, 95% confidence interval: 1.1 to 1.5) and those reporting higher numbers of partners (adjusted odds ratio 3.5, 95% confidence interval: 3.0 to 4.0). Median time between tests among MSM diagnosed with HIV (233 days) was greater than for HIV-negative MSM (189 days) (P = 0.03). CONCLUSIONS: Although testing has increased, testing frequency among many MSM remains suboptimal. To optimize "seek, test, treat" based HIV prevention strategies, new approaches to increase testing uptake and early HIV detection among MSM are needed. PMID- 25835607 TI - Determination of HIV Status in African Adults With Discordant HIV Rapid Tests. AB - BACKGROUND: In resource-limited settings, HIV infection is often diagnosed using 2 rapid tests. If the results are discordant, a third tie-breaker test is often used to determine HIV status. This study characterized samples with discordant rapid tests and compared different testing strategies for determining HIV status in these cases. METHODS: Samples were previously collected from 173 African adults in a population-based survey who had discordant rapid test results. Samples were classified as HIV positive or HIV negative using a rigorous testing algorithm that included two fourth-generation tests, a discriminatory test, and 2 HIV RNA tests. Tie-breaker tests were evaluated, including rapid tests (1 performed in-country), a third-generation enzyme immunoassay, and two fourth generation tests. Selected samples were further characterized using additional assays. RESULTS: Twenty-nine samples (16.8%) were classified as HIV positive and 24 of those samples (82.8%) had undetectable HIV RNA. Antiretroviral drugs were detected in 1 sample. Sensitivity was 8.3%-43% for the rapid tests; 24.1% for the third-generation enzyme immunoassay; 95.8% and 96.6% for the fourth-generation tests. Specificity was lower for the fourth-generation tests than the other tests. Accuracy ranged from 79.5% to 91.3%. CONCLUSIONS: In this population-based survey, most HIV-infected adults with discordant rapid tests were virally suppressed without antiretroviral drugs. Use of individual assays as tie-breaker tests was not a reliable method for determining HIV status in these individuals. More extensive testing algorithms that use a fourth-generation screening test with a discriminatory test and HIV RNA test are preferable for determining HIV status in these cases. PMID- 25835609 TI - Perspective: The RNA exosome, cytokine gene regulation and links to autoimmunity. AB - The RNA exosome is a highly conserved exoribonuclease complex that is involved in RNA processing, quality control and turnover regulation. The exosome plays pleiotropic functions by recruiting different cofactors that regulate its target specificity. Recently, the exosome has been implicated in the regulation of immune processes including cytokine production and negative regulation of innate sensing of nucleic acids. Careful regulation of such mechanisms is critical to avoid a breakdown of self-tolerance and the pathogenesis of autoimmune disorders. This perspective briefly introduces the exosome, its its normal function in RNA biology and summarizes regulatory roles of the RNA exosome in immunity. Finally we discuss how dysregulation of exosome function can lead to autoimmune disease. PMID- 25835610 TI - Increased Rho-kinase-mediated prostate contractions associated with impairment of beta-adrenergic-cAMP-signaling pathway by chronic nitric oxide deficiency. AB - Impairment of nitric oxide (NO) - cyclic GMP signaling pathway is likely to contribute to human begnin prostate hyperplasia (BPH). In the present study we have used a model of chronic NO synthesis inhibition to evaluate the functional alterations of prostate smooth muscle (PSM) machinery, and involvement of Rho kinase pathway. Wistar rats were treated with the NO inhibitor N(omega)-nitro-l arginine methyl ester (L-NAME, 20mg/kg/day; 4 weeks), after which contractile responses to phenylephrine (alpha1-adrenoceptor agonist; 1nM to 100uM), carbachol (muscarinic agonist; 1nM to 1mM) and alpha,beta-methylene ATP (P2X receptor agonist; 1-10uM), as well as to electrical-field stimulation (EFS; 1-32Hz) were evaluated. PSM relaxations to isoproterenol (non-selective beta-adrenoceptor agonist, 0.1nM to 10uM) and sodium nitroprusside (NO donor, 1nM to 10mM) were also evaluated. The ratio prostate weight/body weight was 22% greater (P<0.05) in L-NAME compared with control group. The PSM contractions to phenylephrine, carbachol and alpha,beta-methylene ATP were higher in L-NAME (Emax: 3.85+/-0.25, 3.52+/-0.35 and 2.03+/-0.2mN, respectively) compared with control group (Emax: 3.08+/-0.17, 2.37+/-0.18 and 1.57+/-0.18mN, respectively). The PSM contractions induced by EFS were also significantly greater in L-NAME group. Prior incubation with the Rho-kinase inhibitor Y27632 (1uM) fully reversed the enhanced contractions to phenylephrine and carbachol. Isoproterenol-induced PSM relaxations were 34% lower in L-NAME group, which was associated with reduced levels of cAMP in prostate tissue. The relaxations to sodium nitroprusside remained unaltered in L-NAME group. In summary, chronic NO deficiency leads to increased Rho-kinase-mediated PSM contractile responses accompanied by impairment of beta-adrenergic-cAMP-signaling pathway. PMID- 25835611 TI - (+)-Borneol alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice. AB - Chronic pain is a major public health problem categorized as inflammatory or neuropathic, each involving impaired GABAergic control in the spinal cord of mammals. (+)-Borneol, a bicyclic monoterpene present in the essential oil of plants, is used for analgesia and anesthesia in traditional Chinese medicine. It has been reported that (+)-borneol directly potentiates GABA activity at recombinant human GABAA receptors. Although borneol has antinociceptive effect on acute pain models, little is known about its effect on chronic pain and its mechanism. Here we report that (+)-borneol has remarkable anti-hyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation (SNL), and inflammatory hypersensitivity was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Both oral administration (125, 250 or 500 mg/kg) and intrathecal injection (i.t.) (15, 30 and 60 MUg) of (+)-borneol reduced mechanical hypersensitivity dose-dependently in SNL and CFA models. The anti-hyperalgesic effects of (+)-borneol were abolished by a selective GABAA receptor (GABAAR) antagonist bicuculline (i.t., at 30 min after (+)-borneol injection). Furthermore, (+)-borneol (500 mg/kg, p.o. or 60 MUg, i.t.) did not influence motor function. These findings suggest that (+)-borneol may ameliorate mechanical hyperalgesia by enhancing GABAAR-mediated GABAergic transmission in the spinal cord, and could serve as a therapeutic for chronic pain. PMID- 25835612 TI - [Statins diabetogenicity: are all the same? state of art]. AB - Statins are the cornerstone of cardiovascular prevention for general population, and in patients with type 2 diabetes mellitus (T2DM). However, statin therapy predisposes to type 2 diabetes, particularly in patients with predisposition to this condition. Some statins have been associated with increases in blood glucose in patients with or without DM2, and others have shown to have neutral effects, varying from one another their glucose or diabetogenic capacity. In many statin trials the incidence of DM2 has not been systematically evaluated and others the power to detect differences between statins is lacking. Evidence highest quality available comes from the meta-analysis of controlled clinical trials. The only controlled clinical trial to evaluate the incidence of new-onset T2DM is the J PREDICT conducted with pitavastatin in patients with abnormal glucose tolerance. Preliminary results of this study show that pitavastatin is associated with a significant decrease in the incidence of de novo T2DM compared to only modification lifestyle. Therefore, pitavastatin may be an appropriate therapeutic alternative of choice to reduce vascular risk in patients with T2DM or at risk of presenting it. PMID- 25835613 TI - [Guide recommendations for diagnosis and treatment of abdominal aortic aneurysm]. PMID- 25835614 TI - Sonochemical synthesis of two new copper(II) complexes with azo ligands derived from anthranilic acid and beta-naphtol. AB - Nanostructures of two new copper(II) complexes, (CuL1), 0.5EtOH. 1.5H2O (1), [H2L1=5-(4-Carboxy phenyl azo) anthranilic acid], (Cu(L2)2) (2), [HL2=1-(4 Carboxy phenyl azo) 2-naphtol] have been synthesized by the reaction of H2L1 and HL2 with Cu(OAc)2 . H2O through sonochemical process. Calcination of the nano sized compounds 1-2 yield CuO nanoparticles at 550-450 degrees C under air atmosphere. Metallic copper nanoparticles were prepared by direct calcination of compound 2 in surfactant at 180 degrees C. These nanostructures were characterized by X-ray powder diffraction (XRD) and Scanning Electron Microscopy (SEM). Thermal stability of compounds 1-2 was studied by thermal gravimetric (TG) and differential thermal analyses (DTA). PMID- 25835615 TI - Oncology scan-New treatment and no treatment: enduring issues in the management of prostate cancer. PMID- 25835616 TI - Fate of manuscripts rejected from the Red Journal. AB - PURPOSE: To evaluate characteristics associated with higher rates of acceptance for original manuscripts submitted for publication to the International Journal of Radiation Oncology * Biology * Physics (IJROBP) and describe the fate of rejected manuscripts. METHODS AND MATERIALS: Manuscripts submitted to the IJROBP from May 1, 2010, to August 31, 2010, and May 1, 2012, to August 31, 2012, were evaluated for author demographics and acceptance status. A PubMed search was performed for each IJROBP-rejected manuscript to ascertain whether the manuscript was ultimately published elsewhere. The Impact Factor of the accepting journal and the number of citations of the published manuscript were also collected. RESULTS: Of the 500 included manuscripts, 172 (34.4%) were accepted and 328 (65.6%) were rejected. There was no significant difference in acceptance rates according to gender or degree of the submitting author, but there were significant differences seen based on the submitting author's country, rank, and h-index. On multivariate analysis, earlier year submitted (P<.0001) and higher author h-index (P=.006) remained significantly associated with acceptance into the IJROBP. Two hundred thirty-five IJROBP-rejected manuscripts (71.7%) were ultimately published in a PubMed-listed journal as of July 2014. There were no significant differences in any submitting author characteristics. Journals accepting IJROBP-rejected manuscripts had a lower median [interquartile range] 2013 impact factor compared with the IJROBP (2.45 [1.53-3.71] vs 4.176). The IJROBP-rejected manuscripts ultimately published elsewhere had a lower median [interquartile range] number of citations (1 [0-4] vs 6 [2-11]; P<.001), which persisted on multivariate analysis. CONCLUSIONS: The acceptance rate for manuscripts submitted to the IJROBP is approximately one-third, and approximately 70% of rejected manuscripts are ultimately published in other PubMed-listed journals, but these ultimate-destination journals usually have a lower impact factor, leading to fewer citations and overall visibility. PMID- 25835617 TI - A hypothesis: indirect cell death in the radiosurgery era. PMID- 25835618 TI - Evolving traditions on the technology journey. PMID- 25835619 TI - Research on quality and safety: what are we missing? PMID- 25835620 TI - What makes a physics article appealing to a clinical audience? PMID- 25835621 TI - Attenuation of the DNA damage response by transforming growth factor-beta inhibitors enhances radiation sensitivity of non-small-cell lung cancer cells in vitro and in vivo. AB - PURPOSE: To determine whether transforming growth factor (TGF)-beta inhibition increases the response to radiation therapy in human and mouse non-small-cell lung carcinoma (NSCLC) cells in vitro and in vivo. METHODS AND MATERIALS: TGF beta-mediated growth response and pathway activation were examined in human NSCLC NCI-H1299, NCI-H292, and A549 cell lines and murine Lewis lung cancer (LLC) cells. Cells were treated in vitro with LY364947, a small-molecule inhibitor of the TGF-beta type 1 receptor kinase, or with the pan-isoform TGF-beta neutralizing monoclonal antibody 1D11 before radiation exposure. The DNA damage response was assessed by ataxia telangiectasia mutated (ATM) or Trp53 protein phosphorylation, gammaH2AX foci formation, or comet assay in irradiated cells. Radiation sensitivity was determined by clonogenic assay. Mice bearing syngeneic subcutaneous LLC tumors were treated with 5 fractions of 6 Gy and/or neutralizing or control antibody. RESULTS: The NCI-H1299, A549, and LLC NSCLC cell lines pretreated with LY364947 before radiation exposure exhibited compromised DNA damage response, indicated by decreased ATM and p53 phosphorylation, reduced gammaH2AX foci, and increased radiosensitivity. The NCI-H292 cells were unresponsive. Transforming growth factor-beta signaling inhibition in irradiated LLC cells resulted in unresolved DNA damage. Subcutaneous LLC tumors in mice treated with TGF-beta neutralizing antibody exhibited fewer gammaH2AX foci after irradiation and significantly greater tumor growth delay in combination with fractionated radiation. CONCLUSIONS: Inhibition of TGF-beta before radiation attenuated DNA damage recognition and increased radiosensitivity in most NSCLC cells in vitro and promoted radiation-induced tumor control in vivo. These data support the rationale for concurrent TGF-beta inhibition and RT to provide therapeutic benefit in NSCLC. PMID- 25835622 TI - Is intermediate radiation dose escalation with concurrent chemotherapy for stage III non-small-cell lung cancer beneficial? A multi-institutional propensity score matched analysis. AB - PURPOSE: The clinical benefits and risks of dose escalation (DE) for stage III non-small-cell lung cancer (NSCLC) remain uncertain despite the results from Radiation Therapy Oncology Group (RTOG) protocol 0617. There is significant heterogeneity of practice, with many clinicians prescribing intermediate dose levels between the 0617 study arms of 60 and 74 Gy. This study investigated whether this strategy is associated with any survival benefits/risks by analyzing a large multi-institutional database. METHODS AND MATERIALS: An individual patient database of stage III NSCLC patients treated with radical intent concurrent chemoradiation therapy was created (13 institutions, n=1274 patients). Patients were divided into 2 groups based on tumor Biological Effective Dose at 10 Gy (BED 10): those receiving standard dose (SD; n=552), consisting of 72Gy <= BED 10 <= 76.8 Gy (eg 60-64 Gy/30-32 fractions [fr]), and those receiving intermediate dose (ID; n=497), consisting of 76.8Gy < BED 10 < 100.8 Gy (eg >64 Gy/32 fr and <74 Gy/37 fr), with lower-dose patients (n=225) excluded from consideration. Patients were then matched using propensity scores, leading to 2 matched groups of 196 patients. Outcomes were compared using various statistics including interquartile range (IQR), Kaplan-Meier curves, and adjusted Cox regression analysis. RESULTS: Matched groups were found to be balanced except for N stage (more N3 disease in SD), median treatment year (SD in 2003; ID in 2007), platinum and taxane chemotherapy (SD in 28%; ID in 39%), and median follow-up (SD were 89 months; ID were 40 months). Median dose fractionation was 60 Gy/30 fr in SD (BED 10 IQR: 72.0-75.5 Gy) and 66 Gy/33 fr (BED 10 IQR: 78.6-79.2 Gy) in ID. Survival curves for SD and ID matched cohorts were statistically similar (P=.27); however, a nonstatistically significant trend toward better survival for ID was observed after 15 months (median survival SD: 19.3 months; ID: 21.0 months). There was an increase in grades III to V lung toxicity associated with ID (13.0% vs 4.9%, respectively). CONCLUSIONS: No significant overall survival benefits were found with intermediate DE; however, more grade III or greater lung toxicity was observed. The separation of survival curves after 15 months of follow-up suggests that a small overall survival improvement associated with intermediate DE cannot be excluded. PMID- 25835623 TI - Prospective evaluation of severe skin toxicity and pain during postmastectomy radiation therapy. AB - PURPOSE: To prospectively capture acute toxicities and pain associated with postmastectomy radiation therapy (PMRT), to analyze patient and treatment risk factors for severe side effects. METHODS AND MATERIALS: Women referred for PMRT were prospectively enrolled and assessed weekly during and after radiation therapy. The endpoint included severe National Cancer Institute Common Terminology Criteria for Adverse Effects grade 3 moist desquamation, other skin symptoms, and pain. RESULTS: Of 257 patients, 73 (28.4%) experienced extensive moist desquamation, 84 (32.7%) Common Terminology Criteria for Adverse Effects skin toxicity grade 3, and 57 (22.2%) a pain impacting on daily life activities. Among symptoms only grade 3 moist desquamation was significantly associated with severe pain (P<.001). On multivariate analysis, smoking, high-energy photons, and skin bolus were significantly associated with severe moist desquamation. Skin toxicity doubled for smokers, with 40% severe pain, 48% grade 3 moist desquamation, and 64% grade 3 skin toxicity. Without skin bolus 4.2% had severe pain, none moist desquamation, and 2.1% grade 3 skin toxicity. When skin bolus was used on alternate days, the frequency increased to 15% for pain, 22% for moist desquamation, and 26% for grade 3 skin toxicity. When bolus was used daily, 32% had pain, 41% moist desquamation, and 47% grade 3 skin toxicity. Symptoms peaked 1 to 2 weeks after the end of PMRT. CONCLUSIONS: The present cohort study suggests excessive radiation toxicity after PMRT. Among factors associated with an increase of toxicity are smoking habits and the use of skin bolus. PMID- 25835624 TI - Role of the technical aspects of hypofractionated radiation therapy treatment of prostate cancer: a review. AB - The increasing use of moderate (<35 fractions) and extreme (<5 fractions) hypofractionated radiation therapy in prostate cancer is yielding favorable results, both in terms of maintained biochemical response and toxicity. Several hypofractionation (HF) schemes for the treatment of prostate cancer are available, although there is considerable variability in the techniques used to manage intra-/interfraction motion and deliver radiation doses. We performed a review of the published studies on HF regimens as a topic of interest for the Stereotactic Ablative Radiotherapy working group, which is part of the Italian Association of Medical Physics. Aspects of organ motion management (imaging for contouring, target volume definition, and rectum/bladder preparation) and treatment delivery (prostate localization, image guided radiation therapy strategy and frequency) were evaluated and categorized to assess outcome relative to disease control and toxicity. Despite the heterogeneity of the data, some interesting trends that emerged from the review might be useful in identifying an optimum HF strategy. PMID- 25835625 TI - Rates and durability of response to salvage radiation therapy among patients with refractory or relapsed aggressive non-Hodgkin lymphoma. AB - PURPOSE: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics. METHODS AND MATERIALS: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treated with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model. RESULTS: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy. CONCLUSIONS: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter TTLR, suggesting that radiation dose escalation, addition of radiosensitizers, or a combination of both may be indicated in these patients. PMID- 25835626 TI - Predictors of radiation therapy noncompliance in an urban academic cancer center. AB - PURPOSE: To quantify the frequency of patient noncompliance in an urban radiation oncology department and identify predictors of noncompliance. METHODS AND MATERIALS: We identified patients treated with external beam radiation therapy (RT) with curative intent in our department from 2007 to 2012 for 1 of 7 commonly treated malignancies. Patients who missed 2 or more scheduled RT appointments were deemed "noncompliant." An institutional database was referenced to obtain clinical and demographic information for each patient, as well as a quantitative estimate of each patient's socioeconomic status. Logistic regression was used to identify factors associated with RT noncompliance. RESULTS: A total of 2184 patients met eligibility criteria. Of these, 442 (20.2%) were deemed "noncompliant." On multivariate analysis, statistically significant predictors of noncompliance included diagnosis of head-and-neck, cervical, or uterine cancer, treatment during winter months, low socioeconomic status, and use of a long treatment course (all P<.05). CONCLUSION: This is the first large effort examining patient noncompliance with daily RT. We have identified demographic, clinical, and treatment-related factors that can be used to identify patients at high risk for noncompliance. These findings may inform future strategies to improve adherence to prescribed therapy. PMID- 25835627 TI - Need for consensus when prescribing stereotactic body radiation therapy for prostate cancer. PMID- 25835628 TI - In regard to Duchesne et al. PMID- 25835629 TI - In reply to Jenkins. PMID- 25835630 TI - In regard to Duchesne et al. PMID- 25835631 TI - In regard to Brink et al. PMID- 25835632 TI - In reply to Yamazaki et al. PMID- 25835633 TI - In Regard to Hodges et al. PMID- 25835638 TI - Receptor tyrosine kinase-like orphan receptor 1: a novel target for cancer immunotherapy. AB - INTRODUCTION: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family. ROR1 is selectively overexpressed in a number of solid and hematological malignancies without significant expression in normal adult tissues. There are also some lines of evidence, which support the critical role of ROR1 in tumorigenesis. These characteristics introduce ROR1 as a suitable target for selective cancer immunotherapy. ROR1 targeting using different approaches such as siRNA, tyrosine kinase inhibitors and antibody induces tumor growth suppression in cancer cells. AREAS COVERED: The current review focuses on ROR1 structure and biological functions, expression profiles in normal and malignant tissues and its potential therapeutic applications in different malignancies. We aimed to encompass almost all important aspects of ROR1 biology and its importance in tumor targeted therapy approaches based on published papers in this field. EXPERT OPINION: Considering ROR1 unique characters, it seems that it can pass most of the criteria for being an ideal target for cancer immunotherapy. ROR1 unique expression on cancer cells with subtle expression on normal tissues make it a suitable target with minimum potential side effects using different cancer therapy approaches such as mAb therapy, peptide and protein vaccination, cell therapy and small molecules. PMID- 25835639 TI - Is Trichomonas tenax a Parasite or a Commensal? AB - Trichomonas tenax is considered a commensal organism found under poor oral hygiene conditions. T. tenax presents morphological similarities with T. vaginalis, and there are doubts concerning whether this protist is a parasite and whether it is a genetic variant of T. vaginalis. This study aimed to investigate the capacity of T. tenax to cause mammalian cell damage and compare its cytotoxicity with that of T. vaginalis. Protozoan-host cell interaction assays were performed with Madin-Darby canine kidney, HeLa, and gum cells and 3D spheroids, which were examined by scanning electron and transmission electron microscopy. Cellular viability experiments were also performed. T. tenax attached and had different forms when interacting with mammalian cells and caused damage with time-dependent host-cell viability. We observed that T. tenax produced plasma membrane projections and phagocytosed portions of the mammalian cells. In addition, T. tenax caused membrane blebbing and apoptotic bodies in HeLa cells, thus inducing cell death. Spheroids were also used in interaction assays with T. tenax and they were damaged by these cells. This study shows that T. tenax fulfills the requisites of a parasite, causing damage to different mammalian cells and behaving similarly to T. vaginalis when in contact with target cells in vitro. PMID- 25835640 TI - Cannabis: the never-ending, nefarious nepenthe of the 21st century: what should the clinician know? PMID- 25835637 TI - Interaction of thrombospondin1 and CD36 contributes to obesity-associated podocytopathy. AB - Obesity is associated with podocyte injury and the development of proteinuria. Elevated plasma free fatty acid is one of the characteristics of obesity and has been linked to podocyte dysfunction. However, the mechanisms remain unclear. In the current study, we examined the effect of saturated free fatty acid (FFA) on human podocyte apoptosis and function in vitro. The mechanism and its in vivo relevance were also determined. We found that FFA treatment induced human podocyte apoptosis and dysfunction, which was associated with increased expression of a matricellular protein-thrombospondin1 (TSP1). FFA stimulated TSP1 expression in podocytes at the transcriptional levels through activation of MAPK pathway. Addition of purified TSP1 to cell culture media induced podocyte apoptosis and dysfunction. Tis effect is though a TGF-beta independent mechanism. Moreover, peptide treatment to block TSP1 binding to its receptor-CD36 attenuated FFA induced podocyte apoptosis, suggesting that TSP1/CD36 interaction mediates FFA-induced podocyte apoptosis. Importantly, using a diet-induced obese mouse model, in vivo data demonstrated that obesity-associated podocyte apoptosis and dysfunction were attenuated in TSP1 deficient mice as well as in CD36 deficient mice. Taken together, these studies provide novel evidence that the interaction of TSP1 with its receptor CD36 contributes to obesity--associated podocytopathy. PMID- 25835641 TI - Hepatoprotective and Renoprotective Effects of Lavender (Lavandula stoechas L.) Essential Oils Against Malathion-Induced Oxidative Stress in Young Male Mice. AB - We aimed in the present study to investigate the hepato- and nephroprotective effects of Lavandula stoechas essential oils (LSEO) against malathion-induced oxidative stress in young male mice as well as the possible mechanism implicated in such protection. Animals were divided into eight groups of 12 each: Control, malathion (200 mg/kg b.w.); Various doses of LSEO (10, 30, and 50 mg/kg b.w.), malathion+various doses of LSEO. Malathion and LSEO were daily per orally (p.o.) administered by intragastric gavage during 30 days. We initially found that malathion treatment induced body weight gain decrease as well as a clear nephro- and hepatotoxicity as assessed by significant relative liver and kidney weight increase and related hemodynamic parameters deregulation. Malathion exposure of mice also induced a considerable perturbation of metabolic parameters. On the other hand, we showed that malathion administration was accompanied by an oxidative stress status assessed by an increase of malondialdehyde (MDA) and hydrogen peroxide (H2O2) levels as well as a depletion of sulfhydril group content (-SH) and antioxidant enzyme activities such as catalase (CAT) and glutathione peroxidase (GPx), total superoxide dismutase (SOD), Cu/Zn-SOD, Mn SOD, and Fe-SOD in the kidney and liver. More importantly, LSEO treatment abolished all malathion-induced body gain loss, liver and kidney relative weight increase, hemodynamic and metabolic disorders, as well as hepatic and renal oxidative stress. In conclusion, our data suggest that LSEO exerted potential hepato- and nephroprotective effects against malathion-induced oxidative stress in mice. The beneficial effect of LSEO might be related, in part, to its antioxidant properties. PMID- 25835642 TI - Double-blind randomized controlled trial comparing misoprostol and oxytocin for management of the third stage of labor in a Nigerian hospital. AB - OBJECTIVE: To compare the efficacy of oral misoprostol with that of oxytocin for active management of the third stage of labor (AMTSL). METHODS: A double-blind randomized control trial was undertaken at a center in Ilorin, Nigeria, between January and June 2013. Every other eligible patient (in the first stage of labor at term, to have a spontaneous vaginal delivery, and no/low risk of postpartum hemorrhage [PPH]) were randomly assigned with computer-generated random numbers to receive oral misoprostol (600MUg) plus placebo injection or oral placebo plus oxytocin injection (1mL of 10IU) in the third stage of labor. The primary outcome was amount of blood loss during delivery. RESULTS: Mean postpartum blood loss was 325.85+/-164.72mL in the 100 patients given misoprostol and 303.95+/-163.33mL in the 100 patients given oxytocin (P=0.391). PPH (>=500mL blood loss) was recorded in 15 (15.0%) patients given misoprostol and 14 (14.0%) given oxytocin (P=0.841). Shivering, pyrexia, and diarrhea were all significantly more common in the misoprostol group (P<0.01 for all). CONCLUSION: The efficacy of oral misoprostol was similar to that of intramuscular oxytocin. Adverse effects associated with misoprostol were transient and self-limiting. Thus, oral misoprostol is efficacious and a good alternative to oxytocin for AMTSL. Pan African Clinical Trials Registry:PACTR201407000825227. PMID- 25835643 TI - Eye Care Service Use and Its Determinants in Marginalized Communities in Pakistan: The Karachi Marine Fishing Communities Eye and General Health Survey. AB - PURPOSE: To examine gender, ethnic, and socioeconomic differences in access to eye care services in marine fishing communities in Karachi, Pakistan. METHODS: The Karachi Marine Fishing Communities Eye and General Health Survey was a door to-door, cross-sectional survey conducted between March 2009 and April 2010 in fishing communities in Keamari, Karachi, located on the coast of the Arabian Sea. Adults aged >=50 years living on three islands and in four coastal areas were enrolled. Participants underwent a detailed interview regarding sociodemographics, eye problems and eye care service use, testing of presenting and best-corrected visual acuity with a reduced logMAR chart, and detailed eye examination. RESULTS: A total of 700 people were planned to be included in the study; 638 (91.1%) were interviewed and examined. Most participants were extremely poor and had no formal education. Only 45.3% (95% confidence interval, CI, 41.4-49.2%) of participants reported having had an eye examination in the past; 12.1% (95% CI 9.5-14.6%) and 30.9% (95% CI 27.3-34.5%) had seen an eye doctor within the last year or prior 5 years, respectively. In the multivariable analysis, ethnicity was the strongest independent predictor of eye care service use, followed by self-reported eye problems and diabetes. Ethnic Bengalis were 4.2 times less likely (adjusted odds ratio 0.24, 95% CI 0.15-0.38; p < 0.001) to have had an eye examination in the past than Kutchis. CONCLUSIONS: Despite a high prevalence of visual impairment and blindness, levels of eye care examinations in fishing communities, especially among ethnic Bengalis, are disappointingly low. Such communities deserve particular attention in Vision 2020 and other national and international strategies and plans. PMID- 25835644 TI - Formation and Mechanism of Superhydrophobic/Hydrophobic Surfaces Made from Amphiphiles through Droplet-Mediated Evaporation-Induced Self-Assembly. AB - Superhydrophobic/hydrophobic surfaces have attracted wide attention because of their broad applications in various regions, including coating, textile, packaging, electronic devices, and bioengineering. Many studies have been focused on the fabrication of superhydrophobic/hydrophobic surfaces using natural materials. In this paper, superhydrophobic/hydrophobic surfaces were formed by an amphiphilic natural protein, zein, using electrospinning. Water contact angle (WCA) and scanning electron microscopy (SEM) were used to characterize the hydrophobicity and surface morphology of the electrospun structures. The highest WCA of the zein electrospun surfaces could reach 155.5 +/- 1.4 degrees . To further understand the mechanism of superhydrophobic surface formation from amphiphiles using electrospinning, a synthetic amphiphilic polymer was selected, and also, a method similar to electrospinning, spray drying, was tried. The electrospun amphiphilic polymer surface showed a high hydrophobicity with a WCA of 141.4 +/- 0.7 degrees . WCA of the spray-dried zein surface could reach 125.3 +/- 2.1 degrees . The secondary structures of the zein in the electrospun film and cast-dried film were studied using ATR-FTIR, showing that alpha-helix to beta sheet transformation happened during the solvent evaporation in the cast drying process but not in the electrospinning process. A formation mechanism was proposed on the basis of the orientation of the amphiphiles during the solvent evaporation of different fabrication methods. The droplet-based or jet-based evaporation during electrospinning and spray drying led to the formation of the superhydrophobic/hydrophobic surface by the accumulation of the hydrophobic groups of the amphiphiles on the surface, while the surface-based evaporation during cast drying led to the formation of the hydrophilic surface by the accumulation of the hydrophilic groups of the amphiphiles on the surface. PMID- 25835645 TI - Evaluation of a multiple sclerosis cluster among nurses in an inpatient oncology ward. PMID- 25835646 TI - Small-fiber neuropathy in pompe disease: first reported cases and prospective screening of a clinic cohort. AB - BACKGROUND: Prior autopsy reports demonstrate glycogen deposition in Schwann cells of the peripheral nerves in patients with infantile and late-onset Pompe disease (LOPD), but little is known about associated clinical features. CASE REPORT: Here, we report the first confirmed cases of small-fiber neuropathy (SFN) in LOPD and present the results of a first attempt at screening for SFN in this patient population. After confirming small-fiber neuropathy in 2 LOPD patients, 44 consecutive Pompe patients (iOPD=7, LOPD n=37) presenting to the Duke University Glycogen Storage Disease Program between September 2013 and November 2014 were asked to complete the 21-item Small-Fiber Neuropathy Screening List (SFNSL), where a score of >=11 is considered to be a positive screen. Fifty percent of patients had a positive SFN screen (mean score 11.6, 95% CI 9.0-14.2). A modest correlation between the SFNSL score and current age was seen (r=0.38, p=0.01), along with a correlation with duration of ERT (r=0.31, p=0.0495). Trends toward correlation with forced vital capacity and age at diagnosis were also present. Women had a higher mean SFNSL score (14.2) than men (8.2, p=0.017). CONCLUSIONS: SFN may occur in association with Pompe disease and precede the diagnosis. Further studies are needed to determine its true prevalence and impact. PMID- 25835648 TI - Spectral dispersion modeling of virtually imaged phased array by using angular spectrum of plane waves. AB - We present an analytical treatment for the relatively new spectral disperser termed virtually imaged phased array (VIPA). Angular spectrum representation of the input Gaussian beam helps us obtain an exact analytic dispersion model and a dispersion law for a general VIPA by using the principle of multiple-beam interference. The consideration of the optical aberrations caused by refractions makes our model more accurate and practical than previous models. The validity of the proposed dispersion law has been validated theoretically by comparing with previous results. Some considerations of using a VIPA are also provided. PMID- 25835647 TI - Immunomodulatory and Antileishmanial Activity of Phenylpropanoid Dimers Isolated from Nectandra leucantha. AB - Three phenylpropanoid dimers (1-3) including two new metabolites were isolated from the extract of the twigs of Nectandra leucantha using antileishmanial bioassay-guided fractionation. The in vitro antiparasitic activity of the isolated compounds against Leishmania donovani parasites and mammalian cytotoxicity and immunomodulatory effects were evaluated. Compounds 1-3 were effective against the intracellular amastigotes within macrophages, with IC50 values of 26.7, 17.8, and 101.9 MUM, respectively. The mammalian cytotoxicity, given by the 50% cytotoxic concentration (CC50), was evaluated against peritoneal macrophages. Compounds 1 and 3 were not toxic up to 290 MUM, whereas compound 2 demonstrated a CC50 value of 111.2 MUM. Compounds 1-3 also suppressed production of disease exacerbatory cytokines IL-6 and IL-10 but had minimal effect on nitric oxide production in L. donovani-infected macrophages, indicating that antileishmanial activity of these compounds is mediated via an NO-independent mechanism. Therefore, these new natural products could represent promising scaffolds for drug design studies for leishmaniasis. PMID- 25835649 TI - Joint robustness security in optical OFDM access system with Turbo-coded subcarrier rotation. AB - This paper proposes a novel robust physical secure method for optical orthogonal frequency division multiplexing (OFDM) access system based on Turbo-coded subcarrier rotation. It can realize a secure communication while keep robustness to channel noise. The subcarrier rotation is controlled by the interleaver module of Turbo coding, which is under the charge of Logistic map. The random puncturing can further enhance the security. The channel feedback can ensure the puncturing module working at a suitable coding rate. A 72.28 Gb/s encrypted 16QAM-OFDM signal is successfully demonstrated in the experiment. The results show robust performance under different channel noise conditions and good resistance to illegal optical network unit (ONU). PMID- 25835650 TI - Photo-assisted proton exchange and chemical etching on Fe-doped lithium niobate crystals. AB - We report the photo-assisted proton exchange and chemical etching on Fe-doped LiNbO(3) crystals. Selective proton exchange and chemical etching are realized through the 455nm-laser irradiation on the crystal surface in pyrophosphoric acid. Optical microscopy and Micro-IR spectroscopy analysis show that the hydrogen incorporation is confined spatially by the laser irradiation. Moreover, under the laser irradiation, + z surface is found to be more easily etched than z surface. This unexpected etching anisotropy is attributed to the photogalvanic effect of the crystal. PMID- 25835651 TI - Tunable beam shaping with a phased array acousto-optic modulator. AB - We demonstrate the generation of Bessel beams using an acousto-optic array based on a liquid filled cavity surrounded by a cylindrical multi-element ultrasound transducer array. Conversion of a Gaussian laser mode into a Bessel beam with tunable order and position is shown. Also higher-order Bessel beams up to the fourth order are successfully generated with experimental results very closely matching simulations. PMID- 25835652 TI - CDOM-DOC relationship in contrasted coastal waters: implication for DOC retrieval from ocean color remote sensing observation. AB - Increasing our knowledge on dissolved organic carbon (DOC) spatio-temporal distribution in the coastal ocean represents a crucial challenge for better understanding the role of these ecosystems in the global oceanic carbon cycle. The assessment of DOC concentration from the absorption properties of the colored part of the dissolved organic matter (a(cdom)) was investigated from an extensive data set covering a variety of coastal environments. Our results confirmed that variation in the a(cdom)(412) to DOC ratio (a*(cdom)(412)) can be depicted from the CDOM spectral slope in the UV domain (S(275-295)). They also evidenced that regional first order variation in both a*(cdom)(412) and S(275-295) are highly correlated to variation in a(cdom)(412). From these observations, generalized relationships for estimating a*(cdom)(412) from S(275-295) or a(cdom)(412) were parameterized from our development sites (N = 158; English Channel, French Guiana, Hai Phong Bay) and tested against an independent data set covering others coastal regions (N = 223; French Polynesia, Rhone River estuary, Gulf of Maine, Chesapeake Bay, Southern Middle Atlantic Bight) demonstrating the possibility to derive DOC estimates from in situ CDOM optical properties with an average accuracy of ~16% over very contrasted coastal environments (with DOC ranging from 50 to 250 umol.L(-1)). The applicability of these generalized approaches was evaluated in the context of ocean color remote sensing observation emphasizing the limits of S(275-295)-based formulations and the potential for a(cdom)-based approaches to represent a compelling alternative for assessing synoptic DOC distribution. PMID- 25835653 TI - Nonlinear interaction in differential mode delay managed mode-division multiplexed transmission systems. AB - We analyze the impact of Differential Mode Delay (DMD) Management on the nonlinear impairments in mode-division multiplexed transmission systems. It is found out that DMD Management can lead to a degraded performance, due to enhanced intermodal nonlinear interaction. This can be attributed to an increased correlation of co-propagating channels, similar to the effects that show up in dispersion managed single-mode systems. PMID- 25835654 TI - Femtosecond laser-induced periodic surface structures on silicon upon polarization controlled two-color double-pulse irradiation. AB - Two-color double-fs-pulse experiments were performed on silicon wafers to study the temporally distributed energy deposition in the formation of laser-induced periodic surface structures (LIPSS). A Mach-Zehnder interferometer generated parallel or cross-polarized double-pulse sequences at 400 and 800 nm wavelength, with inter-pulse delays up to a few picoseconds between the sub-ablation 50-fs pulses. Multiple two-color double-pulse sequences were collinearly focused by a spherical mirror to the sample. The resulting LIPSS characteristics (periods, areas) were analyzed by scanning electron microscopy. A wavelength-dependent plasmonic mechanism is proposed to explain the delay-dependence of the LIPSS. These two-color experiments extend previous single-color studies and prove the importance of the ultrafast energy deposition for LIPSS formation. PMID- 25835655 TI - Electro-optical 1 x 2, 1 x N and N x N fiber-optic and free-space switching over 1.55 to 3.0 MUm using a Ge-Ge(2)Sb(2)Te(5)-Ge prism structure. AB - New device designs are proposed and theoretical simulations are performed on electro-optical routing switches in which light beams enter and exit the device either from free space or from lensed fibers. The active medium is a ~100 nm layer of phase change material (Ge(2)Sb(2)Te(5) or GeTe) that is electrically "triggered" to change its phase, giving "self-holding" behavior in each of two phases. Electrical current is supplied to that film by a pair of transparent highly doped conducting Ge prisms on both sides of the layer. For S-polarized light incident at ~80 degrees on the film, a three-layer Fabry-Perot analysis, including dielectric loss, predicts good 1 x 2 and 2 x 2 switch performance at infrared wavelengths of 1.55, 2.1 and 3.0 MUm, although the performance at 1.55 MUm is degraded by material loss and prism mismatch. Proposals for in-plane and volumetric 1 x 4 and 4 x 4 switches are also presented. An unpolarized 1 x 2 switch projects good performance at mid infrared. PMID- 25835656 TI - On the anisotropy of stress-distribution induced in glasses and crystals by non ablative femtosecond laser exposure. AB - Femtosecond laser exposure in the non-ablative regime induces a variety of bulk structural modifications, in which anisotropy may depend on the polarization of the writing beam. In this work, we investigate the correlation between polarization state and stress anisotropy. In particular, we introduce a methodology that allows for rapid analysis and visualization of laser-induced stress anisotropy in glasses and crystals. Using radial and azimuthal polarization, we also demonstrate stress states that are nearly isotropic. PMID- 25835657 TI - Spectral broadband anastigmatic Wadsworth imaging spectrometer. AB - A new advanced optical design based on the Wadsworth mounting for a broadband stigmatic, coma-free practical spectrometer with high imaging quality is presented. By the addition of an inclined cylindrical lens with a wedge angle, the stigmatic imaging conditions in a broad waveband have been obtained by our analysis. An example which presents excellent optical performances over a spectral broadband of 380nm centered at 570nm has been designed to certify the analysis. PMID- 25835658 TI - Microfluidic tunable inkjet-printed metamaterial absorber on paper. AB - In this paper, we propose a novel microfluidic tunable metamaterial (MM) absorber printed on a paper substrate in silver nanoparticle ink. The metamaterial is designed using a periodic array consisting of square patches. The conductive patterns are inkjet-printed on paper using silver nanoparticle inks. The microfluidic channels are laser-etched on polymethyl methacrylate (PMMA). The conductive patterns on paper and the microfluidic channels on PMMA are bonded by an SU-8 layer that is also inkjet-printed on the conductive patterns. The proposed MM absorber provides frequency-tuning capability for different fluids in the microfluidic channels. We performed full-wave simulations and measurements that confirmed that the resonant frequency decreased from 4.42 GHz to 3.97 GHz after the injection of distilled water into the microfluidic channels. For both empty and water-filled channels, the absorptivity is higher than 90% at horizontal and vertical polarizations. PMID- 25835659 TI - Fabrication of 3D photonic components on bulk crystalline silicon. AB - We have fabricated three dimensional photonic components such as waveguides and beam splitters from crystalline silicon using a process based on one or more ion irradiation steps with different energies and fluences, followed by electrochemical anodization and thermal annealing. We first demonstrate the fabrication of multilevel silicon waveguides and then extend this process to make multilevel beam splitters, in which three output waveguides are distributed over two depths. The dimensions of the waveguides can be defined within a range from 0.5 MUm to several micrometers simply by varying the ion beam fluence. PMID- 25835660 TI - Orthogonal and parallel lattice plasmon resonance in core-shell SiO(2)/Au nanocylinder arrays. AB - Height induced coupling behavior between the plasmonic modes and diffraction orders were studied in the core-shell SiO(2)/Au nanocylinder arrays (NCAs) using finite difference time domain (FDTD) simulations. New lattice plasmon modes (LPMs) are observed in the structures with high aspect ratio. Specifically, parallel coupling between the plasmonic modes and diffraction orders is obtained here, which shows different coupling behavior from orthogonal LPMs. Electromagnetic (EM) field distributions indicate that horizontal propagation of the magnetic or electric field component is responsible for the generation of these orthogonal and parallel LPMs, respectively. Radiative loss could be effectively suppressed when the height increases. This is important for the applications of fluorescence enhancement and nano laser. Further studies confirm that the LPMs associated with the superstrate diffraction orders could be well maintained even when the Au coating is imperfect. The interference from the substrate associated LPMs could be eliminated by cutting off the corresponding diffraction waves by inducing a Si(3)N(4) substrate. This study of coupling behavior in the core-shell NCAs enables a novel route to design and optimize the LPMs for applications of bio-sensing and nano laser. PMID- 25835661 TI - Soliton's eigenvalue based analysis on the generation mechanism of rogue wave phenomenon in optical fibers exhibiting weak third order dispersion. AB - One of the extraordinary aspects of nonlinear wave evolution which has been observed as the spontaneous occurrence of astonishing and statistically extraordinary amplitude wave is called rogue wave. We show that the eigenvalues of the associated equation of nonlinear Schrodinger equation are almost constant in the vicinity of rogue wave and we validate that optical rogue waves are formed by the collision between quasi-solitons in anomalous dispersion fiber exhibiting weak third order dispersion. PMID- 25835662 TI - A 2.95 GHz, femtosecond passive harmonic mode-locked fiber laser based on evanescent field interaction with topological insulator film. AB - By utilizing the pulsed laser deposition (PLD) method, we fabricated a kind of microfiber-based topological insulator (TI) saturable absorber (SA) which has inherent merits of effective and robust properties. We also proposed a newly explanation for the impact of nonlinear effect of SA on the harmonic mode-locking (HML) behavior. Upon employing on the SA, we achieved stable fundamental mode locking (FML) at central wavelength of 1562.4 nm with pulse duration as short as 320 fs. By adjusting the intracavity polarization state at maximum pump power of 395 mW, we obtained stable femtosecond harmonic soliton pulse generation with repetition rate of 2.95 GHz and output power of 45.3 mW. Our results demonstrated that the microfiber-based TI PLD film SA is a promising device for practical multi-GHz ultrashort pulses generation. PMID- 25835663 TI - Spontaneous formation of 10-MUm-scale periodic patterns in transverse-scanning femtosecond laser processing. AB - We report spontaneous formation of 10-MUm-scale periodic patterns in transverse scanning femtosecond (fs) laser processing inside a glass substrate. The formation of the periodic patterns was critically dependent on the distance of the focus from the back surface; they formed only when fs pulses were focused slightly inside (~ a few micrometers) from the back surface. The periods ranged from 7 to 16 MUm, which is much longer than the distance between neighboring irradiation spots (0.1-1 MUm in the present experiments), the diameter of the individual modified spots (about 2 MUm), and the wavelength (0.8 MUm). The patterns formed without any intentional modulation; just by scanning the sample at a constant speed during irradiation of fs laser pulses. The dependence on scanning speed and repetition rate of the laser were also investigated, and a possible formation scenario for this "long" periodic pattern was described. PMID- 25835664 TI - Seamless full color holographic printing method based on spatial partitioning of SLM. AB - The holographic wavefront printer decodes the wavefront coming from a three dimensional object from a computer generated hologram displayed on a spatial light modulator. By recording this wavefront as an analog volume hologram this printing method is highly suitable for realistic color 3D imaging. We propose in the paper spatial partitioning of the spatial light modulator to perform mosaic delivery of exposures at primary colors for seamless reconstruction of a white light viewable color hologram. The method is verified for a 3 * 3 color partitioning scheme by a wavefront printer with demagnification of the light beam diffracted from the modulator. PMID- 25835665 TI - Selective mode multiplexer based on phase plates and Mach-Zehnder interferometer with image inversion function. AB - We propose a novel mode multiplexer based on phase plates followed by a Mach Zehnder interferometer (MZI) with image inversion. After the higher-order modes are selectively converted from fundamental linear-polarized (LP) modes by the phase plates, the converted modes are coupled without fundamental loss using MZI with image inversion, in which the original spatial pattern and inverted pattern of the optical signal are interfered. Our scheme is also applicable to the coupling of degenerated LP modes such as LP(11a) and LP(11b). First, we numerically and experimentally evaluate the performance of the mode converter based on phase plates. The mode converter is suitable as long as the five LP modes such as LP(01), LP(11ab) and LP(21ab) are sustained in a few-mode fiber (FMF), although the crosstalk due to excitation of undesirable modes is unavoidable when the higher-order modes over LP(02) are sustained in FMF. Next, we develop and characterize the proposed mode multiplexers based on phase plates and MZIs with image inversion. The insertion loss is suppressed to around 3 dB for mode multiplexing of LP(11a) and LP(11b). Using a fabricated mode multiplexer for LP(31a) and LP(31b), we measure the bit-error rate performance of single polarization mode-multiplexed quadrature-phase shift keying optical signals. PMID- 25835666 TI - Single mode operation with mid-IR hollow fibers in the range 5.1-10.5 um. AB - Single mode beam delivery in the mid-infrared spectral range 5.1-10.5 MUm employing flexible hollow glass waveguides of 15 cm and 50 cm lengths, with metallic/dielectric internal layers and a bore diameter of 200 MUm were demonstrated. Three quantum cascade lasers were coupled with the hollow core fibers. For a fiber length of 15 cm, we measured losses down to 1.55 dB at 5.4 MUm and 0.9 dB at 10.5 MUm. The influence of the launch conditions in the fiber on the propagation losses and on the beam profile at the waveguide exit was analyzed. At 10.5 um laser wavelength we found near perfect agreement between measured and theoretical losses, while at ~5 um and ~6 um wavelengths the losses were higher than expected. This discrepancy can be explained considering an additional scattering loss effect, which scales as 1/lambda(2) and is due to surface roughness of the metallic layer used to form the high-reflective internal layer structure of the hollow core waveguide. PMID- 25835667 TI - Harmonic mode locking of bound-state solitons fiber laser based on MoS(2) saturable absorber. AB - We present a kind of harmonic mode locking of bound-state solitons in a fiber laser based on molybdenum disulfide (MoS(2)) saturable absorber (SA). The mode locker is fabricated by depositing MoS(2) nanosheets on a D-shaped fiber (DF). In the fiber laser, two solitons form the bound-state pulses with a temporal separation of 3.4 ps, and the bound-state pulses are equally distributed at a repetition rate of 125 MHz, corresponding to 14th harmonics of fundamental cavity repetition rate (8.968 MHz). Single- and multiple-pulses emissions are also observed by changing the pump power and optimizing the DF based MoS(2) SA. Our experiment demonstrates an interesting operation regime of mode-locked fiber laser, and shows that DF based MoS(2) SA can work as a promising high-power mode locker in ultrafast lasers. PMID- 25835668 TI - 2000-fold parallelized dual-color STED fluorescence nanoscopy. AB - Stimulated Emission Depletion (STED) nanoscopy enables multi-color fluorescence imaging at the nanometer scale. Its typical single-point scanning implementation can lead to long acquisition times. In order to unleash the full spatiotemporal resolution potential of STED nanoscopy, parallelized scanning is mandatory. Here we present a dual-color STED nanoscope utilizing two orthogonally crossed standing light waves as a fluorescence switch-off pattern, and providing a resolving power down to 30 nm. We demonstrate the imaging capabilities in a biological context for immunostained vimentin fibers in a circular field of view of 20 um diameter at 2000-fold parallelization (i.e. 2000 "intensity minima"). The technical feasibility of massively parallelizing STED without significant compromises in resolution heralds video-rate STED nanoscopy of large fields of view, pending the availability of suitable high-speed detectors. PMID- 25835669 TI - All-fiber mode-group-selective photonic lantern using graded-index multimode fibers. AB - We demonstrate the first all-fiber mode-group-selective photonic lantern using multimode graded-index fibers. Mode selectivity for mode groups LP(01), LP(11) and LP(21)+LP(02) is 20-dB, 10-dB and 7-dB respectively. The insertion loss when butt coupled to multimode graded-index fiber is below 0.6-dB. The use of the multimode graded-index fibers in the taper can significantly reduce the adiabaticity requirement. PMID- 25835670 TI - Mode-multiplexed transmission over conventional graded-index multimode fibers. AB - We present experimental results for combined mode-multiplexed and wavelength multiplexed transmission over conventional graded-index multimode fibers. We use mode-selective photonic lanterns as mode couplers to precisely excite a subset of the modes of the multimode fiber and additionally to compensate for the differential group delay between the excited modes. Spatial mode filters are added to suppress undesired higher order modes. We transmit 30-Gbaud QPSK signals over 60 WDM channels, 3 spatial modes, and 2 polarizations, reaching a distance of 310 km based on a 44.3 km long span. We also report about transmission experiments over 6 spatial modes for a 17-km single-span experiment. The results indicate that multimode fibers support scalable mode-division multiplexing approaches, where modes can be added over time if desired. Also the results indicate that mode-multiplexed transmission distance over 300 km are possible in conventional multimode fibers. PMID- 25835671 TI - Actio et reactio in optical binding. AB - The symmetry in action and reaction between interacting particulate matter breaks down when the interaction is mediated by an out-of-equilibrium environment. Nevertheless, even in this case, the space translational invariance still imposes the conservation of canonical momentum. Here we show that optical binding of an asymmetric material system can result in non-reciprocal interactions between constituents. We demonstrate that a non-conservative force applies to the center of mass of an optically bound dimer of dissimilar particles, which leads to an unexpected action in the transversal direction. The sign and the magnitude of this positional force depend on the abrupt phase transitions in the properties of the asymmetric dimer. PMID- 25835672 TI - Study on the crucial conditions for efficient third harmonic generation using a metal-hybrid-metal plasmonic slot waveguide. AB - We provide a comprehensive study on the efficient third harmonic generation (THG) in a lossy metal-hybrid-metal asymmetric plasmonic slot waveguide (MHM) to develop a method for efficient THG by focusing on the modal phase-matching condition (PMC), the third-order nonlinear susceptibility of the nonlinear interactive material, and the pump-harmonic modal overlap in conjunction with reasonable linear propagation loss. In addition to the PMC and the nonlinear material, the stimulated THG process can be greatly enhanced by the large pump harmonic modal overlap. With 1 W pump power, simulation results present that THG conversion efficiency up to 2.79 * 10(-4) within 4.5 ????m MHM can be achieved. PMID- 25835673 TI - Arbitrary GRIN component fabrication in optically driven diffusive photopolymers. AB - We introduce a maskless lithography tool and optically-initiated diffusive photopolymer that enable arbitrary two-dimensional gradient index (GRIN) polymer lens profiles. The lithography tool uses a pulse-width modulated deformable mirror device (DMD) to control the 8-bit gray-scale intensity pattern on the material. The custom polymer responds with a self-developing refractive index profile that is non-linear with optical dose. We show that this nonlinear material response can be corrected with pre-compensation of the intensity pattern to yield high fidelity, optically induced index profiles. The process is demonstrated with quadratic, millimeter aperture GRIN lenses, Zernike polynomials and GRIN Fresnel lenses. PMID- 25835674 TI - Terahertz waveguiding between parallel dielectric films. AB - We report a study of terahertz waveguiding between parallel dielectric films, a system that can be viewed as a planar analogue of hollow core fibres that exploit anti-resonant reflection optical waveguiding (ARROW). With the aid of time domain waveguide mode imaging, the frequency dependent transition from ARROW to total internal reflection guiding in the individual films as the film separation is reduced and the effect on the transmission of adding variably spaced cladding layers are clearly revealed. Good agreement for the transmission, dispersion and loss is obtained with simple analytical models for film separations greater than about five wavelengths suggesting that the same models could be usefully used to predict the behavior in the case of the technologically more important cylindrical geometry. PMID- 25835675 TI - Compactly packaged monolithic four-wavelength VCSEL array with 100-GHz wavelength spacing for future-proof mobile fronthaul transport. AB - We report a cost-effective transmitter optical sub-assembly using a monolithic four-wavelength vertical-cavity surface-emitting laser (VCSEL) array with 100-GHz wavelength spacing for future-proof mobile fronthaul transport using the data rate of common public radio interface option 6. The wavelength spacing is achieved using selectively etched cavity control layers and fine current adjustment. The differences in operating current and output power for maintaining the wavelength spacing of four VCSELs are <1.4 mA and <1 dB, respectively. Stable operation performance without mode hopping is observed, and error-free transmission under direct modulation is demonstrated over a 20-km single-mode fiber without any dispersion-compensation techniques. PMID- 25835676 TI - Vertical plasmonic resonance coupler. AB - Efficient wavelength-selective coupling of lights between sub-wavelength plasmonic waveguides and free space is theoretically investigated. The idea is based on a new type of vertical resonance coupling devices built on plasmonic metal/insulator/metal (MIM) waveguides. The device structure consists of a vertical grating coupler in a resonance cavity formed by two distributed Bragg reflectors (DBRs). With the metal loss included, maximum coupling efficiency around 50% can be obtained at the 1550 nm wavelength with a filtering 3 dB bandwidth around 20 nm (7 nm for the lossless case), demonstrating the feasibility of the idea for achieving high efficiency wavelength-selective vertical coupling through optical resonance. By utilizing this coupler, a plasmonic add-drop device is proposed and theoretically demonstrated. This kind of compact wavelength selective coupling devices shall have the potential to open up a new avenue of photonics circuitry at nanoscale. PMID- 25835677 TI - Neutron guide optimisation for a time-of-flight neutron imaging instrument at the European Spallation Source. AB - A neutron transport system for the planned imaging instrument ODIN at the future European Spallation Source (ESS) based on neutron optical components was designed and optimized. Different ways of prompt pulse suppression were studied. The spectral performance of the optimal neutron guide configuration is presented. In addition, the influence of the gaps in the guide system needed for the required chopper configuration was investigated. Given that the requirements for an imaging instrument located on a long guide system and hosting a complex chopper system are extremely demanding in terms of spectral and divergence needs, this study can be beneficial for a wide range of instruments in various ways. PMID- 25835678 TI - MicroStructure Element Method (MSEM): viscous flow model for the virtual draw of microstructured optical fibers. AB - We propose a new method to accurately model the structural evolution of a microstructured fiber (MOF) during its drawing process, given its initial preform structure and draw conditions. The method, applicable to a broad range of MOFs with high air-filling fraction and thin glass membranes, is an extension of the Discrete Element Method; it determines forces on the nodes in the microstructure to progressively update their position along the neck-down region, until the fiber reaches a final frozen state. The model is validated through simulation of 6 Hollow Core Photonic Band Gap Fibers (HC-PBGFs) and is shown to predict accurately the final fiber dimensions and cross-sectional distortions. The model is vastly more capable than other state of the art models and allows fast exploration of wide drawing parameter spaces, eliminating the need for expensive and time-consuming empirical parameter scans. PMID- 25835679 TI - Geometrical optics in the near field: local plane-interface approach with evanescent waves. AB - We show that geometrical models may provide useful information on light propagation in wavelength-scale structures even if evanescent fields are present. We apply a so-called local plane-wave and local plane-interface methods to study a geometry that resembles a scanning near-field microscope. We show that fair agreement between the geometrical approach and rigorous electromagnetic theory can be achieved in the case where evanescent waves are required to predict any transmission through the structure. PMID- 25835680 TI - All-fiber multiwavelength thulium-doped laser assisted by four-wave mixing in highly germania-doped fiber. AB - An all-fiber multiwavelength Tm-doped laser assisted by four-wave mixing (FWM) in highly Germania-doped highly nonlinear fiber (HG-HNLF) has been experimentally demonstrated. Benefiting from the high nonlinearity of the HG-HNLF, intensity dependent gain caused by FWM is introduced into the laser cavity to mitigate the gain competition in Tm-doped fiber. Thanks to a 50-m HG-HNLF, 9, 22, and 36 lasing lines with considering 10-dB, 20-dB, and 30-dB bandwidth, respectively is obtained at room temperature with wavelength spacing of 0.86 nm. More than 30-nm broad-band lasing can be obtained. The stability of the proposed fiber laser has also been studied. Repeat measurements show the power fluctuations and wavelength drifts of the lasing lines are less than 1.6 dB and 0.05 nm, respectively. The laser performances without the assistance of HG-HNLF have fewer center wavelengths lasing, which indicates that FWM in HG-HNLF plays an important role for the multiwavelength laser operation. PMID- 25835681 TI - Watch-hand-like optical rogue waves in three-wave interactions. AB - We investigate the resonant interaction of three optical pulses of different group velocity in quadratic media and report on the novel watch-hand-like super rogue wave patterns. In addition to having a giant wall-like hump, each rogue wave hand involves a peak amplitude more than five times its background height. We attribute such peculiar structures to the nonlinear superposition of six Peregrine-type solitons. The robustness has been confirmed by numerical simulations. This stability along with the non-overlapping distribution property may facilitate the experimental diagnostics and observation of these super rogue waves. PMID- 25835682 TI - Active resonance wavelength stabilization for silicon microring resonators with an in-resonator defect-state-absorption-based photodetector. AB - We propose and demonstrate active resonance wavelength stabilization for silicon microring resonators with an in-resonator defect-state-absorption (DSA)-based photodetector (PD) for optical interconnects. We integrate an electro-optic (EO) tuner and a thermo-optic (TO) tuner on the microring, which are both feedback controlled following a photocurrent threshold-detection method. Our BF(2)-ion implanted DSA-based PIN PD exhibits a cavity-enhanced sub-bandgap responsivity at 1550 nm of 3.3 mA/W upon -2 V, which is 550-fold higher than that exhibited by an unimplanted PIN diode integrated on the same microring. Our experiment reveals active stabilization of the resonance wavelength within a tolerance of 0.07 nm upon a step increment of the stage temperature by 7 degrees C. Upon temperature modulations between 23 degrees C and 32 degrees C and between 18 degrees C and 23 degrees C, the actively stabilized resonance exhibits a transmission power fluctuation within 2 dB. We observe open eye diagrams at a data transmission rate of up to 30 Gb/s under the temperature modulations. PMID- 25835683 TI - Robust and tunable 16.375Gb/s dual-band optical OFDM transmissions over directly modulated VCSEL-based 200m OM2 MMFs. AB - Utilizing low-cost, 2.2GHz modulation bandwidth, uncooled and standalone directly modulated VCSEL (DM-VCSEL)-based real-time dual-band optical OFDM (OOFDM) transmitters, aggregated 16.375Gb/s transmissions of OOFDM signals having bandwidths approximately 3.8 times higher than the VCSEL manufacturer-specified modulation bandwidths, are experimentally demonstrated, for the first time, over 200m OM2 MMF links based on intensity modulation and direct detection. The aggregated signal transmission capacities of the aforementioned links vary by just 8% for various OM2 MMFs ranging from 100m to 500m, and by just 10% over a 1GHz passband carrier frequency detuning range. Such dual-band OOFDM adaptability induced excellent performance robustness and large passband frequency tunability can significantly relax the requirements on VCSEL modulation bandwidth for achieving specific transmission performances for cost-sensitive application scenarios such as data centers. PMID- 25835684 TI - Flexible dynamic measurement method of three-dimensional surface profilometry based on multiple vision sensors. AB - Single vision sensor cannot measure an entire object because of their limited field of view. Meanwhile, multiple rigidly-fixed vision sensors for the dynamic vision measurement of three-dimensional (3D) surface profilometry are complex and sensitive to strong environmental vibrations. To overcome these problems, a novel flexible dynamic measurement method for 3D surface profilometry based on multiple vision sensors is presented in this paper. A raster binocular stereo vision sensor is combined with a wide-field camera to produce a 3D optical probe. Multiple 3D optical probes are arranged around the object being measured, then many planar targets are set up. These planar targets function as the mediator to integrate the local 3D data measured by the raster binocular stereo vision sensors into the coordinate system. The proposed method is not sensitive to strong environmental vibrations, and the positions of these 3D optical probes need not be rigidly-fixed during the measurement. The validity of the proposed method is verified in a physical experiment with two 3D optical probes. When the measuring range of raster binocular stereo vision sensor is about 0.5 m * 0.38 m * 0.4 m and the size of the measured object is about 0.7 m, the accuracy of the proposed method could reach 0.12 mm. Meanwhile, the effectiveness of the proposed method in dynamic measurement is confirmed by measuring the rotating fan blades. PMID- 25835685 TI - Far-field imaging beyond diffraction limit using single sensor in combination with a resonant aperture. AB - Far-field imaging beyond the diffraction limit is a long sought-after goal in various imaging applications, which requires usually mechanical scanning or an array of antennas. Here, we propose to solve this challenging problem using a single sensor in combination with a spatio-temporal resonant aperture antenna. We theoretically and numerically demonstrate that such resonant aperture antenna is capable of converting part evanescent waves into propagating waves and delivering them to far fields. The proposed imaging concept provides the unique ability to achieve super resolution for real-time data when illuminated by broadband electromagnetic waves, without the harsh requirements such as near- field scanning, mechanical scanning, or antenna arrays. We expect the imaging methodology to make breakthroughs in super-resolution imaging in microwave, terahertz, optical, and ultrasound regimes. PMID- 25835686 TI - Adjustable diffractive spiral phase plates. AB - We report on the fabrication and the experimental demonstration of Moire diffractive spiral phase plates with adjustable helical charge. The proposed optical unit consists of two axially stacked diffractive elements of conjugate structure. The joint transmission function of the compound system corresponds to that of a spiral phase plate where the angle of mutual rotation about the central axis enables continuous adjustment of the helical charge. The diffractive elements are fabricated by gray-scale photolithography with a pixel size of 200 nm and 128 phase step levels in fused silica. We experimentally demonstrate the conversion of a TEM(00) beam into approximated Laguerre-Gauss (LG) beams of variable helical charge, with a correspondingly variable radius of their ring shaped intensity distribution. PMID- 25835687 TI - Laser forward transfer using structured light. AB - A digital micromirror device (DMD) is used to spatially structure a 532 nm laser beam to print features spatially congruent to the laser spot in a laser-induced forward transfer (LIFT) process known as laser decal transfer (LDT). The DMD is a binary (on/off) spatial light modulator and its resolution, half-toning and beam shaping properties are studied using LDT of silver nanopaste layers. Edge enhanced "checkerboard" beam profiles led to a ~30% decrease in the laser transfer fluence threshold (compared to a reference "checkerboard" profile) for a 20-pixel bitmap pattern and its resulting 10-MUm square feature. PMID- 25835688 TI - Improving the quality of filament-impaired images in Kerr media by statistical averaging. AB - In focusing Kerr media, small-scale filamentation is the major obstacle to imaging at high light intensities. In this article, we experimentally and numerically demonstrate a method based on statistical averaging to reduce the detrimental effects of filamentation on the reconstructed images. The experiments are performed with femtosecond optical pulses propagating through a nonlinear liquid (toluene). We use digital holography to capture the transmitted optical image. The reverse propagation of the captured field is numerically performed using a numerical solution of the nonlinear Schrodinger equation. Because of their intrinsic sensitivity to measurement noise, filaments fail to propagate back on their initial trajectories and parasitic filaments form. The principle of the method is the introduction of artificial perturbations on the measurement, which spatially displace the parasitic filaments. By averaging the reconstruction over many realizations of the artificial perturbation, we show that the reconstruction improves the quality of the images. Finally, in order to identify the different regimes of optical power for which the filaments are time reversible, we also derive an analytical estimate for the condition number of the nonlinear propagator. PMID- 25835689 TI - Modeling vanadium dioxide phase transition due to continuous-wave optical signals. AB - Vanadium dioxide (VO(2)) is a material that undergoes thermal phase transition resulting in drastic changes in its material properties. The phase change can also be brought on by optical pumping. Several experimental results have been presented in the literature dealing with such phase transitions brought on by optical pumping. In this manuscript we present a theoretical framework, which addresses this problem by self consistently solving the electromagnetic problem and the thermodynamic problem using a multiphysics approach when such transitions are thermally mediated, as is the case with continuous-wave optical pumps. Such an analysis provides us with insights into the transition process and also helps explain the conditions under which some of the observed experimental results like bistability takes place. Such optically induced phase transition materials also present the intriguing possibility of ultrahigh nonlinearity where the input optical signal essentially converts a dielectric into a plasmonic material. These materials can find significant applications in nonlinear metatronics. PMID- 25835690 TI - Observation of grating regeneration by direct CO(2) laser annealing. AB - In this work, we have demonstrated for the first time grating regeneration in hydrogenated fibers by direct CO(2) laser annealing. During the annealing process, the center wavelength redshifts as the intensity of the focused CO(2) laser on the grating is elevated. The reflectivity of the grating begins to decay as the temperature induced in the grating approaches the erasure temperature. The grating is completely erased and regenerated afterwards. The observed spectral results have provided the proof of occurrence of dehydroxylation and stress relaxation in the fiber core during the annealing process. Regenerated gratings with low loss, good temperature sensitivities and sustainability have been successfully developed by this technique. PMID- 25835691 TI - Residual vibration reduction of white-light scanning interferometry by input shaping. AB - White-light scanning interferometry is widely used for precision metrology of engineering surfaces. It needs a mechanical scanning for capturing an interferogram that determines where the surface of a measured sample is located. The residual vibration during the scanning procedure distorts the interferogram and it reduces the accuracy and the precision of the system. The residual vibration becomes bigger as the proportional gain gets higher for the fast response. So it is hard to achieve the fast and precise measurement simultaneously. In this study, input shaping which convolves a reference signal with the input shaper is investigated to reduce the residual vibration of the scanning system. The step response data is analyzed using Continuous Wavelet Transform (CWT) to design the input shaper. Using proposed method, the residual vibration of the white light scanning interferometry is reduced and it achieved both faster measurement speed and more accurate measurement. PMID- 25835692 TI - Ultra-broadband wavelength-swept Tm-doped fiber laser using wavelength-combined gain stages. AB - A wavelength-swept thulium-doped fiber laser system employing two parallel cavities with two different fiber gain stages is reported. The fiber gain stages were tailored to provide emission in complementary bands with external wavelength dependent feedback cavities sharing a common rotating polygon mirror for wavelength scanning. The wavelength-swept laser outputs from the fiber gain elements were spectrally combined by means of a dichroic mirror and yielded over 500 mW of output with a scanning range from ~1740 nm to ~2070 nm for a scanning frequency of ~340 Hz. PMID- 25835693 TI - Micro optical diffusion sensor using a comb-driven micro Fresnel mirror. AB - We have developed a novel micro optical diffusion sensor (MODS) with a newly proposed comb-driven-micro Fresnel mirror (CD-MFM) scanner to detect structural changes in biological samples. By controlling the fringe spacing of the excitation laser beam, we can tune the decay time to obtain quick and precise measurements. In this study, the pre-tilted mirror is rotated by vertical comb driven actuators; the resulting change in the mirror angle alters the fringe spacing. The validity of the proposed mirror scanner is confirmed in simulations and in an experiment using a fabricated prototype device. PMID- 25835694 TI - Nonlinear Photonics 2014: introduction. AB - International Conference "Nonlinear Photonics-2014" took place in Barcelona, Spain on July 27-31, 2014. It was a part of the "Advanced Photonics Congress" which is becoming a traditional notable event in the world of photonics. The current focus issue of Optics Express contains contributions from the participants of the Conference and the Congress. The articles in this focus issue by no means represent the total number of the congress contributions (around 400). However, it demonstrates wide range of topics covered at the event. The next conference of this series is to be held in 2016 in Australia, which is the home of many researchers working in the field of photonics in general and nonlinear photonics in particular. PMID- 25835695 TI - Advanced modulation formats for 400-Gbps short-reach optical inter-connection. AB - Besides the long-haul optical networks covering over thousands of kilometers for backbone transmission, short reach optical networks (SR-ONs) are widely deployed in metro-area for aggregation and accessing. The SR-ONs include the metro optical transport networks (Metro-OTN), optical access networks or other optical inter connection systems with even shorter distance. As predicted, the growing bandwidth demanding from SR-ONs will be much more than that from the long-haul optical networks in the near future. Besides, there are tremendous amounts of optical terminals and end-users in SR-ONs compared with the long-haul transmission systems and thus will induce large cost and huge energy consumption. So, the power and cost efficiency should be the key consideration for SR-ONs besides the transmission performance. To improve the power and cost efficiency in SR-ONs, advanced modulations and detection techniques based on low power, low cost and integrated optical modulators should be utilized. In this paper, different advanced modulation formats have been discussed. 56Gbps PAM4, 112Gbps poly-binary and 100Gbps DMT that can be used to realize 400-Gbps SR-ONs for different applications have also been demonstrated respectively. In addition, low cost and low-power opto-electronic components suitable for SR-ONs, the impairments induced by all kinds of defects and bandwidth limitation of opto electronic components and the corresponding compensation techniques based on DSP algorithms have also been discussed in the experiments. PMID- 25835696 TI - Towards low timing phase noise operation in fiber lasers mode locked by graphene oxide and carbon nanotubes at 1.5 um. AB - We investigate the timing phase noise of fiber lasers mode locked by graphene oxide (GO) and carbon nanotubes (CNTs), respectively, integrated in a linear cavity fiber laser in the reflecting operation. Due to the shorter decay time of the GO and CNTs, weaker slow saturable absorber effects are expected and mode locked lasers based on these two saturable absorbers exhibit low excess timing phase noise coupled from the laser intensity noise. Compared with a reference laser mode locked by semiconductor saturable absorber mirror (SESAM), GO based laser obtains a timing phase noise reduction of 7 dB at 1 kHz and a timing jitter reduction of 45% experimentally whereas CNTs based laser obtains a timing phase noise reduction of 3 dB and a timing jitter reduction of 29%. This finding suggests that saturable absorbers with short decay time have the potential for achieving mode locking operation with low timing phase noise, which is important for applications including frequency metrology, high-precision optical sampling, clock distribution and optical sensing. PMID- 25835697 TI - Optical pulse compression reflectometry: proposal and proof-of-concept experiment. AB - This paper proposes a novel reflectometry based on the frequency modulation pulse compression technology, called optical pulse compression reflectometry (OPCR). Linear frequency modulation (LFM) pulse is taken as an example to implement the OPCR. Its working principle and theoretical analysis are demonstrated. The spatial resolution is determined by the sweeping range of the LFM rather than the pulse width, which overcomes the tradeoff between spatial resolution and measurement range in the conventional pulse-based optical time domain reflectometry. The influence of the laser's phase noise on the integrated side lobe ratio and peak side lobe ratio is theoretically studied. Thanks to the continuous acquisition nature of the OPCR, time averaging is valid to eliminate the influence and results in the measurement range of the OPCR beyond a few times of the source coherent length. A proof-of-concept experiment of the OPCR is carried out to verify the spatial resolution and measurement range. PMID- 25835698 TI - Quantitative imaging using high-energy X-ray phase-contrast CT with a 70 kVp polychromatic X-ray spectrum. AB - Imaging of large and dense objects with grating-based X-ray phase-contrast computed tomography requires high X-ray photon energy and large fields of view. It has become increasingly possible due to the improvements in the grating manufacturing processes. Using a high-energy X-ray phase-contrast CT setup with a large (10 cm in diameter) analyzer grating and operated at an acceleration tube voltage of 70 kVp, we investigate the complementarity of both attenuation and phase contrast modalities with materials of various atomic numbers (Z). We confirm experimentally that for low-Z materials, phase contrast yields no additional information content over attenuation images, yet it provides increased contrast-to-noise ratios (CNRs). The complementarity of both signals can be seen again with increasing Z of the materials and a more comprehensive material characterization is thus possible. Imaging of a part of a human cervical spine with intervertebral discs surrounded by bones and various soft tissue types showcases the benefit of high-energy X-ray phase-contrast system. Phase-contrast reconstruction reveals the internal structure of the discs and makes the boundary between the disc annulus and nucleus pulposus visible. Despite the fact that it still remains challenging to develop a high-energy grating interferometer with a broad polychromatic source with satisfactory optical performance, improved image quality for phase contrast as compared to attenuation contrast can be obtained and new exciting applications foreseen. PMID- 25835699 TI - Speckle-free femtosecond red-green-blue (RGB) source from a fiber laser driven spectrally efficient two zero dispersion wavelength fiber source. AB - We report a novel ultrafast red-green-blue (RGB) laser source based on second harmonic generation from a two zero dispersion wavelength (TZDW) fiber continuum source. The TZDW fiber source consists of a custom-built Yb:fiber amplifier and a commercially available TZDW photonic crystal fiber (PCF) which enables low noise and efficient frequency conversion from the 1035 nm pump source to two spectrally localized pulses centered at 850 nm and 1260 nm with 39.6% and 33.7% power efficiencies. With angularly multiplexed simultaneous phase matching, we achieve mW average power of red, green and blue pulses at 630 nm, 517 nm and 426 nm from single pass second harmonic generation. With broad RGB bandwidths of 7.4 nm, 3.2 nm and 5.2 nm, the source is inherently speckle-free while maintaining an excellent color rendering capability with higher than 99.7% excitation purity of the RGB color primaries, leading to the coverage of 192% NTSC color gamut (CIE 1976). The reported source features a simple system geometry; its potential in power scaling is discussed with currently available technologies. PMID- 25835700 TI - Tunable multiple phase-coupled plasmon-induced transparencies in graphene metamaterials. AB - We demonstrate the existence of multiple electromagnetically induced transparencies (EIT)-like spectral responses in graphene metamaterials consisting of a series of self-assembled graphene Fabry-Perot (FP) cavities. By exploiting the graphene plasmon resonances and phase-coupling effects, the transfer matrix model is established to theoretically predict the EIT-like responses, and the calculated results coincide well with numerical simulations. It is found that high-contrast (~90%) multiple EIT-like windows are observed over a broad range of mid-infrared. Additionally, these optical responses can be efficiently tuned by altering the Fermi level in graphene and the separations of FP cavities. The proposed scheme paves the way toward control of the multiple EIT-like responses, enabling exploration of the on-chip multifunctional electro-optic devices including multi-channel-selective filters, sensors, and modulators. PMID- 25835701 TI - Determination of the nonlinear optical coefficients of the BaGa(4)Se(7) crystal. AB - The second-order nonlinear optical (NLO) coefficients of the BaGa(4)Se(7) crystal were experimentally determined through the Maker Fringe Technique for the first time. The values of the two major nonlinear tensor elements d11 and d13 were 24.3 and 20.4 pm/V, respectively. These results were in agreement with the ones obtained through theoretical calculations. PMID- 25835702 TI - Saturable absorption behavior of free-standing graphene polymer composite films over broad wavelength and time ranges. AB - A comparative research on saturable absorption (SA) behavior dependence on wavelength and pulse duration was performed for graphene polymer composites. Free standing graphene-polyvinyl alcohol (PVA) composite films were fabricated by using solution cast method in combination of liquid phase exfoliation. SA responses were observed by using an open-aperture Z-scan technique for 340 fs pulses at 1030 nm and 515 nm from a mode-locked fiber laser, and 6 ns pulses at 1064 nm and 532 nm from a Q-switched Nd:YAG laser. The graphene films possess better SA property, i.e., larger SA coefficient and figure of merit (FOM), and lower saturation intensity I(s), for ns pulses than that for fs pulses at the similar near infrared (NIR) wavelength. For fs pulses, the films show better SA response at 1030 nm than that at 515 nm. By employing slow and fast SA modelling, the excited state and ground state absorption cross sections were estimated to be ~10(-17) cm(2), and the ratio was ~0.6 at NIR for both fs and ns pulses. PMID- 25835703 TI - Large size crystalline vs. co-sintered ceramic Yb(3+):YAG disk performance in diode pumped amplifiers. AB - A comprehensive experimental benchmarking of Yb(3+):YAG crystalline and co sintered ceramic disks of similar thickness and doping level is presented in the context of high average power laser amplifier operation. Comparison is performed considering gain, depolarization and wave front deformation quantitative measurements and analysis. PMID- 25835704 TI - Spectral design of temperature-invariant narrow bandpass filters for the mid infrared. AB - The ability of narrow bandpass filters to discriminate wavelengths between closely-separated gas absorption lines is crucial in many areas of infrared spectroscopy. As improvements to the sensitivity of infrared detectors enables operation in uncontrolled high-temperature environments, this imposes demands on the explicit bandpass design to provide temperature-invariant behavior. The unique negative temperature coefficient (dn/dT<0) of Lead-based (Pb) salts, in combination with dielectric materials enable bandpass filters with exclusive immunity to shifts in wavelength with temperature. This paper presents the results of an investigation into the interdependence between multilayer bandpass design and optical materials together with a review on invariance at elevated temperatures. PMID- 25835705 TI - Power functions improving the performance of color-difference formulas. AB - Color-difference formulas modified by power functions provide results in better agreement with visually perceived color differences. Each of the modified color difference formulas proposed here adds only one relevant parameter to the corresponding original color-difference formula. Results from 16 visual data sets and 11 color-difference formulas indicate that the modified formulas achieve an average decrease of 5.7 STRESS (Standardized Residual Sum of Squares) units with respect to the original formulas, signifying an improvement of 17.3%. In particular, for these 16 visual data sets, the average decrease for the current CIE/ISO recommended color-difference formula CIEDE2000 modified by an exponent 0.70 was 5.4 STRESS units (17.5%). The improvements of all modified color difference formulas with respect to the original ones held for each of the 16 visual data sets and were statistically significant in most cases, particularly for all data sets with color differences close to the threshold. Results for 2 additional data sets with color pairs in the blue and black regions of the color space confirmed the usefulness of the proposed power functions. The main reason of the improvements found for the modified color-difference formulas with respect to the original color-difference formulas seems to be the compression provided by power functions. PMID- 25835706 TI - Hybrid time-frequency domain equalization for LED nonlinearity mitigation in OFDM based VLC systems. AB - A novel hybrid time-frequency domain equalization scheme is proposed and experimentally demonstrated to mitigate the white light emitting diode (LED) nonlinearity in visible light communication (VLC) systems based on orthogonal frequency division multiplexing (OFDM). We handle the linear and nonlinear distortion separately in a nonlinear OFDM system. The linear part is equalized in frequency domain and the nonlinear part is compensated by an adaptive nonlinear time domain equalizer (N-TDE). The experimental results show that with only a small number of parameters the nonlinear equalizer can efficiently mitigate the LED nonlinearity. With the N-TDE the modulation index (MI) and BER performance can be significantly enhanced. PMID- 25835707 TI - Maternal and foetal outcomes following natural vaginal versus caesarean section (c-section) delivery in women with bleeding disorders and carriers. AB - BACKGROUND: Bleeding disorders are uncommon but may pose significant bleeding complications during pregnancy, labour and following delivery for both the woman and the foetus. While many bleeding disorders in women tend to improve in pregnancy, thus decreasing the haemorrhagic risk to the mother at the time of delivery, some do not correct or return quite quickly to their pre-pregnancy levels in the postpartum period. Therefore, specific measures to prevent maternal bleeding and foetal complications during childbirth, are required. The safest method of delivery to reduce morbidity and mortality in these women is controversial. OBJECTIVES: To assess the optimal mode of delivery in women with, or carriers of, bleeding disorders. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the Cochrane Pregnancy and Childbirth Group's Trials Register as well as trials registries and the reference lists of relevant articles and reviews.Date of last search of the Group's Trials Registers: 13 January 2015. SELECTION CRITERIA: Randomised controlled trials and all types of controlled clinical trials investigating the optimal mode of delivery in women with, or carriers of, any type of bleeding disorder during pregnancy were eligible for the review. DATA COLLECTION AND ANALYSIS: No trials matching the selection criteria were eligible for inclusion MAIN RESULTS: No results from randomized controlled trials were found. AUTHORS' CONCLUSIONS: The review did not identify any randomised controlled trials investigating the safest mode of delivery and associated maternal and foetal complications during delivery in women with, or carriers of, a bleeding disorder. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials, case studies) to decide upon the optimal mode of delivery to ensure the safety of both mother and foetus.Given the ethical considerations, the rarity of the disorders and the low incidence of both maternal and foetal complications, future randomised controlled trials to find the optimal mode of delivery in this population are unlikely to be carried out. Other high quality controlled studies (such as risk allocation designs, sequential design, and parallel cohort design) are needed to investigate the risks and benefits of natural vaginal and caesarean section in this population or extrapolation from other clinical conditions that incur a haemorrhagic risk to the baby, such as platelet alloimmunisation. PMID- 25835708 TI - Labia Majora Augmentation with De-epithelialized Labial Rim (Minora) Flaps as an Auxiliary Procedure for Labia Minora Reduction. AB - BACKGROUND: Esthetic surgery of external female genitalia remains an uncommon procedure. This article describes a novel, de-epithelialized, labial rim flap technique for labia majora augmentation using de-epithelialized labia minora tissue otherwise to be excised as an adjunct to labia minora reduction. METHODS: Ten patients were included in the study. The protruding segments of the labia minora were de-epithelialized with a fine scissors or scalpel instead of being excised, and a bulky section of subcutaneous tissue was obtained. Between the outer and inner surfaces of the labia minora, a flap with a subcutaneous pedicle was created in continuity with the de-epithelialized marginal tissue. A pocket was dissected in the labium majus, and the flap was transposed into the pocket to augment the labia majora. RESULTS: Mean patient age was 39.9 (+/-13.9) years, mean operation time was 60 min, and mean follow-up period was 14.5 (+/-3.4) months. There were no major complications (hematoma, wound dehiscence, infection) following surgery. No patient complained of postoperative difficulty with coitus or dyspareunia. All patients were satisfied with the final appearance. CONCLUSION: Several methods for labia minora reduction have been described. Auxiliary procedures are required with labia minora reduction for better results. Nevertheless, few authors have taken into account the final esthetic appearance of the whole female external genitalia. The described technique in this study is indicated primarily for mild atrophy of the labia majora with labia minora hypertrophy; the technique resulted in perfect patient satisfaction with no major complications or postoperative coital problems. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 25835709 TI - Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis. AB - Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with >=9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone. PMID- 25835710 TI - Vibrotactile perception in finger pulps and in the sole of the foot in healthy subjects among children or adolescents. AB - AIMS: To evaluate vibrotactile perception at different frequencies in fingers and in foot in healthy girls and boys. METHODS: Vibration perception thresholds (VPTs) were measured in 283 healthy (8-20 years), consecutively included, girls (n=146) and boys (n=137); i.e., 269 children after excluding those with diseases or disorders possibly affecting the nervous system. Thresholds were measured in finger pulps of index and little fingers (seven frequencies; 8-500 Hz) and at first and fifth metatarsal head and at heel in the sole of the foot (six frequencies; 8-250 Hz;) using Multi Frequency Tactilometry. RESULTS: VPTs, divided in six groups by age and gender (i.e., 8-10 years, 11-15 years and 16-20 years), at all three sites in the sole increased with higher frequencies, but without gender differences. Thresholds at 64 and 125 Hz were generally higher at heel compared to metatarsal heads. VPTs in finger pulps of index and little fingers, with no finger differences, had a different pattern with increasing thresholds with frequency, but with lower thresholds at 64 and 125 Hz. Thresholds at lower frequencies were higher in finger pulps, while at higher frequencies VPTs were lower in finger pulps than in the sole of the foot; thus, vibration perception in the sole was better than perception in finger pulps at lower frequencies and opposite at higher frequencies. VPTs were higher among adolescents than in younger children in the foot, while thresholds were lower in the finger pulps among adolescents, particularly in index finger. Thresholds in finger pulps of index and little fingers, particularly at higher frequencies, correlated with each other, which the three sites in the sole also did. CONCLUSIONS: VPTs in fingers and in feet are different as related to frequency in healthy girls and boys. Multi Frequency Tactilometry is a future valuable method to detect neuropathy in children and adolescents. PMID- 25835711 TI - Differential response of NADP-dehydrogenases and carbon metabolism in leaves and roots of two durum wheat (Triticum durum Desf.) cultivars (Karim and Azizi) with different sensitivities to salt stress. AB - Wheat (Triticum durum Desf.) is a common Mediterranean species of considerable agronomic importance. Salinity is one of the major threats to sustainable agricultural production mainly because it limits plant productivity. After exposing the Karim and Azizi durum wheat cultivars, which are of agronomic significance in Tunisia, to 100mM NaCl salinity, growth parameters (dry weight and length), proline content and chlorophylls were evaluated in their leaves and roots. In addition, we analyzed glutathione content and key enzymatic activities, including phosphoenolpyruvate carboxylase (PEPC), NADP-isocitrate dehydrogenase (NADP-ICDH), NADP-malic enzyme (NADP-ME), glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH), involved in the carbon metabolism and NADPH-generating system. The sensitivity index indicates that cv Karim was more tolerant to salinity than cv Azizi. This higher tolerance was corroborated at the biochemical level, as cv Karim showed a greater capacity to accumulate proline, especially in leaves, while the enzyme activities studied were differentially regulated in both organs, with NADP-ICDH being the only activity to be unaffected in all organs. In summary, the data indicate that higher levels of proline accumulation and the differential responses of some key enzymes involved in the carbon metabolism and NADPH regeneration contribute to the salinity tolerance mechanism and lead to increased biomass accumulation in cv Karim. PMID- 25835712 TI - Splicing defects in ABCD1 gene leading to both exon skipping and partial intron retention in X-linked adrenoleukodystrophy Tunisian patient. AB - X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and adrenal cortex secondary to mutations in the ABCD1 gene that encodes a peroxisomal membrane protein: the adrenoleukodystrophy protein. The disease is characterized by high concentrations of very long-chain fatty acids in plasma, adrenal, testicular and nervous tissues. Various types of mutations have been identified in the ABCD1 gene: point mutations, insertions, and deletions. To date, more than 40 point mutations have been reported at the splice junctions of the ABCD1 gene; only few functional studies have been performed to explore these types of mutations. In this study, we have identified de novo splice site mutation c.1780+2T>G in ABCD1 gene in an X-ALD Tunisian patient. Sequencing analysis of cDNA showed a minor transcript lacking exon 7 and a major transcript with a partial intron 7 retention due to activation of a new intronic cryptic splice site. Both outcomes lead to frameshifts with premature stop codon generation in exon 8 and intron 7 respectively. To the best of our knowledge, the current study demonstrates that a single splicing mutation affects the ABCD1 transcripts and the ALDP protein function. PMID- 25835713 TI - Can reproductive health voucher programs improve quality of postnatal care? A quasi-experimental evaluation of Kenya's safe motherhood voucher scheme. AB - This study tests the group-level causal relationship between the expansion of Kenya's Safe Motherhood voucher program and changes in quality of postnatal care (PNC) provided at voucher-contracted facilities. We compare facilities accredited since program inception in 2006 (phase I) and facilities accredited since 2010 2011 (phase II) relative to comparable non-voucher facilities. PNC quality is assessed using observed clinical content processes, as well as client-reported outcome measures. Two-tailed unpaired t-tests are used to identify differences in mean process quality scores and client-reported outcome measures, comparing changes between intervention and comparison groups at the 2010 and 2012 data collection periods. Difference-in-differences analysis is used to estimate the reproductive health (RH) voucher program's causal effect on quality of care by exploiting group-level differences between voucher-accredited and non-accredited facilities in 2010 and 2012. Participation in the voucher scheme since 2006 significantly improves overall quality of postnatal care by 39% (p=0.02), where quality is defined as the observable processes or components of service provision that occur during a PNC consultation. Program participation since phase I is estimated to improve the quality of observed maternal postnatal care by 86% (p=0.02), with the largest quality improvements in counseling on family planning methods (IRR 5.0; p=0.01) and return to fertility (IRR 2.6; p=0.01). Despite improvements in maternal aspects of PNC, we find a high proportion of mothers who seek PNC are not being checked by any provider after delivery. Additional strategies will be necessary to standardize provision of packaged postnatal interventions to both mother and newborn. This study addresses an important gap in the existing RH literature by using a strong evaluation design to assess RH voucher program effectiveness on quality improvement. PMID- 25835714 TI - Health-related quality of life of latin-american immigrants and spanish-born attended in spanish primary health care: socio-demographic and psychosocial factors. AB - BACKGROUND: This study compares the health-related quality of life of Spanish born and Latin American-born individuals settled in Spain. Socio-demographic and psychosocial factors associated with health-related quality of life are analyzed. METHODS: A cross-sectional Primary Health Care multi center-based study of Latin American-born (n = 691) and Spanish-born (n = 903) outpatients from 15 Primary Health Care Centers (Madrid, Spain). The Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) was used to assess health-related quality of life. Socio-demographic, psychosocial, and specific migration data were also collected. RESULTS: Compared to Spanish-born participants, Latin American-born participants reported higher health-related quality of life in the physical functioning and vitality dimensions. Across the entire sample, Latin American-born participants, younger participants, men and those with high social support reported significantly higher levels of physical health. Men with higher social support and a higher income reported significantly higher mental health. When stratified by gender, data show that for men physical health was only positively associated with younger age. For women, in addition to age, social support and marital status were significantly related. Both men and women with higher social support and income had significantly better mental health. Finally, for immigrants, the physical and mental health components of health-related quality of life were not found to be significantly associated with any of the pre-migration factors or conditions of migration. Only the variable "exposure to political violence" was significantly associated with the mental health component (p = 0.014). CONCLUSIONS: The key factors to understanding HRQoL among Latin American-born immigrants settled in Spain are age, sex and social support. Therefore, strategies to maintain optimal health outcomes in these immigrant communities should include public policies on social inclusion in the host society and focus on improving social support networks in order to foster and maintain the health and HRQoL of this group. PMID- 25835715 TI - Expression of p53, p21(CIP1/WAF1) and eIF4E in the adjacent tissues of oral squamous cell carcinoma: establishing the molecular boundary and a cancer progression model. AB - The present study evaluated the expression of key molecules and the status of DNA in both oral squamous cell carcinoma (OSCC) and adjacent tissues to establish a molecular surgical boundary and provide a cancer progression model. Biopsy samples from 50 OSCC patients were divided into T (cancer), P1 (0-0.5 cm), P2 (0.5-1 cm), P3 (1-1.5 cm) and P4 (1.5-2 cm) groups based on the distances from the visible boundary of the primary focus. Twenty samples of normal mucosa were used as controls. We used immunohistochemical staining and flow cytometry to evaluate p53, p21(CIP1/WAF1), eIF4E and Ki-67 expression and to determine DNA status, respectively. Sub-mucosal invasion was present in the P1 and P2 groups as determined by haematoxylin and eosin staining. Mutant p53 expression decreased gradually from cancerous to normal mucosae, whereas p21(CIP1/WAF1) expression displayed an opposite trend. eIF4E expression decreased from cancerous to normal mucosae. Ki-67 expression, the heteroploidy ratio, S-phase fraction and proliferative index decreased gradually with the distance from the tumour centre. Based on these results, we suggest that the resection boundary in OSCC surgery should be beyond 2 cm from the tumour. Additionally, the adjacent tissues of the primary focus could be used as a model for assessing cancer progression. PMID- 25835716 TI - Parentage of overlapping offspring of an arboreal-breeding frog with no nest defense: implications for nest site selection and reproductive strategy. AB - Overlapping offspring occurs when eggs are laid in a nest containing offspring from earlier reproduction. Earlier studies showed that the parentage is not always obvious due to difficulties in field observation and/or alternative breeding tactics. To unveil the parentage between overlapping offspring and parents is critical in understanding oviposition site selection and the reproductive strategies of parents. Amplectant pairs of an arboreal-breeding frog, Kurixalus eiffingeri, lay eggs in tadpole-occupied nests where offspring of different life stages (embryos and tadpoles) coexist. We used five microsatellite DNA markers to assess the parentage between parents and overlapping offspring. We also tested the hypothesis that the male or female frog would breed in the same breeding site because of the scarcity of nest sites. Results showed varied parentage patterns, which may differ from the phenomenon of overlapping egg clutches reported earlier. Parentage analyses showed that only 58 and 25% of the tadpole-occupied stumps were reused by the same male and female respectively, partially confirming our prediction. Re-nesting by the same individual was more common in males than females, which is most likely related to the cost of tadpole feeding and/or feeding schemes of females. On the other hand, results of parentage analyses showed that about 42 and 75% of male and female respectively bred in tadpole-occupied stumps where tadpoles were genetically unrelated. Results of a nest-choice experiment revealed that 40% of frogs chose tadpole occupied bamboo cups when we presented identical stumps, without or with tadpoles, suggesting that the habitat saturation hypothesis does not fully explain why frogs used the tadpole-occupied stumps. Several possible benefits of overlapping offspring with different life stages were proposed. Our study highlights the importance of integrating molecular data with field observations to better understand the reproductive biology and nest site selection of anuran amphibians. PMID- 25835717 TI - Comparison of different methods for work accidents investigation in hospitals: A Portuguese case study. AB - BACKGROUND: The hospital environment has many occupational health risks that predispose healthcare workers to various kinds of work accidents. OBJECTIVE: This study aims to compare different methods for work accidents investigation and to verify their suitability in hospital environment. METHODS: For this purpose, we selected three types of accidents that were related with needle stick, worker fall and inadequate effort/movement during the mobilization of patients. A total of thirty accidents were analysed with six different work accidents investigation methods. RESULTS: The results showed that organizational factors were the group of causes which had the greatest impact in the three types of work accidents. CONCLUSIONS: The methods selected to be compared in this paper are applicable and appropriate for the work accidents investigation in hospitals. However, the Registration, Research and Analysis of Work Accidents method (RIAAT) showed to be an optimal technique to use in this context. PMID- 25835718 TI - Management of health and safety in micro companies in Cyprus: Results on ergonomic issues. AB - BACKGROUND: Ergonomics in Cyprus is a rather neglected area of safety. The size of the country, the lack of scientific expertise, the nature of the economy and the nature of the majority of the enterprises make it a case, different from the average. OBJECTIVE: The aims of the survey were to examine the views and perceptions of employees and owners/managers on safety issues of micro-firms in Cyprus, to collect information on accidents and other aspects of safety performance in micro-firms and to cross-check the above data with data collected from safety inspectors for the above firms. METHODS: The authors with the collaboration of the Department of Labour Inspection of the Republic of Cyprus collected information from a relatively large number of micro companies in a National survey. Information from employees, employers and labour inspectors was drawn. RESULTS: Particular emphasis is paid on the exploration of the relationship of the non-use of personal protection equipment with a number of factors. Results show the resistance of employees to the use of PPE (Personal Protective Equipment) and GPM (General Protective Measures). CONCLUSIONS: The results of the survey are in line with the relevant literature. Micro firms illustrate several interesting findings that are discussed in detail in the paper. PMID- 25835719 TI - Is it important to know the load mass in lifting tasks to prevent falls? AB - BACKGROUND: Lifting objects without knowing its weight may result in postural imbalances and be a risk factor for falls. OBJECTIVE: The aim of this study was to examine the influence of the load knowledge in postural balance when lifting different weight loads. METHODS: Thirteen male subjects (23.8 +/- 3.1 years; 73.5 +/- 7.8 kg; 179.1 +/- 7.5 cm; foot length, 25.7 +/- 1.2 cm) participated in the study. The effect of the weight overestimation on the postural stability was measured by the Index of Proximity to Stability Boundary (IPSB) and through the anterior-posterior and medio-lateral lengths displacements of the Center of Pressure (CoP). RESULTS: The results showed an increase in the IPSB when the 5 kg lifting task was performed with load knowledge. Moreover, the length of the antero-posterior and medio-lateral CoP displacement was reduced in the 5 kg lift with knowledge. CONCLUSIONS: Results showed that the lack of the loads' knowledge may lead to balance loss. Thus, when the preparation processes are not adequate, picking up similar objects with different loads may increase the risk of fall, mainly when a light weight is suddenly lifted up after a heavy one. PMID- 25835721 TI - Human action quality evaluation based on fuzzy logic with application in underground coal mining. AB - BACKGROUND: The work system is defined by its components, their roles and the relationships between them. Any work system gravitates around the human resource and the interdependencies between human factor and the other components of it. Researches in this field agreed that the human factor and its actions are difficult to quantify and predict. OBJECTIVE: The objective of this paper is to apply a method of human actions evaluation in order to estimate possible risks and prevent possible system faults, both at human factor level and at equipment level. METHODS: In order to point out the importance of the human factor influence on all the elements of the working systems we propose a fuzzy logic based methodology for quality evaluation of human actions. This methodology has a multidisciplinary character, as it gathers ideas and methods from: quality management, ergonomics, work safety and artificial intelligence. RESULTS: The results presented refer to a work system with a high degree of specificity, namely, underground coal mining and are valuable for human resources risk evaluation pattern. CONCLUSIONS: The fuzzy logic evaluation of the human actions leads to early detection of possible dangerous evolutions of the work system and alarm the persons in charge. PMID- 25835720 TI - Multilevel model of safety climate for furniture industries. AB - BACKGROUND: Furniture companies can analyze their safety status using quantitative measures. However, the data needed are not always available and the number of accidents is under-reported. Safety climate scales may be an alternative. However, there are no validated Portuguese scales that account for the specific attributes of the furniture sector. OBJECTIVE: The current study aims to develop and validate an instrument that uses a multilevel structure to measure the safety climate of the Portuguese furniture industry. METHODS: The Safety Climate in Wood Industries (SCWI) model was developed and applied to the safety climate analysis using three different scales: organizational, group and individual. A multilevel exploratory factor analysis was performed to analyze the factorial structure. The studied companies' safety conditions were also analyzed. RESULTS: Different factorial structures were found between and within levels. In general, the results show the presence of a group-level safety climate. The scores of safety climates are directly and positively related to companies' safety conditions; the organizational scale is the one that best reflects the actual safety conditions. CONCLUSIONS: The SCWI instrument allows for the identification of different safety climates in groups that comprise the same furniture company and it seems to reflect those groups' safety conditions. The study also demonstrates the need for a multilevel analysis of the studied instrument. PMID- 25835722 TI - Will I be able to do my work at 60? An analysis of working conditions that hinder active ageing. AB - BACKGROUND: Most developed countries have considered population ageing as one of the economic challenges that need to be overcome. Managing ageing has led to consideration of a number of policies where it is essential to increase the employment rate for older workers. OBJECTIVE: This study aims to analyze the working conditions which tend to be perceived as hindering continuity in the workplace at the age of 60. PARTICIPANTS: 1234 workers from different sectors and socio-professional categories (52% men and 48% women; 64.5% younger than 45 years old). METHODS: A quantitative overview was adopted with the use of logistic regression models. The INSAT was used (Work and Health Questionnaire). RESULTS: Apart from factors of great physical constraint, other less visible aspects play a role in the idea of workers not being able to continue to work by the age of 60, namely factors linked to work organizational options and relationships with others. CONCLUSIONS: Working conditions have a great influence in the idea of inability to perform the same type of work at 60. This notion does not only apply to older workers. In fact, even younger workers under certain working conditions hold the same view, thus raising social concerns that should be taken into account by public policies. PMID- 25835723 TI - Measurable results: Reducing staff injuries on a specialty psychiatric unit for patients with developmental disabilities. AB - BACKGROUND: Quality improvement initiative focused on staff injury reduction on a specialized inpatient psychiatric unit which offers acute stabilization for children and adolescents with complex high-risk behaviors. OBJECTIVE: To utilize quality improvement principles and interventions to reduce staff injuries on a specialized inpatient child/adolescent psychiatric unit. PARTICIPANTS: Direct care clinical staff within an inpatient psychiatric unit for patients with co occurring developmental disabilities and psychiatric illness were the focus of the initiative. Direct care clinical staff and clinical administrators were the active participants in the quality improvement initiative, focusing upon the interactions between staff and patients. METHODS: OSHA-recordable injuries were documented to guide initiatives and measure outcomes on weekly run charts with raw data measures of all staff injuries and the number of days elapsed between injuries. Rapid Plan, Do, Study, Act (PDSA) cycles were utilized to test interventions and guide decision making. RESULTS: Three months of a structured and systematic intervention trial produced the first adopted interventions in August 2011. The following six months reflected a 65% reduction of staff injuries (from 2.2 injuries per week to 0.77 injuries per week). Between January and August 2011, there were eight OSHA-recordable injuries with an average of 26.5 days between injuries. The average number of days between OSHA-recordable injuries has increased from 26.5 days at baseline to 124 days. CONCLUSIONS: An initiative utilizing quality improvement principles reduced staff injuries on an inpatient specialized psychiatric unit. Reliability principles, system adaption, and engagement of the frontline nursing clinicians have proven to be foundational and vital to guide the initiative. PMID- 25835724 TI - Perceptions of horizontal violence in staff nurses and intent to leave. AB - BACKGROUND: The impact of horizontal violence is multifaceted. From the impact upon the individual, the unit, and the institution, horizontal violence affects professional nursing activities in a variety of aspects of health care. OBJECTIVE: To examine registered nurses' experiences with horizontal violence and explore the relationship between horizontal violence and intent to leave. PARTICIPANTS: A random sample of 300 registered nurses from a Midwestern hospital received the Briles' Sabotage Savvy Questionnaire (BSSQ), the Michigan Organizational Assessment Questionnaire (MOAQ) Intent to Turnover measure, and a Demographic questionnaire. METHODS: Descriptive correlational study was implemented. Questionnaires were distributed to the selected registered nurses. Descriptive and correlational statistics were calculated. RESULTS: Horizontal violence had been experienced by nurses of all ages and experience. Based upon measurement tools, examples of horizontal violence were: Being held responsible for coworkers' duties; Reprimanded or confronted in front of others; Failure to be acknowledged or confronted in front of others; and Untrue information about you being passed or exchanged. Correlations indicated a significant, positive relationship between perceptions of horizontal violence and intent to leave. Results also indicated the longer nurses were employed the more likely to perceive themselves as victims of horizontal violence. Additionally, results associated with the MOAQ, age and years employed indicated that older nurses and those with increasing years of employment were less likely to leave. Younger nurses indicated more willingness to leave a position due to perceived horizontal violence than older nurses. CONCLUSIONS: Activities to address the impact of perceived horizontal violence are needed. Workplace strategies may include mentoring, ongoing assessment of organizational climate, and zero tolerance for horizontal violence. PMID- 25835726 TI - Co-ordinating meals and exercise for diabetes management. PMID- 25835725 TI - Abrogation of adenosine A1 receptor signalling improves metabolic regulation in mice by modulating oxidative stress and inflammatory responses. AB - AIMS/HYPOTHESIS: Adenosine is an important regulator of metabolism; however, the role of the A1 receptor during ageing and obesity is unclear. The aim of this study was to investigate the effects of A1 signalling in modulating metabolic function during ageing. METHODS: Age-matched young and aged A 1 (also known as Adora1)-knockout (A1(-/-)) and wild-type (A1(+/+)) mice were used. Metabolic regulation was evaluated by body composition, and glucose and insulin tolerance tests. Isolated islets and islet arterioles were used to detect islet endocrine and vascular function. Oxidative stress and inflammation status were measured in metabolic organs and systemically. RESULTS: Advanced age was associated with both reduced glucose clearance and insulin sensitivity, as well as increased visceral adipose tissue (VAT) in A1(+/+) compared with A1(-/-) mice. Islet morphology and insulin content were similar between genotypes, but relative changes in in vitro insulin release following glucose stimulation were reduced in aged A1(+/+) compared with A1(-/-) mice. Islet arteriolar responses to angiotensin II were stronger in aged A1(+/+) mice, this being associated with increased NADPH oxidase activity. Ageing resulted in multiple changes in A1(+/+) compared with A1(-/-) mice, including enhanced NADPH oxidase-derived O2(-) formation and NADPH oxidase isoform 2 (Nox2) protein expression in pancreas and VAT; elevated levels of circulating insulin, leptin and proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6 and IL-12); and accumulation of CD4(+) T cells in VAT. This was associated with impaired insulin signalling in VAT from aged A1(+/+) mice. CONCLUSIONS/INTERPRETATION: These studies emphasise that A1 receptors regulate metabolism and islet endocrine and vascular functions during ageing, including via the modulation of oxidative stress and inflammatory responses, among other things. PMID- 25835727 TI - Impact of cancer on use of glucose-lowering drug treatment in individuals with diabetes: potential mechanisms. Reply to Pouwer F [letter]. PMID- 25835728 TI - XAV939-mediated ARTD activity inhibition in human MB cell lines. AB - Diphtheria toxin-like ADP-ribosyltransferases 1 and 5 (ARTD-1, ARTD-5) are poly ADP-ribose enzymes (PARP) involved in non-homologous end-joining (NHEJ), which is the major pathway of double-strand break (DSB) repair. In addition, ARTD-5, or Tankyrase (TNKS), is a positive regulator of the WNT signaling implicated in the development and biological behavior of many neoplasms, such as Medulloblastoma (MB), in which radiotherapy is an essential part of the treatment. The use of radiosensitizing agents may improve the therapeutic index in MB patients by increasing the efficacy of radiotherapy, while reducing toxicity to the neuroaxis. ARTD-5 seems to be a good molecular target for improving the current treatment of MB. In this study, we used the small molecule XAV939, a potent ARTD 5 inhibitor with a slight affinity for ARTD-1, in different human MB cell lines. XAV939 inhibited the WNT pathway and DNA-PKcs in our MB cells, with many biological consequences. The co-administration of XAV939 and ionizing radiations (IR) inhibited MB cells proliferation and clonogenic capacity, decreased their efficacy in repairing DNA damage, and increased IR-induced cell mortality. In conclusion, our in vitro data show that XAV939 could be a very promising small molecule in MB treatment, and these results lay the basis for further in vivo studies with the aim of improving the current therapy available for MB patients. PMID- 25835730 TI - Calciphylaxis: from the disease to the diseased. AB - Calciphylaxis, or calcific uremic arteriolopathy, is a vascular ossification calcification disease involving cutaneous or visceral arterioles, with ischemic damage of the surrounding tissues, usually in the setting of chronic kidney disease. Pathogenesis is still unclear and probably comprises the participation of vascular smooth muscle cells, endothelial cells and macrophages surrounded by a uremic and/or pro-calcifying environment. According to the original concept of calcific uremic arteriolopathy coined by Hans Selye, risk factors may be divided into sensitizers and challengers and their knowledge is useful in clinical practice to pre-emptively identify both uremic and non-uremic 'at risk' patients and guide treatment. Systemic calcific uremic arteriolopathy is a rarity. Cutaneous calcific uremic arteriolopathy is more frequent and clinically presents as a first phase of cutaneous hardening and erythema, followed by a second phase of ulcerations and scars; these two phases are probably associated with the initial development of arteriolar lesion and tissue ischemic damage, respectively. Clinical history, physical examination, laboratory analysis, histology and imaging are the main tools to exclude important differential diagnoses and obtain a definitive diagnosis. Treatment is generally unrewarding and consists of rigorous control of comorbid conditions, anti-oxidant, anti inflammatory and antithrombotic strategies, avoidance of iatrogeny and wound and pain management. Prognosis remains poor in terms of morbidity and mortality. Efforts should be made towards a greater awareness of calcific uremic arteriolopathy, development of better therapies and improvement of clinical outcomes. PMID- 25835732 TI - Standard operating procedures in experimental liver research: time to achieve uniformity. PMID- 25835729 TI - Shake, rattle, and roll: Impact of the dynamics of flavivirus particles on their interactions with the host. AB - Remarkable progress in structural biology has equipped virologists with insight into structures of viral proteins and virions at increasingly high resolution. Structural information has been used extensively to address fundamental questions about virtually all aspects of how viruses replicate in cells, interact with the host, and in the design of antiviral compounds. However, many critical aspects of virology exist outside the snapshots captured by traditional methods used to generate high-resolution structures. Like all proteins, viral proteins are not static structures. The conformational flexibility and dynamics of proteins play a significant role in protein-protein interactions, and in the structure and biology of virus particles. This review will discuss the implications of the dynamics of viral proteins on the biology, antigenicity, and immunogenicity of flaviviruses. PMID- 25835733 TI - The carbon tetrachloride model in mice. AB - Recently, the need for more standardized operation procedures in experimental liver fibrosis research was suggested due to dramatic changes in European animal welfare rules. Here, we present a short series of standard operation procedures (SOPs) summarizing the most relevant and widely accepted experimental models for the induction of liver injury leading to liver fibrosis. The described procedures are based on the long-term experience of the Collaborative Research Centre 'Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease' (http://www.sfbtrr57.rwth-aachen.de/), which is supported by the German Research Foundation (SFB/TRR57). These SOPs will help to improve standardization of fibrosis models and to increase the comparability of data between different laboratories with the aim of reducing animal experimentation according to the principle that was proposed in 1959 by Russell and Burch as an ethical framework for conducting scientific experiments with animals, namely the replacement, refinement and reduction (3R) principle. In the first section we focus on the carbon tetrachloride (CCl4) model in mice, which is the toxic model of liver fibrosis induction most commonly used worldwide. PMID- 25835731 TI - An overview of the Families Improving Together (FIT) for weight loss randomized controlled trial in African American families. AB - BACKGROUND: The Families Improving Together (FIT) randomized controlled trial tests the efficacy of integrating cultural tailoring, positive parenting, and motivational strategies into a comprehensive curriculum for weight loss in African American adolescents. The overall goal of the FIT trial is to test the effects of an integrated intervention curriculum and the added effects of a tailored web-based intervention on reducing z-BMI in overweight African American adolescents. DESIGN AND SETTING: The FIT trial is a randomized group cohort design the will involve 520 African American families with an overweight adolescent between the ages of 11-16 years. The trial tests the efficacy of an 8 week face-to-face group randomized program comparing M + FWL (Motivational Plus Family Weight Loss) to a comprehensive health education program (CHE) and re randomizes participants to either an 8-week on-line tailored intervention or control on-line program resulting in a 2 (M + FWL vs. CHE group) * 2 (on-line intervention vs. control on-line program) factorial design to test the effects of the intervention on reducing z-BMI at post-treatment and at 6-month follow-up. INTERVENTION: The interventions for this trial are based on a theoretical framework that is novel and integrates elements from cultural tailoring, Family Systems Theory, Self-Determination Theory and Social Cognitive Theory. The intervention targets positive parenting skills (parenting style, monitoring, communication); cultural values; teaching parents to increase youth motivation by encouraging youth to have input and choice (autonomy-support); and provides a framework for building skills and self-efficacy through developing weight loss action plans that target goal setting, monitoring, and positive feedback. PMID- 25835734 TI - The concanavalin A model of acute hepatitis in mice. AB - The intravenous injection of the plant lectin concanavalin A (ConA) is a widely used model for acute immune-mediated hepatitis in mice. In contrast to several other models for acute hepatic damage, ConA-induced injury is primarily driven by the activation and recruitment of T cells to the liver. Hence, the ConA model has unique features with respect to its pathogenesis and important similarities to immune-mediated hepatitis in humans, such as autoimmune hepatitis, acute viral hepatitis or distinct entities of drug toxicity leading to immune activation. However, the ConA model has considerable variability, depending on the preparation of the compound, genetic background of the mice, sex, age and microbial environment of the animal facility barrier. This standard operating procedure (SOP) comprises a detailed protocol for the ConA application, including preparation of ConA working solution, handling of the animals, choice of the appropriate conditions and endpoints, as well as efficient dose-finding. PMID- 25835735 TI - Standard operating procedures in experimental liver research: thioacetamide model in mice and rats. AB - In addition to carbon tetrachloride (CCl4), thioacetamide (TAA) represents a second widely used model for the induction of experimental liver fibrosis, but can also be employed for the development of acute liver failure and liver tumours. While TAA itself is not hepatotoxic, its reactive metabolites covalently bind to proteins and lipids thereby causing oxidative stress and centrilobular necrosis. Compared with CCl4, TAA leads to more periportal infiltrates and more pronounced ductal proliferation. While TAA has been shown to induce liver fibrosis development in several different mouse strains, wide variations in the administration routes, doses and treatment durations have been reported. Therefore, an adoption of a universal standard operating procedure for the administration of TAA is urgently needed. For that purpose, we are presenting here two TAA models (intraperitoneal administration of 150 mg/kg of TAA three times per week for 11 weeks in rats, and TAA administration in drinking water at 300 mg/L for 2-4 months in mice) with which we have had success in reliably and reproducibly developing chronic liver injury and fibrosis. PMID- 25835736 TI - Acetaminophen-induced acute liver injury in mice. AB - The induction of acute hepatic damage by acetaminophen (N-acetyl-p-aminophenol [APAP]), also termed paracetamol, is one of the most commonly used experimental models of acute liver injury in mice. The specific values of this model are the highly reproducible, dose-dependent hepatotoxicity of APAP and its outstanding translational importance, because acetaminophen overdose is one of the most frequent reasons for acute liver failure (ALF) in humans. However, preparation of concentrated APAP working solutions, application routes, fasting period and variability due to sex, genetic background or barrier environment represent important considerations to be taken into account before implementing this model. This standard operating procedure (SOP) provides a detailed protocol for APAP preparation and application in mice, aimed at facilitating comparability between research groups as well as minimizing animal numbers and distress. The mouse model of acetaminophen poisoning therefore helps to unravel the pathogenesis of APAP-induced toxicity or subsequent immune responses in order to explore new therapeutic interventions for improving the prognosis of ALF in patients. PMID- 25835737 TI - Lipopolysaccharide-induced inflammatory liver injury in mice. AB - The intraperitoneal application of lipopolysaccharide (LPS) alone or in combination with other hepatotoxins is an experimental model for inducing systemic and hepatic inflammation in rodents applied worldwide. The endotoxin is recognized by the LPS-binding protein. This complex binds together with the lymphocyte antigen 96 (MD2) and the pattern-recognition receptor CD14 to members of the toll-like receptor family. The activated receptor complex in turn transduces signals to well characterized intracellular cascades that result in a multifaceted network of intracellular responses ending in inflammation. The most prominent among these is the activation of the NF-kappaB pathway and the production of a multitude of inflammatory cytokines. Although the application of LPS is in general easy to perform, unintended variations in preparation of the injection solution or in handling of the animals might affect the reproducibility or the outcome of a specific experiment. Here, we present a well-standardized protocol that allows for an induction of highly reproducible acute hepatic inflammation in mice. Furthermore, examples of appropriate readouts for the resulting inflammatory response are given. PMID- 25835738 TI - Mouse models of metabolic liver injury. AB - Metabolic liver injury is one of the fastest growing health problems worldwide. Alcoholic and non-alcoholic fatty livers have been shown to be associated with progression to end-stage liver diseases, as well as to liver cancers, in humans. More importantly, there are no validated therapies for these disorders, therefore intensive research is required in this area. This review of standard operation procedures focuses on the experimental models of fatty liver disease in the mouse. Firstly, use of these experimental models might improve understanding of underlying mechanisms, and secondly this might help to test potential therapeutic options. This article includes, besides a short historic background, an insight into the pathobiochemical mechanisms and detailed experimental procedures as well as the practical implementation of these models. PMID- 25835739 TI - Diethylnitrosamine (DEN)-induced carcinogenic liver injury in mice. AB - The toxic properties of various nitrosamines in animals and humans are well established. The parenteral or oral administration of the smallest quantities of diethylnitrosamine (DEN) or dimethylnitrosamine (DMN) results in severe liver damage. Most prominent are intense neutrophilic infiltration, extensive centrilobular haemorrhagic necrosis, bile duct proliferation, fibrosis, and bridging necrosis that ends in hepatocarcinogenesis. Due to the robustness of the induced hepatic alterations, the application of DEN in rodents has become an attractive experimental model for studies aimed at understanding the pathogenetic alterations underlying the formation of liver cancer, which represents one of the most common malignancies in humans worldwide. However, several studies have shown that the hepatocarcinogenic effects of nitrosamines might vary with the genetic background of the animals, their sex, their age, and other factors that might impact the outcome of experimentation. We present general guidelines for working with DEN, and a detailed protocol that allows the establishment of highly reproducible liver cancer in mice. The outcome of liver injury after the application of DEN in mice, as estimated by the formation of cirrhosis and cancer, appears to be a suitable animal model for the analysis of some aspects and processes that promote the pathogenesis of hepatocellular carcinoma in humans. PMID- 25835740 TI - Induction of experimental obstructive cholestasis in mice. AB - The induction of experimental obstructive cholestasis is a reliable model for cholestatic liver diseases in rodents. Bile duct ligation (BDL) in mice provokes typical time-dependent morphological and structural changes in the liver, ranging from liver cell injury and elevated serum enzyme levels after several days, to a severe inflammatory response in the liver after 5-7 days, up to an advanced hepatic fibrosis as soon as three to four weeks after surgical ligation of the common biliary duct. Upon BDL induction, hepatic stellate cells become activated and transdifferentiate into myofibroblasts that produce extracellular matrix proteins such as collagen. In principle, the periportal fibrosis induced by BDL in rat livers is reversible. After the relief of a biliary obstruction, the liver has the capacity to revert to a nearly normal histological architecture and a fully normal biochemical function. When BDL surgery is performed by an experienced scientist, this model has very high reproducibility among all fibrotic models. All these factors corroborate the outstanding value of this model for basic and translational research in biomedicine and hepatology. Nevertheless, this model can result in significant variations when surgery is carried out by untrained personnel or when unconscious modifications are implemented that affect the quality of the intervention. A detailed protocol is provided here for the provision of reliable and reproducible BDL in mice. PMID- 25835741 TI - Partial hepatectomy in mice. AB - The surgical procedure of two-thirds partial hepatectomy (PH) in rodents was first described more than 80 years ago by Higgins and Anderson. Nevertheless, this technique is still a state-of-the-art method for the community of liver researchers as it allows the in-depth analysis of signalling pathways involved in liver regeneration and hepatocarcinogenesis. The importance of PH as a key method in experimental hepatology has even increased in the last decade due to the increasing availability of genetically-modified mouse strains. Here, we propose a standard operating procedure (SOP) for the implementation of PH in mice, which is based on our experience of more than 10 years. In particular, the SOP offers all relevant background information on the PH model and provides comprehensive guidelines for planning and performing PH experiments. We provide established recommendations regarding optimal age and gender of animals, use of appropriate anaesthesia and biometric calculation of the experiments. We finally present an easy-to-follow step-by-step description of the complete surgical procedure including required materials, critical steps and postoperative management. This SOP especially takes into account the latest changes in animal welfare rules in the European Union but is still in agreement with current international regulations. In summary, this article provides comprehensive information for the legal application, design and implementation of PH experiments. PMID- 25835742 TI - Strategic assessment of fisheries independent monitoring programs in the gulf of Mexico. AB - This study evaluates information produced from 14 fisheries independent monitoring programs (FIM) in the Gulf of Mexico. We consider the uniqueness of information from each program and its usefulness in estimating fisheries management indices. Biomass values of 35 functional groups are extracted from an operating model (Ecospace) with a method that replicates the patterns of historic FIM samplings. Observation error is added to these data in order to create a set of pseudo data that replicate the type and quality of information obtained from FIM programs. The pseudo data were put into a separate fishery assessment model (Pella-Tomlinson) to determine management indices of each functional group (maximum sustainable yield (MSY), biomass at MSY, and fishing mortality at MSY). These indices are compared against values in Ecospace, and against previously published single-species stock assessments. We also evaluate the full suite of information derived from FIM within an ecosystem context, considering whether functional roles are over- or under-sampled, and whether sampling effort is proportional to the value of fish stocks. Results reveal that model derived fishery indices closely matched published indices for the majority of the functional groups, economic and ecological evaluation suggests that several piscivorous functional groups are under-sampled include forage base species that are likely to indirectly support fisheries for piscivores, and sampling efforts are not proportional to the value of some fish stocks. Following ecological modelling we performed statistical analyses on historic FIM catch data to identify optimal species-specific sampling months and gear-types that can be used to refine future FIM sampling efforts. PMID- 25835743 TI - Nxf1 natural variant E610G is a semi-dominant suppressor of IAP-induced RNA processing defects. AB - Endogenous retroviruses and retrotransposons contribute functional genetic variation in animal genomes. In mice, Intracisternal A Particles (IAPs) are a frequent source of both new mutations and polymorphism across laboratory strains. Intronic IAPs can induce alternative RNA processing choices, including alternative splicing. We previously showed IAP I?1 subfamily insertional mutations are suppressed by a wild-derived allele of the major mRNA export factor, Nxf1. Here we show that a wider diversity of IAP insertions present in the mouse reference sequence induce insertion-dependent alternative processing that is suppressed by Nxf1CAST alleles. These insertions typically show more modest gene expression changes than de novo mutations, suggesting selection or attenuation. Genome-wide splicing-sensitive microarrays and gene-focused assays confirm specificity of Nxf1 genetic modifier activity for IAP insertion alleles. Strikingly, CRISPR/Cas9-mediated genome editing demonstrates that a single amino acid substitution in Nxf1, E610G, is sufficient to recreate a quantitative genetic modifier in a co-isogenic background. PMID- 25835744 TI - Internet Use and Access Among Pregnant Women via Computer and Mobile Phone: Implications for Delivery of Perinatal Care. AB - BACKGROUND: The use of Internet-based behavioral programs may be an efficient, flexible method to enhance prenatal care and improve pregnancy outcomes. There are few data about access to, and use of, the Internet via computers and mobile phones among pregnant women. OBJECTIVE: We describe pregnant women's access to, and use of, computers, mobile phones, and computer technologies (eg, Internet, blogs, chat rooms) in a southern United States population. We describe the willingness of pregnant women to participate in Internet-supported weight-loss interventions delivered via computers or mobile phones. METHODS: We conducted a cross-sectional survey among 100 pregnant women at a tertiary referral center ultrasound clinic in the southeast United States. Data were analyzed using Stata version 10 (StataCorp) and R (R Core Team 2013). Means and frequency procedures were used to describe demographic characteristics, access to computers and mobile phones, and use of specific Internet modalities. Chi-square testing was used to determine whether there were differences in technology access and Internet modality use according to age, race/ethnicity, income, or children in the home. The Fisher's exact test was used to describe preferences to participate in Internet-based postpartum weight-loss interventions via computer versus mobile phone. Logistic regression was used to determine demographic characteristics associated with these preferences. RESULTS: The study sample was 61.0% white, 26.0% black, 6.0% Hispanic, and 7.0% Asian with a mean age of 31.0 (SD 5.1). Most participants had access to a computer (89/100, 89.0%) or mobile phone (88/100, 88.0%) for at least 8 hours per week. Access remained high (>74%) across age groups, racial/ethnic groups, income levels, and number of children in the home. Internet/Web (94/100, 94.0%), email (90/100, 90.0%), and Facebook (50/100, 50.0%) were the most commonly used Internet technologies. Women aged less than 30 years were more likely to report use of Twitter and chat rooms compared to women 30 years of age or older. Of the participants, 82.0% (82/100) were fairly willing or very willing to participate in postpartum lifestyle intervention. Of the participants, 83.0% (83/100) were fairly willing or very willing to participate in an Internet intervention delivered via computer, while only 49.0% (49/100) were fairly willing or very willing to do so via mobile phone technology. Older women and women with children tended to be less likely to desire a mobile phone based program. CONCLUSIONS: There is broad access and use of computer and mobile phone technology among southern US pregnant women with varied demographic characteristics. Pregnant women are willing to participate in Internet-supported perinatal interventions. Our findings can inform the development of computer- and mobile phone-based approaches for the delivery of clinical and educational interventions. PMID- 25835745 TI - The effects of 1alpha, 25-dihydroxyvitamin D3 and transforming growth factor beta3 on bone development in an ex vivo organotypic culture system of embryonic chick femora. AB - Transforming growth factor-beta3 (TGF-beta3) and 1alpha,25-dihydroxyvitamin D3 (1alpha,25 (OH) 2D3) are essential factors in chondrogenesis and osteogenesis respectively. These factors also play a fundamental role in the developmental processes and the maintenance of skeletal integrity, but their respective direct effects on these processes are not fully understood. Using an organotypic bone rudiment culture system the current study has examined the direct roles the osteotropic factors 1alpha,25 (OH)2D3 and TGF-beta3 exert on the development and modulation of the three dimensional structure of the embryonic femur. Isolated embryonic chick femurs (E11) were organotypically cultured for 10 days in basal media, or basal media supplemented with either 1alpha,25 (OH) 2D3 (25 nM) or TGF beta3 (5 ng/mL & 15 ng/mL). Analyses of the femurs were undertaken using micro computed tomography (MUCT), histology and immunohistochemistry. 1alpha,25 (OH)2D3 supplemented cultures enhanced osteogenesis directly in the developing femurs with elevated levels of osteogenic markers such as type 1 collagen. In marked contrast organotypic femur cultures supplemented with TGF-beta3 (5 ng/mL & 15 ng/mL) demonstrated enhanced chondrogenesis with a reduction in osteogenesis. These studies demonstrate the efficacy of the ex vivo organotypic embryonic femur culture employed to elucidate the direct roles of these molecules, 1alpha,25 (OH) 2D3 and TGF-beta3 on the structural development of embryonic bone within a three dimensional framework. We conclude that 1alpha,25(OH)2D and TGF-beta3 modify directly the various cell populations in bone rudiment organotypic cultures effecting tissue metabolism resulting in significant changes in embryonic bone growth and modulation. Understanding the roles of osteotropic agents in the process of skeletal development is integral to developing new strategies for the recapitulation of bone tissue in later life. PMID- 25835746 TI - Strong field laser control of photochemistry. AB - Strong ultrashort laser pulses have opened new avenues for the manipulation of photochemical processes like photoisomerization or photodissociation. The presence of light intense enough to reshape the potential energy surfaces may steer the dynamics of both electrons and nuclei in new directions. A controlled laser pulse, precisely defined in terms of spectrum, time and intensity, is the essential tool in this type of approach to control chemical dynamics at a microscopic level. In this Perspective we examine the current strategies developed to achieve control of chemical processes with strong laser fields, as well as recent experimental advances that demonstrate that properties like the molecular absorption spectrum, the state lifetimes, the quantum yields and the velocity distributions in photodissociation processes can be controlled by the introduction of carefully designed strong laser fields. PMID- 25835749 TI - Band-gap tunability and dynamical instability in strained monolayer and bilayer phosphorenes. AB - Very recently, field-effect transistors based on few-layer phosphorene crystals with a thickness of down to a few nanometres were successfully fabricated, triggering interest in this new functional two-dimensional material. In this work, we apply first-principles calculations to studying the evolution of electronic and phononic structures with out-of-plane strain for monolayer and bilayer phosphorenes. It is found that the vertical stress can be used to tune the band gap of a semiconducting phosphorene in a wide range. On the other hand, the vertical stress can make the phosphorene lattice become dynamically unstable and surface reconstruction or structural phase transition may occur. Due to the interlayer van der Waals coupling, the dynamically stable range of bilayer phosphorene under vertical stress is wider than that of monolayer phosphorene. It is proposed whether or not a semiconductor-semimetal transition occurring in a strained phosphorene is determined not only by its band gap closing, but also by its lattice stability against strain. This information is essential for the strain engineering of phosphorene and future device fabrication. PMID- 25835747 TI - Occurrence of Distal Colorectal Neoplasia Among Whites and Blacks Following Negative Flexible Sigmoidoscopy: An Analysis of PLCO Trial. AB - BACKGROUND: It is unclear whether the higher rate of colorectal cancer (CRC) among non-Hispanic blacks (blacks) is due to lower rates of CRC screening or greater biologic risk. OBJECTIVE: We aimed to evaluate whether blacks are more likely than non-Hispanic whites (whites) to develop distal colon neoplasia (adenoma and/or cancer) after negative flexible sigmoidoscopy (FSG). DESIGN: We analyzed data of participants with negative FSGs at baseline in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial who underwent repeat FSGs 3 or 5 years later. Subjects with polyps or masses were referred to their physicians for diagnostic colonoscopy. We collected and reviewed the records of diagnostic evaluations. PARTICIPANTS: Our analytic cohort consisted of 21,550 whites and 975 blacks. MAIN MEASURES: We did a comparison by race (whites vs. blacks) in the findings of polyps or masses at repeat FSG, the follow-up of abnormal test results and the detection of colorectal neoplasia at diagnostic colonoscopy. KEY RESULTS: At the follow-up FSG examination, 304 blacks (31.2 %) and 4183 whites (19.4 %) had abnormal FSG, [adjusted relative risk (RR) = 1.00; 95 % confidence interval (CI), 0.90-1.10]. However, blacks were less likely to undergo diagnostic colonoscopy (76.6 % vs. 83.1 %; RR = 0.90; 95 % CI, 0.84 0.96). Among all included patients, blacks had similar risk of any distal adenoma (RR = 0.86; 95 % CI, 0.65-1.14) and distal advanced adenoma (RR = 1.01; 95 % CI, 0.60-1.68). Similar results were obtained when we restricted our analysis to compliant subjects who underwent diagnostic colonoscopy (RR = 1.01; 95 % CI, 0.80 1.29) for any distal adenoma and (RR = 1.18; 95 % CI, 0.73-1.92) for distal advanced adenoma. CONCLUSIONS: We did not find any differences between blacks and whites in the risk of distal colorectal adenoma 3-5 years after negative FSG. However, follow-up evaluations were lower among blacks. PMID- 25835748 TI - Organization and dynamics of tryptophan residues in brain spectrin: novel insight into conformational flexibility. AB - Brain spectrin enjoys overall structural and sequence similarity with erythroid spectrin, but less is known about its function. We utilized the fluorescence properties of tryptophan residues to monitor their organization and dynamics in brain spectrin. Keeping in mind the functional relevance of hydrophobic binding sites in brain spectrin, we monitored the organization and dynamics of brain spectrin bound to PRODAN. Results from red edge excitation shift (REES) indicate that the organization of tryptophans in brain spectrin is maintained to a considerable extent even after denaturation. These results are supported by acrylamide quenching experiments. To the best of our knowledge, these results constitute the first report of the presence of residual structure in urea denatured brain spectrin. We further show from REES and time-resolved emission spectra that PRODAN bound to brain spectrin is characterized by motional restriction. These results provide useful information on the differences between erythroid spectrin and brain spectrin. PMID- 25835750 TI - A Nonenzymatic Hairpin DNA Cascade Reaction Provides High Signal Gain of mRNA Imaging inside Live Cells. AB - Enzyme-free signal amplification has enabled sensitive in vitro detection of biomolecules such as proteins and nucleic acids. However, monitoring targets of interest in live cells via enzyme-free amplification is still challenging, especially for analytes with low concentrations. To the best of our knowledge, this paper reports the first attempt to perform mRNA imaging inside live cells, using a nonenzymatic hairpin DNA cascade reaction for high signal gain, termed a hairpin DNA cascade amplifier (HDCA). In conventional nucleic acid probes, such as linear hybridization probes, mRNA target signaling occurs in an equivalent reaction ratio (1:1), whereas, in HDCA, one mRNA target is able to yield multiple signal outputs (1:m), thus achieving the goal of signal amplification for low expression mRNA targets. Moreover, the recycled mRNA target in the HDCA serves as a catalyst for the assembly of multiple DNA duplexes, generating the fluorescent signal of reduced MnSOD mRNA expression, thus indicating amplified intracellular imaging. This programmable cascade reaction presents a simple and modular amplification mechanism for intracellular biomarkers of interest, providing a significant boost to the search for clues leading to the accurate identification and effective treatment of cancers. PMID- 25835752 TI - A new approach to treatment of vulvo-vaginal atrophy. PMID- 25835751 TI - 17beta-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. AB - Several formulations combining estrogens and progestins for hormone therapy (HT) have been approved worldwide for the treatment of menopausal symptoms, yet recent data indicate a decline in their use and an increase in compounded bioidentical HT. Up to now, no single product combining natural 17beta-estradiol and progesterone has been approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A phase 3 trial (REPLENISH) is underway to study a novel oral formulation of solubilized 17beta-estradiol and natural progesterone combined in a single gelatin capsule (TX-001HR; TherapeuticsMD, Inc, Boca Raton, FL) for treating vasomotor symptoms (VMS) in postmenopausal women. The REPLENISH trial evaluates the efficacy and safety of TX-001HR (4 doses) versus placebo for the reduction of moderate to severe VMS frequency and severity at 4 and 12 weeks and evaluates the endometrial safety of the combinations at 1 year. TX-001HR contains hormones that are molecularly identical to endogenous estradiol and progesterone and is intended as an option for women who prefer bioidentical hormones; further, it does not contain peanut oil, a common allergen. The constituents of TX-001HR, in a pharmacokinetic report, showed similar bioavailability and safety compared with reference estradiol tablets and micronized progesterone capsules administered together. Published data suggest a safer profile of estradiol and natural progesterone compared with HT containing conjugated equine estrogens and progestins. This report summarizes the methodology of the REPLENISH trial and reviews the evidence suggesting clinical differences between HT containing progesterone or progestins, and estradiol or conjugated equine estrogens. PMID- 25835753 TI - Safety of selective serotonin reuptake inhibitor treatment in recovering stroke patients. AB - INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are widely used for psychiatric complications after stroke. Studies have indicated additional effects, and SSRIs could potentially be used as enhancers of stroke recovery. However, beneficial effects should be weighed against potential adverse effects. In particular, the possible association with cerebrovascular events has raised concern. AREAS COVERED: We review the literature on cerebrovascular events associated with SSRI treatment after stroke. The possible beneficial effects of SSRI treatment for stroke recovery and survival, and potential safety concerns, are discussed. EXPERT OPINION: Evidence suggests that SSRIs may enhance stroke recovery. Most studies on cerebrovascular risk are from non-stroke populations and little is known about recurrent events and mortality post-stroke. In non stroke populations treatment has been associated with increased risk of intracerebral and intracranial hemorrhage; however the absolute risk is low. The association between SSRIs and ischemic stroke is less clear. Randomized stroke trials indicate that treatment is safe and well tolerated, and the most common side effects are often benign and transient. The trials are small however and not powered to detect potential differences in cerebrovascular events. We await several ongoing large randomized trials before SSRIs can be recommended as a routine pharmacotherapy in stroke recovery. PMID- 25835754 TI - New three-fold interpenetrated uranyl organic framework constructed by terephthalic acid and imidazole derivative. AB - A new 3-fold interpenetrated uranyl organic framework, UO2(bdc)(dmpi), was hydrothermally synthesized using 1,4-benzenedicarboxylic acid (H2bdc) and 1-(4 (1H-imidazol-1-yl)-2,5-dimethylphenyl)-1H-imidazole (dmpi). This framework, which was determined by synchrotron radiation X-ray, exhibited a new 3-fold interpenetrated (2,4)-connected topology with the Schlafli symbol of (12(6))(12)2. Additionally, large incurvation happened to the bond angle of [O=U=O](2+), which was always arranged in a rigorous line. Computational results based on density functional theory (DFT) indicated that the bent geometry of uranyl in UO2(bdc)(dmpi) was mainly due to the higher charge populations in the valence 6d shells of uranium, rendered by the electronegative imidazoles. PMID- 25835755 TI - The synergistic effect of BCR signaling inhibitors combined with an HDAC inhibitor on cell death in a mantle cell lymphoma cell line. AB - Mantle cell lymphoma (MCL) is a B cell malignancy characterized by aberrant expression of cyclin D1 due to a t(11;14) translocation. MCL is refractory to conventional chemotherapy, and treatment remains challenging. We investigated the efficacy of the histone deacetylase (HDAC) inhibitor vorinostat combined with one of several B-cell receptor (BCR) signaling inhibitors on MCL cell death and the underlying mechanisms, using MCL cell lines. The Bruton's tyrosine kinase inhibitor PCI-32765 and the spleen tyrosine kinase inhibitor R406 showed synergistic effects with vorinostat on growth inhibition. Treatment with PCI 32765 or R406 alone induced 27.3 +/- 2.1 or 25.1 +/- 3.2% apoptosis. When combined with vorinostat, these apoptotic fractions significantly increased to 50.8 +/- 4.9 and 63.1 +/- 5.0%, respectively. Activation of caspase-3 and poly (ADP-ribose) polymerase cleavage were markedly increased. We performed gene expression profiling following treatment with the combination of vorinostat and individual BCR signaling inhibitors using a microarray, and differentially expressed genes were identified. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the nuclear factor (NF)-kappaB signaling pathway was significantly enriched following treatment with the combination of vorinostat and R406. Protein expression analysis confirmed the down-regulation of NF kappaB1/p105 and cyclin D1, suggesting inhibition of the NF-kappaB pathway. Taken together, the combination of an HDAC inhibitor and a BCR signaling inhibitor may be a novel therapeutic strategy for MCL. PMID- 25835756 TI - Treatment Options for Pediatric Patent Ductus Arteriosus: Systematic Review and Meta-analysis. AB - BACKGROUND: Patent ductus arteriosus (PDA) in the nonpremature pediatric patient is currently treated by surgical ligation or catheter occlusion. There is no clear superiority of one technique over the other. This meta-analysis compares the clinical outcomes of the two treatment options for PDA. METHODS: We performed a literature search of MEDLINE, Embase, PubMed, and the Cochrane database of randomized controlled trials (RCTs) that took place between 1950 and February 2014 and hand-searched references from included studies. We excluded studies of adult or premature patients and those without a direct comparison between surgical and catheter-based treatments of PDAs. Outcomes of interest were reintervention, total complications, length of stay, and cost. RESULTS: One thousand three hundred thirty-three manuscripts were screened. Eight studies fulfilled the inclusion criteria (one RCT and seven observational studies [N = 1,107]). In pooled observational studies, there were significantly decreased odds (OR, 0.12; 95% CI, 0.03-0.42) for reintervention in the surgical ligation group but insignificantly higher odds for overall complications (OR, 2.01; 95% CI, 0.68 5.91). There were no complications reported in the RCT, but surgical ligation was associated with decreased odds for reintervention and a longer length of stay. Funnel plots revealed a possible publication bias and a quality review identified comparability bias. CONCLUSIONS: Both therapies have comparable outcomes. Reintervention is more common with catheter-based treatment, but overall complication rates are not higher and hospital stay is shorter. Our data span > 2 decades and may not reflect current surgical and catheterization outcomes. Large, randomized, prospective studies may help determine the optimal treatment strategy. PMID- 25835757 TI - Combination of microvascular medial femoral condyle and iliac crest flap for hemi midface reconstruction. AB - In midface defects including the orbit (Brown class III and IV), no single flap can provide adequate reconstruction. In this technical note, the combination of vascularized iliac crest flap and vascularized medial femoral condyle flap (MFC) is described. The vascularized iliac crest flap is reported to be the gold standard for maxilla reconstruction. There is, however, no consensus on the best method for orbital and nasal wall reconstruction. The MFC flap can be harvested as a thin corticoperiosteal flap or as an osteomyocutaneous flap. Due to the periosteal blood supply, this flap can be customized for an individual defect of the upper hemi-midface. It is therefore of great benefit in orbital and nasal wall reconstruction. By combining the deep circumflex iliac artery (DCIA) bone flap and the MFC flap, the best standard reconstruction technique of the hemi maxilla can be combined with a new anatomical precise microvascular reconstruction technique of the orbit. A nearly symmetric midface appearance can be achieved. PMID- 25835758 TI - Low-intensity pulsed ultrasound enhances bone morphogenetic protein expression of human mandibular fracture haematoma-derived cells. AB - We previously demonstrated that human mandibular fracture haematoma-derived cells (MHCs) play an important role in mandibular fracture healing and that low intensity pulsed ultrasound (LIPUS) accelerates this effect by stimulating various osteogenic cytokines. In the present study, we investigated how LIPUS affects the expression of bone morphogenetic proteins (BMPs), which are also known to have the ability to induce bone formation. MHCs were isolated from human mandibular fracture haematomas and the cells were divided into two groups: a LIPUS (+) group and a LIPUS (-) group, both of which were cultured in osteogenic medium. LIPUS was applied to the LIPUS (+) group 20 min a day for 4, 8, 14, and 20 days (1.5 MHz, 30 mW/cm(2)). Real-time PCR and immunofluorescence studies were carried out to determine the expression of BMP-2, 4, and 7. Compared to the LIPUS (-) group, gene expression levels were significantly increased in the LIPUS (+) group for BMP-2 on day 20 (67.38 +/- 26.59 vs. 11.52 +/- 3.42, P < 0.001), for BMP-4 on days 14 (45.12 +/- 11.06 vs. 9.20 +/- 2.88, P = 0.045) and 20 (40.96 +/- 24.81 vs. 3.22 +/- 1.53, P = 0.035), and for BMP-7 on day 8 (48.11 +/- 35.36 vs. 7.03 +/- 3.96, P = 0.034). These findings suggest that BMP-2, 4, and 7 may be mediated by LIPUS therapy during the bone repair process. PMID- 25835759 TI - Effect of unilateral mandibular distraction osteogenesis on mandibular morphology in rabbits with antigen-induced temporomandibular joint arthritis. AB - Aim was to evaluate effect of unilateral distraction osteogenesis (DO) on mandibular morphology in rabbits with antigen-induced arthritis in the temporomandibular joint (TMJ). Forty 8-week-old rabbits were divided into four groups. In groups A,C, arthritis was induced in the right TMJ. Groups A,B underwent DO. Group D served as control group. Cephalometric analysis of mandibular angle, mandibular ramus height, mandibular collum height, and total posterior mandibular height was done on CT-scans preoperatively (T0), after distraction (T1), and at euthanasia (T2). Two-factor ANOVA evaluated the effect of DO and antigen-induced arthritis. No effect of DO or arthritis was observed on mandibular angle or mandibular collum height. For T0-T1, DO increased mandibular ramus height 12.3% (95% CI 5.2-19.4%) in group B (P=0.001) and total posterior mandibular height 6.2% (95% CI 0.3-12.1%) in group A (P=0.04) and 10.0% (95% CI 4.3-15.7%) in group B (P=0.001). For T1-T2, no significant changes occurred in arthritic rabbits (group A). In conclusion, DO increased total posterior mandibular height in rabbits with arthritis. Postoperatively, no significant effect of DO was observed in rabbits with arthritis. Mandibular DO could be a viable treatment modality in patients with TMJ-arthritis. PMID- 25835760 TI - The journey continues. AB - Here is the second special issue of the journal Acta BioMedica, dedicated to the health professions.The publication of the first issue gave rise to diverse reactions - all positive - in the relevant circles. PMID- 25835761 TI - The metaphors of collaboration, or the social construction of collaborative interactions between health professionals. AB - This article illustrates the ways in which symbolic representations of reality, embodied in metaphors and language, can affect collaborative interactions in the current situation of social and economic change. We assume that corporate transformation and organizational configurations influence health professionals' representations in largely unconscious ways and, with these, their everyday practice. On the basis of empirical data collected through 13 focus groups in an Italian hospital, our intention is to show the extent to which joint working can be linked to three main metaphors each matching specific forms of social and professional interaction. The three metaphors of collaboration constitute different attempts to interpret social and organizational changes in proactive - encouraging social innovation - or defensive terms - as actions of cultural resistance. The three metaphors are: apparatus, family and team. In different ways, the first two represent forms of resistance to change and are widely present within organizations. The latter, on the other hand, consists of a proactive way to deal with ongoing social and organizational change. This metaphor testifies to the existence of a different approach to collaborative interactions, a perspective related to specific combinations of organizational and professional characteristics. This study indicates that organizational change and collaboration can be strengthened by metaphors that illustrate open, plural and highly heterogeneous professional settings. PMID- 25835762 TI - Ambivalent stereotypes of nurses and physicians: impact on students' attitude toward interprofessional education. AB - BACKGROUND AND AIM OF THE WORK: Nurse-physician stereotypes have been proposed as a factor hindering interprofessional collaboration among practitioners and interprofessional learning among nursing and medical students. Using socio psychological theories about ambivalent stereotypes, the present work aimed to analyse: a) the content of nurse and physician stereotypes held by nursing and medical students and b) the role of auto-stereotype on students' attitude toward interprofessional education (IPE). Methods. A cross-sectional on-line survey was adopted and a questionnaire was emailed to 205 nursing students and 151 medical students attending an Italian university. RESULTS: Nursing and medical students shared the stereotypical belief that nurses are warmer but less competent than physicians. Nurses and physicians were basically depicted with ambivalent stereotypes: nurses were seen as communal, socially competent and caring but less competent, not agentic and less autonomous, while physicians were seen as agentic, competent and autonomous, but less communal, less collectivist and less socially competent. Moreover, a professional stereotypical image impacted the students' attitude toward IPE. More precisely, when nurses and physicians were seen with classic ambivalent stereotypes, both nursing and medical students were less favourable towards interprofessional education programmes. CONCLUSIONS: The content of professional stereotypes of healthcare students was still linked to classical views of nurses as caring and physicians as curing. This seemed to limit students' attitude and intention to be engaged in IPE. PMID- 25835763 TI - Threats to identity: lipodystrophy and identity changes in people with HIV/AIDS (PWA). AB - BACKGROUND AND AIM: PWA today have to face new problems associated with their disease state. One of these is tied to bodily changes that are related to HAART (lipodystrophy syndrome, LDS). Applying the Identity Process Theory (Breakwell, 1986), this research aimed to study the impact that LDS body changes may have on the identity of PWA. METHOD: One hundred and eight patients (79 M and 29 F, ranging from 35 to 75 years old) at a North Italian clinic completed a questionnaire composed of scales measuring the perception of threats to the identity of PWA, physicians' and patients' assessment of LDS, time from diagnosis, disclosure and perceived social support. RESULTS: Results showed that lipodystrophy changes represent a new aspect of the disease that PWA need to handle in terms of identity: the changes resulted in 'loss of the self' and constituted a particular threat to the dimension of personal identity whereby bodily changes called more into question the principles of self-esteem and distinctness. LDS, however, lead to a multiple identity threat that is aggravated by patients' perception of the severity of their bodily changes and by the perception of a lack of friendship and social support. CONCLUSIONS: The study highlights how complex, cyclical and dynamic are the effects that HIV status can have on the sick person: they are no longer only clinical, but also psychological and psychosocial. PMID- 25835764 TI - Correlation between quality of cardiopulmonary resuscitation and self-efficacy measured during in-hospital cardiac arrest simulation; preliminary results. AB - BACKGROUND: The concept of self-assess it's a central mechanism in human agency for behavior change and should translate to desirable practice patterns. There are no many studies that have investigated the relationship between the perception of the ability to perform cardiopulmonary resuscitation (CPR) and the quality of the same. The aim of this work is to investigate the relation between physiological and psychosocial variables in cardiac resuscitation in order to improve the involvement and motivation of professionals in training courses. METHODS: During the year 2012, 322 medical staff of Ospedale-Universitario of Parma were trained to basic life support defibrillation (BLSD). Before started the course the partecipants were randomly selected among the staff working in the same department to create a team of two persons and involved in a simulation that reproduced the first five minutes that occurs for a cardiac arrest in a medical or surgical department in our hospital before the intervention of the hospital emergency team. Before and after simulation to each participant was asked to answer a self-efficacy questionnaire on a 10-point scale on the management of cardiac. During simulation were registered the activation time of the emergency response system, hands-on time, defibrillation time, number of compression and correct compression rate. RESULTS: Activation time of the emergency response system was 70.52 +/- 78.77 seconds. In 55 teams was not made the allert. The defibrillation time was 148.63 +/- 58.43 seconds. In 44 teams the defibrillator were used within 120 seconds, in 36 (22.1%) it was not used. Hands-on time average was of 166.20 +/- 62.9 seconds. The mean number of compression was 216.22 +/- 115.57. The percentage of satisfactory compression was 9.97 +/- 21.23 %. The level of self-efficacy was under the average for the 35.6%, while the 26.8% of the participants had a medium level of 5 and the 38.5% of the sample declared to feel an efficacy level included in 6-10. The sense of self efficacy after the simulation was constant in the 38.3% of the sample, while increased in the 30.5% and decreased in the 31.2%. We found no significant correlations between self efficacy levels and specific results in scenario acting before simulation, instead, after the simulation the skills performances are much more correlated with self-efficacy. CONCLUSIONS: The medical staff reported an individual's perception of good efficacy in the management of simulation of cardiac arrest, but it does not correspond to a high skills. An open question is if and how these psychosocial variables may play a role in improving the quality of CPR and if knowledge of the low capacity to manage a cardiac arrest can be translated into the need for the medical staff to be regularly engaged in BLSD retraining. PMID- 25835765 TI - Strangers in a strange land: work experiences of foreign nurses in Parma's territory. AB - PURPOSE: The purpose of this research is to explore, investigate and describe experiences and points of view of foreign nurses working in the area of Parma. We focalize particularly on two areas of interest: negativities and positivities in experiences related to the process of integration into the new working environment. BACKGROUND: The literature search has revealed that the phenomenon of "nursing immigration" is numerically significant in Italy and more particularly in Emilia Romagna. From studies conducted in other countries (UK, USA, Canada, Australia and Iceland) there are two categories of factors which influence the process of integration of foreign nurses in the new working environment, facilitators and barriers. METHOD: For this study we followed the phenomenological method . A total of twelve foreign nurses were interviewed in the months of October and November 2013 in the territory of Parma working in various professional fields (medicine, critical care and surgery). We did not impose any structure to interviews so that respondents were free to express their lived experiences spontaneously. All interviews were recorded, transcribed verbatim and analyzed by the method of Giorgi (1970). RESULTS: Results obtained from the analysis of interviews revealed seven themes, divided in positivities and negativities. Positivities are psycho-social support (Italian colleagues, fellow countrymen, patients), opportunities of cultural enrichment, positive work ethic. negativities are difficulty of language and communication, and inequalities racial prejudice, differences in care practices and inadequate opportunities for professional growth related to the Italian working environment. CONCLUSIONS: The study concludes by pointing out the importance of the role that foreign nurses can play in our health care system and how the results of this search can help all professionals in the health sector to have a greater understanding of their experiences. This knowledge can make a contribution to the development of new quantitative research in the same area and then to the formation of new strategies for hospitality and support. PMID- 25835766 TI - Factors affecting women's well-being during the experience of acute myocardial infarction: a literature review. AB - BACKGROUND AND AIM OF THE WORK: Many factors influence the experience of acute myocardial infarction (AMI) and the well-being of affected patients; gender differences emerge in the patterns of influence, and women's specificity is frequently highlighted. The purpose of this literature review is exploring in depth the experience of AMI in women. METHODS: We selected and analyzed 44 articles on five factors strongly affecting women's well-being after AMI: the delay in seeking treatment for symptoms, medical treatment, therapeutic adherence, social support and coping strategies. RESULTS: The studies have attributed gender differences in the delay in seeking care for symptoms partly to a lack of information, but especially to socially built factors, such as the stereotypic belief of cardiac diseases as "male diseases". Studies on the medical treatment show that women are less likely to undergo diagnostic tests and clinical treatment compared to men, but women's older age may counterbalance the gender effect. Compared to men, therapeutic adherence appears lower in women, who find lifestyle changes more difficult to achieve; however, women rely more on social support, affecting positively their well-being. Also, women use more emotion-focused, evasive or fatalistic coping strategies; they are likely to minimize the severity of symptoms, to try to control the disease and to protect the significant others from the negative consequences of the infarction. CONCLUSIONS: Most studies highlight gender differences in the experience of AMI and in the patterns of influence of the factors we analyzed. PMID- 25835767 TI - The hypothesis of contact in nursing: a narrative review of the literature. AB - BACKGROUND AND AIM: In Social Psychology, in relation to the effects of contact, there are two theoretical strands apparently fighting against each other: to one side, the contact hypothesis of Allport according to which, the meeting between members of different groups can, if managed in favorable conditions, reduce prejudice, on the other side, the Social Identity Theory of Tajfel and Turner, according to which the comparison between people belonging to different groups may actually generate an attitude of ingroup favoritism and outgroup discrimination. The aim of this review was to analyze how the literature has dealt with the problem of contact with people from different cultures in relation to its outcomes taking into account the environment of nursing. METHOD: Systematic review. RESULTS: There is sufficient evidence that contacts by race / ethnicity, present in nursing-education settings, in the relationship among nurse practitioners, and between nurses and patients, they produce discriminations and prejudices. The contact in the workplace shows however, also favorable outcomes, highlighting then contradictory results. CONCLUSIONS: The scarcity of material available in the literature and the inconsistency of results, both as regards to the effects of the contact in the training nursing, and as regards to the effects of the contact in relation to the quality of care provided, does not allow definitive conclusions to support the usefulness of the contact in nursing in terms of reducing prejudices and discriminations. It would therefore be advisable to investigate more deeply the effects of contact in the nursing environment. PMID- 25835768 TI - The Health Professions: developments in legislation and training, from student application to employment. AB - BACKGROUND AND AIM: The legislation and training of health workers have undergone various changes during the course of the last 90 years. In addition to the Degrees Medicine in Surgery and Dentistry, with a duration of six years, the Faculty of Medicine and Surgery also offers three-year degree courses in the 22 health professions, including Nursing, Obstetrics, Physiotherapy, Speech Therapy, Laboratory work, Radiology, Neurophysiopathology and Dietetics. METHOD: A data research study was carried out over the last 18 years, on the legislation and training requirements for health workers, including the availability of University places and the applications presented, as well as the number of university lecturers and the employment opportunities. RESULTS: Data reveal a steady increase from 1997 to 2011 in the number of student admission applications for Medicine and Surgery as well as for the other Health Professions, reaching a peak in 2012 and currently continuing to fall. The trend is different for lecturers, who, apart from a slight increase up to 2008, have remained at around 9400 in number since 1997. CONCLUSIONS: The drop in applications for places would appear to be linked to the fall in employment in the last six years, from 86% in 2007 to 62% in 2012. Although the health sector is still in first place among all the other sectors, careful reflection would seem to be warranted on the part of the Regions and the Ministries of Health and University Education when defining the annual training requirements for each of the 22 Health Professions. PMID- 25835769 TI - Desalination by Membrane Distillation using Electrospun Polyamide Fiber Membranes with Surface Fluorination by Chemical Vapor Deposition. AB - Fibrous membranes of poly(trimethyl hexamethylene terephthalamide) (PA6(3)T) were fabricated by electrospinning and rendered hydrophobic by applying a conformal coating of poly(1H,1H,2H,2H-perfluorodecyl acrylate) (PPFDA) using initiated chemical vapor deposition (iCVD). A set of iCVD-treated electrospun PA6(3)T fiber membranes with fiber diameters ranging from 0.25 to 1.8 MUm were tested for desalination using the air gap membrane distillation configuration. Permeate fluxes of 2-11 kg/m2/h were observed for temperature differentials of 20-45 degrees C between the feed stream and condenser plate, with rejections in excess of 99.98%. The liquid entry pressure was observed to increase dramatically, from 15 to 373 kPa with reduction in fiber diameter. Contrary to expectation, for a given feed temperature the permeate flux was observed to increase for membranes of decreasing fiber diameter. The results for permeate flux and salt rejection show that it is possible to construct membranes for membrane distillation even from intrinsically hydrophilic materials after surface modification by iCVD and that the fiber diameter is shown to play an important role on the membrane distillation performance in terms of permeate flux, salt rejection, and liquid entry pressure. PMID- 25835770 TI - Small groups, big gains: efficacy of a tier 2 phonological awareness intervention with preschoolers with early literacy deficits. AB - PURPOSE: The purpose of the present study was to evaluate the efficacy of a phonological awareness (PA) intervention, designed for Tier 2 instruction in a Response to Intervention (RTI) model, delivered to small groups of preschoolers. METHOD: A multiple-baseline design across participants was used to evaluate the efficacy of the intervention on low-income preschool children's PA skills. A trained interventionist delivered small group sessions 3 to 4 days a week and ensured children received frequent opportunities to respond and contingent feedback. Participants received 28 to 36 lessons that lasted about 10 min each and focused on PA and alphabet knowledge. Initiation of intervention was staggered across 3 triads, and 7 children completed the study. RESULTS: The intervention produced consistent gains on weekly progress monitoring assessments of the primary outcome measure for first sound identification (First Sound Fluency). Most children also demonstrated gains on other measures of PA and alphabet knowledge. CONCLUSIONS: Results provide support for the application of a small group intervention consistent with an RTI framework and document the potential benefits of the intervention to learners who need early literacy instruction beyond the core curriculum. PMID- 25835771 TI - The prognostic ability of the STarT Back Tool was affected by episode duration. AB - PURPOSE: The prognostic ability of the STarT Back Tool (SBT) reportedly varies, but the factors affecting this are unclear. This study investigated the influences of care setting (chiropractic, GP, physiotherapy, spine centre), episode duration (0-2, 3-4, 4-12, >12 weeks), and outcome time period (3, 6, 12 months) on SBT prognostic ability. METHODS: This was a secondary analysis of data from three primary care cohorts [chiropractic (n = 416), GP (n = 265), and physiotherapy (n = 200) practices] and one cohort from a secondary care outpatient spine centre (n = 974) in Denmark. Care pathways were not systematically affected by SBT risk subgroup (non-stratified care). Using generalised estimating equations, we investigated statistical interactions between SBT risk subgroups and potentially influential factors on the prognostic ability of the SBT subgroups, when Roland Morris Disability Questionnaire scores were the outcome. RESULTS: SBT risk subgroup, age, care setting, and episode duration were all independent prognostic factors. The only investigated factor that modified the prognostic ability of the SBT subgroups was episode duration. CONCLUSIONS: These results indicate that the prognostic ability of the SBT in these non-stratified care settings was unaffected by care setting on its own. However, the prognosis of patients is affected by diverse clinical characteristics that differ between patient populations, many of which are not assessed by the SBT. When controlling for some of those factors and testing potential interactions, the results showed that only episode duration affected the SBT prognostic ability and, specifically, that the SBT was less predictive in very acute patients (<2 weeks duration). PMID- 25835772 TI - Viral hepatitis and anti-phospholipid antibodies positivity: A systematic review and meta-analysis. AB - BACKGROUND: Anti-phospholipid antibodies positivity is associated with several clinical conditions, including infectious diseases. AIMS: We performed a meta analysis evaluating the association of hepatitis B and C with anti-phospholipid antibody positivity and with anti-phospholipid antibody-related thrombotic complications. METHODS: Studies evaluating the association of viral hepatitis with anti-cardiolipin, anti-beta2 glycoprotein-I and lupus anticoagulant antibodies and anti-phospholipid antibody-related thrombotic events were systematically searched. RESULTS: 20 studies (2319 cases, 1901 controls) were included. The analyses showed that viral hepatitis is associated with the presence of anti-cardiolipin and anti-beta2 glycoprotein-I antibodies. The association with anticardiolipin antibodies was confirmed in both hepatitis B (OR 11.22, 95% CI: 6.68-18.84) and hepatitis C (OR 11.26, 95% CI: 6.82-18.59). Similarly, compared to controls, anti-beta2 glycoprotein-I antibodies were found more frequently in hepatitis B (OR 14.07, 95% CI: 3.06-64.66) and hepatitis C (OR 5.64, 95% CI: 1.69-18.77). Moreover, 11 studies (257 cases, 1079 controls) showed a higher prevalence of venous and/or arterial thrombosis in patients with hepatitis and anti-cardiolipin antibody positivity compared hepatitis alone (OR 3.29, 95% CI: 1.79-6.07). This result was consistently confirmed in hepatitis C (OR 3.64, 95% CI: 1.78-7.46) but not in hepatitis B. CONCLUSIONS: Viral hepatitis is significantly associated with anti-phospholipid antibody positivity and with anti-phospholipid antibody-related thrombotic complications. PMID- 25835773 TI - A comparison of muscle stiffness and musculoarticular stiffness of the knee joint in young athletic males and females. AB - The objective of this study was to investigate the gender-specific differences in peak torque (PT), muscle stiffness (MS) and musculoarticular stiffness (MAS) of the knee joints in a young active population. Twenty-two male and twenty-two female recreational athletes participated. PT of the knee joint extensor musculature was assessed on an isokinetic dynamometer, MS of the vastus lateralis (VL) muscle was measured in both relaxed and contracted conditions, and knee joint MAS was quantified using the free oscillation technique. Significant gender differences were observed for all dependent variables. Females demonstrated less normalized PT (mean difference (MD)=0.4Nm/kg, p=0.005, eta(2)=0.17), relaxed MS (MD=94.2N/m, p<.001, eta(2)=0.53), contracted MS (MD=162.7N/m, p<.001, eta(2)=0.53) and MAS (MD=422.1N/m, p<.001, eta(2)=0.23) than males. MAS increased linearly with the external load in both genders with males demonstrating a significantly higher slope (p=0.019) than females. The observed differences outlined above may contribute to the higher knee joint injury incidence and prevalence in females when compared to males. PMID- 25835774 TI - Acute hyperkinetic syndrome due to ephedrone abuse. AB - OBJECTIVES: A new form of manganese poisoning is related to the intravenous use of self-prepared methcathinone hydrochloride (ephedrone). Manganese encephalopathy typically manifests as a levodopa-resistant parkinsonism. MAIN POINTS: A 32-year-old drug-addicted man with acute gait disturbances after the ephedrone injections was presented. Choreic movements, severe postural instability, and "cock-walk" gait were observed. Magnetic resonance imaging T1 images showed high signal intensity of white matter in the basal ganglia and pituitary gland, and T2 images showed decreased signal mostly of globus pallidus with decreased N-acetylaspartate and choline levels in MR spectroscopy. CONCLUSIONS: The unusual pattern of MR imaging may explain the unusual clinical symptoms with dominant hyperkinetic syndrome. PMID- 25835775 TI - Economic losses occurring due to brucellosis in Indian livestock populations. AB - Brucellosis is a serious public health issue in India. Estimation of economic losses occurring due to brucellosis is required to help formulate prevention and control strategies, but has not been done in India. We estimated economic losses due to brucellosis by sourcing prevalence data from epidemiological surveys conducted in India. Data for livestock populations were obtained from official records. Probability distributions were used for many of the input parameters to account for uncertainty and variability. The analysis revealed that brucellosis in livestock is responsible for a median loss of US $ 3.4 billion (5th-95th percentile 2.8-4.2 billion). The disease in cattle and buffalo accounted for 95.6% of the total losses occurring due to brucellosis in livestock populations. The disease is responsible for a loss of US $ 6.8 per cattle, US$18.2 per buffalo, US $ 0.7 per sheep, US $ 0.5 per goat and US $ 0.6 per pig. These losses are additional to the economic and social consequences of the disease in humans. The results suggest that the disease causes significant economic losses in the country and should be controlled on a priority basis. PMID- 25835777 TI - A comparative study of open, laparoscopic and robotic partial nephrectomy in obese patients. PMID- 25835778 TI - Asiaticoside attenuates lipopolysaccharide-induced acute lung injury via down regulation of NF-kappaB signaling pathway. AB - Asiaticoside (AS), a triterpene glycoside isolated from Centella asiatica, has been shown to possess potent anti-inflammatory activity. However, the detailed molecular mechanisms of AS on lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in mice are scanty. The purpose of this study was to evaluate the effect of AS on LPS-induced mouse ALI via down-regulation of NF-kappaB signaling pathway. We investigated the efficacy of AS on cytokine levels induced by LPS in bronchoalveolar lavage fluid (BALF) and RAW 264.7 cells. The production of cytokine (TNF-alpha and IL-6) was measured by enzyme-linked immunosorbent assay (ELISA). The lung wet-to-dry weight ratios were measured in LPS-challenged mice, and lung histopathologic changes observed via paraffin section were assessed. To further study the mechanism of AS protective effects on ALI, the activation of NF kappaB p65 subunit and the degradation of IkappaBalpha were tested by western blot assay. We found that AS treatment at 15, 30 or 45mg/kg dose-dependently attenuated LPS-induced pulmonary inflammation by reducing inflammatory infiltration, histopathological changes, descended cytokine production, and pulmonary edema initiated by LPS. Furthermore, our results suggested that AS suppressed inflammatory responses in LPS-induced ALI through inhibition of the phosphorylation of NF-kappaB p65 subunit and the degradation of its inhibitor IkappaBalpha, and might be a new preventive agent of ALI in the clinical setting. PMID- 25835779 TI - Guiding efficient microbial synthesis of non-natural chemicals by physicochemical properties of reactants. AB - The recent progress in sustainable chemistry and in synthetic biology increased the interest of chemical and pharmaceutical industries to implement microbial processes for chemical synthesis. However, most organisms used in biotechnological applications are not evolved by Nature for the production of hydrophobic, non-charged, volatile, or toxic compounds. In order to overcome this discrepancy, bioprocess design should consist of an integrated approach addressing pathway, cellular, reaction, and process engineering. Highlighting selected examples, we show that surprisingly often Nature provides conceptual solutions to enable chemical synthesis. Complemented by established methods from (bio)chemical and metabolic engineering, these concepts offer potential strategies yet to be explored and translated into innovative technical solutions enabling sustainable microbial production of non-natural chemicals. PMID- 25835780 TI - Validity and reliability of smartphone magnetometer-based goniometer evaluation of shoulder abduction--A pilot study. AB - BACKGROUND: Goniometers are commonly used by physical therapists to measure range of-motion (ROM) in the musculoskeletal system. These measurements are used to assist in diagnosis and to help monitor treatment efficacy. With newly emerging technologies, smartphone-based applications are being explored for measuring joint angles and movement. OBJECTIVE: This pilot study investigates the intra- and inter-rater reliability as well as concurrent validity of a newly-developed smartphone magnetometer-based goniometer (MG) application for measuring passive shoulder abduction in both sitting and supine positions, and compare against the traditional universal goniometer (UG). DESIGN: This is a comparative study with repeated measurement design. METHODS: Three physical therapists utilized both the smartphone MG and a traditional UG to measure various angles of passive shoulder abduction in a healthy subject, whose shoulder was positioned in eight different positions with pre-determined degree of abduction while seated or supine. Each therapist was blinded to the measured angles. Concordance correlation coefficients (CCCs), Bland-Altman plotting methods, and Analysis of Variance (ANOVA) were used for statistical analyses. RESULTS: Both traditional UG and smartphone MG were reliable in repeated measures of standardized joint angle positions (average CCC > 0.997) with similar variability in both measurement tools (standard deviation (SD) +/- 4 degrees ). Agreement between the UG and MG measurements was greater than 0.99 in all positions. CONCLUSION: Our results show that the smartphone MG has equivalent reliability compared to the traditional UG when measuring passive shoulder abduction ROM. With concordant measures and comparable reliability to the UG, the newly developed MG application shows potential as a useful tool to assess joint angles. PMID- 25835781 TI - Mitochondrial dysfunction in skeletal muscle during experimental Chagas disease. AB - Trypanosoma cruzi invasion and replication in cardiomyocytes and other tissues induce cellular injuries and cytotoxic reactions, with the production of inflammatory cytokines and nitric oxide, both sources of reactive oxygen species. The myocyte response to oxidative stress involves the progression of cellular changes primarily targeting mitochondria. Similar alterations could be taking place in mitochondria from the skeletal muscle; if that is the case, a simple skeletal muscle biopsy would give information about the cardiac energetic production that could be used as a predictor of the chagasic cardiopathy evolution. Therefore, in the present paper we studied skeletal muscle mitochondrial structure and the enzymatic activity of citrate synthase and respiratory chain complexes I to IV (CI-CIV), in Albino Swiss mice infected with T. cruzi, Tulahuen strain and SGO Z12 and Lucky isolates, along the infection. Changes in the mitochondrial structure were detected in 100% of the mitochondria analyzed from the infected groups: they all presented at least 1 significant abnormality such as increase in their matrix or disorganization of their cristae, which are probably related to the enzymatic dysfunction. When we studied the Krebs cycle functionality through the measurement of the specific citrate synthase activity, we found it to be significantly diminished during the acute phase of the infection in Tulahuen and SGO Z12 infected groups with respect to the control one; citrate synthase activity from the Lucky group was significantly increased (p<0.05). The activity of this enzyme was reduced in all the infected groups during the chronic asymptomatic phase (p<0.001) and return to normal values (Tulahuen and SGO Z12) or increased its activity (Lucky) by day 365 post infection (p.i.). When the mitochondrial respiratory chain was analyzed from the acute to the chronic phase of the infection through the measurement of the activity of complexes I to IV, the activity of CI remained similar to control in Tulahuen and Lucky groups, but was significantly augmented in the SGO Z12 one in the acute and chronic phases (p<0.05). CII increased its activity in Tulahuen and Lucky groups by day 75 p.i. and in SGO Z12 by day 365 p.i. (p<0.05). CIII showed a similar behavior in the 3 infected groups, remaining similar to control values in the first two stages of the infection and significantly increasing later on (p<0.0001). CIV showed an increase in its activity in Lucky throughout all stages of infection (p<0.0001) and an increase in Tulahuen by day 365days p.i. (p<0.0001); SGO Z12 on the other hand, showed a decreased CIV activity at the same time. The structural changes in skeletal muscle mitochondria and their altered enzyme activity began in the acute phase of infection, probably modifying the ability of mitochondria to generate energy; these changes were not compensated in the rest of the phases of the infection. Chagas is a systemic disease, which produces not only heart damage but also permanent skeletal muscle alterations. PMID- 25835782 TI - KRAS gene mutation in a series of unselected colorectal carcinoma patients with prognostic morphological correlations: a pyrosequencing method improved by nested PCR. AB - INTRODUCTION: Inhibition of EGFR is a strategy for treating metastatic colorectal cancer (CRC) patients. KRAS sequencing is mandatory for selecting wild-type tumor patients who might benefit from this treatment. DNA from formalin-fixed paraffin embedded (FFPE) tissues is commonly used for routine clinical detection of mutations, and its amplification succeeds only when all preanalytical histological processes have been controlled. In cases that are not properly processed, the DNA results can be poor, with low peak pyrosequencing findings. We designed and tested a pair of forward and reverse primers for a nested PCR method, followed by pyrosequencing, in a single Latin American institution series of 422 unselected CRC patients, correlating KRAS mutations with pathological and clinical data. MATERIALS AND METHODS: Patient DNA samples from tumors were obtained by scraping or laser microdissection of cells from FFPE tissue and extracted using a commercial kit. DNA was first amplified by PCR using 2 primers that we designed; then, nested PCR was performed with the amplicon from the preamplification PCR using the KRAS PyroMarkTM Q96 V2.0 kit (Qiagen). Pathological data were retrieved from pathology reports. RESULTS: KRAS mutation was observed in 33% of 421 cases. Codon 12 was mutated in 76% of cases versus codon 13 in 24%. Right-sided CRCs harbored more KRAS mutations than left-sided tumors, as did tumors that presented with perineural invasion. CONCLUSION: Our findings in this Latin American population are consistent with the literature regarding the frequency of KRAS mutations in CRC, their distribution between codons 12 and 13, and type of nucleotide substitution. By combining nested PCR and pyrosequencing, we achieved a high rate of conclusive results in testing KRAS mutations in CRC samples - a method that can be used as an ancillary test for failed assays by conventional PCR. PMID- 25835783 TI - Diagnostic performance of HPV E6/E7, hTERT, and Ki67 mRNA RT-qPCR assays on formalin-fixed paraffin-embedded cervical tissue specimens from women with cervical cancer. AB - Human papillomavirus (HPV) is a major cause of cervical cancer, which is the third most common cancer in women. Human telomerase reverse transcriptase (hTERT) and Ki67 are tumor cell markers indicating cancer cell proliferation in cancer patients, and activation of hTERT and Ki67 leads to progressive cervical carcinogenesis. In the present study, we evaluated the CervicGen HPVE6/E7 mRNA RT qDx assay, which detects 16 HPV high-risk (HR) genotypes (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68 and 69), and the CervicGen hTERT and Ki67 mRNA RT-qDx assay using 117 formalin-fixed paraffin-embedded (FFPE) cervical cancer tissue samples. The diagnostic validity of the CervicGen HPV RT-qDx assay for detecting histologically proven prevalent squamous cell carcinoma (SCC) was 94% sensitivity, 100% specificity, 77.8% positive predictive value (PPV), and 78.9% negative predictive value (NPV). The most common HPV genotypes detected in FFPE cervical cancer tissue samples were HPV 16 (56%) and HPV 18 (10%). The positivity rate of hTERT and Ki67 mRNA expressions in FFPE cervical cancer tissue samples on RT-qPCR was 65% and 93% respectively. Moreover, the positivity rates were 92% for a combination of HPV E6/E7 and hTERT mRNA expressions, 97% for HPV E6/E7 and Ki67 mRNA expressions, and 99% (99/100) for the combination of HPV E6/E7, hTERT, and Ki67 mRNA expressions. These data showed that SSC FFPE cervical cancer tissue samples correlated more strongly with high Ki67 mRNA expressions than with hTERT mRNA expressions. Notably, hTERT and Ki67 mRNA expression level was increased in high-grade cervical lesions, but was very low in normal samples. Our findings suggest that the combination of HPV E6/E7, hTERT, and Ki67 mRNA expression levels could be used in a complementary manner in diagnosing high grade cervical lesions. Further studies are required to evaluate these assays as a useful predictive tool for screening low-grade cervical lesions. PMID- 25835784 TI - Lipophilic constituents from two processed products and three different parts of Changium smyrnioides Wolff. AB - This article reports the lipophilic chemical composition of different processed products (Changii Radix, Changii Radix Alba) and parts (root bark, leaf and fruit) of Changium smyrnioides Wolff.. The lipophilic constituents were extracted with petroleum ether in Soxhlet apparatus, subsequently identified and determined by gas chromatography-mass spectroscopy (GC-MS). Yield of lipophilic constituents from Changii Radix (3.65%) was about three times more than Changii Radix Alba's (1.07%), which indicated processing by boiling in water had an impact on the content of lipophilic constituents. Moreover, the major compounds in different processed products and parts were found to be fatty acids and sesquiterpenes. The results are a contribution for the lipophilic chemical composition and can serve as a reference for product development of Changium smyrnioides Wolff.. PMID- 25835785 TI - Clinical application of antenatal genetic diagnosis of osteogenesis imperfecta type IV. AB - BACKGROUND: Clinical analysis and genetic testing of a family with osteogenesis imperfecta type IV were conducted, aiming to discuss antenatal genetic diagnosis of osteogenesis imperfecta type IV. MATERIAL/METHODS: Preliminary genotyping was performed based on clinical characteristics of the family members and then high throughput sequencing was applied to rapidly and accurately detect the changes in candidate genes. RESULTS: Genetic testing of the III5 fetus and other family members revealed missense mutation in c.2746G>A, pGly916Arg in COL1A2 gene coding region and missense and synonymous mutation in COL1A1 gene coding region. CONCLUSIONS: Application of antenatal genetic diagnosis provides fast and accurate genetic counseling and eugenics suggestions for patients with osteogenesis imperfecta type IV and their families. PMID- 25835786 TI - Football practice and urinary incontinence: Relation between morphology, function and biomechanics. AB - Current evidence points to a high prevalence of urinary incontinence among female athletes. In this context, this study aims to assess if structural and biomechanical characteristics of the pubovisceral muscles may lead to urine leakage. Clinical and demographic data were collected, as well as pelvic Magnetic Resonance Imaging. Furthermore, computational models were built to verify if they were able to reproduce similar biomechanical muscle response as the one measured by dynamic imaging during active contraction by means of the percent error. Compared to the continent ones (n=7), incontinent athletes (n=5) evidenced thicker pubovisceral muscles at the level of the midvagina (p=0.019 and p=0.028 for the right and left sides, respectively). However, there were no differences neither in the strength of contraction in the Oxford Scale or in the displacement of the pelvic floor muscles during simulation of voluntary contraction, which suggests that urine leakage may be related with alterations in the intrafusal fibers than just the result of thicker muscles. Additionally, we found similar values of displacement retrieved from dynamic images and numerical models (6.42 +/- 0.36 mm vs. 6.10 +/- 0.47 mm; p=0.130), with a percent error ranging from 1.47% to 17.20%. However, further refinements in the mechanical properties of the striated skeletal fibers of the pelvic floor muscles and the inclusion of pelvic organs, fascia and ligaments would reproduce more realistically the pelvic cavity. PMID- 25835788 TI - Meniscus replacement: Influence of geometrical mismatches on chondroprotective capabilities. AB - The chondroprotective success of meniscal transplantation is variable. Poorly controlled factors such as a geometrical mismatch of the implant may be partly responsible. Clinical data, animal studies and cadaver experiments suggest that smaller transplants perform better than oversized, but clear evidence is lacking. The hypothesis of this study is that smaller menisci outperform larger ones because they distribute stresses more effectively at those particular locations that receive the highest loads. Consequently, collagen in the adjacent cartilage is protected from damage due to overstraining. Experimentally it is not possible to measure load distribution and collagen strain inside articular cartilage (AC). Therefore, a numerical model was used to determine the mechanical conditions throughout the depth of the AC. Meniscus implants with different sizes and mechanical properties were evaluated. These were compared with healthy and with meniscectomized joints. To account for the time-dependent behavior 600s of loading was simulated; results were visualized after 1s and 600s. Simulations showed that AC's strains strongly depended on implant size and loading duration. They depended less on the stiffness of the implant material. With an oversized implant, collagen strains were particularly large in the femoral AC initially and further increased upon sustained loading. The severest compressive strains occurred after sustained loading in the meniscectomized joint. Strains with an undersized meniscus were comparable to a perfectly sized implant. In conclusion, these results support the hypothesis that an undersized implant may outperform an oversized one because it distributes stresses better in the most intensely loaded joint area. PMID- 25835789 TI - A viscoelastic model for axonal microtubule rupture. AB - Axon is an important part of the neuronal cells and axonal microtubules are bundles in axons. In axons, microtubules are coated with microtubule-associated protein tau, a natively unfolded filamentous protein in the central nervous system. These proteins are responsible for cross-linking axonal microtubule bundles. Through complimentary dimerization with other tau proteins, bridges are formed between nearby microtubules creating bundles. Formation of bundles of microtubules causes their transverse reinforcement and has been shown to enhance their ability to bear compressive loads. Though microtubules are conventionally regarded as bearing compressive loads, in certain circumstances during traumatic brain injuries, they are placed in tension. In our model, microtubule bundles were formed from a large number of discrete masses. We employed Standard Linear Solid model (SLS), a viscoelastic model, to computationally simulate microtubules. In this study, we investigated the dynamic responses of two dimensional axonal microtubules under suddenly applied end forces by implementing discrete masses connected to their neighboring masses with a Standard Linear Solid unit. We also investigated the effect of the applied force rate and magnitude on the deformation of bundles. Under tension, a microtubule fiber may rupture as a result of a sudden force. Using the developed model, we could predict the critical regions of the axonal microtubule bundles in the presence of varying end forces. We finally analyzed the nature of microtubular failure under varying mechanical stresses. PMID- 25835787 TI - Computational study of false vocal folds effects on unsteady airflows through static models of the human larynx. AB - Compressible large eddy simulation is employed to numerically investigate the laryngeal flow. Symmetric static models of the human larynx with a divergent glottis are considered, with the presence of false vocal folds (FVFs). The compressible study agrees well with that of the incompressible study. Due to the high enough Reynolds number, the flow is unsteady and develops asymmetric states downstream of the glottis. The glottal jet curvature decreases with the presence of FVFs or the ventricular folds. The gap between the FVFs stretches the flow structure and reduces the jet curvature. The presence of FVFs has a significant effect on the laryngeal flow resistance. The intra-glottal vortex structures are formed on the divergent wall of the glottis, immediately downstream of the separation point. The vortices are then convected downstream and characterized by a significant negative static pressure. The FVFs are a main factor in the generation of stronger vortices, and thus on the closure of the TVFs. The direct link between the FVFs geometry and the motion of the TVFs, and by extension to the voice production, is of interest for medical applications as well as future research works. The presence of the FVFs also changes the dominant frequencies in the velocity and pressure spectra. PMID- 25835790 TI - Dimensionless analysis of valveless pumping in a thick-wall elastic tube: Application to the tubular embryonic heart. AB - The physical mechanism that drives blood flow in the valveless tubular embryonic heart is still debatable whether it is peristaltic flow or valveless dynamic suction. Previous studies of valveless pumping were concerned with either the role of the excitation parameters or the mechanisms that generate the unidirectional outflow. In this study, a dimensionless one-dimensional (1D) analysis of the valveless pumping due to local excitation at an asymmetric longitudinal location was performed for non-uniform thick-wall elastic tubes, including tubes with local bulging and tapering. A general tube law that accounts for wall thicknesses was implemented for describing the physically realistic dynamics of the tube and the two-step MacCormack algorithm was utilized for the numerical analysis. A comprehensive analysis was conducted to explore the affecting roles of the system (e.g., tube geometry) and the working (e.g., Strouhal number and flow friction parameter) parameters on the net outflow of the pump. The maximal positive net outflow in all the tested cases always occurred when the natural Strouhal number was about pi. Flow reversals were observed only for relatively low friction parameters. A local bulging at the site of excitation and thick walls contributed to larger outflows, while tube tapering reduced the net outflow. PMID- 25835791 TI - A data mining approach to optimize pellets manufacturing process based on a decision tree algorithm. AB - The present study is focused on the thorough analysis of cause-effect relationships between pellet formulation characteristics (pellet composition as well as process parameters) and the selected quality attribute of the final product. The shape using the aspect ratio value expressed the quality of pellets. A data matrix for chemometric analysis consisted of 224 pellet formulations performed by means of eight different active pharmaceutical ingredients and several various excipients, using different extrusion/spheronization process conditions. The data set contained 14 input variables (both formulation and process variables) and one output variable (pellet aspect ratio). A tree regression algorithm consistent with the Quality by Design concept was applied to obtain deeper understanding and knowledge of formulation and process parameters affecting the final pellet sphericity. The clear interpretable set of decision rules were generated. The spehronization speed, spheronization time, number of holes and water content of extrudate have been recognized as the key factors influencing pellet aspect ratio. The most spherical pellets were achieved by using a large number of holes during extrusion, a high spheronizer speed and longer time of spheronization. The described data mining approach enhances knowledge about pelletization process and simultaneously facilitates searching for the optimal process conditions which are necessary to achieve ideal spherical pellets, resulting in good flow characteristics. This data mining approach can be taken into consideration by industrial formulation scientists to support rational decision making in the field of pellets technology. PMID- 25835792 TI - Basic concepts and techniques of dental implants. AB - Dental implants provide completely edentulous and partial edentulous patients the function and esthetics they had with natural dentition. It is critical to understand and apply predictable surgical principles when treatment planning and surgically restoring edentulous spaces with implants. This article defines basic implant concepts that should be meticulously followed for predictable results when treating patients and restoring dental implants. Topics include biological and functional considerations, biomechanical considerations, preoperative assessments, medical history and risk assessments, oral examinations, radiographic examinations, contraindications, and general treatment planning options. PMID- 25835793 TI - Three-dimensional imaging and guided surgery for dental implants. AB - Clinicians worldwide are increasingly adopting guided surgical applications for dental implants. Clinicians are becoming more aware of the benefits of proper planning through advanced imaging modalities and interactive treatment planning applications. All aspects of the planning phase are based on sound surgical and restorative fundamentals. As an integral part of the implant team, dental laboratories have now moved from analog to the digital world, providing the necessary support to the new digital workflow. PMID- 25835794 TI - Treatment planning for restorative implantology. AB - In this article, current literature on fixed and removable prosthodontics is reviewed along with evidence-based systematic reviews, including advice from those in the dental profession with years of experience, which help restorative dentists manage and treat their cases successfully. Treatment planning for restorative implantology should be looked at in 4 sections: (1) review of past medical history, (2) oral examination and occlusion, (3) dental imaging (ie, cone beam computed tomography), and (4) fixed versus removable prosthodontics. These 4 concepts of treatment planning, along with proper surgical placements of the implant(s), result in successful cases. PMID- 25835796 TI - Short implants: are they a viable option in implant dentistry? AB - Short-length implants (<10 mm) can be used effectively in atrophic maxillae or mandibles even with crown/implant ratios that previously would have been considered excessive. Short implants can support either single or multiple units and can be used for fixed prostheses or overdentures. The use of short-length implants may avoid the need for complicated bone augmentation procedures, thus allowing patients who were either unwilling or unable for financial or medical reasons to undergo these advanced grafting techniques to be adequately treated. PMID- 25835795 TI - Tissue response: biomaterials, dental implants, and compromised osseous tissue. AB - Tissue response represents an important feature in biocompatibility in implant procedures. This review article highlights the fundamental characteristics of tissue response after the implant procedure. This article also highlights the tissue response in compromised osseous conditions. Understanding the histologic events after dental implants in normal and abnormal bone reinforces the concept of case selection in dental implants. PMID- 25835797 TI - Treatment of peri-implantitis and the failing implant. AB - Appropriate treatment of implants is becoming increasingly important for the general dentist as the number of implants placed per year continues to increase. Early diagnosis of peri-implantitis is imperative; initiating the correct treatment protocol depends on a proper diagnosis. Several risk factors exist for the development of peri-implantitis, which can guide patient selection and treatment planning. Treatment of peri-implantitis should be tailored to the severity of the lesion (as outlined by the cumulative interceptive supportive treatment protocol), ranging from mechanical debridement to explantation. Several surgical and nonsurgical treatment alternatives exist. There is little consensus on superior treatment methods. PMID- 25835798 TI - Immediate placement and immediate loading: surgical technique and clinical pearls. AB - Dental implants have had tremendous improvement since their initial introduction into clinical practice. With ongoing advances in implant technology and materials, better data emerge to allow shorter time between placement and restoration. This allows the restorative dentist and surgeon to provide improved treatment options to patients. Most evidence that exists supports the practice of immediately placed (after extraction) and immediately loaded implants. Additional high-quality studies are still needed to develop specific guidelines for a standardized approach to immediate rehabilitation. PMID- 25835799 TI - Implant-related nerve injuries. AB - Injuries to branches of the trigeminal nerves are a known complication during dental implant placement. These injuries tend to be more severe than those experienced during other dentoalveolar procedures. This article reviews the types of nerve injuries and areas and situations of which clinicians should be cognizant when placing dental implants. Strategies to avoid injuries, and a management algorithm for suspected nerve injuries, are also discussed. PMID- 25835800 TI - Maxillary sinus augmentation. AB - Pneumatization of the maxillary sinus secondary to posterior maxillary tooth loss is an extremely common finding. Significant atrophy of the maxilla prevents implant placement in this region. For several decades, sinus augmentation has been used to develop these sites for dental implant placement. The main techniques for increasing the vertical bone height of the posterior maxilla are the transalveolar and lateral antrostomy approaches. The clinical and radiographic examinations dictate the appropriate method for each clinical situation. Both techniques have been shown to have high success rates. However, practitioners must be aware of potential complications and how to address them. PMID- 25835801 TI - Surgical techniques for augmentation in the horizontally and vertically compromised alveolus. AB - The deficient alveolar ridge has been an impediment to the placement of dental implants in the past. A greater comprehension of bone biophysiology and biotechnology has greatly increased the surgical options available to rehabilitate these patients. Technology and regenerative science has also allowed clinicians to simplify some of the approaches to these patients. This article presents the authors' perspective on the current surgical treatment methodologies that have been most beneficial in reconstructing atrophic alveolar bone. PMID- 25835802 TI - Autogenous bone harvest for implant reconstruction. AB - Autogenous bone harvest is the gold standard for restoring deficiencies of the recipient site. A deficient site requires adequate grafting before placement of implants; therefore, proper understanding of the wide variety of grafting options is the key to successfully planned implant dentistry. This provides general dentists with a better understanding of autogenous bone harvest and the variety of techniques available to provide the best outcomes for the patient. PMID- 25835803 TI - Contemporary "All-on-4" concept. AB - Restoration of the atrophic edentulous maxilla and mandible with implant retained prostheses has involved the use of axially placed implants in regions of the maxilla and mandible based on the adequate availability of bone, often using a staged surgical approaches. Anatomic limitations including pneumatized maxillary sinus, proximity of the inferior alveolar nerve and lack of available native bone have many clinicians performing traditional grafting procedure prior to implant placement. Utilization of the "All-on-4" concept has overcome these anatomic restrictions by allowing placement of 2 vertical and 2 angled implants in the premaxilla and anterior mandible. This technique has enabled immediate placement of full arch fixed restoration at the time of implant surgery if sufficient torque is achieved. It has biomechanical advantages including increasing in A-P spread, enhancing load distribution with cross arch stabilization, shorten cantilever, longer implants to be placed by titling them posteriorly, and maintenance of marginal bone height. High implant survival rates of in the maxilla (92.5-100%), in the mandible (93-100%) and restoration (99.2-100%) prove that the "All-on-4" concept is a viable treatment option for edentulous patients with atrophic alveolar ridges circumventing these traditional grafting procedures. PMID- 25835804 TI - Soft tissue surgery for implants. AB - Adequate quality and quantity of soft tissue plays an integral part in the esthetic outcome of dental implants. Adequate band of attached tissue decreases the incidence of mucositis and improves hygiene around implants. This article discusses a variety of techniques for soft tissue augmentation. Soft tissue grafting can be achieved at various stages of implant therapy. Epithelial connective tissue grafts are commonly used to increase the band of attached tissue. Subepithelial connective tissue grafts are great for increasing soft tissue thickness and improving the gingival biotype. PMID- 25835805 TI - Bone morphogenic protein: application in implant dentistry. AB - Alveolar bone that is insufficient to support implant placement due to lack of height or width may be augmented with grafting materials including bone morphogenic protein to create sites that are adequate for implant placement and long-term stability of implant-supported prosthesis. Bone morphogenic protein can be used alone or in concert with other bone graft materials as an alternative to invasive allograft bone harvesting procedures. PMID- 25835806 TI - Implant surface material, design, and osseointegration. AB - The structural and functional union of the implant with living bone is greatly influenced by the surface properties of the implant. The success of a dental implant depends on the chemical, physical, mechanical, and topographic characteristics of its surface. The influence of surface topography on osseointegration has translated to shorter healing times from implant placement to restoration. This article presents a discussion of surface characteristics and design of implants, which should allow the clinician to better understand osseointegration and information coming from implant manufacturers, allowing for better implant selection. PMID- 25835807 TI - Implant procedures for the general dentist. PMID- 25835808 TI - Investigation of the Effect of the Tortuous Pore Structure on Water Diffusion through a Polymer Film Using Lattice Boltzmann Simulations. AB - Understanding how the pore structure influences the mass transport through a porous material is important in several applications, not the least in the design of polymer film coatings intended to control drug release. In this study, a polymer film made of ethyl cellulose and hydroxypropyl cellulose was investigated. The 3D structure of the films was first experimentally characterized using confocal laser scanning microscopy data and then mathematically reconstructed for the whole film thickness. Lattice Boltzmann simulations were performed to compute the effective diffusion coefficient of water in the film and the results were compared to experimental data. The local porosities and pore sizes were also analyzed to determine how the properties of the internal film structure affect the water effective diffusion coefficient. The results show that the top part of the film has lower porosity, lower pore size, and lower connectivity, which results in a much lower effective diffusion coefficient in this part, largely determining the diffusion rate through the entire film. Furthermore, the local effective diffusion coefficients were not proportional to the local film porosity, indicating that the results cannot be explained by a single tortuosity factor. In summary, the proposed methodology of combining microscopy data, mass transport simulations, and pore space analysis can give valuable insights on how the film structure affects the mass transport through the film. PMID- 25835809 TI - Serotypes and Pulsotypes diversity of Listeria monocytogenes in a beef-processing environment. AB - Utensils and equipment from meat-processing facilities are considered relevant cross-contamination points of Listeria monocytogenes to foods, demanding tracking studies to identify their specific origins, and predict proper control. The present study aimed to detect L. monocytogenes in a beef-processing facility, investigating the diversity of serotypes and pulsotypes in order to identify the possible contamination routes. Surface samples from knives (n=26), tables (n=78), and employees hands (n=74) were collected before and during the procedures from a beef-processing facility, in addition to surface samples of end cuts: round (n=32), loin (n=30), and chuck (n=32). All samples were subjected to L. monocytogenes screening according ISO 11.290-1, and the obtained isolates were subjected to serotyping and pulsed-field gel electrophoresis. Listeria spp. were identified in all processing steps, in 61 samples, and L. monocytogenes was detected in 17 samples, not being found only in knives. Eighty-five isolates were identified as L. monocytogenes, from serotypes 1/2c (n=65), 4b (n=13), and 1/2b (n=7), being grouped in 19 pulsotypes. Considering these results, cross contamination among hands, tables, and beef cuts could be identified. The obtained data indicated the relevance of cross-contamination in the beef processing facility, and the occurrence of serotypes 1/2b and 4b in beef cuts distributed for retail sale is a public health concern. PMID- 25835810 TI - Expert elicitation as a means to attribute 28 enteric pathogens to foodborne, waterborne, animal contact, and person-to-person transmission routes in Canada. AB - Enteric illness contributes to a significant burden of illness in Canada and globally. Understanding its sources is a critical step in identifying and preventing health risks. Expert elicitation is a powerful tool, used previously, to obtain information about enteric illness source attribution where information is difficult or expensive to obtain. Thirty-one experts estimated transmission of 28 pathogens via major transmission routes (foodborne, waterborne, animal contact, person-to-person, and other) at the point of consumption. The elicitation consisted of a (snowball) recruitment phase; administration of a pre survey to collect background information, an introductory webinar, an elicitation survey, a 1-day discussion, survey readministration, and a feedback exercise, and surveys were administered online. Experts were prompted to quantify changes in contamination at the point of entry into the kitchen versus point of consumption. Estimates were combined via triangular probability distributions, and medians and 90% credible-interval estimates were produced. Transmission was attributed primarily to food for Bacillus cereus, Clostridium perfringens, Cyclospora cayetanensis, Trichinella spp., all three Vibrio spp. categories explored, and Yersinia enterocolitica. Multisource pathogens (e.g., transmitted commonly through both water and food) such as Campylobacter spp., four Escherichia coli categories, Listeria monocytogenes, Salmonella spp., and Staphylococcus aureus were also estimated as mostly foodborne. Water was the primary pathway for Giardia spp. and Cryptosporidium spp., and person-to-person transmission dominated for six enteric viruses and Shigella spp. Consideration of the point of attribution highlighted the importance of food handling and cross-contamination in the transmission pathway. This study provides source attribution estimates of enteric illness for Canada, considering all possible transmission routes. Further research is necessary to improve our understanding of poorly characterized pathogens such as sapovirus and E. coli subgroups in Canada. PMID- 25835812 TI - 77Se NMR spectroscopy as a sensitive probe for Hammett sigma constants. AB - Herein we showcase the use of a combination of (1)H, (13)C, and (77)Se NMR spectroscopy as a sensitive tool for correlation analysis. A series of substituted O-aryl selenocarbamates [ArOC(Se)N(CH3)2] and Se-aryl selenocarbamates [ArSeC(O)N(CH3)2] have been investigated by means of (1)H, (13)C, and (77)Se NMR spectroscopy. We have determined the (1)H, (13)C, and (77)Se chemical shift values as well as both one- and two-bond heteronuclear (13)C-(77)Se coupling constants, and the changes in both the chemical shift values and the coupling constants were found to obey linear free energy relationships with Hammett's sigma(p) and sigma(p)(-) constants. For the eight studied O-aryl selenocarbamates, we observe linear free energy correlations with two of the (13)C and (77)Se chemical shift values and as well as one (13)C-(77)Se coupling constant. With the five examples of Se-aryl selenocarbamates, linear correlations are observed with three different (13)C-(77)Se coupling constants. The strong internal consistency validates the use of (77)Se NMR spectroscopy for correlation analysis. PMID- 25835811 TI - Array comparative genomic hybridization identifies a heterozygous deletion of exon 3 of the RYR2 gene. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a heritable cardiac disorder characterized by life-threatening ventricular tachycardia caused by exercise or acute emotional stress. The standard diagnostic screening involves Sanger-based sequencing of 45 of the 105 translated exons of the RYR2 gene, and copy number changes of a limited number of exons that are detected using multiplex ligation-dependent probe amplification (MLPA). METHODS: In the current study, a previously validated bespoke array comparative genomic hybridization (aCGH) technique was used to detect copy number changes in the RYR2 gene in a 43-year-old woman clinically diagnosed with CPVT. RESULTS: The CGH array detected a 1.1 kb deletion encompassing exon 3 of the RYR2 gene. This is the first report using the aCGH technique to screen for mutations causing CPVT. CONCLUSIONS: The aCGH method offers significant advantages over MLPA in genetic screening for heritable cardiac disorders. PMID- 25835813 TI - Minimally invasive bone-saving orbitotomy for removal of optic nerve cysticercosis. AB - A 32-year-old man previously being managed for multiple neurocysticercosis presented with a reduction in vision and pain on eye movement. Fundus examination revealed disc edema with venous dilatation. MRI showed a localized hypointensity on T1 weighted images and hyperintensity on T2 weighted images suggestive of a cyst in the optic nerve sheath. Medical therapy with albendazole and steroids did not improve vision. Surgical removal of the cyst was achieved by a modified lateral orbital exploration using a lateral canthal incision without bone removal, with full recovery of vision. Histopathological examination confirmed cysticercosis. PMID- 25835814 TI - Ethanol Extract of Sarcodon asparatus Mitigates Inflammatory Responses in Lipopolysaccharide-Challenged Mice and Murine Macrophages. AB - A number of compounds isolated from mushrooms have exhibited disease-modifying effects. We sought to investigate the mechanisms responsible for the anti inflammatory effects of an extract from the mushroom species Sarcodon asparatus (SAE). Male BALB/c mice (N=42; 6 weeks old) were randomly assigned to four treatment groups. Intraperitoneal administration of SAE significantly attenuated lipopolysaccharide (LPS)-mediated increases in alanine aminotransferase (ALT) activity. LPS also increased serum levels of proinflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha, which were dose-dependently and significantly attenuated by SAE. Correlative relationships between serum ALT activity and proinflammatory cytokines suggested that SAE-mediated suppression of liver injury was partly attributable to the attenuation of serum inflammatory responses. SAE significantly decreased hepatic NO(*) production and subsequent 3-nitrotyrosine formation, and the hepatic NO(*) production significantly correlated with serum ALT and cytokine levels, suggesting that SAE mitigates liver injury in association with inflammatory processes, likely by suppressing NO(*) production. Anti-inflammatory activity and further mechanisms of SAE were evaluated using RAW264.7 with LPS challenge. Noncytotoxic levels of SAE significantly attenuated NO(*) production in RAW264.7 cells and also markedly suppressed the expression of iNOS and other proinflammatory mediators, including COX-2 and IL-6, which were upregulated in the presence of LPS. SAE inhibited the phosphorylation of p65, an observation that occurred independently of IKKalphabeta-mediated IkappaBalpha phosphorylation. Collectively, our results demonstrate that SAE suppressed NO(*) mediated inflammation by inhibiting p65 transcriptional activation without affecting IKKalphabeta-mediated IkappaBalpha phosphorylation. Further studies are warranted to examine the major compounds responsible for these effects and the mechanisms responsible for the p65 phosphorylation observed. PMID- 25835820 TI - Dispersion and monochromatization of x-rays using a beryllium prism. AB - We demonstrate experimentally and numerically that an x-ray prism made of beryllium can be used to disperse and monochromatize x-rays. A polished beryllium cuboid was employed as refractive and dispersive optics. The results of a proof of-principle experiment and methods of performance optimization are presented. The spatial separation of undulator harmonics and their subsequent selection using a slit are described. A numerical study, assuming realistic beam and beamline parameters, suggests that undulator harmonics can be spatially separated in the range from 3 keV to beyond 20 keV, while maintaining throughput above 50%. Refractive optics is particularly suitable for low-repetition-rate sources such as free-electron lasers and other LINAC-based short-pulse sources. PMID- 25835821 TI - Comparison of femtosecond laser ablation of aluminum in water and in air by time resolved optical diagnosis. AB - The dynamic process of material ejection and shock wave evolution during one single femtosecond laser pulse ablation of aluminum target in water and air is experimentally investigated by employing pump-probe technique. Shadowgraphs and digital holograms with high temporal resolution are recorded, which intuitively reveal the characteristics of femtosecond laser ablation in the water-confined environment. The experimental result indicates that the liquid significantly restrict the diffusion of the ejected material, and it has a considerable effect on the attenuation of the shock wave. In addition, the expansion Mach wave generated by the ultrasonic expansion of the shock wave is observed. PMID- 25835819 TI - Brief report: Correlates of inpatient psychiatric admission in children and adolescents with eating disorders. AB - OBJECTIVE: To examine the prevalence and importance of psychological, behavioural, and situational correlates of impending psychiatric inpatient admissions in children and adolescents with eating disorders. METHOD: The sample consisted of 285 patients (8-17 years, M = 14.4, SD = 1.49) with DSM-5 eating disorders assessed between 2006 and 2013 from the Helping to Outline Pediatric Eating Disorders (HOPE) Project. The sample was split into two groups, those with (n = 38) and without (n = 247) impending psychiatric admission; Discriminant function analysis was used to examine correlates. RESULTS: The prevalence of impending psychiatric admission was 13.3%. Suicidal ideation provided the greatest discriminating power, followed by eating pathology, depressive symptoms, anxiety, multiple methods of weight control, binge eating, and family functioning. CONCLUSIONS: Earlier recognition of comorbid symptoms in eating disorders in the community may reduce the number of young people with eating disorders who present needing critical psychiatric care. PMID- 25835822 TI - Contact poling of Rb:KTiOPO(4) using a micro-structured silicon electrode. AB - A contact poling technique for domain engineering of ferroelectrics using a micro structured silicon electrode is demonstrated on Rb:KTiOPO4. High quality QPM gratings were reproducibly fabricated. The silicon electrode is reusable and the technique potentially suitable when complex structures with sub MUm features are to be domain engineered, which otherwise is incompatible with conventional photolithography. A non-negligible domain broadening was seen and attributed to a low nucleation rate using this type of electrode. However, under the appropriate poling conditions, this could be exploited to obtain a QPM grating with a short pitch (2 MUm), equal to half of the electrode period. PMID- 25835823 TI - High confinement, high yield Si(3)N(4) waveguides for nonlinear optical applications. AB - In this paper we present a novel fabrication technique for silicon nitride (Si(3)N(4)) waveguides with a thickness of up to 900 nm, which are suitable for nonlinear optical applications. The fabrication method is based on etching trenches in thermally oxidized silicon and filling the trenches with Si(3)N(4). Using this technique no stress-induced cracks in the Si(3)N(4) layer were observed resulting in a high yield of devices on the wafer. The propagation losses of the obtained waveguides were measured to be as low as 0.4 dB/cm at a wavelength of around 1550 nm. PMID- 25835824 TI - Tomography of spatial mode detectors. AB - Transformation and detection of photons in higher-order spatial modes usually requires complicated holographic techniques. Detectors based on spatial holograms suffer from non-idealities and should be carefully calibrated. We report a novel method for analyzing the quality of projective measurements in spatial mode basis inspired by quantum detector tomography. It allows us to calibrate the detector response using only gaussian beams. We experimentally investigate the inherent inaccuracy of the existing methods of mode transformation and provide a full statistical reconstruction of the POVM (positive operator valued measure) elements for holographic spatial mode detectors. PMID- 25835825 TI - Optical encryption using photon-counting polarimetric imaging. AB - We present a polarimetric-based optical encoder for image encryption and verification. A system for generating random polarized vector keys based on a Mach-Zehnder configuration combined with translucent liquid crystal displays in each path of the interferometer is developed. Polarization information of the encrypted signal is retrieved by taking advantage of the information provided by the Stokes parameters. Moreover, photon-counting model is used in the encryption process which provides data sparseness and nonlinear transformation to enhance security. An authorized user with access to the polarization keys and the optical design variables can retrieve and validate the photon-counting plain-text. Optical experimental results demonstrate the feasibility of the encryption method. PMID- 25835826 TI - Snapshot phase shift fringe projection 3D surface measurement. AB - We propose a novel snapshot phase shift fringe projection three-dimensional (3D) surface measurement method using polarization-coded light illumination and polarization camera. The light from the light source is split into two beams, one is left circularly polarized and the other is right circularly polarized, to illuminate the object simultaneously. A four-channel division of focal plane (DoFP) polarization camera is employed to capture the light reflected from the object surface. Four images with a phase shift of pi/2 are extracted from the snapshot image and then analyzed to reconstruct a 3D object surface. The proposed method is the first snapshot phase shift fringe projection approach for 3D surface imaging. It is insensitive to motion and has the potential for ultrafast 3D surface imaging. PMID- 25835827 TI - Cascaded interferometers structure based on dual-pass Mach-Zehnder interferometer and Sagnac interferometer for dual-parameter sensing. AB - In this article, we propose and demonstrate a cascaded interferometers structure based on a dual-pass Mach-Zehnder interferometer (DP-MZI) and a Sagnac interferometer (SI) for simultaneous measurement of strain and lateral stress. The cascaded interferometers configuration consists of a SI structure following with a MZI setup. By inserting a section of polarization-maintaining photonic crystal fiber (PM-PCF) in the sensing loop of the SI structure, an inline interference between the two orthogonal polarization modes of PM-PCF, as well as the interference between the sensing arm and the reference arm of the DP-MZI, i.e., the cascaded interferometers with dual interference, are realized. Theoretical study shows that the reflection spectrum of such cascaded interferometers is consisted of two parts: the big spectrum envelope owing to the SI and the fine interference fringes as a result of the DP-MZI. Experimental results show that the SI achieves the sensitivity of lateral stress and strain 1.28 nm/kPa, 0.78 pm/uepsilon, respectively, while the DP-MZI achieves -0.009 nm/kPa and 5.65 pm/uepsilon, demonstrating the ability for dual parameters measurement with high accuracy. PMID- 25835828 TI - High-quality near-field beam achieved in a high-power laser based on SLM adaptive beam-shaping system. AB - We demonstrate a high-power laser system with a high-quality near-field beam by using a liquid-crystal spatial light modulator (SLM). An efficient spatial beam shaping algorithm is discussed which can improve the output nearfield beam quality effectively. Both small-signal and large-signal amplification situation of the laser are considered in the beam shaping algorithm. The experimental results show that the near field fluence modulation of output is improved from 1.99:1 to 1.26:1 by using the liquid-crystal SLM. Obvious uniform spatial fluence distribution and near-field beam quality improvement are observed. PMID- 25835829 TI - Spherical and sub-wavelength longitudinal magnetization generated by 4pi tightly focusing radially polarized vortex beams. AB - Based on the vector diffraction theory and the inverse Faraday effect, we numerically study the light-induced magnetization near the focus of a 4pi high numerical aperture focusing configuration under the illumination of two counter- propagating radially polarized hollow Gaussian vortex beams. The simulated results demonstrate that, by selecting higher-order vortex beam modes (e.g. n=4with n - the beam order) and proper truncation parameter (e.g. beta=1.75 with beta- the ratio of the pupil radius to the incident beam waist), spherical and sub-wavelength longitudinal magnetization can be generated in the vicinity of focus. Such special magnetization feature is attributed to not only the interaction between optical vortices and the radially polarized beams, but also the completely destructive interference of azimuthal components and the constructive interference of the longitudinal component of the two counter propagating radially polarized vortex beams. This spherical and sub-wavelength longitudinal magnetization distribution may be of interest for applications in all-optical magnetic recording and confocal and magnetic resonance microscopy. PMID- 25835830 TI - Heterogeneously integrated photonic-crystal lasers on silicon for on/off chip optical interconnects. AB - We demonstrate the continuous-wave operation of lambda-scale embedded active region photonic-crystal (LEAP) lasers at room temperature, which we fabricated on a Si wafer. The on-Si LEAP lasers exhibit a threshold current of 31 MUA, which is the lowest reported value for any type of semiconductor laser on Si. This reveals the great potential of LEAP lasers as light sources for on- or off-chip optical interconnects with ultra-low power consumption in future information communication technology devices including CMOS processors. PMID- 25835831 TI - Numerical modeling of femtosecond laser inscribed IR gratings in photonic crystal fibers. AB - During grating inscription in photonic crystal fibers (PCFs) the intensity of the inscribing laser beam is non-uniformly distributed over the core region due to the interaction with the air holes in the fiber's microstructure. In this paper we model and study the non-uniformity of the index modification and its influence on the grating reflection spectra, taking into account the non-linear nature of the index change. For femtosecond laser inscription pulses at 800 nm, we show that the intensity redistribution in the PCF core region can result in Type II index changes even if the peak intensity of the incident beam is well below the corresponding threshold. Our coupled mode analysis reveals that the non-uniform nature of the index change can seriously affect the reflectivity of the grating due to a limited overlap of the guided mode with the transverse index modulation profile for almost all angular orientations of the PCFs with respect to the inscription beam. We also evaluate the influence of PCF tapering and we found that for the considered PCF a significant increase in the induced index change and reflectivity is observed only for taper diameters below 40 MUm. PMID- 25835832 TI - Flexible terabit/s Nyquist-WDM super-channels using a gain-switched comb source. AB - Terabit/s super-channels are likely to become the standard for next-generation optical networks and optical interconnects. A particularly promising approach exploits optical frequency combs for super-channel generation. We show that injection locking of a gain-switched laser diode can be used to generate frequency combs that are particularly well suited for terabit/s super-channel transmission. This approach stands out due to its extraordinary stability and flexibility in tuning both center wavelength and line spacing. We perform a series of transmission experiments using different comb line spacings and modulation formats. Using 9 comb lines and 16QAM signaling, an aggregate line rate (net data rate) of 1.296 Tbit/s (1.109 Tbit/s) is achieved for transmission over 150 km of standard single mode fiber (SSMF) using a spectral bandwidth of 166.5 GHz, which corresponds to a (net) spectral efficiency of 7.8 bit/s/Hz (6.7 bit/s/Hz). The line rate (net data rate) can be boosted to 2.112 Tbit/s (1.867 Tbit/s) for transmission over 300 km of SSMF by using a bandwidth of 300 GHz and QPSK modulation on the weaker carriers. For the reported net data rates and spectral efficiencies, we assume a variable overhead of either 7% or 20% for forward- error correction depending on the individual sub-channel quality after fiber transmission. PMID- 25835833 TI - Simulation investigation of tensile strained GeSn fin photodetector with Si(3)N(4) liner stressor for extension of absorption wavelength. AB - In this paper, we design a biaxial tensile strained GeSn photodetector with fin structure wrapped in Si(3)N(4) liner stressor. A large biaxial tensile strain is induced in GeSn fins by the expansion of Si(3)N(4) liner stressor. The distribution of tensile strain in GeSn fins was calculated by a finite element simulation. It is observed that magnitude of the strain increases with the reduction of fin thickness T(fin). Under the biaxial tensile strain, the direct band gap E(G,Gamma) of GeSn fin photodetector is significantly reduced by lowering Gamma conduction valley in energy and lifting of degeneracy of valence bands. As the 30 nm Si(3)N(4) liner stressor expanses by 1%, a E(G,Gamma) reduction of ~0.14 eV is achieved in Ge(0.92)Sn(0.08) fins with a T(fin) of 100 nm. The cut-off wavelengths of strained Ge(0.96)Sn(0.04), Ge(0.92)Sn(0.08) and Ge(0.90)Sn(0.10) fin photodetectors with a T(fin) of 100 nm are extended to 2.4, 3.3, and 4 MUm, respectively. GeSn fin photodetector integrated with Si(3)N(4) liner stressor provides an effective technique for extending the absorption edge of GeSn with Sn composition less than 10% to mid-infrared wavelength. PMID- 25835834 TI - 980nm pumped erbium doped tellurium oxide planar rib waveguide laser and amplifier with gain in S, C and L band. AB - A thin film based erbium doped tellurium oxide (TeO2) waveguide amplifier producing gain from 1500nm to 1640nm when pumped at 980nm is demonstrated. At measured internal gains exceeding 14dB lasing due to end facet reflection set in producing the first tellurite waveguide laser. High gains were observed despite significant upconversion, whose impact appears to be mitigated to some extent by residual OH contamination. The device displayed no photosensitive effects from either the high pumping intensities used or the intracavity intensity at 1550nm. PMID- 25835835 TI - Experimental quantification of surface optical nonlinearity in GaP nanopillar waveguides. AB - We report on surface second-order optical nonlinearity in single GaP nanopillars (nanowaveguides). The relative contribution of optical nonlinearity from the surface and the bulk is resolved by mode confinement analysis and polarization measurements. By investigating the thickness of nonlinear region at the surface of nanopillars, we estimated the nonlinear coefficient to be ~15 times higher at the surface with respect to the bulk. The presented results are interesting both from the fundamental aspects of light-matter interaction and for future nonlinear nanophotonic devices with smaller footprint. PMID- 25835836 TI - Millisecond laser machining of transparent materials assisted by nanosecond laser. AB - A new form of double pulse composed of a nanosecond laser and a millisecond laser is proposed for laser machining transparent materials. To evaluate its advantages and disadvantages, experimental investigations are carried out and the corresponding results are compared with those of single millisecond laser. The mechanism is discussed from two aspects: material defects and effects of modifications induced by nanosecond laser on thermal stress field during millisecond laser irradiation. It is shown that the modifications of the sample generated by nanosecond laser improves the processing efficiency of subsequent millisecond laser, while limits the eventual size of modified region. PMID- 25835837 TI - High resolution double-sided diffractive optics for hard X-ray microscopy. AB - The fabrication of high aspect ratio metallic nanostructures is crucial for the production of efficient diffractive X-ray optics in the hard X-ray range. We present a novel method to increase their structure height via the double-sided patterning of the support membrane. In transmission, the two Fresnel zone plates on the two sides of the substrate will act as a single zone plate with added structure height. The presented double-sided zone plates with 30 nm smallest zone width offer up to 9.9% focusing efficiency at 9 keV, that results in a factor of two improvement over their previously demonstrated single-sided counterparts. The increase in efficiency paves the way to speed up X-ray microscopy measurements and allows the more efficient utilization of the flux in full-field X-ray microscopy. PMID- 25835838 TI - Three dimensional multi-molecule tracking in thick samples with extended depth-of field. AB - We present a non-z-scanning multi-molecule tracking system with nano-resolution in all three dimensions and extended depth of field (DOF), which based on distorted grating (DG) and double-helix point spread function (DH-PSF) combination microscopy (DDCM). The critical component in DDCM is a custom designed composite phase mask (PM) combining the functions of DG and DH-PSF. The localization precision and the effective DOF of the home-built DDCM system based on the designed PM were tested. Our experimental results show that the three dimensional (3D) localization precision for the three diffraction orders of the grating are sigma(-1st)(x, y, z) = (6.5 nm, 9.2nm, 23.4 nm), sigma(0th)(x, y, z) = (3.7 nm, 2.8nm, 10.3 nm), and sigma(+1s)(x, y, z) = (5.8 nm, 6.9 nm, 18.4 nm), respectively. Furthermore, the total effective DOF of the DDCM system is extended to 14 MUm. Tracking experiment demonstrated that beads separated over 12 MUm along the axial direction at some instants can be localized and tracked successfully. PMID- 25835839 TI - Strong magneto-optical effects due to surface states in three-dimensional topological insulators. AB - We show that a thin film of a three-dimensional topological insulator such as Bi(2)Se(3)or Bi(2)Te(3) can exhibit strong linear and nonlinear magneto-optical effects in a transverse magnetic field. In particular, one can achieve an almost complete circular polarization of an incident terahertz or mid-infrared radiation and an efficient four-wave mixing. PMID- 25835840 TI - Engineered liquid crystal anchoring energies with nanopatterned surfaces. AB - The anchoring energy of liquid crystals was shown to be tunable by surface nanopatterning of periodic lines and spaces. Both the pitch and height were varied using hydrogen silsesquioxane negative tone electron beam resist, providing for flexibility in magnitude and spatial distribution of the anchoring energy. Using twisted nematic liquid crystal cells, it was shown that this energy is tunable over an order of magnitude. These results agree with a literature model which predicts the anchoring energy of sinusoidal grooves. PMID- 25835841 TI - High sensitivity 10Gb/s Si photonic receiver based on a low-voltage waveguide coupled Ge avalanche photodetector. AB - We demonstrate low-voltage germanium waveguide avalanche photodetectors (APDs) with a gain * bandwidth product above 100GHz. A photonic receiver based on such a Ge APD, including a 0.13MUm SiGe BiCMOS low-noise trans-impedance amplifier and a limiting amplifier, is realized. A 5.8dB sensitivity improvement is demonstrated at -5.9V bias at an avalanche gain of 6 through bit error ratio measurements. The absolute sensitivity in avalanche mode is -23.4dBm and -24.4dBm at a bit error ratio of 1 * 10(-12) and 1 * 10(-9) respectively. PMID- 25835842 TI - Photo-induced voltage in nano-porous gold thin film. AB - We report an experimental study of generation of photo-induced voltage in nano porous gold (NPG) thin film under the radiation of obliquely incident nanosecond laser light in visible regions. For s- polarized light, negative voltage is observed along the incident plane for positive incident angles, while for p- polarized light, positive voltage is observed for wavelength longer than 510 nm, while it turns to negative for shorter wavelengths. The transverse voltage for various polarized light is explained in terms of symmetry of configuration and that of microscopically random but macroscopically isotropic NPG. PMID- 25835843 TI - High-efficiency CW all-fiber parametric oscillator tunable in 0.92-1 MUm range. AB - Continuous tuning over 80 nm is demonstrated for the anti-Stokes wave generated in an optical parametric oscillator (OPO) based on a birefringent photonic crystal fiber pumped by a CW Ytterbium-doped fiber laser tuned around 1.05 MUm (within 4 nm only). An influence of the pump laser linewidth and polarization state on the fiber OPO threshold and efficiency is studied. Slope efficiency of parametric generation at 931 nm reaches 19% for ~0.1 nm linearly polarized pump with threshold power of ~5W. At that, the generated linewidth amounts to about 1 nm. PMID- 25835844 TI - Broadband RF front-end using microwave photonics filter. AB - We propose and demonstrate a novel RF front-end with broadened processing bandwidth, where a tunable microwave photonic filter based on optical frequency comb (OFC) is incorporated to accomplish simultaneous down-conversion and filtering. By designing additional phase shaping and time delay controlling, the frequency tunability of the system could be enhanced. More importantly, the beating interferences generated from broadband RF input could also be suppressed, which help to break the limitation on the processing bandwidth. In our experiments, a photonics RF receiver front-end for RF input with wide bandwidth of almost 20 GHz was realized using 10-GHz-space OFC, where the center frequency of the pass band signals could be tuned continuously. PMID- 25835845 TI - Frequency modulation based continuous-wave terahertz homodyne system. AB - In this study, inspired by the frequency-modulated continuous-wave (FMCW) method, an operation scheme of continuous-wave (CW) terahertz (THz) homodyne system is proposed and evaluated. For this purpose, we utilized the fast and stable wavelength tuning characteristics of a dual-mode laser (DML) as a beating source. Using the frequency-modulated THz waves generated by DML, a cost-effective and robust operation of CW THz system to be applicable to the measurements of thickness or refractive index of a sample is demonstrated. We believe that the proposed scheme shows a potential to the implementations of compact and fast CW THz measurement systems that can be useful in many THz applications. PMID- 25835846 TI - Optoelectronic method for inline compensation of XPM in long-haul optical links. AB - We propose an optoelectronic subsystem for inline compensation of XPM-induced phase noise in long-haul optical links. Based on intensity-dependent phase rotation, these compensators are used to suppress XPM on a span-by-span basis. Using a 7-channel hybrid WDM system as a test case, our simulations show that this technique is effective at suppressing XPM in dispersion managed and unmanaged links for various transmission distances. PMID- 25835847 TI - Three-dimensional efficient dispersive alternating-direction-implicit finite difference time-domain algorithm using a quadratic complex rational function. AB - Efficient unconditionally stable FDTD method is developed for the electromagnetic analysis of dispersive media. Toward this purpose, a quadratic complex rational function (QCRF) dispersion model is applied to the alternating-direction-implicit finite-difference time-domain (ADI-FDTD) method. The 3-D update equations of QCRF ADI-FDTD are derived using Maxwell's curl equations and the constitutive relation. The periodic boundary condition of QCRF-ADI-FDTD is discussed in detail. A 3-D numerical example shows that the time-step size can be increased by the proposed QCRF-ADI-FDTD beyond the Courant-Friedrich-Levy (CFL) number, without numerical instability. It is observed that, for refined computational cells, the computational time of QCRF-ADI-FDTD is reduced to 28.08 % of QCRF FDTD, while the L2 relative error norm of a field distribution is 6.92 %. PMID- 25835848 TI - Experimental investigation on the nonlinear tolerance of root M-shaped pulse in spectrally efficient coherent transmissions. AB - We experimentally demonstrate improved intra-channel nonlinearity tolerance of the root M-shaped pulse (RMP) with respect to the root raised cosine (RRC) pulse in spectrally efficient 128 Gbit/s PDM-16QAM coherent transmission systems. In addition we evaluate the impact of dispersion map and fiber dispersion parameter on the intra-channel nonlinearity tolerance of the RRC pulse and the RMP via both simulation and experimentation. The RMP is shown to have a better nonlinear tolerance than the RRC pulse for most investigated scenarios except for links with zero residual dispersion percentage per span or the zero dispersion region of a fiber. Therefore, the RMP is suitable for extending the maximum reach of spectrally efficient coherent transmission systems in legacy links in addition to currently intensively studied standard single mode fiber (SSMF) based dispersion unmanaged links. PMID- 25835849 TI - Raman amplification of pure side-seeded higher-order modes in hydrogen-filled hollow-core PCF. AB - We use Raman amplification in hydrogen-filled hollow-core kagome photonic crystal fiber to generate high energy pulses in pure single higher-order modes. The desired higher-order mode at the Stokes frequency is precisely seeded by injecting a pulse of light from the side, using a prism to select the required modal propagation constant. An intense pump pulse in the fundamental mode transfers its energy to the Stokes seed pulse with measured gains exceeding 60 dB and output pulse energies as high as 8 uJ. A pressure gradient is used to suppress stimulated Raman scattering into the fundamental mode at the Stokes frequency. The growth of the Stokes pulse energy is experimentally and theoretically investigated for six different higher-order modes. The technique has significant advantages over the use of spatial light modulators to synthesize higher-order mode patterns, since it is very difficult to perfectly match the actual eigenmode of the fiber core, especially for higher-order modes with complex multi-lobed transverse field profiles. PMID- 25835850 TI - Improved WDM performance of a fibre optical parametric amplifier using Raman assisted pumping. AB - We experimentally demonstrate a Raman-Assisted Fibre Optical Parametric Amplifier (RA-FOPA) with 20dB net gain using wavelength division multiplexed signals. We report amplification of 10x58Gb/s 100GHz-spaced QPSK signals and show that by appropriate tuning of the parametric pump power and frequency, gain improvement of up to 5dB can be achieved for the RA-FOPA compared with combined individual contributions from the parametric and Raman pumps. We compare the RA-FOPA with an equivalent-gain conventional FOPA and find that four-wave mixing crosstalk is substantially reduced by up to 5.8 +/- 0.4dB using the RA-FOPA. Worst-case performance penalty of the RA-FOPA is found to be only 1.0 +/- 0.2dB over all measured OSNRs, frequencies and input powers, making it an attractive proposal for future communications systems. PMID- 25835851 TI - Broadband standoff detection of large molecules by mid-infrared active coherent laser spectrometry. AB - A widely tunable active coherent laser spectrometer (ACLaS) has been demonstrated for standoff detection of broadband absorbers in the 1280 to 1318 cm-1 spectral region using an external cavity quantum cascade laser as a mid-infrared source. The broad tuning range allows detection and quantification of vapor phase molecules, such as dichloroethane, ethylene glycol dinitrate, and tetrafluoroethane. The level of confidence in molecular mixing ratios retrieved from interfering spectral measurements is assessed in a quantitative manner. A first qualitative demonstration of condensed phase chemical detection on nitroacetanilide has also been conducted. Detection performances of the broadband ACLaS have been placed in the context of explosive detection and compared to that obtained using distributed feedback quantum cascade lasers. PMID- 25835852 TI - Bio-inspired variable imaging system simplified to the essentials: modelling accommodation and gaze movement. AB - A combination of an aspherical hybrid diffractive-refractive lens with a flexible fluidic membrane lens allows the implementation of a light sensitive and wide aperture optical system with variable focus. This approach is comparable to the vertebrate eye in air, in which the cornea offers a strong optical power and the flexible crystalline lens is used for accommodation. Also following the natural model of the human eye, the decay of image quality with increasing field position is compensated, in the optical system presented here, by successively addressing different tilting angles which mimics saccadic eye-movements. The optical design and the instrumental implementation are presented and discussed, and the working principle is demonstrated. PMID- 25835853 TI - Silicon hybrid (de)multiplexer enabling simultaneous mode and wavelength-division multiplexing. AB - On-chip simultaneous mode and wavelength division-multiplexing (MWDM) is proposed using a tapered directional coupler and multimode interference (MMI) waveguide. A simulation is performed on the two different MWDM architectures, in which, two waveguide eigenmodes and two wavelength channels (1310/1550nm) are multiplexed. One of the proposed devices is compact (6MUm x 100MUm) and exhibits insertion loss as low as 1.2dB with a cross-talk of (-18dB). PMID- 25835854 TI - Backscattering-immune one-way surface magnetoplasmons at terahertz frequencies. AB - Surface magnetoplasmons (SMPs) in a basic physical model for the terahertz regime, which consists of a semi-infinite magnetized semiconductor with dielectric cladding terminated by a metal slab, are theoretically investigated. The dispersion properties of such SMPs are analyzed and examined in detail. It is shown that SMPs may follow three different kinds of dispersion diagrams, depending on the applied dc magnetic field intensity. Complete one-way propagation that operates within the band gap of the semiconductor is available for SMPs, and the one-way bandwidth reaches a maximum at a certain magnetic field intensity. Regular modes guided by the dielectric layer are also analyzed. These modes may cause the (complete) SMP one-way region to be compressed or even removed, but they can be suppressed by reducing the dielectric layer thickness. Owing to the mirror effect of the metal slab, one-way propagating and backscattering-immune basic SMPs can exhibit a larger propagation length than those sustained by a single dielectric-semiconductor interface. PMID- 25835855 TI - Dielectric-based subwavelength metallic meanders for wide-angle band absorbers. AB - We propose nano-meanders that can achieve wide-angle band absorption in visible regime. The nano-meander consists of a subwavelength dielectric grating covered by continuous ultra-thin Aluminum film (less than one tenth of the incident wavelength). The excited photonic resonant modes, such as cavity mode, surface plasmonic mode and Rayleigh-Wood anomaly, are discussed in detail. Nearly total resonant absorption due to funneling mechanism in the air nano-groove is almost invariant with large incident angle in transverse magnetic polarization. From both the structural geometry and the nanofabrication point of view, the light absorber has a very simple geometrical structure and it is easy to be integrated into complex photonic devices. The highly efficient angle-robust light absorber can be potential candidate for a range of passive and active photonic applications, including solar-energy harvesting as well as producing artificial colors on a large scale substrate. PMID- 25835856 TI - Hexagonal liquid crystal lens array for 3D endoscopy. AB - A liquid crystal lens array with a hexagonal arrangement is investigated experimentally. The uniqueness of this study exists in the fact that using convex ring electrode provides a smooth and controllable applied potential profile across the aperture to manage the phase profile. We observed considerable differences between flat electrode and convex-ring electrode; in particular the lens focal length is variable in a wider range from 2.5cm to infinity. This study presents several noteworthy characteristics such as low driving voltage; 30 MUm cell gap and the lens is electrically switchable between 2D/3D modes. We demonstrate a hexagonal LC-lens array for capturing 3D images by using single sensor using integral imaging. PMID- 25835857 TI - Optical single-sideband OFDM transmission based on a two-segment EAM. AB - This paper presents a novel optical single-sideband (SSB) OFDM modulation scheme using a two-segment electro-absorption modulator (EAM). Differences in the chirp characteristics of two segments of the EAM make it possible to design driving signals capable of suppressing one of the optical sidebands, such that the optical OFDM signal does not suffer from frequency-selective power fading following dispersive fiber transmission. Our experiment results demonstrate optical OFDM transmissions at 13.5-Gbps over a 0 ~ 200-km IM/DD system without the need for dispersion compensation and distance-dependent bit- and power loading. PMID- 25835858 TI - Single channel 112Gbit/sec PAM4 at 56Gbaud with digital signal processing for data centers applications. AB - 112Gbit/sec DSP-based single channel transmission of PAM4 at 56Gbaud over 15GHz of effective analog bandwidth is experimentally demonstrated. The DSP enables use of mature 25G optoelectronics for 2-10km datacenter intra-connections, and 8Tbit/sec over 80km interconnections between data centers. PMID- 25835859 TI - Planar-type polarization beam splitter based on a bridged silicon waveguide coupler. AB - We demonstrate a compactly integrated polarization beam splitter (PBS) with high polarization extinction ratios greater than 20 dB over the full C-band wavelength range based on a simple bridged silicon nanowaveguide directional coupler. The PBS device is designed via three dimensional finite-difference time-domain (3D FDTD) simulation, and fabricated experimentally. The optimum dimension of the bridge waveguide is determined to be 7.5-MUm-long and 500 nm-wide for 250-nm thick silicon core. At the 1,550-nm wavelength, the measured polarization extinction ratios (PERs) of the PBS device are 22.5 dB and 22.9 dB for TE and TM polarization modes, respectively, and its corresponding insertion losses (ILs) are about 2.1 dB and 1.8 dB, both PERs and ILs within the maximum error range of +/- 2.0 dB. PMID- 25835860 TI - Nanoscale roughness micromilled silica evanescent refractometer. AB - We demonstrate machining of precision slots in silica with nanoscale roughness for applications in photonics. Using our in-house developed milling system we have achieved machined slots with surface roughness of 3.0 nm (Sa) and 17 um depth of cut. This result represents eight times improvement in surface roughness and forty times increase in depth of cut than previously reported. We also demonstrate integration of these milled slots with UV-written waveguides and Bragg gratings to create optical refractometers, based on monitoring Fabry-Perot spectral fringe changes. PMID- 25835861 TI - Terahertz isolator based on nonreciprocal magneto-metasurface. AB - A magneto-metasurface with nonreciprocal terahertz (THz) transmission has been proposed to form a THz isolator. Importantly, we have discussed the two necessary conditions for THz nonreciprocal transmission in the metasurface: (1) There should be magneto-optical responses for THz waves in the metasurface; (2) The transmission system of the metasurface needs to be asymmetric for forward and backward waves. These two conditions lead to the time reversal symmetry breaking of system, and the magnetoplasmon mode splitting and nonreciprocal resonance enhancement can be observed in the asymmetry magneto-metasurface. Moreover, the isolation dependences and tunability on the external magnetic field and temperature have also been investigated, which shows that the best operating state with a high isolation can be designed. The numerical simulations show a maximum isolation of 43 dB and a 10 dB operating bandwidth of 20 GHz under an external magnetic field of 0.3 T, and the insertion loss is smaller than 1.79 dB. This low-loss, high isolation, easy coupling THz isolator has broadly potentials for THz application systems. PMID- 25835862 TI - Efficient free-space read-out of WGM lasers using circular micromirrors. AB - Lasing from whispering-gallery mode (WGM) resonators occurs omnidirectional in azimuthal plane. Most applications of WGM resonators require spectral analysis with off-chip detectors, where in-plane emission and beam divergence hinder efficient detection. We demonstrate redirecting WGM laser emission from all azimuthal angles using a circular micromirror placed around the cavity. By collecting reflections off the micromirror via free-space optics, read-out intensity improved by one order of magnitude. Blocking vertically emitted spontaneous emission and recording reflections off the micromirror only, signal to-noise ratio improved from 4.6 dB to 15 dB. Our read-out concept may be applied to arbitrary WGM cavity geometries without deteriorating the cavity's quality factor. PMID- 25835863 TI - Heat accumulation in ultra-short pulsed scanning laser ablation of metals. AB - High average laser powers can have a serious adverse impact on the ablation quality in ultra-short pulsed laser material processing of metals. With respect to the scanning speed, a sharp transition between a smooth, reflective and an uneven, dark ablated surface is observed. Investigating the influence of the sample temperature, it is experimentally shown that this effect stems from heat accumulation. In a numerical heat flow simulation, the critical scanning speed indicating the change in ablation quality is determined in good agreement with the experimental data. PMID- 25835864 TI - Near-zero pretilt alignment of liquid crystals using polyimide films doped with UV-curable polymer. AB - We propose an alignment method for the near-zero pretilt angle of liquid crystals (LCs) using polyimide films doped with a UV-curable polymer. The near-zero pretilt angle can be obtained by UV curing of reactive mesogen monomers mixed with planar alignment material while a vertical electric field is applied to an LC cell assembled after the rubbing process. We demonstrated that the pretilt angle can be decreased from 2.390 degrees to 0.082 degrees by employing the proposed method. PMID- 25835865 TI - Beam shaping of complex amplitude with separate constraints on the output beam. AB - We present a beam shaping technique in controlling the complex amplitude of an optical beam. The constraint on the amplitude of the output beam in the Gerchberg Saxton algorithm is replaced with constraints both on the amplitude and phase of the output beam in the proposed method. The total areas of the constrained regions and free regions on the complex amplitude of the output beam in the proposed method are maintained. An output beam with arbitrary complex amplitude can be realized with the proposed method. The computing result from the proposed method is a phase-only distribution, which can be fabricated as diffractive optical element for higher diffraction efficiency. Both simulations and experiments are present and the effectiveness of the proposed method is verified. PMID- 25835866 TI - A diffuser-based three-dimensional measurement of polarization-dependent scattering characteristics of optical films for 3D-display applications. AB - We propose an accurate and easy-to-use three-dimensional measurement method using a diffuser plate to analyze the scattering characteristics of optical films. The far-field radiation pattern of light scattered by the optical film is obtained from the illuminance pattern created on the diffuser plate by the light. A mathematical model and calibration methods were described, and the results were compared with those obtained by a direct measurement using a luminance meter. The new method gave very precise three-dimensional polarization-dependent scattering characteristics of scattering polarizer films, and it can play an effective role in developing high performance polarization-selective screens for 3D display applications. PMID- 25835867 TI - Excimer laser induced quantum well intermixing: a reproducibility study of the process for fabrication of photonic integrated devices. AB - Excimer (ultraviolet) laser-induced quantum well intermixing (UV-Laser-QWI) is an attractive technique for wafer level post-growth processing and fabrication of a variety of monolithically integrated photonic devices. The results of UV-Laser QWI employed for the fabrication of multibandgap III-V semiconductor wafers have demonstrated the attractive character of this approach although the process accuracy and reproducibility have remained relatively weakly covered in related literature. We report on a systematic investigation of the reproducibility of this process induced with a KrF excimer laser. The influence of both the irradiation with different laser doses and the annealing temperatures on the amplitude of intermixing in InGaAs/InGaAsP/InP quantum well heterostructures has been evaluated based on the photoluminescence measurements. Under optimized conditions, the process allows to blue shift the bandgap of a heterostructure by more than 100 nm with a remarkable 5.3% relative standard deviation. PMID- 25835868 TI - An 11.6 W output, 6 kHz linewidth, single-polarization EDFA-MOPA system with a (13)C(2)H(2) frequency stabilized fiber laser. AB - We demonstrate a record high CW output power of 11.6 W and an ultra-narrow linewidth of 6 kHz in an all-fiber master oscillator and power amplifier (MOPA) fiber laser system. The master oscillator is a (13)C(2)H(2) frequency-stabilized single-polarization fiber laser with a 100 mW output. The power amplifier section consists of a core-pumped polarization-maintained erbium-doped fiber pumped by a 1480 nm cascaded Raman fiber laser. A total electric-to-optical conversion efficiency with a record high value of 12% was achieved with an all-fiber configuration. PMID- 25835869 TI - Propagation properties of partially coherent electromagnetic hyperbolic-sine Gaussian vortex beams through non-Kolmogorov turbulence. AB - Propagation properties of partially coherent electromagnetic hyperbolic-sine Gaussian (PCESHG) vortex beams through non-Kolmogorov atmospheric turbulence, including the spectral degree of polarization and evolution behavior of coherent vortices and average intensity are investigated in detail by using the extended Huygens-Fresnel principle and the spatial power spectrum of the refractive index of non-Kolmogorov turbulence. It is shown that the motion, creation and annihilation of the coherent vortices of PCESHG vortex beams in non-Kolmogorov turbulence may appear with the increasing propagation distance, and the distance for the conservation of the topological charge depends on the turbulence parameters and beam parameters. In additions, the evolution behavior of coherent vortices, average intensity and spectral degree of polarization vary significantly for different values of the generalized exponent parameter and the generalized refractive-index structure parameter of non-Kolmogorov turbulence, and the beam parameters as well as the propagation distance. PMID- 25835870 TI - Time-bin entangled photon pair generation from Si micro-ring resonator. AB - We demonstrate time-bin entanglement generation in telecom wavelength using a 7 MUm radius Si micro-ring resonator pumped by a continuous wave laser. The resonator structure can enhance spontaneous four wave mixing, leading to a photon pair generation rate of about 90-100 Hz with a laser pump power of as low as 3.92 dBm (0.41 mW). We succeed in observing time-bin entanglement with the visibility over 92%. Moreover, wavelength-tunability of the entangled photon pair is demonstrated by changing the operation temperature. PMID- 25835871 TI - Refractive index sensitivity of nano-film coated long-period fiber gratings. AB - We demonstrate the fabrication of long-period fiber gratings (LPFGs) coated with high index nano-film using the atomic layer deposition (ALD) technology. Higher index sensitivity can be achieved in the transition region of the coated LPFGs. For the LPFG coated by nano-film with a thickness of 100 nm, the high index sensitivity of 3000 nm/RIU and the expanded index sensitive range are obtained. The grating contrast of the over-coupled LPFGs and conventional LPFGs are measured and the over-coupled gratings are found to have a higher contrast in the transition region. The cladding modes transition is observed experimentally with increasing surrounding index using an infrared camera. The theoretical model of the hybrid modes in four-layer cylindrical waveguide is proposed for numerical simulation. The experimental results are well consistent with theoretical analysis. PMID- 25835872 TI - Observation of a new interference phenomenon in internal conical diffraction. AB - Conical diffraction is observed in biaxial materials when a beam of light is directed along one of the two optic axis directions. When the beam is directed close to but not along an optic axis, a rich interference pattern is observed beyond the material. We observe some of the previously predicted low intensity interference patterns, representing a qualitatively new optical phenomenon in biaxial materials. PMID- 25835873 TI - Utilization of multi-band OFDM modulation to increase traffic rate of phosphor LED wireless VLC. AB - To increase the traffic rate in phosphor-LED visible light communication (VLC), a multi-band orthogonal frequency division multiplexed (OFDM) modulation is first proposed and demonstrated. In the measurement, we do not utilize optical blue filter to increase modulation bandwidth of phosphor-LED in the VLC system. In this proposed scheme, different bands of OFDM signals are applied to different LED chips in a LED lamp, this can avoid the power fading and nonlinearity issue by applying the same OFDM signal to all the LED chips in a LED lamp. Here, the maximum increase percentages of traffic rates are 41.1%, 17.8% and 17.8% under received illuminations of 200, 500 and 1000 Lux, respectively, when the proposed three-band OFDM modulation is used in the VLC system. In addition, the analysis and verification by experiments are also performed. PMID- 25835874 TI - Few-mode fiber based optical sensors. AB - Few-mode fibers (FMFs) have found applications in optical communications and sensors with attractive features that standard single mode fiber (SSMF) do not possess. We report our recent progress on FMF based optical sensors, and show the potential of utilizing the spatial dimension for multi-parameter sensing with discrimination capability. We first show a discrete type FMF sensor based on interferometer structure with a short FMF, utilizing the modal interference between either the polarizations (x and y) or the spatial modes (LP(01) and LP(11)). We then show a distributed type FMF sensor by generating the stimulated Brillouin scattering (SBS) in a long FMF. We characterize the Brillouin gain spectrum (BGS) with a pump-probe configuration, and measure the temperature and strain coefficients for LP(01) and LP(11) modes. The proposed FMF based optical sensor can be applied to sensing a wide range of parameters. PMID- 25835875 TI - Time-division-multiplexed few-mode passive optical network. AB - We demonstrate the first few-mode-fiber based passive optical network, effectively utilizing mode multiplexing to eliminate combining loss for upstream traffic. Error-free performance has been achieved for 20-km low-crosstalk 3-mode transmission in a commercial GPON system carrying live Ethernet traffic. The alternative approach of low modal group delay is also analyzed with simulation results over 10 modes. PMID- 25835876 TI - Scaling silicon photonic switch fabrics for data center interconnection networks. AB - With the rapidly increasing aggregate bandwidth requirements of data centers there is a growing interest in the insertion of optically interconnected networks with high-radix transparent optical switch fabrics. Silicon photonics is a particularly promising and applicable technology due to its small footprint, CMOS compatibility, high bandwidth density, and the potential for nanosecond scale dynamic connectivity. In this paper we analyze the feasibility of building silicon photonic microring based switch fabrics for data center scale optical interconnection networks. We evaluate the scalability of a microring based switch fabric for WDM signals. Critical parameters including crosstalk, insertion loss and switching speed are analyzed, and their sensitivity with respect to device parameters is examined. We show that optimization of physical layer parameters can reduce crosstalk and increase switch fabric scalability. Our analysis indicates that with current state-of-the-art devices, a high radix 128 * 128 silicon photonic single chip switch fabric with tolerable power penalty is feasible. The applicability of silicon photonic microrings for data center switching is further supported via review of microring operations and control demonstrations. The challenges and opportunities for this technology platform are discussed. PMID- 25835877 TI - Experimental study of PAM-4, CAP-16, and DMT for 100 Gb/s short reach optical transmission systems. AB - Advanced modulation formats combined with digital signal processing and direct detection is a promising way to realize high capacity, low cost and power efficient short reach optical transmission system. In this paper, we present a detailed investigation on the performance of three advanced modulation formats for 100 Gb/s short reach transmission system. They are PAM-4, CAP-16 and DMT. The detailed digital signal processing required for each modulation format is presented. Comprehensive simulations are carried out to evaluate the performance of each modulation format in terms of received optical power, transmitter bandwidth, relative intensity noise and thermal noise. The performance of each modulation format is also experimentally studied. To the best of our knowledge, we report the first demonstration of a 112 Gb/s transmission over 10km of SSMF employing single band CAP-16 with EML. Finally, a comparison of computational complexity of DSP for the three formats is presented. PMID- 25835878 TI - Evaluating the coherence and time-domain profile of quantum cascade laser frequency combs. AB - Recently, much attention has been focused on the generation of optical frequency combs from quantum cascade lasers. We discuss how fast detectors can be used to demonstrate the mutual coherence of such combs, and present an inequality that can be used to quantitatively evaluate their performance. We discuss several technical issues related to shifted wave interference Fourier Transform spectroscopy (SWIFTS), and show how such measurements can be used to elucidate the time-domain properties of such combs, showing that they can possess signatures of both frequency-modulation and amplitude-modulation. PMID- 25835879 TI - Orbital angular momentum entanglement via fork-poling nonlinear photonic crystals. AB - We report a compact scheme for the generation and manipulation of photon pairs entangled in the orbital angular momentum (OAM) from the fork-poling quadratic nonlinear crystal. The chi(2)-modulation in this crystal is designed for fulfilling a tilted quasi-phase-matching geometry to ensure the efficient generation of entangled photons as well as for transferring of topological charge of the crystal to the photon pairs. Numerical results show that the OAM of photon pair is anti-correlated and the degree of OAM entanglement can be enhanced by modulating the topological charge of crystal, which indicates a feasible extension to high-dimensional OAM entanglement. These studies suggest that the fork-poling nonlinear photonic crystal a unique platform for compact generation and manipulation of high-dimensional and high-order OAM entanglement, which may have potential applications in quantum communication, quantum cryptography and quantum remote sensing. PMID- 25835880 TI - Ultrafast self-gating Bragg diffraction of exploding nanocrystals in an X-ray laser. AB - In structural determination of crystalline proteins using intense femtosecond X ray lasers, damage processes lead to loss of structural coherence during the exposure. We use a nonthermal description for the damage dynamics to calculate the ultrafast ionization and the subsequent atomic displacement. These effects degrade the Bragg diffraction on femtosecond time scales and gate the ultrafast imaging. This process is intensity and resolution dependent. At high intensities the signal is gated by the ionization affecting low resolution information first. At lower intensities, atomic displacement dominates the loss of coherence affecting high-resolution information. We find that pulse length is not a limiting factor as long as there is a high enough X-ray flux to measure a diffracted signal. PMID- 25835881 TI - On the complex point spread function in interferometric cross-polarisation microscopy. AB - The ability to characterize the Point Spread Function(PSF) is crucial in practical microscopy, but requires knowledge of the complex PSF for approaches that detect fields instead of intensities. Here we experimentally measure and theoretically model the volumetric amplitude and phase response of an Interferometric Cross-polarisation Microscope to demonstrate the technique's capability to provide confocal-like images of weakly birefringent structures in living cells. We find the axial FWHM of the amplitude PSF to be 0.70 +/- 0.01 MUm and 0.83 MUm for model and measurement, respectively, on par with confocal microscopy. Ultimately retaining both amplitude and phase information will however enable approaches for improved localisation of objects. PMID- 25835882 TI - Waveguides in single-crystal lithium niobate thin film by proton exchange. AB - The proton exchanged (PE) planar and channel waveguides in a 500 nm thick single crystal lithium niobate thin film (lithium niobate on insulator, LNOI) were studied. The mature PE technique and strong confinement of light in the LN single crystal thin film were used. The single mode and cut-off conditions of the channel waveguides were obtained by finite difference simulation. The results showed that the single mode channel waveguide would form if the width of the PE region was between 0.75 MUm and 2.1 MUm in the beta(4) phase. The channel waveguide in LNOI had a much smaller mode size than that in the bulk material due to the high-refractive-index contrast. The mode size reached as small as 0.6 MUm(2). in simulation. In the experiment, the refractive index and phase transition after PE in LNOI were analyzed using the prism coupling method and X ray diffraction. Three different width waveguides (5 MUm, 7 MUm and 11 MUm) were optically characterized. Near-field intensity distribution showed that their mode sizes were 3.3 MUm(2).,5 MUm(2). and 7 MUm(2). The propagation losses were evaluated to be about 16 dB/cm, 12 dB/cm and 11 dB/cm, respectively. The results indicate that PE is a promising method for building more complicated photonic integrated circuits in single-crystal LN thin film. PMID- 25835883 TI - High-capacity and low-cost long-reach OFDMA PON based on distance-adaptive bandwidth allocation. AB - We propose and experimentally demonstrate a distance-adaptive bandwidth allocation scheme to realize high-capacity long-reach orthogonal frequency division multiple access passive optical network (OFDMA PON) with cost-effective electro-absorption modulator (EAM). In our scheme, the subcarriers in downstream OFDM signal are properly allocated to the optical network units (ONUs) with different fiber transmission lengths. By this means, the detrimental influence of power fading induced by dispersion and chirp can be avoided, thus all OFDM subcarriers can be modulated with high-order quadrature amplitude modulation (QAM) format, leading to a high transmission capacity. A proof-of-concept experiment is performed, in which three ONUs with transmission distances of 25, 50, and 100 km are assigned with different subcarriers, respectively. By using distance-adaptive bandwidth allocation technique, an OFDM signal of 34.5 Gb/s is successfully delivered to the ONUs with a bit error ratio (BER) lower than 2 * 10(-3). PMID- 25835884 TI - Time resolved photo-luminescent decay characterization of mercury cadmium telluride focal plane arrays. AB - The minority carrier lifetime is a measurable material property that is an indication of infrared detector device performance. To study the utility of measuring the carrier lifetime, an experiment has been constructed that can time resolve the photo-luminescent decay of a detector or wafer sample housed inside a liquid nitrogen cooled Dewar. Motorized stages allow the measurement to be scanned over the sample surface, and spatial resolutions as low as 50um have been demonstrated. A carrier recombination simulation was developed to analyze the experimental data. Results from measurements performed on 4 mercury cadmium telluride focal plane arrays show strong correlation between spatial maps of the lifetime, dark current, and relative response. PMID- 25835885 TI - Engineering optical properties of a graphene oxide metamaterial assembled in microfluidic channels. AB - The dense packing of two dimensional flakes by van der Waals forces has enabled the creation of new metamaterials with desirable optical properties. Here we assemble graphene oxide sheets into a three dimensional metamaterial using a microfluidic technique and confirm their ordering via measurements of ellipsometric parameters, polarized optical microscopy, polarized transmission spectroscopy, infrared spectroscopy and scanning electron microscopy. We show that the produced metamaterials demonstrate strong in-plane optical anisotropy (Deltan~0.3 at n~1.5-1.8) combined with low absorption (k<0.1) and compare them with as-synthesized samples of graphene oxide paper. Our results pave the way for engineered birefringent metamaterials on the basis of two dimensional atomic crystals including graphene and its derivatives. PMID- 25835886 TI - Direct 15-GHz mode-spacing optical frequency comb with a Kerr-lens mode-locked Yb:Y(2)O(3) ceramic laser. AB - A 15-GHz mode spacing optical frequency comb based on a Kerr-lens mode-locked Yb:Y2O3 ceramic laser has been developed. Individual modes were clearly resolved by a commercial spectrometer. To demonstrate the long-term operation of the optical frequency comb, a single longitudinal mode was phase locked to a frequency-stabilized continuous wave laser and the repetition rate to a radio frequency standard. To the best of our knowledge, 15 GHz is the largest reported mode spacing (repetition rate) for both a Kerr-lens mode-locked laser and a direct femtosecond laser based-optical frequency comb. PMID- 25835887 TI - 1-GHz harmonically pumped femtosecond optical parametric oscillator frequency comb. AB - We present the first example of a femtosecond optical parametric oscillator frequency comb harmonically-pumped by a 333-MHz Ti:sapphire laser to achieve a stabilized signal comb at 1-GHz mode spacing in the 1.1-1.6-um wavelength band. Simultaneous locking of the comb carrier-envelope-offset and repetition frequencies is achieved with uncertainties over 1 s of 0.27 Hz and 5 mHz respectively, which are comparable with those of 0.27 Hz and 1.5 mHz achieved for 333-MHz fundamental pumping. The phase-noise power-spectral density of the CEO frequency integrated from 1 Hz-64 kHz was 2.8 rad for the harmonic comb, 1.0 rad greater than for fundamental pumping. The results show that harmonic operation does not substantially compromise the frequency-stability of the comb, which is shown to be limited only by the Rb atomic frequency reference used. PMID- 25835888 TI - Anti-resonant hexagram hollow core fibers. AB - Various simple anti-resonant, single cladding layer, hollow core fiber structures are examined. We show that the spacing between core and jacket glass and the shape of the support struts can be used to optimize confinement loss. We demonstrate the detrimental effect on confinement loss of thick nodes at the strut intersections and present a fabricated hexagram fiber that mitigates this effect in both straight and bent condition by presenting thin and radially elongated nodes. This fiber has loss comparable to published results for a first generation, multi-cladding ring, Kagome fiber with negative core curvature and has tolerable bend loss for many practical applications. PMID- 25835889 TI - Mid-infrared optical nonlinearities of chalcogenide glasses in Ge-Sb-Se ternary system. AB - Optical nonlinearities of chalcogenide glasses in the Ge-Sb-Se ternary system are investigated at mid-infrared wavelengths (2000 and 2500 nm) with femtosecond Z scan technique. Strong nonlinear refraction in the chalcogenide glasses is observed at 2000 nm, due to three-photon absorption resonance. In addition, the variation in the nonlinear refraction (gamma) of the Ge-Sb-Se glasses shows two jumpoints as mean co-ordination number (MCN) approaches 2.4 or 2.7, consistent with the theoretical predication. PMID- 25835890 TI - Versatile long cavity widely tunable pulsed Yb-doped fiber laser with up to 27655th harmonic mode locking order. AB - We report flexible dissipative soliton generation from an all-fiberized all normal-dispersion (ANDi) long cavity actively mode locked ytterbium doped fiber laser based on improved harmonic mode locking technique. The laser is featured with unusually wide and fine tunabilities in repetition rate and operating wavelength, meanwhile superior stability is maintained. The repetition rate of the laser can be flexibly controlled from 226 kHz to 6.25 GHz (corresponding to the highest 27655th order harmonic mode locking) in the interval of 226 kHz, while supermode suppression is confined above 50 dB and the pulse duration is retained in the range of 38 ps~80 ps. As high as 4.3 nJ pulse energy can be achieved with a low pump power of 160 mW when operating at the fundamental mode locking regime. The operating wavelength of the laser can be tuned in the wide range of 1005 nm~1100 nm. As far as we know, it is the first demonstration of up to ten thousands order stable harmonic mode locking in ANDi fiber laser, which manifests the capability of generating both high energy pulse and ultra-high repetition rate pulse in a single ANDi cavity. The destabilization of dissipative soliton under strong pump is also demonstrated. PMID- 25835891 TI - Optical quality assessment of whole slide imaging systems for digital pathology. AB - Whole Slide Imaging (WSI) systems are high-throughput automated microscopes for digital pathology applications. We present a method for testing and monitoring the optical quality of WSI-systems using a measurement of the through-focus Optical Transfer Function (OTF) obtained from the edge response of a custom made resolution target, composed of sagittal and tangential edges. This enables quantitative analysis of a number of primary aberrations. The curvature of the best focus as a function of spatial frequency is indicative for spherical aberration, the argument of the OTF quantifies for coma, and the best focus as a function of field position for sagittal and tangential edges allows assessment of astigmatism and field curvature. The statistical error in the determined aberrations is typically below 20 mlambda. We use the method to compare different tube lens designs and to study the effect of objective lens aging. The results are in good agreement with direct measurement of aberrations based on Shack Hartmann wavefront sensing with a typical error ranging from 10 mlambda to 40 mlambda. PMID- 25835892 TI - Virtual-source diffusion approximation for enhanced near-field modeling of photon migration in low-albedo medium. AB - Most analytical methods for describing light propagation in turbid medium exhibit low effectiveness in the near-field of a collimated source. Motivated by the Charge Simulation Method in electromagnetic theory as well as the established discrete source based modeling, we herein report on an improved explicit model for a semi-infinite geometry, referred to as "Virtual Source" (VS) diffuse approximation (DA), to fit for low-albedo medium and short source-detector separation. In this model, the collimated light in the standard DA is analogously approximated as multiple isotropic point sources (VS) distributed along the incident direction. For performance enhancement, a fitting procedure between the calculated and realistic reflectances is adopted in the near-field to optimize the VS parameters (intensities and locations). To be practically applicable, an explicit 2VS-DA model is established based on close-form derivations of the VS parameters for the typical ranges of the optical parameters. This parameterized scheme is proved to inherit the mathematical simplicity of the DA approximation while considerably extending its validity in modeling the near-field photon migration in low-albedo medium. The superiority of the proposed VS-DA method to the established ones is demonstrated in comparison with Monte-Carlo simulations over wide ranges of the source-detector separation and the medium optical properties. PMID- 25835893 TI - Switchable dual-wavelength Q-switched and mode-locked fiber lasers using a large angle tilted fiber grating. AB - We proposed and demonstrated pulsed fiber lasers Q-switched and mode-locked by using a large-angle tilted fiber grating, for the first time to our best knowledge. Owing to the unique polarization properties of the large-angle tilted fiber grating (LA-TFG), i.e. polarization-dependent loss and polarization-mode splitting, switchable dual-wavelength Q-switched and mode-locked pulses have been achieved with short and long cavities, respectively. For the mode-locking case, the laser was under the operation of nanosecond rectangular pulses, due to the peak-power clamping effect. With the increasing pump power, the durations of both single- and dual-wavelength rectangular pulses increase. It was also found that each filtered wavelength of the dual-wavelength rectangular pulse corresponds to an individual nanosecond rectangular pulse by employing a tunable bandpass filter. PMID- 25835894 TI - GaSb-based SESAM mode-locked Tm:YAG ceramic laser at 2 um. AB - Tunable and mode-locked laser operation near 2 um based on different Tm-doped YAG ceramics, 4 at.% and 10 at.%, is demonstrated. Several designs of GaSb-based surface-quantum-well SESAMs are characterized and studied as saturable absorbers for mode-locking. Best mode-locking performance was achieved using an antireflection-coated near-surface quantum-well SESAM, resulting in a pulse duration of ~3 ps and ~150 mW average output power at 89 MHz. All mode-locked Tm:YAG ceramic lasers operated at 2012 nm, with over 133 nm demonstrated tuning for continuous-wave operation. PMID- 25835895 TI - Influence of laser-induced air breakdown on femtosecond laser ablation of aluminum. AB - We investigated the influence of laser-induced air breakdown on the femtosecond laser ablation of aluminum target using time-resolved pump-probe shadowgraphic imaging method. The early-stage plasma expanding dynamics and subsequent expanding behaviors of shockwaves and material ejection plume were analyzed through shadowgraphs recorded at different time delays. The dominated mechanisms were clarified at different stages during femtosecond laser pulses ablating aluminum, which provide very valuable information for ultrashort laser ablation of metals. PMID- 25835896 TI - Carrier density dependence of plasmon-enhanced nonradiative energy transfer in a hybrid quantum well-quantum dot structure. AB - An array of Ag nanoboxes fabricated by helium-ion lithography is used to demonstrate plasmon-enhanced nonradiative energy transfer in a hybrid quantum well-quantum dot structure. The nonradiative energy transfer, from an InGaN/GaN quantum well to CdSe/ZnS nanocrystal quantum dots embedded in an ~80 nm layer of PMMA, is investigated over a range of carrier densities within the quantum well. The plasmon-enhanced energy transfer efficiency is found to be independent of the carrier density, with an efficiency of 25% reported. The dependence on carrier density is observed to be the same as for conventional nonradiative energy transfer. The plasmon-coupled energy transfer enhances the QD emission by 58%. However, due to photoluminescence quenching effects an overall increase in the QD emission of 16% is observed. PMID- 25835897 TI - CEP-stable, sub-6 fs, 300-kHz OPCPA system with more than 15 W of average power. AB - We report on a CEP-stable OPCPA system reaching multi-GW peak powers at 300 kHz repetition rate. It delivers 15 W of average power, over 50 uJ of compressed pulse energy and a pulse duration below 6 fs. By implementing an additional pump seed-synchronization, the output parameters are stabilized over hours with power fluctuations of less than 1.5%. PMID- 25835898 TI - Application of attitude jitter detection based on short-time asynchronous images and compensation methods for Chinese mapping satellite-1. AB - Given the recent development in high-resolution (HR) optical satellites, the study of both attitude jitter (AJ) detection and compensation has become increasingly essential to improving the radiometric and geometric quality of HR images. A group of HR optical stereo mapping satellites in China, mapping satellite-1 (MS-1) has launched two satellites and will launch one satellite to build a satellite network. The geometric accuracy of the launched MS-1 satellites is greater than 80 m because of the AJ caused by the instability of the platform. AJ detection and compensation are critical issues that must be addressed to improve the accuracy of geo-positioning and mapping before launching a new satellite. The present study employs a method of jitter detection based on short time asynchronous images to detect MS-1 jitter. The adjacent overlapping areas of an original panchromatic image are used as detection images instead of the traditional multispectral images, and a differential recursion optimal estimation filter is proposed for the optimal estimation and elimination of the gross errors of the registration data procedure, thereby increasing the detection accuracy. The space variant blurring model and viewing angles correction method are employed for the radiometric and geometric jitter compensation of images, respectively. The methods of radiometric objective evaluation indices and geometric checkpoint are then utilised to evaluate the quality of jitter compensation. Finally, the DeZhou regional image (ShanDong province, China) from MS-1 is used as the experimental data. Results for the AJ of MS-1 are analysed and reported for the first time. The assessment results obtained show that both radiometric and geometric qualities greatly increase after the jitter compensation procedure. Thus, the work of this study for jitter detection and compensation effectively addresses the jitter of MS-1 HR optical satellites. PMID- 25835899 TI - Advanced coding techniques for few mode transmission systems. AB - We experimentally verify the advantage of employing advanced coding schemes such as space-time coding and 4 dimensional modulation formats to enhance the transmission performance of a 3-mode transmission system. The performance gain of space-time block codes for extending the optical signal-to-noise ratio tolerance in multiple-input multiple-output optical coherent spatial division multiplexing transmission systems with respect to single-mode transmission performance are evaluated. By exploiting the spatial diversity that few-mode-fibers offer, with respect to single mode fiber back-to-back performance, significant OSNR gains of 3.2, 4.1, 4.9, and 6.8 dB at the hard-decision forward error correcting limit are demonstrated for DP-QPSK 8, 16 and 32 QAM, respectively. Furthermore, by employing 4D constellations, 6 * 28Gbaud 128 set partitioned quadrature amplitude modulation is shown to outperform conventional 8 QAM transmission performance, whilst carrying an additional 0.5 bit/symbol. PMID- 25835900 TI - Role of the mirror's reflectivity in forward-pumped random fiber laser. AB - In this paper, we thoroughly analyze the role of the point reflector's reflectivity in the performance of forward-pumped random fiber laser, in both the long- and short-cavity cases. The results show that the power performance is sensitive to the small reflection added on the pump side of the fiber end, whereas both the power distribution and threshold tend to be stable when the reflectivity reaches a relatively high level (>0.4). Moreover, for the short cavity case (e.g. 500m), the maximum achievable 1st-oder random lasing output can even increase when the reflectivity decreases from 0.9 to 0.01, due to the different lasing power distributions with different reflectivity values. This work reveals a new and unique property of random fiber lasers and provides insights into their design for the applications such as distributed amplification and high power sources. PMID- 25835901 TI - Tailored surface birefringence by femtosecond laser assisted wet etching. AB - Surface texturing is demonstrated by the combination of wet etching and ultrafast laser nanostructuring of silica glass. Using potassium hydroxide (KOH) at room temperature as an etchant of laser modified glass, we show the polarization dependent linear increase in retardance reaching a threefold value within 25 hours. The dispersion control of birefringence by the etching procedure led to achromatic behaviour over the entire visible spectral range. The mechanism of enhanced KOH etching selectivity after femtosecond laser exposure is discussed and correlated to the formation of various laser-induced defects, such as silicon rich oxygen deficiency and color centers. PMID- 25835902 TI - Mode coupling at connectors in mode-division multiplexed transmission over few mode fiber. AB - In mode-division multiplexed (MDM) transmission systems, mode coupling is responsible for inter-modal crosstalk. We consider the transmission of modulated signals over a few-mode fiber (FMF) having low mode coupling and large differential mode group delay in the presence of a non-ideal fiber connection responsible for extra mode coupling. In this context, we first analytically derive the coupling matrix of the multimode connector and we numerically study the dependence of the matrix coefficients as a function of the butt-joint connection characteristics. The numerical results are then validated through an experiment with a five-mode setup. Finally, through numerical simulations, we assess the impact of the connector on the signal quality investigating different receiver digital signal processing (DSP) schemes. PMID- 25835903 TI - Diffusive random laser modes under a spatiotemporal scope. AB - At present the prediction and characterization of the emission output of a diffusive random laser remains a challenge, despite the variety of investigated materials and theoretical interpretations given up to now. Here, a new mode selection method, based on spatial filtering and ultrafast detection, which allows to separate individual lasing modes and follow their temporal evolution is presented. In particular, the work explores the random laser behavior of a ground powder of an organic-inorganic hybrid compound based on Rhodamine B incorporated into a di-ureasil host. The experimental approach gives direct access to the mode structure and dynamics, shows clear modal relaxation oscillations, and illustrates the lasing modes stochastic behavior of this diffusive scattering system. The effect of the excitation energy on its modal density is also investigated. Finally, imaging measurements reveal the dominant role of diffusion over amplification processes in this kind of unconventional lasers. PMID- 25835904 TI - Tb/s physical random bit generation with bandwidth-enhanced chaos in three cascaded semiconductor lasers. AB - We experimentally demonstrate fast physical random bit generation from bandwidth enhanced chaos by using three-cascaded semiconductor lasers. The bandwidth enhanced chaos is obtained with the standard bandwidth of 35.2 GHz, the effective bandwidth of 26.0 GHz and the flatness of 5.6 dB, whose waveform is used for random bit generation. Two schemes of single-bit and multi-bit extraction methods for random bit generation are carried out to evaluate the entropy rate and the maximum random bit generation rate. For single-bit generation, the generation rate at 20 Gb/s is obtained for physical random bit sequences. For multi-bit generation, the maximum generation rate at 1.2 Tb/s ( = 100 GS/s * 6 bits * 2 data) is equivalently achieved for physical random bit sequences whose randomness is verified by using both NIST Special Publication 800-22 and TestU01. PMID- 25835905 TI - 500 kHz OPCPA delivering tunable sub-20 fs pulses with 15 W average power based on an all-ytterbium laser. AB - An optical parametric chirped pulse amplifier fully based on Yb lasers at 500 kHz is described. Passive optical-synchronization is achieved between a fiber laser pumped white-light and a 515 nm pump produced with a 200 W picosecond Yb:YAG InnoSlab amplifier. An output power up to 19.7 W with long-term stability of 0.3% is demonstrated for wavelength tunable pulses between 680 nm and 900 nm and spectral stability of 0.2%; 16.5 W can be achieved with a bandwidth supporting 5.4 fs pulses. We demonstrate compression of 30 uJ pulses to sub-20 fs duration with a prism compressor, suitable for high harmonic generation. PMID- 25835906 TI - Observation of focal point shift in solid immersion mirror. AB - Focal point shift in a solid immersion mirror of a high numerical-aperture is experimentally demonstrated with a scanning near-field optical microscope. The solid immersion mirror focuses light by a two-dimensional parabolic reflective surface integrated in a planar waveguide. The focal point shifts inward along the optical axis for metallized surface. The amount of shift from its geometrical node depends on the wavelength of the incident light and is determined to be roughly one-fifth of the wavelength. PMID- 25835907 TI - Influence of Stark splitting levels on the lasing performance of Yb(3+) in phosphate and fluorophosphate glasses. AB - Lasing properties have been investigated for Yb(3+) doped glasses with similar emission cross sections (sigma(emi)) and lifetime while possessing different Stark levels. Narrow Stark splitting of Yb(3+)-phosphate glass is responsible for severe heat generation, narrow emission band and much smaller sigma(emi) at lasing wavelength, making Yb(3+)-phosphate glass unsuccessful to achieve laser output, whereas 1.166W cw laser was obtained in Yb(3+)-fluorophosphate (FP) glass with broader Stark splitting. Analysis on laser system levels reveals that under room temperature, Yb(3+) laser is quasi-3.13-level in phosphate glass and quasi 3.36-level in FP glass. These demonstrations suggest that unless the Stark splitting is enlarged, conventional Yb(3+)-phosphate glass is not a good gain medium for bulk Yb(3+)-laser. PMID- 25835908 TI - Simultaneous measurement of NO and NO(2) by dual-wavelength quantum cascade laser spectroscopy. AB - The concept of a multi-wavelength quantum cascade laser emitting at two or more spectrally well-separated wavelengths is highly appealing for applied spectroscopy, as it allows detecting several species with compact and cost efficient optical setups. Here we present a practical realization of such a dual wavelength setup, which is based on a room-temperature quantum cascade laser emitting single-mode at 1600 cm-1 and 1900 cm-1 and is thus well-suited for simultaneous NO and NO2 detection. Operated in a time division multiplexed mode, our spectrometer reaches detection limits of 0.5 and 1.5 ppb for NO2 and NO, respectively. The performance of the system is validated against the well-established chemiluminescence detection while measuring the NOx emissions on an automotive test-bench, as well as upon monitoring the pollution at a suburban site. PMID- 25835909 TI - High temperature operation of far infrared (lambda ~20 um) InAs/AlSb quantum cascade lasers with dielectric waveguide. AB - We demonstrate the high temperature operation, up to 80 degrees C, of quantum cascade lasers emitting at a wavelength of 20 um. The lasers are based on the InAs/AlSb materials and take benefit of a low loss plasmon-enhanced dielectric waveguide. The waveguide consists of doped InAs cladding layers and low-doped InAs spacers. For 2.9-mm-long devices, the threshold current density is 4.3 kA/cm2 and the measured peak output power is 7 mW at room temperature. The cavity length dependence of the threshold currents also indicates that very large optical gain is achieved and effectively overcome the strong free carrier absorption. PMID- 25835910 TI - Microlensless interdigitated photoconductive terahertz emitters. AB - We report here fabrication of interdigitated photoconductive antenna (iPCA) terahertz (THz) emitters based on plasmonic electrode design. Novel design of this iPCA enables it to work without microlens array focusing, which is otherwise required for photo excitation of selective photoconductive regions to avoid the destructive interference of emitted THz radiation from oppositely biased regions. Benefit of iPCA over single active region PCA is, photo excitation can be done at larger area hence avoiding the saturation effect at higher optical excitation density. The emitted THz radiation power from plasmonic-iPCAs is ~2 times more than the single active region plasmonic PCA at 200 mW optical excitation, which will further increase at higher optical powers. This design is expected to reduce fabrication cost of photoconductive THz sources and detectors. PMID- 25835911 TI - Electro-optical switching at 1550 nm using a two-state GeSe phase-change layer. AB - New designs for electro-optical free-space and waveguided 2 x 2 switches are presented and analyzed at the 1.55 MUm telecoms wavelength. The proposed devices employ a ~10 nm film of GeSe that is electrically actuated to transition the layer forth-and-back from the amorphous to the crystal phase, yielding a switch with two self-sustaining states. This phase change material was selected for its very low absorption loss at the operation wavelength, along with its electro refraction Deltan ~0.6. All switches are cascadeable into N x M devices. The free space prism-shaped structures use III-V prism material to match the GeSe crystal index. The Si/GeSe/Si "active waveguides" are quite suitable for directional coupler switches as well as Mach-Zehnder devices-all of which have an active length 16x less than that in the free-carrier art. PMID- 25835912 TI - Optical injection locking to optical frequency combs for superchannel coherent detection. AB - Optical injection locking characteristics of a distributed feedback laser are experimentally investigated for multiple-wavelength injection. Using a three wavelength source generated by intensity modulation as the injected signal, it was found that the presence of adjacent lines could cause disturbance to the locking if a minimum guard band between the respective locking limits of two adjacent lines was not observed. With a 21-line comb with 20 GHz line spacing as the injected signal, the injection locking range was observed to become asymmetrical in relation to the laser free-running frequency under high-power injection conditions and was found to be dependent on whether the laser was locked to lines located at centre and or edges of the comb. Finally, the use of the injection locked laser as a seed laser for generating a local oscillator (LO) comb for superchannel coherent detection was investigated and the phase error between the input and LO combs analysed. PMID- 25835913 TI - Optical wireless transmission of 405 nm, 1.45 Gbit/s optical IM/DD-OFDM signals through a 4.8 m underwater channel. AB - In this paper, we experimentally demonstrate wireless transmission of optical intensity modulation/direct detection-orthogonal frequency division multiplexing (IM/DD-OFDM) signals in an underwater channel using a field programmable gate array based real-time transmitter. The real-time transmission of a 405 nm 1.45 Gbit/s optical OFDM signal through a 4.8 m underwater channel with an error vector magnitude of approximately 10% was successfully achieved. PMID- 25835914 TI - High directional backlight using an integrated light guide plate. AB - A high directional backlight system that combined a composite microstructure light guide plate (LGP) with a collimated light source was proposed for eco displays. The collimated planar light was expanded from a point light source and guided towards the normal direction by utilizing the micro-prism array on LGP. High uniformity of spatial luminous, 91%, with a narrow viewing cone of +/- 4 degrees can be achieved without additional optical films. Moreover, compared to the conventional backlight, only 5% of power consumption was needed to keep the same luminance, hence, the optical efficiency increased by a factor of 1.47. PMID- 25835915 TI - Surface profiling of X-ray mirrors for shaping focused beams. AB - Grazing incidence mirrors are a standard optic for focusing X-rays. Active mirrors, whose surface profile can be finely adjusted, allow control of beam shape and size at the sample. However, progress towards their routine use for beam shaping has been hampered by the strong striations in reflected beams away from the focal plane. Re-entrant (partly concave and partly convex) surface modifications are proposed for shaping X-ray beams to a top-hat in the focal plane while reducing the striations caused by unavoidable polishing errors. A method for constructing such surfaces with continuous height and slope (but only piecewise continuous curvature) will be provided. Ray tracing and wave propagation calculations confirm its effectiveness. A mirror system is proposed allowing vertical beam sizes in the range 0.5 to 10MUm. A prototype will be fabricated and is expected to have applications on many synchrotron X-ray beamlines. PMID- 25835916 TI - Fan-in/out polymer optical waveguide for a multicore fiber fabricated using the mosquito method. AB - A fan-in/out polymer optical waveguide with 25-MUm cores and 40-MUm interchannel pitch is fabricated for a multimode multicore fiber using a microdispenser. We design a fan-in/out structure to which the Mosquito method is applicable since the Mosquito method is capable of drawing a circular graded-index core three dimensionally. Then, we experimentally fabricate a 10-cm long fan-in/out polymer waveguide with seven cores, which is expected to connect a multicore fiber and a fiber ribbon. A minimum insertion loss of 5.26 dB at 850-nm wavelength for a 10 cm long fan-in/out waveguide is experimentally observed. Causes of variation in the insertion loss and interchannel pitch are discussed. PMID- 25835918 TI - Advanced in situ metrology for x-ray beam shaping with super precision. AB - We report a novel method for in situ metrology of an X-ray bimorph mirror by using the speckle scanning technique. Both the focusing beam and the "tophat" defocussed beam have been generated by optimizing the bimorph mirror in a single iteration. Importantly, we have demonstrated that the angular sensitivity for measuring the slope error of an optical surface can reach accuracy in the range of two nanoradians. When compared with conventional ex-situ metrology techniques, the method enables a substantial increase of around two orders of magnitude in the angular sensitivity and opens the way to a previously inaccessible region of slope error measurement. Such a super precision metrology technique will be beneficial for both the manufacture of polished mirrors and the optimization of beam shaping. PMID- 25835917 TI - On the dispersion management of fluorite whispering-gallery mode resonators for Kerr optical frequency comb generation in the telecom and mid-infrared range. AB - Optical whispering gallery mode (WGM) resonators have been very attracting platforms for versatile Kerr frequency comb generations. We report a systematic study on the material dispersion of various optical materials that are capable of supporting quality factors above 109. Using an analytical approximation of WGM resonant frequencies in disk resonators, we investigate the effect of the geometry and transverse mode order on the total group-velocity dispersion (GVD). We demonstrate that the major radii and the radial mode indices play an important role in tailoring the GVD of WGM resonators. In particular, our study shows that in WGM disk-resonators, the polar families of modes have very similar GVD, while the radial families of modes feature dispersion values that can differ by up to several orders of magnitude. The effect of these giant dispersion shifts are experimentally evidenced in Kerr comb generation with magnesium fluoride. From a more general perspective, this critical feature enables to push the zero-dispersion wavelength of fluorite crystals towards the mid-infrared (mid-IR) range, thereby allowing for efficient Kerr comb generation in that spectral range. We show that barium fluoride is the most interesting crystal in this regard, due to its zero dispersion wavelength (ZDW) at 1.93 MUm and an optimal dispersion profile in the mid-IR regime. We expect our results to facilitate the design of different platforms for Kerr frequency comb generations in both telecommunication and mid-IR spectral ranges. PMID- 25835919 TI - Nonlinear coupling between a nitrogen-vacancy-center ensemble and a superconducting qubit. AB - By exchange of virtual microwave photon induced by a transmission line resonator, the nonlinear interaction between a nitrogen-vacancy-center ensemble (NVE) and a superconducting charge qubit is achieved in circuit quantum electrodynamics, where the nonlinear coupling results from the second order of the coupling between the magnetic field of the transmission line resonator and the charge qubit. In our case, the nonlinear coupling can be much enhanced by a factor of the total spin number in the NVE. As an application, we present a potentially practical scheme to realize the squeezing of the NVE using the nonlinear coupling, which is within reach of the currently available technology. PMID- 25835920 TI - Towards a 100 Gb/s visible light wireless access network. AB - Potential visible light communication (VLC) data rates at over 10 Gb/s have been recently demonstrated using light emitting diodes (LEDs). The disadvantage is, LEDs have an inherent trade-off between optical efficiency and bandwidth. Consequently, laser diodes (LDs) can be considered as a very promising alternative for better utilization of the visible light spectrum for communication purposes. This work investigates the communication capabilities of off-the-shelf LDs in a number of scenarios with illumination constraints. The results indicate that optical wireless access data rates in the excess of 100 Gb/s are possible at standard indoor illumination levels. PMID- 25835921 TI - Blue-detuned optical ring trap for Bose-Einstein condensates based on conical refraction. AB - We present a novel approach for the optical manipulation of neutral atoms in annular light structures produced by the phenomenon of conical refraction occurring in biaxial optical crystals. For a beam focused to a plane behind the crystal, the focal plane exhibits two concentric bright rings enclosing a ring of null intensity called the Poggendorff ring. We demonstrate both theoretically and experimentally that the Poggendorff dark ring of conical refraction is confined in three dimensions by regions of higher intensity. We derive the positions of the confining intensity maxima and minima and discuss the application of the Poggendorff ring for trapping ultra-cold atoms using the repulsive dipole force of blue-detuned light. We give analytical expressions for the trapping frequencies and potential depths along both the radial and the axial directions. Finally, we present realistic numerical simulations of the dynamics of a 87Rb Bose-Einstein condensate trapped inside the Poggendorff ring which are in good agreement with corresponding experimental results. PMID- 25835922 TI - Quantum cascade laser combs: effects of modulation and dispersion. AB - Frequency comb formation in quantum cascade lasers is studied theoretically using a Maxwell-Bloch formalism based on a modal decomposition, where dispersion is considered. In the mid-infrared, comb formation persists in the presence of weak cavity dispersion (500 fs2 mm-1) but disappears when much larger values are used (30'000 fs2 mm-1). Active modulation at the round-trip frequency is found to induce mode-locking in THz devices, where the upper state lifetime is in the tens of picoseconds. Our results show that mode-locking based on four-wave mixing in broadband gain, low dispersion cavities is the most promising way of achieving broadband quantum cascade laser frequency combs. PMID- 25835923 TI - Monte Carlo analysis of the terahertz difference frequency generation susceptibility in quantum cascade laser structures. AB - Based on self-consistent ensemble Monte Carlo simulations coupled to the optical field dynamics, we investigate the giant nonlinear susceptibility giving rise to terahertz difference frequency generation in quantum cascade laser structures. Specifically, the dependence on temperature, bias voltage and frequency is considered. It is shown that the optical nonlinearity is temperature insensitive and covers a broad spectral range, as required for widely tunable room temperature terahertz sources. The obtained results are consistent with available experimental data. PMID- 25835924 TI - Terahertz dual-band metamaterial absorber based on graphene/MgF(2) multilayer structures. AB - We design an ultra-thin terahertz metamaterial absorber based on graphene/MgF(2) multilayer stacking unit cells arrayed on an Au film plane and theoretically demonstrate a dual-band total absorption effect. Due to strong anisotropic permittivity, the graphene/MgF(2) multilayer unit cells possess a hyperbolic dispersion. The strong electric and magnetic dipole resonances between unit cells make the impedance of the absorber match to that of the free space, which induces two total absorption peaks in terahertz range. These absorption peaks are insensitive to the polarization and nearly omnidirectional for the incident angle. But the absorption intensity and frequency depend on material and geometric parameters of the multilayer structure. The absorbed electromagnetic waves are finally converted into heat and, as a result, the absorber shows a good nanosecond photothermal effect. PMID- 25835925 TI - Highly efficient and perfectly vertical chip-to-fiber dual-layer grating coupler. AB - A novel high-efficiency silicon-chip-to-fiber grating coupler is investigated here. By introducing a dual layer grating structure with an inter-layer lateral shift to mimic 45 degrees tilted mirror behavior, perfectly vertical coupling is successfully demonstrated. Our numerical results show that a peak silicon-chip-to fiber coupling efficiency about 70% is possible near 1550 nm. Meanwhile, for the entire telecom C-band, i.e. wavelengths from 1530 nm to 1565 nm, the coupling efficiency is > 50% and the back reflection is less than < 1%. Our proposed high performance silicon perfectly vertical coupling structure is suitable for interfacing with multi-core fiber platform, which may play an important role in the future CMOS photonic integration technology. PMID- 25835926 TI - Modeling the anisotropic electro-optic interaction in hybrid silicon ferroelectric optical modulator. AB - We present a numerical method to accurately model the electro-optic interaction in anisotropic materials. Specifically, we combine a full-vectorial finite difference optical mode solver with a radio-frequency solver to analyze the overlap between optical modes and applied electric field. This technique enables a comprehensive understanding on how electro-optic effects modify individual elements in the permittivity tensor of a material. We demonstrate the interest of this approach by designing a modulator that leverages the Pockels effect in a hybrid silicon-BaTiO3 slot waveguide. Optimized optical confinement in the active BaTiO3 layer as well as design of travelling-wave index matched electrodes is presented. Most importantly, we show that the overall electro-optic modulation is largely governed by off-diagonal elements in the permittivity tensor. As most of active electro-optic materials are anisotropic, this method paves the way to better understand the physics of electro-optic effects and to improve optical modulators. PMID- 25835927 TI - Role of antenna modes and field enhancement in second harmonic generation from dipole nanoantennas. AB - We study optical second harmonic generation from metallic dipole antennas with narrow gaps. Enhancement of the fundamental-frequency field in the gap region plays a marginal role on conversion efficiency. In the symmetric configuration, i.e., with the gap located at the center of the antenna axis, reducing gap size induces a significant red-shift of the maximum conversion efficiency peak. Either enhancement or inhibition of second-harmonic emission may be observed as gap size is decreased, depending on the antenna mode excited at the harmonic frequency. The second-harmonic signal is extremely sensitive to the asymmetry introduced by gap's displacements with respect to the antenna center. In this situation, second harmonic light can couple to all the available antenna modes. We perform a multipolar analysis that allows engineering the far-field SH emission and find that the interaction with quasi-odd-symmetry modes generates radiation patterns with a strong dipolar component. PMID- 25835928 TI - Quantitative measurement of binary liquid distributions using multiple-tracer x ray fluorescence and radiography. AB - The complex geometry and large index-of-refraction gradients that occur near the point of impingement of binary liquid jets present a challenging environment for optical interrogation. A simultaneous quadruple-tracer x-ray fluorescence and line-of-sight radiography technique is proposed as a means of distinguishing and quantifying individual liquid component distributions prior to, during, and after jet impact. Two different pairs of fluorescence tracers are seeded into each liquid stream to maximize their attenuation ratio for reabsorption correction and differentiation of the two fluids during mixing. This approach for instantaneous correction of x-ray fluorescence reabsorption is compared with a more time intensive approach of using stereographic reconstruction of x-ray attenuation along multiple lines of sight. The proposed methodology addresses the need for a quantitative measurement technique capable of interrogating optically complex, near-field liquid distributions in many mixing systems of practical interest involving two or more liquid streams. PMID- 25835929 TI - Acceleration of computer-generated holograms using tilted wavefront recording plane method. AB - Computer Generated Holograms (CGH) are generated on computers; however, a great deal of computational power is required because the quality of the image is proportional to the number of point light sources of a 3D object. The Wavefront Recording Plane (WRP) method is an algorithm that enables reduction of the amount of calculations required. However, the WRP method also has a defect; it is not effective in the case of a 3D object with a deep structure. In this study, we propose two improved WRP methods: "Least Square Tilted WRP method" and "RANSAC Multi-Tilted WRP method." PMID- 25835930 TI - Anisotropic model for the fabrication of annealed and reverse proton exchanged waveguides in congruent lithium niobate. AB - An anisotropic model for the fabrication of annealed and reverse proton exchange waveguides in lithium niobate is presented. We characterized the anisotropic diffusion properties of proton exchange, annealing and reverse proton exchange in Z-cut and X-cut substrates using planar waveguides. Using this model we fabricated high quality channel waveguides with propagation losses as low as 0.086 dB/cm and a coupling efficiency with optical fiber of 90% at 1550 nm. The splitting ratio of a set of directional couplers is predicted with an accuracy of +/- 0.06. PMID- 25835931 TI - Characterization of the frequency stability of an optical frequency standard at 1.39 um based upon noise-immune cavity-enhanced optical heterodyne molecular spectroscopy. AB - Frequency fluctuations of an optical frequency standard at 1.39 um have been measured by means of a highly-sensitive optical frequency discriminator based on the fringe-side transmission of a high finesse optical resonator. Built on a Zerodur spacer, the optical resonator exhibits a finesse of 5500 and a cavity mode width of about 120 kHz. The optical frequency standard consists of an extended-cavity diode laser that is tightly stabilized against the center of a sub-Doppler H(2) (18)O line, this latter being detected by means of noise-immune cavity-enhanced optical heterodyne molecular spectroscopy. The emission linewidth has been carefully determined from the frequency-noise power spectral density by using a rather simple approximation, known as beta-line approach, as well as the exact method based on the autocorrelation function of the laser light field. It turns out that the linewidth of the optical frequency standard amounts to about 7 kHz (full width at half maximum) for an observation time of 1 ms. Compared to the free-running laser, the measured width corresponds to a line narrowing by a factor of ~220. PMID- 25835932 TI - Observation of photonic spin Hall effect with phase singularity at dielectric metasurfaces. AB - Observation of photonic spin Hall effect (SHE) near the phase singularity at dielectric metasurfaces is presented. The structured metasurface works as a space variant Pancharatnam-Berry phase element and produces a vortex beam with phase singularity. The dynamical vortex phase is introduced to eliminate or enhance the phase singularity, thus realizing the manipulation of spin-dependent Pancharatnam Berry phase. The spin-orbit coupling near the singularity of the Pancharatnam Berry phase leads to the observation of the photonic SHE which manifests itself as spin-dependent splitting. The underlying mechanism is significantly different from previously reported cases. It thereby provides an alternative way to manipulate the spin states of photons. PMID- 25835933 TI - Robust fast direct integral equation solver for quasi-periodic scattering problems with a large number of layers. AB - We present a new boundary integral formulation for time-harmonic wave diffraction from two-dimensional structures with many layers of arbitrary periodic shape, such as multilayer dielectric gratings in TM polarization. Our scheme is robust at all scattering parameters, unlike the conventional quasi-periodic Green's function method which fails whenever any of the layers approaches a Wood anomaly. We achieve this by a decomposition into near- and far-field contributions. The former uses the free-space Green's function in a second-kind integral equation on one period of the material interfaces and their immediate left and right neighbors; the latter uses proxy point sources and small least-squares solves (Schur complements) to represent the remaining contribution from distant copies. By using high-order discretization on interfaces (including those with corners), the number of unknowns per layer is kept small. We achieve overall linear complexity in the number of layers, by direct solution of the resulting block tridiagonal system. For device characterization we present an efficient method to sweep over multiple incident angles, and show a 25* speedup over solving each angle independently. We solve the scattering from a 1000-layer structure with 3 * 105 unknowns to 9-digit accuracy in 2.5 minutes on a desktop workstation. PMID- 25835934 TI - Optimum heterodyning angle for heterodyned optical Kerr gated ballistic imaging. AB - We perform heterodyned optical Kerr gated (HOKG) ballistic imaging of an object hidden behind a turbid medium using a femtosecond laser. The experimental results show that an optimum heterodyning angle should be selected to acquire the highest spatial resolution of the HOKG imaging system. The optimum heterodyning angle depends on the scattering parameters of the turbid media, and it decreases with increasing optical density or decreasing thickness of the turbid medium. PMID- 25835935 TI - Performance analysis of communication links based on VCSEL and silicon photonics technology for high-capacity data-intensive scenario. AB - To face the increased demand for bandwidth, cost-effectiveness and simplicity of future Ethernet data communications, a comparison between two different solutions based on directly-modulated VCSEL sources and Silicon Photonics technologies is carried out. Also by exploiting 4-PAM modulation, the transmission of 50-Gb/s and beyond capacity per channel is analyzed by means of BER performance. Applications for optical backplane, very short reach and in case of client-optics networks and intra and inter massive data centers communications (up to 10 km) are taken into account. A comparative analysis based on the power consumption is also proposed. PMID- 25835936 TI - Optimized SNR simultaneous multispectral photoacoustic imaging with laser diodes. AB - Multispectral photoacoustic laser diode systems have multiple wavelengths available simultaneously. In addition to multispectral imaging, this can be exploited to increase the signal to noise ratio (SNR) by combining these wavelengths to form a combined image, but at the loss of spectral information. Here, a novel signal processing concept is introduced, which optimizes the SNR in the reconstructions of single wavelength data from combined acquisitions while simultaneously permitting to obtain a higher SNR fused image from the same data. The concept is derived for an arbitrary number of wavelengths; it is also applicable at low pulse repetition frequencies. The concept is applied in an experiment using two wavelengths, verifying the theoretical results. PMID- 25835937 TI - Tracking radiometric responsivity of optical sensors without on-board calibration systems-case of the Chinese HJ-1A/1B CCD sensors. AB - The radiometric stability of satellite sensors is crucial for generating highly consistent remote sensing measurements and products. We have presented a radiometric responsivity tracking method designed especially for optical sensors without on-board calibration systems. Using a temporally stable desert site with high reflectance, the sensor responsivity was simulated using the Second Simulation of the Satellite Signal in the Solar Spectrum (6S) radiative transfer model (RTM) with information from validated MODIS atmospheric data. Next, radiometric responsivity drifting was identified using a linear regression of the time series bidirectional reflectance distribution function (BRDF) normalized coefficients. The proposed method was applied to Chinese HJ-1A/1B charge-coupled device (CCD) sensors, which have been on-orbit operations for more than 5 years without continuous assessment of their radiometric performance. Results from the Dunhuang desert site between 2008 and 2013 indicated that the CCD sensors degraded at various rates, with the most significant degradation occurring in the blue bands, ranging from 2.8% to 4.2% yr-1. The red bands were more stable, with a degradation rate of 0.7-3.1% yr-1. A cross-sensor comparison revealed the least degradation for the HJ-1A CCD1 (blue: 2.8%; green: 2.8%; red: 0.7%; and NIR: 0.9% yr-1), whereas the degradation of HJ-1B CCD1 was most pronounced (blue: 3.5%; green: 4.1%; red: 2.3%; and NIR: 3.4% yr-1). The uncertainties of the method were evaluated theoretically based on the propagation of uncertainties from all possible sources of the RT simulations. In addition, a cross comparison with matchup ground-based absolute calibration results was conducted. The comparison demonstrated that the method was useful for continuously monitoring the radiometric performance of remote sensors, such as HJ-1A/1B CCD and GaoFen (GF) series (China's latest high definition Earth observation satellite), and indicated the potential use of the method for high-precision absolute calibration. PMID- 25835938 TI - Free-space propagation of optical coherence lattices and periodicity reciprocity. AB - We examine paraxial propagation of recently introduced optical coherence lattices in free space and demonstrate a novel phenomenon of periodicity reciprocity between their intensity and coherence properties. The periodicity reciprocity arises because an aperiodic source intensity profile of an optical coherence lattice evolves into a lattice-like far-field profile, while the periodic spectral degree of coherence at the source becomes aperiodic on free-space propagation. We discuss how the discovered periodicity reciprocity can make optical coherence lattices attractive for robust free-space optical communications. PMID- 25835939 TI - Feedback-controlled Raman dissipative solitons in a fiber laser. AB - Energy of chirped dissipative solitons (DS) generated in fiber lasers may exceed a threshold of stimulated Raman scattering (SRS) leading to formation of a noisy Raman pulse (RP). As we demonstrated recently, a feedback loop providing re injection of the Raman pulse into the laser cavity can form a Raman dissipative soliton (RDS) with similar characteristics to those of the main dissipative soliton. Here, we present the results of feedback optimization of the generated RDS spectra. First experimental results of coherent combining of DS and RDS are also shown. PMID- 25835940 TI - Large-scale fabrication of flexible metallic nanostructure pairs using interference ablation. AB - Paired one- and two-dimensional metallic nanostructures are created directly by exposing a thin gold film to the interference pattern between ultraviolet laser pulses, where the gold film is coated onto a soft substrate and is sandwiched by another soft slab. Metallic films in the bright fringes are melted and transformed into nanodroplets that are ejected onto the soft slab forming stretchable nanoisland structures. The pattern of the remaining films is coincident with the dark fringes. Thus, complementary metallic nanostructure pairs were fabricated using a single laser pulse. Fano resonance can be observed in the spectroscopic response of the fabricated nanostructures for TM and TE polarizations simultaneously. This nanofabrication technique may provide an annealing-free approach for the fabrication of flexible metallic nanostructures on a large scale and with low cost. PMID- 25835941 TI - Non-invasive biopsy of doped-ions inside optical substrate by modified two-photon microscopy. AB - Doped-ion based optical elements play key roles in optical signal processes, including amplification, absorption, wavelength-filtering, lighting, and polarizing plate. Non-invasively mapping the spatial distribution of the ion concentrations in these optical elements is highly desirable either during the fabrication process or to determine their optical qualities. In this work, we applied modified two-photon fluorescence (m-TPF) microscopy to trace the ion distributions deep inside the optical elements. For demonstration purposes, polyvinyl alcohol (PVA) polymer films inside polarizing plates are taken as an example, where the spatial distributions of Iodine-dyed ions were measured by the m-TPF microscope in a fast and non-invasive way. The durability of the polarizer films can be distinguished from the axial distribution of the Iodine-dyed ions, without the need to perform a biopsy. This proposed method and demonstrated results show great potential for monitoring the spatial distributions of doped ions in the optical elements quickly and non-destructively, which would be of great benefit in both scientific research and industrial applications. PMID- 25835942 TI - A user-friendly two-color super-resolution localization microscope. AB - We report a robust two-color method for super-resolution localization microscopy. Two-dye combination of Alexa647 and Alexa750 in an imaging buffer containing COT and using TCEP as switching regent provides matched and balanced switching characteristics for both dyes, allowing simultaneous capture of both on a single camera. Active sample locking stabilizes sample with 1nm accuracy during imaging. With over 4,000 photons emitted from both dyes, two-color superresolution images with high-quality were obtained in a wide range of samples including cell cultures, tissue sections and yeast cells. PMID- 25835943 TI - Testing the Maxwell-Boltzmann distribution using Brownian particles. AB - We report on shot-noise limited measurements of the instantaneous velocity distribution of a Brownian particle. Our system consists of a single micron-sized glass sphere held in an optical tweezer in a liquid in equilibrium at room temperature. We provide a direct verification of a modified Maxwell-Boltzmann velocity distribution and modified energy equipartition theorem that account for the kinetic energy of the liquid displaced by the particle. Our measurements confirm the distribution over a dynamic range of more than six orders of magnitude in count-rate and five standard deviations in velocity. PMID- 25835944 TI - Conservation planning for biodiversity and wilderness: a real-world example. AB - Several of the most important conservation prioritization approaches select markedly different areas at global and regional scales. They are designed to maximize a certain biodiversity dimension such as coverage of species in the case of hotspots and complementarity, or composite properties of ecosystems in the case of wilderness. Most comparisons between approaches have ignored the multidimensionality of biodiversity. We analyze here the results of two species based methodologies-hotspots and complementarity-and an ecosystem-based methodology-wilderness-at local scale. As zoning of protected areas can increase the effectiveness of conservation, we use the data employed for the management plan of the Peneda-Geres National Park in Portugal. We compare the approaches against four criteria: species representativeness, wilderness coverage, coverage of important areas for megafauna, and for regulating ecosystem services. Our results suggest that species- and ecosystem-based approaches select significantly different areas at local scale. Our results also show that no approach covers well all biodiversity dimensions. Species-based approaches cover species distribution better, while the ecosystem-based approach favors wilderness, areas important for megafauna, and for ecosystem services. Management actions addressing different dimensions of biodiversity have a potential for contradictory effects, social conflict, and ecosystem services trade-offs, especially in the context of current European biodiversity policies. However, biodiversity is multidimensional, and management and zoning at local level should reflect this aspect. The consideration of both species- and ecosystem-based approaches at local scale is necessary to achieve a wider range of conservation goals. PMID- 25835945 TI - Improving ecological response monitoring of environmental flows. AB - Environmental flows are now an important restoration technique in flow-degraded rivers, and with the increasing public scrutiny of their effectiveness and value, the importance of undertaking scientifically robust monitoring is now even more critical. Many existing environmental flow monitoring programs have poorly defined objectives, nonjustified indicator choices, weak experimental designs, poor statistical strength, and often focus on outcomes from a single event. These negative attributes make them difficult to learn from. We provide practical recommendations that aim to improve the performance, scientific robustness, and defensibility of environmental flow monitoring programs. We draw on the literature and knowledge gained from working with stakeholders and managers to design, implement, and monitor a range of environmental flow types. We recommend that (1) environmental flow monitoring programs should be implemented within an adaptive management framework; (2) objectives of environmental flow programs should be well defined, attainable, and based on an agreed conceptual understanding of the system; (3) program and intervention targets should be attainable, measurable, and inform program objectives; (4) intervention monitoring programs should improve our understanding of flow-ecological responses and related conceptual models; (5) indicator selection should be based on conceptual models, objectives, and prioritization approaches; (6) appropriate monitoring designs and statistical tools should be used to measure and determine ecological response; (7) responses should be measured within timeframes that are relevant to the indicator(s); (8) watering events should be treated as replicates of a larger experiment; (9) environmental flow outcomes should be reported using a standard suite of metadata. Incorporating these attributes into future monitoring programs should ensure their outcomes are transferable and measured with high scientific credibility. PMID- 25835946 TI - Farmer-managed natural regeneration enhances rural livelihoods in dryland west Africa. AB - Declining agricultural productivity, land clearance and climate change are compounding the vulnerability of already marginal rural populations in West Africa. 'Farmer-Managed Natural Regeneration' (FMNR) is an approach to arable land restoration and reforestation that seeks to reconcile sustained food production, conservation of soils, and protection of biodiversity. It involves selecting and protecting the most vigorous stems regrowing from live stumps of felled trees, pruning off all other stems, and pollarding the chosen stems to grow into straight trunks. Despite widespread enthusiasm and application of FMNR by environmental management and development projects, to date, no research has provided a measure of the aggregate livelihood impact of community adoption of FMNR. This paper places FMNR in the context of other agroforestry initiatives, then seeks to quantify the value of livelihood outcomes of FMNR. We review published and unpublished evidence about the impacts of FMNR, and present a new case study that addresses gaps in the evidence-base. The case study focuses on a FMNR project in the district of Talensi in the semi-arid Upper East Region in Ghana. The case study employs a social return on investment analysis, which identifies proxy financial values for non-economic as well as economic benefits. The results demonstrate income and agricultural benefits, but also show that asset creation, increased consumption of wild resources, health improvements, and psycho-social benefits created more value in FMNR-adopting households during the period of the study than increases in income and agricultural yields. PMID- 25835947 TI - Vagus nerve stimulation for partial seizures. AB - BACKGROUND: Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with medically refractory epilepsy. VNS consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator. The majority of people given a diagnosis of epilepsy have a good prognosis, and their seizures will be controlled by treatment with a single antiepileptic drug (AED), but up to 20%-30% of patients will develop drug-resistant epilepsy, often requiring treatment with combinations of AEDs. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of vagus nerve stimulation when used as an adjunctive treatment for people with drug-resistant partial epilepsy. This is an updated version of a Cochrane review published in Issue 7, 2010. OBJECTIVES: To determine:(1) The effects on seizures of VNS compared to controls e.g. high-level stimulation compared to low-level stimulation (presumed sub-therapeutic dose); and(2) The adverse effect profile of VNS compared to controls e.g. high-level stimulation compared to low-level stimulation. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (23 February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 23 February 2015), MEDLINE (1946 to 23 February 2015), SCOPUS (1823 to 23 February 2015), ClinicalTrials.gov (23 February 2015) and ICTRP (23 February 2015). No language restrictions were imposed. SELECTION CRITERIA: The following study designs were eligible for inclusion: randomised, double-blind, parallel or crossover studies, controlled trials of VNS as add-on treatment comparing high and low stimulation paradigms (including three different stimulation paradigms - duty cycle: rapid, mid and slow) and VNS stimulation versus no stimulation or a different intervention. Eligible participants were adults or children with drug-resistant partial seizures not eligible for surgery or who failed surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. The following outcomes were assessed: (a) 50% or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) adverse effects; (d) quality of life; (e) cognition; (f) mood. Primary analyses were intention-to-treat. Sensitivity best and worst case analyses were also undertaken to account for missing outcome data. Pooled Risk Ratios (RR) with 95% confidence intervals (95% Cl) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, pooled RRs and 99% CI's were calculated. MAIN RESULTS: Five trials recruited a total of 439 participants and between them compared different types of VNS stimulation therapy. Baseline phase ranged from 4 to 12 weeks and double-blind treatment phases from 12 to 20 weeks in the five trials. Overall, two studies were rated as having a low risk of bias and three had an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies of VNS is difficult due to the frequency of stimulation related side effects such as voice alteration; this may limit the validity of the observed treatment effects. Four trials compared high frequency stimulation to low frequency stimulation and were included in quantitative syntheses (meta analyses).The overall risk ratio (95% CI) for 50% or greater reduction in seizure frequency across all studies was 1.73 (1.13 to 2.64) showing that high frequency VNS was over one and a half times more effective than low frequency VNS. For this outcome, we rated the evidence as being moderate in quality due to incomplete outcome data in one included study; however results did not vary substantially and remained statistically significant for both the best and worst case scenarios. The risk ratio (RR) for treatment withdrawal was 2.56 (0.51 to 12.71), however evidence for this outcome was rated as low quality due to imprecision of the result and incomplete outcome data in one included study. The RR of adverse effects were as follows: (a) voice alteration and hoarseness 2.17 (99% CI 1.49 to 3.17); (b) cough 1.09 (99% CI 0.74 to 1.62); (c) dyspnea 2.45 (99% CI 1.07 to 5.60); (d) pain 1.01 (99% CI 0.60 to 1.68); (e) paresthesia 0.78 (99% CI 0.39 to 1.53); (f) nausea 0.89 (99% CI 0.42 to 1.90); (g) headache 0.90 (99% CI 0.48 to 1.69); evidence of adverse effects was rated as moderate to low quality due to imprecision of the result and/or incomplete outcome data in one included study. No important heterogeneity between studies was found for any of the outcomes. AUTHORS' CONCLUSIONS: VNS for partial seizures appears to be an effective and well tolerated treatment in 439 included participants from five trials. Results of the overall efficacy analysis show that VNS stimulation using the high stimulation paradigm was significantly better than low stimulation in reducing frequency of seizures. Results for the outcome "withdrawal of allocated treatment" suggest that VNS is well tolerated as withdrawals were rare. No significant difference was found in withdrawal rates between the high and low stimulation groups, however limited information was available from the evidence included in this review so important differences between high and low stimulation cannot be excluded . Adverse effects associated with implantation and stimulation were primarily hoarseness, cough, dyspnea, pain, paresthesia, nausea and headache, with hoarseness and dyspnea more likely to occur on high stimulation than low stimulation. However, the evidence on these outcomes is limited and of moderate to low quality. Further high quality research is needed to fully evaluate the efficacy and tolerability of VNS for drug resistant partial seizures. PMID- 25835948 TI - Diagnostic confidence of run-off CT-angiography as the primary diagnostic imaging modality in patients presenting with acute or chronic peripheral arterial disease. AB - OBJECTIVES: To investigate the reliability of CT-angiography of the lower extremities (run-off CTA) to derive a treatment decision in patients with acute and chronic peripheral artery disease (PAD). MATERIALS AND METHODS: 314 patients referred for run-off CTA were includ-ed in this retrospective study. First, diagnostic confidence of run-off CTA to derive a treat-ment decision was assessed in an interdisciplinary vascular conference using a 2 point scale (sufficient or not sufficient diagnostic confidence) and compared with the image quality eval uated by two readers in consensus in four different levels (abdominopelvic, thigh, calf, foot arteries). Second, reliability of treatment decision was verified in all patients undergoing re-vascularization therapy. RESULTS: Diagnostic confidence of run-off CTA to derive a treatment deci-sion was sufficient in all patients with acute and in 97% of patients (215/221) with chronic PAD, whereas the rate of run-off CTA with non-diagnostic image quality was considerably higher in the calf and foot level (acute vs. chronic; calf: 28% vs.17%; foot: 52% vs. 20%). Reliability of treatment decision was superior for patients with chronic (123/133 = 92%) than for patients with acute PAD (64/78 = 82%, P = 0.02). CONCLUSION: Run-off CTA is a reliable imaging modality for primary diag-nostic work-up of patients with acute and chronic PAD. PMID- 25835949 TI - Influences of operating conditions on continuous lactulose synthesis in an enzymatic membrane reactor system: A basis prior to long-term operation. AB - Lactulose synthesis was performed in a continuous stirred enzymatic membrane reactor. Each investigated operating condition (agitation, pH, feed molar ratio of lactose to fructose (mL/mF ratio), hydraulic residence time (HRT)) had an influence on reaction performances, in terms of lactulose concentration, productivity and selectivity. Lactulose concentration was maximum at an mL/mF ratio of 1/2. Higher than this ratio, synthesis of galactooligosaccharides was promoted rather than lactulose. At mL/mF ratios lower than 1/2, enzyme inhibition was pronounced to the detriment of lactulose production. At 7 or 9h HRT, higher lactulose concentrations were obtained than at shorter HRTs. Applying an mL/mF ratio of 1/2 and an HRT of 9h in a long-term operation, nearly constant lactulose concentration was reached after 23h and lasted up to 32h with a mean concentration of 14.51+/-0.07g/L and a reaction selectivity of 0.075 0.080mollactulose/molcons.lactose. After 7d, lactulose concentration reduced by 31%. A continuous synthesis of lactulose at lab-scale was shown to be amenable using a membrane reactor process. Moreover, for process evaluation, this study can bridge the gap between batch laboratory scale and continuous full-scale operation regarding lactulose synthesis. PMID- 25835950 TI - A new application of aptamer: One-step purification and immobilization of enzyme from cell lysates for biocatalysis. AB - Aptamers are nucleic acid-based high affinity ligands that are able to capture their corresponding target through molecular recognition. In this study, several DNA aptamers with high affinity and specificity for beta-glucuronidases (PGUS-E) were obtained by our modified SELEX method. Among them, Apt5 and Apt9 were selected as representatives and covalently linked to magnetic beads, respectively. The aptamer-modified magnetic beads were characterized and successfully applied to one-step purification and immobilization of PGUS-E from the complex cell lysates. By conveniently adjusting the pH and ion strength, the PGUS-E purities reached 84% for Apt5-modified beads and 88% for Apt9-modified beads. Moreover, the maximum PGUS-E capturing capacity of the Apt5 and Apt9 modified magnetic beads were found to be 31.75MUg/mg and 32.95MUg/mg, respectively. The immobilized PGUS-E on aptamer-based magnetic beads showed good reusability, and the conversion of glycyrrhizin still remained more than 70% after 7 cycles. In addition, the aptamer-modified beads support can be easily regenerated, and the conversion rate of glycyrrhizin (GL) was still 62% after the 7th cycle of regeneration. This investigation can be easily extended to other enzyme systems and may help open a generic route to develop a novel enzyme immobilization technology for biocatalysis based on aptamer. PMID- 25835951 TI - Genome sequence of Pseudomonas parafulva CRS01-1, an antagonistic bacterium isolated from rice field. AB - Pseudomonas parafulva (formerly known as Pseudomonas fulva) is an antagonistic bacterium against several rice bacterial and fungal diseases. The total genome size of P. parafulva CRS01-1 is 5,087,619 bp with 4389 coding sequences (CDSs), 77 tRNAs, and 7 rRNAs. The annotated full genome sequence of the P. parafulva CRS01-1 strain might shed light on its role as an antagonistic bacterium. PMID- 25835952 TI - Lack of multisensory integration in hemianopia: no influence of visual stimuli on aurally guided saccades to the blind hemifield. AB - In patients with visual hemifield defects residual visual functions may be present, a phenomenon called blindsight. The superior colliculus (SC) is part of the spared pathway that is considered to be responsible for this phenomenon. Given that the SC processes input from different modalities and is involved in the programming of saccadic eye movements, the aim of the present study was to examine whether multimodal integration can modulate oculomotor competition in the damaged hemifield. We conducted two experiments with eight patients who had visual field defects due to lesions that affected the retinogeniculate pathway but spared the retinotectal direct SC pathway. They had to make saccades to an auditory target that was presented alone or in combination with a visual stimulus. The visual stimulus could either be spatially coincident with the auditory target (possibly enhancing the auditory target signal), or spatially disparate to the auditory target (possibly competing with the auditory tar-get signal). For each patient we compared the saccade endpoint deviation in these two bi-modal conditions with the endpoint deviation in the unimodal condition (auditory target alone). In all seven hemianopic patients, saccade accuracy was affected only by visual stimuli in the intact, but not in the blind visual field. In one patient with a more limited quadrantano-pia, a facilitation effect of the spatially coincident visual stimulus was observed. We conclude that our results show that multisensory integration is infrequent in the blind field of patients with hemianopia. PMID- 25835953 TI - Isotopic incorporation rates and discrimination factors in mantis shrimp crustaceans. AB - Stable isotope analysis has provided insights into the trophic ecology of a wide diversity of animals. Knowledge about isotopic incorporation rates and isotopic discrimination between the consumer and its diet for different tissue types is essential for interpreting stable isotope data, but these parameters remain understudied in many animal taxa and particularly in aquatic invertebrates. We performed a 292-day diet shift experiment on 92 individuals of the predatory mantis shrimp, Neogonodactylus bredini, to quantify carbon and nitrogen incorporation rates and isotope discrimination factors in muscle and hemolymph tissues. Average isotopic discrimination factors between mantis shrimp muscle and the new diet were 3.0 +/- 0.6 0/00 and 0.9 +/- 0.3 0/00 for carbon and nitrogen, respectively, which is contrary to what is seen in many other animals (e.g. C and N discrimination is generally 0-1 0/00 and 3-4 0/00, respectively). Surprisingly, the average residence time of nitrogen in hemolymph (28.9 +/- 8.3 days) was over 8 times longer than that of carbon (3.4 +/- 1.4 days). In muscle, the average residence times of carbon and nitrogen were of the same magnitude (89.3 +/- 44.4 and 72.8 +/- 18.8 days, respectively). We compared the mantis shrimps' incorporation rates, along with rates from four other invertebrate taxa from the literature, to those predicted by an allometric equation relating carbon incorporation rate to body mass that was developed for teleost fishes and sharks. The rate of carbon incorporation into muscle was consistent with rates predicted by this equation. Our findings provide new insight into isotopic discrimination factors and incorporation rates in invertebrates with the former showing a different trend than what is commonly observed in other animals. PMID- 25835954 TI - Intra-operative tissue oxygen tension is increased by local insufflation of humidified-warm CO2 during open abdominal surgery in a rat model. AB - INTRODUCTION: Maintenance of high tissue oxygenation (PtO2) is recommended during surgery because PtO2 is highly predictive of surgical site infection and colonic anastomotic leakage. However, surgical site perfusion is often sub-optimal, creating an obstructive hurdle for traditional, systemically applied therapies to maintain or increase surgical site PtO2. This research tested the hypothesis that insufflation of humidified-warm CO2 into the abdominal cavity would increase sub peritoneal PtO2 during open abdominal surgery. MATERIALS AND METHODS: 15 Wistar rats underwent laparotomy under general anesthesia. Three sets of randomized cross-over experiments were conducted in which the abdominal cavity was subjected to alternating exposure to 1) humidified-warm CO2 & ambient air; 2) humidified warm CO2 & dry-cold CO2; and 3) dry-cold CO2 & ambient air. Sub-peritoneal PtO2 and tissue temperature were measured with a polarographic oxygen probe. RESULTS: Upon insufflation of humidified-warm CO2, PtO2 increased by 29.8 mmHg (SD 13.3; p<0.001), or 96.6% (SD 51.9), and tissue temperature by 3.0 degrees C (SD 1.7 p<0.001), in comparison with exposure to ambient air. Smaller, but significant, increases in PtO2 were seen in experiments 2 and 3. Tissue temperature decreased upon exposure to dry-cold CO2 compared with ambient air (-1.4 degrees C, SD 0.5, p = 0.001). CONCLUSIONS: In a rat model, insufflation of humidified-warm CO2 into the abdominal cavity during open abdominal surgery causes an immediate and potentially clinically significant increase in PtO2. The effect is an additive result of the delivery of CO2 and avoidance of evaporative cooling via the delivery of the CO2 gas humidified at body temperature. PMID- 25835955 TI - Associations of sedentary behaviour, physical activity, blood pressure and anthropometric measures with cardiorespiratory fitness in children with cerebral palsy. AB - BACKGROUND: Children with cerebral palsy (CP) have poor cardiorespiratory fitness in comparison to their peers with typical development, which may be due to low levels of physical activity. Poor cardiorespiratory fitness may contribute to increased cardiometabolic risk. PURPOSE: The aim of this study was to determine the association between sedentary behaviour, physical activity and cardiorespiratory fitness in children with CP. An objective was to determine the association between cardiorespiratory fitness, anthropometric measures and blood pressure in children with CP. METHODS: This study included 55 ambulatory children with CP [mean (SD) age 11.3 (0.2) yr, range 6-17 yr; Gross Motor Function Classification System (GMFCS) levels I and II]. Anthropometric measures (BMI, waist circumference and waist-height ratio) and blood pressure were taken. Cardiorespiratory fitness was measured using a 10 m shuttle run test. Children were classified as low, middle and high fitness according to level achieved on the test using reference curves. Physical activity was measured by accelerometry over 7 days. In addition to total activity, time in sedentary behaviour and light, moderate, vigorous, and sustained moderate-to-vigorous activity (>=10 min bouts) were calculated. RESULTS: Multiple regression analyses revealed that vigorous activity (beta = 0.339, p<0.01), sustained moderate-to-vigorous activity (beta = 0.250, p<0.05) and total activity (beta = 0.238, p<0.05) were associated with level achieved on the shuttle run test after adjustment for age, sex and GMFCS level. Children with high fitness spent more time in vigorous activity than children with middle fitness (p<0.05). Shuttle run test level was negatively associated with BMI (r2 = -0.451, p<0.01), waist circumference (r2 = -0.560, p<0.001), waist-height ratio (r2 = -0.560, p<0.001) and systolic blood pressure (r2 = -0.306, p<0.05) after adjustment for age, sex and GMFCS level. CONCLUSIONS: Participation in physical activity, particularly at a vigorous intensity, is associated with high cardiorespiratory fitness in children with CP. Low cardiorespiratory fitness is associated with increased cardiometabolic risk. PMID- 25835956 TI - Hepatocyte Growth Factor Gene-Modified Mesenchymal Stem Cells Augment Sinonasal Wound Healing. AB - This study was designed to investigate the effects of hepatocyte growth factor (HGF) transgenic mesenchymal stem cells (HGF-MSCs) on wound healing in the sinonasal mucosa and nasal epithelial cells (NECs). We also sought to determine whether HGF-MSCs and MSCs can migrate into the injured mucosa and differentiate into ciliated cells. Human HGF-overexpressing umbilical cord MSCs (hHGF-UCMSCs) were established, and upregulation of hHGF expression was confirmed by real-time PCR (RT-PCR) and enzyme-linked immunosorbant assay (ELISA). To investigate the paracrine effect of human MSCs (hMSCs) on nasal epithelial repair, hMSC- and HGF MSC-conditioned media (CM) were used in NEC proliferation assays and in an in vitro scratch-wound repair model. The in vivo sinonasal wound-healing model was established, and all enrolled rabbits were randomly assigned to four groups: the GFP-MSC group, the HGF-MSC group, the Ad-HGF group, and the surgery control group. The average decreased diameter was recorded, and the medial wall of the maxillary sinus was removed for histological analysis and scanning electron microscopy. Collagen deposition in the wound tissue was detected via Masson trichrome (M&T) staining. The distribution of MSCs and HGF-MSCs was observed by immunofluorescence. MSCs improved nasal wound healing both in vivo and in vitro. HGF overexpression in MSCs augmented the curative effects. Reduced collagen deposition and transforming growth factor beta1 (TGF-beta1) expression were detected in the HGF-MSC group compared with the MSC-, Ad-HGF-, and phosphate buffered saline-treated groups based on M&T staining and ELISA. The enhanced therapeutic effects of HGF-MSCs were accompanied by decreased level of the fibrogenic cytokine TGF-beta1. In addition, both HGF-MSCs and MSCs can migrate to the injured mucosa and epithelial layer. PMID- 25835957 TI - Self-Antigen Presentation by Keratinocytes in the Inflamed Adult Skin Modulates T Cell Auto-Reactivity. AB - Keratinocytes have a pivotal role in the regulation of immune responses, but the impact of antigen presentation by these cells is still poorly understood, particularly in a situation where the antigen will be presented only in adult life. Here, we generated a transgenic mouse model in which keratinocytes exclusively present a myelin basic protein (MBP) peptide covalently linked to the major histocompatibility complex class II beta-chain, solely under inflammatory conditions. In these mice, inflammation caused by epicutaneous contact sensitizer treatment resulted in keratinocyte-mediated expansion of MBP-specific CD4(+) T cells in the skin. Moreover, repeated contact sensitizer application preceding a systemic MBP immunization reduced the reactivity of the respective CD4(+) T cells and lowered the symptoms of the resulting experimental autoimmune encephalomyelitis. This downregulation was CD4(+) T-cell-mediated and dependent on the presence of the immune modulator Dickkopf-3. Thus, presentation of a neo self-antigen by keratinocytes in the inflamed, adult skin can modulate CD4(+) T cell auto-aggression at a distal organ. PMID- 25835958 TI - The Dunedin Multidisciplinary Health and Development Study: overview of the first 40 years, with an eye to the future. AB - The Dunedin Multidisciplinary Health and Development Study began more than four decades ago. Unusual at the time, it was founded as a multidisciplinary research enterprise, and was strongly supported by the Dunedin community, both professional and lay, in its early years. Seven research themes have evolved over the past 40 years focusing on mental health and neuro-cognition, cardiovascular risk, respiratory health, oral health, sexual and reproductive health, and psychosocial functioning. A seventh, more applied theme, seeks to maximise the value of the Study findings for New Zealand's indigenous people-Maori (or tangata whenua transl people of the land). The study has published over 1200 papers and reports to date, with almost 2/3 of these being in peer-reviewed journals. Here we provide an overview of the study, its history, leadership structure, scientific approach, operational foci, and some recent examples of work that illustrate the following: (a) the value of multidisciplinary data; (b) how the study is well positioned to address contemporary issues; and (c) how research can simultaneously address multiple audiences-from researchers and theoreticians to policy makers and practitioners. Near-future research plans are described, and we end by reflecting upon the core aspects of the study that portend future useful contributions. PMID- 25835959 TI - Physical diseases as predictors of suicide in older adults: a nationwide, register-based cohort study. AB - PURPOSE: The objective of the study was to examine the association between 39 physical diseases and death by suicide in older adults. METHODS: Individual-level register data on all older adults aged 65 years and over living in Denmark during 1990-2009 (N = 1,849,110) were analysed. Rate ratios were calculated for 39 physical diseases while adjusting for period, age group, conjugal status, income, physical comorbidity, and psychiatric disorders. RESULTS: In all, 4792 older adults aged 65+ died by suicide during the follow-up of >16 million person-years. Gastrointestinal cancer was linked to a rate ratio of 2.5 (95 % CI 1.9-3.5) in men while excess suicide risk for women with brain cancer was 3.5 (95 % CI 1.1 10.8) within three years of diagnosis. Men and women diagnosed with liver diseases within three years experienced a 2.7- (95 % CI 1.7-4.2) and 4.0- (95 % CI 2.5-6.4) fold higher risk of suicide, respectively, than those not diagnosed. Elevated risks of suicide were identified for lung cancer, gastrointestinal cancer, breast cancer, genital cancer, bladder cancer, lymph node cancer, epilepsy, cerebrovascular diseases, cataract, heart diseases, chronic obstructive pulmonary disorders (COPD), gastrointestinal disease, liver disease, arthritis, osteoporosis, prostate disorders, male genital disorders, and spinal fracture when compared to persons not diagnosed within three years. CONCLUSIONS: Multiple physical diseases were linked to increased risks of suicide in older adults. Increased attention to suicidal ideation and risk assessment might be warranted during the diagnosis and treatment of these disorders. PMID- 25835960 TI - Labor inclusion of individuals with disabilities: Managers' conceptions as a contributing factor. AB - OBJECTIVE: This study aims to analyze the managers' conceptions involved in the process of labor inclusion in 18 supermarkets with 5,000 employees, 300 of whom with disabilities. METHODS: A group of 90 managers working with people with disability completed a Conceptions of Disability Inventory (CDI) about their conceptions of people with disabilities. Their responses were categorized as follows: (a) disability as a spiritual manifestation; b) disability as a deviation from normality; (c) disability based on assumptions of inclusion; (d) disability assessed from performance criteria; (e) disability assessed from the connection established with the work organization; (f) disability conceived by contracting benefits, and (g) disability based on the perception of the need for training. RESULTS: Based on the outcomes of the Pearson Correlation Matrix, significant linear correlations were found in seven managers' conceptions of disability. The results also indicate that the managers' conceptions contributed to differentiated inclusionist actions based on their perceptions related to people with disabilities. CONCLUSIONS: This study data contributes to identifying the best practices in labor inclusion. The outcomes of the present study could lead to development of a public policy aimed towards humanizing job alternatives for people with disability. PMID- 25835961 TI - Using the International Classification of Functioning, Disability and Health (ICF) to address facilitators and barriers to participation at work. AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) was approved by the World Health Assembly in 2001. Ten years later, strong arguments have arisen regarding the added value of ICF to the policies on employment and the outcomes at the workplace. As a conceptual framework, ICF has universality because of its inclusive and comprehensive view of human functioning. At a practical level ICF can be used to quantify the impact of impairment on an individual's ability to act in his/her environment and to assess interventions to minimize the impact of disability and maximize functioning. OBJECTIVE: To explore key indicators of social participation (life habits) of persons with disabilities, particularly related to work, among environmental and personal factors. METHODOLOGY/PARTICIPANTS: Data were collected by self administered questionnaires from a convenience sample of 149 working-age persons with disabilities. RESULTS: Social participation is a construct composed by multiple components and employment domain is the strongest indicator of participation. Correlations between social participation and personal factors, such as self-efficacy and attitudes towards disability were moderate. Those who are employed scored higher quality of life in terms of satisfaction with life, more positive attitudes toward disabilities and higher self-efficacy than the ones who are retired or unemployed. Persons using adapted wheelchair and those who were involved in wheelchair selection scored higher in social participation in general, performance at work, and quality of life. Age and disability duration were not associated with participants' employment status. DISCUSSION AND CONCLUSIONS: These findings suggest that rehabilitation and vocational agents, like physiotherapists and other professionals, should have knowledge and understanding of the multiple factors that influence persons with disabilities' participation at work. Programs should provide appropriate wheelchairs, skills training, empowerment and problem-solving strategies in labour activities and occupational environment to promote employment of working-age persons with disabilities. PMID- 25835962 TI - The process of aging: A case study approach implementing an ergonomics evaluation of the built environment for the elderly in Brazil. AB - BACKGROUND: The phenomenon of aging is increasing worldwide. Various problems accompany it since aging makes the elderly undergo a decline in their natural functions. As such, senility can present itself as a barrier for everyday activities. OBJECTIVE: This article presents a research that deals with the study of collective residences for the elderly. It seeks to identify configurations of these homes by seeking shortcomings and/or successful solutions. METHODS: The Ergonomic Methodology for the Built Environment was applied. The method of the approach is qualitative and consists of multi-case study. RESULTS: Through the methodological approach, conflicts in the environment created by missing or inadequate elements were identified. Also, the opinions and suggestions from the elderly were analyzed, which shows their perception of the environment in use. CONCLUSIONS: The situations detected in this study indicate the occurrence of problems, exacerbated by the multiple deficiencies found in the user population of the environments analyzed. Thus it highlights the importance of there being future studies that are better targeted on designing environments for the elderly. PMID- 25835965 TI - Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists. AB - Platelet-derived MPs (PMPs) are a heterogeneous population of microvesicles released from platelets upon activation and apoptosis. Different platelet activations may affect PMP protein profiles and roles in intercellular communication. Here, we performed a quantitative proteomics study to characterize the protein content of PMPs generated by four differentially activated platelet samples. We selected known physiological agonists for platelet activation such as ADP, thrombin and collagen. Thrombin, which is mostly used to generate PMPs in vitro, was set as control. Platelets were activated by following a known agonist strength scale in which ADP was the weakest activation and thrombin and collagen stimulations were the strongest ones. Our proteomic analysis allowed the quantification of 3383 proteins, of which 428 membrane and 131 soluble proteins were found as significantly different in at least one of the analyzed conditions. Activation with stronger agonists led to the enrichment of proteins related to platelet activation in PMPs. In addition, proteins involved in platelet degranulation and proteins from the electron transport chain were less abundant in PMPs when stronger activation was used. Collectively, our data describe the most detailed characterization of PMPs after platelet physiological activation. Furthermore, we show that PMP protein content is highly dependent on the type of physiological agonist involved in platelet stimulation. BIOLOGICAL SIGNIFICANCE: Platelet-derived MPs (PMPs) are a population of vesicles generated upon platelet activation by various stimuli known to be involved in several physiological and pathological processes. This manuscript investigates the protein profile of PMPs obtained by performing four different activation protocols using mass spectrometry-based quantitative proteomics. By following a known physiological agonist strength scale our findings suggest a biological link between agonist strength and proteins associated to platelet mediated processes such as activation and degranulation. These data may provide new insights for understanding PMP biological role and formation. PMID- 25835966 TI - Label-free quantitative proteomic analysis reveals strong involvement of complement alternative and terminal pathways in human glomerular sclerotic lesions. AB - Since glomerular sclerosis frequently accompanies various glomerular diseases at the end stages, it is challenging to differentiate ubiquitous biological processes underlying this pathology from those critically involved in specific diseases. Furthermore, in-depth proteomic profile of human glomerular sclerosis remains limited. In this study, human glomeruli with intermediate (i-GS) and advanced (GS) sclerotic lesions, which were excluded from specific renal diseases and assumed to be aging-related, were laser captured from macroscopically normal cortex distant from urological carcinoma, and subjected to label-free quantitative proteomic analysis. We explicate an evident increase of membrane attack complex in i-GS and GS with an up-going tendency, which is accompanied by increasing of inhibitory regulators of alternative and terminal pathways. GO annotation and IPA pathway analysis agree to these results. Proteomic findings are validated by immunohistochemical studies which indicate that alternative and terminal pathways are positively involved in the glomerular sclerosis seen in distinct renal diseases. Furthermore, proteomic analysis also demonstrates remarkable increases of complement factor B in GS and TGF-beta1 in both GS and i GS. Identification of complement factor B implicates that on-site activation of alternative pathway may occur in injured glomeruli and stepwise increase of TGF beta1 suggests its contribution to the progression of glomerulosclerosis. BIOLOGICAL SIGNIFICANCE: This study provides in-depth quantitative proteomic profiles of human glomeruli with intermediate and advanced sclerotic lesions. It reveals that the over-expression of alternative and terminal pathway components is significantly involved in human glomerulosclerosis seen in distinct renal diseases. Proteomic identification of the increased TGF-beta1 provides supporting evidence for the role of podocyte apoptosis leading to human glomerulosclerosis. PMID- 25835967 TI - Erratum. PMID- 25835968 TI - Glutathione S-transferase O2 gene rs157077 polymorphism predicts response to transarterial chemoembolization in hepatocellular carcinoma. AB - Some genetic alterations of glutathione S-transferase omega 2 (GSTO2) have been reported to increase the risk of many malignancies, including hepatocellular carcinoma (HCC); however, their prognostic capability remained unresolved in HCC patients treated with transarterial chemoembolization (TACE). To fill this gap, we genotyped three well-defined polymorphisms in GSTO2 to assess whether they can predict overall survival among 228 HCC patients under TACE treatment. The median follow-up time and survival time were 22.0 months (range 3.0-60.0) and 19.2 months, respectively. Only one of three polymorphisms examined, rs157077, was significantly associated with overall survival of TACE-treated HCC (P = 0.003), and its mutant allele conferred a higher risk of death than its wild homozygotes (hazard ratio 1.58, 95 % confidence interval 1.17-2.14). Moreover, carriers of this mutant allele had higher tissue GSTO2 expression, reinforcing the prognostic capability of GSTO2 rs157077 for HCC, especially in combination with age and tumor-node-metastasis (TNM) stage. Taken together, we for the first time provided evidence supporting the prognostic role of GSTO2 in the progression of TACE treated HCC. PMID- 25835969 TI - Transcription factor decoy: a pre-transcriptional approach for gene downregulation purpose in cancer. AB - Gene therapy as a therapeutic approach has been the dream for many scientists around the globe. Many strategies have been proposed and applied for this purpose, yet the void for a functional safe method is still apparent. Since most of the diseases are caused by undesirable upregulation (oncogenes) or downregulation (tumor suppressor genes) of genes, major gene therapy's techniques affect gene expression. Most of the methods are used in post-transcriptional level such as RNA inhibitory (RNAi) and splice-switching oligonucleotides (SSOs). RNAi blocks messenger RNA (mRNA) translation by mRNA degradation or interruption between attachments of mRNA with ribosomes' subunits. However, one of the novel methods is the usage of transcription factor targeted decoys. DNA decoys are the new generation of functional gene downregulatory oligonucleotides which compete with specific binding sites of transcription factors. Considering the exponential growth of this technique in both in vitro and in vivo studies, in this paper, we aim to line out the description, design, and application of decoys in research and therapy. PMID- 25835970 TI - Role of Lgr5-positive cells in colorectal cancer. AB - The molecular regulation of the growth of colorectal cancer (CRC) cells is not completely understood. Here, we report expression of Lgr5, a stem cell marker for the intestine and hair follicle, in some of the CRC cells in the patients. To determine the role of Lgr5-positive cells in the tumorigenesis of CRCs, we prepared an adeno-associated virus (AAV) that carries diphtheria toxin fragment A (DTA) under the control of Lgr5 promoter (AAV-pLgr5-DTA). Transduction of several CRC cell lines with this virus selectively killed Lgr5-positive cells, resulting in significant inhibition of the CRC cell growth in vitro and in vivo. Thus, our data highlight a potential role of Lgr5-positive cells in the tumorigenesis of CRCs, and suggest that treating these Lgr5-positive cells in CRCs may substantially improve the outcome of CRC therapy. PMID- 25835971 TI - A polysaccharide from the alkaline extract of Glycyrrhiza inflata induces apoptosis of human oral cancer SCC-25 cells via mitochondrial pathway. AB - In the present study, we isolated and characterized a homogenous polysaccharide (GIAP1) from the alkaline extract of the roots of Glycyrrhiza inflata. The anti tumor activity of GIAP1 toward human oral cancer SCC-25 cells and the underlying mechanisms were also examined in vitro. GIAP1 dose-dependently inhibited the proliferation of SCC-25 cells via inducing apoptosis. Moreover, GIAP1 downregulated Bax/Bcl-2 ratio, disrupted the mitochondrial membrane potential (MMP), and caused the release of cytochrome c to cytosol. Besides, GIAP1 triggered activation of capase-3 and caspase-9, as well as the degradation of poly (ADP-ribose) polymerase (PARP). In addition, the caspase-3 or caspase-9 inhibitor significantly inhibited GIAP1-induced apoptosis in SCC-25 cells. Collectively, we can conclude that the GIAP1 induces apoptosis in SCC-25 cells via a mitochondrial pathway. PMID- 25835972 TI - Temozolomide may induce cell cycle arrest by interacting with URG4/URGCP in SH SY5Y neuroblastoma cells. AB - Temozolomide (TMZ) is an alkylating drug used usually in glioma treatment by inducing the apoptosis in glioma cell. The aim of the study is to investigate the anticancer mechanism of TMZ in SH-SY5Y human neuroblastoma cell line. Cytotoxic effects of TMZ were determined by using XTT assay. IC50 doses in the SH-SY5Y were detected as 5 mM. Expression profiles of novel genes URG4/URGCP, CCND1, CCND2, CDK4, and BCL2 were determined by real-time PCR. The apoptotic effects of TMZ were evaluated with TUNEL method. Furthermore, effects of TMZ on colony formation and invasion were investigated in this study. It was observed that TMZ in SH-SY5Y cell line caused a significant decrease in the gene expressions of URG4/URGCP, CCND1, CCND2, CDK4, and BCL2. According to TUNEL assay results, TMZ markedly induced apoptosis in SH-SY5Y cell line. It was found that TMZ in SH-SY5Y cell line suppressed invasion and colony formation using matrigel invasion chamber and colony formation assay, respectively. To conclude, it is thought that TMZ demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis, invasion, and colony formation on SH-SY5Y cells. TMZ may be an effective agent for treatment of neuroblastoma as a single or in combination with other drugs. PMID- 25835973 TI - Long noncoding RNA SPRY4-IT1 predicts poor patient prognosis and promotes tumorigenesis in gastric cancer. AB - Gastric cancer (GC) is the second common cause of cancer-related death worldwide. Long noncoding RNAs (lncRNAs) are emerging as novel regulators in the cancer paradigm. However, investigation of lncRNAs on GC is still in its infancy. In this study, we focused on lncRNA SPRY4 intronic transcript 1 (SPRY4-IT1) and investigated its expression pattern, clinical significance, biological function, and molecular mechanism in GC. SPRY4-IT1 expression was examined, and its correlation with clinicopathological characteristics and patient prognosis was analyzed. A series of assays were performed to understand the role of SPRY4-IT1 in GC. SPRY4-IT1 expression was elevated in GC tissues and cell lines, and SPRY4 IT1 levels were highly positively correlated with tumor size, invasion depth, distant metastasis, TNM stage, and reduced overall survival (OS) and disease-free survival (DFS). A multivariate analysis showed that SPRY4-IT1 expression is an independent prognostic factor of OS and DFS in patients with GC. Additionally, the results of in vitro assays showed that the suppression of SPRY4-IT1 expression in GC cell line MKN-45 significantly reduced cell proliferation, colony formation, and cell migration/invasion. Moreover, the tumorigenic effects of SPRY4-IT1 were partially mediated by the regulation of certain cyclins and matrix metalloproteinases (MMPs)-related genes. Our data suggest that SPRY4-IT1 plays a critical role in GC tumorigenesis and may represent a novel prognostic marker and potential therapeutic target in patients with GC. PMID- 25835974 TI - Note of clarification of data in the paper titled X-ray repair cross complementing group 1 codon 399 polymorphism and lung cancer risk: an updated meta-analysis. AB - We read with great interest the paper titled "X-ray repair cross-complementing group 1 codon 399 polymorphism and lung cancer risk: an updated meta-analysis" published by Wang et al in Tumor Biology, 2014, 35:411-418. Their results suggest that codon 399 polymorphism of XRCC1 gene might contribute to individual's susceptibility to lung cancer in Asian population and especially in nonsmoking Chinese women. The result is encouraging. Nevertheless, several key issues are worth noticing. PMID- 25835975 TI - Ginsenoside Rh2 inhibits metastasis of glioblastoma multiforme through Akt regulated MMP13. AB - Glioblastoma multiforme (GBM) is the most malignant type of primary brain tumor. Although the growth of the tumor cells in a relatively closed space may partially account for its malignancy, highly invasive nature of glioblastoma cells has been suggested to be the main reason for the failure of current therapeutic approaches. Ginsenoside Rh2 (GRh2) has recently been shown to significantly suppress the growth and survival of GBM through inhibiting epidermal growth factor receptor signaling, whereas its effects on the invasion and metastasis have not been examined. Here, we showed that GRh2 dose-dependently decreased GBM cell invasiveness in both scratch wound healing assay and Transwell cell migration assay. Moreover, the inhibitory effects of GRh2 on cell migration seemed to be conducted through decreased expression of matrix metalloproteinase (MMP)-13. Furthermore, using specific inhibitors, we found that GRh2 inhibited MMP13 through PI3k/Akt signaling pathway. Finally, high MMP13 levels were detected in GBM specimen from the patients. Together, these data suggest that GRh2 may suppress GBM migration through inhibiting Akt-mediated MMP13 activation. Thus, our data highlight a previous unappreciated role for GRh2 in suppressing GBM cell metastasis. PMID- 25835977 TI - Prognostic significance of SLC9A9 in patients with resectable esophageal squamous cell carcinoma. AB - The survival rate of esophageal squamous cell cancer (ESCC) patients is still dismal. Therefore, novel prognostic biomarkers are critically needed for patients with ESCC. SLC9A9 has been reported to be downregulated in hormone-sensitive prostate cancer; however, the correlations between SLC9A9 and ESCC prognosis are unclear. The aim of this study is to evaluate the expression and prognostic significance of SLC9A9 in resectable ESCC. Fresh frozen or paraffin-embedded samples were collected from 167 or 59 patients with resectable ESCC, respectively. The expression of SLC9A9 was assessed by reverse transcription and quantitative real-time polymerase chain reaction analysis (167 patients) and immunohistochemistry (61 patients). The expression of SLC9A9 was not associated with patient clinicopathological characteristics at both transcription and protein levels. The 5-year overall survival in the high SLC9A9 messenger RNA (mRNA) group (n = 106) was poorer than that in the low expression group (n = 61) (34.6 vs. 65.9 %, P < 0.001). Notably, higher SLC9A9 protein expression was also correlated with lower 5-year overall survival (33.1 vs. 66.5 %, P = 0.023). Moreover, multivariate analysis revealed that SLC9A9 mRNA (HR, 2.41; 95 % CI, 1.47-3.97; P = 0.001) and protein (HR, 2.31; 95 %CI, 1.06-5.02; P = 0.034) were independent prognostic factors. In conclusion, the expression of SLC9A9 can be a prognostic predictor for ESCC. PMID- 25835978 TI - Lifetime effectiveness of mifamurtide addition to chemotherapy in nonmetastatic and metastatic osteosarcoma: a Markov process model analysis. AB - The mortality and progression rates in osteosarcoma differ depending on the presence of metastasis. A decision model would be useful for estimating long-term effectiveness of treatment with limited clinical trial data. The aim of this study was to explore the lifetime effectiveness of the addition of mifamurtide to chemotherapy for patients with metastatic and nonmetastatic osteosarcoma. The target population was osteosarcoma patients with or without metastasis. A Markov process model was used, whose time horizon was lifetime with a starting age of 13 years. There were five health states: disease-free (DF), recurrence, post recurrence disease-free, post-recurrence disease-progression, and death. Transition probabilities of the starting state, DF, were calculated from the INT 0133 clinical trials for chemotherapy with and without mifamurtide. Quality adjusted life-years (QALY) increased upon addition of mifamurtide to chemotherapy by 10.5 % (10.13 and 9.17 QALY with and without mifamurtide, respectively) and 45.2 % (7.23 and 4.98 QALY with and without mifamurtide, respectively) relative to the lifetime effectiveness of chemotherapy in nonmetastatic and metastatic osteosarcoma, respectively. Life-years gained (LYG) increased by 10.1 % (13.10 LYG with mifamurtide and 11.90 LYG without mifamurtide) in nonmetastatic patients and 42.2 % (9.43 LYG with mifamurtide and 6.63 LYG without mifamurtide) in metastatic osteosarcoma patients. The Markov model analysis showed that chemotherapy with mifamurtide improved the lifetime effectiveness compared to chemotherapy alone in both nonmetastatic and metastatic osteosarcoma. Relative effectiveness of the therapy was higher in metastatic than nonmetastatic osteosarcoma over lifetime. However, absolute lifetime effectiveness was higher in nonmetastatic than metastatic osteosarcoma. PMID- 25835976 TI - Isothiocyanates: a class of bioactive metabolites with chemopreventive potential. AB - In recent years, growing interest has been focused on the field of chemoprevention using natural therapies. The reason to turn toward "natural" remedies is associated with diverse beneficial pharmacological properties of natural compounds. Isothiocyanates (ITCs), the major pharmacological active constituents of cruciferous vegetables, are derived from the enzymatic hydrolysis of glucosinolates (GSLs). ITCs govern many intracellular targets including cytochrome P 450 (CYP) enzymes, proteins involved in antioxidant response, tumorigenesis, apoptosis, cell cycle, and metastasis. Investigation of the mechanisms of anti-cancer drugs has given important information regarding the use of natural chemopreventive compounds. This extensive review covers various molecular aspects of the interactions of ITCs with their recognized cellular targets involved in cancer treatment in order to enhance anti-tumor outcome with decreased toxicity to patients. PMID- 25835979 TI - Correction: Early stage lung cancer detection in systemic sclerosis does not portend survival benefit: a cross sectional study. PMID- 25835980 TI - On the mechanism of methanol photooxidation to methylformate and carbon dioxide on TiO2: an operando-FTIR study. AB - This work is a mechanistic study of total and partial methanol photooxidation using operando FTIR coupled to gas phase analysis techniques (gas-IR and MS). Methoxy and formate/formyl species play a key role in the reaction. Methoxy species are formed by thermal and photochemical dissociation of methanol. The formation of methylformate is favored by a high surface coverage by methoxy species. Surface and/or bridged oxygen atoms are also important actors. Steady State Isotopic Transient Kinetic Analysis (SSITKA) experiments showed that the limiting step is the conversion of chemisorbed formyl/formate and that methylformate is a secondary product from a reaction between methoxy and neighboring formyl species. Methanol concentration, among other reaction parameters, influences greatly the selectivity of photooxidation. PMID- 25835981 TI - Gas phase condensation of superparamagnetic iron oxide-silica nanoparticles- control of the intraparticle phase distribution. AB - Spherical, softly agglomerated and superparamagnetic nanoparticles (NPs) consisting of maghemite (gamma-Fe2O3) and amorphous silica (SiO2) were prepared by CO2 laser co-vaporization (CoLAVA) of hematite powder (alpha-Fe2O3) and quartz sand (SiO2). The alpha-Fe2O3 portion of the homogeneous starting mixtures was gradually increased (15 mass%-95 mass%). It was found that (i) with increasing iron oxide content the NPs' morphology changes from a nanoscale SiO2 matrix with multiple gamma-Fe2O3 inclusions to Janus NPs consisting of a gamma-Fe2O3 and a SiO2 hemisphere to gamma-Fe2O3 NPs each carrying one small SiO2 lens on its surface, (ii) the multiple gamma-Fe2O3 inclusions accumulate at the NPs' inner surfaces, and (iii) all composite NPs are covered by a thin layer of amorphous SiO2. These morphological characteristics are attributed to (i) the phase segregation of iron oxide and silica within the condensed Fe2O3-SiO2 droplets, (ii) the temperature gradient within these droplets which arises during rapid cooling in the CoLAVA process, and (iii) the significantly lower surface energy of silica when compared to iron oxide. The proposed growth mechanism of these Fe2O3-SiO2 composite NPs during gas phase condensation can be transferred to other systems comprising a glass-network former and another component that is insoluble in the regarding glass. Thus, our model will facilitate the development of novel functional composite NPs for applications in biomedicine, optics, electronics, or catalysis. PMID- 25835982 TI - Prevalence and Predictors of Non-Alcoholic Fatty Liver Disease in Morbidly Obese South Indian Patients Undergoing Bariatric Surgery. AB - BACKGROUND: Numerous studies worldwide have identified a high prevalence of non alcoholic fatty liver disease (NAFLD) among morbidly obese subjects. Several predictors have been found to be associated with NAFLD and its histological high risk components. Similar data from India is lacking. We aimed to determine the prevalence and the predictors of NAFLD and its histological high-risk components in a cohort of Indians with morbid obesity undergoing bariatric surgery. Safety of a routine intraoperative liver biopsy was also assessed. METHODS: There were 134 morbidly obese patients who underwent bariatric surgery with concomitant liver biopsy. These were assessed for NAFLD and its histological high-risk components. Clinical, biochemical, and histological features were evaluated, and predictors of NAFLD, non-alcoholic steatohepatitis (NASH), fibrosis, and advanced fibrosis were identified. RESULTS: Mean BMI was 44.66 +/- 9.81. Eighty-eight (65.7 %) showed NAFLD. Forty-five (33.6 %) showed NASH and 42 (31.3 %) showed fibrosis both not mutually exclusive. Nineteen (14.1 %) showed advanced fibrosis. Higher alanine aminotransferase (ALT) independently predicted NAFLD and was significantly associated with NASH and fibrosis. Type 2 diabetes mellitus (T2DM) and the metabolic syndrome were significantly associated with fibrosis. Systemic hypertension (HT) independently predicted NASH and fibrosis. There were no intraoperative or postoperative complications related to the liver biopsy. CONCLUSIONS: NAFLD has a high prevalence among morbidly obese patients. Elevated ALT, HT, T2DM, and the metabolic syndrome are predictors for NAFLD and its high risk histological components. Routine intraoperative liver biopsy is safe in morbidly obese undergoing bariatric surgery for diagnosing NAFLD. PMID- 25835983 TI - Bariatric Surgery Worldwide 2013. AB - BACKGROUND: The first global survey of bariatric/metabolic surgery based on data from the nations or national groupings of the International Federation for the Surgery of Obesity and Metabolic Diseases (IFSO) was published in 1998, followed by reports in 2003, 2009, 2011, and 2012. In this survey, we report a global overview of worldwide bariatric surgery in 2013. MATERIALS AND METHODS: A questionnaire evaluating the number and the type of bariatric procedure performed in 2013 was emailed to all members of bariatric societies belonging to IFSO. Trend analyses from 2003 to 2013 were also performed. RESULTS: There were 49/54 (90.7%) responders; 37 of the 49 with national registries. The total number of bariatric procedures performed worldwide in 2013 was 468,609, 95.7% carried out laparoscopically. The highest number (n = 154,276) was from the USA/Canada region. The most commonly performed procedure in the world was Roux-en-Y gastric bypass (RYGB), 45%; followed by sleeve gastrectomy (SG), 37%; and adjustable gastric banding (AGB), 10%. Most significant were the rise in prevalence of SG from 0 to 37% of the world total from 2003 to 2013, and the fall in AGB of 68% from its peak in 2008 to 2013. CONCLUSIONS: SG is currently the most frequently performed procedure in the USA/Canada and in the Asia/Pacific regions, and second to RYGB in the Europe and Latin/South America regions. The accuracy of the IFSO based world survey of procedures would be enhanced if each nation or national group would create a national registry. PMID- 25835986 TI - Corrigendum. AB - In the Editorial 'Creature Comfort? Animal Assistance in Therapeutic Work with Children and Young People' published in Clinical Child Psychology and Psychiatry, Volume 19, Number 2, April 2014, pp. 165-168, DOI: 10.1177/1359104513517446, author Keren Bachi's name was spelt incorrectly, in the text and references, as Keren Bach. The editor apologises for this error and any confusion it may have caused. PMID- 25835984 TI - Catalytic Soman Scavenging by the Y337A/F338A Acetylcholinesterase Mutant Assisted with Novel Site-Directed Aldoximes. AB - Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of the soman-acetylcholinesterase (AChE) conjugate known as aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE are ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, sarin, and paraoxon, inhibition. We here demonstrate that ex vivo, in whole human blood, 1 MUM soman was detoxified within 30 min when supplemented with 0.5 MUM Y337A/F338A AChE and 100 MUM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of 42 pyridinium aldoximes, and 5 imidazole 2-aldoxime N-propylpyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2-3-fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack. PMID- 25835985 TI - Islamic Personal Religiosity as a Moderator of Job Strain and Employee's Well Being: The Case of Malaysian Academic and Administrative Staff. AB - Presently, there is increased in research on job strain and the effects of religiosity on employee well-being. Despite increased recognition of religiosity as a moderator of well-being, limited research has focused on Islamic perspective of moderating job strain. This study examines the moderating effects of Islamic personal religiosity on the relationship between job strain and employee well being in Malaysian universities. One hundred and seventeen (117) Muslim academic and administrative staff from four public universities were sampled. Data were collected via questionnaires, and our findings show that the effect of job strain on well-being is significant for employees and that personal religiosity of employees contributed to alleviating job strain and enhancing well-being. Thus, the study concludes that Islamic personal religiosity moderates the relationship between job strain and employee well-being. PMID- 25835987 TI - The binaural masking-level difference of mandarin tone detection and the binaural intelligibility-level difference of mandarin tone recognition in the presence of speech-spectrum noise. AB - Binaural hearing involves using information relating to the differences between the signals that arrive at the two ears, and it can make it easier to detect and recognize signals in a noisy environment. This phenomenon of binaural hearing is quantified in laboratory studies as the binaural masking-level difference (BMLD). Mandarin is one of the most commonly used languages, but there are no publication values of BMLD or BILD based on Mandarin tones. Therefore, this study investigated the BMLD and BILD of Mandarin tones. The BMLDs of Mandarin tone detection were measured based on the detection threshold differences for the four tones of the voiced vowels /i/ (i.e., /i1/, /i2/, /i3/, and /i4/) and /u/ (i.e., /u1/, /u2/, /u3/, and /u4/) in the presence of speech-spectrum noise when presented interaurally in phase (S0N0) and interaurally in antiphase (SpiN0). The BILDs of Mandarin tone recognition in speech-spectrum noise were determined as the differences in the target-to-masker ratio (TMR) required for 50% correct tone recognitions between the S0N0 and SpiN0 conditions. The detection thresholds for the four tones of /i/ and /u/ differed significantly (p<0.001) between the S0N0 and SpiN0 conditions. The average detection thresholds of Mandarin tones were all lower in the SpiN0 condition than in the S0N0 condition, and the BMLDs ranged from 7.3 to 11.5 dB. The TMR for 50% correct Mandarin tone recognitions differed significantly (p<0.001) between the S0N0 and SpiN0 conditions, at -13.4 and -18.0 dB, respectively, with a mean BILD of 4.6 dB. The study showed that the thresholds of Mandarin tone detection and recognition in the presence of speech spectrum noise are improved when phase inversion is applied to the target speech. The average BILDs of Mandarin tones are smaller than the average BMLDs of Mandarin tones. PMID- 25835988 TI - The evolutionary origination and diversification of a dimorphic gene regulatory network through parallel innovations in cis and trans. AB - The origination and diversification of morphological characteristics represents a key problem in understanding the evolution of development. Morphological traits result from gene regulatory networks (GRNs) that form a web of transcription factors, which regulate multiple cis-regulatory element (CRE) sequences to control the coordinated expression of differentiation genes. The formation and modification of GRNs must ultimately be understood at the level of individual regulatory linkages (i.e., transcription factor binding sites within CREs) that constitute the network. Here, we investigate how elements within a network originated and diversified to generate a broad range of abdominal pigmentation phenotypes among Sophophora fruit flies. Our data indicates that the coordinated expression of two melanin synthesis enzymes, Yellow and Tan, recently evolved through novel CRE activities that respond to the spatial patterning inputs of Hox proteins and the sex-specific input of Bric-a-brac transcription factors. Once established, it seems that these newly evolved activities were repeatedly modified by evolutionary changes in the network's trans-regulators to generate large-scale changes in pigment pattern. By elucidating how yellow and tan are connected to the web of abdominal trans-regulators, we discovered that the yellow and tan abdominal CREs are composed of distinct regulatory inputs that exhibit contrasting responses to the same Hox proteins and Hox cofactors. These results provide an example in which CRE origination underlies a recently evolved novel trait, and highlights how coordinated expression patterns can evolve in parallel through the generation of unique regulatory linkages. PMID- 25835989 TI - The thylakoid membrane protein CGL160 supports CF1CF0 ATP synthase accumulation in Arabidopsis thaliana. AB - The biogenesis of the major thylakoid protein complexes of the photosynthetic apparatus requires auxiliary proteins supporting individual assembly steps. Here, we identify a plant lineage specific gene, CGL160, whose homolog, atp1, co-occurs with ATP synthase subunits in an operon-like arrangement in many cyanobacteria. Arabidopsis thaliana T-DNA insertion mutants, which no longer accumulate the nucleus-encoded CGL160 protein, accumulate less than 25% of wild-type levels of the chloroplast ATP synthase. Severe cosmetic or growth phenotypes result under either short day or fluctuating light growth conditions, respectively, but this is ameliorated under long day constant light growth conditions where the growth, ATP synthase activity and photosynthetic electron transport of the mutants are less affected. Accumulation of other photosynthetic complexes is largely unaffected in cgl160 mutants, suggesting that CGL160 is a specific assembly or stability factor for the CF1CF0 complex. CGL160 is not found in the mature assembled complex but it does interact specifically with subunits of ATP synthase, predominantly those in the extrinsic CF1 sub-complex. We suggest therefore that it may facilitate the assembly of CF1 into the holocomplex. PMID- 25835990 TI - The effect of point defects on diffusion pathway within alpha-Fe. AB - The diffusion mechanism of point defects within alpha-Fe with a single vacancy is investigated using the density functional theory. Calculation reveals that H has a slight effect towards Fe diffusion to a vacancy. He has a strong binding with a vacancy; therefore, Fe diffusion is unlikely to happen. The diffusion of C and N from a vacancy has a high barrier. However, Fe diffusion to a vacancy decreases if the C and N diffuse from a vacancy. Thus, the effect of interstitial atoms within alpha-Fe with a single vacancy towards diffusion and a possible diffusion pathway is discussed. PMID- 25835991 TI - Worldwide distribution of the NS3 gene 80K polymorphism among circulating hepatitis C genotype 1 viruses: implication for simeprevir usage. AB - OBJECTIVES: Several direct-acting agents against the hepatitis C virus (HCV) NS3 protease and NS5b polymerase have been developed in recent years to improve treatment of this viral infection. Of these, simeprevir is currently recommended for HCV genotype 1 and 4 infections, but genotypic assessment for the presence of 80K is required prior to simeprevir administration due to the reduced susceptibility of genotype 1 viruses carrying that polymorphism. Because the prevalence of 80K at baseline in genotype 1 viruses varies between reports, we wanted to assess its worldwide prevalence. METHODS: Over 3000 HCV genotype 1 sequences reported from drug-naive subjects distributed around the world were retrieved from the HCV Los Alamos and GenBank databases. These were categorized into subtypes and geographical provenance (continent and country), and the presence of the 80K and 80R polymorphisms was visually inspected and counted. RESULTS: Disparate prevalence of 80K was observed depending on the country/continent analysed. While in resource-rich areas (USA, Western Europe and Australia) a high prevalence of 80K was seen in HCV subtype 1a, in emerging countries, such as Brazil, this prevalence was very low (<1%). HCV subtype 1b sequences from France also displayed a significant occurrence of 80K (6.1%). 80R, on the other hand, was negligible worldwide. CONCLUSIONS: The genotypic assessment of 80K in HCV subtype 1a prior to simeprevir administration in emerging countries with significant numbers of HCV infection is questionable, while it should be performed for subtype 1b in certain developed countries. PMID- 25835992 TI - Description of IMP-31, a novel metallo-beta-lactamase found in an ST235 Pseudomonas aeruginosa strain in Western Germany. AB - OBJECTIVES: The objective of this study was to characterize a novel IMP-type metallo-beta-lactamase (MBL) found in an MDR clinical isolate of Pseudomonas aeruginosa. METHODS: The P. aeruginosa isolate NRZ-00156 was recovered from an inguinal swab from a patient hospitalized in Western Germany and showed high MICs of carbapenems. MBL production was analysed by Etest for MBLs, an EDTA combined disc test and an EDTA bioassay. Typing of the isolate was performed by MLST. Genetic characterization of the new blaIMP gene was performed by sequencing the PCR products. A phylogenetic tree was constructed. The novel blaIMP gene was expressed in Escherichia coli TOP10 and the enzyme was subjected to biochemical characterization. RESULTS: The P. aeruginosa isolate NRZ-00156 expressed the ST235 allelic profile and was resistant to all the beta-lactams tested except aztreonam. The isolate was positive for MBL production and harboured a new IMP allele, blaIMP-31, located on a disrupted class I integron [also carrying the blaOXA-35, aac(6')-Ib, aac(3)-Ic and aphA15 genes]. Its closest relative was IMP 35, with 96.7% amino acid identity. Expression of blaIMP-31 demonstrated that E. coli TOP10 producing IMP-31 had elevated resistance to all the beta-lactams tested except aztreonam. Kinetic data were obtained for both IMP-31 and IMP-1. In comparison with IMP-1, IMP-31 showed weaker hydrolytic activity against all the beta-lactams tested, which resulted from lower kcat values. CONCLUSIONS: The characterization of the new IMP-type gene blaIMP-31 from an ST235 P. aeruginosa isolate indicates an ongoing spread of highly divergent IMP-type carbapenemases in clinical P. aeruginosa strains and highlights the continuous need for the prevention of nosocomial infections caused by MDR Gram-negative bacteria. PMID- 25835993 TI - Confinement of single polysilane chains in coordination nanospaces. AB - Understanding the intrinsic properties of single conducting polymer chains is of interest, largely for their applications in molecular devices. In this study, we report the accommodation of single polysilane chains with hole-transporting ability in porous coordination polymers (PCPs), [Al(OH)(L)]n (1a; L = 2,6 naphthalenedicarboxylate, channel size = 8.5 * 8.5 A(2), 1b; L = 4,4' biphenyldicarboxylate, channel size = 11.1 * 11.1 A(2)). Interestingly, the isolation of single polysilane chains increased the values of carrier mobility in comparison with that in the bulk state due to the elimination of the slow interchain hole hopping. Moreover, even when the chains are isolated one another, the main chain conformation of polysilane could be controlled by changing the pore environment of PCPs, as evidenced by Raman spectroscopy, solid-state NMR measurements, and molecular dynamics simulation. Hence, we succeeded in varying the conducting property of single polysilane chains. Additionally, polysilanes have a drawback, photodegradation under ultraviolet light, which should be overcome for the application of polysilanes. It is noteworthy that the accommodation of polysilane in the nanopores did not exhibit photodegradation. These results highlight that PCP-polysilane hybrids are promising candidates for further use in the field of molecular electronics. PMID- 25835994 TI - The journey from the past to the future. PMID- 25835995 TI - The mouse and the mousetrap. PMID- 25835996 TI - Author's response. PMID- 25835997 TI - Justification for computed tomography scanning. PMID- 25835998 TI - Effectiveness of 3 methods of anchorage reinforcement. PMID- 25835999 TI - Authors' response. PMID- 25836000 TI - Orthodontic profiles: Albert H. Ketcham. PMID- 25836001 TI - "No way, Jose". PMID- 25836002 TI - Three-dimensional computed tomography analysis of airway volume changes between open and closed jaw positions. AB - INTRODUCTION: Airway dimensions are closely linked to the bone and soft-tissue craniofacial anatomy. Reduction of the airway is seen with airway disorders and can impair function. The purpose of this retrospective study was to determine whether changing from open to closed jaw position affects the volume of the nasal cavity, nasopharynx, and oropharynx; the soft palate; the soft-tissue thickness of the airway; and the most constricted area of the airway. METHODS: Following reliability studies, in this retrospective study, we analyzed cone-beam computed tomography scans taken in both closed and open jaw positions of 60 subjects who were undergoing diagnosis and treatment of temporomandibular disorders. On each scan, condyle-fossa measurements, volumes of airway segments (nasal cavity, nasopharynx, oropharynx), soft palate areas, soft tissue thicknesses of the airway, and the most constricted area of the airway and its location were measured using Dolphin imaging software (version 11.5; Patterson Dental Supply, Chatsworth, Calif). Differences between the 2 jaw positions were analyzed with paired t tests, accepting P <=0.05 as significant. RESULTS: Significant changes in airway dimensions were found between the closed and open jaw positions. With jaw opening, the nasopharynx volume increased, whereas the oropharynx volume decreased. Significant decreases were also found for measurements of basion to posterior airway wall, cervical vertebrae to posterior airway wall, most constricted area, nasal cavity volume, and soft palate area when the jaw was open. CONCLUSIONS: Changing jaw position significantly affects airway dimensions. PMID- 25836003 TI - Pattern of maxillary and mandibular proximal enamel thickness at the contact area of the permanent dentition from first molar to first molar. AB - INTRODUCTION: Proximal enamel thickness (PET) at the mesial and distal contact areas of the complete permanent dentition has not been previously reported. Anatomic investigation of PET is essential for interproximal reduction treatment. Our objectives were to measure the PETs of the complete maxillary and mandibular dentitions at the contact areas, to compare the PETs of adjacent teeth, and to evaluate the vertical position of each contact area. METHODS: We evaluated 720 extracted teeth; of these, 109 intact teeth were selected. The mesial and distal contact areas were demarcated, and each tooth was embedded in transparent epoxy resin. Blocks were prepared so that the 2 demarcated contact areas were exposed, and 6 measurements were taken and statistically analyzed. RESULTS: Both jaws showed the same PET pattern characterized by 5 features: PET increased progressively from incisor (0.63 mm) to first molar (1.48 mm). Per tooth, mesial and distal PET did not differ. Total maxillary (26.86 mm) and mandibular (24.52 mm) PETs were similar. Paired PETs at the interproximal interface were similar, with the exception of the lateral incisor-canine interfaces. From incisor to first molar, the contact area becomes located farther gingivally. CONCLUSIONS: The existing guideline of maximal 0.5-mm interproximal reduction per 2 adjacent teeth should be kept in the anterior region and could be increased to 1 mm in the posterior region, when an equal amount is removed. PMID- 25836005 TI - Prospective assessment of maxillary advancement effects: maxillary incisor exposure, and upper lip and nasal changes. AB - INTRODUCTION: Our aim was to assess changes in maxillary incisor exposure, and upper lip and nasal soft tissues with maxillary advancement with or without impaction, accounting for the use of cinch sutures and VY closures. METHODS: This was a prospective study of 41 consecutive patients undergoing maxillary advancement with or without impaction. Lateral cephalometric radiographs and clinical measurements were taken preoperatively and up to 6 months postoperatively by 1 examiner. RESULTS: Thirty-one patients (19 female, 12 male) with a mean age of 25.5 years (range, 16.9-49.9 years) completed the study. Twenty-six received bimaxillary surgery. Fifteen had simple closures, 6 had cinch sutures, and 10 had alar base cinch and VY closures. The mean amounts of maxillary advancement and impaction were 3.34 and 1.6 mm, respectively. Soft tissues followed increasingly more closely the hard tissue advancement from pronasale to stomion superius. Mean maxillary incisor exposure increased at rest (0.5 mm) and on smiling (1.0 mm). The nasolabial angle increased (1.88 degrees ) because of columella upturning. Alar base width (3.09 mm) significantly increased. CONCLUSIONS: Soft to hard tissue horizontal ratios increased progressively from pronasale to stomion superius. Alar base cinch and VY closures increased these further. Maxillary incisor display changes were partly explained by presurgical upper lip thickness and soft tissue manipulation. Nasolabial angle increased, and cinch sutures seemed to increase this further. Alar base width increased significantly, and the cinch sutures did not significantly limit this. PMID- 25836004 TI - Hounsfield unit change in root and alveolar bone during canine retraction. AB - INTRODUCTION: The objective of this study was to determine the Hounsfield unit (HU) changes in the alveolar bone and root surfaces during controlled canine retractions. METHODS: Eighteen maxillary canine retraction patients were selected for this split-mouth design clinical trial. The canines in each patient were randomly assigned to receive either translation or controlled tipping treatment. Pretreatment and posttreatment cone-beam computed tomography scans of each patient were used to determine tooth movement direction and HU changes. The alveolar bone and root surface were divided into 108 divisions, respectively. The HUs in each division were measured. Mixed-model analysis of variance was applied to test the HU change distribution at the P <0.05 significance level. RESULTS: The HU changes varied with the directions relative to the canine movement. The HU reductions occurred at the root surfaces. Larger reductions occurred in the divisions that were perpendicular to the moving direction. However, HUs decreased in the alveolar bone in the moving direction. The highest HU reduction was at the coronal level. CONCLUSIONS: HU reduction occurs on the root surface in the direction perpendicular to tooth movement and in the alveolar bone in the direction of tooth movement when a canine is retracted. PMID- 25836006 TI - Differences of treatment outcomes between self-ligating brackets with microimplant and headgear anchorages in adults with bimaxillary protrusion. AB - INTRODUCTION: Our aim was to determine differences between the outcomes of treatment using microimplant anchorage compared with headgear anchorage in adult patients with bimaxillary protrusion treated with self-ligating brackets. METHODS: Thirty-one adult orthodontic patients (13 men, 18 women; age, 25.87 +/- 3.37 years) who were diagnosed with bimaxillary protrusion were selected. All patients were treated with self-ligating brackets and maximum anchorage after extraction of 4 first premolars. Group 1 received microimplant anchorage, and group 2 received headgear. Lateral cephalometric radiographs were obtained before and after treatment. Differences in the skeletal and dental parameters between and within groups were analyzed. RESULTS: No significant difference was observed in the mean treatment times between the groups (21.93 +/- 3.10 vs 23.88 +/- 2.68 months). There was no significant difference in skeletal measurements before or after treatment in patients who received microimplant anchorage. Patients who received headgear anchorage had an increase of the mandibular plane angle. The microimplant anchorage group had greater anterior tooth retraction and less maxillary molar mesialization than did the headgear group. CONCLUSIONS: In both the anteroposterior and vertical directions, microimplant anchorage achieved better control than did the traditional headgear appliance during the treatment of bimaxillary protrusion. PMID- 25836007 TI - Contribution of malocclusion and female facial attractiveness to smile esthetics evaluated by eye tracking. AB - INTRODUCTION: There is disagreement in the literature concerning the importance of the mouth in overall facial attractiveness. Eye tracking provides an objective method to evaluate what people see. The objective of this study was to determine whether dental and facial attractiveness alters viewers' visual attention in terms of which area of the face (eyes, nose, mouth, chin, ears, or other) is viewed first, viewed the greatest number of times, and viewed for the greatest total time (duration) using eye tracking. METHODS: Seventy-six viewers underwent 1 eye tracking session. Of these, 53 were white (49% female, 51% male). Their ages ranged from 18 to 29 years, with a mean of 19.8 years, and none were dental professionals. After being positioned and calibrated, they were shown 24 unique female composite images, each image shown twice for reliability. These images reflected a repaired unilateral cleft lip or 3 grades of dental attractiveness similar to those of grades 1 (near ideal), 7 (borderline treatment need), and 10 (definite treatment need) as assessed in the aesthetic component of the Index of Orthodontic Treatment Need (AC-IOTN). The images were then embedded in faces of 3 levels of attractiveness: attractive, average, and unattractive. During viewing, data were collected for the first location, frequency, and duration of each viewer's gaze. RESULTS: Observer reliability ranged from 0.58 to 0.92 (intraclass correlation coefficients) but was less than 0.07 (interrater) for the chin, which was eliminated from the study. Likewise, reliability for the area of first fixation was kappa less than 0.10 for both intrarater and interrater reliabilities; the area of first fixation was also removed from the data analysis. Repeated-measures analysis of variance showed a significant effect (P <0.001) for level of attractiveness by malocclusion by area of the face. For both number of fixations and duration of fixations, the eyes overwhelmingly were most salient, with the mouth receiving the second most visual attention. At times, the mouth and the eyes were statistically indistinguishable in viewers' gazes of fixation and duration. As the dental attractiveness decreased, the visual attention increased on the mouth, approaching that of the eyes. AC-IOTN grade 10 gained the most attention, followed by both AC-IOTN grade 7 and the cleft. AC IOTN grade 1 received the least amount of visual attention. Also, lower dental attractiveness (AC-IOTN 7 and AC-IOTN 10) received more visual attention as facial attractiveness increased. CONCLUSIONS: Eye tracking indicates that dental attractiveness can alter the level of visual attention depending on the female models' facial attractiveness when viewed by laypersons. PMID- 25836008 TI - Effects of tooth root contact on the stability of orthodontic anchor screws in the maxilla: Comparison between self-drilling and self-tapping methods. AB - INTRODUCTION: We evaluated the effects of screw placement angle on the frequency of root contact and the effects of root contact on screw stability, comparing self-drilling and self-tapping methods. METHODS: In total, 80 patients with 142 screws (diameter, 1.6 mm; length, 8.0 mm) were included. Cone-beam computed tomography images were taken. Cortical bone thickness, interroot distance, shortest distance between the screw and adjacent tooth root, and screw placement angle were measured. RESULTS: The success rates of the screws were 91.5% for the self-drilling method and 94.4% for the self-tapping method (P >0.05). The self drilling screws tended to contact the distal tooth roots in the right maxilla. In the self-drilling method, the failure rate was significantly higher in the root contact group than in the no-contact group (P <0.05). CONCLUSIONS: The success rate was not significantly different between the self-drilling and the self tapping methods in the maxilla. Avoidance of tooth root contact may improve the success rate more in the self-drilling method than in the self-tapping method. PMID- 25836009 TI - Deciduous-dentition malocclusion predicts orthodontic treatment needs later: findings from a population-based birth cohort study. AB - INTRODUCTION: Estimating orthodontic treatment need in the permanent dentition using information from the deciduous-dentition malocclusion may assist in defining the time for appropriate orthodontic intervention. Our objective was to investigate whether malocclusion in the deciduous teeth predicts orthodontic treatment need in the permanent dentition. METHODS: Two oral health studies nested in a birth cohort were carried out at ages 6 (n = 359) and 12 (n = 339) years. Open bite, crossbite, and canine malocclusion were assessed in the deciduous teeth. Orthodontic treatment need was determined in the permanent dentition using the dental esthetic index. Prevalence ratios were estimated using 2 dental esthetic index cutoff points: highly desirable/mandatory orthodontic treatment and only mandatory orthodontic treatment. We tested all combinations of the deciduous malocclusion and the outcomes, controlling for confounders. RESULTS: Children with only open bite and those with concurrent open bite and canine malocclusion were more likely to have either highly desirable/mandatory orthodontic treatment or only mandatory orthodontic treatment needs by age 12. The combination of crossbite and open bite in the deciduous teeth was associated with the highest risk of need for mandatory orthodontic treatment. CONCLUSIONS: Malocclusion in the deciduous teeth is a risk factor for orthodontic treatment need in the permanent dentition. Children with malocclusion at a young age should be monitored regularly, and caregivers may be able to better prepare for possible orthodontic treatment. PMID- 25836010 TI - Nonsurgical approach to Class I open-bite malocclusion with extrusion mechanics: a 3-year retention case report. AB - Anterior open bite is one of the most challenging malocclusions for orthodontic treatment. The high incidence of relapse is a major concern. Therefore, accurate initial examination, diagnosis, treatment plan, and consideration of habitual risk factors are crucial for a successful outcome without unwanted sequelae. Excellent patient compliance for retainer wear is also a critical factor. This case report shows the 3-year stability of a nonsurgical and nonextraction orthodontic treatment of a 5-mm anterior open-bite malocclusion in a 12-year-old girl with extrusion mechanics and habit modification. After 2 years of orthodontic treatment, excellent outcomes were achieved. With an appropriate retention protocol, the long-term stability of the treatment was favorable. PMID- 25836011 TI - Digital casts in orthodontics: a comparison of 4 software systems. AB - INTRODUCTION: The introduction of digital cast models is inevitable in the otherwise digitized everyday life of orthodontics. The introduction of this new technology, however, is not straightforward, and selecting an appropriate system can be difficult. The aim of the study was to compare 4 orthodontic digital software systems regarding service, features, and usability. METHODS: Information regarding service offered by the companies was obtained from questionnaires and Web sites. The features of each software system were collected by exploring the user manuals and the software programs. Replicas of pretreatment casts were sent to Cadent (OrthoCAD; Cadent, Carlstadt, NJ), OthoLab (O3DM; OrthoLab, Poznan, Poland), OrthoProof (DigiModel; OrthoProof, Nieuwegein, The Netherlands), and 3Shape (OrthoAnalyzer; 3Shape, Copenhagen, Denmark). The usability of the programs was assessed by experts in interaction design and usability using the "enhanced cognitive walkthrough" method: 4 tasks were defined and performed by a group of domain experts while they were observed by usability experts. RESULTS: The services provided by the companies were similar. Regarding the features, all 4 systems were able to perform basic measurements; however, not all provided the peer assessment rating index or the American Board of Orthodontics analysis, simulation of the treatment with braces, or digital articulation of the casts. All systems demonstrated weaknesses in usability. However, OrthoCAD and 03DM were considered to be easier to learn for first-time users. CONCLUSIONS: In general, the usability of these programs was poor and needs to be further developed. Hands on training supervised by the program experts is recommended for beginners. PMID- 25836012 TI - The sampling distribution. PMID- 25836014 TI - 8 - N rule and chemical bonding in main-group MgAgAs-type compounds. AB - The chemical bonding of main-group MgAgAs-type compounds is analyzed with quantum chemical direct-space techniques. A new bonding concept is developed that unites the former ionic bonding and polyanionic network models. Polar and nonpolar contributions to the bonding are extracted by the combined analysis of electron density and electron localizability. A direct-space representation of the 8 - N rule is introduced. In this approach, the anions' heteropolar bonds are treated as a superposition of covalent (nonpolar) and lone-pair closed-shell (polar) contributions. The relation between covalent (nonpolar) and lone-pair (polar) character is obtained with the ELI-D/QTAIM basin intersection technique. This ratio depends on the constituting elements. On basis of this approach, MgAgAs type compounds are compared with Zintl phases, where covalent bonds and lone pairs are spatially separated. PMID- 25836015 TI - Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism. AB - INTRODUCTION: Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. AREAS COVERED: ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. EXPERT OPINION: The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment. PMID- 25836016 TI - Oscillations for a delayed predator-prey model with Hassell-Varley-type functional response. AB - In this paper, a delayed predator-prey model with Hassell-Varley-type functional response is investigated. By choosing the delay as a bifurcation parameter and analyzing the locations on the complex plane of the roots of the associated characteristic equation, the existence of a bifurcation parameter point is determined. It is found that a Hopf bifurcation occurs when the parameter tau passes through a series of critical values. The direction and the stability of Hopf bifurcation periodic solutions are determined by using the normal form theory and the center manifold theorem due to Faria and Maglhalaes (1995). In addition, using a global Hopf bifurcation result of Wu (1998) for functional differential equations, we show the global existence of periodic solutions. Some numerical simulations are presented to substantiate the analytical results. Finally, some biological explanations and the main conclusions are included. PMID- 25836013 TI - Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma. AB - BACKGROUND: Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma. METHODS: Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor beta2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method. RESULTS: In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008). CONCLUSIONS: Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness. PMID- 25836017 TI - Characterization and structure of the polysaccharide produced by Pseudomonas fluorescens strain TF7 isolated from an arid region of Algeria. AB - Many bacteria possess a natural ability to synthesize and excrete exopolysaccharides which are widely varied in structure and function. These bacteria have the ability to solubilize inorganic phosphorus, which is important to promote growth and increase crop yields. The objective of this study is to select an adaptive strain to the constraints of erratic rainfall and large temperature variations and to determine the possible synergistic effects of its EPS and organic acid on tricalcium phosphate (TCP) solubilization. The strain TF7 isolated from an arid region of Algeria was characterized on the basis of its morphological and physiological traits. Polysaccharide production and the phosphate-solubilizing activity of the strain were evaluated using sucrose and tricalcium phosphate. This EPS was studied by sugar analysis as well as proton NMR spectra. The 16S rRNA gene sequence of this strain shared a similarity of more than 96% with Pseudomonas fluorescens. The maximum polysaccharide productivity was estimated at 4.5g.L(-1) after 5 days. The analyzed sugar was comprised of fructose, glucose, and mannose in a ratio of 4:1:0.6. NMR spectra indicated that the polysaccharide produced by the strain was levan with beta-(2 >6)-linked fructose units in accordance with the generally accepted structure. The strain TF7 solubilizes phosphate and forms a clear halo around the colony. The phosphate-solubilizing index is 2.33. PMID- 25836018 TI - Doxycycline kills human lice through its activity on their bacterial symbiont. PMID- 25836019 TI - Intracellular accumulation of boceprevir according to plasma concentrations and pharmacogenetics. AB - Boceprevir (BOC) is a directly-acting antiviral agent for the treatment of hepatitis C virus genotype 1 (HCV-1) infection. It is a mixture of two stereoisomers, the inactive R and the active S isomers. No data have previously been published on BOC intracellular accumulation. In this study, BOC isomer concentrations in peripheral blood mononuclear cells (PBMCs) and plasma were determined. The influence of various single nucleotide polymorphisms (SNPs) on plasma and intracellular drug exposure at Week 4 of triple therapy were also evaluated. Plasma and intracellular BOC concentrations were determined at the end of the dosing interval (C(trough)) using a UPLC-MS/MS validated method. Allelic discrimination was performed through real-time PCR. Median plasma concentrations were 65.97 ng/mL for the S isomer and 36.31 ng/mL for the R isomer; the median S/R plasma concentration ratio was 1.66. The median PBMC concentration was 2285.88 ng/mL for the S isomer; the R isomer was undetectable within PBMCs. The median S isomer PBMC/plasma concentration ratio was 28.59. A significant positive correlation was found between plasma and PBMC S isomer concentrations. ABCB1 1236, SLC28A2 124 and IL28B rs12979860 SNPs were associated with the S isomer PBMC/plasma concentration ratio. In regression models, S isomer plasma levels and FokI polymorphism were able to predict S isomer intracellular exposure, whereas SNPs in AKR1, BCRP1 and SLC28A2 predicted the S isomer PBMC/plasma concentration ratio. No similar data regarding BOC pharmacogenetics and pharmacokinetics have been published previously. This study adds a novel and useful overview of the pharmacological properties of this drug. PMID- 25836020 TI - Assessment and Treatment of Cognition and Communication Skills in Adults With Acquired Brain Injury via Telepractice: A Systematic Review. AB - PURPOSE: This is a systematic review of assessment and treatment of cognitive and communicative abilities of individuals with acquired brain injury via telepractice versus in person. The a priori clinical questions were informed by previous research that highlights the importance of considering any functional implications of outcomes, determining disorder- and setting-specific concerns, and measuring the potential impact of diagnostic accuracy and treatment efficacy data on interpretation of findings. METHOD: A literature search of multiple databases (e.g., PubMed) was conducted using key words and study inclusion criteria associated with the clinical questions. RESULTS: Ten group studies were accepted that addressed assessment of motor speech, language, and cognitive impairments; assessment of motor speech and language activity limitations/participation restrictions; and treatment of cognitive impairments and activity limitations/participation restrictions. In most cases, equivalence of outcomes was noted across service delivery methods. CONCLUSIONS: Limited findings, lack of diagnostic accuracy and treatment efficacy data, and heterogeneity of assessments and interventions precluded robust evaluation of clinical implications for telepractice equivalence and the broader area of telepractice efficacy. Future research is needed that will build upon current knowledge through replication. In addition, further evaluation at the impairment and activity limitation/participation restriction levels is needed. PMID- 25836021 TI - Diagnostic Role of Magnetic Resonance Imaging in Obstructive Sleep Apnea Syndrome. AB - We aim to review the diagnostic role of magnetic resonance (MR) imaging in obstructive sleep apnea syndrome (OSAS). Basic background about sleep apnea, MR anatomy of the pharyngeal airway, and MR imaging sequences applied in obstructive sleep apnea are discussed. Static and dynamic MR imaging is used in the assessment of patients with OSAS. Magnetic resonance imaging can detect the level, degree, and cause of obstruction in the upper airway that guide the clinical diagnosis and treatment. Imaging is used for prediction of treatment outcome and monitoring and follow-up of patients with OSAS after therapy. PMID- 25836022 TI - Characterization of Liver Tumors by Diffusion-Weighted Imaging: Comparison of Diagnostic Performance Using the Mean and Minimum Apparent Diffusion Coefficient. AB - PURPOSE: To determine the minimum apparent diffusion coefficient (ADC(min)) values of benign and malignant hepatic lesions based on diffusion-weighted imaging and to compare the diagnostic performance of ADC(min) and mean ADC (ADC(mean)) values for differentiating between benign and malignant tumors of the liver. MATERIALS AND METHODS: We retrospectively subjected 240 patients with 195 malignant (hepatocellular carcinoma [HCC], n = 137; metastases, n = 44; cholangiocellular carcinoma [CCC], n = 14) and 45 benign tumors (hemangiomas, n = 37; focal nodular hyperplasia [FNH], n = 8). Both ADC(mean) and ADC(min) were evaluated independently by 2 readers, the sensitivity and specificity for the detection of malignancy were calculated, and receiver operating characteristic (ROC) curves were generated. To determine interobserver agreement, we calculated the Pearson correlation coefficient. RESULTS: Mean ADC (*10 mm/s) was 1.19 for malignant (HCC, 1.15; metastasis, 1.23; CCC, 1.51) and 2.01 for benign tumors (hemangioma, 2.09; FNH, 1.52; P < 0.001). Minimum ADC was 0.81 for malignant (HCC, 0.79; metastasis, 0.81; CCC, 0.91) and 1.62 for benign tumors (hemangioma, 1.66; FNH, 1.28; P < 0.001). The sensitivity, specificity, and the calculated area under the ROC curve for diagnosing malignant lesions were 86.2%, 86.7%, and 0.942 (reader 1) and 88.7%, 88.9%, and 0.939 (reader 2) for ADC(mean); they were of 92.3%, 97.8%, and 0.984 (reader 1) and 94.9%, 97.8%, and 0.983 (reader 2) for ADC(min). CONCLUSIONS: Mean ADC and ADC(min) were valuable for differentiating between malignant and benign hepatic lesions. The area under the ROC curve of ADC(min) was significant higher than that of ADC(mean). PMID- 25836023 TI - Computed Tomography and Magnetic Resonance Manifestations of Spinal Pigmented Villonodular Synovitis. AB - OBJECTIVE: To study computed tomography (CT) and magnetic resonance imaging (MRI) findings of spinal pigmented villonodular synovitis (PVNS), with the aim of improving diagnostic accuracy. METHODS: Findings from CT (n = 7) and MRI (n = 5) of 7 cases of spinal PVNS, diagnosed by pathological examination, were retrospectively analyzed. RESULTS: One case presented with a small lesion, whereas the remaining 6 cases showed lobulated soft tissue masses centering on the facet joints, with lytic expansive destruction of the bone. The CT density of lesions in 3 cases was similar to that of the surrounding muscles, whereas the remaining 4 cases had lesions that were slightly hypodense relative to muscle. Among 5 cases for which MRI was available, 1 lesion was small with a hypointense edge, 1 manifested homogenous intensity without any obvious hypointense nodule, and multiple hypointensity nodules were visible in the remaining cases. CONCLUSIONS: The CT and MR manifestations of spinal PVNS have certain characteristics and can provide the basis for the preoperative diagnosis. PMID- 25836024 TI - Imaging Manifestation of Adenoid Cystic Carcinoma of the Breast. AB - OBJECTIVE: This study aimed to describe the imaging features of adenoid cystic carcinoma (ACC) of the breast using multimode imaging. MATERIALS AND METHODS: The findings from mammography, sonography, magnetic resonance imaging, or digital breast tomosynthesis in 11 patients with histopathologically confirmed ACC of the breast were reviewed. The imaging criteria included location, shape, size, number, margin, calcification, attenuation, echo and/or signal intensity, internal mass enhancement pattern, and dynamic-enhancement characteristics. RESULTS: On mammography (n = 9), ACC demonstrated as an irregular or lobulated mass with indistinct or spiculated margins. Sonographically (n = 11), ACCs appeared as a hypoechoic solid or heterogeneous mass with minimum vascularity on color Doppler examination. With regard to magnetic resonance imaging (n = 9), 2 of the largest masses had an extensive high T2-weighted imaging (T2WI) signal and hypointense internal septations, which demonstrated delayed enhancement. Dynamic enhancement illustrated washout kinetics. The 7 smaller masses appeared isointense on T2WI, and their internal septations were unenhanced. Among them, 5 demonstrated plateau kinetics and 2 demonstrated persistent kinetics. CONCLUSIONS: Although ACC is a rare event in the breast, we believe that the following signs may suggest the diagnosis of this entity: a well-defined border, extensive high T2WI signals, and internal septations that demonstrate delayed enhancement in larger lesions. PMID- 25836026 TI - A Framework for Sexual Decision-Making Among Female Sex Workers in Jamaica. AB - The Jamaican government has provided targeted HIV and sexually transmitted infection prevention, treatment, and other services for female sex workers (FSW) since 1989. HIV prevalence among FSW declined from 20 to 12% between 1989 and 1994, then to 9% in 2005, 5% in 2008, and 4.1% in 2011. This article distills the literature and two decades of experience working with FSW in Jamaica. Drawing on the constant comparative method, we put forward an innovative conceptual framework for explaining sexual decision-making and risk behaviors within both transactional and relational sexual situations. This framework helps fill the gaps in existing models that focus on individual behaviors. The model identifies interactions between environmental and structural elements of sex work, and three individual-level factors: risk perception, perceived relationship intimacy, and perceived control, as the four primary mediating factors influencing sexual decision-making among FSW. We propose that other factors such as violence, socioeconomic vulnerability, and policy/legal frameworks influence sexual decision-making through these primary mediating factors. This conceptual model may offer a useful framework for planning and evaluating prevention interventions among sex workers. However, it remains to be tested in order to establish its value. PMID- 25836025 TI - Metabolic alterations induce oxidative stress in diabetic and failing hearts: different pathways, same outcome. AB - SIGNIFICANCE: Several authors have proposed a link between altered cardiac energy substrate metabolism and reactive oxygen species (ROS) generation. A cogent evidence of this association has been found in diabetic cardiomyopathy (dCM); however, experimental findings in animal models of heart failure (HF) and in human myocardium also seem to support the coexistence of the two alterations in HF. CRITICAL ISSUES: Two important questions remain open: whether pathological changes in metabolism play an important role in enhancing oxidative stress and whether there is a common pathway linking altered substrate utilization and activation of ROS-generating enzymes, independently of the underlying cardiac pathology. In this regard, the comparison between dCM and HF is intriguing, in that these pathological conditions display very different cardiac metabolic phenotypes. RECENT ADVANCES: Our literature review on this topic indicates that a vast body of knowledge is now available documenting the relationship between the metabolism of energy substrates and ROS generation in dCM. In some cases, biochemical mechanisms have been identified. On the other hand, only a few and relatively recent studies have explored this phenomenon in HF and their conclusions are not consistent. FUTURE DIRECTIONS: Better methods of investigation, especially in vivo, will be necessary to test whether the metabolic fate of certain substrates is causally linked to ROS production. If successful, these studies will place a new emphasis on the potential clinical relevance of metabolic modulators, which might indirectly mitigate cardiac oxidative stress in dCM, HF, and, possibly, in other pathological conditions. PMID- 25836027 TI - Body Image in Young Gender Dysphoric Adults: A European Multi-Center Study. AB - The alteration of sex-specific body features and the establishment of a satisfactory body image are known to be particularly relevant for individuals with Gender Dysphoria (GD). The aim of the study was to first develop new scales and examine the psychometric properties of the Hamburg Body Drawing Scale (Appelt & Straubeta 1988). For the second part of this study, the satisfaction with different body features in young GD adults before cross-sex treatment were compared to female and male controls. Data collection took place within the context of the European Network for the Investigation of Gender Incongruence (ENIGI) including 135 female-to-male (FtMs) and 115 male-to-female (MtFs) young GD adults and 235 female and 379 male age-adjusted controls. The five female and six male body feature subscales revealed good internal consistency. The ENIGI sample reported less satisfaction with overall appearance (d = 0.30) and with all of their body features than controls, but no subgroup differences for sexual orientation (FtM and MtF) and Age of Onset (FtM) were found. Body dissatisfaction was higher with regard to sex-specific body features (largest effect sizes of d = 3.21 for Genitalia in FtMs and d = 2.85 for Androgen-responsive features and genitalia in MtFs) than with those that appeared less related to the natal sex (d = 0.64 for Facial features in FtMs and d = 0.59 for Body shape in MtFs). Not only medical body modifying interventions, but also psychosocial guidance with regard to body image might be helpful for GD individuals before transitioning. PMID- 25836028 TI - Environmental enrichment reverses histone methylation changes in the aged hippocampus and restores age-related memory deficits. AB - A decline in long-term memory (LTM) formation is a common feature of the normal aging process, which corresponds with abnormal expression of memory-related genes in the aged hippocampus. Epigenetic modulation of chromatin structure is required for proper transcriptional control of genes, such as the brain-derived neurotrophic factor (Bdnf) and Zif268 in the hippocampus during the consolidation of new memories. Recently, the view has emerged that aberrant transcriptional regulation of memory-related genes may be reflective of an altered epigenetic landscape within the aged hippocampus, resulting in memory deficits with aging. Here, we found that baseline resting levels for tri-methylation of histone H3 at lysine 4 (H3K4me3) and acetylation of histone H3 at lysine 9 and 14 (H3K9,K14ac) were altered in the aged hippocampus as compared to levels in the hippocampus of young adult rats. Interestingly, object learning failed to increase activity dependent H3K4me3 and di-methylation of histone H3 at lysine 9 (H3K9me2) levels in the hippocampus of aged adults as compared to young adults. Treatment with the LSD-1 histone demethylase inhibitor, t-PCP, increased baseline resting H3K4me3 and H3K9,K14ac levels in the young adult hippocampus, while young adult rats exhibited similar memory deficits as observed in aged rats. After environmental enrichment (EE), we found that object learning induced increases in H3K4me3 levels around the Bdnf, but not the Zif268, gene region in the aged hippocampus and rescued memory deficits in aged adults. Collectively, these results suggest that histone lysine methylation levels are abnormally regulated in the aged hippocampus and identify histone lysine methylation as a transcriptional mechanism by which EE may serve to restore memory formation with aging. PMID- 25836029 TI - Preparation of cross-linked, multilayer-coated fluorescent microspheres with functional groups on the surface for bioconjugation. AB - This study is to develop a method for preparing fluorescent microspheres with steady and strong fluorescence as well as the surface functionality for bioconjugation. Layer-by-layer technique was employed to introduce poly(phenylenevinylene) (PPV) precursor, diazoresin (DAR), and polyanion, including poly(acrylic acid) (PAA) and poly(sodium-p-styrenesulfonate) (PSS), onto the substrate polystyrene-divinylbenzene microspheres with sulfonic groups on the surface (SPSDVB). The conversion of PPV precursor into fluorescent PPV as well as the cross-linking reaction between DAR and polyanion, were accomplished simultaneously in the following thermal treatment. After optimizing the DAR concentration, the selection of polyelectrolytes and the coating sequence, the cross-linked multilayer coated PPV microspheres, SPSDVB-(PPV/PSS/DAR/PAA) spheres, were prepared. These spheres were found to have uniform size with a clear core-shell structure and display even and strong fluorescence, based on the characterization by flow cytometry, microscopy, and photophysics. They were found to be stable and highly resistant to common solvents and even "dissociation agent", as well as possess good thermal stability and photostability. The feasibility of conjugating biomolecules on the surface of spheres was also demonstrated. PMID- 25836030 TI - Intrathoracic extramedullary haemopoiesis in a patient with hereditary spherocytosis. PMID- 25836031 TI - Microscale technology and biocatalytic processes: opportunities and challenges for synthesis. AB - Despite the expanding presence of microscale technology in chemical synthesis and energy production as well as in biomedical devices and analytical and diagnostic tools, its potential in biocatalytic processes for pharmaceutical and fine chemicals, as well as related industries, has not yet been fully exploited. The aim of this review is to shed light on the strategic advantages of this promising technology for the development and realization of biocatalytic processes and subsequent product recovery steps, demonstrated with examples from the literature. Constraints, opportunities, and the future outlook for the implementation of these key green engineering methods and the role of supporting tools such as mathematical models to establish sustainable production processes are discussed. PMID- 25836032 TI - Relevance of the plasma membrane calcium-ATPase in the homeostasis of calcium in the fetal liver. AB - During the early stages of development, the embryo depends on the placenta as provider of oxygen and calcium, among other essential compounds. Although fetal liver accomplishes a well-known haematopoietic function, its contribution to calcium homeostasis upon development is poorly understood. The homeostasis of cell calcium contributes to diverse signaling pathways across developmental stages of most tissues and the calcium-ATPase located at the plasma membrane (PMCA) helps pumping excess calcium into the extracellular space. To date, the understanding of the equilibrium shift between PMCA isoforms during liver development is still missing. This review focuses on the characterization of the hepatic PMCA along the early stages of development, followed by a description of modern approaches to study calcium homeostasis involving several types of pluripotent cells. The application of interdisciplinary techniques to improve our understanding of liver development and the role calcium homeostasis plays in the definition of pathogenesis is also discussed. PMID- 25836033 TI - Anammox cultivation in a closed sponge-bed trickling filter. AB - A feasibility study was carried out to assess the cultivation of Anammox bacteria in lab-scale closed sponge-bed trickling filter (CSTF) reactors, namely: CSTF-1 at 20 degrees C and CSTF-2 at 30 degrees C. Stable conditions were reached from day 66 in CSTF-2 and from day 104 in CSTF-1. The early stability of CSTF-2 is attributable to the influence of temperature; nevertheless, by day 405, the nitrogen removal performed by CSTF-1 increased up to similar values of CSTF-2. The maximum total nitrogen removal efficiency was 82% in CSTF-1 and 84% in CSTF 2. After more than 400 days of operation, CSTF-1 and CSTF-2 were capable to attain a total nitrogen removal efficiency of 74+/-5% and 78+/-4% with a total nitrogen conversion rate of 1.52 and 1.60kg-N/m(sponge)(3)d, respectively. The proposed technology could be a suitable alternative for mainstream nitrogen removal in post-treatment units via the Anammox conversion pathway. PMID- 25836034 TI - Biogas production from brewery spent grain enhanced by bioaugmentation with hydrolytic anaerobic bacteria. AB - Lignocellulosic substrates are widely available but not easily applied in biogas production due to their poor anaerobic degradation. The effect of bioaugmentation by anaerobic hydrolytic bacteria on biogas production was determined by the biochemical methane potential assay. Microbial biomass from full scale upflow anaerobic sludge blanket reactor treating brewery wastewater was a source of active microorganisms and brewery spent grain a model lignocellulosic substrate. Ruminococcus flavefaciens 007C, Pseudobutyrivibrio xylanivorans Mz5(T), Fibrobacter succinogenes S85 and Clostridium cellulovorans as pure and mixed cultures were used to enhance the lignocellulose degradation and elevate the biogas production. P. xylanivorans Mz5(T) was the most successful in elevating methane production (+17.8%), followed by the coculture of P. xylanivorans Mz5(T) and F. succinogenes S85 (+6.9%) and the coculture of C. cellulovorans and F. succinogenes S85 (+4.9%). Changes in microbial community structure were detected by fingerprinting techniques. PMID- 25836035 TI - Hybrid system up-flow constructed wetland integrated with microbial fuel cell for simultaneous wastewater treatment and electricity generation. AB - An innovative design of upflow constructed wetland-microbial fuel cell (UFCW-MFC) planted with cattail was used for simultaneous wastewater treatment and electricity generation. The electrodes material employed in the study was carbon felt. The main aim of this study is to assess the performance of the UFCW coupling with MFC in term of ability to treat wastewater and the capability to generate bioelectricity. The oxidation reduction potential (ORP) and dissolved oxygen (DO) profile showed that the anaerobic and aerobic regions were well developed in the lower and upper bed, respectively, of UFCW-MFC. Biodegradation of organic matter, nitrification and denitrification was investigated and the removal efficiencies of COD, NO3(-), NH4(+) were 100%, 40%, and 91%, respectively. The maximum power density of 6.12 mW m(-2) and coulombic efficiency of 8.6% were achieved at electrode spacing of anode 1 (A1) and cathode (15 cm). PMID- 25836036 TI - Rheological and fractal hydrodynamics of aerobic granules. AB - The structural and hydrodynamic features for granules were characterized using settling experiments, predefined mathematical simulations and ImageJ-particle analyses. This study describes the rheological characterization of these biologically immobilized aggregates under non-Newtonian flows. The second order dimensional analysis defined as D2=1.795 for native clusters and D2=1.099 for dewatered clusters and a characteristic three-dimensional fractal dimension of 2.46 depicts that these relatively porous and differentially permeable fractals had a structural configuration in close proximity with that described for a compact sphere formed via cluster-cluster aggregation. The three-dimensional fractal dimension calculated via settling-fractal correlation, U?l(D) to characterize immobilized granules validates the quantitative measurements used for describing its structural integrity and aggregate complexity. These results suggest that scaling relationships based on fractal geometry are vital for quantifying the effects of different laminar conditions on the aggregates' morphology and characteristics such as density, porosity, and projected surface area. PMID- 25836037 TI - Bioaugmentation of biogas production by a hydrogen-producing bacterium. AB - The rate-limiting nature of the hydrogen concentration prevailing in the anaerobic digester has been recognized, but the associated alterations in the microbial community are unknown. In response to the addition of Enterobacter cloacae cells in laboratory anaerobic digesters, the level of biogas production was augmented. Terminal restriction fragment length polymorphism (T-RFLP) and real-time polymerase chain reaction (Real-Time PCR) were used to study the survival of mesophilic hydrogen-producing bacteria and the effects of their presence on the composition of the other members of the bacterial community. E. cloacae proved to maintain a stable cell number and to influence the microbial composition of the system. Bioaugmentation by a single strain added to the natural biogas-producing microbial community was demonstrated. The community underwent pronounced changes as a result of the relatively slight initial shift in the microbiological system, responding sensitively to the alterations in local hydrogen concentration. PMID- 25836038 TI - Opportunities to improve the areal oil productivity of microalgae. AB - Microalgae are often considered as a promising alternative source of vegetable oils. These oils can be used for food and biofuel applications. Productivities that are projected for large-scale microalgal oil production are, however, often poorly supported by scientific evidence and based on too optimistic assumptions. To facilitate the inclusion of the microalgal physiology in these projections, existing knowledge and novel scientific insights were condensed into a mechanistic model that describes photosynthesis and carbon partitioning during nitrogen starvation. The model is validated using experimental data from both wild-type and a starchless mutant of Scenedesmus obliquus. The model is subsequently used to quantify how reactor design, process design, and strain improvement can improve the oil productivity from 2.1 to up to 10.9 g m(-2) day( 1). These projected productivities are used to reflect on commonly assumed oil productivities and it is concluded that the microalgal oil productivity is often overestimated several folds. PMID- 25836039 TI - Ionic liquids for the concomitant use in extremophiles lysis and extremozymes extraction. AB - Ionic liquids have been successfully proposed to modify membrane permeability in cultures of a model extremophilic bacterium Thermus thermophilus HB27, which makes up the first time that aqueous solutions of these molten salts are applied in downstream stages of this kind of microorganisms. The presence of 1g/L of C10MIMCl entails a great solubilisation of cell biomass, thus allowing the release of intracellular and membrane-bound enzyme. The influence on the enzyme activity of two inorganic salts such as Na2CO3 and (NH4)2SO4, selected on the basis of their high salting out potential and biocompatibility with enzymes, respectively, was investigated. In parallel, their ability to trigger phase segregation was confirmed in the presence of the enzyme crude, leading to very high levels of enzyme extraction (96%). The validity of the strategy was confirmed by operating at bioreactor scale, and the main bioprocess parameters were obtained by modelling the experimental data. PMID- 25836040 TI - Enzymatic saccharification and bioethanol production from Cynara cardunculus pretreated by steam explosion. AB - The correct choice of the specific lignocellulosic biomass pretreatment allows obtaining high biomass conversions for biorefinery implementations and cellulosic bioethanol production from renewable resources. Cynara cardunculus (cardoon) pretreated by steam explosion (SE) was involved in second-generation bioethanol production using separate hydrolysis and fermentation (SHF) or simultaneous saccharification and fermentation (SSF) processes. Steam explosion pretreatment led to partial solubilisation of hemicelluloses and increased the accessibility of residual polysaccharides towards enzymatic hydrolysis revealing 64% of sugars yield against 11% from untreated plant material. Alkaline extraction after SE pretreatment of cardoon (CSEOH) promoted partial removal of degraded lignin, tannins, extractives and hemicelluloses thus allowing to double glucose concentration upon saccharification step. Bioethanol fermentation in SSF mode was faster than SHF process providing the best results: ethanol concentration 18.7 g L(-1), fermentation efficiency of 66.6% and a yield of 26.6g ethanol/100 g CSEOH or 10.1 g ethanol/100 g untreated cardoon. PMID- 25836041 TI - Primitive neuroectodermal tumor of the kidney in a young male: Case report and review of literature. AB - Primitive neuroectodermal tumor of the kidney is a rare tumor. A total of approximately 79 primary renal cases have been reported to date. Primitive neuroectodermal tumors occur preferentially in the soft-tissues of the paravertebral region and chest wall, less frequently in extremities, with a slight male predominance. We report a case of primitive neuroectodermal tumor of the kidney in a 17-year-old male with a pre-operative diagnosis of renal cell carcinoma-stage 4. The patient underwent radical nephrectomy and histopathological examination revealed a highly aggressive tumor of monotonous sheets of round cells with focal areas of rosette formations and high mitotic rate with Ki67 index of 25-30%. Tumor cells were positive for CD 99 confirming the diagnosis of primitive neuroectodermal tumor. Primitive neuroectodermal tumor of the kidney needs to be kept in mind as a differential diagnosis in young adults presenting with a large kidney mass. PMID- 25836042 TI - Association of anorectal malformation and intestinal malrotation. AB - BACKGROUND: Patients born with anorectal malformations (ARM) frequently have other congenital anomalies that are well-defined; however, limited data exist examining the relationship of ARM with malrotation. METHODS: A 10-year retrospective review was performed to examine all patients treated at a regional children's medical center with a diagnosis of ARM. Data were collected to identify malrotation, vertebral, anorectal, cardiac, tracheo-esophageal fistula, renal, radial, limb (VACTERL) anomalies, the type of ARM, operative procedures performed, and long-term bowel management. RESULTS: One hundred forty-six patients were identified. Upper gastrointestinal evaluation was performed in 21 patients (14.4%), while contrast enemas were performed in 22 patients (15.1%). Seven patients were found to have malrotation (4.8%) and 6/7 of these patients had 2 or more VACTERL anomalies. CONCLUSIONS: Patients with ARM and 2 or more VACTERL anomalies should undergo screening for malrotation. Patients with intestinal malrotation, ARM, and poor potential for bowel control should have their appendix preserved during a Ladd's procedure. PMID- 25836043 TI - Women in surgical leadership positions: further assessment and future planning needed. PMID- 25836046 TI - Two new eunicellin diterpenoids from the South China Sea gorgonian Muricella sibogae and their bioactivities. AB - A systematic re-study on gorgonian Muricella sibogae from South China Sea yielded 10 eunicellin-based diterpenoids including two new ones, sibogins C and D (1 and 2). Their structures were elucidated by extensive spectroscopic analyses (1D and 2D NMR, IR and MS) and by comparison with data reported in literatures. All the isolates were tested for cytotoxic and antifouling activities. Compounds 3 and 5 showed significant antifouling activity against the green mussel Perna viridis, and especially 3 was suggested as a potent low-toxic antifouling agent with a large LC50/EC50 value of 18.6. This was the first report on the antifouling activity of the eunicellin-type diterpenoids against the green mussel. PMID- 25836044 TI - White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke. AB - Most of the successes in experimental models of stroke have not translated well to the clinic. One potential reason for this failure is that stroke mainly afflicts the elderly and the majority of experimental stroke studies rely on data gathered from young adult animals. Therefore, in the present study we established a reliable, reproducible model of stroke with low mortality in aged (18month) male mice and contrasted their pathophysiological changes with those in young (2month) animals. To this end, mice were subjected to permanent tandem occlusion of the left distal middle cerebral artery (dMCAO) with ipsilateral common carotid artery occlusion (CCAO). Cerebral blood flow (CBF) was evaluated repeatedly during and after stroke. Reduction of CBF was more dramatic and sustained in aged mice. Aged mice exhibited more severe long-term sensorimotor deficits, as manifested by deterioration of performance in the Rotarod and hanging wire tests up to 35d after stroke. Aged mice also exhibited significantly worse long-term cognitive deficits after stroke, as measured by the Morris water maze test. Consistent with these behavioral observations, brain infarct size and neuronal tissue loss after dMCAO were significantly larger in aged mice at 2d and 14d, respectively. The young versus aged difference in neuronal tissue loss, however, did not persist until 35d after dMCAO. In contrast to the transient difference in neuronal tissue loss, we found significant and long lasting deterioration of white matter in aged animals, as revealed by the loss of myelin basic protein (MBP) staining in the striatum at 35d after dMCAO. We further examined the expression of M1 (CD16/CD32) and M2 (CD206) markers in Iba-1(+) microglia by double immunofluorescent staining. In both young and aged mice, the expression of M2 markers peaked around 7d after stroke whereas the expression of M1 markers peaked around 14d after stroke, suggesting a progressive M2-to-M1 phenotype shift in both groups. However, aged mice exhibited significantly reduced M2 polarization compared to young adults. Remarkably, we discovered a strong positive correlation between favorable neurological outcomes after dMCAO and MBP levels or the number of M2 microglia/macrophages. In conclusion, our studies suggest that the distal MCAO stroke model consistently results in ischemic brain injury with long-term behavioral deficits, and is therefore suitable for the evaluation of long-term stroke outcomes. Furthermore, aged mice exhibit deterioration of functional outcomes after stroke and this deterioration is linked to white matter damage and reductions in M2 microglia/macrophage polarization. PMID- 25836047 TI - Estrogen receptor alpha polymorphisms, estradiol level, and occurrence of atherosclerosis risk factors in healthy postmenopausal women. AB - BACKGROUND: The objective of the study was to analyze the relationship between interaction of polymorphisms in the estrogen receptor alpha gene (Eralpha) and estradiol (E2), and the occurrence of selected atherosclerosis risk factors in postmenopausal women without the diagnosis of a cardiovascular disease. MATERIAL/METHODS: The study covered 210 women, a minimum of 2 years after menopause, with FSH >30 mlU/ml, aged 50-60 years, with no chronic diseases diagnosed. In the women examined, the levels of estradiol, total cholesterol, HDL cholesterol, LDL-cholesterol, and triglycerides were determined, as well as height, waist circumference (W), hip circumference (R), and arterial hypertension. The BMI and W/H ratio were calculated. Genotyping of the ER-alpha polymorphism was performed using a polymerase chain reaction and restriction enzymes (PCR-RFLP). The alleles of the XbaI polymorphism were defined as A and G: heterozygote AG, wild type GG and homozygote AA. The alleles of PvuII polymorphism were defined as T and C: heterozygote TC, homozygote TT, and wild type CC. RESULTS: The concentration of endogenous estradiol and ERalpha XbaI and PuvII polymorphisms as independent parameters did not significantly affect the BMI, waist circumference, W/H ratio, levels of CHOL, HDL, LDL, TG, or LDL/HDL, nor the systole and diastole in the postmenopausal women in the study. CONCLUSIONS: The presented study suggests that ERalpha XbaI AA polymorphism may intensify the beneficial effect of estradiol on the distribution of fatty tissue after menopause; ERalpha XbaI GG and PuvII TC genotypes may intensify the beneficial effect of estradiol on HDL level; ERalpha PuvII TT genotype unfavorably modifies the relation between concentration of estradiol and systolic pressure after menopause. PMID- 25836045 TI - The slow forgetting of emotional episodic memories: an emotional binding account. AB - Emotional events are remembered better than neutral events, and this emotion advantage becomes particularly pronounced over time. The time-dependent effects of emotion impact upon recollection rather than on familiarity-based recognition, and they influence the recollection of item-specific details rather than contextual details. Moreover, the amygdala, but not the hippocampus, is crucial for producing these effects. Time-dependent effects of emotion have been attributed to an emotional consolidation process whereby the amygdala gradually facilitates the storage of emotional memories by other medial temporal lobe regions. However, we propose that these effects can be better understood by an emotional binding account whereby the amygdala mediates the recollection of item emotion bindings that are forgotten more slowly than item-context bindings supported by the hippocampus. PMID- 25836048 TI - Analysis of computer-aided techniques for virtual planning in nasoalveolar moulding. AB - We compared two methods of planning virtual alveolar moulding as the first step in nasoalveolar moulding to provide the basis for an automated process to fabricate nasoalveolar moulding appliances by using computer-assisted design and computer-aided manufacturing (CAD/CAM). First, the initial intraoral casts taken from seven newborn babies with complete unilateral cleft lip and palate were digitised. This was repeated for the target models after conventional nasoalveolar moulding had been completed. The initial digital model for each patient was then virtually modified by two different modelling techniques to achieve the corresponding target model: parametric and freeform modelling with the software Geomagic((r)). The digitally-remodelled casts were quantitatively compared with the actual target model for each patient, and the comparison between the two modified models and the target model showed that freeform modelling of the initial cast was successful (mean (SD) deviation n=7, +0.723 (0.148) to -0.694 (0.157)mm) but needed continuous orientation and was difficult to automate. The results from the parametric modelling (mean (SD) deviation, n=7, +1.168 (0.185) to -1.067 (0.221)mm) were not as good as those from freeform modelling. During parametric modelling, we found some irregularities on the surface, and transverse growth of the maxilla was not accounted for. However, this method seems to be the right one as far as automation is concerned. In addition, an external algorithm must be implemented because the function of the commercial software is limited. PMID- 25836050 TI - Highly sensitive determination of dialkyl phosphinate acids in environmental samples by ion chromatography tandem mass spectrometry. AB - Dialkyl phosphinate acids (DPAs) are the hydrolysates of aluminum dialkyl phosphinates (ADPs), one class of emerging phosphorus flame retardants since brominated flame retardants have been gradually phased out in recent years. It has been found that once dissolved in water, ADPs are completely hydrolyzed and exist as DPAs. However, there is no report on the determination of DPAs in environmental water samples. For the first time, we developed a method for the analysis of trace DPAs and ADPs in different environmental samples, including waters, soils and sediments. In this proposed method, MAX cartridges were employed for the purification, and ion chromatography (IC) tandem mass spectrometry (MS) method with large volume injection (200MUL) and postcolumn addition of methanol and NH3.H2O were employed for the determination of DPAs and ADPs. The matrix effects were <16% for water samples and <25% for soil/sediment samples, which were greatly improved in comparison to the liquid chromatography (LC) tandem MS determination. Determined at three fortified levels of 0.02MUg/L, 0.2MUg/L and 1.0MUg/L, the mean recoveries were from 75.8% to 110.2%, with an acceptable coefficient of variation (3.3-20%, n=6) for water samples. The limits of the method were 3.5-9.3ng/L for DPAs in environmental water samples, and 0.06 0.09MUg/kg for DPAs and ADPs in soil and sediment samples. For soil and sediment samples, results determined by the present IC-MS method were in good agreement with that determined by LC-MS in our previous study. PMID- 25836049 TI - Reversed phase and cation exchange liquid chromatography with spectrophotometric and elemental/molecular mass spectrometric detection for S-adenosyl methionine/S adenosyl homocysteine ratios as methylation index in cell cultures of ovarian cancer. AB - S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are essential compounds in the carbon metabolic cycle that have clinical implications in a broad range of disease conditions. The measurement of the ratio SAM/SAH also called methylation index, has become a way of monitoring the DNA methylation of a cell which is an epigenetic event with important clinical implications in diagnosis; therefore the development of suitable methods to accurately quantify these compounds is mandatory. This work illustrates the comparison of three independent methods for the determination of the methylation index, all of them based on the chromatographic separation of the two species (SAM and SAH) using either ion-pairing reversed phase or cation exchange chromatography. The species detection was conducted using either molecular absorption spectrophotometry (HPLC UV) or mass spectrometry with electrospray (ESI-MS/MS) as ionization source or inductively coupled plasma (DF-ICP-MS) by monitoring the S-atom contained in both analytes. The analytical performance characteristics of the three methods were critically compared obtaining best features for the combination of reversed phase HPLC with ESI-MS in the MRM mode. In this case, detection limits of about 0.5ngmL(-1) for both targeted analytes permitted the application of the designed strategy to evaluate the effect of cisplatin on the changes of the methylation index among epithelial ovarian cancer cell lines sensitive (A2780) and resistant (A2780CIS) to this drug after exposition to cisplatin. PMID- 25836051 TI - Thermo-responsive adsorbent for size-selective protein adsorption. AB - A thermo-responsive random copolymer, POEGMA (poly(oligoethylene glycol) methacrylate) grafted on cationized agarose adsorbent was used for size selective protein adsorption. The effects of OEGMA300 ((oligoethylene glycol) methyl ether methacrylate, Mn=300g/mol) content and temperature on the adsorption of bovine serum albumin (BSA) were evaluated. Increasing the content of OEGMA300 resulted a reduction in BSA adsorption due to the enhanced shielding effect of OEGMA300 chains. Grafting of POEGMA chains onto cationized agarose adsorbent reduced the BSA adsorption by more than 95% at 26.5 degrees C, which is below the LCST (lower critical solution temperature) of POEGMA. The BSA adsorption capacities for adsorbents grafted with 10 and 20mol% of OEGMA300 decreased by 48% and 46% respectively at 38 degrees C, a temperature higher than their LCSTs. The temperature-dependent adsorption of BSA on the adsorbents was attributed to changes in the polymer conformation. The thermal transition of grafted POEGMA conformation exposed the ligand when the temperature was increased. Myoglobin (Myo), which was smaller than BSA, its adsorption behavior was less dependent on the polymer conformation. The adsorption of myoglobin onto the adsorbent with and without POEGMA showed similar percentage of reduction whereas the adsorption of BSA onto the adsorbent with POEGMA decreased by 7.6 times compared to the one without POEGMA. The packed bed of POEGMA grafted adsorbent was used for flow through separation of a protein mixture consisted of virus-like particle, Hepatitis B virus-like particle (HBVLP), BSA and insulin aspart. The recovery of HBVLP in 20mol% of OEGMA300 grafted adsorbent was increased by 19% compared to ungrafted adsorbent. The flow through of BSA can be reduced by increasing the operating temperature above LCST of 20mol% of OEGMA300 while the smaller protein, insulin aspart, remained adsorbed onto the cationized surface. Hence, this thermo responsive adsorbent has a potential for size-selective separation of protein especially for the recovery of large biomolecule. PMID- 25836052 TI - Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system. AB - In the treatment of arthritic diseases, oral or systemic administration of anti inflammatory substances, such as p38 MAPK inhibitors, is hampered by numerous side effects. To overcome them, formulations of rapid and extended drug delivery systems were studied in intra-articular administration. For the first time, VX 745, a highly selective p38 MAPK inhibitor, demonstrated in vivo bioactivity, similar to dexamethasone activity, following intra-articular administration in an antigen-induced arthritic (AIA) mouse model. The in vitro bioactivity of VX-745 was also shown on synoviocytes, reducing the IL-6 concentration. Process and formulation parameters (i.e., polymer concentration, aqueous/organic phase ratio, emulsification speed and process, and evaporation pressure) and particle characterisation (i.e., drug loading, size of particle, and surface aspect) were extensively examined to produce optimised formulations. Indeed, a burst release provides a rapid saturation of intracellular p38 MAPK to relieve patients from pain and inflammation. Then, drug diffusion would be sufficient to maintain an effective dose over 2-3 months. This study confirms the effectiveness of encapsulated p38 MAPK inhibitors in extended drug delivery systems and seems to be a promising strategy for intra-articular treatment. PMID- 25836053 TI - In-vitro simulation of luminal conditions for evaluation of performance of oral drug products: Choosing the appropriate test media. AB - BACKGROUND: Biorelevant media for evaluation of dosage form performance in the gastrointestinal lumen were first introduced in the late 1990s. Since then, a variety of additional media have been proposed, making it now possible to simulate most regions in the gastrointestinal tract in both prandial states. However, recent work suggests that the complexity and degree of biorelevance required to predict in-vivo release varies with the drug, dosage form and dosing conditions. OBJECTIVE: The aim of this commentary was to establish which levels of biorelevant media are appropriate to various combinations of active pharmaceutical ingredient(s), dosage form and dosing conditions. With regard to their application, a decision tree for the selection of the appropriate biorelevant medium/media is proposed and illustrative case scenarios are provided. Additionally, media to represent the distal small intestine in both prandial states are presented. CONCLUSION: The newly proposed levels of biorelevance and accompanying decision tree may serve as a useful tool during formulation development in order to ensure high quality, predictive performance results without unnecessary complexity of media. In future work, further specific case examples will be evolved, which will additionally address the need to take gastrointestinal passage times and type and intensity of agitation into consideration. PMID- 25836054 TI - A retrospective evaluation of retigabine in patients with cognitive impairment with highly drug-resistant epilepsy. AB - PURPOSE: The purpose of this study was to evaluate retrospectively the efficacy and tolerability of retigabine (RTG) in residential patients of an epilepsy center. METHOD: We used an industry-independent noninterventional retrospective evaluation on the basis of paper and electronic records plus interrogation of the treating neurologists. All patients (N=20; 7 females; mean age: 31.8, range: 18 54years) started on RTG between May 2011 and March 2012 were included. Evaluation was carried out after 6, 12, and 24months. Changes in seizure frequency were measured as the number of seizures during three months on RTG compared with a three-month baseline period. The Clinical Global Impression scale was applied to include qualitative changes in seizure severity. All but one patient had symptomatic (structural; one patient: metabolic) or cryptogenic focal or multifocal epilepsy. All had grade III drug-resistant epilepsy and cognitive deficits of different degrees. RESULTS: The retention rates were 60% after 6months, 35% after 12months, and 20% after 24months. At 12months, there were 2 responders (10%): one had a >90% seizure reduction and the other had a >50% seizure reduction. Another 5 patients were still on RTG because of minor improvements. The reasons for discontinuation in 13 patients were adverse effects (6), lack of effect (6), and both (1). Cognitive or emotional changes were the side effects that most frequently led to discontinuation. Beyond the 12-month evaluation, 3 patients were discontinued as a consequence of the FDA warning regarding retinal pigmentation and discoloration of skin and nails in patients exposed to RTG. One patient had a moderate blue-gray finger coloring. Ophthalmological changes were not discovered. CONCLUSION: Retigabine proved to be useful only for a small minority of patients in a sample of patients with particularly difficult-to-treat epilepsy. PMID- 25836055 TI - Depressive symptoms in younger women and men with acute myocardial infarction: insights from the VIRGO study. AB - BACKGROUND: Depression was recently recognized as a risk factor for adverse medical outcomes in patients with acute myocardial infarction (AMI). The degree to which depression is present among younger patients with an AMI, the patient profile associated with being a young AMI patient with depressive symptoms, and whether relevant sex differences exist are currently unknown. METHODS AND RESULTS: The Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study enrolled 3572 patients with AMI (67.1% women; 2:1 ratio for women to men) between 2008 and 2012 (at 103 hospitals in the United States, 24 in Spain, and 3 in Australia). Information about lifetime history of depression and depressive symptoms experienced over the past 2 weeks (Patient Health Questionnaire; a cutoff score >=10 was used for depression screening) was collected during index AMI admission. Information on demographics, socioeconomic status, cardiovascular risk, AMI severity, perceived stress (14-item Perceived Stress Scale), and health status (Seattle Angina Questionnaire, EuroQoL 5D) was obtained through interviews and chart abstraction. Nearly half (48%) of the women reported a lifetime history of depression versus 1 in 4 in men (24%; P<0.0001). At the time of admission for AMI, more women than men experienced depressive symptoms (39% versus 22%, P<0.0001; adjusted odds ratio 1.64; 95% CI 1.36 to 1.98). Patients with more depressive symptoms had higher levels of stress and worse quality of life (P<0.001). Depressive symptoms were more prevalent among patients with lower socioeconomic profiles (eg, lower education, uninsured) and with more cardiovascular risk factors (eg, diabetes, smoking). CONCLUSIONS: A high rate of lifetime history of depression and depressive symptoms at the time of an AMI was observed among younger women compared with men. Depressive symptoms affected those with more vulnerable socioeconomic and clinical profiles. PMID- 25836056 TI - Disparities in cardiovascular research output and citations from 52 African countries: a time-trend, bibliometric analysis (1999-2008). AB - BACKGROUND: Cardiovascular research output and citations of publications from Africa have historically been low yet may be increasing. However, data from the continent are limited. METHODS AND RESULTS: To evaluate the cardiovascular research output and citations from 52 African countries between 1999 and 2008, we created a bibliometric filter to capture cardiovascular research articles published in the Web of Knowledge based on specialist journals and title words. Two coauthors with expertise in cardiovascular medicine tested and refined this filter to achieve >90% precision and recall. We matched retrieved records with their associated citation reports and calculated the running 5-year citation count postpublication, including the year of publication. Publications from Africa were identified by author addresses. South Africa published 872 cardiovascular research papers, Egypt 393, Tunisia 264, and Nigeria 192 between 1999 and 2008. The number of publications increased over the time period for a small number of countries (range 0.1 to 4.8 more publications per year by fractional count). Most countries' citations were low (<50), but citations were greatest for South Africa (7063), Egypt (2557), Tunisia (903), and Nigeria (540). The same countries had the greatest annual increase in 5-year citation index values: 65 (95% CI: 30, 99) for South Africa, 46 (34, 58) for Egypt, 22 (15, 28) for Tunisia, and 8 (2, 14) for Nigeria. The burden of cardiovascular disease had a weak and inconsistent relationship to cardiovascular publications (r(2)=0.07, P=0.05). Greater gross domestic product was associated with more cardiovascular publications in 2008 (r(2)=0.53, P<0.0001). CONCLUSIONS: The increases in cardiovascular research outputs from Africa are concentrated in a few countries. The reasons for regional differences in research outputs require further investigation, particularly relative to competing disease burdens. Higher prioritization of cardiovascular research funding from African countries is warranted. PMID- 25836058 TI - Disparities in Human Papillomavirus Vaccine Literacy and Vaccine Completion Among Asian American Pacific Islander Undergraduates: Implications for Cancer Health Equity. AB - PURPOSE: Low rates of human papillomavirus (HPV) vaccination among young Asian American and Pacific Islander (AAPI) women need to be addressed, particularly given the high incidence of cervical cancer in this population. The current study aims to investigate predictors of HPV vaccination in young AAPI and non-Latina white (NLW) women. METHODS: A secondary data analysis was conducted of a health survey administered to college-aged women (N = 2,270) at a large public university in the Midwest. Andersen's behavioral model of health services utilization guided the study theoretically, and hierarchical logistic regression analysis was conducted to investigate research aim. RESULTS: NLW women had a significantly higher rate of vaccine completion than AAPI women (NLW = 60.7%; AAPI = 38.6%). NLW women also scored higher on all 5 measures of HPV vaccine literacy than AAPI women. Both groups of undergraduate women reported that increasing age, knowledge about HPV, greater use of gynecological services, and knowing someone who had cancer were significant factors related to HPV vaccination completion. In the NLW group, father's income was also found to be a predictor of HPV vaccination completion. CONCLUSIONS: Rate and predictors of HPV vaccination completion vary between NLW and AAPI women. Greater promotion of HPV literacy and gynecological service use should be made to young AAPI women to increase their HPV uptake. Further research should examine sociocultural factors that could hinder or promote HPV vaccination in young AAPI women. PMID- 25836057 TI - Treatment, behavioral, and psychosocial components of cardiovascular disease risk among survivors of childhood and young adult cancer. PMID- 25836059 TI - Understanding the Effects of Bidentate Directing Groups: A Unified Rationale for sp(2) and sp(3) C-H Bond Activations. AB - Bidentate directing group (DG) strategy is a promising way to achieve sp(2) and more inert sp(3) C-H bond activations in transition metal (TM) catalysis. In this work, we systematically explored the assisting effects exerted by bidentate DGs in the C-H bond activations. Through DFT calculations and well-defined comparative analysis, we for the first time unified the rationale of the reactivity promoted by bidentate DG in sp(2) and sp(3) C-H activations, which are generally consistent with available experimental discoveries about the C-H activation reactivity up to date. In addition to the general rationale of the reactivity, the assisting effects of several typical bidentate DGs were also quantitatively evaluated and compared to reveal their relative promoting ability for C-H activation reactivity. Finally, the effect of the ligating group charge and the position of the ligating group charge in bidentate DGs were also investigated, based on which new types of DGs were designed and proposed to be potentially effective in C-H activation. The deeper understanding and new insight about the bidentate DG strategy gained in this work would help to enhance its further experimental development in sp(2) and sp(3) C-H bond activations. PMID- 25836060 TI - Outcome of inferior and superior rectus recession in Graves' orbitopathy patients. AB - PURPOSE: To evaluate the surgical effect of unilateral inferior rectus recession (IR-group) with or without a recession of contralateral superior rectus (IR-SR group) on squint angle and motility restrictions in Graves' Orbitopathy (GO) patients. DESIGN: Retrospective case series. MATERIALS AND METHODS: Primary outcome parameters were the changes of squint angle 3 months and 6-12 months postoperatively. As in a previous study, success was defined as a postoperative vertical squint angle of <=3 degrees in primary position and on downgaze. Secondary outcome parameters were the influence of surgery on duction range and influence of muscle size on dose-effect response. RESULTS: Fifty-six patients were included in the study; 31 patients in the IR-group and 25 patients in the IR SR-group. The amount of (fixed suture) recession ranged from 2 mm to 7 mm. Vertical deviations in primary position changed from 8.0 degrees [95% CI 6.6-9.7 degrees ] to 1.0 degrees [95% CI -0.4-6.5 degrees ] in the IR-group and from 17.0 degrees [95% CI 15.7-20.0 degrees ] to 1.5 degrees [95% CI 0.8-2.9 degrees ] in the IR-SR-group. The success rate was 74% in the IR-group and 64% in the IR SR-group. Elevation significantly improved in both groups (IR-group p = 0.007; IR SR- group p = 0.000). The volume of vertical rectus muscles as assessed on CT scans did not influence the dose-effect response. CONCLUSIONS: The highest success rate and highest reduction of depression was found in the IR-group. The total duction range remained stable after strabismus surgery (IR-group) or improved (IR-SR-group). Both squint angle and cyclodeviation remained stable during long time follow-up (6-12 months after surgery). PMID- 25836062 TI - GPC light shaping a supercontinuum source. AB - Generalized Phase Contrast (GPC) is a versatile tool for efficiently rerouting and managing photon energy into speckle-free contiguous spatial light distributions. We have previously shown theoretically and numerically that a GPC Light Shaper shows robustness to shift in wavelength and can maintain both projection length scale and high efficiency over a range [0.75lambda(0); 1.5lambda(0)] with lambda(0) as the characteristic design wavelength. With this performance across multiple wavelengths and the recent availability of tabletop supercontinuum lasers, GPC light shaping opens the possibility for creatively incorporating various multi-wavelength approaches into spatially shaped excitations that can enable new broadband light applications. We verify this new approach using a supercontinuum light source, interfaced with a compact GPC light shaper. Our experiments give ~70% efficiency, ~3x intensity gain, and ~85% energy savings, limited, however, by the illumination equipment, but still in very good agreement with theoretical and numerical predictions. PMID- 25836061 TI - A novel biometric authentication approach using ECG and EMG signals. AB - Security biometrics is a secure alternative to traditional methods of identity verification of individuals, such as authentication systems based on user name and password. Recently, it has been found that the electrocardiogram (ECG) signal formed by five successive waves (P, Q, R, S and T) is unique to each individual. In fact, better than any other biometrics' measures, it delivers proof of subject's being alive as extra information which other biometrics cannot deliver. The main purpose of this work is to present a low-cost method for online acquisition and processing of ECG signals for person authentication and to study the possibility of providing additional information and retrieve personal data from an electrocardiogram signal to yield a reliable decision. This study explores the effectiveness of a novel biometric system resulting from the fusion of information and knowledge provided by ECG and EMG (Electromyogram) physiological recordings. It is shown that biometrics based on these ECG/EMG signals offers a novel way to robustly authenticate subjects. Five ECG databases (MIT-BIH, ST-T, NSR, PTB and ECG-ID) and several ECG signals collected in-house from volunteers were exploited. A palm-based ECG biometric system was developed where the signals are collected from the palm of the subject through a minimally intrusive one-lead ECG set-up. A total of 3750 ECG beats were used in this work. Feature extraction was performed on ECG signals using Fourier descriptors (spectral coefficients). Optimum-Path Forest classifier was used to calculate the degree of similarity between individuals. The obtained results from the proposed approach look promising for individuals' authentication. PMID- 25836063 TI - Simultaneous measurement of pressure and temperature by employing Fabry-Perot interferometer based on pendant polymer droplet. AB - We investigated a novel and ultracompact polymer-capped Fabry-Perot interferometer, which is based on a polymer capped on the endface of a single mode fiber (SMF). The proposed Fabry-Perot interferometer has advantages of easy fabrication, low cost, and high sensitivity. The variation of the Fabry-Perot cavity length can be easily controlled by using the motors of a normal arc fusion splicer. Moreover, the enhanced mechanical strength of the Fabry-Perot interferometer makes it suitable for high sensitivity pressure and temperature sensing in harsh environments. The proposed interferometer exhibits a wavelength shift of the interference fringes that corresponds to a temperature sensitivity of 249 pm/ degrees C and a pressure sensitivity of 1130 pm/MPa, respectively, around the wavelength of 1560 nm. PMID- 25836064 TI - A one-shot-projection method for measurement of specular surfaces. AB - In this paper, a method is proposed to measure the shapes of specular surfaces with one-shot-projection of structured laser patterns. By intercepting the reflection of the reflected laser pattern twice with two diffusive planes, the closed form solution is achieved for each reflected ray. The points on the specular surface are reconstructed by computing the intersections of the incident rays and the reflected rays. The proposed method can measure both static and dynamic specular shapes due to its one-shot-projection, which is beyond the capability of most of state of art methods that need multiple projections. To our knowledge, the proposed method is the only method so far that could yield the closed form solutions for the dynamic and specular surfaces. PMID- 25836065 TI - Temperature sensor based on a hybrid ITO-silica resonant cavity. AB - Integrated optical devices comprised of multiple material systems are able to achieve unique performance characteristics, enabling applications in sensing and in telecommunications. Due to ease of fabrication, the majority of previous work has focused on polymer-dielectric or polymer-semiconductor systems. However, the environmental stability of polymers is limited. In the present work, a hybrid device comprised of an indium tin oxide (ITO) coating on a silicon dioxide toroidal resonant cavity is fabricated. Finite element method simulations of the optical field in the multi-material device are performed, and the optical mode profile is significantly altered by the high index film. The quality factor is also measured and is material loss limited. Additionally, its performance as a temperature sensor is characterized. Due to the high thermo-optic coefficient of ITO and the localization of the optical field in the ITO layer, the hybrid temperature sensor demonstrates a nearly 3-fold improvement in performance over the conventional silica device. PMID- 25836066 TI - A sensor-data-based denoising framework for hyperspectral images. AB - Many denoising approaches extend image processing to a hyperspectral cube structure, but do not take into account a sensor model nor the format of the recording. We propose a denoising framework for hyperspectral images that uses sensor data to convert an acquisition to a representation facilitating the noise estimation, namely the photon-corrected image. This photon corrected image format accounts for the most common noise contributions and is spatially proportional to spectral radiance values. The subsequent denoising is based on an extended variational denoising model, which is suited for a Poisson distributed noise. A spatially and spectrally adaptive total variation regularisation term accounts the structural proposition of a hyperspectral image cube. We evaluate the approach on a synthetic dataset that guarantees a noise-free ground truth, and the best results are achieved when the dark current is taken into account. PMID- 25836067 TI - Sum decomposition of Mueller-matrix images and spectra of beetle cuticles. AB - Spectral Mueller matrices measured at multiple angles of incidence as well as Mueller matrix images are recorded on the exoskeletons (cuticles) of the scarab beetles Cetonia aurata and Chrysina argenteola. Cetonia aurata is green whereas Chrysina argenteola is gold-colored. When illuminated with natural (unpolarized) light, both species reflect left-handed and near-circularly polarized light originating from helicoidal structures in their cuticles. These structures are referred to as circular Bragg reflectors. For both species the Mueller matrices are found to be nondiagonal depolarizers. The matrices are Cloude decomposed to a sum of non-depolarizing matrices and it is found that the cuticle optical response, in a first approximation can be described as a sum of Mueller matrices from an ideal mirror and an ideal circular polarizer with relative weights determined by the eigenvalues of the covariance matrices of the measured Mueller matrices. The spectral and image decompositions are consistent with each other. A regression-based decomposition of the spectral and image Mueller matrices is also presented whereby the basic optical components are assumed to be a mirror and a circular polarizer as suggested by the Cloude decomposition. The advantage with a regression decomposition compared to a Cloude decomposition is its better stability as the matrices in the decomposition are determined a priori. The origin of the depolarizing features are discussed but from present data it is not possible to conclude whether the two major components, the mirror and the circular polarizer are laterally separated in domains in the cuticle or if the depolarization originates from the intrinsic properties of the helicoidal structure. PMID- 25836068 TI - Plasma-mediated photothermal effects in ultrafast laser irradiation of gold nanoparticle dimers in water. AB - The intention of this paper is to study the physical mechanism underlying the response of gold nanoparticle (AuNP) dimers to a near-infrared off-resonance femtosecond pulse laser in aqueous medium. We show that the strongly localized field enhancement in the gap distance and around nanoparticles significantly reduces the laser fluence threshold to achieve an optical breakdown in comparison with an AuNP monomer. This optical breakdown results from highly localized plasma in surrounding media where the nanoparticles stay intact. Also the impact of the gap distance, field polarization, laser fluence and pulse duration on the energy deposition in plasma is presented. These results can be used to make nanoscale plasmonic devices for variety of absorption-based applications. PMID- 25836069 TI - A near-field light probe with an optical slot-waveguide structure. AB - In this study, we present a new design for an optical near-field probe with a slot-waveguide structure and evaluate it using a finite-difference time-domain simulation. Our model, with a 50-nm slot core, enables illumination around the tip of the probe using a small optical spot 50-250 nm wide with 20%-30% transmission efficiency. Based on the high-index-contrast structure in a slot waveguide, a nanosized optical spot is easily generated, which is impossible with a normal slab waveguide. Similar properties of optical spot and transmission efficiency are obtained for different geometric configurations of flat-faced and tapered dielectric slot waveguides in illumination mode. The transmission efficiency of our models is the same or higher than that in conventional metallic tapered optical probes. When operating in illumination and collection modes, a near-field light reflected at 50-200-nm-wide measured objects is clearly observed, and a spatial resolution of ~50 nm is obtained. These findings suggest the potential for slot-waveguide structures to expand the versatility of nanosized optical probes. PMID- 25836070 TI - High resolution Fourier domain optical coherence tomography in the 2 MUm wavelength range using a broadband supercontinuum source. AB - A 220 nm bandwidth supercontinuum source in the two-micron wavelength range has been developed for use in a Fourier domain optical coherence tomography (FDOCT) system. This long wavelength source serves to enhance probing depth in highly scattering material with low water content. We present results confirming improved penetration depth in high opacity paint samples while achieving the high axial resolution needed to resolve individual paint layers. This is the first FDOCT developed in the 2 MUm wavelength regime that allows fast, efficient capturing of 3D image cubes at a high axial resolution of 13 MUm in air (or 9 MUm in paint). PMID- 25836071 TI - Reducing polarization-fluctuation induced drift in resonant fiber optic gyro by using single-polarization fiber. AB - A novel hybrid single-polarization (SP) fiber ring resonator is demonstrated by using a polarization-maintaining coupler formed by splicing a section of SP fiber into the resonator. The SP fiber selectively eliminates the unwanted resonance by introducing high loss for the unwanted eigenstates of polarization in the resonator. The calculated result shows that this hybrid SP resonator is a good candidate for a tactical-grade performance gyro with a high environmental temperature stability. The experiment shows that the desired resonance in the resonator can keep an excellent stability in a wide temperature range, thus the temperature-dependent polarization-fluctuation drift in the resonant fiber optic gyro is sufficiently suppressed. As a result, a random walk coefficient of 0.08 degrees /?h and a typical bias stability below 0.3 degrees /h for an integration time of 300 s have been carried out. PMID- 25836072 TI - Phase regeneration for polarization-division multiplexed signals based on vector dual-pump nondegenerate phase sensitive amplification. AB - The polarization-division multiplexing (PDM) technology is a practical method to double the transmission capacity, and the corresponding phase regeneration (PR) for PDM signals is meaningful and necessary to extend the transmission distance and increase the transparency for the phase-encoded PDM system. Those reported PDM PR schemes either utilized polarization-diversity technique or required special PDM format. In order to overcome these issues, the PR for the PDM phase modulated signals is proposed and theoretically demonstrated in this paper, based on the vector dual-pump nondegenerate phase sensitive amplification (PSA). The theoretical model is established and the detailed characteristics are investigated to optimize the PR performance. Results show an obvious phase squeezing for the degraded 80 Gbit/s PDM differential phase-shift keying (DPSK) signals, and the error vector magnitude (EVM) of the regenerated signals on dual polarization states can be improved from 22.58% and 21.39% to 4.57% and 4.63%, respectively. Furthermore, the applicability of the proposed scheme for PDM quaternary-phase shift keying (QPSK) signals is investigated. The proposed scheme can be useful and promising in current PDM based coherent fiber-optic communication. PMID- 25836073 TI - Topological edge plasmon modes between diatomic chains of plasmonic nanoparticles. AB - We study the topological edge plasmon modes between two "diatomic" chains of identical plasmonic nanoparticles. Zak phase for longitudinal plasmon modes in each chain is calculated analytically by solutions of macroscopic Maxwell's equations for particles in quasi-static dipole approximation. This approximation provides a direct analogy with the Su-Schrieffer-Heeger model such that the eigenvalue is mapped to the frequency dependent inverse-polarizability of the nanoparticles. The edge state frequency is found to be the same as the single particle resonance frequency, which is insensitive to the separation distances within a unit cell. Finally, full electrodynamic simulations with realistic parameters suggest that the edge plasmon mode can be realized through near-field optical spectroscopy. PMID- 25836074 TI - Ultra-broadband terahertz perfect absorber by exciting multi-order diffractions in a double-layered grating structure. AB - Terahertz (THz) perfect absorber, as a useful functional device, has attracted considerable attention. Traditional metamaterial perfect absorbers are usually in response to single-frequency or multi-frequency owing to the resonance features of the metal-based sub-wavelength structure. In this paper, a simple double layered doped-silicon grating structure was designed to realize an ultra broadband and polarization-independent THz perfect absorber. Both theoretical and experimental results demonstrate that the incident THz waves ranging from 0.59 to 2.58 THz can be efficiently absorbed with an absorptivity of more than 95% and a bandwidth of about 2.0 THz. The excellent characteristic of this broad-bandwidth THz perfect absorber is mainly resulted from the air gap mode resonance together with the first-order and the second-order grating diffractions. PMID- 25836075 TI - Efficient coupling of a sub-5-nm-gap plasmonic crystal cavity with an integrated waveguide. AB - An effective engineering method for efficient coupling between a tightly focused sub-5-nm-gap plasmonic crystal cavity and an integrated waveguide is proposed. A three-dimensionally tapered 2-nm-gap plasmonic crystal cavity exhibiting a mode volume of 6x10(-6) (lambda/n)(3) can efficiently couple to an integrated waveguide with over 90% efficiency by optimally selecting the number of air-holes in the plasmonic crystal. The field intensity is accordingly maximized, and its enhancement reaches to 205,000 for the light incident from the waveguide. Here, the optimal coupling is achieved by matching the radiation rate of the cavity mode to its absorption rate. In addition, the strongly enhanced field intensity boosts the spontaneous emission rate of the dipole emitter embedded in the cavity. The maximum radiative Purcell enhancement is calculated to be 362,000 where the quantum efficiency exceeds 50%. PMID- 25836076 TI - Terahertz volatile gas sensing by using polymer microporous membranes. AB - A compact, inexpensive, low loss, highly sensitive gas sensor is important for various biomedical and industrial applications. However, current gas sensors still have an inadequate study in terahertz (THz) frequency range. In this study, simple multilayer-stacked microporous polymer membranes are experimentally validated in the THz regime for organic vapor sensing under ambient atmosphere and room temperature. The hydrophilic porous polymer structure provides a large surface area to adsorb polar vapors, and exhibits excellent discrimination in different types of organic vapors based on distinct dipole moments. Various concentrations of volatile vapors can also be successfully distinguished by detecting the limits of low ppm concentrations. Furthermore, the microporous structural gas sensor has a reasonable response time in repeat usage. This study would provide new perspectives on toxic gas sensing and exhaled breath detection applications in the THz spectral frequency. PMID- 25836077 TI - Generation of 360 degrees three-dimensional display using circular-aligned OLED microdisplays. AB - A 360 degrees all-around multiview three-dimensional (3D) display system is proposed by using coarse-pitch circular-aligned OLED microdisplays. The magnified virtual color images projected from microdisplays serve as stereo images, which can create separate eyeboxes for the viewer. Through inserting baffles, a transitional stereo image assembled by two spatially complementary segments from adjacent stereo images is presented to a complementary fusing zone (CFZ) which locates between adjacent eyeboxes. For a moving observation point, the spatial ratio of the two complementary segments evolves gradually, resulting in continuously changing transitional stereo images and thus overcoming the problem of discontinuous moving parallax. Such a controllable light-ray fusing technology, assured by the inherent large divergent angle of OLED pixels, decreases the required number of display panels for 360 degrees multiview 3D display greatly. A prototype display system with only 67 full-color OLED microdisplays is set up to demonstrate the 360 degrees 3D color display. The develop system is freed from the dependence on mechanical moving elements, high speed components and diffusion screens. PMID- 25836078 TI - Hidden image recovery using a biased photorefractive crystal in the Fourier plane of an optical imaging system. AB - Self-diffraction can be induced using a biased photorefractive crystal in the Fourier plane of an imaging system where the light beam intensity is naturally high due to the concentration effect of an optical lens. The spatial frequency spectrum of the output image is proportional to the optical power density distribution in the Fourier plane. A photorefractive crystal with small size can be used and hence an reduced amount of biased voltage is needed to obtain significant diffraction effect in the image plane. When the input image is an overlay of a signal and a noise pattern, theoretic model reveals that the induced diffraction in the Fourier plane may be preferably applied on the noise pattern. In order to illustrate the effect experimentally, a signal from a weakly illuminated object is coupled with an overwhelming noise pattern and then the hidden signal is successfully recovered using a SBN61 crystal with an applied voltage of 800 V in the Fourier plane. Such technology can be employed in encrypted spatial communication systems for security purposes. PMID- 25836079 TI - Numerical analysis of resolution enhancement in laser scanning microscopy using a radially polarized beam. AB - The spatial resolution characteristics in confocal laser scanning microscopy (LSM) and two-photon LSM utilizing a higher-order radially polarized Laguerre Gaussian (RP-LG) beam are numerically analyzed. The size of the point spread function (PSF) and its dependence on the confocal pinhole size are compared with practical LSM using a circularly polarized Gaussian beam on the basis of vector diffraction theory. The spatial frequency response in terms of the optical transfer function (OTF) is also evaluated for LSM using the RP-LG beam. The smaller focal spot characteristics of higher-order RP-LG beams contribute to a dramatic enhancement of the lateral spatial resolution in confocal LSM and two photon LSM. PMID- 25836080 TI - Large data centers interconnect bottlenecks. AB - Large data centers interconnect bottlenecks are dominated by the switch I/O BW and the front panel BW as a result of pluggable modules. To overcome the front panel BW and the switch ASIC BW limitation one approach is to either move the optics onto the mid-plan or integrate the optics into the switch ASIC. Over the last 4 years, VCSEL based optical engines have been integrated into the packages of large-scale HPC routers, moderate size Ethernet switches, and even FPGA's. Competing solutions based on Silicon Photonics (SiP) have also been proposed for integration into HPC and Ethernet switch packages but with better integration path through the use of TSV (Through Silicon Via) stack dies. Integrating either VCSEL or SiP based optical engines into complex ASIC package that operates at high temperatures, where the required reliability is not trivial, one should ask what is the technical or the economic advantage before embarking on such a complex integration. High density Ethernet switches addressing data centers currently in development are based on 25G NRZ signaling and QSFP28 optical module that can support up to 3.6 Tb of front panel bandwidth. PMID- 25836081 TI - Anomalous forward scattering of dielectric gain nanoparticles. AB - For usual lossy and lossless dielectric spherical particles, it can never realize zero forward scattering, since their Mie expansion coefficients cannot be totally offset at forward direction. By introducing suitable gain in dielectric spherical particles, we find that the electric and magnetic dipolar responses can achieve complete destructive interference at forward direction under certain incident wavelength. When the radius of particle is much smaller than the incident wavelength, the quadrupole and other higher order Mie coefficients are negligible, thus zero forward scattering can be observed and simultaneously backscattering will get enhanced. However, if the quadrupole Mie coefficients are of the same order of magnitude with dipolar terms, coherent effect between them may result in the scattering minimum and maximum shift away from forward and backward directions, respectively. These results may provide new insight into the manipulation of light scattering direction at nanoscale. PMID- 25836082 TI - Object tracking mask-based NLUT on GPUs for real-time generation of holographic videos of three-dimensional scenes. AB - A new object tracking mask-based novel-look-up-table (OTM-NLUT) method is proposed and implemented on graphics-processing-units (GPUs) for real-time generation of holographic videos of three-dimensional (3-D) scenes. Since the proposed method is designed to be matched with software and memory structures of the GPU, the number of compute-unified-device-architecture (CUDA) kernel function calls and the computer-generated hologram (CGH) buffer size of the proposed method have been significantly reduced. It therefore results in a great increase of the computational speed of the proposed method and enables real-time generation of CGH patterns of 3-D scenes. Experimental results show that the proposed method can generate 31.1 frames of Fresnel CGH patterns with 1,920 * 1,080 pixels per second, on average, for three test 3-D video scenarios with 12,666 object points on three GPU boards of NVIDIA GTX TITAN, and confirm the feasibility of the proposed method in the practical application of electro holographic 3-D displays. PMID- 25836083 TI - Simultaneous atmospheric nitrous oxide, methane and water vapor detection with a single continuous wave quantum cascade laser. AB - A continuous wave (CW) quantum cascade laser (QCL) based absorption sensor system was demonstrated and developed for simultaneous detection of atmospheric nitrous oxide (N(2)O), methane (CH(4)), and water vapor (H(2)O). A 7.73-um CW QCL with its wavelength scanned over a spectral range of 1296.9-1297.6 cm(-1) was used to simultaneously target three neighboring strong absorption lines, N(2)O at 1297.05 cm(-1), CH(4) at 1297.486 cm(-1), and H(2)O at 1297.184 cm(-1). An astigmatic multipass Herriott cell with a 76-m path length was utilized for laser based gas absorption spectroscopy at an optimum pressure of 100 Torr. Wavelength modulation and second harmonic detection was employed for data processing. Minimum detection limits (MDLs) of 1.7 ppb for N(2)O, 8.5 ppb for CH(4), and 11 ppm for H(2)O were achieved with a 2-s integration time for individual gas detection. This single QCL based multi-gas detection system possesses applications in environmental monitoring and breath analysis. PMID- 25836084 TI - Re-evaluation of literature values of silver optical constants. AB - Silver has unique optical properties for topical applications such as plasmonics. The two most widely used silver optical data sets are the Palik handbook compilation and that determined by Johnson and Christy. Unfortunately these are inconsistent making realistic modelling of the likely performance of silver in optical applications difficult, with modelling producing either highly optimistic or very pessimistic results, depending on application. By critical examination and duplication of the original experiments leading to the widely accepted literature values, we show that both data sets have drawbacks and conclude that there is a need for an improved data set for realistic simulation of experimentally obtainable properties. PMID- 25836085 TI - Fiber-coupled high-speed asynchronous optical sampling with sub-50 fs time resolution. AB - We present a fiber-coupled pump-probe system with a sub-50 fs time resolution and a nanosecond time window, based on high-speed asynchronous optical sampling. By use of a transmission grism pulse compressor, we achieve pump pulses with a pulse duration of 42 fs, an average power of 300 mW and a peak power exceeding 5 kW at a pulse repetition rate of 1 GHz after 6 m of optical fiber. With this system we demonstrate thickness mapping of soft X-ray mirrors at a sub-nm thickness resolution on a cm(2) scan area. In addition, terahertz field generation with resolved spectral components of up to 3.5 THz at a GHz frequency resolution is demonstrated. PMID- 25836086 TI - Experimental demonstration of iterative post-equalization algorithm for 37.5 Gbaud PM-16QAM quad-carrier Terabit superchannel. AB - We experimentally demonstrate a quad-carrier 1-Tb/s solution with 37.5-GBaud PM 16QAM signal over 37.5-GHz optical grid at 6.7 b/s/Hz net spectral efficiency. Digital Nyquist pulse shaping at the transmitter and post-equalization at the receiver are employed to mitigate the impairments of joint inter-symbol interference (ISI) and inter-channel-interference (ICI) symbol degradation. The post-equalization algorithms consist of one sample/symbol based decision-directed least mean square (DD-LMS) adaptive filter, digital post filter and maximum likelihood sequence estimation (MLSE), and a positive iterative process among them. By combining these algorithms, the improvement as much as 4-dB OSNR (0.1nm) at SD-FEC limit (Q(2) = 6.25 corresponding to BER = 2.0e-2) is obtained when compared to no such post-equalization process, and transmission over 820-km EDFA only standard single-mode fiber (SSMF) link is achieved for two 1.2-Tb/s signals with the averaged Q(2) factor larger than 6.5 dB for all sub-channels. Additionally, 50-GBaud 16QAM operating at 1.28 samples/symbol in a DAC is also investigated and successful transmission over 410-km SSMF link is achieved at 62.5-GHz optical grid. PMID- 25836087 TI - Type-II second-harmonic-generation properties of YCOB and GdCOB single crystals. AB - As excellent nonlinear optical (NLO) crystals, YCa(4)O(BO(3))(3) (YCOB) and GdCa(4)O(BO(3))(3) (GdCOB) have been paid much attention since their first appearance in 1990's. From that time to now, almost all of related researches and applications have focused on their type-I phase-matching (PM) configurations which possess large effective NLO coefficient (d(eff)). In this paper, type-II second-harmonic-generation (SHG) properties of these two crystals are reported, including PM curve, d(eff), angular acceptance and walk-off angle. Both of the type-II SHG experiments for 1064 and 1320 nm have indicated that the optimum directions which have maximum d(eff) locate in the second octant, i.e. (90 degrees < theta< 180 degrees , 0 degrees < phi < 90 degrees ). For a (112 degrees , 81.3 degrees )-cut, 24 mm long YCOB crystal, the largest type-II SHG conversion efficiency of a 1064 nm Nd:YAG pico-second laser is 55%, which reaches the same level of the optimum type-I sample. To our knowledge this is the first time that type-II SHG performance of YCOB and GdCOB crystals is investigated intensively. Our research has shown that the smaller d(eff) of type-II PM can be compensated by its larger angular acceptance and less beam walk-off. The same level SHG conversion efficiency implies for such type crystals the type-II components have the potential to replace type-I ones and obtain important NLO applications in the future. PMID- 25836088 TI - Theoretical and experimental analysis of channel mismatch in time-wavelength interleaved optical clock based on mode-locked laser. AB - We demonstrate a theoretical model of channel mismatch effect in a mode-locked laser based time-wavelength interleaved optical clock generation system. The channel mismatch effect includes clock timing mismatch, amplitude mismatch, and pulse shape mismatch. An explicit expression of this model is derived for 2 channel simple system and a numerical simulation of multiple-channel complicated system is carried out. In comparison with the experimental measurement, the feasibility of the theoretical model is verified for calibration and compensation of the channel mismatches. PMID- 25836089 TI - Room temperature fabrication of ZnO/ST-cut quartz SAW UV photodetector with small temperature coefficient. AB - Room-temperature fabricated ZnO/ST-cut quartz is adopted for SAW ultraviolet (UV) photodetector. The ST-cut quartz substrate and ZnO layer are used for SAW excitation and photodetection, respectively. High resolution x-ray diffraction (XRD) and photoluminescence (PL) measurement indicate that high quality ZnO films can be deposited on ST-cut quartz using radio frequency (RF) sputtering. As the SAW devices under UV illumination (6 mW/cm(2)), a downshift in frequency of about 35 KHz can be observed. The observed small temperature coefficient of frequency (TCF) indicates that SAW devices exhibit good temperature stability. The results present feasibility of using ZnO/ST-cut quartz SAW photodetectors in ultraviolet region. PMID- 25836090 TI - The delay spread in fibers for SDM transmission: dependence on fiber parameters and perturbations. AB - Contrary to single mode fibers, where random imperfections are responsible for polarization-mode dispersion, modal dispersion (MD) in multi-mode fiber structures for space-division multiplexed (SDM) transmission, originates chiefly from the intrinsic non-degeneracy of the propagating modes, also known as modal birefringence. The presence of random imperfections in such fibers has a positive aspect, as it reduces the intrinsic MD, and in the limit of strong coupling it causes the signal delay spread to increase with the square root of the propagation distance, rather than linearly, as would be the case in an ideal fiber. In this paper we derive a formula that relates the signal delay spread to the fiber geometry and to the statistical properties of the structural fiber perturbations. The derived formula provides insight into the MD phenomenon and facilitates the design of low-MD multi-mode fiber structures. PMID- 25836091 TI - Modeling and performance metrics of MIMO-SDM systems with different amplification schemes in the presence of mode-dependent loss. AB - Mode-dependent loss (MDL) is a major factor limiting the achievable information rate in multiple-input multiple-output space-division multiplexed systems. In this paper we show that its impact on system performance, which we quantify in terms of the capacity reduction relative to a reference MDL-free system, may depend strongly on the operation of the inline optical amplifiers. This dependency is particularly strong in low mode-count systems. In addition, we discuss ways in which the signal-to-noise ratio of the MDL-free reference system can be defined and quantify the differences in the predicted capacity loss. Finally, we stress the importance of correctly accounting for the effect of MDL on the accumulation of amplification noise. PMID- 25836092 TI - Pixel-wise orthogonal decomposition for color illumination invariant and shadow free image. AB - In this paper, we propose a novel, effective and fast method to obtain a color illumination invariant and shadow-free image from a single outdoor image. Different from state-of-the-art methods for shadow-free image that either need shadow detection or statistical learning, we set up a linear equation set for each pixel value vector based on physically-based shadow invariants, deduce a pixel-wise orthogonal decomposition for its solutions, and then get an illumination invariant vector for each pixel value vector on an image. The illumination invariant vector is the unique particular solution of the linear equation set, which is orthogonal to its free solutions. With this illumination invariant vector and Lab color space, we propose an algorithm to generate a shadow-free image which well preserves the texture and color information of the original image. A series of experiments on a diverse set of outdoor images and the comparisons with the state-of-the-art methods validate our method. PMID- 25836093 TI - Practical limitations of near-field goniophotometer measurements imposed by a dynamic range mismatch. AB - Within near-field goniophotometry, measurement results of both an imaging luminance measurement device and a photometer detector are combined to generate the luminous intensity distribution of a light source. The simultaneous use of these two detectors may engender incorrect measurement results, due to their difference in dynamic range. In this paper, near-field and far-field based luminous intensity distribution measurements of two luminaires are presented, in order to exemplify the problem. Results demonstrate that the distributions obtained from near-field measurements may deviate from the correct intensity distribution, by an amount of up to 16% of the total luminous flux of the luminaire. A method to check for the correctness of the luminous intensity distribution from the near-field measurement, the so-called sanity check, is discussed. To conclude, some possible solutions to eliminate the dynamic range mismatch induced errors are treated. PMID- 25836094 TI - Linearized electro-optic racetrack modulator based on double injection method in silicon. AB - Racetrack-based modulator of increased linearity for optical links is presented and analyzed. The modulator is referred to as FLAME - Finer Linearity Amplitude Modulation Element. Linearity is improved via the introduction of a Double Injection approach. Large spurious-free-dynamic-range (SFDR) of 132dB.Hz(4/5) can thus be theoretically obtained. The FLAME is studied for silicon platform and requires small footprint size (100 * 50um2) and low operation voltage, 2.5V. This makes the FLAME an appealing candidate for large scale integration in RF photonics. PMID- 25836095 TI - Band shifting for ocean color multi-spectral reflectance data. AB - An approach to perform band shifting applied to multi-spectral ocean remote sensing reflectance RRS values in the visible spectral range is presented. The band-shifting scheme aims at expressing RRS at a wavelength not originally part of the spectrum from data at neighboring bands. The scheme relies on the determination of inherent optical properties (IOPs) by a bio-optical model, the calculation of the IOPs at the target wavelength using the spectral shapes assumed for each IOP, and the operation of the bio-optical model in forward mode to express RRS at the target wavelength. The performance of the band-shifting scheme applied to bands typical of satellite missions is assessed with hyper spectral data sets obtained from radiative transfer simulations or from field measurements. The relative error epsilon on the conversion factors from 488 to 490 nm is mostly within 1%. Analogous results are obtained for conversions in the red spectral domain (665, 667 and 670 nm) only for synthetic data sets. The range of epsilon for conversions between green bands (547, 555 and 560 nm) is within 2% to 5% depending on the data set considered. Similar results are obtained when RRS values are computed at 510 nm from data at 488 and 531 nm. In the case of the assessment with simulated data, all band-shifting operations are characterized by an epsilon range within 2% for all conversions when the concentration of chlorophyll-a is lower than 1 mg m(-3). Applied to satellite data, the band shifting scheme noticeably improves the agreement between RRS data from different missions. PMID- 25836096 TI - Engineering plasmon dispersion relations: hybrid nanoparticle chain-substrate plasmon polaritons. AB - We consider the dispersion relations of the optical excitations in a chain of silver nanoparticles situated above a metal substrate and show that they are hybrid plasmon polaritons, composed of localized surface plasmons and surface plasmon polaritons. We demonstrate a strong dependence of the system's optical properties on the plasma frequency of the substrate and that choosing the appropriate plasma frequency allows one to engineer the modes to have a very high, very low or even negative group velocity. For the latter, Poynting vector calculations reveal opposite phase and energy propagation. We expect that our results will contribute to the design of nano-optical devices with specific transport properties. PMID- 25836097 TI - Tailoring dielectric resonator geometries for directional scattering and Huygens' metasurfaces. AB - In this paper we describe a methodology for tailoring the design of metamaterial dielectric resonators, which represent a promising path toward low-loss metamaterials at optical frequencies. We first describe a procedure to decompose the far field scattered by subwavelength resonators in terms of multipolar field components, providing explicit expressions for the multipolar far fields. We apply this formulation to confirm that an isolated high-permittivity dielectric cube resonator possesses frequency separated electric and magnetic dipole resonances, as well as a magnetic quadrupole resonance in close proximity to the electric dipole resonance. We then introduce multiple dielectric gaps to the resonator geometry in a manner suggested by perturbation theory, and demonstrate the ability to overlap the electric and magnetic dipole resonances, thereby enabling directional scattering by satisfying the first Kerker condition. We further demonstrate the ability to push the quadrupole resonance away from the degenerate dipole resonances to achieve local behavior. These properties are confirmed through the multipolar expansion and show that the use of geometries suggested by perturbation theory is a viable route to achieve purely dipole resonances for metamaterial applications such as wave-front manipulation with Huygens' metasurfaces. Our results are fully scalable across any frequency bands where high-permittivity dielectric materials are available, including microwave, THz, and infrared frequencies. PMID- 25836098 TI - Chaos time delay signature suppression and bandwidth enhancement by electrical heterodyning. AB - We numerically investigated the chaos time delay signature (TDS) suppression and bandwidth enhancement by electrical heterodyning. Chaos signals generated with a semiconductor laser subject to optical feedback typically have distinct loop frequency peaks in their power spectra corresponding to the reciprocals of the time delays, which deteriorates the performance in applications including chaos radar/lidar and fast random bit generation. By electrically heterodyning the chaos signal with a single frequency local oscillator, we show that the power in the chaos spectrum can be redistributed and a smoother spectrum with a broader effective bandwidth can be obtained. Compared with the chaos directly generated from a semiconductor laser subject to optical feedback, the amplitudes of the TDS (rho(TDS)) measured under different feedback strengths can be suppressed up to 63% and the effective bandwidths can be enhanced up to 46% in average after the electrical heterodyning is applied. PMID- 25836099 TI - Refractive index insensitive temperature sensor based on specialty triple-clad fiber. AB - A refractive index (RI) insensitive temperature sensor based on specialty triple clad fiber (STCF) is proposed. Based on coupling mode theory, the STCF can be equivalent to a rod waveguide and two tube waveguides. Then the cladding mode resonance characteristic of STCF is analyzed by calculating different mode dispersion curves, which indicates that it works only on the mode resonance from core to the fluorine-doped silica cladding, and finally a resonance wavelength can be obtained. Two straightforward experiments are performed to prove its sensing properties. Experimental results show that it has sensitivities of 72.17 pm/ degrees C at temperature range from 35 degrees C~95 degrees C with characteristics of insensitive to external RI in the range from 1.3450 to 1.4607. Thus, this proposed sensor can be used for solution temperature monitoring in real time. PMID- 25836100 TI - Dispersion engineering of plasmonic nanocomposite for ultrathin broadband optical absorber. AB - We theoretically study the metal-insulator-metal (MIM) structure based ultrathin broadband optical absorber which consists of a metallic substrate, a dielectric middle layer, and a nanostructured metallic top layer. It is found that, there exists an effective permittivity, epsilonnull, for the top nanostructured metallic layer which leads to unit-absorption (zero-reflection) of the MIM structure. Importantly, this epsilonnull exhibits abnormal dispersion behaviors. Both its real and imaginary parts increase monotonically with the wavelength. To obtain such naturally non-existing permittivity, we investigate the optical properties of two typical types of metal-dielectric nanocomposites, namely, thoroughly mingled composites using Bruggeman's effective medium theory, and more realistic Au nanosphere-in-dielectric structures using numerical permittivity retrieval techniques. We demonstrate that the epsilonnull-type dispersions, and consequently, perfect absorption can be obtained over a broad spectral range when the filling factor of the metal component is close to the percolation threshold. The result not only explains the recently reported broadband absorbers made of randomly deposited Au nanoparticles [M. K. Hedayati, et al, Adv. Mater. 23, 5410 (2011)], but also provides theoretical guidelines for designing ultrathin broadband plasmonic absorbers for a wealthy of important applications. PMID- 25836101 TI - Design and performance of 10-Gb/s L-band REAM-SOA for OLT Transmitter in next generation access networks. AB - We present a 10-Gb/s L-band reflective electro-absorption modulator integrated with a semiconductor optical amplifier (REAM-SOA) having improved transmission performance at very low input power of seed light. To decrease the input power of seed light, the absorption characteristics of the REAM are adjusted to reduce the amplified spontaneous emission light returned into the SOA, suppressing the gain saturation effect of the SOA. At a considerably low input power of -16 dBm, the REAM-SOA exhibits a low transmission penalty of about 1.2 dB after 50-km SMF transmission. Over a wide input power range from -16 dBm to 5 dBm, a penalty of less than 1.6 dB is achieved at 50-km transmission. PMID- 25836102 TI - Lidar remote sensing of laser-induced incandescence on light absorbing particles in the atmosphere. AB - Carbon aerosol is now recognized as a major uncertainty on climate change and public health, and specific instruments are required to address the time and space evolution of this aerosol, which efficiently absorbs light. In this paper, we report an experiment, based on coupling lidar remote sensing with Laser Induced-Incandescence (LII), which allows, in agreement with Planck's law, to retrieve the vertical profile of very low thermal radiation emitted by light absorbing particles in an urban atmosphere over several hundred meters altitude. Accordingly, we set the LII-lidar formalism and equation and addressed the main features of LII-lidar in the atmosphere by numerically simulating the LII-lidar signal. We believe atmospheric LII-lidar to be a promising tool for radiative transfer, especially when combined with elastic backscattering lidar, as it may then allow a remote partitioning between strong/less light absorbing carbon aerosols. PMID- 25836103 TI - Low voltage polymer network liquid crystal for infrared spatial light modulators. AB - We report a low-voltage and fast-response polymer network liquid crystal (PNLC) infrared phase modulator. To optimize device performance, we propose a physical model to understand the curing temperature effect on average domain size. Good agreement between model and experiment is obtained. By optimizing the UV curing temperature and employing a large dielectric anisotropy LC host, we have lowered the 2pi phase change voltage to 22.8V at 1.55MUm wavelength while keeping response time at about 1 ms. Widespread application of such a PNLC integrated into a high resolution liquid-crystal-on-silicon (LCoS) for infrared spatial light modulator is foreseeable. PMID- 25836104 TI - Stochastic Simulator for modeling the transition to lasing. AB - A Stochastic Simulator (SS) is proposed, based on a semiclassical description of the radiation-matter interaction, to obtain an efficient description of the lasing transition for devices ranging from the nanolaser to the traditional "macroscopic" laser. Steady-state predictions obtained with the SS agree both with more traditional laser modeling and with the description of phase transitions in small-sized systems, and provide additional information on fluctuations. Dynamical information can easily be obtained, with good computing time efficiency, which convincingly highlights the role of fluctuations at threshold. PMID- 25836105 TI - 3D mapping of intensity field about the focus of a micrometer-scale parabolic mirror. AB - We report on the fabrication and diffraction-limited characterization of parabolic focusing micromirrors. Sub-micron beam waists are measured for mirrors with 10-MUm radius aperture and measured fixed focal lengths in the range from 24 MUm to 36 MUm. Optical characterization of the 3D intensity in the near-field produced when the device is illuminated with collimated light is performed using a modified confocal microscope. Results are compared directly with angular spectrum simulations, yielding strong agreement between experiment and theory, and identifying the competition between diffraction and focusing in the regime probed. PMID- 25836106 TI - Directional excitation of graphene surface plasmons. AB - We propose a scheme to directionally couple light into graphene plasmons by placing a graphene sheet on a magneto-optical substrate. When a magnetic field is applied parallel to the surface, the graphene plasmon dispersion relation becomes asymmetric in the forward and backward directions. It is possible to achieve unidirectional excitation of graphene plasmons with normally incident illumination by applying a grating to the substrate. The directionality can be actively controlled by electrically gating the graphene, or by varying the magnetic bias. This scheme may have applications in graphene-based opto electronics and sensing. PMID- 25836107 TI - Mitigation of nonlinearities using conjugate data repetition. AB - We investigate a time-domain implementation of generalized phase-conjugated twin waves which we call conjugate data repetition. A theory based on time-domain perturbation analysis explaining the mitigation of nonlinear effects is provided, and the concept is evaluated using numerical simulations. Compared to PM-QPSK at the same channel bit rate, the single-channel transmission reach in a conventional system with standard single-mode fiber of conjugate data repetition QPSK is increased by approximately a factor of 2. PMID- 25836108 TI - Multi-cavity optoelectronic oscillators using multicore fibers. AB - We propose the use of both homogeneous and heterogeneous multicore fibers to implement multi-cavity optoelectronic oscillators. We present design equations and examples that show the potential for unique performance in terms of spectral selectivity, tunability and high-frequency operation. PMID- 25836109 TI - Optical chaos and hybrid WDM/TDM based large capacity quasi-distributed sensing network with real-time fiber fault monitoring. AB - An optical chaos and hybrid wavelength division multiplexing/time division multiplexing (WDM/TDM) based large capacity quasi-distributed sensing network with real-time fiber fault monitoring is proposed. Chirped fiber Bragg grating (CFBG) intensity demodulation is adopted to improve the dynamic range of the measurements. Compared with the traditional sensing interrogation methods in time, radio frequency and optical wavelength domains, the measurand sensing and the precise locating of the proposed sensing network can be simultaneously interrogated by the relative amplitude change (RAC) and the time delay of the correlation peak in the cross-correlation spectrum. Assisted with the WDM/TDM technology, hundreds of sensing units could be potentially multiplexed in the multiple sensing fiber lines. Based on the proof-of-concept experiment for axial strain measurement with three sensing fiber lines, the strain sensitivity up to 0.14% RAC/MUepsilon and the precise locating of the sensors are achieved. Significantly, real-time fiber fault monitoring in the three sensing fiber lines is also implemented with a spatial resolution of 2.8 cm. PMID- 25836111 TI - Self-focusing in multicore fibers. AB - Self-focusing is the ultimate power limit of single mode fiber amplifiers. As fiber technology is approaching this limit, ways to mitigate self-focusing are becoming more and more important. Here we show a theoretical analysis of this limitation in coupled multicore fibers. Significant scaling of the self-focusing limit is possible even for coupled multicore fibers if the out-of-phase mode is chosen. On the other hand the in-phase mode can - depending on the coupling strength - be prone to instabilities. PMID- 25836110 TI - Polarization dynamic patterns of vector solitons in a graphene mode-locked fiber laser. AB - Multiple polarization dynamic patterns of vector solitons, including fundamental solitons, bunched solitons, loosely or tightly bound states and harmonic mode locking have been observed experimentally in an erbium-doped fiber ring laser with graphene as a saturable absorber. By carefully adjusting the pump power and the orientation of the intra-cavity polarization controller, either polarization rotation or polarization locked operation have all been achieved for the above vector solitons. This is the first time that high order harmonic mode locking of polarization rotation vector solitons has been achieved. The signal to noise ratio of our system was ~51 dB, which indicates that the laser operated with high stability. PMID- 25836112 TI - Single-mode high-power interband cascade lasers for mid-infrared absorption spectroscopy. AB - For high-sensitivity absorption spectroscopy, single-mode light sources capable of emitting high optical output power in the 3 to 5 um wavelength range are vital. Here, we report on interband cascade lasers that emit 20 mW of optical power in a single spectral mode at room temperature and up to 40 mW at 0 degrees C using second-order laterally coupled Bragg gratings for distributed feedback. The lasers employ a double-ridge design with a narrow 3-um-wide top ridge to confine the optical mode and a 9-um-wide ridge for current confinement. The lasers were developed for an integrated cavity output spectroscopy instrument for stratospheric detection of hydrogen chloride at a wavelength of 3.3746 um and emit at the target wavelength with more than 34 mW of single-mode power. PMID- 25836113 TI - Development of a grating-based interferometer for six-degree-of-freedom displacement and angle measurements. AB - A grating-based interferometer for 6-DOF displacement and angle measurement is proposed in this study. The proposed interferometer is composed of three identical detection parts sharing the same light source. Each detection part utilizes three techniques: heterodyne, grating shearing, and Michelson interferometries. Displacement information in the three perpendicular directions (X, Y, Z) can be sensed simultaneously by each detection part. Furthermore, angle information (thetaX, thetaY, thetaZ) can be obtained by comparing the displacement measurement results between two corresponding detection parts. The feasibility and performance of the proposed grating-based interferometer are evaluated in displacement and angle measurement experiments. In comparison with the internal capacitance sensor built into the commercial piezo-stage, the measurement resolutions of the displacement and angle of our proposed interferometer are about 2 nm and 0.05 MUrad. PMID- 25836114 TI - Negative dispersion of birefringence of smectic liquid crystal-polymer composite: dependence on the constituent molecules and temperature. AB - We investigated the dependence of the negative dispersion of birefringence of smectic liquid crystal-polymer composites on the constituent molecules and temperature. The dispersion of birefringence was significantly varied from positive dispersion to negative dispersion by the change of the relative fraction of the constituent monomers. For the temperature dependence of the dispersion, a composite with more fraction of monomers located at the inter-layer space showed a wider temperature range of the negative dispersion of birefringence. PMID- 25836115 TI - Enhanced efficiency of AlGaInP disk laser by in-well pumping. AB - The performance of a 665-nm GaInP disk laser operated continuous-wave at 15 degrees C both in-well-pumped at 640 nm and barrier pumped at 532 nm is reported. The efficiency with respect to the absorbed power was enhanced by 3.5 times when using a 640-nm pump instead of a 532-nm pump. In-well pumping which is based on the absorption of the pump photons within the quantum-well heterostructures of the gain region instead of short-wavelength absorption in the barrier and spacer regions reduces the quantum defect between pump and laser photon and hence the heat generation. A slope efficiency of 60% with respect to the absorbed pump power was obtained by in-well pumping at 15 degrees C. Continuous-wave laser operation was further demonstrated at heat sink temperatures of up to 55 degrees C. Both the measurement of photoluminescence and COMSOL simulation show that the overall heat load in the in-well pumped laser is smaller than in the barrier pumped laser. These results demonstrate the potential of optical in-well pumping for the operation of red AlGaInP disk lasers if combined with means for efficient pump-light absorption. PMID- 25836116 TI - Recent advances in silicon-based passive and active optical interconnects. AB - Silicon photonics has experienced phenomenal transformations over the last decade. In this paper, we present some of the notable advances in silicon-based passive and active optical interconnect components, and highlight some of our key contributions. Light is also cast on few other parallel technologies that are working in tandem with silicon-based structures, and providing unique functions not achievable with any single system acting alone. With an increasing utilization of CMOS foundries for silicon photonics fabrication, a viable path for realizing extremely low-cost integrated optoelectronics has been paved. These advances are expected to benefit several application domains in the years to come, including communication networks, sensing, and nonlinear systems. PMID- 25836117 TI - Heterogeneously integrated long-wavelength VCSEL using silicon high contrast grating on an SOI substrate. AB - We report an electrically pumped hybrid cavity AlGaInAs-silicon long-wavelength VCSEL using a high contrast grating (HCG) reflector on a silicon-on-insulator (SOI) substrate. The VCSEL operates at silicon transparent wavelengths ~1.57 MUm with >1 mW CW power outcoupled from the semiconductor DBR, and single-mode operation up to 65 degrees C. The thermal resistance of our device is measured to be 1.46 K/mW. We demonstrate >2.5 GHz 3-dB direct modulation bandwidth, and show error-free transmission over 2.5 km single mode fiber under 5 Gb/s direct modulation. We show a theoretical design of SOI-HCG serving both as a VCSEL reflector as well as waveguide coupler for an in-plane SOI waveguide, facilitating integration of VCSEL with in-plane silicon photonic circuits. The novel HCG-VCSEL design, which employs scalable flip-chip eutectic bonding, may enable low cost light sources for integrated optical links. PMID- 25836118 TI - Size dependence of bandgaps in a two-dimensional plasmonic crystal with a hexagonal lattice. AB - The optical properties of surface plasmon polaritons (SPPs) are investigated at the G point in a two-dimensional plasmonic crystal with a hexagonal lattice (Hex PlC). The cathodoluminescence (CL) technique combined with a scanning transmission electron microscope (STEM) are used to produce spectral images of the SPP standing waves at the G point and identify the four types of band-edge modes predicted by group theory. The systematic measurement of the band-edge energies employed here is used to determine the characteristic dependence of each band-edge mode on the structure parameters, which provides some criteria for the design of plasmonic devices with Hex-PlCs. PMID- 25836119 TI - Full wave model of image formation in optical coherence tomography applicable to general samples. AB - We demonstrate a highly realistic model of optical coherence tomography, based on an existing model of coherent optical microscopes, which employs a full wave description of light. A defining feature of the model is the decoupling of the key functions of an optical coherence tomography system: sample illumination, light-sample interaction and the collection of light scattered by the sample. We show how such a model can be implemented using the finite-difference time-domain method to model light propagation in general samples. The model employs vectorial focussing theory to represent the optical system and, thus, incorporates general illumination beam types and detection optics. To demonstrate its versatility, we model image formation of a stratified medium, a numerical point-spread function phantom and a numerical phantom, based upon a physical three-dimensional structured phantom employed in our laboratory. We show that simulated images compare well with experimental images of a three-dimensional structured phantom. Such a model provides a powerful means to advance all aspects of optical coherence tomography imaging. PMID- 25836120 TI - Origins of modal loss of antiresonant hollow-core optical fibers in the ultraviolet. AB - Recently, a novel antiresonant hollow core fiber was introduced having promising UV guiding properties. Accompanying simulations predicted ten times lower loss than observed experimentally. Increasing loss is observed in many antiresonant fibers with the origin being unknown. Here, two possible reasons for the enhanced loss are discussed: strand thickness variation and surface roughness scattering. Our analysis shows that the attenuation is sensitive to thickness variations of the strands surrounding the hollow-core which strongly increase loss at short wavelengths. The contribution of surface roughness stays below the dB/km level and can be neglected. Thus, preventing structural irregularities by improved fabrication approaches is essential for decreasing loss. PMID- 25836121 TI - Effect of initial frequency chirp on Airy pulse propagation in an optical fiber. AB - We study both analytically and numerically the propagation dynamics of an initially chirped Airy pulse in an optical fiber. It is found that the linear propagation of an initially chirped Airy pulse depends considerably on whether the second-order dispersion parameter beta(2) and chirp C have the same or opposite signs. For beta(2)C<0, the chirped Airy pulse first undergoes an initial compression phase, then reaches a breakup area as depending on the values of C, and then experiences a lossy inversion transformation such that it continues to propagate with an opposite acceleration. The chirped Airy pulse is always dispersed during propagation in the case of beta(2)C>0. The impact of truncation coefficient and Kerr nonlinearity on the chirped Airy pulse propagation is also disclosed separately. PMID- 25836122 TI - Protein biosensing with fluorescent microcapillaries. AB - Capillaries with a high-index fluorescent coating represent a new type of whispering-gallery-mode (WGM) microcavity sensor. By coating silicon quantum dots (Si-QDs) onto the channel wall of a microcapillary, a cylindrical microcavity forms in which the optical confinement arises from the index contrast at the interface between the QD layer and the glass capillary wall. However, the ability to functionalize the QD layer for biosensing applications is an open question, since the layer consists of a mixture of Si-QDs embedded in a glassy SiOx matrix. Here, we employ a polyelectrolyte (PE) multilayer approach to functionalize the microcapillary inner surface and demonstrate the potential of this refractive index sensing platform for label-free biosensing applications, using biotin neutravidin as a specific interaction model. PMID- 25836123 TI - Analytic spatial and temporal temperature profile in a finite laser rod with input laser pulses. AB - In this communication, we present an analytic expression of the thermal load in a cylindrical laser rod. We consider a pump beam with Gaussian temporal and spatial profile, which permits, using superposition of the single pulse solution, an explicit calculation of the optical path length difference across the radial direction of the rod and of the transient thermal focal length changes for a variable pump repetition rate and pulse width. We have chosen to model Ti:Al(2)O(3) as a specific example, however our solution is completely general and can be applied to any materials with cylindrical geometry employing a stable laser cavity design. PMID- 25836124 TI - Impact of relay placement on diversity order in adaptive selective DF relay assisted FSO communications. AB - The impact of relay placement on diversity order in adaptive selective decode-and forward (DF) cooperative strategies is here investigated in the context of free space optical (FSO) communications over atmospheric turbulence channels with pointing errors when line of sight is available. The irradiance of the transmitted optical beam here considered is susceptible to moderate-to-strong turbulence conditions, following a gamma-gamma (GG) distribution together with a misalignment fading model where the effect of beam width, detector size and jitter variance is considered. Novel closed-form approximate bit error-rate (BER) expressions are obtained for a cooperative FSO communication setup with N relays, assuming that these relays are located in an area similar to an annulus around source or destination node. An analytical expression is here found that determines the best selection criterion based on the knowledge of the channel state information (CSI) of source-relay or relay-destination links in order to significantly increase the diversity order corresponding to the cooperative strategy under study. It is concluded that the highest diversity order is achieved when the relation beta(SR(min)) > beta(SD) + beta(R(min)D) is satisfied, wherein beta(SR(min)), beta(R(min)D) and beta(SD) are parameters corresponding to the atmospheric turbulence conditions of source-relay and relay-destination link with the greatest scintillation index, and source-destination link, respectively. PMID- 25836125 TI - On the benefit of DMT modulation in nonlinear VLC systems. AB - In a visible light communication (VLC) system, the nonlinear characteristic of the light emitting diode (LED) in transmitter is a limiting factor of system performance. Modern modulation signals with large peak-to-power-ratio (PAPR) suffers uneven distortion. The nonlinear response directly impacts the intensity modulation and direct detection VLC system with pulse-amplitude modulation (PAM). The amplitude of the PAM signal is distorted unevenly and large signal is vulnerable to noise. Orthogonal linear transformations, such as discrete multi tone (DMT) modulation, can spread the nonlinear effects evenly to each data symbol, thus perform better than PAM signals. In this paper, we provide theoretical analysis on the benefit of DMT modulation in nonlinear VLC system. We show that the DMT modulation is a better choice than the PAM modulation for the VLC system as the DMT modulation is more robust against nonlinearity. We also show that the post-distortion nonlinear elimination method, which is applied at the receiver, can be a reliable solution to the nonlinear VLC system. Simulation results show that the post-distortion greatly improves the system performance for the DMT modulation. PMID- 25836126 TI - Compact high power mid-infrared optical parametric oscillator pumped by a gain switched fiber laser with "figure-of-h" pulse shape. AB - We demonstrate a compact high power mid-infrared (MIR) optical parametric oscillator (OPO) pumped by a gain-switched linearly polarized, pulsed fiber laser. The gain-switched fiber laser was constructed with a piece of Yb doped polarization maintaining (PM) fiber, a pair of fiber Bragg gratings written into the matched passive PM fiber and 6 pigtailed pump laser diodes working at 915 nm with 30 W output peak power each. By modulating the pulse width of the pump laser diode, simple pedestal-free pulse shape or pedestal-free trailing pulse shape ("figure-of-h" as we call it) could be achieved from the gain-switched fiber laser. The laser was employed as the pump of a two-channel, periodically poled magnesium oxide lithium niobate-based OPO system. High power MIR emission was generated with average output power of 5.15 W at 3.8 MUm channel and 8.54 W at 3.3 MUm channel under the highest pump power of 45 W. The corresponding pump-to idler conversion efficiency was computed to be 11.7% and 19.1%, respectively. Experimental results verify a significant improvement to signal-to-idler conversion efficiency by using "figure-of-h" pulses over simple pedestal-free pulses. Compared to the master oscillator power amplifier (MOPA) fiber laser counterpart, the presented gain switched fiber laser is more attractive in OPO pumping due to its compactness and simplicity which are beneficial to construction of OPO systems for practical MIR applications. PMID- 25836127 TI - Theoretical analysis and design guideline for focusing subwavelength gratings. AB - We propose a planar dielectric reflector with focusing ability using concentric circular subwavelength gratings (CC-SWGs). The two-dimensional focusing ability of CC-SWGs is investigated by the rigorous coupled-wave analysis (RCWA) and finite element method (FEM). By designing the concentric circular pattern of the grating surface, a focusing reflector with high numerical aperture (NA) and high reflectivity is constructed. A CC-SWG reflector with a diameter of 32.6MUm and a focal length of 6MUm is investigated, which exhibits high focusing ability at normal incidence with a radially polarized plane wave. At the reflection focal plane, the full-width-half-maximum (FWHM) of the electric field intensity is 0.89MUm. Numerical aperture value as high as 0.93 is achieved for the reflector with very high reflectivity of 92%. PMID- 25836128 TI - Characterization of energy transfer for passively Q-switched laser ignition. AB - Miniaturized passively Q-switched Nd:YAG/Cr(4+):YAG lasers are promising candidates as spark sources for sophisticated laser ignition. The influence of the complex spatial-temporal pulse profile of such lasers on the process of plasma breakdown and on the energy transfer is studied. The developed measurement technique is applied to an open ignition system as well as to prototypes of laser spark plugs. A detected temporal breakdown delay causes an advantageous separation of plasma building phase from energy transfer. In case of fast rising laser pulses, an advantageous reduction of the plasma breakdown delay occurs instead. PMID- 25836129 TI - Impact of broadened laser line-shape on retrievals of atmospheric species from lidar sounding absorption spectra. AB - We examine the impact of broadened laser line-shape on retrievals of atmospheric species from lidar-sounding absorption spectra. The laser is assumed to be deterministically modulated into a stable, nearly top-hat frequency comb to suppress the stimulated Brillouin scattering, allowing over 10-fold pulse energy increase without adding measurement noise. Our model remains accurate by incorporating the laser line-shape factor into the effective optical depth. Retrieval errors arising from measurement noise and model bias are analyzed parametrically and numerically to provide deeper insight. The stable laser line shape broadening minimally degrades the column-averaged retrieval, but can significantly degrade the multiple-layer retrievals. PMID- 25836130 TI - Optical bistability in a one-dimensional photonic crystal resonator using a reverse-biased pn-junction. AB - Optical bistability provides a simple way to control light with light. We demonstrate low-power thermo-optical bistability caused by the Joule heating mechanism in a one-dimensional photonic crystal (PC) nanobeam resonator with a moderate quality factor (Q ~8900) with an embedded reverse-biased pn-junction. We show that the photocurrent induced by the linear absorption in this compact resonator considerably reduces the threshold optical power. The proposed approach substantially relaxes the requirements on the input optical power for achieving optical bistability and provides a reliable way to stabilize the bistable features of the device. PMID- 25836131 TI - Saturable Lorentz model for fully explicit three-dimensional modeling of nonlinear optics. AB - Inclusion of the instantaneous Kerr nonlinearity in the FDTD framework leads to implicit equations that have to be solved iteratively. In principle, explicit integration can be achieved with the use of anharmonic oscillator equations, but it tends to be unstable and inappropriate for studying strong-field phenomena like laser filamentation. In this paper, we show that nonlinear susceptibility can be provided instead by a harmonic oscillator driven by a nonlinear force, chosen in a way to reproduce the polarization obtained from the solution of the quantum mechanical two-level equations. The resulting saturable, nonlinearly driven, harmonic oscillator model reproduces quantitatively the quantum mechanical solutions of harmonic generation in the under-resonant limit, up to the 9th harmonic. Finally, we demonstrate that fully explicit leapfrog integration of the saturable harmonic oscillator is stable, even for the intense laser fields that characterize laser filamentation and high harmonic generation. PMID- 25836132 TI - Extremely compact hybrid III-V/SOI lasers: design and fabrication approaches. AB - In this manuscript we discuss state of the art hybrid integration techniques and III-V/Si active components with an emphasis on hybrid distributed feedback (DFB) lasers for telecom applications. We review our work on ultra-compact III-V/Si DFB lasers and further describe design considerations and challenges associated with electrically pumped hybrid lasers. We conclude with a perspective on DFB lasers with extremely small footprint, a direction for future research with potential applications to densely-packed optical interconnects. PMID- 25836133 TI - High power spiral cavity quantum cascade superluminescent emitter. AB - Quantum Cascade devices with an emission wavelength centered around 5 MUm have been shaped into compact, yet long (8 mm and 12 mm) spiral cavities to increase mid-infrared superluminescence (SL) power. Up to ~57 mW of SL power at 250 K is obtained with a Gaussian emission spectrum with a full width at half maximum of 56 cm(-1) and a coherence length of ~107 MUm. PMID- 25836134 TI - The MBE growth and optimization of high performance terahertz frequency quantum cascade lasers. AB - The technique of molecular beam epitaxy has recently been used to demonstrate the growth of terahertz frequency GaAs/AlGaAs quantum cascade lasers (QCL) with Watt level optical output powers. In this paper, we discuss the critical importance of achieving accurate layer thicknesses and alloy compositions during growth, and demonstrate that precise growth control as well as run-to-run growth reproducibility is possible. We also discuss the importance of minimizing background doping level in maximizing QCL performance. By selecting high performance active region designs, and optimizing the injection doping level and device fabrication, we demonstrate total optical (two-facet) output powers as high as 1.56 W. PMID- 25836135 TI - Difference-frequency generation of ultrashort pulses in the mid-IR using Yb-fiber pump systems and AgGaSe(2). AB - We employ AgGaSe(2) for difference-frequency generation between signal and idler of synchronously-pumped picosecond / femtosecond OPOs at 80 / 53 MHz. Continuous tuning in the picosecond regime is achieved from 5 to 18 um with average power of 140 mW at 6 um. In the femtosecond regime the tunability extends from 5 to 17 um with average power of 69 mW at 6 um. Maximum single pulse energies of >1 nJ in both cases represent the highest values at such high repetition rates. PMID- 25836136 TI - Scheduling for indoor visible light communication based on graph theory. AB - Visible light communication (VLC) has drawn much attention in the field of high rate indoor wireless communication. While most existing works focused on point-to point VLC technologies, few studies have concerned multiuser VLC, where multiple optical access points (APs) transmit data to multiple user receivers. In such scenarios, inter-user interference constitutes the major factor limiting the system performance. Therefore, a proper scheduling scheme has to be proposed to coordinate the interference and optimize the whole system performance. In this work, we aim to maximize the sum rate of the system while taking into account user fairness by appropriately assigning LED lamps to multiple users. The formulated scheduling problem turns out to be a maximum weighted independent set problem. We then propose a novel and efficient resource allocation method based on graph theory to achieve high sum rates. Moreover, we also introduce proportional fairness into our scheduling scheme to ensure the user fairness. Our proposed scheduling scheme can, with low complexity, achieve more multiplexing gains, higher sum rate, and better fairness than the existing works. PMID- 25836137 TI - Interscale mixing microscopy: numerically stable imaging of wavelength- scale objects with sub-wavelength resolution and far field measurements. AB - We present an imaging technique that allows the recovery of the profile of wavelength-scale objects with deep subwavelength resolution based on far-field intensity measurements. The approach, interscale mixing microscopy (IMM), relies on diffractive elements positioned in the near-field proximity of an object in order to scatter information carried by evanescent waves into propagating part of the spectrum. A combination of numerical solutions of Maxwell equations and nonlinear fitting is then used to recover the information about the object based on far-field intensity measurements. It is demonstrated that IMM has the potential to recover wavelength/20 features of wavelength-scale objects in the presence of 10% noise. PMID- 25836138 TI - Diffractive interface theory: nonlocal susceptibility approach to the optics of metasurfaces. AB - We present a formalism for understanding the electromagnetism of metasurfaces, optically thin composite films with engineered diffraction. The technique, diffractive interface theory (DIT), takes explicit advantage of the small optical thickness of a metasurface, eliminating the need for solving for light propagation inside the film and providing a direct link between the spatial profile of a metasurface and its diffractive properties. Predictions of DIT are compared with full-wave numerical solutions of Maxwell's equations, demonstrating DIT's validity and computational advantages for optically thin structures. Applications of the DIT range from understanding of fundamentals of light-matter interaction in metasurfaces to efficient analysis of generalized refraction to metasurface optimization. PMID- 25836139 TI - Phase noise characteristics of microwave signals generated by semiconductor laser dynamics. AB - Phase noise of the period-one (P1) nonlinear dynamical oscillation in an optically injected semiconductor laser is numerically investigated. The P1 dynamics causes the laser output intensity to oscillate at a widely tunable frequency for photonic microwave generation, although the intrinsic spontaneous emission in the laser inevitably degrades the microwave signal and manifests as the oscillation phase noise. To characterize the phase noise, the P1 microwave linewidth is first numerically examined through the rate equations with a Langevin term. The P1 microwave linewidth is found to vary with the injection parameters. It is nearly minimized when the microwave power maximizes. Owing to the laser nonlinearities, the P1 microwave linewidth can even be smaller than the free-running optical linewidth. By adding an optical feedback to the laser, the P1 microwave linewidth is found to reduce as the feedback strength and feedback delay increase, in which an inverse-square dependency is followed asymptotically. By modification to a dual-loop feedback, noisy side peaks around the central P1 frequency are effectively suppressed through the Vernier effect. The dual-loop feedback maintains a low phase noise variance over a wide tuning range of the P1 frequency, while allowing long delay times for significant P1 microwave linewidth narrowing. PMID- 25836140 TI - Graphene plasmonics for tuning photon decay rate near metallic split-ring resonator in a multilayered substrate. AB - Study of photon decay rate is essential to various optical devices, where graphene is an emerging building block due to its electrical tunability. In this paper, we study photon decay rate of a quantum emitter near a metallic split-ring resonator, which is embedded in a multilayered substrate incorporating a graphene layer. Analyzing photon decay rate in such a complex multilayered system is not only computationally challenging but also highly important to experimentally realizable devices. First, the dispersion relation of graphene plasmonics supported at a dieletric/graphene/dielectric structure is investigated systematically. Meanwhile, the dispersion relation of metallic plasmonics supported at a dielectric/metal structure is studied comparatively. According to our investigation, graphene offers several flexible tuning routes for manipulating photon decay rate, including tunable chemical potential and the emitter's position and polarization. Next, considering plasmonic waves in a graphene sheet occur in the infrared regime, we carefully design a metallic split ring resonating around the same frequency range. Consequently, this design enables a mutual interaction between graphene plasmonics and metallic plasmonics. The boundary element method with a multilayered medium Green's function is adopted in the numerical simulation. Blue-shifted and splitting resonance peaks are theoretically observed, which suggests a strong mode coupling. Moreover, the mode coupling has a switch on-off feature via electrostatically doping the graphene sheet. This work is helpful to dynamically manipulate photon decay rate in complex optical devices. PMID- 25836141 TI - Tailoring the amplification of attosecond pulse through detuned X-ray FEL undulator. AB - We demonstrate that the amplification of attosecond pulse in X-ray free electron laser (FEL) undulator can be tailored. The characteristic of the amplification of an isolated attosecond pulse in the FEL undulator is investigated. An isolated 180 attoseconds full width half maximum (FWHM) pulse at 1.25 nm with a spectral bandwidth of 1% is injected into an undulator. The simulation results show that for a direct seeding of 3MW, the seed is amplified to the peak power of 106 GW (40 MUJ, an output pulse-width of 383 attoseconds) in the presence of a detuning at FEL resonance condition in 100-m long undulator. We note that the introduction of detuning leads to the better performance compared to the case without detuning: shorter by 15.5% in a pulse-width and higher by 76.6% in an output power. Tapering yields a higher power (116% increases in the output power compared to the case without detuning) but a longer pulse (15.4% longer in the pulse-width). It was observed that +/- Deltalambda(r)/8 (Deltalambda(r)/lambda(r) ~1%) is the maximum degree of detuning, beyond which the amplification becomes poor: lower in the output power and longer in the pulse duration. The minimum power for a seed pulse needs to be higher than 1 MW for the successful amplification of an attosecond pulse at 1.25 nm. Also, the electron beam energy spread must be less than 0.1% for a suitable propagation of attosecond pulse along the FEL undulator under this study. PMID- 25836142 TI - Color-tunable electroluminescence from Eu-doped TiO(2)/p(+)-Si heterostructured devices: engineering of energy transfer. AB - We report on color-tunable electroluminescence (EL) from TiO(2):Eu/p(+)-Si heterostructured devices using different TiO(2):Eu films in terms of Eu content and annealing temperature. It is found that the Eu-related emissions are activated by the energy transferred from TiO(2) host via oxygen vacancies, at the price of weakened oxygen-vacancy-related emissions. Both the higher Eu content and the higher annealing temperature for TiO(2):Eu films facilitate the aforementioned energy transfer. In this context, the dominant EL from the TiO(2):Eu/p(+)-Si heterostructured devices can be transformed from oxygen-vacancy related emissions into Eu-related emissions with increasing Eu-content and annealing temperature for TiO(2):Eu films, exhibiting different colors of emanated light. We believe that this work sheds light on developing silicon-based red emitters using the Eu-doped oxide semiconductor films. PMID- 25836143 TI - Influence of oceanic turbulence on propagation of a radial Gaussian beam array. AB - The analytical expression for the root-mean-square (Rms) beam width of the radial Gaussian beam array propagating in oceanic turbulence is derived, where the coherent combination is considered. Meanwhile, the analytical expression for effect of the turbulence on the beam F is also obtained. Giving a comparison of results of F calculated by the analytical expression and the previously integrating one, it can be seen that the two results are in agreement with each other exactly. Further, the influences of the rate of dissipation of mean-squared temperaturechi(T), the rate of dissipation of kinetic energy per unit mass of seawater epsilonand the ratio of temperature to salinity contribution to the refractive index spectrum w are investigated. The results indicate that the Rms beam width increases as chi(T) increases, epsilondecreases and the salinity induced turbulence dominates. Moreover, the changings of effective radius of curvature with mentioned above parameters are studied. The strength of turbulence determines the value of effective radius of curvature, and which decreases aschi(T) and w increases, and epsilondecreases. PMID- 25836144 TI - Room temperature ammonia sensing using tapered multimode fiber coated with polyaniline nanofibers. AB - We demonstrate an ammonia sensor composed of a tapered multimode fiber coated with polyaniline nanofibers that operates at room temperature (26 degrees C). The optical properties of the polyaniline layer changes when it is exposed to ammonia, leading to a change in the absorption of evanescent field. The fiber sensor was tested by exposing it to ammonia at different concentrations and the absorbance is measured using a spectrophotometer system. Measured response and recovery times are about 2.27 minutes and 9.73 minutes, respectively. The sensor sensitivity can be controlled by adjusting the tapered fiber diameter and the highest sensitivity is achieved when the diameter is reduced to 20 um. PMID- 25836145 TI - Electrically tuneable lateral leakage loss in liquid crystal clad shallow-etched silicon waveguides. AB - We demonstrate electrical tuning of the lateral leakage loss of TM-like modes in nematic liquid crystal (LC) clad shallow-etched Silicon-on-Insulator (SOI) waveguides. The refractive index of the LC layer can be modulated by applying a voltage over it. This results in a modulation of the effective index of the SOI waveguide modes. Since the leakage loss is linked to these effective indices, tunable leakage loss of the waveguides is achieved. We switch the wavelength at which the minimum in leakage loss occurs by 39.5nm (from 1564nm to 1524.5nm) in a 785nm wide waveguide. We show that the leakage loss in this waveguide can either be increased or decreased by modulating the refractive index of the LC cladding at a fixed wavelength. PMID- 25836146 TI - Transfer of orbital angular momentum through sub-wavelength waveguides. AB - Data capacity of optical communication is achieving its limit owing to the non linear effect of optical fiber. As an effective alternative, light carrying orbital angular momentum can greatly increase the capacity for its unprecedented degree of freedom. We demonstrate the propagation of orbital angular momentum with topological charge of 1 and 2 in plasmonic circular waveguide with sub wavelength diameter with little propagation loss of 2.73 dB/MUm, which has never been observed in optical fibers with sub-wavelength diameter. We also confirm that lights carrying orbital angular momentum can be maintained in sharp bended sub-wavelength waveguide. This plasmonic waveguide may serve as a key component in on-chip systems involving OAM. PMID- 25836147 TI - Accelerated synthesis algorithm of polygon computer-generated holograms. AB - For the real-time computation of computer-generated holograms (CGHs), various accelerated algorithms have been actively investigated. This paper proposes a novel concept of sparse computation of polygon CGH, which is inspired by an observation of the sparsity in the angular spectrum of a unit triangular polygon and present the accelerated algorithm using the intrinsic sparsity in the polygon CGH pattern for the enhancement of computational efficiency effectively. It is shown with numerical results that computation efficiency can be greatly improved without degrading the quality of holographic image. PMID- 25836148 TI - Compact light source for ultrabroadband coherent anti-Stoke Raman scattering (CARS) microscopy. AB - A compact light source module for ultrabroadband coherent anti-Stoke Raman scattering (CARS) microscopy was developed. It mainly consists of a nanosecond microchip laser, a photonic crystal fiber for Stokes light generation, and a single mode polarization maintaining fiber for pump light propagation. It is alignment-free and relatively low-cost compared with previous light sources of CARS microscopy. By using an assembled module, we successfully observed an ultrabroadband CARS spectrum and a CARS image of a murine adipocyte. The module is expected to greatly spread the CARS microscopy to various fields by its extreme easiness to handle. PMID- 25836149 TI - Thermal and high speed modulation characteristics for AlGaInAs/InP microdisk lasers. AB - Thermal and high speed modulation characteristics are investigated for a unidirectional-emission microdisk laser with a radius of 7 MUm surrounded by BCB cladding layer, with a threshold current of 1.5 mA at the temperature of 287 K. The lasing spectra under different widths of pulsed current are measured to characterize the temperature rise during the pulse period, and the thermal distribution in the microdisk laser is simulated by the finite-element modeling technique. A temperature rise of 25 K is estimated for the microdisk laser biased at 20 mA. Furthermore, small signal modulation response with 3dB bandwidth up to 20 GHz is obtained for the microdisk laser at the biasing current of 18 mA, and eye-diagrams at the modulation bit rates of 20, 25, and 30 GHz are also measured at the temperature of 287 K. PMID- 25836150 TI - Study on DFB semiconductor laser array integrated with grating reflector based on reconstruction-equivalent-chirp technique. AB - A 4-channel distributed feedback (DFB) semiconductor laser array with incorporation of a grating reflector utilizing reconstruction-equivalent-chirp technique is theoretically studied and experimentally demonstrated. By integrating with a grating reflector, 40% increase of slope efficiency, about 10mA decrease of threshold current and 7dB increase of side mode suppression ratio (SMSR) are achieved with a deviation of wavelength spacing being less than 0.07nm. The SMSRs of all the lasers are higher than 60dB. PMID- 25836151 TI - Sharp Fano resonance induced by a single layer of nanorods with perturbed periodicity. AB - In this paper, we report the formation of extremely sharp (Quality factor Q~ + infinity) FR in a single layer of dielectric nanorods with perturbed periodicity. The interference between the broadband Fabry-Perot (F-P) resonance and defect induced dark mode results in refractive index sensitivity (S) of 1312.75 nm/RIU and figure of merit (FOM) of 500, offering an excellent platform for biological sensing and detection. PMID- 25836152 TI - Free-space communications over exponentiated Weibull turbulence channels with nonzero boresight pointing errors. AB - In this paper, we present analytical expressions for the performance of urban free-space optical (FSO) communication systems under the combined influence of atmospheric turbulence- and misalignment-induced fading (pointing errors). The atmospheric turbulence channel is modeled by the exponentiated Weibull (EW) distribution that can accurately describe the probability density function (PDF) of the irradiance fluctuations associated with a transmitted Gaussian-beam wave and a finite-sized receiving aperture. The nonzero boresight pointing error PDF model, which is recently proposed for considering the effects of both boresight and jitter, is adopted in analysis. We derive a novel expression for the composite PDF in terms of a convergent double series involving a Meijer's G function. Based on the statistical results mentioned above, exact expressions for the average bit error rate of on-off keying modulation scheme and the outage probability are developed. To provide more insight, we also perform an asymptotic error rate analysis at high average signal-to-noise ratio. Our analytical results indicate that the diversity gain for the zero boresight case is determined only by the ratio between the equivalent beamwidth at the receiver and the jitter standard deviation, while for the nonzero boresight case, the diversity gain is related to the ratio of the equivalent beamwidth to the jitter variance as well as the parameter of the EW distribution. PMID- 25836153 TI - Near-infrared grating-assisted SPR optical fiber sensors: design rules for ultimate refractometric sensitivity. AB - Plasmonic optical fiber sensors are continuously developed for (bio)chemical sensing purposes. Recently, surface plasmon resonance (SPR) generation was achieved in gold-coated tilted fiber Bragg gratings (TFBGs). These sensors probe the surrounding medium with near-infrared narrowband resonances, which enhances both the penetration depth of the evanescent field in the external medium and the wavelength resolution of the interrogation. They constitute a unique configuration to probe all the fiber cladding modes individually. We use them to analyze the modal distribution of gold-coated telecommunication-grade optical fibers immersed in aqueous solutions. Theoretical investigations with a finite difference complex mode solver are confirmed by experimental data obtained on TFBGs. We show that the refractometric sensitivity varies with the mode order and that the global SPR envelope shift in response to surrounding refractive index (SRI) changes higher than 1e-2 RIU (refractive index unit) can be ~25% bigger than the local SPR mode shift arising from SRI changes limited to 1e-4 RIU. We bring clear evidence that the optimum gold thickness for SPR generation lies in the range between 50 and 70 nm while a cladding diameter decrease from 125 um to 80 um enhances the refractometric sensitivity by ~20%. Finally, we demonstrate that the ultimate refractometric sensitivity of cladding modes is ~550 nm/RIU when they are probed by gold-coated TFBGs. PMID- 25836154 TI - Multi-perturbation stochastic parallel gradient descent method for wavefront correction. AB - The multi-perturbation stochastic parallel gradient descent (SPGD) method for adaptive optics is presented in this work. The method is based on a new architecture. The incoming beam with distorted wavefront is split into N sub beams. Each sub-beam is modulated by a wavefront corrector and its performance metric is measured subsequently. Adaptive system based on the multi-perturbation SPGD can operate in two modes - the fast descent mode and the modal basis updating mode. Control methods of the two operation modes are given. Experiments were carried out to prove the effectiveness of the proposed method. Analysis as well as experimental results showed that the two operation modes of the multi perturbation SPGD enhance the conventional SPGD in different ways. The fast descent mode provides faster convergence than the conventional SPGD. The modal basis updating mode can optimize the modal basis set for SPGD with global coupling. PMID- 25836155 TI - Optical-coupling of distant spins via collective enhancement in multi-mode whispering gallery resonators. AB - The quantum coupling of spatially distant spins via optical photons using cavity quantum electrodynamic (cQED) methods has proved experimentally challenging due to the large spin-photon coupling strengths required. To achieve such coupling strengths using traditional cQED methods requires either individual spins and ultra-small cavities or an ensemble of identical spins coupled to larger cavities. In this work we describe a method to couple distant spins via the collective enhanced coupling to a large ensemble ~ N, of degenerate optical Whispering Gallery Modes (WGM) in a spherical resonator where the spins are spatially located at the antipodes. The setup can be scaled-up to build 1D, 2D and 3D cQED lattices to enable quantum simulation or computing. PMID- 25836156 TI - Nanosecond UV laser-induced fatigue effects in the bulk of synthetic fused silica: a multi-parameter study. AB - Multiple-pulse S-on-1 laser damage experiments were carried out in the bulk of synthetic fused silica at 355 nm and 266 nm. Two beam sizes were used for each wavelength and the pulse duration was 8 ns. The results showed a fatigue effect that is due to cumulative material modifications. The modifications have a long lifetime and the fatigue dynamics are independent of the used beam sizes but differ for the two wavelengths. Based on the fact that, in the context of material-modification induced damage, the damage thresholds for smaller beams are higher than for larger beams, we discuss possible mechanisms of damage initiation. PMID- 25836157 TI - Optomechanical nonlinearity enhanced optical sensors. AB - We propose and investigate an ultra-sensitive optical sensor system based on optomechanically induced nonlinear effects in high-Q optical resonators. In both dispersive and dissipative optomechanical systems, a positive feedback is formed between the optical resonance frequency and the mechanical displacement, which results in nonlinear transmission spectra different from a Lorentzian profile. Given the same resonator design, the optomechanical nonlinearity can increase the overall sensitivity by at least two orders of magnitude. Further improvement is possible by employing the phase sensitive detection. For the stable operation of the proposed sensor, we also analyze the requirement on the input power and the optomechanical coupling rate to overcome the thermal-optically induced frequency shift. PMID- 25836158 TI - Laser frequency stabilization using a dispersive line shape induced by Doppler Effect. AB - We report a simple and robust Doppler-free spectroscopic technique to stabilize a laser frequency to the atomic transition. By employing Doppler Effect on the atomic beam, we obtained a very stable dispersive signal with a high signal-to noise ratio and no Doppler-background, which served as an error signal to electronically stabilize a laser frequency without modulation. For validating the performance of this technique, we locked a DFB laser to the (133)Cs D2 line and observed an efficient suppression of the frequency noise and a long-term reduction of the frequency drifts in a laboratory environment. PMID- 25836159 TI - High power tandem-pumped thulium-doped fiber laser. AB - We propose a cascaded tandem pumping technique and show its high power and high efficient operation in the 2-MUm wavelength region, opening up a new way to scale the output power of the 2-MUm fiber laser to new levels (e.g. 10 kW). Using a 1942 nm Tm(3+) fiber laser as the pump source with the co- (counter-) propagating configuration, the 2020 nm Tm(3+) fiber laser generates 34.68 W (35.15W) of output power with 84.4% (86.3%) optical-to-optical efficiency and 91.7% (92.4%) slope efficiency, with respect to launched pump power. It provides the highest slope efficiency reported for 2-MUm Tm(3+)-doped fiber lasers, and the highest output power for all-fiber tandem-pumped 2-MUm fiber oscillators. This system fulfills the complete structure of the proposed cascaded tandem pumping technique in the 2-MUm wavelength region (~1900 nm -> ~1940 nm -> ~2020 nm). Numerical analysis is also carried out to show the power scaling capability and efficiency of the cascaded tandem pumping technique. PMID- 25836160 TI - Relationship between two- and three-photon coherence in a ladder-type atomic system. AB - We investigated the relationship between two- and three-photon coherence in terms of the transition routes and coupling field intensities in a Doppler-broadened ladder-type atomic system for the 5S(1/2)-5P(3/2)-5D(5/2) transition in (87)Rb atoms. Three-photon electromagnetically induced absorption (TPEIA) due to three photon coherence was observed in the only transition route that exhibited a dominant two-photon coherence effect. We showed that two-photon coherence is a necessary condition for three-photon coherence phenomena. A comparison of the relative magnitudes of the electromagnetically induced transparency and TPEIA as a function of the coupling field intensity revealed that the increase of three photon coherence was faster than that of two-photon coherence. Considering three photon coherence in a Doppler-broadened ladder-type three-level atomic system, the relation between two- and three-photon coherence was numerically calculated. PMID- 25836161 TI - Micro-bending vector sensor based on six-air-hole grapefruit microstructure fiber using lateral offset splicing. AB - A one-dimensional micro-bending vector sensor based on two-mode interference has been introduced. This device was fabricated by lateral offset splicing a piece of six-air-hole grapefruit microstructure fiber (GMF) with single mode fiber (SMF). Variation of effective mode index occurred by micro-bending was investigated in simulation and experiment. This device exhibits micro-bending sensitivities of 0.441 nm/m(-1) and -0.754 nm/m(-1) at 0 degrees and 180 degrees bending orientations, respectively. Moreover, this sensor is immune to surrounding refractive index (SRI) and presents a low crosstalk of temperature. PMID- 25836162 TI - Determination of cavity length of cavity-resonator-integrated guided-mode resonance filter. AB - A cavity-resonator-integrated guided-mode resonance filter is a kind of narrowband filters, which uses a resonance effect of a waveguide cavity. Two experimental methods for determining the cavity length were investigated in order to estimate the response time of the filter. SiO(2)-based filters for operation at 1540-nm wavelength were fabricated and their cavity lengths were determined from measured resonance wavelengths. In the both of methods, the cavity length determined to be 65 MUm and the response time was estimated to be 4 psec. PMID- 25836163 TI - Stand-off Raman spectrometer for identification of liquids in a pressurized gas pipelines. AB - a stand-off Raman spectrometer has been developed to make observations of liquid samples within a gas pipeline. The instrument is based on a static Fourier Transform spectrometer. The high etendue offered by the instrument enabled four liquid samples to be measured from a distance of 2.4 m within a gas pipeline. Liquids were identified with depths less than 5 mm demonstrating that the concept is viable for active pipeline measurement. PMID- 25836164 TI - Robust copyright protection using multiple ownership watermarks. AB - Generally, conventional transform (DWT and DFT, etc.) -based watermarking techniques provide only one spectrum plane for embedding the watermark, thus the embedding watermark information can be easily removed. To solve this problem, we propose an efficient cellular automata (CA) based watermarking method that CA transform (CAT) with various gateway values can provide many transform planes for watermark embedding according to various CA rules. In this paper, multiple ownership watermarks are first recorded in the form of an elemental image array (EIA), simultaneously, and then the recorded EIA as the watermark data is embedded into the CAT coefficient. An additional advantage of this proposed method is that EIA is composed of many elemental images and each elemental image has its own property of watermarks. Even though most data of elemental images are lost, the watermarks can be reconstructed from the remaining elemental images successfully. Experimental results show that the proposed technique provides good image quality and is robust in varying degree to some image processing attacks. PMID- 25836165 TI - Demonstration of full 4*4 Mueller polarimetry through an optical fiber for endoscopic applications. AB - A novel technique to measure the full 4 * 4 Mueller matrix of a sample through an optical fiber is proposed, opening the way for endoscopic applications of Mueller polarimetry for biomedical diagnosis. The technique is based on two subsequent Mueller matrices measurements: one for characterizing the fiber only, and another for the assembly of fiber and sample. From this differential measurement, we proved theoretically that the polarimetric properties of the sample can be deduced. The proof of principle was experimentally validated by measuring various polarimetric parameters of known optical components. Images of manufactured and biological samples acquired by using this approach are also presented. PMID- 25836166 TI - Estimating phycocyanin pigment concentration in productive inland waters using Landsat measurements: a case study in Lake Dianchi. AB - Using remote sensing reflectance (R(rs)(lambda), sr(-1)) and phycocyanin (PC, mg m(-3)) pigment data as well as other bio-optical data collected from two cruises in September and December 2009 in Lake Dianchi (a typical plateau lake of China), we developed a practical approach to estimate PC concentrations that could be applied directly to Landsat measurements. The visible and near-IR bands as well as their band ratios of simulated Landsat data were used as inputs to the algorithms, where the algorithm coefficients for each Landsat sensor were determined through multivariate regressions. The coefficients of determination (R(2)) between the R(rs)-modeled and measured PC were all > 0.97 for the spectral bands corresponding to Landsat 8 OLI, Landsat 7 ETM + , Landsat 5 TM, and Landsat 4 TM, with mean absolute percentage errors (MAPE) < 10% for PC ranging between ~80 and 700 mg m(-3) (n = 14). The algorithms were further evaluated using an independent data set (n = 14), yielding larger but still acceptable MAPE (~30%) for PC ranging between ~80 and 500 mg m(-3). Application of the approach to Landsat 8 measurements over Lake Dianchi suggests potential use of the approach for periodical assessment of the lake's bloom conditions, yet its empirical nature together with the lack of specific narrow bands on Landsat sensors to explicitly account for the PC absorption around 625 nm calls for extra caution when applied to other eutrophic lakes. PMID- 25836167 TI - Potentials and challenges of using orbital angular momentum communications in optical interconnects. AB - Ultra-short- and short-reach optical interconnects are the new high growth applications for optical communications. High capacity density, high spectral efficiency, low cost, low power consumption, and fast configurability are some of the key requirements for potential optical transmission technology candidates. Based on recent progress in orbital angular momentum multiplexed optical transmission and optical device technologies, this paper discusses the potentials and challenges of using orbital angular momentum multiplexing in optical interconnect applications scenarios to meet above requirements. PMID- 25836168 TI - Bright and dark plasmon resonances of nanoplasmonic antennas evanescently coupled with a silicon nitride waveguide. AB - In this work we investigate numerically and experimentally the resonance wavelength tuning of different nanoplasmonic antennas excited through the evanescent field of a single mode silicon nitride waveguide and study their interaction with this excitation field. Experimental interaction efficiencies up to 19% are reported and it is shown that the waveguide geometry can be tuned in order to optimize this interaction. Apart from the excitation of bright plasmon modes, an efficient coupling between the evanescent field and a dark plasmonic resonance is experimentally demonstrated and theoretically explained as a result of the propagation induced phase delay. PMID- 25836169 TI - Programmable multiport optical circuits in opaque scattering materials. AB - We propose and experimentally verify a method to program the effective transmission matrix of general multiport linear optical circuits in random multiple-scattering materials by phase modulation of incident wavefronts. We demonstrate the power of our method by programming linear optical circuits in white paint layers with 2 inputs and 2 outputs, and 2 inputs and 3 outputs. Using interferometric techniques we verify our ability to program any desired phase relation between the outputs. The method works in a deterministic manner and can be directly applied to existing wavefront-shaping setups without the need of measuring a transmission matrix or to rely on sensitive interference measurements. PMID- 25836170 TI - Broadband terahertz amplification in a heterogeneous quantum cascade laser. AB - We demonstrate a broadband terahertz amplifier based on ultrafast gain switching in a quantum cascade laser. A heterogeneous active region is processed into a coupled cavity metal-metal waveguide device and provides broadband terahertz gain that allows achieving an amplification bandwidth of more than 500 GHz. The temporal and spectral evolution of a terahertz seed pulse, which is generated in an integrated emitter section, is presented and an amplification factor of 21 dB is reached. Furthermore, the quantum cascade amplifier emission spectrum of the emerging sub-nanosecond terahertz pulse train is measured by time-domain spectroscopy and reveals discrete modes between 2.14 and 2.68 THz. PMID- 25836171 TI - Design and experimental demonstration of a large pedestal thulium-doped fibre. AB - We present a novel large-mode-area thulium-doped fibre with a large pedestal design. We discuss the advantages of this large pedestal fibre in the context of overcoming limitations imposed by cleaving and splicing tolerances. Finally we demonstrate the use of such a fibre in constructing monolithic fibre lasers operating at 1.95 um with 170 W of output power, 0.1 nm line-width and a diffraction limited beam quality of M(2)(X,Y) = 1.02, 1.03. PMID- 25836172 TI - 87 W, narrow-linewidth, linearly-polarized 1178 nm photonic bandgap fiber amplifier. AB - High-power narrow-linewidth photonic bandgap fiber amplifier was demonstrated. In order to suppress stimulated Brillouin scattering, the seed linewidth was broadened by applying a random phase noise with an electro-optical modulator. A factor of 15 in terms of Brillouin gain suppression can be theoretically expected. An 87 W linearly-polarized (11 dB PER) and narrow-linewidth (780 MHz FWHM) output was obtained. PMID- 25836173 TI - Inverse scattering designs of dispersion-engineered planar waveguides. AB - We have introduced a semi-analytical IS technique suitable for multipole, rational function reflection coefficients, and used it for the design of dispersion-engineered planar waveguides. The technique is used to derive extensive dispersion maps, including higher dispersion coefficients, corresponding to three-, five- and seven-pole reflection coefficients. It is shown that common features of dispersion-engineered waveguides such as refractive index trenches, rings and oscillations come naturally from this approach when the magnitude of leaky poles in increased. Increasing the number of poles is shown to offer a small but measureable change in higher order dispersion with designs dominated by a three pole design with a leaky pole pair of the smallest modulus. PMID- 25836174 TI - Long-haul quasi-single-mode transmissions using few-mode fiber in presence of multi-path interference. AB - We study long-haul Quasi-Single-mode (QSM) systems in which signals are transmitted in the fundamental modes of a few-mode fiber (FMF) while keeping other system components such as amplifiers and receivers are kept single-moded. The large-effective-area nature of the FMF fundamental modes improves system nonlinear tolerance in the expense of mode coupling along FMF transmissions which induces multi-path interference (MPI) and needs to be compensated. We analytically investigate 6-spatial-polarization mode QSM transmission systems in presence of MPI and show that in the weak coupling regime, the QSM channel is a Gaussian random process in frequency. MPI compensation filters are derived and performance penalties due to MPI and signal loss from higher-order modes are characterized. We also experimentally demonstrate 256 Gb/s polarization multiplexed (PM)-16-QAM QSM transmissions over a record distance of 2600 km with 100-km span using decision directed least mean square (DD-LMS) algorithm for MPI compensation. PMID- 25836175 TI - Incoherent on-off keying with classical and non-classical light. AB - We analyze the performance of on-off keying (OOK) and its restricted version pulse position modulation (PPM) over a lossy narrowband optical channel under the constraint of a low average photon number, when direct detection is used at the output. An analytical approximation for the maximum PPM transmission rate is derived, quantifying the effects of photon statistics on the communication efficiency in terms of the g((2)) second-order intensity correlation function of the light source. Enhancement attainable through the use of sub-Poissonian light is discussed. PMID- 25836176 TI - Nanoparticle containing channel waveguides produced by a multi-energy masked ion implantation process. AB - We present the fabrication and characterization of channel waveguides based on composites containing silver nanoparticles. The substrate employed is silica and the nanoparticles were produced by a masked ion-implantation technique. Multiple implantation processes were made at different energies in order to produce waveguides with an appropriate width. We also present results for the characterization of the waveguiding properties of the devices produced. PMID- 25836177 TI - Large bandwidth mode order converter by differential waveguides. AB - In this article, we propose a large bandwidth mode-order converter design by dielectric waveguides with equal lengths but different cross-sectional areas. The efficient conversion between even and odd modes is verified by inducing required phase difference between the equal length waveguides of different widths. Y junctions are composed of both tapered mode splitter and combiner to connect mono mode waveguide to multi-mode waveguide. The converted mode profiles at the output port show that the device operates successfully at designed wavelengths with wide bandwidth. This study provides a novel technique to implement compact mode order converters and direction selective/sensitive photonic structures. PMID- 25836179 TI - General considerations for the miniaturization of radiative antennae. AB - The small size of plasmonic nanostructures compared to the wavelength of light is one of their most distinct and defining characteristics. It results in the strong compression of an incident wave to intense hot spots which have been used most remarkably for molecular sensing and nanoscale lasers. But another important direction for research is to use this ability to design miniaturized interconnects and modulators between fast, loss-less photonic components. Here we show that despite their high absorption, conductors are still the best materials to reach the sub-wavelength regime for efficient antennae when compared to polar crystals and high-index dielectrics, two classes of material which have shown a lot of potential recently in nanophotonic applications. By identifying the relevant dimensionless properties for the three materials considered, we present an unified understanding of the behaviour of sub-wavelength components which are at the heart of current photonic research and cast the upper achievable limits for radiative antennae crucial to the development of real-life implementation. PMID- 25836178 TI - Strong opto-electro-mechanical coupling in a silicon photonic crystal cavity. AB - We fabricate and characterize a microscale silicon opto-electromechanical system whose mechanical motion is coupled capacitively to an electrical circuit and optically via radiation pressure to a photonic crystal cavity. To achieve large electromechanical interaction strength, we implement an inverse shadow mask fabrication scheme which obtains capacitor gaps as small as 30 nm while maintaining a silicon surface quality necessary for minimizing optical loss. Using the sensitive optical read-out of the photonic crystal cavity, we characterize the linear and nonlinear capacitive coupling to the fundamental omega(m)/2pi = 63 MHz in-plane flexural motion of the structure, showing that the large electromechanical coupling in such devices may be suitable for realizing efficient microwave-to-optical signal conversion. PMID- 25836180 TI - Narrow-linewidth short-pulse III-V-on-silicon mode-locked lasers based on a linear and ring cavity geometry. AB - Picosecond-pulse III-V-on-silicon mode-locked lasers based on linear and ring extended cavity geometries are presented. In passive mode-locked operation a 12 kHz -3dB linewidth of the fundamental RF tone at 4.7 GHz is obtained for the linear cavity geometry and 16 kHz for the ring cavity geometry. Stabilization of the repetition rate of these devices using hybrid mode-locking is also demonstrated. PMID- 25836181 TI - Anisotropic exciton relaxation in nanostructured metal (Zn and F(16)Zn) phthalocyanine. AB - We report ultrafast excited state dynamics of zinc phthalocyanine and zinc hexadecafluoro phthalocyanine thin films which have nanorod-like structures. Excitons in the singlet states undergo multi-exponential relaxation processes to the ground state and the singlet lifetime within a few tens of picoseconds is attributed to the diffusion-limited exciton annihilation process. Diffusive migration of the singlet excitons shows the anisotropic lifetimes depending on the polarization of probe beam. Similar anisotropy is observed in the X-ray diffraction data which exhibits long-range alignment of molecular columns along the long axis of nanorod, whereas disordered arrangement in lateral direction to the axis of nanorod. PMID- 25836182 TI - Electrical control of second harmonic generation in a graphene-based plasmonic Fano structure. AB - We propose a strategy for active control of second harmonic generation (SHG) in a plasmonic Fano structure by electrically doping its underlying monolayer graphene. A detailed theoretical model for the proposed scheme is developed and numerical simulations are carried out to demonstrate the operation. Specifically, we show that a merely 30 meV change in graphene Fermi level can result in 45 times increase in SHG peak intensity, accompanied by a resonance wavelength shift spanning 220 nm. Further analysis uncovers that such tunability in SHG arises from the Fermi-level-modulated graphene permittivity, the real and imaginary parts of which dominate the resonance wavelength and the intensity of SHG, respectively. PMID- 25836183 TI - Advanced modulation formats for high-performance short-reach optical interconnects. AB - The explosive growth of the traffic between data centers has led to an urgent demand for high-performance short-reach optical interconnects with data rate beyond 100G per wavelength and transmission distance over hundreds of kilometers. Since direct detection (DD) provides a cost-efficient solution for short-reach interconnects, various advanced modulation formats have been intensively studied to improve the performance of DD for high-performance short-reach optical interconnects. In this paper, we report the recent progress on the advanced DD modulation formats that provide superior electrical spectral efficiency (SE) and transmission reach beyond that of simple direct modulation (DM) based direct detection (DM/DD). We first provide a review of the current advanced modulation formats for high-performance short-reach optical interconnects. Among these formats, Stokes vector direct detection (SV-DD) achieves the highest electrical spectrum efficiency, presenting itself as a promising candidate for future short reach networks. We then expound some novel algorithms to achieve high-performance SV-DD systems under severe impairments of either polarization mode dispersion (PMD) or polarization dependent loss (PDL). PMID- 25836184 TI - Safe range of free space light propagation calculation in single precision. AB - Calculations of free space light propagation, such as those used in digital holography, deal with distances much longer than a wavelength. Computer representation of real numbers must therefore provide enough precision to handle this situation. We show that single precision must be used with the utmost care, which is especially important in GPU calculations. We also show that Fresnel approximation significantly improves single precision calculations for distances bigger than about one metre. PMID- 25836185 TI - Impact of rare earth element clusters on the excited state lifetime evolution under irradiation in oxide glasses. AB - Rare earth doped active glasses and fibers can be exposed to ionizing radiations in space and nuclear applications. In this work, we analyze the evolution of (2)F(5/2) excited state lifetime in Yb(3+) ions in irradiated aluminosilicate glasses by electrons and gamma rays. It is found that the variation of lifetimes depends on the Yb(3+) clusters content of the glasses for irradiation doses in the 10(2)- 1.5?10(9) Gy range. In particular, glasses with high clustering show a smaller decrease in lifetime with increasing radiation dose. This behavior is well correlated to the variation in paramagnetic defects concentration determined by electron paramagnetic resonance. This effect is also observed in Yb(3+) doped phosphate and Er(3+) doped aluminosilicate glasses, inferring that clustering plays an important role in irradiation induced quenching. PMID- 25836186 TI - Multi-milliwatt mid-infrared supercontinuum generation in a suspended core chalcogenide fiber. AB - A low-loss suspended core As(38)Se(62) fiber with core diameter of 4.5 MUm and a zero-dispersion wavelength of 3.5 MUm was used for mid-infrared supercontinuum generation. The dispersion of the fiber was measured from 2.9 to 4.2 MUm and was in good correspondence with the calculated dispersion. An optical parametric amplifier delivering 320 fs pulses with a peak power of 14.8 kW at a repetition rate of 21 MHz was used to pump 18 cm of suspended core fiber at different wavelengths from 3.3 to 4.7 MUm. By pumping at 4.4 MUm with a peak power of 5.2 kW coupled to the fiber a supercontinuum spanning from 1.7 to 7.5 MUm with an average output power of 15.6 mW and an average power >5.0 MUm of 4.7 mW was obtained. PMID- 25836187 TI - On-chip grating coupler array on the SOI platform for fan-in/fan-out of MCFs with low insertion loss and crosstalk. AB - We report the design and fabrication of a compact multi-core fiber fan-in/fan-out using a grating coupler array on the SOI platform. The grating couplers are fully etched, enabling the whole circuit to be fabricated in a single lithography and etching step. Thanks to the apodized design for the grating couplers and the introduction of an aluminum reflective mirror, a highest coupling efficiency of 3.8 dB with 3 dB coupling bandwidth of 48 nm and 1.5 dB bandwidth covering the whole C band, together with crosstalk lower than -32 dB are demonstrated. PMID- 25836188 TI - Polarization evolution of ultrashort pulses in air. AB - Measurements of polarization of filamenting light pulses at 800 nm are presented. Electronic nonlinearity, molecular alignment and nonlinear losses all contribute to modify the polarization of a femtosecond filamenting pulse. The polarization is modified in each stage of preparation, filamentation and divergence after the filament. PMID- 25836189 TI - Radiative recombination rate measurement by the optically pumped variable stripe length method. AB - Using the optically pumped variable stripe length technique we demonstrate that, through calibration of measured spontaneous emission spectra, it is possible to determine the total radiative recombination rate for a gain material as a function of the intrinsic quasi-Fermi level separation. Specifically we compare the room temperature optical characteristics of a self-assembled InP/GaInP quantum dot material measured using both optical and electrical pumping. The comparison reveals good agreement between gain and emission spectra measured with the two techniques, for the same inversion, from which we conclude that the carrier distributions in each case are equivalent. The results demonstrate that the optically pumped experiment can provide a good measure of the overall radiative efficiency. PMID- 25836190 TI - Platinum germanides for mid- and long-wave infrared plasmonics. AB - Platinum germanides (PtGe) were investigated for infrared plasmonic applications. Layers of Pt and Ge were deposited and annealed. X-ray diffraction identified PtGe(2) and Pt(2)Ge(3) phases, and x-ray photo-electron spectroscopy determined vertical atomic composition profiles for the films. Complex permittivity spectra were measured by ellipsometry over the 2 to 15 MUm wavelength range. Surface plasmon polariton (SPP) characteristics such as propagation length and field penetration depth were calculated. Photon-to-SPP couplers in the form of 1D lamellar gratings were fabricated and characterized in the range 9 - 10.5 MUm via wavelength-dependent specular reflection spectra for multiple angles of incidence. The observed resonances compare well with calculated spectra for SPP excitation on PtGe(2). Platinum germanides are CMOS compatible and may serve as SPP hosts for on-chip mid-IR plasmonic components with tighter field confinement than noble-metal hosts. PMID- 25836191 TI - Self-calibrating common-path interferometry. AB - A quantitative phase measuring technique is presented that estimates the object phase from a series of phase shifted interferograms that are obtained in a common path configuration with unknown phase shifts. The derived random phase shifting algorithm for common-path interferometers is based on the Generalized Phase Contrast theory [pl. Opt.40(2), 268 (2001)10.1063/1.1404846], which accounts for the particular image formation and includes effects that are not present in two beam interferometry. It is shown experimentally that this technique can be used within common-path configurations employing nonlinear liquid crystal materials as self-induced phase filters for quantitative phase imaging without the need of phase shift calibrations. The advantages of such liquid crystal elements compared to spatial light modulator based solutions are given by the cost-effectiveness, self-alignment, and the generation of diminutive dimensions of the phase filter size, giving unique performance advantages. PMID- 25836192 TI - Numerical far field simulations with the fast Fourier transformation and Fourier space interpolation. AB - As more complicated microscope systems are engineered, the amount of effects taken into account rises steadily. In this context we experienced the need for a simulation approach, that will deliver the intensity distribution in space and time for scanning laser microscopes. To achieve this goal, the frequency space representation of microscope objectives was used and adapted to determine their solution of the electromagnetic wave equation. We describe the steps necessary to efficiently implement an approach to simulate multidimensional solutions of the wave equation. This includes the connection between the back focal plane and the Fourier space representation as well as a proper interpolation method for the latter. The error-potential of our least erroneous interpolation, the power of hann (POH) interpolation, is compared to other common interpolation methods. Finally we demonstrate the current potential of the approach by simulating an "expanding" optical vortex focus. PMID- 25836194 TI - Young's double-slit experiment: noise-resolution duality. AB - Statistical aspects of Young's double-slit diffraction experiment are analysed quantitatively. It is shown that the signal-to-noise ratio and the spatial resolution in the detected diffraction pattern satisfy a duality relationship which implies that both of them cannot be improved simultaneously beyond a certain limit if the total number of particles forming the image is fixed. As a consequence of this duality, it is possible to estimate the minimal number of particles that have to be detected in order for two slits separated by a given distance to be resolved with a confidence level corresponding to a pre-defined signal-to-noise ratio, e.g. according to the Rose criterion. These results are related to the recently introduced imaging system quality characteristic which combines the spatial resolution and the noise sensitivity, and allows one to estimate the efficiency with which imaging quanta are utilised in a system to deliver maximal amount of information about the imaged object. The presented results can be useful for applications where the imaging quanta are at a premium or where minimization of the radiation dose is important. PMID- 25836195 TI - High power, widely tunable, narrowband superfluorescent source at 2 MUm based on a monolithic Tm-doped fiber amplifier. AB - We present a widely tunable narrowband superfluorescent source near 2 MUm employing a monolithic Tm-doped fiber amplifier (TDFA), and the output power exceeds 250 W. A broadband superfluorescent source with a narrowband tunable band pass filter was used as the seed source. The spectra of the seed source can be tuned in a range of ~1930-2030 nm with full width at half maximum (FWHM) of ~1.7 nm. The Tm-doped fiber amplifier scales up the power of the seed source to a level of more than 250 W with a tuning range of ~35 nm (1966-2001 nm) and a FWHM of ~1.5-2.0 nm, and the slope efficiency is about 0.50. The output power is limited by the available pump power, and the tuning range is limited by the amplifier spontaneous emission at other wavelengths. Higher output power can be achieved if launching more pump power into the amplifier, and the tuning range can be further improved by optimizing the parameters of the TDFA. To the best of our knowledge, this is the first demonstration on a widely tunable narrowband superfluorescent source at 2 MUm with average output power exceeding 250 W. PMID- 25836193 TI - Pulse-shaping based two-photon FRET stoichiometry. AB - Forster Resonance Energy Transfer (FRET) based measurements that calculate the stoichiometry of intermolecular interactions in living cells have recently been demonstrated, where the technique utilizes selective one-photon excitation of donor and acceptor fluorophores to isolate the pure FRET signal. Here, we present work towards extending this FRET stoichiometry method to employ two-photon excitation using a pulse-shaping methodology. In pulse-shaping, frequency dependent phases are applied to a broadband femtosecond laser pulse to tailor the two-photon excitation conditions to preferentially excite donor and acceptor fluorophores. We have also generalized the existing stoichiometry theory to account for additional cross-talk terms that are non-vanishing under two-photon excitation conditions. Using the generalized theory we demonstrate two-photon FRET stoichiometry in live COS-7 cells expressing fluorescent proteins mAmetrine as the donor and tdTomato as the acceptor. PMID- 25836196 TI - Polarization sensitive optical frequency domain imaging system for endobronchial imaging. AB - A polarization sensitive endoscopic optical frequency domain imaging (PS-OFDI) system with a motorized distal scanning catheter is demonstrated. It employs a passive polarization delay unit to multiplex two orthogonal probing polarization states in depth, and a polarization diverse detection unit to detect interference signal in two orthogonal polarization channels. Per depth location four electro magnetic field components are measured that can be represented in a complex 2x2 field matrix. A Jones matrix of the sample is derived and the sample birefringence is extracted by eigenvalue decomposition. The condition of balanced detection and the polarization mode dispersion are quantified. A complex field averaging method based on the alignment of randomly pointing field phasors is developed to reduce speckle noise. The variation of the polarization states incident on the tissue due to the circular scanning and catheter sheath birefringence is investigated. With this system we demonstrated imaging of ex vivo chicken muscle, in vivo pig lung and ex vivo human lung specimens. PMID- 25836197 TI - Converting optical scanning holograms of real objects to binary Fourier holograms using an iterative direct binary search algorithm. AB - In this paper, we present a three-dimensional holographic imaging system. The proposed approach records a complex hologram of a real object using optical scanning holography, converts the complex form to binary data, and then reconstructs the recorded hologram using a spatial light modulator (SLM). The conversion from the recorded hologram to a binary hologram is achieved using a direct binary search algorithm. We present experimental results that verify the efficacy of our approach. To the best of our knowledge, this is the first time that a hologram of a real object has been reconstructed using a binary SLM. PMID- 25836198 TI - Precise calibration of linear camera equipped with cylindrical lenses using a radial basis function-based mapping technique. AB - The linear camera equipped with cylindrical lenses has prominent advantages in high-precision coordinate measurement and dynamic position-tracking. However, the serious distortion of the cylindrical lenses limits the application of this camera. To overcome this obstacle, a precise two-step calibration method is developed. In the first step, a radial basis function-based (RBF-based) mapping technique is employed to recover the projection mapping of the imaging system by interpolating the correspondence between incident rays and image points. For an object point in 3D space, the plane passing through the object point in camera coordinate frame can be calculated accurately by this technique. The second step is the calibration of extrinsic parameters, which realizes the coordinate transformation from the camera coordinate frame to world coordinate frame. The proposed method has three aspects of advantage. Firstly, this method (black box calibration) is still effective even if the distortion is high and asymmetric. Secondly, the coupling between extrinsic parameters and other parameters, which is normally occurred and may lead to the failure of calibration, is avoided because this method simplifies the pinhole model and only extrinsic parameters are concerned in the simplified model. Thirdly, the nonlinear optimization, which is widely used to refine camera parameters, is better conditioned since fewer parameters are needed and more accurate initial iteration value is estimated. Both simulative and real experiments have been carried out and good results have been obtained. PMID- 25836199 TI - High speed, high strength microwelding of Si/glass using ps-laser pulses. AB - A novel microwelding procedure to join Si-to-glass using ps-laser pulses with high repetition rates is presented. The procedure provides weld joint with mechanical strength as high as 85 MPa and 45 MPa in sample pairs of Si/aluminosilicate (Si/SW-Y) and Si/borosilicate (Si/Borofloat 33), respectively, which are higher than anodic bonding, at high spatial resolution (< 20 um) and very high throughput without pre- and post-heating. Laser-matter interaction analysis indicates that excellent weld joint of Si/glass is obtained by avoiding violent evaporation of Si substrate using ps-laser pulses. Laser welded Si/glass samples can be singulated along the weld lines by standard blade dicer without defects, demonstrating welding by ps-laser pulses is applicable to wafer-level packaging. PMID- 25836200 TI - Polarization or phase insensitive fiber parametric amplifier with clamped output phase. AB - This paper proposes a low polarization- or phase-dependent fiber parametric amplifier system with a clamped output phase, which consists of an orthogonally pumped nonlinear fiber and a fiber loop with a polarization beam splitter. Numerical calculations show that the proposed system exhibits a constant output phase, low insensitive to the signal input phase or polarization state. PMID- 25836201 TI - Simultaneous and localized measurement of diffusion and flow using optical coherence tomography. AB - We report on the simultaneous and localized measurement of the diffusion coefficient and flow velocity based on the normalized autocorrelation function using optical coherence tomography (OCT). Our results on a flowing suspension of polystyrene spheres show that the flow velocity and the diffusion coefficient can be reliably estimated in a regime determined by the sample diffusivity, the local flow velocity, and the Gaussian beam waist. We experimentally demonstrate that a smaller beam waist results in an improvement of the velocity sensitivity at the expense of the precision and accuracy of the estimation of the diffusion coefficient. Further, we show that the decay of the OCT autocorrelation function due to flow depends only on the Gaussian beam waist irrespective of the sample position with respect to the focus position. PMID- 25836202 TI - Cramer-Rao bounds for determination of electric and magnetic susceptibilities in metasurfaces. AB - Accurate and robust characterization of metasurfaces and metamaterials in terms of effective parameters is critical to the design of novel metadevices. We compute the Cramer-Rao lower bounds on the variance of any estimator for both the electric and magnetic surface susceptibilities of metasurfaces. We show that retrieval of such effective properties is inherently difficult around resonances, most notably for low-loss metasurfaces. We also put forth a least-squares estimator to mitigate this difficulty for the normal components of susceptibility tensors, which are observed to be the most ill-behaved. The present work is relevant to the development of loss-compensated metasurfaces for which noise has to be closely considered for accurate and robust device characterization. PMID- 25836204 TI - Spatiotemporal dynamics of multimode optical solitons. AB - As optical fiber communications and fiber lasers approach fundamental limits there is considerable interest in multimode fibers. In nonlinear science, they represent an exciting environment for complex nonlinear waves. As in single-mode fiber, solitons may be particularly important. Multimode solitons consist of synchronized, non-dispersive pulses in multiple spatial modes, which interact via the Kerr nonlinearity of the fiber. They are expected to exhibit novel spatiotemporal characteristics, dynamics and, like single-mode solitons, may provide a convenient intuitive tool for understanding more complex nonlinear phenomena in multimode fibers. Here we explore experimentally and numerically basic properties and spatiotemporal behaviors of these solitons: their formation, fission, and Raman dynamics. PMID- 25836203 TI - High numerical aperture Fourier ptychography: principle, implementation and characterization. AB - Fourier ptychography (FP) utilizes illumination control and computational post processing to increase the resolution of bright-field microscopes. In effect, FP extends the fixed numerical aperture (NA) of an objective lens to form a larger synthetic system NA. Here, we build an FP microscope (FPM) using a 40X 0.75NA objective lens to synthesize a system NA of 1.45. This system achieved a two-slit resolution of 335 nm at a wavelength of 632 nm. This resolution closely adheres to theoretical prediction and is comparable to the measured resolution (315 nm) associated with a standard, commercially available 1.25 NA oil immersion microscope. Our work indicates that Fourier ptychography is an attractive method to improve the resolution-versus-NA performance, increase the working distance, and enlarge the field-of-view of high-resolution bright-field microscopes by employing lower NA objectives. PMID- 25836205 TI - Experimental solution for scattered imaging of the interference of plasmonic and photonic mode waves launched by metal nano-slits. AB - Using an L-shaped metal nanoslit to generate waves of the pure photonic and plasmonic modes simultaneously, we perform an experimental solution for the scattered imaging of the interference of the two waves. From the fringe data of interference, the amplitudes and the wavevector components of the two waves are obtained. The initial phases of the two waves are obtained from the phase map reconstructed with the interference of the scattered image and the reference wave in the interferometer. The difference in the wavevector components gives rise to an additional phase delay. We introduce the scattering theory under Kirchhoff's approximation to metal slit regime and explain the wavevector difference reasonably. The solution of the quantities is a comprehensive reflection of excitation, scattering and interference of the two waves. By decomposing the polarized incident field with respect to the slit element, the scattered image produced by slit of arbitrary shape can be solved with the nanoscale Huygens Fresnel principle. This is demonstrated by the experimental intensity pattern and phase map produced by a ring-slit and its consistency with the calculated results. PMID- 25836206 TI - Multiband and broadband polarization-insensitive perfect absorber devices based on a tunable and thin double split-ring metamaterial. AB - We demonstrate a polarization-insensitive perfect absorber with multiband and broadband absorption based on a tunable and thin metamaterial, which consists of a double split-ring microstructure (DSRM) on double-layer and a coating substrate. The multiband absorption at different frequencies and broadband absorption with the relative bandwidth of 90.63% from 5.69GHz to 15.12GHz, of which the absorptivity is larger than 90%, can be achieved by changing the rotary angle of the proposed DSRM perfect metamaterial absorber (DSRM-PMA). The advantages of polarized-insensitivity, wide bandwidth and multiband absorption are illuminated by the angular absorptions and the surface current distributions. The DSRM-PMA device with similar geometry in simulation is fabricated and tested to clearly validate the functionality of our design. The simulated and experimental results indicate that the DSRM-PMA performs multiband and broadband absorptions with the rotary angle of 0 degrees and 90 degrees respectively. PMID- 25836208 TI - Efficient hyperconcentration of nonlocal multipartite entanglement via the cross Kerr nonlinearity. AB - We propose two schemes for concentration of hyperentanglement of nonlocal multipartite states which are simultaneously entangled in the polarization and spatial modes. One scheme uses an auxiliary single-photon state prepared according to the parameters of the less-entangled states. The other scheme uses two less-entangled states with unknown parameters to distill the maximal hyperentanglement. The procrustean concentration is realized by two parity check measurements in both the two degrees of freedom. Nondestructive quantum nondemolition detectors based on cross-Kerr nonlinearity are used to implement the parity check, which makes the unsuccessful instances reusable in the next concentration round. The success probabilities in both schemes can be made to approach unity by iteration. Moreover, in both schemes only one of the N parties has to perform the parity check measurements. Our schemes are efficient and useful for quantum information processing involving hyperentanglement. PMID- 25836207 TI - Portable waveguide display system with a large field of view by integrating freeform elements and volume holograms. AB - A compact waveguide display system integrating freeform elements and volume holograms is presented here for the first time. The use of freeform elements can broaden the field of view, which limits the applications of a holographic waveguide. An optimized system can achieve a diagonal field of view of 45 degrees when the thickness of the waveguide planar is 3mm. Freeform-elements in-coupler and the volume holograms out-coupler were designed in detail in our study, and the influence of grating configurations on diffraction efficiency was analyzed thoroughly. The off-axis aberrations were well compensated by the in-coupler and the diffraction efficiency of the optimized waveguide display system could reach 87.57%. With integrated design, stability and reliability of this monochromatic display system were achieved and the alignment of the system was easily controlled by the record of the volume holograms, which makes mass production possible. PMID- 25836209 TI - Fully programmable and scalable optical switching fabric for petabyte data center. AB - We present a converged EPS and OCS switching fabric for data center networks (DCNs) based on a distributed optical switching architecture leveraging both WDM & SDM technologies. The architecture is topology adaptive, well suited to dynamic and diverse *-cast traffic patterns. Compared to a typical folded-Clos network, the new architecture is more readily scalable to future multi-Petabyte data centers with 1000 + racks while providing a higher link bandwidth, reducing transceiver count by 50%, and improving cabling efficiency by more than 90%. PMID- 25836210 TI - Coupled cavity terahertz quantum cascade lasers with integrated emission monitoring. AB - We demonstrate the on-chip generation and detection of terahertz radiation in coupled cavity systems using a single semiconductor heterostructure. Multiple sections of a terahertz quantum cascade laser structure in a double-metal waveguide are optically coupled and operate either as a laser or an integrated emission monitor. A detailed analysis of the photon-assisted carrier transport in the active region below threshold reveals the detection mechanism for photons emitted by the very same structure above threshold. Configurations with a single laser cavity and two coupled laser cavities are studied. It is shown that the integrated detector can be used for spatial sensing of the light intensity within a coupled cavity. PMID- 25836211 TI - Simultaneous multi-parameter measurement using Sagnac loop hybrid interferometer based on a highly birefringent photonic crystal fiber with two asymmetric cores. AB - We have experimentally investigated the multi-parameter sensing characteristics in a novel all-fiber Sagnac loop hybrid interferometer based on a highly birefringent photonic crystal fiber with two asymmetric cores. The sensor device was based on a combination of two types of in-fiber interferences, the intra-core mode Sagnac interference and the inter-core-mode Mach-Zehnder interference due to the distinct birefringent properties associated with the asymmetric cores. Fast Fourier transform analysis on the transmission spectra of the device exhibited six clear peaks in the spatial frequency domain. By examining the phase shift responses of two distinct Sagnac and one Mach-Zehnder interference peaks, the response matrix that enable simultaneous measurement of torsion, strain, and temperature could be obtained. The proposed all-fiber Sagnac loop hybrid interferometer has the advantages such as simplicity of the device structure, compact device size, and capability for simultaneous sensing of multiple parameters. PMID- 25836212 TI - Sub-harmonic periodic pulse train recovery from aperiodic optical pulse sequences through dispersion-induced temporal self-imaging. AB - Temporal self-imaging effects (TSIs) are observed when a periodic pulse train propagates through a first-order dispersive medium. Under specific dispersion conditions, either an exact, rate multiplied or rate divided image of the input signal is reproduced at the output. TSI possesses an interesting self-restoration capability even when acting over an aperiodic train of pulses. In this work, we investigate and demonstrate, for the first time to our knowledge, the capability of TSI to produce periodic sub-harmonic (rate-divided) pulse trains from aperiodic sequences. We use this inherent property of the TSI to implement a novel, simple and reconfigurable sub-harmonic optical clock recovery technique from RZ-OOK data signals. The proposed technique features a very simple realization, involving only temporal phase modulation and first-order dispersion and it allows one to set the repetition rate of the reconstructed clock signal in integer fractions (sub-harmonics) of the input bit rate. Proof-of-concept experiments are reported to validate the proposed technique and guidelines for optimization of the clock-recovery process are also outlined. PMID- 25836213 TI - Flexible, fast, and low-cost production process for polymer based diffractive optics. AB - The generation of diffractive optical elements often requires time and cost consuming production techniques such as photolithography. Especially in research and development, small series of diffractive microstructures are needed and flexible and cost effective fabrication techniques are desirable to enable the fabrication of versatile optical elements on a short time scale. In this work, we introduce a novel process chain for fabrication of diffractive optical elements in various polymers. It is based on a maskless lithography process step, where a computer generated image of the optical element is projected via a digital mirror device and a microscope setup onto a silicon wafer coated with photosensitive resist. In addition, a stitching process allows us to microstructure a large area on the wafer. After development, a soft stamp of the microstructure is made from Polydimethylsiloxane, which is used as a mold for the subsequent hot embossing process, where the final diffractive optical element is replicated into thermoplastic polymer. Experimental results are presented, which demonstrate the applicability of the process. PMID- 25836214 TI - High-efficiency BAlGaN/AlN quantum well structures for optoelectronic applications in ultraviolet spectral region. AB - Light emission characteristics of ultraviolet (UV) B(x)Al(y)Ga(1-x-y)N/AlN quantum well (QW) structures were using the multiband effective-mass theory. The TE-polarized spontaneous emission is found to be significantly improved owing to the decrease in the lattice-mismatch between the well and the substrate with the inclusion of boron. However, the spontaneous emission peak begins to decrease when the boron composition exceeds a critical value (x = 0.08 for y = 0.2), which is mainly due to an increase in the heavy-hole effective mass. In addition, in the case of QW structures with higher Al composition (y > 0.5), the light emission is shown to decrease with increasing the boron composition because the characteristic of the topmost valence subband is changed to the crystal-field splitoff hole band. Hence, we expect that B(x)Al(y)Ga(1-x-y)N/AlN QW structures with y < 0.5 can be used as a TE-polarized light source with a high efficiency. PMID- 25836215 TI - Photophoretic trapping of airborne particles using ultraviolet illumination. AB - We demonstrate photophoretic trapping of micron-sized absorbing particles in air using pulsed and continuous-wave (CW) ultraviolet laser illumination at wavelengths of 351 nm and 244 nm. We compared the particle trapping dynamics in two trapping geometries consisting of a hollow optical cone formed by light propagating either with or against gravity. This comparison allowed us to isolate the influence of the photophoretic force from the radiative pressure and the convective forces. We found that the absorbing spherical particles tested experienced a positive photophoretic force, whereas the spatially irregular, non spherical particles tested experienced a negative photophoretic force. By using two trapping geometries, both spherical and non-spherical absorbing particles could be trapped and held securely in place. The position of the trapped particles exhibited a standard deviation of less than 1 um over 20 seconds. Moreover, by operating in the UV and deep-UV where the majority of airborne materials are absorptive, the system was able to trap a wide range of particle types. Such a general purpose optical trap could enable on-line characterization of airborne particles when coupled with interrogation techniques such as Raman spectroscopy. PMID- 25836216 TI - Multichannel nonlinear distortion compensation using optical phase conjugation in a silicon nanowire. AB - We experimentally demonstrate compensation of nonlinear distortion caused by the Kerr effect in a 3 * 32-Gbaud quadrature phase-shift keying (QPSK) wavelength division multiplexing (WDM) transmission system. We use optical phase conjugation (OPC) produced by four-wave mixing (FWM) in a 7-mm long silicon nanowire. A clear improvement in Q-factor is shown after 800-km transmission with high span input power when comparing the system with and without the optical phase conjugation module. The influence of OSNR degradation introduced by the silicon nanowire is analysed by comparing transmission systems of three different lengths. This is the first demonstration of nonlinear compensation using a silicon nanowire. PMID- 25836217 TI - Simultaneous dual-wavelength imaging of nonfluorescent tissues with 3D subdiffraction photothermal microscopy. AB - Multi-wavelength microscopic imaging is essential to visualize a variety of nanoscale cellular components with high specificity and high spatial resolution. However, previous techniques are based on fluorescence, and thus cannot visualize nonfluorescent species, which are much less suffered from photodamage or photobleaching and hence are intrinsically useful in wider range of optical microscopy. Here, we show that simultaneous multi-wavelength imaging of nonfluorescent species can be achieved with the use of a photothermal microscope. Dual-wavelength subdiffraction imaging of biological tissues stained with hematoxylin and eosin is demonstrated. Three-dimensional label-free imaging of mouse melanoma tissue section is also presented to demonstrate the effectiveness of the enhanced spatial resolution. Our technique can be implemented using cost effective and compact laser diodes and is applicable for various types of both fluorescent and nonfluorescent tissues. PMID- 25836218 TI - Wavelength-size hybrid Si-VO(2) waveguide electroabsorption optical switches and photodetectors. AB - Ultra-compact waveguide electroabsorption optical switches and photodetectors with micron- and sub-micron lengths and compatible with silicon (Si) waveguides are demonstrated using the insulator-metal phase transition of vanadium dioxide (VO(2)). A 1 MUm long hybrid Si-VO(2) device is shown to achieve a high extinction ratio of 12 dB and a competitive insertion loss of 5 dB over a broad bandwidth of 100 nm near lambda = 1550 nm. The device, operated as a photodetector, can measure optical powers less than 1 MUW with a responsivity in excess of 10 A/W. With volumes that are about 100 to 1000 times smaller than today's active Si photonic components, the hybrid Si-VO(2) devices show the feasibility of integrating transition metal oxides on Si photonic platforms for nanoscale electro-optic elements. PMID- 25836219 TI - Tunable narrow band difference frequency THz wave generation in DAST via dual seed PPLN OPG. AB - We report a widely tunable narrowband terahertz (THz) source via difference frequency generation (DFG). A narrowband THz source uses the output of dual seeded periodically poled lithium niobate (PPLN) optical parametric generators (OPG) combined in the nonlinear crystal 4-dimthylamino-N-methyl-4-stilbazolium tosylate (DAST). We demonstrate a seamlessly tunable THZ output that tunes from 1.5 THz to 27 THz with a minimum bandwidth of 3.1 GHz. The effects of dispersive phase matching, two-photon absorption, and polarization were examined and compared to a power emission model that consisted of the current accepted parameters of DAST. PMID- 25836220 TI - Modal analysis in 2D media with variable disorder. AB - Modal properties of 2D disordered optical structures have been numerically analyzed, in the Mid-IR region, varying the amount of scattering and the disorder level. The modal properties study has been carried out through the use of Finite Element Method, highlighting the localized regime transition and investigating the quality factor. The results have been interpreted in a statistical fashion, investigating light diffusion in these structures with the help of Monte Carlo Method. An alternative measure of randomness weight has been proposed to support the numerical results. PMID- 25836221 TI - Optical nonreciprocity with large bandwidth in asymmetric hybrid slot waveguide coupler. AB - On-chip broadband optical nonreciprocal transmission based on asymmetric hybrid slot waveguide (HSW) coupler is proposed. Filled with flint glass LaSF-010 and organic material DDMEBT in slots, respectively, two branches of an asymmetric HSW coupler have very distinct nonlinear coefficients, yet very close effective indexes. Since asymmetric coupler with low linear mismatch has a large free spectral range, the results show that our device has a 10-dB nonreciprocal transmission bandwidth (NTB) as large as about 66 nm corresponding to 80-mW operating power. The NTB could be even larger when the incident power is raised. This indicates over two orders of magnitude enhancement compared to previous on chip passive schemes. Owing to the large NTB, the device also functions properly for sub-picosecond pulses. Our scheme paves a path toward practical all-optical nonreciprocal applications. PMID- 25836222 TI - Angle dependent Fiber Bragg grating inscription in microstructured polymer optical fibers. AB - We report on an incidence angle influence on inscription of the Fiber Bragg Gratings in Polymethyl methacrylate (PMMA) microstructured polymer optical fibers. We have shown experimentally that there is a strong preference of certain angles, labeled GK, over the other ones. Angles close to GK showed fast start of inscription, rapid inscription and stronger gratings. We have also shown that gratings can be obtained at almost any angle but their quality will be lower if they are not around GK angle. Our experimental results verify earlier numerical and experimental predictions of Marshall et al. PMID- 25836223 TI - Second-order rogue wave breathers in the nonlinear Schrodinger equation with quadratic potential modulated by a spatially-varying diffraction coefficient. AB - Nonlinear Schrodinger equation with simple quadratic potential modulated by a spatially-varying diffraction coefficient is investigated theoretically. Second order rogue wave breather solutions of the model are constructed by using the similarity transformation. A modal quantum number is introduced, useful for classifying and controlling the solutions. From the solutions obtained, the behavior of second order Kuznetsov-Ma breathers (KMBs), Akhmediev breathers (ABs), and Peregrine solitons is analyzed in particular, by selecting different modulation frequencies and quantum modal parameter. We show how to generate interesting second order breathers and related hybrid rogue waves. The emergence of true rogue waves - single giant waves that are generated in the interaction of KMBs, ABs, and Peregrine solitons - is explicitly displayed in our analytical solutions. PMID- 25836224 TI - Optical interconnects: recent advances and future challenges. AB - This focus issue is a collection of 17 invited papers showcasing the recent advances and the future challenges of optical interconnect technology. These papers represent multiple key areas that include the enabling devices and components, advances in the system and sub-system technologies as well as networking and its applications. PMID- 25836225 TI - On the scalability of ring fiber designs for OAM multiplexing. AB - The promise of the infinite-dimensionality of orbital angular momentum (OAM) and its application to free-space and fiber communications has attracted immense attention in recent years. In order to facilitate OAM-guidance, novel fibers have been proposed and developed, including a class of so-called ring-fibers. In these fibers, the wave-guiding region is a high-index annulus instead of a conventional circular core, which for reasons related to polarization-dependent differential phase shifts for light at waveguide boundaries, leads to enhanced stability for OAM modes. We review the theory and implementation of this nascent class of waveguides, and discuss the opportunities and limitations they present for OAM scalability. PMID- 25836226 TI - Contradiction within wave optics and its solution within a particle picture. AB - It is shown that the condition provided by paraxial wave optics for the resonance frequencies of the eigenmodes of an optical resonator leads to a contradiction, if the resonator is divided into subcavities. Moreover, it is shown that the results obtained in this way imply a violation of energy conservation. Since for nearly plane waves, paraxial wave optics becomes exact within wave optics, this contradiction also concerns wave optics. A solution for this problem is proposed within a particle picture as presented recently by the author. It is based on a consideration of the change of momentum of a photon bouncing between two equiphase surfaces with vanishing distance. This leads to a transverse force exerted on the photon. Assigning a relativistic mass to the photon leads to a Schrodinger equation describing a transverse motion of the photon. In this way the transverse modes of an optical resonator can be understood as the quantum mechanical eigenfunctions of a single photon. PMID- 25836227 TI - High-Q resonant cavities for terahertz quantum cascade lasers. AB - We report on the realization and characterization of two different designs for resonant THz cavities, based on wire-grid polarizers as input/output couplers, and injected by a continuous-wave quantum cascade laser (QCL) emitting at 2.55 THz. A comparison between the measured resonators parameters and the expected theoretical values is reported. With achieved quality factor Q ~ 2.5 * 10(5), these cavities show resonant peaks as narrow as few MHz, comparable with the typical Doppler linewidth of THz molecular transitions and slightly broader than the free-running QCL emission spectrum. The effects of the optical feedback from one cavity to the QCL are examined by using the other cavity as a frequency reference. PMID- 25836228 TI - Optofluidic tunable manipulation of microparticles by integrating graded-index fiber taper with a microcavity. AB - We propose and demonstrate optofluidic tunable manipulation of polystyrene microparticles based on the combination of a graded-index fiber (GIF) taper and a microcavity. The tunability on the manipulation length is experimentally explored by changing the balance between the optical force and the microfluidic flow force, as well as by tuning the focus of light emitting from the GIF taper via adjusting the length of an air microcavity. By optimizing the geometric shape of the GIF taper, as well as the flow rate and laser power, a manipulation length of 177 MUm is achieved, more than 4 times longer than the state-of-the-art optical fiber tweezers. This method has advantages of high flexibility, ease of fabrication and use, integration with microfluidics and has the potential for optofluidic sensing applications. PMID- 25836229 TI - Ultra-stable and versatile widefield cryo-fluorescence microscope for single molecule localization with sub-nanometer accuracy. AB - We developed a stand-alone cryostat with optical access to the sample which can be adapted to any epi-fluorescence microscope for single-molecule fluorescence spectroscopy and imaging. The cryostat cools the sample to a cryogenic temperature of 89 K, and allows for imaging single molecules using an air objective with a numerical aperture of 0.7. An important property of this system is its excellent thermal and mechanical stability, enabling long-time observations of samples over several hours with negligible drift. Using this system, we performed photo-bleaching studies of Atto647N dye molecules, and find an improvement of the photostability of these molecules by more than two orders of magnitude. The resulting increased photon numbers of several millions allow for single-molecule localization accuracy of sub-nanometer. PMID- 25836230 TI - All-optical 1st- and 2nd-order differential equation solvers with large tuning ranges using Fabry-Perot semiconductor optical amplifiers. AB - We experimentally demonstrate an all-optical temporal computation scheme for solving 1st- and 2nd-order linear ordinary differential equations (ODEs) with tunable constant coefficients by using Fabry-Perot semiconductor optical amplifiers (FP-SOAs). By changing the injection currents of FP-SOAs, the constant coefficients of the differential equations are practically tuned. A quite large constant coefficient tunable range from 0.0026/ps to 0.085/ps is achieved for the 1st-order differential equation. Moreover, the constant coefficient p of the 2nd order ODE solver can be continuously tuned from 0.0216/ps to 0.158/ps, correspondingly with the constant coefficient q varying from 0.0000494/ps(2) to 0.006205/ps(2). Additionally, a theoretical model that combining the carrier density rate equation of the semiconductor optical amplifier (SOA) with the transfer function of the Fabry-Perot (FP) cavity is exploited to analyze the solving processes. For both 1st- and 2nd-order solvers, excellent agreements between the numerical simulations and the experimental results are obtained. The FP-SOAs based all-optical differential-equation solvers can be easily integrated with other optical components based on InP/InGaAsP materials, such as laser, modulator, photodetector and waveguide, which can motivate the realization of the complicated optical computing on a single integrated chip. PMID- 25836231 TI - Broadband silicon photonic directional coupler using asymmetric-waveguide based phase control. AB - We design and demonstrate broadband directional couplers that use asymmetric waveguide based phase control sections, on the silicon-on-insulator platform. Broadband directional couplers with various power splitting ratios, including 10%/90%, 20%/80%, 30%/70%, 40%/60% and 50%/50%, were realized for both transverse electric (TE) and transverse magnetic (TM) modes. Some of the devices exhitbit bandwidths in excess of 100 nm, and all in excess of 75 nm. The footprints of the TE mode couplers are 32 MUm *1.3 MUm, or less, and those of the TM mode couplers are 13 MUm *1.3 MUm, or less. PMID- 25836232 TI - Simple method for locking birefringent resonators. AB - We report on a simple method of locking a laser to a birefringent cavity using polarization spectroscopy. The birefringence of the resonator permits the simple extraction of an error signal by using one polarization state as a phase reference for another state. No modulation of the light or the resonator is required, reducing the complexity of the laser locking setup. This method of producing an error signal can be used on most birefringent optical resonators, even if the details of birefringence and eigenpolarizations are not known. This technique is particularly well suited for fiber ring resonators due to the inherent birefringence of the fiber and the unknown nature of that birefringence. We present an experimental demonstration of this technique using a fiber ring. PMID- 25836233 TI - Near-infrared luminescence of bismuth in fluorine-doped-core silica fibres. AB - Photoluminescence spectra and decay kinetics of bismuth inclusions in silica optical fibres containing fluorine additive in the core glass are studied in the vicinity of a wavelength of 1420 nm at temperatures of 80-900 K under a continuous wave (CW) and a pulsed diode laser pump at a wavelength of 808 nm. At high fluorine concentration and low temperatures, luminescence decay kinetics becomes essentially bi-exponential, typical lifetimes being 720 and 1200 us. Hydrogen and deuterium loading at pressures of up to 125 bar leads to a decrease of the steady-state luminescence intensity and lifetime. We attribute this to the appearance of an energy transfer bridge from bismuth clusters to vibrational degrees of freedom of diatomic molecules. It is found that in the presence of H(2) or D(2) molecules experiencing random walking in silica, luminescence decay kinetics stop following a single exponential function even in fluorine-free silica-core fibre, deviation from the single exponent being greater at higher temperatures. The induced quenching rate increases with the increase of temperature as well and is greater for H(2) molecules. All conditions being equal, the equilibrium concentration of hydrogen molecules is greater in heavily fluorinated silica. At temperatures below ~250 K, the presence of dissolved molecules has no effect, which speaks for the primary importance of having rotational degrees of freedom of migrating interstitial diatomic molecules in an excited state for effective quenching of bismuth electronic excitations. It is found that the influence of dissolved deuterium is weaker than that of hydrogen. We attribute this feature to a greater angular momentum of the D(2) molecule and correspondingly smaller energy of the molecule's rotational quantum. The results of the experiments show that bismuth clusters mainly located in voids of the silica network, rather than bismuth point defects, are responsible for near infrared luminescence. PMID- 25836234 TI - Spatially-resolved Rayleigh scattering for analysis of vector mode propagation in few-mode fibers. AB - We use high-resolution imaging of Rayleigh scattered light through the side of few-mode optical fibers to measure the local spatial structure of propagating vector fields. We demonstrate the technique by imaging both pure modes and superpositions of modes in the LP01 and LP11 families. Direct imaging not only gives high-resolution beat length measurements, but also records the local propagation dynamics including those due to perturbations. The imaging setup uses polarization discrimination to monitor both the transverse and the longitudinal polarization components simultaneously. PMID- 25836235 TI - Energy-saving framework for passive optical networks with ONU sleep/doze mode. AB - This paper proposes an energy-saving passive optical network framework (ESPON) that aims to incorporate optical network unit (ONU) sleep/doze mode into dynamic bandwidth allocation (DBA) algorithms to reduce ONU energy consumption. In the ESPON, the optical line terminal (OLT) schedules both downstream (DS) and upstream (US) transmissions in the same slot in an online and dynamic fashion whereas the ONU enters sleep mode outside the slot. The ONU sleep time is maximized based on both DS and US traffic. Moreover, during the slot, the ONU might enter doze mode when only its transmitter is idle to further improve energy efficiency. The scheduling order of data transmission, control message exchange, sleep period, and doze period defines an energy-efficient scheme under the ESPON. Three schemes are designed and evaluated in an extensive FPGA-based evaluation. Results show that whilst all the schemes significantly save ONU energy for different evaluation scenarios, the scheduling order has great impact on their performance. In addition, the ESPON allows for a scheduling order that saves ONU energy independently of the network reach. PMID- 25836236 TI - Approaching conversion limit with all-dielectric solar cell reflectors. AB - Metallic back reflectors has been used for thin-film and wafer-based solar cells for very long time. Nonetheless, the metallic mirrors might not be the best choices for photovoltaics. In this work, we show that solar cells with all dielectric reflectors can surpass the best-configured metal-backed devices. Theoretical and experimental results all show that superior large-angle light scattering capability can be achieved by the diffuse medium reflectors, and the solar cell J-V enhancement is higher for solar cells using all-dielectric reflectors. Specifically, the measured diffused scattering efficiency (D.S.E.) of a diffuse medium reflector is >0.8 for the light trapping spectral range (600nm 1000nm), and the measured reflectance of a diffuse medium can be as high as silver if the geometry of embedded titanium oxide(TiO(2)) nanoparticles is optimized. Moreover, the diffuse medium reflectors have the additional advantage of room-temperature processing, low cost, and very high throughput. We believe that using all-dielectric solar cell reflectors is a way to approach the thermodynamic conversion limit by completely excluding metallic dissipation. PMID- 25836237 TI - Color uniformity in spotlights optimized with reflectors and TIR lenses. AB - We analyze the color uniformity in the far field of spotlight systems to estimate visual perception with a merit function derived from human factor experiments. A multi-colored light-emitting diode (LED) light engine with different light mixing levels is combined with several reflectors and total internal reflection (TIR) lenses. The optimized systems are analyzed at several color uniformity levels with regard to the efficiency, peak luminous intensity and dimensions. It is shown that these properties cannot all be optimized at the same time. Furthermore, excellent color uniformity can be reached by a light mixing layer in the light engine or by adding mixing elements to the secondary optics. PMID- 25836239 TI - Vanadium dioxide nanogrid films for high transparency smart architectural window applications. AB - This study presents a novel approach towards achieving high luminous transmittance (T(lum)) for vanadium dioxide (VO(2)) thermochromic nanogrid films whilst maintaining the solar modulation ability (DeltaT(sol)). The perforated VO(2)-based films employ orderly-patterned nano-holes, which are able to favorably transmit visible light dramatically but retain large near-infrared modulation, thereby enhancing DeltaT(sol). Numerical optimizations using parameter search algorithms have implemented through a series of Finite Difference Time Domain (FDTD) simulations by varying film thickness, cell periodicity, grid dimensions and variations of grid arrangement. The best performing results of T(lum) (76.5%) and DeltaT(sol) (14.0%) are comparable, if not superior, to the results calculated from nanothermochromism, nanoporosity and biomimic nanostructuring. It opens up a new approach for thermochromic smart window applications. PMID- 25836240 TI - Nanoparticle scattering layer for improving light extraction efficiency of organic light emitting diodes. AB - Nanoparticle scattering layer based on polymer-metal oxide composite is successfully introduced to enhance the light extraction efficiency of organic light emitting diodes (OLEDs). We find that the density and the distribution of nanoparticles is the key factor to maximize the light extraction efficiency of pristine OLEDs by out-coupling the unusable light with the scattering film. In our experiment, 71 wt% of Al(2)O(3) mixed with polymer matrix shows the increase of light extraction efficiency of 40%. This method is expected to play a critical role to create the low-power OLED application such as OLED lightings with simple fabrication process and low cost. PMID- 25836241 TI - Study on the correlations between color rendering indices and the spectral power distributions: comment. AB - This is a comment on a recently published paper by Lin at el. [Optics Express 22(S4), A1029 (2014)]. The original article suffers three fatal defects as follow: (1) Some peak distortions are not present in the spectral loss simulation due to large wavelength step; (2) The correlations between the modulated deviations (MDs) and the color rendering indices (CRIs) are poor at high CRI region; (3) How to determine the optimal peak wavelengths of multi-peak LED in the guideline for the CRI optimization does not make any statement. There are poor correlations between the MDs and CRIs at high CRI region. PMID- 25836242 TI - Study on the correlations between color rendering indices and the spectral power distributions: reply to comment. AB - We demonstrate the strong theory strength of our original article [Optics Express 22 (S4), A1029 (2014)] and the statements in the comment letter were wrong because it was based on misunderstanding of our article. PMID- 25836243 TI - Liquid-crystal-modulated correlated color temperature tunable light-emitting diode with highly accurate regulation. AB - A precise correlated color temperature (CCT) tuning method for light-emitting diodes (LEDs) has been developed and is demonstrated in this article. By combining LEDs and a liquid crystal (LC) cell, a light source with continuous CCT variation along a straight track on the chromaticity diagram is achieved. Moreover, the manner of CCT variation can be modulated by choosing appropriate LEDs and phosphors to yield a variation going from 3800 K to 6100 K with the track near the black-body locus. By adapting various developed LC technologies for diverse demands, the performance and applications of LEDs can be greatly improved. PMID- 25836244 TI - Design and demonstration of high efficiency anti-glare LED luminaires for indoor lighting. AB - An anti-glare luminaire design is proposed to reduce the effect of glare and the multi-shadow while preserving high optical efficiency, high illumination uniformity and low unified glare rating (UGR). Comparison to the traditional direct light emitting diode (LED) luminaire in optical simulations showed an enhancement of the illumination uniformity from 64.9% to 80.0%. The optical efficiency was 79.5%, and the UGR value was controlled under 18.8. For the actual measurement, the finished product had an illumination uniformity of 77.0%, optical efficiency of 76.0%, UGR value of 19.0, and efficacy of 81.4 lm/w. Through this design, the lighting performance was greatly enhanced. PMID- 25836245 TI - Photonic crystal enhanced silicon cell based thermophotovoltaic systems. AB - We report the design, optimization, and experimental results of large area commercial silicon solar cell based thermophotovoltaic (TPV) energy conversion systems. Using global non-linear optimization tools, we demonstrate theoretically a maximum radiative heat-to-electricity efficiency of 6.4% and a corresponding output electrical power density of 0.39 W cm(-2) at temperature T = 1660 K when implementing both the optimized two-dimensional (2D) tantalum photonic crystal (PhC) selective emitter, and the optimized 1D tantalum pentoxide - silicon dioxide PhC cold-side selective filter. In addition, we have developed an experimental large area TPV test setup that enables accurate measurement of radiative heat-to-electricity efficiency for any emitter-filter-TPV cell combination of interest. In fact, the experimental results match extremely well with predictions of our numerical models. Our experimental setup achieved a maximum output electrical power density of 0.10W cm(-2) and radiative heat-to electricity efficiency of 1.18% at T = 1380 K using commercial wafer size back contacted silicon solar cells. PMID- 25836246 TI - Improvement in light harvesting of dye-sensitized solar cells with antireflective and hydrophobic textile PDMS coating by facile soft imprint lithography. AB - We demonstrated the improved conversion efficiency (eta) of dye-sensitized solar cells (DSSCs) using the textile-patterned polydimethylsiloxane (PDMS) antireflection layers prepared by metal-coated textile master molds by a simple soft imprint lithography. When light propagates through the textile-patterned surface of PDMS (i.e., textile PDMS) laminated on the outer glass surface deposited with fluorine-doped tin oxide (i.e., FTO/glass), both the transmitted and diffused lights into the photo-anode of DSSCs were simultaneously enhanced. Compared to the bare FTO/glass, the textile PDMS increased the total transmittance from 82.3 to 85.1% and its diffuse transmittance was significantly increased from 5.9 to 78.1% at 550 nm of wavelength. The optical property of textile PDMS was also theoretically analyzed by the finite-difference time-domain simulation. By laminating the textile PDMS onto the outer glass surface of DSSCs, the eta was enhanced from 6.04 to 6.51%. Additionally, the fabricated textile PDMS exhibited a hydrophobic surface with water contact angle of ~123.15 degrees . PMID- 25836247 TI - Improving LED CCT uniformity using micropatterned films optimized by combining ray tracing and FDTD methods. AB - Although the light-emitting diode (LED) has revolutionized lighting, the non uniformity of its correlated color temperature (CCT) still remains a major concern. In this context, to improve the light distribution performance of remote phosphor LED lamps, we employ a micropatterned array (MPA) optical film fabricated using a low-cost molding process. The parameters of the MPA, including different installation configurations, positioning, and diameters, are optimized by combining the finite-difference time-domain and ray-tracing methods. Results show that the sample with the upward-facing convex-cone MPA film that has a diameter of half of that of the remote phosphor glass, and is tightly affixed to the inward surface of the remote phosphor glass renders a superior light distribution performance. When compared with the case in which no MPA film is used, the deviation of the CCT distribution decreases from 1033 K to 223 K, and the corresponding output power of the sample is an acceptable level of 85.6%. We perform experiments to verify our simulation results, and the two sets of results exhibit a close agreement. We believe that our approach can be used to optimize MPA films for various lighting applications. PMID- 25836249 TI - Improvement of light quality by DBR structure in white LED. AB - This study demonstrates the application of DBR structure into the remote phosphor structure to improve the angular correlated color temperature (CCT) deviation in white light-emitting diodes (WLEDs). In the experiment, the LED device with DBR structure yielded a higher luminous efficiency than a conventional structure. The CCT deviation can be improved from 1758K to 280K in a range of -70 to 70 degree and the luminous flux increases more than 10% due to the enhancement of the light extraction of the blue light. Moreover, the reflectance of the different DBR structures is analyzed with different angles to reveal the reasons of such improvements. As the result, this LED device with DBR structure shows the great potential to use as the next generation lighting source. PMID- 25836251 TI - Nonradiative recombination--critical in choosing quantum well number for InGaN/GaN light-emitting diodes. AB - In this work, InGaN/GaN light-emitting diodes (LEDs) possessing varied quantum well (QW) numbers were systematically investigated both numerically and experimentally. The numerical computations show that with the increased QW number, a reduced electron leakage can be achieved and hence the efficiency droop can be reduced when a constant Shockley-Read-Hall (SRH) nonradiative recombination lifetime is used for all the samples. However, the experimental results indicate that, though the efficiency droop is suppressed, the LED optical power is first improved and then degraded with the increasing QW number. The analysis of the measured external quantum efficiency (EQE) with the increasing current revealed that an increasingly dominant SRH nonradiative recombination is induced with more epitaxial QWs, which can be related to the defect generation due to the strain relaxation, especially when the effective thickness exceeds the critical thickness. These observations were further supported by the carrier lifetime measurement using a pico-second time-resolved photoluminescence (TRPL) system, which allowed for a revised numerical modeling with the different SRH lifetimes considered. This work provides useful guidelines on choosing the critical QW number when designing LED structures. PMID- 25836252 TI - Effect of transmittance on luminescence properties of phosphor-in-glass for LED packaging. AB - The transmittance of phosphor-in-glass (PIG) color converter material was studied as a factor affecting the luminescence properties of light emitting diode packaging; it is closely related to the residual pores of sintered glass. In this study, the correlation between porosity and optical properties of the glass and PIG plates was investigated. The transmittance, luminescence properties, and porosity were measured by UV-visible spectrometer, integrating sphere and scanning electron microscope, respectively. Transmittance of the sintered glass plate and the luminous efficacy of the PIG plate both increase with decreased porosity, while the light scattering coefficient decreases. Luminescence properties such as emission intensity and color coordinates are also influenced by transmittance of the PIG plate. PMID- 25836253 TI - Sensitized intense near-infrared downconversion quantum cutting three-photon luminescence phenomena of the Tm(3+) ion activator in Tm(3+)Bi(3+):YNbO(4) powder phosphor. AB - In present study, the intense sensitized three photon near-infrared quantum cutting luminescence of Tm(3+) ion activator in Tm(3+)Bi(3+):YNbO(4) powder phosphor is reported. It is induced both by [{(1)G(4)->(3)H(4), (3)H(6)->(3)H(5)} or {(1)G(4)->(3)H(5), (3)H(6)->(3)H(4)}] and {(3)H(4)->(3)F(4), (3)H(6)->(3)F(4)} cross-energy transfer. We found that the 1820.0 nm (3)F(4)->(3)H(6) luminescence intensity of Tm(0.08)Bi(0.01)Y(0.91)NbO(4) powder phosphor excited by 302.0 nm is 151 and 8.38 times larger, compared to Tm(0.005)Y(0.995)NbO(4) excited by 302.0 and 468.0 nm, in which the quantum cutting takes place between Tm(3+) ions and Bi(3+) ion only acts as sensitizer. To the knowledge of the authors, it is the first time that the effective Bi(3+) sensitized near-infrared quantum cutting of Tm(3+) ion activator has been reported. It can facilitate the probing of the next generation environmentally friendly germanium solar cell. PMID- 25836254 TI - Modulation of optical transmittance and conductivity by the period, linewidth and height of Au square mesh electrodes. AB - Metal transparent conductive electrode (TCE) with surface plasmons has been extensively studied for light absorption enhancement in solar cells and light extraction in Light-Emitting Diodes etc. But its transparent conductive properties and surface plasmons are controlled by its micromorphologies and microstructures. In this work, photoelectric coupling effects and optical transmittance modulations of period, linewidth and height of Au nanowire in square mesh electrode were investigated detailedly using a comprehensive finite difference time domain calculation stimulation, and then Au square mesh TCEs with the 500 nm in period, 70 nm in height and linewidth ranging from 60 to 100 nm were fabricated using electron beam lithography. The measured results showed that the optical transmittance of the TCEs is about 70% in the 350-700 nm wavelength range and over 80% in the 700-1000 nm range, which accord with the theoretical simulation results. Optical transmittance is affected by reflection loss, localized surface plasmon resonances and surface plasmon polarizations (SPPs) absorption loss, concerned about geometry parameters. SPPs dip peak position exhibits a blue-shift from 844 to 812 nm and the width of peak increases with increasing the linewidth from 60 to 100 nm, The measured surface resistivity of the TCEs with the 500 nm in period, 50 nm in height and 50 nm in linewidth is about 74.5 Omega/m(2), about two times bigger than that of commercial indium tin oxide glass. PMID- 25836255 TI - Electrophoretic deposited TiO(2) pigment-based back reflectors for thin film solar cells. AB - Highly reflective coatings with strong light scattering effect have many applications in optical components and optoelectronic devices. This work reports titanium dioxide (TiO(2)) pigment-based reflectors that have 2.5 times higher broadband diffuse reflection than commercially produced aluminum or silver based reflectors and result in efficiency enhancements of a single-junction amorphous Si solar cell. Electrophoretic deposition is used to produce pigment-based back reflectors with high pigment density, controllable film thickness and site specific deposition. Electrical conductivity of the pigment-based back reflectors is improved by creating electrical vias throughout the pigment-based back reflector by making holes using an electrical discharge / dielectric breakdown approach followed by a second electrophoretic deposition of conductive nanoparticles into the holes. While previous studies have demonstrated the use of pigment-based back reflectors, for example white paint, on glass superstrate configured thin film Si solar cells, this work presents a scheme for producing pigment-based reflectors on complex shape and flexible substrates. Mechanical durability and scalability are demonstrated on a continuous electrophoretic deposition roll-to-roll system which has flexible metal substrate capability of 4 inch wide and 300 feet long. PMID- 25836256 TI - Metal electrode-free perovskite solar cells with transfer-laminated conducting polymer electrode. AB - We report perovskite solar cells with a new device structure that employ highly conductive polymer poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) ( PEDOT: PSS) as the top electrode replacing commonly used metal electrodes. The PEDOT: PSS top electrode is prepared from its aqueous solution through a transfer lamination technique rather than direct spin-coating, which converts the CH(3)NH(3)PbI(3) into PbI(2). Perovskite solar cells with the structure of glass/FTO/c-TiO(2)/m-TiO(2)/CH(3)NH(3)PbI(3)/spiro-OMeTAD/PEDOT:PSS yield a maximum open-circuit voltage (V(OC)) of 1.02 V, and a maximum power conversion efficiency (PCE) of 11.29% under AM1.5 100 mW/cm(2) illumination. The whole device was fabricated in air without high-vacuum deposition which simplifies the processing and lowers the threshold of both scientific research and industrial production of perovskite solar cells. PMID- 25836257 TI - Plasmonic effects in ultrathin amorphous silicon solar cells: performance improvements with Ag nanoparticles on the front, the back, and both. AB - Thin-film hydrogenated amorphous silicon (a-Si:H) solar cells that are free standing over a 2x2 mm area have been fabricated with thicknesses of 150 nm, 100 nm, and 60 nm. Silver nanoparticles (NPs) created on the front and/or back surfaces of the solar cells led to improvement in performance measures such as current density, overall efficiency, and external quantum efficiency. The effect of changing silver nanoparticle size and incident light angle was tested. Finite Difference Time-Domain simulations are presented as a way to understand the experimental results as well as guide future research efforts. PMID- 25836259 TI - Correction: Accumulation of oxidized LDL in the tendon tissues of C57BL/6 or apolipoprotein E knock-out mice that consume a high fat diet: potential impact on tendon health. PMID- 25836258 TI - Association between ankylosing spondylitis and the miR-146a and miR-499 polymorphisms. AB - miRNAs are small, non-coding RNAs that regulate the expression of multiple target genes at the post-transcriptional level. Single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and have been implicated in the pathogenesis of multiple forms of arthritis, including rheumatoid arthritis (RA) and osteoarthritis. The present study explored the association between ankylosing spondylitis (AS) and two single nucleotide polymorphisms (SNPs), miR-146a rs2910164G>C and miR-499 rs3746444T>C, in a Han Chinese population. A case control study consisting of 102 subjects with AS and 105 healthy controls was designed. The two miRNA SNPs were identified by direct sequencing. Subsequently, their gene and genotype frequencies were compared with healthy controls. A significant difference was observed in the miR-146a rs2910164G>C SNP. The frequency of the G allele was markedly higher in the AS patients than in the healthy controls (P = 0.005, Pc = 0.01, OR = 1.787), and the frequency of the GG genotype was higher in AS patients than in controls (P = 0.014, Pc = 0.042, OR = 2.516). However, no significant association was found between the miR-499 rs3746444T>C variant and susceptibility to AS. This is the first study to address the association between the miR-146a rs2910164G>C and miR-499 rs3746444T>C polymorphisms and AS, and it suggests a potential pathogenic factor for AS. Further studies are needed to validate our findings in a larger series, as well as in other ethnic backgrounds. PMID- 25836260 TI - Effects of hemin and nitrite on intestinal tumorigenesis in the A/J Min/+ mouse model. AB - Red and processed meats are considered risk factors for colorectal cancer (CRC); however, the underlying mechanisms are still unclear. One cause for the potential link between CRC and meat is the heme iron in red meat. Two pathways by which heme and CRC promotion may be linked have been suggested: fat peroxidation and N nitrosation. In the present work we have used the novel A/J Min/+ mouse model to test the effects of dietary hemin (a model of red meat), and hemin in combination with nitrite (a model of processed meat) on intestinal tumorigenesis. Mice were fed a low Ca2+ and vitamin D semi-synthetic diet with added hemin and/or nitrite for 8 weeks post weaning, before termination followed by excision and examination of the intestinal tract. Our results indicate that dietary hemin decreased the number of colonic lesions in the A/J Min/+ mouse. However, our results also showed that the opposite occurred in the small intestine, where dietary hemin appeared to stimulate tumor growth. Furthermore, we find that nitrite, which did not have an effect in the colon, appeared to have a suppressive effect on tumor growth in the small intestine. PMID- 25836261 TI - Application of allogeneic bone marrow cells in view of residual alloreactivity: sirolimus but not cyclosporine evolves tolerogenic properties. AB - BACKGROUND: Application of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity. METHODS: The rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) -> LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry. RESULTS: Mixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC. CONCLUSION: Srl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism. PMID- 25836262 TI - A universal mariner transposon system for forward genetic studies in the genus Clostridium. AB - DNA transposons represent an essential tool in the armoury of the molecular microbiologist. We previously developed a catP-based mini transposon system for Clostridium difficile in which the expression of the transposase gene was dependent on a sigma factor unique to C. difficile, TcdR. Here we have shown that the host range of the transposon is easily extended through the rapid chromosomal insertion of the tcdR gene at the pyrE locus of the intended clostridial target using Allele-Coupled Exchange (ACE). To increase the effectiveness of the system, a novel replicon conditional for plasmid maintenance was developed, which no longer supports the effective retention of the transposon delivery vehicle in the presence of the inducer isopropyl beta-D-1-thiogalactopyranoside (IPTG). As a consequence, those thiamphenicol resistant colonies that arise in clostridial recipients, following plating on agar medium supplemented with IPTG, are almost exclusively due to insertion of the mini transposon into the genome. The system has been exemplified in both Clostridium acetobutylicum and Clostridium sporogenes, where transposon insertion has been shown to be entirely random. Moreover, appropriate screening of both libraries resulted in the isolation of auxotrophic mutants as well as cells deficient in spore formation/germination. This strategy is capable of being implemented in any Clostridium species. PMID- 25836263 TI - Baclofen for alcohol withdrawal. AB - BACKGROUND: The treatment baclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane review published in Issue 2, 2013. OBJECTIVES: To assess the efficacy and safety of baclofen for people with AWS. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Specialised Register (searched 13 January 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1), MEDLINE (1966 to January 2015), EMBASE (1980 to January 2015), and CINAHL (1982 to January 2015). We also searched registers of ongoing trials, including ClinicalTrials.gov, the ISRCTN registry, and the European Clinical Trials Database. At the same time, we handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language. SELECTION CRITERIA: We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non randomised, or quasi-randomised trials. We included both parallel group and cross over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed references retrieved for possible inclusion. Any disagreements were resolved by an independent party. We contacted study authors for additional information where needed. We collected adverse effects information from the trials. MAIN RESULTS: Two RCTs with a total of 81 participants were eligible according to the inclusion criteria. One study suggested that both baclofen and diazepam significantly decreased the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) score, without any significant difference between the two interventions. The other study showed no significant difference in CIWA-Ar score between baclofen and placebo, but a significantly decreased dependence on high-dose benzodiazepines with baclofen compared to placebo. Only one study reported on the safety of baclofen, without any side effects. AUTHORS' CONCLUSIONS: The evidence for recommending baclofen for AWS is insufficient. We therefore need more well-designed RCTs to prove its efficacy and safety. PMID- 25836264 TI - Comparison of metal concentrations in the organs of two fish species from the Zabol Chahnimeh reservoirs, Iran. AB - This study was conducted to measure the Cd, Pb, Cu, Zn, Cr, Co, Ni, and Fe concentrations in organs of Cyprinus carpio and Hypophthalmichthys molitrix, in Zabol Chahnimeh reservoirs, Iran. The highest Pb, Cu, Co, Ni, and Fe concentrations in both fish species were observed in the gill of C. carpio at 0.70, 3.7, 0.7, 0.8 and 31.2 ug/g, respectively; while the highest concentrations of Cd, Zn, and Cr were found in the gill of H. molitrix at 0.13, 22.5, and 0.5 ug/g, respectively. The maximum allowable fish consumption rate for an adult person (71.5 kg body weight) were 10.64, 0.677, 0.558, 1.17, and 0.92 kg/day based on Cd, Cu, Cr, Zn, and Fe levels respectively. Results showed that the Cd, Cu, Zn, and Pb (except of Pb in H. molitrix) concentrations in the muscle of both fish species are below levels of concern for human consumption. PMID- 25836265 TI - Magnesium Contamination in Soil at a Magnesite Mining Region of Liaoning Province, China. AB - Magnesite is the world's most important source material for magnesia refractory production, and Haicheng City in Liaoning Province, China has been called "the magnesium capital of the world." However, magnesite mining in these areas has caused serious environmental problems. Field investigations have shown that the soil profile of many sites in the mining region are contaminated by magnesium, and the magnesium-enriched crusts that have formed on the soil surface have affected ecologically important soil functions, particularly reduced water penetration rate. Laboratory experiment revealed that anionic polyacrylamide and calcium dihydrogen phosphate can be used to improve soil condition, and have positive effects on soil function. The findings of this study are of significance in the magnetite mining areas, providing clear options for the remediation of soils that should be carried out immediately. PMID- 25836266 TI - Distributions and concentrations of thallium in Korean soils determined by single and sequential extraction procedures. AB - The objectives of this study were to investigate the distribution of thallium in soils collected near suspected areas such as cement plants, active and closed mines, and smelters and to examine the extraction of thallium in the soils using 19 single chemical and sequential chemical extraction procedures. Thallium concentrations in soils near cement plants were distributed between 1.20 and 12.91 mg kg(-1). However, soils near mines and smelters contained relatively low thallium concentrations ranging from 0.18 to 1.09 mg kg(-1). Thallium extractability with 19 single chemical extractants from selected soils near cement plants ranged from 0.10% to 8.20% of the total thallium concentration. In particular, 1.0 M NH4Cl, 1.0 M (NH4)2SO4, and 1.0 M CH3COONH4 extracted more thallium than other extractants. Sequential fractionation results of thallium from different soils such as industrially and artificially contaminated soils varied with the soil properties, especially soil pH and the duration of thallium contamination. PMID- 25836267 TI - IgG4-Related Hypertrophic Pachymeningitis at the Falx Cerebrii with Brain Parenchymal Invasion: A Case Report. AB - BACKGROUND: Hypertrophic pachymeningitis has been described as a manifestation of a number of conditions, like infection and neoplasms such as dural carcinomatosis or lymphomas. IgG4-related hypertrophic pachymeningitis is a new entity identified during the past decade and most reports described pachymeningeal involvement only. CASE DESCRIPTION: We present a 58-year-old woman with isolated IgG4 hypertrophic pachymeningitis at the falx cerebrii that exhibited cerebral parenchymal invasion. She initially presented with left lower limb weakness. Magnetic resonance imaging of brain showed a contrast enhancing lesion located at the falx and that eroded into the right frontal lobe. Subsequent excisional biopsy confirmed the lesion with brain parenchyma invasion. The pathologic diagnosis was IgG4-related disease. She had no evidence of extracranial involvement. CONCLUSIONS: Overall, this is an uncommon condition that may exhibit parenchymal invasion. Surgical biopsy would serve to establish a definitive diagnosis, and prompt comprehensive management of what is essentially a systemic and treatable condition. PMID- 25836268 TI - Addressing the Efficacy of Intra-arterial Treatment in Acute Ischemic Strokes. PMID- 25836269 TI - Acute Onset of Guillain-Barre Syndrome After Elective Spinal Surgery. AB - BACKGROUND: Guillain-Barre syndrome (GBS) is an acute peripheral neuropathy caused by an autoimmune response against myelin of peripheral nerves. GBS has been reported after surgery, in general, and after spinal surgery, in particular. In most cases, GBS developed 1-3 weeks after surgery. METHODS: Report of 2 cases of GBS after elective spine surgery that developed in the immediate postoperative period. RESULTS: Within 1 and 3 hours after surgery, respectively, both patients developed ascending loss of motor and sensory function. They were taken back urgently to the operating room for wound exploration to ensure that an epidural hematoma had not developed. Cerebrospinal fluid studies and electromyography/nerve conduction velocity were then rapidly obtained and were compatible with acute inflammatory demyelinating polyradiculoneuropathy. Therapy was initiated with administration of intravenous immunoglobulin and plasmapheresis. Both patients made substantial motor recovery during the course of 1-2 years but have residual sensory abnormalities. CONCLUSIONS: GBS developing acutely after spinal surgery is a rare occurrence but should be considered in the differential diagnosis of neurological deterioration after surgery. Rapid diagnosis and treatment are essential for recovery of neurological function. PMID- 25836270 TI - Turning Point of Acute Stroke Therapy: Mechanical Thrombectomy as a Standard of Care. PMID- 25836271 TI - Three Randomized Controlled Trials Confirm the Benefits of Mechanical Endovascular Therapy in Acute Ischemic Stroke. PMID- 25836272 TI - Historical Vignette of Infamous Gunshot Injury to Spine: "An Ailment not to be Treated"? AB - The increasing prevalence and gloomy socioeconomic consequence of spine injury remain a concern in modern medicine. In this article, we highlight the infamous gunshot spinal injuries of a few eminent personalities across multiple centuries and their sociopolitical impact in context with the evolution of modern medicine. The role of available medicine in these victims was not more than a mere watcher, thus substantiating an infamous quote from ancient literature that describes spine injury as "an ailment not to be treated." PMID- 25836273 TI - Time Is Brain: A Critical Analysis of the EXTEND-IA and ESCAPE Trials. PMID- 25836274 TI - We Need to Consult Our Patients with Cervical Spondylotic Myelopathy on Strong Data. PMID- 25836275 TI - Unraveling the genome structure of cyanobacterial podovirus A-4L with long direct terminal repeats. AB - The freshwater cyanobacterial virus (cyanophage) A-4L, a podovirus, can infect the model cyanobacterium Anabaena sp. strain PCC 7120 resulting in a high burst size and forming concentric plaques on its lawns. The complete genome sequence of A-4L was determined by the combination of high-throughput sequencing, terminal transferase-mediated polymerase chain reaction and restriction mapping. It contains 41,750 bp with 810 bp direct terminal repeats and 38 potential open reading frames. As compared with other cyanobacterial podoviruses in diverse ecosystems, the A-4L has the longest terminal repeat and shares similar genome organizations with freshwater members. Furthermore, phylogenetic analysis based on concatenated sequences of eight core proteins indicated that freshwater cyanobacterial podoviruses were clustered together and distinct from marine counterparts, suggesting a clear divergence in the cyanobacterial podovirus lineage between freshwater and marine ecosystems. Our findings uncover the unique genome structure of A-4L which contains long direct terminal repeats, and create the first model system to address knowledge gaps in understanding cyanobacterial virus-host interactions at the molecular level. PMID- 25836276 TI - Functional comparison of RNA silencing suppressor between the p5 protein of rice grassy stunt virus and the p3 protein of rice stripe virus. AB - Rice grassy stunt virus (RGSV) is a member of the genus Tenuivirus, which includes rice stripe virus (RSV), as the type species. A viral suppressor of RNA silencing (VSR) of RGSV has not been identified, whereas the p3 protein of RSV (RSVp3) encoded by the viral-sense (v) strand of RNA3 has been reported to act as a VSR. In this study, we examined the VSR function of the p5 protein of RGSV (RGSVp5), encoded by vRNA5. Expecting it to correspond to the vRNA3 of RSV, we compared the VSR function of RGSVp5 with that of RSVp3. In an Agrobacterium mediated transient expression assay using a transgenic line of Nicotiana benthamiana that expressed green fluorescent protein and the wild type, RGSVp5 suppressed sense transgene-mediated post-transcriptional gene silencing (S-PTGS), inverted-repeat (IR) transgene-induced PTGS (IR-PTGS), and the systemic spread of GFP silencing, as in the case with RSVp3. By contrast, a gel mobility shift assay revealed that RGSVp5 did not have any distinct binding activity with 21-, 22-, or 24-nucleotide small interfering RNA (siRNA) duplexes, whereas RSVp3 binds to all three sizes of siRNA duplexes. Furthermore, the transiently expressed p5 protein fused with GFP was dispersed mainly in the cytoplasm, whereas the GFP-fused p3 protein of RSV was localized both in the nucleus and in the cytoplasm. Our results suggest that RGSVp5 functions as a VSR but that the suppression mechanism of RNA silencing and the subcellular localization of RGSVp5 differ from those of the analogous VSR, RSVp3, even in the same genus. PMID- 25836277 TI - Cellular stress responses in hepatitis C virus infection: Mastering a two-edged sword. AB - Hepatitis C virus (HCV) infection affects chronically more than 150 million humans worldwide. Chronic HCV infection causes severe liver disease and hepatocellular carcinoma. While immune response-mediated events are major players in HCV pathogenesis, the impact that viral replication has on cellular homeostasis is increasingly recognized as a necessary contributor to pathological manifestations of HCV infection such as steatosis, insulin-resistance or liver cancer. In this review, we will briefly overview the different cellular stress pathways that are induced by hepatitis C virus infection, the response that the cell promotes to attempt regaining homeostasis or to induce dysfunctional cell death, and how the virus co-opts these response mechanisms to promote both viral replication and survival of the infected cell. We will review the role of unfolded protein and oxidative stress responses as well as the role of auto- and mitophagy in HCV infection. Finally, we will discuss the recent discovery of a cellular chaperone involved in stress responses, the sigma-1 receptor, as a cellular factor required at the onset of HCV infection and the potential molecular events underlying the proviral role of this cellular factor in HCV infection. PMID- 25836278 TI - N-H...S and C-H...S hydrogen bonds in two tetraalkylammonium dithiobiurea(1-) inclusion compounds. AB - Two inclusion compounds of dithiobiurea and tetrapropylammonium and tetrabutylammonium are characterized and reported, namely tetrapropylammonium carbamothioyl(carbamothioylamino)azanide, C12H28N(+).C2H5N4S2(-), (1), and tetrabutylammonium carbamothioyl(carbamothioylamino)azanide, C16H36N(+).C2H5N4S2( ), (2). The results show that in (1), the dithiobiurea anion forms a dimer via N H...N hydrogen bonds and the dimers are connected into wide hydrogen-bonded ribbons. The guest tetrapropylammonium cation changes its character to become the host molecule, generating pseudo-channels containing the aforementioned ribbons by C-H...S contacts, yielding the three-dimensional network structure. In comparison, in (2), the dithiobiurea anions are linked via N-H...S interactions, producing one-dimensional chains which pack to generate two-dimensional hydrogen bonded layers. These layers accommodate the guest tetrabutylammonium cations, resulting in a sandwich-like layer structure with host-guest C-H...S contacts. PMID- 25836279 TI - Reversible phase transition of 2-carboxypyridinium perchlorate-pyridinium-2 carboxylate (1/1). AB - The title salt, C6H6NO2(+).ClO4(-).C6H5NO2, was crystallized from an aqueous solution of equimolar quantities of perchloric acid and pyridine-2-carboxylic acid. Differential scanning calorimetry (DSC) measurements show that the compound undergoes a reversible phase transition at about 261.7 K, with a wide heat hysteresis of 21.9 K. The lower-temperature polymorph (denoted LT; T = 223 K) crystallizes in the space group C2/c, while the higher-temperature polymorph (denoted RT; T = 296 K) crystallizes in the space group P2/c. The relationship between these two phases can be described as: 2a(RT) = a(LT); 2b(RT) = b(LT); c(RT) = c(LT). The crystal structure contains an infinite zigzag hydrogen-bonded chain network of 2-carboxypyridinium cations. The most distinct difference between the higher (RT) and lower (LT) temperature phases is the change in dihedral angle between the planes of the carboxylic acid group and the pyridinium ring, which leads to the formation of different ten-membered hydrogen-bonded rings. In the RT phase, both the perchlorate anions and the hydrogen-bonded H atom within the carboxylic acid group are disordered. The disordered H atom is located on a twofold rotation axis. In the LT phase, the asymmetric unit is composed of two 2-carboxypyridinium cations, half an ordered perchlorate anion with ideal tetrahedral geometry and a disordered perchlorate anion. The phase transition is attributable to the order-disorder transition of half of the perchlorate anions. PMID- 25836280 TI - Synthesis, crystal structure and magnetic properties of (acetato kappa2O,O')bis(5,5'-dimethyl-2,2'-bipyridine-kappa2N,N')nickel(II) perchlorate monohydrate. AB - The title hydrated ionic complex, [Ni(CH3COO)(C12H12N2)2]ClO4.H2O or [Ni(ac)(5,5' dmbpy)2]ClO4.H2O (where 5,5'-dmbpy is 5,5'-dimethyl-2,2'-bipyridine and ac is acetate), (1), was isolated as violet crystals from the aqueous ethanolic nickel acetate-5,5'-dmbpy-KClO4 system. Within the complex cation, the Ni(II) atom is hexacoordinated by two chelating 5,5'-dmbpy ligands and one chelating ac ligand. The mean Ni-N and Ni-O bond lengths are 2.0628 (17) and 2.1341 (15) A, respectively. The water solvent molecule is disordered over two partially occupied positions and links two complex cations and two perchlorate anions into hydrogen-bonded centrosymmetric dimers, which are further connected by pi-pi interactions. The magnetic properties of (1) at low temperatures are governed by the action of single-ion anisotropy, D, which arises from the reduced local symmetry of the cis-NiO2N4 chromophore. The fitting of the variable-temperature magnetic data (2-300 K) gives g(iso) = 2.134 and D/hc = 3.13 cm(-1). PMID- 25836281 TI - A two-dimensional silver(I) coordination polymer constructed from 4 aminophenylarsonate and triphenylphosphane: poly[[(MU3-4-aminophenylarsonato kappa3N:O:O)(triphenylphosphane-kappaP)silver(I)] monohydrate]. AB - The title compound, {[Ag(C6H7AsNO3)(C18H15P)].H2O}n, has been synthesized from the reaction of 4-aminophenylarsonic acid with silver nitrate, in aqueous ammonia, with the addition of triphenylphosphane (PPh3). The Ag(I) centre is four coordinated by one amino N atom, one PPh3 P atom and two arsonate O atoms, forming a severely distorted [AgNPO2] tetrahedron. Two Ag(I)-centred tetrahedra are held together to produce a dinuclear [Ag2O2N2P2] unit by sharing an O-O edge. 4-Aminophenylarsonate (Hapa(-)) adopts a MU3-kappa(3)N:O:O-tridentate coordination mode connecting two dinuclear units, resulting in a neutral [Ag(Hapa)(PPh3)]n layer lying parallel to the (101) plane. The PPh3 ligands are suspended on both sides of the [Ag(Hapa)(PPh3)]n layer, displaying up and down orientations. There is an R2(2)(8) hydrogen-bonded dimer involving two arsonate groups from two Hapa(-) ligands related by a centre of inversion. Additionally, there are hydrogen-bonding interactions involving the solvent water molecules and the arsonate and amine groups of the Hapa(-) ligands, and weak pi-pi stacking interactions within the [Ag(Hapa)(PPh3)]n layer. These two-dimensional layers are further assembled by weak van der Waals interactions to form the final architecture. PMID- 25836282 TI - Tetrahydroberberine, a pharmacologically active naturally occurring alkaloid. AB - Tetrahydroberberine (systematic name: 9,10-dimethoxy-5,8,13,13a-tetrahydro-6H benzo[g][1,3]benzodioxolo[5,6-a]quinolizine), C20H21NO4, a widely distributed naturally occurring alkaloid, has been crystallized as a racemic mixture about an inversion center. A bent conformation of the molecule is observed, with an angle of 24.72 (5) degrees between the arene rings at the two ends of the reduced quinolizinium core. The intermolecular hydrogen bonds that play an apparent role in crystal packing are 1,3-benzodioxole -CH2...OCH3 and -OCH3...OCH3 interactions between neighboring molecules. PMID- 25836283 TI - Inversion twinning in a second polymorph of the hydrochloride salt of the recreational drug ethylone. AB - A second polymorph of the hydrochloride salt of the recreational drug ethylone, C12H16NO3(+).Cl(-), is reported [systematic name: (+/-)-2-ethylammonio-1-(3,4 methylenedioxyphenyl)propane-1-one chloride]. This polymorph, denoted form (A), appears in crystallizations performed above 308 K. The originally reported form (B) [Wood et al. (2015). Acta Cryst. C71, 32-38] crystallizes preferentially at room temperature. The conformations of the cations in the two forms differ by a 180 degrees rotation about the C-C bond linking the side chain to the aromatic ring. Hydrogen bonding links the cations and anions in both forms into similar extended chains in which any one chain contains only a single enantiomer of the chiral cation, but the packing of the ions is different. In form (A), the aromatic rings of adjacent chains interleave, but pack equally well if neighbouring chains contain the same or opposite enantiomorph of the cation. The consequence of this is then near perfect inversion twinning in the structure. In form (B), neighbouring chains are always inverted, leading to a centrosymmetric space group. The question as to why the polymorphs crystallize at slightly different temperatures has been examined by density functional theory (DFT) and lattice energy calculations and a consideration of packing compactness. The free energy (DeltaG) of the crystal lattice for polymorph (A) lies some 52 kJ mol(-1) above that of polymorph (B). PMID- 25836285 TI - Three cocrystals and a cocrystal salt of pyrimidin-2-amine and glutaric acid. AB - Four new cocrystals of pyrimidin-2-amine and propane-1,3-dicarboxylic (glutaric) acid were crystallized from three different solvents (acetonitrile, methanol and a 50:50 wt% mixture of methanol and chloroform) and their crystal structures determined. Two of the cocrystals, namely pyrimidin-2-amine-glutaric acid (1/1), C4H5N3.C6H8O4, (I) and (II), are polymorphs. The glutaric acid molecule in (I) has a linear conformation, whereas it is twisted in (II). The pyrimidin-2-amine glutaric acid (2/1) cocrystal, 2C4H5N3.C6H8O4, (III), contains glutaric acid in its linear form. Cocrystal-salt bis(2-aminopyrimidinium) glutarate-glutaric acid (1/2), 2C4H6N3(+).C6H6O4(2-).2C6H8O4, (IV), was crystallized from the same solvent as cocrystal (II), supporting the idea of a cocrystal-salt continuum when both the neutral and ionic forms are present in appreciable concentrations in solution. The diversity of the packing motifs in (I)-(IV) is mainly caused by the conformational flexibility of glutaric acid, while the hydrogen-bond patterns show certain similarities in all four structures. PMID- 25836284 TI - Unexpected proline coordination in the copper chain polymer [Cu(MU-Cl)2(MU-DL proline-kappa2O:O')]1infinity. AB - In catena-poly[copper(II)-di-MU-chlorido-MU-proline-kappa(2)O:O'], [CuCl2(C5H9NO2)]n, two symmetry-independent metal cations adopt distorted octahedral coordination, typical for d(9) Jahn-Teller systems. Each chloride bridge is involved in both a short and a very long interaction with a Cu(II) centre. The centrosymmetric crystal structure contains homochiral chains of opposite handedness which extend along the shortest lattice parameter (i.e. a). The O:O'-bridging coordination mode of proline, although a common motif for such complexes in general, is remarkable for Cu(II); the vast majority of amino acid derivatives of this cation are characterized by N,O-chelation. PMID- 25836286 TI - Evidence for stereoelectronic effects in the N-C-N group of 8,10,12-triaza-1 azoniatetracyclo[8.3.1.1(8,12).0(2,7)]pentadecane 4-nitrophenolate 4-nitrophenol monosolvate from the protonation of aminal (2R,7R)-1,8,10,12 tetraazatetracyclo[8.3.1.1(8,12).0(2,7)]pentadecane: X-ray and natural bond orbital analysis. AB - The title molecular salt, C11H21N4(+).C6H4NO3(-).C6H5NO3, (II), crystallizes with two independent three-component aggregates in the asymmetric unit. In the cations, the cyclohexane rings fused to the cage azaadamantane systems both adopt a chair conformation. In the crystal structure, the aggregates are connected by C H...O hydrogen bonds, forming a supramolecular unit enclosing an R4(4)(24) ring motif. These units are linked via C-H...O and C-H...N hydrogen bonds, forming a three-dimensional network. Even hydrogen-bond formation to one of the N atoms is enough to induce structural stereoelectronic effects in the normal donor >acceptor direction. The C-N bond distances provide structural evidence for a strong anomeric effect. The structure also displays O-H...O and N-H...O hydrogen bonding. Geometric optimization and natural bond orbital (NBO) analysis of (II) were undertaken by utilizing DFT/B3LYP with the 6-31+G(d,p) basis set. NBO second order perturbation theory calculations indicate donor-acceptor interactions between nitrogen lone pairs and the antibonding orbital of the C-C and C-N bonds for the protonated polyamine, in agreement with the occurrence of bond-length and bond-angle changes within the aminal cage structure. PMID- 25836287 TI - A three-dimensional cadmium(II) coordination polymer with unequal homochiral double-stranded concentric helical chains. AB - A homochiral helical three-dimensional coordination polymer, poly[[(MU2-acetato kappa(3)O,O':O)(hydroxido-kappaO)(MU4-5-nicotinamido-1H-1,2,3,4-tetrazol-1-ido kappa(5)N(1),O:N(2):N(4):N(5))(MU3-5-nicotinamido-1H-1,2,3,4-tetrazol-1-ido kappa(4)N(1),O:N(2):N(4):N(5))dicadmium(II)] 0.75-hydrate], {[Cd2(C7H5N6O)2(CH3COO)(OH)].0.75H2O}n, was synthesized by the reaction of cadmium acetate, N-(1H-tetrazol-5-yl)isonicotinamide (H-NTIA), ethanol and H2O under hydrothermal conditions. The asymmetric unit contains two crystallographically independent Cd(II) cations, two deprotonated 5-nicotinamido 1H-1,2,3,4-tetrazol-1-ide (NTIA(-)) ligands, one acetate anion, one hydroxide anion and three independent partially occupied water sites. The two Cd(II) cations, with six-coordinated octahedral and seven-coordinated pentagonal bipyramidal geometries are located on general sites. The tetrazole group of one symmetry-independent NTIA(-) ligand links one of the independent Cd(II) cations into 61 helical chains, while the other NTIA(-) ligand links the other independent Cd(II) cations into similar but unequal 61 helical chains. These chains, with a pitch of 24.937 (5) A, intertwine into a double-stranded helix. Each of the double-stranded 61 helices is further connected to six adjacent helical chains through an acetate MU2-O atom and the tetrazole group of the NTIA( ) ligand into a three-dimensional framework. The helical channel is occupied by the isonicotinamide groups of NTIA(-) ligands and two helices are connected to each other through the pyridine N and carbonyl O atoms of isonicotinamide groups. In addition, N-H...O and O-H...N hydrogen bonds exist in the complex. PMID- 25836289 TI - A square-planar hydrated cationic tetrakis(methimazole)gold(III) complex. AB - The cationic pseudo-square-planar complex tetrakis(1-methyl-2,3-dihydro-1H imidazole-2-thione-kappaS)gold(III) trichloride sesquihydrate, [Au(C4H6N2S)4]Cl3.1.5H2O, was isolated as dark-red crystals from the reaction of chloroauric acid trihydrate (HAuCl4.3H2O) with four equivalents of methimazole in methanol. The Au(III) atoms reside at the corners of the unit cell on an inversion center and are bound by the S atoms of four methimazole ligands in a planar arrangement, with S-Au-S bond angles of approximately 90 degrees . PMID- 25836288 TI - A monoclinic form of dendocarbin A: a borderline case of one-dimensional isostructural polymorphism. AB - The title compound, dendocarbin A [systematic name: (1R,5aS,9aS,9bR)-1-hydroxy 6,6,9a-trimethyldodecahydronaphtho[1,2-c]furan-3-one], C15H22O3, is a sesquiterpene lactone isolated from Drimys winteri var chilensis. The monoclinic phase described herein displays an identical molecular structure to the orthorhombic phase that we reported previously [Paz Robles et al. (2014). Acta Cryst. C70, 1007-1010], while varying significantly in chain pitch, and can thus be considered as a borderline case of one-dimensional isostructural polymorphism. PMID- 25836290 TI - Three isotypic polymeric complexes with rare earth cations, but-2-enoate anions and 4,4'-(ethane-1,2-diyl)dipyridine and 4,4'-(ethene-1,2-diyl)dipyridine bridging ligands. AB - Three isotypic rare earth complexes, catena-poly[[aquabis(but-2-enoato kappa(2)O,O')yttrium(III)]-bis(MU-but-2-enoato)-kappa(3)O,O':O;kappa(3)O:O,O' [aquabis(but-2-enoato-kappa(2)O,O')yttrium(III)]-MU-4,4'-(ethane-1,2 diyl)dipyridine-kappa(2)N:N'], [Y2(C4H5O2)6(C12H12N2)(H2O)2], the gadolinium(III) analogue, [Gd2(C4H5O2)6(C12H12N2)(H2O)2], and the gadolinium(III) analogue with a 4,4'-(ethene-1,2-diyl)dipyridine bridging ligand, [Gd2(C4H5O2)6(C12H10N2)(H2O)2], are one-dimensional coordination polymers made up of centrosymmetric dinuclear [M(but-2-enoato)3(H2O)]2 units (M = rare earth), further bridged by centrosymmetric 4,4'-(ethane-1,2-diyl)dipyridine or 4,4'-(ethene-1,2 diyl)dipyridine spacers into sets of chains parallel to the [201] direction. There are intra-chain and inter-chain hydrogen bonds in the structures, the former providing cohesion of the linear arrays and the latter promoting the formation of broad planes parallel to (010). PMID- 25836291 TI - A one-dimensional zinc(II) coordination polymer based on mixed multidentate N- and O-donor ligands. AB - In the title coordination polymer, catena-poly[[bis[{1-[(1H-benzimidazol-2-yl kappaN(3))methyl]-1H-tetrazole}zinc(II)]-bis(MU4-pentane-1,5-dioato 1:2:1':2'kappa(4)O(1):O(1'):O(5):O(5'))] methanol disolvate], {[Zn(C5H6O4)(C9H8N6)].CH3OH}n, each Zn(II) ion is five-coordinated by four O atoms from four glutarate ligands and by one N atom from a 1-[(1H-benzimidazol-2 yl)methyl]-1H-tetrazole (bimt) ligand, leading to a slightly distorted square pyramidal coordination environment. Two Zn(II) ions are linked by four bridging glutarate carboxylate groups to generate a dinuclear [Zn2(CO2)4] paddle-wheel unit. The dinuclear units are further connected into a one-dimensional chain via the glutarate ligands. The bimt ligands coordinate to the Zn(II) ions in a monodentate mode and are pendant on both sides of the main chain. In the crystal, the chains are linked by O-H...O and N-H...O hydrogen bonds into a two dimensional layered structure. Adjacent layers are further packed into a three dimensional network through van der Waals forces. A thermogravimetric analysis was carried out and the photoluminescent behaviour of the polymer was investigated. PMID- 25836292 TI - One- and two-dimensional polymers from proline and calcium bromide. AB - Reactions of calcium bromide with enantiopure and racemic proline in aqueous solution lead to two solids in which the zwitterionic amino acid acts as a bridging ligand between neighbouring cations. Depending on the chirality of the amino acid, topologically very different products are obtained. With racemic proline, bromide acts as a simple uncoordinated counter-anion for the cationic heterochiral chains in catena-poly[[aquacalcium(II)]-MU-aqua-MU3-DL-proline-MU2 DL-proline], {[Ca(C5H9NO2)2(H2O)2]Br2}n. In agreement with chemical intuition, only carboxylate and aqua O atoms coordinate the alkaline earth cation in a low symmetry arrangement. In contrast, L-proline affords the two-dimensional network poly[dibromidobis(MU2-L-proline)calcium(II)], [CaBr2(C5H9NO2)2]n, with an unexpected CaBr2 unit in a more regular coordination sphere. PMID- 25836293 TI - A new two-dimensional anionic cadmium(II) polymer constructed through thiocyanate coordination bridges. AB - A new cadmium-thiocyanate complex, poly[4-(dimethylamino)pyridin-1-ium [di-MU thiocyanato-kappa(2)N:S;kappa(2)S:N-thiocyanato-kappaN-cadmium(II)]], {(C7H11N2)[Cd(NCS)3]}n, was synthesized by the reaction of cadmium thiocyanate and 4-(dimethylamino)pyridine hydrochloride in aqueous solution. In the crystal structure, each Cd(II) ion is square-pyramidally coordinated by three N and two S atoms from five different thiocyanate ligands, four of which are bridging. The thiocyanate ligands play different roles in the build up of the structure; one role results in the formation of [Cd2(NCS)2] building blocks, while the other links the building blocks and cations via N-H...S hydrogen bonds. The N-H...S hydrogen bonds and weak pi-pi stacking interactions are involved in the formation of both a two-dimensional network structure and the supramolecular network. PMID- 25836294 TI - Four oxoindole-linked alpha-alkoxy-beta-amino acid derivatives. AB - Four structures of oxoindolyl alpha-hydroxy-beta-amino acid derivatives, namely, methyl 2-{3-[(tert-butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-methoxy-2 phenylacetate, C24H28N2O6, (I), methyl 2-{3-[(tert-butoxycarbonyl)amino]-1-methyl 2-oxoindolin-3-yl}-2-ethoxy-2-phenylacetate, C25H30N2O6, (II), methyl 2-{3-[(tert butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-[(4-methoxybenzyl)oxy]-2 phenylacetate, C31H34N2O7, (III), and methyl 2-[(anthracen-9-yl)methoxy]-2-{3 [(tert-butoxycarbonyl)amino]-1-methyl-2-oxoindolin-3-yl}-2-phenylacetate, C38H36N2O6, (IV), have been determined. The diastereoselectivity of the chemical reaction involving alpha-diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N-H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether-linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N H...O hydrogen-bond interactions. In contrast, the remaining three structures are sustained by C-H...O hydrogen-bond interactions. PMID- 25836295 TI - An investigation of polyhedral deformation in two mixed-metal diarsenates: SrZnAs2O7 and BaCuAs2O7. AB - Two isostructural diarsenates, SrZnAs2O7 (strontium zinc diarsenate), (I), and BaCuAs2O7 [barium copper(II) diarsenate], (II), have been synthesized under hydrothermal conditions and characterized by single-crystal X-ray diffraction. The three-dimensional open-framework crystal structure consists of corner-sharing M2O5 (M2 = Zn or Cu) square pyramids and diarsenate (As2O7) groups. Each As2O7 group shares its five corners with five different M2O5 square pyramids. The resulting framework delimits two types of tunnels aligned parallel to the [010] and [100] directions where the large divalent nine-coordinated M1 (M1 = Sr or Ba) cations are located. The geometrical characteristics of the M1O9, M2O5 and As2O7 groups of known isostructural diarsenates, adopting the general formula M1(II)M2(II)As2O7 (M1(II) = Sr, Ba, Pb; M2(II) = Mg, Co, Cu, Zn) and crystallizing in the space group P21/n, are presented and discussed. PMID- 25836296 TI - A new phosphorothioic triamide structure: P(S)[NHCH2C6H5]3. AB - The structure of N,N',N''-tribenzylphosphorothioic triamide, C21H24N3PS, (I), and analysis of the bond-angle sums at the N atoms for this compound, and for 74 structures with a P(S)[N]3 skeleton and the N atom in a three-coordinate geometry found in the Cambridge Structural Database [CSD; Groom & Allen (2014). Angew. Chem. Int. Ed. 53, 662-671], are reported. For (I), the bond-angle sum at one of the N atoms [359 (1) degrees ] shows a nearly planar configuration, while the other two show a nonplanar geometry with bond-angle sums of 342 (1) and 347 (1) degrees . The location of the atoms attached to the nonplanar N atoms suggests an anti orientation of the corresponding lone electron pairs (LEPs) on these N atoms with respect to the P=S group. For 74 structures with a P(S)[N]3 skeleton and with the N atom in a three-coordinate geometry, the bond-angle sums at the N atoms were found to be in the range 293-360 degrees . Among 307 such three coordinate N atoms, 39% (120 N atoms) have bond-angle sums in the range 359-360 degrees , in accordance with sp(2) hybridization, and 45% (138 N atoms) have bond angle sums in the range 352-359 degrees , with hybridization close to sp(2). For the orientation of the LEP with respect to the P=S group, the anti orientation was found to be a general rule for N atoms, with the corresponding bond-angle sums deviating by more than 8 degrees from the planar value of 360 degrees . In the title structure, the S atom takes part in intermolecular (N-H...)(N-H...)S hydrogen bonds, connecting the molecules into extended chains parallel to the b axis. The co-operation of one N atom in an N-H...S hydrogen bond as an H-atom donor, and in an N-H...N hydrogen bond as an acceptor, is a novel feature of the crystal structure. PMID- 25836297 TI - Identification of mouse T follicular helper cells by flow cytometry. AB - T follicular helper (Tfh) cells are a subset of CD4(+) T cells that accumulate in the B cell-rich regions of secondary lymphoid organs and provide activation signals essential for long-lived humoral immunity. Herein, we describe a flow cytometric cell-based approach to identify Tfh cells within the total leukocyte population isolated from the spleen, lymph nodes, and Peyer's patches of mice. This protocol focuses on markers that have established relevance in Tfh cell differentiation and function allowing its use across varied settings of infection and immunity. PMID- 25836298 TI - Identification of follicular T helper cells in tissue sections. AB - Follicular T helper (Tfh) cells are a critical population of CD4 T helper cells that are primarily localized in the germinal centers (GCs) to help B cell maturation and antibody production. Tfh cells can be identified in tissue sections based on the expression of a panel of classical Tfh surface makers, transcription marker(s), and effector-function cytokines, as well as by their unique anatomic proximity to other GC cells, including follicular dendritic cells (FDC) and GC B cells. Here, we describe an immunofluorescence staining method for visualization of GC Tfh cells in frozen spleen tissue sections of the autoimmune BXD2 mouse using a confocal imaging strategy. Tfh cells were characterized based on the expression of CD4, CXCR5, Bcl6, IL-21, and IL-17. PMID- 25836299 TI - Tracking early T follicular helper cell differentiation in vivo. AB - T follicular helper (Tfh) cells provide essential help to B cells for the generation of high-affinity antibodies. These mechanisms provide the basis for the success of modern vaccines, but dysregulated Tfh cell responses are also linked to autoimmune diseases. In addition to their established role in driving humoral immunity, Tfh cells are gaining attention for their role in other processes of the adaptive immune system. For example, Tfh cells may serve as transitional differentiation intermediates during effector and memory T-helper cell differentiation and as a reservoir of HIV-infected cells. While B cells are required for the full maturation and maintenance of Tfh cell responses, they are dispensable for the initial induction of the Tfh cell phenotype, which occurs at the priming stage through interaction with dendritic cells. Nevertheless, the precise mechanisms of these early events during Tfh cell differentiation remain relatively unknown. Here, we describe a method for tracking early Tfh cell differentiation by following cell division kinetics and phenotypic changes of recently activated antigen-specific CD4(+) T cells in vivo. As an example, we use this method to visualize the requirements for T cell-expressed CD28 for the differentiation of CXCR5(+)Bcl6(+) Tfh cells. PMID- 25836300 TI - Tracking by flow cytometry antigen-specific follicular helper T cells in wild type animals after protein vaccination. AB - Flow cytometry is a valuable technology used in immunology to characterize and enumerate the different cell subpopulations specific for a nonself-antigen in the context of an ongoing immune response. Among them, follicular helper T cells are the cognate regulators of B cells in secondary lymphoid tissues. Thus, tracking them is of high interest especially in the context of protein vaccination. For this purpose, transgenic antigen-receptor mouse models have been largely used. It is now clear that transgenic models are not always the best means to study the dynamics of the immune response since they can modify the response. In this chapter, we describe how to track endogenous antigen-specific follicular helper T cells by flow cytometry after protein vaccination in nonmodified wild-type animals, which ultimately provides a comprehensive way to enumerate, characterize, and isolate these particular cells in vivo. PMID- 25836301 TI - Retroviral vector expression in TCR transgenic CD4+ T cells. AB - The regulation of gene expression is key to understand the function of genes of interest. To explore the biological functions of genes, transgenic knock-in or knockout technologies have served as invaluable tools. While recent advances in molecular biology have introduced new techniques (i.e., CRISPR mediated gene editing) (Cong et al., Science 339(6121):819-823, 2013; Wang et al., Cell 153(4):910-918, 2013) for the generation of transgenic mice in a relatively short period of time, it can still take a long time to test biological hypotheses from scratch to design how to generate knock-in or knockout mice. Here, we describe methods to manipulate gene expression in T cell receptor (TCR) transgenic CD4 T cells, which allow us to investigate gene functions in the study of differentiation pathways of follicular helper T (Tfh) cells. PMID- 25836302 TI - Two-photon microscopy for imaging germinal centers and T follicular helper cells. AB - One of the principle features of immune cells is their dynamic nature. Lymphocytes circulate in the blood between secondary lymphoid organs and tissues in an effort to maximize the likelihood of a rapid and appropriate immune response to invading pathogens and tissue damage. Conventional experimental techniques such as histology and flow cytometry have greatly increased our understanding of immune cells, but in the last decade, two-photon microscopy has revolutionized our ability to interrogate the dynamic behavior of immune cells, a facet so critical to their function. Two-photon microscopy relies on the excitation of fluorophores by simultaneous application of two photons of longer wavelength light. This allows a greater depth of imaging with minimal photodamage. Thus, living tissues can be imaged, including immune cells in lymph nodes. This technique has been used to interrogate the events occurring in a germinal center response and the interactions between cells in the germinal center, including T follicular helper cells (Tfh), germinal center B cells, and follicular dendritic cells (FDC). Herein, a method is described by which the interactions between Tfh and B cells within a germinal center in a popliteal lymph node can be imaged in a live mouse. PMID- 25836303 TI - In vivo induction of T-follicular helper cells by modulation of regulatory T cell function. AB - Regulatory T cells, particularly their follicular resident subset, T-follicular regulatory cells, play a critical role in the maintenance of immune homeostasis and prevention of the expansion of T-follicular helper cells. One of the key mechanisms used by these cells is CTLA-4 dependent suppression of inflammation. In this chapter, we detail methods to increase the formation of T-follicular helper cells following vaccination by either depleting Treg cells, via Foxp3 linked diphtheria toxin receptor, or blocking CTLA-4 function by the use of antibodies. PMID- 25836304 TI - Assessing T follicular helper cell function in vivo: antigen-specific B cell response to hapten and affinity maturation. AB - The mechanisms controlling affinity maturation have been extensively studied over the last 20 years and the central role of T follicular helper cells (Tfh) in this process has now been clearly established. In order to analyze how Tfh impact on affinity maturation several models have been developed. This chapter aims to present three different techniques to evaluate antigen-specific B cell response and affinity maturation using the NP system: Flow cytometric single cell sorting and sequence analysis, ELISA and ELISpot. They have the advantages of being applicable on all types of mice independently of the presence of a transgenic BCR and to give multiple readout of the antigen-specific immune response and affinity maturation. Although first developed more than 20 years ago, these techniques are still considered to be the gold standard for the analysis of affinity maturation in vivo. PMID- 25836305 TI - The SW(HEL) system for high-resolution analysis of in vivo antigen-specific T dependent B cell responses. AB - T cell-dependent B cell responses generate optimal antibodies to combat foreign antigens. Naive B cells responding to antigen undergo a complex series of differentiation events and cell fate decisions to provide long-lived memory B cells and plasma cells. Historically, B cell biologists have been challenged by the task of investigating rare antigen-specific B cells in an in vivo setting such that their interactions with antigen, regulation and migration may be accurately tracked. We have developed the SW(HEL) experimental system capable of accurately monitoring B cells that interact with a protein antigen and then subsequently undergo isotype switching, somatic hypermutation, and affinity maturation within germinal centers (GC) to generate high-affinity antibodies. Here we provide a comprehensive description of the procedures involved in establishing and using the SW(HEL) system to assess B cell responses to a foreign antigen. This system can provide a valuable measure of the functional capabilities of T follicular helper cells, whose role is ultimately to support and shape long-term humoral immunity. PMID- 25836306 TI - Triggering positive selection of germinal center B cells by antigen targeting to DEC-205. AB - Germinal centers (GCs) are the site of maturation of antibody affinity and are thus of key importance to humoral immunity. The study of B-cell dynamics and selection within the GC has been hampered by the limited number of techniques available to manipulate GC output in vivo. Here, we describe an approach to trigger positive selection of B cells in vivo by targeting antigen specifically to a subpopulation of GC B cells via the surface lectin DEC-205 and forcing their interaction with T follicular helper cells. Targeted GC B cells can then be followed over time as they progress through the stages of positive selection. PMID- 25836307 TI - Detection of mouse natural killer T follicular helper (NKT(FH)) cells by flow cytometry. AB - Natural killer T follicular helper (NKT(FH)) cell, a recently identified B-cell helper innate cell population, can be easily missed due to its low frequency and the fact that it only forms upon immunization or infection with glycolipid containing antigens or microbes. Here, we describe our in-house optimized protocol to detect these mouse NKT(FH) cells by multiparameter flow cytometer. PMID- 25836308 TI - Identification of Foxp3+ T follicular regulatory (Tfr) cells by flow cytometry. AB - Flow cytometry is a technology that allows multiparametric analysis of individual cells. As a consequence, it is among the most commonly used tools for the study of immune cells. It is useful both for the study of ex vivo cell populations isolated from experimental animals or human tissue and for characterizing the phenotype of cultured cells. The phenotypic analysis is based on antibodies associated to different fluorophores that specifically bind to key molecules. Genetically modified mouse strains that express a reporter gene under the control of a promoter of interest offer an important alternative for the staining of intracellular molecules without the need to permeabilize the cell membrane. In this chapter, we describe how Foxp3(+) follicular regulatory T (Tfr) cells, a population of regulatory T (Treg) cells related to T follicular helper (Tfh) cells and involved in the regulation of germinal centers (GC), can be identified by flow cytometry. PMID- 25836309 TI - In vitro assay to sensitively measure T(FR) suppressive capacity and T(FH) stimulation of B cell responses. AB - T follicular helper (T(FH)) cells stimulate, whereas T follicular regulatory (T(FR)) cells inhibit, B cell responses. Despite the potent immunoregulatory roles for TFR cells in controlling the magnitude of antibody production, the precise mechanisms by which T(FR) cells exert their suppressive effects are not yet clear. The lack of specific assays to assess T(FR) cell function separately from differentiation has hindered progress in elucidating T(FR) cell function. This is due, in part, to difficulty in separating T(FR) cells from phenotypically similar, but functionally different, T(FH) cells. Here we describe an in vitro approach for sensitively and quantitatively assessing the capacity of T(FR) cells to suppress T(FH)-mediated B cell antibody production utilizing both ELISA and flow cytometry to measure B cell responses. Beyond assessing T(FR) function, this assay system can also be used to sensitively measure T(FH) stimulatory capacity as well as B cell function. PMID- 25836310 TI - Flow cytometric detection and isolation of human tonsil or lymph node T follicular helper cells. AB - T-follicular helper (Tfh) cells have emerged as an independent CD4(+) helper T cell lineage required for antigen-selected germinal center B-cell survival, class switch recombination, and differentiation into long-lived plasma cells. The quantification and function of Tfh subsets are currently extensively explored in humans with infectious diseases, cancer, or autoimmune disorders. Reliable methods to identify and isolate human Tfh cells in patients and healthy donors are necessary to perform these studies. Here, we propose a classical and robust flow cytometric method to detect and isolate Tfh cells from human secondary lymphoid organs based on the expression of CXCR5, PD-1, and CD25 in the CD4(+) T cell population. An alternative protocol using anti-ICOS and anti-Bcl-6 antibodies and requiring fixation and permeabilization steps without a decrease of detection of membrane markers is also described. PMID- 25836311 TI - Human Tfh and Tfr cells: identification and assessment of their migration potential. AB - The ability of follicular T cells to migrate into B-cell follicles is central for them to participate in germinal center responses. The chemokine receptor CXCR5 is expressed by both Tfh and Tfr cells and is the defining marker for follicular T cells. In addition, Tfh and Tfr cells express additional chemokine receptors to enable them to interact with B cells and other cell types. CXCR5(+) Tfh and Tfr cells are divided into CCR7(+) perifollicular cells and CCR7(-) follicular cells. Most of the CXCR5(+) CCR7(-) Tfh cells reside in germinal centers and are called GC T cells. The methods to identify human Tfh and Tfr cell subsets based on chemokine receptors and other antigens and assess their migration potential are provided in this article. PMID- 25836312 TI - Analysis of human blood memory T follicular helper subsets. AB - Human blood contains a memory counterpart of T follicular helper (T(FH)) cells. Blood T(FH) cells are composed of subsets that differ in phenotype and function. Recent studies show that analysis of blood circulating memory T(FH) cells can provide clues to understand the mode of actions of vaccines and the pathogenesis of human autoimmune diseases. We will describe here a detailed protocol to analyze the memory T(FH) subsets in human whole blood samples. We will also describe a protocol to assess the helper capacity of blood memory T(FH) subsets. PMID- 25836313 TI - Flow cytometric analysis of circulating follicular helper T (Tfh) and follicular regulatory T (Tfr) populations in human blood. AB - Follicular helper T (Tfh) cells are the helper T-cell subset that localizes in germinal centers within secondary lymphoid organs. They support B cells to produce high-affinity antibodies and generate B-cell memory. By contrast, follicular regulatory T (Tfr) cells localize in germinal centers to suppress B cell responses. Coordinately regulating antibody responses, Tfh and Tfr cells play a critical role for vaccination, infectious disease control, and the development of autoimmune diseases. Although bona fide Tfh and Tfr cells are hardly detected in human blood, circulating Tfh and Tfr memory cells in blood can be used to investigate their functions in health and disease. We have developed a comprehensive flow cytometric analysis to define different circulating Tfh and Tfr populations within CXCR5(+) CD4(+) T-cell population in human blood, based on numerous cell surface markers including CD25, CD127, CCR7, PD-1, CXCR3, and CCR6. PMID- 25836314 TI - Quantifying helper cell function of human TFH cells in vitro. AB - Blood-circulating CXCR5(+) CD4(+) T cells and T follicular helper (TFH) cells, which participate in germinal center (GC) reactions within secondary lymphoid organs, are specialized in providing help to B cells. This chapter describes ways to isolate TFH-like cells out of peripheral blood or tonsils and to quantify their B cell helper function. This comprises different co-culture approaches of TFH-like cells and B cells and the evaluation of their capacity to induce immunoglobulin secretion and plasma cell differentiation. In addition, B cell helper function of CD4 T cells can be estimated indirectly by quantifying the expression of B cell helper cytokines and co-stimulatory and TFH-associated molecules. PMID- 25836315 TI - Effect of young sibling visitation on respiratory syncytial virus activity in a NICU. AB - OBJECTIVE: To determine whether the restriction of young sibling (<13 years) visitation in the neonatal intensive care unit (NICU) during the respiratory syncytial virus (RSV) season was associated with a reduction in the rate of RSV infection among NICU patients. STUDY DESIGN: A retrospective chart review of all RSV positive infants from the 2001-2010 RSV seasons. The 2001-2006 RSV seasons (group 1) contained 639 admissions and the 2007-2010 (group 2, with sibling restriction) contained 461 admissions. Groups were compared by using the Fisher's Exact Test. RESULTS: There was a reduction of RSV positive infants from 6.7% in Group 1 to 1.7% in Group 2 (P<0.0001). There was a reduction of symptomatic infants from the number of infants with symptomatic RSV infection from 23/639 infants with young sibling visitation to 2/461 (P<0.001). CONCLUSION: Exclusion of young sibling visitors <13 years of age during RSV season was associated with a significant reduction in the number of RSV positive infants in the NICU. PMID- 25836316 TI - Maternal pregnancy weight gain and cord blood iron status are associated with eosinophilia in infancy. AB - OBJECTIVE: Allergic disease is multifactorial in origin. Because iron nutrition affects immune responses and maternal pregnancy weight gain impairs fetal iron delivery while increasing fetal demands for growth, the study examined maternal pregnancy weight gain, newborn iron status and an index of atopic disease, infant eosinophilia. STUDY DESIGN: Within a larger prospective study of healthy newborns at risk for developing iron deficiency anemia, umbilical cord iron indicators were compared to infant eosinophil counts. RESULT: Infants who developed eosinophilia exhibited higher cord reticulocyte-enriched zinc protoporphyrin/heme ratio, P<0.05 and fewer cord ferritin values in the highest (best) quartile, P<0.05. If cord ferritin was in the upper three quartiles, the negative predictive value for infant eosinophilia was 90%. High maternal pregnancy weight gain predicted infant eosinophil counts, P<0.04, and contributed to cord ferritin predicting eosinophilia, P<0.003. CONCLUSION: Poor fetal iron status may be an additional risk factor for infant eosinophilia. PMID- 25836317 TI - Growth and developmental outcome of infants with in-utero exposure to methadone vs buprenorphine. AB - OBJECTIVE: To compare early growth and developmental outcome of infants with in utero exposure to low-dose methadone (<100 mg per day), high-dose methadone (?100 mg per day) and buprenorphine. STUDY DESIGN: A retrospective review of infants with in-utero methadone and buprenorphine exposure who were evaluated at the Southcoast Developmental Pediatric clinic in New Bedford, MA, USA was completed. Growth data and developmental testing results during infancy were compared among the groups. RESULT: Infants in the high-dose methadone group had lower head circumference z scores and a lower mean score on the Alberta Infant Motor Scale (AIMS). Regression results confirmed an association between methadone dose and head circumference z score and AIMS score. CONCLUSION: Exposure to maternal methadone dose in excess of 100 mg is associated with a reduction in infant head circumference when compared with buprenorphine or lower dose methadone, and may have a negative impact on motor skill development during early infancy. PMID- 25836318 TI - Prospective, controlled study of an intervention to reduce errors in neonatal antibiotic orders. AB - OBJECTIVE: To evaluate the effectiveness of an interactive computerized order set with decision support (ICOS-DS) in preventing medication errors in neonatal late onset sepsis (LOS). STUDY DESIGN: Prospective, controlled comparison of error rates in antibiotic orders for neonates admitted to the Medical University of South Carolina neonatal intensive care unit with suspected LOS (after postnatal day of life 3) prior to (n=153) and after (n=146) implementation of the ICOS-DS. Antibiotic orders were independently evaluated by two pharmacists for prescribing errors, potential errors and omissions. Prescribing errors included>10% overdoses or underdoses, inappropriate route, schedule or antibiotic, drug-drug or drug disease interactions, and incorrect patient demographics. Potential errors included misspelled drugs, leading decimals, trailing zeroes, impractical doses and error-prone abbreviations. Multiple errors and omissions in an order were counted individually. RESULTS: Overall error rate per order decreased from 1.7 to 0.8 (P<0.001) and potential error rate from 1.0 to 0.06 (P<0.001). The reduction in omission error rate per order from 0.2 to 0.1 was not significant (P=0.17). The prescribing error rate per order increased from 0.4 to 0.7 (P=0.03) because of the use of incorrect patient weights (P<0.001). Renal dysfunction was significantly associated with an increased risk of prescribing errors (odds ratio=3.7, P=0.01) which was not significantly different for handwritten versus ICOS-DS orders (P=0.15). CONCLUSIONS: The ICOS-DS significantly improved the quality of neonatal LOS antibiotic orders although the use of incorrect patient weights was increased. In both groups, orders for patients with renal dysfunction were at risk for prescribing errors. Further evaluation of interventions to promote medication safety for this population is needed. PMID- 25836319 TI - Standard methods based on last menstrual period dates misclassify and overestimate US preterm births. AB - OBJECTIVE: To compare number of US preterm births based on obstetric versus last menstrual period (LMP) estimates and evaluate their correlations with clinical risk indicators associated with prematurity. STUDY DESIGN: Preterm births were assessed from LMP, per standard practice, and, separately, from obstetric estimates using the 2012 Natality Public Use File. Percentages of infants with neonatal intensive care unit (NICU) admission and low birth weight (LBW) were calculated. RESULT: More births were <37 weeks gestational age (GA) by reported LMP (11.4%) versus obstetric estimates (9.5%). Among infants preterm by LMP, but born at 37-41 weeks by obstetric estimates, there were 5.7% NICU admission and 7.7% LBW rates versus 25.2% and 35.4%, respectively, of those preterm by obstetric estimates but born 37-41 weeks by LMP assessments. CONCLUSION: Obstetric estimates provide the most clinically relevant estimates of US preterm births. Assessments calculated from LMP alone may overestimate prematurity incidence by ~20%. PMID- 25836320 TI - The impact of altitude on birth weight depends on further mother- and infant related factors: a population-based study in an altitude range up to 1600 m in Austria between 1984 and 2013. AB - OBJECTIVE: A negative impact of altitude on birth weight has been demonstrated for medium to high-altitude countries. STUDY DESIGN: The present study aims to show a similar effect for a lower altitude range up to 1600 m in the country of Austria and to adjust for several further risk factors related to mother and infant. In addition, we analyzed whether the effect of altitude influenced birth weight independently or interacted with other factors. For the purpose of this study, almost 1.9 million individual birth certificates of Austrian newborns born between 1984 and 2013 were analyzed. In a multivariate linear regression model, birth weight was associated with altitude of living address and following variables: sex, birth length, gestational age, level of education, maternal age, year of birth, parity, time to previous birth and marital status. RESULT: Birth weight decreased by 150 g/1000 m altitude, demonstrating a clear effect of altitude on birth weight also in a low to medium altitude level. Additionally, we could show that this effect also depends on other factors, namely gestational age, education of the mother, sex, birth length, year of birth and time to previous delivery. All variables interacted significantly (p<0.0001) with altitude. CONCLUSION: We observed a negative effect of altitude in an altitude range up to 1600 m. Furthermore, this effect also depends on other risk factors. Therefore, unadjusted estimates as described in many studies may be biased. This population-based study describes the effect of low-to-medium altitude on birth weight in central Europe over a period of 30 years. PMID- 25836321 TI - ADHD and developmental speech/language disorders in late preterm, early term and term infants. AB - OBJECTIVE: We sought to compare the long-term neurodevelopmental outcomes of late preterm, early term and term infants while controlling for a wide range of maternal complications and comorbidities. STUDY DESIGN: Data for the study was obtained from the South Carolina Medicaid claims and vital records databases from 1 January 2000 to 31 December 2003. We included infants weighing between 1500 and 4500 g, born between 34 0/7 and 41 6/7 weeks, and with no congenital anomalies. Outcome measures were based on the presence of ICD-9-CM codes for attention deficit hyperactivity disorders and developmental speech or language disorders. RESULT: A total of 3270 late preterm (LPIs), 11,527 early term (ETIs) and 24,005 term infants met the eligibility criteria. Rates for all outcome variables were statistically significant and elevated for LPI, but adjusted hazard ratios (AHRs) were only significant for the risk of developmental speech and/or language delay (LPI: AHR 1.36 95% confidence interval (CI) 1.23 to 1.50; ETI: AHR 1.27 95% CI 1.17 to 1.37). CONCLUSION: Late preterm and early term deliveries have adverse long-term neurodevelopmental outcomes, and these outcomes should be considered when determining the timing of delivery. PMID- 25836322 TI - Lost in translation? English- and Spanish-speaking women's perceptions of gestational weight gain safety, health risks and counseling. AB - OBJECTIVE: To determine English- and Spanish-speaking women's perceptions on gestational weight gain (GWG) counseling. STUDY DESIGN: We administered a written survey to 279 pregnant women regarding GWG counseling and knowledge. We compared English- and Spanish-speaking women's responses using X(2)-tests and logistic regression analyses. RESULT: Seventy-four (27%) women completed the survey in Spanish and 205 (73%) in English. More Spanish compared with English speakers did not know if their provider recommended weight gain goals (26% vs 10%, odds ratio (OR) 3.2, confidence interval (CI) 1.5 to 6.5); if there are risks to excessive GWG for mother (27% vs 11%, OR 3.1, CI 1.5 to 6.4) or infant (38% vs 16%, OR 3.3, CI 1.7 to 6.3); or if exercise (15% vs 1%, OR 12.1, CI 3.0 to 69.1) or weight loss (35% v 12%, OR 4.0, CI 2.0 to 8.0) were safe during pregnancy. CONCLUSION: Significant differences exist between Spanish- and English-speaking women's perception of GWG counseling, which may be due to language or cultural barriers. PMID- 25836323 TI - Ovarian embryonal rhabdomyosarcoma is a rare manifestation of the DICER1 syndrome. AB - Embryonal rhabdomyosarcoma (ERMS), a soft tissue sarcoma, is one of the most common pediatric cancers. Certain ERMSs are associated with the DICER1 syndrome, a tumor predisposition syndrome caused by germ-line DICER1 mutations. Characteristic somatic mutations have also been identified in DICER1-associated tumor types. These "hotspot" mutations affect the catalytic activity of the DICER1 ribonuclease IIIb domain. Primary ovarian ERMS (oERMS) is extremely rare. We present a case of a 6-year-old girl with an oERMS harboring 2 DICER1 mutations. The girl also exhibited other DICER1 phenotypes: cystic nephroma (CN) and multinodular goiter. Somatic investigations of the CN identified a hotspot DICER1 mutation different from that in the oERMS. Significantly, the CN presented at 12 years of age, which is much older than the previously reported age range of susceptibility. This report documents the occurrence of DICER1 mutations in a case of oERMS, expanding the spectrum of DICER1-associated tumors. PMID- 25836324 TI - [Molecular pathology for breast cancer: Importance of the gene expression profile]. AB - Gene expression arrays are currently used to guide therapy decisions in breast cancer. The indications for gene expression tests are especially important in the group of hormone receptor negative, HER2 positive tumors to decide whether endocrine therapy alone is sufficient or additional chemotherapy is necessary. In this group of luminal tumors conventional clinicopathological parameters are often not suitable to select patients who would benefit from an endocrine therapy alone. Gene expression tests can provide additional information and, therefore, support decision-making and avoid unnecessary chemotherapy. There are a variety of test systems available which poses the questions of which tests should be selected for which patients and how the test results should be evaluated in a direct comparison. This report provides information about three currently available gene expression tests (i.e. OncotypeDx(r), Endopredict(r) and PAM50/Prosigna(r)), comments on similarities and differences and discusses the impact on therapy decisions. The focus of this article is on a discussion of clinical studies that have compared the different molecular tests in the same clinical study cohort. These investigations allow a first comparative evaluation of the various assays for breast cancer. PMID- 25836325 TI - Amplified electron transfer at poly-ethylene-glycol (PEG) grafted electrodes. AB - "Amplified" electron transfer is observed purely based on electron transfer kinetic effects at modified carbon surfaces. An anodic attachment methodology is employed to modify the surface of glassy carbon or boron doped diamond electrodes with poly-ethylene glycols (PEGs) for polymerisation degrees of n = 4.5 to 9.1 (PEG200 to PEG400). Voltammetry and impedance data for aqueous Fe(CN)6(3-/4-) suggest systematic PEG structure-dependent effects on the standard rate constant for heterogeneous electron transfer as a function of PEG deposition conditions and average polymer chain length. Tunnel distance coefficients are polymerisation degree dependent and estimated for shorter PEG chains, beta = 0.17 A(-1) for aqueous Fe(CN)6(3-/4-), consistent with a diffuse water-PEG interface. In contrast, electron transfer to 1,1'-ferrocene-dimethanol (at 1 mM concentration) appears un-impeded by PEG grafts. Mediated or "amplified" electron transfer to Fe(CN)6(3-/4-) based on the 1,1'-ferrocene-dimethanol redox shuttle is observed for both oxidation and reduction with estimated bimolecular rate constants for homogeneous electron transfer of kforward = 4 * 10(5) mol dm(3) s(-1) and kbackward = 1 * 10(5) mol dm(3) s(-1). Digital simulation analysis suggests an additional resistive component within the PEG graft double layer. PMID- 25836326 TI - The second best arterial graft to the left coronary system in off-pump bypass surgery: a propensity analysis of the radial artery with a proximal anastomosis to the ascending aorta versus the right internal thoracic artery. AB - OBJECTIVE: The second best arterial graft to the left coronary artery (LCA) system between the radial artery (RA) and the right internal thoracic artery (RITA) has been unknown. Moreover, a composite RA may be inferior to direct aorta RA bypass grafting. The aim of the present study is to compare clinical outcomes between the RA anastomosed to the aorta and the RITA as a second arterial graft to the LCA. METHODS: A total of 805 patients received off-pump coronary arterial bypass grafting between 2000 and 2013. Of these patients, 232 received the bilateral internal thoracic arteries (BITA) and 152 received left internal thoracic arteries (LITA) + RA anastomosed to the aorta, following the inclusion criteria. Patients (1) received at least two arterial grafts in the LCA, (2) did not have renal insufficiency, and (3) did not receive composite RA grafts. A propensity score-matched analysis was performed, resulting in 118 matched pairs. RESULTS: There was no difference in operative mortality and stroke rate between the matched groups; however, the mean operation time was significantly shorter in the LITA + RA and the incidence of mediastinitis was lower in the LITA + RA (BITA: 2.5 %, LITA + RA: 0 %, p < 0.01). Kaplan-Meier cumulative mortality and freedom from cardiac events were similar. The long-term patency rates of the RITA and the RA were similar at 5 years (RITA: 78 %, RA: 84 %, p = 0.55). CONCLUSIONS: The RA anastomosed to the aorta appears to have good long-term outcomes, similar to the RITA as the second arterial graft. Furthermore, the choice of RA avoids sternal complications and shortens the operation time compared to the use of BITA. PMID- 25836327 TI - Akira Masaoka (1930-2014): a great surgeon and a special musician. PMID- 25836328 TI - A modified Bentall procedure in a patient with a displaced left coronary ostium. AB - We encountered a 63-year-old female in whom the left coronary ostium was located close to the commissure between the right and left coronary cusps, and performed aortic root replacement leaving the left coronary artery and surrounding the sinus of Valsalva. The sinus of Valsalva, prosthetic valve cuff, and prosthetic vessel were sutured together when the region other than the left coronary artery containing sinus of Valsalva was sutured. The hemostatic effect of our procedure, which is for cases in which preparation of a coronary button is difficult, was favorable and antegrade coronary arterial blood flow could be maintained. PMID- 25836329 TI - Pulmonary metastasectomy: outcomes and issues according to the type of surgical resection. AB - According to a recent report by the Committee for Scientific Affairs of the Japanese Association for Thoracic Surgery, pulmonary metastasectomy accounted for as many as 10.2 % of all entry cases of general thoracic surgery, and its use is increasing year by year. Accordingly, many studies have examined the surgical procedures used during pulmonary metastasectomy for metastases from primary tumors affecting various organs as well as the outcomes of and indications for such procedures, but some problems remain. In this article, the following questions related to the surgical approach and the type of resection used during pulmonary metastasectomy are reviewed: (1) Wedge resection--what is a safe margin for preventing local recurrence? (2) What is the clinical significance of node sampling/dissection during pulmonary metastasectomy? and (3) When is segmentectomy necessary? In addition, we discuss: (4) open thoracotomy vs. video assisted thoracoscopic surgery (VATS), (5) repeated metastasectomy for pulmonary metastases, (6) the surgical approach for bilateral pulmonary metastasectomy, (7) pneumonectomy, and (8) pulmonary metastasectomy combined with resection of the neighboring organs. PMID- 25836330 TI - TGF-beta suppression of HBV RNA through AID-dependent recruitment of an RNA exosome complex. AB - Transforming growth factor (TGF)-beta inhibits hepatitis B virus (HBV) replication although the intracellular effectors involved are not determined. Here, we report that reduction of HBV transcripts by TGF-beta is dependent on AID expression, which significantly decreases both HBV transcripts and viral DNA, resulting in inhibition of viral replication. Immunoprecipitation reveals that AID physically associates with viral P protein that binds to specific virus RNA sequence called epsilon. AID also binds to an RNA degradation complex (RNA exosome proteins), indicating that AID, RNA exosome, and P protein form an RNP complex. Suppression of HBV transcripts by TGF-beta was abrogated by depletion of either AID or RNA exosome components, suggesting that AID and the RNA exosome involve in TGF-beta mediated suppression of HBV RNA. Moreover, AID-mediated HBV reduction does not occur when P protein is disrupted or when viral transcription is inhibited. These results suggest that induced expression of AID by TGF-beta causes recruitment of the RNA exosome to viral RNP complex and the RNA exosome degrades HBV RNA in a transcription-coupled manner. PMID- 25836331 TI - High ionic strength depresses muscle contractility by decreasing both force per cross-bridge and the number of strongly attached cross-bridges. AB - An increase in ionic strength (IS) lowers Ca(2+) activated tension in muscle fibres, however, its molecular mechanism is not well understood. In this study, we used single rabbit psoas fibres to perform sinusoidal analyses. During Ca(2+) activation, the effects of ligands (ATP, Pi, and ADP) at IS ranging 150-300 mM were studied on three rate constants to characterize elementary steps of the cross-bridge cycle. The IS effects were studied because a change in IS modifies the inter- and intra-molecular interactions, hence they may shed light on the molecular mechanisms of force generation. Both the ATP binding affinity (K1) and the ADP binding affinity (K 0) increased to 2-3x, and the Pi binding affinity (K5) decreased to 1/2, when IS was raised from 150 to 300 mM. The effect on ATP/ADP can be explained by stereospecific and hydrophobic interaction, and the effect on Pi can be explained by the electrostatic interaction with myosin. The increase in IS increased cross-bridge detachment steps (k2 and k-4), indicating that electrostatic repulsion promotes these steps. However, IS did not affect attachment steps (k-2 and k4). Consequently, the equilibrium constant of the detachment step (K2) increased by ~100%, and the force generation step (K4) decreased by ~30%. These effects together diminished the number of force generating cross-bridges by 11%. Force/cross-bridge (T56) decreased by 26%, which correlates well with a decrease in the Debye length that limits the ionic atmosphere where ionic interactions take place. We conclude that the major effect of IS is a decrease in force/cross-bridge, but a decrease in the number of force generating cross-bridge also takes place. The stiffness during rigor induction did not change with IS, demonstrating that in-series compliance is not much affected by IS. PMID- 25836332 TI - Why do workaholics experience depression? A study with Chinese University teachers. AB - This study focuses on the relationships of workaholism to job burnout and depression of university teachers. The direct and indirect (via job burnout) effects of workaholism on depression were investigated in 412 Chinese university teachers. Structural equation modeling and bootstrap method were used. Results revealed that workaholism, job burnout, and depression significantly correlated with each other. Structural equation modeling and bootstrap test indicated the partial mediation role of job burnout on the relationship between workaholism and depression. The findings shed some light on how workaholism influenced depression and provided valuable evidence for prevention of depression in work. PMID- 25836333 TI - Hay fever in childhood, traits Neuroticism and Conscientiousness as independent predictors of the occurrence of hay fever in adulthood. AB - The study investigated the associations between social and psychological factors in childhood and adulthood and the occurrence of adulthood hay fever in a longitudinal birth cohort study. A total of 5780 participants with data on parental social class, childhood hay fever up to age 7 years, childhood cognitive ability at age 11 years, educational qualifications at age 33 years, personality traits, occupational levels and adult hay fever (all measured at age 50 years) were included in the study. Using logistic regression analyses, results showed that childhood hay fever identified by medical doctors and traits Emotional Stability and Conscientiousness were significantly and independently associated with the occurrence of hay fever in adulthood. PMID- 25836334 TI - Opisthorchiasis: an overlooked danger. PMID- 25836335 TI - TAT and HA2 facilitate cellular uptake of gold nanoparticles but do not lead to cytosolic localisation. AB - The methods currently available to deliver functional labels and drugs to the cell cytosol are inefficient and this constitutes a major obstacle to cell biology (delivery of sensors and imaging probes) and therapy (drug access to the cell internal machinery). As cell membranes are impermeable to most molecular cargos, viral peptides have been used to bolster their internalisation through endocytosis and help their release to the cytosol by bursting the endosomal vesicles. However, conflicting results have been reported on the extent of the cytosolic delivery achieved. To evaluate their potential, we used gold nanoparticles as model cargos and systematically assessed how the functionalisation of their surface by either or both of the viral peptides TAT and HA2 influenced their intracellular delivery. We evaluated the number of gold nanoparticles present in cells after internalisation using photothermal microscopy and their subcellular localisation by electron microscopy. While their uptake increased when the TAT and/or HA2 viral peptides were present on their surface, we did not observe a significant cytosolic delivery of the gold nanoparticles. PMID- 25836336 TI - Evaluation of interictal autonomic function during attack and remission periods in cluster headaches. AB - OBJECTIVE: To investigate which part of the autonomic system is mainly involved and assess the sensitivity of face sympathetic skin response in cluster headache. MATERIAL AND METHODS: The study sample consisted of 19 drug-free cluster headache patients (16 males, three females) and 19 healthy volunteers. Demographic features and pain characteristics were thoroughly identified. Dysautonomic symptoms were evaluated during attack and remission periods of cluster headache patients. Orthostatic hypotension, R-R interval variation and sympathetic skin responses obtained from the face and four extremities were evaluated and the sensitivity of face sympathetic skin responses was assessed in contrast to extremity sympathetic skin responses. RESULTS: All sympathetic skin responses of face and extremities could be obtained during attack and remission periods. On the symptomatic side, mean latency of face sympathetic skin responses was longer compared to the asymptomatic side and controls (p = 0.02, p = 0.004). There were no differences in latency or amplitude of extremity sympathetic skin responses between symptomatic and asymptomatic sides and controls. No significant relationship was determined between sympathetic skin responses, R-R interval variation, orthostatic hypotension and cluster headache clinical features. CONCLUSION: Sympathetic hypoactivity of the face seems to predominate the pathophysiology of cluster headache. Face sympathetic skin responses might be more sensitive compared to extremity sympathetic skin response in demonstrating dysautonomic symptoms in cluster headache patients. PMID- 25836337 TI - The effects of drought and shade on the performance, morphology and physiology of Ghanaian tree species. AB - In tropical forests light and water availability are the most important factors for seedling growth and survival but an increasing frequency of drought may affect tree regeneration. One central question is whether drought and shade have interactive effects on seedling growth and survival. Here, we present results of a greenhouse experiment, in which seedlings of 10 Ghanaian tree species were exposed to combinations of strong seasonal drought (continuous watering versus withholding water for nine weeks) and shade (5% irradiance versus 20% irradiance). We evaluated the effects of drought and shade on seedling survival and growth and plasticity of 11 underlying traits related to biomass allocation, morphology and physiology. Seedling survival under dry conditions was higher in shade than in high light, thus providing support for the "facilitation hypothesis" that shade enhances plant performance through improved microclimatic conditions, and rejecting the trade-off hypothesis that drought should have stronger impact in shade because of reduced root investment. Shaded plants had low biomass fraction in roots, in line with the trade-off hypothesis, but they compensated for this with a higher specific root length (i.e., root length per unit root mass), resulting in a similar root length per plant mass and, hence, similar water uptake capacity as high-light plants. The majority (60%) of traits studied responded independently to drought and shade, indicating that within species shade- and drought tolerances are not in trade-off, but largely uncoupled. When individual species responses were analysed, then for most of the traits only one to three species showed significant interactive effects between drought and shade. The uncoupled response of most species to drought and shade should provide ample opportunity for niche differentiation and species coexistence under a range of water and light conditions. Overall our greenhouse results suggest that, in the absence of root competition shaded tropical forest tree seedlings may be able to survive prolonged drought. PMID- 25836338 TI - Direct Aqueous-Phase Synthesis of Sub-10 nm "Luminous Pearls" with Enhanced in Vivo Renewable Near-Infrared Persistent Luminescence. AB - Near-infrared (NIR) persistent luminescence nanoparticles (PLNPs), possessing unique NIR PL properties, have recently emerged as important materials for a wide variety of applications in chemistry and biology, for which they must endure high temperature solid-state annealing reactions and subsequent complicated physical post-treatments. Herein, we report on a first direct aqueous-phase chemical synthesis route to NIR PLNPs and present their enhanced in vivo renewable NIR PL. Our method leads to monodisperse PLNPs as small as ca. 8 nm. Such sub-10 nm nanocrystals are readily dispersed and functionalized, and can form stable colloidal solutions in aqueous solution and cell culture medium for biological applications. Under biotissue-penetrable red-light excitation, we found that such nanocrystals possess superior renewable PL photoluminescence in vitro and in vivo compared to their larger counterparts currently made by existing methods. We believe that this solid-state-reaction-free chemical approach overcomes the current key roadblock in regard to PLNP development, and thus will pave the way to broad use of these advanced miniature "luminous pearls" in photonics and biophotonics. PMID- 25836340 TI - Fano resonances in hexagonal zigzag graphene rings under external magnetic flux. AB - We study transport properties of hexagonal zigzag graphene quantum rings connected to semi-infinite nanoribbons. Open two-fold symmetric structures support localized states that can be traced back to those existing in the isolated six-fold symmetric rings. Using a tight-binding Hamiltonian within the Green's function formalism, we show that an external magnetic field promotes these localized states to Fano resonances with robust signatures in transport. Local density of states and current distributions of the resonant states are calculated as a function of the magnetic flux intensity. For structures on corrugated substrates we analyze the effect of strain by including an out-of plane centro-symmetric deformation in the model. We show that small strains shift the resonance positions without further modifications, while high strains introduce new ones. PMID- 25836339 TI - Low Physical Function in Maintenance Hemodialysis Patients Is Independent of Muscle Mass and Comorbidity. AB - OBJECTIVES: It is unknown whether muscle wasting accounts for impaired physical function in adults on maintenance hemodialysis (MHD). DESIGN: Observational study. SETTING: Outpatient dialysis units and a fall clinic. SUBJECTS: One hundred eight MHD and 122 elderly nonhemodialysis (non-HD) participants. EXPOSURE VARIABLE: Mid-thigh muscle area was measured by magnetic resonance imaging. MAIN OUTCOME MEASURE: Physical function was measured by distance walked in 6 minutes. RESULTS: Compared with non-HD elderly participants, MHD participants were younger (49.2 +/- 15.8 vs. 75.3 +/- 7.1 years; P < .001) and had higher mid-thigh muscle area (106.2 +/- 26.8 vs. 96.1 +/- 21.1 cm2; P = .002). However, the distance walked in 6 minutes was lower in MHD participants (322.9 +/- 110.4 vs. 409.0 +/- 128.3 m; P < .001). In multiple regression analysis adjusted for demographics, comorbid conditions, and mid-thigh muscle area, MHD patients walked significantly less distance (-117 m; 95% confidence interval: -177 to -56 m; P < .001) than the non-HD elderly. CONCLUSIONS: Even when compared with elderly non-HD participants, younger MHD participants have poorer physical function that was not explained by muscle mass or comorbid conditions. We speculate that the uremic milieu may impair muscle function independent of muscle mass. The mechanism of impaired muscle function in uremia needs to be established in future studies. PMID- 25836341 TI - Effect of archwire cross-section changes on force levels during complex tooth alignment with conventional and self-ligating brackets. AB - INTRODUCTION: Our objective was to investigate the effect of archwire cross section increases on the levels of force applied to teeth during complex malalignment correction with various archwire-bracket combinations using an experimental biomechanical setup. METHODS: The study comprised 3 types of orthodontic brackets: (1) conventional ligating brackets (Victory Series [3M Unitek, Monrovia, Calif] and Mini-Taurus [Rocky Mountain Orthodontics, Denver, Colo]), (2) self-ligating brackets (SmartClip, a passive self-ligating bracket [3M Unitek]; and Time3 [Rocky Mountain Orthodontics, Denver, Colo] and SPEED [Strite Industries, Cambridge, Ontario, Canada], both active self-ligating brackets), and (3) a conventional low-friction bracket (Synergy [Rocky Mountain Orthodontics]). All brackets had a nominal 0.022-in slot size. The brackets were combined with 0.014-in and 0.016-in titanium memory wires, Therma-Ti archwires (American Orthodontics, Sheboygan, Wis). The archwires were tied to the conventional brackets with both stainless steel ligatures of size 0.010-in and elastomeric rings. A malocclusion of the maxillary central incisor displaced 2 mm gingivally (x-axis) and 2 mm labially (z-axis) was simulated. RESULTS: The forces recorded when using the 0.014-in archwires ranged from 1.7 +/- 0.1 to 5.0 +/- 0.3 N in the x-axis direction, and from 1.2 +/- 0.1 to 5.5 +/- 0.3 N in the z-axis direction. When we used the 0.016-in archwires, the forces ranged from 2.6 +/- 0.1 to 6.0 +/- 0.3 N in the x-axis direction, and from 2.0 +/- 0.2 to 6.0 +/- 0.4 N in the z-axis direction. Overall, the increases ranged from 16.0% to 120.0% in the x-axis and from 10.4% to 130.0% in the z-axis directions. CONCLUSIONS: Increasing the cross section of the wire increased the force level invariably with all brackets. Wires of size 0.014 in produced relatively high force levels, and the force level increased with 0.016-in wires. PMID- 25836342 TI - Consecutive condylectomy and molar intrusion using temporary anchorage devices as an alternative for correcting facial asymmetry with condylar hyperplasia. AB - This case report demonstrates the successful treatment of facial asymmetry with condylar hyperplasia with limited surgical and orthodontic treatment. A high condylectomy was performed to shorten the elongated condyle and to remove its active growth site. The maxillary molars on the affected side were then orthodontically intruded using temporary anchorage devices to improve the occlusal cant and posterior open bite of the unaffected side. This combined surgical-orthodontic treatment provided a satisfactory outcome without additional orthognathic surgery. PMID- 25836343 TI - Restoration of a vertical alveolar bone defect by orthodontic relocation of a mesially impacted mandibular first molar. AB - An impacted mandibular first molar tends to cause serious bone defects of the adjacent teeth. When choosing between the 2 typical treatment options-extraction or orthodontic relocation of the impacted tooth-the decision should be based on assessment of the prognosis. A 22-year-old man with severe mesioangulation and impaction of the mandibular first molar and a related vertical bone defect on the distal side of the second premolar was treated with extraction of the second molar and orthodontic relocation of the first molar with a retromolar miniscrew. Comprehensive orthodontic treatment involving premolar extraction was conducted. Strategic extraction of the molar and adequate orthodontic movement helped to restore the bone structure on the affected side. This case report suggests the effectiveness of restoration of bone defects by using viable periodontal tissues around the impacted tooth for the longevity of the periodontium. PMID- 25836344 TI - Litigation and legislation. Deliberations on duty and deportment. PMID- 25836345 TI - The evolution of bonding in orthodontics. AB - In the early days of fixed-appliance orthodontic treatment, brackets were welded to gold or stainless steel bands. Before treatment, the orthodontist had to create enough space around each tooth to accommodate the bands, and then those spaces had to be closed at the end of treatment, when the bands were removed. This was time-consuming for the orthodontist and uncomfortable for the patient. Banded appliances frequently caused gingival trauma when fitted, and decalcification could occur under the band. In the mid-1960s, Dr George Newman, an orthodontist in Orange, New Jersey, and Professor Fujio Miura, chair of the Department of Orthodontics at Tokyo Medical and Dental University in Japan, pioneered the bonding of orthodontic brackets to enamel. Many developments have occurred in the decades that followed, including many new adhesives, sophisticated base designs, new bracket materials, faster or more efficient curing methods, self-etching primers, fluoride-releasing agents, and sealants. The purpose of this article is to review the history of orthodontic bonding, especially the materials used in the bonding process. PMID- 25836347 TI - Effects of sandblasting before orthophosphoric acid etching on lingual enamel: in vitro roughness assessment. AB - INTRODUCTION: In this study, we evaluated changes in lingual enamel roughness due to sandblasting with 27-, 50-, and 90-MUm aluminum oxide particles followed by 37% orthophosphoric acid etching. METHODS: Twenty-four maxillary premolars were included in the study. The lingual enamel roughness of 20 teeth was evaluated using a laser confocal microscope before and after enamel conditioning. Group 1 (control) was etched with 37% orthophosphoric acid; groups 2, 3, and 4 were sandblasted with 27-, 50-, and 90-MUm aluminum oxide particles, respectively, before acid etching. The lingual surfaces of the other 4 teeth were evaluated using scanning electron microscopy after they had received one of the conditioning methods under study. Paired t tests were used to compare the roughness parameters obtained before and after conditioning in each group, and 1 way analysis of variance was used to compare the surface roughness between groups. The significance level was set at 5% for all statistical analyses. RESULTS: The 4 conditioning methods significantly increased the roughness of the lingual enamel. However, the roughness increases in the groups that were sandblasted with 27-, 50-, and 90-MUm aluminum oxide particles before orthophosphoric acid etching were statistically greater than was the increase in the group conditioned only with orthophosphoric acid. Scanning electron microscopy showed different conditioning patterns among specimens that were conditioned only with orthophosphoric acid and those sandblasted with aluminum oxide before acid etching. CONCLUSIONS: Lingual enamel conditioning with aluminum oxide sandblasting before acid etching results in greater roughness and produces a conditioning pattern different from that of acid etching alone. PMID- 25836346 TI - Surface and interfacial analysis of sandblasted and acid-etched enamel for bonding orthodontic adhesives. AB - INTRODUCTION: The purposes of this study were to characterize enamel surfaces treated with sandblasting, acid etching, or sandblasting followed by acid etching for bonding of orthodontic adhesives and to evaluate the enamel-adhesive interfaces. METHODS: Buccal premolar surfaces were sandblasted, acid etched, sandblasted and subsequently acid etched, or left intact. For 2 treatments (acid etching and sandblasting plus acid etching), orthodontic brackets were bonded for resin infiltration assessment. Surface roughness and enamel loss were evaluated by optical profilometry, and surface morphology and elemental composition were examined by low-vacuum scanning electron microscope/energy dispersive x-ray analysis, whereas interfacial resin infiltration was assessed by high-vacuum scanning electron microscopy. Differences were statistically analyzed by 1-way analysis of variance and Tukey-Kramer multiple comparison tests or t tests (alpha = 0.05). RESULTS: The sandblasted and sandblasted-plus-acid-etched groups showed higher surface roughness values than the acid-etched group. Sandblasting plus acid etching removed more enamel than did sandblasting or acid etching alone. Sandblasting plus acid etching demonstrated a more uniform type I etching pattern, without alumina particles implanted in the enamel, unlike sandblasting. No difference was found in the extent of resin infiltration between the bonded acid-etched and sandblasted-plus-acid-etched groups, although the latter showed improved infiltration characteristics. CONCLUSIONS: Sandblasting-plus-acid etching treatment creates a rough enamel surface, typical of type I etching, with the greatest extent of enamel loss, free of alumina interferences, demonstrating the same extent of resin infiltration as acid etching, but exhibiting improved infiltration quality. PMID- 25836348 TI - Effect of methacrylated-based antibacterial monomer on orthodontic adhesive system properties. AB - INTRODUCTION: Antibacterial adhesives were developed to reduce the incidence of white spot lesions in orthodontic patients. Compounds that contain triazine are known as effective antibacterial agents. The aims of this study were to develop an experimental orthodontic adhesive containing 1,3,5-triacryloylhexahydro-1,3,5 triazine (TAT) and to characterize it. METHODS: TAT was added in 3 concentrations (10%, 15%, and 20%) to the experimental orthodontic adhesive. Antibacterial activity was assayed by brain-heart infusion broth dilution against Streptococcus mutans. The degree of conversion was measured using Fourier transform infrared spectroscopy, and solvent degradation was evaluated by Knoop microhardness before and after immersion in ethanol for 2 hours. The shear bond strength of metal brackets bonded to bovine enamel surface was assessed. RESULTS: All experimental adhesives reduced bacterial growth. The addition of 15% and 20% TAT increased the degree of conversion compared with the control group (0%) and the 10% group. All groups showed a decrease in hardness after ethanol immersion, and there was also a decrease in the percentage of variation of Knoop hardness in the experimental adhesives containing TAT, whereas the shear bond strength increased. CONCLUSIONS: Orthodontic adhesives containing TAT are promising antibacterial materials, especially those with 15% and 20% TAT. PMID- 25836350 TI - The pleasure of your company... PMID- 25836349 TI - Surface deterioration and elemental composition of retrieved orthodontic miniscrews. AB - INTRODUCTION: This study provides insight into surface and elemental analyses of orthodontic retrieved miniscrew implants (MSIs). The sole purpose was to investigate the behavior of MSIs while they are in contact with bone and soft tissues, fluids, and food in the oral cavity. The information thus gathered may help to understand the underlying process of success or failure of MSIs and can be helpful in improving their material composition and design. METHODS: The study was carried out on 28 titanium-alloy MSIs (all from the same manufacturer) split into 3 groups: 18 MSIs were retrieved after successful orthodontic treatment, 5 were failed MSIs, and 5 were as-received MSIs serving as the controls. All MSIs were subjected to energy dispersive x-ray microanalysis to investigate the changes in surface elemental composition and to scanning electron microscopy to analyze their surface topography. Data thus obtained were subjected to suitable statistical analyses. RESULTS: Scanning electron microscope analysis showed surface manufacturing imperfections of the as-received MSIs in the form of stripes. Their elemental composition was confirmed to the specifications of the American Society for Testing of Materials for surgical implants. Retrieved MSIs exhibited generalized surface dullness; variable corrosion; craters in the head, neck, body, and tip regions; and blunting on tips and threads. Energy dispersive x-ray analyses showed deposition of additional elements: calcium had greater significance in its proportion in the body region by 0.056 weight percent; iron was seen in greater proportion in the failed retrieved MSIs compared with the successful miniscrews; cerium was seen in greater proportions in the head region by 0.128 weight percent and in the neck region by 0.147 weight percent than in the body and tip regions of retrieved MSIs. CONCLUSIONS: Retrieved MSIs showed considerable surface and structural alterations such as dullness, corrosion, and blunting of threads and tips. Their surfaces showed interactions and adsorption of several elements, such as calcium, at the body region. A high content of iron was found on the failed MSIs, and cerium was seen in the head and neck regions of retrieved MSIs. PMID- 25836351 TI - Relapse in FEV1 Decline After Steroid Withdrawal in COPD. AB - BACKGROUND: We previously observed that 30 months of inhaled corticosteroid (ICS) treatment can attenuate FEV1 decline in COPD, but it is unclear whether withdrawal induces a relapse. We hypothesized that FEV1 decline, airway hyperresponsiveness (AHR), and quality of life (QOL) deteriorate after ICS cessation even after prolonged use. METHODS: One hundred fourteen patients with moderate to severe COPD finished randomized 6-month or 30-month treatment with fluticasone (500 MUg bid), 30-month treatment with fluticasone and salmeterol (500/50 MUg bid), or placebo (first part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease [GLUCOLD] study [GL1]). The subsequent 5 years, patients were prospectively followed annually, treated by their physician (GLUCOLD follow-up study [GL2]). Postbronchodilator FEV1, AHR, and QOL were initially recorded at baseline, at 30 months (GL1), and annually during GL2. Analysis was performed by linear mixed-effects models. RESULTS: Among 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICSs during GL1, but only using ICSs 0% to 50% of the time during GL2 (n = 56 of 79), had significantly accelerated annual FEV1 decline compared with GL1 (difference GL2-GL1 [95% CI]: 30-month treatment with fluticasone and salmeterol, -68 mL/y [-112 to -25], P = .002; 30-month treatment with fluticasone, -73 mL/y [-119 to -26], P = .002), accompanied by deterioration in AHR and QOL. CONCLUSIONS: ICS discontinuation after 30 months in COPD can worsen lung function decline, AHR, and QOL during 5-year follow-up. This suggests that ICS treatment lacks sustained disease-modifying effect after treatment cessation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00158847; URL: www.clinicaltrials.gov. PMID- 25836353 TI - Identifying the spatial and temporal variability of economic opportunity costs to promote the adoption of alternative land uses in grain growing agricultural areas: an Australian example. AB - Grain growers face many future challenges requiring them to adapt their land uses to changing economic, social and environmental conditions. To understand where to make on ground changes without significant negative financial repercussions, high resolution information on income generation over time is required. We propose a methodology which utilises high resolution yield data collected with precision agriculture (PA) technology, gross margin financial analysis and a temporal standardisation technique to highlight the spatial and temporal consistency of farm income. On three neighbouring farms in Western Australia, we found non linear relationships between income and area. Spatio-temporal analysis on one farm over varying seasons found that between 37 and 49% (1082-1433ha) of cropping area consistently produced above the selected income thresholds and 43-32% (936 1257ha) regularly produced below selected thresholds. Around 20% of area showed inconsistent temporal variation in income generation. Income estimated from these areas represents the income forgone if a land use change is undertaken (the economic opportunity cost) and the average costs varied spatially from $190+/ 114/ha to $560+/-108/ha depending on what scenario was chosen. The interaction over space and time showed the clustering of areas with similar values at a resolution where growers make input decisions. This new evidence suggests that farm area could be managed with two strategies: (a) one that maximises grain output using PA management in temporally stable areas which generate moderate to high income returns and (b) one that proposes land use change in low and inconsistent income returning areas where the financial returns from an alternative land use may be comparable. The adoption of these strategies can help growers meet the demand for agricultural output and offer income diversity and adaptive capacity to deal with the future challenges to agricultural production. PMID- 25836352 TI - Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity. AB - INTRODUCTION: The study of xenobiotic metabolism and toxicity has been greatly aided by the use of genetically modified mouse models and metabolomics. AREAS COVERED: Gene knockout mice can be used to determine the enzymes responsible for the metabolism of xenobiotics in vivo and to examine the mechanisms of xenobiotic induced toxicity. Humanized mouse models are especially important because there exist marked species differences in the xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing CYPs and nuclear receptors including the pregnane X receptor, the major regulator of xenobiotic metabolism and transport were produced. With genetically modified mouse models, metabolomics can determine the metabolic map of many xenobiotics with a level of sensitivity that allows the discovery of even minor metabolites. This technology can be used for determining the mechanism of xenobiotic toxicity and to find early biomarkers for toxicity. EXPERT OPINION: Metabolomics and genetically modified mouse models can be used for the study of xenobiotic metabolism and toxicity by: i) comparison of the metabolomics profiles between wild-type and genetically modified mice, and searching for genotype-dependent endogenous metabolites; ii) searching for and elucidating metabolites derived from xenobiotics; and iii) discovery of specific alterations of endogenous compounds induced by xenobiotics-induced toxicity. PMID- 25836354 TI - Three-dimensional display of peripheral nerves in the wrist region based on MR diffusion tensor imaging and maximum intensity projection post-processing. AB - OBJECTIVES: To achieve 3-dimensional (3D) display of peripheral nerves in the wrist region by using maximum intensity projection (MIP) post-processing methods to reconstruct raw images acquired by a diffusion tensor imaging (DTI) scan, and to explore its clinical applications. METHODS: We performed DTI scans in 6 (DTI6) and 25 (DTI25) diffusion directions on 20 wrists of 10 healthy young volunteers, 6 wrists of 5 patients with carpal tunnel syndrome, 6 wrists of 6 patients with nerve lacerations, and one patient with neurofibroma. The MIP post-processing methods employed 2 types of DTI raw images: (1) single-direction and (2) T2 weighted trace. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of the median and ulnar nerves were measured at multiple testing sites. Two radiologists used custom evaluation scales to assess the 3D nerve imaging quality independently. RESULTS: In both DTI6 and DTI25, nerves in the wrist region could be displayed clearly by the 2 MIP post-processing methods. The FA and ADC values were not significantly different between DTI6 and DTI25, except for the FA values of the ulnar nerves at the level of pisiform bone (p=0.03). As to the imaging quality of each MIP post-processing method, there were no significant differences between DTI6 and DTI25 (p>0.05). The imaging quality of single-direction MIP post-processing was better than that from T2-weighted traces (p<0.05) because of the higher nerve signal intensity. CONCLUSIONS: Three dimensional displays of peripheral nerves in the wrist region can be achieved by MIP post-processing for single-direction images and T2-weighted trace images for both DTI6 and DTI25. The FA and ADC values of the median nerves can be accurately measured by using DTI6 data. Adopting 6-direction DTI scan and MIP post processing is an efficient method for evaluating peripheral nerves. PMID- 25836355 TI - IGF-I in major depression and antidepressant treatment response. AB - We analyzed insulin-like growth factor I (IGF-I) in serum of 78 inpatients with depression and 92 healthy controls. Patients were selected according to remission status after 6 weeks of antidepressant treatment with remission defined by Hamilton depression rating scale (HAM-D) 21-item score <10 (39 remitters and 39 non-remitters). IGF-I was analyzed in patients at admission and after 6 weeks of psychopharmacological treatment. IGF-I levels were compared between patients and controls and between remitters and non-remitters with general linear model using age, gender, and body mass index as covariates. In patients, IGF-I levels were significantly higher at admission (p=3.29E-04) and in week 6 (p=0.002) compared to controls. Furthermore, non-remitters showed significantly higher IGF-I levels at admission (p=0.046) and a trend for higher IGF-I levels in week 6 (p=0.11) compared to remitters. In remitters change in IGF-I levels during treatment was significantly correlated with change in cortisol levels (p=0.019). A genetic association analysis of polymorphisms in 10 genes contributing to the IGF-I system (IGF1, IGF1R, IGFBP1 to IGFBP7, and IGFBPL1) in the currently largest genetic databases for major depression (Psychiatric Genomics Consortium) revealed nominal associations with susceptibility for depression and treatment response, although results did not remain significant after multiple testing correction. In our study, elevated IGF-I levels were significantly associated with depression and impaired treatment response. Based on these findings IGF-I signaling could play a role in the pathophysiology of depression and could possibly influence the response to antidepressant treatment. PMID- 25836356 TI - Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders. AB - Modern neuropsychopharmacology commenced in the 1950s with the serendipitous discovery of first-generation antipsychotics and antidepressants which were therapeutically effective yet had marked adverse effects. Today, a broader palette of safer and better-tolerated agents is available for helping people that suffer from schizophrenia, depression and other psychiatric disorders, while complementary approaches like psychotherapy also have important roles to play in their treatment, both alone and in association with medication. Nonetheless, despite considerable efforts, current management is still only partially effective, and highly-prevalent psychiatric disorders of the brain continue to represent a huge personal and socio-economic burden. The lack of success in discovering more effective pharmacotherapy has contributed, together with many other factors, to a relative disengagement by pharmaceutical firms from neuropsychiatry. Nonetheless, interest remains high, and partnerships are proliferating with academic centres which are increasingly integrating drug discovery and translational research into their traditional activities. This is, then, a time of transition and an opportune moment to thoroughly survey the field. Accordingly, the present paper, first, chronicles the discovery and development of psychotropic agents, focusing in particular on their mechanisms of action and therapeutic utility, and how problems faced were eventually overcome. Second, it discusses the lessons learned from past successes and failures, and how they are being applied to promote future progress. Third, it comprehensively surveys emerging strategies that are (1), improving our understanding of the diagnosis and classification of psychiatric disorders; (2), deepening knowledge of their underlying risk factors and pathophysiological substrates; (3), refining cellular and animal models for discovery and validation of novel therapeutic agents; (4), improving the design and outcome of clinical trials; (5), moving towards reliable biomarkers of patient subpopulations and medication efficacy and (6), promoting collaborative approaches to innovation by uniting key partners from the regulators, industry and academia to patients. Notwithstanding the challenges ahead, the many changes and ideas articulated herein provide new hope and something of a framework for progress towards the improved prevention and relief of psychiatric and other CNS disorders, an urgent mission for our Century. PMID- 25836357 TI - TNF-alpha-induced depressive-like phenotype and p38(MAPK) activation are abolished by ascorbic acid treatment. AB - We investigated the effects of ascorbic acid on depressive-like behavior induced by tumor necrosis factor (TNF-alpha) in mice. Additionally, we examined the effects of combined administration of ascorbic acid and antidepressants, MK-801 and 7-nitroindazole in mice exposed or not to TNF-alpha and the capacity of TNF alpha and ascorbic acid to modulate hippocampal and cerebrocortical phosphorylation of extracellular signal-regulated kinase (ERK), p38(MAPK) and c Jun N-terminal kinase (JNK). In control animals, ascorbic acid reduced the immobility time in the tail suspension test (TST). Unilateral intracerebroventricular administration of TNF-alpha produced a depressive-like behavior in the TST, and the treatment with ascorbic acid prevented this effect. Sub-effective dose of ascorbic acid combined with sub-effective doses of fluoxetine, imipramine, bupropion, MK-801 or 7-nitroindazole produced a synergistic antidepressant-like effect in mice exposed or not to TNF-alpha. No treatment caused significant alterations in the locomotor activity of mice. Administration of TNF-alpha increased the phosphorylation of p38(MAPK) in hippocampus and cerebral cortex, and the treatment with ascorbic acid prevented this effect. Ascorbic acid increased phosphorylation of ERK1 in the hippocampus of saline- and TNF-alpha-treated animals, however it did not produce alterations in the cerebral cortex. No effects on phosphorylation of ERK2 or JNK were found. The observed effect of ascorbic acid seems to be associated, at least partially, with a reduced p38(MAPK) phosphorylation, activation of the monoaminergic systems as well as inhibition of N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) synthesis. PMID- 25836358 TI - Label-free imaging and biochemical characterization of bovine sperm cells. AB - A full label-free morphological and biochemical characterization is desirable to select spermatozoa during preparation for artificial insemination. In order to study these fundamental parameters, we take advantage of two attractive techniques: digital holography (DH) and Raman spectroscopy (RS). DH presents new opportunities for studying morphological aspect of cells and tissues non invasively, quantitatively and without the need for staining or tagging, while RS is a very specific technique allowing the biochemical analysis of cellular components with a spatial resolution in the sub-micrometer range. In this paper, morphological and biochemical bovine sperm cell alterations were studied using these techniques. In addition, a complementary DH and RS study was performed to identify X- and Y-chromosome-bearing sperm cells. We demonstrate that the two techniques together are a powerful and highly efficient tool elucidating some important criterions for sperm morphological selection and sex-identification, overcoming many of the limitations associated with existing protocols. PMID- 25836359 TI - Biconically tapered fiber optic probes for rapid label-free immunoassays. AB - We report use of U-shaped biconically tapered optical fibers (BTOF) as probes for label-free immunoassays. The tapered regions of the sensors were functionalized by immobilization of immunoglobulin-G (Ig-G) and tested for detection of anti-IgG at concentrations of 50 ng/mL to 50 ug/mL. Antibody-antigen reaction creates a biological nanolayer modifying the waveguide structure leading to a change in the sensor signal, which allows real-time monitoring. The kinetics of the antibody (mouse Ig-G)-antigen (rabbit anti-mouse IgG) reactions was studied. Hydrofluoric acid treatment makes the sensitive region thinner to enhance sensitivity, which we confirmed by experiments and simulations. The limit of detection for the sensor was estimated to be less than 50 ng/mL. Utilization of the rate of the sensor peak shift within the first few minutes of the antibody-antigen reaction is proposed as a rapid protein detection method. PMID- 25836360 TI - Heterogeneity of competition at decameter scale: patches of high canopy leaf area in a shade-intolerant larch stand transpire less yet are more sensitive to drought. AB - Small differences in the sensitivity of stomatal conductance to light intensity on leaf surfaces may lead to large differences in total canopy transpiration (EC) with increasing canopy leaf area (L). Typically, the increase of L would more than compensate for the decrease of transpiration per unit of leaf area (EL), resulting in concurrent increase of EC. However, highly shade-intolerant species, such as Larix principis-rupprechtii Mayr., may be so sensitive to increased shading that such compensation is not complete. We hypothesized that in such a stand, windfall-induced spatial variation at a decameter scale would result in greatly reduced EL in patches of high L leading to lower EC than low competition patches of sparse canopy. We further hypothesized that quicker extraction of soil moisture in patches of lower competition will result in earlier onset of drought symptoms in these patches. Thus, patches of low L will transition from light to soil moisture as the factor dominating EL. This process should progressively homogenize EC in the stand even as the variation of soil moisture is increasing. We tested the hypotheses utilizing sap flux of nine trees, and associated environmental and stand variables. The results were consistent with only some of the expectations. Under non-limiting soil moisture, EL was very sensitive to the spatial variation of L, decreasing sharply with increasing L and associated decrease of mean light intensity on leaf surfaces. Thus, under the conditions of ample soil moisture maximum EC decreased with increasing patch-scale L. Annual EC and biomass production also decreased with L, albeit more weakly. Furthermore, variation of EC among patches decreased as average stand soil moisture declined between rain events. However, contrary to expectation, high L plots which transpired less showed a greater EL sensitivity to decreasing stand-scale soil moisture, suggesting a different mechanism than simple control by decreasing soil moisture. We offer potential explanations to the observed phenomenon. Our results demonstrate that spatial variation of L at decameter scale, even within relatively homogeneous, single-species, even-aged stands, can produce large variation of transpiration, soil moisture and biomass production and should be considered in 1-D soil-plant-atmosphere models. PMID- 25836361 TI - Seasonal variability of foliar photosynthetic and morphological traits and drought impacts in a Mediterranean mixed forest. AB - The Mediterranean region is a hot spot of climate change vulnerable to increased droughts and heat waves. Scaling carbon fluxes from leaf to landscape levels is particularly challenging under drought conditions. We aimed to improve the mechanistic understanding of the seasonal acclimation of photosynthesis and morphology in sunlit and shaded leaves of four Mediterranean trees (Quercus ilex L., Pinus halepensis Mill., Arbutus unedo L. and Quercus pubescens Willd.) under natural conditions. Vc,max and Jmax were not constant, and mesophyll conductance was not infinite, as assumed in most terrestrial biosphere models, but varied significantly between seasons, tree species and leaf position. Favourable conditions in winter led to photosynthetic recovery and growth in the evergreens. Under moderate drought, adjustments in the photo/biochemistry and stomatal/mesophyllic diffusion behaviour effectively protected the photosynthetic machineries. Severe drought, however, induced early leaf senescence mostly in A. unedo and Q. pubescens, and significantly increased leaf mass per area in Q. ilex and P. halepensis. Shaded leaves had lower photosynthetic potentials but cushioned negative effects during stress periods. Species-specificity, seasonal variations and leaf position are key factors to explain vegetation responses to abiotic stress and hold great potential to reduce uncertainties in terrestrial biosphere models especially under drought conditions. PMID- 25836362 TI - Photocurrent generation in diamond electrodes modified with reaction centers. AB - Photoactive reaction centers (RCs) are protein complexes in bacteria able to convert sunlight into other forms of energy with a high quantum yield. The photostimulation of immobilized RCs on inorganic electrodes result in the generation of photocurrent that is of interest for biosolar cell applications. This paper reports on the use of novel electrodes based on functional conductive nanocrystalline diamond onto which bacterial RCs are immobilized. A three dimensional conductive polymer scaffold grafted to the diamond electrodes enables efficient entrapment of photoreactive proteins. The electron transfer in these functional diamond electrodes is optimized through the use of a ferrocene-based electron mediator, which provides significant advantages such as a rapid electron transfer as well as high generated photocurrent. A detailed discussion of the generated photocurrent as a function of time, bias voltage, and mediators in solution unveils the mechanisms limiting the electron transfer in these functional electrodes. This work featuring diamond-based electrodes in biophotovoltaics offers general guidelines that can serve to improve the performance of similar devices based on different materials and geometries. PMID- 25836363 TI - Posterior urethral valve with unilateral vesicoureteral reflux and patent urachus: A rare combination of urinary tract anomaliess. AB - Posterior urethral valve (PUV) is a common cause of lower urinary tract obstruction in male infants with an incidence of 1:5000-8000. PUV continues to be a significant cause of morbidity and ongoing renal damage in infants and children. It can coexist with vesicoureteral reflux (VUR) in about 50% of cases and also with patent urachus in about one-third of cases. It is a case of a 22 day-old full-term male child who presented with poor urinary stream and progressive abdominal distension of 5-day duration as well as leakage of clear fluid from umbilicus of 1-day duration. Abdominopelvic ultrasonography showed bilateral hydronephrosis. Micturating cystourethrogram also showed features of bladder outlet obstruction and PUV. In addition, a grade V left VUR and a fistulous tract between the dome of the urinary bladder and the umbilicus, which was consistent with a patent urachus was demonstrated. In conclusion, this case demonstrates a rare combination of congenital urinary tract anomalies involving PUV, left VUR and patent urachus. PMID- 25836364 TI - Correction: DNA barcoding in pencilfishes (Lebiasinidae: Nannostomus) reveals cryptic diversity across the Brazilian Amazon. PMID- 25836365 TI - Sweetpotato- and cereal-based infant foods: protein quality assessment, and effect on body composition using sprague dawley rats as a model. AB - The Protein Digestibility Corrected Amino Acid Score (PDCAAS) of sweetpotato based complementary foods (OFSP ComFa and CFSP ComFa) and cereal-based infant products (Weanimix and Cerelac) was assessed using 3 wk-old male Sprague Dawley rats weighing between 53-67 g as a model for human infants. Also, the effect of consumption of the infant formulations on lean mass, bone mass content and fat mass was evaluated by Dual-Energy X-ray Absorptiometry (DEXA) using 6 wk-old Sprague Dawley rats (initial weight, 206-229 g). The ComFa products and Weanimix are household-level formulations, and Cerelac is a commercial infant cereal. The true protein digestibility score for Cerelac was 96.27%, and about 1.8% (P<0.0001) higher than that for OFSP ComFa, CFSP ComFa and Weanimix. However, OFSP ComFa had the highest un-truncated PDCAAS by a difference of 4.1%, than CFSP ComFa, and about 20% difference compared with both the Weanimix and Cerelac. All the products investigated had PDCAAS greater than 70%, the minimum protein quality requirement for complementary foods. Among the rats assigned to the four formulations, their bone mass and fat mass composition were not significantly different (P=0.08 and P=0.85, respectively). However, the rats on CFSP ComFa had higher lean mass than those on Cerelac (321.67 vs. 297.19 g; P=0.03). The findings from the PDCAAS and the DEXA-measured body composition studies indicate that complementary foods could be formulated from readily available agricultural resources at the household-level to support growth as would a nutritionally adequate industrial-manufactured infant cereal. Nonetheless, it should be noted that the findings of our studies are based on an animal model. PMID- 25836366 TI - Factors affecting dengue prevention practices: nationwide survey of the Malaysian public. AB - BACKGROUND: Efforts to stamp dengue in many dengue endemic countries has met little success. There is a need to re-examine and understand how the public at large view the dengue prevention efforts. This study aimed to examine the demographic factors, theoretical constructs of the Health Belief Model and knowledge about dengue and how these influence the practice of dengue prevention. METHODS: A national telephone survey was carried out with 2,512 individuals of the Malaysian public aged 18-60 years. RESULTS: The majority (73%) of the Malaysian public had a total dengue prevention score of 51-100 (of a possible score of 1-100). Multivariate analysis suggests significant correlates of higher dengue prevention practices with demographic background, perception of susceptibility to dengue, perceived density of mosquitoes in the neighbourhood and knowledge about dengue. Households of lower income of which the majority (40.7%) were from the rural areas, were associated with the highest odds [OR = 1.33; 95%CI = 1.09-1.67; p = 0.004] of dengue prevention. Dengue prevention practices were also less likely to be undertaken in neighbourhoods where the responders perceived there is no and/or low density of mosquitoes. Dengue prevention practices are also less likely to be practiced by skilled workers [OR = 0.78; 95%CI = 0.63-0.95; p = 0.029] compared to those unemployed. Higher perceived susceptibility to dengue was associated with higher dengue prevention practices and participants with higher dengue knowledge were found to have a higher level of involvement in dengue prevention practices. CONCLUSION: Results from the study suggest that in formulating approaches to contain dengue, strategies should be developed to cultivate dengue prevention practices among urban population and target areas with low density of mosquitoes where public perceived a less likely chance of getting dengue. Dengue prevention campaigns should focus on messages highlighting the risk of contracting dengue and education to increase knowledge about dengue. PMID- 25836367 TI - VUV and mid-UV photoabsorption cross sections of thin films of guanine and uracil: application on their photochemistry in the solar system. AB - We present a photostability study of two nucleobases, guanine and uracil. For the first time, the photoabsorption cross-section spectra of these molecules in the solid phase were measured in the VUV and mid-UV domain (115<=lambda<=300 nm). They show a quite similar absorption level throughout this wavelength range, highlighting the importance of considering the whole VUV and UV domain during photolysis experiments in the laboratory. Their photolysis constant (J) can be estimated from those measurements as follows: 2.2*10(-2) s(-1)+/-11% for guanine and 5.3*10(-2) s(-1)+/-14% for uracil. This work shows that (i) measuring kinetic constants from a direct and "traditional" photolysis of a thin sample in the laboratory suffers strong limitations and (ii) achieving this measurement requires comprehensive modeling of the radiative transfer that occurs in any sample not optically thin (i.e.,<=2 nm). Moreover, this work has provided other data of interest: the refractive index of solid guanine and of uracil at 650 nm are 1.52 (+/-0.01) and 1.39 (+/-0.02), respectively, and the integrated IR band strengths (A) of solid guanine between 3700 and 2120 cm(-1) (3.4*10(-16) cm.molecule(-1)+/-13%) and of solid uracil between 3400 and 1890 cm(-1) (2.1*10( 16) cm.molecule(-1)+/-21%). PMID- 25836368 TI - Transcriptome analysis and gene expression profiling of abortive and developing ovules during fruit development in hazelnut. AB - BACKGROUND: A high ratio of blank fruit in hazelnut (Corylus heterophylla Fisch) is a very common phenomenon that causes serious yield losses in northeast China. The development of blank fruit in the Corylus genus is known to be associated with embryo abortion. However, little is known about the molecular mechanisms responsible for embryo abortion during the nut development stage. Genomic information for C. heterophylla Fisch is not available; therefore, data related to transcriptome and gene expression profiling of developing and abortive ovules are needed. METHODOLOGY/PRINCIPAL FINDINGS: In this study, de novo transcriptome sequencing and RNA-seq analysis were conducted using short-read sequencing technology (Illumina HiSeq 2000). The results of the transcriptome assembly analysis revealed genetic information that was associated with the fruit development stage. Two digital gene expression libraries were constructed, one for a full (normally developing) ovule and one for an empty (abortive) ovule. Transcriptome sequencing and assembly results revealed 55,353 unigenes, including 18,751 clusters and 36,602 singletons. These results were annotated using the public databases NR, NT, Swiss-Prot, KEGG, COG, and GO. Using digital gene expression profiling, gene expression differences in developing and abortive ovules were identified. A total of 1,637 and 715 unigenes were significantly upregulated and downregulated, respectively, in abortive ovules, compared with developing ovules. Quantitative real-time polymerase chain reaction analysis was used in order to verify the differential expression of some genes. CONCLUSIONS/SIGNIFICANCE: The transcriptome and digital gene expression profiling data of normally developing and abortive ovules in hazelnut provide exhaustive information that will improve our understanding of the molecular mechanisms of abortive ovule formation in hazelnut. PMID- 25836369 TI - Ultrasonic extraction of anthocyanin from Clitoria ternatea flowers using response surface methodology. AB - The ultrasonic extraction (UE) method of anthocyanin from Clitoria ternatea flowers using response surface methodology (RSM) was performed in this study. By using RSM, the objective is to optimise the extraction yield of anthocyanin from C. ternatea which is influenced by various factors, including the extraction temperature, time, ratio of solvent to solid and ultrasonic power. The empirical model was investigated by performing first-level optimisation in a two-level factorial design with Design Expert 7 software. In comparison with the conventional solvent extraction, UE showed a 246.48% better extraction yield and produced an anthocyanin extract with a radical scavenging activity of 68.48% at the optimised factors of 50 degrees C, 150 min, 15 mL/g and 240 W. PMID- 25836371 TI - Influence of sodium salicylate on rosmarinic acid, carnosol and carnosic acid accumulation by Salvia officinalis L. shoots grown in vitro. AB - OBJECTIVES: To evaluate sodium salicylate (NaSA) as an elicitor of rosmarinic acid (RA) and phenolic diterpenes, carnosol (C) and carnosic acid (CA) production, in a culture of Salvia officinalis shoots. RESULTS: In sage shoots grown in vitro, 28 polyphenolic compounds (phenolic acids, flavonoids, and phenolic diterpenes) were identified. In shoots treated for 1 week with increasing NaSA concentrations, the content of C increased from 2.3 in control to 5.7 mg g(-1) DW in shoots treated with 500 uM NaSA. In shoots that were recovered on basal medium for 3 weeks, the maximal amount of C (14 mg/g(-1) DW) was with 150 uM NaSA treatment. In treated and recovered shoots, the increase in C was accompanied with a decrease in CA, resulting in 1.9-fold increase in the C/CA ratio. Accumulation of RA was not affected by the NaSA treatment. However, elicitation by NaSA was accompanied with growth retardation. CONCLUSIONS: NaSA can improve C production in sage shoot culture, probably by stimulating the conversion of CA to C. PMID- 25836370 TI - Glucocorticoids suppress renal cell carcinoma progression by enhancing Na,K ATPase beta-1 subunit expression. AB - Glucocorticoids are commonly used as palliative or chemotherapeutic clinical agents for treatment of a variety of cancers. Although steroid treatment is beneficial, the mechanisms by which steroids improve outcome in cancer patients are not well understood. Na,K-ATPase beta-subunit isoform 1 (NaK-beta1) is a cell cell adhesion molecule, and its expression is down-regulated in cancer cells undergoing epithelial-to mesenchymal-transition (EMT), a key event associated with cancer progression to metastatic disease. In this study, we performed high throughput screening to identify small molecules that could up-regulate NaK-beta1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-beta1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK beta1 expression at the cell surface, enhance cell-cell adhesion, attenuate motility and invasiveness and induce mesenchymal to epithelial like transition of renal cell carcinoma (RCC) cells in vitro. Treatment of NaK-beta1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-beta1. Furthermore, we demonstrated that these compounds attenuate tumor growth in subcutaneous RCC xenografts and reduce local invasiveness in orthotopically-implanted tumors. Our results strongly indicate that the addition of glucocorticoids in the treatment of RCC may improve outcome for RCC patients by augmenting NaK-beta1 cell-cell adhesion function. PMID- 25836372 TI - A low-cost solid-liquid separation process for enzymatically hydrolyzed corn stover slurries. AB - Solid-liquid separation of intermediate process slurries is required in some process configurations for the conversion of lignocellulosic biomass to transportation fuels. Thermochemically pretreated and enzymatically hydrolyzed corn stover slurries have proven difficult to filter due to formation of very low permeability cakes that are rich in lignin. Treatment of two different slurries with polyelectrolyte flocculant was demonstrated to increase mean particle size and filterability. Filtration flux was greatly improved, and thus scaled filter unit capacity was increased approximately 40-fold compared with unflocculated slurry. Although additional costs were accrued using polyelectrolyte, techno economic analysis revealed that the increase in filter capacity significantly reduced overall production costs. Fuel production cost at 95% sugar recovery was reduced by $1.35 US per gallon gasoline equivalent for dilute-acid pretreated and enzymatically hydrolyzed slurries and $3.40 for slurries produced using an additional alkaline de-acetylation preprocessing step that is even more difficult to natively filter. PMID- 25836373 TI - Strategies to achieve high-solids enzymatic hydrolysis of dilute-acid pretreated corn stover. AB - Three strategies were presented to achieve high solids loading while maximizing carbohydrate conversion, which are fed-batch, splitting/thickening, and clarifier processes. Enzymatic hydrolysis was performed at water insoluble solids (WIS) of 15% using washed dilute-acid pretreated corn stover. The carbohydrate concentration increased from 31.8 to 99.3g/L when the insoluble solids content increased from 5% to 15% WIS, while the final carbohydrate conversion was decreased from 78.4% to 73.2%. For the fed-batch process, a carbohydrate conversion efficiency of 76.8% was achieved when solid was split into 60:20:20 ratio, with all enzymes added first. For the splitting/thickening process, a carbohydrate conversion of 76.5% was realized when the filtrate was recycled to simulate a steady-state process. Lastly, the clarifier process was evaluated and the highest carbohydrate conversion of 81.4% was achieved. All of these results suggests the possibility of enzymatic hydrolysis at high solids to make the overall conversion cost-competitive. PMID- 25836374 TI - Struvite for composting of agricultural wastes with termite mound: Utilizing the unutilized. AB - Although, compost is the store house of different plant nutrients, there is a concern for low amount of major nutrients especially nitrogen content in prepared compost. The present study deals with preparation of compost by using agricultural wastes with struvite (MgNH4PO4.6H2O) along with termite mound. Among four composting mixtures, 50kg termite mound and 2.5kg struvite with crop residues (stover of ground nut: 361.65kg; soybean: 354.59kg; potato: 357.67kg and mustard: 373.19kg) and cow dung (84.90kg) formed a good quality compost within 70days of composting having nitrogen, phosphorus and potassium as 21.59, 3.98 and 34.6gkg(-1), respectively. Multivariate analysis of variance revealed significant differences among the composts. The four composts formed two (pit 1, pit 2 and pit 3, pit 4) different groups. Two principal components expressed more than 97% of the total variability. Hierarchical cluster analysis resulted two homogeneous groups of composts. PMID- 25836375 TI - Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation. AB - ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES 62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNgamma mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed. PMID- 25836376 TI - Anthelmintic, anti-inflammatory and antioxidant effects of Garcinia mangostana extract in hamster opisthorchiasis. AB - Administration of praziquantel for treatment of liver fluke infection may affect the host, with mild and severe effects after treatment caused by host immune response. Therefore, we focused on the antioxidant property, inflammatory and anthelmintic effects of the traditional folk medicine, G. mangostana pericarp extract, in hamster opisthorchiasis. Syrian hamsters were divided into four groups: normal (control) (N); administered G. mangostana alone (GM); infected with Opisthorchis viverrini alone (OV); and infected with O. viverrini and administered G. mangostana extract for 1.5 months (OVGM). Hamster livers were collected 45 days after infection to determine histopathological changes, i.e. aggregation of inflammatory cells. The morphology of adult O. viverrini (body size and sizes of reproductive organs) was analyzed, as well as worm burden, eggs per worm and eggs per gram of feces. Toxicity was tested by kidney function (blood urea nitrogen and creatinine); the results demonstrated that G. mangostana had no renal toxic effect. ABTS radical-scavenging assay indicated that the extract had antioxidant property. Reduction in aggregation of inflammatory cells surrounding the hepatic bile duct, especially at the hilar region, was found in the OVGM group. Worm burden was similar in both infected groups (treated or untreated with G. mangostana), but the average size of adults in the OV group was larger than in the OVGM group; moreover, eggs per worm and eggs per gram of feces were also comparatively higher. The present study suggests that G. mangostana extract possesses anti-inflammatory and antioxidant properties and can interfere with parasite development by affecting adult size and egg production. This may be useful for controlling the spread of OV infection and other parasites in endemic areas. PMID- 25836377 TI - Fathers' and Mothers' Verbal Responsiveness and the Language Skills of Young Children With Autism Spectrum Disorder. AB - PURPOSE: In this observational study, we examined the interactions of 16 young children with autism spectrum disorder (ASD) and their parents to investigate (a) differences in verbal responsiveness used by fathers and mothers in interactions with their children with ASD and (b) concurrent associations between the language skills of children with ASD and the verbal responsiveness of both fathers and mothers. METHOD: Parent verbal responsiveness was coded from video recordings of naturalistic parent-child play sessions using interval-based coding. Child language skills were measured by the Preschool Language Scale-Fourth Edition (Zimmerman, Steiner, & Pond, 2002). RESULTS: For both fathers and mothers, parent verbal responsiveness was positively associated with child language skills. Mothers' responsiveness was also significantly associated with child cognition. After controlling for child cognition, fathers' verbal responsiveness continued to be significantly related to child language skills. CONCLUSIONS: Although other studies have documented associations between mothers' responsiveness and child language, this is the 1st study to document a significant concurrent association between child language skills of children with ASD and the verbal responsiveness of fathers. Findings of this study warrant the inclusion of fathers in future research on language development and intervention to better understand the potential contributions fathers may make to language growth for children with ASD over time as well as to determine whether coaching fathers to use responsive verbal strategies can improve language outcomes for children with ASD. PMID- 25836378 TI - A Novel and Intuitive Method of Displaying and Interacting with Mass Difference Information: Application to Oligonucleotide Drug Impurities. AB - A new method is presented for determining relationships between components in complex analytical systems. The method uses the mass differences between peaks in high resolution electrospray ionization (ESI) mass spectra. It relates peaks that share common mass differences. The method is based on the fundamental assumption that peaks in the spectra having the same exact mass difference are related by the same chemical moiety/substructure. Moreover, the presence (or absence/loss) of the same chemical moiety from a series of molecules may reflect similarities in the mechanisms of formation of each molecule. The determined mass differences in the spectra are used to automatically differentiate the types of components in the samples. Contour plots and summary plots of the summed total ion signal as a function of the mass difference are generated, which form powerful tools for the rapid and automated determination of the components in the samples and for comparisons with other samples. For the first time, in this work a unique profile contour plot has been developed that permits the interactive interrogation of the mass range by mass difference data matrix to obtain valuable information about components that share a common mechanism of formation, and all possible mechanisms of formation linked to a selected precursor molecule. The method can be used as an additional and complementary method to the existing analytical methods to determine relationships between components in complex chemical systems. PMID- 25836380 TI - The effect of thermal annealing on the charge transfer dynamics of a donor acceptor copolymer and fullerene: F8T2 and F8T2:PCBM. AB - Ultrafast charge delocalization dynamics in an internal donor-acceptor copolymer poly(9,9-dioctylfluorenyl-co-bithiophene) (F8T2) and its blend with the fullerene derivative [6,6]-phenyl C61 butyric acid methyl ester (PCBM) was studied by resonant Auger spectroscopy measured around sulfur K-edge using the core-hole clock approach. The effect of thermal annealing on the charge transfer delocalization times (tauCT) was also investigated. Two main transitions with S 1s -> pi* and S 1s -> sigma*(S-C) character were measured at the S 1s NEXAFS spectra. Poor charge delocalization was observed for as cast polymeric films at photon energies corresponding to the S 1s -> pi* transition, which may suggest a weak pi-electronic coupling due to weak polymer crystallinity and chain stacking. Enhancement in the charge transfer process for photon energies close to the resonance maximum was observed for thermally annealed F8T2 and its blends. Atomic Force Microscopy (AFM) topography for as cast F8T2:PCBM shows a top position of PCBM units relative to the polymer, homogeneously distributed on the film surface. This configuration improves the charge delocalization through S 1s -> pi* molecular orbitals for the as cast blended film, suggesting a strong pi electronic coupling. A new rearrangement of F8T2:PCBM film was found after thermal annealing, leading to a more efficient electron transfer channel through sigma* molecular orbitals. PMID- 25836381 TI - The two roads of passionate goal pursuit: links with appraisal, coping, and academic achievement. AB - BACKGROUND AND OBJECTIVES: In this research, we tested the role of cognitive appraisals in explaining why harmonious and obsessive passion dimensions are related to distinct forms of coping and explored if performance was impacted by these appraisal and coping processes. DESIGN: Undergraduate students (N = 489) participated in a longitudinal study and completed three surveys throughout the course of an academic year. METHODS: Participants completed assessments of both passion dimensions (Time 1), reported how they were appraising and coping with the mid-year examination period (Time 2), and provided consent to obtain their final grade in Introductory Psychology (Time 3). The hypothesized model was tested using structural equation modeling. RESULTS: Harmonious and obsessive passion dimensions were linked with approach and avoidant coping responses, respectively. Cognitive appraisals, particularly appraisals of challenge and uncontrollability, played an indirect role in these relationships. In addition, both appraisals and coping responses had an indirect effect in the relationship between passion dimensions and final grade. CONCLUSIONS: These results identify cognitive appraisal as a reason why passion dimensions are linked with distinct coping tendencies and demonstrate the role of appraisal and coping processes in the journey to passionate goal attainment. PMID- 25836379 TI - Electrocardiographic right and left bundle branch block patterns in athletes: prevalence, pathology, and clinical significance. AB - Differentiating benign electrocardiographic (ECG) patterns in athletes from those representative of underlying cardiac pathology is both clinically relevant and challenging. Complete right (RBBB) and left (LBBB) bundle branch block are relatively rare in asymptomatic athletic populations, and current expert consensus guidelines recommend further clinical investigation upon detection of either ECG pattern. However, present data suggest that typical RBBB is not associated with structural cardiac pathology and may alternatively represent an ECG marker of exercise-induced right ventricular remodeling. In accordance with current guidelines, the presence of asymptomatic LBBB in athletes is not associated with normal exercise physiology and more likely indicative of underlying cardiac pathology. While long-term outcomes for asymptomatic athletes with RBBB or LBBB remain unknown, current evidence regarding these ECG patterns should be considered to improve the specificity of future athlete-specific ECG interpretation guidelines. PMID- 25836382 TI - Distribution and elevated soil pools of mercury in an acidic subtropical forest of southwestern China. AB - Tieshanping catchment in southwest China was supposed to a large pool of atmospheric mercury. This work was aimed to examine THg (total mercury) concentrations, pools and influence factors in the acidic forest. THg concentrations were highly elevated in the study area, which was significantly depended on TOM (total organic matter) concentrations and altitudinal elevation, whereas negatively correlated with soil pH. The pools of mercury accumulated in soils were correlated strongly with the stocks of TOM and altitude, ranged from 5.9 to 32 mg m(-2) and averaged 14.5 mg m(-2), indicating that the acidic forest was a great sink of atmospheric mercury in southwest China. THg concentrations in stream waters decreased with altitude increasing and regression analyses showed that soil/air exchange flux would be increased with the decrease of altitude. Present results suggest that elevation increasing decreases THg losses as low THg concentrations in runoffs and volatilization from soils. PMID- 25836383 TI - Competitive binding between miR-122 and p68 onto hepatitis C viral RNA. AB - BACKGROUND: Liver-specific microRNA (miR)-122 has been shown to be involved in regulating translation of hepatitis C viral (HCV) RNA. This study aimed to explore the molecular mechanism of miR-122 in regulating HCV RNA translation initiation. MATERIAL/METHODS: In human liver hepatocellular carcinoma cell line HepG2, UV cross-link assay was performed on a large scale to identify RNA-binding proteins with gradient concentrations of miR-122. Analytical ultracentrifugation was then used to separate the translation initiation complexes. All RNA-binding proteins were then identified by Western blotting. RESULTS: The binding of 68 kDa protein (p68) to HCV RNA was suppressed by the addition of miR-122 via the competitive binding assay. Such inhibition can be eliminated by the addition of 2'-O-methylated oligonucleotides. This binding suppression was determined to be specific for miR-122, which used the mature single-stranded RNA to suppress the binding of p68 onto HCV RNA. This binding inhibition was further validated by using authentic miR-122 with conserved regions and mutated sequences. CONCLUSIONS: The binding of p68 onto HCV RNA can be specifically inhibited by miR 122 via a competitive binding process. PMID- 25836384 TI - Positive Testing for Neisseria gonorrhoeae and Chlamydia trachomatis and the Risk of Pelvic Inflammatory Disease in IUD Users. AB - BACKGROUND: Unintended pregnancies are a major public health problem in the United States, and intrauterine devices (IUDs) are among the most effective reversible birth control methods available. Historically, there have been concerns about IUD use and infection among young and/or high-risk women that may increase the risk of pelvic inflammatory disease (PID) and subsequent infertility. METHODS: The Contraceptive CHOICE Project (CHOICE) was a prospective cohort study of over 9,000 women 14-45 years of age residing in the St. Louis area who were interested in initiating a new form of reversible contraception. At enrollment, participants were counseled regarding long-acting contraceptive methods with the goal of increasing awareness of all reversible methods available. Participants were also tested for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) during enrollment and were provided with contraception at no cost for 2-3 years. RESULTS: We estimate the frequency of self-reported PID in new IUD users compared with women using other contraceptive methods. Among both new IUD users who tested positive for GC and/or CT and those who tested negative, the PID rate was 1% or below. CONCLUSIONS: Our results demonstrate that IUD use is safe for all women, including women at high risk for sexually transmitted infections. PMID- 25836385 TI - Developing a Research Agenda on Resident-to-Resident Aggression: Recommendations From a Consensus Conference. AB - This article provides an overview of the development of a research agenda on resident-to-resident aggression (RRA) in long-term care facilities by an expert panel of researchers and practitioners. A 1-day consensus-building workshop using a modified Delphi approach was held to gain consensus on nomenclature and an operational definition for RRA, to identify RRA research priorities, and to develop a roadmap for future research on these priorities. Among the six identified terms in the literature, RRA was selected. The top five priorities were: (a) developing/assessing RRA environmental interventions; (b) identification of the environmental factors triggering RRA; (c) incidence/prevalence of RRA; (d) developing/assessing staff RRA education interventions; and (e) identification of RRA perpetrator and victim characteristics. Given the significant harm RRA poses for long-term care residents, this meeting is an important milestone, as it is the first organized effort to mobilize knowledge on this under-studied topic at the research, clinical, and policy levels. PMID- 25836386 TI - Longitudinal study of Escherichia coli O157 shedding and super shedding in dairy heifers. AB - A longitudinal study was conducted to assess the methods available for detection of Escherichia coli O157 and to investigate the prevalence and occurrence of long term shedding and super shedding in a cohort of Australian dairy heifers. Samples were obtained at approximately weekly intervals from heifers at pasture under normal management systems. Selective sampling techniques were used with the aim of identifying heifers with a higher probability of shedding or super shedding. Rectoanal mucosal swabs (RAMS) and fecal samples were obtained from each heifer. Direct culture of feces was used for detection and enumeration. Feces and RAMS were tested by enrichment culture. Selected samples were further tested retrospectively by immunomagnetic separation of enriched samples. Of 784 samples obtained, 154 (19.6%) were detected as positive using culture methods. Adjusting for selective sampling, the prevalence was 71 (15.6%) of 454. In total, 66 samples were detected as positive at >10(2) CFU/g of which 8 were >10(4) CFU/g and classed as super shedding. A significant difference was observed in detection by enriched culture of RAMS and feces. Dairy heifers within this cohort exhibited variable E. coli O157 shedding, consistent with previous estimates of shedding. Super shedding was detected at a low frequency and inconsistently from individual heifers. All detection methods identified some samples as positive that were not detected by any other method, indicating that the testing methods used will influence survey results. PMID- 25836387 TI - Determining the potential link between irrigation water quality and the microbiological quality of onions by phenotypic and genotypic characterization of Escherichia coli isolates. AB - The potential transfer of human pathogenic bacteria present in irrigation water onto fresh produce was investigated, because surface water sources used for irrigation purposes in South Africa have increasingly been reported to be contaminated with enteric bacterial pathogens. A microbiological analysis was performed of a selected river in Limpopo Province, South Africa, that is often contaminated with raw sewage from municipal sewage works and overhead irrigated onions produced on a commercial farm. Counts of Escherichia coli, coliforms, aerobic bacteria, fungi, and yeasts and the prevalence of E. coli O157:H7, Salmonella, and Listeria monocytogenes were determined. Identities of bacterial isolates from irrigation water and onions were confirmed using matrix-assisted laser desorption ionization-time of flight mass spectrometry, PCR, and biochemical tests. To establish a potential link between the microbiological quality of the irrigation source and the onions, the E. coli isolates from both were subjected to antibiotic resistance, virulence gene, and enterobacterial repetitive intergenic consensus PCR analyses. River water E. coli counts exceeded South African Department of Water Affairs and World Health Organization irrigation water guidelines. Counts of aerobic bacteria, coliforms, fungi, and yeasts of onions from the market were acceptable according to Department of Health Directorate, Food Control, South Africa, microbiological guidelines for ready-to-eat fresh fruits and vegetables. E. coli O157:H7, Salmonella, and L. monocytogenes were not detected in onions, whereas only Salmonella was detected in 22% of water samples. Matrix-assisted laser desorption ionization-time of flight mass spectrometry and PCR identification of E. coli isolates from water and onions correlated. Of the 45 E. coli isolates from water and onions, 42.2% were resistant to multiple antibiotics. Virulence genes eae, stx1, and stx2 were detected in 2.2, 6.6, and 2.2% of the E. coli isolates, respectively. Phenotypic (antimicrobial) and genotypic (virulence gene prevalence, DNA fingerprinting) analyses showed a link between river, dam, irrigation pivot point, and onion E. coli isolates. PMID- 25836388 TI - Survival of Salmonella and Escherichia coli O157:H7 on strawberries, basil, and other leafy greens during storage. AB - The survival of Salmonella and Escherichia coli O157:H7 on strawberries, basil leaves, and other leafy greens (spinach leaves, lamb and butterhead lettuce leaves, baby leaves, and fresh-cut iceberg lettuce) was assessed at cold (<7 degrees C) and ambient temperatures. All commodities were spot inoculated with E. coli O157:H7 or Salmonella to obtain an initial inoculum of 5 to 6 log and 4 to 5 log CFU/g for strawberries and leafy greens, respectively. Samples were air packed. Strawberries were stored at 4, 10, 15, and 22 degrees C and basil leaves and other leafy greens at 7, 15, and 22 degrees C for up to 7 days (or less if spoiled before). Both Salmonella and E. coli O157:H7 showed a gradual decrease in numbers if inoculated on strawberries, with a similar reduction observed at 4, 10, and 15 degrees C (2 to 3 log after 5 days). However, at 15 degrees C (and 10 degrees C for E. coli O157:H7), the survival experiment stopped before day 7, as die-off of both pathogens below the lower limit of detection was achieved or spoilage occurred. At 22 degrees C, strawberries were moldy after 2 or 4 days. At that time, a 1- to 2-log reduction of both pathogens had occurred. A restricted die-off (on average 1.0 log) and increase (on average , 0.5 log) of both pathogens on basil leaves occurred after 7 days of storage at 7 and 22 degrees C, respectively. On leafy greens, a comparable decrease as on basil was observed after 3 days at 7 degrees C. At 22 degrees C, both pathogens increased to higher numbers on fresh-cut iceberg and butterhead lettuce leaves (on average 1.0 log), probably due to the presence of exudates. However, by using spot inoculation, the increase was rather limited, probably due to minimized contact between the inoculum and cell exudates. Avoiding contamination, in particular, at cultivation (and harvest or postharvest) is important, as both pathogens survive during storage, and strawberries, basil, and other leafy green leaves are consumed without inactivation treatment. PMID- 25836389 TI - Survival of Salmonella on chamomile, peppermint, and green tea during storage and subsequent survival or growth following tea brewing. AB - The survival of Salmonella on dried chamomile flowers, peppermint leaves, and green tea leaves stored under different conditions was examined. Survival and growth of Salmonella was also assessed after subsequent brewing using dried inoculated teas. A Salmonella enterica serovar cocktail was inoculated onto different dried tea leaves or flowers to give starting populations of approximately 10 log CFU/g. The inoculum was allowed to dry (at ambient temperature for 24 h) onto the dried leaves or flowers prior to storage under 25 and 35 degrees C at low (<30% relative humidity [RH]) and high (>90% RH) humidity levels. Under the four storage conditions tested, survival followed the order 25 degrees C with low RH > 35 degrees C with low RH > 25 degrees C with high RH > 35 degrees C with high RH. Salmonella losses at 25 degrees C with low RH occurred primarily during drying, after which populations showed little decline over 6 months. In contrast, Salmonella decreased below detection after 45 days at 35 degrees C and high RH in all teas tested. The thermal resistance of Salmonella was assessed at 55 degrees C immediately after inoculation of tea leaves or flowers, after drying (24 h) onto tea leaves or flowers, and after 28 days of storage at 25 degrees C with low RH. All conditions resulted in similar D-values (2.78 +/- 0.12, 3.04 +/- 0.07, and 2.78 +/- 0.56, at 0 h, 24 h, and 28 days, respectively), indicating thermal resistance of Salmonella in brewed tea did not change after desiccation and 28 days of storage. In addition, all brewed teas tested supported the growth of Salmonella. If Salmonella survives after storage, it may also survive and grow after a home brewing process. PMID- 25836390 TI - Rapid and early detection of Salmonella serotypes with hyperspectral microscopy and multivariate data analysis. AB - This study was designed to evaluate hyperspectral microscope images for early and rapid detection of Salmonella serotypes Enteritidis, Heidelberg, Infantis, Kentucky, and Typhimurium at incubation times of 6, 8, 10, 12, and 24 h. Images were collected by an acousto-optical tunable filter hyperspectral microscope imaging system with a metal halide light source measuring 89 contiguous wavelengths every 4 nm between 450 and 800 nm. Pearson correlation values were calculated for incubation times of 8, 10, and 12 h and compared with data for 24 h to evaluate the change in spectral signatures from bacterial cells over time. Regions of interest were analyzed at 30% of the pixels in an average cell size. Spectral data were preprocessed by applying a global data transformation algorithm and then subjected to principal component analysis (PCA). The Mahalanobis distance was calculated from PCA score plots for analyzing serotype cluster separation. Partial least-squares regression was applied for calibration and validation of the model, and soft independent modeling of class analogy was utilized to classify serotype clusters in the training set. Pearson correlation values indicate very similar spectral patterns for reduced incubation times ranging from 0.9869 to 0.9990. PCA score plots indicated cluster separation at all incubation times, with incubation time Mahalanobis distances of 2.146 to 27.071. Partial least-squares regression had a maximum root mean squared error of calibration of 0.0025 and a root mean squared error of validation of 0.0030. Soft independent modeling of class analogy correctly classified values at 8 h (98.32%), 10 h (96.67%), 12 h (88.33%), and 24 h (98.67%) with the optimal number of principal components (four or five). The results of this study suggest that Salmonella serotypes can be classified by applying a PCA to hyperspectral microscope imaging data from samples after only 8 h of incubation. PMID- 25836391 TI - Use of the ecf1 gene to detect Shiga toxin-producing Escherichia coli in beef samples. AB - Escherichia coli O157:H7 and six serovars (O26, O103, O121, O111, O145, and O45) are frequently implicated in severe clinical illness worldwide. Standard testing methods using stx, eae, and O serogroup-specific gene sequences for detecting the top six non-O157 STEC bear the disadvantage that these genes may reside, independently, in different nonpathogenic organisms, leading to false-positive results. The ecf operon has previously been identified in the large enterohemolysin-encoding plasmid of eae-positive Shiga toxin-producing E. coli (STEC). Here, we explored the utility of the ecf operon as a single marker to detect eae-positive STEC from pure broth and primary meat enrichments. Analysis of 501 E. coli isolates demonstrated a strong correlation (99.6%) between the presence of the ecf1 gene and the combined presence of stx, eae, and ehxA genes. Two large studies were carried out to determine the utility of an ecf1 detection assay to detect non-O157 STEC strains in enriched meat samples in comparison to the results using the U. S. Department of Agriculture Food Safety and Inspection Service (FSIS) method that detects stx and eae genes. In ground beef samples (n = 1,065), the top six non-O157 STEC were detected in 4.0% of samples by an ecf1 detection assay and in 5.0% of samples by the stx- and eae-based method. In contrast, in beef samples composed largely of trim (n = 1,097), the top six non O157 STEC were detected at 1.1% by both methods. Estimation of false-positive rates among the top six non-O157 STEC revealed a lower rate using the ecf1 detection method (0.5%) than using the eae and stx screening method (1.1%). Additionally, the ecf1 detection assay detected STEC strains associated with severe illness that are not included in the FSIS regulatory definition of adulterant STEC. PMID- 25836392 TI - Quantifying the effect of hand wash duration, soap use, ground beef debris, and drying methods on the removal of Enterobacter aerogenes on hands. AB - Hand washing is recognized as a crucial step in preventing foodborne disease transmission by mitigating crosscontamination among hands, surfaces, and foods. This research was undertaken to establish the importance of several keys factors (soap, soil, time, and drying method) in reducing microorganisms during hand washing. A nonpathogenic nalidixic acid-resistant Enterobacter aerogenes surrogate for Salmonella was used to assess the efficacy of using soap or no soap for 5 or 20 s on hands with or without ground beef debris and drying with paper towel or air. Each experiment consisted of 20 replicates, each from a different individual with ~ 6 log CFU/ml E. aerogenes on their hands. A reduction of 1.0 +/ 0.4 and 1.7 +/- 0.8 log CFU of E. aerogenes was observed for a 5-s wash with no soap and a 20-s wash with soap, respectively. When there was no debris on the hands, there was no significant difference between washing with and without soap for 20 s (P > 0.05). Likewise, there was no significant difference in the reductions achieved when washing without soap, whether or not debris was on the hands (P > 0.05). A significantly greater reduction (P < 0.05) in E. aerogenes (0.5 log CFU greater reduction) was observed with soap when there was ground beef debris on the hands. The greatest difference (1.1 log CFU greater average reduction) in effectiveness occurred when ground beef debris was on the hands and a 20-s wash with water was compared with a 20-s wash with soap. Significantly greater (P < 0.05) reductions were observed with paper towel drying compared with air (0.5 log CFU greater reductions). Used paper towels may contain high bacterial levels (>4.0 log CFU per towel) when hands are highly contaminated. Our results support future quantitative microbial risk assessments needed to effectively manage risks of foodborne illness in which food workers' hands are a primary cause. PMID- 25836393 TI - Effect of oxygen stress on growth and survival of Clostridium perfringens, Campylobacter jejuni, and Listeria monocytogenes under different storage conditions. AB - This study investigated the growth and survival of three foodborne pathogens (Clostridium perfringens, Campylobacter jejuni, and Listeria monocytogenes) in beef (7% fat) and nutrient broth under different oxygen levels. Samples were tested under anoxic (<0.5%), microoxic (6 to 8%), and oxic (20%) conditions during storage at 7 degrees C for 14 days and at 22 degrees C for 5 days. Two initial inoculum concentrations were used (1 and 2 log CFU per g of beef or per ml of broth). The results show that C. perfringens could grow in beef at 22 degrees C, with an increase of approximately 5 log under anoxic conditions and a 1-log increase under microoxic conditions. However, C. perfringens could not survive in beef held at 7 degrees C under microoxic and oxic storage conditions after 14 days. In an anoxic environment, C. perfringens survived in beef samples held at 7 degrees C, with a 1-log reduction. A cell decline was observed at 2 log under these conditions, with no surviving cells at the 1-log level. However, the results show that C. jejuni under microoxic conditions survived with declining cell numbers. Significant increases in L. monocytogenes (5 to 7 log) were observed in beef held at 22 degrees C for 5 days, with the lowest levels recovered under anoxic conditions. L. monocytogenes in refrigerated storage increased by a factor of 2 to 4 log. It showed the greatest growth under oxic conditions, with significant growth under anoxic conditions. These findings can be used to enhance food safety in vacuum-packed and modified atmosphere-packaged food products. PMID- 25836394 TI - Evaluation of novel micronized encapsulated essential oil-containing phosphate and lactate blends for growth inhibition of Listeria monocytogenes and Salmonella on poultry bologna, pork ham, and roast beef ready-to-eat deli loaves. AB - Essential oils and their constituents are reported to possess potent antimicrobial activity, but their use in food processing is limited because of low solubility in aqueous systems and volatilization during processing. Two proprietary noncommercial essential oil-containing phosphate blends were evaluated for antimicrobial activity against Salmonella enterica cocktail (SC) and Listeria monocytogenes (Lm)-inoculated deli meat products made from pork, poultry, or beef. Four treatments were tested on restructured cured pork ham, emulsified chicken bologna, and restructured beef loaf: nonencapsulated essential oil with phosphate version 1 at 0.45% of final batch (EOV145; chicken and pork, or EEOV245 beef), micronized encapsulated essential oil with phosphate version 2 at 0.60% of final batch (EEOV260), a 2.0% potassium lactate (PL) control, and a negative control (CN) with no applied antimicrobial agent. Compared with the CN, none of the antimicrobial agents (EEOV260, EOV145, PL) successfully limited Lm or SC growth to <2.0 log cycles over 49 days or 35 days of refrigerated storage, respectively. The PL and EEOV260-treated ham loaves did show Lm growth limiting ability of up to 1 log cycle by days 35 and 42. On formed roast beef, the EEOV260 was able to extend the lag phase and inhibited the growth of Lm in the same manner as the PL. For SC-treated samples, the following effects were observed: in poultry bologna treated with EEOV260, a lag-phase extension was observed through 35 days of storage compared with the other samples. For pork deli loaves, the EEOV260 inhibited growth of SC at days 21 and 28 to the same level of efficacy as PL (0.5 log cycle). In roast beef samples, on day 35, the SC growth was inhibited ca. 0.5 log CFU/g by EEOV260 when compared with the CN. In conclusion the EEOV260 can function to replace PL to limit Salmonella and Lm growth in ready-to-eat deli products. Further testing is needed to ensure consumer acceptability. PMID- 25836395 TI - Effectiveness of sanitizing products on controlling selected pathogen surrogates on retail deli slicers. AB - The objectives of this study were (i) to assess the efficacy of quaternary ammonium chloride-based wet foam (WF) and dry foam (DF) sanitizer systems (600 ppm) for reducing Listeria innocua (a nonpathogenic surrogate of Listeria monocytogenes) or a 100.0 MUg/ml rifampin-resistant Salmonella Typhimurium LT2 (a nonpathogenic surrogate of Salmonella enterica serovar Typhimurium) on niche and transfer point areas of an unwashed retail deli slicer as compared with traditional chlorine (Cl(-)) treatment (200 ppm) and (ii) to compare sanitizer surface contact times (10 and 15 min) for pathogen surrogate control. Turkey frankfurter slurries inoculated with L. innocua or Salmonella Typhimurium were used to inoculate seven high-risk sites on a commercial slicer. After 30 min of bacterial attachment, slicers were dry wiped to remove excess food matter, followed by a randomly assigned sanitizer treatment. Surviving pathogen surrogate cells were enumerated on modified Oxford's agar not containing antimicrobic supplement (L. innocua) or on tryptic soy agar supplemented with 100 MUg/ml rifampin (Salmonella Typhimurium LT2). Replicate-specific L. innocua and Salmonella Typhimurium reductions were calculated as log CFU per square centimeter of control minus log CFU per square centimeter of enumerated survivors for each site. For both organisms, all sanitizer treatments differed from each other, with Cl(-) producing the least reduction and WF the greatest reduction. A significant (P < 0.05) site-by-treatment interaction was observed. The results of the study indicate that quaternary ammonium chloride sanitizers (600 ppm) applied by both WF and DF were more effective at reducing L. innocua and Salmonella Typhimurium than a traditional Cl sanitizer (200 ppm) on unwashed slicer surfaces. PMID- 25836396 TI - Efficient reduction of pathogenic and spoilage microorganisms from apple cider by combining microfiltration with UV treatment. AB - Thermal pasteurization can achieve the U. S. Food and Drug Administration required 5-log reduction of pathogenic Escherichia coli O157:H7 and Cryptosporidium parvum in apple juice and cider, but it can also negatively affect the nutritional and organoleptic properties of the treated products. In addition, thermal pasteurization is only marginally effective against the acidophilic, thermophilic, and spore-forming bacteria Alicyclobacillus spp., which is known to cause off-flavors in juice products. In this study, the efficiency of a combined microfiltration (MF) and UV process as a nonthermal treatment for the reduction of pathogenic and nonpathogenic E. coli, C. parvum, and Alicyclobacillus acidoterrestris from apple cider was investigated. MF was used to physically remove suspended solids and microorganisms from apple cider, thus enhancing the effectiveness of UV and allowing a lower UV dose to be used. MF, with ceramic membranes (pore sizes, 0.8 and 1.4 MUm), was performed at a temperature of 10 degrees C and a transmembrane pressure of 155 kPa. The subsequent UV treatment was conducted using at a low UV dose of 1.75 mJ/cm(2). The combined MF and UV achieved more than a 5-log reduction of E. coli, C. parvum, and A. acidoterrestris. MF with the 0.8-MUm pore size performed better than the 1.4-MUm pore size on removal of E. coli and A. acidoterrestris. The developed nonthermal hurdle treatment has the potential to significantly reduce pathogens, as well as spores, yeasts, molds, and protozoa in apple cider, and thus help juice processors improve the safety and quality of their products. PMID- 25836397 TI - Isothermal target and probe amplification assay for the real-time rapid detection of Staphylococcus aureus. AB - Staphylococcus aureus, the species most commonly associated with staphylococcal food poisoning, is one of the most prevalent causes of foodborne disease in Korea and other parts of the world, with much damage inflicted to the health of individuals and economic losses estimated at $120 million. To reduce food poisoning outbreaks by implementing prevention methods, rapid detection of S. aureus in foods is essential. Various types of detection methods for S. aureus are available. Although each method has advantages and disadvantages, high levels of sensitivity and specificity are key aspects of a robust detection method. Here, we describe a novel real-time isothermal target and probe amplification (iTPA) method that allows the rapid and simultaneous amplification of target DNA (the S. aureus nuc gene) and a fluorescence resonance energy transfer-based signal probe under isothermal conditions at 61 degrees C or detection of S. aureus in real time. The assay was able to specifically detect all 91 S. aureus strains tested without nonspecific detection of 51 non-S. aureus strains. The real-time iTPA assay detected S. aureus at an initial level of 10(1) CFU in overnight cultures of preenriched food samples (kiwi dressing, soybean milk, and custard cream). The advantage of this detection system is that it does not require a thermal cycler, reducing the cost of the real-time PCR and its footprint. Combined with a miniaturized fluorescence detector, this system can be developed into a simplified quantitative hand-held real-time device, which is often required. The iTPA assay was highly reliable and therefore may be used as a rapid and sensitive means of identifying S. aureus in foods. PMID- 25836398 TI - Effects of acetic acid and arginine on pH elevation and growth of Bacillus licheniformis in an acidified cucumber juice medium. AB - Bacillus licheniformis has been shown to cause pH elevation in tomato products having an initial pH below 4.6 and metabiotic effects that can lead to the growth of pathogenic bacteria. Because of this, the organism poses a potential risk to acidified vegetable products; however, little is known about the growth and metabolism of this organism in these products. To clarify the mechanisms of pH change and growth of B. licheniformis in vegetable broth under acidic conditions, a cucumber juice medium representative of a noninhibitory vegetable broth was used to monitor changes in pH, cell growth, and catabolism of sugars and amino acids. For initial pH values between pH 4.1 to 6.0, pH changes resulted from both fermentation of sugar (lowering pH) and ammonia production (raising pH). An initial pH elevation occurred, with starting pH values of pH 4.1 to 4.9 under both aerobic and anaerobic conditions, and was apparently mediated by the arginine deiminase reaction of B. licheniformis. This initial pH elevation was prevented if 5 mM or greater acetic acid was present in the brine at the same pH. In laboratory media, under favorable conditions for growth, data indicated that growth of the organism was inhibited at pH 4.6 with protonated acetic acid concentrations of 10 to 20 mM, corresponding to 25 to 50 mM total acetic acid; however, growth inhibition required greater than 300 mM citric acid (10-fold excess of the amount in processed tomato products) products under similar conditions. The data indicate that growth and pH increase by B. licheniformis may be inhibited by the acetic acid present in most commercial acidified vegetable products but not by the citric acid in many tomato products. PMID- 25836399 TI - Analysis of older adults' domestic kitchen storage practices in the United Kingdom: identification of risk factors associated with listeriosis. AB - Increased listeriosis incidence among older adults (>= 60 years) has been reported internationally, with many cases reported to be sporadic and associated with ready-to-eat (RTE) food products with extended refrigerated shelf life. Given that the home kitchen is recognized as a significant location where foodborne illnesses are acquired, it is important that consumers implement safe food practices to minimize risks. This is crucial for vulnerable consumers, such as older adults. Consumer food safety recommendations in the United Kingdom to reduce the risk of listeriosis at home include (i) following "use-by" dates on unopened prepacked RTE food products, (ii) consuming RTE food products within 2 days of opening, and (iii) ensuring the safe operating temperatures of domestic refrigerators (<= 5 degrees C). This study utilized observation, self-reporting, and microbiological analysis to determine actual food storage practices to identify behavioral risk factors. A domestic kitchen survey was conducted in older adult (>= 60 years) consumers' domestic kitchens (n = 100) in South Wales, United Kingdom. Forty-one percent of foods in home refrigerators were beyond the use-by date, of which 11% were unopened RTE food products commonly associated with listeriosis. Sixty-six percent of opened RTE foods had been or were intended to be stored beyond the recommended 2 days after opening. Older adults failed to ensure safe refrigeration temperatures, with 50% of central storage and 85% of door storage areas operating at temperatures >5 degrees C. Older refrigerators operated at significantly (P < 0.05) higher temperatures. Given that Listeria monocytogenes was isolated in 2% of kitchens, these findings suggest that storage malpractices may have a greater effect on the potential risk of listeriosis than its presence alone. The study has determined that many older adults fail to adhere to recommendations and subject RTE foods associated with L. monocytogenes to prolonged storage at unsafe temperatures which may render food unsafe for consumption. PMID- 25836400 TI - Regional variations in home canning practices and the risk of foodborne botulism in the Republic of Georgia, 2003. AB - Foodborne botulism is a severe, paralytic illness caused by ingestion of preformed neurotoxins produced by Clostridium botulinum. In 2003, we conducted a population-based household survey of home canning practices to explore marked regional variations in botulism incidence in the Republic of Georgia (ROG). We designed a cluster sampling scheme and subdivided each of the 10 regions of the ROG into a variable number of strata. Households were selected from each stratum using a two-step cluster sampling methodology. We administered a questionnaire about home canning practices to household members responsible for food preparation. Using multivariate logistic regression analysis, we modeled high (eastern ROG) against low (western ROG) incidence areas. Overall, we surveyed 2,742 households nationwide. Home canning with a capping device hermetically sealing the lid covering the jar was practiced by 1,909 households (65.9%; 95% confidence interval [CI]: 59.8 to 72.1%). Canning was more prevalent in regions of low botulism incidence (34 versus 32%; P < 0.01). When compared with low botulism areas, the following practices were associated with an increased risk in high-botulism areas: >= 6 months between canning vegetables and consuming them (adjusted odds ratio [aOR] = 2.1; 95% CI: 1.3 to 3.5) and adding any of the following ingredients to the jar at time of preparation: >1 tablespoon of salt per liter (aOR = 5.1; 95% CI: 1.2 to 22.6); vinegar (aOR = 2.2; 95% CI: 1.3 to 3.7), and greens (aOR = 5.6; 95% CI: 1.7 to 18.2). The following practices were associated with a decreased risk in high-botulism areas: >57 jars canned per household annually (aOR = 0.5; 95% CI: 0.3 to 0.9), covering or immersing vegetables in boiling water before placing them into the jar (aOR = 0.3 95% CI: 0.2 to 0.6), covering or immersing vegetables in boiling water after placing them into the jar (aOR = 0.4; 95% CI: 0.2 to 0.9), or adding garlic (aOR = 0.2; 95% CI: 0.1 to 0.5) or aspirin (aOR = 0.1; 95% CI: 0.1 to 0.2) to the jar at the time of preparation. PMID- 25836401 TI - Prevalence, resistance patterns, and risk factors for antimicrobial resistance in bacteria from retail chicken meat in Colombia. AB - As a step toward implementing the Colombian Integrated Program for Antimicrobial Resistance Surveillance (COIPARS), this study aimed to establish the baseline antimicrobial resistance patterns of Salmonella serovars, Escherichia coli, and Enterococcus spp. isolates in retail poultry meat from independent stores and from a main chain distributor center. MICs of the isolates were determined for antimicrobials used both in humans and animals, using an automated system. Salmonella serovars were isolated from 26% of the meat samples and E. coli from 83%, whereas Enterococcus faecalis and Enterococcus faecium were detected in 81 and 13% of the meat samples, respectively. A principal finding of concern in this study was that almost 98% of isolates tested were multidrug resistant. Ceftiofur, enrofloxacin, nalidixic acid, and tetracycline were the antimicrobials that showed the highest frequency of resistance among Salmonella and E. coli isolates. For enterococci, 61.5% of E. faecium isolates were found to be resistant to quinupristin-dalfopristin; this is significant because it is used to treat nosocomial infections when vancomycin resistance is present. Vancomycin resistance was detected in 4% of the E. faecalis isolates. The results of our study highlight the need for rapid implementation of an integrated program for surveillance of antimicrobial resistance by the Colombian authorities in order to monitor trends, raise awareness, and help promote practices to safeguard later generation antimicrobial agents. PMID- 25836402 TI - Occurrence and antimicrobial resistance of enterococci isolated from organic and conventional retail chicken. AB - Antibiotic-resistant bacteria existing in agricultural environments may be transferred to humans through food consumption or more multifaceted environmental paths of exposure. Notably, enterococcal infections are becoming more challenging to treat as their resistance to antibiotics intensifies. In this study, the prevalence and antibiotic resistance profiles of enterococci in organic and conventional chicken from retail stores were analyzed. Of the total 343 retail chicken samples evaluated, 282 (82.2%) were contaminated with Enterococcus spp. The prevalence was higher in organic chicken (62.5%) than conventional chicken (37.5%). Enterococcus isolates were submitted to susceptibility tests against 12 antimicrobial agents. Among the isolates tested, streptomycin had the highest frequencies of resistance (69.1 and 100%) followed by erythromycin (38.5 and 80.0%), penicillin (14.1 and 88.5%), and kanamycin (11.3 and 76.9%) for organic and conventional isolates, respectively. Chloramphenicol had the lowest frequency (0.0 and 6.6%, respectively). The predominant species in raw chicken was E. faecium (27.3%), followed by E. gallinarum (6.0%), E. casseliflavus (2.1%), and E. durans (1.4%). These species were also found to be resistant to three or more antibiotics. The data indicated that antibiotic-resistant enterococci isolates were found in chicken whether it was organic or conventional. However, enterococci isolates that were resistant to antibiotics were less common in organic chicken (31.0%) when compared with those isolated from conventional chicken (43.6%). The results of this study suggest that raw retail organic and conventional chickens could be a source of antibiotic-resistant enterococci. PMID- 25836403 TI - Effect of allyl isothiocyanate against Anisakis larvae during the anchovy marinating process. AB - Allyl isothiocyanate (AITC), is a natural compound found in plants belonging to the family Cruciferae and has strong antimicrobial activity and a biocidal activity against plants parasites. Anisakidosis is a zoonotic disease caused by the ingestion of larval nematodes in raw, almost raw, and marinated and/or salted seafood dishes. The aim of this work was to evaluate the effect of AITC against Anisakis larvae and to study its potential use during the marinating process. The effects of AITC against Anisakis larvae were tested in three experiment: in vitro with three liquid media, in semisolid media with a homogenate of anchovy muscle, and in a simulation of two kinds of anchovy fillets marinating processes. For all tests, the concentrations of AITC were 0, 0.01, 0.05, and 0.1%. Significant activity of AITC against Anisakis larvae was observed in liquid media, whereas in the semisolid media, AITC was effective only at higher concentrations. In anchovy fillets, prior treatment in phosphate buffer solution (1.5% NaCl, pH 6.8) with 0.1% AITC and then marination under standard conditions resulted in a high level of larval inactivation. AITC is a good candidate for further investigation as a biocidal agent against Anisakis larvae during the industrial marinating process. PMID- 25836404 TI - Analysis of the essential oil of Illicium henryi Diels root bark and its insecticidal activity against Liposcelis bostrychophila Badonnel. AB - Water-distilled essential oil from Illicium henryi (Illiciaceae) root bark was analyzed by gas chromatography-mass spectrometry. Thirty-four compounds, accounting for 97.86% of the total oil, were identified. The main components of the essential oil of I. henryi root bark were safrole (46.12%), myristicin (20.39%), and 1,8-cineole (6.17%), followed by alpha-cadinol (3.784%) and linalool (3.22%). The essential oil had higher levels of phenylpropanoids (66.89%) than of monoterpenoids (14.83%) and sesquiternoids (16.14%). Three constituents were isolated from the oil based on bioactivity fractionation. The essential oil possessed fumigant toxicity against booklice (Liposcelis bostrychophila), with a 50% lethal concentration (LC50) of 380.39 MUg/liter of air, while the two isolated constituents myristicin and safrole had LC50s of 121.95 and 322.54 MUg/liter, respectively. Another constituent, 1,8-cineole, showed weaker toxicity, with an LC50 of 1,120.43 MUg/liter. The essential oil also exhibited contact toxicity against L. bostrychophila, with an LC50 of 96.83 MUg/cm(2). Myristicin (LC50, 18.74 MUg/cm(2)) and safrole (LC50, 69.28 MUg/cm(2)) exhibited stronger acute toxicity than 1,8-cineole (LC50, 1,049.41 MUg/cm(2)) against the booklice. The results indicated that the essential oil and its constituent compounds have potential for development into natural insecticides for control of psocids in stored grains. PMID- 25836405 TI - Quantitative data analysis to determine best food cooling practices in U.S. restaurants. AB - Data collected by the Centers for Disease Control and Prevention (CDC) show that improper cooling practices contributed to more than 500 foodborne illness outbreaks associated with restaurants or delis in the United States between 1998 and 2008. CDC's Environmental Health Specialists Network (EHS-Net) personnel collected data in approximately 50 randomly selected restaurants in nine EHS-Net sites in 2009 to 2010 and measured the temperatures of cooling food at the beginning and the end of the observation period. Those beginning and ending points were used to estimate cooling rates. The most common cooling method was refrigeration, used in 48% of cooling steps. Other cooling methods included ice baths (19%), room-temperature cooling (17%), ice-wand cooling (7%), and adding ice or frozen food to the cooling food as an ingredient (2%). Sixty-five percent of cooling observations had an estimated cooling rate that was compliant with the 2009 Food and Drug Administration Food Code guideline (cooling to 41 degrees F [5 degrees C] in 6 h). Large cuts of meat and stews had the slowest overall estimated cooling rate, approximately equal to that specified in the Food Code guideline. Pasta and noodles were the fastest cooling foods, with a cooling time of just over 2 h. Foods not being actively monitored by food workers were more than twice as likely to cool more slowly than recommended in the Food Code guideline. Food stored at a depth greater than 7.6 cm (3 in.) was twice as likely to cool more slowly than specified in the Food Code guideline. Unventilated cooling foods were almost twice as likely to cool more slowly than specified in the Food Code guideline. Our data suggest that several best cooling practices can contribute to a proper cooling process. Inspectors unable to assess the full cooling process should consider assessing specific cooling practices as an alternative. Future research could validate our estimation method and study the effect of specific practices on the full cooling process. PMID- 25836406 TI - Belgian and Spanish consumption data and consumer handling practices for fresh fruits and vegetables useful for further microbiological and chemical exposure assessment. AB - A consumer survey was organized in Spain and Belgium to obtain consumption data and to gain insight into consumer handling practices for fresh vegetables consumed raw or minimally processed (i.e., heads of leafy greens, bell peppers, tomatoes, fresh herbs, and precut and packed leafy greens) and fruits to be consumed without peeling (i.e., apples, grapes, strawberries, raspberries, other berries, fresh juices, and precut mixed fruit). This information can be used for microbiological and/or chemical food safety research. After extensive cleanup of rough databases for missing and extreme values and age correction, information from 583 respondents from Spain and 1,605 respondents from Belgium (18 to 65 years of age) was retained. Daily intake (grams per day) was calculated taking into account frequency and seasonality of consumption, and distributions were obtained that can be used in quantitative risk assessment for chemical hazards with chronic effects on human health. Data also were recalculated to obtain discrete distributions of consumption per portion and the corresponding frequency of consumption, which can be used in acute microbiological risk assessment or outbreak investigations. The ranked median daily consumption of fruits and vegetables was similar in Spain and Belgium: apple > strawberry > grapes > strawberries and raspberries; and tomatoes > leafy greens > bell peppers > fresh herbs. However, vegetable consumption was higher (in terms of both portion and frequency of consumption) in Spain than in Belgium, whereas the opposite was found for fruit consumption. Regarding consumer handling practices related to storage time and method, Belgian consumers less frequently stored their fresh produce in a refrigerator and did so for shorter times compared with Spanish consumers. Washing practices for lettuce heads and packed leafy greens also were different. The survey revealed differences between these two countries in consumption and consumer handling practices, which can have an impact on outcomes of future microbiological or chemical risk assessment studies. PMID- 25836407 TI - Genetic characterization of Escherichia coli isolated from cattle carcasses and feces in Mexico state. AB - Meat of bovine origin is one of the major vehicles in the transmission of verotoxigenic Escherichia coli (VTEC) to human consumers. This pathogen can produce serious human illness, including bloody diarrhea and hemolytic uremic syndrome. The aim of the current study was to characterize E. coli isolates (mainly VTEC strains) belonging to several serotypes in samples from cattle carcasses and feces of three municipal slaughter plants from Mexico State. The genetic diversity and molecular relatedness among the isolates was evaluated with multiple-locus variable-number tandem repeat analysis (MLVA). To our knowledge, and with the exception of E. coli O157:H7, this is the first time that serotypes analyzed here have been subtyped by MLVA in Mexico. MLVA typing grouped the 37 strains from this study into 30 distinct genotypes, 26 of which were unique. These findings indicate that cattle carcasses and feces from slaughter plants in Mexico are a source of VTEC that are genetically diverse in terms of serotypes and virulence profiles. The presence of these pathogens in carcasses indicates the high probability of the spread of VTEC strains during slaughter and processing. PMID- 25836408 TI - Molecular characterization of Salmonella paratyphi B dT+ and Salmonella Heidelberg from poultry and retail chicken meat in Colombia by pulsed-field gel electrophoresis. AB - Salmonella Paratyphi B dT+ variant (also termed Salmonella Java) and Salmonella Heidelberg are pathogens of public health importance that are frequently isolated from poultry. As a step toward implementing the Colombian Integrated Program for Antimicrobial Resistant Surveillance, this study characterized molecular patterns of Salmonella Paratyphi B dT+ and Salmonella Heidelberg isolated from poultry farms, fecal samples, and retail chicken meat using pulsed-field gel electrophoresis (PFGE). The objective of this study was to determine the genetic relationship among isolates and to determine potential geographically predominant genotypes. Based on PFGE analysis, both serovars exhibited high heterogeneity: the chromosomal DNA fingerprints of 82 Salmonella Paratyphi B dT+ isolates revealed 42 PFGE patterns, whereas the 21 isolates of Salmonella Heidelberg revealed 10 patterns. Similar genotypes of both serovars were demonstrated to be present on farms and in retail outlets. For Salmonella Paratyphi B dT+, closely genetically related strains were found among isolates coming from different farms and different integrated poultry companies within two departments (Santander and Cundinamarca) and also from farms located in the two geographically distant departments. For Salmonella Heidelberg, there were fewer farms with genetically related isolates than for Salmonella Paratyphi B dT+. A possible dissemination of similar genotypes of both serovars along the poultry production chain is hypothesized, and some facilitating factors existing in Colombia are reviewed. PMID- 25836409 TI - Zoonotic species of the genus Arcobacter in poultry from different regions of Costa Rica. AB - In recent years, emerging pathogens have received special attention due to their consequences for public health. Given that Arcobacter has been isolated in Costa Rica from commercial meat poultry samples, the aim of this research was to determine its isolation frequency from laying hens, broilers, ducks, and geese and to compare two types of samples, namely, cloacal swabs and stool collection. Arcobacter was isolated from 22 (11%) of the 200 samples examined. Fifteen (55%), eight (30%), and four (15%) of the isolated strains were identified as A. butzleri, A. cryareophilus, and Arcobacter spp., respectively. Also, there is a statistically significant difference among the isolation frequencies of Arcobacter for the types of samples evaluated, yielding more isolates from stool samples than from cloacal swab collection. This work describes the distribution of Arcobacter in farm animals as potential sources for its spread from animal derived products. PMID- 25836410 TI - Microbiological diversity and prevalence of spoilage and pathogenic bacteria in commercial fermented alcoholic beverages (beer, fruit wine, refined rice wine, and yakju). AB - The present study examined 469 commercially available fermented alcoholic beverages (FABs), including beer (draft, microbrewed, and pasteurized), fruit wine (grape and others), refined rice wine, and yakju (raw and pasteurized). Samples were screened for Escherichia coli and eight foodborne pathogens (Bacillus cereus, Campylobacter jejuni, Clostridium perfringens, Escherichia coli O157:H7, Listeria monocytogenes, Salmonella spp., Staphylococcus aureus, and Yersinia enterocolitica), and the aerobic plate count, lactic acid bacteria, acetic acid bacteria, fungi, and total coliforms were also enumerated. Microbrewed beer contained the highest number of microorganisms (average aerobic plate count, 3.5; lactic acid bacteria, 2.1; acetic acid bacteria, 2.0; and fungi, 3.6 log CFU/ml), followed by draft beer and yakju (P < 0.05), whereas the other FABs contained , 25 CFU/25 ml microorganisms. Unexpectedly, neither microbial diversity nor microbial count correlated with the alcohol content (4.7 to 14.1%) or pH (3.4 to 4.2) of the product. Despite the harsh conditions, coliforms (detected in 23.8% of microbrewed beer samples) and B. cereus (detected in all FABs) were present in some products. B. cereus was detected most frequently in microbrewed beer (54.8% of samples) and nonpasteurized yakju (50.0%), followed by pasteurized yakju (28.8%), refined rice wine (25.0%), other fruit wines (12.3%), grape wine (8.6%), draft beer (5.6%), and pasteurized beer (2.2%) (P < 0.05). The finding that spore-forming B. cereus and coliform bacteria can survive the harsh conditions present in alcoholic beverages should be taken into account (alongside traditional quality indicators such as the presence of lactic acid-producing bacteria, acetic acid-producing bacteria, or both) when developing manufacturing systems and methods to prolong the shelf life of high quality FAB products. New strategic quality management plans for various FABs are needed. PMID- 25836411 TI - Growth Inhibition of Listeria monocytogenes, Salmonella enterica, and Escherichia coli O157:H7 by D-tryptophan as an incompatible solute. AB - Under osmotic stress, bacterial cells uptake compatible solutes such as glycine betaine to maintain homeostasis. It is unknown whether incompatible solutes exist that are similar in structure to compatible solutes but have adverse physiological effects on bacterial physiology. The objective of this study was to evaluate solute incompatibility of various amino acids against bacterial growth. Bacterial growth was evaluated by changes in optical density at 595 nm in peptone yeast-glucose (PYG) broth. Twenty-three amino acids with L and/or D isomers were examined for the effect of bacterial growth inhibition. Among the various amino acids examined, D-tryptophan (~ 40 mM) in PYG broth supplemented with 0 to 4% (wt/vol) salt inhibited the growth of Listeria monocytogenes, Salmonella enterica, and Escherichia coli O157:H7 at 25 degrees C. D-Tryptophan (30 to 40 mM) completely inhibited the growth of E. coli O157:H7 and Salmonella in the presence of >3% salt, but the growth of L. monocytogenes was not completely inhibited under the same conditions. Low concentrations of salt (0 to 2% NaCl) with D-tryptophan did not significantly inhibit the growth of all bacteria except L. monocytogenes, which was relatively inhibited at 0% NaCl. The effect of D tryptophan differed depending on the bacterial species, illustrating the difference between gram-positive and gram-negative bacteria. These results indicate that the uptake of D-tryptophan as a compatible solute during osmotic stress may inhibit bacterial growth. The antibacterial effect of D-tryptophan found in this study suggests that D-tryptophan could be used as a novel preservative for controlling bacterial growth in foods. PMID- 25836412 TI - Aerobic plate counts and ATP levels correlate with Listeria monocytogenes detection in retail delis. AB - Listeria monocytogenes is a foodborne pathogen that causes an estimated 1,591 cases of illness and 255 deaths annually in the United States, the majority of which are attributed to ready-to-eat deli meats processed in retail delis. Because retail delis distribute product directly to consumers, rapid methods to validate cleaning and sanitation are needed to improve retail food safety. This study investigated the relationships among ATP levels, standard aerobic plate count (APC), and L. monocytogenes presence in fully operational delis. Fifteen full-service delis were concurrently sampled for ATP, APC, and L. monocytogenes during preoperational hours once monthly for 3 months. Fifteen additional delis were recruited for 6 months of operational sampling (n = 30). A 1-log increase in APC was equivalent to a 3.3-fold increase in the odds of detecting L. monocytogenes (P < 0.001) and a 1.9-log increase in L monocytogenes population (P = 0.03). An ATP level increase of 1 log relative light unit correlated to a 0.22 log increase in APC (P < 0.001). A preoperational ATP level mean increase by 1 log relative light unit increased the odds of detecting L. monocytogenes concurrently fourfold. A 0.5-log increase in mean ATP level during preoperational sampling corresponded to a 2% increase in the predicted L. monocytogenes prevalence during operation (P < 0.01). Additionally, 10 statistically representative sites were identified and recommended for use in sanitation monitoring programs. Our data support the use of ATP as a rapid method to validate effective cleaning and sanitation to reduce L. monocytogenes in retail delis. PMID- 25836413 TI - Effect of extrinsic factors on the production of guaiacol by Alicyclobacillus spp. AB - Alicyclobacillus spp. is of significance to the fruit juice industry due to the production of guaiacol. Studies on Alicyclobacillus regarding guaiacol focus mainly on novel ways to detect guaiacol or evaluate guaiacol-producing potential of isolated Alicyclobacillus. Basic studies on factors that induce or affect the production of guaiacol and the conversion pathway of vanillic acid to guaiacol are not available. The goal of this study was to evaluate how extrinsic factors can affect the production of guaiacol by Alicyclobacillu s isolates. Guaiacol producing Alicyclobacillus isolates 1016 and 1101 were used in this study and the effects of temperature (25 to 55 degrees C), pH (3.0 to 5.5), and oxygen concentration on guaiacol production in laboratory media was investigated. Maximum production of guaiacol by isolate 1016 was detected within 9 h when incubated at 43 degrees C, pH 4.0, under microaerophilic conditions. Isolate 1101 produced detectable amounts of guaiacol within 8 h at pH 5.0. However, maximum guaiacol production was achieved within 14 h by isolate 1101 when incubated at 50 degrees C. Our results indicate that the production of guaiacol, contrary to common belief, is a rapid reaction under desirable conditions specific to each isolate. The results of this study can be useful for developing rapid guaiacol monitoring methods for Alicyclobacillus-related spoilage or be applied to more detailed enzyme-related studies. PMID- 25836414 TI - Occurrence of ochratoxin a contamination and detection of ochratoxigenic Aspergillus species in retail samples of dried fruits and nuts. AB - Ochratoxin A (OTA) is a mycotoxin produced by several species of Aspergillus and Penicillium and is a potential contaminant of a wide variety of food products. To determine the incidence of OTA contamination in dried fruits and tree nuts, retail packaged and bulk raisins, dates, figs, prunes, almonds, pistachios, and walnuts were collected from small and large supermarkets in seven areas of the United States between 2012 and 2014. Of the 665 samples analyzed, OTA was detected in 48 raisin samples, 4 fig samples, 4 pistachio samples, and 1 date sample. OTA contamination levels ranged from 0.28 to 15.34 ng/g in dried fruits and 1.87 to 890 ng/g in pistachios; two raisin samples and one pistachio sample exceeded the European Union regulatory limit of 10 ng/g. PCR detection of potential OTA-producing Aspergillus species revealed the presence of A. niger, A. welwitschiae, and A. carbonarius in 20, 7, and 7 of the 57 OTA-contaminated samples, respectively. However, OTA-producing A. carbonarius was isolated from only one raisin sample, and no other OTA-producing Aspergillus species were found. These results suggest that raisins are more frequently contaminated with low levels of OTA than are other dried fruits and nuts and that Aspergillus species are the likely source of that contamination. PMID- 25836415 TI - Composition, diffusion, and antifungal activity of black mustard (Brassica nigra) essential oil when applied by direct addition or vapor phase contact. AB - In this study, we characterized the essential oil (EO) of black mustard (Brassica nigra) and quantified its antimicrobial activity, when applied by direct contact into the liquid medium or by exposure in the vapor phase (in laboratory media or in a bread-type product), against the growth of Aspergillus niger, Aspergillus ochraceus, or Penicillium citrinum. Allyl-isothiocyanate (AITC) was identified as the major component of B. nigra EO with a concentration of 378.35 mg/ml. When B. nigra EO was applied by direct contact into the liquid medium, it inhibited the growth of A. ochraceus and P. citrinum when the concentration was 2 MUl/ml of liquid medium (MIC), while for A. niger, a MIC of B. nigra EO was 4 MUl/ml of liquid medium. Exposure of molds to B. nigra EO in vapor phase showed that 41.1 MUl of B. nigra EO per liter of air delayed the growth of P. citrinum and A. niger by 10 days, while A. ochraceus growth was delayed for 20 days. Exposure to concentrations >= 47 MUl of B. nigra EO per liter of air (MIC) inhibited the growth of tested molds by 30 days, and they were not able to recover after further incubation into an environment free of EO (fungicidal effect). Adsorbed AITC was quantified by exposing potato dextrose agar to B. nigra EO in a vapor phase, exhibiting that AITC was retained at least 5 days when testing EO at its MIC or with higher concentrations. Mustard EO MIC was also effective against the evaluated molds inhibiting their growth for 30 days in a bread-type product when exposed to EO by vapor contact, demonstrating its antifungal activity. PMID- 25836416 TI - Associations between weather and microbial load on fresh produce prior to harvest. AB - Contaminated produce causes approximately 1 million cases of foodborne illness and 1 billion dollars in damages to the U.S. economy annually. The environmental conditions, especially weather, that influence the inoculation, proliferation, and dispersal of microbial load on produce are not well understood. Using a mixed models approach, we examined the relationship of temperature and precipitation to microbial indicators of contamination on fresh produce on the farm over a week long period prior to harvest. Between 2000 and 2002, we assayed for four microbial indicators of contamination (aerobic plate count, Enterococcus, total coliforms, and Escherichia coli) on 10 produce types in 15 fields in the southern United States. The sample collection times varied, with most occurring between January and May. We collected hourly weather data for the corresponding time period and location. Our results indicated that there was a significant association between the average daily temperature (20 degrees C) and both log aerobic plate count (e.g., an increase of 0.074 log CFU/g [standard error {SE}, 0.023] per degrees C increase in weekly average temperature) and log Enterococcus (e.g., an increase of 0.15 log CFU/g [SE, 0.031] per degrees C increase in weekly average temperature) for approximately 5 days prior to sample collection. Daily total precipitation was significantly associated with log coliforms on 2 days (~0.11 log CFU/g [SE, 0.06] per mm of precipitation) during the week-long lag period prior to harvest. Our results suggest that microbial indicator concentrations may increase as the temperature increases. Precipitation may have a positive but complex relationship with microbial indicators, as precipitation may create moist conditions conducive to bacterial growth, spread contamination onto the field, or wash contamination off of the plant. PMID- 25836417 TI - Rapid detection of Lactobacillus kefiranofaciens in kefir grain and kefir milk using newly developed real-time PCR. AB - Lactobacillus kefiranofaciens is an indicator microorganism for kefir and a key factor in kefir grain formation and kefiran production. We designed a novel real time PCR primer and probe set, LKF_KU504, for the rapid detection of L. kefiranofaciens. In inclusivity and exclusivity tests, only 14 L. kefiranofaciens strains were positive among 61 microorganisms, indicating 100 % sensitivity and specificity. The LKF_KU504 set also differentiated kefir milk from 30 commercial nonkefir yogurts. The levels of L. kefiranofaciens in kefir grain and kefir milk were significantly different, indicating L. kefiranofaciens was more concentrated in kefir grain than in kefir milk. PMID- 25836418 TI - BAFF receptors and ligands create independent homeostatic niches for B cell subsets. AB - The BAFF family of receptors and ligands controls B cell homeostasis and selection. Recent studies reveal distinct sources and roles for systemic versus locally produced BAFF. Moreover, the notion that differential BAFF receptor expression patterns establish independent homeostatic and selective niches has been strengthened. Finally, unique roles for BAFF family members in the regulation of antigen experienced and innate B cell subsets have been revealed. Herein, we overview current knowledge in these areas, emphasizing recent findings that inform these ideas. PMID- 25836419 TI - Mitochondrial iron and energetic dysfunction distinguish fibroblasts and induced neurons from pantothenate kinase-associated neurodegeneration patients. AB - Pantothenate kinase-associated neurodegeneration is an early onset autosomal recessive movement disorder caused by mutation of the pantothenate kinase-2 gene, which encodes a mitochondrial enzyme involved in coenzyme A synthesis. The disorder is characterised by high iron levels in the brain, although the pathological mechanism leading to this accumulation is unknown. To address this question, we tested primary skin fibroblasts from three patients and three healthy subjects, as well as neurons induced by direct fibroblast reprogramming, for oxidative status, mitochondrial functionality and iron parameters. The patients' fibroblasts showed altered oxidative status, reduced antioxidant defence, and impaired cytosolic and mitochondrial aconitase activities compared to control cells. Mitochondrial iron homeostasis and functionality analysis of patient fibroblasts indicated increased labile iron pool content and reactive oxygen species development, altered mitochondrial shape, decreased membrane potential and reduced ATP levels. Furthermore, analysis of induced neurons, performed at a single cell level, confirmed some of the results obtained in fibroblasts, indicating an altered oxidative status and signs of mitochondrial dysfunction, possibly due to iron mishandling. Thus, for the first time, altered biological processes have been identified in vitro in live diseased neurons. Moreover, the obtained induced neurons can be considered a suitable human neuronal model for the identification of candidate therapeutic compounds for this disease. PMID- 25836423 TI - Experimental observation of aberration cancellation in entangled two-photon beams. AB - In this work we show that using two-photon correlation imaging and a suitably prepared source of photon pairs, antisymmetric optical aberrations of an imaging system can be cancelled out. The conditions under which this cancellation takes place are discussed. PMID- 25836422 TI - Targeting P(2)X(7) receptor for the treatment of central post-stroke pain in a rodent model. AB - Stroke is a leading cause of death and disability in industrialized countries. Approximately 8-14% of stroke survivors suffer from central post-stroke pain (CPSP) when hemorrhagic stroke occurs in lateral thalamic regions, which severely affects their quality of life. Because the mechanisms of CPSP are not well understood, effective treatments have not been developed. In the present study, we tested the hypothesis that persistent CPSP is caused by P(2)X(7)receptor activation after brain tissue damage and subsequent elevations in inflammatory cytokines. A thalamic hemorrhagic rat model was used, characterized by thermal and mechanical allodynia that develops in the subacute to chronic phases upon CPSP onset. We found a significant increase in P(2)X(7) expression in reactive microglia/macrophages in thalamic peri-lesion tissues at 5 weeks post-hemorrhage. Thalamic P(2)X(7) receptors were directly involved in pain transmission and hypersensitivity. The systemic targeting of P(2)X(7) receptors during the acute stage of hemorrhage rescued abnormal pain behaviors and neuronal activity in the thalamocingulate pathway by reducing reactive microglia/macrophage aggregation and associated inflammatory cytokines. After CPSP onset, the targeting of interleukin-1beta reversed abnormal pain sensitivity. The aberrant spontaneous thalamocortical oscillations in rats with CPSP were modulated by blocking P(2)X(7) receptors. Taken together, our results suggest that targeting P(2)X(7) may be bi-effective in the treatment of CPSP, as both a pain blocker and immunosuppressant that inhibits inflammatory damage to brain tissue. P(2)X(7)receptors may serve as a potential target to prevent the occurrence of CPSP and may be beneficial for the recovery of patients from stroke. PMID- 25836424 TI - Biaxial crystal alpha-BaTeMo(2)O(9): theory study of large birefringence and wide band polarized prisms design. AB - alpha-BaTeMo(2)O(9) is a novel biaxial crystal with wide-band transmittance spectrum. The refractive index dispersion curves and birefringence of the alpha BaTeMo(2)O(9) crystal were obtained in spectral range of 0.4~5 MUm. The origin of the birefringence for the crystal has been calculated and interpreted on the basis of the crystal structure combined with theoretical studies. The polarized directions and formulations of refractive index of optical waves in biaxial alpha BaTeMo(2)O(9) were investigated by solving the refractive index ellipsoid equations. Furthermore, polarized prisms based on the alpha-BaTeMo(2)O(9) crystal used in spectral ranges of 0.4~2.7 MUm and 0.48~4.5 MUm were designed and characterized. The extinction ratios of both prisms were determined to be larger than 10000:1, which would satisfy the practical requirements. The impacts on extinction ratio for biaxial and uniaxial crystals were also discussed. To our knowledge, it is the first report about biaxial crystals for the polarized prisms, and the results show that the alpha-BaTeMo(2)O(9) crystal is a promising material for polarized optical components, especially in the range of 3~5 MUm. PMID- 25836421 TI - Albumin induces excitatory synaptogenesis through astrocytic TGF-beta/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. AB - Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-beta) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-beta-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-beta inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-beta-pathway as a potential strategy for the prevention of PIE. PMID- 25836420 TI - Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. AB - Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6months, by 12months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression. PMID- 25836425 TI - Dual broadband metamaterial absorber. AB - We propose polarization-independent and dual-broadband metamaterial absorbers at microwave frequencies. This is a periodic meta-atom array consisting of metal dielectric-multilayer truncated cones. We demonstrate not only one broadband absorption from the fundamental magnetic resonances but additional broadband absorption in high-frequency range using the third-harmonic resonance, by both simulation and experiment. In simulation, the absorption was over 90% in 3.93 6.05 GHz, and 11.64-14.55 GHz. The corresponding experimental absorption bands over 90% were 3.88-6.08 GHz, 9.95-10.46 GHz and 11.86-13.84 GHz, respectively. The origin of absorption bands was elucidated. Furthermore, it is independent of polarization angle owing to the multilayered circular structures. The design is scalable to smaller size for the infrared and the visible ranges. PMID- 25836426 TI - Modulation instability in amplitude modulated dispersion oscillating fibers. AB - We investigate theoretically and experimentally the modulation instability process in a dispersion oscillating fiber characterized by an amplitude modulation of its group velocity dispersion. We developed an analytical model that allows us to calculate the parametric gain in these fibers and to predict the position of the quasi-phase matched modulation instability sidelobes. The two fundamental frequencies characterizing the dispersion profile lead to the splitting of the original multiple sidelobes generated in basic sinusoidally varying dispersion oscillating fibers. These theoretical predictions are confirmed by experiments. PMID- 25836427 TI - Gain-guided index-antiguided fiber with a Fabry-Perot layer for large mode area laser amplifiers. AB - We propose a modified gain-guided index-antiguided (GGIAG) fiber structure for large mode area laser amplifiers, in which a thin dielectric layer is placed between the low-index core and the high-index cladding. The introduced dielectric layer functions as a Fabry-Perot etalon. By letting the resonant wavelength of the Fabry-Perot layer coincide with the signal wavelength, the signal is gain guided in the fiber core. Moreover, the pump is confined in the low-index core owing to the antiresonant reflection originated from the Fabry-Perot layer. Numerical results indicate that the leakage loss of the pump can be minified over two orders of magnitude in the proposed structure, and thus the end-pumping efficiency could be enhanced significantly. PMID- 25836428 TI - Performance analysis of an all-optical OFDM system in presence of non-linear phase noise. AB - The potential for higher spectral efficiency has increased the interest in all optical orthogonal frequency division multiplexing (OFDM) systems. However, the sensitivity of all-optical OFDM to fiber non-linearity, which causes nonlinear phase noise, is still a major concern. In this paper, an analytical model for estimating the phase noise due to self-phase modulation (SPM), cross-phase modulation (XPM), and four-wave mixing (FWM) in an all-optical OFDM system is presented. The phase noise versus power, distance, and number of subcarriers is evaluated by implementing the mathematical model using Matlab. In order to verify the results, an all-optical OFDM system, that uses coupler-based inverse fast Fourier transform/fast Fourier transform without any nonlinear compensation, is demonstrated by numerical simulation. The system employs 29 subcarriers; each subcarrier is modulated by a 4-QAM or 16-QAM format with a symbol rate of 25 Gsymbol/s. The results indicate that the phase variance due to FWM is dominant over those induced by either SPM or XPM. It is also shown that the minimum phase noise occurs at -3 dBm and -1 dBm for 4-QAM and 16-QAM, respectively. Finally, the error vector magnitude (EVM) versus subcarrier power and symbol rate is quantified using both simulation and the analytical model. It turns out that both EVM results are in good agreement with each other. PMID- 25836429 TI - Fully computed holographic stereogram based algorithm for computer-generated holograms with accurate depth cues. AB - We propose an algorithm based on fully computed holographic stereogram for calculating full-parallax computer-generated holograms (CGHs) with accurate depth cues. The proposed method integrates point source algorithm and holographic stereogram based algorithm to reconstruct the three-dimensional (3D) scenes. Precise accommodation cue and occlusion effect can be created, and computer graphics rendering techniques can be employed in the CGH generation to enhance the image fidelity. Optical experiments have been performed using a spatial light modulator (SLM) and a fabricated high-resolution hologram, the results show that our proposed algorithm can perform quality reconstructions of 3D scenes with arbitrary depth information. PMID- 25836430 TI - Linear compression of chirped pulses in optical fibre with large step-index mode area. AB - The possibilities and limitations of linear compression of positively chirped pulses in the negative-dispersion region of a step-index large mode-area single mode optical fibre are investigated for the first time. Analytical formulae for critical values of radiation power are found, below which pedestal-free pulse compression is possible down to the Fourier limit. It is demonstrated that at radiation powers exceeding these critical values, there exists an optimal compressing fibre length, over which laser pulses reach the minimum of the time bandwidth product, and beyond which irreversible pulse deformation occurs. The modelling results agree well with the experimental data. PMID- 25836431 TI - Enhanced emission of 2.86 MUm from diode-pumped Ho(3+)/Yb(3+)-codoped PbF(2) crystal. AB - A novel Ho(3+)Yb(3+)-codoped PbF(2) mid-IR laser crystal was successfully grown and analyzed. Enhanced emission at 2.86 MUm was observed from the crystal under excitation of a common 970 nm laser diode for the first time. The effect of Yb(3+) codoping on the 2.86 MUm photoluminescence of Ho(3+) was investigated. In comparison to Ho(3+)-singly doped PbF(2) crystal, the Ho(3+)/Yb(3+)-codoped PbF(2) crystal possessed comparable quantum efficiency (88.8%), and fluorescence branching ratio (20.52%) along with a larger calculated emission cross section (1.90*10(-20) cm(2)) corresponding to the laser transition (5)I(6)->(5)I(7) of Ho(3+). It was found that the introduced Yb(3+) enhanced the 2.86 MUm emission by depopulating the Ho(3+):(5)I(7) level. The energy transfer (ET) efficiency from Yb(3+):(2)F(5/2) to Ho(3+):(5)I(6) is as high as 96.7%, indicating that Yb(3+) ion is an effective sensitizer for Ho(3+) ion in PbF(2) crystal. These results suggest that Ho(3+)/Yb(3+)-codoped PbF(2) crystal may become an attractive host for developing solid state lasers at around 2.86 MUm under a conventional 970 nm LD pump. PMID- 25836432 TI - Metasurfaces based dual wavelength diffractive lenses. AB - We demonstrate experimentally and by simulations a method for using thin nanostructured plasmonic metasurfaces to design diffractive Fresnel zone plate lenses that focus pairs of wavelengths to a single focal point. The metasurfaces are made of tightly packed cross and rod shaped optical nanoantennas with strong polarization and wavelength selectivity. This selectivity allows multiplexing two different lenses with low spectral crosstalk on the same substrate and to address any superposition of the two colors at the focus of the lenses by controlling the polarization of light. This concept can open the door to use ultrathin diffractive lenses in fluorescence microscopy and in stimulated emission depletion microscopy. PMID- 25836433 TI - Design of ultra-compact triplexer with function-expansion based topology optimization. AB - In this paper, in order to optimize wavelength selective photonic devices using the function-expansion-based topology optimization method, several expansion functions are considered and the influence on the optimized structure based on each expansion function was investigated. Although the Fourier series is conventionally used in the function-expansion-based method, the optimized structure sometimes has a complicated refractive index distribution. Therefore, we employed a sampling function and a pyramid function to obtain a simpler structure through the optimal design. A triplexer was designed by using our method, and the comparison between the optimized structures based on the three expansion functions was also discussed in detail. PMID- 25836434 TI - Raman shift and strain effect in high-Q photonic crystal silicon nanocavity. AB - We have precisely measured the Raman shift of photonic crystal silicon heterostructure nanocavities for Raman laser applications. We utilized a near infrared excitation laser of wavelength 1.42 MUm in order to avoid local sample heating and exploited two high-Q nanocavity modes to calibrate the Raman frequency. The measured Raman shift was 15.606 THz (520.71 cm(-1)) with a small uncertainty of 1.0 * 10(-3) THz. In addition, we investigated the compressive stress generated in a photonic crystal slab in which a ~5.1 * 10(-3) THz blue shift of the Raman peak and a slight warpage of the slab were observed. We also demonstrated that the stress could be eliminated by using a cantilever structure. PMID- 25836435 TI - Efficient silicon polarization rotator based on mode-hybridization in a double stair waveguide. AB - We present a compact silicon polarization rotator (PR) based on mode hybridization by breaking the cross-sectional symmetry of a double-stair waveguide. The device fabrication is fully compatible with the commonly used silicon photonics processes with no extra masks required. The dependence of device performance on the double-stair waveguide dimensions is investigated using FDTD simulations. Characterizations of the fabricated devices reveal that the 23 MUm-long PR exhibits a polarization extinction ratio (PER) of >17 dB in the wavelength range of 1500-1540 nm. The maximum PER exceeds 30 dB at 1518 nm. PMID- 25836436 TI - Plasmon enhanced Raman scattering effect for an atom near a carbon nanotube. AB - Quantum electrodynamics theory of the resonance Raman scattering is developed for an atom in a close proximity to a carbon nanotube. The theory predicts a dramatic enhancement of the Raman intensity in the strong atomic coupling regime to nanotube plasmon near-fields. This resonance scattering is a manifestation of the general electromagnetic surface enhanced Raman scattering effect, and can be used in designing efficient nanotube based optical sensing substrates for single atom detection, precision spontaneous emission control, and manipulation. PMID- 25836437 TI - Generation of hyper-entanglement on polarization and energy-time based on a silicon micro-ring cavity. AB - In this paper, hyper-entanglement on polarization and energy-time is generated based on a silicon micro-ring cavity. The silicon micro-ring cavity is placed in a fiber loop connected by a polarization beam splitter. Photon pairs are generated by the spontaneous four wave mixing (SFWM) in the cavity bi directionally. The two photon states of photon pairs propagate along the two directions of the fiber loop and are superposed in the polarization beam splitter with orthogonal polarizations, leading to the polarization entanglement generation. On the other hand, the energy-time entanglement is an intrinsic property of photon pairs generated by the SFWM, which maintains in the process of the state superposition. The property of polarization entanglement is demonstrated by the two photon interferences under two non-orthogonal polarization bases. The property of energy-time entanglement is demonstrated by the Franson type interference under two non-orthogonal phase bases. The raw visibilities of all the measured interference fringes are higher than 1/2, the bench mark for violation of the Bell inequality. It indicates that silicon micro ring cavity is a promising candidate to realize high performance hyper entanglement generation. PMID- 25836438 TI - Modeling of surface plasmon resonance in metalized optical waveguides with low V number by eigenmode expansion method. AB - The paper reports on the numerical study of surface plasmon resonance excitation in a bent metal-coated single mode optical fiber with a low V-number. It was shown that by choosing a proper combination of normalized frequency, bend radius, and metal film thickness one can achieve strong coupling between the fundamental mode guided by the fiber core, and symmetric surface plasmon mode supported by the metal layer applied to the fiber cladding. The effect is demonstrated to allow precision refractive index measurement, with spectral sensitivity and resolution estimated at 70 MUm/refractive index unit and 3?10(-7), respectively. PMID- 25836439 TI - Adaptive state observer and PD control for dynamic perturbations in optical systems. AB - High-performance objectives pose strict limitations on residual errors present in the system. External mechanical influences can induce structural vibrations in the optical system which causes a displacement of the lenses present in the system. This will influence the imaging performance, causing degraded images or broadened structures in a lithographic processes. In this paper an adaptive state observer for the detection of structural vibrations of the optical elements of an imaging system based on a series of wavefront tilt measurements is introduced. The observer output is used as an input for a closed-loop PD control to mitigate the lens displacements directly. PMID- 25836440 TI - Optical sideband generation up to room temperature with mid-infrared quantum cascade lasers. AB - Mid-infrared (MIR) sideband generation on a near infrared (NIR) optical carrier is demonstrated within a quantum cascade laser (QCL). By employing an externally injected NIR beam, E(NIR), that is resonant with the interband transitions of the quantum wells in the QCL, the nonlinear susceptibility is enhanced, leading to both frequency mixing and sideband generation. A GaAs-based MIR QCL (E(QCL) = 135 meV) with an aluminum-reinforced waveguide was utilized to overlap the NIR and MIR modes with the optical nonlinearity of the active region. The resulting difference sideband (E(NIR) - E(QCL)) shows a resonant behavior as a function of NIR pump wavelength and a maximum second order nonlinear susceptibility, chi((2)), of ~1 nm/V was obtained. Further, the sideband intensity showed little dependence with the operating temperature of the QCL, allowing sideband generation to be realized at room temperature. PMID- 25836441 TI - High performance computing for a 3-D optical diffraction tomographic application in fluid velocimetry. AB - Optical Diffraction Tomography has been recently introduced in fluid velocimetry to provide three dimensional information of seeding particle locations. In general, image reconstruction methods at visible wavelengths have to account for diffraction. Linear approximation has been used for three-dimensional image reconstruction, but a non-linear and iterative reconstruction method is required when multiple scattering is not negligible. Non-linear methods require the solution of the Helmholtz equation, computationally highly demanding due to the size of the problem. The present work shows the results of a non-linear method customized for spherical particle location using GPU computing and a made-to measure storing format. PMID- 25836442 TI - Fully programmable spectrum sliced chirped microwave photonic filter. AB - A novel chirped microwave photonic filter (MPF) capable of achieving a large radio frequency (RF) group delay slope and a single passband response free from high frequency fading is presented. The design is based upon a Fourier domain optical processor (FD-OP) and a single sideband modulator. The FD-OP is utilized to generate both constant time delay to tune the filter and first order dispersion to induce the RF chirp, enabling full software control of the MPF without the need for manual adjustment. An optimized optical parameter region based on a large optical bandwidth >750 GHz and low slicing dispersion < +/- 1 ps/nm is introduced, with this technique greatly improving the RF properties including the group delay slope magnitude and passband noise. Experimental results confirm that the structure simultaneously achieves a large in-band RF chirp of -4.2 ns/GHz, centre frequency invariant tuning and independent reconfiguration of the RF amplitude and phase response. Finally, a stochastic study of the device passband noise performance under tuning and reconfiguration is presented, indicating a low passband noise <-120 dB/Hz. PMID- 25836444 TI - Improvement of light extraction in organic light-emitting diodes using a corrugated microcavity. AB - Based on the phase separation effect in the film formation process of Polystyrene and Poly(methyl methacrylate) blend solution, bottom-emitting organic light emitting diodes (OLEDs) with corrugated microcavity was demonstrated. This device exhibited high efficiency, broad spectra and Lambertian angular emission. Compared with the traditional bottom-emitting OLEDs with ITO anode and the planar microcavity OLEDs, about 57% and 41% enhancement for external quantum efficiency was achieved in this corrugated microcavity OLEDs respectively. This improvement can be understood by the scattering effect of the quasi-periodic characteristic of this corrugated microcavity which reduces the optical loss at surface plasmon polariton modes and wave-guided modes. This work provides a simple as well as efficienct method to recover trapped light in OLEDs, which will benefit the low cost fabrication process. PMID- 25836445 TI - Absolute optical thickness measurement of transparent plate using excess fraction method and wavelength-tuning Fizeau interferometer. AB - The absolute optical thickness of a transparent plate 6-mm thick and 10 mm in diameter was measured by the excess fraction method and a wavelength-tuning Fizeau interferometer. The optical thickness, defined by the group refractive index at the central wavelength, was measured by wavelength scanning. The optical thickness deviation, defined by the ordinary refractive index, was measured using the phase-shifting technique. Two kinds of optical thicknesses, measured by discrete Fourier analysis and the phase-shifting technique, were synthesized to obtain the optical thickness with respect to the ordinary refractive index using Sellmeier equation and least-square fitting. PMID- 25836443 TI - Wigner analysis of three dimensional pupil with finite lateral aperture. AB - A three dimensional (3D) pupil is an optical element, most commonly implemented on a volume hologram, that processes the incident optical field on a 3D fashion. Here we analyze the diffraction properties of a 3D pupil with finite lateral aperture in the 4-f imaging system configuration, using the Wigner Distribution Function (WDF) formulation. Since 3D imaging pupil is finite in both lateral and longitudinal directions, the WDF of the volume holographic 4-f imager theoretically predicts distinct Bragg diffraction patterns in phase space. These result in asymmetric profiles of diffracted coherent point spread function between degenerate diffraction and Bragg diffraction, elucidating the fundamental performance of volume holographic imaging. Experimental measurements are also presented, confirming the theoretical predictions. PMID- 25836446 TI - Gigashot optical degradation in silica optics at 351 nm. AB - As applications of lasers demand higher average powers, higher repetition rates, and longer operation times, optics will need to perform well under unprecedented conditions. We investigate the optical degradation of fused silica surfaces at 351 nm for up to 10(9) pulses with pulse fluences up to 12 J/cm(2). The central result is that the transmission loss from defect generation is a function of the pulse intensity, I(p), and total integrated fluence, phi(T), and is influenced by oxygen partial pressure. In 10(-6) Torr vacuum, at low I(p), a transmission loss is observed that increases monotonically as a function of number of pulses. As the pulse intensity increases above 13 MW/cm(2), the observed transmission losses decrease, and are not measureable for 130 MW/cm(2). A physical model which supports the experimental data is presented to describe the suppression of transmission loss at high pulse intensity. Similar phenomena are observed in anti reflective sol-gel coated optics. Absorption, not scattering, is the primary mechanism leading to transmission loss. In 2.5 Torr air, no transmission loss was detected under any pulse intensity used. We find that the absorption layer that leads to transmission loss is less than 1 nm in thickness, and results from a laser-activated chemical process involving photo-reduction of silica within a few monolayers of the surface. The competition between photo-reduction and photo oxidation explains the measured data: transmission loss is reduced when either the light intensity or the O(2) concentration is high. We expect processes similar to these to occur in other optical materials for high average power applications. PMID- 25836447 TI - Ultrafast tunable chirped phase-change metamaterial with a low power. AB - We numerically demonstrate an all-optical tunable dual-band double negative (DNG) index chirped metamaterial (MM) in the mid-infrared (M-IR) region. This MM possesses an ultrafast and significant tunability under low pump light power, realized by combining phase change material (PCM). It has a configuration of elliptical nanohole array (ENA) penetrating through metal/PCM/metal (Au Ge(2)Sb(2)Te(5)-Au) films. Here, we consider the case when the chirp is introduced by displacing the positions of the ENA along the short axis of the elliptical apertures inside the primitive cell, which can achieve multiple internal surface-plasmon polariton (SPP) modes at the inner metal-dielectric interfaces of the structure and thus providing a dual-band negative index with simultaneous negative permittivity and permeability. The influence of amorphous and crystalline states of Ge(2)Sb(2)Te(5) on the effective optical parameters of the structure is analyzed. Switching between these states provides a large wavelength shift of the structure's effective optical parameters. A photothermal model is used to study the temporal variation of the temperature of the Ge(2)Sb(2)Te(5) layer to show a potential to switch the phase of Ge(2)Sb(2)Te(5) by optical heating. Generation of the tunable dual-band DNG index presents clear advantages as it possesses a fast tuning time of 0.4 ns, a low pump light intensity of 7.3MUW/MUm(2), and a large tunable wavelength range of 978 nm. We expect that our design may have potential applications in actively tunable multi band nanodevices. PMID- 25836448 TI - An ultrastable Michelson interferometer for high-resolution spectroscopy in the XUV. AB - We developed an ultra-stable and accurately-controllable Michelson interferometer to be used in a deeply unbalanced arm configuration for split-pulse XUV Ramsey type spectroscopy with high-order laser harmonics. The implemented active and passive stabilization systems allow one to reach instabilities in the nanometer range over meters of relative optical path differences. Producing precisely delayed pairs of pump pulses will generate XUV harmonic pulses that may significantly improve the achievable spectral resolution and the precision of absolute frequency measurements in the XUV. PMID- 25836449 TI - Welding of PMMA by a femtosecond fiber laser. AB - Developing versatile joining techniques to weld transparent materials on a micrometer scale is of great importance in a growing number of applications, especially for the fabrication and assembly of biomedical devices. In this paper, we report on fs-laser microwelding of two transparent layers of polymethyl methacrylate (PMMA) based on nonlinear absorption and localized heat accumulation at high repetition rates. A fiber CPA laser system was used delivering 650-fs pulses at 1030 nm with repetition rates in the MHz regime. The laser-induced modifications produced by the focused beam into the bulk PMMA were firstly investigated, trying to find a suitable set of process parameters generating continuous and localized melting. Results have been evaluated based on existing heat accumulation models. Then, we have successfully laser welded two 1-mm-thick PMMA layers in a lap-joint configuration. Sealing of the sample was demonstrated through static and dynamic leakage tests. This fs-laser micro-welding process does not need any pre-processing of the samples or any intermediate absorbing layer. Furthermore, it offers several advantages compared to other joining techniques, because it prevents contamination and thermal distortion of the samples, thus being extremely interesting for application in direct laser fabrication of microfluidic devices. PMID- 25836450 TI - Broadband cascaded four-wave mixing and supercontinuum generation in a tellurite microstructured optical fiber pumped at 2 MUm. AB - We demonstrate the broadband cascaded four-wave mixing (FWM) and supercontinuum (SC) generation in a tellurite MOF which is made from 76.5TeO(2)-6ZnO-11.5Li(2)O 6Bi(2)O(3) (TZLB, mol%) glass. By using a 2-MUm picosecond laser with the center wavelength of ~1958 nm as the pump source, the broadband FWM with the frequency separation of ~1.1 THz is obtained. The bandwidth of the frequency comb spans a range of ~630 nm from ~1620 to 2250 nm at the average pump power of ~125 mW. With the average pump power increasing to ~800 mW, the broadband mid-infrared SC generation with the spectrum from ~900 to 3900 nm is observed. Changing the pump source to a femtosecond laser (optical parametric oscillator, OPO) with the center wavelength of ~2000 nm, solitons and dispersive waves (DWs) are obtained. PMID- 25836451 TI - Continuously active interferometer stabilization and control for time-bin entanglement distribution. AB - We describe a new method enabling continuous stabilization and fine-level phase control of time-bin entanglement interferometers. Using this technique we demonstrate entangled photon transmission through 50 km of standard single-mode fiber. This technique reuses the entangled-pair generation pump which is co propagated with the transmitted entangled photons. The co-propagating pump adds minimal noise to the entangled photons which are characterized by measuring a two photon interference fringe. PMID- 25836452 TI - Energy scaling of terahertz-wave parametric sources. AB - Terahertz-wave parametric oscillators (TPOs) have advantages of room temperature operation, wide tunable range, narrow line-width, good coherence. They have also disadvantage of small pulse energy. In this paper, several factors preventing TPOs from generating high-energy THz pulses and the corresponding solutions are analyzed. A scheme to generate high-energy THz pulses by using the combination of a TPO and a Stokes-pulse-injected terahertz-wave parametric generator (spi-TPG) is proposed and demonstrated. A TPO is used as a source to generate a seed pulse for the surface-emitted spi-TPG. The time delay between the pump and Stokes pulses is adjusted to guarantee they have good temporal overlap. The pump pulses have a large pulse energy and a large beam size. The Stokes beam is enlarged to make its size be larger than the pump beam size to have a large effective interaction volume. The experimental results show that the generated THz pulse energy from the spi-TPG is 1.8 times as large as that obtained from the TPO for the same pumping pulse energy density of 0.90 J/cm(2) and the same pumping beam size of 3.0 mm. When the pumping beam sizes are 5.0 and 7.0 mm, the enhancement times are 3.7 and 7.5, respectively. The spi-TPG here is similar to a difference frequency generator; it can also be used as a Stokes pulse amplifier. PMID- 25836453 TI - Characterizing the polarization and cross-polarization of electromagnetic vortex pulses in the space-time and space-frequency domain. AB - The dynamics of the degree of polarization and the degree of cross-polarization for electromagnetic pulsed vortex beams in dispersive media are explored both in the space-time and space-frequency domains. It is shown that the impacts, arising from the second-order dispersion coefficient and the temporal coherence length, on the variations of the temporal degree of polarization are distinctly different from those on the spectral degree of polarization. Besides, we also suggest a method to access the measurement of the orbital angular momentum of pulsed vortex beams through the mapping relationship between the distribution of the temporal degree of cross-polarization and the number of topological charge. PMID- 25836454 TI - Wavelength conversion in Er(3+) doped chalcogenide fibers for optical gas sensors. AB - We report for the first time the conversion of incoherent infrared light around 4.4um into a near-infrared signal at 810nm in erbium-doped GaGeSbS fibers and bulk glass samples. This energy conversion is made possible by pumping erbium doped chalcogenide samples at 982 nm and simultaneously exciting them with a 4.4um infrared signal. This result paves the way for the development of an "all optical" gas sensor able to detect various gas traces using a remote detection based on commercial silica fibers. PMID- 25836455 TI - Active mode-locking of mid-infrared quantum cascade lasers with short gain recovery time. AB - We investigate the dynamics of actively modulated mid-infrared quantum cascade lasers (QCLs) using space- and time-domain simulations of coupled density matrix and Maxwell equations with resonant tunneling current taken into account. We show that it is possible to achieve active mode locking and stable generation of picosecond pulses in high performance QCLs with a vertical laser transition and a short gain recovery time by bias modulation of a short section of a monolithic Fabry-Perot cavity. In fact, active mode locking in QCLs with a short gain recovery time turns out to be more robust to the variation of parameters as compared to previously studied lasers with a long gain recovery time. We investigate the effects of spatial hole burning and phase locking on the laser output. PMID- 25836456 TI - Prospects and merits of metal-clad semiconductor lasers from nearly UV to far IR. AB - Using metal-clad (or plasmonic) waveguide structures in semiconductor lasers carries a promise of reduced size, threshold, and power consumption. This promise is put to a rigorous theoretical test, that takes into account increased waveguide loss, Auger recombination, and Purcell enhancement of spontaneous recombination. The conclusion is that purported benefits of metal waveguides are small to nonexistent for all the band-to-band and intersubband lasers operating from UV to Mid-IR range, with a prominent exception of far-IR and THz quantum cascade lasers. For these devices, however, metal waveguides already represent the state of the art, and the guiding mechanism in them has far more in common with a ubiquitous transmission line than with plasmonics. PMID- 25836457 TI - Effect of multiple scattering to optical forces on a sphere near an optical waveguide. AB - We have investigated the effect of multiple scattering to optical forces on a particle in the evanescent field produced by an optical waveguide. Considering the multiple scattering between the sphere and the waveguide, we extend the formalism based on transition matrix and reflection matrix to calculate the optical forces on a sphere near an optical waveguide. Numerical results show that the influence that multiple scattering has on the optical forces can't be ignored, especially when the structure resonance of the particle arises. Moreover, the effect of multiple scattering to optical forces is also studied in detail on the condition that the distance between the sphere and the waveguide is within the effective operating distance. PMID- 25836458 TI - Highly asymmetric near infrared light transmission in an all-dielectric grating on-mirror photonic structure. AB - We demonstrate a photonic structure, composed of a dielectric quarter-wavelength stack topped with a transmission phase grating, designed to exhibit a significant asymmetry in the near infrared light transmission for waves propagating in opposite directions. The asymmetry, defined as the difference between the intensity transmission coefficients, reaches 0.72 +/- 0.06 for a single wavelength and exceeds 0.2 over a spectral range spanning from 700 to 850 nm for one incident polarization and 750-800 nm for both polarizations. The experimental results are consistent with the numerical model of light propagation in the structure. PMID- 25836460 TI - Production rate enhancement of size-tunable silicon nanoparticles by temporally shaping femtosecond laser pulses in ethanol. AB - This paper proposes an efficient approach for production-rate enhancement and size reduction of silicon nanoparticles produced by femtosecond (fs) double-pulse ablation of silicon in ethanol. Compared with a single pulse, the production rate is ~2.6 times higher and the mean size of the NPs is reduced by ~1/5 with a delay of 2 ps. The abnormal enhancement in the production rate is obtained at pulse delays Deltat > 200 fs. The production-rate enhancement is mainly attributed to high photon absorption efficiency. It is caused by an increase in localized transient electron density, which results from the first sub-pulse ionization of ethanol molecules before the second sub-pulse arrives. The phase-change mechanism at a critical point might reduce nanoparticle size. PMID- 25836459 TI - Spectral fractionation detection of gold nanorod contrast agents using optical coherence tomography. AB - We demonstrate the proof of concept of a novel Fourier-domain optical coherence tomography contrast mechanism using gold nanorod contrast agents and a spectral fractionation processing technique. The methodology detects the spectral shift of the backscattered light from the nanorods by comparing the ratio between the short and long wavelength halves of the optical coherence tomography signal intensity. Spectral fractionation further divides the halves into sub-bands to improve spectral contrast and suppress speckle noise. Herein, we show that this technique can detect gold nanorods in intralipid tissue phantoms. Furthermore, cellular labeling by gold nanorods was demonstrated using retinal pigment epithelial cells in vitro. PMID- 25836461 TI - 105 W ultra-narrowband nanosecond pulsed laser at 2 MUm based on monolithic Tm doped fiber MOPA. AB - We present a high power ultra-narrowband pulsed fiber amplifier at 2 MUm. A single frequency fiber laser was modulated by a phase modulator and an intensity modulator to serve as the ultra-narrowband pulsed seed laser with a bandwidth of 307 MHz. The pulsed seed laser was amplified by a monolithic Tm-doped fiber master oscillator power amplifier (MOPA). The average output power reaches 105 W with a slope efficiency of 0.41. The output pulse train has a repetition rate of 1 MHz and a pulse width of 66 ns. The output power is limited by the onset of stimulated Brillouin scattering. Higher output power can be achieved by further broadening the linewidth or narrowing the pulse width to several nanoseconds. To the best of our knowledge, this is the first demonstration on a monolithic ultra narrowband nanosecond pulsed MOPA at 2 MUm with an average power exceeding 100 W. PMID- 25836462 TI - Uncertainty quantification of silicon photonic devices with correlated and non Gaussian random parameters. AB - Process variations can significantly degrade device performance and chip yield in silicon photonics. In order to reduce the design and production costs, it is highly desirable to predict the statistical behavior of a device before the final fabrication. Monte Carlo is the mainstream computational technique used to estimate the uncertainties caused by process variations. However, it is very often too expensive due to its slow convergence rate. Recently, stochastic spectral methods based on polynomial chaos expansions have emerged as a promising alternative, and they have shown significant speedup over Monte Carlo in many engineering problems. The existing literature mostly assumes that the random parameters are mutually independent. However, in practical applications such assumption may not be necessarily accurate. In this paper, we develop an efficient numerical technique based on stochastic collocation to simulate silicon photonics with correlated and non-Gaussian random parameters. The effectiveness of our proposed technique is demonstrated by the simulation results of a silicon on-insulator based directional coupler example. Since the mathematic formulation in this paper is very generic, our proposed algorithm can be applied to a large class of photonic design cases as well as to many other engineering problems. PMID- 25836464 TI - Gigahertz single source IIR microwave photonic filter based on coherence managed multi-longitudinal-mode fiber laser. AB - In this paper, we propose to use a multi-longitudinal-mode (MLM) laser as the source of an infinite-impulse response (IIR) microwave photonic filter (MPF) to obtain GHz level free spectral range (FSR). The response function of such an IIR MPF and the degree of coherence of the laser are discussed theoretically. The degree of coherence of the MLM laser shows a periodic structure which is significantly different to that of single mode lasers. By engineering the degree of coherence of the MLM laser, we are able to control the stability of the IIR MPFs with different Q factors. It is found that stable IIR-MPF with GHz level FSR can be realized with an MLM laser and its stability can be enhanced if the coherence of the laser is managed. Based on the theoretical analysis, we fabricate an IIR-MPF based on an MLM erbium doped fiber laser. The impacts of the mode spacing Deltanu and the bandwidth to the stability are investigated experimentally. A stable IIR-MPF with an FSR of 0.59 GHz is realized and the relative fluctuation of the response curve is optimized to be less than 2%. Besides stable response, the IIR-MPF is reconfigurable by tuning the central wavelength of the laser in a range of 20 nm. PMID- 25836463 TI - Determining the rotational mobility of a single molecule from a single image: a numerical study. AB - Measurements of the orientational freedom with which a single molecule may rotate or 'wobble' about a fixed axis have provided researchers invaluable clues about the underlying behavior of a variety of biological systems. In this paper, we propose a measurement and data analysis procedure based on a widefield fluorescence microscope image for quantitatively distinguishing individual molecules that exhibit varying degrees of rotational mobility. Our proposed technique is especially applicable to cases in which the molecule undergoes rotational motions on a timescale much faster than the framerate of the camera used to record fluorescence images. Unlike currently available methods, sophisticated hardware for modulating the polarization of light illuminating the sample is not required. Additional polarization optics may be inserted in the microscope's imaging pathway to achieve superior measurement precision, but are not essential. We present a theoretical analysis, and benchmark our technique with numerical simulations using typical experimental parameters for single molecule imaging. PMID- 25836465 TI - La/B(4)C multilayer mirrors with an additional wavelength suppression. AB - In this paper, the authors report on La/B(4)C multilayer mirrors designed for an incidence angle of 45 degrees with both maximum reflectivity at a wavelength of 6.7 nm and reflectivity suppression at a wavelength of 20.1 nm. These mirrors were deposited for the EIS-TIMER at the FERMI@Elettra Free Electron Laser. The multilayer structure and optical properties were characterized using grazing incidence X-ray reflectometry with Cu-K(alpha) radiation and EUV reflectometry in the spectral region of 6.5 - 21.0 nm. An anti-reflective coating designed at the wavelength of 20.1 nm had to be deposited on top of the high reflective La/B(4)C multilayer mirror optimized at a wavelength of 6.7 nm. Measured reflectivities of 53.4% at the wavelength of 6.72 nm and 0.15% at the wavelength of 20.1 nm were simultaneously achieved. It is shown that the reflectivity loss at the wavelength of 6.7 nm due to the utilization of antireflective coating designed at the wavelength of 20.1 nm can be minimized up to 1.0%. PMID- 25836466 TI - Distributed acoustic and vibration sensing via optical fractional Fourier transform reflectometry. AB - Distributed acoustic sensing has been traditionally implemented using optical reflectometry. Here we describe an alternative to the common interrogation approaches. According to the new method the frequency of the source is varied sinusoidally with time. For a sufficiently high scan frequency there is a position along the fiber, z(0), for which the roundtrip time is half the scan period. Back-reflections from this point will generate a linear chirp at the receiver output. The Fractional Fourier Transform (FrFT) is used to analyze the receiver output and yields the reflection profile at z(0) and its vicinity. The method, which enables high spatial resolution at long distances with high scan rates, is demonstrated by detecting deliberate perturbations in the Rayleigh backscatter profile at the end of a 20km fiber with a scanning frequency of ~2.5kHz. The spatial resolution at this range and scan-rate is characterized by a measurement of the backscatter profile from a FBG's-array and is found to be ~2.8m. PMID- 25836467 TI - Polarizing ytterbium-doped all-solid photonic bandgap fiber with ~1150um(2) effective mode area. AB - We demonstrate an Yb-doped polarizing all-solid photonic bandgap fiber for single polarization and single-mode operation with an effective mode area of ~1150um(2), a record for all-solid photonic bandgap fibers. The differential polarization mode loss is measured to be >5dB/m over the entire transmission band with a 160nm bandwidth and >15dB/m on the short wavelength edge of the band. A 2.6m long fiber was tested in a laser configuration producing a linearly polarized laser output with a PER value of 21dB without any polarizer, the highest for any fiber lasers based on polarizing fibers. PMID- 25836468 TI - Polar-grids based source-target mapping construction method for designing freeform illumination system for a lighting target with arbitrary shape. AB - The freeform optical system plays a key role in illumination engineering, and several methods have been reported to manage the design of such system. In this paper, an approach to generate the polar-grids based flux transportation mapping for an arbitrarily-shaped target is proposed based on the conventional variable separation method. The source emitting grid is divided along the azimuth angle and the zenith angle respectively under the spherical coordinate system. Then, the target grid is achieved by solving the flux integral equations in polar coordinates using separation of variables method. When establishing the target grid along the polar radius, a strategy based on uniformly scaling down the external contour of the target is introduced. According to the mapping, a smooth freeform surface is then generated using the geometric construction method according to Snell's law. Finally, an iterative feedback process is adopted to compensate the deterioration of the target distribution caused by surface construction errors and the extension of a real source. Based on this method, a series of freeform lenses are designed for a 1 * 1 mm(2) LED source to generate uniform, Gaussian and multiple-rings illumination distributions within different target regions. High-performance optical systems with the light utilization efficiency eta over 0.8 and the relative standard deviation (RSD) of the simulated illumination distribution less than 0.1 are obtained simultaneously for all the cases. PMID- 25836469 TI - Optical Nyquist pulse generation using a time lens with spectral slicing. AB - Optical Nyquist pulse generation based on a time lens with subsequent optical filtering is proposed. A nearly chirp-free 10-GHz 8.1-ps Nyquist pulse generator is experimentally demonstrated. By inserting group velocity dispersion (GVD) between cascaded phase and amplitude modulators, 11 tones ultraflat optical frequency comb (OFC) of 10-GHz frequency spacing within 0.9 dB power variation is obtained. The quasi-rectangular shape spectrum is then filtered out with a tunable rectangular-shaped optical band-pass filter (OBPF) and the quasi-linear chirp is compensated by a segment of standard single mode fiber (SSMF). By changing the wavelength of the continuous wave (CW) light, nearly chirp-free Nyquist pulses over C band are obtained. Furthermore, simultaneous dual wavelength pulse generation is also demonstrated. PMID- 25836470 TI - Broadband extreme ultraviolet probing of transient gratings in vanadium dioxide. AB - Nonlinear spectroscopy in the extreme ultraviolet (EUV) and soft x-ray spectral range offers the opportunity for element selective probing of ultrafast dynamics using core-valence transitions (Mukamel et al., Acc. Chem. Res. 42, 553 (2009)). We demonstrate a step on this path showing core-valence sensitivity in transient grating spectroscopy with EUV probing. We study the optically induced insulator to-metal transition (IMT) of a VO(2) film with EUV diffraction from the optically excited sample. The VO(2) exhibits a change in the 3p-3d resonance of V accompanied by an acoustic response. Due to the broadband probing we are able to separate the two features. PMID- 25836471 TI - Electro-optical modulation with immunity to optical damage by bipolar operation in potassium lithium tantalate niobate. AB - A method for suppressing the formation of optical damage in quadratic electrooptic devices operated at short wavelengths is presented. Formation of optical damage is attributed to the generation of a trapped space charge induced by photoionization of impurity ions by the propagating beam. It is shown that in potassium lithium tantalate niobate where the electrooptic effect is quadratic, operating the electrooptic device by a bipolar driving voltage prevents the space charge from accumulating, which inhibits the formation of the optical damage. A 6 hours continuous operation of electrooptic modulator for a 30 W/cm(2) at lambda = 445 nm input beam is demonstrated. PMID- 25836472 TI - Polarization microscope using a near infrared full-Stokes imaging polarimeter. AB - This paper presents a polarization microscope using an infrared (IR) full-Stokes imaging polarimeter. The IR polarimeter utilizes an optimized interference-based micropolarizer design, and provides full-Stokes images with resolution of 1608 * 1208 at 35 frames/second. The device fabrication, instrument calibration, performance evaluation, and measurement results are presented. The measurement error of the imaging polarimeter is less than 3.5%, and the standard deviations are less than 2%. PMID- 25836473 TI - Tunable and switchable dual-wavelength Tm-doped mode-locked fiber laser by nonlinear polarization evolution. AB - We propose and demonstrate a tunable and switchable dual-wavelength ultra-fast Tm doped fiber laser. The tunability is based on nonlinear polarization evolution (NPE) technique in a passively mode-locked laser cavity. The NPE effect induces wavelength-dependent loss in the cavity to effectively alleviate mode competition and enables the multiwavelength mode locking. The laser exhibits tunable dual wavelength mode locking over a wide range from 1852 to 1886 nm. The system has compact structure and both the wavelength tuning and switching capabilities can be realized by controlling the polarization in the fiber ring cavity. PMID- 25836474 TI - Precise localized thinning and vertical taper fabrication for silicon photonics using a modified local oxidation of silicon (LOCOS) fabrication process. AB - This paper presents a method to locally fine tune silicon-on-insulator (SOI) device layer thickness for the fabrication of optimal silicon photonics devices. Very precise control of thickness can be achieved with a modified local oxidation of silicon (LOCOS) process. The fabrication process is robust, complementary metal-oxide-semiconductor (CMOS) compatible and has the advantage of creating vertical tapers (~5.3 um long for ~210 nm of height) required for impedance matching between sections of different height. The technology is demonstrated by fabricating a TE-pass filter. PMID- 25836475 TI - Mechanically tunable organic vertical-cavity surface emitting lasers (VCSELs) for highly sensitive stress probing in dual-modes. AB - Herein, we report a straight forward stress probing method based on mechanically tunable organic VCSELs via dual detecting-modes. By designing the active layer thickness, uploaded stress was measured simultaneously by the laser wavelength and mode separations, facilitating highly sensitive stress detection in broad ranges. Single-mode laser emission with low threshold and narrow line-width was characterized, which could be tuned continuously within 8 nm. The probing sensitivity and resolution were estimated to be 60 Pa and 5.6 nm/KPa respectively, which were ~160-folds higher than previous results. PMID- 25836476 TI - Observation of self-trapping and rotation of higher-band gap solitons in two dimensional photonic lattices. AB - We demonstrate self-trapping and rotation of higher-band dipole and quadruple like gap solitons by single-site excitation in a two-dimensional square photonic lattice under self-focusing nonlinearity. Experimental results show that the second-band dipole gap solitons reside in the first photonic (Bragg reflection) gap, whereas the quadruple-like gap solitons are formed in an even higher photonic gap, resulting from modes of the third-band. Moreover, both dipole and quadruple-like gap solitons exhibit dynamical rotation around the lattice principle axes and the direction of rotation is changing periodically during propagation, provided that they are excited under appropriate initial conditions. In the latter case, the nonlinear rotation is accompanied by periodic transitions between quadruple and doubly-charged vortex states. Our numerical simulations find good agreement with the experimental observations. PMID- 25836477 TI - Mid-IR photoluminescence of Fe(2+) and Cr(2+) ions in ZnSe crystal under excitation in charge transfer bands. AB - Spectroscopic characterization of Fe:ZnSe(Cr:ZnSe) crystals under visible excitation into the charge transfer bands of Transition Metal ions were studied. The excitation efficiencies of mid-IR photoluminescence between (5)T(2)((5)E) and (5)E((5)T(2)) states via direct relaxation to the upper laser levels and via metastable upper (3)T(1) were investigated. It was demonstrated that the latter route is the dominant process for Cr(2+) ions and could provide sufficient pump rate for mid-IR lasing. The pump efficiencies via direct relaxation to the upper laser levels were estimated to be <2% for both ions under 532 nm excitation wavelength. PMID- 25836478 TI - Dynamic laser-induced effects in nanocomposite systems based on the cadmium sulfide quantum dots in a silicate matrix. AB - In this paper we study the laser-induced modification of optical properties of nanocomposite based on cadmium sulphide quantum dots encapsulated into thiomalic acid shell which were embedded into a porous silica matrix. It was found that exposure to laser radiation at lambda = 405.9 nm leads to modification of optical properties of nanocomposite. For this exposed area there is a significant amount of photodynamic changes under subsequent exposure to laser radiation at lambda = 405.9 nm, namely photoabsorption and photorefraction which were studied at lambda = 633 nm. The value of these effects dependent on the concentration of quantum dots and modifying radiation parameters. Moreover, it has dependence from polarization of exposure radiation. PMID- 25836479 TI - Fabrication and characterization of free-standing, high-line-density transmission gratings for the vacuum UV to soft X-ray range. AB - We present state-of-the-art high resolution transmission gratings, applicable for spectroscopy in the vacuum ultraviolet (VUV) and the soft X-ray (SRX) wavelength range, fabricated with a novel process using ultraviolet based nano imprint lithography (UV-NIL). Free-standing, high-line-density gratings with up to 10,000 lines per mm and various space-to-period ratios were fabricated. An optical characterization of the gratings was carried out in the range from 17 to 34 nm wavelength using high-harmonic generation in a capillary waveguide filled with Ne, and around 13.5 nm wavelength (from 10 to 17 nm) using a Xenon discharge plasma. PMID- 25836480 TI - Optimization of particle size for high birefringence and fast switching time in electro-optical switching of graphene oxide dispersions. AB - In order to use graphene oxide (GO) dispersions for electro-optical applications, both a high GO concentration and a high electrical sensitivity are essential; however, these have not been achieved to date. Here, we report that by optimizing the mean size of GO particles to approximately 0.5 MUm, one can obtain a high GO concentration of up to 2 wt% and high electrical sensitivity simultaneously. By reducing the mean GO-particle size, the interparticle interaction and the rotational viscosity can be significantly reduced, and a high-concentration isotropic phase can be obtained. As a result, the maximum birefringence increases and the dynamic response becomes faster. However, further decrease of the mean size below 0.1 MUm causes a decrease in the anisotropy of electrical polarizability, resulting in the reduction of the electrical sensitivity of GO dispersions. PMID- 25836481 TI - Dynamics of solid-state lasers pumped by mode-locked lasers. AB - We analyze the dynamics of mode-locked pumped solid-state lasers focusing on the transition between mode-locked and CW behavior. Where the ratio of the pump and laser cavity lengths is a rational number, 'rational-harmonic mode-locking' is obtained. When the cavity length is detuned away from such resonances, modulated continuous output is generated. The transition from mode-locked to modulated CW operation is explored experimentally for a Ce:LiCAF laser operating at 290 nm and pumped by a 78.75 MHz mode-locked frequency quadrupled Nd:YVO(4) laser. Both CW output and mode-locked output with pulse repetition rates up to 1.1 GHz were achieved. A rate equation model is developed to predict optimum cavity lengths for achieving CW output with minimized modulation. PMID- 25836482 TI - Demonstration of a fully integrated superconducting receiver with a 2.7 THz quantum cascade laser. AB - We demonstrate for the first time the integration of a superconducting hot electron bolometer (HEB) mixer and a quantum cascade laser (QCL) on the same 4-K stage of a single cryostat, which is of particular interest for terahertz (THz) HEB/QCL integrated heterodyne receivers for practical applications. Two key issues are addressed. Firstly, a low power consumption QCL is adopted for preventing its heat dissipation from destroying the HEB's superconductivity. Secondly, a simple spherical lens located on the same 4-K stage is introduced to optimize the coupling between the HEB and the QCL, which has relatively limited output power owing to low input direct current (DC) power. Note that simulation techniques are used to design the HEB/QCL integrated heterodyne receiver to avoid the need for mechanical tuning. The integrated HEB/QCL receiver shows an uncorrected noise temperature of 1500 K at 2.7 THz, which is better than the performance of the same receiver with all the components not integrated. PMID- 25836483 TI - Multi-port admittance model for quantifying the scattering response of loaded plasmonic nanorod antennas. AB - In this paper we demonstrate the feasibility of using multiport network theory to describe the admittance properties of a longitudinally loaded plasmonic nanorod antenna. Our analysis reveals that if the appropriate terminal ports are defined across the nanorod geometry then the corresponding voltage and current quantities can be probed and thus it becomes feasible to extract the admittance matrix of the structure. Furthermore, it is demonstrated that by utilizing cylindrical dielectric waveguide theory, closed form expressions can be derived that uniquely characterize the loading material in terms of its admittance. The combination of the admittance matrix information along with the load admittance expressions provides an effective methodology for computing the nanorod's input admittance/impedance for arbitrary loading scenarios. This is important because the admittance resonances are associated with the structure's scattering peaks which are excited by a plane wave polarized parallel to its long dimension. Subsequently, the proposed approach provides a fast and computationally efficient circuit-based methodology to predict and custom engineer the scattering properties of a loaded plasmonic nanorod without having to rely on repetitive lengthy full wave simulations. PMID- 25836484 TI - Size-dependence of the Lorentz friction for surface plasmons in metallic nanospheres. AB - An inclusion of the Lorentz friction to the damping of plasmons in metallic nanosphere is performed within the random phase approximation quasiclassical approach. The explanation of the experimentally observed anomalous red shift of plasmon resonance frequency with increase of the metallic particle radius for a large size limit is given and the perfect coincidence of the measured plasmon resonance red shift for Au nanospheres with radii 10 - 75 nm and the theory with accurately included Lorentz friction is demonstrated. PMID- 25836485 TI - An approach to increase efficiency of DOE based pupil shaping technique for off axis illumination in optical lithography. AB - Off axis illumination (OAI) is one of the key resolution enhancement technologies in projection lithography system. Recently, phase type diffractive optical elements (DOEs) are adopted by most of the lithography machine manufactures to realize OAI. In general, the efficiency of the OAI unit is the main consideration compared with uniformity. However, the main goal of the traditional constraint of iterative Fourier transformation algorithm (IFTA) is used to optimize the SNR, while diffraction efficiency is the secondary consideration. Therefore a constraint for IFTA is well designed to increase the efficiency of DOE in this paper. This constraint can guarantee the pole balance at the same time. The main idea of this constraint is to apply amplitude and phase freedoms in the signal window and to control the total energy of each pole. Based on the proposed constraint several DOEs are designed for high NA lithography illumination system. And remarkable improvement in the efficiency is observed compared with the traditional constraint. Furthermore, the efficiency and uniformity could be weighted by adjusting the parameter with extending this constraint to general case. To demonstrate the proposed constraints, experiments are carried out where a spatial light modulator is utilized to represent DOEs. PMID- 25836486 TI - Beam pen lithography based on focused laser diode beam with single microlens fabricated by excimer laser. AB - A method is proposed to minimize the focused spot size of an elliptically diverging laser diode beam by means of a circular aperture and a single plano convex aspherical microlens. The proposed microlens is fabricated using an excimer laser dragging method and has two different profiles in the x- and y-axis directions. The focused spot size of the beam is examined both numerically and experimentally. The feasibility of the proposed approach for beam pen lithography applications is demonstrated by patterning dotted, straight-line and spiral features on a photo resist layer followed by thin gold layer deposition and metal lift-off. The minimum feature size for dotted pattern is around 2.57 MUm, while the minimum line-widths for straight-line and spiral pattern are 3.05 MUm and 4.35 MUm, respectively. Thus, the technique can be applied to write any arbitrary pattern for high-resolution lithography. PMID- 25836487 TI - Modeling the specular spectral reflectance of partially ordered alumina nanopores on an aluminum substrate. AB - Anodizing of aluminum generates a porous alumina layer comprising cylindrical nanopores (300 nm diameter) extending essentially perpendicular to the substrate. The pore distribution over the surface exhibits a short-distance order close to hexagonal arrangement. On the contrary, long-distance order cannot be defined: the arrangement is not periodic. Visual observation of such nanoporous layers shows a reddish specular reflectance consistent with reflectance spectrum measurements. This work is a parametric study aiming at demonstrating that color effects are caused by the presence of disorder illustrated by the deviations from periodicity in terms of nanopore location and nanopore radius. Using the method of Rigorous Coupled Wave Analysis (RCWA), the reflectance spectrum has been simulated. Although our calculations were done using a simple one-dimensional (1D) model, a fair fit with experimental results is found. PMID- 25836488 TI - Compressive spectrum sensing of radar pulses based on photonic techniques. AB - We present a photonic-assisted compressive sampling (CS) system which can acquire about 10(6) radar pulses per second spanning from 500 MHz to 5 GHz with a 520-MHz analog-to-digital converter (ADC). A rectangular pulse, a linear frequency modulated (LFM) pulse and a pulse stream is respectively reconstructed faithfully through this system with a sliding window-based recovery algorithm, demonstrating the feasibility of the proposed photonic-assisted CS system in spectral estimation for radar pulses. PMID- 25836489 TI - Multiple-channel wavelength conversions in a photonic crystal cavity. AB - We demonstrate multiple-channel wavelength conversions of second harmonic and sum frequency generations in a silicon carbide photonic crystal cavity. The cavity is designed to have multiple modes including a nanocavity mode and Fabry-Perot modes. Multiple-channel wavelength conversions in the nanocavity and Fabry-Perot modes are shown experimentally. Furthermore, we investigate the polarization characteristics of wavelength-converted light. The experimental results of the polarization are in good agreement with calculation. PMID- 25836490 TI - Approaching coherent performance in differential detection via diversity. AB - Digital self-coherent detection (DSCD) can be employed to approach coherent performance in optical receivers by digitally reconstructing the samples of the electrical field without employing a local oscillator. One major deficiency of this scheme is the abrupt loss of field reconstruction, and consequently phase tracking, immediately following the occurrence of a low intensity sample. A cross polarization DSCD scheme is introduced to mitigate this problem via diversity. The proposed scheme, termed X-DSCD, provides significantly improved signal reconstruction capabilities while doubling the achievable communication rate as compared to the original single-polarization DSCD scheme: two different and independent symbol streams are transmitted via two linear polarizations. X-DSCD performance is analyzed for the case of two cross-polarized, Gaussian signals. The analysis is supported by simulation results. Introducing coding into the system, the error performance attained by X-DSCD is shown to potentially approach that of a coherent receiver. PMID- 25836491 TI - Enhanced plasmonic light absorption engineering of graphene: simulation by boundary-integral spectral element method. AB - Graphene's relatively poor absorption is an essential obstacle for designing graphene-based photonic devices with satisfying photo-responsivity. To enhance the tunable light absorption of graphene, appropriate excitation of localized surface plasmon resonance is considered as a promising approach. In this work, the strategy of incorporating periodic cuboid gold nanoparticle (NP) cluster arrays and cylindrical gold NP arrays with Bragg reflectors into graphene-based photodetectors are theoretically studied by the boundary-integral spectral element method (BI-SEM). With the BI-SEM, the models can be numerically analyzed with excellent accuracy and efficiency. Numerical simulation shows that the proposed structures can effectively engineer the light absorption in graphene by tuning plasmon resonance. In the spectra of 300 nm to 1000 nm, a maximum light absorption of 67.54% is observed for the graphene layer with optimal parameters of the photodetector model. PMID- 25836492 TI - Down- and up-conversion of femtosecond light pulse excitation into visible luminescence in cerium-doped Lu(2)SiO(5)-Gd(2)SiO(5) solid solution crystals co doped with Sm(3+) or Dy(3+). AB - Luminescence phenomena following femtosecond pulse excitation in UV and IR of Ce(3+) + Sm(3+) and Ce(3+) + Dy(3+) systems in Lu(2)SiO(5) - Gd(2)SiO(5) single crystals are investigated. Effect of excitation wavelength in the UV on Ce(3+) luminescence is interpreted assuming selective excitation of weakly interacting Ce1 and Ce2 sites. IR-excited up-converted spectra differ as compared to UV excited spectra in that the contribution of Sm(3+) or Dy(3+) luminescence is higher and the Ce(3+) luminescence originates essentially in Ce1 sites. It has been concluded that excitation mechanism of up-conversion involves energy transfer from free electrons created in conduction band of the host. PMID- 25836493 TI - Carrier-envelope-phase stabilized terawatt class laser at 1 kHz with a wavelength tunable option. AB - We demonstrate a chirped-pulse-amplified Ti:Sapphire laser system operating at 1 kHz, with 20 mJ pulse energy, 26 femtosecond pulse duration (0.77 terawatt), and excellent long term carrier-envelope-phase (CEP) stability. A new vibrational damping technique is implemented to significantly reduce vibrational noise on both the laser stretcher and compressor, thus enabling a single-shot CEP noise value of 250 mrad RMS over 1 hour and 300 mrad RMS over 9 hours. This is, to the best of our knowledge, the best long term CEP noise ever reported for any terawatt class laser. This laser is also used to pump a white-light-seeded optical parametric amplifier, producing 6 mJ of total energy in the signal and idler with 18 mJ of pumping energy. Due to preservation of the CEP in the white light generated signal and passive CEP stability in the idler, this laser system promises synthesized laser pulses spanning multi-octaves of bandwidth at an unprecedented energy scale. PMID- 25836494 TI - High efficiency THz generation in DSTMS, DAST and OH1 pumped by Cr:forsterite laser. AB - We investigated Terahertz generation in organic crystals DSTMS, DAST and OH1 directly pumped by a Cr:forsterite laser at central wavelength of 1.25 MUm. This pump laser technology provides a laser-to-THz energy conversion efficiency higher than 3 percent. Phase-matching is demonstrated over a broad 0.1-8 THz frequency range. In our simple setup we achieved hundred MUJ pulses in tight focus resulting in electric and magnetic field larger than 10 MV/cm and 3 Tesla. PMID- 25836495 TI - Polarization effects in polymer FBGs: study and use for transverse force sensing. AB - Bragg gratings photo-inscribed in polymer optical fibers (POFs) are more sensitive to temperature and pressure than their silica counterparts, because of their larger thermo-optic coefficient and smaller Young's modulus. Polymer optical fiber Bragg gratings (POFBGs) are most often photo-written in poly(methylmethacrylate) (PMMA) based materials using a continuous-wave 325 nm HeCd laser. In this work, we present the first study about birefringence effects in POFBGs manufactured in different types of fiber. To achieve this, highly reflective (> 90%) gratings were produced with the phase mask technique. Their spectral response was then monitored in transmission with polarized light. Polarization dependent loss (PDL) and differential group delay (DGD) were computed from the Jones matrix eigenanalysis using an optical vector analyzer. Maximum values exceeding several dB and a few picoseconds were obtained for the PDL and DGD, respectively. An inverse scattering technique applied to the experimental data provided an estimate of the photo-induced birefringence value arising from the side fabrication process. The response to lateral force was finally investigated for various incident directions using the PDL response of FBGs manufactured in step-index POFs. As the force induced birefringence adds to the photo-induced one, a force dependent evolution of the PDL maximum value was noticed, with a good temperature-insensitivity. PMID- 25836496 TI - Light-driven dynamic Archimedes spirals and periodic oscillatory patterns of topological solitons in anisotropic soft matter. AB - Oscillatory and excitable systems commonly exhibit formation of dynamic non equilibrium patterns. For example, rotating spiral patterns are observed in biological, chemical, and physical systems ranging from organization of slime mold cells to Belousov-Zhabotinsky reactions, and to crystal growth from nuclei with screw dislocations. Here we describe spontaneous formation of spiral waves and a large variety of other dynamic patterns in anisotropic soft matter driven by low-intensity light. The unstructured ambient or microscope light illumination of thin liquid crystal films in contact with a self-assembled azobenzene monolayer causes spontaneous formation, rich spatial organization, and dynamics of twisted domains and topological solitons accompanied by the dynamic patterning of azobenzene group orientations within the monolayer. Linearly polarized incident light interacts with the twisted liquid crystalline domains, mimicking their dynamics and yielding patterns in the polarization state of transmitted light, which can be transformed to similar dynamic patterns in its intensity and interference color. This shows that the delicate light-soft-matter interaction can yield complex self-patterning of both. We uncover underpinning physical mechanisms and discuss potential uses. PMID- 25836497 TI - A multi-pass pumping scheme for thin disk lasers with good anti-disturbance ability. AB - A multi-pass pumping scheme for thin disk lasers consisting of dual parabolic mirrors with conjugated relationship is presented. The anti-disturbance ability of pumping is analyzed by ray tracing method under different kinds of disturbances. Both theoretical and experiment results show that disturbances in this system won't lead to a misalignment of each pumping spot, but only the position of superposed pumping spot on disk crystal will be changed. Compared with the multi-pass pumping scheme consisting of parabolic mirror and folding prisms, this pumping scheme has a better anti-disturbance ability. PMID- 25836498 TI - Mode-locked Tm,Ho:KLu(WO(4))(2) laser at 2060 nm using InGaSb-based SESAMs. AB - Passive mode-locking of a Tm,Ho:KLu(WO(4))(2) laser operating at 2060 nm using different designs of InGaAsSb quantum-well based semiconductor saturable absorber mirrors (SESAMs) is demonstrated. The self-starting mode-locked laser delivers pulse durations between 4 and 8 ps at a repetition rate of 93 MHz with maximum average output power of 155 mW. Mode-locking performance of a Tm,Ho:KLu(WO(4))(2) laser is compared for usage of a SESAM to a single-walled carbon nanotube saturable absorber. PMID- 25836499 TI - Real-time mode decomposition for few-mode fiber based on numerical method. AB - Today a specific attention has been paid to look into the modal characteristics of the high-power laser beam. And the instantaneous monitoring and analyzing on modal content via the mode decomposition technique will provide a novel route. We implement the first-ever experimental investigation on the real-time mode decomposition technique for few-mode laser beam based on stochastic parallel gradient descent algorithm. It will reduce the cost and the complexity of the mode decomposition system. We have succeeded to decompose the mode spectra as well as calculating the beam quality factor at about 9 Hz monitoring rate, while the high agreement between the measured and reconstructed intensity profiles in each frame indicating the high accuracy and stability during the process. By employing a fiber-squeezing-based polarization controller, the modal content under test can be time-varying automatically. PMID- 25836500 TI - Ytterbium-doped glass-ceramics for optical refrigeration. AB - We report for the first time the characterization of glass-ceramics for optical refrigeration. Ytterbium-doped nanocrystallites were grown in an oxyfluoride glass matrix of composition 2YbF(3):30SiO(2)-15Al(2)O(3)-25CdF(2)-22PbF(2) 4YF(3), forming bulk glass-ceramics at three different crystalisation levels. The samples are compared with a corresponding uncrystalised (glass) sample, as well as a Yb:YAG sample which has presented optical cooling. The measured X-ray diffraction spectra, and thermal capacities of the samples are reported. We also report for the first time the use of Yb:YAG as a reference for absolute photometric quantum efficiency measurement, and use the same setup to characterize the glass and glass-ceramic samples. The cooling figure-of-merit was measured by optical calorimetry using a fiber Bragg grating and found to depend on the level of crystallization of the sample, and that samples with nanocrystallites result in higher quantum efficiency and lower background absorption than the pure-glass sample. In addition to laser-induced cooling, the glass-ceramics have the potential to serve as a reference for quantum efficiency measurements. PMID- 25836501 TI - Achromatic wave plate in THz frequency region based on parallel metal plate waveguides with a pillar array. AB - We demonstrated an achromatic wave plate based on parallel metal plate waveguides in the high THz frequency region. The metal plates have periodic rough structures on the surface, which allow slow transverse magnetic wave propagation and fast transverse electric wave propagation. A numerical simulation showed that the height of the periodic roughness is important for optimizing the birefringence. We fabricated stacked metal plates containing two types of structures by chemical etching. An array of small pillars on the metal plates allows higher frequency optimization. We experimentally demonstrated an achromatic quarter-wave plate in the frequency region from 2.0 to 3.1 THz. PMID- 25836502 TI - Nonlinear properties of dispersion engineered InGaP photonic wire waveguides in the telecommunication wavelength range. AB - We propose high index contrast InGaP photonic wires as a platform for the integration of nonlinear optical functions in the telecom wavelength window. We characterize the linear and nonlinear properties of these waveguide structures. Waveguides with a linear loss of 12 dB/cm and which are coupled to a single mode fiber through gratings with a -7.5 dB coupling loss are realized. From four wave mixing experiments, we extract the real part of the nonlinear parameter gamma to be 475 +/- 50 W(-1)m(-1) and from nonlinear transmission measurements we infer the absence of two-photon absorption and measure a three-photon absorption coefficient of (2.5 +/- 0.5) x 10(-2) cm(3)GW(-2). PMID- 25836503 TI - One-way absorber for linearly polarized electromagnetic wave utilizing composite metamaterial. AB - This paper presents the proposal and practical design of a one-way absorber for selective linearly polarized electromagnetic (EM) wave. The EM wave polarization rotation property has been combined with polarization selective absorption utilizing a composite metamaterial slab. The energy of certain linearly polarized EM wave can be absorbed along one particular incident direction, but will be fully transmitted through the opposite direction. For the cross polarized wave, the direction dependent propagation properties are totally reversed. A prototype designed with a total slab thickness of only one-sixth of the operating wavelength is verified through both full-wave simulation and experimental measurement in the microwave regime. It achieves absorption efficiency over 83% along one direction, while transmission efficiency over 83% along the opposite direction for one particular linearly polarized wave. The proposed one-way absorber can be applied in EM devices achieving asymmetric transmission for linearly polarized wave or polarization control. The composite metamaterial that combines different functionalities into one design may provide more potential in metamaterial designs for various applications. PMID- 25836504 TI - Quantum dot SOA/silicon external cavity multi-wavelength laser. AB - We report a hybrid integrated external cavity, multi-wavelength laser for high capacity data transmission operating near 1310 nm. This is the first demonstration of a single cavity multi-wavelength laser in silicon to our knowledge. The device consists of a quantum dot reflective semiconductor optical amplifier and a silicon-on-insulator chip with a Sagnac loop mirror and microring wavelength filter. We show four major lasing peaks from a single cavity with less than 3 dB power non-uniformity and demonstrate error-free 4 * 10 Gb/s data transmission. PMID- 25836505 TI - Two-shot fringe pattern phase-amplitude demodulation using Gram-Schmidt orthonormalization with Hilbert-Huang pre-filtering. AB - Gram-Schmidt orthonormalization is a very fast and efficient method for the fringe pattern phase demodulation. It requires only two arbitrarily phase-shifted frames. Images are treated as vectors and upon orthogonal projection of one fringe vector onto another the quadrature fringe pattern pair is obtained. Orthonormalization process is very susceptible, however, to noise, uneven background and amplitude modulation fluctuations. The Hilbert-Huang transform based preprocessing is proposed to enhance fringe pattern phase demodulation by filtering out the spurious noise and background illumination and performing fringe normalization. The Gram-Schmidt orthonormalization process error analysis is provided and its filtering-expanded capabilities are corroborated analyzing DSPI fringes and performing amplitude demodulation of Bessel fringes. Synthetic and experimental fringe pattern analyses presented to validate the proposed technique show that it compares favorably with other pre-filtering schemes, i.e., Gaussian filtering and continuous wavelet transform. PMID- 25836506 TI - Linearly interpolated sub-symbol optical phase noise suppression in CO-OFDM system. AB - An optical phase noise suppression algorithm, LI-SCPEC, based on phase linear interpolation and sub-symbol processing is proposed for CO-OFDM system. By increasing the temporal resolution of carrier phase tracking through dividing one symbol into several sub-blocks, i.e., sub-symbols, inter-carrier-interference (ICI) mitigation is achieved in the proposed algorithm. Linear interpolation is employed to obtain a reliable temporal reference for sub-symbol phase estimation. The new algorithm, with only a few number of sub-symbols (N(B) = 4), can provide a considerably larger laser linewidth tolerance than several other ICI mitigation algorithms as demonstrated by Monte-Carlo simulations. Numerical analysis verifies that the best performance is achieved with an optimal and moderate number of sub-symbols. Complexity analysis shows that the required number of complex-valued multiplications is independent of the number of sub-symbols used in the proposed algorithm. PMID- 25836507 TI - An optical monitoring method for depositing dielectric layers of arbitrary thickness using reciprocal of transmittance. AB - An approach extracting information of both optical monitoring signal and phase thickness of deposited layer on a trace diagram is proposed. Realtime fitting and calculation are performed to get both practical thickness and refractive index of deposited layer with the assist of quartz crystal monitoring for keeping steady rate of deposition. Monitoring error of thickness using this approach is analyzed. It was used to obtain the refractive indices and thickness of Ge layer and SiO layer in in situ measurement mode, and the results were compared with those of ex-situ spectral measurement using infrared spectrometer. The effectiveness of the proposed monitoring method was verified by fabricating narrow bandpass filter consisting of quarter-wave and non-quarter-wave layers. PMID- 25836508 TI - Empirical concentration bounds for compressive holographic bubble imaging based on a Mie scattering model. AB - We use compressive in-line holography to image air bubbles in water and investigate the effect of bubble concentration on reconstruction performance by simulation. Our forward model treats bubbles as finite spheres and uses Mie scattering to compute the scattered field in a physically rigorous manner. Although no simple analytical bounds on maximum concentration can be derived within the classical compressed sensing framework due to the complexity of the forward model, the receiver operating characteristic (ROC) curves in our simulation provide an empirical concentration bound for accurate bubble detection by compressive holography at different noise levels, resulting in a maximum tolerable concentration much higher than the traditional back-propagation method. PMID- 25836509 TI - Improvement of diffraction efficiency of flat-panel coherent backlight for holographic displays. AB - Coherent backlight is an essential component for holographic displays. In this paper, a compact design of edge-lit coherent backlight featuring two holographic optical elements for two-dimensional beam expansion is presented. Its diffraction efficiency is numerically studied using the coupled-wave theory. In experiments, the diffraction efficiency is measured as 4.3% and the feasibility of this design is verified by reconstructing 3D images with a spatial light modulator. PMID- 25836510 TI - Polymer waveguides for electro-optical integration in data centers and high performance computers. AB - To satisfy the intra- and inter-system bandwidth requirements of future data centers and high-performance computers, low-cost low-power high-throughput optical interconnects will become a key enabling technology. To tightly integrate optics with the computing hardware, particularly in the context of CMOS compatible silicon photonics, optical printed circuit boards using polymer waveguides are considered as a formidable platform. IBM Research has already demonstrated the essential silicon photonics and interconnection building blocks. A remaining challenge is electro-optical packaging, i.e., the connection of the silicon photonics chips with the system. In this paper, we present a new single mode polymer waveguide technology and a scalable method for building the optical interface between silicon photonics chips and single-mode polymer waveguides. PMID- 25836511 TI - Proposal for a broadband THz refractive-index sensor based on quantum-cascade laser arrays. AB - Many molecules have strong and characteristic rotational and vibrational transitions at terahertz (THz) frequencies, which makes this frequency range unique for applications in spectroscopic sensing of chemical and biological species. Here, we propose a broadband THz sensor based on arrays of single-mode QCLs, which could be utilized for sensing of the refractive-index of solids or liquids in reflection geometry. The proposed scheme does not require expensive THz detectors and consists of no movable parts. A recently developed antenna feedback geometry is utilized to enhance optical coupling between two single-mode QCLs, which facilitates optical downconversion of the THz frequency signal to microwave regime. Arrays of THz QCLs emitting at discrete frequencies could be utilized to provide more than 2 THz of spectral coverage to realize a broadband, low-cost, and portable THz sensor. PMID- 25836512 TI - Monolithic polarization maintaining fiber chirped pulse amplification (CPA) system for high energy femtosecond pulse generation at 1.03 um. AB - A monolithic polarization maintaining fiber chirped pulse amplification system with 25 cm Yb(3+)-doped high efficiency media fiber that generates 62 uJ sub-400 fs pulses with 25 W at 1.03 um has recently been demonstrated. PMID- 25836513 TI - High-order multilayer coated blazed gratings for high resolution soft x-ray spectroscopy. AB - A grand challenge in soft x-ray spectroscopy is to drive the resolving power of monochromators and spectrometers from the 10(4) achieved routinely today to well above 10(5). This need is driven mainly by the requirements of a new technique that is set to have enormous impact in condensed matter physics, Resonant Inelastic X-ray Scattering (RIXS). Unlike x-ray absorption spectroscopy, RIXS is not limited by an energy resolution dictated by the core-hole lifetime in the excitation process. Using much higher resolving power than used for normal x-ray absorption spectroscopy enables access to the energy scale of soft excitations in matter. These excitations such as magnons and phonons drive the collective phenomena seen in correlated electronic materials such as high temperature superconductors. RIXS opens a new path to study these excitations at a level of detail not formerly possible. However, as the process involves resonant excitation at an energy of around 1 keV, and the energy scale of the excitations one would like to see are at the meV level, to fully utilize the technique requires the development of monochromators and spectrometers with one to two orders of magnitude higher energy resolution than has been conventionally possible. Here we investigate the detailed diffraction characteristics of multilayer blazed gratings. These elements offer potentially revolutionary performance as the dispersive element in ultra-high resolution x-ray spectroscopy. In doing so, we have established a roadmap for the complete optimization of the grating design. Traditionally 1st order gratings are used in the soft x-ray region, but we show that as in the optical domain, one can work in very high spectral orders and thus dramatically improve resolution without significant loss in efficiency. PMID- 25836514 TI - Design and fabrication of SOI micro-ring resonators based on sub-wavelength grating waveguides. AB - Standard silicon photonic strip waveguides offer a high intrinsic refractive index contrast; this permits strong light confinement, leading to compact bends, which in turn facilitates the fabrication of devices with small footprints. Sub wavelength grating (SWG) based waveguides can allow the fabrication of low loss devices with specific, engineered optical properties. The combination of SWG waveguides with optical micro-resonators can offer the possibility of achieving resonators with properties different from the traditional SOI rings. One important property that SWG rings can offer is decreased light confinement in the waveguide core; this improves the resonator's sensitivity to changes in the cladding refractive index, making the rings ideal for refractive index sensing applications. In this paper, we present the design and experimental characterization of SWG based rings realized on SOI chips without upper cladding (permitting their use as sensors). The fabricated rings offer quality factors in the range of ~1k-6k, depending on SWG parameters. Based on the comparison of experimental and simulated data we expect sensitivities exceeding 383 nm/RIU in water and 270 nm/RIU in air, showing excellent potential for use in sensing applications. PMID- 25836515 TI - Optically pumped microplasma rare gas laser. AB - The optically pumped rare-gas metastable laser is a chemically inert analogue to three-state optically pumped alkali laser systems. The concept requires efficient generation of electronically excited metastable atoms in a continuous-wave (CW) electric discharge in flowing gas mixtures near atmospheric pressure. We have observed CW optical gain and laser oscillation at 912.3 nm using a linear micro discharge array to generate metastable Ar(4s, 1s(5)) atoms at atmospheric pressure. We observed the optical excitation of the 1s(5) -> 2p(9) transition at 811.5 nm and the corresponding fluorescence, optical gain and laser oscillation on the 2p(10) <-> 1s(5) transition at 912.3 nm, following 2p(9)->2p(10) collisional energy transfer. A steady-state kinetics model indicates efficient collisional coupling within the Ar(4s) manifold. PMID- 25836516 TI - Characterization of temporal pulse broadening for horizontal propagation in strong anisotropic atmospheric turbulence. AB - The on-axis two-frequency mutual coherence function (MCF) for beam waves propagating along a horizontal path in strong anisotropic atmospheric turbulence is theoretically formulated by making use of the extended Huygens-Fresnel principle. Based on this formulation, a new closed-form expression for the mean square temporal width of Gaussian-beam-wave pulses passing horizontally through strong anisotropic atmospheric turbulence is developed. With the help of this expression, the increments of mean square temporal pulse width due to strong anisotropic atmospheric turbulence under various conditions are further calculated. Results show that the increment of mean square temporal pulse width due to strong anisotropic atmospheric turbulence is basically proportional to the effective anisotropic factor in most situations of interest, with the possible exception of cases in which both the Fresnel ratio and spectral index become relatively small; increasing the effective anisotropic factor can reduce the number of the said exceptions; the turbulence-induced increment of mean square temporal pulse width enlarges as the spectral index increases with a fixed value of the nondimensional turbulence-strength parameter. It is also illustrated that a significant enlargement in the turbulence-induced increment of mean square temporal pulse width occurs by changing the Fresnel ratio from a large to a tiny value if both the effective anisotropic factor and spectral index are relatively small. PMID- 25836517 TI - Ultra-weak FBG and its refractive index distribution in the drawing optical fiber. AB - For the online writing of ultra-weak fiber Bragg gratings (FBGs) in the drawing optical fibers, the effects of the intensity profile, pulse fluctuation and pulse width of the excimer laser, as well as the transverse and longitudinal vibrations of the optical fiber have been investigated. Firstly, using Lorentz-Loren equation, Gladstone-Dale mixing rule and continuity equation, we have derived the refractive index (RI) fluctuation along the optical fiber and the RI distribution in the FBG, they are linear with the gradient of longitudinal vibration velocity. Then, we have prepared huge amounts of ultra-weak FBGs in the non-moving optical fiber and obtained their reflection spectra, the measured reflection spectra shows that the intensity profile and pulse fluctuation of the excimer laser, as well as the transverse vibration of the optical fiber are little responsible for the inconsistency of ultra-weak FBGs. Finally, the effect of the longitudinal vibration of the optical fiber on the inconsistency of ultra-weak FBGs has been discussed, and the vibration equations of the drawing optical fiber are given in the appendix. PMID- 25836518 TI - Bilayer graphene based surface passivation enhanced nano structured self-powered near-infrared photodetector. AB - A simple methyl-terminated (-CH(3)) surface passivation approach has been employed to enhance the performance of the bilayer graphene/Si nanohole array (BLG/SiNH array) Schottky junction based self-powered near infrared photodetector (SPNIRPD). The as-fabricated SPNIRPD exhibits high sensitivity to light at near infrared region at zero bias voltage. The I(light)/I(dark) ratio measured is 1.43 * 10(7), which is more than an order of magnitude improvement compared with the sample without passivation (~6.4 * 10(5)). Its corresponding responsivity and detectivity are 0.328 AW(-1) and 6.03 * 10(13) cmHz(1/2)W(-1), respectively. The demonstrated results have confirmed the high-performance SPNIRPD compared with the photo-detectors of similar type and its great potential application in future optoelectronic devices. PMID- 25836519 TI - Temperature-controlled picosecond-pulsed high frequency second-harmonic generation by a periodically poled stoichiometric LiTaO(3). AB - We report experimental results of second-harmonic (SH) generation (SHG) by a quasi-phase-matched periodically poled Mg-doped stoichiometric LiTaO(3) crystal for 1030 nm input radiation of 18 ps pulse duration, within the range of peak input laser intensity I = 0.1-9.5 GW/cm(2) and under repetition rate 10-20 kHz. For I>3 GW/cm(2) SHG efficiency achieves the saturation level of eta~0.35 which can be maintained within a wide range of I = 3-9.5 GW/cm(2). The loss of SHG efficiency observed for I>5 GW/cm(2) can be recovered to the level of eta~0.35 by using temperature-controlled operation. By applying our experimental data we find the value of two-photon absorption (TPA) coefficient for 515 nm radiation, beta~1.1-2.7 cm/GW, agreeing well with the theoretical estimate beta~2.6 cm/GW. Our analysis suggests that the inhibition of SHG efficiency, its saturation and stabilization are due to a combined mechanism including: (i) non-steady-state ps effect scaled by ~zeta(-2)[1-exp(-zeta)](2) as compared with the efficiency for ns pulsed operation (zeta = L/V2tauP , L is the crystal length, tauP is the pulse duration and V(2) is the group velocity of SH); (ii) dephasing caused by the spectral bandwidth of the input radiation (~300 GHz); (iii) thermal dephasing caused by TPA of SH; and (iv) strong SH attenuation by TPA of order ~I(2) ( 1)dI2/dz~-(0.8-8) cm(-1) for I = 1-9.5 GW/cm(2). PMID- 25836520 TI - Fourier ptychographic reconstruction using Wirtinger flow optimization. AB - Recently Fourier Ptychography (FP) has attracted great attention, due to its marked effectiveness in leveraging snapshot numbers for spatial resolution in large field-of-view imaging. To acquire high signal-to-noise-ratio (SNR) images under angularly varying illuminations for subsequent reconstruction, FP requires long exposure time, which largely limits its practical applications. In this paper, based on the recently reported Wirtinger flow algorithm, we propose an iterative optimization framework incorporating phase retrieval and noise relaxation together, to realize FP reconstruction using low SNR images captured under short exposure time. Experiments on both synthetic and real captured data validate the effectiveness of the proposed reconstruction method. Specifically, the proposed technique could save ~ 80% exposure time to achieve similar retrieval accuracy compared to the conventional FP. Besides, we have released our source code for non-commercial use. PMID- 25836521 TI - Coherent amplification of attosecond light pulses in the water-window spectral region. AB - We present a theoretical study on coherent extreme ultraviolet (XUV) attosecond pulse amplification mediated by nonlinear parametric enhanced forward scattering occurring in the interaction of a strong femtosecond infrared (IR) laser pulse combined with a weak attosecond XUV pulse train with an atom. We predict large amplification of XUV radiation when the IR strong pulse and the XUV weak pulse are optimally phased. We study high-order harmonic processes (HHG) in He, He(+) and Ne(++), and show how although the HHG yield is largely affected by the particular atom used as target, nonlinear parametric XUV amplification is only weakly affected. We conclude that XUV nonlinear parametric attosecond pulse amplification can be most efficiently observed by using atoms with a high ionization potential and that the nonlinear amplification is robust at high photon energies where HHG is not efficient, such as in the water-window spectral region. PMID- 25836522 TI - Optical phased array radiating optical vortex with manipulated topological charges. AB - Optical antennas are key elements in quantum optics emitting and sensing, and behave wide range applications in optical domain. However, integration of optical antenna radiating orbital angular momentum is still a challenge in nano-scale. We theoretically demonstrate a sub-wavelength phased optical antenna array, which manipulates the distribution of the orbital angular momentum in the near field. Orbital angular momentum with topological charge of 4 can be obtained by controlling the phase distribution of the fundamental mode orbital angular momentum in each antenna element. Our results indicate this phased array may be utilized in high integrated optical communication systems. PMID- 25836523 TI - High-power passively mode-locked Nd:YVO(4) laser using SWCNT saturable absorber fabricated by dip coating method. AB - Passive mode locked laser is typically achieved by the Semiconductor Saturable absorber Mirror, SESAM, saturable absorber, which is produced by expensive and complicated metal organic chemical vapor deposition method. Carbon based single wall carbon nanotube (SWCNT), saturable absorber, is a promising material which is capable to produce stable passive mode-locking in the high power laser cavity over a wide operational wavelength range. This study has successfully demonstrated the high power mode locking laser system operating at 1 micron by using SWCNT based absorbers fabricated by dip coating method. The proposed fabrication method is practical, simple and cost effective for fabricating SWCNT saturable absorber. The demonstrated high power Nd:YVO(4) mode-locked laser operating at 1064nm have maximum output power up to 2.7W,with the 167MHz repetition rate and 3.1 ps pulse duration, respectively. The calculated output pulse energy and peak power are 16.1nJ and 5.2kW, respectively. PMID- 25836524 TI - Research of micro-prism distribution on the bottom surface of the small-size integrated light guide plate. AB - The luminance uniformity of the backlight module (BLM) importantly depends on the microstructure distribution on the bottom surface of the light guide plate (LGP). Based on the small-size integrated LGP (ILGP) proposed, we put forward a distribution expression of micro-prisms on the bottom surface of the ILGP, and present the relational expressions between the coefficients of the analytical expression and the structural parameters of the ILGP, such as the light guide length L, width of the ILGP W, thickness of the ILGP H, and space between light emitting diodes (LEDs) d. Then, the research results above are applied to the design of the small-size ILGPs. Not only can the micro-structure distributions on the bottom surface of the ILGPs be directly given, but also the simulation results show that the luminance uniformities of the integrated BLMs are higher than 85%. The research indicates that the expressions proposed in this paper are correct and effective, and have important guiding significances and referential value. PMID- 25836525 TI - Optical field enhancement of nanometer-sized gaps at near-infrared frequencies. AB - We report near-field and far-field measurements of transmission through nanometer sized gaps at near-infrared frequencies with varying the gap size from 1 nm to 10 nm. In the far-field measurements, we excluded direct transmission on the metal film surface via interferometric method. Kirchhoff integral formalism was used to relate the far-field intensity to the electric field at the nanogaps. In near field measurements, field enhancement factors of the nanogaps were quantified by measuring transmission of the nanogaps using near-field scanning optical microscopy. All the measurements produce similar field enhancements of about ten, which we put in the context of comparing with the giant field enhancements in the terahertz regime. PMID- 25836526 TI - 3-D ice shape measurements using mid-infrared laser scanning. AB - A general approach based on mid-infrared (MIR) laser scanning is proposed to measure the 3-D ice shape no matter whether the ice is composed of clear ice, rime ice, mixed ice, or even supercooled water droplets or films. This is possible because MIR radiation penetrates ice and water only within a depth of less than 10 micrometers. First, an MIR laser point scanning technique is implemented and verified on transparent glass and clear ice. Then, to improve efficiency, an MIR laser line scanning method is developed and validated on different models. At last, several sequential MIR laser line scans are applied to trace the 3-D shape evolution of the continuous ice accretion on an airfoil in an icing wind tunnel. The ice growth process can be well observed in the results. The MIR scan shows a good agreement with the traditional visible laser scan on a plastic replication of the final ice shape made by the mold and casting method. PMID- 25836527 TI - Theoretical study of pre-formed hole geometries on femtosecond pulse energy distribution in laser drilling. AB - Maxwell's wave equation was solved for fs laser drilling of silicon. The pre formed hole wall's influence on the propagation behavior of subsequent laser pulses was investigated. The laser intensity at hole bottom shows distinct profile as compared with that at hole entrance. The multi-peaks and ring structure of the laser intensity were found at hole bottom. The position of maximum laser intensity (MLI) in relation to the wall taper angle was studied. It was found that the position of the MLI point would be closer to the hole entrance with increasing taper angle. This observation provides valuable information in predicting the position of plasma plume which is a key factor influencing laser drilling process. The elliptical entrance hole shape and zonal structure at the hole bottom reported in the literatures have been reasonably explained using the laser intensity distribution obtained in the present model. PMID- 25836528 TI - Depth-encoded synthetic aperture optical coherence tomography of biological tissues with extended focal depth. AB - Optical coherence tomography (OCT) has proven to be able to provide three dimensional (3D) volumetric images of scattering biological tissues for in vivo medical diagnostics. Unlike conventional optical microscopy, its depth-resolving ability (axial resolution) is exclusively determined by the laser source and therefore invariant over the full imaging depth. In contrast, its transverse resolution is determined by the objective's numerical aperture and the wavelength which is only approximately maintained over twice the Rayleigh range. However, the prevailing laser sources for OCT allow image depths of more than 5 mm which is considerably longer than the Rayleigh range. This limits high transverse resolution imaging with OCT. Previously, we reported a novel method to extend the depth-of-focus (DOF) of OCT imaging in Mo et al.Opt. Express 21, 10048 (2013)]. The approach is to create three different optical apertures via pupil segmentation with an annular phase plate. These three optical apertures produce three OCT images from the same sample, which are encoded to different depth positions in a single OCT B-scan. This allows for correcting the defocus-induced curvature of wave front in the pupil so as to improve the focus. As a consequence, the three images originating from those three optical apertures can be used to reconstruct a new image with an extended DOF. In this study, we successfully applied this method for the first time to both an artificial phantom and biological tissues over a four times larger depth range. The results demonstrate a significant DOF improvement, paving the way for 3D high resolution OCT imaging beyond the conventional Rayleigh range. PMID- 25836529 TI - 100 Gbit/s WDM transmission at 2 um: transmission studies in both low-loss hollow core photonic bandgap fiber and solid core fiber. AB - We show for the first time 100 Gbit/s total capacity at 2 um waveband, using 4 * 9.3 Gbit/s 4-ASK Fast-OFDM direct modulation and 4 * 15.7 Gbit/s NRZ-OOK external modulation, spanning a 36.3 nm wide wavelength range. WDM transmission was successfully demonstrated over 1.15 km of low-loss hollow core photonic bandgap fiber (HC-PBGF) and over 1 km of solid core fiber (SCF). We conclude that the OSNR penalty associated with the SCF is minimal, while a ~1-2 dB penalty was observed after the HC-PBGF probably due to mode coupling to higher-order modes. PMID- 25836530 TI - Experimental generation of 8.4 dB entangled state with an optical cavity involving a wedged type-II nonlinear crystal. AB - Entangled state of light is one of the essential quantum resources in quantum information science and technology. Especially, when the fundamental principle experiments have been achieved in labs and the applications of continuous variable quantum information in the real world are considered, it is crucial to design and construct the generation devices of entangled states with high entanglement and compact configuration. We have designed and built an efficient and compact light source of entangled state, which is a non-degenerate optical parametric amplifier (NOPA) with the triple resonance of the pump and two subharmonic modes. A wedged type-II KTP crystal inside the NOPA is used for implementing frequency-down-conversion of the pump field to generate the optical entangled state and achieving the dispersion compensation between the pump and the subharmonic waves. The EPR entangled state of light with quantum correlations of 8.4 dB for both amplitude and phase quadratures are experimentally produced by a single NOPA under the pump power of 75 mW. PMID- 25836531 TI - 2048 QAM (66 Gbit/s) single-carrier coherent optical transmission over 150 km with a potential SE of 15.3 bit/s/Hz. AB - We describe a 2048 QAM single-carrier coherent optical transmission over 150 km in detail. The OSNR at the transmitter was increased by 5 dB and the phase noise at the receiver was reduced from 0.35 to 0.17 degrees compared with a previous 1024 QAM transmission. Furthermore, we employed an A/D converter with a higher ENOB (7 bit) to guarantee the SNR of the digital QAM data, and introduced a polarization-demultiplexing algorithm to fast track the polarization state transition. As a result, a 66 Gbit/s polarization-multiplexed 2048 QAM signal was successfully transmitted within an optical bandwidth of 3.6 GHz including a pilot tone, and a potential SE of 15.3 bit/s/Hz under a 20% FEC overhead was achieved. PMID- 25836532 TI - Precision and broadband frequency swept laser source based on high-order modulation-sideband injection-locking. AB - A precision and broadband laser frequency swept technique is experimentally demonstrated. Using synchronous current compensation, a slave diode laser is dynamically injection-locked to a specific high-order modulation-sideband of a narrow-linewidth master laser modulated by an electro-optic modulator (EOM), whose driven radio frequency (RF) signal can be agilely, precisely controlled by a frequency synthesizer, and the high-order modulation-sideband enables multiplied sweep range and tuning rate. By using 5th order sideband injection locking, the original tuning range of 3 GHz and tuning rate of 0.5 THz/s is multiplied by 5 times to 15 GHz and 2.5 THz/s respectively. The slave laser has a 3 dB-linewidth of 2.5 kHz which is the same to the master laser. The settling time response of a 10 MHz frequency switching is 2.5 us. By using higher-order modulation-sideband and optimized experiment parameters, an extended sweep range and rate could be expected. PMID- 25836533 TI - Investigation of the thermal lens effect of the TGG crystal in high-power frequency-doubled laser with single frequency operation. AB - The thermal lens effect of the TGG crystal is investigated theoretically and experimentally. The theoretical analysis is demonstrated by the experimental measurements on a home-made frequency-doubled Nd:YVO(4) laser with single frequency operation. In the presence of the thermal lens effect of the TGG crystal, the output power can be optimized by shortening the distance between the cavity mirrors of M(3) and M(4) (two plane-concave mirrors placed at two sides of the second-harmonic generator). Consequently, a single-frequency laser with output power of 18.7 W at 532 nm is obtained. The power stability and the beam quality M(2) are better than +/-0.4% for 5 hours and 1.08, respectively. Meanwhile, we observe and discuss a bistability-like phenomenon of the laser in the cases of increasing and decreasing the incident pump power. PMID- 25836534 TI - Controlled excitation of higher radial order whispering gallery modes with metallic diffraction grating. AB - Metallic diffraction grating coupler is investigated for controlled excitation of whispering gallery modes (WGMs) of different radial orders. Based on effective mode index calculations and finite difference time domain method, it is found that higher radial order WGMs can be separated from the fundamental modes by sending them into the opposite propagation direction. By phase-matching designs, the metallic diffraction grating provides extra freedom to switch propagation directions, and is able to selectively enhance or suppress different radial-order WGMs. Such structure offers a simple and practical configuration for various WGM applications including liquid sensing, band pass filtering and fiber lasers. PMID- 25836535 TI - Double-layered nitrocellulose membrane sample holding technique for THz and FIR spectroscopic measurements. AB - In terahertz (THz) and far-infrared (FIR) spectroscopic measurements, weak absorption spectral features due to small quantities of test sample can be masked by undesirable etalon fringe artifacts caused by multiple reflections within a pellet or a rigid sample holder. A double-layered nitrocellulose (NC) membrane structure is proposed in this paper as an alternative holder for small quantities of either dry or wet pure (no added polyethylene powder) samples with significantly reduced etalon artifacts. Utilizing a THz time-domain spectroscopy system and a synchrotron source, we demonstrate the performance of the NC structure across the THz/FIR spectrum, benchmarking against pellets holding similarly small quantities of alpha-lactose powder either with or without different grades of polyethylene powder. With only pure samples to consider, scattering can be mitigated effectively in NC-derived spectra to reduce their baselines. PMID- 25836536 TI - Self-imaging of orbital angular momentum (OAM) modes in rectangular multimode interference waveguides. AB - We study the propagation of orbital angular momentum (OAM) modes in rectangular multimode waveguides. Due to the multimode interference effect, an OAM mode input forms self-images at certain propagation distances. As OAM modes can be decomposed as the superposition of a pair of quarter-wave phase-shifted even and odd modes, their symmetry properties lead to two different self-imaging categories - forming the OAM-maintaining and the field-splitting self-images. We analyze these phenomena using multimode interference theory, and establish the rules governing the OAM-maintaining self-imaging, which allows the multi-mode interference waveguides to be used as OAM mode splitters and couplers. PMID- 25836537 TI - High-speed terahertz reflection three-dimensional imaging using beam steering. AB - High-speed terahertz (THz) reflection three-dimensional (3D) imaging is demonstrated using electronically-controlled optical sampling (ECOPS) and beam steering. ECOPS measurement is used for scanning an axial range of 7.8 mm in free space at 1 kHz scan rate while a transverse range of 100 * 100 mm(2) is scanned using beam steering instead of moving an imaging target. Telecentric f-theta lenses with axial and non-axial symmetry have been developed for beam steering. It is experimentally demonstrated that the non-axially symmetric lens has better characteristics than the axially symmetric lens. The total scan time depends on the number of points in a transverse range. For example, it takes 40 s for 200 * 200 points and 10 s for 100 * 100 points. To demonstrate the application of the imaging technique to nondestructive testing, THz 3D tomographic images of a glass fiber reinforced polymer sample with artificial internal defects have been acquired using the lenses for comparison. PMID- 25836538 TI - Combining efficiency degraded by gain in passively phase-locked laser arrays: contribution of the spectral filtering. AB - Passive phase-locking of laser arrays is usually less efficient when the operating point is far above the laser threshold. We investigated the contribution due to the spectral filtering effect induced by the coupled cavities. Experiments carried out on a basic dual-arm laser as well as modeling show that some laser combining losses arise from the spectral filtering whose transmission windows have a non-uniform profile. A simple analytical model of the laser confirms this interpretation. PMID- 25836539 TI - Polarization evolution of radially polarized partially coherent vortex fields: role of Gouy phase of Laguerre-Gauss beams. AB - In the framework of the paraxial approximation, we derive the analytical expressions for describing the effect of the Gouy phase of Laguerre-Gauss beams on the polarization evolution of partially coherent vortex fields whose electric field vector at some transverse plane exhibits a radially polarized behavior. At each transverse plane, the polarization distribution across the beam profile is characterized by means of the percentage of irradiance associated with the radial or azimuthal components. The propagation laws for these percentages are also presented. As an illustrative example, we analyze a radially polarized partially coherent vortex beam. PMID- 25836540 TI - Shack-Hartmann wavefront sensing based on binary-aberration-mode filtering. AB - Spot centroid detection is required by Shack-Hartmann wavefront sensing since the technique was first proposed. For a Shack-Hartmann wavefront sensor, the standard structure is to place a camera behind a lenslet array to record the image of spots. We proposed a new Shack-Hartmann wavefront sensing technique without using spot centroid detection. Based on the principle of binary-aberration-mode filtering, for each subaperture, only one light-detecting unit is used to measure the local wavefront slopes. It is possible to adopt single detectors in Shack Hartmann wavefront sensor. Thereby, the method is able to gain noise benefits from using singe detectors behind each subaperture when used for sensing rapid varying wavefront in weak light. Moreover, due to non-discrete pixel imaging, this method is a potential solution for high measurement precision with fewer detecting units. Our simulations demonstrate the validity of the theoretical model. In addition, the results also indicate the advantage in measurement accuracy. PMID- 25836541 TI - Adiabatic passage for three-dimensional entanglement generation through quantum Zeno dynamics. AB - We propose an adiabatic passage approach to generate two atoms three-dimensional entanglement with the help of quantum Zeno dynamics in a time-dependent interacting field. The atoms are trapped in two spatially separated cavities connected by a fiber, so that the individual addressing is needless. Because the scheme is based on the resonant interaction, the time required to generate entanglement is greatly shortened. Since the fields remain in vacuum state and all the atoms are in the ground states, the losses due to the excitation of photons and the spontaneous transition of atoms are suppressed efficiently compared with the dispersive protocols. Numerical simulation results show that the scheme is robust against the decoherences caused by the cavity decay and atomic spontaneous emission. Additionally, the scheme can be generalized to generate N-atom three-dimensional entanglement and high-dimensional entanglement for two spatially separated atoms. PMID- 25836542 TI - Proof of concept of fiber dispersed Raman spectroscopy using superconducting nanowire single-photon detectors. AB - Due to its high molecular specificity, Raman spectroscopy is a well-established analytical tool. Usually the inelastically scattered Raman light is spectrally dispersed by a spectrometer. Here, we present an alternative method, using an optical fiber as dispersive element. As the group velocity within the fiber is wavelength-dependent, different Raman bands arrive at different times at the detector. In combination with time-correlated single-photon counting, Raman spectra can be measured in the time domain. As detector we implemented a Superconducting Nanowire Single-Photon Detector (SNSPD), which possesses a timing accuracy of about 20 ps. Within this contribution we show first results of Raman spectra measured in the time domain using gradient index fibers of varying length. PMID- 25836543 TI - Geometric correction of atmospheric turbulence-degraded video containing moving objects. AB - Long-distance surveillance is a challenging task because of atmospheric turbulence that causes time-varying image shifts and blurs in images. These distortions become more significant as the imaging distance increases. This paper presents a new method for compensating image shifting in a video sequence while keeping real moving objects in the video unharmed. In this approach, firstly, a highly accurate and fast optical flow technique is applied to estimate the motion vector maps of the input frames and a centroid algorithm is employed to generate a geometrically correct frame in which there is no moving object. The second step involves applying an algorithm for detecting real moving objects in the video sequence and then restoring it with those objects unaffected. The performance of the proposed method is verified by comparing it with that of a state-of-the-art approach. Simulation experiments using both synthetic and real-life surveillance videos demonstrate that this method significantly improves the accuracy of image restoration while preserving moving objects. PMID- 25836544 TI - Analytical modeling and tolerance analysis of a linear variable filter for spectral order sorting. AB - This paper proposes an innovative method to overcome the low production rate of current linear variable filter (LVF) fabrication. During the fabrication process, a commercial coater is combined with a local mask on a substrate. The proposed analytical thin film thickness model, which is based on the geometry of the commercial coater, is developed to more effectively calculate the profiles of LVFs. Thickness tolerance, LVF zone width, thin film layer structure, transmission spectrum and the effects of variations in critical parameters of the coater are analyzed. Profile measurements demonstrate the efficacy of local mask theory in the prediction of evaporation profiles with a high degree of accuracy. PMID- 25836545 TI - Nanophotonic coherent imager. AB - An integrated silicon nanophotonic coherent imager (NCI), with a 4 * 4 array of coherent pixels is reported. In the proposed NCI, on-chip optical processing determines the intensity and depth of each point on the imaged object based on the instantaneous phase and amplitude of the optical wave incident on each pixel. The NCI operates based on a modified time-domain frequency modulated continuous wave (FMCW) ranging scheme, where concurrent time-domain measurements of both period and the zero-crossing time of each electrical output of the nanophotonic chip allows the NCI to overcome the traditional resolution limits of frequency domain detection. The detection of both intensity and relative delay enables applications such as high-resolution 3D reflective and transmissive imaging as well as index contrast imaging. We demonstrate 3D imaging with 15MUm depth resolution and 50MUm lateral resolution (limited by the pixel spacing) at up to 0.5-meter range. The reported NCI is also capable of detecting a 1% equivalent refractive index contrast at 1mm thickness. PMID- 25836546 TI - Transport properties of disordered photonic crystals around a Dirac-like point. AB - At the Dirac-like point at the Brillouin zone center, the photonic crystals (PhCs) can mimic a zero-index medium. In the band structure, an additional flat band of longitudinal mode will intersect the Dirac cone. This longitudinal mode can be excited in PhCs with finite sizes at the Dirac-like point. By introducing positional shift in the PhCs, we study the dependence of the longitudinal mode on the disorder. At the Dirac-like point, the transmission peak induced by the longitudinal mode decreases as the random degree increases. However, at a frequency slightly above the Dirac-like point, in which the longitudinal mode is absent, the transmission is insensitive to the disorder because the effective index is still near zero and the effective wavelength in the PhC is very large. PMID- 25836547 TI - Thermal analysis of optical reference cavities for low sensitivity to environmental temperature fluctuations. AB - The temperature stability of optical reference cavities is significant in state of-the-art ultra-stable narrow-linewidth laser systems. In this paper, the thermal time constant and thermal sensitivity of reference cavities are analyzed when reference cavities respond to environmental perturbations via heat transfer of thermal conduction and thermal radiation separately. The analysis as well as simulation results indicate that a reference cavity enclosed in multiple layers of thermal shields with larger mass, higher thermal capacity and lower emissivity is found to have a larger thermal time constant and thus a smaller sensitivity to environmental temperature perturbations. The design of thermal shields for reference cavities may vary according to experimentally achievable temperature stability and the coefficient of thermal expansion of reference cavities. A temperature fluctuation-induced length instability of reference cavities as low as 6 * 10(-16) on a day timescale can be achieved if a two-layer thermal shield is inserted between a cavity with the coefficient of thermal expansion of 1 * 10( 10) /K and an outer vacuum chamber with temperature fluctuation amplitude of 1 mK and period of 24 hours. PMID- 25836548 TI - Dielectric loaded graphene plasmon waveguide. AB - Dielectric loaded graphene plasmon waveguide (DLGPW) is proposed and investigated. An analytical model based on effective-index method is presented and verified by the finite element method simulations. The mode effective index, propagation loss, cutoff wavelength of higher order modes and single-mode operation region were derived at mid-infrared spectral region. By changing Fermi energy level, the propagation properties of fundamental mode could be tuned flexibly. The structure of the DLGPW is simple and easy for fabrication. It provided a new freedom to manipulate the graphene surface plasmons, which may led to new applications in actively tunable integrated optical devices. PMID- 25836549 TI - Rapid fabrication of thermoplastic polymer refractive microlens array using contactless hot embossing technology. AB - A thermoplastic polymer refractive microlens array has been rapidly fabricated by contactless hot embossing technology through the stainless steel template with micro through-holes array, which has a diameter of 150 um and a pitch of 185 um. By optimizing the technical parameters including heating and demoulding temperature, loading pressure, loading and pressure holding time, a series of high quality microlenses arrays of different sags could be obtained. In addition, the sag and the radius of curvature of the microlens are controllable. The geometrical and optical properties of the microlenses are measured and the influence of temperature and pressure duration on the optical properties of the microlenses are analysed. The results show good surface features and optical performances. Unlike previous contactless hot embossing, a low cost and durable stainless steel template was utilized instead of silicon or nickel mold to avoid valuable equipments and complicated fabrication procedure. Besides, the whole contactless hot embossing process was absence of vacuum equipment. We think that the technology could be an attractive high flexibility method for enhancing efficiency and reducing cost. PMID- 25836550 TI - Quantum cascade lasers: 20 years of challenges. AB - We review the most recent technological and application advances of quantum cascade lasers, underlining the present milestones and future directions from the Mid-infrared to the Terahertz spectral range. Challenges and developments, which are the subject of the contributions to this focus issue, are also introduced. PMID- 25836551 TI - Design, fabrication and characterization of a specially apodized chirped grating for reciprocal second harmonic generation. AB - A specially-designed apodized chirped PPLN based on particular positioning of poled regions within the periods has been realized theoretically and experimentally to demonstrate the reciprocal response in the SHG spectra over a 30-nm bandwidth, for up-chirp and down-chirp directions. The simulation results are compared with another apodized chirped PPLN for which the placement of poled regions is deviated from optimum positions. The average power difference is less than 0.75 dB and the standard deviations of extrema on second harmonic power responses are 1.34 dB and 1.64 dB for two up-chirp and down-chirp directions respectively. PMID- 25836552 TI - THz waveguide adapters for efficient radiation out-coupling from double metal THz QCLs. AB - We report the development of on-chip optical components designed to improve the out-coupling of double-metal terahertz (THz) frequency quantum cascade lasers (QCLs). A visible reshaping of the optical beam is achieved, independent of the precise waveguide configuration, by direct incorporation of cyclic-olefin copolymer (COC) dielectric optical fibers onto the QCL facet. A major improvement is further achieved by incorporating a micromachined feed-horn waveguide, assembled around the THz QCL and integrated with a slit-coupler. In its first implementation, we obtain a +/- 20 degrees beam divergence, offering the potential for high-efficiency radiation coupling from a metal-metal waveguide into optical fibers. PMID- 25836553 TI - Impact of interface roughness distributions on the operation of quantum cascade lasers. AB - We study the impact of interface roughness on the operation of mid-IR and THz quantum cascade lasers. Particular emphasis is given towards the differences between the Gaussian and exponential roughness distribution functions, for which we present results from simulation packages based on nonequilibrium Green's functions and density matrices. The Gaussian distribution suppresses scattering at high momentum transfer which enhances the lifetime of the upper laser level in mid-IR lasers. For THz lasers, a broader range of scattering transitions is of relevance, which is sensitive to the entire profile of the interface fluctuations. Furthermore we discuss the implementation of interface roughness within a two band model. PMID- 25836554 TI - Defect analysis of UV high-reflective coatings used in the high power laser system. AB - By considering the rapid change of standing-wave electric-field and assuming the interface defect distribution, an improved model is developed to analyze the defect density distribution and assess the damage performance of high-reflective coatings. Two kinds of high-reflective coatings deposited by e-beam evaporation (EBE) and ion beam sputtering (IBS) techniques are analyzed with this method. The lower overall damage threshold is the major feature for the coatings deposited by IBS method according to the defect parameters extracted from the model. Typical damage morphologies of coatings are also measured and analyzed. The assumption of interface defects is supported by the damage behavior. The damage mechanisms of two high-reflective coatings are attributed to the formation of molten pool and mechanical ejection. The influence of the incident angle on the damage probability is also considered and numerically calculated. The defect analysis model improved here is suitable for high-reflective coatings. PMID- 25836555 TI - The lensing effect of trapped particles in a dual-beam optical trap. AB - In dual-beam optical traps, two counterpropagating, divergent laser beams emitted from opposing laser fibers trap and manipulate dielectric particles. We investigate the lensing effect that trapped particles have on the beams. Our approach makes use of the intrinsic coupling of a beam to the opposing fiber after having passed the trapped particle. We present measurements of this coupling signal for PDMS particles, as well as a model for its dependence on size and refractive index of the trapped particle. As a more complex sample, the coupling of inhomogeneous biological cells is measured and discussed. We show that the lensing effect is well captured by the simple ray optics approximation. The measurements reveal intricate details, such as the thermal lens effect of the beam propagation in a dual-beam trap. For a particle of known size, the model further allows to infer its refractive index simply from the coupling signal. PMID- 25836556 TI - Creating electron vortex beams with light. AB - We propose an all-optical method of creating electron vortices utilizing the Kapitza-Dirac effect. This technique uses the transfer of orbital angular momentum from photons to free electrons creating electron vortex beams in the process. The laser intensities needed for this experiment can be obtained with available pulsed lasers and the resulting electron beams carrying orbital angular momentum will be particularly useful in the study of magnetic materials and chiral plasmonic structures in ultrafast electron microscopy. PMID- 25836557 TI - Two-way fiber-wireless convergence systems based on two-stage injection-locked VCSELs transmitter and optical interleaver. AB - A two-way fiber-wireless convergence system based on a two-stage injection-locked 1.55-MUm vertical-cavity surface-emitting lasers (VCSELs) transmitter and an optical interleaver (IL) to deliver intensity-modulated and phase-remodulated millimeter-wave (MMW) data signals over a 40-km single-mode fiber (SMF) and a 5-m radio frequency (RF) wireless transport is proposed and experimentally demonstrated. Bit error rate (BER) and eye diagram perform brilliantly through a serious investigation in systems. Such a two-way fiber-wireless convergence system is a promising option, it reveals a prominent one to present its advancement in integration of distribute fiber and in-house network. PMID- 25836558 TI - Theory of terahertz generation by optical rectification using tilted-pulse fronts. AB - A model for terahertz (THz) generation by optical rectification using tilted pulse-fronts is developed. It simultaneously accounts for in two spatial dimensions (2-D) (i) the spatio-temporal variations of the optical pump pulse imparted by the tilted-pulse-front setup, (ii) the nonlinear coupled interaction of THz and optical radiation, (iii) self-phase modulation and (iv) stimulated Raman scattering. The model is validated by quantitative agreement with experiments and analytic calculations. We show that the optical pump beam is significantly broadened in the transverse-momentum (kx) domain as a consequence of its spectral broadening due to THz generation. In the presence of this large frequency and transverse-momentum (or angular) spread, group velocity dispersion causes a spatio-temporal break-up of the optical pump pulse which inhibits further THz generation. The implications of these effects on energy scaling and optimization of optical-to-THz conversion efficiency are discussed. This suggests the use of optical pump pulses with elliptical beam profiles for large optical pump energies. Furthermore, it is seen that optimization of the setup is highly dependent on optical pump conditions. Trade-offs in optimizing the optical-to-THz conversion efficiency on the spatial and spectral properties of THz radiation are discussed to guide the development of such sources. PMID- 25836559 TI - Scanning-free BOTDA based on ultra-fine digital optical frequency comb. AB - We realize a scanning-free Brillouin optical time domain analyzer (BOTDA) based on an ultra-fine digital optical frequency comb (DOFC) with 1.95MHz frequency spacing and 2GHz bandwidth. The DOFC can be used to reconstruct the Brillouin gain spectrum (BGS) and locate the Brillouin frequency shift (BFS) without frequency scanning and thus can improve the measurement speed about 100 times compared with the conventional BOTDA. This scanning-free BOTDA scheme has also been demonstrated experimentally with 51.2m spatial resolution over 10km standard single mode fiber (SSMF) and with resolution of 1.5 degrees C for temperature and 43.3MUepsilon for strain measurement respectively. PMID- 25836560 TI - Enhanced signal coupling in wide-field fiber-coupled imagers. AB - Some high-performance imaging systems, including wide angle "monocentric" lenses made of concentric spherical shells, form a deeply curved image surface coupled to focal plane sensors by optical fiber bundles with a curved input and flat output face. However, refraction at the angled input facet limits the range of input angles, even for fiber bundles with numerical aperture 1. Here we investigate using a curved beam deflector near the focal surface to increase the field of view and improve spatial resolution at the edges of the field of view. We show the field of view of such an imager can be increased from approximately 60 degrees (full width at half maximum intensity) to over 90 degrees using an embossed refractive microprism array, where the prism angle varies across the aperture to maintain coupling. We describe a proof-of-principle experiment using a f = 17.8mm fiber-coupled monocentric singlet lens, and show that a local region of microprisms embossed into a thin layer of SU-8 photopolymer can increase the field of view by 50%. PMID- 25836561 TI - Quantitative index of arbitrary molar concentration for coherent anti-Stoke Raman scattering (CARS) spectroscopy and microscopy. AB - We propose a simple quantitative index for coherent anti-Stoke Raman scattering (CARS) spectroscopy and microscopy. Unlike previous similar indices, it can be applied to samples with arbitrary molar concentration, and it is robust against environmental change. Concentrations of aqueous hydrogen peroxide solution and lipid concentration distribution in a live murine adipocyte were successfully quantified by the new index. The index can be obtained in a broad range of CARS setups and it is readily applicable to quantitative CARS microscopy for deep inspection of samples such as biological specimens. PMID- 25836562 TI - Photonic-lantern-based coherent LIDAR system. AB - In this work, a photonic-lantern-based coherent LIDAR system is experimentally demonstrated and the voltage signal-to-noise ratio improvement is analyzed. A voltage signal-to-noise ratio (SNR(V)) improvement of 2.8 is demonstrated experimentally for photonic-lantern-based coherent receivers relative to single mode coherent receivers. The voltage signal-to-noise ratio improvement is obtained when other parameters are kept constant. We have also analyzed the effect of random optical power distribution among the single-mode fibers. We found that the distribution does not significantly impact the SNR(V) improvement. The mean value of voltage signal-to-noise ratio improvement is found to be ~ 2.4. PMID- 25836563 TI - Vertically coupled microring resonators using one epitaxial growth step and single-side lithography. AB - A new concept for the fabrication of integrated microring resonators, requiring only one single epitaxial growth and two single-side lithographic steps, is proposed in what is the simplest fabrication scheme for vertical microrings published to date. The approach is based on two vertically stacked phase matched core layers. The effect of bus waveguide, coupling region and ring structure parameters is theoretically analyzed. Numerical calculations predict high performance devices with quality factors of over 10000. The scheme can feature both active and passive regions, allowing the fabrication of microring lasers. PMID- 25836564 TI - Incoherent structured illumination improves optical sectioning and contrast in multiphoton super-resolution microscopy. AB - Three-dimensional super-resolution imaging in thick, semi-transparent biological specimens is hindered by light scattering, which increases background and degrades both contrast and optical sectioning. We describe a simple method that mitigates these issues, improving image quality in our recently developed two photon instant structured illumination microscope without requiring any hardware modifications to the instrument. By exciting the specimen with three laterally structured, phase-shifted illumination patterns and post-processing the resulting images, we digitally remove both scattered and out-of-focus emissions that would otherwise contaminate our raw data. We demonstrate the improved performance of our approach in biological samples, including pollen grains, primary mouse aortic endothelial cells cultured in a three-dimensional collagen matrix and live tumor like cell spheroids. PMID- 25836565 TI - Grating integrated single mode microring laser. AB - Microring and microdisk lasers are potential candidates for small footprint, low threshold in-plane integrated lasers; however, they exhibit multimode lasing spectra and bistability. Here, we theoretically propose and experimentally demonstrate a novel approach for achieving single mode lasing in microring lasers. Our approach is based on increasing the radiation loss of all but one of the resonant modes of microring resonators by integrating second order gratings on the microrings' waveguide. We present single mode operation of electrically pumped semiconductor microring lasers whose lasing modes are lithographically selected via the second order grating. We also show that adding the grating does not increase the lasing threshold current significantly. PMID- 25836566 TI - Manipulating photoinduced voltage in metasurface with circularly polarized light. AB - Recently, the concept of metasurface has provided one an unprecedented opportunity and ability to control the light in the deep subwavelength scale. However, so far most efforts are devoted to exploiting the novel scattering properties and applications of metasurface in optics. Here, I theoretically and numerically demonstrate that longitudinal and transverse photoinduced voltages can be simultaneously realized in the proposed metasurface utilizing the magnetic resonance under the normal incidence of circularly polarized light, which may extend the concept and functionality of metasurface into the electronics and may provide a potential scheme to realize a nanoscale tunable voltage source through a nanophotonic roadmap. The signs of longitudinal and transverse photoin-duced voltages can be manipulated by tuning the resonant frequency and the handedness of circularly polarized light, respectively. Analytical formulae of photoinduced voltage are presented based on the theory of symmetry of field. This work may bridge nanophotonics and electronics, expands the capability of metasurface and has many potential applications. PMID- 25836567 TI - Fabricating subwavelength dot-matrix surface structures of molybdenum by transient correlated actions of two-color femtosecond laser beams. AB - Two-dimensional matrix of subwavelength dot structures are directly generated on molybdenum surfaces by focusing two-color femtosecond laser pulses through an optical lens. In contrast to the traditional fabrication approaches, the spatial periodicities of such surface structures are demonstrated to rely on the time delay of two laser beams through transient correlation between their ultrafast dynamic processes, in spite of their different colors and polarizations. The structure orientations can be tuned effectively via the laser polarization. Discussion suggests a new possible flexible way towards the nanoscale sophisticated material processing for many potential applications. PMID- 25836568 TI - Automatic identification of oculomotor behavior using pattern recognition techniques. AB - In this paper, a methodological scheme for identifying distinct patterns of oculomotor behavior such as saccades, microsaccades, blinks and fixations from time series of eye's angular displacement is presented. The first step of the proposed methodology involves signal detrending for artifacts removal and estimation of eye's angular velocity. Then, feature vectors from fourteen first order statistical features are formed from each angular displacement and velocity signal using sliding, fixed-length time windows. The obtained feature vectors are used for training and testing three artificial neural network classifiers, connected in cascade. The three classifiers discriminate between blinks and non blinks, fixations and non-fixations and saccades and microsaccades, respectively. The proposed methodology was tested on a dataset from 1392 subjects, each performing three oculomotor fixation conditions. The average overall accuracy of the three classifiers, with respect to the manual identification of eye movements by experts, was 95.9%. The proposed methodological scheme provided better results than the well-known Velocity Threshold algorithm, which was used for comparison. The findings of the present study indicate that the utilization of pattern recognition techniques in the task of identifying the various eye movements may provide accurate and robust results. PMID- 25836569 TI - Use of the gum elastic bougie during endotracheal intubation in emergent patients with difficult airways. PMID- 25836570 TI - A route to the heterocyclic cluster of the E-series of thiopeptide antibiotics. AB - A concise route to the 3-hydroxypyridine core of thiopeptide antibiotics such as nocathiacin is described. Key phases of the sequence involve a modified Hantzsch pyridine construction and a chemoselective Peng deprotection of a phenolic MOM ether. PMID- 25836571 TI - Generating primary cultures of murine cardiac myocytes and cardiac fibroblasts to study viral myocarditis. AB - Viruses can induce direct damage to cardiac myocytes and cardiac fibroblasts resulting in myocarditis and impaired cardiac function. Cardiac myocytes and cardiac fibroblasts display different capacities to support viral infection and generate a protective antiviral response. This chapter provides detailed protocols for generation and characterization of primary cultures of murine cardiac myocytes and cardiac fibroblasts, offering a powerful tool to probe cell type-specific responses that determine protection against viral myocarditis. PMID- 25836572 TI - Enrichment of cardiomyocytes in primary cultures of murine neonatal hearts. AB - In vitro culture of neonatal murine cardiomyocytes is vital for understanding the functions of the heart. Cardiomyocyte cultures are difficult to maintain because they do not proliferate after birth. The maintenance of primary cultures of viable and functional cardiomyocytes is considerably affected by the yield from initial steps of isolation procedures. This protocol describes an efficient and rapid method for isolation and maintenance of long-term cultures of neonatal murine cardiomyocytes by effectively shortening the trypsin enzyme digestion period and the cardiomyocyte enrichment step. PMID- 25836573 TI - Deep sequencing of cardiac microRNA-mRNA interactomes in clinical and experimental cardiomyopathy. AB - MicroRNAs are a family of short (~21 nucleotide) noncoding RNAs that serve key roles in cellular growth and differentiation and the response of the heart to stress stimuli. As the sequence-specific recognition element of RNA-induced silencing complexes (RISCs), microRNAs bind mRNAs and prevent their translation via mechanisms that may include transcript degradation and/or prevention of ribosome binding. Short microRNA sequences and the ability of microRNAs to bind to mRNA sites having only partial/imperfect sequence complementarity complicate purely computational analyses of microRNA-mRNA interactomes. Furthermore, computational microRNA target prediction programs typically ignore biological context, and therefore the principal determinants of microRNA-mRNA binding: the presence and quantity of each. To address these deficiencies we describe an empirical method, developed via studies of stressed and failing hearts, to determine disease-induced changes in microRNAs, mRNAs, and the mRNAs targeted to the RISC, without cross-linking mRNAs to RISC proteins. Deep sequencing methods are used to determine RNA abundances, delivering unbiased, quantitative RNA data limited only by their annotation in the genome of interest. We describe the laboratory bench steps required to perform these experiments, experimental design strategies to achieve an appropriate number of sequencing reads per biological replicate, and computer-based processing tools and procedures to convert large raw sequencing data files into gene expression measures useful for differential expression analyses. PMID- 25836574 TI - Next-generation sequencing technology in the genetics of cardiovascular disease. AB - In recent years, next-generation sequencing (NGS) technologies have revolutionized approaches to genetic studies, making whole-genome sequencing a possible way for obtaining global genomic information. At present, three most NGS platforms are used in genetics for clonally amplified templates. These technologies share general processing steps but differing in specific technical details that determine their limits or advantages. NGS has been recently shown to have great potential for identifying novel causative mutations in different disorders. It is expected that the NGS will be increasingly important in the study of inherited and complex traits such as cardiovascular diseases (CVDs). Indeed, the identification and characterization of genes that enhance prediction of CVDs risk remain an important challenge for improving prevention and treatment. PMID- 25836575 TI - Computational cardiac electrophysiology: implementing mathematical models of cardiomyocytes to simulate action potentials of the heart. AB - Mathematical models are now an important tool for studying cardiac electrophysiology and arrhythmias. Utilizing these models to quantify behavior and make predictions requires solving the models computationally using numerical schemes. We discuss different solution methods and other computational considerations for simulating cardiac action potentials in single cells and multicellular preparations. PMID- 25836576 TI - Methods of myofibrillogenesis modeling. AB - Organization in the heart is important on multiple length scales. Myofibrillogenesis processes control the assembly of this multi-scale architecture. Understanding myofibrillogenesis might allow us to better control self-assembly of cardiac tissues. One approach consists of creating phenomenological models and comparing these models to in vitro data from primary myocytes. In this chapter, we present a method for building these models to recapitulate different aspects of myofibrillogenesis. We present a specific example for a cardiomyocyte model, but the same procedure can be used to model fibrillogenesis with other mechanisms such as motility. In sum, the models allow for a better understanding of mechanisms behind self-assembly. PMID- 25836577 TI - Using the mechanical bidomain model to analyze the biomechanical behavior of cardiomyocytes. AB - The mechanical bidomain model provides a macroscopic description of cardiac tissue biomechanics and also predicts the microscopic coupling between the extracellular matrix and the intracellular cytoskeleton of cardiomyocytes. The goal of this chapter is to introduce the mechanical bidomain model, to describe the mathematical methods required to solve the model equations, and to predict where the membrane forces acting on integrin proteins coupling the intracellular and extracellular spaces are large. PMID- 25836578 TI - Fabrication of a myocardial patch with cells differentiated from human-induced pluripotent stem cells. AB - The incidence of cardiovascular disease represents a significant and growing health-care challenge to the developed and developing world. The ability of native heart muscle to regenerate in response to myocardial infarct is minimal. Tissue engineering and regenerative medicine approaches represent one promising response to this difficulty. Here, we present methods for the construction of a cell-seeded cardiac patch with the potential to promote regenerative outcomes in heart muscle with damage secondary to myocardial infarct. This method leverages iPS cells and a fibrin-based scaffold to create a simple and commercially viable tissue-engineered cardiac patch. Human-induced pluripotent stem cells (hiPSCs) can, in principle, be differentiated into cells of any lineage. However, most of the protocols used to generate hiPSC-derived endothelial cells (ECs) and cardiomyocytes (CMs) are unsatisfactory because the yield and phenotypic stability of the hiPSC-ECs are low, and the hiPSC-CMs are often purified via selection for expression of a promoter-reporter construct. In this chapter, we describe an hiPSC-EC differentiation protocol that generates large numbers of stable ECs and an hiPSC-CM differentiation protocol that does not require genetic manipulation, single-cell selection, or sorting with fluorescent dyes or other reagents. We also provide a simple but effective method that can be used to combine hiPSC-ECs and hiPSC-CMs with hiPSC-derived smooth muscle cells to engineer a contracting patch of cardiac cells. PMID- 25836580 TI - Isolation, culturing, and characterization of cardiac muscle cells from nonhuman primate heart tissue. AB - Cardiac safety pharmacology requires in vitro testing of all drug candidates before clinical trials in order to ensure they are screened for cardiotoxic effects which may result in severe arrhythmias and, ultimately, cardiomyopathy (Chi, Nat Rev Drug Discov 12:565-567, 2013). Given the physiological similarities between nonhuman primates and humans, isolated primate cardiac muscle cells are an ideal animal model for such in vitro testing. The aims of this chapter are to describe two methods for isolating and culturing primate cardiac muscle cells. One method uses mechanical dissociation of the tissue followed by placing the small pieces onto a Petri dish and culturing these tissue explants. The other method also uses mechanical dissociation but is then followed by enzymatic digestion and culturing of the cell suspension. Methods are also described for phenotypically characterizing cardiac muscle cells by flow cytometry. Based on the location within the heart tissue chosen for cell isolation, a dividing population of cardiac muscle cells expressing cardiomyocyte cell markers was obtained. PMID- 25836581 TI - Mouse embryonic stem cell-derived cardiac myocytes in a cell culture dish. AB - Embryonic stem (ES) cells are pluripotent stem cells capable of self-renewal and have broad differentiation potential yielding cell types from all three germ layers. In the absence of differentiation inhibitory factors, when cultured in suspension, ES cells spontaneously differentiate and form three-dimensional cell aggregates termed embryoid bodies (EBs). Although various methods exist for the generation of EBs, the hanging drop method offers reproducibility and homogeneity from a predetermined number of ES cells. Herein, we describe the in vitro differentiation of mouse embryonic stem cells into cardiac myocytes using the hanging drop method and immunocytochemistry to identify cardiomyogenic differentiation. In brief, ES cells, placed in droplets on the lid of culture dishes following a 2-day incubation, yield embryoid bodies, which are resuspended and plated. 1-2 weeks following plating of the EBs, spontaneous beating areas can be observed and staining for specific cardiac markers can be achieved. PMID- 25836579 TI - Efficient differentiation of cardiomyocytes from human pluripotent stem cells with growth factors. AB - Human pluripotent stem cells have tremendous replicative capacity and demonstrated potential to generate functional cardiomyocytes. These cardiomyocytes represent a promising source for cell replacement therapy to treat heart disease and may serve as a useful tool for drug discovery and disease modeling. Efficient cardiomyocyte differentiation, a prerequisite for the application of stem cell-derived cardiomyocytes, can be achieved with a growth factor-guided method. Undifferentiated cells are sequentially treated with activin A and BMP4 in a serum-free and insulin-free medium and then maintained in a serum-free medium with insulin. This method yields as much as >75% cardiomyocytes in the differentiation culture within 2 weeks, and the beating cardiomyocytes have expected molecular, cellular, and electrophysiological characteristics. In this chapter, we describe in detail the differentiation protocol and follow-up characterization focusing on immunocytochemistry, quantitative RT-PCR, and flow cytometry analysis. PMID- 25836582 TI - Cryopreservation of neonatal cardiomyocytes. AB - Cardiomyocytes are frequently used for in vitro models for cardiac research. The isolation of cells is time-consuming and, due to the cells limited proliferative abilities, must be performed frequently. To reduce the time requirements and the impact on research animals, we describe a method for cryopreserving neonatal rat cardiomyocytes (NRCMs), and subsequently thawing them for use in assays. PMID- 25836583 TI - Evaluation of sarcomeric organization in human pluripotent stem cell-derived cardiomyocytes. AB - High-resolution optical imaging provides valuable window in examining transitional and systemic changes in cellular processes. The relative spatial relationship of structural, transport, and signaling proteins, surface antigens, and transcription factors may reveal developmental state of the cellular system. Here, we describe the use of confocal microscopy to evaluate the organization of sarcomeric structural proteins, sarcoplasmic channel proteins, and cardiac transcription factors in human pluripotent stem cell (PSC)-derived cardiomyocytes. PMID- 25836584 TI - Electrotonic coupled metabolic purification of chick cardiomyocytes. AB - Cardiomyocytes isolated from chick and rodent are widely used in studying cardiac physiology. However, contaminating non-cardiomyocytes are an inherent problem that hinders downstream analysis. Here, we report a novel electrical stimulation coupled with metabolic selection method using cytosine arabinoside (AraC) to efficiently eliminate contaminating cells in isolating chick embryonic cardiomyocytes. Compared with conventional methods of pre-plating or AraC alone, electrical stimulation coupled with AraC increased the percentage purity of cardiomyocytes by 2-6-fold with added effect of improved contractile function and maturation. This simple method could be useful in isolating and maintaining purified cardiomyocytes for long-term studies of cardiac physiology. PMID- 25836585 TI - Gene transfer into cardiac myocytes. AB - Traditional methods for DNA transfection are often inefficient and toxic for terminally differentiated cells, such as cardiac myocytes. Vector-based gene transfer is an efficient approach for introducing exogenous cDNA into these types of primary cell cultures. In this chapter, separate protocols for adult rat cardiac myocyte isolation and gene transfer with recombinant adenovirus are provided and are routinely utilized for studying the effects of sarcomeric proteins on myofilament function. PMID- 25836586 TI - Analysis of 4D myocardial wall motion during early stages of chick heart development. AB - 4D myocardial wall motion analysis (3D structure over time) during early embryonic stages of chick heart development provides a comprehensive view to characterize the biomechanical environment of cardiac growth. Myocardial wall strains, velocity, and area shortening over the cardiac cycle are common wall motion assessments and can be accurately measured from 4D datasets. Here, we describe how to employ a variety of image modalities (optical, ultrasound, and optical coherence tomography imaging) and analysis techniques to extract quantitative measures of myocardial wall motion. PMID- 25836587 TI - The stability of epigenetic factor ASXL1 is regulated through ubiquitination and USP7-mediated deubiquitination. PMID- 25836588 TI - Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. AB - Mutations in isocitrate dehydrogenase 1/2 (IDH1/2(MT)) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2 hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower- to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1(MT) and IDH2(MT) are ancestral in up to 14/74 (19%) vs 34/99 (34%; P=0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2(MT) was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1(MT) cases were associated with a worse prognosis than subclonal IDH1(MT) cases, whereas the position of IDH2(MT) within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1(MT) cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2(MT) cases. Our data demonstrate important clinical and biological differences between IDH1(MT) and IDH2(MT) myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2(MT) inhibitors of IDH1/2(MT) patients. PMID- 25836590 TI - Retention of the stemness of mouse adipose-derived stem cells by their expansion on human bone marrow stromal cell-derived extracellular matrix. AB - Mesenchymal stem cells (MSCs) usually lose their stemness during in vitro expansion as they are deprived of their niche environment. Cell-extracellular matrix (ECM) interaction is known to play important roles in preserving the stemness of the cells in their stem cell niche environment. Previously, coating with bone marrow MSC (BMSC)-derived ECM was found able to maintain the differentiation potential of in vitro cultured MSCs. This study aimed to determine if this ECM coating could also maintain the stemness of cultured murine adipose-derived stem cells (ASCs) using a regular culture flask as a control. Cells were expanded in ECM-coated and ECM-noncoated flasks for two and four passages and then harvested for various analyses. The results showed that ASCs exhibited fibroblast-like spindle morphology in ECM-coated flasks, whereas ASCs gradually spread and enlarged in the ECM-noncoated flasks. After three and five passages, both groups of cells exhibited similar cytokinetics in the MSC culture medium (MesenPRO RSTM Medium). However, when cultured in Dulbecco's modified Eagles medium (DMEM) plus 10% fetal bovine serum, coating group cells exhibited more potent proliferation than control group cells with a significant difference in both passages 3 and 5 (p<0.01). When seeded at low density (500 cells/10-cm dish), coating group cells formed significantly more and larger sized cell colonies than control group cells with significant difference in cell colony numbers between two groups (p<0.05). In addition, coated colony cells were much smaller and more compactly arranged compared to control colony cells. Furthermore, ASCs expanded in coated flasks exhibited greater potentials for adipogenic, osteogenic, and chondrogenic differentiations than the cells expanded in regular flasks. Quantitatively, the Oil Red O staining area, Alizarin staining area, and Toluidine Blue staining area were all significantly larger than the respective staining areas of control cells (p<0.05). Real-time polymerase chain reaction also revealed significantly higher gene expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma), adipocyte protein 2 (aP2), CCAAT/enhancer-binding protein (C/EBP), Runx2, osteocalcin, Sox9, collagen II, and aggrecan in ECM-coated group cells than in control group cells (p<0.05). Collectively, these results suggest that human BMSC decellular ECM coating helps to preserve the stemness of cultured murine ASCs. PMID- 25836589 TI - Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells. AB - We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials. PMID- 25836591 TI - Ischemic Compression After Dry Needling of a Latent Myofascial Trigger Point Reduces Postneedling Soreness Intensity and Duration. AB - OBJECTIVE: To investigate the effect of ischemic compression (IC) versus placebo and control on reducing postneedling soreness of 1 latent myofascial trigger point and on improving cervical range of motion (CROM) in asymptomatic subjects. DESIGN: A randomized, double-blind, placebo-controlled trial with 72-hour follow up. SETTING: A university community. PARTICIPANTS: Asymptomatic volunteers (N = 90: 40 men and 50 women) aged 18 to 39 years (mean +/- standard deviation [SD]: 22 +/- 3 years). INTERVENTION: All subjects received a dry needling application over the upper trapezius muscle. Participants were then randomly divided into 3 groups: a treatment group who received IC over the needled trapezius muscle, a placebo group who received sham IC, and a control group who did not receive any treatment after needling. MAIN OUTCOME MEASURES: Visual analog scale (VAS; during needling, at posttreatment and 6, 12, 24, 48, and 72 hours) and CROM (at preneedling, postneedling, and 24 and 72 hours). RESULTS: Subjects in the IC group showed significantly lower postneedling soreness than the placebo and the control group subjects immediately after treatment (mean +/- standard deviation [SD]: IC, 20.1 +/- 4.8; placebo, 36.7 +/- 4.8; control, 34.8 +/- 3.6) and at 48 hours (mean +/- SD: IC, 0.6 +/- 1; placebo, 4.8 +/- 1; control, 3.8 +/- 0.7). In addition, subjects in the dry needling+IC group showed significantly lower postneedling soreness duration (P = .026). All subjects significantly improved CROM in contralateral lateroflexion and both homolateral and contralateral rotations, but only the improvements found in the IC group reached the minimal detectable change. CONCLUSIONS: IC can potentially be added immediately after dry needling of myofascial trigger point in the upper trapezius muscle because it has the effect of reducing postneedling soreness intensity and duration. The combination of dry needling and IC seems to improve CROM in homolateral and contralateral cervical rotation movements. PMID- 25836592 TI - Sequential delivery of angiogenic growth factors improves revascularization and heart function after myocardial infarction. AB - Treatment of ischemia through therapeutic angiogenesis faces significant challenges. Growth factor (GF)-based therapies can be more effective when concerns such as GF spatiotemporal presentation, bioactivity, bioavailability, and localization are addressed. During angiogenesis, vascular endothelial GF (VEGF) is required early to initiate neovessel formation while platelet-derived GF (PDGF-BB) is needed later to stabilize the neovessels. The spatiotemporal delivery of multiple bioactive GFs involved in angiogenesis, in a close mimic to physiological cues, holds great potential to treat ischemic diseases. To achieve sequential release of VEGF and PDGF, we embed VEGF in fibrin gel and PDGF in a heparin-based coacervate that is distributed in the same fibrin gel. In vitro, we show the benefits of this controlled delivery approach on cell proliferation, chemotaxis, and capillary formation. A rat myocardial infarction (MI) model demonstrated the effectiveness of this delivery system in improving cardiac function, ventricular wall thickness, angiogenesis, cardiac muscle survival, and reducing fibrosis and inflammation in the infarct zone compared to saline, empty vehicle, and free GFs. Collectively, our results show that this delivery approach mitigated the injury caused by MI and may serve as a new therapy to treat ischemic hearts pending further examination. PMID- 25836594 TI - Treatment of Orbital Roof Blow-Up Fracture Using a Superior Blepharoplasty Incision. AB - In orbital roof blow-up fractures, reduction can be achieved easily using an approach from the anterior cranial fossa but the procedure is highly invasive. In contrast, an orbital approach using a superior blepharoplasty incision is minimally invasive. However, if bone fragments are adhered to the dura mater, there is a risk of dura mater injury when fragments are moved for reduction. In blow-in fractures, reduction is performed by pushing the bone fragments against the anterior cranial fossa. In contrast, the procedure is difficult for blow-up fractures because bone fragments must be pulled out into the orbit through the anterior cranial fossa. Orbital blow-up fractures are often associated with intracranial injuries and frequently treated by an approach from the anterior cranial fossa. There has not yet been a report that discusses whether reduction of bone fragments should be performed in blow-up fracture without intracranial injury. In this report, we describe two cases of orbital roof blow-up fracture that did not require treatment for intracranial injury and that were treated using an orbital approach. The treatment involved only the release of orbital fat entrapped between bone fragments and did not involve reduction. The treatment outcomes were good in both cases. PMID- 25836593 TI - Exosomes as drug delivery vehicles for Parkinson's disease therapy. AB - Exosomes are naturally occurring nanosized vesicles that have attracted considerable attention as drug delivery vehicles in the past few years. Exosomes are comprised of natural lipid bilayers with the abundance of adhesive proteins that readily interact with cellular membranes. We posit that exosomes secreted by monocytes and macrophages can provide an unprecedented opportunity to avoid entrapment in mononuclear phagocytes (as a part of the host immune system), and at the same time enhance delivery of incorporated drugs to target cells ultimately increasing drug therapeutic efficacy. In light of this, we developed a new exosomal-based delivery system for a potent antioxidant, catalase, to treat Parkinson's disease (PD). Catalase was loaded into exosomes ex vivo using different methods: the incubation at room temperature, permeabilization with saponin, freeze-thaw cycles, sonication, or extrusion. The size of the obtained catalase-loaded exosomes (exoCAT) was in the range of 100-200nm. A reformation of exosomes upon sonication and extrusion, or permeabilization with saponin resulted in high loading efficiency, sustained release, and catalase preservation against proteases degradation. Exosomes were readily taken up by neuronal cells in vitro. A considerable amount of exosomes was detected in PD mouse brain following intranasal administration. ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD. Overall, exosome-based catalase formulations have a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders. PMID- 25836595 TI - Erratum to: Stress response signaling and virulence: insights from entomopathogenic fungi. PMID- 25836597 TI - Spirostanol steroids from the roots of Allium tuberosum. AB - Three new spirostanol saponins named tuberosines A-C (1-3), together with three known ones tuberoside O (4), 25(S)-Schidigera-saponin D5 (5), and shatavarin IV (6) were isolated from the roots of Allium tuberosum. Their structures were established on the basis of extensive spectroscopic analyses. Whereas compounds 5 and 6 exhibited potent antibacterial activities against Bacillus subtilis (32 MUg/mL) and Escherichia coli (16 MUg/mL), the new saponin 2 showed only moderate antibacterial activities against these pathogens. The relationship between the antibacterial activities and the structures of these saponins are described. PMID- 25836596 TI - BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication. AB - BRCA1 and BRCA2 mutation carriers are predisposed to develop breast and ovarian cancers, but the reasons for this tissue specificity are unknown. Breast epithelial cells are known to contain elevated levels of oxidative DNA damage, triggered by hormonally driven growth and its effect on cell metabolism. BRCA1- or BRCA2-deficient cells were found to be more sensitive to oxidative stress, modeled by treatment with patho-physiologic concentrations of hydrogen peroxide. Hydrogen peroxide exposure leads to oxidative DNA damage induced DNA double strand breaks (DSB) in BRCA-deficient cells causing them to accumulate in S phase. In addition, after hydrogen peroxide treatment, BRCA deficient cells showed impaired Rad51 foci which are dependent on an intact BRCA1-BRCA2 pathway. These DSB resulted in an increase in chromatid-type aberrations, which are characteristic for BRCA1 and BRCA2-deficient cells. The most common result of oxidative DNA damage induced processing of S-phase DSB is an interstitial chromatid deletion, but insertions and exchanges were also seen in BRCA deficient cells. Thus, BRCA1 and BRCA2 are essential for the repair of oxidative DNA damage repair intermediates that persist into S-phase and produce DSB. The implication is that oxidative stress plays a role in the etiology of hereditary breast cancer. PMID- 25836598 TI - Ultrasound assessment of gastric volume in critically ill patients: response to Gultekin et al. PMID- 25836599 TI - Understanding the setting of PEEP from esophageal pressure in patients with ARDS. PMID- 25836600 TI - Methylglyoxal modulates axonal excitability in diabetic polyneuropathy: A potential pathophysiological link? PMID- 25836601 TI - Safety of titanium rods used for spinal stabilization during repetitive magnetic stimulation. PMID- 25836602 TI - Prevalence and prescription of antidepressants in depression with somatic comorbidity in Asia: the Research on East Asian Psychotropic Prescription Patterns study. AB - BACKGROUND: Depression is often comorbid with chronic somatic diseases. Few previous studies have investigated the prevalence of somatic diseases in depression or the prescription pattern of antidepressants in comorbidly depressed patients in Asia. This study aimed to investigate the prevalence of somatic comorbidity (SC) in depression and compared the prescriptions of antidepressants in depressed patients with and without SC. METHODS: A total of 2320 patients treated with antidepressants in 8 Asian countries were examined, and a diagnosis was based on the International Classification of Disease, 10 th revision. We listed 17 common chronic somatic diseases. Patients' socio-demographic and clinical characteristics and psychotropic drug prescriptions were recorded using a standardized protocol and data collection procedure. RESULTS: Of the patients examined, 1240 were diagnosed with depression and 30% of them (n = 375) had SC. The most common comorbid condition was diabetes (23.7%). The patients with SC were more likely to seek help at a general hospital (74.7% vs. 47.2%), and had a higher incidence of symptoms involving sadness, disturbed sleep, and poor appetite. Noradrenergic and specific serotonergic antidepressant was prescribed more for patients with SC than for those without SC (30.4% vs. 22.9%). CONCLUSIONS: SC is common in depressed Asian patients. It is important to strengthen the recognition of depression, especially in general hospitals and when patients report some somatic discomfort. It is also a matter of urgency to establish evidence-based guidelines for the use of new antidepressants in depressed patients with SC. PMID- 25836603 TI - Influence of peritoneal transport characteristics on nutritional status and clinical outcome in Chinese diabetic nephropathy patients on peritoneal dialysis. AB - BACKGROUND: High peritoneal transport status was previously thought to be a poor prognostic factor in peritoneal dialysis (PD) patients. However, its effect on diabetic nephropathy PD patients is unclear in consideration of the adverse impact of diabetes itself. The purpose of this study was to investigate the influence of peritoneal transport characteristics on nutritional status and clinical outcome in diabetic nephropathy patients on PD. METHODS: One hundred and two diabetic nephropathy patients on PD were enrolled in this observational cohort study. According to the initial peritoneal equilibration test result, patients were divided into two groups: Higher transport group (HT, including high and high average transport) and lower transport group (LT, including low and low average transport). Demographic characteristics, biochemical data, dialysis adequacy, and nutritional status were evaluated. Clinical outcomes were compared. Risk factors for death-censored technique failure and mortality were analyzed. RESULTS: Compared with LT group (n = 37), serum albumin was significantly lower and the incidence of malnutrition by subjective global assessment was significantly higher in HT group (n = 65) (P < 0.05). Kaplan-Meier analyses showed that death-censored technique failure and mortality were significantly increased in HT group compared with that in LT group. On multivariate Cox analyses, higher peritoneal transport status and lower residual renal function (RRF) were independent predictors of death-censored technique failure when adjusted for serum albumin and total weekly urea clearance (Kt/V). Independent predictors of mortality were advanced age, anemia, hypoalbuminemia, and lower RRF, but not higher peritoneal transport status. CONCLUSIONS: Higher peritoneal transport status has an adverse influence on nutrition for diabetic nephropathy patients on PD. Higher peritoneal transport status is a significant independent risk factor for death-censored technique failure, but not for mortality in diabetic nephropathy patients on PD. PMID- 25836604 TI - Posterior reduction and monosegmental fusion with intraoperative three dimensional navigation system in the treatment of high-grade developmental spondylolisthesis. AB - BACKGROUND: The treatment of high-grade developmental spondylolisthesis (HGDS) is still challenging and controversial. In this study, we investigated the efficacy of the posterior reduction and monosegmental fusion assisted by intraoperative three-dimensional (3D) navigation system in managing the HGDS. METHODS: Thirteen consecutive HGDS patients were treated with posterior decompression, reduction and monosegmental fusion of L5/S1, assisted by intraoperative 3D navigation system. The clinical and radiographic outcomes were evaluated, with a minimum follow-up of 2 years. The differences between the pre- and post-operative measures were statistically analyzed using a two-tailed, paired t-test. RESULTS: At most recent follow-up, 12 patients were pain-free. Only 1 patient had moderate pain. There were no permanent neurological complications or pseudarthrosis. The magnetic resonance imaging showed that there was no obvious disc degeneration in the adjacent segment. All radiographic parameters were improved. Mean slippage improved from 63.2% before surgery to 12.2% after surgery and 11.0% at latest follow-up. Lumbar lordosis changed from preoperative 34.9 +/- 13.3 degrees to postoperative 50.4 +/- 9.9 degrees , and 49.3 +/- 7.8 degrees at last follow-up. L5 incidence improved from 71.0 +/- 11.3 degrees to 54.0 +/- 11.9 degrees and did not change significantly at the last follow-up 53.1 +/- 15.4 degrees . While pelvic incidence remained unchanged, sacral slip significantly decreased from preoperative 32.7 +/- 12.5 degrees to postoperative 42.6 +/- 9.8 degrees and remained constant to the last follow-up 44.4 +/- 6.9 degrees . Pelvic tilt significantly decreased from 38.4 +/- 12.5 degrees to 30.9 +/- 8.1 degrees and remained unchanged at the last follow-up 28.1 +/- 11.2 degrees . CONCLUSIONS: Posterior reduction and monosegmental fusion of L5/S1 assisted by intraoperative 3D navigation are an effective technique for managing high-grade dysplastic spondylolisthesis. A complete reduction of local deformity and excellent correction of overall sagittal balance can be achieved. PMID- 25836605 TI - Mast Quadrant-assisted minimally invasive modified transforaminal lumbar interbody fusion: single incision versus double incision. AB - BACKGROUND: The concept of minimally invasive techniques is to make every effort to reduce tissue damage. Certainly, reducing skin incision is an important part of these techniques. This study aimed to investigate the clinical feasibility of Mast Quadrant-assisted modified transforaminal lumbar interbody fusion (TLIF) with a small single posterior median incision. METHODS: During the period of March 2011 to March 2012, 34 patients with single-segment degenerative lumbar disease underwent the minimally invasive modified TLIF assisted by Mast Quadrant with a small single posterior median incision (single incision group). The cases in this group were compared to 37 patients with single-segment degenerative lumbar disease in the double incision group. The perioperative conditions of patients in these two groups were statistically analyzed and compared. The Oswestry Disability Index (ODI) scores, Visual Analog Scale (VAS) scores, and sacrospinalis muscle damage evaluation indicators before operation and 3, 12 months postoperation were compared. RESULTS: A total of 31 and 35 cases in the single incision and double incision groups, respectively, completed at least 12 months of systemic follow-up. The differences in perioperative conditions between the two groups were not statistically significant. The incision length of the single incision group was significantly shorter than that of the double incision group (P < 0.01). The ODI and VAS scores of patients in both groups improved significantly at 3 and 12 months postoperation. However, these two indicators at 3 and 12 months postoperation and the sacrospinalis muscle damage evaluation indicators at 3 months postoperation did not differ significantly between the two groups (P >= 0.05). CONCLUSIONS: Mast Quadrant-assisted modified TLIF with a small single posterior median incision has excellent clinical feasibility compared to minimally invasive TLIF with a double paramedian incision. PMID- 25836606 TI - Rapid detection and identification of infectious pathogens based on high throughput sequencing. AB - BACKGROUND: The dilemma of pathogens identification in patients with unidentified clinical symptoms such as fever of unknown origin exists, which not only poses a challenge to both the diagnostic and therapeutic process by itself, but also to expert physicians. METHODS: In this report, we have attempted to increase the awareness of unidentified pathogens by developing a method to investigate hitherto unidentified infectious pathogens based on unbiased high-throughput sequencing. RESULTS: Our observations show that this method supplements current diagnostic technology that predominantly relies on information derived five cases from the intensive care unit. This methodological approach detects viruses and corrects the incidence of false positive detection rates of pathogens in a much shorter period. Through our method is followed by polymerase chain reaction validation, we could identify infection with Epstein-Barr virus, and in another case, we could identify infection with Streptococcus viridians based on the culture, which was false positive. CONCLUSIONS: This technology is a promising approach to revolutionize rapid diagnosis of infectious pathogens and to guide therapy that might result in the improvement of personalized medicine. PMID- 25836607 TI - Efficacy and safety of 120-W thulium:yttrium-aluminum-garnet vapoenucleation of prostates compared with holmium laser enucleation of prostates for benign prostatic hyperplasia. AB - BACKGROUND: This study compared the efficacy and safety between 120-W thulium:yttrium-aluminum-garnet (Tm:YAG) vapoenucleation of prostates (ThuVEP) and holmium laser enucleation of prostates (HoLEP) for patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). METHODS: A retrospective analysis of 88 consecutive patients with symptomatic BPH was carried out, who underwent either 120-W ThuVEP or HoLEP nonrandomly. Patient demographics and peri-operative and 12-month follow-up data were analyzed with the International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum flow rate (Qmax), postvoid residual urine volume (PVR), and rates of peri operative and late complications. RESULTS: The patients in each group showed no significant difference in preoperative parameters. Compared with the HoLEP group, patients in the 120-W ThuVEP group required significantly shorter time for laser enucleation (58.3 +/- 12.8 min vs. 70.5 +/- 22.3 min, P = 0.003), and resulted in a significant superiority in laser efficiency (resected prostate weight/laser enucleation time) for 120-W Tm:YAG laser compared to holmium:YAG laser (0.69 +/- 0.18 vs. 0.61 +/- 0.19, P = 0.048). During 1, 6, and 12 months of follow-ups, the procedures did not demonstrate a significant difference in IPSS, QoL score, Qmax, or PVR (P > 0.05). Mean peri-operative decrease of hemoglobin in the HoLEP group was similar to the ThuVEP group (17.1 +/- 12.0 g/L vs. 15.2 +/- 10.1 g/L, P = 0.415). Early and late incidences of complications were low and did not differ significantly between the two groups of 120-W ThuVEP and HoLEP patients (P > 0.05). CONCLUSIONS: 120-W ThuVEP and HoLEP are potent, safe and efficient modalities of minimally invasive surgeries for patients with LUTS due to BPH. Compared with HoLEP, 120-W ThuVEP offers advantages of reduction of laser enucleation time and improvement of laser efficiency. PMID- 25836608 TI - Evaluation of PIMA point-of-care CD4 analyzer in Yunnan, China. AB - BACKGROUND: CD4 count is used to determine antiretroviral therapy (ART) eligibility. In China, flow cytometers are mostly located in urban areas with limited access by patients residing in remote areas. In an attempt to address this issue, we conducted a study to validate the performance of Alere PIMA point of-care CD4 analyzer. METHODS: Venous and finger-prick blood specimens were collected from HIV-positive participants from two voluntary counseling and testing sites in Yunnan Province. Both venous and finger-prick blood specimens were tested with the PIMA analyzer. Venous blood specimens tested with the Becton Dickinson FACSCalibur were used as a reference. RESULTS: Venous specimens from 396 and finger-prick specimens from 387 persons were available for analysis. CD4 counts by PIMA correlated well with those from FACSCalibur with an R2 of 0.91 for venous blood and 0.81 for finger-prick blood. Compared to FACSCalibur, the PIMA analyzer yielded lower counts with a mean bias of - 47.0 cells/MUl (limit of agreement, [LOA]: -204-110 cells/MUl) for venous blood and -71.0 cells/MUl (LOA: 295-153 cells/MUl) for finger-prick blood. For a CD4 threshold of 350 cells/MUl, the positive predictive value (PPV) of PIMA was 84.2% and 75.7% and the negative predictive value (NPV) was 97.6% and 95.8% for venous and finger-prick blood, respectively. For an ART threshold of 500 cells/MUl, the corresponding PPV was 90.3% and 84.0% and NPV was 94.3% and 93.4%, respectively. CONCLUSIONS: CD4 counting using venous blood with PIMA analyzers is a feasible alternative to a large flow cytometer to determine ART eligibility. PMID- 25836609 TI - Incidence and clinical characteristics of pulmonary hypertension in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Pulmonary hypertension (PH) frequently complicates the course of idiopathic pulmonary fibrosis (IPF) patients and is associated with significantly worse outcomes. The aim of the present study was to investigate the incidence of PH in IPF patients and evaluate the correlation between clinical parameters and systolic pulmonary artery pressure (sPAP). METHODS: Hospitalized patients with IPF, who were evaluated for sPAP by Doppler echocardiography from January 2004 to December 2011, were enrolled in our study. Patients were defined as PH by an estimated sPAP > 50 mmHg and graded as PH likely, PH possible and PH unlikely, based on the 2009 European Society of Cardiology/European Respiratory Society PH Guidelines. The correlations between clinical parameters and sPAP were analyzed by multiple linear regression. RESULTS: Totally, 119 IPF patients were enrolled in our study and 28 (23.5%), 20 (16.8%) and 71 (59.7%) patients were PH likely, PH possible and PH unlikely, respectively. Borg dyspnea score was positively correlated with sPAP, r = 0.467, P < 0.001. Oxygen saturation was negatively correlated with sPAP, r = -0.416, P < 0.001. Diffusing capacity of the lung for carbon monoxide percentage predicted was negatively correlated with sPAP, r = 0.424, P = 0.003. N-terminal fragment of pro-brain natriuretic peptide and pulmonary artery width was positively correlated with sPAP, r = 0.452, P = 0.011 and r = 0.513, P < 0.001, respectively. CONCLUSIONS: The incidence of PH in IPF patients was 23.5% in a single center of China. PH may worsen the dyspnea, right heart dysfunction and decrease the life quality of the patients with IPF. PMID- 25836610 TI - Thin-section computed tomography detects long-term pulmonary sequelae 3 years after novel influenza A virus-associated pneumonia. AB - BACKGROUND: The aim of this research was to evaluate long-term pulmonary sequelae on paired inspiration-expiration thin-section computed tomography (CT) scans 3 years after influenza A (H1N1) virus-associated pneumonia, and to analyze the affecting factors on pulmonary fibrosis. METHODS: Twenty-four patients hospitalized with H1N1 virus-associated pneumonia at our hospital between September 2009 and January 2010 were included. The patients underwent thin section CT 3 years after recovery. Abnormal pulmonary lesion patterns (ground glass opacity, consolidation, parenchymal bands, air trapping, and reticulation) and evidence of fibrosis (architectural distortion, traction bronchiectasis, or honeycombing) were evaluated on follow-up thin-section CT. Patients were assigned to Group 1 (with CT evidence of fibrosis) and Group 2 (without CT evidence of fibrosis). Demographics, rate of mechanical ventilation therapy, rate of intensive care unit admission, cumulative prednisolone-equivalent dose, laboratory tests results (maximum levels of alanine aminotransferase, aspartate transaminase [AST], lactate dehydrogenase [LDH], and creatine kinase [CK]), and peak radiographic opacification of 24 patients during the course of their illness in the hospital were compared between two groups. RESULTS: Parenchymal abnormality was present in 17 of 24 (70.8%) patients and fibrosis occurred in 10 of 24 (41.7%) patients. Patients in Group 1 (10/24; 41.7%) had a higher rate of mechanical ventilation therapy (Z = -2.340, P = 0.019), higher number of doses of cumulative prednisolone-equivalent (Z = -2.579, P = 0.010), higher maximum level of laboratory tests results (AST [Z = -2.140, P = 0.032], LDH [Z = -3.227, P = 0.001], and CK [Z = -3.345, P = 0.019]), and higher peak opacification on chest radiographs (Z = -2.743, P = 0.006) than patients in group 2 (14/24; 58.3%). CONCLUSIONS: H1N1 virus-associated pneumonia frequently is followed by long-term pulmonary sequelae, including fibrotic changes, in lung parenchyma. Patients who need more steroid therapy, need more mechanical ventilation therapy, had higher laboratory tests results (maximum levels of AST, LDH, and CK), and had higher peak opacification on chest radiographs during treatment are more likely to develop lung fibrosis. PMID- 25836611 TI - Treatment and outcome of epileptogenic temporal cavernous malformations. AB - BACKGROUND: The aim of this study is to explore the treatment and outcome of epileptogenic temporal lobe cavernous malformations (CMs). METHODS: We analyzed retrospectively the profiles of 52 patients diagnosed as temporal lobe CMs associated with epilepsy. Among the 52 cases, 11 underwent a direct resection of CM along with the adjacent zone of hemosiderin rim without electrocorticogram (ECoG) monitoring while the other 41 cases had operations under the guidance of ECoG. Forty-six patients were treated by lesionectomy + hemosiderin rim while the other six were treated by lesionectomy + hemosiderin rim along with extended epileptogenic zone resection. The locations of lesions, the duration of illness, the manifestation, the excision ranges and the outcomes of postoperative follow up were analyzed, respectively. RESULTS: All of the 52 patients were treated by microsurgery. There was no neurological deficit through the long-term follow-up. Outcomes of seizure control are as follows: 42 patients (80.8%) belong to Engel Class I, 5 patients (9.6%) belong to Engel Class II, 3 patients (5.8%) belong to Engel Class III and 2 patients (3.8%) belong to Engel Class IV. CONCLUSION: Patients with epilepsy caused by temporal CMs should be treated as early as possible. Resection of the lesion and the surrounding hemosiderin zone is necessary. Moreover, an extended excision of epileptogenic cortex or cerebral lobes is needed to achieve a better prognosis if the ECoG indicates the existence of an extra epilepsy onset origin outside the lesion itself. PMID- 25836612 TI - Incidence and risk factors of retinopathy of prematurity in two neonatal intensive care units in North and South China. AB - BACKGROUND: To investigate the incidence and risk factors of retinopathy of prematurity (ROP) in two Neonatal Intensive Care Units in North and South of China, respectively. METHODS: We studied data concerning 472 infants with gestational age (GA) <= 34 weeks or birth weight (BW) <= 2000 g who were admitted to the Zhujiang Hospital of Southern Medical University and the Fourth Hospital of Shijiazhuang between January 1, 2011 and December 31, 2011. Clinical information about perinatal neonates was collected and was confirmed by reviewing medical charts. The incidence and severity of ROP were assessed in the screened population. Main outcome measures are the incidence and severity of ROP. The relationship of clinical risk factors and the development of ROP were analyzed. RESULTS: The overall incidence of ROP was 12.7%, and the overall incidence of type 1 ROP was 2.3%; 9.4% of infants in Zhujiang Hospital had ROP compared to 15.0% infants in the Fourth Hospital of Shijiazhuang developed ROP, and the difference is statistically significant. ROP was significantly associated with GA (odds ratio [OR]: 0.77 [0.62-0.95], P = 0.015), BW (OR: 0.998 [0.996-0.999], P = 0.008), maternal supplemental oxygen administration before and during delivery (OR: 4.27 [1.21-15.10], P = 0.024) and preeclampsia (OR: 6.07 [1.73-21.36] P = 0.005). The risk factors for ROP are different in two hospitals. In Zhujiang Hospital, BW is the independent risk factors for ROP while GA, BW and preeclampsia in the Fourth Hospital in Shijiazhuang Conclusions: Retinopathy of prematurity incidence is different based on area. Incidence of ROP is still high in China. More efforts need to prevent ROP. PMID- 25836613 TI - Propofol ameliorates calpain-induced collapsin response mediator protein-2 proteolysis in traumatic brain injury in rats. AB - BACKGROUND: Collapsin response mediator protein-2 (CRMP2), a multifunctional cytosolic protein highly expressed in the brain, is degraded by calpain following traumatic brain injury (TBI), possibly inhibiting posttraumatic neurite regeneration. Lipid peroxidation (LP) is involved in triggering postinjury CRMP2 proteolysis. We examined the hypothesis that propofol could attenuate LP, calpain induced CRMP2 degradation, and brain injury after TBI. METHODS: A unilateral moderate controlled cortical impact injury was induced in adult male Sprague Dawley rats. The animals were randomly divided into seven groups: Sham control group, TBI group, TBI + propofol groups (including propofol 1 h, 2 h, and 4 h groups), TBI + U83836E group and TBI + fat emulsion group. The LP inhibitor U83836E was used as a control to identify that antioxidation partially accounts for the potential neuroprotective effects of propofol. The solvent of propofol, fat emulsion, was used as the vehicle control. Ipsilateral cortex tissues were harvested at 24 h post-TBI. Immunofluorescent staining, Western blot analysis, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling were used to evaluate LP, calpain activity, CRMP2 proteolysis and programmed cell death. The data were statistically analyzed using one-way analysis of variance and a paired t-test. RESULTS: Propofol and U83836E significantly ameliorated the CRMP2 proteolysis. In addition, both propofol and U83836E significantly decreased the ratio of 145-kDa alphaII-spectrin breakdown products to intact 270-kDa spectrin, the 4-hydroxynonenal expression and programmed cell death in the pericontusional cortex at 24 h after TBI. There was no difference between the TBI group and the fat emulsion group. CONCLUSIONS: These results demonstrate that propofol postconditioning alleviates calpain-mediated CRMP2 proteolysis and provides neuroprotective effects following moderate TBI potentially by counteracting LP and reducing calpain activation. PMID- 25836614 TI - Study of clinical practical model of urinary system injury. AB - BACKGROUND: In order to improve the clinical treatment level of urinary system injury, it is necessary to build up an animal model of urinary system wound, which is not only analogous to real clinical practice, but also simple and practical. METHODS: We have developed the third generation of firearm fragment wound generator based on the first and the second producer. The best explosive charge of the blank cartridge was selected by gradient powder loading experiments. The firearm fragment injuries were made to the bulbous urethra of 10 New Zealand male rabbits. One week preoperatively and 2, 4 and 8 weeks postoperatively, all the animals underwent urethroscopy and urethrography. At 2, 4 and 8 weeks postoperatively, two animals were randomly selected and killed, and the urethra was cut off for pathological examination. RESULTS: The shooting distance of the third generation of firearm fragment wound generator is 2 cm. The best explosive charge of the blank cartridge is 1 g of nitrocotton. All rabbits survived the procedures and stayed alive until they were killed. Injuries were limited to bulbous urethra and distal urethra. Round damaged areas, 1-1.5 cm in length, on the ventral wall were observed. Ureteroscopy results showed that canal diameter gradually shrank by over 50% in 9 rabbits. The rate of success was 90%. Urethrography result noted that a 1-1.3 cm stricture was formed at the bulbous urethra. Histology results of injured stricture urethra showed that fibrous connective tissue hyperplasia and hyaline degeneration caused further stricture in the canal. CONCLUSIONS: The third generation of firearm fragment wound generator imitates the bullet firing process and is more accurate and repeatable. The corresponding rabbit model of traumatic complex urethral stricture simulates the real complex clinical conditions. This animal model provides a standardized platform for clinical researches on treating traumatic injuries to the urinary system. PMID- 25836615 TI - In vivo confocal microscopic observation of lamellar corneal transplantation in the rabbit using xenogenic acellular corneal scaffolds as a substitute. AB - BACKGROUND: The limiting factor to corneal transplantation is the availability of donors. Research has suggested that xenogenic acellular corneal scaffolds (XACS) may be a possible alternative to transplantation. This study aimed to investigate the viability of performing lamellar corneal transplantation (LCT) in rabbits using canine XACS. METHODS: Fresh dog corneas were decellularized by serial digestion, and LCT was performed on rabbit eyes using xenogeneic decellularized corneal matrix. Cellular and morphological changes were observed by slit-lamp, light, and scanning electron microscopy at 7, 30 and 90 days postoperatively. Immunocytochemical staining for specific markers such as keratin 3, vimentin and MUC5AC, was used to identify cells in the graft. RESULTS: Decellularized xenogenic corneal matrix remained transparent for about 1-month after LCT. The recipient cells were able to survive and proliferate into the grafts. Three months after transplantation, grafts had merged with host tissue, and graft epithelialization and vascularization had occurred. Corneal nerve fibers were able to grow into the graft in rabbits transplanted with XACS. CONCLUSIONS: Xenogenic acellular corneal scaffolds can maintain the transparency of corneal grafts about 1-month and permit growth of cells and nerve fibers, and is, therefore, a potential substitute or carrier for a replacement cornea. PMID- 25836616 TI - MiR-27a promotes hepatocellular carcinoma cell proliferation through suppression of its target gene peroxisome proliferator-activated receptor gamma. AB - BACKGROUND: MicroRNAs (miRNAs) function as essential posttranscriptional modulators of gene expression, and are involved in a wide range of physiologic and pathologic states, including cancer. Numerous miRNAs are deregulated in hepatocellular carcinoma (HCC). This study aimed to investigate the role of miR 27a in the development of HCC. METHODS: The expression of MiR-27a was measured by quantitative real-time polymerase chain reaction (qRT-PCR). 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to examine changes in the viability of HepG2, Bel-7402, Bel-7404 hepatoma cell lines associated with up-regulation or down-regulation of miR-27a. A dual-luciferase activity assay was used to verify a target gene of miR-27a. Immunohistochemistry, qRT-PCR, Western blotting analysis, and cell cycle and apoptosis flow cytometric assays were used to elucidate the mechanism by which miR-27a modulates liver cancer cell proliferation. RESULTS: The expression of miR-27a was significantly increased in HCC tissues and HepG2, Bel-7402, Bel-7404 hepatoma cell lines (P < 0.05). We also found that the down-regulation of miR-27a in HepG2 cells dramatically inhibited proliferation, blocked the G1 to S cell cycle transition and induced apoptosis (P < 0.05). In addition, miR-27a directly targeted the 3'- untranslated region of peroxisome proliferator-activated receptor gamma (PPAR-gamma), and ectopic miR 27a expression suppressed PPAR-gamma expression on the mRNA and protein levels. The rosiglitazone-induced overexpression of PPAR-gamma attenuated the effect of miR-27a in HCC cells. CONCLUSIONS: Our findings suggested that miRNA-27a promoted HCC cell proliferation by regulating PPAR-gamma expression. MiR-27a may provide a potential therapeutic strategy for HCC treatment. PMID- 25836617 TI - Infection-stimulated anemia results primarily from interferon gamma-dependent, signal transducer and activator of transcription 1-independent red cell loss. AB - BACKGROUND: Although the onset of anemia during infectious disease is commonly correlated with production of inflammatory cytokines, the mechanisms by which cytokines induce anemia are poorly defined. This study focused on the mechanism research. METHODS: Different types of mice were infected perorally with Toxoplasma gondii strain ME49. At the indicated times, samples from each mouse were harvested, processed, and analyzed individually. Blood samples were analyzed using a Coulter Counter and red blood cell (RBC) survival was measured by biotinylation. Levels of tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), and inducible protein 10 (IP-10) mRNA in liver tissue were measured by real-time polymerase chain reaction. RESULTS: T. gondii infected mice exhibited anemia due to a decrease in both erythropoiesis and survival time of RBC in the circulation (P < 0.02). In addition, infection stimulated anemia was associated with fecal occult, supporting previous literature that hemorrhage is a consequence of T. gondii infection in mice. Infection-induced anemia was abolished in interferon gamma (IFNgamma) and IFNgamma receptor deficient mice (P < 0.05) but was still evident in mice lacking TNF-alpha, iNOS, phagocyte NADPH oxidase or IP-10 (P < 0.02). Neither signal transducer and activator of transcription 1 (STAT1) deficient mice nor 129S6 controls exhibited decreased erythropoiesis, but rather suffered from an anemia resulting solely from increased loss of circulating RBC. CONCLUSIONS: Infection stimulated decrease in erythropoiesis and losses of RBC have distinct mechanistic bases. These results show that during T. gondii infection, IFNgamma is responsible for an anemia that results from both a decrease in erythropoiesis and a STAT1 independent loss of circulating RBC. PMID- 25836618 TI - Phloroglucinol protects the urinary bladder via inhibition of oxidative stress and inflammation in a rat model of cyclophosphamide-induced interstitial cystitis. AB - BACKGROUND: Phloroglucinol plays an important role in oxidative stress and inflammatory responses. The effects of phloroglucinol have been proven in various disease models. The aim of the present study was to investigate the efficacy and possible mechanisms of phloroglucinol in the treatment of interstitial cystitis (IC). METHODS: Thirty-two female Sprague-Dawley (SD) rats were used in this study. IC was induced by intraperitoneal injection of cyclophosphamide (CYP). Rats were randomly allocated to one of four groups (n = 8 per group): A control group, which was injected with saline (75 mg/kg; i.p.) instead of CYP on days 1, 4, and 7; a chronic IC group, which was injected with CYP (75 mg/kg; i.p.) on days 1, 4, and 7; a high-dose (30 mg/kg) phloroglucinol-treated group; and a low dose (15 mg/kg) phloroglucinol-treated group. On day 8, the rats in each group underwent cystometrography (CMG), and the bladders were examined for evidence of oxidative stress and inflammation. Statistical analysis was performed by analysis of variance (ANOVA) followed by least square difference multiple comparison post hoc test. RESULTS: Histological evaluation showed that bladder inflammation in CYP-treated rats was suppressed by phloroglucinol. CMG revealed that the CYP treatment induced overactive bladder in rats that was reversed by phloroglucinol. Up-regulated tumor necrosis factor-alpha and interleukin-6 expression in the CYP treated rats were also suppressed in the phloroglucinol treated rats. CYP treatment significantly increased myeloperoxidase activity as well as the decreased activities of catalase of the bladder, which was reversed by treatment with phloroglucinol. CONCLUSIONS: The application of phloroglucinol suppressed oxidative stress, inflammation, and overactivity in the bladder. This may provide a new treatment strategy for IC. PMID- 25836619 TI - Efficacy and safety of onabotulinumtoxinA in treating neurogenic detrusor overactivity: a systematic review and meta-analysis. AB - BACKGROUND: OnabotulinumtoxinA is widely used in treating neurogenic detrusor overactivity (NDO). We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug for treating NDO. METHODS: We searched the following databases: Medline, EMBASE, and the Cochrane Controlled Trials Register. All published randomized double-blind, placebo-controlled trials of onabotulinumtoxinA for the treatment of NDO were identified in the analysis. The reference lists of the retrieved studies were also investigated. RESULTS: Four publications involving a total of 807 patients were identified in the analysis, which compared onabotulinumtoxinA with placebo. The changes of the mean number of urinary incontinence per week (the standardized mean difference [SMD] = -10.91, 95% confidence intervals [CIs] = -14.18--7.63, P < 0.0001); maximum cystometric capacity (SMD = 146.09, 95% CI = 126.19-165.99, P < 0.0001) and maximum detrusor pressure (SMD = -32.65, 95% CI = -37.83--27.48, P < 0.0001) indicated that onabotulinumtoxinA was more effective than the placebo, despite the doses of onabotulinumtoxinA. Safety assessments primarily localized to the urinary tract indicated onabotulinumtoxinA were often associated with more complications. Urinary tract infections (relative risk [RR] =1.48, 95% CI = 1.20-1.81, P = 0.0002); hematuria (RR = 1.81, 95% CI = 1.00-3.24, P = 0.05) and urinary retention (RR = 5.87, 95% CI = 3.61-9.56, P < 0.0001). CONCLUSIONS: This meta analysis indicates that onabotulinumtoxinA to be an effective treatment for NDO with side effects primarily localized to urinary tract. PMID- 25836620 TI - J wave syndromes: a decade of progress. AB - OBJECTIVE: The objective was to provide a brief history of J wave syndromes and to summarize our current understanding of their molecular, ionic, cellular mechanisms, and clinical features. We will also discuss the existing debates and further direction in basic and clinical research for J wave syndromes. DATA SOURCES: The publications on key words of "J wave syndromes", "early repolarization syndrome (ERS)", "Brugada syndrome (BrS)" and "ST-segment elevation myocardial infarction (STEMI)" were comprehensively reviewed through search of the PubMed literatures without restriction on the publication date. STUDY SELECTION: Original articles, reviews and other literatures concerning J wave syndromes, ERS, BrS and STEMI were selected. RESULTS: J wave syndromes were firstly defined by Yan et al. in a Chinese journal a decade ago, which represent a spectrum of variable phenotypes characterized by appearance of prominent electrocardiographic J wave including ERS, BrS and ventricular fibrillation (VF) associated with hypothermia and acute STEMI. J wave syndromes can be inherited or acquired and are mechanistically linked to amplification of the transient outward current (I to )-mediated J waves that can lead to phase 2 reentry capable of initiating VF. CONCLUSIONS: J wave syndromes are a group of newly highlighted clinical entities that share similar molecular, ionic and cellular mechanism and marked by amplified J wave on the electrocardiogram and a risk of VF. The clinical challenge ahead is to identify the patients with J wave syndromes who are at risk for sudden cardiac death and determine the alternative therapeutic strategies to reduce mortality. PMID- 25836622 TI - Incidence and concurrent laparoscopic repair of hypertrophic pyloric stenosis and patent processus vaginalis. PMID- 25836621 TI - Insulin neuroprotection and the mechanisms. AB - OBJECTIVE: To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action. DATA SOURCES: The study is based on the data from PubMed. STUDY SELECTION: Articles were selected with the search terms "insulin", "blood glucose", "neuroprotection", "brain", "glycogen", "cerebral ischemia", "neuronal necrosis", "glutamate", "gamma-aminobutyric acid". RESULTS: Insulin has neuroprotection. The mechanisms include the regulation of neurotransmitter, promoting glycogen synthesis, and inhibition of neuronal necrosis and apoptosis. Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia. CONCLUSIONS: Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6-9 mmol/L. PMID- 25836623 TI - Small lymphocytic lymphoma/chronic lymphocytic leukemia with chromothripsis in an old woman. PMID- 25836624 TI - A trick to control the bleeding in cardiovascular surgery. PMID- 25836625 TI - Fronts of internal Emergency Medicine research for years to come. PMID- 25836626 TI - An unusual complication related to invasive electroencephalography monitoring: nonhemorrhagic subdural fluid collection. PMID- 25836627 TI - One craniotomy at the highest altitude in the world and follow-up study. PMID- 25836628 TI - Clinical assessment of countermovement jump landing kinematics in early adolescence: Sex differences and normative values. AB - BACKGROUND: Adolescent females have been reported to have a higher risk of non contact knee joint injuries compared to their male counterparts, with deficiencies in neuromuscular control being purported to be the primary differentiating factor. As such, assessment of movement quality during functional screening tests in this population is warranted. Widespread implementation of such screening requires clinically accessible screening measures and normative data. Therefore, the aim of the present study was to provide normative data for clinical analysis of landing kinematics in early adolescent male and female athletes, with a corollary of determining whether a difference between the sexes is evident with such screening. METHODS: Ninety seven male and 84 female athletes (mean age=13+/-1.41years) in the first year of high school participated. Each participant performed 3 countermovement jump trials. Frontal and sagittal plane knee joint angles were recorded by video cameras for both dominant and non dominant limbs. A multivariate analysis of variance (MANOVA) was used to determine the effect of sex on the dependent variables. FINDINGS: Males displayed significantly greater knee flexion prior to initial contact (P<0.001) and knee varus displacement (P<0.001). No differences were observed between males and females for max knee flexion (P>0.05). INTERPRETATION: Early adolescent female athletes demonstrate less desirable landing biomechanics than their male peers. The first year in high school, when early adolescent females are first exposed to high school sports, may be an ideal time to assess movement quality during functional tasks and intervene with injury prevention programs if necessary. PMID- 25836629 TI - Reading difficulties in Spanish adults with dyslexia. AB - Recent studies show that dyslexia persists into adulthood, even in highly educated and well-read people. The main characteristic that adults with dyslexia present is a low speed when reading. In Spanish, a shallow orthographic system, no studies about adults with dyslexia are available; and it is possible that the consistency of the orthographic system favours the reading fluency. The aim of this study was to get an insight of the reading characteristics of Spanish adults with dyslexia and also to infer the reading strategies that they are using. For that purpose, a group of 30 dyslexics (M age = 32 years old) and an age-matched group of 30 adults without reading disabilities completed several phonological and reading tasks: phonological awareness tasks, rapid automatic naming, lexical decision, word and pseudoword reading, letter detection and text reading. The results showed that highly educated Spanish dyslexics performed significantly worse than the control group in the majority of the tasks. Specifically, they showed difficulties reading long pseudowords, indicating problems in automating the grapheme-phoneme rules, but they also seem to present difficulties reading words, which indicate problems with the lexical route. It seems that the Spanish dyslexic adults, as in deep orthographies, continue having difficulties in phonological awareness tasks, rapid naming and reading. PMID- 25836630 TI - Pre-existing Mobile Cardiac Thrombus and the Risk of Early Recurrent Embolism after Intravenous Thrombolysis: A Case Report. AB - BACKGROUND: Early recurrence of an embolism is rarely observed in patients with stroke treated with intravenous thrombolysis. Pre-existing cardiac thrombus is thought as a risk factor for recurrent embolism, although the relationship remains unclear. METHODS: The present patient was a 30-year-old man with acute ischemic stroke. Transthoracic echocardiography performed before thrombolysis demonstrated an intraventricular mobile thrombus, and the patient was treated with intravenous thrombolysis 183 minutes after the onset of stroke. During thrombolysis, he suffered from a peripheral artery embolism, without further signs of neurologic deterioration. Repeated transthoracic echocardiography showed the disappearance of the intraventricular thrombus. However, follow-up magnetic resonance imaging disclosed new ischemic lesions at the splenium of the corpus callosum, and body computed tomography showed infarction of the spleen and kidney. The peripheral artery embolism improved spontaneously without further evidence of recurrent embolism. RESULTS: This is the first report to provide findings of an intracardiac mobile thrombus before thrombolysis and to demonstrate the acceleration of detachment of the thrombus during thrombolysis. CONCLUSIONS: Because there are currently no guidelines for the use of intravenous thrombolysis for acute ischemic stroke associated with a pre-existing intracardiac thrombus with respect to the efficacy and safety, physicians should pay special attention to similar cases. PMID- 25836631 TI - Stroke rehabilitation and risk of mortality: a population-based cohort study stratified by age and gender. AB - BACKGROUND: To determine the survival of patients with stroke for up to 10 years after a first-time stroke and to investigate whether stroke rehabilitation within the first 3 months reduced long-term mortality in these patients. METHODS: We used the medical claims data for a random sample of 1 million insured Taiwanese registered in the year 2000. A total of 7767 patients admitted for a first-time stroke between 2000 and 2005; 1285 (16.7%) received rehabilitation within the first 3 months after stroke admission. The other 83.3% of patients served as a comparison cohort. A Cox proportional hazards model was used to estimate the relative risk of mortality in relation to the rehabilitation intervention. RESULTS: In all, 181 patients with rehabilitation and 1123 controls died, representing respective mortality rates of 25.0 and 32.7 per 1000 person-years. Rehabilitation was significantly associated with a lower risk of mortality (hazard ratio .68, 95% confidence interval .58-.79). Such a beneficial effect tended to be more obvious as the frequency of rehabilitation increased (P for the trend <.0001) and was more evident in female patients. CONCLUSIONS: Stroke rehabilitation initiated in the first 3 months after a stroke admission may significantly reduce the risk of mortality for 10 years after the stroke. PMID- 25836632 TI - Utility of High-b-Value Diffusion-Weighted Magnetic Resonance Imaging in Evaluating Reversible Medial Longitudinal Fasciculus Syndrome Caused by Acute Brainstem Ischemia. AB - BACKGROUND: Medial longitudinal fasciculus (MLF) syndrome refers to a gaze disorder characterized by impaired adduction on the ipsilateral side to the injured MLF, with dissociated nystagmus of the contralateral abducting eye. The most common cause of the MLF syndrome is ischemic stroke. However, acute ischemic change in the MLF may be undetectable even on diffusion-weighted magnetic resonance imaging (DW-MRI) partly because of its small size and specific brainstem location. CASE REPORT: Herein, we present the first reported case of MLF syndrome in which, compared with the standard-b-value DWI, a higher b-value DWI revealed more clearly a small infarction in the dorsal pons in the acute stage. CONCLUSIONS: We suggest that high-b-value DWI can be a useful diagnostic method for patients with MLF syndrome caused by possible brainstem ischemia and thus supportive for deciding the optimal treatment for such patients. PMID- 25836635 TI - Enhanced localization, energy anomalous diffusion and resonant mode in harmonic chains with correlated mass-spring disorder. AB - In this work, we study the vibrational modes and energy spreading in a harmonic chain model with diluted second-neighbors couplings and correlated mass-spring disorder. While all nearest neighbor masses are coupled by an elastic spring, second neighbors springs are introduced with a probability pD. The masses are randomly distributed according to the site connectivity mi = m0 (1 + 1/n(alpha)(I), where ni is the connectivity of the site i and alpha is a tunable exponent. We show that maximum localization of the vibrational modes is achieved for alpha ? 3/4. The time-evolution of the energy wave-packet is followed after an initial localized excitation. While the participation number remains finite, the energy spread is shown to be sub-diffusive after a displacement and super diffusive after an impulse excitation. These features are related to the development of a power-law tail in the wave-packet distribution. Further, we unveil that the spring dilution leads to the emergence of a resonant localized state which is signaled by a van Hove singularity in the density of states. PMID- 25836634 TI - Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. AB - The cross-coupling of sp(3)-hybridized organoboron reagents via photoredox/nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Analysis of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resolution (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calculations suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity observed in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings. PMID- 25836633 TI - Hantaan virus infection induces both Th1 and ThGranzyme B+ cell immune responses that associated with viral control and clinical outcome in humans. AB - Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4(+)T cells in viral control have been extensively studied. However, the contribution of CD4(+)T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4(+)T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B(+) cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4(+)T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4(+)T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4(+)T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127(hi)) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4(+)T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4(+)T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection. PMID- 25836636 TI - Imaging of pulmonary involvement in rheumatic disease. AB - Lung disease commonly occurs in connective tissue diseases (CTD) and is an important cause of morbidity and mortality. Imaging is central to the evaluation of CTD-associated pulmonary complications. In this article, a general discussion of radiologic considerations is followed by a description of the pulmonary appearances in individual CTDs, and the imaging appearances of acute and nonacute pulmonary complications. The contribution of imaging to monitoring disease, evaluating treatment response, and prognostication is reviewed. Finally, we address the role of imaging in the challenging multidisciplinary evaluation of interstitial lung disease where there is an underlying suspicion of an undiagnosed CTD. PMID- 25836637 TI - Histopathology of lung disease in the connective tissue diseases. AB - The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjogren syndrome, and mixed CTD. PMID- 25836638 TI - Determining respiratory impairment in connective tissue disease-associated interstitial lung disease. AB - Connective tissue diseases (CTDs) can affect the lungs through diseases of the chest wall, pleura, vasculature, airways, and parenchyma. Interstitial lung disease (ILD) is a common complication of CTD associated with increased morbidity and mortality. This article describes the evaluation of respiratory impairment in patients with CTD and summarizes the evidence that guides diagnosis and management of CTD-ILD. Patients with CTD with suspected ILD should undergo clinical, physiologic, and radiologic studies to evaluate for the presence of ILD, and these results should be integrated in a multidisciplinary setting to guide diagnosis and management. Screening for ILD may also be appropriate in asymptomatic patients with high-risk features. PMID- 25836639 TI - Lung disease in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) affects approximately 1% of the US population frequently has extra-articular manifestations. Most compartments of the lung are susceptible to disease. Interstitial lung disease (ILD) and airways disease are the most common forms of RA-related lung disease. RA-ILD carries the worst prognosis and most often manifests in a histologic pattern of usual interstitial pneumonia or nonspecific interstitial pneumonia. There have been no large, well controlled prospective studies investigating therapies for RA-ILD. Treatment usually entails immunomodulatory agents. Further studies are needed to better understand pathogenic mechanisms of disease that lead to lung involvement in these patients. PMID- 25836641 TI - Pulmonary complications of inflammatory myopathy. AB - Pulmonary complications cause significant morbidity and mortality in the idiopathic inflammatory myopathies. Advances in biomarker discovery have facilitated clinical phenotyping, allowing investigators to better define at-risk patient subsets and to potentially gauge disease activity. This serologic characterization has complemented more traditional assessment tools. Pharmacologic management continues to rely on the use of corticosteroids, often in combination with additional immunosuppressive agents. The rarity of myositis associated interstitial lung disease and lack of controlled trials have limited analyses of treatment efficacy, mandating the development of standardized outcome measures and improvement of data sharing between disciplines. PMID- 25836640 TI - Interstitial lung disease in scleroderma. AB - Systemic sclerosis is a heterogeneous disease of unknown etiology with limited effective therapies. It is characterized by autoimmunity, vasculopathy, and fibrosis and is clinically manifested by multiorgan involvement. Interstitial lung disease is a common complication of systemic sclerosis and is associated with significant morbidity and mortality. The diagnosis of interstitial lung disease hinges on careful clinical evaluation and pulmonary function tests and high-resolution computed tomography. Effective therapeutic options are still limited. Several experimental therapies are currently in early-phase clinical trials and show promise. PMID- 25836642 TI - Pulmonary manifestations of Sjogren syndrome, systemic lupus erythematosus, and mixed connective tissue disease. AB - Interstitial lung disease is a common and often life-threatening manifestation of different connective tissue disorders, often affecting its overall prognosis. Systemic lupus erythematosus, Sjogren syndrome, and mixed connective tissue disease, although all unique diseases, can have lung manifestations as an important part of these conditions. This article reviews the different pulmonary manifestations seen in these 3 systemic rheumatologic conditions. PMID- 25836643 TI - Management of connective tissue disease-associated interstitial lung disease. AB - A thorough, often multidisciplinary assessment to determine extrathoracic versus intrathoracic disease activity and degrees of impairment is needed to optimize the management of connective tissue disease (CTD)-associated interstitial lung disease (ILD). Pharmacologic intervention with immunosuppression is the mainstay of therapy for all forms of CTD-ILD, but should be reserved for those that show clinically significant and/or progressive disease. The management of CTD-ILD is not yet evidence based and there is a need for controlled trials across the spectrum of CTD-ILD. Nonpharmacologic management strategies and addressing comorbidities or aggravating factors should be included in the comprehensive treatment plan for CTD-ILD. PMID- 25836644 TI - Connective tissue disease-associated pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival. PMID- 25836645 TI - Pulmonary vasculitis. AB - Pulmonary vasculitis encompasses inflammation in the pulmonary vasculature with involved vessels varying in caliber from large elastic arteries to capillaries. Small pulmonary capillaries are the vessels most commonly involved in vasculitis affecting the lung. The antineutrophil cytoplasmic antibody-associated vasculitides, which include granulomatosis with polyangiitis (formerly Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome), are the small vessel vasculitides in which pulmonary vasculitis is most frequently observed and are the major focus of this review. Vasculitic involvement of the large pulmonary vessels as may occur in Behcet syndrome and Takayasu arteritis is also discussed. PMID- 25836647 TI - Demystifying lung disease in the rheumatic diseases. PMID- 25836648 TI - [Review of published cases of hepatic choristoma. Differential diagnosis of umbilical cord masses]. PMID- 25836649 TI - CPAP and High-Flow Nasal Cannula Oxygen in Bronchiolitis. AB - Severe respiratory failure develops in some infants with bronchiolitis because of a complex pathophysiologic process involving increased airways resistance, alveolar atelectasis, muscle fatigue, and hypoxemia due to mismatch between ventilation and perfusion. Nasal CPAP and high-flow nasal cannula (HFNC) oxygen may improve the work of breathing and oxygenation. Although the mechanisms behind these noninvasive modalities of respiratory support are not well understood, they may help infants by way of distending pressure and delivery of high concentrations of warmed and humidified oxygen. Observational studies of varying quality have suggested that CPAP and HFNC may confer direct physiologic benefits to infants with bronchiolitis and that their use has reduced the need for intubation. No trials to our knowledge, however, have compared CPAP with HFNC in bronchiolitis. Two randomized trials compared CPAP with oxygen delivered by low flow nasal cannula or face mask and found some improvements in blood gas results and some physiologic parameters, but these trials were unable to demonstrate a reduction in the need for intubation. Two trials evaluated HFNC in bronchiolitis (one comparing it with headbox oxygen, the other with nebulized hypertonic saline), with the results not seeming to suggest important clinical or physiologic benefits. In this article, we review the pathophysiology of respiratory failure in bronchiolitis, discuss these trials in detail, and consider how future research studies may be designed to best evaluate CPAP and HFNC in bronchiolitis. PMID- 25836650 TI - On the road to elimination of Rhodesiense human African trypanosomiasis: first WHO meeting of stakeholders. PMID- 25836651 TI - Training improves the capacity of visual working memory when it is adaptive, individualized, and targeted. AB - The current study investigated whether training improves the capacity of visual working memory using individualized adaptive training methods. Two groups of participants were trained for two targeted processes, filtering and consolidation. Before and after the training, the participants, including those with no training, performed a lateralized change detection task in which one side of the visual display had to be selected and the other side ignored. Across ten day training sessions, the participants performed two modified versions of the lateralized change detection task. The number of distractors and duration of the consolidation period were adjusted individually to increase the task difficulty of the filtering and consolidation training, respectively. Results showed that the degree of improvement shown during the training was positively correlated with the increase in memory capacity, and training-induced benefits were most evident for larger set sizes in the filtering training group. These results suggest that visual working memory training is effective, especially when it is adaptive, individualized, and targeted. PMID- 25836652 TI - Models for estimating projections for disease prevalence and burden: a systematic review focusing on chronic obstructive pulmonary disease. AB - OBJECTIVE: Epidemiological models for estimating the prevalence and burden of disease inform health policy and service planning decisions. Our aim was to describe the challenges in evaluating such models using the example of epidemiological models for chronic obstructive pulmonary disease (COPD). METHODS: Two reviewers searched Medline, Embase, CAB Abstracts and World Health Organization (WHO) Databases from 1980 to November 2013 for epidemiological models of COPD prevalence and burden. Two reviewers extracted data and assessed the quality of the studies. We then undertook a descriptive and narrative synthesis of data. RESULTS: We identified 22 models employing a variety of techniques to calculate the prevalence and/or burden of COPD. Models calculated prevalence and/or mortality or other facet of disease burden using demographics and risk factors or trends, Markov-type modelling and microsimulation modelling. The six models which scored highly on the quality framework were: the Peabody model, which generated estimates of COPD prevalence; the WHO DISMOD II model which produced burden estimates in terms of disability adjusted life years with COPD and life years lost to COPD; the Atsou model which gave the life expectancy gains of individual smokers who quit smoking and associated costs; two Dutch COPD models which produced estimates of mortality and health care costs related to COPD; and the Pichon-Riviere model which gave the costs and cost effectiveness of smoking quit programmes. CONCLUSIONS: The field of chronic disease modelling is burgeoning. As a result, policy makers need to understand how to interpret epidemiological models and their data sources. PMID- 25836653 TI - A comparison of corn (Zea mays L.) residue and its biochar on soil C and plant growth. AB - In order to properly determine the value of charring crop residues, the C use efficiency and effects on crop performance of biochar needs to be compared to the un-charred crop residues. In this study we compared the addition of corn stalks to soil, with equivalent additions of charred (300 degrees C and 500 degrees C) corn residues. Two experiments were conducted: a long term laboratory mineralization, and a growth chamber trial with proso millet plants. In the laboratory, we measured soil mineral N dynamics, C use efficiency, and soil organic matter (SOM) chemical changes via infrared spectroscopy. The 300 degrees C biochar decreased plant biomass relative to a nothing added control. The 500 degrees C biochar had little to no effect on plant biomass. With incubation we measured lower soil NO3 content in the corn stalk treatment than in the biochar amended soils, suggesting that the millet growth reduction in the stalk treatment was mainly driven by N limitation, whereas other factors contributed to the biomass yield reductions in the biochar treatments. Corn stalks had a C sequestration use efficiency of up to 0.26, but charring enhanced C sequestration to values that ranged from 0.64 to 1.0. Infrared spectroscopy of the soils as they mineralized showed that absorbance at 3400, 2925-2850, 1737 cm-1, and 1656 cm-1 decreased during the incubation and can be regarded as labile SOM, corn residue, or biochar bands. Absorbances near 1600, 1500-1420, and 1345 cm-1 represented the more refractory SOM moieties. Our results show that adding crop residue biochar to soil is a sound C sequestration technology compared to letting the crop residues decompose in the field. This is because the resistance to decomposition of the chars after soil amendment offsets any C losses during charring of the crop residues. PMID- 25836655 TI - Air pressure-induced iridocornea contact in a patient with primary angle closure observed with a dynamic Scheimpflug analyzer. AB - PURPOSE: To report air pressure-induced corneal deformation and iridocornea contact in eyes with primary angle closure (PAC) during intraocular pressure (IOP) measurement performed using a novel noncontact tonometer. METHODS: A single case report. RESULTS: We report a patient with bilateral angle closure. One eye had acute PAC and the other had PAC. The latter was evaluated by the movements of the cornea and iris during IOP measurement using a noncontact tonometer. During the examination, the corneal endothelium and the iris came into contact at the mid-peripheral pupillary area in the left eye with PAC during the corneal reaction to an air puff. In contrast, the corneal endothelium in the pupillary area did not come into contact with the iris. CONCLUSIONS: Although we observed only 1 case and there could be limitations in its interpretation, IOP measurements using a noncontact tonometer may create mechanical stress on the corneal endothelium in eyes with PAC with a very shallow anterior chamber. PMID- 25836654 TI - Profiling invasiveness in head and neck cancer: recent contributions of genomic and transcriptomic approaches. AB - High-throughput molecular profiling approaches have emerged as precious research tools in the field of head and neck translational oncology. Such approaches have identified and/or confirmed the role of several genes or pathways in the acquisition/maintenance of an invasive phenotype and the execution of cellular programs related to cell invasion. Recently published new-generation sequencing studies in head and neck squamous cell carcinoma (HNSCC) have unveiled prominent roles in carcinogenesis and cell invasion of mutations involving NOTCH1 and PI3K patwhay components. Gene-expression profiling studies combined with systems biology approaches have allowed identifying and gaining further mechanistic understanding into pathways commonly enriched in invasive HNSCC. These pathways include antigen-presenting and leucocyte adhesion molecules, as well as genes involved in cell-extracellular matrix interactions. Here we review the major insights into invasiveness in head and neck cancer provided by high-throughput molecular profiling approaches. PMID- 25836656 TI - Retinal Nerve Fiber Layer Thickness Measurement Repeatability for Cirrus HD-OCT Retinal Tracking System During Eye Movement. AB - PURPOSE: To investigate the repeatability of peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained using Cirrus high-definition optical coherence tomographic (Cirrus HD-OCT) retinal tracking system during various types of eye movements. MATERIALS AND METHODS: We included 20 healthy eyes, 40 glaucomatous eyes of elderly patients, and 17 eyes with pathologic nystagmus. For healthy eyes, RNFL thickness measurements were obtained under 3 conditions: (1) without eye movement, fixated on the device's internal target, (2) with horizontal eye movement, and (3) with vertical eye movement during scan acquisition. Each session was performed 3 times with and without the use of the retinal tracking system. The repeatability of RNFL thickness measurements obtained with and without the retinal tracking was compared within each session and among the sessions. RESULTS: In healthy eyes, measurements obtained without the use of a retinal tracking system showed lower repeatability when measurements were obtained with eye movements than without (P<0.05). However, when retinal tracking system was used, measurement repeatability under conditions with eye movements was similar to that achieved without eye movement (P>0.05) and higher than that obtained without the use of a retinal tracking system (P<0.05). In elderly glaucomatous patients, the retinal tacking system did not significantly improve measurement repeatability during fixation (P>0.05). In eyes with pathologic nystagmus, the tracking system did not follow eye movement and scan acquisition was not processed. CONCLUSIONS: Cirrus HD-OCT retinal tracking system may enhance RNFL thickness measurement repeatability under certain, but not all, eye movement conditions. PMID- 25836657 TI - Elevated Intraocular Pressure in Patients Undergoing Penetrating Keratoplasty and Descemet Stripping Endothelial Keratoplasty. AB - PURPOSE: Our aim was to compare changes in intraocular pressure (IOP) and management of glaucoma in patients undergoing either penetrating keratoplasty (PK) or Descemet stripping endothelial keratoplasty (DSEK). METHOD: A retrospective review of all patients who underwent primary corneal transplantation at Sydney Eye Hospital (Sydney, Australia) from January 2008 to December 2010 was performed. Eyes with comparable indications and either primary PK or DSEK with 12 months of follow-up were included. Data on IOP and antiglaucoma management postoperatively were collected. An IOP elevation of >=30% from baseline or an absolute IOP of >24 at 1 year postoperatively was significant. RESULTS: Sixty-one eyes from 61 patients met the inclusion criteria. Comparable eyes had undergone either PK (n=28, 46%) or DSEK (n=33, 54%). In patients without prior glaucoma (n=39), 29% of those in the PK group and 28% in the DSEK group required a change in therapy to control IOP (P=0.970). If there was prior glaucoma (n=22), the PK group required a change in 71% of patients compared with the DSEK group, 63% (P=0.665). In both groups of patients, PK and DSEK, elevation of IOP of at least 30% from baseline to 1 year was seen in 39% (P=0.993) regardless of glaucoma status. CONCLUSIONS: Elevation of IOP is a serious consequence of both PK and DSEK, even despite maximal medical therapy in certain cases. DSEK has an equivalent incidence of IOP elevation to PK in comparable patients. Careful monitoring of IOP and appropriate therapy should be instituted to prevent progression to glaucoma. PMID- 25836658 TI - Mathematical Modeling of Outflow Facility Increase With Trabecular Meshwork Bypass and Schlemm Canal Dilation. AB - PURPOSE: To mathematically model the conventional aqueous humor outflow system with trabecular meshwork (TM) bypass and Schlemm canal (SC) dilation. METHODS: The SC was modeled as a rectangular channel with the TM modeled as a permeable membrane. The collector channels (CCs) were modeled as fluid sinks distributed along the outer wall of SC. Two different implants were investigated in this study. The Hydrus Microstent (scaffold) was modeled with a TM bypass and a dilated region in SC that was 7 or 15 mm long and approximately 5-fold larger than the normal height of SC (h0). The iStent trabecular microbypass was modeled with a similar structure except that the dilated region in SC was 1 mm long and 25% larger than h0. RESULTS: Creation of a TM bypass structure would increase the pressure in the surrounding regions inside the SC and make it close to the intraocular pressure. SC dilation would increase the pressure more uniformly in the dilated region. The pressure increase led to higher flow rates in SC and CCs, and subsequently increased outflow facility (C). If CCs were uniformly distributed, the increase in C was the smallest after implantation of 1 microbypass, compared with that after implantation of 2 microbypasses or 1 scaffold. If CCs were nonuniformly distributed, the magnitude of increase in C was sensitive to the location of implant, and the sensitivity was higher for the microbypass than the scaffold. CONCLUSION: The study showed that creation of TM bypass and SC dilation significantly increased outflow facility, and the amount of increase correlated with the length of dilated regions in SC. PMID- 25836659 TI - Automated Registration of Multimodal Optic Disc Images: Clinical Assessment of Alignment Accuracy. AB - PURPOSE: To determine the accuracy of automated alignment algorithms for the registration of optic disc images obtained by 2 different modalities: fundus photography and scanning laser tomography. MATERIALS AND METHODS: Images obtained with the Heidelberg Retina Tomograph II and paired photographic optic disc images of 135 eyes were analyzed. Three state-of-the-art automated registration techniques Regional Mutual Information, rigid Feature Neighbourhood Mutual Information (FNMI), and nonrigid FNMI (NRFNMI) were used to align these image pairs. Alignment of each composite picture was assessed on a 5-point grading scale: "Fail" (no alignment of vessels with no vessel contact), "Weak" (vessels have slight contact), "Good" (vessels with <50% contact), "Very Good" (vessels with >50% contact), and "Excellent" (complete alignment). Custom software generated an image mosaic in which the modalities were interleaved as a series of alternate 5*5-pixel blocks. These were graded independently by 3 clinically experienced observers. RESULTS: A total of 810 image pairs were assessed. All 3 registration techniques achieved a score of "Good" or better in >95% of the image sets. NRFNMI had the highest percentage of "Excellent" (mean: 99.6%; range, 95.2% to 99.6%), followed by Regional Mutual Information (mean: 81.6%; range, 86.3% to 78.5%) and FNMI (mean: 73.1%; range, 85.2% to 54.4%). CONCLUSIONS: Automated registration of optic disc images by different modalities is a feasible option for clinical application. All 3 methods provided useful levels of alignment, but the NRFNMI technique consistently outperformed the others and is recommended as a practical approach to the automated registration of multimodal disc images. PMID- 25836660 TI - Deep Sclerectomy With a New Nonabsorbable Uveoscleral Implant (Esnoper-Clip): 1 Year Outcomes. AB - PURPOSE: To report the safety and the effectiveness of deep sclerectomy (DS) with a new nonabsorbable uveoscleral hema implant (Esnoper-Clip) designed to increase trabecular and uveoscleral outflow and to achieve higher intrascleral blebs. MATERIALS AND METHODS: Twenty-seven eyes of 27 patients with open-angle glaucoma, who underwent DS with an Esnoper-Clip implant, were included in this study. All patients were followed up after 12 months. RESULTS: A significant decrease in intraocular pressure was observed after surgery, changing from a preoperative mean of 26.6+/-5.2 mm Hg to a postoperative mean of 15.3+/-5 mm Hg (P<0.001) at 12 months. There was also a significant reduction in the number of glaucoma drugs needed, varying from 2.5 per patient to 0.3 (P<0.001) 1 year after surgery. The main intrascleral lake height and volume at 12 months was 0.7+/-0.1 mm and 3.9+/ 1.3 mm, respectively. No intraoperative complications occurred. The main postoperative complications were a positive Seidel test result at 24 hours in 2 eyes (7.4%), hyphema in 2 eyes (7.4%), and choroidal detachment in 1 eye (3.7%). All these complications resolved successfully. The need for additional mitomycin C injections was recorded in 4 eyes (14.8%), twice in 2 of them. Twelve eyes (44.4%) underwent postsurgical Nd:YAG laser goniopuncture with a mean time between surgery and this procedure of 4.3 months. Mean intraocular pressure after Nd:YAG laser goniopuncture decreased from 19.2 to 15.5 mm Hg (P<0.001). CONCLUSION: DS with an uveoscleral hema implant (Esnoper-Clip) is a safe and effective technique for the management of open-angle glaucoma. PMID- 25836661 TI - Clinical Variability of Primary Congenital Glaucoma in a Spanish Family With Cyp1b1 Gene Mutations. AB - BACKGROUND: Primary congenital glaucoma (PCG) is a rare disease. In around a third of Spanish patients, the disease is attributed to mutations in the CYP1B1 gene inherited in an autosomal recessive manner. Such mutations are the main known genetic cause of PCG. CASE REPORT: We describe the case of a family with 3 of 7 siblings diagnosed with PCG. In a genetic study of the CYP1B1 gene, 2 null mutations were identified in the affected siblings (R355fsX69/T404fsX38). Two of the 4 healthy siblings were heterozygous for mutation R355fsX69 and the remaining 2 had no mutations. The healthy parents were found to be heterozygous for mutations T404fsX38 (mother) and R355fsX69 (father). High variation in the expression of PCG was observed, especially in terms of disease onset and severity: Patient 1 in the eldest affected sibling, PCG was diagnosed at 8 years of age and is presently stable after 60 months of medical treatment; patient 2 the second affected child underwent surgery at 7 days of age. Today, at 104 months, she has undergone 2 operations on the right eye and 3 on the left eye; patient 3 the youngest sibling, the disease also manifested at birth and the boy underwent surgery at 4 days. Currently he is 84 months old, he has required 7 operations for glaucoma, 3 in the right eye and 4 in the left. CONCLUSIONS: This clinical case reveals the etiological relationship between CYP1B1 mutations and PCG. In addition, it indicates a highly variable clinical picture associated with a single disease genotype mainly affecting disease onset and progression. PMID- 25836662 TI - Correlation Between Inter-Eye Difference in Average Retinal Nerve Fiber Layer Thickness and Afferent Pupillary Response as Measured by an Automated Pupillometer in Glaucoma. AB - PURPOSE: To assess the correlations between the relative afferent pupillary defect measured by a binocular, computerized, and commercially available pupillometer and the inter-eye differences in average retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD OCT) and visual field index (VFI) and mean deviation (MD) measured by automated static perimetry in patients with glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty four patients with open-angle glaucoma. METHODS: Pupillary constriction amplitudes were measured with an automated pupillometer. SD-OCT imaging of the circumpapillary RNFL and automated static perimetry were performed within 6 months of pupillometry. MAIN OUTCOME MEASURES: Main outcome measures included Spearman correlation coefficients between relative afferent pupillary defect as measured by pupillometry and inter-eye differences in average RNFL thickness, VFI, and MD. RESULTS: Correlation coefficients between relative afferent pupillary defect and inter-eye difference in average RNFL thickness, MD, and VFI were -0.81 (P<0.001), -0.73 (P<0.001), and -0.68 (P<0.001), respectively. CONCLUSIONS: The automated pupillometer quantifies asymmetry in afferent pupillary responses in proportion to structural and functional asymmetry as measured SD-OCT and automated static perimetry. PMID- 25836663 TI - Ocular Biometrics of Myopic Eyes With Narrow Angles. AB - PURPOSE: The purpose of this study was to compare the ocular biometrics between myopic patients with and without narrow angles. METHODS: Patients with a stable myopic refraction (myopia worse than -1.00 D spherical equivalent) were prospectively recruited. Angle status was assessed using gonioscopy and biometric measurements were performed using an anterior segment optical coherence tomography and an IOLMaster. RESULTS: A total of 29 patients (58 eyes) were enrolled with 13 patients (26 eyes) classified as having narrow angles and 16 patients (32 eyes) classified as having open angles. Baseline demographics of age, sex, and ethnicity did not differ significantly between the 2 groups. The patients with narrow angles were on average older than those with open angles but the difference did not reach statistical significance (P=0.12). The central anterior chamber depth was significantly less in the eyes with narrow angles (P=0.05). However, the average lens thickness, although greater in the eyes with narrow angles, did not reach statistical significance (P=0.10). Refractive error, axial lengths, and iris thicknesses did not differ significantly between the 2 groups (P=0.32, 0.47, 0.15). CONCLUSIONS: Narrow angles can occur in myopic eyes. Routine gonioscopy is therefore recommended for all patients regardless of refractive error. PMID- 25836664 TI - Current and potential carbon stocks in Moso bamboo forests in China. AB - Bamboo forests provide important ecosystem services and play an important role in terrestrial carbon cycling. Of the approximately 500 bamboo species in China, Moso bamboo (Phyllostachys pubescens) is the most important one in terms of distribution, timber value, and other economic values. In this study, we estimated current and potential carbon stocks in China's Moso bamboo forests and in their products. The results showed that Moso bamboo forests in China stored about 611.15 +/- 142.31 Tg C, 75% of which was in the top 60 cm soil, 22% in the biomass of Moso bamboos, and 3% in the ground layer (i.e., bamboo litter, shrub, and herb layers). Moso bamboo products store 10.19 +/- 2.54 Tg C per year. The potential carbon stocks reach 1331.4 +/- 325.1 Tg C, while the potential C stored in products is 29.22 +/- 7.31 Tg C a(-1). Our results indicate that Moso bamboo forests and products play a critical role in C sequestration. The information gained in this study will facilitate policy decisions concerning carbon sequestration and management of Moso bamboo forests in China. PMID- 25836665 TI - Label-Free Luminescent Switch-On Probe for Ochratoxin A Detection Using a G Quadruplex-Selective Iridium(III) Complex. AB - A library of six luminescent Ir(III) complexes were synthesized and studied for their capacity to function as probes for G-quadruplex DNA. The novel Ir(III) complex 1 was discovered to be selective for G-quadruplex structures and was subsequently used for the construction of a label-free G-quadruplex-based ochratoxin A (OTA) sensing platform in aqueous solution. The assay exhibited linearity for OTA in the range of 0 to 60 nM (R2=0.9933), and the limit of detection for OTA was 5 nM. Furthermore, this assay was highly selective for OTA over its structurally related analogues. PMID- 25836666 TI - Calpain-10 Activity Underlies Angiotensin II-Induced Aldosterone Production in an Adrenal Glomerulosa Cell Model. AB - Aldosterone is a steroid hormone important in the regulation of blood pressure. Aberrant production of aldosterone results in the development and progression of diseases including hypertension and congestive heart failure; therefore, a complete understanding of aldosterone production is important for developing more effective treatments. Angiotensin II (AngII) regulates steroidogenesis, in part through its ability to increase intracellular calcium levels. Calcium can activate calpains, proteases classified as typical or atypical based on the presence or absence of penta-EF-hands, which are involved in various cellular responses. We hypothesized that calpain, in particular calpain-10, is activated by AngII in adrenal glomerulosa cells and underlies aldosterone production. Our studies showed that pan-calpain inhibitors reduced AngII-induced aldosterone production in 2 adrenal glomerulosa cell models, primary bovine zona glomerulosa and human adrenocortical carcinoma (HAC15) cells, as well as CYP11B2 expression in the HAC15 cells. Although AngII induced calpain activation in these cells, typical calpain inhibitors had no effect on AngII-elicited aldosterone production, suggesting a lack of involvement of classical calpains in this process. However, an inhibitor of the atypical calpain, calpain-10, decreased AngII-induced aldosterone production. Consistent with this result, small interfering RNA (siRNA)-mediated knockdown of calpain-10 inhibited aldosterone production and CYP11B2 expression, whereas adenovirus-mediated overexpression of calpain-10 resulted in increased AngII-induced aldosterone production. Our results indicate that AngII-induced activation of calpain-10 in glomerulosa cells underlies aldosterone production and identify calpain-10 or its downstream pathways as potential targets for the development of drug therapies for the treatment of hypertension. PMID- 25836667 TI - Reprogramming Mouse Cells With a Pancreatic Duct Phenotype to Insulin-Producing beta-Like Cells. AB - Reprogramming technology has opened the possibility of converting one cell type into another by forced expression of transgenes. Transduction of adenoviral vectors encoding 3 pancreatic transcription factors, Pdx1, Ngn3, and MafA, into mouse pancreas results in direct reprogramming of exocrine cells to insulin producing beta-like cells. We hypothesized that cultured adult pancreatic duct cells could be reprogrammed to become insulin-producing beta-cells by adenoviral mediated expression of this same combination of factors. Exocrine were isolated from adult mouse insulin 1 promoter (MIP)-green fluorescent protein (GFP) transgenic mice to allow new insulin-expressing cells to be detected by GFP fluorescence. Cultured cells were transduced by an adenoviral vector carrying a polycistronic construct Ngn3/Pdx1/MafA/mCherry (Ad-M3C) or mCherry sequence alone as a control vector. In addition, the effects of glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4 (Ex-4) on the reprogramming process were examined. GFP(+) cells appeared 2 days after Ad-M3C transduction; the reprogramming efficiency was 8.6 +/- 2.6% by day 4 after transduction. Ad-M3C also resulted in increased expression of beta-cell markers insulin 1 and 2, with enhancement by Ex 4. Expression of other beta-cell markers, neuroD and GLP-1 receptor, were also significantly up-regulated. The amount of insulin release into the media and insulin content of the cells were significantly higher in the Ad-M3C-transduced cells; this too was enhanced by Ex-4. The transduced cells did not secrete insulin in response to increased glucose, indicating incomplete differentiation to beta-cells. Thus, cultured murine adult pancreatic cells with a duct phenotype can be directly reprogrammed to insulin-producing beta-like cells by adenoviral delivery of 3 pancreatic transcription factors. PMID- 25836668 TI - [Alcohol use in young adolescents. A survey in French secondary schools]. AB - Among young adolescents, early use of alcohol has been shown to be related to later alcohol use disorders and alcohol-related problems in numerous epidemiologic studies. However, if drinking problems are now well documented in young people, few data are available on alcohol use in children and young adolescents. The purpose of this study was to examine the perceptions and attitudes with respect to alcohol use among young adolescents entering their first year of secondary school (mean age, 11.5 years). Data were collected from the ESPACE program, a preventive program conducted in the educational district of Limoges, France. Of the 2268 respondents with complete data, 73.4% (77.1% in males vs. 69.9% in females; P<0.001) reported having tasted alcohol drinks and 3.7% (4.9% in males vs. 2.6% in females; P=0.004) having experienced drunkenness at least once. Of these adolescents, 5.4% (8.5% in males vs. 2.4% in females, P<0.001) reported consuming alcohol at least once per month, which may be considered as a sort of regular drinking pattern. Taking age, sex, and level of alcohol consumption into account, experience of drunkenness (21.9% in regular users vs. 3.7% in occasional users), tobacco use (25.8% in regular users vs. 12.6% in occasional users and 1.5% in nonusers) and cannabis use (6.0% in regular users vs. 0.9% in occasional users and 0.2% in nonusers) were found to be significantly more frequent in regular alcohol users than in other students (P<0.001). Data analysis also showed that regular alcohol users felt significantly more frequently depressed, lacking self-assurance, dissatisfied with their physical appearance and their way of life, and they felt that they exhibited significantly more impairments in their interactions with parents, peers, and the school environment. Similarly, they were found to have significantly more frequently an inclination for risk behaviors and a significantly more positive view of drinking than other students. These results look almost like those reported in adolescents and young people, and show that the alcohol abuse pattern is drawn early in childhood. They also highlight the value of epidemiologic investigations for planning preventive interventions. PMID- 25836669 TI - Correction: Network meta-analysis using R: a review of currently available automated packages. PMID- 25836670 TI - Investigation of different sparsity transforms for the PICCS algorithm in small animal respiratory gated CT. AB - Respiratory gating helps to overcome the problem of breathing motion in cardiothoracic small-animal imaging by acquiring multiple images for each projection angle and then assigning projections to different phases. When this approach is used with a dose similar to that of a static acquisition, a low number of noisy projections are available for the reconstruction of each respiratory phase, thus leading to streak artifacts in the reconstructed images. This problem can be alleviated using a prior image constrained compressed sensing (PICCS) algorithm, which enables accurate reconstruction of highly undersampled data when a prior image is available. We compared variants of the PICCS algorithm with different transforms in the prior penalty function: gradient, unitary, and wavelet transform. In all cases the problem was solved using the Split Bregman approach, which is efficient for convex constrained optimization. The algorithms were evaluated using simulations generated from data previously acquired on a micro-CT scanner following a high-dose protocol (four times the dose of a standard static protocol). The resulting data were used to simulate scenarios with different dose levels and numbers of projections. All compressed sensing methods performed very similarly in terms of noise, spatiotemporal resolution, and streak reduction, and filtered back-projection was greatly improved. Nevertheless, the wavelet domain was found to be less prone to patchy cartoon like artifacts than the commonly used gradient domain. PMID- 25836671 TI - Comparative genomic analysis of two novel sporadic Shiga toxin-producing Escherichia coli O104:H4 strains isolated 2011 in Germany. AB - A large outbreak of gastrointestinal disease occurred in 2011 in Germany which resulted in almost 4000 patients with acute gastroenteritis or hemorrhagic colitis, 855 cases of a hemolytic uremic syndrome and 53 deaths. The pathogen was an uncommon, multiresistant Escherichia coli strain of serotype O104:H4 which expressed a Shiga toxin characteristic of enterohemorrhagic E. coli and in addition virulence factors common to enteroaggregative E. coli. During post epidemic surveillance of Shiga toxin-producing E. coli (STEC) all but two of O104:H4 isolates were indistinguishable from the epidemic strain. Here we describe two novel STEC O104:H4 strains isolated in close spatiotemporal proximity to the outbreak which show a virulence gene panel, a Shiga toxin mediated cytotoxicity towards Vero cells and aggregative adherence to Hep-2 cells comparable to the outbreak strain. They differ however both from the epidemic strain and from each other, by their antibiotic resistance phenotypes and some other features as determined by routine epidemiological subtyping methods. Whole genome sequencing of these two strains, of ten outbreak strain isolates originating from different time points of the outbreak and of one historical sporadic EHEC O104:H4 isolate was performed. Sequence analysis revealed a clear phylogenetic distance between the two variant strains and the outbreak strain finally identifying them as epidemiologically unrelated isolates from sporadic cases. These findings add to the knowledge about this emerging pathogen, illustrating a certain diversity within the bacterial core genome as well as loss and gain of accessory elements. Our results do also support the view that distinct new variants of STEC O104:H4 repeatedly might originate from yet unknown reservoirs, rather than that there would be a continuous diversification of a single epidemic strain established and circulating in Germany after the large outbreak in 2011. PMID- 25836672 TI - Apolipoprotein CIII regulates lipoprotein-associated phospholipase A2 expression via the MAPK and NFkappaB pathways. AB - Apolipoprotein CIII (apo CIII), a small glycoprotein that binds to the surfaces of certain lipoproteins, is associated with inflammatory and atherogenic responses in vascular cells. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as an inflammatory biomarker and potential therapeutic target for cardiovascular disease (CVD). Here, we report that apo CIII increases Lp-PLA2 mRNA and protein levels in dose- and time- dependent manner in human monocytic THP-1 cells, and the increase can be abolished by MAPK and NFkappaB pathway inhibitors. Lp-PLA2 inhibitor, 1-linoleoyl glycerol attenuates the inflammation induced by apo CIII. In turn, exogenous Lp-PLA2 expression upregulates apo CIII and the upregulation can be inhibited by 1-linoleoyl glycerol in HepG2 cells. Moreover, plasma Lp-PLA2 level is correlated with apo CIII expression in pig liver. In vivo, Lp-PLA2 expression in monocytes and its activity in serum were significantly increased in human apo CIII transgenic porcine models compared with wild-type pigs. Our results suggest that Lp-PLA2 and apo CIII expression level is correlated with each other in vitro and in vivo. PMID- 25836673 TI - A chicken model of pharmacologically-induced Hirschsprung disease reveals an unexpected role of glucocorticoids in enteric aganglionosis. AB - The enteric nervous system originates from neural crest cells that migrate in chains as they colonize the embryonic gut, eventually forming the myenteric and submucosal plexus. Failure of the neural crest cells to colonize the gut leads to aganglionosis in the terminal gut, a pathological condition called Hirschsprung disease (HSCR) in humans, also known as congenital megacolon or intestinal aganglionosis. One of the characteristics of the human HSCR is its variable penetrance, which may be attributable to the interaction between genetic factors, such as the endothelin-3/endothelin receptor B pathway, and non-genetic modulators, although the role of the latter has not well been established. We have created a novel HSCR model in the chick embryo allowing to test the ability of non-genetic modifiers to alter the HSCR phenotype. Chick embryos treated by phosphoramidon, which blocks the generation of endothelin-3, failed to develop enteric ganglia in the very distal bowel, characteristic of an HSCR-like phenotype. Administration of dexamethasone influenced the phenotype, suggesting that glucocorticoids may be environmental modulators of the penetrance of the aganglionosis in HSCR disease. PMID- 25836674 TI - The Drosophila TIPE family member Sigmar interacts with the Ste20-like kinase Misshapen and modulates JNK signaling, cytoskeletal remodeling and autophagy. AB - TNFAIP8 and other mammalian TIPE family proteins have attracted increased interest due to their associations with disease-related processes including oncogenic transformation, metastasis, and inflammation. The molecular and cellular functions of TIPE family proteins are still not well understood. Here we report the molecular and genetic characterization of the Drosophila TNFAIP8 homolog, CG4091/sigmar. Previous gene expression studies revealed dynamic expression of sigmar in larval salivary glands prior to histolysis. Here we demonstrate that in sigmar loss-of-function mutants, the salivary glands are morphologically abnormal with defects in the tubulin network and decreased autophagic flux. Sigmar localizes subcellularly to microtubule-containing projections in Drosophila S2 cells, and co-immunoprecipitates with the Ste20-like kinase Misshapen, a regulator of the JNK pathway. Further, the Drosophila TNF ligand Eiger can induce sigmar expression, and sigmar loss-of-function leads to altered localization of pDJNK in salivary glands. Together, these findings link Sigmar to the JNK pathway, cytoskeletal remodeling and autophagy activity during salivary gland development, and provide new insights into TIPE family member function. PMID- 25836675 TI - Xrn1/Pacman affects apoptosis and regulates expression of hid and reaper. AB - Programmed cell death, or apoptosis, is a highly conserved cellular process that is crucial for tissue homeostasis under normal development as well as environmental stress. Misregulation of apoptosis is linked to many developmental defects and diseases such as tumour formation, autoimmune diseases and neurological disorders. In this paper, we show a novel role for the exoribonuclease Pacman/Xrn1 in regulating apoptosis. Using Drosophila wing imaginal discs as a model system, we demonstrate that a null mutation in pacman results in small imaginal discs as well as lethality during pupation. Mutant wing discs show an increase in the number of cells undergoing apoptosis, especially in the wing pouch area. Compensatory proliferation also occurs in these mutant discs, but this is insufficient to compensate for the concurrent increase in apoptosis. The phenotypic effects of the pacman null mutation are rescued by a deletion that removes one copy of each of the pro-apoptotic genes reaper, hid and grim, demonstrating that pacman acts through this pathway. The null pacman mutation also results in a significant increase in the expression of the pro apoptotic mRNAs, hid and reaper, with this increase mostly occurring at the post transcriptional level, suggesting that Pacman normally targets these mRNAs for degradation. Our results uncover a novel function for the conserved exoribonuclease Pacman and suggest that this exoribonuclease is important in the regulation of apoptosis in other organisms. PMID- 25836676 TI - Drug use by the breastfeeding mother: a medical and societal challenge. PMID- 25836677 TI - ABM clinical protocol #21: guidelines for breastfeeding and substance use or substance use disorder, revised 2015. AB - A central goal of The Academy of Breastfeeding Medicine is the development of clinical protocols for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 25836678 TI - Pharmacokinetics and bioavailability of a therapeutic enzyme (idursulfase) in cynomolgus monkeys after intrathecal and intravenous administration. AB - Intravenous enzyme replacement therapy with iduronate-2-sulfatase is an approved treatment for Hunter syndrome, however, conventional intravenous delivery cannot treat the neurologic manifestations of the disease due to its limited central nervous system penetration. Intrathecal administration of iduronate-2-sulfatase for delivery to the central nervous system is currently under investigation. The objective of this study was to evaluate the pharmacokinetics of idursulfase in the central nervous system of cynomolgus monkeys (Macaca fasicularis) after intravenous and intrathecal administration. Twenty-seven monkeys, treatment-naive to enzyme replacement therapy, were placed into 4 groups according to body weight: Group 1 was administered 0.5 mg/kg idursulfase intravenously, Groups 2-4 were administered an intrathecal formulation (1-, 10-, and 30-mg doses). Blood samples and cerebrospinal fluid (sampled at the cisterna magna or lumbar level) were collected at the same time points for 72 hours post dosing. Following intravenous administration, a high maximum serum concentration and rapid distribution of iduronate-2-sulfatase out of the central compartment were observed (elimination half-life: 4.3 hours). Iduronate-2-sulfatase exposure in the cerebrospinal fluid was limited, suggesting intravenous administration provided minimal penetration of the blood-brain barrier. Following intrathecal administration, a high maximum observed concentration was immediately noted and elimination half-life ranged between 7.8-10 hours and 5.9-6.7 hours (cisterna magna and lumbar sampling, respectively). Cerebrospinal fluid pharmacokinetic profiles at different doses of iduronate-2-sulfatase were similar and the dose/exposure relationship was proportional. After intrathecal administration, movement of iduronate-2-sulfatase from cerebrospinal fluid to serum was observed (systemic bioavailability was 40-83%). The clear penetration of iduronate-2 sulfatase into the cerebrospinal fluid and the dose response suggest that intrathecal delivery of iduronate-2-sulfatase may be suitable for treating the central nervous system manifestations associated with Hunter syndrome. PMID- 25836679 TI - The extent of irradiation-induced long-term visceral organ damage depends on cranial/brain exposure. AB - In case of high-dose radiation exposure, mechanisms controlling late visceral organ damage are still not completely understood and may involve the central nervous system. To investigate the influence of cranial/brain irradiation on late visceral organ damage in case of high-dose exposure, Wistar rats were irradiated at 12 Gy, with either the head and fore limbs or the two hind limbs protected behind a lead wall (head- and hind limbs-protected respectively), which allows long-term survival thanks to bone marrow protection. Although hind limbs- and head-protected irradiated rats exhibited similar hematopoietic and spleen reconstitution, a late body weight loss was observed in hind limbs-protected rats only. Histological analysis performed at this time revealed that late damages to liver, kidney and ileum were attenuated in rats with head exposed when compared to animals whose head was protected. Plasma measurements of inflammation biomarkers (haptoglobin and the chemokine CXCL1) suggest that the attenuated organ damage in hind limbs-protected rats may be in part related to reduced acute and chronic inflammation. Altogether our results demonstrate the influence of cranial/brain exposure in the onset of organ damage. PMID- 25836680 TI - The influence of novel CT reconstruction technique and ECG-gated technique on image quality and patient dose of cardiac computed tomography. AB - The aim of the present study was to compare image quality and patient dose in cardiac computed tomography angiography (CTA) in terms of volume computed tomography dose index (CTDI vol), dose length product (DLP) and effective dose, when changing from filtered back projection (FBP) to adaptive iterative dose reduction (AIDR) reconstruction techniques. Further aim was to implement prospective electrocardiogram (ECG) gating for patient dose reduction. The study was performed with Aquilion ONE 320-row CT of Toshiba Medical Systems. Analysis of cardiac CT protocols was performed before and after integration of the new software. The AIDR technique showed more than 50 % reduction in CTDIvol values and 57 % in effective dose. The subjective evaluation of clinical images confirmed the adequate image quality acquired by the AIDR technique. The preliminary results indicated significant dose reduction when using prospective ECG gating by keeping the adequate diagnostic quality of clinical images. PMID- 25836681 TI - Determination of backscatter factors in breast tomosynthesis using MCNPX simulations and measurements. AB - The perspective of adding digital breast tomosynthesis (DBT) to standard mammography in screening raises concerns regarding the dose absorbed by the fibroglandular breast tissue. Thus, it is important to estimate accurately the mean glandular dose (MGD), although there are no standard protocols for dosimetry, concerning DBT. This study aims at introducing backscatter factors (BSF) to calculate the entrance surface air kerma (ESAK), directly on patients or phantoms, in order to be introduced in the formalism proposed by Dance et al. MCNPX simulations were performed, to mimic a DBT acquisition, for a wide range of X-ray spectra. A homogeneous breast phantom with 50 % of glandular tissue was considered and several thicknesses were evaluated. Dose measurements were performed, to validate and support the simulation results. The BSF may indicate a real MGD estimation in vivo for DBT examinations and contribute for the improvement of the current guidelines used in these applications. PMID- 25836682 TI - Dual-energy contrast-enhanced digital mammography: patient radiation dose estimation using a Monte Carlo code. AB - Mammography is a standard procedure that facilitates breast cancer detection. Initial results of contrast-enhanced digital mammography (CEDM) are promising. The purpose of this study is to assess the CEDM radiation dose using a Monte Carlo code. EGSnrc MC code was used to simulate the interaction of photons with matter and estimate the glandular dose (Dg). A voxel female human phantom with a 2-8-cm breast thickness range and a breast glandular composition of 50 % was applied. Dg values ranged between 0.96 and 1.45 mGy (low and high energy). Dg values for a breast thickness of 5.0 cm and a glandular fraction of 50 % for craniocaudal and mediolateral oblique view were 1.12 (low energy image contribution is 0.98 mGy) and 1.07 (low energy image contribution is 0.95 mGy), respectively. The low kV part of CEDM is the main contributor to total glandular breast dose. PMID- 25836683 TI - Examination frequency and population dose from medical X-ray examinations in Sudan in 2010. AB - This study was performed to estimate examination frequency and collective and per caput effective doses arising from medical X-ray procedures in Sudan, 2010. Information was collected from 30 hospitals performing radiography, computed tomography (CT), fluoroscopy and interventional radiology (IR) procedures. The estimated annual number of examinations was 33 million radiographic X-ray procedures (99 %), 0.34 million CT exams per year (14 % paediatrics CT), 0.02 million fluoroscopy and IR procedures. The estimated annual number of examinations was 326 per 1000 people. The estimated annual collective and per caput effective doses from medical X-ray procedures mount 7197 man Sv and 0.18 mSv, respectively. The study offered the first projection of frequency and population dose from medical X-ray examinations in Sudan and provides estimates of the impact of the medical X-ray procedures at the national level. PMID- 25836684 TI - Establishment of diagnostic reference levels for dental panoramic radiography in Greece. AB - The purpose of the present study was to present the national diagnostic reference levels (DRL) established for panoramic dental examinations in Greece. The establishment of DRL, as a tool for the optimisation of radiological procedures, is a requirement of national regulations. Measurements performed by the Greek Atomic Energy Commission on 90 panoramic systems have been used for the derivation of DRL values. DRL values have been proposed for exposure settings of different patient types (child, small adult and standard adult), both for film and digital imaging. The DRLs for different patient types are grouped in three categories: children, small adults (corresponding to female) and average adults (corresponding to male). Proposed DRLs for these groups are 2.2, 3.3 and 4.1 mGy, respectively. In order to investigate the correlation of DRLs with the available imaging modalities (CR, DR and film), this parameter was taken into account. DR imaging DRL is the lowest at 3.5 mGy, CR imaging the highest at 4.2 mGy and film imaging at 3.7 mGy. In order to facilitate comparison with other studies, kerma width product values were calculated from Ki, air and field size. PMID- 25836686 TI - Optimising delineation accuracy of tumours in PET for radiotherapy planning using blind deconvolution. AB - Positron emission tomography (PET) imaging has been proven to be useful in radiotherapy planning for the determination of the metabolically active regions of tumours. Delineation of tumours, however, is a difficult task in part due to high noise levels and the partial volume effects originating mainly from the low camera resolution. The goal of this work is to study the effect of blind deconvolution on tumour volume estimation accuracy for different computer-aided contouring methods. The blind deconvolution estimates the point spread function (PSF) of the imaging system in an iterative manner in a way that the likelihood of the given image being the convolution output is maximised. In this way, the PSF of the imaging system does not need to be known. Data were obtained from a NEMA NU-2 IQ-based phantom with a GE DSTE-16 PET/CT scanner. The artificial tumour diameters were 13, 17, 22, 28 and 37 mm with a target/background ratio of 4:1. The tumours were delineated before and after blind deconvolution. Student's two-tailed paired t-test showed a significant decrease in volume estimation error (p < 0.001) when blind deconvolution was used in conjunction with computer-aided delineation methods. A manual delineation confirmation demonstrated an improvement from 26 to 16 % for the artificial tumour of size 37 mm while an improvement from 57 to 15 % was noted for the small tumour of 13 mm. Therefore, it can be concluded that blind deconvolution of reconstructed PET images may be used to increase tumour delineation accuracy. PMID- 25836685 TI - A study to establish international diagnostic reference levels for paediatric computed tomography. AB - The article reports results from the largest international dose survey in paediatric computed tomography (CT) in 32 countries and proposes international diagnostic reference levels (DRLs) in terms of computed tomography dose index (CTDI vol) and dose length product (DLP). It also assesses whether mean or median values of individual facilities should be used. A total of 6115 individual patient data were recorded among four age groups: <1 y, >1-5 y, >5-10 y and >10 15 y. CTDIw, CTDI vol and DLP from the CT console were recorded in dedicated forms together with patient data and technical parameters. Statistical analysis was performed, and international DRLs were established at rounded 75th percentile values of distribution of median values from all CT facilities. The study presents evidence in favour of using median rather than mean of patient dose indices as the representative of typical local dose in a facility, and for establishing DRLs as third quartile of median values. International DRLs were established for paediatric CT examinations for routine head, chest and abdomen in the four age groups. DRLs for CTDI vol are similar to the reference values from other published reports, with some differences for chest and abdomen CT. Higher variations were observed between DLP values, based on a survey of whole multi phase exams. It may be noted that other studies in literature were based on single phase only. DRLs reported in this article can be used in countries without sufficient medical physics support to identify non-optimised practice. Recommendations to improve the accuracy and importance of future surveys are provided. PMID- 25836687 TI - Nuclear medicine examinations of children in Russia. AB - The number and specification of radionuclide examinations, administrated activity and effective doses were collected during 2011-13 for 4944 paediatric patients from 10 nuclear medicine (NM) departments of some Russian regions. The kidney examinations account for about 70 % of paediatric NM examinations in general hospitals. Diagnostics of all other organs contribute from 2 to 8 % each in the total number of paediatric examinations. Administrated activities of radiopharmaceuticals are approximately proportional to the child's age, and variations between different hospitals usually are within the factor of 3-4 and for some types of examination up to 10. The range of the effective dose due to paediatric NM examinations is roughly estimated as 2-6 mSv per examination, approximately the same as in adults. Some examinations (heart, thyroid, whole body) result in doses of younger children that are 2-3 times higher than the doses of adults. Effective doses in paediatric positron emission tomography (PET) diagnostics are in the range of 4-10 mSv per examination and are higher compared with the dose of adult patients. The application of combined radiodiagnostic technologies (single photon emission computer tomography with roentghen computer tomography [SPECT/CT] or PET with roetghen computer tomography [PET/CT]) increases the effective dose of patients by the factor of 1.5-2 for the skeleton or whole body examinations. PMID- 25836688 TI - Optimisation of paediatric chest radiography. AB - The purpose of this work is to present the algorithm for the optimisation of paediatric chest radiography aimed to reduce patient doses at keeping adequate image quality. Optimal tube voltage, tube current and exposure time, use of automatic or manual exposure control and use of antiscatter grid were recommended for different age groups and depending on the patient size. The optimised protocols and radiography technique resulted in decrease in Entrance surface air kerma and effective dose values in a factor of between 1.5 and over 5 for different age groups. Image quality was assessed to be of sufficient diagnostic quality. PMID- 25836689 TI - CT scanning in children and risk of cancer: what three large-scale studies have demonstrated. AB - That irradiation from diagnostic CT examinations has caused cancers in a small minority of young patients in the past is no longer controversial. Three recent studies from the UK, Australia and the USA have published data supporting a small but real risk of a CT scan in early life being associated with a later risk of malignancy, due solely to the CT scan. The American study showed a temporary increase in the frequency of CT scanning of children with regrettably large variation in radiation dose per scan. Most of the patients in the published studies had their CT examinations over a decade ago, and it is likely in more recent years that widespread reductions in tube current-time product (mAs) have substantially lessened the radiation burden to children from CT. It must be remembered that CT is a very useful clinical test. Whenever CT is justified, the clinical benefit virtually always outweighs the longer term very small risk of malignancy. PMID- 25836690 TI - Fetal radiation dose in computed tomography. AB - The connection between recorded volumetric CT dose index (CTDI vol) and determined mean fetal dose (Df) was examined from metal-oxide-semiconductor field effect transistor dose measurements on an anthropomorphic female phantom in four stages of pregnancy in a 64-slice CT scanner. Automated tube current modulation kept the mean Df fairly constant through all pregnancy stages in trauma (4.4-4.9 mGy) and abdomino-pelvic (2.1-2.4 mGy) protocols. In pulmonary angiography protocol, the mean Df increased exponentially as the distance from the end of the scan range decreased (0.01-0.09 mGy). For trauma protocol, the relative mean Df as a function of gestational age were in the range 0.80-0.97 compared with the mean CTDI vol. For abdomino-pelvic protocol, the relative mean Df was 0.57-0.79 and for pulmonary angiography protocol, 0.01-0.05 compared with the mean CTDI vol, respectively. In conclusion, if the fetus is in the primary beam, the CTDI vol can be used as an upper estimate of the fetal dose. If the fetus is not in the primary beam, the fetal dose can be estimated by considering also the distance of the fetus from the scan range. PMID- 25836691 TI - Performance evaluation of two computed radiography systems and patient dose in pelvic examination. AB - This study was carried out to evaluate the performance of two computed radiography (CR) units. These evaluations became necessary following the introduction of CR systems in Sudan. Evaluation of the CR systems was performed using physical image quality parameters: signal transfer property, modulation transfer function, normalised noise power spectrum, detective quantum efficiency and the subjective contrast detail detectability. Patient dose was measured in terms of entrance surface air kerma estimated from tube output and exposure factors for 100 patients who had undergone pelvic X-ray examinations. Fuji computed radiography velocity system with columnar screen dose results was much lower than those using CR975 system with granular screen. Patient doses delivered by both systems were within the international diagnostic reference levels. PMID- 25836692 TI - Effect of the glandular composition on digital breast tomosynthesis image quality and dose optimisation. AB - In the image quality assessment for digital breast tomosynthesis (DBT), a breast phantom with an average percentage of 50 % glandular tissue is seldom used, which may not be representative of the breast tissue composition of the women undergoing such examination. This work aims at studying the effect of the glandular composition of the breast on the image quality taking into consideration different sizes of lesions. Monte Carlo simulations were performed using the state-of-the-art computer program PENELOPE to validate the image acquisition system of the DBT equipment as well as to calculate the mean glandular dose for each projection image and for different breast compositions. The integrated PENELOPE imaging tool (PenEasy) was used to calculate, in mammography, for each clinical detection task the X-ray energy that maximises the figure of merit. All the 2D cranial-caudal projections for DBT were simulated and then underwent the reconstruction process applying the Simultaneous Algebraic Reconstruction Technique. Finally, through signal-to-noise ratio analysis, the image quality in DBT was assessed. PMID- 25836693 TI - Description and benefits of dynamic collimation in digital breast tomosynthesis. AB - X-ray field to image receptor active area alignment is usually tested in mammographic QC. In digital breast tomosynthesis (dBT), the source moves during the acquisition, generating a displacement of the X-ray beam edges relative to the detector, in or out of the detector active area. To minimise unnecessary radiation while maximising the useful field of view, a solution consisting in adjusting the collimation with the source rotation was implemented on the GE SenoClaire dBT system. This solution is described and tested using three different methods based on: (1) images from the detector, (2) a non-screen film and (3) a semi-conductor tool providing the X-ray intensity profile. Method 1 demonstrated a maximum positioning error of 0.3 mm. Method 2 was found non applicable; Method 3 provided measurements within 1.5 mm. Dynamic collimation enables maintaining an X-ray field to detector congruence comparable with 2D. Measuring the position of the X-ray field edges using a dedicated tool makes routine QC possible. PMID- 25836694 TI - Establishment of diagnostic reference levels in computed tomography for paediatric patients in Sudan: a pilot study. AB - Paediatric patients are recognised to be at higher risk of developing radiation induced cancer than adults. The purpose of this pilot study was to evaluate the radiation doses to paediatric patients during computed tomography (CT) procedures in order to propose local diagnostic reference levels (DRLs). A total of 296 patients (aged 6-10 y) were investigated in 8 hospitals equipped with 64-, 16- and dual-slice CT machines. The mean dose length product values were 772, 446 and 178 mGy cm for head, abdomen and chest, respectively. Imaging protocols were not adapted to the patient's weight in certain CT machines. The results confirmed that paediatric patients are exposed to an unnecessary radiation dose. The established DRLs were higher than those available in other countries. This study showed the need for harmonisation of the practice in CT departments and radiation dose optimisation. PMID- 25836695 TI - Patient grouping for dose surveys and establishment of diagnostic reference levels in paediatric computed tomography. AB - There has been confusion in literature on whether paediatric patients should be grouped according to age, weight or other parameters when dealing with dose surveys. The present work aims to suggest a pragmatic approach to achieve reasonable accuracy for performing patient dose surveys in countries with limited resources. The analysis is based on a subset of data collected within the IAEA survey of paediatric computed tomography (CT) doses, involving 82 CT facilities from 32 countries in Asia, Europe, Africa and Latin America. Data for 6115 patients were collected, in 34.5 % of which data for weight were available. The present study suggests that using four age groups, <1, >1-5, >5-10 and >10-15 y, is realistic and pragmatic for dose surveys in less resourced countries and for the establishment of DRLs. To ensure relevant accuracy of results, data for >30 patients in a particular age group should be collected if patient weight is not known. If a smaller sample is used, patient weight should be recorded and the median weight in the sample should be within 5-10 % from the median weight of the sample for which the DRLs were established. Comparison of results from different surveys should always be performed with caution, taking into consideration the way of grouping of paediatric patients. Dose results can be corrected for differences in patient weight/age group. PMID- 25836696 TI - Radiation effects and risks: overview and a new risk perception index. AB - Uncertainty provides opportunities for differences in perception, and radiation risks at low level of exposures involved in few computed tomography scans fall in this category. While there is good agreement among national and international organisations on risk probability of cancer, risk perception has barely been dealt with by these organisations. Risk perception is commonly defined as the subjective judgment that people make about the characteristics and severity of a risk. Severity and latency are important factors in perception. There is a need to connect all these. Leaving risk perception purely as a subjective judgement provides opportunities for people to amplifying risk. The author postulates a risk perception index as severity divided by latency that becomes determining factor for risk perception. It is hoped that this index will bring rationality in risk perception. PMID- 25836697 TI - Eight years of quality control in Bulgaria: impact on mammography practice. AB - The requirements for quality control (QC) in diagnostic radiology were introduced in Bulgarian legislation in 2005. Hospital medical physicists and several private medical physics groups provide QC services to radiology departments. The aim of this study was to analyse data from QC tests in mammography and to investigate the impact of QC introduction on mammography practice in the country. The study was coordinated by the National Centre of Radiobiology and Radiation Protection. All medical physics services were requested to fill in standardised forms with information about most important parameters routinely measured during QC. All QC service providers responded. Results demonstrated significant improvement of practice since the introduction of QC, with reduction of established deviations from 65 % during the first year to 7 % in the last year. The systems that do not meet the acceptability criteria were suspended from use. Performance of automatic exposure control and digital detectors are not regularly tested because of the absence of requirements in the legislation. The need of updated guidance and training of medical physicists to reflect the change in technology was demonstrated. PMID- 25836698 TI - Dose reduction in chest CT examination. AB - Computed tomography (CT) examinations involve relatively high doses to patients. The objectives of this study were to optimise the radiation dose for patient during CT chest scan and to estimate the lifetime cancer risk. A total of 50 patients were studied: control group (A) (38 patients) and optimisation group (B) (12 patients). The optimisation protocol was based on CT pitch increment and lowering tube current. The mean volume CT dose index (CTDI vol) was 21.17 mGy and dose length product (DLP) was 839.0 mGy cm for Group A, and CTDI vol was 8.3 mGy and DLP was 339.7 for Group B. The overall cancer risk was estimated to be 8.0 and 3.0 cancer incidence per million for Groups A and B, respectively. The patient dose optimisation during CT chest was investigated. Lowering tube current and pitch increment achieved a radiation dose reduction of up to 60 % without compromising the diagnostic findings. PMID- 25836699 TI - Radiation protection of linac bunkers. A user-friendly approach. AB - A well-known but complex formalism for the calculation of the leakage dose at the entrance of the linac maze was considered and simplified. These simplifications were based partly on the literature and partly on the authors' own measurements. The authors have included photon scatter originating from the irradiated patient in the formalism. A formalism for two different types of bunkers was developed, and the authors have obtained simple formulas to calculate the dose at the maze entrance for both bunker types. PMID- 25836700 TI - Mixed nutcracker syndrome with left renal vein duplication: A severe and exceptional presentation in an 18-year-old boy. AB - The nutcracker syndrome (NCS) is rare and often misdiagnosed because it embraces an extended non-pathognomonic spectrum of symptoms that imply a difficult diagnosis. Ultimately it may be associated with substantial morbidity and even life-threatening events. Mixed NCS with renal vein duplication is an exceptional variety, have previously been reported to the best of our knowledge. We report a rare case of an 18-year-old boy who presented with a long history of abdominal, pelvic and left flank pain, fatigue and higher bilateral varicocele. Computed tomographic angiography, Doppler ultrasonography and venography were performed revealed left renal vein duplication with dilated retroaortic and preaortic branchs, entrapped respectively between the aorta and the vertebral column and in the aortico-mesenteric space, with extensive and complex varices of the deep pelvic venous plexus; promoting the mixed renal NCS. Auto transplantation of the left kidney was suggested, but refused by the patient; and only the varicocele was managed. The patient is still suffering from his severe initial symptoms. Diagnosis is difficult and should be considered in patients with inexplicable flank or abdominal pain. Our purpose is to raise clinician's awareness for this condition so that they will be more likely to diagnose it. This will facilitate prompt diagnosis and treatment. PMID- 25836701 TI - Transition from fetus to newborn. AB - The fetus to newborn transition is a complex physiologic process that requires close monitoring. Approximately 10% of all newborns require some support in facilitating a successful transition after delivery. Clinicians should be aware of the physiologic processes and pay close regard to the newborn's cardiopulmonary transition at birth to provide appropriate treatment and therapies as required. Trained Personnel in the Neonatal Resuscitation program should be available at the delivery for all newborns to ensure that immediate and appropriate care is provided to achieve the best possible outcomes for those babies not smoothly transitioning to extrauterine life. PMID- 25836702 TI - Initial assessment and management of the newborn. AB - This article summarizes the initial assessment of normal newborns and describes a few of the common variations that may occur. These variations require a pediatric provider to reassure anxious new parents and provide follow-up communication with the subsequent primary care provider. PMID- 25836703 TI - Sensory development. AB - Sensory development is complex, with both morphologic and neural components. Development of the senses begins in early fetal life, initially with structures and then in-utero stimulation initiates perception. After birth, environmental stimulants accelerate each sensory organ to nearly complete maturity several months after birth. Vision and hearing are the best studied senses and the most crucial for learning. This article focuses on the cranial senses of vision, hearing, smell, and taste. Sensory function, embryogenesis, external and genetic effects, and common malformations that may affect development are discussed, and the corresponding sensory organs are examined and evaluated. PMID- 25836704 TI - Metabolic screening and postnatal glucose homeostasis in the newborn. AB - Although individual metabolic diseases are relatively uncommon, inherited metabolic diseases collectively represent a more common cause of disease in the neonatal period than is generally appreciated. Newborn screening is among the most successful public health programs today. Every day, newborns considered to be at risk for hypoglycemia are screened. The definition of clinically significant hypoglycemia remains among the most confused and contentious issues in neonatology. There are 2 "competing" methods of defining hypoglycemia that suggest very different levels for management: one based on metabolic endocrinologic hormones and another that uses outcome data to determine threshold levels of risk. PMID- 25836705 TI - Common genetic and epigenetic syndromes. AB - Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes. PMID- 25836706 TI - Neonatal nutrition. AB - Optimal nutrition in infancy is the foundation of health in later life. Based on the demonstrated health benefits of human milk, breastfeeding should be the primary means of nutrition for most infants. Although many mothers experience some problems with breastfeeding, health professionals can use simple strategies to overcome most of these problems. For infants who cannot breastfeed, standard infant formulas support adequate nutrition and growth. Gastroesophageal reflux is a common feeding-related event and occurs in most infants; it is part of normal physiology and requires no intervention. Gastroesophageal reflux disease occurs in a small number of infants necessitating the use of an algorithm-based evaluation and management strategy. PMID- 25836707 TI - Management of the late preterm infant: not quite ready for prime time. AB - Preterm births account for 12.5% of all births in the United States. The preterm birth rate has increased by 33% over the last 2 decades. Late and premature infants do not develop the serious and chronic conditions of the extreme premature infant. However, there is growing evidence that these infants are not as healthy as previously thought and do in fact have an increase in morbidity and mortality compared with term infants. This article summarizes the epidemiology of late preterm infants and the associated morbidities associated with their prematurity. PMID- 25836708 TI - Neonatal respiratory distress: a practical approach to its diagnosis and management. AB - Respiratory disorders are the most frequent cause of admission to the special care nursery both in term and preterm infants. Pediatricians and primary care providers may encounter newborn infants with respiratory distress in their office, emergency room, delivery room, or during physical assessment in the newborn nursery. The authors have proposed a practical approach to diagnose and manage such infants with suggestions for consulting a neonatologist at a regional center. Their objective is that practicing pediatricians should be able to assess and stabilize such infants, and transfer to or consult a neonatologist, cardiologist, or pulmonologist after reading this article. PMID- 25836709 TI - Cardiac evaluation of the newborn. AB - The physical examination of the term newborn's cardiovascular system is reviewed detailing the normal and abnormal variants that can be found within the first few days after birth. The authors discuss the pathophysiologic changes that occur in the presence of congenital heart disease and how these changes affect the clinical presentation. The major common cardiac defects are described and discussed. Pulse oximetry screening is reviewed in detail indicating its value in the early detection of most cases of critical congenital heart disease. Finally, the reader is given several suggestions on diagnosis, stabilization, and when to refer to specialists. PMID- 25836710 TI - A practical guide to the diagnosis, treatment, and prevention of neonatal infections. AB - Neonatal infections continue to cause morbidity and mortality in infants. Among approximately 400,000 infants followed nationally, the incidence rates of early onset sepsis infection within 3 days of life are 0.98 cases per 1000 live births. Newborn infants are at increased risk for infections because they have relative immunodeficiency. This article provides evidence-based practical approaches to the diagnosis, management, and prevention of neonatal infections. PMID- 25836711 TI - Common hematologic problems in the newborn nursery. AB - "Common red blood cell disorders encountered in the normal newborn nursery include hemolytic disease of the newborn and resultant hyperbilirubinemia, anemia, and polycythemia. A less frequent clinically relevant hematologic issue in newborns to be covered herein is thrombocytopenia." PMID- 25836712 TI - Neonatal medications. AB - Neonatal abstinence syndrome (NAS) is reaching epidemic proportions related to perinatal use of opioids. There are many approaches to assess and manage NAS, including one we have outlined. A standardized approach is likely to reduce length of stay and variability in practice. Circumcision is a frequent, painful procedure performed in the neonatal period. The rationale for providing analgesia is presented as well as a review of methods. Pharmacogenomics and pharmacogenetics have expanded our understanding of diseases and their drug therapy. Some applications of pharmacogenomics to the neonatal period are presented, along with pediatric challenges of developmental expression of drug metabolizing enzymes. PMID- 25836713 TI - Discharge planning. AB - Hospital discharge is a time of transition for infants and families that requires oversight of common postnatal adaptations, screening tests, and establishment of necessary follow-up care. Preterm infants face additional medical problems that vary in complexity by the degree of prematurity. Infants born at lowest gestational ages are at highest risks for complicated neonatal course and adverse long-term outcomes. Successful transition from hospital to home care is essential to improved outcomes for high-risk infants. PMID- 25836714 TI - The healthy and sick newborn. PMID- 25836715 TI - The problem baby: too much information. PMID- 25836716 TI - Host-imposed manganese starvation of invading pathogens: two routes to the same destination. AB - During infection invading pathogens must acquire all essential nutrients, including first row transition metals, from the host. To combat invaders, the host exploits this fact and restricts the availability of these nutrients using a defense mechanism known as nutritional immunity. While iron sequestration is the most well-known aspect of this defense, recent work has revealed that the host restricts the availability of other essential elements, notably manganese (Mn), during infection. Furthermore, these studies have revealed that the host utilizes multiple strategies that extend beyond metal sequestration to prevent bacteria from obtaining these metals. This review will discuss the mechanisms by which bacteria attempt to obtain the essential first row transition metal ion Mn during infection, and the approaches utilized by the host to prevent this occurrence. In addition, this review will discuss the impact of host-imposed Mn starvation on invading bacteria. PMID- 25836717 TI - Accuracy of Molecular Data Generated with FFPE Biospecimens: Lessons from the Literature. AB - Formalin-fixed and paraffin-embedded (FFPE) tissue biospecimens are a valuable resource for molecular cancer research. Although much can be gained from their use, it remains unclear whether the genomic and expression profiles obtained from FFPE biospecimens accurately reflect the physiologic condition of the patient from which they were procured, or if such profiles are confounded by biologic effects from formalin fixation and processing. To assess the physiologic accuracy of genomic and expression data generated with FFPE specimens, we surveyed the literature for articles investigating genomic and expression endpoints in case matched FFPE and fresh or frozen human biospecimens using the National Cancer Institute's Biospecimen Research Database (http://biospecimens.cancer.gov/brd). Results of the survey revealed that the level of concordance between differentially preserved biospecimens varied among analytical parameters and platforms but also among reports, genes/transcripts of interest, and tumor status. The identified analytical techniques and parameters that resulted in strong correlations between FFPE and frozen biospecimens may provide guidance when optimizing molecular protocols for FFPE use; however, discrepancies reported for similar assays also illustrate the importance of validating protocols optimized for use with FFPE specimens with a case-matched fresh or frozen cohort for each platform, gene or transcript, and FFPE processing regime. On the basis of evidence published to date, validation of analytical parameters with a properly handled frozen cohort is necessary to ensure a high degree of concordance and confidence in the results obtained with FFPE biospecimens. PMID- 25836718 TI - Mesoscopic and macroscopic optoacoustic imaging of cancer. AB - Optoacoustic imaging combines the rich contrast of optical methods with the resolution of ultrasound imaging. It can therefore deliver optical visualization of cancer far deeper in tissue than optical microscopy and other conventional optical imaging methods. Technological progress and novel contrast media have resulted in optoacoustic imaging being propagated to basic cancer research and in clinical translation projects. We briefly review recent technological advances, showcase the ability to resolve unique cancer biomarkers based on spectral features at different imaging scales, and highlight the imaging performance achieved in preclinical and clinical imaging applications. . PMID- 25836719 TI - Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors. AB - Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. PMID- 25836720 TI - Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb. AB - Baseline blood concentrations of metals are important references for monitoring metal exposure in environmental and occupational settings. The purpose of this study was to determine the blood levels of manganese (Mn), copper (Cu), zinc (Zn), lead (Pb), and cadmium (Cd) among the residents (aged 12-60 years old) living in the suburb southwest of Beijing in China and to compare the outcomes with reported values in various developed countries. Blood samples were collected from 648 subjects from March 2009 to February 2010. Metal concentrations in the whole blood were determined by ICP-MS. The geometric means of blood levels of Mn, Cu, Zn, Pb and Cd were 11.4, 802.4, 4665, 42.6, and 0.68 ug/L, respectively. Male subjects had higher blood Pb than the females, while the females had higher blood Mn and Cu than the males. There was no gender difference for blood Cd and Zn. Smokers had higher blood Cu, Zn, and Cd than nonsmokers. There were significant age-related differences in blood levels of all metals studied; subjects in the 17 30 age group had higher blood levels of Mn, Pb, Cu, and Zn, while those in the 46 60 age group had higher Cd than the other age groups. A remarkably lower blood level of Cu and Zn in this population as compared with residents of other developed countries was noticed. Based on the current study, the normal reference ranges for the blood Mn were estimated to be 5.80-25.2 MUg/L; for blood Cu, 541 1475 MUg/L; for blood Zn, 2349-9492 MUg/L; for blood Pb, <100 MUg/L; and for blood Cd, <5.30 MUg/L in the general population living in Beijing suburbs. PMID- 25836721 TI - Serum selenium and lipid levels: Associations observed in the National Health and Nutrition Examination Survey (NHANES) 2011-2012. AB - Selenium is an essential micronutrient, and due to its antioxidant activity, is hypothesized to be beneficial to cardiovascular health. However, the evidence for an association between selenium and health markers such as lipid levels has been mixed. This may be due to substantial variability in the level of selenium intake between populations and potential non-linearity of selenium-health outcome associations. We used the 2011-2012 National Health and Nutrition Examination Survey (NHANES) to examine the relationship between serum selenium and lipid levels among participants aged 12 years and older. Associations were evaluated using both linear regression models, as well as ordinal logistic regression and quantile regression models to allow for potential non-linear relationships. In all models, potential confounders of sex, age group, race/ethnicity, educational attainment and cotinine were included. Overall, 40% of participants had total cholesterol levels classified as borderline or elevated, and total cholesterol increased with increasing selenium (p=0.01). A similar pattern was seen for triglycerides (p=0.02). LDL cholesterol was also associated with selenium but not in a linear fashion; HDL cholesterol did not vary with selenium. Multivariate quantile regression showed significant associations between selenium and total cholesterol, LDL cholesterol, and triglycerides. The effect of selenium was stronger with increasing quantile for total cholesterol and for triglycerides. In contrast, for LDL cholesterol the association was positive in the 10th and 50th percentiles, but (non-significant and) negative in the 90th percentile. These results show that while selenium may impact cardiovascular health via effects on lipid levels, the associations may not be linear. PMID- 25836722 TI - Carbon-metal interfaces analyzed by aberration-corrected TEM: how copper and nickel nanoparticles interact with MWCNTs. AB - Experimental confirmation for the stronger interaction of Ni with multi-walled carbon nanotubes (MWCNTs) compared to Cu with MWCNTs is presented. The interfaces between Cu (Ni) nanoparticles side-on oriented onto MWCNTs are analyzed with high spatial resolution electron energy-loss spectroscopy (EELS) of the carbon K-edge. The EEL spectra reveal a rehybridization from sp(2) to sp(3) hybridized carbon of the outermost MWCNT layer at the Ni interface, but no such rehybridization can be observed at the Cu interface. The EELS results are supported by transmission electron microscopy (TEM) images, which show a better wetting behavior of Ni and a smaller gap at the Ni-MWCNT interface, as compared to the corresponding Cu interfaces. The different behavior of Cu and Ni can be explained in terms of differing valence d-orbital occupancy. For the successful experimental demonstration of this effect the use of a soft chemical metal deposition technique is crucial. PMID- 25836723 TI - POINT: Does the Risk of Electronic Cigarettes Exceed Potential Benefits? Yes. PMID- 25836724 TI - Visualization of the Peripheral Branches of the Mandibular Division of the Trigeminal Nerve on 3D Double-Echo Steady-State with Water Excitation Sequence. AB - BACKGROUND AND PURPOSE: Although visualization of the extracranial branches of the cranial nerves has improved with advances in MR imaging, only limited studies have assessed the detection of extracranial branches of the mandibular nerve (V3). We investigated the detectability of the branches of V3 on a 3D double-echo steady-state with water excitation sequence. MATERIALS AND METHODS: We retrospectively evaluated the detectability of the 6 branches of the V3, the masseteric, buccal, auriculotemporal, lingual, inferior alveolar, and mylohyoid nerves, by using a 5-point scale (4, excellent; 3, good; 2, fair; 1, poor; and 0, none) in 86 consecutive patients who underwent MR imaging with the 3D double-echo steady-state with water excitation sequence. Weighted kappa analysis was used to calculate interobserver variability among the 3 readers. RESULTS: The detection of the lingual and inferior alveolar nerves was the most successful, with excellent average scores of 3.80 and 3.99, respectively. The detection of the masseteric, the buccal, and the auriculotemporal nerves was good, with average scores of 3.31, 2.67, and 3.11, respectively. The mylohyoid nerve was difficult to detect with poor average scores of 0.62. All nerves had excellent interobserver variability across the 3 readers (average weighted kappa value, 0.95-1.00). CONCLUSIONS: The 3D double-echo steady-state with water excitation sequence demonstrated excellent visualization of the extracranial branches of V3 in most patients. The 3D double-echo steady-state with water excitation sequence has the potential for diagnosing V3 pathologies and preoperatively identifying peripheral cranial nerves to prevent surgical complications. PMID- 25836725 TI - Using Texture Analysis to Determine Human Papillomavirus Status of Oropharyngeal Squamous Cell Carcinomas on CT. AB - BACKGROUND AND PURPOSE: Human papillomavirus-associated oropharyngeal squamous cell carcinoma is increasing in prevalence and typically occurs in younger patients than human papillomavirus-negative squamous cell carcinoma. While imaging features of human papillomavirus-positive versus human papillomavirus negative squamous cell carcinoma nodal metastases have been described, characteristics distinguishing human papillomavirus-positive from human papillomavirus-negative primary squamous cell carcinomas have not been well established. The purpose of this project was to evaluate the use of texture features to distinguish human papillomavirus-positive and human papillomavirus negative primary oropharyngeal squamous cell carcinoma. MATERIALS AND METHODS: Following institutional review board approval, 40 patients with primary oropharyngeal squamous cell carcinoma and known human papillomavirus status who underwent contrast-enhanced CT between December 2009 and October 2013 were included in this study. Segmentation of the primary lesion was manually performed with a semiautomated graphical-user interface. Following segmentation, an in house-developed texture analysis program extracted 42 texture features from each segmented volume. A t test was used to evaluate differences in texture parameters between human papillomavirus-positive and human papillomavirus-negative squamous cell carcinomas. RESULTS: Of the 40 included patients, 29 had human papillomavirus-positive oropharyngeal squamous cell carcinoma and 11 had human papillomavirus-negative oropharyngeal squamous cell carcinoma. Significant differences were seen in the histogram parameters median (P = .006) and entropy (P = .016) and squamous cell carcinoma entropy (P = .043). CONCLUSIONS: There are statistically significant differences in some texture features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal tumors. Texture analysis may be considered an adjunct to the evaluation of human papillomavirus status and characterization of squamous cell carcinoma. PMID- 25836726 TI - Comeback victory. PMID- 25836727 TI - Degree of Collaterals and Not Time Is the Determining Factor of Core Infarct Volume within 6 Hours of Stroke Onset. AB - BACKGROUND AND PURPOSE: Growth of the core infarct during the first hours of ischemia onset is not well-understood. We hypothesized that factors other than time from onset of ischemia contribute to core infarct volume as measured by MR imaging. MATERIALS AND METHODS: Prospectively collected clinical and imaging data of consecutive patients with stroke presenting between March 2008 and April 2013 with anterior circulation large-vessel occlusion and MR imaging performed within 6 hours from the time of onset were reviewed. The association of time from onset, clinical, and radiographic features with DWI volume was assessed by using chi(2) and Mann-Whitney U tests. RESULTS: Of 91 patients, 21 (23%) underwent MR imaging within 0-3 hours from onset, and 70 (76%), within 3-6 hours. Median MR imaging infarct volume was similar in both timeframes, (24.7 versus 29.4 mL, P = .906), and there was no difference in the proportion of patients with large infarct volumes (>=70 mL, 23.8% versus 22.8%, P = .928). Using receiver operating characteristic analysis, we detected no association between the time from onset and MR imaging infarct volume (area under the curve = 0.509). In multivariate analysis, CTA collaterals (>50% of the territory) (adjusted OR, 0.192; 95% CI, 0.04-0.9; P = .046), CTA ASPECTS (adjusted OR, 0.464; 95% CI, 0.3-0.8; P = .003), and a history of hyperlipidemia (adjusted OR, 11.0; 95% CI, 1.4-88.0; P = .023) (but not time from stroke onset to imaging) were independent predictors of MR imaging infarct volume. CONCLUSIONS: Collateral status but not time from stroke onset to imaging was a predictor of the size of core infarct in patients with anterior circulation large-vessel occlusion presenting within 6 hours from onset. PMID- 25836728 TI - Prognostic Value of Dynamic Susceptibility Contrast-Enhanced and Diffusion Weighted MR Imaging in Patients with Glioblastomas. AB - BACKGROUND AND PURPOSE: Prediction of survival in patients with glioblastomas is important for individualized treatment planning. This study aimed to assess the prognostic utility of presurgical dynamic susceptibility contrast and diffusion weighted imaging for overall survival in patients with glioblastoma. MATERIALS AND METHODS: MR imaging data from pathologically proved glioblastomas between June 2006 to December 2013 in 58 patients (mean age, 62.7 years; age range, 22-89 years) were included in this retrospective study. Patients were divided into long survival (>=15 months) and short survival (<15 months) groups, depending on overall survival time. Patients underwent dynamic susceptibility contrast perfusion and DWI before surgery and were treated with chemotherapy and radiation therapy. The maximum relative cerebral blood volume and minimum mean diffusivity values were measured from the enhancing part of the tumor. RESULTS: Maximum relative cerebral blood volume values in patients with short survival were significantly higher compared with those who demonstrated long survival (P < .05). No significant difference was observed in the minimum mean diffusivity between short and long survivors. Receiver operator curve analysis demonstrated that a maximum relative cerebral blood volume cutoff value of 5.79 differentiated patients with low and high survival with an area under the curve of 0.93, sensitivity of 0.89, and specificity of 0.90 (P < .001), while a minimum mean diffusivity cutoff value of 8.35 * 10(-4)mm(2)/s had an area under the curve of 0.55, sensitivity of 0.71, and specificity of 0.47 (P > .05) in separating the 2 groups. CONCLUSIONS: Maximum relative cerebral blood volume may be used as a prognostic marker of overall survival in patients with glioblastomas. PMID- 25836729 TI - Predicting the Prognosis of Oral Tongue Carcinoma Using a Simple Quantitative Measurement Based on Preoperative MR Imaging: Tumor Thickness versus Tumor Volume. AB - BACKGROUND AND PURPOSE: Several studies indicated that tumor thickness or tumor volume might be helpful predictors for the prognosis of oral tongue squamous cell carcinoma. Our aim was to compare the value of tumor thickness versus tumor volume measurement based on preoperative MR imaging in predicting the prognosis of oral tongue squamous cell carcinoma, especially focusing on lymph node metastases and local recurrence. MATERIALS AND METHODS: Clinical, pathologic, and imaging data of patients with 46 oral tongue squamous cell carcinomas were retrospectively studied. Logistic regression analysis was used to evaluate the prognostic value of tumor thickness and tumor volume based on MR imaging. Receiver operating characteristic analysis was applied for the optimal cutoff value for the identified risk variable for prognosis. RESULTS: A higher intraclass correlation coefficient was achieved for the measurement of tumor thickness compared with tumor volume (0.990 versus 0.972). Multivariate analysis showed that tumor thickness was a significant predictor of lymph node metastases (P = .024), while tumor volume was not a significant predictor of either lymph node metastases or local recurrence (P > .05). Receiver operating characteristic results indicated that setting a tumor thickness of 8.5 mm as a cutoff value could achieve the optimal diagnostic efficiency for predicting lymph node metastases (area under the curve, 0.753; sensitivity, 0.889; specificity, 0.536). CONCLUSIONS: Tumor thickness based on preoperative MR imaging was useful in predicting the prognosis of oral tongue squamous cell carcinoma, especially lymph node metastases, in our patient population, while tumor volume was not. PMID- 25836730 TI - ER-mitochondria contact sites in yeast: beyond the myths of ERMES. AB - A standout feature of eukaryotic cells is the presence of organelles with distinct chemical compositions and physical properties, which aid in the accomplishment of specialized metabolic tasks. This complex topology, however, makes a permanent crosstalk between the organelles a necessity for the coordination of cellular function. While molecule exchange between organelles via the vesicular transport system has been extensively studied, communication via direct connections has only recently become a new matter of interest. These direct connections termed membrane contact sites (MCSs) represent zones of close proximity (10-30nm) between two organelles. Research in the past years has revealed a number of MCSs especially between the ER and almost every other organelle [1(*)]. In particular, the MCSs between the ER and the mitochondria have undergone intense investigation. While the quest for ER-mitochondria MCS components in human cells has led to the revelation of an ever growing number of potential factors, studies in the simpler eukaryote Saccharomyces cerevisiae revealed the actual existence of a molecular tether between the two organelles [2(**)]. PMID- 25836732 TI - Telepractice Versus In-Person Delivery of Voice Therapy for Primary Muscle Tension Dysphonia. AB - PURPOSE: The purpose of this study was to investigate the utility of telepractice for delivering flow phonation exercises to persons with primary muscle tension dysphonia (MTD). METHOD: Fourteen participants with a diagnosis of primary MTD participated, 7 on site and 7 at remote locations. Each participant received 12 treatment sessions across 6 weeks. Treatment consisted of flow phonation voice therapy exercises. Auditory-perceptual, acoustic, aerodynamic, and quality-of life measures were taken before and after treatment. RESULTS: Perceptual and quality-of-life measures were significantly better posttreatment and were statistically equivalent across groups. Acoustic and aerodynamic measures improved in both groups, but changes did not reach statistical significance. Results for the 2 service delivery groups were comparable, with no significant differences observed for perceptual and quality-of-life measures. CONCLUSIONS: Although the American Speech-Language-Hearing Association supports the use of telepractice for speech-language pathology services, evidence for the use of telepractice for providing behavioral treatment to patients with MTD has been lacking. The results of this study indicate that flow phonation exercises can be successfully used for patients with MTD using telepractice. PMID- 25836733 TI - Negative regulation of hepatitis B virus replication by forkhead box protein A in human hepatoma cells. AB - Hepatitis B virus (HBV) replication is controlled by liver-enriched transcriptional factors, including forkhead box protein A (FOXA) members. Here, we found that FOXA members are directly and indirectly involved in HBV replication in human hepatic cells. HBV replication was elevated in HuH-7 treated with individual FOXA members-specific siRNA. Reciprocally, the downregulation of HBV replication was observed in FOXA-induced HuH-7. However, the mechanism of downregulation is different among FOXA members at the level of HBV RNA transcription, such as precore/pg RNA and 2.1 kb RNA. In addition, FOXA1 and FOXA2 suppressed nuclear hormone receptors, such as HNF4alpha, that are related to HBV replication. PMID- 25836734 TI - Functional and structural insights into the piRNA factor Maelstrom. AB - PIWI-interacting RNA (piRNA) is a germline-specific class of small non-coding RNAs that repress transposons in the gonads. Mael, which comprises a high mobility group box and a MAEL domain, is one of the key players in piRNA-mediated transposon silencing. However, the mechanism whereby Mael is involved in this pathway remains unknown. Recent biochemical and structural studies, along with bioinformatic analyses of Mael-associating RNAs in vivo, have shed light on the functional aspects of Mael in the piRNA pathway. We summarize the current understanding of Mael functions in the piRNA pathway, particularly in Drosophila and in mice. PMID- 25836735 TI - Photochemical chromophore isomerization in histidine kinase rhodopsin HKR1. AB - Histidine kinase rhodopsin 1 is a photoreceptor in green algae functioning as a UV-light sensor. It switches between a UV-absorbing state (Rh-UV) and a blue absorbing state (Rh-Bl) with a protonated retinal Schiff base (RSB) cofactor in a mixture of 13-trans,15-anti and 13-cis,15-syn isomers. The present spectroscopic study now shows that cofactor-protein assembly stabilizes the protonated 13 trans,15-anti RSB isomer. Formation of the active photoswitch requires the photoinduced conversion to Rh-UV. The transitions between the Rh-Bl isomers and the deprotonated 13-cis,15-anti and 13-trans,15-syn isomers of Rh-UV proceed via multiple photoisomerizations of one or simultaneously two double bonds. PMID- 25836736 TI - The oxidative pentose phosphate pathway in the haloarchaeon Haloferax volcanii involves a novel type of glucose-6-phosphate dehydrogenase--The archaeal Zwischenferment. AB - The oxidative pentose phosphate pathway (OPPP), catalyzing the oxidation of glucose-6-phosphate to ribulose-5-phosphate is ubiquitous in eukarya and bacteria but has not yet been reported in archaea. In haloarchaea a putative 6 phosphogluconate dehydrogenase (6PGDH) is annotated, whereas a gene coding for glucose-6-phosphate dehydrogenase (Glc6PDH) could not be identified. Here we report the purification and characterization of a novel type of Glc6PDH in Haloferax volcanii that is not related to bacterial and eukaryal Glc6PDHs and the encoding gene is designated as azf (archaeal zwischenferment). Further, recombinant H. volcanii 6PGDH was characterized. Deletion mutant analyses indicate that both, Glc6PDH and 6PGDH, are functionally involved in pentose phosphate formation in vivo. This is the first report on the operation of the OPPP in the domain of archaea. PMID- 25836738 TI - Online matrix removal platform for coupling gel-based separations to whole protein electrospray ionization mass spectrometry. AB - A fractionation method called gel-eluted liquid fraction entrapment electrophoresis (GELFrEE) has been used to dramatically increase the number of proteins identified in top-down proteomic workflows; however, the technique involves the use of sodium dodecyl sulfate (SDS), a surfactant that interferes with electrospray ionization. Therefore, an efficient removal of SDS is absolutely required prior to mass analysis. Traditionally, methanol/chloroform precipitation and spin columns have been used, but they lack reproducibility and are difficult to automate. Therefore, we developed an in-line matrix removal platform to enable the direct analysis of samples containing SDS and salts. Only small molecules like SDS permeate a porous membrane and are removed in a manner similar to cross-flow filtration. With this device, near-complete removal of SDS is accomplished within 5 min and proteins are subsequently mobilized into a mass spectrometer. The new platform was optimized for the analysis of GELFrEE fractions enriched for histones extracted from human HeLa cells. All four core histones and their proteoforms were detected in a single spectrum by high resolution mass spectrometry. The new method versus protein precipitation/resuspension showed 2- to 10-fold improved signal intensities, offering a clear path forward to improve proteome coverage and the efficiency of top-down proteomics. PMID- 25836739 TI - Expression of the class 1 histone deacetylases HDAC8 and 3 are associated with improved survival of patients with metastatic melanoma. AB - Prior studies have shown that combinations of histone deacetylase (HDAC) and BRAF inhibitors (BRAFi) have synergistic effects on BRAFi-resistant melanoma through enhanced apoptosis and inhibition of the cAMP-dependent drug resistance pathway. However, little is known about the expression of various HDACs and their associations with BRAF/NRAS mutation status, clinicopathologic characteristics, and patient outcome. The present study extensively profiled HDAC class 1 and their targets/regulators utilizing immunohistochemistry in human melanoma samples from patients with stage IV melanoma, known BRAF/NRAS mutational status, and detailed clinicopatholgical data. HDAC8 was increased in BRAF-mutated melanoma (P=0.016), however, no association between expression of other HDACs and NRAS/BRAF status was identified. There was also a correlation between HDAC1, HDAC8 expression, and phosphorylated NFkappab p65 immunoreactivity (P<0.001). Increased cytoplasmic HDAC8 immunoreactivity was independently associated with an improved survival from both diagnosis of primary melanoma and from first detection of stage IV disease to melanoma death on multivariate analysis (HR 0.992, 95% CI 0.987-0.996; P<0.001 and HR 0.993, 95% CI 0.988-0.998; P=0.009, respectively). These results suggest not only that HDAC8 may be a prognostic biomarker in melanoma, but also provide important data regarding the regulation of HDACs in melanoma and a rational basis for targeting them therapeutically. PMID- 25836737 TI - Pediatric obesity. An introduction. AB - The prevalence of child and adolescent obesity in the United States increased dramatically between 1970 and 2000, and there are few indications that the rates of childhood obesity are decreasing. Obesity is associated with myriad medical, psychological, and neurocognitive abnormalities that impact children's health and quality of life. Genotypic variation is important in determining the susceptibility of individual children to undue gains in adiposity; however, the rapid increase in pediatric obesity prevalence suggests that changes to children's environments and/or to their learned behaviors may dramatically affect body weight regulation. This paper presents an overview of the epidemiology, consequences, and etiopathogenesis of pediatric obesity, serving as a general introduction to the subsequent papers in this Special Issue that address aspects of childhood obesity and cognition in detail. PMID- 25836740 TI - Associations between size-fractionated particulate air pollution and blood pressure in a panel of type II diabetes mellitus patients. AB - Little is known regarding how the size distribution of particulate matter (PM) air pollution influences its effect on blood pressure (BP), especially among patients with diabetes. The objective of this study was to explore the short-term associations between size-fractionated PM and BP among diabetes patients. We scheduled 6 repeated BP examinations every 2 weeks from 13 April 2013 to 30 June 2013 in a panel of 35 type 2 diabetes mellitus patients recruited from an urban community in Shanghai, China. We measured real-time PM concentrations in the size range of 0.25 to 10 MUm. We used linear mixed-effect models to examine the short term association of size-fractionated PM and BP after controlling for individual characteristics, mean temperature, relative humidity, day of the week, years with diabetes and use of antihypertensive medication. The association with systolic BP and pulse pressure strengthened with decreasing diameter. The size fractions with the strongest associations were 0.25 to 0.40 MUm for number concentrations and <= 2.5 MUm for mass concentrations. Furthermore, these effects occurred immediately even after 0-2h and lasted for up to 48 h following exposure. An interquartile range increase in 24-h average number concentrations of PM0.25-0.40 was associated with increases of 3.61 mmHg in systolic BP and 2.96 mmHg in pulse pressure. Females, patients younger than 65 years of age and patients without antihypertensive treatment were more susceptible to these effects. Our results revealed important size and temporal patterns of PM in elevating BP among diabetes patients in China. PMID- 25836741 TI - Removing the economic burden of road traffic injuries from patients: a successful model. PMID- 25836742 TI - Cu-Catalyzed Consecutive Hydroxylation and Aerobic Oxidative Cycloetherification under Microwave Conditions: Entry to 2-Arylbenzofuran-3-carboxylic Acids. AB - A convenient one-pot synthesis of 2-arylbenzofuran-3-carboxylic acids from (E)-2 (2-bromophenyl)-3-phenylacrylic acids via Cu-catalyzed consecutive hydroxylation and aerobic oxidative cycloetherification under microwave conditions has been developed. This protocol employed the reagent combination of Cu(OAc)2, 1,10-phen, and KOH in DMSO/H2O (1:1), all of which are cost-effective, readily available, and easily removable from the reaction mixture. Utilizing this synthetic protocol, various 2-arylbenzofuran-3-carboxylic acids as well as the natural product moracin M have been synthesized in satisfactory yields under mild conditions. PMID- 25836743 TI - Effects of alkyl chain length on the optoelectronic properties and performance of pyrrolo-perylene solar cells. AB - While the impact of alkyl side-chain length on the photovoltaic properties of conjugated polymers and their performance in bulk heterojunction (BHJ) solar cells has been studied extensively, analogous studies on pyrrolo-perylene-based polymers have not received adequate attention. To explore these effects, we synthesized two copolymers based on N-annulated pyrrolo-perylene and consisting of cyano group substituents on thiophene vinylene thiophene units with two different alkyl groups of 2-decyltetradecyl and 7-decylnonadecyl, and we studied them with regard to chemical structure and photovoltaic performance. UV-vis spectroscopy and cyclic voltammetry studies showed that variations in alkyl chain length affect crystallization, light absorption, and the highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels. These factors have a pronounced impact on the morphology of BHJ thin films and their charge carrier separation and transportation characteristics, which, in turn, influences photovoltaic properties. PMID- 25836745 TI - HLA class II alleles in the Otomi population of the Mezquital Valley: a genetic approach to the history of interethnic migrations in the Mexican Central Plateau. AB - From a historical and genetic point of view, the Otomi of the Mezquital Valley are a frontier people that have played an important role in the population dynamics of the Mexican Central Plateau. Due to the antiquity of their presence in the area, the Otomi may be bearers of ancient genetic variability, shared mainly today with other groups belonging to the Otomanguean linguistic family and with the Nahua. In this study we analyzed the HLA class II allele frequencies reported in Mexican indigenous populations, in order to provide an intraregional level historical perspective of the genetic relationships between the Otomi of the Mezquital Valley and indigenous populations from other regions of Mexico. We examined genetic variation in HLA-DRB1 and -DQB1 loci in 66 nonrelated individuals belonging to seven indigenous communities from the Ixmiquilpan municipality in the Mezquital Valley, in the State of Hidalgo, Mexico. The variability of the HLA-DRB1 gene among the Otomi of the Mezquital Valley was mainly concentrated in five alleles: -DRB1*08:02 (31.06%), -DRB1*04:07 (25.77%), DRB1*14:06 (7.55%), -DRB1*14:02 (6.06%), and -DRB1*16:02 (4.55%); these alleles have been previously described in other indigenous populations. The most frequent alleles at the HLA-DQB1 locus were -DQB1*03:02 (34.09%), -DQB1*04:02 (31.03%), and -DQB1*03:01 (19.7%). Furthermore, the HLA-DQB1*02:02 allele was found in the Otomi group with a frequency of 2.27%; this allele has not been reported in Mexican indigenous populations. In conclusion, the genetic constitution of the Otomi population is intermediate to the northern groups and the genetic variability shared by the peoples of the central regions of Mexico. Furthermore, HLA-DRB1 and -DQB1 allelic variability among the Otomi provides insight into the historical processes implied in the biological admixture with European, Asian, and African populations as well as in the admixture with the population of Mexico City associated with long-standing migratory processes. PMID- 25836746 TI - A homogenizing process of selection has maintained an "ultra-slow" acetylation NAT2 variant in humans. AB - N-Acetyltransferase 2 (NAT2) is an important enzyme involved in the metabolism of a wide spectrum of naturally occurring xenobiotics, including therapeutic drugs and common environmental carcinogens. Extensive polymorphism in NAT2 gives rise to a wide interindividual variation in acetylation capacity, which influences individual susceptibility to various drug-induced adverse reactions and cancers. Striking patterns of geographic differentiation have been described for the main slow acetylation variants of the NAT2 gene, suggesting the action of natural selection at this locus. In the present study, we took advantage of whole-genome sequence data available from the 1000 Genomes project to investigate the global patterns of population genetic differentiation at NAT2 and determine whether they are atypical compared with the remaining variation of the genome. The nonsynonymous substitution c.590G>A (rs1799930) defining the slow NAT2*6 haplotype cluster exhibited an unusually low FST value compared with the genome average (FST = 0.006, P = 0.016). It was indicated as the most likely target of a homogenizing process of selection promoting the same allelic variant in globally distributed populations. The rs1799930 A allele has been associated with the slowest acetylation capacity in vivo, and its substantial correlation with the subsistence strategy adopted by past human populations suggests that it may have conferred a selective advantage in populations shifting from foraging to agricultural and pastoral activities in the Neolithic period. Results of neutrality tests further supported an adaptive evolution of the NAT2 gene through either balancing selection or directional selection acting on multiple standing slow acetylation variants. PMID- 25836752 TI - Dance for PD: a preliminary investigation of effects on motor function and quality of life among persons with Parkinson's disease (PD). AB - In 2001, Dance for Parkinson's disease (DfPD((r))) classes for persons with Parkinson's disease and care partners were developed by Brooklyn Parkinson Group and Mark Morris Dance Group. A previous assessment suggested that individuals experience positive benefits from DfPD((r)). The current preliminary uncontrolled study investigated the effects of a dance intervention on several motor and quality of life aspects of PD following 16 sessions (8 weeks; 20 h) taught by professional dancers/teachers. A mixed methods design was used to determine the effects of the class. Assessment instruments administered at baseline and post intervention included the Hoehn and Yahr, UPDRS (part III), Berg Balance Scale, Beck Depression Inventory, and PDQ-39 and individual interviews after the last class. Hoehn and Yahr scores ranged from 1 to 4. UPDRS III total scores and sub scores of gait and tremor improved following the intervention (P < 0.05). During interviews participants reported physical, emotional, and social benefits. Despite the diversity of baseline measures post-class interview results were consistently positive across the sample. Twelve of 14 subjects (mean age 66.2) with idiopathic PD completed the sessions. After 4 years, four participants regularly attended DfPD((r)) classes. The low attrition rate and continued attendance suggest notable adherence to the DfPD((r)) class. The importance of the results is both clinical and conceptual, highlighting the value of using both quantitative and qualitative data to evaluate the benefits of dance with PD. PMID- 25836744 TI - Population genetic structure of traditional populations in the Peruvian Central Andes and implications for South American population history. AB - Molecular-based characterizations of Andean peoples are traditionally conducted in the service of elucidating continent-level evolutionary processes in South America. Consequently, genetic variation among "western" Andean populations is often represented in relation to variation among "eastern" Amazon and Orinoco River Basin populations. This west-east contrast in patterns of population genetic variation is typically attributed to large-scale phenomena, such as dual founder colonization events or differing long-term microevolutionary histories. However, alternative explanations that consider the nature and causes of population genetic diversity within the Andean region remain underexplored. Here we examine population genetic diversity in the Peruvian Central Andes using data from the mtDNA first hypervariable region and Y-chromosome short tandem repeats among 17 newly sampled populations and 15 published samples. Using this geographically comprehensive data set, we first reassessed the currently accepted pattern of western versus eastern population genetic structure, which our results ultimately reject: mtDNA population diversities were lower, rather than higher, within Andean versus eastern populations, and only highland Y-chromosomes exhibited significantly higher within-population diversities compared with eastern groups. Multiple populations, including several highland samples, exhibited low genetic diversities for both genetic systems. Second, we explored whether the implementation of Inca state and Spanish colonial policies starting at about ad 1400 could have substantially restructured population genetic variation and consequently constitute a primary explanation for the extant pattern of population diversity in the Peruvian Central Andes. Our results suggest that Peruvian Central Andean population structure cannot be parsimoniously explained as the sole outcome of combined Inca and Spanish policies on the region's population demography: highland populations differed from coastal and lowland populations in mtDNA genetic structure only; highland groups also showed strong evidence of female-biased gene flow and/or effective sizes relative to other Peruvian ecozones. Taken together, these findings indicate that population genetic structure in the Peruvian Central Andes is considerably more complex than previously reported and that characterizations of and explanations for genetic variation may be best pursued within more localized regions and defined time periods. PMID- 25836754 TI - Strain engineering the work function in monolayer metal dichalcogenides. AB - We use first-principles density functional theory to investigate the effect of both tensile and compressive strain on the work functions of various metal dichalcogenide monolayers. We find that for all six species considered, including MoS2, WS2, SnS2, VS2, MoSe2 and MoTe2, that compressive strain of up to 10% decreases the work function continuously by as much as 1.0 eV. Large enough tensile strain is also found to decrease the work function, although in some cases we observe an increase in the work function for intermediate values of tensile strain. This work function modulation is attributed to a weakening of the chalcogenide-metal bonds and an increase in total energy of each system as a function of strain. Values of strain which bring the metal atoms closer together lead to an increase in electrostatic potential energy, which in turn results in an increase in the vacuum potential level. The net effect on the work function can be explained in terms of the balance between the increases in the vacuum potential levels and Fermi energy. PMID- 25836753 TI - Sensitivity and specificity of a novel classifier for the early diagnosis of dengue. AB - BACKGROUND: Dengue is the commonest arboviral disease of humans. An early and accurate diagnosis of dengue can support clinical management, surveillance and disease control and is central to achieving the World Health Organisation target of a 50% reduction in dengue case mortality by 2020. METHODS: 5729 children with fever of <72 hrs duration were enrolled into this multicenter prospective study in southern Vietnam between 2010-2012. A composite of gold standard diagnostic tests identified 1692 dengue cases. Using statistical methods, a novel Early Dengue Classifier (EDC) was developed that used patient age, white blood cell count and platelet count to discriminate dengue cases from non-dengue cases. RESULTS: The EDC had a sensitivity of 74.8% (95%CI: 73.0-76.8%) and specificity of 76.3% (95%CI: 75.2-77.6%) for the diagnosis of dengue. As an adjunctive test alongside NS1 rapid testing, sensitivity of the composite test was 91.6% (95%CI: 90.4-92.9%). CONCLUSIONS: We demonstrate that the early diagnosis of dengue can be enhanced beyond the current standard of care using a simple evidence-based algorithm. The results should support patient management and clinical trials of specific therapies. PMID- 25836755 TI - Impact of chronic lead exposure on metal distribution and biological effects to periphyton. AB - Chronic Pb exposure microcosm studies were carried out on two different periphyton communities over the course of 3 weeks to link Pb distribution to biological effects in periphyton. We show that three-week exposures of periphyton to 20.6 +/- 0.4 MUM PbT (330 nM Pb(2+)) did not have observable biological effects on photosynthesis, respiration, extracellular enzymatic activities, or biomass accrual. Metal distribution studies showed that the majority of Pb was associated with the operationally defined sorbed and non-EDTA-exchangeable fractions, and relatively little with extracellular polymeric substances (EPS). No significant effects of Pb on Fe and Mn distributions were observed, whereas higher Cu accumulation occurred from increased free Cu(2+) in the exposure medium. High Fe:C and Mn:C ratios indicated the presence of inorganic Fe and Mn material associated with the non-EDTA-exchangeable fraction, which likely sequesters Pb and explains the absence of measurable biological effects. Although no toxic effects of Pb were observed on the periphytic organisms themselves, periphyton can be a significant source of Pb to grazing organisms in aquatic ecosystems. PMID- 25836757 TI - Model development for the assessment of terrestrial and aquatic habitat quality in conservation planning. AB - There is a growing pressure of human activities on natural habitats, which leads to biodiversity losses. To mitigate the impact of human activities, environmental policies are developed and implemented, but their effects are commonly not well understood because of the lack of tools to predict the effects of conservation policies on habitat quality and/or diversity. We present a straightforward model for the simultaneous assessment of terrestrial and aquatic habitat quality in river basins as a function of land use and anthropogenic threats to habitat that could be applied under different management scenarios to help understand the trade-offs of conservation actions. We modify the InVEST model for the assessment of terrestrial habitat quality and extend it to freshwater habitats. We assess the reliability of the model in a severely impaired basin by comparing modeled results to observed terrestrial and aquatic biodiversity data. Estimated habitat quality is significantly correlated with observed terrestrial vascular plant richness (R(2)=0.76) and diversity of aquatic macroinvertebrates (R(2)=0.34), as well as with ecosystem functions such as in-stream phosphorus retention (R(2)=0.45). After that, we analyze different scenarios to assess the suitability of the model to inform changes in habitat quality under different conservation strategies. We believe that the developed model can be useful to assess potential levels of biodiversity, and to support conservation planning given its capacity to forecast the effects of management actions in river basins. PMID- 25836758 TI - Monitoring drinking water, sanitation, and hygiene in non-household settings: Priorities for policy and practice. AB - Inadequate drinking water, sanitation, and hygiene (WaSH) in non-household settings, such as schools, health care facilities, and workplaces impacts the health, education, welfare, and productivity of populations, particularly in low and middle-income countries. There is limited knowledge on the status of WaSH in such settings. To address this gap, we reviewed international standards, international and national actors, and monitoring initiatives; developed the first typology of non-household settings; and assessed the viability of monitoring. Based on setting characteristics, non-household settings include six types: schools, health care facilities, workplaces, temporary use settings, mass gatherings, and dislocated populations. To-date national governments and international actors have focused monitoring of non-household settings on schools and health care facilities with comparatively little attention given to other settings such as workplaces and markets. Nationally representative facility surveys and national management information systems are the primary monitoring mechanisms. Data suggest that WaSH coverage is generally poor and often lower than in corresponding household settings. Definitions, indicators, and data sources are underdeveloped and not always comparable between countries. While not all countries monitor non-household settings, examples are available from countries on most continents suggesting that systematic monitoring is achievable. Monitoring WaSH in schools and health care facilities is most viable. Monitoring WaSH in other non-household settings would be viable with: technical support from local and national actors in addition to international organizations such as WHO and UNICEF; national prioritization through policy and financing; and including WaSH indicators into monitoring initiatives to improve cost-effectiveness. International consultations on targets and indicators for global monitoring of WaSH post-2015 identified non-household settings as a priority. National and international monitoring systems will be important to better understand status, trends, to identify priorities and target resources accordingly, and to improve accountability for progressive improvements in WaSH in non-household settings. PMID- 25836759 TI - Is the fact of parenting couples cohabitation affecting the serum levels of persistent organohalogen pollutants? AB - Organohalogen compounds constitute one of the important groups of persistent organic pollutants (POPs). Among them, due to their long-term health effects, one should pay attention on organochlorine pesticides, polychlorinated biphenyls (PCBs) and perfluoroalkylated substances (PFASs). This paper is an attempt to answer the question about relation between the fact of cohabitation by couples expecting a child and the level of the organohalogen compounds in the blood serum of both parents. The study was done on a population of parent couples from Greenland, Poland and Ukraine, from whom blood samples were collected in order to establish the levels of marker organohalogen compounds. We selected, as the representative of these compounds, the most persistent metabolite of DDT, i.e. p,p'-DDE, the most frequently detected PCB congener - CB-153, and PFOS and PFOA as the representatives of PFASs. The results show that in case of all compounds under study the highest concentrations were present always in men in relation to the levels detected in the blood serum of their female partners, regardless of the country of origin of the couple. A positive correlation was noted between the concentrations of the studied compounds in the blood serum of men and women in parenting couples. In some cases these correlations were statistically significant, e.g. for concentrations of p,p'-DDE in pairs from Greenland and Ukraine, of CB-153 in pairs from Poland and Ukraine, and of PFOS for parents from Greenland and Poland, while for PFOA - only for couples from Greenland. The concentrations of the compounds included in the study were similar to the levels found in general population in other countries. Our results show that the exposure to POPs resulting from cohabitation plays a role in the general exposure to these compounds. PMID- 25836760 TI - Multicomponent Nanomaterials with Complex Networked Architectures from Orthogonal Degradation and Binary Metal Backfilling in ABC Triblock Terpolymers. AB - Selective degradation of block copolymer templates and backfilling the open mesopores is an effective strategy for the synthesis of nanostructured hybrid and inorganic materials. Incorporation of more than one type of inorganic material in orthogonal ways enables the synthesis of multicomponent nanomaterials with complex yet well-controlled architectures; however, developments in this field have been limited by the availability of appropriate orthogonally degradable block copolymers for use as templates. We report the synthesis and self-assembly into cocontinuous network structures of polyisoprene-block-polystyrene-block poly(propylene carbonate) where the polyisoprene and poly(propylene carbonate) blocks can be orthogonally removed from the polymer film. Through sequential block etching and backfilling the resulting mesopores with different metals, we demonstrate first steps toward the preparation of three-component polymer inorganic hybrid materials with two distinct metal networks. Multiblock copolymers in which two blocks can be degraded and backfilled independently of each other, without interference from the other, may be used in a wide range of applications requiring periodically ordered complex multicomponent nanoarchitectures. PMID- 25836761 TI - Editor's Spotlight/Take 5: Future Patient Demand for Shoulder Arthroplasty by Younger Patients: National Projections. PMID- 25836756 TI - Transcriptional and epigenetic regulation of autophagy in aging. AB - Macroautophagy is a major intracellular degradation process recognized as playing a central role in cell survival and longevity. This multistep process is extensively regulated at several levels, including post-translationally through the action of conserved longevity factors such as the nutrient sensor TOR. More recently, transcriptional regulation of autophagy genes has emerged as an important mechanism for ensuring the somatic maintenance and homeostasis necessary for a long life span. Autophagy is increased in many long-lived model organisms and contributes significantly to their longevity. In turn, conserved transcription factors, particularly the helix-loop-helix transcription factor TFEB and the forkhead transcription factor FOXO, control the expression of many autophagy-related genes and are important for life-span extension. In this review, we discuss recent progress in understanding the contribution of these transcription factors to macroautophagy regulation in the context of aging. We also review current research on epigenetic changes, such as histone modification by the deacetylase SIRT1, that influence autophagy-related gene expression and additionally affect aging. Understanding the molecular regulation of macroautophagy in relation to aging may offer new avenues for the treatment of age-related diseases. PMID- 25836762 TI - Your Best Life: Perfectionism--The Bane of Happiness. PMID- 25836763 TI - Chromatin modifiers and histone modifications in bone formation, regeneration, and therapeutic intervention for bone-related disease. AB - Post-translational modifications of chromatin such as DNA methylation and different types of histone acetylation, methylation and phosphorylation are well appreciated epigenetic mechanisms that confer information to progeny cells during lineage commitment. These distinct epigenetic modifications have defined roles in bone, development, tissue regeneration, cell commitment and differentiation, as well as disease etiologies. In this review, we discuss the role of these chromatin modifications and the enzymes regulating these marks (methyltransferases, demethylases, acetyltransferases, and deacetylases) in progenitor cells, osteoblasts and bone-related cells. In addition, the clinical relevance of deregulated histone modifications and enzymes as well as current and potential therapeutic interventions targeting chromatin modifiers are addressed. PMID- 25836764 TI - In vivo mechanical loading rapidly activates beta-catenin signaling in osteocytes through a prostaglandin mediated mechanism. AB - The response of the skeleton to loading appears to be mediated through the activation of the Wnt/beta-catenin signaling pathway and osteocytes have long been postulated to be the primary mechanosensory cells in bone. To examine the kinetics of the mechanoresponse of bone and cell types involved in vivo, we performed forearm loading of 17-week-old female TOPGAL mice. beta-catenin signaling was observed only in embedded osteocytes, not osteoblasts, at 1h post loading, spreading to additional osteocytes and finally to cells on the bone surface by 24h. This early activation at 1h appeared to be independent of receptor (Lrp5/6) mediated activation as it occurred in the presence of the inhibitors sclerostin and/or Dkk1. The COX-2 inhibitor, Carprofen, blocked the activation of beta-catenin signaling and decline in sclerostin positive osteocytes post-loading implying an important role for prostaglandin. In vitro, PI3K/Akt activation was shown to be required for beta-catenin nuclear translocation downstream from prostaglandin in MLO-Y4 osteocyte-like cells supporting this mechanism. Downstream targets of beta-catenin signaling, sclerostin and Dkk1, were also examined and found to be significantly downregulated in osteocytes in vivo at 24h post-loading. The pattern of initially activated osteocytes appeared random and in order to understand this heterogeneous expression, a novel finite element model of the strain field in the ulna was developed, which predicts highly variable local magnitudes of strain experienced by osteocytes. In summary, both in vivo and in vitro models show the rapid activation of beta-catenin in response to load through the early release of prostaglandin and that strain fields in the bone are extremely heterogeneous resulting in heterogeneous activation of the beta-catenin pathway in osteocytes in vivo. PMID- 25836765 TI - Low attention impairs optimal incorporation of prior knowledge in perceptual decisions. AB - When visual attention is directed away from a stimulus, neural processing is weak and strength and precision of sensory data decreases. From a computational perspective, in such situations observers should give more weight to prior expectations in order to behave optimally during a discrimination task. Here we test a signal detection theoretic model that counter-intuitively predicts subjects will do just the opposite in a discrimination task with two stimuli, one attended and one unattended: when subjects are probed to discriminate the unattended stimulus, they rely less on prior information about the probed stimulus' identity. The model is in part inspired by recent findings that attention reduces trial-by-trial variability of the neuronal population response and that they use a common criterion for attended and unattended trials. In five different visual discrimination experiments, when attention was directed away from the target stimulus, subjects did not adjust their response bias in reaction to a change in stimulus presentation frequency despite being fully informed and despite the presence of performance feedback and monetary and social incentives. This indicates that subjects did not rely more on the priors under conditions of inattention as would be predicted by a Bayes-optimal observer model. These results inform and constrain future models of Bayesian inference in the human brain. PMID- 25836767 TI - Eosinophilic granulomatosis with polyangiitis (EGPA) and PRES: a case-based review of literature in ANCA-associated vasculitides. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-sized vessel systemic necrotizing vasculitis and belongs to the family of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The involvement of central nervous system in this condition is pretty rare. Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity described for the first time by Hinchey et al. (N Engl J Med 334(8):494-500, 1996) and characterized by MRI findings of reversible subcortical vasogenic edema predominantly in the white matter of posterior cerebral lobes. There are few case reports describing the concurrence of PRES with ANCA-associated vasculitides. We describe a case of PRES in a patient with a diagnosis of EGPA with a concise review of the literature. The exact cause of this syndrome is unknown. It has been related to eclampsia, drug-induced hypertension, renal insufficiency and also to rheumatologic diseases. Endothelial injury, hypertension and immunosuppressive medications can compromise the regulation of cerebral blood flow. In ANCA-associated vasculitides, patients presenting with symptoms of PRES represent a challenge to treatment with immunosuppressive medications. However, since an inflammatory process might be implicated, judicious use of these agents along with tight control of blood pressure and a supportive therapy may contribute to the resolution of the encephalopathic syndrome treating at the same time other manifestation related to the rheumatologic disease. Larger clinical studies are warranted to optimize the management of vasculitis-associated PRES. PMID- 25836768 TI - Effect of mycophenolate mofetil on the white blood cell count and the frequency of infection in systemic lupus erythematosus. AB - Leukopenia is a common manifestation of SLE. Addition of immunosuppressive therapy in a SLE patient who is already leukopenic is a clinical concern. It could worsen leukopenia, increase the risk of infection, or both. The aim of this study was to analyze the immediate effect of mycophenolate mofetil on the white blood cell count and the rate of infection in SLE patients. Two hundred and forty four patients within the Hopkins Lupus Cohort who were newly started on mycophenolate mofetil were included in the study. The white blood cell count and interval infection history on the day mycophenolate mofetil was started were compared with the white blood cell count and interval infection history at the next visit. The study was based on 244 patients who began taking mycophenolate mofetil in the cohort. The study population included 47 % African Americans, 44 % Caucasians, and 9 % other ethnicities. There was a slight but not statistically significant increase in the white blood cell count (6.63 vs. 7.01), after starting mycophenolate mofetil. Patients with a baseline white blood cell count <3000/mm(3) did have a statistically significant increase in the white blood cell count after starting mycophenolate mofetil (2.57 vs. 5.13, P = 0.0047). We also found a statistically significant increase in the risk of bacterial infection (but not viral infection) after starting mycophenolate mofetil (4 vs. 9 %, P = 0.0036). Leukopenia does not worsen with mycophenolate mofetil. However, mycophenolate mofetil appears to slightly increase the rate of bacterial (but not viral) infection. PMID- 25836769 TI - Transient receptor potential melastatin-4 is involved in hypoxia-reoxygenation injury in the cardiomyocytes. AB - Ischemic heart disease still remains the most common cause of cardiac death. During ischemia-reperfusion (I/R), reactive oxygen species (ROS) are produced in excess in cardiac tissue, where they induce cell death. Our previous study showed that 9-phenanthrol (9-Phe), a specific inhibitor of the TRPM4 channel, preserves cardiac contractile function and protects the heart from I/R injury-related infarction in the excised rat heart. Accordingly, we hypothesized that TRPM4 channels are involved in the 9-Phe-mediated cardioprotection against ROS-induced injury. In rats, intravenous 9-Phe mitigated the development of myocardial infarction caused by the occlusion of the left anterior descending artery. Immunohistochemical analysis indicated that TRPM4 proteins are expressed in ventricular myocytes susceptible to I/R injury. Hydrogen peroxide (H2O2) is among the main ROS overproduced during I/R. In the cardiomyocyte cell line H9c2, pretreatment with 9-Phe prevented cell death induced by conditions mimicking I/R, namely 200 MUM H2O2 and hypoxia-reoxygenation. Gene silencing of TRPM4 preserved the viability of H9c2 cardiomyocytes exposed to 200 MUM H2O2. These results suggest that the cardioprotective effects of 9-Phe are mediated through the inhibition of the TRPM4 channels. PMID- 25836766 TI - Selection and spread of artemisinin-resistant alleles in Thailand prior to the global artemisinin resistance containment campaign. AB - The recent emergence of artemisinin resistance in the Greater Mekong Subregion poses a major threat to the global effort to control malaria. Tracking the spread and evolution of artemisinin-resistant parasites is critical in aiding efforts to contain the spread of resistance. A total of 417 patient samples from the year 2007, collected during malaria surveillance studies across ten provinces in Thailand, were genotyped for the candidate Plasmodium falciparum molecular marker of artemisinin resistance K13. Parasite genotypes were examined for K13 propeller mutations associated with artemisinin resistance, signatures of positive selection, and for evidence of whether artemisinin-resistant alleles arose independently across Thailand. A total of seven K13 mutant alleles were found (N458Y, R539T, E556D, P574L, R575K, C580Y, S621F). Notably, the R575K and S621F mutations have previously not been reported in Thailand. The most prevalent artemisinin resistance-associated K13 mutation, C580Y, carried two distinct haplotype profiles that were separated based on geography, along the Thai Cambodia and Thai-Myanmar borders. It appears these two haplotypes may have independent evolutionary origins. In summary, parasites with K13 propeller mutations associated with artemisinin resistance were widely present along the Thai-Cambodia and Thai-Myanmar borders prior to the implementation of the artemisinin resistance containment project in the region. PMID- 25836770 TI - Effects of chronic exposure to electromagnetic waves on the auditory system. AB - CONCLUSION: The results support that chronic electromagnetic field exposure may cause damage by leading to neuronal degeneration of the auditory system. OBJECTIVES: Numerous researches have been done about the risks of exposure to the electromagnetic fields that occur during the use of these devices, especially the effects on hearing. The aim of this study is to evaluate the effects of the electromagnetic waves emitted by the mobile phones through the electrophysiological and histological methods. METHODS: Twelve adult Wistar albino rats were included in the study. The rats were divided into two groups of six rats. The study group was exposed to the electromagnetic waves over a period of 30 days. The control group was not given any exposure to the electromagnetic fields. After the completion of the electromagnetic wave application, the auditory brainstem responses of both groups were recorded under anesthesia. The degeneration of cochlear nuclei was graded by two different histologists, both of whom were blinded to group information. RESULTS: The histopathologic and immunohistochemical analysis showed neuronal degeneration signs, such as increased vacuolization in the cochlear nucleus, pyknotic cell appearance, and edema in the group exposed to the electromagnetic fields compared to the control group. The average latency of wave in the ABR was similar in both groups (p > 0.05). PMID- 25836771 TI - In vitro selection of deoxyribozymes active with Cd(2+) ions resulting in variants of DNAzyme 8-17. AB - In vitro selection was performed to search for RNA-cleaving DNAzymes catalytically active with Cd(2+) ions from the oligonucleotide combinatorial library with a 23-nucleotide random region. All the selected, catalytically active variants turned out to belong to the 8-17 type DNAzyme. Three DNAzymes were prepared in shortened, cis-acting versions which were subjected to a detailed study of the kinetic properties and metal ion preferences. Although the selection protocol was designed for Cd(2+)-dependent DNAzymes, the variants showed broader metal ion specificity. They preferred Cd(2+) but were also active with Mn(2+) and Zn(2+), suggesting that binding of the catalytic ion does not require an extremely specific coordination pattern. The unexpected decrease of the catalytic activity of the variants along with the temperature increase suggested that some changes occurred in their structures or the rate-limiting step of the reaction was changed. Two elements of the catalytic core of DNAzyme 1/VIIWS, the nucleotide at position 12 and the three-base-pair hairpin motif, were mutated. The presence of a purine residue at position 12 was crucial for the catalytic activity but the changes at that position had a relatively small influence on the metal ion preferences of this variant. The middle base pair of the three-base-pair hairpin was changed from A-T to C-G interaction. The catalytic activity of the mutated variant was increased with Zn(2+), decreased with Mn(2+), and was not changed in the presence of Cd(2+) ions. Clearly, this base pair was important for defining the metal ion preferences of the DNAzyme 1/VIIWS. PMID- 25836772 TI - TV-based conjugate gradient method and discrete L-curve for few-view CT reconstruction of X-ray in vivo data. AB - High-resolution, three-dimensional (3D) imaging of soft tissues requires the solution of two inverse problems: phase retrieval and the reconstruction of the 3D image from a tomographic stack of two-dimensional (2D) projections. The number of projections per stack should be small to accommodate fast tomography of rapid processes and to constrain X-ray radiation dose to optimal levels to either increase the duration of in vivo time-lapse series at a given goal for spatial resolution and/or the conservation of structure under X-ray irradiation. In pursuing the 3D reconstruction problem in the sense of compressive sampling theory, we propose to reduce the number of projections by applying an advanced algebraic technique subject to the minimisation of the total variation (TV) in the reconstructed slice. This problem is formulated in a Lagrangian multiplier fashion with the parameter value determined by appealing to a discrete L-curve in conjunction with a conjugate gradient method. The usefulness of this reconstruction modality is demonstrated for simulated and in vivo data, the latter acquired in parallel-beam imaging experiments using synchrotron radiation. PMID- 25836773 TI - Boosting light emission from Si-based thin film over Si and SiO(2) nanowires architecture. AB - Silicon (Si)-based light emitting thin film has been a key ingredient for all-Si based optoelectronics. Besides material engineering, adopting a novel 3D photonic architecture represents an effective strategy to boost light excitation and extraction from Si-based thin film material. We here explore the use of a nanowires (NW) framework, grown via vapor-liquid-solid mode, to achieve strongly enhanced yellow-green luminescence from SiN(x)O(y)/NW core-shell structure, with an order of magnitude enhancement compared to co-deposited planar references. We found that choosing geometrically-identical but different NW cores (Si or SiO(2)) can lead to profound influence on the overall light emission performance. Combining parametric investigation and theoretical modeling, we have been able to evaluate the key contributions arising from different mechanisms that include near-field enhancement, 3D light trapping and enhanced light extraction. These new findings indicate a new and effective strategy for strong Si-based thin film light emitting source, while being generic enough to be applicable in a wide variety of other thin film materials. PMID- 25836774 TI - Damage threshold of platinum coating used for optics for self-seeding of soft X ray free electron laser. AB - We investigated the experimental damage threshold of platinum coating on a silicon substrate illuminated by soft x-ray radiation at grazing incidence angle of 2 degrees. The coating was the same as the blazed grating used for the soft X ray self-seeding optics of the Linac Coherent Light Source free electron laser. The irradiation condition was chosen such that the absorbed dose was similar to the maximum dose expected for the grating. The expected dose was simulated by solving the Helmholtz equation in non-homogenous media. The experiment was performed at 900 eV photon energy for both single pulse and multi-shot conditions. We have not observed single shot damage. This corresponds to a single shot damage threshold being higher than 3 J/cm(2). The multiple shot damage threshold measured for 10 shots and about 600 shots was determined to be 0.95 J/cm(2) and 0.75 J/cm(2) respectively. The damage threshold occurred at an instantaneous dose which is higher that the melt dose of platinum. PMID- 25836775 TI - Coherent beam combining with an ultrafast multicore Yb-doped fiber amplifier. AB - Active coherent beam combination using a 7-non-coupled core, polarization maintaining, air-clad, Yb-doped fiber is demonstrated as a monolithic and compact power-scaling concept for ultrafast fiber lasers. A microlens array matched to the multicore fiber and an active phase controller composed of a spatial light modulator applying a stochastic parallel gradient descent algorithm are utilized to perform coherent combining in the tiled aperture geometry. The mitigation of nonlinear effects at a pulse energy of 8.9 uJ and duration of 860 fs is experimentally verified at a repetition rate of 100 kHz. The experimental combining efficiency results in a far field central lobe carrying 49% of the total power, compared to an ideal value of 76%. This efficiency is primarily limited by group delay differences between cores which is identified as the main drawback of the system. Minimizing these group delay issues, e.g. by using short and straight rod-type multicore fibers, should allow a practical power scaling solution for femtosecond fiber systems. PMID- 25836776 TI - Development of ocean color algorithms for estimating chlorophyll-a concentrations and inherent optical properties using gene expression programming (GEP). AB - This paper proposes new inversion algorithms for the estimation of Chlorophyll-a concentration (Chla) and the ocean's inherent optical properties (IOPs) from the measurement of remote sensing reflectance (Rrs). With in situ data from the NASA bio-optical marine algorithm data set (NOMAD), inversion algorithms were developed by the novel gene expression programming (GEP) approach, which creates, manipulates and selects the most appropriate tree-structured functions based on evolutionary computing. The limitations and validity of the proposed algorithms are evaluated by simulated Rrs spectra with respect to NOMAD, and a closure test for IOPs obtained at a single reference wavelength. The application of GEP derived algorithms is validated against in situ, synthetic and satellite match-up data sets compiled by NASA and the International Ocean Color Coordinate Group (IOCCG). The new algorithms are able to provide Chla and IOPs retrievals to those derived by other state-of-the-art regression approaches and obtained with the semi- and quasi-analytical algorithms, respectively. In practice, there are no significant differences between GEP, support vector regression, and multilayer perceptron model in terms of the overall performance. The GEP-derived algorithms are successfully applied in processing the images taken by the Sea Wide Field-of view Sensor (SeaWiFS), generate Chla and IOPs maps which show better details of developing algal blooms, and give more information on the distribution of water constituents between different water bodies. PMID- 25836778 TI - Evaluation of partial coherence correction in X-ray ptychography. AB - Coherent X-ray Diffraction Imaging (CDI) and X-ray ptychography both heavily rely on the high degree of spatial coherence of the X-ray illumination for sufficient experimental data quality for reconstruction convergence. Nevertheless, the majority of the available synchrotron undulator sources have a limited degree of partial coherence, leading to reduced data quality and a lower speckle contrast in the coherent diffraction patterns. It is still an open question whether experimentalists should compromise the coherence properties of an X-ray source in exchange for a higher flux density at a sample, especially when some materials of scientific interest are relatively weak scatterers. A previous study has suggested that in CDI, the best strategy for the study of strong phase objects is to maintain a high degree of coherence of the illuminating X-rays because of the broadening of solution space resulting from the strong phase structures. In this article, we demonstrate the first systematic analysis of the effectiveness of partial coherence correction in ptychography as a function of the coherence properties, degree of complexity of illumination (degree of phase diversity of the probe) and sample phase complexity. We have also performed analysis of how well ptychographic algorithms refine X-ray probe and complex coherence functions when those variables are unknown at the start of reconstructions, for noise-free simulated data, in the case of both real-valued and highly-complex objects. PMID- 25836777 TI - Continuous motion scan ptychography: characterization for increased speed in coherent x-ray imaging. AB - Ptychography is a coherent diffraction imaging (CDI) method for extended objects in which diffraction patterns are acquired sequentially from overlapping coherent illumination spots. The object's complex transmission function can be reconstructed from those diffraction patterns at a spatial resolution limited only by the scattering strength of the object and the detector geometry. Most experiments to date have positioned the illumination spots on the sample using a move-settle-measure sequence in which the move and settle steps can take longer to complete than the measure step. We describe here the use of a continuous "fly scan" mode for ptychographic data collection in which the sample is moved continuously, so that the experiment resembles one of integrating the diffraction patterns from multiple probe positions. This allows one to use multiple probe mode reconstruction methods to obtain an image of the object and also of the illumination function. We show in simulations, and in x-ray imaging experiments, some of the characteristics of fly-scan ptychography, including a factor of 25 reduction in the data acquisition time. This approach will become increasingly important as brighter x-ray sources are developed, such as diffraction limited storage rings. PMID- 25836779 TI - Research of far-field diffraction intensity pattern in hot atomic Rb sample. AB - In this work we present a study of the far-field diffraction intensity patterns in the Rb atomic medium. It is found that the far-field diffraction intensity patterns are intimately related to the incident frequency, power, the atomic number density and the position of the sample. The results demonstrate that the far-field diffraction intensity patterns can sensitively reflect the nonlinear optical properties of the medium. The information obtained is of meaning in the application fields, such as the nonlinearity of the medium measuring, optical limiting. PMID- 25836780 TI - High performance, low dissipation quantum cascade lasers across the mid-IR range. AB - In this work, we present the development of low consumption quantum cascade lasers across the mid-IR range. In particular, short cavity single-mode lasers with optimised facet reflectivities have been fabricated from 4.5 to 9.2 MUm. Threshold dissipated powers as low as 0.5 W were obtained in continuous wave operation at room temperature. In addition, the beneficial impact of reducing chip length on laser mounting yield is discussed. High power single-mode lasers from the same processed wafers are also presented. PMID- 25836782 TI - Sensing nitrous oxide with QCL-coupled silicon-on-sapphire ring resonators. AB - We report the initial evaluation of a mid-infrared QCL-coupled silicon-on sapphire ring resonator gas sensor. The device probes the N(2)O 2241.79 cm(-1) optical transition (R23 line) in the nu(3) vibrational band. N(2)O concentration is deduced using a non-linear least squares fit, based on coupled-mode theory, of the change in ring resonator Q due to gas absorption losses in the evanescent portion of the waveguide optical mode. These early experiments demonstrated response to 5000 ppmv N(2)O. PMID- 25836781 TI - 1.01 kW superfluorescent source in all-fiberized MOPA configuration. AB - We present a high power all-fiberized master oscillator power amplifier (MOPA) structured superfluorescent source based on dual-cladding ytterbium-doped fiber. The seed source is a 0.814 W homemade amplified spontaneous emission (ASE) source. Two-stage high power fiber amplifier is utilized to boost the seed power to 1.01 kW with a beam quality of M(x)(2) = 1.688 and M(y)(2) = 1.728. The central wavelength of the output light is 1074.4 nm, and the full width at half maximum (FWHM) linewidth is about 8.1 nm. No self pulsing or relaxation oscillation effect is observed and the power fluctuation is less than 2% in 100 seconds continuous operating. In additional, spectral evolution effects of central-wavelength-drifting and linewidth-narrowing of broadband amplification in high power superfluorescent source system are investigated. To the best of our knowledge, this is the first demonstration of an all-fiberized superfluorescent source with output power exceeding kilowatt. PMID- 25836783 TI - Double bi-material cantilever structures for complex surface plasmon modulation. AB - A complex modulation structure of surface plasmon polaritons using double bi material cantilevers is proposed. It is shown with numerical analysis that the thermally controlled mechanical actuation of double bi-material cantilevers can modulate the amplitude and phase of surface plasmon polaritons across a full complex modulation range independently and simultaneously. The complex modulation structures designed for visible wavelengths are presented and their multi wavelength integration is discussed. PMID- 25836784 TI - Compensation of spectral and RF errors in swept-source OCT for high extinction complex demodulation. AB - We provide a framework for compensating errors within passive optical quadrature demodulation circuits used in swept-source optical coherence tomography (OCT). Quadrature demodulation allows for detection of both the real and imaginary components of an interference fringe, and this information separates signals from positive and negative depth spaces. To achieve a high extinction (~60 dB) between these positive and negative signals, the demodulation error must be less than 0.1% in amplitude and phase. It is difficult to construct a system that achieves this low error across the wide spectral and RF bandwidths of high-speed swept source systems. In a prior work, post-processing methods for removing residual spectral errors were described. Here, we identify the importance of a second class of errors originating in the RF domain, and present a comprehensive framework for compensating both spectral and RF errors. Using this framework, extinctions >60 dB are demonstrated. A stability analysis shows that calibration parameters associated with RF errors are accurate for many days, while those associated with spectral errors must be updated prior to each imaging session. Empirical procedures to derive both RF and spectral calibration parameters simultaneously and to update spectral calibration parameters are presented. These algorithms provide the basis for using passive optical quadrature demodulation circuits with high speed and wide-bandwidth swept-source OCT systems. PMID- 25836785 TI - Dual-comb modelocked laser. AB - In this paper we present the first semiconductor disk laser (SDL) emitting simultaneously two collinearly overlapping cross-polarized gigahertz modelocked pulse trains with different pulse repetition rates. Using only a simple photo detector and a microwave spectrum analyzer directly down-converts the frequency comb difference from the optical to the microwave frequency domain. With this setup, the relative carrier-envelope-offset (CEO) frequency can be accessed directly without an f-to2f interferometer. A very compact design is obtained using the modelocked integrated external-cavity surface emitting laser (MIXSEL) which is part of the family of optically pumped SDLs and similar to a vertical external cavity surface emitting laser (VECSEL) but with both gain and saturable absorber integrated into the same semiconductor wafer (i.e. MIXSEL chip). We then simply added an additional intracavity birefringent crystal inside the linear straight cavity between the output coupler and the MIXSEL chip which splits the cavity beam into two collinear but spatially separated cross-polarized beams on the MIXSEL chip. This results in two modelocked collinear and fully overlapping cross-polarized output beams with adjustable pulse repetition frequencies with excellent noise performance. We stabilized both pulse repetition rates of the dual comb MIXSEL. PMID- 25836786 TI - Analysis and minimization of spacing error of holographic gratings recorded with spherical collimation lenses. AB - This research proposes a feedback method to adjust the dual-beam exposure system with spherical collimation lenses to achieve gratings with low spacing error. Through theoretical analysis and numerical calculation, it is proved that the interference aberration can be analyzed with the Zernike polynomials and the adjustment errors can be estimated according to the linear relationship between the errors and the polynomial coefficients. Moreover moving the substrate along its normal is proposed to decrease the spacing error but keep the grating's period unchanged. In the experiments, the wavefront measurement results of the +/ 1st orders are used to deduce the spacing error. Based on the feedback adjustment method, the grating with a spacing error of 0.03 lambda within 70 mm * 70 mm is fabricated with the collimation lenses of 0.6 lambda spherical aberration. PMID- 25836787 TI - Plasmon-modulated photoluminescence from gold nanostructures and its dependence on plasmon resonance, excitation energy, and band structure. AB - Two distinct single-photon plasmon-modulated photo-luminescence processes are generated from nanostructured gold surfaces by tuning the spectral overlap of the incident laser source, localized surface plasmon resonance band, and the interband transitions between the d and sp bands, near the X- and L-symmetry points of the electronic band structure of gold. In the main section of the article, the characteristics of these photoluminescence processes are described and discussed. In the last section, the background continuum accompanying surface enhanced Raman scattering (SERS) spectra from benzenethiol and 4-mercaptopyridine self-assembled monolayers chemisorbed on nanostructured gold surfaces is shown to originate from plasmon-modulated photoluminescence. PMID- 25836788 TI - Sensitivity-directed refinement for designing broadband blocking filters. AB - We developed a new method aimed at designing short-pass filters, long-pass filters and filters blocking sidebands of Fabry-Perot bandpasses. The method is an automated version of a non-straightforward empirical approach invented as a result of many years' experience in design and production of optical coatings. The method allows obtaining near-quarter-wave solutions in a few seconds. In many cases these solutions are more advantageous for deposition systems. PMID- 25836789 TI - Effects of periodic forcing on the temporally correlated spikes of a semiconductor laser with feedback. AB - Optical excitable devices that mimic neuronal behavior can be building-blocks of novel, brain-inspired information processing systems. A relevant issue is to understand how such systems represent, via correlated spikes, the information of a weak external input. Semiconductor lasers with optical feedback operating in the low frequency fluctuations regime have been shown to display optical spikes with intrinsic temporal correlations similar to those of biological neurons. Here we investigate how the spiking laser output represents a weak periodic input that is implemented via direct modulation of the laser pump current. We focus on understanding the influence of the modulation frequency. Experimental sequences of inter-spike-intervals (ISIs) are recorded and analyzed by using the ordinal symbolic methodology that identifies and characterizes serial correlations in datasets. The change in the statistics of the various symbols with the modulation frequency is empirically shown to be related to specific changes in the ISI distribution, which arise due to different phase-locking regimes. A good qualitative agreement is also found between simulations of the Lang and Kobayashi model and observations. This methodology is an efficient way to detect subtle changes in noisy correlated ISI sequences and may be applied to investigate other optical excitable devices. PMID- 25836790 TI - Pulse polarization evolution and control in the wake of molecular alignment inside a filament. AB - The polarization evolution and control of a femtosecond laser pulse in the wake of molecular alignment inside a laser filament was investigated. A weak probe pulse was delayed with respect to the field-free revivals of the pre-excited rotational wave-packets created by an infrared filamenting pulse in nitrogen gas. 30 degrees was set between the pump and probe's initial linear polarization directions in order to control the output probe's polarization ellipse. The detailed physical response of the probe's polarization states was analyzed in the wake of alignment and dephasing of molecular N(2). The probe's polarization was modulated by varying the retarded time between the pump and probe pulses. PMID- 25836791 TI - Holographic projection with field-dependent aberration correction. AB - We present an algorithm for the computation of computer-generated holograms projecting arbitrary patterns through optical reconstruction systems with strong field-dependent aberrations. The algorithm is based on a modification of the iterative Fourier transform algorithm. Aberrations are specified using Zernike polynomials. The trade-off between reconstruction error and diffraction efficiency can be altered using a simple constant within the algorithm. We show first experimental results for the correction of the reconstruction through a strongly aberrated Fourier system. PMID- 25836792 TI - High efficiency demagnetization cooling by suppression of light-assisted collisions. AB - Demagnetization cooling utilizes dipolar relaxations that couple the internal degree of freedom (spin) to the external (angular momentum) in order to cool an atomic cloud efficiently. Optical pumping into a dark state constantly recycles the atoms that were thermally excited to higher spin states. The net energy taken away by a single photon is very favorable since the lost energy per atom is the Zeeman energy rather than the recoil energy. As the density of the atomic sample rises the presence of the photons leads to limiting processes. In our previous publication [Volchkov et al. (2014)] we have shown that light-assisted collisions are such an important limiting process. In this paper we suppress light-assisted collisions by detuning the optical pumping light such that the Condon point coincides with the first node of the ground state wave function of two colliding atoms. This leads to an increased cooling efficiency chi >= 17 as well as to increased maximum densities of n ~ 1 . 10(20) m(-3). However, due to the high number of involved molecular states the net suppression is not strong enough to reach quantum degeneracy. PMID- 25836793 TI - Passively Q-switched nanosecond erbium-doped fiber laser with MoS(2) saturable absorber. AB - Passively Q-switched nanosecond pulsed erbium-doped fiber laser based on MoS(2) saturable absorber (SA) is experimentally demonstrated. The high quality MoS(2) SA deposited on the broadband high-reflectivity mirror with a large modulation depth of 9% was prepared by pulsed laser deposition method. By inserting the MoS(2) SA into an erbium-doped fiber laser, stable Q-switched operation can be achieved with the shortest pulse width of 660 ns, the maximum pulse energy up to 152 nJ and pulse repetition rates varying from 116 to 131 kHz. The experimental results further verify that MoS(2) possesses the potential advantage for stable Q switched pulse generation at 1.5 MUm. PMID- 25836794 TI - A bio-inspired analog silicon retina with Michaelis-Menten auto-adaptive pixels sensitive to small and large changes in light. AB - In this paper, we present: (i) a novel analog silicon retina featuring auto adaptive pixels that obey the Michaelis-Menten law, i.e. V=V(m) I(n)/I(n)+sigma(n); (ii) a method of characterizing silicon retinas, which makes it possible to accurately assess the pixels' response to transient luminous changes in a +/-3-decade range, as well as changes in the initial steady-state intensity in a 7-decade range. The novel pixel, called M(2)APix, which stands for Michaelis-Menten Auto-Adaptive Pixel, can auto-adapt in a 7-decade range and responds appropriately to step changes up to +/-3 decades in size without causing any saturation of the Very Large Scale Integration (VLSI) transistors. Thanks to the intrinsic properties of the Michaelis-Menten equation, the pixel output always remains within a constant limited voltage range. The range of the Analog to Digital Converter (ADC) was therefore adjusted so as to obtain a Least Significant Bit (LSB) voltage of 2.35mV and an effective resolution of about 9 bits. The results presented here show that the M(2)APix produced a quasi-linear contrast response once it had adapted to the average luminosity. Differently to what occurs in its biological counterparts, neither the sensitivity to changes in light nor the contrast response of the M(2)APix depend on the mean luminosity (i.e. the ambient lighting conditions). Lastly, a full comparison between the M(2)APix and the Delbruck auto-adaptive pixel is provided. PMID- 25836795 TI - Optimization, tolerance analysis and implementation of a Stokes polarimeter based on the conical refraction phenomenon. AB - Recently, we introduced the basic concepts behind a new polarimeter device based on conical refraction (CR), which presents several appealing features compared to standard polarimeters. To name some of them, CR polarimeters retrieve the polarization state of an input light beam with a snapshot measurement, allow for substantially enhancing the data redundancy without increasing the measuring time, and avoid instrumental errors owing to rotating elements or phase-to voltage calibration typical from dynamic devices. In this article, we present a comprehensive study of the optimization, robustness and parameters tolerance of CR based polarimeters. In addition, a particular CR based polarimetric architecture is experimentally implemented, and some concerns and recommendations are provided. Finally, the implemented polarimeter is experimentally tested by measuring different states of polarization, including fully and partially polarized light. PMID- 25836796 TI - 256 * 2 SPAD line sensor for time resolved fluorescence spectroscopy. AB - We present a CMOS chip 256 * 2 single photon avalanche diode (SPAD) line sensor, 23.78 um pitch, 43.7% fill factor, custom designed for time resolved emission spectroscopy (TRES). Integrating time-to-digital converters (TDCs) implement on chip mono-exponential fluorescence lifetime pre-calculation allowing timing of 65k photons/pixel at 200 Hz line rate at 40 ps resolution using centre-of-mass method (CMM). Per pixel time-correlated single-photon counting (TCSPC) histograms can also be generated with 320 ps bin resolution. We characterize performance in terms of dark count rate, instrument response function and lifetime uniformity for a set of fluorophores with lifetimes ranging from 4 ns to 6 ns. Lastly, we present fluorescence lifetime spectra of multicolor microspheres and skin autofluorescence acquired using a custom built spectrometer. In TCSPC mode, time resolved spectra are acquired within 5 minutes whilst in CMM mode spectral lifetime signatures are acquired within 2 ms for fluorophore in cuvette and 200 ms for skin autofluorescence. We demonstrate CMOS line sensors to be a versatile tool for time-resolved fluorescence spectroscopy by providing parallelized and flexible spectral detection of fluorescence decay. PMID- 25836797 TI - Surface-enhanced mid-infrared spectroscopy using a quantum cascade laser. AB - We report on the successful measurement of surface-enhanced infrared vibrational spectra from a few nanometer thick organic semiconductor layers on samples with resonant plasmonic nanoantennas arranged in arrays. For the first time, a setup with a tunable quantum cascade laser as the light source in mid-infrared range is used. The combination of the quantum cascade laser with a microbolometer array for infrared light allows to map an area 2.8 * 3.1 mm(2) with a spatial resolution of about 9 MUm, a bandwidth from 1170 to 1300 cm(-1), and a spectral resolution of 2.5 cm(-1) within only five minutes versus 16 hours using a conventional FTIR micro-spectrometer. We present a quantitative comparison of the experimental results from the setup with the quantum cascade laser with those from the FTIR micro-spectrometer. PMID- 25836798 TI - Gap bridging in joining of glass using ultra short laser pulses. AB - Glass welding by ultra-short laser pulses provides hermetic welding seams with high mechanical stability. The required distance between the samples must be extremely small (<100nm), otherwise cracks will form inside the seam reducing its stability. However, to achieve such small gaps the roughness of the samples must be small enough necessitating additional polishing. Additionally, Van-der-Waals forces grow substantial at such distances thereby effectively preventing sample movement and an easy and precise sample alignment. Here we present a method utilizing ultra-short laser pulses which exploits a volume expansion of irradiated glass enabling the joining of glass plates across gaps of up to 1um. PMID- 25836799 TI - Femtosecond laser induced periodic surface structure on poly-L-lactic acid. AB - Laser-induced periodic surface structure (LIPSS) is one of the most remarkable nanostructures formed only by a simple procedure of laser irradiation that enables to control cell behaviors. To the best of our knowledge, however, LIPSS formation on a scaffold-usable biodegradable polymer had not been succeede d probably due to relatively-low glass transition temperature and melting temperature of such polymers. In this study, we demonstrate LIPSS formation on a poly-L-lactic acid (PLLA), a versatile biodegradable polymer which has been widely used in clinical practice. Experimental results revealed that the repetition rate of femtosecond laser is one of the key parameters for LIPSS formation on PLLA, suggesting that thermal properties and photochemical reactions should be considered. The present study expands the potential of femtosecond laser processing for fabrication of highly-biocompatible scaffold in tissue engineering. PMID- 25836800 TI - Polarization tailored novel vector beams based on conical refraction. AB - Coherent vector beams with involved states of polarization (SOP) are widespread in the literature, having applications in laser processing, super-resolution imaging and particle trapping. We report novel vector beams obtained by transforming a Gaussian beam passing through a biaxial crystal, by means of the conical refraction phenomenon. We analyze both experimentally and theoretically the SOP of the different vector beams generated and demonstrate that the SOP of the input beam can be used to control both the shape and the SOP of the transformed beam. We also identify polarization singularities of such beams for the first time and demonstrate their control by the SOP of the input beam. PMID- 25836801 TI - The Lissajous lens: a three-dimensional absolute optical instrument without spherical symmetry. AB - We propose a three dimensional optical instrument with an isotropic gradient index in which all ray trajectories form Lissajous curves. The lens represents the first absolute optical instrument discovered to exist without spherical symmetry (other than trivial cases such as the plane mirror or conformal maps of spherically-symmetric lenses). An important property of this lens is that a three dimensional region of space can be imaged stigmatically with no aberrations, with a point and its image not necessarily lying on a straight line with the lens center as in all other absolute optical instruments. In addition, rays in the Lissajous lens are not confined to planes. The lens can optionally be designed such that no rays except those along coordinate axes form closed trajectories, and conformal maps of the Lissajous lens form a rich new class of optical instruments. PMID- 25836803 TI - Intensity impulse response of SDM links. AB - We study the response of space-division multiplexed fiber links to an excitation by a short impulse of the optical intensity. We show that, in the presence of full mixing, the intensity impulse response is Gaussian, confirming recently reported experimental observations, and relate its variance to the mean square of the mode dispersion vector of the link tau(->). The good agreement between our theory and the previously published experiments provides solid foundations to the random coupling model of SDM fiber links, and provides a tool for efficient design of MIMO-DSP receivers. PMID- 25836802 TI - Wavelength-selective switch with direct few mode fiber integration. AB - The first realization of a wavelength-selective switch (WSS) with direct integration of few mode fibers (FMF) is fully described. The free-space optics FMF-WSS dynamically steers spectral information-bearing beams containing three spatial modes from an input port to one of nine output ports using a phase spatial light modulator. Sources of mode dependent losses (MDL) are identified, analytically analyzed and experimentally confirmed on account of different modal sensitivities to fiber coupling in imperfect imaging and at spectral channel edges due to mode clipping. These performance impacting effects can be reduced by adhering to provided design guidelines, which scale in support of higher spatial mode counts. The effect on data transmission of cascaded passband filtering and MDL build-up is experimentally investigated in detail. PMID- 25836804 TI - Enhanced phase stability in passive analog photonic links with coherent Rayleigh noise reduction. AB - Minimizing phase fluctuation along passive analog fiber link is proposed and experimentally demonstrated. By utilizing three different optical wavelengths, we could significantly reduce the effect of coherent Rayleigh noise (CRN). In addition, a phase-locked loop is employed for dynamic phase fluctuation compensation. The RMS phase jitter within two-hour period is reduced to ~1.7131 ps over 40-km fiber link. PMID- 25836805 TI - Surface-mode model of the extraordinary optical transmission without plasmons. AB - We propose a microscopic surface-mode model for the extraordinary optical transmission (EOT) through subwavelength metallic slit array covered with a thin dielectric layer under illumination of transverse-electric (TE) polarization. Remarkably, surface plasmon polarizations (SPPs) do not exist for this polarization. It is commonly believed that the waveguide mode in the dielectric layer plays a role similar to that of the SPP in classical EOT. To check the intuitive belief, we derive a surface-mode model by considering the multiple scattering process of the fundamental waveguide mode and neglecting all other residual field in the thin dielectric layer. The model captures the main feature of EOT and provides a phase-matching condition to predict the transmission resonance. Quantitative comparison between fully-vectorial calculations and model predictions shows that besides the fundamental waveguide mode, other residual field in the thin dielectric layer also contributes to the EOT without SPP. PMID- 25836806 TI - Non-Markovian dynamics of a two-level system in the presence of hierarchical environments. AB - Dynamics of an open system is vividly influenced by the structure of environments. This paper studies in detail the dynamics of a two-level atom in the presence of an overall environment composed of two hierarchies. The first hierarchy is just a single lossy cavity while the second hierarchy consists of a number of other lossy cavities. The atom is coupled directly to the first hierarchy but indirectly to the second one via the couplings between the two hierarchies. We show that even when the coupling between the atom and the first hierarchy is weak the atom's dynamics can become non-Markovian if the number of cavities in the second hierarchy or/and the coupling between the two hierarchies are large enough. We also analyze the case when the coupling between the atom and the first hierarchy is strong and show that the non-Markovian dynamics exhibits different patterns depending on both the number of cavities in the second hierarchy and the coupling between the two hierarchies. PMID- 25836807 TI - Joint timing and frequency synchronization based on weighted CAZAC sequences for reduced-guard-interval CO-OFDM systems. AB - A novel joint symbol timing and carrier frequency offset (CFO) estimation algorithm is proposed for reduced-guard-interval coherent optical orthogonal frequency-division multiplexing (RGI-CO-OFDM) systems. The proposed algorithm is based on a constant amplitude zero autocorrelation (CAZAC) sequence weighted by a pseudo-random noise (PN) sequence. The symbol timing is accomplished by using only one training symbol of two identical halves, with the weighting applied to the second half. The special structure of the training symbol is also utilized in estimating the CFO. The performance of the proposed algorithm is demonstrated by means of numerical simulations in a 115.8-Gb/s 16-QAM RGI-CO-OFDM system. PMID- 25836808 TI - Microcavity enhanced directional transmission through a subwavelength plasmonic slit. AB - We show numerically that a compact structure, consisting of multiple optical microcavities at both the entrance and exit sides of a subwavelength plasmonic slit, can lead to greatly enhanced directional transmission through the slit. The microcavities can increase the reflectivity at both sides of the slit, and therefore the resonant transmission enhancement. In addition, the microcavities can greatly improve the impedance matching, and therefore the coupling between free-space waves and the slit mode. An optimized structure with two microcavities on both the entrance and exit sides of the slit leads to ~16 times larger transmission cross section per unit angle in the normal direction compared to the optimized reference slit without microcavities. We also show numerically that the operation frequency range for high emission in the normal direction is broad. PMID- 25836809 TI - Plasmonic achromatic doublet lens. AB - An achromatic doublet lens (ADL) for surface plasmon polaritons (SPPs) is designed. Similar to the conventional ADL, the proposed plasmonic ADL is composed of two lens layers with different dispersion relations. Considering these layers as effective media, their refractive indices with respect to the free-space wavelength are calculated. Geometric parameters of the lens are initially set according to the geometrical optic theory, and then optimized by reduced dimensional calculations. The performance of proposed device is verified by using full-wave simulations and compared with a double-convex plasmonic lens to verify its achromatic characteristics. It is shown that the standard deviation of the focal length shift is reduced from 668 nm to 168 nm, after introducing the ADL. PMID- 25836810 TI - Frequency- and spectrally-encoded confocal microscopy. AB - We describe a three-dimensional microscopy technique based on spectral and frequency encoding. The method employs a wavelength-swept laser to illuminate a specimen with a spectrally-dispersed line focus that sweeps over the specimen in time. The spatial information along each spectral line is further mapped into different modulation frequencies. Spectrally-resolved detection and subsequent Fourier analysis of the back-scattered light from the specimen therefore enable high-speed, scanner-free imaging of the specimen with a single-element photodetector. High-contrast, three-dimensional imaging capability of this method is demonstrated by presenting images of various materials and biological specimens. PMID- 25836811 TI - VO(2) based waveguide-mode plasmonic nano-gratings for optical switching. AB - In this paper, we present one dimensional plasmonic narrow groove nano-gratings, covered with a thin film of VO(2) (Vanadium Dioxide), as novel optical switches. These narrow groove gratings couple the incident optical radiation to plasmonic waveguide modes leading to high electromagnetic fields in the gaps between the nano-gratings. Since VO(2) changes from its semiconductor to its metallic phase on heating, on exposure to infra-red light, or on application of voltage, the optical properties of the underlying plasmonic grating also get altered during this phase transition, thereby resulting in significant switchability of the reflectance spectra. Moreover, as the phase transition in VO(2) can occur at femto-second time-scales, the VO(2)-coated plasmonic optical switch described in this paper can potentially be employed for ultrafast optical switching. We aim at maximizing this switchability, i.e., maximizing the differential reflectance (DR) between the two states (metallic and semiconductor) of this VO(2) coated nano grating. Rigorous Coupled Wave Analysis (RCWA) reveals that the switching wavelengths - i.e., the wavelengths at which the values of the differential reflectance between VO(2) (S) and VO(2) (M) phases are maximum - can be tuned over a large spectral regime by varying the nano-grating parameters such as groove width, depth of the narrow groove, grating width, and thickness of the VO(2) layer. A comparison of the proposed ideal nano-gratings with various types of non-ideal nano-gratings - i.e., nano-gratings with non-parallel sidewalls - has also been carried out. It is found that significant switchability is also present for these non-ideal gratings that are easy to fabricate. Thus, we propose highly switchable and wide-spectra VO(2) based narrow groove nano-gratings that do not have a complex structure and can be easily fabricated. PMID- 25836812 TI - Optical micro-knot resonator hydrophone. AB - We present results of what are believed to be the first underwater acoustic sensor using an optical micro-knot resonator. The mechanism involves straining the micro-fibre loop of the knot via an appropriate encapsulation material. The micro-knot sensor exhibited a spectral full-width half-depth of 37.7pm with a Q factor of 41100 after deconvolution with the source. The shift in wavelength at 1550nm was observed to be around 67pm RMS when exposed to underwater acoustic excitation at 40Hz demonstrating a normalized sensitivity of -288 dB re MUPa(-1), or 5.83 fm/Pa. PMID- 25836813 TI - Fully integrated hybrid silicon two dimensional beam scanner. AB - In this work we present the first fully-integrated free-space beam-steering chip using the hybrid silicon platform. The photonic integrated circuit (PIC) consists of 164 optical components including lasers, amplifiers, photodiodes, phase tuners, grating couplers, splitters, and a photonic crystal lens. The PIC exhibited steering over 23 degrees x 3.6 degrees with beam widths of 1 degrees x 0.6 degrees . PMID- 25836814 TI - Dynamic self-diffraction in MoS(2) nanoflake solutions. AB - We observe dynamic self-diffraction in MoS(2) supernatant solutions with laser for the first time, and conduct dynamic data simulation and analysis. Observation results indicate that self-diffraction can be divided in three stages: in the first stage, laser changes from Gauss beam to symmetric diffraction rings because of the force from laser. In the second stage, diffraction rings become asymmetric vertically because of gravity. In the third stage, diffraction rings become asymmetric horizontally, as a result of fine structure of laser. We obtain the dynamic distribution of MoS(2) nanoflake in solution under the effect of laser by dynamic diffraction image simulation. PMID- 25836815 TI - Numerical investigation of all-optical add-drop multiplexing for spectrally overlapping OFDM signals. AB - We propose a novel architecture for all-optical add-drop multiplexing of OFDM signals. Sub-channel extraction is achieved by means of waveform replication and coherent subtraction from the OFDM super-channel. Numerical simulations have been carried out to benchmark the performance of the architecture against critical design parameters. PMID- 25836816 TI - Flexible inkjet-printed metamaterial absorber for coating a cylindrical object. AB - In this paper, a novel flexible inkjet-printed metamaterial absorber is proposed. The unit cell of the metamaterial is designed with a modified Jerusalem-cross ring resonator and is inkjet printed with silver nanoparticle ink on a flexible polymer film. All fabrication processes are performed using a commercial printer (EPSON WF-7011). The absorber's flexibility and absorption performance are demonstrated by measuring the absorption ratio after coating the proposed absorber on a cylindrical object with a radius of 4.56 cm. An absorption rate exceeding 99% is achieved at 9.21 GHz for both flat and cylindrical surfaces. In addition, the cylindrical model attains an absorption rate higher than 96% for all polarization angles, and a high absorption rate of 95% is preserved until the incident angle is less than 30p. PMID- 25836817 TI - Spatial mapping of refractive index based on a plasmonic tapered channel waveguide. AB - A tapered plasmonic channel waveguide can be used for index sensing by spatial mapping of the scattering field intensity. A numerical simulation shows that this waveguide reflects the plasmonic channel waveguide mode at various points as the refractive index of an analyte changes, and a strong outgoing scattering wave appears at the reflection point. One can measure the index change by detecting variations in the scattering point. In the case of a unit index change, the scattering point moved 2670 nm, which can be observed by an imaging system. Detection limit of the index change is estimated as 0.12. However, the limit can be further reduced by increasing the tapered length or decreasing the tapered angle of the structure. PMID- 25836818 TI - Experimental study of fs-laser induced sub-100-nm periodic surface structures on titanium. AB - In this work the formation of laser-induced periodic surface structures (LIPSS) on a titanium surface upon irradiation by linearly polarized femtosecond (fs) laser pulses with a repetition rate of 1 kHz in air environment was studied experimentally. In particular, the dependence of high-spatial-frequency-LIPSS (HSFL) characteristics on various laser parameters: fluence, pulse number, wavelength (800 nm and 400 nm), pulse duration (10 fs - 550 fs), and polarization was studied in detail. In comparison with low-spatial-frequency-LIPSS (LSFL), the HSFL emerge at a much lower fluence with orientation perpendicular to the ridges of the LSFL. It was observed that these two types of LIPSS demonstrate different fluence, shot number and wavelength dependencies, which suggest their origin is different. Therefore, the HSFL formation mechanism cannot be described by the widely accepted interference model developed for describing LSFL formation. PMID- 25836819 TI - CMOS-compatible optical switching concept based on strain-induced refractive index tuning. AB - In this paper we present a planar lightwave switching mechanism based on large refractive index variations induced by electrically-driven strain control in a CMOS-compatible photonic platform. Feasibility of the proposed concept, having general validity, is numerically analyzed in a specific case-study given by a Mach-Zehnder Interferometer with Ge waveguides topped by a piezoelectric stressor. The stressor can be operated in order to dynamically tune the strain into the two interferometric arms. The strain modifies the Ge band structure and can induce refractive index variations up to 0.05. We demonstrate that this approach can enable ultra-compact devices featuring low loss propagation for light wavelengths below the waveguide band gap energy, high extinction ratios (>30 dB) and low intrinsic insertion losses (2 dB). The operation wavelength can be extended in the whole FIR spectrum by using SiGe(Sn) alloy waveguides. PMID- 25836820 TI - Modeling of a diode four-side symmetrically pumped alkali vapor amplifier. AB - Considering the amplified spontaneous emission, the saturation effect and the energy distributions of the incident pump and seed lasers, a physical model is established to describe the kinetic process and the output performance of a four sided diode pumped alkali vapor laser amplifier. According to the experimental parameters of a single-side pumped configuration with a diffuse type hollow cylinder cavity, energy distributions in the cell and influences of several important factors are simulated and analyzed. The model is validated by comparing the simulation result with the experimental data, which shows the model can provide an effective way for designing an efficient diode four-side symmetrically pumped alkali vapor laser amplifier. PMID- 25836821 TI - Intermodal and cross-polarization four-wave mixing in large-core hybrid photonic crystal fibers. AB - Degenerate four-wave mixing is considered in large mode area hybrid photonic crystal fibers, combining photonic bandgap guidance and index guidance. Co- and orthogonally polarized pump, signal and idler fields are considered numerically by calculating the parametric gain and experimentally by spontaneous degenerate four-wave mixing. Intermodal and birefringence assisted intramodal phase matching is observed. Good agreement between calculations and experimental observations is obtained. Intermodal four-wave mixing is achieved experimentally with a conversion efficiency of 17%. PMID- 25836822 TI - Simulation of generation of dissipative soliton, dissipative soliton resonance and noise-like pulse in Yb-doped mode-locked fiber lasers. AB - we report three types of pulse generation in Yb-doped nonlinear polarization rotation mode-locked fiber lasers in all-normal-dispersion regime through simulation, including dissipative soliton, dissipative soliton resonance and noise-like pulse. We distinguish the different conditions of generating such different pulses by analyzing the transmission curve of saturable absorber, which plays a key role in pulse shaping. PMID- 25836823 TI - MMI resonators based on metal mirrors and MMI mirrors: an experimental comparison. AB - We report, to the best of our knowledge, the first experimental proof of MMI based resonators. The resonators have been designed and fabricated on a micron scale silicon photonics platform and are based on different reflectors suitably placed on two of the four ports of 2x2 MMIs with uneven splitting ratios, namely 85:15 and 72:28. The reflectors are either based on aluminum mirrors or on all dielectric MMI mirrors. Performances of the different designs are compared with each other and with numerical simulations. Finesse values as high as 13.1 (9.9) have been measured in best aluminum (all-dielectric) resonators, corresponding to a quality factor of 5.8.10(3) (12.5.10(3)) and mirror reflectivity exceeding 92% (88%). PMID- 25836824 TI - Performance analysis of large-scale OXC that enables dynamic modular growth. AB - We investigate the performance of our recently proposed novel subsystem modular OXC node that achieves graceful modular growth without any service disruption. Simulation experiments under a realistic traffic increase scenario verify that the node architecture offers almost the same performance as the conventional large scale OXC node, while greatly reducing the number of WSSs needed and allowing the use of small degree WSSs. It is shown that both the number of WSSs traversed and total end-to-end optical loss can be substantially reduced. PMID- 25836825 TI - Multiview three-dimensional display with continuous motion parallax through planar aligned OLED microdisplays. AB - Existing multiview three-dimensional (3D) display technologies encounter discontinuous motion parallax problem, due to a limited number of stereo-images which are presented to corresponding sub-viewing zones (SVZs). This paper proposes a novel multiview 3D display system to obtain continuous motion parallax by using a group of planar aligned OLED microdisplays. Through blocking partial light-rays by baffles inserted between adjacent OLED microdisplays, transitional stereo-image assembled by two spatially complementary segments from adjacent stereo-images is presented to a complementary fusing zone (CFZ) which locates between two adjacent SVZs. For a moving observation point, the spatial ratio of the two complementary segments evolves gradually, resulting in continuously changing transitional stereo-images and thus overcoming the problem of discontinuous motion parallax. The proposed display system employs projection type architecture, taking the merit of full display resolution, but at the same time having a thin optical structure, offering great potentials for portable or mobile 3D display applications. Experimentally, a prototype display system is demonstrated by 9 OLED microdisplays. PMID- 25836826 TI - Effect of the object 3D shape on the viscoelastic testing in optical tweezers. AB - Viscoelastic testing of biological cells has been performed with the optical tweezers and stretcher. Historically, the cells were modeled by the spring dashpot network or the power-law models, which can however characterize only the homogeneous, isotropic viscoelastic material, but not the 3D cell itself. Our mechanical and finite element analyses show that the cell elongations are different significantly for different cell 3D shapes in the creep testing. In the dynamic testing the loss tangent, which is measurable directly in the experiment, is not sensitive to the cell shape. However, the stress-strain hysteresis loop still depends on the cell 3D shape. PMID- 25836827 TI - Binary phase oscillation of two mutually coupled semiconductor lasers. AB - A two-site Ising model is implemented as an injection-locked laser network consisting of a single master laser and two mutually coupled slave lasers. We observed ferromagnetic and antiferromagnetic orders in the in-phase and out-of phase couplings between the two slave lasers. Their phase difference is locked to either 0 or pi even if the coupling path is continuously modulated. The system automatically selects the oscillation frequency to satisfy the in-phase or out-of phase coupling condition, when the mutual coupling dominates over the injection locking by the master laser. PMID- 25836828 TI - Polarized vortices in optical speckle field: observation of rare polarization singularities. AB - Using a recent method able to characterize the polarimetry of a random field with high polarimetric and spatial accuracy even near places of destructive interference, we study polarized optical vortices at a scale below the transverse correlation width of a speckle field. We perform high accuracy polarimetric measurements of known singularities described with an half-integer topological index and we study rare integer index singularities which have, to our knowledge, never been observed in a speckle field. PMID- 25836829 TI - Amplifying optical rotation using a coupled waveguide and ring resonator. AB - Measuring optical rotations in materials is a useful tool in many experimental studies. Research may be limited by the ability to measure small rotations due to weak interactions. We propose a novel scheme wherein we use a coupled waveguide and ring resonator to amplify the effects of optical rotation, potentially opening new avenues for investigation. Our proposed device can increase the resulting optical rotation by up to six orders of magnitude. PMID- 25836830 TI - Highly sensitive liquid level monitoring system utilizing polymer fiber Bragg gratings. AB - A novel and highly sensitive liquid level sensor based on a polymer optical fiber Bragg grating (POFBG) is experimentally demonstrated. Two different configurations are studied and both configurations show the potential to interrogate liquid level by measuring the strain induced in a POFBG embedded in a silicone rubber diaphragm, which deforms due to hydrostatic pressure variations. The sensor exhibits a highly linear response over the sensing range and a good repeatability. For comparison, a similar sensor using a FBG inscribed in silica fiber is fabricated, which displays a sensitivity that is a factor of 5 smaller than the POFBG. The temperature sensitivity is studied and a novel multi-sensor arrangement proposed which has the potential to provide level readings independent of temperature and the liquid density. PMID- 25836831 TI - A smart load-sensing system using standardized mechano-luminescence measurement. AB - The mechano-luminescence (ML) of phosphors has stirred a great deal of interest for its potential application in inexpensive, non-destructive load sensors. However, the most serious drawback of ML phosphors has been responses that differ according to the loading conditions. This has led to a lack of standardization in realizing smart ML sensor applications. We improved the applicability of ML phosphors to that of a smart, standardized load sensor by detecting ML based on the UV excitation above the threshold power density during the entire loading process. The ML behavior under these conditions was completely different from that of conventional ML behavior with UV excitation turned off. The ML output was clearly represented as a simple linear function of the applied load under conditions that could be either static or dynamic. In addition, neither a ML loss angle nor hysteresis behavior was observed under these ML measurement conditions. PMID- 25836832 TI - Ultra-narrow band perfect absorbers based on plasmonic analog of electromagnetically induced absorption. AB - A novel plasmonic metamaterial consisting of the solid (bar) and the inverse (slot) compound metallic nanostructure for electromagnetically induced absorption (EIA) is proposed in this paper, which is demonstrated to achieve an ultra-narrow absorption peak with the linewidth less than 8 nm and the absorptivity exceeding 97% at optical frequencies. This is attributed to the plasmonic EIA resonance arising from the efficient coupling between the magnetic response of the slot (dark mode) and the electric resonance of the bar (bright mode). To the best of our knowledge, this is the first time that the plasmonic EIA is used to realize the narrow-band perfect absorbers. The underlying physics are revealed by applying the two-coupled-oscillator model. The near-perfect-absorption resonance also causes an enhancement of about 50 times in H-field and about 130 times in E field within the slots. Such absorber possesses potential for applications in filter, thermal emitter, surface enhanced Raman scattering, sensing and nonlinear optics. PMID- 25836833 TI - Laser-induced plasmas in ambient air for incoherent broadband cavity-enhanced absorption spectroscopy. AB - The emission from a laser-induced plasma in ambient air, generated by a high power femtosecond laser, was utilized as pulsed incoherent broadband light source in the center of a quasi-confocal high finesse cavity. The time dependent spectra of the light leaking from the cavity was compared with those of the laser-induced plasma emission without the cavity. It was found that the light emission was sustained by the cavity despite the initially large optical losses of the laser induced plasma in the cavity. The light sustained by the cavity was used to measure part of the S(1) <- S(0) absorption spectrum of gaseous azulene at its vapour pressure at room temperature in ambient air as well as the strongly forbidden gamma-band in molecular oxygen: b(1)Sigma(g)(+)(nu'=2)<-X(3)Sigma(g)( )(nu''=0). PMID- 25836834 TI - Extend the field of view of selective plan illumination microscopy by tiling the excitation light sheet. AB - Selective Plane Illumination Microscopy (SPIM) is attractive for its ability to acquire 3D images with high 3D spatial resolution, good optical sectioning capability and high imaging speed. However, tradeoffs have to be made when a large field of view (FOV) is required, results in lower axial resolution or worse optical sectioning capability. Here, we present a novel method for 3D imaging by SPIM that is capable to maintain its high 3D spatial resolution and good optical sectioning capability within a large FOV. Instead of trying to generate a large and uniformly thick excitation light sheet, the method tiles a relative small light sheet quickly to multiple positions within the image plane by defocusing the excitation beam used to create the light sheet, and takes one additional image at each position, so that a large FOV can be imaged by repeating this process and stitching all images together. By implementing this method, light sheets with thin thickness and good excitation light confinement can be used for SPIM imaging with slightly compromised imaging speed. The method was investigated through both numerical simulation and experiments, and the imaging performance was demonstrated by imaging fluorescent particles embedded in agarose gel and live C. elegans embryos. PMID- 25836835 TI - Direct measurement of axial optical forces. AB - Direct measurement of optical forces based on recording the change of momentum between the in- and outgoing light does not have specific requirements on particle size or shape, or on beam shape. Thus this approach overcomes many of the limitations of force measurements based on position measurements, which require frequent calibration. In this work we validate the achievable accuracy for direct force measurements in the axial direction for a single beam optical tweezers setup, based on numerical simulations and experimental investigations of situations, where the true force is known. We find that for typical experimental situations a good accuracy with an error of less than 1 % of the maximum force can be achieved, independent of particle size or refractive index, provided that the total amount of light scattered in the backward direction is also taken into account, which is easy to accomplish experimentally. Due to the inherent particle shape independence of the direct force measurement method, these findings support that it provides accurate results for 3D force measurements for particles of arbitrary shape. PMID- 25836836 TI - Prediction of metallic nano-optical trapping forces by finite element-boundary integral method. AB - The hybrid of finite element and boundary integral (FE-BI) method is employed to predict nano-optical trapping forces of arbitrarily shaped metallic nanostructures. A preconditioning strategy is proposed to improve the convergence of the iterative solution. Skeletonization is employed to speed up the design and optimization where iteration has to be repeated for each beam configuration. The radiation pressure force (RPF) is computed by vector flux of the Maxwell's stress tensor. Numerical simulations are performed to validate the developed method in analyzing the plasmonic effects as well as the optical trapping forces. It is shown that the proposed method is capable of predicting the trapping forces of complex metallic nanostructures accurately and efficiently. PMID- 25836837 TI - In vivo neuroimaging through the highly scattering tissue via iterative multi photon adaptive compensation technique. AB - For in vivo deep tissue imaging, high order wavefront measurement and correction is needed for handling the severe wavefront distortion. Towards such a goal, we have developed the iterative multi-photon adaptive compensation technique (IMPACT). In this work, we explore using IMPACT to perform calcium imaging of neocortex through the intact skull of adult mice, and to image through the highly scattering white matter on the hippocampus surface. PMID- 25836838 TI - Method for wavelength stabilization of pulsed difference frequency laser at 1572 nm for CO(2) detection lidar. AB - High-accuracy on-line wavelength stabilization is required for differential absorption lidar (DIAL), which is ideal for precisely measuring atmospheric CO(2) concentration. Using a difference-frequency laser, we developed a ground-based 1.57-MUm pulsed DIAL for performing atmospheric CO(2) measurements. Owing to the system complexity, lacking phase, and intensity instability, the stabilization method was divided into two parts-wavelength calibration and locking-based on saturated absorption. After obtaining the on-line laser position, accuracy verification using statistical theory and locking stabilization using a one dimensional template matching method, namely least-squares matching (LSM), were adopted to achieve wavelength locking. The resulting system is capable of generating a stable wavelength. PMID- 25836839 TI - Optimization of sampling pattern and the design of Fourier ptychographic illuminator. AB - Fourier ptychography (FP) is a recently developed imaging approach that facilitates high-resolution imaging beyond the cutoff frequency of the employed optics. In the original FP approach, a periodic LED array is used for sample illumination, and therefore, the scanning pattern is a uniform grid in the Fourier space. Such a uniform sampling scheme leads to 3 major problems for FP, namely: 1) it requires a large number of raw images, 2) it introduces the raster grid artefacts in the reconstruction process, and 3) it requires a high-dynamic range detector. Here, we investigate scanning sequences and sampling patterns to optimize the FP approach. For most biological samples, signal energy is concentrated at low-frequency region, and as such, we can perform non-uniform Fourier sampling in FP by considering the signal structure. In contrast, conventional ptychography perform uniform sampling over the entire real space. To implement the non-uniform Fourier sampling scheme in FP, we have designed and built an illuminator using LEDs mounted on a 3D-printed plastic case. The advantages of this illuminator are threefold in that: 1) it reduces the number of image acquisitions by at least 50% (68 raw images versus 137 in the original FP setup), 2) it departs from the translational symmetry of sampling to solve the raster grid artifact problem, and 3) it reduces the dynamic range of the captured images 6 fold. The results reported in this paper significantly shortened acquisition time and improved quality of FP reconstructions. It may provide new insights for developing Fourier ptychographic imaging platforms and find important applications in digital pathology. PMID- 25836840 TI - High power tunable femtosecond ultraviolet laser source based on an Yb-fiber laser pumped optical parametric oscillator. AB - We report a high average power tunable 51 MHz femtosecond ultraviolet (UV) laser source based on an intra-cavity sum frequency mixing optical parametric oscillator (OPO) pumped by a fiber laser. The UV laser is generated by sum frequency generation (SFG) between the second harmonic of a mode-locked Yb-fiber laser and the signal of the OPO. A non-collinear configuration is used in the SFG to compensate the group velocity mismatch, and to increase the SFG conversion efficiency dramatically. Tunable ultraviolet pulses within the wavelength range from 385 to 400 nm have been produced with a maximum average power of 402 mW and a pulse width of 286 fs at 2 W Yb-fiber laser pump, corresponding to 20.1% near infrared to UV conversion efficiency at 387 nm. To our knowledge, this is the first demonstration of tunable femtosecond UV pulse generation from a fiber laser pumped OPO, and is also the highest average power tunable UV femtosecond pulses from an OPO. PMID- 25836841 TI - Efficient assessment method of on-board modulation transfer function of optical remote sensing sensors. AB - Modulation transfer function (MTF) can be used to evaluate the imaging performance of on-board optical remote sensing sensors, as well as recover and restore images to improve imaging quality. Laboratory measurement approaches for MTF have achieved high precision. However, they are not yet suitable for on-board measurement. In this paper, a new five-step approach to calculate MTF of space optical remote sensing sensors is proposed. First, a pixel motion model is used to extract the conditional sub-frame images. Second, a mathematical morphology algorithm and a correlation-homomorphic filter algorithm are used to eliminate noise and enhance sub-frame image. Third, an image partial differentiation determines the accurate position of edge points. Fourth, a model optical function is used to build a high-resolution edge spread function. Finally, MTF is calculated by derivation and Fourier transform. The experiment shows that the assessment method of MTF is superior to others. PMID- 25836842 TI - Optoelectronic performance optimization for transparent conductive layers based on randomly arranged silver nanorods. AB - Optoelectronic performance of transparent conductive layers (TCLs) based on randomly arranged silver (Ag) nanorods (NRs) is simulated. Models for calculation of optical and electronic properties were proposed founded on finite-difference time-domain method and percolation theory respectively. Obtained simulation results are well conformed to experimental data. The influence of angle deviation of NR crossings on the transmittance and sheet resistance are demonstrated. The balance between transmittance and sheet resistance which can be easily set by varying the combinations of NR radius and NR number is shown. Our results demonstrate that randomly arranged Ag layers are promising candidates for flexible TCLs. PMID- 25836843 TI - Feed-forward carrier phase recovery for offset-QAM Nyquist WDM transmission. AB - Due to the half symbol delay between in-phase and quadrature components for offset quadrature amplitude modulation (OQAM) signal, phase noise cannot only lead to constellation rotation but also introduce additional crosstalk. Therefore, OQAM signal has very poor tolerance to the laser linewidth. Here, we carry out a semi-analytical investigation of phase noise induced crosstalk during OQAM Nyquist WDM transmission, and find that the carrier phase recovery (CPR) has to be implemented prior to the inter-symbol-interference (ISI) equalization. Then, after a function separation of polarization de-multiplexing and ISI equalization, we propose a new DSP flow with a linewidth-tolerant blind feed forward CPR scheme for OQAM signal. Its effectiveness is verified under the scenario of 5-channel 28-Gbaud polarization multiplexing (PM) OQAM Nyquist WDM systems. A tolerance of linewidth and symbol duration products of 6.5*10(-4) and 1.1*10(-4) is secured for 4-OQAM and 16-OQAM, respectively, given 1-dB required OSNR penalty at BER = 10(-3). PMID- 25836844 TI - An exact surface-integral approach for accurate interferometric microscopy of single nanoparticles. AB - We present a half-plane surface-integral equation (SIE) approach for modeling the optical phase response of a single nanowire under phase-stepping interferometric (PSI) microscopy. This approach calculates scattered fields exactly from the Helmholtz equation in this 2D problem, obviating the need for ray-optic approximations. It is demonstrated that refractive index metrology is enabled by this method, with precision as low as 7 * 10(-5) possible for current state-of the-art PSI microscopes. For nanowires of known refractive index, radii as small as 0.001lambda are shown to yield a measurable phase signal and are therefore potentially measurable by this approach. Measurements are also demonstrated to be relatively insensitive to the spectral and coherence characteristics of the light source, the illumination conditions, and variations in nanowire cross-section shape. Prospects for measuring both the radius and refractive index simultaneously, and scope for generalizing this approach to arbitrary nanoparticle shapes are discussed. PMID- 25836845 TI - Optical information authentication using compressed double-random-phase-encoded images and quick-response codes. AB - In this paper, we develop a new optical information authentication system based on compressed double-random-phase-encoded images and quick-response (QR) codes, where the parameters of optical lightwave are used as keys for optical decryption and the QR code is a key for verification. An input image attached with QR code is first optically encoded in a simplified double random phase encoding (DRPE) scheme without using interferometric setup. From the single encoded intensity pattern recorded by a CCD camera, a compressed double-random-phase-encoded image, i.e., the sparse phase distribution used for optical decryption, is generated by using an iterative phase retrieval technique with QR code. We compare this technique to the other two methods proposed in literature, i.e., Fresnel domain information authentication based on the classical DRPE with holographic technique and information authentication based on DRPE and phase retrieval algorithm. Simulation results show that QR codes are effective on improving the security and data sparsity of optical information encryption and authentication system. PMID- 25836846 TI - Bi-SERS sensing and enhancement by Au-Ag bimetallic non-alloyed nanoparticles on amorphous and crystalline silicon substrate. AB - We have demonstrated Au-Ag bimetallic non-alloy nanoparticles (BNNPs) on thin a Si film and c-Si substrate for high SERS enhancement, low cost, high sensitivity and reproducible SERS substrate with bi-SERS sensing properties where two different SERS peak for Au NPs and Ag NPs are observed on single SERS substrate. The isolated Au-Ag bimetallic NPs, with uniform size and spacing distribution, are suitable for uniform high density hotspot SERS enhancement. The SERS enhancement factor of Au-Ag BNNPs is 2.9 times higher compared to Ag NPs on similar substrates due to the increase of the localized surface plasmon resonance effect. However there is a decrement of SERS peak intensity at specific wavenumbers when the surrounding refractive index increases due to out-phase hybridization of Au NPs. The distinct changes of the two different SERS peaks on single Au-Ag BNNPs SERS substrate due to Au and Ag NPs independently show possible application for bi-molecular sensing. PMID- 25836847 TI - Surface plasmon polaritons at linearly graded semiconductor interfaces. AB - New results are reported on investigation of dispersion curves for surface plasmon polaritons (SPPs) at an inhomogenously doped semiconductor/dielectric interface whereby the dielectric is represented by the same undoped semiconductor. The doped semiconductor is described by its frequency-dependent permittivity that varies with the depth. It is shown that a transition layer (TL) with a linear change in carrier concentration supports one branch dispersion curve regardless of the TL thickness. The obtained dispersion curves reach a maximum at a finite frequency depending on the TL thickness, and subsequently asymptotically approach the zero frequency in the shortwave limit. Therefore two surface plasmon modes are supported at a given frequency: a long-wave mode with a positive group velocity and a short-wave mode with a negative group velocity. A condition of a zero group velocity can be satisfied by tuning the TL layer. It is shown that the conventional dispersion relation for SPPs at a TL with a zero thickness is an asymptotic solution, and the convergence of real dispersion curves is point-wise instead of an expected uniform convergence. PMID- 25836848 TI - External cavity diode laser-based detection of trace gases with NICE-OHMS using current modulation. AB - We combine an external cavity diode laser with noise-immune cavity-enhanced optical heterodyne molecular spectroscopy (NICE-OHMS) using current modulation. With a finesse of 1600, we demonstrate noise equivalent absorption sensitivities of 4.1 x 10(-10) cm(-1) Hz(-1/2), resulting in sub-ppbv detection limits for Doppler-broadened transitions of CH(4) at 6132.3 cm(-1), C(2)H(2) at 6578.5 cm( 1) and HCN at 6541.7 cm(-1). The system is used for hydrogen cyanide detection from sweet almonds. PMID- 25836849 TI - Quantum cascade detector utilizing the diagonal-transition scheme for high quality cavities. AB - A diagonal optically active transition in a quantum cascade detector is introduced as optimization parameter to obtain quality factor matching between a photodetector and a cavity. A more diagonal transition yields both higher extraction efficiency and lower noise, while the reduction of the absorption strength is compensated by the resonant cavity. The theoretical limits of such a scheme are obtained, and the impact of losses and cavity processing variations are evaluated. By optimizing the quantum design for a high quality cavity, a specific detectivity of 10(9) Jones can be calculated for lambda = 8MUm and T = 300K. PMID- 25836850 TI - Pulse-shaping mechanisms in passively mode-locked thulium-doped fiber lasers. AB - Different pulse-shaping mechanisms were investigated experimentally and numerically in passively mode-locked thulium-doped fiber lasers. Conventional solitons were demonstrated in a passively semiconductor saturable absorber mirror mode-locked anomalous dispersion thulium-doped fiber laser. With normal dispersion fiber and spectral filter added in cavity, pulse-shaping processes were theoretically analyzed in the presence of dispersion map and dissipation in thulium-doped fiber lasers. The existence of parabolic pulse as nonlinear attraction was proved and distinct pulse intensity profiles evolution from Gaussian shape to parabolic shape was proposed in dissipative dispersion-managed thulium-doped fiber lasers. PMID- 25836851 TI - High energy transmission annular beam X-ray diffraction. AB - We demonstrate material phase retrieval by linearly translating extended polycrystalline samples along the symmetry axis of an annular beam of high-energy X-rays. A series of pseudo-monochromatic diffraction images are recorded from the dark region encompassed by the beam. We measure Bragg maxima from different annular gauge volumes in the form of bright spots in the X-ray diffraction intensity. We present the experiment data from three materials with different crystallographic structural properties i.e. near ideal, large grain size and preferred orientation. This technique shows great promise for analytical inspection tasks requiring highly penetrating radiation such as security screening, medicine and non-destructive testing. PMID- 25836852 TI - Analysis of angle of arrival fluctuations for optical waves' propagation through weak anisotropic non-Kolmogorov turbulence. AB - Analytical expressions for the variance of angle of arrival (AOA) fluctuations based on the Rytov approximation theory are derived for plane and spherical waves' propagation through weak anisotropic non-Kolmogorov turbulence atmosphere. The anisotropic spectrum model based on the assumption of circular symmetry in the orthogonal plane throughout the path is adopted and it includes the same degree of anisotropy along the direction of propagation for all the turbulence cells size in the inertial sub-range. The derived expressions consider a single anisotropic coefficient describing the turbulence anisotropic property and a general spectral power law value in the range 3 to 4. They reduce correctly to the previously published analytic expressions for the cases of plane and spherical waves' propagation through weak isotropic non-Kolmogorov turbulence for the special case of anisotropic factor equaling one. To reduce the complexity of the analytical results, the asymptotic-fit expressions are also derived and they fit well with the close-form ones. These results are useful for understanding the potential impact of deviations from the standard isotropic non-Kolmogorov turbulence atmosphere. PMID- 25836854 TI - Novel control of plasma expansion direction aimed at very low pressure laser induced plasma spectroscopy. AB - A plasma confinement approach has been applied to enhance the signal intensity of laser-induced plasma in low pressure conditions down to 10(-2) torr. Detection of plasma emission spectrum is a daunting task at low pressure due to the low electron density and the short persistence time of plasma that undergoes a rapid expansion. Here we devised a spatial confinement setup that increases the electron density at various range of low pressures. A confining window is placed above the sample surface to control the direction of the expanding plasma aimed at optimizing the efficiency of the low pressure detection. More ions, atoms, and molecules can reach the detector by a direction-controlled confinement of an otherwise freely expanding plasma. The spectral intensities of neutral atoms increased up to 4 times with a single laser pulse by the proposed confining method at 1 torr. The signal of doubly ionized carbon atom which was detectable only at low pressure is also enhanced 4 times. The results of this study provide an important guideline for strengthening the otherwise weak signals at low pressure by controlling the plasma expansion direction. PMID- 25836853 TI - Realization of "trapped rainbow" in 1D slab waveguide with surface dispersion engineering. AB - We present a design of a one dimensional dielectric waveguide that can trap a broadband light pulse with different frequency component stored at different positions, effectively forming a "trapped rainbow" [Nature 450, 397 (2007)]. The spectrum of the rainbow covers the whole visible range. To do this, we first show that the dispersion of a SiO(2) waveguide with a Si grating placed on top can be engineered by the design parameter of the grating. Specifically, guided modes with zero group velocity(frozen modes) can be realized. Negative Goos-Hanchen shift along the surface of the grating is responsible for such a dispersion control. The frequency of the frozen mode is tuned by changing the lateral feature parameters (period and duty cycle) of the grating. By tuning the grating feature point by point along the waveguide, a light pulse can be trapped with different frequency components frozen at different positions, so that a "rainbow" is formed. The device is expected to have extremely low ohmic loss because only dielectric materials are used. A planar geometry also promises much reduced fabrication difficulty. PMID- 25836855 TI - Novel formulation of the M model through the Generalized-K distribution for atmospheric optical channels. AB - In this paper, a novel and deeper physical interpretation on the recently published Malaga or M statistical distribution is provided. This distribution, which is having a wide acceptance by the scientific community, models the optical irradiance scintillation induced by the atmospheric turbulence. Here, the analytical expressions previously published are modified in order to express them by a mixture of the known Generalized-K and discrete Binomial and Negative Binomial distributions. In particular, the probability density function (pdf) of the M model is now obtained as a linear combination of these Generalized-K pdf, in which the coefficients depend directly on the parameters of the M distribution. In this way, the Malaga model can be physically interpreted as a superposition of different optical sub-channels each of them described by the corresponding Generalized-K fading model and weighted by the M dependent coefficients. The expressions here proposed are simpler than the equations of the original M model and are validated by means of numerical simulations by generating M -distributed random sequences and their associated histogram. This novel interpretation of the Malaga statistical distribution provides a valuable tool for analyzing the performance of atmospheric optical channels for every turbulence condition. PMID- 25836856 TI - Femtosecond harmonic mode-locking of a fiber laser based on a bulk-structured Bi(2)Te(3) topological insulator. AB - We experimentally demonstrate femtosecond harmonic mode-locking of a fiber laser using a bulk-structured Bi(2)Te(3) topological insulator (TI)-deposited on a side polished fiber as a mode-locker. A bulk-structured Bi(2)Te(3) TI film was prepared at a thickness of ~20 MUm using a mechanical exfoliation method. Using the mode-locker in an erbium-doped fiber ring cavity, it was experimentally shown that harmonically mode-locked pulses with temporal widths of 630 ~700 fs could readily be generated upto the 55th harmonics. The pulse repetition rate was shown to be tunable from the fundamental resonance frequency of 14.07 MHz to the harmonic frequency of 773.85 MHz with increasing pump power. The pumping efficiency was measured at ~3.36 MHz/mW. The side mode suppression ratio (SMSR) was observed to be more than 27.3 dB over all harmonic orders, while the corresponding signal-to-noise ratio (SNR) ranged from 46.3 to 63 dB. PMID- 25836857 TI - Highly efficient second harmonic generation in hyperbolic metamaterial slot waveguides with large phase matching tolerance. AB - Highly efficient second harmonic generation (SHG) bridging the mid-infrared (IR) and near-IR wavelengths in a coupled hyperbolic metamaterial waveguide with a nonlinear-polymer-filled nanoscale slot is theoretically investigated. By engineering the geometrical parameters, the collinear phase matching condition is satisfied between the even hybrid modes at the fundamental frequency (3,100 nm) and the second harmonic (1,550 nm). Two modes manifest the great field overlap and the significant field enhancement in the nonlinear integration area (i.e. the slot), which leads to extreme large nonlinear coupling coefficient. For a low pumping power of 100 mW, the device length is as short as 2.19 um and the normalized conversion efficiency comes up to more than 6.37 * 10(5) W(-1)cm(-2) which outperforms that of the plasmonic-based structures. Moreover, the efficient SHG can be achieved with great phase matching tolerance, i.e., a small theoretical fabrication-error sensitivity to filling ratio and a broad pump bandwidth in a compact device length of 2.19 um using 100 mW pump. The proposed scheme links the mature near-IR devices to the mid-IR regime and have a great potential for integrated chip-scale all-optical signal processes. PMID- 25836858 TI - Diffraction manipulation by four-wave mixing. AB - We suggest a scheme to manipulate paraxial diffraction by utilizing the dependency of a four-wave mixing process on the relative angle between the light fields. A microscopic model for four-wave mixing in a Lambda-type level structure is introduced and compared to recent experimental data. We show that images with feature size as low as 10 MUm can propagate with very little or even negative diffraction. The mechanism is completely different from that conserving the shape of spatial solitons in nonlinear media, as here diffraction is suppressed for arbitrary spatial profiles. At the same time, the gain inherent to the nonlinear process prevents loss and allows for operating at high optical depths. Our scheme does not rely on atomic motion and is thus applicable to both gaseous and solid media. PMID- 25836860 TI - Superlinear growth of Rayleigh scattering-induced intensity noise in single-mode fibers. AB - Rayleigh scattering generates intensity noise close to an optical carrier that propagates in a single-mode optical fiber. This noise degrades the performance of optoelectronic oscillators and RF-photonic links. When using a broad linewidth laser, we previously found that the intensity noise power scales linearly with optical power and fiber length, which is consistent with guided entropy mode Rayleigh scattering (GEMRS), a third order nonlinear scattering process, in the spontaneous limit. In this work, we show that this behavior changes significantly with the use of a narrow linewidth laser. Using a narrow linewidth laser, we measured the bandwidth of the intensity noise plateau to be 10 kHz. We found that the scattered noise power scales superlinearly with fiber length up to lengths of 10 km in the frequency range of 500 Hz to 10 kHz, while it scales linearly in the frequency range of 10 Hz to 100 Hz. These results suggest that the Rayleigh scattering-induced intensity noise cannot be explained by third-order nonlinear scattering in the spontaneous limit, as previously hypothesized. PMID- 25836859 TI - Passively mode-locked III-V/silicon laser with continuous-wave optical injection. AB - We demonstrate electrically pumped two-section mode locked quantum well lasers emitting at the L-band of telecommunication wavelength on silicon utilizing die to wafer bonding techniques. The mode locked lasers generate pulses at a repetition frequency of 30 GHz with signal to noise ratio above 30 dB and 1 mW average output power per facet. Optical injection-locking scheme was used to improve the noise properties of the pulse trains of passively mode-locked laser. The phases of the mode-locked frequency comb are shown to be coherent with that of the master continuous-wave (CW) laser. The radio-frequency (RF)-line-width is reduced from 7.6 MHz to 150 kHz under CW optical injection. The corresponding pulse-to-pulse jitter and integrated RMS jitter are 29.7 fs/cycle and 1.0 ps, respectively. The experimental results demonstrate that optical injection can reduce the noise properties of the passively mode locked III-V/Si laser in terms of frequency linewidth and timing jitter, which makes the devices attractive for photonic analog-to-digital converters and clock generation and recovery. PMID- 25836861 TI - Polarimetric 3D integral imaging in photon-starved conditions. AB - We develop a method for obtaining 3D polarimetric integral images from elemental images recorded in low light illumination conditions. Since photon-counting images are very sparse, calculation of the Stokes parameters and the degree of polarization should be handled carefully. In our approach, polarimetric 3D integral images are generated using the Maximum Likelihood Estimation and subsequently reconstructed by means of a Total Variation Denoising filter. In this way, polarimetric results are comparable to those obtained in conventional illumination conditions. We also show that polarimetric information retrieved from photon starved images can be used in 3D object recognition problems. To the best of our knowledge, this is the first report on 3D polarimetric photon counting integral imaging. PMID- 25836862 TI - Generation and evolution of mode-locked noise-like square-wave pulses in a large anomalous-dispersion Er-doped ring fiber laser. AB - In a passively mode-locked Erbium-doped fiber laser with large anomalous dispersion, we experimentally demonstrate the formation of noise-like square-wave pulse, which shows quite different features from conventional dissipative soliton resonance (DSR). The corresponding temporal and spectral characteristics of a variety of operation states, including Q-switched mode-locking, continuous-wave mode-locking and Raman-induced noise-like pulse near the lasing threshold, are also investigated. Stable noise-like square-wave mode-locked pulses can be obtained at a fundamental repetition frequency of 195 kHz, with pulse packet duration tunable from 15 ns to 306 ns and per-pulse energy up to 200 nJ. By reducing the linear cavity loss, stable higher-order harmonic mode-locking had also been observed, with pulse duration ranging from 37 ns at the 21st order harmonic wave to 320 ns at the fundamental order. After propagating along a piece of long telecom fiber, the generated square-wave pulses do not show any obvious change, indicating that the generated noise-like square-wave pulse can be considered as high-energy pulse packet for some promising applications. These experimental results should shed some light on the further understanding of the mechanism and characteristics of noise-like square-wave pulses. PMID- 25836863 TI - Angular scan optical coherence tomography imaging and metrology of spherical gradient refractive index preforms. AB - The fabrication of high-performance spherical gradient refractive index (S-GRIN) optics requires nondestructive metrology techniques to inspect the samples. We have developed an angular-scan, swept-source-based, Fourier-domain optical coherence tomography (OCT) system centered at 1318 nm with 5 mm imaging depth capable of 180 degrees polar scan and 360 degrees azimuthal scan to investigate polymeric S-GRIN preforms. We demonstrate a method that enables simultaneous mapping of the group optical thickness, physical thickness, the radially-averaged group refractive index, and the transmitted wavefront of the S-GRIN preforms. The angular scan OCT imaging and metrology enables direct visualization, molding uniformity characterization, and optical property evaluations of the preforms. The results on two generations of S-GRIN preforms are discussed that showcase the evolution of the manufacturing process in response to the OCT metrology feedback. PMID- 25836864 TI - Blind symbol synchronization for direct detection optical OFDM using a reduced number of virtual subcarriers. AB - Symbol synchronization constitutes a major component in optical OFDM transceivers. In this paper, we propose reducing the complexity of a blind symbol synchronization technique for direct detection OFDM receivers based on virtual subcarriers by optimizing the number and location of the virtual subcarriers. Compared to the system design in our previous study, this new technique offers a reduction of 92% in the number of virtual subcarriers (from 26 to 2 in a system with 50 data carrying subchannels) resulting in significant savings in complexity with a minimal penalty. Moreover, it offers an increase in the system capacity as more subcarriers can be used to transmit data. The technique was assessed experimentally using a transmission system of direct detection 16-QAM optical OFDM operating at a data rate of 30.65 Gb/s over 23.3 km SSMF with BER of 10(-3). Negligible penalty was observed at high received powers. However, at low received powers, the number of averaging symbols had to be increased in order to improve the robustness of the method. PMID- 25836865 TI - Steady-state ab initio laser theory for complex gain media. AB - We derive and test a generalization of the steady-state ab initio laser theory (SALT) to treat complex gain media. The generalized theory (C-SALT) is able to treat atomic and molecular gain media with diffusion and multiple lasing transitions, and semiconductor gain media in the free carrier approximation including fully the effect of Pauli blocking. The key assumption of the theory is stationarity of the level populations, which leads to coupled self-consistent equations for the populations and the lasing modes that fully include the effects of openness and non-linear spatial hole-burning. These equations can be solved efficiently for the steady-state lasing properties by a similar iteration procedure as in SALT, where a static gain medium with a single transition is assumed. The theory is tested by comparison to much less efficient finite difference time domain (FDTD) methods and excellent agreement is found. Using C SALT to analyze the effects of varying gain diffusion constant we demonstrate a cross-over between the regime of strong spatial hole burning with multimode lasing to a regime of negligible spatial hole burning, leading to gain-clamping, and single mode lasing. The effect of spatially inhomogeneous pumping combined with diffusion is also studied and a relevant length scale for spatial inhomogeneity to persist under these conditions is determined. For the semiconductor gain model, we demonstrate the frequency shift due to Pauli blocking as the pumping strength changes. PMID- 25836866 TI - Design optimization of single and double layer Graphene phase modulators in SOI. AB - In this paper we report on an electro-refractive modulator based on single or double-layer graphene on top of silicon waveguides. The graphene layers are biased to the transparency condition in order to achieve phase modulation with negligible amplitude modulation. By means of a detailed study of both the electrical and optical properties of graphene and silicon, as well as through optimization of the geometrical parameters, we show that the proposed devices may theoretically outperform existing modulators both in terms of V(pi)L and of insertion losses. The overall figures of merit of the proposed devices are as low as 8.5 and 2dB?V for the single and double layer cases, respectively. PMID- 25836867 TI - Design of flat-band superprism structures for on-chip spectroscopy. AB - We present a systematic design procedure of photonic crystal (PhC) superprism structures for on-chip spectroscopic applications. In specific, we propose a new figure of merit, namely the angular-group-dispersion-bandwidth-product (AGDBP) to quantitatively describe the spectroscopic performance of PhC superprism structures, and an optimum PhC structure for spectroscopic applications should have large angular group dispersion over a large bandwidth, i.e., a flat-top dispersion profile. We demonstrate the advantage of such a new design consideration by optimizing the geometry of a two-dimensional parallelogram lattice PhC superprism structure. The performance of such a superprism spectrometer is further analyzed numerically using finite-difference time-domain simulations, which out-performs current implementations in terms of the number of achievable output spectral channels. PMID- 25836868 TI - Tunable optical bistability of dielectric/nonlinear graphene/dielectric heterostructures. AB - We have established the theoretical relation of nonlinear optical response with respect to the dielectric/nonlinear graphene/dielectric heterostructures and further demonstrated the tunable optical bistability at terahertz frequencies. It is shown that the hysteretic behavior is strongly dependent on the Fermi energy of graphene, and the threshold electric fields could be correspondingly adjusted with the continuous tuning of Fermi Energy level. It is clear that the bistable thresholds can be lowered dramatically by decreasing the Fermi energy of graphene, at the same time the optical hysteresis width is narrowed. Moreover, we have confirmed that the optical bistability can be tuned by adjusting the incident illumination angle, or by varying the thickness and permittivity of the dielectric slabs. Our contribution might provide a new avenue of fabricating graphene based optical switching device that could even operate at terahertz regime. PMID- 25836869 TI - Monolithic optical phased-array transceiver in a standard SOI CMOS process. AB - Monolithic microwave phased arrays are turning mainstream in automotive radars and high-speed wireless communications fulfilling Gordon Moores 1965 prophecy to this effect. Optical phased arrays enable imaging, lidar, display, sensing, and holography. Advancements in fabrication technology has led to monolithic nanophotonic phased arrays, albeit without independent phase and amplitude control ability, integration with electronic circuitry, or including receive and transmit functions. We report the first monolithic optical phased array transceiver with independent control of amplitude and phase for each element using electronic circuitry that is tightly integrated with the nanophotonic components on one substrate using a commercial foundry CMOS SOI process. The 8 * 8 phased array chip includes thermo-optical tunable phase shifters and attenuators, nano-photonic antennas, and dedicated control electronics realized using CMOS transistors. The complex chip includes over 300 distinct optical components and over 74,000 distinct electrical components achieving the highest level of integration for any electronic-photonic system. PMID- 25836870 TI - Photonic microwave stabilization for period-one nonlinear dynamics of semiconductor lasers using optical modulation sideband injection locking. AB - Photonic microwave generation using period-one nonlinear dynamics of semiconductor lasers suffers from poor spectral purity. A stabilization approach based on optical modulation sideband injection locking is investigated. An optical signal carrying a highly correlated modulation sideband comb simultaneously injection-locks the regeneration of the optical carrier and the lower oscillation sideband in the dynamics, establishing a phase-locking between the two spectral components. A linewidth of below 1 Hz is therefore achieved for microwave generation up to at least 40 GHz. Because of the frequency multiplication in yielding the comb-like optical signal, only an electronic microwave reference at the tenth subharmonic or higher of the generated microwave frequency is required. PMID- 25836871 TI - Table screen 360-degree holographic display using circular viewing-zone scanning. AB - A table screen 360-degree holographic display is proposed, with an increased screen size, having an expanded viewing zone over all horizontal directions around the table screen. It consists of a microelectromechanical systems spatial light modulator (MEMS SLM), a magnifying imaging system, and a rotating screen. The MEMS SLM generates hologram patterns at a high frame rate, the magnifying imaging system increases the screen of the MEMS SLM, and the reduced viewing zones are scanned circularly by the rotating screen. The viewing zones are localized to practically realize wavefront reconstruction. An experimental system has been constructed. The generation of 360-degree three-dimensional (3D) images was achieved by scanning 800 reduced and localized viewing zones circularly. The table screen had a diameter of 100 mm, and the frame rate of 3D image generation was 28.4 Hz. PMID- 25836872 TI - Temporal cloak based on tunable optical delay and advance. AB - A temporal cloak scheme based on tunable optical delay and advance is theoretically proposed. An input optical signal is divided into two parts, and the front part is advanced while the rear part is delayed. A temporal gap which contains negligible optical energy is opened to hide events from observers, which can be closed by doing the inverse process. Different from the previous schemes that use continuous wave light, we use an optical data stream as the probe beam. Simulations have been done to investigate performance of the temporal cloak. The developed scheme can be applied in fiber-optical signal processing and secure communications. PMID- 25836873 TI - Double plasmonic nanodisks design for electromagnetically induced transparency and slow light. AB - An analog of plasmonic system for electromagnetically induced transparency (EIT), in which a small nanodisk with a big side-coupled-nanodisk is directly coupled to the metal-insulator -metal (MIM) waveguide, has been proposed and investigated theoretically and numerically. When the resonant frequencies of the two nanodisks differ not too much, a powerful EIT-like effect can be obtained, and the transparency window can be easily tuned by adjusting the radii of the two nanodisks. The plasmonic device can be used as a high-performance EIT-like filter with transmission over 80% and full width at half-maximum (FWHM) less than 30nm, besides, the novel structure shows a high group index over 355. The system paves a new way toward highly integrated optical circuits and networks, especially for wavelength-selective, ultrafast switching, light storage and nonlinear devices. PMID- 25836874 TI - Refractometric monitoring of dissolution and fluid flow with distributed feedback dye laser sensor. AB - Monitoring the dissolution of solid material in liquids and monitoring of fluid flow is of significant interest for applications in chemistry, food production, medicine, and especially in the fields of microfluidics and lab on a chip. Here, real-time refractometric monitoring of dissolution and fast fluid flow with DFB dye laser sensors with an optical imaging spectroscopy setup is presented. The dye laser sensors provide both low detection limits and high spatial resolution. It is demonstrated how the materials NaCl, sucrose, and bovine serum albumin show characteristic dissolution patterns. The unique feature of the presented method is a high frame rate of up to 20 Hz, which is proven to enable the monitoring of fast flow of a sucrose solution jet into pure water. PMID- 25836875 TI - Design and performance of a dual-laser instrument for multiple isotopologues of carbon dioxide and water. AB - A design and results for an instrument with a quantum cascade laser and an antimonide diode laser to measure simultaneously and with high precision seven isotopologues of carbon dioxide and water vapor. Methods and results for determining the effects that limit absorption noise at the level of 5x10(-6) are presented and discussed. PMID- 25836876 TI - Efficient method for the calculation of dissipative quantum transport in quantum cascade lasers. AB - We present a novel and very efficient method for calculating quantum transport in quantum cascade lasers (QCLs). It follows the nonequilibrium Green's function (NEGF) framework but sidesteps the calculation of lesser self-energies by replacing them by a quasi-equilibrium expression. This method generalizes the phenomenological Buttiker probe model by taking into account individual scattering mechanisms. It is orders of magnitude more efficient than a fully self consistent NEGF calculation for realistic devices. We apply this method to a new THz QCL design which works up to 250 K - according to our calculations. PMID- 25836877 TI - Optical transport, lifting and trapping of micro-particles by planar waveguides. AB - Optical waveguides can be used to trap and transport micro-particles. The particles are held close to the waveguide surface by the evanescent field and propelled forward. We propose a new technique to lift and trap particles above the surface of the waveguides. This is made possible by a gap between two opposing, planar waveguides. The field emitted from each of the waveguide ends diverge fast, away from the substrate and into the cover-medium. By combining two fields propagating at an angle upwards and coming from opposite sides of a gap, particles can be stably lifted and trapped at the crossing of the two fields. Thus, particles are transported by waveguides leading to a gap, where they are lifted away from the substrate and trapped. The experiments are supported by numerical simulations of the forces on the micro-particles. Fluorescence imaging is used to track the particles in 3D with a precision of 50 nm. PMID- 25836878 TI - Single shot telecentricity measurement by Fourier space grid separation. AB - The experimental documentation of the properties of an optical system represents a particular challenge. Besides the measurement of focal quality and field distortions, telecentric systems have to yield a parallel beam propagation direction. In this paper we propose a method to test, document and optimize the telecentricity of a laser scanning system by scanning two crossed polka dot beam splitters at once. By separating both beam splitters in Fourier space we were able to detect tilting angles below 2 . 10(-3) rad for four different laser wavelengths within the same optical system. By this we determined the optimum system parameters for our scanning laser optical tomography (SLOT) setup. PMID- 25836879 TI - Photonic jet with ultralong working distance by hemispheric shell. AB - Micro-particle assisted nano-imaging has proven its success in the past few years since it can magnify the nano-objects, especially the metallic objects, into an image then collected by a conventional microscope. Micro-shell, which is a novel design of micro-particle in the configuration of a hemisphere with a hollow core region, is proposed and optimized in this paper in order to obtain a long photonic jet far away from its flat surface, thus increasing its working distance. Its dependence on the configuration and refractive index is investigated numerically. A micro-shell with the outer and inner radii of 5 and 2.5 um and the refractive index of 1.5 can focus the incident light of 400 nm wavelength 2.7 um away from the micro-shell flat surface, although the photonic jet intensity decreases to 25.8% compared to the solid hemisphere. Meanwhile, the photonic jet length of the micro-shell under the incident light of 400 nm and 1000 nm wavelengths are 1.7 um and 4.3 um, respectively, because its hollow core region tends to reduce the angle variation of the Poynting vectors in the photonic jet. With the long working distance and long photonic jet, the micro shell could be used to scan over a sample to obtain a large area image when coupled with a conventional microscope, which is especially useful for the samples with the rough surfaces. PMID- 25836880 TI - Differential absorption lidar for volcanic CO(2) sensing tested in an unstable atmosphere. AB - Motivated by the need for an extremely durable and portable instrument to quantify volcanic CO(2) we have produced a corresponding differential absorption lidar (DIAL). It was tested on a volcano (Vulcano, Italy), sensing a non-uniform volcanic CO(2) signal under turbulent atmospheric conditions. The measured CO(2) mixing ratio trend agrees qualitatively well but quantitatively poorly with a reference CO(2) measurement. The disagreement is not in line with the precision of the DIAL determined under conditions that largely exclude atmospheric effects. We show evidence that the disagreement is mainly due to atmospheric turbulence. We conclude that excluding noise associated with atmospheric turbulence, as commonly done in precision analysis of DIAL instruments, may largely underestimate the error of measured CO(2) concentrations in turbulent atmospheric conditions. Implications for volcanic CO(2) sensing with DIAL are outlined. PMID- 25836881 TI - 1.7-MUm spectroscopic spectral-domain optical coherence tomography for imaging lipid distribution within blood vessel. AB - We have developed a spectroscopic optical coherence tomography (OCT) for imaging lipid distribution within blood vessel in order to detect coronary artery plaque. A 1.7-MUm spectral-domain OCT with A-scan rate of 47 kHz is fabricated using a broadband light source based on super-luminescent diodes and spectrometers based on extended InGaAs line sensors. We demonstrate imaging of lipid distribution in an in vitro artery model with lipid. The sensitivity and specificity in the differentiation between artery and lipid are 87% and 90% in the training, respectively. The validation test also shows detection of lipid with an accuracy over 90%. PMID- 25836882 TI - Carbon irradiated semi insulating GaAs for photoconductive terahertz pulse detection. AB - We report here a photoconductive material for THz detection with sub-picosecond carrier lifetime made by C(12) (Carbon) irradiation on commercially available semi-insulating (SI) GaAs. We are able to reduce the carrier lifetime of SI-GaAs down to sub-picosecond by irradiating it with various irradiation dosages of Carbon (C(12)) ions. With an increase of the irradiation dose from ~10(12) /cm(2) to ~10(15) /cm(2) the carrier lifetime of SI-GaAs monotonously decreases to 0.55 picosecond, whereas that of usual non-irradiated SI-GaAs is ~70 picosecond. This decreased carrier lifetime has resulted in a strong improvement in THz pulse detection compared with normal SI-GaAs. Improvement in signal to noise ratio as well as in detection bandwidth is observed. Carbon irradiated SI-GaAs appears to be an economical alternative to low temperature grown GaAs for fabrication of THz devices. PMID- 25836883 TI - Highly sensitive refractive index sensor based on cascaded microfiber knots with Vernier effect. AB - We propose and experimentally demonstrate a refractive index (RI) sensor based on cascaded microfiber knot resonators (CMKRs) with Vernier effect. Deriving from high proportional evanescent field of microfiber and spectrum magnification function of Vernier effect, the RI sensor shows high sensitivity as well as high detection resolution. By using the method named "Drawing-Knotting-Assembling (DKA)", a compact CMKRs is fabricated for experimental demonstration. With the assistance of Lorentz fitting algorithm on the transmission spectrum, sensitivity of 6523nm/RIU and detection resolution up to 1.533 * 10(-7)RIU are obtained in the experiment which show good agreement with the numerical simulation. The proposed all-fiber RI sensor with high sensitivity, compact size and low cost can be widely used for chemical and biological detection, as well as the electronic/magnetic field measurement. PMID- 25836884 TI - Highly-sensitive gas pressure sensor using twin-core fiber based in-line Mach Zehnder interferometer. AB - A Mach-Zehnder interferometer based on a twin-core fiber was proposed and experimentally demonstrated for gas pressure measurements. The in-line Mach Zehnder interferometer was fabricated by splicing a short section of twin-core fiber between two single mode fibers. A micro-channel was created to form an interferometer arm by use of a femtosecond laser to drill through one core of the twin-core fiber. The other core of the fiber was remained as the reference arm. Such a Mach-Zehnder interferometer exhibited a high gas pressure sensitivity of 9.6 nm/MPa and a low temperature cross-sensitivity of 4.4 KPa/ degrees C. Moreover, ultra-compact device size and all-fiber configuration make it very suitable for highly-sensitive gas pressure sensing in harsh environments. PMID- 25836885 TI - Obtaining new local minima in lens design by constructing saddle points. AB - We show that in the lens design landscape saddle points exist that are closely related to local minima of simpler problems. On the basis of this new theoretical insight we develop a systematic and efficient saddle-point method that uses a priori knowledge for obtaining new local minima. In contrast with earlier saddle point methods, the present method can create both positive and negative lenses. As an example, by successively using the method a good-quality local minimum is obtained from a poor-quality one. The method could also be applicable in other global optimization problems that satisfy the requirements discussed in this paper. PMID- 25836886 TI - Eight-state trellis-coded optical modulation with signal constellations of four dimensional M-ary quadrature-amplitude modulation. AB - We apply the eight-state trellis-coded modulation (TCM) using signal constellations of four-dimensional M-ary quadrature-amplitude modulation (4D MQAM) to optical communication systems for the first time to our knowledge. In the TCM scheme, the free distance of the trellis diagram is equal to the minimum distance between constellation points in partitioned subsets, which enlarges the coding gain effectively. In fact, its asymptotic power efficiency is 3-dB larger than that of the set-partitioned 4D-MQAM (SP-4D-MQAM) format, while their spectral efficiencies are the same. Such theoretical predictions are confirmed through computer simulations on eight-state TCM with constellations of 4D-4QAM (i.e., 4D quadrature phase-shift keying: 4D-QPSK) and 4D-16QAM. In particular, eight-state TCM with 4D-QPSK constellations is practically important because of its simple encoder structure, relatively low computational cost, and high coding gain against dual-polarization QPSK (DP-QPSK) and SP-4D-QPSK. Through measurements of its bit-error rate (BER) performance, we confirm that the coding gain against DP-QPSK is about 3 dB at BER=10(-3). PMID- 25836887 TI - Holistic random encoding for imaging through multimode fibers. AB - The input numerical aperture (NA) of multimode fiber (MMF) can be effectively increased by placing turbid media at the input end of the MMF. This provides the potential for high-resolution imaging through the MMF. While the input NA is increased, the number of propagation modes in the MMF and hence the output NA remains the same. This makes the image reconstruction process underdetermined and may limit the quality of the image reconstruction. In this paper, we aim to improve the signal to noise ratio (SNR) of the image reconstruction in imaging through MMF. We notice that turbid media placed in the input of the MMF transforms the incoming waves into a better format for information transmission and information extraction. We call this transformation as holistic random (HR) encoding of turbid media. By exploiting the HR encoding, we make a considerable improvement on the SNR of the image reconstruction. For efficient utilization of the HR encoding, we employ sparse representation (SR), a relatively new signal reconstruction framework when it is provided with a HR encoded signal. This study shows for the first time to our knowledge the benefit of utilizing the HR encoding of turbid media for recovery in the optically underdetermined systems where the output NA of it is smaller than the input NA for imaging through MMF. PMID- 25836888 TI - Tensile-strained germanium microdisk electroluminescence. AB - We report room temperature electroluminescence of tensile-strained germanium microdisks. The strain is transferred into the microdisks using silicon nitride stressors. Carrier injection is achieved with Schottky contacts on n-type doped germanium. We show that a biaxial tensile-strain up to 0.72% can be transferred by optimizing the carrier injection profile. The transferred strain is measured by the electroluminescence spectral red-shift and compared to finite element modeling. We discuss the impact of this strain level to achieve population inversion in germanium. PMID- 25836889 TI - Rabi oscillations and stimulated mode conversion on the subwavelength scale. AB - We study stimulated mode conversion and dynamics of Rabi-like oscillations of weights of guided modes in deeply subwavelength guiding structures, whose dielectric permittivity changes periodically in the direction of light propagation. We show that despite strong localization of the fields of eigenmodes on the scales below the wavelength of light, even weak longitudinal modulation couples modes of selected parity and causes periodic energy exchange between them, thereby opening the way for controllable transformation of the internal structure of subwavelength beams. The effect is reminiscent of Rabi oscillations in multilevel quantum systems subjected to the action of periodic external fields. By using rigorous numerical solution of the full set of the Maxwell's equations, we show that the effect takes place not only in purely dielectric, but also in metallic-dielectric structures, despite the energy dissipation inherent to the plasmonic waveguides. The stimulated conversion of subwavelength light modes is possible in both linear and nonlinear regimes. PMID- 25836890 TI - Automated mode locking in nonlinear polarization rotation fiber lasers by detection of a discontinuous jump in the polarization state. AB - A strategy to align a mode-locked fiber laser with nonlinear polarization rotation is presented. This strategy is based on measurements of the output polarization state. It is shown that, as the angle of a motorized polarization controller inside the cavity is swept, the laser eventually reaches a mode-locked regime and the values of the Stokes parameters undergo an abrupt change. The sensing of this sudden variation is thus used to detect the mode-locking condition and a feedback mechanism drives the alignment of the polarization controller to force mode locking. PMID- 25836891 TI - Comment on "Optimal detection angle in sub-diffraction resolution photothermal microscopy: application for high sensitivity imaging of biological tissues". AB - A recent publication [Opt. Express, 22(16), 18833-18842 (2014)] discusses the optimal detection aperture in photothermal single particle microscopy. This new theory is in contradiction with rigorous ab-initio electrodynamic calculations. Nonetheless, the experimentally verified conclusion that a maximum signal occurs at a finite numerical detection aperture remains valid and is in accord with existing models. PMID- 25836892 TI - "Optimal detection angle in sub-diffraction resolution photothermal microscopy: application for high sensitivity imaging of biological tissues": reply. AB - The differences between our model and existing models are rationalized in terms of the experimental conditions. The theory in [Opt. Express 22(16), 18833-18842 (2014)] is applicable when the temperature increase is moderate (~1 K) and the spatial extend of refractive index being modulated is comparable to or smaller than the wavelength, which are in accordance with our experiment. PMID- 25836893 TI - Multi-kW peak power acousto-optically tunable thulium-doped fiber laser system. AB - We demonstrate a core-pumped Q-switched thulium-doped fiber laser system with fast tunability capability over 100 nm without any movable part. With up to 7 kW peak power in a diffraction-limited beam, this source is well adapted for pumping a frequency agile mid-IR parametric oscillator or amplifier based on Quasi-Phase Match single-period crystals. PMID- 25836894 TI - Versatile SERS sensing based on black silicon. AB - Black Si (b-Si) with gold or silver metal coating has been shown to be an extremely effective substrate for surface-enhanced Raman scattering (SERS). Here, we demonstrate that it is also a highly versatile SERS platform, as it supports a wide range of surface functionalizations. In particular, we report the use of a molecularly imprinted polymer (MIP) coating and a hydrophobic coating on b-Si to establish two different sensing modalities. First, using a MIP layer on Au-coated b-Si, we show selective sensing of two closely related varieties of tetracycline. Second, a hydrophobic coating was used to concentrate the analyte adsorbed on gold colloidal nanoparticles, thus increasing the sensitivity of the measurement by an order of magnitude. In this experiment, Au nanoparticles and analyte were mixed just before SERS measurements and were concentrated by drop-drying on the super-hydrophobic b-Si. These approaches are promising for SERS measurements that are sensitive to the aging of bare plasmonic metal-coated substrates. PMID- 25836895 TI - Planar optical correlators integrated with binary optical lens. AB - Planar optical correlators (POCs) can achieve smaller volume of optical system and hence have important applications to identify dynamic targets in complex scenarios. POCs, however, generally have serious astigmatism and optical efficiency loss introduced by its refractive lens with a zigzag optical beam. To conquer the disadvantages of POCs, we propose a type of binary optical planar integrated optical correlator. The correlator incorporates two pieces of reflective binary optical lens as Fourier transform lens and one spatial light modulator as a programmable filter. The off-axis aberrations commonly occurred in POCs can be corrected by using reflective binary optical lens instead of refractive lens. As a model of hybrid numerical-optical correlator using optoelectronic interface, the proposal is helpful to improve the integration and flexibility and robustness of POCs. PMID- 25836896 TI - Sub-micron silicon nitride waveguide fabrication using conventional optical lithography. AB - We demonstrate a novel technique to fabricate sub-micron silicon nitride waveguides using conventional contact lithography with MEMS-grade photomasks. Potassium hydroxide anisotropic etching of silicon facilitates line reduction and roughness smoothing and is key to the technique. The fabricated waveguides is measured to have a propagation loss of 0.8dB/cm and nonlinear coefficient of gamma = 0.3/W/m. A low anomalous dispersion of <100ps/nm/km is also predicted. This type of waveguide is highly suitable for nonlinear optics. The channels naturally formed on top of the waveguide also make it promising for plasmonics and quantum efficiency enhancement in sensing applications. PMID- 25836897 TI - Simplified flexible-PON upstream transmission using pulse position modulation at ONU and DSP-enabled soft-combining at OLT for adaptive link budgets. AB - We demonstrate a flexible modulation and detection scheme for upstream transmission in passive optical networks using pulse position modulation at optical network unit, facilitating burst-mode detection with automatic decision threshold tracking, and DSP-enabled soft-combining at optical line terminal. Adaptive receiver sensitivities of -33.1 dBm, -36.6 dBm and -38.3 dBm at a bit error ratio of 10(-4) are respectively achieved for 2.5 Gb/s, 1.25 Gb/s and 625 Mb/s after transmission over a 20-km standard single-mode fiber without any optical amplification. PMID- 25836898 TI - A nanotweezer system for evanescent wave excited surface enhanced Raman spectroscopy (SERS) of single nanoparticles. AB - We experimentally demonstrate the integration of near-field optical tweezers with surface enhanced Raman scattering (SERS) spectroscopy by using the optical evanescent wave from a silicon nitride waveguide to trap single shell-isolated metallic nanoparticles (NPs) and simultaneously excite SERS signals of Raman reporter molecules adsorbed on the surface of the trapped metallic NPs. Both evanescent wave excited Stokes and anti-Stokes SERS spectra of waveguide trapped single silver (Ag) NPs were acquired, which were compared to their far-field SERS spectra. We investigated the trapping of bare and shell-isolated metallic NPs and determined that the addition of a shell to the metallic NPs minimized particle induced laser damage to the waveguide, which allowed for the stable acquisition of the SERS spectra. This work realizes a new nanophotonic approach, which we refer to as near-field light scattering Raman (NLS-Raman), for simultaneous near field optical trapping and SERS characterization of single metallic NPs. PMID- 25836899 TI - Ultra-narrow linewidth measurement based on Voigt profile fitting. AB - We study the method of Voigt profile fitting for ultra-narrow linewidth measurement. It filters out the effect of the spectrum broadening due to the 1/f frequency noise and extracts out the Lorentzian lineshape from the measured spectrum. The resolution is thus greatly promoted than the direct measurement from the self-heterodyne technique. We apply this method to an ultra-narrow linewidth (~40 Hz by heterodyne beat technique) Brillouin/erbium fiber laser. The linewidth estimated from Voigt fitting method is indicated to be more accurate. In contrast, the linewidths estimated direct from the 3-dB and the 20-dB heterodyne-spectrum width are far over the true linewidth of the BEFL. The Voigt fitting method provides an efficient tool for ultra-narrow-linewidth measurement. And compared with heterodyne beat technique, it is applicable for all types of lasers. PMID- 25836900 TI - 65-fs Yb-doped fiber laser system with gain-narrowing compensation. AB - We report a broadband Yb-doped fiber laser system with a gain-narrowing compensator comprised of multiple dielectric layers. Utilizing this filter, we obtained broadband pulses over a bandwidth of 1020-1080 nm directly from the amplifier. After the dispersion compensation, the chirped pulse amplification system delivered 65-fs pulses with energies of 100 nJ and a repetition rate of 3 MHz. PMID- 25836901 TI - Ultra-compact and broadband Si photonics polarization rotator by self-alignment process. AB - An ultra-simple polarization rotator is demonstrated on SOI platform with self aligned process to enhance performance repeatability and manufactural yield. The polarization rotation is essentially achieved by the symmetry breaking of a channel waveguide with a single-sided slab. The two-step lithography enabling this structure is fully compatible with the mainstream process flow of Si photonic integration. A polarization conversion efficiency of 93% is obtained at 1560nm in less than 10MUm light propagation length. The merit of flat-band operation (> 100nm) by using asymmetric waveguide for polarization rotation is inherited. PMID- 25836902 TI - Simple and efficient absorption filter for single photons from a cold atom quantum memory. AB - The ability to filter unwanted light signals is critical to the operation of quantum memories based on neutral atom ensembles. Here we demonstrate an efficient frequency filter which uses a vapor cell filled with (85)Rb and a buffer gas to attenuate both residual laser light and noise photons by nearly two orders of magnitude with little loss to the single photons associated with our cold (87)Rb quantum memory. This simple, passive filter provides an additional 18 dB attenuation of our pump laser and erroneous spontaneous emissions for every 1 dB loss of the single photon signal. We show that the addition of a frequency filter increases the non-classical correlations and the retrieval efficiency of our quantum memory by ~ 35%. PMID- 25836903 TI - High-contrast linear optical pulse compression using a temporal hologram. AB - Temporal holograms can be realized by temporal amplitude-only modulation devices and used for generation and processing of complex (amplitude and phase) time domain signals. Based on the temporal hologram concept, we numerically and experimentally demonstrate a novel design for linear optical pulse compression using temporal modulation of continuous-wave light combined with dispersion. The newly introduced scheme overcomes the undesired background problem that is intrinsic to designs based on temporal zone plates, while also offering an energy efficiency of ~25%. This pulse compression scheme can ideally provide an arbitrarily high time-bandwidth product using a low peak-power modulation driving signal, though in practice it is limited by the achievable modulation bandwidth and dispersion amount. PMID- 25836904 TI - Fringe projection 3D microscopy with the general imaging model. AB - Three-dimensional (3D) imaging and metrology of microstructures is a critical task for the design, fabrication, and inspection of microelements. Newly developed fringe projection 3D microscopy is presented in this paper. The system is configured according to camera-projector layout and long working distance lenses. The Scheimpflug principle is employed to make full use of the limited depth of field. For such a specific system, the general imaging model is introduced to reach a full 3D reconstruction. A dedicated calibration procedure is developed to realize quantitative 3D imaging. Experiments with a prototype demonstrate the accessibility of the proposed configuration, model, and calibration approach. PMID- 25836905 TI - Fano resonance in all-dielectric binary nanodisk array realizing optical filter with efficient linewidth tuning. AB - In this research paper, we study the Fano resonance originating from the interaction of in-phased lattice collective resonance and anti-phased lattice collective resonance supported by a binary silicon nanodisk array. Experimental results agree well with the calculations using finite-difference-time-domain method and show a strong dependence of such Fano lineshapes on the radius difference of the particles in the array. Further calculations demonstrate that such binary silicon nanodisk array can be used as an optical filter and offers an efficient way to tune the linewidth simply by changing the radius of the particles, linewidth from 12 nm to 0.7 nm and corresponding Q factor from 72 to 1290 as the radius R(2) increasing from 60 nm to 115 nm. Such scheme possessing the merits of being easily fabricated, simulated, and tuned is very promising for practical applications. PMID- 25836906 TI - Residual strain sensor using Al-packaged optical fiber and Brillouin optical correlation domain analysis. AB - We propose a distributed residual strain sensor that uses an Al-packaged optical fiber for the first time. The residual strain which causes Brillouin frequency shifts in the optical fiber was measured using Brillouin optical correlation domain analysis with 2 cm spatial resolution. We quantified the Brillouin frequency shifts in the Al-packaged optical fiber by the tensile stress and compared them for a varying number of Al layers in the optical fiber. The Brillouin frequency shift of an optical fiber with one Al layer had a slope of 0.038 MHz/MUepsilon with respect to tensile stress, which corresponds to 78% of that for an optical fiber without Al layers. After removal of the stress, 87% of the strain remained as residual strain. When different tensile stresses were randomly applied, the strain caused by the highest stress was the only one detected as residual strain. The residual strain was repeatedly measured for a time span of nine months for the purpose of reliability testing, and there was no change in the strain except for a 4% reduction, which is within the error tolerance of the experiment. A composite material plate equipped with our proposed Al-packaged optical fiber sensor was hammered for impact experiment and the residual strain in the plate was successfully detected. We suggest that the Al-packaged optical fiber can be adapted as a distributed strain sensor for smart structures, including aerospace structures. PMID- 25836907 TI - Hybrid Si-VO(2)-Au optical modulator based on near-field plasmonic coupling. AB - We present a computational design for an integrated electro-optic modulator based on near-field plasmonic coupling between gold nanodisks and a thin film of vanadium dioxide on a silicon substrate. Active modulation is achieved by applying a time-varying electric field to initiate large changes in the refractive index of vanadium dioxide. Significant decrease in device footprint (200 nm x 560 nm) and increase in extinction ratio per unit length (9 dB/um) compared to state-of-the-art photonic and plasmonic modulators are predicted. PMID- 25836908 TI - All-optical switching of nematic liquid crystal films driven by localized surface plasmons. AB - We have demonstrated an all-optical technique for reversible in-plane and out-of plane switching of nematic liquid crystal molecules in few micron thick films. Our method leverages the highly localized electric fields ("hot spots") and plasmonic heating that are generated in the near-field region of densely packed gold nanoparticle layers optically excited on-resonance with the localized surface plasmon absorption. Using polarized microscopy and transmission measurements, we observe this switching from homeotropic to planar over a temperature range starting at room temperature to just below the isotropic transition, and at on-resonance excitation intensity less than 0.03 W/cm(2). In addition, we controllably vary the in-plane directionality of the liquid crystal molecules in the planar state by altering the linear polarization of the incident excitation. Using discrete dipole simulations and control measurements, we establish spectral selectivity in this new and interesting perspective for photonic application using low light power. PMID- 25836909 TI - Dispersion-tunable designer-plasmonic resonator with enhanced high-order resonances. AB - We propose and experimentally demonstrate an approach to efficiently tune the dispersion of a designer-plasmonic resonator, or a plasmonic 'meta-atom', by incorporating an extra ground plane underneath. We demonstrate that this ground plane is able to enhance resonances, and the enhancing effect can render those higher-order azimuthal modes, being absent in previously reported designer plasmonic resonators, experimentally observable. After incorporating the ground plane, all resonance modes are red shifted with their Q factors enhanced. By increasing the separation from the planar resonator to the underneath ground plane, all enhanced modes are blue shifted with Q factors decreased slightly, whose trend is opposite to increasing the thickness of a dielectric substrate of a common meta-atom without a ground. These results may find potential applications in tunable designer-plasmonic sensors and plasmonic metamaterial designs. PMID- 25836910 TI - Mid-infrared supercontinuum generation using dispersion-engineered Ge(11.5)As(24)Se(64.5) chalcogenide channel waveguide. AB - We numerically investigate mid-infrared supercontinuum (SC) generation in dispersion-engineered, air-clad, Ge(11.5)As(24)Se(64.5) chalcogenide-glass channel waveguides employing two different materials, Ge(11.5)As(24)Se(64.5) or MgF(2) glass for their lower cladding. We study the effect of waveguide parameters on the bandwidth of the SC at the output of 1-cm-long waveguide. Our results show that output can vary over a wide range depending on its design and the pump wavelength employed. At the pump wavelength of 2 MUm the SC never extended beyond 4.5 MUm for any of our designs. However, supercontinuum could be extended to beyond 5 MUm for a pump wavelength of 3.1 MUm. A broadband SC spanning from 2 MUm to 6 MUm and extending over 1.5 octave could be generated with a moderate peak power of 500 W at a pump wavelength of 3.1 MUm using an air clad, all-chalcogenide, channel waveguide. We show that SC can be extended even further when MgF(2) glass is used for the lower cladding of chalcogenide waveguide. Our numerical simulations produced SC spectra covering the wavelength range 1.8-7.7 MUm (> two octaves) by using this geometry. Both ranges exceed the broadest SC bandwidths reported so far. Moreover, we realize it using 3.1 MUm pump source and relatively low peak power pulses. By employing the same pump source, we show that SC spectra can cover a wavelength range of 1.8-11 MUm (> 2.5 octaves) in a channel waveguide employing MgF(2) glass for its lower cladding with a moderate peak power of 3000 W. PMID- 25836911 TI - Phase-locked arrays of surface-emitting graded-photonic-heterostructure terahertz semiconductor lasers. AB - We have demonstrated that a hybrid laser array, combining graded-photonic heterostructure terahertz semiconductor lasers with a ring resonator, allows the relative phase (either symmetric or anti-symmetric) between the sources to be fixed by design. We have successfully phase-locked up to five separate lasers. Compared with a single device, we achieved a clear narrowing of the output beam profile. PMID- 25836912 TI - Energetic mid-IR femtosecond pulse generation by self-defocusing soliton-induced dispersive waves in a bulk quadratic nonlinear crystal. AB - Generating energetic femtosecond mid-IR pulses is crucial for ultrafast spectroscopy, and currently relies on parametric processes that, while efficient, are also complex. Here we experimentally show a simple alternative that uses a single pump wavelength without any pump synchronization and without critical phase-matching requirements. Pumping a bulk quadratic nonlinear crystal (unpoled LiNbO(3) cut for noncritical phase-mismatched interaction) with sub-mJ near-IR 50 fs pulses, tunable and broadband (~ 1,000 cm(-1)) mid-IR pulses around 3.0 MUm are generated with excellent spatio-temporal pulse quality, having up to 10.5 MUJ energy (6.3% conversion). The mid-IR pulses are dispersive waves phase-matched to near-IR self-defocusing solitons created by the induced self-defocusing cascaded nonlinearity. This process is filament-free and the input pulse energy can therefore be scaled arbitrarily by using large-aperture crystals. The technique can readily be implemented with other crystals and laser wavelengths, and can therefore potentially replace current ultrafast frequency-conversion processes to the mid-IR. PMID- 25836913 TI - Computationally effective solution of the inverse problem in time-of-flight spectroscopy. AB - Photon time-of-flight (PTOF) spectroscopy enables the estimation of absorption and reduced scattering coefficients of turbid media by measuring the propagation time of short light pulses through turbid medium. The present investigation provides a comparison of the assessed absorption and reduced scattering coefficients from PTOF measurements of intralipid 20% and India ink-based optical phantoms covering a wide range of optical properties relevant for biological tissues and dairy products. Three different models are used to obtain the optical properties by fitting to measured temporal profiles: the Liemert-Kienle model (LKM), the diffusion model (DM) and a white Monte-Carlo (WMC) simulation-based algorithm. For the infinite space geometry, a very good agreement is found between the LKM and WMC, while the results obtained by the DM differ, indicating that the LKM can provide accurate estimation of the optical parameters beyond the limits of the diffusion approximation in a computational effective and accurate manner. This result increases the potential range of applications for PTOF spectroscopy within industrial and biomedical applications. PMID- 25836914 TI - All-fiber Mach-Zehnder interferometer based on two liquid infiltrations in a photonic crystal fiber. AB - We propose a novel all-fiber Mach-Zehnder interferometer (MZI) fabricated by infiltrating two separated liquid sections along a PCF. Due to the reduced effective index difference between the core region and the liquid-filled cladding region, the guided field in the liquid sections possesses a larger mode field area and can simultaneously induce the core mode and cladding modes of the empty PCF to form a MZI. The measured results demonstrate that very clear interference spectra can be obtained. By increasing the length of the MZIs, the decreased average fringe spacing can be observed. We have also measured the temperature sensitivity of our proposed PCF-based MZIs. Due to the existence of the two liquid sections, the temperature sensitivities can be enlarged to -0.176nm/ degrees C and -0.53dB/ degrees C. PMID- 25836915 TI - Continuously tunable true-time delays with ultra-low settling time. AB - Ultra-fast, continuously tunable true-time delays are key components in many microwave and optical communications subsystems. In this paper, we introduce and demonstrate a new implementation method of a continuously tunable true-time delay featuring a settling time in the order of tens of picoseconds. Our solution relies on the splitting and combining of complementary phased shifted spectra (CPSS). It works for large bandwidth signals, has a low complexity, offers moderate losses, and can be fully integrated. PMID- 25836916 TI - Experimental demonstration of propagation characteristics of mid-infrared photonic crystal waveguides in silicon-on-sapphire. AB - We provide the first experimental demonstration of optical transmission characteristics of a W1 photonic crystal waveguide in silicon on sapphire at mid infrared wavelength of 3.43 MUm. Devices are studied as a function of lattice constant to tune the photonic stop band across the single wavelength of the source laser. The shift in the transmission profile as a function of temperature and refractive index is experimentally demonstrated and compared with simulations. In addition to zero transmission in the stop gap, propagation losses less than 20 dB/cm are observed for group indices greater than 20 below the light line while more than 300 dB/cm propagation losses are observed above the light line, characteristic of the waveguiding behavior of photonic crystal line defect modes. PMID- 25836917 TI - Noise reduction and signal-to-noise ratio improvement of atomic magnetometers with optical gradiometer configurations. AB - In the field of biomagnetic measurement, optically-pumped atomic magnetometers (OPAMs) have attracted significant attention. With the improvement of signal response and the reduction of sensor noise, the sensitivity of OPAMs is limited mainly by environmental magnetic noise. To reduce this magnetic noise, we developed the optical gradiometer, in which the differential output of two distinct measurement areas inside a glass cell was obtained directly via the magneto-optical rotation of one probe beam. When operating in appropriate conditions, the sensitivity was improved by the differential measurement of the optical gradiometer. In addition, measurements of the pseudo-magnetic noise and signal showed the improvement of the signal-to-noise ratio. These results demonstrate the feasibility of our optical gradiometer as an efficient method for reducing the magnetic noise. PMID- 25836918 TI - One-week administration of hydroxytyrosol to humans does not activate Phase II enzymes. AB - The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes' expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the "hormesis hypothesis" that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622). PMID- 25836919 TI - A1-adenosine acute withdrawal response and cholecystokinin-8 induced contractures are regulated by Ca(2+)- and ATP-activated K(+) channels. AB - In isolated guinea-pig ileum (GPI), the A1-adenosine acute withdrawal response is under the control of several neuronal signalling systems, including the MU/kappa opioid and the cannabinoid CB1 systems. It is now well established that after the stimulation of the A1-adenosine system, the indirect activation of both MU/kappa opioid and CB1 systems is prevented by the peptide cholecystokinin-8 (CCk-8). In the present study, we have investigated the involvement of the Ca(2+)/ATP activated K(+) channels in the regulation of both acute A1-withdrawal and CCk-8 induced contractures in the GPI preparation. Interestingly, we found that: (a) the A1-withdrawal contracture is inhibited by voltage dependent Ca(2+)-activated K(+) channels, Kv, while it is enhanced by the voltage independent Ca(2+) activated K(+) channels, SKCa; (b) in the presence of CCk-8, the inhibitory effect of the A1 agonist, CPA, on the peptide induced contracture is significantly enhanced by the voltage independent Ca(2+)-activated K(+) channel, SKCa; and (c) the A1-withdrawal contracture precipitated in the presence of CCk-8 is controlled by the ATP-sensitive potassium channels, KATP. Our data suggest, for the first time, that both Ca(2+)- and ATP-activated K(+) channels are involved in the regulation of both A1-withdrawal precipitated and CCk-8 induced contractures. PMID- 25836920 TI - Altered expression of connexin 43 and related molecular partners in a pig model of left ventricular dysfunction with and without dipyrydamole therapy. AB - Gap junctions (GJ) mediate electrical coupling between cardiac myocytes, allowing the spreading of the electrical wave responsible for synchronized contraction. GJ function can be regulated by modulation of connexon densities on membranes, connexin (Cx) phosphorylation, trafficking and degradation. Recent studies have shown that adenosine (A) involves Cx43 turnover in A1 receptor-dependent manner, and dipyridamole increases GJ coupling and amount of Cx43 in endothelial cells. As the abnormalities in GJ organization and regulation have been described in diseased myocardium, the aim of the present study was to assess the regional expression of molecules involved in GJ regulation in a model of left ventricular dysfunction (LVD). For this purpose the distribution and quantitative expression of Cx43, its phosphorylated form pS368-Cx43, PKC phosphorylated substrates, RhoA and A receptors, were investigated in experimental models of right ventricular pacing induced LVD, undergoing concomitant dipyridamole therapy or placebo, and compared with those obtained in the myocardium from sham-operated minipigs. Results demonstrate that an altered pattern of factors involved in Cx43-made GJ regulation is present in myocardium of a dysfunctioning left ventricle. Furthermore, dipyridamole treatment, which shows a mild protective role on left ventricular function, seems to act through modulating the expression and activation of these factors as confirmed by in vitro experiments on cardiomyoblastic cell line H9c2 cells. PMID- 25836921 TI - Oral curcumin has anti-arthritic efficacy through somatostatin generation via cAMP/PKA and Ca(2+)/CaMKII signaling pathways in the small intestine. AB - Curcumin (CUR) has been proven to be clinically effective in rheumatoid arthritis (RA) therapy, but its low oral bioavailability eclipses existent evidence that attempts to explain the underlying mechanism. Small intestine, the only organ exposed to a relatively high concentration of CUR, is the main site that generates gut hormones which are involved in the pathogenesis of RA. This study aims at addressing the hypothesis that one or more gut hormones serve as an intermediary agent for the anti-arthritic action of CUR. The protein and mRNA levels of gut hormones in CUR-treated rats were analyzed by ELISA and RT-PCR. Somatostatin (SOM) depletor and receptor antagonist were used to verify the key role of SOM in CUR-mediated anti-arthritic effect. The mechanisms underlying CUR induced upregulation of SOM levels were explored by cellular experiments and immunohistochemical staining. The data showed that oral administration of CUR (100 mg/kg) for consecutive two weeks in adjuvant-induced arthritis rats still exhibited an extremely low plasma exposure despite of a dramatic amelioration of arthritis symptoms. When injected intraperitoneally, CUR lost anti-arthritic effect in rats, suggesting that it functions in an intestine-dependent manner. CUR elevated SOM levels in intestines and sera, and SOM depletor and non selective SOM receptor antagonist could abolish the inhibitory effect of CUR on arthritis. Immunohistochemical assay demonstrated that CUR markedly increased the number of SOM-positive cells in both duodenum and jejunum. In vitro experiments demonstrated that CUR could augment SOM secretion from intestinal endocrine cells, and this effect could be hampered by either MEK1/2 or Ca(2+)/calmodulin dependent kinase II (CAMKII) inhibitor. In summary, oral administration of CUR exhibits anti-arthritic effect through augmenting SOM secretion from the endocrine cells in small intestines via cAMP/PKA and Ca(2+)/CaMKII signaling pathways. PMID- 25836923 TI - Ebola virus disease. PMID- 25836922 TI - Administration of a multistrain probiotic product (VSL#3) to women in the perinatal period differentially affects breast milk beneficial microbiota in relation to mode of delivery. AB - Probiotic supplementation to a mother during the perinatal period can have a positive impact on the breast milk composition. The aim of our study was to evaluate the effect of oral supplementation with the probiotic VSL#3, during late pregnancy and lactation, on breast milk levels of beneficial bacteria and some functional components (oligosaccharides and lactoferrin) potentially able to have a positive influence on the microbiota. Breast milk microbiota was analyzed by conventional and quantitative real-time PCR. In a double-blind, placebo controlled, randomized trial, 66 women took daily either the probiotic (n=33) or a placebo (n=33). Intergroup analysis demonstrated that the amounts of both lactobacilli and bifidobacteria were significantly higher in the colostrum and mature milk of the mothers taking VSL#3 in comparison to those taking placebo. The analysis of bacterial strains and species present in breast milk of VSL#3 supplemented mothers indicated that the administered probiotic microorganisms did not pass from maternal gut to mammary gland. In women with vaginal delivery, significantly higher amounts of lactobacilli and bifidobacteria were detected in colostrum and mature milk of probiotic treated group in comparison to placebo group, whereas no significant difference was observed between groups in women who had caesarean section, neither in colostrum nor in mature milk. Milk levels of oligosaccharides and lactoferrin were similar in placebo and probiotic supplemented groups at all timepoints and regardless of the mode of delivery. Our results indicate a probiotic-dependent modulation of breast milk microbiota in vaginally delivering women, possibly exerted through a systemic effect. PMID- 25836924 TI - Cardiomyoblast (h9c2) differentiation on tunable extracellular matrix microenvironment. AB - Extracellular matrices (ECM) obtained from in vitro-cultured cells have been given much attention, but its application in cardiac tissue engineering is still limited. This study investigates cardiomyogenic potential of fibroblast-derived matrix (FDM) as a novel ECM platform over gelatin or fibronectin, in generating cardiac cell lineages derived from H9c2 cardiomyoblasts. As characterized through SEM and AFM, FDM exhibits unique surface texture and biomechanical property. Immunofluorescence also found fibronectin, collagen, and laminin in the FDM. Cells on FDM showed a more circular shape and slightly less proliferation in a growth medium. After being cultured in a differentiation medium for 7 days, H9c2 cells on FDM differentiated into cardiomyocytes, as identified by stronger positive markers, such as alpha-actinin and cTnT, along with more elevated gene expression of Myl2 and Tnnt compared to the cells on gelatin and fibronectin. The gap junction protein connexin 43 was also significantly upregulated for the cells differentiated on FDM. A successive work enabled matrix stiffness tunable; FDM crosslinked by 2wt% genipin increased the stiffness up to 8.5 kPa, 100 times harder than that of natural FDM. The gene expression of integrin subunit alpha5 was significantly more upregulated on FDM than on crosslinked FDM (X-FDM), whereas no difference was observed for beta1 expression. Interestingly, X-FDM showed a much greater effect on the cardiomyoblast differentiation into cardiomyocytes over natural one. This study strongly indicates that FDM can be a favorable ECM microenvironment for cardiomyogenesis of H9c2 and that tunable mechanical compliance induced by crosslinking further provides a valuable insight into the role of matrix stiffness on cardiomyogenesis. PMID- 25836925 TI - Nuclear export of messenger RNA. AB - Transport of messenger RNA (mRNA) from the nucleus to the cytoplasm is an essential step of eukaryotic gene expression. In the cell nucleus, a precursor mRNA undergoes a series of processing steps, including capping at the 5' ends, splicing and cleavage/polyadenylation at the 3' ends. During this process, the mRNA associates with a wide variety of proteins, forming a messenger ribonucleoprotein (mRNP) particle. Association with factors involved in nuclear export also occurs during transcription and processing, and thus nuclear export is fully integrated into mRNA maturation. The coupling between mRNA maturation and nuclear export is an important mechanism for providing only fully functional and competent mRNA to the cytoplasmic translational machinery, thereby ensuring accuracy and swiftness of gene expression. This review describes the molecular mechanism of nuclear mRNA export mediated by the principal transport factors, including Tap-p15 and the TREX complex. PMID- 25836926 TI - EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression. AB - DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSbeta, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation induced compartmentalization and inactivation for MSH3. PMID- 25836927 TI - Epidemiology of bladder cancer. AB - Bladder cancer incidence is higher in old men, shows geographic variation, and is mostly an environmental disease. Cigarette smoking, occupational exposures, water arsenic, Schistosoma haematobium infestation, and some medications are the best established risk factors. Low-penetrance genetic factors also contribute to its origin, some through interaction with environmental factors. Bladder cancer has high prevalence and a low mortality, being largely a chronic disease. Data on environmental and genetic factors involved in the disease outcome are inconclusive. PMID- 25836928 TI - Molecular biology of bladder cancer. AB - Classic as well as more recent large-scale genomic analyses have uncovered multiple genes and pathways important for bladder cancer development. Genes involved in cell-cycle control, chromatin regulation, and receptor tyrosine and PI3 kinase-mammalian target of rapamycin signaling pathways are commonly mutated in muscle-invasive bladder cancer. Expression-based analyses have identified distinct types of bladder cancer that are similar to subsets of breast cancer, and have prognostic and therapeutic significance. These observations are leading to novel therapeutic approaches in bladder cancer, providing optimism for therapeutic progress. PMID- 25836929 TI - Diagnosis and staging of bladder cancer. AB - Bladder cancer (BCa) is a heterogeneous disease with a variable natural history. Most patients (70%) present with superficial tumors (stages Ta, T1, or carcinoma in situ). However, 3 out of 10 patients present with muscle-invasive disease (T2 4) with a high risk of death from distant metastases. Moreover, roughly between 50% and 70% of superficial tumors do recur, and approximately 10% to 20% of them progress to muscle-invasive disease. However, BCa has a relatively low ratio of mortality versus incidence of new cases. In consequence, there is the danger of overdiagnosis and overtreatment. PMID- 25836930 TI - Management of low-risk and intermediate-risk non-muscle-invasive bladder carcinoma. AB - Non-muscle-invasive bladder cancer is a highly recurrent disease. The health care costs for non-muscle-invasive bladder cancer are a major burden for society. Bladder cancer treatment starts with a presumed complete transurethral resection of a bladder tumor. Despite international guidelines for perioperative and/or adjuvant intravesical instillation therapy in non-muscle-invasive bladder cancer, adequate worldwide application is lacking. In patients who do get adjuvant intravesical instillations, recurrences are still frequent. New therapies in non muscle-invasive bladder cancer are unsatisfactory and still experimental. PMID- 25836931 TI - High-risk nonmuscle invasive bladder cancer. AB - Please also verify that the expansion of HGT1 is OK as set: The risk of progression for high-grade T1 (HGT1) cancer has been recently established at 21% using updated information on large series and a meta-analysis. These outcomes are better than those classically expected supporting the rule of thirds for HGT1. The main limitation of this subgroup is that most studies are retrospective observational studies, which, compared with randomized controlled trials, are subject to various selection biases, carrying a higher risk of uncontrolled confounding factors, with potential preferential reporting of positive findings. PMID- 25836932 TI - Nonurothelial bladder cancer and rare variant histologies. AB - At present, radical cystectomy is a mainstay in the management of all bladder cancers, whether of conventional urothelial histology or variant. However, in the case of some variants, it is clearly not enough and multimodal therapy is an imperative. In other cases, systemic therapy might be ineffective or even detrimental if it leads to delay in surgery (ie, squamous cell carcinoma). Thus, identification of variant histology is a critical part of bladder cancer staging because such histology may require appropriately tailored therapy. PMID- 25836933 TI - New trends in the surgical management of invasive bladder cancer. AB - Radical cystectomy with urinary diversion is one of the most complex urologic procedures and is associated with significant morbidity and mortality. Although it remains the gold standard for treatment of advanced localized disease, survival has not changed substantially over the preceding decades, and high complication rates and prolonged hospital stays remain common. However, recent years have seen the development of robotic-assisted radical cystectomy, trials on the benefit of extended lymph node dissection, and evidence supporting the role of Enhanced Recovery After Surgery protocols. This article reviews recent trends in surgical management of muscle-invasive bladder cancer. PMID- 25836934 TI - Diagnosis and management of upper tract urothelial carcinoma. AB - While UTUC is relatively uncommon, it has an aggressive natural history and poor prognosis, which has not substantially improved over the past two decades. Nevertheless, continued research has led to the discovery of risk factors improving the prevention and early detection of UTUC. Although RNU remains the standard treatment for localized invasive UTUC, nephron-sparing surgery for selected patients has made considerable progress in the recent years. The stagnation in the prognosis of UTUC over the past two decades highlights the necessity for incorporating multimodal approaches including refinements in systemic chemotherapy and radiotherapy to attain better outcomes for patients with UTUC. PMID- 25836935 TI - Bladder preservation strategies. AB - Although cystectomy remains the standard for treatment of muscle-invasive bladder cancer in the United States, there exist potentially curative alternatives for a selected subset of these patients in organ preservation using concurrent chemotherapy with radiation following an aggressive transurethral resection of the tumor. Chemotherapy and radiotherapy in combination, with salvage cystectomy for invasive recurrence, have produced 10-year disease-specific survival rates of 60% to 65% with overall survival similar to that of cystectomy in selected patients. Fine-tuning of the chemoradiotherapy sequencing, timing, and fractionation has been reported in both single-center and cooperative group publications from North America and Europe. PMID- 25836936 TI - Perioperative therapy for muscle invasive bladder cancer. AB - Muscle invasive bladder cancer (MIBC) is an aggressive disease associated with poor survival rates. High rates of relapse, despite radical cystectomy, suggest that administration of systemic therapy in the perioperative period may improve clinical outcomes. Neoadjuvant treatment with cisplatin-based combination regimens is an established standard of care and has improved long-term survival in MIBC. As the use of neoadjuvant chemotherapy steadily increases, clinicians still need to decide about administering adjuvant chemotherapy to patients with high-risk disease. This review examines in detail the latest evidence available for both neoadjuvant and adjuvant chemotherapy, and highlights pertinent studies. PMID- 25836937 TI - First-line treatment and prognostic factors of metastatic bladder cancer for platinum-eligible patients. AB - Metastatic urothelial carcinoma is primarily a disease of the elderly, with a median overall survival of approximately 15 months. Cisplatin-based combination chemotherapy is standard first-line treatment for eligible patients, with carboplatin-based regimens used as an alternative for patients considered unfit to receive cisplatin. Prognostic models incorporating clinical risk factors have been validated, and molecular characteristics that predict for treatment response are under investigation. This review summarizes the current status of first-line treatment of metastatic urothelial carcinoma in platinum-eligible patients as well as prognostic and predictive models in this disease. PMID- 25836938 TI - First-line treatment of metastatic disease: cisplatin-ineligible patients. AB - More than 50% of patients with advanced urothelial carcinoma are not eligible for the standard treatment with cisplatin-based chemotherapy. In general, cisplatin ineligible patients with metastatic urothelial cancer experience poor outcomes with standard treatment, although substantial heterogeneity exists. Baseline variables associated with poor prognosis include borderline performance status, presence of visceral metastases, liver metastases, and low hemoglobin. Although no standard treatment has been defined for cisplatin-ineligible patients, recommendations regarding carboplatin-based combination chemotherapy versus single-agent chemotherapy versus best supportive care are typically based on performance status and renal function. The clinical development of novel agents is of considerable interest. PMID- 25836939 TI - Second-line therapies in metastatic urothelial carcinoma. AB - Patients with relapsed or refractory urothelial carcinoma (UC) face a poor prognosis and a dearth of available treatment options that improve their survival. End-organ function and performance status play a vital role in the choice of second-line therapies. Evidence supporting the use of cytotoxic chemotherapy, as single agents or in combination, arises from small phase 2 studies with modest responses. With the evolution of genomic testing in UC, several pathways amenable to available targeted therapies have emerged. Encouraging patient participation in clinical trials is critical to improve patient outcomes and to advance the current modest treatment armamentarium. PMID- 25836940 TI - Future directions and targeted therapies in bladder cancer. AB - There are substantial unmet needs for patients with metastatic urothelial carcinoma (UC). First-line cisplatin-based chemotherapy regimens yield a median survival of 12 to 15 months and long-term survival in 5% to 15%. Salvage systemic therapy yields a median survival of 6 to 8 months. Hence, the discovery of novel therapeutic targets is of paramount importance. Recent molecular analyses have provided insights regarding molecular tumor tissue alterations on multiple platforms. A multidisciplinary effort using innovative clinical trial designs and exploiting preclinical signals of robust activity guided by predictive biomarkers may provide much needed clinical advances in therapy for advanced UC. PMID- 25836941 TI - Therapeutic opportunities in the intrinsic subtypes of muscle-invasive bladder cancer. AB - Recent studies revealed that muscle-invasive bladder cancers segregate into intrinsic basal and luminal subtypes that are similar to those described for breast cancer. Each subtype is enriched with potentially clinically actionable genomic alterations and epigenetic signatures; there are associations between tumor subtype and sensitivity to conventional cisplatin-based chemotherapy. The authors review biological and clinical characteristics of the intrinsic subtypes and describe their implications for the development of conventional and targeted agents. The role that tumor plasticity seems to play in basal and luminal bladder cancer biology and its potential effects on the development of therapeutic resistance is also discussed. PMID- 25836942 TI - Bladder cancer. PMID- 25836943 TI - Lower serum 25 (OH) D concentrations in type 1 diabetes: A meta-analysis. AB - OBJECTIVE: Vitamin D may have protective effects against type 1 diabetes (T1D). However, the results of current cross-sectional studies have been inconsistent. We aimed to examine the association of serum vitamin D and T1D by conducting a meta-analysis. METHODS: Multiple databases were searched until April 2014 to identify relevant studies. The search term was "serum vitamin D" and "type 1 diabetes". Random effects model was used to calculate the pooled risk estimate. The data were accessed by software Review manager 5.2. RESULTS: We included a total of 23 studies (11 studies with 1900 participants of children or adolescents and 13 studies with 3494 participants of adults) in our meta-analysis. In children or adolescents, serum 25(OH) D in T1D was 5.69 ng/ml [95% confidence interval (CI) (2.82-8.55, P<0.0001) lower than in healthy controls. In adults, serum 25(OH) D in T1D was 2.61 ng/ml [95% confidence interval (CI) (1.13-4.09, P=0.0005) lower than in healthy controls. We did not find evidence of publication bias. CONCLUSION: Serum 25OHD is significantly lower in patients with T1D than in healthy controls. PMID- 25836944 TI - Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity. AB - Non-alcoholic fatty liver disease (NAFLD) is common in diabetes and obesity but few have clinically significant liver fibrosis. Improved risk-assessment is needed as the commonly used clinical-risk algorithm, the NAFLD fibrosis score (NFS), is often inconclusive. AIMS: To determine whether circulating fibroblast activation protein (cFAP), which is elevated in cirrhosis, has value in excluding significant fibrosis, particularly combined with NFS. METHODS: cFAP was measured in 106 with type 2 diabetes who had transient elastography (Cohort 1) and 146 with morbid obesity who had liver biopsy (Cohort 2). RESULTS: In Cohort 1, cFAP (per SD) independently associated with median liver stiffness (LSM) >= 10.3 kPa with OR of 2.0 (95% CI 1.2-3.4), p=0.006. There was 0.12 OR (95% CI 0.03-0.61) of LSM >= 10.3 kPa for those in the lowest compared with the highest FAP tertile (p=0.010). FAP levels below 730 pmol AMC/min/mL had 95% NPV for LSM >= 10.3 kPa and reclassified 41% of 64 subjects from NFS 'indeterminate-risk' to 'low-risk'. In Cohort 2, cFAP (per SD), associated with 1.7 fold (95% CI 1.1-2.8) increased odds of significant fibrosis (F >= 2), p=0.021, and low cFAP reclassified 49% of 73 subjects from 'indeterminate-risk' to 'low-risk'. CONCLUSIONS: Lower cFAP, when combined with NFS, may have clinical utility in excluding significant fibrosis in diabetes and obesity. PMID- 25836945 TI - Effects of sitagliptin on the serum creatinine in Japanese type 2 diabetes. AB - We found a slight elevation of serum creatinine in the subjects treated with sitagliptin for 2 years and a correlation between creatinine elevation and HbA1c reduction. These results suggest that creatinine elevation is associated with activation of incretin, most possibly with up-regulation of diuretic activity of GLP-1. PMID- 25836946 TI - Pulmonary capillary permeability and pulmonary microangiopathy in diabetes mellitus. AB - Significant increase in permeability surface (PS) in patients with diabetes confirms pulmonary microcirculation damage in these patients. PMID- 25836947 TI - Comprehensive bedside point of care testing in critical ED patients: a before and after study. AB - OBJECTIVE: We determined the effects of comprehensive point-of-care testing (POCT) on process of care in critically ill emergency department (ED) patients. We hypothesized that POCT would shorten ED length of stay (LOS), reduce time to test results, and reduce time to completion of intravenous (IV) contrast computed tomography (CT) imaging compared with central lab testing. METHODS: A before and after study was performed in ED patients triaged to the critical care area. During the before period, traditional lab testing was performed, whereas in the after period, bedside POCT devices were introduced in all 15 critical care beds with 5 testing cartridges (chemistry with hemoglobin and hematocrit, troponin I, brain natriuretic peptide, lactate, and international normalized ratio [INR]). Clinical protocols indicated when POCT should be used. RESULTS: The numbers of critical ED patients before and after introducing POCT were 1405 and 981 respectively. Test turnaround (minutes) was significantly reduced with bedside POCT for all five tests. Use of POCT reduced the median [interquartile range] time to completion of IV contrast CT by 81 minutes (96 [55-214] vs 177 [78-300]; P = .004). Point-of-care testing significantly reduced median ED LOS in patients who received an IV contrast CT (260 [180-410] vs 347 [347 (202-523]; P = .03). CONCLUSIONS: Introduction of comprehensive bedside POCT in critical ED patients is associated with significant reductions in test turnaround, and time to completion of CT scanning when IV contrast is required. ED LOS was also reduced in the latter population. PMID- 25836948 TI - Multimodality diagnosis and surgical management of prosthetic valve endocarditis complicated with perivalvular abscess formation. PMID- 25836949 TI - [An immobilising malignant phyllodes tumour of the breast]. AB - Phyllodes tumours of the breast are rare occurrences, but they can reach huge dimensions. Descriptions of tumours whereby the women are immobilised as a consequence of the size of the tumour, are hard to find in the literature. In this presentation we show a case of a woman in otherwise healthy condition with a giant phyllodes tumour of her left breast. Because of the weight of the tumour, the patient could not leave her bed for more than 6 months. PMID- 25836950 TI - Factors influencing meat emulsion properties and product texture: A review. AB - Emulsion-based meat products play an important role in modern meat industry. Though meat batters have been prepared traditionally since long back in the history, the scientific principles and the knowhow are significantly important in the case of commercial products. In India, the market for emulsion meat products is gaining importance in the recent years and the native producers are in critical need for the scientific basis of production of emulsion meat products with better yield, good sensory qualities and nutrition. Hence, this review will throw light on some of the important factors which influence the properties of meat emulsion such as stability, structure, etc. and the product texture and yield as the revealed by past researches which will be useful to the meat processors in their practical application in preparing meat emulsion products. PMID- 25836951 TI - Accounting for linear transformations of EEG and MEG data in source analysis. AB - Analyses of electro- and magnetoencephalography (EEG, MEG) data often involve a linear modification of signals at the sensor level. Examples include re referencing of the EEG, computation of synthetic gradiometer in MEG, or the removal of artifactual independent components to clean EEG and MEG data. A question of practical relevance is, if such modifications must be accounted for by adapting the physical forward model (leadfield) before subsequent source analysis. Here, we show that two scenarios need to be differentiated. In the first scenario, which corresponds to re-referencing the EEG and synthetic gradiometer computation in MEG, the leadfield must be adapted before source analysis. In the second scenario, which corresponds to removing artifactual components to 'clean' the data, the leadfield must not be changed. We demonstrate and discuss the consequences of wrongly modifying the leadfield in the latter case for an example. Future EEG and MEG studies employing source analyses should carefully consider whether and, if so, how the leadfield must be modified as explicated here. PMID- 25836952 TI - Timing and Strategy for Weaning From Venoarterial ECMO are Complex Issues. AB - OBJECTIVE: Weaning from venoarterial extracorporeal membrane oxygenation (VA ECMO) usually is performed without clear guidelines; yet, patients still die after removal of extracorporeal circulation because of inadequate heart or end organ recovery. The aim of the study was to address the weaning procedure, analyzing the hemodynamic and echocardiographic picture of patients weaned and to identify predictors of poor outcome among this population. DESIGN: Observational study. SETTING: University hospital. PARTICIPANTS: One hundred twenty-nine VA ECMO cases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-nine patients (38%) were weaned, 7 (5.4%) were bridged to a ventricular assist device, and 6 (5.2%) were listed for heart transplantation. Weaned patients showed a significant increase of pulse pressure (35 [0-50] mmHg before ECMO, 59 [53-67] mmHg at weaning, 61 [51-76] mmHg after ECMO (p<0.001]) and reduction of dose of inotropes (inotropic score [as defined in the text] 20 [14-40] before ECMO, 10 [3 15] at weaning, and 10 [5-15] after ECMO, p<0.001). Left ventricular ejection fraction (LVEF) increased from 19 (0-22.5)% before ECMO to 35 (22-55)% after ECMO (p<0.001). A significant improvement of right ventricular (RV) function was observed in weaned patients (RV dysfunction from 52% to 21%, p<0.001). Among weaned patients, 15 (31%) died. Patients who died after weaning had longer ECMO duration compared to discharged patients (8 [5-11] v 4 [2-6] days, p = 0.01) and more transfusions (22 [10-37] v 7 [0.5-15] units, p = 0.02); survival was lower in patients with central ECMO (postcardiotomy) compared to peripheral ECMO (p = 0.045). Mortality was higher in those with persistence of RV failure, continuous venovenous hemofiltration, higher inotropic score, lower systolic pressure, or higher leucocyte count at weaning. CONCLUSIONS: Successful weaning from ECMO is a multifaceted process, which encompasses consistent recovery of myocardial and end organ function; LVEF, though improved, is still low at weaning. Hospital survival is correlated significantly to the duration of ECMO support and to bleeding complications. PMID- 25836953 TI - Efficacy of fibrinogen concentrate compared with cryoprecipitate for reversal of the antiplatelet effect of clopidogrel in an in vitro model, as assessed by multiple electrode platelet aggregometry, thromboelastometry, and modified thromboelastography. AB - OBJECTIVES: The management of dual-antiplatelet therapy when patients present for surgical revascularization is a clinical challenge. Whether increasing fibrinogen levels can restore hemostasis in this context is not established but may represent increased platelet glycoprotein fibrinogen binding, altered adenosine diphosphate (ADP)-dependent platelet activation, or an increase in formation of soluble fibrin as a component of whole blood clot. DESIGN: The study hypothesis was that fibrinogen concentrate would normalize in vitro hemostatic parameters after clopidogrel loading. The effect was compared with cryoprecipitate. SETTING: University Hospital PARTICIPANTS: Elective coronary catheter studies INTERVENTIONS: Assessment of platelet aggregation was made using whole blood platelet impedance. Viscoelastic assessment also was made using whole blood rotational thromboelastometry and modified thromboelastography. Twenty patients presenting for cardiac catheterization on dual-antiplatelet therapy were studied. Whole blood was titrated with increasing amounts of cryoprecipitate and fibrinogen concentrate. Samples then were diluted 40% with normal saline and further titrated. MEASUREMENT AND MAIN RESULTS: The principal finding of the study was that fibrinogen supplementation primarily improved assays of fibrin formation. Improvement in platelet aggregation response to ADP and TRAP was not observed. Neither cryoprecipitate nor fibrinogen concentrate, at the concentrations used, were able to improve the amplitude at 30 minutes (A30) in the modified TEG-ADP assay. Furthermore, they produced comparable amplitudes at 30 minutes despite a twofold difference in fibrinogen supplementation. CONCLUSIONS: Fibrinogen supplementation may play a role in the hemostatic resuscitation of patients on dual-antiplatelet therapy, but there is no evidence in this in vitro study that there is a specific platelet effect involved that would allow for platelet substitution. PMID- 25836954 TI - A Retrospective Examination of the Efficacy of Paravertebral Block for Patients Requiring Intraoperative High-Dose Unfractionated Heparin Administration During Thoracoabdominal Aortic Aneurysm Repair. AB - OBJECTIVE: Postoperative respiratory complications are serious and frequently observed among patients who undergo thoracoabdominal aortic aneurysm (TAAA) repair. Paravertebral block (PVB) can provide effective analgesia for relief of postoperative thoracotomy pain and may reduce respiratory complications. However, the impact of PVB on postoperative pain and respiratory function in patients who undergo TAAA repair requiring intraoperative high-dose heparin administration is unknown. This study examined the efficacy of PVB on postoperative pain and respiratory function after TAAA repairs. DESIGN: Retrospective, observational cohort study. SETTING: Single center in Japan. PARTICIPANTS: Fifty-eight consecutive patients who underwent TAAA repair from March 2013 to October 2014. INTERVENTIONS: Application of thoracic PVB. MEASUREMENT AND MAIN RESULTS: A total of 56 patients were analyzed. Two patients were excluded because 1 patient was dead within 24 hours after surgery and 1 patient was 9 years old. Patients with PVB were defined as group P (n = 17), and patients without PVB as group C (n = 39). There was no significant difference in baseline characteristics between the 2 groups. Both postoperative pain at rest and postoperative pain while coughing were assessed using a numeric rating scale (NRS); the incidence of reintubation and noninvasive positive-pressure ventilation (NPPV) also were compared between the 2 groups. The NRS score of postoperative pain at rest was significantly lower in group P (group P: Median 2, interquartile range 1 to 3; group C: Median 6, interquartile range 5 to 7; p = 0.000), and the NRS score of postoperative pain while coughing was significantly lower in group P (group P: Median 5, interquartile range 3.5 to 6.5; group C: Median 8, interquartile range 7 to 10; p = 0.000). Reintubation rate was significantly lower in group P (group P: 0%, group C: 23%, p = 0.045); the incidences of NPPV (group P: 12%, group C: 46%, p = 0.016) and postoperative pneumonia were significantly lower in group P (group P: 0%, group C: 28%, p = 0.024). CONCLUSIONS: PVB significantly reduced postoperative pain at rest and while coughing and significantly reduced the reintubation rate, the rate of NPPV use, and postoperative pneumonia without complications. PVB could be a safe and an effective analgesic method that reduces postoperative respiratory exacerbation in patients who undergo TAAA repair. PMID- 25836955 TI - Probing the factor structure of metabolic syndrome in Sardinian genetic isolates. AB - BACKGROUND AND AIMS: Owing to the multiplicity of the key components of metabolic syndrome (MetS), its diagnosis is very complex. The lack of a unique definition is responsible for the prevalence variability observed among studies; therefore, a definition based on continuous variables was recommended. The aim of this study was to compare competing models of the MetS factor structure for selecting the one that explains the best clustering pattern and to propose an algorithm for computing MetS as a continuous variable. METHODS AND RESULTS: Data were from isolated Sardinian populations (n = 8102). Confirmatory factor analysis (CFA) and two-group CFA by gender were performed to evaluate the sex-specific factor structure of MetS. After selecting the best model, an algorithm was obtained using factor loadings/residual variances. The quality of the MetS score was evaluated by the receiver operating characteristics curve and the area under the curve. Cross-validation was performed to validate the score and to determine the best cut point. The best fit model was a bifactor one with a general factor (MetS) and three specific factors (f1: obesity/adiposity trait; f2: hypertension/blood pressure trait; and f3: lipid trait). Gender-specific algorithms were implemented to obtain MetS scores showing a good diagnostic performance (0.80 specificity and 0.80 sensitivity for the cut point). Furthermore, cross-validation confirmed these results. CONCLUSION: These analyses suggested that the bifactor model was the most representative one. In addition, they provided a score and a cut point that are both clinically accessible and interpretable measures for MetS diagnosis and likely useful for evaluating the association with adverse cardiovascular disease and diabetes and for investigating the MetS genetic component. PMID- 25836956 TI - Special issue: global 3Rs efforts - making progress and gaining momentum. PMID- 25836957 TI - Russell and Burch's 3Rs then and now: the need for clarity in definition and purpose. AB - Russell and Burch's The Principles of Humane Experimental Technique was first published in 1959. A Special Edition containing the original text was reissued in 1992, after its ideas had gained widespread interest in the scientific community. In the Principles, Russell and Burch proposed a new applied science that would improve the treatment of laboratory animals while advancing the quality of science in studies that use animals. They introduced and defined the terms replacement, reduction, and refinement, which subsequently have become known as 'alternatives' or 'alternative methods' for minimizing the potential for animal pain and distress in biomedical research. Here we describe and explain the original definitions of the 3Rs in the Principles, examine how current definitions differ among themselves and from Russell and Burch's definitions, and suggest relevant considerations for evaluating all definitions of the 3Rs. PMID- 25836958 TI - Creative implementation of 3Rs principles within industry programs: beyond regulations and guidelines. AB - The industry involved with using animals as an essential part of research has supported the theory and philosophy of the 3Rs for years. However, both the culture and approach surrounding the 3Rs is evolving rapidly, and many institutions are attempting to surpass the regulations and guidelines to implement the 3Rs for improved science and animal welfare. Regulatory documents and guidelines such as the Animal Welfare Act, the Guide for the Care and Use of Laboratory Animals, the Public Health Service Policy on Humane Care and Use of Laboratory Animals, and the US Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training clearly outline how the IACUC should address the 3Rs, but there are many additional paradigms and resources that an institution can use to promote the 3Rs creatively. We review the legal mandates and guidelines that institutions must or should follow, and we present some creative approaches toward their compliance, including the creation of full-time dedicated 3Rs roles as well as temporary 3Rs-focused positions such as visiting scientist and postdoctoral fellowships and internships. We also discuss how to creatively achieve 3Rs progress through internal committees and working groups, involvement in 3Rs consortia, recognizing 3Rs advances through awards programs, and creating 3Rs volunteer opportunities. Adherence to regulations and guidelines creates a solid foundation for good animal care and science, and creative 3Rs approaches enable the growth of a robust animal welfare culture that enhances the potential for 3Rs benefits to animals and science. PMID- 25836959 TI - Using dried blood spot sampling to improve data quality and reduce animal use in mouse pharmacokinetic studies. AB - Traditional pharmacokinetic analysis in nonclinical studies is based on the concentration of a test compound in plasma and requires approximately 100 to 200 MUL blood collected per time point. However, the total blood volume of mice limits the number of samples that can be collected from an individual animal often to a single collection per mouse-thus necessitating dosing multiple mice to generate a pharmacokinetic profile in a sparse-sampling design. Compared with traditional methods, dried blood spot (DBS) analysis requires smaller volumes of blood (15 to 20 MUL), thus supporting serial blood sampling and the generation of a complete pharmacokinetic profile from a single mouse. Here we compare plasma derived data with DBS-derived data, explain how to adopt DBS sampling to support discovery mouse studies, and describe how to generate pharmacokinetic and pharmacodynamic data from a single mouse. Executing novel study designs that use DBS enhances the ability to identify and streamline better drug candidates during drug discovery. Implementing DBS sampling can reduce the number of mice needed in a drug discovery program. In addition, the simplicity of DBS sampling and the smaller numbers of mice needed translate to decreased study costs. Overall, DBS sampling is consistent with 3Rs principles by achieving reductions in the number of animals used, decreased restraint-associated stress, improved data quality, direct comparison of interanimal variability, and the generation of multiple endpoints from a single study. PMID- 25836960 TI - Miniaturized blood sampling techniques to benefit reduction in mice and refinement in nonhuman primates: applications to bioanalysis in toxicity studies with antibody-drug conjugates. AB - Minimizing the number of animals in regulatory toxicity studies while achieving study objectives to support the development of future medicines contributes to good scientific and ethical practices. Recent advances in technology have enabled the development of miniaturized blood sampling methods (including microsampling and dried blood spots) applicable to toxicokinetic determinations of small molecule drugs. Implementation of miniaturized blood sampling methods in the context of biotherapeutic drugs is desirable because a limitation to this type of medicine remains the total blood volume needed from a single animal to support toxicokinetic determinations of several analytes (parent drug, metabolites[s], antidrug antibodies, and so forth). We describe here the technical details, applicability, and relevance of new miniaturized blood sampling procedures in mice and nonhuman primates in the context of the toxicologic evaluation of biotherapeutic drugs consisting of antibody-drug conjugates developed for oncology indications. These examples illustrate how these techniques can benefit the reduction of animal usage in mouse toxicity studies by decreasing the number of animals dedicated to toxicokinetic determinations and the refinement of practices in nonhuman primate toxicity studies by decreasing the blood volume repeatedly drawn for toxicokinetic determinations. PMID- 25836962 TI - Improving prediction of carcinogenicity to reduce, refine, and replace the use of experimental animals. AB - Cancer risk assessment of new pharmaceuticals is crucial to protect public health. However, clinical trials lack the duration needed to clearly detect drug related tumor emergence, and biomarkers suggestive of increased cancer risk from a drug typically are not measured in clinical trials. Therefore, the carcinogenic potential of a new pharmaceutical is extrapolated predominately based on 2-y bioassays in rats and mice. A key drawback to this practice is that the results are frequently positive for tumors and can be irrelevant to human cancer risk for reasons such as dose, mode of action, and species specificity. Alternative approaches typically strive to reduce, refine, and replace rodents in carcinogenicity assessments by leveraging findings in short-term studies, both in silico and in vivo, to predict the likely tumor outcome in rodents or, more broadly, to identify a cancer risk to patients. Given the complexities of carcinogenesis and the perceived impracticality of assessing risk in the course of clinical trials, studies conducted in animals will likely remain the standard by which potential cancer risks are characterized for new pharmaceuticals in the immediate foreseeable future. However, a weight-of-evidence evaluation based on short-term toxicologic, in silico, and pharmacologic data is a promising approach to identify with reasonable certainty those pharmaceuticals that present a likely cancer risk in humans and, conversely, those that do not present a human cancer risk. PMID- 25836963 TI - A new path forward: the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). AB - In 2000, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was congressionally established, with representatives from Federal regulatory and research agencies that require, use, generate, or disseminate toxicologic and safety testing information. For over 15 y, ICCVAM and the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) have worked together to promote the development, validation, and regulatory acceptance of test methods that replace, reduce, or refine the use of animals in regulatory testing. In 2013, both NICEATM and ICCVAM underwent major changes to their operating paradigms, to increase the speed and efficiency of regulatory approval and industry adoption of 3Rs testing methods within the United States and internationally. Accordingly, increased emphasis has been placed on international activities, primarily through interaction with the Organization for Economic Cooperation and Development and participation in the International Cooperation on Alternative Test Methods. In addition, ICCVAM has committed to increasing public awareness of and transparency about federal agencies' 3R activities and to fostering interactions with stakeholders. Finally, although it continues to support ICCVAM, NICEATM's work now includes validation support for Tox21, a collaboration aimed at identifying in vitro methods and computational approaches for testing chemicals to better understand and predict hazards to humans and the environment. The combination of more efficient operating paradigms, increased international collaboration, improved communication and interaction with stakeholders, and active participation in Tox21 likely will substantially increase the number of 3Rs methods developed and used in the United States and internationally. PMID- 25836961 TI - The use of systematic reviews and reporting guidelines to advance the implementation of the 3Rs. AB - In 1959, Russell and Burch published The Principles of Humane Experimental Technique, which included concrete advice on factors that they considered would govern progress in the implementation of these principles (enunciated as the 3Rs [Replacement, Reduction, and Refinement in animal-based studies]). One challenge to the implementation of the 3Rs was identified as information retrieval. Here, we further explore this challenge-the need for 'research on research'-and the role that systematic reviews and reporting guidelines can play in implementation of the 3Rs. First, we examine the 2-fold nature of the challenge of information retrieval: 1) the identification of relevant publications spread throughout a large population of nonrelevant publications and 2) the incomplete reporting of relevant details within those publications. Second, we evaluate how systematic reviews and reporting guidelines can be used generally to address this challenge. Third, we assess the explicit reporting of the 3Rs in a cohort of preclinical animal systematic reviews. Our results show that Reduction methods are the most commonly reported by authors of systematic reviews but that, in general, reporting on how findings relate to the 3Rs is limited at best. Although systematic reviews are excellent tools for resolving the challenge of information retrieval, their utility for making progress in implementation of the 3Rs may be limited unless authors improve their reporting of these principles. PMID- 25836964 TI - Roles of the International Council for Laboratory Animal Science (ICLAS) and International Association of Colleges of Laboratory Animal Medicine (IACLAM) in the Global Organization and Support of 3Rs Advances in Laboratory Animal Science. AB - Practical implementation of the 3Rs at national and regional levels around the world requires long-term commitment, backing, and coordinated efforts by international associations for laboratory animal medicine and science, including the International Association of Colleges of Laboratory Animal Medicine (IACLAM) and the International Council for Laboratory Animal Science (ICLAS). Together these organizations support the efforts of regional organization and communities of laboratory animal science professionals as well as the development of local associations and professional colleges that promote the training and continuing education of research facility personnel and veterinary specialists. The recent formation of a World Organization for Animal Health (OIE) Collaborating Center for Laboratory Animal Science and Welfare emphasizes the need for research into initiatives promoting laboratory animal welfare, particularly in emerging economies and regions with nascent associations of laboratory animal science. PMID- 25836965 TI - The evolution of animal welfare and the 3Rs in Brazil, China, and India. AB - Increasingly, scientific collaborations and contracts cross country borders. The need for assurance that the quality of animal welfare and the caliber of animal research conducted are equivalent among research partners around the globe is of concern to the scientific and laboratory animal medicine communities, the general public, and other key stakeholders. Therefore, global harmonization of animal care and use standards and practices, with the welfare of the animals as a cornerstone, is essential. In the evolving global landscape of enhanced attention to animal welfare, a widely accepted path to achieving this goal is the successful integration of the 3Rs in animal care and use programs. Currently, awareness of the 3Rs, their implementation, and the resulting animal care and use standards and practices vary across countries. This variability has direct effects on the animals used in research and potentially the data generated and may also have secondary effects on the country's ability to be viewed as a global research partner. Here we review the status of implementation of the 3Rs worldwide and focus on 3 countries-Brazil, China and India-with increasing economic influence and an increasing footprint in the biomedical research enterprise. PMID- 25836966 TI - Making progress and gaining momentum in global 3Rs efforts: how the European pharmaceutical industry is contributing. AB - Animal research together with other investigational methods (computer modeling, in vitro tests, etc) remains an indispensable part of the pharmaceutical research and development process. The European pharmaceutical industry recognizes the responsibilities inherent in animal research and is committed to applying and enhancing 3Rs principles. New nonsentient, ex vivo, and in vitro methods are developed every day and contribute to reducing and, in some instances, replacing in vivo studies. Their utility is however limited by the extent of our current knowledge and understanding of complex biological systems. Until validated alternative ways to model these complex interactions become available, animals remain indispensable in research and safety testing. In the interim, scientists continue to look for ways to reduce the number of animals needed to obtain valid results, refine experimental techniques to enhance animal welfare, and replace animals with other research methods whenever feasible. As research goals foster increasing cross-sector and international collaboration, momentum is growing to enhance and coordinate scientific innovation globally-beyond a single company, stakeholder group, sector, region, or country. The implementation of 3Rs strategies can be viewed as an integral part of this continuously evolving science, demonstrating the link between science and welfare, benefiting both the development of new medicines and animal welfare. This goal is one of the key objectives of the Research and Animal Welfare working group of the European Federation of Pharmaceutical Industries and Associations. PMID- 25836967 TI - Pioneering better science through the 3Rs: an introduction to the national centre for the replacement, refinement, and reduction of animals in research (NC3Rs). AB - The National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is an independent scientific organization that is based in the United Kingdom, which was set up by the government to lead the discovery and application of new technologies and approaches that minimize the use of animals in research and improve animal welfare. The NC3Rs uses a range of strategies to improve and advance science through application of the 3Rs. These include funding basic research, open innovation (CRACK IT), and programs run by inhouse scientists. We present several case studies from the NC3Rs portfolio, featuring asthma research, the use of nonhuman primates in monoclonal antibody development, and CRACK IT. Finally, we anticipate the future, as we use our experience to move into new research fields and expand toward international collaboration. Here we highlight how equipping scientists with relevant and emerging 3Rs tools can help overcome the challenges and limitations of the use of animals in research to the benefit of the whole bioscience community. PMID- 25836968 TI - The European Partnership for Alternative Approaches to Animal Testing (EPAA): promoting alternative methods in Europe and beyond. AB - Here in we introduce the European Partnership for Alternative Approaches to Animal Testing (EPAA) and its activities, which are focused on international cooperation toward alternative methods. The EPAA is one of the leading organizations in Europe for the promotion of alternative approaches to animal testing. Its innovative public-private partnership structure enables a consensus driven dialogue across 7 industry sectors to facilitate interaction between regulators and regulated stakeholders. Through a brief description of EPAA's activities and organizational structure, we first articulate the value of this collaboration; we then focus on 2 key projects driven by EPAA. The first project aims to address research gaps on stem cells for safety testing, whereas the second project strives for an approach toward demonstration of consistency in vaccine batch release testing. We highlight the growing need for harmonization of international acceptance and implementation of alternative approaches and for increased international collaboration to foster progress on nonanimal alternatives. PMID- 25836970 TI - Consideration and checkboxes: incorporating ethics and science into the 3Rs. AB - Members of the research community aim to both produce high-quality research and ensure that harm is minimized in animals. The primary means of ensuring these goals are both met is the 3Rs framework of replacement, reduction, and refinement. However, some approaches to the 3Rs may result in a 'check box mentality' in which IACUC members, researchers, administrators, and caretakers check off a list of tasks to evaluate a protocol. We provide reasons for thinking that the 3Rs approach could be enhanced with more explicit discussion of the ethical assumptions used to arrive at an approved research protocol during IACUC review. Here we suggest that the notion of moral considerability, and all of the related issues it gives rise to, should be incorporated into IACUC discussions of 3Rs deliberations during protocol review to ensure that animal wellbeing is enhanced within the constraints of scientific investigation. PMID- 25836971 TI - Correction: Functional genomics unique to week 20 post wounding in the deep cone/fat dome of the Duroc/Yorkshire porcine model of fibroproliferative scarring. PMID- 25836969 TI - Predicting the future: opportunities and challenges for the chemical industry to apply 21st-century toxicity testing. AB - Interest in applying 21st-century toxicity testing tools for safety assessment of industrial chemicals is growing. Whereas conventional toxicology uses mainly animal-based, descriptive methods, a paradigm shift is emerging in which computational approaches, systems biology, high-throughput in vitro toxicity assays, and high-throughput exposure assessments are beginning to be applied to mechanism-based risk assessments in a time- and resource-efficient fashion. Here we describe recent advances in predictive safety assessment, with a focus on their strategic application to meet the changing demands of the chemical industry and its stakeholders. The opportunities to apply these new approaches is extensive and include screening of new chemicals, informing the design of safer and more sustainable chemical alternatives, filling information gaps on data-poor chemicals already in commerce, strengthening read-across methodology for categories of chemicals sharing similar modes of action, and optimizing the design of reduced-risk product formulations. Finally, we discuss how these predictive approaches dovetail with in vivo integrated testing strategies within repeated-dose regulatory toxicity studies, which are in line with 3Rs principles to refine, reduce, and replace animal testing. Strategic application of these tools is the foundation for informed and efficient safety assessment testing strategies that can be applied at all stages of the product-development process. PMID- 25836972 TI - Relationship between trusting behaviors and psychometrics associated with social network and depression among young generation: a pilot study. AB - Maladaptive social interaction and its related psychopathology have been highlighted in psychiatry especially among younger generations. In Japan, novel expressive forms of psychiatric phenomena such as "modern-type depression" and "hikikomori" (a syndrome of severe social withdrawal lasting for at least six months) have been reported especially among young people. Economic games such as the trust game have been utilized to evaluate real-world interpersonal relationships as a novel candidate for psychiatric evaluations. To investigate the relationship between trusting behaviors and various psychometric scales, we conducted a trust game experiment with eighty-one Japanese university students as a pilot study. Participants made a risky financial decision about whether to trust each of 40 photographed partners. Participants then answered a set of questionnaires with seven scales including the Lubben Social Network Scale (LSNS) 6 and the Patient Health Questionnaire (PHQ)-9. Consistent with previous research, male participants trusted partners more than female participants. Regression analysis revealed that LSNS-family (perceived support from family) for male participants, and item 8 of PHQ-9 (subjective agitation and/or retardation) for female participants were associated with participants' trusting behaviors. Consistent with claims by social scientists, our data suggest that, for males, support from family was negatively associated with cooperative behavior toward non-family members. Females with higher subjective agitation (and/or retardation) gave less money toward males and high attractive females, but not toward low attractive females in interpersonal relationships. We believe that our data indicate the possible impact of economic games in psychiatric research and clinical practice, and validation in clinical samples including modern-type depression and hikikomori should be investigated. PMID- 25836973 TI - Analysis of genomic regions of Trichoderma harzianum IOC-3844 related to biomass degradation. AB - Trichoderma harzianum IOC-3844 secretes high levels of cellulolytic-active enzymes and is therefore a promising strain for use in biotechnological applications in second-generation bioethanol production. However, the T. harzianum biomass degradation mechanism has not been well explored at the genetic level. The present work investigates six genomic regions (~150 kbp each) in this fungus that are enriched with genes related to biomass conversion. A BAC library consisting of 5,760 clones was constructed, with an average insert length of 90 kbp. The assembled BAC sequences revealed 232 predicted genes, 31.5% of which were related to catabolic pathways, including those involved in biomass degradation. An expression profile analysis based on RNA-Seq data demonstrated that putative regulatory elements, such as membrane transport proteins and transcription factors, are located in the same genomic regions as genes related to carbohydrate metabolism and exhibit similar expression profiles. Thus, we demonstrate a rapid and efficient tool that focuses on specific genomic regions by combining a BAC library with transcriptomic data. This is the first BAC-based structural genomic study of the cellulolytic fungus T. harzianum, and its findings provide new perspectives regarding the use of this species in biomass degradation processes. PMID- 25836974 TI - Hidden penile fracture: An unusual presentation and review of literature. AB - Penile fractures, a not so uncommon urological emergency, mostly present with a characteristic history and physical examination. Here, we present an atypical case where even in the absence of physical findings, a characteristic history led us to penile exploration and timely repair, highlighting the importance of careful history-taking in these cases. PMID- 25836975 TI - Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. AB - BACKGROUND: Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects. METHODS: Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise. RESULTS: In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16 h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16 h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured. CONCLUSION: EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets. PMID- 25836977 TI - A Monte Carlo study of an energy-weighted algorithm for radionuclide analysis with a plastic scintillation detector. AB - Nuisance and false alarms due to naturally occurring radioactive material (NORM) are major problems facing radiation portal monitors (RPMs) for the screening of illicit radioactive materials in airports and ports. Based on energy-weighted counts, we suggest an algorithm that distinguishes radioactive nuclides with a plastic scintillation detector that has poor energy resolution. Our simulation study, using a Monte Carlo method, demonstrated that man-made radionuclides can be separated from NORM by using a conventional RPM. PMID- 25836976 TI - Scavenger receptor SREC-I mediated entry of TLR4 into lipid microdomains and triggered inflammatory cytokine release in RAW 264.7 cells upon LPS activation. AB - Scavenger receptor associated with endothelial cells I (SREC-I) was shown to be expressed in immune cells and to play a role in the endocytosis of peptides and antigen presentation. As our previous studies indicated that SREC-I required intact Toll-like receptor 4 (TLR4) expression for its functions in tumor immunity, we examined potential interactions between these two receptors. We have shown here that SREC-I became associated with TLR4 on binding bacterial lipopolysaccharides (LPS) in RAW 264.7 and HEK 293 cells overexpressing these two receptors. The receptors then became internalized together in intracellular endosomes. SREC-I promoted TLR4-induced signal transduction through the NF-kB and MAP kinase pathways, leading to enhanced inflammatory cytokine release. Activation of inflammatory signaling through SREC-I/TLR4 complexes appeared to involve recruitment of the receptors into detergent-insoluble, cholesterol-rich lipid microdomains that contained the small GTPase Cdc42 and the non-receptor tyrosine kinase c-src. Under conditions of SREC-I activation by LPS, TLR4 activity required Cdc42 as well as cholesterol and actin polymerization for signaling through NF-kB and MAP kinase pathways in RAW 264.7 cells. SREC-I appeared to respond differently to another ligand, the molecular chaperone Hsp90 that, while triggering SREC-I-TLR4 binding caused only faint activation of the NF kB pathway. Our experiments therefore indicated that SREC-I could bind LPS and might be involved in innate inflammatory immune responses to extracellular danger signals in RAW 264.7 cells or bone marrow-derived macrophages. PMID- 25836978 TI - Production scale purification of Ge-68 and Zn-65 from irradiated gallium metal. AB - Germanium-68 (Ge-68) is produced by proton irradiation of a gallium metal target, purified by organic extraction and used in a medical isotope generator to produce Gallium-68 PET imaging agents. The purpose of this work was to implement a production scale separation of Ge-68 and Zn-65 that does not use organic solvents and uses a limited number of columns. The current separation approach was modified to use AG1 resin and/or Sephadex((c)) G25 with zinc spikes to purify Ge 68 with near quantitative recovery. The purified Ge-68 meets DOE specifications. Methods utilizing zinc spikes resulted in the purist Ge-68 produced at Brookhaven National Lab with no other impurities by ICP-OES. During process optimization approximately 2.5 Ci of Ge-68 was purified utilizing the different processing methods, and the material was sold to the Nuclear Medicine community between 2012 2013. PMID- 25836979 TI - Rebuttal From Drs Avdalovic and Murin. PMID- 25836980 TI - Evidence-Based Systematic Review: Effects of Speech-Language Pathology Treatment for Individuals With Paradoxical Vocal Fold Motion. AB - PURPOSE: In this article, our goal was to determine the state of the evidence and the effect of speech-language pathology (SLP) treatment for individuals with paradoxical vocal fold motion (PVFM). METHOD: The American Speech-Language Hearing Association's National Center for Evidence-Based Practice in Communication Disorders searched 22 electronic databases using key words related to PVFM, speech or voice treatment, and behavioral intervention for articles published through July 2013. Identified articles were systematically evaluated to assess the quality of the evidence using a modification of the American Speech Language-Hearing Association's critical appraisal scheme. RESULTS: Sixty-five articles met the search criteria. Only 2 out of the 65 articles were judged to contain adequate evidence to evaluate the effect of SLP treatment for PVFM. All 65 articles exemplify the state of the evidence for SLP treatment for PVFM. CONCLUSION: The state of the evidence for the use of SLP treatment is in its infancy, with a majority of articles in the exploratory stage of research. Consequently, few clinical implications can be drawn at this time. SLP treatment for PVFM is promising; however, there is clearly a pressing need for systematic experimental studies that involve a control group to further the evidence base. PMID- 25836981 TI - Impact of Georgia's teenage and adult driver responsibility act: 15-year follow up. AB - OBJECTIVE: This study was designed to investigate the 15-year impact of Georgia's graduated drivers' licensing (GDL) law, the "Teenage and Adult Driver Responsibility Act" (TADRA), on fatality crashes among young drivers. METHODS: Fatality Analysis Reporting System (FARS) data for Georgia and Census denominators were used to determine fatal crash rates (FCRs) of drivers ages 16 through 19 who passed through the Georgia GDL system during the 5.5 years prior to through 15.5 years after TADRA's implementation. FCRs of younger drivers were compared to those of drivers ages 20-54 and 55-75 and compared by gender. Attention was given to speeding- and alcohol-related crashes, 2 foci of TADRA. RESULTS: The decline in FCRs has been maintained and even increased through 15.5 years after passage of the law. Extending the curfew and further limiting passengers (passed in 2001) and driver's education and supervised driving requirements (added in 2007) may have contributed. The greatest declines were among 16- and 17-year-olds; most of the gains were among male drivers. The changes were greatest for alcohol- and speeding-related crashes. Those 18 and 19 years old did not demonstrate an increase in FCR over the period studied. CONCLUSION: Georgia's graduated licensing law, TADRA, has maintained and in some instances increased in effectiveness over the 15.5 years since its inception. Though national research suggests that GDL laws are associated with increased crash rates among 18- to 19-year-old drivers, this has not occurred in Georgia; 18- and 19-year-olds demonstrated no change or reductions in FCR over the 20.5 year period evaluated. Declines were greatest for those driving behaviors targeted by the law. PMID- 25836983 TI - Greeting from the President of the Japanese Society for Investigative Dermatology (JSID). PMID- 25836982 TI - Unwinding the mechanisms of a DEAD-box RNA helicase in cancer. PMID- 25836984 TI - Greetings from the new Secretary-General of the Japanese Society for Investigative Dermatology (JSID). PMID- 25836985 TI - Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma. AB - BACKGROUND & AIMS: Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to determine body mass index (BMI) accurately, and many factors contribute to the development of HCC. We performed a case-control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. METHODS: We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI of 30 kg/m(2) or greater were considered obese. RESULTS: Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios were 2.6 (95% confidence interval [CI], 1.4-4.4), 2.3 (95% CI, 1.2-4.4), and 3.6 (95% CI, 1.5-8.9) for the entire population, for men, and for women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P < .001). Moreover, there was a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC. CONCLUSIONS: Early adulthood obesity is associated with an increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC. PMID- 25836986 TI - Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. AB - BACKGROUND & AIMS: Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial. METHODS: Patients with mild to moderately active UC (n = 50) were assigned to groups that underwent FMT with feces from healthy donors or were given autologous fecal microbiota (control); each transplant was administered via nasoduodenal tube at the start of the study and 3 weeks later. The study was performed at the Academic Medical Center in Amsterdam from June 2011 through May 2014. The composite primary end point was clinical remission (simple clinical colitis activity index scores <=2) combined with >=1-point decrease in the Mayo endoscopic score at week 12. Secondary end points were safety and microbiota composition by phylogenetic microarray in fecal samples. RESULTS: Thirty-seven patients completed the primary end point assessment. In the intention-to-treat analysis, 7 of 23 patients who received fecal transplants from healthy donors (30.4%) and 5 of 25 controls (20.0%) achieved the primary end point (P = .51). In the per-protocol analysis, 7 of 17 patients who received fecal transplants from healthy donors (41.2%) and 5 of 20 controls (25.0%) achieved the primary end point (P = .29). Serious adverse events occurred in 4 patients (2 in the FMT group), but these were not considered to be related to the FMT. At 12 weeks, the microbiota of responders in the FMT group was similar to that of their healthy donors; remission was associated with proportions of Clostridium clusters IV and XIVa. CONCLUSIONS: In this phase 2 trial, there was no statistically significant difference in clinical and endoscopic remission between patients with UC who received fecal transplants from healthy donors and those who received their own fecal microbiota, which may be due to limited numbers. However, the microbiota of responders had distinct features from that of nonresponders, warranting further study. ClinicalTrials.gov Number: NCT01650038. PMID- 25836989 TI - Corrigendum: metastatic breast carcinomas display genomic and transcriptomic heterogeneity. PMID- 25836990 TI - Susceptibility losses in heating of magnetic core/shell nanoparticles for hyperthermia: a Monte Carlo study of shape and size effects. AB - Optimizing the heating properties of magnetic nanoparticles is of great importance for hyperthermia applications. Recent experimental results show that core/shell nanoparticles could give an increased specific absorption rate (SAR) compared to the magnetic oxide nanoparticles currently used. We have developed a modified phenomenological model based on the linear Neel-Brown relaxation model to calculate the SAR due to susceptibility losses in complex nanoparticles with ferromagnetic (FM) core/ferrimagnetic (FiM) shell morphology. We use the Monte Carlo (MC) simulation technique with the implementation of the Metropolis algorithm to investigate the effect of size and shape on the magnetisation behaviour of complex ferromagnetic/ferrimagnetic nanoparticles covered by a surfactant layer. The findings of our simulations are used as an input in our modified model for the calculation of the SAR. Our calculations show that for all the sizes and shapes the complex FM/FiM nanoparticles give higher SAR values than the pure ferrimagnetic ones due to their higher core saturation magnetisation. For all sizes the nanoparticles with the truncated cuboctahedral shape give the highest SAR values and the cubic ones the lowest ones. The decrease in the surfactant thickness results in an increase of the SAR values. Our results have the same characteristics as the available experimental data from Fe/Fe3O4 nanoparticles, confirming that the complex nanoparticles with core/shell morphology can optimise the heating properties for hyperthermia. PMID- 25836987 TI - Rapamycin Inhibition of mTOR Reduces Levels of the Na+/H+ Exchanger 3 in Intestines of Mice and Humans, Leading to Diarrhea. AB - BACKGROUND & AIMS: The immunosuppressant rapamycin frequently causes noninfectious diarrhea in organ transplant recipients. We investigated the mechanisms of this process. METHODS: We performed a retrospective analysis of renal transplant recipients treated with rapamycin from 2003 through 2010 at Albany Medical College, collecting data on serum levels of rapamycin. Levels of the Na+/H+ exchanger 3 (NHE3) were measured in human ileal biopsy specimens from patients who did and did not receive rapamycin (controls), in ileum tissues from rats or mice given rapamycin, and in mice with intestine-specific disruption of mammalian target of rapamycin (Mtor) (mTOR(f/f):Villin-cre mice) or Atg7 (Atg7(flox/flox); Villin-Cre). Exchange activity and intestinal water absorption were measured using a pH-sensitive dye and small intestine perfusion, respectively. RESULTS: Episodes of noninfectious diarrhea occurred in organ recipients after increases in serum levels of rapamycin. The expression of NHE3 was reduced in the ileal brush border of patients with diarrhea. In rats and mice, continuous administration of low doses of rapamycin reduced levels of NHE3 in intestinal tissues; this effect was not observed in mice with intestinal deletion of ATG7, indicating that autophagy is required for the reduction. Administration of single high doses of rapamycin to mice, to model the spikes in rapamycin levels that occur in patients with severe diarrheal episodes, resulted in reduced phosphorylation of S6 and AKT in ileal tissues, indicating inhibition of the mTOR complex (mTORC1 and mTORC2). The intestines of mice with intestine specific deletion of mTOR were dilated and contained large amounts of liquid stools; they also had reduced levels of total NHE3 and NHERF1 compared with control mice. We observed a significant reduction in Na(+)/H(+) exchange activity in ileum tissues from these mice. CONCLUSIONS: Rapamycin inhibition of mTOR reduces levels of NHE3 and Na(+)/H(+) exchange activity in intestinal tissues of patients and rodents. This process appears to require the autophagic activity mediated by ATG7. Loss of mTOR regulation of NHE3 could mediate the development of diarrhea in patients undergoing rapamycin therapy. PMID- 25836991 TI - Neuropeptides as lung cancer growth factors. AB - This manuscript is written in honor of the Festschrift for Abba Kastin. I met Abba at a Society for Neuroscience meeting and learned that he was Editor-in Chief of the Journal Peptides. I submitted manuscripts to the journal on "Neuropeptides as Growth Factors in Cancer" and subsequently was named to the Editorial Advisory Board. Over the past 30 years I have published dozens of manuscripts in Peptides and reviewed hundreds of submitted manuscripts. It was always rewarding to interact with Abba, a consummate professional. When I attended meetings in New Orleans I would sometimes go out to dinner with him at the restaurant "Commanders Palace". When I chaired the Summer Neuropeptide Conference we were honored to have him receive the Fleur Strand Award one year in Israel. I think that his biggest editorial contribution has been the "Handbook of Biologically Active Peptides." I served as a Section Editor on "Cancer/Anticancer Peptides" and again found that it was a pleasure working with him. This review focuses on the mechanisms by which bombesin-like peptides, neurotensin and vasoactive intestinal peptide regulate the growth of lung cancer. PMID- 25836992 TI - High throughput screening methods for assessing antibiofilm and immunomodulatory activities of synthetic peptides. AB - The recent observation that certain cationic peptides possess potent antibiofilm activity demonstrated that small peptides could be used to treat biofilm associated infections. Other so-called innate defense regulator peptides possess potent immunomodulatory properties such as leukocyte recruitment and suppression of harmful inflammation. A peptide that directly targets biofilm cells while favorably modulating the immune response would be particularly advantageous for treating serious skin infections caused by Staphylococcus aureus. In the present work, using SPOT-synthesized peptide arrays on cellulose membranes, we outline a strategy for systematically assessing the antibiofilm activity of hundreds of IDR 1002 (VQRWLIVWRIRK-NH2) and IDR-HH2 (VQLRIRVAVIRA-NH2) peptide variants against MRSA biofilms. In addition, the ability of these peptides to stimulate production of a monocyte chemoattractant protein (MCP-1) and suppress LPS-induced interleukin (IL)-1beta production in human peripheral blood mononuclear cells (PBMCs) was evaluated. These results informed the synthesis of second-generation peptides resulting in a new peptide, IDR-2009 (KWRLLIRWRIQK-NH2), with enhanced MCP-1 stimulatory activity, favorable IL-1beta suppression characteristics and strong antibiofilm activity against MRSA and Pseudomonas aeruginosa biofilms. This work provides a proof-of-concept that multiple peptide activities can be optimized simultaneously to generate novel sequences that possess a variety of biological properties. PMID- 25836994 TI - Alcohol Consumption in Healthy OPRM1 G Allele Carriers and Its Association with Impulsive Behavior. AB - AIMS: A link between alcohol use disorders (AUD) and impulsivity is well established. As there is evidence for the heritability of AUD, the investigation of the underlying genetic disposition for both conditions is an important issue. An association between AUD and a coding single nucleotide polymorphism (SNP) (rs1799971 encoding an Asn40Asp amino acid substitution, A118G) within the u opioid receptor 1 gene (OPRM1) has been reported. Therefore we tested the association between the OPRM1 A118G polymorphism and drinking as well as impulsive behavior in social drinkers. METHODS: A total of 214 healthy male social drinkers were recruited. Each participant was genotyped for the OPRM1 A118G variant. Alcohol use was assessed with items of the Alcohol Use Disorders Identification Test (AUDIT). Impulsivity was assessed using the UPPS impulsive behavior scale. For statistical analyses, we considered correlations, t-tests and ordinal regression models using SPSS V21. RESULTS: In total, 49 out of 214 participants were carriers of the OPRM1 118G allele. On average the OPRM1 118G carriers showed a slightly higher propensity for alcohol drinking. Higher drinking frequency among the G allele carriers was linked with higher urgency and perseveration subscores of impulsivity. CONCLUSION: Our results suggest a genetically influenced higher propensity for alcohol drinking among social drinkers carrying the 118G allele of the OPRM1 gene. The positive correlation between urgency and a higher drinking frequency among the OPRM1 118G hint towards a functional meaning of the opioid system in the regulation of impulsivity. PMID- 25836993 TI - Altered amygdala connectivity in urban youth exposed to trauma. AB - Early life trauma exposure represents a potent risk factor for the development of mental illnesses such as anxiety, depression and post-traumatic stress disorder. Moreover, deleterious consequences of trauma are exacerbated in youth living in impoverished, urban environments. A priori probability maps were used to examine resting-state functional connectivity (FC) of the amygdala in 21 trauma-exposed, and 21 age- and sex-matched urban children and adolescents (youth) without histories of trauma. Intrinsic FC analyses focused on amygdala-medial prefrontal circuitry, a key emotion regulatory pathway in the brain. We discovered reduced negative amygdala-subgenual cingulate connectivity in trauma-exposed youth. Differences between groups were also identified in anterior insula and dorsal anterior cingulate to amygdala connectivity. Overall, results suggest a model in which urban-dwelling trauma-exposed youth lack negative prefrontal to amygdala connectivity that may be critical for regulation of emotional responses. Functional changes in amygdala circuitry might reflect the biological embedding of stress reactivity in early life and mediate enhanced vulnerability to stress related psychopathology. PMID- 25836995 TI - [Management of Patients with Preexisting Cardiac Complications during Thoracic Surgery for Lung Cancer]. AB - In patients with preoperative cardiac complications such as myocardial ischemia, arrhythmia, or congestive heart failure, it is important to offer any necessary medical treatments, such as anticoagulation therapy, prior to surgery. This study investigated the perioperative results of surgical treatment for primary lung cancer in patients with cardiac complications. Data relating to 467 patients who underwent lung resection for lung cancer between April 2010 and March 2014 were collected. Perioperative factors for patients with preoperative cardiac complications and patients without preoperative cardiac complications were compared. Perioperative factors were also compared for a heparin bridging group and non-heparin bridging group in 53 anti-coagulation therapy patients. RESULTS: Fifty-three (11.3%) patients had preoperative cardiac complications;the majority of these had ischemic heart disease( n=31, 58.5%), while a significant minority had atrial fibrillation( n=14, 33.3 %). Of these, 42 patients(79.2%)were receiving anti-coagulation therapy;pre-operative bridging anti-coagulation using heparin was performed in 19 patients(45.2%). There were significant differences between those patients with preoperative cardiac complications, and those without preoperative cardiac complications, in terms of sex( male;81.1% vs 65.7%, p=0.024), mean age(73.1+/-1.0 year vs 68.4+/-0.7 year, p=0.001), and duration (days) of hospitalization after surgery(10.1+/-2.4 vs 7.8+/-2.0, p=0.023). There were significant differences between patients who received pre-operative heparin bridging anticoagulation, compared with those who did not, in terms of age(70.8+/ 1.2 year vs 76.8+/-0.9 year, p=0.001)and duration (days) of hospitalization after surgery(10.5+/-2.1 vs 7.5+/-1.3, p=0.005). CONCLUSION: Fifty-three(11.3%)patients had preoperative cardiac complications. Recent changes in the demographics of surgical candidates, in terms of age, have increased the number of patients with surgical risk factors. Perioperative patient management has become more important than before. PMID- 25836996 TI - [Perioperative management of primary lung cancer patients with cardiovascular comorbidities]. AB - The number of patients with cardiovascular comorbidities is increasing due to aged society. We evaluated perioperative management of primary lung cancer patients with cardiovascular comorbidities. Between 2010 and 2013, 458 patients underwent lung cancer surgery at out hospital. 60(13%)patients had cardiovascular comorbidities (excluding hypertension and arrhythmia). Forty three(72%) patients were angina pectoris and myocardial infarction, and 7 (12%)were valve disease. In patients with cardiovascular comorbidities, high age, renal dysfunction, low % diffusing capacity for carbon monoxide and limited lymph node dissection were significantly seen. There was one patient with no symptoms of angina with the calcification of coronary artery detected by chest computed tomography(CT)before surgery. Percutaneous coronary artery intervention followed elective lung surgery was successfully performed. Short-term surgical results of patients with cardiovascular comorbidities were acceptable compared to those without. PMID- 25836997 TI - [Perioperative management of lung cancer patients with cardiovascular complications]. AB - Lung cancer patients with cardiovascular complications often require antithrombotic therapy. In this study, we discuss the present conditions and future problems associated with the perioperative management of such patients. We examined 36 lung cancer patients undergoing surgery who received antithrombotic therapy for cardiovascular complications. Twenty-one patients were administered unfractionated heparin in the perioperative period (heparin group). Fifteen patients were not administered unfractionated heparin in the perioperative period (no-heparin group). No significant intergroup differences were observed in operating time, intraoperative blood loss, duration of chest tube placement, and the number of hospitalization days. However, 2 serious cases of thromboembolism developed after surgery. One was a case of pulmonary thromboembolism and the other was one of superior mesenteric artery thromboembolism. These results suggest that the appropriate perioperative usage of heparin enables the standard surgical treatment of lung cancer patients with cardiovascular complications. We recommend the use of low-molecular-weight heparin or low-dose unfractionated heparin as the antithrombotic agent after lung cancer surgery. PMID- 25836998 TI - [Perioperative Management of Lung Cancer Patients with atrial fibrillation being treated by antiplatelet or anticoagulant therapy]. AB - In an aging society, the high incidence of surgery for the patients with ischemic heart disease(IHD)or atrial fibrillation(Af) under antiplatelet or anticoagulant therapy is a great problem. Interruption of antiplatelet or anticoagulant oral agents in the perioperative period may increase the risk of coronary or cerebral events. We retrospectively reviewed the surgical outcomes for lung cancer patients with IHD or Af. We reviewed 135 patients with lung cancer(41~88 years;97 men) who had preoperative oral administration of antiplatelet or anticoagulant drugs for IHD or Af between 2005 and 2012 at 2 centers, and analyzed retrospectively the perioperative medications and complications. IHD, Af and vasospastic angina(VSA) were complicated in 94, 33 and 8 patients, respectively. Drugeluted and bare-metal stents had been placed in 18 and 19 patients. Oral agents were aspirin in 68 patients, ticlopidine in 10 patients, clopidogrel in 15 patients and warfarin in 25 patients. These agents were stopped 2 to 60 days before surgery. Perioperative heparinization was performed in 22 patients. Oral agents were restarted after confirmation of hemostasis and no need for further invasive treatment. The surgical procedures were lobectomy in 88 patients, segmentectomy in 19 and partial resection in 25. There were no hemorrhagic or thromboembolic complications in a perioperative period except 1 case of pulmonary hemorrhage and 1 case of cerebral infarction. No perioperative hospital death was documented. Short-term interruption of antiplatelet or anticoagulant drugs before lung cancer surgery and heparinization was acceptable from the view of perioperative outcomes. PMID- 25836999 TI - [Investigation of lung cancer patients with cardiovascular disease]. AB - BACKGROUND: According to the aging in Japan, surgery of lung cancer with cardiovascular disease is increasing. Among them, the merger of the heart and large blood vessel disease would be expected to be directly linked to the perioperative management. MATERIALS AND METHODS: We conducted a retrospective analysis of 1,005 patients who had undergone surgical resection of primary lung adenocarcinoma between January 1997 and June 2014 at Hokkaido University Hospital. Among them, 81 patients had more than one cardiovascular disease. RESULTS: The median age was 71 years old. Men are 62 cases(76%). 64 cases (79%)had smoking history. Ischemic heart disease( IHD) was 29 cases(33%), followed by atrial fibrillation(Af), arrhythmia other than Af, valve disease and macrovascular disease. Anticoagulant or antiplatelet therapy were preoperatively done in 41% of IHD cases, 39% of Af cases. Thirty four% of IHD, 50% of vascular disease received the treatment other than medication. Video-assisted thoracic surgery was performed in 67 cases(83%). Lobectomy, sublobectomy were performed for 59 cases(73%), 19 cases(23%), respectively. Postoperative complications were occurred in 32 cases(40%). Two patients(2.5%)died in hospital without discharge. Univariate analysis revealed tumor size, pStage, lymph node dissection, operation time or blood loss were correlated with postoperative complication. CONCLUSIONS: For the patients with cardiovascular disease, careful evaluation of surgical indication, perioperative management is required. PMID- 25837000 TI - [Management of patients with ischemic heart disease in lung cancer resection]. AB - We reviewed the medical records of 1,047 consecutive patients with lung cancer who underwent surgery between April 2005 and March 2014. Among them 49 patients(4.7%)had concomitant ischemic heart disease. Coronary angiography showed coronary artery stenosis in 41 patients, of whom 14 patients received bare metal stents and 9 patients received drug-eluting stents. Three patients underwent plain old balloon angioplasty. Coronary artery bypass graft were performed in 5 patients. Eight patients with coronary spastic angina were also included in the present study. Aspirin administration was continued in 9 patients and heparinization was performed in 14 patients during the perioperative period. Postoperative major adverse cardiac events within 30-days occurred in 3 patients(6.1%)resulting in a single fatality(2.0%). No major cardiac events, including stent thrombosis, developed in patient who received coronary stent. Perioperative aspirin administration and heparinization were not significantly associated with intraoperative bleeding during the operation. PMID- 25837001 TI - [Strategies for lung cancer with ischemic heart disease]. AB - For lung cancer surgery which merged ischemic heart disease to need coronary artery treatments, the strategy is demanded on the timing of each treatment. Our department conforms to American College of Chest Physicians( ACCP) guideline and treatment strategies are decided as follows. 1) If right heart load has already occurred, we choose limited surgery for lung cancer. 2) Two-stage surgery is performed with principle. Coronary artery treatment is given priority to against left main trunk disease and unstable angina. 3) Simultaneous surgery is chosen for lung cancer more than stage II or lung cancer pressing neighboring organ and vessel not to be able to wait coronary artery treatments. Since 2007, we performed 4 simultaneous surgeries and experienced 3 pneumonia cases, 1 patient died in 5 months. We must decide a strategy in consideration of progress of the lung cancer and cardiac urgency. PMID- 25837002 TI - [Perioperative management for surgery against lung cancer in patients with receiving coronary stent implantation]. AB - Increasing in patients with cardiac disease, it is estimated that the patients with receiving coronary artery stents implantation occur frequently at the time of surgery against lung cancer. However, the anti-thrombotic therapy in perioperative period is not well established. We reviewed the medical records of 934 patients who underwent pulmonary resection for primary lung cancer in our institute from March 1997 to November 2014. The cardiac disease was observed 101 patients, including 9 patients were implanted bare-metal stents( BMS) and 6 patients were done drug-eluting stents( DES). The interval to surgery after stent implantation was almost over 1-month in BMS-group (median:18 months) and more than 1-year in DES-group( median:22.5 months). The anti-thrombotic therapy was interrupted less than 14-days in almost cases. The patients with receiving coronary artery stents implantation expected to be increased more in future, perioperative anti-thrombotic management protocols must be established. PMID- 25837003 TI - [Simultaneous pulmonary resection and endovascular repair for patients with coexisting primary lung cancer and aneurysm]. AB - The surgical strategy for coexisting lung cancer and aneurysm is controversial owing to the risk of aneurysm rupture during the perioperative period of pulmonary resection. We performed simultaneous pulmonary resection and endovascular repair in 2 patients with coexisting lung cancer and aneurysm. Case 1:A 74-year-old man presented at our hospital with cT2aN0M0 lung cancer and a 5.0 cm abdominal aortic aneurysm. Because computed tomography indicated the possibility of advanced lung cancer, we decided to perform simultaneous surgery for lung cancer and the aneurysm. Under general anesthesia, endovascular aneurysm repair was performed before right lower lobectomy with lymphadenectomy. The postoperative course was uneventful, and the patient was discharged on postoperative day 12. Case 2:A 72-year-old man presented at our hospital with cT2aN1M0 lung cancer, a 5.0 cm left internal iliac artery aneurysm, and right renal cell carcinoma( RCC). Because the lung cancer was advanced and the patients needed following surgical treatment for RCC, we decided to perform simultaneous surgery for lung cancer and the aneurysm. Under general anesthesia, endovascular aneurysm repair was performed before right upper lobectomy with lymphadenectomy. The postoperative course was uneventful, and the patient was discharged on postoperative day 11. PMID- 25837004 TI - [Combined resection of the aorta in primary lung cancer cases]. AB - OBJECTIVE: The purpose of this study was to evaluate the results of a combined resection of the thoracic aorta and primary lung cancer. SUBJECTS AND METHODS: In all 8 patients who underwent the procedure in our hospital chest computed tomography( CT) and magnetic resonance imaging( MRI) showed lung cancers invading the aorta. We evaluated the clinical and pathological staging according to the General Rules for Clinical and Pathological Records of Lung Cancer( 7th edition, in Japanese). RESULT: The mean age was 50.9 years old. Eight patients underwent thoracic aorta resection along with a left pneumonectomy (n=5), left upper lobectomy (n=3). Five patients received total replacement of the descending aorta with an artificial vessel. Three patients received a patch graft for repair of the defect in the thoracic aorta. Three postoperative major complications occurred, including postoperative bleeding, postoperative pneumonia, tachycardia. Operative death did not occur in any patients. The median survival time of patients with postoperative pathologic was 1,485 days, 5-year survivals were 50% in all patients. CONCLUSION: We conclude that clinicians must be aware of the possibility of overestimation in radiological diagnosis of thoracic aorta invasion in non-small cell lung cancer. In primary lung cancer patients with aortic invasion who was suspected by preoperative examination, the treatment policy should be carefully considered. PMID- 25837005 TI - [Aortic Root Reimplantation for Extra-cardiac Unruptured Sinus of Valsalva Aneurysm]. AB - Aneurysms of the sinus of Valsalva are rare. We report a case of extra-cardiac unruptured aneurysm of the sinus of Valsalva with moderate aortic regurgitation (AR). A 57-year-old woman was referred to our institution because of AR. Echocardiography showed moderate AR and computed tomographic scanning demonstrated an extra-cardiac aneurysm of the unruptured sinus of Valsalva, which extended from the right sinus of Valsalva to the non-coronary sinus of Valsalva. She underwent aortic root reimplantation procedure with a Valsalva graft. Although mild AR was observed postoperatively, her postoperative course was uneventful. PMID- 25837006 TI - [Cavernous hemangioma of the right cardiac chamber;report of a case]. AB - Cardiac cavernous hemangioma is an extremely rare benign tumor. A 53-year-old female had undergone resection of left breast cancer 9 years before, and her clinical course had been uneventful for nearly 9 years. She then experienced sudden fatigability and palpitations. Pericardial effusion and a tumor-like lesion, pressing the right side of the heart, were detected by echocardiography, computed tomography and magnetic resonance imaging. Though her symptoms were ameliorated with pericardial puncture, she was referred to our department for a definitive diagnosis and, if indicated, tumor resection. At surgery the tumor was poorly demarcated and most of it was resected under extracorporeal circulation. The histopathological examination revealed it was cavernous hemangioma. The patient's postoperative course has been uneventful without recurrence for approximately 2 years. PMID- 25837007 TI - [Pericardiectomy of effusive constrictive pericarditis with an ultrasonic scalpel; report of a case]. AB - Effusive constrictive pericarditis is a rare clinical entity characterized by concurrent pericardial effusion and visceral pericardial constriction. The most effective therapy for this state is pericardiectomy with complete removal of the parietal and visceral membranes, although the perioperative mortality and morbidity can be high. We presented a case of a 45-year-old man in whom a visceral pericardiectomy with waffle procedure was successfully performed using an ultrasonic scalpel without use of cardiopulmonary bypass. His postoperative course was uneventful and cardiac hemodynamics restored to normal. There were no signs or symptoms of recurrence in 2 years of follow-up. PMID- 25837008 TI - Chlorin e6 Conjugated Poly(dopamine) Nanospheres as PDT/PTT Dual-Modal Therapeutic Agents for Enhanced Cancer Therapy. AB - Photodynamic therapy (PDT), using a combination of chemical photosensitizers (PS) and light, has been successfully applied as a noninvasive therapeutic procedure to treat tumors by inducing apoptosis or necrosis of cancer cells. However, most current clinically used PS have suffered from the instability in physiological conditions which lead to low photodynamic therapy efficacy. Herein, a highly biocompatible poly(dopamine) (PDA) nanoparticle conjugated with Chlorin e6 (referenced as the PDA-Ce6 nanosphere) was designed as a nanotherapeutic agent to achieve simultaneous photodynamic/photothermal therapy (PDT/PTT). Compared to the free Ce6, the PDA-Ce6 nanosphere exhibited significantly higher PDT efficacy against tumor cells, because of the enhanced cellular uptake and subsequently greater reactive oxygen species (ROS) production upon laser irradiation at 670 nm. Meanwhile, the PDA-Ce6 nanosphere could be also used as a photoabsorbing agent for PTT, because of the excellent photothermal conversion ability of PDA nanoparticle under laser irradiation at 808 nm. Moreover, our prepared nanosphere had extremely low dark toxicity, while excellent phototoxicity under the combination laser irradiation of 670 and 808 nm, both in vitro and in vivo, compared to any single laser irradiation alone. Therefore, our prepared PDA-Ce6 nanosphere could be applied as a very promising dual-modal phototherapeutic agent for enhanced cancer therapy in future clinical applications. PMID- 25837010 TI - Seed priming with BABA (beta-amino butyric acid): a cost-effective method of abiotic stress tolerance in Vigna radiata (L.) Wilczek. AB - The effects of beta-amino butyric acid (BABA) on abiotic stress tolerance potential of three Vigna radiata varieties were studied. The reduction in the growth of seedlings subjected to NaCl/polyethylene glycol (PEG) stress is alleviated by BABA seed priming, which also enhanced photosynthetic pigment content and photosynthetic and mitochondrial activities, and also modified the chlorophyll a fluorescence-related parameters. Moreover, BABA seed priming reduced malondialdehyde content in the seedlings and enhanced the accumulation of proline, total protein, total carbohydrate, nitrate reductase activity, and activities of antioxidant enzymes like guaiacol peroxidase and superoxide dismutase. Most of these positive features of BABA priming were predominantly exhibited when the plants were encountered with stress (NaCl/PEG). The BABA content in the BABA-treated green gram seeds and seedlings was also detected and quantified with high-performance thin layer chromatography (HPTLC), and it revealed that the priming effect of BABA initiated in seeds and further gets carried over to the seedlings. It was concluded that BABA seed priming improved the drought and salinity stress tolerance potential of all the three green gram varieties, and it was evident in the NaCl-tolerant variety Pusa Vishal as compared to Pusa Ratna (abiotic stress sensitive) and Pusa 9531(drought tolerant). Dual mode in cost effectiveness of BABA priming is evident from: (1) the positive features of priming are being exhibited more during the exposure of plants to stress, and (2) priming of seedlings can be carried out by BABA application to seeds at very low concentration and volume. PMID- 25837009 TI - Characterization of natural leaf senescence in tobacco (Nicotiana tabacum) plants grown in vitro. AB - Leaf senescence is a highly regulated final phase of leaf development preceding massive cell death. It results in the coordinated degradation of macromolecules and the subsequent nutrient relocation to other plant parts. Very little is still known about early stages of leaf senescence during normal leaf ontogeny that is not triggered by stress factors. This paper comprises an integrated study of natural leaf senescence in tobacco plants grown in vitro, using molecular, structural, and physiological information. We determined the time sequence of ultrastructural changes in mesophyll cells during leaf senescence, showing that the degradation of chloroplast ultrastructure fully correlated with changes in chlorophyll content. The earliest degenerative changes in chloroplast ultrastructure coinciding with early chromatin condensation were observed already in mature green leaves. A continuum of degradative changes in chloroplast ultrastructure, chromatin condensation and aggregation, along with progressive decrease in cytoplasm organization and electron density were observed in the course of mesophyll cells ageing. Although the total amounts of endogenous cytokinins gradually increased during leaf ontogenesis, the proportion of bioactive cytokinin forms, as well as their phosphate precursors, in total cytokinin content rapidly declined with ageing. Endogenous indole-3-acetic acid (IAA) levels were strongly reduced in senescent leaves, and a decreasing tendency was also observed for abscisic acid (ABA) levels. Senescence-associated tobacco cysteine proteases (CP, E.C. 3.4.22) CP1 and CP23 genes were induced in the initial phase of senescence. Genes encoding glutamate dehydrogenase (GDH, E.C. 1.4.1.2) and one isoform of cytosolic glutamine synthetase (GS1, E.C. 6.3.1.2) were induced in the late stage of senescence, while chloroplastic GS (GS2) gene showed a continuous decrease with leaf ageing. PMID- 25837012 TI - Anilide formation from thioacids and perfluoroaryl azides. AB - A metal-free method for fast and clean anilide formation from perfluoroaryl azide and thioacid is presented. The reaction proved highly efficient, displaying fast kinetics, high yield, and good chemoselectivity. The transformation was compatible with various solvents and tolerant to a wide variety of functional groups, and it showed high performance in polar protic/aprotic media, including aqueous buffer systems. PMID- 25837013 TI - Protected Fe valence in quasi-two-dimensional alpha-FeSi2. AB - We report the first comprehensive study of the high temperature form (alpha phase) of iron disilicide. Measurements of the magnetic susceptibility, magnetization, heat capacity and resistivity were performed on well characterized single crystals. With a nominal iron d(6) configuration and a quasi-two dimensional crystal structure that strongly resembles that of LiFeAs, alpha-FeSi2 is a potential candidate for unconventional superconductivity. Akin to LiFeAs, alpha-FeSi2 does not develop any magnetic order and we confirm its metallic state down to the lowest temperatures (T = 1.8 K). However, our experiments reveal that paramagnetism and electronic correlation effects in alpha-FeSi2 are considerably weaker than in the pnictides. Band theory calculations yield small Sommerfeld coefficients of the electronic specific heat gamma = Ce/T that are in excellent agreement with experiment. Additionally, realistic many-body calculations further corroborate that quasi-particle mass enhancements are only modest in alpha-FeSi2. Remarkably, we find that the natural tendency to vacancy formation in the iron sublattice has little influence on the iron valence and the density of states at the Fermi level. Moreover, Mn doping does not significantly change the electronic state of the Fe ion. This suggests that the iron valence is protected against hole doping and indeed the substitution of Co for Fe causes a rigid-band like response of the electronic properties. As a key difference from the pnictides, we identify the smaller inter-iron layer spacing, which causes the active orbitals near the Fermi level to be of a different symmetry in alpha-FeSi2. This change in orbital character might be responsible for the lack of superconductivity in this system, providing constraints on pairing theories in the iron based pnictides and chalcogenides. PMID- 25837014 TI - Dynamic Kinetic Asymmetric Amination of Alcohols: From A Mixture of Four Isomers to Diastereo- and Enantiopure alpha-Branched Amines. AB - The first dynamic kinetic asymmetric amination of alcohols via borrowing hydrogen methodology is presented. Under the cooperative catalysis by an iridium complex and a chiral phosphoric acid, alpha-branched alcohols that exist as a mixture of four isomers undergo racemization by two orthogonal mechanisms and are converted to diastereo- and enantiopure amines bearing adjacent stereocenters. The preparation of diastereo- and enantiopure 1,2-amino alcohols is also realized using this catalytic system. PMID- 25837011 TI - Calcium alleviates cadmium-induced inhibition on root growth by maintaining auxin homeostasis in Arabidopsis seedlings. AB - Cadmium (Cd) toxicity has been widely studied in different plant species. However, the mechanism involved in its toxicity and the cell response to Cd has not been well established. In the present study, we investigated the possible mechanism of calcium (Ca) in protecting Arabidopsis from Cd toxicity. The results showed that 50 MUM Cd significantly inhibited the seedling growth and decreased the chlorophyll content in Arabidopsis. Specifically, the primary root (PR) length was decreased but the lateral root (LR) number was increased under Cd stress. Furthermore, Cd enhanced the hydrogen peroxide (H2O2) content and lipid peroxidation as indicated by malondialdehyde (MDA) accumulation. Cd also altered the level and the distribution of auxin in PR tips (as evidenced by DR5::GUS and PIN:GFP reporter expression) and the expression of several putative auxin biosynthetic, catabolic, and transport pathway-related genes. Application of 3 mM Ca alleviated the inhibition of Cd on the root growth. Ca application not only led to reducing oxidative injuries but also restoring the normal auxin transport and distribution in Arabidopsis root under Cd stress. Taken together, these results suggest that Ca alleviates the root growth inhibition caused by Cd through maintaining auxin homeostasis in Arabidopsis seedlings. PMID- 25837015 TI - TNF-alpha gene polymorphisms and juvenile idiopathic arthritis: Influence on disease outcome and therapeutic response. AB - OBJECTIVE: To investigate the genetic contribution of TNF-alpha gene polymorphisms on the disease course and therapeutic response in patients with juvenile idiopathic arthritis (JIA). METHODS: 74 Caucasian patients with JIA were recruited with a control group of 77 healthy children. DNA was extracted for analysis of TNF-alpha gene promoter polymorphisms at positions -163, -244, -238, 376, and -308. RESULTS: No SNPs at position -163 were observed, while we observed only SNPs at positions -244 and -376 in the controls. No differences were observed in the prevalence of SNPs at -238 and -308 between JIA and controls. In JIA patients no significant differences were observed between the -238 and -308 G/A genotypes and different disease phenotypes. We observed a significant lower disease activity expressed in the carriers of -308 GG genotype with respect to GA and AA genotypes after 6 (p = 0.008 and p = 0.013, respectively) and 12 months of disease (p = 0.02 and p = 0.08, respectively). Also the -238 GG genotypes showed a better disease course after 12 months of disease. Moreover, the -238/-308 GG genotypes presented the higher reduction of disease activity both after 6 (p < 0.01 vs GA and p < 0.01 vs AA) and 12 months from baseline (p < 0.01 vs GA and p < 0.01 vs AA). After 12 months of biologic therapy, a significant higher disease activity was observed in patients with genotype -308 AA respect to both GA (p = 0.012) and GG (p = 0.016). CONCLUSIONS: JIA patients carrying the TNF-alpha -308 GA/AA and -238 GA genotypes are associated with a worse prognosis and with a lower response to anti-TNF-alpha drugs. PMID- 25837016 TI - Comparison of Intravenous plus Oral Pantoprazole Therapy and Oral Pantoprazole Alone for Preventing Gastrointestinal Bleeding in Acute Coronary Syndrome Patients with High Bleeding Risk. AB - BACKGROUND: It is unclear whether intravenous proton pump inhibition is more effective than oral administration in preventing gastrointestinal (GI) bleeding in high bleeding risk patients with acute coronary syndromes (ACS). METHODS AND RESULTS: A total of 504 patients with ACS and high bleeding risk were randomly assigned into two groups. Study group (n=252) received intravenous pantoprazole for five days and subsequent oral pantoprazole for 12 months. Control group (n=252) received oral pantoprazole for 12 months. Major adverse cardiac events (death, re-infarction, re-revascularisation and stroke) and GI bleeding were registered after a follow-up of 12 months. No statistically significant differences were found in the major adverse cardiac events between the two groups after the follow-up (p >0.05). The incidence of major GI bleeding in the study group was lower than in the control group (1.2% vs. 3.9%, p=0.049). The bleeding rates in the first 30 days in the study group were also lower than in the control group (0.3% vs. 2.7%, p=0.032). CONCLUSIONS: The main outcome of cardiac events did not differ between the treatment groups. Intravenous plus oral pantoprazole therapy seemed more effective than oral therapy alone in the prevention of GI bleeding in high bleeding risk patients with ACS. PMID- 25837017 TI - Levosimendan Improves Neurological Outcome in a Swine Model of Asphyxial Cardiac Arrest. AB - BACKGROUND: In asphyxial cardiac arrest, the severe hypoxic stress complicates the resuscitation efforts and results in poor neurological outcomes. Our aim was to assess the effects of levosimendan on a swine model of asphyxial cardiac arrest. METHODS: Asphyxial cardiac arrest was induced in 20 Landrace/Large White piglets, which were subsequently left untreated for four minutes. The animals were randomised to receive adrenaline alone (n=10, Group A) and adrenaline plus levosimendan (n=10, Group B). All animals were resuscitated according to the 2010 European Resuscitation Council guidelines. Haemodynamic variables were measured before arrest, during arrest and resuscitation, and during the first 30 minutes after return of spontaneous circulation (ROSC), while survival and neurologic alertness score were measured 24 hours later. RESULTS: Return of spontaneous circulation was achieved in six animals (60%) from Group A and nine animals (90%) from Group B (p=0.303). During the first minute of cardiopulmonary resuscitation, coronary perfusion pressure was significantly higher in Group B (p=0.046), but there was no significant difference at subsequent time points until ROSC. Although six animals (60%) from each group survived after 24 hours (p=1.000), neurologic examination was significantly better in the animals of Group B (p<0.01). CONCLUSIONS: The addition of levosimendan to adrenaline improved coronary perfusion pressure immediately after the onset of cardiopulmonary resuscitation and resulted in better 24-hour neurological outcome. PMID- 25837018 TI - Differential Effects of Prevention and Reversal Treatment with Lisinopril on Left Ventricular Remodelling in a Rat Model of Heart Failure. AB - BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors such as lisinopril, represent the front line pharmacological treatment for heart failure, which is characterised by marked left ventricular (LV) dilatation and hypertrophy. This study sought to determine whether initiating treatment with ACE inhibitors at different stages in the remodelling process would alter the efficacy of treatment. METHODS: To this end, LV size and function were determined in the aortocaval (AV) fistula model of volume overload-induced heart failure. Sprague Dawley rats were assigned to sham, untreated AV fistula (21 weeks), AV fistula treated with lisinopril (21 weeks), or AV fistula treated with lisinopril from six to 21 weeks post-fistula groups. RESULTS: Administration of lisinopril for the entire 21-week period prevented LV dilatation, attenuated myocardial hypertrophy and prevented changes in myocardial compliance and contractility, whereas delaying initiation of treatment until six weeks post-fistula attenuated LV dilatation and hypertrophy, however, the delayed onset of treatment had no beneficial effect on ventricular compliance or systolic function. CONCLUSIONS: The results demonstrate differential effects that can occur with ACE inhibitors depending on the stage during the remodelling process at which treatment is administered. PMID- 25837019 TI - Cost-Effectiveness Analysis of Fondaparinux vs Enoxaparin in Non-ST Elevation Acute Coronary Syndrome in Thailand. AB - BACKGROUND: Non-ST elevation acute coronary syndrome (NSTE-ACS) imposes a significant health and economic burden on a society. Anticoagulants are recommended as standard therapy by various clinical practice guidelines. Fondaparinux was introduced and evaluated in a number of large randomised, controlled trials. This study therefore aimed to determine the cost-effectiveness of fondaparinux versus enoxaparin in the treatment of NSTE-ACS in Thailand. METHODS: A two-part construct model comprising a one-year decision tree and a Markov model was developed to capture short and long-term costs and outcomes from the perspective of provider and society. Effectiveness data were derived from OASIS-5 trial while bleeding rates were derived from the Thai Acute Coronary Syndrome Registry (TACSR). Costs data were based on a Thai database and presented in the year of 2013. Both costs and outcomes were discounted by 3% annually. A series of sensitivity analyses were performed. RESULTS: The results showed that compared with enoxaparin, fondaparinux was a cost-saving strategy (lower cost with slightly higher effectiveness). Cost of revascularisation with major bleeding had a greater impact on the amount of cost saved both from societal and provider perspectives. With a threshold of 160,000 THB ((4,857.3 USD) per QALY in Thailand, fondaparinux was about 99% more cost-effective compared with enoxaparin. CONCLUSION: Fondaparinux should be considered as a cost-effective alternative when compared to enoxaparin for NSTE-ACS based on Thailand's context, especially in the era of limited healthcare resources. PMID- 25837020 TI - Giant Cervico-mediastinal Well-differentiated Liposarcoma. AB - Liposarcomas are rare entities and those located in the neck and mediastinum are exceptional. We report the case of a 58 year-old Caucasian male who presented with dysphonia, mild dysphagia to solids, dyspnoea at exertion and cough due to a giant mass of the neck originating from the deep cervical space at C6 vertebral level spreading into the posterior mediastinum. The lesion, that was associated with a right vocal cord palsy, caused severe lateral displacement of the trachea and oesophagus. The case has been managed by complete surgical resection through a combined cervical and thoracic approach associated with a tracheostomy due to the risk of bilateral recurrent nerve dysfunction at the end of the intervention. The tumour was diagnosed as a encapsulated low-grade liposarcoma. Six months after surgery the tracheostomy was closed. At 24 months clinical and radiological follow-up the patient is doing well and disease free. PMID- 25837021 TI - A novel autophagy-independent, oncosuppressive function of BECN1: Degradation of MCL1. AB - The discovery that heterozygous disruption of Becn1 in mice leads to spontaneous tumor development was the first direct link arguing for a predominantly tumor suppressor function of autophagy. However, the mechanisms by which BECN1 restrains tumorigenesis and whether autophagy-independent functions of BECN1 contribute to its tumor-restraining potential remained unexplored. We recently described a novel function of BECN1-regulation of oncogene MCL1 protein levels. Our results show that BECN1 regulates MCL1 levels in an inverse-reciprocal manner, whereby changes in the levels of one of the 2 proteins inversely affects the proteasomal degradation of the other. Importantly, this mechanism is independent of autophagy and of the physical interaction between BECN1 and MCL1. In vitro and in vivo analysis using several models, including patient-derived melanoma cells and tissue samples from patients with melanocytic lesions at different stages, showed that the identified mechanism of inverse coregulation between BECN1 and MCL1 significantly contributes to their opposing roles in tumorigenesis. PMID- 25837023 TI - Bioremediation of Petrochemical Wastewater Containing BTEX Compounds by a New Immobilized Bacterium Comamonas sp. JB in Magnetic Gellan Gum. AB - In this study, we investigated the bioremediation of petrochemical wastewater containing BTEX compounds by immobilized Comamonas sp. JB cells. Three kinds of magnetic nanoparticles were evaluated as immobilization supports for strain JB. After comparison with Fe3O4 and a-Fe2O3 nanoparticles, r-Fe2O3 nanoparticle was selected as the optimal immobilization support. The highest biodegradation activity of r-Fe2O3-magnetically immobilized cells was obtained when the concentration of r-Fe2O3 nanoparticle was 120 mg L(-1). Additionally, the recycling experiments demonstrated that the degradation activity of r-Fe2O3 magnetically immobilized cells was still high and led to less toxicity than untreated wastewater during the eight recycles. qPCR suggested the concentration of strain JB in r-Fe2O3-magnetically immobilized cells was evidently increased after eight cycles of degradation experiments. These results supported developing efficient biocatalysts using r-Fe2O3-magnetically immobilized cells and provided a promising technique for improving biocatalysts used in the bioremediation of not only petrochemical wastewater but also other hazardous wastewater. PMID- 25837024 TI - Exploring the knowledge behind predictions in everyday cognition: an iterated learning study. AB - Making accurate predictions about events is an important but difficult task. Recent work suggests that people are adept at this task, making predictions that reflect surprisingly accurate knowledge of the distributions of real quantities. Across three experiments, we used an iterated learning procedure to explore the basis of this knowledge: to what extent is domain experience critical to accurate predictions and how accurate are people when faced with unfamiliar domains? In Experiment 1, two groups of participants, one resident in Australia, the other in China, predicted the values of quantities familiar to both (movie run-times), unfamiliar to both (the lengths of Pharaoh reigns), and familiar to one but unfamiliar to the other (cake baking durations and the lengths of Beijing bus routes). While predictions from both groups were reasonably accurate overall, predictions were inaccurate in the selectively unfamiliar domains and, surprisingly, predictions by the China-resident group were also inaccurate for a highly familiar domain: local bus route lengths. Focusing on bus routes, two follow-up experiments with Australia-resident groups clarified the knowledge and strategies that people draw upon, plus important determinants of accurate predictions. For unfamiliar domains, people appear to rely on extrapolating from (not simply directly applying) related knowledge. However, we show that people's predictions are subject to two sources of error: in the estimation of quantities in a familiar domain and extension to plausible values in an unfamiliar domain. We propose that the key to successful predictions is not simply domain experience itself, but explicit experience of relevant quantities. PMID- 25837022 TI - Distribution and risk factors for Plasmodium and helminth co-infections: a cross sectional survey among children in Bagamoyo district, coastal region of Tanzania. AB - BACKGROUND: Plasmodium and soil transmitted helminth infections (STH) are a major public health problem, particularly among children. There are conflicting findings on potential association between these two parasites. This study investigated the Plasmodium and helminth co-infections among children aged 2 months to 9 years living in Bagamoyo district, coastal region of Tanzania. METHODS: A community-based cross-sectional survey was conducted among 1033 children. Stool, urine and blood samples were examined using a broad set of quality controlled diagnostic methods for common STH (Ascaris lumbricoides, hookworm, Strongyloides stercoralis, Enterobius vermicularis, Trichuris trichura), schistosoma species and Wuchereria bancrofti. Blood slides and malaria rapid diagnostic tests (mRDTs) were utilized for Plasmodium diagnosis. RESULTS: Out of 992 children analyzed, the prevalence of Plasmodium infection was 13% (130/992), helminth 28.5% (283/992); 5% (50/992) had co-infection with Plasmodium and helminth. The prevalence rate of Plasmodium, specific STH and co-infections increased significantly with age (p < 0.001), with older children mostly affected except for S. stercoralis monoinfection and co-infections. Spatial variations of co-infection prevalence were observed between and within villages. There was a trend for STH infections to be associated with Plasmodium infection [OR adjusted for age group 1.4, 95% CI (1.0-2.1)], which was more marked for S. stercoralis (OR = 2.2, 95% CI (1.1-4.3). Age and not schooling were risk factors for Plasmodium and STH co-infection. CONCLUSION: The findings suggest that STH and Plasmodium infections tend to occur in the same children, with increasing prevalence of co-infection with age. This calls for an integrated approach such as using mass chemotherapy with dual effect (e.g., ivermectin) coupled with improved housing, sanitation and hygiene for the control of both parasitic infections. PMID- 25837026 TI - Beriberi in Cambodia. AB - Beriberi had plagued humans for centuries. It was responsible for over 50% of infant deaths in the Philippines in the early 1900s. But since the discovery of its cause and treatment it has become a rarity, or has it? PMID- 25837025 TI - Volumetric measurement of compensatory hypertrophy in the contralateral normal kidney by the tumor growth. AB - PURPOSE: We evaluated the association between tumor size and preoperative volumetric kidney parameters measured with CT in patients with renal cell carcinoma (RCC). METHODS: We prospectively identified 1118 patients who underwent radical or partial nephrectomy for RCC between 2011 and 2014. Contrast-enhanced CT was performed within three months before surgery. Kidney volume was measured using a tissue segmentation tool program from CT images. We classified patients into three groups depending on tumor size (A: <=4 cm, B: 4-7 cm, C: >7 cm). The preoperative volumetric kidney parameters were compared and multivariable linear regression was used to analyze potential factors associated with compensatory hypertrophy of the contralateral normal kidney before surgery. RESULTS: Patients in group C had a significantly larger contralateral normal kidney volume than patients in A and B (A: 170.0 mL, B: 171.7 mL, C: 187.2 mL, p < 0.001). The contralateral kidney volume was not significantly different between groups A and B (p > 0.05). However, tumor-side real kidney volume in group C was significantly smaller than that of groups A and B (A: 168.8 mL, B: 164.9 mL, C: 150.9 mL, p < 0.001). On multivariable analysis, increased contralateral kidney volume was positively associated with male gender, higher BMI, DM, higher preoperative GFR, and tumor size (>7 cm), and negatively associated with older age (p < 0.05). Tumor size had the strongest positive association with contralateral kidney volume (>7 cm, partial regression coefficient = 30.2). CONCLUSIONS: Tumor size (>7 cm) is the strongest factor associated with compensatory hypertrophy in the contralateral normal kidney before surgery. PMID- 25837027 TI - Efficient enhancement of magnetic anisotropy by optimizing the ligand-field in a typically tetranuclear dysprosium cluster. AB - The perturbation to the ligand field around the lanthanide ion may significantly contribute to the magnetic dynamics of single molecule magnets. This can be demonstrated by two typical Dy4 cluster-based single molecular magnets (SMMs), [Dy4X2(MU3-OH)2(MU-OH)2(2,2-bpt)4(H2O)4]X2.2H2O.4EtOH (X = Cl and Br for and , respectively), which were constructed by using 3,5-bis(pyridin-2-yl)-1,2,4 triazole (2,2-bptH) as the polynuclear-chelating ligand. Alternating-current (ac) magnetic susceptibility measurements show that the energy barriers in complexes and were immensely enhanced by comparing with our previous work due to the optimization of the ligand field around Dy(III) ions. Remarkably, their high thermal active barriers at 190 K () and 197 K () under a zero applied external dc magnetic field are also among the highest within the reported tetranuclear lanthanide-based SMMs. PMID- 25837028 TI - Global Lung Function Initiative equations improve interpretation of FEV1 decline among patients with cystic fibrosis. PMID- 25837029 TI - Noninvasive identification of left-sided heart failure in a population suspected of pulmonary arterial hypertension. AB - Exclusion of pulmonary hypertension secondary to left-sided heart disease (left heart failure (LHF)) is pivotal in the diagnosis of pulmonary arterial hypertension (PAH). In case of doubt, invasive measurements are recommended. The aim of the present study was to investigate whether it is possible to diagnose LHF using noninvasive parameters in a population suspected of PAH.300 PAH and 80 LHF patients attended our pulmonary hypertension clinic before August 2010, and were used to build the predictive model. 79 PAH and 55 LHF patients attended our clinic from August 2010, and were used for prospective validation.A medical history of left heart disease, S deflection in V1 plus R deflection in V6 in millimetres on ECG, and left atrial dilation or left valvular heart disease that is worse than mild on echocardiography were independent predictors of LHF. The derived risk score system showed good predictive characteristics: R(2)=0.66 and area under the curve 0.93. In patients with a risk score >=72, there is 100% certainty that the cause of pulmonary hypertension is LHF. Using this risk score system, the number of right heart catheterisations in LHF may be reduced by 20%.In a population referred under suspicion of PAH, a predictive model incorporating medical history, ECG and echocardiography data can diagnose LHF noninvasively in a substantial percentage of cases. PMID- 25837030 TI - Sleeping on animal fur is related to asthma outcomes in later childhood. AB - Animal furs might represent a "proxy" for high and diverse microbial exposures within a critical time window of immune development. We assessed whether sleeping on animal fur shortly after birth is associated with asthma and atopy up to the age of 10 years. LISAplus participants (n=2441) from Munich and Leipzig, Germany, were included in the analysis. Animal fur exposure, cofactors and health outcomes were obtained periodically up to 10 years of age by parental questionnaires. Information on specific IgE to aeroallergens was available at 10 years. Cytokine producing peripheral T-cells were assessed in a subgroup of children at 2 and 3 years. Confounder-adjusted associations were evaluated using logistic regression analyses. Sleeping on animal fur was very common (55%). In adjusted logistic regression analyses, sleeping on animal fur was inversely associated with recurrent early wheezing at 4 years (adjusted OR 0.75, 95% CI 0.61-0.93) and current asthma at 6 years (adjusted OR 0.56, 95% CI 0.31-1.01). Furthermore, sleeping on animal fur during the first 3 months of life was significantly associated with a persistently stimulated interferon-gamma response until the age of 3 years. Animal fur could be an effective measure of creating environments associated with higher microbial exposure. PMID- 25837032 TI - Validation of two predictive models for survival in pulmonary arterial hypertension. AB - The French Pulmonary Hypertension Network (FPHN) registry and the Registry to Evaluate Early And Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) have developed predictive models for survival in pulmonary arterial hypertension (PAH). In this collaboration, we assess the external validity (or generalisability) of the FPHN ItinerAIR-HTAP predictive equation and the REVEAL risk score calculator. Validation cohorts approximated the eligibility criteria defined for each model. The REVEAL cohort comprised 292 treatment-naive, adult patients diagnosed <1 year prior to enrolment with idiopathic, familial or anorexigen-induced PAH. The FPHN cohort comprised 1737 patients with group 1 PAH. Application of FPHN parameters to REVEAL and REVEAL risk scores to FPHN demonstrated estimated hazard ratios that were consistent between studies and had high probabilities of concordance (hazard ratios of 0.72, 95% CI 0.64-0.80, and 0.73, 95% CI 0.70-0.77, respectively). The REVEAL risk score calculator and FPHN ItinerAIR-HTAP predictive equation showed good discrimination and calibration for prediction of survival in the FPHN and REVEAL cohorts, respectively, suggesting prognostic generalisability in geographically different PAH populations. Once prospectively validated, these may become valuable tools in clinical practice. PMID- 25837031 TI - The genetic basis of idiopathic pulmonary fibrosis. AB - Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis. PMID- 25837033 TI - Linezolid for multidrug-resistant tuberculosis in HIV-infected and -uninfected patients. PMID- 25837034 TI - The relationship between asthma and suicidal behaviours: a systematic literature review. AB - Asthma is a highly prevalent chronic condition worldwide, and is particularly common in younger people compared to other chronic conditions. Asthma can result in a number of symptoms that are detrimental to the quality of life of sufferers. The aim of the present systematic literature review was to analyse the existing literature on the relationship between asthma and fatal and nonfatal suicidal behaviours. Articles were retrieved from Scopus, PubMed, ProQuest and Web of Knowledge. We searched for the terms (suicid* OR self-harm) AND (asthma* OR "bronchial hyperreactivity") published in English-language peer-reviewed journals between 1990 and December 2014. Original research papers providing empirical evidence about the potential link between asthma and suicidal behaviours were included. The initial search identified 746 articles. Specific limiting criteria reduced the number of articles to the 19 articles that were finally included in the systematic review. The review found a potential link between asthma and suicide mortality, ideation and attempts across the age groups. Limitations of the review include the restriction to English-language papers published within the chosen time period, the limited number of papers involving suicide mortality, and the fact that the majority of papers originated from the USA. PMID- 25837036 TI - Occupational exposures and fluorescent oxidation products in 723 adults of the EGEA study. PMID- 25837035 TI - Effects of quitting cannabis on respiratory symptoms. AB - Smoking cannabis is associated with symptoms of bronchitis. Little is known about the persistence of symptoms after stopping cannabis use. We assessed associations between changes in cannabis use and respiratory symptoms in a population-based cohort of 1037 young adults. Participants were asked about cannabis and tobacco use at ages 18, 21, 26, 32 and 38 years. Symptoms of morning cough, sputum production, wheeze, dyspnoea on exertion and asthma diagnoses were ascertained at the same ages. Frequent cannabis use was defined as >=52 occasions over the previous year. Associations between frequent cannabis use and respiratory symptoms were analysed using generalised estimating equations with adjustments for tobacco smoking, asthma, sex and age. Frequent cannabis use was associated with morning cough (OR 1.97, p<0.001), sputum production (OR 2.31, p<0.001) and wheeze (OR 1.55, p<0.001). Reducing or quitting cannabis use was associated with reductions in the prevalence of cough, sputum and wheeze to levels similar to nonusers.Frequent cannabis use is associated with symptoms of bronchitis in young adults. Reducing cannabis use often leads to a resolution of these symptoms. PMID- 25837037 TI - Global and regional trends in COPD mortality, 1990-2010. AB - Between 1990 and 2010, chronic obstructive pulmonary disease (COPD) moved from the fourth to third most common cause of death worldwide. Using data from the Global Burden of Disease programme we quantified regional changes in the number of COPD deaths and COPD mortality rates between 1990 and 2010. We estimated the proportion of the change that was attributable to gross national income per capita and an index of cumulative smoking exposure, and quantified the difference in mortality rates attributable to demographic changes. Despite a substantial decrease in COPD mortality rates, COPD deaths fell only slightly, from three million in 1990 to 2.8 million in 2010, because the mean age of the population increased. The number of COPD deaths in 2010 would have risen to 5.2 million if the age- and sex-specific mortality rates had remained constant. Changes in smoking led to only a small increase in age- and sex-specific mortality rates, which were strongly associated with changes in gross national income. The increased burden of COPD mortality was mainly driven by changes in age distribution, but age- and sex-specific rates fell as incomes rose. The rapid response to increasing affluence suggests that changes in COPD mortality are not entirely explained by changes in early life. PMID- 25837038 TI - Lung cancer screening feasibility in Australia. PMID- 25837039 TI - Mortality among patients with pleural effusion undergoing thoracentesis. AB - Of the 1.5 million people diagnosed with pleural effusion in the USA annually, ~178 000 undergo thoracentesis. While it is known that malignant pleural effusion portends a poor prognosis, mortality of patients with nonmalignant effusions has not been well studied.This prospective cohort study evaluated 308 patients undergoing thoracentesis. Chart review was performed to obtain baseline characteristics. The aetiology of the effusions was determined using standardised criteria. Mortality was determined at 30 days and 1 year.247 unilateral and 61 bilateral thoracenteses were performed. Malignant effusion had the highest 30-day (37%) and 1-year (77%) mortality. There was substantial patient 30-day and 1-year mortality with effusions due to multiple benign aetiologies (29% and 55%), congestive heart failure (22% and 53%), and renal failure (14% and 57%, respectively). Patients with bilateral, relative to unilateral, pleural effusion were associated with higher risk of death at 30 days and 1 year (17% versus 47% (hazard ratio (HR) 2.58, 95% CI 1.44-4.63) and 36% versus 69% (HR 2.32, 95% CI 1.55-3.48), respectively).Patients undergoing thoracentesis for pleural effusion have high short- and long-term mortality. Patients with malignant effusion had the highest mortality followed by multiple benign aetiologies, congestive heart failure and renal failure. Bilateral pleural effusion is distinctly associated with high mortality. PMID- 25837040 TI - Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry. AB - After introduction of the new international guidelines on idiopathic pulmonary fibrosis (IPF) in 2011, we investigated clinical management practices for patients with IPF according to physicians' diagnoses. A prospective, multicenter, noninterventional study with comprehensive quality measures including on-site source data verification was performed in Germany. 502 consecutive patients (171 newly diagnosed, 331 prevalent; mean+/-SD age 68.7+/-9.4 years, 77.9% males) with a mean disease duration of 2.3+/-3.5 years were enrolled. IPF diagnosis was based on clinical assessments and high-resolution computed tomography (HRCT) in 90.2%, and on surgical lung biopsy combined with histology in 34.1% (lavage in 61.8%). The median 6-min walk distance was 320 m (mean 268+/-200 m). The mean forced vital capacity was 72+/-20% pred and diffusing capacity of the lung for carbon monoxide was 35+/-15% pred. No drugs were administered in 17.9%, oral steroids in 23.7%, N-acetylcysteine in 33.7%, pirfenidone in 44.2% and other drugs in 4.6% of patients. Only 2.8% of the cohort was listed for lung transplantation. IPF patients were diagnosed in line with the new guidelines. They had more severe disease than those enrolled in recent randomised controlled trials. In addition to HRCT, the frequency of lung biopsies was surprisingly high. Treatment patterns varied substantially. PMID- 25837043 TI - Optimization of phase modulation with arbitrary waveform generators for optical spectral control and suppression of stimulated Brillouin scattering. AB - We investigate the use of an arbitrary waveform generator to phase-modulate a laser source and externally broaden its linewidth. Through nonlinear optimization in a computer, we find modulation signals that produce top-hat-shaped optical spectra of discrete lines with highest total power within a limited bandwidth and limited peak spectral power density. The required modulation bandwidth is comparable to the targeted optical bandwidth. Such spectra are attractive for suppressing stimulated Brillouin scattering in optical fiber. Experimentally, we generate 15 lines in a 0.5 GHz optical linewidth. However, the method can also be used to generate other optical spectra. PMID- 25837041 TI - A randomised trial of lung sealant versus medical therapy for advanced emphysema. AB - Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3 and 6-month analysis.57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility. PMID- 25837044 TI - Dissipative soliton resonance and reverse saturable absorption in graphene oxide mode-locked all-normal-dispersion Yb-doped fiber laser. AB - We observed dissipative soliton resonance phenomenon in a graphene oxide mode locked Yb-doped fiber laser, which delivered square-shaped pulse of 0.52 ns~60.8 ns and single pulse energy of 159.4 nJ at 1064.9 nm. The 3 dB-bandwidth of Lorentz-shaped spectrum was 0.19 nm. We pointed out that the reverse saturable absorption played a big role in generating square-shaped or flat-top pulses, which verified by additional simulation work. PMID- 25837045 TI - Ultra-high tunable liquid crystal-plasmonic photonic crystal fiber polarization filter. AB - A novel ultra-high tunable photonic crystal fiber (PCF) polarization filter is proposed and analyzed using finite element method. The suggested design has a central hole infiltrated with a nematic liquid crystal (NLC) that offers high tunability with temperature and external electric field. Moreover, the PCF is selectively filled with metal wires into cladding air holes. Results show that the resonance losses and wavelengths are different in x and y polarized directions depending on the rotation angle phi of the NLC. The reported filter of compact device length 0.5 mm can achieve 600 dB / cm resonance losses at phi = 90 degrees for x-polarized mode at communication wavelength of 1300 mm with low losses of 0.00751 dB / cm for y-polarized mode. However, resonance losses of 157.71 dB / cm at phi = 0 degrees can be achieved for y-polarized mode at the same wavelength with low losses of 0.092 dB / cm for x-polarized mode. PMID- 25837046 TI - Effect of structure and composition on optical properties of Er-Sc silicates prepared from multi-nanolayer films. AB - Polycrystalline Er-Sc silicates (Er(x)Sc(2-x)SiO5 and Er(x)Sc(2-x)Si2O7) were fabricated using multilayer nanostructured films of Er2O3/SiO2/Sc2O3 deposited on SiO2/Si substrates by RF- sputtering and thermal annealing at high temperature. RBS, TEM, GIXD, and PL results show the presence of Er(x)Sc(2-x)SiO5 with an emission peak at 1528 nm for annealing from 900 to 1100 degrees C, and Er(x)Sc(2 x)Si2O7 with an emission peak at 1537 nm for higher annealing temperature. The PL intensity of the Er(x)Sc(2-x)Si2O7 phase is five times stronger than that of the Er(x)Sc(2-x)SiO5 phase at 1250 degrees C. From PLE and PL spectra of Er(x)Sc(2 x)Si2O7 thin film, we schematically illustrate the Er3+ Stark energy levels of 4I(13/2) to 4I(15/2) manifolds due to the crystal field strength effect of Sc3+. Temperature-dependent PL of the Er(x)Sc(2-x)Si2O7 phase exhibits a variation of the full-width at half-maximum (FWHM) from 1.1 to 2.3 nm. The narrow FWHM is due to the small ionic radii of Sc3+, which enhance the crystal field strength affecting the optical properties of Er3+ ions located at the well-defined lattice sites of Sc silicate. A large excitation cross-section (sigma(ex)) is equal to 3.0x10-20 cm2 at lambda(ex) = 1527.6 nm. PMID- 25837047 TI - Trapping surface plasmon polaritons on ultrathin corrugated metallic strips in microwave frequencies. AB - It has been demonstrated that an ultrathin uniformly corrugated metallic strip is a good plasmonic waveguide in microwave and terahertz frequencies to propagate spoof surface plasmon polaritons (SPPs) with well confinement and small loss (Shen et al., PNAS 110, 40-45, 2013). Here, we propose a simple method to trap SPP waves on the ultrathin corrugated metallic strips in broad band in the microwave frequencies. By properly designing non-uniform corrugations with gradient-depth grooves, we show that the SPP waves are slowed down gradually and then reflected at pre-designed positions along the ultrathin metallic strip when the frequency varies. We design and fabricate the ultrathin gradient-corrugation metallic strip on a thin dielectric film. Both numerical simulation and measurement results validate the efficient trapping of SPP waves in broadband from 9 to 14 GHz. This proposal is a promising candidate for slow-wave devices in both microwave and terahertz regimes. PMID- 25837042 TI - Global genome and transcriptome analyses of Magnaporthe oryzae epidemic isolate 98-06 uncover novel effectors and pathogenicity-related genes, revealing gene gain and lose dynamics in genome evolution. AB - Genome dynamics of pathogenic organisms are driven by pathogen and host co evolution, in which pathogen genomes are shaped to overcome stresses imposed by hosts with various genetic backgrounds through generation of a variety of isolates. This same principle applies to the rice blast pathogen Magnaporthe oryzae and the rice host; however, genetic variations among different isolates of M. oryzae remain largely unknown, particularly at genome and transcriptome levels. Here, we applied genomic and transcriptomic analytical tools to investigate M. oryzae isolate 98-06 that is the most aggressive in infection of susceptible rice cultivars. A unique 1.4 Mb of genomic sequences was found in isolate 98-06 in comparison to reference strain 70-15. Genome-wide expression profiling revealed the presence of two critical expression patterns of M. oryzae based on 64 known pathogenicity-related (PaR) genes. In addition, 134 candidate effectors with various segregation patterns were identified. Five tested proteins could suppress BAX-mediated programmed cell death in Nicotiana benthamiana leaves. Characterization of isolate-specific effector candidates Iug6 and Iug9 and PaR candidate Iug18 revealed that they have a role in fungal propagation and pathogenicity. Moreover, Iug6 and Iug9 are located exclusively in the biotrophic interfacial complex (BIC) and their overexpression leads to suppression of defense-related gene expression in rice, suggesting that they might participate in biotrophy by inhibiting the SA and ET pathways within the host. Thus, our studies identify novel effector and PaR proteins involved in pathogenicity of the highly aggressive M. oryzae field isolate 98-06, and reveal molecular and genomic dynamics in the evolution of M. oryzae and rice host interactions. PMID- 25837048 TI - Fast optical frequency sweeping using voltage controlled oscillator driven single sideband modulation combined with injection locking. AB - An ultrafast optical frequency sweeping technique for narrow linewidth lasers is reported. This technique exploits the large frequency modulation bandwidth of a wideband voltage controlled oscillator (VCO) and a high speed electro-optic dual parallel Mach-Zehnder modulator (DPMZM) which works on the state of carrier suppressed single sideband modulation(CS-SSB). Optical frequency sweeping of a narrow linewidth fiber laser with 3.85 GHz sweeping range and 80 GHz/MUs tuning speed is demonstrated, which is an extremely high tuning speed for frequency sweeping of narrow linewidth lasers. In addition, injection locking technique is adopted to improve the sweeper's low optical power output and small side-mode suppression ratio (SMSR). PMID- 25837049 TI - Transition of correlated-electron emission in nonsequential double ionization of Ar atoms. AB - Emission of the two electrons released from nonsequential double ionization of argon atoms is anticorrelated at lower laser intensities but is correlated at higher laser intensities. Such a transition is caused by the momentum change of recollision-induced-ionization (RII) electrons. At lower laser intensities, the Coulomb repulsion between the two RII electrons dominates the motion of electrons and pushes them leaving the laser field back-to-back. At higher laser intensities, the drift momentum obtained from the laser field dominates the motion of electrons and drives them leaving the laser field side-by-side. PMID- 25837050 TI - Multi-band transmissions of chiral metamaterials based on Fabry-Perot like resonators. AB - In this paper, a multi-layered metallic structure is proposed, which consists of split-ring resonators on both sides of two dielectric substrates. Numerical results reveal that the structure realizes a high magnitude of 0.94, three bands and broadband (more than 8 GHz) asymmetric transmission for linearly polarized wave. These properties are not observed in previous works. In order to better know these transmission properties, the Fabry-Perot like resonance model has been introduced to analyze the enhancement mechanism of asymmetric transmission in the multi-layered structure. The physical mechanism of linearly polarized wave conversion and asymmetric transmission based on electric fields and currents distribution is also analyzed in detail, respectively. PMID- 25837051 TI - Broad baseband nonlinear distortion mitigation using digital pre- and post distortion in OFDM-based WDM LR-PON. AB - We propose a new technique for mitigation of nonlinear distortion of broadband signals due to electrical/optical conversions and fibre transmission. This technique uses memory polynomials on signals on their original format. The performance improvement is assessed experimentally for an orthogonal frequency division multiplexing signal, with 750 MHz of bandwidth (centred at 1.5 GHz) and carrying 1.25 Gbps, transmitted along a wavelength division multiplexing long reach passive optical network. It is shown that, in back-to-back, an error vector magnitude improvement of 4.1 dB and 11.8 dB can be achieved with digital pre distortion and digital post-distortion, respectively. With 125 km of single-mode fibre transmission, these improvements are reduced to about 1 dB and 3 dB, respectively. PMID- 25837052 TI - Speckle-based volume holographic microscopy for optically sectioned multi-plane fluorescent imaging. AB - Structured illumination microscopy has been widely used to reconstruct optically sectioned fluorescence images in wide-field fashion; however, it still requires axial scanning to obtain multiple depth information of a volumetric sample. In this paper, a new imaging scheme, called speckle-based volume holographic microscopy system, is presented. The proposed system incorporates volumetric speckle illumination and multiplexed volume holographic gratings to acquire multi plane images with optical sectioning capability, without any axial scanning. We present the design, implementation, and experimental image data demonstrating the proposed system's ability to simultaneously obtain wide-field, optically sectioned, and multi-depth resolved images of fluorescently labeled microspheres and tissue structures. PMID- 25837053 TI - Improvement of light extraction of LYSO scintillator by using a combination of self-assembly of nanospheres and atomic layer deposition. AB - The self-assembled monolayer periodic array of polystyrene spheres conformally coated with TiO2 layer using atomic layer deposition is designed to obtain a further enhancement of light extraction for LYSO scintillator. The maximum enhancement is 149% for the sample with polystyrene spheres conformally coated with TiO2 layer, while the enhancement is only 76% for the sample with only polystyrene spheres. Such further enhancement could be contributed from the additional modes forming by TiO2 layer due to its high refractive index, which can be approved by the simulation of electric field distribution. The experimental results are agreement with the simulated results. Furthermore, the prepared structured layer exhibits an excellent combination with the surface of scintillator, which is in favor of the practical application. Therefore, it is safely concluded that the combination of self-assembly method and atomic layer deposition is a promising approach to obtain a significant enhancement of light extraction for a large area. This method can be extended to many other luminescent materials and devices. PMID- 25837054 TI - Translation-reduced ion beam figuring. AB - A translation-reduced ion beam figuring (TRIBF) technique for five-axis ion beam figuring (IBF) plants is proposed to process large size components which cannot be processed in the traditional way. This novel technique enhances the capability of five-axis IBF plants by taking advantage of their rotation axes. The IBF kinematic model is described and the TRIBF processing technique is established by solving the motion parameters. Verification experiments are conducted on a 150 mm diameter planar mirror. This mirror was processed by TRIBF technique with only a 100 mm translation stage. The surface error was reduced from initial 10.7 nm rms to 1.3 nm rms within 97 minute processing time. The result indicates that the TRIBF processing technique is feasible and effective. PMID- 25837055 TI - Discrimination of "specific" and "nonspecific" binding in two-dimensional photonic crystals. AB - In this paper, we propose a design for a 2D slab photonic crystal (PhC) virus sensor and an associated signal analysis methodology that together enable single virus detection while rejecting false positives that occur due to non-specific interactions of serum proteins and small molecules with the sensor surface. The slab-PhC design takes advantage of both the optical and geometrical properties of its incorporated structures by physically limiting virus infiltration to only the most sensitive region of the PhC sensor, while allowing simultaneous measurement of both site-selective virus infiltration and non-specific small molecule accumulation across the device. Notably, the proposed sensor transducer is compatible with both standard semiconductor fabrication procedures and lab-on-a chip style microfluidic delivery systems. 3D finite-difference time-domain electromagnetic field computation results are presented, the outcomes of which indicate that both specific (target) virus capture and non-specific (non-target) binding can be simultaneously measured and discerned from one another. This type of capacity for background-corrected, single-pathogen target detection would provide a new and novel advancement toward sensitive, label-free virus diagnostics. PMID- 25837056 TI - Porous silicon ring resonator for compact, high sensitivity biosensing applications. AB - A ring resonator is patterned on a porous silicon slab waveguide to produce a compact, high quality factor biosensor with a large internal surface area available for enhanced recognition of biological and chemical molecules. The porous nature of the ring resonator allows molecules to directly interact with the guided mode. Quality factors near 10,000 were measured for porous silicon ring resonators with a radius of 25 MUm. A bulk detection sensitivity of 380 nm/RIU was measured upon exposure to salt water solutions. Specific detection of nucleic acid molecules was demonstrated with a surface detection sensitivity of 4 pm/nM. PMID- 25837057 TI - Nanocavity absorption enhancement for two-dimensional material monolayer systems. AB - Here we propose a strategy to enhance the light-matter interaction of two dimensional (2D) material monolayers based on strong interference effect in planar nanocavities, and overcome the limitation between optical absorption and the atomically-thin thickness of 2D materials. By exploring the role of spacer layers with different thicknesses and refractive indices, we demonstrate that a nanocavity with an air spacer layer placed between a graphene monolayer and an aluminum reflector layer will enhance the exclusive absorption in the graphene monolayer effectively, which is particularly useful for the development of atomically-thin energy harvesting/conversion devices. PMID- 25837058 TI - Modulation mechanism of multi-azimuthal masks on the redistributions of focused azimuthally polarized beams. AB - We propose a theoretical model to semi-quantitatively describe the modulation mechanism of multi-azimuthal masks on the focal fields of azimuthally polarized (AP) beam. With this model, we cannot only explain the redistributions of the polarization and intensity at the focal plane, but also consciously manage the focal fields by designing the mask structure parameters, such as the symmetry, area, and phase retardation of the sector photic regions. Our results may supply a guideline to realize the manipulation on the polarizations, angular momenta, and the distribution of focused fields. PMID- 25837059 TI - Constructing metamaterials from subwavelength pixels with constant indices product. AB - We investigate a two-dimensional metamaterial template constructed from different pixels through a conservation law of effective indices: If the product of refractive indices along the principal axes is invariant for different anisotropic materials in a two-dimensional space, the product of indices of the effective medium remains constant after mixing these materials. Such effective media of constant indices product can be implemented using metamaterial structures. The orientation of the metamaterial structure in a single pixel controls the direction of the principal axis of the effective medium. Different pixels are assembled into an array to obtain reconfigurable anisotropy of the effective medium. These considerations would be useful for constructing reconfigurable metamaterials and transformation media with area-preserving maps. PMID- 25837060 TI - Measurement of small light absorption in microparticles by means of optically induced rotation. AB - The absorption parameters of micro-particles have been associated with the induced spin exerted upon the particle, when embedded in a circularly polarized coherent field. The induced rotational speed is theoretically analyzed, showing the influence of the beam parameters, the parameters of the particle and the tribological parameters of the surrounding fluid. The theoretical findings have been adequately confirmed in experiments. PMID- 25837061 TI - Mode- and wavelength-division multiplexed transmission using all-fiber mode multiplexer based on mode selective couplers. AB - We propose all-fiber mode multiplexer composed of two consecutive LP11 mode selective couplers that allows for the multiplexing of LP01 mode and two-fold degenerate LP11 modes. We demonstrate WDM transmission of 32 wavelength channels with 100 GHz spacing, each carrying 3 modes of 120 Gb/s polarization division multiplexed quadrature phase shifted keying (PDM-QPSK) signal, over 560 km of few mode fiber (FMF). Long distance transmission is achieved by 6*6 multiple-input multiple-output digital signal processing and modal differential group delay compensated link of FMF. The all-fiber mode multiplexer has considerable potential to be used in mode- and wavelength-division multiplexed transmission. PMID- 25837062 TI - Generation of polarization-resolved wideband unpredictability-enhanced chaotic signals based on vertical-cavity surface-emitting lasers subject to chaotic optical injection. AB - A system framework is proposed and analyzed for generating polarization-resolved wideband unpredictability-enhanced chaotic signals based on a slave vertical cavity surface-emitting laser (S-VCSEL) driven by an injected optical chaos signal from a master VCSEL (M-VCSEL) under optical feedback. After calculating the time series outputs from the M-VCSEL under optical feedback and the S-VCSEL under chaotic optical injection by using the spin-flip model (SFM), the unpredictability degree (UD) is evaluated by permutation entropy (PE), and the bandwidth of the polarization-resolved outputs from the M-VCSEL and S-VCSEL are numerically investigated. The results show that, under suitable parameters, both the bandwidth and UD of two polarization components (PCs) outputs from the S VCSEL can be enhanced significantly compared with that of the driving chaotic signals output from the M-VCSEL. By simulating the influences of the feedback and injection parameters on the bandwidth and UD of the polarization-resolved outputs from S-VCSEL, related operating parameters can be optimized. PMID- 25837063 TI - Broadband superluminescence, 5.9 MUm to 7.2 MUm, of a quantum cascade gain device. AB - The broadband electroluminescence of a quantum cascade device based on a multi color active region covering the wavelengths 5.9 MUm - 7.2 MUm was measured. Anti reflection coatings were applied on both cleaved facets to remove the Fabry-Perot cavity and prevent the device from lasing. This allows the latter to be studied either as a superluminescent diode or a single-pass amplifier in order to determine its suitability as a source for low speckle imaging applications. At 243 K, the amplified spontaneous emission has a peak power of 38 MUW that agrees well with a simple model of spontaneous emission intensity. The light of a similar structure could be modulated up to 1 GHz, limited by the RC constant of the device. The peak gain was measured from high-resolution luminescence spectra and determined to be 6.3 cm-1, corresponding to a single-pass gain of 1.89. PMID- 25837064 TI - Forces due to pulsed beams in optical tweezers: linear effects. AB - We present a method for the precise calculation of optical forces due to a tightly-focused pulsed laser beam using generalized Lorenz-Mie theory or the T matrix method. This method can be used to obtain the fields as a function of position and time, allowing the approximate calculation of weak non-linear effects, and provides a reference calculation for validation of calculations including non-linear effects. We calculate forces for femtosecond pulses of various widths, and compare with forces due to a continuous wave (CW) beam. The forces are similar enough so that the continuous beam case provides a useful approximation for the pulsed case, with trap parameters such as the radial spring constant usually differing by less than 1% for pulses of 100 fs or longer. For large high-index (e.g., polystyrene, with n = 1.59) particles, the difference can be as large as 3% for 100 fs pulses, and up to 8% for 25 fs pulses. A weighted average of CW forces for individual spectral components of the pulsed beam provides a simple improved approximation, which we use to illustrate the physical principles responsible for the differences between pulsed and CW beams. PMID- 25837065 TI - Elliptical silicon nanowire photodetectors for polarization-resolved imaging. AB - Polarization-resolved imaging offers many advantages over conventional imaging because it provides additional information on materials and scenes. In this study, we present an image sensor pixel for polarization-resolved imaging based on an all-silicon nanowire device. As the structure has an intrinsically polarization-dependent response, it is not necessary to employ a polarizer. We fabricate pixels consisting of etched vertical silicon nanowires with elliptical cross-sections that incorporate vertical p-i-n junctions. Our photocurrent measurement reveals that the spectral responsivities are dependent on the polarization state of incident light. Polarization-resolved imaging is performed with fabricated devices. This approach is different from conventional approaches using polarization filters because absorbed light in the elliptical nanowire is converted to photocurrent while light absorbed by a polarization filter is discarded. PMID- 25837066 TI - Sensitive and ultra-fast species detection using pulsed cavity ringdown spectroscopy. AB - Pulsed cavity ringdown spectroscopy (CRDS) is used to develop a novel, ultra fast, high-sensitivity diagnostic for measuring species concentrations in shock tube experiments. The diagnostic is demonstrated by monitoring trace concentrations of ethylene in the mid-IR region near 949.47 cm-1. Each ringdown measurement is completed in less than 1 us and the time period between successive pulses is 10 us. The high sensitivity diagnostic has a noise-equivalent detection limit of 1.08 x 10-5 cm-1 which enables detection of 15 ppm ethylene at fuel pyrolysis conditions (1845 K and 2 bar) and 294 ppb ethylene under ambient conditions (297 K and 1 bar). To our knowledge, this is the first successful application of the cavity ringdown method to the measurement of species time histories in a shock tube. PMID- 25837067 TI - Tunable circular polarization selective surfaces for low-THz applications using patterned graphene. AB - This paper demonstrates a new type of frequency tunable polarization selective surface operating at low THz, which is devised by utilizing the unique features of graphene. The device is comprised of an infinite array of identical unit cells in three layers. Multiple graphene dipoles are placed on the top and bottom layers to form the vertical and horizontal electric field filters. Using this new configuration, the proposed device exhibits reflection for the incident Left-Hand Circular-Polarization (LHCP) waves and becomes transparent to the incoming Right Hand-Circular-Polarization (RHCP) waves. The excited localized surface plasmonic resonance mode on the graphene based unit cells significantly reduces the physical dimension of the device. The unit cell dimension of the proposed design is in the order of 0.18 wavelengths in comparison to conventional metallic structures, where it is of order a half a wavelength. In the full wave analysis, the graphene based polarization selective surfaces exhibit an isolation of 21 dB for LHCP waves and a transmission loss of around 5.1 dB for waves with RHCP characteristics. The performance has also been examined under oblique incidence. The results fully verify that the proposed planar device operates properly for incident angles up to 40 degrees . The tuning effect of the described device is investigated by varying the chemical potentials of graphene. Significant frequency reconfiguration capability is achieved in the isolation of LHCP incident waves, and meanwhile, for RHCP incidence, the transmission rate remains reasonably high. PMID- 25837068 TI - High-resolution and fast-response fiber-optic temperature sensor using silicon Fabry-Perot cavity. AB - We report a fiber-optic sensor based on a silicon Fabry-Perot cavity, fabricated by attaching a silicon pillar on the tip of a single-mode fiber, for high resolution and high-speed temperature measurement. The large thermo-optic coefficient and thermal expansion coefficient of the silicon material give rise to an experimental sensitivity of 84.6 pm/ degrees C. The excellent transparency and large refractive index of silicon over the infrared wavelength range result in a visibility of 33 dB for the reflection spectrum. A novel average wavelength tracking method has been proposed and demonstrated for sensor demodulation with improved signal-to-noise ratio, which leads to a temperature resolution of 6 * 10 4 degrees C. Due to the high thermal diffusivity of silicon, a response time as short as 0.51 ms for a sensor with an 80-um-diameter and 200-um-long silicon pillar has been experimentally achieved, suggesting a maximum frequency of ~2 kHz can be reached, to address the needs for highly dynamic environmental variations such as those found in the ocean. PMID- 25837069 TI - Angle algorithm based on Hough transform for imaging polarization navigation sensor. AB - Polarization navigation is a promising orientation-determination method inspired by insects' foraging behavior that offers the advantages of autonomous and high precision. In this paper, using the solar meridian as an azimuth reference is proposed. The model of the distribution pattern of the polarized skylight projected onto an imaging sensor is analyzed. The sufficient features of the solar meridian are proven. According to these features, an angle algorithm for an imaging polarization navigation sensor based on a machine-vision algorithm is proposed. In consideration of noise in images, the relation between the measured angle and the noise in images is modeled. This model cannot only optimize the threshold tolerance R in the algorithm but also describe the effects of several primary factors that can affect the measuring precision. In the simulation test, the measurement accuracy was better than 0.34 degrees . When the algorithm was tested on the polarization-detection system, the measurement accuracy was better than 0.37 degrees . PMID- 25837070 TI - Far-field correlation of bidirectional tracking beams due to wave-front deformation in inter-satellites optical communication links. AB - In some applications of optical communication systems, such as inter-satellites optical communication, the correlation of the bidirectional tracking beams changes in far-field as a result of wave-front deformation. Far-field correlation model with wave-front deformation on tracking stability is established. Far-field correlation function and factor have been obtained. Combining with parameters of typical laser communication systems, the model is corrected. It shows that deformation pointing-tracking errors theta(A) and theta(B), far-field correlation factor delta depend on RMS of deformation error rms, which decline with a increasing rms including Tilt and Coma. The principle of adjusting far-field correlation factor with wave-front deformation to compensate deformation pointing tracking errors has been given, through which the deformation pointing-tracking error is reduced to 18.12" (Azimuth) and 17.65" (Elevation). Work above possesses significant reference value on optimization design in inter-satellites optical communication. PMID- 25837071 TI - Complex rotational dynamics of multiple spheroidal particles in a circularly polarized, dual beam trap. AB - We examine the rotational dynamics of spheroidal particles in an optical trap comprising counter-propagating Gaussian beams of opposing helicity. Isolated spheroids undergo continuous rotation with frequencies determined by their size and aspect ratio, whilst pairs of spheroids display phase locking behaviour. The introduction of additional particles leads to yet more complex behaviour. Experimental results are supported by numerical calculations. PMID- 25837072 TI - Optical beam and its operation in low dimensional space. AB - This paper proposes the concept of low dimensional optical beam and operator. In low dimensional space, beam (or operator) is decomposed into a limited number of orthogonalized low dimensional beams (or operators) through the singular value decomposition. It is possible to generate an unconventional beam by these low dimensional beams. Low dimensional operator allows independent operation of orthogonal dimensions which may produce greater freedoms. Storage space and computation resource are saved dramatically by using this method. Experimental realization of this scheme is briefly discussed at the end. PMID- 25837073 TI - Two-party secret key distribution via a modified quantum secret sharing protocol. AB - We present and demonstrate a novel protocol for distributing secret keys between two and only two parties based on N-party single-qubit Quantum Secret Sharing (QSS). We demonstrate our new protocol with N = 3 parties using phase-encoded photons. We show that any two out of N parties can build a secret key based on partial information from each other and with collaboration from the remaining N - 2 parties. Our implementation allows for an accessible transition between N-party QSS and arbitrary two party QKD without modification of hardware. In addition, our approach significantly reduces the number of resources such as single photon detectors, lasers and dark fiber connections needed to implement QKD. PMID- 25837074 TI - Digital generation of shape-invariant Bessel-like beams. AB - Bessel beams have been extensive studied to date but are always created over a finite region inside the laboratory. Means to overcome this consider multi element refractive designs to create beams that have a longitudinal dependent cone angle, thereby allowing for a far greater quasi non-diffracting propagation region. Here we outline a generalized approach for the creation of shape invariant Bessel-like beams with a single phase-only element, and demonstrate it experimentally with a phase-only spatial light modulator. Our experimental results are in excellent agreement with theory, suggesting an easy-to-implement approach for long range, shape-invariant Bessel-like beams. PMID- 25837075 TI - Effect of the gradient of complex refractive index at boundary of turbid media on total internal reflection. AB - We analyze the existence of non-uniformity at the boundary of turbid media, and develop a gradient complex refractive index multilayered model in terms of this fact. Our model reveals the physics mechanism of the discrepancies between experimental data above the critical angle and the fitting curve with Fresnel's Formula. Also, from the perspective of the energy flow, reflectance R is obtained by the simplified models. We get complex refractive indexes and reflectance curves by fitting experimental data of 20% and 30% Intralipid solutions and rutile TiO2 powder suspension with two different methods. Compared with Fresnel's Formula, our model can fit experimental data better. PMID- 25837076 TI - Asymmetric polarization-based frequency scanning interferometer. AB - An asymmetric polarization-based frequency scanning interferometer is proposed using the asymmetric polarimetric method. The proposed system controls the polarization direction of the beam using a polarizer and wave plate, along with a conventional interferometer system. By controlling the wave plate, it is possible to asymmetrically modulate the magnitude of the object and reference beam, which are divided by the polarizing beam splitter. Based on this principle, if the target object consists of both transparent and opaque parts with different polarization characteristics, each part can be measured. After a fast Fourier transform of the acquired interference signal, the shape of the object is obtained by analyzing its spectrum. The proposed system is evaluated in terms of measurement accuracy and noise robustness through a series of experiments to show the effectiveness of the system. PMID- 25837077 TI - Improved time-resolved acousto-optic technique for optical fiber analysis of axial non-uniformities by using edge interrogation. AB - The time-resolved acousto-optic technique demonstrated recently to be a very useful method for the analysis of fiber axial non-uniformities, able to detect variations of fiber diameter in the nanometric scale with a spatial resolution of few cm. An edge interrogation approach is proposed to improve further the performance of this technique. The detection of subnanometer fiber diameter changes or sub-ppm changes of the core refractive index is demonstrated. PMID- 25837078 TI - Nanoscale welding aerosol sensing based on whispering gallery modes in a cylindrical silica resonator. AB - We report an experimental technique where one uses a standard silica fiber as a cylindrical whispering gallery mode (WGM) resonator to sense airborne nanoscale aerosols produced by electric arc welding. We find that the accumulation of aerosols on the resonator surface induces a measurable red-shift in resonance frequency, and establish an empirical relation that links the magnitude of resonance shift with the amount of aerosol deposition. The WGM quality factors, by contrast, do not decrease significantly, even for samples with a large percentage of surface area covered by aerosols. Our experimental results are discussed and compared with existing literature on WGM-based nanoparticle sensing. PMID- 25837079 TI - Retina layer segmentation using kernel graph cuts and continuous max-flow. AB - Circular scan Spectral-Domain Optic Coherence Tomography imaging (SD-OCT) is one of the best tools for diagnosis of retinal diseases. This technique provides more comprehensive detail of the retinal morphology and layers around the optic disc nerve head (ONH). Since manual labelling of the retinal layers can be tedious and time consuming, accurate and robust automated segmentation methods are needed to provide the thickness evaluation of these layers in retinal disorder assessments such as glaucoma. The proposed method serves this purpose by performing the segmentation of retinal layers boundaries in circular SD-OCT scans acquired around the ONH. The layers are detected by adapting a graph cut segmentation technique that includes a kernel-induced space and a continuous multiplier based max-flow algorithm. Results from scan images acquired with Spectralis (Heidelberg Engineering, Germany) prove that the proposed method is robust and efficient in detecting the retinal layers boundaries in images. With a mean root-mean-square error (RMSE) of 0.0835 +/- 0.0495 and an average Dice coefficient of 0.9468 +/- 0.0705 pixels for the retinal nerve fibre layer thickness, the proposed method demonstrated effective agreement with manual annotations. PMID- 25837080 TI - Temporal coupled mode theory of standing wave resonant cavities for infrared photodetection. AB - Standing wave resonating cavities have been proposed in the past to increase the performance of infrared detectors by minimizing the volume of photogeneration, hence the noise, while maintaining the same quantum efficiency. We present an approach based on the temporal coupled mode theory to explain their behavior and limitations. If the ratio of the imaginary part of the absorber's dielectric function to the index of the incident medium epsilon"(d)/n0 is larger than 1.4, then the absorption cross section sigma(a) can attain its maximum value, which for an isolated cavity is approximately 2lambda/pi. Besides, for sigma(a) to exceed the cavity width, the incident medium refractive index must be close to unity. Metallic loss is negligible in the infrared, making those resonators suitable for integration in infrared photodetectors. PMID- 25837082 TI - Demonstration of ultra-low NA rare-earth doped step index fiber for applications in high power fiber lasers. AB - In this paper, we report the mode area scaling of a rare-earth doped step index fiber by using low numerical aperture. Numerical simulations show the possibility of achieving an effective area of ~700 um2 (including bend induced effective area reduction) at a bend diameter of 32 cm from a 35 MUm core fiber with a numerical aperture of 0.038. An effective single mode operation is ensured following the criterion of the fundamental mode loss to be lower than 0.1 dB/m while ensuring the higher order modes loss to be higher than 10 dB/m at a wavelength of 1060 nm. Our optimized modified chemical vapor deposition process in conjunction with solution doping process allows fabrication of an Yb-doped step index fiber having an ultra-low numerical aperture of ~0.038. Experimental results confirm a Gaussian output beam from a 35 MUm core fiber validating our simulation results. Fiber shows an excellent laser efficiency of ~81%and aM2 less than 1.1. PMID- 25837081 TI - Generation of multi-millijoule red-shifted pulses for seeding stimulated Raman backscattering amplifiers. AB - The efficient generation of redshifted pulses from chirped femtosecond joule level Bessel beam pulses in gases is studied. The redshift spans from a few 100 cm-1 to several 1000 cm-1 corresponding to a shift of 50-500 nm for Nd:glass laser systems. The generated pulses have an almost perfect Gaussian beam profile insensitive of the pump beam profile, and are much shorter than the pump pulses. The highest measured energy is as high as 30 mJ, which is significantly higher than possible with solid state nonlinear frequency shifters. PMID- 25837083 TI - Nonlinear compression of high energy fiber amplifier pulses in air-filled hypocycloid-core Kagome fiber. AB - We report on the generation of 34 fs and 50 uJ pulses from a high energy fiber amplifier system with nonlinear compression in an air-filled hypocycloid-core Kagome fiber. The unique properties of such fibers allow bridging the gap between solid core fibers-based and hollow capillary-based post-compression setups, thereby operating with pulse energies obtained with current state-of-the-art fiber systems. The overall transmission of the compression setup is over 70%. Together with Yb-doped fiber amplifier technologies, Kagome fibers therefore appear as a promising tool for efficient generation of pulses with durations below 50 fs, energies ranging from 10 to several hundreds of uJ, and high average powers. PMID- 25837084 TI - Clipped speckle autocorrelation metric for spot size characterization of focused beam on a diffuse target. AB - The clipped speckle autocorrelation (CSA) metric is proposed for estimating the laser beam energy concentration on a remote diffuse target in a laser beam projection system with feedback information. Using the second order statistics of the intensity distribution of the fully developed speckle and the relation of the autocorrelation functions for the clipped and unclipped speckles, we present the theoretical expression of this metric as a function of the normalized CSA function. The simulation technique based on the equivalence of the spatial average and the ensemble time average is provided. Based on this simulation technique, we analyze the influence of the surface roughness of the target on this metric and then show the influencing factors of the metric performance, for example the finite sample effect and aperture size of the observation system. Experimental results are illustrated to examine the capability of this metric and the correctness of the discussion about the metric performance. PMID- 25837085 TI - Coherent pulse stacking amplification using low-finesse Gires-Tournois interferometers. AB - We demonstrate a new technique of coherent pulse stacking (CPS) amplification to overcome limits on achievable pulse energies from optical amplifiers. CPS uses reflecting resonators without active cavity-dumpers to transform a sequence of phase- and amplitude-modulated optical pulses into a single output pulse. Experimental validation with a single reflecting resonator demonstrates a near theoretical stacked peak-power enhancement factor of ~2.5 with 92% and 97.4% efficiency for amplified nanosecond and femtosecond pulses. We also show theoretically that large numbers of equal-amplitude pulses can be stacked using sequences of multiple reflecting resonators, thus providing a new path for generating very high-energy pulses from ultrashort pulse fiber amplifier systems. PMID- 25837086 TI - Numerical study of multi-conjugate large area wavefront correction for deep tissue microscopy. AB - Wavefront distortion fundamentally limits the achievable imaging depth and quality in thick tissue. Wavefront correction can help restore the diffraction limited focus albeit with a small field of view (FOV), which limits its imaging applications. In this work, we numerically investigate whether the multi conjugate configuration, originally developed for astronomical adaptive optics, may increase the correction FOV in random turbid media. The results show that the multi-conjugate configuration can significantly improve the correction area compared to the widely adopted pupil plane correction. Even in the simple case of single-conjugation, it still outperforms the pupil plane correction. This study provides a guideline for designing the optimal wavefront correction system in deep tissue imaging. PMID- 25837087 TI - Difference-frequency generation of optical radiation from two-color x-ray pulses. AB - We describe the process of difference-frequency generation of short optical pulses from two-color X-ray pulses. By assuming 1011 photons per X-ray pulse, we predict that the optical count rate can exceed 107 photons per pulse. Similar to other effects involving nonlinear interactions of X-rays and optical radiation, the effect we describe can be used for microscopic studies of chemical bonds and as a probe for light-matter interactions on the atomic scale. Since the X-ray damage threshold is much higher than the optical damage threshold, the efficiency of difference-frequency generation from two X-ray pulses is expected to be orders of magnitude higher than the efficiency of effects such as sum/difference frequency mixing between X-rays and optical intense short-pulse sources. PMID- 25837088 TI - Large area photonic crystal cavities: a local density approach. AB - Large area photonic crystal cavities are devices of interest for photovoltaics, optoelectronics, and solid-state lighting. However, depending on their dimensions they pose a large computational challenge. Here, we use a local density approach to avoid direct simulation of the device. We capture the effect of both ideal and distorted photonic crystals in an effective mass and an effective potential. We use these to map the problem of calculating the electromagnetic field modes to solving a simple time-independent Schrodinger equation. We show that, in the case that the hole radius varies quadratically as a function of position, the eigenmodes of the photonic crystals can be described by the corresponding eigenmodes of the quantum harmonic oscillator with typical agreements well above 90%. PMID- 25837089 TI - Performance analysis of commercial multiple-input-multiple-output access point in distributed antenna system. AB - In this paper, we experimentally investigate the throughput of IEEE 802.11n 2x2 multiple-input-multiple-output (MIMO) signals in a radio-over-fiber-based distributed antenna system (DAS) with different fiber lengths and power imbalance. Both a MIMO-supported access point (AP) and a spatial-diversity supported AP were separately employed in the experiments. Throughput measurements were carried out with wireless users at different locations in a typical office environment. For the different fiber length effect, the results indicate that MIMO signals can maintain high throughput when the fiber length difference between the two remote antenna units (RAUs) is under 100 m and falls quickly when the length difference is greater. For the spatial diversity signals, high throughput can be maintained even when the difference is 150 m. On the other hand, the separation of the MIMO antennas allows additional freedom in placing the antennas in strategic locations for overall improved system performance, although it may also lead to received power imbalance problems. The results show that the throughput performance drops in specific positions when the received power imbalance is above around 13 dB. Hence, there is a trade-off between the extent of the wireless coverage for moderate bit-rates and the area over which peak bit-rates can be achieved. PMID- 25837090 TI - Raw data normalization for a multi source inverse geometry CT system. AB - A multi-source inverse-geometry CT (MS-IGCT) system consists of a small 2D detector array and multiple x-ray sources. During data acquisition, each source is activated sequentially, and may have random source intensity fluctuations relative to their respective nominal intensity. While a conventional 3rd generation CT system uses a reference channel to monitor the source intensity fluctuation, the MS-IGCT system source illuminates a small portion of the entire field-of-view (FOV). Therefore, it is difficult for all sources to illuminate the reference channel and the projection data computed by standard normalization using flat field data of each source contains error and can cause significant artifacts. In this work, we present a raw data normalization algorithm to reduce the image artifacts caused by source intensity fluctuation. The proposed method was tested using computer simulations with a uniform water phantom and a Shepp Logan phantom, and experimental data of an ice-filled PMMA phantom and a rabbit. The effect on image resolution and robustness of the noise were tested using MTF and standard deviation of the reconstructed noise image. With the intensity fluctuation and no correction, reconstructed images from simulation and experimental data show high frequency artifacts and ring artifacts which are removed effectively using the proposed method. It is also observed that the proposed method does not degrade the image resolution and is very robust to the presence of noise. PMID- 25837091 TI - Optimization-free optical focal field engineering through reversing the radiation pattern from a uniform line source. AB - A simple and flexible method is presented for the generation of optical focal field with prescribed characteristics. By reversing the field pattern radiated from a uniform line source, for which the electric current is constant along its extent, situated at the focus of a 4Pi focusing system formed by two confocal high-NA objective lenses, the required illumination distribution at the pupil plane for creating optical focal field with desired properties can be obtained. Numerical example shows that an arbitrary length optical needle with extremely high longitudinal polarization purity and consistent transverse size of ~0.36lambda over the entire depth of focus (DOF) can be created with this method. Coaxially double-focus with spot size of ~0.36lambda in the transversal direction and ~lambda in the axial direction separated by a prescribed spacing is illustrated as another example. The length of optical needle field and the interval between double-focus are determined by the length of uniform line source. These engineered focal fields may found potential applications in particle acceleration, optical microscopy, optical trapping and manipulations. PMID- 25837092 TI - Valid point detection in fringe projection profilometry. AB - Fringe projection profilometry has become one of the most popular 3D information acquisition techniques being developed over the past three decades. However, the general and practical issues on valid point detection, including object segmentation, error correction and noisy point removal, have not been studied thoroughly. Furthermore, existing valid point detection techniques require multiple case-dependent thresholds which increase processing inconvenience. In this paper, we proposed a new valid point detection framework, which includes the k-means clustering for automatic background segmentation, unwrapping error correction based on theoretical analysis, and noisy point detection in both temporal and spatial directions with automatic threshold setting. Experimental results are given to validate the proposed framework. PMID- 25837093 TI - Leveraging master-slave OpenFlow controller arrangement to improve control plane resiliency in SD-EONs. AB - In this paper, we study how to improve the control plane resiliency of software defined elastic optical networks (SD-EONs) and design a master-slave OpenFlow (OF) controller arrangement. Specifically, we introduce two OF controllers (OF Cs), i.e., the master and slave OF-Cs, and make them work in a collaborative way to protect the SD-EON against controller failures. We develop a controller communication protocol (CCP) to facilitate the cooperation of the two OF-Cs. With the CCP, the master OF-C (M-OF-C) can synchronize network status to the slave OF C (S-OF-C) in real time, while S-OF-C can quickly detect the failure of M-OF-C and take over the network control and management (NC&M) tasks timely to avoid service disruption. We implement the proposed framework in an SD-EON control plane testbed built with high-performance servers, and perform NC&M experiments with different network failure scenarios to demonstrate its effectiveness. Experimental results indicate that the proposed system can restore services in both the data and control planes of SD-EON jointly while maintaining relatively good scalability. To the best of our knowledge, this is the first demonstration that realizes control plane resiliency in SD-EONs. PMID- 25837094 TI - Towards ten-watt-level 3-5 um Raman lasers using tellurite fiber. AB - Raman lasers based on mid-infrared fibers operating at 3-5 um atmospheric transparency window are attractive sources for several applications. Compared to fluoride and chalcogenide fibers, tellurite fibers are more advantageous for high power Raman fiber laser sources at 3-5 um because of their broader Raman gain bandwidth, much larger Raman shift and better physical and chemical properties. Here we report on our simulations for the development of 10-watt-level 3-5 um Raman lasers using tellurite fibers as the nonlinear gain medium and readily available continuous-wave (cw) and Q-switched erbium-doped fluoride fiber lasers at 2.8 um as the pump sources. Our results show that a watt-level or even ten watt-level fiber laser source in the 3-5 um atmospheric transparency window can be achieved by utilizing the 1st- and 2nd-order Raman scattering in the tellurite fiber. The presented numerical study provides valuable guidance for future 3-5 um Raman fiber laser development. PMID- 25837095 TI - THz quartz-enhanced photoacoustic sensor for H2S trace gas detection. AB - We report on a quartz-enhanced photoacoustic (QEPAS) gas sensing system for hydrogen sulphide (H2S) detection. The system architecture is based on a custom quartz tuning fork (QTF) optoacoustic transducer with a novel geometry and a quantum cascade laser (QCL) emitting 1.1 mW at a frequency of 2.913 THz. The QTF operated on the first flexion resonance frequency of 2871 Hz, with a quality factor Q = 17,900 at 20 Torr. The tuning range of the available QCL allowed the excitation of a H2S rotational absorption line with a line-strength as small as S = 1.13.10-22 cm/mol. The measured detection sensitivity is 30 ppm in 3 seconds and 13 ppm for a 30 seconds integration time, which corresponds to a minimum detectable absorption coefficient alpha(min) = 2.3.10-7 cm-1 and a normalized noise-equivalent absorption NNEA = 4.4.10-10 W.cm-1.Hz(-1/2), several times lower than the values previously reported for near-IR and mid-IR H2S QEPAS sensors. PMID- 25837096 TI - High speed prototype quantum key distribution system and long term field trial. AB - Securing information in communication networks is an important challenge in today's world. Quantum Key Distribution (QKD) can provide unique capabilities towards achieving this security, allowing intrusions to be detected and information leakage avoided. We report here a record high bit rate prototype QKD system providing a total of 878 Gbit of secure key data over a 34 day period corresponding to a sustained key rate of around 300 kbit/s. The system was deployed over a standard 45 km link of an installed metropolitan telecommunication fibre network in central Tokyo. The prototype QKD system is compact, robust and automatically stabilised, enabling key distribution during diverse weather conditions. The security analysis includes an efficient protocol, finite key size effects and decoy states, with a quantified key failure probability of epsilon = 10-10. PMID- 25837097 TI - Generation of spatial Bessel beams using holographic metasurface. AB - We propose to use backward radiations of leaky waves supported by a holographic metasurface to produce spatial Bessel beams in the microwave frequency regime. The holographic metasurface consists of a grounded dielectric slab and a series of metal patches. By changing the size of metal patches, the surface-impedance distribution of the holographic metasurface can be modulated, and hence the radiation properties of the leaky waves can be designed to realize Bessel beams. Both numerical simulations and experiments verify the features of spatial Bessel beams, which may be useful in imaging applications or wireless power transmissions with the dynamic focal-depth controls. PMID- 25837098 TI - Bent-fiber intermodal interference based dual-channel fiber optic refractometer. AB - We present a novel dual-channel fiber optic interferometer based on intermodal interference from single-mode fiber (SMF) bending. This dual-channel interferometer has simple structure, consisting of two bare fiber semicircular bending regions with different bending radiuses connected by a section of straight fiber. A dual-channel interferometer with bending radiuses of 4 mm and 4.3 mm is fabricated and refractive index (RI) sensing is realized by measuring the wavelength shift of the resonance dips in the transmission spectrum of the dual-channel interferometer. In the RI range of 1.3403 to 1.3726, the corresponding RI sensitivities for these two channels are 207 and 245 nm/RIU (refractive index unit) and the RI resolutions are about 6.57 * 10-5 RIU and 5.55 * 10-5 RIU, respectively. PMID- 25837099 TI - Diffraction-limited real-time terahertz imaging by optical frequency up conversion in a DAST crystal. AB - Real-time terahertz (THz) wave imaging has wide applications in areas such as security, industry, biology, medicine, pharmacy, and the arts. This report describes real-time room-temperature THz imaging by nonlinear optical frequency up-conversion in an organic 4-dimethylamino-N'-methyl-4'-stilbazolium tosylate (DAST) crystal, with high resolution reaching the diffraction limit. THz-wave images were converted to the near infrared region and then captured using an InGaAs camera in a tandem imaging system. The resolution of the imaging system was analyzed. Diffraction and interference of THz wave were observed in the experiments. Videos are supplied to show the interference pattern variation that occurs with sample moving and tilting. PMID- 25837100 TI - Highly controllable optical bistability effect in a 2 MUm Tm:YAG ceramic laser at room temperature. AB - A highly controllable optical bistability in a Tm:YAG ceramic laser system is reported, which is attributed to the thermal-induced change in the stability of the resonator. The width of the bistable region can be tuned in a large scale from 0.8 W to 6.3 W. At nearly semi-confocal cavity configuration, a second lasing condition was observed in the bistable region with a modulated shape of the laser beam and a broadened laser spectrum. The influence of the temperature on the bistable laser operation was also discussed in detail. To our knowledge, this is the first report on the optical bistability effect in Tm:YAG ceramic lasers. PMID- 25837102 TI - Five-photon UV upconversion emissions of Er3+ for temperature sensing. AB - Under 980 nm excitation, the temperature dependence of five-photon UV (256 and 276 nm) upconversion luminescence in Yb3+-Er3+ codoped beta-NaLuF4 nanocrystals was studied from 303 K to 523 K. The 4D(7/2) and 4G(9/2) levels of Er3+ are confirmed to be thermally coupled levels. They are the highest energy states for optical thermometry known so far. By using fluorescence intensity ratio technique, optical temperature sensing characteristics based on the 4D(7/2)/4G(9/2) -> 4I(15/2) transitions of Er3+ were reported here for the first time. The obtained sensitivity of this UV-based sensor is higher than that of green-based optical thermometer in low temperature range. PMID- 25837101 TI - Determination of localization accuracy based on experimentally acquired image sets: applications to single molecule microscopy. AB - Fluorescence microscopy is a photon-limited imaging modality that allows the study of subcellular objects and processes with high specificity. The best possible accuracy (standard deviation) with which an object of interest can be localized when imaged using a fluorescence microscope is typically calculated using the Cramer-Rao lower bound, that is, the inverse of the Fisher information. However, the current approach for the calculation of the best possible localization accuracy relies on an analytical expression for the image of the object. This can pose practical challenges since it is often difficult to find appropriate analytical models for the images of general objects. In this study, we instead develop an approach that directly uses an experimentally collected image set to calculate the best possible localization accuracy for a general subcellular object. In this approach, we fit splines, i.e. smoothly connected piecewise polynomials, to the experimentally collected image set to provide a continuous model of the object, which can then be used for the calculation of the best possible localization accuracy. Due to its practical importance, we investigate in detail the application of the proposed approach in single molecule fluorescence microscopy. In this case, the object of interest is a point source and, therefore, the acquired image set pertains to an experimental point spread function. PMID- 25837103 TI - An optimization procedure for the design of all-optical switches based on metal dielectric nanocomposites. AB - We present a procedure to optimize the performance of all-optical switches based on metal-dielectric nanocomposites. The management of constructive and destructive interference between the third-, fifth- and seventh-order susceptibilities allowed characterization of optimal conditions for ultrafast switching with reduced losses. Proof-of-principle experiments with metal-colloids are reported to validate the method. PMID- 25837104 TI - Fast generation of digital holograms based on warping of the wavefront recording plane. AB - This paper reports a fast method for generating a 2048x2048 digital Fresnel hologram at a rate of over 100 frames per second. Briefly, the object wave of an image is nonuniformally sampled and generated on a wavefront recording plane (WPR) that is close to the object scene. The sampling interval at each point on the WRP image is then modulated according to the depth map. Subsequently, the WRP image is converted into a hologram. The hologram generated with our proposed method, which is referred to as the warped WRP (WWRP) hologram, is capable of presenting a 3-D object with faster speed as compared with existing methods. PMID- 25837105 TI - Topological insulator Bi2Se3 based Q-switched Nd:LiYF4 nanosecond laser at 1313 nm. AB - We report on a1.3 MUm Q-switched laser operation based on LD-end-pumped Nd:LiYF4 (YLF) crystal firstly using few-layer topological insulator (TI) Bi2Se3 as saturable absorber (SA). The TI Bi2Se3 SA is fabricated by transferring the liquid-phase-exfoliated Bi2Se3 nanosheets onto a BK7 glass substrate. After a free-running laser operation, the TI Bi2Se3 SA is inserted into the concave-plano laser cavity and finally a stable Q-switched laser operation is achieved with a maximum average output power of close to 0.2 W corresponding to a pulse repetition rate of 161.3 kHz, a shortest pulse width of 433 ns and a pulse energy of about 1.23 MUJ. The results experimentally extend the promising application of the 2D material, few-layer TI Bi2Se3, in solid state lasers (SSLs). PMID- 25837106 TI - Wide spectral and wavelength-tunable dissipative soliton fiber laser with topological insulator nano-sheets self-assembly films sandwiched by PMMA polymer. AB - Topological insulators have been theoretically predicted as promising candidates for broadband photonics devices due to its large bulk band gap states in association with the spin-momentum-locked mass-less Dirac edge/surface states. Unlike the bulk counterpart, few-layer topological insulators possess some intrinsic optical advantages, such as low optical loss, low saturation intensity and high concentration of surface state. Herein, we use a solvothermal method to prepare few-layer Bi2Te3 flakes. By sandwiching few-layer Bi2Te3 flakes with polymethyl methacrylate (PMMA) polymer, a novel light modulation device had been successfully fabricated with high chemical and thermal stabilities as well as excellent mechanical durability, originating from the contribution of PMMA acting as buffer layers that counteract excessive mechanical bending within the fragile Bi2Te3 flakes. The incorporation of the as-fabricated PMMA-TI-PMMA as saturable absorber, which could bear long-term mechanical loadings, into the fiber laser cavity generated the stable dissipative soliton mode-locking with a 3-dB spectral bandwidth up to 51.62 nm and tunable wavelength range of 22 nm. Our work provides a new way of fabricating PMMA-TI-PMMA sandwiched composite structure as saturable absorber with promising applications for laser operation. PMID- 25837107 TI - Registration of optical imagery and LiDAR data using an inherent geometrical constraint. AB - A novel method for registering imagery with Light Detection And Ranging (LiDAR) data is proposed. It is based on the phenomenon that the back-projection of LiDAR point cloud of an object should be located within the object boundary in the image. Using this inherent geometrical constraint, the registration parameters computation of both data sets only requires LiDAR point clouds of several objects and their corresponding boundaries in the image. The proposed registration method comprises of four steps: point clouds extraction, boundary extraction, back projection computation and registration parameters computation. There are not any limitations on the geometrical and spectral properties of the object. So it is suitable not only for structured scenes with man-made objects but also for natural scenes. Moreover, the proposed method based on the inherent geometrical constraint can register two data sets derived from different parts of an object. It can be used to co-register TLS (Terrestrial Laser Scanning) LiDAR point cloud and UAV (Unmanned aerial vehicle) image, which are obtaining more attention in the forest survey application. Using initial registration parameters comparable to POS (position and orientation system) accuracy, the performed experiments validated the feasibility of the proposed registration method. PMID- 25837108 TI - In-phased second harmonic wave array generation with intra-Talbot-cavity frequency-doubling. AB - The Talbot cavity is one promising method to synchronize the phase of a laser array. However, it does not achieve the lowest array mode with the same phase but the highest array mode with the anti-phase between every two adjacent lasers, which is called out-phase locking. Consequently, their far-field images exhibit 2 peak profiles. We propose intra-Talbot-cavity frequency-doubling. By placing a nonlinear crystal in a Talbot cavity, the Talbot cavity generates an out-phased fundamental wave array, which is converted into an in-phase-locked second harmonic wave array at the nonlinear crystal. We demonstrate numerical calculations and experiments on intra-Talbot-cavity frequency-doubling and obtain an in-phase-locked second harmonic wave array for a Nd:YVO4 array laser. PMID- 25837109 TI - Frequency combs and platicons in optical microresonators with normal GVD. AB - We predict the existence of a novel type of the flat-top dissipative solitonic pulses, "platicons", in microresonators with normal group velocity dispersion (GVD). We propose methods to generate these platicons from cw pump. Their duration may be altered significantly by tuning the pump frequency. The transformation of a discrete energy spectrum of dark solitons of the Lugiato Lefever equation into a quasicontinuous spectrum of platicons is demonstrated. Generation of similar structures is also possible with bi-harmonic, phase/amplitude modulated pump or via laser injection locking. PMID- 25837110 TI - Tm3+ doped barium gallo-germanate glass single-mode fibers for 2.0 MUm laser. AB - Tm3+ doped barium gallo-germanate (BGG) glass has emerged as a promising 2.0 MUm laser material offering excellent optical property. Unfortunately, low anti crystallization ability and high OH- content of the glass have hindered the fabrication of high-quality optical fibers. In this paper, La2O3 and Y2O3 were added into BGG glass to enhance the glass anti-crystallization ability. Additionally, the optimized Reaction Atmosphere Procedure (RAP) was utilized to minimize OH- content. Continuous Tm3+ doped BGG glass single-mode (SM) fibers were successfully obtained by the rod-in-tube technique for the first time to our best knowledge. A 140 mW all-fiber laser at 1.95 MUm was demonstrated using a 9.7 cm-long as-drawn Tm3+ doped BGG glass SM fiber upon excitation of a home-made 1568 nm fiber laser. PMID- 25837111 TI - Generation of bright attosecond x-ray pulse trains via Thomson scattering from laser-plasma accelerators: errata. AB - We report and correct a couple of calculation errors in the x-ray flux and maximum peak brightness in our paper [Opt. Express 22, 32098 (2014)]. PMID- 25837113 TI - Angle-of-arrival reception for optical wireless location technology. AB - An optical wireless location (OWL) system is introduced for indoor positioning. The OWL system makes use of a mobile photoreceiver that facilitates triangulation by measuring angle-of-arrival (AOA) bearings from LEDs in an optical beacon grid. The photoreceiver has three photodiodes (PDs), arranged in a corner-cube, to facilitate differential photocurrent sensing of the incident light AOA, by way of azimuthal phi and polar theta angles. The AOA error for indoor positioning is characterized empirically. Optical AOA positioning is shown to have a fundamental advantage over known optical received signal strength (RSS) positioning, as AOA estimation is insensitive to power and alignment imbalances of the optical beacon grid. The OWL system is built, and a performance comparison is carried out between optical AOA and RSS positioning. It is shown that optical AOA positioning can achieve a mean 3-D positioning error of only 5 cm. Experimental design and future prospects of optical AOA positioning are discussed. PMID- 25837112 TI - MultiFocus Polarization Microscope (MF-PolScope) for 3D polarization imaging of up to 25 focal planes simultaneously. AB - We have developed an imaging system for 3D time-lapse polarization microscopy of living biological samples. Polarization imaging reveals the position, alignment and orientation of submicroscopic features in label-free as well as fluorescently labeled specimens. Optical anisotropies are calculated from a series of images where the sample is illuminated by light of different polarization states. Due to the number of images necessary to collect both multiple polarization states and multiple focal planes, 3D polarization imaging is most often prohibitively slow. Our MF-PolScope system employs multifocus optics to form an instantaneous 3D image of up to 25 simultaneous focal-planes. We describe this optical system and show examples of 3D multi-focus polarization imaging of biological samples, including a protein assembly study in budding yeast cells. PMID- 25837114 TI - On the use of the Type I and II scheme for classifying ultrafast laser direct write photonics. AB - The use of the Type I and Type II scheme, first introduced and used by fiber Bragg grating researchers, has recently been adopted by the ultrafast laser direct-write photonics community to classify the physical geometry of waveguides written into glasses and crystals. This has created confusion between the fiber Bragg grating and direct-write photonics community. Here we propose a return to the original basis of the classification based on the characteristics of the material modification rather than the physical geometry of the waveguide. PMID- 25837115 TI - Sub-milliampere threshold operation of butt-jointed built-in membrane DFB laser bonded on Si substrate. AB - We fabricated GaInAsP/InP waveguide-integrated lateral-current-injection (LCI) membrane distributed feedback (DFB) lasers on a Si substrate by using benzocyclobutene (BCB) adhesive bonding for on-chip optical interconnection. The integration ofa butt-jointed built-in (BJB) GaInAsP passive waveguide was performed by organometallic vapor-phase epitaxy (OMVPE).By introducing a strongly index-coupled DFB structure with a 50-um-long cavity, a threshold current of 230 uA was achieved for a stripe width of 0.8 um under room-temperature continuous wave (RT-CW) conditions. The maximum output power of 32 uW was obtained. The lasing wavelength and submode suppression ratio (SMSR) were 1534 nm and 28 dB, respectively, at a bias current of 1.2 mA. PMID- 25837116 TI - Ultrashort stretched-pulse L-band laser using carbon-nanotube saturable absorber. AB - In the paper, a passively mode-locked erbium-doped fiber ring laser in the long wavelength band (L-band) is presented by using a single-wall nanotube saturable absorber (SWNT-SA). The optical properties of the SWNT-SA are compared with those in the C-band in view of the absorbance spectrum and the power-dependent transmittance of the SWNT-SA film. The effects of the net cavity dispersion and the length of the erbium-doped fiber (EDF) on L-band stretched pulse generation are discussed. The designed stretched-pulse L-band laser has a net dispersion of 0.017-ps2 and generates ultrashort (110 fs), broad-spectrum (41 nm) pulses with a signal-to-noise ratio over 70 dB. PMID- 25837117 TI - Quantum phase gate for optical qubits with cavity quantum optomechanics. AB - We show that a cavity optomechanical system formed by a mechanical resonator simultaneously coupled to two modes of an optical cavity can be used for the implementation of a deterministic quantum phase gate between optical qubits associated with the two intracavity modes. The scheme is realizable for sufficiently strong single-photon optomechanical coupling in the resolved sideband regime, and is robust against cavity losses. PMID- 25837118 TI - Acidity measurement of iron ore powders using laser-induced breakdown spectroscopy with partial least squares regression. AB - Laser-induced breakdown spectroscopy (LIBS) with partial least squares regression (PLSR) has been applied to measuring the acidity of iron ore, which can be defined by the concentrations of oxides: CaO, MgO, Al2O3, and SiO2. With the conventional internal standard calibration, it is difficult to establish the calibration curves of CaO, MgO, Al2O3, and SiO2 in iron ore due to the serious matrix effects. PLSR is effective to address this problem due to its excellent performance in compensating the matrix effects. In this work, fifty samples were used to construct the PLSR calibration models for the above-mentioned oxides. These calibration models were validated by the 10-fold cross-validation method with the minimum root-mean-square errors (RMSE). Another ten samples were used as a test set. The acidities were calculated according to the estimated concentrations of CaO, MgO, Al2O3, and SiO2 using the PLSR models. The average relative error (ARE) and RMSE of the acidity achieved 3.65% and 0.0048, respectively, for the test samples. PMID- 25837119 TI - Metric of color-space coverage for wide-gamut displays. AB - Assessing the coverage of the color space of Recommendation ITU-R BT.2020 (Rec. 2020) has become increasingly important in the design of wide-gamut displays, and an appropriate metric for measuring the display gamut size is urgently needed. Display manufactures calculate the area ratios of their displays' RGB triangles to a standard RGB triangle in the CIE 1931 xy or CIE 1976 u'v' chromaticity diagram to indicate the displays' relative gamut size. However, they typically fail to mention which of the two diagrams the metric is based on. This paper shows that the ratios calculated in the two chromaticity diagrams are highly inconsistent, and that the Rec. 2020 area-coverage ratios for wide-gamut displays in the xy diagram are much more correlated to the Rec. 2020 volume-coverage ratios in some color-appearance spaces than the Rec. 2020 area-coverage ratios in the u'v' diagram. This paper recommends the use of the xy diagram for area coverage ratio calculations for wide-gamut displays. PMID- 25837120 TI - Plasmon excitation on flat graphene by s-polarized beams using four-wave mixing. AB - Graphene plasmons have received significant attention recently due to its attractive properties such as high spatial confinement and tunability. However, exciting plasmons on graphene effectively still remains a challenge owing to the large wave-vector mismatch between the optical beam in air and graphene plasmon. In this paper, we present a novel scheme capable of exciting graphene surface plasmons (GSPs) on a flat suspended graphene by using only s-polarized optical beams through four-wave mixing (FWM) process, where the GSPs fields were derived analytically based on the Green's function analysis, under the basis of momentum conservation. By incorporating the merits of nonlinear optics, the presented scheme avoids any patterning of either graphene or substrate. We believe that the proposed scheme potentially paves the way towards an efficient pure optical excitation, switching and modulation of GSPs for realizing graphene-based nano photonic and optoelectronic integrated circuits. PMID- 25837121 TI - Multi-pulse time delay integration method for flexible 3D super-resolution range gated imaging. AB - Constructing flexible regular-shaped range-intensity profiles by the convolution of illuminator laser pulse and sensor gate pulse is crucial for 3D super resolution range-gated imaging. However, ns-scale rectangular-shaped laser pulse with tunable pulse width is difficult to be obtained, especially for pulsed solid stated lasers. In this paper we propose a multi-pulse time delay integration (MPTDI) method to reshape range-intensity profiles (RIP) free from the above limitation of pulsed lasers. An equivalent laser pulse temporal shaping model is established to evaluate and optimize the MPTDI method. By using MPTDI, the RIP shape and depth of viewing can both be flexibly changed as desired. Here typical triangular and trapezoidal RIPs are established for 3D imaging under triangular and trapezoidal range-intensity correlation algorithms. In addition, a prototype experiment is demonstrated to prove the feasibility of MPTDI. PMID- 25837122 TI - Multimode phase-matched third-harmonic generation in sub-micrometer-wide anatase TiO2 waveguides. AB - Third-harmonic generation (THG) has applications ranging from wavelength conversion to pulse characterization, and has important implications for quantum sources of entangled photons. However, on-chip THG devices are nearly unexplored because bulk techniques are difficult to adapt to integrated photonic circuits. Using sub-micrometer-wide polycrystalline anatase TiO2 waveguides, we demonstrate third-harmonic generation on a CMOS-compatible platform. We correlate higher conversion efficiencies with phase-matching between the fundamental pump mode and higher-order signal modes. Using scattered light, we estimate conversion efficiencies as high as 2.5% using femtosecond pulses, and thus demonstrate that multimode TiO2 waveguides are promising for wideband wavelength conversion and new applications ranging from sensors to triplet-photon sources. PMID- 25837123 TI - Numerical simulation of the displayed image on the entire screen of autostereoscopic displays. AB - A three-dimensional simulation model calculating the optical intensity distribution for the entire screen of an autostereoscopic display at a given eye position was developed in this study. A parallax barrier array was used for the optical model and reverse ray tracing of light from the observer's eye to the subpixels through the slits of the barrier was performed based on reverse geometrical optics. By investigating the optical behavior of the displayed image for the nine-view design condition for various viewing distances, we found the inhomogeneous crosstalk from the unwanted views and predicted segmented images which were comprised of multiple images from different views on the entire display screen. From the results, our simulation model shows good potentiality for predicting the displayed image on the entire display screen of autostereoscopic displays for various positions of the observer's eye with sufficient calculation speed. PMID- 25837124 TI - Graded index porous optical fibers - dispersion management in terahertz range. AB - A graded index porous optical fiber incorporating an air-hole array featuring variable air-hole diameters and inter-hole separations is proposed, fabricated, and characterized in a view of the fiber potential applications in low-loss, low dispersion terahertz guidance. The proposed fiber features simultaneously low modal and intermodal dispersions, as well as low loss in the terahertz spectral range. We experimentally demonstrate that graded index porous fibers exhibit smaller pulse distortion, larger bandwidth, and higher excitation efficiency when compared to fibers with uniform porosity. PMID- 25837125 TI - Nonlinear characterization of Ge28Sb12Se60 bulk and waveguide devices. AB - Single-mode Ge28Sb12Se60 strip waveguides, fabricated with thermal evaporation and lift-off, were demonstrated at 1.03 um. The linear and nonlinear optical properties of these waveguides were shown to be similar to bulk samples, with differences attributed to small variations in composition of ~4 atomic % or less. From z-scan measurements at 1.03 um using circularly polarized, ~200 fs pulses at 374 kHz, Ge28Sb12Se60 was found to have a nonlinear refractive index ~130 x fused silica and a two-photon absorption coefficient of 3.5 cm/GW. Given the large two photon absorption coefficient, this material shows promise for optical limiting applications at 1 um. PMID- 25837126 TI - Coupling of spatially partially coherent beams into planar waveguides. AB - The second-order coherence theory of partially spatially coherent light and the overlap integral method are applied to study the end-coupling of stationary multimode light beams into planar waveguides. A method is presented for the determination of the cross-spectral density function of the guided field. Examples are given on the effects of spatial coherence, lateral shift, angular tilt, and defocusing of the incident beam on the coupling efficiency, spatial coherence, and propagation characteristics of the guided field. PMID- 25837127 TI - Engineering of near-IR photon pairs to be factorable in space-time and entangled in polarization. AB - We present a source of near-infrared photon pairs based on the process of spontaneous parametric downconversion (SPDC), for which the joint signal-idler quantum state is designed to be factorable in the frequency-time and in the transverse position-momentum degrees of freedom. Our technique is based on the use of a broadband pump and vector group velocity matching between the pump, signal, and idler waves. We show experimentally that a source based on this technique can be configured for the generation of: i) pure heralded single photons, and ii) polarization-entangled photon pairs which are free from spectral correlations, in both cases without resorting to spectral filtering. While critical for many applications in optical quantum information processing, such a source has not previously been demonstrated. PMID- 25837128 TI - Accurate approach to capillary-supported optical diffraction tomography. AB - A new holographic data processing path for accurate quantitative tomographic reconstruction of 3D samples placed in a cylindrical capillary is proposed. The method considers strong unintentional focusing effects induced by the inner cylindrical boundary of the vessel: 1) introduction of cylindrical wave illumination of a sample, and 2) object wave deformation. The first issue is addressed by developing an arbitrary illumination tomographic reconstruction algorithm based on filtered backpropagation, while the second by a novel correction algorithm utilizing the optical rays analysis. Moreover, the processing path includes a novel holographic method for correction of spherical aberration related to refraction at a planar surface. Utility of the developed data processing path is proven with numerical simulations and experimental measurement of a specially prepared test sample. PMID- 25837129 TI - Theoretical investigation of tensile strained GeSn waveguide with Si3N4 liner stressor for mid-infrared detector and modulator applications. AB - We theoretically investigate a tensile strained GeSn waveguide integrated with Si3N4 liner stressor for the applications in mid-infrared (MIR) detector and modulator. A substantial tensile strain is induced in a 1 * 1 MUm2 GeSn waveguide by the expansion of 500 nm Si3N4 liner stressor and the contour plots of strain are simulated by the finite element simulation. Under the tensile strain, the direct bandgap E(G,Gamma) of GeSn is significantly reduced by lowering the Gamma conduction valley in energy and lifting of degeneracy of valence bands. Absorption coefficients of tensile strained GeSn waveguides with different Sn compositions are calculated. As the Si3N4 liner stressor expands by 1%, the cut off wavelengths of tensile strained Ge(0.97)Sn(0.03), Ge(0.95)Sn(0.05), and Ge(0.90)Sn(0.10) waveguide photodetectors are extended to 2.32, 2.69, and 4.06 MUm, respectively. Tensile strained Ge(0.90)Sn(0.10) waveguide electro-absorption modulator based on Franz-Keldysh (FK) effect is demonstrated in theory. External electric field dependence of cut-off wavelength and propagation loss of tensile strained Ge(0.90)Sn(0.10) waveguide is observed, due to the FK effect. PMID- 25837130 TI - Adaptive quadrature-polybinary detection in super-Nyquist WDM systems. AB - We propose an adaptive detection technique in super-Nyquist wavelength-division multiplexed (WDM) polarization-division-multiplexed quadrature-phase-shift-keying (PDM-QPSK) systems, where a QPSK signal is digitally converted to a quadrature n level polybinary signal followed by a MLSE detector at the receiver, and study the performance of quadrature-duobinary and quadrature four-level polybinary signals using this detection technique. We change the level of the quadrature polybinary modulation at the coherent receiver according to the channel spacing of a super-Nyquist system. Numerical studies show that the best performance can be achieved by choosing different modulation levels at the receiver in adaption to the channel spacing. In the experiment, we demonstrate the transmission of 3 channel 112-Gbit/s PDM-QPSK signals at a 20-GHz channel spacing, which is detected as a quadrature four-level polybinary signal, with performance comparable to PDM 16-ary quadrature-amplitude modulation (16QAM) at the same bit rate. PMID- 25837131 TI - Hand-manageable graphene sticker for ultrafast mode-locked fiber lasers. AB - We have developed a graphene sticker prepared by simply detaching graphene directly grown on a self-catalytic gamma-Al2O3 substrate with a spin-coated polymer film. Our scheme is highlighted by the metal-free and bare-hand manageable process. The sticker is attached onto the flat surface of a D-shaped fiber to demonstrate an efficient fiber mode-locked laser. The 1-ps output pluses have the center wavelength, spectral width, and repetition rate of 1558.2 nm, 5.42 nm, and 4.77 MHz, respectively. PMID- 25837132 TI - Low loss mid-infrared ZBLAN waveguides for future astronomical applications. AB - Photonic technologies will be at the heart of future terrestrial planet hunting interferometers. In particular the mid-infrared spectral region between 3.5 - 4.2 MUm is the ideal window for hunting for young extra-solar planets, since the planet is still hot from its formation and thus offers a favorable contrast with respect to the parent star compared to other spectral regions. This paper demonstrates two basic photonic building blocks of such an instrument, namely single-mode waveguides with propagation losses as low as 0.29+/-0.03 dB/cm at a wavelength of 4 MUm as well as directional couplers with a constant splitting ratio across a broad wavelength band of 500 nm. The devices are based on depressed cladding waveguides inscribed into ZBLAN glass using the femtosecond laser direct-write technique. This demonstration is the first stepping stone towards the realization of a high transmission mid-infrared nulling interferometer. PMID- 25837133 TI - Passive optical interconnects at top of the rack: offering high energy efficiency for datacenters. AB - This paper introduces a new concept, namely passive optical interconnect at top of the rack in the datacenter networks, and investigates several architectures, which use only passive optical components to interconnect different servers. In such a manner, the proposed schemes are able to offer higher bandwidth and significantly improve energy efficiency compared to their electronic counterpart that is based on commodity switches. The proposed passive optical interconnect schemes are experimentally demonstrated in order to validate the transmission performance. Besides, an assessment in terms of energy consumption and cost has also been carried out, which shows our proposed concept can significantly outperform the conventional commodity switches on energy efficiency while keeping the cost in the similar level. PMID- 25837134 TI - Upstream dispersion management supporting 100 km differential reach in TWDM-PON. AB - An optical dispersion compensator (ODC) with negative dispersion value in optical line terminal (OLT) is proposed to manage the chromatic dispersion of 10 Gb/s upstream directly-modulated signals from users with 100 km differential distances, achieving a maximal 51.9 dB loss budget thanks to the positive chirp of the directly-modulated signals and the characteristics of access networks that lower loss budget is required for the users at shorter transmission distance. The optimal dispersion value of the ODC is determined by the maximal distance of the users and the objective is to guarantee the loss budget monotonically improved with the increase of reach, therefore supporting differential reach. Experimental results show that it is a potential solution for practical implementation of long reach and high splitting-ratio time and wavelength division multiplexed passive optical network (TWDM-PON). PMID- 25837135 TI - From laser ultrasonics to optical manipulation. AB - During the interaction of a laser pulse with the surface of a solid object, the object always gains momentum. The delivered force impulse is manifested as propulsion. Initially, the motion of the object is composed of elastic waves that carry and redistribute the acquired momentum as they propagate and reflect within the solid. Even though only ablation- and light-pressure-induced mechanical waves are involved in propulsion, they are always accompanied by the ubiquitous thermoelastic waves. This paper describes 1D elastodynamics of pulsed optical manipulation and presents two diametrical experimental observations of elastic waves generated in the confined ablation and in the radiation pressure regime. PMID- 25837136 TI - Enabling area-selective potential-energy engineering in InGaN/GaN quantum wells by post-growth intermixing. AB - We report on a unique area-selective, post-growth approach in engineering the quantum-confined potential-energy profile of InGaN/GaN quantum wells (QWs) utilizing metal/dielectric-coating induced intermixing process. This led to simultaneous realization of adjacent regions with peak emission of 2.74 eV and 2.82 eV with a high spatial resolution (~1 MUm) at the coating boundary. The potential profile softening in the intermixed QW light-emitting diode (LED) was experimentally and numerically correlated, shedding light on the origin of alleviated efficiency droop from 30.5% to 16.6% (at 150 A/cm2). The technique is advantageous for fabricating high efficiency light-emitters, and is amenable to monolithic integration of nitride-based photonic devices. PMID- 25837137 TI - Q-switched operation of a femtosecond-laser-inscribed Yb:YAG channel waveguide laser using carbon nanotubes. AB - We demonstrate a diode-pumped femtosecond-laser-inscribed Yb:YAG channel waveguide laser, Q-switched by using single-walled carbon nanotubes (SWCNTs) near 1029 nm. We used saturable absorber mirrors (SAMs) fabricated by depositing SWCNTs on three different output couplers. Best performance of the 9.3-mm-long ultra-compact Q-switched waveguide laser is obtained with an output coupling transmission of 20%. In this case, a maximum average output power of 60 mW with a corresponding pulse energy of 37.7 nJ and a pulse duration of 88 ns at 1.59-MHz repetition rate were achieved. The highest pulse energy of 39.2 nJ and the shortest pulse duration of 78 ns were obtained with 30% and 10% output couplers, respectively. PMID- 25837138 TI - Removal of line artifacts on mesh boundary in computer generated hologram by mesh phase matching. AB - Mesh-based computer generated hologram enables realistic and efficient representation of three-dimensional scene. However, the dark line artifacts on the boundary between neighboring meshes are frequently observed, degrading the quality of the reconstruction. In this paper, we propose a simple technique to remove the dark line artifacts by matching the phase on the boundary of neighboring meshes. The feasibility of the proposed method is confirmed by the numerical and optical reconstruction of the generated hologram. PMID- 25837139 TI - Optical side-band cooling of a low frequency optomechanical system. AB - For experimental investigations of macroscopic quantum superpositions and the possible role of gravitational effects on the reduction of the corresponding quantum wave function it is beneficial to consider large mass, low frequency optomechanical systems. We report optical side-band cooling from room temperature for a 1.5*10-10 kg (mode mass), low frequency side-band resolved optomechanical system based on a 5 cm long Fabry-Perot cavity. By using high-quality Bragg mirrors for both the stationary and the micromechanical mirror we are able to construct an optomechanical cavity with an optical linewidth of 23 kHz. This, together with a resonator frequency of 315 kHz, makes the system operate firmly in the side-band resolved regime. With the presented optomechanical system parameters cooling close to the ground state is possible. This brings us one step closer to creating and verifying macroscopic quantum superpositions. PMID- 25837140 TI - Generation of microswimmers from passive Brownian particles in a spherically aberrated optical trap. AB - We induce spontaneous motion that is both directed and complex in micron-sized asymmetric Brownian particles in a spherically aberrated optical trap to generate microswimmers. The aberrated optical trap is prepared in a slightly modified optical tweezers configuration where we use a refractive index mismatched cover slip leading to the formation of an annular intensity distribution near the trap focal plane. Asymmetric scattering from a micro-particle trapped in this annular trap gives rise to a net tangential force on the particle causing it to revolve spontaneously in the intensity ring. The rate of revolution can be controlled from sub-Hz to a few Hz by changing the intensity of the trapping light. Theoretical simulations performed using finite-difference time-domain method verify the experimental observations. We also experimentally demonstrate simultaneous spin and revolution of a micro-swimmer which shows that complex motion can be achieved by designing a suitable shape of a micro-swimmer in the optical potential. PMID- 25837141 TI - SIMPEL: circuit model for photonic spike processing laser neurons. AB - We propose an equivalent circuit model for photonic spike processing laser neurons with an embedded saturable absorber-a simulation model for photonic excitable lasers (SIMPEL). We show that by mapping the laser neuron rate equations into a circuit model, SPICE analysis can be used as an efficient and accurate engine for numerical calculations, capable of generalization to a variety of different types of laser neurons with saturable absorber found in literature. The development of this model parallels the Hodgkin-Huxley model of neuron biophysics, a circuit framework which brought efficiency, modularity, and generalizability to the study of neural dynamics. We employ the model to study various signal-processing effects such as excitability with excitatory and inhibitory pulses, binary all-or-nothing response, and bistable dynamics. PMID- 25837142 TI - High sensitive refractometers based on lossy mode resonances (LMRs) supported by ITO coated D-shaped optical fibers. AB - Tin doped indium oxide (ITO) coatings fabricated onto D-shaped optical fibers are presented as the supporting medium for Lossy Mode Resonances (LMRs) generation. The characteristic geometry of ITO-coated D-shaped optical fibers enables to observe experimentally LMRs obtained with both TM and TE polarized light (LMR(TM) and LMR(TE)). This permits to obtain a maximum transmission decay of 36 dB with a LMR spectral width of 6.9 nm, improving that obtained in previous works, where the LMRs were a combination of an LMR(TM) and an LMR(TE). Surrounding medium refractive index (SMRI) sensitivity characterization of LMR(TM) has been performed obtaining a maximum sensitivity of 8742 nm/RIU in the range 1.365-1.38 refractive index units (RIU) which overcomes that of surface plasmon resonance based optical fiber devices presented in recent works. PMID- 25837143 TI - Diffraction in a stratified region of a high numerical aperture Fresnel zone plate: a simple and rigorous integral representation. AB - An algorithm for calculating the field distribution of a high numerical aperture Fresnel zone plate (FZP) in stratified media is presented, which is based on the vector angular spectrum method. The diffraction problem of FZP is solved for the case of a multilayer film with planar interfaces perpendicular to the optical axis. The solution is obtained in a rigorous mathematical manner and it satisfies the homogeneous wave equations. The electric strength vector of the transmitted and reflected field in the multilayer media is obtained for any polarized beam normally incident onto a binary phase circular FZP. For radially-, azimuthally- and linearly-polarized beam, the electric field in the focal region can be simplified as double or single integral, which can be readily used for numerical computation. PMID- 25837144 TI - POF misalignment model based on the calculation of the radiation pattern using the Hankel transform. AB - Here, we propose a method to estimate misalignment losses that is based on the calculation of the radiated angular power distribution as light propagates through space using the fiber far field pattern (FFP) and simplifying and speeding calculations with the Hankel transform. This method gives good estimates for combined transversal and longitudinal losses at short, intermediate and long offset distances. In addition, the same methodology can be adapted to describe not only scalar loss but also its angular dependence caused by misalignments. We show that this approach can be applied to upgrade a connector matrix included in a propagation model that is integrated into simulation software. This way, we assess the effects of misalignments at different points in the link and are able to predict the performance of different layouts at system level. PMID- 25837145 TI - Ultrafast imaging of terahertz Cherenkov waves and transition-like radiation in LiNbO3. AB - We use ultrafast phase-contrast imaging to directly observethe cone-like terahertz (THz) Cherenkov wave generated by optical rectification of femtosecond laser pulses focused into bulk lithium niobate (LiNbO3) single crystals. The transverse imaging geometry allows the Cherenkov angle, THz wave velocity, and optical pump pulse group velocity to be measured. Furthermore, transition-like THz radiation generated by the femtosecond laser pulse at the air-crystal boundary is observed. The effect of optical pump pulse polarization on the generation of THz Cherenkov waves and transition-like radiation in LiNbO3 is also investigated. PMID- 25837146 TI - Measuring Bragg gratings in multimode optical fibers. AB - Fiber Bragg gratings (FBG) in multimode optical fibers provide a means for cost effictive devices resulting in simplified and robust optic sensor systems. Parasitic mode effects in optical components of the entire measurement system strongly influence the measured multi-resonance reflection spectrum. Using a mode transfer matrix formalism we can describe these complex mode coupling effects in multimode optical systems in more detail. We demonstrate the accordance of the theory by two experiments. With this formalism it is possible to understand and optimize mode effects in multimode fiber optic systems. PMID- 25837147 TI - Wavelength selective mode division multiplexing on a silicon chip. AB - Multiplexing of optical modes in waveguides is demonstrated using coupled vertical gratings. The device utilizes sinusoidally corrugated waveguides of different widths with a period designed to multiplex information at 1.55 um. The design, fabrication and characterization of devices is performed. Multiplexing of modes is demonstrated in optical structures which support 3 and 5 quasi-TE modes. The design utilizes counter-propagating modes in periodic structures, thus enabling the device to combine its mode division multiplexing capabilities with wavelength division multiplexing functionalities to further augment the multiplexing capacity of the device. PMID- 25837148 TI - Diode-pumped tape casting planar waveguide YAG/Nd:YAG/YAG ceramic laser. AB - We demonstrated the efficient guided laser action in a diode-pumped YAG/Nd:YAG/YAG ceramic planar waveguide produced by tape casting and vacuum sintering technology for the first time to the best of our knowledge. In the regime of continuous wave operation, a maximum output power of 840 mW corresponding to the slope efficiency of 65% was achieved. During passively Q switched operation, by replacing the dichroic mirror with graphene-oxide based output coupler, we obtained the stable pulse trains with the shortest pulse duration of 179 ns at a pulse repetition rate of 930 kHz which resulted in the single pulse energy of 221 nJ. PMID- 25837149 TI - Fabrication and characterization of periodically patterned silica fiber structures for enhanced second-order nonlinearity. AB - We develop and characterize a UV ablation technique that can be used to pattern soft materials such as polymers and nonlinear molecules self-assembled over silica microstructures. Using this method, we fabricate a spatially periodic coating of nonlinear film over a thin silica fiber taper for second harmonic generation (SHG). Experimentally, we find that the second harmonic signal produced by the taper with periodic nonlinear coating is 15 times stronger than the same taper with uniform nonlinear coating, which suggests that quasi-phase matching is at least partially achieved in the patterned nonlinear silica taper. The same technique can also be used to spatially pattern other types of functional nanomaterials over silica microstructures with curved surfaces, as demonstrated by deposition of gold nanoparticles in patterned structures. PMID- 25837150 TI - Enhanced nonreciprocal effects in magnetoplasmonic systems supporting simultaneously localized and propagating plasmons. AB - Perforated magnetoplasmonic Au/Co/Au multilayers support both localized and propagating surface plasmon resonances. The presence of holes produces an enhancement of the magnetic field modulation of the propagating surface plasmon wavevector with respect to the isostructural continuous film in the spectral region corresponding to the hole associated localized plasmon resonance. This is due to the increased electromagnetic field in the surrounding area of the resonant hole, and the subsequent additional contribution to the magnetic modulation of the continuous film. This novel concept that gives rise to enhanced magnetic field induced nonreciprocal effects can be of interest in the development of innovative platforms for sensing applications, optical isolators and modulators. PMID- 25837151 TI - Quantum effects in the optical response of extended plasmonic gaps: validation of the quantum corrected model in core-shell nanomatryushkas. AB - Electron tunneling through narrow gaps between metal nanoparticles can strongly affect the plasmonic response of the hybrid nanostructure. Although quantum mechanical in nature, this effect can be properly taken into account within a classical framework of Maxwell equations using the so-called Quantum Corrected Model (QCM). We extend previous studies on spherical cluster and cylindrical nanowire dimers where the tunneling current occurs in the extremely localized gap regions, and perform quantum mechanical time dependent density functional theory (TDDFT) calculations of the plasmonic response of cylindrical core-shell nanoparticles (nanomatryushkas). In this axially symmetric situation, the tunneling region extends over the entire gap between the metal core and the metallic shell. For core-shell separations below 0.5 nm, the standard classical calculations fail to describe the plasmonic response of the cylindrical nanomatryushka, while the QCM can reproduce the quantum results. Using the QCM we also retrieve the quantum results for the absorption cross section of the spherical nanomatryushka calculated by V. Kulkarni et al. [Nano Lett. 13, 5873 (2013)]. The comparison between the model and the full quantum calculations establishes the applicability of the QCM for a wider range of geometries that hold tunneling gaps. PMID- 25837152 TI - Modulation behaviors of surface plasmon coupled light-emitting diode. AB - The modulation bandwidths of the light-emitting diodes (LEDs) of different mesa sizes with and without surface plasmon (SP) coupling effect are compared. Due to the significant increase of carrier decay rate, within the size range of LED square-mesa from 60 through 300 micron and the injected current-density range from 139 through 1667 A/cm2, the SP coupling can lead to the enhancement of modulation bandwidth by 44-48%, independent of the variations of LED mesa size or injected current level. The enhancement ratios of modulation bandwidth of the samples with SP coupling with respect to those of the samples without SP coupling are lower than the corresponding ratios of the square-root of photoluminescence decay rate due to the increases of their RC time constants (the product of device resistance and capacitance). The increases of the RC time constants in the samples with SP coupling are attributed to the increases of their device resistance levels when the Ag nanoparticles and GaZnO dielectric interlayer are added to the LED surface for effectively inducing SP coupling. PMID- 25837153 TI - An energy adjustable linearly polarized passively Q-switched bulk laser with a wedged diffusion-bonded Nd:YAG/Cr4+:YAG crystal. AB - An energy adjustable passively Q-switched laser is demonstrated with a composite Nd:YAG/Cr4+:YAG crystal by applying a wedged interface inside the crystal. The theoretical model of the monolithic laser resonator is explored to show the energy adjustable feature with different initial transmissions of the saturable absorber at the horizontal axis. By adjusting the pump beam location across the Nd:YAG crystal, the output pulse energy can be flexibly changed from 10.9 MUJ to 17.6 MUJ while maintaining the same output efficiency. The polarization state of the laser output is found to be along with the polarization of the C-mount pump diode. Finally, the behavior of the multi-transverse-mode oscillation is also discussed for eliminating the instability of the pulse train. PMID- 25837154 TI - Focus issue introduction: Advanced solid-state lasers (ASSL) 2014. AB - The editors introduce the focus issue on "Advanced Solid-State Lasers (ASSL) 2014," which is based on the topics presented at a congress of the same name held in Shanghai, China, from October 27 to November 1, 2014. This focus issue, jointly prepared by Optics Express and Optical Materials Express, includes 28 contributed papers (21 for Optics Express and 7 for Optical Materials Express) selected from the voluntary submissions by attendees who presented at the congress and have extended their work into complete research articles. We hope this focus issue offers a useful snapshot of the variety of topical discussions held at the congress and will contribute to the further expansion of the associated research areas. PMID- 25837156 TI - Cell-secreted signals shape lymphoma identity. AB - Sequencing data show that both specific genes and a number of signaling pathways are recurrently mutated in various types of lymphoma. DNA sequencing analyses of lymphoma have identified several aberrations that might affect the interaction between malignant cells and the tumor microenvironment. Microenvironmental functions are essential to lymphoma; they provide survival and proliferation signals and license immune evasion. It is plausible that interventions that aim to destroy tumor-microenvironment interactions may improve responses to therapeutics. Accordingly, the identification of extrinsic factors and their downstream intracellular signaling targets has led to much progress in understanding tumor-microenvironment interactions. Lymphoma cells are differently influenced by cells' interactions with components of their microenvironment; these cell extrinsic factors include soluble and immobilized factors, the extracellular matrix, and signals presented by neighboring cells. Soluble factors, which are often cell-secreted autocrine and paracrine factors, comprise a significant fraction of targetable molecules. To begin to understand how intercellular communication is conducted in lymphoma, a first order of study is deciphering the soluble factors secreted by malignant cells and microenvironmental cells. These soluble factors are shed into the interstitial fluid in lymphoma and can be conveniently explored using mass spectrometry. Protein components can be detected and quantified, thus enabling the routine navigation of the soluble part of the microenvironment. Elucidating functional and signaling states affords a new paradigm for understanding cancer biology and devising new therapies. This review summarizes knowledge in this field and discusses the utility of studying tumor-secreted factors. PMID- 25837157 TI - Microenvironmental abnormalities induced by viral cooperation: Impact on lymphomagenesis. AB - When stringent criteria have been used, the Epstein Barr virus (EBV), the Kaposi's sarcoma herpesvirus (KSHV), human immunodeficiency virus type 1 (HIV-1) and human hepatitis C virus (HCV) have been identified with sufficient evidence to be causative agents of non-Hodgkin's Lymphomas. Initially, single viral infection was considered fully responsible for the oncogenic properties of each virus, while it is now established that in many cases, multiple viral agents collaborate as cofactors in inducing lymphomas, especially in the presence of HIV dependent immunodeficiency. Viruses cooperate by using their specific pathogenetic mechanisms in different combinations. The aim of this review is to describe the cooperation between different viruses in the development of lymphomas including the evidences supporting their pathogenetic role. Viral cooperation, a mechanism by which different viruses coinfecting human tissues have synergistic or regulatory effects on carcinogenesis, targets neoplastic B cells as well as cells of the microenvironment, such as reactive T-cells, B cells and macrophages, as well as non-immune cells such as endothelial cells, that contribute to tumor microenvironment. The most important viral genes involved in cooperation include HIV-1 tat and vpu, EBV LMP-1 and EBNA-2 and KSHV KIE2, Rta and LANA. Lymphomagenesis related to viral cooperation represents an interesting topic where microenvironmental abnormalities may be particularly relevant, particularly because antiviral targeted therapies and therapies producing the reconstitution of the immune system may constitute areas of interest aiming at improving the outcome of virus associated lymphomas. While the immune component of the lymphoma microenvironment can be easily studied by immunological and molecular techniques, the definition of the non-immune component of the lymphoma microenvironment is largely incomplete and may be the issue of future investigations. Understanding the pathogenetic role of viral infection in specific malignancies and defining microenvironmental abnormalities and mechanisms of viral carcinogenesis are important steps toward precise diagnosis and accurate treatment strategies for HIV-associated cancers. PMID- 25837155 TI - Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy. AB - Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically matched control subjects. Genotype-phenotype correlation studies suggested a co segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy. PMID- 25837158 TI - Variability in reference point microindentation and recommendations for testing cortical bone: location, thickness and orientation heterogeneity. AB - Reference Point Indentation (RPI) has been proposed as a new clinical tool to aid the diagnosis of Osteoporosis. This study has examined the performance of the tool within entire femurs to improve the understanding of the mechanical properties of bone and also to guide future RPI testing to optimize repeatability of results obtained using the technique. Human, bovine, porcine and rat femurs were indented along three longitudinal axes: anterior and posterior: medial and lateral as well as around the circumference of the femoral head and neck. Cortical and subchondral bone thickness was measured using CT and radiography. The study shows that in some samples, bone is too thin to support the high loads applied with the technique and in these cases, RPI values are highly influenced by thickness. The technique will be useful in the mid-shaft region where cortical thickness is greatest, providing previously established guidelines are followed to optimize measurement repeatability, including performing multiple measurements per sample and investigating multiple samples. The study has also provided evidence that RPI values vary significantly with test site, hence mechanical properties should not be inferred from RPI findings alone away from the test site, even within the same bone. In conclusion, RPI appears to be a useful tool for scientific investigation; however further work is required to examine the feasibility of using RPI for assessing differences between healthy and diseased bone in a clinical setting. PMID- 25837159 TI - Estrogen Modulates Bone Morphogenetic Protein-Induced Sclerostin Expression Through the Wnt Signaling Pathway. AB - Clinical data show that estrogen levels are inversely associated with the production of sclerostin, a Wnt antagonist that recently attracted great attention over the use of its antibody in the anabolic treatment of osteoporotic conditions. However, the molecular link between sclerostin expression and estrogen signaling is not yet known. We investigated the mechanisms by which estrogen modulates sclerostin (SOST) gene expression at the cellular level in human osteoblast cells in association with bone morphogenetic protein (BMP)2 signaling given that BMP2 is a potential inducer of SOST in human mesenchymal stromal cells (hMSCs). 17beta-Estradiol (E2) alone had no effect on SOST expression, which was significantly induced by treatment with BMP2 in hMSCs and osteoblasts derived from the mandibles of female donors. However, E2 suppressed the induction of SOST and other BMP2 target genes by BMP2 in hMSCs. E2 signaling was independent of the Smad pathway, which plays a critical role in SOST induction mediated by BMP2. Instead, E2 increased the transcriptional expression of beta-catenin and levels of its activated form. Silencing of the gene encoding estrogen receptor (ER)alpha decreased E2 activity in beta-catenin activation and the suppression of SOST induction by BMP2, but had no influence on BMP2-mediated SOST induction in the same conditions. Similar results were obtained after treatment with ERalpha antagonist as a Wnt inhibitor. In human osteoblasts, the effect of E2 on SOST expression was either suppressive or absent, depending on the cell donor. Interestingly, the SOST expression pattern after treatment with BMP2 or BMP2/E2 in human osteoblasts showing a pattern of E2 suppression on SOST induction by BMP2 correlated with the ratio of receptor activator of nuclear factor kappa-B ligand (RANKL) to osteoprotegerin (OPG) expression. These results demonstrate that estrogen signaling in osteoblasts negatively regulates SOST expression in an indirect manner through interaction with BMP2 signaling and that this regulation involves the Wnt/ERalpha and beta-catenin pathways. This study highlights several interactions between estrogen and BMP cascades in osteoblasts that may provide a basis for therapeutic intervention for the modification of bone mass density. PMID- 25837160 TI - Descending genicular artery free flaps: Multi-purpose tissue transfers in limb reconstruction. AB - BACKGROUND: The descending genicular artery supplies skin, muscle, tendon, and bone structures in the medial knee area. Three types of skin perforator including musculocutaneous perforators through the vastus medialis (descending genicular artery perforator (DGAP)-vm), direct cutaneous perforators (DGAP), and saphenous artery perforators (SAP) can be elevated for the skin flap component. METHODS: This study included a prospective cohort of all patients in whom a descending genicular artery free flap was attempted in our center since January 2009. Data on patients' characteristics, type of injuries, the surgical procedures, and their outcomes were obtained for a minimum of 6 months postoperatively. FINDINGS: This cohort includes 22 descending genicular artery flaps for skin, bone, and tendon reconstruction after extensive soft tissue injury and/or bone nonunion. Of these, six were medial femoral condyle bone grafts, seven were skin flaps from the medial knee, and nine composite osteocutaneous or tendo-osteocutaneous flaps. Favorable outcome was achieved in 20 of 22 cases. We use the DGAP and DGAP-vm in 15 of 16 cutaneous and osteocutaneous flaps. CONCLUSION: The descending genicular artery flap offers a wide range of simple and composite flaps. Recognition of all types of skin perforators should enhance the options, the chance of success, and the popularity of the flap. PMID- 25837161 TI - One muscle two functions: Reconstructing a complex facial defect and providing facial reanimation with a split functional latissimus dorsi flap. PMID- 25837162 TI - Severance Hospital: bringing modern medicine to Korea. PMID- 25837163 TI - Expression of sarcosine metabolism-related proteins in invasive lobular carcinoma: comparison to invasive ductal carcinoma. AB - PURPOSE: The aims of this study were to compare the expression of sarcosine metabolism-related proteins between invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) and to determine the implications of these results. MATERIALS AND METHODS: Tissue microarrays were constructed, containing 30 samples from normal breast tissue, 114 samples from patients with ILC, and 692 samples from patients with IDC. Immunohistochemical staining was performed to examine the expression of sarcosine metabolism-related proteins [glycine N-methyltransferase, sarcosine dehydrogenase, and l-pipecolic acid oxidase (PIPOX)]. RESULTS: The sarcosine metabolic phenotype differed between ILC and IDC (p<0.001). In IDC, sarcosine metabolic phenotype was distributed as null type (61.7%)>low sarcosine type (30.4%)>high sarcosine type (5.0%)>intermediate type (2.9%). However, in ILC, the sarcosine metabolic phenotype was distributed as low sarcosine type (61.4%)>null type (32.5%)>intermediate type (5.3%)>high sarcosine type (0.9%). PIPOX showed higher expression in ILC than in IDC (p<0.001) and correlated with androgen receptor (AR) positivity (p=0.001) in ILC. CONCLUSION: Expression of sarcosine metabolism-related proteins differed between ILC and IDC. Low sarcosine type was the majority sarcosine metabolic phenotype of ILC. PIPOX expression was predominant in ILC and correlated with AR positivity. PMID- 25837164 TI - Left atrial function following surgical ablation of atrial fibrillation: prospective evaluation using dual-source cardiac computed tomography. AB - PURPOSE: The Maze procedure has shown excellent efficacy in the elimination of atrial fibrillation (AF); however, little is known about the quality of functional recovery in the left atrium (LA) following successful sinus rhythm conversion by the Maze procedure. MATERIALS AND METHODS: We prospectively enrolled 12 patients (aged 52.5+/-10.1 years, 1 female) with valvular AF undergoing mitral valve surgery combined with the Maze procedure. Parameters of LA function in three anatomic compartments [anterior, posterior, and LA appendage (LAA)] were evaluated using electrocardiography-gated dual-source cardiac CT at one month and at six months after surgery. Twelve subjects matched by age, gender, and body surface area served as controls. RESULTS: At one month after surgery, ejection fraction (EF) and emptying volume (EV) of the LA were 14.9+/ 7.4% and 21.3+/-9.7 mL, respectively, and they were significantly lower than those of the control group (EF, 47.9+/-11.2%; EV, 46.0+/-10.7%; p<0001). These values did not significantly change throughout late periods (p=0.22 and 0.21, respectively). Functional contributions of the anterior, posterior, and appendage compartments (EV of each compartment/overall EV) were 80.4%, -0.9%, and 20.5%, respectively, for those with LAA preservation (n=6); 100.1%, -0.1%, and 0% for those with LAA resection (n=6; p<0.05); and 62.2%, 28.2%, and 9.7% in the control subjects (p<0.001). CONCLUSION: Contractile functions of the LA significantly decreased after the Maze procedure. Functional contributions of three compartments of the LA were also altered. The influence of LAA preservation on postoperative LA functions needs to be evaluated through studies of larger populations. PMID- 25837165 TI - Brachial-ankle pulse wave velocity as a screen for arterial stiffness: a comparison with cardiac magnetic resonance. AB - PURPOSE: Despite technical simplicity and the low cost of brachial-ankle pulse wave velocity (BA-PWV), its use has been hampered by a lack of data supporting its usefulness and reliability. The aim of this study was to evaluate the usefulness of BA-PWV to measure aortic stiffness in comparison to using cardiovascular magnetic resonance (CMR). MATERIALS AND METHODS: A total of 124 participants without cardiovascular risk factors volunteered for this study. BA PWV was measured using a vascular testing device. On the same day, using CMR, cross-sectional areas for distensibility and average blood flow were measured at four aortic levels: the ascending, upper thoracic descending, lower thoracic descending, and abdominal aorta. RESULTS: Compared to PWV measured by CMR, BA-PWV values were significantly higher and the differences therein were similar in all age groups (all p<0.001). There was a significant correlation between BA-PWV and PWV by CMR (r=0.697, p<0.001). Both BA-PWV and PWV by CMR were significantly and positively associated with age (r=0.652 and 0.724, p<0.001). The reciprocal of aortic distensibility also demonstrated a statistically significant positive correlation with BA-PWV (r=0.583 to 0.673, all p<0.001). CONCLUSION: BA-PWV was well correlated with central aortic PWV and distensibility, as measured by CMR, regardless of age and sex. PMID- 25837166 TI - IL28B is associated with outcomes of chronic HBV infection. AB - PURPOSE: The role of IL28B gene variants and expression in hepatitis B virus (HBV) infections are not well understood. Here, we evaluated whether IL28B gene expression and rs12979860 variations are associated with HBV outcomes. MATERIALS AND METHODS: IL28B genetic variations (rs12979860) were genotyped by pyrosequencing of DNA samples from 137 individuals with chronic HBV infection [50 inactive carriers (IC), 34 chronic hepatitis B (CHB), 27 cirrhosis, 26 hepatocellular carcinoma (HCC)], and 19 healthy controls. IL28A/B mRNA expression in peripheral blood mononuclear cells was determined by qRT-PCR, and serum IL28B protein was measured by ELISA. RESULTS: Patients with IL28B C/C genotype had greater IL28A/B mRNA expression and higher IL28B protein levels than C/T patients. Within the various disease stages, compared to IC and healthy controls, IL28B expression was reduced in the CHB, cirrhosis, and HCC cohorts (CHB vs. IC, p=0.02; cirrhosis vs. IC, p=0.01; HCC vs. IC, p=0.001; CHB vs. controls, p<0.01; cirrhosis vs. controls, p<0.01; HCC vs. controls, p<0.01). When stratified with respect to serum HBV markers in the IC and CHB cohorts, IL28B mRNA and protein levels were higher in HBeAg-positive than negative individuals (p=0.01). Logistic regression analysis revealed that factors associated with high IL28B protein levels were C/C versus C/T genotype [p=0.016, odds ratio (OR)=0.25, 95% confidence interval (CI)=0.08-0.78], high alanine aminotransferase values (p<0.001, OR=8.02, 95% CI=2.64-24.4), and the IC stage of HBV infection (p<0.001). CONCLUSION: Our data suggest that IL28B genetic variations may play an important role in long-term development of disease in chronic HBV infections. PMID- 25837167 TI - Detection of plasma BRAF(V600E) mutation is associated with lung metastasis in papillary thyroid carcinomas. AB - PURPOSE: The BRAF(V600E) mutation represents a novel indicator of the progression and aggressiveness of papillary thyroid carcinoma (PTC). The purpose of this study was to determine the clinical significance of free circulating mutant BRAF(V600E) in predicting the advanced disease of PTC. MATERIALS AND METHODS: Seventy seven matched tumor and plasma samples obtained from patients with both benign and PTC were analyzed for BRAF(V600E) mutation using a peptide nucleic acid (PNA) clamp real-time polymerase chain reaction (PCR). RESULTS: The BRAF(V600E) mutation was absent in tumor DNA samples obtained from patients with benign follicular adenomas or adenomatous goiter. In contrast, 49 of 72 (68.1%) PTC tumors were positive for the BRAF(V600E) mutation. Among them, 3 (6.1%) patients with PTC were positive for BRAF(V600E) mutation in plasma and tumor. However, all 3 patients (100%) had lateral lymph node and lung metastasis. CONCLUSION: These findings suggest that the BRAF(V600E) mutation can be detected using a PNA clamp real-time PCR in the blood of PTC patients with lung metastasis. Future studies are warranted to determine clinical significance of serum BRAF(V600E) mutation in large prospective studies. PMID- 25837168 TI - Effect of socio-economic status on the prevalence of diabetes. AB - PURPOSE: As Korean society has become industrialized and westernized, the prevalence of diabetes has increased rapidly. Environmental factors, especially socio-economic status (SES), may account for the increased prevalence of diabetes. We evaluated the associations between the prevalence of diabetes and SES as reflected by household income and education level. MATERIALS AND METHODS: This study was based on data obtained from the fifth Korea National Health and Nutrition Examination Survey, conducted in 2010-2012. Diabetes referred to a fasting plasma glucose >=126 mg/dL in the absence of known diabetes, previous diagnosis of diabetes made by a physician, and/or current use of oral hypoglycemic agents or insulin. RESULTS: Household income and education level were inversely associated with the prevalence of diabetes among individuals aged 30 years or older. These associations were more prominent in females aged 30-64 years. According to household income, the odds ratio (OR) [95% confidence interval (CI)] for the lowest quartile group versus the highest quartile group was 4.96 (2.87-8.58). According to education level, the OR (95% CI) for the lowest quartile group versus the highest quartile group was 8.02 (4.47-14.4). CONCLUSION: Public policies for the prevention and management of diabetes should be targeted toward people of lower SES, especially middle-aged females. PMID- 25837169 TI - Pre-clinical efficacy and safety evaluation of human amniotic fluid-derived stem cell injection in a mouse model of urinary incontinence. AB - PURPOSE: Stem cell-based therapies represent new promises for the treatment of urinary incontinence. This study was performed to assess optimized cell passage number, cell dose, therapeutic efficacy, feasibility, toxicity, and cell trafficking for the first step of the pre-clinical evaluation of human amniotic fluid stem cell (hAFSC) therapy in a urinary incontinence animal model. MATERIALS AND METHODS: The proper cell passage number was analyzed with hAFSCs at passages 4, 6, and 8 at week 2. The cell dose optimization included 1*104, 1*105, and 1*106 cells at week 2. The in vivo cell toxicity was performed with 0.25*106, 0.5*106, and 1*106 cells at weeks 2 and 4. Cell tracking was performed with 1*106 cells at weeks 2 and 4. RESULTS: The selected optimal cell passage number was smaller than 6, and the optimal cell dose was 1*106 for the mouse model. In our pre-clinical study, hAFSC-injected animals showed normal values for several parameters. Moreover, the injected cells were found to be non-toxic and non tumorigenic. Furthermore, the injected hAFSCs were rarely identified by in vivo cell trafficking in the target organs at week 2. CONCLUSION: This study demonstrates for the first time the pre-clinical efficacy and safety of hAFSC injection in the urinary incontinence animal model and provides a basis for future clinical applications. PMID- 25837170 TI - The effect of specialized continuous renal replacement therapy team in acute kidney injury patients treatment. AB - PURPOSE: Continuous renal replacement therapy (CRRT) has been established for critically ill acute kidney injury (AKI) patients. In addition, some centers consist of a specialized CRRT team (SCT) with physicians and nurses. To our best knowledge, however, ona a few studies have yet been carried out on the superiority of SCT management. MATERIALS AND METHODS: A total of 551 patients, who received CRRT between January 2008 and March 2009, were divided into two groups based on the controller of CRRT. The impact of the CRRT management on 28 day mortality was compared between two groups by Kaplan-Meier curve and Cox analysis. RESULTS: During the study period, the number of filters used, down-time per day, and intensive care unit length of day were significantly higher in non SCT group than in SCT group (6.2 hrs vs. 5.0 hrs, p=0.042; 5.0 hrs vs. 3.8 hrs, p<0.001; 27.5 days vs. 21.1 days, p=0.027, respectively), while net ultrafiltration rate was significantly lower in non-SCT group than SCT group (28.0 mL/kg/hr vs. 29.5 mL/kg/hr, p=0.043, respectively). In addition, 28-day mortality rate was significantly lower in SCT group than with non-SCT group (p=0.031). Moreover, Cox regression analysis showed that 28-day mortality rate was significantly lower in SCT control group, even after adjusting for age, gender, severity scores, biomarkers, risk, injury, failure, loss, and end-stage renal disease, and contributing factors (hazard ratio 0.91, p=0.046). CONCLUSION: A well-trained CRRT team could be beneficial for mortality improvement of AKI patients requiring CRRT. PMID- 25837171 TI - Improving survival rate of Korean patients initiating dialysis. AB - PURPOSE: The aim of this study was to investigate whether the survival rate among Korean dialysis patients changed during the period between 2005 and 2008 in Korea. MATERIALS AND METHODS: A total of 32357 patients who began dialysis between January 1, 2005 and December 31, 2008 were eligible for analysis. Baseline demographics, comorbidities, and mortality data were obtained from the database of the Health Insurance Review & Assessment Service. RESULTS: Kaplan Meier curves according to the year of dialysis initiation showed that the survival rate was significantly different (log-rank test, p=0.005), most notably among peritoneal dialysis (PD) patients (p<0.001), although not among hemodialysis (HD) patients (p=0.497). In multivariate analysis, however, patients initiating either HD or PD in 2008 also had a significantly lower risk of mortality compared to those who began dialysis in 2005. Subgroup survival analysis among patients initiating dialysis in 2008 revealed that the survival rate of PD patients was significantly higher than that of HD patients (p=0.001), and the survival benefit of PD over HD remained in non-diabetic patients aged less than 65 years after adjustment of covariates. CONCLUSION: Survival of Korean patients initiating dialysis from 2005 to 2008 has improved over time, particularly in PD patients. In addition, survival rates among patients initiating dialysis in 2008 were different according to patients' age and diabetes, thus we need to consider these factors when dialysis modality should be chosen. PMID- 25837172 TI - Significance of myositis autoantibody in patients with idiopathic interstitial lung disease. AB - PURPOSE: Some patients with interstitial lung disease (ILD) related to connective tissue disease (CTD) have a delayed diagnosis of the underlying CTD when the ILD is categorized as idiopathic. In this study, we evaluated the frequency of myositis autoantibodies in patients diagnosed with idiopathic ILD and investigated the clinical significance stemming from the presence of the antibodies. MATERIALS AND METHODS: A total 32 patients diagnosed with idiopathic ILD were enrolled in this study. We analyzed a panel of 11 myositis autoantibody specificities in the patients using a line blot immunoassay. Then, we divided them into myositis autoantibody-positive and -negative groups and compared the clinical features and laboratory data between the two groups. RESULTS: Of the 32 idiopathic ILD patients, 12 patients had myositis autoantibodies encompassing 9 specificities, except for anti-Mi-2 and anti-PM-Scl 100 (12/32, 38%). Anti synthetase autoantibodies including Jo-1, EJ, OJ, PL-7, and PL-12 were present in 7 patients (7/32, 22%). The group with myositis autoantibodies presented more frequently with the symptom of mechanic's hand and showed abnormal pulmonary function test results with low forced vital capacity, diffusing capacity for carbon monoxide, total lung capacity, and high lactate dehydrogenase values in blood when compared with the group without myositis antibodies. CONCLUSION: We strongly suggest that patients undergo an evaluation of myositis autoantibodies, if they are diagnosed with idiopathic ILD in the presence of clinical characteristics including mechanic's hand, arthralgia, and autoantibodies which are insufficient to make a diagnosis of a specific CTD category. PMID- 25837173 TI - The utility of three screening questionnaires for obstructive sleep apnea in a sleep clinic setting. AB - PURPOSE: The aim of this study was to determine the diagnostic value of three screening questionnaires in identifying Korean patients at high risk for obstructive sleep apnea (OSA) in a sleep clinic setting in Korea. MATERIALS AND METHODS: Data were collected from 592 adult patients with suspected OSA who visited a sleep center. All patients completed the Sleep Apnea of Sleep Disorder Questionnaire (SA-SDQ), the Berlin questionnaire, and the STOP-Bang questionnaire. Estimated OSA risk was compared to a diagnosis of OSA. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each questionnaire. RESULTS: The prevalence of OSA was 83.6% using an apnea-hypopnea index (AHI) >=5/h and 58.4% for an AHI >=15/h. The STOP-Bang questionnaire had a high sensitivity (97% for AHI >=5/h, 98% for AHI >=15/h), but the specificity was low (19% and 11%, respectively). In contrast, the sensitivity of the SA-SDQ was not high enough (68% for AHI >=5/h, 74% for AHI >=15/h) to be useful in a clinical setting, whereas the specificity was relatively good (66% and 61%, respectively). The sensitivity and specificity values of the Berlin questionnaire fell between those of the STOP-Bang questionnaire and the SA-SDQ. CONCLUSION: The STOP-Bang questionnaire may be useful for screening OSA in a sleep clinic setting, but its specificity is lower than the acceptable level for this purpose. A new screening questionnaire with a high sensitivity and acceptable specificity is therefore needed in a sleep clinic setting. PMID- 25837174 TI - Efficacy of percutaneous epidural neuroplasty does not correlate with dural sac cross-sectional area in single level disc disease. AB - PURPOSE: Percutaneous epidural neuroplasty (PEN) is a minimally invasive treatment. The efficacy of PEN has been relatively well investigated; however, the relationship between the clinical effectiveness of PEN and the severity of spinal canal stenosis by disc material has not yet been established. The purpose of this study was to compare clinical outcomes of PEN according to the dural sac cross-sectional area in single level disc disease. MATERIALS AND METHODS: This study included 363 patients with back pain from single level disc disease with and without radiculopathy. Patients were categorized into groups according to spinal canal compromise by disc material: Category 1, less or more than 50%; and Category 2, three subgroups with lesser than a third, between a third and two thirds, and more than two thirds. Clinical outcomes were assessed according to the Visual Analog Scale (VAS) score for back pain and leg pain and Odom's criteria at 1, 3, 6, 12, and 24 months after treatment. RESULTS: The demographic data showed no difference between groups according to spinal canal compromise by disc material except age (older age correlated with more spinal canal compromise). The dural sac cross-sectional area did not correlate with the VAS scores for back and leg pain after PEN in single level disc disease in Groups 1 and 2. Odom's criteria after PEN were also not different according to dural sac cross-sectional area by disc material. CONCLUSION: PEN is an effective procedure in treating single level lumbar disc herniation without affecting dural sac cross sectional area. PMID- 25837175 TI - Relations between Eastern four pillars theory and Western measures of personality traits. AB - PURPOSE: The present study investigated the validity of personality classification using four pillars theory, a tradition in China and northeastern Asia. MATERIALS AND METHODS: Four pillars analyses were performed for 148 adults on the basis of their birth year, month, day, and hour. Participants completed two personality tests, the Korean version of Temperament and Character Inventory Revised-Short Version (TCI) and the Korean Inventory of Interpersonal Problems; scores were correlated with four pillars classification elements. Mean difference tests (e.g., t-test, ANOVA) were compared with groups classified by four pillars index. RESULTS: There were no significant correlations between personality scale scores and total yin/yang number (i.e., the 8 heavenly or earthly stems), and no significant between-groups results for classifications by yin/yang day stem and the five elements. There were significant but weak (r=0.18-0.29) correlations between the five elements and personality scale scores. For the six gods and personality scales, there were significant but weak (r=0.18-0.25) correlations. Features predicted by four pillars theory were most consistent when participants were grouped according to the yin/yang of the day stem and dominance of yin/yang numbers in the eight heavenly or earthly stems. CONCLUSION: Although the major criteria of four pillars theory were not independently correlated with personality scale scores, correlations emerged when participants were grouped according to the composite yin/yang variable. Our results suggest the utility of four pillars theory (beyond fortune telling or astrology) for classifying personality traits and making behavioral predictions. PMID- 25837176 TI - Abnormal brain activity in social reward learning in children with autism spectrum disorder: an fMRI study. AB - PURPOSE: We aimed to determine whether Autism Spectrum Disorder (ASD) would show neural abnormality of the social reward system using functional MRI (fMRI). MATERIALS AND METHODS: 27 ASDs and 12 typically developing controls (TDCs) participated in this study. The social reward task was developed, and all participants performed the task during fMRI scanning. RESULTS: ASDs and TDCs with a social reward learning effect were selected on the basis of behavior data. We found significant differences in brain activation between the ASDs and TDCs showing a social reward learning effect. Compared with the TDCs, the ASDs showed reduced activity in the right dorsolateral prefrontal cortex, right orbitofrontal cortex, right parietal lobe, and occipital lobe; however, they showed increased activity in the right parahippocampal gyrus and superior temporal gyrus. CONCLUSION: These findings suggest that there might be neural abnormality of the social reward learning system of ASDs. Although this study has several potential limitations, it presents novel findings in the different neural mechanisms of social reward learning in children with ASD and a possible useful biomarker of high-functioning ASDs. PMID- 25837177 TI - Mean platelet volume is elevated in patients with psoriasis vulgaris. AB - PURPOSE: This retrospective study was done to investigate the mean platelet volume (MPV) level in patients with psoriasis vulgaris and its relationship with disease severity. MATERIALS AND METHODS: We undertook a cross-sectional study on 176 patients and 101 healthy controls to examine the association between MPV and psoriasis. Various clinical and laboratory parameters were analyzed and compared. RESULTS: Platelet distribution width and MPV were significantly higher in patients with psoriasis than controls. In addition, there was positive correlation between Psoriasis Area Severity Index (PASI) and MPV. When psoriasis patients were grouped into mild psoriasis (PASI<10) and moderate to severe psoriasis (PASI>=10), the MPV of the latter group was significantly elevated. Nevertheless, patients with higher MPV level (MPV>=10.4 fL) did not show higher PASI than lower MPV level (MPV<10.4 fL). MPV levels significantly decreased after improvements of psoriasis with various treatments. The variations of MPV and PASI also showed significant correlation. CONCLUSION: We have shown that MPV is increased in psoriasis patients and correlates with disease severity. Therefore, MPV levels may be considered as a marker of disease severity of psoriasis. PMID- 25837178 TI - Prevalence of vitiligo and associated comorbidities in Korea. AB - PURPOSE: Vitiligo prevalence and its associated comorbidities rate have been reported variably among different populations. We aimed to determine the prevalence of vitiligo in Korea along with the baseline rate of comorbidities and compared the risks to the general population using hospital visit information of the total population in Korea. MATERIALS AND METHODS: We assessed demographic characteristics of vitiligo patients in Korean population from 2009 to 2011 in a nationwide data from Health Insurance Review Assessment Service. Patients who had at least one visit to Korea's primary, secondary, or tertiary referral hospitals with International Classification of Diseases, 10th Revision, Clinical Modification diagnosis code for vitiligo were identified. As a supplementary study, comorbidities associated with vitiligo were selected for further review to calculate relative risks compared to the general population. RESULTS: The annual prevalence of vitiligo determined by hospital-visiting rate in Korea was 0.12% to 0.13% over a three year period. In sync with other previous epidemiological studies, there was bimodal distribution among the age groups and no difference between genders. Also, vitiligo in Korean population was associated with various autoimmune/non-autoimmune diseases such as thyroiditis, atopic dermatitis, and psoriasis. CONCLUSION: This study was by far the most comprehensive review on prevalence of vitiligo using a data of total population in Korea. The prevalence is within a range of those reported in previous literatures, and increased risk of comorbidities such as thyroid diseases and psoriasis in vitiligo might aid clinicians in the initial work up of vitiligo patients and concurrent follow ups. PMID- 25837179 TI - A network analysis of 15O-H2O PET reveals deep brain stimulation effects on brain network of Parkinson's disease. AB - PURPOSE: As Parkinson's disease (PD) can be considered a network abnormality, the effects of deep brain stimulation (DBS) need to be investigated in the aspect of networks. This study aimed to examine how DBS of the bilateral subthalamic nucleus (STN) affects the motor networks of patients with idiopathic PD during motor performance and to show the feasibility of the network analysis using cross sectional positron emission tomography (PET) images in DBS studies. MATERIALS AND METHODS: We obtained [15O]H2O PET images from ten patients with PD during a sequential finger-to-thumb opposition task and during the resting state, with DBS On and DBS-Off at STN. To identify the alteration of motor networks in PD and their changes due to STN-DBS, we applied independent component analysis (ICA) to all the cross-sectional PET images. We analysed the strength of each component according to DBS effects, task effects and interaction effects. RESULTS: ICA blindly decomposed components of functionally associated distributed clusters, which were comparable to the results of univariate statistical parametric mapping. ICA further revealed that STN-DBS modifies usage-strengths of components corresponding to the basal ganglia-thalamo-cortical circuits in PD patients by increasing the hypoactive basal ganglia and by suppressing the hyperactive cortical motor areas, ventrolateral thalamus and cerebellum. CONCLUSION: Our results suggest that STN-DBS may affect not only the abnormal local activity, but also alter brain networks in patients with PD. This study also demonstrated the usefulness of ICA for cross-sectional PET data to reveal network modifications due to DBS, which was not observable using the subtraction method. PMID- 25837180 TI - Retrospective assessment of the validity of robotic surgery in comparison to open surgery for pediatric choledochal cyst. AB - PURPOSE: We evaluated the validity of robotic surgery (RS) for pediatric choledochal cyst (CC) in comparison to open surgery (OS). MATERIALS AND METHODS: From January 2009 to April 2013, clinical data from 79 consecutive pediatric patients with CC, who underwent RS (n=36) or OS (n=43) performed by a single pediatric surgeon, were analyzed retrospectively. RESULTS: In the RS group, the age of the patients was significantly older, compared to the OS group. Operation and anesthesia times were significantly longer in the RS group than the OS group. Fluid input rates to maintain the same urine output were significantly smaller in the RS group than the OS group. The American Society of Anesthesiologists (ASA) physical status, length of postoperative hospital stay, and the incidence of surgical complications did not differ significantly between the two groups. CONCLUSION: Although early complications could not be avoided during the development of robotic surgical techniques, RS for pediatric CC showed results comparable to those for OS. We believe that RS may be a valid and alternative surgery for pediatric CC. After further development of robotic surgical systems and advancement of surgical techniques therewith, future prospective studies may reveal more positive results. PMID- 25837181 TI - First metatarsal proximal opening wedge osteotomy for correction of hallux valgus deformity: comparison of straight versus oblique osteotomy. AB - PURPOSE: The aim of this study was to compare clinical and radiographic outcomes of proximal opening wedge osteotomy using a straight versus oblique osteotomy. MATERIALS AND METHODS: We retrospectively reviewed 104 consecutive first metatarsal proximal opening wedge osteotomies performed in 95 patients with hallux valgus deformity. Twenty-six feet were treated using straight metatarsal osteotomy (group A), whereas 78 feet were treated using oblique metatarsal osteotomy (group B). The hallux valgus angle (HVA), intermetatarsal angle (IMA), distal metatarsal articular angle, and distance from the first to the second metatarsal (distance) were measured for radiographic evaluation, whereas the American Orthopaedic Foot and Ankle Society (AOFAS) forefoot score was used for clinical evaluation. RESULTS: Significant corrections in the HVA, IMA, and distance from the first to the second metatarsal were obtained in both groups at the last follow-up (p<0.001). There was no difference in the mean IMA correction between the 2 groups (6.1+/-2.7 degrees in group A and 6.0+/-2.1 degrees in group B). However, a greater correction in the HVA and distance from the first to the second metatarsal were found in group B (HVA, 13.2+/-8.2 degrees ; distance, 25.1+/-0.2 mm) compared to group A (HVA, 20.9+/-7.7 degrees ; distance, 28.1+/ 0.3 mm; p<0.001). AOFAS scores were improved in both groups. However, group B demonstrated a greater improvement relative to group A (p=0.005). CONCLUSION: Compared with a straight first metatarsal osteotomy, an oblique first metatarsal osteotomy yielded better clinical and radiological outcomes. PMID- 25837182 TI - Bilateral occurrence and morphologic analysis of complete discoid lateral meniscus. AB - PURPOSE: The aim of the study was to investigate and analyze bilateral incidence and morphology of complete discoid lateral meniscus (DLM) with possible relation to tears and symptoms in knee joints. MATERIALS AND METHODS: Thirty-eight consecutive patients with symptomatic or already-torn complete DLM on magnetic resonance imaging in a unilateral knee underwent diagnostic arthroscopy on both knee joints upon agreement. The presence and shape of complete DLM as well as presence and pattern of tear were recorded accordingly. RESULTS: In total, 89.5% (34 of 38 patients) showed bilateral complete DLM, and 84.2% yielded bilateralism with identical shape. Cape-slab was the most frequent shape, comprising 68.8% of patients with identically-shaped bilateral DLM overall. Tear patterns were more frequent, in the order of longitudinal, simple horizontal, radial, and degenerative; however, the morphological shape of complete DLM was not significantly related to tear incidence or pattern. Meniscus tears and knee symptoms occurred in the contralateral knee with incidences of 32.4% and 26.5% in patients with bilateral complete DLM, respectively. CONCLUSION: Based on these findings, more aggressive warning on the presence of discoid pathology and the need for evaluation on the contralateral knee should be considered during consultation with patients with symptomatic complete DLM in a unilateral knee in the outpatient clinic. PMID- 25837183 TI - Stimulating effect of a novel synthesized sulfonamido-based gallate ZXHA-TC on primary osteoblasts. AB - PURPOSE: This study is intended to investigate the effects of plants or plant derived antioxidants on prevention of osteoporosis through the maintenance of reactive oxygen species (ROS) at a favorable level. MATERIALS AND METHODS: In this study, a novel antioxidant, namely 3,4,5-Trihydroxy-N-[4-(5-hydroxy-6 methoxy-pyrimidin-4-ylsulfamoyl)-phenyl]-benzamide (ZXHA-TC) was synthesized from gallic acid and sulfadimoxine. Its effect on osteoblast metabolism was investigated via the detection of cell proliferation, cell viability, production of ROS, and expression of osteogenic-specific genes including runt-related transcription factor 2 (RUNX2), bone sialoprotein (BSP), osteocalcin (OCN), alpha 1 type I collagen (COL1A1), and osteogenic-related proteins after treatment for 2, 4, and 6 days respectively. RESULTS: The results showed that ZXHA-TC has a stimulating effect on the proliferation and osteogenic differentiation of primary osteoblasts by promoting cell proliferation, cell viability, and the expression of genes BSP and OCN. Productions of bone matrix and mineralization were also increased by ZXHA-TC treatment as a result of up-regulation of COL1A1 and alkaline phosphatase (ALP) at the early stage and down-regulation of both genes subsequently. A range of 6.25*10-3 microg/mL to 6.25*10-1 microg/mL is the recommended dose for ZXHA-TC, within which 6.25*10-2 MUg/mL showed the best performance. CONCLUSION: This study may hold promise for the development of a novel agent for the treatment of osteoporosis. PMID- 25837184 TI - Effect of a sleep aid in analgesia after arthroscopic rotator cuff repair. AB - PURPOSE: The aim of this study was to evaluate the effects and safety of a sleep aid for postoperative analgesia in patients undergoing arthroscopic rotator cuff repair. MATERIALS AND METHODS: Seventy-eight patients were prospectively assigned to either the zolpidem group (multimodal analgesia+zolpidem; 39 patients) or the control group (multimodal analgesia; 39 patients). Self-rated pain levels were assessed twice a day using a visual analog scale (VAS). The need for additional rescue analgesic, duration of functional recovery, and adverse effects were assessed for the first 5 days after surgery. RESULTS: The mean number of times that additional rescue analgesic was required during 5 days after surgery was 2.1+/-2.0 in the zolpidem group and 3.3+/-2.8 in the control group, a significant difference. There were no significant differences between the two groups in mean VAS pain scores during the first 5 days after surgery, although the zolpidem group had lower VAS pain scores than the control group. Additionally, there were no significant differences in duration of functional recovery and adverse effects between the two groups. CONCLUSION: The use of zolpidem for analgesia after arthroscopic rotator cuff repair provided a significant reduction in the need for rescue analgesic without increasing adverse effects. Nevertheless, mean VAS pain scores during the first 5 days after surgery did not differ between the zolpidem group and the control group. PMID- 25837185 TI - Effect of antifreeze protein on mouse ovarian tissue cryopreservation and transplantation. AB - PURPOSE: To investigate the effect of antifreeze protein (AFP) supplementation on ovarian vitrification and transplantation. MATERIALS AND METHODS: In this experimental study, we researched a total of 182 ovaries from 4-week-old ICR mice. The equilibration solution included 20% ethylene glycol (EG), and the vitrification solution included 40% EG, 18% Ficoll, and 0.3 M sucrose. Intact ovaries were first suspended in 1 mL of equilibration solution for 10 min, and then mixed with 0.5 mL of vitrification solution for 5 min. Ovaries were randomly assigned to 3 groups and 0, 5, or 20 mg/mL of type III AFP was added into the vitrification solution (control, AFP5, and AFP20 groups, respectively). The vitrified ovaries were evaluated after warming and 2 weeks after autotransplantation. The main outcome measurements are follicular morphology and apoptosis assessed by histology and the TUNEL assay. RESULTS: A significantly higher intact follicle ratio was shown in the AFP treated groups (control, 28.9%; AFP5, 42.3%; and AFP20, 44.7%). The rate of apoptotic follicles was significantly lower in the AFP treated groups (control, 26.6%; AFP5, 18.7%; and AFP20, 12.6%). After transplantation of the vitrified-warmed ovaries, a significantly higher intact follicle ratio was shown in the AFP20 group. The rate of apoptotic follicles was similar among the groups. CONCLUSION: The results of the present study suggest that supplementing AFP in the vitrification solution has beneficial effects on the survival of ovarian tissue during cryopreservation and transplantation. PMID- 25837186 TI - Triglyceride is a useful surrogate marker for insulin resistance in Korean women with polycystic ovary syndrome. AB - PURPOSE: To evaluate lipid profiles and liver enzymes as surrogate markers used for recognizing insulin resistance in Korean women with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: 458 women with PCOS were divided into two groups: non-obese with a body mass index (BMI)<25.0 kg/m2 and obese with a BMI>=25.0 kg/m2. Anthropometric measures and blood sampling for hormone assay, liver enzymes, lipid profiles and 75 g oral glucose tolerance test were performed. Insulin resistance was defined as homeostasis model assessment of insulin resistance (HOMA-IR)>=2.5. Areas under the receiver operating characteristic (ROC) curves were used to compare the power of serum markers. Multiple linear regression analysis was used to evaluate the contribution of each confounding factor for HOMA-IR. RESULTS: In non-obese and obese groups, the ROC curve analyses demonstrated that the best marker for insulin resistance was triglyceride (TG), with the areas under the ROC curve of 0.617 and 0.837, respectively. Low-density lipoprotein cholesterol (LDL-C) was the significant marker for insulin resistance with areas under the ROC curve of 0.698 in obese group, but not significant in non-obese group. TG and LDL-C were significantly associated with HOMA-IR in both non-obese and obese PCOS women by multiple linear regression analysis. The optimal cut-off points of TG>=68.5 was a marker for predicting insulin resistance in non-obese PCOS patients and TG>=100.5 in obese group. CONCLUSION: TG can be used as a useful marker for insulin resistance in Korean women with PCOS, especially for obese patients. PMID- 25837187 TI - Pregnancy outcomes in women with moyamoya disease: experiences at a single center in Korea. AB - PURPOSE: Moyamoya disease (MMD) occurs predominantly in Korean and Japanese women. The aim of this study was to investigate clinical features and pregnancy outcomes in women with MMD. MATERIALS AND METHODS: We conducted a retrospective chart review of women with MMD who visited our Department of Obstetrics and Gynecology between January 2005 and October 2013. For all study subjects, clinical features, demographic characteristics, and perinatal outcomes were recorded. RESULTS: We identified 28 pregnancies in 22 patients who had been diagnosed with MMD. The mean maternal age at delivery was 31.9+/-3.5 years old. The mean gestational age at delivery was 38.0+/-0.9 weeks. Among the 28 pregnancies, 25 (92.5%) underwent cesarean section; 19 (76.0%) of them were performed under regional anesthesia and six (24.0%) under general anesthesia. The mean newborn weight was 3233.7+/-348.2 g. The 5-minute Apgar score in 85% of the newborns was higher than 8, with no other apparent complications. During the puerperal period, transient ischemic attack symptom or seizure occurred in 4 cases, although patients recovered within a few days. CONCLUSION: For pregnant women with MMD, it is important to control blood pressure and prevent hyperventilation during the intrapartum period, and the best methods of delivery and anesthesia should be considered to avoid unfavorable sequelae. Additionally, a multidisciplinary approach (i.e., neurosurgery) is necessary to constantly manage underlying diseases. PMID- 25837188 TI - The difference of lymphocyte subsets including regulatory T-cells in umbilical cord blood between AGA neonates and SGA neonates. AB - PURPOSE: This study aimed to compare the regulatory T cells in cord blood of appropriate for gestational age (AGA) neonates with those of small for gestational age (SGA) neonates. MATERIALS AND METHODS: Umbilical cord blood was collected upon labor in 108 healthy full-term (between 37 and 41 gestational weeks) neonates, who were born between November 2010 and April 2012. Among them, 77 samples were obtained from AGA neonates, and 31 samples were obtained from SGA neonates. Regulatory T cells and lymphocyte subsets were determined using a flow cytometer. Student's t-test for independent samples was used to compare differences between AGA and SGA neonates. RESULTS: Regulatory T cells in cord blood were increased in the SGA group compared with normal controls (p=0.041). However, cytotoxic T cells in cord blood were significantly decreased in the SGA group compared with normal controls (p=0.007). CONCLUSION: This is the first study to compare the distribution of lymphocyte subsets including regulatory T cells in cord blood between AGA neonates and SGA neonates. PMID- 25837190 TI - Predictors of thyroid gland involvement in hypopharyngeal squamous cell carcinoma. AB - PURPOSE: Decision to perform concurrent ipsilateral thyroidectomy on patients with hypopharyngeal cancer is important, and unnecessary thyroidectomy should be avoided if oncologically feasible. We hypothesized that concurrent ipsilateral thyroidectomy is not routinely required to prevent occult metastasis. This study aimed to determine the prevalence of histological thyroid invasion in patients with hypopharyngeal cancer, and to refine the indications for prophylactic ipsilateral thyroidectomy in patients with hypopharyngeal cancer. MATERIALS AND METHODS: A retrospective review of the medical records from the Department of Otolaryngology at Yonsei University College of Medicine was conducted from January 1994 to December 2009. A total of 49 patients underwent laryngopharyngectomy with thyroidectomy as a primary treatment of hypopharyngeal cancer. RESULTS: The incidence of thyroid gland involvement was 10.2%. The most common route of invasion was direct extension through the thyroid cartilage. Thyroid cartilage invasion (p=0.034) was the most significant factor associated with thyroid invasion. Disease-specific survival at 5 years was lower in patients with than without thyroid gland invasion (26.7% vs. 55.2%, respectively; p=0.032). Disease-free survival at 5 years was also lower in patients with than without thyroid gland invasion (20.0% vs. 52.1%, respectively; p=0.024). CONCLUSION: Ipsilateral thyroidectomy in combination with total laryngopharyngectomy is indicated when invasion of the thyroid cartilage is suspected in patients with hypopharyngeal cancer. PMID- 25837189 TI - Intraocular lens power estimation in combined phacoemulsification and pars plana vitrectomy in eyes with epiretinal membranes: a case-control study. AB - PURPOSE: To evaluate the accuracy of postoperative refractive outcomes of combined phacovitrectomy for epiretinal membrane (ERM) in comparison to cataract surgery alone. MATERIALS AND METHODS: Thirty-nine eyes that underwent combined phacovitrectomy with intraocular lens (IOL) implantation for cataract and ERM (combined surgery group) and 39 eyes that received phacoemulsification for cataract (control group) were analyzed, retrospectively. The predicted preoperative refractive aim was compared with the results of postoperative refraction. RESULTS: In the combined surgery group, refractive prediction error by A-scan and IOLMaster were -0.305+/-0.717 diopters (D) and -0.356+/-0.639 D, respectively, compared to 0.215+/-0.541 and 0.077+/-0.529 in the control group, showing significantly more myopic change compared to the control group (p=0.001 and p=0.002, respectively). Within each group, there was no statistically significant difference in refractive prediction error between A-scan and IOLMaster (all p>0.05). IOL power calculation using adjusted A-scan measurement of axial length based on the macular thickness of the normal contralateral eye still resulted in significant postoperative refractive error (all p<0.05). Postoperative refraction calculated with adjusted axial length based on actual postoperative central foveal thickness change showed the closest value to the actual postoperative achieved refraction (p=0.599). CONCLUSION: Combined phacovitrectomy for ERM resulted in significantly more myopic shift of postoperative refraction, compared to the cataract surgery alone, for both A-scan and IOLMaster. To improve the accuracy of IOL power estimation in eyes with cataract and ERM, sequential surgery for ERM and cataract may need to be considered. PMID- 25837191 TI - Expectorant and antitussive effect of Hedera helix and Rhizoma coptidis extracts mixture. AB - PURPOSE: This study aims to investigate the additive effect of the Hedera helix (HH) and Rhizoma coptidis (RC) extracts mixture on antitussive and expectorant activities in animals. MATERIALS AND METHODS: The expectorant assay was performed with phenol red secretion in mice trachea. Mice or guinea pigs were randomly divided into groups of 8 each, including negative and positive control groups. After gastric administration of the test extracts in mice, 2.5% phenol red solution (0.2 mL) was intraperitoneally injected. Trachea was dissected and optical density of tracheal secretion was measured. After gastric administration of the test extracts in guinea pigs, the antitussive activities were assessed using a citric acid-induced cough measurement. RESULTS: The extracts of HH and RC significantly increased tracheal secretion and inhibited cough. The mixture of HH and RC extracts in a 1:1 concentration at a dose of 200 mg/kg showed a more potent effect on phenol red secretion (25.25+/-3.14) and cough inhibition (61.25+/-5.36) than the individual use of each extracts [phenol red secretion; HH 13.39+/-4.22 (p=0.000), RC 20.78+/-2.50 (p=0.010), cough inhibition; HH 9.89+/ 4.14 (p=0.010), RC 30.25+/-7.69 (p=0.000)]. A 3:1 ratio mixture of HH to RC demonstrated an optimal expectorant effect (p<0.001), and this mixture showed expectorant and antitussive effects in a dose-dependent manner. CONCLUSION: This study provides evidence for antitussive and expectorant effect of a 3:1 mixture of HH and RC, which may be a useful therapeutic option for respiratory diseases. PMID- 25837192 TI - Hypoxia increases epithelial permeability in human nasal epithelia. AB - PURPOSE: The nasal mucosa is the first site to encounter pathogens, and it forms continuous barriers to various stimuli. This barrier function is very important in the innate defense mechanism. Additionally, inflammation of the nasal sinus is known to be a hypoxic condition. Here, we studied the effect of hypoxia on barrier function in normal human nasal epithelial (NHNE) cells. MATERIALS AND METHODS: The expression levels of various junction complex proteins were assessed in hypoxia-stimulated NHNE cells and human nasal mucosal tissues. We performed real-time polymerase chain reaction analysis, western blotting, and immunofluorescence assays to examine differences in the mRNA and protein expression of ZO-1, a tight junction protein, and E-cadherin in NHNE cells. Moreover, we evaluated the trans-epithelial resistance (TER) of NHNE cells under hypoxic conditions to check for changes in permeability. The expression of ZO-1 and E-cadherin was measured in human nasal mucosa samples by western blotting. RESULTS: Hypoxia time-dependently decreased the expression of ZO-1 and E-cadherin at the gene and protein levels. In addition, hypoxia decreased the TER of NHNE cells, which indicates increased permeability. Human nasal mucosa samples, which are supposed to be hypoxic, showed significantly decreased levels of ZO-1 and E cadherin expression compared with control. CONCLUSION: Our results demonstrate that hypoxia altered the expression of junction complex molecules and increased epithelial permeability in human nasal epithelia. This suggests that hypoxia causes barrier dysfunction. Furthermore, it may be associated with innate immune dysfunction after encountering pathogens. PMID- 25837193 TI - Sparing effects of sufentanil on epidural ropivacaine in elderly patients undergoing transurethral resection of prostate surgery. AB - PURPOSE: This study examined the sparing effect of sufentanil on the median effective concentration (EC50) of epidural ropivacaine in elderly patients undergoing elective transurethral resection of prostate (TURP). MATERIALS AND METHODS: This was a prospective randomized double-blind dose-response study. Fifty eight elderly patients with American Society of Anesthesiologists physical status I-II who were scheduled for TURP surgery under epidural anesthesia were randomly allocated to a group receiving 15 mL of ropivacaine (group R) or a group receiving ropivacaine plus 5 MUg of sufentanil (group RS). The concentration of ropivacaine was determined by a Dixon's up-and-down sequential allocation. The first participant received 0.3% of ropivacaine in both groups and subsequent concentrations were determined by the response of the previous patient in the same group. The EC50 of epidural ropivacaine was analyzed using the Dixon and Massey method. RESULTS: The EC50 of ropivacaine during TURP surgery was 0.186% (95% confidence interval, 0.173-0.200%) in group R, and 0.136% (95% confidence interval, 0.127-0.144%) in group RS (p<0.01). No differences in Bromage scale of motor block examination and the onset time of sensory block were observed. CONCLUSION: Administration of 5 MUg of epidural sufentanil caused a 37% reduction in the EC50 of epidural ropivacaine in elderly patients who underwent TURP surgery. Thus, sufentanil addition during surgery of TURP can decrease the dose of ropivacaine anesthesia required. PMID- 25837194 TI - Comparison of ultrasound-guided axillary brachial plexus block techniques: perineural injection versus single or double perivascular infiltration. AB - PURPOSE: We compared three methods of ultrasound-guided axillary brachial plexus block, which were single, and double perivascular (PV) infiltration techniques, and a perineural (PN) injection technique. MATERIALS AND METHODS: 78 patients of American Society of Anesthesiologists physical status I-II undergoing surgery of the forearm, wrist, or hand were randomly allocated to three groups. 2% lidocaine with epinephrine 5 MUg/mL was used. The PN group (n=26) received injections at the median, ulnar, and radial nerve with 8 mL for each nerve. The PV1 group (n=26) received a single injection of 24 mL at 12-o'clock position of the axillary artery. The PV2 group (n=26) received two injections of 12 mL each at 12 o'clock and 6-o'clock position. For all groups, musculocutaneous nerve was blocked separately. RESULTS: The PN group (391.2+/-171.6 sec) had the longest anesthetic procedure duration than PV1 (192.8+/-59.0 sec) and PV2 (211.4+/-58.6 sec). There were no differences in onset time. The average induction time was longer in PN group (673.4+/-149.6 sec) than PV1 (557.6+/-194.9 sec) and PV2 (561.5+/-129.8 sec). There were no differences in the success rate (89.7% vs. 86.2% vs. 89.7%). CONCLUSION: The PV injection technique consisting of a single injection in 12-o'clock position above the axillary artery in addition to a musculocutaneous nerve block is equally effective and less time consuming than the PN technique. Therefore, the PV technique is an alternative method that may be used in busy clinics or for difficult cases. PMID- 25837195 TI - Dietary calcium and Framingham Risk Score in vitamin D deficient male (KNHANES 2009-2011). AB - PURPOSE: The association between excess calcium intake and cardiovascular mortality has already been reported. In the present study, we investigated the relation between dietary calcium intake and Framingham Risk Score (FRS) according to serum 25-hydroxyvitamin D [25(OH)D] status. MATERIALS AND METHODS: A total of 7809 subjects (3452 males and 4357 female) aged over 40 years were selected for this cross-sectional study from data obtained from the Korea National Health and Nutrition Examination Survey (2008-2011). Daily dietary calcium intake was categorized into <300, 300-600, 600-900, 900-1200, and >1200 mg/day and serum 25(OH)D concentration classified into <50, 50-75, >75 mmol/L. The FRS was compared by the daily dietary calcium intake categories according to 25(OH)D concentration after adjustment with relevant variables in both genders. RESULTS: Higher FRS was observed in males with both <300 mg and >1200 mg of dietary calcium intake and females with <300 mg of dietary calcium intake without adjustment. The significantly higher FRS remained in the <300 mg and >1200 mg of dietary calcium intake groups in both genders after adjustments for relevant variables. FRS was significantly higher in the group with >1200 mg of dietary calcium intake and serum 25(OH)D <50 nmol/L, which was the male only vitamin D deficient group. CONCLUSION: Very low (<300 mg/day) and excess (>1200 mg/day) dietary calcium intake were related with higher FRS in both genders. In particular, higher FRS was observed in the excess (>1200 mg/day) dietary calcium intake male group under vitamin D deficiency (<50 nmol/L). PMID- 25837196 TI - Mortality, length of stay, and inpatient charges for heart failure patients at public versus private hospitals in South Korea. AB - PURPOSE: This study compared in-hospital mortality within 30 days of admission, lengths of stay, and inpatient charges among patients with heart failure admitted to public and private hospitals in South Korea. MATERIALS AND METHODS: We obtained health insurance claims data for all heart failure inpatients nationwide between November 1, 2011 and May 31, 2012. These data were then matched with hospital-level data, and multi-level regression models were examined. A total of 8406 patients from 253 hospitals, including 31 public hospitals, were analyzed. RESULTS: The in-hospital mortality rate within 30 days of admission was 0.92% greater and the mean length of stay was 1.94 days longer at public hospitals than at private hospitals (mortality: 5.18% and 4.26%, respectively; LOS: 12.08 and 10.14 days, respectively). The inpatient charges were 11.4% lower per case and 24.5% lower per day at public hospitals than at private hospitals. After adjusting for patient- and hospital-level confounders, public hospitals had a 1.62-fold higher in-hospital mortality rate, a 16.5% longer length of stay, and an 11.7% higher inpatient charge per case than private hospitals, although the charges of private hospitals were greater in univariate analysis. CONCLUSION: We recommend that government agencies and policy makers continue to monitor quality of care, lengths of stay in the hospital, and expenditures according to type of hospital ownership to improve healthcare outcomes and reduce spending. PMID- 25837197 TI - Jak1/Stat3 is an upstream signaling of NF-kappaB activation in Helicobacter pylori-induced IL-8 production in gastric epithelial AGS cells. AB - Helicobacter pylori (H. pylori) induces the activation of nuclear factor-kB (NF kappaB) and cytokine expression in gastric epithelial cells. The Janus kinase/signal transducers and activators of transcription (Jak/Stat) cascade is the inflammatory signaling in various cells. The purpose of the present study is to determine whether H. pylori-induced activation of NF-kappaB and the expression of interleukin-8 (IL-8) are mediated by the activation of Jak1/Stat3 in gastric epithelial (AGS) cells. Thus, gastric epithelial AGS cells were infected with H. pylori in Korean isolates (HP99) at bacterium/cell ratio of 300:1, and the level of IL-8 in the medium was determined by enzyme-linked immonosorbent assay. Phospho-specific and total forms of Jak1/Stat3 and IkappaBalpha were assessed by Western blot analysis, and NF-kappaB activation was determined by electrophoretic mobility shift assay. The results showed that H. pylori induced the activation of Jak1/Stat3 and IL-8 production, which was inhibited by a Jak/Stat3 specific inhibitor AG490 in AGS cells in a dose-dependent manner. H. pylori-induced activation of NF-kappaB, determined by phosphorylation of IkappaBalpha and NF kappaB-DNA binding activity, were inhibited by AG490. In conclusion, Jak1/Stat3 activation may mediate the activation of NF-kappaB and the expression of IL-8 in H. pylori-infected AGS cells. Inhibition of Jak1/Stat3 may be beneficial for the treatment of H. pylori-induced gastric inflammation, since the activation of NF kappaB is inhibited and inflammatory cytokine expression is suppressed. PMID- 25837198 TI - Metallic foreign body in heart mimicking moderator band. AB - A foreign body in heart is rare, but it is more frequently encountered than the past as iatrogenic causes are increasing. Clinicians should be aware that foreign body could be mistaken for normal structure of heart. In order for accurate diagnosis, multi-imaging modalities should be used for information of exact location, mobility and hemodynamic effects. A decision to intervene should be made based on potential harms harbored by foreign bodies. Endovascular retrieval should be considered as an option. However, when fatal complications occur or when foreign bodies are embedded deeply, a surgical removal should be attempted. PMID- 25837199 TI - Chronic cavitary pulmonary histoplasmosis in a non-HIV and immunocompromised patient without overseas travel history. AB - Korea is not known as an endemic area for Histoplasma. However, we experienced a case of histoplasmosis in a person who had never been abroad. A 65-year-old female was admitted to the hospital for evaluation of multiple lung nodules. A computed tomography (CT) scan of the chest showed multiple ill-defined consolidations and cavitations in all lobes of both lungs. The patient underwent a CT-guided lung biopsy, and a histopathology study showed findings compatible with histoplasmosis. Based on biopsy results and clinical findings, the patient was diagnosed with chronic cavitary pulmonary histoplasmosis. The patient recovered completely following itraconazole treatment. This is the first case report of pulmonary histoplasmosis unconnected with either HIV infection or endemicity in Korea. PMID- 25837200 TI - Erratum to "Optimal effect-site concentration of remifentanil for inhibiting response to laryngeal mask airway removal during emergence" by Park SJ, et al. (Yonsei Med J 2015;56:529-34). PMID- 25837201 TI - Climate change impacts on environmental and human exposure to mercury in the arctic. AB - This paper reviews information from the literature and the EU ArcRisk project to assess whether climate change results in an increase or decrease in exposure to mercury (Hg) in the Arctic, and if this in turn will impact the risks related to its harmful effects. It presents the state-of-the art of knowledge on atmospheric mercury emissions from anthropogenic sources worldwide, the long-range transport to the Arctic, and it discusses the likely environmental fate and exposure effects on population groups in the Arctic under climate change conditions. The paper also includes information about the likely synergy effects (co-benefits) current and new climate change polices and mitigation options might have on mercury emissions reductions in the future. The review concludes that reductions of mercury emission from anthropogenic sources worldwide would need to be introduced as soon as possible in order to assure lowering the adverse impact of climate change on human health. Scientific information currently available, however, is not in the position to clearly answer whether climate change will increase or decrease the risk of exposure to mercury in the Arctic. New research should therefore be undertaken to model the relationships between climate change and mercury exposure. PMID- 25837202 TI - Integrating environmental and human health databases in the great lakes basin: themes, challenges and future directions. AB - Many government, academic and research institutions collect environmental data that are relevant to understanding the relationship between environmental exposures and human health. Integrating these data with health outcome data presents new challenges that are important to consider to improve our effective use of environmental health information. Our objective was to identify the common themes related to the integration of environmental and health data, and suggest ways to address the challenges and make progress toward more effective use of data already collected, to further our understanding of environmental health associations in the Great Lakes region. Environmental and human health databases were identified and reviewed using literature searches and a series of one-on-one and group expert consultations. Databases identified were predominantly environmental stressors databases, with fewer found for health outcomes and human exposure. Nine themes or factors that impact integration were identified: data availability, accessibility, harmonization, stakeholder collaboration, policy and strategic alignment, resource adequacy, environmental health indicators, and data exchange networks. The use and cost effectiveness of data currently collected could be improved by strategic changes to data collection and access systems to provide better opportunities to identify and study environmental exposures that may impact human health. PMID- 25837203 TI - A potential synergy between incomplete arsenic methylation capacity and demographic characteristics on the risk of hypertension: findings from a cross sectional study in an arsenic-endemic area of inner Mongolia, China. AB - Inefficient arsenic methylation capacity has been associated with various health hazards induced by arsenic. In this study, we aimed to explore the interaction effect of lower arsenic methylation capacity with demographic characteristics on hypertension risk. A total of 512 adult participants (126 hypertension subjects and 386 non-hypertension subjects) residing in an arsenic-endemic area in Inner Mongolia, China were included. Urinary levels of inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured for all subjects. The percentage of urinary arsenic metabolites (iAs%, MMA%, and DMA%), primary methylation index (PMI) and secondary methylation index (SMI) were calculated to assess arsenic methylation capacity of individuals. Results showed that participants carrying a lower methylation capacity, which is characterized by lower DMA% and SMI, have a higher risk of hypertension compared to their corresponding references after adjusting for multiple confounders. A potential synergy between poor arsenic methylation capacity (higher MMA%, lower DMA% and SMI) and older age or higher BMI were detected. The joint effects of higher MMA% and lower SMI with cigarette smoking also suggest some evidence of synergism. The findings of present study indicated that inefficient arsenic methylation capacity was associated with hypertension and the effect might be enhanced by certain demographic factors. PMID- 25837204 TI - Cholesterol overload impairing cerebellar function: the promise of natural products. AB - The cerebellum is the part of the brain most involved in controlling motor and cognitive function. The surface becomes convoluted, forming folia that have a characteristic internal structure of three layers including molecular, Purkinje cell, and granular layer. This complex neural network gives rise to a massive signal-processing capability. Cholesterol is a major constituent, derived by de novo synthesis and the blood-brain barrier. Cholesterol is tightly regulated between neurons and glia-that is, astrocytes, microglia, and oligodendrocytes-and is essential for normal brain development. The axon is wrapped by myelin (cholesterol, phospholipids, and glycosphingolipids) and made up of membranes of oligodendrocytes, separated by periodic gaps in the myelin sheath, called nodes of Ranvier. Hypercholesterolemia is associated with increased oxidative stress and the development of neurotoxicity and Alzheimer's disease. Treatment with natural products has been found to support improved brain function and reduce low density-lipoprotein cholesterol level. Fish oil is one such product; among the many plant products are: Morus alba leaves, fruit, and bark; pomegranate fruit and peel; Barley beta - glucans; date palm; and Allium sativum. The therapeutic potential was discussed in relation with the antilipidemic drugs, statins (HMG CoA reductase inhibitors). PMID- 25837205 TI - Effects of non-soy legume consumption on C-reactive protein: a systematic review and meta-analysis. AB - OBJECTIVES: Because of conflicting results of presented studies, the aim of this systematic review and meta-analysis of randomized clinical trials (RCTs) was to examine the effect of non-soy legume intake on inflammatory markers and C reactive protein (CRP). METHODS: We searched Pubmed, ISI Web of Knowledge, SCOPUS, and Google Scholar for relevant studies up to July 2013, using medical subject headings [MeSH] and other related keywords. Nine RCTs were systematically reviewed to examine the effect of non-soy legume consumption on inflammatory markers. Eight studies involving 464 participants were included in the meta analysis. RESULTS: The results of the meta-analysis showed that non-soy legume consumption had a trend toward a significant effect on decreasing CRP and high sensitivity (hs)-CRP concentrations (mean difference (MD) = -0.21; 95% confidence interval [CI], -0.44 to 0.02; P = 0.068). There was no overall effect of non-soy legume consumption on CRP or hs-CRP levels in either the parallel or crossover study designs. Our subgroup analysis of CRP type and study design, showed that non-soy legume intake had a significant effect on CRP levels in parallel studies (MD = -1.01; 95% CI, -1.78 to -0.23; P = 0.011) and a significant effect on hs CRP levels (MD = -0.53; 95% CI, -0.95 to -0.11; P = 0.014) and in the crossover sub group (MD = -0.68; 95% CI, -1.28 to -0.08; P = 0.026). CONCLUSIONS: This review of RCTs showed that non-soy legume consumption may contribute to reductions in CRP and hs-CRP concentrations. However, further controlled clinical trials are needed to investigate the effect of non-soy legume intake on other inflammatory markers. PMID- 25837206 TI - The effect of cactus pear (Opuntia ficus-indica) on body weight and cardiovascular risk factors: a systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVES: Hundreds of dietary supplements are currently marketed as weight loss supplements. However, the advertised health claims of effectiveness for most of these have not been proven. The aim of this study was to critically appraise and evaluate the evidence for effectiveness of cactus pear, Opuntia ficus-indica (OFI), using data from published randomized clinical trials. METHODS: We conducted electronic searches in Medline, Embase, Amed, Cinahl, and the Cochrane Library. No restrictions on age, time, or language were imposed. The risk for bias in the studies included was assessed using the Cochrane Collaboration criteria. Two reviewers independently determined the eligibility of included studies, assessed reporting quality, and extracted data. RESULTS: We identified seven eligible studies, of which five were included. The studies varied in design and reporting quality. Meta-analysis revealed a nonsignificant difference in body weight between OFI and controls (mean difference = -0.83 kg; 95% confidence interval, -2.49 to 0.83; I(2) = 93%). Significant reductions in body mass index, percentage body fat, systolic and diastolic blood pressures, and total cholesterol were observed. Adverse events included gastric intolerance and flu symptoms. CONCLUSION: The evidence from randomized clinical trials does not indicate that supplementation with OFI generates statistically significant effects on body weight. Consumption of OFI can cause significant reductions in percentage body fat, blood pressure, and total cholesterol. Few clinical trials evaluating the effects of OFI have been published. They vary in design and methodology, and are characterized by inconsistent quality of reporting. Further clinical trials evaluating the effects of OFI on body composition and metabolic parameters are warranted. PMID- 25837207 TI - Switching to a 10-day Mediterranean-style diet improves mood and cardiovascular function in a controlled crossover study. AB - OBJECTIVES: Even short-term adherence to a Mediterranean-style diet may benefit aspects of psychological functioning. The aim of the present study was to assess the effects of switching to a 10-d Mediterranean-style diet on mood, cognition, and cardiovascular measures. METHODS: Using a crossover design, 24 women were randomly assigned to either the diet change (where they switched to a Mediterranean-style diet) or no diet change (normal diet) condition for 10 days before switching to the other condition for the same duration. Mood, cognition, and cardiovascular measures of blood pressure, blood flow velocity, and arterial stiffness were assessed at baseline and at the completion of the two diets (days 11 and 22). RESULTS: Independent of whether the Mediterranean-style diet was undertaken before or after the crossover, it was associated with significantly elevated contentment and alertness, and significantly reduced confusion. Additionally, aspects of cognition, such as memory recall, improved significantly as a result of switching to the Mediterranean-style diet. Regarding cardiovascular measures, there was a significant reduction in augmentation pressure associated with the Mediterranean-style diet intervention, but blood flow velocity through the common carotid artery did not change. CONCLUSIONS: This Mediterranean-style diet has the potential to enhance aspects of mood, cognition, and cardiovascular function in a young, healthy adult sample. PMID- 25837208 TI - Association between the APOB rs1469513 polymorphism and obesity is modified by dietary fat intake in Koreans. AB - OBJECTIVE: The apolipoprotein B (APOB) gene has been reported to be a candidate gene for individual susceptibility to dyslipidemia and obesity. The aim of this study was to investigate the effect of the APOB rs1469513 polymorphism on plasma lipid profiles and obesity-related phenotypes, together with their modulation by dietary intake in Korean individuals. METHODS: We analyzed the plasma lipid profiles, obesity-related phenotypes, and dietary intake of 6470 Korean aged 40 to 59 y from the KoGES (Korean Genome Epidemiology Study) database. The effects of APOB rs1469513 on traits, the interaction of APOB rs1469513 and dietary intake on traits were analyzed. RESULTS: Plasma levels of total cholesterol (P = 0.001) and low-density lipoprotein cholesterol (P = 0.010), body weight (P = 0.048), and body mass index (P = 0.029) were significantly different in carriers of the A allele and minor G allele of APOB rs1469513. Among individuals whose fat intake was above the median, the difference for the body mass index across genotypes is 1.14% (AA 24.66 kg/m(2) versus AG+GG 24.94 kg/m(2), P = 0.004) and carriers of the minor G allele had increased odds of being obese (Odds ratios, 1.31; 95% confidence interval, 1.09-1.57; P = 0.004) compared with homozygotes for the A allele. CONCLUSIONS: Our findings support a significant association between the APOB rs1469513 variant, plasma lipid profiles, and obesity-related phenotypes. This association has the potential to be modified by dietary fat intake. These results may offer proof that the differences between normal weight and overweight/obese individuals might partly result from different SNPs. PMID- 25837209 TI - Vitamin D deficiency and inadequacy in a correctional population. AB - OBJECTIVES: Adequate nutrition among inmates at correctional facilities may prevent a variety of diseases and conditions. Vitamin D is a nutrient of particular interest to incarcerated populations; however, research in this area is sparse. Therefore, the aim of this study was to assess vitamin D status among inmates in a prison in southern Arizona, a sun-replete region of the United States. METHODS: We conducted a cross-sectional study of circulating concentrations of 25-hydroxycholecalciferol [25(OH)D] among short-term (group 1; <6 wk; n = 29) and long-term (group 2; >1 y; n = 30) inmates at The Fourth Avenue Jail in Maricopa County (Phoenix) Arizona. RESULTS: The long-term inmates in group 2 had statistically significantly lower levels of 25(OH)D (13.9 +/- 6.3 ng/mL) compared with group 1 (25.9 +/- 12.4; P < 0.0001). Defining vitamin D deficiency as circulating concentrations of 25(OH)D < 20 ng/mL, 37.9% of inmates in group 1 and 90% of those in group 2 were deficient. After adjusting for body mass index and age, the odds ratio (95% confidence interval) for deficiency in group 2 was 18.7 (4.1-84.9) compared with group 1. CONCLUSIONS: This study demonstrates the presence of vitamin D deficiency at the Fourth Avenue Jail in Maricopa County, Arizona, particularly among inmates who have been housed at the facility for >1 y. Because marked vitamin D deficiency is associated with a myriad of adverse health outcomes, consideration should be given to providing dietary or supplemental vitamin D to inmates at correctional facilities. PMID- 25837211 TI - The personal nutrition-related attitudes and behaviors of Australian optometrists: is there evidence for an evidence-based approach? AB - OBJECTIVE: The aim of this study was to investigate the personal nutrition related attitudes and behaviors of Australian optometrists and, in particular, their understanding of the evidence relating to the merit of specific dietary supplements, as applicable to their own health. METHODS: An online survey was distributed to optometrists registered in Australia (N = 4242). Respondents anonymously provided information regarding their demographic characteristics (age, sex, practice location and modality), diet and lifestyle behaviors (assessment of self-perceived diet quality, smoking status), and nutritional supplement intake (including the rationale for consumption). RESULTS: Completed surveys were received from 283 practitioners. Although most respondents considered themselves to eat a healthy, balanced diet, approximately 75% indicated taking nutritional supplements in the preceding year. The four most common supplements were fish oil/omega-3 (62%), multivitamins (54%), vitamin C (30%), and vitamin D (29%). In addition to vitamin D, which was typically recommended by a general medical practitioner for an established deficiency, the other three supplement categories were consumed on the basis of the respondents' self-assessment and decision. Analyses of the motivations for taking these supplements highlighted a significant misunderstanding of the evidence; furthermore, these practitioners appeared to base their personal behaviors on this misinterpretation. CONCLUSIONS: These findings demonstrate scope for optometrists to enhance their critical thinking and/or understanding of the available evidence relating to the merit, or otherwise, of nutritional supplementation in managing their own health, and more broadly, improving their understanding of what a healthy diet is and its role in eye health. PMID- 25837210 TI - Vitamin A and retinol-binding protein deficiency among chronic liver disease patients. AB - OBJECTIVE: Vitamin A deficiency (VAD) is associated with the progression of chronic liver disease (CLD). The aim in this study was to assess levels of serum retinol and retinol-binding protein (RBP) as well as liver vitamin A stores in the presence of liver cirrhosis and hepatocellular carcinoma. METHODS: We ascertained the serum retinol and RBP levels of randomly selected CLD patients divided into two groups, one given 1500 UI (n = 89) and the other receiving 2500 UI (n = 89) doses of retinyl palmitate for the relative dose response test. Blood samples were collected in a fasting state and 5 and 7 h after supplementation. RESULTS: The prevalence of VAD was 62.4%. There was a progressive drop in serum retinol (P < 0.001) and RBP (P = 0.002) according to the severity of the liver disease, and a greater prevalence of severe VAD was noted in cirrhosis Child & Pugh C (52.8%). Fifty percent of the patients presented a low availability of RBP relative to retinol concentration, and there was no peak in RBP levels regardless of the dose of retinyl palmitate administered. CONCLUSIONS: Our findings suggest serum retinol and RBP are relevant as indicators of vitamin A nutritional status in the presence of CLD. Liver vitamin A store cannot be evaluated using the RDR test because CLD causes a reduction in RBP synthesis and interferes with the mobilization of endogenous vitamin A. Considering how the patients already showed a drop in RBP relative to retinol concentrations, it is reasonable to assume vitamin A supplementation may trigger harmful effects in CLD patients. PMID- 25837212 TI - Effect of pistachio nut consumption on endothelial function and arterial stiffness. AB - OBJECTIVES: Previous studies have demonstrated beneficial effects of regular consumption of pistachio nuts on glycemic, lipid, and oxidative stress parameters. The aim of this study was to determine its effect on vascular health, which has not been adequately studied so far. METHODS: In this open label, randomized parallel-group study, 60 adults with mild dyslipidemia were randomized to lifestyle modification (LSM) alone or LSM with consumption of 80 g (in-shell) pistachios (equivalent to 40 g or 1.5 oz shelled pistachios) daily for 3 mo. Biochemical parameters, brachial artery flow-mediated vasodilation (BAFMD), and carotid-femoral and brachial-ankle pulse wave velocity (cfPWV and baPWV, respectively) were measured before and after the intervention. RESULTS: At 3 mo, there was no change in any of the clinical or biochemical parameters in the LSM group. However, the patients in the pistachio group had a significant increase in high-density lipoprotein cholesterol (HDL-C; 35.7 +/- 8.8 mg/dL versus 37.8 +/- 10.1 mg/dL; P = 0.04) and a reduction in low-density lipoprotein cholesterol (137.2 +/- 32.6 mg/dL versus 127.6 +/- 34.0 mg/dL; P = 0.02), total cholesterol (TC)-to-HDL-C ratio (5.8 +/- 1.3 mg/dL versus 5.3 +/- 1.1 mg/dL; P = 0.001), and fasting blood sugar (88.8 +/- 7.1 mg/dL versus 86.6 +/- 6.3 mg/dL; P = 0.05). Additionally, whereas LSM alone was associated with no improvement in BAFMD or PWV, individuals in the pistachio group had significant reduction in left baPWV (1261.7 +/- 187.5 cm/sec versus 1192.4 +/- 152.5 cm/sec; P = 0.02) and statistically nonsignificant improvement in most other parameters, including BAFMD. As a result, at 3 mo the patients in the pistachio group had lower cfPWV (770.9 +/- 96.5 cm/sec versus 846.4 +/- 162.0 cm/sec; P = 0.08), lower left baPWV (1192.4 +/- 152.5 cm/sec versus 1326.3 +/- 253.7 cm/sec; P = 0.05), and lower average baPWV (1208.2 +/- 118.4 cm/sec versus 1295.8 +/- 194.1 cm/sec; P = 0.08) compared with the LSM group. Two-way analysis of variance revealed significant treatment effect of pistachio consumption on cfPWV, left baPWV, average baPWV, and BAFMD (P = 0.037, 0.01, 0.07, and 0.046, respectively). CONCLUSIONS: The present study demonstrates that regular consumption of pistachio nuts not only improves glycemic and lipid parameters, but also results in improvements in vascular stiffness and endothelial function. Importantly, these improvements were seen in apparently healthy individuals and with a diet (including pistachios) and exercise regimen that every adult individual is expected to follow. PMID- 25837213 TI - Dietary intake of minerals in relation to depressive symptoms in Japanese employees: the Furukawa Nutrition and Health Study. AB - OBJECTIVE: Although intake of minerals has been suggested to be beneficial against depression, epidemiologic data from free-living settings are limited. The aim of this study was to determine the cross-sectional associations between the intake of magnesium, calcium, iron, and zinc and the prevalence of depressive symptoms in Japanese employees. METHODS: Participants were 1792 men and 214 women ages 19 to 69 y. Dietary intake was assessed using a validated, brief self administered diet history questionnaire. Participants with depressive symptoms were defined as those with a scale score of >=16 on the Center for Epidemiologic Studies Depression Scale. RESULTS: The prevalence of depressive symptoms was 27.8%. Intakes of magnesium, calcium, iron, and zinc were inversely associated with the prevalence of depressive symptoms. The multivariate adjusted odds ratios (95% confidence interval) of having depressive symptoms were 0.63 (0.44-0.91), 0.64 (0.47-0.88), 0.59 (0.40-0.87), and 0.63 (0.45-0.87) in the highest versus lowest tertiles of magnesium, calcium, iron, and zinc, respectively. CONCLUSION: Results suggest that higher dietary intake of magnesium, calcium, iron, and zinc is associated with lower prevalence of depressive symptoms in Japanese employees. PMID- 25837214 TI - Tomato juice supplementation in young women reduces inflammatory adipokine levels independently of body fat reduction. AB - OBJECTIVES: Lycopene is a carotene and phytochemical known to protect against metabolic diseases. It is found in red fruits and vegetables, predominantly tomatoes. This study aimed to show the supplementation effect of tomato juice on indices associated with metabolic health and adipokine profiles in generally healthy people. METHODS: A total of 30 young females (20- to 30-years-old) with a body mass index (BMI) >= 20 were recruited, of whom 25 completed the entire study. The subjects continued with their normal diet and exercise schedule, but were given 280 mL of tomato juice (containing 32.5 mg of lycopene) daily for 2 mo. Metabolic indices, including anthropometric data and serum levels of glucose, lipids, adipokines, lycopene, and antioxidants, were compared pre- and postintervention. RESULTS: Tomato juice supplementation significantly reduced body weight, body fat, waist circumference, BMI, and serum levels of cholesterol, monocyte chemoattractant protein-1 (MCP-1), and thiobarbituric reactive substances, while significantly increasing serum levels of adiponectin, triglyceride, and lycopene. When subjects were stratified by body fat change, i.e., reduction or non-reduction (including increase or no change), the tomato juice-induced reduction in waist circumference, serum cholesterol, and MCP-1 levels and increase in adiponectin and lycopene levels were seen in both subgroups. The changes in waist circumference, cholesterol, MCP-1, and adiponectin levels remained significant after adjusting for each covariable individually, with the exception of lycopene. CONCLUSIONS: These results show that daily tomato juice supplementation reduces waist circumference, as well as serum cholesterol and inflammatory adipokine levels in young healthy women and that these effects are unrelated to body fat changes. PMID- 25837215 TI - Association of dietary acid load with cardiovascular disease risk factors in patients with diabetic nephropathy. AB - OBJECTIVE: An association between dietary acid load and cardiovascular disease risk has been reported in epidemiologic studies; however, there are no reports to our knowledge of this association in patients with diabetic nephropathy (DN). Therefore, the aim of this study was to examine the association between dietary acid load, based on potential renal acid load (PRAL) and protein:potassium ratio (Pro:K) scores, and cardiovascular disease risk factors in individuals with DN. METHODS: In this cross-sectional study, we randomly enrolled 547 patients with DN. Dietary intake was assessed using a validated food frequency questionnaire. Biochemical and anthropometric measures were assessed using standard methods. RESULTS: Participants had a mean age of 66.8 y and body mass index of 24 kg/m(2). After controlling for potential confounders, participants in the low PRAL group had lower hemoglobin (Hb)A1c (5.7% +/- 0.5% versus 7.8% +/- 0.5%; P = 0.01), triacylglycerols (246.9 +/- 2.3 mg/dL versus 257.4 +/- 2.3 mg/dL; P = 0.006), systolic blood pressure (103.6 +/- 0.7 mm Hg versus 106.1 +/- 0.7 mm Hg; P = 0.03), and lower creatinine and fasting blood sugar compared with the high PRAL group. Pro:K was positively related to HbA1c (5.8% +/- 0.5% versus 7.6% +/- 0.5%; P = 0.03), but inversely associated with low-density lipoprotein and waist circumference. CONCLUSIONS: We found that both PRAL and Pro:K were positively related to HbA1c in the setting of DN, whereas other biochemical and kidney related markers varied with PRAL and Pro:K status. Future studies are warranted to clarify the clinical outcomes of dietary acid load in older populations as well as in patients with chronic kidney disease. PMID- 25837216 TI - Effects of ginger on serum glucose, advanced glycation end products, and inflammation in peritoneal dialysis patients. AB - OBJECTIVE: The aim of this study was to investigate the effects of ginger supplementation on serum glucose, advanced glycation end products, oxidative stress, and systemic and vascular inflammatory markers in patients on peritoneal dialysis (PD). METHODS: In this randomized, double-blind, placebo-controlled trial, 36 patients on PD were randomly assigned to either the ginger or the placebo group. The patients in the ginger group received 1000 mg/d ginger for 10 wk, whereas the placebo group received corresponding placebos. At baseline and the end of week 10, serum concentrations of glucose, carboxymethyl lysine, pentosidine, malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule type 1 (sICAM-1), soluble vascular cell adhesion molecule type 1 (sVCAM-1), and sE-selectin were measured after a 12- to 14-h fast. RESULTS: Serum fasting glucose decreased significantly up to 20% in the ginger group at the end of week 10 compared with baseline (P < 0.05), and the reduction was significant in comparison with the placebo group (P < 0.05). There were no significant differences between the two groups in mean changes of serum carboxymethyl lysine, pentosidine, MDA, hs-CRP, sICAM-1, sVCAM-1, and sE selectin. CONCLUSION: This study indicated that daily administration of 1000 mg ginger reduces serum fasting glucose, which is a risk factor for hyperinsulinemia, dyslipidemia, peritoneal membrane fibrosis, and cardiovascular disease, in patients on PD. PMID- 25837217 TI - Dietary contributors to glycemic load in the REasons for Geographic and Racial Differences in Stroke study. AB - OBJECTIVE: High dietary glycemic load (GL) has been associated with an increased risk for chronic diseases, including type 2 diabetes, coronary heart disease, and selected cancers. The aim of this study was to identify the main food and food group contributors to dietary GL in a representative sample of US adults to inform future interventions. METHODS: Participants were from the REGARDS (REasons for Geographic and Racial Differences in Stroke) study, a longitudinal cohort of 30 239 community-dwelling black and white women and men ages >=45 y from throughout the United States. Diet was assessed with a food frequency questionnaire. The amount of each carbohydrate food, and its glycemic index, were used to calculate GL values for each carbohydrate food reported. These were totaled to estimate the mean total daily GL for each participant. Individual carbohydrate foods also were collapsed into 18 carbohydrate food groups, and the portion of the total GL contributed by each carbohydrate food and food group was determined. Analyses were conducted overall, by race/sex groups, and by region. RESULTS: Sweetened beverages were the main contributors to GL overall (12.14 median percentage [median %] of daily GL), by far the largest contributors in black men (17.79 median %) and black women (16.43 median %), and major contributors in white men (12.02 median %) and white women (11.22 median %). Other important contributors to GL overall and in all race/sex groups and regions included breads, starchy side dishes, and cereals. CONCLUSIONS: In this US cohort of white and black adults, sweetened beverages were major contributors to GL overall, especially in black participants. This information may help to inform future interventions targeting reduction in dietary GL. PMID- 25837218 TI - Dairy consumption is associated with a lower prevalence of metabolic syndrome among young adults from Ribeirao Preto, Brazil. AB - OBJECTIVE: It has been suggested that a greater dairy consumption is a contributing factor to a lower prevalence of metabolic syndrome (MetS) as a result of the possible actions of some milk nutrients. However, results remain controversial. The aim of this study was to examine the association between dairy consumption and MetS and its components. METHODS: Dairy consumption and biochemical and anthropometric parameters were determined in 2031 young adults ages 23 to 25 y. Food consumption was assessed using a food frequency questionnaire. The estimated habitual portion of dairy products consumed daily was divided into quintiles. The criteria of the International Diabetes Federation (IDF) and of the Joint Interim Statement (JIS) were used for the classification of MetS. Nonadjusted and adjusted odds ratios (ORs) were estimated by logistic regression. RESULTS: The prevalence of MetS was 11.9% by the IDF criteria and 9% by the JIS criteria. A greater dairy consumption was associated with a lower prevalence of MetS according to both IDF (OR, 0.61; 95% confidence interval [CI], 0.38-0.97) and JIS (OR, 0.62; 95% CI, 0.39-0.98) criteria when the last quintile was compared with the first. The association persisted in the model adjusted for demographic, socioeconomic, dietary, and lifestyle variables according to the IDF (OR, 0.53; 95% CI, 0.30-0.93) and was borderline according to the JIS (OR, 0.59; 95% CI, 0.34-1.00), but lost significance when data were adjusted for calcium in both models. CONCLUSIONS: A greater dairy consumption is associated with a lower prevalence of MetS, with calcium probably being the nutrient responsible for this association. PMID- 25837219 TI - Dietary diversity as a proxy measure of blood antioxidant status in women. AB - OBJECTIVE: Dietary diversity is recognized as a key indicator of dietary quality. However, its association with blood antioxidant levels has not been investigated. The aim of this study was to assess the association of the dietary diversity score (DDS) with blood antioxidant status in women who attend the sports clubs of a municipality in western Tehran, Iran. METHODS: A cross-sectional survey was conducted with 397 randomly selected women from the sport clubs of a Tehran municipality. Sociodemographic data were recorded and the women's weight and height were measured. Body mass index (BMI) was calculated by dividing the weight (kg) by height squared (m(2)). A 24-h recall questionnaire was used to estimate food intake. Biochemical indices, including serum total antioxidant capacity (TAC) and erythrocyte activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), were measured in 90 women selected randomly from all participants. DDS was computed according to the guidelines of the Food and Agriculture Organization. The mean of SOD, TAC and GPx were compared across DDS quartiles after adjustment for age, education level, physical activity, energy intake, and BMI using analysis of covariance test. RESULTS: The mean of TAC, SOD, and GPx was linearly increased with increasing the quartile of DDS, after adjustment for age, education level, physical activity, energy intake, and BMI (Ptrend < 0.001). Significant differences were observed for intake of different food groups, except cereals and white roots, between the DDS quartiles. CONCLUSION: DDS is associated with blood antioxidant markers. Increasing the dietary diversity might be associated with a reduction in oxidative stress. PMID- 25837220 TI - Statistical review of US macronutrient consumption data, 1965-2011: Americans have been following dietary guidelines, coincident with the rise in obesity. AB - BACKGROUND: For almost 50 y, the US National Health and Nutrition Examination Survey (NHANES) has measured the caloric consumption, and body heights and weights of Americans. The aim of this study was to determine, based on that data, how macronutrient consumption patterns and the weight and body mass index in the US adult population have evolved since the 1960s. METHODS: We conducted the first comprehensive analysis of the NHANES data, documenting how macronutrient consumption patterns and the weight and body mass index in the US adult population have evolved since the 1960s. RESULTS: Americans in general have been following the nutrition advice that the American Heart Association and the US Departments of Agriculture and Health and Human Services have been issuing for more than 40 y: Consumption of fats has dropped from 45% to 34% with a corresponding increase in carbohydrate consumption from 39% to 51% of total caloric intake. In addition, from 1971 to 2011, average weight and body mass index have increased dramatically, with the percentage of overweight or obese Americans increasing from 42% in 1971 to 66% in 2011. CONCLUSIONS: Since 1971, the shift in macronutrient share from fat to carbohydrate is primarily due to an increase in absolute consumption of carbohydrate as opposed to a change in total fat consumption. General adherence to recommendations to reduce fat consumption has coincided with a substantial increase in obesity. PMID- 25837221 TI - Duodenal-jejunal exclusion improves insulin resistance in type 2 diabetic rats by upregulating the hepatic insulin signaling pathway. AB - OBJECTIVES: Previous studies have shown duodenal-jejunal exclusion (DJE) results in the rapid resolution of type 2 diabetes; however, the underlying mechanism is unknown. This study aimed to measure the hepatic expression of insulin receptor substrate-2 (IRS-2) and glucose transporter-2 (GLUT-2) in type 2 diabetic rats post-DJE, and to investigate their roles in improved hepatic insulin resistance and glucose intolerance. METHODS: Type 2 diabetic Sprague-Dawley (SD) rats were randomly divided into DJE operation (DO) and control (DC) groups. Normal SD rats were also divided into DJE operation and control groups. Fasting plasma glucose and insulin concentrations were measured, and the quantitative insulin sensitivity check index (QUICKI) and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) were calculated. Eight weeks postoperation, the hepatic IRS 2 and GLUT-2 protein and mRNA levels were measured using western blotting and reverse transcription polymerase chain reaction, respectively. RESULTS: The fasting blood glucose in the DO group decreased from a preoperative level of 20.21 +/- 2.14 mmol/L to 8.50 +/- 2.19 mmol/L (P < 0.05) 8 wk post-DJE. A change in the QUICKI revealed a dramatic increase, and HOMA-IR showed a significant decrease in the DO group (P < 0.05). Additionally, the IRS-2 and GLUT-2 protein and mRNA levels at 8 wk postoperation were significantly increased in the DO group compared with the DC group. CONCLUSIONS: DJE led to upregulated hepatic IRS 2 and GLUT-2 expression in the hepatic insulin signaling pathway and improved insulin sensitivity in type 2 diabetic rats. PMID- 25837222 TI - Chia (Salvia hispanica L.) enhances HSP, PGC-1alpha expressions and improves glucose tolerance in diet-induced obese rats. AB - OBJECTIVE: The aim of this study was to investigate the effects of chia seed and chia oil on heat shock protein (HSP) and related parameters in diet-induced obese rats. METHODS: Animals were divided in six groups: control, high-fat and high fructose diet (HFF), and HFF with chia seed or chia oil in short (6-wk) and long (12-wk) treatments. Plasma indicators of glucose tolerance and liver damage, skeletal muscle expression of antioxidant enzymes, and proteins controlling oxidative energy metabolism were determined. The limit of significance was set at P < 0.05. RESULTS: The HFF diet induced glucose intolerance, insulin resistance, oxidative stress, and altered parameters related to obesity complications. The consumption of chia seed or chia oil did not reduce body weight gain or abdominal fat accumulation. However, chia seed and chia oil in both treatments improved glucose and insulin tolerance. Chia oil in both treatments induced expression of HSP70 and HSP25 in skeletal muscle. Short treatment with chia seed increased expression of HSP70, but not HSP25. Chia oil in both treatments restored superoxide dismutase and glutathione peroxidase expression. Extended treatment with chia seed and short treatment with chia oil restored peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) expression. CONCLUSION: Chia oil restored the antioxidant system and induced the expression of a higher number of proteins than chia seed. The present study demonstrated new properties and molecular mechanisms associated with the beneficial effects of chia seed and chia oil consumption in diet-induced obese rats. PMID- 25837223 TI - Regulation of skeletal muscle protein synthetic and degradative signaling by alanyl-glutamine in piglets challenged with Escherichia coli lipopolysaccharide. AB - OBJECTIVE: The aim of this study was to investigate the effects of alanyl glutamine (Ala-Gln) on skeletal muscle protein synthetic and degradative signaling in piglets challenged with Escherichia coli lipopolysaccharide (LPS). METHODS: Piglets were arranged in a 2 * 2 factorial design and the main effects were LPS challenge (0 or 100 units) and diets (0.62% Ala or 0.5% Ala-Gln). After treatment with either Ala or Ala-Gln for 10 d, piglets were injected twice with either saline or LPS on days 11 and 15. RESULTS: During days 11 to 15 (postchallenge), LPS challenge affected the growth performance of piglets. Ala Gln supplementation tended to alleviate the reduction of the average daily weight gain (P = 0.071) and the average daily feed intake (P = 0.087) of the LPS challenged piglets. LPS challenge increased the concentrations of cytokines in plasma (P < 0.05), however, Ala-Gln supplementation prevented the elevation of cortisol induced by LPS challenge (P < 0.05). Moreover, Ala-Gln supplementation increased the mRNA expressions of insulin-like growth factor-1 signaling and Akt (P < 0.05). Ala-Gln supplementation also increased the phosphorylation abundance of the mammalian target of rapamycin, eIF-4 E binding protein 1 and ribosomal protein S6 kinase 1 (P < 0.05). Additionally, Ala-Gln supplementation down regulated the mRNA abundances of toll-like receptor 4 (TLR4), muscle atrophy F box, and muscle RING finger 1, which are associated with protein degradation induced by LPS challenge. CONCLUSION: Ala-Gln supplementation had beneficial effects in improving protein synthesis signaling of skeletal muscle, and reversed the deleterious changes of signaling molecules in muscle atrophy mainly through down-regulation of Akt/FOXO and TLR4 signaling pathways induced by LPS challenge. PMID- 25837224 TI - Refeeding with glucose rather than fructose elicits greater hepatic inflammatory gene expression in mice. AB - OBJECTIVE: We previously reported that refeeding after a 48-h fast, used as a study model of starvation and refeeding, promotes acute liver inflammatory gene expression, which is at least partly mediated by toll-like receptor 2 (TLR2). We also previously demonstrated that dietary carbohydrates play critical roles in this process. The aim of this study was to compare the outcomes of refeeding with different carbohydrate sources. METHODS: Mice were fasted for 46 h and then refed with 1.5% (w/w) agar gel containing 19% carbohydrate (sources: alpha-cornstarch, glucose, sucrose, or fructose). The liver expression of inflammatory and other specific genes was then sequentially measured for the first 14 h after refeeding initiation. RESULTS: Fasting for 46 h up-regulated the liver expression of endogenous ligands for TLRs (HspA5, Hsp90 aa1, and Hspd1). Refeeding with agar gel containing alpha-cornstarch or glucose increased the liver expression of Tlr2, proinflammatory genes (Cxcl2, Cxcl10, Cxcl1, Nfkb1, Nfkb2, RelB, Sectm1alpha, Il1beta), stress response genes (Atf3, Asns, Gadd45 a, Perk, Inhbe), detoxification genes (Hmox1, Gsta1, Abca8b), genes involved in tissue regeneration (Gdf15, Krt23, Myc, Tnfrsf12a, Mthfd2), and genes involved in tumor suppression (p53, Txnrd1, Btg2). This refeeding also moderately but significantly elevated the serum levels of alanine aminotransferase. These effects were attenuated in mice refed with agar gel containing sucrose or fructose. CONCLUSION: Dietary glucose, rather than fructose, plays a critical role in refeeding-induced acute liver inflammatory gene expression and moderate hepatocyte destruction. Further studies are recommended regarding the role of these effects in liver inflammation and, consequently, liver dysfunction. PMID- 25837225 TI - Parenteral glutamine supplementation in combination with enteral nutrition improves intestinal immunity in septic rats. AB - OBJECTIVES: The gut-associated lymphoid tissue is continuously exposed to antigens in the gut lumen and becomes the first line of defense against enteric bacteria and associated toxin. The aim of this study was to investigate the effects of parenteral glutamine (GLN) supplementation in combination with enteral nutrition (EN) on intestinal mucosal immunity in septic rats by cecal ligation and puncture (CLP). METHODS: Male Sprague-Dawley rats were randomly assigned into four groups: A sham CLP + EN + saline group (n = 10), a sham CLP + EN + GLN group (n = 10), a CLP + EN + saline group (n = 10), and a CLP + EN + GLN group (n = 10). At 2 h after CLP or sham CLP, all rats in each of the four groups received an identical enteral nutrition solution as their base formula. Then, the rats in the sham CLP + EN + GLN group and CLP + EN + GLN group were given 0.35 g GLN/kg body weight daily for 7 d, all at the same time, via a tail vein injection; whereas those in the sham CLP + EN + saline group and CLP + EN + saline group were daily administered isovolumic sterile 0.9% saline for comparison. All rats in each of the four groups were given 290 kcal/kg body wt/d for 7 d. At the end of the seventh day after the nutritional program was finished, all rats were euthanized and the entire intestine was collected. Total Peyer's patches (PP) cell yield was counted by a hemocytometer. The percentage of PP lymphocyte subsets was analyzed by flow cytometry. The number of intestinal lamina propria IgA plasma cells was determined by the immunohistochemistry technique. The intestinal immunoglobulin A (IgA) levels were assessed by ELISA. PP apoptosis was evaluated by terminal deoxyuridine nick-end labeling. RESULTS: The results revealed total PP cell yield, the numbers of PP lymphocyte subsets, intestinal lamina propria IgA plasma cells, and intestinal IgA levels in the CLP + EN + GLN group were significantly increased when compared with the CLP + EN + saline group (P < 0.05). On the other hand, the number of TUNEL-stained cells within PPs in the CLP + EN + GLN group was markedly decreased as compared with the CLP + EN + saline group (P < 0.05). CONCLUSION: The results of this study show that parenteral glutamine supplementation in combination with enteral nutrition may attenuate PP apoptosis, increase PP cell yield and intestinal lamina propria IgA plasma cells, and subsequently improve intestinal mucosal immunity. Clinically, these results suggest therapeutic efforts at improving intestinal immunity may contribute to the prevention and treatment of sepsis. PMID- 25837226 TI - Open letter to the Secretaries of the U.S. Departments of Agriculture and Health and Human Services on the creation of the 2015 Dietary Guidelines for Americans. PMID- 25837227 TI - Correcting an imbalance. PMID- 25837228 TI - Posterior tibial translation resulting from the posterior drawer manoeuver in cadaveric knee specimens: a systematic review. AB - PURPOSE: The purpose of this systematic review of cadaver-based biomechanical studies is to accurately quantify how much posterior tibial translation occurs during posterior drawer testing in normal and PCL-deficient knees. METHODS: A search of the electronic databases, MEDLINE and EMBASE, was performed to identify relevant cadaveric studies that reported posterior tibial translation during posterior drawer testing. Studies were combined to determine overall increase in posterior tibial translation after PCL sectioning at 90 degrees of flexion. Methodological quality of included studies was assessed by two reviewers using a novel clinometric tool. An intraclass correlation coefficient with 95 % confidence intervals (CIs) was used to determine agreement between reviewers on quality scores. RESULTS: Combined analysis of 244 cadaveric specimens from 23 studies in which the PCL was sectioned yielded a mean net increase in tibial translation of 10.7 mm (95 % CI 9.68-11.8) with posterior drawer testing. Posterior tibial translation among cadaveric specimens with no disruption to any ligamentous structures was found to be 5.4 mm (95 % CI 4.3-6.6). CONCLUSIONS: Cadaveric data support previous study findings of >8 mm of posterior tibial translation on stress radiographs being indicative of isolated PCL insufficiency. Use of fixed reference points and strict control of tibial rotation are imperative to ensure accurate results in cadaveric studies and in the clinical setting when performing the posterior drawer examination. LEVEL OF EVIDENCE: III. PMID- 25837230 TI - Mass casualty disasters: who should run the show? AB - BACKGROUND: A clear command structure ensures quality patient care despite overwhelmed resources during a mass casualty incident (MCI). The American College of Surgeons has stated that surgeons should strive to occupy these leadership roles. OBJECTIVE: We sought to identify whether surgeons, as compared to emergency physicians, are sufficiently prepared to assume command in the event of a mass disaster. METHODS: We surveyed hospital-affiliated surgeons and emergency physicians to assess their knowledge of MCI response principles and to gauge opinions regarding who should be in charge during a disaster. RESULTS: One hundred and forty-nine (58%) surveys were completed, 78 by surgeons and 71 by emergency physicians. Both groups demonstrated a critical lack of knowledge regarding fundamental principles and key logistical components of preparedness and MCI response. Surgeons as a group were even less prepared than emergency physicians. Of those surgeons who had reviewed their hospital's disaster plan, half (50%) still did not know where to report for an MCI activation. Nonetheless, both groups believed they had sufficient training and both asserted they ought to occupy command positions during a disaster scenario. CONCLUSIONS: Errors in disaster triage have been known to increase mortality as well as the monetary cost of disaster response. Funding exists to improve hospital preparedness, but surgeons are lagging behind emergency physicians in taking advantage of these opportunities. Overall, it is imperative that physicians improve their understanding of the MCI response protocols they will be tasked to implement should disaster strike. PMID- 25837231 TI - American Academy of Emergency Medicine Position Statement: Safety of Droperidol Use in the Emergency Department. AB - BACKGROUND: Droperidol (Inapsine(r), Glaxosmithkline, Brent, UK) is a butyrophenone used in emergency medicine practice for a variety of uses. QT prolongation is a well-known adverse effect of this class of medications. Of importance to note, QT prolongation is noted with multiple medication classes, and droperidol increases QT interval in a dose-dependent fashion among susceptible individuals. The primary goal of this literature search was to determine the reported safety issues of droperidol in emergency department management of patients. METHODS: A MEDLINE literature search was conducted from January 1995 to January 2014 and limited to human studies written in English for articles with keywords of droperidol/Inapsine. Guideline statements and nonsystematic reviews were excluded. Studies identified then underwent a structured review from which results could be evaluated. RESULTS: There were 542 papers on droperidol screened, and 35 appropriate articles were rigorously reviewed in detail and recommendations given. CONCLUSION: Droperidol is an effective and safe medication in the treatment of nausea, headache, and agitation. The literature search did not support mandating an electrocardiogram or telemetry monitoring for doses < 2.5 mg given either intramuscularly or intravenously. Intramuscular doses of up to 10 mg of droperidol seem to be as safe and as effective as other medications used for sedation of agitated patients. PMID- 25837232 TI - Novel Use of Glidescope Indirect Laryngoscopy for Insertion of a Minnesota Tube for Variceal Bleeding. AB - BACKGROUND: With improvements in endoscopic and interventional radiologic therapies, insertion of gastroesophageal balloon tamponade catheters, commonly known as Sengstaken-Blakemore or Minnesota tubes, is a rarely performed procedure for esophageal or gastric variceal bleeding. In small hospitals or freestanding emergency departments, endoscopic or interventional radiology (IR) therapies might not be available, so patients with exsanguinating variceal bleeding must be stabilized or temporized for transport to larger hospitals. Occasionally, tamponade devices are necessary as a rescue therapy for failed endoscopic or IR therapies or can be used as definitive therapy in select cases. In addition to being rarely performed, there are multiple technical complications associated with blind insertion of tamponade catheters. DISCUSSION: We describe a novel use of indirect laryngoscopy using a Glidescope for assisting in placement of a Minnesota tube in 4 patients with exsanguinating esophageal bleeding. CONCLUSIONS: Insertion of a Minnesota tube for bleeding esophageal or gastric varices is an uncommon, technically challenging procedure that can be lifesaving, and is something emergency physicians, intensivists, and gastroenterologists should be capable of performing. Addition of indirect laryngoscopy may help to improve rapid, safe, and successful placement of these devices. PMID- 25837229 TI - The human NAD metabolome: Functions, metabolism and compartmentalization. AB - The metabolism of NAD has emerged as a key regulator of cellular and organismal homeostasis. Being a major component of both bioenergetic and signaling pathways, the molecule is ideally suited to regulate metabolism and major cellular events. In humans, NAD is synthesized from vitamin B3 precursors, most prominently from nicotinamide, which is the degradation product of all NAD-dependent signaling reactions. The scope of NAD-mediated regulatory processes is wide including enzyme regulation, control of gene expression and health span, DNA repair, cell cycle regulation and calcium signaling. In these processes, nicotinamide is cleaved from NAD(+) and the remaining ADP-ribosyl moiety used to modify proteins (deacetylation by sirtuins or ADP-ribosylation) or to generate calcium-mobilizing agents such as cyclic ADP-ribose. This review will also emphasize the role of the intermediates in the NAD metabolome, their intra- and extra-cellular conversions and potential contributions to subcellular compartmentalization of NAD pools. PMID- 25837234 TI - Cyprus in crisis: Recent changes in the pharmaceutical market and options for further reforms without sacrificing access to or quality of treatment. AB - The pharmaceutical market in Cyprus has been characterised by high volume and a steep increase in per-capita expenditure over the past decade. Most importantly, the market is fragmented due to the absence of universal health insurance, and the uninsured have to rely exclusively on the private market. The objective of this study is to examine the weaknesses of the Cypriot pharmaceutical market before the financial crisis; to discuss the measures recently introduced after recommendations by the Troika; and to propose interventions that can improve access to pharmaceuticals and efficiency without compromising health outcomes. Apart from the introduction of new pharmaceutical policies, we also recommend the swift implementation of universal health insurance. PMID- 25837233 TI - Moral implications of obstetric technologies for pregnancy and motherhood. AB - Drawing on sociological and anthropological studies, the aim of this article is to reconstruct how obstetric technologies contribute to a moral conception of pregnancy and motherhood, and to evaluate that conception from a normative point of view. Obstetrics and midwifery, so the assumption, are value-laden, value producing and value-reproducing practices, values that shape the social perception of what it means to be a "good" pregnant woman and to be a "good" (future) mother. Activities in the medical field of reproduction contribute to "kinning", that is the making of particular social relationships marked by closeness and special moral obligations. Three technologies, which belong to standard procedures in prenatal care in postmodern societies, are presently investigated: (1) informed consent in prenatal care, (2) obstetric sonogram, and (3) birth plan. Their widespread application is supposed to serve the moral (and legal) goal of effecting patient autonomy (and patient right). A reconstruction of the actual moral implications of these technologies, however, reveals that this goal is missed in multiple ways. Informed consent situations are marked by involuntariness and blindness to social dimensions of decision-making; obstetric sonograms construct moral subjectivity and agency in a way that attribute inconsistent and unreasonable moral responsibilities to the pregnant woman; and birth plans obscure the need for a healthcare environment that reflects a shared decision-making model, rather than a rational-choice-framework. PMID- 25837235 TI - The paradox of non-evidence based, publicly funded complementary alternative medicine in the English National Health Service: An explanation. AB - Despite the unproven effectiveness of many practices that are under the umbrella term 'complementary alternative medicine' (CAM), there is provision of CAM within the English National Health Service (NHS). Moreover, although the National Institute for Health and Care Excellence was established to promote scientifically validated medicine in the NHS, the paradox of publicly funded, non evidence based CAM can be explained as linked with government policy of patient choice and specifically patient treatment choice. Patient choice is useful in the political and policy discourse as it is open to different interpretations and can be justified by policy-makers who rely on the traditional NHS values of equity and universality. Treatment choice finds expression in the policy of personalised healthcare linked with patient responsibilisation which finds resonance in the emphasis CAM places on self-care and self-management. More importantly, however, policy-makers also use patient choice and treatment choice as a policy initiative with the objective of encouraging destabilisation of the entrenched healthcare institutions and practices considered resistant to change. This political strategy of system reform has the unintended, paradoxical consequence of allowing for the emergence of non-evidence based, publicly funded CAM in the NHS. The political and policy discourse of patient choice thus trumps evidence based medicine, with patients that demand access to CAM becoming the unwitting beneficiaries. PMID- 25837236 TI - Intraoperative spinal cord monitoring using combined motor and sensory evoked potentials recorded from the spinal cord during surgery for intramedullary spinal cord tumor. AB - OBJECTIVES: The risk of postoperative neurological impairment mandates the use of intraoperative spinal cord monitoring (IOM) during intramedullary spinal cord tumor (IMSCT) surgery. We have used spinal cord evoked potential after electrical stimulation of the cord(Sp-SCEP) to monitor the sensory tract, and SCEP after electrical stimulation to the brain (Br-SCEP) to monitor the motor tract. Both Sp SCEP and Br-SCEP are stable under general anesthesia. We assessed the clinical utility of these multimodal spinal cord monitoring methods in a retrospective study of a cohort of patients undergoing IMSCT surgery. METHODS: Thirteen patients with IMSCTs underwent tumor resection using Sp-SCEP and/or Br-SCEP. RESULTS: Four patients underwent surgery using only Sp-SCEP monitoring, resulting in two false negatives. Nine patients underwent surgery monitored by Br-SCEP and Sp-SCEP. In three of the nine cases, Br-SCEP amplitude fell by 50% from control levels, despite there being no change in Sp-SCEP. In one of the nine cases, Sp SCEP amplitude fell to 50% of control levels, but Br-SCEP amplitude was stable. CONCLUSIONS: During IMSCT surgery, localized regions of the cord may be damaged. Multimodal monitoring should be used to monitor.Combining Sp-SCEP and Br-SCEP is a useful means of monitoring the sensory and motor tracts. PMID- 25837237 TI - Brain diffusion changes in unilateral carotid artery stenosis with non-shunt endarterectomy: Correlation with white matter lesions. AB - OBJECTIVE: Carotid stenosis is associated with hemodynamic cerebral ischemia. Diffusion-weighted MR imaging allows for the assessment of changes related to alterations in tissue integrity. The aim of this study was to investigate (a) whether white matter lesions (WML) and apparent diffusion coefficient (ADC) values differ between ipsilateral and contralateral hemispheres, (b) whether ADC values are related to WMLs and common vascular risk factors, and (c) whether ADC values differ after carotid endarterectomy (CEA) without a shunt in patients with unilateral internal carotid artery stenosis (ICAS). METHODS: Twenty-five patients (16 men, 9 women; mean age of 68 years) with unilateral ICAS (>= 70% carotid stenosis) were assessed with brain MRI before and after CEA, prospectively. Two experienced radiologists scored the WMLs. Bilateral ADC values in anterior and posterior periventricular WM, occipital WM, and thalamus were evaluated on preoperative and postoperative MRI. Differences in ADC values and WML scores between the two hemispheres were assessed and associations between ADC values, WML scores, and explanatory variables (e.g., age, sex, vascular risk factors) were analyzed. RESULTS: WMLs were significantly greater and ADC values were elevated in the ipsilateral cerebral WM. After CEA, ADC values rapidly decreased but remained higher than within the contralateral hemisphere. Ipsilateral hemispheric ADC values were associated with basal ganglia WMLs. No association between ADC values and vascular risk factors was found. CONCLUSION: ICAS is associated with increased diffusion in normal-appearing WM in comparison to more prominent chronic ischemic lesions. CEA has a partial effect on diffusion. These cerebral changes may be related to chronic low-grade ischemic damage that is induced by ICAS. PMID- 25837238 TI - Abnormally high levels of anti-collagen type IV IgG antibodies in the serum of patients with a clinically isolated syndrome correlate with an increased risk of conversion to MS. AB - OBJECTIVE: To investigate anti-collagen-type-IV serum antibodies (ACIVAbs) levels in patients with clinically isolated syndrome (CIS), and to determine their predictive value for conversion into multiple sclerosis (MS). MATERIAL AND METHODS: Serum levels of IgM and IgG ACIVAbs in 40 untreated patients with CIS (13 male, mean age 34.85+/-11.4 years, range 16-58 years) were compared to those of 27 gender- and age-matched healthy controls. ACIVAbs were quantified using ELISA. Patients were followed for 5 years by clinical examination and MRI studies. RESULTS: Thirty two patients (80%) converted to MS (converted CIS, C-CIS group) while the rest 8 (20%) did not (non-converted CIS, NC-CIS). The C-CIS patients had significantly higher levels of IgG ACIVAb compared to NC-CIS while the IgM levels did not differ between C-CIS and NC-CIS. Conversion to MS occurred in 66% of patients with IgG ACIVAbs levels exceeding the 95th percentile found in controls. IgG ACIVAbs levels correlated positively with the serum levels of matrix metalloproteinases type 9 (r = 0.37; p = 0.003) and inversely with those of tissue inhibitor of metalloproteinases type 1 (r = -0.43; p = 0.0008). CONCLUSION: High serum levels of IgG ACIVAbs in patients with CIS correlate strongly with increased risk of conversion to MS. PMID- 25837239 TI - Surgery of brain aneurysm in a BrainSuite((r)) theater: A review of 105 cases. AB - INTRODUCTION: The BrainSuite((r)) is a highly integrated operating theater designed mainly for brain tumor surgery. The issues concerning its routine use in vascular neurosurgery have not been discussed in literature to date. We report our experience of surgical treatment of cerebral aneurysms in the BrainSuite((r)), with a view to evaluating safety, feasibility, advantages, disadvantages, and contraindications. MATERIAL AND METHODS: Retrospectively, we reviewed all the patients affected by ruptured and unruptured aneurysms that underwent craniotomy with clipping between January 2007 and May 2013 and a subsequent minimum 12-month follow up. Intraoperative DWI, MRA, and volumetric MRI were always performed in order to evaluate vessel patency and early ischemic lesions. The usefulness of navigation was also evaluated in terms of loss/gain of time and its effectiveness as a surgical aid to both the localization of small distal aneurysms and the preoperative planning of the clipping strategies to adopt. RESULTS: A total of 105 patients were included in this report. Of these, 39 and 66 were affected, respectively, by ruptured and unruptured aneurysms. The mean age was 56.1 and the male-to-female ratio was 1:2.9. The aneurysms affected, with progressively descending incidence, the MCA, ACoA, ICA bifurcation, PComA, A2, A1-A2, and C6 segment of the ICA in 40 (38.1%), 23 (22%), 15 (14.3%), 7 (6.6%), 7 (6.6%), 7 (6.6%), and 6 (5.8%) cases, respectively. The aneurysms were clipped and completely excluded from blood circulation in all cases and no difficulty was encountered in positioning and fixing the patients' heads, despite the particular head holder of the BrainSuite((r)). MRI created no interference or problems in cases of carotid exposure at the neck, while harvesting of the lower limb saphenous vein was not feasible due to the vicinity of the operating field to the magnet. Intraoperative angiography was never performed since an angiogram is not compatible with the BrainSuite. Intraoperative DWI, MRA, and volumetric MRI proved to be effective tools for post-clipping evaluation of the patency of the parent vessels and their collateral branches as well as of aneurismal occlusion. This was also checked doubly by availing also of intraoperative micro Doppler ultrasonography. Intraoperative DWI also permitted us to evaluate the presence of initial ischemic lesions as possible consequences of both direct arterial occlusion and early vasospasm related to surgical manipulation. Intraoperative navigation of brain aneurysm with 3D-model reconstructions may be of some use to younger surgeons when planning the clipping strategies and localizing the aneurysm particularly in cases, respectively, of large-complex aneurysms where the sac involves collateral branches and small aneurisms affecting both distal ACA and MCA aneurysms. The outcomes for patients, evaluated according to the GOS (Glasgow outcome score), associated significantly with the preoperative HH (Hunt and Hess) scale grading. Patients with high HH scores (IV and V) in particular showed the highest incidence of unfavorable outcome (GOS=1 or 2) CONCLUSIONS: The BrainSuite((r)) theater is completely suited to brain aneurysm surgery but only in cases where a combined endovascular approach may be required. It provides some advantages and few limitations compared to a normally equipped neurosurgical operating theater; our experience shows that the technological advances of this complex operating room are useful though not essential in aneurysm surgery. PMID- 25837240 TI - Driving among high school students - United States, 2013. AB - During 2004-2013, the number of passenger vehicle drivers aged 16-19 years involved in fatal crashes in the United States declined by 55% from 5,724 to 2,568.* In addition to graduated driver licensing (GDL) programs and safer vehicles,? other possible contributors to the decline include adolescents waiting longer to get their driver licenses and driving less. The crash risk for drivers of any age is highest during the first months of independent driving, and this risk is highest for the youngest teenage drivers. To estimate the percentage of high school students aged >=16 years who have driven during the past 30 days, by age, race/ethnicity, and location, CDC analyzed 2013 data from the national Youth Risk Behavior Survey (YRBS) and YRBS data collected by 42 states and 21 large urban school districts. Nationwide, 76.3% of high school students aged >=16 years reported having driven during the 30 days before the survey; 83.2% of white students had driven compared with <70% of black and Hispanic students. Across 42 states, the percentage of students who drove ranged from 53.8% to 90.2%. Driving prevalence was higher in the midwestern and mountain states. Across the 21 large urban school districts, the percentage of drivers varied more than twofold from 30.2% to 76.0%. This report provides the most detailed evidence to date that the percentage of students who drive varies substantially depending on where they live. Such information will be vital as states and communities consider potential ways to improve safety for older teenage novice drivers and plan for safe, affordable transportation options for those who do not drive. PMID- 25837241 TI - Importation and domestic transmission of Shigella sonnei resistant to ciprofloxacin - United States, May 2014-February 2015. AB - In December 2014, PulseNet, the national molecular subtyping network for foodborne disease, detected a multistate cluster of Shigella sonnei infections with an uncommon pulsed-field gel electrophoresis (PFGE) pattern. CDC's National Antimicrobial Resistance Monitoring System (NARMS) laboratory determined that isolates from this cluster were resistant to ciprofloxacin, the antimicrobial medication recommended to treat adults with shigellosis. To understand the scope of the outbreak and to try to identify its source, CDC and state and local health departments conducted epidemiologic and laboratory investigations. During May 2014-February 2015, PulseNet identified 157 cases in 32 states and Puerto Rico; approximately half were associated with international travel. Nine of the cases identified by PulseNet, and another 86 cases without PFGE data, were part of a related outbreak of ciprofloxacin-resistant shigellosis in San Francisco, California. Of 126 total isolates with antimicrobial susceptibility information, 109 (87%) were nonsusceptible to ciprofloxacin (108 were resistant, and one had intermediate susceptibility). Travelers need to be aware of the risks of acquiring multidrug-resistant pathogens, carefully wash their hands, and adhere to food and water precautions during international travel. Clinicians should request stool cultures and antimicrobial susceptibilities when they suspect shigellosis, and counsel shigellosis patients to follow meticulous hygiene regimens while ill. PMID- 25837242 TI - Ebola virus disease in a humanitarian aid worker - New York City, October 2014. AB - In late October 2014, Ebola virus disease (Ebola) was diagnosed in a humanitarian aid worker who recently returned from West Africa to New York City (NYC). The NYC Department of Health and Mental Hygiene (DOHMH) actively monitored three close contacts of the patient and 114 health care personnel. No secondary cases of Ebola were detected. In collaboration with local and state partners, DOHMH had developed protocols to respond to such an event beginning in July 2014. These protocols included safely transporting a person at the first report of symptoms to a local hospital prepared to treat a patient with Ebola, laboratory testing for Ebola, and monitoring of contacts. In response to this single case of Ebola, initial health care worker active monitoring protocols needed modification to improve clarity about what types of exposure should be monitored. The response costs were high in both human resources and money: DOHMH alone spent $4.3 million. However, preparedness activities that include planning and practice in effectively monitoring the health of workers involved in Ebola patient care can help prevent transmission of Ebola. PMID- 25837243 TI - CDC Grand Rounds: the future of cancer screening. AB - Cancer is the second leading cause of death in the United States, with 52% of deaths caused by cancers of the lung and bronchus, female breast, uterine cervix, colon and rectum, oral cavity and pharynx, prostate, and skin (melanoma). In the 1930s, uterine cancer, including cancer of the uterine cervix, was the leading cause of cancer deaths among women in the United States. With the advent of the Papanicolaou (Pap) test in the 1950s to detect cellular level changes in the cervix, cervical cancer death rates declined significantly. Since this first cancer screening test, others have been developed that detect the presence of cancer through imaging procedures (e.g., mammography, endoscopy, and computed tomography) and laboratory tests (e.g., fecal occult blood tests). PMID- 25837244 TI - Update on progress in electronic reporting of laboratory results to public health agencies - United States, 2014. AB - Since 2010, CDC has provided resources from the Prevention and Public Health Fund of the Affordable Care Act to 57 state, local, and territorial health departments through the Epidemiology and Laboratory Capacity for Infectious Diseases cooperative agreement to assist with implementation of electronic laboratory reporting (ELR)* from clinical and public health laboratories to public health agencies. To update information from a previous report about the progress in implementing ELR in the United States, CDC examined regular communications between the agency and the 57 health departments during 2012-2014. The results indicated that, as of July 2014, 67% of the approximately 20 million laboratory reports received annually for notifiable conditions were received electronically, compared with 62% in July 2013. These electronic reports were received by 55 of the 57 jurisdictions and came from 3,269 (up from nearly 2,900 in July 2013) of approximately 10,600 reporting laboratories. The proportion of laboratory reports received electronically varied by jurisdiction. In 2014, compared with 2013, the number of jurisdictions receiving >75% of laboratory reports electronically was higher (21 versus 14), and the number of jurisdictions receiving <25% of reports electronically was lower (seven versus nine). National implementation of ELR continues to increase and appears it might reach 80% of total laboratory report volume by 2016. PMID- 25837245 TI - Acute Mountain Sickness, Hypoxia, Hypobaria and Exercise Duration each Affect Heart Rate. AB - In this study, we quantified the changes in post-exercise resting heart rate (HRrst) associated with acute mountain sickness (AMS), and compared the effects of hypobaric hypoxia (HH) and normobaric hypoxia (NH) on HRrst. We also examined the modulating roles of exercise duration and exposure time on HRrst. Each subject participated in 2 of 6 conditions: normobaric normoxia (NN), NH, or HH (4 400 m altitude equivalent) combined with either 10 or 60 min of moderate cycling at the beginning of an 8-h exposure. AMS was associated with a 2 bpm higher HRrst than when not sick, after taking into account the ambient environment, exercise duration, and SpO2. In addition, HRrst was elevated in both NH and HH compared to NN with HRrst being 50% higher in HH than in NH. Participating in long duration exercise led to elevated resting HRs (0.8-1.4 bpm higher) compared with short exercise, while short exercise caused a progressive increase in HRrst over the exposure period in both NH and HH (0.77-1.2 bpm/h of exposure). This data suggests that AMS, NH, HH, exercise duration, time of exposure, and SpO2 have independent effects on HRrst. It further suggests that hypobaria exerts its own effect on HRrst in hypoxia. Thus NH and HH may not be interchangeable environments. PMID- 25837247 TI - Does Vibration Warm-up Enhance Kinetic and Temporal Sprint Parameters? AB - The aim of this study was to investigate the efficacy of vibration warm-up to enhance sprint performance. 12 males involved in representative team sports performed 4 warm-up conditions in a randomised order performed at least 24 h apart; VbX warm-up (VbX-WU); Neural activation warm-up (Neu-WU); Dynamic warm-up (Dyn-WU) and Control (No VbX). Participants completed 5 m sprint at 30 s, 2:30 min and 5 min post warm-up where sprint time, kinetics, and temporal components were recorded. There was no significant (p>0.05) main effect or interaction effect between the split sprint times of 1 m, 2.5 m, and 5 m. There was a condition effect where vertical mean force was significantly higher (p<0.05) in Dyn-WU and Control compared to Neu-WU. No other significant (p>0.05) main and interaction effects in sprint kinetic and temporal parameters existed. Overall, all 4 warm-up conditions produced comparable results for sprint performance, and there was no detrimental effect on short-duration sprint performance using VbX WU. Therefore, VbX could be useful for adding variety to the training warm-up or be included into the main warm-up routine as a supplementary modality. PMID- 25837246 TI - Effects of Swimming on the Inflammatory and Redox Response in a Model of Allergic Asthma. AB - In this study we hypothesized that swimming during sensitization phase could result in a preventive effect in mice with allergic asthma. Swiss mice were divided into 4 groups: Control and Swimming (non-sensitized), OVA and OVA+Swimming (sensitized). The allergic inflammation was induced by 2 intraperitoneal injections and 4 aerosol challenges using ovalbumin. Swimming sessions were performed at high intensity over 3 weeks. 48 h after the last challenge mice were euthanized. Swimming decreased OVA-increased total IgE, IL-1, IL-4, IL-5 and IL-6 levels, as well as the number of total cells, lymphocytes and eosinophils in bronchoalveolar lavage fluid, (p<0.05). Simultaneously, swimming also increased IL-10 and glutathione levels in the Swimming and OVA+Swimming groups (p<0.05). The levels of glutathione peroxidase and catalase were increased only in the Swimming group when compared to all groups (p<0.05). 21 days of swimming resulted in an attenuation of pulmonary allergic inflammation followed by an increase of glutathione levels in the OVA group. Swimming only increased the levels of glutathione peroxidase and catalase in non-sensitized mice (p<0.05). These data suggest that the pulmonary anti-inflammatory effects produced by 3 weeks of high-intensity swimming in this model of OVA-induced asthma may be, at least partly, modulated by reduced oxidative stress and increased IL-10 production. PMID- 25837249 TI - WITHDRAWN: WSTF Phosphorylation Specifically Links H3K9ac with H4K16ac through PCAF/WSTF/MOF Complex. AB - This article has been withdrawn by the authors. PMID- 25837248 TI - Bordetella pertussis Lipid A Recognition by Toll-like Receptor 4 and MD-2 Is Dependent on Distinct Charged and Uncharged Interfaces. AB - Lipid A in LPS activates innate immunity through the Toll-like receptor 4 (TLR4) MD-2 complex on host cells. Variation in lipid A has significant consequences for TLR4 activation and thus may be a means by which Gram-negative bacteria modulate host immunity. However, although even minor changes in lipid A structure have been shown to affect downstream immune responses, the mechanism by which the TLR4 MD-2 receptor complex recognizes these changes is not well understood. We previously showed that strain BP338 of the human pathogen Bordetella pertussis, the causative agent of whooping cough, modifies its lipid A by the addition of glucosamine moieties that promote TLR4 activation in human, but not mouse, macrophages. Using site-directed mutagenesis and an NFkappaB reporter assay screen, we have identified several charged amino acid residues in TLR4 and MD-2 that are important for these species-specific responses; some of these are novel for responses to penta-acyl B. pertussis LPS, and their mutation does not affect the response to hexa-acylated Escherichia coli LPS or tetra-acylated lipid IVA. We additionally show evidence that suggests that recognition of penta-acylated B. pertussis lipid A is dependent on uncharged amino acids in TLR4 and MD-2 and that this is true for both human and mouse TLR4-MD-2 receptors. Taken together, we have demonstrated that the TLR4-MD-2 receptor complex recognizes variation in lipid A molecules using multiple sites for receptor-ligand interaction and propose that host-specific immunity to a particular Gram-negative bacterium is, at least in part, mediated by very subtle tuning of one of the earliest interactions at the host-pathogen interface. PMID- 25837250 TI - Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion. AB - Genomic heterogeneity is characteristic of glioblastoma (GBM). In many GBMs, the EGF receptor gene (EGFR) is amplified and may be truncated to generate a constitutively active form of the receptor called EGFRvIII. EGFR gene amplification and EGFRvIII are associated with GBM progression, even when only a small fraction of the tumor cells express EGFRvIII. In this study, we show that EGFRvIII-positive GBM cells express significantly increased levels of cellular urokinase receptor (uPAR) and release increased amounts of soluble uPAR (suPAR). When mice were xenografted with human EGFRvIII-expressing GBM cells, tumor derived suPAR was detected in the plasma, and the level was significantly increased compared with that detected in plasma samples from control mice xenografted with EGFRvIII-negative GBM cells. suPAR also was increased in plasma from patients with EGFRvIII-positive GBMs. Purified suPAR was biologically active when added to cultures of EGFRvIII-negative GBM cells, activating cell signaling and promoting cell migration and invasion. suPAR did not significantly stimulate cell signaling or migration of EGFRvIII-positive cells, probably because cell signaling was already substantially activated in these cells. The activities of suPAR were replicated by conditioned medium (CM) from EGFRvIII-positive GBM cells. When the CM was preincubated with uPAR-neutralizing antibody or when uPAR gene expression was silenced in cells used to prepare CM, the activity of the CM was significantly attenuated. These results suggest that suPAR may function as an important paracrine signaling factor in EGFRvIII-positive GBMs, inducing an aggressive phenotype in tumor cells that are EGFRvIII-negative. PMID- 25837251 TI - "Velcro" engineering of high affinity CD47 ectodomain as signal regulatory protein alpha (SIRPalpha) antagonists that enhance antibody-dependent cellular phagocytosis. AB - CD47 is a cell surface protein that transmits an anti-phagocytic signal, known as the "don't-eat-me" signal, to macrophages upon engaging its receptor signal regulatory protein alpha (SIRPalpha). Molecules that antagonize the CD47 SIRPalpha interaction by binding to CD47, such as anti-CD47 antibodies and the engineered SIRPalpha variant CV1, have been shown to facilitate macrophage mediated anti-tumor responses. However, these strategies targeting CD47 are handicapped by large antigen sinks in vivo and indiscriminate cell binding due to ubiquitous expression of CD47. These factors reduce bioavailability and increase the risk of toxicity. Here, we present an alternative strategy to antagonize the CD47-SIRPalpha pathway by engineering high affinity CD47 variants that target SIRPalpha, which has restricted tissue expression. CD47 proved to be refractive to conventional affinity maturation techniques targeting its binding interface with SIRPalpha. Therefore, we developed a novel engineering approach, whereby we augmented the existing contact interface via N-terminal peptide extension, coined "Velcro" engineering. The high affinity variant (Velcro-CD47) bound to the two most prominent human SIRPalpha alleles with greatly increased affinity relative to wild-type CD47 and potently antagonized CD47 binding to SIRPalpha on human macrophages. Velcro-CD47 synergizes with tumor-specific monoclonal antibodies to enhance macrophage phagocytosis of tumor cells in vitro, with similar potency as CV1. Finally, Velcro-CD47 interacts specifically with a subset of myeloid-derived cells in human blood, whereas CV1 binds all myeloid, lymphoid, and erythroid populations interrogated. This is consistent with the restricted expression of SIRPalpha compared with CD47. Herein, we have demonstrated that "Velcro" engineering is a powerful protein-engineering tool with potential applications to other systems and that Velcro-CD47 could be an alternative adjuvant to CD47 targeting agents for cancer immunotherapy. PMID- 25837252 TI - The substrate-free and -bound crystal structures of the duplicated taurocyamine kinase from the human parasite Schistosoma mansoni. AB - The taurocyamine kinase from the blood fluke Schistosoma mansoni (SmTK) belongs to the phosphagen kinase (PK) family and catalyzes the reversible Mg(2+) dependent transfer of a phosphoryl group between ATP and taurocyamine. SmTK is derived from gene duplication, as are all known trematode TKs. Our crystallographic study of SmTK reveals the first atomic structure of both a TK and a PK with a bilobal structure. The two unliganded lobes present a canonical open conformation and interact via their respective C- and N-terminal domains at a helix-mediated interface. This spatial arrangement differs from that observed in true dimeric PKs, in which both N-terminal domains make contact. Our structures of SmTK complexed with taurocyamine or l-arginine compounds explain the mechanism by which an arginine residue of the phosphagen specificity loop is crucial for substrate specificity. An SmTK crystal was soaked with the dead end transition state analog (TSA) components taurocyamine-NO3 (2-)-MgADP. One SmTK monomer was observed with two bound TSAs and an asymmetric conformation, with the first lobe semiclosed and the second closed. However, isothermal titration calorimetry and enzyme kinetics experiments showed that the two lobes function independently. A small angle x-ray scattering model of SmTK-TSA in solution with two closed active sites was generated. PMID- 25837253 TI - Mutation in Osteoactivin Promotes Receptor Activator of NFkappaB Ligand (RANKL) mediated Osteoclast Differentiation and Survival but Inhibits Osteoclast Function. AB - We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in the Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb(+)). In these D2J mice, micro-computed tomography and histomorphometric analyses revealed increased cortical thickness, whereas total porosity and eroded surface were significantly reduced in D2J mice compared with wild-type controls, and these results were corroborated by lower serum levels of CTX-1. Contrary to these observations and counterintuitively, temporal gene expression analyses supported up-regulated osteoclastogenesis in D2J mice and increased osteoclast differentiation rates ex vivo, marked by increased number and size. The finding that MAPK was activated in early differentiating and mature D2J osteoclasts and that survival of D2J osteoclasts was enhanced and mediated by activation of the AKT-GSK3beta pathway supports this observation. Furthermore, this was abrogated by the addition of recombinant OA to cultures, which restored osteoclastogenesis to wild-type levels. Moreover, mix and match co-cultures demonstrated an induction of osteoclastogenesis in D2J osteoblasts co-cultured with osteoclasts of D2J or wild-type. Last, in functional osteo-assays, we show that bone resorption activity of D2J osteoclasts is dramatically reduced, and these osteoclasts present an abnormal ruffled border over the bone surface. Collectively, these data support a model whereby OA/Gpnmb acts as a negative regulator of osteoclast differentiation and survival but not function by inhibiting the ERK/AKT signaling pathways. PMID- 25837254 TI - Integrin engagement by the helical RGD motif of the Helicobacter pylori CagL protein is regulated by pH-induced displacement of a neighboring helix. AB - Arginine-aspartate-glycine (RGD) motifs are recognized by integrins to bridge cells to one another and the extracellular matrix. RGD motifs typically reside in exposed loop conformations. X-ray crystal structures of the Helicobacter pylori protein CagL revealed that RGD motifs can also exist in helical regions of proteins. Interactions between CagL and host gastric epithelial cell via integrins are required for the translocation of the bacterial oncoprotein CagA. Here, we have investigated the molecular basis of the CagL-host cell interactions using structural, biophysical, and functional analyses. We solved an x-ray crystal structure of CagL that revealed conformational changes induced by low pH not present in previous structures. Using analytical ultracentrifugation, we found that pH-induced conformational changes in CagL occur in solution and not just in the crystalline environment. By designing numerous CagL mutants based on all available crystal structures, we probed the functional roles of CagL conformational changes on cell surface integrin engagement. Together, our data indicate that the helical RGD motif in CagL is buried by a neighboring helix at low pH to inhibit CagL binding to integrin, whereas at neutral pH the neighboring helix is displaced to allow integrin access to the CagL RGD motif. This novel molecular mechanism of regulating integrin-RGD motif interactions by changes in the chemical environment provides new insight to H. pylori-mediated oncogenesis. PMID- 25837255 TI - Spatial Control of Epsin-induced Clathrin Assembly by Membrane Curvature. AB - Epsins belong to the family of highly conserved clathrin-associated sorting proteins that are indispensable for clathrin-mediated endocytosis, but their precise functions remain unclear. We have developed an assay system of budded supported membrane tubes displaying planar and highly curved membrane surfaces to analyze intrinsic membrane curvature preference shown by clathrin-associated sorting proteins. Using real-time fluorescence microscopy, we find that epsin preferentially partitions to and assembles clathrin on highly curved membrane surfaces. Sorting of epsin to regions of high curvature strictly depends on binding to phosphatidylinositol 4,5-bisphosphate. Fluorescently labeled clathrins rapidly assemble as foci, which in turn cluster epsin, while maintaining tube integrity. Clathrin foci grow in intensity with a typical time constant of ~75 s, similar to the time scales for coated pit formation seen in cells. Epsin therefore effectively senses membrane curvature to spatially control clathrin assembly. Our results highlight the potential role of membrane curvature in orchestrating the myriad molecular interactions necessary for the success of clathrin-mediated membrane budding. PMID- 25837256 TI - Sodium content in packaged foods by census division in the United States, 2009. AB - Excess sodium intake correlates positively with high blood pressure. Blood pressure varies by region, but whether sodium content of foods sold varies across regions is unknown. We combined nutrition and sales data from 2009 to assess the regional variation of sodium in packaged food products sold in 3 of the 9 US census divisions. Although sodium density and concentration differed little by region, fewer than half of selected food products met Food and Drug Administration sodium-per-serving conditions for labeling as "healthy." Regional differences in hypertension were not reflected in differences in the sodium content of packaged foods from grocery stores. PMID- 25837257 TI - A comparison of cardiometabolic risk factors in households in rural Uganda with and without a resident with type 2 diabetes, 2012-2013. AB - INTRODUCTION: Few studies have examined the health consequences of living in a household with a person who has been diagnosed with type 2 diabetes (T2D). We assessed the association of sharing a household with a person with diagnosed T2D and risk factors for cardio-metabolic diseases in Uganda, a low-income country. METHODS: Ninety households with 437 residents in southwestern Uganda were studied from December 2012 through March 2013. Forty-five of the households had a member with diagnosed T2D (hereafter "diabetic household"), and 45 households had no member with diagnosed T2D (hereafter "nondiabetic household"). We compared glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), hypertension, anthropometry, aerobic capacity, physical activity, nutrition, smoking, and diabetes-related knowledge of people without diagnosed T2D living in diabetic and nondiabetic households. RESULTS: People living in diabetic households had a significantly higher level of diabetes-related knowledge, lower levels of FPG (5.6 mmol/L vs 6.0 mmol/L), and fewer smoked (1.3% vs 12.9%) than residents of nondiabetic households. HbA1c was significantly lower in people aged 30 years or younger (5.2% vs 5.4%) and in males (5.2% vs 5.4%) living in diabetic households compared to residents of nondiabetic households. No differences were found between the 2 types of households in overweight and obesity, upper-arm fat area, intake of staple foods or cooking oil, or physical activity. CONCLUSIONS: Sharing a household with a person with T2D may have unexpected benefits on the risk factor profile for cardio-metabolic diseases, probably because of improved health behaviors and a closer connection with the health care system. Thus, future studies should consider the household for interventions targeting primary and secondary prevention of T2D. PMID- 25837258 TI - Identifying postpartum intervention approaches to reduce cardiometabolic risk among American Indian women with prior gestational diabetes, Oklahoma, 2012-2013. AB - INTRODUCTION: Innovative approaches are needed to reduce cardiometabolic risk among American Indian women with a history of gestational diabetes. We assessed beliefs of Oklahoma American Indian women about preventing type 2 diabetes and cardiovascular disease after having gestational diabetes. We also assessed barriers and facilitators to healthy lifestyle changes postpartum and intervention approaches that facilitate participation in a postpartum lifestyle program. METHODS: In partnership with a tribal health system, we conducted a mixed-method study with American Indian women aged 19 to 45 years who had prior gestational diabetes, using questionnaires, focus groups, and individual interviews. Questionnaires were used to identify women's cardiometabolic risk perceptions and feasibility and acceptability of Internet or mobile phone technology for delivery of a postpartum lifestyle modification program. Focus groups and individual interviews were conducted to identify key perspectives and preferences related to a potential program. RESULTS: Participants were 26 women, all of whom completed surveys; 11 women participated in focus group sessions, and 15 participated in individual interviews. Most women believed they would inevitably develop diabetes, cardiovascular disease, or both; however, they were optimistic that they could delay onset with lifestyle change. Most women expressed enthusiasm for a family focused, technology-based intervention that emphasizes the importance of delaying disease onset, provides motivation, and promotes accountability while accommodating women's competing priorities. CONCLUSIONS: Our findings suggest that an intervention that uses the Internet, text messaging, or both and that emphasizes the benefits of delaying disease onset should be tested as a novel, culturally relevant approach to reducing rates of diabetes and cardiovascular disease in this high-risk population. PMID- 25837260 TI - Correction: Researcher perspectives on publication and peer review of data. PMID- 25837259 TI - Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells. AB - In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERalpha) positive breast cancer cell survival and growth. This raises the question of how the ERalpha positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERalpha positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERalpha positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERalpha positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERalpha breast cancer cells by suppressing anoikis. PMID- 25837261 TI - Angiosarcoma of penis: Case report of an aggressive penile cancer. AB - Angiosarcoma is a very rare mesenchymal tumor of penis. Though extremely unusual, it should be considered in the differential diagnosis in patients presenting with a penile growth or a localized subcutaneous penile lesions as they are very aggressive and there is a high chance of recurrence. One such case is reported here, which was aggressively treated with total penectomy and the patient did not show any recurrence in 2 years of follow-up. PMID- 25837262 TI - The National Breast and Cervical Cancer Early Detection Program: 25 Years of public health service to low-income women. AB - This article presents an overview of the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a valuable and successful national public health program in the USA that will soon celebrate its 25th anniversary. Simulation modeling and other analyses have demonstrated that the NBCCEDP has significantly reduced breast and cervical cancer mortality among low-income uninsured and underinsured women in the USA, a major goal of the original legislation. The NBCCEDP has also served to build cancer prevention and control capacity in state and local health agencies and created strong and unique public private partnerships aimed at improving women's health. As such, the impact of NBCCEDP extends beyond the millions of women served by the program to include increased public health system capacity and effectiveness regarding cancer early detection and control for all women. PMID- 25837263 TI - Periodontal bone loss and risk of epithelial ovarian cancer. AB - PURPOSE: Periodontitis, a chronic inflammatory response to pathogenic bacteria in the oral microbiome, is common among adults. It is associated with several medical conditions, including cardiovascular diseases, and potentially with esophageal, lung, oral, and pancreatic cancer. One of the proposed mechanisms behind these associations is systemic inflammation, which has also been implicated in ovarian cancer etiology. The aim of this study was to evaluate association between ovarian cancer and periodontal bone loss. METHODS: The association between periodontal bone loss, a marker of periodontitis, and risk of epithelial ovarian cancer was estimated among 60,560 participants of the prospective Nurses' Health Study using Cox proportional hazards analysis. Competing risks analysis was used to estimate association by histologic subtype. RESULTS: We did not observe an increased risk of ovarian cancer among participants with periodontal bone loss (HR 0.86, 95% CI 0.64-1.15). Among women younger than 69 years, periodontal bone loss was associated with a 40 % (HR 0.60, 95% CI 0.36-0.98) decreased ovarian cancer risk, while there was no association in women older than 69 (HR 1.09, 95% CI 0.75-1.58), although this difference did not reach statistical significance (p-heterogeneity = 0.06). We observed a suggestive decreased risk for serous tumors (HR 0.76, 95% CI 0.53-1.09). The number of natural teeth and root canals, other metrics of oral health, were not associated with ovarian cancer risk. CONCLUSION: Our results do not support an increased ovarian cancer risk in women with periodontal bone loss; however, there was a significant decrease in risk in women younger than 69. Given the unexpected association between periodontal bone loss and ovarian cancer risk in younger women, further research is warranted. PMID- 25837264 TI - Inflammatory response to nano- and microstructured hydroxyapatite. AB - The proliferation and activation of leukocytes upon contact with a biomaterial play a crucial role in the degree of inflammatory response, which may then determine the clinical failure or success of an implanted biomaterial. The aim of this study was to evaluate whether nano- and microstructured biomimetic hydroxyapatite substrates can influence the growth and activation of macrophage like cells. Hydroxyapatite substrates with different crystal morphologies consisting of an entangled network of plate-like and needle-like crystals were evaluated. Macrophage proliferation was evaluated on the material surface (direct contact) and also in extracts i.e. media modified by the material (indirect contact). Additionally, the effect of supplementing the extracts with calcium ions and/or proteins was investigated. Macrophage activation on the substrates was evaluated by quantifying the release of reactive oxygen species and by morphological observations. The results showed that differences in the substrate's microstructure play a major role in the activation of macrophages as there was a higher release of reactive oxygen species after culturing the macrophages on plate-like crystals substrates compared to the almost non-existent release on needle-like substrates. However, the difference in macrophage proliferation was ascribed to different ionic exchanges and protein adsorption/retention from the substrates rather than to the texture of materials. PMID- 25837265 TI - Narrative Intervention for Children With Autism Spectrum Disorder (ASD). AB - PURPOSE: This study was conducted to determine whether a narrative intervention program that targeted the use of mental state and causal language resulted in positive gains in narrative production for children with autism spectrum disorder (ASD). METHOD: Five children (2 girls and 3 boys) who had been diagnosed with ASD participated in the study. Children ranged in age from 8 to 12 years and were recruited through an autism clinic. Intervention was provided for two 50-min individual sessions per week for a total of 21-33 sessions (depending on the student). Children's spontaneous stories, collected weekly, were analyzed for overall story complexity, story structure, and the use of mental state and causal language. Following a multiple-baseline across-participants design, data were collected for lagged baseline and intervention phases over a 6-month period. RESULTS: All of the children made gains on all 3 measures of narration after participating in the instruction, with clear changes in level for all 5 children and changes in trend for 4 of the 5 children. The gains were maintained after intervention was discontinued. CONCLUSION: The results demonstrate the efficacy of the 3-phase narrative instruction program for improving the fictional narration abilities of children with ASD. PMID- 25837266 TI - COUNTERPOINT: Does the Risk of Electronic Cigarettes Exceed Potential Benefits? No. PMID- 25837267 TI - Identifying risky drivers with simulated driving. AB - OBJECTIVE: The present study aimed to examine whether high-risk drivers differ from low-risk drivers in driving behavior in a simulated environment. METHOD: The 2 risk groups including 36 drivers (18 males and 18 females) performed driving tasks in a simulated environment. The simulated driving behaviors are compared between the 2 risk groups. RESULTS: The high-risk drivers drove much faster and exhibited larger offsets of the steering wheel than did the low-risk drivers in events without incidents. Additionally, the high-risk drivers used turn signals and horns less frequently than the low-risk drivers. CONCLUSIONS: The present study revealed that the high-risk group differed from the low-risk group in driving behavior in a simulated environment. These results also suggest that simulated driving tasks might be useful tools for the evaluation of drivers' potential risks. PMID- 25837268 TI - Variability in prefrontal hemodynamic response during exposure to repeated self selected music excerpts, a near-infrared spectroscopy study. AB - Music-induced brain activity modulations in areas involved in emotion regulation may be useful in achieving therapeutic outcomes. Clinical applications of music may involve prolonged or repeated exposures to music. However, the variability of the observed brain activity patterns in repeated exposures to music is not well understood. We hypothesized that multiple exposures to the same music would elicit more consistent activity patterns than exposure to different music. In this study, the temporal and spatial variability of cerebral prefrontal hemodynamic response was investigated across multiple exposures to self-selected musical excerpts in 10 healthy adults. The hemodynamic changes were measured using prefrontal cortex near infrared spectroscopy and represented by instantaneous phase values. Based on spatial and temporal characteristics of these observed hemodynamic changes, we defined a consistency index to represent variability across these domains. The consistency index across repeated exposures to the same piece of music was compared to the consistency index corresponding to prefrontal activity from randomly matched non-identical musical excerpts. Consistency indexes were significantly different for identical versus non identical musical excerpts when comparing a subset of repetitions. When all four exposures were compared, no significant difference was observed between the consistency indexes of randomly matched non-identical musical excerpts and the consistency index corresponding to repetitions of the same musical excerpts. This observation suggests the existence of only partial consistency between repeated exposures to the same musical excerpt, which may stem from the role of the prefrontal cortex in regulating other cognitive and emotional processes. PMID- 25837269 TI - Radiation exposure and safety practices during pediatric central line placement. AB - PURPOSE: Pediatric surgeons routinely use fluoroscopy for central venous line (CVL) placement. We examined radiation safety practices and patient/surgeon exposure during fluoroscopic CVL. METHODS: Fluoroscopic CVL procedures performed by 11 pediatric surgeons in 2012 were reviewed. Fluoroscopic time (FT), patient exposure (mGy), and procedural data were collected. Anthropomorphic phantom simulations were used to calculate scatter and dose (mSv). Surgeons were surveyed regarding safety practices. RESULTS: 386 procedures were reviewed. Median FT was 12.8 seconds. Median patient estimated effective dose was 0.13 mSv. Median annual FT per surgeon was 15.4 minutes. Simulations showed no significant difference (p=0.14) between reported exposures (median 3.5 mGy/minute) and the modeled regression exposures from the C-arm default mode (median 3.4 mGy/minute). Median calculated surgeon exposure was 1.5 mGy/year. Eight of 11 surgeons responded to the survey. Only three reported 100% lead protection and frequent dosimeter use. CONCLUSION: We found nonstandard radiation training, safety practices, and dose monitoring for the 11 surgeons. Based on simulations, the C-arm default setting was typically used instead of low dose. While most CVL procedures have low patient/surgeon doses, every effort should be used to minimize patient and occupational exposure, suggesting the need for formal hands-on training for nonradiologist providers using fluoroscopy. PMID- 25837270 TI - Intervention effects of puerarin on blood stasis in rats revealed by a (1)H NMR based metabonomic approach. AB - Puerarin possesses a wide spectrum of biological activities including ameliorating effects on blood stasis, but the definite mechanism of this effect is still not known. In this study, a (1)H NMR-based plasma and urinary metabonomic approach was applied to comprehensively and holistically investigate the therapeutic effects of puerarin on blood stasis and its underlying mechanisms. Puerarin was injected intraperitoneally once daily for consecutive 7 days. The blood stasis rat model was established by placing the rats in ice-cold water during the time interval between two injections of adrenaline. With pattern recognition analysis, a clear separation of blood stasis model group and healthy control group was achieved and puerarin pretreatment group was located much closer to the control group than the model group, which was consistent with results of hemorheology studies. 15 and 10 potential biomarkers associated with blood stasis in plasma and urine, respectively, which were mainly involved in energy metabolism, lipid and membrane metabolisms, amino acid metabolism and gut microbiota metabolism, were identified. Puerarin could prevent blood stasis through partially regulating the disturbed metabolic pathways. This work highlights that metabonomics is a valuable tool for studying the essence of blood stasis as well as evaluating the efficacy of the corresponding drug treatment. PMID- 25837271 TI - Alopecurone B reverses doxorubicin-resistant human osteosarcoma cell line by inhibiting P-glycoprotein and NF-kappa B signaling. AB - Doxorubicin (DOX) was first used in osteosarcoma in the early 1970s as a first line antineoplastic drug. However, the occurrence of drug resistance in chemotherapeutic treatment has greatly restricted its use. When resistance to DOX treatment occurs, osteosarcoma may become not only resistant to the drug originally administered but also to a wide variety of structurally and mechanistically unrelated drugs. Thus, there is an urgent need to find ways of reversing DOX chemotherapy resistance in osteosarcoma. Plant-derived agents have great potential in preventing the onset of the carcinogenic process and enhancing the efficacy of conventional antitumor drugs. Alopecurone B (ALOB), a flavonoid, is isolated from Traditional Chinese Medicine Sophora alopecuroides L., and is reported to have potent inhibitory effect on multidrug resistance associated protein 1. In this study, a DOX-resistant osteosarcoma cell line (MG-63/DOX) was established by increasing the concentration gradient of DOX in a stepwise manner. MTT assay, flow cytometry analysis, dual-luciferase reporter gene assay, quantitative real-time polymerase chain reaction and Western blot analysis were applied to investigate the reversing effect of ALOB and its underlying mechanisms. The results indicated that ALOB mediated the resistance of MG-63/DOX cells to DOX by inhibiting P-glycoprotein function, transcription and expression. Besides, ALOB also enhanced the sensitivity of MG-63/DOX cells to other conventional chemotherapeutic drugs. Cell viability assay confirmed the reversing activity of ALOB. Furthermore, ALOB increased DOX-induced apoptosis at nontoxic concentration. In addition, ALOB showed inhibitory effect on NF-kappaB transcription in a DOX-independent manner. Furthermore, NF-kappaB signaling was suppressed by ALOB in an IKK-dependent manner. These studies not only demonstrate that ALOB is a potential agent for reversal of drug resistant cancers, but also testify that ALOB reverses multidrug resistance by inhibiting P-glycoprotein via NF-kappaB signaling. PMID- 25837272 TI - Garlic for hypertension: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: In the past decade, garlic has become one of the most popular complementary therapies for blood pressure (BP) control used by hypertensive patients. Numerous clinical studies have focused on the BP-lowering effect of garlic, but results have been inconsistent. Overall, there is a dearth of information available to guide the clinical community on the efficacy of garlic in hypertensive patients. AIM: To systematically review the medical literature to investigate the current evidence of garlic for the treatment of hypertension. METHODS: PubMed, the Cochrane Library and EMBASE were searched for appropriate articles from their respective inceptions until August 2014. Randomized, placebo controlled trials comparing garlic vs. a placebo in patients with hypertension were considered. Papers were independently reviewed by two reviewers and were analyzed using Cochrane software Revman 5.2. RESULTS: A total of seven randomized, placebo-controlled trials were identified. Compared with the placebo, this meta-analysis revealed a significant lowering effect of garlic on both systolic BP (WMD: -6.71 mmHg; 95% CI: -12.44 to -0.99; P = 0.02) and diastolic BP (WMD: -4.79 mmHg; 95% CI: -6.60 to -2.99; P < 0.00001). No serious adverse events were reported in any of the trials. CONCLUSION: The present review suggests that garlic is an effective and safe approach for hypertension. However, more rigorously designed randomized controlled trials focusing on primary endpoints with long-term follow-up are still warranted before garlic can be recommended to treat hypertensive patients. PMID- 25837273 TI - Scopoletin has a potential activity for anti-aging via autophagy in human lung fibroblasts. AB - Autophagy was known to be associated with aging in addition to cancer and neurodegeneration. The effects of scopoletin on autophagy and anti-aging were investigated in human lung fibroblast cell line, IMR 90. Here we show that scopoletin induces autophagy. It is also identified that the modulation of p53 by scopoletin are related to the induction of autophagy. Moreover, the level of SA beta-Gal staining, an aging marker, is reduced by scopoletin. In addition, while the expression levels of histone deacetylases such as HDAC1, SIRT1 and SIRT6 are increased in IMR 90 cells in the presence of scopoletin, the expression levels of histone acetyltransferases are decreased. Furthermore, scopoletin enhances the level of transcription factors such as Nrf-2and p-FoxO1 related to anti-aging. In addition, scopoletin modulates the reprogramming proteins. Therefore, these findings suggest that scopoletin could exert a positive effect on anti-aging related to autophagy through modulation of p53 in human lung fibroblasts. PMID- 25837274 TI - 4-Methylthiobutyl isothiocyanate (Erucin) from rocket plant dichotomously affects the activity of human immunocompetent cells. AB - Isothiocyanates (ITC) from the Brassicaceae plant family are regarded as promising for prevention and treatment of cancer. However, experimental settings consider their therapeutic action without taking into account the risk of unwanted effects on healthy tissues. In the present study we investigated the effects of Eruca sativa seed extract containing MTBITC (Erucin) and pure Erucin from rocket plant on healthy cells of the human immune system in vitro. Hereby, high doses of the plant extract as well as of Erucin inhibited cell viability of human lymphocytes via induction of apoptosis to comparable amounts. Non-toxic low concentrations of the plant extract and pure Erucin altered the expression of the interleukin (IL)-2 receptor but did not affect further T cell activation, proliferation and the release of the effector molecules interferon (IFN)-gamma and IL-2 of T-lymphocytes. However, the activity of NK-cells was significantly reduced by non-toxic concentrations of the plant extract and pure Erucin. These results indicate that the plant extract and pure Erucin interfere with the function of human T lymphocytes and decreases the activity of NK-cells in comparable concentrations. Long-term clinical studies with ITC-enriched plant extracts from Brassicaceae should take this into account. PMID- 25837275 TI - Vitexin protects brain against ischemia/reperfusion injury via modulating mitogen activated protein kinase and apoptosis signaling in mice. AB - Vitexin is a major bioactive flavonoid compound derived from the dried leaf of hawthorn (Crataegus pinnatifida), a widely used conventional folk medicine in China. Recent studies have shown that vitexin presents neuroprotective effects in vitro. Whether this protective effect applies to the cerebral ischemia/reperfusion (I/R) injury remains elusive. In the present study, we examined the potential neuroprotective effect of vitexin against cerebral I/R injury and underlying mechanisms. A focal cerebral I/R model in male Kunming mice was induced by middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 22 h. The neurological function and infarct volume were assessed by using Long's five-point scale system and triphenyl-tetrazolium chloride (TTC) staining technique, respectively. Neuronal damage was evaluated by histological staining. Extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 phosphorylation, and apoptosis were measured via Western blot at 24 h after reperfusion. As a result, systemic vitexin treatment significantly reduced neurological deficit, cerebral infarct volume and neuronal damage when compared with the I/R group. Western blot analyses revealed that vitexin markedly upregulated p-ERK1/2 and downregulated p-JNK and p-p38. Meanwhile, vitexin increased Bcl-2 expression and suppressed the overexpression of Bax in the I/R injury mice. In conclusion, the results indicate that vitexin protects brain against cerebral I/R injury, and this effect may be regulated by mitogen-activated protein kinase (MAPK) and apoptosis signaling pathways. PMID- 25837276 TI - The eudesmanolide tanapsin from Tanacetum oshanahanii and its acetate induce cell death in human tumor cells through a mechanism dependent on reactive oxygen species. AB - In this study the cytotoxicities of two species of Tanacetum were evaluated against human tumor cells. Tanacetum oshanahanii extract was more cytotoxic than Tanacetum ptarmiciflorum. Analyses of both extracts of Tanacetum by ultrahigh performance liquid chromatography-tandem mass spectrometry revealed that T. oshanahanii extract contains the eudesmanolide tanapsin, while T. ptarmiciflorum lacks this sesquiterpene lactone. Tanapsin was cytotoxic against leukemia and melanoma cells, including cells that overexpress Bcl-2 and Bcl-xL, with IC50 values of approximately 10 uM, but not against quiescent or proliferating human peripheral blood mononuclear cells. Treatment of cells with tanapsin induced apoptosis. This was prevented by the non-specific caspase inhibitor z-VAD-fmk, and reduced by the selective caspase-3/7 inhibitor z-DEVD-fmk. Tanapsin acetate was also cytotoxic against leukemia and melanoma cells and a potent apoptotic inducer. Tanapsin-induced cell death was found to be associated with (i) the loss of inner mitochondrial membrane potential (DeltaPsim) and release of mitochondrial cytochrome c, (ii) the activation of multiple caspases and the mitogen-activated protein kinase pathway, and (iii) an increase in reactive oxygen species generation. Generation of reactive oxygen species in response to tanapsin seems to play a crucial role in the cell death process since the antioxidant N-acetyl-l-cysteine blocked both ROS generation and cell death. PMID- 25837278 TI - Could EU herbal monographs contribute to Malta's treatment armamentarium? AB - Ten years have passed since Directive 2004/24/EC regulating herbal medicinal products across the EU were published. The directive created the Committee on Herbal Medicinal Products within the European Medicines Agency whose remit includes the creation and publishing of official EU monographs on herbal medicinal products. These monographs include the official uses of the products and their evidence for efficacy and safety. To this effect, we are interested in analysing the potential impact herbal product EU monographs could have on the therapeutic treatment options available for prescribers in Malta. Therefore our aim was two-fold. First, to rationalise the spread of indications of the herbal substances listed in the community herbal monograph inventory and subsequently determine if these herbal substances could potentially contribute to the treatment options available in our local scenario (Malta). 128 EU monographs were analysed resulting in a total of 230 indications which subsequently codified into 42 unique ATC codes. The Malta Medicines List contains 1456 unique ATC codes. Comparative analysis of the Malta Medicines List revealed that the 21 therapeutic areas had 4 or less pharmaceutically used substances (5th level ATC codes) registered and therefore in our opinion are areas with limited therapeutic choice. The following 4 therapeutic areas, A05 bile and liver therapy, A13 tonics, A15 appetite stimulants and D03 preparations for treatment of wounds and ulcers, could potentially benefit from the registration of herbal medicinal products according to the EU herbal monographs. If such registration is effected the aforementioned areas would no longer be considered limited because more than 4 therapeutic choices would be available to prescribers. This study is the first study across the EU to analyse the potential impact of published EU herbal monographs on therapeutic coverage in an EU member state and confirms the notion that herbal products could potentially increase the treatment options available in areas where few medical products have been registered due to Malta's small market size. PMID- 25837277 TI - Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial. AB - BACKGROUND: We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder. HYPOTHESIS: We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events. STUDY DESIGN: Phase II randomized placebo controlled clinical trial. METHODS: 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models. RESULTS: Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p = 0.79, p = 0.28, and p = 0.17, respectively). The decline in HAM-D scores was greater for sertraline (-8.2, 95% confidence interval [CI], 12.7 to -3.6) versus R. rosea (-5.1, 95% CI: -8.8 to -1.3) and placebo (-4.6, 95% CI: -8.6 to -0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44-8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38 5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p = 0.012). CONCLUSIONS: Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression. PMID- 25837279 TI - Development of a standardized and effect-optimized herbal extract of Wedelia chinensis for prostate cancer. AB - Herbal medicine is a popular complementary or alternative treatment for prostate cancer. Wedelia chinensis has at least three active compounds, wedelolactone, luteolin, and apigenin synergistically inhibiting prostate cancer cell growth in vitro. Here, we report a systematic study to develop a standardized and effect optimized herbal extract, designated as W. chinensis extract (WCE) to facilitate its future scientific validation and clinical use. Ethanolic extract of dried W. chinensis plant was further condensed, acid hydrolyzed, and enriched with preparative chromatography. The chemical compositions of multiple batches of the standardized preparation WCE were quantified by LC/MS/MS, and biological activities were analyzed by in vitro and in vivo assays. Furthermore, the pharmacokinetics of the holistic WCE were compared with the combination of the equivalent principal active compounds through oral administration. The results indicated that quantitative chemical assay and PSA (prostate-specific antigen) reporter assay together are suitable to measure the quality and efficacy of a standardized Wedelia extract on a xenograft tumor model. The presence of minor concomitant compounds in WCE prolonged the systemic exposure to the active compounds, thus augmented the anti-tumor efficacy of WCE. In conclusion, a combination of LC/MS/MS and PSA reporter assay is suitable to qualify a standardized preparation of WCE. Furthermore, the pharmacokinetics and oral bioavailability of active compounds demonstrate that holistic WCE exerted additional pharmacological synergy beyond the multi-targeted therapeutic effects caused by more than one active compound. WCE merits a higher priority to be studied for use in prostate cancer treatment. PMID- 25837280 TI - Salvia plebeia extract inhibits the inflammatory response in human rheumatoid synovial fibroblasts and a murine model of arthritis. AB - Salvia plebeia R. Br. has been used to treat a variety of inflammatory diseases and as an antioxidant in many countries, including Korea and China. In this study, we investigated the effects of S. plebeia extract (SPE) on inflammatory arthritis and the underlying mechanisms of action. We used a collagen-induced arthritis (CIA) mouse model. TNF-alpha-stimulated rheumatoid arthritis (RA) synovial fibroblasts were used to elucidate the underlying mechanisms of action. Oral administration of SPE improved the clinical arthritis score, footpad thickness, and histologic changes, as well as serum IgG1 and IgG2a levels. SPE administration inhibited Th1/Th2/Th17 phenotype CD4(+) T lymphocyte expansion in inguinal lymph node and expression of inflammatory mediators such as cytokines, MMP-1, and MMP-3 in the ankle joint tissue. SPE significantly suppressed the expression of cytokines and MMP-1 by down-regulating NF-kappaB, Akt, and mitogen activated protein kinases in RA synovial fibroblasts. Taken together, these results indicate that SPE is therapeutically efficacious against chronic inflammatory arthritis, suggesting that SPE is a candidate for treating RA. PMID- 25837281 TI - The floating forest: traditional knowledge and use of matupa vegetation islands by riverine peoples of the central Amazon. AB - Matupas are floating vegetation islands found in floodplain lakes of the central Brazilian Amazon. They form initially from the agglomeration of aquatic vegetation, and through time can accumulate a substrate of organic matter sufficient to grow forest patches of several hectares in area and up to 12 m in height. There is little published information on matupas despite their singular characteristics and importance to local fauna and people. In this study we document the traditional ecological knowledge of riverine populations who live near and interact with matupas. We expected that their knowledge, acquired through long term observations and use in different stages of the matupa life cycle, could help clarify various aspects about the ecology and natural history of these islands that field biologists may not have had the opportunity to observe. Research was carried out in five riverine communities of the Amana Sustainable Development Reserve (Brazil). Semi-structured interviews were conducted with 45 inhabitants in order to register local understandings of how matupas are formed, biotic/abiotic factors related to their occurrence, the plants and animals that occur on them, their ecological relevance, and local uses. Local people elucidated several little-known aspects about matupa ecology, especially regarding the importance of seasonal dynamics of high/low water for matupas formation and the relevance of these islands for fish populations. Soil from matupas is especially fertile and is frequently gathered for use in vegetable gardens. In some cases, crops are planted directly onto matupas, representing an incipient agricultural experiment that was previously undocumented in the Amazon. Matupas are also considered a strategic habitat for fishing, mainly for arapaima (Arapaima gigas). The systematic study of traditional ecological knowledge proved to be an important tool for understanding this little-known Amazonian landscape. PMID- 25837282 TI - The Dorsal Agranular Insular Cortex Regulates the Cued Reinstatement of Cocaine Seeking, but not Food-Seeking, Behavior in Rats. AB - Prior studies suggest that the insular cortex (IC), and particularly its posterior region (the PIc), is involved in nicotine craving and relapse in humans and rodents. The present experiments were conducted to determine whether the IC and its different subregions regulate relapse to cocaine-seeking behavior in rats. To address this issue, male Sprague-Dawley rats underwent cocaine self administration followed by extinction training and reinstatement tests. Before each reinstatement, the PIc or the more anterior dorsal agranular IC (AId) was inactivated to determine their roles in the reinstatement to cocaine seeking. In contrast to the nicotine findings, PIc inactivation had no effect on cue-induced reinstatement for cocaine seeking. However, AId inactivation reduced cued reinstatement while having no effect on cocaine-prime reinstatement. AId inactivation had no effect on reinstatement of food-seeking behavior induced by cues, a food-prime, or cues+food-prime. Based on previous work hypothesizing a role for corticotropin-releasing factor (CRF) in the IC during craving and relapse, a subsequent experiment found that CRF receptor-1 (CRF1) blockade in the AId similarly reduced cued reinstatement. Our results suggest that the AId, along with CRF1 receptors in this region, regulates reinstatement to cocaine seeking, but not food seeking, depending on the type of reinstatement, whereas PIc activity does not influence cue-induced reinstatement. PMID- 25837283 TI - Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue. AB - Histone deacetylases (HDACs) are promising therapeutic targets for neurological and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the molecular, cellular and behavioral level are limited. Therefore, we interrogated the biological effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compounds for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine density, while HDAC3 inhibition was ineffective. Genome-wide gene expression analysis by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathological brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy. PMID- 25837284 TI - Treatment Outcome-Related White Matter Differences in Veterans with Posttraumatic Stress Disorder. AB - Posttraumatic stress disorder (PTSD) is a debilitating disorder that has been associated with brain abnormalities, including white matter alterations. However, little is known about the effect of treatment on these brain alterations. To investigate the course of white matter alterations in PTSD, we used a longitudinal design investigating treatment effects on white matter integrity using diffusion tensor imaging (DTI). Diffusion tensor and magnetization transfer images were obtained pre- and posttreatment from veterans with (n=39) and without PTSD (n=22). After treatment, 16 PTSD patients were remitted, and 23 had persistent PTSD based on PTSD diagnosis. The dorsal and hippocampal cingulum bundle, stria terminalis, and fornix were investigated as regions of interest. Exploratory whole-brain analyses were also performed. Groups were compared with repeated-measures ANOVA for fractional anisotropy (FA), and magnetization transfer ratio. Persistently symptomatic PTSD patients had increasing FA of the dorsal cingulum over time, and at reassessment these FA values were higher than both combat controls and the remitted PTSD group. Group-by-time interactions for FA were found in the hippocampal cingulum, fornix, and stria terminalis, posterior corona radiata, and superior longitudinal fasciculus. Our results indicate that higher FA of the dorsal cingulum bundle may be an acquired feature of persistent PTSD that develops over time. Furthermore, treatment might have differential effects on the hippocampal cingulum, fornix, stria terminalis, posterior corona radiata, and superior longitudinal fasciculus in remitted vs persistent PTSD patients. This study contributes to a better understanding of the neural underpinnings of PTSD treatment outcome. PMID- 25837285 TI - Comparison of the Japanese Orthopaedic Association (JOA) score and modified JOA (mJOA) score for the assessment of cervical myelopathy: a multicenter observational study. AB - OBJECTIVES: The Japanese Orthopaedic Association (JOA) score is widely used to assess the severity of clinical symptoms in patients with cervical compressive myelopathy, particularly in East Asian countries. In contrast, modified versions of the JOA score are currently accepted as the standard tool for assessment in Western countries. The objective of the present study is to compare these scales and clarify their differences and interchangeability and verify their validity by comparing them to other outcome measures. MATERIALS AND METHODS: Five institutions participated in this prospective multicenter observational study. The JOA and modified JOA (mJOA) proposed by Benzel were recorded preoperatively and at three months postoperatively in patients with cervical compressive myelopathy who underwent decompression surgery. Patient reported outcome (PRO) measures, including Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), the Short Form-12 (SF-12) and the Neck Disability Index (NDI), were also recorded. The preoperative JOA score and mJOA score were compared to each other and the PRO values. A Bland-Altman analysis was performed to investigate their limits of agreement. RESULTS: A total of ninety two patients were included. The correlation coefficient (Spearman's rho) between the JOA and mJOA was 0.87. In contrast, the correlations between JOA/mJOA and the other PRO values were moderate (|rho| = 0.03 - 0.51). The correlation coefficient of the recovery rate between the JOA and mJOA was 0.75. The Bland-Altman analyses showed that limits of agreement were 3.6 to -1.2 for the total score, and 55.1% to -68.8% for the recovery rates. CONCLUSIONS: In the present study, the JOA score and the mJOA score showed good correlation with each other in terms of their total scores and recovery rates. Previous studies using the JOA can be interpreted based on the mJOA; however it is not ideal to use them interchangeably. The validity of both scores was demonstrated by comparing these values to the PRO values. PMID- 25837286 TI - Differential interaction of hGDH1 and hGDH2 with manganese: Implications for metabolism and toxicity. AB - Manganese (Mn) is an essential trace element that serves as co-factor for many important mammalian enzymes. In humans, the importance of this cation is highlighted by the fact that low levels of Mn cause developmental and metabolic abnormalities and, on the other hand, chronic exposure to excessive amounts of Mn is characterized by neurotoxicity, possibly mediated by perturbation of astrocytic mitochondrial energy metabolism. Here we sought to study the effect of Mn on the two human glutamate dehydrogenases (hGDH1 and hGDH2, respectively), key mitochondrial enzymes involved in numerous cellular processes, including mitochondrial metabolism, glutamate homeostasis and neurotransmission, and cell signaling. Our studies showed that, compared to magnesium (Mg) and calcium (Ca), Mn exerted a significant inhibitory effect on both human isoenzymes with hGDH2 being more sensitive than hGDH1, especially under conditions of low ADP levels. Specifically, in the presence of 0.25 mM ADP, the Mn IC50 was 1.14 +/- 0.02 mM and 1.54 +/- 0.08 mM for hGDH2 and for hGDH1, respectively (p = 0.0001). Increasing Mn levels potentiated this differential effect, with 3 mM Mn inhibiting hGDH2 by 96.5% and hGDH1 by 70.2%. At 1 mM ADP, the Mn IC50 was 1.84 +/- 0.02 mM and 2.04 +/- 0.07 mM (p = 0.01) for hGDH2 and hGDH1, respectively, with 3 mM Mn inhibiting hGDH2 by 93.6% and hGDH1 by 70.9%. These results were due to the sigmoidal inhibitory curve of Mn that was more pronounced for hGDH2 than for hGDH1. Indeed, at 0.25 mM, the Hill coefficient value was higher for hGDH2 (3.42 +/- 0.20) than for hGDH1 (1.94 +/- 0.25; p = 0.0002) indicating that interaction of Mn with hGDH2 was substantially more co-operative than for hGDH1. These findings, showing an enhanced sensitivity of the hGDH2 isoenzyme to Mn, especially at low ADP levels, might be of pathophysiological relevance under conditions of Mn neurotoxicity. PMID- 25837287 TI - Glutaminases in brain: Multiple isoforms for many purposes. AB - Glutaminase is expressed in most mammalian tissues and cancer cells, but recent studies are now revealing a considerably degree of complexity in its pattern of expression and functional regulation. Novel transcript variants of the mammalian glutaminase Gls2 gene have been recently found and characterized in brain. Co expression of different isoforms in the same cell type would allow cells to fine tune their Gln/Glu levels under a wide range of metabolic states. Moreover, the discovery of protein interacting partners and novel subcellular localizations, for example nucleocytoplasmic in neurons and astrocytes, strongly suggest non neurotransmission roles for Gls2 isoforms associated with transcriptional regulation and cellular differentiation. Of note, Gls isoforms have been considered as an important trophic factor for neuronal differentiation and postnatal development of brain regions. On the other hand, glutaminases are taking center stage in tumor biology as new therapeutic targets to inhibit metabolic reprogramming of cancer cells. Interestingly, glutaminase isoenzymes play seemingly opposing roles in cancer cell growth and proliferation; this issue will be also succinctly discussed with special emphasis on brain tumors. PMID- 25837288 TI - Associations between infant temperament, maternal stress, and infants' sleep across the first year of life. AB - Effects of temperament and maternal stress on infant sleep behaviors were explored longitudinally. Negative temperament was associated with sleep problems, and with longer sleep latency and night wakefulness, whereas maternal stress was associated with day sleep duration, suggesting infant and maternal characteristics affect sleep differentially. PMID- 25837289 TI - Galectin-3 binding protein links circulating microparticles with electron dense glomerular deposits in lupus nephritis. AB - OBJECTIVE: A high level of galectin-3-binding protein (G3BP) appears to distinguish circulating cell-derived microparticles in systemic lupus erythematosus (SLE). The aim of this study is to characterize the population of G3BP-positive microparticles from SLE patients compared to healthy controls, explore putative clinical correlates, and examine if G3BP is present in immune complex deposits in kidney biopsies from patients with lupus nephritis. METHODS: Numbers of annexin V-binding and G3BP-exposing plasma microparticles from 56 SLE patients and 36 healthy controls were determined by flow cytometry. Quantitation of microparticle-associated G3BP, C1q and immunoglobulins was obtained by liquid chromatography tandem mass spectrometry (LC-MS/MS). Correlations between microparticle-G3BP data and clinical parameters were analyzed. Co-localization of G3BP with in vivo-bound IgG was examined in kidney biopsies from one non-SLE control and from patients with class IV (n = 2) and class V (n = 1) lupus nephritis using co-localization immune electron microscopy. RESULTS: Microparticle-G3BP, microparticle-C1q and microparticle-immunoglobulins were significantly (P < 0.01) increased in SLE patients by LC-MS/MS. Three G3BP exposing microparticle populations could be discerned by flow cytometry, including two subpopulations that were significantly increased in SLE samples (P = 0.01 and P = 0.0002, respectively). No associations of G3BP-positive microparticles with clinical manifestations or disease activity were found. Immune electron microscopy showed co-localization of G3BP with in vivo-bound IgG in glomerular electron dense immune complex deposits in all lupus nephritis biopsies. CONCLUSIONS: Both circulating microparticle-G3BP numbers as well as G3BP expression are increased in SLE patients corroborating G3BP being a feature of SLE microparticles. By demonstrating G3BP co-localized with deposited immune complexes in lupus nephritis, the study supports cell-derived microparticles as a major autoantigen source and provides a new understanding of the origin of immune complexes occurring in lupus nephritis. PMID- 25837290 TI - Harm Reduction Agencies as a Potential Site for Buprenorphine Treatment. AB - BACKGROUND: Harm reduction agencies complement addiction treatment by providing diverse services that improve the health of people who use drugs. Buprenorphine maintenance treatment (BMT) is an effective opioid addiction treatment that may be provided from flexible settings, potentially including harm reduction agencies. This study investigated attitudes toward different potential sites for BMT (harm reduction agencies, general medical clinics, and drug treatment programs) among harm reduction clients. METHODS: Using computer-based interviews, participants indicated preferred potential site for BMT (harm reduction agency, drug treatment program, or general medical clinic), interest in BMT by potential site, motivation for treatment, and barriers to BMT. Multivariable logistic regression was used to determine factors associated with harm reduction agency preference. RESULTS: Of 102 opioid users, the most preferred potential site for BMT was a harm reduction agency (51%), whereas fewer preferred general medical clinics (13%), drug treatment programs (12%), or were not interested in BMT (25%). In multivariable analysis, experiencing >=1 barrier to BMT was strongly associated with preferring harm reduction agencies (adjusted odds ratio [aOR] = 3.39, 95% confidence interval [CI]: 1.00-11.43). CONCLUSIONS: The potential to initiate BMT at harm reduction agencies is highly favorable among harm reduction clients, especially among those experiencing barriers to BMT. Offering BMT at harm reduction agencies could improve access to treatment, but studies are needed to determine safety and efficacy of this approach. PMID- 25837295 TI - Start-up of granule-based denitrifying reactors with multiple magnesium supplementation strategies. AB - In the present work, the effect of Mg(2+) supplementation on the start-up of a denitrification process and the granulation of denitrifying sludge was investigated in three upflow anaerobic sludge blanket (UASB) reactors. The reactors R1 and R2 were continuously and intermittently, respectively, supplied with 50 mg L(-1) Mg(2+), whereas R0 was used as the control. The nitrogen loading rate (NLR) and organic loading rate (OLR) gradually increased, and extremely high values were obtained (36.0 kgN m(-3) d(-1) and 216.0 kgCOD m(-3) d(-1), respectively). Granulation occurred in R1 first, but the reactor capacities were comparable. Suffering from starvation, the R0-R2 performances were comparable. At the end of the experiment, the average diameter of the granules in R0, R1, and R2 were 1.67, 1.72 and 1.68 mm, respectively, and the settling velocities of the granules in R1 and R2 were 1.14-fold the speed of R0. The specific denitrifying activity (SDA) of the sludge from the reactors supplied with Mg(2+) was greater than the reactor without Mg(2+). Intermittent Mg(2+) supplementation was identified as the best choice to be utilized to cultivate denitrifying granules, which was consistent with kinetic analysis. PMID- 25837296 TI - A new method for determining the sources of airborne particles. AB - Air quality is a major issue for humans owing to the fact that the content of particles in the atmosphere has multiple implications for life quality, ecosystem dynamics and environment. Scientists are therefore particularly interested in discovering the origin of airborne particles. A new method has been developed to model the relationship between the emission surface and the total amount of airborne particles at a given distance, employing olive pollen and olive groves as examples. A third-degree polynomial relationship between the air particles at a particular point and the distance from the source was observed, signifying that the nearest area to a point is not that which is most correlated with its air features. This work allows the origin of airborne particles to be discovered and could be implemented in different disciplines related to atmospheric aerosol, thus providing a new approach with which to discover the dynamics of airborne particles. PMID- 25837297 TI - What drives successful implementation of pollution prevention and cleaner technology strategy? The role of innovative capability. AB - Firms that are dynamic and prepared to implement environmental strategies have a potential competitive advantage over their industry counterparts. Therefore, it is important to understand, what capabilities are required to implement proactive environmental strategies. The paper discusses the attributes of innovative capability required by firms in order to adopt pollution prevention and cleaner technology strategies. Empirical results show that process and behavioral innovativeness are required by firms to implement a pollution prevention strategy. In addition to process and behavioral innovativeness, firms need a top management with high risk-taking ability as well as market, product, and strategic innovativeness to implement a cleaner technology strategy. The paper proposes some important managerial implications on the basis of the above research findings. PMID- 25837298 TI - Soil organic carbon stocks assessment in Mediterranean natural areas: a comparison of entire soil profiles and soil control sections. AB - Soil organic carbon (SOC) is an important part of the global carbon (C) cycle. In addition, SOC is a soil property subject to changes and highly variable in space and time. Over time, some researches have analyzed entire soil profile (ESP) by pedogenetic horizons and other researches have analyzed soil control sections (SCS) to different thickness. However, very few studies compare both methods (ESP versus SCS). This research sought to analyze the SOC stock (SOCS) variability using both methods (ESP and SCS) in The Despenaperros Natural Park, a nature reserve that consists of a 76.8 km(2) forested area in southern Spain. Thirty four sampling points were selected in the study zone. Each sampling point was analyzed in two different ways, as ESP (by horizons) and as SCS with different depth increments (0-25, 25-50, 50-75 and 75-100 cm). The major goal of this research was to study the SOCS variability at regional scale. The soils investigated in this study included Phaeozems, Cambisols, Regosols and Leptosols. Total SOCS in the Despenaperros Natural Park was over 28.2% greater when SCS were used compared to ESP, ranging from 0.8144 Tg C (10,604.2 Mg km(-2)) to 0.6353 Tg C (8272.1 Mg km(-2)) respectively (1 Tg = 10(12) g). However, when the topsoil (surface horizon and superficial section control) was analyzed, this difference increased to 59.8% in SCS compared to ESP. The comparison between ESP and SCS showed the effect of mixing pedogenetic horizons when depth increments were analyzed. This indicates an overestimate of T-SOCS when sampling by SCS. PMID- 25837299 TI - Phthalocyanine-nanocarbon ensembles: from discrete molecular and supramolecular systems to hybrid nanomaterials. AB - Phthalocyanines (Pcs) are macrocyclic and aromatic compounds that present unique electronic features such as high molar absorption coefficients, rich redox chemistry, and photoinduced energy/electron transfer abilities that can be modulated as a function of the electronic character of their counterparts in donor-acceptor (D-A) ensembles. In this context, carbon nanostructures such as fullerenes, carbon nanotubes (CNTs), and, more recently, graphene are among the most suitable Pc "companions". Pc-C60 ensembles have been for a long time the main actors in this field, due to the commercial availability of C60 and the well established synthetic methods for its functionalization. As a result, many Pc-C60 architectures have been prepared, featuring different connectivities (covalent or supramolecular), intermolecular interactions (self-organized or molecularly dispersed species), and Pc HOMO/LUMO levels. All these elements provide a versatile toolbox for tuning the photophysical properties in terms of the type of process (photoinduced energy/electron transfer), the nature of the interactions between the electroactive units (through bond or space), and the kinetics of the formation/decay of the photogenerated species. Some recent trends in this field include the preparation of stimuli-responsive multicomponent systems with tunable photophysical properties and highly ordered nanoarchitectures and surface supported systems showing high charge mobilities. A breakthrough in the Pc nanocarbon field was the appearance of CNTs and graphene, which opened a new avenue for the preparation of intriguing photoresponsive hybrid ensembles showing light-stimulated charge separation. The scarce solubility of these 1-D and 2-D nanocarbons, together with their lower reactivity with respect to C60 stemming from their less strained sp(2) carbon networks, has not meant an unsurmountable limitation for the preparation of variety of Pc-based hybrids. These systems, which show improved solubility and dispersibility features, bring together the unique electronic transport properties of CNTs and graphene with the excellent light-harvesting and tunable redox properties of Pcs. A singular and distinctive feature of these Pc-CNT/graphene (single- or few-layers) hybrid materials is the control of the direction of the photoinduced charge transfer as a result of the band-like electronic structure of these carbon nanoforms and the adjustable electronic levels of Pcs. Moreover, these conjugates present intensified light harvesting capabilities resulting from the grafting of several chromophores on the same nanocarbon platform. In this Account, recent progress in the construction of covalent and supramolecular Pc-nanocarbon ensembles is summarized, with a particular emphasis on their photoinduced behavior. We believe that the high degree of control achieved in the preparation of Pc-carbon nanostructures, together with the increasing knowledge of the factors governing their photophysics, will allow for the design of next-generation light-fueled electroactive systems. Possible implementation of these Pc-nanocarbons in high performance devices is envisioned, finally turning into reality much of the expectations generated by these materials. PMID- 25837300 TI - Chemically functionalized single-walled carbon nanotubes enhance the glutamate uptake characteristics of mouse cortical astrocytes. AB - Using a radioactive glutamate uptake assay and immunolabeling, we report that single-walled carbon nanotubes, chemically functionalized with polyethylene glycol (SWCNT-PEG), delivered as a colloidal solute, cause an increase in the uptake of extracellular glutamate by astrocytes and an increase in the immunoreactivity of the glutamate transporter GLAST on their cell surface, which is likely a consequence of an increase in the immunoreactivity of glial fibrillary acidic protein. Additional corollary is that astrocytes exposed to SWCNT-PEG became larger and stellate, morphological characteristics of maturation and heightened activity of these glial cells. These results imply that SWCNT-PEG could potentially be used as a viable candidate for neural prosthesis applications, perhaps to alleviate the death toll of neurons due to glutamate excitotoxicity, a pathological process observed in brain and spinal cord injuries. PMID- 25837301 TI - L-Alanylglutamine inhibits signaling proteins that activate protein degradation, but does not affect proteins that activate protein synthesis after an acute resistance exercise. AB - SustamineTM (SUS) is a dipeptide composed of alanine and glutamine (AlaGln). Glutamine has been suggested to increase muscle protein accretion; however, the underlying molecular mechanisms of glutamine on muscle protein metabolism following resistance exercise have not been fully addressed. In the present study, 2-month-old rats climbed a ladder 10 times with a weight equal to 75 % of their body mass attached at the tail. Rats were then orally administered one of four solutions: placebo (PLA-glycine = 0.52 g/kg), whey protein (WP = 0.4 g/kg), low dose of SUS (LSUS = 0.1 g/kg), or high dose of SUS (HSUS = 0.5 g/kg). An additional group of sedentary (SED) rats was intubated with glycine (0.52 g/kg) at the same time as the ladder-climbing rats. Blood samples were collected immediately after exercise and at either 20 or 40 min after recovery. The flexor hallucis longus (FHL), a muscle used for climbing, was excised at 20 or 40 min post exercise and analyzed for proteins regulating protein synthesis and degradation. All supplements elevated the phosphorylation of FOXO3A above SED at 20 min post exercise, but only the SUS supplements significantly reduced the phosphorylation of AMPK and NF-kB p65. SUS supplements had no effect on mTOR signaling, but WP supplementation yielded a greater phosphorylation of mTOR, p70S6k, and rpS6 compared with PLA at 20 min post exercise. However, by 40 min post exercise, phosphorylation of mTOR and rpS6 in PLA had risen to levels not different than WP. These results suggest that SUS blocks the activation of intracellular signals for MPB, whereas WP accelerates mRNA translation. PMID- 25837302 TI - Effects of Bond Location on the Ignition and Reaction Pathways of trans-Hexene Isomers. AB - Chemical structure and bond location are well-known to impact combustion reactivity. The current work presents new experimental autoignition and speciation data on the three trans-hexene isomers (1-hexene, trans-2-hexene, and trans-3-hexene), which describe the effects of the location of the carbon-carbon double bond. Experiments were conducted with the University of Michigan rapid compression facility to determine ignition delay times from pressure time histories. Stoichiometric (phi = 1.0) mixtures at dilution levels of buffer gas:O2 = 7.5 (mole basis) were investigated at an average pressure of 11 atm and temperatures from 837 to 1086 K. Fast gas sampling and gas chromatography were also used to quantitatively measure 13 stable intermediate species formed during the ignition delay period of each isomer at a temperature of ~900 K. The measured ignition delay times and species measurements were in good agreement with previous experimental studies at overlapping conditions. The results were modeled using a gasoline surrogate reaction mechanism from Lawrence Livermore National Laboratory, which contains a submechanism for the trans-hexene isomers. The model predictions captured the overall autoignition characteristics of the hexene isomers well (within a factor of 2), as well as the time histories of several of the intermediate species (e.g., propene). However, there were discrepancies between the model predictions and the experimental data for some species, particularly for the 3-hexene isomer. PMID- 25837303 TI - Anisotropy of the magnetoviscous effect in a ferrofluid with weakly interacting magnetite nanoparticles. AB - The anisotropy of the magnetoviscous effect of a ferrofluid has been studied in a specially designed slit die viscometer, which allows three distinct orientations of the magnetic field with respect to the fluid flow. The corresponding Miesowicz viscosity coefficients were determined in dependence of the shear rate and the magnetic field intensity to gain a comprehensive magnetorheological characterization of the fluid. The particles in the fluid have a mean diameter of 13 nm corresponding to an interaction parameter of lambda ~ 1.3 for magnetite. Thus, the fluid can be expected to show a transition from non-interacting individual particles to microstructures with chain-like associated particles when the magnetic field intensity is increased and the shear rate is decreased. The observed field and shear dependent anisotropy of the magnetoviscous effect is explained coherently in terms of these microstructural changes in the fluid. PMID- 25837304 TI - Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia. AB - Recent findings implicate alterations in glutamate signaling, leading to aberrant synaptic plasticity, in schizophrenia. Matrix metalloproteinase-9 (MMP-9) has been shown to regulate glutamate receptors, be regulated by glutamate at excitatory synapses, and modulate physiological and morphological synaptic plasticity. By means of functional gene polymorphism, gene responsiveness to antipsychotics and blood plasma levels MMP-9 has recently been implicated in schizophrenia. This commentary critically reviews these findings based on the hypothesis that MMP-9 contributes to pathological synaptic plasticity in schizophrenia. PMID- 25837306 TI - Visualizing unresolved scalar couplings by real-time J-upscaled NMR. AB - Scalar coupling patterns contain a wealth of structural information. The determination, especially of small scalar coupling constants, is often prevented by merging the splittings with the signal line width. Here we show that real-time J-upscaling enables the visualization of unresolved coupling constants in the acquisition dimension of one-dimensional (1D) or multidimensional NMR spectra. This technique, which works by introducing additional scalar coupling evolution delays within the recording of the FID (free induction decay), not only stretches the recorded coupling patterns but also actually enhances the resolution of multiplets, by reducing signal broadening by magnetic field inhomogeneities during the interrupted data acquisition. Enlarging scalar couplings also enables their determination in situations where the spectral resolution is limited, such as in the acquisition dimension of heteronuclear broadband decoupled HSQC (heteronuclear single quantum correlation) spectra. PMID- 25837305 TI - Healthy worker survivor bias in the Colorado Plateau uranium miners cohort. AB - Cohort mortality studies of underground miners have been used to estimate the number of lung cancer deaths attributable to radon exposure. However, previous studies of the radon-lung cancer association among underground miners may have been subject to healthy worker survivor bias, a type of time-varying confounding by employment status. We examined radon-mortality associations in a study of 4,124 male uranium miners from the Colorado Plateau who were followed from 1950 through 2005. We estimated the time ratio (relative change in median survival time) per 100 working level months (radon exposure averaging 130,000 mega electron volts of potential alpha energy per liter of air, per working month) using G-estimation of structural nested models. After controlling for healthy worker survivor bias, the time ratio for lung cancer per 100 working level months was 1.168 (95% confidence interval: 1.152, 1.174). In an unadjusted model, the estimate was 1.102 (95% confidence interval: 1.099, 1.112)-39% lower. Controlling for this bias, we estimated that among 617 lung cancer deaths, 6,071 person-years of life were lost due to occupational radon exposure during follow-up. Our analysis suggests that healthy worker survivor bias in miner cohort studies can be substantial, warranting reexamination of current estimates of radon's estimated impact on lung cancer mortality. PMID- 25837307 TI - Antithrombin heparin binding site deficiency: A challenging diagnosis of a not so benign thrombophilia. AB - BACKGROUND: Hereditary antithrombin (AT) deficiency is a rare autosomal dominant disorder characterised by decreased AT activity in plasma and predisposition to recurrent venous thromboembolism (VTE). Thrombotic risk is thought to vary according to the subtype of deficiency, with Heparin Binding Site (HBS) deficiencies being the less thrombogenic. OBJECTIVES AND METHODS: The study population consisted of 82 genetically confirmed HBS deficient patients sharing six different mutations. Plasma samples of 35 of them, including one homozygous patient, were used for the evaluation of 4 commercial activity assays in their ability to diagnose HBS deficiency. We assessed mutation-specific prevalence of venous and arterial thrombosis and the contribution of additional thrombophilic risk factors. RESULTS AND CONCLUSIONS: Only one assay showed 100% sensitivity for all HBS mutations. The other ones failed mainly in the cases with p.Pro73Leu and p.Arg79His mutations. Shortening of incubation time resulted in an increase in sensitivity. In one patient, a novel HBS mutation, p.Asn77His, was identified, a quite exceptional and important finding given the restricted number of causal mutations reported so far in AT HBS deficiency. The overall prevalence of VTE in our study population (35%) was higher than previously reported (6-8%) in these patients. The presence of additional thrombophilic risk factors such as Factor V Leiden or prothrombin gene mutation G20210A contributed to a higher risk of VTE. Interestingly, the p.Pro73Leu and p.Arg79His mutations were associated with a high prevalence of arterial thrombosis. Our data suggest that AT HBS deficiencies are probably more prevalent and less benign than previously assumed. PMID- 25837308 TI - Improving the approach to non-diagnostic aspirates: learning from each other. PMID- 25837310 TI - Plasmodium knowlesi: from severe zoonosis to animal model. AB - Plasmodium knowlesi malaria is a newly described zoonosis in Southeast Asia. Similarly to Plasmodium falciparum, P. knowlesi can reach high parasitaemia in the human host and both species cause severe and fatal illness. Interpretation of host-parasite interactions in studies of P. knowlesi malaria adds a counterpoint to studies on P. falciparum. However, there is no model system for testing the resulting hypotheses on malaria pathophysiology or for developing new interventions. Plasmodium knowlesi is amenable to genetic manipulation in vitro and several nonhuman primate species are susceptible to experimental infection. Here, we make a case for drawing on P. knowlesi as both a human pathogen and an experimental model to lift the roadblock between malaria research and its translation into human health benefits. PMID- 25837309 TI - PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells. AB - Recent studies have revealed in normal thyroid tissue the presence of the transcript of several phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of cyclic nucleotides. In this work, we analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs) presenting or not BRAF V600E mutation and classified according to ATA risk criteria. Furthermore, we tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. PDE5 gene and protein expression were analyzed in two different cohorts of PTCs by real-time PCR using a TaqMan micro-fluid card system and Western blot. MTT and migration assay were used to evaluate the effects of PDE5 inhibitors on proliferation and migration of TPC-1, BCPAP, and 8505C cells. In a first series of 36 PTCs, we found higher expression levels of PDE5A in tumors versus non-tumor (normal) tissues. PTCs with BRAF mutation showed higher levels of mRNA compared with those without mutation. No significant differences were detected between subgroups with low and intermediate ATA risk. Upregulation of PDE5 was also detected in tumor tissue proteins. Similar results were obtained analyzing the second cohort of 50 PTCs. Moreover, all tumor tissues with high PDE5 levels showed reduction of Thyroglobulin, TSH receptor, Thyroperoxidase, and NIS transcripts. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. Our findings demonstrate for the first time an overexpression of PDE5 in PTCs, and the ability of PDE5 inhibitors to block the proliferation of thyroid cancer cells in culture, therefore, suggesting that specific inhibition of PDE5 may be proposed for the treatment of these tumors. PMID- 25837311 TI - The role of estrogens and estrogen receptor signaling pathways in cancer and infertility: the case of schistosomes. AB - Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. Schistosomiasis haematobia also appears to negatively influence fertility, and is particularly associated with female infertility. Given that estrogens and estrogen receptors are key players in human reproduction, we speculate that schistosome estrogen-like molecules may contribute to infertility through hormonal imbalances. Here, we review recent findings on the role of estrogens and estrogen receptors on both carcinogenesis and infertility associated with urogenital schistosomiasis and discuss the basic hormonal mechanisms that might be common in cancer and infertility. PMID- 25837313 TI - Effectiveness and safety of short course liposomal amphotericin B (AmBisome) as first line treatment for visceral leishmaniasis in Bangladesh. AB - BACKGROUND: Bangladesh is one of the endemic countries for Visceral Leishmaniasis (VL). Medecins Sans Frontieres (MSF) ran a VL treatment clinic in the most endemic district (Fulbaria) between 2010 and 2013 using a semi-ambulatory regimen for primary VL of 15 mg/kg Liposomal Amphotericin-B (AmBisome) in three equal doses of 5 mg/kg. The main objective of this study was to analyze the effectiveness and safety of this regimen after a 12 month follow-up period by retrospective analysis of routinely collected program data. A secondary objective was to explore risk factors for relapse. METHODS AND PRINCIPAL FINDINGS: Our analysis included 1521 patients who were initially cured, of whom 1278 (84%) and 1179 (77.5%) were followed-up at 6 and 12 months, respectively. Cure rates at 6 and 12 months were 98.7% (1262/1278) and 96.4% (1137/1179), respectively. Most relapses (26/39) occurred between 6 and 12 months after treatment. Serious adverse events (SAE) were recorded for 7 patients (0.5%). Odds of relapse at 12 months were highest in the youngest and oldest age groups. There was some evidence that spleen size measured on discharge (one month after initiation of treatment) was associated with risk of relapse: OR=1.25 (95% CI 1.01 to 1.55) per cm below lower costal margin (P=0.04). CONCLUSIONS: Our study demonstrates that 15 mg/kg AmBisome in three doses of 5 mg/kg is an effective (>95% cure rate) and safe (<1% SAE) treatment for primary VL in Bangladesh. The majority of relapses occurred between 6 and 12 months, justifying the use of a longer follow-up period when feasible. Assessment of risk of relapse based on easily measured clinical parameters such as spleen size could be incorporated in VL treatment protocols in resource-poor settings where test-of-cure is not always feasible. PMID- 25837312 TI - Proteomics characterization of exosome cargo. AB - Characterization of exosomal cargo is of significant interest because this cargo can provide clues to exosome biogenesis, targeting, and cellular effects and may be a source of biomarkers for disease diagnosis, prognosis and response to treatment. With recent improvements in proteomics technologies, both qualitative and quantitative characterization of exosomal proteins is possible. Here we provide a brief review of exosome proteomics studies and provide detailed protocols for global qualitative, global quantitative, and targeted quantitative analysis of exosomal proteins. In addition, we provide an example application of a standard global quantitative analysis followed by validation via a targeted quantitative analysis of urine exosome samples from human patients. Advantages and limitations of each method are discussed as well as future directions for exosome proteomics analysis. PMID- 25837314 TI - Endometriosis and mild bleeding disorders. PMID- 25837315 TI - Development of a particle-trap preconcentration-soft ionization mass spectrometric technique for the quantification of mercury halides in air. AB - Measurement of oxidized mercury, Hg(II), in the atmosphere poses a significant analytical challenge as Hg(II) is present at ultra-trace concentrations (picograms per cubic meter air). Current technologies are sufficiently sensitive to measure the total Hg present as Hg(II) but cannot determine the chemical speciation of Hg(II). We detail here the development of a soft ionization mass spectrometric technique coupled with preconcentration onto nano- or microparticle based traps prior to analysis for the measurement of mercury halides in air. The current methodology has comparable detection limits (4-11 pg m(-3)) to previously developed techniques for the measurement of total inorganic mercury in air while allowing for the identification of HgX2 in collected samples. Both mercury chloride and mercury bromide have been sporadically detected in Montreal urban and indoor air using atmospheric pressure chemical ionization-mass spectrometry (APCI-MS). We discuss limitations and advantages of the current technique and discuss potential avenues for future research including quantitative trace measurements of a larger range of mercury compounds. PMID- 25837316 TI - [Forms of age-related macular degeneration]. AB - Age-related macular degeneration (AMD) is the major reason for blindness affecting about 50 % of blind people in Germany. Early forms of AMD with drusen and pigment epithelium changes can be detected in 20 % of patients over 65 years old. The dry form of AMD causes slow deterioration of visual acuity, which cannot currently be adequately treated. In contrast development of a choroidal neovascularization (CNV) membrane results in rapid visual loss which will become permanent if treatment is not started immediately. Using anti-vascular endothelial growth factor (VEGF) agents stabilization and improvement of visual acuity is possible. Special types of AMD, such as retinal angiomatous proliferation and polypoidal choroidal vasculopathy are much less common. The natural course of the diseases can be very different, end stages often result in scarring and anti-VEGF agents are only weakly effective. PMID- 25837317 TI - A combination of chorea, myoclonus, and dystonia in a patient with pontocerebellar hypoplasia type 2: a video case presentation. PMID- 25837318 TI - Anti-NMDA receptor encephalitis possibly triggered by measles virus. PMID- 25837319 TI - A frontal syndrome due to a brainstem lesion. PMID- 25837320 TI - Circulating levels of obestatin and copeptin in obese and nonobese women with polycystic ovary syndrome. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies, affecting 5-8% of reproductive-age women. It is associated with insulin resistance, central obesity, type 2 diabetes mellitus, dyslipidemia, and cardiovascular diseases. The current study was undertaken to evaluate serum copeptin and obestatin levels, carotid artery intima-media thickness, and brachial artery flow mediated dilatation in obese and nonobese women with PCOS and age-matched healthy controls and to investigate their relationship with each other and with clinical, metabolic, and hormonal parameters and cardiovascular risk factors. METHOD: In the study population, we analyzed 60 patients with PCOS and 30 age-matched healthy women as controls. The patients with PCOS were divided into two groups based on body mass index (BMI): obese group (BMI>30kg/m(2), n=30) or nonobese group (BMI<30kg/m(2), n=30). History was obtained and a physical examination, peripheral venous blood sampling, and carotid and brachial artery ultrasonography were performed. Serum copeptin and obestatin levels, total testosterone, C-reactive protein (CRP), glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, homeostasis model assessment for insulin resistance (HOMA-IR), carotid artery intima-media thickness (CIMT), and brachial artery flow-mediated vasodilation (FMD) were determined and compared among the groups. RESULTS: Women with PCOS, especially obese ones, had higher triglycerides, HOMA-IR, total testosterone, CRP, systolic and diastolic blood pressure, and waist-to-hip ratio (WHR), and lower HDL. Serum obestatin levels were significantly lower in the obese PCOS group than they were in the nonobese and control groups (p<0.001). Serum copeptin levels were significantly higher in the obese PCOS group than they were in the nonobese PCOS and control groups (p<0.001). CIMT values were similar among the groups (p>0.05). Brachial artery FMD was lower in the PCOS groups than it was in the control group (p<0.001). Obestatin and FMD values were negatively correlated with cardiovascular risk factors, whereas copeptin was positively correlated. A significant positive correlation was found between copeptin, BMI, WHR, hirsutism score, total testosterone, and HOMA-IR. There was no correlation between CIMT, copeptin, obestatin, and FMD. A positive correlation was seen between CIMT, BMI, triglycerides, and HOMA-IR. CONCLUSION: Copeptin and obestatin may provide useful information regarding future cardiovascular risk in PCOS patients as copeptin was positively correlated and obestatin was negatively correlated with cardiovascular risk factors. PMID- 25837322 TI - Henoch-Schonlein purpura complicated by acalculous cholecystitis and intussusception, and following recurrent appendicitis. AB - Henoch-Schonlein purpura (HSP) is the most common childhood systemic vasculitis. Gastro-intestinal involvement occurs in two-thirds of patients. The characteristic skin lesions generally precede abdominal symptoms or present concurrently. A 7-year-old boy presented with intussusception and acalculous cholecystitis and had a cholecystectomy. Two weeks later he was re-admitted with features typical of HSP which responded to corticosteroids. Eleven months later he presented with abdominal pain and recurrence of HSP and, at laparotomy, there was acute appendicitis. This is the first case of a child presenting with HSP complicated by acalculous cholecystitis. PMID- 25837321 TI - Effects of different media supplements on the production of an active recombinant plant peroxidase in a Pichia pastoris Deltaoch1 strain. AB - Recombinant protein production in microorganisms is one of the most studied areas of research in biotechnology today. In this respect the yeast Pichia pastoris is an important microbial production host due to its capability of secreting the target protein and performing posttranslational modifications. In a recent study, we described the development of a robust bioprocess for a glyco-engineered recombinant P. pastoris strain where the native alpha-1,6-mannosyltransfrease OCH1 was knocked out (Deltaoch1 strain). This strain produced the glycosylated enzyme horseradish peroxidase (HRP) with more homogeneous and shorter surface glycans than the respective benchmark strain. However, the recombinant Deltaoch1 strain was physiologically impaired and thus hard to cultivate. We faced cell cluster formation, cell lysis and consequent intensive foam formation. Thus, we investigated the effects of the 3 process parameters temperature, pH and dissolved oxygen concentration on (1) cell physiology, (2) cell morphology, (3) cell lysis, (4) productivity and (5) product purity in a multivariate manner. However, not only process parameters might influence these characteristics, but also media supplements might have an impact. Here, we describe the effects of different heme-precursors as well as of a protease-inhibitor cocktail on the production of active HRP in therecombinant P. pastoris Deltaoch1strain. PMID- 25837324 TI - Retraction. Lipomatosis of the terminal ileum and ileocaecal valve: multidetector CT findings. PMID- 25837323 TI - Dynamics of chemical bond: general discussion. PMID- 25837325 TI - Endometrial osseous metaplasia: an unusual cause of infertility. AB - Osseous metaplasia of the endometrium is a rare disorder associated with the presence of bone in the uterine endometrium. Most patients with this condition presenting with infertility do so owing to the presence of a foreign body in the endometrium. We report a case of a 38-year-old woman who presented with secondary infertility due to osseous metaplasia in the endometrial cavity. She conceived spontaneously after hysteroscopic removal of the bony fragments from the uterus. Uterine osseous metaplasia is a rare cause of infertility that can be easily managed by hysteroscopic removal of the bony fragments, which results in return of fertility. PMID- 25837327 TI - Valvular atrial fibrillation: rheumatic mitral valve disease. PMID- 25837326 TI - Preclinical evaluation of cyclin dependent kinase 11 and casein kinase 2 survival kinases as RNA interference targets for triple negative breast cancer therapy. AB - INTRODUCTION: Targeted therapies for aggressive breast cancers like triple negative breast cancer (TNBC) are needed. The use of small interfering RNAs (siRNAs) to disable expression of survival genes provides a tool for killing these cancer cells. Cyclin dependent kinase 11 (CDK11) is a survival protein kinase that regulates RNA transcription, splicing and mitosis. Casein kinase 2 (CK2) is a survival protein kinase that suppresses cancer cell death. Eliminating the expression of these genes has potential therapeutic utility for breast cancer. METHODS: Expression levels of CDK11 and CK2 mRNAs and associated proteins were examined in breast cancer cell lines and tissue arrays. RNA expression levels of CDC2L1, CDC2L2, CCNL1, CCNL2, CSNK2A1, CSNK2A2, and CSNK2B genes in breast cancer subtypes were analyzed. Effects following transfection of siRNAs against CDK11 and CK2 in cultured cells were examined by viability and clonal survival assays and by RNA and protein measures. Uptake of tenfibgen (TBG) nanocapsules by TNBC cells was analyzed by fluorescence-activated cell sorting. TBG nanocapsules delivered siRNAs targeting CDK11 or CK2 in mice carrying TNBC xenograft tumors. Transcript cleavage and response parameters were evaluated. RESULTS: We found strong CDK11 and CK2 mRNA and protein expression in most human breast cancer cells. Immunohistochemical analysis of TNBC patient tissues showed 100% of tumors stained positive for CDK11 with high nuclear intensity compared to normal tissue. The Cancer Genome Atlas analysis comparing basal to other breast cancer subtypes and to normal breast revealed statistically significant differences. Down-regulation of CDK11 and/or CK2 in breast cancer cells caused significant loss of cell viability and clonal survival, reduced relevant mRNA and protein expression, and induced cell death changes. TBG nanocapsules were taken up by TNBC cells both in culture and in xenograft tumors. Treatment with TBG- siRNA to CDK11 or TBG- siRNA to CK2alphaalpha' nanocapsules induced appropriate cleavage of CDK11 and CK2alpha transcripts in TNBC tumors, and caused MDA-MB-231 tumor reduction, loss of proliferation, and decreased expression of targeted genes. CONCLUSIONS: CDK11 and CK2 expression are individually essential for breast cancer cell survival, including TNBC. These genes serve as promising new targets for therapeutic development in breast cancer. PMID- 25837328 TI - Public Health Climate Change Adaptation Planning Using Stakeholder Feedback. AB - CONTEXT: Public health climate change adaptation planning is an urgent priority requiring stakeholder feedback. The 10 Essential Public Health Services can be applied to adaptation activities. OBJECTIVE: To develop a state health department climate and health adaptation plan as informed by stakeholder feedback. DESIGN: With Centers for Disease Control and Prevention (CDC) funding, the New York State Department of Health (NYSDOH) implemented a 2010-2013 climate and health planning process, including 7 surveys on perceptions and adaptation priorities. PARTICIPANTS: New York State Department of Health program managers participated in initial (n = 41, denominator unknown) and follow-up (72.2%) needs assessments. Surveillance system information was collected from 98.1% of surveillance system managers. For adaptation prioritization surveys, participants included 75.4% of NYSDOH leaders; 60.3% of local health departments (LHDs); and 53.7% of other stakeholders representing environmental, governmental, health, community, policy, academic, and business organizations. Interviews were also completed with 38.9% of other stakeholders. RESULTS: In 2011 surveys, 34.1% of state health program directors believed that climate change would impact their program priorities. However, 84.6% of state health surveillance system managers provided ideas for using databases for climate and health monitoring/surveillance. In 2012 surveys, 46.5% of state health leaders agreed they had sufficient information about climate and health compared to 17.1% of LHDs (P = .0046) and 40.9% of other stakeholders (nonsignificant difference). Significantly fewer (P < .0001) LHDs (22.9%) were incorporating or considering incorporating climate and health into planning compared to state health leaders (55.8%) and other stakeholders (68.2%). Stakeholder groups agreed on the 4 highest priority adaptation categories including core public health activities such as surveillance, coordination/collaboration, education, and policy development. CONCLUSIONS: Feedback from diverse stakeholders was utilized by NYSDOH to develop its Climate and Health Strategic Map in 2013. The CDC Building Resilience Against Climate Effects (BRACE) framework and funding provides a collaborative model for state climate and health adaptation planning. PMID- 25837329 TI - [Listening to the real world for monitoring the clinical practice guidelines]. PMID- 25837330 TI - [Nursing activities score: differences in nursing workload in three intensive care units]. AB - INTRODUCTION: The activities that impact on the nursing workload in an intensive care unit have not been described. AIM: To retrospectively analyze the nursing workload in the three intensive care units-ICU (general, neurosurgery and cardiac surgery) of the same department with the Nursing Activities Score (NAS) to describe the nursing interventions that mostly impact on the workload. METHODS: Retrospective observational study. Patients admitted from January 2006 to December 2012 were included in the study. The NAS was completed every 24 hours around 6 am. RESULTS: Patients included in the study were 7588; their mean NAS score was 61.7 +/- 19.02%; 75.9 +/- 1.44 in General ICU, 61.6 +/- 2.46 Neuro ICU, 62.5 +/- 3.06 in the Cardiosurgical ICU. The items that mostly impacted on the nursing workload were the need of monitoring and titration, the hygiene procedures, and the Mobilization and positioning. The three procedures were performed with different frequencies in the three ICUs. CONCLUSIONS: The results confirm that the minimum required care in ICUs is around 950 minutes/day. The differences observed in the three ICUs were determined by the different clinical severity and caring complexity of the patients. PMID- 25837331 TI - [Continuous monitoring of endotracheal tube cuff pressure: best practice in intensive care unit]. AB - INTRODUCTION: The endotracheal tube cuff pressure must be maintained within an optimal range of 20-30 cmH2O, which ensures ventilation, prevents aspiration of secretions and guarantees a good tracheal perfusion. AIMS: To describe changes in the endotracheal tube cuff pressure over time through a continuous monitoring device, and assess the number of nursing actions. METHODS: Observation of 72 patients admitted to a general ICU and monitored for 12 hours, with a continuos monitoring device of endotracheal tube cuff pressure (PressureEasy((r))). RESULTS: During the first four hours 4 cases (5.6%) of underinflated cuff were observed, and 5 (6.9%) of overinflation. From the fifth to the eighth hour 7 (9.7%) patients showed a pressure <20 cmH2O, and 3 (4.2%) >30 cmH2O. During the last four hours 22 cases (30.5%) of underinflated cuff, and 4 (5.6%) of overinflation were observed. More than half of the patients (n=38, 52.8%) did not require any intervention of inflation or deflation of the cuff, 25 (34.7%) only one and 7 (9.7%) patients two, and twe patients, three. The majority of patients required the inflation of the cuff. CONCLUSION: Our study supports the need of continuous endotracheal tube cuff pressure monitoring to promptly identify deviations from the pressure ranges, allowing their rapid correction. PMID- 25837332 TI - [Unplanned extubations in adult intensive care units: an update]. AB - INTRODUCTION: Unplanned extubations (UEs) in adult Intensive Care Units (ICUs), have recently become an indicator of quality and safety of care. METHOD: A literature review published 10 years ago was updated to analyze any changes in UEs. RESULTS: The cumulative incidence of UEs varied between 0.3% and 27%, before 2000, and more recently, from 0.5% to 35.8%, without substantial changes. The rate of Self Extubations (SE) outweighed the Accidental Extubation (AE), amounting to 50%-100% of all UE. The reintubations rate ranged between 1.81% and 88%. The UEs increase the length of the mechanical ventilation, of ICU and hospital stay, and according to few studies the rate of death with UEs is lower. Major risk factors for UE are: APACHE II score >=17, agitation, physical restraints, administration of midazolam, and higher levels of consciousness. The implementation of ABCDE bundle in ICUs did not involve additional risks of UE. The prevention includes a sedation with drugs different from benzodiazepines, an early detection of patients' readiness to weaning trial from mechanical ventilation, and the adequate stabilization of the endotracheal tube, with securing systems passing behind the patient's neck. The use of physical restraints is inconsistent, since it can be a risk factor for SE. CONCLUSIONS: For preventing UEs the surveillance of nursing staff is fundamental, if the staffing is adequate to the real workloads in ICU. PMID- 25837333 TI - [Continuity of care: the concordance of discharge planning between public and private hospitals and district]. AB - INTRODUCTION: A good post hospital discharge planning facilitates the discharge, improves patients' health conditions and decreases the social costs. AIM: To assess the agreement of the discharge settings suggested by the public or private hospitals and by the district. METHOD: A random sample of 318 over 1152 discharge reports send in 2013 by Hospitals to the District service of ASLTO2 - Piedmont Region was selected. RESULTS: The agreement for discharge planning between public hospitals and District was 57.4% (50% for private hospitals), with differences according to the discharge setting: 75.3% for Home care, 61.3% for Nursing Homes, 44.4% long term rehabilitation, 42.9% for the Hospice and only 7.4% for specialized Nursing Homes. Reasons for lack of agreement were an inappropriate assessment of patients or family resources and of discharge settings. CONCLUSIONS: The District is in a better position for assessing the range services to be offered the to patients, their living and family conditions and thus, to identify the most suitable post discharge settings. PMID- 25837334 TI - [Guided clinical practice guidelines: how to blunt the weapon of evidence]. AB - The public should trust practice guidelines only if the recommendations accurately reflect the underlying evidence about benefits and harms to individual patients. However, the process of development of clinical practice guidelines is fraught with problem, conflicts and controversies. A few examples, starting from the guidelines on osteoporosis are presented and commented on. PMID- 25837335 TI - [When life needs routine, imagination, listening]. AB - When life needs routine, imagination, listening. Barbara is a 44 years old oncologist, married and with two children, that tells through others but also with her own words of her cancer, until death. Giuseppe is a laboratory technician, researcher, mountaineer, promoter of humanitarian initiatives Bosnia and Croatia; his lateral amyotrophic sclerosis is told by his wife, in a booklet written after his death. Their two stories are the occasions for reflecting on the importance and role of closeness, listening, dreaming, narrating in improving the quality of life and care: none of these words are included in the guidelines. PMID- 25837336 TI - [The late arousal of WHO on Ebola virus]. AB - The late arousal of WHO on Ebola virus. The Ebola crisis brought to surface some problems in the coordination and readiness of the international community to face an infective challenge that, although originating in a part of the planet, could become a global epidemic. Ebola is still making victims and the answer to face and prevent future emergencies involves strengthening and upgrading of national health systems, investments in the education of doctors and nurses (many health professionals were victims of Ebola), in providing better salaries to attract more health professionals and a in a better and coordinated use of the army. A stronger WHO could play an important role. PMID- 25837337 TI - [The prison nurse: analysis of the evolution of the legislative framework]. AB - The evolution of the role of prison nurses through the Italian legislation is presented, analyzing the implication of the transfer of competences from the Law ministry to the National Health Service. Until 60 years ago scarce attention was paid to the health of prisoners and only in the years 70' nurses were formally included in the staff of the prisons. PMID- 25837338 TI - Violence against nurses in the triage area: An Italian qualitative study. AB - AIM: This qualitative study aims to investigate the feelings experienced by nurses following episodes of violence in the workplace. BACKGROUND: Numerous studies show that healthcare professionals are increasingly finding themselves victims of violence; of all professionals, nurses in the Emergency Department and especially those performing triage are one of the staff categories which most frequently experience these episodes during their work. INTRODUCTION: In Italy, this phenomenon has been studied very little in comparison to other countries but has recently been gaining increasing attention. Few studies have investigated the feelings experienced by nurses following episodes of violence in the workplace. METHODS: For this study a phenomenological approach was used. Assumptions and previous findings were set aside (bracketing). A purposive sample of 9 nurses coming from 7 different Emergency Department in the region of Tuscany, Italy was interviewed during a focus group meeting. The data analysis was carried out using the Colaizzi method. RESULTS: Data analysis revealed 10 significant themes/responses. The quality of reporting was guaranteed by adopting the COREQ criteria. DISCUSSION: Data analysis revealed that nurses feel that violent episodes are "inevitable" and that they feel they have grown accustomed to high levels of violence, that they suffer feelings of "inadequacy" but also that they are aware that they themselves can trigger conflict with patients, and again suffer the feeling of "being alone" in facing these problems and a sense of "being left on their own" by the institution and feeling "hurt", "scared", "angry" and have a sense that "it is not fair". Last but not least, "the gender difference" appears to play an important role in the emotional response. CONCLUSIONS: To suffer episodes of violence has serious and severe "hidden costs" which are just as important as the direct, tangible costs. PMID- 25837339 TI - Fracture toughness of esthetic dental coating systems by nanoindentation and FIB sectional analysis. AB - Improving the esthetics of Ti-based dental implants is the last challenge remaining in the optimization process. The optical issues were recently solved by the application of highly and selectively reflective coatings on Ti implants. This work focuses on the mechanical durability of these esthetic ceramic based coating systems (with and without adhesion layers). The coating systems (Ti-ZrO2, Ti-Al-ZrO2, Ti-Ti-Al-ZrO2, Ti-Ag-ZrO2, Ti-Ti-Ag-ZrO2, Ti-Bragg and Ti-TiO2-Bragg) were subjected to nanoindentation experiments and examined using scanning electron microscopy and focused ion beam cross sectional analysis. Three coating systems contained adhesion layers (10nm of Ti or 60nm of TiO2 layers). The fracture toughness of selected samples was assessed applying two different models from literature, a classical for bulk materials and an energy-based model, which was further developed and adjusted. The ZrO2 based coating systems (total film thickness<200nm) followed a circumferential cracking behavior in contrast to Bragg coated samples (total film thickness around 1.5MUm), which showed radial cracking emanating from the indent corners. For Ti-ZrO2 samples, a fracture toughness between 2.70 and 3.70MPam(1/2) was calculated using an energy-based model. The classical model was applied to Bragg coated samples and their fracture toughness ranged between 0.70 and 0.80MPam(1/2). Furthermore, coating systems containing an additional layer (Ti-Ti-Al-ZrO2, Ti-Ti-Ag-ZrO2 and Ti-TiO2-Bragg) showed an improved adhesion between the substrate and the coating. The addition of a Ti or TiO2 layer improved the adhesion between substrate and coating. The validity of the models for the assessment of the fracture toughness depended on the layer structure and fracture profile of the samples investigated here (classical model for thick coatings and energy-based model for thin coatings). PMID- 25837341 TI - Two-body wear comparison of zirconia crown, gold crown, and enamel against zirconia. AB - PROBLEM STATEMENT: Full zirconia crowns have recently been used for dental restorations because of their mechanical properties. However, there is little information about their wear characteristics against enamel, gold, and full zirconia crowns. PURPOSE: The purpose of this study was to compare the wear rate of enamel, gold crowns, and zirconia crowns against zirconia blocks using an in vitro wear test. MATERIALS AND METHODS: Upper specimens were divided into three groups: 10 enamels (group 1), 10 gold crowns (group 2, Type III gold), and 10 zirconia crowns (group 3, Prettau((r))Zirkon 9H, Zirkonzahn, Italy). Each of these specimens was wear tested against a zirconia block (40*30*3mm(3)) as a lower specimen (30 total zirconia blocks). Each specimen of the groups was abraded against the zirconia block for 600 cycles at 1Hz with 15mm front-to-back movement on an abrading machine. Moreover, the load applied during the abrading test was 50N, and the test was performed in a normal saline emulsion for 10min. Three-dimensional images were taken before and after the test, and the statistical analysis was performed using the Krushal-Wallis test and Mann-Whitney test (p=0.05). RESULTS: The mean volume loss of group 1 was 0.47mm(3), while that of group 2 and group 3 was 0.01mm(3). CONCLUSION: The wear volume loss of enamels against zirconia was higher than that of gold and zirconia crowns. Moreover, according to this result, zirconia crowns are not recommended for heavy bruxers. PMID- 25837340 TI - Correlations between transmural mechanical and morphological properties in porcine thoracic descending aorta. AB - Determination of correlations between transmural mechanical and morphological properties of aorta would provide a quantitative baseline for assessment of preventive and therapeutic strategies for aortic injuries and diseases. A multimodal and multidisciplinary approach was adopted to characterize the transmural morphological properties of descending porcine aorta. Histology and multi-photon microscopy were used for describing the media layer micro architecture in the circumferential-radial plane, and Fourier Transform infrared imaging spectroscopy was utilized for determining structural protein, and total protein content. The distributions of these quantified properties across the media thickness were characterized and their relationship with the mechanical properties from a previous study was determined. Our findings indicate that there is an increasing trend in the instantaneous Young's modulus (E), elastic lamella density (ELD), structural protein (SPR), total protein (TPR), and elastin and collagen circumferential percentage (ECP and CCP) from the inner towards the outer layers. Two regions with equal thickness (inner and outer halves) were determined with significantly different morphological and material properties. The results of this study represent a substantial step toward anatomical characterization of the aortic wall building blocks and establishment of a foundation for quantifying the role of microstructural components on the functionality of aorta. PMID- 25837342 TI - Mechanical properties and cytotoxicity of nanoplate-like hydroxyapatite/polylactide nanocomposites prepared by intercalation technique. AB - Hydroxyapatite (HAp) in the forms of fiber, needle, and whisker has been employed as fillers in polymer composites. Herein, nanoplate-like HAp synthesized by template-assisted self-assembly was used to reinforce polylactide (PLA) nanocomposites via the solution intercalation method. Dynamic and static mechanical properties and cytotoxicity of the as-prepared HAp/PLA nanocomposites were assessed in addition to characterizations by XRD, FTIR, and TGA. XRD analysis confirms the formation of exfoliated structure in the HAp/PLA nanocomposites. The HAp/PLA nanocomposites exhibit better static and dynamic mechanical properties than unreinforced PLA. Furthermore, the HAp/PLA nanocomposite with an optimum HAp content of 20wt% (20HAp/PLA) demonstrates not only the best mechanical performance but also the highest thermal stability among the nanocomposite samples. Cell studies using a mouse fibroblast cell line (L929) suggest that 20HAp/PLA shows excellent biocompatibility, which makes it a promising material for biomedical applications. PMID- 25837343 TI - Mechanical properties and corrosion behavior of Mg-Gd-Ca-Zr alloys for medical applications. AB - Magnesium alloys are promising candidates for biomedical applications. In this work, influences of composition and heat treatment on the microstructure, the mechanical properties and the corrosion behavior of Mg-Gd-Ca-Zr alloys as potential biomedical implant candidates were investigated. Mg5Gd phase was observed at the grain boundaries of Mg-10Gd-xCa-0.5Zr (x=0, 0.3, 1.2wt%) alloys. Increase in the Ca content led to the formation of additional Mg2Ca phase. The Ca additions increased both the compressive and the tensile yield strengths, but reduced the ductility and the corrosion resistance in cell culture medium. After solution heat treatment, the Mg5Gd particles dissolved in the Mg matrix. The compressive strength decreased, while the corrosion resistance improved in the solution treated alloys. After ageing at 200 degrees C, metastable beta' phase formed on prismatic planes and a new type of basal precipitates have been observed, which improved the compressive and tensile ultimate strength, but decreased the ductility. PMID- 25837344 TI - Carbamate pesticide-induced apoptosis in human T lymphocytes. AB - We previously found that carbamate pesticides induced significant apoptosis in human natural killer cells. To investigate whether carbamate pesticides also induce apoptosis in human T lymphocytes, in the present study Jurkat human T cells were treated in vitro with thiram, maneb, carbaryl or ziram. Apoptosis was determined by FITC-Annexin-V/PI staining. To explore the mechanism of apoptosis, intracellular levels of active caspase 3 and mitochondrial cytochrome-c release were determined by flow cytometry. We found that thiram, ziram, maneb and carbaryl also induced apoptosis in a time- and dose-dependent manner in the human T cells. However, the strength of the apoptosis-inducing effect differed among the pesticides, with the: thiram > ziram > maneb > carbaryl. Moreover, thiram significantly increased the intracellular level of active caspase 3 and caspase inhibitors significantly inhibited apoptosis. Thiram also significantly caused mitochondrial cytochrome-c release. These findings indicate that carbamate pesticides can induce apoptosis in human T cells, and the apoptosis is mediated by the activation of caspases and the release of mitochondrial cytochrome-c. PMID- 25837345 TI - High resolution spatial and temporal mapping of traffic-related air pollutants. AB - Vehicle traffic is one of the most significant emission sources of air pollutants in urban areas. While the influence of mobile source emissions is felt throughout an urban area, concentrations from mobile emissions can be highest near major roadways. At present, information regarding the spatial and temporal patterns and the share of pollution attributable to traffic-related air pollutants is limited, in part due to concentrations that fall sharply with distance from roadways, as well as the few monitoring sites available in cities. This study uses a newly developed dispersion model (RLINE) and a spatially and temporally resolved emissions inventory to predict hourly PM2.5 and NOx concentrations across Detroit (MI, USA) at very high spatial resolution. Results for annual averages and high pollution days show contrasting patterns, the need for spatially resolved analyses, and the limitations of surrogate metrics like proximity or distance to roads. Data requirements, computational and modeling issues are discussed. High resolution pollutant data enable the identification of pollutant "hotspots", "project-level" analyses of transportation options, development of exposure measures for epidemiology studies, delineation of vulnerable and susceptible populations, policy analyses examining risks and benefits of mitigation options, and the development of sustainability indicators integrating environmental, social, economic and health information. PMID- 25837346 TI - Assessment of foetal exposure to the homogeneous magnetic field harmonic spectrum generated by electricity transmission and distribution networks. AB - During the last decades studies addressing the effects of exposure to Extremely Low Frequency Electromagnetic Fields (ELF-EMF) have pointed out a possible link between those fields emitted by power lines and childhood leukaemia. They have also stressed the importance of also including in the assessment the contribution of frequency components, namely harmonics, other than the fundamental one. Based on the spectrum of supply voltage networks allowed by the European standard for electricity quality assessment, in this study the exposure of high-resolution three-dimensional models of foetuses to the whole harmonic content of a uniform magnetic field with a fundamental frequency of 50 Hz, was assessed. The results show that the main contribution in terms of induced electric fields to the foetal exposure is given by the fundamental frequency component. The harmonic components add some contributions to the overall level of electric fields, however, due to the extremely low permitted amplitude of the harmonic components with respect to the fundamental, their amplitudes are low. The level of the induced electric field is also much lower than the limits suggested by the guidelines for general public exposure, when the amplitude of the incident magnetic field is set at the maximum permitted level. PMID- 25837347 TI - Temporal dynamics and drivers of ecosystem metabolism in a large subtropical shallow lake (lake Taihu). AB - With continuous measurements of dissolved oxygen, temperature, irradiance, and wind speed, as well as frequent measurements of pH, oxidation-reduction potential, and algal chlorophyll, temporal dynamics and drivers of ecosystem metabolism in a large nutrient-rich shallow lake (Lake Taihu) are tested in this study. The results show that the dissolved oxygen concentrations in the lake fluctuate annually. They increase in autumn and winter with a peak value of 14.19 mg.L-1 in winter, and decrease in spring and summer with a trough value of 6.40 mg.L-1 in summer. Gross primary production (GPP), ecosystem respiration (R), and net ecosystem production (NEP) increase in summer, with their peak values in late summer and autumn, and decrease in winter and spring. Mean values of GPP, R and NEP are 1.75 +/- 0.06 (Mean +/- SE), 1.52 +/- 0.05, and 0.23 +/- 0.03 g O2 m-3.d 1, respectively. It is also found that water temperature and surface irradiance are the best predictors of GPP and R, while water temperature (wind speed) has a significantly positive (negative) relationship with NEP. The findings in this study suggest that Lake Taihu is a net autotrophic ecosystem, and water temperature and surface irradiance are the two important drivers of lake metabolism. PMID- 25837348 TI - Longitudinal changes in functioning and disability in patients with disorders of consciousness: the importance of environmental factors. AB - Disorders of consciousness are neurological conditions associated with low levels of functioning which pose a serious challenge to public health systems. The current study aimed to examine longitudinal changes in functioning in patients with disorders of consciousness and to identify associated biopsychosocial factors using the International Classification of Functioning, Disability, and Health. An Italian sample of 248 patients was assessed longitudinally. Differences in relative variability (an index of change that controls for baseline levels) between acute and chronic patients and predictors of relative variability in "Activities & Participation" were examined. Results showed that there were subgroups of patients whose functioning improved over time. The number of problems in "Activities & Participation" decreased in acute patients over time, whereas in chronic patients, an increase was found. The significant difference in relative variability for the environmental factor "support and relationships" reflects the increase in facilitators in acute patients, whereas the number of facilitators in chronic patients remained unchanged over time. Age at event, time from event, and relative variability in "Environmental Factors" were significant predictors of relative variability in "Activities & Participation". It is of clinical relevance that patients with disorders of consciousness are kept in a supportive and facilitative environment, in order to prevent a decline in their functioning. Moreover, caregivers should receive tailored support in order to enhance and facilitate appropriate care of patients with disorders of consciousness. PMID- 25837349 TI - Diuron in water: functional toxicity and intracellular detoxification patterns of active concentrations assayed in tandem by a yeast-based probe. AB - A study on the acute and chronic effects of the herbicide diuron was carried out. The test, basing on a yeast cell probe, investigated the interference with cellular catabolism and possible self-detoxification capacity of Saccharomyces cerevisiae. Aerobic respiration was taken as the toxicological end-point. Percentage interference (%r) with cellular respiration was measured in water by increased dissolved O2 concentration (ppm) after exposure to different doses. Interference was calculated through the comparison of respiratory activity of exposed and non-exposed cells. Short-term and long-term (6 and 24 h respectively) exposures were also considered. The test for short-term exposure gave positive %r values except that for 10-6 M (11.11%, 11.76%, 13.33% and 0% for 10-10 M, 10-8 M, 10-7 M and 10-6 M respectively). In the case of long-term exposure the test showed positive %r values, but less effect than short-term exposure until 10-8 M and much higher at 10-6 M (7.41%, 8.82%, 11.76% and 6.06% for 10-10 M, 10-8 M, 10 7 M and 10-6 M respectively). The findings of aerobic respiration as toxicological end-point were in agreement with known mechanisms of toxicity and intracellular detoxification for both the doses and exposure times employed. PMID- 25837350 TI - When self-reliance is not safe: associations between reduced help-seeking and subsequent mental health symptoms in suicidal adolescents. AB - The majority of suicidal adolescents have no contact with mental health services, and reduced help-seeking in this population further lessens the likelihood of accessing treatment. A commonly-reported reason for not seeking help is youths' perception that they should solve problems on their own. In this study, we explore associations between extreme self-reliance behavior (i.e., solving problems on your own all of the time), help-seeking behavior, and mental health symptoms in a community sample of adolescents. Approximately 2150 adolescents, across six schools, participated in a school-based suicide prevention screening program, and a subset of at-risk youth completed a follow-up interview two years later. Extreme self-reliance was associated with reduced help-seeking, clinically significant depressive symptoms, and serious suicidal ideation at the baseline screening. Furthermore, in a subset of youth identified as at-risk at the baseline screening, extreme self-reliance predicted level of suicidal ideation and depressive symptoms two years later even after controlling for baseline symptoms. Given these findings, attitudes that reinforce extreme self-reliance behavior may be an important target for youth suicide prevention programs. Reducing extreme self-reliance in youth with suicidality may increase their likelihood of appropriate help-seeking and concomitant reductions in symptoms. PMID- 25837351 TI - Temporal latency between pelvic floor trauma and presentation for prolapse surgery: a retrospective observational study. AB - INTRODUCTION AND HYPOTHESIS: Levator avulsion is an etiological factor for female pelvic organ prolapse (POP) and generally occurs during a first vaginal birth. However, most women with POP present decades later. This study aimed to estimate latency between pelvic floor trauma and presentation for POP surgery. METHODS: This was a retrospective observational study in a tertiary urogynecological unit to which 354 patients presented for evaluation prior to prolapse surgery between June 2011 and December 2012. All underwent an interview, clinical assessment [International Continence Society Pelvic Organ Prolapse Quantification score (ICS POPQ) and 4D translabial ultrasound (US). Postprocessing analysis of US volumes was blinded against clinical data. The main outcome measure was temporal latency between first vaginal birth and prolapse presentation in women with levator avulsion. RESULTS: Three hundred and fifty-four patients presented with symptoms of prolapse, of whom 115 (32 %) were found to have an avulsion of the levator ani muscle. Of these, 30 patients were excluded due to previous prolapse surgery, leaving 85, all of whom showed significant prolapse on US and/or clinical staging. Mean latency between first vaginal delivery and presentation was 33.5 (3 66.3) years. There were no associations between latency and potential predictors, except for maternal age at first birth, which was associated with shorter latency (r = -0.45 , P < 0.001). There was a trend toward shorter latency after forceps delivery (P = 0.09). CONCLUSIONS: Average latency between first birth and presentation for prolapse surgery in women with avulsion was 33.5 (3-66) years. Maternal age at first vaginal birth and possibly forceps delivery were associated with shorter time to presentation. PMID- 25837353 TI - Use of cataract surgery in urban Beijing: a post screening follow-up of the elderly with visual impairment due to age-related cataract. AB - OBJECTIVE: To understand the perception for the use of cataract surgical services in a population of acceptors and non-acceptors of cataract surgery in urban Beijing. METHODS: From a community-based screening program a total of 158 patients with presenting visual acuity of less than 6/18 on either eye due to age related cataract were informed about the possibility of surgical treatment. These patients were interviewed and re-examined 36 to 46 months after initial screening. The main reasons for not accepting surgery were obtained using a questionnaire. Vision function and vision-related quality of life scores were assessed in those who received and did not receive surgery. RESULTS: At the follow-up examination 116 of the 158 patients were available and 36 (31.0%) had undergone cataract surgery. Cases who chose surgery had higher education level than those who did not seek surgery (OR=2.64, 95% CI: 1.08-6.63, P=0.02). There were no significant differences in vision function (P=0.11) or quality of life scores (P=0.16) between the surgery group and the non-surgery group. Main reasons for not having surgery included no perceived need (50.0%), feeling of being "too old" (19.2%), and worry about the quality of surgery (9.6%). Cost was cited by 1 (1.9%) subject as the main reason for not seeking surgery. CONCLUSIONS: The data suggest that in China's capital urban center for patients with moderate visual impairment there is a relative low acceptance rate of cataract surgery, mainly due to people's perception of marginal benefits of surgery. Cost is not a determining factor as barrier to undergo surgery and patients with poorer education are less likely to undertake surgery. PMID- 25837352 TI - medplot: a web application for dynamic summary and analysis of longitudinal medical data based on R. AB - In biomedical studies the patients are often evaluated numerous times and a large number of variables are recorded at each time-point. Data entry and manipulation of longitudinal data can be performed using spreadsheet programs, which usually include some data plotting and analysis capabilities and are straightforward to use, but are not designed for the analyses of complex longitudinal data. Specialized statistical software offers more flexibility and capabilities, but first time users with biomedical background often find its use difficult. We developed medplot, an interactive web application that simplifies the exploration and analysis of longitudinal data. The application can be used to summarize, visualize and analyze data by researchers that are not familiar with statistical programs and whose knowledge of statistics is limited. The summary tools produce publication-ready tables and graphs. The analysis tools include features that are seldom available in spreadsheet software, such as correction for multiple testing, repeated measurement analyses and flexible non-linear modeling of the association of the numerical variables with the outcome. medplot is freely available and open source, it has an intuitive graphical user interface (GUI), it is accessible via the Internet and can be used within a web browser, without the need for installing and maintaining programs locally on the user's computer. This paper describes the application and gives detailed examples describing how to use the application on real data from a clinical study including patients with early Lyme borreliosis. PMID- 25837354 TI - Lipopolysaccharide challenge induces long pentraxin 3 expression in mice independently from acute lung injury. AB - OBJECTIVE: To determine whether the onset of acute lung injury (ALI) induces the up-regulation of pentraxin 3 (PTX3) expression in mice and whether PTX3 concentration in the biofluid can help recognizing sepsis-induced ALI. METHODS: Wild-type C57BL/6 mice (12-14 weeks old) were randomly divided into 3 groups. Mice in the group 1 (n=12) and group 2 (n=12) were instilled with lipopolysaccharide via intratracheal or intraperitoneal routes, respectively. Mice in the group 3 (n=8) were taken as blank controls. Pulmonary morphological and functional alterations were measured to determine the presence of experimental ALI. PTX3 expression in the lung was quantified at both protein and mRNA levels. PTX3 protein concentration in blood and bronchoalveolar lavage fluid was measured to evaluate its ability to diagnose sepsis-induced ALI by computing area under receiver operator characteristic curve (AUROCC). RESULTS: ALI was commonly confirmed in the group 1 but never in the other groups. PTX3 expression was up-regulated indiscriminately among lipopolysaccharide-challenged mice. PTX3 protein concentration in the biofluid was unable to diagnose sepsis-induced ALI evidenced by its small AUROCC. PTX3 concentration in bronchoalveolar lavage fluid did not correlate with that in serum. CONCLUSIONS: Lipopolysaccharide challenges induced PTX3 expression in mice regardless of the presence of ALI. PTX3 may act as an indicator of inflammatory response instead of organ injury per se. PMID- 25837355 TI - Reliability of a novel Cobb protractor for measuring the Cobb angle of radiograph in scoliosis. AB - OBJECTIVE: To introduce a novel Cobb protractor and assess its reliability and rapidity for measuring Cobb angle in scoliosis patients. METHODS: The novel Cobb protractor had two endplate markers. A measurement was performed just to align the two markers to each endplate of the curve. The Cobb angle on the posteroanterior radiographs of 24 patients clinically diagnosed with adolescent idiopathic scoliosis was measured by three orthopedic surgeons with both standard Cobb method and the new technique, and the time of measurement was recorded. Intraclass correlation coefficients (ICCs) were calculated to assess the reliability of the new method. RESULTS: The time for a measurement with the new tool was approximately 10 seconds less than the time that used to finish a measurement with the standard method (P<0.05). The overall mean Cobb angle for the major curve of the 24 patients was 47.8 degrees . The mean overall intraobserver and interobserver ICC was 0.971 and 0.971 for the Cobb method group, while the overall intraobserver ICC and the interobserver was 0.985 and 0.979 for the new tool group. CONCLUSIONS: The novel Cobb protractor could perform quick measurement and measure almost all forms of radiographs. The Cobb protractor might be an ideal instrument to measure the Cobb angle. PMID- 25837356 TI - Role of removing stasis and reducing heat formula in clearance of proximal ureteral calculi after ureteroscopic Ho:YAG laser lithotripsy: a prospective randomized study. AB - OBJECTIVE: To prospectively evaluate the efficacy of Removing Stasis and Reducing Heat Formula in accelerating calculus clearance and improving lower urinary tract symptoms of patients with proximal ureteral calculi after ureteroscopic Ho:YAG laser lithotripsy. METHODS: A total of 138 patients with proximal ureteral calculi underwent ureteroscopic Ho:YAG laser lithotripsy by a single endocrinologist. Stone size varied from 10 to 15 mm. After operation, the patients were randomly divided into three groups: the control group (group A), tamsulosin group (group B), and Removing Stasis and Reducing Heat Formula group (group C). The treatment lasted for 4 weeks or until stone clearance. The primary and secondary outcomes of the three groups at follow-up were assessed. RESULTS: Of the 131 patients available for follow-up, 44 cases were in the group A, 45 in the group B, and 42 in the group C, respectively. The stone free rate at 2 weeks in the groups B and C were significantly higher than that in the group A (95.56%, 97.62% vs. 79.55%; all P<0.05). The ureteral colic rate and mean time of fragment expulsion were significantly reduced in the groups B (4.44% and 7.86+/-4.99 days) and C (2.43% and 6.76+/-4.37 days) compared with the group A (22.73% and 11.54+/ 9.89 days, all P<0.05). On the day of double-J ureteric stent removal, the group C differed significantly from the group A in the total International Prostate Symptom Score, irritative subscore, obstructive subscore, and quality of life score (all P<0.05). CONCLUSION: Removing Stasis and Reducing Heat Formula in the medical expulsive therapy might be an effective modality for patients with calculus in the proximal uretera after ureteroscopic Ho:YAG laser lithotripsy. PMID- 25837357 TI - Redo coronary artery bypass grafting: on-pump and off-pump coronary artery bypass grafting revascularization techniques. AB - OBJECTIVE: To analyze the short-term outcomes of redo coronary artery bypass grafting (CABG) using on-pump and off-pump CABG techniques. METHODS: From January 2003 to August 2013, non-randomized 80 patients were treated with redo CABG in the Department of Cardiac Surgery, Peking University Third Hospital. Among these patients, 40 underwent on-pump CABG technique (redo-ONCAB group) and 40 underwent off-pump CABG technique (redo-OPCAB group). Furthermore, transmyocardial laser revascularization was performed in high-risk patients who were not suitable to conventional grafting. Clinical data of the two groups were recorded and analyzed including operation time, coronary grafts, incomplete revascularization, postoperative ventilation, perioperative stroke, and low output syndrome, etc. RESULTS: There were no significantly differences in age, gender distribution, incidences of hypertension, stroke, and other clinical characteristics between redo-OPCAB group and redo-ONCAB group (all P>0.05), except for incidences of renal dysfunction and pulmonary disease (all P<0.05). The number of grafting vessels in the redo-ONCAB and redo-OPCAB groups was 2.1 +/- 0.74 and 1.4 +/-0.52 respectively. There was significant difference between the two groups (P=0.0243). Compared with the redo-ONCAB group, there was shorter operation time (P=0.0045), postoperative ventilation (P=0.0211) and intensive care unit stay (P=0.0400), as well as fewer use of platelet (P=0.0338) and blood transfusion (P=0.0034) in the redo-OPCAB group. The incidence of incomplete revascularization (P=0.0253) and the use of transmyocardial laser revascularization (P=0.0052) were higher in the redo-OPCAB group than those in the redo-ONCAB group (all P<0.05). However, no significant differences were showed for the incidence of the use of intra aortic balloon pump and continuous renal replacement therapy, perioperative stroke, low output syndrome, and in-hospital mortality between the two groups (all P>0.05). CONCLUSION: Redo CABG is the safety and efficacy surgical procedure, and redo OPCAB technique with better outcomes is commended especially in high-risk patients. PMID- 25837358 TI - MRI evaluation of lateral geniculate body in normal aging brain using quantitative susceptibility mapping. AB - OBJECTIVE: To investigate the changes of lateral geniculate body (LGB) in the normal aging brain using quantitative susceptibility mapping (QSM) technique. METHODS: Magnetic resonance (MR) phase and magnitude images were acquired from enhanced gradient echo T2 star weighted angiography sequence with 16 echoes on 3.0T MR system using the head coil with 32 channels. Morphology Enabled Dipole Inversion (MEDI) method was applied for QSM, and the susceptibility value of LGB was measured by region of interest (ROI) drawn manually on three orthogonal planes. RESULTS: LGB of the middle-aged group had a higher susceptibility value (0.16+/-0.05 ppm) than that of the youth group (0.12+/-0.05 ppm) and elderly group (0.13+/-0.03 ppm) (all P<0.05). Partial correlation analysis demonstrated that there was significantly positive correlation between susceptibility value and age in the youth group (r=0.71, P<0.05). CONCLUSION: LGB could clearly be identified on QSM in the brain in vivo. PMID- 25837359 TI - Total glycosides of Ranunculus japonius prevent hypertrophy in cardiomyocytes via alleviating chronic Ca(2+) overload. AB - OBJECTIVE: To evaluate the in vitro anti-hypertrophic effect of total Glycosides of Ranunculus Japonius (TGRJ). METHODS: Neonatal rat cardiomyocytes were cultured and hypertrophy was induced by administrating isoproterenol (ISO, 10 umol/L) or angiotensin 2 (Ang 2, 1 umol/L) for 48 hours. In the treatment groups, cells were pretreated with TGRJ (0.3 g/L) for 30 minutes prior to hypertrophic stimuli. The anti-hypertrophic effects of TGRJ were examined by measuring cell size, total protein content, and protein synthesis. Intracellular free Ca(2+) concentration ([Ca(2+)]i) was evaluated using fluorescence dye Fura-2/AM. Sacroplasmic/endoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a), atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and beta-myosin heavy chain (beta-MHC) protein expression levels were measured by Western blotting . SERCA2a activity was assayed by p-nitrophenal phosphate disodium salt hexahydrate method. RESULTS: Increased cell size, total protein content, and protein synthesis following ISO or Ang 2 stimulation were significantly inhibited by pretreatment with TGRJ (all P<0.05). This anti-hypertrophic effect of TGRJ was confirmed by its suppressing effect on elevated expression of the three hypertrophic related genetic markers, ANP, BNP, and beta-MHC. In addition, TGRJ inhibited ISO or Ang 2 induced up-regulation of [Ca(2+)]i under chronic but not acute conditions. And ISO or Ang 2 induced down-regulation of SERCA2a expression and activity was also effectively rectified by TGRJ pretreatment. CONCLUSIONS: The results of present study suggested that TGRJ could prevent ISO or Ang 2 induced cardiac hypertrophy through improving chronic [Ca(2+)]i disorder, might via normalizing SERCA2a expression and activity. PMID- 25837360 TI - Association between two polymorphisms of follicle stimulating hormone receptor gene and susceptibility to polycystic ovary syndrome: a meta-analysis. AB - OBJECTIVE: To investigate the association between two polymorphisms of follicle stimulating hormone receptor (FSHR) gene and polycystic ovary syndrome (PCOS) susceptibility. METHODS: Case-control studies on relationship of Thr307Ala and Asn680Ser polymorphisms in FSHR gene and PCOS susceptibility were searched from PubMed, ISI web of knowledge, EBSCO, and China National Knowledge Infrastructure (CNKI) databases up to March 21, 2013. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effect model based on heterogeneity test in 5 genotype models analyses. RESULTS: A total of 11 studies were included in the Meta-analysis. The random-effect analysis showed Asn680Ser was significantly associated with the reduced susceptibility to PCOS with dominant model (Asn/Asn+Asn/Ser vs. Ser/Ser, OR=0.83, 95% CI: 0.69-1.00), recessive model (Asn/Asn vs. Asn/Ser+ Ser/Ser, OR=0.84, 95% CI: 0.72-0.98), homozygote comparison (Asn/Asn vs. Ser/Ser, OR=0.79, 95% CI: 0.63-0.98), and the allele contrast (Asn vs. Ser, OR=0.87, 95% CI: 0.79-0.97) respectively(P=0.02, I(2)=56.0%), being protective factors for PCOS. However, no significant associations were found between Thr307Ala and PCOS. CONCLUSION: There might be a significant association between Asn680Ser polymorphism and PCOS. PMID- 25837361 TI - Effects of sunitinib malate on growth of human bladder transitional cell line T24 in vitro. AB - OBJECTIVE: To investigate the growth-inhibitory effect of sunitinib malate on human bladder transitional cell carcinoma (TCC) in vitro. METHODS: Human bladder TCC cell line T24 was cultured and exposed to graded concentrations of sunitinib malate for 72 hours in vitro to determine the sensitivities to drug. Cell viability was measured by MTT assay. Cell apoptotic morphology was observed by fluorescence microscope following DAPI staining. Band expressions of Fas, Fas ligand, poly (ADP-ribose) polymerase (PARP) and beta-actin were analyzed by Western blot. Wound healing process of T24 cells exposed to sunitinib malate was assayed. RESULTS: Sunitinib malate exerted a concentration-dependent and time dependent inhibitory effect on the T24 cell lines. Fluorescence microscopy showed that small vacuoles appeared in the nuclei of T24 cells and the vacuoles were bigger with higher drug concentrations. The expressions of Fas ligand and PARP in T24 cells treated with sunitinib malate exhibited a concentration-dependent increase. Moreover sunitinib malate suppressed the wound healing process in a concentration-dependent manner. CONCLUSION: Sunitinib malate exerted marked inhibitory activity against bladder cancer cell line T24. PMID- 25837362 TI - Calyceal diverticulum mimicking simple parapelvic cyst: a case report. AB - Calyceal diverticulum is a cystic intrarenal cavity lined by nonsecretory transitional epithelium that communicates with the collecting system via a narrow isthmus or infundibulum. It is a rare anatomic anomaly with an incidence of 0.2% to 0.6% in the patients undergoing renal imaging.1 Single imaging modality usually cannot differentiate calyceal diverticulum from other cystic renal diseases.2 Here, we report a 60-year-old male who was reliably diagnosed with calyceal diverticulum by retrograde urography combined with non-enhanced computed tomography (CT) and magnetic resonance urography (MRU). PMID- 25837363 TI - Systemic lupus erythematosus and antiphospholipid syndrome related retinal vasculitis mimicking ocular cysticercosis: a case report. AB - Making accurate and timely diagnosis is often challenging when patients with a systemic disease first present with ocular manifestations. The possibility that vasculitis associated with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) can be misdiagnosed as cysticercosis has not been discussed in the literatures. PMID- 25837364 TI - Conjunctival langerhans cell histiocytosis: a case report. AB - Langerhans cell histiocytosis (LCH) is a rare disease, mainly involving the bone, skin, lung, liver, spleen, and skin.1 The heterogenenous nature of LCH makes it difficult to diagnose. Not only do the involved organs vary from case to case, but also its natural history. Herein, we describe a rare case of conjuctival LCH in an Asian woman. PMID- 25837365 TI - [Tonsillectomy]. PMID- 25837366 TI - [Upper airway stimulation in obstructive sleep apnea]. AB - The stimulation of the upper airway represents an effective treatment option in case of CPAP failure in patients with moderate to severe obstructive sleep apnea. The stimulation with respiratory sensing (Inspire Medical Systems) has shown a high level of evidence in larger cohorts and longer follow-up studies. Whether the results of the stimulation without respiratory sensing (ImThera Medical) can be compared with the therapy with sensing, remains open up to now. Additional data are awaited after the planned phase III study THN#2. To optimize both procedure and to provide long term results, more studies are needed. The workgroup "sleep medicine" of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery supports theses activities with the help of the newly founded task force "Neurostimulation in Sleep Apnea". PMID- 25837368 TI - [Informed consent at lost patient information sheet]. PMID- 25837369 TI - [Allergic rhinitis in the context of chronic rhinosinusitis]. AB - Chronic Rhinosinusitis is one of the most frequent chronic diseases. A major cause is allergic rhinitis. Both illnesses and the combination of both, which is the topic of this educational article, as well as the clarification and therapy of differential diagnoses are belonging in the hands of the otorhinolaryngologist. Finally, it is not completely understood which mechanisms of the allergic inflammation in the nose lead or predispose in the individual patient to the development of a chronic sinus disease. A series of excellent national and international guidelines have been published supporting the otorhinolaryngologist in diagnostics and treatment of patients with allergic rhinosinusitis. This article presents the most important and actual diagnostic and therapeutic procedures for the treatment of this important chronic disease in children and adults. PMID- 25837370 TI - [Question: Please explain midfacial fractures. Forms, therapy?]. PMID- 25837371 TI - [Support - anesthesia, surgery, instrument update, navigation technique, etc. 1]. PMID- 25837372 TI - Analysis of threats to research validity introduced by audio recording clinic visits: Selection bias, Hawthorne effect, both, or neither? AB - OBJECTIVE: To identify factors associated with participant consent to record visits; to estimate effects of recording on patient-clinician interactions. METHODS: Secondary analysis of data from a randomized trial studying communication about depression; participants were asked for optional consent to audio record study visits. Multiple logistic regression was used to model likelihood of patient and clinician consent. Multivariable regression and propensity score analyses were used to estimate effects of audio recording on 6 dependent variables: discussion of depressive symptoms, preventive health, and depression diagnosis; depression treatment recommendations; visit length; visit difficulty. RESULTS: Of 867 visits involving 135 primary care clinicians, 39% were recorded. For clinicians, only working in academic settings (P=0.003) and having worked longer at their current practice (P=0.02) were associated with increased likelihood of consent. For patients, white race (P=0.002) and diabetes (P=0.03) were associated with increased likelihood of consent. Neither multivariable regression nor propensity score analyses revealed any significant effects of recording on the variables examined. CONCLUSION: Few clinician or patient characteristics were significantly associated with consent. Audio recording had no significant effect on any of the 6 dependent variables examined. PRACTICE IMPLICATIONS: Benefits of recording clinic visits likely outweigh the risks of bias in this setting. PMID- 25837373 TI - A summary of seven- and eight-membered ring sultam syntheses via three Michael addition reactions. AB - A series of seven- and eight-membered ring -N,O-, -N,N-, and -N,S-sultams were effectively synthesized via tandem reactions involving oxa-, aza-, and thia Michael addition to vinyl sulfonamides. These reactions are summarized here since they enrich current synthetic methodologies for sultams and provide a good example of sultam diversity-oriented synthesis. All reactions proceeded under relatively mild and environmentally friendly conditions, and all these reactions are quite suitable for the rapid preparation of sultam compound libraries, which are valuable for biological activity explorations. PMID- 25837374 TI - Crystal structure of the FLT3 kinase domain bound to the inhibitor Quizartinib (AC220). AB - More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an "Abl-like" inactive conformation with the activation loop stabilized in the "DFG-out" orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations. PMID- 25837375 TI - The alternative role of DNA methylation in splicing regulation. AB - Although DNA methylation was originally thought to only affect transcription, emerging evidence shows that it also regulates alternative splicing. Exons, and especially splice sites, have higher levels of DNA methylation than flanking introns, and the splicing of about 22% of alternative exons is regulated by DNA methylation. Two different mechanisms convey DNA methylation information into the regulation of alternative splicing. The first involves modulation of the elongation rate of RNA polymerase II (Pol II) by CCCTC-binding factor (CTCF) and methyl-CpG binding protein 2 (MeCP2); the second involves the formation of a protein bridge by heterochromatin protein 1 (HP1) that recruits splicing factors onto transcribed alternative exons. These two mechanisms, however, regulate only a fraction of such events, implying that more underlying mechanisms remain to be found. PMID- 25837376 TI - Molecular signatures of nicotinoid-pathogen synergy in the termite gut. AB - Previous studies in lower termites revealed unexpected synergies between nicotinoid insecticides and fungal entomopathogens. The present study investigated molecular mechanisms of nicotinoid-pathogen synergy in the lower termite Reticulitermes flavipes, using the nicotinoid, imidacloprid, in combination with fungal and bacterial entomopathogens. Particular focus was placed on metatranscriptome composition and microbial dynamics in the symbiont rich termite gut, which houses diverse mixes of protists and bacteria. cDNA microarrays containing a mix of host and protist symbiont oligonucleotides were used to simultaneously assess termite and protist gene expression. Five treatments were compared that included single challenges with sublethal doses of fungi (Metharizium anisopliae), bacteria (Serratia marcescens) or imidacloprid, and dual challenges with fungi + imidacloprid or bacteria + imidacloprid. Our findings point towards protist dysbiosis and compromised social behavior, rather than suppression of stereotypical immune defense mechanisms, as the dominant factors underlying nicotinoid-pathogen synergy in termites. Also, greater impacts observed for the fungal pathogen than for the bacterial pathogen suggest that the rich bacterial symbiont community in the R. flavipes gut (>5000 species-level phylotypes) exists in an ecological balance that effectively excludes exogenous bacterial pathogens. These findings significantly advance our understanding of antimicrobial defenses in this important eusocial insect group, as well as provide novel insights into how nicotinoids can exert deleterious effects on social insect colonies. PMID- 25837377 TI - Imaging and analysis of microcalcifications and lipid/necrotic core calcification in fibrous cap atheroma. AB - The presence of microcalcifications (uCalcs) >5 um within the cap of human fibroatheroma has been shown to produce a 200-700% increase in peak circumferential stress, which can transform a stable plaque into a vulnerable one, whereas uCalcs < 5 um do not appear to increase risk. We quantitatively examine the possibility to distinguish caps with uCalcs > 5 um based on the gross morphological features of fibroatheromas, and the correlation between the size and distribution of uCalcs in the cap and the calcification in the lipid/necrotic core beneath it. Atherosclerotic lesions (N = 72) were imaged using HR-MUCT at 2.1-MUm resolution for detailed analysis of atheroma morphology and composition, and validated using non-decalcified histology. At 2.1-MUm resolution one observes four different patterns of calcification within the lipid/necrotic core, and is able to elucidate the 3D spatial progression of the calcification process using these four patterns. Of the gross morphological features identified, only minimum cap thickness positively correlated with the existence of uCalcs > 5 um in the cap. We also show that uCalcs in the cap accumulate in the vicinity of the lipid/necrotic core boundary with few on the lumen side of the cap. HR-MUCT enables three-dimensional assessment of soft tissue composition, lipid content, calcification patterns within lipid/necrotic cores and analysis of the axial progression of calcification within individual atheroma. The distribution of uCalcs within the cap is highly non-uniform and decreases sharply as one proceeds from the lipid pool/necrotic core boundary to the lumen. PMID- 25837378 TI - A case series of two cases of juxta-adrenal schwannoma presenting as adrenal mass lesion and review of the literature. AB - Schwannomas are rare tumors in the retroperitoneal location. They can pose a diagnostic dilemma when presenting as an adrenal mass lesion due to their imaging characteristics. We report two cases of juxta-adrenal schwannomas presenting as symptomatic adrenal mass lesions. In both the cases, the clinical examination and functional evaluation was unremarkable and the radiological examination revealed a mixed intense adrenal mass lesion in one case with predominantly hyperintense areas and a very hyperintense lesion in another, in T2-weighted images, mimicking a adrenocortical malignancy and a pheochromocytoma respectively. Both cases were treated by surgical excision. Histopathological examination established the correct diagnosis of schwannoma, which was confirmed by immunohistochemical staining. Juxta-adrenal schwannoma is rare tumors of the retroperitoneum, which should also be borne in mind whenever encountering large nonsecreting adrenal tumors. We report a unique imaging characteristic, which helps in preoperative identification these rare lesions. PMID- 25837379 TI - Respecting the circle of life: one year outcomes from a randomized controlled comparison of an HIV risk reduction intervention for American Indian adolescents. AB - Potential for widespread transmission of HIV/AIDS among American Indian (AI) adolescents exists, yet no evidence-based interventions (EBIs) have been adapted and evaluated with this population. Intensive psychoeducation may improve knowledge and decision-making which could potentially translate to reductions in HIV risk behaviors. A peer group randomized controlled comparison of an adapted EBI vs. control was delivered over an eight-day summer basketball camp in one reservation-based tribal community to adolescents ages 13-19. Outcome data were gathered immediately post-camp and at 6 and 12 months follow-up. Self-selected peer groups were randomized to intervention (n = 138) or control (n = 129) conditions for a total sample of 267 participants (56.2% female), mean age 15.1 years (SD = 1.7). Intervention participants had better condom use self-efficacy post-camp (Adjusted Mean Difference [AMD] = -0.75, p < 0.005) and at 6 (AMD = 0.44, p < 0.005) and 12 months (AMD = -0.23, p < 0.05) follow-up. Intervention participants also had higher HIV prevention and transmission knowledge (post camp: AMD = 0.07, p < 0.01; 6 months: AMD = 0.06, p < 0.01) were more likely to believe condoms prevent sexually transmitted infections (post-camp: RR = 1.41, p < 0.005; 6 months: RR = 1.34, p < 0.05), to talk with an adult about HIV/AIDS (post-camp: RR=1.78, p < 0.005; 6 months: RR = 1.14, p < 0.005), had higher partner negotiation efficacy related to substance use during sex (post-camp: AMD = 0.37, p < 0.01), and were more likely to intend to use a condom (post-camp: RR = 1.39, p < 0.01). The adapted intervention had short- and medium-term impacts on AI adolescent risk for HIV/AIDS, but attenuated at 12 months. Intervention delivery through a community-based camp is feasible and acceptable with strong retention. Additional study is needed to evaluate the adapted intervention's impact on sexual risk behaviors and if booster sessions and parent involvement translate to long-term impacts. PMID- 25837381 TI - Rebuttal From Dr Middlekauff. PMID- 25837380 TI - Gestational diabetes: differences between the current international diagnostic criteria and implications of switching to IADPSG. AB - AIMS: To highlight the differences between eight international expert panel diagnostic criteria (either current or outdated but in use) for the diagnosis of gestational diabetes mellitus (GDM) and implications of switching to the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criterion. METHODS: 2337 pregnant women underwent a 75-g oral glucose tolerance test as part of a universal screening protocol. The GDM prevalence and number of women classified differently were compared between the criteria of the American Diabetes Association (2003); Australasian Diabetes in Pregnancy Society (1998); the Canadian Diabetes Association, CDA (2003 & 2013); the European Association for the Study of Diabetes (1996); IADPSG (2010); the New Zealand Society for the Study of Diabetes (2004) and the World Health Organization (1999). RESULTS: The prevalence varied from 9.2% to 45.3% with the different criteria. The IADPSG compared a) best with CDA 2013 [356(15.2%) women classified differently, (kappa, k=68.3%)] and b) worst with CDA 2003 [843 (36.1%) women classified differently, (k=21.8%)]; p<0.001.Switching to IADPSG from the original criteria would increase the prevalence 1.5-4.9 times. CONCLUSIONS: In 2015, the various international guidelines for GDM continue to show major discrepancies in the prevalence and the women classified dissimilarly. A consensus on a single global guideline would be a giant leap forward. PMID- 25837382 TI - Hematological and serum biochemical parameters of blood in adolescent rats and histomorphological changes in the jejunal epithelium and liver after chronic exposure to cadmium and lead in the case of supplementation with green tea vs black, red or white tea. AB - Rats were used to check whether regular consumption of black, red, or white tea would have a protective effect similar to the action of green tea on the intestine and liver in the case of exposure to Cd and Pb within the limits of human environmental exposure to these elements. Rats at the age of 6 weeks were divided into the control and four groups supplemented with green (GT), black (BT), red (RT), or white (WT) tea extracts. Their diet (except the control) was mixed with 7 mg Cd/kg and 50mg Pb/kg. The experiment lasted 12 weeks. The effects of administration of tea in Cd- and Pb-poisoned rats on plasma biochemical parameters and the jejunal epithelium and liver were determined. The highest body mass was found in the GT group. The highest hemoglobin and Fe concentrations were in the control and GT groups. The highest activity of AST was in groups poisoned with Cd and Pb independently on supplementation. The highest ALT activity was in BT and RT groups with lower content of polifenoles. Pb and Cd disturbed the liver leading to necrosis and fatty degenerative changes, and a loss of normal architecture of the hepatocytes. Rats from the GT group had the highest cell proliferation rate in intestinal glands and the largest absorptive surface. Black, red, and white tea exerted a varied impact on the histological structure and innervation of the small intestine wall as well as on the absorptive function of small intestine mucosa in rats poisoned with Pb and Cd than green tea. On the other hand, taking into account the number of apoptotic cells, the effect of the teas was the same. Moreover, it is clear that long term exposure to Cd and Pb contamination causes toxic effect in the liver. PMID- 25837383 TI - Imaging centrosomes and cilia in the mouse kidney. AB - The centrosome and cilium are evolutionarily conserved components of the microtubule cytoskeleton, and act as a cellular signaling center that regulates the activity of numerous developmental signaling pathways. Several genetic syndromes, called the ciliopathies, are associated with defects in the structure or function of the centrosome-cilium complex. In the mammalian kidney, these organelles are found at the apical surface of renal epithelial cells lining the various segments of the nephron, where they relay information from the extracellular environment to the interior of the cell. Cilium-based signaling plays an important role in the development and homeostasis of mammalian kidneys, and ciliary dysfunction is implicated in the pathogenesis of cystic kidney disease. Given the importance of centrosomes and cilia in renal function, techniques used to visualize these organelles, analyze their composition, and test their functionality have become essential in many studies of kidney development and disease. Fluorescence microscopy is a powerful, widely used technique that has enhanced our understanding of molecular mechanisms that regulate the assembly, maintenance, and function of these organelles in various organs. Here, we present detailed steps for the isolation of kidneys from adult and embryonic mice, describe protocols to label centrosomes and cilia in renal tissues, and methods used to culture and image kidneys ex vivo. PMID- 25837384 TI - Ependymal cell differentiation, from monociliated to multiciliated cells. AB - Primary and motile cilia differ in their structure, composition, and function. In the brain, primary cilia are immotile signalling organelles present on neural stem cells and neurons. Multiple motile cilia are found on the surface of ependymal cells in all brain ventricles, where they contribute to the flow of cerebrospinal fluid. During development, monociliated ependymal progenitor cells differentiate into multiciliated ependymal cells, thus providing a simple system for studying the transition between these two stages. In this chapter, we provide protocols for immunofluorescence staining of developing ependymal cells in vivo, on whole mounts of lateral ventricle walls, and in vitro, on cultured ependymal cells. We also provide a list of markers we currently use to stain both types of cilia, including proteins at the ciliary membrane and tubulin posttranslational modifications of the axoneme. PMID- 25837385 TI - Observing planar cell polarity in multiciliated mouse airway epithelial cells. AB - The concerted movement of cilia propels inhaled contaminants out of the lungs, safeguarding the respiratory system from toxins, pathogens, pollutants, and allergens. Motile cilia on the multiciliated cells (MCCs) of the airway epithelium are physically oriented along the tissue axis for directional motility, which depends on the planar cell polarity (PCP) signaling pathway. The MCCs of the mouse respiratory epithelium have emerged as an important model for the study of motile ciliogenesis and the PCP signaling mechanism. Unlike other motile ciliated or planar polarized tissues, airway epithelial cells are relatively easily accessible and primary cultures faithfully model many of the essential features of the in vivo tissue. There is growing interest in understanding how cells acquire and polarize motile cilia due to the impact of mucociliary clearance on respiratory health. Here, we present methods for observing and quantifying the planar polarized orientation of motile cilia both in vivo and in primary culture airway epithelial cells. We describe how to acquire and evaluate electron and light microscopy images of ciliary ultrastructural features that reveal planar polarized orientation. Furthermore, we describe the immunofluorescence localization of PCP pathway components as a simple readout for airway epithelial planar polarization and ciliary orientation. These methods can be adapted to observe ciliary orientation in other multi- and monociliated cells and to detect PCP pathway activity in any tissue or cell type. PMID- 25837387 TI - Cilia in photoreceptors. AB - Retina is a neurosensory tissue lining the back of the eye and is responsible for light detection and relaying the signal to the visual cortex in the brain. Mammalian retina consists of six major types of neurons (including photoreceptors; rods and cones) and one type of glial cells arranged in distinct layers. Photoreceptors are the most abundant cell types accounting for approximately 60% of all cells in the retina. Owing to their unique structure and function as ciliated neurons and their vast majority, dysfunction and degeneration of photoreceptors is associated with several inherited blindness disorders, such as retinitis pigmentosa, cone-rod degeneration, and age-related macular degeneration. Therefore, it is imperative to examine the structure and function of photoreceptors so that better understanding of the pathogenesis of associated diseases can be obtained for designing therapeutic modalities. In this chapter, we will provide detailed methods for analyzing photoreceptor function (electroretinography), structure, and biochemical analysis of sensory cilia of photoreceptors using mammalian retina as model system. These methods are widely used to assess photoreceptor development and degeneration during disease. PMID- 25837386 TI - Imaging and analyzing primary cilia in cardiac cells. AB - The primary cilium is a small sensory organelle that is required for different aspects of embryonic development, including the formation of the heart. The structure and composition of cilia have been extensively studied, so that several markers of primary cilia have now been identified. However, the role of cilia in specific cell types remains poorly understood. We describe here a series of approaches to image primary cilia in the rodent heart or in primary cultures of cells dissociated from the heart. As the cilium is a marker of cell polarity, we also provide, for quantitative image analysis of cilium orientation, tools which are generally applicable to other types of tissues. PMID- 25837388 TI - Analysis of primary cilia in the developing mouse brain. AB - Stem and progenitor cells in the developing mammalian brain are highly polarized cells that carry a primary cilium protruding into the brain ventricles. Here, cilia detect signals present in the cerebrospinal fluid that fills the ventricles. Recently, striking observations have been made regarding the dynamics of primary cilia in mitosis and cilium reformation after cell division. In neural progenitors, primary cilia are not completely disassembled during cell division, and some ciliary membrane remnant can be inherited by one daughter cell that tends to maintain a progenitor fate. Furthermore, newborn differentiating cells grow a primary cilium on their basolateral plasma membrane, in spite of them possessing apical membrane and adherens junctions, and thus change the environment to which the primary cilium is exposed. These phenomena are proposed to be involved in cell fate determination and delamination of daughter cells in conjunction with the production of neurons. Here, we describe several methods that can be used to study the structure, localization, and dynamics of primary cilia in the developing mouse brain; these include time-lapse imaging of live mouse embryonic brain tissues, and analysis of primary cilia structure and localization using correlative light- and electron- and serial-block-face scanning electron microscopy. PMID- 25837389 TI - In vivo investigation of cilia structure and function using Xenopus. AB - Cilia are key organelles in development and homeostasis. The ever-expanding complement of cilia associated proteins necessitates rapid and tractable models for in vivo functional investigation. Xenopus laevis provides an attractive model for such studies, having multiple ciliated populations, including primary and multiciliated tissues. The rapid external development of Xenopus and the large cells make it an especially excellent platform for imaging studies. Here we present embryological and cell biological methods for the investigation of cilia structure and function in X. laevis, with a focus on quantitative live and fixed imaging. PMID- 25837390 TI - A quantitative approach to study endothelial cilia bending stiffness during blood flow mechanodetection in vivo. AB - Primary cilia are necessary for shear stress sensing in different developing organs such as the kidneys and blood vessels. In endothelial cells (ECs), primary cilia bend in response to blood flow forces and are necessary for flow sensing as well as for the control of angiogenesis. The different parameters guiding cilia bending reflect the forces generated at the surface of the ECs and the mechanical properties of the endothelial cilia. Here, we present an approach allowing the calculation of the bending rigidity of endothelial cilia based on live imaging. The method relies on segmentation and mathematical modeling to extract the critical parameters needed for the calculation. PMID- 25837391 TI - Quantitative description of fluid flows produced by left-right cilia in zebrafish. AB - Motile cilia generate directional flows that move mucus through airways, cerebrospinal fluid through brain ventricles, and oocytes through fallopian tubes. In addition, specialized monocilia beat in a rotational pattern to create asymmetric flows that are involved in establishing the left-right (LR) body axis during embryogenesis. These monocilia, which we refer to as "left-right cilia," produce a leftward flow of extraembryonic fluid in a transient "organ of asymmetry" that directs asymmetric signaling and development of LR asymmetries in the cardiovascular system and gastrointestinal tract. The asymmetric flows are thought to establish a chemical gradient and/or activate mechanosensitive cilia to initiate calcium ion signals and a conserved Nodal (TGFbeta) pathway on the left side of the embryo, but the mechanisms underlying this process remain unclear. The zebrafish organ of asymmetry, called Kupffer's vesicle, provides a useful model system for investigating LR cilia and cilia-powered fluid flows. Here, we describe methods to visualize flows in Kupffer's vesicle using fluorescent microspheres and introduce a new and freely available MATLAB particle tracking code to quantitatively describe these flows. Analysis of normal and aberrant flows indicates this approach is useful for characterizing flow properties that impact LR asymmetry and may be more broadly applicable for quantifying other cilia flows. PMID- 25837392 TI - Efficient live fluorescence imaging of intraflagellar transport in mammalian primary cilia. AB - Intraflagellar transport (IFT) is a motile process critical for building most cilia, including those of mammalian cells. Defects in IFT lead to short or missing cilia, and in animals can cause defects in development, for example, in hedgehog-mediated signaling, as well as disease symptoms such as polycystic kidney disease or retinal degeneration. Understanding how IFT works is thus a high priority in ciliary biology. Imaging of living cells has played a key role in understanding the mechanism of IFT and this is particularly the case in mammalian cells where biochemical analysis of IFT is extremely difficult due to the difficulty of isolating cilia away from the rest of the cell. Imaging IFT in living mammalian cells requires solution to several problems: constructing cell lines that express fluorescent-protein-tagged IFT proteins, obtaining cell populations with a high degree of ciliation, confocal or TIRF imaging with sufficient time resolution and signal-to-noise ratio to observe the majority of IFT particles as they travel back and forth inside the cilium, and analyzing the image data to extract quantitative measurements of IFT. We describe optimized solutions to each of these technical challenges. Using the approaches described here, mammalian cultured cells become powerful platforms for quantitative analysis of IFT dynamics. PMID- 25837393 TI - Analysis of soluble protein entry into primary cilia using semipermeabilized cells. AB - The primary cilium is a protrusion from the cell surface that serves as a specialized compartment for signal transduction. Many signaling factors are known to be dynamically concentrated within cilia and to require cilia for their function. Yet protein entry into primary cilia remains poorly understood. To enable a mechanistic analysis of soluble protein entry into cilia, we developed a method for semipermeabilization of mammalian cells in which the plasma membrane is permeabilized while the ciliary membrane remains intact. Using semipermeabilized cells as the basis for an in vitro diffusion-to-capture assay, we uncovered a size-dependent diffusion barrier that restricts soluble protein exchange between the cytosol and the cilium. The manipulability of this in vitro system enabled an extensive characterization of the ciliary diffusion barrier and led us to show that the barrier is mechanistically distinct from those at the axon initial segment and the nuclear pore complex. Because semipermeabilized cells enable a range of experimental perturbations that would not be easily feasible in intact cells, we believe this methodology will provide a unique resource for investigating primary cilium function in development and disease. PMID- 25837394 TI - Methods for imaging individual cilia in living echinoid embryos. AB - The embryos of echinoids (sea urchins and sand dollars) serve as excellent models for studying cilia differentiation and stages of the cilia life cycle including ciliogenic initiation, growth, maintenance, and retraction. Early in echinoid development, uniform motile cilia form on all cells simultaneously but then rapidly differentiate into multiple cilia types that differ in morphology, motility, and signaling sensitivity. Metal ion treatments that shift germ layer boundaries and thereby "animalize" or "vegetalize" embryos can be used to enrich for low-abundance cilia types rendering those specialized cilia and the differentiation processes they exhibit much easier to study. The experimental advantages of having robust cilia growth and differentiation is tempered by the challenge of restraining ciliated embryos well enough to view the process of ciliogenesis live. We have developed four observation chambers as modifications of the Kiehart chamber for long-term light microscopic imaging of ciliated echinoid embryos. One of these systems employs paramagnetic beads to render ciliated larvae magnetic so they can be gently and reversibly trapped directly under the objective lens. With this magnetic trapping system, the larva can be positioned and repositioned until they achieve the orientation with the clearest view of any cilia of interest. These methods of gentle embryo restraint allow normal embryo development and the normal ciliogenic cycle and ciliary differentiation processes to continue in direct view. Sequential image series can then be collected and analyzed to quantitatively study the wide spectrum of cilia behaviors and properties that arise in developing echinoid embryos. PMID- 25837395 TI - The planarian Schmidtea mediterranea as a model for studying motile cilia and multiciliated cells. AB - In the past few years, the freshwater planarian Schmidtea mediterranea has emerged as a powerful model system to study the assembly and function of cilia. S. mediterranea is a free-living flatworm that uses the beating of cilia on its ventral epidermis for locomotion. The ventral epidermis is composed of a single layer of multiciliated cells highly similar to the multiciliated cells that line the airway, the brain ventricles, and the oviducts in humans. The genome of S. mediterranea has been sequenced and efficient methods for targeting gene expression by RNA interference (RNAi) are available. Locomotion defects induced by perturbing the expression of ciliary genes can be often detected by simple visual screening, and more subtle defects can be detected by measuring locomotion speed. Cilia are present in large numbers and are directly accessible, which facilitates analyses by immunofluorescence and electron microscopy. Here we describe a set of methods for maintaining planarians in the lab. These include gene knockout by RNAi, cilia visualization by immunofluorescence, transmission electron microscopy, and live imaging. PMID- 25837396 TI - Quantitative analysis of flagellar proteins in Drosophila sperm tails. AB - The cilium has a well-defined structure, which can still accommodate some morphological and molecular composition diversity to suit the functional requirements of different cell types. The sperm flagellum of the fruit fly Drosophila melanogaster appears as a good model to study the genetic regulation of axoneme assembly and motility, due to the wealth of genetic tools publically available for this organism. In addition, the fruit fly's sperm flagellum displays quite a long axoneme (~1.8mm), which may facilitate both histological and biochemical analyses. Here, we present a protocol for imaging and quantitatively analyze proteins, which associate with the fly differentiating, and mature sperm flagella. We will use as an example the quantification of tubulin polyglycylation in wild-type testes and in Bug22 mutant testes, which present defects in the deposition of this posttranslational modification. During sperm biogenesis, flagella appear tightly bundled, which makes it more challenging to get accurate measurements of protein levels from immunostained specimens. The method we present is based on the use of a novel semiautomated, macro installed in the image processing software ImageJ. It allows to measure fluorescence levels in closely associated sperm tails, through an exact distinction between positive and background signals, and provides background corrected pixel intensity values that can directly be used for data analysis. PMID- 25837397 TI - Imaging cilia in Drosophila melanogaster. AB - Drosophila melanogaster is a powerful genetic model organism to understand the function of proteins in specific cellular processes. Cilia have been extensively studied in Drosophila playing various sensory functions that are essential for fly survival. Indeed, flies defective in cilia formation cannot walk, fly, or feed properly. Drosophila harbors different types of cilia that can be motile or immotile or that can show compartimentalized (intraflagellar transport (IFT) dependent) or cytoplasmic (IFT-independent) mode of assembly. Therefore, Drosophila represents an advantageous model organism to study the function of novel ciliary candidates and to address specific questions such as their requirement for IFT-dependent processes versus other aspects of cilia-associated functions. This chapter describes protocols to visualize cilia by direct or indirect fluorescent labeling and protocols to analyze ciliary ultrastructure by electron microscopy. PMID- 25837398 TI - Studying G protein-coupled receptors: immunoblotting, immunoprecipitation, phosphorylation, surface labeling, and cross-linking protocols. AB - Primary cilia are signaling organelles that have been shown to coordinate cellular responses to extracellular cues during physiological processes ranging from organ patterning to cell cycle regulation. A variety of receptors, including G protein-coupled receptors (GPCRs), downstream effectors (adenylyl cyclases), and second messengers, such as calcium, accumulate in the ciliary compartment. Isolation of GPCRs is essential for studying posttranslational modifications, intracellular trafficking, and protein-protein interactions that are important in downstream signaling. However, the presence of multiple hydrophobic transmembrane domains, and the inherent conformational flexibility of GPCRs make their extraction from membranes and solubilization particularly challenging. Here, we describe detailed methods for immunoblotting and immunoprecipitation of GPCRs from whole cell extracts. These methods are applicable for studying other multipass transmembrane proteins (such as adenylyl cyclases). We also describe methods for determining GPCR phosphorylation, surface labeling by biotinylation, and cross-linking to detect transient interactions with other proteins. These methods are amenable for studying both ciliary and nonciliary GPCRs in the context of cellular signaling pathways. PMID- 25837399 TI - Image analysis of Caenorhabditis elegans ciliary transition zone structure, ultrastructure, molecular composition, and function. AB - The transition zone (TZ) at the ciliary base has emerged as an important regulator of the composition and functions of cilia, which are microtubule-based structures extending from the surfaces of most eukaryotic cells, serving motility, chemo-/mechano-/photosensation and developmental signaling roles. Possessing distinct ultrastructural features such as microtubule-membrane spanning Y-links, the ~0.2-1.0-MUm long TZ is thought to act as a gated cytosolic (size dependent) and membrane diffusion barrier that drives ciliary compartmentalization by preventing unregulated protein exchange between the cilium and the rest of the cell. Multiple proteins associated with ciliary diseases (ciliopathies) such as Meckel-Gruber syndrome (MKS) and nephronophthisis are specifically found in the TZ, and work from a number of model systems, including Chlamydomonas reinharditii, Caenorhabditis elegans and the mouse indicates TZ-gating and associated ciliogenic functions for a number of these proteins. Here we present a suite of assays for probing the structure, function, and molecular composition of the C. elegans TZ, with emphasis on TZ ultrastructure, diffusion barrier kinetics, MKS module assembly hierarchy, and TZ dependent behaviors. PMID- 25837401 TI - Axonemal motility in Chlamydomonas. AB - Motile cilia and flagella rapidly propagate bending waves and produce water flow over the cell surface. Their function is important for the physiology and development of various organisms including humans. The movement is based on the sliding between outer doublet microtubules driven by axonemal dyneins, and is regulated by various axonemal components and environmental factors. For studies aiming to elucidate the mechanism of cilia/flagella movement and regulation, Chlamydomonas is an invaluable model organism that offers a variety of mutants. This chapter introduces standard methods for studying Chlamydomonas flagellar motility including analysis of swimming paths, measurements of swimming speed and beat frequency, motility reactivation in demembranated cells (cell models), and observation of microtubule sliding in disintegrating axonemes. Most methods may be easily applied to other organisms with slight modifications of the medium conditions. PMID- 25837400 TI - Genetic and genomic approaches to identify genes involved in flagellar assembly in Chlamydomonas reinhardtii. AB - Flagellar assembly requires intraflagellar transport of components from the cell body to the flagellar tip for assembly. The understanding of flagellar assembly has been aided by the ease of biochemistry and the availability of mutants in the unicellular green alga, Chlamydomonas reinhardtii. In this chapter, we discuss means to identify genes involved in these processes using forward and reverse genetics. In particular, the ease and low cost of whole genome sequencing (WGS) will help to make gene identification easier and promote the understanding of this important process. PMID- 25837402 TI - Posttranscriptional control over rapid development and ciliogenesis in Marsilea. AB - Marsilea vestita is a semiaquatic fern that produces its spores (meiotic products) as it undergoes a process of natural desiccation. During the period of desiccation, the spores mature, and produce large quantities of pre-mRNA, which is partially processed and stored in nuclear speckles and can remain stable during a period of extended quiescence in the dry spore. Rehydration of the spores initiates a highly coordinated developmental program, featuring nine successive mitotic division cycles that occur at precise times and in precise planes within the spore wall to produce 39 cells, 32 of which are spermatids. The spermatids then undergo de novo basal body formation, the assembly of a massive cytoskeleton, nuclear and cell elongation, and finally ciliogenesis, before being released from the spore wall. The entire developmental program requires only 11 h to reach completion, and is synchronous in a population of spores rehydrated at the same time. Rapid development in this endosporic gametophyte is controlled posttranscriptionally, where stored pre-mRNAs, many of which are intron-retaining transcripts, are unmasked, processed, and translated under tight spatial and temporal control. Here, we describe posttranscriptional mechanisms that exert temporal and spatial control over this developmental program, which culminates in the production of ~140 ciliary axonemes in each spermatozoid. PMID- 25837403 TI - Total internal reflection fluorescence microscopy of intraflagellar transport in Tetrahymena thermophila. AB - Live imaging has become a powerful tool in studies of ciliary proteins. Tetrahymena thermophila is an established ciliated model with well-developed genetic and biochemical approaches, but its large size, complex shape, and the large number of short and overlapping cilia, have made live imaging of ciliary proteins challenging. Here we describe a method that combines paralysis of cilia by nickel ions and total internal reflection microscopy for live imaging of fluorescent proteins inside cilia of Tetrahymena. Using this method, we quantitatively documented the intraflagellar transport in Tetrahymena. PMID- 25837404 TI - Ciliary heterogeneity within a single cell: the Paramecium model. AB - Paramecium is a single cell able to divide in its morphologically differentiated stage that has many cilia anchored at its cell surface. Many thousands of cilia are thus assembled in a short period of time during division to duplicate the cell pattern while the cell continues swimming. Most, but not all, of these sensory cilia are motile and involved in two main functions: prey capture and cell locomotion. These cilia display heterogeneity, both in their length and their biochemical properties. Thanks to these properties, as well as to the availability of many postgenomic tools and the possibility to follow the regrowth of cilia after deciliation, Paramecium offers a nice opportunity to study the assembly of the cilia, as well as the genesis of their diversity within a single cell. In this paper, after a brief survey of Paramecium morphology and cilia properties, we describe the tools and the protocols currently used for immunofluorescence, transmission electron microscopy, and ultrastructural immunocytochemistry to analyze cilia, with special recommendations to overcome the problem raised by cilium diversity. PMID- 25837405 TI - Imaging intraflagellar transport in trypanosomes. AB - Trypanosoma brucei is a flagellated eukaryotic pathogen responsible for sleeping sickness in central Africa. Because of the presence of a long motile flagellum (>20 MUm) and its amenity to genetic manipulation, it is becoming an attractive model to study the assembly and the functions of cilia and flagella. In recent years, several aspects have been investigated, especially intraflagellar transport (IFT) that has been exhaustively characterized at the light microscopy level. In this manuscript, we review various methods to express fluorescent fusion proteins and to record IFT in living trypanosomes in normal or mutant contexts. We present an approach for separating anterograde and retrograde IFT, hence facilitating quantification of train speed, frequency, and size. A statistical analysis to discriminate different subpopulations of IFT trains is also summarized. These methods have proven their efficiency for the study of IFT in trypanosomes and could be applied to any other organism. PMID- 25837406 TI - Scanning and three-dimensional electron microscopy methods for the study of Trypanosoma brucei and Leishmania mexicana flagella. AB - Three-dimensional electron microscopy tools have revolutionized our understanding of cell structure and molecular complexes in biology. Here, we describe methods for studying flagellar ultrastructure and biogenesis in two unicellular parasites Trypanosoma brucei and Leishmania mexicana. We describe methods for the preparation of these parasites for scanning electron microscopy cellular electron tomography, and serial block face scanning electron microscopy (SBFSEM). These parasites have a highly ordered cell shape and form, with a defined positioning of internal cytoskeletal structures and organelles. We show how knowledge of these can be used to dissect cell cycles in both parasites and identify the old flagellum from the new in T. brucei. Finally, we demonstrate the use of SBFSEM three-dimensional models for analysis of individual whole cells, demonstrating the excellent potential this technique has for future studies of mutant cell lines. PMID- 25837407 TI - Surface functionalization of nanodiamond with phenylphosphonate. AB - HYPOTHESIS: This work explores arylation of oxidized nanodiamond (OND) and carboxylated nanodiamond (CND) using phenylphosphonate (PPA) to produce PPA grafted nanodiamond (PPA@ND). The specific hypothesis is that PPA can be readily grafted onto the surfaces of OND and CND particles via the nanodiamonds' reactive oxygen-rich surface functional groups. EXPERIMENTS: This work explores the effect of varying reaction conditions (reactant ratio, heat, sonication) on PPA graft density and grafting mode. The products were characterized by a variety of techniques including: (31)P MAS NMR and FTIR to confirm PPA grafting, XPS to estimate PPA grafted amounts, and TGA to assess thermal stability. The utility of PPA functionalization for improving ND dispersion in organic solvents was evaluated using dynamic light scattering. FINDINGS: The results confirm PPA grafting on both OND and CND, quantify the extent of PPA grafting, and suggest primarily bidentate grafting. For PPA grafting on OND, the grafted amount does not depend on PPA:ND ratio, application of heat, or use of sonication. The grafted amount of PPA on CND was significantly lower than that on OND. TGA data indicates that grafted PPA improves the thermal stability of both OND and CND. The starting OND disperses in water as aggregates with approximately 100 nm particle size. However, PPA-grafted OND does not disperse at all in water: thus grafted PPA changes the ND surface from hydrophilic to hydrophobic. PPA@OND prepared without sonication does not completely disperse in either DMF or toluene. Only PPA@OND prepared with sonication disperses well in these solvents, suggesting that sonication promotes more complete exposure of the ND surface to PPA grafting. PMID- 25837408 TI - On the scattered light by dilute aqueous dispersions of nanogel particles. AB - This work deals with the scattered light by nanoparticles formed by a temperature sensitive polymer networks, namely nanogel particles. The scattered light is measured as a function of the scattering angle at temperatures below and above the volume phase transition temperature (VPTT) of nanogel particles. Our experimental results indicate that nanogel particles have a core-shell structure, formed by a uniform highly cross-linked core surrounded by a fuzzy shell where the polymer density decays to zero gradually for swollen configurations and sharply for shrunken states. The theoretical fitting of the experimental curves shows that the scattered light at low angle obeys a decreasing power law with the scattering vector, q(-alpha). The value of exponent alpha provides information about the radial dependence of the polymer density at the external shell of the particles for swollen nanogels, and about the degree of roughness of the surface for the case of shrunken nanogels. On the one hand, at low temperatures (below the VPPT), the nanogel particle is in the swollen state and the light scattering data show that its shell structure follows a fractal behaviour, with a polymer density that decays as r(alpha-3), where r is the distance to the particle centre. On the other hand, above the VPPT the results indicate that nanogel collapses into a core of uniform polymer density and a rough shell, with a fractal surface dimension of 2.5. PMID- 25837409 TI - An empirical Bayes safety evaluation of tram/streetcar signal and lane priority measures in Melbourne. AB - OBJECTIVE: Streetcars/tram systems are growing worldwide, and many are given priority to increase speed and reliability performance in mixed traffic conditions. Research related to the road safety impact of tram priority is limited. This study explores the road safety impacts of tram priority measures including lane and intersection/signal priority measures. METHOD: A before-after crash study was conducted using the empirical Bayes (EB) method to provide more accurate crash impact estimates by accounting for wider crash trends and regression to the mean effects. Before-after crash data for 29 intersections with tram signal priority and 23 arterials with tram lane priority in Melbourne, Australia, were analyzed to evaluate the road safety impact of tram priority. RESULTS: The EB before-after analysis results indicated a statistically significant adjusted crash reduction rate of 16.4% after implementation of tram priority measures. Signal priority measures were found to reduce crashes by 13.9% and lane priority by 19.4%. A disaggregate level simple before-after analysis indicated reductions in total and serious crashes as well as vehicle-, pedestrian , and motorcycle-involved crashes. In addition, reductions in on-path crashes, pedestrian-involved crashes, and collisions among vehicles moving in the same and opposite directions and all other specific crash types were found after tram priority implementation. CONCLUSIONS: Results suggest that streetcar/tram priority measures result in safety benefits for all road users, including vehicles, pedestrians, and cyclists. Policy implications and areas for future research are discussed. PMID- 25837410 TI - Assessment of Reliable Change Using 95% Credible Intervals for the Differences in Proportions: A Statistical Analysis for Case-Study Methodology. AB - PURPOSE: Case-study methodology studying change is often used in the field of speech-language pathology, but it can be criticized for not being statistically robust. Yet with the heterogeneous nature of many communication disorders, case studies allow clinicians and researchers to closely observe and report on change. Such information is valuable and can further inform large-scale experimental designs. In this research note, a statistical analysis for case-study data is outlined that employs a modification to the Reliable Change Index (Jacobson & Truax, 1991). The relationship between reliable change and clinical significance is discussed. Example data are used to guide the reader through the use and application of this analysis. METHOD: A method of analysis is detailed that is suitable for assessing change in measures with binary categorical outcomes. The analysis is illustrated using data from one individual, measured before and after treatment for stuttering. CONCLUSIONS: The application of this approach to assess change in categorical, binary data has potential application in speech-language pathology. It enables clinicians and researchers to analyze results from case studies for their statistical and clinical significance. This new method addresses a gap in the research design literature, that is, the lack of analysis methods for noncontinuous data (such as counts, rates, proportions of events) that may be used in case-study designs. PMID- 25837411 TI - Synthesis and structure of dicopper(II) complexes bridged by N-(5-chloro-2 hydroxyphenyl)-N'-[3-(methy lamino)propyl]oxamide: evaluation of DNA/protein binding, DNA cleavage, and in vitro anticancer activity. AB - Three new dicopper(II) complexes bridged by N-(5-chloro-2-hydroxyphenyl)-N'-[3 (methylamino)-propyl]oxamide (H3chmpoxd) and end-capped with 1,10-phenanthroline (phen); 2,2'-diamino-4,4'-bithiazole (dabt); and 2,2'-bipyridine (bpy), namely [Cu2(chmpoxd)(H2O)(phen)](ClO4)?CH3CN (1), [Cu2(chmpoxd)(dabt)(C2H5OH)](NO3) (2) and [Cu2(chmpoxd)(H2O)(bpy)](NO3)?CH3CN (3), were synthesized and structurally characterized. The single-crystal X-ray diffraction analysis revealed that both the copper(II) ions bridged by the cis-chmpoxd(3-) ligands in the three complexes are in square-planar and square-pyramidal environments, respectively. The reactivity towards herring sperm DNA (HS-DNA) and protein bovine serum albumin (BSA) indicated that these copper(II) complexes can interact with the DNA in the mode of intercalation, and bind to BSA responsible for quenching of tryptophan fluorescence by the static quenching mechanism. The cytotoxicity and DNA cleavage suggested that all the dicopper(II) complexes are active against the selected tumor cell lines, and the complex 1 exhibits the cleavage capacity for plasmid DNA. PMID- 25837412 TI - Biological assessment of neonicotinoids imidacloprid and its major metabolites for potentially human health using globular proteins as a model. AB - The assessment of biological activities of imidacloprid and its two major metabolites, namely 6-chloronicotinic acid and 2-imidazolidone for nontarget organism, by employing essentially functional biomacromolecules, albumin and hemoglobin as a potentially model with the use of circular dichroism (CD), fluorescence, extrinsic 8-anilino-1-naphthalenesulfonic acid (ANS) fluorescence as well as molecular modeling is the theme of this work. By dint of CD spectra and synchronous fluorescence, it was clear that the orderly weak interactions between amino acid residues within globular proteins were disturbed by imidacloprid, and this event led to marginally alterations or self-regulations of protein conformation so as to lodge imidacloprid more tightly. Both steady state and time-resolved fluorescence suggested that the fluorescence of Trp residues in proteins was quenched after the presence of imidacloprid, corresponding to noncovalent protein-imidacloprid complexes formation and, the reaction belongs to moderate association (K=1.888/1.614*10(4)M(-1) for albumin/hemoglobin imidacloprid, respectively), hydrogen bonds and pi stacking performed a vital role in stabilizing the complexes, as derived from thermodynamic analysis and molecular modeling. With the aid of hydrophobic ANS experiments, subdomain IIA and alpha1beta2 interface of albumin and hemoglobin, respectively, were found to be preserved high-affinity for imidacloprid. These results ties in with the subsequently molecular modeling laying imidacloprid in the Sudlow's site I and close to Trp-213 residue on albumin, while settling down B/Trp-37 residue nearby in hemoglobin, and these conclusions further confirmed by site-directed mutagenesis and molecular dynamics simulation. But, at the same time, several crucial noncovalent bonds came from other amino acid residues, e.g. Arg-194 and Arg-198 (albumin) and B/Arg-40, B/Asp-99 and B/Asn-102 (hemoglobin) cannot be ignored completely. Based on the comparative studies of binding modes between imidacloprid and its two primary metabolites with globular proteins, it is evident to us that the noncovalent interactions of 6-chloronicotinic acid and 2 imidazolidone with biopolymers are not always to be decreased obviously as a result of the relatively small molecular structures of these metabolites, compared with parent compound imidacloprid. Conversely, this could probably strengthen the weak interactions existed in the macromolecules-metabolites conjugation, or rather, the metabolites such as 6-chloronicotinic acid and 2 imidazolidone contributed drastically to the overall toxicity of imidacloprid. PMID- 25837413 TI - Predictors of functional outcome in individuals at high clinical risk for psychosis at six years follow-up. AB - BACKGROUND: The long-term functional status of subjects at ultra high risk for psychosis (HR) is relatively under investigated. This study explores baseline predictors of long-term functional outcome in HR subjects who did not convert to psychosis during a 6 years follow-up period. METHODS: A total of 154 HR were followed up for an average of 6 years. The primary outcome variable was global assessment of functioning at the last follow-up visit as assessed with the Global Assessment of Functioning tool. A multinomial logistic regression was performed to identify potential predictors of functional outcome. RESULTS: Baseline and follow-up data on functioning was available for 92 HR. Twenty-four (43%) individuals who did not convert to psychosis reported poor functioning at follow up. Baseline scores in the GAF (Exp(b) = 0.857; 95% CIs: 0.75/0.97), employment status (Exp(b) = 0.029; 95% CIs: 0.00/0.268), and CAARMS total scores (Exp(b) = 1.976; 95% CIs: 1.00/1.14) predicted functional outcome in HR subjects at 6 years. CONCLUSIONS: Despite the preventive treatments received, many individuals who did not convert to full-blown psychosis in the longer term do not functionally remit. These individuals are lower functioning, unemployed and have higher symptom loading at the time of their presentation to the prodromal clinic. Our study suggests the need for innovative treatments targeting long term functional status beyond the prevention of psychosis onset in the HR population. PMID- 25837414 TI - Development and applications of AlphaScreen-based FcRn binding assay to characterize monoclonal antibodies. AB - IgG antibodies are important pharmaceutical molecules that successfully treat a variety of human diseases. The neonatal Fc receptor (FcRn) interacts with IgG Fc in the CH2-CH3 domain and plays a key role in IgG antibody homeostasis and affects its pharmacokinetic properties. An in vitro FcRn binding assay could be a highly valuable complementary tool to assess IgG antibody pharmacokinetics in IgG engineering and screening during the early optimization stage. In addition, it could be useful in biological characterization studies for antibody minor variants, process optimization, and comparability study at later stages of antibody development. Here we developed a homogeneous AlphaScreen-based FcRn assay to assess the binding of FcRn to IgG antibody in vitro. The assay is found to be accurate, precise, specific, and simple: donor beads loaded with FcRn and acceptor beads loaded with IgG1 mAb1 are mixed together with sample IgG at various dilutions and incubated for 1h before acquiring data with a fluorescence reader. This assay can run up to four samples per plate in 2h, which is time and cost effective compared with other FcRn binding methods such as cell-based fluorescent-activated cell scan and surface plasma resonance. Our data demonstrated that this assay is suitable for assessing the FcRn binding in vitro and provides a platform approach that can be readily applied to various antibodies. PMID- 25837415 TI - Interleukin-10 conjugated electrospun polycaprolactone (PCL) nanofibre scaffolds for promoting alternatively activated (M2) macrophages around the peripheral nerve in vivo. AB - Macrophages play a key role in tissue regeneration following peripheral nerve injury by preparing the surrounding parenchyma for regeneration, however, they can be damaging if the response is excessive. Interleukin 10 (IL-10) is a cytokine that promotes macrophages toward an anti-inflammatory/wound healing state (M2 phenotype). The bioactive half-life of IL-10 is dependent on the cellular microenvironment and ranges from minutes to hours in vivo. Our objective was to extend the in vivo bioavailability and bioactivity of IL-10 by attaching the protein onto nanofibrous scaffolds and demonstrating increased expression levels of M2 macrophages when placed around healthy intact peripheral nerves. IL 10 was adsorbed and covalently bound to electrospun poly(epsilon-caprolactone) (PCL) nanofibrous scaffolds. In vivo bioavailability and bioactivity of IL-10 was confirmed by wrapping IL-10 conjugated nanofibres around the sciatic nerves of Wistar rats and quantifying M2 macrophages immunohistochemically double labelled with ED1 and either arginase 1 or CD206. IL-10 remained immobilised to PCL scaffolds for more than 120 days when stored in phosphate buffered saline at room temperature and for up to 14d ays when implanted around the sciatic nerve. IL-10 conjugated nanofibres successfully induced macrophage polarisation towards the M2 activated state within the scaffold material as well as the adjacent tissue surrounding the nerve. PCL biofunctionalised nanofibres are useful for manipulating the cellular microenvironment. Materials such as these could potentially lead to new therapeutic strategies for nervous tissue injuries as well as provide novel investigative tools for biological research. PMID- 25837416 TI - An active contour model for the segmentation of images with intensity inhomogeneities and bias field estimation. AB - Intensity inhomogeneity causes many difficulties in image segmentation and the understanding of magnetic resonance (MR) images. Bias correction is an important method for addressing the intensity inhomogeneity of MR images before quantitative analysis. In this paper, a modified model is developed for segmenting images with intensity inhomogeneity and estimating the bias field simultaneously. In the modified model, a clustering criterion energy function is defined by considering the difference between the measured image and estimated image in local region. By using this difference in local region, the modified method can obtain accurate segmentation results and an accurate estimation of the bias field. The energy function is incorporated into a level set formulation with a level set regularization term, and the energy minimization is conducted by a level set evolution process. The proposed model first appeared as a two-phase model and then extended to a multi-phase one. The experimental results demonstrate the advantages of our model in terms of accuracy and insensitivity to the location of the initial contours. In particular, our method has been applied to various synthetic and real images with desirable results. PMID- 25837417 TI - Profiling DNA methylome landscapes of mammalian cells with single-cell reduced representation bisulfite sequencing. AB - The heterogeneity of DNA methylation within a population of cells necessitates DNA methylome profiling at single-cell resolution. Recently, we developed a single-cell reduced-representation bisulfite sequencing (scRRBS) technique in which we modified the original RRBS method by integrating all the experimental steps before PCR amplification into a single-tube reaction. These modifications enable scRRBS to provide digitized methylation information on ~1 million CpG sites within an individual diploid mouse or human cell at single-base resolution. Compared with the single-cell bisulfite sequencing (scBS) technique, scRRBS covers fewer CpG sites, but it provides better coverage for CpG islands (CGIs), which are likely to be the most informative elements for DNA methylation. The entire procedure takes ~3 weeks, and it requires strong molecular biology skills. PMID- 25837418 TI - Dissecting protein reaction dynamics in living cells by fluorescence recovery after photobleaching. AB - Proteins within most macromolecular complexes or organelles continuously turn over. This turnover results from association and dissociation reactions that are mediated by each of the protein's functional domains. Thus, studying organelle or macromolecular formation from the bottom up using theoretical and computational modeling approaches will necessitate the determination of all of these reaction rates in vivo. Yet current methods for examining protein dynamics either necessitate highly specialized equipment or limit themselves to basic measurements. In this protocol, we describe a broadly applicable method based on fluorescence recovery after photobleaching (FRAP) for determining how many reaction processes participate in the turnover of any given protein of interest, for characterizing their apparent association and dissociation rates, and for determining their relative importance in the turnover of the overall protein population. Experiments were performed in melanoma M2 cells expressing mutant forms of ezrin that provide a link between the plasma membrane and the cortical actin cytoskeleton. We also describe a general strategy for the identification of the protein domains that mediate each of the identified turnover processes. Our protocol uses widely available laser-scanning confocal microscopes, open-source software, graphing software and common molecular biology techniques. The entire FRAP experiment preparation, data acquisition and analysis require 3-4 d. PMID- 25837419 TI - RNAi-based biosynthetic pathway screens to identify in vivo functions of non nucleic acid-based metabolites such as lipids. AB - The field of metabolomics continues to catalog new compounds, but their functional analysis remains technically challenging, and roles beyond metabolism are largely unknown. Unbiased genetic/RNAi screens are powerful tools to identify the in vivo functions of protein-encoding genes, but not of nonproteinaceous compounds such as lipids. They can, however, identify the biosynthetic enzymes of these compounds-findings that are usually dismissed, as these typically synthesize multiple products. Here, we provide a method using follow-on biosynthetic pathway screens to identify the endpoint biosynthetic enzyme and thus the compound through which they act. The approach is based on the principle that all subsequently identified downstream biosynthetic enzymes contribute to the synthesis of at least this one end product. We describe how to systematically target lipid biosynthetic pathways; optimize targeting conditions; take advantage of pathway branchpoints; and validate results by genetic assays and biochemical analyses. This approach extends the power of unbiased genetic/RNAi screens to identify in vivo functions of non-nucleic acid-based metabolites beyond their metabolic roles. It will typically require several months to identify a metabolic end product by biosynthetic pathway screens, but this time will vary widely depending, among other factors, on the end product's location in the pathway, which determines the number of screens required for its identification. PMID- 25837420 TI - Classical olfactory conditioning in the oriental fruit fly, Bactrocera dorsalis. AB - The oriental fruit fly, Bactrocera dorsalis, is a serious pest of fruits and vegetables. Methyl eugenol (ME), a male attractant, is used to against this fly by mass trapping. Control effect may be influenced by learning, which could modify the olfactory response of the fly to this attractant. To collect the behavioral evidence, studies on the capability of this fly for olfactory learning are necessary. We investigated olfactory learning in male flies with a classical olfactory conditioning procedure using restrained individuals under laboratory conditions. The acquisition of the proboscis extension reflex was used as the criterion for conditioning. A high conditioned response level was found in oriental fruit flies when an odor was presented in paired association with a sucrose reward but not when the odor and sucrose were presented unpaired. We also found that the conditioning performance was influenced by the odor concentration, intertrial interval, and starvation time. A slight sensitization elicited by imbibing sucrose was observed. These results indicate that oriental fruit flies have a high capacity to form an olfactory memory as a result of classical conditioning. PMID- 25837421 TI - Toxicological importance of human biomonitoring of metallic and metalloid elements in different biological samples. AB - Human biomonitoring has become an important tool for the assessment of internal doses of metallic and metalloid elements. These elements are of great significance because of their toxic properties and wide distribution in environmental compartments. Although blood and urine are the most used and accepted matrices for human biomonitoring, other non-conventional samples (saliva, placenta, meconium, hair, nails, teeth, breast milk) may have practical advantages and would provide additional information on health risk. Nevertheless, the analysis of these compounds in biological matrices other than blood and urine has not yet been accepted as a useful tool for biomonitoring. The validation of analytical procedures is absolutely necessary for a proper implementation of non conventional samples in biomonitoring programs. However, the lack of reliable and useful analytical methodologies to assess exposure to metallic elements, and the potential interference of external contamination and variation in biological features of non-conventional samples are important limitations for setting health based reference values. The influence of potential confounding factors on metallic concentration should always be considered. More research is needed to ascertain whether or not non-conventional matrices offer definitive advantages over the traditional samples and to broaden the available database for establishing worldwide accepted reference values in non-exposed populations. PMID- 25837422 TI - Complete remission of Waldenstrom's associated generalized crystal-storing histiocytosis of IgM lambda subtype with bortezomib-based combination chemotherapy. PMID- 25837423 TI - Quantification of Left Ventricular Linear, Areal and Volumetric Dimensions: A Phantom and in Vivo Comparison of 2-D and Real-Time 3-D Echocardiography with Cardiovascular Magnetic Resonance. AB - Two-dimensional echocardiography and real-time 3-D echocardiography have been reported to underestimate human left ventricular volumes significantly compared with cardiovascular magnetic resonance. We investigated the ability of 2-D echocardiography, real-time 3-D echocardiography and cardiovascular magnetic resonance to delineate dimensions of increasing complexity (diameter-area-volume) in a multimodality phantom model and in vivo, with the aim of elucidating the main cause of underestimation. All modalities were able to delineate phantom dimensions with high precision. In vivo, 2-D and real-time 3-D echocardiography underestimated short-axis end-diastolic linear and areal and all left ventricular volumetric dimensions significantly compared with cardiovascular magnetic resonance, but not short-axis end-systolic linear and areal dimensions. Underestimation increased successively from linear to volumetric left ventricular dimensions. When analyzed according to the same principles, 2-D and real-time 3 DE echocardiography provided similar left ventricular volumes. In conclusion, echocardiographic underestimation of left ventricular dimensions is due mainly to inherent technical differences in the ability to differentiate trabeculated from compact myocardium. Identical endocardial border definition criteria are needed to minimize differences between the modalities and to ensure better comparability in clinical practice. PMID- 25837424 TI - Visualizing the stress distribution within vascular tissues using intravascular ultrasound elastography: a preliminary investigation. AB - A methodology for computing the stress distribution of vascular tissue using finite element-based, intravascular ultrasound (IVUS) reconstruction elastography is described. This information could help cardiologists detect life-threatening atherosclerotic plaques and predict their propensity to rupture. The calculation of vessel stresses requires the measurement of strain from the ultrasound images, a calibrating pressure measurement and additional model assumptions. In this work, we conducted simulation studies to investigate the effect of varying the model assumptions, specifically Poisson's ratio and the outer boundary conditions, on the resulting stress fields. In both simulation and phantom studies, we created vessel geometries with two fibrous cap thicknesses to determine if we could detect a difference in peak stress (spatially) between the two. The results revealed that (i) Poisson's ratios had negligible impact on the accuracy of stress elastograms, (ii) the outer boundary condition assumption had the greatest effect on the resulting modulus and stress distributions and (iii) in simulation and in phantom experiments, our stress imaging technique was able to detect an increased peak stress for the vessel geometry with the smaller cap thickness. This work is a first step toward understanding and creating a robust stress measurement technique for evaluating atherosclerotic plaques using IVUS elastography. PMID- 25837425 TI - Altered circadian rhythm and metabolic gene profile in rats subjected to advanced light phase shifts. AB - The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT), brown adipose tissue (BAT) and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level. PMID- 25837426 TI - Dinitrosyl iron complexes (DNICs): from biomimetic synthesis and spectroscopic characterization toward unveiling the biological and catalytic roles of DNICs. AB - Dinitrosyl iron complexes (DNICs) have been recognized as storage and transport agents of nitric oxide capable of selectively modifying crucial biological targets via its distinct redox forms (NO(+), NO(*) and NO(-)) to initiate the signaling transduction pathways associated with versatile physiological and pathological responses. For decades, the molecular geometry and spectroscopic identification of {Fe(NO)2}(9) DNICs ({Fe(NO)x}(n) where n is the sum of electrons in the Fe 3d orbitals and NO pi* orbitals based on Enemark-Feltham notation) in biology were limited to tetrahedral (CN = 4) and EPR g-value ~2.03, respectively, due to the inadequacy of structurally well-defined biomimetic DNICs as well as the corresponding spectroscopic library accessible in biological environments. The developed synthetic methodologies expand the scope of DNICs into nonclassical square pyramidal and trigonal bipyramidal (CN = 5) and octahedral (CN = 6) {Fe(NO)2}(9) DNICs, as well as two/three accessible redox couples for mononuclear {Fe(NO)2}(9/10) and dinuclear [{Fe(NO)2}(9/10) {Fe(NO)2}(9/10)] DNICs with biologically relevant S/O/N ligation modes. The unprecedented molecular geometries and electronic states of structurally well defined DNIC models provide the foundation to construct a spectroscopic library for uncovering the identity of DNICs in biological environments as well as to determine the electronic structures of the {Fe(NO)2} core in qualitative and quantitative fashions by a wide range of spectroscopic methods. On the basis of (15)N NMR, electron paramagnetic resonance (EPR), IR, cyclic voltammetry (CV), superconducting quantum interference device (SQUID) magnetometry, UV-vis, single crystal X-ray crystallography, and Fe/S K-edge X-ray absorption and Fe Kbeta X ray emission spectroscopies, the molecular geometry, ligation modes, nuclearity, and electronic states of the mononuclear {Fe(NO)2}(9/10) and dinuclear [{Fe(NO)2}(9/10)-{Fe(NO)2}(9/10)] DNICs could be characterized and differentiated. In addition, Fe/S K-edge X-ray absorption spectroscopy of tetrahedral DNICs deduced the qualitative assignment of Fe/NO oxidation states of {Fe(NO)2}(9) DNICs as a resonance hybrid of {Fe(II)((*)NO)(NO(-))}(9) and {Fe(III)(NO(-))2}(9) electronic states; the quantitative NO oxidation states of [(PhS)3Fe(NO)](-), [(PhS)2Fe(NO)2](-), and [(PhO)2Fe(NO)2](-) were further achieved by newly developed valence to core Fe Kbeta X-ray emission spectroscopy as -0.58 +/- 0.18, -0.77 +/- 0.18, and -0.95 +/- 0.18, respectively. The in-depth elaborations of electronic structures provide credible guidance to elucidate (a) the essential roles of DNICs modeling the degradation and repair of [Fe-S] clusters under the presence of NO, (b) transformation of DNIC into S-nitrosothiol (RSNO)/N-nitrosamine (R2NNO) and NO(+)/NO(*)/NO(-), (c) nitrite/nitrate activation producing NO regulated by redox shuttling of {Fe(NO)2}(9) and {Fe(NO)2}(10) DNICs, and (d) DNICs as H2S storage and cellular permeation pathway of DNIC/Roussin's red ester (RRE) for subsequent protein S-nitrosylation. The consolidated efforts on biomimetic synthesis, inorganic spectroscopy, chemical reactivity, and biological functions open avenues to the future designs of DNICs serving as stable inorganic NO(+)/NO(*)/NO(-) donors for pharmaceutical applications. PMID- 25837427 TI - Large-Scale Persistent Network Reconfiguration Induced by Ketamine in Anesthetized Monkeys: Relevance to Mood Disorders. AB - BACKGROUND: Ketamine is a highly attractive candidate for developing fast-onset antidepressant agents; however, the relevant brain circuits that underlie sustained, efficacious antidepressant effects remain largely unknown. METHODS: We used a holistic scheme combining whole-brain resting-state fMRI and graph theoretical analysis to examine the sustained effects on brain networks after administration of a single dose of ketamine and to identify the brain regions and circuits preferentially targeted by ketamine. Topological differences in functional networks of anesthetized macaque monkeys were compared between ketamine (.5 mg/kg) and saline treatment after 18 hours. RESULTS: We observed persistent global reconfiguration of small-world properties in response to ketamine intake, accompanied by large-scale downregulation of functional connectivity, most prominently in the orbital prefrontal cortex, the subgenual and posterior cingulate cortices, and the nucleus accumbens. Intriguingly, intrinsic connectivity with the medial prefrontal areas in the reward circuits were selectively downregulated. Global and regional regulations of the brain networks precisely opposed the maladaptive alterations in the depressed brain. CONCLUSIONS: Our results demonstrated that local synaptic plasticity triggered by blockade of N-methyl-D-aspartic acid receptors was capable of translating into prolonged network reconfiguration in the distributed cortico-limbic-striatal circuit, providing mechanistic insight into developing specific loci or circuit targeted, long-term therapeutics. PMID- 25837428 TI - Transcriptome analysis and its application in identifying genes associated with fruiting body development in basidiomycete Hypsizygus marmoreus. AB - To elucidate the mechanisms of fruit body development in H. marmoreus, a total of 43609521 high-quality RNA-seq reads were obtained from four developmental stages, including the mycelial knot (H-M), mycelial pigmentation (H-V), primordium (H-P) and fruiting body (H-F) stages. These reads were assembled to obtain 40568 unigenes with an average length of 1074 bp. A total of 26800 (66.06%) unigenes were annotated and analyzed with the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Eukaryotic Orthologous Group (KOG) databases. Differentially expressed genes (DEGs) from the four transcriptomes were analyzed. The KEGG enrichment analysis revealed that the mycelium pigmentation stage was associated with the MAPK, cAMP, and blue light signal transduction pathways. In addition, expression of the two-component system members changed with the transition from H-M to H-V, suggesting that light affected the expression of genes related to fruit body initiation in H. marmoreus. During the transition from H-V to H-P, stress signals associated with MAPK, cAMP and ROS signals might be the most important inducers. Our data suggested that nitrogen starvation might be one of the most important factors in promoting fruit body maturation, and nitrogen metabolism and mTOR signaling pathway were associated with this process. In addition, 30 genes of interest were analyzed by quantitative real-time PCR to verify their expression profiles at the four developmental stages. This study advances our understanding of the molecular mechanism of fruiting body development in H. marmoreus by identifying a wealth of new genes that may play important roles in mushroom morphogenesis. PMID- 25837429 TI - Changes in bone mineral density following long-term simultaneous pancreas-kidney transplantation. AB - The symptoms of chronic renal disease-related mineral and bone disease improve significantly in patients after successful simultaneous pancreas-kidney transplantation (SPKT); however, bone pathology is still present even after many post-transplant years. The aim of this study was to analyze the bone densitometry in different periods after SPKT. Three-point densitometry was performed with the dual-energy X-ray absorptiometry (DXA) technique. Serum levels of alkaline phosphatase (ALP), total serum calcium, phosphate and parathyroid hormone were analyzed as markers of mineral metabolism. The study population consisted of 48 patients (28 females, 20 males) with a mean age of 35 +/- 6 years and mean 24 +/- 6 years of prior diabetes. Mean period of maintenance dialysis was 36 +/- 26 months. The median time from SPKT and DXA measurement was 0.53, 26.2 and 41.9 months, respectively. Based on the DXA technique, 35.4 % of patients were categorized as having osteoporosis at the lumbar spine and 39.6 % at the femoral neck. Patients with diagnosed osteoporosis had significantly higher levels of ALP (OR = 1.5; 95 % CI = 1.1-2.2; p < 0.05 at the lumbar spine; OR = 1.4; 95 % CI = 1.0-1.9; p < 0.05 at the femoral neck). In addition, subjects with lumbar osteoporosis were characterized by a significantly lower body mass index (BMI) (OR = 0.5; 95 % CI = 0.3-0.9; p < 0.05). In the long-term follow-up, BMD increased significantly at the lumbar spine (T-score -1.86 +/- 1.07 to -1.08 +/- 0.89) and femoral neck (T-score -2.12 +/- 0.78 to -1.63 +/- 0.65). A multivariate linear model identified a BMI increase as a significant factor associated with improvement in BMD. Results of our study led us to conclude that, according to three-point densitometry, BMD among patients with functioning kidney and pancreas grafts improved. Increased serum levels of ALP were significantly associated with a decrease in BMD, suggesting a higher risk of osteoporosis. BMI gain was predictive of BMD improvement. PMID- 25837430 TI - Evaluation of crystallographic orientation of biological apatite in vertebral cortical bone in ovariectomized cynomolgus monkeys treated with minodronic acid and alendronate. AB - Quantitative analysis of the orientational distribution of biological apatite (BAp) crystals is proposed as a new index of bone quality. This study aimed to analyze BAp c-axis orientation in ovariectomized (OVX) monkeys treated with amino bisphosphonates minodronic acid and alendronate as reference. Sixty female monkeys aged 9-17 years were divided into five groups: one sham group and four OVX groups. The sham group and one OVX group were treated daily with vehicle for 17 months. The other three groups were treated daily with minodronic acid at doses of 0.015 and 0.15 mg/kg, and alendronate at 0.5 mg/kg orally, respectively. The seventh lumbar vertebrae were subjected to analysis of the preferential BAp c axis orientation in the ventral cortical bone. The BAp c-axis orientation along the craniocaudal axis was significantly increased in the OVX monkeys. The high dose of minodronic acid suppressed the OVX-induced increase in the BAp c-axis orientation, whereas alendronate showed a non-significant tendency to suppress the increase in the orientation. In analysis with other parameters, the BAp c axis orientation was positively correlated with bone formation indices in biochemical markers and bone histomorphometry and negatively correlated with the increase in lumbar bone mineral density. On the other hand, the BAp c-axis orientation was not correlated with bone resorption indices, except for the eroded surface. These results indicate that the increase in BAp c-axis orientation was ameliorated by minodronic acid treatment in OVX monkeys, mainly by suppression of bone formation increase. PMID- 25837432 TI - The effects of size and surface modification of amorphous silica particles on biodistribution and liver metabolism in mice. AB - Engineered nanoparticles, with unconventional properties, are promising platforms for biomedical applications. Since they may interact with a wide variety of biomolecules, it is critical to understand the impact of the physicochemical properties of engineered nanoparticles on biological systems. In this study, the effects of particle size and surface modification alone or in combination of amorphous silica particles (SPs) on biological responses were determined using a suite of general toxicological assessments and metabonomics analysis in mice model. Our results suggested that amino or carboxyl surface modification mitigated the liver toxicity of plain-surface SPs. 30 nm SPs with amino surface modification were found to be the most toxic SPs among all the surface-modified SP treatments at the same dosage. When treatment dose was increased, submicro sized SPs with amino or carboxyl surface modification also induced liver toxicity. Biodistribution studies suggested that 70 nm SPs were mainly accumulated in liver and spleen regardless of surface modifications. Interestingly, these two organs exhibited different uptake trends. Furthermore, metabonomics studies indicated that surface modification plays a more dominant role to affect the liver metabolism than particle size. PMID- 25837433 TI - Chemoradiation therapy reduces aldehyde dehydrogenase 1 expression in cervical cancer but does not improve patient survival. AB - Aldehyde dehydrogenase 1 (ALDH-1) is a cancer stem cell marker whose overexpression can predict the prognosis of several human cancers. In this study, we assessed ALDH-1 expression in cervical cancer tissues and investigated the usefulness of ALDH-1 expression levels for the prediction of patient response to chemoradiation therapy and survival. Tissue samples from 74 patients were examined via immunostaining with ALDH-1 antibody before and after chemoradiation therapy. Twenty-nine of the 74 cervical cancer cases exhibited ALDH-1 expression (39.19 %) in the pre-treatment tissue samples; however, only 19 of these 39 cases exhibited ALDH-1 expression (48.72 %) in post-treatment tissue samples, indicating that chemoradiotherapy eliminated the ALDH-1 positive tumor stem cells in cervical cancer. However, patient disease-free survival was not associated with ALDH-1 expression (11.78 +/- 1.95 vs. 12.50 +/- 1.91 months in ALDH-1 positive and -negative tumors, respectively). This study indicates that the reduction of the cancer stem cell population via chemoradiotherapy may not be sufficient to improve patient survival. Thus, the clinical value of ALDH-1 expression in cervical cancer may need to be re-examined. PMID- 25837434 TI - Socio-demographic and geographic variations in the utilization of hormone therapy in older women with breast cancer after Medicare Part-D coverage. AB - No study has previously reported the utilization and adherence to hormone therapy for Medicare Part-D beneficiaries with breast cancer. This study was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked data to assess socio-demographic, geographic, and other variations in the receipt of hormone therapy among patients with hormone receptor-positive breast cancer and to assess adherence to hormone therapy within 1-year follow-up. The percentage of patients who received hormone therapy was calculated and stratified by chemotherapy status (yes or no). Logistic regression models were performed to assess the variations associated with the use of selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and hormone therapy (SERMs or AIs). Of 25,128 women with hormone receptor-positive breast cancer in 2006-2009 who were enrolled in Medicare Part-D program, 70.8 % received hormone therapy, 22.2 % received SERM, and 56.9 % received AIs. Among those receiving chemotherapy, significant predictors of receiving hormone therapy included age, tumor stage, surgery type, radiation therapy; significant predictors of receiving SERM included race, year of diagnosis, and tumor stage; and significant predictors of receiving AI included age, race, socioeconomic status, geographic location, tumor stage, and radiation therapy. For those without receiving chemotherapy, most of the above factors were significant, but differed across each drug class. In conclusion, over two-thirds of hormone receptor-positive breast cancer patients received hormone therapy, and still 29.2 % of patients did not receive it. Tumor and clinical factors are the most significant predictors for the receipt of hormone therapy. PMID- 25837435 TI - The impact of hypoxemia on serum total and free prostate-specific antigen levels in patients with chronic obstructive pulmonary disease. AB - Prostate-specific antigen (PSA) is the most important biochemical marker in the diagnosis and follow-up of patients with prostate cancer. In recent years, a relationship between PSA levels and hypoxic conditions has been described. However, no study has investigated the PSA levels in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the impact of hypoxemia on serum total (tPSA) and free PSA (fPSA) levels in patients with COPD. Between January 2010 and January 2014, 95 male patients who hospitalized for acute exacerbations of COPD and 80 control subjects were enrolled in the study. Serum tPSA and fPSA levels and f/tPSA ratios were determined in all patients on the first day of hospitalization (exacerbation) and 7 days after the treatment (stable state). Statistical analysis included paired t test and Mann-Whitney U test. No statistically significant differences were found between COPD and control groups with regard to the baseline characteristics, except for smoking status. The levels of serum tPSA and fPSA during exacerbation of COPD were significantly higher than the levels of the stable period (p < 0.01), whereas f/tPSA ratio did not change (p > 0.05). Hypoxemia during acute exacerbation of COPD can cause a rise in serum tPSA and fPSA levels, but f/tPSA ratio is not affected. Acute exacerbation of COPD may be added to list of the events in which PSA measurements must be interpreted with caution. PMID- 25837437 TI - Terpenoids Isolated From the Shoot of Plectranthus hadiensis Induces Apoptosis in Human Colon Cancer Cells Via the Mitochondria-Dependent Pathway. AB - The plant Plectranthus hadiensis is a rich source of many bioactive phytochemicals, especially terpenoids. The terpenoid fraction was isolated and phytochemical characterization was done using GC-MS. The aim of the present study was to find out the antiproliferative activity and the mechanism of cell death induction by the terpenoid fraction on human colon cancer cells (HCT-15). MTT assay was performed with different concentrations of the fraction (10, 20, and 50 ug/mL) to obtain IC50 value for 24 h to induce cell death. The induction of apoptosis were studied by Hoechst staining, acridine orange/ethidium bromide staining, Comet assay, DNA fragmentation, and caspase-3 activity assays. The mechanism of apoptosis induction was studied by expression analysis of antiapoptotic Bcl-2 and proapoptotic Bax using RT-PCR and also by Western blot analysis of proteins involved in the apoptotic pathway. The terpenoid fraction induced significant morphological changes and DNA fragmentation in the cells. Positive Hoechst staining and acridine orange/ethidium bromide staining indicated apoptosis induction by the fraction. DNA fragmentation, which is a characteristic feature of apoptosis, was also observed. Upregulation of caspase-3 activity and proapoptotic Bax, and the downregulation of antiapoptotic Bcl-2 and COX-2 confirmed that the apoptosis induction was via the mitochondria-dependent pathway. PMID- 25837438 TI - Statistical completion of a partially identified graph with applications for the estimation of gene regulatory networks. AB - We study the estimation of a Gaussian graphical model whose dependent structures are partially identified. In a Gaussian graphical model, an off-diagonal zero entry in the concentration matrix (the inverse covariance matrix) implies the conditional independence of two corresponding variables, given all other variables. A number of methods have been proposed to estimate a sparse large scale Gaussian graphical model or, equivalently, a sparse large-scale concentration matrix. In practice, the graph structure to be estimated is often partially identified by other sources or a pre-screening. In this paper, we propose a simple modification of existing methods to take into account this information in the estimation. We show that the partially identified dependent structure reduces the error in estimating the dependent structure. We apply the proposed method to estimating the gene regulatory network from lung cancer data, where protein-protein interactions are partially identified from the human protein reference database. The application shows that proposed method identified many important cancer genes as hub genes in the constructed lung cancer network. In addition, we validated the prognostic importance of a newly identified cancer gene, PTPN13, in four independent lung cancer datasets. The results indicate that the proposed method could facilitate studying underlying lung cancer mechanisms and identifying reliable biomarkers for lung cancer prognosis. PMID- 25837439 TI - Expression and characterization of camel chymosin in Pichia pastoris. AB - Chymosin efficiently coagulates milk and so is widely used in commercial cheese production. Traditional chymosin production requires the slaughter of a large numbers of unweaned calves. In the present study, a full-length camel prochymosin gene was synthesized and cloned into the pPIC9K vector, which was then inserted into the yeast strain, Pichia pastoris GS115. Expression of the chymosin gene in yeast was under the control of an AOX1 inducible promoter. The yeast system produced approximately 37mg/L of recombinant enzyme under lab conditions. SDS PAGE of the raw supernatant revealed two molecular bands, which were approximately 42kDa and 45kDa in size. The 45kDa band disappeared after treatment of the supernatant with N-glycosidase F (PNGase F), indicating that the recombinant protein was partially glycosylated. When subjected to a low pH, recombinant prochymosin was converted into mature and active chymosin. The active chymosin was capable of specifically hydrolyzing kappa-casein. A pH of 5.04, and temperature range of 45-50 degrees C, was optimum for milk clotting activity. Maximum milk clotting activity was detected with the inclusion of 20-40mM CaCl2. The recombinant enzyme was highly active and stable over a wide pH range (from 2.5 to 6.5) at 20 degrees C for 8h. Thermostability of the recombinant enzyme was also analyzed. Pilot-scale production (300mg/L) was attained using a 5L fermenter. We demonstrated that expression of the camel chymosin gene in P. pastoris could represent an excellent system for producing active camel chymosin for potential use in the commercial production of cheese. PMID- 25837440 TI - Mucosal-associated invariant T cells are numerically and functionally deficient in patients with mycobacterial infection and reflect disease activity. AB - Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections. The aims of this study were to examine the levels of MAIT cells in pulmonary tuberculosis (TB) and nontuberculous mycobacteria (NTM) lung disease patients, to evaluate the clinical relevance of MAIT cell levels, and to investigate the functions of MAIT cells. Patients with pulmonary TB (n = 35), NTM (n = 29), and healthy controls (n = 75) were enrolled in the study. MAIT cell levels and functions were measured by flow cytometry. Circluating MAIT cell levels were found to be reduced in TB and NTM patients. MAIT cell deficiency reflects a variety of clinical conditions. In particular, MAIT cell numbers were significantly correlated with sputum AFB positivity, extent of disease, hemoglobin levels, lymphocyte counts, CRP and ESR levels. MAIT cells in TB patients failed to produce interferon-gamma irrespective of the mode of stimulation, whereas NTM patients displayed a defect in MR1-dependent signaling pathway. Notably, an elevated expression of programmed death-1 was also associated with MAIT cell deficiency in TB. This study shows that MAIT cells are numerically and functionally deficient in TB and NTM patients and these deficiencies could contribute to immune system dysreguation in mycobacterial infection. PMID- 25837441 TI - The impact of anti-tuberculous antibiotics and corticosteroids on cytokine production in QuantiFERON-TB Gold In Tube assays. AB - INTRODUCTION: The ability to monitor and confirm adequate treatment of latent TB infection (LTBI) would be a major advance. The potential immunomodulatory effects of anti-tuberculous drugs and steroids need to be considered in assessing the utility of cytokine-based assays for this purpose. METHODS: We determined whether anti-tuberculous antibiotics or dexamethasone affect the production of IFN-gamma and other potential cytokine biomarkers (TNF-alpha, IL-1ra, IL-2, IL-10, IL-13, IP-10, MIP-1beta) in the QuantiFERON-TB Gold In-Tube (QFT-IT) assay. Blood from ten adults with LTBI was added to one standard set of QFT-IT tubes and five further sets containing therapeutic concentrations of either isoniazid, rifampicin, isoniazid and rifampicin, ciprofloxacin or dexamethasone. Resulting supernatants were analysed by ELISA (QFT-IT assay IFN-gamma) and xMAP-Luminex assays (all cytokines). RESULTS: Anti-tuberculous antibiotics had only a limited effect on categorical QFT-IT assay results and the production of cytokines. In contrast, dexamethasone resulted in a change in categorical results from positive to negative in four of ten patients, and caused a marked reduction in IL-13 and IL-1ra responses. CONCLUSION: Substantial changes in TB-antigen-induced IFN-gamma and other cytokine responses during treatment likely primarily reflect host immunological changes rather than immunomodulatory effects of anti-tuberculous antibiotics. Results from cytokine-based assays in patients on corticosteroids should be interpreted with caution. PMID- 25837442 TI - Pharmacokinetic variability of clindamycin and influence of rifampicin on clindamycin concentration in patients with bone and joint infections. AB - PURPOSE: Clindamycin, a lincosamide antibiotic with a good penetration into bone, is widely used for treating bone and joint infections by Gram-positive pathogens. To be active against Staphylococcus spp, its concentration at the infection site, C, must be higher than 2* the minimal inhibitory concentration (MIC). The aims of the work were to study the determinants of plasma clindamycin trough concentration, C min, especially the effect of co-treatment with rifampicin, and the consequences on clinical outcome. METHODS: An observational study was performed, involving patients hospitalized for a bone and joint infection who received clindamycin as part of their antibiotic treatment. Target C min was 1.7 mg/L, to reach the desired bone concentration/MIC >2, assuming a 30% diffusion into bone and MIC = 2.5 mg/L. RESULTS: Sixty one patients (mean age: 56.8 years, 57.4% male) were included between 2007 and 2011. 72.1% underwent a surgery on a foreign material, and 91.1% were infected by at least a Gram-positive micro organism. Median C min value was 1.39 mg/L, with 58% of the values below the threshold value of 1.7 mg/L. Median C min was significantly lower for patients taking rifampicin (0.46 vs 1.52 mg/L, p = 0.034). No patient with rifampicin co administration reached the target concentration (maximal C min: 0.85 mg/L). After a median follow-up of 17 months (1.5-38 months), 4 patients relapsed, 2 died and 47 (88.7% of the patients with known outcome) were cured, independently of association with rifampicin. CONCLUSIONS: This study shows the high inter variability of plasma clindamycin concentration and confirms that co-treatment with rifampicin significantly decreases clindamycin trough concentrations. PMID- 25837443 TI - Identification of glycoproteins containing specific glycans using a lectin chemical method. AB - Glycosylation is one of the most common protein modifications. Each glycoprotein can be glycosylated at multiple glycosites, and each glycosites can be modified by different glycans. Due to this heterogeneity of glycosylation, it has proven difficult to study the structure-function relationship of specific glycans and their affected glycoproteins. Here, we report a novel method for rapid and quantitative identification of glycoproteins containing specific glycans. Lectin affinity isolations are followed by chemical immobilization of the captured glycopeptides, allowing the identification of glycoproteins containing specific glycans by subsequent mass spectrometry. The application of the method should be useful to facilitate our understanding of how changes in glycan associate with diseases, and to discover novel glycoproteins with certain glycans that could serve as biomarkers or therapeutic targets. PMID- 25837444 TI - Enhancement of memory consolidation by the histone deacetylase inhibitor sodium butyrate in aged rats. AB - Here we show that a systemic injection of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) immediately after training in a step-down inhibitory avoidance task produced an enhancement of memory consolidation that persisted across consecutive retention tests during 14 days in aged rats, while it did not significantly affect memory in young adults. Control aged and young adult rats showed comparable basal levels of memory retention. Our results suggest that HDACis can display memory-enhancing effects specific for aged animals, even in the absence of age-related memory impairment. PMID- 25837445 TI - Differential phosphorylation of NMDAR1-CaMKII-MAPKs in the rat nucleus accumbens following chronic ethanol exposure. AB - Previous studies suggest that the nucleus accumbens shell (AcbSh) and core (AcbC) regions may have distinct roles in ethanol consumption. N-Methyl-d-aspartate receptor 1 (NMDAR1), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinases (ERKs) have been demonstrated to contribute to and possibly interact in the molecular mechanism underlying ethanol dependence and relapse. However, little is known regarding the mechanisms underlying the effects of ethanol exposure, withdrawal, and re-exposure, particularly with regard to NMDAR1-CaMKII-ERK signaling in accumbens subregions. In the present study, rats were provided with a 6% ethanol solution as their only drinking source. We found that ethanol exerted locomotor stimulant and anxiolytic effects in open field behaviors. Phosphorylation of NMDAR1, CaMKII and ERK was significantly decreased in the AcbSh and AcbC following chronic ethanol exposure. Ethanol withdrawal increased phospho-NMDAR1 and phospho-CaMKII expression in the AcbSh. Ethanol withdrawal also induced an increase of phospho-ERK1/2 in both the AcbSh and AcbC, while ethanol re-exposure decreased phospho-ERK in the AcbSh. These results indicated that the activation of NMDAR1-CaMKII-ERK signaling in the AcbSh but not the AcbC would contribute more to ethanol drinking and chronic ethanol-related negative emotional states. PMID- 25837446 TI - Mechanical characterization of the rat and mice skin tissues using histostructural and uniaxial data. AB - The skin tissue has been shown to behave like a nonlinear anisotropic material. This study was aimed to employ a constitutive fiber family equation to characterize the nonlinear anisotropic mechanical behavior of the rat and mice skin tissues in different anatomical locations, including the abdomen and back, using histostructural and uniaxial data. The rat and mice skin tissues were excised from the animals' body and then the histological analyses were performed on each skin type to determine the mean fiber orientation angle. Afterward, the preconditioned skin tissues were subjected to a series of quasi-static axial and circumferential loads until the incidence of failure. The crucial role of fiber orientation was explicitly added into a proposed strain energy density function. The material coefficients were determined using the constrained nonlinear optimization method based on the axial and circumferential extension data of the rat and mice samples at different anatomical locations. The material coefficients of the skins were given with R(2) >= 0.998. The results revealed a significant load-bearing capacity and stiffness of the rat abdomen compared to the rat back tissues. In addition, the mice abdomen showed a higher stiffness in the axial direction in comparison with circumferential one, while the mice back displayed its highest stiffness in the circumferential direction. The material coefficients of the rat and mice skin tissues were determined and well compared to the experimental data. The optimized fiber angles were also compared to the experimental histological data, and in all cases less than 11.85% differences were observed in both the skin tissues. PMID- 25837448 TI - EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice. AB - A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners. PMID- 25837449 TI - Robot-assisted gait training might be beneficial for more severely affected children with cerebral palsy. AB - PURPOSE: Robot-assisted gait training (RAGT) can complement conventional therapies in children with cerebral palsy. We investigated changes in walking related outcomes between children with different Gross Motor Function Classification System (GMFCS) levels and the dose-response relationship. METHODS: Data from 67 children (3.9-19.9 years) with GMFCS levels II-IV were evaluated retrospectively. Every child received RAGT with the Lokomat complementing a multidisciplinary rehabilitation program. Changes in various walking-related outcomes were assessed. RESULTS: Walking-related outcomes did not improve differently between GMFCS level groups. Significant within-group improvements were mainly observed in children with GMFCS level IV. A dose-response relationship was present for children with GMFCS levels III and IV. CONCLUSIONS: Our results indicated that, although children with a GMFCS level IV walked less during an average Lokomat session, they experienced significant improvements in walking-related outcomes. Further, training dose correlated with changes in walking-related outcomes. However, between-group differences in changes in walking-related outcomes were not significant. PMID- 25837447 TI - Phylogenetic and individual variation in gastropod central pattern generators. AB - Gastropod molluscs provide a unique opportunity to explore the neural basis of rhythmic behaviors because of the accessibility of their nervous systems and the number of species that have been examined. Detailed comparisons of the central pattern generators (CPGs) underlying rhythmic feeding and swimming behaviors highlight the presence and effects of variation in neural circuits both across and within species. The feeding motor pattern of the snail, Lymnaea, is stereotyped, whereas the feeding motor pattern in the sea hare, Aplysia, is variable. However, the Aplysia motor pattern is regularized with operant conditioning or by mimicking learning using the dynamic clamp to change properties of CPG neurons. Swimming evolved repeatedly in marine gastropods. Distinct neural mechanisms underlie dissimilar forms of swimming, with homologous neurons playing different roles. However, even similar swimming behaviors in different species can be produced by distinct neural mechanisms, resulting from different synaptic connectivity of homologous neurons. Within a species, there can be variation in the strength and even valence of synapses, which does not have functional relevance under normal conditions, but can cause some individuals to be more susceptible to lesion of the circuit. This inter- and intra-species variation provides novel insights into CPG function and plasticity. PMID- 25837450 TI - The use of Bayesian networks to assess the quality of evidence from research synthesis: 1. AB - BACKGROUND: The grades of recommendation, assessment, development and evaluation (GRADE) approach is widely implemented in systematic reviews, health technology assessment and guideline development organisations throughout the world. A key advantage to this approach is that it aids transparency regarding judgments on the quality of evidence. However, the intricacies of making judgments about research methodology and evidence make the GRADE system complex and challenging to apply without training. METHODS: We have developed a semi-automated quality assessment tool (SAQAT) l based on GRADE. This is informed by responses by reviewers to checklist questions regarding characteristics that may lead to unreliability. These responses are then entered into the Bayesian network to ascertain the probabilities of risk of bias, inconsistency, indirectness, imprecision and publication bias conditional on review characteristics. The model then combines these probabilities to provide a probability for each of the GRADE overall quality categories. We tested the model using a range of plausible scenarios that guideline developers or review authors could encounter. RESULTS: Overall, the model reproduced GRADE judgements for a range of scenarios. Potential advantages over standard assessment are use of explicit and consistent weightings for different review characteristics, forcing consideration of important but sometimes neglected characteristics and principled downgrading where small but important probabilities of downgrading are accrued across domains. CONCLUSIONS: Bayesian networks have considerable potential for use as tools to assess the validity of research evidence. The key strength of such networks lies in the provision of a statistically coherent method for combining probabilities across a complex framework based on both belief and evidence. In addition to providing tools for less experienced users to implement reliability assessment, the potential for sensitivity analyses and automation may be beneficial for application and the methodological development of reliability tools. PMID- 25837451 TI - The Qur'an and the development of rational thinking. AB - In this study, the means utilized by the Qur'an in actualizing the possibilities of all intellect to face the problem of blind imitation of ancestors were elaborated. Rationality as meant by the Qur'an and embodied in its unique style is presented. Furthermore, the Qur'anic documentation of the role of practical demonstration on the individual's mind as well as the societies' collective mind is pointed out. In addition, the study shows how the Qur'an guides people to the proper use of reason within a scientific framework of mind. PMID- 25837452 TI - The relationship between cervical and lumbar spine lesions in rheumatoid arthritis with a focus on endplate erosion. AB - STUDY DESIGN: A cross-sectional imaging study. OBJECTIVE: To investigate the relationship between cervical and lumbar spine lesions in patients with rheumatoid arthritis (RA), and to analyze associated factors in those with concurrent cervical and lumbar endplate erosion (EE). SUMMARY OF BACKGROUND DATA: Both the lumbar and cervical spines are often involved in RA, but little is known about the relationship between cervical and lumbar lesions. EE is often found in the spine of RA patients, but its prevalence and associated factors have not been well studied. METHODS: We enrolled 201 RA patients in this study. Cervical lesions (horizontal and vertical atlantoaxial dislocation, subaxial subluxation) and lumbar lesions (vertebral fracture, scoliosis, spondylolisthesis) were evaluated on plain radiographs. EE was evaluated on sagittal T1-weighted magnetic resonance images, and graded into 4 categories. The prevalence of each lesion was calculated, and correlations between general cervical and lumbar lesions and between cervical and lumbar EE were analyzed. To assess the clinical condition of RA, we evaluated disease duration, Steinbrocker stage, modified Stanford Health Assessment Questionnaire results, and Disease Activity Score for 28 joints with the erythrocyte sedimentation rate. Factors associated with concurrent lumbar and cervical EE were analyzed using multiple logistic regression analysis. RESULTS: Cervical lesions were found in 42.3% of patients and lumbar lesions in 56.2%. There was no significant correlation between the presence of cervical and the presence of lumbar lesions, but patients with cervical subaxial subluxation were significantly more likely to have lumbar spondylolisthesis. Cervical EE (>=1 points) was found in 61.2% of patients and lumbar EE in 39.3%. Total cervical EE score was significantly correlated with lumbar EE score. Moderate/high disease activity, Steinbrocker stage IV, and severe cervical or lumbar disk degeneration were associated with concurrent cervical and lumbar EE. CONCLUSIONS: Some cervical lesions are significantly associated with lumbar spinal lesions. Concurrent cervical and lumbar EE are related to RA disease activity and peripheral joint deterioration, suggesting that RA activity may play an important role in total spinal involvement. PMID- 25837453 TI - Juvenile Swine Surgical Alveolar Cleft Model to Test Novel Autologous Stem Cell Therapies. AB - Reconstruction of craniofacial congenital bone defects has historically relied on autologous bone grafts. Engineered bone using mesenchymal stem cells from the umbilical cord on electrospun nanomicrofiber scaffolds offers an alternative to current treatments. This preclinical study presents the development of a juvenile swine model with a surgically created maxillary cleft defect for future testing of tissue-engineered implants for bone generation. Five-week-old pigs (n=6) underwent surgically created maxillary (alveolar) defects to determine critical sized defect and the quality of treatment outcomes with rib, iliac crest cancellous bone, and tissue-engineered scaffolds. Pigs were sacrificed at 1 month. Computed tomography scans were obtained at days 0 and 30, at the time of euthanasia. Histological evaluation was performed on newly formed bone within the surgical defect. A 1 cm surgically created defect healed with no treatment, the 2 cm defect did not heal. A subsequently created 1.7 cm defect, physiologically similar to a congenitally occurring alveolar cleft in humans, from the central incisor to the canine, similarly did not heal. Rib graft treatment did not incorporate into adjacent normal bone; cancellous bone and the tissue-engineered graft healed the critical-sized defect. This work establishes a juvenile swine alveolar cleft model with critical-sized defect approaching 1.7 cm. Both cancellous bone and tissue engineered graft generated bridging bone formation in the surgically created alveolar cleft defect. PMID- 25837454 TI - [Fenoldopam in patients with acute kidney injury after cardiac surgery]. PMID- 25837455 TI - [Assessment of left ventricular outflow tract obstruction according to the latest European guidelines on hypertrophic cardiomyopathy]. PMID- 25837456 TI - [Molecular genetic testing according to the latest European guidelines on hypertrophic cardiomyopathy]. PMID- 25837457 TI - [Risk of sudden death according to the latest European guidelines on hypertrophic cardiomyopathy]. PMID- 25837458 TI - [Vagus nerve stimulation for the treatment of heart failure]. AB - In the last two decades, the autonomic imbalance characterized by vagal withdrawal and sympathetic increase has been shown to play a major role in the progression and prognosis of heart failure. Therefore, modulation of the autonomic nervous system (neuromodulation) with the aim to restore autonomic balance is gaining increasing interest as a potential therapy for patients with heart failure. Recently, different non-pharmacological approaches to neuromodulation have been evaluated in phase II and III clinical trials. Electrical vagus nerve stimulation is the most studied. This technique showed excellent results in preclinical studies, but at present the clinical experience is limited to a few studies, the results of which are apparently conflicting.This review discusses the preclinical and clinical experience of vagal stimulation in heart failure, in order to help understand the complexity of the methodology and our still limited knowledge of the dose-response relationship, which make difficult to interpret and compare the results of studies conducted with different designs and evaluating different devices and stimulation protocols. PMID- 25837459 TI - [Heart rate modulation in stable ischemic heart disease: what we have learned from the SIGNIFY study?]. AB - Elevated heart rate is a marker of cardiovascular risk in patients with stable coronary artery disease. The addition of ivabradine to standard therapy to reduce heart rate did not improve outcomes in the recent SIGNIFY trial. Moreover, a significant interaction between the effect of ivabradine among subgroups with and without angina with a worse outcome in patients in CCS class >II at baseline was detected. The explanation for this surprising finding despite a significant reduction in angina and myocardial revascularization procedures is uncertain. A J curve for heart rate was not demonstrated. We speculate a significant interference on adverse events (mainly atrial fibrillation and consequently acute coronary syndromes) and on the outcome of unfavorable interactions between ivabradine and diltiazem, verapamil and strong inhibitors of CYP3A4 (4.6% of the total population). Excluding this subgroup, there are no significant changes in outcomes between the two treatment groups (ivabradine and placebo). In conclusion, heart rate is a marker of risk but is not a risk factor and/or a target of therapy in patients with stable coronary artery disease and preserved ventricular systolic function. Standard doses of ivabradine are indicated for treatment of angina as an alternative or in addition to beta-blockers, but should not be administered in association with CYP3A4 inhibitors or heart rate-lowering calcium antagonists. PMID- 25837461 TI - [Ebstein's anomaly: diagnosis and surgical treatment]. AB - Ebstein's anomaly is a rare congenital heart disorder secondary to a malformation of the tricuspid valve and right ventricle. The heterogeneous spectrum of presentation of its structural anomalies and associated cardiomyopathy accounts for a widely varied clinical and hemodynamic manifestation of the pathology and its impact on timing of diagnosis and prognosis. Neonatal Ebstein's anomaly is characterized by reduced survival, while an average risk of mortality per year of 1% to 1.4% has been reported in infancy and adulthood. Medical management and a careful clinical and echocardiographic follow-up are advisable for all asymptomatic patients and those with minimal abnormalities. Surgical correction is recommended in presence of progressive dilation of the right atrium and right ventricle, development of right ventricular dysfunction, occurrence of supraventricular or ventricular arrhythmias or episodes of paradoxical embolization, reduced exercise capacity, or significant desaturation. Prosthetic valve replacement or repair of the tricuspid valve are both common strategies in the correction of tricuspid regurgitation. During the last three decades, important contributions in the development of repair techniques were driven from the experience of Danielson, Carpentier and da Silva, with satisfactory results in terms of safety and durability at long-term follow-up. PMID- 25837460 TI - [Why NAO: Know How. Why and how to choose the new oral anticoagulant in cardiological clinical practice]. AB - Although it is well recognized that warfarin dramatically reduces the risk for ischemic stroke, its use for stroke prevention in patients with atrial fibrillation is often inadequate. Even among patients with other known risk factors for stroke (e.g., high blood pressure) and no contraindications to warfarin, warfarin therapy is prescribed in less than 60% of cases. In addition, safety and efficacy of warfarin therapy depend on adequate anticoagulation effect, but time in therapeutic range is 63%. Notably, major bleeding and intracranial hemorrhage represent a feared, though infrequent, complication. Aspirin monotherapy for stroke prevention in patients with atrial fibrillation should be discouraged, as it does not provide adequate protection against stroke and is associated with a significant increase in bleeding complications. New oral anticoagulants have a favorable risk-benefit profile, resulting in significant reductions in stroke, intracranial hemorrhage and mortality, with similar rates of major bleeding compared to warfarin but increased risk for gastrointestinal bleeding. The present review describes the new oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban with a focus on the results from major randomized clinical trials and meta-analyses. It also provides practical suggestions for their use in daily clinical practice, introducing a dedicated, novel application for smartphones and tablets. PMID- 25837462 TI - [A matter of perspective: multimodality imaging of a giant cardiac mass]. AB - A newborn was suspected of having situs inversus with levocardia based on chest X ray. Echocardiography ruled out this hypothesis but revealed a giant cardiac mass that was confirmed by magnetic resonance imaging. Coronary angiography showed that the right coronary artery ran on the surface of the mass, and only partial debulking surgery was performed to relieve right heart compression. Histological examination classified the mass as cardiac fibroma. Complex diagnostic work-up allowed correct anatomic definition of the mass as well as its relationship with adjacent structures, and helped guide surgical planning. PMID- 25837463 TI - [Letter to the editor]. PMID- 25837464 TI - [Electrocardiographic diagnosis of interatrial block]. PMID- 25837465 TI - Increased normalized pulmonary transit times and pulmonary blood volumes in cardiomyopathic cats with or without congestive heart failure. AB - OBJECTIVES: To estimate heart rate-normalized pulmonary transit times (nPTTs) in cardiomyopathic cats with or without congestive heart failure (CHF). To assess potential associations of echocardiographic variables and nPTT and to evaluate nPTT as a test for the presence of CHF. ANIMALS: Forty-eight privately owned cats. METHODS: nPTT was measured using echocardiography and the ultrasound contrast media SonoVue((r)) in 3 groups of cats: healthy cats (group 1), cats with cardiomyopathy (CM) but without CHF (group 2), and cats with CM and CHF (group 3). Interrelations between pulmonary blood volume (PBV), nPTT, stroke volume (SV), and echocardiographic variables were investigated by means of linear univariate and multivariate analysis. RESULTS: Median nPTT values in group 1, group 2, and group 3 were 3.63 (interquartile range [IQR], 3.20-4.22), 6.09 (IQR, 5.0-7.02), and 8.49 (IQR, 7.58-11.04), respectively. Values were significantly different between all 3 groups. Median PBVs in group 1, group 2, and group 3 were 27.94 mL (IQR, 21.02-33.17 mL), 42.83 mL (IQR, 38.46-50.36 mL) and 49.48 mL (IQR, 38.84-64.39 mL). SV, PBV, and shortening fraction <30% were significant predictors of nPTT. nPTT and left atrial to aortic root (LA:AO) ratio, not SV, were the main predictors of PBV. CONCLUSION: nPTT may be useful as a test for the presence of CHF in cats with CM and as a measure of cardiac performance. nPTT and LA:AO ratios predict CHF with equal accuracy. Increased PBV is significantly associated with higher nPTT and LA:AO ratios. PMID- 25837466 TI - Antibody specific epitope prediction-emergence of a new paradigm. AB - The development of accurate tools for predicting B-cell epitopes is important but difficult. Traditional methods have examined which regions in an antigen are likely binding sites of an antibody. However, it is becoming increasingly clear that most antigen surface residues will be able to bind one or more of the myriad of possible antibodies. In recent years, new approaches have emerged for predicting an epitope for a specific antibody, utilizing information encoded in antibody sequence or structure. Applying such antibody-specific predictions to groups of antibodies in combination with easily obtainable experimental data improves the performance of epitope predictions. We expect that further advances of such tools will be possible with the integration of immunoglobulin repertoire sequencing data. PMID- 25837468 TI - In vitro investigation of self-assembled nanoparticles based on hyaluronic acid deoxycholic acid conjugates for controlled release doxorubicin: effect of degree of substitution of deoxycholic acid. AB - Self-assembled nanoparticles based on a hyaluronic acid-deoxycholic acid (HD) chemical conjugate with different degree of substitution (DS) of deoxycholic acid (DOCA) were prepared. The degree of substitution (DS) was determined by titration method. The nanoparticles were loaded with doxorubicin (DOX) as the model drug. The human cervical cancer (HeLa) cell line was utilized for in vitro studies and cell cytotoxicity of DOX incorporated in the HD nanoparticles was accessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, cellular uptake of fluorescently labeled nanoparticles was also investigated. An increase in the degree of deoxycholic acid substitution reduced the size of the nanoparticles and also enhanced their drug encapsulation efficiency (EE), which increased with the increase of DS. A higher degree of deoxycholic acid substitution also lead to a lower release rate and an initial burst release of doxorubicin from the nanoparticles. In summary, the degree of substitution allows the modulation of the particle size, drug encapsulation efficiency, drug release rate, and cell uptake efficiency of the nanoparticles. The herein developed hyaluronic acid-deoxycholic acid conjugates are a good candidate for drug delivery and could potentiate therapeutic formulations for doxorubicin-mediated cancer therapy. PMID- 25837467 TI - Computational tools for epitope vaccine design and evaluation. AB - Rational approaches will be required to develop universal vaccines for viral pathogens such as human immunodeficiency virus, hepatitis C virus, and influenza, for which empirical approaches have failed. The main objective of a rational vaccine strategy is to design novel immunogens that are capable of inducing long term protective immunity. In practice, this requires structure-based engineering of the target neutralizing epitopes and a quantitative readout of vaccine-induced immune responses. Therefore, computational tools that can facilitate these two areas have played increasingly important roles in rational vaccine design in recent years. Here we review the computational techniques developed for protein structure prediction and antibody repertoire analysis, and demonstrate how they can be applied to the design and evaluation of epitope vaccines. PMID- 25837469 TI - Study of linkage between glutathione pathway and the antibiotic resistance of Escherichia coli from patients' swabs. AB - In this work, we focused on the differences between bacterial cultures of E. coli obtained from swabs of infectious wounds of patients compared to laboratory E. coli. In addition, blocking of the protein responsible for the synthesis of glutathione (gamma-glutamylcysteine synthase-GCL) using 10 mM buthionine sulfoximine was investigated. Each E. coli showed significant differences in resistance to antibiotics. According to the determined resistance, E. coli were divided into experimental groups based on a statistical evaluation of their properties as more resistant and more sensitive. These groups were also used for finding the differences in a dependence of the glutathione pathway on resistance to antibiotics. More sensitive E. coli showed the same kinetics of glutathione synthesis while blocking GCL (Km 0.1 uM), as compared to non-blocking. In addition, the most frequent mutations in genes of glutathione synthetase, glutathione peroxidase and glutathione reductase were observed in this group compared to laboratory E.coli. The group of "more resistant" E. coli exhibited differences in Km between 0.3 and 0.8 uM. The number of mutations compared to the laboratory E. coli was substantially lower compared to the other group. PMID- 25837471 TI - Glycolic acid-catalyzed deamidation of asparagine residues in degrading PLGA matrices: a computational study. AB - Poly(lactic-co-glycolic acid) (PLGA) is a strong candidate for being a drug carrier in drug delivery systems because of its biocompatibility and biodegradability. However, in degrading PLGA matrices, the encapsulated peptide and protein drugs can undergo various degradation reactions, including deamidation at asparagine (Asn) residues to give a succinimide species, which may affect their potency and/or safety. Here, we show computationally that glycolic acid (GA) in its undissociated form, which can exist in high concentration in degrading PLGA matrices, can catalyze the succinimide formation from Asn residues by acting as a proton-transfer mediator. A two-step mechanism was studied by quantum-chemical calculations using Ace-Asn-Nme (Ace = acetyl, Nme = NHCH3) as a model compound. The first step is cyclization (intramolecular addition) to form a tetrahedral intermediate, and the second step is elimination of ammonia from the intermediate. Both steps involve an extensive bond reorganization mediated by a GA molecule, and the first step was predicted to be rate-determining. The present findings are expected to be useful in the design of more effective and safe PLGA devices. PMID- 25837470 TI - Male reproductive cancers and infertility: a mutual relationship. AB - Reproductive dysfunction and malignancies related to the male gender represent a serious health concern, whose incidence has significantly risen over the past years. Prior to treatment, testicular or prostate cancer patients often display poor semen characteristics similar to subfertile or infertile patients. This fact is underscored by cases where the malignancy is often diagnosed in males who undergo a general fertility screening. This review aims to examine the associations between male infertility and reproductive cancers focusing on common etiologies and biological mechanisms underlining these pathologies. Furthermore, we discuss compelling epidemiological data hypothesizing that male reproductive failure may act as a precursor of future andrological malignancies, including testicular or prostate cancer, thus providing a stimulus for a more specific research in male reproductive health and emphasizing the importance of this relation for physicians taking care of male patients with a reproductive disease. PMID- 25837472 TI - Residue Asn277 affects the stability and substrate specificity of the SMG1 lipase from Malassezia globosa. AB - Thermostability and substrate specificity are important characteristics of enzymes for industrial application, which can be improved by protein engineering. SMG1 lipase from Malassezia globosa is a mono- and diacylglycerol lipase (MDL) that shows activity toward mono- and diacylglycerols, but no activity toward triacylglycerols. SMG1 lipase is considered a potential biocatalyst applied in oil/fat modification and its crystal structure revealed that an interesting residue-Asn277 may contribute to stabilize loop 273-278 and the 3104 helix which are important to enzyme characterization. In this study, to explore its role in affecting the stability and catalytic activity, mutagenesis of N277 with Asp (D), Val (V), Leu (L) and Phe (F) was conducted. Circular dichroism (CD) spectral analysis and half-life measurement showed that the N277D mutant has better thermostability. The melting temperature and half-life of the N277D mutant were 56.6 degrees C and 187 min, respectively, while that was 54.6 degrees C and 121 min for SMG1 wild type (WT). Biochemical characterization of SMG1 mutants were carried out to test whether catalytic properties were affected by mutagenesis. N277D had similar enzymatic properties as SMG1 WT, but N277F showed a different substrate selectivity profile as compared to other SMG1 mutants. Analysis of the SMG1 3D model suggested that N277D formed a salt bridge via its negative charged carboxyl group with a positively charged guanidino group of R227, which might contribute to confer N277D higher temperature stability. These findings not only provide some clues to understand the molecular basis of the lipase structure/function relationship but also lay the framework for engineering suitable MDL lipases for industrial applications. PMID- 25837473 TI - Role of the cell envelope stress regulators BaeR and CpxR in control of RND-type multidrug efflux pumps and transcriptional cross talk with exopolysaccharide synthesis in Erwinia amylovora. AB - The purpose of this study was to identify the role of the cell envelope stress sensing systems BaeSR and CpxARP in regulation of multidrug efflux and exopolysaccharide synthesis in Erwinia amylovora. We have previously reported that BaeR activates transcription of the RND-type efflux pumps AcrD and MdtABC. In this study, we found that a cpxR-deficient mutant was highly susceptible to beta-lactams, aminoglycosides and lincomycin, whereas a baeR mutant showed no change in antimicrobial sensitivity. However, overexpression of BaeR in a mutant lacking the major RND pump AcrB increased resistance of E. amylovora to several compounds that are not substrates of AcrD or MdtABC. Furthermore, we observed that overexpression of BaeR significantly increased amylovoran production. Moreover, the expression of RND-type efflux pumps was changed in regulatory mutants of exopolysaccharide production. Our data suggest that BaeSR and CpxARP regulate additional mechanisms, beside efflux, which are responsible for antimicrobial resistance of E. amylovora. PMID- 25837474 TI - [Organizational socialization in the first three years of nursing profession: strategies to decrease turnover intention]. AB - INTRODUCTION: In the first years of nursing profession, new-graduate nurses' turnover intention is a relevant issue due to both the tangible and intangible costs it generates to health care organizations, such as selection and recruitment costs, ward team burden in the onboarding process and the possibility to enhance ward team stability in order to provide an effective and safe nusing care. Organizational socialization is the main factor involved in these dynamics of turnover intention in the first years of nursing profession. AIMS: This study aims to identify the main factors involved in the organizational socialization process to reduce turnover intention in the first 3 years of nursing profession. METHODS: 101 new-graduate nurses have been enrolled within the first three years of nursing profession. They have been stratified looking at tenure and years in nursing. Organizational Socialization Inventory scale has been used to assess the onboarding process and 4 items to assess turnover intention. RESULTS: Turnover intention is of 23% in the first year in nursing, and it's over the 26% starting from the second year. The onboarding process explains over the 26% of the variance in turnover intention, and over the 36% in the sub-sample with a stable tenure. Unstable tenured nurses prefer to acquire those competences useful to perform their work, while stable tenure nurses aim to search for professional growth opportunities and integration in the ward-team, in order to reduce turnover intention. CONCLUSION: Turnover intention is relevant in the first three years of nursing profession. According to the different tenure, different strategies are necessary to plan an effective onboarding process and enhance nursing retention. PMID- 25837475 TI - [Emotional Leadership: a survey on the emotional skills expressed by nursing management]. AB - INTRODUCTION: The emotional leadership applied to nursing management is a new topic in the Italian nursing literature, but of great interest internationally. There is a close correlation between nursing leaders with a well-developed emotional intelligence and nurses working well-being. SCOPE: This study investigates knowledge about the emotional leadership and emotional competence in nursing management. METHODS: The survey was conducted using a questionnaire devised for the purpose, validated and administered to 130 managers, head nurses and nurses in a hospital in Rome. RESULTS: Analysis of data shows a great interest in the subject. 90% of the sample showed that it is essential for managerial roles, be aware and able to manage their own and others' emotions to generate wellbeing at work. Emotional competencies are considered important just as theoretical, technical and social skills to a effective leadership on nursing. CONCLUSIONS: This study is one of the first Italian survey on the importance of the development of emotional intelligence in nursing leadership to improve wellbeing at work. Results of the survey should be confirmed by further studies. The emotional skills could be improved in nursing education programs and used as a yardstick for the nursing managers selection. PMID- 25837476 TI - [Observational study on interruptions during nurses work in two surgical wards of a hospital in Liguria]. AB - INTRODUCTION: Interrumption that occur during nursing practice are hazardous for patient safety, resulting in a heavy cognitive load for the health care professionals and increases the risk of making mistakes. METHODS: An observational study was carried out in UU.OO operation of Neurosurgery and Vascular Surgery at a hospital in Liguria. The observation lasted one months, from July 1st, 2012 to August 1st, 2012. For data collection were used three form, one for each work shift, in which each health care professional had to report what activity was interrupted and why. RESULTS: A total of 7744 interruptium (in 5676 in Neurosurgery and 2068 Vascular Surgery). The major source of interruption was the bell, followed by the phone and relatives' questions. In general, activities interrupted were mainly made beds / hygiene care, administration and preparation of medication, handover and completion of the nursing documentation CONCLUSIONS: Interrumption will be an inevitable part of nursing practice, because of its very nature. It is therefore necessary to intervene on interruptions deemed avoidable and organizational variables that generate them, in order to increase patient safety and improve care activities. PMID- 25837477 TI - ["Notte della Taranta": new competences of the Disaster Manager Nurse]. AB - The disaster manager nurse is a new professional figure working in the field of rescue in environments struck by natural disasters, of land management, of contingency plans for the healthcare, of the setting up of Advanced Medical Posts and the management of events in which are foreseen a great influx of people. Analyzing the Advanced Medical Post set up during the "Notte della Taranta", a folk music festival that sees every years a large attendance, over 100.000 people we have predicted required human and logistic resources to health coverage of this event and to value criticality assessment of the scenario. A organized and precautionary response is basic to reduce consequences duty by the imbalance between required and available resources. PMID- 25837478 TI - [Taking care of foreign users: what training is needed for the healthcare workers at the Municipal Health and Science Agency of Torino?]. AB - INTRODUTION: Immigration is growing and immigrants' presence is important also in the health care system, thereby services reorientation and a multicultural approach are needed. OBJECTIVE: To explore health care professionals' training needs of Turin Azienda Citta della Salute e della Scienza in taking care of foreign users. METHODS: An ad hoc 4-sections questionnaire was built: (1) Knowledge, attitudes and perceptions; (2) Lived and Training; (3) Improvement in cultural competence; (4) Socio-demographic data. Questions were dichotomous (yes/no), closed and short open. Doctors, nurses, speech therapists and support staff of the "Head and Neck" Department were involved. RESULTS: One hundred seventy-six operators answered (75%). Less than 20% (n=34) knew the normative concerning immigrants' health services use; tubercolosis, venereal diseases and AIDS were believed to be the most frequent diseases in foreign users. Female sex (p=0.008) and allied health care profile (trend p=0051) were significantly associated to consider clients' values important, while a previous training was associated to the need of improving their knowledge (p=0.0002). The most important training needs were: meaning of illness and care, perception of prevention, hygiene and self-care practices and perception of care. Among the most effective strategies: lecture and discussion, group work and filmography. CONCLUSION: The analysis shows the main needing education areas and the training strategies which operators considered more effective. PMID- 25837479 TI - [Index of Caring Complexity as a management tool in a surgical setting: an observational study]. AB - INTRODUCTION: Among different methods of nursing classification, the Index of Caring Complexity (ICC) is a management tool to evaluate appropriateness of nursing procedures, integrate health-care support workers and to monitor the need of nursing staff. The objective of this observational study was to apply the ICC method in a surgical ward of the Marche Region (Italy), to determine the nursing staff level. METHODS: From 1 January to 30 April 2010, all data of patients admitted for more than 48 hours were collected. The determination of nursing staff level derived from the five patient classification on the basis of the complexity/gravity "scores" of data flow obtained during the caring process. RESULTS: The ICC method showed a staffing of 11 nurses: a staff shortage of three nurse, if compared to the actual staff. The ICC method also demonstrate its strength as a useful tool to reorganize care. The ICA showed that the most frequent nursing activities :"Apply postures to facilitate breathing "(83%),"Prepare/provide appropriate foods in temperature/texture/quantity "(100%); "Providing aids for elimination needs" (80.7%); "Help in dressing" (82.7%); "Transfer from stretcher to bed" (83.4%); "Remaking bed/unit sick" (100%); "Monitoring of vital signs" (100%); "Health Education" (100%); "Nursing Assessment" (100%); "Management and treatment of intravascular devices" (100%); "Performing instrumental exams". CONCLUSIONS: Assess the most frequent nursing activities, allows: to better distribute activities among professionals, identify nurses' competencies and activities to be prescribed to health-care support workers. PMID- 25837480 TI - Therapeutic education to cancer patients: experiences of Italian nurses. AB - INTRODUCTION: Therapeutic patient' education is a complex process requiring a proper level of communication between the patient and the healthcare professional. Nurses play a key role in providing the patients and their families with educational activities. OBJECTIVE: This paper is the report of a study which investigates the experiences of some Italian nurses with regards to their role in therapeutic education to cancer patients. METHODS: Qualitative research. Semi structured interviews were carried out with 52 nurses working in different Local Health Service Units of two northern Italy regions: Piedmont and Valle d'Aosta. To identify categories and items arising from the data, the researchers used a qualitative content analysis. RESULTS: The interview format was classified into six main categories: a) Patient education as daily care activity; b) Relevance of communication and dialogue for educational purposes; c) Relative usefulness of written information; d) Therapeutic education recording; e) Patients' feedbacks as a tool for assessing therapeutic education; and f) Difficult communication. CONCLUSIONS: The experience of nurses in terms of their professional role in therapeutic education for cancer patients shows the steady presence of educational activities carried out in a non-planned way. This research confirms the need to launch educational interventions for nurses. IMPLICATIONS FOR PRACTICE: It is essential to implement an action plan to promote opportunities of professional training in the field since among the most frequent reasons for project failure in therapeutic education is the lack of expert human resources. PMID- 25837481 TI - Erratum to: Bioinformatics study of the 3-hydroxy-3-methylglotaryl-coenzyme A reductase (HMGR) gene in Gramineae. PMID- 25837483 TI - The effect of ethanol on reversal learning in honey bees (Apis mellifera anatolica): Response inhibition in a social insect model. AB - We investigated the effects of ethanol on reversal learning in honey bees (Apis mellifera anatolica). The rationale behind the present experiment was to determine the species generality of the effect of ethanol on response inhibition. Subjects were originally trained to associate either a cinnamon or lavender odor with a sucrose feeding before a reversal of the conditioned stimuli. We administered 15 MUL of ethanol at varying doses (0%, 2.5%, 5%, 10%, or 20%) according to group assignment. Ethanol was either administered 5 min before original discrimination training or 5 min before the stimuli reversal. We analyzed the effects of these three manipulations via a recently developed individual analysis that eschews aggregate assessments in favor of a model that conceptualizes learning as occurring in individual organisms. We measured responding in the presence of conditioned stimuli associated with a sucrose feeding, responding in the presence of conditioned stimuli associated with distilled water, and responding in the presence of the unconditioned stimulus (sucrose). Our analyses revealed the ethanol dose manipulation lowered responding for all three measures at increasingly higher doses, which suggests ethanol served as a general behavioral suppressor. Consistent with previous ethanol reversal literature, we found administering ethanol before the original discrimination phase or before the reversal produced inconsistent patterns of responding at varying ethanol doses. PMID- 25837482 TI - The effects of postnatal alcohol exposure and galantamine on the context pre exposure facilitation effect and acetylcholine efflux using in vivo microdialysis. AB - Fetal alcohol spectrum disorders (FASD) are characterized by damage to multiple brain regions, including the hippocampus, which is involved in learning and memory. The acetylcholine neurotransmitter system provides major input to the hippocampus and is a possible target of developmental alcohol exposure. Alcohol (3.0 g/kg/day) was administered via intubation to male rat pups (postnatal day [PD] 2-10; ethanol-treated [ET]). Controls received a sham intubation (IC) or no treatment (NC). Acetylcholine efflux was measured using in vivo microdialysis (PD 32-35). ET animals were not different at baseline, but had decreased K(+)/Ca(2+) induced acetylcholine efflux compared to NC animals and an enhanced acetylcholine response to galantamine (acetylcholinesterase inhibitor; 2.0 mg/kg) compared to both control groups. A separate cohort of animals was tested in the context pre exposure facilitation effect task (CPFE; PD 30-32) following postnatal alcohol exposure and administration of galantamine (2.0 mg/kg; PD 11-30). Neither chronic galantamine nor postnatal alcohol exposure influenced performance in the CPFE task. Using immunohistochemistry, we found that neither alcohol exposure nor behavioral testing significantly altered the density of vesicular acetylcholine transporter or alpha7 nicotinic acetylcholine receptor in the ventral hippocampus (CA1). In the medial septum, the average number of choline acetyltransferase (ChAT+) cells was increased in ET animals that displayed the context-shock association; there were no changes in IC and NC animals that learned the context shock association or in any animals that were in the control task that entailed no learning. Taken together, these results indicate that the hippocampal acetylcholine system is significantly disrupted under conditions of pharmacological manipulations (e.g., galantamine) in alcohol-exposed animals. Furthermore, ChAT was up-regulated in ET animals that learned the CPFE, which may account for their ability to perform this task. In sum, developmental alcohol exposure may disrupt learning and memory in adolescence via a cholinergic mechanism. PMID- 25837484 TI - Negative feedback loop between p66Shc and ZEB1 regulates fibrotic EMT response in lung cancer cells. AB - The epithelial-to-mesenchymal transition (EMT) program is crucial for the epithelial cancer progression and fibrotic diseases. Our previous work has demonstrated that p66Shc, a focal adhesion-associated adaptor protein, is frequently downregulated in lung cancers and its depletion promotes metastasis behavior through anoikis resistance. However, mechanism underlying loss of p66Shc and EMT response is not fully understood. Here, we showed that p66Shc deficiency enhanced the expression of ZEB1, the known mesenchymal transcription factor and consequently increased Vimentin, and decreased epithelial markers of E-cadherin and beta-catenin. p66Shc depletion also increased cell invasion and migration. In addition, ChIP and luciferase assays showed that these effects were directly mediated by ZEB1 repression of p66Shc promoter. Thus, our findings define a critical role of p66Shc in the suppression of fibrotic EMT response with a negative feedback loop between p66Shc and ZEB1 in lung epithelial cancer cells. PMID- 25837485 TI - Alzheimer's disease-related amyloid-beta induces synaptotoxicity in human iPS cell-derived neurons. AB - Human induced pluripotent stem cell (iPSC)-derived neurons have been proposed to be a highly valuable cellular model for studying the pathomechanisms of Alzheimer's disease (AD). Studies employing patient-specific human iPSCs as models of familial and sporadic forms of AD described elevated levels of AD related amyloid-beta (Abeta). However, none of the present AD iPSC studies could recapitulate the synaptotoxic actions of Abeta, which are crucial early events in a cascade that eventually leads to vast brain degeneration. Here we established highly reproducible, human iPSC-derived cortical cultures as a cellular model to study the synaptotoxic effects of Abeta. We developed a highly efficient immunopurification procedure yielding immature neurons that express markers of deep layer cortical pyramidal neurons and GABAergic interneurons. Upon long-term cultivation, purified cells differentiated into mature neurons exhibiting the generation of action potentials and excitatory glutamatergic and inhibitory GABAergic synapses. Most interestingly, these iPSC-derived human neurons were strongly susceptible to the synaptotoxic actions of Abeta. Application of Abeta for 8 days led to a reduction in the overall FM4-64 and vGlut1 staining of vesicles in neurites, indicating a loss of vesicle clusters. A selective analysis of presynaptic vesicle clusters on dendrites did not reveal a significant change, thus suggesting that Abeta impaired axonal vesicle clusters. In addition, electrophysiological patch-clamp recordings of AMPA receptor-mediated miniature EPSCs revealed an Abeta-induced reduction in amplitudes, indicating an impairment of postsynaptic AMPA receptors. A loss of postsynaptic AMPA receptor clusters was confirmed by immunocytochemical stainings for GluA1. Incubation with Abeta for 8 days did not result in a significant loss of neurites or cell death. In summary, we describe a highly reproducible cellular AD model based on human iPSC-derived cortical neurons that enables the mechanistic analysis of Abeta-induced synaptic pathomechanisms and the development of novel therapeutic approaches. PMID- 25837486 TI - Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs. AB - Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors. PMID- 25837488 TI - Pd(II)-catalyzed P(O)R(1)R(2)-directed asymmetric C-H activation and dynamic kinetic resolution for the synthesis of chiral biaryl phosphates. AB - An efficient method of Pd(II)-catalyzed P(O)R(1)R(2)-directed asymmetric C-H activation and dynamic kinetic resolution for synthesis of chiral phosphinate ligands has been performed and exhibits a wide scope of substrates and an excellent diastereomeric ratio (>95:5). PMID- 25837489 TI - Orthogonal moments for determining correspondence between vessel bifurcations for retinal image registration. AB - Retinal image registration is a necessary step in diagnosis and monitoring of Diabetes Retinopathy (DR), which is one of the leading causes of blindness. Long term diabetes affects the retinal blood vessels and capillaries eventually causing blindness. This progressive damage to retina and subsequent blindness can be prevented by periodic retinal screening. The extent of damage caused by DR can be assessed by comparing retinal images captured during periodic retinal screenings. During image acquisition at the time of periodic screenings translation, rotation and scale (TRS) are introduced in the retinal images. Therefore retinal image registration is an essential step in automated system for screening, diagnosis, treatment and evaluation of DR. This paper presents an algorithm for registration of retinal images using orthogonal moment invariants as features for determining the correspondence between the dominant points (vessel bifurcations) in the reference and test retinal images. As orthogonal moments are invariant to TRS; moment invariants features around a vessel bifurcation are unaltered due to TRS and can be used to determine the correspondence between reference and test retinal images. The vessel bifurcation points are located in segmented, thinned (mono pixel vessel width) retinal images and labeled in corresponding grayscale retinal images. The correspondence between vessel bifurcations in reference and test retinal image is established based on moment invariants features. Further the TRS in test retinal image with respect to reference retinal image is estimated using similarity transformation. The test retinal image is aligned with reference retinal image using the estimated registration parameters. The accuracy of registration is evaluated in terms of mean error and standard deviation of the labeled vessel bifurcation points in the aligned images. The experimentation is carried out on DRIVE database, STARE database, VARIA database and database provided by local government hospital in Pune, India. The experimental results exhibit effectiveness of the proposed algorithm for registration of retinal images. PMID- 25837487 TI - In vitro evidence for senescent multinucleated melanocytes as a source for tumor initiating cells. AB - Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS(61K) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation. PMID- 25837490 TI - Portrayal of the human resource crisis and accountability in healthcare: a qualitative analysis of ugandan newspapers. AB - BACKGROUND: Uganda is one of the 57 countries with a critical shortage of health workers. The aim of this study was to determine how the human resources and health service crisis was covered in Ugandan newspapers and, in particular, how the newspapers attributed accountability for problems in the health services. METHODS: We collected all articles related to health workers and health services for the calendar year 2012 in the two largest national newspapers in Uganda (collection on daily basis) and in one local newspaper (collection on weekly basis). These articles were analysed qualitatively regarding the main themes covered and attribution of accountability. RESULTS: The two more urban national newspapers published 229 articles on human resources and health services in Uganda (on average over two articles per week), whereas the local more rural newspaper published only a single article on this issue in the 12 month period. The majority of articles described problems in the health service without discussing accountability. The question of accountability is raised in only 46% of articles (106 articles). The responsibility of the government was discussed in 50 articles (21%), and negligence, corruption and misbehaviour by individual health workers was reported in 56 articles (25%). In the articles about corruption (n=35), 60% (21 articles) mention corruption by health workers and 40% (14 articles) mention corruption by government officials. Six articles defended the situation of health workers in Uganda. CONCLUSIONS: The coverage of accountability in the Ugandan newspapers surveyed is insufficient to generate informed debate on what political actions need to be taken to improve the crisis in health care and services. There exists not only an "inverse care law" but also an "inverse information law": those sections of society with the greatest health needs and problems in accessing quality health care receive the least information about health services. PMID- 25837491 TI - Observational tools for measuring parent-infant interaction: a systematic review. AB - The quality of the parent-infant interaction is essential for the infant's development and is most objectively measured by observation. The existing observational tools for assessing parent-infant interaction were identified and described, and their psychometric soundness was evaluated. Twenty electronic databases from inception through June 2013 were searched. Validity was evaluated in five domains (test content, response process, internal structure, relations to other variables, and consequences). Of the 23,961 citations identified, 24 tools were included. Most tools demonstrated a valid rating procedure, reproducibility, and discriminant validity, based on studies with credible quality. The tools lacked factorial and predictive validity, and standardized norms. Further refinement of the existing tools is needed, particularly in the domains of content validity and consequential validity. The synthesized validity evidence and descriptions of the tools reported in this review might guide clinicians and researchers in the selection of an appropriate tool. PMID- 25837492 TI - Substance-use and sexual harm reduction strategies of methamphetamine-using men who have sex with men and inject drugs. AB - Research indicates that men who have sex with men (MSM), use methamphetamine, and inject drugs are at high risk of HIV infection and they employ multiple harm reduction strategies simultaneously to reduce that risk. In this study, we identified substances most commonly injected and harm reduction strategies most often employed by methamphetamine-using MSM, used latent class analysis (LCA) to identify patterns of harm reduction strategies, and differentiated MSM within each class by individual characteristics. We analyzed data from 284 participants who completed an online cross-sectional survey. Commonly injected substances were methamphetamine (93.70%), gamma-hydroxybutyrate/gamma-butyrolactone (41.55%), flunitrazepam (40.49%), and cocaine (35.56%). The substance-use strategies most often used were avoidance of sharing needles (85.92%) and use of bleach to clean drug paraphernalia (64.08%). The sexual strategy most often used was avoidance of condomless anal intercourse (CAS) while using drugs (77.11%). Using an LCA approach, we identified three classes distinguishable by age, race/ethnicity, and outness. One class (19%) employed lay strategies to reduce harm: they avoided sharing drug preparation equipment, serosorted when sharing needles and equipment or having CAS, and practiced withdrawal when having CAS. The largest class (53%) combined sexual and substance-use strategies: they avoided sharing needles, used bleach to clean needles and equipment, avoided CAS when using drugs, and used extra lubricant when having CAS. The remaining class (28%) employed only substance-use rather than sexual strategies. More MSM of color were in the substance-use class, and more young, non-Hispanic White men were in the lay class. The low utilization of sexual strategies by younger, non-Hispanic White men in the lay class is concerning as they are just as likely as older, non Hispanic White men in the combined class to have CAS with multiple male partners. Interventionists should consider these differences when developing interventions tailored to methamphetamine-using MSM. PMID- 25837493 TI - Young-age prostate cancer. AB - Although prostate cancer is a disease of the elderly, its diagnosis is not uncommonly made in men younger than 55 years. Both ethnic, familial and genetic factors play a role in the early onset of prostate cancer, but the biology, particularly of low-grade prostate cancers detected at young age is not well understood. Autopsy studies have shown a high prevalence of Gleason score 6 prostate cancers in men under 55 years, but mortality of prostate cancer at this young age is almost negligible. Recently, a number of susceptibility genes such as BRCA2 and HOXB13 were reported, each with their own specific biological and histopathology features. In this review, we provide an update on the most recent findings in young-age prostate cancer. PMID- 25837494 TI - Epilepsy and recommendations for breastfeeding. AB - PURPOSE: The objective of this paper is to provide a synopsis of benefits and potential harmful effects of exposure to antiepileptic drugs (AEDs) via breastmilk, and present recommendations for breastfeeding in women with epilepsy. METHODS: The article is based on a discretionary selection of English language articles retrieved by a literature search in the PubMed database, the LactMed database, and the authors' clinical experience. RESULTS: Breastfeeding is associated with benefits for the infant, including nutrition, protection against infectious and immunological disease, and promotion of development and psychological attachment. Exposure to AEDs via breastmilk could potentially produce side effects or negatively affect development. Most studies on AED transfer through breastmilk report infant serum levels well below the limit of an expected pharmacological effect. Some drugs have the potential to reach significant serum levels in breastfed infants, such as barbiturates, benzodiazepines, lamotrigine, and ethosuximide. Thus, breastfed infants should be monitored for side effects. Still, adverse symptoms are rarely reported in breastfed infants of mothers taking AEDs, and prospective studies have failed to demonstrate any negative developmental effects in children that have been exposed to AEDs via breastmilk. The nursing infant's degree of drug exposure can be minimized by breastfeeding when drug concentrations in the milk are low, reducing maternal AED dosage to prepregnancy levels, and administering mixed nutrition. CONCLUSION: Most AEDs are considered safe or moderately safe during breastfeeding. Mothers with epilepsy should be encouraged to breastfeed, provided careful monitoring of the infant. PMID- 25837495 TI - Identification of location of nerve catheters using pumping maneuver and M-Mode-a novel technique. AB - BACKGROUND: Optimum positioning of the nerve catheter is crucial for a successful nerve block. We present a novel technique for confirmation of catheter position. METHODS: We are describing a novel technique for localization of the shaft and tip of the peripheral nerve catheter. After introduction of the catheter 3 to 5 cm beyond the needle tip and removal of the needle, the guide wire was reintroduced and was moved inward and outward rapidly. This movement produced the color Doppler effect along the track of the catheter and the catheter tip that helped us verify the proper positioning of the catheter. RESULTS: We used our technique in a cadaveric study for bilateral supraclavicular brachial plexus block, followed by a series of 5 patients undergoing femoral, sciatic (anterior approach), popliteal (2 patients), and brachial plexus blocks. Catheters were also identified on M-Mode sonography during pumping maneuver and during the injection of medications. CONCLUSION: Pumping maneuver and M-Mode can be additional tools in the array of modalities applied to verify proper positioning of a nerve catheter. PMID- 25837496 TI - Histologic Artifacts of Autolytic Muller Cell Foot Process Swelling in Postmortem Examination of Infant Eyes: Potential Pitfall in the Evaluation of Traumatic Retinal Hemorrhages. AB - IMPORTANCE: Retinal hemorrhages are an important sequela of fatal head trauma. The accurate pathologic diagnosis of retinal hemorrhages has critical implications for determination of the manner of death. OBSERVATIONS: We describe an autolytic postmortem histologic artifact of eosinophilic Muller cell foot process swelling that mimics a nerve fiber layer hemorrhage. From April 24, 2012, through November 11, 2014, we conducted postmortem examination of the eyes of 23 infants and children who were referred to our institution for possible nonaccidental head trauma. A focal artifact of Muller cell foot process swelling was identified in most patients (16 of 23) up to 4 years of age. Three infants, all of whom were younger than 3 months, demonstrated diffusely swollen Muller cell foot processes with intensely eosinophilic cytoplasm that mimicked erythrocytes of nerve fiber layer hemorrhages. The difference in the mean age between patients with diffuse eosinophilic artifacts (1.7 months) and patients with only a multifocal, focal, or absent artifact (13.3 months) was 11.6 months (95% CI, 6.5-16.7 months). Glycophorin C immunohistochemical analysis was useful to differentiate this artifact from nerve fiber layer hemorrhage. CONCLUSIONS AND RELEVANCE: Our case review demonstrates an artifact of eosinophilic Muller cell foot processes swelling in postmortem examination of young infant eyes, a potential pitfall in the diagnosis of retinal hemorrhages. Our findings have important implications for the diagnosis of retinal hemorrhages in potential cases of nonaccidental head injury. PMID- 25837497 TI - Bilateral primary adrenal non-Hodgkin's lymphoma without adrenal insufficiency. AB - We are presenting a rare case of bilateral adrenal non-Hodgkin's lymphoma (NHL) that presented as a primary malignancy. An 83-year-old man presented with newly discovered bilateral adrenal incidentalomas, fatigue, and 30 pound weight loss. Of the 116 cases of primary adrenal NHL reported, over half have presented bilaterally and occur with adrenal insufficiency. Therefore, the finding of bilateral adrenal masses requires an urgent work-up of the functional status of the adrenal gland as well as a thorough analysis of the imaging characteristics seen on noncontrast computed tomography (CT) in order to maximize patient survival. Adrenal function testing was normal. Repeat CT imaging revealed rapidly growing lesions with high attenuations; both masses >10 HU. Histological examination of core biopsies discovered malignant lymphoma with no known past history of lymphoma. Our case coincides with the literature, which states that a mass with attenuation >10 HU in the adrenal glands has a high risk of malignancy. PMID- 25837498 TI - Enhanced adsorption of trivalent arsenic from water by functionalized diatom silica shells. AB - The potential of porous diatom silica shells as a naturally abundant low-cost sorbent for the removal of arsenic in aqueous solutions was investigated in a batch study. The objective of this work was to chemically modify the silica shells of a diatom Melosira sp. with bifunctional (thiol and amino) groups to effectively remove arsenic in its toxic As(III) form (arsenite) predominant in the aquatic environment. Sorption experiments with this novel sorbent were conducted under varying conditions of pH, time, dosage, and As(III) concentration. A maximum adsorption capacity of 10.99 mg g-1 was achieved within 26 h for a solution containing 12 mg L-1 As(III) at pH 4 and sorbent dosage of 2 g L-1. The functionalized diatom silica shells had a surface morphological change which was accompanied by increased pore size at the expense of reduced specific surface area and total pore volume. As(III) adsorption was best fitted with the Langmuir-Freundlich model, and the adsorption kinetic data using pore surface diffusion model showed that both the external (film) and internal (intraparticle) diffusion can be rate-determining for As(III) adsorption. Fourier transform infrared spectroscopy (FTIR) indicated that the thiol and amino groups potentially responsible for As(III) adsorption were grafted on the surface of diatom silica shells. X-ray photoelectron spectroscopy (XPS) further verified that this unique sorbent proceeded via a chemisorption mechanism through the exchange between oxygen-containing groups of neutral As(III) and thiol groups, and through the surface complexation between As(III) and protonated nitrogen and hydroxyl groups. Results indicate that this functionalized bioadsorbent with a high As(III) adsorption capacity holds promise for the treatment of As(III) containing wastewater. PMID- 25837500 TI - Mortality from road traffic accidents in a rapidly urbanizing Chinese city: A 20 year analysis in Shenzhen, 1994-2013. AB - OBJECTIVE: This study aimed to describe the trends of motorization and mortality rates from road traffic accidents and examine their associations in a rapidly urbanizing city in China, Shenzhen. METHODS: Using data from the Shenzhen Deaths Registry between 1994 and 2013, we calculated the annual mortality rates of road traffic accidents, in addition to the age- and sex-specific mortality rates and their annual percentage changes (APCs) for the period of 2000-2013. We also examined the associations between mortality rate of road traffic accidents and traffic growth with Spearman's rank correlation analysis and a log-linear model derived from Smeed's law. RESULTS: A total of 20,196 deaths due to road traffic accidents, including 14,391 (71.3%) male deaths and 5,805 (28.7%) female deaths, were recorded in Shenzhen from 1994 to 2013. The annual mortality rates in terms of deaths per population and deaths per vehicle changed in similar patterns, demonstrating an increase since 1994 and peaking in 1997, followed by a steady decrease thereafter. The decrease in mortality was faster in individuals aged 20 year or older compared to those younger than 20 years. The mortality rates in term of deaths per population were positively correlated with the total number of vehicles per kilometer of road but negatively correlated with the motorization rate in term of vehicles per population. The estimated model for deaths due to road traffic accidents in relation to the total population and the number of registered vehicles was ln (deaths/10,000 vehicles) = -1.902 * ln (vehicles/population) - 1.961. The coefficient was statistically significant (P < .001) and the coefficient of determination was 0.966, indicating a good model fit. CONCLUSIONS: We described a generally decreasing trend in the mortality rates of road traffic accidents in a rapidly urbanizing Chinese city based observations in the 20-year period from 1994 to 2013. The decreased mortality rate may be explained by the expansion of road network construction, improved road safety regulations and management, as well as more accessible ambulance services in recent years. Nevertheless, road traffic accidents remain a universal problem of great public health concern in the whole population. PMID- 25837499 TI - A phase I dose-escalation study of lenalidomide in combination with gemcitabine in patients with advanced pancreatic cancer. AB - PURPOSE: Lenalidomide have both immunomodulatory and anti-angiogenic properties which could confer anti-cancer effects. The aim of this study was to assess the feasibility of combining lenalidomide with the standard treatment gemcitabine in pancreatic cancer patients with advanced disease. PATIENTS AND METHODS: Eligible patients had locally advanced or metastatic adenocarcinoma of the pancreas. Patients received lenalidomide days 1-21 orally and gemcitabine 1000 mg/m2 intravenously (days 1, 8 and 15), each 28 day cycle. Three cohorts of lenalidomide were examined (Cohort I = 15 mg, Cohort II = 20 mg and Cohort III = 25 mg daily). The maximum tolerated dose (MTD) of lenalidomide given in combination with gemcitabine was defined as the highest dose level at which no more than one out of four (25%) subjects experiences a dose-limiting toxicity (DLT). Patients should also be able to receive daily low molecular weight heparin (LMWH) (e.g. dalteparin 5000 IU s.c. daily) as a prophylactic anticoagulant for venous thromboembolic events (VTEs). Twelve patients (n = 4, n = 3 and n = 5 in cohort I, II and III, respectively) were enrolled in this study. RESULTS: Median duration of treatment was 11 weeks (range 1-66), and median number of treatment cycles were three (range 1-14). The only DLT was a cardiac failure grade 3 in cohort III. Frequent treatment-related adverse events (AEs) (all grades) included neutropenia, leucopenia and fatigue (83% each, but there was no febrile neutropenia); thrombocytopenia (75%); dermatological toxicity (75%); diarrhea and nausea (42% each); and neuropathy (42%). DISCUSSION: This phase I study demonstrates the feasibility of the combination of lenalidomide and gemcitabine as first-line treatment in patients with advanced pancreatic cancer. The tolerability profile demonstrated in the dose escalation schedule of lenalidomide suggests the dosing of lenalidomide to be 25 mg daily on days 1-21 with standard dosing of gemcitabine and merits further evaluation in a phase II trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01547260. PMID- 25837501 TI - Paenibacillus curdlanolyticus B-6 xylanase Xyn10C capable of producing a doubly arabinose-substituted xylose, alpha-L-Araf-(1->2)-[alpha-L-Araf-(1->3)]-D-Xylp, from rye arabinoxylan. AB - Paenibacillus curdlanolyticus B-6 Xyn10C is a single module xylanase consisting of a glycoside hydrolase family-10 catalytic module. The recombinant enzyme, rXyn10C, was produced by Escherichia coli and characterized. rXyn10C was highly active toward soluble xylans derived from rye, birchwood, and oat spelt, and slightly active toward insoluble wheat arabinoxylan. It hydrolyzed xylooligosaccharides larger than xylotetraose to produce xylotriose, xylobiose, and xylose. When rye arabinoxylan and oat spelt xylan were treated with the enzyme and the hydrolysis products were analyzed by thin layer chromatography (TLC), two unknown hydrolysis products, U1 and U2, were detected in the upper position of xylose on a TLC plate. Electrospray ionization mass spectrometry and enzymatic analysis using Bacillus licheniformis alpha-L-arabinofuranosidase Axh43A indicated that U1 was alpha-L-Araf-(1->2)-[alpha-L-Araf-(1->3)]-D-Xylp and U2 was alpha-L-Araf-(1->2)-D-Xylp, suggesting that rXyn10C had strong activity toward a xylosidic linkage before and after a doubly arabinose-substituted xylose residue and was able to accommodate an alpha-1,2- and alpha-1,3-linked arabinose substituted xylose unit in both the -1 and +1 subsites. A molecular docking study suggested that rXyn10C could accommodate a doubly arabinose-substituted xylose residue in its catalytic site, at subsite -1. This is the first report of a xylanase capable of producing alpha-L-Araf-(1->2)-[alpha-L-Araf-(1->3)]-D-Xylp from highly arabinosylated xylan. PMID- 25837502 TI - Effect of some redox mediators on FAD fluorescence of glucose oxidase from Penicillium adametzii LF F-2044.1. AB - Glucose oxidase (GOx) of Penicillium adametzii LF F-2044.1 recovered by ultrafiltration, was characterized by spectrophotometric and spectrofluorometric methods. It was shown that spectra of GOx from P. adametzii are typical for flavoproteins. Optimal buffer composition was chosen. It was determined that the GOx is the most efficiently interacting with substrate (glucose) in phosphate buffer at pH 7.0 with kkat/KM=15,217+/-550M(-1)s(-1). P. adametzii GOx fluorescence in the presence of different redox mediators (9,10-phenanthroline 5,6-dione, 9,10-phenanthrenequinone, 1,4-benzoquinone, methylene blue, ferrocene, ferrocenecarboxylic acid, alpha-methylferrocenemethanol, ferrocenecarboxaldehyde) was evaluated. Maximal differences in fluorescence emission intensity were observed in the presence of ferrocene and 9,10-phenanthrenequinone. PMID- 25837503 TI - Synergistic effect and application of xylanases as accessory enzymes to enhance the hydrolysis of pretreated bagasse. AB - Recently, the new trend in the second-generation ethanol industry is to use mild pretreatments, in order to reduce costs and to keep higher content of hemicellulose in the biomass. Nevertheless, a high enzyme dosage is still required in the conversion of (hemi)cellulose. The interaction between cellulases and xylanases seems to be an effective alternative to reduce enzyme loading in the saccharification process. At first, to evaluate the synergism of xylanases on bagasse degradation, we have produced two xylanases from glycoside hydrolase family 10 (GH10) and three xylanases from glycoside hydrolase family 11 (GH11), from two thermophilic organisms, Thermobifida fusca and Clostridium thermocellum, and one mesophilic organism, Streptomyces lividans. Peracetic acid (PAA) pretreated bagasse was used as substrate. The combination of XynZ-C (GH10, from C. thermocellum), and XlnB (GH11, from S. lividans) presented the highest degree of synergy after 6h (3.62). However, the combination of XynZ-C and Xyn11A (GH11, from T. fusca) resulted in the highest total yield of reducing sugars. To evaluate the synergism between xylanases and cellulases, commercial cellulase preparation from Trichoderma reesei was combined with the selected xylanases, XynZ-C and Xyn11A. About 2-fold increase was observed in the concentration of reducing sugars, when both xylanases, XynZ-C and Xyn11A, were added together with T. reesei cellulases in the reaction mixture. PMID- 25837504 TI - Tackling codon usage bias for heterologous expression in Rhodobacter sphaeroides by supplementation of rare tRNAs. AB - The photosynthetic Rhodobacter species are promising alternative expression hosts in bioproduction and biorefinery due to their unique metabolic capacities. With prominent inner membrane areas and efficient endogenous translocation machineries, they are especially attractive for membrane protein expression. However, codon usage bias could be a limitation in the engineering of Rhodobacter species and has seldom been investigated. In this study, we tackled the codon bias of Rhodobacter by functionally expressing 8 rare tRNAs of Rhodobacter sphaeroides with a multi-copy vector. The impact of tRNA supplementation was evaluated through monitoring expression levels of two heterologous proteins with different phylogenetic origins, a membrane subunit of the riboflavin transporter, RibU, from Lactobacillus acidophilus La-14 and a decaheme cytochrome, MtrA, from Shewanella oneidensis. Our results showed that the performances were closely related to medium composition and rare codon percentages of raw DNA sequences. Provision of rare tRNAs has increased RibU production by 7.7-folds and 2.86-fold in minimal medium and rich medium, respectively, while MtrA levels were increased by 1-fold in minimal medium. The present study confirms the presence of codon bias in R. sphaeroides and offers a facile tool for improving heterologous expression of rare-codon containing genes. We anticipate that this tRNA supplementation system can be further extended to other species of Rhodobacter, and thus will facilitate the engineering of purple bacteria for interesting applications in microbial technology. PMID- 25837505 TI - The final acylation step in aromatic dithiolopyrrolone biosyntheses: identification and characterization of the first bacterium N-benzoyltransferase from Saccharothrix algeriensis NRRL B-24137. AB - The last step in the biosynthesis of dithiolopyrrolone antibiotics was thought to involve the transfer of acyl group from acyl-CoA to pyrrothine/holothin core. In Saccharothrix algeriensis NRRL B-24137, two acyltransferases, an acetyltransferase and a benzoyltransferase were proposed to catalyze this step. We have previously identified, in Sa. algeriensis genome, two open read frames, actA and actB patiently encoded these enzymes. This study focuses primarily on the characterization of the protein encoded by actA. After cloning and expressing of actA in Escherichia coli BL21, the recombinant protein encoded by actA was purified. Selectivity of ActA for pyrrothine/holothin as substrate and different acyl-CoA as co-substrate was evaluated using two acyls-groups, linear and aromatic. The enzyme was shown to prefer aromatic groups over linear groups as donor group; further neither product nor transfer was observed for linear groups. Therefore ActA has been determined to be a pyrrothine/holothin N benzoyltransferase which can either pyrrothine (Km of 72MUM) or holothin (Km of 129.5MUM) as substrates and benzoyl-CoA (Km of 348.65 and 395.28MUM) as co substrates for pyrrothine and holothin, respectively. The optimum pH and temperature has been shown to be 8, 40 degrees C, respectively. ActA is the first enzyme characterized as N-benzoyltransferase in bacteria. PMID- 25837506 TI - Development of reproducible assays for polygalacturonase and pectinase. AB - Polygalacturonase and pectinase activities reported in the literature were measured by several different procedures. These procedures do not give comparable results, partly owing to the complexity of the substrates involved. This work was aimed at developing consistent and efficient assays for polygalacturonase and pectinase activities, using polygalacturonic acid and citrus pectin, respectively, as the substrate. Different enzyme mixtures produced by Aspergillus niger and Trichoderma reesei with different inducing carbon sources were used for the method development. A series of experiments were conducted to evaluate the incubation time, substrate concentration, and enzyme dilution. Accordingly, for both assays the recommended (optimal) hydrolysis time is 30min and substrate concentration is 5g/L. For polygalacturonase, the sample should be adjusted to have 0.3-0.8U/mL polygalacturonase activity, because in this range the assay outcomes were consistent (independent of dilution factors). Such a range did not exist for the pectinase assay. The recommended procedure is to assay the sample at multiple (at least 2) dilution factors and determine, by linear interpolation, the dilution factor that would release reducing sugar equivalent to 0.4g/L d galacturonic acid, and then calculate the activity of the sample accordingly (dilution factor*0.687U/mL). Validation experiments showed consistent results using these assays. Effects of substrate preparation methods were also examined. PMID- 25837507 TI - A facile enzymatic synthesis of geranyl propionate by physically adsorbed Candida rugosa lipase onto multi-walled carbon nanotubes. AB - In view of several disadvantages as well as adverse effects associated with the use of chemical processes for producing esters, alternative techniques such as the utilization of enzymes on multi-walled carbon nanotubes (MWCNTs), have been suggested. In this study, the oxidative MWCNTs prepared using a mixture of HNO3 and H2SO4 (1:3 v/v) were used as a supportive material for the immobilization of Candida rugosa lipase (CRL) through physical adsorption process. The resulting CRL-MWCNTs biocatalysts were utilized for synthesizing geranyl propionate, an important ester for flavoring agent as well as in fragrances. Enzymatic esterification of geraniol with propionic acid was carried out using heptane as a solvent and the efficiency of CRL-MWCNTs as a biocatalyst was compared with the free CRL, considering the incubation time, temperature, molar ratio of acid:alcohol, presence of desiccant as well as its reusability. It was found that the CRL-MWCNTs resulted in a 2-fold improvement in the percentage of conversion of geranyl propionate when compared with the free CRL, demonstrating the highest yield of geranyl propionate at 6h at 55 degrees C, molar ratio acid: alcohol of 1:5 and with the presence of 1.0g desiccant. It was evident that the CRL-MWCNTs biocatalyst could be reused for up to 6 times before a 50% reduction in catalytic efficiency was observed. Hence, it appears that the facile physical adsorption of CRL onto F-MWCNTs has improved the activity and stability of CRL as well as served as an alternative method for the synthesis of geranyl propionate. PMID- 25837508 TI - An efficient ribitol-specific dehydrogenase from Enterobacter aerogenes. AB - An NAD(+)-dependent ribitol dehydrogenase from Enterobacter aerogenes KCTC 2190 (EaRDH) was cloned and successfully expressed in Escherichia coli. The complete 729-bp gene was amplified, cloned, expressed, and subsequently purified in an active soluble form using nickel affinity chromatography. The enzyme had an optimal pH and temperature of 11.0 and 45 degrees C, respectively. Among various polyols, EaRDH exhibited activity only toward ribitol, with Km, Vmax, and kcat/Km values of 10.3mM, 185Umg(-1), and 30.9s(-1)mM(-1), respectively. The enzyme showed strong preference for NAD(+) and displayed no detectable activity with NADP(+). Homology modeling and sequence analysis of EaRDH, along with its biochemical properties, confirmed that EaRDH belongs to the family of NAD(+) dependent ribitol dehydrogenases, a member of short-chain dehydrogenase/reductase (SCOR) family. EaRDH showed the highest activity and unique substrate specificity among all known RDHs. Homology modeling and docking analysis shed light on the molecular basis of its unusually high activity and substrate specificity. PMID- 25837509 TI - Development of a transparent, non-cytotoxic, silver ion-exchanged glass with antimicrobial activity and low ion elution. AB - We investigated the antimicrobial, cytotoxicity, skin irritation, and ion elution behaviors of glass doped with silver ions with respect to its application to electronic equipment such as phones and tablet screens. The microbes tested were Escherichia coli, Staphylococcus aureus, and Penicillium funiculosum. AgNO3 powder was spread on both sides of aluminosilicate glass, and it was heated to 250-280 degrees C for 10min. Under optimized heating conditions (260 degrees C, 10min), the antimicrobial activity of ion-exchanged glass against bacteria and fungi was over 99.9% after 24 weeks. The glass failed to irritate the skin of experimental animals and was considered non-cytotoxic. The maximum amount of Ag ions that were eluted from the ion-exchanged glass into drinking water was measured at 0.037+/-0.003MUgL(-1), an amount which is several orders of magnitude below the standard limit of 0.1mgL(-1) in drinking water. Ag ion-exchanged glass had characteristics suitable for use as a display screen, such as a light transmittance of 90% and a surface roughness of 0.704nm. Our findings suggest that glass doped with silver ions is more hygienic than non-doped glass is, and should be applied to display screens and glassware. PMID- 25837510 TI - Magnetosomes extracted from Magnetospirillum magneticum strain AMB-1 showed enhanced peroxidase-like activity under visible-light irradiation. AB - Magnetosomes are intracellular structures produced by magnetotactic bacteria and are magnetic nanoparticles surrounded by a lipid bilayer membrane. Magnetosomes reportedly possess intrinsic enzyme mimetic activity similar to that found in horseradish peroxidase (HRP) and can scavenge reactive oxygen species depending on peroxidase activity. Our previous study has demonstrated the phototaxis characteristics of Magnetospirillum magneticum strain AMB-1 cells, but the mechanism is not well understood. Therefore, we studied the relationship between visible-light irradiation and peroxidase-like activity of magnetosomes extracted from M. magneticum strain AMB-1. We then compared this characteristic with that of HRP, iron ions, and naked magnetosomes using 3,3',5,5'-tetramethylbenzidine as a peroxidase substrate in the presence of H2O2. Results showed that HRP and iron ions had different activities from those of magnetosomes and naked magnetosomes when exposed to visible-light irradiation. Magnetosomes and naked magnetosomes had enhanced peroxidase-like activities under visible-light irradiation, but magnetosomes showed less affinity toward substrates than naked magnetosomes under visible-light irradiation. These results suggested that the peroxidase-like activity of magnetosomes may follow an ordered ternary mechanism rather than a ping-pong mechanism. This finding may provide new insight into the function of magnetosomes in the phototaxis in magnetotactic bacteria. PMID- 25837511 TI - Usage of polarization-sensitive optical coherence tomography for investigation of collagen cross-linking. AB - To investigate morphological alternation in corneal stroma induced by collagen cross-linking (CXL) treatment, polarization-sensitive optical coherence tomography (PS-OCT) capable of providing scattering, phase retardation, and degree of polarization uniformity (DOPU) images were employed on fresh bovine cornea. Significant corneal thickness reduction was observed after the CXL procedure, and its variation was quantitatively analyzed. From the scattering contrast, a hyperscattering region was observed in the anterior of the cornea immediately after the CXL procedure and its range increased with time. Within the scattering region, a slow increase was observed in the phase retardation image, and a discriminable characteristic was found in the DOPU image. A global threshold value was empirically determined from the averaged DOPU depth profile in order to locate the effective cross-linking depth. In addition to the standard protocol, an accelerated CXL procedure shortening the treatment time with higher intensity of ultraviolet-A (UV-)A power was also performed. From the measurement results after the two different CXL protocols, different cross-linking aspects were found and their difference was discussed in terms of the effectiveness of cross-linking. Based on this study, we believe that PS-OCT could be a promising optical imaging modality to evaluate the progression and effectiveness of the riboflavin/UV-A induced corneal collagen cross-linking. PMID- 25837512 TI - Ribosome. The complete structure of the 55S mammalian mitochondrial ribosome. AB - Mammalian mitochondrial ribosomes (mitoribosomes) synthesize mitochondrially encoded membrane proteins that are critical for mitochondrial function. Here we present the complete atomic structure of the porcine 55S mitoribosome at 3.8 angstrom resolution by cryo-electron microscopy and chemical cross-linking/mass spectrometry. The structure of the 28S subunit in the complex was resolved at 3.6 angstrom resolution by focused alignment, which allowed building of a detailed atomic structure including all of its 15 mitoribosomal-specific proteins. The structure reveals the intersubunit contacts in the 55S mitoribosome, the molecular architecture of the mitoribosomal messenger RNA (mRNA) binding channel and its interaction with transfer RNAs, and provides insight into the highly specialized mechanism of mRNA recruitment to the 28S subunit. Furthermore, the structure contributes to a mechanistic understanding of aminoglycoside ototoxicity. PMID- 25837514 TI - Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. AB - By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike cells to asymmetrically sort aged and young mitochondria, and these are important for maintaining stemness properties. PMID- 25837513 TI - Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. AB - T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-beta usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity. PMID- 25837515 TI - Structural biology. Structures of the CRISPR-Cmr complex reveal mode of RNA target positioning. AB - Adaptive immunity in bacteria involves RNA-guided surveillance complexes that use CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas) proteins together with CRISPR RNAs (crRNAs) to target invasive nucleic acids for degradation. Whereas type I and type II CRISPR-Cas surveillance complexes target double-stranded DNA, type III complexes target single-stranded RNA. Near-atomic resolution cryo-electron microscopy reconstructions of native type III Cmr (CRISPR RAMP module) complexes in the absence and presence of target RNA reveal a helical protein arrangement that positions the crRNA for substrate binding. Thumblike beta hairpins intercalate between segments of duplexed crRNA:target RNA to facilitate cleavage of the target at 6-nucleotide intervals. The Cmr complex is architecturally similar to the type I CRISPR-Cascade complex, suggesting divergent evolution of these immune systems from a common ancestor. PMID- 25837516 TI - Sequence analysis and identification of new isoform of EP4 receptors in different atlantic salmon tissues (Salmo salar L.) and its role in PGE2 induced immunomodulation in vitro. AB - PGE2 plays an important role in a broad spectrum of physiological and pathological processes mediated through a membrane-bound G protein-coupled receptor (GPCR) called EP receptor. In mammals, four subtypes of EP receptor (EP 1-4) are identified and each of them functions through different signal transduction pathways. Orthologous EP receptors have also been identified in other non-mammalian species, such as chicken and zebrafish. EP4 is the only identified PGE2 receptor to date in Atlantic salmon but its tissue distribution and function have not been studied in any detail. In this study, we first sequenced EP4 receptor in different tissues and found that the presence of the 3nt deletion in the 5' untranslated region was accompanied by silent mutation at nt 668. While attempting to amplify the same sequence in TO cells (an Atlantic salmon macrophage-like cell line), we failed to obtain the full-length product. Further investigation revealed different isoform of EP4 receptor in TO cells and we subsequently documented its presence in different Atlantic salmon tissues. These two isoforms of EP4 receptor share high homology in their first half of sequence but differ in the second half part with several deletion segments though the final length of coding sequence is the same for two isoforms. We further studied the immunomodulation effect of PGE2 in TO cells and found that PGE2 inhibited the induction of CXCL-10, CCL-4, IL-8 and IL-1beta genes expression in a time dependent manner and without cAMP upregulation. PMID- 25837517 TI - Cryoglobulinemia Vasculitis. AB - Cryoglobulinemic vasculitis (CryoVas) is a small-vessel vasculitis involving mainly the skin, the joints, the peripheral nervous system, and the kidneys. Type I CryoVas is single monoclonal immunoglobulins related to an underlying B-cell lymphoproliferative disorder. Type II and III cryoglobulins, often referred to as mixed cryoglobulinemia, consist of polyclonal immunoglobulin (Ig)G with or without monoclonal IgM with rheumatoid factor activity. Hepatitis C virus (HCV) infection represents the main cause of mixed CryoVas. The 10-year survival rates are 63%, 65%, and 87% in HCV-positive mixed CryoVas, HCV-negative mixed CryoVas, and type I CryoVas patients, respectively. In HCV-positive patients, baseline poor prognostic factors include the presence of severe liver fibrosis, and central nervous system, kidney, and heart involvement. Treatment with antivirals is associated with a good prognosis, whereas use of immunosuppressants (including corticosteroids) is associated with a poor outcome. In HCV-negative patients, pulmonary and gastrointestinal involvement, renal insufficiency, and age > 65 years are independently associated with death. Increased risk of lymphoma also should be underlined. Treatment of type I CryoVas is that of the hemopathy; specific treatment also includes plasma exchange, corticosteroids, rituximab, and ilomedine. In HCV-CryoVas with mild-to-moderate disease, an optimal antiviral treatment should be given. For HCV-CryoVas with severe vasculitis (ie, worsening of renal function, mononeuritis multiplex, extensive skin disease, intestinal ischemia...) control of disease with rituximab, with or without plasmapheresis, is required before initiation of antiviral therapy. Other immunosuppressants should be given only in case of refractory forms of CryoVas, frequently associated with underlying B-cell lymphoma. PMID- 25837518 TI - The new lipid guidelines: what do primary care clinicians think? AB - BACKGROUND: Little is known about the opinions of primary care clinicians regarding the newly released 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Prevention of Primary and Secondary Atherosclerotic Disease. This survey was created to assess the awareness, attitudes, and practices of primary care clinicians on adoption of the new guidelines and to explore obstacles to implementation and suggestions for improving shared decision-making. METHODS: Six hundred practicing clinicians within the San Francisco Bay Area Collaborative Research Network were invited to participate in this cross-sectional, Internet-based pilot survey of primary care clinicians. These survey data were collected in March 2014, approximately 4 months after the release of the new guidelines and 1 month after the release of the ACC/AHA risk estimator application. RESULTS: One hundred eighty-three clinicians responded to the survey. Of those respondents, 176 (96%) were aware of the guidelines. The majority (64%) reported implementing the new guidelines with at least some of their patients, while a minority (25%) reported adopting the guidelines for many of their patients. Disagreeing with the guidelines was the main hindrance to adoption. CONCLUSIONS: While many primary care clinicians are aware of the new guidelines, a substantial proportion has yet to implement them into their clinical practice, and obstacles remain for full adoption. Further understanding of clinicians' views, opinions, and needs is necessary to optimize the approach to lipid management and ensure integration into current practice. PMID- 25837519 TI - Size distribution of air bubbles entering the brain during cardiac surgery. AB - BACKGROUND: Thousands of air bubbles enter the cerebral circulation during cardiac surgery, but whether high numbers of bubbles explain post-operative cognitive decline is currently controversial. This study estimates the size distribution of air bubbles and volume of air entering the cerebral arteries intra-operatively based on analysis of transcranial Doppler ultrasound data. METHODS: Transcranial Doppler ultrasound recordings from ten patients undergoing heart surgery were analysed for the presence of embolic signals. The backscattered intensity of each embolic signal was modelled based on ultrasound scattering theory to provide an estimate of bubble diameter. The impact of showers of bubbles on cerebral blood-flow was then investigated using patient specific Monte-Carlo simulations to model the accumulation and clearance of bubbles within a model vasculature. RESULTS: Analysis of Doppler ultrasound recordings revealed a minimum of 371 and maximum of 6476 bubbles entering the middle cerebral artery territories during surgery. This was estimated to correspond to a total volume of air ranging between 0.003 and 0.12 mL. Based on analysis of a total of 18667 embolic signals, the median diameter of bubbles entering the cerebral arteries was 33 MUm (IQR: 18 to 69 MUm). Although bubble diameters ranged from ~5 MUm to 3.5 mm, the majority (85%) were less than 100 MUm. Numerous small bubbles detected during cardiopulmonary bypass were estimated by Monte-Carlo simulation to be benign. However, during weaning from bypass, showers containing large macro-bubbles were observed, which were estimated to transiently affect up to 2.2% of arterioles. CONCLUSIONS: Detailed analysis of Doppler ultrasound data can be used to provide an estimate of bubble diameter, total volume of air, and the likely impact of embolic showers on cerebral blood flow. Although bubbles are alarmingly numerous during surgery, our simulations suggest that the majority of bubbles are too small to be harmful. PMID- 25837520 TI - Keep calm and carry on: improved frustration tolerance and processing speed by transcranial direct current stimulation (tDCS). AB - Cognitive control (CC) of attention is a major prerequisite for effective information processing. Emotional distractors can bias and impair goal-directed deployment of attentional resources. Frustration-induced negative affect and cognition can act as internal distractors with negative impact on task performance. Consolidation of CC may thus support task-oriented behavior under challenging conditions. Recently, transcranial direct current stimulation (tDCS) has been put forward as an effective tool to modulate CC. Particularly, anodal, activity enhancing tDCS to the left dorsolateral prefrontal cortex (dlPFC) can increase insufficient CC in depression as indicated by a reduction of attentional biases induced by emotionally salient stimuli. With this study, we provide first evidence that, compared to sham stimulation, tDCS to the left dlPFC enhances processing speed measured by an adaptive version of the Paced Auditory Serial Addition Task (PASAT) that is typically thwarted by frustration. Notably, despite an even larger amount of error-related negative feedback, the task-induced upset was suppressed in the group receiving anodal tDCS. Moreover, inhibition of task related negative affect was correlated with performance gains, suggesting a close link between enhanced processing speed and consolidation of CC by tDCS. Together, these data provide first evidence that activity enhancing anodal tDCS to the left dlPFC can support focused cognitive processing particularly when challenged by frustration-induced negative affect. PMID- 25837522 TI - Unique cytokine and chemokine patterns in bronchoalveolar lavage are associated with specific causative pathogen among HIV infected patients with pneumonia, in Medellin, Colombia. AB - We wanted to investigate the pro-inflammatory cytokine/chemokine profile associated with the etiological agents identified in HIV patients. Immunosuppressed patients admitted to two hospitals in Medellin, Colombia, with clinical and radiographic diagnosis of pneumonia were enrolled in the study. After consent, bronchoalveolar lavage (BAL) was collected for bacterial, mycobacterial and fungal diagnosis. All patients were followed for a year. A stored BAL sample was used for cytokine/chemokine detection and measurement using commercial, magnetic human cytokine bead-based 19-plex assays. Statistical analysis was performed by assigning cytokine/chemokine concentrations levels into <25 percentile (lower), 25-75 percentile (normal) and >75 percentile (higher). Principal component analysis (PCA) and Kruskal-Wallis analysis were conducted to identify the clustering of cytokines with the various infectious etiologies (fungi, Mycobacterium tuberculosis - MTB, and bacteria). Average age of patients was 35, of whom 77% were male, and the median CD4 count of 33cells/MUl. Of the 57 HIV infected patients, in-hospital mortality was 12.3% and 33% died within a year of follow up. The PCA revealed increased IL-10, IL-12, IL-13, IL-17, Eotaxin, GCSF, MIP-1alpha, and MIP-1beta concentrations to be associated with MTB infection. In patients with proven fungal infection, low concentrations of IL 1RA, IL-8, TNF-alpha and VEGF were identified. Bacterial infections displayed a distinct cytokine pattern and were not misclassified using the MTB or fungi cytokine patterns (p-value<0.0001). Our results indicate a unique pattern of pro inflammatory cytokine/chemokine, allowing differentiation between bacterial and non-bacterial pathogens. Moreover, we found distinct, if imperfectly discriminatory, cytokine/chemokine patterns associated with MTB and fungal infections. PMID- 25837521 TI - Schizophrenia detection and classification by advanced analysis of EEG recordings using a single electrode approach. AB - Electroencephalographic (EEG) analysis has emerged as a powerful tool for brain state interpretation and diagnosis, but not for the diagnosis of mental disorders; this may be explained by its low spatial resolution or depth sensitivity. This paper concerns the diagnosis of schizophrenia using EEG, which currently suffers from several cardinal problems: it heavily depends on assumptions, conditions and prior knowledge regarding the patient. Additionally, the diagnostic experiments take hours, and the accuracy of the analysis is low or unreliable. This article presents the "TFFO" (Time-Frequency transformation followed by Feature-Optimization), a novel approach for schizophrenia detection showing great success in classification accuracy with no false positives. The methodology is designed for single electrode recording, and it attempts to make the data acquisition process feasible and quick for most patients. PMID- 25837523 TI - The contribution of mycosporine-like amino acids, chromophoric dissolved organic matter and particles to the UV protection of sea-ice organisms in the Baltic Sea. AB - The effects of ultraviolet radiation (UVR) on the synthesis of mycosporine-like amino acids (MAAs) in sea-ice communities and on the other UV-absorption properties of sea ice were studied in a three-week long in situ experiment in the Gulf of Finland, Baltic Sea in March 2011. The untreated snow-covered ice and two snow-free ice treatments, one exposed to wavelengths > 400 nm (PAR) and the other to full solar spectrum (PAR + UVR), were analysed for MAAs and absorption coefficients of dissolved (aCDOM) and particulate (ap) fractions, the latter being further divided into non-algal (anap) and algal (aph) components. Our results showed that the diatom and dinoflagellate dominated sea-ice algal community responded to UVR down to 25-30 cm depth by increasing their MAA : chlorophyll-a ratio and by extending the composition of MAA pool from shinorine and palythine to porphyra-334 and an unknown compound with absorption peaks at ca. 335 and 360 nm. MAAs were the dominant absorbing components in algae in the top 10 cm of ice, and their contribution to total absorption became even more pronounced under UVR exposure. In addition to MAAs, the high absorption by chromophoric dissolved organic matter (CDOM) and by deposited atmospheric particles provided UV-protection for sea-ice organisms in the exposed ice. Efficient UV-protection will especially be of importance under the predicted future climate conditions with more frequent snow-free conditions. PMID- 25837526 TI - Traditional Chinese medication for cardiovascular disease. PMID- 25837528 TI - Intraoperative Methadone for the Prevention of Postoperative Pain: A Randomized, Double-blinded Clinical Trial in Cardiac Surgical Patients. AB - BACKGROUND: The intensity of pain after cardiac surgery is often underestimated, and inadequate pain control may be associated with poorer quality of recovery. The aim of this investigation was to examine the effect of intraoperative methadone on postoperative analgesic requirements, pain scores, patient satisfaction, and clinical recovery. METHODS: Patients undergoing cardiac surgery with cardiopulmonary bypass (n = 156) were randomized to receive methadone (0.3 mg/kg) or fentanyl (12 MUg/kg) intraoperatively. Postoperative analgesic requirements were recorded. Patients were assessed for pain at rest and with coughing 15 min and 2, 4, 8, 12, 24, 48, and 72 h after tracheal extubation. Patients were also evaluated for level of sedation, nausea, vomiting, itching, hypoventilation, and hypoxia at these times. RESULTS: Postoperative morphine requirements during the first 24 h were reduced from a median of 10 mg in the fentanyl group to 6 mg in the methadone group (median difference [99% CI], -4 [-8 to -2] mg; P < 0.001). Reductions in pain scores with coughing were observed during the first 24 h after extubation; the level of pain with coughing at 12 h was reduced from a median of 6 in the fentanyl group to 4 in the methadone group (-2 [-3 to -1]; P < 0.001). Improvements in patient-perceived quality of pain management were described in the methadone group. The incidence of opioid-related adverse events was not increased in patients administered methadone. CONCLUSIONS: Intraoperative methadone administration resulted in reduced postoperative morphine requirements, improved pain scores, and enhanced patient-perceived quality of pain management. PMID- 25837529 TI - Wheat-related disorders reviewed: making a grain of sense. AB - Wheat-related disorders have become a growing area of clinical and scientific interest and can be categorized broadly as: autoimmune-mediated; allergic; and non-autoimmune/non-allergic conditions. Non-celiac gluten sensitivity (NCGS) and non-celiac wheat sensitivity (NCWS) present on this spectrum as disorders associated with adverse gastrointestinal and extra-intestinal manifestations following exposure to gluten and/or other wheat-related constituents. NCGS/NCWS is increasingly considered in patients with unexplained symptoms after the exclusions of celiac disease and wheat allergy. As objective diagnostic data and specific biomarkers are lacking, response to a gluten-free/wheat-free diet can confirm the presence of NCGS/NCWS. An association with irritable bowel syndrome has been detected, and the effects of other food components, such as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, may contribute. Our organization and synthesis of extant knowledge pertaining to wheat-related disorders may advance current practice and research efforts toward an improved understanding of NCGS/NCWS as an evolving clinical entity. PMID- 25837530 TI - Cough variant asthma patients are more depressed and anxious than classic asthma patients. AB - OBJECTIVE: Many recent studies have indicated that depression and anxiety are more common in asthmatic patients than in the general population and psychological stress can lead to asthma exacerbations, but no study specifically targets cough variant asthma (CVA) patients. The purpose of this study was to evaluate depression and anxiety levels in CVA patients compared with classic asthma patients and to identify the psychological features of CVA patients. METHODS: Fifty-nine outpatients with CVA and 128 outpatients with classic asthma were interviewed about psychosomatic and psychiatric symptoms, and they underwent three psychological tests: Self-rating Depression Scale (SDS), State-Trait Anxiety Inventory (STAI), and Comprehensive Asthma Inventory (CAI). They were ultimately screened for major and minor depression, dysthymia, panic disorder, generalized anxiety disorder, social anxiety disorder, and other anxiety disorders. RESULTS: CVA patients showed higher SDS and STAI scores than classic asthma patients, and mood disorders and anxiety disorders were more common than in classic asthma outpatients. The psychological factors 'frustration', 'fright into illness', and 'distorted lifestyle' were more prominent in CVA patients than in classic asthma patients. CONCLUSION: CVA patients are on average more depressed and anxious than classic asthma outpatients. Though CVA appears pathologically to be just an early stage of typical asthma, the psychological stress may often be more serious than in asthma controlled by medication, which may explain why CVA cannot be controlled by a bronchodilator alone and patients often require no less intense therapy than for severe asthma. PMID- 25837531 TI - Social support, marital adjustment, and psychological distress among women with primary infertility in Pakistan. AB - This study aimed to identify prevalence rates of psychological distress among Pakistani women seeking help for primary infertility. The associations of social support, marital adjustment, and sociodemographic factors with psychological distress were also examined. A total of 177 women with primary infertility were interviewed from one hospital in Islamabad using a Self-Reporting Questionnaire, the Multidimensional Scale of Perceived Social Support, and the Locke-Wallace Marital Adjustment Test. The data were collected between November 2012 and March 2013. The prevalence of psychological distress was 37.3 percent. The results of the logistic regression suggested that marital adjustment and social support were significantly negatively associated with psychological distress in this sample. These associations were not confounded by any of the demographic variables controlled in the multivariable regression models. The role of perceived social support and adjustment in marriage among women experiencing primary infertility are important factors in understanding their psychological distress. The results of this small-scale effort highlight the need for social and familial awareness to help tackle the psychological distress related to infertility. Future research needs to focus on the way the experience of infertility is conditioned by social structural realities. New ways need to be developed to better take into account the process and nature of the infertility experience. PMID- 25837532 TI - Dose-response effect of fluoride dentifrice on remineralisation and further demineralisation of erosive lesions: A randomised in situ clinical study. AB - OBJECTIVE: The objective was to evaluate the ability of fluoride in a conventional, non-specialised sodium fluoride-silica dentifrice to promote tooth remineralisation and enamel fluoride uptake (EFU), and assess the resistance of the newly formed mineral to attack by dietary acid, across the concentration range used in mass-market dentifrices. METHODS: Subjects wore a palatal appliance containing eight polished bovine enamel specimens, each including an early erosive lesion. In a randomised full-crossover sequence, 62 healthy subjects were treated with dentifrices containing four different fluoride concentrations: no fluoride; 250ppm, 1150ppm and 1426ppm fluoride. At each treatment visit, under supervision, subjects brushed with 1.5g dentifrice and rinsed once while wearing the appliance; the appliance was removed after a 4-h remineralisation period and effects on the enamel specimens determined. The primary efficacy variable was surface microhardness recovery (SMHR); others included EFU, relative erosion resistance (RER) and comparative erosion resistance. RESULTS: Highly significant linear and, with the exception of SMHR, quadratic dose-response relationships were observed between all efficacy variables and fluoride concentration. For SMHR, EFU and RER, values for the different fluoride concentrations were statistically resolved from one another, with the exception of the two highest fluoride concentrations. The degree of remineralisation and the acid resistance of enamel after treatment were closely related to EFU. CONCLUSION: After a single brushing, conventional non-specialised sodium fluoride-silica dentifrices promoted remineralisation of early enamel lesions, and imparted increased acid resistance to the enamel surface, in a dose-dependent manner at least up to 1500ppm fluoride. CLINICAL SIGNIFICANCE: Enamel erosive tissue loss is an increasing concern, associated with modern diets. This study demonstrated that sodium fluoride, in a conventional non-specialised dentifrice formulation, can promote repair of the earliest stages of enamel erosion after a single application, in a dose-dependent fashion across the fluoride concentration range used in mass-market dentifrices. This study is registered in the GlaxoSmithKline Study Register (ID RH01299), available at: www.gsk clinicalstudyregister.com/study/RH01299. PMID- 25837533 TI - Addressing missing participant outcome data in dental clinical trials. AB - Missing outcome data are common in clinical trials and despite a well-designed study protocol, some of the randomized participants may leave the trial early without providing any or all of the data, or may be excluded after randomization. Premature discontinuation causes loss of information, potentially resulting in attrition bias leading to problems during interpretation of trial findings. The causes of information loss in a trial, known as mechanisms of missingness, may influence the credibility of the trial results. Analysis of trials with missing outcome data should ideally be handled with intention to treat (ITT) rather than per protocol (PP) analysis. However, true ITT analysis requires appropriate assumptions and imputation of missing data. Using a worked example from a published dental study, we highlight the key issues associated with missing outcome data in clinical trials, describe the most recognized approaches to handling missing outcome data, and explain the principles of ITT and PP analysis. PMID- 25837534 TI - Transvaginal Natural Orifice Transluminal Endoscopic Nephrectomy in a Series of 63 Cases: Stepwise Transition From Hybrid to Pure NOTES. AB - BACKGROUND: The feasibility of hybrid transvaginal NOTES (natural orifice transluminal endoscopic surgery) nephrectomy (HTNN) has already been demonstrated. However, pure transvaginal NOTES nephrectomy (PTNN) has been limited to animal experiments with only one report of its use in humans. OBJECTIVE: To describe our initial experience with HTNN and a stepwise transition towards PTNN. DESIGN, SETTING, AND PARTICIPANTS: Between May 2010 and September 2011, 63 patients underwent nephrectomy (60 HTNNs and 3 PTNNs) in our institution, including 45 patients with benign renal disease and 18 patients with malignant renal disease. SURGICAL PROCEDURE: Of the HTNNs, 33 were performed using two umbilical trocars and one transvaginal trocar, and 27 were performed using one umbilical trocar and a transvaginal multi-instrument access port; 3 PTNNs were performed using a self-developed, three-channel ZOU-port without any transumbilical assistance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All data referring to patient demographics, surgery, pathology, and perioperative outcomes were recorded. Sexual function was assessed with the Female Sexual Function Index (FSFI) questionnaire before and after surgery. The cosmetic result was investigated by administering the Patient Scar Assessment Questionnaire and Scoring System (PSAQ). RESULTS AND LIMITATIONS: A total of 59 HTNNs and 3 PTNNs were successfully performed. One patient was converted to open surgery because of injury to the inferior vena cava. The mean operative time was 130min (range: 100 260min) for HTNN and 193min (range: 180-210min) for PTNN. The mean estimated blood loss was 150ml. The mean postoperative hospital stay was 7.4 d. Forty-eight patients completed the FSFI questionnaire, and analysis did not show differences in FSFI scores before and after surgery. The better cosmetic results were confirmed by the PSAQ score. CONCLUSIONS: HTNN is feasible and safe in appropriate patients. Existing instruments are adequate for HTNN, but significant improvement is still needed. PTNN is technically challenging, but is feasible and may be performed safely. Further improvement of instruments is necessary for PTNN. Clinical investigation in comparison to the established techniques should take place to evaluate the outcome of technique. PATIENT SUMMARY: Pure transvaginal natural orifice transluminal endoscopic nephrectomy (PTNN) is technically challenging but feasible and may be performed safely. Further improvements in instruments are necessary for PTNN. PMID- 25837535 TI - Multi-Quadrant Biopsy Technique Improves Diagnostic Ability in Large Heterogeneous Renal Masses. AB - PURPOSE: Percutaneous biopsy obtained from a single location is prone to sampling error in large heterogeneous renal masses, leading to nondiagnostic results or failure to detect poor prognostic features. We evaluated the accuracy of percutaneous biopsy for large renal masses using a modified multi-quadrant technique vs a standard biopsy technique. MATERIALS AND METHODS: Clinical and pathological data for all patients with cT2 or greater renal masses who underwent percutaneous biopsy from 2009 to 2014 were reviewed. The multi-quadrant technique was defined as multiple core biopsies from at least 4 separate solid enhancing areas in the tumor. The incidence of nondiagnostic findings, sarcomatoid features and procedural complications was recorded, and concordance between biopsy specimens and nephrectomy pathology was compared. RESULTS: A total of 122 biopsies were performed for 117 tumors in 116 patients (46 using the standard biopsy technique and 76 using the multi-quadrant technique). Median tumor size was 10 cm (IQR 8-12). Biopsy was nondiagnostic in 5 of 46 (10.9%) standard and 0 of 76 (0%) multi-quadrant biopsies (p=0.007). Renal cell carcinoma was identified in 96 of 115 (82.0%) tumors and nonrenal cell carcinoma tumors were identified in 21 (18.0%). One complication occurred using the standard biopsy technique and no complications were reported using the multi-quadrant technique. Sarcomatoid features were present in 23 of 96 (23.9%) large renal cell carcinomas studied. Sensitivity for identifying sarcomatoid features was higher using the multi quadrant technique compared to the standard biopsy technique at 13 of 15 (86.7%) vs 2 of 8 (25.0%) (p=0.0062). CONCLUSIONS: The multi-quadrant percutaneous biopsy technique increases the ability to identify aggressive pathological features in large renal tumors and decreases nondiagnostic biopsy rates. PMID- 25837536 TI - Cystocele Repair by Autologous Rectus Fascia Graft: the Pubovaginal Cystocele Sling. AB - PURPOSE: The autologous rectus fascia pubovaginal sling has been a safe and effective means of correcting stress urinary incontinence. We tested the feasibility of using a larger graft to correct cystocele with or without stress urinary incontinence. MATERIALS AND METHODS: Between January 2006 and October 2010, 30 patients with symptomatic cystocele underwent the pubovaginal cystocele sling procedure, including 14 with and 16 without concomitant stress urinary incontinence. The technique is a modification of the standard pubovaginal sling procedure. A large trapezoidal (major base 6 cm, minor base 4 cm and height 5 cm) rectus fascia graft is used with 4 instead of 2 sutures to suspend the graft corners. The 2 sutures at the level of the mid urethra are tied above the rectus muscles in a tension-free manner while the 2 sutures at the level of the cervical fold are tied with tension. Data on anatomical outcomes (Baden-Walker classification), functional outcomes (PFIQ-7), post-void residual urine volume and urinary tract infection were prospectively collected. RESULTS: At a mean followup of 62.6 months (range 46 to 98) there was no recurrence in the anterior compartment. There was 1 recurrence involving the apical and posterior compartments. All patients reported a statistically significant improvement in PFIQ-7 score. When present preoperatively, post-void residual urine volume, urinary tract infection and stress urinary incontinence ceased in all cases. The only complication was donor site wound dehiscence without fascial involvement. CONCLUSIONS: The autologous pubovaginal cystocele sling seems to be a safe, effective technique to correct cystocele with or without stress urinary incontinence. PMID- 25837537 TI - Introduction. PMID- 25837538 TI - Eliminating a need for esophagectomy: endoscopic treatment of Barrett esophagus with early esophageal neoplasia. AB - Over the past several years, endoscopic ablation and resection have become a new standard of care in the management of Barrett esophagus (BE) with high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC). Risk factors for failure of endoscopic therapy and the need for subsequent esophagectomy have not been well elucidated. The aims of this study were to determine the efficacy of radiofrequency ablation (RFA) with or without endoscopic mucosal resection (EMR) in the management of BE with HGD or IMC, to discern factors predictive of endoscopic treatment failure, and to assess the effect of endoscopic therapies on esophagectomy volume at our institution. Data were obtained retrospectively for all patients who underwent endoscopic therapies or esophagectomy for a diagnosis of BE with HGD or IMC in our department between January 1, 2004, and December 31, 2012. Complete remission (CR) of BE or HGD or IMC was defined as 2 consecutive biopsy sessions without BE or HGD or IMC and no subsequent recurrence. Recurrence was defined by the return of BE or HGD or IMC after initial remission. Progression was defined as worsening of HGD to IMC or worsening of IMC to submucosal neoplasia or beyond. Overall, 57 patients underwent RFA with or without EMR for BE with HGD (n = 45) or IMC (n = 12) between 2007 and 2012, with a median follow-up duration of 35.4 months (range: 18.5-52.0 months). The 57 patients underwent 181 ablation sessions and more than half (61%) of patients underwent EMR as a component of treatment. There were no major procedural complications or deaths, with only 2 minor complications including 1 symptomatic stricture requiring dilation. Multifocal HGD or IMC was present in 43% (25/57) of patients. CR of IMC was achieved in 100% (12/12) at a median of 6.1 months, CR of dysplasia was achieved in 79% (45/57) at a median of 11.5 months, and CR of BE was achieved in 49% (28/57) at a median of 18.4 months. Following initial remission, 28% of patients (16/57) had recurrence of dysplasia (n = 12) or BE (n = 4). Progression to IMC occurred in 7% (4/57). All patients without CR continue endoscopic treatment. No patient required esophagectomy or developed metastatic disease. Overall, 6 patients died during the follow-up interval, none from esophageal cancer. Factors associated with failure to achieve CR of BE included increasing length of BE (6.0 +/- 0.6 vs 4.0 +/- 0.6cm, P = 0.03) and shorter duration of follow-up (28.5 +/- 3.8 months vs 49.0 +/- 5.8 months, P = 0.004). Shorter surveillance duration (17.8 +/- 7.6 months vs 63.9 +/- 14.4 months, P = 0.009) and shorter follow-up (21.1 +/- 6.1 months vs 43.2 +/- 4.1 months) were the only significant factors associated with failure to eradicate dysplasia. Our use of esophagectomy as primary therapy for BE with HGD or IMC has diminished since we began using endoscopic therapies in 2007. From a maximum of 16 esophagectomies per year for early Barrett neoplasia in 2006, we performed only 3 esophageal resections for such early disease in 2012, all for IMC, and we have not performed an esophagectomy for HGD since 2008. Although recurrence of BE or dysplasia/IMC was not uncommon, RFA with or without EMR ultimately resulted in CR of IMC in all patients, CR of HGD in the majority (79%), and CR of BE in nearly half (49%). No patient treated endoscopically for HGD or IMC subsequently required esophagectomy. In patients with BE with HGD or IMC, RFA and EMR are safe and highly effective. The use of endoscopic therapies appears justified as the new standard of care in most cases of BE with early esophageal neoplasia. PMID- 25837539 TI - Editorial commentary: Endoscopically closing doors. PMID- 25837540 TI - Incidence and risk factors for respiratory complications in patients undergoing esophagectomy for malignancy: a NSQIP analysis. AB - Respiratory complications are the most frequent adverse events in patients undergoing esophagectomy for cancer, and their occurrence may negatively affect postoperative recovery and outcomes. We queried the American College of Surgeons National Surgical Quality Improvement Program dataset to study the rate and influence of pneumonia, unplanned intubation, and ventilator dependency >48 hours on the early outcomes after esophagectomy and risk factors for their development. We included adult patients with an esophageal or gastric cancer diagnosis who were treated with esophagectomy between 2005 and 2012 and grouped them into 2 categories with respect to development of respiratory complications. Early surgical outcomes (including 30-day mortality, overall morbidity, return to operating room, and length of hospital stay) were compared. Risk factors associated with respiratory complications after esophagectomy were assessed using modified Poisson regression. A total of 2945 patients were identified and respiratory complications were observed in 687 (23.3%) of them. We observed a significant decrease in respiratory complication rates after esophagectomy throughout the studied years. Patients who developed respiratory complications were older and had more comorbidities and longer operative time. These patients also had statistically significantly higher rates of 30-day mortality and overall morbidity and were more likely to return to the operating room and to stay in the hospital longer. On multivariable analysis, numerous factors, including advanced age, smoking, alcohol use, dyspnea, history of chronic obstructive pulmonary disease, and prolonged operative time, were found to be risk factors for developing respiratory complications. As the development of respiratory complications leads to worse early surgical outcomes after esophagectomy, efforts should be made to prevent their occurrence by identifying patients with significant risk factors. PMID- 25837541 TI - Editorial commentary: Esophageal complications: what are the real results? PMID- 25837542 TI - Technical performance score as predictor for post-discharge reintervention in valve-sparing tetralogy of Fallot repair. AB - Recognition of late problems following repair of tetralogy of Fallot (TOF) with a transannular patch has stimulated modifications to preserve pulmonary valve (PV) function. This study assesses the ability of technical performance score (TPS) to determine the need for post-discharge reinterventions (RIs) in valve-sparing TOF repair. We retrospectively reviewed 157 patients following valve-sparing repair of TOF from 2007-2012. We assigned TPS as Class 1 (optimal), Class 2 (adequate), or Class 3 (inadequate) based on discharge echo and clinical criteria. Preoperative, discharge, and follow-up PV Z scores and post-discharge RIs were documented. Reasons for Class 2 or 3 designation were right ventricular outflow tract (RVOT) gradient in 52, pulmonary regurgitation in 13, residual ventricular septal defects in 7, both RVOT gradient and ventricular septal defects in 13, and both RVOT gradient and pulmonary regurgitation in 37 patients. Median follow-up was 19.6 (range: 0.1-86.1) months. Class 3 patients had a significantly longer median intensive care unit and hospital stay compared with Class 1 (3 vs 2 days [P = 0.015] and 7 vs 5 days [P < 0.001], respectively). Post-discharge RIs were significantly lower in Class 1 vs Class 2 and Class 3 (P = 0.003). Class 1 patients had significantly larger PV Z scores compared with Class 2 or Class 3 patients (P < 0.001). TPS is associated with post-discharge RI rate after valve sparing TOF repair. Preoperative PV Z score is highly correlated with Class I TPS. Patient selection based on preoperative PV Z scores may help determine if valve-sparing approach is appropriate, thus minimizing the need for RIs. PMID- 25837544 TI - You be the judge: is long-term benefit worth the early risk? PMID- 25837543 TI - Editorial commentary: Technical performance anxiety: utility of the technical performance scale in predicting later intervention after repair of tetralogy of Fallot. PMID- 25837545 TI - The theory, practice, and future of process improvement in general thoracic surgery. AB - Process improvement, in its broadest sense, is the analysis of a given set of actions with the aim of elevating quality and reducing costs. The tenets of process improvement have been applied to medicine in increasing frequency for at least the last quarter century including thoracic surgery. This review outlines the theory underlying process improvement, the currently available data sources for process improvement and possible future directions of research. PMID- 25837546 TI - The International Thymic Malignancy Interest Group thymic initiative: a state-of the-art study of thymic malignancies. AB - Thymic malignancies are relatively rare tumors. A general lack of knowledge, misconceptions about benignancy, confusion about the definition of terms, and variability in reporting of outcomes have further hampered progress in these diseases. The International Thymic Malignancy Interest Group has emerged to counter these challenges and has brought together a worldwide multidisciplinary community determined to improve outcomes for these patients. Although the organization is young (initiated in 2010), major early accomplishments have created a foundation and infrastructure for scientific research. These include consensus definitions of terms, an unprecedented global database, development of practical clinical resources and, together with the International Association for the Study of Lung Cancer, development of proposals for the first formal stage classification of these malignant tumors. Many articles have been published or are under way, and a second phase of projects building on the early success is proceeding. The greatest accomplishment of the International Thymic Malignancy Interest Group lies in the establishment of an open culture of collaboration and the engagement of a broad group of individuals united by a common mission. It is a testament to what can be achieved, despite ongoing and inherent challenges, by determination and a collective effort. PMID- 25837547 TI - Current readings: Window-of-opportunity trials for thoracic malignancies. AB - Recent major advances in metastatic non-small cell lung cancer have occurred with the identification of molecular biomarker targets and administration of novel agents with resulting improvement in clinical outcomes. In the early-stage setting, personalized therapy with novel agents and molecular profiling are being incorporated into neoadjuvant "window-of-opportunity" trials. These important studies enable biomarker research and an expedited analysis of the efficacy of the targeted agent. However, there are significant limitations to window-of opportunity trials. The aim of this article is to review the current window-of opportunity trials of neoadjuvant targeted agents for thoracic malignancies, discuss the benefits and limitations of these trials, and propose more optimal alternative trial end points. Neoadjuvant trials of resectable non-small cell lung cancer and mesothelioma that are ongoing or under development and relevant to thoracic surgeons are also discussed. The success of these trials will depend on a collaborative multidisciplinary effort, especially from the field of thoracic surgery. PMID- 25837548 TI - Current readings: Failed hiatal hernia repair. AB - Recurrent hiatal hernia is noted in up to 70% of patients undergoing reoperative antireflux procedure. Role of short esophagus vis-a-vis a need for Collis gastroplasty, mesh reinforcement of hiatus, and access of surgery (thoracotomy vs laparotomy) have been debated. The aim of this article is to review selected recent publications that address these issues. PMID- 25837549 TI - Creativity is linked to ambition across the bipolar spectrum. AB - OBJECTIVE: Beyond evidence for an association, little is known about the mechanism linking creativity bipolar spectrum conditions. Theory suggests that ambition, which is heightened in bipolar disorder (BD) and associated with creativity in the general population, might be an important variable. The overarching aim of this project was to evaluate whether ambition is related to creativity among those with bipolar spectrum conditions. METHOD: Across two studies, we examined correlations between a validated self-report measure of ambition, the WASSUP, and creativity. In Study One, 22 individuals diagnosed with BD who self-identified as highly creative completed the WASSUP and a measure of lifetime creative accomplishment. In Study Two, 221 undergraduates completed the WASSUP, a measure of mania risk (the Hypomanic Personality Scale, HPS) and a measure designed to assess creativity in business projects and tasks. RESULTS: In Study One, WASSUP scores were significantly elevated compared to normative levels in BD, and WASSUP scores were correlated with lifetime creative accomplishment within the artistic sample. In Study Two, mania risk was related to greater ambition and creativity, and ambition was also directly related to greater creativity. LIMITATIONS: Both studies were limited by the reliance on self reported ambition. CONCLUSION: Ambition could be one important component of creative success across the bipolar spectrum. PMID- 25837550 TI - Modifiable partner factors associated with perinatal depression and anxiety: a systematic review and meta-analysis. AB - BACKGROUND: Perinatal distress is a significant public health problem that adversely impacts the individual and their family. The primary objective of this systematic review and meta-analysis was to identify factors that partners can modify to protect each other from developing perinatal depression and anxiety. METHOD: In accordance with the PRISMA statement, we reviewed the risk and protective factors associated with perinatal depression and anxiety symptoms that partners can potentially modify without professional assistance (PROSPERO reference CRD42014007524). Participants were new or expectant parents aged 16 years or older. The partner factors were sub-grouped into themes (e.g., instrumental support) based on a content analysis of the scale items and measure descriptions. A series of meta-analyses were conducted to estimate the pooled effect sizes of associations. RESULTS: We included 120 publications, reporting 245 associations with depression and 44 with anxiety. Partner factors with sound evidence that they protect against both perinatal depression and anxiety are: emotional closeness and global support. Partner factors with a sound evidence base for depression only are communication, conflict, emotional and instrumental support, and relationship satisfaction. LIMITATIONS: This review is limited by the lack of generalizability to single parents and the inability to systematically review moderators and mediators, or control for baseline symptoms. CONCLUSION: The findings suggest that future prevention programs targeting perinatal depression and anxiety should aim to enhance relationship satisfaction, communication, and emotional closeness, facilitate instrumental and emotional support, and minimize conflict between partners. PMID- 25837551 TI - Cross-cultural adaptation, validation and factor structure of the Insight Scale for Affective Disorders. AB - BACKGROUND: In the last few decades, several tools for studying insight in bipolar disorders have been used. Olaya and colleagues developed the Insight Scale for Affective Disorders (ISAD), which consists of a scale measuring insight through hetero evaluation for patients with mood disorders. The objective of this work is to translate and adapt the original English version of the ISAD to Brazilian Portuguese (ISAD-BR) and to conduct an evaluation of its psychometric properties. METHODS: Adaptation procedures included translation/back-translation and consultation with a panel of experts. 95 patients with the diagnosis of Type 1 bipolar disorder were evaluated with the final version of the ISAD-BR, which was applied, simultaneously, but independently, by two examiners. Internal consistency and inter-rater reliability were explored and the latent structure of the scale was investigated with principal axis factoring and promax rotation. A second-order factor analysis was conducted to test if the scale had a hierarchical factor structure. RESULTS: The ISAD-BR showed good internal consistency and good inter-rater reliability. The analysis pointed to a four factor solution of the ISAD-BR: awareness of symptoms associated with activity/energy; awareness of having a disorder; awareness of self-esteem and feelings of pleasure; and awareness of social functioning and relationships. The second order factor analysis indicated a hierarchical factor structure for the ISAD-BR, with the four lower-order factors loading on a single higher-order factor. CONCLUSIONS: Insight into bipolar disorder is a multidimensional construct, covering different aspects of the condition and its symptomatology. Nevertheless, insight about activity/energy changes may be a crucial aspect of insight into bipolar disorder. PMID- 25837553 TI - Patterning gold nanoparticles in liquid environment with high ionic strength for local fabrication of up to 100 MUm long metallic interconnections. AB - Metallic interconnections were fabricated in situ using the FluidFM as scanning probe lithography tool. In contrast to other SPL tools, the closed fluidic circuit of the FluidFM enables a pressure-controlled deposition of metallic nanoparticles in liquid environment. Taking advantage of the salt concentration of the liquid environment (i.e. the ionic strength) to tailor the resulting particle density in the deposited layer, a protocol was established for direct patterning of conductive interconnecting structures. The FluidFM microchannel was filled with an aqueous solution of negatively charged gold nanoparticles (AuNPs) to be delivered onto a glass surface coated with a polycation favoring electrostatic adhesion. The deposited structures were analyzed both topographically and electrically to optimize the external parameters such as contact time, salt concentration of the liquid environment and size of the AuNPs. Using this optimized protocol we succeeded in the local fabrication of conductive metallic wires between two prefabricated macroelectrodes in liquid environment. In a subsequent step, the conductivity of the deposited structure was improved by gold annealing. PMID- 25837552 TI - Effects of increased surface coverage of polyvinylpyrrolidone over a polysulfone hemofilter membrane on permeability and cell adhesion during continuous hemofiltration. AB - The purpose of the present study was to evaluate the adhesiveness of blood cells and the solute removal performance change of modified polysulfone membranes which have increased polyvinylpyrrolidone (PVP) coverage over their surface. Continuous hemofiltration (CHF) experiments for 24 h were carried out using an ex vivo hemofilter evaluation system to compare a modified polysulfone hemofilter (SHG) with the conventional polysulfone hemofilter (SH). The 25 and 50 % cutoff values of the sieving coefficient of dextran after CHF and the protein concentration in the filtrate was higher in SHG, indicating that less fouling occurred in the SHG membrane. Adhesion of blood cells after 24 h of CHF was significantly higher in the case of SH than in the case of SHG. Blood cell adhesion and membrane fouling were reduced with the use of a polysulfone membrane modified with increased PVP coverage over the surface. PMID- 25837554 TI - Mechanism of Co-C bond photolysis in methylcobalamin: influence of axial base. AB - A mechanism of Co-C bond photolysis in the base-off form of the methylcobalamin cofactor (MeCbl) and the influence of its axial base on Co-C bond photodissociation has been investigated by time-dependent density functional theory (TD-DFT). At low pH, the MeCbl cofactor adopts the base-off form in which the axial nitrogenous ligand is replaced by a water molecule. Ultrafast excited state dynamics and photolysis studies have revealed that a new channel for rapid nonradiative decay in base-off MeCbl is opened, which competes with bond dissociation. To explain these experimental findings, the corresponding potential energy surface of the S1 state was constructed as a function of Co-C and Co-O bond distances, and the manifold of low-lying triplets was plotted as a function of Co-C bond length. In contrast to the base-on form of MeCbl in which two possible photodissociation pathways were identified on the basis of whether the Co-C bond (path A) or axial Co-N bond (path B) elongates first, only path B is active in base-off MeCbl. Specifically, path A is inactive because the energy barrier associated with direct dissociation of the methyl ligand is higher than the barrier of intersection between two different electronic states: a metal-to ligand charge transfer state (MLCT), and a ligand field state (LF) along the Co-O coordinate of the S1 PES. Path B initially involves displacement of the water molecule, followed by the formation of an LF-type intermediate, which possesses a very shallow energy minimum with respect to the Co-C coordinate. This LF-type intermediate on path B may result in either S1/S0 internal conversion or singlet radical pair generation. In addition, intersystem crossing (ISC) resulting in generation of a triplet radical pair is also feasible. PMID- 25837556 TI - Chronic exposure to aluminum, nickel, thallium and uranium and their relationship with essential elements in human whole blood and blood serum. AB - This study aimed to evaluate the influence of exposure to aluminum, nickel, thallium and uranium on the metabolism of essential elements in humans, as well as the relationship between uranium, thallium, nickel, and aluminum and essential elements (Ca, Mg, Zn, Se, Mn, Co, Cr, and Mo) in the whole blood and blood serum of healthy men who were occupationally exposed. This study included 97 healthy men, 31-64 years age, including 70 workers in a thermo power plant and 27 control subjects. The results showed that chronic, moderate exposure of trace elements (Al, Ni, Tl, and U) lead to decreased serum chromium (SCr) and blood molybdenum levels (BMo), whereas by the results achieved in terms of correlations between non-essential and essential elements, non-essential elements such as uranium, thallium, nickel, and aluminum, despite their concentration within the reference values, are strongly competitive with essential elements in biochemical processes. PMID- 25837557 TI - Comparative estimation of soil and plant pollution in the impact area of air emissions from an aluminium plant after technogenic load reduction. AB - The work provides a comparative analysis of changes in soil properties in the last 10-13 years along the pollution gradient of air emissions from Kandalaksha aluminium plant in connection with the reduction of their volume. The content of the priority pollutant fluorine (F) in atmospheric precipitation and in the organic horizon of soil in the plant impact zone significantly decreased in 2011 2013 compared to 2001. The aluminium concentrations reduced only in immediate proximity to the plant (2 km). The fluorine, calcium (Ca) and magnesium (Mg) concentrations are higher in liquid phase compared to solid phase thus these elements can migrated to greater distances from the pollution source (up to 15-20 km). Silicon (Si), aluminium (Al), iron (Fe) and phosphorus (P) can be found only in solid phases and in fall-out within the 5 km. The acidity of soil litter reduced by 2 pH units in the proximity to the plot within the 2 km. The zone of maximum soil contamination decreased from 2.5 km to 1.5 km from the emission source, the zones of heavy and moderate pollution reduced by 5 km in connection with the reduction of pollutant emissions in the plant. A high correlation between the fluorine concentrations in vegetables and litter was found. Higher fluorine concentrations in the soil result in its accumulation in plants. Mosses accumulate fluorine most intensively. PMID- 25837555 TI - Factors associated with blood lead concentrations of children in Jamaica. AB - Lead is a heavy metal known to be detrimental to neurologic, physiologic, and behavioral health of children. Previous studies from Jamaica reported that mean lead levels in soil are four times that of lead levels in some other parts of the world. Other studies detected lead levels in fruits and root vegetables, which were grown in areas with lead contaminated soil. In this study, we investigate environmental factors associated with blood lead concentrations in Jamaican children. The participants in this study comprised 125 typically developing (TD) children (ages 2-8 years) who served as controls in an age- and sex-matched case control study that enrolled children from 2009-2012 in Jamaica. We administered a questionnaire to assess demographic and socioeconomic information as well as potential exposures to lead through food. Using General Linear Models (GLMs), we identified factors associated with blood lead concentrations in Jamaican children. The geometric mean blood lead concentration (GMBLC) in the sample of children in this study was 2.80 MUg dL(-1). In univariable GLM analyses, GMBLC was higher for children whose parents did not have education beyond high school compared to those whose parents had attained this level (3.00 MUg dL(-1) vs. 2.31 MUg dL(-1); P = 0.05), children living near a high traffic road compared to those who did not (3.43 MUg dL(-1) vs. 2.52 MUg dL(-1); P < 0.01), and children who reported eating ackee compared to those who did not eat this fruit (2.89 MUg dL( 1) vs. 1.65 MUg dL(-1); P < 0.05). In multivariable analysis, living near a high traffic road was identified as an independent risk factor for higher adjusted GMBLC (3.05 MUg dL(-1) vs. 2.19 MUg dL(-1); P = 0.01). While our findings indicate that GMBLC in Jamaican children has dropped by at least 62% during the past two decades, children living in Jamaica still have GMBLC that is twice that of children in more developed countries. In addition, we have identified significant risk factors for higher blood lead concentrations in Jamaican children. We believe increasing awareness among parents regarding these risk factors could potentially lead to a lower level of lead exposure in Jamaican children. PMID- 25837558 TI - Iron-based catalysts for photocatalytic ozonation of some emerging pollutants of wastewater. AB - A synthetic secondary effluent containing an aqueous mixture of emerging contaminants (ECs) has been treated by photocatalytic ozonation using Fe(3+) or Fe3O4 as catalysts and black light lamps as the radiation source. For comparative purposes, ECs have also been treated by ultraviolet radiation (UVA radiation, black light) and ozonation (pH 3 and 7). With the exception of UVA radiation, O3 based processes lead to the total removal of ECs in the mixture. The time taken to achieve complete degradation depends on the oxidation process applied. Ozonation at pH 3 is the most effective technique. The addition of iron based catalysts results in a slight inhibition of the parent compounds degradation rate. However, a positive effect is experienced when measuring the total organic carbon (TOC) and the chemical oxygen demand (COD) removals. Photocatalytic oxidation in the presence of Fe(3+) leads to 81% and 88% of TOC and COD elimination, respectively, compared to only 23% and 29% of TOC and COD removals achieved by single ozonation. The RCT concept has been used to predict the theoretical ECs profiles in the homogeneous photocatalytic oxidation process studied. Treated wastewater effluent was toxic to Daphnia magna when Fe(3+) was used in photocatalytic ozonation. In this case, toxicity was likely due to the ferryoxalate formed in the process. Single ozonation significantly reduced the toxicity of the treated wastewater. PMID- 25837559 TI - The removal of Microcystis ichthyoblabe cells and its hepatotoxin microcystin-LR during electrooxidation process using Pt/Ti electrodes. AB - Electrooxidation is widely used to remove harmful organic and inorganic substances as well as pathogenic microorganisms. This study investigates the removal of Microcystis ichthyoblabe cells and their hepatotoxin microcystin-LR by the electrooxidation process using Pt/Ti electrodes. Additionally, the morphology changes and cell sizes were determined by scanning electron microscopy and a particle size analyzer, respectively. The algal cells were severely damaged by the electrooxidation process. During the initial treatment, intracellular microcystin-LR was released from the cells, increasing the extracellular microcystin-LR concentration. The electrooxidation charge required to remove cells and MC-LR was 3 * 10(4) C and 6 * 10(4) C, respectively. The removal efficiencies of M. ichthyoblabe cells and microcystin-LR were insensitive to initial cell density, initial microcystin-LR concentration and solution conductivity, but were heavily reduced at large algal suspension volume. Therefore, to achieve simultaneous removal of Microcystis cells and their MC, it is necessary to control the volume of algal suspension. PMID- 25837560 TI - Assessment of heavy metals pollution using AVS-SEM and fractionation techniques in Edku Lagoon sediments, Mediterranean Sea, Egypt. AB - A method is presented to evaluate the fractionation of metals (Fe, Zn, Cu, Pb, Cd and Ni), acid volatile sulfide (AVS) and simultaneously extracted metals (SEM) in Edku lagoon sediments. Thirteen sediment samples were collected from the study area in the period of 2010-2011 to assess the potential bioavailability and toxicity of the selected metals. According to classification of the Interim Sediment Quality Quidelines (ISQG), five stations near the drains exhibited 10% toxic probability. The high AVS and low ?SEM ranges in Summer were identified as 6-138 and 0.86-3.3 umol g(-1) dry wet, respectively which are referring to the low mobility of heavy metals in this season and vice versa for winter (2.5-23.9 and 1.16-3.82 umol g(-1) dry wet, respectively). According to the evaluation of USEPA, all sediment samples showed ?SEM/AVS < 1 and SigmaSEM-AVS < 0 and this indicates that Edku lagoon sediments didn't cause any adverse effects. Meanwhile, the calculations of the global contamination factor (GCF) and the individual contamination factors (ICF) using fractionation technique gave values of 111.644 and 84.555 in El Bosily drain and station 1 near the cages of fish farm, respectively due to possible contamination. Interestingly, the collected data refer that the mobility and bioavailability of heavy metals in Edku lagoon sediments posed a low risk of adverse biological effects due to cadmium, copper, lead, nickel and zinc in all evaluated stations. PMID- 25837561 TI - Microalgae: cultivation techniques and wastewater phycoremediation. AB - Generation of liquid and gaseous effluents is associated with almost all anthropogenic activities. The discharge of these effluents into the environment without treatment has reduced the availability and quality of natural resources, representing a serious threat to the balance of different ecosystems and human health. Universal access to water and global warming are topics of intense concern and are listed as priorities in the vast majority of global scientific, social and political guidelines. Conventional techniques to treat liquid and gaseous effluents pose economic and/or environmental limitations that prevent their use in certain applications. The technique of phycoremediation, which uses microalgae, macroalgae, and cyanobacteria for the removal or biotransformation of pollutants, is an emerging technology that has been highlighted due to its economic viability and environmental sustainability. This literature review discusses different techniques of microalgae cultivation and their use in the phycoremediation of contaminants in wastewater. PMID- 25837562 TI - Microbacterium oxydans and Microbacterium liquefaciens: a biological alternative for the treatment of Ni-V-containing wastes. AB - The present study evaluated 15 isolates obtained of environmental samples capable of tolerating high Ni and V concentrations. Those coded as MNSH2-PHGII-1, MNSH2 PHGII-2 and MV-PHGII-2 showed a minimum inhibitory concentration higher than 200 ppm for Ni and V and showed removal percentages corresponding to 84, 75 and 26% for Ni and 60, 55 and 20.3% for V, respectively, in liquid medium. When spent catalyst was added at 16% (w/v) pulp density, the highest Ni and V removal corresponded to MNSH2-PHGII-1 and MNSH2-PHGII-2, which were identified as Microbacterium oxydans and Microbacterium liquefaciens respectively, Microbacterium oxydans was able to remove Ni at the extent of 45.4% and V at 30.4% while Microbacterium liquefaciens removed Ni at 51% and V at 41.4% from the spent catalyst. The isolate MV-PHGII-2 identified also as Microbacterium oxydans showed the lowest removal for Ni and V corresponding to 16% and 9.5%, respectively. This is the first report where strains of Microbacterium were tested for their abilities to remove Ni and V from spent catalyst, suggesting its potential use in the treatment of this solid industrial waste. PMID- 25837563 TI - Effects of biosurfactant-producing bacteria on biodegradation and transport of phenanthrene in subsurface soil. AB - This study investigated the effects of surfactant-producing microorganism, Pseudomonas aeruginosa ATCC 9027, on phenanthrene (PHE) biodegradation by two different PHE-degrading bacteria (Isolate P5-2 and Pseudomonas strain R) in soil. Phenanthrene mineralization experiments were conducted with soils inoculated with one of PHE-degraders and/or the surfactant-producer. Influence of co-inoculation with the surfactant-producing bacteria on phenanthrene transport and biodegradation was also examined in soil columns. P. strain R mineralized phenanthrene faster and to a greater extent than Isolate P5-2 in the test soil. Co-inoculation with the surfactant-producing bacteria significantly enhanced phenanthrene biodegradation by P. strain R but it did not affect the biodegradation by Isolate P5-2 in both batch and column systems. Production of biosurfactants by P. aeruginosa ATCC 9027 was negligible under the given conditions. This study demonstrated that bioaugmentation with surfactant producing bacteria could enhance in situ bioremediation of soils contaminated with polycyclic aromatic hydrocarbons (PAHs) and the beneficial effect of the bioaugmentation depended on types of PAH-degrading microorganisms present. PMID- 25837564 TI - Two-stage electrochemical treatment of bio-digested distillery spent wash using stainless steel and aluminum electrodes. AB - The objective of this study was to determine the effectiveness of two-stage electro-coagulation (EC) process using multi-parameter optimization for treating bio-digested distillery spent wash by stainless steel (SS) and aluminum (Al) electrodes. Operating parameters have been optimized and treatment efficiency of SS and Al electrodes have been compared by central composite design of response surface analysis in terms of COD, color and total organic carbon (TOC) removal. Individual and interactive effects of four independent parameters namely initial pH (pHo: 2-10 and 4-10 for SS and Al electrodes, respectively), current density (j: 30.86-154.32 A m(-2)), inter-electrode distance (g: 0.5-2.5 cm) and electrolysis time (t: 30-150 min) on the COD, color and TOC removal efficiency were evaluated for both the electrodes. SS electrode was found to be more effective for the removal of COD, color and TOC with removal efficiencies of 70%, 93% and 72%, respectively, as compared to Al electrode, which showed respective removal efficiencies of 59%, 80% and 55%. A two-stage EC process was also conducted to study the predominance of different types of electrodes, and to increase the efficiency of EC process. Results shows that SS followed by Al electrode (with total COD, color and TOC removal efficiency of 81%, 94% and 78%, respectively) was found to be more effective than Al followed by SS electrode combination (with total COD, color and TOC removal efficiency of 78%, 89% and 76%, respectively). Present study shows that EC process can be used as an additional step to bio-methanation process so as to meet effluent discharge standards in distilleries. PMID- 25837565 TI - Environmental footprint of constructed wetlands treating wastewater. AB - The aim of the study is to determine environmentally friendlier construction materials for constructed wetland facilities treating wastewater. This is done by computing the environmental footprint of the facility based on the methodology of life cycle assessment (LCA). This methodology reveals the dominant aggravating processes during the construction of a constructed wetland (CW) and can help to create alternative environmentally friendlier solutions. This methodology was applied for the determination of the overall environmental profile of a hybrid CW facility. The LCA was applied first to the facility as originally designed, where reinforced concrete was used in some components. Then, alternative construction materials to reinforced concrete were used, such as earth covered with high density polyethylene (HDPE) or clay, and LCA was applied again. Earth structures were found to have reduced environmental impact compared to concrete ones, and clay was found environmentally friendlier compared to HDPE. Furthermore, estimation of the construction costs of the three scenarios indicate that the last scenario is also the least expensive. PMID- 25837566 TI - Effects of black liquor shocks on activated sludge treatment of bleached kraft pulp mill wastewater. AB - Kraft pulp mills use activated sludge systems to remove organic matter from effluents. Process streams may appear as toxic spills in treatment plant effluents, such as black liquor, which is toxic to microorganisms of the activated sludge. The present study evaluates the effects of black liquor shocks in activated sludge systems. Four black liquor shocks from 883 to 3,225 mg chemical oxygen demand-COD L(-1) were applied during 24 hours in a continuously operating lab-scale activated sludge system. Removal efficiencies of COD, color and specific compounds were determined. Moreover, specific oxygen uptake rate (SOUR), sludge volumetric index (SVI) and indicator microorganisms were evaluated. Results show that the addition of black liquor caused an increase in COD removal (76-67%) immediately post shock; followed two days later by a decrease (-19-50%). On the other hand, SOUR ranged between 0.152 and 0.336 mgO2 g(-1) volatile suspended solids-VSS* min(-1) during shocks, but the initial value was reestablished at hour 24. When the COD concentration of the shock was higher than 1,014 mg/L, the abundance of stalked ciliates and rotifers dropped. Finally, no changes in SVI were observed, with values remaining in the range 65.8-40.2 mL g(-1) total suspended solids-TSS during the entire operating process. Based on the results, the principal conclusion is that the activated sludge system with the biomass adapted to the kraft pulp effluent could resist a black liquor shock with 3,225 mgCOD L(-1) of concentration during 24 h, under this study's conditions. PMID- 25837567 TI - Activity of Andrographolide and Its Derivatives on HPV16 Pseudovirus Infection and Viral Oncogene Expression in Cervical Carcinoma Cells. AB - Andrographolide (Androg) has been reported to contain antiviral and antitumor activities, but the effects of Androg on human papillomavirus (HPV) infection and cervical cancer have not been elucidated. This study investigated the effects of Androg and its derivatives, namely, 14-deoxy-11,12-didehydroandrographolide (14 DDA) and 3,19-isopropylidene andrographolide (IPAD), on HPV16 pseudovirus (HPV16PsV) infectivity, HPV16 E6 oncogene expression and cervical cancer cell apoptosis. The result demonstrated that all compounds inhibited HPV16PsV infection and that 14-DDA showed the highest potency. Only Androg suppressed long control region (LCR) transcription activity of HPV16 in transiently transfected C33A cells and significantly inhibited E6 oncogene expression in SiHa cells in a dose-dependent manner. A twofold subcytotoxic concentration of IPAD exhibited an inhibitory effect on E6 oncogene expression at 48-h posttreatment. Interestingly, p53 protein was restored in a downstream process and was detected earlier by IPAD treatment than by Androg treatment. This result corresponded to the level of cell apoptosis and cell cycle arrest at the G2/M phase. E6 oncogene expression was also suppressed in CaSki cells treated with Androg and IPAD leading to cell apoptosis. These findings imply that Androg and its derivatives have different activities and may be effective agents for HPV prevention and cervical cancer treatment. PMID- 25837568 TI - SplitCore Technology Allows Efficient Production of Virus-Like Particles Presenting a Receptor-Contacting Epitope of Human IgE. AB - Immunoglobulin E (IgE) plays a central role in type I hypersensitivity including allergy and asthma. Novel treatment strategy envisages development of a therapeutic vaccine designed to elicit autologous blocking antibodies against the IgE. We sought to develop an IgE-epitope antigen that induces antibodies against a receptor-contacting epitope on human IgE molecule. We designed the VLP immunogens which utilize hepatitis B virus core protein (HBcAg) as a carrier, and present arrays of the receptor-contacting epitopes of the human IgE on their surfaces. FG loop from the IgE domain Cepsilon3 was engineered into the HBcAg. Two constructs explore a well-established approach of insertion into a main immunodominant region of the HBcAg. Third construct is different in that the carrier is produced in a form of an assembly of two polypeptide chains which upon expression remain associated in a stable VLP-forming subunit (SplitCore technology). No VLPs were isolated from E.coli expressing the IgE-epitope antigens with contiguous sequences. On the contrary, the SplitCore antigen carrying the FG loop efficiently formed the VLPs. Immunization of mice with the VLPs presenting receptor-contacting epitope of the IgE elicited antibodies recognizing the human IgE in ELISA. PMID- 25837569 TI - A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): a retrospective cohort study. AB - BACKGROUND: Enterovirus D68 was implicated in a widespread outbreak of severe respiratory illness across the USA in 2014 and has also been reported sporadically in patients with acute flaccid myelitis. We aimed to investigate the association between enterovirus D68 infection and acute flaccid myelitis during the 2014 enterovirus D68 respiratory outbreak in the USA. METHODS: Patients with acute flaccid myelitis who presented to two hospitals in Colorado and California, USA, between Nov 24, 2013, and Oct 11, 2014, were included in the study. Additional cases identified from Jan 1, 2012, to Oct 4, 2014, via statewide surveillance were provided by the California Department of Public Health. We investigated the cause of these cases by metagenomic next-generation sequencing, viral genome recovery, and enterovirus D68 phylogenetic analysis. We compared patients with acute flaccid myelitis who were positive for enterovirus D68 with those with acute flaccid myelitis but negative for enterovirus D68 using the two tailed Fisher's exact test, two-sample unpaired t test, and Mann-Whitney U test. FINDINGS: 48 patients were included: 25 with acute flaccid myelitis, two with enterovirus-associated encephalitis, five with enterovirus-D68-associated upper respiratory illness, and 16 with aseptic meningitis or encephalitis who tested positive for enterovirus. Enterovirus D68 was detected in respiratory secretions from seven (64%) of 11 patients comprising two temporally and geographically linked acute flaccid myelitis clusters at the height of the 2014 outbreak, and from 12 (48%) of 25 patients with acute flaccid myelitis overall. Phylogenetic analysis revealed that all enterovirus D68 sequences associated with acute flaccid myelitis grouped into a clade B1 strain that emerged in 2010. Of six coding polymorphisms in the clade B1 enterovirus D68 polyprotein, five were present in neuropathogenic poliovirus or enterovirus D70, or both. One child with acute flaccid myelitis and a sibling with only upper respiratory illness were both infected by identical enterovirus D68 strains. Enterovirus D68 viraemia was identified in a child experiencing acute neurological progression of his paralytic illness. Deep metagenomic sequencing of cerebrospinal fluid from 14 patients with acute flaccid myelitis did not reveal evidence of an alternative infectious cause to enterovirus D68. INTERPRETATION: These findings strengthen the putative association between enterovirus D68 and acute flaccid myelitis and the contention that acute flaccid myelitis is a rare yet severe clinical manifestation of enterovirus D68 infection in susceptible hosts. FUNDING: National Institutes of Health, University of California, Abbott Laboratories, and the Centers for Disease Control and Prevention. PMID- 25837570 TI - Can sequence data predict enterovirus D68 infection outcome? PMID- 25837571 TI - High resolution synoptic salinity mapping to identify groundwater--surface water discharges in lowland rivers. AB - Quantifying distributed lateral groundwater contributions to surface water (GW-SW discharges) is a key aspect of tracking nonpoint-source pollution (NPSP) within a watershed. In this study, we characterized distributed GW-SW discharges and associated salt loading using elevated GW specific conductance (SC) as a tracer along a 38 km reach of the Lower Merced River in Central California. High resolution longitudinal surveys for multiple flows (1.3-150 m(3) s(-1)) revealed river SC gradients that mainly decreased with increasing flow, suggesting a dilution effect and/or reduced GW-SW discharges due to hydraulic gradient reductions. However, exceptions occurred (gradients increasing with increasing flow), pointing to complex spatiotemporal influences on GW-SW dynamics. The surveys revealed detailed variability in salinity gradients, from which we estimated distributed GW-SW discharge and salt loading using a simple mixing model. Modeled cumulative GW discharges for two surveys unaffected by ungauged SW discharges were comparable in magnitude to differential gauging-based discharge estimates and prior GW-SW studies along the same river reach. Ungauged lateral inlets and sparse GW data limited the study, and argue for enhancing monitoring efforts. Our approach provides a rapid and economical method for characterizing NPSP for gaining rivers in the context of integrated watershed modeling and management. PMID- 25837572 TI - Fast and sensitive total protein and Peptide assays for proteomic analysis. AB - The determination of total protein content is one of the most frequent analytical tasks in biochemistry and molecular biology. Here we evaluate measurements of tryptophan fluorescence (WF) for total protein determination in whole tissue lysates and for peptide quantification in protein digests. We demonstrate that the fluorescence spectrometry of tryptophan offers a simple, sensitive, and direct method for protein and peptide assays. The WF assay is fully compatible with SDS and other solutes that are commonly used for lysis of tissue and cells. We found that the content of tryptophan varies only a little between mouse tissues (1.16 +/- 0.08% of total amino acids) and is similar in human cells (1.19 +/- 0.06%). Therefore, free tryptophan can be used as a universal standard. We show that the assay can be carried out on a standard fluorescence spectrometer with cuvettes as well as in a 96-well format using a plate reader. The method is particularly suitable for determination of peptide content in diluted samples. Notably, the whole sample can be recovered after the measurement. PMID- 25837573 TI - The strategy and early clinical outcome of full-endoscopic L5/S1 discectomy through interlaminar approach. AB - OBJECTIVE: To analyze the surgical strategy, safety and clinical outcome of full endoscopic discectomy through interlaminar approach in the case of L5/S1 intervertebral disc excision. METHODS: From April 2011 to December 2011, 72 cases of intracanalicular non-contained disc herniations at L5/S1 level were treated with full-endoscopic discectomy through interlaminar approach. L5/S1 disc herniation was divided into three types according to position of herniated disc related to S1 nerve root: axilla type, ventral type and shoulder type. Axilla approach was selected for axilla type while shoulder approach was selected for ventral type and shoulder type. After operation, MRI was reexamined to evaluate the resection completeness of prolapsed disc material. Visual analog scales (VAS) of low back pain and sciatica, and Oswestry disability index (ODI) were recorded in certain preoperative and postoperative time points. MacNab scores were evaluated at the 12-month follow-up. RESULTS: All operations were completed without conversion to other surgical techniques. Average operation time was 45 min (20-80 min). Only one reoccurrence was revised with microendoscopic discectomy. No nerve injury and infection were complicated. Postoperative ODI and VAS of low back pain and sciatica were significantly decreased in each time point (P < 0.05). MacNab scores of 12-month follow-up include 44 excellent, 26 good, 1 fair and 1 poor. CONCLUSION: With proper selection between axilla approach and shoulder approach according to the sites of prolapsed or sequestered disc materials, full-endoscopic L5/S1 discectomy through interlaminar approach is a safe, rational and effective minimally invasive spine surgery technique with excellent clinical short-term outcomes. PMID- 25837574 TI - Prevention of venous thromboembolic complications with and without intermittent pneumatic compression in neurosurgical cranial procedures using intraoperative magnetic resonance imaging. A retrospective analysis. AB - OBJECT: To evaluate the introduction of intraoperative and postoperative pneumatic compression additionally to the use of compression stockings, low molecular weight heparin-LMWH and early mobilization, a retrospective study in cranial neurosurgery using intraoperative MRI was performed. METHODS: A retrospective analysis of 207 neurosurgical patients using intraoperative MRI was performed. A group of 86 patients was treated with the additional use of intraoperative and postoperative pneumatic compression until mobilization out of bed. One hundred twenty-one patients were treated without the use of additional pneumatic compression. Postoperatively the patients were screened for deep venous thrombosis by ultrasound and pulmonary embolism by CT-scan if suspicious. Statistical analysis was performed. RESULTS: The development of deep venous thrombosis was reduced from 9.9% to 3.5% in our patients with the additional use of intraoperative and postoperative pneumatic compression. That is a 64.6% relative risk reduction to develop deep venous thrombosis with the use of intraoperative and postoperative pneumatic compression. An additional 52% relative risk reduction was found for the chance of developing pulmonary embolism. In the 15 patients with detected deep venous thrombosis, the OR-time was more than 100 min longer than in the 192 patients without detected deep venous thrombosis. The difference between both groups was significant. CONCLUSION: This study demonstrates the benefit of pneumatic compression with a risk reduction for the development of thromboembolic complications. OR-time is another risk factor that attributes to a significant risk for the development of thromboembolic complications. PMID- 25837575 TI - Spinal cord injury in pediatric age in Spain. Reality of a national reference center. AB - The aim of this study was to analyze the incidence and the main characteristics of ambulant children with spinal cord injury (SCI) treated at the Unit of Biomechanics and Technical Assistance, at the National Spinal Cord Injury Hospital in Toledo, Spain. To date, there are no detailed studies on the effects of this disease in children regarding their walking ability. MATERIAL AND METHODS: A retrospective study was performed including all patients attending the unit between January 2006 and December 2013, who were aged 18 years or younger and who were outpatients able to walk independently for at least 10 m, with or without technical aids. RESULTS: Forty-eight patients were included in this study (25 males and 23 females) aged between 2 and 18 years (mean age, 12 +/- 2.31 years). The etiology of SCI ranged between congenital (33.33%), traumatic (29.16%), and neoplastic (8.33%), and the level of injury varied between cervical (31.25%), lumbar (29.16%), a non-spinal origin (20.83%), dorsal (16.66%), and sacral (2.08%). The mean score on the Barthel Index was 82.61, the mean value of the Functional Independence Measure (FIM) locomotion score was 6.4, and 29 patients did not require the use of walking aids (WISCI 20). CONCLUSION: The findings of this study contribute to the knowledge regarding the situation of children with SCI in Spain. The incidence of pediatric SCI is very low; however, the provision of care remains a personal and social challenge. PMID- 25837576 TI - Healing calvarial eosinophilic granuloma or healing skull fracture? PMID- 25837577 TI - Brief account on the head injury of a noble youngster in the sixteenth century (Prince Don Carlos, heir to Philip II of Spain, 1545-1568). PMID- 25837578 TI - Dissecting Molecular Evolution in the Highly Diverse Plant Clade Caryophyllales Using Transcriptome Sequencing. AB - Many phylogenomic studies based on transcriptomes have been limited to "single copy" genes due to methodological challenges in homology and orthology inferences. Only a relatively small number of studies have explored analyses beyond reconstructing species relationships. We sampled 69 transcriptomes in the hyperdiverse plant clade Caryophyllales and 27 outgroups from annotated genomes across eudicots. Using a combined similarity- and phylogenetic tree-based approach, we recovered 10,960 homolog groups, where each was represented by at least eight ingroup taxa. By decomposing these homolog trees, and taking gene duplications into account, we obtained 17,273 ortholog groups, where each was represented by at least ten ingroup taxa. We reconstructed the species phylogeny using a 1,122-gene data set with a gene occupancy of 92.1%. From the homolog trees, we found that both synonymous and nonsynonymous substitution rates in herbaceous lineages are up to three times as fast as in their woody relatives. This is the first time such a pattern has been shown across thousands of nuclear genes with dense taxon sampling. We also pinpointed regions of the Caryophyllales tree that were characterized by relatively high frequencies of gene duplication, including three previously unrecognized whole-genome duplications. By further combining information from homolog tree topology and synonymous distance between paralog pairs, phylogenetic locations for 13 putative genome duplication events were identified. Genes that experienced the greatest gene family expansion were concentrated among those involved in signal transduction and oxidoreduction, including a cytochrome P450 gene that encodes a key enzyme in the betalain synthesis pathway. Our approach demonstrates a new approach for functional phylogenomic analysis in nonmodel species that is based on homolog groups in addition to inferred ortholog groups. PMID- 25837579 TI - Maximum-Likelihood Phylogenetic Inference with Selection on Protein Folding Stability. AB - Despite intense work, incorporating constraints on protein native structures into the mathematical models of molecular evolution remains difficult, because most models and programs assume that protein sites evolve independently, whereas protein stability is maintained by interactions between sites. Here, we address this problem by developing a new mean-field substitution model that generates independent site-specific amino acid distributions with constraints on the stability of the native state against both unfolding and misfolding. The model depends on a background distribution of amino acids and one selection parameter that we fix maximizing the likelihood of the observed protein sequence. The analytic solution of the model shows that the main determinant of the site specific distributions is the number of native contacts of the site and that the most variable sites are those with an intermediate number of native contacts. The mean-field models obtained, taking into account misfolded conformations, yield larger likelihood than models that only consider the native state, because their average hydrophobicity is more realistic, and they produce on the average stable sequences for most proteins. We evaluated the mean-field model with respect to empirical substitution models on 12 test data sets of different protein families. In all cases, the observed site-specific sequence profiles presented smaller Kullback-Leibler divergence from the mean-field distributions than from the empirical substitution model. Next, we obtained substitution rates combining the mean-field frequencies with an empirical substitution model. The resulting mean field substitution model assigns larger likelihood than the empirical model to all studied families when we consider sequences with identity larger than 0.35, plausibly a condition that enforces conservation of the native structure across the family. We found that the mean-field model performs better than other structurally constrained models with similar or higher complexity. With respect to the much more complex model recently developed by Bordner and Mittelmann, which takes into account pairwise terms in the amino acid distributions and also optimizes the exchangeability matrix, our model performed worse for data with small sequence divergence but better for data with larger sequence divergence. The mean-field model has been implemented into the computer program Prot_Evol that is freely available at http://ub.cbm.uam.es/software/Prot_Evol.php. PMID- 25837580 TI - Escherichia coli morphological changes and lipid A removal induced by reduced pressure nitrogen afterglow exposure. AB - Lipid A is a major hydrophobic component of lipopolysaccharides (endotoxin) present in the membrane of most Gram-negative bacteria, and the major responsible for the bioactivity and toxicity of the endotoxin. Previous studies have demonstrated that the late afterglow region of flowing post-discharges at reduced pressure (1-20 Torr) can be used for the sterilization of surfaces and of the reusable medical instrumentation. In the present paper, we show that the antibacterial activity of a pure nitrogen afterglow can essentially be attributed to the large concentrations of nitrogen atoms present in the treatment area and not to the UV radiation of the afterglow. In parallel, the time variation of the inactivation efficiency quantified by the log reduction of the initial Escherichia coli (E. coli) population is correlated with morphologic changes observed on the bacteria by scanning electron microscopy (SEM) for increasing afterglow exposure times. The effect of the afterglow exposure is also studied on pure lipid A and on lipid A extracted from exposed E. coli bacteria. We report that more than 60% of lipid A (pure or bacteria-extracted) are lost with the used operating conditions (nitrogen flow QN2 = 1 standard liter per minute (slpm), pressure p = 5 Torr, microwave injected power PMW = 200 W, exposure time: 40 minutes). The afterglow exposure also results in a reduction of the lipid A proinflammatory activity, assessed by the net decrease of the redox-sensitive NFkappaB transcription factor nuclear translocation in murine aortic endothelial cells stimulated with control vs afterglow-treated (pure and extracted) lipid A. Altogether these results point out the ability of reduced pressure nitrogen afterglows to neutralize the cytotoxic components in Gram-negative bacteria. PMID- 25837581 TI - Role of the store-operated calcium entry protein, STIM1, in neutrophil chemotaxis and infiltration into a murine model of psoriasis-inflamed skin. AB - Stromal interaction molecule 1 (STIM1) is a Ca(2+) sensor protein that initiates store-operated calcium entry (SOCE). STIM1 is known to be involved in the chemoattractant signaling pathway for FPR1 in cell lines, but its role in in vivo functioning of neutrophils is unclear. Plaque-type psoriasis is a chronic inflammatory skin disorder associated with chemoattractants driving neutrophils into the epidermis. We investigated the involvement of STIM1 in neutrophil chemotaxis in vitro, as well as during chronic psoriatic inflammation. To this end, we used conditional knockout (KO) mice lacking STIM1 in cells of myeloid lineage (STIM1(fl/fl) LysM-cre). We demonstrate that STIM1 is required for chemotaxis because of multiple chemoattractants in mouse neutrophils in vitro. Using an imiquimod-induced psoriasis-like skin model, we show that KO mice had less neutrophil infiltration in the epidermis than controls, whereas neither chemoattractant production in the epidermis nor macrophage migration was decreased. KO mice displayed a more rapid reversal of the outward signs of psoriasis (plaques). Thus, KO of STIM1 impairs neutrophil contribution to psoriatic inflammation. Our data provide new insights to our understanding of how STIM1 orchestrates the cellular behavior underlying chemotaxis and illustrate the important role of SOCE in a disease-related pathologic model. PMID- 25837583 TI - Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival. AB - Factor-inhibiting hypoxia-inducible factor (HIF)-1 (FIH-1) is an asparaginyl beta hydroxylase enzyme that was initially found to hydroxylate the HIF-alpha, preventing its transcriptional activity and leading to adaptive responses to hypoxia. More recently, other substrates, such as neurogenic locus notch homolog (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulation was never investigated. Given the key function of Notch in angiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells. We report that FIH-1 silencing in HUVECs results in reduced growth and increased apoptosis. The knockdown of FIH is associated with increased Notch2 activity, leading to enhanced expression of the Notch target hairy/enhancer-of-split related with YRPW motif protein 1 (Hey-1). Consistent with recent findings showing that Notch2 suppresses survivin (a key inhibitor of apoptosis), FIH targeting in HUVECs leads to selective repression of survivin in endothelial cells, thus promoting cell apoptosis and growth arrest. Our data support the concept that FIH-1 may interact with Notch2 and repress its activity, thereby playing a critical role in controlling the survival of vascular endothelial cells. These findings might pave the way toward novel, antiangiogenic strategies in disorders that are characterized by excessive vascular growth, such as cancer and rheumatoid arthritis. PMID- 25837582 TI - IGF1 stimulates crypt expansion via differential activation of 2 intestinal stem cell populations. AB - Insulin-like growth factor 1 (IGF1) has potent trophic effects on normal or injured intestinal epithelium, but specific effects on intestinal stem cells (ISCs) are undefined. We used Sox9-enhanced green fluorescent protein (EGFP) reporter mice that permit analyses of both actively cycling ISCs (Sox9-EGFP(Low)) and reserve/facultative ISCs (Sox9-EGFP(High)) to study IGF1 action on ISCs in normal intestine or during crypt regeneration after high-dose radiation-induced injury. We hypothesized that IGF1 differentially regulates proliferation and gene expression in actively cycling and reserve/facultative ISCs. IGF1 was delivered for 5 days using subcutaneously implanted mini-pumps in uninjured mice or after 14 Gy abdominal radiation. ISC numbers, proliferation, and transcriptome were assessed. IGF1 increased epithelial growth in nonirradiated mice and enhanced crypt regeneration after radiation. In uninjured and regenerating intestines, IGF1 increased total numbers of Sox9-EGFP(Low) ISCs and percentage of these cells in M-phase. IGF1 increased percentages of Sox9-EGFP(High) ISCs in S-phase but did not expand this population. Microarray revealed that IGF1 activated distinct gene expression signatures in the 2 Sox9-EGFP ISC populations. In vitro IGF1 enhanced enteroid formation by Sox9-EGFP(High) facultative ISCs but not Sox9-EGFP(Low) actively cycling ISCs. Our data provide new evidence that IGF1 activates 2 ISC populations via distinct regulatory pathways to promote growth of normal intestinal epithelium and crypt regeneration after irradiation. PMID- 25837584 TI - Cyclophilin-D: a resident regulator of mitochondrial gene expression. AB - Cyclophilin-D (Cyp-D) is a mitochondrial matrix peptidyl-prolyl isomerase. Because cyclophilins can regulate nuclear gene expression, we examined whether Cyp-D could regulate mitochondrial gene expression. We demonstrated in HEK 293T cells that transfected Cyp-D interacts with mitochondrial transcription factors B1 and B2 (TFB2M) but not with mitochondrial transcription factor A. We also demonstrated that Cyp-D interacts in vivo with TFB2M. Genetic silencing of Cyp-D and pharmacologic inhibition of Cyp-D markedly reduced mitochondrial transcription to 18 +/- 5% (P < 0.05) and 24 +/- 3% (P < 0.05) of respective controls. The level of interaction between Cyp-D and TFB2M correlated with the level of nascent mitochondrial RNA intensity (r = 0.896; P = 0.0156). Cyp-D silencing down-regulated mitochondrial transcripts initiated from the heavy strand promoter 2 [i.e., NADH dehydrogenase 1 (ND1) by 11-fold, P < 0.005; cytochrome oxidase 1 (COX1) by 4-fold, P < 0.001; and ATP synthase subunit 6 (ATP6) by 6.5-fold, P < 0.005); but not NADH dehydrogenase 6 (ND6)], which is initiated from the light strand promoter. Cyp-D silencing reduced mitochondrial membrane potential and cellular oxygen consumption (from 59 +/- 5 to 34 +/- 1 umol oxygen/min/10(6) cells, P < 0.001); the latter without a statistically significant reversal after uncoupling electron transport from ATP synthesis, consistent with down-regulation of electron transport complexes. Accordingly, these studies provide novel evidence that Cyp-D could play a key role in regulating mitochondrial gene expression. PMID- 25837585 TI - Negative cooperativity across beta1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 beta1-adrenoceptor binding conformation. AB - At the beta1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at the primary high-affinity catecholamine conformation while also exerting agonist effects of its own through a secondary low-affinity conformation. A recent mutagenesis study identified transmembrane region (TM)4 of the beta1-adrenoceptor as key for this low-affinity conformation. Others suggested that TM4 has a role in beta1-adrenoceptor oligomerization. Here, assessment of the dissociation rate of a fluorescent analog of CGP 12177 [bordifluoropyrromethane tetramethylrhodamine-(+/-)CGP 12177 (BODIPY-TMR-CGP)] at the human beta1 adrenoceptor expressed in Chinese hamster ovary cells revealed negative cooperative interactions between 2 distinct beta1-adrenoceptor conformations. The dissociation rate of 3 nM BODIPY-TMR-CGP was 0.09 +/- 0.01 min(-1) in the absence of competitor ligands, and this was enhanced 2.2- and 2.1-fold in the presence of 1 uM CGP 12177 and 1 uM propranolol, respectively. These effects on the BODIPY TMR-CGP dissociation rate were markedly enhanced in beta1-adrenoceptor homodimers constrained by bimolecular fluorescence complementation (9.8- and 9.9-fold for 1 uM CGP 12177 and 1 uM propranolol, respectively) and abolished in beta1 adrenoceptors containing TM4 mutations vital for the second conformation pharmacology. This study suggests that negative cooperativity across a beta1 adrenoceptor homodimer may be responsible for generating the low-affinity pharmacology of the secondary beta1-adrenoceptor conformation. PMID- 25837587 TI - Correction: Trapping particles using waveguide-coupled gold bowtie plasmonic tweezers. PMID- 25837586 TI - Spontaneous Cdc42 polarization independent of GDI-mediated extraction and actin based trafficking. AB - The small Rho-family GTPase Cdc42 is critical for cell polarization and polarizes spontaneously in absence of upstream spatial cues. Spontaneous polarization is thought to require dynamic Cdc42 recycling through Guanine nucleotide Dissociation Inhibitor (GDI)-mediated membrane extraction and vesicle trafficking. Here, we describe a functional fluorescent Cdc42 allele in fission yeast, which demonstrates Cdc42 dynamics and polarization independent of these pathways. Furthermore, an engineered Cdc42 allele targeted to the membrane independently of these recycling pathways by an amphipathic helix is viable and polarizes spontaneously to multiple sites in fission and budding yeasts. We show that Cdc42 is highly mobile at the membrane and accumulates at sites of activity, where it displays slower mobility. By contrast, a near-immobile transmembrane domain-containing Cdc42 allele supports viability and polarized activity, but does not accumulate at sites of activity. We propose that Cdc42 activation, enhanced by positive feedback, leads to its local accumulation by capture of fast diffusing inactive molecules. PMID- 25837588 TI - Modification of nanocrystalline WO3 with a dicationic perylene bisimide: applications to molecular level solar water splitting. AB - [(N,N'-Bis(2-(trimethylammonium)ethylene) perylene 3,4,9,10-tetracarboxylic acid bisimide)(PF6)2] (1) was observed to spontaneously adsorb on nanocrystalline WO3 surfaces via aggregation/hydrophobic forces. Under visible irradiation (lambda > 435 nm), the excited state of 1 underwent oxidative quenching by electron injection (kinj > 10(8) s(-1)) to WO3, leaving a strongly positive hole (Eox ~ 1.7 V vs SCE), which allows to drive demanding photo-oxidation reactions in photoelectrochemical cells (PECs). The casting of IrO2 nanoparticles (NPs), acting as water oxidation catalysts (WOCs) on the sensitized electrodes, led to a 4-fold enhancement in photoanodic current, consistent with hole transfer from oxidized dye to IrO2 occurring on the microsecond time scale. Once the interaction of the sensitizer with suitable WOCs is optimized, 1/WO3 photoanodes may hold potentialities for the straightforward building of molecular level devices for solar fuel production. PMID- 25837589 TI - Correction: a recombinant avian leukosis virus subgroup J for directly monitoring viral infection and the selection of neutralizing antibodies. PMID- 25837590 TI - Semiautomatic Analysis on Computed Tomography in Locally Advanced or Metastatic Non-Small Cell Lung Cancer: Reproducibility and Prognostic Significance of Unidimensional and 3-dimensional Measurements. AB - PURPOSE: The aim of the study was to compare both reproducibility and prognostic value of lesion size measurements obtained manually and semiautomatically on computed tomography in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Manual axial longest diameter, semiautomatic axial longest diameter, and volume of NSCLC lesions were independently analyzed by 4 readers at baseline and after at least 1 cycle of platinum-based chemotherapy. The prognostic value of the proportional change in lesion size between baseline and follow-up CT was evaluated using either RECIST or experimental thresholds derived from the quartiles of the changes as assessed manually or semiautomatically. RESULTS: Semiautomatic axial longest diameter (concordance correlation coefficient [CCC]: 0.980 to 0.987; variation coefficient [VC%]: 6% to 7.3%) and volume (CCC: 0.974 to 0.991; VC%: 5.6% to 9.5%) were more reproducible than manual axial longest diameter (CCC: 0.950 to 0.984; VC%: 6.4% to 11.7%). RECIST categories did not stratify patients with different survival durations. For 3/4 readers, a decrease of <= 70% in lesion volume was associated with shorter survival (median survival: 11 mo, P < 0.05; hazard ratio: 5 to 22.2, P < 0.05). CONCLUSIONS: In advanced NSCLC, semiautomatic measures were more reproducible than manual diameter, and volumetric measurement may better predict patient survival. PMID- 25837591 TI - ACR Appropriateness Criteria(r) acute respiratory illness in immunocompromised patients. AB - The respiratory system is often affected by complications of immunodeficiency, typically manifesting clinically as acute respiratory illness. Ongoing literature reviews regarding the appropriateness of imaging in these patients are critical, as advanced medical therapies including stem cell transplantation, chemotherapy, and immunosuppressive therapies for autoimmune disease continue to keep the population of immunosuppressed patients in our health care system high. This ACR Appropriateness Criteria topic describes clinical scenarios of acute respiratory illness in immunocompromised patients with cough, dyspnea, chest pain, and fever, in those with negative, equivocal, or nonspecific findings on chest radiography, in those with multiple, diffuse, or confluent opacities on chest radiography, and in those in whom noninfectious disease is suspected. The use of chest radiography, chest computed tomography, transthoracic needle biopsy, and nuclear medicine imaging is discussed in the context of these clinical scenarios. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or is not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25837592 TI - A TatABC-type Tat translocase is required for unimpaired aerobic growth of Corynebacterium glutamicum ATCC13032. AB - The twin-arginine translocation (Tat) system transports folded proteins across the cytoplasmic membrane of bacteria and the thylakoid membrane of plant chloroplasts. Escherichia coli and other Gram-negative bacteria possess a TatABC type Tat translocase in which each of the three inner membrane proteins TatA, TatB, and TatC performs a mechanistically distinct function. In contrast, low-GC Gram-positive bacteria, such as Bacillus subtilis, use a TatAC-type minimal Tat translocase in which the TatB function is carried out by a bifunctional TatA. In high-GC Gram-positive Actinobacteria, such as Mycobacterium tuberculosis and Corynebacterium glutamicum, tatA, tatB, and tatC genes can be identified, suggesting that these organisms, just like E. coli, might use TatABC-type Tat translocases as well. However, since contrary to this view a previous study has suggested that C. glutamicum might in fact use a TatAC translocase with TatB only playing a minor role, we reexamined the requirement of TatB for Tat-dependent protein translocation in this microorganism. Under aerobic conditions, the misassembly of the Rieske iron-sulfur protein QcrA was identified as a major reason for the severe growth defect of Tat-defective C. glutamicum mutant strains. Furthermore, our results clearly show that TatB, besides TatA and TatC, is strictly required for unimpaired aerobic growth. In addition, TatB was also found to be essential for the secretion of a heterologous Tat-dependent model protein into the C. glutamicum culture supernatant. Together with our finding that expression of the C. glutamicum TatB in an E. coli DeltatatB mutant strain resulted in the formation of an active Tat translocase, our results clearly indicate that a TatABC translocase is used as the physiologically relevant functional unit for Tat-dependent protein translocation in C. glutamicum and, most likely, also in other TatB-containing Actinobacteria. PMID- 25837593 TI - DnaK protein alleviates toxicity induced by citrate-coated gold nanoparticles in Escherichia coli. AB - A number of previously reported studies suggest that synthetic gold nanoparticles (AuNPs) are capable of stabilising proteins against heat stress in vitro. However, it remains to be understood if AuNPs confer stability to proteins against cellular stress in vivo. Heat shock proteins (Hsps) are conserved molecules whose main role is to facilitate folding of other proteins (chaperone function). Hsp70 (called DnaK in prokaryotes) is one of the most prominent molecular chaperones. Since gold nanoparticles exhibit chaperone-like function in vitro, we investigated the effect of citrate-coated gold nanoparticles on the growth of E. coli BB1553 cells that possess a deleted dnaK gene. We further investigated the effects of the AuNPs on the solubility of the E. coli BB1553 proteome. E. coli BB1553 cells exposed to AuNPs exhibited cellular defects such as filamentation and plasma membranes pulled off the cell wall. The toxic effects of the AuNPs were alleviated by transforming the E. coli BB1553 cells with a construct expressing DnaK. We also noted that cells in which DnaK was restored exhibited distinct zones to which the nanoparticles were restricted. Our study suggests a role for DnaK in alleviating nanoparticle induced stress in E. coli. PMID- 25837595 TI - Strengths and challenges faced by school-aged children with unilateral CP described by the Five To Fifteen parental questionnaire. AB - PURPOSE: The purpose of this study was to describe motor and non-motor (e.g. cognitive, social, and behavioral) challenges faced in daily life by children with unilateral cerebral palsy (UCP). METHODS: In this cross-sectional study, parents completed the Five to Fifteen questionnaire and provided demographic information for 46 children aged 6-15 years (mean 11.01 +/- 2.89 SD). RESULTS: Most children were reported to have problems in both motor and non-motor domains, ranging from 20 to 92% depending on the domain. Perception and learning were the non-motor functions most commonly reported as challenging (63 and 65%, respectively). The total number of problems was significantly higher in age groups above 9 years. The correlation between all domains was high, but was consistently higher with the fine motor sub-domain, which could be used to predict executive function, perception, memory, and learning outcomes (R2=0.502, 0.642, 0.192, 0.192). CONCLUSION: Most children with CP have everyday challenges beyond their primary motor deficiencies. PMID- 25837594 TI - High fat diet causes depletion of intestinal eosinophils associated with intestinal permeability. AB - The development of intestinal permeability and the penetration of microbial products are key factors associated with the onset of metabolic disease. However, the mechanisms underlying this remain unclear. Here we show that, unlike liver or adipose tissue, high fat diet (HFD)/obesity in mice does not cause monocyte/macrophage infiltration into the intestine or pro-inflammatory changes in gene expression. Rather HFD causes depletion of intestinal eosinophils associated with the onset of intestinal permeability. Intestinal eosinophil numbers were restored by returning HFD fed mice to normal chow and were unchanged in leptin-deficient (Ob/Ob) mice, indicating that eosinophil depletion is caused specifically by a high fat diet and not obesity per se. Analysis of different aspects of intestinal permeability in HFD fed and Ob/Ob mice shows an association between eosinophil depletion and ileal paracelullar permeability, as well as leakage of albumin into the feces, but not overall permeability to FITC dextran. These findings provide the first evidence that a high fat diet causes intestinal eosinophil depletion, rather than inflammation, which may contribute to defective barrier integrity and the onset of metabolic disease. PMID- 25837596 TI - A rational approach to estimating the surgical demand elasticity needed to guide manpower reallocation during contagious outbreaks. AB - BACKGROUND: Emerging infectious diseases continue to pose serious threats to global public health. So far, however, few published study has addressed the need for manpower reallocation needed in hospitals when such a serious contagious outbreak occurs. AIM: To quantify the demand elasticity of the major surgery types in order to guide future manpower reallocation during contagious outbreaks. MATERIALS AND METHODS: Based on a nationwide research database in Taiwan, we extracted the monthly volumes of major surgery types for the period 1998-2003, which covered the SARS period, in order to carry out a time series analysis. The demand elasticity of each surgery type was then estimated by autoregressive integrated moving average (ARIMA) analysis. RESULTS: During the study period, the surgical volumes of most selected surgery types either increased or remained steady. We categorized these surgery types into low-, moderate- and high-elastic groups according to their demand elasticity. Appendectomy, 'open reduction of fracture with internal fixation' and 'free skin graft' were in the low demand elasticity group. Transurethral prostatectomy and extracorporeal shockwave lithotripsy (ESWL) were in the high demand elasticity group. The manpower of the departments carrying out the surgeries with low demand elasticity should be maintained during outbreaks. In contrast, departments in charge of surgeries mainly with high demand elasticity, like urology departments, may be in a position to have part of their staff reallocated. CONCLUSIONS: Taking advantage of the demand variation during the SARS period in 2003, we adopted the concept of demand elasticity and used a time series approach to figure out an effective index of demand elasticity for various types of surgery that could be used as a rational reference to carry out manpower reallocation during contagious outbreak situations. PMID- 25837597 TI - The Trend of Inflammatory Bowel Diseases in Taiwan: A Population-Based Study. AB - BACKGROUND AND AIM: The purpose of this study was to estimate the sex- and age specific incidence rates of inflammatory bowel diseases (IBD) in Taiwan. Site specific cancer occurred in patients with IBD would be reported, too. METHODS: A retrospective study by analyzing the data from the National Health Insurance Research Database of Taiwan. RESULTS: Between 2000 and 2010, the overall incidence rate of Crohn's disease (CD) and ulcerative colitis (UC) was 0.208 and 0.838 per 100,000 person-years. For male, the incidence rate of CD was 0.195 (95 % CI 0.113-0.276) per 100,000 persons in 2000 and increased to 0.318 (95 % CI 0.216-0.421) per 100,000 persons in 2010. For female, the incidence rate of CD was 0.092 (95 % CI 0.035-0.149) per 100,000 persons in 2000 and increased to 0.210 (95 % CI 0.128-0.293) per 100,000 persons in 2010. For male, the incidence rate of UC was 0.690 (95 % CI 0.537-0.843) per 100,000 persons in 2000 and increased to 1.351 (95 % CI, 1.140-1.562) per 100,000 persons in 2010. For female, the incidence rate of UC was 0.386 (95 % CI 0.269-0.503) per 100,000 persons in 2000 and increased to 0.858 (95 % CI 0.691-1.024) per 100,000 persons in 2010. Among the CD patients, 0.19 % had colorectal cancers (1/519). Among the UC patients, 0.24 % had colorectal cancers (5/2098). CONCLUSIONS: This nationwide population-based longitudinal epidemiological study of IBD in Taiwan provides data for future global comparisons. PMID- 25837598 TI - Mesoscopic structure of neuronal tracts from time-dependent diffusion. AB - Interpreting brain diffusion MRI measurements in terms of neuronal structure at a micrometer level is an exciting unresolved problem. Here we consider diffusion transverse to a bundle of fibers, and show theoretically, as well as using Monte Carlo simulations and measurements in a phantom made of parallel fibers mimicking axons, that the time dependent diffusion coefficient approaches its macroscopic limit slowly, in a (ln t)/t fashion. The logarithmic singularity arises due to short range disorder in the fiber packing. We identify short range disorder in axonal fibers based on histological data from the splenium, and argue that the time dependent contribution to the overall diffusion coefficient from the extra axonal water dominates that of the intra-axonal water. This dominance may explain the bias in measuring axon diameters in clinical settings. The short range disorder is also reflected in the asymptotically linear frequency dependence of the diffusion coefficient measured with oscillating gradients, in agreement with recent experiments. Our results relate the measured diffusion to the mesoscopic structure of neuronal tissue, uncovering the sensitivity of diffusion metrics to axonal arrangement within a fiber tract, and providing an alternative interpretation of axonal diameter mapping techniques. PMID- 25837599 TI - Electrophysiological signatures of spontaneous BOLD fluctuations in macaque prefrontal cortex. AB - Spontaneous brain activity is ubiquitous across brain structures and states. Determining the role of these metabolically costly intrinsic events may be critical for understanding the brain's fundamental physiological principles that govern cognition and behavior. To date, most investigations of large-scale fluctuations and their coupling have been conducted using electro- or magneto encephalography, modalities that are limited in their ability to spatially resolve the origin of the signals. Invasive, electrophysiological local field potential (LFP) recordings are limited in their spatial range and studies combining the approach with functional imaging have been primarily relegated to sensory/motor areas with little basis in which to extrapolate findings to evolutionarily newer prefrontal cortical regions. Here, we acquired spontaneous fMRI data in two anesthetized macaque monkeys (Macaca fascicularis) at 7 T together with simultaneous recordings of intracortical LFPs recorded bilaterally from the prefrontal cortex (area 9/46d). High (beta-low gamma) and low (delta theta) band-limited power (BLP) ranges of the LFP frequencies were anticorrelated in the absence of any explicit stimuli. Beyond the high LFP-BLP signal being correlated with BOLD activity at the recording site, the high and low LFP-BLP envelopes were shown to be significantly correlated with spontaneous BOLD activity recorded from positively and negatively connected prefrontal network regions, respectively. The results suggest that complementary changes in low and high frequency bands may be an intrinsic property of LFPs, that local prefrontal cortical activity is related to spontaneous BOLD fluctuations, and further, that LFP-BLPs may be correlated at a network level. PMID- 25837600 TI - An automated pipeline for constructing personalized virtual brains from multimodal neuroimaging data. AB - Large amounts of multimodal neuroimaging data are acquired every year worldwide. In order to extract high-dimensional information for computational neuroscience applications standardized data fusion and efficient reduction into integrative data structures are required. Such self-consistent multimodal data sets can be used for computational brain modeling to constrain models with individual measurable features of the brain, such as done with The Virtual Brain (TVB). TVB is a simulation platform that uses empirical structural and functional data to build full brain models of individual humans. For convenient model construction, we developed a processing pipeline for structural, functional and diffusion weighted magnetic resonance imaging (MRI) and optionally electroencephalography (EEG) data. The pipeline combines several state-of-the-art neuroinformatics tools to generate subject-specific cortical and subcortical parcellations, surface tessellations, structural and functional connectomes, lead field matrices, electrical source activity estimates and region-wise aggregated blood oxygen level dependent (BOLD) functional MRI (fMRI) time-series. The output files of the pipeline can be directly uploaded to TVB to create and simulate individualized large-scale network models that incorporate intra- and intercortical interaction on the basis of cortical surface triangulations and white matter tractograpy. We detail the pitfalls of the individual processing streams and discuss ways of validation. With the pipeline we also introduce novel ways of estimating the transmission strengths of fiber tracts in whole-brain structural connectivity (SC) networks and compare the outcomes of different tractography or parcellation approaches. We tested the functionality of the pipeline on 50 multimodal data sets. In order to quantify the robustness of the connectome extraction part of the pipeline we computed several metrics that quantify its rescan reliability and compared them to other tractography approaches. Together with the pipeline we present several principles to guide future efforts to standardize brain model construction. The code of the pipeline and the fully processed data sets are made available to the public via The Virtual Brain website (thevirtualbrain.org) and via github (https://github.com/BrainModes/TVB-empirical-data-pipeline). Furthermore, the pipeline can be directly used with High Performance Computing (HPC) resources on the Neuroscience Gateway Portal (http://www.nsgportal.org) through a convenient web-interface. PMID- 25837601 TI - Simultaneous multi-slice Turbo-FLASH imaging with CAIPIRINHA for whole brain distortion-free pseudo-continuous arterial spin labeling at 3 and 7 T. AB - Simultaneous multi-slice (SMS) or multiband (MB) imaging has recently been attempted for arterial spin labeled (ASL) perfusion MRI in conjunction with echo planar imaging (EPI) readout. It was found that SMS-EPI can reduce the T1 relaxation effect of the label and improve image coverage and resolution with little penalty in signal-to-noise ratio (SNR). However, EPI still suffers from geometric distortion and signal dropout from field inhomogeneity effects especially at high and ultrahigh magnetic fields. Here we present a novel scheme for achieving high fidelity distortion-free quantitative perfusion imaging by combining pseudo-continuous ASL (pCASL) with SMS Turbo-FLASH (TFL) readout at both 3 and 7 T. Bloch equation simulation was performed to characterize and optimize the TFL-based pCASL perfusion signal. Two MB factors (3 and 5) were implemented in SMS-TFL pCASL and compared with standard 2D TFL and EPI pCASL sequences. The temporal SNR of SMS-TFL pCASL relative to that of standard TFL pCASL was 0.76 +/- 0.10 and 0.74 +/- 0.11 at 7 T and 0.70 +/- 0.05 and 0.65 +/- 0.05 at 3T for MB factor of 3 and 5, respectively. By implementing background suppression in conjunction with SMS-TFL at 3T, the relative temporal SNR improved to 0.84 +/- 0.09 and 0.79 +/- 0.10 for MB factor of 3 and 5, respectively. Compared to EPI pCASL, significantly increased temporal SNR (p<0.001) and improved visualization of orbitofrontal cortex were achieved using SMS-TFL pCASL. By combining SMS acceleration with TFL pCASL, we demonstrated the feasibility for whole brain distortion-free quantitative mapping of cerebral blood flow at high and ultrahigh magnetic fields. PMID- 25837602 TI - Participation and contribution in crowdsourced surveys. AB - This paper identifies trends within and relationships between the amount of participation and the quality of contributions in three crowdsourced surveys. Participants were asked to perform a collective problem solving task that lacked any explicit incentive: they were instructed not only to respond to survey questions but also to pose new questions that they thought might-if responded to by others-predict an outcome variable of interest to them. While the three surveys had very different outcome variables, target audiences, methods of advertisement, and lengths of deployment, we found very similar patterns of collective behavior. In particular, we found that: the rate at which participants submitted new survey questions followed a heavy-tailed distribution; the distribution in the types of questions posed was similar; and many users posed non-obvious yet predictive questions. By analyzing responses to questions that contained a built-in range of valid response we found that less than 0.2% of responses lay outside of those ranges, indicating that most participants tend to respond honestly to surveys of this form, even without explicit incentives for honesty. While we did not find a significant relationship between the quantity of participation and the quality of contribution for both response submissions and question submissions, we did find several other more nuanced participant behavior patterns, which did correlate with contribution in one of the three surveys. We conclude that there exists an optimal time for users to pose questions early on in their participation, but only after they have submitted a few responses to other questions. This suggests that future crowdsourced surveys may attract more predictive questions by prompting users to pose new questions at specific times during their participation and limiting question submission at non-optimal times. PMID- 25837603 TI - Formal consensus method to evaluate the conformity of prescription of a recently approved chemotherapy treatment in an observatory study. AB - Cabazitaxel is a second line chemotherapy drug recently approved for the treatment of metastatic castration-resistant prostate cancer. A first panel of French experts and a second independent panel of European experts were convened to assess the conformity of prescription of cabazitaxel with a Delphi consensus method. A two-round modified Delphi consensus process was conducted. This methodology is based on experts' opinion obtained in a systematic manner. The process was divided into five steps: (i) elaboration of the questionnaire, (ii) rating, (iii) analysis, (iv) discussion of the points with absence of consensus following rating of the questionnaire, and (v) final reporting. Consensus was defined according to RAND method and all analyses were conducted according to the same methodology. At the end of the two rounds of rating and a synthesis meeting, of the 26 items included in the Summary of Product Characteristics (SPC), 11 items were judged appropriate with strong consensus by the two independent panels of experts. These items can therefore be considered of prime importance to evaluate conformity of cabazitaxel prescription in the context of observatory studies as well as in further clinical trials using this new taxane. Our findings further provide important evidence about the value of the Delphi consensus and highlight a requirement for "conformity" standards to assist practitioners in a safe chemotherapy drug prescription. PMID- 25837604 TI - Three-Dimensional In Vitro Skin and Skin Cancer Models Based on Human Fibroblast Derived Matrix. AB - Three-dimensional in vitro skin and skin cancer models help to dissect epidermal dermal and tumor-stroma interactions. In the model presented here, normal human dermal fibroblasts isolated from adult skin self-assembled into dermal equivalents with their specific fibroblast-derived matrix (fdmDE) over 4 weeks. The fdmDE represented a complex human extracellular matrix that was stabilized by its own heterogeneous collagen fiber meshwork, largely resembling a human dermal in vivo architecture. Complemented with normal human epidermal keratinocytes, the skin equivalent (fdmSE) thereof favored the establishment of a well-stratified and differentiated epidermis and importantly allowed epidermal regeneration in vitro for at least 24 weeks. Moreover, the fdmDE could be used to study the features of cutaneous skin cancer. Complementing fdmDE with HaCaT cells in different stages of malignancy or tumor-derived cutaneous squamous cell carcinoma cell lines, the resulting skin cancer equivalents (fdmSCEs) recapitulated the respective degree of tumorigenicity. In addition, the fdmSCE invasion phenotypes correlated with their individual degree of tissue organization, disturbance in basement membrane organization, and presence of matrix metalloproteinases. Together, fdmDE-based models are well suited for long-term regeneration of normal human epidermis and, as they recapitulate tumor-specific growth, differentiation, and invasion profiles of cutaneous skin cancer cells, also provide an excellent human in vitro skin cancer model. PMID- 25837605 TI - First diabetic retinopathy prevalence study in Portugal: RETINODIAB Study- evaluation of the screening programme for Lisbon and Tagus Valley region. AB - BACKGROUND/AIMS: In Portugal, so far, there is no study or even accurate data on the prevalence of diabetic retinopathy (DR), based on a large representative sample and on a long-term follow-up. The objective of our study was to determine the prevalence of DR based on a national screening community-based programme. METHODS: A 5-year retrospective analysis of the RETINODIAB screening programme results was implemented in Lisbon and Tagus Valley area between July 2009 and October 2014. We estimated the prevalence of retinopathy for all patients with type 2 diabetes and studied the association between known risk factors and retinopathy emergence at their first screening. RESULTS: Throughout this period, from a total of 103 102 DR readable screening examinations, 52 739 corresponded to patients who attended RETINODIAB screening at entry. Globally, DR was detected in 8584 patients (16.3%). Of these, 5484 patients (10.4%) had mild non proliferative (NP) DR, 1457 patients (2.8%) had moderate NPDR and 672 (1.3%) had severe NPDR. Finally, 971 patients (1.8%) had proliferative DR requiring urgent referral to an ophthalmologist. The presence of any DR, non-referable DR or referable DR was strongly associated with increasing duration of diabetes and earlier age at diagnosis. CONCLUSIONS: The prevalence rate of DR in our study (16.3%) was slightly lower than other published international data. The RETINODIAB network proved to be an effective screening programme as it improved DR screening in Lisbon and Tagus Valley surrounding area. PMID- 25837606 TI - Combined conjunctival rotational autograft with 0.02% mitomycin C in primary pterygium surgery: a long-term follow-up study. AB - BACKGROUND/AIMS: To compare the long-term outcomes of primary pterygium surgery with combined conjunctival rotational autograft and mitomycin C (CRA-MMC), mitomycin C alone (MMC) and limbal conjunctival autograft (LCAU). METHODS: The outcomes of primary pterygium excision followed by conjunctival rotational autograft (CRA) combined with intraoperative 0.02% MMC for 5 min (group 1, CRA MMC, n=61) were compared with historical control groups consisting of, pterygium excision with MMC (group 2, n=47), and, pterygium excision with limbal conjunctival autograft (LCAU) (group 3, n=29). The main outcome measures were recurrence rate and complications. RESULTS: The mean follow-up period was 101+/-3 months, 138+/-2 and 137+/-2 months in the CRA-MMC, MMC and LCAU groups respectively. Recurrence was noted in one patient (1.6%) in the CRA-MMC, 12 patients with MMC (25.5%) and 2 patients with LCAU (6.9%). The difference in recurrence rate between CRA-MMC and MMC was statistically significant (p<0.001). Early postoperative complications included 3 conjunctival cysts (1 from the CRA MMC, 2 with MMC alone), 2 symblephara (1 in the MMC group, 1 in the LCAU group), and 1 granuloma in the CRA-MMC group. CONCLUSIONS: Pterygium excision followed by CRA-MMC or LCAU are effective means of preventing recurrence. The use of CRA-MMC in pterygium excision may be considered for cases where conventional autograft harvesting is contraindicated or when large grafts for double-head pterygium are required. PMID- 25837607 TI - Morpho-functional correlation of fundus autofluorescence in Stargardt disease. AB - BACKGROUND: To correlate patterns in short-wavelength (SW) and near-infrared (NIR) fundus autofluorescence (FAF) with morpho-functional outcomes in eyes affected by Stargardt disease. METHODS: Fifty-four eyes of 27 patients were prospectively enrolled. All patients underwent a complete ophthalmologic examination including SW-FAF, NIR-FAF, microperimetry and spectral-domain optical coherence tomography (SD-OCT). The main outcome measures were identification of a correlation between NIR-FAF and SW-FAF patterns within the foveal region and best corrected visual acuity (BCVA) values. Secondary outcome measures were correlation of FAF patterns with SD-OCT findings and retinal sensitivity on microperimetry. RESULTS: Eyes showing a pattern of foveal hyper-FAF on NIR-FAF had a higher BCVA than eyes with a reduced FAF signal (0.44+/-0.23 LogMAR vs 1.08+/-0.19, p<0.001). Similarly, mean sensitivity within 2 degrees of the foveal region was significantly better (6.45+/-2.39 dB) in eyes with hyper-FAF than in eyes with hypo-FAF (0.23+/-0.45 dB, p<0.001). Moreover, eyes with hyper FAF on SW-FAF did not present a significant difference in BCVA (0.73+/-0.31 vs 0.83+/-0.43, p=0.335) and mean retinal sensitivity (4.34+/-3.91 dB vs 2.33+/ 2.96, p=0.07) compared with the subgroup with foveal hypo-FAF. The integrity of both the photoreceptor inner/outer segment junction and the photoreceptor outer segment/retinal pigmented epithelium junction was significantly correlated with a preserved BCVA and a foveal hyper-FAF pattern on NIR-FAF. CONCLUSIONS: Our data suggest that NIR-FAF patterns correlate with morpho-functional outcomes in eyes affected by Stargardt disease. Longitudinal investigations are warranted to assess more precisely the actual contribution of NIR-FAF in the clinical characterisation of Stargardt disease. PMID- 25837608 TI - Clinical features and diagnostic evaluation of 83 biopsy-proven sarcoid uveitis cases. AB - AIMS: To determine the clinical features of patients with uveitis with biopsy proven sarcoidosis, document differences in these features according to ethnicity, age and sex, and assess the diagnostic value of biochemical and imaging examinations. METHODS: Retrospective study of 83 biopsy-proven sarcoid uveitis cases seen at two Departments of Internal Medicine and two Departments of Ophthalmology between April 2004 and March 2014. RESULTS: Caucasian patients presented with uveitis at a later age than non-Caucasian (58 years vs 41 years; p=0.001) and had more often a chronic form (78.3% vs 43.8%; p=0.01). Women had higher rates of chronic macular oedema than men (48.3% vs 14.3%; p=0.01). There were no statistically significant differences between patients aged <=50 years and patients aged >50 years. ACE levels were high (>62 U/L) in 61.7% and lysozyme levels high (>16.7 mg/L) in 83.9% of tested patients. Chest X-rays and CTs were suggestive of sarcoidosis in 62.8% and 91.2% of cases, respectively. Among 21 patients with positive tomography and negative X-rays, 13 were Caucasian women >50 years. Endoscopic ultrasound-guided fine-needle aspiration of intrathoracic nodes contributed to the diagnosis in 7 patients with normal labial salivary gland and transbronchial biopsies. Any of the enzyme tests together with any of the imaging tests identified 100% of the patients. CONCLUSIONS: In this largest European series of biopsy-proven sarcoidosis to date, the outstanding diagnostic ability of enzyme test plus imaging test couple suggests that the recourse to invasive procedures should be limited to patients with ocular involvement that would justify systemic treatments. PMID- 25837609 TI - [What has been happening in the nursing profession for several months?]. PMID- 25837610 TI - [Italian Center for ICNP research and development]. PMID- 25837611 TI - [Self-care assessment in type-2 diabetes: the Italian translation and validation of the Summary of Diabetes Self-Care Activities]. AB - INTRODUCTION: Self-care represents a key factor for diabetes patients to maintain quality of life and to prevent serious disease complications. Self-care standardized assessment tools are needed to evaluate and to promote self-care in diabetes patients. The Summary of Diabetes Self-Care Activities Scale (SDSCA) has been widely used in clinical and research settings and has been translated in many languages. Validity and reliability of this self-report scale were reported by several studies. However, SDSCA has not yet been translated, culturally adapted and tested in the Italian context. The aim of this methodological research was to translate and to provide a first validation study of the Italian SDSCA - 11 item Version. METHODS: A process of translation, back-translation and semantic concordance evaluation has been performed in order to translate the SDSCA into Italian language in collaboration with the original authors. A cross sectional survey has been planned to test internal consistency and test -retest reliability on a convenience sample of 80 type 2 diabetes patients. As secondary objective, SDSCA criterion validity has been explored referring to a range of clinical outcomes as glicated emoglobin and presence of complications. RESULTS: A description of respondents' self-care abilities is provided for the whole sample and for sub-groups by gender, age, instruction and income levels. Cronbach's Alfa and Intraclass Correlation Coefficient showed acceptable values considering the multidimensionality of SDSCA. High values were obtained in 3 out of 5 sub-classes of items. As in previous studies, specific diet and physical exercise sub-classes showed limited internal consistency. Cohen's Kappa Concordance Correlation Coefficient and t-test demonstrated high test-retest reliability of SDSCA. Overall SDSCA score did not show significant correlations with selected clinical outcomes; however 3 SDSCA single items significantly correlated with glicated emoglobin, complications and the clinical judgment of the diabetes case manager nurse. CONCLUSION: Further researches involving larger samples are needed to integrate data about Italian SDSCA performances, especially concerning construct and criterion validity. However, based on these preliminary results, SDSCA could find relevant applications in clinical settings to systematically evaluate, to compare over time and to improve specific self-care abilities of diabetes patients. PMID- 25837612 TI - [The model of Human Caring: results of a pre- and post-intervention study with a control group]. AB - INTRODUCTION: The "Human Caring" model is a philosophy of care based on individual centrality and which, although developed within nursing discipline, could be used by all professionals who take care of individuals. Nurses who work within the field of Mental Health, is subjected to a considerable emotional burden and it is believed that the introduction of this model can have a positive impact. OBJECTIVE: To evaluate the effects of the introduction of the model Human Caring in the Department of Mental Health Asl Cuneo 1, in order to improve health care professionals' well-being and patients' perception with respect to care and assistance. METHOD: A pre and post intervention design approach with control group where variables were measured before (T0) and after (T1) the implementation of the model of care Human Caring. RESULTS: 80 health care professionals and 125 clients were observed. Results show a non statistically significant difference between the pre and post test both for health care professionals and clients. CONCLUSIONS: Human Caring model does not seem to have a positive impact in the short term. However, it is arguably a protective action for health care professionals that further studies should deeply explore with longer period of follow-up. PMID- 25837613 TI - [The use of expressive writing in the course of care for cancer patients to reduce emotional distress: analysis of the literature]. AB - AIM: The emotional distress represents one of the symptoms most frequently reported in the cancer patient in therapy, increasing the risk of developing a disease depressive. Through the analysis of the literature we want to assess whether the use of expressive writing on cancer patients in their care pathway compared to the use of writing neutral reduces emotional distress. METHOD: The bibliographic search was conducted using the databases CINAHL, PubMed, Cochrane Library and PsycInfo. RESULTS: The results of research conducted on 7 randomized controlled trials, including 3 pilot studies have shown after expressive writing sessions (experimental group) versus neutral writing (control group) a significant reduction in distress in the experimental group early stages of cancer (p = 0,0183); in patients with a diagnosis of metastatic assigned to the group expressive writing there was a statistically significant relevance in the reduction of mood disorders (p = 0,03).Were determined statistically significant group differences also with respect to some measure on the quality of sleep (p = 0,04). The expressive writing did not produce significant reductions in psychological distress and improvements in physical health (p > 0,20) in patients diagnosed with metastatic disease of long duration and, in the palliative care there have been results of feasibility for poor adherence at follow-up. CONCLUSION: From the results it is evident that the strategies of expressive writing improves the management of the disease, reduce the physical and psychological symptoms related to the tumor while reducing the emotional distress in patients at an early stage of the disease. PMID- 25837614 TI - [The ability of Decision Making in nursing students and user satisfaction: a quasi-experimental study]. AB - AIM: The aim of the study is to measure 3rd year students' ability on decision making before and after the internship, where different educational strategies were experienced evaluating self perceived clients satisfaction. METHODS: This is a quasi-experimental pre-post intervention study 14 students of the 3rd year was asked to elaborate six clinical cases, for a total of 84 health care plans both before and after the clinical internship. During the internship discussions led by tutors, briefing and debriefing sessions once a week were set up and health care plans developed by students were used. The Newcastle Satisfaction with Nursing Scales questionnaire was used to detect clients satisfaction administered both during the internship and later on. RESULTS: Students have shown an increase from 19 to 69% in the ability to detect priority health care problems in the post test as well as in developing correct nursing interventions, from 24 to 33%.Related factors and defining characteristics are improved at the limit of statistical significance. Clients claim they were fully satisfied with received care both with nursing students and without. CONCLUSIONS: Experimented educational strategies seems to be significantly related to the ability of nursing intervention/decision making. The internship has proven to be an effective model of education. PMID- 25837615 TI - [The graduate, the head nurse and the nursing supervisor. A descriptive study of the competence of recent graduates]. AB - The study describes the representations of nursing graduate, by professionals involved in their socialization work. The study is a qualitative one. A convenience sample of 19 individuals was set up, graduate nurses (10), head nurses (6) and nurses' manager (3)were interviewed. A semi structured interviewed was carried out. aimed at investigate their own beliefs about relational competence, technical-operational and organizational skills, desired and held by graduates. The interviews were audio recorded and transcribed. The corpus was analyzed using appropriate software, comparing the three roles involved with respect to the three areas of expertise. Results show a lack of relational competences and emotional control by Graduates both with colleagues and patients. In addition to this, an overall reluctance of established teams to adopt new working methods and graduate competences too focused on theory. The results with respect to competences highlight the need to strength the training with respect to care and relationship with patients for recent graduate, the difficulty of management to set up technical and operational innovations, the need for an interactional approach of the three professional profiles. The study proposes actions aimed at a better graduates' social and professional integration using the contributions of professionals directly involved in the organization. Furthermore positive action were suggested both during university studies and within organizational contexts in nursing profession. PMID- 25837616 TI - Distraction as a technique to control pain in pediatric patients during venipuncture. A narrative review of literature. AB - INTRODUCTION: Distraction is a non-pharmacological intervention aimed to reduce procedural pain in children. Venipuncture is one of the most widely used diagnostic and therapeutic procedure in pediatric patients. Analgesia during venipuncture may be efficiently achieved with distracting techniques. OBJECTIVE: To describe active and passive distraction techniques to reduce distress in children undergoing venipuncture. METHOD: Data from CINHAL, PubMed, ILISI and Cochrane's databases were used to review existing literature and primary and secondary studies published between 2003 and 2014 were included. Queries were obtained with keywords such as distraction, complementary therapies, pain, pediatric, the Boolean operators AND and OR were used. RESULT: Twenty eligible articles out of the one hundred and forty-three retrieved (20/143) were selected; among these there were 3 systematic and 5 narrative reviews, 11 experimental and quasi-experimental studies and 1 observational study. Active and passive distraction techniques seemed extremely effective to reduce distress and pain in children undergoing venipuncture. Modest evidence of efficacy and absent side effects support this approach. CONCLUSION: Further RCTs are needed to compare the different types of existing active and passive distraction techniques. The presence of parents and the location where painful procedures are administered should be included in the assessment of this approach. PMID- 25837617 TI - Worst Souvenir Ever? The Increasing Trend of Travel-Related Dermatoses / Votre pire souvenir? La tendance croissante aux dermatoses du voyage. PMID- 25837618 TI - Methacrylate allergy presenting as a persistent eczematous plaque on the dorsal hand of a dental assistant: peculiar behaviours make for bizarre patterns of dermatitis. PMID- 25837619 TI - Basal cell carcinoma arising from epidermal cyst. PMID- 25837620 TI - The need for encryption in mobile teledermatology. PMID- 25837621 TI - RE: The Need for Encryption in Mobile Teledermatology. PMID- 25837622 TI - Managing comorbidities in patients with chronic heart failure: first, do no harm. AB - Heart failure (HF) affects approximately 5.1 million adults in the USA, with expectations of a rise to nearly 8 million adults by 2030. Patients with HF are at increased risk for morbidity/mortality, and comorbidities can further complicate care for these patients. Diabetes mellitus, chronic pain, arrhythmias, and depression are diagnoses that often coexist with HF. Medications commonly used to treat these comorbidities may induce or worsen HF symptoms, so determining appropriate drug therapy is important. Healthcare providers must understand the relationship between these medications and HF in order to improve prescribing practices to increase patient safety and reduce morbidity and mortality. This manuscript discusses the association between certain medications used to treat the aforementioned diagnoses and their relationship to HF. The purpose of this article is to provide guidance on which pharmacologic options require special consideration, increased monitoring, or complete avoidance in HF patients with diabetes mellitus, chronic pain, arrhythmias, and/or depression. PMID- 25837624 TI - 'Acceptability' of a new oral suspension formulation of mercaptopurine in children with acute lymphoblastic leukaemia. AB - AIM: The aim of this questionnaire-based survey was to determine the 'acceptability' of Xaluprine(r), a new oral liquid formulation of mercaptopurine, when administered chronically to children during the maintenance treatment phase of acute lymphoblastic leukaemia. PATIENTS AND METHODS: This was a single centre survey of children (aged 3 to 16 years) and their parents at a routine follow-up visit during the maintenance phase of acute lymphoblastic leukaemica treatment. The questionnaire probed for their views on overall acceptability such as taste, smell, incidences of vomiting, ease and willingness to take Xaluprine(r) on a daily basis, and utilised a 5-point facial hedonic scale (1 = bad, 5 = good) as well as open/closed questions. RESULTS: Twenty-two children were recruited; 17 (77%) scored taste between 3 and 5 ('okay' to 'good') and 20 (91%) scored smell between 3 and 5. Only four children (18%) reported an aftertaste. Of the five children (23%) who scored taste as 1 or 2 ('bad'), three found taking all oral medicines difficult. Six children (27%) reported vomiting, but this was not considered related to Xaluprine(r). Seven children (32%) sometimes complained that they did not want to take Xaluprine(r); 15 (68%) never complained. In response to the question, 'How easy is it for you to take Xaluprine(r)?' 18 children (82%) reported that it was 'Easy all the time.' This was more favourable than other oral liquid medicines that they were taking concurrently. CONCLUSION: The results of this survey show that Xaluprine(r) has good overall acceptability in the paediatric population and suggests that Xaluprine(r) is an important, alternative, age-appropriate formulation of mercaptopurine. PMID- 25837623 TI - Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription. AB - Protein quality control is essential for clearing misfolded and aggregated proteins from the cell, and its failure is associated with many neurodegenerative disorders. Here, we identify two genes, ufd-2 and spr-5, that when inactivated, synergistically and robustly suppress neurotoxicity associated with misfolded proteins in Caenorhabditis elegans. Loss of human orthologs ubiquitination factor E4 B (UBE4B) and lysine-specific demethylase 1 (LSD1), respectively encoding a ubiquitin ligase and a lysine-specific demethylase, promotes the clearance of misfolded proteins in mammalian cells by activating both proteasomal and autophagic degradation machineries. An unbiased search in this pathway reveals a downstream effector as the transcription factor p53, a shared substrate of UBE4B and LSD1 that functions as a key regulator of protein quality control to protect against proteotoxicity. These studies identify a new protein quality control pathway via regulation of transcription factors and point to the augmentation of protein quality control as a wide-spectrum antiproteotoxicity strategy. PMID- 25837625 TI - Optimizing culture medium composition to improve oligodendrocyte progenitor cell yields in vitro from subventricular zone-derived neural progenitor cell neurospheres. AB - Neural Stem and Progenitor Cells (NSC/NPC) are gathering tangible recognition for their uses in cell therapy and cell replacement therapies for human disease, as well as a model system to continue research on overall neural developmental processes in vitro. The Subventricular Zone is one of the largest NSC/NPC niches in the developing mammalian Central Nervous System, and persists through to adulthood. Oligodendrocyte progenitor cell (OPC) enriched cultures are usefull tools for in vitro studies as well as for cell replacement therapies for treating demyelination diseases. We used Subventricular Zone-derived NSC/NPC primary cultures from newborn mice and compared the effects of different growth factor combinations on cell proliferation and OPC yield. The Platelet Derived Growth Factor-AA and BB homodimers had a positive and significant impact on OPC generation. Furthermore, heparin addition to the culture media contributed to further increase overall culture yields. The OPC generated by this protocol were able to mature into Myelin Basic Protein-expressing cells and to interact with neurons in an in vitro co-culture system. As a whole, we describe an optimized in vitro method for increasing OPC. PMID- 25837626 TI - Seeing the unseen--bioturbation in 4D: tracing bioirrigation in marine sediment using positron emission tomography and computed tomography. AB - Understanding spatial and temporal patterns of bioirrigation induced by benthic fauna ventilation is critical given its significance on benthic nutrient exchange and biogeochemistry in coastal ecosystems. The quantification of this process challenges marine scientists because faunal activities and behaviors are concealed in an opaque sediment matrix. Here, we use a hybrid medical imaging technique, positron emission tomography and computed tomography (PET/CT) to provide a qualitative visual and fully quantitative description of bioirrigation in 4D (space and time). As a study case, we present images of porewater advection induced by the well-studied lugworm (Arenicola marina). Our results show that PET/CT allows more comprehensive studies on ventilation and bioirrigation than possible using techniques traditionally applied in marine ecology. We provide a dynamic three-dimensional description of bioirrigation by the lugworm at very high temporal and spatial resolution. Results obtained with the PET/CT are in agreement with literature data on lugworm ventilation and bioirrigation. Major advantages of PET/CT over methods commonly used are its non-invasive and non destructive approach and its capacity to provide information that otherwise would require multiple methods. Furthermore, PET/CT scan is versatile as it can be used for a variety of benthic macrofauna species and sediment types and it provides information on burrow morphology or animal behavior. The lack of accessibility to the expensive equipment is its major drawback which can only be overcome through collaboration among several institutions. PMID- 25837627 TI - A family with atypical Hailey Hailey disease--is there more to the underlying genetics than ATP2C1? AB - The autosomal dominant Hailey Hailey disease (HHD) is caused by mutations in the ATP2C1 gene encoding for human secretory pathway Ca2+/Mn2+ ATPase protein (hSPCA1) in the Golgi apparatus. Clinically, HHD presents with erosions and hyperkeratosis predominantly in the intertrigines. Here we report an exome next generation sequencing (NGS) based analysis of ATPase genes in a Greek family with 3 HHD patients presenting with clinically atypical lesions mainly localized on the neck and shoulders. By NGS of one HHD-patient and in silico SNP calling and SNP filtering we identified a SNP in the expected ATP2C1 gene and SNPs in further ATPase genes. Verification in all 3 affected family members revealed a heterozygous frameshift deletion at position 2355_2358 in exon 24 of ATP2C1 in all three patients. 7 additional SNPs in 4 ATPase genes (ATP9B, ATP11A, ATP2B3 and ATP13A5) were identified. The SNPs rs138177421 in the ATP9B gene and rs2280268 in the ATP13A5 gene were detected in all 3 affected, but not in 2 non affected family members. The SNPs in the ATP2B3 and ATP11A gene as well as further SNPs in the ATP13A5 gene could not be confirmed in all affected family members. One may speculate that besides the level of functional hSPCA1 protein, levels of other ATPase proteins may influence expressivity of the disease and might also contribute, as in this case, to atypical presentations. PMID- 25837628 TI - Efficiency of ITS sequences for DNA barcoding in Passiflora (Passifloraceae). AB - DNA barcoding is a technique for discriminating and identifying species using short, variable, and standardized DNA regions. Here, we tested for the first time the performance of plastid and nuclear regions as DNA barcodes in Passiflora. This genus is a largely variable, with more than 900 species of high ecological, commercial, and ornamental importance. We analyzed 1034 accessions of 222 species representing the four subgenera of Passiflora and evaluated the effectiveness of five plastid regions and three nuclear datasets currently employed as DNA barcodes in plants using barcoding gap, applied similarity-, and tree-based methods. The plastid regions were able to identify less than 45% of species, whereas the nuclear datasets were efficient for more than 50% using "best match" and "best close match" methods of TaxonDNA software. All subgenera presented higher interspecific pairwise distances and did not fully overlap with the intraspecific distance, and similarity-based methods showed better results than tree-based methods. The nuclear ribosomal internal transcribed spacer 1 (ITS1) region presented a higher discrimination power than the other datasets and also showed other desirable characteristics as a DNA barcode for this genus. Therefore, we suggest that this region should be used as a starting point to identify Passiflora species. PMID- 25837629 TI - Role of long-range protein dynamics in different thymidylate synthase catalyzed reactions. AB - Recent studies of Escherichia coli thymidylate synthase (ecTSase) showed that a highly conserved residue, Y209, that is located 8 A away from the reaction site, plays a key role in the protein's dynamics. Those crystallographic studies indicated that Y209W mutant is a structurally identical but dynamically altered relative to the wild type (WT) enzyme, and that its turnover catalytic rate governed by a slow hydride-transfer has been affected. The most challenging test of an examination of a fast chemical conversion that precedes the rate-limiting step has been achieved here. The physical nature of both fast and slow C-H bond activations have been compared between the WT and mutant by means of observed and intrinsic kinetic isotope effects (KIEs) and their temperature dependence. The findings indicate that the proton abstraction step has not been altered as much as the hydride transfer step. Additionally, the comparison indicated that other kinetic steps in the TSase catalyzed reaction were substantially affected, including the order of the substrate binding. Enigmatically, although Y209 is H bonded to 3'-OH of 2'-deoxyuridine-5'-mono-phosphate (dUMP), its altered dynamics is more pronounced on the binding of the remote cofactor, (6R)-N5,N10-methylene 5,6,7,8-tetrahydrofolate (CH2H4folate), revealing the importance of long-range dynamics of the enzymatic complex and its catalytic function. PMID- 25837630 TI - Enhancement of phenol biodegradation by Pseudochrobactrum sp. through ultraviolet induced mutation. AB - The phenol-degrading efficiency of Pseudochrobactrum sp. was enhanced by ultraviolet (UV) irradiation. First, a bacterial strain, Pseudochrobactrum sp. XF1, was isolated from the activated sludge in a coking plant. It was subjected to mutation by UV radiation for 120 s and a mutant strain with higher phenol degrading efficiency, Pseudochrobactrum sp. XF1-UV, was selected. The mutant strain XF1-UV was capable of degrading 1800 mg/L phenol completely within 48 h and had higher tolerance to hydrogen ion concentration and temperature variation than the wild type. Haldane's kinetic model was used to fit the exponential growth data and the following kinetic parameters were obtained: MUmax = 0.092 h 1, Ks = 22.517 mg/L, and Ki = 1126.725 mg/L for XF1, whereas MUmax = 0.110 h-1, Ks = 23.934 mg/L, and Ki = 1579.134 mg/L for XF1-UV. Both XF1 and XF1-UV degraded phenol through the ortho-pathway; but the phenol hydroxylase activity of XF1-UV1 was higher than that of XF1, therefore, the mutant strain biodegraded phenol faster. Taken together, our results suggest that Pseudochrobactrum sp. XF1-UV could be a promising candidate for bioremediation of phenol-containing wastewaters. PMID- 25837631 TI - Development of an efficient electroporation method for iturin A-producing Bacillus subtilis ZK. AB - In order to efficiently introduce DNA into B. subtilis ZK, which produces iturin A at a high level, we optimized seven electroporation conditions and explored an efficient electroporation method. Using the optimal conditions, the electroporation efficiency was improved to 1.03 * 10(70 transformants/MUg of DNA, an approximately 10,000-fold increase in electroporation efficiency. This efficiency is the highest electroporation efficiency for B. subtilis and enables the construction of a directed evolution library or the knockout of a gene in B. subtilis ZK for molecular genetics studies. In the optimization process, the combined effects of three types of wall-weakening agents were evaluated using a response surface methodology (RSM) design, which led to a two orders of magnitude increase in electroporation efficiency. To the best of our limited knowledge, this study provides the first demonstration of using an RSM design for optimization of the electroporation conditions for B. subtilis. To validate the electroporation efficiency, a case study was performed and a gene (rapC) was inactivated in B. subtilis ZK using a suicide plasmid pMUTIN4. Moreover, we found that the rapC mutants exhibited a marked decrease in iturin A production, suggesting that the rapC gene was closely related to the iturin A production. PMID- 25837633 TI - Correction: Mezei, Z.A., et al; Factor XIII B subunit polymorphisms and the risk of coronary artery disease. Int. J. Mol. Sci. 2015, 16, 1143-1159. PMID- 25837632 TI - Characterization and structure prediction of partial length protein sequences of pcoA, pcoR and chrB genes from heavy metal resistant bacteria from the Klip River, South Africa. AB - The Klip River has suffered from severe anthropogenic effects from industrial activities such as mining. Long-term exposure to heavy metal pollution has led to the development of heavy metal resistant strains of Pseudomonas sp. KR23, Lysinibacillus sp. KR25, and E. coli KR29. The objectives of this study were to characterize the genetics of copper and chromate resistance of the isolates. Copper and chromate resistance determinants were cloned and sequenced. Open reading frames (ORFs) related to the genes CopA and CopR were identified in E. coli KR29, PcoA in Lysinibacillus sp. KR25 and none related to chromate resistance were detected. The 3D-models predicted by I-TASSER disclose that the PcoA proteins consist of beta-sheets, which form a part of the cupredoxin domain of the CopA copper resistance family of genes. The model for PcoR_29 revealed the presence of a helix turn helix; this forms part of a DNA binding protein, which is part of a heavy metal transcriptional regulator. The bacterial strains were cured using ethidium bromide. The genes encoding for heavy metal resistance and antibiotic resistance were found to be located on the chromosome for both Pseudomonas sp. (KR23) and E. coli (KR29). For Lysinibacillus (KR25) the heavy metal resistance determinants are suspected to be located on a mobile genetic element, which was not detected using gel electrophoresis. PMID- 25837634 TI - Effect of comprehensive oncogenetics training interventions for general practitioners, evaluated at multiple performance levels. AB - General practitioners (GPs) are increasingly called upon to identify patients at risk for hereditary cancers, and their genetic competencies need to be enhanced. This article gives an overview of a research project on how to build effective educational modules on genetics, assessed by randomized controlled trials (RCTs), reflecting the prioritized educational needs of primary care physicians. It also reports on an ongoing study to investigate long-term increase in genetic consultation skills (1-year follow-up) and interest in and satisfaction with a supportive website on genetics among GPs. Three oncogenetics modules were developed: an online Continuing Professional Development (G-eCPD) module, a live genetic CPD module, and a "GP and genetics" website (huisartsengenetica.nl) providing further genetics information applicable in daily practice. Three assessments to evaluate the effectiveness (1-year follow-up) of the oncogenetic modules were designed: 1.An online questionnaire on self-reported genetic competencies and changes in referral behaviour, 2.Referral rates from GPs to clinical genetics centres and 3.Satisfaction questionnaire and visitor count analytics of supportive genetics website. The setting was Primary care in the Netherlands and three groups of study participants were included in the reported studies:. Assessment 1. 168 GPs responded to an email invitation and were randomly assigned to an intervention or control group, evaluating the G-eCPD module (n = 80) or the live module (n = 88). Assessment 2. Referral rates by GPs were requested from the clinical genetics centres, in the northern and southern parts of the Netherlands (Amsterdam and Maastricht), for the two years before (2010 [n = 2510] and 2011 [n = 2940]) and the year after (2012 [n = 2875]) launch of the oncogenetics CPD modules and the website. Assessment 3. Participants of the website evaluation were all recruited online. When they visited the website during the month of February 2013, a pop-up invitation came up. Of the 1350 unique visitors that month, only 38 completed the online questionnaire. Main outcomes measure showed long-term (self-reported) genetic consultation skills (i.e. increased genetics awareness and referrals to clinical genetics centres) among GPs who participated in the oncogenetic training course, and interest in and satisfaction with the supportive website. 42 GPs (52%) who previously participated in the G-eCPD evaluation study and 50 GPs (57%) who participated in the live training programme responded to the online questionnaire on long-term effects of educational outcome. Previous RCTs showed that the genetics CPD modules achieved sustained improvement of oncogenetic knowledge and consultation skills (3-months follow-up). Participants of these RCTs reported being more aware of genetic problems long term; this was reported by 29 GPs (69%) and 46 GPs (92%) participating in the G-eCPD and live module evaluation studies, respectively (Chisquare test, p<0.005). One year later, 68% of the respondents attending the live training reported that they more frequently referred patients to the clinical genetics centres, compared to 29% of those who attended the online oncogenetics training (Chisquare test, p<0.0005). However, the clinical genetics centres reported no significant change in referral numbers one year after the training. Website visitor numbers increased, as did satisfaction, reflected in a 7.7 and 8.1 (out of 10) global rating of the website (by G-eCPD and live module participants, respectively). The page most often consulted was "family tree drawing". Self-perceived genetic consultation skills increased long-term and GPs were interested in and satisfied with the supportive website. Further studies are necessary to see whether the oncogenetics CPD modules result in more efficient referral. The results presented suggest we have provided a flexible and effective framework to meet the need for effective educational programmes for non geneticist healthcare providers, enabling improvement of genetic medical care. PMID- 25837635 TI - Silicon-mediated resistance in a susceptible rice variety to the rice leaf folder, Cnaphalocrocis medinalis Guenee (Lepidoptera: Pyralidae). AB - The rice leaf folder, Cnaphalocrocis medinalis (Guenee), is one of the most destructive rice pests in Asian countries. Rice varieties resistant to the rice leaf folder are generally characterized by high silicon content. In this study, silicon amendment, at 0.16 and 0.32 g Si/kg soil, enhanced resistance of a susceptible rice variety to the rice leaf folder. Silicon addition to rice plants at both the low and high rates significantly extended larval development and reduced larval survival rate and pupation rate in the rice leaf folder. When applied at the high rate, silicon amendment reduced third-instars' weight gain and pupal weight. Altogether, intrinsic rate of increase, finite rate of increase and net reproduction rate of the rice leaf folder population were all reduced at both the low and high silicon addition rates. Although the third instars consumed more in silicon-amended treatments, C:N ratio in rice leaves was significantly increased and food conversion efficiencies were reduced due to increased silicon concentration in rice leaves. Our results indicate that reduced food quality and food conversion efficiencies resulted from silicon addition account for the enhanced resistance in the susceptible rice variety to the rice leaf folder. PMID- 25837636 TI - Morphometric parameters of extraocular rectus muscles evaluated by dynamic multipositional magnetic resonance. AB - PURPOSE: To establish normal values of morphologic parameters of extraocular rectus muscles visualized in different gaze positions by means of an accessible method of dynamic-multipositional magnetic resonance imaging (dmMRI). METHODS: Twenty eyes of 10 healthy, orthotropic subjects were examined. A 1.5T scanner (Avanto) with standard head coil was used. The protocol of dmMRI included 6 gaze positions in 10 degrees intervals in which 13-second, orbital, T2 sequences were performed in quasi-coronal plane. The measurements of extraocular rectus muscles shape, sectional area, and volume were obtained with use of ImageJ 1.38x (NIH) software. RESULTS: Relative change in cross-sectional area between position of rest and gaze of action of each muscle appears to be significant just in the medial and posterior parts of their belly. The maximal cross-section area increases significantly when the muscle contracts (21% to 32% depending on the muscle). The superior rectus must be assessed along with levator palpebrae as the distinction between their bellies is difficult. Relative change in partial muscle volume on contraction ranged from 12.3% to 21.6% depending on the muscle. Muscle contraction results in more circular shape of its belly while relaxation is more of an ellipse. CONCLUSIONS: Dynamic-multipositional MRI performed in the proposed manner is an accessible and repeatable method for visualization of extraocular rectus muscles. Assessment of morphometric parameters such as muscle shape, maximal cross-section area, and partial muscle volume is easy with digital imaging software. PMID- 25837638 TI - Meta-analysis of retinal changes in unilateral amblyopia using optical coherence tomography. AB - PURPOSE: To evaluate retinal changes in unilateral amblyopia using optical coherence tomography. METHODS: Major literature databases were searched for relevant studies. The primary outcome parameters were foveal minimum thickness (FMT), mean foveal thickness (MFT), mean macular thickness (MMT), and peripapillary retinal nerve fiber layer (pRNFL) thickness. Efficacy estimates were evaluated by standardized mean difference (SMD) and 95% confidence interval (CI) for changes in the outcomes of interest. RESULTS: This meta-analysis included 28 clinical trials involving 408 patients .The FMT, MFT, and MMT in the amblyopic eyes was significantly greater than that of the fellow eyes (SMD = 0.22, 95% CI 0.05-0.39, p = 0.011; SMD = 0.21, 95% CI 0.06-0.36, p = 0.005; SMD = 0.21, 95% CI 0.08-0.35, p = 0.002, respectively). Only FMT was significantly increased in the amblyopia group compared with the normal control group (SMD = 0.38, 95% CI 0.19-0.57, p<0.00001). Analysis showed that pRNFL thickness in the amblyopic eyes was thicker than in the fellow eyes (SMD = 0.13, 95% CI 0.02-0.24, p = 0.016). We did not find that those outcome measures differ between strabismic and anisometropic amblyopia. CONCLUSIONS: The pooled evidence indicates that the amblyopic process may involve the retina, especially the macula. A thicker foveola was found in the amblyopic eyes when compared with visually normal control eyes. Further larger-scale studies especially involving emmetropic normal subjects will be valuable. PMID- 25837637 TI - Clinical analysis of 23-gauge vitrectomy for the treatment of acute endophthalmitis after cataract surgery. AB - PURPOSE: We performed a retrospective study to evaluate the surgical efficacy and timing of 23-G vitrectomy for acute endophthalmitis following cataract surgery, and to determine when silicone oil tamponade and intraocular lens (IOL) removal are indicated during vitrectomy for endophthalmitis. METHODS: We enrolled 21 patients (21 eyes) diagnosed with acute endophthalmitis following cataract surgery who underwent endoscope-assisted 23-G vitrectomy using a wide-angle noncontact lens. Silicone oil tamponade was performed when retinal tear or detachment occurred. The IOL was not removed during primary vitrectomy. Postoperative systemic broad-spectrum antibiotics were used. RESULTS: All infections were controlled by treatment. Best-corrected visual acuity was >0.05 in 14 patients (66.7%) after treatment, which was significantly higher than that before treatment (2/21, 9.5%). Two patients experienced retinal detachment at 10 and 14 days after primary vitrectomy; the IOL was removed during secondary surgery, and silicone oil tamponade was performed. One patient experienced endophthalmitis recurrence 2 months after vitrectomy; secondary surgery was performed to remove the peripheral vitreous body, the pars plana of the ciliary body, and the IOL and capsule. CONCLUSIONS: Vitrectomy should be performed when acute endophthalmitis is diagnosed following cataract surgery. Silicone oil tamponade should be performed only when retinal break or detachment occurs. The IOL does not necessarily require removal. PMID- 25837639 TI - Intraocular lens power changes after mitomycin trabeculectomy. AB - PURPOSE: To evaluate biometric changes after mitomycin C augmented trabeculectomy and their effect on intraocular lens (IOL) power calculation using different formulas. METHODS: In this prospective, interventional case series study, 34 eyes of 31 phakic glaucoma patients who were scheduled for primary trabeculectomy were enrolled. Using a noncontact biometry device (Lenstar, Haag-Streit AG, Koeniz, Switzerland), axial length (AL), mean corneal power, and IOL power were calculated with the Hoffer Q, Holladay, and SRK/T formulas 1 day before surgery and compared to those obtained 3 and 6 months after the operation. Bland-Altman plot was used to determine agreement between preoperative and postoperative IOL power values. RESULTS: The AL was significantly decreased at month 3 (-0.14 +/- 0.13 mm) and month 6 (-0.14 +/- 0.15 mm) as compared to baseline values (both p values <0.001). Mean corneal power increased significantly at month 3 (0.41 +/- 0.46 D; p<0.001) and month 6 (0.27 +/- 0.47 D; p = 0.008). Using different formulas, IOL power did not change significantly after the operation (all ps>=0.17). The IOL power changes using the Hoffer Q formula were -0.09 +/- 0.76 (p = 0.505) and 0.14 +/- 0.9 D (p = 0.442) at 3 and 6 months, respectively; corresponding values were -0.1 +/- 0.75 (p = 0.427) and 0.16 +/- 0.79 D (p = 0.319) for Holladay and 0.01 +/- 0.64 (p = 0.895) and 0.2 +/- 0.71 D (p = 0.17) employing the SRK/T formula. CONCLUSIONS: Despite significant changes in AL and corneal power after trabeculectomy, IOL power calculation remains unchanged; therefore adjustment of IOL power calculation after trabeculectomy seems unnecessary. PMID- 25837640 TI - Choroidal and peripapillary retinal nerve fiber layer thickness in adults with anisometropic amblyopia. AB - PURPOSE: To evaluate choroidal thickness, macular thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness in amblyopic eyes compared to fellow and normal control eyes using high-definition spectral-domain optical coherence tomography (SD-OCT). METHODS: Fifty-four without any systemic problem and ocular disease participated in this prospective study. Inclusion criteria included individuals older than 18 years with anisometropic amblyopia. Choroidal thickness, central macular thickness (CMT), and RNFL thickness were measured by using enhanced depth imaging SD-OCT. The choroidal thickness was measured at the fovea and at 500 um intervals from the foveal center in both temporal and nasal directions. Axial length measurements of the cases were also recorded. RESULTS: Mean peripapillary RNFL thickness of the amblyopic, fellow, and control eyes was 107.5 +/- 15.5 um, 109.3 +/- 12.7 um, and 108.8 +/- 8.6 um, respectively (p = 0.343). The average CMT was 231.7 +/- 14.7 um in amblyopic eyes, 232.5 +/- 15.7 MUm in fellow eyes, and 230.8 +/- 14.8 um in control eyes (p = 0.599). Mean subfoveal choroidal thickness was significantly greater in the amblyopic eyes than in the fellow and control eyes (396.3 +/- 104.3 um, 361.0 +/- 103.9 um, 390.6 +/- 91.7 um). Mean axial measurement in amblyopic eyes was 22.7 +/- 1.3 mm (20.5-26.1), in fellow eyes 23.1 +/- 0.9 mm (20.9-25.0), and in control eyes 23.3 +/- 0.9 mm. CONCLUSIONS: In adults with anisometropic amblyopia, subfoveal, temporal, and nasal choroidal thickness of amblyopic eyes are significantly thicker than in fellow eyes. However, no significant differences in peripapillary RNFL thickness or CMT were found between amblyopic and fellow or control eyes. PMID- 25837641 TI - Choroidal neovascular membrane following hormonal stimulation for in vitro fertilization. AB - PURPOSE: To report the onset of choroidal neovascularization (CNV) following hormonal stimulation for in vitro fertilization (IVF) in a healthy young woman. METHODS: A 31-year-old woman presented with visual impairment following hormonal stimulation for IVF. Clinical history was collected and best-corrected visual acuity (BCVA), complete eye examination, optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography were -performed. RESULTS: Clinical history was negative with the exception of the use of medications for IVF in the previous weeks. Ocular examination revealed the presence of a CNV in the right eye, confirmed by OCT and FA, with a BCVA of 0.7 decimal units. Possible ocular and systemic diseases associated with CNV development were investigated and excluded. Treatment with 3 monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) was effective in reducing CNV size and restoring visual acuity. CONCLUSIONS: This is the first report describing the development of CNV following hormonal stimulation for IVF. The development of CNV may be associated with changes of sex hormones, cytokines, and angiogenic factor levels, including VEGF, induced by hormonal stimulation. PMID- 25837643 TI - Changes in the cornea related to sickle cell disease: a pilot investigation. AB - PURPOSE: To investigate corneal structural changes (central corneal thickness, endothelial cell count, and cellular morphology) in patients with sickle cell disease (SCD). METHODS: This prospective study included 56 patients with SCD and 50 age- and sex-matched healthy subjects without any eye disease aside from refractive errors. Endothelial cell density (ECD), percentage of hexagonality, and the coefficient of variation in cell size (CV) were measured using noncontact specular microscopy, and central corneal thickness (CCT) was measured by pachymetry. RESULTS: The mean CCT value was 509.6 +/- 20.7 MUm in the study group and 520.8 +/- 23.6 MUm in the control group. The mean ECD, CV, and percentage of hexagonality values in the study group were 2712 +/- 335 cells/mm2, 34.5 +/- 5.3%, and 57.2 +/- 6.6%, respectively, and 3030 +/- 247 cells/mm2, 31.6 +/- 5.0%, and 60.4 +/- 6.9% in the control group, respectively. Endothelial cell density (p = 0.001), CCT (p = 0.011), CV (p = 0.005), and percentage of hexagonality values (p = 0.018) were significantly different between the study and control groups. CONCLUSIONS: The results of the current study indicate that patients with SCD had considerable morphologic changes in the structure of the cornea when compared to healthy subjects. PMID- 25837644 TI - Undiagnosed patent foramen ovale as a rare cause for branch retinal artery occlusion. AB - PURPOSE: To present the case of a man with branch retinal artery occlusion (BRAO) and concomitant patent foramen ovale (PFO), which was first diagnosed during the evaluation of BRAO. METHODS: A 35-year-old man presented with blurred vision in the left eye for 2 days. His best-corrected visual acuity (BCVA) was 6/6 in the right eye and 6/12 in the left eye. He had no ophthalmic or medical history. RESULTS: Ophthalmologic examination revealed a left inferior BRAO, confirmed by fluorescein angiography. The patient underwent a thorough diagnostic workup. Cardiologic examination with transesophageal echocardiography revealed a right-to left shunt across a PFO. The patient was treated with clopidogrel and at the 15 day review, BCVA in his left eye was 6/7.5 and the retinal edema was resolved, as detected on optical coherence tomography, but relative afferent pupillary defect was persistent. The patient had developed no other embolic event at the 9-month follow-up, having undergone an operation for PFO repair. CONCLUSIONS: Patent foramen ovale, although usually asymptomatic, should be considered among the potential causes of BRAO, especially in young patients. Prompt diagnosis and liaison with cardiologists is important to help prevent ocular or systemic embolic events and associated morbidity. PMID- 25837645 TI - Comparison of refractive error and central corneal thickness in neonates of diabetic and healthy mothers. AB - PURPOSE: To determine the refractive error and central corneal thickness of neonates born to diabetic mothers and to compare these parameters with those of healthy neonates born to healthy mothers. METHODS: This prospective, cross sectional study was conducted on 16 consecutive full-term neonates born to diabetic mothers and 17 full-term healthy neonates. The neonates underwent ophthalmic examination within the first week of life. Refractive measurements were assessed by retinoscopy. Central corneal thickness was recorded by using ultrasound pachymeter. RESULTS: The mean spherical equivalent for both eyes in the diabetic group was +2.9 +/- 2.6 and significantly greater than that of the nondiabetic group (+1.3 +/- 2.1 D) (p = 0.008). The mean sphere value was +2.6 +/ 2.4 D in the diabetic group and +1.0 +/- 2.0 D in the nondiabetic group, significantly higher in the diabetic group (p = 0.008). In both groups, mean astigmatism was less than 1.00 D, it was lower in the diabetic group, and there was no statistically significant difference between groups (p = 0.95). There were 2 patients in each group with anisometropia. The mean central corneal thickness in the nondiabetic group was 542.9 +/- 21.9 MUm whereas it was 592.0 +/- 40.2 MUm in the diabetic group, which was significantly thicker (p = 0.05). CONCLUSIONS: Our study revealed that neonates of diabetic mothers seem to be more hypermetropic compared to full-term healthy neonates; however, we did not observe any significant astigmatism in either group. Neonates of diabetic mothers had thicker corneas. PMID- 25837646 TI - Correction: Multimorbidity patterns in a national representative sample of the Spanish adult population. PMID- 25837647 TI - Traffic and Criminal Behavior of Adults with Attention Deficit-Hyperactivity with a Prospective Follow-Up from Birth to the Age of 40 Years. AB - OBJECTIVE: The purpose of this study was to investigate whether individuals with attention deficit-hyperactivity disorder (ADHD) followed up to age 40 have a higher mortality, more involvement in criminal behavior, increased traffic accidents, and frequency or registered violations against traffic rules or whether they have been more frequently victims to crimes. METHODS: The ADHD cohort (N = 122) born in 1971-1974 was isolated at the age of 9 years from the base cohort of 865 children who had known risk factors at birth and were still alive at the age of 5 years. Ninety-four healthy individuals born during the same years served as control subjects. None of the individuals with ADHD had used psychostimulants before their adolescence. The follow-up data were available from the newborn period until the ages of 5 and 9 years. At the ages of 16 and 30, the data were collected via questionnaire. For this study, the national police registers (last 5 years) were examined for traffic violations, crimes, or being an object of a criminal act when the persons reached the age of 40 years. RESULTS: Ten men and one woman with ADHD but none of the controls had died by the age of 40. Three died of disease-related incidents, and 8 (13%) died of abnormal causes such as suicide (3), traffic accident (2), substance abuse (2), or violence (1). During the follow-up period, individuals with ADHD had been involved in violent behavior or economic criminality more frequently than the control subjects. They were also more commonly victims of criminal acts. No difference was found in traffic citations between those with ADHD and control subjects (at 35-40 years) when all traffic crimes were considered. A difference was not observed in the frequency of traffic accidents. However, there was a significant difference in drunk driving (at the ages of 30 and 35-40) and the number of persons without a driver's license. DISCUSSION: Subjects with ADHD showed an elevated risk of being involved in criminality and had a higher risk of dying before the age of 40 years. The early detection of ADHD in childhood and appropriate treatments and family support may decrease criminality and save both money and human distress. PMID- 25837648 TI - Shockwave therapy for refractory angina: promising but not definitive. PMID- 25837649 TI - Can optical coherence tomography objectively assess neointimal pattern after stenting? PMID- 25837650 TI - Clinoidal meningioma associated with an internal carotid artery aneurysm. AB - Coexistence of primary brain neoplasms with intracranial aneurysms is rare but presents a diagnostic and therapeutic challenge to healthcare providers. We describe the case of a 60-year-old woman who had a left internal carotid artery aneurysm with a small ipsilateral clinoidal meningioma. The meningioma was an unexpected finding encountered during the surgery for aneurysmal clipping. Both the lesions were dealt with simultaneously. PMID- 25837651 TI - Phlegmasia cerulea dolens in a teenage boy found to have Factor V Leiden. AB - A 16-year-old boy with morbid obesity and asthma presented with 1 week of progressive right leg pain, swelling and discolouration that started 1 week after a minor fall. Ultrasound and then CT with contrast revealed a large occlusive deep venous thrombosis (DVT) extending from the calf through the inferior vena cava bifurcation. Heparin was initiated and catheter-directed thrombolysis with tissue plasminogen activator and balloon angioplasty were performed with good flow postprocedure, however, the clot reaccumulated after several days and the procedure had to be repeated. After this occurred twice more, finally a right common iliac and femoral vein stent was placed to prevent clot reaccumulation and vein stenosis. Hypercoagability testing revealed activated protein C resistance and genetic testing confirmed homozygous Factor V Leiden (FVL). Family history was significant for maternal lower extremity DVT at age 21 and possible DVT in the patient's maternal grandmother. PMID- 25837652 TI - Anterior mediastinal mass due to thoracic splenosis. PMID- 25837653 TI - Psychosis post corona radiata and lentiform nucleus infarction. AB - Complications of stroke can include neuropsychiatric symptoms. However, post stroke psychosis is rare. We report a case where an acute presentation of psychosis, depression and fluctuating cognitive impairment in a middle-aged man turned out to be related to a silent brain infarction. The patient had a background of poorly controlled type 2 diabetes mellitus with glycated haemoglobin level of 9.0-11.0%, hypertension and ischaemic heart disease. His CT brain results showed multifocal infarct with hypodensities at bilateral lentiform nucleus and bilateral corona radiata. His strong genetic predisposition of psychosis and a history of brief psychotic disorder with complete remission 3 years prior to the current presentation might possibly contribute to his post stroke atypical neuropsychiatric presentation, and posed diagnostic challenges. He showed marked improvement with risperidone 6 mg nocte, chlorpromazine 50 mg nocte and fluvoxamine of 200 mg nocte. The need of comprehensive treatments to modify his stroke risk factors was addressed. PMID- 25837654 TI - Diabetic ketoacidosis in the setting of HNF1A-maturity onset diabetes of the young. AB - A female patient was treated for type 1 diabetes following presentation at 12 years of age with hyperglycaemia, polydipsia and weight loss. Eleven years later, while screening relatives attending a genetic diabetes clinic, she was identified as potentially harbouring a mutation in the hepatocyte nuclear factor 1A (HNF1A) gene. Biochemical testing supported the diagnosis of HNF1A-maturity onset diabetes of the young (MODY) and genetic screening was positive for a heterozygous mutation in the HNF1A gene. The patient transitioned from insulin to sulfonylurea therapy. Three years later, in the setting of poor metabolic control, the patient presented to the emergency department with a history of nausea, vomiting and palpitations. A diagnosis of diabetic ketoacidosis (DKA) was confirmed and successfully treated. Although a diagnosis of HNF1A-MODY is rarely considered in a patient with a history of DKA, we demonstrate that DKA is possible in the setting of non-compliance with sulfonylurea therapy. PMID- 25837655 TI - The three faces of herpes simplex epithelial keratitis: a steroid-induced situation. PMID- 25837656 TI - Suspected ovarian molar pregnancy after assisted reproductive technology conception: a diagnostic challenge. AB - A 32-year-old patient with primary infertility received in vitro fertilisation (IVF) therapy. Four weeks later she developed intermittent left iliac fossa pain. Transvaginal ultrasound showed an empty uterus and an adnexal mass adjacent to the right ovary. Serum beta-human chronic gonadotropin was 33,492 IU/L. At laparoscopy a mass attached to right ovary, suggestive of a right ovarian ectopic pregnancy, was excised. Histological examination confirmed an ovarian ectopic gestation, but noted enlarged chorionic villi and trophoblastic atypia, which raised the suspicion of molar pregnancy. Subsequent p57 immunohistochemistry and DNA ploidy studies excluded a mole, however. Cases of suspected molar disease in ectopic pregnancy present a diagnostic challenge for both clinicians and histopathologists, and establishing a definitive diagnosis may be difficult. PMID- 25837657 TI - Herlyn-Werner-Wunderlich syndrome: a rare cause of acute urinary retention in an adolescent girl. PMID- 25837658 TI - Eosinophilic ulcer of the tongue: a rare and confusing clinical entity. AB - Eosinophilic ulcers are rare, benign, reactive and often self-limiting lesions of the oral cavity. Although the aetiology is not clear, trauma is believed to play a role in their development. Clinically, the lesion manifests as an isolated ulcer, with raised, indurated borders and a yellow fibrinous floor; because of its long duration it often leads to the suspicion of squamous cell carcinoma. Although the ulcer is benign in nature, a biopsy is necessary to rule out malignancy. Histopathologically, the ulcer is characterised by the presence of dense inflammatory infiltrate extending into the deeper muscle layers with sheets of lymphocytes intermixed with eosinophils. This is a case report of a 65-year old woman with an eosinophilic ulcer on the lateral border of the tongue. The ulcer healed rapidly after an incisional biopsy and topical steroid application. The final diagnosis was achieved following clinical and histopathological examination. PMID- 25837659 TI - Cellulose nanomaterials in water treatment technologies. AB - Cellulose nanomaterials are naturally occurring with unique structural, mechanical and optical properties. While the paper and packaging, automotive, personal care, construction, and textiles industries have recognized cellulose nanomaterials' potential, we suggest cellulose nanomaterials have great untapped potential in water treatment technologies. In this review, we gather evidence of cellulose nanomaterials' beneficial role in environmental remediation and membranes for water filtration, including their high surface area-to-volume ratio, low environmental impact, high strength, functionalizability, and sustainability. We make direct comparison between cellulose nanomaterials and carbon nanotubes (CNTs) in terms of physical and chemical properties, production costs, use and disposal in order to show the potential of cellulose nanomaterials as a sustainable replacement for CNTs in water treatment technologies. Finally, we comment on the need for improved communication and collaboration across the myriad industries invested in cellulose nanomaterials production and development to achieve an efficient means to commercialization. PMID- 25837660 TI - Evaluating the clinical impact of a genomic classifier in prostate cancer using individualized decision analysis. AB - BACKGROUND: Currently there is controversy surrounding the optimal way to treat patients with prostate cancer in the post-prostatectomy setting. Adjuvant therapies carry possible benefits of improved curative results, but there is uncertainty in which patients should receive adjuvant therapy. There are concerns about giving toxicity to a whole population for the benefit of only a subset. We hypothesized that making post-prostatectomy treatment decisions using genomics based risk prediction estimates would improve cancer and quality of life outcomes. METHODS: We developed a state-transition model to simulate outcomes over a 10 year horizon for a cohort of post-prostatectomy patients. Outcomes included cancer progression rates at 5 and 10 years, overall survival, and quality-adjusted survival with reductions for treatment, side effects, and cancer stage. We compared outcomes using population-level versus individual-level risk of cancer progression, and for genomics-based care versus usual care treatment recommendations. RESULTS: Cancer progression outcomes, expected life-years (LYs), and expected quality-adjusted life-years (QALYs) were significantly different when individual genomics-based cancer progression risk estimates were used in place of population-level risk estimates. Use of the genomic classifier to guide treatment decisions provided small, but statistically significant, improvements in model outcomes. We observed an additional 0.03 LYs and 0.07 QALYs, a 12% relative increase in the 5-year recurrence-free survival probability, and a 4% relative reduction in the 5-year probability of metastatic disease or death. CONCLUSIONS: The use of genomics-based risk prediction to guide treatment decisions may improve outcomes for prostate cancer patients. This study offers a framework for individualized decision analysis, and can be extended to incorporate a wide range of personal attributes to enable delivery of patient centered tools for informed decision-making. PMID- 25837661 TI - Small molecule inhibitor of formin homology 2 domains (SMIFH2) reveals the roles of the formin family of proteins in spindle assembly and asymmetric division in mouse oocytes. AB - Dynamic actin reorganization is the main driving force for spindle migration and asymmetric cell division in mammalian oocytes. It has been reported that various actin nucleators including Formin-2 are involved in the polarization of the spindle and in asymmetric cell division. In mammals, the formin family is comprised of 15 proteins. However, their individual roles in spindle migration and/or asymmetric division have not been elucidated yet. In this study, we employed a newly developed inhibitor for formin family proteins, small molecule inhibitor of formin homology 2 domains (SMIFH2), to assess the functions of the formin family in mouse oocyte maturation. Treatment with SMIFH2 during in vitro maturation of mouse oocytes inhibited maturation by decreasing cytoplasmic and cortical actin levels. In addition, treatment with SMIFH2, especially at higher concentrations (500 MUM), impaired the proper formation of meiotic spindles, indicating that formins play a role in meiotic spindle formation. Knockdown of the mDia2 formins caused a similar decrease in oocyte maturation and abnormal spindle morphology, mimicking the phenotype of SMIFH2-treated cells. Collectively, these results suggested that besides Formin-2, the other proteins of the formin, including mDia family play a role in asymmetric division and meiotic spindle formation in mammalian oocytes. PMID- 25837662 TI - Mini percutaneous nephrolithotomy in the treatment of renal and upper ureteral stones: Lessons learned from a review of the literature. AB - The aim of this review is to present the most recent data regarding the indications of mini percutaneous nephrolithotomy (PCNL), the results and the complications of the method. Medline was searched from 1997 to January 2014, restricted to English language. The Medline search used a strategy including medical subject headings and free-text protocols. PCNL is a well-established treatment option for patients with large and complex renal calculi. In order to decrease morbidity associated with larger instruments like blood loss, postoperative pain and potential renal damage, a modification of the technique of standard PCNL has been developed. This is performed with a miniature endoscope via a small percutaneous tract (11-20 F) and was named as minimally invasive or mini-PCNL. This method was initially described as an alternative percutaneous approach to large renal stones in a pediatric patient population. Furthermore, it has become a treatment option for adults as well, and it is used as a treatment for calculi of various sizes and locations. However, the terminology has not been standardized yet, and the procedure lacks a clear definition. Nevertheless, mini PCNL can achieve comparable stone-free rates to the conventional method, even for large stones. It is a safe procedure, and no major complications are reported. Although less invasiveness has not been clearly demonstrated so far, mini-PCNL is usually related to less blood loss and shorter hospital stay than the standard method. PMID- 25837663 TI - Mutations of the human interferon alpha-2b gene in brain tumor patients exposed to different environmental conditions. AB - This study was aimed at finding out mutations of an anticancerous, antiviral and immunomodulatory gene (human interferon alpha-2b) in low- and high-grade brain tumor patients and correlate from hematological profiles. A molecular analysis was performed in which DNAs were extracted from brain biopsy samples of brain tumor patients. The gene was amplified through the PCR technique, and genetic data from sequencing were analyzed by bioinformatics to determine how mutations will lead to changes in human interferon alpha 2b protein in patients. A total of 38% gene mutations were identified among brain tumor patients. The highest percentage of (36%) frameshift mutations was identified. Hematological analysis shows modulations in the 'lymphocytes' parameter in a majority (64%) of the brain tumor patients. Environmental factors have been reported as risks of brain cancer. Patients were found to be under environmental stress from contaminated drinking water and from local gamma radiations. Brain tumor patients were found to have various mutations in an immunomodulating human interferon alpha-2b gene. These patients had immunosuppression that was further affirmed from their hematological profiles. This analysis may be helpful to develop certain biomarkers that may be used to develop novel immunotherapeutical drugs, which enhance a better immune response. PMID- 25837664 TI - BCR/ABL oncogene-induced PI3K signaling pathway leads to chronic myeloid leukemia pathogenesis by impairing immuno-modulatory function of hemangioblasts. AB - An increasing number of studies indicate that during development, endothelial and hematopoietic cells derive from common progenitors named hemangioblasts that have important roles in the pathogenesis. This is particularly true in chronic myeloid leukemia (CML). Here, we isolated fetal liver kinase-1-positive (Flk1(+)) cells from CML patients and found they expressed BCR/ABL-specific CML oncogene. We examined their biological characteristics as well as immunological functions and further detected the possible molecular mechanism involved in the leukemia genesis. We showed that CML patient-derived Flk1(+)CD31(-)CD34(-) mesenchymal stem cells (MSCs) had normal morphology, phenotype and karyotype but appeared impaired immuno-modulatory function. The capacity of Flk1(+)CD31(-)CD34(-) MSCs from CML patients to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have dampening immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response might originate from MSCs rather than hematopoietic stem cells (HSCs). These Ph(+) putative CML hemangioblast upregulated TGF-beta1 and resultantly activated matrix metalloproteinase-9 (MMP-9) to enhance s-KitL and s-ICAM-1 secretion, which activated c-kit(+) HSCs from the quiescent state to the proliferative state. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor (NF)-kappaB signaling pathway was involved in CML pathogenesis. Flk1(+)CD31(-)CD34(-) MSCs that express BCR/ABL leukemia oncogene are hemangioblasts and they have a critical role in the progression of CML through PI3K/Akt/NF-kappaB signaling pathway. PMID- 25837665 TI - Adenoviral-mediated imaging of gene transfer using a somatostatin receptor cytosine deaminase fusion protein. AB - Suicide gene therapy is a process by which cells are administered a gene that encodes a protein capable of converting a nontoxic prodrug into an active toxin. Cytosine deaminase (CD) has been widely investigated as a means of suicide gene therapy owing to the enzyme's ability to convert the prodrug 5-fluorocytosine (5 FC) into the toxic compound 5-fluorouracil (5-FU). However, the extent of gene transfer is a limiting factor in predicting therapeutic outcome. The ability to monitor gene transfer, non-invasively, would strengthen the efficiency of therapy. In this regard, we have constructed and evaluated a replication deficient adenovirus (Ad) containing the human somatostatin receptor subtype 2 (SSTR2) fused with a C-terminal yeast CD gene for the non-invasive monitoring of gene transfer and therapy. The resulting Ad (AdSSTR2-yCD) was evaluated in vitro in breast cancer cells to determine the function of the fusion protein. These studies demonstrated that both the SSTR2 and yCD were functional in binding assays, conversion assays and cytotoxicity assays. In vivo studies similarly demonstrated the functionality using conversion assays, biodistribution studies and small animal positron-emission tomography (PET) imaging studies. In conclusion, the fusion protein has been validated as useful for the non-invasive imaging of yCD expression and will be evaluated in the future for monitoring yCD based therapy. PMID- 25837666 TI - Voice outcomes following radiation versus laser microsurgery for T1 glottic carcinoma: systematic review and meta-analysis. AB - OBJECTIVE: Systematic review of literature on patient-reported voice handicap following T1 glottic squamous cell carcinoma treatment using transoral laser microsurgery or radiation therapy. DATA SOURCES: PubMed, Web of Science, and Scopus (1997-2013). REVIEW METHODS: These data sources were searched for papers reporting Voice Handicap Index (VHI) after treatment of early glottic carcinoma. Review and reference cross-checking were performed using a priori selection criteria. Study data were abstracted and publication quality categorized independently by 2 authors. Corresponding authors were contacted to maximize data for analysis. Meta-analysis was performed only with studies that included both treatment modalities, to reduce heterogeneity and maximize rigor; random effects modeling was used to pool results. RESULTS: Eighteen publications were identified that reported VHI data following surgery and radiotherapy for T1 glottic carcinoma. No studies were randomized. When studies that reported multiple T stages or systematic treatment selection bias were excluded, 8 retrospective cohort studies describing 362 patients were suitable for meta-analysis. Follow-up time (mean, 47 months; range, 1-298 mo) and extent of surgical excision varied across studies. Six studies showed no VHI difference between treatment arms; 2 favored radiotherapy over surgery (1 of which reported transmuscular cordectomy for all surgical patients); and none favored surgery. Meta-analysis showed no significant difference in posttreatment VHI between radiotherapy and surgery (mean difference, -5.52; 95% confidence interval, -11.40, 0.36; heterogeneity I (2) = 61%, P = .01). CONCLUSION: VHI scores were comparable following transoral laser microsurgery and radiation therapy for T1 glottic carcinoma in the current literature, suggesting no clinically significant difference in functional voice outcomes between treatment types. PMID- 25837667 TI - High risks of HIV transmission for men who have sex with men--a comparison of risk factors of HIV infection among MSM associated with recruitment channels in 15 cities of China. AB - OBJECTIVE: While the HIV epidemic varies greatly by region and population group throughout China, the HIV incidence among men who have sex with men (MSM) continues to rise at an alarmingly fast pace. We seek to analyze the risk factors associated with HIV infection among MSM recruited from different channels in large urban centers across China, in an attempt to shed light on the design of future targeted intervention strategies. METHODS: A total of 33,684 MSM from 14 cities and one province were recruited from July to December 2011. Demographic (e.g. age, marital status, education) and behavioral (e.g. condom use, HIV testing history) data were collected using information collection cards. Blood samples were also collected to test for HIV and Syphilis. RESULTS: Participants were recruited from five different channels, and all demonstrated distinct characteristics. The overall rate of positive HIV screening was 6.27% and the rate of syphilis infection was 6.50%. Participants recruited from bathhouses had the highest HIV (11.80%) and syphilis infection rates (11.20%). Participants who were infected with syphilis had the highest HIV-positive screening rate (13.75%; 95% CI OR, 2.33-3.06). living in the southwest region of the country (11.64%; OR=2.76, 95%CI OR 2.19-3.47), Being >20 years of age (P<0.001), living in the southwest region of the country (OR=2.76, 95%CI 2.19-3.47), not having sex with female over the previous 3 months (OR=1.27, 95%CI 1.09-1.48), no condom use during the last anal intercourse (OR=1.54, 95%CI 1.39-1.70) and other factors were all associated with a higher probability of having an HIV-positive test result. CONCLUSION: Depending on the way they are recruited, more targeted interventions are required to prevent the spread of HIV/AIDS among MSM with different characteristics and behaviors. Results from this study could provide evidence for researchers to conduct further studies and policy-makers to establish more effective and strategic interventions for MSM in China. PMID- 25837668 TI - Identification of 3-methylbutanoyl glycosides in green Coffea arabica beans as causative determinants for the quality of coffee flavors. AB - The quality of coffee green beans is generally evaluated by the sensory cupping test, rather than by chemical compound-based criteria. In this study, we examined the relationship between metabolites and cupping scores for 36 varieties of beans, using a nontargeted LC-MS-based metabolic profiling technique. The cupping score was precisely predicted with the metabolic information measured using LC MS. Two markers that strongly correlated with high cupping scores were determined to be isomers of 3-methylbutanoyl disaccharides (3MDs; 0.01-0.035 g/kg of beans) by spectroscopic analyses after purification, and one of them was a novel structure. Further, both the 3MDs were determined to be precursors of 3 methylbutanoic acid that enhance the quality of coffee. The applicability of 3MDs as universal quality indicators was validated with another sample set. It was concluded that 3MDs are the causative metabolites determining beverage quality and can be utilized for green bean selection and as key compounds for improving the beverage quality. PMID- 25837669 TI - Geographic variation of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and hepatocellular carcinoma in the United States. AB - BACKGROUND: Intrahepatic (ICC) and extrahepatic cholangiocarcinomas (ECC) are tumors that arise from cholangiocytes in the bile duct, but ICCs are coded as primary liver cancers while ECCs are coded as biliary tract cancers. The etiology of these tumors is not well understood. It has been suggested that the etiology of ICC is more similar to that of another type of liver cancer, hepatocellular carcinoma (HCC), than to the etiology of ECC. If this is true, geographic incidence patterns and trends in ICC incidence should be more similar to that of HCC than ECC. METHODS: To examine this hypothesis, data from the North American Association of Central Cancer Registries Cancer in North America data file were analyzed. Incidence rates and joinpoint trends were calculated by demographic subgroup. County-level incidence rates were mapped. RESULTS: Overall incidence rates, racial distribution, male:female ratio, and peak ages were more similar between ICC and ECC than with HCC. During 2000-2009, average annual incidence rates of ECC increased. During 2005-2009, average annual ICC incidence rates also increased. High rates for all three cancer sites were found in the Pacific region, particularly Hawaii and Alaska. Rates of ICC and ECC were also high in the Northeast and the upper Midwest, while rates of HCC were high in the South. CONCLUSIONS: Demographic patterns and geographical variation were more closely related between ICC and ECC than HCC, suggesting that the etiology of ICC and ECC may be similar. Increasing rates of both tumors suggest that further etiology studies are warranted. PMID- 25837670 TI - A Role for Astrocytes in Sensing the Brain Microenvironment and Neuro-Metabolic Integration. AB - Astrocytes occupy a strategic position in the brain where they can act as an interface between neurones and blood vessels, and neurones and the cerebro-spinal fluid. This location is ideal for functioning as interoceptors, as they may sense changes in brain microenvironment and contribute to the adaptive homeostatic responses coordinated by neuronal networks. Here we briefly review some of the recent evidence, which implicates the involvement of astrocytes in the central nervous control of breathing, sympathetic tone and blood glucose levels. L lactate appears a potentially crucial signaling molecule in the communication between astrocytes and neurones. Based on the available evidence, we conclude that astrocytes contribute to the homeostasis by playing a significant role in the brain's interoceptive mechanisms. PMID- 25837672 TI - Repair of articular osteochondral defects of the knee joint using a composite lamellar scaffold. AB - OBJECTIVES: The major problem with repair of an articular cartilage injury is the extensive difference in the structure and function of regenerated, compared with normal cartilage. Our work investigates the feasibility of repairing articular osteochondral defects in the canine knee joint using a composite lamellar scaffold of nano-beta-tricalcium phosphate (beta-TCP)/collagen (col) I and II with bone marrow stromal stem cells (BMSCs) and assesses its biological compatibility. METHODS: The bone-cartilage scaffold was prepared as a laminated composite, using hydroxyapatite nanoparticles (nano-HAP)/collagen I/copolymer of polylactic acid-hydroxyacetic acid as the bony scaffold, and sodium hyaluronate/poly(lactic-co-glycolic acid) as the cartilaginous scaffold. Ten-to 12-month-old hybrid canines were randomly divided into an experimental group and a control group. BMSCs were obtained from the iliac crest of each animal, and only those of the third generation were used in experiments. An articular osteochondral defect was created in the right knee of dogs in both groups. Those in the experimental group were treated by implanting the composites consisting of the lamellar scaffold of beta-TCP/col I/col II/BMSCs. Those in the control group were left untreated. RESULTS: After 12 weeks of implantation, defects in the experimental group were filled with white semi-translucent tissue, protruding slightly over the peripheral cartilage surface. After 24 weeks, the defect space in the experimental group was filled with new cartilage tissues, finely integrated into surrounding normal cartilage. The lamellar scaffold of beta TCP/col I/col II was gradually degraded and absorbed, while new cartilage tissue formed. In the control group, the defects were not repaired. CONCLUSION: This method can be used as a suitable scaffold material for the tissue-engineered repair of articular cartilage defects. Cite this article: Bone Joint Res 2015;4:56-64. PMID- 25837671 TI - MicroRNA 181b regulates decorin production by dermal fibroblasts and may be a potential therapy for hypertrophic scar. AB - Hypertrophic scarring is a frequent fibroproliferative complication following deep dermal burns leading to impaired function and lifelong disfigurement. Decorin reduces fibrosis and induces regeneration in many tissues, and is significantly downregulated in hypertrophic scar and normal deep dermal fibroblasts. It was hypothesized that microRNAs in these fibroblasts downregulate decorin and blocking them would increase decorin and may prevent hypertrophic scarring. Lower decorin levels were found in hypertrophic scar as compared to normal skin, and in deep as compared to superficial dermis. A decorin 3' un translated region reporter assay demonstrated microRNA decreased decorin in deep dermal fibroblasts, and microRNA screening predicted miR- 24, 181b, 421, 526b, or 543 as candidates. After finding increased levels of mir-181b in deep dermal fibroblasts, it was demonstrated that TGF-beta1 stimulation decreased miR-24 but increased miR-181b and that hypertrophic scar and deep dermis contained increased levels of miR-181b. By blocking miR-181b with an antagomiR, it was possible to increase decorin protein expression in dermal fibroblasts. This suggests miR-181b is involved in the differential expression of decorin in skin and wound healing. Furthermore, blocking miR-181b reversed TGF-beta1 induced decorin downregulation and myofibroblast differentiation in hypertrophic scar fibroblasts, suggesting a potential therapy for hypertrophic scar. PMID- 25837673 TI - Combined multivariate statistical techniques, Water Pollution Index (WPI) and Daniel Trend Test methods to evaluate temporal and spatial variations and trends of water quality at Shanchong River in the Northwest Basin of Lake Fuxian, China. AB - Understanding spatial and temporal variations in river water quality and quantitatively evaluating the trend of changes are important in order to study and efficiently manage water resources. In this study, an analysis of Water Pollution Index (WPI), Daniel Trend Test, Cluster Analysis and Discriminant Analysis are applied as an integrated approach to quantitatively explore the spatial and temporal variations and the latent sources of water pollution in the Shanchong River basin, Northwest Basin of Lake Fuxian, China. We group all field surveys into 2 clusters (dry season and rainy season). Moreover, 14 sampling sites have been grouped into 3 clusters for the rainy season (highly polluted, moderately polluted and less polluted sites) and 2 clusters for the dry season (highly polluted and less polluted sites) based on their similarities and the level of pollution during the two seasons. The results show that the main trend of pollution was aggravated during the transition from the dry to the rainy season. The Water Pollution Index of Total Nitrogen is the highest of all pollution parameters, whereas the Chemical Oxygen Demand (Chromium) is the lowest. Our results also show that the main sources of pollution are farming activities alongside the Shanchong River, soil erosion and fish culture at Shanchong River reservoir area and domestic sewage from scattered rural residential area. Our results suggest that strategies to prevent water pollutionat the Shanchong River basin need to focus on non-point pollution control by employing appropriate fertilizer formulas in farming, and take the measures of soil and water conservation at Shanchong reservoir area, and purifying sewage from scattered villages. PMID- 25837674 TI - Upgrading prostate cancer following proton beam therapy. AB - Pre- and post-radiation therapy (RT) effects on prostate histology have not been rigorously studied, but there appears to be a correlation between escalating radiation dosage and increasing post-RT histologic changes. Despite this dose response relationship, radiation-induced changes may be heterogenous among different patients and even within a single tumor. When assessing residual tumor it is important to understand biopsy evaluation in the post-RT setting. We present the case of a poorly differentiated prostate adenocarcinoma following proton beam RT in a 45-year-old man with pre-RT Gleason 4 + 3 = 7 disease diagnosed in the setting of an elevated serum prostate-specific antigen level. PMID- 25837675 TI - MAP17 (PDZKIP1) Expression Determines Sensitivity to the Proteasomal Inhibitor Bortezomib by Preventing Cytoprotective Autophagy and NFkappaB Activation in Breast Cancer. AB - MAP17 is a small nonglycosylated membrane protein that is overexpressed in a high percentage of carcinomas. High levels of MAP17 enhance the tumorigenic properties of tumor cells by increasing oxidative stress, which is dependent on Na(+) coupled cotransport. Here, we show that MAP17 is associated with proteins involved in protein degradation and that proteasome inhibition induces autophagy. To analyze whether MAP17 could also alter this process, we used the proteasome inhibitor bortezomib (Velcade, PS-341), which is approved for the treatment of multiple myeloma and mantle cell lymphoma, although it has a high rate of resistance emergence and poor efficacy in solid tumors. We provide evidence that bortezomib induces a cytoprotective effect by activating autophagy and NFkappaB nuclear translocation, responses that are repressed in the presence of high levels of MAP17 both in vitro and in vivo. Indeed, patients with multiple myeloma treated with bortezomib showed higher response rates and a longer time to progression associated with increased levels of MAP17 expression. The MAP17 induced sensitivity to bortezomib is dependent on the oxidative status of the cells and the activity of Na(+)-coupled transporters because treatment with antioxidants or the inhibitor furosemide restores the cytoprotective activity induced by bortezomib. Therefore, bortezomib induces a prosurvival response through cytoprotective autophagy and NFkappaB nuclear translocation, which is repressed by high levels of MAP17. We propose that the levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematologic malignancies and in other tissues that are not commonly responsive to the drug. PMID- 25837677 TI - On the origin of differential phase contrast at a locally charged and globally charge-compensated domain boundary in a polar-ordered material. AB - Differential phase contrast (DPC) imaging in the scanning transmission electron microscope is applied to the study of a charged antiphase domain boundary in doped bismuth ferrite. A clear differential signal is seen, which matches the expected direction of the electric field at the boundary. However, further study by scanned diffraction reveals that there is no measurable deflection of the primary diffraction disc and hence no significant free E-field in the material. Instead, the DPC signal arises from a modulation of the intensity profile within the primary diffraction disc in the vicinity of the boundary. Simulations are used to show that this modulation arises purely from the local change in crystallographic structure at the boundary and not from an electric field. This study highlights the care that is required when interpreting signals recorded from ferroelectric materials using both DPC imaging and other phase contrast techniques. PMID- 25837676 TI - Growth of the obligate anaerobe Desulfovibrio vulgaris Hildenborough under continuous low oxygen concentration sparging: impact of the membrane-bound oxygen reductases. AB - Although obligate anaerobe, the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough (DvH) exhibits high aerotolerance that involves several enzymatic systems, including two membrane-bound oxygen reductases, a bd-quinol oxidase and a cc(b/o)o3 cytochrome oxidase. Effect of constant low oxygen concentration on growth and morphology of the wild-type, single (Deltabd, Deltacox) and double deletion (Deltacoxbd) mutant strains of the genes encoding these oxygen reductases was studied. When both wild-type and deletion mutant strains were cultured in lactate/sulfate medium under constant 0.02% O2 sparging, they were able to grow but the final biomasses and the growth yield were lower than that obtained under anaerobic conditions. At the end of the growth, lactate was not completely consumed and when conditions were then switched to anaerobic, growth resumed. Time-lapse microscopy revealed that a large majority of the cells were then able to divide (over 97%) but the time to recover a complete division event was longer for single deletion mutant Deltabd than for the three other strains. Determination of the molar growth yields on lactate suggested that a part of the energy gained from lactate oxidation was derived toward cells protection/repairing against oxidative conditions rather than biosynthesis, and that this part was higher in the single deletion mutant Deltabd and, to a lesser extent, Deltacox strains. Our data show that when DvH encounters oxidative conditions, it is able to stop growing and to rapidly resume growing when conditions are switched to anaerobic, suggesting that it enters active dormancy sate under oxidative conditions. We propose that the pyruvate-ferredoxin oxidoreductase (PFOR) plays a central role in this phenomenon by reversibly switching from an oxidative-sensitive fully active state to an oxidative insensitive inactive state. The oxygen reductases, and especially the bd-quinol oxidase, would have a crucial function by maintaining reducing conditions that permit PFOR to stay in its active state. PMID- 25837678 TI - Ten simple rules to win a Nobel Prize. PMID- 25837679 TI - Role of cysteine residues in the structure, stability, and alkane producing activity of cyanobacterial aldehyde deformylating oxygenase. AB - Aldehyde deformylating oxygenase (AD) is a key enzyme for alkane biosynthesis in cyanobacteria, and it can be used as a catalyst for alkane production in vitro and in vivo. However, three free Cys residues in AD may impair its catalytic activity by undesired disulfide bond formation and oxidation. To develop Cys deficient mutants of AD, we examined the roles of the Cys residues in the structure, stability, and alkane producing activity of AD from Nostoc punctiforme PCC 73102 by systematic Cys-to-Ala/Ser mutagenesis. The C71A/S mutations reduced the hydrocarbon producing activity of AD and facilitated the formation of a dimer, indicating that the conserved Cys71, which is located in close proximity to the substrate-binding site, plays crucial roles in maintaining the activity, structure, and stability of AD. On the other hand, mutations at Cys107 and Cys117 did not affect the hydrocarbon producing activity of AD. Therefore, we propose that the C107A/C117A double mutant is preferable to wild type AD for alkane production and that the double mutant may be used as a pseudo-wild type protein for further improvement of the alkane producing activity of AD. PMID- 25837680 TI - Liver Disease, Systemic Inflammation, and Growth Using a Mixed Parenteral Lipid Emulsion, Containing Soybean Oil, Fish Oil, and Medium Chain Triglycerides, Compared With Soybean Oil in Parenteral Nutrition-Fed Neonatal Piglets. AB - BACKGROUND: The optimal parenteral lipid emulsion for neonates should reduce the risk of intestinal failure-associated liver disease and inflammation, while supporting growth and development. This could be best achieved by balanced content of omega-6 and omega-3 polyunsaturated fatty acids (PUFAs). Using a neonatal piglet model of parenteral nutrition (PN), we compared a 100% soy oil based emulsion (omega-6:omega-3 PUFA: 7:1) with a mixed lipid emulsion comprising 30% soy oil, 30% medium-chain triglycerides, 25% olive oil, and 15% fish oil (omega-6:omega-3 PUFA: approximately 2.5:1) with regard to liver disease, inflammation, and fatty acid content in plasma and brain. METHOD: Neonatal piglets, 3-6 days old, underwent jugular catheter insertion for isonitrogenous, isocaloric PN delivery over 14 days. The IL group (n = 8) was treated with Intralipid; the ML group (n = 10) was treated with the mixed lipid (SMOFlipid). Bile flow, liver chemistry, C-reactive protein (CRP), and PUFA content in plasma phospholipids and brain were compared. RESULTS: Compared with the IL group, ML treated piglets had increased bile flow (P = .008) and lower total bilirubin (P = .001) and CRP (P = .023) concentrations. The omega-6 long-chain PUFA content was lower in plasma and brain for the ML group. The key omega-3 long-chain PUFA for neonatal development, docosahexaenoic acid (DHA), was not different between groups. CONCLUSION: The mixed lipid, having less omega-6 PUFA and more omega-3 PUFA, was able to prevent liver disease and reduce systemic inflammation in PN fed neonatal piglets. However, this lipid did not increase plasma or brain DHA status, which would be desirable for neonatal developmental outcomes. PMID- 25837681 TI - Descemet Membrane Endothelial Keratoplasty: To Do or Not to Do? PMID- 25837683 TI - 2'-Fluorination of tricyclo-DNA controls furanose conformation and increases RNA affinity. AB - The synthesis of 2'-fluoro tricyclo-DNA pyrimidine nucleosides with fluorine in the ribo-configuration and their incorporation into oligodeoxynucleotides was accomplished. Unlike the parent tc-T nucleoside, the 2'F-RNA-tc-T unit occurs in the 2'-exo conformation in the crystal. Specifically, F-RNA-tc-T was found to stabilize duplexes with RNA by +2 to +4 degrees C in Tm/mod. F-RNA-tc nucleosides mix well with the DNA backbone and thus open up possibilities of using shorter and mixed-(DNA/tc-DNA) backbone oligonucleotides for therapeutic applications. PMID- 25837684 TI - Transient eigenmodes analysis of single-impact cantilever dynamics combining Fourier and wavelet transforms. AB - The transient eigenmode structure of an interacting cantilever during a single impact on different surfaces evidences the excitation of higher flexural modes and low frequency oscillations. The frequency shift of the fundamental mode after the tip comes into contact with the sample surface allows calculating the tip sample interaction stiffness and evidences the role of capillary condensation and surface wettability on the cantilever dynamics. Wavelet transforms are used to trace the origin of spectral features in the cantilever spectra and calculate force gradients of the tip-sample interaction. PMID- 25837682 TI - Expanding our understanding of sequence-function relationships of type II polyketide biosynthetic gene clusters: bioinformatics-guided identification of Frankiamicin A from Frankia sp. EAN1pec. AB - A large and rapidly increasing number of unstudied "orphan" natural product biosynthetic gene clusters are being uncovered in sequenced microbial genomes. An important goal of modern natural products research is to be able to accurately predict natural product structures and biosynthetic pathways from these gene cluster sequences. This requires both development of bioinformatic methods for global analysis of these gene clusters and experimental characterization of select products produced by gene clusters with divergent sequence characteristics. Here, we conduct global bioinformatic analysis of all available type II polyketide gene cluster sequences and identify a conserved set of gene clusters with unique ketosynthase alpha/beta sequence characteristics in the genomes of Frankia species, a group of Actinobacteria with underexploited natural product biosynthetic potential. Through LC-MS profiling of extracts from several Frankia species grown under various conditions, we identified Frankia sp. EAN1pec as producing a compound with spectral characteristics consistent with the type II polyketide produced by this gene cluster. We isolated the compound, a pentangular polyketide which we named frankiamicin A, and elucidated its structure by NMR and labeled precursor feeding. We also propose biosynthetic and regulatory pathways for frankiamicin A based on comparative genomic analysis and literature precedent, and conduct bioactivity assays of the compound. Our findings provide new information linking this set of Frankia gene clusters with the compound they produce, and our approach has implications for accurate functional prediction of the many other type II polyketide clusters present in bacterial genomes. PMID- 25837685 TI - Novel CuCo2O4/graphitic carbon nitride nanohybrids: Highly effective catalysts for reducing CO generation and fire hazards of thermoplastic polyurethane nanocomposites. AB - Novel spinel copper cobaltate (CuCo2O4)/graphitic carbon nitride (g-C3N4) (named C-CuCo2O4) nanohybrids with different weight ratios of g-C3N4 to CuCo2O4 were successfully synthesized via a facile hydrothermal method. Then the nanohybrids were added into the thermoplastic polyurethane (TPU) matrix to prepare TPU nanocomposites using a master batch-melt compounding approach. Morphological analysis indicated that CuCo2O4 nanoparticles were uniformly distributed on g C3N4 nanosheets. Thermal analysis revealed that C-CuCo2O4-7 (proportion of g-C3N4 to CuCo2O4 of 93/7) was an optimal nanohybrid for the properties improvement of TPU. Incorporation of C-CuCo2O4-7 into TPU led to significant improvements in the onset decomposition temperature, temperature at maximal mass loss rate and char yields. The heat release rate and total heat release of TPU/C-CuCo2O4-7 decreased by 37% and 31.3%, respectively, compared with those of pure TPU. Furthermore, the amounts of pyrolysis gaseous products, including combustible volatiles and carbon monoxide (CO), were remarkably reduced, whereas, non-flammable gas (carbon dioxide) increased. Excellent dispersion of C-CuCo2O4-7 in TPU host was achieved, due to the synergistic effect between g-C3N4 and CuCo2O4. Enhancements in the thermal stability and flame retardancy were attributed to the explanations that g C3N4 nanosheets showed the physical barrier effect and catalytic nitrogen monoxide (NO) decomposition, and that CuCo2O4 catalyzes the reaction of CO with NO and increased char residues. PMID- 25837686 TI - Selective histone deacetylase 6 inhibition prolongs survival in a lethal two-hit model. AB - BACKGROUND: Hemorrhagic shock (HS) followed by a subsequent insult ("second hit") often initiates an exaggerated systemic inflammatory response and multiple organ failure. We have previously demonstrated that valproic acid, a pan histone deacetylase inhibitor, could improve survival in a rodent "two-hit" model. In the present study, our goal was to determine whether selective inhibition of histone deacetylase 6 with Tubastatin A (Tub-A) could prolong survival in a two-hit model where HS was followed by sepsis from cecal ligation and puncture (CLP). METHODS: C57Bl/6J mice were subjected to sublethal HS (30% blood loss) and then randomly divided into two groups (n = 13 per group) such as Tub-A group (treatment) and vehicle (VEH) group (control). The Tub-A group was given an intraperitoneal injection of Tub-A (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO). The VEH group was injected with DMSO (1 MUl/g body weight). After 24 h, all mice were subjected CLP followed immediately by another dose of Tub-A or DMSO. Survival was monitored for 10 d. In a parallel study, peritoneal irrigation fluid and liver tissue from Tub-A- or DMSO-treated mice were collected 3 h after CLP. Enzyme linked immunosorbent assay was performed to quantify activity of the myeloperoxidase and concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) in the peritoneal irrigation fluid. RNA was isolated from the liver tissue, and real-time polymerase chain reaction was performed to measure relative messenger RNA levels of TNF-alpha and IL-6. RESULTS: Treatment with Tub-A significantly improved survival compared with that of the control (69.2% versus 15.4%). In addition, Tub-A significantly suppressed myeloperoxidase activity (169.9 +/- 8.4 ng/mL versus 70.4 +/- 17.4 ng/mL; P < 0.01) and reduced levels of cytokines TNF-alpha and IL-6 in the peritoneal fluid (TNF-alpha: 105.7 +/- 4.7 versus 7.4 +/- 2.4 pg/mL; IL-6: 907.4 +/- 2.3 versus 483.6 +/- 1.6 pg/mL; P < 0.01) compared with those in the VEH control. Gene expression measured by real-time polymerase chain reaction confirmed that Tub-A inhibits transcription of TNF-alpha and IL-6. CONCLUSIONS: Tub-A treatment significantly improves survival, attenuates inflammation, and downregulates TNF-alpha and IL-6 gene expression in a rodent two-hit model. PMID- 25837687 TI - Origin of Enhanced Reactivity of a Microsolvated Nucleophile in Ion Pair SN2 Reactions: The Cases of Sodium p-Nitrophenoxide with Halomethanes in Acetone. AB - In a kinetic experiment on the SN2 reaction of sodium p-nitrophenoxide with iodomethane in acetone-water mixed solvent, Humeres et al. (J. Org. Chem. 2001, 66, 1163) found that the reaction depends strongly on the medium, and the fastest rate constant was observed in pure acetone. The present work tries to explore why acetone can enhance the reactivity of the title reactions. Accordingly, we make a mechanistic study on the reactions of sodium p-nitrophenoxide with halomethanes (CH3X, X = Cl, Br, I) in acetone by using a supramolecular/continuum model at the PCM-MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p) level, in which the ion pair nucleophile is microsolvated by one to three acetone molecules. We compared the reactivity of the microsolvated ion pair nucleophiles with solvent-free ion pair and anionic ones. Our results clearly reveal that the microsolvated ion pair nucleophile is favorable for the SN2 reactions; meanwhile, the origin of the enhanced reactivity induced by microsolvation of the nucleophile is discussed in terms of the geometries of transition state (TS) structures and activation strain model, suggesting that lower deformation energies and stronger interaction energies between the deformed reactants in the TS lead to the lower overall reaction barriers for the SN2 reaction of microsolvated sodium p-nitrophenoxide toward halomethanes in acetone. PMID- 25837688 TI - The metabolism of 4-bromoaniline in the bile-cannulated rat: application of ICPMS ((79/81)Br), HPLC-ICPMS & HPLC-oaTOFMS. AB - 1. An excretion balance study was performed following i.p. administration of 4 bromoaniline (50 mg kg(-1)) to bile-cannulated rats, using bromine-detected ((79/81)Br) ICPMS for quantification. Approximately 90% of the dose was recovered in urine (68.9 +/- 3.6%) and bile (21.4 +/- 1.4%) by 48 h post-administration. 2. HPLC-ICPMS ((79/81)Br) was used to selectively detect and profile the major urinary and biliary-excreted metabolites and determined that the 0-12 h urine contained at least 21 brominated metabolites with 19 bromine-containing peaks observed in the 6-12 h bile samples. 3. The urinary and biliary metabolites were subsequently profiled using HPLC-oaTOFMS. By exploiting the distinctive bromine isotope pattern ca. 60 brominated metabolites were detected in the urine in negative electrospray ionisation (ESI) mode while bile contained ca. 21. 4. While a large number of bromine-containing metabolites were detected, the profiles were dominated by a few major components with the bulk of the 4-bromoaniline-related material in urine accounted for by 4-bromoanaline O-sulfate (~75% of the total by ICPMS, 84% by TOFMS). In bile a hydroxylated N-acetyl compound was the major metabolite detected, forming some ~65% of the 4-bromoaniline-related material by ICPMS (37% by TOFMS). PMID- 25837689 TI - Establishment of pharmacophore and VolSurf models to predict the substrates of UDP-glucuronosyltransferase1A3. AB - 1.UDP-glucuronosyltransferase1A3 (UGT1A3) catalyzes glucuronidation of numerous xenobiotics/drugs. Here, we aimed to establish substrate selectivity models for UGT1A3 using the pharmacophore and VolSurf approaches. 2.Fifty structurally diverse substrates of UGT1A3 were collated from the literature. These substrates were divided into training (n=34) and test sets (n=16). The pharmacophore model was developed using the Discovery Studio 2.5 software. A user-defined feature (i.e. the glucuronidation site) was included in the program for model generation. The VolSurf model was derived using the VolSurf program implemented in SYBYL 8.0 software. 3.The pharmacophore model consisted of three features (i.e. one glucuronidation site and two hydrogen-bond acceptors). The activities of 81% of test set substrates were adequately predicted (deviated by less than one-log unit) by the model, suggestive of a satisfactory predictive power. The refined VolSurf model based on 22 molecular descriptors was statistically significant (r(2)=0.793, q(2)=0.606). It also processed a good predictability as the activities of 14 test set compounds were well predicted. The VolSurf model highlighted the chemical features (including large molecule size, hydrophilic regions and hydrogen-bonding groups) contributing to favored glucuronidation by UGT1A3. 4.In conclusion, two predictive 3D-QSAR models (i.e. the pharmacophore and VolSurf models) for UGT1A3 were successfully established. These models contributed to an improved understanding of the substrate preference of UGT1A3 and a more comprehensive prediction of UGT-mediated metabolism. PMID- 25837690 TI - Pharmacokinetics and tissue distribution study of novel potent antiplatelet agent S007-867 in mice using HPLC-MS/MS. AB - 1. S007-867 is a novel antiplatelet agent that shows promising in vitro and in vivo efficacy. For further development and better pharmacological elucidation, we characterized pharmacokinetics and tissue distribution of S007-867 in a mouse model. 2. A sensitive, selective and robust LC-MS/MS method was developed and validated in the mouse plasma and tissue for quantification of S007-867. The chromatographic separation was performed on Waters Symmetry Shield C18 column (150 * 4.6 mm, 5 um) using methanol and ammonium acetate buffer. 3. S007-867 was rapidly absorbed and distributed to various tissues. Following single oral administration of S007-867 in the mouse, the concentration was in the order of C intestine > C liver > C kidney > C heart > C spleen > C lungs > C brain. Tissue to plasma area under the plasma curve ratio suggested that the maximum amount of drug was found in the intestine and liver. Half life of S007-867 was found longer in the heart (8.08 h), spleen (~ 7.94 h) and kidney (~ 15.41 h) as compared with other tissues. 4. The preclinical pharmacokinetics and tissue distribution data obtained using this LC-MS/MS method are expected to assist the future clinical investigations of S007-867 as a promising antiplatelet agent. PMID- 25837692 TI - The clinical and laboratory evaluation of the patient with erythrocytosis. AB - Erythrocytosis is frequently encountered as an incidental abnormality on laboratory testing that reveals persistent elevation of the hematocrit level (>52% in men and >48% in women). In many cases, erythrocytosis is the manifestation of an underlying cardiopulmonary process, drug-induced due to androgens, or secondary to smoking, rather than a primary bone marrow disorder such as polycythemia vera. A systematic approach to the clinical and laboratory evaluation of each patient is indicated to consider diverse differential diagnosis possibilities and to identify the underlying etiology of erythrocytosis in order to formulate appropriate subspecialist referral and management plans. A thorough medical history and meticulous physical examination supplemented by a focused initial laboratory evaluation will enable the general practitioner to ascertain the etiology of erythrocytosis in the majority of cases. Patients with clinical and laboratory features suggestive of polycythemia vera and those patients without an apparent underlying condition known to cause erythrocytosis benefit from early referral to a hematologist for further specialized diagnostic evaluation and therapy considerations. PMID- 25837691 TI - Investigating breast cancer cell behavior using tissue engineering scaffolds. AB - Despite early detection through the use of mammograms and aggressive intervention, breast cancer (BC) remains a clinical dilemma. BC can resurge after >10 years of remission. Studies indicate that BC cells (BCCs) with self-renewal and chemoresistance could be involved in dormancy. The majority of studies use in vitro, two-dimensional (2-D) monolayer cultures, which do not recapitulate the in vivo microenvironment. Thus, to determine the effect of three-dimensional (3-D) microenvironment on BCCs, this study fabricated tissue engineering scaffolds made of poly (epsilon-caprolactone) (PCL) having aligned or random fibers. Random and aligned fibers mimic, respectively, the random and highly organized collagen fibers found in the tumor extracellular matrix. Chemoresistant BCCs were obtained by treating with carboplatin. Western blot analysis of carboplatin resistant (treated) MDA-MB-231 (highly invasive, basal-like) and T47D (low-invasive, luminal) BCCs showed an increase in Bcl-2, Oct-4 and Sox-2, suggesting protection from apoptosis and increase in stem-like markers. Further studies with MDA-MB-231 BCCs seeded on the scaffolds showed little to no change in cell number over time for non-treated BCCs whereas on tissue culture polystyrene (TCP), non-treated BCCs displayed a significant increase in cell number at days 4 and 7 as compared to day 1 (p<0.05). Treated BCCs did not proliferate on TCP and the fibrous scaffolds. Little to no cyclin D1 was expressed for non-treated BCCs on TCP. On fibrous scaffolds, non-treated BCCs stained for cyclin D1 during the 7-day culture period. Treated BCCs expressed cyclin D1 on TCP and fibrous scaffolds during the 7-day culture period. Proliferation, viability and cell cycle analysis indicated that this 3-D culture prompted the aggressive BCCs to adopt a dormant phenotype, while the treated BCCs retained their phenotype. The findings indicate that random and aligned fibrous PCL scaffolds may provide a useful system to study how the 3-D microenvironment affects the behavior of BCCs. PMID- 25837693 TI - Models for predicting the adult height and age at first menstruation of girls with idiopathic central precocious puberty. AB - BACKGROUND: It is difficult to determine whether to treat a given girl who has idiopathic central precocious puberty (CPP) with gonadotropin-releasing hormone analog (GnRHa) in terms of adult height (AH). The objective was to provide an easy tool for predicting AH and age at first menstruation at initial evaluation to help guide the decision regarding whether to treat. METHODS: Data analysis using multiple linear regression models was performed in 134 girls with CPP. Among them 78 were given GnRHa because of low predicted AH (n=45), pubertal luteinising hormone (LH)/follicle-stimulating hormone peaks (FSH) ratio (n=50) and/or high plasma estradiol concentration (n=45). 56 girls were followed without treatment. RESULTS: In the whole population, the actual AH (162.1+/-5.61 cm) was similar to target height (161.7+/-4.91 cm) and to AH predicted by the Bayley and Pinneau method (161.9+/-7.98 cm). Separated models for treated and untreated girls provide very close estimations, leading to a unique formula for both groups. The AH (cm) could be calculated at the initial evaluation: 2.21 (height at initial evaluation, SD) + 2.32 (target height, SD) - 1.83 (LH/FSH peaks ratio) + 159.68. The actual AH was lower than the calculated AH by more than 1 SD (5.6 cm) in 11 girls (8.0%). The time between onset of puberty and first menstruation (in untreated girls) can be estimated with: 10.9 - 0.57 (LH/FSH peaks ratio). The formulae are available at http://www.kamick.org/lemaire/med/girls-cpp15.html. CONCLUSIONS: We established formulae that can be used at an initial evaluation to predict the AH, and the time between onset of puberty and first menstruation after spontaneous puberty. The similarity of the formulae for both groups suggests that the treatment had no significant effect on the AH. However, the criteria used to select treatment suggest that it prevents the deterioration of AH in cases with rapidly evolving form of CPP. PMID- 25837694 TI - The Position of the Patella and Extensor Mechanism Affects Intraoperative Compartmental Loads During Total Knee Arthroplasty: A Pilot Study Using Intraoperative Sensing to Guide Soft Tissue Balance. AB - The achievement of a well-balanced total knee arthroplasty is necessary for long term success. We hypothesize that the dislocation of the patella during surgery affects the distribution of loads in the medial and lateral compartments. Intraoperative load sensors were used to record medial and lateral compartment loads in 56 well-balanced TKAs. Loads were recorded in full extension, relaxed extension, at 45 and 90 degrees of flexion at full gravity-assisted flexion, with the patella in four different positions: dislocated (everted and not), located, and located and secured with two retinacular sutures. The loads in the lateral compartment in flexion were higher with a dislocated patella than with a located patella (P<0.001). A lateralized extensor mechanism artificially increases in the lateral compartment loads in flexion during TKA surgery. Instruments that allow intraoperative soft tissue balance with the patella in a physiologic position are more likely to replicate postoperative compartment loads. LEVEL OF EVIDENCE: II (prospective comparative study). PMID- 25837695 TI - Spatial distribution and temporal evolution of DRONPA-fused SNAP25 clusters in adrenal chromaffin cells. AB - Sub-diffraction imaging of plasma membrane localized proteins, such as the SNARE (Soluble NSF Attachment Protein Receptor) proteins involved in exocytosis, in fixed cells have resulted in images with high spatial resolution, at the expense of dynamical information. Here, we have imaged localized fluorescence bursts of DRONPA-fused SNAP-25 molecules in live chromaffin cells by Total Internal Reflection Fluorescence (TIRF) imaging. We find that this method allows tracking protein cluster dynamics over relatively long times (~20 min.), partly due to the diffusion into the TIRF field of fresh molecules, making possible the simultaneous identification of cluster size, location and temporal evolution. The results indicate that the DRONPA-fused SNAP-25 clusters display rich dynamics, going from staying constant to disappearing and reappearing in specific cluster domains within minutes. PMID- 25837696 TI - Pharmacological Evidence for 5-HT6 Receptor Modulation of 5-HT Neuron Firing in Vivo. AB - 5-Hydroxytryptamine (5-HT) neurons in the midbrain dorsal raphe nucleus (DRN) are implicated in the drug treatment and pathophysiology of a wide variety of neuropsychiatric disorders. Accumulating evidence suggests that 5-HT6 receptors may be located and functional in the DRN; therefore, 5-HT6 receptor ligands may have potential as novel modulators of 5-HT neurotransmission. The current study investigated the effect of intravenous (i.v.) administration of the selective 5 HT6 receptor agonist, WAY-181187, and antagonist, SB-399885, on the firing of 5 HT neurons in the DRN in vivo. Extracellular recordings were made in the DRN of anesthetized rats, and single 5-HT neurons were identified on the basis of electrophysiological properties combined with juxtacellular labeling and postmortem immunohistochemical analysis. WAY-181187 (1-4 mg/kg i.v.) caused a dose-dependent increase in 5-HT neuron firing rate. In comparison, SB-399885 (0.125-1 mg/kg i.v.) caused a dose-dependent decrease in 5-HT neuron firing rate, an effect reversed by WAY-181187 (3 mg/kg i.v.). These effects of WAY-181187 and SB-399885 were observed in two separate sets of experiments. In summary, the current data show the modulation of 5-HT neuronal firing by the 5-HT6 ligands WAY 181187 and SB-399885 and are consistent with the presence of 5-HT6 receptor mediated positive feedback control of 5-HT neurons. PMID- 25837697 TI - The Relationship of Perceived Risk and Biases in Perceived Risk to Fracture Prevention Behavior in Older Women. AB - BACKGROUND: A bias in perceived risk for health outcomes, including fracture, exists. PURPOSE: We compared perceived risk and biases in perceived risk for fracture to fracture preventive behavior. METHODS: Women over age 55 (n = 2874) completed a survey five times over 5 years, and data was pulled from the medical record. Perceived risk was measured by asking women to rate their risk of fracture compared to similar women. Actual risk was measured using FRAX score. Bias was measured using an interaction between perceived and actual risk. RESULTS: Higher perceived risk was related to lower quality of life and self reported health, more medication and calcium use, increased bone density scan use, and less walking. Bias was only associated with less medication use. Neither perceived risk nor bias predicted medication adherence. CONCLUSIONS: Perceived risk, but not bias, may predict different fracture prevention behaviors. Clinicians may need to base interventions on risk perceptions. PMID- 25837698 TI - Pediatric Pain Management in the Emergency Department: The Triage Nurses' Perspective. AB - Understanding triage nurses' perspectives of pain management is essential for timely pain care for children in the emergency department. Objectives of this study were to describe the triage pain treatment protocols used, knowledge of pain management modalities, and barriers and attitudes towards implementation of pain treatment protocols. METHODS: A paper-based survey was administered to all triage nurses at three Canadian pediatric emergency departments, between December 2011 and January 2012. RESULTS: The response rate was 86% (n=126/147). The mean respondent age was 40 years (standard deviation [SD] 9.3) with 8.6 years (SD 7.7) of triage experience. General triage emergency department (GTED) nurses rated adequacy of triage pain treatment lower than pediatric-only triage emergency department (PTED) nurses (P < .001). GTED nurses reported a longer acceptable delay between triage time and administration of analgesia than PTED nurses (P < .002). Most nurses rated more comfort with a protocol involving administration of acetaminophen (97 mm, interquartile range [IQR] 92, 99) or ibuprofen (97 mm, IQR 93, 100) than for oral morphine (67 mm, IQR 35, 94) or oxycodone (57 mm, IQR 15, 81). The top three reported barriers to triage-initiated pain protocols were monitoring capability, time, and access to medications. Willingness to implement a triage-initiated pain protocol was rated as 81 mm (IQR 71, 96). DISCUSSION: Triage nurses are willing to implement pain protocols for children in the emergency department, but differences in comfort and experience exist between PTED and GTED nurses. Provision of triage initiated pain protocols and associated education may empower nurses to improve care for children in pain in the emergency department. PMID- 25837699 TI - Type I interferon response is delayed in human astrovirus infections. AB - Type I interferon (IFN) activation and its subsequent effects are important in the response to viral infections. Here we show that human astroviruses (HAstVs), which are important agents of acute gastroenteritis in children, induce a mild and delayed IFN response upon infecting CaCo-2 cells. Although IFN-beta mRNA is detected within infected cells and supernatant from infected cells show antiviral activity against the replication of other well-known IFN-sensitive viruses, these responses occur at late stages of infection once genome replication has taken place. On the other hand, HAstV replication can be partially reduced by the addition of exogenous IFN, and inhibition of IFN activation by BX795 enhances viral replication, indicating that HAstVs are IFN-sensitive viruses. Finally, different levels of IFN response were observed in cells infected with different HAstV mutants with changes in the hypervariable region of nsP1a/4, suggesting that nsP1a/4 genotype may potentially have clinical implications due to its correlation with the viral replication phenotype and the antiviral responses induced within infected cells. PMID- 25837700 TI - Impact of physician specialty on quality care for patients hospitalized with decompensated cirrhosis. AB - BACKGROUND: Decompensated cirrhosis is a common precipitant for hospitalization, and there is limited information concerning factors that influence the delivery of quality care in cirrhotic inpatients. We sought to determine the relation between physician specialty and inpatient quality care for decompensated cirrhosis. DESIGN: We reviewed 247 hospital admissions for decompensated cirrhosis, managed by hospitalists or intensivists, between 2009 and 2013. The primary outcome was quality care delivery, defined as adherence to all evidence based specialty society practice guidelines pertaining to each specific complication of cirrhosis. Secondary outcomes included new complications, length of-stay, and in-hospital death. RESULTS: Overall, 147 admissions (59.5%) received quality care. Quality care was given more commonly by intensivists, compared with hospitalists (71.7% vs. 53.1%, P = .006), and specifically for gastrointestinal bleeding (72% vs. 45.8%, P = .03) and hepatic encephalopathy (100% vs. 63%, P = .005). Involvement of gastroenterology consultation was also more common in admissions in which quality care was administered (68.7% vs. 54.0%, P = .023). Timely diagnostic paracentesis was associated with reduced new complications in admissions for refractory ascites (9.5% vs. 46.6%, P = .02), and reduced length of-stay in admissions for spontaneous bacterial peritonitis (5 days vs. 13 days, P = .02). CONCLUSIONS: Adherence to quality indicators for decompensated cirrhosis is suboptimal among hospitalized patients. Although quality care adherence appears to be higher among cirrhotic patients managed by intensivists than by hospitalists, opportunities for improvement exist in both groups. Rational and cost-effective strategies should be sought to achieve this end. PMID- 25837701 TI - Geometry-controllable graphene layers and their application for supercapacitors. AB - A facile and ultrafast method for geometry controllable and vertically transformative 3D graphene architectures is demonstrated. The 2D stacked graphene layers produced by exfoliation of graphite were transformed, e.g., from horizontal to vertical, by applying electric charge (-2 V with 1-3 MUAh/cm2). The three-dimensionally transformed graphene layers have maximized surface area as well as high specific capacitance, 410 F g(-1) in LiClO4/PC electrolyte, which is 4.4 times higher than that of planar (stacked) graphene layers. Furthermore, they can remarkably exhibit 87% of retained capacitance as the scan rate is increased from 100 to 1000 mV s(-1), unlike planar graphene, which displays 61% retention under the same conditions. PMID- 25837702 TI - Oxidative stress and human spermatozoa: diagnostic and functional significance of aldehydes generated as a result of lipid peroxidation. AB - Oxidative stress is known to compromise human sperm function and to activate the intrinsic apoptotic cascade in these cells. One of the key features of oxidatively stressed spermatozoa is the induction of a lipid peroxidation process that results in the formation of aldehydes potentially capable of disrupting sperm function through the formation of adducts with DNA and key proteins. In this study, we have examined the impact of a range of small molecular mass aldehydes generated as a consequence of lipid peroxidation on human sperm function and also compared the two most commonly formed compounds, 4 hydroxynonenal (4HNE) and malondialdehyde (MDA), for their relative ability to reflect a state of oxidative stress in these cells. Dramatic differences in the bioactivity of individual aldehydes were observed, that generally correlated with the second order rate constants describing their interaction with the model nucleophile, glutathione. Our results demonstrate that acrolein and 4HNE were the most reactive lipid aldehydes, inhibiting sperm motility while augmenting reactive oxygen species production, lipid peroxidation, oxidative DNA damage and caspase activation, in a dose-dependent manner (P < 0.001). In contrast, a variety of saturated aldehydes and the well-known marker of oxidative stress, MDA, were without effect on this cell type. While MDA was not cytotoxic per se, its generation did reflect the induction of oxidative stress in vivo and in vitro in a manner that was highly correlated with the bioactive lipid aldehyde, 4HNE. Despite such overall correlations, individual patient samples were observed in which either MDA or 4HNE predominated. Given the relative cytotoxicity of 4HNE, we propose that this aldehyde should be the preferred criterion for diagnosing oxidative stress in the male germ line. PMID- 25837703 TI - Functional outcomes of early versus delayed pyeloplasty in prenatally diagnosed pelvi-ureteric junction obstruction. AB - Although initial conservative management is popular in the management of antenatally detected pelvi ureteric junction (PUJ) obstruction [1-3], several authors [4,5] have questioned this approach and expressed concern about failure to recover the function lost during expectant management following surgery. In this single center prospective study, we have compared the functional outcomes following early versus delayed pyeloplasty in SFU grade 3-4 PUJ obstruction. METHODS: Among those children, who presented between 2004 and 2013, with prenatal diagnoses of unilateral PUJ obstruction (n = 886), those with SFU grade 1 or 2 hydronephrosis on USG (n = 533) were excluded. In the remaining 353 children with SFU grade 3 and 4 hydronephrosis, 243 had obstructive pattern on radionuclide scan. After excluding those with severely impaired or supranormal split renal function (SRF), palpable mass, single kidney status, bilateral disease and associated other urological anomalies a total of 126 children were included in the study group. Parents who were unwilling for a frequent follow-up underwent early pyeloplasty, (Group I: n = 62) while the remaining underwent initial conservative management, with 3 monthly USG and nuclear scans (Group II; n = 64). In this group pyeloplasty was performed whenever there was deterioration in SRF >10%, or urine infection or pain during the follow-up. A standard open dismembered pyeloplasty was performed by the same surgeon in all patients. Radionuclide scan was performed at 1 year, at the same center using the same protocol, to assess final SRF and drainage. The functional outcomes were compared using student's t test and chi square test. RESULTS: Group I comprised of 62 patients while Group II 64 patients. The mean age at pyeloplasty was 2.8 months in group I while 12.5 months in group II. There was no significant difference in the initial antero posterior diameter (APD) between the groups; 30.2 (+/-3.2) mm in group I and 29.6 (+/-3.7) mm in group II. At 1-year follow up after surgery, there was improvement in the APD, 16.8 (+/-4.2) mm in group I and 18.2 (+/-4.5) mm in group II, with no significant difference between them. In group I, the initial mean SRF was 34.1% (+/-6.4) and there was significant improvement (p = 0.01) in mean SRF to 37.2 (+/-7.1) at 1-year follow up after surgery. In group II, the mean SRF was 35.9 (5.7) initially and there was a deterioration to 32.6 (+/-5.5) before surgery (Figure). At 1-year follow up after surgery, there was a marginal improvement to 33.5 (5.6), however it was significantly lower compared to the initial SRF (p = 0.01). Compared to initial function, at 1-year follow up after pyeloplasty, SRF improved in significantly higher number of patients; 17/62 (27.4%) in group I while only 7/64 (10.9%) in group II (p = 0.03) (Table). There was significantly fewer patients with deterioration in final SRF at 8/62 (12.9%) in group I compared to 22/64 (34.4%) in group II (p = 0.03). DISCUSSION: Although several publications [1-3] have reported functional recovery during initial conservative treatment of PUJ obstruction, in our study a large proportion of patients (80%) in Group II had loss of function during follow-up. This is probably because the study population included only SFU grade 3-4 with obstructive renogram. Several authors have expressed concern about irreversible loss of renal function during expectant management [4,5]. Findings of our study reveal that irrespective of initial SRF, early pyeloplasty in prenatally diagnosed SFU grade 3-4 PUJ obstruction leads to significant improvement of SRF, while delayed pyeloplasty leads to a marginal but, significant loss. This fact should be highlighted to parents so that informed decisions can be made regarding early versus delayed surgery. PMID- 25837704 TI - Commentary to 'Renal damage detected by DMSA despite normal renal ultrasound in children with febrile UTI'. PMID- 25837705 TI - The effect of parenteral testosterone administration prior to hypospadias surgery: A prospective, randomized and controlled study. AB - INTRODUCTION: The goal of hypospadias surgery is to provide a functionally and cosmetically normal penis. Whether this goal will be to the patient's satisfaction depends largely on the original anatomy, surgical technique and surgeon's experience. It has been suggested that androgen administration is associated with better outcomes in hypospadias repair; however, few studies have included control groups and the issue is still controversial. PURPOSE: To evaluate the effects of parenteral testosterone administration on the results of hypospadias repair in children with untreated hypospadias. MATERIALS AND METHODS: A total of 182 children with midshaft or distal hypospadias and a mean age of 30 months (range 18-52 months) were enrolled in this study. Consecutive children were randomly allocated to the study group (testosterone administration) (Group 1, n = 91) or control group (Group 2, n = 91). Only children with a flat urethral plate were included in this study. The control group did not receive any pre operative treatment. Children with a previous history of hypospadias repair and any proven endocrine disorder were excluded. The study children received 2 mg/kg testosterone enanthate monthly for two months before surgery. Tubularized incised plate (TIP) urethroplasty, with or without chordee correction, was performed for all children in both groups by the same urologist. Hypospadias repair was performed 4 weeks after the second dose of testosterone administration. Postoperative complications were recorded, including: urethrocutaneous fistulas, urethral diverticula, meatal stenosis, and glanular dehiscence. The mean stretched penile length and circumference were measured at baseline and at 1 month and 2 months post operation. All children were examined every month for any adverse affects to testosterone treatment, like pubic and axillary hair, and height acceleration, up to 3 months post operation. RESULTS: An increase in penile length (from 28.1 +/- 2.2 mm to 38.5 +/- 2.6 mm) (P = 0.001) and penile circumference (from 35.1 +/- 1.6 mm to 45.5 +/- 2.2 mm) (P = 0.001) were noticed in all but four children in Group 1. The actual values for increase in penile length in the study group were, 22.0%, 35.0% and 36.0%, at postinjection months 1, 2 and 3, respectively (P = 0.01, P = 0.001 and P = 0.001, respectively) (Figure). The actual values for increase in penile circumference in the study group were, 16.0%, 27.0% and 29.0%, at postinjection months 1, 2 and 3, respectively (P=0.01, P=0.001 and P =0.001, respectively). The overall complication rates were significantly higher in Group 2 [12 children, 13.18%) compared to Group 1 (five children, 5.45%) (P=0.03). Urethrocutaneous fistula was the most common complication in both groups (four children [4.39%] in Group 1 and seven children [7.69%] in Group 2) (P=0.02), followed by meatal stenosis (one child [1.09%] in Group 1 and three children [3.29%] in Group 2) (P=0.03). All children in Group 1 developed pigmentation of the genitalia, and scant pubic hair appeared in 14 of them. These side effects disappeared by the 3 months postoperation follow-up visit. DISCUSSION: Tubularized incised plate urethroplasty is a popular reconstructive method for hypospadias repair and is widely accepted by pediatric urologists. It is a reliable and simple technique with low complication rates. Testosterone administration before hypospadias repair decreases complication rates, reduces the need for reoperation and results in better cosmetic outcomes. Some studies have demonstrated temporary side effects like pubic hair growth and aggressive behavior, which gradually became normalized after treatment cessation. Nowadays, many pediatric urologists administer testosterone prior to hypospadias surgery; however, this can be variable. CONCLUSION: Parenteral testosterone administration before hypospadias repair is beneficial in decreasing complication rates. PMID- 25837706 TI - Prepubertal presentation of varicocele does not affect outcomes. AB - INTRODUCTION: Varicoceles in prepubertal boys are uncommon and little is known of the natural history. Historically, a large percentage of these boys have undergone surgical repair with the belief that such early presentation carried a worse prognosis, making assessment of longitudinal outcomes difficult. OBJECTIVE: While there may be concern that varicocele could represent a progressive disease and therefore prepubertal presentation would portend a worse prognosis, we hypothesized that there would be no difference between the prepubertal boys and other adolescents with varicocele. STUDY DESIGN: We retrospectively reviewed a database of boys at a single institution with a documented left-sided varicocele between 1995 and 2011. Inclusion criteria were one or more of the following: 1. Clinician-documented Tanner 1 status, 2. Right testis orchidometric or ultrasound calculated volume of <=3 cc's. Patients were drawn from a prospectively maintained database of all boys presenting to the outpatient urology clinic receiving a diagnosis of varicocele. A cohort of adolescent boys was assembled by matching as closely as possible with respect to testis volume disparity and grade of varicocele. All matches were within 2% of volume difference. Volume was calculated using the length*width*height*0.71 formula. Testis size disparity was set to a threshold of >=20% using the Lambert formula: (VolumeRight - VolumeLeft)/VolumeRight*100%. Our primary outcome was defined as hypotrophy or the need for surgery for hypotrophy at the termination of the study. We planned a single subgroup analysis of boys based on presentation with or without hypotrophy. The decision for surgery or observation was made by the individual clinician at the time of patient assessment. RESULTS: On presentation, the prepubertal cohort was younger (10.8 vs 14.1 years), and with smaller left (2.4 vs 11.6 cc) and right (2.4 vs 11.6 cc) testis volume. There were no significant differences with respect to varicocele grade and volume differentials at presentation. At the end of the study, 76% of the prepubertal cohort had neither hypotrophy nor the requirement for operation, compared with 83% of the matched cohort (P = 0.71, Fisher's exact test). Similarly, there were no significant differences in outcome when comparing prepubertal boys with initial symmetry or hypotrophy to their matched cohort of older adolescents. DISCUSSION: The prepubertal varicocele is a rare clinical problem for which little data exists to guide the clinician. In a review of Pubmed indexed English language manuscripts, we were only able to find five papers with information on Tanner stage; only 31 prepubertal boys have longitudinal data reported. This study approximately doubles the number of boys for whom such data is available in the literature. Our chief limitation was sample size. A power analysis indicated that a final analysis cohort of 90 prepubertal boys would be required to detect a 20% difference in outcome between that group and a matched cohort of pubertal or post pubertal boys. We propose that given the lack of evidence for worse outcomes in prepubertal boys with varicocele that prepubertal status, in and of itself, not be considered an additional indication for correction of varicocele. CONCLUSION: In our retrospective cohort of prepubertal boys with left testis varicocele and their matched cohort, we did not detect a difference in the rate of good outcomes, defined as the absence of hypotrophy and lack of need for surgical intervention. While we may have suspected, as have others, that prepubertal presentation would have conveyed a more pressing need to intervene, it is likely that these boys represent the very same patients that we see more commonly later in their adolescence, and should thus be managed in a similarly conservative fashion. PMID- 25837707 TI - Diagnosis of constipation does not correlate with trans-abdominal ultrasound of rectal distention. AB - INTRODUCTION: Constipation has been shown to have a significant impact on lower urinary tract symptoms (LUTS) in children, and treatment of constipation in children with bowel bladder dysfunction (BBD) has been shown to improve or completely resolve LUTS in many cases. Recent studies utilizing trans-abdominal ultrasound (US) to assess stool burden have correlated diagnosis of constipation with US appearance of rectal stool. An US scoring tool was published in 2008 to assess stool burden, showing linear correlation with constipation severity by symptom questionnaire in an outpatient pediatric constipation clinic population. We hypothesized that this US scoring tool would correlate with constipation symptoms in our outpatient pediatric urology population. METHODS: In 2010, our pediatric urology outpatient clinic began administering a previously published validated BBD questionnaire to new toilet-trained patients, containing three questions addressing bowel function. Patients in our clinic undergoing trans abdominal US of the bladder also have assessment of their stool burden by the previously published US scoring tool. We retrospectively reviewed patient charts beginning in June 2013 who had undergone trans-abdominal US of the bladder, gathering data on the first 100 patients with a complete BBD questionnaire and a completed stool burden US scoring tool. RESULTS: Chart review of 272 consecutive patients was required to enroll 100 patients with a completed US scoring of stool burden and a completed BBD questionnaire. Of these 272 patients, 225 (82%) had a complete scoring of stool burden during their US examination. BBD questionnaires were complete in 107 of 272 patients (39%). Median patient age was 8.2 years, with 69% of patients being female. The most common diagnosis was incontinence or bladder dysfunction (41%). Only one patient (1%) had constipation as the primary diagnosis for their visit. Linear regression analysis showed no correlation of US score to patient reported frequency of bowel movement, frequency of hard stool, frequency of fecal incontinence, or all three symptoms combined. When investigating the subgroup of patients who had diagnoses of BBD/incontinence, this group was seen to have higher mean symptom scores than the entire cohort as a whole, but US scores were still widely variable and again did not correlate with symptom scores. CONCLUSION: US examination has previously been shown to correlate with symptom severity for children with chronic constipation in a pediatric constipation clinic setting. However, in a pediatric urology outpatient clinic setting at our institution, US examination did not correlate with patient reported symptoms. PMID- 25837708 TI - Photodynamic therapy as a new treatment modality for inflammatory and infectious conditions. AB - Photodynamic therapy (PDT) is currently used as a minimally invasive therapeutic modality for cancer. Whereas antitumor treatment regimens require lethal doses of photosensitizer and light, sublethal doses may have immunomodulatory effects, antibacterial action and/or regenerative properties. A growing body of evidence now indicates that non-lethal PDT doses can alleviate inflammation or treat established soft-tissue infections in various murine models of arthritis, experimental encephalomyelitis, inflammatory bowel disease and chronic skin ulcers. Furthermore, PDT is already used in clinical application and clinical trial for the treatment of psoriasis, chronic wounds and periodontitis in humans. Sublethal PDT should be regarded as a new viable option for the treatment of inflammatory conditions. PMID- 25837711 TI - Validation of the German Version of the Social Functioning Scale (SFS) for schizophrenia. AB - Deficits in social functioning are a core symptom of schizophrenia and an important criterion for evaluating the success of treatment. However, there is little agreement regarding its measurement. A common, often cited instrument for assessing self-reported social functioning is the Social Functioning Scale (SFS). The study aimed to investigate the reliability and validity of the German translation. 101 patients suffering from schizophrenia (SZ) and 101 matched controls (C) (60 male / 41 female, 35.8 years in both groups) completed the German version. In addition, demographic, clinical, and functional data were collected. Internal consistency was investigated calculating Cronbach's alpha for SFS full scale (alpha: .81) and all subscales (alpha: .59-.88). Significant bivariate correlation coefficients were found between all subscales as well as between all subscales and full scale (p <.01). For the total sample, principal component analysis gave evidence to prefer a single-factor solution (eigenvalue >= 1) accounting for 48.5 % of the variance. For the subsamples, a two-component solution (SZ; 57.0 %) and a three-component solution (C; 65.6 %) fitted best, respectively. For SZ and C, significant associations were found between SFS and external criteria. The main factor "group" emerged as being significant. C showed higher values on both subscales and full scale. The sensitivity of the SFS was examined using discriminant analysis. 86.5% of the participants could be categorized correctly to their actual group. The German translation of the SFS turned out to be a reliable and valid questionnaire comparable to the original English version. This is in line with Spanish and Norwegian translations of the SFS. Concluding, the German version of the SFS is well suited to become a useful and practicable instrument for the assessment of social functioning in both clinical practice and research. It accomplishes commonly used external assessment scales. PMID- 25837709 TI - Modeling transmembrane domain dimers/trimers of plexin receptors: implications for mechanisms of signal transmission across the membrane. AB - Single-pass transmembrane (TM) receptors transmit signals across lipid bilayers by helix association or by configurational changes within preformed dimers. The structure determination for such TM regions is challenging and has mostly been accomplished by NMR spectroscopy. Recently, the computational prediction of TM dimer structures is becoming recognized for providing models, including alternate conformational states, which are important for receptor regulation. Here we pursued a strategy to predict helix oligomers that is based on packing considerations (using the PREDDIMER webserver) and is followed by a refinement of structures, utilizing microsecond all-atom molecular dynamics simulations. We applied this method to plexin TM receptors, a family of 9 human proteins, involved in the regulation of cell guidance and motility. The predicted models show that, overall, the preferences identified by PREDDIMER are preserved in the unrestrained simulations and that TM structures are likely to be diverse across the plexin family. Plexin-B1 and -B3 TM helices are regular and tend to associate, whereas plexin-A1, -A2, -A3, -A4, -C1 and -D1 contain sequence elements, such as poly-Glycine or aromatic residues that distort helix conformation and association. Plexin-B2 does not form stable dimers due to the presence of TM prolines. No experimental structural information on the TM region is available for these proteins, except for plexin-C1 dimeric and plexin-B1 - trimeric structures inferred from X-ray crystal structures of the intracellular regions. Plexin-B1 TM trimers utilize Ser and Thr sidechains for interhelical contacts. We also modeled the juxta-membrane (JM) region of plexin-C1 and plexin B1 and show that it synergizes with the TM structures. The structure and dynamics of the JM region and TM-JM junction provide determinants for the distance and distribution of the intracellular domains, and for their binding partners relative to the membrane. The structures suggest experimental tests and will be useful for the interpretation of future studies. PMID- 25837710 TI - Ovarian hormones and borderline personality disorder features: Preliminary evidence for interactive effects of estradiol and progesterone. AB - Cyclical fluctuations in the ovarian hormones 17beta-estradiol (E2; estrogen) and progesterone (P4) predict emotions, cognitive processes, and behaviors relevant to Borderline Personality Disorder (BPD); however, there are individual differences in sensitivity to normal hormone shifts. This study examined associations of naturally occurring hormonal changes with concurrent BPD feature expression. Forty women sampled for a flat distribution of the PAI-BOR (n=10 where T<50, n=10 where 5070) provided four weekly saliva samples and psychological assessments. Across most outcomes (e.g., BPD features, felt rejection, anger rumination, negative urgency) P4 deviation (from one's person mean) moderated the effect of current E2 deviation (from one's person mean) among women high (+1 SD) in trait BPD features such that E2 deviation was negatively associated with symptoms only when P4 was higher-than usual. Cyclical hormone changes (e.g., higher P4 in the luteal phase; E2 fluctuations at ovulation and in the luteal phase) may impact BPD feature expression among at-risk women. PMID- 25837712 TI - Synaptic optical imaging platforms: Examining pharmacological modulation of neurotransmitter release at discrete synapses. AB - Chemical synapses are not only fundamental functional units of the brain but also anatomical and functional biomarkers of numerous brain disorders. Therefore, new experimental readouts of synaptic function are needed--with the spatial resolution of single synapses and the scale to image large ensembles of synapses in specific circuits--for the study of both acute and chronic effects of pharmacological agents on synaptic plasticity in living mammals. In this article we discuss the design and use of fluorescent false neurotransmitters (FFNs) as an important step in the development of versatile synaptic imaging platforms. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. PMID- 25837714 TI - Neuromyelitis optica spectrum disorders with multiple brainstem manifestations: a case report. AB - BACKGROUND: Multiple brainstem manifestations have been rarely reported during the same attack in neuromyelitis optica spectrum disorders (NMOSD). CASE PRESENTATION: We describe a 39-year-old Asian woman presenting multiple brainstem manifestations including intractable nausea and vomiting, vertigo, diplopia, facial palsy, hypogeusia, ophthalmoplegia, hemiplegia, dysphagia and tonic spasm during the same attack. Hypogeusia was transient and recovered without any immunotherapy. The brain MRIs showed progressive multiple lesions in the brainstem. NMO-IgG (aquaporin4-antibody, AQP4-Ab) were positive in both serum and cerebral spinal fluid. The symptoms and signs were controlled after immunosuppressive therapy. No relapse happened during the 15-month follow-up. CONCLUSION: This report emphasizes multiple brainstem manifestations during the same attack in NMOSD and the most characteristic symptom was reversible hypogeusia. PMID- 25837713 TI - Focal experimental injury leads to widespread gene expression and histologic changes in equine flexor tendons. AB - It is not known how extensively a localised flexor tendon injury affects the entire tendon. This study examined the extent of and relationship between histopathologic and gene expression changes in equine superficial digital flexor tendon after a surgical injury. One forelimb tendon was hemi-transected in six horses, and in three other horses, one tendon underwent a sham operation. After euthanasia at six weeks, transected and control (sham and non-operated contralateral) tendons were regionally sampled (medial and lateral halves each divided into six 3 cm regions) for histologic (scoring and immunohistochemistry) and gene expression (real time PCR) analysis of extracellular matrix changes. The histopathology score was significantly higher in transected tendons compared to control tendons in all regions except for the most distal (P <= 0.03) with no differences between overstressed (medial) and stress-deprived (lateral) tendon halves. Proteoglycan scores were increased by transection in all but the most proximal region (P < 0.02), with increased immunostaining for aggrecan, biglycan and versican. After correcting for location within the tendon, gene expression for aggrecan, versican, biglycan, lumican, collagen types I, II and III, MMP14 and TIMP1 was increased in transected tendons compared with control tendons (P < 0.02) and decreased for ADAMTS4, MMP3 and TIMP3 (P < 0.001). Aggrecan, biglycan, fibromodulin, and collagen types I and III expression positively correlated with all histopathology scores (P < 0.001), whereas lumican, ADAMTS4 and MMP14 expression positively correlated only with collagen fiber malalignment (P < 0.001). In summary, histologic and associated gene expression changes were significant and widespread six weeks after injury to the equine SDFT, suggesting rapid and active development of tendinopathy throughout the entire length of the tendon. These extensive changes distant to the focal injury may contribute to poor functional outcomes and re-injury in clinical cases. Our data suggest that successful treatments of focal injuries will need to address pathology in the entire tendon, and that better methods to monitor the development and resolution of tendinopathy are required. PMID- 25837716 TI - Impact of casing damaging on aflatoxin B1 concentration during the ripening of dry-fermented meat sausages. AB - The aim of this article is to investigate the impact of casing damaging on the formation of aflatoxin B1 (AFB1) during the ripening of dry-fermented meat sausages. The level of AFB1 contamination was determined in 24 samples using the ELISA immunoassay throughout a six-month production period. While with intact casing samples no contamination was observed throughout the whole production process, in damaged casing samples AFB1 was detected in the ripening end-stages in the range of 1.62-4.49 MUg/kg. The results showed that casing damaging occurring during long-term ripening of dry-fermented sausages can cause AFB1 contamination, possibly arising on the grounds of diffusion of this mycotoxin from the product surface to its interior. PMID- 25837717 TI - Editorial: HSA-based drug development and drug delivery systems. PMID- 25837715 TI - Genetic and childhood trauma interaction effect on age of onset in bipolar disorder: An exploratory analysis. AB - INTRODUCTION: This study investigated whether early life trauma mediates genetic effects on the age at onset (AAO) of bipolar disorder. METHOD: Data from the BiGS Consortium case samples (N=1119) were used. Childhood traumatic events were documented using the Childhood Life Events Scale (CLES). Interaction between occurrence of childhood trauma and common genetic variants throughout the genome was tested to identify single nucleotide polymorphic gene variants (SNPs) whose effects on bipolar AAO differ between individuals clearly exposed (CLES>=2) and not exposed (CLES=0) to childhood trauma. RESULTS: The modal response to the CLES was 0 (N=480), but an additional 276 subjects had CLES=1, and 363 subjects reported 2 or more traumatic lifetime events. The distribution of age at onset showed a broad peak between ages 12 and 18, with the majority of subjects having onset during that period, and a significant decrease in age of onset with the number of traumatic events. No single SNP showed a statistically significant interaction with the presence of traumatic events to impact bipolar age at onset. However, SNPs in or near genes coding for calcium channel activity-related proteins (Gene Ontology: 0005262) were found to be more likely than other SNPs to show evidence of interaction using the INRICH method (p<0.001). LIMITATIONS: Retrospective ascertainment of trauma and AAO. CONCLUSION: Interaction effects of early life trauma with genotype may have a significant effect on the development and manifestation of bipolar disorder. These effects may be mediated in part by genes involved in calcium signaling. PMID- 25837718 TI - Exogenous ochronosis: a comprehensive review of the diagnosis, epidemiology, causes, and treatments. AB - Exogenous ochronosis (EO) can be an unintended psychologically troubling condition for patients who are already being treated for longer-term hyperpigmentation disorders such as melasma. Early diagnosis is key in order that the offending agent can be stopped to prevent further disfiguring discoloration. EO can be diagnosed in the right clinical setting with the aid of dermatoscopy, which can assist in early diagnosis and may negate the need for a biopsy. Laser modalities using Q-switched lasers of longer wavelengths and combination laser dermabrasion treatments have shown the most significant results with minimal adverse events. However, further large-scale studies are needed to determine optimal treatment modalities. Although considered uncommon, the incidence of EO will likely continue to increase with the growth of immigrant populations and the use of skin-lightening agents above the FDA's recommended over-the-counter concentrations, without the guidance of a dermatologist. PMID- 25837719 TI - Flexible adaptive paradigms for fMRI using a novel software package 'Brain Analysis in Real-Time' (BART). AB - In this work we present a new open source software package offering a unified framework for the real-time adaptation of fMRI stimulation procedures. The software provides a straightforward setup and highly flexible approach to adapt fMRI paradigms while the experiment is running. The general framework comprises the inclusion of parameters from subject's compliance, such as directing gaze to visually presented stimuli and physiological fluctuations, like blood pressure or pulse. Additionally, this approach yields possibilities to investigate complex scientific questions, for example the influence of EEG rhythms or fMRI signals results themselves. To prove the concept of this approach, we used our software in a usability example for an fMRI experiment where the presentation of emotional pictures was dependent on the subject's gaze position. This can have a significant impact on the results. So far, if this is taken into account during fMRI data analysis, it is commonly done by the post-hoc removal of erroneous trials. Here, we propose an a priori adaptation of the paradigm during the experiment's runtime. Our fMRI findings clearly show the benefits of an adapted paradigm in terms of statistical power and higher effect sizes in emotion-related brain regions. This can be of special interest for all experiments with low statistical power due to a limited number of subjects, a limited amount of time, costs or available data to analyze, as is the case with real-time fMRI. PMID- 25837720 TI - Effects of ankle-foot orthoses on functional recovery after stroke: a propensity score analysis based on Japan rehabilitation database. AB - OBJECTIVES: The purpose of the present study was to investigate potential effects of ankle-foot orthoses (AFOs) on the functional recovery of post-acute stroke patients following rehabilitation. SUBJECTS AND METHODS: This study is a retrospective cohort study. Participants were in-hospital stroke patients registered in the Japan Rehabilitation Database between 2005 and 2012. A total of 1862 patients were eligible after applying exclusion criteria. Propensity score analysis was applied to adjust for potential bias and to create two comparable groups. An additional subset analysis focused on Functional Independence Measure (FIM) scores on admission. RESULTS: In this sample, 30.7% of 1863 eligible patients were prescribed AFOs. Propensity score matched analysis showed that patients with AFOs had significantly higher scores than those without them for discharge FIM (mean: 91.3 vs 85.8; p=0.02), FIM gain (mean: 28.9 vs 23.5; p<0.001), and FIM efficiency (mean: 0.27 vs 0.22; p<0.001). Inverse probability weighting analysis showed similar results. In the subset analysis, patients with AFOs had significantly higher discharge FIM compared with those without them in the low admission FIM subgroup only. In addition, patients with AFOs performed independent exercise more than those without them (p<0.001). CONCLUSIONS: These data suggest that stroke survivors may have better functional recovery if they are prescribed an AFO than if they are not prescribed an AFO. The use of AFOs is considered to be a feasible option to improve functional recovery of stroke rehabilitation patients. PMID- 25837721 TI - Uptake of L-cystine via an ABC transporter contributes defense of oxidative stress in the L-cystine export-dependent manner in Escherichia coli. AB - Intracellular thiols like L-cystine and L-cystine play a critical role in the regulation of cellular processes. Here we show that Escherichia coli has two L cystine transporters, the symporter YdjN and the ATP-binding cassette importer FliY-YecSC. These proteins import L-cystine, an oxidized product of L-cystine from the periplasm to the cytoplasm. The symporter YdjN, which is expected to be a new member of the L-cystine regulon, is a low affinity L-cystine transporter (Km = 1.1 MUM) that is mainly involved in L-cystine uptake from outside as a nutrient. E. coli has only two L-cystine importers because DeltaydjNDeltayecS mutant cells are not capable of growing in the minimal medium containing L cystine as a sole sulfur source. Another protein YecSC is the FliY-dependent L cystine transporter that functions cooperatively with the L-cystine transporter YdeD, which exports L-cystine as reducing equivalents from the cytoplasm to the periplasm, to prevent E. coli cells from oxidative stress. The exported L-cystine can reduce the periplasmic hydrogen peroxide to water, and then generated L cystine is imported back into the cytoplasm via the ATP-binding cassette transporter YecSC with a high affinity to L-cystine (Km = 110 nM) in a manner dependent on FliY, the periplasmic L-cystine-binding protein. The double disruption of ydeD and fliY increased cellular levels of lipid peroxides. From these findings, we propose that the hydrogen peroxide-inducible L-cystine/L cystine shuttle system plays a role of detoxification of hydrogen peroxide before lipid peroxidation occurs, and then might specific prevent damage to membrane lipids. PMID- 25837722 TI - Laparoscopic retroperitoneoscopic nephrectomy and partial nephrectomy in children. AB - OBJECTIVES: The aim was to evaluate our experience in the retroperitoneal laparoscopic approach in total and partial nephrectomies in children. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 41 patients who underwent retroperitoneal laparoscopic total or partial nephrectomies performed in our center from 2004 to 2012. We looked at the demographic data, age at surgery, indication, operative time, surgical complications, conversion to open surgery and operative complications. RESULTS: Thirty-five total and six partial nephrectomies (upper pole) were performed. The mean age was 84 months (7-175). Vesicoureteric reflux, pelviureteric junction obstruction, and multicystic dysplastic kidney disease were the main underlying pathologies. The mean operative time was 158 min (60-280). There were no intraoperative complications (surgical and anesthetic), and no significant blood loss was observed. Conversion to open surgery was necessary in two cases caused by failure to progress due to difficult anatomy during the partial nephrectomies. No major postoperative complications were noted. The mean hospital stay was 2.5 days (1-5). A drain was used in 12 cases and was removed after a mean of 2 days. CONCLUSIONS: Laparoscopic retroperitoneoscopic renal surgery can be carried out safely and effectively in children. Still, this procedure is more challenging and requires an excellent image of the retroperitoneal space, especially when partial nephrectomies are concerned. PMID- 25837723 TI - Impact of the new density reporting laws: radiologist perceptions and actual behavior. AB - RATIONALE AND OBJECTIVES: To assess radiologists' perceptions of how the new Breast Density Notification Act (BDNA) of Pennsylvania would affect their breast density reporting and their actual reporting patterns after implementation. MATERIALS AND METHODS: Under an institutional review board-approved protocol, we surveyed 21 radiologists about how they believe the new law affected their breast density reporting patterns and analyzed actual changes for 16 respondents before and after the law took effect. Three hundred consecutive reports were assessed for each radiologist before and after the effective date. The distributions of reported density Breast Imaging Reporting and Data System (BI-RADS) (1-4) were compared using a type III test in the context of an ordinal mixed model accounting for between-reader variability and adjusting for age (PROC GLIMMIX, SAS, version 9.3) using a two-sided .05 significance level. RESULTS: Seventeen radiologists responded to the survey; however, one retired shortly after responding. Of the 16 respondents, 56% (nine of 16) did not favor the law, 13% (two of 16) were in favor, and 31% (five of 16) were neutral. The fraction perceived that after implementation, they rated more, equally, or less frequently breasts as scattered fibroglandular densities (BI-RADS 2) versus heterogeneously dense rating (BI-RADS 3) was 50% (eight of 16), 44% (seven of 16), and 6% (one of 16), respectively. In practice, 44% (seven of 16) performed differently than their survey answers. Fourteen of 16 radiologists increased the frequency of reported BI-RADS 2 scores after BDNA implementation with seven having statistically significant (P < .05) increases after adjusting for age differences. CONCLUSIONS: Radiologists' reporting patterns changed, at least for a short duration, after the new density reporting law and for some of the radiologists in an unexpected way. PMID- 25837724 TI - Fabrication and Characterization of Nanoporous Niobia, and Nanotubular Tantala, Titania and Zirconia via Anodization. AB - Valve metals such as titanium (Ti), zirconium (Zr), niobium (Nb) and tantalum (Ta) that confer a stable oxide layer on their surfaces are commonly used as implant materials or alloying elements for titanium-based implants, due to their exceptional high corrosion resistance and excellent biocompatibility. The aim of this study was to investigate the bioactivity of the nanostructures of tantala (Ta2O5), niobia (Nb2O5), zirconia (ZrO2) and titania (TiO2) in accordance to their roughness and wettability. Therefore, four kinds of metal oxide nanoporous and nanotubular Ta2O5, Nb2O5, ZrO2 and TiO2 were fabricated via anodization. The nanosize distribution, morphology and the physical and chemical properties of the nanolayers and their surface energies and bioactivities were investigated using SEM-EDS, X-ray diffraction (XRD) analysis and 3D profilometer. It was found that the nanoporous Ta2O5 exhibited an irregular porous structure, high roughness and high surface energy as compared to bare tantalum metal; and exhibited the most superior bioactivity after annealing among the four kinds of nanoporous structures. The nanoporous Nb2O5 showed a uniform porous structure and low roughness, but no bioactivity before annealing. Overall, the nanoporous and nanotubular layers of Ta2O5, Nb2O5, ZrO2 and TiO2 demonstrated promising potential for enhanced bioactivity to improve their biomedical application alone or to improve the usage in other biocompatible metal implants. PMID- 25837725 TI - Inertia-enhanced pinched flow fractionation. AB - Separating target particles or cells from a heterogeneous mixture is often critical to many chemical and biomedical applications. Pinched flow fractionation (PFF) is a microfluidic technique that utilizes the laminar flow profile to continuously separate particles by size. We demonstrate that the flow-induced inertial lift force in microchannels can be exploited to significantly increase the particle displacement in PFF due to its strong size dependence. This inertia enhanced PFF (iPFF) technique can offer at least one-order-of-magnitude higher particle throughput than PFF does at the same sheath flow rate. Moreover, it is able to work effectively in a large range of Reynolds number that spans more than 1 order of magnitude in the current study. In addition, iPFF is found to work most effectively in a rectangular microchannel with a width-to-height aspect ratio of around 2. PMID- 25837726 TI - Music, clicks, and their imaginations favor differently the event-based timing component for rhythmic movements. AB - The involvement or noninvolvement of a clock-like neural process, an effector independent representation of the time intervals to produce, is described as the essential difference between event-based and emergent timing. In a previous work (Bravi et al. in Exp Brain Res 232:1663-1675, 2014a. doi: 10.1007/s00221-014-3845 9 ), we studied repetitive isochronous wrist's flexion-extensions (IWFEs), performed while minimizing visual and tactile information, to clarify whether non temporal and temporal characteristics of paced auditory stimuli affect the precision and accuracy of the rhythmic motor performance. Here, with the inclusion of new recordings, we expand the examination of the dataset described in our previous study to investigate whether simple and complex paced auditory stimuli (clicks and music) and their imaginations influence in a different way the timing mechanisms for repetitive IWFEs. Sets of IWFEs were analyzed by the windowed (lag one) autocorrelation-wgamma(1), a statistical method recently introduced for the distinction between event-based and emergent timing. Our findings provide evidence that paced auditory information and its imagination favor the engagement of a clock-like neural process, and specifically that music, unlike clicks, lacks the power to elicit event-based timing, not counteracting the natural shift of wgamma(1) toward positive values as frequency of movements increase. PMID- 25837727 TI - The structural and functional role of the three tryptophan residues in Pin1. AB - Pin1, the only known isomerase catalyzing phosphorylated pSer/pThr-Pro motifs in proteins, plays unique roles in human diseases notably cancers and Alzheimer's disease. Herein, site-directed mutagenesis was employed to construct the tryptophan mutants of Pin1, including W11L, W34L, and W73L. Spectral methodologies, activity measurement, and proteinase resistance analysis were used to investigate the structural and functional role of the tryptophan residues in Pin1. In general, W11 and W34 are essential to the structure and the function of Pin1, because their mutations influence the structure of WW domain of Pin1, potentially attenuate the binding affinity of Pin1 to substrates, and thus inhibit the enzymatic activity of Pin1. Particularly, W11 mutation results in significantly varied structural features of Pin1 as revealed by fluorescence and circular dichroism (CD) spectroscopies, and decreases the enzymatic activity, thermal stability, and proteinase resistance of Pin1, all of which give an explanation for the high conservation of W11 in vivo. The synchronous fluorescence spectra indicate that W11 and W34 mutations possibly block their energy transfer to Y23 or Y24, suggesting the structural rearrangement in WW domain. By contrast, W73 is of minor importance for the structure and the function of Pin1, because the parameters of W73L observed in several experiments are very similar to wild-type Pin1. These observations are very beneficial for further understanding the structural and functional characteristics of Pin1 and for unveiling the pathogenesis of Pin1-related diseases especially those caused by tryptophan mutations. PMID- 25837728 TI - Influence of pH on the decay of beta-carotene radical cation in aqueous Triton X 100: A laser flash photolysis study. AB - The identification of the spectral information of carotenoid neutral radicals is essential for studying their reactivities towards O2 and thereby evaluating their role in the antioxidant-prooxidant properties of the corresponding carotenoid. Recently, it was reported that beta-carotene neutral radical (beta-CAR) has an absorption maximum at 750 nm. This contradicts the results of many reports that show carotenoid neutral radicals (CAR) absorb in the same or near to the spectral region as their parent carotenoids. In this manuscript, the influence of pH on the decay of beta-carotene radical cation (beta-CAR-H(+)), generated in an aqueous solution of 2% Triton X-100 (TX-100), was investigated, employing laser flash photolysis (LFP) coupled with kinetic absorption spectroscopy, to identify the absorption bands of the beta-carotene neutral radicals. By increasing the pH value of the solution, the decay of beta-CAR-H(+) is enhanced and this enhancement is not associated with the formation of any positive absorption bands over the range 550-900 nm. By comparing these results with the literature, it can be concluded that beta-carotene neutral radicals most probably absorb within the same spectral range as that of beta-carotene. The reaction pathways of the reaction of beta-CAR-H(+) with (-)OH have been discussed. PMID- 25837729 TI - Attentional network deficits in children with autism spectrum disorder. AB - STATEMENT OF PURPOSE: Individuals with autism spectrum disorder (ASD) often demonstrate deficient attentional ability, but the specific nature of the deficit is unclear. The Attention Networks model provides a useful approach to deconstruct this attentional deficit into its component parts. METHOD: Fifty-two neurotypical (NT) children and 14 children with ASD performed the child version of the Attention Network Test (ANT). The latter requires participants to indicate the direction of a centre target stimulus, which is presented above/below fixation and sometimes flanked by either congruent or incongruent distractor stimuli. RESULTS: Relative to NT children, those with ASD were: (1) slower to react to spatially cued trials and (2) more error prone on executive (conflict) attention trials. CONCLUSIONS: Young children with ASD have intact alerting attention, but less-efficient orienting and executive attention. PMID- 25837730 TI - Reply to letter to the editor concerning: "Are paediatric operations evidence based?". PMID- 25837731 TI - A Paleogene origin for crown passerines and the diversification of the Oscines in the New World. AB - In this study, we present a detailed family-level phylogenetic hypothesis for the largest avian order (Aves: Passeriformes) and an unmatched multi-calibrated, relaxed clock inference for the diversification of crown passerines. Extended taxon sampling allowed the recovery of many challenging clades and elucidated their position in the tree. Acanthisittia appear to have diverged from all other passerines at the early Paleogene, which is considerably later than previously suggested. Thus, Passeriformes may be younger and represent an even more intense adaptive radiation compared to the remaining avian orders. Based on our divergence time estimates, a novel hypothesis for the diversification of modern Suboscines is proposed. According to this hypothesis, the first split between New and Old World lineages would be related to the severing of the Africa-South America biotic connection during the mid-late Eocene, implying an African origin for modern Eurylaimides. The monophyletic status of groups not recovered by any subsequent study since their circumscription, viz. Sylvioidea including Paridae, Remizidae, Hyliotidae, and Stenostiridae; and Muscicapoidea including the waxwing assemblage (Bombycilloidea) were notable topological findings. We also propose possible ecological interactions that may have shaped the distinct Oscine distribution patterns in the New World. The insectivorous endemic Oscines of the Americas, Vireonidae (Corvoidea), Mimidae, and Troglodytidae (Muscicapoidea), probably interfered with autochthonous Suboscines through direct competition. Thus, the Early Miocene arrival of these lineages before any other Oscines may have occupied the few available niches left by Tyrannides, constraining the diversification of insectivorous Oscines that arrived in the Americas later. The predominantly frugivorous-nectarivorous members of Passeroidea, which account for most of the diversity of New World-endemic Oscines, may not have been subjected to competition with Tyrannides. In fact, the vast availability of frugivory niches combined with weak competition with the autochthonous passerine fauna may have been crucial for passeroids to thrive in the New World. PMID- 25837732 TI - Family matters: The first molecular phylogeny of the Onchidorididae Gray, 1827 (Mollusca, Gastropoda, Nudibranchia). AB - Recent investigations into the evolution of the Onchidorididae using morphological based methods have resulted in low support for relationships among genera. This study aims to determine if molecular data corroborates recent morphological interpretations of the evolution of Onchidorididae. Five genetic markers: 16S, 18S, 28S, cytochrome c oxidase 1 (COI) and histone 3 (H3), were sequenced from 32 species comprising Onchidorididae and five other families, three from Phanerobranchia and two from Cryptobranchia. Phylogenies were estimated using maximum likelihood, and Bayesian inference analyses; with both yielding similar topologies. Molecular analyses resulted in high support for the monophyly of the suctorian clade and the placement of the genera within Onchidorididae. However, the Onchidorididae forms a paraphyletic grouping due to the recovery of the Goniodorididae and the Akiodorididae nested within family. In addition, the placement of Corambe as the most derived member of Onchidorididae is contradicted by the present study. Rather it is sister to a large clade that includes Acanthodoris and the species traditionally placed in Onchidoris and Adalaria, now defined as Onchidorididae. We have chosen to maintain Corambidae as a distinct taxon (including Corambe and Loy), sister to Onchidorididae. We also maintain Goniodorididae, Akiodorididae and Calycidoridae (including Calycidoris and Diaphorodoris), which along with the Onchidorididae and Corambidae comprise the suctorian superfamily Onchidoridoidea. Ancestral character reconstruction also suggests that the formation of a gill pocket, a character that currently defines the Cryptobranchia, may have evolved multiple times from an ancestor that lacked the ability to retract its gills into a fully formed gill pocket. The diversity of gill morphology displayed by the Onchidoridoidea will help give new insight into the evolution of this complex character within the Nudibranchia. PMID- 25837733 TI - Genetic divergence and diversity in the Mona and Virgin Islands Boas, Chilabothrus monensis (Epicrates monensis) (Serpentes: Boidae), West Indian snakes of special conservation concern. AB - Habitat fragmentation reduces the extent and connectivity of suitable habitats, and can lead to changes in population genetic structure. Limited gene flow among isolated demes can result in increased genetic divergence among populations, and decreased genetic diversity within demes. We assessed patterns of genetic variation in the Caribbean boa Chilabothrus monensis (Epicrates monensis) using two mitochondrial and seven nuclear markers, and relying on the largest number of specimens of these snakes examined to date. Two disjunct subspecies of C. monensis are recognized: the threatened C. m. monensis, endemic to Mona Island, and the rare and endangered C. m. granti, which occurs on various islands of the Puerto Rican Bank. Mitochondrial and nuclear markers revealed unambiguous genetic differences between the taxa, and coalescent species delimitation methods indicated that these snakes likely are different evolutionary lineages, which we recognize at the species level, C. monensis and C. granti. All examined loci in C. monensis (sensu stricto) are monomorphic, which may indicate a recent bottleneck event. Each population of C. granti exclusively contains private mtDNA haplotypes, but five of the seven nuclear genes assayed are monomorphic, and nucleotide diversity is low in the two remaining markers. The faster pace of evolution of mtDNA possibly reflects the present-day isolation of populations of C. granti, whereas the slower substitution rate of nuDNA may instead mirror the relatively recent episodes of connectivity among the populations facilitated by the lower sea level during the Pleistocene. The small degree of overall genetic variation in C. granti suggests that demes of this snake could be managed as a single unit, a practice that would significantly increase their effective population size. PMID- 25837734 TI - Eligibility for low-dose computerized tomography screening among asbestos-exposed individuals. AB - OBJECTIVES: The study aimed to incorporate an estimate of risk for asbestos exposure in the Canadian Cancer Risk Management Lung Cancer (CRMM-LC) microsimulation model. METHODS: In CRMM-LC, a 3-year probability of developing lung cancer can be derived from different risk profiles. An asbestos-exposed cohort was simulated and different scenarios of low-dose computerized tomography (LDCT) screening were simulated. RESULTS: As annual LDCT screening among non asbestos-exposed individuals is less cost-effective than biennial screening, all the scenarios modeled for an asbestos-exposed cohort were biennial. For individuals with a two-fold risk of asbestos-induced lung cancer to be eligible for biennial LDCT screening, a smoking history of >=15 pack-years would be necessary. For non-smokers with asbestos exposure resulting in a relative risk (RR) for lung cancer, it is not cost-effective to screen those with a RR of 5, but it is cost-effective to screen those with a RR of 10 (the heavily exposed). CONCLUSION: Asbestos-exposed individuals with an estimated two-fold or more risk of lung cancer from asbestos-exposure are eligible for LDCT screening at all ages from 55-74 years if they have a cigarette smoking history of >=15 pack-years. Asbestos-exposed individuals who are lifelong non-smokers are eligible for LDCT screening at all ages from 55-74 years if they have accumulated a degree of asbestos exposure resulting in an estimated risk of lung cancer of >=10. PMID- 25837735 TI - Vitamin D, muscle and bone: Integrating effects in development, aging and injury. AB - Beyond the established effects of muscle loading on bone, a complex network of hormones and growth factors integrates these adjacent tissues. One such hormone, vitamin D, exerts broad-ranging effects in muscle and bone calcium handling, differentiation and development. Vitamin D also modulates muscle and bone-derived hormones, potentially facilitating cross-talk between these tissues. In the clinical setting, vitamin D deficiency or mutations of the vitamin D receptor result in generalized atrophy of muscle and bone, suggesting coordinated effects of vitamin D at these sites. In this review, we discuss emerging evidence that vitamin D exerts specific effects throughout the life of the musculoskeletal system - in development, aging and injury. From this holistic viewpoint, we offer new insights into an old debate: whether vitamin D's effects in the musculoskeletal system are direct via local VDR signals or indirect via its systemic effects in calcium and phosphate homeostasis. PMID- 25837736 TI - Tumours and tumour mimics in the olecranon. AB - Lesions in the olecranon are rare and may be identified during the investigation of a clinically suspected abnormality or as an incidental finding. This review describes the spectrum of tumours and tumour-like lesions that can involve the olecranon and illustrates the radiographic, CT, and MRI appearances that may facilitate diagnosis. A variety of pathological processes affecting the olecranon are presented and discussed including the epidemiology and imaging features. PMID- 25837737 TI - Driver injury severity related to inclement weather at highway-rail grade crossings in the United States. AB - OBJECTIVE: Previous studies on crash modeling at highway-rail grade crossings were aimed at exploring the factors that are likely to increase the crash frequencies at highway-rail grade crossings. In recent years, modeling driver's injury severity at highway-rail grade crossings has received interest. Because there were substantial differences among different weather conditions for driver's injury severity, this study attempts to explore the impact of weather influence on driver injury at highway-rail grade crossing. METHOD: Utilizing the most recent 10 years (2002-2011) of highway-rail grade crossing accident data, this study applied a mixed logit model to explore the determinants of driver injury severity under different weather conditions at highway-rail grade crossing. RESULTS: Analysis results indicate that drivers' injury severity at highway-rail grade crossings is strongly different for different weather conditions. It was found that the factors significantly impacting driver injury severity at highway-rail grade crossings include motor vehicle speed, train speed, driver's age, gender, area type, lighting condition, highway pavement, traffic volume, and time of day. CONCLUSIONS: The findings of this study indicate that crashes are more prevalent if vehicle drivers are driving at high speed or the oncoming trains are high speed. Hence, a reduction in speed limit during inclement weather conditions could be particularly effective in moderating injury severity, allowing more reaction time for last-minute maneuvering and braking in moments before impacts. In addition, inclement weather-related crashes were more likely to occur in open areas and highway-rail grade crossings without pavement and lighting. Paved highway-rail grade crossings with installation of lights could be particularly effective in moderating injury severity. PMID- 25837738 TI - Overexpression of the carbohydrate binding module of strawberry expansin2 in Arabidopsis thaliana modifies plant growth and cell wall metabolism. AB - Several cell wall enzymes are carbohydrate active enzymes that contain a putative Carbohydrate Binding Module (CBM) in their structures. The main function of these non-catalitic modules is to facilitate the interaction between the enzyme and its substrate. Expansins are non-hydrolytic proteins present in the cell wall, and their structure includes a CBM in the C-terminal that bind to cell wall polymers such as cellulose, hemicelluloses and pectins. We studied the ability of the Expansin2 CBM (CBMFaEXP2) from strawberry (Fragaria x ananassa, Duch) to modify the cell wall of Arabidopsis thaliana. Plants overexpressing CBMFaEXP2 were characterized phenotypically and biochemically. Transgenic plants were taller than wild type, possibly owing to a faster growth of the main stem. Cell walls of CBMFaEXP2-expressing plants were thicker and contained higher amount of pectins. Lower activity of a set of enzymes involved in cell wall degradation (PG, beta Gal, beta-Xyl) was found, and the expression of the corresponding genes (AtPG, Atbeta-Gal, Atbeta-Xyl5) was reduced also. In addition, a decrease in the expression of two A. thaliana Expansin genes (AtEXP5 and AtEXP8) was observed. Transgenic plants were more resistant to Botrytis cinerea infection than wild type, possibly as a consequence of higher cell wall integrity. Our results support the hypothesis that the overexpression of a putative CBM is able to modify plant cell wall structure leading to modulation of wall loosening and plant growth. These findings might offer a tool to controlling physiological processes where cell wall disassembly is relevant, such as fruit softening. PMID- 25837739 TI - Identification and characterization of phosphodiesterases that specifically degrade 3'3'-cyclic GMP-AMP. AB - Cyclic dinucleotides act as intracellular second messengers, modulating a variety of cellular activities including innate immune activation. Although phosphodiesterases (PDEs) hydrolyzing c-di-GMP and c-di-AMP have been identified, no PDEs for cGAMPs have been reported. Here we identified the first three cGAMP specific PDEs in V. cholerae (herein designated as V-cGAP1/2/3). V-cGAPs are HD GYP domain-containing proteins and specifically break 3'3'-cGAMP, but not other forms of cGAMP. 3'3'-cGAMP is first linearized by all three V-cGAPs to produce 5' pApG, which is further hydrolyzed into 5'-ApG by V-cGAP1. In this two-step reaction, V-cGAP1 functions as both a PDE and a 5'-nucleotidase. In vivo experiments demonstrated that V-cGAPs play non-redundant roles in cGAMP degradation. The high specificity of V-cGAPs on 3'3'-cGAMP suggests the existence of specific PDEs for other cGAMPs, including 2'3'-cGAMP in mammalian cells. The absolute requirement of the GYP motif for 3'3'-cGAMP degradation suggests that HD domain-containing PDEs in eukaryotes are probably unable to hydrolyze cGAMPs. The fact that all V-cGAPs attack 3'3'-cGAMP on one specific phosphodiester bond suggests that PDEs for other cGAMPs would utilize a similar strategy. These results will provide valuable information for identification and characterization of mammalian 2'3'-cGAMP-specific PDEs in future studies. PMID- 25837740 TI - Aggression and violence against primary care physicians-a nationwide questionnaire survey. AB - BACKGROUND: International studies show that aggressive behavior against primary care physicians is not an uncommon occurrence. There has been no systematic study to date of the nature and frequency of such occurrences in Germany. METHODS: A four-page questionnaire was sent to a nationwide random sample of 1500 primary care physicians. It contained questions about the type, frequency, severity, and site of aggressive behavior against the physician. RESULTS: 831 (59%) of 1408 correctly delivered questionnaires could be included in the analysis. 91% of the respondents (95% confidence interval [CI], 89%-93%) said they had been the object of aggressive behavior at some time in their career as a primary care physician, 73% (95% CI, 70%-76%) in the previous 12 months. Severe aggression or violence had been experienced by 23% (95% CI, 20%-25%) in their entire career and 11% (95% CI, 8%-13%) in the previous year. The vast majority of respondents said they felt safe in their offices. 66% of female and 34% of male respondents said they did not feel safe making house visits while on on-call duty. CONCLUSION: The frequency and extent of aggression and violence against primary care physicians in Germany is comparable to those reported by international studies. Strategies for dealing with this problem should be developed. In particular, the issue of safety on emergency call needs to be addressed. PMID- 25837741 TI - Preventing inadvertent perioperative hypothermia. AB - BACKGROUND: 25-90% of all patients undergoing elective surgery suffer from inadvertent postoperative hypothermia, i.e., a core body temperature below 36 degrees C. Compared to normothermic patients, these patients have more frequent wound infections (relative risk [RR] 3.25, 95% confidence interval [CI] 1.35 7.84), cardiac complications (RR 4.49, 95% CI 1.00-20.16), and blood transfusions (RR 1.33, 95% CI 1.06-1.66). Hypothermic patients feel uncomfortable, and shivering raises oxygen consumption by about 40%. METHODS: This guideline is based on a systematic review of the literature up to and including October 2012 and a further one from November 2012 to August 2014. The recommendations were developed and agreed upon by representatives of five medical specialty societies in a structured consensus process. RESULTS: The patient's core temperature should be measured 1-2 hours before the start of anesthesia, and either continuously or every 15 minutes during surgery. Depending on the nature of the operation, the site of temperature measurement should be oral, naso-/oropharyngeal, esophageal, vesical, or tympanic (direct). The patient should be actively prewarmed 20-30 minutes before surgery to counteract the decline in temperature. Prewarmed patients must be actively warmed intraoperatively as well if the planned duration of anesthesia is longer than 60 minutes (without prewarming, 30 minutes). The ambient temperature in the operating room should be at least 21 degrees C for adult patients and at least 24 degrees C for children. Infusions and blood transfusions that are given at rates of >500 mL/h should be warmed first. Perioperatively, the largest possible area of the body surface should be thermally insulated. Emergence from general anesthesia should take place at normal body temperature. Postoperative hypothermia, if present, should be treated by the administration of convective or conductive heat until normothermia is achieved. Shivering can be treated with medications. CONCLUSION: Inadvertent perioperative hypothermia can adversely affect the outcome of surgery and the patient's postoperative course. It should be actively prevented. PMID- 25837742 TI - Far removed from patients. PMID- 25837743 TI - Significance of the respiratory rate in emergency medicine. PMID- 25837744 TI - In reply. PMID- 25837745 TI - Positive psychological effects. PMID- 25837746 TI - Different procedures should be on offer. PMID- 25837747 TI - In reply. PMID- 25837748 TI - Association of N-terminal pro-B-type natriuretic peptide with contrast-induced nephropathy and long-term outcomes in patients with chronic kidney disease and relative preserved left ventricular function. AB - The aim of the present article was to evaluate the association of N-terminal pro B-type natriuretic peptide (NT-pro-BNP) with contrast-induced nephropathy (CIN) and long-term outcomes in patients with chronic kidney disease (CKD) and relative preserved left ventricular function (LVF) undergoing percutaneous coronary intervention (PCI). We prospectively enrolled 1203 consecutive patients with CKD and preserved LVF undergoing elective PCI. The primary end point was the development of CIN, defined as an absolute increase in serum creatinine (SCr) >=0.5 mg/dL, from baseline within 48 to 72 hours after contrast medium exposure. CIN incidence varied from 2.2% to 5.2%. Univariate logistic analysis showed that lg-NT-pro-BNP was significantly associated with CIN (odds ratio [OR] = 3.93, 95% confidence interval [CI], 2.22-6.97, P < 0.001). Furthermore, lg-NT-pro-BNP remained a significant predictor of CIN (OR = 3.30, 95% CI, 1.57-6.93, P = 0.002), even after adjusting for potential confounding risk factors. These results were confirmed by using other CIN criteria, which were defined as elevations of the SCr by 25% or 0.5 and 0.3 mg/dL from the baseline. The best cutoff value of lg-NT-pro-BNP for detecting CIN was 2.73 pg/mL (537 pg/mL) with 73.1% sensitivity and 70.0% specificity according to the receiver operating characteristic (ROC) analysis (C statistic = 0.754, 95% CI, 0.67-0.84, P < 0.001). In addition, NT-pro-BNP >=537 pg/mL (2.73 pg/mL, lg-NT-pro-BNP) was associated with an increased risk of all-cause mortality and composite end points during 2.5 years of follow-up. NT-pro-BNP >=537 pg/mL is independently associated with an increased risk of CIN with different definitions and poor clinical outcomes in patients with CKD and relative preserved LVF undergoing PCI. PMID- 25837749 TI - Genetic association between PER3 genetic polymorphisms and cancer susceptibility: a meta-analysis. AB - The genes along the circadian pathways control and modulate circadian rhythms essential for the maintenance of physiological homeostasis through self-sustained transcription-translation feedback loops. PER3 (period 3) is a circadian pathway gene and its variants (rs1012477, 4/5-repeat) have frequently been associated with human cancer. The mixed findings, however, make the role of the 2 variants in cancer susceptibility elusive. We aimed in this article to clarify the association of PER3 variants with cancer. We collected genetic data from 8 studies, providing 6149 individuals for rs1012477 and 5241 individuals for 4/5 repeat. Based on the genotype and allele frequency, we chose the fixed-effects model to estimate risk of cancer. Overall analysis did not suggest a global role of rs1012477 in cancer susceptibility. For PER3 4/5-repeat variant, we found a moderate increase in risk of cancer among individuals with the 5-allele compared to individuals with the 4-allele, although this association was not statistically significant (homozygous model: odds ratio [OR] 1.17, 95% confidence interval [CI] 0.81-1.67; recessive model: OR 1.17, 95% CI 0.82-1.67). No substantial heterogeneity was revealed in this analysis. Our meta-analysis provides no evidence supporting a global association of PER3 genetic variants with the incidence of cancer. PMID- 25837750 TI - Negative impact of preoperative platelet-lymphocyte ratio on outcome after hepatic resection for intrahepatic cholangiocarcinoma. AB - The elevated platelet-to-lymphocyte ratio (PLR), determined using an easy blood test based on platelet and lymphocyte counts, is reported to be a predictor of poor survival in patients with several cancers. The prognostic role of preoperative PLR in patients with intrahepatic cholangiocarcinoma (ICC) has, until now, been rarely investigated. The purpose of our study was to evaluate the prognostic significance of PLR in a large cohort of ICC patients after hepatic resection. We obtained data from 322 consecutive nonmetastatic ICC patients who underwent hepatectomy without preoperative therapy between 2005 and 2011. Clinicopathological parameters, including PLR, were evaluated. Overall survival (OS) and recurrence-free survival (RFS) were assessed using the Kaplan-Meier method. Using multivariate Cox regression models, the independent prognostic value of preoperative PLR was determined. Our results showed that PLR represents an independent adverse prognostic factor for OS and RFS in ICC patients using univariate and multivariate analyses. The optimal PLR cutoff value was 123 using receiver operating curve analyses. The 5-year OS and RFS rates after hepatectomy were 30.3% and 28.9% for the group with PLR 123 greater, compared with 46.2% and 39.4% for the group with PLR less than 123 (P = 0.0058 and 0.0153, respectively). In addition, high PLR values were associated with tumor size (P = 0.020). Our results suggest that preoperative PLR might represent a novel independent prognostic factor for OS and RFS in ICC patients with hepatic resection. PMID- 25837751 TI - Prospective, randomized comparison of same-day dose of 2 different bowel cleanser for afternoon colonoscopy: picosulfate, magnesium oxide, and citric acid versus polyethylene glycol. AB - For afternoon colonoscopy, same-day administration of sodium picosulfate, magnesium oxide, and citric acid (PM/Ca) is recommended. However, few studies have evaluated the bowel-cleansing efficacy and safety of this regimen. The aim of this study was to compare the bowel-cleansing efficacy, side effects, and patient's tolerability of a same-day split administration of PM/Ca with polyethylene glycol (PEG) for afternoon colonoscopy. Patients were randomly assigned to a PM/Ca group or a PEG group. The PM/Ca group consumed 1 sachet of PM/Ca at 06:00 and 1 sachet of PM/Ca 4 hours before the colonoscopy. They also took 2 tablets of bisacodyl before sleep on the night before. The PEG group consumed 2 L of PEG at 06:00 and 2 L of PEG 4 hours before the colonoscopy. All subjects were instructed to finish the bowel cleanser or fluid at least 2 hours before colonoscopy. All colonoscopic examinations were performed in the afternoon on the same day. The bowel-cleansing efficacy was scored using 2 scales: the Ottawa Bowel Preparation Scale (OBPS) and the Aronchick scale. Ease of using the bowel cleanser was rated from 1 (very easy) to 5 (very difficult). Two hundred nine patients underwent colonoscopy. The bowel-cleansing scores by OBPS did not differ between groups (5.0 vs 4.9, P = 0.63). Ease of using the bowel cleanser was superior in the PM/Ca group (P < 0.01). The cleansing efficacy of PM/Ca administered on the day of colonoscopy is comparable to that of PEG. Patients prefer PM/Ca. PMID- 25837752 TI - Cerebral air embolism following the removal of a central venous catheter in the absence of intracardiac right-to-left shunting: a case report. AB - Air embolism following central venous catheter (CVC) removal is a relatively uncommon complication. Despite its rare occurrence, an air embolism can lead to serious outcomes. One of the most fatal complications is cerebral air embolism. We report a case of cerebral air embolism that occurred after the removal of a CVC in a patient with an underlying idiopathic pulmonary fibrosis, subcutaneous emphysema, pneumomediastinum, and a possible intrapulmonary shunt. Although the patient had a brief period of recovery, his condition deteriorated again, and retention of carbon dioxide was sustained due to aggravation of pneumonia. Despite full coverage of antibiotics and maximum care with the ventilator, the patient died about 5 weeks after the removal of the CVC. We suggest that strict compliance to protocols is required even while removing the catheter. Furthermore, additional caution to avoid air embolism is demanded in high-risk patients, such as in this case. PMID- 25837753 TI - Diagnostic value of Wilms tumor 1 and CD44 in Langerhans cell sarcoma: case series of 4 patients. AB - Langerhans cell sarcoma (LCS) is a rare tumor with markedly malignant cytological features originating from Langerhans cells. LCS diagnosis is difficult and requires differentiation from other malignant tumors and Langerhans cell histiocytosis (LCH). Immunochemical antibodies, such as langerin, S-100 protein, and CD1a, have been used to diagnose LCS, but the results are crossed with LCH. To determine more significant biomarkers of LCS, we studied the expression and distribution pattern of Wilms tumor 1 (WT1) and cluster of differentiation 44 (CD44) in LCS. A broad panel of antibodies was used for immunohistochemical technology. Simultaneously, dual immunofluorescence staining examination and fluorescence in situ hybridization staining methods were used to study the location of WT1 and CD44 in LCS tumor cells. The results showed that tumor cells expressed WT1, CD44, and other special Langerhans cell markers (langerin, CD1a, and S-100 protein). LCS cells in all the cases showed normal cytogenetic findings without overexpression of WT1 and CD44. The expression of WT1 and CD44 was observed on langerin tumor cells by dual immunofluorescence staining examination in LCS. Our results suggest that WT1 and CD44 are potential biomarkers for LCS diagnosis. Clear understanding of their functional roles may further explain the pathogenesis of this highly malignant tumor and develop some novel immunotherapy strategies. PMID- 25837754 TI - Association between severity and the determinant-based classification, Atlanta 2012 and Atlanta 1992, in acute pancreatitis: a clinical retrospective study. AB - Recently, the determinant-based classification (DBC) and the Atlanta 2012 have been proposed to provide a basis for study and treatment of acute pancreatitis (AP). The present study aimed to evaluate the association between severity and the DBC, the Atlanta 2012 and the Atlanta 1992, in AP. Patients admitted to our center with AP from January 2007 to July 2013 were reviewed retrospectively. Patients were assigned to severity categories for all the 3 classification systems. The primary outcomes include long-term clinical prognosis (mortality and length-of-hospital stay), major complications (intraabdominal hemorrhage, multiple-organ dysfunction, single organ failure [OF], and sepsis) and clinical interventions (surgical drainage, continuous renal replace therapy [CRRT] lasting time, and mechanical ventilation [MV] lasting time). The classification systems were validated and compared in terms of these abovementioned primary outcomes. A total of 395 patients were enrolled in this retrospective study with an overall 8.86% in-hospital mortality. Intraabdominal hemorrhage was present in 27 (6.84%) of the patients, multiple-organ dysfunction in 73(18.48%), single OF in 67 (16.96%), and sepsis in 73(18.48%). For each classification system, different categories regarding severity were associated with statistically different clinical mortality, major complications, and clinical interventions (P < 0.05). However, the Atlanta 2012 and the DBC performed better than the Atlanta 1992, and they were comparable in predicting mortality (area under curve [AUC] 0.899 and 0.955 vs 0.585, P < 0.05); intraabdominal hemorrhage (AUC 0.930 and 0.961 vs 0.583, P < 0.05), multiple-organ dysfunction (AUC 0.858 and 0.881 vs 0.595, P < 0.05), sepsis (AUC 0.826 and 0.879 vs 0.590, P < 0.05), and surgical drainage (AUC 0.900 and 0.847 vs 0.606, P < 0.05). For continuous variables, the Atlanta 2012 and the DBC were also better than the Atlanta 1992, and they were similar in predicting CRRT lasting time (Somer D 0.379 and 0.360 vs 0.210, P < 0.05) and MV lasting time (Somer D 0.344 and 0.336 vs 0.186, P < 0.05). All the 3 classification systems accurately classify the severity of AP. However, the Atlanta 2012 and the DBC performed better than the Atlanta 1992, and they were comparable in predicting long-term clinical prognosis, major complications, and clinical interventions. PMID- 25837755 TI - Dopamine transporter single-photon emission computerized tomography supports diagnosis of akinetic crisis of parkinsonism and of neuroleptic malignant syndrome. AB - Akinetic crisis (AC) is akin to neuroleptic malignant syndrome (NMS) and is the most severe and possibly lethal complication of parkinsonism. Diagnosis is today based only on clinical assessments yet is often marred by concomitant precipitating factors. Our purpose is to evidence that AC and NMS can be reliably evidenced by FP/CIT single-photon emission computerized tomography (SPECT) performed during the crisis. Prospective cohort evaluation in 6 patients. In 5 patients, affected by Parkinson disease or Lewy body dementia, the crisis was categorized as AC. One was diagnosed as having NMS because of exposure to risperidone. In all FP/CIT, SPECT was performed in the acute phase. SPECT was repeated 3 to 6 months after the acute event in 5 patients. Visual assessments and semiquantitative evaluations of binding potentials (BPs) were used. To exclude the interference of emergency treatments, FP/CIT BP was also evaluated in 4 patients currently treated with apomorphine. During AC or NMS, BP values in caudate and putamen were reduced by 95% to 80%, to noise level with a nearly complete loss of striatum dopamine transporter-binding, corresponding to the "burst striatum" pattern. The follow-up re-evaluation in surviving patients showed a recovery of values to the range expected for Parkinsonisms of same disease duration. No binding effects of apomorphine were observed. By showing the outstanding binding reduction, presynaptic dopamine transporter ligand can provide instrumental evidence of AC in Parkinsonism and NMS. PMID- 25837756 TI - Factors influencing the dosimetry for high-intensity focused ultrasound ablation of uterine fibroids: a retrospective study. AB - The aim of this article is to analyze factors affecting sonication dose and build a dosimetry model of high-intensity focused ultrasound (HIFU) ablation for uterine fibroids. Four hundred and three patients with symptomatic uterine fibroids who underwent HIFU were retrospectively analyzed. The energy efficiency factor (EEF) was set as dependent variable, and the factors possibly affecting sonication dose included age, body mass index, size of uterine fibroid, abdominal wall thickness, the distance from uterine fibroid dorsal side to sacrum, the distance from uterine fibroid ventral side to skin, location of uterus, location of uterine fibroids, type of uterine fibroids, abdominal wall scar, signal intensity on T2-weighted imaging (T2WI), and enhancement type on T1-weighted imaging (T1WI) were set as predictors to build a multiple regression model. The size of uterine fibroid, distance from fibroid ventral side to skin, location of uterus, location of uterine fibroids, type of uterine fibroids, signal intensity on T2WI, and enhancement type on T1WI had a linear correlation with EEF. The distance from fibroid ventral side to skin, enhancement type on T1WI, size of uterine fibroid, and signal intensity on T2WI were eventually incorporated into the dosimetry model. The distance from fibroid ventral side to skin, enhancement type on T1WI, size of uterine fibroid, and signal intensity on T2WI can be used as dosimetric predictors for HIFU for uterine fibroids. PMID- 25837757 TI - Fibulin-1 is downregulated through promoter hypermethylation in colorectal cancer: a CONSORT study. AB - Fibulin-1 (FBLN1) is involved in the progression of some types of cancer. However, the role of FBLN1 in colorectal cancer (CRC) has not been examined. The purpose of this study was to understand the molecular mechanisms and clinical significance of FBLN1 inactivation in CRC. The expression of FBLN1 in CRC tissues and adjacent normal tissues was analyzed by immunohistochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Methylation-specific polymerase chain reaction (MSP) and bisulfite sequencing PCR (BSP) were performed to examine the methylation status of the FBLN1 gene promoter. Furthermore, the methylated level of FBLN1 was analyzed with the clinicopathological characteristics. Immunohistochemical analysis and qRT-PCR analysis showed that FBLN1 protein and messenger RNA (mRNA) levels in tumor tissues were both significantly decreased compared with that in adjacent nontumor tissues. The methylation rate of FBLN1 promoter was significantly higher in CRC tissues than that in adjacent nontumor tissues (P < 0.001). In addition, the correlation between FBLN1 hypermethylation, protein expression, and overall survival (OS) was statistically significant. Our results indicated that the FBLN1 gene may be a novel candidate of tumor suppressor gene in CRC, and that promoter hypermethylation of FBLN1 is an important reason for its downregulation and is also a good predictor of OS for CRC. PMID- 25837758 TI - Gouty arthritis of the spine in a renal transplant patient: a clinical case report: an unusual presentation of a common disorder. AB - Axial gout is a well-documented but uncommon manifestation of gout. Its mimicking nature and the impracticality of axial joint aspiration might considerably delay its diagnosis. We report a case in a normouricemic renal transplant recipient, whereby the primary symptom of severe neck pain suggested pyogenic spondylodiscitis as an initial tentative diagnosis. Clinical findings included a high C-reactive protein concentration and elevated body temperature. The patient did not respond to empiric antibiotic treatment and suffered consecutive attacks of severe wrist and ankle pain in conjunction with a persistent fever. Blood and joint cultures were negative, but analysis of aspirated ankle joint fluid revealed monosodium urate crystals. A dual-energy computed tomography scan confirmed the presence of monosodium urate crystals in the costovertebral joints. Colchicine treatment dramatically improved the patient's clinical condition. Axial gout should be considered in transplant recipients with severe neck or back pain, fever, and increased inflammatory parameters with a high likelihood of an infectious etiology, despite the presence of paradoxically normal or even decreased serum urate concentrations. Dual-energy computed tomography is a noninvasive technique of possible benefit in the detection of axial gout when joint fluid aspiration is not deemed safe. PMID- 25837759 TI - The effect of corneal irregularity on astigmatism measurement by automated versus ray tracing keratometry. AB - The aim of this study was to compare the effect of corneal irregularity on astigmatism assessment using automated keratometry (AK) (IOLMaster) versus ray tracing keratometry (Pentacam). This is an observational case series approved by the institutional review board of Dongguk University Hospital, Goyang, South Korea. A total of 207 eyes of 207 cataract patients were included. Preoperative corneal astigmatism was measured by both IOLMaster and Pentacam. Corneal irregularity index (IR) was calculated in Fourier analysis map of Pentacam. AK by IOLMaster and total corneal refractive power (TCRP, 3 mm and 4 mm zone analysis with pupil centered) by Pentacam were selected and the difference between the 2 measurements (delta Delta) was calculated using vector analysis. Ocular residual astigmatism (ORA) after cataract surgery was calculated by subtracting 6-month postoperative refractive astigmatism (RA) measurements from corresponding preoperative values (AK, TCRP3, and TCRP4). The mean irregularity index measured was 0.042 +/- 0.019 mm (mean +/- standard deviation) and was positively correlated with age and magnitude of corneal astigmatism (P < 0.001 and P < 0.05). The difference (Delta) between TCRPs and AK (DeltaTCRPs-AK) was 0.43 +/- 0.37 (TCRP3) and 0.39 +/- 0.35 (TCRP4) diopters. Linear regression analysis revealed that age (P < 0.001), IR (P < 0.001), and AK (P < 0.001) were positively correlated with DeltaTCRPs-AK. In highly irregular corneas (IR over 0.77 diopters: mean + 2 standard deviation), postoperative ORAs calculated using TCRPs were significantly lower than ORAs calculated using AK. Corneal irregularities significantly impact astigmatism assessment by IOLMaster (AK) and Pentacam (TCRPs). Compared with AK, TCRPs were more accurate in predicting postoperative residual astigmatism in highly irregular corneas. PMID- 25837760 TI - The catalase C-262T gene polymorphism and cancer risk: a systematic review and meta-analysis. AB - Many studies suggest that catalase C-262T gene polymorphism is associated with cancer risk, but with inconsistent results. This study aimed to summarize the overall association between catalase C-262T polymorphism and cancer risk. Literature search was performed in PubMed, Embase, and other databases, studies regarding the association between catalase C-262T polymorphism and cancer risk were identified, and data were retrieved and analyzed by using Review Manager 5.0.24 and STATA 12.0. A total of 18 publications with 22 case-control studies, including 9777 cancer patients and 12,223 controls, met the inclusion criteria. Meta-analysis results showed significant association between catalase C-262 T polymorphism and cancer risk (TT vs CT + CC: odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.03-1.31, P = 0.01). Subgroup analyses stratified by cancer types suggested the catalase C-262T polymorphism was significantly associated with an increased prostate cancer risk (TT vs CT + CC: OR = 1.61, 95% CI = 1.17-2.22, P = 0.004); for subgroup analyses stratified by ethnicity, no associations between this polymorphism and Asians or whites were identified (CT + TT vs CC: OR = 1.11, 95% CI = 0.98-1.26, P = 0.09 for whites; OR = 1.19, 95% CI = 0.78-1.80, P = 0.42 for Asians). In summary, the catalase C-262T polymorphism may be a risk factor for cancer with cancer type-specific effects. Further studies should be performed to confirm these findings. PMID- 25837761 TI - Added value of using a cocktail of F-18 sodium fluoride and F-18 fluorodeoxyglucose in positron emission tomography/computed tomography for detecting bony metastasis: a case report. AB - Current nuclear imaging of the skeletal system is achieved using technetium-99m (Tc-99m) methylene diphosphonate (MDP), F-18 sodium fluoride (NaF), or F-18 fluorodeoxyglucose (FDG). However, comparisons of these are rare in the literature. We present a case of a 51-year-old female with suspicious lung cancer due to main symptoms of dyspnea, nonproductive cough, and pleural pain. Tc-99m MDP whole-body bone scan (WBBS) showed multiple bony metastases. Five days later, positron emission tomography/computed tomography (PET/CT) images using both F-18 NaF and a cocktail of F-18 NaF and F-18 FDG were obtained on the same day 2 hours apart. The former showed more foci and precisely showed bony lesions compared to those obtained using Tc-99m MDP WBBS. However, the latter demonstrated more extensive radiotracer uptake, especially in osteolytic lesions, and additional soft tissue lesions in the left axillary and surpraclavicular nodes as well as the left pleura. Surgical biopsy was performed in left axillary nodes, and the metastatic carcinoma was found to be of breast origin. This case demonstrated that a cocktail of F-18 NaF and F-18 FDG could be useful in PET/CT for not only detecting more skeletal lesions but also guiding biopsies accurately to the affected tissue. PMID- 25837762 TI - Huge gap between clinical efficacy and community effectiveness in the treatment of chronic hepatitis C: a nationwide survey in Taiwan. AB - Peginterferon/ribavirin provides a substantially high treatment efficacy for chronic hepatitis C virus (HCV) infections in Asians. Whether the clinical efficacy can be translated to community effectiveness remains unclear. The disease awareness, treatment accessibility, recommendations, acceptance, and barriers to anti-HCV treatment were explored to clarify the issue with a 3-step nationwide investigation in Taiwan. A crude HCV-infected population was estimated using databases from 3 large-scale surveillance studies and age-/geographic specific population database. HCV awareness and accessibility were investigated at the patient level in 58,129 residents. The recommendations/acceptances and barriers to treatment at the provider level were evaluated using a prospective, nationwide approach to 89 gastroenterologists/hepatologists. The estimated 10 year interval age-adjusted anti-HCV-seropositive population is 745,109 (3.28%), with an anticipated HCV-viremic population of 554,361. Of anti-HCV-seropositive subjects, 36.2% had disease awareness. Among those with awareness, 39.6% had accessibility. The recommendation/acceptance rate of antiviral therapy was 70.6%. The treatment rate was 10.1% and 13.7% for the anti-HCV-seropositive and HCV viremic population, respectively. With an anticipated treatment success rate of 80% in Taiwan, 8.1% of the anti-HCV-seropositive and 10.9% of the HCV-viremic population achieved successful treatment. The major treatment barriers were fear of adverse effects (37%), major disorders (17.6%), ineligibility for insurance reimbursement (17.6%), and lack of therapy awareness (11.3%). Despite the high rates of treatment response and nationwide coverage of insurance reimbursement, there remains a large gap between clinical efficacy and community effectiveness in anti-HCV treatment in Taiwan. Increasing disease awareness/treatment accessibility and introducing new therapeutic strategies with high tolerability are warranted. PMID- 25837763 TI - Newly detected pulmonary nontuberculous mycobacterial infection and peripheral lung cancers in patients during follow-up of idiopathic interstitial pneumonia: comparison of CT findings. AB - This article describes the difference between the computed tomography (CT) findings in patients with newly detected pulmonary nontuberculous mycobacterial infection (NTM-IIP) and Cancer-IIP. We retrospectively evaluated 35 NTM-IIP and 78 Cancer-IIP patients in reference to their null idiopathic interstitial pneumonia CT (n = 113), using >10 years of data. Two independent radiologists analyzed the CT characteristics and the axial location of the main opacity. The interobserver agreement was good (kappa > 0.771). The NTM-IIP patients were older (P = 0.034). The median size of the main opacity in the NTM-IIP (27 mm; 11-73) was larger (19 mm; 5-60; P = 0.002). Consolidation (n = 30; 85.7%; odds ratio [OR], 45) and cavities (n = 14; 40%, OR, 25) were more common in NTM-IIP (all P < 0.001). The midst of the fibrotic cysts including honeycomb cysts (n = 16; 45.7%, OR, 4.95) was more common in NTM-IIP (P = 0.006). NTM-IIP appeared larger, with more frequent consolidation and cavities, and was more likely to have been located in the midst of the fibrotic cysts including honeycomb cysts at the CT, which showed that it was older than Cancer-IIP. PMID- 25837764 TI - Mini-flank supra-12th rib incision for open partial nephrectomy for renal tumor with RENAL nephrometry score >=10: an innovation of traditional open surgery. AB - The skill of supra-12th rib mini-flank approach for open partial nephrectomy (MI OPN) provides an advanced operative method for renal tumor. Compared with laparoscopic and robotic surgery, it may be a feasible selection for the complex renal tumors. We describe our techniques and results of MI-OPN in complex renal tumors with high RENAL nephrometry score (RENAL nephrometry score >=10). Fifty five patients diagnosed with renal tumors between January 2009 and July 2013 were included in this study. Eligibility criteria comprised of patients with complex renal tumor (RENAL score >=10) being candidates for partial nephrectomy (PN). All patients received MI-OPN and all surgeries were performed by a single urologist. The preoperative workup comprised of medical history, physical examination, and routine laboratory tests. Serum creatinine was recorded preoperatively and 2 to 3 months after operation. Operative time, ischemia time, blood loss, operative and postoperative complications, renal function, and pathology parameters were recorded. MI-OPN was successfully performed in all cases. Mean tumor size was 4.7 cm (range: 2.5-8.1). Mean warm ischemia time was 28.1 minutes (range: 21-39), mean operative time was 105 minutes (range: 70-150) and mean estimated blood loss was 68 mL (range: 10-400). Mean postoperative hospital stay was 6.5 days (range: 5-12). Postoperative complications were found in 3 patients (5.5%). The mean pre- and postoperative serum creatinine levels were 76.2 MUmol/L (range: 47-132) and 87.1 MUmol/L (range: 61-189) with significant difference (P = 0.004). The mean pre- and postoperative estimated glomerular filtration rate (eGFR) were 91.5 (range: 34-133) and 82.5 (range: 22-126.5), respectively with significant difference (P = 0.024). In an average follow-up of 19.9 months (range: 8-50), no local recurrence or systemic progression occurred. In conclusion, MI-OPN can combine the benefits of both minimal invasive and traditional open partial nephrectomy (OPN) techniques with a smaller incision. It is an innovation of traditional OPN and suitable for the complex renal tumors with high RENAL nephrometry score safely and effectively. PMID- 25837765 TI - Differential expression of hypertension-associated microRNAs in the plasma of patients with white coat hypertension. AB - White coat hypertension (WCH) is a high cardiovascular risk condition, and a fundamental understanding of the cause and pathophysiology of the disorder is still lacking. Recent studies demonstrated that microRNAs (miRNAs) are involved in hypertension; however, the roles of miRNAs in WCH are not known. The expressions of selected 10 miRNAs were investigated independently in plasma samples from 30 hypertension (HT) patients, 30 WCH patients, and 30 normotensive (NT) subjects. MiR-21, miR-122, miR-637, and let-7e expression levels were significantly upregulated in the HT group compared with the NT groups (P = 0.017, P = 0.022, P = 0.048, and P = 0.013, respectively). MiR-122 and miR-637 expressions were also significantly upregulated in the WCH group compared with the NT group (P = 0.048 and P = 0.039, respectively). MiR-296-5p expression level was significantly downregulated in HT patients and upregulated in the WCH patients compared with the NT group (P = 0.049 and P = 0.039, respectively). Additionally, the ambulatory 24-hour and daytime systolic and diastolic blood pressures were negatively correlated with miR-296-5p. MiR-296 and miR-637 had area under the curve (AUC) values of 0.778 and 0.774, respectively, which demonstrates their sufficiency to distinguish WCH from NT individuals. MiR-296 and miR-637 had AUC values of 0.868 and 0.680, respectively, which shows their potential to distinguish WCH from HT individuals. We report for the first time a plasma miRNA profile for WCH patients and demonstrate a novel link between miRNA and WCH. These findings may reveal crucial insights into the development of WCH. PMID- 25837766 TI - Risk of erectile dysfunction in transfusion-naive thalassemia men: a nationwide population-based retrospective cohort study. AB - Based on the mechanism of pathophysiology, thalassemia major or transfusion dependent thalassemia patients may have an increased risk of developing organic erectile dysfunction resulting from hypogonadism. However, there have been few studies investigating the association between erectile dysfunction and transfusion-naive thalassemia populations. We constructed a population-based cohort study to elucidate the association between transfusion-naive thalassemia populations and organic erectile dysfunction. This nationwide population-based cohort study involved analyzing data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database, with a follow-up period extending to the end of 2011. We identified men with transfusion-naive thalassemia and selected a comparison cohort that was frequency-matched with these according to age, and year of diagnosis thalassemia at a ratio of 1 thalassemia man to 4 control men. We analyzed the risks for transfusion-naive thalassemia men and organic erectile dysfunction by using Cox proportional hazards regression models. In this study, 588 transfusion-naive thalassemia men and 2337 controls were included. Total 12 patients were identified within the thalassaemia group and 10 within the control group. The overall risks for developing organic erectile dysfunction were 4.56-fold in patients with transfusion-naive thalassemia men compared with the comparison cohort after we adjusted for age and comorbidities. Our long-term cohort study results showed that in transfusion-naive thalassemia men, there was a higher risk for the development of organic erectile dysfunction, particularly in those patients with comorbidities. PMID- 25837767 TI - Association between catalase gene polymorphisms and risk of chronic hepatitis B, hepatitis B virus-related liver cirrhosis and hepatocellular carcinoma in Guangxi population: a case-control study. AB - Reactive oxygen species (ROS) play critical roles in hepatocarcinogenesis. The catalase (CAT) enzyme is involved in the repair of ROS. Therefore, we investigate the association between CAT gene polymorphisms and the risk of hepatocellular carcinoma (HCC). A total of 715 subjects were divided into 4 groups: 111 chronic hepatitis B (CHB) patients, 90 hepatitis B virus (HBV)-related liver cirrhosis (LC) patients, 266 HBV-HCC patients, and 248 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect CAT gene rs1001179, rs769217, and rs7943316 polymorphisms. Binary logistic regression analyses adjusting for sex, age, ethnicity, smoking and alcohol consumption, and body mass index suggested that subjects carrying the rs769217 T allele were at marginally increased risk of CHB, LC, and HCC, with adjusted odds ratios (ORs) of 1.51 (95% confidence interval [CI] = 1.04-2.20, P = 0.029), 1.48 (95% CI = 1.03-2.14, P = 0.035), and 1.51 (95% CI = 1.14-1.98, P = 0.004), respectively. Similarly, those individuals carrying the rs769217 TT genotype had a moderately increased risk of CHB, LC, and HCC, with adjusted ORs of 2.11 (95% CI = 1.05-4.22, P = 0.035), 2.00 (95% CI, 1.01-3.95, P = 0.047), and 1.93 (95% CI = 1.14-3.28, P = 0.015), respectively. Moreover, subjects carrying the rs769217 CT genotype and at least 1 copy of the T allele (dominant model) were 1.78 times and 1.83 times more likely to develop HCC, respectively (OR = 1.78, 95% CI = 1.16 2.73, P = 0.009 and OR = 1.83, 95% CI = 1.23-2.71, P = 0.003). This association between CAT rs769217 T alleles and HCC risk is significantly strengthened among men, nonsmokers, nondrinkers, and among individuals <50 years of age. Furthermore, we found 1 high-risk haplotype GTA for CHB (OR = 1.45, 95% CI = 1.05 2.01) and 1 protective haplotype GCA for HCC risk (OR = 0.67, 95% CI = 0.52 0.87). We did not found any significant difference in CAT rs1001179 and rs7943316 polymorphisms between controls and cases. Our findings suggest that the CAT rs769217 T allele is associated with increased risk of CHB, HBV-LC, and HBV-HCC in Guangxi population. PMID- 25837768 TI - Nonintubated thoracoscopic lobectomy for lung cancer using epidural anesthesia and intercostal blockade: a retrospective cohort study of 238 cases. AB - Intubated general anesthesia with single-lung ventilation has been considered mandatory for thoracoscopic lobectomy for nonsmall cell lung cancer. Few reports of thoracoscopic lobectomy without tracheal intubation are published, using either thoracic epidural anesthesia (TEA) or intercostal blockade. The comparisons of perioperative outcomes of nonintubated thoracoscopic lobectomy using epidural anesthesia and intercostal blockade are not reported previously. From September 2009 to August 2014, a total of 238 patients with lung cancer who underwent nonintubated thoracoscopic lobectomy were recruited from our prospectively maintained database of all patients undergoing nonintubated thoracoscopic surgery using TEA or intercostal blockade. A multiple regression analysis, adjusting for preoperative variables, was performed to compare the perioperative outcomes of the 2 anesthesia methods. Overall, 130 patients underwent nonintubated thoracoscopic lobectomy using epidural anesthesia whereas 108 had intercostal blockade. The 2 groups were similar in demographic data, except for sex, preoperative lung function, physical status classification, and history of smoking. After adjustment for the preoperative variables, nonintubated thoracoscopic lobectomy using intercostal blockade was associated with shorter durations of anesthetic induction and surgery (P < 0.001). Furthermore, hemodynamics were more stable with less use of vasoactive drugs (odds ratio: 0.53; 95% confidence interval [CI], 0.27 to 1.04; P = 0.064) and less blood loss (mean difference: -55.2 mL; 95% CI, -93 to -17.3; P = 0.004). Postoperatively, the 2 groups had comparable incidences of complications. Patients in the intercostal blockade group had a shorter average duration of chest tube drainage (P = 0.064) but a similar average length of hospital stay (P = 0.569). Conversion to tracheal intubation was required in 13 patients (5.5%), and no in-hospital mortality occurred in either group. Nonintubated thoracoscopic lobectomy using either epidural anesthesia or intercostal blockade is feasible and safe. Intercostal blockade is a simpler alternative to epidural anesthesia for nonintubated thoracoscopic lobectomy in selected patients with lung cancer. PMID- 25837769 TI - Rapid Removal of Atmospheric CO2 by Urban Soils. AB - The measured calcium carbonate content of soils to a depth of 100 mm at a large urban development site has increased over 18 months at a rate that corresponds to the sequestration of 85 t of CO2/ha (8.5 kg of CO2 m(-2)) annually. This is a consequence of rapid weathering of calcium silicate and hydroxide minerals derived from the demolition of concrete structures, which releases Ca that combines with CO2 ultimately derived from the atmosphere, precipitating as calcite. Stable isotope data confirm an atmospheric origin for carbonate carbon, and 14C dating indicates the predominance of modern carbon in the pedogenic calcite. Trial pits show that carbonation extends to depths of >=1 m. Work at other sites shows that the occurrence of pedogenic carbonates is widespread in artificially created urban soils containing Ca and Mg silicate minerals. Appropriate management of fewer than 12000 ha of urban land to maximize calcite precipitation has the potential to remove 1 million t of CO2 from the atmosphere annually. The maximal global potential is estimated to be approximately 700-1200 Mt of CO2 per year (representing 2.0-3.7% of total emissions from fossil fuel combustion) based on current rates of production of industry-derived Ca- and Mg bearing materials. PMID- 25837770 TI - An accurate and sensitive Coomassie Brilliant Blue G-250-based assay for protein determination. AB - In this protocol we present a rapid and sensitive assay for the accurate determination of protein concentration. The assay is a modification of a previous method, and measures minimum 0.2 MUg protein. PMID- 25837771 TI - A combinatorial biophysical approach; FTSA and SPR for identifying small molecule ligands and PAINs. AB - Biophysical methods have emerged as attractive screening techniques in drug discovery both as primary hit finding methodologies, as in the case of weakly active compounds such as fragments, and as orthogonal methods for hit validation for compounds discovered through conventional biochemical or cellular assays. Here we describe a dual method employing fluorescent thermal shift assay (FTSA), also known as differential scanning fluorimetry (DSF) and surface plasmon resonance (SPR), to interrogate ligands of the kinase p38alpha as well as several known pan-assay interference compounds (PAINs) such as aggregators, redox cyclers, and fluorescence quenchers. This combinatorial approach allows for independent verification of several biophysical parameters such as KD, kon, koff, DeltaG, DeltaS, and DeltaH, which may further guide chemical development of a ligand series. Affinity values obtained from FTSA curves allow for insight into compound binding compared with reporting shifts in melting temperature. Ligand p38 interaction data were in good agreement with previous literature. Aggregators and fluorescence quenchers appeared to reduce fluorescence signal in the FTSAs, causing artificially high shifts in Tm values, whereas redox compounds caused either shifts in affinity that did not agree between FTSA and SPR or a depression of FTSA signal. PMID- 25837772 TI - Force majeure: Will climate change affect our ability to attain Good Environmental Status for marine biodiversity? AB - The EU Marine Strategy Framework Directive (MSFD) requires that Good Environmental Status (GEnS), is achieved for European seas by 2020. These may deviate from GEnS, its 11 Descriptors, targets and baselines, due to endogenic managed pressures (from activities within an area) and externally due to exogenic unmanaged pressures (e.g. climate change). Conceptual models detail the likely or perceived changes expected on marine biodiversity and GEnS Descriptors in the light of climate change. We emphasise that marine management has to accommodate 'shifting baselines' caused by climate change particularly during GEnS monitoring, assessment and management and 'unbounded boundaries' given the migration and dispersal of highly-mobile species. We suggest climate change may prevent GEnS being met, but Member States may rebut legal challenges by claiming that this is outside its control, force majeure or due to 'natural causes' (Article 14 of the MSFD). The analysis is relevant to management of other global seas. PMID- 25837773 TI - Intersex in the clam Scrobicularia plana (Da Costa): Widespread occurrence in English Channel estuaries and surrounding areas. AB - Estuarine clams Scrobicularia plana were sampled from 108 intertidal locations around the English Channel and adjacent areas. Although S. plana is believed to be a strict gonochorist, 58% of the populations sampled included intersexed individuals (described as male clams exhibiting ovotestis). Over the entire region, on average, 8.6% of male clams exhibited intersex, although proportions of affected males ranged from 0% to 53% depending on location. The severity of intersex was assessed using a simple classification scale, with the majority of individuals showing low levels of impact. Sex ratios were significantly skewed at some sites. There were no significant relationships between incidence or severity of intersex; or with size or parasitism of individual clams. Intersex in S. plana is a useful tool to assess endocrine disruptive effects in estuaries, although mechanisms of impact and causative agents remain uncertain. PMID- 25837774 TI - Mercury concentrations in the prey of apex piscivores from a large subtropical estuary. AB - Estuaries are important ecosystems for mercury methylation and accumulation, yet few studies have quantified mercury levels in prey species that expose large estuarine piscivores to contamination. We measured mercury concentrations in key prey species from the Indian River Lagoon, Florida, USA, to characterize variability and assess the spatial distribution of mercury levels throughout the estuary. Mean mercury concentrations ranged from 0.015mg/kg in Mugil cephalus to 0.222mg/kg in Bairdiella chrysoura and varied considerably in some species. Spatial variation was observed within species, but a universal geographic pattern among species was not apparent, likely reflecting the broad habitat-use patterns associated with the estuarine-transient life histories of many of these common prey species. In contrast, estuarine-resident species, such as B. chrysoura, may be useful indicators of regional mercury methylation potential and bioaccumulation in biota. These results can advance future studies that relate dietary mercury uptake and mercury level variations in estuarine piscivores. PMID- 25837775 TI - Microplankton dynamics under heavy anthropogenic pressure. The case of the Bahia Blanca Estuary, southwestern Atlantic Ocean. AB - Quantifying biotic feedbacks in response to environmental signals is fundamental to assess ecosystem perturbation. We analyzed the joint effects of eutrophication, derived from sewage pollution, and climate at the base of the pelagic food web in the Bahia Blanca Estuary (SW Atlantic Ocean). A two-year survey of environmental conditions and microplankton communities was conducted in two sites affected by contrasting anthropogenic eutrophication conditions. Under severe eutrophication, we found higher phytoplankton abundance consistently dominated by smaller sized, non siliceous species, while microzooplankton abundance remained lower and nutrient stoichiometry showed conspicuous deviations from the Redfield ratio. Phytoplankton growth in such conditions appeared controlled by phosphorous. In turn, microplankton biomass and phytoplankton size ratio (<20MUm:>20MUm) displayed a saturation relationship with nutrients in the highly eutrophic area, although mean phytoplankton growth was similar in both eutrophic systems. The strength of links within the estuarine network, quantified through path analysis, showed enhanced relationships under larger anthropogenic eutrophication, which fostered the climate influence on microplankton communities. Our results show conspicuous effects of severe sewage pollution on the ecological stoichiometry, i.e., N and P excess with respect to Si, altering nutrient ratios for microplankton communities. This warns on wide consequences on food web dynamics and ultimately in ecosystem assets of coastal pelagic environments. PMID- 25837776 TI - Recent and near-future advances in nucleic acid-based diagnosis of stroke. AB - Stroke is a leading cause of death and disability in adults, but at present, treatment for ischemic stroke reaches only a small percentage of patients. This is because of the very short time window for treatment and the time-consuming evaluation involved. Intense efforts are underway to find novel approaches to expedite stroke diagnosis and treatment. In this review, we provide the rationale for the use of blood-based nucleic acid biomarkers to advance stroke diagnosis. We describe mRNA markers identified in genomic profiling of circulating leukocytes and then outline technological issues involved in the application of these results. We then describe the novel point-of-care technology that is in development for the rapid detection of multiple mRNA molecules in circulating leukocytes. PMID- 25837777 TI - Correction to "Microbacterins A and B, new peptaibols from the deep sea actinomycete Microbacterium sediminis sp. nov. YLB-01(T)". PMID- 25837778 TI - Enhanced Production of Resveratrol, Piceatannol, Arachidin-1, and Arachidin-3 in Hairy Root Cultures of Peanut Co-treated with Methyl Jasmonate and Cyclodextrin. AB - Peanut (Arachis hypogaea) produces stilbenoids upon exposure to abiotic and biotic stresses. Among these compounds, the prenylated stilbenoids arachidin-1 and arachidin-3 have shown diverse biological activities with potential applications in human health. These compounds exhibit higher or novel biological activities in vitro when compared to their nonprenylated analogues piceatannol and resveratrol, respectively. However, assessment of these bioactivities in vivo has been challenging because of their limited availability. In this study, hairy root cultures of peanut were induced to produce stilbenoids upon treatment with elicitors. Co-treatment with 100 MUM methyl jasmonate (MeJA) and 9 g/L methyl beta-cyclodextrin (CD) led to sustained high levels of resveratrol, piceatannol, arachidin-1, and arachidin-3 in the culture medium when compared to other elicitor treatments. The average yields of arachidin-1 and arachidin-3 were 56 and 148 mg/L, respectively, after co-treatment with MeJA and CD. Furthermore, MeJA and CD had a synergistic effect on resveratrol synthase gene expression, which could explain the higher yield of resveratrol when compared to treatment with either MeJA or CD alone. Peanut hairy root cultures were shown to be a controlled and sustainable axenic system for the production of the diverse types of biologically active stilbenoids. PMID- 25837780 TI - Laurus nobilis L. Seed Extract Reveals Collateral Sensitivity in Multidrug Resistant P-Glycoprotein-Expressing Tumor Cells. AB - The frequent failure of standard cancer chemotherapy requires the development of novel drugs capable of killing otherwise drug-resistant tumors. Here, we have investigated a chloroform extract of Laurus nobilis seeds. Fatty acids and 23 constituents of the volatile fraction were identified by gas chromotography/flame ionization detection (GC/FID) and gas chromatography/mass spectrometry (GC/MS), in good agreement with (1)H NMR (nuclear magnetic resonance) spectrum. Multidrug resistant P-glycoprotein-expressing CEM/ADR5000 leukemia cells were hypersensitive (collaterally sensitive) toward this extract compared to drug sensitive CCRF-CEM cells, whereas CEM/ADR5000 cells were 2586-fold resistant to doxorubicin as control drug. Collateral sensitivity was verified by measurement of apoptotic cells by flow cytometry. The log10IC50 values of 3 compounds in the extract (limonene, eucalyptol, oleic acid) did not correlate with mRNA expression of the P-glycoprotein-coding ABCB1/MDR1 gene and accumulation of the P glycoprotein substrate rhodamine in the NCI panel of tumor cell lines. A microarray-based profile of 20 genes predicted resistance to doxorubicin and 7 other anticancer drugs involved in the multidrug resistance phenotype but not to limonene, eucalyptol and oleic acid. In conclusion, our results show that Laurus nobilis seed extract is suitable to kill multidrug-resistant P-glycoprotein expressing tumor cells. PMID- 25837779 TI - The diagnosis and treatment of aplastic anemia: a review. AB - Aplastic anemia is a rare disorder characterized by suppression of bone marrow function resulting in progressive pancytopenia. A trigger-related abnormal T cell response facilitated by some genetic predisposition has been postulated as the pathogenetic mechanism leading to the overproduction of bone marrow-inhibiting cytokines. Immuno-mediated pathogenesis is confirmed by the response to immunosuppressive treatment (IST) (cyclosporin A+ATG), which represents the first choice therapy for patients <40 years when a matched sibling donor (MSD) is not available for transplant. MSD hematopoietic stem cell transplantation (HSCT) is associated with cure in ~90 % of patients. IST up-front provides an overall survival (OS) rate of above 90 %, but a response rate of about 60 %. Front-line matched unrelated donor (MUD) appears to be a viable option in children with similar OS and event-free survival to that in MSD HSCT. MUD HSCT post-IST failure proved to be a very good rescue strategy. Haploidentical donors/cord blood transplants or alternative immunosuppressive therapies, such as alemtuzumab, may represent valid tools for resistant/relapsing cases. New promising strategies, such as eltrombopag, are now under investigation. Patients should be offered an accurate diagnostic work-up in order to rule out other underlying disorders, primarily constitutional marrow failures, which may require different approaches. PMID- 25837781 TI - Quality of outcome data in total hip arthroplasty: comparison of registry data and worldwide non-registry studies from 5 decades. AB - PURPOSE: This systematic review assessed evidence on outcome (revision rate for all reasons) following hip arthroplasty from its beginning 5 decades ago. METHODS: We evaluated all studies from all current hip implants since their market introduction in 1962 regarding "revision rate per 100 observed component years". Data were compared with arthroplasty registries. RESULTS: A total of 54 different hip implants were included: for 81% (44 of 54) data is either absent or poor; for 30% (16 of 54) not a single publication could be found. For 52% (28 of 54) less than 100 revisions for all reasons are published in non-registry studies. The remaining 10 implants (19%) comprise 92638 primary implants with 4473 revisions. Control group were the same implants with 111658 primary cases and 3029 revisions from arthroplasty registries. A systematic developer bias as in knee arthroplasty could not be found but several independent authors were found to significantly bias the literature. The overall revision rates per 100 observed component years from non-registry studies (and joint registries) are 0.4 (0.5) for stems, 0.7 (0.7) for cups and 1.4 (2.1) for resurfacing systems. CONCLUSIONS: For 81% of all hip implants assessed limited evidence exists from non-registry studies regarding outcome (revision rate) even 5 decades after market introduction. For the remaining 19% of implants no systematic developer bias could be found but several individual authors significantly biased results of single implants. We therefore ask for a more active publication of new implants. PMID- 25837782 TI - Piriformis syndrome: treatment of a rare cause of posterior hip pain with fluoroscopic-guided injection. AB - INTRODUCTION: Piriformis syndrome involves the irritation of the piriformis muscle due to various reasons that are primarily related to anatomical variation or sciatic nerve compression due to contraction caused by overuse. In this study, we aimed to define an injection method that is easy to apply, safe, simple and repeatable. MATERIALS AND METHODS: We administered percutaneous lidocaine and depomedrol injections into the hips of 28 patients (14 men and 14 women) under fluoroscopic control. Bipolar injections of the piriformis muscle were performed at the medial pole, the intersection of the sciatic notch and the sacroiliac joint, and at the lateral pole of the femoral insertion region. Each injection was 5 cc, and the contrast agent was observed after the dyeing process. RESULTS: Clinical examinations were performed before and 6 weeks after the injections. The average of Harris Hip Score increased from a pre-injection score of 44.5 to a post-injection score of 68.5, and the Visual Analog Scale scores decreased from 8.3 to 4.2 (p<0.05). COMMENTS: Our findings lead to the conclusion that fluoroscopy-guided percutaneous local anaesthetic and corticosteroid injection is a simple and effective piriformis syndrome treatment that can feasibly be effectively performed by orthopaedic surgeons. PMID- 25837783 TI - Acaricidal activity of essential oils from Lippia alba genotypes and its major components carvone, limonene, and citral against Rhipicephalus microplus. AB - The goal of the present study was to evaluate the acaricidal potential of Lippia alba essential oil, citral chemotypes (LA-10 and LA-44 genotypes) and carvone chemotypes (LA-13 and LA-57 genotypes), as well as purified citral and enantiomers of carvone and limonene. Efficacy against Rhipicephalus microplus was assessed by the larval packet and the engorged female immersion tests. Citral chemotypes had greater larvicidal activity than carvone chemotypes, and this was further supported by larvicidal and adulticidal activity of purified citral with LC50 values of 7.0 and 29.8 mg/mL, respectively. While purified enantiomers of carvone exhibited greater larvicidal activity than those of limonene, enantioselectivity of limonene was observed with R-(+) displaying significantly higher efficacy (LC50 of 31.2mg/mL) than S-(-) (LC50 of 54.5mg/mL). The essential oils and purified compounds were much less toxic toward engorged adult females, with the exception of citral, and this may be due to limited cuticular penetration. PMID- 25837784 TI - Human migration and pig/pork import in the European Union: What are the implications for Taenia solium infections? AB - Taenia solium taeniasis/cysticercosis is a neglected zoonotic disease complex occurring primarily in developing countries. Though claimed eradicated from the European Union (EU), an increasing number of human neurocysticercosis cases is being detected. Risk factors such as human migration and movement of pigs/pork, as well as the increasing trend in pig rearing with outside access are discussed in this review. The entry of a tapeworm carrier into the EU seems a lot more plausible than the import of infected pork. The establishment of local transmission in the EU is presently very unlikely. However, considering the potential changes in risk factors, such as the increasing trend in pig farming with outdoor access, the increasing human migration from endemic areas into the EU, this situation might change, warranting the establishment of an early warning system, which should include disease notification of taeniasis/cysticercosis both in human and animal hosts. As currently human-to-human transmission is the highest risk, prevention strategies should focus on the early detection and treatment of tapeworm carriers, and should be designed in a concerted way, across the EU and across the different sectors. PMID- 25837785 TI - A new strategy for co-composting dairy manure with rice straw: Addition of different inocula at three stages of composting. AB - In considering the impact of inoculation time and the characteristics of composting material and inoculants on the usefulness of inoculation, a new composting strategy has been proposed and studied, in which three inocula were inoculated at three stages of composting process respectively: inoculum A (Thermoactinomyces sp. GF1 and GF2) was inoculated before fermentation to increase or maintain high temperature of pile, inoculum B (Coprinus cinerea and Coprinus comatus) was inoculated after thermophilic phase to promote degradation of lignin, and inoculum C (Trichoderma harzianum and Rhizopus oryzae) was inoculated after 30-day fermentation to promote degradation of cellulose. The results showed that the inoculations could significantly enhance the temperature of pile and the degradation of lignocelluloses. When inocula A, B, and C were inoculated into pile, temperature increased from 25 degrees C to 65 degrees C, from 33 degrees C to 39 degrees C and from 33 degrees C to 38 degrees C respectively and 35% lignin and 43% cellulose had been degraded in inoculated pile compared to the degradation of 15% lignin and 25% cellulose in control pile. As a result, the C/N ratio dropped more rapidly degraded in the inoculated pile (reached 20 after 33-day fermentation) than that in the control pile (reached 21.7 after 45-day fermentation). In addition, the volume loss in inoculated pile (76.5%) was higher than that in control pile (53.2%). The study, therefore, indicated that inoculating proper microorganisms at appropriate time improved the composting process and our new composting strategy would be propitious to the co composting dairy manure with rice straw. PMID- 25837786 TI - Life cycle assessment of integrated waste management systems for alternative legacy scenarios of the London Olympic Park. AB - This paper presents the results of the life cycle assessment (LCA) of 10 integrated waste management systems (IWMSs) for 3 potential post-event site design scenarios of the London Olympic Park. The aim of the LCA study is to evaluate direct and indirect emissions resulting from various treatment options of municipal solid waste (MSW) annually generated on site together with avoided emissions resulting from energy, materials and nutrients recovery. IWMSs are modelled using GaBi v6.0 Product Sustainability software and results are presented based on the CML (v.Nov-10) characterisation method. The results show that IWMSs with advanced thermal treatment (ATT) and incineration with energy recovery have the lowest Global Warming Potential (GWP) than IWMSs where landfill is the primary waste treatment process. This is due to higher direct emissions and lower avoided emissions from the landfill process compared to the emissions from the thermal treatment processes. LCA results demonstrate that significant environmental savings are achieved through substitution of virgin materials with recycled ones. The results of the sensitivity analysis carried out for IWMS 1 shows that increasing recycling rate by 5%, 10% and 15% compared to the baseline scenario can reduce GWP by 8%, 17% and 25% respectively. Sensitivity analysis also shows how changes in waste composition affect the overall result of the system. The outcomes of such assessments provide decision-makers with fundamental information regarding the environmental impacts of different waste treatment options necessary for sustainable waste management planning. PMID- 25837787 TI - Continuous process of the vacuum ultraviolet- (VUV-) photochemical oxidation of thiophene in the gas phase. AB - Thiophene was taken as a model compound for investigations on the efficiency of a continuous process of the vacuum-ultraviolet- (VUV-) photochemically initiated oxidation and mineralization of sulfur containing organic compounds in the gas phase. In the presence of molecular oxygen, atomic oxygen and ozone were photochemically generated and are assumed to initiate or participate in the (thermal) oxidation network. Addition of water vapor for an additional initiation of the oxidation by hydroxyl radicals did not accelerate the process. For comparison, thiophene was exposed to ozone and oxidized under otherwise the same experimental conditions, but complete mineralization was only found in the photochemical process and for relatively small concentrations of the substrate. The result may be explained by low rates of secondary thermal reactions of a number of identified intermediate products. Combining already published results and mechanistic hypotheses with the results of the present work, pathways of oxidative degradation are proposed. The photolysis of thiophene in molecular nitrogen confirmed earlier findings. PMID- 25837788 TI - Correction: Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses. PMID- 25837789 TI - Assessment of apoptotic cells in the wall of thrombophlebitic saphenous vein. AB - INTRODUCTION: Programmed cell death plays a critical role in various physiological processes. In the present study, we investigated its possible pathogenic role in primary varicose veins. We studied histological changes in surgical specimens from thrombophlebitic saphenous veins. In thrombophlebitic saphenous, varicose, and healthy veins, we also determined the number of apoptotic cells, and investigated apoptosis in the role of the pathogenesis of varicose veins. METHODS: Forty-four specimens of thrombophlebitic saphenous veins and simple varicose veins were collected. Thirteen samples of normal great saphenous veins were also collected (control group). Apoptosis of venous walls was determined by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and immunofluorescence methods. The corpuscular number per high power field was counted under light microscopy. RESULTS: A significantly higher apoptotic ratio of the intima and media were observed in control veins as compared with thrombophlebitic saphenous veins and simple varicose veins (p < 0.01). A significant difference was not observed between thrombophlebitic saphenous veins and simple varicose veins (p > 0.05). A significant difference was not seen between the intima and media of the three groups (p > 0.05). CONCLUSION: In the walls of thrombophlebitic saphenous veins and varicose veins, the apoptotic indices were clearly decreased. The results suggest that the process of programmed cell death was inhibited in walls of thrombophlebitic saphenous veins and varicose veins. PMID- 25837790 TI - Intra-arterial injection of sclerosants: Report of three cases treated with systemic steroids. AB - Intra-arterial injection of sclerosants is a significant but uncommon complication of sclerotherapy that may result in extensive tissue necrosis and in rare cases digit or limb amputation. We have managed three cases in the past 10 years. One patient was referred for immediate treatment following intra-arterial injection of liquid polidocanol. The other two had undergone foam sclerotherapy with polidocanol and sodium tetradecyl sulphate, respectively. All patients were treated with a combination of oral steroids (prednisone 0.5-1 mg/kg) and systemic anticoagulants (enoxaparin 1.5 mg/kg daily subcutaneous injection). One case progressed to skin ulceration where prednisone was started five days after the adverse event and prematurely stopped after four weeks. The other cases did not progress to necrosis or other long-term sequelae. In these patients, prednisone was commenced immediately and slowly reduced over the following 12 weeks. The inflammation that follows ischemia plays a significant role in tissue necrosis and the immediate management of this adverse event may benefit from anti inflammatory measures and in particular systemic steroid therapy unless contraindicated. PMID- 25837791 TI - Investigating the use of support vector machine classification on structural brain images of preterm-born teenagers as a biological marker. AB - Preterm birth has been shown to induce an altered developmental trajectory of brain structure and function. With the aid support vector machine (SVM) classification methods we aimed to investigate whether MRI data, collected in adolescence, could be used to predict whether an individual had been born preterm or at term. To this end we collected T1-weighted anatomical MRI data from 143 individuals (69 controls, mean age 14.6y). The inclusion criteria for those born preterm were birth weight <= 1500g and gestational age < 37w. A linear SVM was trained on the grey matter segment of MR images in two different ways. First, all the individuals were used for training and classification was performed by the leave-one-out method, yielding 93% correct classification (sensitivity = 0.905, specificity = 0.942). Separately, a random half of the available data were used for training twice and each time the other, unseen, half of the data was classified, resulting 86% and 91% accurate classifications. Both gestational age (R = -0.24, p<0.04) and birth weight (R = -0.51, p < 0.001) correlated with the distance to decision boundary within the group of individuals born preterm. Statistically significant correlations were also found between IQ (R = -0.30, p < 0.001) and the distance to decision boundary. Those born small for gestational age did not form a separate subgroup in these analyses. The high rate of correct classification by the SVM motivates further investigation. The long-term goal is to automatically and non-invasively predict the outcome of preterm-born individuals on an individual basis using as early a scan as possible. PMID- 25837792 TI - Plasmonic AuNP/g-C3N4 Nanohybrid-based Photoelectrochemical Sensing Platform for Ultrasensitive Monitoring of Polynucleotide Kinase Activity Accompanying DNAzyme Catalyzed Precipitation Amplification. AB - A convenient and feasible photoelectrochemical (PEC) sensing platform based on gold nanoparticles-decorated g-C3N4 nanosheets (AuNP/g-C3N4) was designed for highly sensitive monitoring of T4 polynucleotide kinase (PNK) activity, using DNAzyme-mediated catalytic precipitation amplification. To realize our design, the AuNP/g-C3N4 nanohybrid was initially synthesized through in situ reduction of Au(III) on the g-C3N4 nanosheets, which was utilized for the immobilization of hairpin DNA1 (HP1) on the sensing interface. Thereafter, a target-induced isothermal amplification was automatically carried out on hairpin DNA2 (HP2) in the solution phase through PNK-catalyzed 5'-phosphorylation accompanying formation of numerous trigger DNA fragments, which could induce generation of hemin/G-quadruplex-based DNAzyme on hairpin DNA1. Subsequently, the DNAzyme could catalyze the 4-chloro-1-naphthol (4-CN) oxidation to produce an insoluble precipitation on the AuNP/g-C3N4 surface, thereby resulting in the local alternation of the photocurrent. Experimental results revealed that introduction of AuNP on the g-C3N4 could cause a ~100% increase in the photocurrent because of surface plasmon resonance-enhanced light harvesting and separation of photogenerated e-/h+ pairs. Under the optimal conditions, the percentage of photocurrent decrement (DeltaI/I0, relative to background signal) increased with the increasing PNK activity in a dynamic working range from 2 to 100 mU mL(-1) with a low detection limit (LOD) of 1.0 mU mL(-1). The inhibition effect of adenosine diphosphate also received a good performance in PNK inhibitor screening research, thereby providing a useful scheme for practical use in quantitative PNK activity assay for life science and biological research. PMID- 25837793 TI - Meta-awareness and the involuntary memory spectrum: Reply to Meyer, Otgaar, and Smeets (2015). AB - In their commentary, Meyer, Otgaar, and Smeets (2015) raise several important issues about the definitions, characteristics and applications of various involuntary cognitive phenomena. Here we respond to the comments of Meyer et al. in ways that we hope will advance understanding of these issues, and inform future research. In particular, we have focused on the characteristics of involuntary phenomena-particularly in relation to meta-awareness-and the clinical relevance of mind-wandering. PMID- 25837795 TI - Asymmetries in spatial perception are more prevalent under explicit than implicit attention. AB - Observers typically show systematic errors in spatial perception when asked to bisect a line. We examined whether misbisection relates to the extent by which the midpoint is scrutinized explicitly. Participants were required to position a soccer goalkeeper at the exact midpoint of the goal line, drawing explicit attention to the midpoint of the line. Subsequently, they carried out a penalty kick to score a goal, without eliciting explicit attention for the centre of the goal for choosing the side to which to kick the ball. We found that participants positioned the goalkeeper to the right of the centre, confirming the previously reported rightward bias for line bisections in extra-personal space. Although participants (erroneously) believed that the goalkeeper stood in the centre, they kicked the ball to the bigger side of the goal more often. These findings indicate that asymmetries in spatial perception are more evident with explicit than implicit attention. PMID- 25837794 TI - Unconscious manipulation of free choice by novel primes. AB - The extent to which non-conscious perception can influence behaviour has been a topic of considerable controversy in psychology for decades. Although a challenging task, convincing empirical demonstrations have emerged suggesting that non-consciously perceived 'prime' stimuli can influence motor responses to subsequent targets. Interestingly, recent studies have shown that the influence of masked primes is not restricted to target-elicited responses, but can also bias free-choices between alternative behaviours. The present experiment extends these findings by showing that free-choices could also be biased by novel primes that never appeared as targets and therefore could not trigger acquired stimulus response (S-R) mappings. This new evidence suggests that free-choice behaviour can be influenced by non-consciously triggered semantic representations. Furthermore, the results reported here support accounts of masked priming that posit an automatic semantic categorisation of non-consciously perceived visual stimuli. PMID- 25837796 TI - Near-Death Experiences in patients with locked-in syndrome: Not always a blissful journey. AB - Memories of Near-Death Experiences (NDEs) most often are recounted as emotionally positive events. At present, no satisfactory explanatory model exists to fully account for the rich phenomenology of NDEs following a severe acute brain injury. The particular population of patients with locked-in syndrome (LIS) provides a unique opportunity to study NDEs following infratentorial brain lesions. We here retrospectively characterized the content of NDEs in 8 patients with LIS caused by an acute brainstem lesion (i.e., "LIS NDEs") and 23 NDE experiencers after coma with supratentorial lesions (i.e., "classical NDEs"). Compared to "classical NDEs", "LIS NDEs" less frequently experienced a feeling of peacefulness or well being. It could be hypothesized that NDEs containing less positive emotions might have a specific neuroanatomical substrate related to impaired pontine/paralimbic connectivity or alternatively might be related to the emotional distress caused by the presence of conscious awareness in a paralyzed body. PMID- 25837797 TI - Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer. AB - OBJECTIVE: Metabolic alternations are deemed a hallmark of cancer cells. Among many metabolic pathways, glycolysis and lipogenesis are essential metabolic processes in cancer cells. In this study, we examined the prognostic impact of the combined expression of glycolysis-related glucose transporter 1 (GLUT1) and ATP-citrate lyase (ACLY), which are important molecules in lipogenesis, in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: GLUT1 and ACLY expression in 134 NSCLC specimens were determined by immunohistochemistry using a tissue microarray (TMA). We examined the overall survival of patients with GLUT1-, ACLY- or GLUT+ACLY-positive expression using Kaplan-Meier analysis. We analyzed the prognostic impact of combined GLUT1 and ACLY expression according to lymph node status using multivariate Cox analysis. RESULTS: Patients with GLUT1- or ACLY-positive expression exhibited poorer overall survival compared with GLUT1- or ACLY-negative patients. GLUT1 positive/ACLY-positive expression status was associated with the worst overall survival, in contrast with GLUT1 negative/ACLY-negative expression status, which was correlated with the best overall survival (P=0.003). GLUT1-positive/ACLY positive expression was significantly correlated with poor prognosis in node negative but not in node-positive patients. Multivariate Cox analysis indicated combined expression of GLUT1 and ACLY was an independent prognostic factor for overall survival in node-negative patients with NSCLC (P=0.049). CONCLUSION: These results suggest that the combined expression of GLUT1 and ACLY could be a more valuable prognostic factor than their individual expression in node-negative patients with NSCLC. PMID- 25837798 TI - Successful treatment with alectinib after crizotinib-induced esophageal ulceration. AB - Crizotinib was the first clinically available inhibitor of the tyrosine kinase ALK, and next-generation ALK inhibitors, such as alectinib, are now under development. Although crizotinib is generally well tolerated, severe esophageal injury has been reported as a rare but serious adverse event of crizotinib therapy. We now describe the successful treatment with alectinib of a patient who developed crizotinib-induced esophageal ulceration. PMID- 25837799 TI - Can EGFR mutations in plasma or serum be predictive markers of non-small-cell lung cancer? A meta-analysis. AB - BACKGROUND: The detection of epidermal growth factor receptor (EGFR) mutations in plasma or serum has previously been reported to be feasible for non-small-cell lung cancer (NSCLC). However, not all results indicate a consistency between EGFR mutation status in the plasma or serum and that in tissues. METHODS: A meta analysis was performed to evaluate the overall accuracy of EGFR mutation detection in plasma or serum. Publications up to December 2014 were searched for using the PubMed, Embase and Web of Science databases. Sensitivity, specificity and other accuracy measures were pooled using the bivariate mixed-effects regression model. RESULTS: Twenty-six studies were included in this meta analysis. The pooled specificity, sensitivity, positive and negative likelihood ratios, and diagnostic odds ratios were 0.97 (95% confidence interval (CI): 0.93 0.99), 0.65 (95% CI: 0.54-0.74), 24.9 (95% CI: 9.2-67.2), 0.36 (95% CI: 0.27 0.48), and 69 (95% CI: 24-202), respectively. The summary receiver operating characteristic curve was 0.89 (95% CI: 0.86-0.91). CONCLUSIONS: The detection of EGFR mutations in plasma or serum is a noninvasive method to confirm EGFR mutation status in patients with NSCLC. However, more work is necessary to identify which method can raise the sensitivity of EGFR mutation detection. PMID- 25837800 TI - Implementing and sustaining an early rehabilitation program in a medical intensive care unit: A qualitative analysis. AB - PURPOSE: Early rehabilitation programs in a medical intensive care unit can improve patient outcomes, but clinicians face barriers in implementing and sustaining such programs. We sought to describe a multidisciplinary team perspective regarding how to implement and sustain a successful early rehabilitation program. METHODS: Semistructured interviews were conducted with 20 staff and faculty who were involved in the early rehabilitation program at the Johns Hopkins Hospital Medical Intensive Care Unit. Transcripts were evaluated using the Consolidated Framework of Implementation Research Theory. RESULTS: Four major constructs emerged as important, as follows: (1) necessary components, (2) implementation strategies, (3) perceived barriers, and (4) positive outcomes. All participants reported that staff buy-in was necessary, whereas having a multidisciplinary team with good communication among team members was reported as helpful by 90% of participants. The most common barrier reported was increased staff workload (80%). All participants (100%) noted improved patient outcomes as an important benefit, and 95% reported improved job satisfaction. CONCLUSIONS: This qualitative study of a successful early rehabilitation program highlights the importance of assessing and engaging a multidisciplinary team before implementation and the positive outcomes of early rehabilitation on staff by improving job satisfaction and changing the culture of a hospital unit. PMID- 25837803 TI - Mapping public engagement with research in a UK University. AB - Notwithstanding that 'public engagement' is conceptualised differently internationally and in different academic disciplines, higher education institutions largely accept the importance of public engagement with research. However, there is limited evidence on how researchers conceptualise engagement, their views on what constitutes engagement and the communities they would (or would not) like to engage with. This paper presents the results of a survey of researchers in the Open University that sought to gather data to fill these gaps. This research was part of an action research project designed to embed engagement in the routine practices of researchers at all levels. The findings indicate that researchers have a relatively narrow view of public engagement with research and the communities with which they interact. It also identified that very few strategically evaluate their public engagement activities. We conclude by discussing some of the interventions we have introduced with the aim of broadening and deepening future researcher engagement. PMID- 25837802 TI - Immunogenicity, protective efficacy, and non-replicative status of the HSV-2 vaccine candidate HSV529 in mice and guinea pigs. AB - HSV-2 vaccine is needed to prevent genital disease, latent infection, and virus transmission. A replication-deficient mutant virus (dl5-29) has demonstrated promising efficacy in animal models of genital herpes. However, the immunogenicity, protective efficacy, and non-replicative status of the highly purified clinical vaccine candidate (HSV529) derived from dl5-29 have not been evaluated. Humoral and cellular immune responses were measured in mice and guinea pigs immunized with HSV529. Protection against acute and recurrent genital herpes, mortality, latent infection, and viral shedding after vaginal HSV-2 infection was determined in mice or in naive and HSV-1 seropositive guinea pigs. HSV529 replication and pathogenicity were investigated in three sensitive models of virus replication: severe combined immunodeficient (SCID/Beige) mice inoculated by the intramuscular route, suckling mice inoculated by the intracranial route, and vaginally-inoculated guinea pigs. HSV529 immunization induced HSV-2-neutralizing antibody production in mice and guinea pigs. In mice, it induced production of specific HSV-2 antibodies and splenocytes secreting IFNgamma or IL-5. Immunization effectively prevented HSV-2 infection in all three animal models by reducing mortality, acute genital disease severity and frequency, and viral shedding. It also reduced ganglionic viral latency and recurrent disease in naive and HSV-1 seropositive guinea pigs. HSV529 replication/propagation was not detected in the muscles of SCID/Beige mice, in the brains of suckling mice, or in vaginal secretions of inoculated guinea pigs. These results confirm the non-replicative status, as well as its immunogenicity and efficacy in mice and guinea pigs, including HSV-1 seropositive guinea pigs. In mice, HSV529 produced Th1/Th2 characteristic immune response thought to be necessary for an effective vaccine. These results further support the clinical investigation of HSV529 in human subjects as a prophylactic vaccine. PMID- 25837801 TI - Early levosimendan administration is associated with decreased mortality after cardiac surgery. AB - PURPOSE: The aim of this study was to assess the effects on postoperative outcome of levosimendan with respect to timing of its administration in cardiac surgery patients. MATERIALS AND METHODS: Levosimendan administration was triggered by a severely reduced left ventricular systolic function (left ventricular ejection fraction, <35%) and/or signs of a low cardiac output syndrome. A total of 159 patients were retrospectively assigned depending on an early (perioperatively up to the first hour after intensive care unit [ICU] admission) vs late (later than the first hour after ICU admission) start of treatment. RESULTS: Patients receiving levosimendan after the first hour of ICU admission (n = 89) had a significantly increased inhospital (P = .004) and 1-year (P = .027) mortality. Duration of mechanical ventilation (P = .002), incidence of renal dysfunction (P = .002), and need of renal replacement therapy (P = .032) were significantly increased in the late start group. A late start of levosimendan treatment was associated with an odds ratio of 2.258 (95% confidence interval, 1.139-4.550; P = .021) for inhospital mortality and an adjusted hazard ratio of 1.827 (95% confidence interval, 1.155-2.890; P = .010) for 1-year survival. CONCLUSIONS: Findings of this retrospective analysis favor an "early," that is, intraoperatively up to the first hour after ICU admission, start of perioperative levosimendan treatment to maximize its ability to reduce mortality and morbidity. PMID- 25837804 TI - Physical activities during pregnancy and type of delivery in nulliparae. AB - The aim of this study was to investigate changes in physical activity across pregnancy and the relationship between trimester-specific physical activity and unplanned caesarean sections (CSs). A cohort study design was carried out. A cohort of 150 pregnant women was established when they received prenatal care at 29-40 weeks of gestation at a medical centre in northern Taiwan. Participants were asked to recall the amounts of physical activity in which they had engaged in the three trimesters as assessed by the Pregnancy Physical Activity Questionnaire (PPAQ). Overall self-reported physical activity for the cohort decreased by 31% in the first trimester compared to the pre-gravid period, then increased in the second trimester and remained stable until delivery. A repeated measures analysis of variance was used to evaluate the data and revealed significantly more physical activity during the second trimester than in the first and third trimesters (F = 36.471, P = 0.000). In addition, there was a significant difference between normal spontaneous delivery and unplanned CS groups (F = 4.770, P = 0.031). Logistic regression determined that the odds ratio of undergoing a CS increased by 0.644 (95% confidence interval: 0.429-0.968) for women in the third trimester who performed low levels of physical activity. Results support the benefits of physical activity, and professionals are encouraged to provide pregnant women with information on recommendations for physical activity, particularly in terms of reducing unplanned CSs. PMID- 25837805 TI - Elution study of unreacted TEGDMA from bulk-fill composite (SDRTM Dentsply) using HPLC. AB - PURPOSE: The study evaluates the dynamics of unreacted TEGDMA monomer elution from new generation of flowable bulk fill composite resin (SDRTM Dentsply). MATERIAL AND METHODS: Polymerised specimens of SDRTM composite (7mm diameter and 4mm thick) were placed in four solutions: 100% ethanol, 75% ethanol, distilled water and 100% methanol. The concentration of the eluted TEGDMA was measured using the HLPC method after 0.5, 1, 2 and 3h as well as after 1, 3, 7, 14, 21 and 31 days. RESULTS: During the first 24h of storage in each medium, a significant elution of TEGDMA was observed (100% ethanol - 12.5MUg/g, 75% ethanol - 8.4MUg/g, distilled water - 5.4MUg/g and 100% methanol - 7MUg/g). The elution time of the TEGDMA into 100% ethanol, 75% ethanol, distilled water and 100% methanol was 14, 7, 3 and 1 day, respectively. After 31 days, total concentrations of TEGDMA were as follows: 100% ethanol - 16MUg/g, 75% ethanol - 9.4MUg/g, distilled water - 6MUg/g and 100% methanol - 7MUg/g. CONCLUSIONS: The TEGDMA was released from the SDRTM composite into each solution used. The TEGDMA concentration and the time of its elution depend on the type of the solvent. In an aqueous environment, the SDRTM composite exhibits a high chemical stability compared to other solutions. The direct toxicity towards to the dental pulp is established during the first hours after the placement of resin. PMID- 25837808 TI - Iranian risk model as a predictive tool for retinopathy in patients with type 2 diabetes. AB - OBJECTIVE: Diabetic retinopathy (DR) is the leading cause of blindness in patients with type 1 or type 2 diabetes. The gold standard for the detection of DR requires expensive equipment. This study was undertaken to develop a simple and practical scoring system to predict the probability of DR. METHODS: A total of 1782 patients who had first-degree relatives with type II diabetes were selected. Eye examinations were performed by an expert ophthalmologist. Biochemical and anthropometric predictors of DR were measured. Logistic regression was used to develop a statistical model that can be used to predict DR. Goodness of fit was examined using the Hosmer-Lemeshow test and the area under the receiver operating characteristic (ROC) curve. RESULTS: The risk model demonstrated good calibration and discrimination (ROC area=0.76) in the validation sample. Factors associated with DR in our model were duration of diabetes (odds ratio [OR]=2.14, confidence interval [CI] 95%=1.87 to 2.45); glycated hemoglobin (A1C) (OR=1.21, CI 95%=1.13 to 1.30); fasting plasma glucose (OR=1.83, CI 95%=1.28 to 2.62); systolic blood pressure (OR=1.01, CI 95%= 1.00 to 1.02); and proteinuria (OR=1.37, CI 95%=1.01 to 1.85). The only factor that had a protective effect against DR were body mass index and education level (OR=0.95, CI 95%=0.92 to 0.98). CONCLUSIONS: The good performance of our risk model suggests that it may be a useful risk-prediction tool for DR. It consisted of the positive predictors like A1C, diabetes duration, sex (male), fasting plasma glucose, systolic blood pressure and proteinuria, as well as negative risk factors like body mass index and education level. PMID- 25837807 TI - Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study. AB - BACKGROUND: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection. METHODS: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels <= 120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (>= 1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression. RESULTS: Among 643 individuals with acute HCV, 162 with well characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P = 0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83). CONCLUSIONS: Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance. PMID- 25837809 TI - Are Behavioural Interventions Doomed to Fail? Challenges to Self-Management Support in Chronic Diseases. AB - Self-management and self-management support are concepts very familiar to those of us in diabetes care. These concepts require openness to understanding the behaviours of persons with diabetes broadly, not only behaviours restricted to the biomedical perspective. Understanding the importance of health behaviour change and working within the Expanded Chronic Care Model define the context within which self-management support should occur. The purpose of this perspective is to identify a potential limitation in existing self-management support initiatives. This potential limitation reflects provider issues, not patient issues; that is, true self-management support might require changes by healthcare providers. Specifically, although behavioural interventions within the context of academic research studies are evidence based, behaviour change interventions implemented in general practice settings might prove less effective unless healthcare providers are able to shift from a practice based on the biomedical model to a practice based on the self-management support model. The purpose of this article is to facilitate effective self-management support by encouraging providers to switch from a model of care based on the expert clinician encountering the uninformed help seeker (the biomedical model) to one guided by collaboration grounded in the principles of description, prediction and choice. Key to understanding the value of making this shift are patient-centered communication principles and the tenets of complexity theory. PMID- 25837810 TI - Descemet Membrane Endothelial Keratoplasty--Reply. PMID- 25837811 TI - Symptom Clusters in Ovarian Cancer Patients With Chemotherapy After Surgery: A Longitudinal Survey. AB - BACKGROUND: Ovarian cancer is 1 of the most common malignancies in the female reproductive system. Identification of symptom clusters in ovarian cancer patients may improve management of symptoms. OBJECTIVE: The objective of this article is to explore the changes in symptom clusters in ovarian cancer patients with adjuvant chemotherapy after surgery at different time points. METHODS: Basic details of the patients were documented and a longitudinal investigation was carried out. We used the Memorial Symptom Assessment Scale to examine 115 Chinese ovarian cancer patients' symptom experience at 4 time points: days before chemotherapy (T1), chemotherapy cycle 1 (T2), chemotherapy cycle 3 (T3), and chemotherapy cycle 6 (T4). The exploratory factor analysis was performed to determine the numbers and components of symptom clusters. RESULTS: Symptom clusters varied at different time points, which were classified as pain-related symptom cluster, psychological symptom cluster, menopausal symptom cluster, gastrointestinal symptom cluster, body image symptom cluster, and peripheral neurologic symptom cluster. The gastrointestinal symptom cluster and body image symptom cluster appeared at T1 and remained consistent at T3 and T4, whereas the peripheral neurologic symptom cluster was noted at T3 and T4. CONCLUSIONS: Clinicians should prioritize symptom management interventions with ovarian cancer patients to focus on the most severe symptom cluster: psychological symptom cluster at T1, gastrointestinal symptom cluster at T2, and body image symptom cluster at T3 and T4. IMPLICATIONS FOR PRACTICE: The ability to predict symptom clusters in ovarian cancer patients receiving chemotherapy may help to make optimized clinical decision in advance to alleviate patients' symptoms and improve their life quality. PMID- 25837812 TI - Scroto-perineal hidradenitis suppurativa complicated by giant scrotal elephantiasis. AB - Scrotal elephantiasis has been a recognized complication of inguinal node irradiation, filarial infection, tumor involvement and surgical lymphatic destruction, but has rarely been reported in association with hidradenitis suppurativa (HS). HS, also known as acne inversa, is a chronic and often debilitating disease primarily affecting the axillae, inframammary regions and perineum. The location of the lesions may lead to social embarrassment and failure to seek medical treatment. Scroto-preineal HS complicated by scrotal elephantiasis is a distressing disease. Excisional surgery with reconstruction is the recommended treatment with a high likelihood of good outcome. We present a 38 year-old male patient with long-standing scroto-perineal HS complicated by giant scrotal elephantiasis. PMID- 25837813 TI - Allicin from garlic inhibits the biofilm formation and urease activity of Proteus mirabilis in vitro. AB - Several virulence factors contribute to the pathogenesis of Proteus mirabilis. This study determined the inhibitory effects of allicin on urease, hemolysin and biofilm of P. mirabilis ATCC 12453 and its antimicrobial activity against 20 clinical isolates of P. mirabilis. Allicin did not inhibit hemolysin, whereas it did inhibit relative urease activity in both pre-lysed (half-maximum inhibitory concentration, IC50 = 4.15 MUg) and intact cells (IC50 = 21 MUg) in a concentration-dependent manner. Allicin at sub-minimum inhibitory concentrations (2-32 MUg mL(-1)) showed no significant effects on the growth of the bacteria (P > 0.05), but it reduced biofilm development in a concentration-dependent manner (P < 0.001). A higher concentration of allicin was needed to inhibit the established biofilms. Using the microdilution technique, the MIC90 and MBC90 values of allicin against P. mirabilis isolates were determined to be 128 and 512 MUg mL(-1), respectively. The results suggest that allicin could have clinical applications in controlling P. mirabilis infections. PMID- 25837814 TI - Complete genome sequence of Selenomonas ruminantium subsp. lactilytica will accelerate further understanding of the nature of the class Negativicutes. AB - Selenomonas ruminantium subsp. lactilytica, a strictly anaerobic ruminal bacterium, possesses typical Gram-negative cell surface structure comprising cytoplasmic membrane, peptidoglycan layer and outer membrane, whereas its 16S rRNA-based taxonomy shows that the bacteria belongs to Gram-positive Firmicutes. Complete genome analysis showed that genes or gene clusters involved in Gram negative cell structure were scattered in the S. ruminantium genome, and might provide the new insight of phylogenetic relationship between the bacterium and other bacterial species. PMID- 25837815 TI - Uptake of chitosan-derived D-glucosamine oligosaccharides in Streptomyces coelicolor A3(2). AB - The csnR gene, localized at the beginning of an operon, csnR-K, which organization is conserved through many actinomycete genomes, was previously shown to repress the transcription of the chitosanase gene csnA in Streptomyces lividans. However, knowledge on the function of the whole csnR-K operon in the metabolism of chitosan (an N-deacetylated derivative of chitin) remained limited. Mutants of S. coelicolor A3(2) harboring partial or total deletions of the csnR-K operon were analyzed for their capacity to uptake glucosamine oligosaccharides (GlcN)n. The csnR-K operon was autoregulated by CsnR repressor and its transcription was inducible by GlcN oligosaccharides. The operon controlled the uptake of GlcN oligosaccharides in S. coelicolor A3(2), with a minor contribution to the consumption of monomeric GlcN but not chitin-related N-acetylated derivatives. The deletion of the whole operon abolished the uptake of GlcN oligosaccharides. The CsnEFG transporter encoded by this operon is the front door for the assimilation of chitosan-derived hydrolysis products in S. coelicolor A3(2). The ATP-binding component MsiK was essential for CsnEFG transport function. Also, deletion of msiK abolished the induction of csnA transcription by GlcN oligosaccharides. PMID- 25837816 TI - Glycerophosphorylcholine regulates Haemophilus influenzae glpQ gene expression. AB - An important virulence strategy adopted by Haemophilus influenzae to establish a niche on the mucosal surface of the host is the phosphorylcholine (ChoP) decoration of its lipopolysaccharides, which promotes adherence to the host cells. Haemophilus influenzae is able to use glycerophosphorylcholine (GPC) from host for ChoP synthesis. Utilization of GPC requires glpQ, which encodes a glycerophosphodiester phosphodiesterase enzyme. In this study, we investigate the transcriptional regulation of glpQ gene using real-time PCR and transcriptional fusion of H. influenzae glpQ promoter to the Escherichia coli lacZ reporter gene. The glpQ promoter activities were examined under environmental conditions including changes in temperature, oxygen, high salt and minimal growth medium. Our data showed that under room temperature and anaerobic conditions, the glpQ gene expression levels were significantly higher than under other growth conditions. In addition, the glpQ gene expression levels were upregulated in the presence of GPC. These results suggest that H. influenzae may upregulate glpQ expression in response to different environments it encounters during infection, from the airway surfaces (room temperature) to deep tissues (anaerobic). Upregulation of glpQ by GPC may allow efficient use of abundant GPC from mammalian cells by H. influenzae as a source of nutrient and for ChoP decoration of lipopolysaccharide that facilitates bacterial adhesion to host cells and growth during infection. PMID- 25837817 TI - Inefficient translocation of a truncated O unit by a Salmonella Wzx affects both O-antigen production and cell growth. AB - Bacterial Wzx flippases translocate (flip) short oligosaccharide repeat units (O units) across the inner membrane into the periplasm, which is a critical step in the assembly of many O antigens, capsules and other surface polysaccharides. There is enormous diversity in O antigens and capsules in particular, even within species. Wzx proteins are similarly diverse, but it has been widely accepted that they have significant specificity only for the first sugar of an O unit. In this study, we analysed the Wzx from the Salmonella enterica group C2 O antigen gene cluster, which is a unique and divergent member of a set of gene clusters that produce galactose-initiated O antigens. We demonstrate that this Wzx has a strong preference for the presence of an abequose side-branch, which manifests in a reduction of long-chain O antigen and a major growth defect. This contributes to a growing body of evidence that, contrary to earlier proposals, Wzx flippases commonly exhibit a strong preference for the structure of their native O unit. PMID- 25837818 TI - Family 13 carbohydrate-binding module of alginate lyase from Agarivorans sp. L11 enhances its catalytic efficiency and thermostability, and alters its substrate preference and product distribution. AB - The carbohydrate-binding module (CBM) in polysaccharide hydrolases plays a key role in the hydrolysis of cellulose, xylan and chitin. However, the function of CBM in alginate lyases has not been elucidated. A new alginate lyase gene, alyL2, was cloned from the marine bacterium Agarivorans sp. L11 by using degenerate and site-finding PCR. The alginate lyase, AlyL2, contained an N-terminal CBM13 and a C-terminal catalytic family 7 polysaccharide lyase (PL7) module. To better understand the function of CBM13 in alginate lyase AlyL2, the full-length enzyme (AlyL2-FL) and its catalytic module (AlyL2-CM) were expressed in Escherichia coli and characterized. The specific activity and catalytic efficiency of AlyL2-FL were approximately twice those of AlyL2-CM. The half-lives of AlyL2-FL were 4.7 6.6 times those of AlyL2-CM at 30-50 degrees C. In addition, the presence of CBM13 in AlyL2 changed its substrate preference and increased the percentage of disaccharides from 50.5% to 64.6% in the total products. This first report of the function of CBM13 in alginate lyase provides new insights into the degradation of alginate by marine microorganisms. PMID- 25837819 TI - Improving the quality of biomarker discovery research: the right samples and enough of them. AB - BACKGROUND: Biomarker discovery research has yielded few biomarkers that validate for clinical use. A contributing factor may be poor study designs. METHODS: The goal in discovery research is to identify a subset of potentially useful markers from a large set of candidates assayed on case and control samples. We recommend the PRoBE design for selecting samples. We propose sample size calculations that require specifying: (i) a definition for biomarker performance; (ii) the proportion of useful markers the study should identify (Discovery Power); and (iii) the tolerable number of useless markers amongst those identified (False Leads Expected, FLE). RESULTS: We apply the methodology to a study of 9,000 candidate biomarkers for risk of colon cancer recurrence where a useful biomarker has positive predictive value >= 30%. We find that 40 patients with recurrence and 160 without recurrence suffice to filter out 98% of useless markers (2% FLE) while identifying 95% of useful biomarkers (95% Discovery Power). Alternative methods for sample size calculation required more assumptions. CONCLUSIONS: Biomarker discovery research should utilize quality biospecimen repositories and include sample sizes that enable markers meeting prespecified performance characteristics for well-defined clinical applications to be identified. IMPACT: The scientific rigor of discovery research should be improved. PMID- 25837823 TI - Tip-enhanced Raman mapping of local strain in graphene. AB - We demonstrate local strain measurements in graphene by using tip-enhanced Raman spectroscopy (TERS). We find that a single 5 nm particle can induce a radial strain over a lateral distance of ~170 nm. By treating the particle as a point force on a circular membrane, we find that the strain in the radial direction (r) is ? r-(2 3),in agreement with force-displacement measurements conducted on suspended graphene flakes. Our results demonstrate that TERS can be used to map out static strain fields at the nanoscale, which are inaccessible using force displacement techniques. PMID- 25837822 TI - Exposure profiles of mercury in human hair at a terai belt of North India. AB - Human hair is frequently used as a bioindicator of mercury exposure. Mercury (Hg) has for centuries been a useful metal in a variety of applications. Unfortunately, this usefulness is counterbalanced by its neurotoxicological health impact. The US Environmental Protection Agency recommends keeping the hair Hg level <1.0 ug/g. Therefore, an investigation has been performed in order to ascertain the hair Hg levels among the people living at the terai belt of North India. Hair samples were collected from 111 individuals and were placed in an identified plastic bag, stapled to prevent the shift of the hair strand. Samples were analyzed by combustion, gold amalgamation, atomic absorption spectrometry (C GA-AAS). The mean Hg level in hair was 0.28 ug/g for the whole group ranging from 0.0012 to 1.9091 ug/g. The mean hair Hg levels were 0.16 ug/g for men and 0.12 ug/g for women, indicating that men had higher hair Hg levels than women. Total hair Hg was found to be significantly associated with age, gender and fish consumption frequency. 98 % of the total sample had hair Hg concentrations less than 1.0 ug/g, i.e, within safe dose, whereas only 2 % had Hg concentrations greater than 1.0 ug/g, thereby exceeding the safe dose. PMID- 25837821 TI - Inherited genetic variants associated with occurrence of multiple primary melanoma. AB - Recent studies, including genome-wide association studies, have identified several putative low-penetrance susceptibility loci for melanoma. We sought to determine their generalizability to genetic predisposition for multiple primary melanoma in the international population-based Genes, Environment, and Melanoma (GEM) Study. GEM is a case-control study of 1,206 incident cases of multiple primary melanoma and 2,469 incident first primary melanoma participants as the control group. We investigated the odds of developing multiple primary melanoma for 47 SNPs from 21 distinct genetic regions previously reported to be associated with melanoma. ORs and 95% confidence intervals were determined using logistic regression models adjusted for baseline features (age, sex, age by sex interaction, and study center). We investigated univariable models and built multivariable models to assess independent effects of SNPs. Eleven SNPs in 6 gene neighborhoods (TERT/CLPTM1L, TYRP1, MTAP, TYR, NCOA6, and MX2) and a PARP1 haplotype were associated with multiple primary melanoma. In a multivariable model that included only the most statistically significant findings from univariable modeling and adjusted for pigmentary phenotype, back nevi, and baseline features, we found TERT/CLPTM1L rs401681 (P = 0.004), TYRP1 rs2733832 (P = 0.006), MTAP rs1335510 (P = 0.0005), TYR rs10830253 (P = 0.003), and MX2 rs45430 (P = 0.008) to be significantly associated with multiple primary melanoma, while NCOA6 rs4911442 approached significance (P = 0.06). The GEM Study provides additional evidence for the relevance of these genetic regions to melanoma risk and estimates the magnitude of the observed genetic effect on development of subsequent primary melanoma. PMID- 25837825 TI - Correction: Possible influence of B chromosomes on genes included in immune response and parasite burden in Apodemus flavicollis. PMID- 25837820 TI - Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci. AB - BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. PMID- 25837824 TI - Loss of serum and glucocorticoid-regulated kinase 3 (SGK3) does not affect proliferation and survival of multiple myeloma cell lines. AB - Multiple myeloma (MM) is a generally fatal plasma cell cancer that often shows activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway. Targeted pharmacologic therapies, however, have not yet progressed beyond the clinical trial stage, and given the complexity of the PI3K/Akt signalling system (e.g. multiple protein isoforms, diverse feedback regulation mechanisms, strong variability between patients) it is mandatory to characterise its ramifications in order to better guide informed decisions about the best therapeutic approaches. Here we explore whether serum and glucocorticoid-regulated kinase 3 (SGK3), a potential downstream effector of PI3K, plays a role in oncogenic signalling in MM cells--either in concert with or independent of Akt. SGK3 was expressed in all MM cell lines and in all primary MM samples tested. Four MM cell lines representing a broad range of intrinsic Akt activation (very strong: MM.1s, moderate: L 363 and JJN-3, absent: AMO-1) were chosen to test the effects of transient SGK3 knockdown alone and in combination with pharmacological inhibition of Akt, PI3K-p110alpha, or in the context of serum starvation. Although the electroporation protocol led to strong SGK3 depletion for at least 5 days its absence had no substantial effect on the activation status of potential downstream substrates, or on the survival, viability or proliferation of MM cells in all experimental contexts tested. We conclude that it is unlikely that SGK3 plays a significant role for oncogenic signalling in multiple myeloma. PMID- 25837826 TI - Neural modularity helps organisms evolve to learn new skills without forgetting old skills. AB - A long-standing goal in artificial intelligence is creating agents that can learn a variety of different skills for different problems. In the artificial intelligence subfield of neural networks, a barrier to that goal is that when agents learn a new skill they typically do so by losing previously acquired skills, a problem called catastrophic forgetting. That occurs because, to learn the new task, neural learning algorithms change connections that encode previously acquired skills. How networks are organized critically affects their learning dynamics. In this paper, we test whether catastrophic forgetting can be reduced by evolving modular neural networks. Modularity intuitively should reduce learning interference between tasks by separating functionality into physically distinct modules in which learning can be selectively turned on or off. Modularity can further improve learning by having a reinforcement learning module separate from sensory processing modules, allowing learning to happen only in response to a positive or negative reward. In this paper, learning takes place via neuromodulation, which allows agents to selectively change the rate of learning for each neural connection based on environmental stimuli (e.g. to alter learning in specific locations based on the task at hand). To produce modularity, we evolve neural networks with a cost for neural connections. We show that this connection cost technique causes modularity, confirming a previous result, and that such sparsely connected, modular networks have higher overall performance because they learn new skills faster while retaining old skills more and because they have a separate reinforcement learning module. Our results suggest (1) that encouraging modularity in neural networks may help us overcome the long-standing barrier of networks that cannot learn new skills without forgetting old ones, and (2) that one benefit of the modularity ubiquitous in the brains of natural animals might be to alleviate the problem of catastrophic forgetting. PMID- 25837827 TI - Knowledge and attitude of the population toward cancer prostate Riyadh, Saudi Arabia. AB - AIMS: The aim of the following study is to assess the knowledge and attitude of men, in our region, regarding cancer prostate and its screening practices. SUBJECTS AND METHODS: The field work was conducted in Riyadh City, during the period February through July 2011. It was a population - based cross-sectional study comprising 400 men over 40 years. In addition to socio-demographic data, history of the present and past medical illness, history of prostatic diseases and examination, family history of cancer prostate; participants were inquired about their knowledge and attitude toward prostate cancer (PC) and screening behavior using through two different Likert scales. RESULTS: Only 10% of the respondents had practiced a regular PC examination checkup. Their knowledge about PC was poor and their attitude toward examination and screening was fair, where the mean of total correct knowledge score was 10.25 +/- 2.5 (51.25%), while the mean of total attitude score was 18.3 +/- 4.08 (65.3%). The respondents identified the physicians as the main sources of this information (62.4%), though they were not the main motives for a regular checkup. Knowledge represented the only significant predictor for participants' attitude. CONCLUSION: Beliefs and attitudes have a great impact, at every stage of the cancer continuum, this attitudes depends mainly on level of knowledge and quantity of information provided to patients and their families. Such attitudes should rely on a solid background of proper information and motivation from physicians to enhance and empower attitudes toward PC screening behavior. PMID- 25837828 TI - Towards interferon-free treatment for all HCV genotypes. PMID- 25837829 TI - Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. AB - BACKGROUND: Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. METHODS: In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented >=6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. FINDINGS: Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91.6-100]) in the ribavirin-containing regimen and 90.9% (40/44 [95% CI 78.3-97.5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9.16% [95% CI 19.61 to 1.29]; p=0.086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92.7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. INTERPRETATION: An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. FUNDING: AbbVie. PMID- 25837830 TI - Development of histopathological indices in the digestive gland and gonad of mussels: integration with contamination levels and effects of confounding factors. AB - Bivalve histopathology has become an important tool in aquatic toxicology, having been implemented in many biomonitoring programmes worldwide. However, there are various gaps in the knowledge of many sentinel organisms and the interference of confounding factors. This work aimed (i) to develop a detailed semi-quantitative histopathological index of the digestive gland and gonad of the Mytilus galloprovincialis mussel collected from five sites contaminated with distinct patterns of organic and inorganic toxicants along the Basque coast (SE Bay of Biscay) and (ii) to investigate whether seasonal variability and parasitosis act as confounding factors. A total of twenty-three histopathological alterations were analysed in the digestive gland and gonad following a weighed condition index approach. The alterations were integrated into a single value for a better understanding of the mussels' health status. The digestive gland was consistently more damaged than the gonad. Mussels from the most impacted sites endured the most significant deleterious effects showing inflammation-related alterations together with digestive tubule atrophy and necrosis. Neoplastic diseases were scarce, with only a few cases of fibromas (benign neoplasia). In contrast, in moderately or little impacted sites, contamination levels did not cause significant tissue damage. However, parasites contributed to overestimating the values of histopathological indices (i.e. more severe tissue damage) in mussels from little impacted sites, whilst the opposite occurred in mussels from highly polluted sites. Accordingly, inter-site differences were more pronounced in autumn when natural physiological responses of advanced maturation stages did not interfere in the histological response. In conclusion, although seasonal variability and parasitosis mask the response of histopathological indices, this biomonitoring approach may provide good sensitivity for assessing the health status of mussels if fluctuations of these confounding factors are considered. PMID- 25837831 TI - Expression of Bovine Viral Diarrhea Virus Envelope Glycoprotein E2 in Yeast Pichia pastoris and its Application to an ELISA for Detection of BVDV Neutralizing Antibodies in Cattle. AB - The aim of this article is to express envelope glycoprotein E2 of bovine viral diarrhea virus (BVDV) in yeast Pichia pastoris and its utility as a diagnostic antigen in ELISA. The BVDV E2 gene was cloned into the pPICZalphaA vector followed by integration into the Pichia pastoris strain X-33 genome for methanol induced expression. SDS-PAGE and Western blot results showed that the recombinant BVDV E2 protein (72 kDa) was expressed and secreted into the medium at a concentration of 40 mg/L of culture under optimized conditions. An indirect ELISA was then developed by using the yeast-expressed E2 protein. Preliminary testing of 300 field cattle serum samples showed that the E2 ELISA showed a sensitivity of 91.07% and a specificity of 92.02% compared to the reference virus neutralization test. The concordance between the E2 ELISA and VNT was 91.67%. This study demonstrates feasibility of BVDV E2 protein expression in yeast Pichia pastoris for the first time and its efficacy as an antigen in ELISA for detecting BVDV neutralizing antibodies in cattle. PMID- 25837833 TI - Correction: implications of hybridization, NUMTs, and overlooked diversity for DNA barcoding of eurasian ground squirrels. PMID- 25837832 TI - The Pathogen of the Great Barrier Reef Sponge Rhopaloeides odorabile Is a New Strain of Pseudoalteromonas agarivorans Containing Abundant and Diverse Virulence Related Genes. AB - Sponge diseases have increased dramatically, yet the causative agents of disease outbreaks have eluded identification. We undertook a polyphasic taxonomic analysis of the only confirmed sponge pathogen and identified it as a novel strain of Pseudoalteromonas agarivorans. 16S ribosomal RNA (rRNA) and gyraseB (gyrB) gene sequences along with phenotypic characteristics demonstrated that strain NW4327 was most closely related to P. agarivorans. DNA-DNA hybridization and in silico genome comparisons established NW4327 as a novel strain of P. agarivorans. Genes associated with type IV pili, mannose-sensitive hemagglutinin pili, and curli formation were identified in NW4327. One gene cluster encoding ATP-binding cassette (ABC) transporter, HlyD and TolC, and two clusters related to the general secretion pathway indicated the presence of type I secretion system (T1SS) and type II secretion system (T2SS), respectively. A contiguous gene cluster of at least 19 genes related to type VI secretion system (T6SS) which included all 13 core genes was found. The absence of T1SS and T6SS in nonpathogenic P. agarivorans S816 established NW4327 as the virulent strain. Serine proteases and metalloproteases of the classes S8, S9, M4, M6, M48, and U32 were identified in NW4327, many of which can degrade collagen. Collagenase activity in NW4327 and its absence in the nonpathogenic P. agarivorans KMM 255(T) reinforced the invasiveness of NW4327. This is the first report unambiguously identifying a sponge pathogen and providing the first insights into the virulence genes present in any pathogenic Pseudoalteromonas genome. The investigation supports a theoretical study predicting high abundance of terrestrial virulence gene homologues in marine bacteria. PMID- 25837835 TI - Correlation of ERalpha/ERbeta expression with dendritic and behavioural changes in CUMS mice. AB - In response to chronic stress, oestrogen receptor (ER)alpha acts as an anxiogenic agent as opposed to ERbeta which predominantly acts as an anxiolytic agent. These properties of ER play an important role in mediating anxiety- and depression-like behaviour and physiological responses. However, the precise underlying mechanism remains unclear. In particular, not much is known about the expression of ERalpha and ERbeta in the stress-sensitive brain regions such as the prefrontal cortex, hippocampus and amygdala. Using a rodent model of chronic unpredictable mild stress (CUMS), we report that two weeks of CUMS in young male mice (10+/-2weeks) induces noteworthy changes in the ratio of ERalpha/ERbeta in the prefrontal cortex and hippocampus. While we observed a significant (P<0.05) increase in ERalpha mRNA and protein expression levels, the expression of ERbeta in the prefrontal cortex, hippocampus and amygdala was significantly reduced. This increase in ERalpha expression with concomitant decrease in ERbeta expression was associated with increased anxiety- and depression-like behaviour as observed in elevated plus maze test, open field test, forced swim test and sucrose preference test. In addition to these behavioural changes, we report the decrease of dendritic complexity with concomitant increase in spine density in the medial prefrontal cortex, dorsohippocampal CA3 region and basolateral complex of amygdala (BLA). Taken together, these results suggest that the CUMS-induced increase in the ratio of ERalpha/ERbeta causes dendritic remodeling, which in turn might be responsible for increase in anxiety- and depression-like behaviour in young male mice. PMID- 25837834 TI - Nucleotides Acting at P2Y Receptors: Connecting Structure and Function. AB - Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y2 and P2Y11), ADP (P2Y1, P2Y12, and P2Y13), UTP (P2Y2 and P2Y4), UDP (P2Y6 and P2Y14), and UDP glucose (P2Y14). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the Gi-coupled P2Y12R and two of the Gq coupled P2Y1Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y1, P2Y2, P2Y4, and P2Y12Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs. PMID- 25837836 TI - Pain perception and EEG dynamics: does hypnotizability account for the efficacy of the suggestions of analgesia? AB - We report novel findings concerning the role of hypnotizability, suggestions of analgesia and the activity of the Behavioral Inhibition/Activation System (BIS/BAS) in the modulation of the subjective experience of pain and of the associated EEG dynamics. The EEG of high (highs) and low hypnotizable participants (lows) who completed the BIS/BAS questionnaire was recorded during basal conditions, tonic nociceptive stimulation without (PAIN) and with suggestions for analgesia (AN). Participants scored the perceived pain intensity at the end of PAIN and AN. The EEG midline dynamics was characterized by indices indicating the signal predictability (Determinism) and complexity (Entropy) obtained through the Recurrence Quantification Analysis. The reduced pain intensity reported by highs during AN was partially accounted for by the activity of the Behavioral Activation System. The decreased midline cortical Determinism observed during nociceptive stimulation in both groups independently of suggestions remained significantly reduced only in lows after controlling for the activity of the Behavioral Activation System. Finally, controlling for the activity of the Behavioral Inhibition System abolished stimulation, suggestions and hypnotizability-related differences. Results indicate that the BIS/BAS activity may be more important than hypnotizability itself in pain modulation and in the associated EEG dynamics. PMID- 25837837 TI - Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury. AB - Cardiac troponins are released and cleared slowly after myocardial injury, complicating the diagnosis of early, and recurrent, acute myocardial infarction. Cardiac myosin-binding protein C (cMyC) is a similarly cardiac-restricted protein that may have different release/clearance kinetics. Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release. In rodents, we demonstrate rapid release of cMyC using in vitro and in vivo models of acute myocardial infarction. In patients, with ST elevation myocardial infarction (STEMI, n = 20), undergoing therapeutic ablation of septal hypertrophy (TASH, n = 20) or having coronary artery bypass surgery (CABG, n = 20), serum was collected prospectively and frequently. cMyC appears in the serum as full-length and fragmented protein. Compared to cTnT measured using a contemporary high sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 +/- 3.1 vs 11.8 +/- 3.4 h, P < 0.007; TASH, 9.7 +/- 1.4 vs 21.6 +/- 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 +/- 1.9 vs 4.0 +/- 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 +/- 0.8 vs 22 +/- 5 h, P < 0.0001). Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT. We speculate that these characteristics could enable earlier diagnosis of myocardial infarction and reinfarction in suspected non-STEMI, a population not included in this early translational study. PMID- 25837838 TI - A long way to translation: will cMyC survive? PMID- 25837839 TI - Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics. AB - BACKGROUND: Biosimilars provide safety, purity, and potency similar to those of a reference biologic product. METHODS: An array of protein analytical techniques was used to compare the physicochemical properties of proposed biosimilar filgrastim (EP2006), US-approved originator filgrastim, and EU-approved originator filgrastim. Biological characterization involved surface plasmon resonance spectroscopy analyses and in vitro proliferation assays. A randomized, double-blind, two-way crossover, phase I study in healthy volunteers assessed the pharmacodynamics, pharmacokinetics, and safety profiles of EP2006 and US-approved originator filgrastim (administered as a single subcutaneous 10 ug/kg injection). RESULTS: EP2006 and originator filgrastim (US and EU approved) were highly similar with respect to primary, secondary, and tertiary protein structures; mass, size, purity, charge, and hydrophobicity. No differences in receptor binding affinity were observed, and all samples demonstrated similar in vitro bioactivity. In the phase I study, no statistically significant differences between EP2006 and US-approved originator filgrastim were noted in pharmacodynamic or pharmacokinetic parameters, and all confidence intervals were within the equivalence boundaries. The two products had similar safety profiles. CONCLUSION: These studies provide robust evidence of the structural and functional similarity between the proposed biosimilar filgrastim (EP2006) and the US-approved originator filgrastim. PMID- 25837841 TI - Determination of meningococcal serogroups in formulated monovalent and multivalent polysaccharide and polysaccharide-conjugate vaccines. PMID- 25837840 TI - The classic cadherins in synaptic specificity. AB - During brain development, billions of neurons organize into highly specific circuits. To form specific circuits, neurons must build the appropriate types of synapses with appropriate types of synaptic partners while avoiding incorrect partners in a dense cellular environment. Defining the cellular and molecular rules that govern specific circuit formation has significant scientific and clinical relevance because fine scale connectivity defects are thought to underlie many cognitive and psychiatric disorders. Organizing specific neural circuits is an enormously complicated developmental process that requires the concerted action of many molecules, neural activity, and temporal events. This review focuses on one class of molecules postulated to play an important role in target selection and specific synapse formation: the classic cadherins. Cadherins have a well-established role in epithelial cell adhesion, and although it has long been appreciated that most cadherins are expressed in the brain, their role in synaptic specificity is just beginning to be unraveled. Here, we review past and present studies implicating cadherins as active participants in the formation, function, and dysfunction of specific neural circuits and pose some of the major remaining questions. PMID- 25837842 TI - Salvage high-dose chemotherapy for germ cell tumors. AB - BACKGROUND: Salvage high-dose chemotherapy (HDCT) along with autologous stem cell transplant (ASCT) plays an important role in the management of patients with germ cell tumors (GCT) and progression after first-line cisplatin-based chemotherapy. In this review, the authors will discuss the history of HDCT as salvage management of patients with GCT, improvement in efficacy and safety over the past 25 years, prognostic factors for outcome, and the conflicting data on the optimal initial salvage approach. METHODS: The authors performed a PubMed search of HDCT and GCT to identify articles relevant to this review. After discussion, the articles felt to have contributed most notably to the field were selected for inclusion and summarized. RESULTS: Depending on patient selection and timing of HDCT, durable remission rates with salvage HDCT range between 30% and 63%. The combination of carboplatin and etoposide is the standard regimen for the high dose cycles with more variability in the regimens used for stem cell mobilization. Adding a third agent, particularly an oxazophosphorine (cyclophosphamide and ifosfamide), may add toxicity without increasing efficacy. In addition, sequential (2 or 3 cycle) HDCT regimens appear more effective and safer than single-cycle HDCT regimens. The optimal initial salvage approach (HDCT or conventional-dose chemotherapy) remains an unanswered question and highly controversial. CONCLUSIONS: Salvage HDCT with ASCT can cure a significant proportion of patients with GCT and progression after one or more lines of cisplatin-based chemotherapy and thus plays an important role in the contemporary management of high-risk patients. PMID- 25837843 TI - Role of cyanobacterial exopolysaccharides in phototrophic biofilms and in complex microbial mats. AB - Exopolysaccharides (EPSs) are an important class of biopolymers with great ecological importance. In natural environments, they are a common feature of microbial biofilms, where they play key protective and structural roles. As the primary colonizers of constrained environments, such as desert soils and lithic and exposed substrates, cyanobacteria are the first contributors to the synthesis of the EPSs constituting the extracellular polymeric matrix that favors the formation of microbial associations with varying levels of complexity called biofilms. Cyanobacterial colonization represents the first step for the formation of biofilms with different levels of complexity. In all of the possible systems in which cyanobacteria are involved, the synthesis of EPSs contributes a structurally-stable and hydrated microenvironment, as well as chemical/physical protection against biotic and abiotic stress factors. Notwithstanding the important roles of cyanobacterial EPSs, many aspects related to their roles and the relative elicited biotic and abiotic factors have still to be clarified. The aim of this survey is to outline the state-of-the-art of the importance of the cyanobacterial EPS excretion, both for the producing cells and for the microbial associations in which cyanobacteria are a key component. PMID- 25837844 TI - Exploring the interest in and the usage of the internet among patients eligible for osteoporosis screening. AB - The aim of this study was to evaluate the interest in the Internet and its usage for health-related issues among people eligible for osteoporosis screening. Self administered questionnaires have been distributed to subjects who were screened for osteoporosis and to menopausal women. 177 patients have responded to the survey (64.5 +/- 10.1 years, 88.1% of women). There are 78.5% of Internet users. Among them, 67.2% said searching information about their health and 74.5% said using the Internet for this purpose. All respondents attributed an average score, out of 10, of 5.7 +/- 2.3 regarding the reliability of information that they could find on the Internet. The use of the Internet differs significantly depending on age: those who use the Internet are younger (62.1 +/- 8.91 years) than those who do not use it (73.3 +/- 9.42 years). The socioeconomic status also has an impact on the Internet use: Internet users have a higher education, are more professionally active and have a higher net monthly household income compared to the group of non-users. Even if age and socioeconomic status appear to be determining factors in the use of the Internet for the search of health information in patients eligible for osteoporosis screening, almost 75% of the study population use the Internet for this purpose. Action to promote health through an Internet platform must therefore take these parameters into account. PMID- 25837845 TI - Pediatric reference values for tibial trabecular bone mineral density and bone geometry parameters using peripheral quantitative computed tomography. AB - The purpose of this study was to establish reference data, in relation to age and body height, for tibial trabecular and cortical volumetric bone mineral density, bone mineral content, and cross-sectional bone geometry in healthy children and adolescents using peripheral quantitative computed tomography (pQCT). Over a 2 year period, 432 (207 male and 225 female) healthy children, with an age range of 5 to 19 years, from 6 different geographic areas in Belgium were recruited. Multislice pQCT scanning (XCT2000((r)), Stratec Medizintechnik, Pforzheim, Germany) was performed at the distal metaphysis (at the 4% site) and the distal diaphysis (14 and 38% sites) of the tibia of the dominant leg. Gender-specific centile curves in relation to age and body height were generated with the LMS method for total and trabecular volumetric bone mineral density (at 4% site), bone mineral content, total bone cross-sectional area, periosteal circumference (all at 4, 14, and 38% site), cortical volumetric bone mineral density, endosteal circumference, and cortical thickness (at the 14 and the 38% site). These centile curves can be used for the interpretation of pQCT results at the 4, 14, and 38% site of the tibia in European children and adolescents, at least when a similar methodology is used. PMID- 25837846 TI - Clinical implication of perioperative inflammatory cytokine alteration. AB - Cytokines are key modulators of inflammatory responses, and play an important role in the defense and repair mechanisms following trauma. After traumatic injury, an immuno-inflammatory response is initiated immediately, and cytokines rapidly appear and function as a regulator of immunity. In pathologic conditions, imbalanced cytokines may provide systemic inflammatory responses or immunosuppression. Expression of perioperative cytokines vary by different intensities of surgical trauma and types of anesthesia and anesthetic agents. Inflammatory cytokines play important roles in postoperative organ dysfunction including central nervous system, cardiovascular, lung, liver, and kidney injury. Inhibition of cytokines could protect against traumatic injury in some circumstances, therefore cytokine inhibitors or antagonists might have the potential for reducing postoperative tissue/organ dysfunction. Cytokines are also involved in wound healing and post-traumatic pain. Application of cytokines for the improvement of surgical wound healing has been reported. Anesthesia-related immune response adjustment might reduce perioperative morbidity because it reduces proinflammatory cytokine expression; however, the overall effects of anesthetics on postoperative immune-inflammatory responses needs to be further investigated. PMID- 25837847 TI - Thymopoietin Beta and Gamma Isoforms as a Potential Diagnostic Molecular Marker for Breast Cancer: Preliminary Data. AB - Thymopoietin (TMPO) is an inner nuclear membrane protein, the coding gene named equally, can give arise to six isoforms by alternative splicing. This gene has been found up regulated in several types of cancer. At present work, we evaluated the TMPO isoforms generated by alternative splicing as well as the protein signal detection in breast cancer samples. TMPO expression was analyzed by immunohistochemistry in tissue microarray containing 46 breast tissue samples including normal (n = 6), benign lesions (n = 18) (fibroadenomas (n = 6), fibrocystic changes (n = 6), ductal hyperplasias (n = 6)) and breast carcinoma (n = 22). Isoforms -alpha, -beta and -gamma of TMPO were evaluated using RT-PCR; clinical-pathological correlation analysis were done by mean of X(2). Neither the normal nor the benign lesions of the breast showed positive TMPO immunodetection, whilst 45 % of the breast carcinomas were immunopositive (p = 0.000), nine of ten positives carcinomas correspond to the Luminal A subtype. Further, alpha isoform was present in all breast samples analyzed; however, beta and gamma isoforms were only present in ten (p = 0.003) and 17 (p = 0.000), respectively, in the breast cancer samples. According with the present data, we suggest that TMPObeta and gamma isoforms could provide a potential reliable diagnostic marker for breast cancer. PMID- 25837848 TI - Impact of prior azacitidine on the outcome of allogeneic hematopoietic transplantation for myelodysplastic syndrome. AB - To clarify the clinical impact of prior use of azacitidine (AZA) on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS), we retrospectively reviewed the clinical outcomes of 15 MDS patients who were treated with AZA before allo-HSCT (AZA group). We compared the outcomes of these 15 patients with 52 MDS patients who were solely given the best supportive care (BSC) before allo-HSCT (BSC group). Although patients in the AZA group were older with higher International Prognostic Scoring System (IPSS) scores compared to patients in the BSC group, no significant differences were found between the two groups in overall survival (OS), disease free survival (DFS), cumulative incidence of relapse (CIR) or non-relapse mortality. However, in patients with a higher IPSS score (Int-2/High), pre transplant AZA may provide better OS and DFS and lower CIR. Acute graft-versus host disease rates were similar between the two groups. These results should be reassuring to patients with high-risk MDS receiving AZA before allo-HSCT. PMID- 25837849 TI - Active transporters as enzymes: an energetic framework applied to major facilitator superfamily and ABC importer systems. AB - Active membrane transporters are dynamic molecular machines that catalyse transport across a membrane by coupling solute movement to a source of energy such as ATP or a secondary ion gradient. A central question for many active transporters concerns the mechanism by which transport is coupled to a source of energy. The transport process and associated energetic coupling involve conformational changes in the transporter. For efficient transport, the conformational changes must be tightly regulated and they must link energy use to movement of the substrate across the membrane. The present review discusses active transport using the well-established energetic framework for enzyme mediated catalysis. In particular, membrane transport systems can be viewed as ensembles consisting of low-energy and high-energy conformations. The transport process involves binding interactions that selectively stabilize the higher energy conformations, and in this way promote conformational changes in the system that are coupled to decreases in free energy and substrate translocation. The major facilitator superfamily of secondary active transporters is used to illustrate these ideas, which are then be expanded to primary active transport mediated by ABC (ATP-binding cassette) import systems, with a focus on the well studied maltose transporter. PMID- 25837850 TI - Metallophosphoesterases: structural fidelity with functional promiscuity. AB - Calcineurin-like metallophosphoesterases (MPEs) form a large superfamily of binuclear metal-ion-centre-containing enzymes that hydrolyse phosphomono-, phosphodi- or phosphotri-esters in a metal-dependent manner. The MPE domain is found in Mre11/SbcD DNA-repair enzymes, mammalian phosphoprotein phosphatases, acid sphingomyelinases, purple acid phosphatases, nucleotidases and bacterial cyclic nucleotide phosphodiesterases. Despite this functional diversity, MPEs show a remarkably similar structural fold and active-site architecture. In the present review, we summarize the available structural, biochemical and functional information on these proteins. We also describe how diversification and specialization of the core MPE fold in various MPEs is achieved by amino acid substitution in their active sites, metal ions and regulatory effects of accessory domains. Finally, we discuss emerging roles of these proteins as non catalytic protein-interaction scaffolds. Thus we view the MPE superfamily as a set of proteins with a highly conserved structural core that allows embellishment to result in dramatic and niche-specific diversification of function. PMID- 25837851 TI - Induction of hyaluronan production by oncogenic KSHV and the contribution to viral pathogenesis in AIDS patients. AB - Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), malignancies arising primarily in immunocompromised patients particularly AIDS-patients, which still lack effective therapy. Hyaluronan (HA) is a large glucuronic acid and has been found closely related to multiple functions in cancer cells, although its role in viral oncogenesis remains largely unknown. Here we provide first evidence that KSHV de novo infection induces HA production from primary endothelial cells through upregulation of HA synthase gene 1 (Has1) and a multifunctional glycoprotein, CD147. Further data demonstrate that KSHV-induced HA production requires viral latent protein, LANA (in particular functional domain A) and MAPK/ERK signaling activities. In functions, HA production is necessary for KSHV/LANA-induced primary endothelial cell invasion, a hallmark feature for KS development. For clinical relevance, our data indicate that the KSHV+ group has higher levels of HA and Has1 activities in its plasma than the KSHV- group of cohort HIV-infected patients. Together, our findings provide innovative insights into the mechanisms of oncogenic virus activation of HA production and its role in virus-associated malignancy pathogenesis, which may help to develop novel therapeutic strategies by targeting HA and related signaling. PMID- 25837852 TI - A non-human primate model for investigating drug-induced risk of orthostatic hypotension and sympathetic dysfunction: Preclinical correlate to a clinical test. AB - INTRODUCTION: Drug induced orthostatic hypotension (OH) is an important clinical concern and can be an unexpected hurdle during drug development. OH is defined as an abnormal decrease in blood pressure (BP) triggered by a rapid postural change. The sympathetic nervous system is critical for controlling normal cardiovascular function and compensatory responses to changes in posture. Thus, OH can also serve as a surrogate indicator of sympathetic dysfunction. However, preclinical conscious models for investigating risk of OH and/or sympathetic dysfunction are lacking. Herein, we describe a conscious nonhuman primate (NHP) model which mimics the widely used clinical tilt table test for OH. METHODS: Male, Cynomolgus NHPs (n = 7-8) implanted with radio-telemetry transmitters were placed in modified tilt chairs in a supine position. Subsequently, a 90 degrees head up tilt was performed for 3 min followed by return to the supine position. BP and heart rate were continuously monitored. Test compounds were administered either intravenously or via oral gavage in a crossover design, with blood samples collected at the end of the each tilt to assess total drug concentrations. RESULTS: Tilt responses were assessed following treatment with positive control compounds that cause sympathetic dysfunction; hexamethonium (ganglionic blocker) and prazosin (alpha-1 adrenergic receptor antagonist). Both compounds induced marked OH as evidenced by robust and sustained BP reduction in response to a head up tilt (decrease of 25-35 mmHg for hexamethonium, decrease of 21-44 mmHg for prazosin). OH incidence rates increased in a dose-dependent manner. OH incidences following treatment with minoxidil (vasodilator) were markedly lower to those observed with hexamethonium and prazosin indicating the role of sympathetic dysfunction in causing OH. DISCUSSION: These data demonstrate that the NHP tilt test is a valuable model for investigating OH risk. This model fills an important preclinical gap for assessing such a safety concern and can be applied to programs where a sympathetic deficit and/or OH are anticipated or clinically observed. PMID- 25837853 TI - Assessment of the Effect of Methotrexate Therapy on Bone Metabolism in Patients with Rheumatoid Arthritis. AB - Proinflammatory cytokines and growth factors, which regulate mutual interactions between immune system cells and bone tissue cells, play a major role in the formation of bone changes in rheumatoid arthritis (RA). The aim of the work was to assess serum concentration of osteoprotegerin (OPG), RANKL, Dkk-1 and sclerostin in RA patients compared to a control group and to analyze changes of these concentrations during methotrexate (MTX) therapy. Patients enrolled in the study were 30 women of Caucasian origin aged 30-74 years with RA. Patients with active form of the disease were administered recommended doses of MTX for at least 6 months. The study group was divided into subgroup I-patients with improvement; and subgroup II-patients with no improvement. The control group consisted of 12 healthy women in the age of 41-73. Before MTX therapy, RA patients had higher levels of RANKL (644.97 +/- 477.13 vs. 255.19 +/- 130.26 pmol/l), lower values of OPG/RANKL (0.01 +/- 0.0101 vs. 0.02 +/- 0.0078) and higher levels of Dkk-1 protein (1821.32 +/- 1060.28 vs. 548.52 +/- 36.35 pg/ml) compared to the control group. In the analyzed group of patients (all patients receiving MTX regardless of responder non responder status) after 6 months of therapy, a statistically significant increase in the ratio of OPG/RANKL was found (0.0118 +/- 0.0102 vs. 0.0141 +/- 0.0118; p = 0.02). The index value of OPG/RANKL differed significantly depending on the resultant effect of treatment (0.01702 +/ 0.01274 in the subgroup of improvement vs. 0.00675 +/- 0.00289 in the subgroup without improvement). The difference in the mean concentrations of Dkk-1 before and after treatment with MTX between subgroups I and II was statistically significant (p = 0.002). In subgroup I, mean concentration of Dkk-1 decreased after 6 months of treatment with MTX (2054.72 +/- 1004.74 vs. 1831.70 +/- 851.70 pg/ml); while in subgroup II, the mean concentration of Dkk-1 increased (1214.48 +/- 738.32 vs. 2275.01 +/- 1385.23 pg/ml). There were no statistically significant changes in the mean concentrations of sclerostin before and after treatment with MTX (in whole group treatment with MTX, in subgroup I, and in subgroup II). The results confirm the presence of disorders of bone metabolism in patients with RA. Treatment with MTX affects the value of the ratio of OPG/RANKL and concentration of Dkk-1. PMID- 25837854 TI - Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria. AB - Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD. PMID- 25837855 TI - Evidence for catalytic intermediates involved in generating the chromopyrrolic acid scaffold of rebeccamycin by RebO and RebD. AB - We provide the first experimental evidence for intermediates being involved in catalysis by RebD in generating the chromopyrrolic acid (CPA) scaffold of rebeccamycin. In the presence of its substrates (indole pyruvate imine - IPAI - and H2O2 both produced by the flavoprotein oxidase RebO that oxidizes tryptophan), RebD reacts as a peroxidase forming two IPAI radicals that recombine as a C-C bond in the CPA. When catalase is included to remove H2O2, CPA can still be formed because the IPAI rapidly reduces RebD, which reacts with O2, utilizing oxidase-peroxidase chemistry to produce CPA. Reduced RebD can also react with H2O2 forming Cpd II directly, which can oxidize IPAI. Stopped-flow spectrophotometric studies demonstrated that during the reaction of RebO and RebD with Trp and oxygen, a species with a red-shifted Soret band at 424.5 nm appeared. This species can react with either guaiacol or ABTS to form ferric RebD, suggesting that it is Cpd II of RebD involved in the formation of CPA. In summary, the studies reveal new and unusual aspects peroxidase and peroxygenase chemistry used by RebD in catalyzing carbon-carbon oxidative coupling reactions that are involved in biosynthesis of indolocarbazoles. PMID- 25837857 TI - Predictive molecular biomarkers to guide clinical decision making in kidney cancer: current progress and future challenges. AB - Although the past decade has seen a surfeit of new targeted therapies for renal cell carcinoma (RCC), no predictive molecular biomarker is currently used in routine clinical practice to guide personalized therapy as a companion diagnostic. Many putative biomarkers have been suggested, but none have undergone rigorous validation. There have been considerable advances in the biological understanding of RCC in recent years, with the development of accompanying molecular diagnostics that with additional validation, may be helpful for routine clinical decision making. In this review, we summarize the current understanding of predictive biomarkers in RCC management and also highlight upcoming developments of interest in biomarker research for personalizing RCC diagnostics and therapeutics. PMID- 25837858 TI - Visible-light-promoted conversion of alkyl benzyl ether to alkyl ester or alcohol via O-alpha-sp(3) C-H cleavage. AB - A mild and high-yielding visible-light-promoted conversion of alkyl benzyl ethers to the alkyl esters or alkyl alcohols was developed. Mechanistic studies provided evidence for a radical chain reaction involving the homolytic cleavage of O-alpha sp(3) C-H bonds in the substrate as one of the propagation steps. We propose that alpha-bromoethers are key intermediates in the transformation. PMID- 25837856 TI - Purine biosynthetic enzyme ATase2 is involved in the regulation of early chloroplast development and chloroplast gene expression in Arabidopsis. AB - To investigate the molecular mechanism of chloroplast biogenesis and development, we characterized an Arabidopsis mutant (dg169, delayed greening 169) which showed growth retardation and delayed greening phenotype in leaves. Newly emerged chlorotic leaves recovered gradually with leaf development in the mutant, and the mature leaves showed similar phenotype to those of wild-typewild-type plants. Compared with wild-type, the chloroplasts were oval-shaped and smaller and the thylakoid membranes were less abundant in yellow section of young leaves of dg169. In addition, the functions of photosystem II (PSII) and photosystem I (PSI) were also impaired. Furthermore, the amount of core subunits of PSII and PSI, as well as PSII and PSI complexes reduced in yellow section of young leaves of dg169. Map-based positional cloning identified that phenotype of dg169 was attributed to a point mutation of ATase2 which converts the conserved Ile-155 residue to Asn. ATase2 catalyzes the first step of de novo purine biosynthesis. This mutation resulted in impaired purine synthesis and a significant decrease in ATP, ADP, GTP and GDP contents. The analysis of ATase2-GFP protein fusion showed that ATase2 was localized to nucleoid of chloroplasts. Our results further demonstrated that the levels of PEP-dependent transcripts in yellow section of young leaves of dg169 were decreased while NEP-dependent and both PEP- and NEP dependent transcripts and chloroplast DNA replications were increased. The results in this study suggest that ATase2 plays an essential role in early chloroplast development through maintaining PEP function. PMID- 25837861 TI - Low-fat diet and exercise are more important. PMID- 25837859 TI - Total ankle replacement. AB - BACKGROUND: About 1% of adults suffer from painful osteoarthritis of the ankle. The current literature contains no information on the percentage of such patients who derive long-term relief of symptoms from conservative treatment. Advanced ankle osteoarthritis can be treated with non-joint-preserving measures, such as total ankle replacement and ankle fusion. METHODS: This review is based on selected relevant publications, guidelines from Germany and abroad, and the authors' personal experience. RESULTS: Before surgery is considered, conservative measures such as physiotherapy and orthopedic aids should be used to the fullest possible extent. No randomized trials have yet been published comparing total ankle replacement with ankle fusion. Total ankle replacement with newer types of prosthesis yields good to very good intermediate-term and long-term results, with mean success rates of up to 90% at 10 years (range, 68-100%). Independent risk factors for the failure of ankle replacement are age over 70 years (odds ratio [OR] 3.84), primary osteoarthritis (OR 7.19), post-traumatic osteoarthritis (OR 6.2), and type of prosthesis (e.g., single hydroxyapatite coating: OR 15.04). The average range of motion of the replaced ankle joint is 25 degrees to 30 degrees , with values as high as 60 degrees . CONCLUSION: Total ankle replacement is a good treatment option for complete, end-stage ankle arthritis. It can restore joint function and make the patient mobile with little or no pain. There are, however, many contraindications to be taken into account. There is a need for further studies of the biomechanics of arthritic and replaced ankle joints and for long-term follow-up studies of total ankle replacement. PMID- 25837860 TI - Prevalence trends in lifestyle-related risk factors. AB - BACKGROUND: The regional prevalence of risk factors can vary over time. The Study of Health in Pomerania (SHIP) addresses prevalence trends for common risk factors in a region in northeast Germany. METHODS: A longitudinal study was carried out from 1997 to 2001 (SHIP-0, with 4308 subjects), and a second, independent random sample of the population in the same region was studied from 2008 to 2012 (SHIP Trend, with 4420 subjects). All data were standardized with post-stratification weighting derived from the adult population of the state of Mecklenburg-West Pomerania. RESULTS: SHIP reveals a marked decline of mean alcohol consumption in the adult population, from 5.57 g/day (95% confidence interval, 5.51-5.63) to 3.12 g/day (95% CI 3.09-3.15). The percentage of active smokers among men declined from 38.6% (95% CI 36.0-41.2) to 34.3% (95% CI 32.1-36.6). Simultaneously, however, there was a rightward shift of the BMI distribution, with a marked increase in the prevalence of obesity, from 24.7% to 32.0%. There was a corresponding increase in the prevalence of diabetes, from 9.1% to 13.8%. Compared to eleven years ago, the amount of exercise taken during free time has risen among the elderly, but fallen among young women. CONCLUSION: Tobacco and alcohol consumption have declined over the past decade, although this study may have overestimated these trends through a combination of selection bias and reporting bias. Meanwhile, the northeast German population now has a worse metabolic risk profile, as indicated by the increased prevalence of obesity and diabetes. Society as a whole must take measures to combat this trend. PMID- 25837862 TI - Low-fat diet and exercise are more important. In reply. PMID- 25837863 TI - Further specification required. PMID- 25837864 TI - Further specification required. In reply. PMID- 25837865 TI - Undercounting of large trucks in federal and state crash databases: Extent of problem and how to improve accuracy of truck classifications. AB - OBJECTIVE: Prior research suggested that single-unit trucks are undercounted when using vehicle body codes in the Fatality Analysis Reporting System (FARS). This study explored the extent of the misclassification and undercounting problem for crashes in FARS and state crash databases. METHODS: Truck misclassifications for fatal crashes were explored by comparing the Trucks Involved in Fatal Accidents (TIFA) database with FARS. TIFA used vehicle identification numbers (VINs) and survey information to classify large trucks. This study used VINs to improve the accuracy of large truck classifications in state crash databases from 5 states (Delaware, Maryland, Minnesota, Nebraska, and Utah). RESULTS: The vehicle body type codes resulted in a 19% undercount of single-unit trucks in FARS and a 23% undercount of single-unit trucks in state databases. Tractor-trailers were misclassified less often. Misclassifications occurred most frequently among single-unit trucks in the weight classes of 10,001-14,000 pounds. CONCLUSIONS: The amount of misclassification of large trucks is large enough to potentially affect federal and state decisions on traffic safety. Using information from VINs results in more complete and accurate counts of large trucks involved in crashes. The National Transportation Safety Board recommended actions to improve federal and state crash data. PMID- 25837866 TI - Burn injury associated with home oxygen use in patients with chronic obstructive pulmonary disease. AB - OBJECTIVES: To quantify the risk of burn injury associated with home oxygen use and to examine the risk factors associated with the development of this injury. PATIENTS AND METHODS: We used a nested case-control and a retrospective cohort design to study enrollment and claims data from a national sample of Medicare beneficiaries 66 years and older with a diagnosis of chronic obstructive pulmonary disease (COPD) from January 1, 2001, through December 31, 2010. The primary outcome was burn injury in patients with COPD prescribed home oxygen. RESULTS: In the nested case-control method, patients with burn injury were twice (odds ratio, 2.43; 95% CI, 1.57-3.78) as likely to be prescribed oxygen in the preceding 90 days compared with those without burn injury. In the retrospective cohort study, the absolute risk of burn injury in patients prescribed oxygen therapy was 2.98 per 1000 patients compared with 1.69 per 1000 patients not prescribed oxygen during a 22-month period. The excess risk of a burn injury associated with oxygen was 0.704 per 1000 patients per year, and the number needed to harm was 1421. In multivariable analysis, factors associated with burn injury included male sex, low socioeconomic status, oxygen therapy use, and the presence of 3 or more comorbidities. CONCLUSION: The benefits of oxygen therapy in patients with COPD outweigh the modest risk of burn injury associated with home oxygen use. However, with the increasing number of patients being prescribed oxygen, health care professionals must educate and counsel patients regarding the potential risk of burn injury. PMID- 25837868 TI - The p53 network as therapeutic target in gastroenteropancreatic neuroendocrine neoplasms. AB - Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous and especially the midgut tumors currently lack effective therapy options. Actionable driver mutations as therapeutic targets are rare. Subtype specific data concerning regulatory mechanisms or epigenetic aberrations are necessary for novel clinical trials. Although the p53 protein itself is rarely mutated in GEP NENs, epigenetic and regulatory aberrations interfere with the p53 network activity and might function as s target for novel therapeutic approaches. In this review we analyze the current knowledge about the p53 network in GEP-NENs and discuss three possible strategies that include recovering p53 function, enforcing apoptosis by genotoxic stress induction and restoring silenced gene function, based on in vitro, in vivo and clinical data. PMID- 25837867 TI - Processing deficits for familiar and novel faces in patients with left posterior fusiform lesions. AB - Pure alexia (PA) arises from damage to the left posterior fusiform gyrus (pFG) and the striking reading disorder that defines this condition has meant that such patients are often cited as evidence for the specialisation of this region to processing of written words. There is, however, an alternative view that suggests this region is devoted to processing of high acuity foveal input, which is particularly salient for complex visual stimuli like letter strings. Previous reports have highlighted disrupted processing of non-linguistic visual stimuli after damage to the left pFG, both for familiar and unfamiliar objects and also for novel faces. This study explored the nature of face processing deficits in patients with left pFG damage. Identification of famous faces was found to be compromised in both expressive and receptive tasks. Discrimination of novel faces was also impaired, particularly for those that varied in terms of second-order spacing information, and this deficit was most apparent for the patients with the more severe reading deficits. Interestingly, discrimination of faces that varied in terms of feature identity was considerably better in these patients and it was performance in this condition that was related to the size of the length effects shown in reading. This finding complements functional imaging studies showing left pFG activation for faces varying only in spacing and frontal activation for faces varying only on features. These results suggest that the sequential part based processing strategy that promotes the length effect in the reading of these patients also allows them to discriminate between faces on the basis of feature identity, but processing of second-order configural information is most compromised due to their left pFG lesion. This study supports a view in which the left pFG is specialised for processing of high acuity foveal visual information that supports processing of both words and faces. PMID- 25837869 TI - Ultrasound-Enhanced Subcritical CO2 Extraction of Lutein from Chlorella pyrenoidosa. AB - Lutein is an important pigment of Chlorella pyrenoidosa with many beneficial functions in human health. The main purpose of this study was to extract lutein from C. pyrenoidosa using ultrasound-enhanced subcritical CO2 extraction (USCCE). Effects of operating conditions on the extraction, including extraction pretreatment, temperature, pressure, time, CO2 flow rate, and ultrasonic power, were investigated, and an orthogonal experiment was designed to study the effects of extraction pressure, temperature, cosolvent amount, and time on the extraction yields. The USCCE method was compared with other extraction methods in terms of the yields of lutein and the microstructure of C. pyrenoidosa powder by scanning electron microscopy. A maximal extraction yield of 124.01 mg lutein/100 g crude material was achieved under optimal conditions of extraction temperature at 27 degrees C, extraction pressure at 21 MPa, cosolvent amount at 1.5 mL/g ethanol, and ultrasound power at 1000 W. Compared to other methods, USCCE could significantly increase the lutein extraction yield at lower extraction temperature and pressure. Furthermore, the kinetic models of USCCE and subcritical CO2 extraction (SCCE) of lutein from C. pyrenoidosa were set as E = 130.64 * (1 - e(-0.6599t)) and E = 101.82 * (1 - e(-0.5683t)), respectively. The differences of parameters in the kinetic models indicate that ultrasound was able to enhance the extraction process of SCCE. PMID- 25837870 TI - Structures of human DNA polymerases nu and theta expose their end game. AB - Although the two B-family human DNA polymerases, pol delta and pol epsilon, are responsible for the bulk of nuclear genome replication, at least 14 additional polymerases have roles in nuclear DNA repair and replication. In this issue, newly reported crystal structures of two specialized A-family polymerases, pol delta and pol epsilon, expose these enzymes' strategies for handling aberrant DNA ends. PMID- 25837871 TI - Methylation gets into rhythm with NAD(+)-SIRT1. AB - Circadian regulation of epigenetic chromatin marks drives daily transcriptional oscillation of thousands of genes and is intimately linked to cellular metabolism and bioenergetics. New work links circadian fluctuations in the activity of the SIRT1 deacetylase, a sensor of the cellular energy state, to histone-methylation changes and the circadian expression of clock-controlled genes. PMID- 25837872 TI - How to open a proton pore-more than S4? AB - Pioneering studies in voltage-gated potassium channels have described movement of the voltage-sensing domain (VSD) S4 helix across the membrane electric field in molecular detail, but much less is known regarding opening of the intrinsic proton pore within VSDs of voltage-dependent proton channels. By systematically probing local kinematics, a new study reveals that movements in helix S1 correlate with pore opening and are distinct from voltage-sensing movements of the charged S4 segment. PMID- 25837873 TI - Micro-terminator: 'Hasta la vista, lncRNA!'. AB - Transcriptional termination is an important yet incompletely understood aspect of gene expression. Proudfoot, Jopling and colleagues now identify a new Microprocessor-mediated mechanism of transcriptional termination, which acts specifically on long noncoding transcripts that serve as microRNA precursors. PMID- 25837877 TI - In vivo evaluation of an implantable magnetic suspending left ventricular assist device. AB - PURPOSE: The CH-VAD is an implantable, fully magnetically suspended ventricular assist device developed by the China Heart Biomedical Corporation (Suzhou, China) for full cardiac support. This study was performed to evaluate the reliability, hemocompatibility and end-organ effects of CH-VAD in a 35-day animal model trial. METHODS: The pump was implanted in 6 sheep. The pump inflow was inserted into the left ventricle and the outflow graft was anastomosed to the descending aorta. Data on pump function and the health condition of the animals, including hematologic and biochemical tests, were collected during the study period. When each study was determined to termination, the sheep were humanely euthanized and the end organs were examined macroscopically and histopathologically. Hemolysis was evaluated based on the amount of free hemoglobin in the plasma. RESULTS: Except for one device that stopped operation on postoperative day 25 because of thrombus formation, the devices functioned normally until the scheduled termination. Gross examination of the pump interiors, inflow and outflow, and of the arterial anastomosis sites showed no significant abnormalities. Hematologic and biochemical test results were within normal limits during the study period. Macroscopic and histopathologic examinations of the explanted organs revealed no evidence of ischemia or infarction associated with the device implantation, except for small foci of infarction in the kidneys of two sheep. The free hemoglobin level in plasma peaked at 9.5 mg/dl on postoperative day 5. CONCLUSIONS: The CH-VAD system demonstrated promising reliability and blood handling characteristics without obvious damage to end organs during a 35-day implantation in sheep. PMID- 25837878 TI - Design and evaluation of an intelligent artificial anal sphincter system powered by an adaptive transcutaneous energy transfer system. AB - OBJECTIVES: The aim of this study was to optimize an intelligent artificial anal sphincter system (AASS) II for patients with severe fecal incontinence. METHODS: Redesigning and integrating a pressure sensor into the sphincter prosthesis allows us to reduce the sensor volume and makes it suitable for a chronic, ambulatory application. Furthermore, a close-loop frequency control method was designed for the transcutaneous energy transfer system. Finally, a longer working time of the implanted device was obtained by the low-power design of the hardware and software. The new model was implanted in 2 dogs and studied for periods of up to 5 weeks. RESULTS: The output voltage induced on the load of 30 Omega, for a variation range in k of 0.12 ~ 0.42, was maintained at approximately 6.8 V with a frequency control range of the 270 ~ 320 kHz. The minimum and maximum output voltages of the pressure sensor were found to be 1.7 V and 2.34 V, respectively, which corresponded to a pressure range of 90 ~ 120 kPa with maximum change rate of approximately 3.7% caused by the temperature variations. Moreover, compared with AASS I, the low-power design resulting in 94% reduction in power consumption. CONCLUSIONS: The efficacy of the device in achieving continence and sensing the need to defecate was assessed in an animal model. The technical concept and the design of the AASS II turned out to be capable of fulfilling the medical requirements. PMID- 25837879 TI - Effectiveness of different irrigation procedures for removal of dentin debris from a simulated internal resorption cavity. AB - PURPOSE: The aim of this study was to compare the efficiency of different final irrigation techniques to remove artificially placed dentinal debris from a simulated internal root resorption (IRR) cavity. METHODS: Seventy teeth were prepared using the ProTaper system. The roots were then split longitudinally into two halves, in each of which standardized IRR cavities were prepared. Five teeth were set aside to serve as negative control group. Each cavity of the remaining 65 teeth was filled with dentin debris mixed with 2.5% NaOCl. Another 5 teeth (positive control) were not subjected to the debris removal procedure. Sixty teeth were randomly divided into four experimental groups (n = 15), according to the final irrigation technique used: conventional syringe irrigation (CSI), the Self-Adjusting File (SAF), passive ultrasonic irrigation (PUI), and the EndoActivator (EA). Ten milliliters of 2.5% NaOCl was used during the debris removal procedure. The root halves were disassembled, and the amount of remaining debris was evaluated under a stereomicroscope at 30* magnification. RESULTS: SAF and PUI removed debris significantly better than CSI and EA (P<.05). CSI was the least effective in debris removal (p<0.05). CONCLUSIONS: None of the irrigation techniques used was able to completely remove debris from simulated IRR cavities. PMID- 25837880 TI - Extracorporeal membrane oxygenation after liver transplantation in a patient with hepatopulmonary syndrome and an atrial septal defect. AB - INTRODUCTION: Hepatopulmonary syndrome (HPS) is a rare complication of liver cirrhosis that may result in refractory hypoxemia even after liver transplantation. ECMO has been rarely used after liver transplantation or in patients with HPS. METHODS: We present a patient with HPS who underwent liver transplantation and developed refractory hypoxemia requiring postoperative ECMO support at our institution. During our review of literature we found nine reports of ECMO use for cardiorespiratory failure after liver transplant in the past. RESULTS: Our patient had persistent intrapulmonary shunting and developed severe respiratory failure after liver transplant. Additionally, the patient was found to have an atrial septal defect (ASD) and required percutaneous closure while receiving ECMO support. Literature review suggests that survival among these patients who were supported with ECMO after liver transplant was 50% and catastrophic bleeding complications were described in only one report. CONCLUSIONS: With careful selection of post-liver transplant patients and judicious management of anticoagulation, ECMO can be safely instituted in this cohort. PMID- 25837881 TI - Akt signaling is associated with the berberine-induced apoptosis of human gastric cancer cells. AB - Despite extensive studies on the antitumor properties of berberine, a small molecule derived from Coptidis rhizoma (Huanglian in Chinese) and many other plants, the underlying mechanism remains poorly understood. Here, we found that berberine-induced cell apoptosis in human gastric cancer cells with the increase of the expression level of cleaved poly ADP-ribose polymerase and caspase-3, and the impairment of mitochondrial membrane potential (Deltapsim) in berberine treated gastric cancer cells. In our further studies, the results demonstrated that Akt-related mitochondrial pathway may partly involve in the berberine induced apoptosis in human gastric cancer cells. Moreover, berberine inhibited the Akt/mTOR/p70S6/S6 pathway in berberine-treated BGC-823 cells. Meanwhile, berberine significantly inhibited the activation of Akt and suppressed tumor growth in xenograft nude mice injected with human gastric cancer cells. Thus, our findings reveal that the underlying mechanism that Akt signaling may contribute to berberine-induced cell apoptosis in gastric cancer cells and might represent an important molecular basis for berberine to act as an anticancer agent. PMID- 25837883 TI - High-flux graphene oxide nanofiltration membrane intercalated by carbon nanotubes. AB - A sort of novel high-flux nanofiltration membrane was fabricated by synergistic assembling of graphene and multiwalled carbon nanotubes (MWNTs), in which graphene played the role of molecular sieving and MWNTs expanded the interlayer space between neighbored graphene sheets. The MWNT-intercalated graphene nanofiltration membrane (G-CNTm) showed a water flux up to 11.3 L m(-2) h(-1) bar(-1), more than 2 times that of the neat graphene nanofiltration membrane (GNm), while keeping high dye rejection (>99% for Direct Yellow and >96% Methyl Orange). The G-CNTm also showed good rejection ratio for salt ions (i.e., 83.5% for Na2SO4, 51.4% for NaCl). We also explored the antifouling performance of G CNTm and GNm with bovine serum albumin (BSA), sodium alginate (SA) and humic acid (HA). Both G-CNTm and GNm possessed excellent antifouling performance for SA and HA but inferior for BSA because of the strong interaction between protein and graphene sheets. PMID- 25837882 TI - Combination chemotherapy with bevacizumab and S-1 for elderly patients with metastatic colorectal cancer (BASIC trial). AB - BACKGROUND: Chemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers. METHODS: We conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety. RESULTS: From October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9months, the median OS was 25.0months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%). CONCLUSION: Our results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC. PMID- 25837884 TI - Correction: Heteroplasmy in the mitochondrial genomes of human lice and ticks revealed by high throughput sequencing. AB - [This corrects the article DOI: 10.1371/journal.pone.0073329.]. PMID- 25837885 TI - Congenital neurocristic tumor presenting as an isolated calvarial defect in an infant: case report. AB - In infants, the presence of a cranial defect may be due to a variety of traumatic, inflammatory, neoplastic, and congenital abnormalities. Differentiation between these possible etiologies is facilitated by clinical presentation, patient history, and physical examination. Congenital cutaneous neural crest-derived lesions are unlikely to be considered in a patient presenting with an asymptomatic cranial defect without overlying mass or skin pigmentation. The authors present an unusual case of a 2-month-old infant with an asymptomatic calvarial defect with normal overlying skin. Pathology of the excised tissue showed features consistent with a congenital neurocristic tumor: a pigmented, neural crest-derived hamartomatous tumor that typically presents as a melanotic skin lesion. PMID- 25837886 TI - Encephaloduroarteriosynangiosis and encephalomyoarteriosynangiosis for treatment of moyamoya syndrome in pediatric patients with sickle cell disease. AB - OBJECT Pediatric patients with sickle cell disease (SCD) and moyamoya syndrome (MMS) are at significant risk for cerebrovascular accidents despite chronic transfusion therapy. Encephaloduroarteriosynangiosis (EDAS) and encephalomyoarteriosynangiosis (EMAS) are additional therapeutic options for these patients. To date, the incidence of complications after and efficacy of EDAS and EMAS in stroke prevention in this population have been described in several institutional case series reports, but no randomized prospective trials have been reported. METHODS The authors retrospectively reviewed the cases of all pediatric patients at the University of Alabama at Birmingham with a history of homozygous hemoglobin S (HbS) and sickle cell/beta-thalassemia (SB0 thalassemia) and on chronic transfusion therapy, including 14 patients with MMS who underwent EDAS or EMAS. RESULTS Sixty-two patients with SCD and on chronic transfusion therapy were identified. After exclusion of patients on chronic transfusion therapy for indications other than stroke prevention, 48 patients (77.4%) remained. Of those patients, 14 (29.1%) underwent EDAS or EMAS. Nine (18.8%) and 25 (52.1%) patients were on chronic transfusion therapy for primary or secondary stroke prevention, respectively, but did not undergo EDAS or EMAS. The 14 patients with SCD and radiological evidence of MMS and on chronic transfusion therapy for primary or secondary stroke prevention underwent 21 EDAS or EMAS procedures for progressive vascular disease (92.9% of patients), stroke (71.4%), and/or seizure (7.1%). The mean (+/- SD) time from initiation of chronic transfusion therapy to EDAS or EMAS was 76.8 +/- 58.8 months. Complications included 1 perioperative stroke, 1 symptomatic subdural hygroma, 1 postoperative seizure, and 1 case of intraoperative cerebral edema that required subsequent cranioplasty. Before EDAS or EMAS, the stroke rate was calculated to be 1 stroke per 7.8 patient-years. One additional stroke occurred during the follow-up period (mean follow-up time 33.7 +/- 19.6 months), resulting in a post-EDAS/EMAS stroke rate of 1 stroke per 39.3 patient-years, a 5-fold reduction compared with that in the pre-EDAS/EMAS period. The patients' mean pre-EDAS/EMAS HbS level of 29.5% +/- 6.4% was comparable to the mean post-EDAS/EMAS HbS level of 25.5% +/- 6.1% (p = 0.104). CONCLUSIONS The results of this retrospective case series in a large cohort of pediatric patients with SCD and MMS suggest that EDAS/EMAS provides a stroke-prevention benefit with an acceptably low morbidity rate. Given the combined experience with EDAS and EMAS for this indication at this and other institutions, a prospective clinical trial to assess their efficacy compared with that of chronic transfusion therapy alone is warranted. PMID- 25837887 TI - Ventriculoperitoneal shunt perforations of the gastrointestinal tract. AB - OBJECT The purposes of this study were to evaluate the frequency with which children presented with ventriculoperitoneal (VP) shunt perforations of the gastrointestinal (GI) tract, to determine the type of shunts that caused the perforations, and to compare the stiffness of perforating catheters with the stiffness of catheters from other manufacturers. METHODS Medical records were reviewed of 197 children who were admitted with VP shunt malfunction. Catheter stiffness was evaluated by measuring relative resistance to cross-sectional compression, resistance to column buckling, and elasticity in longitudinal bending. Catheter frictional force was measured per unit length. RESULTS Six children were identified whose VP shunts had perforated the GI tract; 2 shunts subsequently protruded through the anal orifice, 1 protruded through the oral cavity, and 3 presented with subcutaneous abscesses that tracked upward from the intestine to the chest. All perforating shunts were Chhabra shunts. Catheter stiffness and resistance to bending were greatest with a Medtronic shunt catheter, intermediate with a Codman catheter, and least with a Chhabra catheter. Frictional force was greatest with a Chhabra catheter and least with a Medtronic catheter. CONCLUSIONS The frequency of perforations by Chhabra shunts appears to be higher than the frequency associated with other shunts. The increased frequency does not correlate with their stiffness but may reflect their greater frictional forces. PMID- 25837888 TI - Syrinx location and size according to etiology: identification of Chiari associated syrinx. AB - OBJECT Syrinx size and location within the spinal cord may differ based on etiology or associated conditions of the brain and spine. These differences have not been clearly defined. METHODS All patients with a syrinx were identified from 14,118 patients undergoing brain or cervical spine imaging at a single institution over an 11-year interval. Syrinx width, length, and location in the spinal cord were recorded. Patients were grouped according to associated brain and spine conditions including Chiari malformation Type I (CM-I), secondary CM (2 degrees CM), Chiari malformation Type 0 (CM-0), tethered cord, other closed dysraphism, and spinal tumors. Syringes not associated with any known brain or spinal cord condition were considered idiopathic. Syrinx characteristics were compared between groups. RESULTS A total of 271 patients with a syrinx were identified. The most common associated condition was CM-I (occurring in 117 patients [43.2%]), followed by spinal dysraphism (20 [7.4%]), tumor (15 [5.5%]), and tethered cord (13 [4.8%]). Eighty-three patients (30.6%) did not have any associated condition of the brain or spinal cord and their syringes were considered idiopathic. Syringes in patients with CM-I were wide (7.8 +/- 3.9 mm) compared with idiopathic syringes (3.9 +/- 1.0, p < 0.0001) and those associated with tethered cord (4.2 +/- 0.9, p < 0.01). When considering CM-I-associated and idiopathic syringes, the authors found that CM-I-associated syringes were more likely to have their cranial extent in the cervical spine (88%), compared with idiopathic syringes (43%; p < 0.0001). The combination of syrinx width greater than 5 mm and cranial extent in the cervical spine had 99% specificity (95% CI 0.92-0.99) for CM-I-associated syrinx. CONCLUSIONS Syrinx morphology differs according to syrinx etiology. The combination of width greater than 5 mm and cranial extent in the cervical spine is highly specific for CM-I-associated syringes. This may have relevance when determining the clinical significance of syringes in patients with low cerebellar tonsil position. PMID- 25837889 TI - Sleep-disordered breathing in patients with myelomeningocele. AB - OBJECT A paucity of literature examines sleep apnea in patients with myelomeningocele, Chiari malformation Type II (CM-II), and related hydrocephalus. Even less is known about the effect of hydrocephalus treatment or CM-II decompression on sleep hygiene. This study is an exploratory analysis of sleep disordered breathing in patients with myelomeningocele and the effects of neurosurgical treatments, in particular CM-II decompression and hydrocephalus management, on sleep organization. METHODS The authors performed a retrospective review of all patients seen in their multidisciplinary spina bifida clinic (approximately 435 patients with myelomeningocele) to evaluate polysomnographs obtained between March 1999 and July 2013. They analyzed symptoms prompting evaluation, results, and recommended interventions by using descriptive statistics. They also conducted a subset analysis of 9 children who had undergone polysomnography both before and after neurosurgical intervention. RESULTS Fifty two patients had polysomnographs available for review. Sleep apnea was diagnosed in 81% of these patients. The most common presenting symptom was "breathing difficulties" (18 cases [43%]). Mild sleep apnea was present in 26 cases (50%), moderate in 10 (19%), and severe in 6 (12%). Among the 42 patients with abnormal sleep architecture, 30 had predominantly obstructive apneas and 12 had predominantly central apneas. The most common pulmonology-recommended intervention was adjustment of peripheral oxygen supplementation (24 cases [57%]), followed by initiation of peripheral oxygen (10 cases [24%]). In a subset analysis of 9 patients who had sleep studies before and after neurosurgical intervention, there was a trend toward a decrease in the mean number of respiratory events (from 34.8 to 15.9, p = 0.098), obstructive events (from 14.7 to 13.9, p = 0.85), and central events (from 20.1 to 2.25, p = 0.15) and in the apnea-hypopnea index (from 5.05 to 2.03, p = 0.038, not significant when corrected for multiple measures). CONCLUSIONS A large proportion of patients with myelomeningocele who had undergone polysomnography showed evidence of disordered sleep on an initial study. Furthermore, 31% of patients had moderate or severe obstructive sleep apnea. Myelomeningocele patients with an abnormal sleep structure who had undergone nonoperative treatment with peripheral oxygen supplementation showed improvement in the apnea-hypopnea index. Results in this study suggested that polysomnography in patients with myelomeningocele may present an opportunity to detect and classify sleep apnea, identify low-risk interventions, and prevent future implications of sleep-disordered breathing. PMID- 25837890 TI - Down syndrome and moyamoya: clinical presentation and surgical management. AB - OBJECT Moyamoya can cause cerebral ischemia and stroke in Down syndrome (DS) patients. In this study, the authors defined a surgically treated population of patients with DS and moyamoya and compared their clinical presentation, response to surgical treatment, and long-term prognosis with those of the general population of patients with moyamoya but without DS. METHODS This study was a retrospective review of a consecutive operative series of moyamoya patients with DS treated at Boston Children's Hospital from 1985 through 2012. RESULTS Thirty two patients, average age 9.7 years (range 1.8-29.3 years), underwent surgery for moyamoya in association with DS. The majority presented with ischemic symptoms (87% stroke, 42% transient ischemic attacks). Twenty-four patients (75%) had congenital heart disease. Nineteen patients (59%) had bilateral moyamoya on presentation, and 13 presented with unilateral disease, of which 2 progressed to surgery on the opposite side at a later date. Patients were followed for a median of 7.5 years (1-20.2 years) after surgery, with no patients lost to follow-up. Follow-up arteriography demonstrated Matsushima Grade A collaterals in 29 of 39 (74%) hemispheres, Grade B in 5 (13%), and Grade C in 5 (13%). Complications included postoperative strokes in 2 patients, which occurred within 48 hours of surgery in both; one of these patients had arm weakness and the other confusion (both had recovered completely at follow-up). Seizures occurred in 5 patients perioperatively, including one who had a new seizure disorder related to hypocalcemia. CONCLUSIONS Moyamoya disease is a cause of stroke in patients with DS. Both the incidence of preoperative stroke (87% vs 67%) and the average age at diagnosis for children under age 21 (8.4 vs 6.5 years) were greater in patients with DS and moyamoya than in the general moyamoya surgical population, suggesting a possible delay in reaching a correct diagnosis of the cause of cerebral ischemia in the DS patient population. Pial synangiosis provided long-term protection from stroke in all patients treated. PMID- 25837891 TI - Ag@SiO2-entrapped hydrogel microarray: a new platform for a metal-enhanced fluorescence-based protein assay. AB - We developed a novel protein-based bioassay platform utilizing metal-enhanced fluorescence (MEF), which is a hydrogel microarray entrapping silica-coated silver nanoparticles (Ag@SiO2). As a model system, different concentrations of glucose were detected using a fluorescence method by sequential bienzymatic reaction of hydrogel-entrapped glucose oxidase (GOX) and peroxidase (POD) inside a hydrogel microarray. Microarrays based on poly(ethylene glycol)(PEG) hydrogels were prepared by photopatterning a solution containing PEG diacrylate (PEG-DA), photoinitiator, enzymes, and Ag@SiO2. The resulting hydrogel microarrays were able to entrap both enzymes and Ag@SiO2 without leaching and deactivation problems. The presence of Ag@SiO2 within the hydrogel microarray enhanced the fluorescence signal, and the extent of the enhancement was dependent on the thickness of silica shells and the amount of Ag@SiO2. Optimal MEF effects were achieved when the thickness of the silica shell was 17.5 nm, and 0.5 mg mL(-1) of Ag@SiO2 was incorporated into the assay systems. Compared with the standard hydrogel microarray-based assay performed without Ag@SiO2, more than a 4-fold fluorescence enhancement was observed in a glucose concentration range between 10(-3) mM and 10.0 mM using hydrogel microarray entrapping Ag@SiO2, which led to significant improvements in the sensitivity and the limit of detection (LOD). The hydrogel microarray system presented in this study could be successfully combined with a microfluidic device as an initial step to create an MEF-based micro-total analysis-system (MU-TAS). PMID- 25837892 TI - A 'simple anterior fish excluder' (SAFE) for mitigating penaeid-trawl bycatch. AB - Various plastic strips and sheets (termed 'simple anterior fish excluders'-SAFEs) were positioned across the openings of penaeid trawls in attempts at reducing the unwanted bycatches of small teleosts. Initially, three SAFEs (a single wire without, and with small and large plastic panels) were compared against a control (no SAFE) on paired beam trawls. All SAFEs maintained targeted Metapenaeus macleayi catches, while the largest plastic SAFE significantly reduced total bycatch by 51% and the numbers of Pomatomus saltatrix, Mugil cephalus and Herklotsichthys castelnaui by up to 58%. A redesigned SAFE ('continuous plastic') was subsequently tested (against a control) on paired otter trawls, significantly reducing total bycatch by 28% and P. saltatrix and H. castelnaui by up to 42%. The continuous-plastic SAFE also significantly reduced M. macleayi catches by ~7%, but this was explained by ~5% less wing-end spread, and could be simply negated through otter-board refinement. Further work is required to refine the tested SAFEs, and to quantify species-specific escape mechanisms. Nevertheless, the SAFE concept might represent an effective approach for improving penaeid trawl selectivity. PMID- 25837896 TI - Neuro-oncology for the masses. PMID- 25837893 TI - Variation in susceptibility to Wheat dwarf virus among wild and domesticated wheat. AB - We investigated the variation in plant response in host-pathogen interactions between wild (Aegilops spp., Triticum spp.) and domesticated wheat (Triticum spp.) and Wheat dwarf virus (WDV). The distribution of WDV and its wild host species overlaps in Western Asia in the Fertile Crescent, suggesting a coevolutionary relationship. Bread wheat originates from a natural hybridization between wild emmer wheat (carrying the A and B genomes) and the wild D genome donor Aegilops tauschii, followed by polyploidization and domestication. We studied whether the strong selection during these evolutionary processes, leading to genetic bottlenecks, may have resulted in a loss of resistance in domesticated wheat. In addition, we investigated whether putative fluctuations in intensity of selection imposed on the host-pathogen interactions have resulted in a variation in susceptibility to WDV. To test our hypotheses we evaluated eighteen wild and domesticated wheat taxa, directly or indirectly involved in wheat evolution, for traits associated with WDV disease such as leaf chlorosis, different growth traits and WDV content. The plants were exposed to viruliferous leafhoppers (Psammotettix alienus) in a greenhouse trial and evaluated at two time points. We found three different plant response patterns: i) continuous reduction in growth over time, ii) weak response at an early stage of plant development but a much stronger response at a later stage, and iii) remission of symptoms over time. Variation in susceptibility may be explained by differences in the intensity of natural selection, shaping the coevolutionary interaction between WDV and the wild relatives. However, genetic bottlenecks during wheat evolution have not had a strong impact on WDV resistance. Further, this study indicates that the variation in susceptibility may be associated with the genome type and that the ancestor Ae. tauschii may be useful as genetic resource for the improvement of WDV resistance in wheat. PMID- 25837897 TI - Epidemiology and diagnosis of brain tumors. AB - PURPOSE OF REVIEW: Brain tumors consist of a collection of neoplasms arising from within the brain or from systemic tumors that have metastasized to the brain. This article focuses on the most recent findings with regard to epidemiology, clinical presentation, neuroimaging evaluation, and diagnosis of brain tumors. RECENT FINDINGS: Patients with brain tumors may present for care with a variety of signs and symptoms. The most frequent clinical presentations include seizure, headache, fatigue, and cognitive dysfunction. Currently, diagnosis and treatment response is largely evaluated by using MRI. However, molecular imaging may ultimately be better suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered in treatment. Contemporary neuropathology continues to play a key role in the multidisciplinary management of patients with brain tumors. Genetic and environmental risk factors for brain tumors remain largely unclear. SUMMARY: Brain tumors represent a diverse spectrum of highly morbid cancers arising from different cells both from within the brain and from systemic tumors that have metastasized to the brain. The clinical manifestations of intracranial tumors are usually referable to the anatomic area of the brain involved or adjacent structures. The initial diagnosis of intracranial tumors is most efficiently made by imaging, generally MRI, although other techniques are being explored. The clinical manifestations, neuroimaging evaluation, and diagnosis of brain tumors are varied and dependent on the specific manner in which a patient presents for care. To date, specific causes of brain tumors remain elusive. PMID- 25837898 TI - Medical management of patients with brain tumors. AB - PURPOSE OF REVIEW: This review provides management recommendations for medical and neurologic problems in patients with brain tumors, including vasogenic edema, infections, seizures, prophylaxis and treatment of venous thromboembolism, drug interactions, cognitive and emotional problems, palliative symptom management, and long-term sequelae of brain tumors and their therapy. RECENT FINDINGS: Non enzyme-inducing antiepileptic drugs are the preferred category of seizure medication for patients with brain tumors, and levetiracetam is emerging as the drug of choice. Select groups of patients, such as those with cortically based hemorrhagic melanoma metastases, may benefit from prophylactic antiepileptic drug use. Antiangiogenic agents can reduce the steroid requirement of patients with vasogenic edema. Patients with brain tumors remain at risk for infections from the perioperative period through many months after treatment, and steroids may mask signs of infection. Few studies have been done on management of common cognitive issues such as short-term memory deficits and fatigue, but memantine may help delay cognitive deficits in patients receiving whole-brain radiation therapy. Palliative care conversations should begin early in the course of treatment. SUMMARY: Meticulous medical management begins at diagnosis of brain tumors and continues through the active treatment course and into either palliative care strategies or management of long-term sequelae of treatment. During the active treatment phase, problems such as vasogenic edema, seizures, and venous thromboembolism predominate, whereas late complications include the continuing risk of infections; sequelae of radiation such as vascular disease, cavernous angiomas, and cognitive decline; and secondary tumors. Attention to symptom palliation is an important part of the neurologist's role throughout the course of a brain tumor patient's illness. PMID- 25837899 TI - High-grade gliomas. AB - PURPOSE OF REVIEW: This article reviews the standard treatment of patients with high-grade glioma primary brain tumors and discusses promising new therapeutic advances. RECENT FINDINGS: While surgery and radiation remain critical components of the management of patients with high-grade gliomas, chemotherapy has recently been proven to improve the overall survival of patients with glioblastomas and anaplastic oligodendrogliomas. Molecular markers are complementing clinical prognostic factors and, in some cases, are able to guide treatment decisions. Despite aggressive treatment, high-grade gliomas eventually progress, emphasizing the importance of continued development of novel therapies for the treatment of this deadly disease. SUMMARY: The care of patients with high-grade gliomas is challenging, but the experience is highly rewarding. Rapidly developing technology allows for the use of molecular data for improved classification of high-grade gliomas and is beginning to improve our understanding of the pathogenesis and drivers of this disease. Collaboration among investigators will be critical to effectively validate prognostic biomarkers and identify tumors that might benefit from specific therapies. PMID- 25837900 TI - Low-grade gliomas. AB - PURPOSE OF REVIEW: Low-grade gliomas represent one of the most vexing management issues for neuro-oncologists. The relatively long survival compared to other gliomas makes consideration of treatment toxicity, and thus timing of potentially damaging interventions such as surgery, radiation, and chemotherapy, crucial. Moreover, the rarity of these tumors makes clinical trials to ascertain optimal care challenging. RECENT FINDINGS: The discovery that most low-grade gliomas harbor isocitrate dehydrogenase mutations that confer a favorable prognosis has improved diagnosis and risk stratification of these tumors. Although level 1 evidence is still lacking, increasing data support the concept of maximal safe tumor debulking as a first step in tumor management. Preliminary results from a large randomized trial suggest chemotherapy is of comparable effectiveness to radiation therapy. Most important, the final results of a phase 3 trial comparing radiation with or without procarbazine, CCNU (lomustine), and vincristine (PCV) chemotherapy indicate a large survival advantage to combined radiation and chemotherapy. SUMMARY: While the combination of radiation and PCV provides the best proven overall survival with low-grade gliomas, important questions remain. These include whether the better-tolerated temozolomide is as effective as PCV and whether the use of initial chemotherapy as a strategy to defer the potential delayed cognitive toxicity associated with radiation will yield equivalent survival results with a favorable toxicity profile. PMID- 25837901 TI - Primary CNS lymphoma and neurologic complications of hematologic malignancies. AB - PURPOSE OF REVIEW: This article provides a practical clinical approach to diagnose primary CNS lymphoma and recognize neurologic complications of lymphomas and leukemias. This includes current diagnostic and treatment recommendations for primary CNS lymphoma and complications related to hematologic malignancies. RECENT FINDINGS: Primary CNS lymphoma is an uncommon, aggressive non-Hodgkin lymphoma confined to the CNS in the absence of systemic disease. Diagnosis can be made by brain biopsy, CSF analysis, or vitreous fluid analysis. Primary CNS lymphoma is typically diffuse large B cell in histology. Evaluation of extent of disease should be performed before initiation of therapy. Initial induction treatment includes high-dose methotrexate-based chemotherapy. Several studies have demonstrated improved outcome using consolidative whole-brain radiation therapy or high-dose chemotherapy and autologous stem cell transplantation. Neurologic complications can result from direct or indirect effects of leukemia and lymphoma or may be treatment-induced. SUMMARY: Early diagnosis and treatment of patients with primary CNS lymphoma is critical to maintaining neurologic and cognitive function and preserving quality of life. It is important to recognize neurologic complications from leukemia and lymphoma to avoid delays in instituting appropriate treatment. PMID- 25837902 TI - Pediatric brain tumors. AB - PURPOSE OF REVIEW: Pediatric brain tumors differ from those arising in adulthood. This article discusses the presentation, location, histology, new molecular understanding, therapy, and outcome of brain tumors in children. RECENT FINDINGS: Improved biological understanding of pediatric brain tumors is resulting in new molecular-based classification and the development of rationally designed therapeutics. SUMMARY: The presentation of a pediatric brain tumor is dependent on the type of tumor, its location in the nervous system, and the age of the child. Diagnostic workup varies depending on the location of the tumor and the tumor's propensity to disseminate in the nervous system. Survival has improved for pediatric brain tumors, particularly medulloblastoma, as a result of improved surgical techniques and rational use of postoperative radiation and chemotherapy. For medulloblastoma, recent studies have sought to maintain or improve survival while decreasing neurologic sequelae, particularly from radiation in young children. For other childhood brain tumor types, improvements in outcome are not as clear-cut. New molecular insights will likely alter classification, risk stratification, and therapy in the near future. PMID- 25837903 TI - Benign brain tumors and tumors associated with phakomatoses. AB - PURPOSE OF REVIEW: This article reviews the clinical features, diagnostic criteria, molecular genetics, and management of sporadic meningiomas and vestibular schwannomas and tumors associated with the major neurocutaneous disorders. RECENT FINDINGS: Recent advances in cancer genomics are now allowing sequencing of the genome of these tumors to identify oncogenic drivers and possible therapeutic targets. SUMMARY: Sporadic meningiomas and schwannomas, and tumors occurring as part of a neurocutaneous syndrome, have been the subjects of strong biological and therapeutic interest in the past few years; new and exciting therapies are either under investigation or will be in the upcoming years. This article takes an in-depth look at sporadic meningiomas and schwannomas, followed by a review of the phakomatoses and their associated tumors. PMID- 25837904 TI - Nervous system metastases from systemic cancer. AB - PURPOSE OF REVIEW: Metastatic complications affecting the nervous system, including brain metastases, leptomeningeal metastases, dural metastases, metastatic epidural spinal cord compression, intramedullary spinal cord metastases, and neoplastic plexopathy, are associated with significant morbidity and poor prognoses. Early recognition and management are vital to minimizing neurologic decline and maintaining quality of life. RECENT FINDINGS: Several recent randomized clinical trials in patients with brain metastases emphasize the importance of quality of life. Results from the European Organisation for Research and Treatment of Cancer (EORTC) 22952-26001 study suggest that adjuvant whole-brain radiation therapy after surgery or radiosurgery in patients with limited brain metastases may negatively impact some aspects of health-related quality of life, even if the negative effects are only transitory. In a separate study, Radiation Therapy Oncology Group (RTOG) 0614, memantine delayed cognitive decline in patients undergoing whole-brain radiation therapy for brain metastases. SUMMARY: This article summarizes the main clinical features of cancer metastases affecting the nervous system and highlights recent updates in treatment and symptomatic management. PMID- 25837905 TI - Neurologic complications of chemotherapy and radiation therapy. AB - PURPOSE OF REVIEW: Nervous system injury from cancer therapeutics is second only to myelosuppression as the most common toxicity caused by chemotherapy and radiation therapy. RECENT FINDINGS: Neurologic complications can be seen throughout the course of cancer diagnosis and treatment; some toxicities may not develop for years or even decades after completion of treatment, making diagnosis challenging. However, early recognition is critical as modification of therapeutic regimens can diminish long-term consequences of nervous system injury and improve a patient's quality of life. This article addresses the most common neurologic complications seen as a consequence of chemotherapy and radiation therapy in patients with systemic cancer. These common toxicities are likely to be seen with increasing frequency as patients with systemic cancer are living longer and receiving multiple courses of antineoplastic regimens, some of which are lifelong. SUMMARY: Neurotoxicity from cancer therapeutics is common, and early recognition is critical to proper diagnosis and intervention. PMID- 25837906 TI - Paraneoplastic disorders. AB - PURPOSE OF REVIEW: Paraneoplastic disorders are autoimmune diseases associated with risks for specific cancers and marked by specific autoantibodies. They cause diverse clinical syndromes of the central and peripheral nervous systems. RECENT FINDINGS: In the peripheral nervous system, autoimmunity to synaptic or axonal proteins has long been recognized to associate with specific cancers. In these disorders, typified by myasthenia gravis, the antibodies are directly toxic, and recovery with immunotherapy is the rule. In contrast, the classic paraneoplastic syndromes involve a higher risk of cancer, autoantibodies to intracellular proteins (eg, Hu proteins), T-cell-dependent disease mechanisms targeting the CNS or peripheral nervous system, and a poor response to treatment. Following the discovery of N-methyl-D-aspartate (NMDA) receptor antibodies, a new and expanding group of disorders involving autoantibodies to CNS synaptic and neuronal membrane proteins and a favorable response to immunotherapy emerged. A final group of disorders involves antibodies to intracellular synaptic proteins, such as glutamic acid decarboxylase 65 (GAD65), and it is unclear whether these diseases involve antibody or T-cell mechanisms. SUMMARY: Neurologists should recognize the clinical syndromes associated with paraneoplastic disorders, utilize autoantibody and other testing to confirm the diagnosis, understand the pathologic basis of the diseases, and promptly give appropriate therapies. PMID- 25837907 TI - When religious beliefs prohibit a surgical patient's acceptance of blood transfusion. AB - A 49-year-old man who was a Jehovah's Witness presented with intractable epilepsy due to a brain tumor. The neurologist wanted to refer him for tumor resection but was concerned about requesting surgery for someone who would not accept blood products. The neurologist must balance his obligation of beneficence and nonmaleficence with respect for the patient's autonomous decision not to receive blood products.Good communication between patient and doctor is crucial to allow patients to make informed decisions about a choice to refuse transfusion, and doctors must accept the patient's autonomy, even when it conflicts with the moral imperative to provide treatment if it is available. PMID- 25837909 TI - Coding for neuro-oncology. PMID- 25837908 TI - Practical considerations in opioid use for brain neoplasm. AB - Neurologists are often on the front lines of diagnosis for primary and metastatic brain tumors. Patients with brain tumors typically have multiple comorbidities and pain generators beyond headache, necessitating opioid therapy. Opioid-based pain relief and safety in the medically ill patient are complex. While using the lowest-potency opioid with adjunct medications is always prudent, patients with brain tumors frequently require dose escalation. Opioid selection and use is based on the patient's respiratory and cardiac function as well as drug clearance capability. Specific opioid combinations, employing long-acting and short-acting drugs, have greater efficacy in specific patient profiles and make adverse drug reactions, toxicity, abuse, and diversion less likely. PMID- 25837913 TI - Patient management problem. PMID- 25837914 TI - Patient management problem-preferred responses. PMID- 25837916 TI - Place and process in conservation planning for climate change: a reply to Keppel and Wardell-Johnson. PMID- 25837917 TI - Adaptive virulence evolution: the good old fitness-based approach. AB - Infectious diseases could be expected to evolve towards complete avirulence to their hosts if given enough time. However, this is not the case. Often, virulence is maintained because it is linked to adaptive advantages to the parasite, a situation that is often associated with the hypothesis known as the transmission virulence trade-off hypothesis. Here, we argue that this hypothesis has three limitations, which are related to how virulence is defined, the possibility of multiple trade-offs, and the difficulty of testing the hypothesis empirically. By adopting a fitness-based approach, where the relation between virulence and the fitness of the parasite throughout its life cycle is directly assessed, it is possible to address these limitations and to determine directly whether virulence is adaptive. PMID- 25837918 TI - Feedbacks and landscape-level vegetation dynamics. AB - Alternative stable-state theory (ASS) is widely accepted as explaining landscape level vegetation dynamics, such as switches between forest and grassland. This theory argues that webs of feedbacks stabilise vegetation composition and structure, and that abrupt state shifts can occur if stabilising feedbacks are weakened. However, it is difficult to identify stabilising feedback loops and the disturbance thresholds beyond which state changes occur. Here, we argue that doing this requires a synthetic approach blending observation, experimentation, simulation, conceptual models, and narratives. Using forest boundaries and large mammal extinctions, we illustrate how a multifaceted research program can advance understanding of feedback-driven ecosystem change. Our integrative approach has applicability to other complex macroecological systems controlled by numerous feedbacks where controlled experimentation is impossible. PMID- 25837919 TI - Involvement of TRPM2 in a wide range of inflammatory and neuropathic pain mouse models. AB - Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2) in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2 knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain. PMID- 25837920 TI - Effect of oleoylethanolamide on diet-induced nonalcoholic fatty liver in rats. AB - Oleoylethanolamine (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor alpha (PPAR-alpha), has revealed the pharmacological properties in the treatment of obesity, atherosclerosis and other diseases through the modulation of lipid metabolism. To assess whether OEA can also regulate non-alcoholic fatty liver disease (NAFLD) caused by fat accumulation, we administrated OEA or fenofibrate in Sprague Dawley (SD) rats fed with a high fat diet (HFD). After 6 or 17 weeks treatment, OEA (5 mg/kg/day, i.p.) relieved the development of NAFLD compared with control groups by regulating the levels of plasma TG, TC, ALT and AST and liver inflammatory cytokines. Gene expression analysis of liver tissue and plasma from the animal models showed that OEA and fenofibrate both promoted the lipid beta-oxidation by activating PPAR-alpha. Detailed research revealed that OEA inhibited the mRNA expression of lipogenesis in a PPAR-alpha-independant manner, while fenofibrate expressed an opposite effection. In summary, our research results suggested that as a potential lead compound, OEA could improve HFD-induced NAFLD with higher efficacy and safety than fenofibrate. PMID- 25837921 TI - The effects of Zanthoxylum bungeanum extract on lipid metabolism induced by sterols. AB - Variant pharmacological activities of Zanthoxylum bungeanum were determined before. The aim of this study was to assess whether Z. bungeanum could regulate lipid metabolism. The cholesterol overloading HepG2 cells induced by sterols were used as in vitro model to study lipid-lowering activities of the n-butanol (BuOH) fraction isolated from Z. bungeanum (ZBBu). Male apolipoprotein E knockout (apoE KO) mice with high fat diet were used as in vivo model. We firstly demonstrated ZBBu had effects on reversed lipid accumulation, decreased apoB and enhanced apoA1 secretion. It increased the amount of low density lipoprotein receptor (LDLR) protein, also significantly inhibited the expression of SREBP-1 and SREBP 2's target molecule (hydroxy methylglutaryl coenzyme A reductase, HMGCR), which might be active in stimulation of RCT. And the expression of genes involved in RCT, such as CYP27A1, LXR-alpha, ABCG1, was promoted by ZBBu. Furthermore, ZBBu could reduce serum TC, TG levels in apoE-KO mice. Our study indicated that ZBBu could regulate the lipid metabolism through increasing the amount of low density lipoprotein receptor (LDLR) and inducing the expression of genes involved in RCT. PMID- 25837922 TI - Sitagliptin alleviated myocardial remodeling of the left ventricle and improved cardiac diastolic dysfunction in diabetic rats. AB - OBJECTIVE: Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has a biological role in improving the serum levels of glucagon-like peptide 1 (GLP-1). Hence, we sought to determine the effect of sitagliptin on myocardial inflammation, collagen metabolism, lipid content and myocardial apoptosis in diabetic rats. MATERIALS AND METHODS: The type 2 diabetic rat model was induced by low-dose streptozotocin and a high-fat diet. Characteristics of diabetic rats were evaluated by electrocardiography, echocardiography and blood analysis. Cardiac inflammation, fibrosis, cardiomyocyte density, lipid accumulation, and receptor-interacting protein kinase 3 (RIP3) level, related to apoptosis, were detected by histopathologic analysis, RT-PCR and western blot analysis to evaluate the effects of sitagliptin on myocardial remodeling of the left ventricle. RESULTS: Diabetic rats showed myocardial hypertrophy or apoptosis, inflammation, lipid accumulation, myocardial fibrosis, elevated collagen content, RIP3 overexpression, and left-ventricular dysfunction. Sitagliptin could reverse the overexpression of RIP3 and alleviate cellular apoptosis in myocardial tissues. It could significantly improve left-ventricular systolic pressure and +dp/dt max, reduce the E/E' ratio, left ventricular end diastolic pressure, dp/dt max and Tau in diabetic rats. CONCLUSIONS: Sitagliptin might have a myocardial protective effect by inhibiting apoptosis, inflammation, lipid accumulation and myocardial fibrosis in diabetic rats, for a potential role in improving left-ventricular function in diabetes. PMID- 25837923 TI - Involvement of stimulation of alpha7 nicotinic acetylcholine receptors in the suppressive effect of tropisetron on dextran sulfate sodium-induced colitis in mice. AB - Ulcerative colitis (UC) involves chronic inflammation of the large intestine. Several agents are used to treat UC, but adverse side effects are remaining problems. We examined the effect of tropisetron as a new type of drug for UC using a dextran sulfate sodium (DSS)-induced model of colitis in mice. We developed a DSS-induced model of colitis and calculated the Disease Activity Index and colon length. We measured myeloperoxidase activity and determined the protein level and mRNA level of cytokines in the colon. DSS-induced colitis was ameliorated by administration of tropisetron and PNU282987. Pre-administration of methyllycaconitine diminished the suppressive effect of tropisetron upon DSS induced colitis. These findings suggested that alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) were related to the suppressive effect of tropisetron on DSS-induced colitis. Additionally, stimulation of alpha7 nAChRs decreased the colon level of interleukin-6 and interferon-gamma upon DSS administration. Furthermore, stimulation of alpha7 nAChRs decreased macrophage infiltration, with expression of alpha7 nAChR increased by DSS administration. These results suggest that the underlying mechanism of this suppressive effect on DSS-induced colitis is via stimulation of alpha7 nAChRs and involves suppression of expression of pro inflammatory cytokines. Tropisetron could be a new type of therapeutic agent for UC. PMID- 25837924 TI - Nicorandil prevents sirolimus-induced production of reactive oxygen species, endothelial dysfunction, and thrombus formation. AB - Sirolimus (SRL) is widely used to prevent restenosis after percutaneous coronary intervention. However, its beneficial effect is hampered by complications of thrombosis. Several studies imply that reactive oxygen species (ROS) play a critical role in endothelial dysfunction and thrombus formation. The present study investigated the protective effect of nicorandil (NIC), an anti-angina agent, on SRL-associated thrombosis. In human coronary artery endothelial cells (HCAECs), SRL stimulated ROS production, which was prevented by co-treatment with NIC. The preventive effect of NIC on ROS was abolished by 5-hydroxydecanoate but not by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. NIC also inhibited SRL induced up-regulation of NADPH oxidase subunit p22(phox) mRNA. Co-treatment with NIC and SRL significantly up-regulated superoxide dismutase 2. NIC treatment significantly improved SRL-induced decrease in viability of HCAECs. The functional relevance of the preventive effects of NIC on SRL-induced ROS production and impairment of endothelial viability was investigated in a mouse model of thrombosis. Pretreatment with NIC inhibited the SRL-induced acceleration of FeCl3-initiated thrombus formation and ROS production in the testicular arteries of mice. In conclusion, NIC prevented SRL-induced thrombus formation, presumably due to the reduction of ROS and to endothelial protection. The therapeutic efficacy of NIC could represent an additional option in the prevention of SRL-related thrombosis. PMID- 25837925 TI - Daily oral intake of theanine prevents the decline of 5-bromo-2'-deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress. AB - Posttraumatic stress disorder is a long-lasting psychiatric disease with the consequence of hippocampal atrophy in humans exposed to severe fatal stress. We demonstrated a positive correlation between the transient decline of 5-bromo-2' deoxyuridine (BrdU) incorporation in the hippocampal dentate gyrus (DG) and long lasting behavioral abnormalities in mice with traumatic stress. Here, we investigated pharmacological properties of theanine on the declined BrdU incorporation and abnormal behaviors in mice with traumatic stress. Prior daily oral administration of theanine at 50-500 mg/kg for 5 days significantly prevented the decline of BrdU incorporation, while theanine significantly prevented the decline in the DG even when administered for 5 days after stress. Consecutive daily administration of theanine significantly inhibited the prolonged immobility in mice with stress in forced swimming test seen 14 days later. Although traumatic stress significantly increased spontaneous locomotor activity over 30 min even when determined 14 days later, the increased total locomotion was significantly ameliorated following the administration of theanine at 50 mg/kg for 14 days after stress. These results suggest that theanine alleviates behavioral abnormalities together with prevention of the transient decline of BrdU incorporation in the hippocampal DG in adult mice with severe traumatic stress. PMID- 25837926 TI - GFAP antibodies show protective effect on oxidatively stressed neuroretinal cells via interaction with ERP57. AB - The pathogenesis of glaucoma, a common neurodegenerative disease, involves an immunologic component. Changes in the natural autoantibody profile of glaucoma patients were detected, showing not only up-regulated but also down-regulated immunoreactivities. In recent studies we were able to demonstrate that the antibody changes have a large influence on protein profiles of neuroretinal cells. Furthermore we could demonstrate neuroprotective potential of one of the down-regulated antibodies (gamma-synuclein antibody). Anti-GFAP antibody is another antibody found down-regulated in glaucoma patients. Since GFAP expression is intensified in glaucomatous retina, the aim of this study was to detect the effect of GFAP antibodies on neuroretinal cells. This is realized with a viability-test as well as proteomic analysis of cells incubated with GFAP antibodies. Furthermore, possible interaction partners of the GFAP antibody in neuroretinal cells were identified by western blot, mass spectrometry and indirect immunofluorescence staining. We found that the GFAP antibody is able to protect cells from oxidative stress, which is due to changed protein expressions of the actin cytoskeleton. Furthermore we detected a cross-reaction of the antibody to endoplasmic reticulum resident protein 57 on the cell membrane, which seems to lead to a changed signaling in the cells triggering the protective effects. PMID- 25837927 TI - DJ-1-dependent protective activity of DJ-1-binding compound no. 23 against neuronal cell death in MPTP-treated mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is caused by dopaminergic cell death in the substantia nigra, leading to a reduced level of dopamine in the striatum. Oxidative stress is one of the causes of PD. Since symptomatic PD therapies are used, identification of compounds or proteins that inhibit oxidative stress-induced neuronal cell death is necessary. DJ-1 is a causative gene product of familial PD and plays a role in anti-oxidative stress reaction. We have identified various DJ 1-binding compounds, including compound-23, that restored neuronal cell death and locomotion defects observed in neurotoxin-induced PD models. In this study, wild type and DJ-1-knockout mice were injected intraperitoneally with 1 mg/kg of compound-23 and then with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) at 1 h after injection. Five days after administration, the effects of compound-23 on MPTP-induced locomotion deficits, on dopaminergic cell death and on brain dopamine levels were analyzed by rotor rod tests, by staining cells with an anti-TH antibody and by an HPLC, respectively. The results showed that compound-23 inhibited MPTP-induced reduction of retention time on the rotor rod bar, neuronal cell death in the substantia nigra and striatum and dopamine content in wild-type mice but not in DJ-1-knockout mice, indicating a DJ 1-dependent effect of compound-23. PMID- 25837928 TI - Shear stress-induced Ca(2+) elevation is mediated by autocrine-acting glutamate in osteoblastic MC3T3-E1 cells. AB - Mechanical loading is an important regulatory factor in bone homeostasis. Neurotransmitters, such as glutamate and ATP, are known to be released from osteoblasts, but their roles have been less studied. In this study, we investigated the role of transmitter release in mechanotransduction. To identify from where transmitters were released, focal fluid flow was applied to a single cell of MC3T3-E1, mouse calvaria-derived osteoblastic cell line, by using a glass micropipette. Intracellular Ca(2+) elevation induced by the focal shear stress was eliminated by either GdCl3, a mechanosensing channel inhibitor, or removal of extracellular Ca(2+). On the other hand, the focal shear stress-induced Ca(2+) elevation was also significantly suppressed by inositol triphosphate receptor antagonist or vesicular release inhibitors. These results suggest that not only mechanosensitive channel-mediated Ca(2+) influx but also some autocrine transmitters are involved in mechanotransduction. Additionally, glutamate receptor antagonists, but not ATP receptor antagonist, suppressed most of the focal shear stress-induced Ca(2+) elevation. Therefore, it is suggested that glutamate is released from osteoblasts following the activation of mechanosensitive Ca(2+) channels and acts in an autocrine manner. The glutamate release may have a significant role in the initial event of mechanotransduction in bone tissue. PMID- 25837929 TI - Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. AB - Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors. PMID- 25837930 TI - Blonanserin extensively occupies rat dopamine D3 receptors at antipsychotic dose range. AB - Antagonism of the dopamine D3 receptor has been hypothesized to be beneficial for schizophrenia cognitive deficits, negative symptoms and extrapyramidal symptoms. However, recent animal and human studies have shown that most antipsychotics do not occupy D3 receptors in vivo, despite their considerable binding affinity for this receptor in vitro. In the present study, we investigated the D3 receptor binding of blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptors antagonist, in vitro and in vivo. Blonanserin showed the most potent binding affinity for human D3 receptors among the tested atypical antipsychotics (risperidone, olanzapine and aripiprazole). Our GTPgammaS-binding assay demonstrated that blonanserin acts as a potent full antagonist for human D3 receptors. All test-drugs exhibited antipsychotic-like efficacy in methamphetamine-induced hyperactivity in rats. Treatment with blonanserin at its effective dose blocked the binding of [(3)H]-(+)-PHNO, a D2/D3 receptor radiotracer, both in the D2 receptor-rich region (striatum) and the D3 receptor rich region (cerebellum lobes 9 and 10). On the other hand, the occupancies of other test-drugs for D3 receptors were relatively low. In conclusion, we have shown that blonanserin, but not other tested antipsychotics, extensively occupies D3 receptors in vivo in rats. PMID- 25837931 TI - Anti-tumor effect of alpha-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. AB - Pine needle oil from crude extract of pine needles has been used as an anti cancer agent in Traditional Chinese Medicine. The alpha-pinene is a natural compound isolated from pine needle oil which has been shown anti-cancer activity. In previous study, we found that pine needle oil exhibited significant inhibitory effect on hepatoma carcinoma BEL-7402 cells. In this study, we investigate the inhibition of alpha-pinene on hepatoma carcinoma BEL-7402 cells in vitro and in vivo and further explore the mechanism. The results show that liver cancer cell growth was inhibited obviously with inhibitory rate of 79.3% in vitro and 69.1% in vivo, Chk1 and Chk2 levels were upregulated, CyclinB, CDC25 and CDK1 levels were downregulated. PMID- 25837932 TI - Evaluation of edaravone against radiation-induced oral mucositis in mice. AB - Oral mucositis induced by radiotherapy for cancers of the head and neck reduce the quality of life of patients. However, effective therapeutic agents are lacking. Symptomatic treatment involves local anesthesia and analgesia. We focused on the antioxidant effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5 one; Radicut((r))). Oral mucositis was induced on the tongue tips of mice using a single dose of X-rays (20 Gy). To evaluate the protective effect of edaravone (30 and 300 mg/kg), administration was carried out 30 min before irradiation. Survival, oral mucositis score, myeloperoxidase activity, and levels of 2 Thiobarbituric acid reactive substances were measured, and all were improved compared with those of control mice. A significant difference was not found in terms of survival due to edaravone. Histopathologic findings also highlighted the beneficial features of edaravone. Edaravone reduced the production of reactive oxygen species. These findings suggest that the protective effect of edaravone against radiation-induced oral mucositis is through an antioxidant effect. PMID- 25837933 TI - Contraction of gut smooth muscle cells assessed by fluorescence imaging. AB - Here we discuss the development of a novel cell imaging system for the evaluation of smooth muscle cell (SMC) contraction. SMCs were isolated from the circular and longitudinal muscular layers of mouse small intestine by enzymatic digestion. SMCs were stimulated by test agents, thereafter fixed in acrolein. Actin in fixed SMCs was stained with phalloidin and cell length was determined by measuring diameter at the large end of phalloidin-stained strings within the cells. The contractile response was taken as the decrease in the average length of a population of stimulated-SMCs. Various mediators and chemically identified compounds of daikenchuto (DKT), pharmaceutical-grade traditional Japanese prokinetics, were examined. Verification of the integrity of SMC morphology by phalloidin and DAPI staining and semi-automatic measurement of cell length using an imaging analyzer was a reliable method by which to quantify the contractile response. Serotonin, substance P, prostaglandin E2 and histamine induced SMC contraction in concentration-dependent manner. Two components of DKT, hydroxy alpha-sanshool and hydroxy-beta-sanshool, induced contraction of SMCs. We established a novel cell imaging technique to evaluate SMC contractility. This method may facilitate investigation into SMC activity and its role in gastrointestinal motility, and may assist in the discovery of new prokinetic agents. PMID- 25837934 TI - Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor. AB - Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1 trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1 b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) in rats. Furthermore, TASP0443294 reduced the ketamine induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM) sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294. PMID- 25837935 TI - Novel 5-HT5A receptor antagonists ameliorate scopolamine-induced working memory deficit in mice and reference memory impairment in aged rats. AB - Despite the human 5-HT5A receptor being cloned in 1994, the biological function of this receptor has not been extensively characterized due to a lack of specific ligands. We recently reported that the selective 5-HT5A receptor antagonist ASP5736 ameliorated cognitive impairment in several animal models of schizophrenia. Given that areas of the brain with high levels of 5-HT5A receptor expression, such as the hippocampus and cerebral cortex, have important functions in cognition and memory, we evaluated the chemically diverse, potent and brain penetrating 5-HT5A receptor antagonists ASP5736, AS2030680, and AS2674723 in rodent models of cognitive dysfunction associated with dementia. Each of these compounds exhibited a high affinity for recombinant 5-HT5A receptors that was comparable to that of the non-selective ligand of this receptor, lysergic acid diethylamide (LSD). Although each compound had a low affinity for other receptors, 5-HT5A was the only receptor for which all three compounds had a high affinity. Each of the three compounds ameliorated scopolamine-induced working memory deficit in mice and improved reference memory impairment in aged rats at similar doses. Further, ASP5736 decreased the binding of LSD to 5-HT5A receptors in the olfactory bulb of rats in a dose-dependent manner and occupied 15%-50% of brain 5-HT5A receptors at behaviorally effective doses. These results indicate that the 5-HT5A receptor is involved in learning and memory and that treatment with 5-HT5A receptor antagonists might be broadly effective for cognitive impairment associated with not only schizophrenia but also dementia. PMID- 25837936 TI - A protective role of Nox1/NADPH oxidase in a mouse model with hypoxia-induced bradycardia. AB - Although it has been reported that endotoxin-induced expression of Nox1 in the heart contributes to apoptosis in cardiomyocytes, functional role of Nox1 at the physiological expression level has not been elucidated. The aim of this study was to clarify the role of Nox1 under a hypoxic condition using wild-type (WT, Nox1(+/Y)) and Nox1-deficient (Nox1(-/Y)) mice. ECG recordings from anesthetized mice revealed that Nox1(-/Y) mice were more sensitive to hypoxia, resulting in bradycardia, compared to WT mice. Atrial and ventricular electrocardiograms recorded from Langendorff-perfused hearts revealed that hypoxic perfusion more rapidly decreased heart rate in Nox1(-/Y) hearts compared with WT hearts. Sinus node recovery times measured under a hypoxic condition were prolonged more markedly in the Nox1(-/Y) hearts. Sinoatrial node dysfunction of Nox1(-/Y) hearts during hypoxia was ameriolated by the pre-treatment with the Ca(2+) channel blocker nifedipine or the K(+) channel opener pinacidil. Spontaneous action potentials were recorded from enzymatically-isolated sinoatrial node (SAN) cells under a hypoxic condition. There was no significant difference in the elapsed times from the commencement of hypoxia to asystole between WT and Nox1(-/Y) SAN cells. These findings suggest that Nox1 may have a protective effect against hypoxia-induced SAN dysfunction. PMID- 25837937 TI - Analgesic effect of GT-0198, a structurally novel glycine transporter 2 inhibitor, in a mouse model of neuropathic pain. AB - This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2) in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain. PMID- 25837938 TI - Disruption of running activity rhythm following restricted feeding in female mice: Preventive effects of antidepressants. AB - Biological rhythms are critical in the etiology of mood disorders; therefore, effective mood disorder treatments should address rhythm disturbances. Among the variables synchronized with the light-dark cycle, spontaneous activity in rodents is useful for investigating circadian rhythms. However, previous studies have focused only on the increase of wheel-running activity under restricted feeding conditions, while little information is available on circadian rhythm of running activity. In this study, chronometrical analysis was used to assess whether circadian rhythms during wheel-running are altered by restricted feeding and affected by antidepressant drugs. Wheel revolutions were automatically recorded and analyzed using cosinor-rhythmometry in 8-week old ICR albino mice. When feeding was restricted to 1 h per day (21:00-22:00), wheel-running rhythms were reliably disrupted. Female mice exhibited marked alterations in the pattern and extent of wheel-running beginning on day 1. Subchronic treatment with imipramine or paroxetine, as well as tandospirone and (-)-DOI, prevented wheel-running rhythm disruption. Thus, altering the circadian activity rhythms of female mice on a 1-h feeding schedule may be useful for investigating disturbances in biological rhythms. PMID- 25837939 TI - Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements. AB - An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements. PMID- 25837940 TI - Involvement of neuronal nitric oxide synthase in N-methyl-N-nitrosourea-induced retinal degeneration in mice. AB - N-methyl-N-nitrosourea (MNU) is widely used to study the mechanism of retinal degenerative diseases (RDs) because of its selectivity of photoreceptor cell death. Many reports suggest that excessive nitric oxide (NO) plays a crucial role in neuronal cell death. We hypothesized that nitric oxide synthase (NOS)/NO are involved in photoreceptor cell death by MNU. We found that the levels of NO increased after MNU treatment. Furthermore, we demonstrated that neuronal NOS specific inhibitor attenuated photoreceptor cell death by MNU in mice. We believe that our findings might be a new target for the treatment of RDs. PMID- 25837941 TI - OV services: Information for farmers on new TB testing arrangements. PMID- 25837942 TI - Wales premovement TB testing reminder. PMID- 25837943 TI - RCVS knowledge: Toolkits to support evidence-based practice. PMID- 25837944 TI - Wildlife: Beavers back in the wild in England. PMID- 25837945 TI - National Equine Forum: Taking up the reins on equine issues. AB - Gill Harris reports from this year's National Equine Forum, where one of the main themes was the horse industry and government. The forum, held in London on March 5, was attended by more than 200 people with a connection to the equestrian industry. Lord de Mauley, parliamentary undersecretary of state for natural environment and science at Defra, set the course of the proceedings. PMID- 25837946 TI - Veterinary medicines: product update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 25837947 TI - One Health: a doctor's perspective. AB - One Health has been gaining traction over recent years, particularly among veterinarians and veterinary scientists, but the medical sector appears to be less engaged. Here, Josef Jarhult, a doctor practising in Sweden, who is also a proponent of One Health, suggests some reasons why medics have yet to embrace the idea and how this could be overcome. PMID- 25837948 TI - BestBETs for Vets: a way to improve the odds of delivering high-quality care. PMID- 25837951 TI - TB testing. PMID- 25837952 TI - 24/7 practices. PMID- 25837953 TI - TB testing. PMID- 25837962 TI - Learning in the third dimension. AB - Sharon Boyd, Eoghan Clarkson and Brian Mather explain how the Royal (Dick) School of Veterinary Studies is using the latest 3D modelling techniques to help students develop their clinical skills. PMID- 25837963 TI - Ten-minute chat. AB - Having achieved his clinical goals, Aiz Baig did an MBA. He is currently senior product marketing manager with Eickemeyer Veterinary Equipment, helping vets and nurses improve clinical outcomes. PMID- 25837964 TI - Reactive oxygen species and gastric cancer risk: a large nested case-control study in Japan. PMID- 25837965 TI - The global impact of non-communicable diseases on macro-economic productivity: a systematic review. AB - Non-communicable diseases (NCDs) have large economic impact at multiple levels. To systematically review the literature investigating the economic impact of NCDs [including coronary heart disease (CHD), stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on macro-economic productivity. Systematic search, up to November 6th 2014, of medical databases (Medline, Embase and Google Scholar) without language restrictions. To identify additional publications, we searched the reference lists of retrieved studies and contacted authors in the field. Randomized controlled trials, cohort, case-control, cross sectional, ecological studies and modelling studies carried out in adults (>18 years old) were included. Two independent reviewers performed all abstract and full text selection. Disagreements were resolved through consensus or consulting a third reviewer. Two independent reviewers extracted data using a predesigned data collection form. Main outcome measure was the impact of the selected NCDs on productivity, measured in DALYs, productivity costs, and labor market participation, including unemployment, return to work and sick leave. From 4542 references, 126 studies met the inclusion criteria, many of which focused on the impact of more than one NCD on productivity. Breast cancer was the most common (n = 45), followed by stroke (n = 31), COPD (n = 24), colon cancer (n = 24), DM (n = 22), lung cancer (n = 16), CVD (n = 15), cervical cancer (n = 7) and CKD (n = 2). Four studies were from the WHO African Region, 52 from the European Region, 53 from the Region of the Americas and 16 from the Western Pacific Region, one from the Eastern Mediterranean Region and none from South East Asia. We found large regional differences in DALYs attributable to NCDs but especially for cervical and lung cancer. Productivity losses in the USA ranged from 88 million US dollars (USD) for COPD to 20.9 billion USD for colon cancer. CHD costs the Australian economy 13.2 billion USD per year. People with DM, COPD and survivors of breast and especially lung cancer are at a higher risk of reduced labor market participation. Overall NCDs generate a large impact on macro-economic productivity in most WHO regions irrespective of continent and income. The absolute global impact in terms of dollars and DALYs remains an elusive challenge due to the wide heterogeneity in the included studies as well as limited information from low- and middle-income countries. PMID- 25837966 TI - Secular trends and educational differences in the incidence of type 2 diabetes in Finland, 1972-2007. AB - Type 2 diabetes prevalence is rising globally, and varies by socio-economic position. Amongst other factors, rising prevalence may reflect increasing incidence. Worldwide, few studies have examined population-level longitudinal trends in incident type 2 diabetes, and reports on secular trends in diabetes incidence by socio-economic measures such as educational attainment are lacking. Finland has a long-standing, comprehensive disease surveillance infrastructure. Using data collected over four decades from serial FINRISK surveys, the National Drug Reimbursement Register and the National Causes of Death Register, we examined secular trends in type 2 diabetes incidence in Finland from the 1970s to 2007. The diabetes status of 38,689 FINRISK participants aged 30-59 years at baseline assessment and without diagnosed diabetes at the time was followed for 10 years. Among men, incidence of diagnosed, pharmacologically managed type 2 diabetes increased over time. Compared with men surveyed in the 1970s, diabetes incidence was higher among men in the 1980s (adjusted HR 1.44, 95% CI 1.13-1.84) and 1990s (adjusted HR 1.72, 1.32-2.24). Body mass index explained some, but not all of this variation. Increases occurred predominantly among men with low (adjusted HR 1980s: 2.07, 95% CI 1.28-3.35; adjusted HR 1990s: 2.12, 95% CI 1.28 3.53) and middle (adjusted HR 1980s: 1.30, 95% CI 0.85-1.99; adjusted HR 1990s: 1.65, 95% CI 1.05-2.60) educational attainment. No secular changes were apparent among women. This rising diabetes incidence among men over recent decades has occurred despite Finland's sustained health promotion efforts. Renewed public health campaigns are urgently required. In addition to population-level initiatives, lower educational strata should be specifically targeted. PMID- 25837967 TI - Duodenal perforation following esophagogastroduodenoscopy (EGD) with cautery and epinephrine injection for peptic ulcer disease: An interesting case of nonoperative management in the medical intensive care unit (MICU). AB - INTRODUCTION: The utilization of esophagogastroduodenoscopy (EGD) and related procedures continues to rise. Due to this increase in utilization is an inevitable rise in serious complications such as hemorrhage and perforation. One understudied and dreaded complication of EGD causing significant morbidity and mortality is duodenal perforation. PRESENTATION OF CASE: We present the case of a 63-year-old male who presented to our institution's emergency room with dyspepsia, melanic stools, tachycardia, and hypotension. Initial laboratory evaluation was significant for severe anemia, lactic acidosis, and acute kidney injury, while CT scan of the abdomen pelvis did not suggest retroperitoneal hematoma or bowel perforation. An emergent EGD was performed which showed multiple bleeding duodenal ulcers that were cauterized and injected with epinephrine. Post-procedure the patient developed worsening abdominal pain, distension, diaphoresis, and tachypnea, requiring emergent intubation. A CT scan of the abdomen and pelvis with oral contrast confirmed pneumoperitoneum and duodenal perforation. DISCUSSION: Due to the patient's hemodynamic instability and multiple comorbidities, he was treated non-operatively with strict bowel rest and intravenous antibiotics. The patient ultimately had a 19-day hospital course complicated by renal failure requiring hemodialysis and an ischemic limb necessitating above knee amputation. CONCLUSION: This case describes an unsuccessful attempt at nonoperative management of duodenal perforation following EGD. PMID- 25837968 TI - Correction to "constructing quaternary stereogenic centers using tertiary organocuprates and tertiary radicals. total synthesis of trans-clerodane natural products". PMID- 25837969 TI - Measuring the outcome of biomedical research: a systematic literature review. AB - BACKGROUND: There is an increasing need to evaluate the production and impact of medical research produced by institutions. Many indicators exist, yet we do not have enough information about their relevance. The objective of this systematic review was (1) to identify all the indicators that could be used to measure the output and outcome of medical research carried out in institutions and (2) enlist their methodology, use, positive and negative points. METHODOLOGY: We have searched 3 databases (Pubmed, Scopus, Web of Science) using the following keywords: [Research outcome* OR research output* OR bibliometric* OR scientometric* OR scientific production] AND [indicator* OR index* OR evaluation OR metrics]. We included articles presenting, discussing or evaluating indicators measuring the scientific production of an institution. The search was conducted by two independent authors using a standardised data extraction form. For each indicator we extracted its definition, calculation, its rationale and its positive and negative points. In order to reduce bias, data extraction and analysis was performed by two independent authors. FINDINGS: We included 76 articles. A total of 57 indicators were identified. We have classified those indicators into 6 categories: 9 indicators of research activity, 24 indicators of scientific production and impact, 5 indicators of collaboration, 7 indicators of industrial production, 4 indicators of dissemination, 8 indicators of health service impact. The most widely discussed and described is the h-index with 31 articles discussing it. DISCUSSION: The majority of indicators found are bibliometric indicators of scientific production and impact. Several indicators have been developed to improve the h-index. This indicator has also inspired the creation of two indicators to measure industrial production and collaboration. Several articles propose indicators measuring research impact without detailing a methodology for calculating them. Many bibliometric indicators identified have been created but have not been used or further discussed. PMID- 25837971 TI - Primary bladder lymphoma, diffuse large B-cell type: Case report and literature review of 26 cases. AB - Primary lymphoma of the urinary bladder is exceedingly rare, representing 0.2% of all extranodal non-Hodgkin's lymphoma. Although Matsuno et al. and others state the most common type is mucosa-associated lymphoid tissue (MALT) lymphoma, 20% of all the primary lymphomas of the urinary bladder are considered to be high grade neoplasms; the majority being diffuse large B-cell lymphoma (DLBCL). This is a case report of a 48-year-old man that presented with hematuria, frequency, nocturia, and flank pain that was found to have high grade DLBCL. Twenty-six other cases of both low and high grade primary bladder lymphomas were selected in order to provide a thorough comparison of different treatment modalities. Of the cases reviewed, bladder lymphoma was more common in females (2:1). The average age at diagnosis was 63.9 years old (low grade: 68.7 years old, high grade: 58.8 years old). The most common low-grade neoplasm was MALT lymphoma (85.7%). For the low-grade malignancies, the most successful treatments were simple therapies (2 transurethral resection of a bladder tumour [TURBT], 1 antibiotics), solitary chemotherapy, and combination TURBT/chemo; all 3 of which achieved 100% clinical remission (CR) in the cases reviewed. The most common high grade neoplasm was DLBCL (76.9%). The most successful therapies used to treat high grade lesions were solitary chemotherapy (cyclophosphamide, duanorubacin, vincristine, prednisolone [CHOP] or ritoximab, CHOP [R-CHOP]) and combination therapies (2 radiation/CHOP, 2 surgery/CHOP). In the agreement with the current literature, this review has shown that simple therapies (TURBT) are equally as effective as aggressive treatments (chemotherapy, radiation) and should therefore be used as first line treatment in low grade tumors. For high grade malignancies, chemotherapy (R-CHOP or CHOP) alone or combination therapy (CHOP/surgery or CHOP/radiation) is recommended. PMID- 25837970 TI - Prediction of Juvenile-Onset Myopia. AB - IMPORTANCE: Myopia (nearsightedness) has its onset in childhood and affects about one-third of adults in the United States. Along with its high prevalence, myopia is expensive to correct and is associated with ocular diseases that include glaucoma and retinal detachment. OBJECTIVE: To determine the best set of predictors for myopia onset in school-aged children. DESIGN, SETTING, AND PARTICIPANTS: The Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study was an observational cohort study of ocular development and myopia onset conducted at 5 clinical sites from September 1, 1989, through May 22, 2010. Data were collected from 4512 ethnically diverse, nonmyopic school-aged children from grades 1 through 8 (baseline grades 1 through 6) (ages 6 through 13 years [baseline, 6 through 11 years]). MAIN OUTCOMES AND MEASURES: We evaluated 13 candidate risk factors for their ability to predict the onset of myopia. Myopia onset was defined as -0.75 diopters or more of myopia in each principal meridian in the right eye as measured by cycloplegic autorefraction at any visit after baseline until grade 8 (age 13 years). We evaluated risk factors using odds ratios from discrete time survival analysis, the area under the curve, and cross validation. RESULTS: A total of 414 children became myopic from grades 2 through 8 (ages 7 through 13 years). Of the 13 factors evaluated, 10 were associated with the risk for myopia onset (P < .05). Of these 10 factors, 8 retained their association in multivariate models: spherical equivalent refractive error at baseline, parental myopia, axial length, corneal power, crystalline lens power, ratio of accommodative convergence to accommodation (AC/A ratio), horizontal/vertical astigmatism magnitude, and visual activity. A less hyperopic/more myopic baseline refractive error was consistently associated with risk of myopia onset in multivariate models (odds ratios from 0.02 to 0.13, P < .001), while near work, time outdoors, and having myopic parents were not. Spherical equivalent refractive error was the single best predictive factor that performed as well as all 8 factors together, with an area under the curve (C statistic) ranging from 0.87 to 0.93 (95% CI, 0.79-0.99). CONCLUSIONS AND RELEVANCE: Future myopia can be predicted in a nonmyopic child using a simple, single measure of refractive error. Future trials for prevention of myopia should target the child with low hyperopia as the child at risk. PMID- 25837973 TI - The effects of neuropeptide urocortin 2 on the spontaneous discharge and glutamatergic neurotransmission of striatum neurons. AB - The primary cause of the neurodegenerative process that underlies Parkinson's disease (PD) is still unknown. Different mechanisms probably contribute to triggering neuronal death in the nigro-striatum pathway. The neuropeptide urocortin 2 (UCN2) plays an important role in the regulation of striatum (STR) neurons projection. We investigated the effects of UCN2 on spontaneous discharge and glutamatergic responses in STR for a better understanding of the pathogenesis of PD. The experiment used microiontophoresis method to observe the effects of UCN2 on STR neurons' firing rates in vivo. Corticotrophin releasing factor receptor 2 (CRF-R2) selective inhibitor, astressin-2B (AST-2B), was administered simultaneously with UCN2 to investigate the effects of UCN2 on CRF-R2. Moreover, we further explored the effects of UCN2 on glutamatergic responses in STR neurons. We found that UCN2 could significantly inhibit the firing rate of 84% of the tested STR neurons, and its inhibitory effect followed a concentration dependent manner. During the microiontophoresis of GLU, the excitatory firing of glutamatergic neurons could be attenuated by the addition of UCN2, but enhanced by the application of AST-2B. The results suggest that UCN2 could regulate the effects of STR neurotransmitters (GLU) via CRF-R2 and may thereby contribute to the improvement of PD. PMID- 25837974 TI - Factors effective on survival after radical prostatectomy: To what extent is pre operative biopsy Gleason scoring is confident in predicting the prognosis? AB - In the present study, the effect of different grades on independent survival from the biochemical relapse was investigated through comparison of the histological grades of the biopsy and prostatectomy materials in patients undergoing radical prostatectomy (RP). A total of 152 patients undergoing RP following biopsy were retrospectively investigated in an attempt to reveal the effect of discordance between needle biopsy Gleason score and RP Gleason score on prostate specific antigen relapse-free survival. Accordingly, while 58.3% (14/24) survival was seen in the patients in Group 1 (high-graded) with Gleason score 7, 93.7% (15/16) survival has been seen in the patients in Group 2 (low-graded) and Group 3 (same Gleason scores) with Gleason score 7. The difference in-between has been statically found significant (P < 0.001). Similarly, while a 10% (1/10) survival is seen in the patients in Group 1 with Gleason score 8 and above, 75% (3/4) survival has been observed in the patients in Group 2 and 3 with Gleason score 8 and above. Also in this comparison, the difference in-between has been statically found significant (P = 0.041). Eventually, different grading, particularly determination of Gleason score higher than the RP specimen biopsy also bring about bad pathologic parameters and shortened survival periods. PMID- 25837972 TI - Vegetative hyphal fusion and subsequent nuclear behavior in Epichloe grass endophytes. AB - Epichloe species (including the former genus Neotyphodium) are fungal symbionts of many agronomically important forage grasses, and provide their grass hosts with protection from a wide range of biotic and abiotic stresses. Epichloe species include many interspecific hybrids with allodiploid-like genomes, which may provide the potential for combined traits or recombination to generate new traits. Though circumstantial evidence suggests that such interspecific hybrids might have arisen from nuclear fusion events following vegetative hyphal fusion between different Epichloe strains, this hypothesis has not been addressed empirically. Here, we investigated vegetative hyphal fusion and subsequent nuclear behavior in Epichloe species. A majority of Epichloe strains, especially those having a sexual stage, underwent self vegetative hyphal fusion. Vegetative fusion also occurred between two hyphae from different Epichloe strains. Though Epichloe spp. are uninucleate fungi, hyphal fusion resulted in two nuclei stably sharing the same cytoplasm, which might ultimately lead to nuclear fusion. In addition, protoplast fusion experiments gave rise to uninucleate putative hybrids, which apparently had two markers, one from each parent within the same nucleus. These results are consistent with the notion that interspecific hybrids arise from vegetative hyphal fusion. However, we also discuss additional factors, such as post-hybridization selection, that may be important to explain the recognized prevalence of hybrids in Epichloe species. PMID- 25837975 TI - Purification and characterization of a bacteriocin from an oenological strain of Leuconostoc mesenteroides subsp. cremoris. AB - Malolactic fermentation (MLF), which improves organoleptic properties and biologic stability of some wines, may cause wine spoilage if uncontrolled. Bacteriocins were reported as efficient preservatives to control MLF through their bactericidal effect on malolactic bacteria. Leuconostoc mesenteroides subsp. cremoris W3 isolated from wine produces an inhibitory substance that is bactericidal against malolactic bacteria in model wine medium. Treatment of the culture supernatant of strain W3 with proteases eliminated the inhibitory activity, which proved that it is a true bacteriocin and we tentatively termed it mesentericin W3. The bacteriocin inhibited the growth of food-borne pathogenic bacteria such as Enterococcus faecalis, Listeria monocytogenes, and malolactic bacteria. It was active over a wide pH range and stable to organic solvents and heat. Mesentericin W3 was purified to homogeneity by a pH-mediated cell adsorption-desorption method, cation exchange, hydrophobic interaction, and reverse-phase chromatography. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy (MS) and partial amino acid sequence analysis revealed that mesentericin W3 was identical to mesentericin Y105. PMID- 25837976 TI - Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan? AB - BACKGROUND: This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. METHODS: We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. RESULTS: This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". CONCLUSIONS: From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year. PMID- 25837977 TI - Radiation-induced alterations of osteogenic and chondrogenic differentiation of human mesenchymal stem cells. AB - While human mesenchymal stem cells (hMSCs), either in the bone marrow or in tumour microenvironment could be targeted by radiotherapy, their response is poorly understood. The oxic effects on radiosensitivity, cell cycle progression are largely unknown, and the radiation effects on hMSCs differentiation capacities remained unexplored. Here we analysed hMSCs viability and cell cycle progression in 21% O2 and 3% O2 conditions after medical X-rays irradiation. Differentiation towards osteogenesis and chondrogenesis after irradiation was evaluated through an analysis of differentiation specific genes. Finally, a 3D culture model in hypoxia was used to evaluate chondrogenesis in conditions mimicking the natural hMSCs microenvironment. The hMSCs radiosensitivity was not affected by O2 tension. A decreased number of cells in S phase and an increase in G2/M were observed in both O2 tensions after 16 hours but hMSCs released from the G2/M arrest and proliferated at day 7. Osteogenesis was increased after irradiation with an enhancement of mRNA expression of specific osteogenic genes (alkaline phosphatase, osteopontin). Osteoblastic differentiation was altered since matrix deposition was impaired with a decreased expression of collagen I, probably through an increase of its degradation by MMP-3. After induction in monolayers, chondrogenesis was altered after irradiation with an increase in COL1A1 and a decrease in both SOX9 and ACAN mRNA expression. After induction in a 3D culture in hypoxia, chondrogenesis was altered after irradiation with a decrease in COL2A1, ACAN and SOX9 mRNA amounts associated with a RUNX2 increase. Together with collagens I and II proteins decrease, associated to a MMP-13 expression increase, these data show a radiation-induced impairment of chondrogenesis. Finally, a radiation-induced impairment of both osteogenesis and chondrogenesis was characterised by a matrix composition alteration, through inhibition of synthesis and/or increased degradation. Alteration of osteogenesis and chondrogenesis in hMSCs could potentially explain bone/joints defects observed after radiotherapy. PMID- 25837978 TI - Promising perceptions, divergent practices and barriers to integrated malaria prevention in Wakiso district, Uganda: a mixed methods study. AB - BACKGROUND: The World Health Organization recommends use of multiple approaches to control malaria. The integrated approach to malaria prevention advocates the use of several malaria prevention methods in a holistic manner. This study assessed perceptions and practices on integrated malaria prevention in Wakiso district, Uganda. METHODS: A clustered cross-sectional survey was conducted among 727 households from 29 villages using both quantitative and qualitative methods. Assessment was done on awareness of various malaria prevention methods, potential for use of the methods in a holistic manner, and reasons for dislike of certain methods. Households were classified as using integrated malaria prevention if they used at least two methods. Logistic regression was used to test for factors associated with the use of integrated malaria prevention while adjusting for clustering within villages. RESULTS: Participants knew of the various malaria prevention methods in the integrated approach including use of insecticide treated nets (97.5%), removing mosquito breeding sites (89.1%), clearing overgrown vegetation near houses (97.9%), and closing windows and doors early in the evenings (96.4%). If trained, most participants (68.6%) would use all the suggested malaria prevention methods of the integrated approach. Among those who would not use all methods, the main reasons given were there being too many (70.2%) and cost (32.0%). Only 33.0% households were using the integrated approach to prevent malaria. Use of integrated malaria prevention by households was associated with reading newspapers (AOR 0.34; 95% CI 0.22 -0.53) and ownership of a motorcycle/car (AOR 1.75; 95% CI 1.03 - 2.98). CONCLUSION: Although knowledge of malaria prevention methods was high and perceptions on the integrated approach promising, practices on integrated malaria prevention was relatively low. The use of the integrated approach can be improved by promoting use of multiple malaria prevention methods through various communication channels such as mass media. PMID- 25837979 TI - Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection. AB - HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV 1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV 1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies. PMID- 25837980 TI - Biocompatibility of cardiopulmonary bypass circuit with new polymer Senko E Ternal CoatingTM. AB - OBJECTIVE: The aim of this study was to compare the biocompatibility of a new Senko E-Ternal coating (SEC) for cardiopulmonary bypass (CPB) circuits with the well-established poly-2-methoxyethyl acrylate (PMEA) coating. METHODS: Forty patients undergoing aortic valve replacement were randomly assigned to either an SEC-coated group (n = 20) or a PMEA-coated group (n = 20). Clinical data and the following markers were analyzed: platelet count, platelet factor (PF) 4, fibrinogen, fibrinogen degradation products (FDPs), antithrombin III (AT III), thrombin-antithrombin complex (TAT), plasminogen, complement hemolytic activity (CH50), complement 3 (C3) and interleukin-6 (IL-6). Blood samples were obtained at five time points in both groups. RESULTS: CPB time, aortic cross-clamp time and blood loss and transfusion were similar in both groups. There were no significant differences between the groups in terms of platelet count, PF4 and all coagulation and fibrinolytic parameters (FDP, AT III, TAT, and plasminogen) at any time points. Inflammatory markers (CH50, C3 and IL-6) were also similar in both groups at all time points. CONCLUSIONS: The SEC-coated circuit demonstrated equivalent biocompatibility to the PMEA-coated circuit. SEC-coated circuits are, therefore, favorably comparable to PMEA-coated circuits for clinical use in CPB. PMID- 25837981 TI - An arterio-venous bridge for gradual weaning from adult veno-arterial extracorporeal life support. AB - PURPOSE: Weaning from extracorporeal life support (ELS) is particularly challenging when cardiac recovery is slow, largely incomplete and hard to predict. Therefore, we describe an individualized gradual weaning strategy using an arterio-venous (AV) bridge incorporated into the circuit to facilitate weaning. METHODS: Thirty adult patients weaned from veno-arterial ELS using an AV bridge were retrospectively analyzed. Serial echocardiography and hemodynamic monitoring were used to assess cardiac recovery and load responsiveness. Upon early signs of myocardial recovery, an AV bridge with an Hoffman clamp was added to the circuit and weaning was initiated. Support flow was reduced stepwise by 10 15% every 2 to 8 hours while the circuit flow was maintained at 3.5-4.5 L/min. RESULTS: The AV bridge facilitated gradual weaning in all 30 patients (median age: 66 [53-71] years; 21 males) over a median period of 25 [8-32] hours, with a median support duration of 96 [31-181] hours. During weaning, the median left ventricular ejection fraction was 25% [15-32] and the median velocity time integral of the aortic valve was 16 cm [10-23]. Through the weaning period, the mean arterial blood pressure was maintained at 70 mmHg and the activated partial thromboplastin time was 60 +/- 10 seconds without additional systemic heparinization. Neither macroscopic thrombus formation in the ELS circuit during and after weaning nor clinically relevant thromboembolism was observed. CONCLUSION: Incorporation of an AV bridge for weaning from veno-arterial ELS is safe and feasible to gradually wean patients with functional cardiac recovery without compromising the circuit integrity. PMID- 25837982 TI - Versatile, simple-to-use microfluidic cell-culturing chip for long-term, high resolution, time-lapse imaging. AB - Optical long-term observation of individual cells, combined with modern data analysis tools, allows for a detailed study of cell-to-cell variability, heredity, and differentiation. We developed a microfluidic device featuring facile cell loading, simple and robust operation, and which is amenable to high resolution life-cell imaging. Different cell strains can be grown in parallel in the device under constant or changing media perfusion without cross-talk between the cell ensembles. The culturing chamber has been optimized for use with nonadherent cells, such as Saccharomyces cerevisiae, and enables controlled colony growth over multiple generations under aerobic or anaerobic conditions. Small changes in the layout will make the device also useable with bacteria or mammalian cells. The platform can be readily set up in every laboratory with minimal additional requirements and can be operated without technology training. PMID- 25837983 TI - Stability of chitosan-a challenge for pharmaceutical and biomedical applications. AB - Chitosan-one of the natural multifunctional polymers-due to its unique and versatile biological properties is regarded as a useful compound in medical and pharmaceutical technology. Recently, considerable research effort has been made in order to develop safe and efficient chitosan products. However, the problem of poor stability of chitosan-based systems restricts its practical applicability; thus, it has become a great challenge to establish sufficient shelf-life for chitosan formulations. Improved stability can be assessed by controlling the environmental factors, manipulating processing conditions (e.g., temperature), introducing a proper stabilizing compound, developing chitosan blends with another polymer, or modifying the chitosan structure using chemical or ionic agents. This review covers the influence of internal, environmental, and processing factors on the long-term stability of chitosan products. The aim of this paper is also to highlight the latest developments which enable the physicochemical properties of chitosan-based applications to be preserved upon storage. PMID- 25837984 TI - Recent advances in exopolysaccharides from Paenibacillus spp.: production, isolation, structure, and bioactivities. AB - This review provides a comprehensive summary of the most recent developments of various aspects (i.e., production, purification, structure, and bioactivity) of the exopolysaccharides (EPSs) from Paenibacillus spp. For the production, in particular, squid pen waste was first utilized successfully to produce a high yield of inexpensive EPSs from Paenibacillus sp. TKU023 and P. macerans TKU029. In addition, this technology for EPS production is prevailing because it is more environmentally friendly. The Paenibacillus spp. EPSs reported from various references constitute a structurally diverse class of biological macromolecules with different applications in the broad fields of pharmacy, cosmetics and bioremediation. The EPS produced by P. macerans TKU029 can increase in vivo skin hydration and may be a new source of natural moisturizers with potential value in cosmetics. However, the relationships between the structures and activities of these EPSs in many studies are not well established. The contents and data in this review will serve as useful references for further investigation, production, structure and application of Paenibacillus spp. EPSs in various fields. PMID- 25837985 TI - Dietary docosahexaenoic acid and eicosapentaenoic acid influence liver triacylglycerol and insulin resistance in rats fed a high-fructose diet. AB - This study aimed to examine the benefits of different amounts of omega-3 (n-3) polyunsaturated fatty acids from fish oil (FO) on lipid metabolism, insulin resistance and gene expression in rats fed a high-fructose diet. Male Wistar rats were separated into two groups: Control (C, n = 6) and Fructose (Fr, n = 32), the latter receiving a diet containing 63% by weight fructose for 60 days. After this period, 24 animals from Fr group were allocated to three groups: FrFO2 (n = 8) receiving 63% fructose and 2% FO plus 5% soybean oil; FrFO5 (n = 8) receiving 63% fructose and 5% FO plus 2% soybean oil; and FrFO7 (n = 8) receiving 63% fructose and 7% FO. Animals were fed these diets for 30 days. Fructose led to an increase in liver weight, hepatic and serum triacylglycerol, serum alanine aminotransferase and HOMA1-IR index. These alterations were reversed by 5% and 7% FO. FO had a dose-dependent effect on expression of genes related to hepatic beta oxidation (increased) and hepatic lipogenesis (decreased). The group receiving the highest FO amount had increased markers of oxidative stress. It is concluded that n-3 fatty acids may be able to reverse the adverse metabolic effects induced by a high fructose diet. PMID- 25837986 TI - Rapid-maxillary-expansion induced rhinological effects: a retrospective multicenter study. AB - Conventional dental-borne rapid maxillary expansion (RME) leads to a widening of the airways, followed by improved nasal breathing. Although combined skeletal dental appliances are nowadays being inserted increasingly often and provide a force at the center of resistance in the nasomaxillary complex, no study exists so far that shows whether this treatment may improve the expansionary effect on the airways. In this study, low-dose computed tomography (CT) images from 31 patients (average age 14.63 +/- 0.38 years) were examined retrospectively. Both records (T0 = before expansion and T1 = immediately after maximum expansion) were taken in a time interval of 25 days to avoid growth influence. Five patients were treated with Hyrax RME, 6 patients with Hybrid RME, and 20 patients with acrylic cap RME. The total airway volume increased highly significantly (mean +7272.6 mm(3); P < 0.001, power = 0.998), representing an average airway expansion of +11.54 % (2.35 %/mm activation). While the nasopharynx and oropharynx showed highly significant expansion (P < 0.000, power = 0.999), the airway at the laryngopharynx did not change significantly (P > 0.779, power = 0.05). Although the patients were significantly older in the Hybrid RME group (P = 0.006), the positive rhinological effects were comparable within all groups of different appliances (P > 0.316). Hybrid RME may, therefore, be an advisable procedure in patients with nasomaxillary impairment and pronounced patient's age. PMID- 25837987 TI - The treatment of snoring by radiofrequency-assisted uvulopalatoplasty and results after one-session protocol: a prospective, longitudinal, non-randomized study. AB - Snoring is usually caused by the vibration of walls of the soft palate at the pharyngeal level. Its worldwide prevalence is estimated to range between 2 and 85% depending on age, gender or population group. The aim of this study is to determine the degree of improvement that can be subjectively evident in patients treated by snoring with radiofrequency-assisted uvulopalatoplasty based on a one session protocol. This is a prospective, longitudinal, non-randomized study. Patients of both sexes, aged 18 years, who attended to the ENT consultation in a tertiary hospital with snoring during the period of July 2012-July 2013 were included. Age, body mass index, Epworth sleepiness scale were calculated. The volume of snoring of each subject was assessed using a visual analog scale. A total of 27 patients were included in the study; the average age of the sample was 49 years (+/-8.7; min 36/max 74); of these 22 (81.5%) were male and 5 (18.5%) females. The average BMI was 27.07 +/- 2.5 (min 23.15/max 29.39) before the test and after 1 year was 26.75 +/- 2.32 (min 23.11/max 29.56) with no statistically significant differences in BMI before and after surgery (p = 0.407). Preoperative snoring intensity was 8.10 +/- 0.93 according to VAS. We found a statistically significant difference in the post-operative intensity at 3 months of 3.93 +/- 0.88 (p <= 0.05) at 6 months of 4.41 +/- 1.08 (p <= 0.05), and after 1 year 4.90 +/- 0.77 (p <= 0.05). The average rate of ESS was significantly higher preoperatively than post-operative, being 8.76 +/- 3.1 preoperative and 6.93 +/- 1.68 post-operative (p <= 0.05). We conclude that the use of radiofrequency in simple snorers with an apnea/hypopnea index <15 events per hour and a BMI < 30 kg/m(2) in whom clinically proven that the source of snoring is the soft palate, can be treated by one-session protocol, being possible to obtain an improvement of snoring up to 70% of cases by a short follow-up period. PMID- 25837988 TI - Re: 'Protective Effect of Focal Adhesion Kinase against Skeletal Muscle Reperfusion Injury after Acute Limb Ischemia'. PMID- 25837989 TI - Ledipasvir/Sofosbuvir: a review of its use in chronic hepatitis C. AB - The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor ledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir (ledipasvir/sofosbuvir; Harvoni((r))) was recently approved in the US and the EU. The phase III ION trials included treatment-naive (ION-1 and -3) or treatment experienced (ION-2) patients with chronic HCV genotype 1 infection (~20 % of patients in ION-1 and -2 had cirrhosis, whereas no patient in ION-3 had cirrhosis). A sustained virological response 12 weeks' post-treatment (SVR12) was seen in 99 % of treatment-naive patients receiving ledipasvir/sofosbuvir for 12 weeks in ION-1, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. Moreover, in ION-3, an 8-week regimen achieved an SVR12 rate of 94 % overall and 97 % in the subgroup of patients with a baseline HCV RNA level of <6 million IU/mL. SVR12 rates of 94 and 99 % were seen in treatment-experienced patients who received ledipasvir/sofosbuvir for 12 and 24 weeks in ION-2. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infection, in HCV and HIV co infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Oral ledipasvir/sofosbuvir was generally well tolerated. In conclusion, ledipasvir/sofosbuvir is an important new single-tablet regimen that represents a significant advance in the treatment of chronic hepatitis C. PMID- 25837990 TI - Panobinostat: first global approval. AB - Novartis has developed oral and intravenous formulations of panobinostat (Farydak((r))), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical development worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma. PMID- 25837991 TI - Is Direct Antiglobulin Test Crucial in the Evaluation of Neonatal Hyperbilirubinemia? PMID- 25837993 TI - Transport of Free Fatty Acids from Plasma to the Endothelium of Cardiac Muscle: A Theoretical Study. AB - Fatty acids are transported in a multistep process from the plasma to the mitochondria, where they are oxidized in order to meet energy requirements of the myocardium. Some of those steps, mainly the crossing of the involved cells' membranes are far from being understood. Here, by means of mathematical modeling we address the problem of the fatty acid transport from the microvascular compartment to the endothelium. Values of parameters that are incorporated in the model are deduced from relevant experimental work. Concentration profiles are established as solutions of diffusion-reaction equations both numerically and using an analytical asymptotic approximation. The analytical solution accurately determines the fatty acid flux for any set of parameter values in contrast to off the-shelf numerical solvers that fail under quite a few circumstances due to the stiffness of the differential equation system. Sensitivity analysis indicates that in spite of few uncertain parameter values, most of our conclusions are expected to be valid throughout the physiological range of operation. We find that in order to have an adequate fatty acid uptake rate it is essential for the luminal endothelial membrane to have very fast fatty acid transporters and/or specific sites that interact with the albumin-fatty acids complex. PMID- 25837992 TI - Next-generation sequencing reveals the biological significance of the N(2),3 ethenoguanine lesion in vivo. AB - Etheno DNA adducts are a prevalent type of DNA damage caused by vinyl chloride (VC) exposure and oxidative stress. Etheno adducts are mutagenic and may contribute to the initiation of several pathologies; thus, elucidating the pathways by which they induce cellular transformation is critical. Although N(2),3-ethenoguanine (N(2),3-epsilonG) is the most abundant etheno adduct, its biological consequences have not been well characterized in cells due to its labile glycosidic bond. Here, a stabilized 2'-fluoro-2'-deoxyribose analog of N(2),3-epsilonG was used to quantify directly its genotoxicity and mutagenicity. A multiplex method involving next-generation sequencing enabled a large-scale in vivo analysis, in which both N(2),3-epsilonG and its isomer 1,N(2)-ethenoguanine (1,N(2)-epsilonG) were evaluated in various repair and replication backgrounds. We found that N(2),3-epsilonG potently induces G to A transitions, the same mutation previously observed in VC-associated tumors. By contrast, 1,N(2) epsilonG induces various substitutions and frameshifts. We also found that N(2),3 epsilonG is the only etheno lesion that cannot be repaired by AlkB, which partially explains its persistence. Both epsilonG lesions are strong replication blocks and DinB, a translesion polymerase, facilitates the mutagenic bypass of both lesions. Collectively, our results indicate that N(2),3-epsilonG is a biologically important lesion and may have a functional role in VC-induced or inflammation-driven carcinogenesis. PMID- 25837994 TI - A Commensal Strain of Staphylococcus epidermidis Overexpresses Membrane Proteins Associated with Pathogenesis When Grown in Biofilms. AB - Staphylococcus epidermidis has emerged as one of the major nosocomial pathogens associated with infections of implanted medical devices. The most important factor in the pathogenesis of these infections is the formation of bacterial biofilms. Bacteria grown in biofilms are more resistant to antibiotics and to the immune defence system than planktonic bacteria. In these infections, the antimicrobial therapy usually fails and the removal of the biofilm-coated implanted device is the only effective solution. In this study, three proteomic approaches were performed to investigate membrane proteins associated to biofilm formation: (i) sample fractionation by gel electrophoresis, followed by isotopic labelling and LC-MS/MS analysis, (ii) in-solution sample preparation, followed by isotopic labelling and LC-MS/MS analysis and (iii) in-solution sample preparation and label-free LC-MS/MS analysis. We found that the commensal strain S. epidermidis CECT 231 grown in biofilms expressed higher levels of five membrane and membrane-associated proteins involved in pathogenesis: accumulation associated protein, staphylococcal secretory antigen, signal transduction protein TRAP, ribonuclease Y and phenol soluble modulin beta 1 when compared with bacteria grown under planktonic conditions. These results indicate that a commensal strain can acquire a pathogenic phenotype depending on the mode of growth. PMID- 25837995 TI - Erratum to: Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice. PMID- 25837996 TI - The adverse effects of diabetes on osteoarthritis: update on clinical evidence and molecular mechanisms. AB - Projected increases in the prevalence of both diabetes mellitus (DM) and osteoarthritis (OA) ensure their common co-existence. In an era of increasing attention to personalized medicine, understanding the influence of common comorbidities such as DM should result in improved care of patients with OA. In this narrative review, we summarize the literature addressing the interactions between DM and OA spanning the years from 1962 to 2014. We separated studies depending on whether they investigated clinical populations, animal models, or cells and tissues. The clinical literature addressing the influence of DM on OA and its therapeutic outcomes suggests that DM may augment the development and severity of OA and that DM increases risks associated with joint replacement surgery. The few high quality studies using animal models also support an adverse effect of DM on OA. We review strengths and weaknesses of the common rodent models of DM. The heterogeneous literature derived from studies of articular cells and tissues also supports the existence of biochemical and biomechanical changes in articular tissues in DM, and begins to characterize molecular mechanisms activated in diabetic-like environs which may contribute to OA. Increasing evidence from the clinic and the laboratory supports an adverse effect of DM on the development, severity, and therapeutic outcomes for OA. To understand the mechanisms through which DM contributes to OA, further studies are clearly necessary. Future studies of DM-influenced mechanisms may shed light on general mechanisms of OA pathogenesis and result in more specific and effective therapies for all OA patients. PMID- 25837997 TI - Regulation of intestinal IgA responses. AB - The intestine harbors enormous numbers of commensal bacteria and is under frequent attack from food-borne pathogens and toxins. A properly regulated immune response is critical for homeostatic maintenance of commensals and for protection against infection and toxins in the intestine. Immunoglobulin A (IgA) isotype antibodies function specifically in mucosal sites such as the intestines to help maintain intestinal health by binding to and regulating commensal microbiota, pathogens and toxins. IgA antibodies are produced by intestinal IgA antibody secreting plasma cells generated in gut-associated lymphoid tissues from naive B cells in response to stimulations of the intestinal bacteria and components. Research on generation, migration, and maintenance of IgA-secreting cells is important in our effort to understand the biology of IgA responses and to help better design vaccines against intestinal infections. PMID- 25837998 TI - The development and function of thymic B cells. AB - Thymic B cells are a unique population of B lymphocytes that reside at the cortico-medullary junction of the thymus, an organ that is specialized for the development and selection of T cells. These B cells are distinct from peripheral B cells both in terms of their origin and phenotype. Multiple lines of evidence suggest that they develop within the thymus from B lineage-committed progenitors and are not recirculating peripheral B cells. Furthermore, thymic B cells have a highly activated phenotype. Because of their location in the thymic medulla, they have been thought to play a role in T cell negative selection. Thymic B cells are capable of inducing negative selection in a number of model antigen systems, including viral super antigen, peptides from immunoglobulin, and cognate self antigen presented by B cell receptor-mediated uptake. These findings establish thymic B cells as a novel and important population to study; however, much work remains to be done to understand how all of these unique aspects of thymic B cell biology inform their function. PMID- 25838000 TI - Low self-esteem and positive beliefs about smoking: a destructive combination for male college students. AB - INTRODUCTION: Men exhibit higher rates of smoking relative to women (CDC, 2014). Given the associated health and socio-economic consequences, it would be valuable to explore the psychological factors underlying this variance. We contend that positive beliefs about smoking influence this difference, and that self-esteem moderates these beliefs. METHOD: As part of a multi-institutional collaborative study funded by the American Legacy Foundation, 445 participants who reported being either steady or occasional smokers completed a series of questionnaires assessing their beliefs and behaviors involving smoking as well as several dispositional variables. Moderated mediation was used to test for conditional indirect effects. RESULTS: The total, indirect, and direct effects of gender were significant for individuals with lower, but not higher self-esteem. Males with lower self-esteem exhibited more positive beliefs and smoking behavior than females with lower self-esteem. No differences between males and females with higher self-esteem were observed. CONCLUSION: The gender gap in smoking behavior appears to occur primarily among individuals with lower self-esteem. It is a particularly detrimental risk factor for males, as it is related to higher positive views about smoking and increased tobacco consumption. These results highlight the importance of developing multifaceted gender specific belief-based preventative interventions to address smoking related behaviors. PMID- 25837999 TI - The mechanism of ageing: primary role of transposable elements in genome disintegration. AB - Understanding the molecular basis of ageing remains a fundamental problem in biology. In multicellular organisms, while the soma undergoes a progressive deterioration over the lifespan, the germ line is essentially immortal as it interconnects the subsequent generations. Genomic instability in somatic cells increases with age, and accumulating evidence indicates that the disintegration of somatic genomes is accompanied by the mobilisation of transposable elements (TEs) that, when mobilised, can be mutagenic by disrupting coding or regulatory sequences. In contrast, TEs are effectively silenced in the germ line by the Piwi piRNA system. Here, we propose that TE repression transmits the persistent proliferation capacity and the non-ageing phenotype (e.g., preservation of genomic integrity) of the germ line. The Piwi-piRNA pathway also operates in tumorous cells and in somatic cells of certain organisms, including hydras, which likewise exhibit immortality. However, in somatic cells lacking the Piwi-piRNA pathway, gradual chromatin decondensation increasingly allows the mobilisation of TEs as the organism ages. This can explain why the mortality rate rises exponentially throughout the adult life in most animal species, including humans. PMID- 25838001 TI - Attentional bias and treatment adherence in substitute-prescribed opiate users. AB - BACKGROUND: Attentional bias (AB) is implicated in the development and maintenance of substance dependence and in treatment outcome. We assessed the effects of attentional bias modification (ABM), and the relationship between AB and treatment adherence in opiate dependent patients. METHOD: An independent groups design was used to compare 23 opiate dependent patients with 21 healthy controls. Participants completed an AB task before either a control or an ABM task designed to train attention away from substance-related stimuli. Pre- and post-ABM AB and craving were assessed to determine any changes. Relationships between treatment adherence ('using on top' of prescribed opiates or not) and AB, craving and psychopathology were also examined. RESULTS: There was no baseline difference in AB between patients and controls, and no significant effect of ABM on AB or substance craving. However, treatment adherent patients who did not use illicit opiates on top of their prescribed opiates had statistically significantly greater AB away from substance-related stimuli than both participants using on top and controls, and reported significantly lower levels of craving than non-treatment adherent patients. CONCLUSION: Whilst we did not find any significant effects of ABM on AB or craving, patients who were treatment adherent differed from both those who were not and from controls in their attentional functioning and substance craving. These findings are the first to suggest that AB may be a within-treatment factor predictive of adherence to pharmacological treatment and potentially of recovery in opiate users. PMID- 25838002 TI - Toward understanding the role of the neuron-specific BAF chromatin remodeling complex in memory formation. AB - The long-term storage of memory requires the finely tuned coordination of intracellular signaling with the transcriptional, translational and epigenetic regulations of gene expression. Among the epigenetic mechanisms, however, we know relatively little about the involvement of chromatin remodeling-dependent control of gene expression in cognitive brain functions, compared with our knowledge of other such mechanisms (for example, histone modifications and DNA methylation). A few recent studies have implicated the Brm/Brg-associated factor (BAF) chromatin remodeling complex, a mammalian homolog of the yeast Swi/Snf complex, in neuronal structural/functional plasticity and memory formation. The BAF complex was previously known to have a critical role in neurodevelopment, but these recent findings indicate that it also contributes to both cognitive functions in the adult brain and human mental disorders characterized by intellectual disability. In this review, we provide a brief overview of the BAF complexes, introduce recent research findings that link their functions to memory formation, and speculate on the yet-unknown molecular mechanisms that may be relevant to these processes. PMID- 25838003 TI - MyD88-BLT2-dependent cascade contributes to LPS-induced interleukin-6 production in mouse macrophage. AB - Endotoxic responses to bacterial lipopolysaccharide (LPS) are triggered by Toll like receptor 4 (TLR4) and involve the production of inflammatory mediators, including interleukin-6 (IL-6), by macrophages. The detailed mechanism of IL-6 production by macrophages in response to LPS has remained unclear, however. We now show that LPS induces IL-6 synthesis in mouse peritoneal macrophages via the leukotriene B4 receptor BLT2. Our results suggest that TLR4-MyD88 signaling functions upstream of BLT2 and that the generation of reactive oxygen species (ROS) by NADPH oxidase 1 (Nox1) and consequent activation of the transcription factor nuclear factor (NF)-kappaB function downstream of BLT2 in this response. These results suggest that a TLR4-MyD88-BLT2-Nox1-ROS-NF-kappaB pathway contributes to the synthesis of IL-6 in LPS-stimulated mouse macrophages. PMID- 25838004 TI - Education for global oral health: progress in improving awareness and defining competencies. PMID- 25838005 TI - A competency matrix for global oral health. AB - The Lancet Commission on Education of Health Professionals for the 21(st) Century calls for enhancing health education for the needs and challenges of the 21st century to improve health status globally. To complement the Lancet report, this article makes recommendations for including core global health competencies in the education of health care professionals and specific groups of the public who are relevant to oral health in a global context in order to tackle the burden of oral diseases. Experts from various professional backgrounds developed global oral health competencies for four target groups: Group 1 was defined as dental students, residents/trainee specialists (or equivalent), and dentists; Group 2 was community health workers, dental hygienists, and dental therapists (or the equivalent); Group 3 was health professionals such as physicians, physician assistants, nurses, nurse practitioners, and pharmacists; and Group 4 was non health professionals in the public arena such as parents, teachers, decision makers, key opinion leaders, and health and consumer advocates. Key competencies for members of each of the four target groups are presented in a matrix. The suggested competency matrix shows that many other health professions and groups in society have potentially crucial roles in the prevention, control, and management of oral diseases globally. Workforce models including a wider range of professionals working together as a team will be needed to tackle the burden of oral diseases in an integrated way in the broader context of non-communicable diseases. Further discussion and research should be conducted to validate or improve the competencies proposed here with regard to their relevance, appropriateness, and completeness. PMID- 25838006 TI - Impact of the NBDE grading change on postgraduate admissions processes. AB - The aim of this study was to assess the effect of discontinuing the reporting of National Board Dental Examination (NBDE) Part I numerical scores on postgraduate program directors' admissions selection processes. This cross-sectional survey based study collected information about two admissions cycles (2012-13 and 2013 14) from directors of American Dental Education Association Postdoctoral Application Support Service (ADEA PASS(SM)) programs in all postdoctoral training disciplines; the response rate was 54.5%. According to the 2012-13 cycle results, these program directors rated an NBDE Part I score the third most important part of an application, behind grade point average (GPA) and class rank (ranked first and second, respectively). In the 2013-14 cycle, in the absence of an NBDE Part I score, almost all other parts of the application increased in importance for the responding directors, but the relative rank of factors remained almost unchanged. Significantly, 71% of the directors reported that it was now more difficult to select interview candidates, and 76% said they wanted some form of national, numerically scored exam. No significant change was noted between the two years in the number of applications or interviews offered per resident position, although the standard deviation of the number of interviews offered increased in both pediatric dentistry and postdoctoral general dentistry. PMID- 25838007 TI - Factors influencing dental students' specialty choice: a survey of ten graduating classes at one institution. AB - The aim of this study was to survey ten graduating classes at Harvard School of Dental Medicine regarding students' specialty choice and factors influencing that choice. Students were surveyed once in 2008 (for the Classes of 2007-11) and again in 2013 (for the Classes of 2012-16). A prior article reported results regarding students' interest in and experiences with prosthodontics; this article presents results regarding their interest in all dental specialties and factors influencing those interests. Of a total 176 students in the Classes of 2012-16, 143 responded to the survey, for a response rate of 81%, compared to a 95% response rate (167 of total 176 students) for the Classes of 2007-11. The results showed that orthodontics was the most popular specialty choice, followed by oral and maxillofacial surgery. From the 2008 to the 2013 survey groups, there was an increase in the percentages of students planning to pursue oral and maxillofacial surgery, pediatric dentistry, and postdoctoral general dentistry. The educational debt these students expected to accrue by graduation also increased. The largest percentage of students chose "enjoyment of providing the specialty service" as the factor most influencing their specialty choice. "Prior dental school experience" and "faculty influence" were greater influences for students pursuing specialties than those pursuing postdoctoral general dentistry. Increased interest in particular disciplines may be driven by high debt burdens students face upon graduation. Factors related to mentoring especially influenced students pursuing specialties, demonstrating the importance of student experiences outside direct patient care for exposure to the work of specialists beyond the scope of predoctoral training. This finding suggests that dental schools should increase mentoring efforts to help students make career decisions based not on financial burden but rather on personal interest in the specialty, which is likely to have a more satisfying result for them in the long run. PMID- 25838008 TI - Tobacco dependence education in U.S. Dental assisting programs' curricula. AB - The aim of this study was to assess the level of tobacco dependence education (TDE) in the curricula of U.S. dental assisting programs and to compare the findings to those from a similar assessment of dental hygiene curricula. In the 2012-13 academic year, a 51-item survey was sent to directors of all 298 accredited dental assisting programs. Assessed were curricular TDE content, time spent on each topic, expected levels of clinical competence, and resources used. Of the 298 potential participants, 89 programs returned completed surveys, for a response rate of 30%. Of the 13 TDE-related content areas, those most often covered were oral disease related to tobacco use (100%) and general diseases related to tobacco use (93%); those least often covered were stages of (behavior) change (29%), how to develop a comprehensive tobacco intervention program in a private office setting (23%), and strategies for community-based tobacco control (22%). Responding program directors indicated the following levels of tobacco cessation intervention at which students should demonstrate competence: brief, 44%; moderate, 55%; intensive, 8%. Less than half of the reporting programs conducted a formal assessment of clinical competence in any TDE-related skills; however, skills in assessing patient tobacco use and associating head and neck findings to tobacco use were formally or informally assessed by 74% and 61%, respectively. Compared to dental hygiene programs, TDE appeared to play a smaller role in the curricula of dental assisting programs, and dental assisting programs were less likely to formally assess clinical competence in TDE. PMID- 25838009 TI - Patient satisfaction surveys in dental school clinics: a review and comparison. AB - Health care is becoming more patient-centered and, as a result, patients' experiences of care and assessment of satisfaction are taken more seriously. Patient satisfaction influences treatment cooperation, and better cooperation leads to healthier patients in the long term. This generalization clearly applies in the dental school clinic setting. Furthermore, dental school clinics' administrators and clinicians should know about the dimensions of their patient satisfaction in order to provide the highest quality of care. The aim of this study was to review studies published between 1980 and March 2014 to identify the dimensions used to measure patients' satisfaction when they receive services in dental school clinics. The PubMed database was used to access published studies using patient satisfaction surveys in dental school clinics, and the dimensions used in these surveys were then categorized. Through several stages of searching in PubMed, the authors selected 41 articles from a total of 730; after further critical appraisal, nine articles were retained. Five dimensions included in patient surveys were identified: quality, interaction, access, environment, and cost. Determining the dimensions used in patient satisfaction surveys in dental school clinics can assist academic dental institutions in providing the highest quality of care. PMID- 25838010 TI - Are more endodontic consultations needed in dental school clinic settings? A study of treatment decisions at one school. AB - With no previous studies of the occurrence of interdisciplinary consultations for tooth extraction in a dental school clinic setting, the aim of this cross sectional descriptive investigation was to measure and compare the consultation process that occurred among departments at one U.S. dental school for making treatment decisions on tooth extraction. A comprehensive computerized retrieval (Crystal Reports) was used to identify and gather data from patient records from July 1, 2007, to July 1, 2011. Treatment plans and progress notes were analyzed to determine why each tooth had been extracted and which department had recommended the extraction. Results showed that the clinical departments involved in treatment planning decisions were the DMD dental student clinic, Department of Periodontics, and Department of Endodontics. The narrative records of 227 patients who had 516 teeth extracted were examined. About three-fourths (73.26%) of the extracted teeth were extracted based on the recommendation of only one department. Of these extracted teeth, 22.0% (n=114) were previously endodontically treated, and only four were recommended for endodontic consultation prior to extraction. The study found that most extractions were performed without specialty consultations and that the Department of Endodontics was consulted the least of all departments. To foster interdisciplinary collaboration in dental school clinics and help students develop expertise in such collaborations, more specialty consultations are needed for teeth that are treatment planned for extraction in order to preclude needless extraction of potentially salvageable teeth. Doing so will provide benefits for both patient care and students' education. PMID- 25838011 TI - An "XL" endodontics intervention for dental students required to repeat the course: changing frustration to improved grades and attitudes. AB - Given the psychological and financial costs involved with failing a clinical course, especially in developing countries, an alternative educational method was tested with students who had to repeat the year-long endodontic course at the University of Chile Faculty of Dentistry. The objectives of the intervention were to deepen theoretical knowledge and practical experiences, as well as to reinforce personal confidence in an endodontic clinical setting for students who failed the regular endodontic course. The aim of this study was to evaluate the success of this new model of educational intervention. In the study, 28 students who had failed the endodontic course repeated it with an alternative teaching method. The students attended patients immediately following practical competence exams, and they had access to simulated models that used rotary instruments and access cavities and had emergency care practice. Feedback sessions were held after each clinical session. Final grades were compared with those of other students who repeated the course without the intervention from 2007 to 2009. A survey was administered to understand the causes of initial failure and their opinions of the intervention. Students who participated in the alternative course did significantly better than their counterparts from previous years who did not receive the intervention (5.7+/-0.3 vs. 5.4+/-0.2; p<0.05). Their overall perception of the intervention was positive, and the main cause for previous course failure was personal insecurity and slow clinical care performance (54.2% of the students). The intervention course not only improved grades but also generated interest in endodontics, a contrasting perspective to the frustration students usually express after repeating the course. The results of this study support the introduction of similar interventions in endodontics and perhaps other courses. PMID- 25838012 TI - Dental students' perceived preparedness to treat patients in clinic after a fixed prosthodontics course: survey results of a case study. AB - Previous research regarding dental students has found modest predictive value in preclinical didactic course grades in predicting clinical performance, but systematic assessment of students' feedback on their perceived preparedness has received little attention as a preclinical assessment methodology. The aim of this study was to assess the perceptions of the dental students at one U.S. academic dental institution regarding their preparedness for clinical performance following the preclinical fixed prosthodontics course. Third- and fourth-year dental students participated in a survey about their perceived preparedness to diagnose and treat patients with fixed prosthodontics needs in the school's dental clinics. The respondents (79 out of 161 students, for a response rate of 49%) rated each item on a five-point Likert scale. Responses about which preclinical procedures of the course prepared students the least and the best were consistent for the third- and fourth-year students. Less than 60% of all responding students felt prepared for planning complex cases and performing laboratory-related procedures. The findings of this study indicate that improvement is required in teaching students about laboratory procedures and problem-solving to adequately prepare them for clinical treatment of patients with fixed prosthodontics needs. PMID- 25838013 TI - Effects of team-based learning on fixed prosthodontic education in a Japanese School of Dentistry. AB - The aims of this study were to evaluate the quality of team-based learning (TBL) in prosthodontics education for fourth-year dental students at Tokushima University School of Dentistry and to compare this teaching method with traditional lecture-based delivery. Participants in the study were 36 students (22 males and 14 females) who attended the TBL-style fixed prosthodontics course. Ten 60-minute classes were held. The first three were traditional lecture-style classes and were followed by one class introducing the TBL style. The remaining six classes constituted the TBL-format fixed prosthodontics course. The effectiveness of TBL was evaluated through student questionnaires at the end of each class and the results of the term-end examination. The questionnaire revealed high student approval for TBL-style learning, and active group discussion among students during TBL was a key factor in these ratings. In the results of the term-end examination, there were significantly higher scores on the questions that covered TBL-taught material than those covering traditional lecture-taught topics. The results of this study suggest that TBL-style lecture was more effective than traditional-style lecture for teaching fixed prosthodontics and that TBL was a more efficient mode of delivering dental education than traditional lecture-based teaching. PMID- 25838014 TI - Health professions ethics rubric: validation of reliability in an interprofessional health ethics course. AB - The aim of this study was to validate a health professions ethics rubric by an interprofessional team. The rubric was used by two pharmacy and two dental faculty members to score ethics cases submitted by 16 teams comprised of 80 pharmacy and 50 dental students. A debriefing session for each case was moderated by a non-rater faculty member to arrive at a consensus score for the cases. Interrater reliability was calculated for the four raters and the debriefing scores as well as the four raters without the debriefing scores. The overall interrater correlations were in the range of 0.790 to 0.906 for the four raters. Issues ranged from 0.320 to 0.758. Principles ranged from 0.610 to 0.838. Options ranged from 0.655 to 0.843. Analysis ranged from 0.667 to 0.918. Solution ranged from 0.739 to 0.886. With the inclusion of the consensus scores, the interrater correlations were even higher. The best correlations were for the overall score and solution components of the rubric. With further edits in the rubric and enhanced training by faculty raters and changes in the ethics learning session, the revised rubric could be evaluated again for grading. Further training for faculty using the rubric for grading student cases should enhance its reliability. Demonstrating to students the ethical decision making process using the rubric should enhance the validation process. PMID- 25838015 TI - Considerations for use of dental photography and electronic media in dental education and clinical practice. AB - Photography and electronic media are indispensable tools for dental education and clinical practice. Although previous research has focused on privacy issues and general strategies to protect patient privacy when sharing clinical photographs for educational purposes, there are no published recommendations for developing a functional, privacy-compliant institutional framework for the capture, storage, transfer, and use of clinical photographs and other electronic media. The aims of this study were to research patient rights relating to electronic media and propose a framework for the use of patient media in education and clinical care. After a review of the relevant literature and consultation with the University of Washington's director of privacy and compliance and assistant attorney general, the researchers developed a privacy-compliant framework to ensure appropriate capture, storage, transfer, and use of clinical photography and electronic media. A four-part framework was created to guide the use of patient media that reflects considerations of patient autonomy and privacy, informed consent, capture and storage of media, and its transfer, use, and display. The best practices proposed for capture, storage, transfer, and use of clinical photographs and electronic media adhere to the health care code of ethics (based on patient autonomy, nonmaleficence, beneficence, justice, and veracity), which is most effectively upheld by a practical framework designed to protect patients and limit institutional liability. Educators have the opportunity and duty to convey these principles to students who will become the next generation of dentists, researchers, and educators. PMID- 25838016 TI - Development of a mobile device optimized cross platform-compatible oral pathology and radiology spaced repetition system for dental education. AB - Combining active recall testing with spaced repetition increases memory retention. The aim of this study was to evaluate and compare students' perception and utilization of an electronic spaced repetition oral pathology-radiology system in dental hygiene education and predoctoral dental education. The study employed an open-source suite of applications to create electronic "flashcards" that can be individually adjusted for frequency of repetition, depending on a user's assessment of difficulty. Accessible across multiple platforms (iOS, Android, Linux, OSX, Windows) as well as via any web-based browser, this framework was used to develop an oral radiology-oral pathology database of case based questions. This system was introduced in two courses: sophomore oral pathology for dental students and sophomore radiology for dental hygiene students. Students were provided free software and/or mobile tablet devices as well as a database of 300 electronic question cards. Study participants were surveyed on frequency and extent of use. Perception-based surveys were used to evaluate their attitudes towards this technology. Of the eligible students, 12 of 22 (54.5%) dental hygiene and 49 of 107 (45.8%) dental students responded to the surveys. Adoption rates and student feedback were compared between the two groups. Among the respondents, acceptance of this technology with respect to educational usefulness was similar for the dental and dental hygiene students (median=5 on a five-point scale; dental hygiene interquartile range (IQR)=0; dental IQR=1). Only a minority of the survey respondents (25% dental, 33% dental hygiene) took advantage of one of the main benefits of this technology: automated spaced repetition. PMID- 25838018 TI - Improvement of fecal incontinence and quality of life by electrical stimulation and biofeedback for patients with low rectal cancer after intersphincteric resection. AB - OBJECTIVE: To assess the efficacy and benefits of pelvic rehabilitation programs in terms of functional outcomes and quality of life for patients with fecal incontinence and defecation disorders after rectal cancer surgery. DESIGN: Prospective, observational study. SETTING: University hospital physiotherapy clinics. PARTICIPANTS: Patients (N=32) who experienced fecal incontinence after sphincter-saving surgery with the intersphincteric resection (ISR) technique and could follow and cooperate with the treatment schedule were included in the present study. INTERVENTIONS: Pelvic rehabilitation programs included electrical stimulation (ES) and biofeedback (BF). MAIN OUTCOME MEASURES: Functional results, Wexner score, and anorectal manometry were used to assess the clinical outcomes of rehabilitation treatment. RESULTS: Maximum squeeze pressure improved after rehabilitation training (P=.014). There were no statistical differences in resting pressure, resting muscle electromyography, and maximum squeeze electromyography (P=.061, P=.76, and P=.99, respectively). The mean stool frequency was 18.8 per 24 hours before the pelvic intervention program and 7.8 per 24 hours after ES and BF training (P<.001). Of the 32 patients, 27 required antidiarrheal medications before treatment, and after completion of the training, only 9 patients still needed antidiarrheal medications (P<.001). Significant improvements were observed in the Wexner score (17.74 vs 12.93; P<.001). CONCLUSIONS: Our data show that ES and BF are effective in the treatment of fecal incontinence, leading to improvement of quality of life for patients with low rectal cancer after ISR. PMID- 25838019 TI - Evaluating Siebens Domain Management Model for inpatient rehabilitation to increase functional independence and discharge rate to home in geriatric patients. AB - OBJECTIVE: To evaluate the Siebens Domain Management Model (SDMM) for geriatric inpatient rehabilitation (IR) to increase functional independence and dispositions to home. DESIGN: Before and after study. SETTING: IR facility. PARTICIPANTS: During 2010 (preintervention), 429 patients aged >=75 years who were on average admitted to IR 8.2 days postacute care, and during 2012 (postintervention), 524 patients aged >=75 years who were on average admitted to IR 5.5 days postacute care. Case-mix group (CMG) comorbidity tier severity, preadmission living setting, and living support were similar in both groups. INTERVENTION: The SDMM involving weekly adjustments of IR care focused on potential barriers to discharge home. MAIN OUTCOME MEASURES: FIM efficiency, length of stay (LOS), and disposition rates to community/home, acute care, and long-term care (LTC) to compare pre-/postintervention facility data and comparison of facility to national CMG-adjusted data from the Uniform Data System for Medical Rehabilitation for both years (2010/2012). RESULTS: Pre /postintervention group admission FIM scores were similar (t=2.96, P<.003), but the preintervention group had on average 2.6 days greater LOS during IR and greater time to onset of IR (8.2 vs 5.5d) from acute care. Preintervention FIM efficiency was 2.1, whereas postintervention FIM efficiency was 2.76, a significant difference (t=4.1, P<.0001). There were significantly more discharges to the community in the postintervention group (74.4%) than the preintervention group (58.5%, chi(2)=26.2, P<.0001). There were significantly fewer patients discharged to LTC in the postintervention group (chi(2)=30.47, P<.0001). The preintervention group did not significantly differ from the 2010 national data, but the postintervention group significantly differed from the 2012 national data for both greater FIM efficiency (t=-5.5, P<.0001) and greater discharge to community (chi(2)=34, P<.0001). LOS decreased by 2.6 days in the postintervention group compared with the preintervention group, whereas LOS decreased by only 0.6 days nationally from 2010 to 2012, a significant difference with postintervention LOS lower than the national data (t=31.1, P<.0001). CONCLUSIONS: Use of the SDMM during IR in geriatric patients is associated with increased functional independence and discharges to home/community and reduced institutionalization. PMID- 25838020 TI - Bone density in premenopausal women and men under 50 years of age with cerebral palsy. AB - OBJECTIVE: To determine bone mineral density (BMD) z scores in adults with cerebral palsy (CP), an understudied population. DESIGN: Cross-sectional. SETTING: Medical facility. PARTICIPANTS: Adults (N=48; mean age, 34.3+/-5.8y; range, 25-46y) with CP. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: BMD z scores at the lumbar spine and hip using dual-energy x-ray absorptiometry, Gross Motor Function Classification System (GMFCS), body mass index (BMI), and ambulatory status. RESULTS: Mean BMD z scores were -1.40 for the lumbar spine, 1.36 for the total hip, and -1.02 for the femoral neck. The z scores were significantly lower for the nonambulatory group at all 3 sites (P<.05). Significant differences were found among GMFCS levels for the lumbar spine and total hip z scores (P<.05). For the lumbar spine, the mean z scores for level V (the lowest mobility level) were significantly lower than the mean for levels I/II (P=.001), III (P=.002), and IV (P=.013). For the total hip, the mean z scores for level V were significantly lower than the mean for levels I/II (P=.045). A significant positive relationship between the z scores and age was found for the lumbar spine (Spearman rho=.40, P=.005). Significant positive relationships between BMI and z scores were found for all sites (P<.05). CONCLUSIONS: This study contributes to the sparse literature about bone health in adults with CP. In contrast with pediatric data, z scores did not decrease as a function of age in this adult cohort. This information is important for clinicians considering treatment options for this population. PMID- 25838021 TI - Air quality, stroke, and coronary events: results of the Heinz Nixdorf Recall Study from the Ruhr Region. AB - BACKGROUND: Studies have shown that air pollution is associated with cardiopulmonary mortality, but there has been less research of the possible effect of air pollution on stroke and non-fatal coronary events. The Heinz Nixdorf Recall (HNR) study addressed the question of the effect of long-term air pollution on stroke and coronary events. Ambient acoustic noise was also considered as a risk factor. METHODS: The HNR study, initiated in 2000, is a prospective, population-based cohort study in the Ruhr region of Germany. Long term exposure to fine-particle dust (PM10, PM2.5 and PM(2.5abs) [carbon black content]) and traffic noise at the subjects' home addresses were determined using land-use regression and dispersion models, respectively. Strokes and coronary events were ascertained from patient records by an independent end-point committee on the basis of predefined study criteria. The adjusted hazard ratio (HR) was calculated using Cox regression analysis for an increase in concentration from the 5th to the 95th percentile for each exposure. RESULTS: Data from 4433 subjects were evaluated. The incidence of stroke was 2.03 per 1000 person-years (PY), and that of coronary events was 3.87 per 1000 PY. The highest hazard ratios for stroke were seen for PM10 (HR 2.61, 95% confidence interval [CI] 1.13-6.00) and PM2.5 (HR 3.20, 95% CI 1.26-8.09). The highest hazard ratios for coronary events were found for PM10 (HR 1.07, 95% CI 0.56-2.04) and for PM(2.5abs) (HR 1.37, 95% CI 0.80-2.36). CONCLUSION: Long-term exposure to fine particle dust is associated with a higher risk of stroke, regardless of the subject's exposure to noise at his or her home address. The results for coronary events are less clear, but still suggest increased risk. PMID- 25838022 TI - Lyme carditis--diagnosis, treatment and prognosis. AB - BACKGROUND: There are 60,000 to 100,000 new cases of borreliosis in Germany each year. This infectious disease most commonly affects the skin, joints, and nervous system. Lyme carditis is a rare manifestation with potentially lethal complications. METHODS: This review is based on selected publications on the clinical manifestations, diagnosis, and treatment of Lyme carditis, and on the authors' scientific and clinical experience. RESULTS: Lyme carditis is seen in 4% to 10% of all patients with Lyme borreliosis. Whenever the clinical suspicion of Lyme carditis arises, an ECG is mandatory for the detection or exclusion of an atrioventricular conduction block. Patients with a PQ interval longer than 300 ms need continuous ECG monitoring. 90% of patients with Lyme carditis develop cardiac conduction abnormalities, and 60% develop signs of perimyocarditis. Borrelia serology (ELISA) may still be negative in the early phase of the condition, but is always positive in later phases. Cardiac MRI can be used to confirm the diagnosis and to monitor the patient's subsequent course. The treatment of choice is with antibiotics, preferably ceftriaxone. The cardiac conduction disturbances are usually reversible, and the implantation of a permanent pacemaker is only exceptionally necessary. There is no clear evidence at present for an association between borreliosis and the later development of a dilated cardiomyopathy. When Lyme carditis is treated according to the current guidelines, its prognosis is highly favorable. CONCLUSION: Lyme carditis is among the rarer manifestations of Lyme borreliosis but must nevertheless be considered prominently in differential diagnosis because of the potentially severe cardiac arrhythmias that it can cause. PMID- 25838023 TI - Unethical approach. PMID- 25838024 TI - Questionable pooling of data. PMID- 25838025 TI - In reply. PMID- 25838026 TI - Years of life lost. PMID- 25838027 TI - Global burden of disease study is of oncological interest. PMID- 25838028 TI - In reply. PMID- 25838030 TI - An interview with Manuel Salto-Tellez on diagnostic pathology: the future is morphomolecular. AB - Interview with Professor Manuel Salto-Tellez by Claire Raison, Commissioning Editor Professor Manuel Salto-Tellez of Queen's University, Belfast, Northern Ireland is an expert histopathologist and molecular diagnostician. Professor Salto-Tellez is a lead investigator at the Northern Ireland Molecular Pathology Laboratory and also serves as a member of the Editorial Advisory Board for Expert Review of Molecular Diagnostics. In this interview, he proposes directions for the future of molecular pathology and molecular diagnostics, integrating all aspects of pathology toward a common goal. PMID- 25838031 TI - Association between overactive bladder and peri-menopause syndrome: a cross sectional study of female physicians in China. AB - PURPOSE: To determine the detailed association between overactive bladder (OAB) and peri-menopause syndrome (PMpS) in Chinese female physicians of peri menopausal age. METHODS: Data for this study were collected by administering questionnaires eliciting general information (peri-menopausal symptoms and OAB status) to middle-aged female physicians, from the directly affiliated three hospitals of Peking University in China. We used the overactive bladder symptom score (OABSS) to verify the symptoms of OAB and the modified Kupperman menopausal index (KMI) to assess PMpS. RESULTS: Three hundred fifty-one questionnaires were finally evaluated. The average age was 47.1 +/- 5.4 years. Overall, 7.4% of respondents had OAB and 22.6% had PMpS. There was a significant positive correlation between the severity of OAB and prevalence of OAB and PMpS. The prevalence of OAB in women with PMpS (KMI > 15) was significantly increased (18.99 vs. 4.44%; P = 0.000). The average OABSS in women with PMpS was 2.67 +/- 2.15, compared with 1.46 +/- 1.50 in women without PMpS. The average KMI score in women with OAB was 16.04 +/- 10.1, compared with 9.50 +/- 8.13 in women without OAB (P = 0.000). Multivariate logistic regression analysis results showed that only BMI and PMpS were independent risk factors for OAB. CONCLUSIONS: In China, female physicians with menopausal symptoms tend to have a higher prevalence of OAB and more severe symptoms of OAB. PMID- 25838032 TI - Revisiting the tethered ureteral stents in children: a novel modification. AB - PURPOSE: To propose a simple noninvasive method for ureteral stent retrieval using an extraction string sutured to the skin in children. METHODS: A retrospective chart review was performed to gather relevant data from December 2005 to February 2013. After the surgeries, if indicated, a tethered double-J stent was placed in the ureter. A 5-0 non-absorbable Prolene stitch was used as an extraction string passing through the urethra and was sutured to subcoronal skin in boys or inner surface of labia majora in girls. For stent removal, a small amount of 2 % lidocaine jelly was pushed into the urethra 5 min before the procedure. The string was then pulled by continuous and gentle force until the entire stent was out. The suture was then cut to release the stent. No sedation or anesthesia was needed. RESULTS: A total of 378 double-J stents with extraction strings were inserted for a total of 325 patients (61.2 % male). Of the 53 patients with bilateral ureteral stents, one male patient (1.88 %) experienced early stent protrusion from urethral meatus. Two of 272 patients (0.73 %) with unilateral ureteral stent (one male and one female) encountered the same problem. All other stents were extracted successfully using the extraction string without any complications. No upward stent migration or suture site reaction was encountered. CONCLUSION: This method is a safe, easy-to-use, feasible and noninvasive alternative for cystoscopic stent removal with high success rate and minimal complications. This can lead to considerable saving in time and costs for patients, families and healthcare system. PMID- 25838033 TI - The comparison of GLUT-4 and nNOS expression in diabetic and non-diabetic patients with BPH/LUTS. AB - PURPOSE: The aim of this study was to compare glucose transporter-4 (GLUT-4) and neuronal nitric oxide synthase (nNOS) expression in diabetic and non-diabetic patients who underwent TUR-P or transvesical prostatectomy with the diagnosis of BPH. METHODS: Thirty diabetic patients with an average age of 58 and 30 non diabetic patients with that of 56 were included in the study. T-PSA, IPSS, Q max value and prostate volume were compared between the two groups. The stromal and glandular staining scores of GLUT-4 and nNOS expression were compared. Student's t test and Mann-Whitney U test were used for statistical analysis. RESULTS: There was no statistically significant difference in terms of age, IPSS, Qmax and PSA. Patients with diabetes had larger prostate volumes (p = 0.02). Mean GLUT-4 glandular total scores in diabetic and non-diabetic patients were 3.36 +/- 1.21 and 2.1 +/- 1.39, respectively, whereas stromal total scores were 3.63 +/- 1.12 and 2.46 +/- 1.33, and they were both statistically significant (p = 0.028 and p = 0.032, respectively). Glandular total nNOS scores in diabetic and non-diabetic patients were 4.53 +/- 1.0 and 2.80 +/- 1.12, while stromal total scores were 1.76 +/- 1,0 and 2.30 +/- 1.08 and they were found to be statistically significant (p = 0.0001 and p = 0.037, respectively). CONCLUSIONS: GLUT-4 expression was found higher in prostatic tissue of the patients with diabetes mellitus. The expression value of nNOS was higher in the glandular area in diabetic patients, while stromal area expression score was higher in non-diabetic patients. Although our findings indicate important results, carefully designed further studies are needed to better comprehend the role of GLUT-4 and NOS pathways in BPH/LUTS pathophysiology. PMID- 25838034 TI - Endoplasmic Reticulum Stress Response in Non-alcoholic Steatohepatitis: The Possible Role of Physical Exercise. AB - Sedentary lifestyle coupled with excessive consumption of high caloric food has been related to the epidemic increase of non-alcoholic fatty liver disease, which can progress from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and, eventually, may culminate in hepatocellular carcinoma. Although the precise mechanisms underlying the progression of NASH are not completely understood, endoplasmic reticulum (ER) dysfunction seems to play a key role in the process. Hepatic ER stress has been associated to hepatic steatosis, insulin resistance, inflammation, oxidative stress and hepatocyte death, contributing to liver dysfunction. Physical exercise seems to be the most effective preventive and therapeutic non-pharmacological strategy to mitigate several features related to NASH, possibly targeting most of the referred mechanisms associated with the pathophysiology of ER-related NASH. Nevertheless, little is known about the impact of physical exercise on NASH-related ER stress. In this review, we will discuss the ER stress associated to NASH conditions and highlight the possible benefits of physical exercise in the attenuation and/or reversion of NASH-related ER stress. PMID- 25838035 TI - A review of potential metabolic etiologies of the observed association between red meat consumption and development of type 2 diabetes mellitus. AB - Epidemiological studies suggest that red and processed meat consumption is related to an increased risk of type 2 diabetes. However, it is not clearly understood which components of red and processed meat contribute to this increased risk. This review examines potential mechanisms addressing the role of saturated fatty acid, sodium, advanced glycation end products (AGEs), nitrates/nitrites, heme iron, trimethylamine N-oxide (TMAO), branched amino acids (BCAAs) and endocrine disruptor chemicals (EDCs) in the development of type 2 diabetes based on data from published clinical trials and animal models. TMAO which is derived from dietary carnitine and choline by the action of bacterial enzymes followed by oxidation in the liver may be a strong candidate molecule mediating the risk of type 2 diabetes. BCAAs may induce insulin resistance via the mammalian target of rapamycin complex 1 (mTORC1) and ribosomal protein S6 kinase beta 1 (S6k1)-associated pathways. The increased risk associated with processed meat compared with red meat suggests that there are interactions between the saturated fat, salt, and nitrates in processed meat and iron, AGEs and TMAO. Intervention studies are required to clarify potential mechanisms and explore interactions among components, in order to make firm recommendations on red and processed meat consumption. PMID- 25838037 TI - Language Control in Bilinguals: Monitoring and Response Selection. AB - Language control refers to the cognitive mechanism that allows bilinguals to correctly speak in one language avoiding interference from the nontarget language. Bilinguals achieve this feat by engaging brain areas closely related to cognitive control. However, 2 questions still await resolution: whether this network is differently engaged when controlling nonlinguistic representations, and whether this network is differently engaged when control is exerted upon a restricted set of lexical representations that were previously used (i.e., local control) as opposed to control of the entire language system (i.e., global control). In the present event-related functional magnetic resonance imaging study, we investigated these 2 questions by employing linguistic and nonlinguistic blocked switching tasks in the same bilingual participants. We first report that the left prefrontal cortex is driven similarly for control of linguistic and nonlinguistic representations, suggesting its domain-general role in the implementation of response selection. Second, we propose that language control in bilinguals is hierarchically organized with the dorsal anterior cingulate cortex/presupplementary motor area acting as the supervisory attentional system, recruited for increased monitoring demands such as local control in the second language. On the other hand, prefrontal, inferior parietal areas and the caudate would act as the response selection system, tailored for language selection for both local and global control. PMID- 25838036 TI - Changes in Search Path Complexity and Length During Learning of a Virtual Water Maze: Age Differences and Differential Associations with Hippocampal Subfield Volumes. AB - Impairment of hippocampus-dependent cognitive processes has been proposed to underlie age-related deficits in navigation. Animal studies suggest a differential role of hippocampal subfields in various aspects of navigation, but that hypothesis has not been tested in humans. In this study, we examined the association between volume of hippocampal subfields and age differences in virtual spatial navigation. In a sample of 65 healthy adults (age 19-75 years), advanced age was associated with a slower rate of improvement operationalized as shortening of the search path over 25 learning trials on a virtual Morris water maze task. The deficits were partially explained by greater complexity of older adults' search paths. Larger subiculum and entorhinal cortex volumes were associated with a faster decrease in search path complexity, which in turn explained faster shortening of search distance. Larger Cornu Ammonis (CA)1-2 volume was associated with faster distance shortening, but not in path complexity reduction. Age differences in regional volumes collectively accounted for 23% of the age-related variance in navigation learning. Independent of subfield volumes, advanced age was associated with poorer performance across all trials, even after reaching the asymptote. Thus, subiculum and CA1-2 volumes were associated with speed of acquisition, but not magnitude of gains in virtual maze navigation. PMID- 25838038 TI - Beyond Columnar Organization: Cell Type- and Target Layer-Specific Principles of Horizontal Axon Projection Patterns in Rat Vibrissal Cortex. AB - Vertical thalamocortical afferents give rise to the elementary functional units of sensory cortex, cortical columns. Principles that underlie communication between columns remain however unknown. Here we unravel these by reconstructing in vivo-labeled neurons from all excitatory cell types in the vibrissal part of rat primary somatosensory cortex (vS1). Integrating the morphologies into an exact 3D model of vS1 revealed that the majority of intracortical (IC) axons project far beyond the borders of the principal column. We defined the corresponding innervation volume as the IC-unit. Deconstructing this structural cortical unit into its cell type-specific components, we found asymmetric projections that innervate columns of either the same whisker row or arc, and which subdivide vS1 into 2 orthogonal [supra-]granular and infragranular strata. We show that such organization could be most effective for encoding multi whisker inputs. Communication between columns is thus organized by multiple highly specific horizontal projection patterns, rendering IC-units as the primary structural entities for processing complex sensory stimuli. PMID- 25838039 TI - Characteristics of lipid extraction from Chlorella sp. cultivated in outdoor raceway ponds with mixture of ethyl acetate and ethanol for biodiesel production. AB - In this work, neutral lipids (NLs) extraction capacity and selectivity of six solvents were firstly compared. In addition, an eco-friendly solvent combination of ethyl acetate and ethanol (EA/E) was proposed and tested for lipid extraction from Chlorella sp. cultivated in outdoor raceway ponds and effect of extraction variables on lipid yield were intensively studied. Results indicated that lipid extraction yield was increased with solvent to biomass ratio but did not vary significantly when the value exceeded 20:1. Lipid yield was found to be strongly dependent on extraction temperature and time. Finally, fatty acid profiles of lipid were determined and results indicated that the major components were octadecanoic acid, palmitic acid, linoleic acid and linolenic acid, demonstrating that the lipid extracted from the Chlorella sp. cultivated in outdoor raceway ponds by EA/E was suitable feedstock for biodiesel production. PMID- 25838040 TI - Anaerobic digestion performance of vinegar residue in continuously stirred tank reactor. AB - Anaerobic digestion (AD) of vinegar residue was investigated in continuously stirred tank reactor (CSTR). The influence of organic loading rate (OLR) and effluent recirculation on AD performance of vinegar residue was tested. Five OLRs, 1.0, 1.5, 2.0, 2.5, and 3.0 g(vs) L(-1) d(-1), were used. The highest volumetric methane productivity of 581.88 mL L(-1) was achieved at OLR of 2.5 g(vs) L(-1) d(-1). Effluent reflux ratio was set as 50%, the results showed that effluent recirculation could effectively neutralize the acidity of vinegar residue, raise the pH of the feedstock, and enhance the buffering capacity of the AD system. Anaerobic digestion of vinegar residue could be a promising way not only for converting this waste into gas energy but also alleviating environmental pollution which might be useful for future industrial application. PMID- 25838041 TI - Two Japanese Patients With SMA Type 1 Suggest that Axonal-SMN May Not Modify the Disease Severity. AB - BACKGROUND: Spinal muscular atrophy is caused by survival motor neuron gene SMN1 mutations. SMN1 produces a full-length SMN1 protein isoform encoded by exons 1-7, and an axonal-SMN protein isoform encoded by exons 1-3 and intron 3. The axonal SMN protein is expressed only in the embryonic period and plays a significant role in axonal growth. However, there has been no report on contribution of axonal-SMN to spinal muscular atrophy severity until now. PATIENTS: Two Japanese boys with spinal muscular atrophy type 1 in our study presented with generalized muscle weakness and respiratory insufficiency soon after birth and required an artificial ventilator from early infancy. Patient 1 was compound heterozygous for two SMN1 mutations, whole-gene deletion, and an intragenic mutation (c.819_820insT). He retained one copy of SMN1 producing the N-terminal part of SMN1 including axonal-SMN. On the other hand, patient 2 was homozygous for SMN1 deletion. Both of them showed the same copy number of spinal muscular atrophy modifying genes, NAIP and SMN2. These findings suggested that the C-terminal domain of full-length SMN1 determined the severity, irrespective of presence or absence of axonal-SMN expression. CONCLUSION: In patient 1, the C-terminal domain of full-length SMN1 determined spinal muscular atrophy severity, rather than the axonal-SMN, one copy of which could be present and intact. The presence or absence of axonal-SMN may not impact disease severity in spinal muscular atrophy type 1 patients. PMID- 25838042 TI - Narcolepsy in children: a diagnostic and management approach. AB - OBJECTIVE: To provide a diagnostic and management approach for narcolepsy in children. METHODS: Narcolepsy is a chronic disabling disorder characterized by excessive daytime sleepiness, cataplexy, hypnogogic and/or hypnopompic hallucinations, and sleep paralysis. All four features are present in only half of the cases. Excessive daytime sleepiness is the essential feature of narcolepsy at any age and is usually the first symptom to manifest. A combination of excessive daytime sleepiness and definite cataplexy is considered pathognomonic of narcolepsy syndrome. RESULTS: New treatment options have become available over the past few years. Early diagnosis and management can significantly improve the quality of life of patients with narcolepsy with cataplexy. CONCLUSION: This review summarizes the pathophysiology, clinical features, and management options for children with narcolepsy. PMID- 25838043 TI - Amplitude-integrated EEG in newborns with critical congenital heart disease predicts preoperative brain magnetic resonance imaging findings. AB - OBJECTIVE: The study aims are to evaluate cerebral background patterns using amplitude-integrated electroencephalography in newborns with critical congenital heart disease, determine if amplitude-integrated electroencephalography is predictive of preoperative brain injury, and assess the incidence of preoperative seizures. We hypothesize that amplitude-integrated electroencephalography will show abnormal background patterns in the early preoperative period in infants with congenital heart disease that have preoperative brain injury on magnetic resonance imaging. METHODS: Twenty-four newborns with congenital heart disease requiring surgery at younger than 30 days of age were prospectively enrolled within the first 3 days of age at a tertiary care pediatric hospital. Infants had amplitude-integrated electroencephalography for 24 hours beginning close to birth and preoperative brain magnetic resonance imaging. The amplitude-integrated electroencephalographies were read to determine if the background pattern was normal, mildly abnormal, or severely abnormal. The presence of seizures and sleep wake cycling were noted. The preoperative brain magnetic resonance imaging scans were used for brain injury and brain atrophy assessment. RESULTS: Fifteen of 24 infants had abnormal amplitude-integrated electroencephalography at 0.71 (0-2) (mean [range]) days of age. In five infants, the background pattern was severely abnormal. (burst suppression and/or continuous low voltage). Of the 15 infants with abnormal amplitude-integrated electroencephalography, 9 (60%) had brain injury. One infant with brain injury had a seizure on amplitude-integrated electroencephalography. A severely abnormal background pattern on amplitude integrated electroencephalography was associated with brain atrophy (P = 0.03) and absent sleep-wake cycling (P = 0.022). CONCLUSION: Background cerebral activity is abnormal on amplitude-integrated electroencephalography following birth in newborns with congenital heart disease who have findings of brain injury and/or brain atrophy on preoperative brain magnetic resonance imaging. PMID- 25838044 TI - ROP and ATRP Fabricated Dual Targeted Redox Sensitive Polymersomes Based on pPEGMA-PCL-ss-PCL-pPEGMA Triblock Copolymers for Breast Cancer Therapeutics. AB - To minimize cardiotoxicity and to increase the bioavailability of doxorubicin, polymersomes based on redox sensitive amphiphilic triblock copolymer poly(polyethylene glycol methacrylate)-poly(caprolactone)-s-s-poly(caprolactone) poly(polyethylene glycol methacrylate) (pPEGMA-PCL-ss-PCL-pPEGMA) with disulfide linkage were designed and developed. The polymers were synthesized by ring opening polymerization (ROP) of epsilon-caprolactone followed by atom transfer radical polymerization (ATRP) of PEGMA. The triblock copolymers demonstrated various types of nanoparticle morphologies by varying hydrophobic/hydrophilic content of polymer blocks, with PEGMA content of ~18% in the triblock copolymer leading to the formation of polymersomes in the size range ~150 nm. High doxorubicin loading content of ~21% was achieved in the polymersomes. Disulfide linkages were incorporated in the polymeric backbone to facilitate degradation of the nanoparticles by the intracellular tripeptide glutathione (GSH), leading to intracellular drug release. Release studies showed ~59% drug release in pH 5.5 in the presence of 10 mM GSH, whereas only ~19% was released in pH 7.4. In cellular uptake studies, dual targeted polymersomes showed ~22-fold increase in cellular uptake efficiency in breast cancer cell lines (BT474 and MCF-7) as compared to nontargeted polymersomes with higher apoptosis rates. In vivo studies on Ehrlich's ascites tumor (EAT) bearing Swiss albino mouse model showed ~85% tumor regression as compared to free doxorubicin (~42%) without any significant cardiotoxicity associated with doxorubicin. The results indicate enhanced antitumor efficacy of the redox sensitive biocompatible nanosystem and shows promise as a potential drug nanocarrier in cancer therapeutics. PMID- 25838045 TI - From "right to die"...to "code comfort". AB - In 1983, Nancy Cruzan was in a persistent vegetative state from a motor vehicle accident. This led to a landmark "right to die" case and the evolution of important documents outlining one's final wishes. Do Not Resuscitate orders became the standard. New wrinkles in the "end of life" debate include "death with dignity" initiatives and "code comfort" actions. PMID- 25838047 TI - Surgical rehospitalization of the medicare fee-for-service patient: a state-level analysis exploring 30-day readmission factors. AB - PURPOSE OF STUDY: Surgical readmissions are a concern to the integrity of the Medicare Trust Fund and gaining attention from policymakers concerned about solvency. This study explores factors associated with variation in surgical readmission rates across the states and provides implications for Medicare Case Management. PRIMARY PRACTICE SETTING(S): Acute inpatient hospital settings. METHODOLOGY AND SAMPLE: Fifty state-level data and multivariate regression analysis are used. The dependent variable Surgical Discharge 30-day Readmission Rate is based on the Medicare Fee-For-Service beneficiary population with Medicare Part A and B insurance coverage and age 65 years or older, rehospitalized subsequent to an inpatient surgical procedure, occurring within 30 days of their last discharge. RESULTS: Our 2 key explanatory variables-emergency room visit rate and total days of care-are each positively associated with 30-day surgical readmission rate. Age group 65-69 years, native language, physician density, and health care expenditures per capita also influence surgical readmission rate across the states. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Surgical readmission has an association with many different categories of variables-demographic, clinical process, hospital capacity, and patient need. This strongly suggests that Medicare case managers consider the wide range of elements contributing to surgical readmission and take a multifactorial approach to reducing the rehospitalization rate. PMID- 25838049 TI - Assessing the whole person: case managers take a holistic approach to physical and mental health. AB - PURPOSE/OBJECTIVE: Given the prevalence of mental health issues, particularly depressive disorders, in the U.S. population, professional case managers should increase their sensitivity to and awareness of mental illnesses, as well as their impact on physical health. Throughout the case management process, case managers frequently observe behaviors and symptoms such as those associated with depressive disorders. Case managers need to have, at a minimum, a working knowledge of mental and behavioral health issues and be familiar with basic screening tools. This will enable them to become more attuned to symptoms and behaviors that indicate that the individual should be further assessed and diagnosed by a physician. PRIMARY PRACTICE SETTING: Across the case management spectrum, including acute care, accountable care organizations, patient-centered medical homes, physician practices, clinics, occupational health clinics, workers' compensation, and other settings in which case managers work with individuals (clients who receive case management services) and their families/support systems. FINDINGS/CONCLUSIONS: With more than one quarter of the U.S. population affected by a depressive disorder, professional case managers who practice holistically bring together the mental and physical aspects of health. This is particularly important in a health care system and among payer sources that continue to divide the two. Case managers elevate their practice by demonstrating a greater understanding of the interconnectedness of mental and physical health and can positively influence the transdisciplinary care team to take a person-centered approach to address all health issues, in pursuit of the individual's health goals. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Professional case managers must increase their understanding of mental health, becoming more aware of "red flags" that may necessitate a further evaluation and assessment by a mental health professional. They should also hone their communication skills, particularly the use of motivational interviewing techniques, to encourage individuals to discuss their feelings, worries, fears, and anxiety, as well as any potential symptoms of depression, which may range from mild to severe. Without judgment or bias, the case manager, as the advocate, can provide the information, support, or other services needed to address mental health issues, to support and further the individual's health goals. PMID- 25838050 TI - Case managers: a key to reducing readmissions. PMID- 25838051 TI - Advocacy: the key to dignified end of life. PMID- 25838052 TI - The "whole-person" approach: understanding the connection between physical and mental health. PMID- 25838053 TI - Hospital case management: a new view from the C-suite. PMID- 25838054 TI - Meningioma dissemination and growth: a role for microRNAs. PMID- 25838055 TI - Possible role for interleukins as biomarkers for mortality and recurrence in oral cancer. AB - BACKGROUND: Salivary and serum levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) have previously been studied in oral cancer with conflicting results. METHODS: We designed a controlled study to assess the correlation between pretreatment salivary and serum levels of IL-6 and IL-8, and all-cause survival and cancer recurrence in oral cancer patients. RESULTS: Fifty-two oral cancer patients and 52 healthy control cases were selected. In univariate analysis, salivary IL-6 and IL-8 seemed to be more expressed in cases (p<0.001 and p = 0.010, respectively). Multivariate analysis showed that higher pretreatment saliva IL-6 levels were significantly associated with better survival (hazard ratio [HR] = 8.62; 95% confidence interval [95% CI], 1.21-62.50; p = 0.031). CONCLUSIONS: To date, this is the largest prospective controlled study that has analyzed the pretreatment salivary and serum levels of IL-6 and IL-8 in oral cancer patients, suggesting salivary IL-6 as a possible prognostic biomarker. But further validation in a larger sample is still necessary. PMID- 25838056 TI - Palladium-catalyzed picolinamide-directed coupling of C(sp(2))-H and C(sp(2))-H: a straightforward approach to quinolinone and pyridone scaffolds. AB - An unprecedented palladium-catalyzed picolinamide-directed coupling of C(sp(2))-H and C(sp(2))-H has been developed with exclusive formation of the six-membered ring heterocyclics - quinolinone and pyridone. The method employs cyclic hypervalent iodine as oxidant and features good functional-group tolerance. Another advantage of this reaction is that sequential C-H/C-H and C-H/N-H coupling could be achieved. PMID- 25838057 TI - [Acute Retinal Pigment Epitheliitis: spectral-domain optical coherence tomography findings]. AB - PURPOSE: Through a case presentation of Acute Retinal Pigment Epitheliitis (ARPE) we highlight the role of spectral-domain optical coherence tomography (SD-OCT) in the management of this rare entity. MATERIALS AND METHODS: A 29-year-old woman presented for reduced visual acuity in the right eye occurring one week after a viral episode. Fundus examination showed zones of macular hyperpigmentation surrounded by yellowish hypopigmented haloes. Fluorescein angiography noted early hyperfluorescence of the hypopigmented lesions. ICG angiography revealed central hyperfluorescence surrounded by a hypofluorescent halo. SD-OCT showed a linear disruption between the photoreceptor inner/outer segments (IS/OS) and an accumulation of material in the photoreceptor outer segments and retinal pigment epithelium (RPE). Spontaneous normalization of visual acuity was noted after 10 weeks. SD-OCT revealed restored and continuous inner segment and outer segment layers and some persistent deposits in the photoreceptor layer. RESULTS: SD-OCT findings suggest that the initial lesion in ARPE is located at the junction between the photoreceptor outer segments and the apical side of the RPE cells. It would correspond to an accumulation of photoreceptor outer segment debris secondary to RPE dysfunction, which can occur as a post-viral reaction. CONCLUSION: SD-OCT provides very specific information about the topography of retinal lesions during ARPE, allowing a better understanding of its pathogenesis. PMID- 25838059 TI - Looking back and moving forward. PMID- 25838058 TI - [Epidemiologic and etiological characteristics of congenital cataract: study of 59 cases over 10 years]. AB - OBJECTIVE: The goal of this study was to analyze the epidemiology and maternal, prenatal and perinatal risk factors for congenital cataracts. MATERIALS AND METHODS: We conducted a retrospective study of all consecutive cases of congenital cataracts diagnosed and managed at hopital Nord Marseille, France. We describe demographic, personal, maternal and familial characteristics of these patients. RESULTS: We identified 59 children with congenital cataract. The group consists of 31 girls (53%) and 28 boys (47%). Cataract was bilateral in 71% of cases and unilateral in 29% of cases. This group is first divided according to etiological forms. Idiopathic cataract accounts for 63% of patients. Genetic and infectious cataract accounts for 34% and 3%, respectively. According to the clinical presentation, congenital cataract was an isolated finding in 51% of cases. It was associated with ocular abnormalities in 27% of cases and with systemic abnormalities in 22% of cases. The diagnosis was made upon routine screening in 41% of cases. Leucoria and strabismus led to the diagnosis in 24% and 19%, respectively. The average age of diagnosis was 19.7 months. CONCLUSION: Congenital cataract is a relatively rare condition. The description of a series of 59 cases is important as well as the comparison of our results to large epidemiological data previously published. The elucidation of novel risk factors requires consideration at a national or even global scale. PMID- 25838060 TI - A spatial pattern analysis of the halophytic species distribution in an arid coastal environment. AB - Obtaining information about the spatial distribution of desert plants is considered as a serious challenge for ecologists and environmental modeling due to the required intensive field work and infrastructures in harsh and remote arid environments. A new method was applied for assessing the spatial distribution of the halophytic species (HS) in an arid coastal environment. This method was based on the object-based image analysis for a high-resolution Google Earth satellite image. The integration of the image processing techniques and field work provided accurate information about the spatial distribution of HS. The extracted objects were based on assumptions that explained the plant-pixel relationship. Three different types of digital image processing techniques were implemented and validated to obtain an accurate HS spatial distribution. A total of 2703 individuals of the HS community were found in the case study, and approximately 82% were located above an elevation of 2 m. The micro-topography exhibited a significant negative relationship with pH and EC (r = -0.79 and -0.81, respectively, p < 0.001). The spatial structure was modeled using stochastic point processes, in particular a hybrid family of Gibbs processes. A new model is proposed that uses a hard-core structure at very short distances, together with a cluster structure in short-to-medium distances and a Poisson structure for larger distances. This model was found to fit the data perfectly well. PMID- 25838061 TI - Determination of dual parameter auto-sampling trigger thresholds for pollutant load monitoring in various land uses. AB - Environmental pollutants are health hazards and are typically transported during runoff events. Monitoring the loadings of these pollutants with auto-samplers require precise trigger thresholds to effectively account for total maximum daily loads (TMDLs) entering natural water bodies. Traditionally, auto-samplers are triggered by delaying the start of sampling until pollutant wave is present during rainfall event. The rainfall-related triggers are typically limited to small watersheds, where lag and travel times are consistent and predictable. However, in large and more complex watersheds, flow or stage is typically used either by a set threshold on change in instantaneous flow rate or water level. Generally, trigger thresholds are difficult to establish due to seasonal fluctuations in stream flow and variations in rainfall. This study investigated dual parameter trigger based on instantaneous change and variance from a moving average for flow and stage. Nineteen auto-samplers, installed within six watersheds of varying land uses in City of Kissimmee, FL, were evaluated over 3 year period. The results suggested that using 20- to 30-min moving average of 5 min sampling interval for both parameters was sufficient to detect pollutant waves with minimal false triggers. Also, change from average flow rate (?Qave) and a percent change from average stage (?Have%) were found to the preferred parameters. The ?Have% values ranging from -0.012 to 0.20% and ?Qave ranging from 0.014 to 0.850 m(3)/s were found to give effective results for all stations in the study area. It was also observed that these trigger thresholds varied with land use, stream flow condition, and auto-sampler locations within the watershed. PMID- 25838062 TI - Trace element distribution in the snow cover from an urban area in central Poland. AB - This work presents the first results from winter field campaigns focusing on trace metals and metalloid chemistry in the snow cover from an urbanized region in central Poland. Samples were collected between January and March 2013 and trace element concentrations were determined using GF-AAS. A large inter-seasonal variability depending on anthropogenic emission, depositional processes, and meteorological conditions was observed. The highest concentration (in MUg L(-1)) was reported for Pb (34.90), followed by Ni (31.37), Zn (31.00), Cu (13.71), Cr (2.36), As (1.58), and Cd (0.25). In addition, several major anthropogenic sources were identified based on principal component analysis (PCA), among which the most significant was the activity of industry and coal combustion for residential heating. It was stated that elevated concentrations of some trace metals in snow samples were associated with frequent occurrence of south and southeast advection of highly polluted air masses toward the sampling site, suggesting a large impact of regional urban/industrial pollution plumes. PMID- 25838063 TI - Extensive Chaetoceros curvisetus bloom in relation to water quality in Port Blair Bay, Andaman Islands. AB - Blooming of diatom species Chaetoceros curvisetus (Cleve, 1889) was observed in Junglighat Bay and Haddo Harbour of Port Blair Bay of Andaman and Nicobar Islands during June 2010. Physico-chemical parameters, nutrient concentrations and phytoplankton composition data collected from five stations during 2010 were classified as bloom area (BA) and non-bloom area (NBA) and compared. Elevated values of dissolved oxygen were recorded in the BA, and it significantly varied (p < 0.01) from NBA. Among the nutrient parameters studied, nitrate concentration indicated significant variation in BA and NBA (p < 0.01). Phosphate and ammonia concentrations reduced to below detection level (BDL) in the BA and NBA, indicating its utilization. In Junglighat Bay, the C. curvisetus species constituted 93.4 and 69.2% composition of total phytoplankton population during day 1 and day 2, respectively. The bloom forming stations separated out from the non-bloom forming station in non-parametric multidimensional scaling (nMDS) ordinations; cluster analysis powered by SIMPROF test also grouped the stations as BA and NBA. PMID- 25838064 TI - The genetic differentiation of Colocasia esculenta growing in gold mining areas with arsenic contamination. AB - Arsenic is a heavy metal found in contaminated gold mining areas and which can affect plant and animal species. This study aims to determine the concentration of As in the aquatic plant Colocasia esculenta as well as this plant's genetic variability. Sediment and C. esculenta samples were collected from three studied sites at the edge of a stream around a gold mine. The arsenic concentrations in sediment and C. esculenta samples were analyzed using induction coupled plasma mass spectrometry (ICP-MS). Genetic differentiations were studied by random amplified polymorphic DNA (RAPD) with dendrogram construction and analysis of genetic similarity (S). The results showed that the arsenic concentrations in sediment and C. esculenta samples ranged from 4.547 +/- 0.318 to 229.964 +/- 0.978 and 0.108 +/- 0.046 to 0.406 +/- 0.174 mg kg(-1), respectively. To compare the samples studied to the reference site, RAPD fingerprints from 26 primers successfully produced 2301 total bands used for dendrogram construction and S value analysis. The dendrogram construction separates C. esculenta into four clusters corresponding to their sampling sites. The S values of the studied sample sites compared to the reference site are 0.676-0.779, 0.739-0.791, and 0.743-0.783 for sites 1, 2, and 3, respectively, whereas the values of the individuals within each site are as high as 0.980. These results suggest that As accumulation in aquatic plant species should be of concern because of the potential effects of As on aquatic plants as well as humans. PMID- 25838065 TI - Characterization of newly revealed sequences in the infectious myonecrosis virus genome in Litopenaeus vannamei. AB - Infectious myonecrosis virus (IMNV) causes significant economic losses in farmed shrimp, where associated mortality in ponds can reach 70 %. To explore host/pathogen interactions, a next-generation sequencing approach using lymphoid organ tissue from IMNV-infected Litopenaeus vannamei shrimp was conducted. Preliminary sequence assembly of just the virus showed that there were at least an additional 639 bp at the 5' terminus and 23 nt at the 3' terminus as compared with the original description of the IMNV genome (7561 nt). Northern blot and reverse transcription-PCR analysis confirmed the presence of novel sequence at both ends of the genome. Using 5' RACE, an additional 4 nt were discovered; 3' RACE confirmed the presence of 22 bp rather than 23 bp of sequence. Based on these data, the IMNV genome is 8226 bp in length. dsRNA was used to trigger RNA interference (RNAi) and suppress expression of the newly revealed genome sections at the 5' end of the IMNV genome in IMNV-infected L. vannamei. An RNAi trigger targeting a 376 bp length of the 5' UTR did not improve survival of infected shrimp. In contrast, an RNAi trigger targeting a 381 bp sequence in ORF1 improved survival to 82.2 % as compared with 2.2 % survival in positive control animals. These studies revealed the importance of the new genome sections to produce high titre infection, and associated disease and mortality, in infected shrimp. PMID- 25838066 TI - Incidence, Progression, and Associated Risk Factors of Medium Drusen in Age Related Macular Degeneration: Findings From the 15-Year Follow-up of an Australian Cohort. AB - IMPORTANCE: The natural course and prognosis of medium drusen and risk factors associated with the incidence and progression of this lesion type in age-related macular degeneration (AMD) are not well understood. OBJECTIVE: To assess the 15 year incidence and progression of medium drusen and associated risk factors. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort in the Blue Mountains region, west of Sydney, Australia. Included in the study were 3654 participants 49 years or older who attended baseline examinations of the Blue Mountains Eye Study (1992-1994), and 75.8%, 76.7%, and 56.1% of survivors who attended the 5 year, 10-year, and 15-year follow-up examinations, respectively. MAIN OUTCOMES AND MEASURES: Color retinal fundus photographs were obtained at each examination. The incidence and progression of medium drusen (maximum diameter, 63 to <125 um) were assessed using Kaplan-Meier product-limit survival methods, controlling for competing risk of death. Factors associated with a 15-year incidence of medium drusen were assessed using discrete logistic regression models after adjusting for age, sex, smoking status, serum lipid levels, systemic and dietary factors, and CFH rs1061170 and ARMS2 rs10490924 polymorphisms. Associations between lesion characteristics and the progression to late AMD were assessed using generalized estimating equation models and eye-specific data. RESULTS: Among 1317 participants at risk, the 15-year cumulative incidence of medium drusen was 13.9% (n = 281). Increasing age (per decade older) (odds ratio [OR], 1.4; 95% CI, 1.2 1.8) and the presence of at least 3 risk alleles of the CFH rs1061170 or ARMS2 rs10490924 genes (OR, 2.1; 95% CI, 1.1-4.1) were associated with a higher incidence. There was no association between past smoking (OR, 0.8; 95% CI, 0.6 1.1) or current smoking (OR, 0.6; 95% CI, 0.4-1.1) and the development of medium drusen. The progression rate to late AMD in eyes with both medium drusen and retinal pigmentary abnormalities was 4-fold higher than that in eyes with medium drusen alone. Larger total area and central location of medium drusen were associated with a greater likelihood of the progression to worse stages of AMD. CONCLUSIONS AND RELEVANCE: Older age and the presence of CFH and ARMS2 risk alleles are 2 main risk factors associated with the development of medium drusen. The copresence of medium drusen plus retinal pigment epithelium abnormalities signals a greater risk of the progression to late AMD than the presence of medium drusen alone. PMID- 25838067 TI - New insights into Lyme disease. AB - Lyme borreliosis is transmitted through the bite of a tick that is infected by the bacterial spirochete Borrelia burgdorferi. Clinical manifestation of the disease can lead to heart conditions, neurological disorders, and inflammatory disorders. Oxidative stress has been implicated in the pathogenesis of many human diseases. The aim of this study was to investigate the mechanisms of oxidative stress and intracellular communication in Lyme borreliosis patients. Mitochondrial superoxide and cytosolic ionized calcium was measured in peripheral blood mononuclear cells (PBMCs) of Lyme borreliosis patients and healthy controls. Mitochondrial superoxide levels were significantly higher (p<0.0001) in Lyme borreliosis patients (n=32) as compared to healthy controls (n=30). Significantly low (p<0.0001) levels of cytosolic ionized calcium were also observed in Lyme borreliosis patients (n=11) when compared to healthy controls (n=11). These results indicate that there is an imbalance of reactive oxygen species and cytosolic calcium in Lyme borreliosis patients. The results further suggest that oxidative stress and interrupted intracellular communication may ultimately contribute to a condition of mitochondrial dysfunction in the immune cells of Lyme borreliosis patients. PMID- 25838068 TI - Artemisia tilesii Ledeb hairy roots establishment using Agrobacterium rhizogenes mediated transformation. AB - An efficient and rapid protocol for the establishment of Artemisia tilesii "hairy" root culture is reported. Leaf explants of aseptically growing plants were cocultured with Agrobacterium rhizogenes A4 wild strain or A. rhizogenes carrying the plasmids with nptII and ifn-alpha2b genes. Root formation on the explants started in 5-6 days after their cocultivation with bacterial suspension. Prolongation of explant cultivation time on the medium without cefotaxime led to stimulation of root growth. The effects of sucrose concentration as well as of the levels of synthetic indole-3-butyric acid (IBA) and native growth regulator Emistim on the stimulation of A. tilesii "hairy" root growth were studied. Maximum stimulating effect both for the control and for transgenic roots was observed in case of root cultivation on the media supplemented with IBA-up to 7.95- and 9.1-fold biomass increase, respectively. Cultivation on the medium with 10 MUl/L Emistime has also led to the control roots growth stimulation (up to 2.75-fold). Emistime at 5 MUl/L concentration led to 5.46-fold mass increase in only one "hairy" root line. Higher sucrose content (40 g/L) stimulated growth of two hairy root lines but had no effect on growth of the control roots. PMID- 25838069 TI - Pomegranate extract attenuates unilateral ureteral obstruction-induced renal damage by reducing oxidative stress. AB - AIMS: Ureteral obstruction may cause permanent kidney damage at late period. We know that the pomegranate extract (PE) play a strong role on removal of free oxygen radicals and prevention of oxidative stress. In the current study study, we evaluated the effect of PE on kidney damage after unilateral ureteral obstruction (UUO). SETTINGS AND DESIGN: A total of 32 rats were divided into four groups. Group 1 was a control, Group 2 was a sham, Group 3 was rats with UUO and Group 4 was rats with UUO that were given PE (oral 100 MUL/day). After 14 days, rats were killed and their kidneys were taken and blood analysis was performed. SUBJECTS AND METHODS: Tubular necrosis, mononuclear cell infiltration, and interstitial fibrosis scoring were determined histopathologically in a part of kidneys; nitric oxide (NO), malondialdehyde (MDA), and reduced glutathione (GSH) levels were determined in the other part of kidneys. STATISTICAL ANALYSIS USED: Statistical analyses were performed by the Chi-square test and one-way analysis of variance. RESULTS: There was no difference significantly for urea-creatinine levels between groups. Pathologically, there was serious tubular necrosis, mononuclear cell infiltration and fibrosis in Group 3, and there was significantly decreasing for tubular necrosis, mononuclear cell infiltration and fibrosis in Group 4 (P < 0.005). Furthermore, there was significantly increasing for NO and MDA levels; decreasing for GSH levels in Group 3 compared the other groups (P < 0.005). CONCLUSIONS: We think that the PE prevents kidney damage by decreasing oxidative stress in kidney. PMID- 25838070 TI - Enzymatic transesterification of waste vegetable oil to produce biodiesel. AB - An experimental study on enzymatic transesterification was performed to produce biodiesel from waste vegetable oils. Lipase from Pseudomonas cepacia was covalently immobilized on a epoxy-acrylic resin support. The immobilized enzyme exhibited high catalytic specific surface and allowed an easy recovery, regeneration and reutilisation of biocatalyst. Waste vegetable oils - such as frying oils, considered not competitive with food applications and wastes to be treated - were used as a source of glycerides. Ethanol was used as a short chain alcohol and was added in three steps with the aim to reduce its inhibitory effect on lipase activity. The effect of biocatalyst/substrate feed mass ratios and the waste oil quality have been investigated in order to estimate the process performances. Biocatalyst recovery and reuse have been also studied with the aim to verify the stability of the biocatalyst for its application in industrial scale. PMID- 25838071 TI - Enhancement of lipid production and fatty acid profiling in Chlamydomonas reinhardtii, CC1010 for biodiesel production. AB - Lipid from microalgae is one of the putative oil resources to facilitate the biodiesel production during this era of energy dissipation and environmental pollution. In this study, the key parameters such as biomass productivity, lipid productivity and lipid content were evaluated at the early stationary phase of Chlamydomonas reinhardtii, CC1010 cultivated in nutrient starved (nitrogen, phosphorous), glucose (0.05%, 0.1%, 0.15% and 0.2%) and vitamin B12 supplementation (0.001%, 0.002% and 0.003%) in Tris-Acetate-Phosphate (TAP) medium. The lipid content in nitrogen starved media was 61% which is 2.34 folds higher than nutrient sufficient TAP medium. Glucose supplementation has lead to proportional increase in biomass productivity with the increasing concentration of glucose whereas vitamin B12 supplementations had not shown any influence in lipid and biomass production. Further, fatty acid methyl ester (FAME) profiling of C. reinhardtii, CC 1010 has revealed more than 80% of total SFA (saturated fatty acid) and MUFA (mono unsaturated fatty acid) content. Quality checking parameters of biodiesel like cetane number, saponification value, iodine number and degree of unsaturation were analyzed and the biodiesel fuel properties were found to be appropriate as per the international standards, EN 14214 and ASTM D6751. Conclusively, among all the treatments, nitrogen starvation with 0.1% glucose supplementation had yielded high lipid content in C. reinhardtii, CC 1010. PMID- 25838072 TI - Effects of dihydrotestosterone on rat dermal papilla cells in vitro. AB - Androgenetic alopecia involves the action of dihydrotestosterone (DHT) on dermal papilla cells (DPCs) that line the base of the hair follicle. However, the mechanism of DHT action is not completely understood. The effects of DHT on DPCs, regulatory cells that function in follicle growth and the hair cycle, were examined in immortalized cells derived from rat vibrissa follicles. DHT did not affect the proliferation of immortalized DPCs. However, flow cytometry analysis revealed that DHT increased cell-cycle arrest in these cells, which was accompanied by an increase in the p27(kip1) level and by decreases in cyclin E, cyclin D1, and cyclin-dependent kinase 2 levels. DHT treatment resulted in the phosphorylation and nuclear translocation of Smad2/3, a mediator of the transforming growth factor-beta (TGF-beta) signaling pathway, which leads to the catagen phase of the hair cycle. DHT also induced the phosphorylation and nuclear translocation of heat shock protein 27 (HSP27). Moreover, DHT decreased the levels of total and nuclear beta-catenin, an important regulator of hair growth and proliferation, while lithium chloride, a glycogen synthase kinase-3beta inhibitor, attenuated the DHT-induced downregulation of the beta-catenin level. On the other hand, DHT increased the phosphorylation of mammalian target of rapamycin (mTOR), a regulator of proliferation, in immortalized DPCs. These results illustrate that DHT could shorten the duration of the hair growth cycle by initiating cell-cycle arrest, downregulating the beta-catenin level, and upregulating the TGF-beta/Smad and HSP27 level, whereas activation of mTOR by DHT could attenuate the inhibition of hair growth cycle in immortalized DPCs. PMID- 25838073 TI - Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats. AB - Air pollution has been linked to increased incidence of diabetes. Recently, we showed that ozone (O3) induces glucose intolerance, and increases serum leptin and epinephrine in Brown Norway rats. In this study, we hypothesized that O3 exposure will cause systemic changes in metabolic homeostasis and that serum metabolomic and liver transcriptomic profiling will provide mechanistic insights. In the first experiment, male Wistar Kyoto (WKY) rats were exposed to filtered air (FA) or O3 at 0.25, 0.50, or 1.0ppm, 6h/day for two days to establish concentration-related effects on glucose tolerance and lung injury. In a second experiment, rats were exposed to FA or 1.0ppm O3, 6h/day for either one or two consecutive days, and systemic metabolic responses were determined immediately after or 18h post-exposure. O3 increased serum glucose and leptin on day 1. Glucose intolerance persisted through two days of exposure but reversed 18h-post second exposure. O3 increased circulating metabolites of glycolysis, long-chain free fatty acids, branched-chain amino acids and cholesterol, while 1,5 anhydroglucitol, bile acids and metabolites of TCA cycle were decreased, indicating impaired glycemic control, proteolysis and lipolysis. Liver gene expression increased for markers of glycolysis, TCA cycle and gluconeogenesis, and decreased for markers of steroid and fat biosynthesis. Genes involved in apoptosis and mitochondrial function were also impacted by O3. In conclusion, short-term O3 exposure induces global metabolic derangement involving glucose, lipid, and amino acid metabolism, typical of a stress-response. It remains to be examined if these alterations contribute to insulin resistance upon chronic exposure. PMID- 25838075 TI - Factors Influencing Production of Fusaristatin A in Fusarium graminearum. AB - Fusarium graminearum is a ubiquitous plant pathogen, which is able to produce several bioactive secondary metabolites. Recently, the cyclic lipopeptide fusaristatin A was isolated from this species and the biosynthetic gene cluster identified. Fusaristatin A consists of a C24 reduced polyketide and the three amino acids dehydroalanine, beta-aminoisobutyric acid and glutamine and is biosynthesized by a collaboration of a polyketide synthase and a nonribosomal peptide synthetase. To gain insight into the environmental factors, which controls the production of fusaristatin A, we cultivated F. graminearum under various conditions. We developed an LC-MS/MS method to quantify fusaristatin A in F. graminearum extracts. The results showed that yeast extract sucrose (YES) medium was the best medium for fusaristatin A production and that the optimal pH was 7.5 and temperature 25-30 degrees C. Furthermore, production of fusaristatin A was more than four times higher in stationary cultures than in agitated cultures when F. graminearum was grown in liquid YES medium. The results also showed that fusaristatin A was only present in the mycelium and not in the liquid, which suggests that fusaristatin A is stored intracellulally and not exported to the extracellular environment. PMID- 25838074 TI - Cognitive decline is associated with risk aversion and temporal discounting in older adults without dementia. AB - Risk aversion and temporal discounting are preferences that are strongly linked to sub-optimal financial and health decision making ability. Prior studies have shown they differ by age and cognitive ability, but it remains unclear whether differences are due to age-related cognitive decline or lower cognitive abilities over the life span. We tested the hypothesis that cognitive decline is associated with higher risk aversion and temporal discounting in 455 older persons without dementia from the Memory and Aging Project, a longitudinal cohort study of aging in Chicago. All underwent repeated annual cognitive evaluations using a detailed battery including 19 tests. Risk aversion was measured using standard behavioral economics questions: participants were asked to choose between a certain monetary payment versus a gamble in which they could gain more or nothing; potential gamble gains varied across questions. Temporal discounting: participants were asked to choose between an immediate, smaller payment and a delayed, larger one; two sets of questions addressed small and large stakes based on payment amount. Regression analyses were used to examine whether prior rate of cognitive decline predicted level of risk aversion and temporal discounting, controlling for age, sex, and education. Over an average of 5.5 (SD=2.9) years, cognition declined at an average of 0.016 units per year (SD=0.03). More rapid cognitive decline predicted higher levels of risk aversion (p=0.002) and temporal discounting (small stakes: p=0.01, high stakes: p=0.006). Further, associations between cognitive decline and risk aversion (p=0.015) and large stakes temporal discounting (p=0.026) persisted in analyses restricted to persons without any cognitive impairment (i.e., no dementia or mild cognitive impairment); the association of cognitive decline and small stakes temporal discounting was no longer statistically significant (p=0.078). These findings are consistent with the hypothesis that subtle age-related changes in cognition can detrimentally affect individual preferences that are critical for maintaining health and well being. PMID- 25838076 TI - For early-stage oral tongue cancer, depth of invasion and worst pattern of invasion are the strongest pathological predictors for locoregional recurrence and mortality. AB - Despite early diagnosis and treatment, almost 20% of patients with early-stage (cT1-cT2N0) oral tongue squamous cell carcinoma (OTSCC) still die of their disease. The prognosis of OTSCC patients is influenced by several demographic, clinical, and histopathologic factors. The aim of this multicenter international study was to find which of the factors age, gender, stage, grade, lymphocytic host response, perineural invasion, worst pattern of invasion, or depth of invasion has the strongest prognostic power in early-stage OTSCC. Patient data of 479 patients with early-stage (cT1-2N0) OTSCC in Finland, Brazil, and the USA were retrieved and analyzed using Cox proportional hazards regression models. Our results indicate that depth of invasion (DOI) and worst pattern of invasion (WPOI) are the strongest pathological predictors for locoregional recurrence, with a hazard ratio (HR) for 4 mm DOI of 1.67 (95% confidence interval (CI) 1.07 2.60) and HR for WPOI of 1.46 (95% CI 0.95-2.25). In addition, mortality from early OTSCC was also predicted by DOI (HR 2.44, 95% CI 1.34-4.47) and by WPOI (HR 2.34, 95% CI 1.26-4.32). We suggest that clinically early-stage oral tongue carcinomas 4 mm or deeper, or with a growth pattern of small cell islands or satellites, should be considered as high-risk tumors which require multimodality treatment. PMID- 25838077 TI - Pattern of recurrent disease in major salivary gland adenocystic carcinoma. AB - This study aims to evaluate the long-term outcome of major salivary gland adenocystic carcinoma (ACC). This is a retrospective review of 54 cases of ACC during a 35-year period from 1974 to 2009 at the Helsinki University Central Hospital, Helsinki, Finland. Medical records and histological samples were reviewed. All patients had a minimum follow-up time of 5 years or until death. Most of the tumours occurred in the parotid gland (n = 30, 56%) followed by submandibular gland (n = 22, 41%) and sublingual gland (n = 2, 4%). Fifty-two patients (96%) were treated with curative intent. All of these patients except one were primarily treated with surgery, and 29 patients (54%) also received postoperative radiotherapy for their primary tumour. Two patients (4%) received palliative radiotherapy. For those treated with curative intent, 32 patients (62%) had disease recurrence. Twenty-four patients (75%) had their first disease recurrence within 5 years and eight patients (25%) later than 5 years. The difference in the length of recurrence-free time interval (<5 vs. >5 years) had a significant impact on 5-year overall survival (OS) and disease-specific survival (DSS). The OS, DSS and disease-free survival (DFS) across stages I-IV varied between 46-100, 50-100 and 46-100%, respectively. Age over 45 years, T stage, and presence of neck metastases had a significant negative prognostic effect. More than half of the patients had recurrent disease. An extended follow-up for these patients seems feasible as most of the distant metastases were detected within a 10-year period. PMID- 25838078 TI - Next-generation sequencing is highly sensitive for the detection of beta-catenin mutations in desmoid-type fibromatoses. AB - Desmoid-type fibromatoses are locally aggressive and frequently recurrent tumours, and an accurate diagnosis is essential for patient management. The majority of sporadic lesions harbour beta-catenin (CTNNB1) mutations. We used next-generation sequencing to detect CTNNB1 mutations and to compare the sensitivity and specificity of next-generation sequencing with currently employed mutation detection techniques: mutation-specific restriction enzyme digestion and polymerase chain reaction amplification. DNA was extracted from formalin-fixed paraffin-embedded needle biopsy or resection tissue sections from 144 patients with sporadic desmoid-type fibromatoses, four patients with syndrome-related desmoid-type fibromatoses and 11 morphological mimics. Two primer pairs were designed for CTNNB1 mutation hotspots. Using >=10 ng of DNA, libraries were generated by Fluidigm and sequenced on the Ion Torrent Personal Genome Machine. Next-generation sequencing had a sensitivity of 92.36 % (133/144, 95 % CIs: 86.74 to 96.12 %) and a specificity of 100 % for the detection of CTNNB1 mutations in desmoid-type fibromatoses-like spindle cell lesions. All mutations detected by mutation-specific restriction enzyme digestion were identified by next-generation sequencing. Next-generation sequencing identified additional mutations in 11 tumours that were not detected by mutation-specific restriction enzyme digestion, two of which have not been previously described. Next-generation sequencing is highly sensitive for the detection of CTNNB1 mutations. This multiplex assay has the advantage of detecting additional mutations compared to those detected by mutation-specific restriction enzyme digestion (sensitivity 82.41 %). The technology requires minimal DNA and is time- and cost-efficient. PMID- 25838079 TI - Multifocal cytokeratin expression in pleural and abdominal malignant solitary fibrous tumors: an unusual diagnostic pitfall. PMID- 25838080 TI - Sclerosing adenosis as a predictor of breast cancer bilaterality and multicentricity. AB - Breast cancer is occasionally complicated by sclerosing adenosis (SA). Although both lesions usually originate in the terminal duct lobular unit, their pathogenetic relationship has not yet been elucidated. The present study analyzed 63 breast cancer patients with SA (involving a total of 75 breasts) to clarify if coexisting SA increased the frequency of multicentric breast cancer or not. Using the topographical classification proposed in our previous study, breast cancers with SA were classified into the following three types: type A (n = 22), cancer area was completely surrounded by the SA; type B (n = 26), cancer area partially overlapped the SA; and type C (n = 27), cancer area was located separate from the SA. Breast cancers with SA had a significant (P < 0.001) increase in frequency of harboring bilateral and multicentric cancers [17 of 63 (27%) and 15 of 63 (24%), respectively] when compared to breast cancer patients without SA, regardless of topographical type. Breast cancers with SA were less invasive (P < 0.001), of lower histological grade (P = 0.034), and had similar frequency of estrogen receptor-positive (P = 0.21) and HER2-positive (P = 0.74) tumors. In conclusion, contralateral and ipsilateral multicentric breast cancers occurred at a higher frequency in those with SA. Our data suggest that SA is, in addition to lobular neoplasia, a predictor of multicentric breast cancers. PMID- 25838081 TI - Toll-like receptor 9 expression in the natural history of Barrett mucosa. AB - Increased expression of TLR9 in esophageal adenocarcinoma and squamous cell carcinoma correlates with poor prognosis. We have explored the expression and suspected that TLR9 activation might contribute to pathogenesis in esophageal columnar metaplasia-dysplasia-neoplasia sequence, and hence, we have studied the usefulness of TLR9 as a marker for dysplasia. We have determined the expression of TLR9 in specimens with normal esophagus (n = 89), gastric (n = 71), or intestinal metaplasia (n = 56) without dysplasia, and low-grade (n = 51) or high grade dysplasia (n = 40), and esophageal adenocarcinoma (n = 88). We observed linearly increasing TLR9 expression in specimens to be associated with change from normal epithelium to columnar metaplasia and further to dysplasia. ROC curve analysis showed clinically irrelevant sensitivity of 71% and specificity of 67% for TLR9 intensity in detection of low-grade dysplasia. Membrane-associated TLR9 expression detected by immunohistochemistry and immunofluorescence was predominantly associated with foveolar-type dysplasia as detected by HE staining (p = 0.015). TLR9 is expressed in Barrett's esophagus, and dissolution of TLR9 staining increases from nondysplastic epithelium to dysplastic. TLR9 may serve as a new way of recognizing the histopathological origin of dysplasia (adenomatous vs foveolar) with observed subcellular pattern of TLR9. PMID- 25838082 TI - Preferences and Stated Adherence for Antibiotic Treatment of Cystic Fibrosis Pseudomonas Infections. AB - OBJECTIVE: Our objective was to quantify preferences and stated adherence for inhaled antibiotic treatments in cystic fibrosis (CF). METHODS: Adult CF patients and parents of pediatric patients in the US who were members of the Cystic Fibrosis Foundation and who had Pseudomonas aeruginosa at least twice a year completed an online, discrete-choice experiment survey (response rate 4.4 %). Respondents answered five treatment-choice questions evaluating pairs of hypothetical CF treatment profiles. Stated-adherence questions followed two randomly selected treatment-choice questions. Data were analyzed using random parameters logit (RPL). For a combination of attribute levels, the utility is estimated by summing the relevant attribute-level parameter estimates. For the stated-adherence questions, we tabulated the changes in the percentages of respondents who would be 95 % adherent for various changes in inhaled antibiotic medication administration features. RESULTS: The final sample was 271 adult patients and 209 parents. Switching from a 30-min nebulizer twice daily to a 10 min dry powder inhaler (DPI) twice daily was 6.3 times more important for patients and 2.0 times more important for parents than an improvement in dry cough side effect from moderate to mild. Stated adherence for respondents was 20 30 % greater for DPIs versus nebulizers. CONCLUSIONS: Lower frequency of administration, shorter administration times for a given device, and milder dry cough appear to improve stated adherence to antibiotic treatment of CF lung infections. PMID- 25838083 TI - Appraisal of the narcotic drugs and psychotropic substances (amendment) act, 2014. PMID- 25838084 TI - Diagnostic method in psychiatry: Changing times. PMID- 25838085 TI - Regulation of upper airway inflammation facilitates comfortable breathing. PMID- 25838087 TI - Association and management of eosinophilic inflammation in upper and lower airways. AB - This review discussed the contribution of eosinophilic upper airway inflammation includes allergic rhinitis (AR) and chronic rhinosinusitis (CRS) to the pathophysiology and course of asthma, the representative counterpart in the lower airway. The presence of concomitant AR can affect the severity of asthma in patients who have both diseases; however, it is still debatable whether the presence of asthma affects the severity of AR. Hypersensitivity, obstruction and/or inflammation in the lower airway can be detected in patients with AR without awareness or diagnosis of asthma, and AR is known as a risk factor for the new onset of wheeze and asthma both in children and adults. Allergen immunotherapy, pharmacotherapy and surgery for AR can contribute to asthma control; however, a clear preventive effect on the new onset of asthma has been demonstrated only for immunotherapy. Pathological similarities such as epithelial shedding are also seen between asthma and CRS, especially eosinophilic CRS. Abnormal sinus findings on computed tomography are seen in the majority of asthmatic patients, and asthmatic patients with CRS show a significant impairment in Quality of Life (QOL) and pulmonary function as compared to those without CRS. Conversely, lower airway inflammation and dysfunction are seen in non-asthmatic patients with CRS. Treatments for CRS that include pharmacotherapy such as anti leukotrienes, surgery, and aspirin desensitization show a beneficial effect on concomitant asthma. Acting as a gatekeeper of the united airways, the control of inflammation in the nose is crucial for improvement of the QOL of patients with co-existing AR/CRS and asthma. PMID- 25838086 TI - Immunopathology of chronic rhinosinusitis. AB - Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses which persists for at least 12 weeks. CRS can be divided into two phenotypes dependent on the presence of nasal polyps (NPs); CRS with NPs (CRSwNP) and CRS without NPs (CRSsNP). Immunological patterns in the two diseases are known to be different. Inflammation in CRSsNP is rarely investigated and limited studies show that CRSsNP is characterized by type 1 inflammation. Inflammation in CRSwNP is well investigated and CRSwNP in Western countries shows type 2 inflammation and eosinophilia in NPs. In contrast, mixed inflammatory patterns are found in CRSwNP in Asia and the ratio of eosinophilic NPs and non-eosinophilic NPs is almost 50:50 in these countries. Inflammation in eosinophilic NPs is mainly controlled by type 2 cytokines, IL-5 and IL-13, which can be produced from several immune cells including Th2 cells, mast cells and group 2 innate lymphoid cells (ILC2s) that are all elevated in eosinophilic NPs. IL-5 strongly induces eosinophilia. IL-13 activates macrophages, B cells and epithelial cells to induce recruitment of eosinophils and Th2 cells, IgE mediated reactions and remodeling. Epithelial derived cytokines, TSLP, IL-33 and IL-1 can directly and indirectly control type 2 cytokine production from these cells in eosinophilic NPs. Recent clinical trials showed the beneficial effect on eosinophilic NPs and/or asthma by monoclonal antibodies against IL-5, IL-4Ralpha, IgE and TSLP suggesting that they can be therapeutic targets for eosinophilic CRSwNP. PMID- 25838088 TI - Usefulness of modified Pulmonary Index Score (mPIS) as a quantitative tool for the evaluation of severe acute exacerbation in asthmatic children. AB - BACKGROUND: Acute exacerbation of asthma is divided qualitatively into mild, moderate, and severe attacks and respiratory failure. This system is, however, not suitable for estimating small changes in respiratory condition with time and for determining the efficacy of treatments, because it has a qualitative, but not quantitative nature. METHODS: To evaluate the usefulness of quantitative estimation of asthma exacerbation, modified Pulmonary Index Score (mPIS) values were measured in 87 asthmatic children (mean age, 5.0 +/- 0.4 years) during hospitalization. mPIS was calculated by adding the sum of scores for 6 items (scores of 0-3 were given for each item). These consisted of heart rate, respiratory rate, accessory muscle use, inspiratory-to-expiratory flow ratio, degree of wheezing, and oxygen saturation in room air. Measurements were made at visits and at hospitalization and were then made twice a day until discharge. RESULTS: mPIS values were highly correlated among raters. mPIS values at visits were 9.1 +/- 0.1 and 12.6 +/- 0.4 in subjects with moderate and severe attacks, respectively (p < 0.001). mPIS values of subjects requiring continuous inhalation therapy (CIT) with isoproterenol in addition to systemic steroids were significantly higher than the values of those without CIT (12.0 +/- 0.5 and 9.3 +/- 0.2, respectively, p < 0.001). A score of 10 was suggested to be the optimal cutoff for distinguishing between subjects requiring and not requiring CIT, from the perspectives of both sensitivity and specificity. mPIS at hospitalization correlated well with the period until discharge, suggesting that this score was a useful predictor for the clinical course after hospitalization. CONCLUSIONS: mPIS could be a useful tool for several aspects during acute asthma attacks, including the determination of a treatment plan, and prediction of the period of hospitalization in admitted patients, although prospective studies would be required to establish our hypothesis. PMID- 25838089 TI - Effect of inhaled corticosteroids on bronchial asthma in Japanese athletes. AB - BACKGROUND: Asthma has a higher prevalence in athlete populations such as Olympic athletes than in the general population. Correct diagnosis and management of asthma in athletes is important for symptom control and avoidance of doping accusations. However, few reports are available on asthma treatment in the athlete population in clinical practice. In this study, we focused on the clinical efficacy of inhaled corticosteroid (ICS) for asthma in a Japanese athlete population. METHODS: The study subjects included athletes who visited the Niigata Institute for Health and Sports Medicine, Niigata, Japan for athletic tests and who were diagnosed with asthma on the basis of respiratory symptoms and positive results in a bronchodilator or bronchial provocation test such as exercise, hypertonic saline, or methacholine provocation. The athletes received ICS alone for at least 3 months, and the clinical background, sports type, and treatment efficacy were analyzed. RESULTS: The study population comprised 80 athletes (59 men and 21 women) with a median age of 16.0 years. Regarding sports type, 28 athletes engaged in winter sports (35%), 22 in endurance sports (27.5%), and 25 in indoor sports (31.3%). Although ICS is the primary treatment in athlete asthma, 16.3% of the athletes showed an unsatisfactory response to treatment according to the Global Evaluation of Treatment Effectiveness (GETE). These subjects were characterized by a decreased response to methacholine and lower values for FEV1/FVC and type 2 helper T cell (Th2)-associated biomarkers relative to responsive athletes. In multivariate analysis, FEV1/FVC and the logarithm to the base 10 of the IgE level were independently associated with the ICS response. CONCLUSIONS: These data suggest that ICS is effective for asthma in most athletes. However, certain asthmatic athletes are less responsive to ICS than expected. The pathogenesis in these subjects may differ from that of conventional asthma characterized by chronic allergic airway inflammation. PMID- 25838090 TI - The impact of co-existing seasonal allergic rhinitis caused by Japanese Cedar Pollinosis (SAR-JCP) upon asthma control status. AB - BACKGROUND: Seasonal Allergic Rhinitis Caused by Japanese Cedar Pollinosis (SAR JCP) is a most common allergic rhinitis, affecting about 40% in Japan, but the influence from SAR-JCP upon asthma is controversial. The purpose of this study is to investigate the effect of coexistence of SAR-JCP upon control status of asthma using SACRA (Self-Assessment of Allergic Rhinitis and Asthma Questionnaire). METHODS: The design was prospective, single-center, observational study. Asthmatic patients were classified into 3 groups, patients without rhinitis, those with perennial rhinitis or those with SAR-JCP from the results of SACRA. The control status of asthma were evaluated by Visual Analog Scale (VAS) in SACRA and Asthma Control Test (ACT) score. They were evaluated twice, from September to January (nonpollen-season) and February to April (pollen-season) and compared. RESULTS: 451 patients were enrolled and 325 cases (72%) were diagnosed as having comorbidity of rhinitis, among which 173 with only perennial rhinitis, while 152 with SAR-JCP. There was no significant difference in asthma control level measured by VAS and ACT score among 3 groups during nonpollen-season. The asthma control level measured by VAS (1.91-2.95) and ACT score (22.7-21.6) got worse during pollen-season among patients with SAR-JCP, even though 84% received treatment for rhinitis. Although it differed according to criteria, asthma control during pollen-season was impaired in 18-38% asthmatic patients with SAR JCP. CONCLUSION: It is possible to minimize the influence of AR on asthma control by obtaining an accurate diagnosis and providing sufficient treatment for rhinitis. PMID- 25838092 TI - Safety and efficacy of a new regimen of short-term oral immunotherapy with Cry j 1-galactomannan conjugate for Japanese cedar pollinosis: a prospective, randomized, open-label study. AB - BACKGROUND: Short-term oral immunotherapy (OIT) using the Cry j1-galactomannan conjugate for Japanese cedar pollinosis may be effective and relatively safe. However, a treatment regimen has not been established. In the present study, we examined a new OIT regimen with a build-up phase and extended the maintenance phase of OIT to the peak period of the pollen season to enhance the therapeutic effect and safety of OIT. METHODS: A prospective, randomized, open-label trial was conducted over a period of 4 months. Participants were randomly divided into two groups. The OIT group comprised 23 subjects. The build-up phase was initiated 1 month before the expected pollen season. The maintenance phase was continued for 51 days during the peak pollen season. The control group comprised 24 subjects. The symptoms and medication score, levels of allergen-specific serum antibodies throughout the pollen season, and adverse effects with OIT were evaluated. RESULTS: Participants receiving OIT showed significant improvements in total symptom scores, medication score, and total symptom-medication scores throughout the pollen season compared with the control group. The levels of allergen-specific serum IgG4 were significantly increased in the OIT group but not in the control group throughout the cedar pollen season. Importantly, no severe adverse effects were observed with OIT. CONCLUSIONS: The new regimen of short-term OIT using the Cry j1-galactomannan conjugate for Japanese cedar pollinosis is effective, relatively safe and induces immune tolerance. Thus, OIT using allergen-galactomannan conjugates may provide a rapid, effective, and thus convenient immunotherapy for pollinosis instead of SLIT or SCIT. PMID- 25838091 TI - A workshop with practical training for anaphylaxis management improves the self efficacy of school personnel. AB - BACKGROUND: School personnel are required to guarantee a secure school environment for children suffering from severe food allergies. We organized a workshop for school personnel to learn the appropriate management of anaphylaxis that included practical training with an adrenaline auto-injector (AAI). The objective of this study was to evaluate the workshop in terms of the improvement of self-efficacy (SE) of participants to deal with anaphylaxis. METHODS: All 93 school nurses, 73 schoolteachers and 110 childcare workers participating in the study completed a questionnaire before and after the workshop. The SE of the participants was evaluated using an original 15-item questionnaire. RESULTS: Before the workshop, the SE of school nurses was the highest among the profession groups, and being involved with children prescribed an AAI was a common factor associated with a high SE. After the workshop, the SE increased in all groups, but most apparently in school nurses and those involved with children prescribed an AAI. The presence of an emergency plan was positively associated with the SE of schoolteachers only after the workshop, even though no such association existed beforehand. CONCLUSIONS: Practical instruction of school nurses and school personnel involved with children prescribed an AAI resulted in dramatic improvement of the SE. These people are expected to play a central role in the development of an anaphylaxis management plan in their schools. PMID- 25838093 TI - Leukotriene E4 induces MUC5AC release from human airway epithelial NCI-H292 cells. AB - BACKGROUND: Hypersecretion of mucin in the airway epithelium is an important feature of allergic airway diseases. Of the 3 cysteinyl leukotrienes (CysLTs; LTC4 LTD4 and LTE4), only LTE4 is sufficiently stable to be detectable in extracellular fluids. However, LTE4 has received little attention because it binds poorly to the CysLT1 and CysLT2 receptors; therefore, little is known about the effects of LTE4 on mucous secretion. Recently, studies have focused on the P2Y12 receptor as a potential receptor for LTE4, because this receptor is required for LTE4-mediated pulmonary inflammation. In our previous study, we confirmed the expression of P2Y12 receptor in human airway epithelial cells. To clarify the roles of LTE4 in airway epithelial cells, we investigated mucus secretion by LTE4 in vitro. METHODS: Confluent NCI-H292 cells were stimulated with LTE4 (0.01-1 MUM) for 24 h. The release and production of MUC5AC protein, a gel-forming mucin, were evaluated with an enzyme-linked immunosorbent assay. RESULTS: Western blot analysis revealed that NCI-H292 cells expressed P2Y12 receptor protein. LTE4 significantly induced the release of MUC5AC mucin in a dose-dependent manner. Th2 cytokines such as IL-4 (10 ng/mL) and IL-13 (10 ng/mL) accelerated the LTE4-induced release of MUC5AC protein. MRS2935, a P2Y12 receptor antagonist, partially inhibited the LTE4-induced release of MUC5AC protein in the airway. In contrast, MK571, a CysLT1 receptor antagonist, did not affect the release of MUC5AC protein elicited by LTE4. CONCLUSIONS: These results suggest that LTE4 may play some important roles in allergic mucus secretion partially via activation of P2Y12 receptor. PMID- 25838094 TI - Phenotype of asthma related with high serum periostin levels. AB - BACKGROUND: Asthma is a heterogeneous disease composed of various phenotypes. Periostin, a molecule inducible with interleukin (IL)-4 or IL-13 in bronchial epithelial cells, is a biomarker of "TH2-high" asthma. The objective of this study is to examine whether the serum periostin concentrations are correlated with the severity, specific phenotype(s), or comorbidity of asthma. METHODS: Serum concentrations of periostin were measured in 190 Japanese asthmatic patients and 11 healthy controls. The protocol was registered under UMIN 000002980 in the clinical trial registry. RESULTS: The serum concentrations of periostin were significantly higher (P = 0.014) in asthmatics [70.0 (54.0-93.5) ng/ml] than in healthy subjects [57.0 (39.0-63.0) ng/ml], though we found no correlation between serum periostin concentrations and treatment steps required to control asthma. To characterize "high-periostin" phenotype(s), the patients with asthma were divided among tertiles based on the serum concentrations of periostin. The high-periostin group was older at onset of asthma (P = 0.04), had a higher prevalence of aspirin intolerance (P = 0.04) or concomitant nasal disorders (P = 0.03-0.001), higher peripheral eosinophil counts (P < 0.001), and lower pulmonary function (P = 0.02-0.07). The serum concentrations of periostin were particularly high in asthmatic patients complicated by chronic rhinosinusitis with nasal polyps and olfactory dysfunction. In contrast, neither atopic status, control status of asthma, nor quality of life were related with the "high-periostin" phenotype. CONCLUSION: Elevated periostin concentrations in serum were correlated with a specific phenotype of eosinophilic asthma, late onset and often complicated by obstructive pulmonary dysfunction and nasal disorders. PMID- 25838095 TI - Japanese Society of Allergology task force report on standardization of house dust mite allergen vaccines - secondary publication. AB - BACKGROUND: In the 1990s, the Japanese Society of Allergology (JSA) standardized Japanese cedar pollen allergen vaccines. In the present study, the task force for house dust mite (HDM) allergen standardization of the Committee for Allergens and Immunotherapy of JSA reports the standardization of HDM allergen vaccines in Japan. METHODS: In vivo allergenic potency was determined by intradermal testing of 51 Japanese adults with positive serum specific IgE to HDM allergens. In vitro total IgE binding potency was analyzed by competition ELISA using a pooled serum, with sera obtained from 10 allergic patients. The amounts of HDM group 1 (Der 1) and group 2 major allergens in eight HDM allergen extracts were measured by sandwich ELISAs. Correlation between the in vitro total IgE binding potency and major allergen levels was analyzed. RESULTS: We selected a JSA reference HDM extract and determined its in vivo allergenic potency. The in vitro total IgE binding potency significantly correlated with Der 1 content, group 2 allergen content, and their combined amount, indicating that measurement of major allergen contents can be used as a surrogate in vitro assay. CONCLUSIONS: The task force determined the in vivo allergenic potency (100,000 JAU/ml) and Der 1 content (38.5 MUg/ml) of the JSA reference HDM extract, selected the measurement of Der 1 content as the surrogate in vitro assay, and decided that manufacturers can label a HDM allergen extract as having a titer of 100,000 JAU/ml if it contains 22.2 66.7 MUg/ml of Der 1. PMID- 25838096 TI - Primary sclerosing cholangitis in common variable immune deficiency. PMID- 25838097 TI - Familial kiwi fruit allergy: a case report. PMID- 25838098 TI - Oral immunotherapy initiation for multi-nut allergy: a case report. PMID- 25838099 TI - Two cases of allergic contact dermatitis due to skin-whitening cosmetics. PMID- 25838100 TI - Synergistic suppression of Poly(I:C)-induced CCL3 by a corticosteroid and a long acting beta2 agonist in nasal epithelial cells. PMID- 25838101 TI - Antihistaminic drug olopatadine downmodulates T cell chemotaxis toward CCL17 in patients with atopic dermatitis. PMID- 25838102 TI - Fatal anaphylaxis to wheat after gluten-free diet in an adolescent with celiac disease. PMID- 25838103 TI - Prevalences of specific IgE to wheat gliadin components in patients with wheat dependent exercise-induced anaphylaxis. PMID- 25838104 TI - Periostin in the bronchial lavage fluid of asthma patients. PMID- 25838105 TI - A case of contact urticaria inducing anaphylaxis due to liliaceae vegetables in a hand eczema patient. PMID- 25838106 TI - Combined cholinergic urticaria and cold-induced cholinergic urticaria with acquired idiopathic generalized anhidrosis. PMID- 25838107 TI - Structure and Organization of the Engraulidae Family U2 snRNA: An Evolutionary Model Gene? AB - The U2 snRNA multigene family has been analyzed in four species of the Engraulidae family--Engraulis encrasicolus, Engraulis mordax, Engraulis ringens, and Engraulis japonicas--with the object of understanding more about the structure of this multigene family in these pelagic species and studying their phylogenetic relationships. The results showed that the cluster of this gene family in the Engraulis genus is formed by the U2-U5 snRNA with highly conserved sequences of mini- and micro-satellites, such as (CTGT)n, embedded downstream of the transcription unit; findings indicate that this gene family evolved following the concerted model. The phylogenetic analysis of the non-transcribed spacer of cluster U2-U5 snDNA in the 4 species showed that the sequences of the species E. encrasicolus and E. japonicus are closely related; these two are genetically close to E. mordax and slightly more distant from E. ringens. The data obtained by molecular analysis of U2-U5 snDNA and their secondary structure, with the presence of the micro-satellite (CTGT)n and mini-satellites, show clearly that the species E. encrasicolus and E. japonicus are closely related and would be older than E. mordax and E. ringens. PMID- 25838108 TI - Effects of codon usage on gene expression: empirical studies on Drosophila. AB - For most amino acids, more than one codon can be used. Many hypotheses have been put forward to account for patterns of uneven use of synonymous codons (codon usage bias) that most often have been indirectly tested primarily by analyses of patterns. Direct experimental tests of effects of synonymous codon usage are available for unicellular organisms, however empirical data addressing this problem in multicellular eukaryotes are sparse. We have developed a flexible transfecting plasmid that allows us to empirically test the effects of different codons on transcription and translation and present data from Drosophila. We could detect no significant effects of codon usage on transcription. With regard to translation, optimal codons (most used) produce higher levels of protein expression compared to non-optimal codons if the effect of difference in thermodynamic stability of secondary structure of the 5' mRNA ribosome-binding site is controlled for. These results are consistent with what has been found in bacteria and thus expand the generality of these principles to multicellular eukaryotes. PMID- 25838109 TI - Autistic-like traits in adult patients with mood disorders and schizophrenia. AB - Autism spectrum disorder often co-occurs with other psychiatric disorders. Although a high prevalence of autistic-like traits/symptoms has been identified in the pediatric psychiatric population of normal intelligence, there are no reports from adult psychiatric population. This study examined whether there is a greater prevalence of autistic-like traits/symptoms in patients with adult-onset psychiatric disorders such as major depressive disorder (MDD), bipolar disorder, or schizophrenia, and whether such an association is independent of symptom severity. The subjects were 290 adults of normal intelligence between 25 and 59 years of age (MDD, n=125; bipolar disorder, n=56; schizophrenia, n=44; healthy controls, n=65). Autistic-like traits/symptoms were measured using the Social Responsiveness Scale for Adults. Symptom severity was measured using the Positive and Negative Symptoms Scale, the Hamilton Depression Rating Scale, and/or the Young Mania Rating Scale. Almost half of the clinical subjects, except those with remitted MDD, exhibited autistic-like traits/symptoms at levels typical for sub threshold or threshold autism spectrum disorder. Furthermore, the proportion of psychiatric patients that demonstrated high autistic-like traits/symptoms was significantly greater than that of healthy controls, and not different between that of remitted or unremitted subjects with bipolar disorder or schizophrenia. On the other hand, remitted subjects with MDD did not differ from healthy controls with regard to the prevalence or degree of high autistic-like traits/symptoms. A substantial proportion of adults with bipolar disorder and schizophrenia showed high autistic-like traits/symptoms independent of symptom severity, suggesting a shared pathophysiology among autism spectrum disorder and these psychiatric disorders. Conversely, autistic-like traits among subjects with MDD were associated with the depressive symptom severity. These findings suggest the importance of evaluating autistic-like traits/symptoms underlying adult-onset psychiatric disorders for the best-suited treatment. Further studies with a prospective design and larger samples are needed. PMID- 25838110 TI - Survival kinetics of starving bacteria is biphasic and density-dependent. AB - In the lifecycle of microorganisms, prolonged starvation is prevalent and sustaining life during starvation periods is a vital task. In the literature, it is commonly assumed that survival kinetics of starving microbes follows exponential decay. This assumption, however, has not been rigorously tested. Currently, it is not clear under what circumstances this assumption is true. Also, it is not known when such survival kinetics deviates from exponential decay and if it deviates, what underlying mechanisms for the deviation are. Here, to address these issues, we quantitatively characterized dynamics of survival and death of starving E. coli cells. The results show that the assumption--starving cells die exponentially--is true only at high cell density. At low density, starving cells persevere for extended periods of time, before dying rapidly exponentially. Detailed analyses show intriguing quantitative characteristics of the density-dependent and biphasic survival kinetics, including that the period of the perseverance is inversely proportional to cell density. These characteristics further lead us to identification of key underlying processes relevant for the perseverance of starving cells. Then, using mathematical modeling, we show how these processes contribute to the density-dependent and biphasic survival kinetics observed. Importantly, our model reveals a thrifty strategy employed by bacteria, by which upon sensing impending depletion of a substrate, the limiting substrate is conserved and utilized later during starvation to delay cell death. These findings advance quantitative understanding of survival of microbes in oligotrophic environments and facilitate quantitative analysis and prediction of microbial dynamics in nature. Furthermore, they prompt revision of previous models used to analyze and predict population dynamics of microbes. PMID- 25838111 TI - The clinical profile of children with ADHD that require OROS-methylphenidate combined with shorter-acting formulations. AB - Long-acting methylphenidate (MPH) formulations, including OROS-MPH, were found to be effective in alleviating ADHD symptoms throughout the day. However, sustained stimulant activity may lead to prolonged suppression of appetite and insomnia. In this study, we characterized the clinical profile of children and adolescents for whom a once-daily lower dose of OROS-MPH combined with a shorter-acting agent was more tolerable than single higher OROS-MPH dose. In our cohort of 128 children treated with OROS-MPH, 47 (36.7 %) better tolerated a lower dose of OROS-MPH combined with short-acting MPH formulations (Group I). Nevertheless, for the majority (81 patients-63.3 %), a standard single moderate dose of OROS-MPH was sufficient (Group II). The mean daily doses of MPH were: 0.83 +/- 0.21 mg/kg for Group I and 1.06 +/- 0.29 mg/kg for Group II. There were no significant differences in the prevalence of learning disorders, tic disorders, epilepsy and conduct disorders between these two groups. However, anxiety and marginally depression were more prevalent in Group I (46.8 and 9.7 %) than in Group II (27.2 and 1.2 %). Patients in Group I were also more tending to receive psychotherapy than patients in Group II. PMID- 25838112 TI - Cardiovascular pharmacogenomics; state of current knowledge and implementation in practice. AB - Pharmacogenomics (PGx) is the science that examines how an individual's genetic make-up affects the safety and efficacy of therapeutic drugs. PGx of response to cardiovascular (CV) medications is of the most successfully translated branches of PGx into the clinical workout. However, the clinical implementation of PGx of CV drugs is yet far beyond the growth of our understanding of the role of genetics in drug therapy. A considerable amount of efforts have been devoted by the regulatory agents like the food and drug administration (FDA) as well as the expert-based networks such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) to overcome the existing barriers. This has been done, at least in part, for some of the most widely prescribed CV drugs, including clopidogrel, warfarin and simvastatin for which the PGx knowledge have been satisfactorily robust to provoke the CPIC to issue the guidelines for these drugs and the FDA to update the drugs' labeling, both strongly recommended the use of genotype-guided dosing for these medications, provided that the genetic data are available. For other drugs, however, studies have produced contradictory results and further large and well-designed clinical trials are required to expand and confirm the clinical utility of their PGx data. This review paper presents the current state of knowledge in the field of PGx of CV medications and describes the facilities assisting to the translation of PGx data into the clinical practice. Afterward, the existing body of PGx literature of the most-commonly used CV medications is comprehensively discussed. PMID- 25838113 TI - Popularity, similarity, and the network extraversion bias. AB - Using the emergent friendship network of an incoming cohort of students in an M.B.A. program, we examined the role of extraversion in shaping social networks. Extraversion has two important implications for the emergence of network ties: a popularity effect, in which extraverts accumulate more friends than introverts do, and a homophily effect, in which the more similar are two people's levels of extraversion, the more likely they are to become friends. These effects result in a systematic network extraversion bias, in which people's social networks will tend to be overpopulated with extraverts and underpopulated with introverts. Moreover, the most extraverted people have the greatest network extraversion bias, and the most introverted people have the least network extraversion bias. Our finding that social networks were systematically misrepresentative of the broader social environment raises questions about whether there is a societal bias toward believing other people are more extraverted than they actually are and whether introverts are better socially calibrated than extraverts. PMID- 25838114 TI - AAV2 X increases AAV6 rep/cap-driven rAAV production. AB - We have recently identified a new gene, involved in DNA replication, at the far 3' end of the adeno-associated virus type 2 (AAV2) genome. The AAV type 6 (AAV6) genome has a disrupted X open reading frame (ORF) whose two halves, when combined, have full-length homology and comparable size to AAV2 X. Hypothesizing that AAV6 X is inactive, we assessed if AAV2 X augments recombinant (r)AAV2 DNA replication and virion production, but with rep and cap trans-functions of AAV6. Using AAV2 X expressing HEK293 cell lines we show AAV2 X significantly boosts rAAV DNA replication/virion production, driven by AAV6 rep/cap as it does the AAV2 rep/cap system. Protein BLAST search for homology between AAV2 X and various AAV Rep78 proteins suggests that X might be AAV8 Rep78-derived and have some of its activities. These data suggest that AAV2 X, and the corresponding X genes of other AAV types/clades, warrant further study. PMID- 25838116 TI - Confined gold nanoparticles enhance the detection of small molecules in label free impedance aptasensors. AB - A controlled architecture of nanoelectrodes, of a similar size to small molecule binding aptamers, is synthesized inside nanoporous alumina. Gold nanoparticles with a controlled size (about 2 nm) are electrogenerated in the alumina cavities, showing a fast electron transfer process toward ferrocyanide. These uncapped nanoparticles are easily modified with a thiol-containing aptamer for label-free detection of adenosine monophosphate by electrochemical impedance spectroscopy. Our results show that the use of a limited electrical conducting surface inside an insulating environment can be very sensitive to conformational changes, introducing a new approach to the detection of small molecules, exemplified here by the direct and selective detection of adenosine monophosphate at the nanomolar scale. PMID- 25838115 TI - Evaluation of non-reciprocal heterologous immunity between unrelated viruses. AB - Heterologous immunity refers to the phenomenon whereby a history of an immune response against one pathogen can provide a level of immunity to a second unrelated pathogen. Previous investigations have shown that heterologous immunity is not necessarily reciprocal, such as in the case of vaccinia virus (VACV). Replication of VACV is reduced in mice immune to a variety of pathogens, while VACV fails to induce immunity to several of the same pathogens, including lymphocytic choriomeningitis virus (LCMV). Here we examine the lack of reciprocity of heterologous immunity between VACV and LCMV and find that they induce qualitatively different memory CD8 T cells. However, depending on the repertoire of an individual host, VACV can provide protection against LCMV simply by experimentally amplifying the quantity of T cells cross-reactive with the two viruses. Thus, one cause for lack of reciprocity is differences in the frequencies of cross-reactive T cells in immune hosts. PMID- 25838117 TI - Functional inactivation of hypocretin 1 receptors in the medial prefrontal cortex affects the pyramidal neuron activity and gamma oscillations: An in vivo multiple channel single-unit recording study. AB - The hypocretin signaling is thought to play a critical role in maintaining wakefulness via stimulating the subcortical arousal pathways. Although the cortical areas, including the medial prefrontal cortex (mPFC), receive dense hypocretinergic fibers and express its receptors, it remains unclear whether the hypocretins can directly regulate the neural activity of the mPFC in vivo. In the present study, using multiple-channel single-unit recording study, we found that infusion of the SB-334867, a blocker for the Hcrtr1, beside the recording sites within the mPFC substantially exerted an inhibitory effect on the putative pyramidal neuron (PPN) activity in naturally behaving rats. In addition, functional blockade of the Hcrtr1 also selectively reduced the power of the gamma oscillations. The PPN activity and the power of the neural oscillations were not affected after microinjection of the TCS-OX2-29, a blocker for the Hcrtr2, within the mPFC. Together, these data indicate that endogenous hypocretins acting on the Hcrtr1 are required for the normal neural activity in the mPFC in vivo, and thus might directly contribute cortical arousal and mPFC-dependent cognitive processes. PMID- 25838118 TI - Respiratory deficits in a rat model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of the dopaminergic nigrostriatal pathway. In addition to deficits in voluntary movement, PD involves a disturbance of breathing regulation. However, the cause and nature of this disturbance are not well understood. Here, we investigated breathing at rest and in response to hypercapnia (7% CO2) or hypoxia (8% O2), as well as neuroanatomical changes in brainstem regions essential for breathing, in a 6-hydroxydopamine (6-OHDA) rat model of PD. Bilateral injections of 6-OHDA (24MUg/MUl) into the striatum decreased tyrosine hydroxylase (TH(+))-neurons in the substantia nigra pars compacta (SNpc), transcription factor phox2b-expressing neurons in the retrotrapezoid nucleus and neurokinin-1 receptors in the ventral respiratory column. In 6-OHDA-lesioned rats, respiratory rate was reduced at rest, leading to a reduction in minute ventilation. These animals also showed a reduction in the tachypneic response to hypercapnia, but not to hypoxia challenge. These results suggest that the degeneration of TH(+) neurons in the SNpc leads to impairment of breathing at rest and in hypercapnic conditions. Our data indicate that respiratory deficits in a 6-OHDA rat model of PD are related to downregulation of neural systems involved in respiratory rhythm generation. The present study suggests a new avenue to better understand the respiratory deficits observed in chronic stages of PD. PMID- 25838120 TI - Household smoking restrictions among urban residents in China: individual and regional influences. AB - OBJECTIVES: The present study examines individual and regional influences on household smoking restrictions (HSR) in China. METHODS: Participants were 16,866 urban residents, who were identified through a multistage survey sampling process conducted in 21 Chinese cities. The data collection instrument was a self administered questionnaire. The sample was characterized in terms of the prevalence of complete HSRs. Multilevel logistic regression models were used to examine individual and environmental influences on HSR. RESULTS: Almost 22 % of respondents reported HSR. Both individual and regional-level restrictions on smoking in the workplace were associated with HSR. There was a negative association between individual household income and HSR, and positive associations between HSR awareness of secondhand smoking (SHS), and smoking in smoke-free public places, respectively. CONCLUSIONS: This study revealed individual and regional influences on HSR in China. Findings underscore that efforts to restrict smoking in Chinese households should emphasize environmental smoking restrictions, while simultaneously raising public awareness of the perils of SHS. This information should be considered in designing interventions to sustain and promote the adoption of HSR in Chinese and other populations. PMID- 25838119 TI - Minocycline enhances hippocampal memory, neuroplasticity and synapse-associated proteins in aged C57 BL/6 mice. AB - Previous studies have suggested that minocycline can attenuate cognitive deficits in animal models of conditions such as Alzheimer's disease and cerebral ischemia through inhibiting microglia associated anti-inflammatory actions. However the pathway that minocycline targets to enhance cognitive performance is not fully defined. Here we examined the effects of minocycline on learning and memory in aged (22-month-old) C57 BL/6 mice. We treated one group of mice with minocycline (30 mg/kg/day), and another group of mice with donepezil (2 mg/kg/day) as a positive control. The Morris water maze and passive avoidance tests were used to evaluate the effects of minocycline on learning and memory deficits. We also used high-frequency stimulation-induced long-term potentiation and Golgi-Cox staining to assess the effect of minocycline on synaptic plasticity and synaptogenesis. The effects of minocycline on synapse-associated signaling proteins were determined by western blot. We found that minocycline ameliorates cognitive deficits, enhances neuroplasticity, activates brain-derived neurotrophic factor- extracellular signal-regulated kinases signaling and increases expression of Arc, EGR1 and PSD-95 in the CA1 and dentate gyrus regions of the hippocampus in aged mice. The effects of minocycline in aged mice were similar to those of donepezil. Our results suggest that minocycline could improve learning and memory through enhancing synaptic plasticity and synaptogenesis, modulating the expression of synapse-associated signaling proteins, which provide a rationale for exploring the viability of using minocycline treatment in cognitive deficits. PMID- 25838121 TI - Evaluating HIV prevention strategies for populations in key affected groups: the example of Cabo Verde. AB - OBJECTIVES: We used an individual-based model to evaluate the effects of hypothetical prevention interventions on HIV incidence trajectories in a concentrated, mixed epidemic setting from 2011 to 2021, and using Cabo Verde as an example. METHODS: Simulations were conducted to evaluate the extent to which early HIV treatment and optimization of care, HIV testing, condom distribution, and substance abuse treatment could eliminate new infections (i.e., reduce incidence to less than 10 cases per 10,000 person-years) among non-drug users, female sex workers (FSW), and people who use drugs (PWUD). RESULTS: Scaling up all four interventions resulted in the largest decreases in HIV, with estimates ranging from 1.4 (95 % CI 1.36-1.44) per 10,000 person-years among non-drug users to 8.2 (95 % CI 7.8-8.6) per 10,000 person-years among PWUD in 2021. Intervention scenarios prioritizing FWS and PWUD also resulted in HIV incidence estimates at or below 10 per 10,000 person-years by 2021 for all population sub-groups. CONCLUSIONS: Our results suggest that scaling up multiple interventions among entire population is necessary to achieve elimination. However, prioritizing key populations with this combination prevention strategy may also result in a substantial decrease in total incidence. PMID- 25838122 TI - 5-HT3 receptors as important mediators of nausea and vomiting due to chemotherapy. AB - Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. The first generation 5-HT3 receptor antagonists have been very effective in the control of chemotherapy induced emesis in the first 24 h postchemotherapy (acute emesis), but have not been as effective against delayed emesis (24-120 h postchemotherapy). Palonosetron, a second generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity, and a different mechanism of action than the first generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a FDA approved antipsychotic that blocks multiple neurotransmitters: dopamine at D1, D2, D3, D4 brain receptors, serotonin at 5-HT2a, 5-HT2c, 5-HT3, 5 HT6 receptors, catecholamines at alpha1 adrenergic receptors, acetylcholine at muscarinic receptors, and histamine at H1 receptors, has emerged in recent trials as an effective preventative agent for chemotherapy-induced emesis and nausea, as well as a very effective agent for the treatment of breakthrough emesis and nausea. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25838123 TI - Membrane targeting of the yeast exocyst complex. AB - The exocytosis is a process of fusion of secretory vesicles with plasma membrane, which plays a prominent role in many crucial cellular processes, e.g. secretion of neurotransmitters, cytokinesis or yeast budding. Prior to the SNARE-mediated fusion, the initial contact of secretory vesicle with the target membrane is mediated by an evolutionary conserved vesicle tethering protein complex, the exocyst. In all eukaryotic cells, the exocyst is composed of eight subunits - Sec5, Sec6, Sec8, Sec10, Sec15, Exo84 and two membrane-targeting landmark subunits Sec3 and Exo70, which have been described to directly interact with phosphatidylinositol (4,5)-bisphosphate (PIP2) of the plasma membrane. In this work, we utilized coarse-grained molecular dynamics simulations to elucidate structural details of the interaction of yeast Sec3p and Exo70p with lipid bilayers containing PIP2. We found that PIP2 is coordinated by the positively charged pocket of N-terminal part of Sec3p, which folds into unique Pleckstrin homology domain. Conversely, Exo70p interacts with the lipid bilayer by several binding sites distributed along the structure of this exocyst subunit. Moreover, we observed that the interaction of Exo70p with the membrane causes clustering of PIP2 in the adjacent leaflet. We further revealed that PIP2 is required for the correct positioning of small GTPase Rho1p, a direct Sec3p interactor, prior to the formation of the functional Rho1p-exocyst-membrane assembly. Our results show the critical importance of the plasma membrane pool of PIP2 for the exocyst function and suggest that specific interaction with acidic phospholipids represents an ancestral mechanism for the exocyst regulation. PMID- 25838124 TI - TRP channels interaction with lipids and its implications in disease. AB - Transient receptor potential (TRP) proteins are a family of ion channels central for sensory signaling. These receptors and, in particular, those involved in thermal sensing are also involved in pain signaling. Noteworthy, thermosensory receptors are polymodal ion channels that respond to both physical and chemical stimuli, thus integrating different environmental clues. In addition, their activity is modulated by algesic agents and lipidergic substances that are primarily released in pathological states. Lipids and lipid-like molecules have been found that can directly activate some thermosensory channels or modulate their activity by either potentiating or inhibiting it. To date, more than 50 endogenous lipids that can regulate TRP channel activity in sensory neurons have been described, thus representing the majority of known endogenous TRP channel modulators. Lipid modulators of TRP channels comprise lipids from a variety of metabolic pathways, including metabolites of the cyclooxygenase, lipoxygenase and cytochrome-P450 pathways, phospholipids and lysophospholipids. Therefore, TRP channels are able to integrate and interpret incoming signals from the different metabolic lipid pathways. Taken together, the large number of lipids that can activate, sensitize or inhibit neuronal TRP-channels highlights the pivotal role of these molecules in sensory biology as well as in pain transduction and perception. This article is part of a Special Issue entitled: Lipid-protein interactions. Guest Editors: Amitabha Chattopadhyay and Jean-Marie Ruysschaert. PMID- 25838125 TI - Protecting Gram-negative bacterial cell envelopes from human lysozyme: Interactions with Ivy inhibitor proteins from Escherichia coli and Pseudomonas aeruginosa. AB - Lysozymes play an important role in host defense by degrading peptidoglycan in the cell envelopes of pathogenic bacteria. Several Gram-negative bacteria can evade this mechanism by producing periplasmic proteins that inhibit the enzymatic activity of lysozyme. The Escherichia coli inhibitor of vertebrate lysozyme, Ivyc and its Pseudomonas aeruginosa homolog, Ivyp1 have been shown to be potent inhibitors of hen egg white lysozyme (HEWL). Since human lysozyme (HL) plays an important role in the innate immune response, we have examined the binding of HL to Ivyc and Ivyp1. Our results show that Ivyp1 is a weaker inhibitor of HL than Ivyc even though they inhibit HEWL with similar potency. Calorimetry experiments confirm that Ivyp1 interacts more weakly with HL than HEWL. Analytical ultracentrifugation studies revealed that Ivyp1 in solution is a monomer and forms a 30kDa heterodimer with both HL and HEWL, while Ivyc is a homodimer that forms a tetramer with both enzymes. The interaction of Ivyp1 with HL was further characterized by NMR chemical shift perturbation experiments. In addition to the characteristic His-containing Ivy inhibitory loop that binds into the active site of lysozyme, an extended loop (P2) between the final two beta-strands also participates in forming protein-protein interactions. The P2 loop is not conserved in Ivyc and it constitutes a flexible region in Ivyp1 that becomes more rigid in the complex with HL. We conclude that differences in the electrostatic interactions at the binding interface between Ivy inhibitors and distinct lysozymes determine the strength of this interaction. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 25838126 TI - Benchmarking the stability of human detergent-solubilised voltage-gated sodium channels for structural studies using eel as a reference. AB - With the ultimate goal of detailed structural analysis of mammalian and particularly human voltage-gated sodium channels (VGSCs), we have investigated the relative stability of human and rat VGSCs and compared them with electric eel VGSC. We found that NaV1.3 from rat was the most stable after detergent solubilisation. The order of stability was rNaV1.3>hNaV1.2>hNaV1.1>hNaV1.6>hNaV1.3>hNaV1.4. However, a comparison with the VGSC from Electrophorus electricus, which is most similar to NaV1.4, shows that the eel VGSC is considerably more stable in detergent than the human VGSCs examined. We conclude that current methods of structural analysis, such as single particle electron cryomicroscopy (cryoEM), may be most usefully targeted to eel VGSC or rNaV1.3, but that structural analysis on the full spectrum of VGSCs, by methods that require greater stability such as crystallisation and X-ray crystallography, will require further stabilisation of the channel. PMID- 25838127 TI - The E2P-like state induced by magnesium fluoride complexes in the Na,K-ATPase. Kinetics of formation and interaction with Rb(+). AB - The first X-ray crystal structures of the Na,K-ATPase were obtained in the presence of magnesium and fluoride as E2(K2)Mg-MgF4, an E2?Pi-like state capable to occlude K(+) (or Rb(+)). This work presents a functional characterization of the crystallized form of the enzyme and proposes a model to explain the interaction between magnesium, fluoride and Rb(+) with the Na,K-ATPase. We studied the effect of magnesium and magnesium fluoride complexes on the E1-E2 conformational transition and the kinetics of Rb(+) exchange between the medium and the E2(Rb2)Mg-MgF4 state. Our results show that both in the absence and in the presence of Rb(+), simultaneous addition of magnesium and fluoride stabilizes the Na,K-ATPase in an E2 conformation, presumably the E2Mg-MgF4 complex, that is unable to shift to E1 upon addition of Na(+). The time course of conformational change suggests the action of fluoride and magnesium at different steps of the E2Mg-MgF4 formation. Increasing concentrations of fluoride revert along a sigmoid curve the drop in the level of occluded Rb(+) caused by Mg(2+). Na(+)-induced release of Rb(+) from E2(Rb2)Mg-MgF4 occurs at the same rate as from E2(Rb2) but is insensitive to ADP. The rate of Rb(+) occlusion into the E2Mg-MgF4 state is 5 8 times lower than that described for the E2Mg-vanadate complex. Since the E2Mg MgF4 and E2Mg-vanadate complexes represent different intermediates in the E2-P >E2 dephosphorylation sequence, the variation in occlusion rate could provide a tool to discriminate between these intermediates. PMID- 25838128 TI - Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors. AB - RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfralpha2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfralpha2 null mice display comparable early central projection deficits, but Gfralpha2 null RA mechanoreceptors recover later. Loss of Gfralpha1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfralpha1;Gfralpha2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRalpha1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling. PMID- 25838129 TI - Systematic imaging reveals features and changing localization of mRNAs in Drosophila development. AB - mRNA localization is critical for eukaryotic cells and affects numerous transcripts, yet how cells regulate distribution of many mRNAs to their subcellular destinations is still unknown. We combined transcriptomics and systematic imaging to determine the tissue-specific expression and subcellular distribution of 5862 mRNAs during Drosophila oogenesis. mRNA localization is widespread in the ovary and detectable in all of its cell types-the somatic epithelial, the nurse cells, and the oocyte. Genes defined by a common RNA localization share distinct gene features and differ in expression level, 3'UTR length and sequence conservation from unlocalized mRNAs. Comparison of mRNA localizations in different contexts revealed that localization of individual mRNAs changes over time in the oocyte and between ovarian and embryonic cell types. This genome scale image-based resource (Dresden Ovary Table, DOT, http://tomancak-srv1.mpi-cbg.de/DOT/main.html) enables the transition from mechanistic dissection of singular mRNA localization events towards global understanding of how mRNAs transcribed in the nucleus distribute in cells. PMID- 25838130 TI - Switching immune signals on and off. PMID- 25838131 TI - Spreading good news. PMID- 25838133 TI - Burden of Clostridium difficile infection on hospital readmissions and its potential impact under the Hospital Readmission Reduction Program. AB - BACKGROUND: Both Clostridium [corrected] difficile infection (CDI) rates in hospitals and interest in reducing 30-day readmission rates have increased dramatically in the United States. The objective of this study was to characterize the burden of CDI on 30-day hospital readmissions at a tertiary care health-system. METHODS: A patient discharge database was used to identify patients with a CDI diagnosis (ICD-9 code 008.45) during their stay in 2012. Patients were classified as index admissions (CDI discharges) or 30-day readmissions (CDI readmissions). Readmission rates, length of stay (LOS), and time to readmission were assessed among CDI readmissions. RESULTS: Among discharges from the health system (n = 51,353), 615 were diagnosed with CDI (1%). Thirty-day readmissions were more common among CDI discharges (30.1%) than non CDI discharges (14.4%). Average LOS for CDI readmissions was 5-6 days longer than non-CDI readmissions. Time to readmission was shorter among CDI discharges diagnosed on admission than CDI discharges diagnosed later during their hospital stay (median, 7 days). CONCLUSION: Reductions in hospital-onset CDI and readmission of patients with an index CDI can provide tremendous cost savings to hospitals. This calls for better infection control and antibiotic stewardship measures toward CDI management in the hospital and as patients transition to the next level of care. PMID- 25838134 TI - Influence of antimicrobial consumption on gram-negative bacteria in inpatients receiving antimicrobial resistance therapy from 2008-2013 at a tertiary hospital in Shanghai, China. AB - BACKGROUND: Irrational use of antimicrobial agents is a major cause of increased antimicrobial resistance. Effective antibiotic stewardship strategies nationwide or in local health care settings are necessary to reduce antibiotic use and bacteria resistance. METHODS: We evaluated the effectiveness of China's antimicrobial stewardship policy on antimicrobial use and applied time-series analysis methodology to determine the temporal relationship between antibiotic use and gram-negative bacteria resistance at Changhai Hospital from 2008-2013. Isolates investigated included Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. RESULTS: Consumption of 7 restricted-use antibiotics was dramatically reduced. Resistance to ceftazidime in P aeruginosa and A baumannii and resistance to ciprofloxacin in P aeruginosa significantly decreased. By using cross-correlation analysis, associations between ciprofloxacin resistance in P aeruginosa and fluoroquinolones consumption (r = 0.48; lag = 0; P = .02), ceftazidime resistance in P aeruginosa and third generation cephalosporins consumption (r = 0.54; lag = -1; P = .01) were identified. No substantial association between other pairs was found. CONCLUSIONS: Enhanced nationwide antimicrobial stewardship campaigns launched in 2011 have made great achievements in regard to antibiotic use but have had limited effects on the reversal of gram-negative bacteria resistance in health care settings. Sound infection prevention and control programs to reduce the transmission of resistant pathogens for hospitals in China are urgently needed. PMID- 25838135 TI - A case of postoperative breast infection by Mycobacterium fortuitum associated with the hospital water supply. AB - This report describes the first known laboratory-confirmed case of Mycobacterium fortuitum breast infection related to the hospital water supply. The source of the M fortuitum infection was identified by repetitive extragenic palindromic sequence-based polymerase chain reaction genotyping. In addition, we discuss appropriate infection control measures to minimize patient exposure to waterborne pathogens, in particular, in the context of nontuberculous mycobacteria, which is difficult to eradicate from the water supply network. PMID- 25838136 TI - Natural antimicrobials subtilosin and lauramide arginine ethyl ester synergize with conventional antibiotics clindamycin and metronidazole against biofilms of Gardnerella vaginalis but not against biofilms of healthy vaginal lactobacilli. AB - The purpose of this study was to evaluate the ability of clindamycin and metronidazole to synergize with natural antimicrobials against biofilms of bacterial vaginosis (BV)-associated Gardnerella vaginalis. Minimum bactericidal concentrations for biofilm cells (MBCs-B) were determined for each antimicrobial. The MBCs-B of lauramide arginine ethyl ester (LAE), subtilosin, clindamycin and metronidazole were 50, 69.5, 20 and 500 MUg mL(-1), respectively. A checkerboard assay and isobologram were used to analyze the type of interactions between these antimicrobials. The combination of metronidazole with natural antimicrobials did not inhibit planktonic lactobacilli. Clindamycin with either LAE or with subtilosin was inhibitory for planktonic but not for biofilm-associated lactobacilli. All tested antimicrobial combinations were inhibitory for BV associated Mobiluncus curtisii and Peptostreptococcus anaerobius. LAE and subtilosin synergized with clindamycin and metronidazole against biofilms of G. vaginalis but not biofilm-associated vaginal lactobacilli. The biofilms of BV associated pathogens can be controlled by synergistically acting combinations of conventional antibiotics and natural antimicrobials which will help better management of current antibiotics, especially considering robust bacterial resistance. Our findings create a foundation for a new strategy in the effective control of vaginal infections. PMID- 25838137 TI - Cystic Fibrosis Gene Therapy in the UK and Elsewhere. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here. PMID- 25838138 TI - Oncolytic measles virus efficacy in murine xenograft models of atypical teratoid rhabdoid tumors. AB - BACKGROUND: Atypical teratoid rhabdoid tumor (AT/RT) is a rare, highly malignant pediatric tumor of the central nervous system that is usually refractory to available treatments. The aggressive growth, propensity to disseminate along the neuroaxis, and young age at diagnosis contribute to the poor prognosis. Previous studies have demonstrated the efficacy of using oncolytic measles virus (MV) against localized and disseminated models of medulloblastoma. The purpose of this study was to evaluate the oncolytic potential of MV in experimental models of AT/RT. METHODS: Following confirmation of susceptibility to MV infection and killing of AT/RT cells in vitro, nude mice were injected with BT-12 and BT-16 AT/RT cells stereotactically into the caudate nucleus (primary tumor model) or lateral ventricle (disseminated tumor model). Recombinant MV was administered either intratumorally or intravenously. Survival was determined for treated and control animals. Necropsy was performed on animals showing signs of progressive disease. RESULTS: All cell lines exhibited significant killing when infected with MV, all formed syncytia with infection, and all generated infectious virus after infection. Orthotopic xenografts displayed cells with rhabdoid-like cellular morphology, were negative for INI1 expression, and showed dissemination within the intracranial and spinal subarachnoid spaces. Intratumoral injection of live MV significantly prolonged the survival of animals with intracranial and metastatic tumors. CONCLUSION: These data demonstrate that AT/RT is susceptible to MV killing and suggest that the virus may have a role in treating this tumor in the clinical setting. PMID- 25838139 TI - Survival, hypothalamic obesity, and neuropsychological/psychosocial status after childhood-onset craniopharyngioma: newly reported long-term outcomes. AB - BACKGROUND: Quality of life (QoL) and long-term prognosis are frequently, and often severely, impaired in craniopharyngioma (CP) patients. Knowledge of risk factors for long-term outcome is important for optimization of treatment. METHODS: Overall survival (OS) and progression-free survival (PFS), body mass index (BMI), neuropsychological status (EORTCQLQ-C30, MFI-20), and psychosocial status were analyzed in 261 patients with childhood-onset CP diagnosed before 2000 and longitudinally observed in HIT-Endo. RESULTS: Twenty-year OS was lower (P = .006) in CP with hypothalamic involvement (HI) (n = 132; 0.84 +/- 0.04) when compared with CP without HI (n = 82; 0.95 +/- 0.04). OS was not related to degree of resection, sex, age at diagnosis, or year of diagnosis (before/after 1990). PFS (n = 168; 0.58 +/- 0.05) was lower in younger patients (<5 y at diagnosis) (n = 30; 0.39 +/- 0.10) compared with patients aged 5-10 years (n = 66; 0.52 +/- 0.08) and older than 10 years (n = 72; 0.77 +/- 0.06) at diagnosis. PFS was not associated with HI, degree of resection, or sex. HI led to severe weight gain during the first 8-12 years of follow-up (median BMI increase: +4.59SD) compared with no HI (median increase: +1.20SD) (P = .00). During >12 years of follow-up, patients with HI presented no further increase in BMI. QoL in CP patients with HI was impaired by obesity, physical fatigue, reduced motivation, dyspnea, diarrhea, and nonoptimal psychosocial development. CONCLUSIONS: OS and QoL are impaired by HI in long-term survivors of CP. HI is associated with severe obesity, which plateaus after 12 years. OS/PFS are not related to degree of resection, but gross total resection should be avoided in cases of HI to prevent further hypothalamic damage, which exacerbates sequelae. PMID- 25838141 TI - Xanthones from the roots of Maclura cochinchinensis var. gerontogea and their retinoic acid receptor-alpha agonistic activity. AB - A new xanthone (1) and a new naturally occurring xanthone (2) were isolated from the roots of Maclura cochinchinensis (Lour.) Corner var. gerontogea (Sieb. et Zucc.) Ohashi together with 10 known xanthones (3-12). Their structures were established by spectroscopic analyses including 1D and 2D NMR. Their retinoic acid receptor-alpha agonistic activity was evaluated using a luciferase reporter assay. Compound 2, gerontoxanthone A (3), gerontoxanthone B (4), and cudraxanthone I (11) showed moderate concentration-dependent activity. Furthermore, these four xanthones synergistically increased transcriptional activity in this assay in the presence of bexarotene, an RXR agonist. PMID- 25838142 TI - Strigolactam: New potent strigolactone analogues for the germination of Orobanche cumana. AB - Very recently, strigolactones have been conclusively identified as phytohormones. The progresses achieved in this field are culminating in the identification of the molecular receptors involved in the signal transduction mechanism. The exact mechanism of the mode of action of strigolactones still remains to be fully elucidated and we were interested to gain some insight into the mechanism of action of strigolactones by selectively modifying the reactivity of the lactone C ring. Therefore, we report here the synthesis of strigolactams 1 and 16 and their surprisingly good activity on the germination of Orobanche cumana parasitic weed seeds. PMID- 25838140 TI - Dietary chromium supplementation for targeted treatment of diabetes patients with comorbid depression and binge eating. AB - Dietary chromium supplementation for the treatment of diabetes remains controversial. The prevailing view that chromium supplementation for glucose regulation is unjustified has been based upon prior studies showing mixed, modest sized effects in patients with type 2 diabetes (T2DM). Based on chromium's potential to improve insulin, dopamine, and serotonin function, we hypothesize that chromium has a greater glucoregulatory effect in individuals who have concurrent disturbances in dopamine and serotonin function--that is, complex patients with comorbid diabetes, depression, and binge eating. We propose, as suggested by the collective data to date, the need to go beyond the "one size fits all" approach to chromium supplementation and put forth a series of experiments designed to link physiological and neurobehavioral processes in the chromium response phenotype. PMID- 25838143 TI - Synthesis and structure-activity relationship studies of novel [6,6,5] tricyclic oxazolidinone derivatives as potential antibacterial agents. AB - In our previous Letter, we reported the discovery of a novel benzoxazinyl oxazolidinone antibacterial candidate 2. In order to identify a potential backup compound, extensive modifications on the B/C ring and C3 side chain were undertaken. A series of novel [6,6,5] tricyclic analogues were synthesized and their in vitro antibacterial activities were tested against a panel of susceptible and resistant Gram-positive pathogens. Among of them, benzothiazinyl oxazolidinones with acetamide or thioamide as C3 side chains exhibited moderate to good antibacterial activity, such as compounds 54, 58, 59 and 63. In vitro liver microsomal stability was further evaluated and the results manifested that compounds 54 and 58 were both metabolically stable in rat and human liver microsomes. Additionally, insights gained from this investigation should provide directions for the further research of new oxazolidinone antibiotics. PMID- 25838144 TI - Synthesis and biological evaluation of novel HIV-1 protease inhibitors using tertiary amine as P2-ligands. AB - A series of tertiary amine derivatives exhibiting potent HIV-1 protease inhibiting properties were identified. These novel inhibitors were designed based on the structure of Darunavir with modification on the P2 and P2' position. This effort led to discovery of 35e and 38e, which exhibited excellent HIV-1 protease inhibition with IC50 values of 15 nM and 64 nM, respectively. PMID- 25838145 TI - One-pot catalyst free synthesis of novel kojic acid tagged 2-aryl/alkyl substituted-4H-chromenes and evaluation of their antimicrobial and anti-biofilm activities. AB - A number of 3-hydroxy-6-(hydroxymethyl)-2-(2-phenyl-4H-chromen-4-yl)-4H-pyran-4 ones (3) have been synthesized in a one pot catalyst free reaction of 2-hydroxy chalcone (1) with kojic acid (2) in toluene at reflux temperature and evaluated for antimicrobial and anti-biofilm activities. Compounds 3a, 3e, 3f, 3l showed potent antimicrobial activity against Staphylococcus aureus MLS-16 MTCC 2940, Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739, whereas 3b and 3k exhibited excellent activity against Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739, while 3g showed promising activity against Bacillus subtilis MTCC 121 and Escherichia coli MTCC 739. On the other hand, compounds 3a, 3b and 3l showed very good anti-biofilm activity and 3g showed moderate activity against Bacillus subtilis MTCC 121. Whereas, compounds 3a and 3f showed moderate activity against Escherichia coli MTCC 739, while compounds 3a, 3b, 3k and 3l displayed similar activity against Staphylococcus aureus MLS-16 MTCC 2940. PMID- 25838146 TI - Synthesis and potent inhibitory activities of carboxybenzyl-substituted 8-(3-(R) aminopiperidin-1-yl)-7-(2-chloro/cyanobenzyl)-3-methyl-3,7-dihydro-purine-2,6 diones as dipeptidyl peptidase IV (DPP-IV) inhibitors. AB - Fourteen 3-methyl-3,7-dihydro-purine-2,6-dione derivatives 1-14 bearing carboxybenzyl and 2-chloro/cyanobenzyl groups at the N-1 and N-7 positions, respectively, were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors. These compounds were characterized on the basis of NMR ((1)H and (13)C) and ESI MS data. In vitro bioassay indicates that most of these compounds showed moderate to good inhibitory activities against DPP-IV. Among them, compound 13 (IC50=36 nM) exhibited comparable activity with a positive control, Sitagliptin (IC50=16 nM). In addition, the structure-activity relationship of these compounds is also briefly discussed. PMID- 25838147 TI - Substituted pyrrolidin-2-ones: Centrally acting orexin receptor antagonists promoting sleep. Part 2. AB - Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the gamma-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3 hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats. PMID- 25838148 TI - Ultrafast Carrier Dynamics and Hot Electron Extraction in Tetrapod-Shaped CdSe Nanocrystals. AB - The ultrafast carrier dynamics and hot electron extraction in tetrapod-shaped CdSe nanocrystals was studied by femtosecond transient absorption (TA) spectroscopy. The carriers relaxation process from the higher electronic states (CB2, CB3(2), and CB4) to the lowest electronic state (CB1) was demonstrated to have a time constant of 1.04 ps, resulting from the spatial electron transfer from arms to a core. The lowest electronic state in the central core exhibited a long decay time of 5.07 ns in agreement with the reported theoretical calculation. The state filling mechanism and Coulomb blockade effect in the CdSe tetrapod were clearly observed in the pump-fluence-dependent transient absorption spectra. Hot electrons were transferred from arm states into the electron acceptor molecules before relaxation into core states. PMID- 25838149 TI - Diagnostic and prognostic value of serum cystatin C in critically ill children with acute kidney injury. AB - OBJECTIVES: We aimed to evaluate the value of serum cystatin C for detection of acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories in critically ill children and to investigate whether serum cystatin C was associated with outcome. DESIGN: Prospective cohort study. SETTING: PICU of a tertiary-care university hospital. PATIENTS: A heterogeneous population of critically ill children. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood and 24-hour urine samples were collected daily over the first 2 days after PICU admission for measurement of serum cystatin C, serum creatinine, and creatinine clearance. Acute kidney injury was classified by pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease criteria. One hundred twenty-two children were prospectively enrolled; 40 (32.8%) developed acute kidney injury. Serum cystatin C was higher in patients with acute kidney injury compared with those who did not develop acute kidney injury at PICU admission (median, 0.90 mg/L vs 0.51 mg/L) and on the first (1.12 mg/L vs 0.57 mg/L) and second PICU days (1.15 mg/L vs 0.58 mg/L). Serum creatinine was higher in acute kidney injury group only on the first (0.50 mg/dL vs 0.40 mg/dL) and second PICU days (0.60 mg/dL vs 0.40 mg/dL). Serum cystatin C was increasingly higher according to acute kidney injury severity (Failure > Injury > Risk). Area under the receiver operating characteristic curve of cystatin C for acute kidney injury detection was 0.89. Serum cystatin C greater than 0.70 mg/L was associated with longer length of PICU stay (adjusted hazard ratio, 1.64) and prolonged duration of mechanical ventilation (adjusted hazard ratio, 1.82). CONCLUSIONS: Cystatin C is an early and accurate biomarker for acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories, and it is associated with adverse clinical outcomes in a heterogeneous population of critically ill children. PMID- 25838150 TI - Diagnostic Errors in a PICU: Insights From the Morbidity and Mortality Conference. AB - OBJECTIVES: To describe diagnostic errors identified among patients discussed at a PICU morbidity and mortality conference in terms of Goldman classification, medical category, severity, preventability, contributing factors, and occurrence in the diagnostic process. DESIGN: Retrospective record review of morbidity and mortality conference agendas, patient charts, and autopsy reports. SETTING: Single tertiary referral PICU in Baltimore, MD. PATIENTS: Ninety-six patients discussed at the PICU morbidity and mortality conference from November 2011 to December 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-nine of 96 patients (93%) discussed at the PICU morbidity and mortality conference had at least one identified safety event. A total of 377 safety events were identified. Twenty patients (21%) had identified misdiagnoses, comprising 5.3% of all safety events. Out of 20 total diagnostic errors identified, 35% were discovered at autopsy while 55% were reported primarily through the morbidity and mortality conference. Almost all diagnostic errors (95%) could have had an impact on patient survival or safety. Forty percent of errors did not cause actual patient harm, but 25% were severe enough to have potentially contributed to death (40% no harm vs 35% some harm vs 25% possibly contributed to death). Half of the diagnostic errors (50%) were rated as preventable. There were slightly more system-related factors (40%) solely contributing to diagnostic errors compared with cognitive factors (20%); however, 35% had both system and cognitive factors playing a role. Most errors involved vascular (35%) followed by neurologic (30%) events. CONCLUSIONS: Diagnostic errors in the PICU are not uncommon and potentially cause patient harm. Most appear to be preventable by targeting both cognitive- and system-related contributing factors. Prospective studies are needed to further determine how and why diagnostic errors occur in the PICU and what interventions would likely be effective for prevention. PMID- 25838151 TI - Headache disorders foreword. PMID- 25838152 TI - Exploring the Impact of Habitat Size on Phylogeographic Patterning in the Overberg Velvet Worm Peripatopsis overbergiensis (Onychophora: Peripatopsidae). AB - Evolutionary relationships in the velvet worm species, Peripatopsis overbergiensis, were examined in 3 forest areas in the Overberg region of South Africa to explore the impact of historical habitat fragmentation on the population genetic structure of the species. We collected 84 P. overbergiensis specimens from Grootvadersbosch, Koppie Alleen, and Marloth Nature Reserves and sequenced all these specimens for the cytochrome c oxidase subunit I (COI) locus, whereas a subset of 13 specimens were also sequenced for the 18S rRNA locus. Phylogenetic analyses of the 20 unique COI haplotypes revealed 4 genetically distinct clades, a result that is corroborated by the haplotype network. A hierarchical analysis of genetic variation was performed on the COI haplotype data within the 2 large forested areas, Grootvadersbosch and Marloth Nature Reserves, and across all 3 of the sample localities. These results revealed low haplotypic and nucleotide diversity within the largest Grootvadersbosch Nature Reserve forest and high haplotypic and nucleotide diversity within the fragmented Marloth Nature Reserve forest, whereas Koppie Alleen had the lowest haplotypic and nucleotide diversity. Across all 3 main localities statistically significant F ST values were found, together with the absence of shared haplotypes indicating the absence of maternal gene flow. Divergence time estimations based on the 20 COI haplotypes calculated in BEAST suggest a Pleistocene/Holocene divergence between the 4 clades as a result of habitat fragmentation and the aridification of the region. Our results indicate that conservation efforts should also prioritize linked, smaller fragmented habitats together with continuous habitats to maximize the genetic diversity of saproxylic fauna. PMID- 25838153 TI - Effects of crossovers between homeologs on inheritance and population genomics in polyploid-derived salmonid fishes. AB - A whole genome duplication occurred in the ancestor of all salmonid fishes some 50-100 million years ago. Early inheritance studies with allozymes indicated that loci in the salmonid genome are inherited disomically in females. However, some pairs of duplicated loci showed patterns of inheritance in males indicating pairing and recombination between homeologous chromosomes. Nearly 20% of loci in the salmonid genome are duplicated and share the same alleles (isoloci), apparently due to homeologous recombination. Half-tetrad analysis revealed that isoloci tend to be telomeric. These results suggested that residual tetrasomic inheritance of isoloci results from homeologous recombination near chromosome ends and that continued disomic inheritance resulted from homologous pairing of centromeric regions. Many current genetic maps of salmonids are based on single nucleotide polymorphisms and microsatellites that are no longer duplicated. Therefore, long sections of chromosomes on these maps are poorly represented, especially telomeric regions. In addition, preferential multivalent pairing of homeologs from the same species in F1 hybrids results in an excess of nonparental gametes (so-called pseudolinkage). We consider how not including duplicated loci has affected our understanding of population and evolutionary genetics of salmonids, and we discuss how incorporating these loci will benefit our understanding of population genomics. PMID- 25838154 TI - Progressive unilateral nasal congestion, facial pain, and vision change in an immunocompetent patient. PMID- 25838155 TI - Complementary and integrative therapies for lower urinary tract diseases. AB - Consumer use of integrative health care is growing, but evidence-based research on its efficacy is limited. Research of veterinary lower urinary tract diseases could be translated to human medicine because veterinary patients are valuable translational models for human urinary tract infection and urolithiasis. An overview of complementary therapies for lower urinary tract disease includes cranberry supplements, mannose, oral probiotics, acupuncture, methionine, herbs, or herbal preparations. Therapies evaluated in dogs and cats, in vitro canine cells, and other relevant species, in vivo and in vitro, are presented for their potential use as integrative therapies for veterinary patients and/or translational research. PMID- 25838156 TI - The Effect of Exertion on Joint Kinematics and Kinetics During Running Using a Waveform Analysis Approach. AB - About half of all runners sustain a running-related injury every year. Exertion may contribute to risk of injury by altering joint mechanics. The purpose of this study was to examine the effects of exertion on runners' joint mechanics using principal component analysis (PCA). Three-dimensional motion analysis of the lower extremity was performed on 16 healthy female runners before and after their typical training run. PCA was used to determine exertion-related changes in joint mechanics at the ankle, knee, and hip. Statistical significance for repeated measures MANOVA of the retained principal components at each joint and plane of motion was at P < .05. Exercise effects were identified at the ankle (greater rate of eversion [PC2: P = .027], and decreased plantar flexion moment [overall: P = .044] and external rotation moment [PC3: P = .003]), knee (increased adduction [overall: P = .044] and internal rotation [PC3: P = .034], and decreased abduction moment [overall: P = .045]), and hip (increased internal rotation [PC1: P = .013] and range of mid- to late-stance rotation [PC2: P = .009], and decreased internal rotation moment [PC1: P = .001]). The observed changes in running mechanics reflect a gait profile that is often linked to running injury. The effects of more strenuous activity may result in mechanics that present an even greater risk for injury. PMID- 25838157 TI - Pathogenesis of Streptococcus infantarius subspecies coli Isolated from Sea Otters with Infective Endocarditis. AB - The Gram positive bacterial coccus Streptococcus infantarius subspecies coli is increasingly linked with development of fatal vegetative infective endocarditis and septicemia in humans, sea otters (Enhydra lutris) and other animals. However, the pathogenesis of these infections is poorly understood. Using S. infantarius subsp. coli strains isolated from sea otters with infective endocarditis, this study evaluated adherence and invasion of epithelial and endothelial cells, adherence to extracellular matrix components, and macrophage survival. Significant adherence to endothelial-derived cells was observed for 62% of isolates, 24% adhered to epithelial cell lines, and 95% invaded one or both cell types in vitro. The importance of the hyaluronic acid capsule in host cell adherence and invasion was also evaluated. Capsule removal significantly reduced epithelial adherence and invasion for most S. infantarius subsp. coli isolates, suggesting that the capsule facilitates attachment to and invasion of epithelium. Enzyme-linked immunosorbent assay testing revealed that all isolates adhered significantly to the extracellular matrix components collagen IV, fibronectin, laminin and hyaluronic acid. Finally, significant bacterial survival following phagocytosis by macrophages was apparent for 81% of isolates at one or more time points. Taken collectively these findings indicate that S. infantarius subsp. coli has multiple pathogenic properties that may be important to host colonization, invasion and disease. PMID- 25838158 TI - Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform. AB - New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies. Advanced stage non-small-cell lung cancer (NSCLC) was selected for initial studies because of emergence of a number of "druggable" molecular targets, and recent recognition of substantial inter- and intrapatient tumor heterogeneity. Additionally, clonal evolution after targeted therapy interventions make this tumor type ideal for investigation of this platform. Using the immunodeficient NOD scid gamma mouse, > 200 NSCLC tumor biopsies have been xenotransplanted. During the annotation process, patient tumors and subsequent PDXs are compared at multiple levels, including histomorphology, clinically applicable molecular biomarkers, global gene expression patterns, gene copy number variations, and DNA/chromosomal alterations. NSCLC PDXs are grouped into panels of interest according to oncogene subtype and/or histologic subtype. Multiregimen drug testing, paired with next-generation sequencing before and after therapy and timed tumor pharmacodynamics enables determination of efficacy, signaling pathway alterations, and mechanisms of sensitivity-resistance in individual models. This approach should facilitate derivation of new therapeutic strategies and the transition to individualized therapy. PMID- 25838160 TI - Visible-light initiated oxidative cyclization of phenyl propiolates with sulfinic acids to coumarin derivatives under metal-free conditions. AB - A visible-light initiated oxidative cyclization of phenyl propiolates with sulfinic acids has been developed. The arylsulfonylation of alkynes was performed at room temperature under metal-free conditions to generate coumarin derivatives with wide functional group tolerance, good yields and high regioselectivity. PMID- 25838159 TI - Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study. AB - BRCA mutation carriers may use tamoxifen for breast cancer prevention or treatment. Hormone replacement therapy is often prescribed after surgical menopause and oral contraceptives are recommended for ovarian cancer prevention. The objective of this study was to assess the impact of these medications and other risk factors on endometrial cancer risk in BRCA carriers. Women with a BRCA1 or BRCA2 mutation were identified from a registry of mutation carriers. Cases were 83 women who had a diagnosis of endometrial cancer. Controls were 1027 matched women who did not develop endometrial cancer and who had an intact uterus. All women completed a baseline questionnaire, which included questions about ages at menarche and menopause, oral contraceptive use, hormone replacement therapy use, hysterectomy, oophorectomy, breast cancer history and tamoxifen use. We estimated the odds ratio associated with each risk factor in a multivariate analysis. No differences were found between cases and controls in terms of age at menarche, BMI, smoking, or oral contraceptive use. In a multivariate analysis, for women taking estrogen-only hormone replacement therapy, the odds ratio was 0.23 (95% CI 0.03-1.78, p = 0.16), and for women taking progesterone-only hormone replacement therapy the odds ratio was 6.91 (95% CI 0.99-98.1, p = 0.05). The adjusted odds ratio for endometrial cancer associated with a history of tamoxifen use was 3.50 (95% CI 1.51-8.10, p = 0.003). The observed increased risk of endometrial cancer associated with progesterone-only therapy merits further study. PMID- 25838161 TI - Midfoot reconstruction with serratus anterior-rib osteomuscular free flap following oncological resection of synovial sarcoma. AB - During recent decades, the concept of surgical treatment of malignant bone and soft tissue sarcomas has evolved, with the aim of preserving limb function. In this paper we report a case of metatarsal reconstruction by means of serratus and rib free flap after excision of a synovial sarcoma located in the dorsal aspect of the midfoot. Five years after the operation, the patient was free from recurrence and recovered full foot function. Amputation has been widely used in the past and this procedure still remains a valuable option when limb salvage is not possible. Nevertheless, in selected cases, reconstruction by means of composite free flaps may be successfully used for limb preservation in the treatment of malignant foot tumors after surgical excision. PMID- 25838162 TI - Transfer of skills on LapSim virtual reality laparoscopic simulator into the operating room in urology. AB - OBJECTIVE: Assessing the predictive validity of the LapSim simulator within a urology residency program. MATERIALS AND METHODS: Twelve urology residents at McGill University were enrolled in the study between June 2008 and December 2011. The residents had weekly training on the LapSim that consisted of 3 tasks (cutting, clip-applying, and lifting and grasping). They underwent monthly assessment of their LapSim performance using total time, tissue damage and path length among other parameters as surrogates for their economy of movement and respect for tissue. The last residents' LapSim performance was compared with their first performance of radical nephrectomy on anesthetized porcine models in their 4(th) year of training. Two independent urologic surgeons rated the resident performance on the porcine models, and kappa test with standardized weight function was used to assess for inter-observer bias. Nonparametric spearman correlation test was used to compare each rater's cumulative score with the cumulative score obtained on the porcine models in order to test the predictive validity of the LapSim simulator. RESULTS: The kappa results demonstrated acceptable agreement between the two observers among all domains of the rating scale of performance except for confidence of movement and efficiency. In addition, poor predictive validity of the LapSim simulator was demonstrated. CONCLUSIONS: Predictive validity was not demonstrated for the LapSim simulator in the context of a urology residency training program. PMID- 25838163 TI - Vulvar and vaginal reconstruction using the "angel wing" perforator-based island flap. AB - OBJECTIVE: Vulvar and vaginal reconstruction can be challenging for the reconstructive surgeon. The reconstructive goal is to provide wound healing, adequate function, and acceptable appearance. In the present study, we introduce a new design called the "angel wing" flap, which is a modification of a transposition flap and is based on the perforator concept for vulvar and vaginal reconstruction. METHODS: From January 2002 to December 2013, 23 women underwent reconstruction of vulvar and vaginal defects. Causative factors were vulvar cancer in 14 patients, extramammary Paget's disease in 2, vulvar dysplasia in 5, and combined vulvar and vaginal cancer in 2 patients. RESULTS: A total of 41 flaps were applied. All patients underwent surgical reconstruction in a single step using the "angel wing" flap. Flap size ranged from 4*7 to 13*6cm(2) and the operative duration for reconstructive surgery ranged from 30 to 100min. All the flaps survived with good coverage of the defect. Mean follow-up time after the procedure was 16.1months (range, 6-30months). CONCLUSION: In this article, we introduce a simple and easy reconstructive procedure of the "angel wing" flap. For restoring function, as well as for esthetic purposes, the flap was designed in accordance with the defect since the natural contour of the vulva and vagina is three-dimensional. PMID- 25838166 TI - Determination of Sudan Residues in Sausage by Matrix Solid-Phase Dispersion and High-Performance Liquid Chromatography. AB - A method based on matrix solid-phase dispersion and high-performance liquid chromatography was applied to the determination of four Sudan red residues in sausage. The proposed method required only 0.5 g sample. The neutral alumina was used as the dispersant sorbent while n-hexane containing 10% (v/v) acetone was used as the eluting solvent. The recoveries in samples ranged from 76.4 to 111.0% and relative standard deviations were <10.2% with different spiked levels of 0.05 1.50 mg kg(-1). Detection and quantification limits were 5-19 and 18-39 MUg kg( 1), respectively, with linear calibration curves extending up to 2.50 mg g(-1). The results demonstrate that the method can be successfully applied with acceptable recoveries to a broad range of target analytes within a diverse range of sausage. PMID- 25838165 TI - Adults' responsiveness to children's facial expressions. AB - We investigated the effect of young children's (hereafter children's) facial expressions on adult responsiveness. In Study 1, 131 undergraduate students from a midsized university in the midwestern United States rated children's images and videos with smiling, crying, or neutral expressions on cuteness, likelihood to adopt, and participants' experienced distress. Looking times at images and videos along with perception of cuteness, likelihood to adopt, and experienced distress using 10-point Likert scales were measured. Videos of smiling children were rated as cuter and more likely to be adopted and were viewed for longer times compared with videos of crying children, which evoked more distress. In Study 2, we recorded responses from 101 of the same participants in an online survey measuring gender role identity, empathy, and perspective taking. Higher levels of femininity (as measured by Bem's Sex Role Inventory) predicted higher "likely to adopt" ratings for crying images. These findings indicate that adult perception of children and motivation to nurture are affected by both children's facial expressions and adult characteristics and build on existing literature to demonstrate that children may use expressions to manipulate the motivations of even non-kin adults to direct attention toward and perhaps nurture young children. PMID- 25838164 TI - Patterns and utility of routine surveillance in high grade endometrial cancer. AB - OBJECTIVE: To evaluate surveillance methods and their utility in detecting recurrence of disease in a high grade endometrial cancer population. METHODS: We performed a multi-institutional retrospective chart review of women diagnosed with high grade endometrial cancer between the years 2000 and 2011. Surveillance data was abstracted and analyzed. Surveillance method leading to detection of recurrence was identified and compared by stage of disease and site of recurrence. RESULTS: Two hundred and fifty-four patients met the criteria for inclusion. Vaginal cytology was performed in the majority of early stage patients, but was utilized less in advanced stage patients. CA-125 and CT imaging were used more frequently in advanced stage patients compared to early stage. Thirty-six percent of patients experienced a recurrence and the majority of initial recurrences (76%) had a distant component. Modalities that detected cancer recurrences were: symptoms (56%), physical exam (18%), surveillance CT (15%), CA-125 (10%), and vaginal cytology (1%). All local recurrences were detected by symptoms or physical exam findings. While the majority of loco regional and distant recurrences (68%) were detected by symptoms or physical exam, 28% were detected by surveillance CT scan or CA 125. One loco-regional recurrence was identified by vaginal cytology but no recurrences with a distant component detected by this modality. CONCLUSIONS: Symptoms and physical examination identify the majority of high grade endometrial cancer recurrences, while vaginal cytology is the least likely surveillance modality to identify a recurrence. The role of CT and CA-125 surveillance outside of a clinical trial needs to be further reviewed. PMID- 25838167 TI - Determination of Curcuminoids in Curcuma longa Linn. by UPLC/Q-TOF-MS: An Application in Turmeric Cultivation. AB - Cucuma longa Linn. (Fam-Zingiberaceae) is a valued medicinal plant contains curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) as major bioactive constituents. Previously reported analytical methods for analysis of curcuminoids were found to suffer from low resolution, lower sensitivity and longer analytical times. In this study, a rapid, sensitive, selective high throughput ultra high performance liquid chromatography-tandem mass spectrometry (UPLC/Q-TOF-MS) method was developed and validated for the quantification of curcuminoids with an aim to reduce analysis time and enhance efficiency. UPLC/Q TOF-MS analysis showed large variation (1.408-5.027% w/w) of curcuminoids among different samples with respect to their occurrence of metabolite and their concentration. The results showed that Erode (south province) contains highest quantity of curcuminoids and concluded to be the superior varieties. The results obtained here could be valuable for devising strategies for cultivating this medicinal plant. PMID- 25838169 TI - Nanoporous materials as new engineered catalysts for the synthesis of green fuels. AB - This review summarizes the importance of nanoporous materials and their fascinating structural properties with respect to the catalytic and photocatalytic reduction of CO2 to methane, toward achieving a sustainable energy supply. The importance of catalysis as a bridge step for advanced energy systems and the associated environmental issues are stressed. A deep understanding of the fundamentals of these nanoporous solids is necessary to improve the design and efficiency of CO2 methanation. The role of the support dominates the design in terms of developing an efficient methanation catalyst, specifically with respect to ensuring enhanced metal dispersion and a long catalyst lifetime. Nanoporous materials provide the best supports for Ni, Ru, Rh, Co, Fe particles because they can prevent sintering and deactivation through coking, which otherwise blocks the metal surface as carbon accumulates. This review concludes with the major challenges facing the CO2 methanation by nanoporous materials for fuel applications. PMID- 25838168 TI - Signature of positive selection of PTK6 gene in East Asian populations: a cross talk for Helicobacter pylori invasion and gastric cancer endemicity. AB - Analysis of natural selection events is an attractive strategy for identification of functional variants shaped by gene-environmental interactions and human adaptation. Here, we identified PTK6, a Src-related tyrosine kinase gene, underlying positive selection in East Asian populations. Interestingly, PTK6 variant showed significant correlation with gastric cancer incidences which was the highest in East Asian populations. The high prevalence of gastric cancer in East Asians was also believed to be strongly affected by Helicobacter pylori infection and dietary habit. Therefore, we speculated a competitive interaction of cancer-associated molecules for activation/reduction, where PTK6 likely plays a role through CagA-driven signaling pathway after H. pylori infection. This hypothesis was also supported by our gene expression analysis and the dating of the selective event which was estimated to be ~16,500 years ago, much later than H. pylori invasion in human 50,000 years ago. Establishment of cross talk between PTK6 and CagA by functional studies may further elucidate the underlying biology of H. pylori-mediated gastric cancer. PMID- 25838170 TI - Nitric oxide donors and selective carbonic anhydrase inhibitors: a dual pharmacological approach for the treatment of glaucoma, cancer and osteoporosis. AB - Due to the recognized biological role of nitric oxide (NO) donating derivatives and of selective inhibitors of specific human carbonic anhydrase isoforms (CA, EC 4.2.1.1), promising compounds having an aromatic/heterocyclic primary sulfonamide and functionalized with NO-releasing moieties have been designed. These bifunctional agents have been tested in vitro and in vivo to assess their dual pharmacological activity. According to the encouraging results they could be proposed for the treatment of angle-open glaucoma, cancer regression and osteoporosis, in which both NO and CA activities are involved. PMID- 25838171 TI - Chemical compositions and antioxidant activities of polysaccharides from the sporophores and cultured products of Armillaria mellea. AB - Armillaria mellea is a traditional Chinese medicinal and edible mushroom. Many cultured products of A. mellea have been used to develop commercial medicines in recent years. The chemical composition and activities of the major bioactive chemical components-polysaccharides-may be different because of differences in the raw materials used. Four polysaccharides (SP, CMP, CFBP and CFMP) were obtained from wild sporophores and cultured products (including mycelia, fermentation broth and fermentation mixture) of A. mellea. Their yields, carbohydrate contents, monosaccharide compositions, FT-IR spectra, NMR spectroscopy and antioxidant activities were investigated. All of the polysaccharides were composed of xylose, glucose and galactose without protein. Glucose was the dominant monosaccharide in SP, CMP and CFMP, whereas galactose was the dominant monosaccharide in CFBP. SP and CMP showed higher scavenging DPPH* and ABTS*+ activities and reducing power among four polysaccharides. The carbohydrate content and corresponding glucose percentage were positive influences on the antioxidant activities, whereas the corresponding xylose and galactose percentage were negative influences. A. mellea polysaccharides are potential natural antioxidants. Polysaccharides from cultured products, especially mycelia, are good substitutes for SP and are also potential sources for both dietary supplements and food industries. PMID- 25838172 TI - Isolation and characterization of phenolic compounds and anthocyanins from Murta (Ugni molinae Turcz.) fruits. Assessment of antioxidant and antibacterial activity. AB - Berry fruit consumption has become important in the promotion of human health, mainly due to their phenolic compounds, which have been associated with protection against different pathologies, as well as antimicrobial and other biological activities. Consequently, there has been a growing interest in identifying natural antioxidants and antimicrobials from these plants. This study aimed to characterize the phenolic chemical composition and anthocyanin profile of murta (Ugni molinae Turcz.) fruit, and to evaluate the antioxidant and antimicrobial activity of its extracts (ethanolic and methanolic). LC/MS of the ethanolic extracts showed the presence of three major compounds: caffeic acid 3 glu, quercetin-3-glu and quercetin, while in the methanolic acid extract they were cyanidin-3-glucoside, pelargonidin-3-arabinose and delphinidin-3-glucoside. The antioxidant activity of ethanolic extracts (DPPH. and ORAC assays) was higher than that of methanol acid extracts or purified anthocynins. Furthermore, the methanol acid extract showed an inhibitory activity against the bacteria E. coli and S. typhi similar to that of standard antibiotics. The results suggest that the antioxidant activity of the ethanolic extract is regulated by the high content of phenolic compounds and the fruit's characteristic color is due to the content of pelargonidin-3-arabinose and delphinidin-3-glucoside. The obtained results demonstrated the appreciable antioxidant and antibacterial activities, providing opportunities to explore murta extracts as biopreservatives. PMID- 25838173 TI - Strophalloside induces apoptosis of SGC-7901 cells through the mitochondrion dependent caspase-3 pathway. AB - Cardenolides with special chemical structures have been considered as effective anti-cancer drugs in clinic trials. Strophalloside is a cardenolide we recently isolated from Antiaris toxicaria obtained from Hainan, China. The aim of this study was to investigate the possible anticancer effects induced by strophalloside and the underlying molecular mechanism. Gastric carcinoma SGC-7901 cells were treated with strophalloside at various concentrations for different times, and resulting cell viability was determined by the MTT assay, and the motility and invasion of tumor cells were assessed by the Transwell chamber assay. Apoptosis were measured by Annexin V-FITC/PI and Hoechst staining. The changes of mitochondrial transmembrane potential were examined by a JC-1 kit. The expressions of pro-apoptotic protein cytochrome c, caspase-3 and caspase-9 were detected by western blotting analysis. The results showed that strophalloside was capable of reducing cell viability, inhibiting cell growth, and suppressing cell migration and invasion in a time- and dose-dependent manner. Mitochondrial membrane potential declined and the concentration of cytochrome c increased in cytoplasm and caspase-3 and caspase-9 were cleaved into activated states, suggesting that cytochrome c was released from the mitochondrion to cytoplasm and finally activated the caspase-dependent apoptosis pathway. Our results indicate that strophalloside is a potential anticancer drug. PMID- 25838174 TI - Congenital cranial dysinnervation disorder in a boy with congenital mirror movements. AB - "Mirror movements" are an axonal guidance disorder that consists of involuntary contralateral movements that mimic unilateral intentional ones, typically involving the fingers of the hand. They can be isolated or associated with conditions such as Klippel-Feil syndrome, Kallmann syndrome, or congenital hemiplegia. Isolated congenital mirror movements are sometimes caused by autosomal dominant mutation in the genes DCC or RAD51. At least 4 previously reported cases had strabismus, 3 with Moebius syndrome and 1 with Duane retraction syndrome. We report the case of a boy with an unusual incomitant strabismus consistent with orbital dysinnervation and suggest that for some patients with congenital mirror movements the neurological miswiring extends to the orbit, causing congenital cranial dysinnervation disorder. PMID- 25838175 TI - Superior oblique palsy: a complication of endoscopic sinus surgery. AB - A 34-year-old woman with chronic sinusitis and nasal polyps was treated with bilateral pansinusotomy. Postoperatively, she had a unilateral superior oblique paresis. We suspect that superior oblique damage occurred without involvement of the medial rectus because of inadvertent entry of the endoscopic probe through the superior lamina into the left orbit. PMID- 25838176 TI - Correction: aquatic eddy correlation: quantifying the artificial flux caused by stirring-sensitive O2 sensors. PMID- 25838177 TI - Risk of exposure to ticks (Ixodidae) and the prevalence of tick-borne encephalitis virus (TBEV) in ticks in Southern Poland. AB - The article presents the results of the first study on seasonal activity of ticks and prevalence of tick-borne encephalitis virus (TBEV) in nymphs from the Silesian Province (Southern Poland). Previous studies on the prevalence of TBEV in ticks in Poland have been conducted mostly in northern and eastern regions, but none in the Silesian Province itself. The aims of this study were to analyse the seasonal variation in tick populations and compare TBEV prevalence in nymphs from different geographical locations in the Silesia. A total of 5160 questing Ixodes ricinus ticks were collected by the flagging method from 23 localities in southern Poland in 2010. Micro-climatic parameters (air temperature and humidity) were measured in order to estimate their influence on tick population. The highest tick activity was recorded in spring and was positively correlated with relative air humidity (RH). TBEV in the Silesian Province was analysed in 1750 nymphs and an overall prevalence was 0.11% (2 pools out of 175 analysed). The results of this study show that TBEV pool prevalence in nymphs is low in accordance with the low number of TBE cases reported within the region. PMID- 25838178 TI - Anaplasma phagocytophilum in questing Ixodes ricinus ticks from Romania. AB - Granulocytic anaplasmosis is a common vector-borne disease of humans and animals with natural transmission cycle that involves tick vectors, among which Ixodes ricinus is the most important. The present paper reports the prevalence and geographical distribution of A. phagocytophilum in 10,438 questing Ixodes ricinus ticks collected at 113 locations from 40 counties of Romania. The unfed ticks were examined for the presence of A. phagocytophilum by PCR targeting a portion of ankA gene. The overall prevalence of infection was 3.42%, with local prevalences ranging between 0.29% and 22.45%, with an average prevalence of 5.39% in the infected localities. The infection with A. phagocytophilum was detected in 72 out of 113 localities and in 34 out of 40 counties. The highest prevalence was recorded in females followed by males and nymphs. The results and the distribution model have shown a large distribution of A. phagocytophilum, covering Romania's entire territory. This study is the first large scale survey of the presence of A. phagocytophilum in questing I. ricinus ticks from Romania. PMID- 25838179 TI - [Challenges in geriatric rehabilitation: the development of an integrated care pathway]. AB - Coordination and continuity of care within geriatric rehabilitation is challenging. To tackle these challenges, an integrated care pathway within geriatric rehabilitation care (hospital, geriatric rehabilitation and follow-up care in the home situation) has been developed. The aim of this article is to expound the process of developing the integrated care pathway, and to describe and discuss the results of this process (which is the integrated care pathway). Developing the integrated care pathway was done by the guidance of the first four steps of the theoretical framework for implementation of change from Grol and Wensing: (1) development of a specific proposal for change in practice; (2) analysis of current care practice; (3) analysis of the target group and setting; and (4) development and selection of interventions/strategies for change. The organizations involved in geriatric rehabilitation argued that the integrated care pathway should focus on improving the process of care, including transfer of patients, handovers and communication between care organizations. Current practice, barriers and incentives for change were analyzed through literature research, expert consultation, and interviews with the involved caregivers and by establishing working groups of health care professionals, patients and informal caregivers. This resulted in valuable proposals for improvement of the care process, which were gathered and combined in the integrated care pathway. The integrated care pathway entails agreements on (a) the triage process in the hospital; (b) active engagement of patients and informal caregivers in the care process; (c) timely and high quality handovers; and (d) improved communication between caregivers. PMID- 25838180 TI - A comparison of standard PCNL and staged retrograde FURS in pelvis stones over 2 cm in diameter: a prospective randomized study. AB - The aim of the study was to compare percutaneous nephrolithotomy (PCNL) and staged retrograde flexible ureteroscopy (FURS) methods used in the treatment of kidney stones of 2 cm or more in diameter. The study comprised a total of 60 patients with a diagnosis of kidney pelvic stones more than 2 cm in diameter, for whom surgery was planned between January 2013 and January 2014. The patients were randomly allocated to two groups as staged retrograde FURS (Group A) and PCNL (Group B). Comparison of the groups was made with respect to operating time, number of procedures, total treatment time, length of hospital stay, stone-free rates and complications according to the Clavien-Dindo classification. In Group A, the total operating time of multiple sessions was 114.46 min. In Group B, a single session of PCNL was applied to all patients and the mean operating time was 86.8 min (p = 0.014). Mean total treatment time was 2.01 weeks in Group A and 1 week in Group B (p < 0.01). The mean total hospitalization time was 3.66 days in Group A and 3.13 days in Group B (p = 0.037). At the end of the sessions, clinically insignificant residual fragments were observed in ten patients of Group A and one patient of Group B (p = 0.03). No statistically significant difference was determined between the groups in terms of stone-free rates or complications. Although current technology with FURS is effective on large kidney stones, it has no superiority to PCNL due to the need for multiple sessions and long treatment time. PMID- 25838182 TI - Angiogenic potential of early and late outgrowth endothelial progenitor cells is dependent on the time of emergence. AB - BACKGROUND: Recent studies have suggested that late-outgrowth endothelial progenitor cells (EPCs) derived from human peripheral blood mononuclear cells (hPBMNCs) might have higher angiogenic potential than classically-defined early outgrowth EPCs (EOCs). However, it still remains unclear which of "so-called" EPC subpopulations defined in a variety of ways has the highest angiogenic potential. METHODS AND RESULTS: We classified hPBMNC-derived EPC subpopulations by the time of their emergence in culture. EOCs were defined as attached cells on culture days 3-7. Late-outgrowth EPCs, defined as the cell forming colonies with cobblestone appearance since day 10, were further classified as follows: "moderate"-outgrowth EPCs (MOCs) emerging on days 10-16, "late"-outgrowth EPCs (LOCs) on days 17-23, and "very late"-outgrowth EPCs (VOCs) on days 24-30. Flow cytometry analyses showed the clear differences of hematopoietic/endothelial markers between EOC (CD31(+)VE-cadherin(-)CD34(-)CD14(+)CD45(+)) and LOC (CD31(+)VE-cadherin(+)CD34(+)CD14(-)CD45(-)). We found that LOCs had the highest proliferation and tube formation capabilities in vitro along with the highest expression of angiogenic genes including KDR and eNOS. To investigate the in vivo therapeutic efficacies, each EPC subpopulation was intravenously transplanted into immunocompromised mice (total 4 * 10(5) cells) after unilateral hindlimb ischemia surgery. The LOC-treated mice exhibited significantly-enhanced blood flow recovery (flow ratios of ischemic/non-ischemic leg: 0.99+/-0.02 [LOC group] versus 0.67 +/- 0.07 to 0.78 +/- 0.09 [other groups]; P < 0.05) and augmented capillary collateral formation in ischemic leg, which were attributable to their direct engraftment into host angiogenic vessels (approximately 10%) and paracrine effects. CONCLUSION: hPBMNC-derived late-outgrowth EPCs emerging on culture days 17-23 are superior to other EPC subpopulations with regard to therapeutic angiogenic potential. PMID- 25838181 TI - The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish pronephric tubule. AB - Lowe syndrome and Dent-2 disease are caused by mutation of the inositol 5 phosphatase OCRL1. Despite our increased understanding of the cellular functions of OCRL1, the underlying basis for the renal tubulopathy seen in both human disorders, of which a hallmark is low molecular weight proteinuria, is currently unknown. Here, we show that deficiency in OCRL1 causes a defect in endocytosis in the zebrafish pronephric tubule, a model for the mammalian renal tubule. This coincides with a reduction in levels of the scavenger receptor megalin and its accumulation in endocytic compartments, consistent with reduced recycling within the endocytic pathway. We also observe reduced numbers of early endocytic compartments and enlarged vacuolar endosomes in the sub-apical region of pronephric cells. Cell polarity within the pronephric tubule is unaffected in mutant embryos. The OCRL1-deficient embryos exhibit a mild ciliogenesis defect, but this cannot account for the observed impairment of endocytosis. Catalytic activity of OCRL1 is required for renal tubular endocytosis and the endocytic defect can be rescued by suppression of PIP5K. These results indicate for the first time that OCRL1 is required for endocytic trafficking in vivo, and strongly support the hypothesis that endocytic defects are responsible for the renal tubulopathy in Lowe syndrome and Dent-2 disease. Moreover, our results reveal PIP5K as a potential therapeutic target for Lowe syndrome and Dent-2 disease. PMID- 25838183 TI - Weighing the risks: Thrombotic and bleeding events in adults with atrial arrhythmias and congenital heart disease. AB - INTRODUCTION: Atrial arrhythmias are associated to thromboembolism and anticoagulant treatment is installed according to risk profile. This study aimed to assess the rate of thrombotic events and major bleedings in adults with congenital heart disease (CHD) and atrial arrhythmias, as well as to determine the predictive value of specific clinical features and two risk scores for thromboembolism and bleeding. METHODS AND RESULTS: In this retrospective study, a total of 229 adult CHD patients with atrial arrhythmias, were included. Incidence and risk factors of thromboembolism were assessed in patients without a mechanical valve (n = 191), whereas bleeding incidence and risk factors were studied in patients receiving vitamin K antagonists (n = 164). In 13 patients without a mechanical valve thrombotic events occurred, the first thrombotic event rate per year being 1.4%. A total of 29 patients on vitamin K antagonists suffered from major bleedings, at an annual first event rate of 4.4%. CHA2DS2 VASc score and HAS-BLED score predicted thromboembolic and bleeding risk best in a dichotomized form. At a cut-off of >= 2 for high risk the rate of thrombotic events was 3.0% per year compared to 0.7% for a score of <2 (HR 3.7; 95%-CI 1.2 11.5; p = 0.021). A major bleeding rate of 10.8% per year was found in patients on vitamin K antagonists for HAS-BLED >= 2 as opposed to 3.5% with a score of <2 (HR 2.6; 95%-CI: 1.1-6.6; 0.017). CONCLUSION: In adult CHD patients, thrombotic events and major bleedings are important complications of atrial arrhythmias and anticoagulant treatment. Assessment of thromboembolic and bleeding risk in this patients group can be performed with dichotomized CHA2DS2-VASc and HAS-BLED scores respectively. PMID- 25838184 TI - Response to the letter by Vincenzo Sucato et al.: Was there thrombus or not? What about PCI? PMID- 25838186 TI - High-quality t2-weighted 4-dimensional magnetic resonance imaging for radiation therapy applications. AB - PURPOSE: The purpose of this study was to improve triggering efficiency of the prospective respiratory amplitude-triggered 4-dimensional magnetic resonance imaging (4DMRI) method and to develop a 4DMRI imaging protocol that could offer T2 weighting for better tumor visualization, good spatial coverage and spatial resolution, and respiratory motion sampling within a reasonable amount of time for radiation therapy applications. METHODS AND MATERIALS: The respiratory state splitting (RSS) and multi-shot acquisition (MSA) methods were analytically compared and validated in a simulation study by using the respiratory signals from 10 healthy human subjects. The RSS method was more effective in improving triggering efficiency. It was implemented in prospective respiratory amplitude triggered 4DMRI. 4DMRI image datasets were acquired from 5 healthy human subjects. Liver motion was estimated using the acquired 4DMRI image datasets. RESULTS: The simulation study showed the RSS method was more effective for improving triggering efficiency than the MSA method. The average reductions in 4DMRI acquisition times were 36% and 10% for the RSS and MSA methods, respectively. The human subject study showed that T2-weighted 4DMRI with 10 respiratory states, 60 slices at a spatial resolution of 1.5 * 1.5 * 3.0 mm(3) could be acquired in 9 to 18 minutes, depending on the individual's breath pattern. Based on the acquired 4DMRI image datasets, the ranges of peak-to-peak liver displacements among 5 human subjects were 9.0 to 12.9 mm, 2.5 to 3.9 mm, and 0.5 to 2.3 mm in superior-inferior, anterior-posterior, and left-right directions, respectively. CONCLUSIONS: We demonstrated that with the RSS method, it was feasible to acquire high-quality T2-weighted 4DMRI within a reasonable amount of time for radiation therapy applications. PMID- 25838187 TI - Relationship Between Radiation Therapy Dose and Outcome in Patients Treated With Neoadjuvant Chemoradiation Therapy and Surgery for Stage IIIA Non-Small Cell Lung Cancer: A Population-Based, Comparative Effectiveness Analysis. AB - PURPOSE: To compare, using the National Cancer Database, survival, pathologic, and surgical outcomes in patients with stage IIIA non-small cell lung cancer treated with differential doses of neoadjuvant chemoradiation therapy, with the aim to discern whether radiation dose escalation was associated with a comparative effectiveness benefit and/or toxicity risk. METHODS AND MATERIALS: Patients in the National Cancer Database with stage IIIA non-small cell lung cancer treated with neoadjuvant chemoradiation therapy and surgery between 1998 and 2005 were analyzed. Dose strata were divided between 36 to 45 Gy (low-dose radiation therapy, LD-RT), 45 to 54 Gy (inclusive, standard-dose, SD-RT), and 54 to 74 Gy (high-dose, HD-RT). Outcomes included overall survival, residual nodal disease, positive surgical margin status, hospital length of stay, and adverse surgical outcomes (30-day mortality or readmission). RESULTS: The cohort consisted of 1041 patients: 233 (22%) LD-RT, 584 (56%) SD-RT, and 230 (22%) HD RT. The median, 3-year, and 5-year overall survival outcomes were 34.9 months, 48%, and 37%, respectively. On univariable analysis, patients treated with SD-RT experienced prolonged overall survival (median 38.3 vs 31.8 vs 29.0 months for SD RT, LD-RT, and HD-RT, respectively, P=.0089), which was confirmed on multivariable analysis (hazard ratios 0.77 and 0.81 vs LD and HD, respectively). Residual nodal disease was seen less often after HD-RT (25.5% vs 31.8% and 37.5% for HD-RT, LD-RT, and SD-RT, respectively, P=.0038). Patients treated with SD-RT had fewer prolonged hospital stays. There were no differences in positive surgical margin status or adverse surgical outcomes between the cohorts. CONCLUSIONS: Neoadjuvant chemoradiation therapy between 45 and 54 Gy was associated with superior survival in comparison with doses above and below this threshold. Although this conclusion is limited by selection bias, clear candidates for trimodality therapy do not seem to achieve additional benefit with dose escalation. PMID- 25838189 TI - Foreign body sensation in the throat. PMID- 25838185 TI - National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. AB - The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence. PMID- 25838188 TI - Differences Between Colon Cancer Primaries and Metastases Using a Molecular Assay for Tumor Radiation Sensitivity Suggest Implications for Potential Oligometastatic SBRT Patient Selection. AB - PURPOSE: We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases. METHODS AND MATERIALS: Patients were identified from our institutional review board-approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation. RESULTS: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026). CONCLUSIONS: Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort. PMID- 25838190 TI - Hazard perception test for pedestrians. AB - RESEARCH GOAL: This research was aimed to construct and develop a unique system for training of pedestrians - children, adults and older persons - to cross streets safely and especially to detect successfully on-road hazards as pedestrians. For this purpose, an interactive computerized program has been inspired by the format of the popular HPT (hazard perception test) for drivers. METHODS: The HPTP (hazard perception test for pedestrians) includes 10 pairs of video clips that were filmed in various locations but had a similar hazardous element. The clips presented potentially dangerous crossing scenarios such as a vehicle merging from the right side of the road from the perspective of the pedestrian who is trying to cross the street. The participants were asked to press the spacebar key every time they identified an approaching hazard. The participants were instructed to use the arrow keys for moving the viewing panel to the left or to the right in order to enlarge the field of view accordingly. Totally, 359 participants took part. Adults, children, and elders were assigned to two practice groups and three control groups in a 3 (age groups)*5 (experimental groups) design. One practice group underwent pretest, practice, discussion and posttest, the second experimental group through pretest, practice and posttest, one control group that underwent posttest only, the second control group underwent pretest, discussion and posttest and the third control group underwent both pretest and posttest. FINDINGS: The most important finding was that children and adults who underwent practice received higher scores in the posttest compared to the pretest. Also, children who underwent practice increased their use of the arrow keys in the posttest compared to the pretest. Across conditions men scored higher than women on the HPTP, and used the keys more often. Age differences were found, with adults scoring being the highest, followed by children and the older persons. PMID- 25838192 TI - Occupant injury and fatality in general aviation aircraft for which dynamic crash testing is certification-mandated. AB - Towards further improving general aviation aircraft crashworthiness, multi-axis dynamic tests have been required for aircraft certification (14CFR23.562) since 1985. The objective of this study was to determine if occupants in aircraft certified to these higher crashworthiness standards show a mitigated fraction of fatal accidents and/or injury severity. The NTSB aviation database was queried for accidents occurring between 2002 and 2012 involving aircraft certified to, or immune from, dynamic crash testing and manufactured after 1999. Only operations conducted under 14CFR Part 91 were considered. Statistical analysis employed proportion tests and logistic regression. Off-airport landings are associated with high decelerative forces; however for off-airport landings, the fraction of fatal accidents for aircraft subject to, or exempt from, dynamic crash testing was similar (0.53 and 0.60, respectively). Unexpectedly, for on-airport landings a higher fraction of fatalities was evident for aircraft whose certification mandated dynamic crash testing. Improved crashworthiness standards would be expected to translate into a reduced severity of accident injuries. For all accidents, as well as for those deemed survivable, the fraction of minor and serious injuries was reduced for occupants in aircraft certified to the higher crashworthiness standards. Surprisingly, the fraction of occupants fatally injured was not decreased for aircraft subject to dynamic crash tests. To shed light on this unexpected finding flight history, airman demographics and post impact fires for aircraft for which dynamic crash testing is mandatory or exempt was examined. For the former cohort the median distance of the accident flight was nearly 44% higher. Aircraft subject to dynamic crash testing were also involved in a greater fraction (0.25 versus 0.12, respectively) of post-impact fires. Our data suggest that while the more stringent crashworthiness standards have mitigated minor and serious injuries, surprisingly the fraction of occupants fatally injured is unaltered. The unchanged fraction of fatal injuries may reflect partly (a) fatigue associated with longer flight distances and (b) a greater proportion of post-impact fires. PMID- 25838191 TI - Examining the relative effectiveness of different message framing strategies for child passenger safety: recommendations for increased comprehension and compliance. AB - BACKGROUND: Age-appropriate child restraints and rear seating dramatically reduce injury in vehicle crashes. Yet parents and caregivers struggle to comply with child passenger safety (CPS) recommendations, and frequently make mistakes when choosing and installing restraints. The purpose of this research was to evaluate various methods of framing CPS recommendations, and to examine the relative effectiveness on parents' knowledge, attitudes, and behavioral intentions related to best practices and proper use of child restraints. Emphasis framing is a persuasion technique that involves placing focus on specific aspects of the content in order to encourage or discourage certain interpretations of the content. METHOD: A 5 (flyer group) X 2 (time) randomized experiment was conducted in which 300 parent participants answered a pre-survey, viewed one of four flyer versions or a no-education control version, and completed a post-survey. Surveys measured CPS knowledge, attitudes, perceptions of efficacy and risk, and behavioral intentions. The four flyers compared in this study all communicated the same CPS recommendations, but several versions were tested which each employed a different emphasis frame: (1) recommendations organized by the natural progression of seat types; (2) recommendations which focused on avoiding premature graduation; (3) recommendations which explained the risk-reduction rationale behind the information given; or (4) recommendations which were organized by age. In a fifth no-education (control) condition, participants viewed marketing materials. RESULTS: Analyses of covariance and pairwise comparisons indicated the risk-reduction rationale flyer outperformed other flyers for many subscales, and significantly differed from no-education control for the most subscales, including restraint selection, back seat knowledge, rear facing knowledge and attitudes, total efficacy, overall attitudes, and stated intentions. CONCLUSIONS: This research provides insight for increasing caregiver understanding and compliance with CPS information. Recommendations for the field include communicating the rationale behind the information given, using behavior based directives in headers, avoiding age-based headers, and incorporating back seat positioning directives throughout. PMID- 25838193 TI - Implicit attitudes and road safety behaviors. The helmet-use case. AB - We studied the role of implicit attitudes on road safety behaviors. We also explored the methodological benefits of using implicit measures to complement conventional self-reporting instruments. The results suggest that: (a) implicit attitudes are capable of predicting observed differences in the use of protective devices (helmet use); (b) implicit attitudes correlate with the emotional component of the explicit attitudes (e.g., perception of comfort-discomfort), but appear to be independent of the more cognitive components (e.g., perceived benefits); (c) the emotional component of the explicit attitudes appears to be the major predictor of behavior; and (d) implicit measures seem to be more robust against social desirability biases, while explicit measure are more sensitive to such bias. We conclude that indirect and automatic measures serve as an important complement to conventional direct measures (self-reports) because they provide information on psychological processes that are qualitatively different (implicit) and can also be more robust when it comes to response bias. PMID- 25838194 TI - Sintering of ultrathin gold nanowires for transparent electronics. AB - Ultrathin gold nanowires (AuNWs) with diameters below 2 nm and high aspect ratios are considered to be a promising base material for transparent electrodes. To achieve the conductivity expected for this system, oleylamine must be removed. Herein we present the first study on the conductivity, optical transmission, stability, and structure of AuNW networks before and after sintering with different techniques. Freshly prepared layers consisting of densely packed AuNW bundles were insulating and unstable, decomposing into gold spheres after a few days. Plasma treatments increased the conductivity and stability, coarsened the structure, and left the optical transmission virtually unchanged. Optimal conditions reduced sheet resistances to 50 Omega/sq. PMID- 25838195 TI - Acute experimental hip muscle pain alters single-leg squat balance in healthy young adults. AB - BACKGROUND: Clinical musculoskeletal pain commonly accompanies hip pathology and can impact balance performance. Due to the cross-sectional designs of previous studies, and the multifactorial nature of musculoskeletal pain conditions, it is difficult to determine whether pain is a driver of balance impairments in this population. This study explored the effects of experimentally induced hip muscle pain on static and dynamic balance. METHODS: Twelve healthy adults (4 women, mean[SD]: 27.1[3] years) performed three balance tasks on each leg, separately: single-leg standing (eyes closed), single-leg squat (eyes open), forward step (eyes open); before and after hypertonic saline injection (1ml, 5% NaCl) into the right gluteus medius. Range, standard deviation (SD), and velocity of the centre of pressure (CoP) in medio-lateral (ML) and anterior-posterior (AP) directions were considered. RESULTS: During the single-leg squat task, experimental hip pain was associated with significantly reduced ML range (-4[13]%, P=0.028), AP range ( 14[21]%, P=0.005), APSD (-15[28]%, P=0.009), and AP velocity (-6[13]%, P=0.032), relative to the control condition, in both legs. No effect of pain was observed during single-leg standing and forward stepping. Significant between-leg differences in ML velocity were observed during the forward stepping task (P=0.034). DISCUSSION: Pain is a potentially modifiable patient-reported outcome in individuals with hip problems. This study demonstrates that acute hip muscle pain alone, without interference of musculoskeletal pathology, does not lead to the same impairments in balance as exhibited in clinical populations with hip pathologies. This is the first step in understanding how and why balance is altered in painful hip pathologies. PMID- 25838196 TI - Bioconversion of H2/CO 2 by acetogen enriched cultures for acetate and ethanol production: the impact of pH. AB - Syngas fermentation into ethanol and other bioproducts by mixed cultures is considered a promising biotechnology. Effects of pH on product generation and microbial community during H2/CO2 utilization by acetogen enrichment cultures were investigated in this work. The maximum acetate concentration reached 95.41 mmol L(-1) at pH 7, which was 71.7, 21.8 and 50.9% higher than at pH 5, 9 and 11, respectively. The maximum ethanol concentration at pH 7 was 45.7, 50, 72% higher than that at pH 5, 9 and 11, respectively. The CO dehydrogenase (CODH) gene copy number was highest at pH 7, indicating that metabolically active acetogens reached their highest level at pH 7. The CODH gene copy number at pH 9 was lower than at pH 7, but higher than at pH 5 and 11. Correspondingly, the enrichment cultures at pH 7 had the highest species richness and diversity, while those at pH 9 had the second highest diversity, and those at pH 5 and 11 had the lowest diversity. The shift in microbial community structure and the different active acetogen contents resulting from different pHs were responsible for the differences in acetate and ethanol production. PMID- 25838197 TI - Nitrate levels modulate the abundance of Paracoccus sp. in a biofilm community. AB - Conditions required to enhance a particular species efficient in degradative capabilities is very useful in wastewater treatment processes. Paracoccus sp. is known to efficiently reduce nitrogen oxides (NOx) due to the branched denitrification pathway. Individual-based simulations showed that the relative fitness of Paracoccus sp. to Pseudomonas sp. increased significantly with nitrate levels above 5 mM. Spatial structure of the biofilm showed substantially less nitrite levels in the areas of Paracoccus sp. dominance. The simulation was validated in a laboratory reactor harboring biofilm community by fluorescent in situ hybridization, which showed that increasing nitrate levels enhanced the abundance of Paracoccus sp. Different levels of NOx did not display any significant effect on biofilm formation of Paracoccus sp., unlike several other bacteria. This study shows that the attribute of Paracoccus sp. to tolerate and efficiently reduce NOx is conferring a fitness payoff to the organism at high concentrations of nitrate in a multispecies biofilm community. PMID- 25838198 TI - Experience with vertebral artery origin stenting and ostium dilatation: results of treatment and clinical outcomes. AB - BACKGROUND: The vertebral artery (VA) ostium (VAO) is a common stenosis site. Most patients with VAO stenosis refractory to medical treatment are treated endovascularly using stenting. To optimally cover the ostial plaque, which frequently extends into the adjacent subclavian artery, part of the stent must overhang in the subclavian artery. This configuration makes subsequent VA access very challenging in cases of in-stent or distal vertebrobasilar pathology; it also obstructs the distal subclavian artery. OBJECTIVE: To determine whether angioplasty at the ostium with a dual balloon (Flash Ostial) specially designed to allow the subclavian end of the stent to flare might circumvent these problems and, most importantly, provide optimal plaque coverage around the vertebral ostium. METHODS: Between June 2012 and July 2014, 11 patients with symptomatic VAO stenosis refractory to best medical therapy were treated with stenting and dual balloon Flash angioplasty. Demographics, results, and outcomes were reviewed. RESULTS: A total of 12 VAO stenting-dual balloon angioplasty procedures were performed (mean stenosis, 83.6%; range, 78-90%). Nine patients had mild-to moderate (40-60%) contralateral VAO stenosis. The initial average modified Rankin Scale (mRS) score was 1.25. In all cases, immediate postangioplasty angiography showed excellent stent apposition against the VA and around the ostium in the subclavian artery. No permanent perioperative complications or deaths occurred. At a mean follow-up of 10.8 months (range 2-24), all patients had symptom resolution and no evidence of symptomatic restenosis on neuroimaging/Doppler studies; the average mRS score was 0.66. Three patients continued to have previously diagnosed mid-cervical VA stenosis; one of them had postprocedure dissection and an asymptomatic in-stent stenosis at 8 months. CONCLUSIONS: Safety and feasibility were demonstrated using the Ostial Flash system for VAO stenting and angioplasty. No permanent perioperative complications were seen. PMID- 25838199 TI - Onyx embolization in distal dissecting posterior inferior cerebellar artery aneurysms. AB - BACKGROUND: Dissecting aneurysms located along the distal segments of the posterior inferior cerebellar artery (PICA) are extremely rare, accounting for only 0.5-0.7% of all intracranial aneurysms. Treatment of these aneurysms is challenging, both surgically and endovascularly. We present our preliminary experience and clinical data utilizing Onyx as an embolization agent in the treatment of these lesions with proximal parent artery preservation. METHODS: 7 consecutive ruptured peripheral PICA aneurysms, in 7 patients, were treated with superselective Onyx embolization at our institutions. According to the anatomical classification of Lister et al, these aneurysms were located in the lateral medullary segment (n=1), tonsillomedullary segment (n=1), and the telovelotonsillary segment (n=5) of the PICA. Technical feasibility, procedure related complications, angiographic results, follow-up diagnostic imaging, and clinical outcome were evaluated. RESULTS: In all cases, endovascular treatment was successful, with complete occlusion of the aneurysm with proximal parent artery preservation at the final postprocedural angiogram. Procedure related complications were not observed. One patient with a poor clinical condition at admission died during the initial hospital stay due to extensive subarachnoid and intraventricular hemorrhage. No rebleeding or recanalization was noted during follow-up. Two patients had a residual moderate to severe disability at follow up. Favorable outcomes, with no or mild disability, were observed in four of the surviving patients. CONCLUSIONS: Angiographic, diagnostic imaging, and clinical results of our small series indicate that Onyx embolization of dissecting distal PICA aneurysms with parent artery preservation is an effective option with acceptable morbidity and mortality rate, in those cases in which surgical clipping or endovascular coiling of the aneurysmal sac is not suitable. PMID- 25838200 TI - LeftyA sensitive cytosolic pH regulation and glycolytic flux in Ishikawa human endometrial cancer cells. AB - OBJECTIVE: LeftyA, a powerful regulator of stemness, embryonic differentiation, and reprogramming of cancer cells, counteracts cell proliferation and tumor growth. Key properties of tumor cells include enhanced glycolytic flux, which is highly sensitive to cytosolic pH and thus requires export of H(+) and lactate. H(+) extrusion is in part accomplished by Na(+)/H(+) exchangers, such as NHE1. An effect of LeftyA on transport processes has, however, never been reported. The present study thus explored whether LeftyA modifies regulation of cytosolic pH (pHi) in Ishikawa cells, a well differentiated endometrial carcinoma cell model. METHODS: NHE1 transcript levels were determined by qRT-PCR, NHE1 protein abundance quantified by Western blotting, pHi estimated utilizing (2',7'-bis-(2 carboxyethyl)-5-(and-6)-carboxyfluorescein [BCECF] fluorescence, Na(+)/H(+) exchanger activity from Na(+) dependent realkalinization after an ammonium pulse, and lactate concentration in the supernatant utilizing an enzymatic assay and subsequent colorimetry. RESULTS: A 2 h treatment with LeftyA (8 ng/ml) significantly decreased NHE1 transcript levels (by 99.6%), NHE1 protein abundance (by 71%), Na(+)/H(+) exchanger activity (by 55%), pHi (from 7.22 +/- 0.02 to 7.05 +/- 0.02), and lactate release (by 41%). CONCLUSIONS: LeftyA markedly down regulates NHE1 expression, Na(+)/H(+) exchanger activity, pHi, and lactate release in Ishikawa cells. Those effects presumably contribute to cellular reprogramming and growth inhibition. PMID- 25838201 TI - Sevoflurane pretreatment attenuates TNF-alpha-induced human endothelial cell dysfunction through activating eNOS/NO pathway. AB - Endothelial dysfunction induced by oxidative stress and inflammation plays a critical role in the pathogenesis of cardiovascular diseases. The anesthetic sevoflurane confers cytoprotective effects through its anti-inflammatory properties in various pathologies such as systemic inflammatory response syndrome and ischemic-reperfusion injury but mechanism is unclear. We hypothesized that sevoflurane can protect against tumor necrosis factor (TNF)-alpha-induced endothelial dysfunction through promoting the production of endothelium-dependent nitric oxide (NO). Primary cultured human umbilical vein endothelial cells (HUVECs) were pretreated with different concentrations (0.5, 1.5 and 2.5 minimum alveolar concentration, MAC) of sevoflurane for 30 min before TNF-alpha (10 ng/mL) stimulation for 4 h. Sevoflurane pretreatment significantly reduced TNF alpha-induced VCAM-1, ICAM-1, IkappaBalpha, and NF-kappaB activation, and blocked leukocytes adhesion to HUVECs. Meanwhile, sevoflurane (1.5 and 2.5 MAC) significantly induced endothelial nitric oxide synthase (eNOS) phosphorylation and enhanced NO levels both intracellularly and in the cell culture medium. All these cytoprotective effects of sevoflurane were abrogated by NG-nitro-l-arginine methyl ester (l-NAME), a non-specific nitric oxide synthase inhibitor. Collectively, these data indicate that sevoflurane protects against TNF-alpha induced vascular endothelium dysfunction through activation of eNOS/NO pathway and inhibition of NF-kappaB. PMID- 25838202 TI - Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator activated receptor gamma in human hepatocytes and increases lipid accumulation. AB - Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor gamma (PPARgamma), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARgamma overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARgamma by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARgamma overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARgamma, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans. PMID- 25838203 TI - cCMP and cUMP occur in vivo. AB - Mammalian cells contain the cyclic pyrimidine nucleotides cCMP and cUMP. It is unknown whether these tentative new second messenger molecules occur in vivo. We used high performance liquid chromatography quadrupole tandem mass spectrometry to quantitate nucleoside 3',5'-cyclic monophosphates. cCMP was detected in all organs studied, most notably pancreas, spleen and the female reproductive system. cUMP was not detected in organs, probably due to the intrinsically low sensitivity of mass spectrometry to detect this molecule and organ matrix effects. Intratracheal infection of mice with recombinant Pseudomonas aeruginosa harboring the nucleotidyl cyclase toxin ExoY massively increased cUMP in lung. The identity of cCMP and cUMP in organs was confirmed by high performance liquid chromatography quadrupole time of flight mass spectrometry. cUMP also appeared in serum, urine and faeces following infection. Taken together, this report unequivocally shows for the first time that cCMP and cUMP occur in vivo. PMID- 25838204 TI - 1,25-Dihydroxyvitamin D3 preserves intestinal epithelial barrier function from TNF-alpha induced injury via suppression of NF-kB p65 mediated MLCK-P-MLC signaling pathway. AB - Substantial studies have demonstrated the protective effect of 1,25 Dihydroxyvitamin D3 (1,25(OH)2D3) on intestinal barrier function, but the mechanisms are not fully illustrated. In this study, the effect of 1,25(OH)2D3 on TNF-alpha induced barrier dysfunction was further investigated in Caco-2 cell monolayers. The barrier function of Caco-2 monolayers was evaluated by measuring trans-epithelial electrical resistance (TEER) and FITC-Dextran 40,000 Da (FD-40) trans-membrane flux. ZO-1 and Occludin were chosen as markers of the localization of tight junction (TJ) proteins for immunofluorescence. The expression of MLCK and phosphorylation level of myosin light chain (MLC) were measured by immunoblotting. The activation of NF-kB p65 was analyzed by EMSA and immunofluorescence. The results suggest that 1,25(OH)2D3 preserves intestinal epithelial barrier function from TNF-alpha induced injury via suppression of NF kB p65 mediated activation of MLCK-P-MLC signaling pathway. PMID- 25838205 TI - Abundance and genetic damage of barn swallows from Fukushima. AB - A number of studies have assessed or modeled the distribution of the radionuclides released by the accident at the Fukushima-Daiichi Nuclear Power Plant (FDNPP). Few studies however have investigated its consequences for the local biota. We tested whether exposure of barn swallow (Hirundo rustica) nestlings to low dose ionizing radiation increased genetic damage to their peripheral erythrocytes. We estimated external radiation exposure by using thermoluminescent dosimeters, and by measuring radioactivity of the nest material. We then assessed DNA damage by means of the neutral comet assay. In addition, we conducted standard point-count censuses of barn swallows across environmental radiation levels, and estimated their abundance and local age ratio. Radioactivity of nest samples was in the range 479-143,349 Bq kg(-1), while external exposure varied between 0.15 and 4.9 mGy. Exposure to radioactive contamination did not correlate with higher genetic damage in nestlings. However, at higher levels of radioactive contamination the number of barn swallows declined and the fraction of juveniles decreased, indicating lower survival and lower reproduction and/or fledging rate. Thus, genetic damage to nestlings does not explain the decline of barn swallows in contaminated areas, and a proximate mechanism for the demographic effects documented here remains to be clarified. PMID- 25838206 TI - Cognitive Performance: A Cross-Sectional Study on Serum Vitamin D and Its Interplay With Glucose Homeostasis in Dutch Older Adults. AB - OBJECTIVES: First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. DESIGN, SETTING, AND PARTICIPANTS: Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older. MEASUREMENTS: Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores. RESULTS: The overall median MMSE score was 29 (IQR 28-30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29-0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations. CONCLUSION: Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance. PMID- 25838207 TI - Paddling Force Profiles at Different Stroke Rates in Elite Sprint Kayaking. AB - In sprint kayaking the role that paddling technique plays in optimizing paddle forces and resultant kayak kinematics is still unclear. The aim of this study was to analyze the magnitude and shape of the paddle force-time curve at different stroke rates, and their implications for kayak performance. Ten elite kayak paddlers (5 males and 5 females) were analyzed while performing 2000-m on-water trials, at 4 different paces (60, 80, and 100 strokes per minute, and race pace). The paddle and kayak were instrumented with strain gauges and accelerometers, respectively. For both sexes, the force-time curves were characterized at training pace by having a bell shape and at race pace by a first small peak, followed by a small decrease in force and then followed by a main plateau. The force profile, represented by the mean force/peak force ratio, became more rectangular with increasing stroke rate (F[3,40] = 7.87, P < .01). To obtain a rectangular shape to maximize performance, kayak paddlers should seek a stronger water phase with a rapid increase in force immediately after blade entry, and a quick exit before the force dropping far below the maximum force. This pattern should be sought when training at race pace and in competition. PMID- 25838208 TI - Association of self-perceived body image with body mass index and type 2 diabetes The ADDITION-PRO study. AB - OBJECTIVE: Weight loss is important for prevention of type 2 diabetes and an accurate self-perceived body image can promote weight reduction. We evaluated the association of self-perceived body image with body mass index (BMI) and type 2 diabetes. METHODS: Data from the Danish ADDITION-PRO cohort study (2009-2011) were used. A total of 2082 men and women attended a health examination including assessment of BMI, waist circumference, the Stunkard scale of self-perceived obesity and an oral glucose tolerance test for assessment of diabetes risk. RESULTS: Mean (SD) age was 66.2 (6.9) years and 24% were obese (BMI >=30kg/m(2)). However, only 7% of obese men and 11% of obese women perceived themselves as obese. Among obese women, for a given level of BMI and waist circumference, one unit higher self-perceived body image was associated with 52% (95% CI: 14-73) lower risk of having type 2 diabetes and 45% (95% CI: 12-65) lower risk of having pre-diabetes. Overweight, but not obese, men had a 35% (95% CI: 36-56) lower risk of type 2 diabetes per unit increase in body image. CONCLUSIONS: Obese individuals seem to underestimate their body shape. However, having a realistic body image (higher self-perceived obesity) is independently associated with lower diabetes risk. Self-perceived body image might serve as a valuable tool for type 2 diabetes risk assessment. PMID- 25838209 TI - Clinical features and outcomes of nontransitional cell carcinomas of the urinary bladder: Analysis of 125 cases. AB - OBJECTIVES: The aim was to evaluate pathologic diagnosis, treatment and prognosis of 125 patients with nontransitional cell carcinoma of the urinary bladder. MATERIALS AND METHODS: A total of 3590 patients with bladder tumors operated in our clinic between September 1998 and May 2013 were retrospectively evaluated. A total of 125 patients (107 men and 18 women) with nontransitional cell bladder cancer, confirmed by histopathology, were included in this study. The patients' characteristics, including age, gender, smoking history, tumor size, and localization, histological types, pathological tumor stages, treatment modalities, and survival rates were all recorded. RESULTS: Of these tumors, 47 (37.6%) were adenocarcinoma (AC), 42 (33.6%) were squamous cell carcinoma (SCC), 23 (18.4%) were undifferentiated carcinoma (UC), 13 (10.4%) were other types of bladder carcinoma. Sixty-three (50.4%) patients had undergone radical cystectomy and pelvic lymphadenectomy +/- adjuvant treatment (chemotherapy [CT]/radiotherapy) and 52 (41.6%) patients received radiotherapy +/- CT. The median survival time of patients with AC and SCC were significantly higher than patients with UC (AC vs UC, P = 0.001; SCC vs UC, P = 0.000; AC vs. SCC, P = 0.219). Median survival time was significantly higher in radical cystectomy +/- adjuvant treatment group (P < 0.05) in all histological types. CONCLUSION: Prognosis of urinary bladder tumors was directly related to histological type and stage of the tumor. CT or radiotherapy has limited response rates. Early radical cystectomy should be performed to improve prognosis. PMID- 25838210 TI - Distribution and Photochemistry of Polycyclic Aromatic Hydrocarbons in the Baotou Section of the Yellow River During Winter. AB - In this study, ice and water samples were collected from seven sites along the Baotou section of the Yellow River during winter 2013. Total polycyclic aromatic hydrocarbon (PAH) concentrations in the ice and in the water under the ice ranged from 21.3 to 59.4 ng L(-1), and from 38.3 to 222.4 ng L(-1), respectively. The average concentration in water under the ice was approximately 2.5 times greater than the average concentration in the ice phase. Four-ring PAHs dominated and accounted for 68.2 and 76.0 % of the total PAHs in ice and water, respectively. PAH concentrations were highest at sampling site S2 and were also relatively high at sites S4 and S5. PAH sources in ice and in water under the ice were similar. Three components were selected to represent the coal-combustion sources of PAHs. Because it was the main pollutant, and its concentrations were the highest, we examined the photodegradation behavior of fluoranthene and investigated the effects of light-sensitive materials (H2O2, acetone, and sediment) on fluoranthene photodegradation in the ice phase. Results showed that low H2O2 concentrations promoted photoconversion in the initial stage of the reaction and that degradation rates decreased later in the reaction. Likewise, high H2O2 concentrations promoted photoconversion. As acetone concentrations increased, the rates of fluoranthene-degradation decreased. Sediments may also have decreased the degradation rate of fluoranthene. PMID- 25838211 TI - Application of CRISPRi for prokaryotic metabolic engineering involving multiple genes, a case study: Controllable P(3HB-co-4HB) biosynthesis. AB - Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is used to edit eukaryotic genomes. Here, we show that CRISPRi can also be used for fine-tuning prokaryotic gene expression while simultaneously regulating multiple essential gene expression with less labor and time consumption. As a case study, CRISPRi was used to control polyhydroxyalkanoate (PHA) biosynthesis pathway flux and to adjust PHA composition. A pathway was constructed in Escherichia coli for the production of poly(3-hydroxybutyrate-co-4 hydroxybutyrate) [P(3HB-co-4HB)] from glucose. The native gene sad encoding E. coli succinate semi-aldehyde dehydrogenase was expressed under the control of CRISPRi using five specially designed single guide RNAs (sgRNAs) for regulating carbon flux to 4-hydroxybutyrate (4HB) biosynthesis. The system allowed formation of P(3HB-co-4HB) consisting of 1-9mol% 4HB. Additionally, succinate, generated by succinyl-coA synthetase and succinate dehydrogenase (respectively encoded by genes sucC, sucD and sdhA, sdhB) was channeled preferentially to the 4HB precursor by using selected sgRNAs such as sucC2, sucD2, sdhB2 and sdhA1 via CRISPRi. The resulting 4HB content in P(3HB-co-4HB) was found to range from 1.4 to 18.4mol% depending on the expression levels of down-regulated genes. The results show that CRISPRi is a feasible method to simultaneously manipulate multiple genes in E. coli. PMID- 25838213 TI - Cardiovascular outcomes of intravenous iron in perspective of clinical trials and the use of different iron preparations. PMID- 25838212 TI - A new tool for the risk stratification of patients undergoing primary percutaneous coronary intervention with ST-segment elevation myocardial infarction: Bio-Clinical SYNTAX score. PMID- 25838215 TI - Correlation of atrial fibrillation cycle length and fractionation is associated with atrial fibrillation free survival. AB - AIMS: Fractionation of electrograms in atrial fibrillation (AF) is associated with structural and electrical remodeling. We hypothesized that fractionation can also be associated with the AF cycle length (AFCL). This study was aimed at calculating the mean AFCL to fractionation correlation coefficient (mAFCC) and assessing its association with AF free survival after pulmonary vein isolation (PVI). METHODS: In twenty-eight patients, 15-second electrograms during AF were recorded with a twenty-polar catheter at the left and right atrial appendages. The AFCL was determined manually and the number of activations per second was automatically calculated into a fractionation score. The correlation between AFCL and fractionation was assessed with the mAFCC. RESULTS: Mean age was 53 +/- 8 years and 86% had paroxysmal AF. 64% of patients were AF free after a median follow-up of 5.5 years. Baseline characteristics, mean AFCL and fractionation score were not associated with AF free survival after PVI. The mAFCC assessed at the left atrial appendage predicted long-term AF free survival (area under the curve: 0.871. P=0.002), but the mAFCC recorded at the right atrial appendage did not (0.690, P=0.131). CONCLUSION: The mean AFCL mAFCC recorded at the left atrial appendage was a significant predictor of long-term AF free survival. Although not a significant predictor of AF free survival, there was a significant association between mAFCC recorded at the right atrial appendage and AF free survival. PMID- 25838214 TI - Transient QRS amplitude attenuation is associated with clinical recovery in patients with takotsubo cardiomyopathy. AB - BACKGROUND/OBJECTIVES: Low voltage QRS complexes (LQRSV) and amplitude attenuation of QRS voltage (AAQRS) have been described in takotsubo (TC) patients, and postulated as valuable pre-angiographic markers. The aim of this observational study is to evaluate potential diagnostic and prognostic features of QRS amplitude in TC and acute coronary syndrome (ACS) patients. METHODS: Fifty eight patients with TC were matched with 58 patients with ACS according to age, gender, and presence or absence of ST elevation at hospital admission. A 12-lead ECG was recorded within 12h after symptoms onset, the day after coronary angiography (CA) and before hospital discharge. When available, ECGs prior and subsequent to the acute event were also collected. RESULTS: QRS amplitude showed a time related trend, with a first phase characterized by an initial decrease in amplitude in both groups and a second phase, with a progressive recovery of QRS amplitude in TC patients up to pre-event levels, while QRS amplitude in ACS patients remained substantially unchanged from admission onwards. Rise in AAQRS during hospitalization showed a positive linear association with systolic function recovery and both troponin I and CK-MB decrease (all p<0.01) in TC patients. A 20% increase of mean AAQRS from admission is able to predict LVEF recovery and troponin I and CK-MB normalization in TC patients with good sensitivity and specificity. CONCLUSIONS: LQRSV and AAQRS are not reliable in differentiating ACS from TC. However, QRS amplitude attenuation in TC is transient, and is linearly associated with systolic function recovery and cardiac biomarkers normalization. PMID- 25838216 TI - Impaired clopidogrel antiplatelet effects and age: Young patients at risk. PMID- 25838217 TI - Height, weight and body mass index in adults with congenital heart disease. AB - BACKGROUND: High BMI is a risk factor for cardiovascular disease and, in contrast, low BMI is associated with worse prognosis in heart failure. The knowledge on BMI and the distribution in different BMI-classes in adults with congenital heart disease (CHD) are limited. METHODS AND RESULTS: Data on 2424 adult patients was extracted from the Swedish Registry on Congenital Heart Disease and compared to a reference population (n=4605). The prevalence of overweight/obesity (BMI >= 25) was lower in men with variants of the Fontan procedure, pulmonary atresia (PA)/double outlet right ventricle (DORV) and aortic valve disease (AVD) (Fontan 22.0% and PA/DORV 15.1% vs. 43.0%, p=0.048 and p<0.001) (AVD 37.5% vs. 49.3%, p<0.001). Overt obesity (BMI >= 30) was only more common in women with AVD (12.8% vs. 9.0%, p=0.005). Underweight (BMI<18.5) was generally more common in men with CHD (complex lesions 4.9% vs. 0.9%, p<0.001 and simple lesions 3.2% vs. 0.6%, <0.001). Men with complex lesions were shorter than controls in contrast to females that in general did not differ from controls. CONCLUSION: Higher prevalence of underweight in men with CHD combined with a lower prevalence of overweight/obesity in men with some complex lesions indicates that men with CHD in general has lower BMI compared to controls. In women, only limited differences between those with CHD and the controls were found. The complexity of the CHD had larger impact on height in men. The cause of these gender differences as well as possible significance for prognosis is unknown. PMID- 25838218 TI - Multimodality imaging of myocardial revascularization using cardiac shock wave therapy. PMID- 25838219 TI - Intraprocedural thrombotic event during coronary intervention depends on CYP2C19 genotype and is a predictor of future clinical event. PMID- 25838220 TI - A rare localization for non-pulmonary vein trigger of atrial fibrillation: persistent left superior vena cava. PMID- 25838221 TI - Letter regarding Choudhary et al. "Improving the diagnosis of LV non-compaction with cardiac magnetic resonance imaging". PMID- 25838222 TI - Drug-coated balloon angioplasty: An intriguing alternative for the treatment of coronary chronic total occlusions. PMID- 25838223 TI - Advantages of renin inhibition in a patient with reninoma. PMID- 25838224 TI - Anti-toll like receptor 4 (TLR4) therapy diminishes cardiac remodeling regardless of changes in blood pressure in spontaneously hypertensive rats (SHR). PMID- 25838225 TI - Sex differences of troponin test performance in chest pain patients. AB - BACKGROUND: Current guidelines recommend troponin as the preferred biomarker to diagnose acute myocardial infarction (AMI) irrespective of the patient's sex. Recent reports have shown that sex-specific cut-offs should be considered but studies investigating sex-differences in the diagnostic accuracy of cardiac troponins are sparse. OBJECTIVE: To evaluate whether the diagnostic performance of cardiac troponin at admission (cTn) under routine conditions is influenced by patient's sex. METHODS: Between 15th of February 2009 and 15th of February 2010, women (n=1648) and men (n=2305) who presented to the emergency department with chest pain (n=3954) were enrolled. The diagnostic performance of the routine, contemporary sensitive cTn assays (TnI; Stratus(r) CS, Siemens and TnT; Roche Diagnostics) at baseline for the diagnosis of non-ST-elevation myocardial infarction (NSTEMI) was analyzed. RESULTS: NSTEMI was diagnosed in 7.3% (n=287) of all patients. Men were more likely to be diagnosed with NSTEMI (8.8%; n=202) as compared to women (5.2%; n=85; p<0.001). Sensitivity was 56.1% (95% CI: 44.7 67.0%) in women and 70.1% (95% CI: 63.1-76.4%) in men. Specificity was 96.8% (95% CI: 95.6-97.7%) in women and 94.5% (95% CI: 93.3-95.6%) in men. This resulted in a lower positive predictive value (PPV) for women (53.5%; 95% CI: 42.4-64.3) as compared to men (60.8%; 95% CI: 54.1-67.2) and a slightly higher negative predictive value (NPV) for women: 97.1% (95% CI: 96.0-97.9) vs. 96.3% (95% CI: 95.2-97.2) in men. CONCLUSIONS: The findings of this study underline that the performance of cTn for the diagnosis of NSTEMI depends on a patient's sex, with a lower sensitivity and NPV in women. The definition and implementation of sex specific cut-off values for cTn into clinical routine seems to be highly recommendable. PMID- 25838226 TI - Impressive progression of coronary artery disease assessed by serial multimodality imaging in a 40 year-old patient with Behcet's disease. PMID- 25838227 TI - Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I. AB - OBJECTIVE: To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria. METHODS: 1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmol/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods. RESULTS: The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age specific, differences at 99th percentile URL have been identified. CONCLUSION: The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed. PMID- 25838228 TI - Tips and tricks to implant a MitraClip in a patient with previous surgical closure of atrial septal defect. PMID- 25838229 TI - Bland and broken hearted: A case of hyponatremia induced Tako-tsubo cardiomyopathy. PMID- 25838230 TI - Novel insights into an "old" phenomenon: the no reflow. AB - Coronary artery diseases and particularly acute myocardial infarction are the leading causes of mortality and morbidity in western countries. Despite the achievements of the last decades with the advent of double antiplatelet therapy, new antithrombotics and reperfusion strategies (either pharmacological or mechanical), many patients still have adverse cardiovascular events after ST segment elevation acute myocardial infarction; at least some of these adverse events are related to the no reflow phenomenon that occurs after primary percutaneous coronary intervention. In our review we will discuss the various aspects of this phenomenon. PMID- 25838231 TI - Double device left atrial appendage closure with the WATCHMANTM. PMID- 25838232 TI - Association of aging with glomerular filtration changes in cardiac rehabilitation participants with chronic kidney disease. PMID- 25838234 TI - Response to letter by Cheuk-Kit Wong et al.: The deserved values of leads avL and avR in inferior STEMIs should be given! PMID- 25838233 TI - Impact of renal function on changes of plaque characteristics in non-intervened coronary segments after rosuvastatin treatment in patients with angina pectoris and hypertension. PMID- 25838235 TI - Laryngeal preservation in ENT oncology. Retrospective series of 246 patients managed in the Caen University Hospital and Francois Baclesse Cancer Care Center between 1998 and 2008. AB - OBJECTIVES: A 10-year retrospective study investigated factors for survival and laryngeal preservation in advanced laryngeal, hypopharyngeal or epilaryngeal neoplasia. MATERIAL AND METHOD: Two hundred and forty-six patients with advanced cancer of the larynx (17.48%), hypopharynx (48.78%) or epilarynx (33.74%) undergoing primary organ-sparing treatment were included from 1998 to 2008. Treatment comprised chemotherapy followed by radiation therapy for 92.68% of patients, isolated radiation therapy for 1.6% and concomitant or sequential radiation-chemotherapy for 5.7%. General health status, history and tumor status were recorded. Factors influencing survival were analyzed by Kaplan-Meier estimator, log-rank test and Cox models. RESULTS: Median overall survival of the population was 2.3 years and median laryngeal preservation 0.99 years in male patients and 2 years in female patients. Survival correlated significantly with body mass index (BMI; P=0.0004), WHO performance status (P=0.0064), alcohol consumption (P=0.0004) and cessation (P<0.0001) and also T stage (P=0.0038), initial laryngeal mobility (P=0.0002) and post-chemotherapy assessment (P<0.0001). Survival with functional larynx correlated with baseline BMI at first consultation (P=0.016), baseline WHO grade (P=0.0005), laryngeal mobility (P<0.0001), T staging (P=0.0009), and T and/or N chemotherapy response to a classical organ preservation protocol (P<0.0001). CONCLUSION: Over and above established criteria, the present study highlighted the importance of general health and nutritional status during treatment. PMID- 25838236 TI - Overexpression and characterization of a Ca(2+) activated thermostable beta glucosidase with high ginsenoside Rb1 to ginsenoside 20(S)-Rg3 bioconversion productivity. AB - The thermostable beta-glucosidase gene from Thermotoga petrophila DSM 13995 was cloned and overexpressed in Escherichia coli. The activity of the recombinant beta-glucosidase was 21 U/mL in the LB medium. Recombinant beta-glucosidase was purified, and its molecular weight was approximately 81 kDa. The optimal activity was at pH 5.0 and 90 degrees C, and the thermostability of the enzyme was improved by Ca(2+). The beta-glucosidase had high selectivity for cleaving the outer and inner glucopyranosyl moieties at the C-20 carbon of ginsenoside Rb1, which produced the pharmacologically active minor ginsenoside 20(S)-Rg3. In a reaction at 90 degrees C and pH 5.0, 10 g/L of ginsenoside Rb1 was transformed into 6.93 g/L of Rg3 within 90 min, with a corresponding molar conversion of 97.9%, and Rg3 productivity of 4620 mg/L/h. This study is the first report of a GH3-family enzyme that used Ca(2+) to improve its thermostability, and it is the first report on the high substrate concentration bioconversion of ginsenoside Rb1 to ginsenoside 20(S)-Rg3 by using thermostable beta-glucosidase under high temperature. PMID- 25838238 TI - Erratum to: Engineered Serratia marcescens for efficient (3R)-acetoin and (2R,3R) 2,3-butanediol production. PMID- 25838237 TI - Growth retardation of Escherichia coli by artificial increase of intracellular ATP. AB - Overexpression of phosphoenolpyruvate carboxykinase (PCK) was reported to cause the harboring of higher intracellular ATP concentration in Escherichia coli, accompanied with a slower growth rate. For systematic determination of the relationship between the artificial increase of ATP and growth retardation, PCKWT enzyme was directly evolved in vitro and further overexpressed. The evolved PCK67 showed a 60% greater catalytic efficiency than that of PCKWT. Consequently, the PCK67-overexpressing E. coli showed the highest ATP concentration at the log phase of 1.45 MUmol/gcell, with the slowest growth rate of 0.66 h(-1), while the PCKWT-overexpressing cells displayed 1.00 MUmol/gcell ATP concentration with the growth rate of 0.84 h(-1) and the control had 0.28 MUmol/gcell with 1.03 h(-1). To find a plausible reason, PCK-overexpressing cells in a steady state during chemostat growth were applied to monitor intracellular reactive oxygen species (ROS). Higher amount of intracellular ROS were observed as the ATP levels increased. To confirm the hypothesis of slower growth rate without perturbation of the carbon flux by PCK-overexpression, phototrophic Gloeobacter rhodopsin (GR) was expressed. The GR-expressing strain under illumination harbored 81% more ATP concentration along with 82% higher ROS, with a 54% slower maximum growth rate than the control, while both the GR-expressing strain under dark and dicarboxylate transporter (a control membrane protein)-expressing strain showed a lower ATP and increased ROS, and slower growth rate. Regardless of carbon flux changes, the artificial ATP increase was related to the ROS increase and it was reciprocally correlated to the maximum growth rate. To verify that the accumulated intracellular ROS were responsible for the growth retardation, glutathione was added to the medium to reduce the ROS. As a result, the growth retardation was restored by the addition of 0.1 mM glutathione. Anaerobic culture even enabled the artificial ATP-increased E. coli to grow faster than control. Collectively, it was concluded that artificial ATP increases inhibit the growth of E. coli due to the overproduction of ROS. PMID- 25838239 TI - [Attributable risk of co-morbid substance use disorder in poor observance to pharmacological treatment and the occurrence of relapse in schizophrenia]. AB - BACKGROUND: There are numerous risk factors involved in poor (incomplete) compliance to pharmacological treatment, and the associated relapse risk, for patients with schizophrenia. Comorbid substance use disorders are considered as among the most important ones, although how much their presence increase the risk of poorer observance (and higher risk of relapse) has not been yet assessed. This measure would be important, especially if the published literature on the topic provides sufficient material to perform a meta-analysis and to assess different potential biases such as those related to time (new studies are easier to publish when positive) or sample size (small samples might drive the global positive conclusion). METHOD: A PubMed((r)) search was made, screening the following terms between 1996 and august 2014 "Addiction AND (Observance OR Adherence) AND schizophrenia AND (French OR English [Language])" and "(Substance Abuse OR substance dependance) AND Outcome AND schizophrenia AND (French OR English [Language])". Studies were included if they describe two patients groups (schizophrenia with and without present substance use disorder) and assess the studied outcome. MetaWin((r)) version 2 was used for the meta-analysis, while publication time bias relied on non-parametric correlation and the one linked to sample size was assessed through normal quantile plots. An attributable risk was also computered, on the basis of the odds-ratio derived from the meta-analysis and the prevalence of the analyzed trait (associated substance use disorder). RESULTS: Eight studies could be included in the meta-analysis, showing that the presence of a substance use disorder significantly increases the risk of poor observance to pharmacological treatment (OR=2.18 [1.84-2.58]), no significant bias being detected, either linked to time (rho=0.287, P=0.490) or sample size (Kendall's Tau=-0.286, P=0.322). The related attributable risk is 18.50%. Only three studies could be used for the meta-analysis of the risk of relapse associated with the presence of substance use disorders. The corresponding odds ratio is 1.52 [1.19-1.94], and the attributable risk is 31.20%, but the search for biases could not be performed because of the small number of studies. CONCLUSIONS: These results shed light on the importance of comorbid substance use disorder to explain the poor observance frequently observed in patients with schizophrenia. Indeed, having an associated substance use disorder double the risk of poor compliance to pharmacological treatment, this comorbidity explaining a fifth of all factors involved. Although the number of available studies does not allow definite conclusions, the meta-analysis of prospective studies focusing this time of the risk of relapse requiring hospitalization is also in favor of a significant role of associated substance use disorder. These results argue in favor of developing specific strategies to better treat patients with dual diagnoses, i.e. schizophrenia and substance use disorder. PMID- 25838240 TI - Different evolutionary processes in shaping the genetic composition of Dendrobium nobile in southwest China. AB - Knowledge of population genetic structure and intrapopulation genetic variation is important for understanding population dynamics and evolutionary processes. Dendrobium nobile is an endangered traditional Chinese tonic medicine. In order to analyze the population differentiation and genetic diversity in D. nobile and propose proper conservation measurements, we genotyped 102 individual plants from 7 natural populations distributed across southwest China at 9 microsatellite loci. Seven pairs of genomic SSR primers were newly designed, and two pairs were chosen from the EST-SSRs. According to the results, the genetic process of D. nobile on Hainan Island and the Chinese mainland might be affected by different evolutionary processes, the genetic drift caused by founder effect has played an important role in shaping the genetic constitution of the Island population. The population of D. nobile in Hainan Island was highly differentiated and displayed low levels of genetic diversity. For the conservation management plans of D. nobile, we propose that individuals in Hainan Island with rare alleles need to be conserved with top priority, and those individuals with rare alleles and the most common alleles also should be concerned. The seven new microsatellite loci may be informative for further evaluation and conservation of the genetic diversity of D. nobile. PMID- 25838242 TI - The GluN2B subunit of N-methy-D-asparate receptor regulates the radial migration of cortical neurons in vivo. AB - The formation of layered structure of the mammalian neocortex requires a fine organized migration of post-mitotic neurons during early development. However, whether the radial migration is regulated by NMDA receptor and specific subunits remains contradictory and unknown. Here, we reported that in the developing rat cortex, migration of presumptive layer II/III neurons to their deserved destination was regulated by NMDA receptors with GluN2B but not GluN2A subunit. Using in utero electroporation of small interference RNA (siRNA) of distinct NMDA receptor subunits, we found that knockdown GluN1 and GluN2B subunits dramatically delayed the neuronal migration to proper layer II/III, while improperly stayed at lower layers or even the germinal regions, without changing the cell fate. In contrast, knockdown of GluN2A subunit did not impair the neuronal migration. Additionally, the ecotopic neurons by GluN2B RNAi developed to well dendritic differentiation, while the ones by GluN1 RNAi still kept morphology of migrating neurons. Therefore, GluN2B subunit of NMDA receptor plays an essential role in regulating proper neuronal migration and cortical lamination. PMID- 25838243 TI - Input-based structure-specific proficiency predicts the neural mechanism of adult L2 syntactic processing. AB - This study used Event-Related Potentials (ERPs) to explore the role of input based structure-specific proficiency in L2 syntactic processing, using English subject-verb agreement structures as the stimuli. A pre-test/trainings/post-test paradigm of experimental and control groups was employed, and Chinese speakers who learned English as a second language (L2) participated in the experiment. At pre-test, no ERP component related to the subject-verb agreement structures violations was observed in either group. At training session, the experimental group learned the subject-verb agreement structures, while the control group learned other syntactic structures. After two continuously intensive input trainings, at post-test, a significant P600 component related to the subject-verb agreement structures violations was elicited in the experimental group, but not in the control group. These findings suggest that input training improves structure-specific proficiency, which is reflected in the neural mechanism of L2 syntactic processing. PMID- 25838241 TI - The tetrapartite synapse: Extracellular matrix remodeling contributes to corticoaccumbens plasticity underlying drug addiction. AB - Synaptic plasticity has long been known to involve three key elements of neuropil, the presynapse, the postsynapse and adjacent glia. Here we review the role of the extracellular matrix in synaptic plasticity as a necessary component forming the tetrapartite synapse. We describe the role of matrix metalloproteinases as enzymes sculpting extracellular proteins and thereby creating an extracellular signaling domain required for synaptic plasticity. Specifically we focus on the role of the tetrapartite synapse in mediating the effects of addictive drugs at cortico-striatal synapses, and conclude that the extracellular signaling domain and its regulation by matrix metalloproteinases is critical for developing and expressing drug seeking behaviors. PMID- 25838244 TI - Reversible structural transformation and enhanced performance of PEDOT:PSS-based hybrid solar cells driven by light intensity. AB - Hybrid solar cells made of poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) and appropriate amounts of a cosolvent and a fluorosurfactant on planar n-type silicon substrates showed a photoconversion efficiency (PCE) of above 13%. These cells also exhibited stable, reproducible, and high external quantum efficiency (EQE) that was not sensitive to light-bias intensity (LBI). In contrast, solar cells made of pristine PEDOT: PSS showed low PCE and high EQE only under certain measurement conditions. The EQE was found to degrade with increasing LBI. Here we report that the LBI-sensitive variation of EQE of the low-PCE cells is related to a reversible structural transformation from a quinoid to a benzoid structure of PEDOT. PMID- 25838245 TI - Sex Differences During an Overhead Squat Assessment. AB - A disparity exists between the rates of male and female lower extremity injuries. One factor that may contribute to this disparity is high-risk biomechanical patterns that are commonly displayed by females. It is unknown what biomechanical differences exist between males and females during an overhead squat. This study compared lower extremity biomechanics during an overhead squat and ranges of motion between males and females. An electromagnetic motion tracking system interfaced with a force platform was used to quantify peak lower extremity kinematics and kinetics during the descent phase of each squat. Range of motion measurements were assessed with a standard goniometer. Differences between male and female kinematics, kinetics, and ranges of motion were identified with t tests. Males displayed greater peak knee valgus angle, peak hip flexion angle, peak vertical ground reaction forces, and peak hip extension moments. Males also displayed less active ankle dorsiflexion with the knee extended and hip internal and external rotation than females. No other differences were observed. The biomechanical differences between males and females during the overhead squat may result from differences in lower extremity ranges of motion. Therefore, sex specific injury prevention programs should be developed to improve biomechanics and ranges of motion. PMID- 25838246 TI - On the Link between Cognitive Diagnostic Models and Knowledge Space Theory. AB - The present work explores the connections between cognitive diagnostic models (CDM) and knowledge space theory (KST) and shows that these two quite distinct approaches overlap. It is proved that in fact the Multiple Strategy DINA (Deterministic Input Noisy AND-gate) model and the CBLIM, a competence-based extension of the basic local independence model (BLIM), are equivalent. To demonstrate the benefits that arise from integrating the two theoretical perspectives, it is shown that a fairly complete picture on the identifiability of these models emerges by combining results from both camps. The impact of the results is illustrated by an empirical example, and topics for further research are pointed out. PMID- 25838247 TI - The Reduced RUM as a Logit Model: Parameterization and Constraints. AB - Cognitive diagnosis models (CDMs) for educational assessment are constrained latent class models. Examinees are assigned to classes of intellectual proficiency defined in terms of cognitive skills called attributes, which an examinee may or may not have mastered. The Reduced Reparameterized Unified Model (Reduced RUM) has received considerable attention among psychometricians. Markov Chain Monte Carlo (MCMC) or Expectation Maximization (EM) are typically used for estimating the Reduced RUM. Commercial implementations of the EM algorithm are available in the latent class analysis (LCA) routines of Latent GOLD and Mplus, for example. Fitting the Reduced RUM with an LCA routine requires that it be reparameterized as a logit model, with constraints imposed on the parameters. For models involving two attributes, these have been worked out. However, for models involving more than two attributes, the parameterization and the constraints are nontrivial and currently unknown. In this article, the general parameterization of the Reduced RUM as a logit model involving any number of attributes and the associated parameter constraints are derived. As a practical illustration, the LCA routine in Mplus is used for fitting the Reduced RUM to two synthetic data sets and to a real-world data set; for comparison, the results obtained by using the MCMC implementation in OpenBUGS are also provided. PMID- 25838248 TI - Axillary nodal metastases in Italian early breast cancer patients with positive sentinel lymph node: can axillary node dissection be avoided by using predictive nomograms? AB - AIMS AND BACKGROUND: Clinical guidelines recommend axillary lymph node dissection (ALND) in cases of metastatic sentinel lymph node (SNL) in patients with clinically node-negative early breast cancer. However, a relevant number of ALND could be avoided in a subset of patients in whom the risk of non-SNL metastases is low. In order to define this population, several authors have proposed mathematical models, which have been validated in many studies. These studies reached different conclusions regarding which model demonstrated the best statistical discrimination power, mainly due to differences in clinical and pathologic variables used, and particularly differences in the number of dissected SLNs. METHODS: We retrospectively reviewed clinically node-negative patients who underwent ALND in our surgical ward after the diagnosis of breast cancer metastases on SLN biopsy from January 2000 to December 2012. The predictive accuracy of the widely used nomograms to predict the risk of additional nodal disease in our patients with SLN breast cancer metastases was measured by receiver operating characteristic curve. We then attempted to develop a new nomogram by analyzing the dataset. RESULTS: A total of 105 patients were included in this study, with ratio of metastatic lymph node/removed lymph node of about 0.89; we found axillary nodal metastases on ALND in only 31 patients (29.5%). Applied to our dataset, Mayo nomogram showed the best area under the receiving operator characteristic curve (0.74) followed by our model (0.71). Instead, the Memorial Sloan-Kettering model showed poor discrimination, as did Tenon (0.56). CONCLUSIONS: Based on our data, we cannot recommend the clinical use of validated predictive nomograms in order to avoid ALND. We suggest setting up a multicenter Italian study to build a model specific to our setting and based on larger series. PMID- 25838249 TI - A combined smoking cessation intervention within a lung cancer screening trial: a pilot observational study. AB - AIMS AND BACKGROUND: The time of lung cancer screening may provide the ideal setting to discuss and initiate a smoking cessation plan that includes pharmacologic aids. No studies to date have fully investigated the potential effectiveness of such combined approach. METHODS: We prospectively evaluated the biochemically verified 1-year continuous abstinence rate from smoking of 187 persistent smokers enrolled within the Multicentric Italian Lung Detection Trial (MILD), who received a pharmacologic aid to quit smoking with varenicline along with behavioral counseling. The propensity of study subjects to succeed in smoking cessation was also monitored. RESULTS: At 12 months, the continuous abstinence rate from smoking was achieved in 37 out of 187 patients (19.8%), with a propensity to succeed in smoking cessation for the assisted attempt equal to 1.43, as compared to an unassisted MILD patient. At the end of the third month of therapy, 48.7% of subjects showed a continuous abstinence rate, while only 33.7% of patients were abstinent from smoking at 6 months. At baseline, the subgroup of MILD participants who were originally allocated to lung tomography showed higher smoking intensity than those allocated to no screening. CONCLUSIONS: A combined smoking cessation intervention can be implemented with satisfactory results within a lung cancer screening program; this preliminary observation needs to be replicated in a prospective investigation. Clinicians should consider that lung cancer screening may be falsely reassuring for persistent smokers; therefore it should always be coupled with a smoking cessation program. PMID- 25838250 TI - Expression of CBY and methylation of CBY at promoter region in human laryngeal squamous cell carcinoma. AB - AIMS AND BACKGROUND: Chibby (CBY), a beta-catenin binding partner, inhibits Wnt/beta-catenin-mediated transcriptional activation by competing with Tcf/Lef factors for beta-catenin binding and promoting the export of beta-catenin from nucleus to cytoplasm. The regulatory effect of CBY in this signaling pathway suggests its biological importance as a potential tumor suppressor gene. The purposes of this study were to determine whether the expression of CBY was downregulated in human laryngeal squamous cell carcinoma (LSCC) samples, the CpG sites of CBY at the promoter region were methylated in these tumor samples, and reduced expression of CBY was induced by methylation of CBY promoters. METHODS: CBY expression was investigated by quantitative real-time PCR and immunohistochemistry in samples from 36 LSCC patients. The methylation status of the CBY promoter was detected by methylation-specific PCR. RESULTS: Compared with normal laryngeal mucosa, the expression of CBY was downregulated in LSCC samples. The reduced CBY expression rate was 58.33% (21/36) at the mRNA and 66.67% (24/36) at the protein level. The promoters of CBY were methylated in 12/36 tumor samples, partially methylated in 5, and unmethylated in 19 samples. The methylation rate including incomplete methylation was 47.22% (17/36) in tumor samples, while no methylation was detected in normal laryngeal squamous epithelium. Compared with the unmethylated group, the expression of CBY was significantly different in the methylated group (p<0.05) but similar in the partially methylated group (p>0.05). CONCLUSIONS: Our data indicate that CBY expression was downregulated in LSCC, which may be partially caused by methylation of CBY promoters. PMID- 25838251 TI - Novel blood-based microRNA biomarkers for diagnosis of pancreatic cancer: a meta analysis. AB - BACKGROUND: Recently, several studies have shown that blood-based microRNAs in patients with pancreatic cancer (PC) could be aberrantly expressed. The purpose of this meta-analysis was to evaluate blood-based microRNAs as novel biomarkers for diagnosis of PC. METHODS: Eligible studies which had evaluated the diagnostic performance of blood-based microRNAs and had been published from February 2004 to February 2014 were retrieved. The quality of the studies was evaluated with the QUADAS-2 tool. The performance characteristics were pooled using random-effects models. Statistical analysis was performed with STATA and Meta-Disc1.4 software. RESULTS: The global meta-analysis included 12 studies from 8 articles, which contained 1,060 blood-based samples of PC patients and 935 blood-based samples of non-PC patients. Summary results suggested pooled sensitivity of 0.87 (95% confidence interval [95% CI], 0.85-0.89), specificity 0.92 (95% CI, 0.90-0.94), positive likelihood ratio 11.18 (95% CI, 5.57-22.46), negative likelihood ratio 0.16 (95% CI, 0.11-0.23), diagnostic odds ratio 88.98 (95% CI, 39.85-198.69) and the area under the summary receiver operating characteristic (SROC) curve 0.96. CONCLUSIONS: This meta-analysis demonstrated blood-based microRNA expression profiles with the potential to discriminate PC patients from non-PC patients, which have moderate diagnostic accuracy. However, further validation studies are needed for their clinical significance in the diagnosis of PC to be established. PMID- 25838252 TI - Novel 10-fraction breast irradiation in prone and supine position: technical, dosimetric and clinical evaluation. AB - BACKGROUND: The aim of this study was to evaluate retrospectively the planned dose distribution and acute toxicity of adjuvant hypofractionated whole breast radiotherapy (RT) delivered in the prone vs. supine position. METHODS: Twenty four patients were enrolled; 12 underwent adjuvant RT with a supine setup and 12 with a prone setup. We included patients according to breast volume (>=500 mL), disease stage (<=pT2/pN1), and clinical/biological features. Patients received a regimen of 35 Gy in 10 fractions for 2.5 weeks, and a concomitant boost of 3/4 Gy in 1 fraction/week. Target coverage was assessed by volume, V90, V95, V100, V103 and V105. Heart, LADCA and ipsilateral lung doses were evaluated according to volume, maximum dose, mean dose, V14, V10 and V5. We evaluated acute skin toxicity during RT, at the end of treatment, and after 1 month according to RTOG scales. RESULTS: Radiobiological equivalence was warranted with satisfactory BED values: considering alpha/beta = 4 for breast cancer, the 10-fraction schedule equaled 74 or 77 Gy depending on the boost dose (3 Gy vs. 4 Gy, respectively). Toxicity was low and similar for supine and prone treatments. Dose sparing was significant in the ipsilateral lung in the prone position (median Dmax: 28.7 Gy vs. 38.4 Gy; median Dmean: 0.8 Gy vs. 6.3 Gy; median V14: 0.6% vs. 13.5%; median V5: 0 vs. 19.3%, p<0.001). CONCLUSIONS: This novel 10-fraction schedule is feasible and well tolerated; the prone position allows better saving of OARs, with a statistically significant value for the ipsilateral lung. PMID- 25838253 TI - Concomitant trimodality therapy of re-irradiation, chemotherapy and regional hyperthermia for a pretreated inoperable sarcoma recurrence. AB - We hereby present a case of pre-treated unresectable sarcoma recurrence of the trunk which showed an excellent response to concomitant tri-modal therapy, consisting of re-irradiation, chemotherapy and regional hyperthermia even with a strong compromised re-irradiation dose. No significant toxicity of the combined therapy and fast achievement of the pain and neurological symptoms relief are reported. The case shows that concurrent tri-modality treatment can be considered as a therapeutic option for the management of pre-treated unresectable recurrence even in there-irradiation setting. PMID- 25838254 TI - Tivantinib, a new option for second-line treatment of advanced hepatocellular carcinoma? The experience of Italian centers. AB - In the last decades the management of hepatocellular carcinoma (HCC) has undergone significant changes following the introduction of novel therapies such as sorafenib, which have improved patient survival. Nevertheless, HCC is still the third most common cause of cancer-related death worldwide. The evidence-based therapy for advanced HCC that is unsuitable for locoregional treatment is limited to sorafenib, with no second-line option available. This article focuses on the development of the MET inhibitor tivantinib in HCC as a promising treatment option for patients who failed sorafenib. A randomized, placebo-controlled phase II study showed activity of tivantinib in patients with high MET expression. Based on these results, the METIV-HCC phase III study in second-line treatment for MET-high patients was initiated to demonstrate the survival advantage of tivantinib compared to placebo. PMID- 25838255 TI - Modulation depth enhancement of ESEEM experiments using pulse trains. AB - We present a new way to increase the modulation amplitude of electron spin echo envelope modulation (ESEEM) experiments that are based on electron spin coherence. The method uses a train of N refocusing pi-pulses where each one of them redistributes the electron spin coherence among allowed and forbidden EPR transitions. This in turn leads to a significant enhancement of the ESEEM effect, depending on the strength of the hyperfine interaction and the number of applied pulses, N. We derive analytical expressions for a general two-dimensional (2D) scheme which is based on the refocused primary echo and we explore the expected modulation enhancement of various correlation peaks as a function of k (modulation depth parameter) and N. In addition, we inspect two different one dimensional (1D) versions of the method, namely the Carr-Purcell-Meiboom-Gill (CPMG) sequence occurring for t1=t2, and an extension of the primary echo sequence occurring for t2=0. Our study shows that these methods are particularly useful for detecting weak hyperfine couplings of magnetic nuclei having small gn factors and low natural abundances like (13)C and (29)Si. The theoretically predicted features are confirmed by experiments in disordered spin systems. PMID- 25838256 TI - Low involvement of preexisting associations makes retrieval-induced forgetting long lasting. AB - Research has shown that selective retrieval of episodic memories usually leads to forgetting of related memories that compete for retrieval [a phenomenon known as retrieval-induced forgetting (RIF)]. However, there are conflicting data regarding the duration of this incidental kind of forgetting. While some studies have found that this forgetting effect disappears within 24 h after selective retrieval, others suggest that it may last for as long as at least a week. In two experiments, we explored whether discrepancies in the durability of RIF may be due to variations in the type of relationships (preexisting vs. novel) that are present between items associated with a given cue. We explored this issue by manipulating the degree of involvement of preexisting/novel associations among competing items as well as the delay between retrieval practice and test (immediate in Experiment 1 and 24-h delay test in Experiment 2). The results suggest that forgetting lasts longer when the degree of preexisting associations among targets and competitors is low. PMID- 25838257 TI - Familiarity and preference for pitch probability profiles. AB - We investigated familiarity and preference judgments of participants toward a novel musical system. We exposed participants to tone sequences generated from a novel pitch probability profile. Afterward, we either asked participants to identify more familiar or we asked participants to identify preferred tone sequences in a two-alternative forced-choice task. The task paired a tone sequence generated from the pitch probability profile they had been exposed to and a tone sequence generated from another pitch probability profile at three levels of distinctiveness. We found that participants identified tone sequences as more familiar if they were generated from the same pitch probability profile which they had been exposed to. However, participants did not prefer these tone sequences. We interpret this relationship between familiarity and preference to be consistent with an inverted U-shaped relationship between knowledge and affect. The fact that participants identified tone sequences as even more familiar if they were generated from the more distinctive (caricatured) version of the pitch probability profile which they had been exposed to suggests that the statistical learning of the pitch probability profile is involved in gaining of musical knowledge. PMID- 25838258 TI - Injectable and Biodegradable pH-Responsive Hydrogels for Localized and Sustained Treatment of Human Fibrosarcoma. AB - Injectable hydrogels are an important class of biomaterials, and they have been widely used for controlled drug release. This study evaluated an injectable hydrogel formed in situ system by the reaction of a polyethylene glycol derivative with alpha,beta-polyaspartylhydrazide for local cancer chemotherapy. This pH-responsive hydrogel was used to realize a sol-gel phase transition, where the gel remained a free-flowing fluid before injection but spontaneously changed into a semisolid hydrogel just after administration. As indicated by scanning electron microscopy images, the hydrogel exhibited a porous three-dimensional microstructure. The prepared hydrogel was biocompatible and biodegradable and could be utilized as a pH-responsive vector for drug delivery. The therapeutic effect of the hydrogel loaded with doxorubicin (DOX) after intratumoral administration in mice with human fibrosarcoma was evaluated. The inhibition of tumor growth was more obvious in the group treated by the DOX-loaded hydrogel, compared to that treated with the free DOX solution. Hence, this hydrogel with good syringeability and high biodegradability, which focuses on local chemotherapy, may enhance the therapeutic effect on human fibrosarcoma. PMID- 25838259 TI - The Effect of Thigh Marker Placement on Knee Valgus Angles in Vertical Drop Jumps and Sidestep Cutting. AB - Knee valgus angles measured in sidestep cutting and vertical drop jumps are key variables in research on anterior cruciate ligament (ACL) injury causation. These variables are also used to quantify knee neuromuscular control and ACL injury risk. The aims of the current study were to (1) quantify the differences in the calculated knee valgus angles between 6 different thigh marker clusters, (2) investigate the trial ranking based on their knee valgus angles, and (3) investigate the influence of marker clusters on the cross-talk effect. Elite female handball and football players (n = 41) performed sidestep cutting and vertical drop jumping motions. We found systematic differences up to almost 15 degrees of peak valgus between the marker sets in the drop jump test. The Spearman's rank correlation coefficient varied from .505 to .974 among the 6 marker sets. In addition, the cross-talk effect varied considerably between the marker clusters. The results of the current study indicate that the choice of thigh marker cluster can have a substantial impact on the magnitude of knee valgus angle, as well as the trial ranking. A standardized thigh marker cluster, including nonanatomical landmark, is needed to minimize the variation of the measurement. PMID- 25838260 TI - Domestic use of bleach and infections in children: a multicentre cross-sectional study. AB - OBJECTIVE: To report the effects of bleach use at home on the frequency of infections in 9102 school-age children participating in the HITEA project. METHODS: Parents of pupils aged 6-12 years from schools in Barcelona province (Spain), Utrecht province (the Netherlands) and Eastern and Central Finland were administered a questionnaire including questions on the frequency of infections (influenza, tonsillitis, sinusitis, otitis, bronchitis and pneumonia) in the past 12 months and bleach use at home. We developed multivariable mixed-effects multilogistic regression models to obtain relative risk ratios (RRR) and their 95% CI per country, and combined the RRR using random-effects meta-analyses. RESULTS: Bleach use was common in Spain (72%, n=1945) and uncommon in Finland (7%, n=279). Overall, the prevalence of infections (recurrent or once) was higher among children of bleach users. Significant combined associations were shown for influenza only once (RRR=1.20, 95% CI 1.04 to 1.38), recurrent tonsillitis (RRR=1.35, 95% CI 1.07 to 1.71) and any infection (RRR=1.18, 95% CI 1.01 to 1.38). CONCLUSIONS: Passive exposure to cleaning bleach in the home may have adverse effects on school-age children's health by increasing the risk of respiratory and other infections. The high frequency of use of disinfecting irritant cleaning products may be of public health concern, also when exposure occurs during childhood. PMID- 25838261 TI - An Fe/N co-doped graphitic carbon bulb for high-performance oxygen reduction reaction. AB - An Fe/N co-doped graphitic carbon bulb is synthesized by Prussian blue with a pyrolysis temperature as low as 550 degrees C. Fe facilitates the formation of a graphitic structure, while low temperature guarantees high level of nitrogen. The product shows excellent oxygen reduction reaction catalytic activity in both alkaline and acid electrolytes. PMID- 25838262 TI - Key Factors Influencing Implementation of Falls Prevention Exercise Programs in the Community. AB - The study aim was to evaluate the implementation of group- and home-based exercise falls prevention programs delivered through community health agencies to community-dwelling older people. Interviews with program staff were guided by the Diffusion of Innovations theory. Highly consistent themes emerged for the two types of programs. Both had high overall compatibility, high relative advantage, good observability and high inherent trialability--all factors known to strengthen implementation. The level of complexity and low financial compatibility emerged as the strongest potential inhibitors to program implementation in the context examined. The two main factors contributing to complexity were the need to challenge balance safely across a broad range of capability, and practical considerations associated with program delivery. A range of strategies to provide more technical support for exercise program leaders to tailor balance challenge for exercise program leaders may enhance implementation of falls prevention exercise programs. PMID- 25838263 TI - A FRET-ICT dual-quenching fluorescent probe with large off-on response for H2S: synthesis, spectra and bioimaging. AB - A FRET-ICT dual-quenching probe with large off-on fluorescent response upon H2S treatment is reported. The probe can be used for bioimaging of endogenous H2S in living cells. PMID- 25838264 TI - Analysis of Erythrocyte Invasion Mechanisms of Plasmodium falciparum Clinical Isolates Across 3 Malaria-Endemic Areas in Ghana. AB - BACKGROUND: Plasmodium falciparum invades human erythrocytes by using an array of ligands that interact with several receptors, including sialic acid (SA), complement receptor 1 (CR1), and basigin. We hypothesized that in malaria-endemic areas, parasites vary invasion pathways under immune pressure. Therefore, invasion mechanisms of clinical isolates collected from 3 zones of Ghana with different levels of endemicity (from lowest to highest, Accra, Navrongo, and Kintampo) were compared using standardized methods. METHODS: Blood samples were collected from children aged 2-14 years in whom malaria was diagnosed, and erythrocyte invasion phenotypes were determined using the enzymes neuraminidase, chymotrypsin, and trypsin, which differentially cleave receptors from the erythrocyte surface. In addition, antibodies against CR1 and basigin were used to determine the contributions of these receptors to invasion. Gene expression levels of P. falciparum invasion ligands were also examined. RESULTS: The parasites generally expressed SA-independent invasion phenotypes across the malaria-endemic areas, with parasites from Kintampo showing the highest invasion rates in neuraminidase-treated erythrocytes. CR1 was a major mediator of SA independent invasion, while basigin was essential for both SA-dependent and SA independent invasion mechanisms. Furthermore, expression of the basigin ligand PfRh5 was the best predictor of donor parasitemia. CONCLUSIONS: Erythrocyte invasion phenotypes expressed by P. falciparum are influenced by endemicity levels, and the PfRh5-basigin pathway is a potential vaccine target. PMID- 25838265 TI - CCL20 Displays Antimicrobial Activity Against Cryptosporidium parvum, but Its Expression Is Reduced During Infection in the Intestine of Neonatal Mice. AB - CCL20 is a chemokine with antimicrobial activity. We investigated its expression and role during neonatal cryptosporidiosis, a worldwide protozoan enteric disease leading to severe diarrhea. Surprisingly, during infection by Cryptosporidium parvum, CCL20 production by the intestine of neonatal mice is reduced by a mechanism independent both of the enteric flora and of interferon gamma, a key cytokine for the resolution of this infection. However, oral administration of recombinant CCL20 to neonatal mice significantly reduced the parasite load by a mechanism that was independent of immune cell recruitment and occurred instead by direct cytolytic activity on free stages of the parasite. MiR21 functionally targets CCL20 and is upregulated during the infection, thus contributing to the downregulation of the chemokine. Our findings demonstrate for the first time the direct antiparasitic activity of CCL20 against an enteric protozoan and its downregulation during C. parvum infection, which is detrimental to parasite clearance. PMID- 25838266 TI - High-Affinity H7 Head and Stalk Domain-Specific Antibody Responses to an Inactivated Influenza H7N7 Vaccine After Priming With Live Attenuated Influenza Vaccine. AB - Recent studies have shown that live attenuated influenza vaccines (LAIVs) expressing avian influenza virus hemagglutinins (HAs) prime for strong protective antibody responses to an inactivated influenza vaccine (IIV) containing the HA. To better understand this priming effect, we compared H7 HA head and stalk domain specific B-cell responses in H7N7 LAIV-primed subjects and non-H7-primed controls after a single dose of H7N7 IIV. As previously reported, H7N7 LAIV-primed subjects but not control subjects generated strong hemagglutination-inhibiting and neutralizing antibody responses to the H7N7 IIV. Here, we found that the quantity, epitope diversity, and affinity of H7 head-specific antibodies increased rapidly in only H7N7 LAIV-primed subjects after receipt of the IIV. However, all cohorts generated a vigorous, high-affinity, stalk-specific antibody response. Consistent increases in circulating memory B-cell frequencies after receipt of the IIV reflected the specificity of high-affinity antibody production. Our findings emphasize the value of LAIVs as a vehicle for prepandemic vaccination. PMID- 25838267 TI - Differences in Homing Potentials of Streptococcus pneumoniae-Specific Plasmablasts in Pneumococcal Pneumonia and After Pneumococcal Polysaccharide and Pneumococcal Conjugate Vaccinations. AB - BACKGROUND: Mucosal immune mechanisms in the upper and lower respiratory tracts may serve a critical role in preventing pneumonia due to Streptococcus pneumoniae. Streptococcus pneumoniae-specific plasmablasts presumably originating in the lower respiratory tract have recently been found in the circulation in patients with pneumonia. The localization of an immune response can be evaluated by exploring homing receptors on such plasmablasts, yet no data have thus far described homing receptors in pneumonia. METHODS: The expression of alpha4beta7, L-selectin, and cutaneous lymphocyte antigen (CLA) on S. pneumoniae-specific plasmablasts was examined in patients with pneumonia (n = 16) and healthy volunteers given pneumococcal polysaccharide vaccine (PPV; n = 14) or pneumococcal conjugate vaccine (PCV; n = 11). RESULTS: In patients with pneumonia, the proportion of S. pneumoniae-specific plasmablasts expressing L selectin was high, the proportion expressing alpha4beta7 was moderate, and the proportion expressing CLA was low. The homing receptor alpha4beta7 was expressed more frequently in the pneumonia group than in the PPV (P = .000) and PCV (P = .029) groups, L-selectin was expressed more frequently in the PPV group than in the PCV group (P = .014); and CLA was expressed more frequently in the pneumonia group than in the PPV group (P = .001). CONCLUSIONS: The homing receptor profile in patients with pneumonia was unique yet it was closer to that in PCV recipients than in PPV recipients. These data suggest greater mucosal localization for immune response in natural infection, which is clinically interesting, especially considering the shortcomings of vaccines in protecting against noninvasive pneumonia. PMID- 25838268 TI - CTLA4 Immunoglobulin but Not Anti-Tumor Necrosis Factor Therapy Promotes Staphylococcal Septic Arthritis in Mice. AB - BACKGROUND: The development of biologics has greatly increased the quality of life and the life expectancy of many patients with rheumatoid arthritis. However, a large number of these patients have an increased risk of developing serious infections. The aim of this study was to examine differential effects of anti tumor necrosis factor (TNF) treatment and CTLA4 immunoglobulin (Ig) treatment on both immunological response and host defense in a murine model of septic arthritis. METHODS: Abatacept (CTLA4-Ig), etanercept (anti-TNF), or phosphate buffered saline were given to NMRI mice intravenously inoculated with Staphylococcus aureus. The clinical course of septic arthritis and histopathological and radiological changes of joints were compared among the groups. RESULTS: Mice receiving CTLA4-Ig treatment had more-severe septic arthritis, compared with controls and mice receiving anti-TNF treatment. Anti-TNF treatment led to more-severe weight loss and kidney abscesses, as well as a higher bacterial burden in the kidneys. Mice receiving CTLA4-Ig therapy had lower serum levels of interleukin 4, whereas mice receiving anti-TNF therapy had higher levels of TNF-alpha. Both iNOS and arginase-1 expression were reduced in peritoneal macrophages from mice receiving CTLA4-Ig, compared with expression in the anti-TNF group. CONCLUSIONS: CTLA4-Ig therapy significantly increased the susceptibility to S. aureus septic arthritis in mice, whereas anti-TNF therapy deteriorated host bacterial clearance, resulting in more-severe weight loss and kidney abscesses. PMID- 25838269 TI - Ebola Virus GP Gene Polyadenylation Versus RNA Editing. AB - Synthesis of Ebola virus (EBOV) surface glycoprotein (GP) is dependent on transcriptional RNA editing. Northern blot analysis of EBOV-infected cells using GP-gene-specific probes reveals that, in addition to full-length GP messenger RNAs (mRNAs), a shorter RNA is also synthesized, representing >40% of the total amount of GP mRNA. Sequence analysis demonstrates that this RNA is a truncated version of the full-length GP mRNA that is polyadenylated at the editing site and thus lacks a stop codon. An absence of detectable levels of protein synthesis in cellulo is consistent with the existence of tight regulation of the translation of such mRNA. However, nonstop GP mRNA was shown to be only slightly less stable than the same mRNA containing a stop codon, against the general belief in nonstop decay mechanisms aimed at detecting and destroying mRNAs lacking a stop codon. In conclusion, we demonstrate that the editing site indeed serves as a cryptic transcription termination/polyadenylation site, which rarely also functions to edit GP mRNA for expression of surface GP. This new data suggest that the downregulation of surface GP expression is even more dramatic than previously thought, reinforcing the importance of the GP gene editing site for EBOV replication and pathogenicity. PMID- 25838270 TI - Lack of Marburg Virus Transmission From Experimentally Infected to Susceptible In Contact Egyptian Fruit Bats. AB - Egyptian fruit bats (Rousettus aegyptiacus) were inoculated subcutaneously (n = 22) with Marburg virus (MARV). No deaths, overt signs of morbidity, or gross lesions was identified, but microscopic pathological changes were seen in the liver of infected bats. The virus was detected in 15 different tissues and plasma but only sporadically in mucosal swab samples, urine, and fecal samples. Neither seroconversion nor viremia could be demonstrated in any of the in-contact susceptible bats (n = 14) up to 42 days after exposure to infected bats. In bats rechallenged (n = 4) on day 48 after infection, there was no viremia, and the virus could not be isolated from any of the tissues tested. This study confirmed that infection profiles are consistent with MARV replication in a reservoir host but failed to demonstrate MARV transmission through direct physical contact or indirectly via air. Bats develop strong protective immunity after infection with MARV. PMID- 25838272 TI - Science literacy and beyond. PMID- 25838271 TI - Taoist Tai Chi(r) and Memory Intervention for Individuals with Mild Cognitive Impairment. AB - OBJECTIVE: It was hypothesized that a combined Taoist Tai Chi (TTC) and a memory intervention program (MIP) would be superior to a MIP alone in improving everyday memory behaviors in individuals with amnestic mild cognitive impairment (aMCI). A secondary hypothesis was that TTC would improve cognition, self-reported health status, gait, and balance. METHOD: A total of 48 individuals were randomly assigned to take part in MIP + TTC or MIP alone. The TTC intervention consisted of twenty 90 min sessions. Outcome measures were given at baseline, and after 10 and 22 weeks. RESULTS: Both groups significantly increased their memory strategy knowledge and use, ratings of physical health, processing speed, everyday memory, and visual attention. No preferential benefit was found for individuals in the MIP + TTC group on cognition, gait, or balance measures. CONCLUSIONS: Contrary to expectations, TTC exercise did not specifically improve cognition or physical mobility. Explanations for null findings are explored. PMID- 25838273 TI - Financial literacy: Do people know the ABCs of finance? AB - Increasingly, individuals are in charge of their own financial security and are confronted with ever more complex financial instruments. However, there is evidence that many individuals are not well-equipped to make sound saving decisions. This article looks at financial literacy, which is defined as the ability to process economic information and make informed decisions about financial planning, wealth accumulation, debt, and pensions. Failure to plan for retirement, lack of participation in the stock market, and poor borrowing behavior can all be linked to ignorance of basic financial concepts. Financial literacy impacts financial decision making, with implications that apply to individuals, communities, countries, and society as a whole. Given the lack of financial literacy among the population, it may be important to remedy it by adding financial literacy to the school curriculum. PMID- 25838274 TI - Does literacy improve finance? AB - When economists ask questions about basic financial principles, most ordinary people answer incorrectly. Economic experts call this condition "financial illiteracy," which suggests that poor financial outcomes are due to a personal deficit of reading-related skills. The analogy to reading is compelling because it suggests that we can teach our way out of population-wide financial failure. In this comment, we explain why the idea of literacy appeals to policy makers in the advanced industrial nations. But we also show that the narrow skill set laid out by economists does not satisfy the politically inclusive definition of literacy that literacy studies fought for. We identify several channels through which people engage with ideas about finance and demonstrate that not all forms of literacy will lead people to the educational content prescribed by academic economists. We argue that truly financial literate people can defy the demands of financial theory and financial institutions. PMID- 25838275 TI - Recurrent pregnancy loss: drop the heparin needles.... PMID- 25838276 TI - Endogenous miR-29a regulates HSC function in mammals. PMID- 25838277 TI - Platelet biogenesis wears silkworm cocoons. PMID- 25838278 TI - Ironing out the role of Toll-like receptors. PMID- 25838279 TI - Ibrutinib and idelalisib synergistically target BCR-controlled adhesion in MCL and CLL: a rationale for combination therapy. PMID- 25838280 TI - CALR-mutated essential thrombocythemia evolving to chronic myeloid leukemia with coexistent CALR mutation and BCR-ABL translocation. PMID- 25838281 TI - Bridging to transplant with azacitidine in juvenile myelomonocytic leukemia: a retrospective analysis of the EWOG-MDS study group. PMID- 25838282 TI - Unusual cause of acute abdomen in a child--torsion of greater omentum: report of two cases. AB - INTRODUCTION: Torsion of the omentum is twisting along its long axis and a rare cause of acute abdomen. Depending on associated conditions, it is classified as primary and secondary. It may mimic different pathologies presenting as acute abdomen, most common of them being acute appendicitis. Current choice for management of omental torsion is laparoscopic surgery. CASE PRESENTATION: We present two cases of omental torsion of two boys who presented with abdominal pain, nausea and vomiting and underwent emergency laparoscopy. CONCLUSION: Omental torsion is very rare, and its diagnosis is usually made only after surgery. At laparoscopy, omental torsion is suspected when the appendix is normal and the symptoms and findings of torsion are present. Laparoscopy is a safe and effective approach for the diagnosis and management of omental torsion, with the advantages of reduced postoperative pain and hospital stay. PMID- 25838285 TI - Enhancing Adoption of a Home-Based Exercise Program for Mild Balance Dysfunction: A Qualitative Study. AB - INTRODUCTION: The aim was to identify barriers and opportunities facing community health physiotherapists in delivering a home-based balance exercise program to address mild balance dysfunction and, secondly, to understand the perspectives of older people in adopting this program. METHOD: Focus groups, written surveys, and data recording sheets were used with nine older people and five physiotherapists. Focus groups were audio taped, transcribed, and coded independently by two researchers. RESULTS: Thematic content analysis was undertaken. Emerging themes were: engaging in preventive health (various benefits, enhancing independence); adoption of strategies (acceptable design and implementation feasibility); exercising in context (convenience, practicality, and safety); and broader implementation issues (program design, proactive health messages, and a solid evidence base). CONCLUSION: The views of older people and physiotherapists were sought to understand the adoption of a previously successful home-based program for mild balance dysfunction. Understanding the unique context and circumstances for individuals and organizations will enhance adoption. PMID- 25838284 TI - PLZF expression maps the early stages of ILC1 lineage development. AB - Among the variety of tissue-resident NK-like populations recently distinguished from recirculating classical NK (cNK) cells, liver innate lymphoid cells (ILC) type 1 (ILC1s) have been shown to represent a distinct lineage that originates from a novel promyelocytic leukaemia zinc finger (PLZF)-expressing ILC precursor (ILCP) strictly committed to the ILC1, ILC2, and ILC3 lineages. Here, using PLZF reporter mice and cell transfer assays, we studied the developmental progression of ILC1s and demonstrated substantial overlap with stages previously ascribed to the cNK lineage, including pre-pro-NK, pre-NK precursor (pre-NKP), refined NKP (rNKP), and immature NK (iNK). Although they originated from different precursors, the ILC1 and cNK lineages followed a parallel progression at early stages and diverged later at the iNK stage, with a striking predominance of ILC1s over cNKs early in ontogeny. Although a limited set of ILC1 genes depended on PLZF for expression, characteristically including Il7r, most of these genes were also differentially expressed between ILC1s and cNKs, indicating that PLZF together with other, yet to be defined, factors contribute to the divergence between these lineages. PMID- 25838283 TI - Toward major evolutionary transitions theory 2.0. AB - The impressive body of work on the major evolutionary transitions in the last 20 y calls for a reconstruction of the theory although a 2D account (evolution of informational systems and transitions in individuality) remains. Significant advances include the concept of fraternal and egalitarian transitions (lower level units like and unlike, respectively). Multilevel selection, first without, then with, the collectives in focus is an important explanatory mechanism. Transitions are decomposed into phases of origin, maintenance, and transformation (i.e., further evolution) of the higher level units, which helps reduce the number of transitions in the revised list by two so that it is less top-heavy. After the transition, units show strong cooperation and very limited realized conflict. The origins of cells, the emergence of the genetic code and translation, the evolution of the eukaryotic cell, multicellularity, and the origin of human groups with language are reconsidered in some detail in the light of new data and considerations. Arguments are given why sex is not in the revised list as a separate transition. Some of the transitions can be recursive (e.g., plastids, multicellularity) or limited (transitions that share the usual features of major transitions without a massive phylogenetic impact, such as the micro- and macronuclei in ciliates). During transitions, new units of reproduction emerge, and establishment of such units requires high fidelity of reproduction (as opposed to mere replication). PMID- 25838286 TI - Persistent and transient Helicobacter pylori infections in early childhood. AB - BACKGROUND: Helicobacter pylori, the main cause of peptic ulcer disease and gastric cancer in adult populations, is generally acquired during the first years of life. Infection can be persistent or transient and bacterial and host factors determining persistence are largely unknown and may prove relevant for future disease. METHODS: Two cohorts of healthy Chilean infants (313 total) were evaluated every 3 months for 18-57 months to determine pathogen- and host-factors associated with persistent and transient infection. RESULTS: One-third had at least one positive stool ELISA by age 3, with 20% overall persistence. Persistent infections were acquired at an earlier age, associated with more household members, decreased duration of breastfeeding, and nonsecretor status compared to transient infections. The cagA positive strains were more common in persistent stools, and nearly 60% of fully characterized persistent stool samples amplified cagA/vacAs1m1. Persistent children were more likely to elicit a serologic immune response, and both infection groups had differential gene expression profiles, including genes associated with cancer suppression when compared to healthy controls. CONCLUSIONS: These results indicate that persistent H. pylori infections acquired early in life are associated with specific host and/or strain profiles possibly associated with future disease occurrence. PMID- 25838287 TI - Evaluation of fingerstick cryptococcal antigen lateral flow assay in HIV-infected persons: a diagnostic accuracy study. AB - BACKGROUND: Cryptococcus neoformans is the most common cause of adult meningitis in sub-Saharan Africa. The cryptococcal antigen (CRAG) lateral flow assay (LFA) has simplified diagnosis as a point-of-care test approved for serum or cerebrospinal fluid (CSF). We evaluated the accuracy of the CRAG LFA using fingerstick whole blood compared with serum/plasma and CSF for diagnosing meningitis. METHODS: From August 2013 to August 2014, CRAG LFA (IMMY, Norman, Oklahoma) tests were performed on fingerstick whole blood, plasma/serum, and CSF in 207 HIV-infected adults with suspected meningitis in Kampala, Uganda. Venous blood was also collected and centrifuged to obtain serum and/or plasma. CSF was tested after lumbar puncture. RESULTS: Of 207 participants, 149 (72%) had fingerstick CRAG-positive results. There was 100% agreement between fingerstick whole blood and serum/plasma. Of the 149 fingerstick CRAG-positive participants, 138 (93%) had evidence of cryptococcal meningitis with a positive CSF CRAG. Eleven participants (5%) had isolated cryptococcal antigenemia with a negative CSF CRAG and culture, of whom 8 had CSF abnormalities (n = 3 lymphocytic pleocytosis, n = 5 elevated protein, n = 4 increased opening pressure). No persons with cryptococcal meningitis had negative fingersticks. CONCLUSIONS: The 100% agreement between whole blood, serum, and plasma CRAG LFA results demonstrates that fingerstick CRAG is a reliable bedside diagnostic test. Using point-of-care CRAG testing simplifies screening large numbers of patients and enables physicians to prioritize on whom to measure CSF opening pressure using manometers. PMID- 25838288 TI - Treatment Failure in HIV-Infected Children on Second-line Protease Inhibitor Based Antiretroviral Therapy. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected children failing second line antiretroviral therapy (ART) have no access to third-line antiretroviral drugs in many resource-limited settings. It is important to identify risk factors for second-line regimen failure. METHODS: HIV-infected children initiating protease inhibitor (PI)-containing second-line ART within the Program for HIV Prevention and Treatment observational cohort study in Thailand between 2002 and 2010 were included. Treatment failure was defined as confirmed HIV type 1 RNA load >400 copies/mL after at least 6 months on second-line regimen or death. Adherence was assessed by drug plasma levels and patient self-report. Cox proportional hazards regression analyses were used to identify risk factors for failure. RESULTS: A total of 111 children started a PI-based second-line regimen, including 59 girls (53%). Median first-line ART duration was 1.9 years (interquartile range [IQR], 1.4-3.3 years), and median age at second-line initiation was 10.7 years (IQR, 6.3-13.4 years). Fifty-four children (49%) experienced virologic failure, and 2 (2%) died. The risk of treatment failure 24 months after second-line initiation was 41%. In multivariate analyses, failure was independently associated with exposure to first-line ART for >2 years (adjusted hazard ratio [aHR], 1.8; P = .03), age >13 years (aHR, 2.9; P < .001), body mass index-for-age z score < -2 standard deviations at second-line initiation (aHR, 2.8; P = .03), and undetectable drug levels within 6 months following second-line initiation (aHR, 4.5; P < .001). CONCLUSIONS: Children with longer exposure to first-line ART, entry to adolescence, underweight, and/or undetectable drug levels were at higher risk of failing second-line ART and thus should be closely monitored. PMID- 25838289 TI - Dynamic Visual Display of Treatment Response in HIV-Infected Adults. AB - BACKGROUND: Using a dynamic visual display, we examine the changes in human immunodeficiency virus type 1 (HIV-1) plasma viral load and CD4 cell count for 5 years after antiretroviral therapy initiation in a large cohort of patients with HIV. METHODS: Patients at a Centers for AIDS Research Network of Integrated Clinical Systems site who initiated combination antiretroviral therapy between 1 January 2000 and 31 December 2012 were followed for 5 years for HIV-1 plasma viral load, CD4 cell count, and mortality. The joint distribution of CD4 cell count and viral load over time was depicted in an animated display using a bivariate kernel smoother. RESULTS: Within days of therapy initiation, many patients had a suppressed viral load and their median CD4 cell count had increased. However, the median CD4 cell count remained below normal levels throughout follow-up period and the proportion of patients with high viral load occasionally increased, even years after therapy initiation. CONCLUSIONS: The dramatic changes in viral load and CD4 cell count after therapy initiation highlight the overwhelming effectiveness of antiretroviral therapy in the modern era. However, this work also emphasizes the need for pharmaceutical or behavioral interventions to prevent virologic failure and to stimulate complete recovery of normal CD4 cell count. PMID- 25838290 TI - Differential B-cell memory around the 11-month booster in children vaccinated with a 10- or 13-valent pneumococcal conjugate vaccine. AB - BACKGROUND: Both the 10- and 13-valent pneumococcal conjugate vaccines (PCV10 and PCV13) induce immunological memory against Streptococcus pneumoniae infections caused by vaccine serotypes. In addition to comparing serum antibody levels, we investigated frequencies of serotype-specific plasma cells (PCs) and memory B cells (Bmems) as potential predictors of long-term immunity around the booster vaccination at 11 months of age. METHODS: Infants were immunized with PCV10 or PCV13 at 2, 3, 4, and 11 months of age. Blood was collected before the 11-month booster or 7-9 days afterward. Serotype-specific immunoglobulin G (IgG) levels were determined in serum samples by multiplex immunoassay. Circulating specific PCs and Bmems against shared serotypes 1, 6B, 7F, and 19F and against PCV13 serotypes 6A and 19A were measured in peripheral blood mononuclear cells by enzyme-linked immunospot assay. RESULTS: No major differences in IgG levels and PC frequencies between groups were found for the 4 shared serotypes. Notably, PCV13 vaccination resulted in higher frequencies of Bmems than PCV10 vaccination, both before and after the booster dose, for all 4 shared serotypes except for serotype 1 postbooster. For PCV13-specific serotypes 6A and 19A, the IgG levels and frequencies of PCs and Bmems were higher in the PCV13 group, pre- and postbooster, except for PC frequencies prebooster. CONCLUSIONS: Both PCVs are immunogenic and induce measurable IgG, PC, and Bmem booster responses at 11 months. Compared to PCV10, vaccination with PCV13 was associated with overall similar IgG levels and PC frequencies but with higher Bmem frequencies before and after the 11-month booster. The clinical implications of these results need further follow-up. CLINICAL TRIALS REGISTRATION: NTR3069. PMID- 25838292 TI - A new prognostic index for overall survival in malignant pleural mesothelioma: the rPHS (regimen, PS, histology or stage) index. AB - OBJECTIVE: Existing prognostic indices for malignant pleural mesothelioma do not incorporate the recent advances in oncology care. The purpose of this study was to provide a prognostic index for overall survival in malignant pleural mesothelioma patients treated with chemotherapy with pemetrexed or best supportive care in the recent clinical setting. METHODS: A retrospective cohort study was performed in two hospitals in Japan (2007-13). The primary outcome was overall survival. The Cox proportional hazards model was used for multivariable analyses to identify prognostic factors. A final model was chosen based on both clinical and statistical significance. RESULTS: A total of 283 patients (chemotherapy: n = 228, best supportive care: n = 55) were enrolled in the study. On multivariate analysis, regimen including platinum plus pemetrexed, a performance status >0, non-epithelial histological type and Stage IV disease predicted poor overall survival in chemotherapy patients. As hazard ratios of individual risk factors were approximately similar, a prognostic index for overall survival was constructed by counting the risk factors. Median overall survival in chemotherapy patients decreased by each one-point increase in this count: 1030 days for zero; 658 days for one; 373 days for two; 327 days for three; 125 days for four. Internal validation using the bootstrapping technique showed robustness of the model (c-index, 0.677; 95% confidence interval, 0.624 0.729). Further, the discrimination was consistent in best supportive care patients (c-index, 0.799; 95% confidence interval, 0.725-0.874). CONCLUSIONS: This novel index can provide clinicians and malignant pleural mesothelioma patients with a better framework for discussing prognosis at the time of diagnosis. PMID- 25838294 TI - Participation of Korean families at high risk for hereditary breast and ovarian cancer in BRCA1/2 genetic testing. AB - OBJECTIVE: The aim of our study was to determine the rate of participation in genetic testing, to determine the reasons for non-participation and to identify the factors affecting participation in BRCA genetic testing for high-risk patients. METHODS: This study was performed through a retrospective review of 804 individuals who underwent genetic counseling for BRCA1/2 gene mutations at Seoul National University Bundang Hospital between July 2003 and September 2012. RESULTS: In total, 728 (90.5%) individuals underwent BRCA1/2 mutation screening after the initial genetic counseling; 88.2% of 647 probands and 100% of 157 family members were screened. In multivariate analysis, family history of breast cancer and younger age were independent variables affecting participation in genetic testing. Of the 132 people who initially declined genetic testing, 58 (43.9%) postponed the decision, 30 (22.7%) needed time to discuss the issue with family members, 22 (16.7%) did not want to know if they had a BRCA1/2 mutation, and 22 (16.7%) declined the test because of financial problems. When analyzing refusal of testing according to the time period before and after the implementation of national health insurance coverage for BRCA1/2 genetic testing, the critical reason given for refusal was different. After insurance coverage, refusal for financial reason was decreased from 61.1 to 9.6%. CONCLUSIONS: A family history of breast cancer and a younger age were important factors associated with participation in genetic testing. National health insurance decreased the proportion of individuals who did not participate in testing owing to a financial reason. In genetic counseling, we have to understand these issues and consider several factors that may influence an individual's decision to be tested. PMID- 25838295 TI - Functional diversity of the superfamily of K+ transporters to meet various requirements. AB - The superfamily of K+ transporters unites proteins from plants, fungi, bacteria, and archaea that translocate K+ and/or Na+ across membranes. These proteins are key components in osmotic regulation, pH homeostasis, and resistance to high salinity and dryness. The members of the superfamily are closely related to K+ channels such as KcsA but also show several striking differences that are attributed to their altered functions. This review highlights these functional differences, focusing on the bacterial superfamily members KtrB, TrkH, and KdpA. The functional variations within the family and comparison to MPM-type K+ channels are discussed in light of the recently solved structures of the Ktr and Trk systems. PMID- 25838293 TI - Perioperative chemotherapy with ifosfamide and doxorubicin for high-grade soft tissue sarcomas in the extremities (JCOG0304). AB - OBJECTIVE: The efficacy of perioperative chemotherapy for soft tissue sarcomas is controversial and only a few prospective studies of pre-operative chemotherapy for soft tissue sarcomas in the extremities have been reported. We therefore carried out Phase II study of perioperative chemotherapy for patients with soft tissue sarcomas in the extremities. METHODS: Patients with Stage III non-round cell soft tissue sarcomas in the extremities were eligible. The patients were treated with pre-operative chemotherapy consisting doxorubicin 60 mg/m(2) and ifosfamide 10 g/m(2) for three courses. After the tumor resection, two additional courses of the same regimen were carried out. RESULTS: A total of 72 patients were enrolled and 70 patients were eligible. The median age of the patients was 49 years. The major pathological subtypes were synovial sarcoma in 20 and undifferentiated pleomorphic sarcoma in 17 patients. The protocol treatments were completed in 74% of the eligible cases. The 2 and 5-year progression-free survival rates were 75.7% (95% CI, 63.9-84.1%) and 63.8% (95% CI, 51.3-73.9%), respectively. The 5-year overall survival was 82.6% (95% CI, 71.3-89.7%). There was no treatment-related death. Grade 3 or 4 hematological toxicities (leukopenia and neutropenia) were observed in most of the patients. CONCLUSIONS: Although the toxicities of the regimen were significant, pre-operative chemotherapy followed by post-operative chemotherapy using doxorubicin and high-dose ifosfamide was feasible. The outcome of the trial for the patients with high-grade soft tissue sarcomas in the extremities was favorable, and this regimen is promising for further investigation. This trial was registered at the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) as C000000096. PMID- 25838296 TI - Preclinical development of a C6-ceramide NanoLiposome, a novel sphingolipid therapeutic. AB - Despite the therapeutic potential of sphingolipids, the ability to develop this class of compounds as active pharmaceutical ingredients has been hampered by issues of solubility and delivery. Beyond these technical hurdles, significant challenges in completing the necessary preclinical studies to support regulatory review are necessary for commercialization. This review seeks to identify the obstacles and potential solutions in the translation of a novel liposomal technology from the academic bench to investigational new drug (IND) stage by discussing the preclinical development of the Ceramide NanoLiposome (CNL), which is currently being developed as an anticancer drug for the initial indication of hepatocellular carcinoma (HCC). PMID- 25838297 TI - Hybrid rotors in F1F(o) ATP synthases: subunit composition, distribution, and physiological significance. AB - The c ring of the Na+ F1F(o) ATP synthase from the anaerobic acetogenic bacterium Acetobacterium woodii is encoded by three different genes: atpE1, atpE2 and atpE3. Subunit c1 is similar to typical V-type c subunits and has four transmembrane helices with one ion binding site. Subunit c2 and c3 are identical at the amino acid level and are typical F-type c subunits with one ion binding site in two transmembrane helices. All three constitute a hybrid F(o)V(o) c ring, the first found in nature. To analyze whether other species may have similar hybrid rotors, we searched every genome sequence publicly available as of 23 February 2015 for F1F(o) ATPase operons that have more than one gene encoding the c subunit. This revealed no other species that has three different c subunit encoding genes but twelve species that encode one F(o)- and one V(o)-type c subunit in one operon. Their c subunits have the conserved binding motif for Na+. The organisms are all anaerobic. The advantage of hybrid c rings for the organisms in their environments is discussed. PMID- 25838291 TI - In utero exposure to zidovudine and heart anomalies in the ANRS French perinatal cohort and the nested PRIMEVA randomized trial. AB - BACKGROUND: Antiretroviral (ARV) regimens during pregnancy are highly effective in preventing mother-to-child transmission of human immunodeficiency virus (HIV). Congenital heart defects (CHDs) and anomalies in cardiac function have been reported in zidovudine (ZDV)-exposed uninfected children. We explored these associations in a large observational cohort and a randomized clinical trial. METHODS: Since 1986, the French Perinatal Cohort prospectively enrolled all HIV infected women in 90 centers and collected follow-up on their children through 2 years of age. All CHDs were reviewed by a specialist blinded to exposures. Additionally, in a randomized trial (PRIMEVA ANRS 135) of 2 ARV regimens during pregnancy, 1 of which was without nucleoside reverse transcriptase inhibitors, infants had a specific follow-up including echocardiography at 1 month and 12 months. RESULTS: Among 12 888 children included, ZDV exposure in the first trimester was significantly associated with CHD (1.5% vs 0.7%; adjusted odds ratio, 2.2 [95% confidence interval, 1.3-3.7]; P < .001). This association was significant for ventricular septal defects (1.1% vs 0.6%; P = .001) and other CHDs (0.31% vs 0.11%; P = .02). In the randomized trial, among 50 infants, girls (but not boys) exposed in utero to ZDV/lamivudine/ritonavir-boosted lopinavir (LPV/r) had a higher left ventricular shortening fraction at 1 month (40% vs 36%; P = .008), and an increased posterior wall thickness at 1 year (5.4 mm vs 4.4 mm; P = .01) than the LPV/r group. CONCLUSIONS: This study confirms a specific association between in utero exposure to ZDV and CHDs, and a long-lasting postnatal myocardial remodeling in girls. A potential common mechanism, including the involvement of mitochondrial dysfunction, must be explored, and long-term consequences on cardiac function warrant specific attention. CLINICAL TRIALS REGISTRATION: NCT00424814. PMID- 25838298 TI - Sex workers, condoms, and mobility among men in Uzbekistan: implications for HIV transmission. AB - Uzbekistan has one of the fastest growing HIV epidemics in the world. In this study, men who reported mobility were compared to non-mobile men in regard to paying for sex and condom use during paid sex. The sample included 2333 men between the ages of 15 and 59 in Uzbekistan. Generalised linear models were used to assess the relationship between mobility, paid sex, and condom use while adjusting for possible confounders. Of the total sample, 103 (4.4%) reported engaging in paid sex and 43 (42%) reported using condoms while engaging in paid sex. Mobile men were found to have more than three times the odds of paid sex than non-mobile men (OR: 3.209; 95% CI: 2.481, 4.150; p < 0.001). Mobile men were not significantly different from non-mobile men in terms of condom use; however, unmarried men were found to have six times the odds of not using a condom when compared to married men during paid sex (OR: 6.411; 95% CI: 2.502, 16.425; p = 0.004). Only one of the men who reported paid sex also reported using a condom with their spouses at last intercourse. The findings contribute to understanding mobility and HIV risk, and have important implications for HIV prevention interventions. PMID- 25838299 TI - [Epilepsy and high frequency oscillation]. PMID- 25838300 TI - [Endoscopic endonasal extended transsphenoidal approach for parasellar tumors]. PMID- 25838301 TI - [Clinical feathers and treatment of peroneal nerve entrapment neuropathy]. AB - OBJECTIVE: Peroneal nerve entrapment neuropathy (PEN) is generally known as a drop foot with sensory disturbance. However, some patients experience numbness and pain in the affected area without severe paresis due to PEN. We report the clinical features and our surgical results of PEN cases. METHODS: We encountered 17 cases of PEN. The patients were 7 females and 10 males and their ages ranged from 30 to 78 years(average 56.1 years). In these cases, conservative therapy was unsuccessful;therefore, we performed surgical treatment for PEN. RESULTS: Among the 17 cases, 4 were of bilateral and 13 were of unilateral PEN. There was no severe paresis, as in drop foot;however, mild paresis (4/5, manual muscle test, MMT) was noted in 15 cases. In all cases, intermittent claudication presented, which ranged from 10 to 800 m (average 150 m). In 13 cases, radiological abnormality of the lumbar region was noted and 8 cases had a history of lumbar surgery (they had failed back surgery syndrome). In all the cases, we performed neurolysis of the peroneal nerve under local anesthesia;there was no surgical complication. After the surgery, symptoms improved, and the numerical rating of the lower limb improved from 8.6/10 to 0.8/10. Intermittent claudication also improved in all of the cases. CONCLUSIONS: We successfully treated 17 cases of PEN, which had lower limb pain without severe paresis, as in drop foot. Our results indicate that PEN should be recognized as a cause of intermittent claudication. Neurolysis for PEN under local anesthesia is less invasive and is useful for the treatment of lower limb pain. PMID- 25838302 TI - [Shunt passer clamp: a new device to prevent rotation of CSF-shunt passer]. AB - Cerebrospinal fluid shunting is a surgical treatment alternative for hydrocephalus. In general, ventriculoperitoneal (VP) and lumboperitoneal (LP) shunts have been widely practiced as standard procedures. However, these procedures are difficult because the shunt passer often rotates unintentionally. Therefore, we developed a simple device that prevents shunt passer rotation and termed it a "shunt passer-clamp"(SP-C). This device consists of two parts: the first part is the body with a hole through which the passer goes and a "female" screw perpendicular to the hole. The second part is a "male" screw set to the body. The surgeon can attach the SP-C to the shunt passer without the requirement for remodeling. We employed a SP-C for 14 consecutive shunt surgeries and received favorable feedback from the surgeons. Handling was considered "easy" in all cases. The surgical duration was significantly shorter than that if the SP-C was not employed. We conclude that our specially designed SP-C is relatively effective. PMID- 25838303 TI - [A significant increase in intraoperative flash visual evoked potential amplitude during craniopharyngioma surgery-case report]. AB - The flash visual evoked potential (VEP) is a useful diagnostic modality for visual preservation during surgery. Decreased VEP amplitude is recognized to indicate visual deterioration;however, whether intraoperative VEP can detect visual improvement remains unclear. We describe a craniopharyngioma case with a significant increase in VEP amplitude during surgery. A 67-year-old woman presented with progressive gait disturbance and impaired consciousness. Head magnetic resonance imaging demonstrated a sellar-suprasellar tumor compressing the optic chiasm upward with significant ventricular dilation. Her Glasgow Coma Scale was E3V3M5. Visual fields and acuity could not be examined because of impaired consciousness, and she could not see/recognize objects on a table. Preoperative VEP showed reproducible waveforms. Tumor removal by the extended transsphenoidal approach was performed with VEP monitoring. Increased VEP amplitude was observed after dural incision and persisted until the surgery ended. Postoperative VEP waveforms were also reproducible, but visual fields/acuity could not be examined because of cognitive dysfunction. Useful visual function was restored, and she became independent in daily life. The histological diagnosis was craniopharyngioma. The patient underwent ventriculo peritoneal shunting for hydrocephalus 16 days after tumor removal. The postoperative course was uneventful and she was transferred to another hospital for rehabilitation. Intraoperative VEP may indicate visual improvement during surgery, which is a useful objective assessment for visual function in patients with impaired consciousness and cognitive dysfunction. PMID- 25838304 TI - [Stent-assisted embolization for ruptured vertebral artery dissection involving the origin of the posterior inferior cerebellar artery:a case report of staged strategy]. AB - We report a ruptured vertebral artery dissection (VAD) involving the origin of the posterior inferior cerebellar artery(PICA)treated by a staged strategy with stent-assisted coil embolization. A 52-year-old woman was admitted with a ruptured right VAD involving the origin of the developed PICA. Endovascular internal trapping of the enlarged distal VAD was performed (Stage 1). After 1 month, following confirmation of platelet inhabitation (Stage 2) an Enterprise stent (Cordis Neurovascular, Miami Lakes, FL) placement from the PICA to the proximal VA with coil embolization for proximal VAD was performed under dual antiplatelet therapy. The dissected VA segment was occluded by coil embolization and the PICA was preserved. Advantages of this staged treatment are the avoidance of ischemic/hemorrhagic complications due to antithrombotic therapy when stent placement to the PICA is planned during the acute stage of SAH and confirmation of platelet inhabitation before stent placement in second treatment. VAD can be occluded, and this challenging endovascular treatment can be a therapeutic option for a ruptured VAD. PMID- 25838305 TI - [A case of atherothrombotic embolization developing with slowly progressive symptoms and requiring differential diagnosis from metastatic tumor recurrence]. AB - We report a case of atherothrombotic embolization that developed with slowly progressive symptoms and required differential diagnosis from metastatic tumor recurrence. A 64-year-old man with a history of lung cancer and metastatic brain tumor was carefully followed at our outpatient department for tumor recurrence. Five years after surgery for brain metastasis and whole brain radiation therapy, he had no recurrence and systemic disease was well controlled. At a routine follow up in October 2013, he complained of slight right arm dysesthesia. Follow up brain magnetic resonance (MR) imaging revealed no lesion. Two months later, he developed right hemiparesthesia and gait disturbance. Spinal MR imaging was unremarkable. However, at a routine follow up in January 2014, multiple enhancements were detected near the resection cavity and regions delineating the sulci. At first, this was diagnosed as tumor recurrence. However, 3 days later, additional MR imaging detected new multiple small infarctions after worsening right hemiparesis and dysarthria. With the diagnosis of embolic stroke, we searched for an embolic source. Cardiogenic embolization and carotid bifurcation stenosis studies were negative, but severe stenosis and thrombosis were detected near the left common carotid artery origin. This site was in the field of radiation the patient received as treatment for primary lung cancer. PMID- 25838306 TI - [Two cases of cerebral infarction due to focal irradiation for glioma in adults]. AB - Radiation-induced vasculopathy is a complication of radiation therapy. Most reports regarding post-irradiation ischemic stroke with intracranial tumors are restricted to pediatric cases. Here we report two adult cases of delayed brain infarction due to anterior and middle cerebral artery stenosis or occlusion seemingly caused by focal radiation therapy for malignant glioma. Although radiation-induced ischemic stroke in adults is relatively uncommon, it is possible that the morbidity rate of radiation-induced stroke in malignant glioma patients will increase with prolonged survival due to advances in therapy. Therefore, regular evaluation of intracranial vasculature following radiation therapy is necessary. PMID- 25838307 TI - [Rapid spontaneous resolution of acute epidural hematoma in an infant:a case report]. AB - Resolution of acute epidural hematoma (AEDH) usually takes several weeks. The authors present an infantile case of AEDH that rapidly decreased within a day and review the literature. A 7-month-old boy fell from a height of approximately one meter and sustained a head injury. On presentation, a skull fracture in the right temporoparietal region was found and a small AEDH was observed on computed tomography (CT) 1 hr after the injury. He was transferred to our institute because of growing AEDH, shown by CT images taken 3 hr after the injury. We decided to treat him conservatively as he did not exhibit any neurological deficits on admission. CT images 24hr after the injury showed significant reduction of the AEDH. There was also an increase in the subcutaneous hematoma. Follow-up CT images did not show enlargement of the AEDH. The patient was discharged with no neurological deficits 3 days after admission. Rapid resolution of the AEDH might have been due to transmigration of the hematoma into the epicranial layer through the fracture gap. PMID- 25838308 TI - [Required knowledge for stroke specialists (9) asymptomatic cerebrovascular diseases]. PMID- 25838309 TI - Correction. PMID- 25838310 TI - Response to: 'Does MOVES move the needle?' by Dr Meyer. PMID- 25838311 TI - Short-term intravenous sodium nitrite infusion improves cardiac and pulmonary hemodynamics in heart failure patients. AB - BACKGROUND: Nitrite exhibits hypoxia-dependent vasodilator properties, selectively dilating capacitance vessels in healthy subjects. Unlike organic nitrates, it seems not to be subject to the development of tolerance. Currently, therapeutic options for decompensated heart failure (HF) are limited. We hypothesized that by preferentially dilating systemic capacitance and pulmonary resistance vessels although only marginally dilating resistance vessels, sodium nitrite (NaNO2) infusion would increase cardiac output but reduce systemic arterial blood pressure only modestly. We therefore undertook a first-in-human HF proof of concept/safety study, evaluating the hemodynamic effects of short-term NaNO2 infusion. METHODS AND RESULTS: Twenty-five patients with severe chronic HF were recruited. Eight received short-term (5 minutes) intravenous NaNO2 at 10 MUg/kg/min and 17 received 50 MUg/kg/min with measurement of cardiac hemodynamics. During infusion of 50 MUg/kg/min, left ventricular stroke volume increased (from 43.22+/-21.5 to 51.84+/-23.6 mL; P=0.003), with marked falls in pulmonary vascular resistance (by 29%; P=0.03) and right atrial pressure (by 40%; P=0.007), but with only modest falls in mean arterial blood pressure (by 4 mm Hg; P=0.004). The increase in stroke volume correlated with the increase in estimated trans-septal gradient (=pulmonary capillary wedge pressure-right atrial pressure; r=0.67; P=0.003), suggesting relief of diastolic ventricular interaction as a contributory mechanism. Directionally similar effects were observed for the above hemodynamic parameters with 10 MUg/kg/min; this was significant only for stroke volume, not for other parameters. CONCLUSIONS: This first-in-human HF efficacy/safety study demonstrates an attractive profile during short-term systemic NaNO2 infusion that may be beneficial in decompensated HF and warrants further evaluation with longer infusion regimens. PMID- 25838313 TI - Naturally occurring deletions/insertions in HBV core promoter tend to decrease in hepatitis B e antigen-positive chronic hepatitis B patients during antiviral therapy. AB - BACKGROUND: Mutations in HBV core promoter (CP) are suggested to affect viral replication and disease progression. We investigated CP deletion/insertion mutations (Del/Ins) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients before and during antiviral treatment. METHODS: Direct and clone sequencings were used for detection of CP Del/Ins in 12 patients. The dynamic changes of CP Del/Ins were tracked in these cases until week 48 of treatment. The effects of Del/Ins on CP activities and hepatitis B X protein (HBx) were analysed using luciferase assay and sequence comparison, respectively. Furthermore, 292 untreated HBeAg-positive CHB cases were also analysed. RESULTS: Twelve cases with multi-peak PCR direct sequencing electropherograms at baseline were confirmed to have CP Del/Ins by clone sequencing, with detection rates varying from 14.8% to 93.3% of clones analysed. Follow-up studies showed the detection rates of CP Del/Ins in patients decreased from 100% (12/12) at baseline to 16.7% (2/12) at week 48 of treatment (P<0.001), in parallel with a decline in HBV DNA, hepatitis B surface antigen (HBsAg), alanine aminotransferase (ALT) and aspartate transaminase (AST) levels along with an increase in HBeAg loss. Luciferase assay results showed distinct promoter activities among Del/Ins-harbouring CP sequences. Importantly, 71.8% (148/206) of Del/Ins sequences potentially resulted in HBx carboxy-terminal truncations. CP Del/Ins mutations were also found in 27.4% (80/292) of untreated cases. CONCLUSIONS: Naturally occurring complex of CP Del/Ins mutants existed in untreated HBeAg-positive CHB patients. These mutations would affect HBV transcription activities and integrity of HBx, which might correlate with disease progression. Their prevalence decreases on antiviral therapy in parallel with the decline in HBV DNA, HBsAg and ALT and AST levels. PMID- 25838314 TI - Induction of tissue- and stressor-specific kinomic responses in chickens exposed to hot and cold stresses. AB - Defining cellular responses at the level of global cellular kinase (kinome) activity is a powerful approach to deciphering complex biology and identifying biomarkers. Here we report on the development of a chicken-specific peptide array and its application to characterizing kinome responses within the breast (pectoralis major) and thigh (iliotibialis) muscles of poultry subject to temperature stress to mimic conditions experienced by birds during commercial transport. Breast and thigh muscles exhibited unique kinome profiles, highlighting the distinct nature of these tissues. Against these distinct backgrounds, tissue- and temperature-specific kinome responses were observed. In breast, both cold and hot stresses activated calcium-dependent metabolic adaptations. Also within breast, but specific to cold stress, was the activation of ErbB signaling as well as dynamic patterns of phosphorylation of AMPK, a key regulatory enzyme of metabolism. In thigh, cold stress induced responses suggestive of the occurrence of tissue damage, including activation of innate immune signaling pathways and tissue repair pathways (TGF-beta). In contrast, heat stress in thigh activated pathways associated with protein and fat metabolism through adipocytokine and mammalian target of rapamycin (mTOR) signaling. Defining the responses of these tissues to these stresses through conventional markers of pH, glycolytic potential, and meat quality offered a similar conclusion of the tissue- and stressor-specific responses, validating the kinome results. Collectively, the results of this study highlight the unique cellular responses of breast and thigh tissues to heat and cold stresses and may offer insight into the unique susceptibilities, as well as functional consequences, of these tissues to thermal stress. PMID- 25838315 TI - Effects of outdoor access days on growth performance, carcass yield, meat quality, and lymphoid organ index of a local chicken breed. AB - An experiment was conducted to evaluate the effect of outdoor access days on growth performance, carcass yield, meat quality, and lymphoid organ index of a local chicken breed. In total, 864 twenty one-day-old male Suqin yellow chickens, with similar body weight (536+/-36g), were selected and raised in indoor floor pens that measured 1.42*1.42 m (2 m2, 18 birds/m2) in conventional poultry research houses (36 birds per pen). Two hundred and sixteen birds were allowed outdoor access treatments at 21, 28, 35, and 42 d of age, respectively (access to outdoor for 35, 28, 21, and 14 days, respectively). Each treatment was represented by 6 replicates (pens) containing 36 birds (216 birds per treatment). In the outdoor access treatment, the birds had an outdoor free-range paddock that measured 3*8 m (24 m2, 1.5 birds/m2). The body weight of birds at 56 d of age increased linearly with increasing outdoor access days (P<0.001), but there was no effect of the outdoor access days on the body weight at 42 d of age (P=0.161). The daily weight gain, daily feed intake, and feed per gain from 21 to 42 d of age were unaffected by outdoor access days (P=0.401, P=0.463, P=0.223, respectively). However, the daily weight gain and daily feed intake from 42 to 56 and from 21 to 56 d of age increased linearly with increasing outdoor access days (P=0.002, P<0.001; P=0.001, P=0.004; respectively), while the feed per gain tended to decrease linearly from 21 to 56 d of age (P=0.060). The mortality from 21 to 56 d of age was unaffected by outdoor access days (P=0.261). At 56 d of age, the breast yield increased linearly with increasing outdoor access days (P<0.001), while the foot yield decreased linearly (P=0.016). The light (L*) and red (b*) values of leg meat color increased linearly with increasing outdoor access days (P=0.032, P=0.013, respectively). The spleen: the body weight ratio showed a decreasing and then increasing quadratic response to increasing outdoor access days (P=0.047). The litter moisture content at 42 and 56 d of age increased linearly with increasing outdoor access days (P<0.001, P=0.013, respectively). The findings of this study suggest that increasing outdoor access days advantageously affects the body weight, daily weight gain, feed per gain and breast yield as well as the light (L*) and red (b*) values of leg meat color, while decreasing foot yield. PMID- 25838316 TI - Patients with biopsy-proven nephrosclerosis and moderately impaired renal function have a higher risk for cardiovascular disease: 15 years' experience in a single, kidney disease center. AB - BACKGROUND: Nephrosclerosis progresses slowly to end-stage renal disease (ESRD) in only a small percentage of patients. However, because hypertension and nephrosclerosis are normally found simultaneously, nephrosclerosis is a risk factor for cardiovascular disease (CVD). In turn, the onset of CVD may progress to further renal impairment. AIM: To evaluate clinical outcomes and the association between nephrosclerosis and CVD in the long term. DESIGN: Prospective study METHODS: We prospectively assessed 35 patients (male/female: 19/16) with nephrosclerosis aged >30 years at disease onset, attending the Kidney Disease Center, Saitama Medical University, in a single teaching hospital center between 1995 and 2014. Nephrosclerosis was diagnosed in accordance with the criteria outlined in the World Health Organization (WHO) monograph of renal diseases. All patients were followed by means of registries for 10 years to record subsequent events, if any. OUTCOMES: The primary study outcome was correlating the occurrence of CVD, defined as a composite of cardiovascular deaths, nonfatal and fatal myocardial infarction, and stroke, with the development of ESRD or death. RESULTS: The mean age of patients at the time of biopsy was 54.8 +/- 12.7 years (range 33-72 years). Of these patients, seven were affected by nonfatal CVD and two died due to CVD. Only one patient developed ESRD during the follow-up period. Using Kaplan-Meier analysis, risk factors for the primary study outcome were estimated to include an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), systolic blood pressure > 130 mmHg and proteinuria > 1 g/g creatinine. Univariate analysis was used for the assessment of the relative risk for the primary study endpoint of several covariates: age, systolic blood pressure, eGFR and proteinuria at time of renal biopsy. eGFR was found to be the strongest factor determining an event-free period [relative risk (RR) =1.931, p = 0.014]. CONCLUSIONS: Patients with nephrosclerosis are at high risk of CVD when they have moderately advanced renal impairment. PMID- 25838312 TI - Cytosolic phospholipase A2: physiological function and role in disease. AB - The group IV phospholipase A2 (PLA2) family is comprised of six intracellular enzymes (GIVA, -B, -C, -D, -E, and -F) commonly referred to as cytosolic PLA2 (cPLA2)alpha, -beta, -gamma, -delta, -epsilon, and -zeta. They contain a Ser-Asp catalytic dyad and all except cPLA2gamma have a C2 domain, but differences in their catalytic activities and subcellular localization suggest unique regulation and function. With the exception of cPLA2alpha, the focus of this review, little is known about the in vivo function of group IV enzymes. cPLA2alpha catalyzes the hydrolysis of phospholipids to arachidonic acid and lysophospholipids that are precursors of numerous bioactive lipids. The regulation of cPLA2alpha is complex, involving transcriptional and posttranslational processes, particularly increases in calcium and phosphorylation. cPLA2alpha is a highly conserved widely expressed enzyme that promotes lipid mediator production in human and rodent cells from a variety of tissues. The diverse bioactive lipids produced as a result of cPLA2alpha activation regulate normal physiological processes and disease pathogenesis in many organ systems, as shown using cPLA2alpha KO mice. However, humans recently identified with cPLA2alpha deficiency exhibit more pronounced effects on health than observed in mice lacking cPLA2alpha, indicating that much remains to be learned about this interesting enzyme. PMID- 25838317 TI - Characterization of depression among patients at urban primary healthcare centers in Oman. AB - AIM: The aim of this study was to estimate the prevalence and predictors of depression among Oman adult population attending primary healthcare clinics (PHCs) in Muscat Governorate in 2011. METHODOLOGY: A cross-sectional study was conducted on 2005 participants attending 27 different PHCs in Muscat Governorate during 2011. A Patient Health Questionnaire (PHQ-9), together with a socio demographic and relevant clinical data questionnaire was administered. RESULTS: Of the 2005 participants, 61.8% were women and 42.1% were of 25-50 age group. Of the total, 44.4% were employed, of whom 51% were government employees. The prevalence of depression among them was 8.1%. The adjusted odds ratios generated by logistic regression models indicated that depression was significantly associated with age greater than 50 years old (OR = 2.23; 95% CI 1.07, 4.22; P = 0.04), female (OR = 1.34; 95% CI 1.12, 3.82; P = 0.03), married (OR = 1.91; 95% CI 1.11, 3.30; P = 0.02), graduated or attended higher education (OR = 1.40; 95% CI 1.03, 2.66; P = 0.04), working in the private sector if employed (OR = 1.72; 95% CI 1.08, 2.75; P = 0.02), and having chronic illness such as diabetes mellitus, hypertension, asthma, heart, thyroid, and renal diseases (OR = 1.82; 95% CI 1.03, 3.51; P = 0.01). CONCLUSION: The rate of depression appears to be in the lower range compared to rate reported from elsewhere. Some socio-cultural factors that may contribute to the present findings are discussed. PMID- 25838318 TI - Self-image profile in children and adolescents with attention deficit/ hyperactivity disorder and the quality of life in their parents. AB - OBJECTIVE: We explored the impact of clinical response to treatment for Attention Deficit/Hyperactivity Disorder (ADHD) in children and adolescents on the subsequent changes in their self-image profile, the quality of life of their parents, and its effect on socio-demographic variables. METHOD: Conners Rating Scales for Parents (CPRS-R) and for Teachers (CTRS-R) completed at the time of entry to the service were repeated to measure clinical response to treatment; the Self-image Profiles for Children (SIP-C) and Adolescents (SIP-A), the World Health Organization Quality of Life (WHOQoL) questionnaire and postcode data were used to evaluate other domains. RESULTS: Data was collected for 53 boys (84%) and 10 girls (16%) with current mean age 11.5 years. Four-fifths (51/63) received pharmacological treatment and all parents were offered group parent training program. The only subscale in CPRS-R to show significance was the ADHD Index. The CTRS-R demonstrated statistically significant improvement (p < 0.01) in most subscales. On the Self-image Profile, children reported themselves as more Kind (p < 0.012), more Helpful (p < 0.038) and less Bossy (p < 0.047). Comparison of pre- and post-treatment scores on QoL revealed no significant changes; however, correlations of QoL responses against CPRS post-treatment revealed significant negative relationships in a number of instances. Parents living in less deprived areas felt their lives were more meaningful and less likely felt negatively about themselves (p = 0.04, N = 26, rho = 0.405). CONCLUSION: Clinical improvement in ADHD symptoms was positively correlated with some improvement in the Self-image Profile of children and adolescents, but its impact on the QoL in parents was limited. PMID- 25838319 TI - Atypical neuroleptic malignant syndrome in patients treated with aripiprazole and clozapine: a case-series study and short review. AB - OBJECTIVES: Neuroleptic malignant syndrome (NMS) requires emergency treatment and can be fatal. Combined aripiprazole and clozapine therapy is rarely used in clinical settings, and NMS related this combination still lacks evaluation. Herein, we present two cases of atypical NMS treated with aripiprazole and clozapine. METHODS: Case 1 was a schizophrenic male with a history of NMS under treatment with aripiprazole 20 mg. He was hospitalized and maintained with aripiprazole 5 mg and clozapine 225 mg. On the 25th day, atypical NMS occurred with rigidity, elevated creatine kinase, and stupor, which subsided with supportive therapy. He was discharged under treatment with aripiprazole 15 mg and fluoxetine 60 mg. Case 2 was a female with schizoaffective disorder without a history of NMS. She was hospitalized and maintained with clozapine 50 mg and aripirazole 30 mg. On the 11th day, atypical NMS occurred with mild fever, delirium, and rigidity, which subsided under supportive therapy. RESULTS AND CONCLUSIONS: Our cases highlight the atypical features of NMS in patients being treated with combined ari-piprazole and clozapine. Consciousness change, modest elevation of creatine kinase, and leukocytosis were the most consistent findings; hyperthermia accounts for only some of the cases. This is a reminder of the importance of earlier detection of the soft signs and atypical features of NMS under this combined treatment. PMID- 25838321 TI - Differences Between Patients that Made an Impulsive or Premeditated Suicide Attempt in a Mexican Population. AB - OBJECTIVE: We performed a study to identify differences between patients with impulsive suicide attempt and those with premeditated suicide attempt in a Mexican population. METHOD: We studied 144 patients who recently attempted suicide. Impulsive and premeditated suicide attempts were evaluated with the Suicide Intent Scale. These data were divided according to the type of attempt. Subsequently, the characteristics between the two groups were compared. RESULTS: The rate of patients that made an impulsive attempt was 61.8% and only 9.7% of the patients carried out a premeditated suicide attempt. More years of schooling/education and less severity of the attempt were observed in patients that carried out an impulsive suicide attempt (p < 0.001). Alcohol consumption (0.003) and use of cannabis (0.002) were present in patients who premeditated a suicide attempt. CONCLUSIONS: Our findings demonstrate that there are clinical differences among the individuals who carried out an impulsive suicide attempt from those who premeditated an attempt in a Mexican population. As a result, when planning interventions and prevention efforts it may be helpful to consider these clinical differences and demographic characteristics. PMID- 25838320 TI - Social and clinical descriptors of antipsychotic prescription. AB - OBJECTIVE: To identify descriptors of Antipsychotic (AP) prescription, focusing on second generation antipsychotics (SGAs), polypharmacy, and long-acting injections (LAIs). METHODS: Outpatients of the Bologna-Community-Mental-Health Centres with at least one AP prescription were selected. Patients' characteristics, service utilization, and AP prescriptions were collected from administrative databases. Prescriptions were grouped by class (SGA vs. First Generation Antipsychotics), drug combination (polypharmacy vs. monotherapy), and preparation (LAIs vs. regular administration). Multi-variate analyses were performed to identify prescription descriptors among socio-demographic and clinical variables. RESULTS: Among 6,074 patients and 41,121 AP prescriptions, SGAs were used in 70.7% of subjects, AP polypharmacy in 25.3%, and LAIs in 17.5%. SGAs were prescribed more often for young, Italian patients, with higher education, voluntary hospitalization, and high number of visits. Descriptors of AP polypharmacy were: high number of visits and hospitalization, length of treatment, non-urban residency, male gender, unemployment. Characteristics associated to LAI prescription were: long duration of treatment, high number of visits, compulsory admissions, non-Italian nationality, male gender, age > 34, low education, unmarried status. CONCLUSIONS: Besides illness severity, this study identified different socio-demographic descriptors of AP choices, raising concerns on the equity of treatments. Efforts should be directed to investigate appropriateness of AP treatments especially in social disadvantaged populations. PMID- 25838322 TI - BDNF promoter methylation associated with suicidal ideation in patients with breast cancer. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) has been considered a risk factor for suicidality. BDNF secretion is influenced by epigenetic (DNA methylation) and genetic (val66met polymorphism) profiles. We aimed to investigate the independent effects of BDNF promoter methylation status on suicidal ideation as well as the effects of its interaction with the val66met polymorphism in patients with breast cancer. METHODS: A total of279 patients with breast cancer were evaluated 1 week after breast surgery, and 244 (87%) were followed up 1 year later. Suicidal ideation was identified using the item addressing suicidal thoughts on the Beck Depression Inventory. The independent effects of BDNF methylation status on suicidal ideation at two points was investigated using multivariable logistic regression models. The two-way interactive effects of BDNF methylation status and the val66met polymorphism on suicidal ideation were also estimated using the same models. RESULTS: Increased BDNF methylation was significantly associated with suicidal ideation and depression 1 year after breast surgery, and this association was independent of potential covariates, including previous depression, current depressive symptoms, and BDNF genotype. No significant methylation-genotype interactions were found. CONCLUSIONS: The BDNF hypothesis and the epigenetic origin of suicidality in patients with breast cancer were supported. BDNF gene methylation status may be a biological marker for suicidality in patients with breast cancer. PMID- 25838323 TI - A guide to introducing and integrating reflective practices in medical education. AB - It is a significant challenge for any medical education program to provide adequate training in medical knowledge. It can be just as daunting to include appropriate opportunity to learn about and manage the emotional impact of illness experiences, the healing process, and provider-patient relationships. While there may be only a few basic changes to the core of medical knowledge, advances in medical practice regularly have an impact on the nature of patient care. Life long learning is essential to maintain one's competence. However, everything doctors and other medical professionals learn about relationships with patients during their training is relevant for the rest of their career. One primary source of this learning are reflective practices. However, there is no guide or description of or comparison among the distinguishing characteristics of reflective processes. In addition, there are no criteria for the selection or integration of reflective processes in medical training or beyond. This article proposes understanding reflection as a complex, three-level process and identifies dimensions which differentiate a variety of reflective process activities. The discussion includes considerations for selecting which activities might be usefully incorporated in education curricula, and identifies conditions of medical training cultures that will support successful integration. PMID- 25838324 TI - Seeing double: sertraline and diplopia: a case report. AB - OBJECTIVE: To describe the first case of sertraline-induced diplopia. METHOD: Medline and PubMed data search using the words sertraline, Zoloft, diplopia, double vision. A case summary of a patient who developed diplopia from sertraline. RESULT: This case describes a 34-year-old man who developed diplopia after treatment with sertraline. The diplopia resolved after discontinuation of sertraline and redeveloped upon rechallenge. CONCLUSION: Although incidences of diplopia caused by citalopram, another SSRI, have been described, to the best of our knowledge, this is the first reported case of sertraline-induced diplopia. More studies are needed to describe the full mechanism of action of sertraline induced diplopia. PMID- 25838325 TI - Effects of a native parasitic plant on an exotic invader decrease with increasing host age. AB - Understanding changes in the interactions between parasitic plants and their hosts in relation to ontogenetic changes in the hosts is crucial for successful use of parasitic plants as biological controls. We investigated growth, photosynthesis and chemical defences in different-aged Bidens pilosa plants in response to infection by Cuscuta australis. We were particularly interested in whether plant responses to parasite infection change with changes in the host plant age. Compared with the non-infected B. pilosa, parasite infection reduced total host biomass and net photosynthetic rates, but these deleterious effects decreased with increasing host age. Parasite infection reduced the concentrations of total phenolics, total flavonoids and saponins in the younger B. pilosa but not in the older B. pilosa. Compared with the relatively older and larger plants, younger and smaller plants suffered from more severe damage and are likely less to recover from the infection, suggesting that C. australis is only a viable biocontrol agent for younger B. pilosa plants. PMID- 25838326 TI - Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. PMID- 25838327 TI - Anguish, Yearning, and Identity: Toward a Better Understanding of the Pregnant Hispanic Woman's Prenatal Care Experience. AB - The purpose of this phenomenological study was to seek a better understanding of needs and access issues among pregnant, low-income Hispanic women. Hispanic women who attended a community prenatal education program participated in follow-up focus groups to explore their experiences regarding prenatal education, pregnancy resources, access to, and satisfaction with, the care available to them. Focus groups were facilitated by a leader, bilingual in English and Spanish, with knowledge of the Hispanic culture. Sessions were audiotaped, then translated into English for transcription. Data were analyzed according to guidelines by Colaizzi and three themes emerged: pregnant Hispanic women experienced a sense of anguish (la angustia) from questions and unknowns rampant during pregnancy, leading to a yearning (el anhelo) to learn and understand more, but with a desire to do so without sacrificing native identity (la identidad). Implications of these themes for improving prenatal care for this population are explored. PMID- 25838328 TI - Hot carriers in graphene. PMID- 25838329 TI - Weighing in on the body knowledge questionnaire: initial development and pilot testing. AB - PURPOSE: The purpose of this research was to develop and pilot test the Body Knowledge Questionnaire (BKQ), an instrument that measures weight management integration, and to determine its reliability and validity. METHODS: The 27 items of the BKQ were developed through review of the literature on integration and weight management/obesity. The resulting BKQ was pilot tested with 4 groups of individuals with and without type 2 diabetes. Exploratory factor analysis was used to assess the construct validity of the BKQ, and discriminant function analysis and logistic regression were used to establish criterion-related validity. Scale reliability analysis was used to determine the internal consistency of the BKQ and its subscales. RESULTS: Exploratory factor analysis yielded a 2-factor solution, with factor loadings that were fair to excellent (.45-.81). Discriminant function analysis determined that the BKQ subscales could accurately predict the classification of participants into normal- and obese weight groups. Results of the logistic regression showed that the BKQ could reliably distinguish between normal- and obese-weight participants. Internal consistency of the overall BKQ was .87, .89, and .73 for the subscales, Food Centricity and Psychosomatic Awareness. CONCLUSIONS: This research provided preliminary evidence of the validity (content, construct, and criterion) and reliability (internal consistency) of the BKQ. With additional psychometric testing, the BKQ instrument has great potential for use in weight management practice areas, such as diabetes education, dietetics, nursing, and psychology, for use in individual or group weight management programs and program evaluation; or in the development of novel weight management interventions. PMID- 25838330 TI - Primary Mixed Adenoneuroendocrine Carcinoma of the Gallbladder in a 55-Year-Old Female Patient: A Case Report and Review of the Literature. AB - Mixed adenoneuroendocrine carcinomas (MANECs) of the biliary tract are rare tumors, and to date only a few cases arising in the gallbladder have been reported. Their histogenesis is a matter of debate, since the biliary tract normally lacks neuroendocrine cells. However, the immunohistochemical identification of nonneoplastic neuroendocrine cells in both biliary adenocarcinomas and intestinal metaplasia has been documented. Here we report a case of a 55-year-old female patient presenting with right upper quadrant pain, cholelithiasis, and a gallbladder mass identified after cholecystectomy. The histopathologic examination showed a MANEC, composed of an intestinal-type adenocarcinoma and a large cell neuroendocrine carcinoma, arising in a background of enteric metaplasia with extensive high-grade dysplasia. Moreover, we report the presence of focal pancreatic intraepithelial neoplasia-like epithelial lesions, which has not been described for these tumors yet. The histopathologic features of this case provide further support for the theory that MANECs arise following a metaplasia-dysplasia-carcinoma pathway. PMID- 25838331 TI - Characterization of Fibromuscular Pseudocapsule in Renal Cell Carcinoma. AB - Pseudocapsule in renal cell carcinoma (RCC) has been described but little is known about its prevalence and extent. Pseudocapsule was analyzed in 105 RCCs (44 clear cell, 44 chromophobe, 17 papillary). Pseudocapsule was graded as follows: grade 1, thickness comparable to adjacent muscular arteries; grade 2, thickness more than twice the diameter of adjacent muscular arteries; grade 3, grade 2 findings with vasculopathy. Tumor size, tumor regression, and International Society of Urologic Pathology (ISUP) nucleolar grade were recorded. Cases with grade 3 pseudocapsule were stained with elastic silver stain, Alcian blue, smooth muscle actin, and CD31. More clear cell RCCs had pseudocapsule (89%, 39/44) than chromophobe (30%, 13/44) and papillary (35%, 6/17). Average tumor size with pseudocapsule was 3.9 cm; average tumor size without pseudocapsule was 3.8 cm (P = .77). Grade 2 pseudocapsule was common in clear cell RCC (56%, 22/39). Chromophobe and papillary RCC had grade 1 pseudocapsule in 77% (10/13) and 83% (5/6) of cases. Grade 3 pseudocapsule was only seen in clear cell RCC (10%, 4/39). No correlation was noted between degenerative tumor changes, tumor size, ISUP nucleolar grade, and presence and grade of pseudocapsule. Smooth muscle actin and CD31 showed abundant smooth muscle component and rich vasculature within the pseudocapsule. Arterial elastic membrane disruption and/or fibrointimal mucin deposits were present in grade 3 pseudocapsule. Thus, pseudocapsule is rather characteristic and more prominent in clear cell, less frequent in chromophobe, and rare in papillary RCC. Its presence may be evaluated radiologically or in biopsy specimens with scant tumor fragments. PMID- 25838332 TI - Optimal management of allergic rhinitis. AB - Allergic rhinitis (AR), the most common chronic disease in childhood is often ignored, misdiagnosed and/or mistreated. Undertreated AR impairs quality of life, exacerbates asthma and is a major factor in asthma development. It can involve the nose itself, as well as the organs connected with the nose manifesting a variety of symptoms. Evidence-based guidelines for AR therapy improve disease control. Recently, paediatric AR guidelines have been published by the European Academy of Allergy and Clinical Immunology and are available online, as are a patient care pathway for children with AR and asthma from the Royal College of Paediatrics and Child Health. Management involves diagnosis, followed by avoidance of relevant allergens, with additional pharmacotherapy needed for most sufferers. This ranges, according to severity, from saline sprays, through non sedating antihistamines, oral or topical, with minimally bioavailable intranasal corticosteroids for moderate/severe disease, possibly plus additional antihistamine or antileukotriene. The concept of rhinitis control is emerging, but there is no universally accepted definition. Where pharmacotherapy fails, allergen-specific immunotherapy, which is uniquely able to alter long-term disease outcomes, should be considered. The subcutaneous form (subcutaneous immunotherapy) in children has been underused because of concerns regarding safety and acceptability of injections. Sublingual immunotherapy is both efficacious and safe for grass pollen allergy. Further studies on other allergens in children are needed. Patient, carer and practitioner education into AR and its treatment are a vital part of management. PMID- 25838334 TI - Radiofrequency ablation changes the quality of life of children with supraventricular tachycardias. AB - OBJECTIVE: Radiofrequency ablation (RFA) has rapidly become the first-line therapy for children with supraventricular tachycardia (SVT). Recently, more attention has been given to the measurement of health-related quality of life (QoL) in children. The primary aim of this study was to determine if there is a change in the QoL in children with SVT pre and post RFA procedure using the Pediatric Quality of Life Inventory (PedsQL) cardiac inventory. In addition, the study discusses the impact of age, gender and variety of SVT mechanisms on the QoL. DESIGN, SETTING AND PATIENTS: All consecutive children with SVT referred for RFA at Mansoura University Children's Hospital were enrolled in this study. The PedsQL cardiac module questionnaire was given to the children/parents to be filled out before and 1 month following RFA procedure. Evaluated areas were physical, emotional, social, school and psychosocial function. The paired t test was used to test the difference between pre-time and post-time points for the study groups. Demographic and clinical data were collected. RESULTS: The study sample consisted of 38 patients who underwent a successful ablation. The mean age of the patients at the time of RFA procedure was 12.4+/-5.3 years. There was a statistically significant improvement in all measured areas 1 month post successful RFA as compared with pre ablation. Post ablation, the greatest score improvement was in physical functioning. Older children (>12 years) showed the greatest benefit, but gender and type of SVT did not influence outcome. CONCLUSIONS: RFA therapy is useful in improving QoL and perceptions in children with recurrent SVT. PMID- 25838333 TI - The role of infant appetite in extended formula feeding. AB - OBJECTIVE: Parental decision-making around extended formula feeding (12 months+) has not been explored previously. This study tested the hypotheses that extended formula milk use (i) is associated with poorer appetite and (ii) supplements lower food intake. METHODS: Appetite was assessed with the Child Eating Behaviour Questionnaire (CEBQ) in 3854 twin children aged 16 months. Diet was assessed from 3-day diaries in 2714 children at 21 months. Parents reported their children's weight at 24 months. Associations between formula feeding and (1) appetite, (2) energy intake and (3) weight were examined. 35 mothers were interviewed when the children were 7 years old to explore retrospectively their reasons for extended formula feeding. RESULTS: Formula consumers (13% of the sample) scored significantly differently than non-formula consumers on five of the six CEBQ subscales, indicating lower appetite avidity: 'food responsiveness' (2.02 vs 2.22, respectively),'enjoyment of food' (3.99 vs 4.20), 'satiety responsiveness' (2.89 vs 2.65), 'slowness in eating' (2.63 vs 2.46) and 'food fussiness' (2.34 vs 2.14). Formula consumers had a significantly lower percentage of daily energy intake from food (70% vs 74%); however, total daily energy intake did not differ significantly from non-consumers (4315 vs 4373 kJ). At interview, mothers reported supplementing their child's diet with formula because of 'picky eating' and concerns about inadequate food intake. CONCLUSIONS: High formula milk intake is associated with picky-eating behaviours, but seems to act as a substitute for rather than a supplement to solid food. Prospective and intervention studies are needed to determine whether extended formula feeding has an enduring impact on weight trajectories, eating behaviours or health. PMID- 25838335 TI - Individuals Poststroke Do Not Perceive Their Spatiotemporal Gait Asymmetries as Abnormal. AB - BACKGROUND: Following stroke, spatiotemporal gait asymmetries persist into the chronic phases, despite the neuromuscular capacity to produce symmetric walking patterns. This persistence of gait asymmetry may be due to deficits in perception, as the newly established asymmetric gait pattern is perceived as normal. OBJECTIVE: The purpose of this study was to determine the effect of usual overground gait asymmetry on the ability to consciously and unconsciously perceive the presence of gait asymmetry in people poststroke. DESIGN: An observational study was conducted. METHODS: Thirty people poststroke walked overground and on a split-belt treadmill with the belts moving at different speeds (0%-70% difference) to impose varied step length and stance time asymmetries. Conscious awareness and subconscious detection of imposed gait patterns were determined for each participant, and the asymmetry magnitudes at those points were compared with overground gait. RESULTS: For both spatial and temporal asymmetry variables, the asymmetry magnitude at the threshold of awareness was significantly greater than the asymmetry present at the threshold of detection or during overground gait. Participants appeared to identify belt speed differences using the type of gait asymmetry they typically exhibited (ie, step length or stance time asymmetries during overground gait). LIMITATIONS: Very few individuals with severe spatiotemporal asymmetry were tested, and participants were instructed to identify asymmetric belt speeds rather than interlimb movements. CONCLUSIONS: The data suggest that asymmetry magnitudes need to exceed usual overground levels to reach conscious awareness. Therefore, it is proposed that the spatiotemporal asymmetry that is specific to each participant may need to be augmented beyond what he or she usually has during walking in order to promote awareness of asymmetric gait patterns for long-term correction and learning. PMID- 25838336 TI - Discordance Between Distance Ambulated as Part of Usual Care and Functional Exercise Capacity in Survivors of Critical Illness Upon Intensive Care Discharge: Observational Study. AB - BACKGROUND: People who have had a prolonged admission to an intensive care unit (ICU) commonly have profound debilitation and weakness. For the delivery of effective exercise training, an accurate assessment of exercise capacity is essential. OBJECTIVE: The study objectives were to investigate how much ground based walking is undertaken by inpatients recovering from critical illness within 1 week of discharge from an ICU and to evaluate the feasibility and safety of the Six-Minute Walk Test (6MWT) for this population. DESIGN: This was an observational study. METHODS: Within 1 week of discharge from the ICU, functional exercise capacity was measured with the 6MWT. The maximum distance ambulated on the ward in a single session as part of usual clinical management was extracted from the medical notes. The distance achieved during the 6MWT and the maximum distance ambulated on the ward were compared. RESULTS: The participants (N=23) were survivors of a critical illness; their mean age was 57 years (SD=11). The median length of ICU stay was 11 days (interquartile range [IQR]=7). The mean 6 minute walk distance (6MWD) was 179 m (SD=101), and the maximum distance ambulated on the ward was 30 m (IQR=65). There was a moderate association between the distance participants ambulated on the ward and the 6MWD (r=.54). The maximum distance ambulated on the ward, expressed as a percentage of the 6MWD, was 29% (IQR=34%). Five participants (22%) experienced oxygen desaturation (oxygen saturation of <85%) and recovered within 1 minute of resting. LIMITATIONS: The maximum distance ambulated on the ward was estimated with premeasured distances. CONCLUSIONS: Most participants ambulated at a low percentage of their measured exercise capacity. The 6MWT appears to be a safe and useful test for inpatients recently discharged from the ICU. PMID- 25838337 TI - Influence of Physical Therapists' Kinesiophobic Beliefs on Lifting Capacity in Healthy Adults. AB - BACKGROUND: Physical therapists' recommendations to patients to avoid daily physical activity can be influenced by the therapists' kinesiophobic beliefs. Little is known about the amount of influence of a physical therapist's kinesiophobic beliefs on a patient's actual lifting capacity during a lifting test. OBJECTIVE: The objective of this study was to determine the influence of physical therapists' kinesiophobic beliefs on lifting capacity in healthy people. DESIGN: A blinded, cluster-randomized cross-sectional study was performed. METHODS: The participants (n=256; 105 male, 151 female) were physical therapist students who performed a lifting capacity test. Examiners (n=24) were selected from second-year physical therapist students. Participants in group A (n=124) were tested in the presence of an examiner with high scores on the Tampa Scale of Kinesiophobia for health care providers (TSK-HC), and those in group B (n=132) were tested in the presence of an examiner with low scores on the TSK-HC. Mixed model analyses were performed on lifting capacity to test for possible (interacting) effects. RESULTS: Mean lifting capacity was 32.1 kg (SD=13.6) in group A and 39.6 kg (SD=16.4) in group B. Mixed-model analyses revealed that after controlling for sex, body weight, self-efficacy, and the interaction between the examiners' and participants' kinesiophobic beliefs, the influence of examiners' kinesiophobic beliefs significantly reduced lifting capacity by 14.4 kg in participants with kinesiophobic beliefs and 8.0 kg in those without kinesiophobic beliefs. LIMITATIONS: Generalizability to physical therapists and patients with pain should be studied. CONCLUSIONS: Physical therapists' kinesiophobic beliefs negatively influence lifting capacity of healthy adults. During everyday clinical practice, physical therapists should be aware of the influence of their kinesiophobic beliefs on patients' functional ability. PMID- 25838338 TI - Predictors of vocational status in schizophrenia patients--Results from the Polish nationwide survey. AB - BACKGROUND: Steady employment constitutes one of most important aspects of functional recovery in schizophrenia. Therefore, there is a need for understanding clinical and demographic factors predicting vocational status in schizophrenia. METHODS: Clinical and demographic data of 1,010 schizophrenia patients were gathered from public outpatient clinics. We compared patients who maintained employment between the diagnosis time point and the day of assessment, with the patients who were employed in the diagnosis time point but were unemployed on the day of assessment with respect to clinical and demographic variables. RESULTS: Lower educational attainment, lower-income region of residence, medical comorbidities (obesity, diabetes and hypertension), first hospitalization at inpatient unit in comparison with the day hospital, higher total number of hospitalizations and the number of inpatient hospitalizations were found to serve as predictors of unemployment throughout the course of schizophrenia. After application of Bonferroni correction and logistic binary regression analysis, lower educational attainment, higher number of inpatient hospitalizations and obesity predicted unemployment. CONCLUSION: Education, obesity and the number of inpatient hospitalizations seem to predict vocational outcome in schizophrenia. This study warrants further investigation of medical comorbidities in schizophrenia in terms of social consequences in order to indicate the direction of this relationship. PMID- 25838339 TI - A longitudinal study of the health and wellbeing of culturally and linguistically diverse caregivers of people with psychosis in Australia. AB - BACKGROUND: Despite Australia being an ethnically diverse country, there are limited longitudinal studies of the health and wellbeing of culturally and linguistically diverse (CALD) carers of people with psychosis. An Australian population-based survey found that 22.7% of carers of people with mental disorders were born overseas. AIMS: This study aimed to explore the demographic profile, social connectedness, psychological health, quality of life, grief and caregiving consequences of CALD carers of people with psychosis over 12 months. METHOD: This longitudinal study utilised a prevalence survey design and recruited 52 CALD carers who were born in 24 countries outside Australia. A series of validated instruments were administered to assess carer health and wellbeing. RESULTS: Descriptive and inferential analysis of the results suggested that CALD carers experienced social isolation (34.7%), psychological distress (28.9%), moderate grief and caregiving consequences and poorer quality of life than the general population. Younger CALD carers and spouse carers experienced greater negative caregiving consequences than other kinship or friend carers. There were no significant changes in these outcomes over the 12-month period of the study. CONCLUSION: Ethnic-sensitive interventions are needed to better support CALD carers experiencing negative caregiving consequences, especially younger carers or spouses, within the current level of service provision. PMID- 25838340 TI - Response to "Clarification on Rotation Rates of Textured Breast Implants". PMID- 25838341 TI - T-shaped excision of the orbicularis oris muscle: an innovative technique for upper lip lift procedures. AB - BACKGROUND: The lips are a prominent part of the face and they age along with the face. Microsurgery for upper lip lifts is becoming popular because of its association with minimal trauma and rapid recovery. OBJECTIVES: The authors introduced an innovative method of lifting the upper lip. METHODS: From January 2009 to March 2013, a cohort of 30 women underwent an upper lip lift surgical procedure. Patients received local anesthesia for a regional block of the infraorbital nerve. A T-shaped orbicularis oris and a strip of skin were excised. The superior edge of the orbicularis oris muscle was sutured to the base of the nose, and the incision was closed with a continuous intradermal suture. Postoperative follow-up time ranged from 1 to 5 years. RESULTS: At the time of follow-up, the incisional scar was not visible on the patient. The nasolabial angle was 96.20 degrees +/- 1.86 degrees before operation and 88.23 degrees +/ 2.58 degrees after operation. The difference was statistically significant (P = 0.000 and P < 0.001). The upper lip angle was 65.56 degrees +/- 8.60 degrees before operation and 51.90 degrees +/- 3.93 degrees after operation. The difference was statistically significant (P = 0.000) and P < 0.001). After operation, the upper lip appeared to be clearly thickened. CONCLUSIONS: This innovative surgical technique is a simple and effective way to lift the upper lip. PMID- 25838342 TI - Treatment options for relapsed and refractory multiple myeloma. AB - Over the last few decades, significant improvement in outcomes has been observed for myeloma patients, mainly as a result of the use of currently available approved antimyeloma agents, along with combining autologous stem cell transplantation in the treatment of myeloma. With more targeted agents in development, the treatment of a myeloma patient at relapse has become complicated and, as a consequence, results in vast heterogeneity in treatment patterns. Although a consensus on the timing of initiation of treatment, the choice of agents to be used, and the role of transplant is less clear, we describe an evidence-based approach and the factors to consider upon relapse. We describe additional newer agents and targets that are under development, with the goal of achievement of durable remissions for myeloma patients. PMID- 25838343 TI - Pathogenesis beyond the cancer clone(s) in multiple myeloma. AB - Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. PMID- 25838344 TI - Smoldering multiple myeloma. AB - Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an >=80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM. PMID- 25838345 TI - Frontline therapy of multiple myeloma. AB - In the past decade, one of the major advances in the management of patients with symptomatic newly diagnosed multiple myeloma has been the introduction of novel agents, thalidomide, bortezomib, and lenalidomide, as part of frontline treatment in both transplant and nontransplant candidates. These drugs have markedly improved the rate of complete remission, and time to progression, progression free survival, and overall survival have significantly increased. This article focuses on more recent frontline therapeutic approaches both in older patients, not eligible for high-dose therapy and autologous stem cell transplantation (ASCT), and in younger patients eligible for early ASCT. PMID- 25838347 TI - Introduction to a series of reviews on multiple myeloma. PMID- 25838346 TI - New criteria for response assessment: role of minimal residual disease in multiple myeloma. AB - Assessment of minimal residual disease (MRD) is becoming standard diagnostic care for potentially curable neoplasms such as acute lymphoblastic leukemia. In multiple myeloma (MM), the majority of patients will inevitably relapse despite achievement of progressively higher complete remission (CR) rates. Novel treatment protocols with inclusion of antibodies and small molecules might well be able to further increase remission rates and potentially also cure rates. Therefore, MRD diagnostics becomes essential to assess treatment effectiveness. This review summarizes reports from the past 2 decades, which demonstrate that persistent MRD by multiparameter flow cytometry, polymerase chain reaction, next generation sequencing, and positron emission tomography/computed tomography, predicts significantly inferior survival among CR patients. We describe the specific features of currently available techniques for MRD monitoring and outline the arguments favoring new criteria for response assessment that incorporate MRD levels. Extensive data indicate that MRD information can potentially be used as biomarker to evaluate the efficacy of different treatment strategies, help on treatment decisions, and act as surrogate for overall survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in MM, which implies systematic usage of highly sensitive, cost-effective, readily available, and standardized MRD techniques. PMID- 25838348 TI - FlnA binding to PACSIN2 F-BAR domain regulates membrane tubulation in megakaryocytes and platelets. AB - Bin-Amphiphysin-Rvs (BAR) and Fes-CIP4 homology BAR (F-BAR) proteins generate tubular membrane invaginations reminiscent of the megakaryocyte (MK) demarcation membrane system (DMS), which provides membranes necessary for future platelets. The F-BAR protein PACSIN2 is one of the most abundant BAR/F-BAR proteins in platelets and the only one reported to interact with the cytoskeletal and scaffold protein filamin A (FlnA), an essential regulator of platelet formation and function. The FlnA-PACSIN2 interaction was therefore investigated in MKs and platelets. PACSIN2 associated with FlnA in human platelets. The interaction required FlnA immunoglobulin-like repeat 20 and the tip of PACSIN2 F-BAR domain and enhanced PACSIN2 F-BAR domain membrane tubulation in vitro. Most human and wild-type mouse platelets had 1 to 2 distinct PACSIN2 foci associated with cell membrane GPIbalpha, whereas Flna-null platelets had 0 to 4 or more foci. Endogenous PACSIN2 and transfected enhanced green fluorescent protein-PACSIN2 were concentrated in midstage wild-type mouse MKs in a well-defined invagination of the plasma membrane reminiscent of the initiating DMS and dispersed in the absence of FlnA binding. The DMS appeared less well defined, and platelet territories were not readily visualized in Flna-null MKs. We conclude that the FlnA-PACSIN2 interaction regulates membrane tubulation in MKs and platelets and likely contributes to DMS formation. PMID- 25838349 TI - Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs. AB - The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-kappaB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease. PMID- 25838350 TI - Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency. AB - Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia. PMID- 25838351 TI - Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia. AB - Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion. Herein we show the combination of selinexor and ibrutinib elicits a synergistic cytotoxic effect in primary CLL cells and increases overall survival compared with ibrutinib alone in a mouse model of CLL. Selinexor is effective in cells isolated from patients with prolonged lymphocytosis following ibrutinib therapy. Finally, selinexor is effective in ibrutinib-refractory mice and in a cell line harboring the BTK C481S mutation. This is the first report describing the combined activity of ibrutinib and selinexor in CLL, which represents a new treatment paradigm and warrants further evaluation in clinical trials of CLL patients including those with acquired ibrutinib resistance. PMID- 25838352 TI - In vivo delivery of functional Flightless I siRNA using layer-by-layer polymer surface modification. AB - Gene silencing using small interfering RNA has been proposed as a therapy for cancer, viral infections and other diseases. This study aimed to investigate whether layer-by-layer polymer surface modification could deliver small interfering RNA to decrease fibrotic processes associated with medical device implantation. Anti-green fluorescent protein labelled small interfering RNA was applied to tissue culture plates and polyurethane using a layer-by-layer technique with small interfering RNA and poly-L-lysine. In vitro studies showed that the level of down-regulation of green fluorescent protein was directly related to the number of coatings applied. This layer-by-layer coating technique was then used to generate Rhodamine-Flii small interfering RNA-coated implants for in vivo studies of small interfering RNA delivery via subcutaneous implantation in mice. After two days, Rh-positive cells were observed on the implants' surface indicating cellular uptake of the Rhodamine-Flii small interfering RNA. Decreased Flii gene expression was observed in tissue surrounding the Rhodamine-Flii small interfering RNA coated implants for up to seven days post implantation, returning to baseline by day 21. Genes downstream from Flii, including TGF-beta1 and TGF-beta3, showed significantly altered expression confirming a functional effect of the Rhodamine-Flii small interfering RNA on gene expression. This research demonstrates proof-of-principle that small interfering RNA can be delivered via layer-by-layer coatings on biomaterials and thereby can alter the fibrotic process. PMID- 25838353 TI - Codelivery of paclitaxel and small interfering RNA by octadecyl quaternized carboxymethyl chitosan-modified cationic liposome for combined cancer therapy. AB - Conventional therapeutic approaches for cancer are limited by cancer cell resistance, which has impeded their clinical applications. The main goal of this work was to investigate the combined antitumor effect of paclitaxel with small interfering RNA modified by cationic liposome formed from modified octadecyl quaternized carboxymethyl chitosan. The cationic liposome was composed of 3beta [N-(N', N'-dimethylaminoethane)-carbamoyl]-cholesterol, dioleoylphosphatidylethanolamine, and octadecyl quaternized carboxymethyl chitosan. The cationic liposome properties were characterized by Fourier transform infrared spectroscopy, dynamic light scattering and zeta potential measurements, transmission electron microscopy, atomic force microscopy, and gel retardation assay. The cationic liposome exhibited good properties, such as a small particle size, a narrow particle size distribution, a good spherical shape, a smooth surface, and a good binding ability with small interfering RNA. Most importantly, when combined with paclitaxel and small interfering RNA, the composite cationic liposome induced a great enhancement in the antitumor activity, which showed a significantly higher in vitro cytotoxicity in Bcap-37 cells than liposomal paclitaxel or small interfering RNA alone. In conclusion, the results indicate that cationic liposome could be further developed as a codelivery system for chemotherapy drugs and therapeutic small interfering RNAs. PMID- 25838354 TI - Risk of developing diabetes increases with time spent watching TV, study shows. PMID- 25838355 TI - A community for disaster science. PMID- 25838357 TI - Reproductive medicine. Eggs' power plants energize new IVF debate. PMID- 25838358 TI - Toxicology. A child-killing toxin emerges from shadows. PMID- 25838359 TI - Marine science. 'The Blob' invades Pacific, flummoxing climate experts. PMID- 25838360 TI - Scientific publishing. Hoax-detecting software spots fake papers. PMID- 25838361 TI - Infectious diseases. As Ebola wanes, trials jockey for patients. PMID- 25838362 TI - Deepwater Horizon: after the oil. PMID- 25838363 TI - Critics question plans to spray dispersant in future deep spills. PMID- 25838365 TI - Geology. Defining the epoch we live in. PMID- 25838366 TI - Tribology. Tracking antiwear film formation. PMID- 25838367 TI - Gene expression. MicroRNAs silence the noisy genome. PMID- 25838368 TI - Psychology. Infants explore the unexpected. PMID- 25838369 TI - Astronomy. How young stars grow and become focused. PMID- 25838370 TI - Immunology. MULT1plying cancer immunity. PMID- 25838371 TI - Vaccine testing. Ebola and beyond. PMID- 25838372 TI - Cancer immunology and immunotherapy. Realizing the promise. Introduction. PMID- 25838373 TI - The future of immune checkpoint therapy. AB - Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients. PMID- 25838374 TI - Adoptive cell transfer as personalized immunotherapy for human cancer. AB - Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment. PMID- 25838375 TI - Neoantigens in cancer immunotherapy. AB - The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens. PMID- 25838376 TI - T cell exclusion, immune privilege, and the tumor microenvironment. AB - Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy. PMID- 25838378 TI - Cognitive development. Observing the unexpected enhances infants' learning and exploration. AB - Given the overwhelming quantity of information available from the environment, how do young learners know what to learn about and what to ignore? We found that 11-month-old infants (N = 110) used violations of prior expectations as special opportunities for learning. The infants were shown events that violated expectations about object behavior or events that were nearly identical but did not violate expectations. The sight of an object that violated expectations enhanced learning and promoted information-seeking behaviors; specifically, infants learned more effectively about objects that committed violations, explored those objects more, and engaged in hypothesis-testing behaviors that reflected the particular kind of violation seen. Thus, early in life, expectancy violations offer a wedge into the problem of what to learn. PMID- 25838377 TI - Cancer and the microbiota. AB - A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications. PMID- 25838379 TI - Ribosome. The structure of the human mitochondrial ribosome. AB - The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. The head domain of the small subunit, particularly the messenger (mRNA) channel, is highly remodeled. Many intersubunit bridges are specific to the mitoribosome, which adopts conformations involving ratcheting or rolling of the small subunit that are distinct from those seen in bacteria or eukaryotes. An intrinsic guanosine triphosphatase mediates a contact between the head and central protuberance. The structure provides a reference for analysis of mutations that cause severe pathologies and for future drug design. PMID- 25838380 TI - Molecular physics. Production of trilobite Rydberg molecule dimers with kilo Debye permanent electric dipole moments. AB - Permanent electric dipole moments are important for understanding symmetry breaking in molecular physics, control of chemical reactions, and realization of strongly correlated many-body quantum systems. However, large molecular permanent electric dipole moments are challenging to realize experimentally. We report the observation of ultralong-range Rydberg molecules with bond lengths of ~100 nanometers and kilo-Debye permanent electric dipole moments that form when an ultracold ground-state cesium (Cs) atom becomes bound within the electronic cloud of an extended Cs electronic orbit. The electronic character of this hybrid class of "trilobite" molecules is dominated by degenerate Rydberg manifolds, making them difficult to produce by conventional photoassociation. We used detailed coupled-channel calculations to reproduce their properties quantitatively. Our findings may lead to progress in ultracold chemistry and strongly correlated many body physics. PMID- 25838381 TI - Frustrated magnetism. Large thermal Hall conductivity of neutral spin excitations in a frustrated quantum magnet. AB - In frustrated quantum magnets, long-range magnetic order fails to develop despite a large exchange coupling between the spins. In contrast to the magnons in conventional magnets, their spin excitations are poorly understood. Here, we show that the thermal Hall conductivity kappa(xy) provides a powerful probe of spin excitations in the "quantum spin ice" pyrochlore Tb2Ti2O7. The thermal Hall response is large, even though the material is transparent. The Hall response arises from spin excitations with specific characteristics that distinguish them from magnons. At low temperature (<1 kelvin), the thermal conductivity resembles that of a dirty metal. Using the Hall angle, we construct a phase diagram showing how the excitations are suppressed by a magnetic field. PMID- 25838382 TI - Thermoelectrics. Dense dislocation arrays embedded in grain boundaries for high performance bulk thermoelectrics. AB - The widespread use of thermoelectric technology is constrained by a relatively low conversion efficiency of the bulk alloys, which is evaluated in terms of a dimensionless figure of merit (zT). The zT of bulk alloys can be improved by reducing lattice thermal conductivity through grain boundary and point-defect scattering, which target low- and high-frequency phonons. Dense dislocation arrays formed at low-energy grain boundaries by liquid-phase compaction in Bi(0.5)Sb(1.5)Te3 (bismuth antimony telluride) effectively scatter midfrequency phonons, leading to a substantially lower lattice thermal conductivity. Full spectrum phonon scattering with minimal charge-carrier scattering dramatically improved the zT to 1.86 +/- 0.15 at 320 kelvin (K). Further, a thermoelectric cooler confirmed the performance with a maximum temperature difference of 81 K, which is much higher than current commercial Peltier cooling devices. PMID- 25838383 TI - Stellar physics. Observing the onset of outflow collimation in a massive protostar. AB - The current paradigm of star formation through accretion disks, and magnetohydrodynamically driven gas ejections, predicts the development of collimated outflows, rather than expansion without any preferential direction. We present radio continuum observations of the massive protostar W75N(B)-VLA 2, showing that it is a thermal, collimated ionized wind and that it has evolved in 18 years from a compact source into an elongated one. This is consistent with the evolution of the associated expanding water-vapor maser shell, which changed from a nearly circular morphology, tracing an almost isotropic outflow, to an elliptical one outlining collimated motions. We model this behavior in terms of an episodic, short-lived, originally isotropic ionized wind whose morphology evolves as it moves within a toroidal density stratification. PMID- 25838384 TI - Plant biology. Suppression of endogenous gene silencing by bidirectional cytoplasmic RNA decay in Arabidopsis. AB - Plant immunity against foreign gene invasion takes advantage of posttranscriptional gene silencing (PTGS). How plants elaborately avert inappropriate PTGS of endogenous coding genes remains unclear. We demonstrate in Arabidopsis that both 5'-3' and 3'-5' cytoplasmic RNA decay pathways act as repressors of transgene and endogenous PTGS. Disruption of bidirectional cytoplasmic RNA decay leads to pleiotropic developmental defects and drastic transcriptomic alterations, which are substantially rescued by PTGS mutants. Upon dysfunction of bidirectional RNA decay, a large number of 21- to 22-nucleotide endogenous small interfering RNAs are produced from coding transcripts, including multiple microRNA targets, which could interfere with their cognate gene expression and functions. This study highlights the risk of unwanted PTGS and identifies cytoplasmic RNA decay pathways as safeguards of plant transcriptome and development. PMID- 25838385 TI - Gene expression. MicroRNA control of protein expression noise. AB - MicroRNAs (miRNAs) repress the expression of many genes in metazoans by accelerating messenger RNA degradation and inhibiting translation, thereby reducing the level of protein. However, miRNAs only slightly reduce the mean expression of most targeted proteins, leading to speculation about their role in the variability, or noise, of protein expression. We used mathematical modeling and single-cell reporter assays to show that miRNAs, in conjunction with increased transcription, decrease protein expression noise for lowly expressed genes but increase noise for highly expressed genes. Genes that are regulated by multiple miRNAs show more-pronounced noise reduction. We estimate that hundreds of (lowly expressed) genes in mouse embryonic stem cells have reduced noise due to substantial miRNA regulation. Our findings suggest that miRNAs confer precision to protein expression and thus offer plausible explanations for the commonly observed combinatorial targeting of endogenous genes by multiple miRNAs, as well as the preferential targeting of lowly expressed genes. PMID- 25838387 TI - A career is like a love affair. PMID- 25838386 TI - Epigenetics. Restricted epigenetic inheritance of H3K9 methylation. AB - Posttranslational histone modifications are believed to allow the epigenetic transmission of distinct chromatin states, independently of associated DNA sequences. Histone H3 lysine 9 (H3K9) methylation is essential for heterochromatin formation; however, a demonstration of its epigenetic heritability is lacking. Fission yeast has a single H3K9 methyltransferase, Clr4, that directs all H3K9 methylation and heterochromatin. Using releasable tethered Clr4 reveals that an active process rapidly erases H3K9 methylation from tethering sites in wild-type cells. However, inactivation of the putative histone demethylase Epe1 allows H3K9 methylation and silent chromatin maintenance at the tethering site through many mitotic divisions, and transgenerationally through meiosis, after release of tethered Clr4. Thus, H3K9 methylation is a heritable epigenetic mark whose transmission is usually countered by its active removal, which prevents the unauthorized inheritance of heterochromatin. PMID- 25838388 TI - MRI RF array decoupling method with magnetic wall distributed filters. AB - Multi-channel radio-frequency (RF) transmit coil arrays have been developed to mitigate many of the RF challenges associated with ultra-high field ( >= 7T) magnetic resonance imaging (MRI). These arrays can be used for parallel RF transmission to produce spatially tailored RF excitation over the field of view. However, the realization of such arrays remains a challenge due to significant reactive interaction between the array coils, i.e., mutual coupling. In this paper, a novel bandstop filter ("magnetic wall") is used in an MRI RF transmit array to decouple individual coils. The proposed decoupling method is inspired by periodic resonator designs commonly used in frequency selective surfaces and is used as a distributed RF filter to suppress the transmission of RF energy between coils in an array. The decoupling of the magnetic wall (MW) is analyzed in terms of equivalent circuits that include terms for both magnetic and electric coupling for an arbitrary number of MW resonant conductors. Both frequency-and time-domain full-wave simulations were performed to analyze a specific MW structure. The performance of the proposed method is experimentally validated for both first order coupling and higher-order coupling with a three-coil 7T array setup. Analysis and measurements confirm that the rejection band of the MW can be tuned to provide high isolation in the presence of cross coupling between RF array coils. PMID- 25838389 TI - Maternal blood test is more effective than standard screening for Down's syndrome, study shows. PMID- 25838390 TI - Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas. AB - PURPOSE: Novel therapeutic approaches are needed to improve the postoperative management of residual nonfunctioning pituitary adenomas (NFPA), given their high relapse rate. Here, we evaluated the antitumor efficacy of the dual PI3K/mTOR inhibitor NVP-BEZ235 in the only available model of spontaneous NFPAs (MENX rats). EXPERIMENTAL DESIGN: Organotypic cultures of rat primary NFPAs were incubated with NVP-BEZ235 and assessed for cell viability, proliferation, apoptosis, and PI3K/mTOR inhibition. NVP-BEZ235, or placebo, was administered to MENX rats and tumor response was monitored noninvasively by diffusion weighted magnetic resonance imaging (DW-MRI). Following treatment, tumor tissues were investigated for cell proliferation, apoptosis, and PI3K/mTOR inhibition. Genes mediating the cytotoxic activity of NVP-BEZ235 were identified by gene-expression profiling. Among them, Defb1, encoding beta-defensin 1, was further studied for its role in pituitary cells and in human pancreatic neuroendocrine tumor (NET) cells. RESULTS: NVP-BEZ235 showed antiproliferative and pro-cell death activities against NFPAs both in vitro and in vivo, and the response to the drug correlated with inhibition of the PI3K pathway. DW-MRI identified early functional changes (decreased cellularity) in the adenomas before their size was affected and emerged as a useful modality to assess therapy response. The cytotoxic effect of PI3K/mTOR blockade in NFPA was mediated by several genes, including Defb1. NVP BEZ235 treatment induced Defb1 expression in NFPAs in vitro and in vivo, and in pancreatic NET cells. High Defb1 levels sensitized NET cells to PI3K/mTOR inhibition. CONCLUSIONS: Our findings provide rationale for clinical investigation of PI3K/mTOR inhibition in NFPAs and identify novel effectors of PI3K-mediated neuroendocrine cell survival. PMID- 25838391 TI - Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab. AB - PURPOSE: In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance. EXPERIMENTAL DESIGN: We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR). RESULTS: Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation. CONCLUSIONS: The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients. PMID- 25838392 TI - CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19 Redirected CMV-Specific T Cells. AB - PURPOSE: T cells engineered with chimeric antigen receptors (CAR) recognizing CD19 can induce complete remission of B-cell malignancies in clinical trials; however, in some disease settings, CAR therapy confers only modest clinical benefit due to attenuated persistence of CAR T cells. The purpose of this study was to enhance persistence and augment the antitumor activity of adoptively transferred CD19CAR T cells by restimulating CAR(+) T cells through an endogenous cytomegalovirus (CMV)-specific T-cell receptor. EXPERIMENTAL DESIGN: CMV-specific T cells from CMV seropositive healthy donors were selected after stimulation with pp65 protein and transduced with clinical-grade lentivirus expressing the CD19R:CD28:zeta/EGFRt CAR. The resultant bispecific T cells, targeting CMV and CD19, were expanded via CD19 CAR-mediated signals using CD19-expressing cells. RESULTS: The bispecific T cells proliferated vigorously after engagement with either endogenous CMVpp65 T-cell receptors or engineered CD19 CARs, exhibiting specific cytolytic activity and IFNgamma secretion. Upon adoptive transfer into immunodeficient mice bearing human lymphomas, the bispecific T cells exhibited proliferative response and enhanced antitumor activity following CMVpp65 peptide vaccine administration. CONCLUSIONS: We have redirected CMV-specific T cells to recognize and lyse tumor cells via CD19CARs, while maintaining their ability to proliferate in response to CMV antigen stimulation. These results illustrate the clinical applications of CMV vaccine to augment the antitumor activity of adoptively transferred CD19CAR T cells in patients with B-cell malignancies. PMID- 25838393 TI - Molecular Pathways: Targeting Cellular Energy Metabolism in Cancer via Inhibition of SLC2A1 and LDHA. AB - Reprogramming of cellular energy metabolism is widely accepted to be one of the main hallmarks of cancer. The aberrant expression pattern of key regulators in the glycolysis pathway in cancer cells corroborates with the hypothesis that most cancer cells utilize aerobic glycolysis as their main ATP production method instead of mitochondrial oxidative phosphorylation. Overexpression of SLC2A1 and LDHA, both important regulators of the glycolysis pathway, was detected in the premalignant lesions and tumors of lung cancer patients, suggesting the involvement of these proteins in early carcinogenesis and tumor progression in cancer. Preclinical studies demonstrated that inhibiting SLC2A1 or LDHA led to diminished tumor growth in vitro and in vivo. SLC2A1 and LDHA inhibitors, when administered in combination with other chemotherapeutic agents, showed synergistic antitumor effects by resensitizing chemoresistant cancer cells to the chemotherapies. These results indicate that disrupting SLC2A1, LDHA, or other regulators in cancer cell energetics is a very promising approach for new targeted therapies. PMID- 25838394 TI - Intratumoral Heterogeneity: From Diversity Comes Resistance. AB - Tumors consist of a heterogeneous mixture of functionally distinct cancer cells. These functional differences can be caused by varying levels of receptor activity, differentiation, and distinct metabolic and epigenetic states. Intratumoral heterogeneity can lead to interdependence among different subpopulations of cells for sustained tumor growth. In addition, subpopulations can vary widely in their responses to therapeutic agents. As such, it is believed that intratumoral heterogeneity may underlie incomplete treatment responses, acquired and innate resistance, and disease relapse observed in the clinic in response to conventional chemotherapy and targeted agents. PMID- 25838395 TI - Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. AB - Eribulin mesylate (eribulin), an analogue of the marine natural product halichondrin B, is a microtubule-depolymerizing drug that has utility in the treatment of patients with breast cancer. Clinical trial results have demonstrated that eribulin treatment provides a survival advantage to patients with metastatic or locally advanced breast cancer previously treated with an anthracycline and a taxane. Furthermore, a pooled analysis of two pivotal phase III trials has demonstrated that eribulin also improves overall survival in several patient subgroups, including in women with HER2-negative disease and triple-negative breast cancer. This review covers the preclinical research that led to the clinical testing and approval of eribulin, as well as subsequent research that was prompted by distinct and unexpected effects of eribulin in the clinic. Initial studies with halichondrin B demonstrated unique effects on tubulin binding that resulted in distinct microtubule-dependent events and antitumor actions. Consistent with the actions of the natural product, eribulin has potent microtubule-depolymerizing activities and properties that distinguish it from other microtubule-targeting agents. Here, we review new results that further differentiate the effects of eribulin from other agents on peripheral nerves, angiogenesis, vascular remodeling, and epithelial-to-mesenchymal transition. Together, these data highlight the distinct properties of eribulin and begin to delineate the mechanisms behind the increased survival benefit provided by eribulin for patients. PMID- 25838396 TI - Molecular Pathways: Leveraging the BCL-2 Interactome to Kill Cancer Cells- Mitochondrial Outer Membrane Permeabilization and Beyond. AB - The inhibition of apoptosis enables the survival and proliferation of tumors and contributes to resistance to conventional chemotherapy agents and is therefore a very promising avenue for the development of new agents that will enhance current cancer therapies. The BCL-2 family proteins orchestrate apoptosis at the mitochondria and endoplasmic reticulum and are involved in other processes such as autophagy and unfolded protein response (UPR) that lead to different types of cell death. Over the past decade, significant efforts have been made to restore apoptosis using small molecules that modulate the activity of BCL-2 family proteins. The small molecule ABT-199, which antagonizes the activity of BCL-2, is currently the furthest in clinical trials and shows promising activity in many lymphoid malignancies as a single agent and in combination with conventional chemotherapy agents. Here, we discuss strategies to improve the specificity of pharmacologically modulating various antiapoptotic BCL-2 family proteins, review additional BCL-2 family protein interactions that can be exploited for the improvement of conventional anticancer therapies, and highlight important points of consideration for assessing the activity of small-molecule BCL-2 family protein modulators. PMID- 25838397 TI - Upregulation of Periostin and Reactive Stroma Is Associated with Primary Chemoresistance and Predicts Clinical Outcomes in Epithelial Ovarian Cancer. AB - PURPOSE: Up to one third of ovarian cancer patients are intrinsically resistant to platinum-based treatment. However, predictive and therapeutic strategies are lacking due to a poor understanding of the underlying molecular mechanisms. This study aimed to identify key molecular characteristics that are associated with primary chemoresistance in epithelial ovarian cancers. EXPERIMENTAL DESIGN: Gene expression profiling was performed on a discovery set of 85 ovarian tumors with clinically well-defined response to chemotherapies as well as on an independent validation dataset containing 138 ovarian patients from the chemotreatment arm of the ICON7 trial. RESULTS: We identified a distinct "reactive stroma" gene signature that is specifically associated with primary chemoresistant tumors and was further upregulated in posttreatment recurrent tumors. Immunohistochemistry (IHC) and RNA in situ hybridization (RNA ISH) analyses on three of the highest ranked signature genes (POSTN, LOX, and FAP) confirmed that modulation of the reactive stroma signature genes within the peritumoral stromal compartments was specifically associated with the clinical chemoresistance. Consistent with these findings, chemosensitive ovarian cells grown in the presence of recombinant POSTN promoted resistance to carboplatin and paclitaxel treatment in vitro. Finally, we validated the reactive stroma signature in an independent dataset and demonstrated that a high POSTN expression level predicts shorter progression-free survival following first-line chemotherapy. CONCLUSIONS: Our findings highlight the important interplay between cancer and the tumor microenvironment in ovarian cancer biology and treatment. The identified reactive stromal components in this study provide a molecular basis to the further development of novel diagnostic and therapeutic strategies for overcoming chemoresistance in ovarian cancer. PMID- 25838398 TI - Pulmonary vein isolation for persistent atrial fibrillation. Long-term results. AB - BACKGROUND: Pulmonary vein isolation has been employed to eliminate paroxysmal atrial fibrillation. However, the long-term outcome in terms of long-standing persistent atrial fibrillation is unclear. METHODS: One hundred patients with rheumatic mitral valve disease and long-standing (>1 year) persistent atrial fibrillation were operated on between July 1998 and June 2007. Mitral valve surgery and surgical isolation (cut-and-sew) of the pulmonary veins were performed in all cases. Transthoracic echocardiography and 24-h Holter monitoring were obtained after 3 and 6 months and yearly thereafter. RESULTS: Early and late follow-up was 99% and 92% complete, respectively. The endpoint was freedom from atrial fibrillation. There was one (1%) hospital death. Atrial fibrillation was present in 39%, 47%, 63% and 68% of patients at 3 months, 1 year, 3 years, and 5 years after surgery, respectively. The odds ratios for recurrence of atrial fibrillation postoperatively were 1.41 (95% confidence interval 1.14-1.74), 2.17 (95% confidence interval 1.63-2.90), and 3.62 (95% confidence interval 2.44-5.38) at 1 week, 3 years, and 5 years, respectively. Actuarial freedom from atrial fibrillation was 35% at 3 years, and 30% at 5 years. A direct relationship was observed between preoperative left atrial size >6 cm and atrial fibrillation recurrence at 5 years (p < 0.05 odds ratio = 2.5, 95% confidence interval 1.15 - 5.4). CONCLUSIONS: No beneficial effects of simple pulmonary vein isolation for long-standing persistent atrial fibrillation concomitant with rheumatic mitral valve disease were observed. Atrial fibrillation cannot be fully treated using only pulmonary vein isolation. PMID- 25838399 TI - Doctors demand apology for UK diplomat's involvement in Pakistan tobacco meeting. PMID- 25838400 TI - BMA agrees to support legislation to abolish purchaser-provider split. PMID- 25838401 TI - Experimental drug that injured UK volunteers resumes in human trials. PMID- 25838402 TI - Clinical relevance of CYP3A5 genotype on maraviroc exposures. PMID- 25838403 TI - Response to "clinical relevance of CYP3A5 genotype on maraviroc exposures". PMID- 25838404 TI - Correction to: "hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions". PMID- 25838410 TI - Teenagers with back pain. PMID- 25838411 TI - Sick day rules in kidney disease. PMID- 25838412 TI - Antiphospholipid syndrome. PMID- 25838413 TI - The impact of calcium assay change on a local adjusted calcium equation. AB - BACKGROUND: Deriving and validating local adjusted calcium equations is important for ensuring appropriate calcium status classification. We investigated the impact on our local adjusted calcium equation of a change in calcium method by the manufacturer from cresolphthalein complexone to NM-BAPTA. METHODS: Calcium and albumin results from general practice requests were extracted from the Laboratory Information Management system for a three-month period. Results for which there was evidence of disturbance in calcium homeostasis were excluded leaving 13,482 sets of results for analysis. The adjusted calcium equation was derived following least squares regression analysis of total calcium on albumin and normalized to the mean calcium concentration of the data-set. The revised equation (NM-BAPTA calcium method) was compared with the previous equation (cresolphthalein complexone calcium method). RESULTS: The switch in calcium assay resulted in a small change in the adjusted calcium equation but was not considered to be clinically significant. The calcium reference interval differed from that proposed by Pathology Harmony in the UK. CONCLUSIONS: Local adjusted calcium equations should be re-assessed following changes in the calcium method. A locally derived reference interval may differ from the consensus harmonized reference interval. PMID- 25838414 TI - Simple quantitation for potential serum disease biomarker peptides, primarily identified by a peptidomics approach in the serum with hypertensive disorders of pregnancy. AB - BACKGROUND: We previously reported peptide candidates of disease biomarkers for pregnancy-induced hypertension syndrome using a novel peptidomic analytical method, BLOTCHIP(r)-MS. The aim of this study was to establish a sandwich enzyme linked immunosorbent assay system for quantitation of such peptides and to validate their usefulness as disease biomarkers of pregnancy-induced hypertension syndrome including gestational hypertension/pre-eclampsia. METHODS: We focused on three peptide fragments, kininogen-1439-456 (PDA039), kininogen-1438-456 (PDA044) and cysteinyl alpha2-HS-glycoprotein341-367 (PDA071). Using polyclonal antibodies specific for each peptide, suitable conditions for the sandwich enzyme-linked immunosorbent assay system were investigated. The quantitative enzyme-linked immunosorbent assay values were confirmed by quantitative matrix assisted laser desorption/ionization time-of-flight MS analyses. Using the established enzyme linked immunosorbent assay systems, serum samples from gestational hypertension/pre-eclampsia patients and paired serum samples from healthy pregnant females were analysed. RESULTS: The optimum sandwich enzyme-linked immunosorbent assay conditions for PDA039/044 quantitation were developed. Quantitation of PDA071 by enzyme-linked immunosorbent assay failed, presumably due to issues with polyclonal antibody specificity for the native peptide. Bland Altman plots showed a satisfactory correlation between the serum PDA039/044 concentration by enzyme-linked immunosorbent assay and that by quantitative MS analysis. Although the PDA044 concentration showed no significant change during pregnancy, including gestational hypertension/pre-eclampsia patients, the serum PDA039 concentration was significantly increased (P < 0.0001) in the patients. CONCLUSIONS: The simple quantitation technology for PDA039 by enzyme-linked immunosorbent assay was established for the first time. PDA039 confirmed its clinical utility as a disease biomarker for gestational hypertension/pre eclampsia by the enzyme-linked immunosorbent assay system using clinical samples. The information provided from the present study would be a new valuable addition in the field of gestational hypertension/pre-eclampsia research. PMID- 25838415 TI - Highly sensitive reversed-phase high-performance liquid chromatography assay for the detection of Tamm-Horsfall protein in human urine. AB - BACKGROUND: Tamm-Horsfall protein (also known as uromodulin) is the most abundant urinary protein in healthy individuals. Since initially characterized by Tamm and Horsfall, the amount of urinary excretion and structural mutations of Tamm Horsfall protein is associated with kidney diseases. However, currently available assays for Tamm-Horsfall protein, which are mainly enzyme-linked immunosorbent assay-based, suffer from poor reproducibility and might give false negative results. METHODS: We developed a novel, quantitative assay for Tamm-Horsfall protein using reversed-phase high-performance liquid chromatography. A precipitation pretreatment avoided urine matrix interference and excessive sample dilution. High-performance liquid chromatography optimization based on polarity allowed excellent separation of Tamm-Horsfall protein from other major urine components. RESULTS: Our method exhibited high precision (based on the relative standard deviations of intraday [<=2.77%] and interday [<=5.35%] repetitions). The Tamm-Horsfall protein recovery rate was 100.0-104.2%. The mean Tamm-Horsfall protein concentration in 25 healthy individuals was 31.6 +/- 18.8 mg/g creatinine. There was a strong correlation between data obtained by high performance liquid chromatography and enzyme-linked immunosorbent assay (r = 0.906), but enzyme-linked immunosorbent assay values tended to be lower than high performance liquid chromatography values at low Tamm-Horsfall protein concentrations. CONCLUSIONS: The high sensitivity and reproducibility of our Tamm Horsfall protein assay will reduce the number of false negative results of the sample compared with enzyme-linked immunosorbent assay. Moreover, our method is superior to other high-performance liquid chromatography methods, and a simple protocol will facilitate further research on the physiological role of Tamm Horsfall protein. PMID- 25838416 TI - Ronald J. Konopka. PMID- 25838417 TI - Phase response of the Arabidopsis thaliana circadian clock to light pulses of different wavelengths. AB - Light is known as one of the most powerful environmental time cues for the circadian system. The quality of light is characterized by its intensity and wavelength. We examined how the phase response of Arabidopsis thaliana depends on the wavelength of the stimulus light and the type of light perturbation. Using transgenic A. thaliana expressing a luciferase gene, we monitored the rhythm of the bioluminescence signal. We stimulated the plants under constant red light using 3 light perturbation treatments: (1) increasing the red light intensity, (2) turning on a blue light while turning off the red light, and (3) turning on a blue light while keeping the red light on. To examine the phase response properties, we generated a phase transition curve (PTC), which plots the phase after the perturbation as a function of the phase before the perturbation. To evaluate the effect of the 3 light perturbation treatments, we simulated PTCs using a mathematical model of the plant circadian clock and fitted the simulated PTCs to the experimentally measured PTCs. Among the 3 treatments, perturbation (3) provided the strongest stimulus. The results indicate that the color of the stimulus light and the type of pulse administration affect the phase response in a complex manner. Moreover, the results suggest the involvement of interaction between red and blue light signaling pathways in resetting of the plant circadian clock. PMID- 25838418 TI - Twilight dominates over moonlight in adjusting Drosophila's activity pattern. AB - Light is the most important zeitgeber for the synchronization of the Drosophila melanogaster circadian clock. In nature, there is twilight, and the nights are rarely completely dark, a fact that is usually disregarded in lab experiments. Recent studies showed contrary effects of simulated twilight and moonlight on fly locomotor activity, with twilight shifting morning and evening activity into the day and moonlight shifting it into the night. A currently unanswered question is, what may happen to locomotor activity when flies are exposed to more natural conditions in which both moonlight and twilight are simulated? Our data demonstrate that flies are able to integrate twilight and moonlight. However, twilight seems to dominate over moonlight as both, morning and evening activity peaks, take place at dawn or at dusk, respectively, and not during the night. Furthermore, nocturnal activity decreases in the presence of twilight. The compound eyes are essential for this behavior, and by investigating different photoreceptor mutants, we unraveled the importance of photoreceptor cells 7 and 8 for wild-type phases of the activity peaks. To adjust nocturnal activity levels to a wild-type manner, all photoreceptor cells work together in a complex way, with rhodopsin 6 having a prominent role. PMID- 25838419 TI - At-sea trial of 24-h-based submarine watchstanding schedules with high and low correlated color temperature light sources. AB - United States Navy submariners have historically lived with circadian disruption while at sea due to 18-h-based watchschedules. Previous research demonstrated that circadian entrainment improved with 24-h-based watchschedules. Twenty-nine male crew members participated in the study, which took place on an actual submarine patrol. The crew were exposed, first, to experimental high correlated color temperature (CCT = 13,500 K) fluorescent light sources and then to standard issue fluorescent light sources (CCT = 4100 K). A variety of outcome measures were employed to determine if higher levels of circadian-effective light during on-watch times would further promote behavioral alignment to 24-h-based watchschedules. The high CCT light source produced significantly higher circadian light exposures than the low CCT light source, which was associated with significantly greater 24-h behavioral alignment with work schedules using phasor analysis, greater levels of sleep efficiency measured with wrist actigraphy, lower levels of subjective sleepiness measured with the Karolinska Sleepiness Scale, and higher nighttime melatonin concentrations measured by morning urinary 6-sulfatoxymelatonin/creatinine ratios. Unlike these diverse outcome measures, performance scores were significantly worse under the high CCT light source than under the low CCT light source, due to practice effects. As hypothesized, with the exception of the performance scores, all of the data converge to suggest that high CCT light sources, combined with 24-h watchschedules, promote better behavioral alignment with work schedules and greater sleep quality on submarines. Since the order and the type of light sources were confounded in this field study, the results should only be considered as consistent with our theoretical understanding of how regular, 24-h light-dark exposures combined with high circadian light exposures can promote greater behavioral alignment with work schedules and with sleep. PMID- 25838420 TI - GPs in England must report certain patient harms under new rules. PMID- 25838421 TI - High-Density Lipoprotein (HDL) Phospholipid Content and Cholesterol Efflux Capacity Are Reduced in Patients With Very High HDL Cholesterol and Coronary Disease. AB - OBJECTIVE: Plasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with coronary artery disease (CAD), and high HDL-C is generally associated with reduced risk of CAD. Extremely high HDL-C with CAD is an unusual phenotype, and we hypothesized that the HDL in such individuals may have an altered composition and reduced function when compared with controls with similarly high HDL-C and no CAD. APPROACH AND RESULTS: Fifty-five subjects with very high HDL-C (mean, 86 mg/dL) and onset of CAD at the age of ~ 60 years with no known risk factors for CAD (cases) were identified through systematic recruitment. A total of 120 control subjects without CAD, matched for race, sex, and HDL-C level (controls), were identified. In all subjects, HDL composition was analyzed and HDL cholesterol efflux capacity was assessed. HDL phospholipid composition was significantly lower in cases (92 +/- 37 mg/dL) than in controls (109 +/- 43 mg/dL; P=0.0095). HDL cholesterol efflux capacity was significantly lower in cases (1.96 +/- 0.39) than in controls (2.11 +/- 0.43; P=0.04). CONCLUSIONS: In people with very high HDL-C, reduced HDL phospholipid content and cholesterol efflux capacity are associated with the paradoxical development of CAD. PMID- 25838422 TI - Loss of interleukin-21 receptor activation in hypoxic endothelial cells impairs perfusion recovery after hindlimb ischemia. AB - OBJECTIVE: Surgical hindlimb ischemia (HLI) in mice has become a valuable preclinical model to study peripheral arterial disease. We previously identified that the different phenotypic outcomes after HLI across inbred mouse strains is related to a region on the short arm of mouse chromosome 7. The gene coding the interleukin-21 receptor (IL-21R) lies at the peak of association in this region. APPROACH AND RESULTS: With quantitative real-time polymerase chain reaction, we found that a mouse strain with a greater ability to upregulate IL-21R after HLI had better perfusion recovery than a strain with no upregulation after HLI. Immunofluorescent staining of ischemic hindlimb tissue showed IL-21R expression on endothelial cells (ECs) from C57BL/6 mice. An EC-enriched fraction isolated from ischemic hindlimb muscle showed higher Il-21R levels than an EC-enriched fraction from nonischemic limbs. In vitro, human umbilical vein ECs showed elevated IL-21R expression after hypoxia and serum starvation. Under these conditions, IL-21 treatment increased cell viability, decreased cell apoptosis, and augmented tube formation. In vivo, either knockout Il21r or blocking IL-21 signaling by treating with IL-21R-Fc (fusion protein that blocks IL-21 binding to its receptor) in C57BL/6 mice resulted in less perfusion recovery after HLI. Both in vitro and in vivo modulation of the IL-21/IL-21R axis under hypoxic conditions resulted in increased signal transducer and activator of transcription 3 phosphorylation and a subsequent increase in the B-cell lymphoma leukemia-2/BCL-2 associated X protein ratio. CONCLUSION: Our data indicate that IL-21R upregulation and ligand activation in hypoxic ECs may help perfusion recovery by limiting/preventing apoptosis and favoring cell survival and angiogenesis through the signal transducer and activator of transcription 3 pathway. PMID- 25838423 TI - Longitudinal association of carotid plaque presence and intima-media thickness with depressive symptoms in the elderly: the three-city study. AB - OBJECTIVE: To investigate prospectively whether subclinical vascular disease is associated with future depressive symptoms in the elderly. APPROACH AND RESULTS: A multicenter cohort of community-dwelling individuals aged 65 to 85 years was examined for carotid plaque presence and common carotid artery intima-media thickness at baseline and followed up after 2, 4, 7, and 10 years. At baseline and follow-up examinations, depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). High level of depressive symptoms was defined as a CES-D score >16 in men and >22 in women. Among 4125 participants (58% women) at baseline, men more frequently showed carotid plaque presence and had higher mean common carotid artery intima-media thickness than women. After adjustment for major cardiovascular risk factors, carotid plaque presence was associated with a higher CES-D score at the 10-year follow-up in men (+1.46; 95% confidence interval, 0.71-2.20; P<0.001), but not in women. When restricting analyses to individuals without cardiovascular disease at baseline, carotid plaque presence increased the likelihood of high level of depressive symptoms at follow-up examinations in men (odds ratio, 1.47; 95% confidence interval, 1.06-2.05; P=0.022), but not in women. One SD increase in log transformed common carotid artery intima-media thickness was associated with a higher CES-D score at the 10-year follow-up in women (+0.55; 95% confidence interval, 0.16-0.95; P=0.006) and men (+0.40; 95% confidence interval, 0.02-0.78; P=0.037). Common carotid artery intima-media thickness did not increase the likelihood of high level of depressive symptoms at follow-up in both sexes. CONCLUSIONS: Subclinical vascular disease is associated with the progression of depressive symptoms in elderly men and women and the occurrence of high level of depressive symptoms in elderly men. PMID- 25838424 TI - Endothelial epigenetics in biomechanical stress: disturbed flow-mediated epigenomic plasticity in vivo and in vitro. AB - Arterial endothelial phenotype is regulated by local hemodynamic forces that are linked to regional susceptibility to atherogenesis. A complex hierarchy of transcriptional, translational, and post-translational mechanisms is greatly influenced by the characteristics of local arterial shear stress environments. We discuss the emerging role of localized disturbed blood flow on epigenetic mechanisms of endothelial responses to biomechanical stress, including transcriptional regulation by proximal promoter DNA methylation, and post transcriptional and translational regulation of gene and protein expression by chromatin remodeling and noncoding RNA-based mechanisms. Dynamic responses to flow characteristics in vivo and in vitro include site-specific differentially methylated regions of swine and mouse endothelial methylomes, histone marks regulating chromatin conformation, microRNAs, and long noncoding RNAs. Flow mediated epigenomic responses intersect with cis and trans factor regulation to maintain endothelial function in a shear-stressed environment and may contribute to localized endothelial dysfunctions that promote atherosusceptibility. PMID- 25838426 TI - Cellular Cholesterol Accumulation Facilitates Ubiquitination and Lysosomal Degradation of Cell Surface-Resident ABCA1. AB - OBJECTIVE: By excreting cellular cholesterol to apolipoprotein A-I, ATP-binding cassette transporter A1 (ABCA1) mediates the biogenesis of high-density lipoprotein in hepatocytes and prevents foam cell formation from macrophages. We recently showed that cell surface-resident ABCA1 (csABCA1) undergoes ubiquitination and later lysosomal degradation through the endosomal sorting complex required for transport system. Herein, we investigated the relevance of this degradation pathway to the turnover of csABCA1 in hypercholesterolemia. APPROACH AND RESULTS: Immunoprecipitation and cell surface-biotinylation studies with HepG2 cells and mouse peritoneal macrophages showed that the ubiquitination level and degradation of csABCA1 were facilitated by treatment with a liver X receptor (LXR) agonist and acetylated low-density lipoprotein. The effects of an LXR agonist and acetylated low-density lipoprotein on the degradation of csABCA1 were repressed completely by treatment with bafilomycin, an inhibitor of lysosomal degradation, and by depletion of tumor susceptibility gene 101, a major component of endosomal sorting complex required for transport-I. RNAi analysis indicated that LXRbeta inhibited the accelerated lysosomal degradation of csABCA1 by the LXR agonist, regardless of its transcriptional activity. Cell surface coimmunoprecipitation with COS1 cells expressing extracellularly hemagglutinin tagged ABCA1 showed that LXRbeta interacted with csABCA1 and inhibited the ubiquitination of csABCA1. Immunoprecipitates with anti-ABCA1 antibodies from the liver plasma membranes showed less LXRbeta and a higher ubiquitination level of ABCA1 in high-fat diet-fed mice than in normal chow-fed mice. CONCLUSIONS: Under conditions of high cellular cholesterol content, csABCA1 became susceptible to ubiquitination by dissociation of LXRbeta from csABCA1, which facilitated the lysosomal degradation of csABCA1 through the endosomal sorting complex required for transport system. PMID- 25838425 TI - Myocardial Infarction-Associated SNP at 6p24 Interferes With MEF2 Binding and Associates With PHACTR1 Expression Levels in Human Coronary Arteries. AB - OBJECTIVE: Coronary artery disease (CAD), including myocardial infarction (MI), is the main cause of death in the world. Genome-wide association studies have identified dozens of single nucleotide polymorphisms (SNPs) associated with CAD/MI. One of the most robust CAD/MI genetic associations is with intronic SNPs in the gene PHACTR1 on chromosome 6p24. How these PHACTR1 SNPs influence CAD/MI risk, and whether PHACTR1 itself is the causal gene at the locus, is currently unknown. APPROACH AND RESULTS: Using genetic fine-mapping and DNA resequencing experiments, we prioritized an intronic SNP (rs9349379) in PHACTR1 as causal variant. We showed that this variant is an expression quantitative trait locus for PHACTR1 expression in human coronary arteries. Experiments in endothelial cell extracts confirmed that alleles at rs9349379 are differentially bound by the transcription factors myocyte enhancer factor-2. We engineered a deletion of this myocyte enhancer factor-2-binding site using CRISPR/Cas9 genome-editing methodology. Heterozygous endothelial cells carrying this deletion express 35% less PHACTR1. Finally, we found no evidence that PHACTR1 expression levels are induced when stimulating human endothelial cells with vascular endothelial growth factor, tumor necrosis factor-alpha, or shear stress. CONCLUSIONS: Our results establish a link between intronic SNPs in PHACTR1, myocyte enhancer factor-2 binding, and transcriptional functions at the locus, PHACTR1 expression levels in coronary arteries and CAD/MI risk. Because PHACTR1 SNPs are not associated with the traditional risk factors for CAD/MI (eg, blood lipids or pressure, diabetes mellitus), our results suggest that PHACTR1 may influence CAD/MI risk through as yet unknown mechanisms in the vascular endothelium. PMID- 25838427 TI - Lean and Obese Coronary Perivascular Adipose Tissue Impairs Vasodilation via Differential Inhibition of Vascular Smooth Muscle K+ Channels. AB - OBJECTIVE: The effects of coronary perivascular adipose tissue (PVAT) on vasomotor tone are influenced by an obese phenotype and are distinct from other adipose tissue depots. The purpose of this investigation was to examine the effects of lean and obese coronary PVAT on end-effector mechanisms of coronary vasodilation and to identify potential factors involved. APPROACH AND RESULTS: Hematoxylin and eosin staining revealed similarities in coronary perivascular adipocyte size between lean and obese Ossabaw swine. Isometric tension studies of isolated coronary arteries from Ossabaw swine revealed that factors derived from lean and obese coronary PVAT attenuated vasodilation to adenosine. Lean coronary PVAT inhibited K(Ca) and KV7, but not KATP channel-mediated dilation in lean arteries. In the absence of PVAT, vasodilation to K(Ca) and KV7 channel activation was impaired in obese arteries relative to lean arteries. Obese PVAT had no effect on K(Ca) or KV7 channel-mediated dilation in obese arteries. In contrast, obese PVAT inhibited KATP channel-mediated dilation in both lean and obese arteries. The differential effects of obese versus lean PVAT were not associated with changes in either coronary KV7 or K(ATP) channel expression. Incubation with calpastatin attenuated coronary vasodilation to adenosine in lean but not in obese arteries. CONCLUSIONS: These findings indicate that lean and obese coronary PVAT attenuates vasodilation via inhibitory effects on vascular smooth muscle K(+) channels and that alterations in specific factors such as calpastatin are capable of contributing to the initiation or progression of smooth muscle dysfunction in obesity. PMID- 25838428 TI - Liver X receptor activation promotes polyunsaturated fatty acid synthesis in macrophages: relevance in the context of atherosclerosis. AB - OBJECTIVE: Liver X receptors (LXRs) modulate cholesterol and fatty acid homeostasis as well as inflammation. This study aims to decipher the role of LXRs in the regulation of polyunsaturated fatty acid (PUFA) synthesis in macrophages in the context of atherosclerosis. APPROACH AND RESULTS: Transcriptomic analysis in human monocytes and macrophages was used to identify putative LXR target genes among enzymes involved in PUFA biosynthesis. In parallel, the consequences of LXR activation or LXR invalidation on PUFA synthesis and distribution were determined. Finally, we investigated the impact of LXR activation on PUFA metabolism in vivo in apolipoprotein E-deficient mice. mRNA levels of acyl-CoA synthase long-chain family member 3, fatty acid desaturases 1 and 2, and fatty acid elongase 5 were significantly increased in human macrophages after LXR agonist treatment, involving both direct and sterol responsive element binding protein-1-dependent mechanisms. Subsequently, pharmacological LXR agonist increased long chain PUFA synthesis and enhanced arachidonic acid content in the phospholipids of human macrophages. Increased fatty acid desaturases 1 and 2 and acyl-CoA synthase long-chain family member 3 mRNA levels as well as increased arachidonic acid to linoleic acid and docosahexaenoic acid to eicosapentaenoic acid ratios were also found in atheroma plaque and peritoneal foam cells from LXR agonist-treated mice. By contrast, murine LXR-deficient macrophages displayed reduced expression of fatty acid elongase 5, acyl-CoA synthase long-chain family member 3 and fatty acid desaturases 1, as well as decreased cellular levels of docosahexaenoic acid and arachidonic acid. CONCLUSIONS: Our results indicate that LXR activation triggers PUFA synthesis in macrophages, which results in significant alterations in the macrophage lipid composition. Moreover, we demonstrate here that LXR agonist treatment modulates PUFA metabolism in atherosclerotic arteries. PMID- 25838429 TI - Nonclassical patrolling monocyte function in the vasculature. AB - Nonclassical patrolling monocytes are characterized by their unique ability to actively patrol the vascular endothelium under homeostatic and inflammatory conditions. Patrolling monocyte subsets (CX3CR1(high)Ly6C(-) in mouse and CX3CR1(high)CD14(dim)CD16(+) in humans) are distinct from the classical monocyte subsets (CCR2(high)Ly6C(+) in mouse and CCR2(high)CD14(+)CD16(-) in humans) and exhibit unique functions in the vasculature and inflammatory disease. Patrolling monocytes function in several disease settings to remove damaged cells and debris from the vasculature and have been associated with wound healing and the resolution of inflammation in damaged tissues. This review highlights the unique functions of these patrolling monocytes in the vasculature and during inflammation. PMID- 25838430 TI - Identification of Pathogenic Cardiac CD11c+ Macrophages in Nod1-Mediated Acute Coronary Arteritis. AB - OBJECTIVE: Nod1 is an intracellular pattern recognition receptor for bacterial peptidoglycan fragments. We previously reported that a synthetic Nod1 ligand, FK565, induced acute coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanisms underlying this characteristic inflammation have remained elusive. APPROACH AND RESULTS: We found that CD11c(+)MHC class II(+) cells accumulated in the heart of FK565-treated mice before arteritis development. Morphological features and gene expression signatures of the cardiac CD11c(+)MHC class II(+) cells suggested that this population is closely related to macrophages, and thus, we designated them cardiac CD11c(+) macrophages. Nod1 in nonhematopoietic cells, rather than hematopoietic cells, was required for the increase of cardiac CD11c(+) macrophages and arteritis development. Among nonhematopoietic cells, cardiac endothelial cells produced a large amount of chemokines in response to FK565. Endothelial cell-specific blockade of Nod1 signaling suppressed FK565-induced expression of these chemokines, accumulation of cardiac CD11c(+) macrophages, and subsequent coronary arteritis development. We also found that CCR2(+)Ly6C(hi) inflammatory monocytes in peripheral blood supplied precursors of cardiac CD11c(+) macrophages. CCR2-deficient mice or pertussis toxin-treated mice exhibited decreased numbers of cardiac CD11c(+) macrophages and reduced arteritis. CONCLUSIONS: These results suggest that Ly6C(hi) monocytes are recruited to FK565-activated endothelial cells to generate cardiac CD11c(+) macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis. PMID- 25838431 TI - Noninvasive molecular ultrasound monitoring of vessel healing after intravascular surgical procedures in a preclinical setup. AB - OBJECTIVE: Cardiovascular interventions induce damage to the vessel wall making antithrombotic therapy inevitable until complete endothelial recovery. Without a method to accurately determine the endothelial status, many patients undergo prolonged anticoagulation therapy, denying them any invasive medical procedures, such as surgical operations and dental interventions. Therefore, we aim to introduce molecular ultrasound imaging of the vascular cell adhesion molecule (VCAM)-1 using targeted poly-n-butylcyanoacrylate microbubbles (MB(VCAM-1)) as an easy accessible method to monitor accurately the reendothelialization of vessels. APPROACH AND RESULTS: ApoE(-/-) mice were fed with an atherogenic diet for 1 and 12 weeks and subsequently, endothelial denudation was performed in the carotid arteries using a guidewire. Molecular ultrasound imaging was performed at different time points after denudation (1, 3, 7, and 14 days). An increased MB(VCAM-1) binding after 1 day, a peak after 3 days, and a decrease after 7 days was found. After 12 weeks of diet, MB(VCAM-1) binding also peaked after 3 days but remained high until 7 days, indicating a delay in endothelial recovery. Two photon laser scanning microscopy imaging of double fluorescence staining confirmed the exposure of VCAM-1 on the superficial layer after arterial injury only during the healing phase. After complete reendothelialization, VCAM-1 expression persisted in the subendothelial layer but was not reachable for the MBV(CAM-1) anymore. CONCLUSION: Molecular ultrasound imaging with MB(VCAM-1) is promising to assess vascular damage and to monitor endothelial recovery after arterial interventions. Thus, it may become an important diagnostic tool supporting the development of adequate therapeutic strategies to personalize anticoagulant and anti-inflammatory therapy after cardiovascular intervention. PMID- 25838432 TI - Current state and novel approaches of antiplatelet therapy. AB - An unresolved problem with clinical use of antiplatelet therapy is that a significant number of individuals either still get thrombosis or run the risk of life-threatening bleeding. Antiplatelet drugs are widely used clinically, either chronically for people at risk of athero/thrombotic disease or to prevent thrombus formation during surgery. However, a subpopulation may be resistant to standard doses, while the platelet targets of these drugs are also critical for the normal hemostatic function of platelets. In this review, we will briefly examine current antiplatelet therapy and existing targets while focusing on new potential approaches for antiplatelet therapy and improved monitoring of effects on platelet reactivity in individuals, ultimately to improve antithrombosis with minimal bleeding. Primary platelet adhesion-signaling receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor/collagen and other prothrombotic factors are not targeted by drugs in clinical use, but they are of particular interest because of their key role in thrombus formation at pathological shear. PMID- 25838433 TI - The management of acute testicular pain in children and adolescents. PMID- 25838434 TI - A Combination of Screening and Computational Approaches for the Identification of Novel Compounds That Decrease Mast Cell Degranulation. AB - High-content screening of compound libraries poses various challenges in the early steps in drug discovery such as gaining insights into the mode of action of the selected compounds. Here, we addressed these challenges by integrating two biological screens through bioinformatics and computational analysis. We screened a small-molecule library enriched in amphiphilic compounds in a degranulation assay in rat basophilic leukemia 2H3 (RBL-2H3) cells. The same library was rescreened in a high-content image-based endocytosis assay in HeLa cells. This assay was previously applied to a genome-wide RNAi screen that produced quantitative multiparametric phenotypic profiles for genes that directly or indirectly affect endocytosis. By correlating the endocytic profiles of the compounds with the genome-wide siRNA profiles, we identified candidate pathways that may be inhibited by the compounds. Among these, we focused on the Akt pathway and validated its inhibition in HeLa and RBL-2H3 cells. We further showed that the compounds inhibited the translocation of the Akt-PH domain to the plasma membrane. The approach performed here can be used to integrate chemical and functional genomics screens for investigating the mechanism of action of compounds. PMID- 25838435 TI - Atrial flutter: more than just one of a kind. AB - Since its first description about one century ago, our understanding of atrial flutter (AFL) circuits has considerably evolved. One AFL circuit can have variable electrocardiographic (ECG) manifestations depending on the presence of pre-existing atrial lesions, or impaired atrial substrate. Conversely, different (right sided or even left sided) atrial circuits including different mechanisms (macroreentrant, microreentrant, or focal) can present with a very similar surface ECG manifestation. The development of efficient high-resolution electroanatomical mapping systems has improved our knowledge about AFL mechanisms, as well as facilitated their curative treatment with radiofrequency catheter ablation. This article will review ECG features for typical and atypical flutters, and emphasize the limitations for circuit location from the surface ECG. PMID- 25838437 TI - Duration of dual antiplatelet therapy after coronary artery stenting: where is the sweet spot between ischaemia and bleeding? PMID- 25838436 TI - The kidney in heart failure: an update. AB - Heart and kidney are closely related in the clinical syndrome of heart failure (HF). It is now sufficiently clear that renal dysfunction occurs frequently in all phenotypes of HF, and when present, it is associated with higher mortality and morbidity. While the pathophysiology is multifactorial, the most important factors are a reduced renal perfusion and venous congestion. Recent interest has focused on worsening renal function (WRF), a situation strongly related to mortality, but seemingly only when HF status deteriorates. Unfortunately, to date clinicians are unable to identify specifically those patients with a grim prognosis following WRF. Although much has been learned on cardiorenal interaction in HF, still more questions have been left unanswered. The coming decade should provide us with more dedicated epidemiologic, mechanistic, and controlled trials in HF patients with reduced renal function. An updated classification of the cardiorenal syndrome that incorporates recent evidence and points towards areas of interest and uncertainties, and areas where progress is needed could facilitate this process. Ultimately, this should lead to preventive and treatment strategies that can preserve renal function and associated outcome in patients with HF. PMID- 25838438 TI - Under-the-counter acquired acute coronary syndrome: Methaemoglobinaemia. AB - A 73-year-old male suffers a type-2 inferior myocardial infarction and is found unconscious, hypotensive and centrally cyanotic. His arterial blood gas analysis shows a chocolate-brown discoloration, with pO2 45.1 kPa, HbO2 48.9%, MetHb 51%, BE -9 and a lactate of 3.7 mmol/l. Administration of 200 mg of methylene blue intravenously, normalizes the patient's abnormalities. His life-threatening acquired methaemoglobinaemia appears secondary to under-the-counter viagra. PMID- 25838439 TI - Uncontrolled daily pulmonary oedema due to severe mitral regurgitation emergently and effectively corrected by Mitraclip(r) implantation. AB - MitraClip(r) is usually implanted in stable patients. We report the case of a patient having a severe, refractory and daily pulmonary oedema, related to a severe restrictive mitral regurgitation secondary to a primitive dilated cardiomyopathy. A Mitraclip(r) was emergently implanted, with a dramatic long term clinical success. The critical unstable status of a patient should not prevent any Mitraclip(r) implantation. PMID- 25838442 TI - Regulating laboratory-developed tests: devil will be in details. PMID- 25838441 TI - Chimeric antigen receptor T-cell immunotherapy tackles blood cancers. PMID- 25838443 TI - Lung cancer screening poised to expand. PMID- 25838445 TI - New tool improves doctor-patient communication. PMID- 25838447 TI - Caring for Children With Tuberous Sclerosis Complex: What Is the Physical and Mental Health Impact on Caregivers? AB - Disease burden associated with tuberous sclerosis complex, a genetic disorder characterized by benign tumor growth including lesions in multiple organs, puts tremendous demands on families. This analysis examines the physical and mental health burden of tuberous sclerosis complex caregivers in the United States. An institutional review board-approved web-based survey of tuberous sclerosis complex caregivers collected information; descriptive analyses were conducted on age-based subgroups. A total of 275 caregivers of tuberous sclerosis complex patients responded. Mean patient age <= 18 years was 6.9 (+/-4.4) and 42.3 (+/ 18.2) for patients >18 years of age. Caregivers reported multiple tuberous sclerosis complex manifestations and high health care utilization for patients. Caregivers spending more time on doctor visits or researching tuberous sclerosis complex had lower physical and mental health-related quality of life scores and more depressive symptoms. Tuberous sclerosis complex caregivers had significantly lower physical and mental health-related quality of life scores and more depressive symptomatology compared to US healthy adult population norms. PMID- 25838449 TI - BRCA2-branching out too? PMID- 25838450 TI - Uterine cervical cancer volumetry using T2- and diffusion-weighted MR images in patients treated by primary surgery and neoadjuvant chemotherapy. AB - BACKGROUND: Tumor volumetry with magnetic resonance imaging (MRI) is very common; however, the accuracy of such measures remains unclear, especially after treatment. PURPOSE: To determine the accuracy of preoperative volume measurements of uterine cervical carcinomas resected with and without neoadjuvant chemotherapy (NAC) on T2-weighted (T2W) and diffusion-weighted (DWI) MRI. MATERIAL AND METHODS: Twenty-nine consecutive patients with surgically confirmed uterine cervical carcinoma were included in this study. MRI scans were performed before preoperative treatment in 17 patients and after two courses of NAC in 12 patients. In all patients, T2W images and DWI were obtained to measure the tumor diameters. The maximum diameter of the surgical specimens was macroscopically measured. The correlation coefficients between the measured tumor size using T2W imaging and DWI and the size measured on the surgical specimens were calculated for all specimens. RESULTS: The correlation coefficient of the three-dimensional (3D) tumor volume measurement using T2W imaging and DWI was 0.97 in the primary surgery group and was 0.96 in the NAC group. The 3D tumor volume measurement using MRI and the measurement of the actual surgical specimen was 0.55 for T2WI and 0.48 for DWI in the primary surgery group and 0.88 for T2WI and 0.95 for DWI in the NAC group. CONCLUSION: T2WI and DWI can provide accurate 3D tumor volume measurements of uterine cervical carcinomas in patients with and without preoperative chemotherapy, suggesting that tumor volumetry using 3 T MRI after uterus-preserving treatment is feasible. PMID- 25838451 TI - Prevalence of C7 level anomalies at the C7 level: an important landmark for cervical nerve ultrasonography. AB - BACKGROUND: Recently, various examination and intervention techniques using cervical nerve ultrasonography have been developed. The specific shapes of the C7 transverse process and vertebral artery in front of the C7 transverse process have become landmarks. PURPOSE: To determine the prevalence of anomalies and anomalous vertebral artery entrances at the C7 transverse process. MATERIAL AND METHODS: The records of patients who underwent plain or contrast-enhanced neck or cervical spine computed tomography (CT) were reviewed. The examinations were scored for the anomalous presence of anterior tubercles or cervical ribs as well as vertebral artery entrances in the C7 transverse process. The prevalence of anomalies was compared based on patient sex and age. RESULTS: Evaluating the examinations from 2067 patients (1046 men; 1021 women), 1% of patients exhibited an anomalous presence of anterior tubercles, and 0.3% of patients displayed cervical ribs at the C7 transverse process. The prevalence of anomalies process was significantly higher in men aged less than 40 years than in older men (P < 0.001), whereas the prevalence was not higher in women aged less than 40 years than in older women. The prevalence of vertebral artery entry into the C7 transverse foramen was 0.6%. CONCLUSION: Although an anomalous vertebral artery entry into the C7 transverse foramen was rare, the prevalence of an anomaly at the C7 transverse process was higher in men aged less than 40 years. Therefore, we recommend performing CT in younger men before cervical nerve ultrasonographic intervention to avoid misinterpretations at the cervical level. PMID- 25838448 TI - A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer. AB - Deleterious BRCA2 genetic variants markedly increase risk of developing breast cancer. A rare truncating BRCA2 genetic variant, rs11571833 (K3326X), has been associated with a 2.5-fold risk of lung squamous cell carcinoma but only a modest 26% increase in breast cancer risk. We analyzed the association between BRCA2 SNP rs11571833 and upper aerodigestive tract (UADT) cancer risk with multivariable unconditional logistic regression adjusted by sex and combinations of study and country for 5942 UADT squamous cell carcinoma case patients and 8086 control patients from nine different studies. All statistical tests were two-sided. rs11571833 was associated with UADT cancers (odds ratio = 2.53, 95% confidence interval = 1.89 to 3.38, P = 3x10(-10)) and was present in European, Latin American, and Indian populations but extremely rare in Japanese populations. The association appeared more apparent in smokers (current or former) compared with never smokers (P het = .026). A robust association between a truncating BRCA2 variant and UADT cancer risk suggests that treatment strategies orientated towards BRCA2 mutations may warrant further investigation in UADT tumors. PMID- 25838452 TI - Chest CT at a dose below 0.3 mSv: impact of iterative reconstruction on image quality and lung analysis. AB - BACKGROUND: In chest computed tomography (CT), iterative reconstruction (IR) algorithms maintain diagnostic image quality (IQ) while significantly reducing the dose. PURPOSE: To evaluate the impact of IR on IQ of chest CT at effective doses below 0.3 mSv. MATERIAL AND METHODS: Twenty chest CT scans performed at effective dose below 0.3 mSv (CT1) were reconstructed varying three parameters: filtered back-projection and IR iDose(4) algorithms; 512 * 512 and 768 * 768 matrices; and sharp and soft kernels, thus generating eight series per patient. The qualitative evaluation of the IQ was performed by ranking series from 1 to 8 (8 corresponding to the highest rank) which was subsequently compared to quantitative assessment of IQ by using an appropriated merit formula. Intra- and inter-reader IQ ranking reliability was also evaluated using Cohen's kappa. Analysis of lung findings was finally compared between the best CT1 series and the reference CT (CT0). RESULTS: The best series in terms of qualitative and quantitative IQ was obtained using IR, 512(2) matrix and soft kernel. The best CT1 series detected nodules greater than 4 mm with an almost perfect match with CT0. CONCLUSION: Chest CT performed at effective doses below 0.3 mSv may be used to confidently diagnose lesions greater than 4 mm using iDose(4), soft kernel and 512 * 512 matrix. PMID- 25838453 TI - Evaluation of uterine peristalsis using cine MRI on the coronal plane in comparison with the sagittal plane. AB - BACKGROUND: Uterine peristalsis is supposed to be closely related to the early stages of reproduction. Sperms are preferentially transported from the uterine cervix to the side of the tube with the dominant follicle. However, with respect to magnetic resonance imaging (MRI), uterine peristalsis has only been evaluated at the sagittal plane of cine MRI. PURPOSE: To evaluate and compare uterine peristalsis both on sagittal and coronal planes using cine MRI. MATERIAL AND METHODS: Internal ethics committee approval was obtained, and subjects provided informed written consent. Thirty-one women underwent MRI scans in the periovulatory phase of the menstrual cycle. Cine MR images obtained by fast advanced spin echo sequence at 3-T field strength magnet (Toshiba Medical Systems) were visually evaluated by two independent radiologists. The frequency and the direction of peristalsis, and the presence of outer myometrium conduction of signal intensities (OMC), were evaluated. The laterality of the dominant follicle was determined on axial images and compared with the peristaltic direction in fundus. RESULTS: The subjects in which peristaltic directions were more clearly recognized were significantly frequent in coronal planes than in sagittal planes (P < 0.05). There was no significant difference in the peristaltic frequency between the sagittal and the coronal plane. However, the OMC was more recognized in the coronal plane than in the sagittal plane (P < 0.05). Peristaltic waves conducted toward the possible ovulation side were observed in only three of the 10 subjects. CONCLUSION: OMC of uterine peristalsis was better demonstrated in the coronal plane compared to the sagittal plane. PMID- 25838455 TI - Gisbert R, Schenkman M. Physical therapist interventions for Parkinson disease. Phys Ther. 2015;95:299-305. PMID- 25838454 TI - "Knowing is not enough; we must apply. Willing is not enough; we must do". PMID- 25838456 TI - Biventricular repair for common atrioventricular canal defect with parachute left atrioventricular valve. AB - OBJECTIVES: Parachute left atrioventricular (AV) valve can complicate repair of common atrioventricular canal (CAVC), and single-ventricle palliation is sometimes preferred. The goal of this study is to review our single institutional experience in biventricular repair in this patient group. METHODS: The demographic, procedural and outcome data were obtained for all children who underwent biventricular repair for complete CAVC with parachute [single left ventricular (LV) papillary muscle] or forme fruste parachute left AV valve (closely spaced LV papillary muscles) from 2001 to 2012. Primary outcomes were survival, freedom from left AV valve stenosis (defined as an inflow gradient >=7 mmHg and post-capillary pulmonary hypertension) and freedom from left AV valve replacement. RESULTS: A total of 24 patients were included (21 parachutes, 3 forme frustes). There was 1 early death (4.2%). At discharge, no patient had more than-mild regurgitation and 1 had stenosis. During a median follow-up of 3.7 years (IQR 4 months to 5 years), there were 2 late deaths (8.3%), 6 patients (25%) presented significant left AV valve stenosis and 2 patients (8.3%) required valve replacement. Freedom from stenosis was 95 +/- 4.9% at 1 year, 83.1 +/- 8.9% at 3 years, 64.7 +/- 13.5% at 5 years and 51.7 +/- 15.8% at 10 years. Complete cleft closure was not associated with a significantly different freedom from left AV valve reoperation (log-rank test, P = 0.89) or significant stenosis (P = 0.47). CONCLUSION: Biventricular repair in parachute left AV valve and CAVC is feasible with acceptable mortality and freedom from stenosis. The burden of reoperation remains significant in this patient group. PMID- 25838457 TI - Reply to Phan and Yan. PMID- 25838458 TI - Ten-year outcomes of Fontan conversion in Australia and New Zealand demonstrate the superiority of a strategy of early conversion. AB - OBJECTIVE: To investigate the benefits of a strategy of early Fontan conversion. METHODS: Using the Australia and New Zealand Fontan Registry, retrospective analysis of their long-term follow-up data was performed. RESULTS: Between 1990 and 2014, a total of 39 patients underwent surgical conversion in 6 centres at a median age of 23.8 years (IQR: 19.3-28.2), 18.7 +/- 5.0 years post-Fontan. One centre tended to perform conversion earlier: interval since first documented arrhythmia 2.9 +/- 4.0 vs 4.0 +/- 4.2 years, average NYHA Class 2 +/- 0.4 vs 3 +/ 0.9 (P = 0.008), mean number of preop anti-arrhythmics 1 +/- 0.4 vs 2 +/- 0.6 (P = 0.05). Two patients underwent conversion to an extracardiac conduit only, while 36 had concomitant right atrial cryoablation, of which 16 also had pacemaker implantation. Nine patients suffered major cardiac-related complications (7 low output syndrome, 3 ECMO, 3 acute renal failure, one stroke) (2/17 from the early conversion centre and 7/22 of the others; P = 0.14). Four patients died in hospital (10.3%) and 4 late after a median of 0.9 years [95% confidence interval (CI): 0.5-1] after conversion. An additional 2 patients needed transplantation at 1 and 8.8 years after conversion, respectively. The 10-year freedom from heart transplantation was 86% (95% CI: 51-97%). Outcomes from the centre with an early conversion strategy were significantly better: 8-year freedom from death or heart transplantation was 86% (95% CI: 53-96) vs 51% (95% CI: 22-74; log-rank P = 0.007). Eight additional patients required pacemaker implantation and 5 had arrhythmia recurrence. CONCLUSIONS: Fontan conversion is associated with lasting survival outcomes up to 10 years after conversion. A strategy of surgical conversion at earlier stage of failure may be associated with better survival free from transplantation. PMID- 25838459 TI - Minimally invasive Cox-maze procedure, beating-heart epicardial ablation, hybrid procedure and catheter ablation: a call for comparative evidence. PMID- 25838460 TI - Perivenous application of cyanoacrylate tissue sealants reduces intimal and medial thickening of the vein graft and inflammatory responses in a rabbit model of carotid artery bypass grafting. AB - OBJECTIVES: Effective therapies to prevent vein graft failure after coronary artery bypass grafting (CABG) are still lacking. alpha-Cyanoacrylate (alpha-CA, 99% n-octyl-alpha-cyanoacrylate + n-butyl-alpha-cyanoacrylate) has been increasingly used as a tissue sealant for wound closure because of its bacteriostatic, biodegradable and haemostatic properties. As a strong tissue adhesive, alpha-CA might prevent an arterial circulation-induced mechanical stretch on vein graft to attenuate intimal hyperplasia. Here, we investigated the effects of perivenous application of alpha-CA on the vein graft in a rabbit model of carotid artery bypass grafting. METHODS: Healthy New Zealand white rabbits were randomized into no graft, graft or graft + alpha-CA group (n = 10 per group). Rabbit carotid artery was bypassed with the jugular vein. alpha-CA sealants were sprayed on the entire jugular graft including both anastomotic sites after completion of anastomoses. Blood flow parameters and histological characteristics of the vein grafts including vessel wall thickness, number of medial elastic lamina and proliferation index were evaluated 4 weeks after the surgery. The mRNA or protein levels of proinflammatory factors, chemokine (C-C motif) ligand-2 (CCL-2) and tumour necrosis factor-alpha (TNF-alpha) were measured 4 weeks after the operation by quantitative reverse transcription polymerase chain reaction or enzyme-linked immunosorbent assay. RESULTS: Compared with the untreated vein grafts at Week 4 after the operation, the alpha-CA spray significantly improved graft flow (39.4 +/- 1.5 vs 27.8 +/- 2.9 ml/min, P < 0.01), attenuated intimal and medial thickening (116.3 +/- 1.0 vs 159.7 +/- 0.9 MUm, P < 0.01), reduced anti-proliferating cell nuclear antigen proliferation index of the vein grafts (15.0 +/- 0.4 vs 23.6 +/- 0.4%, P < 0.01), decreased the mRNA levels of plasminogen activator inhibitor-1 and CCL-2, and reduced the serum levels of TNF-alpha (92.9 +/- 1.7 vs 102.7 +/- 1.8 pg/ml, P < 0.01). CONCLUSION: Perivenous application of alpha-CA sealants exerts short-term beneficial effects on the vein graft and reduces inflammatory responses in a rabbit model of carotid artery bypass grafting. Long-term effects of alpha-CA on vein graft remodelling and the clinical significance of alpha-CA in CABG remain to be determined in future studies. PMID- 25838461 TI - Three-dimensional Imaging Reveals New Compartments and Structural Adaptations in Odontoblasts. AB - In organized tissues, the precise geometry and the overall shape are critical for the specialized functions that the cells carry out. Odontoblasts are major matrix producing cells of the tooth and have also been suggested to participate in sensory transmission. However, refined morphologic data on these important cells are limited, which hampers the analysis and understanding of their cellular functions. We took advantage of fluorescent color-coding genetic tracing to visualize and reconstruct in 3 dimensions single odontoblasts, pulp cells, and their assemblages. Our results show distinct structural features and compartments of odontoblasts at different stages of maturation, with regard to overall cellular shape, formation of the main process, orientation, and matrix deposition. We demonstrate previously unanticipated contacts between the processes of pulp cells and odontoblasts. All reported data are related to mouse incisor tooth. We also show that odontoblasts express TRPM5 and Piezo2 ion channels. Piezo2 is expressed ubiquitously, while TRPM5 is asymmetrically distributed with distinct localization to regions proximal to and within odontoblast processes. PMID- 25838462 TI - Estrogen receptor mutations found in breast cancer metastases integrated with the molecular pharmacology of selective ER modulators. AB - The consistent reports of mutations at Asp538 and Tyr537 in helix 12 of the ligand-binding domain (LBD) of estrogen receptors (ERs) from antihormone resistant breast cancer metastases constitute an important advance. The mutant amino acids interact with an anchor amino acid, Asp351, to close the LBD, thereby creating a ligand-free constitutively activated ER. Amino acids Asp 538, Tyr 537, and Asp 351 are known to play a role in either the turnover of ER, the antiestrogenic activity of the ER complex, or the estrogen-like actions of selective ER modulators. A unifying mechanism of action for these amino acids to enhance ER gene activation and growth response is presented. There is a range of mutations described in metastases vs low to zero in primary disease, so the new knowledge is of clinical relevance, thereby confirming an additional mechanism of acquired resistance to antihormone therapy through cell population selection pressure and enrichment during treatment. Circulating tumor cells containing ER mutations can be cultured ex vivo, and tumor tissues can be grown as patient derived xenografts to add a new dimension for testing drug susceptibility for future drug discovery. PMID- 25838463 TI - do_x3dna: a tool to analyze structural fluctuations of dsDNA or dsRNA from molecular dynamics simulations. AB - The do_x3dna package has been developed to analyze the structural fluctuations of DNA or RNA during molecular dynamics simulations. It extends the capability of the 3DNA package to GROMACS MD trajectories and includes new methods to calculate the global-helical axis of DNA and bending fluctuations during simulations. The package also includes a Python module dnaMD to perform and visualize statistical analyses of complex data obtained from the trajectories. PMID- 25838464 TI - Using neighborhood cohesiveness to infer interactions between protein domains. AB - MOTIVATION: In recent years, large-scale studies have been undertaken to describe, at least partially, protein-protein interaction maps, or interactomes, for a number of relevant organisms, including human. However, current interactomes provide a somehow limited picture of the molecular details involving protein interactions, mostly because essential experimental information, especially structural data, is lacking. Indeed, the gap between structural and interactomics information is enlarging and thus, for most interactions, key experimental information is missing. We elaborate on the observation that many interactions between proteins involve a pair of their constituent domains and, thus, the knowledge of how protein domains interact adds very significant information to any interactomic analysis. RESULTS: In this work, we describe a novel use of the neighborhood cohesiveness property to infer interactions between protein domains given a protein interaction network. We have shown that some clustering coefficients can be extended to measure a degree of cohesiveness between two sets of nodes within a network. Specifically, we used the meet/min coefficient to measure the proportion of interacting nodes between two sets of nodes and the fraction of common neighbors. This approach extends previous works where homolog coefficients were first defined around network nodes and later around edges. The proposed approach substantially increases both the number of predicted domain-domain interactions as well as its accuracy as compared with current methods. PMID- 25838465 TI - SPARSE: quadratic time simultaneous alignment and folding of RNAs without sequence-based heuristics. AB - MOTIVATION: RNA-Seq experiments have revealed a multitude of novel ncRNAs. The gold standard for their analysis based on simultaneous alignment and folding suffers from extreme time complexity of [Formula: see text]. Subsequently, numerous faster 'Sankoff-style' approaches have been suggested. Commonly, the performance of such methods relies on sequence-based heuristics that restrict the search space to optimal or near-optimal sequence alignments; however, the accuracy of sequence-based methods breaks down for RNAs with sequence identities below 60%. Alignment approaches like LocARNA that do not require sequence-based heuristics, have been limited to high complexity ([Formula: see text] quartic time). RESULTS: Breaking this barrier, we introduce the novel Sankoff-style algorithm 'sparsified prediction and alignment of RNAs based on their structure ensembles (SPARSE)', which runs in quadratic time without sequence-based heuristics. To achieve this low complexity, on par with sequence alignment algorithms, SPARSE features strong sparsification based on structural properties of the RNA ensembles. Following PMcomp, SPARSE gains further speed-up from lightweight energy computation. Although all existing lightweight Sankoff-style methods restrict Sankoff's original model by disallowing loop deletions and insertions, SPARSE transfers the Sankoff algorithm to the lightweight energy model completely for the first time. Compared with LocARNA, SPARSE achieves similar alignment and better folding quality in significantly less time (speedup: 3.7). At similar run-time, it aligns low sequence identity instances substantially more accurate than RAF, which uses sequence-based heuristics. PMID- 25838466 TI - What to expect when you're evaluating healthcare improvement: a concordat approach to managing collaboration and uncomfortable realities. AB - Evaluation of improvement initiatives in healthcare is essential to establishing whether interventions are effective and to understanding how and why they work in order to enable replication. Although valuable, evaluation is often complicated by tensions and friction between evaluators, implementers and other stakeholders. Drawing on the literature, we suggest that these tensions can arise from a lack of shared understanding of the goals of the evaluation; confusion about roles, relationships and responsibilities; data burdens; issues of data flows and confidentiality; the discomforts of being studied and the impact of disappointing or otherwise unwelcome results. We present a possible approach to managing these tensions involving the co-production and use of a concordat. We describe how we developed a concordat in the context of an evaluation of a complex patient safety improvement programme known as Safer Clinical Systems Phase 2. The concordat development process involved partners (evaluators, designers, funders and others) working together at the outset of the project to agree a set of principles to guide the conduct of the evaluation. We suggest that while the concordat is a useful resource for resolving conflicts that arise during evaluation, the process of producing it is perhaps even more important, helping to make explicit unspoken assumptions, clarify roles and responsibilities, build trust and establish open dialogue and shared understanding. The concordat we developed established some core principles that may be of value for others involved in evaluation to consider. But rather than seeing our document as a ready-made solution, there is a need for recognition of the value of the process of co-producing a locally agreed concordat in enabling partners in the evaluation to work together effectively. PMID- 25838467 TI - Integrating the Illness Beliefs Model in clinical practice: a Family Systems Nursing knowledge utilization model. AB - To promote the integration of Family Systems Nursing (FSN) in clinical practice, we need to better understand how nurses overcome the challenges of FSN knowledge utilization. A qualitative exploratory study was conducted with 32 practicing female nurses from hospital and community settings who had received FSN intervention training and skill development based on the Illness Beliefs Model and the Calgary Family Assessment and Intervention Models. The participants were interviewed about how they utilized FSN knowledge in their nursing practice. From the data analysis, a FSN Knowledge Utilization Model emerged that involves three major components: (a) nurses' beliefs in FSN and in their FSN skills, (b) nurses' knowledge utilization strategies to address the challenges of FSN practice, and (c) FSN positive outcomes. The FSN Knowledge Utilization Model describes a circular, incremental, and iterative process used by nurses to integrate FSN in daily nursing practice. Findings point to a need for re-evaluation of educational and management strategies in clinical settings for advancing the practice of FSN. PMID- 25838470 TI - Complete Genome Sequence of Lactobacillus plantarum Strain B21, a Bacteriocin Producing Strain Isolated from Vietnamese Fermented Sausage Nem Chua. AB - Lactobacillus plantarum strain B21 was isolated from Vietnamese sausage (nem chua) and demonstrated broad antimicrobial activity due to the production of bacteriocins. Here, we report the complete genome sequence of this strain (3,284,260 bp). PMID- 25838468 TI - High Parathyroid Hormone Level and Osteoporosis Predict Progression of Coronary Artery Calcification in Patients on Dialysis. AB - Coronary artery calcifications (CACs) are observed in most patients with CKD on dialysis (CKD-5D). CACs frequently progress and are associated with increased risk for cardiovascular events, the major cause of death in these patients. A link between bone and vascular calcification has been shown. This prospective study was designed to identify noninvasive tests for predicting CAC progression, including measurements of bone mineral density (BMD) and novel bone markers in adult patients with CKD-5D. At baseline and after 1 year, patients underwent routine blood tests and measurement of CAC, BMD, and novel serum bone markers. A total of 213 patients received baseline measurements, of whom about 80% had measurable CAC and almost 50% had CAC Agatston scores>400, conferring high risk for cardiovascular events. Independent positive predictors of baseline CAC included coronary artery disease, diabetes, dialysis vintage, fibroblast growth factor-23 concentration, and age, whereas BMD of the spine measured by quantitative computed tomography was an inverse predictor. Hypertension, HDL level, and smoking were not baseline predictors in these patients. Three quarters of 122 patients completing the study had CAC increases at 1 year. Independent risk factors for CAC progression were age, baseline total or whole parathyroid hormone level greater than nine times the normal value, and osteoporosis by t scores. Our results confirm a role for bone in CKD-associated CAC prevalence and progression. PMID- 25838469 TI - Temporal Heterogeneity Metrics in Apoptosis Induced by Anticancer Drugs. AB - The apoptotic process is highly heterogeneous and asynchronous. A long-standing question is how many parameters define the time and reversibility of the apoptotic response at a single-cell level. We characterized at the single-cell and population levels the time sequence of apoptotic events in response to anti cancer drugs using extrinsic and intrinsic apoptotic stimuli. We show that the temporal sequence of major apoptotic events is the same in response to all anti cancer drugs studied: the apoptotic volume decrease and Na+ influx occur rapidly and are tightly coordinated with mitochondrial outer membrane depolarization (MOMP), mitochondrial inner membrane depolarization and a decrease in the production of reactive oxygen species (ROS). Phosphatidylserine externalization usually starts after MOMP and precedes caspase 3/7 activation. Activation of caspases 3/7 is a slow process that always starts after MOMP, with significant delay. Cell-to-cell variability of the MOMP onset is described by Gaussian distribution, whereas the gamma-distribution model describes cellular variability in the duration of MOMP-to-caspase activation stages. Cells from the pre-MOMP stage to the after-caspase 3/7 activation stage coexist for many hours. We demonstrated by FACS that cells in the pre-MOMP stage can recover after apoptotic stimuli, rarely recover after MOMP but before caspase 3/7 activation, and are unable to recover after caspase 3/7 activation. We propose a double-stroke model for apoptosis execution. PMID- 25838471 TI - Draft Genome Sequence of Neurospora crassa Strain FGSC 73. AB - We report the elucidation of the complete genome of the Neurospora crassa (Shear and Dodge) strain FGSC 73, a mat-a, trp-3 mutant strain. The genome sequence around the idiotypic mating type locus represents the only publicly available sequence for a mat-a strain. 40.42 Megabases are assembled into 358 scaffolds carrying 11,978 gene models. PMID- 25838472 TI - Complete Genome Sequence of a Novel Mutation of Seoul Virus Isolated from Suncus murinus in the Fujian Province of China. AB - Suncus murinus has been identified as the host for Seoul virus (SEOV). Here, we report the complete genome sequence of SEOV strain Fj372/2013, which was isolated from the lung tissue of Suncus murinus in the Fujian Province of China. A mutation A38C was observed in an open reading fragment of the middle segment. PMID- 25838473 TI - Complete Genome Sequence of Bifidobacterium longum subsp. infantis Strain CECT 7210, a Probiotic Strain Active against Rotavirus Infections. AB - Bifidobacterium longum subsp. infantis CECT 7210 is a probiotic strain able to inhibit rotavirus in vitro and protect against viral infection in both cell cultures and mice. Here, we report its complete genome sequence, as deciphered by PacBio single-molecule real-time (SMRT) technology. An analysis of the sequence may provide insights into its functional activity. PMID- 25838474 TI - High-Quality Draft Genome Sequence of Actinobacterium Kibdelosporangium sp. MJ126 NF4, Producer of Type II Polyketide Azicemicins, Using Illumina and PacBio Technologies. AB - Here, we report the high-quality draft genome sequence of actinobacterium Kibdelosporangium sp. MJ126-NF4, producer of the type II polyketide azicemicins, obtained using Illumina and PacBio sequencing technologies. The 11.75-Mbp genome contains >11,000 genes and 22 polyketide and nonribosomal peptide natural product gene clusters. PMID- 25838475 TI - Genome Sequence of Fungal Species No.11243, Which Produces the Antifungal Antibiotic FR901469. AB - Fungal species No.11243 was originally isolated from a decayed leaf sample collected in Kyoto, Japan. It produces FR901469, a 1,3-beta-glucan synthase inhibitor. The genome sequence of No.11243 was determined and annotated to obtain useful information for improving productivity of the effective antifungal agent FR901469. PMID- 25838476 TI - Complete genome sequence of a tomato mottle mosaic virus isolate from the United States. AB - Tomato mottle mosaic virus was recently reported from the United States following its original description from Mexico as a novel Tobamovirus species. We present the first complete genome sequence of a tomato mottle mosaic virus isolate from the United States. PMID- 25838477 TI - A Distinct Group II Alphabaculovirus Isolated from a Peridroma Species. AB - The genome sequence of an alphabaculovirus isolated from a Peridroma species indicated that it is a novel member of a group II lineage most closely related to alphabaculoviruses from Spodoptera exigua and Agrotis segetum. It contains a genome of 151,110 nucleotides (nt), with a G+C content of 53.3%. PMID- 25838478 TI - Novel H5 Clade 2.3.4.4 Reassortant (H5N1) Virus from a Green-Winged Teal in Washington, USA. AB - Eurasian (EA)-origin H5N8 clade 2.3.4.4 avian influenza viruses were first detected in North America during December 2014. Subsequent reassortment with North American (AM) low-pathogenic wild-bird-origin avian influenza has generated at least two reassortants, including an EA/AM H5N1 from an apparently healthy wild green-winged teal, suggesting continued ongoing reassortment. PMID- 25838479 TI - Draft Genome Sequence of Clostridium botulinum Strain 277-00 Type B2. AB - We report the draft genome sequence of Clostridium botulinum strain 277-00, which encodes a botulinum neurotoxin B2 associated with a ha gene locus. Strain 277-00 was isolated from a cheese responsible for an outbreak of botulism in Iran in 1997. This strain is closed to the bivalent B2/FA strain IBCA10-7060. PMID- 25838480 TI - Draft Whole-Genome Sequences of 14 Vibrio parahaemolyticus Clinical Isolates with an Ambiguous K Serogroup. AB - Vibrio parahaemolyticus is a bacterial pathogen responsible for mild to severe gastroenteritis, wound infections, and septicemia resulting from the ingestion or handling of raw or undercooked contaminated seafood. Here, we report the draft whole-genome sequences and annotations of 14 Canadian V. parahaemolyticus clinical isolates that were serologically identified as K group II using polyvalent antisera but were not specifically K serogrouped using monovalent antisera. PMID- 25838481 TI - Draft Genome Sequence of Ochrobactrum anthropi Strain ML7 Isolated from Soil Samples in Vinhphuc Province, Vietnam. AB - Ochrobactrum species are widespread in the environment and can colonize a wide variety of habitats. Here, we describe the sequencing of a new environmental isolate of Ochrobactrum anthropi isolated from northern Vietnam. PMID- 25838482 TI - Draft Genome Sequence of Pseudomonas toyotomiensis KF710, a Polychlorinated Biphenyl-Degrading Bacterium Isolated from Biphenyl-Contaminated Soil. AB - Pseudomonas toyotomiensis KF710 utilizes biphenyl and degrades polychlorinated biphenyls (PCBs). Here, we report the genome sequence of the KF710 strain, consisting of 5,596,721 bp with 5,155 coding sequences. The biphenyl catabolic genes were almost identical to those of Pseudomonas pseudoalcaligenes KF707, one of the most well-characterized biphenyl-utilizing strains. PMID- 25838483 TI - Genome Sequence of the Butyrate-Producing Anaerobic Bacterium Anaerostipes hadrus PEL 85. AB - Anaerostipes hadrus PEL 85, which was isolated from human feces, is a Gram positive rod-shaped bacterium. The species may play an important role in gut health, as it was previously reported to produce butyric acid. Here, we present the genome assembly of PEL 85, a novel strain of A. hadrus. PMID- 25838484 TI - Draft Genome Sequence of Enterotoxigenic Escherichia coli Strain E24377A, Obtained from a Tribal Drinking Water Source in India. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrheal disease in humans and animals. Its dissemination can occur through water sources contaminated by it. Here, we report for the first time the draft genome sequence of ETEC strain E24377A, obtained from a tribal drinking water source in India. PMID- 25838485 TI - Draft Genome Sequence of Bioactive-Compound-Producing Cyanobacterium Tolypothrix campylonemoides Strain VB511288. AB - We report here the draft genome sequence of Tolypothrix campylonemoides VB511288, isolated from building facades in Santiniketan, India. The members of this genus produce several compounds of commercial importance. The draft assembly is 10,627,177 bases in 135 scaffolds, and it contains 7,886 protein-coding genes, 994 pseudogenes, 18 rRNA genes, and 76 tRNA genes. PMID- 25838486 TI - Deciphering the Genome Sequences of the Hydrophobic Cyanobacterium Scytonema tolypothrichoides VB-61278. AB - Scytonema tolypothrichoides VB-61278, a terrestrial cyanobacterium, can be exploited to produce commercially important products. Here, we report for the first time a 10-Mb draft genome assembly of S. tolypothrichoides VB-61278, with 214 scaffolds and 7,148 putative protein-coding genes. PMID- 25838487 TI - Draft Genome Sequence of Aneurinibacillus migulanus Strain Nagano. AB - Aneurinibacillus migulanus is characterized by inhibition of growth of a range of plant-pathogenic bacteria and fungi. Here, we report the high-quality draft genome sequences of A. migulanus Nagano. PMID- 25838488 TI - Genome Sequence of Magnetospirillum magnetotacticum Strain MS-1. AB - Here, we report the genome sequence of Magnetospirillum magnetotacticum strain MS 1, which consists of of 36 contigs and 4,136 protein-coding genes. PMID- 25838489 TI - Draft Genome Sequence of Aneurinibacillus migulanus NCTC 7096. AB - Aneurinibacillus migulanus has biocontrol activities against fungal, fungus-like, and bacterial plant pathogens with different levels of efficacy depending on the target pathogens. Here, we report the high-quality draft genome sequence of A. migulanus NCTC 7096. PMID- 25838490 TI - Draft Genome Sequence of Empedobacter (Formerly Wautersiella) falsenii comb. nov. Wf282, a Strain Isolated from a Cervical Neck Abscess. AB - Empedobacter (formerly Wautersiella) falsenii comb. nov. strain Wf282 was isolated from a cervical neck abscess sample from an 18-year-old female patient. The isolate was resistant to many antibiotics, including meropenem and colistin. The total DNA from the multidrug-resistant E. falsenii comb. nov. Wf282 clinical isolate was sequenced. PMID- 25838491 TI - Draft Genome Sequence of Clostridium botulinum B2 450 Strain from Wound Botulism in a Drug User in Italy. AB - Here, we report the draft genome sequence of Clostridium botulinum B2 450, responsible for the first reported case of wound botulism in a drug user in Italy. PMID- 25838492 TI - Genome Sequence of Kosakonia radicincitans Strain YD4, a Plant Growth-Promoting Rhizobacterium Isolated from Yerba Mate (Ilex paraguariensis St. Hill.). AB - Kosakonia radicincitans strain YD4 is a rhizospheric isolate from yerba mate (Ilex paraguariensis St. Hill.) with plant growth-promoting effects on this crop. Genes involved in different plant growth-promoting activities are present in this genome, suggesting its potential as a bioinoculant for yerba mate. PMID- 25838493 TI - Draft Genome Sequence of Pseudomonas sp. nov. H2. AB - We report the draft genome sequence of Pseudomonas sp. nov. H2, isolated from creek sediment in Moscow, ID, USA. The strain is most closely related to Pseudomonas putida. However, it has a slightly smaller genome that appears to have been impacted by horizontal gene transfer and poorly maintains IncP-1 plasmids. PMID- 25838494 TI - Genome Sequence of Bacillus mycoides B38V, a Growth-Promoting Bacterium of Sunflower. AB - Bacillus mycoides B38V is a bacterium isolated from the sunflower rhizosphere that is able to promote plant growth and N uptake. The genome of the isolate has approximately 5.80 Mb and presents sequence codifiers for plant growth-promoting characteristics, such as nitrate reduction and ammonification and iron siderophore uptake. PMID- 25838495 TI - Whole-Genome Shotgun Sequence of the Keratinolytic Bacterium Lysobacter sp. A03, Isolated from the Antarctic Environment. AB - Lysobacter sp. strain A03 is a protease-producing bacterium isolated from decomposing-penguin feathers collected in the Antarctic environment. This strain has the ability to degrade keratin at low temperatures. The A03 genome sequence provides the possibility of finding new genes with biotechnological potential to better understand its cold-adaptation mechanism and survival in cold environments. PMID- 25838496 TI - Genome of Pseudomonas sp. FeS53a, a Putative Plant Growth-Promoting Bacterium Associated with Rice Grown in Iron-Stressed Soils. AB - Pseudomonas sp. FeS53a was isolated from the roots of rice plants cultivated in one area with a well-established history of iron toxicity. The FeS53a genome sequence provides the genetic basis for understanding its lifestyle and survival in association with rice in conditions of iron toxicity. PMID- 25838497 TI - Genome of Rhizobium sp. UR51a, Isolated from Rice Cropped in Southern Brazilian Fields. AB - Rhizobium sp. UR51a is a Gram-negative bacterium isolated from roots of rice plants, and it presents plant growth-promoting abilities. The nutrient uptake in rice plants inoculated with UR51a was satisfactory. The genome of strain UR51a is composed of 5,233,443-bp and harbors 5,079 coding sequences. PMID- 25838498 TI - Genome Sequence of the Mycorrhiza Helper Bacterium Streptomyces sp. Strain AcH 505. AB - A draft genome sequence of Streptomyces sp. strain AcH 505 is presented here. The genome encodes 22 secondary metabolite gene clusters and a large arsenal of secreted proteins, and their comparative and functional analyses will help to advance our knowledge of symbiotic interactions and fungal and plant biomass degradation. PMID- 25838499 TI - Draft Genome Sequence of Streptomyces sp. Strain 150FB, a Mushroom Mycoparasite Antagonist. AB - Streptomyces sp. strain 150FB, isolated from the cap surface of a bolete mushroom, inhibits the growth of the mycoparasitic Sepedonium species. Functional annotation of the strain 150FB draft genome identified 22 putative secondary metabolite biosynthetic gene clusters and genes encoding secreted proteins, which may contribute to the inhibition of the mycoparasite. PMID- 25838500 TI - The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. AB - The amyloid precursor protein (APP) has garnered considerable attention due to its genetic links to Alzheimer's disease. Death receptor 6 (DR6) was recently shown to bind APP via the protein extracellular regions, stimulate axonal pruning, and inhibit synapse formation. Here, we report the crystal structure of the DR6 ectodomain in complex with the E2 domain of APP and show that it supports a model for APP-induced dimerization and activation of cell surface DR6. PMID- 25838501 TI - Do cognitive interventions improve general cognition in dementia? A meta-analysis and meta-regression. AB - OBJECTIVES: To review the efficacy of cognitive interventions on improving general cognition in dementia. METHOD: Online literature databases and trial registers, previous systematic reviews and leading journals were searched for relevant randomised controlled trials. A systematic review, random-effects meta analyses and meta-regression were conducted. Cognitive interventions were categorised as: cognitive stimulation (CS), involving a range of social and cognitive activities to stimulate multiple cognitive domains; cognitive training (CT), involving repeated practice of standardised tasks targeting a specific cognitive function; cognitive rehabilitation (CR), which takes a person-centred approach to target impaired function; or mixed CT and stimulation (MCTS). Separate analyses were conducted for general cognitive outcome measures and for studies using 'active' (designed to control for non-specific therapeutic effects) and non-active (minimal or no intervention) control groups. RESULTS: 33 studies were included. Significant positive effect sizes (Hedges' g) were found for CS with the mini-mental state examination (MMSE) (g=0.51, 95% CI 0.35 to 0.66; p<0.001) compared to non-active controls and (g=0.35, 95% CI 0.06 to 0.64; p=0.019) compared to active controls. Significant benefit was also seen with the Alzheimer's disease Assessment Scale-Cognition (ADAS-Cog) (g=-0.26, 95% CI -0.445 to -0.08; p=0.005). There was no evidence that CT or MCTS produced significant improvements on general cognition outcomes and not enough CR studies for meta analysis. The lowest accepted minimum clinically important difference was reached in 11/17 CS studies for the MMSE, but only 2/9 studies for the ADAS-Cog. Additionally, 95% prediction intervals suggested that although statistically significant, CS may not lead to benefits on the ADAS-Cog in all clinical settings. CONCLUSIONS: CS improves scores on MMSE and ADAS-Cog in dementia, but benefits on the ADAS-Cog are generally not clinically significant and difficulties with blinding of patients and use of adequate placebo controls make comparison with the results of dementia drug treatments problematic. PMID- 25838503 TI - Hospital costs of out-of-hospital cardiac arrest patients treated in intensive care; a single centre evaluation using the national tariff-based system. AB - OBJECTIVES: There is a scarcity of literature reporting hospital costs for treating out of hospital cardiac arrest (OOHCA) survivors, especially within the UK. This is essential for assessment of cost-effectiveness of interventions necessary to allow just allocation of resources within the National Health Service. We set out primarily to calculate costs stratified against hospital survival and neurological outcomes. Secondarily, we estimated cost effectiveness based on estimates of survival and utility from previous studies to calculate costs per quality adjusted life year (QALY). SETTING: We performed a single centre (London) retrospective review of in-hospital costs of patients admitted to the intensive care unit (ICU) following return of spontaneous circulation (ROSC) after OOHCA over 18 months from January 2011 (following widespread introduction of targeted temperature management and primary percutaneous intervention). PARTICIPANTS: Of 69 successive patients admitted over an 18-month period, survival and cerebral performance category (CPC) outcomes were obtained from review of databases and clinical notes. The Trust finance department supplied ICU and hospital costs using the Payment by Results UK system. RESULTS: Of those patients with ROSC admitted to ICU, survival to hospital discharge (any CPC) was 33/69 (48%) with 26/33 survivors in CPC 1-2 at hospital discharge. Cost per survivor to hospital discharge (including total cost of survivors and non survivors) was L50,000, cost per CPC 1-2 survivor was L65,000. Cost and length of stay of CPC 1-2 patients was considerably lower than CPC 3-4 patients. The majority of the costs (69%) related to intensive care. Estimated cost per CPC 1-2 survivor per QALY was L16,000. CONCLUSIONS: The costs of in-hospital patient care for ICU admissions following ROSC after OOHCA are considerable but within a reasonable threshold when assessed from a QALY perspective. PMID- 25838502 TI - Psychotropic drug use in adolescents born with an orofacial cleft: a population based study. AB - OBJECTIVES: Being born with an orofacial cleft (OFC) can, due to an incomplete closure of the lip and/or palate, convey a deviant speech and/or deviant facial aesthetics, which may in turn increase the risk for poor psychological health later in life. Previous investigations have been based on small samples and self reports, not distinguishing between the three different types of OFC: cleft lip (CL), CL and palate (CLP) and cleft palate only (CPO). We present a large population-based study, considering psychotropic drug use as a proxy for poor psychological health and distinguishing between three different types of OFC. DESIGN AND METHODS: Using the Swedish Medical Birth Register, and linking to it the Swedish Prescribed Drug Register, the National Mortality Register, the Emigration Register and the National Inpatient Register, we identified all singletons born to native mothers in Sweden between 1987 and 1993, alive and residing in Sweden at the end of an 18-year follow-up period (N=626 109). We compared psychotropic drug use among individuals with and without OFC during the individuals' adolescence (2005-2008) by multiple logistic regressions, using ORs with 95% CIs. RESULTS: When adjusted for potential confounders, having a CL (OR=1.63, 95% CI 1.08 to 2.46) or a CPO (OR=1.54, 95% CI 1.18 to 2.01) increased the risk of psychotropic drug use. Results were not significant regarding adolescents who had a CLP (OR=1.21, 95% CI 0.81 to 1.80). CONCLUSIONS: Being born with a CL or a CPO increases the risk for psychotropic drug use in adolescence, but not for adolescents born with a CLP. Our findings suggest that, since the three OFC types are associated with different long-term risks of poor psychological health, the three groups should be studied separately concerning long-term psychosocial consequences. PMID- 25838504 TI - Lack of weight recording in patients being administered narrow therapeutic index antibiotics: a prospective cross-sectional study. AB - OBJECTIVES: Patient weight is a key measure for safe medication management and monitoring of patients. Here we report the recording of patient's body weight on admission in three hospitals in West London and its relationship with the prescription of antibiotic drugs where it is essential to have the body weight of the patient. METHODS: A prospective cross-sectional study was conducted in three teaching hospitals in West London. Data were collected during March 2011 September 2011 and July 2012-August 2012, from adult admissions units, medical and surgical wards. Data from each ward were collected on a single day to provide a point prevalence data on weight recording. Patient medication charts, nursing and medical notes were reviewed for evidence of weight and height recording together with all the medication prescribed for the patients. An observational study collecting data on the weight recording process was conducted on two randomly selected wards to add context to the data. RESULTS: Data were collected on 1012 patients. Weight was not recorded for 46% (474) of patients. Eighty-nine patients were prescribed a narrow therapeutic antibiotic, in 39% (35/89) of these weight was not recorded for the patient. Intravenous vancomycin was the most commonly prescribed antibiotic requiring therapeutic monitoring. In total 61 patients were receiving intravenous vancomycin and of these 44% (27/61) did not have their weight recorded. In the observational study, the most frequently identified barrier to weight not being recorded was interruptions to the admission process. CONCLUSIONS: Despite the clinical importance of body weight measurement it is poorly recorded in hospitalised patients, due to interruptions to the workflow and heavy staff workloads. In antibiotics a correct, recent patient weight is required for accurate dosing and to keep drugs within the narrow therapeutic index, to ensure efficacy of prescribing and reduce toxicity. PMID- 25838506 TI - Risk factors for emergency presentation with lung and colorectal cancers: a systematic review. AB - OBJECTIVE: To identify patient and practitioner factors that influence cancer diagnosis via emergency presentation (EP). DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, CINAHL, EBM Reviews, Science and Social Sciences Citation Indexes, Conference Proceedings Citation Index-Science and Conference Proceedings Citation Index-Social Science and Humanities. Searches were undertaken from 1996 to 2014. No language restrictions were applied. STUDY SELECTION: Studies of any design assessing factors associated with diagnosis of colorectal or lung cancer via EP, or describing an intervention to impact on EP, were included. Studies involving previously diagnosed cancer patients, assessing only referral pathway effectiveness, outcomes related to diagnosis or post-EP management were excluded. The population was individual or groups of adult patients or primary care practitioners. Two authors independently screened studies for inclusion. RESULTS: 22 studies with over 200,000 EPs were included, most providing strong evidence. Five were graded 'insufficient', primarily due to missing information rather than methodological weakness. Older patient age was associated with EP for lung and colorectal cancers (OR 1.11-11.03 and 1.19-5.85, respectively). Women were more at risk of EP for lung but not colorectal cancer. Higher deprivation increased the likelihood of lung cancer EP, but evidence for colorectal was less conclusive. Being unmarried (or divorced/widowed) increased the likelihood of EP for colorectal cancer, which was also associated with pain, obstruction and weight loss. Lack of a regular source of primary care, and lower primary care use were positively associated with EP. Only three studies considered practitioner factors, two involving diagnostic tests. No conclusive evidence was found. CONCLUSIONS: Patient-related factors, such as age, gender and deprivation, increase the likelihood of cancer being diagnosed as the result of an EP, while cancer symptoms and patterns of healthcare utilisation are also relevant. Further work is needed to understand the context in which risk factors for EP exist and influence help-seeking. PMID- 25838505 TI - Impact of cardiovascular risk factors and medication use on the efficacy of remote ischaemic conditioning: post hoc subgroup analysis of a randomised controlled trial. AB - OBJECTIVES: Remote ischaemic conditioning (RIC) promotes cardioprotection in patients undergoing primary percutaneous coronary intervention (pPCI) for ST elevation myocardial infarction (STEMI). The effect of RIC may be modified by cardiovascular risk factors and their medications. We examined whether cardiovascular risk factors, lipid and glucose levels, and medication use influenced the efficacy of RIC in patients with STEMI treated with pPCI. DESIGN: Post hoc subgroup analysis of a single-centre randomised controlled trial. PARTICIPANTS: A total of 139 patients with STEMI, randomised during ambulance transport to hospital for pPCI with (n=71) or without (n=68) RIC, met the trial criteria and achieved data for a myocardial salvage index (MSI). INTERVENTIONS: RIC was administered through intermittent arm ischaemia with four cycles of 5 min inflation and 5 min deflation of a blood pressure cuff. PRIMARY OUTCOME MEASURES: MSI, estimated by single-photon emission CT. We evaluated the efficacy of RIC on the MSI in patient subgroups of cardiovascular risk factors, lipid and glucose levels, and medication use. RESULTS: We found no significant difference in the efficacy of RIC in subgroups of cardiovascular risk factors, lipid and glucose levels, and medication use. However, point estimates indicated a reduced effect of RIC among smokers (median difference in MSI between RIC and control groups: 0.02 (95% CI -0.32 to 0.28) in smokers vs 0.25 (95% CI 0.08 to 0.42) in non smokers, p value for interaction=0.13) and an increased effect of RIC in statin users (median difference in MSI between RIC and control groups: 0.34 (95% CI 0.03 to 0.65) in statin users vs 0.09 (95% CI -0.11 to 0.29) in non-statin users, p value for interaction=0.19). CONCLUSIONS: RIC as an adjunct to pPCI seems to improve MSI in our trial population of patients with STEMI regardless of most cardiovascular risk factors and their medications. Our post hoc finding on a limited sample size calls for further investigation in large-scale multicentre trials. TRIAL REGISTRATION NUMBER: NCT00435266. PMID- 25838507 TI - Acupuncture for benign prostatic hyperplasia: a systematic review protocol. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate commonly encountered in older men. BPH has been treated with acupuncture inside and outside China, but its effects are uncertain. This review aims to assess the efficacy and safety of acupuncture therapy for BPH. METHODS AND ANALYSIS: Seven databases will be searched from their inception: the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Chinese Biomedical Database, the China National Knowledge Infrastructure, the VIP Database and Wanfang Database. Randomised controlled clinical trials using acupuncture to treat BPH will be included. Outcome measures included urological symptom scores, urodynamic measures and quality-of-life scales. Adverse events will be assessed and reported for safety evaluation. Study selection and data extraction will be performed by two independent reviewers. Quality assessment (assessment of risk of bias) and data synthesis will be implemented using Review Manager (RevMan) software (V.5.2.3). ETHICS AND DISSEMINATION: Ethical approval is not necessary because this systematic review will not include specific patient data. Updates will be conducted if there is enough new evidence that may cause any change in review conclusions. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014013645. PMID- 25838508 TI - Trading quality for relevance: non-health decision-makers' use of evidence on the social determinants of health. AB - OBJECTIVES: Local government services and policies affect health determinants across many sectors such as planning, transportation, housing and leisure. Researchers and policymakers have argued that decisions affecting wider determinants of health, well-being and inequalities should be informed by evidence. This study explores how information and evidence are defined, assessed and utilised by local professionals situated beyond the health sector, but whose decisions potentially affect health: in this case, practitioners working in design, planning and maintenance of the built environment. DESIGN: A qualitative study using three focus groups. A thematic analysis was undertaken. SETTING: The focus groups were held in UK localities and involved local practitioners working in two UK regions, as well as in Brazil, USA and Canada. PARTICIPANTS: UK and international practitioners working in the design and management of the built environment at a local government level. RESULTS: Participants described a range of data and information that constitutes evidence, of which academic research is only one part. Built environment decision-makers value empirical evidence, but also emphasise the legitimacy and relevance of less empirical ways of thinking through narratives that associate their work to art and philosophy. Participants prioritised evidence on the acceptability, deliverability and sustainability of interventions over evidence of longer term outcomes (including many health outcomes). Participants generally privileged local information, including personal experiences and local data, but were less willing to accept evidence from contexts perceived to be different from their own. CONCLUSIONS: Local-level built environment practitioners utilise evidence to make decisions, but their view of 'best evidence' appears to prioritise local relevance over academic rigour. Academics can facilitate evidence-informed local decisions affecting social determinants of health by working with relevant practitioners to improve the quality of local data and evaluations, and by advancing approaches to improve the external validity of academic research. PMID- 25838509 TI - Industrial hygiene, occupational safety and respiratory symptoms in the Pakistani cotton industry. AB - OBJECTIVES: In the cotton industry of Pakistan, 15 million people are employed and exposed to cotton dust, toxic chemicals, noise and physical hazards. The aim of this study was to determine the prevalence of health symptoms, particularly respiratory symptoms, and to measure cotton dust and endotoxin levels in different textile factories of Faisalabad, Pakistan. METHODS: A cross-sectional investigation was performed in a representative sample of 47 cotton factories in the Faisalabad region in Punjab, Pakistan. Respiratory symptoms of 800 workers were documented by questionnaire. Occupational safety in the factories was assessed by a trained expert following a checklist, and dust and endotoxin levels in different work areas were measured. RESULTS: Prevalence of respiratory disease symptoms (fever, shortness of breath, chest tightness and cough) was generally high and highest in the weaving section of the cotton industry (20-40% depending on symptoms). This section also displayed the poorest occupational safety ratings and the highest levels of inhalable cotton dust (mean+/-SD 4.6+/-2.5 vs 0.95+/ 0.65 mg/m(3) in compact units). In contrast, endotoxin levels were highest in the spinning section (median 1521 EU/m(3)), where high humidity is maintained. CONCLUSIONS: There are still poor working conditions in the cotton industry in Pakistan where workers are exposed to different occupational hazards. More health symptoms were reported from small weaving factories (power looms). There is a dire need for improvements in occupational health and safety in this industrial sector with particular focus on power looms. PMID- 25838510 TI - The association between obesity and severe disability among adults aged 50 or over in nine high-income, middle-income and low-income countries: a cross sectional study. AB - OBJECTIVE: The association between obesity and disability may differ between high income and low-income/middle-income countries but there are no studies comparing this association between these settings. The aim of the study was to assess this association in nine countries using nationally-representative data from the Collaborative Research on Ageing in Europe (COURAGE) study and the WHO's Study on global AGEing and Adult Health (SAGE). DESIGN: Population-based cross-sectional study SETTING: The survey was conducted in China, Finland, Ghana, India, Mexico, Poland, Russia, South Africa and Spain between 2007 and 2012. PARTICIPANTS: 42 116 individuals 50 years and older. The institutionalised and those with limited cognition were excluded. PRIMARY OUTCOME MEASURE: Disability was defined as severe or extreme difficulty in conducting at least one of six types of basic activities of daily living (ADL). RESULTS: The mean body mass index (BMI) ranged from 20.4 kg/m(2) in India to 30.7 kg/m(2) in South Africa. Compared to normal BMI (18.5-24.9 kg/m(2)), BMI>=35 kg/m(2) was associated with significantly higher odds for ADL disability in Finland (OR 4.64), Poland (OR 2.77), South Africa (OR 2.19) and Spain (OR 2.42). Interaction analysis showed that obese individuals in high-income countries were more likely to have ADL limitations than those in low income or middle-income countries. CONCLUSIONS: The higher odds for disability among obese individuals in high-income countries may imply longer life lived with disability due to factors such as the decline in cardiovascular disease mortality. In South Africa, this may have been due to the exceptionally high prevalence of class III obesity. These findings underscore the importance of obesity prevention to reduce the disability burden among older adults. PMID- 25838511 TI - EXPERTS 1-experiences of long-term life-limiting conditions among patients and carers: protocol for a qualitative meta-synthesis and conceptual modelling study. AB - INTRODUCTION: Increasing numbers of the population are living with long-term life limiting conditions with a significant proportion characterised by multimorbidity. Patients with these conditions often experience high volumes of clinical interaction involving them, their caregivers and healthcare providers in complex patterns of organising, coordinating, negotiating and managing care. A better understanding of the sources of experienced complexity and multimorbidity, from the patient perspective is paramount to improve capacity and manage workload to promote improved experience of illness, more effective healthcare utilisation and improved healthcare outcomes. To better understand the sources of complexity we will undertake an evidence synthesis of qualitative studies of patient and informal carer experiences of three common long-term life-limiting conditions. We will investigate what is known about these diseases at different stages in disease progression, treatment regimens and places of care. METHOD AND ANALYSIS: We will include qualitative studies of patients' and carers' (aged >18) accounts of their experiences of healthcare provision in a range of settings and healthcare systems. We will conduct an extensive electronic database search of publications in English between 2000 and 2014. Results and discussions sections of the papers will be regarded as formal data using the constant comparison method of qualitative analysis. From the meta-synthesis results, we will build a conceptual model of mechanisms and processes that shape patients' journeys towards end of life to suggest where in the patient journey new interventions to improve patient and carer experience can be developed and delivered. The study is being conducted between 1 December 2014 and 31 December 2015. ETHICS AND DISSEMINATION: No human subjects or personal data are involved and no ethical issues are anticipated. An important element of dissemination is informing user communities about the practical implications of the work through workshops, meetings and social media. Scientific results will be published in peer reviewed journals and disseminated through conferences. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014014547. PMID- 25838512 TI - Antibodies to myelin oligodendrocyte glycoprotein in idiopathic optic neuritis. AB - OBJECTIVES: To investigate the differences of clinical features, cerebrospinal fluid (CSF), MRI findings and response to steroid therapies between patients with optic neuritis (ON) who have myelin oligodendrocyte glycoprotein (MOG) antibodies and those who have seronegative ON. SETTING: We recruited participants in the department of neurology and ophthalmology in our hospital in Japan. METHODS: We retrospectively evaluated the clinical features and response to steroid therapies of patients with ON. Sera from patients were tested for antibodies to MOG and aquaporin-4 (AQP4) with a cell-based assay. PARTICIPANTS: Between April 2009 and March 2014, we enrolled serial 57 patients with ON (27 males, 30 females; age range 16-84 years) who ophthalmologists had diagnosed as having or suspected to have ON with acute visual impairment and declined critical flicker frequency, abnormal findings of brain MRI, optical coherence tomography and fluorescein fundus angiography at their onset or recurrence. We excluded those patients who fulfilled the diagnostic criteria of neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD), MS McDonald's criteria, and so on. Finally we defined 29 patients with idiopathic ON (14 males, 15 females, age range 16-84 years). RESULTS: 27.6% (8/29) were positive for MOG antibodies and 3.4% (1/29) were positive for AQP4. Among the eight patients with MOG antibodies, five had optic pain (p=0.001) and three had prodromal infection (p=0.179). Three of the eight MOG-positive patients showed significantly high CSF levels of myelin basic protein (p=0.021) and none were positive for oligoclonal band in CSF. On MRIs, seven MOG-positive patients showed high signal intensity on optic nerve, three had a cerebral lesion and one had a spinal cord lesion. Seven of the eight MOG positive patients had a good response to steroid therapy. CONCLUSIONS: Although not proving primary pathogenicity of anti-MOG antibodies, the present results indicate that the measurement of MOG antibodies is useful in diagnosing and treating ON. PMID- 25838513 TI - Efficacy and safety of the glucagon-like peptide-1 receptor agonist liraglutide added to insulin therapy in poorly regulated patients with type 1 diabetes--a protocol for a randomised, double-blind, placebo-controlled study: the Lira-1 study. AB - INTRODUCTION: Intensive insulin therapy is recommended for the treatment of type 1 diabetes (T1D). Hypoglycaemia and weight gain are the common side effects of insulin treatment and may reduce compliance. In patients with insulin-treated type 2 diabetes, the addition of glucagon-like peptide-1 receptor agonist (GLP 1RA) therapy has proven effective in reducing weight gain and insulin dose. The present publication describes a protocol for a study evaluating the efficacy and safety of adding a GLP-1RA to insulin treatment in overweight patients with T1D in a randomised, double-blinded, controlled design. METHODS AND ANALYSIS: In total, 100 patients with type 1 diabetes, poor glycaemic control (glycated haemoglobin (HbA1c) >8%) and overweight (body mass index >25 kg/m(2)) will be randomised to either liraglutide 1.8 mg once daily or placebo as an add-on to intensive insulin therapy in this investigator initiated, double-blinded, placebo controlled parallel study. The primary end point is glycaemic control as measured by changes in HbA1c. Secondary end points include changes in the insulin dose, hypoglyacemic events, body weight, lean body mass, fat mass, food preferences and adverse events. Glycaemic excursions, postprandial glucagon levels and gastric emptying rate during a standardised liquid meal test will also be studied. ETHICS AND DISSEMINATION: The study is approved by the Danish Medicines Authority, the Regional Scientific-Ethical Committee of the Capital Region of Denmark and the Data Protection Agency. The study will be carried out under the surveillance and guidance of the good clinical practice (GCP) unit at Copenhagen University Hospital Bispebjerg in accordance with the ICH-GCP guidelines and the Helsinki Declaration. TRIAL REGISTRATION NUMBER: NCT01612468. PMID- 25838514 TI - Multiple therapeutic effects of progranulin on experimental acute ischaemic stroke. AB - In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (~88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. We found that progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischaemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA binding protein-43 as demonstrated in progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion, progranulin may be a novel therapeutic target that provides vascular protection, anti-neuroinflammation, and neuroprotection related in part to vascular endothelial growth factor, interleukin 10, and TAR DNA-binding protein-43, respectively. PMID- 25838515 TI - Reflectance Photoplethysmography as Noninvasive Monitoring of Tissue Blood Perfusion. AB - In the last decades, photoplethysmography (PPG) has been used as a noninvasive technique for monitoring arterial oxygen saturation by pulse oximetry (PO), whereas near-infrared spectroscopy (NIRS) has been employed for monitoring tissue blood perfusion. While NIRS offers more parameters to evaluate oxygen delivery and consumption in deep tissues, PO only assesses the state of oxygen delivery. For a broader assessment of blood perfusion, this paper explores the utilization of dual-wavelength PPG by using the pulsatile (ac) and continuous (dc) PPG for the estimation of arterial oxygen saturation (SpO2) by conventional PO. Additionally, the Beer-Lambert law is applied to the dc components only for the estimation of changes in deoxyhemoglobin (HHb), oxyhemoglobin (HbO2), and total hemoglobin (tHb) as in NIRS. The system was evaluated on the forearm of 21 healthy volunteers during induction of venous occlusion (VO) and total occlusion (TO). A reflectance PPG probe and NIRS sensor were applied above the brachioradialis, PO sensors were applied on the fingers, and all the signals were acquired simultaneously. While NIRS and forearm SpO2 indicated VO, SpO2 from the finger did not exhibit any significant drop from baseline. During TO, all the indexes indicated the change in blood perfusion. HHb, HbO2, and tHb changes estimated by PPG presented high correlation with the same parameters obtained by NIRS during VO (r(2) = 0.960, r(2) = 0.821, and r(2) = 0.974, respectively) and during TO (r(2) = 0.988, r(2) = 0.940, and r(2) = 0.938, respectively). The system demonstrated the ability to extract valuable information from PPG signals for a broader assessment of tissue blood perfusion. PMID- 25838516 TI - Workspace Shape and Characteristics for Human Two- and Three-Fingered Precision Manipulation. AB - GOAL: To study precision manipulation, which involves repositioning an object in the fingertips and is used in everyday tasks such as writing and key insertion, and also for domain-specific tasks such as small scalpel cuts, using tweezers, and hand soldering. METHODS: In this study, the range of positions (workspace) through which 19 participants manipulated a 3.3-4.1 cm-diameter object are measured with a magnetic tracker. Each participant performed two conditions: a two-finger thumb-index finger condition and a three-finger thumb-index-middle finger condition. RESULTS: The observed workspaces, normalized to a 17.5 cm hand length, are small compared to free-finger trajectories; for the two-finger trials, 68% of points are within 1.05 cm of the centroid and 95% are within 2.31 cm, while the three-finger case shows a narrower distribution, with 68% of points within 0.94 cm of the centroid and 95% of points within 2.19 cm. The longest axis is a long thin arc in the proximal-palmar plane. Analysis of fingertip workspaces shows that the index fingertip workspace volume is the most linear predictor of object workspace (R(2) = 0.98). CONCLUSION: Precision manipulation workspace size and shape is shown, along with how the fingers are used during the manipulation. SIGNIFICANCE: The results have many applications, including normative data for rehabilitation, guidelines for ergonomic device design, and benchmarking prosthetic and robotic hands. PMID- 25838517 TI - Localized Energy-Based Normalization of Medical Images: Application to Chest Radiography. AB - Automated quantitative analysis systems for medical images often lack the capability to successfully process images from multiple sources. Normalization of such images prior to further analysis is a possible solution to this limitation. This work presents a general method to normalize medical images and thoroughly investigates its effectiveness for chest radiography (CXR). The method starts with an energy decomposition of the image in different bands. Next, each band's localized energy is scaled to a reference value and the image is reconstructed. We investigate iterative and local application of this technique. The normalization is applied iteratively to the lung fields on six datasets from different sources, each comprising 50 normal CXRs and 50 abnormal CXRs. The method is evaluated in three supervised computer-aided detection tasks related to CXR analysis and compared to two reference normalization methods. In the first task, automatic lung segmentation, the average Jaccard overlap significantly increased from 0.72+/-0.30 and 0.87+/-0.11 for both reference methods to with normalization. The second experiment was aimed at segmentation of the clavicles. The reference methods had an average Jaccard index of 0.57+/-0.26 and 0.53+/ 0.26; with normalization this significantly increased to . The third experiment was detection of tuberculosis related abnormalities in the lung fields. The average area under the Receiver Operating Curve increased significantly from 0.72+/-0.14 and 0.79+/-0.06 using the reference methods to with normalization. We conclude that the normalization can be successfully applied in chest radiography and makes supervised systems more generally applicable to data from different sources. PMID- 25838518 TI - Estimating diffusion propagator and its moments using directional radial basis functions. AB - The ensemble average diffusion propagator (EAP) obtained from diffusion MRI (dMRI) data captures important structural properties of the underlying tissue. As such, it is imperative to derive an accurate estimate of the EAP from the acquired diffusion data. In this work, we propose a novel method for estimating the EAP by representing the diffusion signal as a linear combination of directional radial basis functions scattered in q-space. In particular, we focus on a special case of anisotropic Gaussian basis functions and derive analytical expressions for the diffusion orientation distribution function (ODF), the return to-origin probability (RTOP), and mean-squared-displacement (MSD). A significant advantage of the proposed method is that the second and the fourth order moment tensors of the EAP can be computed explicitly. This allows for computing several novel scalar indices (from the moment tensors) such as mean-fourth-order displacement (MFD) and generalized kurtosis (GK)-which is a generalization of the mean kurtosis measure used in diffusion kurtosis imaging. Additionally, we also propose novel scalar indices computed from the signal in q-space, called the q space mean-squared-displacement (QMSD) and the q-space mean-fourth-order displacement (QMFD), which are sensitive to short diffusion time scales. We validate our method extensively on data obtained from a physical phantom with known crossing angle as well as on in-vivo human brain data. Our experiments demonstrate the robustness of our method for different combinations of b-values and number of gradient directions. PMID- 25838519 TI - Supervised dictionary learning for inferring concurrent brain networks. AB - Task-based fMRI (tfMRI) has been widely used to explore functional brain networks via predefined stimulus paradigm in the fMRI scan. Traditionally, the general linear model (GLM) has been a dominant approach to detect task-evoked networks. However, GLM focuses on task-evoked or event-evoked brain responses and possibly ignores the intrinsic brain functions. In comparison, dictionary learning and sparse coding methods have attracted much attention recently, and these methods have shown the promise of automatically and systematically decomposing fMRI signals into meaningful task-evoked and intrinsic concurrent networks. Nevertheless, two notable limitations of current data-driven dictionary learning method are that the prior knowledge of task paradigm is not sufficiently utilized and that the establishment of correspondences among dictionary atoms in different brains have been challenging. In this paper, we propose a novel supervised dictionary learning and sparse coding method for inferring functional networks from tfMRI data, which takes both of the advantages of model-driven method and data-driven method. The basic idea is to fix the task stimulus curves as predefined model-driven dictionary atoms and only optimize the other portion of data-driven dictionary atoms. Application of this novel methodology on the publicly available human connectome project (HCP) tfMRI datasets has achieved promising results. PMID- 25838520 TI - Full-space local topology extraction for cross-modal retrieval. AB - With the ever increasing availability of various kinds of multimedia data, cross modal retrieval, which enables information retrieval from various types of data given various types of query, has become a research hotspot. Hashing-based techniques have been developed to solve this problem, however, most previous works cannot capture the shared underlying structure of real-world multimodal data, which degrades their retrieval performances. In this paper, we propose a novel hashing method based on the extraction of the common manifold structure shared among different feature spaces. To faithfully represent the common structure, two kinds of local topology information are exploited in our method. Local angles are incorporated within the extraction of local topology of each feature space, which is then used to learn a common intermediate subspace. After heterogeneous features being embedded into this subspace, local similarities are exploited to extract the local topology between different feature spaces, and learn compact Hamming embeddings to facilitate cross-modal retrieval. The proposed method is referred to as full-space local topology extraction for hashing. Extensive comparisons with other state-of-the-art methods on three benchmark multimedia data sets demonstrate the superiority of our proposed method in terms of retrieval recall and search accuracy. PMID- 25838521 TI - Robust 2D principal component analysis: a structured sparsity regularized approach. AB - Principal component analysis (PCA) is widely used to extract features and reduce dimensionality in various computer vision and image/video processing tasks. Conventional approaches either lack robustness to outliers and corrupted data or are designed for one-dimensional signals. To address this problem, we propose a robust PCA model for two-dimensional images incorporating structured sparse priors, referred to as structured sparse 2D-PCA. This robust model considers the prior of structured and grouped pixel values in two dimensions. As the proposed formulation is jointly nonconvex and nonsmooth, which is difficult to tackle by joint optimization, we develop a two-stage alternating minimization approach to solve the problem. This approach iteratively learns the projection matrices by bidirectional decomposition and utilizes the proximal method to obtain the structured sparse outliers. By considering the structured sparsity prior, the proposed model becomes less sensitive to noisy data and outliers in two dimensions. Moreover, the computational cost indicates that the robust two dimensional model is capable of processing quarter common intermediate format video in real time, as well as handling large-size images and videos, which is often intractable with other robust PCA approaches that involve image-to-vector conversion. Experimental results on robust face reconstruction, video background subtraction data set, and real-world videos show the effectiveness of the proposed model compared with conventional 2D-PCA and other robust PCA algorithms. PMID- 25838522 TI - An approach toward fast gradient-based image segmentation. AB - In this paper, we present and investigate an approach to fast multilabel color image segmentation using convex optimization techniques. The presented model is in some ways related to the well-known Mumford-Shah model, but deviates in certain important aspects. The optimization problem has been designed with two goals in mind. The objective function should represent fundamental concepts of image segmentation, such as incorporation of weighted curve length and variation of intensity in the segmented regions, while allowing transformation into a convex concave saddle point problem that is computationally inexpensive to solve. This paper introduces such a model, the nontrivial transformation of this model into a convex-concave saddle point problem, and the numerical treatment of the problem. We evaluate our approach by applying our algorithm to various images and show that our results are competitive in terms of quality at unprecedentedly low computation times. Our algorithm allows high-quality segmentation of megapixel images in a few seconds and achieves interactive performance for low resolution images. PMID- 25838523 TI - Background subtraction based on low-rank and structured sparse decomposition. AB - Low rank and sparse representation based methods, which make few specific assumptions about the background, have recently attracted wide attention in background modeling. With these methods, moving objects in the scene are modeled as pixel-wised sparse outliers. However, in many practical scenarios, the distributions of these moving parts are not truly pixel-wised sparse but structurally sparse. Meanwhile a robust analysis mechanism is required to handle background regions or foreground movements with varying scales. Based on these two observations, we first introduce a class of structured sparsity-inducing norms to model moving objects in videos. In our approach, we regard the observed sequence as being constituted of two terms, a low-rank matrix (background) and a structured sparse outlier matrix (foreground). Next, in virtue of adaptive parameters for dynamic videos, we propose a saliency measurement to dynamically estimate the support of the foreground. Experiments on challenging well known data sets demonstrate that the proposed approach outperforms the state-of-the-art methods and works effectively on a wide range of complex videos. PMID- 25838524 TI - High-Density Electromyography and Motor Skill Learning for Robust Long-Term Control of a 7-DoF Robot Arm. AB - Myoelectric control offers a direct interface between human intent and various robotic applications through recorded muscle activity. Traditional control schemes realize this interface through direct mapping or pattern recognition techniques. The former approach provides reliable control at the expense of functionality, while the latter increases functionality at the expense of long term reliability. An alternative approach, using concepts of motor learning, provides session-independent simultaneous control, but previously relied on consistent electrode placement over biomechanically independent muscles. This paper extends the functionality and practicality of the motor learning-based approach, using high-density electrode grids and muscle synergy-inspired decomposition to generate control inputs with reduced constraints on electrode placement. The method is demonstrated via real-time simultaneous and proportional control of a 4-DoF myoelectric interface over multiple days. Subjects showed learning trends consistent with typical motor skill learning without requiring any retraining or recalibration between sessions. Moreover, they adjusted to physical constraints of a robot arm after learning the control in a constraint free virtual interface, demonstrating robust control as they performed precision tasks. The results demonstrate the efficacy of the proposed man-machine interface as a viable alternative to conventional control schemes for myoelectric interfaces designed for long-term use. PMID- 25838525 TI - A Model-Based Pharmacokinetics Characterization Method of Engineered Nanoparticles for Pilot Studies. AB - Recent developments on engineered multifunctional nanomaterials have opened new perspectives in oncology. But assessment of both quality and safety in nanomedicine requires new methods for their biological characterization. This paper proposes a new model-based approach for the pre-characterization of multifunctional nanomaterials pharmacokinetics in small scale in vivo studies. Two multifunctional nanoparticules, with and without active targeting, designed for photodynamic therapy guided by magnetic resonance imaging are used to exemplify the presented method. It allows to the experimenter to rapidly test and select the most relevant PK model structure planned to be used in the subsequent explanatory studies. We also show that the model parameters estimated from the in vivo responses provide relevant preliminary information about the tumor uptake, the elimination rate and the residual storage. For some parameters, the accuracy of the estimates is accurate enough to compare and draw significant pre conclusions. A third advantage of this approach is the possibility to optimally refine the in vivo protocol for the subsequent explanatory and confirmatory studies complying with the 3Rs (reduction, refinement, replacement) ethical recommendations. More precisely, we show that the identified model may be used to select the appropriate duration of the MR imaging sessions planned for the subsequent studies. The proposed methodology integrates MRI image processing, continuous-time system identification algorithms and statistical analysis. Except, the choice of the model parameters to be compared and interpreted, most of the processing procedure may be automated to speed up the PK characterization process at an early stage of experimentation. PMID- 25838526 TI - A Battery-Less, Implantable Neuro-Electronic Interface for Studying the Mechanisms of Deep Brain Stimulation in Rat Models. AB - Although deep brain stimulation (DBS) has been a promising alternative for treating several neural disorders, the mechanisms underlying the DBS remain not fully understood. As rat models provide the advantage of recording and stimulating different disease-related regions simultaneously, this paper proposes a battery-less, implantable neuro-electronic interface suitable for studying DBS mechanisms with a freely-moving rat. The neuro-electronic interface mainly consists of a microsystem able to interact with eight different brain regions bi directionally and simultaneously. To minimize the size of the implant, the microsystem receives power and transmits data through a single coil. In addition, particular attention is paid to the capability of recording neural activities right after each stimulation, so as to acquire information on how stimulations modulate neural activities. The microsystem has been fabricated with the standard 0.18 MUm CMOS technology. The chip area is 7.74 mm (2) , and the microsystem is able to operate with a single supply voltage of 1 V. The wireless interface allows a maximum power of 10 mW to be transmitted together with either uplink or downlink data at a rate of 2 Mbps or 100 kbps, respectively. The input referred noise of recording amplifiers is 1.16 MUVrms, and the stimulation voltage is tunable from 1.5 V to 4.5 V with 5-bit resolution. After the electrical functionality of the microsystem is tested, the capability of the microsystem to interface with rat brain is further examined and compared with conventional instruments. All experimental results are presented and discussed in this paper. PMID- 25838527 TI - Self-powered monitoring of repeated head impacts using time-dilation energy measurement circuit. AB - Due to the current epidemic levels of sport-related concussions (SRC) in the U.S., there is a pressing need for technologies that can facilitate long-term and continuous monitoring of head impacts. Existing helmet-sensor technology is inconsistent, inaccurate, and is not economically or logistically practical for large-scale human studies. In this paper, we present the design of a miniature, battery-less, self-powered sensor that can be embedded inside sport helmets and can continuously monitor and store different spatial and temporal statistics of the helmet impacts. At the core of the proposed sensor is a novel time-dilation circuit that allows measurement of a wide-range of impact energies. In this paper an array of linear piezo-floating-gate (PFG) injectors has been used for self powered sensing and storage of linear and rotational head-impact statistics. The stored statistics are then retrieved using a plug-and-play reader and has been used for offline data analysis. We report simulation and measurement results validating the functionality of the time-dilation circuit for different levels of impact energies. Also, using prototypes of linear PFG integrated circuits fabricated in a 0.5 MUm CMOS process, we demonstrate the functionality of the proposed helmet-sensors using controlled drop tests. PMID- 25838529 TI - Hierarchical Theme and Topic Modeling. AB - Considering the hierarchical data groupings in text corpus, e.g., words, sentences, and documents, we conduct the structural learning and infer the latent themes and topics for sentences and words from a collection of documents, respectively. The relation between themes and topics under different data groupings is explored through an unsupervised procedure without limiting the number of clusters. A tree stick-breaking process is presented to draw theme proportions for different sentences. We build a hierarchical theme and topic model, which flexibly represents the heterogeneous documents using Bayesian nonparametrics. Thematic sentences and topical words are extracted. In the experiments, the proposed method is evaluated to be effective to build semantic tree structure for sentences and the corresponding words. The superiority of using tree model for selection of expressive sentences for document summarization is illustrated. PMID- 25838528 TI - An EMG-Controlled Robotic Hand Exoskeleton for Bilateral Rehabilitation. AB - This paper presents a novel electromyography (EMG)-driven hand exoskeleton for bilateral rehabilitation of grasping in stroke. The developed hand exoskeleton was designed with two distinctive features: (a) kinematics with intrinsic adaptability to patient's hand size, and (b) free-palm and free-fingertip design, preserving the residual sensory perceptual capability of touch during assistance in grasping of real objects. In the envisaged bilateral training strategy, the patient's non paretic hand acted as guidance for the paretic hand in grasping tasks. Grasping force exerted by the non paretic hand was estimated in real-time from EMG signals, and then replicated as robotic assistance for the paretic hand by means of the hand-exoskeleton. Estimation of the grasping force through EMG allowed to perform rehabilitation exercises with any, non sensorized, graspable objects. This paper presents the system design, development, and experimental evaluation. Experiments were performed within a group of six healthy subjects and two chronic stroke patients, executing robotic-assisted grasping tasks. Results related to performance in estimation and modulation of the robotic assistance, and to the outcomes of the pilot rehabilitation sessions with stroke patients, positively support validity of the proposed approach for application in stroke rehabilitation. PMID- 25838530 TI - Arrhythmia discrimination using a smart phone. AB - We hypothesize that our smartphone-based arrhythmia discrimination algorithm with data acquisition approach reliably differentiates between normal sinus rhythm (NSR), atrial fibrillation (AF), premature ventricular contractions (PVCs) and premature atrial contraction (PACs) in a diverse group of patients having these common arrhythmias. We combine root mean square of successive RR differences and Shannon entropy with Poincare plot (or turning point ratio method) and pulse rise and fall times to increase the sensitivity of AF discrimination and add new capabilities of PVC and PAC identification. To investigate the capability of the smartphone-based algorithm for arrhythmia discrimination, 99 subjects, including 88 study participants with AF at baseline and in NSR after electrical cardioversion, as well as seven participants with PACs and four with PVCs were recruited. Using a smartphone, we collected 2-min pulsatile time series from each recruited subject. This clinical application results show that the proposed method detects NSR with specificity of 0.9886, and discriminates PVCs and PACs from AF with sensitivities of 0.9684 and 0.9783, respectively. PMID- 25838531 TI - Personalization of Energy Expenditure Estimation in Free Living Using Topic Models. AB - We introduce an approach to personalize energy expenditure (EE) estimates in free living. First, we use topic models to discover activity composites from recognized activity primitives and stay regions in daily living data. Subsequently, we determine activity composites that are relevant to contextualize heart rate (HR). Activity composites were ranked and analyzed to optimize the correlation to HR normalization parameters. Finally, individual-specific HR normalization parameters were used to normalize HR. Normalized HR was then included in activity-specific regression models to estimate EE. Our HR normalization minimizes the effect of individual fitness differences from entering in EE regression models. By estimating HR normalization parameters in free living, our approach avoids dedicated individual calibration or laboratory tests. In a combined free-living and laboratory study dataset, including 34 healthy volunteers, we show that HR normalization in 14-day free-living data improves accuracy compared to no normalization and normalization based on activity primitives only ( 29.4% and 19.8 % error reduction against lab reference). Based on acceleration and HR, both recorded from a necklace, and GPS acquired from a smartphone, EE estimation error was reduced by 10.7 % in a leave one-participant-out analysis. PMID- 25838532 TI - Experimental Path Loss Models for In-Body Communications Within 2.36-2.5 GHz. AB - Biomedical implantable sensors transmitting a variety of physiological signals have been proven very useful in the management of chronic diseases. Currently, the vast majority of these in-body wireless sensors communicate in frequencies below 1 GHz. Although the radio propagation losses through biological tissues may be lower in such frequencies, e.g., the medical implant communication services band of 402 to 405 MHz, the maximal channel bandwidths allowed therein constrain the implantable devices to low data rate transmissions. Novel and more sophisticated wireless in-body sensors and actuators may require higher data rate communication interfaces. Therefore, the radio spectrum above 1 GHz for the use of wearable medical sensing applications should be considered for in-body applications too. Wider channel bandwidths and smaller antenna sizes may be obtained in frequency bands above 1 GHz at the expense of larger propagation losses. Therefore, in this paper, we present a phantom-based radio propagation study for the frequency bands of 2360 to 2400 MHz, which has been set aside for wearable body area network nodes, and the industrial, scientific, medical band of 2400 to 2483.5 MHz. Three different channel scenarios were considered for the propagation measurements: in-body to in-body, in-body to on-body, and in-body to off-body. We provide for the first time path loss formulas for all these cases. PMID- 25838533 TI - From the Symbolic Analysis of Virtual Faces to a Smiles Machine. AB - In this paper, we present an application of symbolic data processing for the design of virtual character's smiling facial expressions. A collected database of virtual character's smiles directly created by users has been explored using symbolic data analysis methods. An unsupervised analysis has enabled us to identify the morphological and dynamic characteristics of different types of smiles as well as of combinations of smiles. Based on the symbolic data analysis, to generate different smiling faces, we have developed procedures to automatically reconstitute smiling virtual faces from a point in a multidimensional space corresponding to a principal component analysis plane. PMID- 25838534 TI - Fast Image-Based Obstacle Detection From Unmanned Surface Vehicles. AB - Obstacle detection plays an important role in unmanned surface vehicles (USVs). The USVs operate in a highly diverse environments in which an obstacle may be a floating piece of wood, a scuba diver, a pier, or a part of a shoreline, which presents a significant challenge to continuous detection from images taken on board. This paper addresses the problem of online detection by constrained, unsupervised segmentation. To this end, a new graphical model is proposed that affords a fast and continuous obstacle image-map estimation from a single video stream captured on board a USV. The model accounts for the semantic structure of marine environment as observed from USV by imposing weak structural constraints. A Markov random field framework is adopted and a highly efficient algorithm for simultaneous optimization of model parameters and segmentation mask estimation is derived. Our approach does not require computationally intensive extraction of texture features and comfortably runs in real time. The algorithm is tested on a new, challenging, dataset for segmentation, and obstacle detection in marine environments, which is the largest annotated dataset of its kind. Results on this dataset show that our model outperforms the related approaches, while requiring a fraction of computational effort. PMID- 25838535 TI - Possibility Distribution-Based Approach for MAGDM With Hesitant Fuzzy Linguistic Information. AB - In group decision making (GDM) with qualitative settings, experts may require several possible linguistic values rather than a single term to express their preferences. A hesitant fuzzy linguistic term set has recently been developed to manage this situation. In line with this development, in this paper, we present a new framework model to address multiple attribute GDM with hesitant fuzzy linguistic information. First, the concept of a possibility distribution is defined. Based on the possibility distributions, some aggregation operators such as the hesitant fuzzy linguistic weighted average operator and the hesitant fuzzy linguistic ordered weighted average operator are proposed. A consensus measure is then defined and a consensus reaching process is given which uses different identification and direction rules compared with the existing methods. A selection process is also described to rank the alternatives. Both processes are necessary to support stakeholders when making rational decisions. Finally, two simulated examples are given to verify the practicability of the proposed approach. PMID- 25838536 TI - Principal Component 2-D Long Short-Term Memory for Font Recognition on Single Chinese Characters. AB - Chinese character font recognition (CCFR) has received increasing attention as the intelligent applications based on optical character recognition becomes popular. However, traditional CCFR systems do not handle noisy data effectively. By analyzing in detail the basic strokes of Chinese characters, we propose that font recognition on a single Chinese character is a sequence classification problem, which can be effectively solved by recurrent neural networks. For robust CCFR, we integrate a principal component convolution layer with the 2-D long short-term memory (2DLSTM) and develop principal component 2DLSTM (PC-2DLSTM) algorithm. PC-2DLSTM considers two aspects: 1) the principal component layer convolution operation helps remove the noise and get a rational and complete font information and 2) simultaneously, 2DLSTM deals with the long-range contextual processing along scan directions that can contribute to capture the contrast between character trajectory and background. Experiments using the frequently used CCFR dataset suggest the effectiveness of PC-2DLSTM compared with other state-of-the-art font recognition methods. PMID- 25838537 TI - Learning to Anticipate Flexible Choices in Multiple Criteria Decision-Making Under Uncertainty. AB - In several applications, a solution must be selected from a set of tradeoff alternatives for operating in dynamic and noisy environments. In this paper, such multicriteria decision process is handled by anticipating flexible options predicted to improve the decision maker future freedom of action. A methodology is then proposed for predicting tradeoff sets of maximal hypervolume, where a multiobjective metaheuristic was augmented with a Kalman filter and a dynamical Dirichlet model for tracking and predicting flexible solutions. The method identified decisions that were shown to improve the future hypervolume of tradeoff investment portfolio sets for out-of-sample stock data, when compared to a myopic strategy. Anticipating flexible portfolios was a superior strategy for smoother changing artificial and real-world scenarios, when compared to always implementing the decision of median risk and to randomly selecting a portfolio from the evolved anticipatory stochastic Pareto frontier, whereas the median choice strategy performed better for abruptly changing markets. Correlations between the portfolio compositions and future hypervolume were also observed. PMID- 25838538 TI - Autophagy: research topic, painting, poem, dance...: The combination of art and information can enhance the enjoyment and effectiveness of learning. PMID- 25838539 TI - CARMing down the SINEs of anarchy: two paths to freedom from paraspeckle detention. AB - A subset of messenger RNAs (mRNAs) that contain inverted Alu elements in their 3' untranslated region are inefficiently exported to the cytoplasm and retained in subnuclear bodies called paraspeckles. The arginine methyltransferase CARM1 (coactivator-associated arginine methyltransferase 1) promotes the nuclear export of these mRNAs by methylating the paraspeckle component p54(nrb), which reduces the binding of p54(nrb) to the inverted Alu elements, and down-regulating synthesis of another paraspeckle component, the long noncoding RNA NEAT1, which inhibits paraspeckle formation. PMID- 25838540 TI - Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. AB - In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity. PMID- 25838541 TI - Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. AB - Functional data indicate that specific histone modification enzymes can be key to longevity in Caenorhabditis elegans, but the molecular basis of how chromatin structure modulates longevity is not well understood. In this study, we profiled the genome-wide pattern of trimethylation of Lys36 on histone 3 (H3K36me3) in the somatic cells of young and old Caenorhabditis elegans. We revealed a new role of H3K36me3 in maintaining gene expression stability through aging with important consequences on longevity. We found that genes with dramatic expression change during aging are marked with low or even undetectable levels of H3K36me3 in their gene bodies irrespective of their corresponding mRNA abundance. Interestingly, 3' untranslated region (UTR) length strongly correlates with H3K36me3 levels and age dependent mRNA expression stability. A similar negative correlation between H3K36me3 marking and mRNA expression change during aging was also observed in Drosophila melanogaster, suggesting a conserved mechanism for H3K36me3 in suppressing age-dependent mRNA expression change. Importantly, inactivation of the methyltransferase met-1 resulted in a decrease in global H3K36me3 marks, an increase in mRNA expression change with age, and a shortened life span, suggesting a causative role of the H3K36me3 marking in modulating age-dependent gene expression stability and longevity. PMID- 25838542 TI - miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. AB - Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia inducible factor 2alpha (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR 182 duplexes. Intravenously administered 182-SNAs penetrated the blood brain/blood-tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM. PMID- 25838543 TI - Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development. AB - Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans-acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not well understood. To address these questions, we generated mice lacking the vertebrate- and neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to nonneural patterns for different classes of splicing events. The main component of the altered AS program comprises 3- to 27-nucleotide (nt) neural microexons, an emerging class of highly conserved AS events associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nt, nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100 and further link these functions to a conserved program of neuronal microexon splicing. PMID- 25838544 TI - A conserved intronic U1 snRNP-binding sequence promotes trans-splicing in Drosophila. AB - Unlike typical cis-splicing, trans-splicing joins exons from two separate transcripts to produce chimeric mRNA and has been detected in most eukaryotes. Trans-splicing in trypanosomes and nematodes has been characterized as a spliced leader RNA-facilitated reaction; in contrast, its mechanism in higher eukaryotes remains unclear. Here we investigate mod(mdg4), a classic trans-spliced gene in Drosophila, and report that two critical RNA sequences in the middle of the last 5' intron, TSA and TSB, promote trans-splicing of mod(mdg4). In TSA, a 13 nucleotide (nt) core motif is conserved across Drosophila species and is essential and sufficient for trans-splicing, which binds U1 small nuclear RNP (snRNP) through strong base-pairing with U1 snRNA. In TSB, a conserved secondary structure acts as an enhancer. Deletions of TSA and TSB using the CRISPR/Cas9 system result in developmental defects in flies. Although it is not clear how the 5' intron finds the 3' introns, compensatory changes in U1 snRNA rescue trans splicing of TSA mutants, demonstrating that U1 recruitment is critical to promote trans-splicing in vivo. Furthermore, TSA core-like motifs are found in many other trans-spliced Drosophila genes, including lola. These findings represent a novel mechanism of trans-splicing, in which RNA motifs in the 5' intron are sufficient to bring separate transcripts into close proximity to promote trans-splicing. PMID- 25838545 TI - In vivo biochemical analyses reveal distinct roles of beta-importins and eEF1A in tRNA subcellular traffic. AB - Bidirectional tRNA movement between the nucleus and the cytoplasm serves multiple biological functions. To gain a biochemical understanding of the mechanisms for tRNA subcellular dynamics, we developed in vivo beta-importin complex coimmunoprecipitation (co-IP) assays using budding yeast. Our studies provide the first in vivo biochemical evidence that two beta-importin family members, Los1 (exportin-t) and Msn5 (exportin-5), serve overlapping but distinct roles in tRNA nuclear export. Los1 assembles complexes with RanGTP and tRNA. Both intron containing pre-tRNAs and spliced tRNAs, regardless of whether they are aminoacylated, assemble into Los1-RanGTP complexes, documenting that Los1 participates in both primary nuclear export and re-export of tRNAs to the cytoplasm. In contrast, beta-importin Msn5 preferentially assembles with RanGTP and spliced, aminoacylated tRNAs, documenting its role in tRNA nuclear re-export. Tef1/2 (the yeast form of translation elongation factor 1alpha [eEF1A]) aids the specificity of Msn5 for aminoacylated tRNAs to form a quaternary complex consisting of Msn5, RanGTP, aminoacylated tRNA, and Tef1/2. Assembly and/or stability of this quaternary complex requires Tef1/2, thereby facilitating efficient re-export of aminoacylated tRNAs to the cytoplasm. PMID- 25838546 TI - The Relationship Between Urinary Total Polyphenols and the Frailty Phenotype in a Community-Dwelling Older Population: The InCHIANTI Study. AB - BACKGROUND: Frailty, an age-related state of increased vulnerability, is associated with a higher risk of multiple adverse events. Studies have suggested that the quality of dietary intake may affect the development of frailty. We hypothesized that frailty in older subjects would be associated with dietary total polyphenols (DTP) intake and its biomarker, urinary total polyphenols (UTP). METHODS: The Invecchiare in Chianti (InCHIANTI) Study is a prospective cohort study set in the Chianti area (Italy). We used data at baseline from 811 participants aged 65 years and older. UTP was determined using the Folin Ciocalteu assay after solid-phase extraction. DTP was estimated using a validated Food Frequency Questionnaire and our own polyphenol database. The frailty, prefrailty, and nonfrailty states were defined according to the Fried and colleagues' criteria. Multinomial logistic regressions adjusted for potential confounders were used to assess the relationship between polyphenols and frailty. RESULTS: Both DTP and UTP concentrations progressively decrease from nonfrail to frail participants. Participants in the highest UTP tertile compared to those in the lowest tertile were significantly less likely to be both frail (odds ratio [OR] = 0.36 [0.14-0.88], p = .025) and prefrail (OR = 0.64 [0.42-0.98], p = .038). Exhaustion and slowness were the only individual frailty criteria significantly associated with UTP tertiles. No significant association was observed between frailty and DTP, after adjustment for covariates. CONCLUSIONS: High concentrations of UTP were associated with lower prevalence of frailty and prefrailty in an older community-dwelling population. A polyphenol-rich diet may protect against frailty in older persons. Our findings should be confirmed in longitudinal studies. PMID- 25838548 TI - Factors that Impact on Interrater Reliability of the Mouse Clinical Frailty Index. PMID- 25838547 TI - Greater Skeletal Muscle Fat Infiltration Is Associated With Higher All-Cause and Cardiovascular Mortality in Older Men. AB - BACKGROUND: Skeletal muscle fat infiltration (myosteatosis) increases with aging, and has been associated with poor metabolic and musculoskeletal health, independent of overall adiposity. Studies examining the relationship of myosteatosis and mortality among older individuals recruited without regard to their health status are sparse. METHODS: We evaluated the association of peripheral computed tomography measured calf myosteatosis (intermuscular fat and muscle density as a measure of intramuscular fat) with mortality in 1,063 community-dwelling older men. Cox proportional hazards models were used to estimate the risk of mortality independent of potential confounders. RESULTS: During a mean follow-up of 7.2 years, 317 participants died. After adjustment for potential covariates and additional adjustment for whole body fat, lower skeletal muscle density was associated with increased all-cause mortality and cardiovascular disease mortality (hazard ratio [95% confidence interval] per standard deviation lower skeletal muscle density: 1.24 [1.09-1.41] and 1.46 [1.15 1.86], respectively), and to some extent with noncardiovascular disease mortality (1.18 [1.0-1.38], p = .053). After adjusting for trunk fat in a separate multivariable model, the association between skeletal muscle density and all cause and cardiovascular disease mortality remained significant (both p < .01), while its association with noncardiovascular disease mortality became of borderline significance (p = .085). No other measures of adiposity, including calf intermuscular fat, were associated with mortality. CONCLUSION: Our study reveals an independent association between skeletal muscle density and mortality in a community-based sample of older, predominantly Caucasian men. Further studies are needed to establish if this association is independent of other ectopic fat depots, and to identify the biological mechanisms underlying this relationship. PMID- 25838549 TI - Limited resection of pancreatic cancer in high-risk patients can result in a second primary. PMID- 25838551 TI - Australian rural, remote and urban community nurses' health promotion role and function. AB - Community nurses have often been 'touted' as potential major contributors to health promotion. Critical literature, however, often states that this has not been the case. Furthermore, most studies examining nurses' role and function have occurred mainly in hospital settings. This is a sequential mixed-methods study of two groups of community nurses from a Sydney urban area (n = 100) and from rural and remote areas (n = 49) within New South Wales, Australia. A piloted questionnaire survey was developed based on the five action areas of the Ottawa Charter for Health Promotion. Following this, 10 qualitative interviews were conducted for both groups, plus a focus group to support or refute survey results. Findings showed that rural and remote nurses had more positive attitudes towards health promotion and its clinical implementation. Survey and interview data confirmed that urban community nurses had a narrower focus on caring for individuals rather than groups, agreeing that time constraints impacted on their limited health promotion role. There was agreement about lack of resources (material and people) to update health promotion knowledge and skills. Rural and remote nurses were more likely to have limited educational opportunities. All nurses undertook more development of personal skills (DPS, health education) than any other action area. The findings highlight the need for more education and resources for community nurses to assist their understanding of health promotion concepts. It is hoped that community nurse leaders will collectively become more effective health promoters and contribute to healthy reform in primary health care sectors. PMID- 25838550 TI - Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer. AB - OBJECTIVES: IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17 associated transcription factors in sporadic and colitis-associated colon cancer in vivo. DESIGN: We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and RORgammat in patients with IBD and CRC. RESULTS: Batf but not retinoic acid-related orphan receptor gammat(RORgammat) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not RORgammat expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not RORgammat was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL 6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor. CONCLUSIONS: Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression. PMID- 25838552 TI - Sun protection during snow sports: an analysis of behavior and psychosocial determinants. AB - This study investigated sun protective behavior during snow sports and its psychosocial determinants. A longitudinal study was conducted among 418 Dutch adults who planned to go on a ski holiday. Participants were asked to fill in a questionnaire before and after their ski trip. In the baseline questionnaire several psychosocial factors were measured (i.e. knowledge, risk perception, worry, attitude, social influence, self-efficacy and intention). At follow-up, sunscreen use and frequency of sunburns were measured. The results showed that, despite their generally high intention, a substantial part of the respondents (40%) did not use sunscreen adequately during their ski holiday. Furthermore, one fourth of the respondents reported at least one sunburn during their ski holiday. Men and younger respondents used sunscreen less frequently and were sunburnt more often. Sunscreen use was predicted by a positive attitude, high self-efficacy levels, high intention, high knowledge and high perceived risk. The background and psychosocial variables explained 32% of the total variance of sunscreen use. Suggestions for future research and interventions are discussed. PMID- 25838553 TI - The Association Between Dialysis Facility Quality and Facility Characteristics, Neighborhood Demographics, and Region. AB - The Centers for Medicare & Medicaid Services (CMS) initiated the End-Stage Renal Disease Quality Incentive Program in 2012. For each dialysis facility, an overall quality performance score is determined based on various quality measures. This article studies the association between the overall dialysis facility quality and facility characteristics, neighborhood demographics, and region. Data from the CMS Payment Year 2014 Dialysis Compare File were used, and were linked to 2010 US Census data (n = 4086). Multiple linear regression was used to examine the association between dialysis facility quality and facility characteristics, neighborhood demographics, and region. The analysis demonstrates that dialysis facility quality varies significantly by facility profit status, chain membership, and facility size. Dialysis facilities in neighborhoods with a higher proportion of African Americans have significantly lower quality. Regional differences in quality exist. PMID- 25838554 TI - Why it's time to recognise Indigenous peoples in the Constitution. AB - OBJECTIVE: This article provides an overview of why it is proposed that the Australian Constitution be changed to recognise Aboriginal and Torres Strait Islander peoples. It then establishes what changes are needed to the Constitution. CONCLUSION: The Australian Constitution fails to recognise Indigenous peoples, and still enables discrimination against them. This provides a sound case for changing the document. PMID- 25838555 TI - Defragmenting paediatric anorexia nervosa: the Flinders Medical Centre Paediatric Eating Disorder Program. AB - OBJECTIVE: To describe the establishment and the main characteristics of the Flinders Medical Centre Paediatric Eating Disorder Program. CONCLUSION: While the programme is still in its infancy, it is hoped that our model of care can provide a sustainable, long term contribution to the management of paediatric eating disorders. PMID- 25838558 TI - What's all the buzz about change management? AB - Change management is more important than ever in healthcare. It is an essential part of the management tool box and to downplay its importance is to risk serious challenges, including failure, in implementing and even more importantly, sustaining change. All too often, change management is something that is handed off to a special department or even contracted out, without due consideration of the need to develop the knowledge and skills in and across the organization. Some basics for successful change management are identified and discussed. PMID- 25838557 TI - Nuclear changes in oral mucosa of alcoholics and crack cocaine users. AB - The effects of drugs of abuse on oral mucosa are only partly understood. The aims of the present study were to: (1) evaluate the frequency of nuclear changes in normal-appearing oral mucosa of alcoholics and crack cocaine users and (2) assess their association with cell proliferation rate. Oral smears were obtained from the border of the tongue and floor of the mouth of 26 crack cocaine users (24 males and 2 females), 29 alcoholics (17 males and 12 females), and 35 controls (17 males and 18 females). Histological slides were submitted to Feulgen staining to assess the frequency of micronuclei (MN), binucleated cells (BN), broken eggs (BE), and karyorrhexis (KR). A significant increase in the frequency of MN was observed in cells exfoliated from the tongue of crack cocaine users (p = 0.01), and alcoholics showed a higher frequency of KR in cells obtained from the floor of the mouth (p = 0.01). Our findings suggest that the use of crack cocaine induces clastogenic effects, whereas alcoholism is associated with higher degrees of keratinization in the floor of the mouth. PMID- 25838559 TI - New structures for challenges in healthcare management. AB - Government initiatives aimed at improving the healthcare available to Canadians pose a significant challenge to leaders responsible for developing and implementing strategies to translate these initiatives into reality. This article presents a new approach to management structures and processes designed to address this challenge. The approach includes new senior leadership skills focusing on collaboration and influence, functional rather than hierarchical teams, and clarity in team mandates and team empowerment to facilitate achievement of expectations. PMID- 25838560 TI - Caring: Everybody's business. AB - As structures become more fluid and less constrained by traditional boundaries, the time is ripe to welcome the blurring lines between government, business, and social purpose organizations. No matter where you sit on the spectrum, organizations must learn from each other, remain grounded in their strengths, and work collectively to make the fabric of our communities richer and stronger. It is here we can realize the ideals of universality and caring at the highest level. PMID- 25838561 TI - A message from the guest editor. PMID- 25838562 TI - A Message from the Editor-in-Chief. PMID- 25838563 TI - Mentoring in healthcare: A rehabilitation hospital's launch of an innovative program for emerging leaders. AB - With enterprise-wide interest by physicians, management, staff, and volunteers in developing future leaders across their organization, this article describes efforts to design, implement, and evaluate an inaugural, 1-year formal mentoring program for the Glenrose Rehabilitation Hospital, Alberta Health Services. Evaluation surveys were analyzed highlighting critical success factors incorporating a broad, diverse mentee/mentor applicant process, well-defined mentee/mentor selection/matching criteria, and use of a formal program to support knowledge acquisition through projects, learning sessions, and presentations. PMID- 25838564 TI - Le mentorat dans le milieu de la sante: un hopital de readaptation lance un programme novateur pour les leaders emergents. AB - Les medecins, la direction, le personnel et les benevoles des entreprises veulent former de futurs leaders au sein de leur organisation. Le present article decrit les efforts pour concevoir, mettre en oeuvre et evaluer un programme de mentorat d'un an utilise pour la premiere fois par le Glenrose Rehabilitation Hospital des Alberta Health Services. Des sondages d'evaluation ont ete analyses pour faire ressortir les facteurs de succes decisifs, qui integraient un vaste processus de candidatures diversifie de mentores et de mentors, des criteres bien definis de selection ou de jumelage de mentores et de mentors et un programme visant a soutenir l'acquisition du savoir par des projets, des seances d'apprentissage et des presentations. PMID- 25838565 TI - Contemplating case mix: A primer on case mix classification and management. AB - Case mix classifications are the frameworks that underlie many healthcare funding schemes, including the so-called activity-based funding. Now more than ever, Canadian healthcare administrators are evaluating case mix-based funding and deciphering how they will influence their organization. Case mix is a topic fraught with technical jargon and largely relegated to government agencies or private industries. This article provides an abridged review of case mix classification as well as its implications for management in healthcare. PMID- 25838566 TI - Complex health conditions and mental health training: How prepared is the frontline service provider? AB - How prepared are frontline service providers for dealing with mental illness in patients with multiple, complex health conditions? The aims of this study were two-fold, to gain insight into the kinds of training and education desired by frontline service providers in a healthcare setting and to compile a list of key questions for health service managers and education leaders to address based on our findings. Over 100 care providers responded to a survey. Over half of the respondents indicated no mental health training, and the majority desired increased training and support. Suggested approaches ranged from regular workshops (eg, case presentations) to systems-level strategies (eg, partnering with mental health organizations). This study provides a critical first look into what frontline service providers identify as being essential to their skill set in working with a complex population and raises important questions for healthcare managers and educators to consider in addressing this gap. PMID- 25838567 TI - Impact of nurse practitioners in primary healthcare fee-for-service practice settings. AB - The Nurse Practitioner (NP) role possesses a high value to Fee-For-Service (FFS) practices in the primary healthcare system. A case study evaluation of the NP roles in three FFS clinics showed positive impacts on patient satisfaction and physician experience. Physicians' FFS expenditures increased 12% after the NP implementation. Although NP services could provide cost savings to the acute care system, financial sustainability of the NP role in FFS practice remains a challenge. PMID- 25838568 TI - Governance standards: A roadmap for increasing safety at care transitions. AB - Reducing the rate of adverse events and preventable harm associated with healthcare delivery is a policy priority across healthcare systems internationally. Care transitions or handovers in clinical care introduce risk to patients that can lead to adverse events. Building on the literature showing the impact of governing boards on the quality and safety of healthcare services, this study builds a predictive model between governance and safety at care transitions. Analysis was based on 490 Canadian healthcare organizations across six sectors of care. Organizational compliance with the Accreditation Canada Governance Standards was shown to be a predictor of organizational performance with the Medication Reconciliation Required Organizational Practice. Results indicate that among a comprehensive set of governance standards, a set of 11 central governance elements predict organizational medication reconciliation practice. Implications for healthcare leaders are discussed including the role of organizational leadership in medication reconciliation practices. The importance of a governance process cycle that encompasses board prioritization of desired goals, monitoring of performance regularly, and communicating results with stakeholders is shown. PMID- 25838569 TI - Hospital stay on acute care units for non-acute reasons: Effects of patient pre hospitalization and admission factors. AB - This study identifies patient risk factors present prior to an acute hospitalization that are associated with occupying acute care beds for non-acute reasons on the 30th day of a hospitalization. Data from 952 adult patients were obtained, among which 333 (35%) were evaluated as non-acute on their 30th day. Inability to move in and out of the bed, cognitive impairment, receiving home or community healthcare services prior to hospitalization, unavailable family resources, a secondary diagnosis within the mental and behavioural category, and age >=75 years were found to increase the risk of occupying acute care beds for non-acute reasons, while patients with a feeding tube were less likely to be non acute at day 30. PMID- 25838570 TI - Ethics, rhetoric, and expectations: Responsibilities and obligations of healthcare systems. PMID- 25838571 TI - L'ethique, la rhetorique et les attentes: les responsabilites et les obligations des systemes de sante. PMID- 25838572 TI - A Message from the Editor-in-Chief. PMID- 25838573 TI - Redressing the inequities in Canadian pharmacare. AB - Canadian healthcare is not universal. Nowhere is this lack of universality more evident than in the payment for drugs in Canada. Canadians without the financial wherewithal cannot access orphan drugs for rare diseases and take-at-home oral cancer drugs and many other pharmaceuticals. In addition to the physical and emotional tolls experienced, patients and survivors and their families and caregivers bear the brunt of an ever-growing financial burden. This article outlines how this happened and what to do about it. PMID- 25838574 TI - Corriger les inegalites du regime d'assurance medicaments canadien. AB - Le systeme de sante canadien n'est pas universel. Le paiement des medicaments au Canada en est le parfait exemple. Les Canadiens qui n'en ont pas les moyens financiers n'ont pas acces aux medicaments orphelins pour soigner des maladies rares, a la chimiotherapie orale a domicile ni a de nombreux autres produits pharmaceutiques. Outre les repercussions physiques et affectives qu'ils subissent, les patients, les survivants, leur famille et les soignants doivent porter un fardeau financier de plus en plus lourd. Le present article expose les origines de cette situation et les mesures necessaires pour la corriger. PMID- 25838575 TI - The journey to include patient and family voices. AB - Traditionally, the roles of patients and their families in healthcare have been passive. Despite claims of patient centredness, care design and decision-making often reflects the provider's perspective. Within Island Health, we knew that the challenges we faced were common to many healthcare organizations. We recognized that we would not be successful in changing to a patient-centred culture unless we had organizational support at the executive level for a patient and family experience strategy. PMID- 25838576 TI - Using the project management office to connect the dots between projects and strategy. AB - Project management is recognized as an essential skill required for healthcare leadership and as a result, Project Management Offices (PMOs) in healthcare organizations have become commonplace. When PMOs are well suited and fit to their organization, they are being valued for their ability to support appropriate trade-offs between investments, capacity, and quality. This article provides an overview of healthcare PMOs and advocates for elevating the role of the healthcare PMO from a monitoring and reporting function to a leader and the engine for strategic change within an organization. PMID- 25838577 TI - Improving transitions between acute mental health and residential care. AB - Care transitions pose safety risks especially for hospitalized seniors with complex medical and mental health conditions. A partnership project improved acceptance and supported successful transitions by redesigning at the following three levels: (1) organization-program to facility agreement outlining accountabilities; (2) unit-adjusting the environment, education, and team processes; and (3) individual care-a transition checklist, a person-centred care plan, and customized transition supports to assist clients, family, and receiving staff. PMID- 25838578 TI - Evidence-informed healthcare through integration of health research. AB - A foundational element of modern healthcare is an evidence-based practice. However, the conduct of research to generate evidence and the subsequent application of research findings are viewed by many Canadian healthcare organizations as separate from healthcare delivery. This mindset impedes effective translation of knowledge into practice. In this article, underlying issues that enable this disintegrated model to persist are described, and strategies to help healthcare organizations achieve integration of research are summarized. PMID- 25838579 TI - Public health partnerships: Does the evidence justify the enthusiasm? AB - Partnerships are commonly identified as a foundational public health strategy. However, despite the prevalence and enthusiasm for partnerships, there are few published evaluations of public health partnerships in the Canadian context, and international literature reports that most partnerships have little to no effect on health outcomes. The contradicting enthusiasm and evidence create a challenging scenario for Canadian public health leaders and practitioners who are encouraged to both engage in partnerships and implement evidence-informed practices. PMID- 25838580 TI - Hardwiring improvement to achieve exceptional outcomes: Staff as leaders driving performance. AB - This article will discuss the experiences of two organizations who have driven process improvement through frontline ownership using the National Health Services' Releasing Time to Care (RTC) program. Through the implementation of RTC, frontline staff learn how to gather information from colleagues, stakeholders, and literature to design potential improvements. PMID- 25838581 TI - Ethically justified decisions. AB - Good Decisions is a framework that assists healthcare leaders to make ethically justified system-level decisions. This article describes some of the features that make a decision ethically justified and discusses the experience of its use in one Canadian health authority. The framework sees the membership and relationships of the decision team, the quality of analysis, the breadth of consultation, and the implementation of and follow up on decisions, as all impacting a decision's ethical justification. PMID- 25838582 TI - Des decisions justifiees sur le plan ethique. AB - Good Decisions est un cadre qui aide les leaders en sante a prendre des decisions systemiques justifiees sur le plan ethique. Le present article decrit quelques unes des caracteristiques qui rendent une decision justifiee sur le plan ethique et expose l'experience de son utilisation dans une regie regionale de la sante canadienne. Le cadre tient compte des membres et des relations de l'equipe de decision, de la qualite de l'analyse, de l'etendue de la consultation ainsi que de l'adoption et du suivi des decisions, qui ont tous des effets sur la justification ethique d'une decision. PMID- 25838583 TI - Non-Spherical Particles for Targeted Drug Delivery. AB - Nano- and microparticles loaded with various bioimaging contrast agents or therapeutic molecules have been increasingly used for the diagnosis and treatment of diseases and tissue defects. These particles, often a filled or hollow sphere, can extend the lifetime of encapsulated biomedical modalities in circulation and in target tissue. However, there is a great need to improve the drug loading and targeting efficiency of these particles. Recently, several simulation and in vitro experimental studies reported that particle shape plays a pivotal role in the targeted delivery of molecules. To better understand these findings and subsequently expedite the use of particles in biomedical applications, this review paper summarizes the methods to prepare non-spherical nano- and micro scaled particles. In addition, this review covers studies reporting the effects of particle shape on the loading, delivery and release of encapsulated bioactive cargos. Finally, it discusses future directions to further improve the properties of non-spherical particles. PMID- 25838584 TI - The challenges and excitement of liver transplantation. PMID- 25838585 TI - Acute liver failure in pregnancy: Challenges and management. AB - Acute liver failure (ALF) in pregnancy negatively affects both maternal and foetal outcome. The spectrum of liver disease in pregnancy may range from mild asymptomatic transaminitis to fatal and irreversible deterioration in liver functions leading to significant morbidity and even mortality. In this comprehensive review, we searched articles published as review articles, clinical trials, and case series in the Medline from 1970 to 2012. The overall outcome of ALF in pregnancy depends on the aetiology, timely diagnosis, prompt management, and early referral to a centre equipped in managing medical or obstetric complication. The foetal outcome is affected by the stage of pregnancy in which the mother has a deterioration of the liver function, with a worst prognosis associated with first or second-trimester liver failure. When ALF complicates pregnancy, liver transplantation is the one of the viable options. Management protocols need to be individualised for each case keeping in mind the risk versus benefit to both the mother and the foetus. PMID- 25838586 TI - Comparative evaluation of the effects of propofol and sevoflurane on cognitive function and memory in patients undergoing laparoscopic cholecystectomy: A randomised prospective study. AB - BACKGROUND AND AIMS: General anaesthesia (GA) may cause post-operative impairment of cognition and memory. This is of importance where time to discharge after anaesthesia is short as after laparoscopic cholecystectomy. This study was conducted to compare the effects of propofol and sevoflurane on cognitive function in the post-operative period. METHODS: After approval of the Ethical Committee, 80 female patients posted for laparoscopic cholecystectomy to be performed under GA were randomly divided into two groups. Propofol was used in Group P and sevoflurane in Group S. Data analysis was done with California verbal learning test (CVLT), digit span test (DST), Rivermead behavioural memory test (RBMT), mini mental state examination (MMSE) score, and semantic memory tests. Aldrete recovery scoring system and visual analogue scale for pain were assessed post-operatively. The level of statistical significance was set at P < 0.05. RESULTS: There was no significant difference in demographic and haemodynamic data. Cognition and explicit memory were affected more in the propofol group in the immediate post-operative period. With majority of tests, such as semantic memory test, MMSE score, DST and RBMT, the difference was insignificant at 2 and 4 h post-operatively. But CVLT values were found to be statistically significant between groups even at 4 h. CONCLUSION: Propofol was associated with significant impact on cognitive functions in comparison to sevoflurane in the immediate post operative period. Sevoflurane anaesthesia might be a better option in day care surgeries. PMID- 25838587 TI - The haemodynamic effects of the perioperative terlipressin infusion in living donor liver transplantation: A randomised controlled study. AB - BACKGROUND AND AIMS: Liver disease is usually accompanied with a decline in systemic vascular resistance (SVR). We decided to assess effects of the peri operative terlipressin infusion on liver donor liver transplantation recipients with respect to haemodynamics and renal parameters. METHODS: After Ethical Committee approval for this prospective randomised controlled study, 50 recipients were enrolled and allotted to control (n = 25) or terlipressin group (n = 25) with simple randomisation method. Terlipressin was infused at 1.0 MUg/kg/h and later titrated 1.0-4.0 MUg/kg/h to maintain mean arterial pressure (MAP) >65 mmHg and SVR index <2600 dyne.s/cm5(/) m2 till day 4. Nor-epinephrine was used as appropriate. Haemodynamic and transoesophageal Doppler parameters (intraoperative), renal function, peak portal vein blood flow velocity (PPV), hepatic artery resistive index (HARI), urine output (UOP), liver enzymes, catecholamine support were compared intra-operatively and 4 days post operatively. Desflurane administration was guided with entropy. RESULTS: Terlipressin maintained better MAP and SVR (P < 0.01) during reperfusion versus controls (66.5 +/- 16.08 vs. 47.7 +/- 4.7 mmHg and 687.7 +/- 189.7 vs. 425.0 +/- 26.0 dyn.s/cm(5)), respectively. Nor epinephrine was used in 5 out of 25 versus 20 in controls. Urea, creatinine and UOP were significantly better with terlipressin. PPV was reduced with terlipressin post-reperfusion versus controls (44.8 +/- 5.2 vs. 53.8 +/- 3.9 ml/s, respectively, P < 0.01) without affecting HARI (0.63 +/- 0.06 vs. 0.64 +/- 0.05, respectively, P > 0.05) and was sustained post-operatively. CONCLUSION: Terlipressin improved SVR and MAP with less need for catecholamines particularly post-reperfusion. Terlipressin reduced PPV without hepatic artery vasoconstriction and improved post-operative UOP. PMID- 25838588 TI - Comparison of neostigmine induced reversal of vecuronium in normal weight, overweight and obese female patients. AB - BACKGROUND AND AIMS: Obese patients are more vulnerable to residual neuromuscular block (NMB) and its associated complications in the post-operative period. This study was carried out to compare neostigmine induced reversal of vecuronium in normal weight, overweight and obese female patients, objectively using neuromuscular (NM) monitoring. METHODS: Twenty female patients each belonging to normal weight, overweight and obese, based on body mass index, requiring general anaesthesia were recruited for this prospective cross sectional study. NMB was induced with vecuronium (0.1 mg/kg) dose based on patient's real body weight (RBW) and monitored using acceleromyographic train of four (TOF). All patients received neostigmine 40 MUg/kg and glycopyrrolate 10 MUg/kg at 25% of spontaneous recovery of first twitch height (T1) of TOF (DUR 25%) and were allowed to recover to TOF ratio of 0.9. Statistical analysis was done using analysis of variance test. RESULTS: Recovery of TOF ratio to 0.5 was comparable in all three groups. Recovery of TOF ratio to 0.7 was delayed in obese (9.82 +/- 3.21 min) compared with normal weight group (7.50 +/- 2.52 min). Recovery of TOF to 0.9 was significantly delayed in both overweight (12.18 +/- 4.29 min) and obese patients (13.78 +/- 4.30 min). DUR 25% was significantly longer in overweight (mean, standard deviation [range]; 30.10 [19-40 min]) and obese (28.8 [12-45 min]) compared with normal weight patients (22.75 [16-30 min]). CONCLUSION: In overweight and obese patients, when vecuronium induction dose is based on RBW, neostigmine induced recovery of NMB is delayed in late phases (TOF 0.7-0.9), which may result in vulnerability for associated complications of incomplete recovery. Ensuring safe recovery thus requires objective NM monitoring. PMID- 25838589 TI - Interscalene brachial plexus block for shoulder arthroscopic surgery: Prospective randomised controlled study of effects of 0.5% ropivacaine and 0.5% ropivacaine with dexamethasone. AB - BACKGROUND AND AIMS: Various adjuvants have been used to prolong the duration of local anaesthetic action after peripheral and regional nerve blocks. We evaluated the effect of dexamethasone on the duration of pain relief in shoulder arthroscopic surgeries performed under interscalene brachial plexus using ropivacaine as local anaesthetic. METHODS: After Ethical Committee approval and informed consent from patients we performed a prospective, randomised, comparative study on patients scheduled for arthroscopic shoulder surgery under interscalene block (ISB). Patients in ropivacaine group (Group R) received 30 ml of 0.5% ropivacaine plus 2 ml normal saline (n = 50) and dexamethasone ropivacaine (Group RD) received 0.5% ropivacaine 30 ml plus 8 mg dexamethasone (4 mg/ml) (n = 50). Duration of analgesia, onset of sensory and motor block, success and failure of block, and complications were recorded and compared. Computer software SPSS version-16 (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Chi-square test and Student's t-test were used and P < 0.05 was considered as significant. RESULTS: The mean duration of analgesia in Group RD was 1103.72 +/- 296.027 min and in Group R it was 551.54 +/- 166.92 min (P = 0.0001). Onset of sensory block in Group RD was 12.24 +/- 1.88 min and in Group R was 13.48 +/- 1.81 min (P = 0.5170). Onset of motor block in Group RD was 16.24 +/- 2.04 min and in Group R was 17.76 +/- 2.21 min (P = 0.2244). Onset of surgical anaesthesia in Group RD was19.46 +/- 1.86 min and in Group R was 20.84 +/- 1.71 min (P = 0.0859). CONCLUSION: Dexamethasone significantly prolonged duration of analgesia of ropivacaine during ISB used for arthroscopic surgeries of shoulder. Dexamethasone when mixed with ropivacaine had no effect on the onset of sensory and motor effects of ISB with ropivacaine. PMID- 25838590 TI - Intrathecal dexmedetomidine as adjuvant for spinal anaesthesia for perianal ambulatory surgeries: A randomised double-blind controlled study. AB - BACKGROUND AND AIM: The newer trend in regional anaesthesia for ambulatory anorectal surgeries advocate use of lower dose of local anaesthetic, providing segmental block with adjuvants such as opioids and alpha2 agonists to prolong analgesia. The current study investigated effects of addition of 5 MUg of dexmedetomidine to 6 mg of hyperbaric bupivacaine on duration of analgesia, sensory and motor block characteristics for perianal ambulatory surgeries. METHODS: This study is a prospective randomised controlled double blind study. Forty adult patients between 18 and 55 years of age were divided into 2 groups. Group D received intrathecal 0.5% hyperbaric bupivacaine 6 mg (1.2 ml) with injection dexmedetomidine 5 MUg in 0.5 ml of normal saline and Group N received intrathecal 0.5% hyperbaric bupivacaine 6 mg (1.2 ml) with 0.5 ml of normal saline. The parameters assessed were time to regression of sensory blockade, motor blockade, ambulation, time to void, first administration of analgesic. Statistical analysis was done using appropriate tests. RESULTS: Time for regression of sensory level and time for first administration of analgesic were prolonged in Group D (430.05 +/- 89.13 min, 459.8 +/- 100.9 min, respectively) in comparison to Group N (301.10 +/- 94.86 min, 321.85 +/- 95.08 min, respectively). However, the duration of motor blockade, time to ambulation, and time to void were also significantly prolonged in Group D (323.05 +/- 54.58 min, 329.55 +/- 54.06 min, 422.30 +/- 87.59 min) than in Group N (220.10 +/- 63.61 min, 221.60 +/ 63.84 min, 328.45 +/- 113.38 min). CONCLUSION: Intrathecal dexmedetomidine 5 MUg added to intrathecal bupivacaine 6 mg as adjuvant may not be suitable for ambulatory perianal surgeries due to prolongation of motor blockade. PMID- 25838591 TI - Anaesthetic concerns during adrenalectomy for Cushing's syndrome with known hyperhomocysteinemia. AB - Maintenance of homeostasis during anaesthesia in the patient with two major metabolic disorders whose systemic effects either compliment or contradict each other is a challenge to the anaesthesiologist. A 25-year-old male patient with Cushing's syndrome and known hyperhomocysteinemia was scheduled for open adrenalectomy. Both these disorders compound the hypercoagulable state and differ in glucose metabolism. In addition, obesity, difficult airway, electrolyte and metabolic derangements that accompany Cushing's syndrome warrant special attention. He was on anticoagulant therapy and inferior vena cava filter following an episode of pulmonary thromboembolism with deep vein thrombosis. Perioperative hydrocortisone was administered. Thoracic epidural catheter was placed at T10-T11 interspace, standard general anaesthesia was administered without nitrous oxide. Patient was extubated following an uneventful procedure and discharged home on 10(th) post-operative day. Understanding the anaesthetic implications and the pathophysiological interactions of multiple metabolic disorders with a potential for multisystem involvement is key to the successful management of these patients. PMID- 25838592 TI - Emergency anaesthetic management of penetrating thoracic trauma: Combining skill with fortuity. PMID- 25838593 TI - Anaesthetic considerations for tracheal resection in oncological thyroid surgeries. PMID- 25838594 TI - Survey of supraglottic airway devices usage in anaesthetic practice in South Indian State. PMID- 25838595 TI - A tryst with a dysmorphic parturient with congenital syphilis. PMID- 25838596 TI - Anaesthetic management of a case of adrenal and extra-adrenal phaeochromocytoma for preoperative embolisation. PMID- 25838597 TI - Myasthenia gravis: A challenge. PMID- 25838598 TI - Delayed recovery of consciousness after elbow arthroscopy. PMID- 25838599 TI - An add-on advantage of isoflurane graphical monitoring: Detection of intraoperative bronchospasm. PMID- 25838600 TI - Acute onset of intracranial subdural haematoma 2 days after spinal anaesthesia. PMID- 25838601 TI - Big cuff: Big problem. PMID- 25838602 TI - Erratum: Anaesthetic considerations in an infant with Beckwith-Weidemann syndrome and hepatoblastoma for partial hepatectomy: Erratum. AB - [This corrects the article on p. 121 in vol. 59, PMID: 25788746.]. PMID- 25838603 TI - Killing Range: Explaining Lethality Variance within a Terrorist Organization. AB - This paper presents an analysis of the Provisional Irish Republican Army's (PIRA) brigade level behavior during the Northern Ireland Conflict (1970-1998) and identifies the organizational factors that impact a brigade's lethality as measured via terrorist attacks. Key independent variables include levels of technical expertise, cadre age, counter-terrorism policies experienced, brigade size, and IED components and delivery methods. We find that technical expertise within a brigade allows for careful IED usage, which significantly minimizes civilian casualties (a specific strategic goal of PIRA) while increasing the ability to kill more high value targets with IEDs. Lethal counter-terrorism events also significantly affect a brigade's likelihood of killing both civilians and high-value targets but in different ways. Killing PIRA members significantly decreases IED fatalities but also significantly decreases the possibility of zero civilian IED-related deaths in a given year. Killing innocent Catholics in a Brigade's county significantly increases total and civilian IED fatalities. Together the results suggest the necessity to analyze dynamic situational variables that impact terrorist group behavior at the sub-unit level. PMID- 25838604 TI - Gene-Environment Interplay: Where We Are, Where We Are Going. AB - The idea that both genetic and environmental influences contribute to behavioral outcomes is widely accepted. However, the practice of examining candidate Gene * Environment interaction (cGxE) is controversial. In this article, we summarize some of the key issues involved in cGxE research and provide recommendations for work in this area. Highlighted challenges include the selection of the gene, the development of the cGxE hypothesis, and the coding of the genotype. To address these challenges and gain confidence in cGxE findings, we recommend using empirical data to select and code genes/variants, using theory to develop cGxE hypotheses and a rigorous and transparent approach to hypothesis testing. Family researchers have much to offer to the study of Gene * Environment research in view of their process-oriented theories that are grounded in decades of nuanced measurement of the environment; implementing these best practices will help deliver on that promise. PMID- 25838605 TI - Diels-Alder reactions of five-membered heterocycles containing one heteroatom. AB - Diels-Alder reactions of five-membered heterocycles containing one heteroatom with an N-arylmaleimide were studied. Cycloaddition of 2,5-dimethylfuran (4) with 2-(4-methylphenyl)maleimide (3) in toluene at 60 degrees C gave bicyclic adduct 5. Cycloadditions of 3 with 2,5-dimethylthiophene (11) and 1,2,5-trimethylpyrrole (14) were also studied. Interestingly, the bicyclic compound 5 cleanly rearranged, with loss of water, when treated with p-toluenesulfonic acid in toluene at 80 degrees C to give 4,7-dimethyl-2-p-tolylisoindoline-1,3-dione (6). PMID- 25838607 TI - Should the next South African census be register-based? PMID- 25838608 TI - Maternal mortality and morbidity in the United States of America. PMID- 25838609 TI - E-procurement in support of universal health coverage. PMID- 25838610 TI - New UN envoy joins campaign to end TB. PMID- 25838611 TI - Cotrimoxazole prophylaxis and antiretroviral therapy: an observational cohort study in China. AB - OBJECTIVE: To assess if cotrimoxazole prophylaxis administered early during antiretroviral therapy (ART) reduces mortality in Chinese adults who are infected with human immunodeficiency virus (HIV). METHODS: We did a retrospective observational cohort study using data from the Chinese national free antiretroviral database. Patients older than 14 years who started ART between 1 January 2010 and 31 December 2012 and had baseline CD4+ T-lymphocyte (CD4+ cell) count less than 200 cells/uL were followed until death, loss to follow-up or 31 December 2013. Hazard ratios (HRs) for several variables were calculated using multivariate analyses. FINDINGS: The analysis involved 23 816 HIV-infected patients, 2706 of whom died during the follow-up. Mortality in patients who did and did not start cotrimoxazole during the first 6 months of ART was 5.3 and 7.0 per 100 person-years, respectively. Cotrimoxazole was associated with a 37% reduction in mortality (hazard ratio, HR: 0.63; 95% confidence interval, CI: 0.56 0.70). Cotrimoxazole in addition to ART reduced mortality significantly over follow-up lasting 6 months (HR: 0.65; 95% CI: 0.59-0.73), 12 months (HR: 0.58; 95% CI: 0.49-0.70), 18 months (HR: 0.49; 95% CI: 0.38-0.63) and 24 months (HR: 0.66; 95% CI: 0.48-0.90). The mortality reduction was evident in patients with baseline CD4+ cell counts less than 50 cells/uL (HR: 0.60; 95% CI: 0.54-0.67), 50 99 cells/uL (HR: 0.66; 95% CI: 0.56-0.78) and 100-199 cells/uL (HR: 0.78; 95% CI: 0.62-0.98). CONCLUSION: Cotrimoxazole prophylaxis started early during ART reduced mortality and should be offered to HIV-infected patients in low- and middle-income countries. PMID- 25838612 TI - Legislation coverage for child injury prevention in China. AB - OBJECTIVE: To examine the extent to which effective interventions to prevent unintentional child injury are reflected in the laws and regulations of China. METHODS: We focused on the six common causes of fatal child injuries - drowning, road traffic injury, falls, poisoning, burns and suffocation. We investigated 27 interventions recommended by the United Nations Children's Fund, the World Health Organization or the European Child Safety Alliance. We searched China National Knowledge Infrastructure and Lawyee for Chinese legislations using keywords and synonyms for the 27 interventions. We reviewed the identified legislations for statements specifying the responsible implementation department. FINDINGS: Seven national laws, nine regulations of the State Council and 46 departmental regulations were found to relate to at least one of the interventions. Although seven of the 27 internationally recommended interventions were covered by Chinese laws, 10 were not covered by any current Chinese law or regulation. None of the interventions against drowning and falls that we investigated was covered by national laws. The implementation responsibilities for effective interventions were either not specified or were assigned to multiple governmental departments in 11 or 20 legislative documents, respectively. CONCLUSION: In Chinese laws and regulations, interventions proven to prevent major causes of unintentional child injuries are underrepresented and the associated implementation responsibilities are often poorly defined. China should include all such interventions in laws and regulations, and assign implementation responsibility for each to a single department of the national government. PMID- 25838614 TI - Congener specific polychlorinated biphenyl metabolism by human intestinal microbe Clostridium species: Comparison with human liver cell line-HepG2. AB - Polychlorobiphenyls (PCBs), which adversely affect human fetal and infant development, are endocrine disrupter and cause neurological disorders. They may also be carcinogenic. It is not known whether these effects are due to whole PCBs or to its metabolites, produced by the human gastrointestinal system primarily the liver and/or by intestinal microbes such as Clostridium sp. The available data show that Clostridium perfringens, the most prominent species of Clostridium occurs in the human gut. C. beijerinckii is a special type of Clostridium present in the gut of autistic children with late onset autism. Since mixed cultures are better PCB metabolizers than single cultures, mixed cultures of Clostridium were used in this work. The first step in PCB degradation is the removal of the chlorine atoms and then the breaking open of the phenyl ring leading to the final degradation product: CO2. In this study, GC-MS analyses were done to examine the effect of Clostridium sp. on PCB-153 and PCB-77 and the metabolites obtained with Clostridium sp. therein. In this paper, we report that the unlike human liver cells which cannot produce any PCB metabolites. Mixed Clostridium spp. can degrade these PCBs. Clostridium spp. and were able to dechlorinate PCB 153 (hexachlorobiphenyl) to pentachlorobiphenyl and PCB 77 (tetrachlorobiphenyl) to trichlorobiphenyl. Despite considerable absorption of PCB 153 (40%) and PCB 77 (50%) in 30 minutes and 1.5 hours respectively by human liver (HepG2) cells, they can not dechlorinate PCBs. It has been observed that slight differences in chemical structures of PCBs such as coplanar (PCB-77) vs. non-coplanar (PCB-153) has significant metabolic effects. PMID- 25838613 TI - The burden of child maltreatment in China: a systematic review. AB - OBJECTIVE: To estimate the health and economic burdens of child maltreatment in China. METHODS: We did a systematic review for studies on child maltreatment in China using PubMed, Embase, PsycInfo, CINAHL-EBSCO, ERIC and the Chinese National Knowledge Infrastructure databases. We did meta-analyses of studies that met inclusion criteria to estimate the prevalence of child neglect and child physical, emotional and sexual abuse. We used data from the 2010 global burden of disease estimates to calculate disability-adjusted life-years (DALYs) lost as a result of child maltreatment. FINDINGS: From 68 studies we estimated that 26.6% of children under 18 years of age have suffered physical abuse, 19.6% emotional abuse, 8.7% sexual abuse and 26.0% neglect. We estimate that emotional abuse in childhood accounts for 26.3% of the DALYs lost because of mental disorders and 18.0% of those lost because of self-harm. Physical abuse in childhood accounts for 12.2% of DALYs lost because of depression, 17.0% of those lost to anxiety, 20.7% of those lost to problem drinking, 18.8% of those lost to illicit drug use and 18.3% of those lost to self-harm. The consequences of physical abuse of children costs China an estimated 0.84% of its gross domestic product - i.e. 50 billion United States dollars - in 2010. The corresponding losses attributable to emotional and sexual abuse in childhood were 0.47% and 0.39% of the gross domestic product, respectively. CONCLUSION: In China, child maltreatment is common and associated with large economic losses because many maltreated children suffer substantial psychological distress and might adopt behaviours that increase their risk of chronic disease. PMID- 25838615 TI - Air Quality in Lanzhou, a Major Industrial City in China: Characteristics of Air Pollution and Review of Existing Evidence from Air Pollution and Health Studies. AB - Air pollution contributes substantially to global health burdens; however, less is known about pollution patterns in China and whether they differ from those elsewhere. We evaluated temporal and spatial heterogeneity of air pollution in Lanzhou, an urban Chinese city (April 2009-December 2012), and conducted a systematic review of literature on air pollution and health in Lanzhou. Average levels were 141.5, 42.3, and 47.2 ug/m3 for particulate matter with an aerodynamic diameter <=10 um (PM10), NO2, and SO2, respectively. Findings suggest some seasonality, particularly for SO2, with higher concentrations during colder months relative to warmer months, although a longer time frame of data is needed to evaluate seasonality fully. Correlation coefficients generally declined with distance between monitors, while coefficients of divergence increased with distance. However, these trends were not statistically significant. PM10 levels exceeded Chinese and other health-based standards and guidelines. The review identified 13 studies on outdoor air pollution and health. Although limited, the studies indicate that air pollution is associated with increased risk of health outcomes in Lanzhou. These studies and the high air pollution levels suggest potentially serious health consequences. Findings can provide guidance to future epidemiological studies, monitor placement programs, and air quality policies. PMID- 25838616 TI - Parent-Child Interactions During the Initial Weeks Following Brain Injury in Young Children. AB - OBJECTIVE: To understand how traumatic brain injury (TBI) affects parent-child interactions acutely following injury. PARTICIPANTS: Young children hospitalized for TBI (n = 80) and orthopedic injuries (OI; n = 113). METHOD: Raters coded videotaped interactions during free play and structured tasks for parental warmth/responsiveness and negativity and child warmth, behavior regulation, and cooperation. Raters also counted parental directives, critical/restricting statements, and scaffolds. RESULTS: Parents of children with TBI exhibited less warm responsiveness and made more directive statements during a structured task than parents in the OI group. Children with TBI displayed less behavior regulation than children with OI. Parental warm responsiveness was more strongly related to child cooperativeness in the OI group than in the TBI group. Child behavior also mediated group differences in parental responsiveness and directiveness. TBI accounted for as much variance in parental behaviors as or more than did sociodemographic factors. CONCLUSION: TBI-related changes in child behavior may negatively influence parent-child interactions and disrupt the reciprocity between parent and child. PMID- 25838617 TI - Relationship of risk assessment to placement characteristics in a statewide child welfare population. AB - Risk assessments allow child and youth services to identify children who are at risk for maltreatment (e.g., abuse, neglect) and help determine the restrictiveness of placements or need for services among youth entering a child welfare system. Despite the use of instruments by many agencies within the U.S. to determine the appropriate placements for youth, research has shown that placement decisions are often influenced by factors such as gender, age, and severity of social-emotional and behavior problems. This study examined ratings of risk across multiple domains using a structured assessment tool used by caseworkers in the Rhode Island child welfare system. The relationship between ratings of risk and placement restrictiveness was also examined. Risk levels varied across placement settings. Multivariate analyses revealed that lower caseworker ratings of parent risk and higher ratings of youth risk were associated with more restrictive placements for youth. Implications for the child welfare system are discussed. PMID- 25838618 TI - Resistin, visfatin, adiponectin, and leptin: risk of breast cancer in pre- and postmenopausal saudi females and their possible diagnostic and predictive implications as novel biomarkers. AB - The mechanisms of obesity-induced breast carcinogenesis are not clear. One hypothesis is that high levels of adipokines could promote breast cancer (BC) development. The aim of this study was to investigate the correlation of resistin, visfatin, adiponectin, and leptin with BC risk in pre- and postmenopausal females. A total of 82 BC newly diagnosed and histologically confirmed patients and 68 age and BMI matched healthy controls were enrolled. Both groups were subdivided into post- and premenopausal subgroups. Resistin, visfatin, adiponectin, and leptin were measured by ELISA. There were significantly higher levels of leptin, resistin, and visfatin in postmenopausal BC patients than their respective controls. Only in postmenopausal subgroups, leptin, resistin, and visfatin levels were positively correlated with TNM staging, tumor size, lymph node (LN) metastasis, and histological grading. In postmenopausal females, multivariate logistic regression analysis revealed that adiponectin, leptin, visfatin, and resistin were risk factors for BC. Our results suggested that serum resistin, leptin, adiponectin, and visfatin levels as risk factors for postmenopausal BC may provide a potential link with clinicopathological features and are promising to be novel biomarkers for postmenopausal BC. PMID- 25838619 TI - The effect of depression on serum VEGF level in Alzheimer's disease. AB - OBJECTIVE: Growing evidence suggests that angiogenesis might represent a new pathogenic mechanism involved in the progression of Alzheimer's disease (AD). Among angiogenic cytokines, vascular endothelial growth factor (VEGF) levels in AD patients have been evaluated, but the results are controversial among studies. We investigated serum levels of VEGF in AD patients with depression, AD patients without depression, and the controls, respectively. The aim of this study is to elucidate the relationship between VEGF, depression, and cognitive impairment in AD. METHODS: The CDR (Clinical Dementia Rating), MMSE-KC (the Mini-Mental Status Examination-Korean version), and SGDS-K (the Korean version of the Geriatric Depression Scale-Short Form) were measured in the subjects. Serum VEGF levels were measured in 24 AD patients with depression, 25 AD patients without depression, and 26 controls, using an enzyme-linked immunosorbent assay kit. RESULTS: Serum VEGF levels in AD patients with depression were significantly higher than AD patients without depression or the control. A correlation was observed between VEGF and scores on SGDS-K, but no correlation was detected between VEGF and MMSE-KC scores. CONCLUSION: Serum VEGF levels in AD patients with depression were higher than those without depression. Depression might be associated with changes in serum levels of VEGF in AD patients. PMID- 25838620 TI - MHC class I chain-related gene a diversity in patients with cutaneous malignant melanoma from southeastern Spain. AB - A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA(*)009 in melanoma patients compared with controls (P = 0.002, Pc = 0.03). Our results also showed an association between MICA(*)009 and HLA-B(*)51 alleles in both patients and controls. This association was stronger in patients than controls (P = 0.015). However, a multivariate logistic regression model showed that neither MICA(*)009 nor the combination MICA(*)009/HLA-B(*)51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis. PMID- 25838621 TI - Uncomplicated malaria in children: The place of rapid diagnostic test. AB - BACKGROUND: Malaria has remained a major cause of morbidity and mortality among the under-five children in Nigeria. Prompt and accurate diagnosis of malaria is necessary in controlling this high burden and preventing unnecessary use of anti malarial drugs. Malaria rapid diagnostic test (MRDT) offers the hope of achieving this goal. However, the performance of these kits among the most vulnerable age group to malaria is inadequate. MATERIALS AND METHODS: In this cross-sectional study, 433 out-patients, aged <5 years with fever or history of fever were enrolled. Each candidate was tested for malaria parasitaemia using ACON; malaria pf. Thick and thin films were also prepared from the same finger prick blood for each candidate. RESULT: Malaria rapid diagnostic test had sensitivity of 8.3%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 74%. The sensitivity of MRDT increased with increasing age. This effect of age on sensitivity was statistically significant (P = 0.007). Similarly parasite density had significant effect on the sensitivity of MRDT (P = <0.001). CONCLUSION: Histidine-rich protein-2 based MRDT is not a reliable mean of diagnosing malaria in the under-five age children with acute uncomplicated malaria. PMID- 25838622 TI - Knowledge of heart disease risk factors among workers in a Nigerian University: A call for concern. AB - INTRODUCTION: Cardiovascular disease is the commonest cause of mortality worldwide. Many risk factors predate the development of cardiovascular diseases. Adequate knowledge of risk factors for cardiovascular diseases is the first step towards effective preventive strategies to combat the cardiovascular diseases burden in any population. This study aims to determine the knowledge of workers in a Nigerian University on risk factors for cardiovascular diseases. MATERIALS AND METHODS: A cross-sectional survey of 206 academic and non-academic staff of Ladoke Akintola University of Technology, Ogbomoso, Nigeria using the Heart Disease Fact Questionnaire (HDFQ). Demographic data were taken. The lipid profile and random blood sugar were taken. Statistical analysis was done using SPSS 17.0. RESULTS: The mean age of the study participants was 45.3 +/- 7.9 years. There were 96 males (46.6%). The mean HDFQ score was 48.6%. Only 41 (19.9%) of participants were assessed to have good knowledge of heart disease risk factors. Majority, 101 (49.0%) had poor knowledge while 64 (31.2%) had fair knowledge of heart disease risk factors. There was no significant difference between prevalence of CV risk factors between those with good or fair or low level of knowledge. Most participants did not have a good level of knowledge about risk factors, prevention, treatment and association with diabetes as it relates to heart diseases. CONCLUSION: Knowledge of heart disease risk factors is low among University workers in Nigeria. Effective education on heart disease risk factors and appropriate preventive strategies are indeed important to reduce cardiovascular disease burden in Nigerian University communities. PMID- 25838623 TI - Maternal perspectives on gestational weight gain: Critical information on developing weight control interventions. AB - BACKGROUND: Our aim was to demonstrate what women reported being counselled about weight gain in pregnancy, their perceptions of inappropriate gestational weight gain (GWG), and plans for weight gain in pregnancy. MATERIALS AND METHODS: A cross-sectional survey of perceptions of prenatal attendees about inappropriate GWG was conducted at the prenatal clinic of a referral tertiary health facility in south western, Nigeria, between January 1, 2013 and June 30, 2013. Primary outcomes were the perceptions of women about risks involved with inappropriate weight gain and the proportion of women who self-reported being counselled at all on GWG, and had the right knowledge of risk(s) involved with inappropriate weight gain during pregnancy. RESULTS: Of the 348 women who completed the survey, approximately four-fifths (82.8%) reported GWG being discussed at all by health care provider. Fewer women (29.3%) believed there were maternal risks with excess weight gain compared to inadequate weight gain (34.8%). With respect to perception of risks of inappropriate weight gain to infants, 23.65 and 18.4%, respectively, believed there were infant risks with excess and inadequate GWG. Overweight women [OR 0.39 (95% CI 0.16-0.98)] and those who received GWG information from more than one type of health care provider [OR 4.71 (95% CI 1.64 13.78)] had significant increased rate of correct knowledge of risks involved with inappropriate GWG. CONCLUSION: The lack of awareness of risks involved with inappropriate GWG by over half of respondents underscores the need for improvement in educational intervention on GWG in our environment. PMID- 25838624 TI - Knowledge and attitudes towards obesity among primary school children in Dar es Salaam, Tanzania. AB - BACKGROUND: Childhood obesity has increased over the past two decades. Child obesity is likely to persist through adulthood and increases the risk of non communicable diseases (NCDs) later in life. This study assessed knowledge and attitudes towards obesity among primary school children in Dar es Salaam, Tanzania. MATERIALS AND METHODS: A cross-sectional study was conducted in randomly selected primary schools in Dar es Salaam. A structured questionnaire was used to assess the knowledge and attitudes. Anthropometric and blood pressure measurements were taken using standard procedures. RESULTS: A total of 446 children were included in the analysis. The mean age of the participants was 11.1 +/- 2.0 years. The mean body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 16.6 +/- 4.0 kg/m(2), 103.9 +/- 10.3 mmHg and 65.6 +/- 8.2 mmHg, respectively. Prevalence of obesity (defined as BMI >95(th) percentile for age and sex) was 5.2%. Half of the children (51.1%) had heard about obesity from teachers at school (20%), radio (19.4%) and books/newspaper (17.3%). Less than half (45.4%) had knowledge about the risk factors for childhood obesity and correctly defined obesity (44.6%). However, a good number of the children (72.1%) were aware that they can be affected by obesity. Majority of them had negative attitude towards obesity and various factors leading to or resulting from childhood obesity. CONCLUSIONS: Knowledge about childhood obesity among primary school children is moderate and have negative attitude towards obesity. Integrating educational programs early in primary schools may be an effective strategy to impact knowledge about obesity and other non-communicable diseases early in childhood. PMID- 25838625 TI - Profile and retrospective analysis of the use of preventive strategies in patients with cervical cancer in South-South Nigeria. AB - BACKGROUND: Cervical cancer is the commonest malignancy of the female genital tract in developing countries, with a global burden of 530,000 new cases annually. This study aims to review the current situation of this important malignancy and to assess the previous use of preventive measures in patients with cervical cancer at the Port Harcourt Teaching Hospital (UPTH), Port Harcourt, Nigeria. MATERIALS AND METHODS: This was a retrospective review of all cases of cervical cancer managed at the UPTH, Port Harcourt, Nigeria, between 1 January 2008 and 31 December, 2012. RESULTS: The prevalence of cervical cancer was 3.53% of all gynaecological admissions. The peak age of incidence was 50-59 years, accounting for 40% of the study population. Women with high parity contributed to 93.3% of the study population. Early coitarche was observed in 78.7% and a history of multiple sexual partners in 65.3%. Vaginal bleeding was the commonest clinical feature seen in all the women studied, followed by pelvic pain in 84% of cases. Advanced-stage cervical cancer was seen in 93.4%. None of the women studied had been previously vaccinated against human papilloma virus (HPV), and only 1.3% had had any form of screening methods for early detection of cervical cancer. CONCLUSION: Cervical cancer remains an important cancer in our environment, and late presentation with advance disease is still the norm despite advances in screening and preventive modalities. The reason for this is buttressed on the finding that despite the availability of these preventive strategies, women in the South-South of Nigeria did not partake of these measures. There is an urgent need to develop programmes to re-sensitise women on the need for screening and vaccination to reduce cancer-associated morbidity and mortality in Port Harcourt, South-South Nigeria. PMID- 25838626 TI - Malnutrition in acutely ill children at the paediatric emergency unit in a tertiary hospital in Nigeria. AB - BACKGROUND: In many developing countries, malnutrition remains an important cause of morbidity and mortality particularly in under-five children. The factors responsible for malnutrition could be immediate, underlying or basic, acting either alone or together. It has been shown that children who are malnourished have poorer outcomes from other illnesses than well-nourished children. It is important therefore to periodically describe the extent and pattern of childhood malnutrition so that effective preventive measures can be put in place. OBJECTIVE: To describe the prevalence and pattern of malnutrition in children presenting with acute illnesses at the Jos University Teaching Hospital. PATIENTS AND METHODS: A cross-sectional descriptive study in children aged 6 to 59 months seen at the paediatric emergency unit from April to October 2012. The subjects were recruited consecutively. Each child had both clinical assessment and appropriate laboratory evaluations done alongside anthropometric measurements. The nutritional/dietary and socio-demographic histories were also obtained. RESULTS: Of the 379 children, 224 (59.1%) were males and 155 (40.9%) females. The median age was 17 months, range (6-57). Wasting (WFH z-scores <=-3 to <-1SD) was evident in one hundred children, giving an overall prevalence of 26.9%. Severe wasting (WFH z-score <-3), was present in 22 (5.9%) children indicating the prevalence of marasmus, whereas only two children (0.53%) had oedematous malnutrition (kwashiorkor). Stunting or chronic malnutrition, (HFA z-scores <=-3 to <-1SD) was present in 67 children (18.0%). Seventeen (4.6%) were severely stunted (HFA z-score <-3). CONCLUSIONS: Wasting was the most common form of malnutrition in the study. PMID- 25838627 TI - Prevalence and predictors for domestic violence among pregnant women in a rural community Northwest, Nigeria. AB - OBJECTIVE: Domestic violence (DV) against women constitutes a violation of human rights. This study aimed at determining the prevalence and predictors for DV among pregnant women in a rural community northwest Nigeria. MATERIALS AND METHODS: A descriptive cross-sectional study which utilised an interviewer administered semi-structured pretested questionnaire. This assessed the type of DV experienced, the perpetrators and the trigger factor. Logistic regression analysis was used to assess the relative effect of determinants, adjusting for other predictor variables. The dependent variable was the occurrence of DV classified as Yes or No and the covariates included variables that were significantly associated with DV. RESULTS: Of the 314 respondents, 108 (34.3%) had experienced at least one form of DV and the types observed are: Verbal violence 79(68.5%); psychological violence72 (66.7%) and physical violence 55(50.9%). The perpetrators were the current husband in 40 (37.0%); co-wives in 33 (30.6%) and in-laws in 25 (23.1%). Of the cases, domestic issues were the trigger factor in 69 (63.9%) of cases and 54 (50%) of, the incidence was never reported. Ethnicity and type of marriage were significantly associated with occurrence of DV ( P <= 0.05) and both remained predictors for DV after controlling for confounders [Adjusted odds ratio (AOR) = 2.20 and 95% C.I = 1.42 11.9; AOR = 4.2 and 95% C.I = 1.36-3.57, respectively]. CONCLUSION: The prevalence of DV in pregnancy is high with women of Hausa/Fulani ethnicity and those in polygamous relationships at a higher risk. Effort should be made to screen pregnant women for DV during antenatal care. PMID- 25838628 TI - Screening for diabetes mellitus in patients with chronic obstructive pulmonary disease in tertiary care hospital in India. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) are common and under diagnosed medical conditions in India. Prevalence of these chronic diseases are high both in rural and urban areas. However, exact prevalence of DM in Indian COPD patients in unclear. Co-morbid conditions like DM have great impact on the outcome of COPD in the form of severity, exacerbations, morbidity and mortality. Hence the present study objective was to screen COPD patients for DM. RESULTS: A total of 1662 patients with COPD (Males = 1264, Female = 398) with mean age 58 +/- 9.6 were screened for DM. Patients with known history of DM were 353 (21.24%) and were enrolled as Known DM cases. Remaining 1309 (78.76%) patients whose DM status was unclear were screened by random blood sugar (RBS). One-hundred and seventy-one subjects had RBS > 110 mg/dl. About 73 (4.39%) subjects had fasting blood sugar (FBS) > 126 mg/dl. They were considered as Newly Diagnosed DM cases. Total number of DM cases in the study including new and known was 426 (25.63%). Number of patients with deranged FBS (FBS between 110 mg/dl to126 mg/dl) was 84 (5.05%). Among the DM patients with COPD 168 (10.11%) had poor glycemic control with HbA1c > 8. Prevalence of DM in present study was 25.63%. CONCLUSION: Prevalence of DM in COPD patients in the present study is 25.63% when actively screened in tertiary care hospital. It is feasible and imperative to screen all COPD patients for DM in all health care facilities routinely. PMID- 25838629 TI - Clinicopathological features of gastric carcinoma in Ibadan, Nigeria, 2000-2011. AB - AIM: The most recent study on the clinicopathological features of gastric carcinoma from the University College Hospital (UCH), Ibadan, was done in 2000. The aim of this study is to update the knowledge on the clinicopathological features of gastric carcinoma diagnosed in the Pathology Department of the UCH Ibadan between 2000 and 2011. MATERIALS AND METHODS: This was a 12-year retrospective review of clinical and demographic data and the histopathological features of gastric cancers diagnosed at the Pathology Department of the UCH. The chi square test, Fisher's exact test, and the t-independent test were used as applicable in the statistical analyses. RESULTS: A total of 117 cases of gastric carcinoma were histologically diagnosed at the Pathology Department of UCH, Ibadan in this period giving a relative ratio frequency of 1.38% for all cancers. It represented 18.4% of all gastrointestinal tract malignancies diagnosed in the same period. There was a male preponderance with male:female ratio of 1.72:1; the middle-aged and elderly made up about 76.1% of cases. The disease was clinically and histologically advanced in 92.8% of cases. Gastric tumours were predominantly antral/ pyloric in 80% of cases and exophytic in 62.3% of cases. The intestinal histotype constituted 47.0% cases although a rise in the diffuse histological type was observed. CONCLUSION: There is a decline in the relative ratio frequency of gastric carcinoma in Ibadan; and a fall in the rate of the intestinal type of gastric carcinoma relative to the diffuse type when compared to previous studies from our centre. PMID- 25838630 TI - Cardio-pulmonary resuscitation in the intensive care unit: An experience from a tertiary hospital in Sub-Saharan Africa. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) is one the most commonly performed procedures in the intensive care unit (ICU). However, success rate of CPR vary widely from 3.1% to 16.5%. PATIENTS AND METHODS: We conducted a retrospective study of all cardiac arrests prompting CPR in our ICU for a period of 12 months. Data retrieved from ICU records included patients demographic characteristics, diagnosis at admission, length of ICU stay, time and day of cardiac arrest, cardiac rhythm, duration of CPR and outcome of CPR. RESULTS: A total of 156 CPRs were performed within the study period with 8.3% success rate. Male: female ratio was 1.2:1. Indications for ICU admission, length of stay in ICU, time and day of cardiac and duration of CPR were found to be determinants of outcome. CONCLUSIONS: There is an urgent need to constitute a cardiac arrest team (CAT) which will be available at all times for improved successful outcome after cardiac arrest in our ICU. PMID- 25838631 TI - Knowledge regarding Ebola Hemorrhagic Fever among private dental practitioners in Tricity, India: A cross-sectional questionnaire study. AB - BACKGROUND: Ebola viral fever, a highly contagious haemorrhagic disease has today become a major public health concern in the developing countries worldwide. AIM: The purpose of this study was to assess knowledge among dental practitioners regarding Ebola Haemorrhagic Fever (Ebola HF) in Tricity, (Chandigarh, Panchkula and Mohali). MATERIALS AND METHODS: A total of 500 private dental practitioners were randomly approached to participate in this cross-sectional survey. A self structured, closed ended questionnaire was administered to each participant to record demographic and professional characteristics followed by their knowledge regarding Ebola HF. Knowledge section included questions related to communicability; symptomatology and diagnostics; at-risk individuals; prevention and treatment; and, virus characteristics of Ebola HF. RESULTS: The results were expressed in percentages. Multivariable linear regression analysis was carried out to assess the association of participants's demographic and professional characteristics with the knowledge scores. Statistically significant difference was seen when mean knowledge scores were compared based on the locality and qualification of the participants (P < 0.05). CONCLUSION: Dental practitioners from urban areas with higher qualification had better knowledge yet there were notable deficiencies regarding the virus characteristics, diagnostics, elimination and treatment. PMID- 25838632 TI - Effect of coconut oil in plaque related gingivitis - A preliminary report. AB - BACKGROUND: Oil pulling or oil swishing therapy is a traditional procedure in which the practitioners rinse or swish oil in their mouth. It is supposed to cure oral and systemic diseases but the evidence is minimal. Oil pulling with sesame oil and sunflower oil was found to reduce plaque related gingivitis. Coconut oil is an easily available edible oil. It is unique because it contains predominantly medium chain fatty acids of which 45-50 percent is lauric acid. Lauric acid has proven anti inflammatory and antimicrobial effects. No studies have been done on the benefits of oil pulling using coconut oil to date. So a pilot study was planned to assess the effect of coconut oil pulling on plaque induced gingivitis. MATERIALS AND METHODS: The aim of the study was to evaluate the effect of coconut oil pulling/oil swishing on plaque formation and plaque induced gingivitis. A prospective interventional study was carried out. 60 age matched adolescent boys and girls in the age-group of 16-18 years with plaque induced gingivitis were included in the study and oil pulling was included in their oral hygiene routine. The study period was 30 days. Plaque and gingival indices of the subjects were assessed at baseline days 1,7,15 and 30. The data was analyzed using paired t test. RESULTS: A statistically significant decrease in the plaque and gingival indices was noticed from day 7 and the scores continued to decrease during the period of study. CONCLUSION: Oil pulling using coconut oil could be an effective adjuvant procedure in decreasing plaque formation and plaque induced gingivitis. PMID- 25838633 TI - Basic life support knowledge and skills of Iranian general dental practitioners to perform cardiopulmonary resuscitation. AB - BACKGROUND: When cardiopulmonary arrest occurs, the dentist's ability to perform cardiopulmonary resuscitation (CPR) is the most important factor to minimize morbidity and mortality. This study assessed the basic life support (BLS) knowledge and performance of general dental practitioners in Hamadan, Iran. MATERIALS AND METHODS: The participants in the study were 80 Iranian general dental practitioners who were chosen randomly. Their CPR knowledge was evaluated by verbal questions and their CPR skills were determined by CPR execution on a special manikin. Nearly 39% (n = 31) of dentists answered none of the questions and only 2.50% (n = 2) answered all of the questions correctly. Thirty six dentists had been participated CPR course after graduation. RESULT: There was a significant difference between dentists who participated in CPR training course and those that did not participate (P value = 0.000). Only 3.75% (n = 3) were able to perform CPR properly. CONCLUSION: The results showed that the amount of CPR knowledge and skills were low in participated Iranian general dental practitioners. However, CPR training courses after graduation increased the amount of knowledge significantly, thus, retraining CPR courses is necessary for dentists. PMID- 25838634 TI - Desmoplastic fibroma of the ulna bone. AB - A fibroma is a benign tumour composed of fibrous connective tissue and they can grow in all organs. They can be classified based on consistency into hard or soft fibroma, based on histological characteristics into desmoplastic, chondromyxoid, ossifying, non-ossifying fibroma. They can also be classified based on tissue of origin or location in the body, it can also be classified into superficial or deep fibroma. This is a report of a 15-year-old Nigerian boy with a recurrent left ulnar tumour which was rapidly growing and has been excised three times. Preoperative investigations, i.e., plain radiograph, full blood count and fine needle aspiration cytology were done. Patient could not afford CT scan which was requested for. First excision was in 2009. Recurred within 1 year and had a repeat excision in 2011. He had a second recurrence 9 months after and had to have another excision. The last tumour excision left only the part of the left ulna that forms the proximal radioulnar joint and elbow joint. Patient has been followed up after the last excision for 18 months with no recurrence. PMID- 25838635 TI - Report of nine cases of Crimean-Congo haemorrhagic fever From Iran. AB - Crimean-Congo haemorrhagic fever (CCHF) is an often fatal viral infection described in about 30 countries around the world. It is transmitted to humans by the bite of an infected tick and by direct contact with blood or tissue from infected humans and livestock. In the following, we report nine cases of CCHF disease. This paper reported nine human CCHF cases, two in Tabas and Bandar Abbas and seven in Yazd. They were 21-, 33-, 28-, 29-, 61, 34, 35, 36 and 52 year-old men. The first, second and third patients were butchers and other patients were farmers. CCHF should be investigated in the patients with fever, bleeding and low platelet counts. PMID- 25838637 TI - Fruit Carts: A Domain and Corpus for Research in Dialogue Systems and Psycholinguistics. AB - We describe a novel domain, Fruit Carts, aimed at eliciting human language production for the twin purposes of (a) dialogue system research and development and (b) psycholinguistic research. Fruit Carts contains five tasks: choosing a cart, placing it on a map, painting the cart, rotating the cart, and filling the cart with fruit. Fruit Carts has been used for research in psycholinguistics and in dialogue systems. Based on these experiences, we discuss how well the Fruit Carts domain meets four desired features: unscripted, context-constrained, controllable difficulty, and separability into semi-independent subdialogues. We describe the domain in sufficient detail to allow others to replicate it; researchers interested in using the corpora themselves are encouraged to contact the authors directly. PMID- 25838636 TI - LANGUAGE EXPERIENCE SHAPES PROCESSING OF PITCH RELEVANT INFORMATION IN THE HUMAN BRAINSTEM AND AUDITORY CORTEX: ELECTROPHYSIOLOGICAL EVIDENCE. AB - Pitch is a robust perceptual attribute that plays an important role in speech, language, and music. As such, it provides an analytic window to evaluate how neural activity relevant to pitch undergo transformation from early sensory to later cognitive stages of processing in a well coordinated hierarchical network that is subject to experience-dependent plasticity. We review recent evidence of language experience-dependent effects in pitch processing based on comparisons of native vs. nonnative speakers of a tonal language from electrophysiological recordings in the auditory brainstem and auditory cortex. We present evidence that shows enhanced representation of linguistically-relevant pitch dimensions or features at both the brainstem and cortical levels with a stimulus-dependent preferential activation of the right hemisphere in native speakers of a tone language. We argue that neural representation of pitch-relevant information in the brainstem and early sensory level processing in the auditory cortex is shaped by the perceptual salience of domain-specific features. While both stages of processing are shaped by language experience, neural representations are transformed and fundamentally different at each biological level of abstraction. The representation of pitch relevant information in the brainstem is more fine grained spectrotemporally as it reflects sustained neural phase-locking to pitch relevant periodicities contained in the stimulus. In contrast, the cortical pitch relevant neural activity reflects primarily a series of transient temporal neural events synchronized to certain temporal attributes of the pitch contour. We argue that experience-dependent enhancement of pitch representation for Chinese listeners most likely reflects an interaction between higher-level cognitive processes and early sensory-level processing to improve representations of behaviorally-relevant features that contribute optimally to perception. It is our view that long-term experience shapes this adaptive process wherein the top-down connections provide selective gating of inputs to both cortical and subcortical structures to enhance neural responses to specific behaviorally-relevant attributes of the stimulus. A theoretical framework for a neural network is proposed involving coordination between local, feedforward, and feedback components that can account for experience-dependent enhancement of pitch representations at multiple levels of the auditory pathway. The ability to record brainstem and cortical pitch relevant responses concurrently may provide a new window to evaluate the online interplay between feedback, feedforward, and local intrinsic components in the hierarchical processing of pitch relevant information. PMID- 25838638 TI - Investigations into Transition Metal Catalyzed Arene Trifluoromethylation Reactions. AB - Trifluoromethyl-substituted arenes and heteroarenes are widely prevalent in pharmaceuticals and agrochemicals. As a result, the development of practical methods for the formation of aryl-CF3 bonds has become an active field of research. Over the past five years, transition metal catalyzed cross-coupling between aryl-X (X = halide, organometallic, or H) and various "CF3" reagents has emerged as a particularly exciting approach for generating aryl-CF3 bonds. Despite many recent advances in this area, current methods generally suffer from limitations such as poor generality, harsh reaction conditions, the requirement for stoichiometric quantities of metals, and/or the use of costly CF3 sources. This Account describes our recent efforts to address some of these challenges by: (1) developing aryl trifluoromethylation reactions involving high oxidation state Pd intermediates, (2) exploiting AgCF3 for C-H trifluoromethylation, and (3) achieving Cu-catalyzed trifluoromethylation with photogenerated CF3*. PMID- 25838640 TI - Comment on "5-azacytidine promotes an inhibitory T-cell phenotype and impairs immune mediated antileukemic activity". PMID- 25838641 TI - Chronic kidney disease in disadvantaged populations. PMID- 25838643 TI - Maternal, fetal and renal outcomes of pregnancy-associated acute kidney injury requiring dialysis. AB - Pregnancy-associated acute kidney injury (PAKI) is encountered frequently in developing countries. We evaluated the maternal, fetal and renal outcomes in women with PAKI who needed at least one session of dialysis. Of the total of 98 cases (mean age 28.85 +/- 5.13 years; mean parity 2.65 +/- 1.28) of PAKI, the most common cause of PAKI was postabortal sepsis. Eighteen patients died; those with oligoanuria, sepsis and central nervous system (CNS) involvement were at greater risk of mortality. The relative risk (RR) of neonatal mortality was lower after with full-term delivery (RR: 0.17, 95% confidence interval (CI): 0.03-0.96, P = 0.02) compared to preterm delivery. Of the 80 surviving patients, 60 (75%) patients achieved complete recovery of renal function at the end of 3 months; and of the remaining 14 had presumed (n = 4) or, biopsy-proven (n = 10) acute patchy cortical necrosis. The RR of non-recovery of renal function was high (RR: 24.7, 95% CI: 3.4- 179.5) in patients who did not recover at 6 weeks. Of the 14 patients with cortical necrosis, 3 (21.42%) became independent of dialysis at 6 months. PAKI patients should be watched for dialysis independency for 6 months. PMID- 25838642 TI - Hepatocyte nuclear factor-1beta: A regulator of kidney development and cystogenesis. AB - The understanding of the genomics of the renal tissue has gathered a considerable interest and is making rapid progress. The molecular mechanisms as well as the precise function of the associated molecular components toward renal pathophysiology have recently been realized. For the cystic kidney disease, the regulation of gene expression affecting epithelial cells proliferation, apoptosis as well as process of differentiation/de-differentiation represent key molecular targets. For the cystic disorders, molecular targets have been identified, which besides lending heterogeneity to cysts may also provide tools to unravel their functional importance to understand the renal tissue homeostasis. This review focuses on providing comprehensive information about the transcriptional regulatory role of hepatocyte nuclear factor-1beta, a homeoprotein, as well as its interacting partners in renal tissue development and pathophysiology. PMID- 25838639 TI - Pivotal roles of GM-CSF in autoimmunity and inflammation. AB - Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells. In autoimmune and inflammatory diseases, Th17 cells have been considered as strong inducers of tissue inflammation. However, recent evidence indicates that GM-CSF has prominent proinflammatory functions and that this growth factor (not IL-17) is critical for the pathogenicity of CD4(+) T cells. Therefore, the mechanism of GM-CSF-producing CD4(+) T cell differentiation and the role of GM-CSF in the development of autoimmune and inflammatory diseases are gaining increasing attention. This review summarizes the latest knowledge of GM-CSF and its relationship with autoimmune and inflammatory diseases. The potential therapies targeting GM-CSF as well as their possible side effects have also been addressed in this review. PMID- 25838644 TI - Focal segmental glomerulosclerosis in renal allografts: Is it possible to diagnose the etiology? AB - Recurrence of FSGS in renal allo grafts is a major cause of graft loss. In this context, we tried to diagnose and classify FSGS in renal allografts. Indications for biopsy included graft dysfunction and/or proteinuria. Three hundred and sixty three graft biopsies were studied over a period of 2 years. We classified FSGS into recurrent FSGS, new-onset primary FSGS and FSGS secondary to chronic humoral rejection, calcineurin inhibitor toxicity, and nephron loss and hyperfiltration injury. Twenty-four cases were diagnosed as FSGS, constituting 6.6%. Secondary FSGS was the most common FSGS in grafts in our study. Incidence of recurrent FSGS may not be accurate as pretransplant biopsy is available in very few cases. PMID- 25838645 TI - Acute kidney injury in patients with human immunodeficiency virus infection. AB - Acute kidney injury (AKI) is an important cause of hospitalization and morbidity in human immunodeficiency virus (HIV)-positive patients. However, the data on AKI in such patients is limited. The aim of the present study was to analyze the incidence, causes and outcome of AKI in HIV-positive patients from our antiretroviral therapy centre. All HIV-positive patients were evaluated for evidence of clinical AKI. AKI was noted in 138/3540 (3.9%) patients. Of 138 AKI patients, 96 (69.6%) had acquired immuno deficiency syndrome and 42 (30.4%) were HIV seropositive. Majority of AKI patients belonged to AKI network (AKIN) Stage II (42%) or III (48.5%) at presentation. Prerenal, intrinsic and postrenal AKI were noted in 53.6%, 44.2% and 2.2% of cases, respectively. Hypovolemia (44.2%) and sepsis (14.5%) contributed to AKI in vast majority of cases. AKI was multifactorial (volume depletion, sepsis and drugs) in 39% of patients. Acute tubular necrosis (ATN) was the most common intrinsic lesion. Acute interstitial nephritis and diffuse endocapillary proliferative glomerulonephritis were noted in five and two cases, respectively. In-hospital mortality was 24.64%. Lower CD4 count, decreased serum albumin level and Stage 4 WHO disease were associated with higher mortality. At 3 months or more follow-up complete recovery of renal function, chronic kidney disease Stage 3-5 and progression to end stage renal disease were noted in 58.69%, 14.5% and 2.2% of cases, respectively. Thus, prerenal factors and ischemic ATN were the most common cause of AKI in HIV infected patients. Recovery of renal function was seen in 59% of cases, but AKI had high in-hospital mortality. PMID- 25838646 TI - Single dose rasburicase in the management of tumor lysis syndrome in childhood acute lymphoblastic leukemia: A case series. AB - Tumor lysis syndrome (TLS) occurs in malignancies with high proliferative potential and tumor burden, such as lymphomas and leukemias. TLS syndrome is an oncologic emergency, requiring prompt intervention. The metabolic derangements cause acute kidney failure and may lead to cardiac arrhythmias, seizures, and death. With the advent of rasburicase, a recombinant urate oxidase, there has been a decline in the TLS-mediated renal failure and the need for dialysis. The recommended regimen and doses pose a heavy financial burden for patients in developing countries like India. With data and studies proving a similar efficacy for the reduced dose and lesser number of rasburicase, we report here a case series of seven children with acute leukemias, whose TLS was managed by a single dose of rasburicase. A retrospective analysis of case records of seven children with acute lymphoblastic leukemia and TLS, admitted to our Pediatric Oncology Unit of our Hospital between the period 2011 and 2013, was done. All our patients responded to a single dose, indicating that in appropriately monitored patients, single dose followed by as-needed dosing can be cost-saving. PMID- 25838647 TI - Prevalence and dynamics of cytomegalovirus infection among patients undergoing chronic hemodialysis. AB - Cytomegalovirus (CMV) is an important pathogen in immunocompromised individuals. The aim of this study was to analyze prevalence and dynamics of CMV infection among patients undergoing chronic hemodialysis. From 2010 to 2012, a total of 162 patients and 160 control subjects were tested for the presence of CMV IgM and IgG antibodies using enzyme-linked immunosorbent assay. IgM/IgG reactive samples were further evaluated for IgG avidity to confirm or rule out recent primary CMV infection. The overall IgG seropositivity was higher in hemodialysis patients compared to controls (90.7% vs. 81.9%; crude odds ratio [OR] =2.02, 95% confidence interval [CI] =1.05-3.89; OR adjusted for age and gender = 2.18, 95% CI = 1.05-4.55). CMV IgG antibody titers were similar in both groups. There was no difference in CMV prevalence between males (87.9%) and females (96.3%). According to age, a progressive increase in seropositivity was observed in both hemodialysis patients and the control group. Three hemodialysis patients (1.9%) developed recurrent CMV infection (positive IgM with high avidity IgG antibodies). In one patient (2.9%), seroconversion was documented during the second year of the follow-up period indicating primary infection. In contrast, in the control group, recent primary CMV infection (positive IgM with low/borderline IgG avidity) was demonstrated in three subjects (1.9%), whereas one (0.6%) developed recurrent infection. On multivariate logistic regression, hemodialysis and older age were significant predictors for CMV seropositivity. PMID- 25838648 TI - Collapsing glomerulopathy following anabolic steroid use in a 16-year-old boy with IgA nephropathy. AB - Collapsing glomerulopathy (CG) is a proliferative podocytopathy, increasingly recognized in a variety of disease conditions. We report a case of CG in a 16 year-old boy with IgA nephropathy (IgAN) who presented with acute kidney injury, marked proteinuria and hypertension following a short period of anabolic steroid use. Although CG has been associated with long-term anabolic steroid use among body builders, there is no data on the effect of anabolic steroid use in persons with underlying renal disease like IgAN. We postulate that development of CG in our patient could be temporally linked to intake of body-building steroids along with a predisposing background renal disease of IgAN. PMID- 25838649 TI - Hypokalemic paralysis due to thyrotoxicosis accompanied by Gitelman's syndrome. AB - A 35-year-old male patient was admitted with fatigue and muscle weakness. He had been on methimazole due to thyrotoxicosis for 2 weeks. Laboratory tests showed overt hyperthyroidism and hypokalemia. Potassium replacement was started with an initial diagnosis of thyrotoxic hypokalemic periodic paralysis. Later on, despite the euthyroid condition and potassium chloride treatment, hypokalemia persisted. Further investigations revealed hyperreninemic hyperaldosteronism. The patient was considered to have Gitelman's syndrome (GS) and all genetic analysis was done. A c. 1145C>T, p. Thr382Met homozygote missense mutation located on solute carrier family 12, member gene 3, exon 9 was detected and GS was confirmed. PMID- 25838650 TI - Heavy and Light chain amyloidosois presenting as complete heart block: A rare presentation of a rare disease. AB - Amyloidosis is an uncommon disease characterized by deposition of proteinaceous material in the extracellular matrix, which results from abnormal protein folding. Even though more than 25 precursor proteins are identified, majority of systemic amyloidosis results from deposition of abnormal immunoglobulin (Ig) light chains. In heavy chain amyloidosis (AH), deposits are derived from both heavy chain alone, whereas in heavy and light chain amyloidosis (AHL), the deposits are derived from Ig heavy chains and light chains. Both AH and AHL are extremely rare diseases. Here, we report an unusual presentation of IgG (lambda) AHL amyloidosis in the background of multiple myeloma, where the initial clinical presentation was complete heart block, which preceded the definitive diagnosis by 18 months. PMID- 25838651 TI - Successful salvage of thrombosed arterio-venous fistula with thrombolytic therapy using tissue plasminogen activator. AB - A functioning vascular access is crucial to the wellbeing of patients on hemodialysis. Thrombosis is the most common complication of arteriovenous fistula (AVF) resulting in late fistula failure; Its treatment is difficult, and results are often suboptimal. Interventional treatment of AVF thrombosis may not be available all the time, and timely application of an available noninterventional treatment may salvage the fistula. We report the successful treatment of AVF thrombosis using local thrombolytic therapy using tissue plasminogen activator in a patient, for the first time in India. PMID- 25838653 TI - Severe peritonitis caused by Citrobacter freundii and successful treatment with double antibiotic coverage. AB - Serratia, Pseudomonas/Providencia, indole-positive Proteus/Acinetobacter/Morganella, Citrobacter, Enterobacter and Hafnia group of organisms cause peritoneal dialysis (PD)-related peritonitis with high morbidity and mortality. Peritonitis caused by Citrobacter freundii is uncommon, and it may lead to catheter removal despite antimicrobial treatment. We describe a case of PD-related peritonitis caused by C. freundii, which was successfully treated with double antibiotic coverage. PMID- 25838652 TI - Immunoglobulin G4-related tubulointerstitial nephritis associated with interstitial pulmonary disease: Report of a case with review of literature. AB - Immunoglobulin G4-related disease (IgG4-RD) is an emerging clinicopathological entity. Renal involvement is dominated by tubulointerstitial nephritis (TIN) with IgG4-positive plasma cells and fibrosis. IgG4-RD commonly affects middle-aged to elderly men with accompanying extra-renal lesions such as sialadenitis, lymphadenopathy, or type 1 autoimmune pancreatitis, all of which respond favorably to corticosteroid therapy. The disease burden of IgG4-related kidney disease (IgG4-RKD) in India remains largely underestimated. We report a case of IgG4-RKD manifesting as TIN associated with interstitial pulmonary disease, illustrating typical clinico-pathologic, serologic, immuno-histochemical, and ultrastructural features of this condition. In view of potential amelioration of renal dysfunction with appropriate therapy, the need for awareness of this condition and early diagnosis is highlighted. PMID- 25838654 TI - Light chain proximal tubulopathy with cast nephropathy in a case of multiple myeloma. AB - The renal diseases most frequently associated with myeloma include cast nephropathy (CN), amyloidosis and monoclonal immunoglobulin deposition disease. Light chain proximal tubulopathy (LCPT) is reported less frequently. Majority of the cases with kappa-restriction present with Fanconi syndrome (FS) and show crystals in proximal tubular epithelial cytoplasm. In contrast, those with lambda restriction are infrequently associated with FS and show cytoplasmic vacuolations in proximal tubular epithelial cytoplasm. Combination of morphologies in kidney affected by plasma cell dyscrasias is rare and co-existence of LCPT and CN is one of the rarest. We report a case of multiple myeloma having this rare combination of morphologies. PMID- 25838655 TI - Obstructive uropathy: Is it always urolithiasis? PMID- 25838656 TI - Expanding the living renal donor pool by using a horseshoe kidney. PMID- 25838657 TI - Tubercular constrictive pericarditis after renal transplantation. PMID- 25838658 TI - Neutrophil lymphocyte ratio in aute renal failure. PMID- 25838659 TI - Membranous nephropathy associated with the use of levodopa-carbidopa combination. PMID- 25838660 TI - Frontal sinus fracture: a case report. AB - In today's world high velocity trauma is not uncommon and most of the road traffic accidents involve trauma to head and neck region. For purposes of initial evaluation, Injury to the frontal bone should be regarded as head injuries. The majority of these patients are victims of automobile accidents or fall from height with multiple injuries requiring a multispecialty team approach and complete evaluation. The standard trauma protocol must be followed with emphasis on ensuring an adequate airway, breathing, circulation, central nervous system status, and cervical-spine. Any other life-threatening injuries take precedence over the sinus fracture. Management of a case of frontal sinus fracture with loss of anterior table is presented. PMID- 25838661 TI - Marsupialization of dentigerous cyst: report of a case. AB - Dentigerous cyst is a common pathologic entity associated with an impacted tooth. The standard treatment for this lesion is enucleation and extraction of the involved tooth. Marsupialization of dentigerous cyst has also been advocated, once in many cases it can maintain the impacted tooth in its cavity and promotes its eruption. This report describes a case of a 13-year-old girl with a large dentigerous cyst associated with mandibular right second molar. The cyst was marsupialized and the patient was checked weekly. Two months after the surgical procedure the impacted tooth was completely erupted without orthodontic traction and therapy. PMID- 25838662 TI - Nasolabial cyst: clinical presentation and differential diagnosis. AB - Nasolabial cyst also known as Klestadt's cyst is relatively rare soft tissue lesion of nasal alar region. It is nonodontogenic in origin and characterized by its extra osseous location. This paper documents clinical presentation, differential diagnosis and surgical management of nasolabial cyst in 25 years old woman. PMID- 25838663 TI - Nevoid Basal cell carcinoma syndrome: a case report and review. AB - Nevoid basal cell carcinoma syndrome, a rare autosomal dominant disorder, comprises of a number of abnormalities such as multiple nevoid basal cell carcinomas, skeletal abnormalities and multiple keratocystic odontogenic tumors. Diagnosis may be difficult because of the variability of expressivity and different ages of onset for different traits of this disorder. The dental clinician may be the first to encounter and identify this syndrome, when the multiple cysts like radiolucencies are discovered on panoramic view. This article reports a case of Nevoid basal cell carcinoma syndrome and provides an overview on diagnosis and management. PMID- 25838664 TI - Bradycardia during temporomandibular joint gap arthroplasty. PMID- 25838665 TI - Traumatic internal maxillary artery pseudoaneurysm with a malunited mandibular fracture. AB - Post-traumatic external carotid artery pseudoaneurysms are very uncommonly encountered in clinical practice. We present the case of a young man who developed pseudoaneurysm 5 weeks after a maxillofacial injury treated elsewhere. PMID- 25838666 TI - Octreotide for conservative management of intractable high output post operative chylous fistula: a case report. AB - A case of high output post neck dissection chylous fistula is presented, which was successfully managed conservatively with octreotide; a long acting somatostatin analogue. Routine measures had failed, and secondary complications precluded thoracoscopic ligation. We discuss the spectrum of problems associated with chylous fistula and review the rationale behind the use of octreotide. PMID- 25838667 TI - Orofacial space infection due to faulty prosthesis. AB - Orofacial space infections are commonly treated by oral and maxillofacial surgeons, even in the post antibiotic era. Pre existing systemic conditions such as diabetes mellitus makes a person more vulnerable to space infection. A prosthesis which is poorly designed often jeopardises the oral health and makes a person susceptible to ulcers of mucosa, which can result in necrosis of mucosa. The sequel of such ulcerations and necrosis would be life threatening Orofacial space infections in medically compromised patients. Here we present a case report of 64 year old diabetic patient presenting with Orofacial space infection as a sequel to necrosis of mucosa caused due to physical and chemical injury by a faulty prosthesis fabricated by a quack practicing dentistry. Submandibular, sublingual and pterygomandibular space were involved leading to trismus and swelling. On forceful mouth opening after extraoral mandibular nerve block, denudation of mucosa was seen distal and lingual to mandibular right second premolar with pus discharge. Radiographic examination revealed no abnormal findings in teeth or bone. The spaces were explored from the opening created by denuded mucosa. Infection control and diabetic control was achieved with antibiotics and oral hypoglycaemic drugs. Patient responded well for the treatment and recovered uneventfully. PMID- 25838668 TI - Goldenhar Syndrome with Tessier's 7 Cleft: Report of a Case. AB - Goldenhar syndrome, a variant of hemifacial microsomia, is a well-known developmental anomaly of maxillofacial skeleton that is apparent at birth. The first and second branchial arch involvement during early embryonic development results in a wide spectrum of anomalies that may include macrostomia and lateral facial clefts. Though clefts of the orofacial region are among the most common congenital facial defects, the occurrence of lateral facial clefts (Tessier 7 cleft) in conditions such as the Goldenhar syndrome, is very rare (<5%). The lateral facial cleft, which results because of improper development of the perioral muscles of the face, gives an appearance of macrostomia giving rise to potential psychological, aesthetic and feeding problems. This clinical report describes the closure of a Tessier 7 cleft and the use of distraction osteogenesis to treat mandibular asymmetry in an 11-year-old female patient with Goldenhar's syndrome. PMID- 25838669 TI - Osteonecrosis of maxilla secondary to bisphosphonate therapy: a case report. AB - Bisphosphonate chemotherapy is commonly used in the treatment of bone diseases such as osteoporosis, Paget disease, and multiple myeloma and to limit bone pain and hypercalcemia associated with malignant metastatic bone lesions. The introduction of bisphosphonate therapy has improved the quality of life in a vast majority of patients. However, since 2003 a growing number of reports have described necrotic bone lesions (bisphosphonate-associated Osteonecrosis of the jaw [BR-ONJ]) a bone lesion affecting maxillofacial bones in patients who have received high dosage chemotherapy with intravenous bisphosphonate therapy especially when the patient undergoes subsequent dental procedures. Sequential removal of sequestra as required seems to be the current conservative approach, but if large-volume debridement becomes necessary, removal of the bone sequestrum with minimal epithelial manipulation associated with topical and systemic antibiotics seem to be the treatment modality of choice. In our case, surgical salvage was performed successfully for BR-ONJ. Our experience indicates that with appropriate technique, primary surgical treatment may offer benefit to selected patients with BR-ONJ. PMID- 25838670 TI - Clear cell odontogenic carcinoma-a rare case report. AB - Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic tumour with female predilection occurring in the anterior region of the mandible with peak age incidence of 5th and 7th decade of life. Here we report a case occurred in the posterior mandible of a 42 year old male patient which highlights the clinicopathologic features of CCOC that were confirmed by histopathologic examination. We add up yet another case of CCOC to the published literature. PMID- 25838671 TI - Myofibroma-a rare entity with unique clinical presentation. AB - Myofibroma and myofibromatosis is a well-recognized spindle cell neoplasm that occurs predominantly in infants and young children. They have been described under different names since 1951. These lesions are a benign fibroblast and myofibroblast proliferation containing a biphasic presentation of spindle shaped cells surrounding a central zone of less differentiated cells focally arranged in a hemangiopericytoma like pattern. Classically these lesions are described in children younger than two, with 2/3rd present at birth and rarely in adults. Controversy exists as to an autosomal dominant or recessive inheritance or to a sporadic occurrence. Presented here is a unique case of myofibroma involving the mandible in a 11 year-old male patient. Clinically it mimicked more like a beningn tumor and not exhibiting any of its classical signs. The diagnosis could be established only after complete excision of the lesion and histopathological examination. There was no recurrence after a follow up period of 4 months. PMID- 25838672 TI - Juvenile ossifying fibroma of the maxilla: a case report. AB - Ossifying fibroma is a benign neoplasm of the bone, usually involving the posterior tooth bearing area of the mandible, predominantly seen in females in 2nd-4th decade of life with 5:1 prediliction. Fibro-osseous lesions other than FD seem to arise from the periodontal membrane. These lesions are usually asymptomatic, well defined clinically and radiologically amenable for enucleation. Fibro-osseous lesions of the jaws, including Juvenile Ossifying Fibroma (JOF), pose diagnostic and therapeutic difficulties due to their clinical, radiological and histological variability. Ossifying fibromas which appear as fast growing mass between 5 and 15 years of age, radiologically well bordered, and consistent with ossifying fibroma histologically, are referred as juvenile (aggressive) ossifying fibroma. We report a case of JOF of left side of the maxilla in an 11 year old girl which is an uncommon site of occurrence. PMID- 25838673 TI - Hypoglossal schwannoma of parapharyngeal space: an unusual case report. AB - Schwannomas are benign tumor of the schwann cells. These are common in eighth, tenth cranial nerves and parasympathetic chain. Hypoglossal schwannomas are rare. Among the hypoglossal schwannomas the intracranial and dumb-bell shaped schwannomas are frequent but extra cranial hypoglossal schwannomas are rare. We describe a parapharyngeal hypoglossal schwannoma in a 25 years female presenting as slow growing mass in right side of the neck. PMID- 25838674 TI - Neonatal osteomyelitis with pathologic fracture of mandible following MRSA septicemia: management and three year follow up. AB - Neonatal septicemia caused by resistant bacteria in intensive care units can be not only life threatening, but may also cause long lasting sequelae. A case of a 2 month old male child with osteomyelitis with pathological fracture of the mandible following methicillin resistant Staphylococcus aureus septicemia is presented. Surgical management, successful outcome and its long term effect on the growth of mandible and dentition is illustrated. PMID- 25838675 TI - Orbital fracture in a professional diver: issues and management. AB - BACKGROUND: We present a case report of a professional diver who sustained a fracture of the left orbital medial wall as well as floor exceeding 50% with orbital fat herniation blocking the maxillary sinus ostium. This may result in a closed cavity within the maxillary sinus that could potentially result in barotraumas during future diving. The aim of his surgery consists of repairing the orbital fracture and to aerating the sinus at the same sitting. METHOD: A transconjunctival approach was used combined with endoscopic sinus surgery approach to the maxillary sinus. The orbital floor fracture was repaired with a titanium plate. A wide middle meatal antrostomy was performed. A size eight Foley's catheter was inserted into the maxillary sinus and the balloon inflated to elevate and support the displaced inferior orbital floor bone fragment. The balloon was left in situ for 4 weeks to support the mobile inferior orbital fragment till adequate bone healing and stability. RESULTS: Patient recovered well. At 3 months post-operatively, the maxillary antrostomy remained patent, and a hyperbaric oxygen challenge test was performed with success. A repeat orbital CT scan 1 day after hyperbaric challenge showed no signs of air leakage, and the bony inferior orbital floor fracture has healed completely with the titanium plate in situ. CONCLUSION: This is the first case report of repair of orbital floor fracture with simultaneous aeration of the maxillary sinus in a professional diver using a combined approach. The patient was able to resume his occupation as a professional diver following surgery. PMID- 25838676 TI - Peripheral ossifying fibroma on edentulous mandibular alveolar mucosa. AB - Peripheral ossifying fibroma (POF) is a reactive gingival overgrowth occurring frequently in the maxillary anterior region of teenagers and young adults. The pink to red growth may be firm to hard in consistency depending on the amount of bone it contains and may become ulcerated as its size increases. POF is commonly associated with poor oral hygiene and early periodontal disease with majority of cases showing no marked underlying bone involvement radiographically. We report an unusual case of a large POF overlying the edentulous mandibular alveolar ridge along with histopathological correlations. This case could be one of the first to demonstrate that there may be a variant of POF affecting edentulous mandibular mucosa that has not been previously recognized. PMID- 25838677 TI - Maxillary osteosarcoma masquerading as chondromyxoid fibroma: report of a case. AB - Osteosarcomas are highly malignant bone tumours. Its appearance in craniofacial bones is a rare entity and accounts for only 1% of all head and neck malignancies. We present an uncommon case report of a 42 year old male patient with osteosarcoma of left maxilla, which was successfully excised under general anesthesia. The patient reported to us with a history of pain, swelling, pus discharge and tooth extraction, which led to the differential diagnosis of suppurative osteomyelitis, dentoalveolar abscess, benign odontogenic tumour, an infected cyst etc. Histopathological examination of incisional biopsy was reported as chondromyxoid fibroma which is a rare benign tumour. However the excisional biopsy specimen was reported as osteosarcoma of maxilla. The clinical presentation, diagnostic challenges and its therapeutic approach are addressed. This case serves to emphasize the need to recognize osteosarcoma when it presents in unexpected locations, especially because of its rarity. PMID- 25838678 TI - Combined orthodontic and surgical therapy for a deeply impacted third molar related with a dentigerous cyst. AB - The dentigerous cysts are the common cause that inhibits the eruption of the teeth. Large dentigerous cysts can cause pathological fractures in mandible. Temporary or permanent inferior alveolar and lingual nerve damage can occur associated with deeply impacted third molar surgery. We treated the dentigerous cyst arised from deeply impacted mandibular third molar with orthodontic extraction combined with the marsupialization therapy. This orthodontic-surgical procedure reduced the risk of nerve damage and pathological fracture of the mandible. PMID- 25838679 TI - Unusual foreign body in mid face. AB - Cases of foreign bodies in the antrum and nasal cavity are reported in the literature but the size and location of foreign body in this case made it unique and challenging. A large exploded fragment was successfully removed through Lefort I osteotomy approach. Foreign bodies in maxilla and antrum can be removed by different approaches: Caldwell-Luc operation, nasal and antral endoscopic surgery. The foreign body was lying horizontally in posterior maxilla occupying both the maxillary sinuses and nasal cavity. The foreign body was so big in size that the nasal endoscopic approach and Caldwell-Luc operation might be inadequate for its retrieval. PMID- 25838680 TI - Penetrating injury of face by a large machine bolt-a rare case report. AB - Foreign bodies are often encountered by oral and maxillofacial surgeons and may present a diagnostic challenge, due to many factors such as nature of foreign body material, the size of the object, difficult access and a close anatomical relationship of the foreign body to vital structures. There are foreign bodies like glass pieces, plastic materials, wooden pieces are not seen in routine radiographs and often misdiagnosed. To reduce the chances of complications presence of foreign body in the patients head and neck region must be thoroughly investigated by the surgeon. Penetrating injuries by blunt object is rare finding in maxillofacial region. Here we present an unusual case of penetrating injury by a large machine bolt (15.0 cm) in a 7 year old child, embedded on left side of face. PMID- 25838681 TI - Chordoma arising from cranial base extending to oropharynx: an unusual presentation. AB - Chordoma is a relatively rare tumor of the skull base thought to originate from embryonic remnants of the notochord. Chordomas arising from the skull base/clivus are typically locally aggressive with lytic bone destruction. When chordomas occur in an extraosseous location, they may mimic other lesions of the nasopharynx and oropharynx. We present a case of primarily extraosseous chordoma involving the oropharynx in an effort to improve the preoperative diagnosis of this rare tumor among the dental fraternity. In addition, we review regional notochordal embryology to explain this variant tumor location. PMID- 25838682 TI - Bilateral Tessier's 7 Cleft with Maxillary Duplication. AB - Tessier's 7 cleft or lateral facial cleft are unusual lesions that result from failure of the embryonic mandibular and maxillary process of the first branchial arch to fuse properly and form the corners of the mouth. It may be seen alone or in combination with other anomalies, accompanied by varying degrees of severity. We report an extremely rare case of bilateral Tessier's 7 cleft along with maxillary duplication, macrostomia, bilateral posterior maxillary cleft, and mandibular retrusion in an 18-year-old male patient. PMID- 25838683 TI - Benign paroxysmal positional vertigo after nonotologic surgery: case series. AB - Benign paroxysmal positional vertigo is one of the most common types of vertigo caused by peripheral vestibular dysfunction. Although head trauma, migraine, long term bed rest, Meniere disease, viral labyrinthitis, and upper respiratory tract infections are believed to be predisposing factors, most cases of benign paroxysmal positional vertigo are idiopathic. Ear surgery is another cause, but after non-otologic surgery, attacks of benign paroxysmal positional vertigo are rare. We describe three cases of benign paroxysmal positional vertigo attacks after non-otologic surgery (one patient after a nasal septoplasty and two patients after dental endodontic treatment) and discuss the pathophysiological mechanism of benign paroxysmal positional vertigo seen after non-otologic surgery, its diagnosis and treatment. PMID- 25838684 TI - Oversized submandibular gland sialolith: a report of two cases. AB - Sialolithiasis is a very common reason in causing obstructive salivary gland disease. Its incidence in males is more than females and children. They usually occur in submandibular ducts or gland and are 1 mm to less than 1 cm and rarely more than 1 cm. If they are more than 15 mm then, are termed as sialoliths of unusual size or giant sialoliths. The literatures have reports of up to 3.5 to 7 cm stones and are rare. The management includes removal of stone and re channelizing the secretions in a functional gland or excision of gland in atrophied glands along with stone. PMID- 25838685 TI - Ipsilateral maxillo-mandibular ossifying fibroma. AB - Ossifying fibroma is a benign fibro-osseous lesion which occurs at various locations in maxillofacial region. A synchronous presentation of this lesion in both, the maxilla and the mandible is a rare occurrence. The present article reports a case of ossifying fibroma in a 45-year-old woman who manifested lesions in the right maxilla and mandible. The clinico-radiologic and histopathologic modalities of diagnosing this entity are evaluated and discussed. PMID- 25838686 TI - Chondrosarcoma of the maxilla extending to the pterygomandibular space: a case report and review of the literature. AB - Chondrosarcomas are rare tumors of which approximately 10 % are found in the maxillofacial region. They range from a well-differentiated growth resembling a benign cartilage tumor to a high-grade malignancy with aggressive local behaviour and the potential to metastasize. We report a case of high-grade chondrosarcoma of the maxilla extending to the pterygomandibular space which was treated with radical surgical excision without neck dissection and postoperative radiotherapy. The diagnosis was a conventional type of chondrosarcoma, Grade III. The postoperative course was uneventful, and the patient has had no recurrence in the 15-year follow-up period. PMID- 25838687 TI - Mantle cell lymphoma of the oral cavity with multiple foci: a case report and review of the literature. AB - Non-Hodgkin lymphomas (NHLs) are often present outside the lymph nodes. Although primary extranodal NHLs form a substantial part of all NHLs, reports on oral primary extra nodal NHLs are rare. Mantle cell lymphoma (MCL) is a rare B-cell neoplasm that has only recently been defined as a distinct entity. MCL of the oral cavity is an uncommon diagnosis. Most oral MCLs occur in an elderly male population and have a possible predilection for the palate. The microscopic diagnosis can be challenging, given its similar appearance to other small cell lymphomas, requiring a comprehensive immunohistochemical panel for the accurate diagnosis. Like MCL occurring in other sites in the body, the prognosis and outcome of oral MCL appears to be poor. PMID- 25838688 TI - Schwannoma in infratemporal fossa in a young patient: a case report. PMID- 25838689 TI - Gnathic desmoplastic fibroma mimicking a dentigerous cyst: a case report. AB - Desmoplastic fibroma (DF) is a rare, well-differentiated fibrous tumor, which is slow in growth but has an aggressive potential. In its clinical and radiographic presentation it mimics many unusual pathologies of the jaws. This case report presents a DF in the mandible, which in its clinical presentation and radiographic appearance mimicked a dentigerous cyst highlighting the importance of detailed histopathological examination in the diagnosis of jaw pathologies. PMID- 25838690 TI - Dentigerous cyst associated with mandibular 2nd molar: an unusual entity. AB - Dentigerous cysts are generally associated with the crowns of impacted or unerupted permanent teeth and are more common in males, in the second and third decades of life. Most dentigerous cysts are mainly developmental in origin but may not be similar for all cases. The purpose of this paper is to present a case of dentigerous cyst with unusual presentation in a 7 year old girl and discuss the variation in etiology, presentation of such a cyst and in its management. PMID- 25838691 TI - Dental Procedures: Is it a Risk Factor for Injectable Dermal Fillers? AB - Dental procedures done in the vicinity of dermal fillers may result in complications of the dermal fillers such as infections which may mimic a dental infection. These infections of dermal fillers must be differentiated from facial cellulitis or from dental infection as treatment for infection from dermal fillers may be prolonged with repeated use of antibiotics, incision and drainage or removal of the filler material itself. Dental surgeons need to be aware of this potential risk in order to recognize and manage it appropriately. PMID- 25838692 TI - Von recklinghausens disease: a series of four cases with variable expression. AB - Though neurofibromatosis type I (NFI) is a fairly common condition, it has a variable expressivity and penetrance. Here we present a series of cases with striking differences in the presentation especially in the oral cavity. NFI, also known as von Recklinghausen's neurofibromatosis, is an autosomal dominantly inherited neurogenetic disorder affecting 1:3000 newborn (Bongiorno et al., Oral Dis 12:125-129, 2006). About 50 % of NFI patients have no family history of the disease. There is no prevalence for gender or race in NFI. Expressivity in NFI is tremendously variable, but subtle phenotypic patterns may exist within subgroups of affected patients. Furthermore, 50 % of cases are sporadic and arise from germ cell mutation (Bongiorno et al., Oral Dis 12:125-129, 2006). The precise constellation of findings in any one individual is extremely variable, both within a family and between different families (Batsakis, Tumors of the head and neck: clinical and pathological considerations, 2nd edn. Williams and Wilkins, Baltimore, pp 313-333, 1979). Only 4-7 % of patients affected by neurofibromatosis exhibit oral manifestations (Guneri et al., Turk J Pediatr 48(2):155-158, 2006). PMID- 25838693 TI - Cavernous sinus thrombophlebitis (sans thrombosis) secondary to odontogenic fascial space infection: an uncommon complication with unusual presentation. AB - We discuss an unusual presentation of non-thrombotic cavernous sinus involvement in a patient who was treated for odontogenic fascial space infection arising from a maxillary molar. The highlights were ipsilateral abducens sparing, contralateral abducens involvement and lack of significant orbital congestion. The patient recovered with conservative treatment. PMID- 25838694 TI - Acute Haemorrhagic Oedema of Infancy (AHOI): A Case Report. AB - Acute haemorrhagic oedema of infancy (AHOI) is a benign variant of leukocytoclastic vasculitis which occurs in children up to 2 years of age. It is considered by some to be a variant of Henoch-Schonlein purpura with its hallmark of prominent facial swelling, purpuric rash without visceral involvement, in an otherwise well child. This condition is well recognised in the paediatric and dermatology literature but despite its impressive facial features, often mimicking more serious pathology like orbital cellulitis, to our knowledge AHOI has not been published in the Oral & Maxillofacial Surgery literature. We present a case of AHOI to raise awareness of this condition in maxillofacial surgery to avoid it being mis- or over-diagnosed. PMID- 25838695 TI - An unusual case of a recurrent seborrheic/epidermal inclusion cyst of the maxillofacial region. AB - A Seborrheic or epidermal inclusion cyst is basically an epidermoid cyst resulting from the traumatic implantation of epidermal elements into the dermis with their subsequent cystic transformation. A case of an epidermal inclusion cyst of the chin region is described in a 72 year old male, whose features were rather unusual, in that it presented as a fixed, indurated, inflamed, and extremely painful swelling associated with two draining extraoral sinuses, mimicking a submental space infection. The cyst was particularly persistent and recurred within a month of its excision and had to be re-excised along with the overlying epithelium. PMID- 25838696 TI - Ludwig's Angina in Pregnancy Necessitating Pre Mature Delivery. AB - Ludwig's angina is a potentially life threatening disease that can arise from odontogenic infections if they are not attended well in advance. Its incidence in pregnancy is rare, but has been reported. Pregnancy is associated with complex physiological changes in the body which can make small dental infections assume grave proportions if not treated appropriately. This article presents a case of a 24 year old, 32 week pregnant lady who reported with swelling around the jaws and neck, difficulty in breathing and swallowing since 2 days. She had to be taken up for pre-term delivery to avoid damage to foetus. Subsequently she underwent multiple debridement of the cellulitis affecting the deep neck spaces and superior mediastinum. Surgical debridement and intravenous antibiotics along with adequate hydration improved the health of the patient before she was discharged. PMID- 25838697 TI - Tuberculous osteomyelitis of the mandible. AB - Although tuberculosis can affect any part of the body involving both soft and hard structures with variable measures; such an occurrence in the cranio-facial bones is relatively rare. Once affecting a bone it is rare for a mycobacterial infection to get directed towards the skin and present as multiple draining sinuses. We report a case of tubercular osteomyelitis of the left body of the mandible in a 19 year old male patient who came to us with complains of persisting pus discharge from multiple sinuses on his face (lateral border of mandible and submandibular region) because of its rarity and clinical interest. One should always have a suspicion of mycobacterial infection in the back of mind when dealing with chronic maxillofacial infections not responding to the usual antibiotic course and local debridement. PMID- 25838698 TI - Management of pseudoaneurysm of internal maxillary artery resulting from trauma. AB - Pseudoaneurysm of internal maxillary artery following trauma is a rare clinical entity. A rapidly growing swelling in the facial region following fracture of the mandibular subcondylar region is an indication of a developing aneurysm. A case of pseudoaneurysm of the internal maxillary artery following condylar fracture of mandible is reported. The case was treated successfully by surgery. PMID- 25838699 TI - Multiple Pathology in a Single Lesion: AOT Associated with Dentigerous Cyst. AB - Odontogenic cysts and tumors are quite common occurrences in jaw bones, although both of them occurring together are rare. The epithelial lining of odontogenic cyst has a potential to transform into neoplastic conditions like squamous cell carcinoma and mucoepidermoid carcinoma, and odontogenic tumors like ameloblastoma and adenomatoid odontogenic tumor. However, the frequency of such cases being encountered is very less. Here, we report a case of adenomatoid odontogenic tumor (AOT) associated with a dentigerous cyst around the crown of an unerupted lateral incisor (follicular variant), in a 14-year-old boy. We also attempt to unravel its mechanism of cytodifferentiation and tumor progression. The origin and nature of such kind of lesions (i.e., independent development of multiple pathologies as a single lesion in a single location, single pathology giving rise to another pathology or a distinct entity/new variant) cannot be explained with certainty at this point of time. The molecular mechanism of tumor development needs to be further elucidated in order to conclude that a different entity called 'hybrid' AOT exists. PMID- 25838700 TI - Schwannoma located in the upper gingival mucosa: case report and literature review. AB - The Schwannoma is a benign tumor that originates from Schwann cells of peripheral motor and sensory nerves. It presents as a solitary, slow growing, smooth surfaced and asymptomatic firm mass. The pre-operative diagnosis is often difficult, and in majority of cases it can only be made during the surgery and the definitive diagnosis obtained by histological study when cells test positive for S-100 protein. In this report, a case of a 20-year-old female patient with a Schwannoma located in the upper gingival mucosa is discussed. The patient was referred to the department of oral and maxillofacial surgery with chief complaint of enlargement of the upper gingival mucosa at the level of upper right premolar. Clinical findings showed characteristics of connective tissue tumor including epulis; however, histologic and immunohistochemical studies revealed it to be a Schwannoma. There has been no sign of recurrence 1 year and 8 months after surgery. PMID- 25838701 TI - Treatment of atrophic mandibular fractures with the pencilboneplate: report of 2 cases. AB - The incidence of fractures of the atrophic edentulous mandible is still low, even with the increasing life expectancy. The reduced blood supply of the sclerotic bone, the diminished contact area between bone fragments and the patient's systemic condition makes the treatment of those fractures a challenge for any professional. Treatment of atrophic mandibular fractures by means of miniplate osteosynthesis has not been the preferred method of fixation by many authors. Yet, many surgeons have applied this type of fixation for the atrophied jaw sections. This paper reports 2 cases of fractured atrophic mandibles treated with the pencilboneplate, a monocortical 2.0 mm titanium, 8 or 10-hole hardware with reinforcement on its middle portion, highlighting important considerations of its use. The pencilboneplate appears to be a valuable option for the treatment of atrophic mandibular fractures, especially by an intra-oral approach, and warrants further biomechanical and clinical studies. PMID- 25838702 TI - Recurrent Mandibular Dislocation in Geriatric Patients: Treatment and Prevention by a Simple and Non-invasive Technique. AB - Dislocation is defined as the complete loss of articular relationship between the articular fossa of the temporal bone and the condyle-disk complex. Most common aetiology of dislocation is wide mouth opening, trauma and use of certain drugs. It is classified as acute, chronic and recurrent. Chronic recurrent dislocation of mandible is a distressing condition especially for geriatric patients. Various non-surgical methods of reduction include Hippocratic method, Awang's gag reflex method, wrist-pivot technique, combined ipsilateral staggering technique, recumbent approach, intermaxillary fixation, injection of a sclerosing solution, autologus blood transfusion and botulinum toxin. In geriatric population, the ridges become atrophic with time and use of any method of reduction which exerts force on mandible increases chances of fracture of mandible. Awang's gag reflex method is a non invasive technique which helps in treatment of chronic recurrent dislocation in geriatric patients. Along with this technique the use of a cervical collar has been reported in this article, which not only acts as a restrainer but also is helpful for cervical spondylosis, a common condition encountered in geriatric population. PMID- 25838703 TI - CT Scan as an Essential Tool in Diagnosis of Non-radiopaque Sialoliths. AB - Sialolithiasis is the second most common disease of the salivary glands and the main cause of salivary gland obstruction. Diagnosis of calculi/sialoliths can be made by means of an elaborate history, precise clinical examination and radiographic support. But all sialoliths do not present with predictable signs and symptoms and radiographic appearance. Sialoliths have a variety of manifestations and they may or may not be radiopaque. Non-radiopaque sialoliths are difficult to diagnose radiographically. Although newer techniques like CBCT, CT virtual sialandoscopy and established techniques like sialography, xeroradiography can be useful in selected cases. A regular CT scan is an excellent tool in the diagnosis of a non-radiopaque sialolith and associated salivary gland changes. CT scan should be considered as an important tool of imaging for diagnosis, treatment planning and follow-up of all cases of sialoliths and associated pathologies of the salivary gland. PMID- 25838704 TI - Salvage of venous congestion using medicinal leeches for traumatic nasal flap. AB - Medicinal leeches are extremely useful and safe in the salvage of venous outflow compromised tissue, particularly in digit replants and various forms of flaps. Although it is unusual for a partial soft tissue avulsion of the face to require medicinal leech therapy, situations may occur in which there is adequate arterial inflow but inadequate venous outflow. In such cases, medicinal leeches may play a very important role in salvaging the soft tissue segment. We report a case of a 34-year-old gentleman who showed signs of venous congestion following primary management for a traumatic nasal flap. Successful salvage of venous congestion was done using medicinal leech therapy, once daily, for 5 days. His recovery deemed satisfactory and uncomplicated. Medicinal leeches are well-known in the treatment of venous congestion or complete venous outflow obstruction in larger pedicled flaps and microvascular transfers. In trauma, it is well established that medicinal leeches are invaluable in treating venous congestion in digit replants and replantation of totally avulsed external ear segments. A limited number of other reports have demonstrated the use of medicinal leeches for salvage of other partially avulsed facial structures. Medicinal leeches have a significant role in the management of traumatic and microvascular flaps, the oral and maxillofacial surgeon should weigh the benefits of such treatment before instituting other expensive or complex treatment modalities. PMID- 25838705 TI - Transoral removal of peripheral osteoma at sigmoid notch of the mandible. AB - Osteoma is a benign osteogenic slow-growing tumor. Though mandible is involved more often than the maxilla only one other case of osteoma sigmoid notch has been mentioned in the English literature till date. Cosmesis and function are the main reasons that dictate the removal of the osteomas, so we preferred to use an intra oral approach to better prevent the scar and achieve good patient acceptance. PMID- 25838706 TI - Sagittal osteotomy for the removal of deeply impacted mandibular molars: a presentation of series of cases. AB - Sagittal osteotomy was primarily described as a treatment for prognathism and retrognathia. It has been rarely reported as an option for the removal of deeply impacted tooth. The principal indication of this approach is when the tooth is deeply impacted on the mandibular ramus or body and it presents intimate relationship between its root and inferior alveolar neurovascular bundles. In this article the author related three rare cases of lower third molar included. Because of the unusual deeply position of these, the SRRO surgery technique was realized to remove them. Sagittal split ramus osteotomy (SSRO) is technically safe and allows the removal of teeth in situations of deeply impacted mandibular ramus, angle or body with minimal trauma in a short time. PMID- 25838707 TI - Conservative Management of Chronic TMJ Dislocation: An Old Technique Revived. AB - A temporomadibular joint (TMJ) dislocation is a condition in which the mandibular condyle is displaced from its articulations and requires manipulation by another individual to return to its normal position. TMJ dislocation is subdivided into acute, chronic recurrent or chronic persistent dislocations. Conservative (closed) or surgical (open) manipulation may be required to reduce the dislocated condyle. We present two cases of bilateral chronic protracted TMJ dislocation since 2 months. Following several unsuccessful attempts of manual reduction the patients were managed conservatively by placing posterior acrylic bite blocks and application of elastic traction which reduced the dislocated condyles satisfactorily in 2-3 weeks time. Every case of prolonged dislocation has its own unique features. Conservative approaches should be attempted initially, more radical treatment being used after these have failed. PMID- 25838708 TI - Reconstructive dilemma after blindness. AB - Blindness associated with mid-facial fractures is rare. Here we present a case of panfacial fracture associated with loss of vision of right eye. The reconstruction of left orbital region posed a challenge, as post surgical vision loss can be a remote complication. Through this case report we highlight our dilemma and describe the different philosophies adopted by other specialties in management. PMID- 25838709 TI - Aggressive nodular fascitis of the mandible in a child: a rare case report. AB - Nodular fascitis is a benign, reactive, fiboproliferative lesion that is thought to represent an over exuberant reaction to injury or inflammation. Its histological picture is very similar to fibro sarcoma. An accurate diagnosis is imperative to avoid unnecessary aggressive treatment. It occurs most commonly in upper extremities, and rarely in the maxillofacial region. We present a case of aggressive intraosseous nodular fascitis of the mandible involving the vital structures in the neck in a 10 year old boy. PMID- 25838710 TI - Metastasis in the gingiva from colon adenocarcinoma. AB - A case of gingival metastatic tumor from a colon adenocarcinoma is reported. The patient had been diagnosed with colon carcinoma and underwent a colectomy with D2 dissection, followed by chemotherapy. Nine months after the initial treatment, she noticed a periodontal gingival swelling at the site of her right lower second premolar and was referred to our clinic. The clinical diagnosis was an epulis granulomatosa or pyogenic granuloma. A metastatic adenocarcinoma in the gingiva from colon carcinoma was identified after the histopathological examination. Although rare, oral metastatic tumors should be included in the differential diagnosis, particularly if the patient has a prior history of malignancies. PMID- 25838711 TI - Malignant fibrous histiocytoma: an uncommon sarcoma with pathological fracture of mandible. AB - BACKGROUND: Tumors composed of cells differentiating as both fibroblasts and histiocytes have been designated fibrous histiocytomas. Only a small percentage of these lesions behave in a malignant fashion, they are called malignant fibrous histiocytoma (MFH).The occurrence of MFH in membranous bones including the mandible is quite unusual. Involvement of the mandible accounts for only 3 % of all MFH bone lesions. Recent literature revealed only a few (30) cases of MFH involving the mandible but not a single case of MFH associated with pathological fracture of the mandible, probably the first such kind of case to support antecedent trauma as an initial proliferative response for its occurence. CASE REPORT: A rare case of MFH involving the mandible and submandibular glands with pathological fracture in a 14-year-old boy is presented with special emphasis on the poor prognosis even after prompt therapy, its controversial histogenesis, high malignant potential, high recurrence rate and tendency to metastasise. The patient was regularly followed up for 11 months post-operatively, during which patient complained of pain in the operated region after 8 to 9 months. Though there was no clinically obvious abnormality seen, the young boy died after 11 months. The clinical, surgical, radiographic and pathological features of this lesion are discussed. DISCUSSION: Malignant fibrous histiocytoma, the most frequent soft tissue sarcoma of adulthood, was first described as a new malignant tumour by O'Brian and Stout in the 1960s and the details of the histopathological features of MFH were first described by Kempson and Kyriakos. Despite the frequency of diagnosis, MFH has remained an enigma as no true cell of origin has ever been identified. Treatment consists of surgical excision and in some cases chemotherapy and radiation. Early and complete surgical removal using wide or radical resection is indicated because of the aggressive nature of the tumor. The combination of infrequent occurrence, varied pathologic features, uncertain histogenesis, numerous subtypes and the many potential sites of presentation makes these tumors a challenge for the diagnostician, surgeon and oncologist. Close follow-up after treatment is important, as local recurrence is common and early metastasis to the lungs is also frequent, which are the reasons for high mortality rate in MFH. PMID- 25838712 TI - Partial avulsion of the right ear treated with a pocket technique: a case report and review of the literature. AB - Avulsive injuries to the ear are not common and are variable in presentation. This article describes a case of subtotal auricular avulsion treated utilizing a pocket. Other techniques used for these types of injuries are reviewed. PMID- 25838713 TI - A rare case of extraskeletal mesenchymal chondrosarcoma with dedifferentiation arising from the buccal space in a young male. AB - Extraskeletal mesenchymal chondrosarcoma (EMCS) is a rare and aggressive pathological variant of chondrosarcoma arising from soft tissues of mainly the extremities, meninges/dura, trunk, and orbits. EMCS comprises only 2 % of all soft tissue sarcomas and only 6 % of them arise from soft tissue in the head and neck region. It usually affects in the second and third decade of life and is common in women. It runs a very rapid clinical course with distant metastases and has poor prognosis and survival rates. Histologically it has a dimorphic presentation of small round mesenchymal cells interspersed with foci of cartilaginous differentiation. Radiographically it appears as a soft tissue lobulated mass with various patterns of calcification. This is the first case of primary and recurrent EMCS originating in the buccal space with unusual features of dedifferentiation. The diagnostic challenges in this case were the inconclusive FNAC results, lack of radiographic evidence of characteristic calcifications and presence of areas of myxoid material and dedifferentiation on histopathology. The clinical, cytological, histological, immunohistochemical, radiographic, PET-CT findings and management with review of literature is presented. The diagnostic and management pitfalls of this extremely rare tumor are also discussed. PMID- 25838714 TI - Maxillo-Mandibular Cemento-ossifying Fibroma: A Rare Case Report. AB - Cemento-ossifying fibroma (COF) is a benign fibro osseous lesion of the jaws which has been described as a demarcated or rarely encapsulated neoplasm consisting of fibrous tissue and varying amounts of mineralized material resembling bone and/or cementum (Dinkar et al. in IJDA 2(4):45-47, 2010). Majority of lesions occur in the mandible and only few cases of COFs of the maxillary sinus and bilateral COFs of the mandible have been reported in literature (Dinkar et al. in IJDA 2(4):45-47, 2010; Tamiolakis et al. in Acta Stomatol Croat 39(3):319-321, 2005; Hamner et al. in Oral Surg Oral Med Oral Pathol 26(4):579-587, 1968; Gunaseelan et al. in Oral Med Oral Pathol Oral Radiol Endod 104:e21-e25, 2007). These lesions have a very low recurrence rate (Ertug et al. in Quintessence Int 35(10):808-810, 2004) and are generally treated by enucleation. In this paper we present a rare case of COF occurring in both the maxilla and mandible of the same patient. Only one such case (Takeda and Fujioka in Int J Oral Maxillofac Surg 16(3):368-371, 1987) has been reported in literature so far. PMID- 25838715 TI - The recycling of autoclaved autografts in mandibular reconstruction: case report and review of literature. AB - Removal of pathological lesions from the mandible can leave a disfiguring appearance in addition to compromising the function of speech and mastication. It therefore becomes imperative to replace the lost part with bone grafts. Autogenous bone grafts-vascularised and non-vascularised, have been in vogue for the same. The probability of using the same resected bone after removal of all pathology has been done for a long time with mixed results in terms of uptake and viability. This paper presents a case of the use of autoclaved resected bone being used for reconstructing the mandible. PMID- 25838716 TI - Non-traumatic Occulomotor Nerve Palsy: A Rare Case Report and Discussion on Etiopathogenesis. AB - The ghost of the past has emerged as the horror of today. The fear of weakness/loss of eyesight following extraction is a common thinking amongst the orthodox people of Indian subcontinent. Occulomotor nerve paralysis following dental extraction is a rare complication. Although these ophthalmic complications in routine practice are rare, some time they do occur and pose difficulty to explain. Occulomotor nerve palsy is amongst the rare reported cases of ocular complication. Here we report a case of spontaneous recovery of occulomotor nerve palsy in an elderly diabetic patient and brief discussion on its etiopathogenesis. PMID- 25838717 TI - Preface BPS Presidential Addresses. PMID- 25838718 TI - Setting up private practice in psychiatry. AB - Setting up a private practice in Mumbai is an onerous task. The present paper looks at the difficulties face by young psychiatrists when starting a private practice in psychiatry. It suggests certain guidelines to be followed to ensure the development of a successful practice. It also suggests methods to gain popularity among patients and society along with the ethics to be followed, knowledge base to be garnered, and the role of using multiple therapies and versatility in private practice. PMID- 25838719 TI - Indian womanhood: some psychological concepts. AB - Indian womanhood today is at crossroads. The present paper discusses the status of Indian womanhood and its psychological underpinnings. It discusses how Indian women have suffered at the hands of their families and society leaving no path but to succumb to psychiatric illness. The role of mental health professionals and family members in supporting and promoting growth and development of the Indian woman is outlined. PMID- 25838720 TI - Looking back at the years 1970-1984: a personal view. AB - This is a psychiatrist's journey through teaching, research and making friends of professional colleagues. It also chronicles the research done in the Department of Psychiatry at KEM Hospital, Mumbai, India and the important influences over the author's life. PMID- 25838721 TI - Child: A Learning Model and a Bi-directional Phenomenon. AB - Forty-five years of work with children has enriched my knowledge. Child development and psychology has made basic concepts of general psychology and abnormal psychology clearer. 'Meanings' have become more meaningful. It has made me a better professional; large number of communication and teaching skill has been the end result of such a long association with diverse groups of children who needed special care. Apart from professional skills as a clinician and as a teacher, it has made me a better person and a better parent. I have been fortunate to work with a large number and different groups of children who were in some way very special. Some were classified under various disabilities or diagnosed under different categories. I also had the privilege of working with different institutions, e.g., child guidance clinics run by a paediatrics department and a psychiatry department of a general hospital and a teaching hospital. Years of association with College of Special Work and Institute of Social Science have made me understand the very important facet of sociocultural influence on the development of human behaviour. I was further fortunate to work with children in closed and open institutions, residential care units and day care units, institutions where court committed children were observed, treated, trained and cared for, destitute children and delinquent children in remand homes, rescue homes and custodial care homes. I was fortunate to be part of the group which dealt with children who were in conflict with the law, belonging to diverse categories like street children, working children, child sex workers and sexually abused children. This paper is a reflection on experience gained over the decades. PMID- 25838722 TI - Psychiatry in Mumbai: What can be done to Expand Services? AB - Mumbai and its suburbs constitute a huge population. There are limited services here in the field of psychiatry, mainly located in major hospitals and teaching centres. There is a need to decentralize services. Psychiatrists themselves have limited resources to plan out community-based services, or set up centres, which would cater to all the requirements of the local population. Hence, it is necessary that a group like the Bombay Psychiatric Society make collective efforts to urge government and municipal authorities to create such facilities at different centres in the city and suburbs. PMID- 25838723 TI - Postgraduate training in psychiatry in India with focus on mumbai. AB - The present article traces the formation of the Indian Psychiatric Society and the progress of post-graduate training in psychiatry in India in general and Mumbai in particular. It covers the standard of psychiatric education, the goals and recommendations for improvisation of residency programmes, and the future of post-graduate psychiatric training. PMID- 25838724 TI - Psychiatric thoughts in ancient India. AB - A review of the literature regarding psychiatric thoughts in ancient India is attempted. Besides interesting reading, many of the concepts are still relevant and can be used in day-to-day practice especially towards healthy and happy living. Certain concepts are surprisingly contemporary and valid today. They can be used in psychotherapy and counselling and for promoting mental health. However, the description and classification of mental illness is not in tune with modern psychiatry. PMID- 25838725 TI - Jaina religion and psychiatry. AB - Jaina religion has existed for thousands of years. Lord Mahavir was the last of the 24 Tirthankaras, 23 having preceded him. The principals of Jaina religion teach us: (1) Self-control, which includes: (a) Control over physiological instinct of hunger and sex; (b) control over desires; (c) control over emotions; (2) meditation; (3) introspection; (4) concentration; and (5) healthy interpersonal relationship. The principles of Jaina Religion can contribute to Positive Mental Health. PMID- 25838726 TI - Doctor-patient relationship in psychiatry. AB - The paper discusses the issue of doctor-patient relationship in view of a changing world with special emphasis on mental health professionals. It takes into account transference and counter-transference issues in doctor-patient relationships. It deals with issues pertaining to consent and liabilities, confidentiality and patient protection. Role of a psychiatrist as a leader in the art of communication is touched upon. In the end issues about professional fees and ethics too is dealt with. PMID- 25838727 TI - Elderly mental health: needs. AB - This paper highlights the mental health needs of the elderly. It tackles the issues of their institutionalisation and community care. Rapid urbanisation in Indian society throws up special problems in elderly care. There is great evidence of a raise in morbidity, mortality, hospitalisation and loss of functional status related to common mental disorders in the elderly patients. Overlap of depression and anxiety is very common with up to almost half of the elderly patients reporting significant depressive and anxiety symptoms. Also, depression is the most common psychiatric disorder in late life. Growth in the elderly population means a direct increase in age related diseases such as dementia and poor mental health outcomes such as depression, anxiety, suicide and serious constraints on the quality of life among elderly individuals. The need to identify new and unmet problem areas and develop efficient therapeutic outcomes for this special population is stressed. PMID- 25838728 TI - In India, psychiatry has come a long way. AB - This Presidential Address of the Bombay Psychiatry Society covers the state of psychiatry in India in 1997. It posits that with the advent of newer brain imaging technologies in India such as computerised tomography, magnetic resonance imaging, single photon emission computerised tomography and brain electrical activity mapping, an era of evidence-based psychiatry in India has arrived. The Address cautions against the dehumanising potential of excessive reliance on technology. The need for a greater emphasis on psychiatry during undergraduate medical education is discussed along with the need to destigmatise psychiatric disorders. Finally, the need to encourage quality research in psychiatric disorders is stressed. PMID- 25838729 TI - Psychiatry and law: past, present and future. AB - It is important that every citizen knows the law of the state. Psychiatry and law both deal with human behaviour. This paper attempts to highlight the interplay between these two by discussing about various legislations like The Family Courts Act 1984, Narcotic Drugs and Psychotropic Substances Act 1985, Juvenile Justice Act 1986, Consumer Protection Act 1986, Persons with Disability Act 1995, The Maintenance and Welfare of Senior Citizens Act 2007. PMID- 25838730 TI - Support system for mental health professionals. AB - This paper talks of support systems for mental health professionals wherein the Bombay Psychiatric Society (BPS) should devote some meetings exclusively to problems pertaining to the profession, e.g., long and odd working hours leading to potentially hazardous practice schedules, unhealthy competitive attitudes and culture. A crash course in self-defence against potentially psychotic patients and drug addicts is advocated as also awareness of the potential hazards in dealing with the litigious paranoid patients, erotomaniacs and some of the difficult hysterical patients. Potential medicolegal problems arise in treating an uncooperative patient without his knowledge and consent on an outpatient department basis, admitting such an uncooperative patient to a nursing home or a hospital, administering electroconvulsive therapies, maintaining detailed clinical records of patients, and legal issues involving smaller psychiatric private nursing homes. This paper stresses on the use of Yoga as a recognised psycho-physiological therapy. Furthermore, it suggests on the need for BPS, as a professional body, to have a cell to guide and help aspiring young professionals in setting up private practice. It points out the need to evolve some concrete programmes that in the long run should help alleviate stresses and strains and promote positive comprehensive health amongst mental health professionals. PMID- 25838731 TI - Modern Parenthood through the Eyes of a Psychiatrist. AB - Child Psychiatry has always described disorders of childhood. Parents form an important dimension of Child Psychiatry since they present the child's behaviour before the therapist. Modern life is full of increasing competition among children, thereby increasing stress among children as well as parents. Modern parents are overly aware, concerned and anxious about their children's future. As a result children get under the pressure of comparison, competition, ambition and goal-setting. All this typically results in the vicious cycle of parental pressures, miscommunication, generation gap etc. No textbook gives clear-cut guidelines about practical aspects of parenting, which is more an art than a science. Dealing with parents in therapy has to take into consideration their psychological make-up and the way it relates with the child. For professionals it is important to empathise with the parents in therapy and at times to share their own experiences of parenting. PMID- 25838732 TI - Invest in family. AB - The family is an integral part of one's life. It is very essential that every individual employed or unemployed invests time therein. The family is a source of support and growth for an individual, and the lack of family support or loneliness may be a causative factor in the genesis of psychiatric disorders, especially depression. In India, family plays a paramount role when it comes to mental health of the individual. Tips on how one should invest time in one's family along with the role of a family in one's personal and social structure are discussed. PMID- 25838733 TI - Crime and psychiatry. AB - Psychiatry and crime are linked in certain ways. On one hand, we have criminal offenders with serious psychopathology; and on the other hand, we have psychiatric patients who may commit criminal offences during the influence of a psychiatric disorder. The psychiatrist in practice has to come in contact with the criminal justice system at some point of time in his career. Forensic psychiatry under whose realm these issues reside is a branch yet underdeveloped in India. The present paper reviews the inter-relationship between crime and psychiatry and the factors involved therein. PMID- 25838734 TI - Mind: explore the space inside. AB - When caught in the dilemma of career choice, a critical conversation helped the writer crystallize the decision to plunge into the field of mental health. The decision just not only kindled interest in psychiatry but passion to study the science of the mind despite the fact that in earlier times psychiatry mainly catered to patients with chronic schizophrenia and uncontrolled bipolar disorder. Weathering the curious glances of colleagues the writer pursued to explore the field of the science of the mind. Not restricting himself to classical trends in private practice, he explored every opportunity to reach out to the common man through writing articles in popular newspapers and also ran a TV Show to respond to people's queries on mental health. He further ventured into training and development of young MBA aspirants and trained himself into an international coach and facilitator. The science of Behavioural Economics beckons him now. PMID- 25838735 TI - The role of a Psychiatric Society: Aligning our aims to needs of the community. AB - Psychiatric Societies and Associations have variegated roles and functions. They provide their members an academic resource and a place for social networking. They also have responsibilities to the profession and to the community they serve. The nature of work they conduct should be aligned to the needs of all stakeholders. Only when there is such harmonious working will the community respect the fraternity and the Association. We, therefore, need to respond to the need of the hour, which in the current time is prevention of suicide in children and adolescents and facilitation of continuing professional development for our members. PMID- 25838736 TI - Role of sports in the development of an individual and role of psychology in sports. AB - Sports helps an individual much more than in the physical aspects alone. It builds character, teaches and develops strategic thinking, analytical thinking, leadership skills, goal setting and risk taking, just to name a few. PMID- 25838737 TI - Mumbai psychiatry: current obstacles. AB - Mumbai, like any other Metro city, has its own share of contentious issues influencing psychiatric management. These could be old ongoing issues like myths about medications, electroconvulsive therapy and counselling, or newer ones like our stand on homosexuality and crime related to psychosocial factors. A range of these issues is considered in this paper along with some possible solutions. Getting due credit and status for psychiatry as a medical branch is also a challenge we need to address. PMID- 25838738 TI - Changing Medical Students' Attitudes to Psychiatry through Newer Teaching Techniques. AB - The significance of mental health in the entire health scenario has increased. However, the representation of psychiatry in the current MBBS curriculum for undergraduate students in India still remains much less than desirable. Further, stigmatising attitudes lessen these future doctors' ability to detect and manage patients with psychological problems despite adequate knowledge about psychiatry. Students believe that psychiatrically ill patients are unpredictable and can be dangerous to others. Some feel that psychiatry is unscientific, imprecise and treatment is not effective. Traditional teaching methods are directed more towards imparting knowledge than changing the attitudes of students. Newer teaching and assessment techniques should be used to bring about attitudinal changes and develop interest among medical students. Case based and problem based learning, small group teaching, simulated patients, using movies, multidisciplinary seminars, integrated teaching, attitude questionnaires, objective structured clinical examinations etc., could be introduced in the curriculum to achieve this objective. PMID- 25838739 TI - Blueprint for an Indian nobel laureate in psychiatry. AB - There are a number of spoofs and light-hearted writings in blogs, journalistic pieces and book form (even from former Nobel Laureates), which attempt at 'understanding' the secret of getting a Nobel. This is not one of them. It is more pedantic without necessarily being dry. It first analyses the meaning of the concept, 'the greatest benefit of mankind', which is the crux of the Nobel Will and the overarching requirement for a Nobel in Medicine. Further discussion in the paper is divided into 5 parts: (1)General qualities for a Nobel: The need to be really bright is a given; what is necessary is to be sufficiently crazy about a research topic to make it an obsession; be ready to forgo many creature comforts for long stretches of time; and after all this, be ready to accept that the Nobel may never happen, yet continue to do a type of research solely because it is intrinsically worth doing.(2)Nobel in Physiology or Medicine: Here, the key is to do fundamental/basic research to answer persistent, nagging, unanswered questions of medicine which others neglect because they are discomforting. Or, find treatments that change the whole manner a disease has been hitherto treated.(3)Nobel in Psychiatry: There are many Nobels waiting to be won, provided: (a) The branch becomes more precise; (b) Science, quantitative study and biology remain its bedrock; and (c) There is an almost obsessive preoccupation with unravelling the mysteries of the brain. One has to choose wisely where to put in efforts, e.g., fields like fundamental research into the causes of psychiatric disorders, especially schizophrenia, depression, bipolar disorders. Or their definitive treatments. Or, work at the cellular or molecular level of the neuron and brain; or, the glandular or genetic level of the systems connected with psychiatric disorders; or, in brain radio imaging. If other, or allied, fields are chosen, to work with finding quantitative data and attempt to pinpoint their precise biological correlates.(4)Indian Nobel in Medicine: There is first the need to give up the colonial mindset that everything trend-setting in science comes only from the West. As also, for Departmental Heads, to protect and nurture those with research excellence rather than the mediocre and the sycophants. For governments, to set up an autonomous Research Excellence Council to expressly and exclusively cater to promoting research excellence, with a sizeable fund to put this into practice.All these four points are summarised as four rules.(5)Indian Nobel in psychiatry: Practical suggestions are presented in the form of an 11 Point Action Plan based on 1-4 above. PMID- 25838740 TI - Template for MSM Submissions. PMID- 25838741 TI - From the Editor's desk. PMID- 25838742 TI - Fertility preservation in female cancer patients: An overview. AB - Fertility preservation is becoming increasingly important to improve the quality of life in cancer survivors. Despite guidelines suggesting that discussion of fertility preservation should be done prior to starting cancer therapies, there is a lack of implementation in this area. A number of techniques are available for fertility preservation, and they can be used individually or together in the same patient to maximize efficiency. Oocyte and embryo cryopreservation are now established techniques but have their limitations. Ovarian tissue cryopreservation though considered experimental at present, has a wider clinical application and the advantage of keeping the fertility window open for a longer time. Both chemotherapy and radiotherapy have a major impact on reproductive potential and fertility preservation procedures should be carried out prior to these treatments. The need for fertility preservation has to be weighed against morbidity and mortality associated with cancer. There is thus a need for a multidisciplinary collaboration between oncologists and reproductive specialists to improve awareness and availability. PMID- 25838743 TI - Revisiting ovarian hyper stimulation syndrome: Towards OHSS free clinic. AB - A rapid development and application of assisted reproductive technologies (ARTs) and ovulation-induction drugs may lead to ovarian hyper stimulation syndrome (OHSS). Young age, low body mass index (BMI), polycystic ovarian syndrome (PCOS), previous OHSS, high follicle count, and elevated serum estradiol (E2) are the certain factors that predispose women to OHSS. Many strategies have been used to reduce or avoid OHSS. Use of human chorionic gonadotropin (hCG) increases ovarian vascular permeability and is responsible for activating the vascular endothelial growth factors (VEGF) pathway and thus the entire cascade, leading to symptomatic OHSS. Gonadotropin-releasing hormone (GnRH) agonists are used as a replacement for hCG for final oocyte maturation in antagonist cycles. Reducing or eliminating the use of hCG and use of GnRH agonist triggered GnRH antagonist cycles and cryopreservation of oocytes or embryos is the most promising approach in making OHSS free clinic a reality. PMID- 25838744 TI - Application of gel-based proteomic technique in female reproductive investigations. AB - Recently, gel-based proteomics has been increasingly applied to investigate proteins involved in female reproductive tract in healthy and disease states. Gel based proteomics coupled by mass spectrometry (MS) facilitate the identification of new proteins playing roles in cellular and molecular interactions underlying female reproductive biology and it is a useful method to identify novel biomarkers of diseases by studying thousands of proteins simultaneously involved in female reproductive tract in healthy state compared to disease state. This review will discuss the best studies areas contributed to female reproductive biology in which gel-based proteomics coupled by MS has been applied to generate proteome of female reproductive tract in a healthy state. PMID- 25838745 TI - Different gonadotropin releasing hormone agonist doses for the final oocyte maturation in high-responder patients undergoing in vitro fertilization/intra cytoplasmic sperm injection. AB - CONTEXT: Efficacy of gonadotropin releasing hormone agonists (GnRH-a) for ovulation in high-responders. AIMS: The aim of the current study is to compare the impact of different GnRH-a doses for the final oocyte maturation on cycle outcomes and ovarian hyperstimulation syndrome (OHSS) rates in high-responder patients undergoing ovarian stimulation. SETTINGS AND DESIGNS: Electronic medical records of a private in vitro fertilization center, a retrospective analysis. SUBJECTS AND METHODS: A total of 77 high-responder cases were detected receiving GnRH-a. Group I consisted of 38 patients who received 1 mg of agonist and Group II consisted of 39 patients who received 2 mg of agonist. STATISTICAL ANALYSIS: In order to compare groups, Student's t-test, Mann-Whitney U-test, Pearson's Chi square test or Fisher's exact test were used where appropriate. A P < 0.05 was considered as statistically significant. RESULTS: Number of retrieved oocytes (17.5 vs. 15.0, P = 0.510), implantation rates (46% vs. 55.1%, P = 0.419) and clinical pregnancy rates (42.1% vs. 38.5%, P = 0.744) were similar among groups. There were no mild or severe OHSS cases detected in Group I. Only 1 mild OHSS case was detected in Group II. CONCLUSION: A volume of 1 or 2 mg leuprolide acetate yields similar outcomes when used for the final oocyte maturation in high responder patients. PMID- 25838746 TI - Prognostic factors associated with clinical pregnancy in in vitro fertilization using pituitary down-regulation with depot and daily low-dose luteal phase gonadotropin releasing hormone agonists: A single center's experience. AB - AIM: To review the experience on depot-dose, and daily low-dose gonadotropin releasing hormone agonist (GnRHa) long protocols and identify prognostic factors. SETTING AND DESIGN: A chart review was conducted on 2106 depot and 1299 daily low dose cycles at a university hospital. METHODS: Clinical parameters were summarized, and prognostic factors of clinical pregnancy for each protocol were identified by logistic regressions. Missing data were imputed using multiple imputations (MI) and the regression models were rerun after MI. RESULTS: Clinical pregnancy rate was 57.5% and 46.9% in the depot and daily low-dose groups, respectively. Logistic regressions with MI identified age (odds ratio [OR]: 0.95, 95% confidence interval [CI]: 0.92-0.98), serum progesterone (OR: 0.62, 95% CI: 0.45-0.84) and endometrial thickness (OR: 1.06, 95% CI: 1.02-1.12) on human chorionic gonadotropin (hCG) day, number of oocytes retrieved (OR: 1.04, 95% CI: 1.01-1.06), fertilization rate (OR: 2.66, 95% CI: 1.46-4.87) and ratio of good quality D3 embryos (OR: 4.31, 95% CI: 2.79-6.67) as prognostic factors in the depot group. Age (OR: 0.95, 95% CI: 0.92-0.98), endometrial thickness on hCG day (OR: 1.09, 95% CI: 1.03-1.15), ratio of good quality D3 embryos (OR: 2.56, 95% CI: 1.59-4.13) and the number of cryopreserved embryos (OR: 1.07, 95% CI: 1.003 1.15) are prognostic for the daily low-dose protocol. Some regression coefficients that are significant under model-wise deletion become nonsignificant after MI. CONCLUSIONS: Age, embryo quality and endometrial thickness on hCG day are important prognostic factors for both 1.0/1.3 mg depot and 0.05/0.1 mg daily low-dose luteal phase GnRHa long protocols. MI is a valuable tool to gauge and address bias caused by missing data in reproductive medicine. PMID- 25838747 TI - Variability between the follicular steroid hormone levels in different follicles of the same patient and between patients. AB - CONTEXT: There is disagreement as to whether the concentration of a substance in follicular fluid is related to the quality of the follicle as a possible reflection of the oocyte quality or whether this concentration is related to the clinical characteristics of the patient. AIM: To establish the variability of steroid hormone levels in follicular fluids from different follicles of the same patient and between patients. SETTINGS AND DESIGN: Prospective cohort study. MATERIALS AND METHODS: In 31 patients who underwent intracytoplasmic sperm injection it was performed an ultrasound guided aspiration of follicular fluid of the first two mature follicles from each ovary. Chemiluminescent microparticle immunoassays were performed to determine the levels of estradiol, progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEA-S). STATISTICAL ANALYSIS: Unconditional mixed model. RESULTS: Variation in estradiol levels between follicles in the same patient was approximately twice the variation between subjects (P = 0.05). In the case of progesterone, the intra-subject variation was similar to the inter-subject variation (P = 0.006). The testosterone levels had a slightly smaller intra-subject variation than inter-subject variation (P = 0.002), and the intra-subject variation in DHEA-S levels was approximately one fifth of the inter-subject variation (P = 0.0003). CONCLUSIONS: The variations in the levels of follicular progesterone and testosterone were similar between patients and between a given patient's follicles; however, the estradiol levels variability was higher among different follicles. The amount of follicular estradiol may be considered a selection tool between the follicles of a given patient. PMID- 25838748 TI - Should men with idiopathic obstructive azoospermia be screened for genitourinary tuberculosis? AB - OBJECTIVE: Infertility may be the sole manifestation of genitourinary tuberculosis (TB) and men with idiopathic obstructive azoospermia are often screened for TB using semen polymerase chain reaction (PCR) test. We assessed the benefits of such screening. DESIGN: Totally, 100 infertile men with idiopathic obstructive azoospermia were screened with a kit-based PCR for semen TB. Confirmatory tests for TB were performed in PCR positive men before administering anti-tubercular therapy (ATT) for 6 months. Semen analysis was repeated to assess benefits of treatment. RESULTS: Seven subjects (7%) had positive semen PCR for TB. Four of them had other clinical evidence of TB (history and physical signs) and were administered ATT. None had any improvement in semen parameters. No subject had any other laboratory evidence of TB and no other subject (96%) was administered ATT. CONCLUSIONS: Screening for TB using semen PCR did not identify any men who would have been missed on clinical evaluation and is thus not indicated in men with idiopathic obstructive azoospermia. PMID- 25838749 TI - Comparison of depression, anxiety, stress, and related factors among women and men with human immunodeficiency virus infection. AB - AIMS: To compare depression, anxiety, stress, and related factors among women and men with human immunodeficiency virus (HIV) infection. SETTINGS AND DESIGN: In this cross-sectional survey conducted between November and September 2013, 200 participants with HIV/acquired immune deficiency syndrome (AIDS) attending Consultation Centers. MATERIALS AND METHODS: Participants with HIV/AIDS were interviewed using the Depression, Anxiety and Stress Scales questionnaire (DASS21 ). RESULTS: There were significant associations between marital status of women and the level of depression (P < 0.05). However, the mean depression and anxiety in women are greater than men (P < 0.05), and the mean stress in men is greater than women (P < 0.05). CONCLUSIONS: HIV infection is related with psychiatric disorders. According to the results, women are more vulnerable to depression and anxiety and they need more care. Management of these psychiatric disorders is very important and requires innovative comprehensive approaches. PMID- 25838750 TI - Lymphangiocele: A very rare cause of primary infertility. AB - There are limited causes of surgically treatable male infertility. Lymphangiocele of scrotum is a very rare condition particularly in adult life. Lymphangiocele causing infertility is further rare and not reported in English literature so far. We report an extremely rare case of lymphangiocele in a 29 years male presenting with male infertility that improved after surgery. PMID- 25838751 TI - Monochorionic triamniotic triplets following conventional in vitro fertilization and blastocyst transfer. AB - Multiple pregnancy in in vitro fertilization (IVF) is on the decline with a reduction in number of embryos transferred. But the risk of monozygotic splitting persists. The risk of monozygotic twinning in women undergoing IVF is reported to be twice that of natural conception, and monochorionic triplets are even rarer at 100 times more than natural conception. We report a case of monochorionic triamniotic (MCTA) triplets following conventional IVF and blastocyst transfer without zona manipulation. This report highlights the possibility of zygotic splitting in IVF in young couples with no family history, in centers with good experience with blastocyst transfer. MCTA triplets carry a high risk of perinatal mortality and morbidity and need multidisciplinary care. Prevention and prediction of zygotic splitting ought to be realized with better reporting and identification of possible risk factors. PMID- 25838752 TI - The Effect of Ankle-Foot Orthoses on Balance Impairment: Single-Case Study. AB - Instability and balance impairment is common in patients with diabetic sensory neuropathy placing them at a higher risk of falling when performing more challenging daily tasks. The report describes the results of a dynamic balance tests of a subject with neuropathy due to the long-standing diabetes. The Computerized Dynamic Posturography was performed with and without ankle-foot orthoses (AFOs). The apparatus provided six test conditions designed to systematically manipulate vestibular, somatosensory, or visual information. With no orthoses the patient had falls performing most of the tests. Bilateral orthoses improved his balance: a derived composite balance score increased four times. In view of these findings, AFOs, in addition to correcting the patient's foot placement during locomotion, could also be expected to improve the maintenance of balance during quiet stance or dynamic perturbation. PMID- 25838753 TI - Preconception counseling and care in the setting of HIV: clinical characteristics and comorbidities. AB - OBJECTIVE: To describe the demographic and clinical characteristics of HIV infected individuals and HIV-affected couples who were referred for preconception counseling (PCC) at a large urban US-based HIV clinic. METHODS: Electronic medical records were reviewed for HIV-infected individuals and HIV-affected couples. Medical, reproductive, surgical, psychosocial, and family history data were abstracted. Univariate analyses were done. RESULTS: There were 8 single HIV infected women and 100 HIV-affected couples who underwent PCC. HIV-infected women were older (mean age 35 years versus 32 years, P = 0.06), were more likely to smoke (23% versus 0%, P < 0.01), and had more medical comorbidities (57% versus 33%, P = 0.04) than HIV-uninfected women. The majority of couples were serodiscordant (77%), and of these couples, 32% had a detectable plasma viral load and 33% report inconsistent condom use. CONCLUSIONS: HIV-infected women have a number of medical and psychosocial issues, including those related to HIV that may increase the risk of adverse pregnancy outcomes and HIV perinatal and sexual transmission. PCC is an important intervention to optimize maternal management to improve perinatal outcomes and minimize transmission risks. PMID- 25838754 TI - Effects of Parkinson's Disease on Fundamental Frequency Variability in Running Speech. AB - In Parkinson's Disease (PD), qualitative speech changes such as decreased variation in pitch and loudness are common, but quantitative vocal changes are not well documented. The variability of fundamental frequency (F0) in 32 individuals (23 male) with PD both ON and OFF levodopa medication was compared with 32 age-matched healthy controls (23 male). Participants read a single paragraph and estimates of fundamental frequency (F0) variability were determined for the entire reading passage as well as for the first and last sentences of the passage separately. F0 variability was significantly increased in controls relative to both PD groups and PD patients showed significantly higher F0 variability while ON medication relative to OFF. No significant effect of group was seen in the change in F0 variability from the beginning to the end of the reading passage. Female speakers were found to have higher F0 variability than males. F0 variability was both significantly reduced in PD relative to controls and significantly increased in patients with PD during use of dopaminergic medications. F0 variability changes over the course of reading a paragraph may not be indicative of PD but rather dependent on non-disease factors such as the linguistic characteristics of the text. PMID- 25838755 TI - A Brief Scale to Measure Problematic Sexually Explicit Media Consumption: Psychometric Properties of the Compulsive Pornography Consumption (CPC) Scale among Men who have Sex with Men. AB - Although the phenomenon of hypersexuality has been described in the literature, and scales of compulsive sexual behavior have been published, the existing measures do not assess compulsive sexually explicit media (SEM) consumption. This study tested the psychometric properties of a new scale, the Compulsive Pornography Consumption (CPC). Exploratory and confirmatory factor analyses results showed good psychometric performance of a five item two factor preoccupation-compulsivity solution. As hypothesized, the scale correlates positively with compulsive sexual behavior, internalized homonegativity, and negatively with sexual self-esteem. The scale will enable researchers to investigate the etiologic factors of compulsive SEM use, and enable clinicians to assess problematic consumption. PMID- 25838756 TI - Late-Stage Fluorination: From Fundamentals to Application. AB - In this brief account, we review work from our lab with a focus on late-stage introduction of fluorine and fluorinated functional groups into small molecules. We attempt to highlight practical developments, which we believe may have potential for industrial applications, and critically reflect on developments that may not yet meet the bar for practical use. PMID- 25838757 TI - Surgical templates for dental implant positioning; current knowledge and clinical perspectives. AB - Dental implants have been used in a variety of different forms for many years. Since the mid-20(th) century, there has been an increase in interest in the implant process for the replacement of missing teeth. Branemark was one of the initial pioneers who applied scientifically based research techniques to develop an endosseous implant that forms an immobile connection with bone. The need for a dental implant to completely address multiple physical and biological factors imposes tremendous constraints on the surgical and handling protocol. Metallic dental implants have been successfully used for decades, but they have serious shortcomings related to their bony union and the fact that their mechanical properties do not match those of bone. However, anatomic limitation and restorative demands encourage the surgeon to gain precision in planning and surgical positioning of dental implants. Ideal placement of the implant facilitates the establishment of favorable forces on the implants and the prosthetic component as well as ensures an aesthetic outcome. Therefore, it is advisable to establish a logical continuity between the planned restoration and the surgical phases, it is essential to use a transfer device that for sure increases the predictability of success. The surgical guide template is fabricated by a dental technician after the presurgical restorative appointments that primarily include determination of occlusal scheme and implant angulations. Here, authors genuinely attempted to review the evolution and clinical applicability of surgical templates used in the placement of dental implants. PMID- 25838758 TI - Spectrum of diseases and diagnostic values of ultrasound in adult patients with nontraumatic acute abdomen in a nigerian tertiary health facility. AB - AIM AND OBJECTIVE: The purpose of this study was to determine the spectrum of disease on abdominal ultrasound (US) and the diagnostic efficacy of US in adult patients with nontraumatic acute abdomen at Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife. MATERIALS AND METHODS: The study population included consecutive 150 adult patients aged 15 years and above presenting with nontraumatic acute abdomen via the adult emergency unit or as inpatients referred to the Radiology Department of OAUTHC, Ile-Ife for abdominal US. MINDRAY D.C-6 real-time US scanner with 3.5, 5.0, and 7.5 MHz probes and Doppler facilities were used to assess the intra-abdominal organs and the findings were compared with the clinical and surgical findings in those cases that were operated. RESULTS: The common spectrum of diseases encountered on US in this study included appendicitis (66 [44%]), ectopic pregnancy (34 [22%]), intestinal obstruction (13 [8.7%]) while the least finding was renal abscess 1 (0.7%). The correlation of US findings with surgical findings in this study showed sensitivity, specificity, and kappa agreement for appendicitis of 83.3%, 100.0%, and 0.808; ectopic pregnancy of 100.0%, 97.8%, and 0.958; acute cholecystitis of 100.0%, 100.0%, and 1.0. However, perforated viscus showed the least sensitivity (60.0%), specificity (99.2%), and kappa agreement 0.654. All the disease entities showed good kappa agreement beyond chance, and they were all statistically significant (P < 0.001). CONCLUSIONS: This study has shown a relatively high sensitivity, specificity and diagnostic accuracy of US in cases of nontraumatic acute abdomen in a careful hand. We, therefore, recommended that these advantages of US should be capitalized upon in settings where other advanced diagnostic modalities are not available. PMID- 25838759 TI - Broomstick Injuries to the Eye; an Emerging Cause of Blindness among Children in Nigeria. AB - BACKGROUND: Ocular trauma among children is responsible for a high incidence of uni-ocular blindness. OBJECTIVE: To evaluate the pattern of presentation and complications from broomstick eye injury at University of Benin Teaching Hospital (UBTH), Benin City with a view to proffering solutions on ways to reduce this trend. MATERIALS AND METHODS: The hospital records of all consecutive patients who suffered ocular trauma from broomstick injury and presented at the eye clinic of the UBTH between 2003 and 2014 were evaluated. Information retrieved from the case records included social demographic characteristics, interval between the occurrence of injury and presentation, mechanism of injury, activity at time of injury, examination findings, treatments and complications. Data were analyzed using SPSS, IBM, Chicago, USA. RESULTS: A total of 20 eyes in 20 patients were seen. They were all children <14 years old. The mean age was 7.10 +/- 4.03 (standard deviation) years. The male: female ratio was 3:1. Twelve children (60%) sustained trauma from broomstick shot as a missile with a rubber band and/or catapult sling by other children and siblings while at play. Ten children (50%) presented within 24 h of occurrence of the injury. Nineteen (95%, n = 19) of the children were blind at presentation in the affected eye with visual acuity ranging from count finger to no light perception. Ninety percent (90%) of the cases were open globe injuries. Only 10% (n = 2) were closed (lamellar) injuries. Most of the patients had multiple complications such as corneal laceration (80%), traumatic cataract (40%), endophthalmitis/panophthalmitis (55%) and orbital cellulitis (15%). CONCLUSION: Ocular trauma from broomstick results in devastating, penetrating eye injury with loss of vision. Young male children are vulnerable as targets of dangerous game-play. Primary prevention is important by sensitization of caregivers and children of the risks. There is a need for effective supervision of children when at play. PMID- 25838760 TI - Abdominal injuries in university of port harcourt teaching hospital. AB - BACKGROUND: Abdominal injury is relatively common in both civilian and military casualties and remains a major source of morbidity and mortality. The mechanism of injury may be blunt or penetrating. Some would require operative intervention, whereas others may be managed conservatively. OBJECTIVE: The aim was to determine the pattern and outcome of management of abdominal injuries in the University of Port Harcourt Teaching Hospital (UPTH). PATIENTS AND METHODS: This was a prospective study of all patients with abdominal injuries seen and managed in UPTH over a 4-year period (from January 1, 2009 to December 31, 2012). Relevant data were recorded and analyzed using Statistical Package for Social Sciences version 16. RESULTS: Forty-five patients were seen during the study period. There were 40 males (88.9%) and five females (11.1%) making a male to female ratio of 8:1. Their ages ranged from 15 to 45 years with a mean of 27.8 +/- 1.6 years and 21 to 30 years was the most commonly affected age group. The mechanism of injury was penetrating in 33 patients (73.3%) and blunt in 12 patients (26.7%). Thirty four patients (75.6%) had an exploratory laparotomy after resuscitation, while 11 (24.4%) were managed conservatively. Small bowel was the most commonly injured organ following penetrating injury, seen in 14 patients (42.4%) while spleen was the most common in blunt injuries, seen in five patients (41.7%). The most common postoperative complication was surgical site infection, seen in four patients (8.9%). Two patients died giving a mortality rate of 4.4%. CONCLUSION: Gunshot to the abdomen is the most common cause of abdominal injury in UPTH. Serious campaign and legislation against militant and criminal activities would help to reduce the incidence. PMID- 25838761 TI - Reduction Mammoplasty in a Developing Country: A 10-year Review (2001-2010) at the National Orthopaedic Hospital, Enugu. AB - CONTEXT: Large breast is a major problem because of associated symptomatology and aesthetic concerns. Reduction mammoplasty (RM) resolves the symptom and at the same time improves the aesthetic appearance of the breast, hence improving self esteem and social integration. AIMS: To describe the pattern of RM in a hospital in the developing world and its impact on postgraduate surgical training. SETTINGS AND DESIGN: A retrospective review of all the RMs done in the National Orthopaedic Hospital, Enugu (a major plastic surgery training center in Nigeria) over a ten-year period (2001-2010), in the developing country of Nigeria. SUBJECTS AND METHODS: All RMs done in the hospital were reviewed after retrieving their records from operation register and medical records department. Fifteen (15) cases were retrieved and analyzed. DATA ANALYSIS: Data was analyzed with Microsoft excel 2007. RESULTS: Average age of female patients who had RM was 26.5 years and 83.3% were single. The most common complaint was abnormally large breast (macromastia). Inferior pedicle technique was commonly used. CONCLUSIONS: The results of RM are remarkable as it impact positively on the quality of life of the patients. However, the level of awareness about the availability of this service is still low in the region as shown by few cases done over the period of review and this impacts negatively on the training. The need for public awareness cannot be overemphasized. PMID- 25838762 TI - Intra-Operative Airway Management in Patients with Maxillofacial Trauma having Reduction and Immobilization of Facial Fractures. AB - BACKGROUND: Despite advancements in airway management, treatment of fractures in the maxillofacial region under general anesthesia remains a unique anesthetic challenge. We reviewed the pattern of airway management in patients with maxillofacial fractures and assessed those challenges associated with the different airway management techniques employed. MATERIALS AND METHODS: The anesthetic chart, theatre and maxillofacial operations records of patients who had reduction and immobilization of various maxillofacial fractures over a 2-year period were reviewed. Information obtained included the patient demographics, mechanisms of injury, types of fractures and details about airway management. Statistical Package for Social Sciences, SPSS version 17.0 was utilized for all data analysis. RESULTS: Fifty-one patients were recruited during the 2-year study period. Mask ventilation was easy in 80-90% of the patients, 80% had Mallampati three or four, while 4 (7.8%) had laryngoscopy grading of 4. There was no statistically significant difference between the fracture groups in terms of the laryngoscopy grading (P = 0.153) but there was statistical significant difference in the technique of airway management (P = 0.0001). Nasal intubation following direct laryngoscopy was employed in 64.7% of the patients, fiber-optic guided nasal intubation was utilized in only 7.8%. None of the patients had tracheostomy either before or during operative management. CONCLUSION: Laryngoscopic grading and not adequacy of mouth opening predicted difficult intubation in this group of patients in the immediate preoperative period. Despite the distortions in the anatomy of the upper airway that may result from maxillofacial fractures, nasal intubation following direct laryngoscopy may be possible in many patients with maxillofacial fractures. PMID- 25838763 TI - Basal cell adenoma-clinicopathological, immunohistochemical analysis and surgical considerations of a rare salivary gland tumor with review of literature. AB - INTRODUCTION: Basal cell adenoma (BCA) of the salivary glands is a rare benign salivary gland tumour. Differentiation of BCA from varied entities involving maxillofacial area is mandatory. AIM: To analyze the clinicopathological, histopathologic features, immunohistochemcal analysis and surgical considerations of this rare entity. MATERIALS AND METHODS: This study included 12 cases of BCA from archives of department reported over the period of 13 years. All the pertaining clinicopathologic features such as incidence, age, sex and site of lesions were assessed. Tissue sections were stained by using panel of immunohistochemical markers, i.e. Pan CK, CK 5/6 and S100, Calponin, p63, CD 117 and smooth muscle actin. RESULTS: BCA was observed in 26-52 years age group (mean age, 38.75 years) with female propensity of 7:5 male to female ratio. It is seen more commonly in parotid gland, followed by upper lip, buccal mucosa and palate. Solid type is the most common histopathologic type followed by tubular, membranous and trabecular. Only one case of membranous type of BCA showed recurrence. Pan CK, CK 5/6 showed strong immunoreactivity, calponin showed moderate staining, p63 and Ki-67 mild staining, whereas CD 117 and SMA showed negative immunostaining. CONCLUSION: Vigilant comprehensive analysis of all the pertaining clinicopathologic and histopathologic features and immunohistochemical analysis are required for differentiating from other lesions with basaloid differentiation having varying prognosis. PMID- 25838764 TI - Laparoscopy may have a role in the drainage of liver abscess: Early experience at Owerri, Nigeria. AB - BACKGROUND: Image-guided percutaneous drainage with antimicrobial agents is the standard modality of treatment of liver abscess. Open surgical drainage, and lately laparoscopic drainage becomes useful in selected patients. Nigeria is awakening late to the laparoscopic surgery revolution. Public health institutions have started making enormous investments in minimal access surgery, which can augment deficient diagnostic capacities. OBJECTIVE: To describe the outcomes of the patients who underwent laparoscopic liver abscess drainage at the Federal Medical Centre, Owerri. MATERIALS AND METHODS: A retrospective analysis of the laparoscopic liver abscess drainage procedures done between the period September 2007 and December 2012 was done. RESULTS: A total of eight patients in the study period were worked up for abscess surgical drainage based on ultrasound (seven cases) and computed tomography (one case) supported localized collection in the liver. Intraoperatively, one patient was noticed to have nodules on the liver that was later confirmed as hepatocellular carcinoma. Operating time ranged from 37 to 126 min. There was no conversion to open surgery. On the follow-up, one patient had residual abscess of 45 mm diameter size, after 6 weeks, and in whose aspirate acid-fast bacilli were identified. CONCLUSION: Laparoscopic drainage should be considered in the management of liver abscess. PMID- 25838765 TI - Patterns, severity, and management of maxillofacial injuries in a suburban South Western Nigeria tertiary center. AB - BACKGROUND: Trauma remains a leading cause of maxillofacial injury globally. Changing etiological factors and patterns of maxillofacial injury continue to be reported and are largely modulated by socio-geographic and environmental factors. It is important to have an in-depth understanding of the pattern and etiology in a particular region before effective preventive measures can be developed. AIM: The aim was to evaluate the patterns, etiological factors, and management of maxillofacial injuries in Ogun state, Nigeria. MATERIALS AND METHODS: A prospective descriptive cohort study of all consecutive patients that presented with maxillofacial injuries at our center between January and December 2013. Information about demographic data, types of maxillofacial and associated injury, etiology of injury, treatment received and complications were collected and analyzed. RESULTS: Seventy patients presented with maxillofacial injury during the study period with a male to female ratio of 4:1. The age range was 9 months to 60 years with a mean of 30.11 +/- standard deviation 14.97 years. Majority of the facial fractures were due to motorcycle related crashes. There were 57.1% mandibular fractures and 55.7% middle third fractures. Closed reduction with maxillo-mandibular fixation was the major method of treatment of facial fractures. Postoperative complications were observed in 11.4% of patients. CONCLUSION: Road traffic crashes (RTCs) remain the leading etiological factor of maxillofacial injuries in our center. Enforcement of stricter traffic regulations and possibly replacement of motorcycles with tricycles for commercial transportation may help to reduce the incidence of RTCs. PMID- 25838766 TI - Diathermy versus Scalpel Incision in a Heterogeneous Cohort of General Surgery Patients in a Nigerian Teaching Hospital. AB - BACKGROUND: The anecdotal fear of using cautery for surgical incisions is still common in surgical practice despite recent evidences. The aim of this study is to compare the results of electrocautery and the scalpel in skin incisions. MATERIALS AND METHODS: This is a prospective randomized double blind study conducted in the Department of Surgery, of a teaching hospital in Ibadan. Patients were randomized to have either scalpel or electrocautery incisions. The duration used in making the skin incision; the incisional blood loss and the ensuing length and depth of the wound were noted. Postoperative pain; duration of wound healing and the occurrence of surgical site infection were also noted. RESULTS: There were 197 patients consisting of the scalpel group (n = 98) and the electrocautery group (n = 99). The ages ranged from 16 to 73 years. The demography, case distribution and body mass index were similar in both groups. The mode of presentation was predominantly elective. The incision time was shorter in the electrocautery group (P < 0.001). The blood loss was less with the diathermy compared to the scalpel (6.53 +/- 3.84 ml vs. 18.16 +/- 7.36 ml, P < 0.001). The cumulative numerical rating scale score for pain was 12.65 (standard deviation [SD] 8.06) and 17.12 (SD 9.49) in the diathermy and scalpel groups respectively (P < 0.001). There was no statistically significant difference in wound infection and wound closure (epithelialization time) (P = 0.206). CONCLUSION: The use of electrocautery in making skin incision is associated with reduced incision time, incisional blood loss, and postoperative pain. PMID- 25838767 TI - The use of nontreated mosquito-net mesh cloth for a tension free inguinal hernia repair: our experience. AB - INTRODUCTION: The prohibitive costs and scarcity of the imported prosthetic mesh for hernioplasty, has prevented its widespread use in most developing countries. We then set out to ascertain the outcome, complications (undue pain, wound infection, recurrence, and mesh extrusion) and cost implications in the use of a nontreated mosquito-net for inguinal hernioplasty. MATERIALS AND METHODS: A prospective study of all consecutive adult patients with uncomplicated inguinal hernia who were admitted for open herniorrhaphy between January 2012 and December, 2013 at the Federal Medical Centre, Ido - Ekiti, South West, Nigeria. A sheet of the nontreated mosquito-net mesh 10 cm Chi 8 cm, autoclaved, a day prior to surgery was used for each patient's hernia repair. The operation sites were exposed and examined 3(rd) and 6(th) postoperative days. Findings were documented for analysis. RESULT: A total of 130 adult patients were recruited for this study of which 115 of the patients were males and 15 were females. Forty-four (41.53%) had inguinal hernia and 76 (58.46%) of them had inguinoscrotal hernia. They all had successful repair and were followed-up for complications for a period of 6 weeks to 6 months at the surgical out-patient department. CONCLUSION: Locally sourced and autoclaved mosquito-net mesh is an effective alternative for hernioplasty especially in situations where commercial mesh is not readily available or affordable. PMID- 25838769 TI - Groin exploration for the nonpalpable testes: a single center experience. AB - BACKGROUND: Management of non-palpable testes in Nigeria can be difficult due to late presentation and poor resources. Surgical exploration is often required for diagnosis and treatment. AIM: This study reviews the management outcome of clinically non-palpable testeis in a tertiary center in Nigeria. MATERIALS AND METHODS: Ten years retrospective review of all clinically non-palpable testes in children aged 2-15years managed at the Obafemi Awolowo University Teaching Hospitals Complex Ile-Ife Nigeria. RESULTS: Thirty two children with 44 testicular units were managed. The right side was involved in 12 (37.5%); left in 8 (25.0%) and bilateral in 12 (37.5%) patients. Pre-operative ultrasound was done in 12 patients with localization in just 4 patients (33.3% success rate). At groin exploration, 34 (77.32%) testicular units were located in the inguinal canal. Eight patients with 10 The remaining 10 (22.7%) testicular units required additional mini-laparotomy for which six (13.6%) and 4 (9.1%) testicular units respectively were either in the retroperitoneum or not found. Of the testes in the groin, twenty two (64.7%) testicular units were normal while 12 (35.3%) were atrophic. Four of the retroperitoneal testes were normal while 2 were atrophic. Eight (22.5%) testicular units among the inguinal group had multi-staged orchidopexy; while 2 each of the retroperitoneal group had orchidectomy, one stage orchidopexy, two staged Fowler Stephens (F-S) procedure or lost to follow up after first stage of F-S procedure. Mean follow up period was 2 months. 2 testicular units each had retracted or vanished respectively during follow up. CONCLUSION: Groin exploration still offers a viable approach Surgical exploration is still useful in to the management of non-palpable testes in low resource environment despite the lack of laparoscopy. PMID- 25838768 TI - A 5-year Review of Darning Technique of Inguinal Hernia Repair. AB - CONTEXT: The Darning technique of inguinal hernia repair is a tissue-based technique with documented low recurrence rate in some parts of the world. Though practiced in our setting, little is documented on its outcome. AIMS: The aim was to review the outcome of Darning technique of inguinal hernia repair in our setting. STUDY DESIGN: A descriptive retrospective study. PATIENTS AND METHODS: Clinical records of all patients who had inguinal hernia repair using the Darning technique between January 2007 and December 2011 in our institution were obtained. Details of sociodemographic data, intraoperative findings and postoperative complications were reviewed. STATISTICAL ANALYSIS USED: simple frequencies, proportions and cross-tabulations. RESULTS: A total of 132 patients whose ages ranged from 15 to 84 years (mean = 49.4 years) with a male: female ratio of 12:1 were studied. Majority of the hernias were right sided (68.9%), mostly indirect (81.8%). The procedures were for emergencies in 17 (12.9%) cases whereas the rest (87.1%) were done electively. Most procedures, 110 (83.3%) were performed under local anesthesia. Surgical site infection was the most common complication occurring in six patients (4.5%), while four patients (3%) had chronic groin pain. At a mean follow-up period of 15 months there were two recurrences (1.5%) both occurring in patients with bilateral hernias (P = 0.001). CONCLUSIONS: The Darning technique of inguinal hernia repair is a safe and effective method for inguinal hernia repair in our setting. PMID- 25838770 TI - Muscular variations during axillary dissection: a clinical study in fifty patients. AB - AIM: The present study was conducted to detect the musculature variations during axillary dissection for breast cancer surgery. METHODS: The anatomy of axilla regarding muscular variations was studied in 50 patients who had an axillary dissection for the staging and treatment of invasive primary breast cancer over one year. RESULTS: In a period of one year, two patients (4%) with axillary arch and one patient (2%) with absent pectoralis major and minor muscles among fifty patients undergoing axillary surgery for breast cancer were identified. CONCLUSIONS: Axillary arch when present should always be identified and formally divided to allow adequate exposure of axillary contents, in order to achieve a complete lymphatic dissection. Complete absence of pectoralis major and minor muscles precludes the insertion of breast implants and worsens the prognosis of breast cancer. PMID- 25838771 TI - Bullhorn hernia: a rare traumatic abdominal wall hernia. AB - Traumatic abdominal wall hernia (TAWH) is rare despite the high prevalence of blunt abdominal trauma. Bullhorn hernia occurs as a result of a direct blow to the abdominal wall by the horn of a bull, which disrupts the muscles and fascia and leads to hernia formation. We report a rare case of bullhorn TAWH in a 70 year-old patient who presented with swelling at the left lumbar region. The patient was managed by immediate surgical intervention. A surgeon must have high index of suspicion for the diagnosis of this condition as missed hernias in this setting pose a high risk of strangulation and gangrene. PMID- 25838772 TI - Basal cell ameloblastoma: a rare histological variant of an uncommon tumor. AB - Ameloblastomas are an inscrutable group of oral tumors. Basal cell ameloblastoma is a rare variant of ameloblastoma with very few cases reported until date. The tumor is composed of more primitive cells and has less conspicuous peripheral palisading. It shows remarkable similarity to basal cell carcinoma, basal cell adenoma and intra-osseous adenoid cystic carcinoma. This report describes the case of a 27-year-old male with an ameloblastoma in the right posterior mandible. Orthopantomography computed tomography and finally histopathological examination directed us toward the confirmatory diagnosis of basal cell variant of ameloblastoma. Considering the rarity of the lesion and histological paradox regarding its diagnosis, we report here an interesting and rare case of basal cell ameloblastoma of the mandible with emphasis on differential diagnosis from other entities with basaloid differentiation having varying prognosis. After surgery, long-term follow-up at regular intervals is recommended as no sufficient statistical information regarding the behavior of this tumor is available. PMID- 25838773 TI - Retrograde Jejuno-gastric Intussusception. AB - Retrograde jejuno-gastric intussusception is a rare complication following gastric surgery. We present a case of retrograde jejuno-gastric intussusception in a 42-year-old female who presented with upper abdominal pain, vomiting and swelling in left hypochondruim. Intussusception was suspected on ultrasound of the abdomen and later confirmed with computed tomography scan. At laparotomy, efferent loop was intussuscepting into stomach. This was reduced and fixed to the abdominal wall and transverse mesocolon. It should be suspected in a patient with the previous history of gastric surgery as it is a rare complication. Early diagnosis and management can prevent further complications like bowel gangrene and its associated morbidity and mortality. PMID- 25838775 TI - To promote vaccination, physicians need to provide booster shots of information. PMID- 25838774 TI - Ensuring First Nations children's access to equitable services through Jordan's Principle: The time to act is now. PMID- 25838776 TI - Point-of-care ultrasound: An emerging technology in Canadian paediatrics. PMID- 25838777 TI - Case 1: A two-year-old boy with fever and widespread vesicular lesions. PMID- 25838778 TI - Case 2: Severe headache and paroxysmal seizures in a 14-year-old boy with cyclic vomiting syndrome. PMID- 25838779 TI - Demographic characteristics and needs of the Canadian urban adolescent mother and her child. AB - INTRODUCTION: There is a paucity of Canadian-based literature on urban adolescent mothers and their children. To inform clinical assessment and interventions and to mitigate the risks that adolescent mothers and their children face, it is essential to understand the characteristics of this high-risk population. METHODS: A retrospective review of 116 adolescent mothers attending an urban academic hospital-based outpatient clinic in Canada from 2005 to 2009 was conducted. The following information was collected: demographic characteristics, maternal maltreatment history, substance use, postpartum depression symptoms, and child socioemotional and developmental functioning. RESULTS: The mean maternal age was 16.1 years and the mean education level was grade 9. Ninety-nine percent of adolescent mothers were single, 47% had a history of child welfare involvement and 18% had previous involvement with the judicial system. More than one-half of participants reported a history of both maltreatment and substance abuse, and 20% of adolescent mothers scored in the clinical range for postpartum depression. A substantial proportion of children scored in the clinical range for behavioural problems, regulatory difficulties and suspected developmental delays. CONCLUSION: The present study serves to illustrate the high-risk nature of urban adolescent mothers. These observations can be used to improve clinical practice for health care providers in community and hospital-based settings working with this population. PMID- 25838780 TI - An innovative on-call system for paediatric residency programs: The alternate night float. AB - BACKGROUND: Night-float systems, in which residents work consecutive nights, have been increasingly adopted in paediatric programs, but may be detrimental to residents' sleep and mood. OBJECTIVE: To describe the self-reported impact of a novel system consisting of two consecutive weeks of 16 h overnight shifts every second day that was piloted at the Children's Hospital of Eastern Ontario (Ottawa, Ontario). METHODS: A survey of 28 senior paediatric residents examined their experience with the alternate night-float system in three domains (patient care, resident professional development and well-being) and their comparison of the system with the traditional overnight on-call system. RESULTS: Twenty-six of 28 residents responded. Nearly all (96%) felt familiar with important details of inpatients and that handover was effective (92%). Results were mixed for professional development, with concerns about the quality of supervisors' feedback and perceived difficulty in attending daytime teaching. All residents believed that the night-float system provided a better learning experience compared with the traditional system. Less than 35% considered fatigue to be a notable problem, although 20% increased use of sleep aids or stimulants beyond their typical use. Ninety-six percent believed their workload was appropriate. All residents felt equally or less fatigued under the night-float system compared with the traditional system. Ninety-six percent recommended that the night-float model continue as the on-call system. CONCLUSIONS: This novel night-float system is an alternative method of providing paediatric inpatient night coverage because it meets duty hour regulations and has strong resident approval. Studies to examine its impact on residents and patient care in comparison with other systems are warranted. PMID- 25838781 TI - Epidemiology and clinical management of tuberculosis in children in Canada. AB - Although often regarded as a foreign disease, latent tuberculosis or tuberculosis disease will be encountered in many clinical situations by the Canadian child health practitioner. There are key differences between tuberculosis in children and adults. In the present article, the changing epidemiology of tuberculosis in children in Canada and around the world, the pathogenesis of infection, diagnostic tests, and clinical management of childhood latent tuberculosis and tuberculosis disease are reviewed. PMID- 25838782 TI - Food insecurity and hunger: A review of the effects on children's health and behaviour. AB - Food insecurity and hunger are significant problems in Canada, with millions of Canadians experiencing some level of food insecurity. The purpose of the present article is to review what is currently known about the effects of food insecurity and hunger on children. Longitudinal studies in Canada indicate that hunger is related to poor health outcomes, including a higher risk of depression and suicidal ideation in adolescents, and chronic conditions, particularly asthma. In addition, nutrient deficiencies, such as iron deficiency, are known to impair learning and cause decreased productivity in school-age children, and maternal depressive disorders. School-based nutrition programs and innovations, such as subsidized food (apples, cheese, soy nuts, carrots and broccoli), are an essential immediate need, but long-term solutions lie in adequate incomes for families. PMID- 25838783 TI - Liquid detergent packets: Small, brightly coloured, convenient and hazardous! PMID- 25838784 TI - Preventing ophthalmia neonatorum. AB - The use of silver nitrate as prophylaxis for neonatal ophthalmia was instituted in the late 1800s to prevent the devastating effects of neonatal ocular infection with Neisseria gonorrhoeae. At that time - during the preantibiotic era - many countries made such prophylaxis mandatory by law. Today, neonatal gonococcal ophthalmia is rare in Canada, but ocular prophylaxis for this condition remains mandatory in some provinces/ territories. Silver nitrate drops are no longer available and erythromycin, the only ophthalmic antibiotic eye ointment currently available for use in newborns, is of questionable efficacy. Ocular prophylaxis is not effective in preventing chlamydial conjunctivitis. Applying medication to the eyes of newborns may result in mild eye irritation and has been perceived by some parents as interfering with mother-infant bonding. Physicians caring for newborns should advocate for rescinding mandatory ocular prophylaxis laws. More effective means of preventing ophthalmia neonatorum include screening all pregnant women for gonorrhea and chlamydia infection, and treatment and follow-up of those found to be infected. Mothers who were not screened should be tested at delivery. Infants of mothers with untreated gonococcal infection at delivery should receive ceftriaxone. Infants exposed to chlamydia at delivery should be followed closely for signs of infection. PMID- 25838785 TI - E-cigarettes: Are we renormalizing public smoking? Reversing five decades of tobacco control and revitalizing nicotine dependency in children and youth in Canada. AB - An electronic cigarette (e-cigarette) is a battery attached to a chamber containing liquid that may (or may not) contain nicotine. The battery heats the liquid and converts it into a vapour, which is inhaled, mimicking tobacco smoking. The e-cigarette does not rely on tobacco as a source of nicotine but, rather, vaporizes a liquid for inhalation. E-liquids are often flavoured and may contain nicotine in various concentrations, although actual amounts are seldom accurately reflected in container labelling. The deleterious effects of nicotine on paediatric health are well established. The use of e-cigarettes in the paediatric age group is on the rise in Canada, as are associated nicotine poisonings. E-devices generate substantial amounts of fine particulate matter, toxins and heavy metals at levels that can exceed those observed for conventional cigarettes. Children and youth are particularly susceptible to these atomized products. Action must be taken before these devices become a more established public health hazard. Policies to denormalize tobacco smoking in society and historic reductions in tobacco consumption may be undermined by this new 'gateway' product to nicotine dependency. PMID- 25838786 TI - Time needed to achieve changes in oxygen concentration at the T-Piece resuscitator during respiratory support in preterm infants in the delivery room. AB - OBJECTIVE: To measure the time needed to achieve changes in fraction of inspired oxygen concentration (FiO2) from the oxygen blender to the facemask during simulated neonatal resuscitation. METHOD: Two oxygen analyzers were placed at each end of the T-Piece. During simulated ventilation, the duration to achieve the set oxygen concentration at the facemask was measured. This was repeated at different gas flow rates (5 L/min, 8 L/min or 10 L/min) and different FiO2 changes (0.21 to 1.0 to 0.21, with stepwise increases and decreases in 0.05, 0.1 and 0.2 increments). RESULTS: A total of 1134 measurements (378 measurements for each flow) were recorded. Overall, the mean (+/- SD) time required to achieve FiO2 changes at 5 L/min, 8 L/min and 10 L/min was 36+/-15 s, 31+/-14 s and 28+/ 14 s, respectively. CONCLUSION: There was a lag time of approximately 30 s to achieve the FiO2 at the facemask. This delay needs to be considered when making serial adjustments to FiO2 during neonatal resuscitation. PMID- 25838787 TI - Polar Effects Control the Gas-phase Reactivity of Charged para-Benzyne Analogs. AB - The gas-phase reactivity of charged para-benzynes is entirely unexplored as they and/or their precursors tend to undergo ring-opening upon their generation. We report here a gas-phase reactivity study of two such benzynes, the 2,5 didehydropyridinium and 5,8-didehydroisoquinolinium cations, generated in a modified dual-linear quadrupole ion trap (DLQIT) mass spectrometer. Both biradicals were found to form diagnostic products with organic molecules, indicating the presence of two radical sites. As opposed to earlier predictions that the singlet-triplet (S-T) splitting controls the radical reactivity of such species, the 2,5-didehydropyridinium cation reacts much faster in spite of its larger S-T splitting. Calculated vertical electron affinities of the radical sites of the para-benzynes, a parameter related to the polarity of the transition states of their reactions, appears to be the most important reactivity controlling factor. PMID- 25838789 TI - SoftKiller, a particle-level pileup removal method. AB - Existing widely used pileup removal approaches correct the momenta of individual jets. In this article we introduce an event-level, particle-based pileup correction procedure, SoftKiller. It removes the softest particles in an event, up to a transverse momentum threshold that is determined dynamically on an event by-event basis. In simulations, this simple procedure appears to be reasonably robust and brings superior jet resolution performance compared to existing jet based approaches. It is also nearly two orders of magnitude faster than methods based on jet areas. PMID- 25838788 TI - An IMS-IMS threshold method for semi-quantitative determination of activation barriers: Interconversion of proline cis<->trans forms in triply protonated bradykinin. AB - Collisional activation of selected conformations by multidimensional ion mobility spectrometry (IMS-IMS), combined with mass spectrometry (MS), is described as a method to determine semi-quantitative activation energies for interconversion of different structures of the nonapeptide bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser Pro-Phe-Arg). This analysis is based on a calibration involving collision-induced dissociation measurements of ions with known dissociation energies (i.e., "thermometer" ions) such as leucine enkephalin, BK, and amino acid-metal cation systems. The energetic barriers between six conformations of [BK+3H]3+ range from 0.23 +/-0.01 to 0.55 +/-0.03 eV. Prior results indicate that the major peaks in the IMS distributions correspond to specific combinations of cis and trans configurations of the three proline residues in the peptide sequence. The analysis allows us to directly assess pathways for specific transitions. The combination of structural assignments, experimentally determined barrier heights, onset of the quasi-equilibrium region, and dissociation threshold are used to derive a semi-quantitative potential energy surface for main features of [BK+3H]3+. PMID- 25838790 TI - Two-loop QCD corrections to the MSSM Higgs masses beyond the effective-potential approximation. AB - We compute the two-loop QCD corrections to the neutral Higgs-boson masses in the Minimal Supersymmetric Standard Model, including the effect of non-vanishing external momenta in the self-energies. We obtain corrections of [Formula: see text] and [Formula: see text], i.e., all two-loop corrections that involve the strong gauge coupling when the only non-vanishing Yukawa coupling is the top one. We adopt either the [Formula: see text] renormalization scheme or a mixed on shell (OS)-[Formula: see text] scheme where the top/stop parameters are renormalized on-shell. We compare our results with those of earlier calculations, pointing out an inconsistency in a recent result obtained in the mixed OS [Formula: see text] scheme. The numerical impact of the new corrections on the prediction for the lightest-scalar mass is moderate, but already comparable to the accuracy of the Higgs-mass measurement at the Large Hadron Collider. PMID- 25838795 TI - Exploring CP violation in the MSSM. AB - We explore the prospects for observing CP violation in the minimal supersymmetric extension of the Standard Model (MSSM) with six CP-violating parameters, three gaugino mass phases and three phases in trilinear soft supersymmetry-breaking parameters, using the CPsuperH code combined with a geometric approach to maximise CP-violating observables subject to the experimental upper bounds on electric dipole moments. We also implement CP-conserving constraints from Higgs physics, flavour physics and the upper limits on the cosmological dark matter density and spin-independent scattering. We study possible values of observables within the constrained MSSM (CMSSM), the non-universal Higgs model (NUHM), the CPX scenario and a variant of the phenomenological MSSM (pMSSM). We find values of the CP-violating asymmetry [Formula: see text] in [Formula: see text] decay that may be as large as 3 %, so future measurements of [Formula: see text] may provide independent information about CP violation in the MSSM. We find that CP violating MSSM contributions to the [Formula: see text] meson mass mixing term [Formula: see text] are in general below the present upper limit, which is dominated by theoretical uncertainties. If these could be reduced, [Formula: see text] could also provide an interesting and complementary constraint on the six CP-violating MSSM phases, enabling them all to be determined experimentally, in principle. We also find that CP violation in the [Formula: see text] and [Formula: see text] couplings can be quite large, and so may offer interesting prospects for future [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] colliders. PMID- 25838798 TI - Propagators and topology. AB - Two popular perspectives on the non-perturbative domain of Yang-Mills theories are either in terms of the gluons themselves or in terms of collective gluonic excitations, i.e. topological excitations. If both views are correct, then they are only two different representations of the same underlying physics. One possibility to investigate this connection is by the determination of gluon correlation functions in topological background fields, as created by the smearing of lattice configurations. This is performed here for the minimal Landau gauge gluon propagator, ghost propagator, and running coupling, both in momentum and position space for SU(2) Yang-Mills theory. The results show that the salient low-momentum features of the propagators are qualitatively retained under smearing at sufficiently small momenta, in agreement with an equivalence of both perspectives. However, the mid-momentum behavior is significantly affected. These results are also relevant for the construction of truncations in functional methods, as they provide hints on necessary properties to be retained in truncations. PMID- 25838799 TI - Passive ankle movement increases cerebral blood oxygenation in the elderly: an experimental study. AB - BACKGROUND: Ankle exercise has been proven to be an effective intervention to increase venous velocity. However, the efficacy of ankle exercise for improving cerebral circulation has not been determined. We hypothesized that ankle exercise in the supine position would be able to increase oxyhemoglobin levels measured at the forehead. METHODS: Seventeen community-dwelling elderly women participated in this study. We recorded blood pressure, heart rate (HR), and oxyhemoglobin (OxyHb) levels from the participants in the supine position. Participants repeated ankle plantar flexion and dorsiflexion movements for 1 min. Two types of exercise were used: active movement and passive movement. We used two-way analysis of variance to assess the differences in mean arterial blood pressure (MAP), HR, and OxyHb between different exercises (active and passive) and times (before and after exercise). RESULTS: The HR and MAP increased during active exercise but not during passive exercise. On the other hand, the levels of OxyHb measured at the forehead were elevated during both active and passive exercises. This increase lasted at least 1 min after exercise. There was no significant difference between active and passive exercise with regard to OxyHb; however, a significant difference was observed between before and after exercise (p < 0.05, eta(2) G = 0.153). CONCLUSIONS: The physiological response of OxyHb to ankle exercise was different from that of the other cardiovascular functions. Both active and passive ankle exercises were able to increase cerebral blood oxygenation, whereas the other cardiovascular functions did not respond to passive exercise. PMID- 25838801 TI - Teaching science writing in an introductory lab course. AB - One challenge that many neuroscience instructors face is how to teach students to communicate within the field. The goal of this project was to improve students' scientific writing in an introductory psychology laboratory course that serves as a feeder course into the neuroscience curriculum. This course included a scaffolded approach - breaking assignments into different sections that build upon each other to allow for more direction and feedback on each section. Students were also provided with examples of scientific writing, given direction on finding and reading journal articles, and were taught how to effectively peer review a paper. Research papers were assessed before (Year 1) and after (Year 2) this scaffolded approach was instituted. The assessment included measures of "Genre Knowledge" for each section of a research paper (abstract, introduction, method, results, discussion) as well as measures of "Writing Elements" (grammar, formatting, clarity, transitions, building to the hypothesis, using evidence). The results indicated that there was an improvement for Genre Knowledge scores when comparing Year 1 to Year 2. However, there was no systematic improvement in Writing Elements. This suggests that this teaching technique was most effective in improving students' ability to write within the scientific genre. The logistics of implementing such an approach are discussed. PMID- 25838800 TI - Physiology of Mechanotransduction: How Do Muscle and Bone "Talk" to One Another? AB - The complexity of cell interactions with their microenvironment and their ability to communicate at the autocrine, paracrine, and endocrine levels has gradually but significantly evolved in the last three decades. The musculoskeletal system has been historically recognized to be governed by a relationship of proximity and function, chiefly dictated by mechanical forces and the work of gravity itself. In this review article, we first provide a historical overview of the biomechanical theory of bone- muscle interactions. Next, we expand to detail the significant evolution in our understanding of the function of bones and muscles as secretory organs. Then, we review and discuss new evidence in support of a biochemical interaction between these two tissues. We then propose that these two models of interaction are complementary and intertwined providing for a new frontier for the investigation of how bone-muscle cross talk could be fully explored for the targeting of new therapies for musculoskeletal diseases, particularly the twin conditions of aging, osteoporosis and sarcopenia. In the last section, we explore the bone-muscle cross talk in the context of their interactions with other tissues and the global impact of these multi-tissue interactions on chronic diseases. PMID- 25838802 TI - Active learning in a neuroethics course positively impacts moral judgment development in undergraduates. AB - The growing neuroscientific understanding of the biological basis of behaviors has profound social and ethical implications. To address the need for public awareness of the consequences of these advances, we developed an undergraduate neuroethics course, Neuroscience and Society, at the University of Minnesota. Course evolution, objectives, content, and impact are described here. To engage all students and facilitate undergraduate ethics education, this course employed daily reading, writing, and student discussion, case analysis, and team presentations with goals of fostering development of moral reasoning and judgment and introducing application of bioethical frameworks to topics raised by neuroscience. Pre- and post-course Defining Issues Test (DIT) scores and student end-of-course reflections demonstrated that course objectives for student application of bioethical frameworks to neuroethical issues were met. The active learning, student-centered pedagogical approaches used to achieve these goals serve as a model for how to effectively teach neuroethics at the undergraduate level. PMID- 25838803 TI - Dark adaptation and purkinje shift: a laboratory exercise in perceptual neuroscience. AB - The systematic measurement of luminance thresholds during dark adaptation usually requires advanced optical equipment not available in most undergraduate classes. Here we describe an easy, inexpensive alternative that uses a printed grayscale to measure visual thresholds. Adaptation curves found with this method are comparable to those found with the technologically advanced tools in the standard literature and even show the shift from cone to rod vision at around 4-8 minutes. The exercise can furthermore be easily combined with a demonstration of the Purkinje shift (the different spectral sensitivity of the rod and cone systems) and of multi-sensory integration across vision, touch and proprioception. The lab allows students to collect, graph and analyze both qualitative and quantitative data. Student ratings of the activity are highly positive, even when compared to other visual neuroscience labs. The activity provides an effective and accessible tool for teaching several important neuroscience concepts, including retinal circuitry, spectral sensitivity, and multi-sensory integration. PMID- 25838804 TI - Brain literate: making neuroscience accessible to a wider audience of undergraduates. AB - The ability to critically evaluate neuroscientific findings is a skill that is rapidly becoming important in non-science professions. As neuroscience research is increasingly being used in law, business, education, and politics, it becomes imperative to educate future leaders in all areas of society about the brain. Undergraduate general education courses are an ideal way to expose students to issues of critical importance, but non-science students may avoid taking a neuroscience course because of the perception that neuroscience is more challenging than other science courses. A recently developed general education cluster course at UCLA aims to make neuroscience more palatable to undergraduates by pairing neuroscientific concepts with philosophy and history, and by building a learning community that supports the development of core academic skills and intellectual growth over the course of a year. This study examined the extent to which the course was successful in delivering neuroscience education to a broader undergraduate community. The results indicate that a majority of students in the course mastered the basics of the discipline regardless of their major. Furthermore, 77% of the non-life science majors (approximately two-thirds of students in the course) indicated that they would not have taken an undergraduate neuroscience course if this one was not offered. The findings also demonstrate that the course helped students develop core academic skills and improved their ability to think critically about current events in neuroscience. Faculty reported that teaching the course was highly rewarding and did not require an inordinate amount of time. PMID- 25838805 TI - A classic improved: minor tweaks yield major benefits in crayfish slow-flexor preparations. AB - Action potentials and the postsynaptic potentials they evoke fill the pages of neuroscience textbooks, but students have relatively few opportunities to record these phenomena on their own. However, the act of making such recordings can be key events in a student's scientific education. The crayfish abdominal slow flexor muscle system is a well-established platform for recording spikes and PSPs. It enables students to see nerves and the muscles they innervate, record spontaneous spikes from several motor axons in these nerves as well as PSPs in their postsynaptic muscle fibers, and interpret these recordings quantitatively. Here we describe an improved method for preparing the slow-flexor system for recording that employs transmitted illumination through the stereo microscope's conventional substage lighting. Oblique transmitted lighting allows students to see the nerve and muscles fibers in each segment clearly and position recording electrodes accurately under visual control. Because students can see the nerves, muscles, and recording electrodes, broken electrode tips are relatively uncommon and the first successful recordings come more quickly. Many kinds of neurons in the CNS have the same pattern of multineuronal, multiterminal innervation that occurs on these muscle fibers. To visualize these innervation patterns on these fibers, we describe an immunohistochemical protocol that labels the GABAergic inhibitory motor axon and all the synaptic vesicles in the synaptic terminals on these muscle fibers. Dual-color images reveal extensive branching of the axons and fields of presynaptic terminals, only some of which are double-labeled for GABA. PMID- 25838806 TI - Mad dogs, vampires, and zombie ants: a multidisciplinary approach to teaching neuroscience, behavior, and microbiology. AB - Viruses, parasites, and some bacteria use host organisms to complete their lifecycle. These infectious agents are able to hijack host processes to replicate and transmit to the next host. While we tend to think of infections as just making us sick, they are also capable of changing host behavior. In fact, many infectious agents are able to mediate host behavior in ways that can enhance transmission of the disease. In this course we explore the process of host behavior mediation by infectious agents, combining aspects of multiple fields including neurobiology, animal behavior, infectious disease microbiology, and epidemiology. The goals for this course are: 1) To explore the neurological and behavioral effects of infectious organisms on their hosts, in particular pathogen mediation of host behavior to the benefit of the pathogen, 2) to introduce students to primary literature in a multidisciplinary field, and 3) when applicable, to address cultural/historical/mythological perspectives that might alter societal norms and pressures and influence the impact of the biological processes of behavior modification by infections. PMID- 25838808 TI - Exercises in Anatomy, Connectivity, and Morphology using Neuromorpho.org and the Allen Brain Atlas. AB - Laboratory instruction of neuroscience is often limited by the lack of physical resources and supplies (e.g., brains specimens, dissection kits, physiological equipment). Online databases can serve as supplements to material labs by providing professionally collected images of brain specimens and their underlying cellular populations with resolution and quality that is extremely difficult to access for strictly pedagogical purposes. We describe a method using two online databases, the Neuromorpho.org and the Allen Brain Atlas (ABA), that freely provide access to data from working brain scientists that can be modified for laboratory instruction/exercises. Neuromorpho.org is the first neuronal morphology database that provides qualitative and quantitative data from reconstructed cells analyzed in published scientific reports. The Neuromorpho.org database contains cross species and multiple neuronal phenotype datasets which allows for comparative examinations. The ABA provides modules that allow students to study the anatomy of the rodent brain, as well as observe the different cellular phenotypes that exist using histochemical labeling. Using these tools in conjunction, advanced students can ask questions about qualitative and quantitative neuronal morphology, then examine the distribution of the same cell types across the entire brain to gain a full appreciation of the magnitude of the brain's complexity. PMID- 25838807 TI - Undergraduate Neuropharmacology: A Model for Delivering College-Level Neuroscience to High School Students in situ. AB - Our university course for non-majors (Biology 100) on the neurobiology of drug addiction was recently retooled for delivery at high schools around the state of Washington in order to engage younger students in the study of psychoactive drugs. Many of these students are earning both high school and university credits (dual-enrollment). This paper outlines the course design principles we used to ensure that high school students are earning valid college credits. We present an analysis of learning gains experienced by both university and high school students as measured by before and after course knowledge surveys. We also describe how assessment strategies used for on-campus students have been transferred to our high school partner teachers and how generous interchange and observation ensure that the high school students are engaging deeply in their study of neuroscience. Indeed, many have had a transformative experience that inspires them to contemplate the field of neuroscience as they transition into university study. PMID- 25838809 TI - A changing tide: what the new 'foundations of behavior' section of the 2015 medical college admissions test(r) might mean for undergraduate neuroscience programs. AB - Each year over 50,000 college students and alumni take the Medical College Admissions Test(r) (MCAT) and apply for admissions to medical school. After an extensive review process, the MCAT has undergone a major revision in form and content in order to better reflect the competencies medical students will need to be successful in their training and practice. Starting in April 2015, for the first time since the test's inception, the MCAT will include social and behavioral sciences content. The new section of the MCAT exam titled "The Psychological, Social and Biological Foundations of Behavior" will test pre health competencies that combine content knowledge with scientific inquiry and reasoning skills. Anticipating growing interest in curriculum related to the new competency based content on the exam, the AAMC (Association of American Medical Colleges) established the Pre-health Collection within MedEdPORTAL's iCollaborative, a free repository of teaching resources. This online space gives faculty members the opportunity to share access to instructional resources in order to prepare or revise courses to include pre-health competencies. As a result of the increased content related to mind-body connections, undergraduate pre-medical students will be more likely to enroll in neuroscience courses to learn these competencies, or declare neuroscience majors, as the typical neuroscience major course requirements now meet most of the suggested pre requisite competencies for medical school. PMID- 25838810 TI - There are so many I want to thank: Inviting the neuroscience classroom into Hollywood(.). PMID- 25838811 TI - Enhanced Conformational Sampling Using Replica Exchange with Collective-Variable Tempering. AB - The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strengths of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers of individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. The method is tested on alanine dipeptide and applied to the difficult problem of conformational sampling in a tetranucleotide. PMID- 25838812 TI - HER-2 assessment in formalin-fixed paraffin-embedded breast cancer tissue by well based reverse phase protein array. AB - BACKGROUND: The human epidermal growth factor receptor-2 (HER-2) expression level is a critical element for determining the prognosis and management of breast cancer. HER-2 targeted therapy in breast cancer depends on the reliable assessment of HER-2 expression status but current standard methods are lacking a rigorous quantitative assay. To address this challenge, we developed an assessment of HER-2 expression method by well-based reverse phase protein array (RPPA). RESULTS: Well-based RPPA is based on a robust protein isolation methodology paired with a novel electrochemiluminescence detection system. HER-2 value of well-based RPPA significantly correlated with dot blotting results (R(2) = 0.939). By well-based RPPA, we successfully detected HER-2 expression in 76 human breast formalin-fixed paraffin-embedded tissue samples. We observed 93.4% (71/76) concordance between well-based RPPA and current HER-2 immunohistochemical assessment guideline. When the cutoff level of HER-2 value was set to 0.689 (HER 2/GAPDH) on the basis of receiver-operating characteristic curve, the area under the curve was 0.975 (95% CI, 0.941-1.000). Sensitivity and specificity of well based RPPA was 92.1% and 94.7%, respectively. CONCLUSIONS: HER-2 value by well based RPPA was correlated with the current HER-2 status guideline, suggesting that this normalized HER-2 assessment may offer advantages over unnormalized current immunohistochemical assessment methods. PMID- 25838813 TI - Differentiation of mucinous from non-mucinous pancreatic cyst fluid using dual stained, 1 dimensional polyacrylamide gel electrophoresis. AB - BACKGROUND: Pancreatic cysts are being increasingly identified in patients. Mucinous cysts have malignant potential whereas non-mucinous cysts do not. Distinguishing potentially malignant cysts from harmless ones by the characterization of cyst fluid contents remains a difficult problem. This study was undertaken to determine whether cyst fluid mucin glycoprotein analysis could differentiate mucinous from non-mucinous pancreatic cysts. METHODS: Cyst fluid from 28 patients who underwent resection of a pancreatic cyst was used for the study. In each case the type of cyst was histologically identified. One dimensional SDS polyacrylamide gel electrophoresis (1D-SDS PAGE) was performed on cyst fluid samples. For the detection of the separated proteins, we employed a novel dual staining technique. The gel was first stained with periodic acid Schiff (PAS), a mucin histochemical stain followed by a secondary protein staining with Simply Blue Safestain (Invitrogen). RESULTS: Visual scoring (based on the presence of mucins) gave a sensitivity of 95%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 88% for prediction of mucinous histology. CONCLUSIONS: One dimensional SDS polyacrylamide gel electrophoresis of pancreatic cyst fluid, followed by mucin (PAS) and protein (Simply Blue Safestain) staining, provides a means of concentrating and visualizing mucins, which allows the accurate differentiation of mucinous from non-mucinous histology in pancreatic cysts. PMID- 25838814 TI - An integrated quantification method to increase the precision, robustness, and resolution of protein measurement in human plasma samples. AB - BACKGROUND: Current quantification methods for mass spectrometry (MS)-based proteomics either do not provide sufficient control of variability or are difficult to implement for routine clinical testing. RESULTS: We present here an integrated quantification (InteQuan) method that better controls pre-analytical and analytical variability than the popular quantification method using stable isotope-labeled standard peptides (SISQuan). We quantified 16 lung cancer biomarker candidates in human plasma samples in three assessment studies, using immunoaffinity depletion coupled with multiple reaction monitoring (MRM) MS. InteQuan outperformed SISQuan in precision in all three studies and tolerated a two-fold difference in sample loading. The three studies lasted over six months and encountered major changes in experimental settings. Nevertheless, plasma proteins in low ng/ml to low MUg/ml concentrations were measured with a median technical coefficient of variation (CV) of 11.9% using InteQuan. The corresponding median CV using SISQuan was 15.3% after linear fitting. Furthermore, InteQuan surpassed SISQuan in measuring biological difference among clinical samples and in distinguishing benign versus cancer plasma samples. CONCLUSIONS: We demonstrated that InteQuan is a simple yet robust quantification method for MS-based quantitative proteomics, especially for applications in biomarker research and in routine clinical testing. PMID- 25838816 TI - Acoustic CR Neuromodulation Therapy for Subjective Tonal Tinnitus: A Review of Clinical Outcomes in an Independent Audiology Practice Setting. AB - OBJECTIVE: To describe the quantitative treatment outcomes of patients undergoing acoustic coordinated reset (CR) neuromodulation at a single independent audiology practice over a 22- to 26-week period as part of an open label, non-randomized, non-controlled observational study. METHODS: Sixty-six patients with subjective tonal tinnitus were treated with acoustic CR neuromodulation with a retrospective review of patient records being performed in order to identify changes of visual analog scale (VAS, n = 66) and in the score of the tinnitus handicap questionnaire (THQ, n = 51). Patients had their tinnitus severity recorded prior to the initiation of therapy using the tinnitus handicap inventory in order to categorize patients into slight up to catastrophic impact categories. THQ and VAS for tinnitus loudness/annoyance were obtained at the patient's initial visit, at 10-14 and 22-26 weeks. RESULTS: Visual analog scale scores were significantly improved, demonstrating a 25.8% mean reduction in tinnitus loudness and a 32% mean reduction in tinnitus annoyance with a clinically significant reduction in percept loudness and annoyance being recorded in 59.1 and 72.7% of the patient group. THQ scores were significantly improved by 19.4% after 22-26 weeks of therapy compared to baseline. CONCLUSION: Acoustic CR neuromodulation therapy appears to be a practical and promising treatment for subjective tonal tinnitus. However, due to the lack of a control group it is difficult to reach an absolute conclusion regarding to what extent the observed effects are related directly to the acoustic CR neuromodulation therapy. Also, as the observed patient group was made up of paying clients it is unknown as to whether this could have caused any additional placebo like effects to influence the final results. PMID- 25838815 TI - Proteomic analysis of human follicular fluid from fertile women. AB - BACKGROUND: Follicular fluid is a unique biological fluid in which the critical events of oocyte and follicular maturation and somatic cell-germ cell communication occur. Because of the intimate proximity of follicular fluid to the maturing oocyte, this fluid provides a unique window into the processes occurring during follicular maturation. A thorough identification of the specific components within follicular fluid may provide a better understanding of intrafollicular signaling, as well as reveal potential biomarkers of oocyte health for women undergoing assisted reproductive treatment. In this study, we used high and low pH HPLC peptide separations followed by mass spectrometry to perform a comprehensive proteomic analysis of human follicular fluid from healthy ovum donors. Next, using samples from a second set of patients, an isobaric mass tagging strategy for quantitative analysis was used to identify proteins with altered abundances after hCG treatment. RESULTS: A total of 742 follicular fluid proteins were identified in healthy ovum donors, including 413 that have not been previously reported. The proteins belong to diverse functional groups including insulin growth factor and insulin growth factor binding protein families, growth factor and related proteins, receptor signaling, defense/immunity, anti-apoptotic proteins, matrix metalloprotease related proteins, and complement activity. In a quantitative analysis, follicular fluid samples from age-matched women undergoing in vitro fertilization oocyte retrieval were compared and 17 follicular fluid proteins were found at significantly altered levels (p < 0.05) between pre-hCG and post-hCG samples. These proteins belong to a variety of functional processes, including protease inhibition, inflammation, and cell adhesion. CONCLUSIONS: This database of FF proteins significantly extends the known protein components present during the peri-ovulatory period and provides a useful basis for future studies comparing follicular fluid proteomes in various fertility, disease, and environmental exposure conditions. We identified 17 differentially expressed proteins after hCG treatment and together these data showed the feasibility for defining biomarkers that illuminate how the ovarian follicle microenvironment is altered in various infertility-related conditions. PMID- 25838817 TI - A robust computational technique for model order reduction of two-time-scale discrete systems via genetic algorithms. AB - A robust computational technique for model order reduction (MOR) of multi-time scale discrete systems (single input single output (SISO) and multi-input multioutput (MIMO)) is presented in this paper. This work is motivated by the singular perturbation of multi-time-scale systems where some specific dynamics may not have significant influence on the overall system behavior. The new approach is proposed using genetic algorithms (GA) with the advantage of obtaining a reduced order model, maintaining the exact dominant dynamics in the reduced order, and minimizing the steady state error. The reduction process is performed by obtaining an upper triangular transformed matrix of the system state matrix defined in state space representation along with the elements of B, C, and D matrices. The GA computational procedure is based on maximizing the fitness function corresponding to the response deviation between the full and reduced order models. The proposed computational intelligence MOR method is compared to recently published work on MOR techniques where simulation results show the potential and advantages of the new approach. PMID- 25838818 TI - Fuzzy emotional semantic analysis and automated annotation of scene images. AB - With the advances in electronic and imaging techniques, the production of digital images has rapidly increased, and the extraction and automated annotation of emotional semantics implied by images have become issues that must be urgently addressed. To better simulate human subjectivity and ambiguity for understanding scene images, the current study proposes an emotional semantic annotation method for scene images based on fuzzy set theory. A fuzzy membership degree was calculated to describe the emotional degree of a scene image and was implemented using the Adaboost algorithm and a back-propagation (BP) neural network. The automated annotation method was trained and tested using scene images from the SUN Database. The annotation results were then compared with those based on artificial annotation. Our method showed an annotation accuracy rate of 91.2% for basic emotional values and 82.4% after extended emotional values were added, which correspond to increases of 5.5% and 8.9%, respectively, compared with the results from using a single BP neural network algorithm. Furthermore, the retrieval accuracy rate based on our method reached approximately 89%. This study attempts to lay a solid foundation for the automated emotional semantic annotation of more types of images and therefore is of practical significance. PMID- 25838819 TI - Ginger and its constituents: role in prevention and treatment of gastrointestinal cancer. AB - Gastrointestinal (GI) cancer, a cancer of different organs of the digestive system, is one of the most common cancers around the world. The incidence and death rate of some of these cancers are very high. Although a large variety of chemotherapeutic agents have been introduced since the last few decades to combat GI cancer, most of them are very expensive and have side effects. Therefore, the compounds derived from natural sources, which are considered to be safe and cost effective, are needed. Ginger (Zingiber officinale) is one of the most widely used natural products consumed as a spice and medicine for treating nausea, dysentery, heartburn, flatulence, diarrhea, loss of appetite, infections, cough, and bronchitis. Experimental studies showed that ginger and its active components including 6-gingerol and 6-shogaol exert anticancer activities against GI cancer. The anticancer activity of ginger is attributed to its ability to modulate several signaling molecules like NF-kappaB, STAT3, MAPK, PI3K, ERK1/2, Akt, TNF alpha, COX-2, cyclin D1, cdk, MMP-9, survivin, cIAP-1, XIAP, Bcl-2, caspases, and other cell growth regulatory proteins. In this review, the evidences for the chemopreventive and chemotherapeutic potential of ginger extract and its active components using in vitro, animal models, and patients have been described. PMID- 25838820 TI - The genetic predisposition and its impact on the diabetes mellitus development in patients with alcoholic chronic pancreatitis. AB - The most common cause of chronic pancreatitis (CP) is alcohol abuse. The aim of the present study was to identify patients with genetic predisposition to CP abusing alcohol. The question posed was whether CP manifests at a younger age and diabetes mellitus develops earlier in individuals with genetic predisposition. The study encompassed 79 patients with alcoholic chronic pancreatitis (ACP) and control group (100 persons). The following mutations were determined: R122H and N29I of PRSS1 and N34S of SPINK1 as well as E366K and E288V of SERPINA 1. No R122H and N291 mutations were observed in the group of ACP patients and in controls. Moreover, there was no E288V mutation. In 79 ACP patients, six SPINK 1 (N34S/wt) mutations were observed. In the control group, one heterozygous SPINK 1N34S gene mutation was found (P = 0.0238). Two PiZ mutations were identified in patients with ACP and one analogical mutation in controls. Amongst patients with ACP as well as SPINK1 and PiZ mutations, the onset of disease was observed earlier and developed earlier. The prevalence of SPINK1 mutation is higher in patients with ACP than in healthy populations. This mutation together with the effects of alcohol accelerates the development of ACP and of diabetes mellitus. PMID- 25838821 TI - Somatostatin analogs in the medical management of occult bleeding of the lower digestive tract. AB - The management of occult bleeding from the lower digestive tract can be very challenging. In cases of identified angiodysplasia, the first line management options can be limited by a number of clinical or anatomical factors and an alternative approach might be required, including the use of medications. Somatostatin analogs have been considered as an effective and well-tolerated alternative management option in a number of cases where the endoscopic therapeutic approach is not practical or is unsuccessful, in patients with coagulopathies or who need concomitant anticoagulation or antiplatelet treatment. Despite the lack of double-blinded randomized placebo-control trials and despite the limitations of the available evidence in the literature, including small sample size, variable dosing, and administration routes, there is a consistent agreement in the literature that somatostatin analogs are a safe, well-tolerated, and effective therapeutic option for managing refractory or occult bleeding from the lower digestive tract, with particular reference to patients with angiodysplasia, where endoscopic or surgical management is either not feasible or unsuccessful and other pharmacological options are not preferred. PMID- 25838822 TI - Landscape ecology and epidemiology of malaria associated with rubber plantations in Thailand: integrated approaches to malaria ecotoping. AB - The agricultural land use changes that are human-induced changes in agroforestry ecosystems and in physical environmental conditions contribute substantially to the potential risks for malaria transmission in receptive areas. Due to the pattern and extent of land use change, the risks or negatively ecosystemic outcomes are the results of the dynamics of malaria transmission, the susceptibility of human populations, and the geographical distribution of malaria vectors. This review focused basically on what are the potential effects of agricultural land use change as a result of the expansion of rubber plantations in Thailand and how significant the ecotopes of malaria-associated rubber plantations (MRP) are. More profoundly, this review synthesized the novel concepts and perspectives on applied landscape ecology and epidemiology of malaria, as well as approaches to determine the degree to which an MRP ecotope as fundamental landscape scale can establish malaria infection pocket(s). Malaria ecotoping encompasses the integrated approaches and tools applied to or used in modeling malaria transmission. The scalability of MRP ecotope depends upon its unique landscape structure as it is geographically associated with the infestation or reinfestation of Anopheles vectors, along with the attributes that are epidemiologically linked with the infections. The MRP ecotope can be depicted as the hotspot such that malaria transmission is modeled upon the MRP factors underlying human settlements and movement activities, health behaviors, land use/land cover change, malaria vector population dynamics, and agrienvironmental and climatic conditions. The systemic and uniform approaches to malaria ecotoping underpin the stratification of the potential risks for malaria transmission by making use of remotely sensed satellite imagery or landscape aerial photography using unmanned aerial vehicle (UAV), global positioning systems (GPS), and geographical information systems (GIS). PMID- 25838823 TI - Incidental adrenal enlargement: an overview from a retrospective study in a chinese population. AB - Aim. To investigate incidental adrenal enlargement clinical characteristics and functional status and analyze functional lesion risk factors. Materials and Methods. This retrospective study included 578 patients with adrenal imaging features showing enlargement. Incidental adrenal enlargement cases (78) were considered eligible. Demographics, functional diagnosis, adrenal imaging features, and concomitant diseases were analyzed. Results. The number of adrenal enlargements and proportion of incidental adrenal enlargement increased each year. Mean patient age was 50.32 years. Thirty-nine cases had unilateral enlargement on the left side and 3 on the right side; 36 had bilateral enlargement. Routine medical checkup was found to have the greatest chance (43.59%) of revealing clinical onsets leading to discovery. Biochemical and functional evaluation revealed 54 (69.23%) cases of nonfunctional lesions, 12 (15.38%) of subclinical Cushing syndrome, 6 (7.69%) of primary hyperaldosteronism, 1 (1.28%) of metastasis, and 5 (6.41%) of unknown functional status. Nodular adrenal enlargement (OR, 7.306; 95% CI, 1.727-28.667; P = 0.006) was a risk factor for functional lesions. Age and lesion location were not significant factors. Conclusion. Incidental adrenal enlargement is a frequent radiographic finding and is accompanied by diverse clinical factors that require proper evaluation and management. Nodular adrenal enlargement was a risk factor. PMID- 25838824 TI - Recent developments in sweat analysis and its applications. AB - Currently, the clinical use of sweat as biofluid is limited. The collection of sweat and its analysis for determining ethanol, drugs, ions, and metals have been encompassed in this review article to assess the merits of sweat compared to other biofluids, for example, blood or urine. Moreover, sweat comprises various biomarkers of different diseases including cystic fibrosis and diabetes. Additionally, the normalization of sampled volume of sweat is also necessary for getting efficient and useful results. PMID- 25838825 TI - Stability-indicating HPLC determination of gemcitabine in pharmaceutical formulations. AB - A simple, sensitive, inexpensive, and rapid stability indicating high performance liquid chromatographic method has been developed for determination of gemcitabine in injectable dosage forms using theophylline as internal standard. Chromatographic separation was achieved on a Phenomenex Luna C-18 column (250 mm * 4.6 mm; 5MU) with a mobile phase consisting of 90% water and 10% acetonitrile (pH 7.00 +/- 0.05). The signals of gemcitabine and theophylline were recorded at 275 nm. Calibration curves were linear in the concentration range of 0.5-50 MUg/mL. The correlation coefficient was 0.999 or higher. The limit of detection and limit of quantitation were 0.1498 and 0.4541 MUg/mL, respectively. The inter- and intraday precision were less than 2%. Accuracy of the method ranged from 100.2% to 100.4%. Stability studies indicate that the drug was stable to sunlight and UV light. The drug gives 6 different hydrolytic products under alkaline stress and 3 in acidic condition. Aqueous and oxidative stress conditions also degrade the drug. Degradation was higher in the alkaline condition compared to other stress conditions. The robustness of the methods was evaluated using design of experiments. Validation reveals that the proposed method is specific, accurate, precise, reliable, robust, reproducible, and suitable for the quantitative analysis. PMID- 25838826 TI - In vitro evaluation of bioactivity of chemically deposited hydroxyapatite on polyether ether ketone. AB - Polyether ether ketone (PEEK) is considered the best alternative material for titanium for spinal fusion cage implants due to its low elasticity modulus and radiolucent property. The main problem of PEEK is its bioinert properties. Coating with hydroxyapatite (HA) showed very good improvement in bioactivity of the PEEK implants. However the existing methods for deposition of HA have some disadvantages and damage the PEEK substrate. In our previous study a new method for deposition of HA on PEEK was presented. In this study cell proliferation of mesenchymal stem cell and apatite formation in simulated body fluid (SBF) tests were conducted to probe the effect of this new method in improvement of the bioactivity of PEEK. The mesenchymal stem cell proliferation result showed better cells proliferation on the treated layer in comparison with untreated PEEK. The apatite formation results showed the growth of the HA on the treated PEEK but there was not any sight of the growth of HA on the untreated PEEK even after 2 weeks. The results showed the new method of the HA deposition improved the bioactivity of the treated PEEK in comparison with the bare PEEK. PMID- 25838827 TI - Primary meningococcal polyarthritis in an adult woman. AB - Primary joint infection caused by the Gram-negative bacteria Neisseria meningitidis is rare. Normally, joint involvement comes secondary to meningitis or severe sepsis caused by this agent. When primary arthritis is seen, monoarthritis is the most common presentation. A meningococcal polyarthritis is described in less than 10 case reports according to current literature. This case report aims to briefly review this rare clinical event in an adult woman with no previous history of rheumatological disease. Early diagnosis of polyarthritis caused by meningococcal bacteria usually present a good prognosis when properly treated. PMID- 25838828 TI - Intravenous administration of bone marrow-derived mesenchymal stem cells induces a switch from classical to atypical symptoms in experimental autoimmune encephalomyelitis. AB - Potent immunosuppressive and regenerative properties of mesenchymal stem cells (MSCs) position them as a novel therapy for autoimmune diseases. This research examines the therapeutic effect of MSCs administration at different disease stages in experimental autoimmune encephalomyelitis (EAE). Classical and atypical scores of EAE, associated with Th1 and Th17 response, respectively, and also Treg lymphocytes, were evaluated. MSCs administration at the onset (EAE+MSConset) induced an important amelioration of the clinical signs and less lasting effect at the peak of EAE (EAE+MSCpeak). No effect was observed when MSCs were applied after EAE stabilization (EAE+MSClate). Surprisingly, EAE atypical signs were detected in EAE+MSCpeak and EAE+MSClate mice. However, no correlation was found in Th17/Th1 ratio. Interestingly, regardless of time administration, MSCs significantly reduced IL-6 and also T-bet, RORgammaT, and Foxp3 mRNA levels in brain samples of EAE mice. The downregulation of IL-6 could restore the well functioning of the blood-brain barrier of EAE mice, correlated with a decreased number of brain infiltrating leukocytes. These results suggest that the inflammatory status is important to be considered for administering MSCs in autoimmune pathologies, leading to a further research to clarify the effect of MSCs for multiple sclerosis. PMID- 25838829 TI - A prospective study of tuberculosis drug susceptibility in sabah, malaysia, and an algorithm for management of isoniazid resistance. AB - Introduction. The burden of tuberculosis is high in eastern Malaysia, and rates of Mycobacterium tuberculosis drug resistance are poorly defined. Our objectives were to determine M. tuberculosis susceptibility and document management after receipt of susceptibility results. Methods. Prospective study of adult outpatients with smear-positive pulmonary tuberculosis (PTB) in Sabah, Malaysia. Additionally, hospital clinicians accessed the reference laboratory for clinical purposes during the study. Results. 176 outpatients were enrolled; 173 provided sputum samples. Mycobacterial culture yielded M. tuberculosis in 159 (91.9%) and nontuberculous Mycobacterium (NTM) in three (1.7%). Among outpatients there were no instances of multidrug resistant M. tuberculosis (MDR-TB). Seven people (4.5%) had isoniazid resistance (INH-R); all were switched to an appropriate second-line regimen for varying durations (4.5-9 months). Median delay to commencement of the second-line regimen was 13 weeks. Among 15 inpatients with suspected TB, 2 had multidrug resistant TB (one extensively drug resistant), 2 had INH-R, and 4 had NTM. Conclusions. Current community rates of MDR-TB in Sabah are low. However, INH-resistance poses challenges, and NTM is an important differential diagnosis in this setting, where smear microscopy is the usual diagnostic modality. To address INH-R management issues in our setting, we propose an algorithm for the treatment of isoniazid-resistant PTB. PMID- 25838830 TI - Sequencing and Phylogenetic Study of Partial NS3 Gene of Iranian GB Virus C/Hepatitis G Virus (HGV) Originated From Hemodialysis Patients in Tehran. AB - BACKGROUND: Hepatitis viruses are one of the most important concerns in the patients on hemodialysis who are at high risk for blood-borne infections. GB virus C (GBV-C)/hepatitis G virus (HGV) is positive-stranded RNA virus with global distribution, which codes structural and nonstructural proteins (such as NS3). OBJECTIVES: Review on literature about Iranian HGV isolates showed that there was no report on sequencing and phylogenetic characteristics of NS3 gene and therefore, this study attempted to answers these challenges. MATERIALS AND METHODS: Briefly, steps followed were as follows: preparation of nucleic acids from three Iranian hemodialysis HGV-positive samples and RNA extraction; reverse transcriptase-PCR (RT-PCR) for amplification of NS3 gene and gel electrophoresis; sequencing and analyzing sequencing data; NCBI Registering; blasting and alignment of sequences; and finally constructing the phylogenetic tree. RESULTS: Nucleotide BLAST results emphasized that most similar sequences to Ir NS3 sequences were those from Europe (Spain, Germany, and the United Kingdom) and the United states and IR sequences were located with five leaves in a branch. In addition, homology of Ir sequences showed96.4% (between IR1 and IR2), 94.9% identity (between IR1 and IR3), and 96.5% identity (between IR2 and IR3).Furthermore, highly variation and significance differences in NS3 between GBC isolates from geographical regions and some little changes in IR sequences were seen. Finally, phylogenetic tree revealed that NS3 genotype of Iranian isolates was probably similar to European countries and USA. CONCLUSIONS: Overall, results of present study were consistent with the data reported earlier base on 5' NTR in Iranian isolates and revealed genotype IR2 is major genotype in Iranian HGV-positive patient. It means there are higher similarities between Iranian and Europe-USA in HGV NS3 gene. PMID- 25838831 TI - The safety of herbal medicine: from prejudice to evidence. PMID- 25838832 TI - Antiviral activity of a zymolytic grain based extract on human immunodeficiency virus type 1 in vitro. AB - Increasing evidence shows that grains may play a role in disease prevention beyond the simple provision of energy and nutrients. It has been reported that some components contained in grains exert their functional effects on viral and bacterial infections and protect against various cancers. However, until now, hardly any intervention studies have investigated the effects of grains or grain based extracts on the inhibition of HIV-1 infection. In this study, the antiviral function of a zymolytic grain based extract (ZGE) was detected in vitro and in rats, and the antiviral mechanism was investigated. Results showed that ZGE had an inhibition effect on HIV-1 infection in vitro with low cytotoxic effects. The study of the mechanism demonstrated that this functional food possibly acted on the viral surface structure protein gp120 which is responsible for cell binding, as well as on the postattachment stage of the virus. The sera of model rats administrated with this food by gavage presented anti-infection abilities against HIV-1 in vitro during a serum concentration associated period of time. These findings provide valuable insights into the application of ZGE on the control of viral load, which may contribute to future anti-HIV treatment with less adverse effects. PMID- 25838833 TI - Traditional Herbal Formula Banhasasim-tang Exerts Anti-Inflammatory Effects in RAW 264.7 Macrophages and HaCaT Keratinocytes. AB - Banhasasim-tang (BHSST) is a Korean traditional herbal formula comprising eight medicinal herbs. The aim of the present study was to investigate the anti inflammatory effect of BHSST using macrophage and keratinocyte cell lines. First, we evaluated the effects of BHSST on inflammatory mediator and cytokine production in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages. BHSST markedly inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin- (IL-) 6. BHSST significantly suppressed the protein expression of toll-like receptor 4 (TLR4) and phosphorylated nuclear factor-kappa B (NF kappaB) p65 in RAW 264.7 cells. Second, we examined whether BHSST influences the production of chemokines and STAT1 phosphorylation in tumor necrosis factor alpha/interferon-gamma TI-stimulated HaCaT keratinocytes. BHSST significantly suppressed the production of RANTES/CCL5, TARC/CCL17, MDC/CCL22, and IL-8 in TI stimulated HaCaT cells. BHSST also suppressed TI-induced phosphorylation of STAT1 in HaCaT cells. These results suggest that BHSST may be useful as an anti inflammatory agent, especially for inflammatory skin diseases. PMID- 25838834 TI - Cytologic diagnosis of adrenal oncocytic pheochromocytoma in a lung cancer patient: Report of a case and review of the literature. AB - Adrenal oncocytic pheochromocytoma is an extremely rare type of pheochromocytoma. To the best of our knowledge, we present the first cytological diagnosis of this variant via fine-needle aspiration in an 81-year-old male patient who was found to have an adrenal mass while undergoing workup of the recently diagnosed lung adenocarcinoma. We describe the cytomorphologic findings in our case and provide a review of the reported cases of adrenal oncocytic pheochromocytoma - all of which appear to be benign, nonfunctional, occur in adults, and have similar morphologic features. The pathologist should be aware of this uncommon diagnostic entity and its potential diagnostic pitfalls. PMID- 25838835 TI - Detection of pAkt protein in imprint cytology of invasive breast cancer: Correlation with HER2/neu, hormone receptors, and other clinicopathological variables. AB - PURPOSE: Akt is a serine/threonine protein kinase and has emerged as a crucial regulator of widely divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Activation of Akt/protein kinase B has been positively associated with human epidermal growth-factor receptor 2 (HER2)/neu overexpression in breast carcinoma and a worse outcome among endocrine treated patients. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. METHODS: Archival tumor tissues from 100 patients with invasive breast carcinoma were analyzed by immunocytochemistry. This study describes the results of immunocytochemical pAkt expression in breast carcinoma imprints, prepared from cut surfaces of freshly removed tumors. Both nuclear and cytoplasmic expressions were evaluated for pAkt. RESULTS: Nuclear and cytoplasmic positive scores of 72% (72/100) and 42% (42/100), respectively, were found. Coexistence of nuclear and cytoplasmic staining was observed in 32 cases (32/100). Nuclear positive staining correlated with HER2/neu overexpression (P = 0.043) and was significantly associated with positive involvement of axillary lymph nodes (P = 0.013). No correlation was found between cytoplasmic pAkt rate and clinicopathological parameters, estrogen receptor, progesterone receptor or HER2/neu expression. CONCLUSIONS: pAkt expression can be evaluated in cytological material and may add valuable information to current prognostic models for breast cancer. pAkt overexpression appears to be linked with potentially aggressive tumor phenotype in invasive breast carcinoma. PMID- 25838836 TI - A novel hybrid dimension reduction technique for undersized high dimensional gene expression data sets using information complexity criterion for cancer classification. AB - Gene expression data typically are large, complex, and highly noisy. Their dimension is high with several thousand genes (i.e., features) but with only a limited number of observations (i.e., samples). Although the classical principal component analysis (PCA) method is widely used as a first standard step in dimension reduction and in supervised and unsupervised classification, it suffers from several shortcomings in the case of data sets involving undersized samples, since the sample covariance matrix degenerates and becomes singular. In this paper we address these limitations within the context of probabilistic PCA (PPCA) by introducing and developing a new and novel approach using maximum entropy covariance matrix and its hybridized smoothed covariance estimators. To reduce the dimensionality of the data and to choose the number of probabilistic PCs (PPCs) to be retained, we further introduce and develop celebrated Akaike's information criterion (AIC), consistent Akaike's information criterion (CAIC), and the information theoretic measure of complexity (ICOMP) criterion of Bozdogan. Six publicly available undersized benchmark data sets were analyzed to show the utility, flexibility, and versatility of our approach with hybridized smoothed covariance matrix estimators, which do not degenerate to perform the PPCA to reduce the dimension and to carry out supervised classification of cancer groups in high dimensions. PMID- 25838837 TI - Predictive models of tumour response to treatment using functional imaging techniques. PMID- 25838838 TI - Automatic segmentation of colon in 3D CT images and removal of opacified fluid using cascade feed forward neural network. AB - PURPOSE: Colon segmentation is an essential step in the development of computer aided diagnosis systems based on computed tomography (CT) images. The requirement for the detection of the polyps which lie on the walls of the colon is much needed in the field of medical imaging for diagnosis of colorectal cancer. METHODS: The proposed work is focused on designing an efficient automatic colon segmentation algorithm from abdominal slices consisting of colons, partial volume effect, bowels, and lungs. The challenge lies in determining the exact colon enhanced with partial volume effect of the slice. In this work, adaptive thresholding technique is proposed for the segmentation of air packets, machine learning based cascade feed forward neural network enhanced with boundary detection algorithms are used which differentiate the segments of the lung and the fluids which are sediment at the side wall of colon and by rejecting bowels based on the slice difference removal method. The proposed neural network method is trained with Bayesian regulation algorithm to determine the partial volume effect. RESULTS: Experiment was conducted on CT database images which results in 98% accuracy and minimal error rate. CONCLUSIONS: The main contribution of this work is the exploitation of neural network algorithm for removal of opacified fluid to attain desired colon segmentation result. PMID- 25838839 TI - Sorting signed permutations by short operations. AB - BACKGROUND: During evolution, global mutations may alter the order and the orientation of the genes in a genome. Such mutations are referred to as rearrangement events, or simply operations. In unichromosomal genomes, the most common operations are reversals, which are responsible for reversing the order and orientation of a sequence of genes, and transpositions, which are responsible for switching the location of two contiguous portions of a genome. The problem of computing the minimum sequence of operations that transforms one genome into another - which is equivalent to the problem of sorting a permutation into the identity permutation - is a well-studied problem that finds application in comparative genomics. There are a number of works concerning this problem in the literature, but they generally do not take into account the length of the operations (i.e. the number of genes affected by the operations). Since it has been observed that short operations are prevalent in the evolution of some species, algorithms that efficiently solve this problem in the special case of short operations are of interest. RESULTS: In this paper, we investigate the problem of sorting a signed permutation by short operations. More precisely, we study four flavors of this problem: (i) the problem of sorting a signed permutation by reversals of length at most 2; (ii) the problem of sorting a signed permutation by reversals of length at most 3; (iii) the problem of sorting a signed permutation by reversals and transpositions of length at most 2; and (iv) the problem of sorting a signed permutation by reversals and transpositions of length at most 3. We present polynomial-time solutions for problems (i) and (iii), a 5-approximation for problem (ii), and a 3-approximation for problem (iv). Moreover, we show that the expected approximation ratio of the 5 approximation algorithm is not greater than 3 for random signed permutations with more than 12 elements. Finally, we present experimental results that show that the approximation ratios of the approximation algorithms cannot be smaller than 3. In particular, this means that the approximation ratio of the 3-approximation algorithm is tight. PMID- 25838841 TI - Assessment of mental distress among prison inmates in Ghana's correctional system: a cross-sectional study using the Kessler Psychological Distress Scale. AB - BACKGROUND: Applying global estimates of the prevalence of mental disorders suggests that about 2.4 million Ghanaians have some form of psychiatric distress. Despite the facts that relatively little community-based treatment is available (only 18 psychiatrists are known to actively practice in Ghana), and that mental disorders are more concentrated among the incarcerated, there is no known research on mental disorders in Ghana prisons, and no forensic mental health services available to those who suffer from them. This study sought to determine the rate of mental distress among prisoners in Ghana. METHODS: This cross sectional research used the Kessler Psychological Distress Scale to estimate the rates and severity of non-specific psychological distress among a stratified probability sample of 89 male and 11 female prisoners in one of the oldest correctional facilities in the country. Fisher's exact test was used to determine the rates of psychological distress within the study population. RESULTS: According to the Kessler Scale, more than half of all respondents had moderate to severe mental distress in the four weeks preceding their interviews. Nearly 70% of inmates with only a primary education had moderate to severe mental distress. Though this was higher than the rates among inmates with more education, it exceeded the rates for those with no education. CONCLUSIONS: The high rate of moderate to severe mental distress among the inmates in this exploratory study should serve as baseline for further studies into mental disorders among the incarcerated persons in Ghana. Future research should use larger samples, include more prison facilities, and incorporate tools that can identify specific mental disorders. PMID- 25838840 TI - MagiCMicroRna: a web implementation of AgiMicroRna using shiny. AB - BACKGROUND: MicroRNA expression can be quantified using sequencing techniques or commercial microRNA-expression arrays. Recently, the AgiMicroRna R-package was published that enabled systematic preprocessing and statistical analysis for Agilent microRNA arrays. Here we describe MagiCMicroRna, which is a user-friendly web interface for this package, together with a new filtering approach. RESULTS: We used MagiCMicroRna to normalize and filter an Agilent miRNA microarray dataset of cancerous and normal tissues from 14 different patients. With the standard filtering procedure, 250 out of 817 microRNAs remained, whereas the new group specific filtering approach resulted in broader datasets for further analysis in most groups (>279 microRNAs remaining). CONCLUSIONS: The user-friendly web interface of MagiCMicroRna enables researchers to normalize and filter Agilent microarrays by the click of one button. Furthermore, MagiCMicroRna provides flexibility in choosing the filtering method. The new group-specific filtering approach lead to an increased number and additional tissue-specific microRNAs remaining for subsequent analysis compared to the standard procedure. The MagiCMicroRna web interface and source code can be downloaded from https://bitbucket.org/mutgx/magicmicrorna.git. PMID- 25838842 TI - Differences in early and late stages of information processing between slow versus fast participants. AB - The human brain is a system consisting of various interconnected neural networks, with functional specialization coexisting with functional integration occurring both; temporally and spatially at many levels. The current study ranked and compared fast and slow participants in processing information by assessing latency and amplitude of early and late Event-Related Potential (ERP) components, including P200, N200, Premotor Potential (PMP) and P300. In addition, the Reaction Time (RT) of participants was compared and related to the respective ERP components. For this purpose, twenty right-handed and healthy individuals were subjected to a classical ERP "Oddball" paradigm. Principal Component Analysis (PCA) and Discriminant Function analyses (DFA) used PRE components and the Reaction Time (RT) to classify individuals. Our results indicate that latencies of P200 (O2 electrode), N200 (O2), PMP (C3) and P300 (Pz) components are significantly reduced in the group of fast responding participants. In addition, the P200 amplitude is significantly increased in the group of fast responding participants. Based on these findings, we suggest that the ERP is able to detect even minimal impairments, in the processing of somatosensory information and cognitive and motor stages. Hence, the study of ERP might also be capable of assessing sensorimotor dysfunctions in healthy old-aged people and in neuropsychiatric patients (suffering from dementia, Parkinson's disease, and other neurological disorders). PMID- 25838844 TI - Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome. AB - BACKGROUND: KBG syndrome, a rare autosomal disorder characterised by distinctive craniofacial and skeletal features and developmental delay, is caused by haploinsufficiency of the ANKRD11 gene. RESULTS: Here we describe two siblings with multiple symptoms characteristic of KBG and their mother with a milder phenotype. In the siblings, array-based comparative genomic hybridization (array CGH) identified an intragenic microduplication affecting ANKRD11 that was absent from the parents' array CGH profiles. Microsatellite analysis revealed the maternal origin of the rearrangement and interphase fluorescent in situ hybridization (i-FISH) experiments identified the rearrangement in low-level mosaicism in the mother. Molecular characterisation of the duplication allele demonstrated the presence of two mutant ANKRD11 transcripts containing a premature stop codon and predicting a truncated non-functional protein. CONCLUSIONS: Similarly to deletions and point mutations, this novel pathogenetic rearrangement causes haploinsufficiency of ANKRD11, resulting in KBG syndrome. PMID- 25838843 TI - Changes in the theta band coherence during motor task after hand immobilization. AB - Many different factors can temporarily or permanently impair movement and impairs cortical organization, e.g. hand immobilization. Such changes have been widely studied using electroencephalography. Within this context, we have investigated the immobilization effects through the theta band coherence analysis, in order to find out whether the immobilization period causes any changes in the inter and intra-hemispheric coherence within the cerebral cortex, as well as to observe whether the theta band provides any information about the neural mechanisms involved during the motor act. We analyzed the cortical changes that occurred after 48 hours of hand immobilization. The theta band coherence was study through electroencephalography in 30 healthy subjects, divided into two groups (control and experimental). Within both groups, the subjects executed a task involving flexion and extension of the index finger, before and after 48 hours. The experimental group, however, was actually submitted to hand immobilization. We were able to observe an increase in the coupling within the experimental group in the frontal, parietal and temporal regions, and a decrease in the motor area. In order to execute manual tasks after some time of movement restriction, greater coherence is present in areas related to attention, movement preparation and sensorimotor integration processes. These results may contribute to a detailed assessment of involved neurophysiological mechanism in motor act execution. PMID- 25838845 TI - The first case of 38,XX (SRY-positive) disorder of sex development in a cat. AB - BACKGROUND: SRY-positive XX testicular disorder of sex development (DSD) caused by X;Y translocations was not yet reported in domestic animals. In humans it is rarely diagnosed and a majority of clinical features resemble those which are typical for Klinefelter syndrome (KS). Here we describe the first case of SRY positive XX DSD in a tortoiseshell cat with a rudimentary penis and a lack of scrotum. RESULTS: Molecular analysis showed the presence of two Y-linked genes (SRY and ZFY) and a normal sequence of the SRY gene. Application of classical cytogenetic techniques revealed two X chromosomes (38,XX), but further FISH studies with the use of the whole X chromosome painting probe and BAC probes specific to the Yp chromosome facilitated identification of Xp;Yp translocation. The SRY gene was localised at a distal position of Xp. The karyotype of the studied case was described as: 38,XX.ish der(X)t(X;Y)(p22;p12)(SRY+). Moreover, the X inactivation status assessed by a sequential R-banding and FISH with the SRY-specific probe showed a random inactivation of the derivative X(SRY) chromosome. CONCLUSIONS: Our study showed that among DSD tortoiseshell cats, apart from XXY trisomy and XX/XY chimerism, also SRY-positive XX cases may occur. It is hypothesized that the extremely rare occurrence of this abnormality in domestic animals, when compared with humans, may be associated with a different organisation of the Yp arm in these species. PMID- 25838846 TI - Principles of Chemical Bonding and Band Gap Engineering in Hybrid Organic Inorganic Halide Perovskites. AB - The performance of solar cells based on hybrid halide perovskites has seen an unparalleled rate of progress, while our understanding of the underlying physical chemistry of these materials trails behind. Superficially, CH3NH3PbI3 is similar to other thin-film photovoltaic materials: a semiconductor with an optical band gap in the optimal region of the electromagnetic spectrum. Microscopically, the material is more unconventional. Progress in our understanding of the local and long-range chemical bonding of hybrid perovskites is discussed here, drawing from a series of computational studies involving electronic structure, molecular dynamics, and Monte Carlo simulation techniques. The orientational freedom of the dipolar methylammonium ion gives rise to temperature-dependent dielectric screening and the possibility for the formation of polar (ferroelectric) domains. The ability to independently substitute on the A, B, and X lattice sites provides the means to tune the optoelectronic properties. Finally, ten critical challenges and opportunities for physical chemists are highlighted. PMID- 25838848 TI - [Tracheobronchial foreign bodies in adults]. PMID- 25838849 TI - [Evaluation and analysis of insomnia in chronic hemodialysis]. PMID- 25838847 TI - Detailed Characterization of a Nanosecond-Lived Excited State: X-ray and Theoretical Investigation of the Quintet State in Photoexcited [Fe(terpy)2]2. AB - Theoretical predictions show that depending on the populations of the Fe 3d xy , 3d xz , and 3d yz orbitals two possible quintet states can exist for the high spin state of the photoswitchable model system [Fe(terpy)2]2+. The differences in the structure and molecular properties of these 5B2 and 5E quintets are very small and pose a substantial challenge for experiments to resolve them. Yet for a better understanding of the physics of this system, which can lead to the design of novel molecules with enhanced photoswitching performance, it is vital to determine which high-spin state is reached in the transitions that follow the light excitation. The quintet state can be prepared with a short laser pulse and can be studied with cutting-edge time-resolved X-ray techniques. Here we report on the application of an extended set of X-ray spectroscopy and scattering techniques applied to investigate the quintet state of [Fe(terpy)2]2+ 80 ps after light excitation. High-quality X-ray absorption, nonresonant emission, and resonant emission spectra as well as X-ray diffuse scattering data clearly reflect the formation of the high-spin state of the [Fe(terpy)2]2+ molecule; moreover, extended X-ray absorption fine structure spectroscopy resolves the Fe ligand bond-length variations with unprecedented bond-length accuracy in time resolved experiments. With ab initio calculations we determine why, in contrast to most related systems, one configurational mode is insufficient for the description of the low-spin (LS)-high-spin (HS) transition. We identify the electronic structure origin of the differences between the two possible quintet modes, and finally, we unambiguously identify the formed quintet state as 5E, in agreement with our theoretical expectations. PMID- 25838850 TI - [Vascular leiomyoma of the forearm: presentation of a case report and review of literature]. PMID- 25838851 TI - [Very rare association: femoral shaft fracture associated with ipsilateral Hoffa fracture]. PMID- 25838852 TI - [Factors associated with tuberculosis in children at the University Hospital Centre Mother-Child Tsaralalana, Antananarivo: a case-control study]. PMID- 25838853 TI - [A palmoplantar pustulosis]. PMID- 25838854 TI - [Circumscribed aplasia cutis congenita of the scalp in a Rwandan child: about an observation]. PMID- 25838855 TI - Challenges in the management of the child with Duchenne muscular dystrophy in a resource poor setting:a case report. AB - Duchenne muscular dystrophy is a progressive genetic disease with no cure at present. Children suffering from this disease eventually become wheelchair bound and die in their late teens. Paediatricians caring for the child with Duchenne Muscular Dystrophy in resource poor settings face a lot challenges. These challenges include: poverty, inadequate multidisciplinary care, emotional burn out of parents and lack of facilities for dystrophin assay or genetic testing. PMID- 25838856 TI - Unilateral multifocal choroidal ischemia revealing a giant cell arteritis: a case report. PMID- 25838857 TI - Appointment keeping for medical review among patients with selected chronic diseases in an urban area of Uganda. AB - INTRODUCTION: Proper management of chronic diseases is important for prevention of disease complications and yet some patients miss appointments for medical review thereby missing the opportunity for proper monitoring of their disease conditions. There is limited information on missed appointments among chronic disease patients in resource limited settings. This study aimed to determine the prevalence of missed appointments for medical review and associated factors among chronic disease patients in an urban area of Uganda. METHODS: Patients or caregivers of children with chronic diseases were identified as they bought medicines from a community pharmacy. They were visited at home to access their medical documents and those whose chronic disease status was ascertained were enrolled. The data was collected using: questionnaires, review of medical documents, and in-depth interviews with chronic disease patients. RESULTS: The prevalence of missed appointments was 42% (95%CI = 35-49%). The factors associated with missed appointments were: monthly income <=30US Dollars (OR = 2.56, CI = 1.25-5.26), affording less than half of prescribed drugs (OR = 3.92, CI = 1.64-9.40), not experiencing adverse events (OR = 2.66, CI = 1.26-5.61), not sure if treatment helps (OR = 2.84, CI = 1.047.77), not having a medicines administration schedule (OR = 6.77, CI = 2.11-21.68), and increasing number of drugs (OR = 0.72, CI = 0.53-0.98). CONCLUSION: Patients missed appointments mainly due to: financial and health system barriers, conflicting commitments with appointments, and perceptions of the disease condition. Patients should be supported with accessible and affordable health services. PMID- 25838858 TI - [Rare cause of intestinal obstruction: intestinal cystic pneumatosis]. PMID- 25838791 TI - Measurement of electroweak production of two jets in association with a Z boson in proton-proton collisions at [Formula: see text]. AB - The purely electroweak (EW) cross section for the production of two jets in association with a Z boson, in proton-proton collisions at [Formula: see text], is measured using data recorded by the CMS experiment at the CERN LHC, corresponding to an integrated luminosity of 19.7[Formula: see text]. The electroweak cross section for the [Formula: see text] final state (with [Formula: see text] or [Formula: see text] and j representing the quarks produced in the hard interaction) in the kinematic region defined by [Formula: see text][Formula: see text], [Formula: see text][Formula: see text], transverse momentum [Formula: see text][Formula: see text], and pseudorapidity [Formula: see text], is found to be [Formula: see text], in agreement with the standard model prediction. The associated jet activity of the selected events is studied, in particular in a signal-enriched region of phase space, and the measurements are found to be in agreement with QCD predictions. PMID- 25838859 TI - An assessment of discriminatory power of office blood pressure measurements in predicting optimal ambulatory blood pressure control in people with type 2 diabetes. AB - INTRODUCTION: Ambulatory blood pressure (BP) measurements (ABPM) predict health outcomes better than office BP, and are recommended for assessing BP control, particularly in high-risk patients. We assessed the performance of office BP in predicting optimal ambulatory BP control in sub-Saharan Africans with type 2 diabetes (T2DM). METHODS: Participants were a random sample of 51 T2DM patients (25 men) drug-treated for hypertension, receiving care in a referral diabetes clinic in Yaounde, Cameroon. A quality control group included 46 non-diabetic individuals with hypertension. Targets for BP control were systolic (and diastolic) BP. RESULTS: Mean age of diabetic participants was 60 years (standard deviation: 10) and median duration of diabetes was 6 years (min-max: 0-29). Correlation coefficients between each office-based variable and the 24-h ABPM equivalent (diabetic vs. non-diabetic participants) were 0.571 and 0.601 for systolic (SBP), 0.520 and 0.539 for diastolic (DBP), 0.631 and 0.549 for pulse pressure (PP), and 0.522 and 0.583 for mean arterial pressure (MAP). The c statistic for the prediction of optimal ambulatory control from office-BP in diabetic participants was 0.717 for SBP, 0.494 for DBP, 0.712 for PP, 0.582 for MAP, and 0.721 for either SBP + DBP or PP + MAP. Equivalents in diabetes-free participants were 0.805, 0.763, 0.695, 0.801 and 0.813. CONCLUSION: Office DBP was ineffective in discriminating optimal ambulatory BP control in diabetic patients, and did not improve predictions based on office SBP alone. Targeting ABPM to those T2DM patients who are already at optimal office-based SBP would likely be more cost effective in this setting. PMID- 25838860 TI - [Bladder carcinoma complicated with iris metastasis]. PMID- 25838861 TI - [Kid Syndrome or Keratitis Ichthyosis-Deafness-syndrome: report of a case]. PMID- 25838864 TI - [Pneumomediastinum complicating eclampsia: report of a case]. PMID- 25838863 TI - [Ovarian tumors in postmenopausal women: report of 100 cases and review of the literature]. PMID- 25838865 TI - Multiple paraneoplastic syndromes revealing non-small cell lung carcinoma. AB - A broad spectrum of paraneoplastic dermatoses is associated with lung cancer. We report herein a 56-year-old man who presented an association of erythroderma, acquired ichthyosis, palmo-plantar keratoderma, hypereosinophilia and hyper IgE. In light of these clinical and biological assessments an underlying malignancy had been suspected. A thoracic, abdominal and pelvic computed tomography showed a left hilar mass. The patient underwent a left pneumonectomy and the histological study had confirmed a non-small cell lung cancer. Recognition of cutaneous paraneoplastic syndromes is important since it leads to prompt diagnosis of an underlying malignancy and consequently a better management and prognosis of the disease. PMID- 25838866 TI - Dexmedetomidine attenuates oxidative stress induced lung alveolar epithelial cell apoptosis in vitro. AB - BACKGROUND: Oxidative stress plays a pivotal role in the lung injuries of critical ill patients. This study investigates the protection conferred by alpha 2 adrenoceptor agonist dexmedetomidine (Dex) from lung alveolar epithelial cell injury induced by hydrogen peroxide (H2O2) and the underlying mechanisms. METHODS: The lung alveolar epithelial cell line, A549, was cultured and then treated with 500 MUM H2O2 with or without Dex (1 nM) or Dex in combination with atipamezole (10 nM), an antagonist of alpha 2 receptors. Their effect on mitochondrial membrane potential (Deltapsi m), reactive oxygen species (ROS), and the cell cycle was assessed by flow cytometry. Cleaved-caspases 3 and 9, BAX, Bcl 2, phospho-mTOR (p-mTOR), ERK1/2, and E-cadherin expression were also determined with immunocytochemistry. RESULTS: Upregulation of cleaved-caspases 3 and 9 and BAX and downregulation of Bcl-2, p-mTOR, and E-cadherin were found following H2O2 treatment, and all of these were reversed by Dex. Dex also prevented the ROS generation, cytochrome C release, and cell cycle arrest induced by H2O2. The effects of Dex were partially reversed by atipamezole. CONCLUSION: Our study demonstrated that Dex protected lung alveolar epithelial cells from apoptotic injury, cell cycle arrest, and loss of cell adhesion induced by H2O2 through enhancing the cell survival and proliferation. PMID- 25838862 TI - Cancer survival in Malawi: a retrospective cohort study. AB - INTRODUCTION: Cancer is a leading cause of morbidity and mortality worldwide with the burden in sub-Saharan Africa projected to double by year 2030 from 715,000 new cases and 542,000 deaths in 2008. However, cancer survival data to inform interventions for early detection, diagnosis and treatment are lacking. METHODS: Cancer survival analysis was conducted on 842 cancer patients registered and followed-up from 2006 to 2013 at NdiMoyo Palliative Care Centre in Salima District, central Malawi. Cancer survival was measured from the time of diagnosis. RESULTS: In both sexes, the common types of cancer were; Kaposi's sarcoma (KS) (48.0%), cervical cancer (21.1%), cancer of oesophagus (14.8%), liver cancer (3.1%) and breast cancer (2.5%). In Males; KS, cancer of the oesophagus, cancer of the liver, bone cancer and non-Hodgkin's lymphoma were the commonest accounting for 67.4%, 19.4%, 3.9%, 1.0% and 1.0% respectively. In females; cancer of the cervix, KS, cancer of the oesophagus, cancer of the breast and cancer of the liver were the top five cancers accounting for 41.6%, 29.2%, 10.3%, 4.9% and 2.3% respectively. Of the 830 cancer patients with complete 5 year follow-up data, the overall median survival time was 9 months. Absolute survival rates at 1, 2, 3, 4 and 5 years or more were 31.8%, 18.0%, 12.5%, 7.8% and 6.0% respectively. The survival rates for top five cancers at 1, 2, 3, and 4 years or more were; KS (n= 397): 47.1%, 30.2%, 21.4% and 13.1%; cancer of the cervix (n = 174): 31.0%, 10.3%, 5.2% and 2.9%; cancer of the oesophagus (n = 124): 4.0%, 2.4%, 1.6% and 1.6%; liver cancer (n = 26): 19.2%, 3.8%, 3.8% and 3.8% and breast cancer (n = 21): 9.5%, 0%, 0%, 0% respectively. The risk of death was high in females than males, in those aged 50 years or more than in those aged less than 50 (p < 0.05). CONCLUSION: This study demonstrated that cancer survival from the time of diagnosis in Malawi was poor with median survival time of about 9 months and only 6% of patients survived for 5 years or more. Improvement of early detection, diagnostic capability, access to treatment and palliative care services could improve cancer survival. PMID- 25838867 TI - Poststroke depression as a factor adversely affecting the level of oxidative damage to plasma proteins during a brain stroke. AB - Poststroke depression, the second most serious psychosomatic complication after brain stroke, leads to delay of the rehabilitation process and is associated with an increased disability and cognitive impairment along with increase in term mortality. Research into the biochemical changes in depression is still insufficiently described. The aim of our study was therefore to evaluate the possible association between plasma protein oxidative/nitrative damages and the development of poststroke depression. We evaluated oxidative/nitrative modifications of specific proteins by measurement of 3-nitrotyrosine and carbonyl groups levels using ELISA test. Additionally, we checked differences in proteins thiol groups by spectrophotometric assay based on reaction between DTNB and thiols. We also evaluated catalase activity in erythrocytes measured as ability to decompose H2O2. Correlation analysis was performed using Spearman's rank. We observed significant (P < 0.001) differences in all oxidative/nitrative stress parameters in brain stroke patients compared to healthy group. Our research shows that oxidative damage of proteins is correlated with the degree of poststroke depression, while nitrative changes do not show any relationship. We demonstrate a positive correlation between the concentration of carbonyl groups and the Geriatric Depression Scale and a negative correlation between the degree of depression and the concentration of -SH groups or catalase activity. PMID- 25838869 TI - Potential therapeutic role of L-carnitine in skeletal muscle oxidative stress and atrophy conditions. AB - The targeting of nutraceutical treatment to skeletal muscle damage is an emerging area of research, driven by the need for new therapies for a range of muscle associated diseases. L-Carnitine (CARN) is an essential nutrient and plays a key role in mitochondrial beta-oxidation and in the ubiquitin-proteasome system regulation. As a dietary supplement to improve athletic performance, CARN has been studied for its potential to enhance beta-oxidation. However, CARN effects on myogenesis, mitochondrial activity, and hypertrophy process are not completely elucidated. This in vitro study aims to investigate CARN role on skeletal muscle remodeling, differentiation process, and myotubes formation. We analyzed muscle differentiation and morphological features in C2C12 myoblasts exposed to 5 mM CARN. Our results showed that CARN was able to accelerate C2C12 myotubes formation and induce morphological changes, characterizing the start of hypertrophy process. In addition, CARN improved AKT activation and downstream cellular signaling pathways involved in skeletal muscle atrophy process prevention. Also, CARN positively regulated the pathways involved in oxidative stress defense. In this work, we provide an interesting novel mechanism of the potential therapeutic use of CARN to treat pathological conditions characterized by skeletal muscle morphological and functional impairment, oxidative stress production, and atrophy process in aging. PMID- 25838871 TI - Reply. PMID- 25838868 TI - Oxidative stress and immune system in vitiligo and thyroid diseases. AB - Vitiligo is an acquired dermatological disease frequently associated with autoimmune thyroid disorders. Several theories have been proposed so far to unravel the complex vitiligo pathogenesis. Currently, the autocytotoxic and the autoimmune theories are the most accredited hypothesis, since they are sustained by several important clinical and experimental evidences. A growing body of evidences shows that autoimmunity and oxidative stress strictly interact to finally determine melanocyte loss. In this scenario, associated thyroid autoimmunity might play an active and important role in triggering and maintaining the depigmentation process of vitiligo. PMID- 25838870 TI - Dietary nitrate is a modifier of vascular gene expression in old male mice. AB - Aging leads to a number of disadvantageous changes in the cardiovascular system. Deterioration of vascular homoeostasis with increase in oxidative stress, chronic low-grade inflammation, and impaired nitric oxide bioavailability results in endothelial dysfunction, increased vascular stiffness, and compromised arterial ventricular interactions. A chronic dietary supplementation with the micronutrient nitrate has been demonstrated to improve vascular function. Healthy dietary patterns may regulate gene expression profiles. However, the mechanisms are incompletely understood. The changes that occur at the gene expression level and transcriptional profile following a nutritional modification with nitrate have not been elucidated. To determine the changes of the vascular transcriptome, we conducted gene expression microarray experiments on aortas of old mice, which were treated with dietary nitrate. Our results highlight differentially expressed genes overrepresented in gene ontology categories. Molecular interaction and reaction pathways involved in the calcium-signaling pathway and the detoxification system were identified. Our results provide novel insight to an altered gene-expression profile in old mice following nitrate supplementation. This supports the general notion of nutritional approaches to modulate age related changes of vascular functions and its detrimental consequences. PMID- 25838872 TI - Morphological study of chordae tendinae in human cadaveric hearts. AB - OBJECTIVES: The chordae tendinae (CT) are strong, fibrous connections between the valve leaflets and the papillary muscles. Dysfunction of the papillary muscles and chordae is frequent. Mitral valve replacement with preservation of CT and papillary muscles may preserve postoperative left ventricular function better than conventional mitral valve replacement in patients with chronic mitral regurgitation. METHODS: The study was carried out on 116 human cadaveric hearts. The heart was opened through the atrioventricular valve to view the constituents of the complex. Origin, attachments, insertions, distribution, branching pattern and gross structure of CT were observed and studied in detail. RESULTS: In the present study more than 21 terminologies of CT were defined by classifying it into six different types. Classification is done according to the origin, attachments, insertion, distribution, branching pattern and gross structure. Terminologies defined are as follows. Apical pillar chordae, Basal pillar chordae, True chordae, False chordae, Interpillar chordae, Pillar wall chordae, Cusp chordae, Cleft chordae, Commissural chordae, First order chordae, Second order chordae, Free zone chordae, Marginal chordae, Rough zone chordae, Straight chordae, Branched-fan shaped chordae, Spiral chordae, Irregular-web chordae, Tendinous chordae, Muscular chordae, Membranous chordae. Basal pillar chordae are found in 9.48%. Mean number of chordae taking origin from apical half of a single papillary muscle or single head of papillary muscle was 9.09 with the range of 3 18. Mean number of the marginal chordae attached to a single cusp was 22.63 ranging from 11 to 35. Strut chordae showed interesting insertion with broad aponeurosis in 38.79% and large muscular flaps in 13.79%. Chordae muscularis were found in 14% and membranous chordae were found in 6%. CONCLUSIONS: This knowledge may prove useful for cardiologists and cardiac surgeons. PMID- 25838873 TI - Assessment of noninvasive risk markers of subclinical atherosclerosis in premenopausal women with previous history of gestational diabetes mellitus. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) is state of carbohydrate intolerance detected first time during pregnancy. GDM represents a significant risk factor for the development of CVD in women. The degree to which women with histories of gestational diabetes are at risk for cardiovascular disease, beyond their predisposition to future diabetes, is still unclear. The aim of our study was to assess the presence of surrogate markers of subclinical atherosclerosis which can be present in them even without developing type 2 diabetes. SUBJECTS AND METHODS: In this descriptive cross-sectional hospital based study, 50 patients 20-45 yrs of age, premenopausal, at least 1 yr past her most recent pregnancy, and not more than 5 yr past her index pregnancy with GDM. These patients and controls who did not have GDM were assessed for carotid intima media thickness,endothelial dysfunction, epicardial fat thickness and other cardiovascular risk factors. RESULTS: Women with pGDM were found to have unfavourable cardiovascular risk parameters. They also demonstrated more frequent occurrence of metabolic syndrome(64% vs 10%) than control subjects. Individual components of MS increased with increasing BMI in both the groups. As far as markers of subclinical atherosclerosis were concerned women with pGDM had significantly higher CIMT, FMD and epicardial fat thickness than control group. CONCLUSION: Women with pGDM, even before development of diabetes have significant differences in CVD risk factors when compared to those who do not have such history. Postpartum screening for glucose intolerance and efforts to minimize modifiable cardiovascular risk factors, including hypertension, viscerall adiposity, and dyslipidemia should be the most effective measures for lowering of cardiovascular risk. PMID- 25838874 TI - Superdominant right coronary artery with double posterior descending artery. AB - Coronary artery anomalies are rare entities. All angiographers and cardiac surgeons need to be familiar with these anatomic variants for proper surgical revasularisation in the presence of coronary artery disease. We report here an interesting case of superdominant right coronary artery with double posterior descending artery. PMID- 25838875 TI - Rituximab induced left bundle branch block. AB - Rituximab (a monoclonal antibody directed against CD 20) therapy can be acutely complicated by infusion reactions and cardiac arrhythmia on rare occasions. We report the first case of a new onset left bundle branch block (LBBB) after rituximab therapy for Wegener's vasculitis. PMID- 25838876 TI - Acute Myocardial Infarction in a Young Lady due to Vitamin B12 Deficiency Induced Hyperhomocysteinemia. AB - Hyper-homocysteinemia is a risk factor for coronary artery disease in young patients. A 32 years old female without any conventional risk factors except obesity presented with acute anterior wall myocardial infarction (MI). Her echocardiography showed anterior wall hypokinesia with moderate left ventricular dysfunction. Angiography showed tight stenosis of the proximal left anterior descending (LAD) and borderline lesion in left circumflex coronary artery (LCX). She underwent percutaneous coronary intervention (PCI) to LAD with good result. Her blood tests showed low vitamin B12, folate and serum iron levels and elevated serum homocysteine level. She was given folic acid and vitamin B12 and her homocysteine levels normalized. This case demonstrates that hyperhomocysteinemia caused by nutritional deficiency of vitamin co factors may lead to MI. Hyperhomocysteinemia should be considered in the evalauation of young people with MI, especially those without conventional risk factors. PMID- 25838877 TI - Atypical early Aspergillus endocarditis post prosthetic mitral valve repair: a case report. AB - A 64-year-old female operated 1 month previous for mitral valve repair presented with acute respiratory distress and dyspnea. Echocardiography showed large echogenic valvular mass measuring 2.3 * 1.3 cm with severe mitral regurgitation and dehiscence of the mitral ring posteriorly. The mass was attached subvalvularly to the ventricular septal-free wall and eroding through it, which required complete aggressive dissection of the infected tissues. Diagnosis was confirmed after resection of the valve by multiple negative blood cultures and positive valvular tissue for Aspergillus fumigatus endocarditis. She was treated with high dose of voriconazole for 3 months. Her postoperative period was complicated by acute-on-chronic renal failure. She responded very well to the management. PMID- 25838878 TI - Saphenous Vein Graft Perforation During Percutaneous Coronary Intervention - A Nightmare to be Avoided. AB - Percutaneous coronary interventions (PCIs) of saphenous vein grafts (SVGs) is challenging and is associated with adverse short- and long-term clinical outcome as compared to native coronary arteries. SVG perforation is rare but catastrophic and needs immediate attention. Various factors predisposing for SVG perforation are old degenerated graft, ulcerated plaque, severe fibrotic, or calcified lesion necessitating high pressure balloon or stent inflation, use of intravascular ultrasound (IVUS) or other atheroablative devices. Management includes prolonged balloon occlusion, reversal of anticoagulation, use of covered stent, and emergency pericadiocentesis if required. PMID- 25838879 TI - Iatrogenic left main coronary artery stenosis following aortic and mitral valve replacement. AB - Iatrogenic coronary artery disease following prosthetic valve implantation is a rare complication. This may result from mechanical injury in the intraoperative period. The use of balloon tip perfusion catheter presumably provides the initial insult with local vessel wall hypoxia. Once the diagnosis of coronary ostial stenosis is established, the procedure of choice is coronary artery bypass surgery. We report a case of a young lady who underwent aortic and mitral valves replacement for infective endocarditis. She was then diagnosed with ostial left main stem coronary stenosis after presenting with atypical symptoms. The patient eventually underwent coronary artery bypass surgery. PMID- 25838880 TI - Transesophageal echocardiographic images of atrial septal defect device closure. PMID- 25838882 TI - History of medicine timeline. PMID- 25838881 TI - The Physician's Little Black Bag. PMID- 25838883 TI - Enantioselective Synthesis of D-alpha-Amino Amides from Aliphatic Aldehydes. AB - Peptides consisting of D-amino amides are highly represented among both biologically active natural products and non-natural small molecules used in therapeutic development. Chemical synthesis of D-amino amides most often involves approaches based on enzymatic resolution or fractional recrystallization of their diastereomeric amine salts, techniques that produce an equal amount of the L amino acid. Enantioselective synthesis, however, promises selective and general access to a specific alpha-amino amide, and may enable efficient peptide synthesis regardless of the availability of the corresponding alpha-amino acid. This report describes the use of a cinchona alkaloid-catalyzed aza-Henry reaction using bromonitromethane, and the integration of its product with Umpolung Amide Synthesis. The result is a straightforward 3-step protocol beginning from aliphatic aldehydes that provides homologated peptides bearing an aliphatic side chain at the resulting D-alpha-amino amide. PMID- 25838884 TI - Operational evaluation of the earlobe arterialized blood collector in critically ill patients. AB - BACKGROUND: The new Earlobe Arterialized Blood Collector (EABC(r)) is a minimally invasive prototype system able to perform capillary blood collection from the earlobe (EL) with minimal training and risk. This system could improve medical emergency management in extreme environments. Consequently, a prospective validation study was designed to evaluate operational performance of the EABC(r) in a cohort of critically ill patients. METHODS: Arterialized capillary blood was sampled from the EL of 55 invasively ventilated patients using the EABC(r) following a validated procedure. Operational characteristics such as the number of cuts and cartridges required, sampling failure/success ratio, bleeding complications, storage requirements and other auxiliary aspects were recorded. Result turnaround laboratory times (TAT) were compared with published references. RESULTS: Blood collection was as easily performed on one earlobe as the other. Twenty-six minutes (mean 25.8; SD = 3.8) were required to obtain results, 15 min for patient preparation (mean 15.3; SD = 2.6) + 11 min for sampling and analysis (mean 11.4; SD = 2.1), which is similar to published hospital reference laboratory TAT. The average number of cartridges required was 1.3 (1-3; mode = 1) with the mean number of cut attempts being 1.2 (1-4; mode = 1). Problems/difficulties occurred in 59% of cases but were mainly attributed to patient's demographic characteristics, with only 10% attributable to the collector (superficial cut, blood leak, collector misalignment and obstructed vision). Haemostasis was quickly achieved with minimum complications. Storage of the complete sampling kit required a 300 * 300 * 300 mm box. Two 9-V batteries were used during the 2-year study period. CONCLUSIONS: The new EABC(r) system concept is safe, fast and easy to use. Observed problems/difficulties are easily amendable with certain design modifications. Definitive versions of the prototype have the potential for significant benefits for isolated and extreme environments in medicine. PMID- 25838885 TI - SmileFinder: a resampling-based approach to evaluate signatures of selection from genome-wide sets of matching allele frequency data in two or more diploid populations. AB - BACKGROUND: Adaptive alleles may rise in frequency as a consequence of positive selection, creating a pattern of decreased variation in the neighboring loci, known as a selective sweep. When the region containing this pattern is compared to another population with no history of selection, a rise in variance of allele frequencies between populations is observed. One challenge presented by large genome-wide datasets is the ability to differentiate between patterns that are remnants of natural selection from those expected to arise at random and/or as a consequence of selectively neutral demographic forces acting in the population. FINDINGS: SmileFinder is a simple program that looks for diversity and divergence patterns consistent with selection sweeps by evaluating allele frequencies in windows, including neighboring loci from two or more populations of a diploid species against the genome-wide neutral expectation. The program calculates the mean of heterozygosity and FST in a set of sliding windows of incrementally increasing sizes, and then builds a resampled distribution (the baseline) of random multi-locus sets matched to the sizes of sliding windows, using an unrestricted sampling. Percentiles of the values in the sliding windows are derived from the superimposed resampled distribution. The resampling can easily be scaled from 1 K to 100 M; the higher the number, the more precise the percentiles ascribed to the extreme observed values. CONCLUSIONS: The output from SmileFinder can be used to plot percentile values to look for population diversity and divergence patterns that may suggest past actions of positive selection along chromosome maps, and to compare lists of suspected candidate genes under random gene sets to test for the overrepresentation of these patterns among gene categories. Both applications of the algorithm have already been used in published studies. Here we present a publicly available, open source program that will serve as a useful tool for preliminary scans of selection using worldwide databases of human genetic variation, as well as population datasets for many non-human species, from which such data is rapidly emerging with the advent of new genotyping and sequencing technologies. PMID- 25838886 TI - Molecular characterization of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization and infection isolates in a Veterans Affairs hospital. AB - BACKGROUND: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is associated with increased infection risk, yet colonization and infection isolates are rarely compared within the same study. The objectives of this study were to compare colonization and infection isolates from a Veterans Administration hospital in Iowa, and to determine the prevalence of livestock associated MRSA (LA-MRSA) colonization and infection in a state with high livestock density. METHODS: All patients with available MRSA isolates collected through routine nasal screening (73%; n = 397) and from infections (27%; n = 148) between December 2010 and August 2012 were included and tested for spa type and presence of PVL and mecA genes. Clinical isolates were tested for antibiotic resistance patterns. Paired colonization and infection isolates were compared for genetic and phenotypic congruity. RESULTS: The most common spa types were t002 (and other CC5-associated strains; 65%) and t008 (and other CC8-associated strains; 20%). No classic LA-MRSA spa types were identified. CC5-associated strains were less likely to be associated with infections (22%; 77/353) compared with CC8-associated strains (49%; 53/109). MRSA colonization was more common among patients with infections (71%) compared with the general screening population (7%). In most cases (82%; 28/34), paired colonization and infection isolates were genetically and phenotypically indistinguishable. CONCLUSIONS: Our data demonstrate a direct link between antecedent nasal colonization and subsequent MRSA infection. Further, our data indicate variability in colonization and infection efficiency among MRSA genotypes, which points to the need to define the molecular determinants underlying emergence of S. aureus strains in the community and nosocomial setting. PMID- 25838887 TI - The physicochemical properties of microwave-assisted encapsulated anthocyanins from Ipomoea batatas as affected by different wall materials. AB - This study focuses on the impact of different wall materials on the physicochemical properties of microwave-assisted encapsulated anthocyanins from Ipomoea batatas. Using the powder characterization technique, purple sweet potato anthocyanin (PSPAs) powders were analysed for moisture content, water activity, dissolution time, hygroscopicity, color and morphology. PSPAs were produced using different wall materials: maltodextrin (MD), gum arabic (GA) and a combination of gum arabic and maltodextrin (GA + MD) at a 1:1 ratio. Each of the wall materials was homogenized to the core material at a core/wall material ratio of 5 and were microencapsulated by microwave-assisted drying at 1100 W. Results indicated that encapsulated powder with the GA and MD combination presented better quality of powder with the lowest value of moisture content and water activity. With respect to morphology, the microcapsule encapsulated with GA + MD showed several dents in coating surrounding its core material, whereas other encapsulated powders showed small or slight dents entrapped onto the bioactive compound. Colorimetric analysis showed changes in values of L, a*, b*, hue and chroma in the reconstituted powder compared to the initial powder. PMID- 25838888 TI - Physiochemical and antioxidant properties of roselle-mango juice blends; effects of packaging material, storage temperature and time. AB - A study was conducted to determine the effects of packaging materials, seasonality, storage temperature and time on physiochemical and antioxidant properties of roselle-mango juice blends. Roselle extract (20%, 40%, 60%, and 80%) was mixed with mango juice and stored in glass and plastic bottles at 4 degrees C and 28 degrees C. Total soluble solids, pH, titratable acidity, reducing sugar, color, vitamin C, total monomeric anthocyanins, total phenols, and antioxidant activity (FRAP) were evaluated in freshly prepared juice, and after, 2, 4, and 6 months of storage. The results showed that total soluble solids, reducing sugars, and pH increased with storage times under different storage time, irrespective of packaging materials. The acidity, color, total monomeric anthocyanin, vitamin C, total phenols, and antioxidant activity decreased during storage irrespective of storage temperature and packaging material. Loss of anthocyanins, total phenols, and vitamin C content were higher in blends stored at 28 degrees C than 4 degrees C. PMID- 25838889 TI - The use of nutrient-optimizing/cost-minimizing software to develop ready-to-use therapeutic foods for malnourished pregnant women in Mali. AB - Malnutrition affects people of all ages in many countries in the developing world. One treatment for malnutrition is the intervention involving ready-to-use therapeutic foods (RUTFs). This study developed RUTFs for pregnant women in Mali using formulation computer software and largely local, plant-based ingredients. Mali has the world's second highest birth rate and infant mortality rate. Nutrient profiles of possible ingredients and their prices from 2004 to 2009 were entered into the software. Computer-selected ingredients included peanuts, cowpeas, and millet as well as rice or barley koji (sources of alpha-amylase and ingredients). Components of the six selected formulations were milled, hydrolyzed with koji alpha-amylase, and heated at 121 degrees C for 15 min. The contents of protein, fat, ash, fiber, carbohydrates, amino acid, and energy of dehydrated products were determined and compared with software-predicted values. Actual and predicted values were comparable: the protein content was 1.45-2.04% higher, and ash content was 0.60-0.89% higher than the predicted values, while the fat content was 0.18-0.88% lower, the lysine content was 0.17-0.25% lower, and fiber content was 0.16% lower to 2.06% higher than the predicted values. The difference in actual and predicted energy levels were 14.8-22.2%. The amount of RUTF needed to meet the requirement of most limiting nutrients, lysine and energy, ranged from 2620 to 3002 g. The costs for producing the RUTFs were substantially lower than importing commercial RUTFs even with increased ingredient prices in Mali from 2004 to 2009. PMID- 25838890 TI - Pig feeds rich in rapeseed products and organic selenium increased omega-3 fatty acids and selenium in pork meat and backfat. AB - The concentration of omega-3 fatty acids and selenium (Se) is generally too low in the Western diet. But as the nutrient composition of pork meat and adipose tissue is influenced by the feed given to the animals, the product can be changed to support nutrient demands. Half (297/594) the pigs were given a feed concentrate based on low-glucosinolate rapeseed products (RS), while the other half was fed a traditional concentrate (Contr): The RS feed had an omega-6/omega 3 ratio of 3.6:1, and the Contr feed had a ratio of 8.9:1, and both feeds were supplemented with 0.4 mg Se/kg (organic Se: inorganic Se, 1:1). There was a small difference in growth rate, but no differences in feed conversion ratio, lean meat percentage, carcass value, and margin per pig for the two groups. There were no differences in meat quality between the two groups, but there were differences in technological fat quality. The RS pigs contained about 2 times more alpha linolenic acid in the backfat and 41% more in the meat (M. longissimus dorsi) compared to the controls. The concentration of EPA, DPA, and DHA were 42% and 20% higher in backfat and meat of the RS pigs compared to the control pigs respectively. The ratio between omega-6/omega-3 fatty acids were 4.7 in the meat and 4.0 in the backfat in the RS pigs, and the corresponding values were 6.6 and 8.0 in the control pigs. The selenium content was 0.3 mg/kg meat in both groups. The study showed that a portion of the present pig meat (175 g) provided the daily recommended intake of Se for men and women and about 1/6 of proposed reference intake of omega-3 LCPUFA (250 mg/day) to reduce the risk of CVD thereby providing a meat that is somewhat healthier for the consumer. PMID- 25838891 TI - Passion fruit juice with different sweeteners: sensory profile by descriptive analysis and acceptance. AB - This study evaluated the effect of different sweeteners on the sensory profile, acceptance, and drivers of preference of passion fruit juice samples sweetened with sucrose, aspartame, sucralose, stevia, cyclamate/saccharin blend 2:1, and neotame. Sensory profiling was performed by 12 trained assessors using quantitative descriptive analysis (QDA). Acceptance tests (appearance, aroma, flavor, texture and overall impression) were performed with 124 consumers of tropical fruit juice. Samples with sucrose, aspartame and sucralose showed similar sensory profile (P < 0.05), without bitter taste, bitter aftertaste, and metallic taste, and samples with sucrose and sucralose did not differ from each other for the attribute sweet aftertaste. Passion fruit flavor affected positively and sweet aftertaste affected negatively the acceptance of the samples. Samples sweetened with aspartame, sucralose, and sucrose presented higher acceptance scores for the attributes flavor, texture, and overall impression, with no significant (P < 0.05) differences between them. Aspartame and sucralose can be good substitutes for sucrose in passion fruit juice. PMID- 25838892 TI - Effect of storage and cooking on the fatty acid profile of omega-3 enriched eggs and pork meat marketed in Belgium. AB - The fatty acids (FA) profile was determined in n-3 enriched (ColumbusTM) Belgian eggs and pork in order to evaluate to what extent the n-3 fatty acids, which are very sensitive to oxidation, are resistant to storage or cooking. In standard eggs or pork, no change of the fatty acid profile was observed after storage or cooking without culinary fat, as well as in ColumbusTM eggs and pork after storage. Some cooking processes (eggs in custard and meat in oven) induced a slight significant loss of n-3 fatty acids in ColumbusTM eggs or pork (11.1% in fat from eggs cooked in custard vs. 15.3% in raw ColumbusTM eggs and 11.0% in fat from oven cooked meat vs. 11.6% in raw ColumbusTM meat). As expected, when ColumbusTM pork is cooked with culinary fat, its fatty acid profile is modified according to the nature of the fat used. PMID- 25838893 TI - Fish peptone development using enzymatic hydrolysis of silver carp by-products as a nitrogen source in Staphylococcus aureus media. AB - Fish peptone was produced using enzymatic hydrolysis of silver carp filleting by products by alcalase and trypsin. Also, the efficiency of the hydrolysates as a nitrogen source in Staphylococcus aureus medium was compared with commercial TSB. The results indicated that the protein hydrolysate from alcalase and trypsin had high protein content (92.92%, 91.53 respectively), and degree of hydrolysis (4.94%, 4.6% respectively).The results showed that silver carp filleting waste can be an efficient source for fish peptone production as a nitrogen source for S. aureus medium. However, the type of the used proteolytic enzyme considerably affected the performance of the resulting peptone despite the same DH. Fish peptone produced by alcalese performed significantly (P < 0.05) better than commercial TSB as a media for the bacteria while the performance of the trypsin peptone was not as good as the commercial medium. PMID- 25838894 TI - Analyzing the antibacterial effects of food ingredients: model experiments with allicin and garlic extracts on biofilm formation and viability of Staphylococcus epidermidis. AB - To demonstrate different effects of garlic extracts and their main antibiotic substance allicin, as a template for investigations on the antibacterial activity of food ingredients. Staphylococcus epidermidis ATCC 12228 and the isogenic biofilm-forming strain ATCC 35984 were used to compare the activity of allicin against planktonic bacteria and bacterial biofilms. The minimal inhibitory concentration (MIC) and the minimum biofilm inhibitory concentration (MBIC) for pure allicin were identical and reached at a concentration of 12.5 MUg/mL. MBICs for standardized garlic extracts were significantly lower, with 1.56 and 0.78 MUg/mL allicin for garlic water and ethanol extract, respectively. Biofilm density was impaired significantly at a concentration of 0.78 MUg/mL allicin. Viability staining followed by confocal laser scanning microscopy showed, however, a 100% bactericidal effect on biofilm-embedded bacteria at a concentration of 3.13 MUg/mL allicin. qRT-PCR analysis provided no convincing evidence for specific effects of allicin on biofilm-associated genes. Extracts of fresh garlic are more potent inhibitors of Staphylococcus epidermidis biofilms than pure allicin, but allicin exerts a unique bactericidal effect on biofilm embedded bacteria. The current experimental protocol has proven to be a valid approach to characterize the antimicrobial activity of traditional food ingredients. PMID- 25838896 TI - Amino acid fortified diets for weanling pigs replacing fish meal and whey protein concentrate: Effects on growth, immune status, and gut health. AB - BACKGROUND: Limited availability of fish meal and whey protein concentrate increases overall feed costs. Availability of increased number of supplemental amino acids including Lys, Met, Thr, Trp, Val, and Ile allows replacing expensive protein supplements to reduce feed costs. This study was to evaluate the effect of replacing fish meal and/or whey protein concentrate in nursery diets with 6 supplemental amino acids on growth performance and gut health of post-weaning pigs. Treatments were 1) FM-WPC: diet with fish meal (FM) and whey protein concentrate (WPC); 2) FM-AA: diet with FM and crystalline amino acids (L-Lys, L Thr, L-Trp, DL-Met, L-Val, and L-Ile); 3) WPC-AA: diet with WPC and crystalline amino acid; and 4) AA: diet with crystalline amino acid. RESULTS: Pigs in FM-AA, WPC-AA, and AA had greater (P < 0.05) ADG and gain:feed than pigs in FM-WPC during wk 1 (phase 1). Plasma insulin concentration of pigs in AA tended to be greater (P = 0.064) than that of FM-WPC at the end of wk 1(phase 1). Plasma concentrations of IgG in AA was lower (P < 0.05) compared with WPC-AA and FW, and FM-AA had lower (P < 0.05) IgG concentration than WPC-AA at the end of wk 1 (phase 1). Concentration of acetate in cecum digesta in FM-AA tended to be greater (P = 0.054) than that of FM-WPC and WPC-AA. Concentration of isovalerate in cecum digesta of pigs in FM-AA was greater (P < 0.05) than that of FW and WPC AA. CONCLUSIONS: This study indicates that use of 6 supplemental amino acids can replace fish meal and/or whey protein concentrate without adverse effects on growth performance, immune status, and gut health of pigs at d 21 to 49 of age. Positive response with the use of 6 supplemental amino acids in growth during the first week of post-weaning may due to increased plasma insulin potentially improving uptake of nutrients for protein synthesis and energy utilization. The replacement of fish meal and/or whey protein concentrate with 6 supplemental amino acids could decrease the crude protein level in nursery diets, and potentially lead to substantial cost savings in expensive nursery diets. PMID- 25838897 TI - Impact of source tissue and ex vivo expansion on the characterization of goat mesenchymal stem cells. AB - BACKGROUND: There is considerable interest in using goats as models for genetically engineering dairy animals and also for using stem cells as therapeutics for bone and cartilage repair. Mesenchymal stem cells (MSCs) have been isolated and characterized from various species, but are poorly characterized in goats. RESULTS: Goat MSCs isolated from bone marrow (BM-MSCs) and adipose tissue (ASCs) have the ability to undergo osteogenic, adipogenic and chondrogenic differentiation. Cytochemical staining and gene expression analysis show that ASCs have a greater capacity for adipogenic differentiation compared to BM-MSCs and fibroblasts. Different methods of inducing adipogenesis also affect the extent and profile of adipogenic differentiation in MSCs. Goat fibroblasts were not capable of osteogenesis, hence distinguishing them from the MSCs. Goat MSCs and fibroblasts express CD90, CD105, CD73 but not CD45, and exhibit cytoplasmic localization of OCT4 protein. Goat MSCs can be stably transfected by Nucleofection, but, as evidenced by colony-forming efficiency (CFE), yield significantly different levels of progenitor cells that are robust enough to proliferate into colonies of integrants following G418 selection. BM-MSCs expanded over increasing passages in vitro maintained karyotypic stability up to 20 passages in culture, exhibited an increase in adipogenic differentiation and CFE, but showed altered morphology and amenability to genetic modification by selection. CONCLUSIONS: Our findings provide characterization information on goat MSCs, and show that there can be significant differences between MSCs isolated from different tissues and from within the same tissue. Fibroblasts do not exhibit trilineage differentiation potential at the same capacity as MSCs, making it a more reliable method for distinguishing MSCs from fibroblasts, compared to cell surface marker expression. PMID- 25838899 TI - Fermented liquid feed for pigs: an ancient technique for the future. AB - Fermented liquid feed is feed that has been mixed with water at a ratio ranging from 1:1.5 to 1:4. By mixing with water, lactic acid bacteria and yeasts naturally occurring in the feed proliferate and produce lactic acid, acetic acid and ethanol which reduces the pH of the mixture. This reduction in pH inhibits pathogenic organisms from developing in the feed. In addition, when this low pH mixture is fed, it reduces the pH in the stomach of pigs and prevents the proliferation of pathogens such as coliforms and Salmonella in the gastrointestinal tract. For piglets, the use of fermented liquid feed offers the possibility of simultaneously providing feed and water, which may facilitate an easier transition from sow's milk to solid feed. Secondly, offering properly produced fermented liquid feed may strengthen the role of the stomach as the first line of defense against possible pathogenic infections by lowering the pH in the gastrointestinal tract thereby helping to exclude enteropathogens. Finally, feeding fermented liquid feed to pigs has been shown to improve the performance of suckling pigs, weaner pigs and growing-finishing pigs. In this review, current knowledge about the use of fermented liquid feed in pig diets will be discussed. This will include a discussion of the desirable properties of fermented liquid feed and factors affecting fermentation. In addition, advantages and disadvantages of fermented liquid feed will be discussed including its effects on gastrointestinal health, intestinal pH and the types of bacteria found in the gastrointestinal tract as well as the effects of fermented liquid feeds on pig performance. PMID- 25838900 TI - A case of myositis of the deltoid muscle of the upper arm developing 1 week after influenza vaccination: case report. AB - We report a case of an elderly man who developed myositis of the deltoid muscle 8 days after influenza vaccination. Adverse reactions to influenza vaccine are generally immediate reactions. However, delayed-type hypersensitivity reactions, although rare, can occur after routine influenza vaccination. PMID- 25838898 TI - Current strategies for reproductive management of gilts and sows in North America. AB - Many advances in genetic selection, nutrition, housing and disease control have been incorporated into modern pork production since the 1950s resulting in highly prolific females and practices and technologies, which significantly increased efficiency of reproduction in the breeding herd. The objective of this manuscript is to review the literature and current industry practices employed for reproductive management. In particular the authors focus on assisted reproduction technologies and their application for enhanced productivity. Modern maternal line genotypes have lower appetites and exceptional lean growth potential compared to females of 20 yr ago. Thus, nutrient requirements and management techniques and technologies, which affect gilt development and sow longevity, require continuous updating. Failure to detect estrus accurately has the greatest impact on farrowing rate and litter size. Yet, even accurate estrus detection will not compensate for the variability in the interval between onset of estrus and actual time of ovulation. However, administration of GnRH analogs in weaned sows and in gilts after withdrawal of altrenogest do overcome this variability and thereby synchronize ovulation, which makes fixed-time AI practical. Seasonal infertility, mediated by temperature and photoperiod, is a persistent problem. Training workers in the art of stockmanship is of increasing importance as consumers become more interested in humane animal care. Altrenogest, is used to synchronize the estrous cycle of gilts, to prolong gestation for 2-3 d to synchronize farrowing and to postpone post-weaning estrus. P.G. 600(r) is used for induction of estrus in pre-pubertal gilts and as a treatment to overcome seasonal anestrous. Sperm cell numbers/dose of semen is significantly less for post cervical AI than for cervical AI. Real-time ultrasonography is used to determine pregnancy during wk 3-5. PGF2alpha effectively induces farrowing when administered within two d of normal gestation length. Ovulation synchronization, single fixed-time AI and induced parturition may lead to farrowing synchronization, which facilitates supervision and reduces stillbirths and piglet mortality. Attendance and assistance at farrowing is important especially to ensure adequate colostrum consumption by piglets immediately after birth. New performance terminologies are presented. PMID- 25838901 TI - A case of granulomatosis with polyangiitis preceded by subacute thyroiditis. AB - Granulomatosis with polyangiitis can be a complication of thyroid disease, not only autoimmune disease but also subacute thyroiditis. PMID- 25838902 TI - Neonatal acute megakaryoblastic leukemia mimicking congenital neuroblastoma. AB - We describe a neonate with abdominal distension, massive hepatomegaly, and high serum neuron-specific enolase level suggestive of congenital neuroblastoma. The patient died of pulmonary hemorrhage after therapy. Autopsy revealed that the tumor cells in the liver indicated acute megakaryocytic leukemia with the RBM15 MKL1 fusion gene. PMID- 25838904 TI - A rare cause of ascites: pseudomyxoma peritonei and a review of the literature. AB - Pseudomyxoma peritonei is rare. The rarity is highlighted by the lack of published evidence regarding management. The latest treatments have altered the prognosis of a once incurable disease. This report serves to both raise awareness and critically appraise the literature regarding the latest management. PMID- 25838903 TI - Primary rectal diffuse large B-cell lymphoma associated with ulcerative colitis: a case report. AB - We need to be aware of primary intestinal lymphoproliferative disease (PILD) associated with ulcerative colitis (UC). We should carefully monitor UC patients, particularly patients who meet the following conditions; a previous Epstein-Barr virus infection, treatment duration ?4 years, male, and age ?50 years. PMID- 25838905 TI - Goodpasture's disease following extracorporeal shock wave lithotripsy: a case report & literature review. AB - Shock wave lithotripsy may unmask epitopes within the glomerular basement membrane, leading to the formation of anti-glomerular basement membrane (GBM) antibodies and clinical disease in susceptible individuals. Although rare, our case highlights the need for vigilant monitoring of renal function following extracorporeal shock wave lithotripsy. This may allow for early recognition, treatment and improved outcome of anti-GBM disease. PMID- 25838906 TI - A case of CLL that was successfully treated resulted in the immediate development of AML from a coexistent myeloid line that had been suppressed. AB - An 83 year-old Caucasian male presented to the emergency room with confusion and lethargy. A complete blood count revealed lymphocytosis, anemia, and thrombocytopenia. A bone marrow examination revealed chronic lymphocytic leukemia (CLL), along with a small population of abnormal immature myeloid cells. Chemotherapy for CLL was started. After one cycle, repeat bone marrow examination revealed normalization of the lymphocyte count and a proliferation of the previously noted myeloid population, consistent with acute myeloid leukemia (AML). This report presents the microscopic, immunophenotypic, and cytogenetic evidence to document the development of AML after one cycle of chemotherapy for CLL. PMID- 25838907 TI - Upper extremity deep vein thrombosis: a complication of an indwelling peripherally inserted central venous catheter. AB - We report a case of peripherally inserted central venous catheter (PICC) associated deep vein thrombosis (DVT). Ultrasound images and video of subclavian thrombus are presented. PICC line-associated DVT, particularly in cancer patients is not uncommon. Point-of-care Emergency Department ultrasound can readily diagnose this complication and device removal is not always necessary. PMID- 25838908 TI - Placenta accreta: adherent placenta due to Asherman syndrome. AB - It is important to be aware of the risk of abnormally invasive placenta in patients with a history of Asherman syndrome and uterine scarring. A prenatal diagnosis by ultrasonography is useful when planning of mode of delivery. PMID- 25838909 TI - A difficult diagnosis of Hodgkin lymphoma due to immune thrombocytopenia. AB - We report a rare clinical presentation of childhood Hodgkin lymphoma with immune thrombocytopenia. Diagnostic biopsy of the abdominal mass was performed after administration of intravenous immunoglobulins, steroids, and platelet transfusion. Concomitant thrombocytopenia complicated the whole diagnosis work up and the initial management of neoplasia. PMID- 25838911 TI - Pediatric ovarian torsion: an uncommon clinical entity. AB - Pediatric ovarian torsion is an infrequent diagnosis and it often mimics acute appendicitis. Most cases are due to underlying ovarian pathology and if left untreated, ovarian torsion may eventually cause peritonitis. Emergency exploratory laparoscopy represents a valuable diagnostic and therapeutic tool in suspected ovarian torsion. PMID- 25838910 TI - Fulminant onset of acute leukemia from normal hematopoiesis within 3 months of follow up for multiple myeloma treated with total therapy protocols. AB - Assiduous surveillance for genetic aberrations is necessary in patients on cytotoxic therapies to detect therapy-related myeloid neoplasms (t-MN). Current modalities include metaphase cytogenetics and FISH. Since t-MN may develop abruptly in cytogenetically normal patients, a discussion exploring additional methods such as SNP-array and targeted-deep-sequencing to detect subchromosomal abnormalities is needed. PMID- 25838912 TI - Disseminated histoplasmosis associated with acquired hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening clinical syndrome caused by uncontrolled activation of lymphocytes and histiocytes resulting in high levels of cytokines. Acquired HLH occurs in autoimmune, inflammatory, infectious, and immunosuppressive disorders. Prompt identification and treatment of an underlying triggering cause improves clinical outcome. PMID- 25838913 TI - A unique complication of SEMS. AB - Intraperitoneal stent migration should also be considered in any individual with no clinical success post stent insertion. PMID- 25838914 TI - Fournier gangrene. AB - Fournier gangrene is a rapidly progressive necrotizing infection of the perineal and genital fascia, often polymicrobial. Severity is increased in older patients, diabetics and the immunocompromised. As in this case, the disease can have an indolent onset. Early recognition and aggressive treatment is important. PMID- 25838916 TI - Comparison in decision-making between bulimia nervosa, anorexia nervosa, and healthy women: influence of mood status and pathological eating concerns. AB - BACKGROUND: Decision-making is reported to be impaired in anorexia nervosa (AN) and bulimia nervosa (BN), but the influence of mood status, pathophysiological eating, and weight concerns on the performance of decision-making ability between AN and BN is still unclear. The aims of this study were to investigate differential impairments in the decision-making process between AN, BN, and healthy controls (HC), and secondly, to explore the role of mood status, such as anxiety, depression, pathological eating, and weight concerns, in decision-making ability. METHODS: Patients suffering from AN (n = 22), BN (n = 36) and age matched HC (n = 51) were assessed for their decision-making abilities using the Iowa Gambling Task (IGT). Self-reported questionnaires including the Eating Disorder Examination Questionnaire (EDE-Q), the Bulimia Investigatory Test, Edinburgh (BITE), the Eating Disorders Inventory, the Maudsley Obsessive Compulsive Inventory measuring obsessive-compulsive traits, the Hospital Anxiety and Depression Scale, and the Toronto Alexithymia Scale were used to assess pathological eating concerns and attitude to feelings. RESULTS: Significant differences in IGT performance were observed between BN and HC. Significant negative correlation was found between IGT performance and the BITE symptom subscale in AN. In BN, there was a negative correlation between the EDE-Q weight concerns subscale and IGT performance. It was also found that increased anxiety, depression, and eating/weight concerns predicted poorer decision-making. CONCLUSION: Different patterns of association between pathological eating concerns/behaviors and performances in decision-making ability were found between AN, BN, and HC. Anxiety, depressive mood status, and eating/weight concerns were related to decision-making ability. PMID- 25838918 TI - Tuberculosis deaths: are we measuring accurately? AB - Death among tuberculosis patients is one of the major reasons for non-attainment of 85% treatment success target set by World Health Organization. In this short paper, we evaluated whether the overall mortality rate in pulmonary tuberculosis is being affected by other comorbid conditions. All new smear positive pulmonary tuberculosis patients (N =336), who started their treatment at the chest clinic of the Penang General Hospital, between March 2010 and February 2011, were followed-up until December 2011. Tuberculosis treatment outcomes were reported according to six treatment outcome categories recommended by World Health Organization. The outcome category 'died' was defined as 'a patient who died due to tuberculosis or other cause during tuberculosis treatment'. Our findings showed that out of 336 smear positive pulmonary tuberculosis patients, 59 (17.6%) died during treatment (mortality rate = 1.003 cases per 1000 person-days of follow-up). Among the deceased patients, the mean age was 55.8 years (SD =16.17) and 49 were male. According to the mortality review forms, 29 deaths were tuberculosis-related, while the remaining 30 patients died due to reasons other than tuberculosis. Cerebrovascular accident (n =7), septicaemia shock (n =4) and acute coronary syndrome (n =4) were the most common non-tuberculosis related reasons for mortality in the patients. If the 30 patients, for whom tuberculosis was incidental to death, are excluded from the final cohort, the proportion of patients in the 'died' outcome category could be reduced to 9.5%. The treatment outcome criterion (i.e., died) set by World Health Organization has limitations. Therefore, it requires improvement for more objective evaluation of the performance of the National Tuberculosis Program. PMID- 25838917 TI - Adherence to treatment guidelines for uncomplicated malaria at two public health facilities in Nigeria; Implications for the 'test and treat' policy of malaria case management. AB - OBJECTIVES: Adherence to treatment guidelines for uncomplicated malaria is critical to the success of malaria case management. Poor adherence has implications for increased malaria burden, in view of the risk of widespread parasite resistance and treatment failures. This study analyzed the diagnostic and prescription pattern for uncomplicated malaria at two public health facilities, south east Nigeria, to assess the current state of compliance to policy guidelines on the use of artemisinin-based combination therapy (ACT). METHODS: Retrospective audit of patients' records, treated for uncomplicated malaria, between the months of January and March 2013, was undertaken at two public health facilities. Demographics, diagnostic information, medication and cost data were extracted. Questionnaires were distributed to providers to assess their malaria treatment intent. Data from the facilities were analyzed and compared for similarities and systematic differences, and conformity to malaria treatment policy, in terms of laboratory diagnosis, use of ACT, co-medication and cost of medication. RESULTS: A total of 2,171 records of patients who had been treated for uncomplicated malaria were analyzed. Of these, 1066 (49%) were sent for laboratory confirmation of malaria using mostly microscopy, out of which 480 (45%) tested positive. 51% (1105) of the prescriptions was on the basis of presumptive treatment. 58% of slide negative results received antimalarial drugs. 93% of patients received ACT, with artemether-lumefantrin, AL (50.5%) as the most prescribed antimalarial drug. Monotherapy accounted for 7% of prescriptions, comprising mostly sulphadoxine + pyrimethamine, SP (46.5%) and monotherapy artemisinin, AS (29.2%). 97% of the prescriptions received at least one co medication. Antibiotics were prescribed to 50% of patients. Overall, median cost of medication was N1160.00 (US$7.48 (US$0.19 - 267.87) per case, higher in tertiary than the secondary facility. There were significant variations in treatment practices between the two facilities. CONCLUSION: Evidence suggests good compliance to policy on the use of ACT as first line treatment for uncomplicated malaria. However, there exists significant scope for improved diagnosis and rational drug use, to enhance accuracy of treatment, reduced wastages and risks of adverse drug reactions, in line with the goals of 'test and treat' policy of malaria case management. PMID- 25838919 TI - Pharmaceutical supply chain risk assessment in Iran using analytic hierarchy process (AHP) and simple additive weighting (SAW) methods. AB - OBJECTIVES: Pharmaceutical supply chain is a significant component of the health system in supplying medicines, particularly in countries where main drugs are provided by local pharmaceutical companies. No previous studies exist assessing risks and disruptions in pharmaceutical companies while assessing the pharmaceutical supply chain. Any risks affecting the pharmaceutical companies could disrupt supply medicines and health system efficiency. The goal of this study was the risk assessment in pharmaceutical industry in Iran considering process's priority, hazard and probability of risks. METHODS: The study was carried out in 4 phases; risk identification through literature review, risk identification in Iranian pharmaceutical companies through interview with experts, risk analysis through a questionnaire and consultation with experts using group analytic hierarchy process (AHP) method and rating scale (RS) and risk evaluation of simple additive weighting (SAW) method. RESULTS: In total, 86 main risks were identified in the pharmaceutical supply chain with perspective of pharmaceutical companies classified in 11 classes. The majority of risks described in this study were related to the financial and economic category. Also financial management was found to be the most important factor for consideration. CONCLUSION: Although pharmaceutical industry and supply chain were affected by current political conditions in Iran during the study time, but half of total risks in the pharmaceutical supply chain were found to be internal risks which could be fixed by companies, internally. Likewise, political status and related risks forced companies to focus more on financial and supply management resulting in less attention to quality management. PMID- 25838921 TI - Use of unripe plantain (Musa paradisiaca) in the management of diabetes and hepatic dysfunction in streptozotocin induced diabetes in rats. AB - AIM: This study aims to investigate the effect of unripe plantain (Musa paradisiaca) on markers of hepatic dysfunction in streptozotocin induced diabetic rats. METHODS: Blood glucose; relative liver weight (RLW); relative kidney weight (RKW); relative heart weight (RHW); relative pancreatic weight (RPW); serum and hepatic serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP); serum amylase, lipase, total, and conjugated bilirubin; and chemical analysis of the test feed were determined using standard techniques. RESULTS: The diabetic rats had significant alteration (P < 0.05) of blood glucose; RLW; RKW; RPW; serum and hepatic AST, ALT, and ALP; serum total and conjugated bilirubin; and serum lipase activities compared with nondiabetic while these parameters were significantly improved (P < 0.05) in the rats fed unripe plantain. There were no significant differences (P > 0.05) in the RHW of the rats in the three groups, as well as significant decreases (P < 0.05) in the amylase levels of the diabetic rats compared with the nondiabetic, but there was nonsignificant increase (P > 0.05) in the amylase levels of the rats fed unripe plantain compared with the nondiabetic rats. The test and standard rat feeds contained considerable amount of proteins, carbohydrates, fats, phenols, and crude fiber. CONCLUSION: Amelioration of acute pancreatitis by unripe plantain could play a key role in its management of diabetes and related complications. PMID- 25838920 TI - PIK3CA rs7640662 (C/G) single nucleotide polymorphism lacks association with breast cancer cases in Persians. AB - Phosphatidylinositol-3-kinase (PI3K) is a group of enzymes involved in cellular growth, proliferation, differentiation, cell motility, intracellular trafficking, and survival that play very important roles in developing breast cancer. PIK3CA is a gene that encodes alpha catalytic subunit of this enzyme. A common polymorphism of PIK3CA, rs7640662 (C/G), was analyzed, and its association to breast cancer cases was determined. In this study, DNA was extracted from peripheral blood samples of 278 women suffering from breast cancer and 128 healthy women. Tetra-primer amplification refractory mutation system polymerase chain reaction (T-ARMS-PCR) method was performed to genotype rs7640662. P values and ODD ratios were measured using SPSS. P value less than 0.05 and ODD ratios more than 1 were considered as significant. All ODD ratios were less than 1, and P values were more than 0.05 showing that rs7640662 (C/G) and breast cancer are not significantly associated. However, the genotypes observed in the Persian population, as an ancient population living in the Middle East, was significantly different from the genotypes reported by HapMap for Asian populations. As a conclusion, rs7640662 was not associated with the risk of breast cancer in a Persian population; however, it was observed that heterozygote (GC) is the most common genotypes in both case and control samples. PMID- 25838922 TI - Impact of scaling and root planing on clinical periodontal status and glycemic levels in prediabetic patients. AB - OBJECTIVE: The aim was to assess the effect of scaling and root planing (SRP) on clinical periodontal parameters and glycemic levels in prediabetic patients. METHODS: Fifty prediabetic patients with periodontal disease were included. Demographic data (age, gender, education status, duration of prediabetes, type of treatment adopted for prediabetes management, and oral hygiene maintenance protocols) were recorded using a questionnaire. Patients were randomly divided into two groups (25 patients/group). In Group 1, SRP alone was performed, in Group 2, SRP + oral doxycycline (100 mg) administration. In both groups, fasting blood glucose (FBG) levels and periodontal parameters (plaque index [PI], bleeding on probing [BOP], and probing depth [PD]) were assessed at baseline and after 6 months. Statistical analysis was performed using one-way analysis of variance. RESULTS: Age, gender, and duration and treatment of prediabetes were comparable among patients in Groups 1 and 2. PI, BOP, and PD significantly reduced in both groups than baseline values. Reduction in periodontal parameters among Groups 1 and 2 were comparable. There was no significant reduction in FBG levels among patients in Groups 1 and 2 after 6 months of SRP. CONCLUSION: SRP was effective in reducing periodontal inflammation in prediabetic patients. FBG levels did not show any significant difference after SRP in both groups. PMID- 25838924 TI - Huge ascending aortic aneurysm with an intraluminal thrombus in an embolic event free patient. AB - We present a case of an 87-year-old male patient with a huge ascending aortic aneurysm, filled by a huge thrombus most probably due to previous dissection. This finding was detected by two-dimensional transthoracic echocardiography and contrast-enhanced computed tomography (CT) angiography scan. The patient refused surgical treatment and was medically treated. Despite the huge and mobile intraluminal thrombus, the patient remained embolic event-free up to 6 years later, and this makes the case unique. PMID- 25838923 TI - Embolization of traumatic and non-traumatic peripheral vascular lesions with Onyx. AB - PURPOSE: The aim of our study is to verify the feasibility and the efficacy of Onyx as embolization agent in the treatment of traumatic and non-traumatic peripheral vascular lesions. MATERIALS AND METHODS: In the period between September 2006 and March 2012, we treated with Onyx 26 patients (14 males/12 females; age range, 18-85 years old; mean age, 65 years old), 11 of which with traumatic peripheral vascular lesions and 15 with non-traumatic vascular lesions (9 neoplastic hemorrhagic lesions, 3 arteriovenous malformations (AVMs) and 3 aneurysms). Follow-up controls were performed with clinical examination and by multidetector computed tomography (MDCT) imaging 1, 6, and 12 months after the procedure. RESULTS: All peripheral vascular lesions were embolized with Onyx; 3 patients with aneurysms were treated with Onyx associated with endovascular coils. Four elective and 22 emergency embolization procedures were performed. In all patients, we obtained cessation of bleeding and the complete and permanent embolization of all vascular lesions. CONCLUSIONS: Onyx is an effective and safe embolization agent for peripheral vascular lesions. PMID- 25838925 TI - Textiloma formation post endovascular repair of abdominal aortic aneurysm. AB - We report a case of an 80-year-old man, who underwent an endovascular repair of an abdominal aortic aneurysm. Surgical access was obtained from both common femoral arteries, and the procedure was uneventful. One month computed tomography (CT) follow-up was without findings. Two months after endovascular aortic aneurysm repair (EVAR), the patient complained of claudication on the left side associated with persistent pain, rigid swelling on the left groin area, and occasional febrile episodes within the last month. Ultrasonography showed fluid collection, and needle aspiration gained pus. It was thought to be local postsurgical infection, and the patient got antibiotics, but he did worse. One month later, computed tomography revealed focal left common femoral artery (CFA) stenosis, edematous appearance of subcutaneous soft tissue in the left groin area, and anterior displacement of the ipsilateral CFA in relation to the right side. Surgical exploration of the region revealed retained, uncapsuled, and partially destroyed surgical gauze, lying just behind the left CFA, which was removed. PMID- 25838926 TI - Multiple simultaneous venous and arterial thromboses in a patient with factor V Leiden disorder: Detection by multislice computed tomography. AB - Arterial thrombosis is extremely rare in patients with factor V Leiden (FVL) mutation. Recent advances in multislice computed tomography (MSCT) technology facilitated diagnosis of thromboembolic events accurately without delay. We report a patient with FVL mutation and acute bilateral lower extremity deep venous thromboses, pulmonary thromboembolism, and acute left anterior descending artery thrombosis, all diagnosed by MSCT. MSCT has been utilized for prompt diagnosis of the concomitant thrombotic pathologies simultaneously. PMID- 25838927 TI - A gallbladder with the "hidden cystic duct": A brief overview of various surgical techniques of the Calot's triangle dissection. AB - We present a case of a middle-aged female who attended for a routine laparoscopic cholecystectomy as a day case surgery. At operation, she was found to have a distended gallbladder with an unusually prominent distal portion. This has made the dissection of the Calot's triangle challenging. As a result, the "critical view of safety" technique was applied. This allowed for the clear Calot's triangle visualization and identification of the cystic duct and artery. This case highlights that the knowledge of various ways of the cystic duct dissection is essential to every surgeon. Furthermore, this helps to adjust the dissection approach on an individual case bases ensuring avoidance of the common bile duct injuries. PMID- 25838929 TI - Health knowledge, attitude and practice among Iranian pilgrims. AB - BACKGROUND: Iran has the highest number of Umrah pilgrims among Islamic countries. Health care plays a major role in fulfilling the Umrah rites. Pilgrims' health situation depends on their health knowledge, attitude, and practice (KAP). OBJECTIVES: In this study, we aimed to determine the health KAP among Iranian Umrah pilgrims. PATIENTS AND METHODS: In this cross-sectional study, 157 Iranian Umrah pilgrims were randomly selected in Mecca, Saudi Arabia in June 2011. Data were collected using a questionnaire. The questionnaire consisted of demographic information (sex, age, degree of education, and resource of health knowledge), health knowledge (5 questions), health attitude (5 questions) and health practice (10 questions). RESULTS: Level of knowledge were very low in 12.1%, low in 25.2%, average in 38.1%, good in 20.4% and very good in 4.2% of respondents. Mean and standard deviation of attitude score was 18.58 +/- 2.20 out of 25 (ranged between 13.00 and 25.00). The pilgrims were given 74.2 % out of total score. The Mean and standard deviation of practice score was 8.19 +/ 1.32 out of 10 (ranged between 3 and 10). Although the old and low educated pilgrims had little knowledge of health tips, they had a good health attitude and practice. CONCLUSIONS: Educational strategy to improve knowledge regarding health related problems and to develop health practices among pilgrims is needed. PMID- 25838928 TI - Pregnancy experiences of first-time fathers in iran: a qualitative interview study. AB - BACKGROUND: Fatherhood, similarly to motherhood, is an important role and responsibility. For accepting this role, one needs to be well-prepared. Awareness of father's experiences of pregnancy can help us to develop plans for the promotion of the role of fatherhood. OBJECTIVES: The purpose of this study was to explore how first time fathers describe their experiences of pregnancy. PATIENTS AND METHODS: The data in this qualitative study were collected by individual open ended interviews in five public health prenatal care clinics in Tehran, Iran, during 2010 - 2011. Participants were 26 Iranian and Moslem first-time fathers living in Tehran, whose partner was in the 32th to 40th week of her normal pregnancy. Qualitative content text analysis was used for analyzing interviews. RESULTS: Through analysis of fathers' experiences of their wives' pregnancy, four categories, as well as associated subcategories, emerged. The categories include: "Emotional responses to pregnancy, Feeling of change, Accepting the reality and satisfaction, Developing identity as a father." These categories describe the phenomenon of "Transition to fatherhood". CONCLUSIONS: Transition to fatherhood extends beyond only moderate mental and social changes, and may be influenced by cultural background and beliefs. Therefore, caregivers should be aware of fathers' changes and needs during pregnancy, and support them while taking into consideration their culture and beliefs. PMID- 25838930 TI - Clinical determinants of left ventricular ejection fraction deterioration in patients suffered from complete left bundle branch block. AB - BACKGROUND: Recently, the deleterious effects of left bundle branch block (LBBB) on left ventricular systolic function have been taken into consideration. OBJECTIVES: The present study aimed to identify underlying factors that predict left ventricular ejection fraction (LVEF) deterioration in patients suffered from complete LBBB. PATIENTS AND METHODS: In a retrospective case-control study, the data of 220 consecutive patients diagnosed with LBBB on their electrocardiograms were assessed. They were referred to Isfahan Heart Center in Isfahan Province, Iran in 2013. LVEF deterioration was defined as a decrease in LVEF at least 10% between the baseline and follow-up echocardiography study. Thus, achieving the LVEF values <= 40% in patients with an initial EF of > 50% was considered LVEF deterioration. RESULTS: Among 220 patients, 40% of LBBB patients suffered LVEF deterioration within 3 months of initial assessment. The group with LVEF deterioration had higher male to female ratio, had higher NYHA score, and suffered more from systolic hypertension than another group. Those with coronary artery disease (CAD) had also significantly lower LVEF than non-CAD ones. Adverse associations were revealed between systolic blood pressure and LVEF measurement (r = -0.193, P = 0.006) as well as between NYHA score and LVEF (r = -0.215, P = 0.002). A multivariable logistic regression model showed that among baseline variables, male gender (OR = 3.218, P < 0.001), history of systolic hypertension (OR = 2.012, P = 0.029), higher NYHA score (OR = 1.623, P = 0.005), and the presence of coronary artery disease (OR = 2.475, P = 0.028) could effectively predict LVEF deterioration in patients with LBBB. CONCLUSIONS: Male gender, history of hypertension, high NYHA score, and the presence of CAD predict LVEF deterioration in patients with LBBB. PMID- 25838931 TI - How does a group of Iranian youth conceptualize their risky sexual experiences? AB - BACKGROUND: There are restrictions as well as lawful and religious prohibition for sexual relationships in Iranian society. OBJECTIVES: This study explores the varied experiential reality of Iranian youth and their risky sexual experiences. PATIENTS AND METHODS: Data collection is based on semi-structured interviews with 30 single young men and women. Observation of interactions of youth in different settings has been another source of information. Interviews were microscopically content analyzed. RESULTS: The accounts of risky sexual experiences included gendered behavioral, cultural, and cognitive factors. In the re-contextualizing process, these accounts were categorized by two main themes: "gendered sexual script" and "cultural scenarios of interpersonal interactions". The notion of "male power" was evident in the responses provided by the participants. Women seldom asked for condom use due to limited knowledge about STIs-HIV/AIDS and unpleasant experiences with condoms. Men had limited knowledge about various sexual modes of HIV and STIs transmission and did not use condoms consistently because they had not seen themselves at risk of STIs or HIV as well as their belief about the decrease of sexual pleasure. CONCLUSIONS: Rising youth awareness, creating a positive attitude, and appropriate knowledge about safe sex practices are seminal. It is also vital to ensure access to gender specific sexual and reproductive health services for youths, empower women, and strengthen their sexual assertiveness as well as the elimination of all forms of gender based inequalities. PMID- 25838932 TI - Effect of Cinnamomum zeylanicumon on Spermatogenesis. AB - BACKGROUND: In modern countries today, herbal medicines are known to help in the treatment of various diseases, as rich sources of antioxidants and minerals. OBJECTIVES: To study the effect of Cinnamomum zeylanicum (C. zeylanicum) on spermatogenesis in rats. MATERIALS AND METHODS: In this experimental study, Wistar male rats (n = 20) were divided into two groups, a control group (n = 10) and a Cinnamomum zeylanicum group (n = 10). The subjects in the cinnamon group received 75 mg/kg/day cinnamon by gavage for 28 days, while the controls received an equal volume of distilled water daily. Animals were kept in standardized conditions. On day 28, a 5 mL blood sample from each rat was taken from tail area to measure testosterone, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and malondialdehyde (MDA) levels. Testes were collected and were then prepared for sperm analysis by the WHO method. RESULTS: Sperm quality parameters, total serum testosterone, SOD, CAT, and GPX levels were significantly increased in the cinnamon group in comparison to controls (P < 0.05). Also, rats in the cinnamon group showed a significant decrease in the level of plasma MDA (P < 0.05) in comparison to controls. There were no significant differences between the groups in testis weight (P > 0.05). CONCLUSIONS: The administration of 75 mg/kg/day cinnamon significantly increased the sperm population, motility and viability, which supports the theory that in mammalians, cinnamon has a beneficial effect on spermatogenesis. PMID- 25838796 TI - Search for dark matter in events with heavy quarks and missing transverse momentum in [Formula: see text] collisions with the ATLAS detector. AB - This article reports on a search for dark matter pair production in association with bottom or top quarks in [Formula: see text] of [Formula: see text] collisions collected at [Formula: see text] TeV by the ATLAS detector at the LHC. Events with large missing transverse momentum are selected when produced in association with high-momentum jets of which one or more are identified as jets containing [Formula: see text]-quarks. Final states with top quarks are selected by requiring a high jet multiplicity and in some cases a single lepton. The data are found to be consistent with the Standard Model expectations and limits are set on the mass scale of effective field theories that describe scalar and tensor interactions between dark matter and Standard Model particles. Limits on the dark matter-nucleon cross-section for spin-independent and spin-dependent interactions are also provided. These limits are particularly strong for low-mass dark matter. Using a simplified model, constraints are set on the mass of dark matter and of a coloured mediator suitable to explain a possible signal of annihilating dark matter. PMID- 25838933 TI - Validity and reliability of the hausa version of multidimensional scale of perceived social support index. AB - BACKGROUND: Social support has been identified as one of the key factors for enhancing the quality of life after stroke. However, a scientific tool that is valid for evaluating social support among stroke survivors in Nigeria has not been developed so far. OBJECTIVES: The objective of this study was to examine the psychometric properties of the Hausa translated versions of the Multidimensional Scale of Perceived Social Support (MSPSS) and to validate it for future use in clinical research in Nigeria. PATIENTS AND METHODS: This cross-sectional study was conducted on a sample of 140 adult stroke survivors attending rehabilitation services at stroke referral centers in Kano, Nigeria. The psychometric analysis of the Hausa-MSPSS involved face, content, criterion and construct validity tests, as well as internal and test-retest reliability. Confirmatory factor analysis was performed to assess validity of the three-factor (Family, Friends and Significant others) model for the Hausa-MSPSS. RESULTS: Based on expert panel, clinicians' review and patients' feedback, the 12 item Hausa-MSPSS had sufficient face, content and criterion validity. In reliability analysis, the Cronbach's alpha was 0.781. In test-retest reliability analysis, the minimum kappa value was 0.673. In Confirmatory factor analysis, the three-factor model was not acceptable. An alternative two-factor model with Family and Friends, as the two domain was found to be acceptable (Chi-square/df < 3, TLI, CFI > 0.9, RMSEA < 0.08). The average variances extracted for the two constructs were 0.5 and 0.7, respectively. The R-squared value between the two constructs was 0.397. Cross validity tested using 1000 bootstrap resamples gave satisfactory results (P = 0.079). CONCLUSIONS: The 11 item Hausa-MSPSS index is valid for the assessment of perceived social support among stroke survivors in Nigeria. PMID- 25838794 TI - Measurements of the [Formula: see text] production cross sections in association with jets with the ATLAS detector. AB - This paper presents cross sections for the production of a [Formula: see text] boson in association with jets, measured in proton-proton collisions at [Formula: see text] with the ATLAS experiment at the large hadron collider. With an integrated luminosity of [Formula: see text], this data set allows for an exploration of a large kinematic range, including jet production up to a transverse momentum of [Formula: see text] and multiplicities up to seven associated jets. The production cross sections for [Formula: see text] bosons are measured in both the electron and muon decay channels. Differential cross sections for many observables are also presented including measurements of the jet observables such as the rapidities and the transverse momenta as well as measurements of event observables such as the scalar sums of the transverse momenta of the jets. The measurements are compared to numerous QCD predictions including next-to-leading-order perturbative calculations, resummation calculations and Monte Carlo generators. PMID- 25838793 TI - Search for invisible particles produced in association with single-top-quarks in proton-proton collisions at [Formula: see text] with the ATLAS detector. AB - A search for the production of single-top-quarks in association with missing energy is performed in proton-proton collisions at a centre-of-mass energy of [Formula: see text] with the ATLAS experiment at the large hadron collider using data collected in 2012, corresponding to an integrated luminosity of [Formula: see text] fb[Formula: see text]. In this search, the [Formula: see text] boson from the top quark is required to decay into an electron or a muon and a neutrino. No deviation from the standard model prediction is observed, and upper limits are set on the production cross-section for resonant and non-resonant production of an invisible exotic state in association with a right-handed top quark. In the case of resonant production, for a spin-[Formula: see text] resonance with a mass of [Formula: see text] GeV, an effective coupling strength above [Formula: see text] is excluded at 95[Formula: see text] confidence level for the top quark and an invisible spin-[Formula: see text] state with mass between [Formula: see text] and [Formula: see text] GeV. In the case of non resonant production, an effective coupling strength above [Formula: see text] is excluded at 95[Formula: see text] confidence level for the top quark and an invisible spin-[Formula: see text] state with mass between [Formula: see text] and [Formula: see text] GeV. PMID- 25838934 TI - Primary intraosseous hydatid cyst of femur. AB - INTRODUCTION: Echinococcosis is a parasitic and zoonotic disease of animals and humans. The cause is Echinococcus granulosus and occasionally, Echinococcus multilocularis. Hydatid cysts are mostly seen in the liver and lungs, although almost all organs and systemscan be involvement. Hydatid cysts seen with bone involvement comprise approximately 3% of all hydatid cysts. Even if a long period of survey is possible, it is still difficult to eradicate the disease and effect a cure. CASE PRESENTATION: In this study, an evaluation was made of a patient referred at Yozgat State Hospital Orthopedics and Traumatology Polyclinic with complaints of pain in her left thigh close to the knee. After examinations of plain radiographs, computerized tomography, magnetic resonance images, and blood parameters, a diagnosis was made of left femoral intramedullary hydatid cyst from excised intraoperative material. Throughout a 6-month follow-up period, there was no recurrence and functional results were good. CONCLUSIONS: Based on this report (of a patient presented with an intramedullary cyst in the long bones), the primary bone hydatid cyst disease should be kept in mind and be investigated in the differential diagnosis. PMID- 25838935 TI - Lessons learnt from the model of instructional system for training community health workers in rural health houses of iran. AB - BACKGROUND: Many experts believe that the "health houses" of Iran have had major effects in increasing health status of Iranian rural community. One of the factors, which was critical to this success is the employment of young women and men from rural communities who serve as multipurpose health workers. They participate in a two-year task-oriented training course. OBJECTIVES: The purpose of this article was to describe the model of training behvarzes as the community health workers who deliver health services to the health houses of Iran. This description included the specific method of recruiting these CHWs, strategies and methods of their training which is different from general academic education. MATERIALS AND METHODS: A descriptive study design was utilized for this analysis in six areas. These areas have been selected according to the expert opinions and experiences of the Center for Health Networks Management. RESULTS: The results showed the specific method of student selection and clear objectives and standards of training related to the health needs of the community. Recruitment of native human resources, the relationship between training and performance are the characteristics, which have been made this system more efficient and responsive to the health system needs. CONCLUSIONS: Development of the job and task analysis to ensure providing the right training needs, applying more evidences through different studies for reforms, more decentralized equipped system with decision-making tools have been proposed for development. PMID- 25838936 TI - Mothers' satisfaction with two systems of providing care to their hospitalized children. AB - BACKGROUND: Despite the paramount importance of the patient's satisfaction, there are limited data on mothers' satisfaction with the nursing care provided to their children in Iranian clinical settings. OBJECTIVES: This study aimed to evaluate mothers' satisfaction with two systems of providing care to their hospitalized children. PATIENTS AND METHODS: This research was a two-group quasi-experimental study. Primarily, the basics of the case method and the functional care delivery systems were educated to the practicing nurses of the study setting. Each system was implemented independently. After the implementation of each system, 200 mothers whose children were hospitalized in the pediatric care ward of Shahid Beheshti Hospital, Kashan, Iran, were invited to respond to the 28 -item Pediatric Family Satisfaction Questionnaire. Study data were analyzed by SPSS v. 16.0. RESULTS: Results were indicative of mothers' satisfaction with medical care delivered by case method as 13.2 +/- 5.2 and by functional method as 13.17 +/- 5.56. Also, no significant difference was seen between two groups (P = 0.4). Mothers' satisfaction with nursing care delivered by case method was 17.7 +/- 4.43 and by functional method was 13.33 +/- 5.69 and there was a significant difference between two groups (P = 0.004). Mothers' satisfaction with accommodations by case method was 16.78 +/- 4.07 and by functional method was 17.9 +/- 6.67 with a significant difference between two groups (P = 0.06). CONCLUSIONS: Improving the quality of care is associated with higher patient's satisfaction. Accordingly, developing and implementing programs for improving nurses' communication and clinical skills can improve both care quality and patient outcomes. PMID- 25838940 TI - Advances in retinal therapeutics. PMID- 25838938 TI - A comparative study of three speckle reducing methods for intima-media thickness ultrasound images. AB - BACKGROUND: Ultrasonic evaluation of intima-media thickness (IMT) is an early marker of assessing the development of atherosclerosis and determining cardiovascular risk. To attain the best possible diagnosis, it is essential that medical images be clear, sharp and without noise and artifacts. OBJECTIVES: Comparison of speckle reducing anisotropic diffusion (SRAD), discrete (DTD) and continuum topological derivative (CTD) on B-mode ultrasound images of common carotid and brachial arteries throughout the cardiac cycle. PATIENTS AND METHODS: In a cross-sectional design, an examination was performed on forty-two human subjects with a mean age of 44 +/- 6 years from April 2013 to June 2013. This study was approved by the ethics committees of Kashan University of Medical Sciences and Beheshti Hospital. An ultrasonic examination of common carotid and brachial arteries of forty-two human subjects was performed. The program was designed in MATLAB software to extract consecutive B-mode images and apply region of interest (ROI) on the IMT of the common carotid and brachial arteries. Then, three different noise reduction filters with the Canny edge detection were used in ROI separately. Finally, the program measured the image quality metrics. RESULTS: According to values of eleven different image quality metrics (mentioned in the main text), there was a significant difference between CTD, DTD and SRAD filters with the Canny edge detection status in the common carotid and brachial arteries throughout the cardiac cycle (all P values < 0.001). For example, peak signal to noise ratios (PSNR) using CTD, DTD and SRAD filters were 95.43 +/- 0.64, 88.86 +/- 0.82 and 73.02 +/- 0.20 in common carotid and 96.39 +/- 1.25, 92.58 +/- 0.11 and 88.27 +/- 0.63 in brachial arteries, respectively (both P values < 0.001). CONCLUSIONS: By measuring image quality metrics, this study showed that DTD and CTD filters with the Canny edge detection respectively, are better than SRAD filter with the Canny detection for speckle suppression and details preservation in both arteries in the ultrasound images. PMID- 25838944 TI - Anti-Oppressive Practice and Reflexive Lifeworld-Led Approaches to Care: A Framework for Teaching Nurses about Social Justice. AB - This paper was initially written for a European Academy of Caring Science workshop and aimed to provide clarity and direction about Caring Science by offering some ideas emerging from the philosophy, themes, and projects of EACS. An underpinning concept for the work of the Academy is the lifeworld. The focus of the workshop was to explore the lifeworld of the patient, student, and carer. The intention was to promote discussion around the need to provide alternative ways to conceptualise caring relevant knowledge, naming phenomena and practices central to caring sciences, and the educational curriculum and its adequacy for caring science. This paper seeks to identify concepts and approaches to understanding oppression, power, and justice which enable nurses to challenge the structures in health care environments which discriminate or disempower clients. Anti-oppressive practice theory and reflexive lifeworld-led approaches to care enable nurses to be critical of their practice. A framework for teaching social justice in health care is offered to augment teaching students to challenge oppressive practice and to assist nurses to reflect and develop conceptual models to guide practices which are central to promoting caring interactions. PMID- 25838939 TI - Lifestyle of the employees working in hamadan public sectors: application of the trans-theoretical model. AB - BACKGROUND: A healthy lifestyle is a valuable source to reduce the prevalence of health problems, and promoteehealth. OBJECTIVES: The current study aimed to evaluate the lifestyle and obesity status of Hamadan public employees and their status based on the trans-theoretical model (TTM). PATIENTS AND METHODS: This analytical cross-sectional study was performed in 2014 on 1200 public employees in Hamadan city, Iran selected through proportional stratified random sampling. Data collection was performed using a three-section questionnaire including demographic characteristics, The FANTASTIC lifestyle questionnaire, and the five part algorithm. Data were analyzed by SPSS-20 using linear regression, Chi square, Fisher exact test, and ANOVA. RESULTS: The mean age of the employees was 38.12 +/- 8.04 years. Most of the employees (61.7%) had favorable lifestyle. About half of the employees were at the preparation stage of TTM. Most of the employees were in a poor condition regarding the physical activity and healthy eating habits. In most of the evaluated items, females got higher scores than males. The associations between lifestyle and age, gender, work experience, income satisfaction, and marital status were significant. Moreover, the associations between obesity and work experience, marital status, number of offspring, and gender were significant (P < 0. 05). Significant predicting variables of obesity were age and work experience; they explained 31.2% variance of obesity (adjusted R(2) = 0.312, R(2) change = 0.01). CONCLUSIONS: Planning health education interventions for employees through effective approaches seems necessary. PMID- 25838946 TI - Methylphenidate Efficacy: Immediate versus Extended Release at Short Term in Mexican Children with ADHD Assessed by Conners Scale and EEG. AB - Attention deficit hyperactivity disorder (ADHD) affects 5-6% of school aged children worldwide. Pharmacological therapy is considered the first-line treatment and methylphenidate (MPH) is considered the first-choice medication. There are two formulations: immediate release (IR) MPH and long-acting (or extended release) formulation (MPH-ER). In this work, we measure the efficacy of treatment for both presentations in one month with Conners' scales and electroencephalography (EEG). Results. for IR group, in parents and teachers Conners test, all items showed significant differences, towards improvement, except for teachers in perfectionism and emotional instability. For ER group in parent's Conners test, the items in which there were no significant differences are psychosomatic and emotional instability. For teachers, there were no significant differences in: hyperactivity and perfectionism. Comparing the Conners questionnaires (parents versus teachers) we find significant differences before and after treatment in hyperactivity, perfectionism, psychosomatics, DSM IV hyperactive-impulsive, and DSM-IV total. In the EEG the Wilcoxon test showed a significant difference (P < 0.0001). As we can see, both presentations are suitable for managing the ADHD and have the same effect on the symptomatology and in the EEG. PMID- 25838937 TI - Comparative study of radiographic and laboratory findings between Beta thalassemia major and Beta thalassemia intermedia patients with and without treatment by hydroxyurea. AB - BACKGROUND: In patients with thalassemia, chronic anemia causes bone marrow expansion and consequently skeletal manifestation in spine, skull, face and rib bones. OBJECTIVES: We aimed to compare chest radiographic findings and facial bone deformity in patients with thalassemia major (TM) and intermedia. PATIENTS AND METHODS: In this cross sectional study, 86 consecutive thalassemia patients referring to the Thalassemia clinic in Shiraz, Southern Iran were evaluated during 2012. Patients were divided into three groups including TM and thalassemia intermedia (TI) with and without taking hydroxyurea (HU). Findings ofchest radiography (trabeculation, rib widening and paraspinal masses) as well as facial bone deformity were evaluated by an expert radiologist. Besides, laboratory findings were measured regarding hemoglobin, ferritin, NRBC and platelet count. RESULTS: All radiologic findings were significantly higher in patients with TI compared to TM (P< 0.05). In patients with TI, only trabeculation was observed with a higher frequency in patients with HU compared to those without HU (68% vs. 27.3%, P= 0.008). In the regression model, from all variables evaluated, only NRBC showed a significant correlation with trabeculation (Exp B = 1.014, CI: 1.004-1.025, P = 0.008) and age showed a significant correlation with paravertebral mass (Exp B = 1.147, CI: 1.03-1.27, P = 0.013). CONCLUSIONS: In patients with TM, bone widening, trabeculation, paraspinal masses and facial bone deformity were lower than patients with TI, whichcan be related to effectiveness of therapy with blood transfusion irrespective of its adverse effects in TM patients. PMID- 25838942 TI - Attenuating Photostress and Glare Disability in Pseudophakic Patients through the Addition of a Short-Wave Absorbing Filter. AB - To evaluate the effects of filtering short wavelength light on visual performance under intense light conditions among pseudophakic patients previously implanted with a clear intraocular lens (IOL). This was a patient-masked, randomized crossover study conducted at 6 clinical sites in the United States between September 2013 and January 2014. One hundred fifty-four bilaterally pseudophakic patients were recruited. Photostress recovery time and glare disability thresholds were measured with clip-on blue-light-filtering and placebo (clear; no blue-light filtration) glasses worn over patients' habitual correction. Photostress recovery time was quantified as the time necessary to regain sight of a grating target after intense light exposure. Glare disability threshold was assessed as the intensity of a white-light annulus necessary to obscure a central target. The order of filter used and test eye were randomized across patients. Photostress recovery time and glare disability thresholds were significantly improved (both P < 0.0001) when patients used blue-light-filtering glasses compared with clear, nonfiltering glasses. Compared with a nonfiltering placebo, adding a clip-on blue-absorbing filter to the glasses of pseudophakic patients implanted with clear IOLs significantly increased their ability to cope with glare and to recover normal viewing after an intensive photostress. This result implies that IOL designs with blue-light-filtering characteristics may be beneficial under intense light conditions. PMID- 25838947 TI - Modulation of Adipocytokines Production and Serum NEFA Level by Metformin, Glimepiride, and Sitagliptin in HFD/STZ Diabetic Rats. AB - Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by hyperglycemia owing to insulin resistance and/or insulin deficiency. Current theories of T2DM pathophysiology include a decline in beta-cells function, a defect in insulin signaling pathways, and a dysregulation of secretory function of adipocytes. This study aimed to investigate the effect of different antidiabetic drugs on serum levels of certain adipocytokines and nonesterified fatty acids (NEFA) in high-fat diet (HFD)/streptozotocin- (STZ-) induced diabetic rats. All treatments significantly decreased serum NEFA level. Metformin and sitagliptin increased serum adiponectin level, whereas they decreased serum leptin level. Glimepiride showed significant decline in serum levels of both adiponectin and leptin. All treatments remarkably ameliorated insulin resistance, suggested by an improvement of glycemic control, a significant reduction in homeostasis model assessment of insulin resistance (HOMA-IR), and a correction in lipid profile. Modulation of adipocytokines production (i.e., increased serum adiponectin and decreased serum leptin) may also underlie the improvement of insulin resistance and could be a possible mechanism for the beneficial cardiovascular effects of metformin and sitagliptin. PMID- 25838945 TI - Emergence: complexity pedagogy in action. AB - Many educators are looking for new ways to engage students and each other in order to enrich curriculum and the teaching-learning process. We describe an example of how we enacted teaching-learning approaches through the insights of complexity thinking, an approach that supports the emergence of new possibilities for teaching-learning in the classroom and online. Our story begins with an occasion to meet with 10 nursing colleagues in a three-hour workshop using four activities that engaged learning about complexity thinking and pedagogy. Guiding concepts for the collaborative workshop were nonlinearity, distributed decision making, divergent thinking, self-organization, emergence, and creative exploration. The workshop approach considered critical questions to spark our collective inquiry. We asked, "What is emergent learning?" and "How do we, as educators and learners, engage a community so that new learning surfaces?" We integrated the arts, creative play, and perturbations within a complexity approach. PMID- 25838953 TI - The Hidden Cost of Untreated Paragangliomas of the Head and Neck: Systemic Reactive (AA) Amyloidosis. AB - We report a case of a 51-year-old man who was diagnosed with systemic reactive (AA) amyloidosis in association with untreated glomus jugulare and glomus caroticum tumors. He refused radiotherapy and renal replacement therapy. Paragangliomas, although rare, should be considered one of the tumors that can result in AA amyloidosis. PMID- 25838957 TI - Synthetic cannabis-induced mania. AB - Synthetic cannabinoids (SC), cannabinoid 1 and cannabinoid 2 receptors agonists, are the psychoactive substances. SC was originally produced to treat medical conditions. Compared to other narcotics, SC is easier to obtain, cheap, and highly potent and has a long half-life. In addition, routine analysis does not detect SC, which has led to widespread use. A case is presented that manic episode was developed with the use of SC. Hospitalization and admission to psychiatric units depending on SC use have been observed mostly with psychosis. Although SC-induced affective symptoms were mentioned in the literature, mania has not been reported before. We aimed to discuss the psychiatric conditions induced by widespread use of SC via our case. PMID- 25838955 TI - Dealing with Pheochromocytoma during the First Trimester of Pregnancy. AB - Purpose. Pheochromocytoma in association with pregnancy is a very rare, without specific symptoms, life-threatening condition, increasing both maternal and fetal mortality up to 50%. The present paper illustrates the case of a pregnant woman, diagnosed with pheochromocytoma, aiming to demonstrate and discuss the difficulties that arouse during the diagnosis and the problems concerning the treatment. Patient. A 34-year-old woman, in the 9th week of pregnancy, complained for headache, sweating, and a feeling of heavy weight on the right renal area. A tumor of 10 cm diameter at the site of the right adrenal was found. Twenty-four hour urine catecholamine and VMA excretion levels were well raised. Results. Multidisciplinary approach treated the patient conservatively. Surgical resection of the tumor was performed after the 14th week of pregnancy at the completion of organogenesis. Neither postoperative complications occurred nor hypertension relapse was recorded. The fetus was delivered without complications at the 36th week. Conclusions. There are no consensus and guidelines for treating pheochromocytoma during pregnancy, especially when it is diagnosed in the first trimester. The week of pregnancy and a multidisciplinary approach will determine whether the pregnancy should be continued or not, as well as the time and the approach of surgical treatment. PMID- 25838948 TI - Conservative treatment of a large facial midroot perforation. AB - Aim. To report on the endodontic and periodontal management of a root and alveolar process perforation in a maxillary front tooth. Summary. Perforation during access cavity preparation is an infrequent complication during endodontic therapy, leading to potential periodontal tissue breakdown. The case described the two-stage management of a massive facial root perforation requiring a connective tissue graft to correct a mucosal fenestration persisting after orthograde repair of the root defect with MTA. PMID- 25838943 TI - Obesity and metabolic phenotypes (metabolically healthy and unhealthy variants) are significantly associated with prevalence of elevated C-reactive protein and hepatic steatosis in a large healthy Brazilian population. AB - BACKGROUND: Among the obese, the so-called metabolically healthy obese (MHO) phenotype is thought to confer a lower CVD risk as compared to obesity with typical associated metabolic changes. The present study aims to determine the relationship of different subtypes of obesity with inflammatory-cardiometabolic abnormalities. METHODS: We evaluated 5,519 healthy, Brazilian subjects (43 +/- 10 years, 78% males), free of known cardiovascular disease. Those with <2 metabolic risk factors (MRF) were considered metabolically healthy, and those with BMI >= 25 kg/m(2) and/or waist circumference meeting NCEP criteria for metabolic syndrome as overweight/obese (OW). High sensitivity C reactive protein (hsCRP) was measured to assess underlying inflammation and hepatic steatosis (HS) was determined via abdominal ultrasound. RESULTS: Overall, 40% of OW individuals were metabolically healthy, and 12% normal-weight had >=2 MRF. The prevalence of elevated CRP (>=3 mg/dL) and HS in MHO versus normal weight metabolically healthy group was 22% versus 12%, and 40% versus 8% respectively (P < 0.001). Both MHO individuals and metabolically unhealthy normal weight (MUNW) phenotypes were associated with elevated hsCRP and HS. CONCLUSION: Our study suggests that MHO and MUNW phenotypes may not be benign and physicians should strive to treat individuals in these subgroups to reverse these conditions. PMID- 25838954 TI - Palliative care for a mentally incompetent end stage renal failure patient: why is it important? AB - People with intellectual disabilities are among the most disadvantaged groups in society. Here we report a mentally incompetent end stage renal failure (ESRF) patient with frequent emergency visits who made a significant improvement in symptoms control and reduction in casualty visits after introduction of renal palliative care service. Multidisciplinary approach would be useful in this case. PMID- 25838958 TI - Amisulpride augmentation for clozapine-refractory positive symptoms: additional benefit in reducing hypersialorrhea. AB - One-third to half of patients taking clozapine suffer from refractory symptoms despite adequate treatment. Among other adverse effects, clozapine-induced hypersalivation (CIH) occurs in approximately half of all patients. This is a case of a 30-year-old male with refractory schizophrenia; in this patient, the remission of residual positive symptoms, as well as the reduction of CIH, was achieved by treatment with clozapine augmented with amisulpride. PMID- 25838951 TI - Thyroid storm precipitated by duodenal ulcer perforation. AB - Thyroid storm is a rare and life-threatening complication of thyrotoxicosis that requires prompt treatment. Thyroid storm is also known to be associated with precipitating events. The simultaneous treatment of thyroid storm and its precipitant, when they are recognized, in a patient is recommended; otherwise such disorders, including thyroid storm, can exacerbate each other. Here we report the case of a thyroid storm patient (a 55-year-old Japanese male) complicated with a perforated duodenal ulcer. The patient was successfully treated with intensive treatment for thyroid storm and a prompt operation. Although it is believed that peptic ulcer rarely coexists with hyperthyroidism, among patients with thyroid storm, perforation of a peptic ulcer has been reported as one of the causes of fatal outcome. We determined that surgical intervention was required in this patient, reported despite ongoing severe thyrotoxicosis, and reported herein a successful outcome. PMID- 25838952 TI - Virus-associated hemophagocytic syndrome in renal transplant recipients: report of 2 cases from a single center. AB - Virus-associated hemophagocytic syndrome (HPS) is a potentially fatal complication of immunosuppression for transplantation. However, it presents with heterogeneous clinical symptoms (fever, disturbed consciousness, and hepatosplenomegaly) and laboratory findings (pancytopenia, elevated hepatic enzyme levels, abnormal coagulation, and hyperferritinemia), impeding diagnosis. Case 1: A 39-year-old female developed fever 4 years after ABO-incompatible living-related renal transplantation. Laboratory findings revealed thrombocytopenia, elevated hepatic enzymes, Epstein-Barr virus (EBV) DNA seropositivity, and hyperferritinemia. EBV-associated HPS was confirmed by bone marrow aspiration. Steroid pulse therapy and etoposide were ineffective. Disseminated intravascular coagulation resulted in multiple organ failure, and the patient died 32 days after disease onset. Case 2: A 67-year-old male was admitted with rotavirus enteritis a month after living-unrelated renal transplantation. He developed sudden-onset high fever, disturbance of consciousness, and tachypnea 8 days after admission. Laboratory findings revealed elevated hepatic enzyme levels, hyperkalemia, and hyperferritinemia. Emergency continuous hemodiafiltration ameliorated the fever, and steroid pulse therapy improved abnormal laboratory values. Varicella-zoster virus meningitis was confirmed by spinal tap. Acyclovir improved consciousness, and he was discharged 87 days after admission. Fatal virus-associated HPS may develop in organ transplant patients receiving immunosuppressive therapy. Pathognomonic hyperferritinemia is useful for differential diagnosis. PMID- 25838956 TI - Complication with removal of a lumbar spinal locking plate. AB - Introduction. The use of locking plate technology for anterior lumbar spinal fusion has increased stability of the vertebral fusion mass over traditional nonconstrained screw and plate systems. This case report outlines a complication due to the use of this construct. Case. A patient with a history of L2 corpectomy and anterior spinal fusion presented with discitis at the L4/5 level and underwent an anterior lumbar interbody fusion (ALIF) supplemented with a locking plate placed anterolaterally for stability. Fifteen months after the ALIF procedure, he returned with a hardware infection. He underwent debridement of the infection site and removal of hardware. Results. Once hardware was exposed, removal of the locking plate screws was only successful in one out of four screws using a reverse thread screw removal device. Three of the reverse thread screw removal devices broke in attempt to remove the subsequent screws. A metal cutting drill was then used to break hoop stresses associated with the locking device and the plate was removed. Conclusion. Anterior locking plates add significant stability to an anterior spinal fusion mass. However, removal of this hardware can be complicated by the inherent properties of the design with significant risk of major vascular injury. PMID- 25838950 TI - Posttraumatic displacement management: lateral luxation and alveolar bone fracture in young permanent teeth with 5 years of follow-up. AB - Dental trauma is an important public health problem due to high prevalence and associated limitations. The external impact accounting for trauma may result in different injury types to teeth and supporting structures. This paper describes a clinical case of tooth trauma in an 8-year-old patient exhibiting the displacement of three permanent teeth with open root apexes. Although the traumatic impact resulted in two injury types to teeth and supporting tissues (lateral luxation and alveolar bone fracture), the therapeutic approach was the same in both situations. The bone and teeth were repositioned by digital pressure, stabilized by semirigid splint, and followed up at every week. After six weeks, the splint was removed. At that moment, the clinical and radiographic findings indicated normal soft/hard tissues and absence of pulp/periodontal pathologies. At the fifth year of follow-up, the treatment success of the case was confirmed, although it has been observed that all lower incisors exhibited pulp obliteration as a consequence of the dental trauma. PMID- 25838960 TI - An unusual long-term survey of a patient with widespread malignant urachal tumor, not given chemotherapy or radiotherapy. AB - The urachus establishes a connection between the dome of the bladder and the umbilicus throughout fetal life. If the urachus does not close completely, malignancy is a potential complication. The primary treatment for malignant urachal tumor is surgical excision. A 61-year-old male patient diagnosed with urachal carcinoma had undergone partial cystectomy 25 years previously. Twenty years later, local recurrence was treated with another partial cystectomy without umbilical remnant excision. Recurrence at the umbilical site was excised 2 years later, but intraperitoneal invasion had occurred, and the patient underwent a total colectomy at that time. Local disease and disseminated metastases in the thorax and intra- and extraperitoneal areas were noted upon admission to our hospital. Urachal carcinomas are usually aggressive tumors, and surgical treatment should include partial or radical cystectomy and excision of the urachus and umbilicus, to prevent local recurrence and distant metastasis. PMID- 25838941 TI - The role of eye movement driven attention in functional strabismic amblyopia. AB - Strabismic amblyopia "blunt vision" is a developmental anomaly that affects binocular vision and results in lowered visual acuity. Strabismus is a term for a misalignment of the visual axes and is usually characterized by impaired ability of the strabismic eye to take up fixation. Such impaired fixation is usually a function of the temporally and spatially impaired binocular eye movements that normally underlie binocular shifts in visual attention. In this review, we discuss how abnormal eye movement function in children with misaligned eyes influences the development of normal binocular visual attention and results in deficits in visual function such as depth perception. We also discuss how eye movement function deficits in adult amblyopia patients can also lead to other abnormalities in visual perception. Finally, we examine how the nonamblyopic eye of an amblyope is also affected in strabismic amblyopia. PMID- 25838959 TI - Primary pulmonary malignant fibrous histiocytoma. AB - Malignant fibrous histiocytoma (MFH) is one of the most common adult soft tissue sarcomas. MFH is very aggressive and is most often found in the extremities and the retroperitoneum, but it can manifest at other sites. Though the lungs are the most common sites of metastasis, they rarely present there as a primary tumor. Our report describes a rare case of a primary MFH tumor in the lung. Careful diagnostic procedure should be followed to ensure the tumor does not have extrapulmonary origins. Though MFH is highly invasive and deadly, surgical excision of the tumor has been shown to be successful. PMID- 25838949 TI - Severe gingival enlargement with coexisting erosive lichen planus in severe chronic periodontitis patient. AB - Plaque induced gingival enlargement is most commonly seen and when encountered simultaneously with erosive lichen planus poses a challenge to the treating dentist. Prognosis of one condition may influence the prognosis of another condition. The presented case highlights the significance of proper diagnosis and the management of simultaneously occurring gingival lesions. A 49-year-old hypertensive female presented with painful enlarged bleeding and suppurating gums with burning sensation on eating food along with long-term usage of antihypertensive drug amlodipine known for its gingival enlargement effect. All these multiple factors led to diagnostic dilemma. Effective management of the gingival enlargement was done by using electrocautery to rehabilitate the functions and esthetics of the patient. Gingival condition was also complicated by the presence of coexisting lichen planus which was predominantly erosive for which topical corticosteroid, antifungal, and antimicrobial agents were prescribed. Eight-month follow-up did not show recurrence of gingival enlargement. Electrocautery is an effective tool for the gingivectomy in severe inflammatory type of gingival enlargement because of rapid postoperative hemostasis. For the management of erosive lichen planus, long-term use of topical corticosteroids is an effective approach. Maintenance of oral hygiene and regular follow-ups are essential for these conditions. PMID- 25838792 TI - Search for resonant diboson production in the [Formula: see text] final state in [Formula: see text] collisions at [Formula: see text] TeV with the ATLAS detector. AB - This paper reports on a search for narrow resonances in diboson production in the [Formula: see text] final state using [Formula: see text] collision data corresponding to an integrated luminosity of [Formula: see text] fb[Formula: see text] collected at [Formula: see text] TeV with the ATLAS detector at the Large Hadron Collider. No significant excess of data events over the Standard Model expectation is observed. Upper limits at the 95 % confidence level are set on the production cross section times branching ratio for Kaluza-Klein gravitons predicted by the Randall-Sundrum model and for Extended Gauge Model [Formula: see text] bosons. These results lead to the exclusion of mass values below 740 and 1590 GeV for the graviton and [Formula: see text] boson respectively. PMID- 25838961 TI - Monoarticular hip involvement in pseudogout. AB - Pseudogout is the acutest form of arthritis in the elderly. Although clinical manifestations vary widely, polyarticular involvement is typical mimicking osteoarthritis or rheumatoid arthritis. Monoarticular involvement is relatively rare and is generally provoked by another medical condition. There are reported cases of hip involvement by pseudogout in monoarticular form. However, all of the cases were presented as septic arthritis. In this report, we present a case of monoarticular hip involvement mimicking soft tissue abscess. We confirmed the pseudogout diagnosis after ultrasonographic evaluation of the involved hip joint and pathological and biochemical analysis of synovial fluid analysis. Diagnosis is important to avoid unnecessary medical and surgical treatment in cases of the bizarre involvement of hip in pseudogout. PMID- 25838962 TI - Orbital Pseudotumor: Uncommon Initial Presentation of IgG4-Related Disease. AB - IgG4-related disease (IgG4-RD) encompasses a group of fibroinflammatory conditions recognized in recent times. The main clinical features include variable degrees of tissue fibrosis, tumorlike expansions, perivascular lymphocytic infiltration rich in IgG4-positive plasma cells, and elevated serum IgG4. A case has been reported of an elderly patient with an unexplained unilateral exophthalmia; biopsy was performed and revealed lymphocytic infiltration, suggesting IgG4-RD. High serum levels of IgG4, in association with a good response to steroid therapy and to the exclusion of other diagnoses, confirmed the hypothesis of orbital pseudotumor by IgG4-RD. PMID- 25838966 TI - Telecytopathology facilitates the use of rapid on-site evaluation in endoscopic ultraound fine needle aspiration of the pancreas to improve patient outcomes. PMID- 25838965 TI - 2014 American Telemedicine Association clinical guidelines for telepathology: Another important step in support of increased adoption of telepathology for patient care. PMID- 25838964 TI - Enterovesical fistula caused by a toothpick. AB - We present a case of enterovesical fistula caused by an accidental ingestion of a foreign body. A 23-year-old man presented to our hospital with pneumaturia, fecaluria, and abdominal pain but no recent possible causes of enterovesical fistula at anamnesis. Cystoscopy, cystography, and also colonoscopy were not able to detect the fistulous tract. Computer tomography (CT) revealed a fistula between bladder and bowels caused by a toothpick accidentally swallowed 2 years earlier. We tried to remove the foreign body endoscopically by cystoscopy and colonoscopy but with no success. The failure of endoscopic procedures required a surgical treatment. The patient underwent laparoscopic segmental resection of the sigmoid colon to remove the fistulous tract and the foreign body. The cystography revealed no external leakage of contrast from the bladder with complete resolution of the problem. PMID- 25838967 TI - Automated discrimination of lower and higher grade gliomas based on histopathological image analysis. AB - INTRODUCTION: Histopathological images have rich structural information, are multi-channel in nature and contain meaningful pathological information at various scales. Sophisticated image analysis tools that can automatically extract discriminative information from the histopathology image slides for diagnosis remain an area of significant research activity. In this work, we focus on automated brain cancer grading, specifically glioma grading. Grading of a glioma is a highly important problem in pathology and is largely done manually by medical experts based on an examination of pathology slides (images). To complement the efforts of clinicians engaged in brain cancer diagnosis, we develop novel image processing algorithms and systems to automatically grade glioma tumor into two categories: Low-grade glioma (LGG) and high-grade glioma (HGG) which represent a more advanced stage of the disease. RESULTS: We propose novel image processing algorithms based on spatial domain analysis for glioma tumor grading that will complement the clinical interpretation of the tissue. The image processing techniques are developed in close collaboration with medical experts to mimic the visual cues that a clinician looks for in judging of the grade of the disease. Specifically, two algorithmic techniques are developed: (1) A cell segmentation and cell-count profile creation for identification of Pseudopalisading Necrosis, and (2) a customized operation of spatial and morphological filters to accurately identify microvascular proliferation (MVP). In both techniques, a hierarchical decision is made via a decision tree mechanism. If either Pseudopalisading Necrosis or MVP is found present in any part of the histopathology slide, the whole slide is identified as HGG, which is consistent with World Health Organization guidelines. Experimental results on the Cancer Genome Atlas database are presented in the form of: (1) Successful detection rates of pseudopalisading necrosis and MVP regions, (2) overall classification accuracy into LGG and HGG categories, and (3) receiver operating characteristic curves which can facilitate a desirable trade-off between HGG detection and false-alarm rates. CONCLUSION: The proposed method demonstrates fairly high accuracy and compares favorably against best-known alternatives such as the state-of-the-art WND-CHARM feature set provided by NIH combined with powerful support vector machine classifier. Our results reveal that the proposed method can be beneficial to a clinician in effectively separating histopathology slides into LGG and HGG categories, particularly where the analysis of a large number of slides is needed. Our work also reveals that MVP regions are much harder to detect than Pseudopalisading Necrosis and increasing accuracy of automated image processing for MVP detection emerges as a significant future research direction. PMID- 25838963 TI - Small Bowel Obstruction Mimicking Acute ST-Elevation Myocardial Infarction. AB - We present a case of a 42-year-old female who presented to our institution with a small bowel obstruction and had emergent surgical decompression. Thirteen days postoperatively, the patient became tachycardic and had worsening epigastric pain. Electrocardiogram showed significant ST-segment elevations in leads II, III, aVF, and V3-V6, suggesting the possibility of acute inferolateral myocardial infarction. Subsequent workup revealed the cause of the ST-elevations to be due to recurrent small bowel obstruction. Although intra-abdominal causes of ST elevation have been reported, our case may be the first to be associated with small bowel obstruction. PMID- 25838968 TI - Default settings of computerized physician order entry system order sets drive ordering habits. AB - BACKGROUND: Computerized physician order entry (CPOE) systems are quickly becoming ubiquitous, and groups of orders ("order sets") to allow for easy order input are a common feature. This provides a streamlined mechanism to view, modify, and place groups of related orders. This often serves as an electronic equivalent of a specialty requisition. A characteristic, of these order sets is that specific orders can be predetermined to be "preselected" or "defaulted-on" whenever the order set is used while others are "optional" or "defaulted-off" (though there is typically the option is to "deselect" defaulted-on tests in a given situation). While it seems intuitive that the defaults in an order set are often accepted, additional study is required to understand the impact of these "default" settings in an order set on ordering habits. This study set out to quantify the effect of changing the default settings of an order set. METHODS: For quality improvement purposes, order sets dealing with transfusions were recently reviewed and modified to improve monitoring of outcome. Initially, the order for posttransfusion hematocrits and platelet count had the default setting changed from "optional" to "preselected." The default settings for platelet count was later changed back to "optional," allowing for a natural experiment to study the effect of the default selections of an order set on clinician ordering habits. RESULTS: Posttransfusion hematocrit values were ordered for 8.3% of red cell transfusions when the default order set selection was "off" and for 57.4% of transfusions when the default selection was "preselected" (P < 0.0001). Posttransfusion platelet counts were ordered for 7.0% of platelet transfusions when the initial default order set selection was "optional," increased to 59.4% when the default was changed to "preselected" (P < 0.0001), and then decreased to 7.5% when the default selection was returned to "optional." The posttransfusion platelet count rates during the two "optional" periods: 7.0% versus 7.5% - were not statistically different (P = 0.620). DISCUSSION: Default settings in CPOE order sets can significantly influence physician selection of laboratory tests. Careful consideration by all stakeholders, including clinicians and pathologists, should be obtained when establishing default settings in order sets. PMID- 25838969 TI - Imaging file management to support international telepathology. AB - BACKGROUND: Telepathology practice across international borders has become increasingly popular. Our telepathology consultation service with a laboratory in China was hampered by latency issues when viewing whole slide images. OBJECTIVE: The aim was to explore data transfer solutions to improve the viewing experience of digital consult cases. METHODS: Whole slide image files residing on a server in China were transferred to our data center in the USA using an open source product (Fast Data Transfer). A faster more automated commercial high speed file transfer software solution (Aspera) was also tested. RESULTS: Transferring files with the open source product provided transfer speeds of 2-3 Mbps, but suffered from intermittent dropped connections. Employing commercial software permitted more reliable transmission of digital files with 75-100 Mbps transfer speeds. CONCLUSIONS: Successful global telepathology requires dedicated image management. Transfer of files to local servers by employing high speed data transfer tools helped overcome network latency issues, improved the overall turn-around time of digital consultations, and enhanced the viewing experience for end-user digital consultants. PMID- 25838970 TI - Enantioselective Cascade Cyclization/Protodemetalation of Polyenes with N3Pt2+ Catalysts. AB - The combination of the N-based pincer ligand PyBOX with Pt2+ leads to new catalysts for the enantioselective cycloisomerization of dienyl- and trienyl-ols. The mechanistic combination of electrophilic cyclization followed by rapid protodemetalation is surprising and leads to a powerful construct for developing new reactions. PMID- 25838971 TI - Mechanistic and Kinetic Studies of the Direct Alkylation of Benzylic Amines: A Formal C(sp3)-H Activation Proceeds Actually via a C(sp2)-H Activation Pathway. AB - Mechanistic investigations of a Rh(I)-catalyzed direct C-H alkylation of benzylic amines with alkenes, formally an C(sp3)-H activation, reveal this reaction to proceed via imine intermediates and, hence, via C(sp2)-H activation. The reaction shows a primary kinetic isotope effect of 4.3 at the benzylic C-H position together with a reversible H-D exchange at the same position, which indicates that there are at least two distinct steps in which the corresponding C-H bonds are broken. The imine intermediates are shown to be converted to the final product under the reaction conditions, and a time course analysis of the alkylated imine intermediate shows that it is formed before the final amine product in the course of the reaction. PMID- 25838972 TI - A Cohort Historical Analysis of the Relationship between Thyroid Hormone Malady and Alpha-Human Herpesvirus Activation. AB - BACKGROUND: A number of physiological factors have been suggested to participate in the alpha- Human Herpesvirus (alphaHHV) reactivation, such as hormonal aberration. Thyroid hormone (TH) was shown to play a suppressive role in Herpes Simplex Virus Type-1 (HSV-1) gene expression and replication in cell culture and animal models. We hypothesize that reactivation of alphaHHV in humans may be due to, at least in part, by TH status. METHODS: Prior to implementing a full-scale population-based prospective inquiry into this hypothesis, a pilot study using a medical claims data base and a case-controlled, retrospective cohort investigation was conducted to develop a hypothetical link between TH complication and alphaHHV reactivation. Using diagnostic codes for treating thyroid disorders and alphaHHV infections as proxies for biologic/clinic outcomes, we queried a large, comprehensive hospital data base to construct two patient cohorts: Cohort 1 was comprised of patients receiving TH diagnoses over a twelve-year period, and Cohort 2 was composed of patients not receiving TH diagnoses during this period. Diagnoses of alphaHHV were recorded for each cohort and the difference in the frequency was examined for statistical significance. Demographic analyses such as age, gender, etc were also performed. RESULTS: Using 2*2 contingency table analyses and Statistical Analysis Software (SAS), an Odds Ratio (OR) of 2.83 was observed for the total population of 21 years old and above with a chi-square of 61.55 and p < 0.001, confirming that a severe significant difference was found between these two cohorts. This result suggested that patients with alphaHHV diagnosis have higher chances to have TH disorders. Additional investigation revealed that female were at higher/significant probability to have both TH and alphaHHV diagnosis, indicating a link of alphaHHV reactivation to a complex hormonal profile difference between genders. Our observation indicated that female patients of 21 years of age and above exhibited a very high incidence (OR of 3.40, p < 0.001) compared to the male groups (OR of 1.91, p < 0.05), indicating the possibility that hormonal alteration in females maybe transient but robust and can lead to alphaHHV reactivation more often than the males. CONCLUSION: These results indicated that TH dysfunction may have implication in alphaHHV pathogenesis and females exhibited much higher probability to suffer alphaHHV reactivation due to TH disruption. Although the results from this pilot study have limitations and require additional controlled clinical examination such as more detailed patient records, lab data, therapeutic outcome, etc, it provides a tool to assess the effects of hormone imbalance on virus reactivation by retrospective analyses using existing large scale data base. PMID- 25838973 TI - CDKN1A and FANCD2 are potential oncotargets in Burkitt lymphoma and multiple myeloma. AB - BACKGROUND: Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM). METHODS: We used EMSA to detect constitutive NF-kappaB/STAT3 activity in BL- and MM-like neoplasms that spontaneously developed in single-transgenic IL6 (interleukin-6) or MYC (c Myc) mice, or in double-transgenic IL6MYC mice. qPCR measurements and analysis of clinical BL and MM datasets were employed to validate candidate NF-kappaB/STAT3 target genes. RESULTS: qPCR demonstrated that IL6- and/or MYC-dependent neoplasms in mice invariably contain elevated mRNA levels of the NF-kappaB target genes, Cdkn1a and Fancd2. Clinical studies on human CDKN1A, which encodes the cell cycle inhibitor and tumor suppressor p21, revealed that high p21 message predicts poor therapy response and survival in BL patients. Similarly, up-regulation of FANCD2, which encodes a key member of the Fanconi anemia and breast cancer pathway of DNA repair, was associated with poor outcome of patients with MM, particularly those with high-risk disease. CONCLUSIONS: Our findings suggest that CDKN1A and FANCD2 are potential oncotargets in BL and MM, respectively. Additionally, the IL-6- and/or MYC-driven mouse models of human BL and MM used in this study may lend themselves to the biological validation of CDKN1A and FANCD2 as molecular targets for new approaches to cancer therapy and prevention. PMID- 25838974 TI - M cell-derived vesicles suggest a unique pathway for trans-epithelial antigen delivery. AB - M cells are a subset of mucosal epithelial cells with specialized capability to transport antigens across the mucosal barrier, but there is limited information on antigen transfer in the subepithelial zone due to the challenges in tracking microparticles and antigens that are transcytosed by this unique cell. Using transgenic reporter mice expressing dsRed in the cytoplasm of M cells and EGFP in myeloid cells, we observed that the M cell basolateral pocket hosts a close interaction between B lymphocytes and dendritic cells. Interestingly, we identified a population of previously undescribed M cell-derived vesicles (MCM) that are constitutively shed into the subepithelial space and readily taken up by CX3CR1(+)CD11b(+) CD11c(+) dendritic cells. These MCM are characterized by their cytoplasmic dsRed confirming their origin from the M cell cytoplasm. MCM showed preferential colocalization in dendritic cells with transcytosed bacteria but not transcytosed polystyrene beads, indicating a selective sorting of cargo fate in the subepithelial zone. The size and number of MCM were found to be upregulated by bacterial transcytosis and soluble toll-like receptor 2 (TLR2) agonist, further pointing to dynamic regulation of this mechanism. These results suggest that MCM provide a unique function by delivering to dendritic cells, various materials such as M cell-derived proteins, effector proteins, toxins, and particles found in the M cell cytoplasm during infection or surveillance. PMID- 25838975 TI - The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. AB - The ability of small blood vessels to undergo rapid, reversible morphological changes is essential for the adaptive response to tissue injury or local infection. A canonical feature of this response is transient hyperpermeability. However, when leakiness is profound or persistent, adverse consequences accrue to the host, including organ dysfunction and shock. A growing body of literature identifies the Tie2 receptor, a transmembrane tyrosine kinase highly enriched in the endothelium, as an important regulator of vascular barrier function in health and in disease. The principal ligands of Tie2, Angiopoietins 1 and 2, exert opposite effects on this receptor in the context of inflammation. This review will focus on recent studies that have illuminated novel aspects of the exquisitely controlled Tie2 signaling axis while proposing unanswered questions and future directions for this field of study. PMID- 25838977 TI - The human knee: A window on the microvasculature. AB - In synovial joints, the lining cells do not have tight junctions with their neighboring cells and they have no underlying basement membrane. Therefore, the synovial fluid within the articular cavity is continuous with the interstitial fluid of the synovial intima. These features, combined with ready access to the space via arthrocentesis, permit quantitative studies of microvascular function in the knees of unanesthetized, volunteer, human subjects both with and without chronic arthritis. This brief article reviews the principal findings of such work over ~40 years at the University of Washington. Examined variables include bidirectional fenestral diffusion of small solutes, effective blood flow, lymphatic drainage, and endothelial pore size and permeability. The latter work introduced a new method using gel filtration chromatography of paired synovial fluid (SF) and serum (S) to obtain essentially continuous SF/S ratios over a range of radii between 1 and 12 nanometers. PMID- 25838976 TI - Epithelial adhesion molecules and the regulation of intestinal homeostasis during neutrophil transepithelial migration. AB - Epithelial adhesion molecules play essential roles in regulating cellular function and maintaining mucosal tissue homeostasis. Some form epithelial junctional complexes to provide structural support for epithelial monolayers and act as a selectively permeable barrier separating luminal contents from the surrounding tissue. Others serve as docking structures for invading viruses and bacteria, while also regulating the immune response. They can either obstruct or serve as footholds for the immune cells recruited to mucosal surfaces. Currently, it is well appreciated that adhesion molecules collectively serve as environmental cue sensors and trigger signaling events to regulate epithelial function through their association with the cell cytoskeleton and various intracellular adapter proteins. Immune cells, particularly neutrophils (PMN) during transepithelial migration (TEM), can modulate adhesion molecule expression, conformation, and distribution, significantly impacting epithelial function and tissue homeostasis. This review discusses the roles of key intestinal epithelial adhesion molecules in regulating PMN trafficking and outlines the potential consequences on epithelial function. PMID- 25838978 TI - Metabolic regulation of intestinal epithelial barrier during inflammation. AB - The gastrointestinal mucosa has proven to be an interesting tissue for which to investigate disease-related metabolism. In this review, we outline some evidence that implicates metabolic signaling as important features of barrier in the healthy and disease. Studies from cultured cell systems, animal models and human patients have revealed that metabolites generated within the inflammatory microenvironment are central to barrier regulation. These studies have revealed a prominent role for hypoxia and hypoxia-inducible factor (HIF) at key steps in adenine nucleotide metabolism and within the creatine kinase pathway. Results from animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF stabilization on disease outcomes and barrier function. Studies underway to elucidate the contribution of immune responses will provide additional insight into how metabolic changes contribute to the complexity of the gastrointestinal tract and how such information might be harnessed for therapeutic benefit. PMID- 25838979 TI - Bacterial protein AvrA stabilizes intestinal epithelial tight junctions via blockage of the C-Jun N-terminal kinase pathway. AB - The Salmonella type III secretory system secretes virulence proteins, called effectors. Effectors are responsible for the alteration of tight junctions (TJ) and epithelial functions in intestinal infection and inflammation. In a previous study, we have demonstrated that a bacterial effector AvrA plays a role in stabilizing TJs and balancing the opposing action of other bacterial effectors. However, the molecular mechanisms by which AvrA-modulates TJ protein expression remain unknown. AvrA possesses acetyltransferase activity toward specific mitogen activated protein kinase kinases (MAPKKs) and potently inhibits the c-Jun N terminal kinase (JNK) pathway in inflammation. Inhibition of the JNK pathway is known to inhibit the TJ protein disassemble. Therefore, we hypothesize that AvrA stabilizes intestinal epithelial TJs via c-Jun and JNK pathway blockage. Using both in vitro and in vivo models, we showed that AvrA targets the c-Jun and JNK pathway that in turn stabilizes TJ protein ZO-1. Inhibition of JNK abolished the effect of AvrA on ZO-1. We further determined that AvrA suppressed the transcription factor activator protein-1, which was regulated by activated JNK. Moreover, we identified the functional domain of AvrA that directly regulated TJs using a series of AvrA mutants. The role of AvrA represents a highly refined bacterial strategy that helps the bacteria survive in the host and dampens the inflammatory response of the host. Our findings have uncovered a novel role of the bacterial protein AvrA in suppressing the inflammatory response of the host through JNK-regulated blockage of epithelial cell barrier function. PMID- 25838981 TI - Epidermal tight junctions in health and disease. AB - The skin, the largest organ of the body, is an essential barrier that under homeostatic conditions efficiently protects and/or minimizes damage from both environmental (e.g. microorganisms, physical trauma, ultraviolet radiation) and endogenous (e.g., cancers, inflammation) factors. This formidable barrier function resides mainly in the epidermis, a dynamic, highly-stratified epithelium. The epidermis has 2 major barrier structures: stratum corneum, the outmost layer and tight junctions, intercellular junctions that seal adjacent keratinocytes in the stratum granulosum, found below the stratum corneum. In recent years there have been significant advances in our understanding of tight junction function, composition and regulation. Herein we review what is known about tight junctions in healthy skin and keratinocyte culture systems and highlight the dynamic crosstalk observed between tight junctions and the cutaneous immune system. Finally we discuss the preliminary observations suggesting that tight junction function or protein expression may be relevant for the pathogenesis of a number of common cutaneous inflammatory and neoplastic conditions. PMID- 25838980 TI - Cytoskeletal mechanisms regulating vascular endothelial barrier function in response to acute lung injury. AB - Endothelial cells (EC) form a semi-permeable barrier between the interior space of blood vessels and the underlying tissues. In acute lung injury (ALI) the EC barrier is weakened leading to increased vascular permeability. It is widely accepted that EC barrier integrity is critically dependent upon intact cytoskeletal structure and cell junctions. Edemagenic agonists, like thrombin or endotoxin lipopolysaccharide (LPS), induced cytoskeletal rearrangement, and EC contractile responses leading to disruption of intercellular contacts and EC permeability increase. The highly clinically-relevant cytoskeletal mechanisms of EC barrier dysfunction are currently under intense investigation and will be described and discussed in the current review. PMID- 25838982 TI - Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. AB - The epithelial tight junction determines the paracellular water and ion movement in the intestine and also prevents uptake of larger molecules, including antigens, in an uncontrolled manner. Claudin-2, one of the 27 mammalian claudins regulating that barrier function, forms a paracellular channel for small cations and water. It is typically expressed in leaky epithelia like proximal nephron and small intestine and provides a major pathway for the paracellular transport of sodium, potassium, and fluid. In intestinal inflammation (Crohn's disease, ulcerative colitis), immune-mediated diseases (celiac disease), and infections (HIV enteropathy), claudin-2 is upregulated in small and large intestine and contributes to diarrhea via a leak flux mechanism. In parallel to that upregulation, other epithelial and tight junctional features are altered and the luminal uptake of antigenic macromolecules is enhanced, for which claudin-2 may be partially responsible through induction of tight junction strand discontinuities. PMID- 25838797 TI - Performance of the ATLAS muon trigger in pp collisions at [Formula: see text] TeV. AB - The performance of the ATLAS muon trigger system is evaluated with proton-proton collision data collected in 2012 at the Large Hadron Collider at a centre-of-mass energy of 8 TeV. It is primarily evaluated using events containing a pair of muons from the decay of [Formula: see text] bosons. The efficiency of the single muon trigger is measured for muons with transverse momentum [Formula: see text] GeV, with a statistical uncertainty of less than 0.01 % and a systematic uncertainty of 0.6 %. The [Formula: see text] range for efficiency determination is extended by using muons from decays of [Formula: see text] mesons, [Formula: see text] bosons, and top quarks. The muon trigger shows highly uniform and stable performance. The performance is compared to the prediction of a detailed simulation. PMID- 25838984 TI - NF-kappaB inhibitors impair lung epithelial tight junctions in the absence of inflammation. AB - NF-kappaB (p50/p65) is the best characterized transcription factor known to regulate cell responses to inflammation. However, NF-kappaB is also constitutively expressed. We used inhibitors of the classical NF-kappaB signaling pathway to determine whether this transcription factor has a role in regulating alveolar epithelial tight junctions. Primary rat type II alveolar epithelial cells were isolated and cultured on Transwell permeable supports coated with collagen for 5 d to generate a model type I cell monolayer. Treatment of alveolar epithelial monolayers overnight with one of 2 different IkappaB kinase inhibitors (BAY 11-7082 or BMS-345541) resulted in a dose-dependent decrease in TER at concentrations that did not affect cell viability. In response to BMS-345541 treatment there was an increase in total claudin-4 and claudin-5 along with a decrease in claudin-18, as determined by immunoblot. However, there was little effect on the total amount of cell-associated claudin-7, occludin, junctional adhesion molecule A (JAM-A), zonula occludens (ZO)-1 or ZO-2. Moreover, treatment with BMS-345541 resulted in altered tight junction morphology as assessed by immunofluorescence microscopy. Cells treated with BMS-345541 had an increase in claudin-18 containing projections emanating from tight junctions ("spikes") that were less prominent in control cells. There also were several areas of cell-cell contact which lacked ZO-1 and ZO-2 localization as well as rearrangements to the actin cytoskeleton in response to BMS-345541. Consistent with an anti inflammatory effect, BMS-345541 antagonized the deleterious effects of lipopolysaccharide (LPS) on alveolar epithelial barrier function. However, BMS 345541 also inhibited the ability of GM-CSF to increase alveolar epithelial TER. These data suggest a dual role for NF-kappaB in regulating alveolar barrier function and that constitutive NF-kappaB function is required for the integrity of alveolar epithelial tight junctions. PMID- 25838983 TI - Blood cells and endothelial barrier function. AB - The barrier properties of endothelial cells are critical for the maintenance of water and protein balance between the intravascular and extravascular compartments. An impairment of endothelial barrier function has been implicated in the genesis and/or progression of a variety of pathological conditions, including pulmonary edema, ischemic stroke, neurodegenerative disorders, angioedema, sepsis and cancer. The altered barrier function in these conditions is often linked to the release of soluble mediators from resident cells (e.g., mast cells, macrophages) and/or recruited blood cells. The interaction of the mediators with receptors expressed on the surface of endothelial cells diminishes barrier function either by altering the expression of adhesive proteins in the inter-endothelial junctions, by altering the organization of the cytoskeleton, or both. Reactive oxygen species (ROS), proteolytic enzymes (e.g., matrix metalloproteinase, elastase), oncostatin M, and VEGF are part of a long list of mediators that have been implicated in endothelial barrier failure. In this review, we address the role of blood borne cells, including, neutrophils, lymphocytes, monocytes, and platelets, in the regulation of endothelial barrier function in health and disease. Attention is also devoted to new targets for therapeutic intervention in disease states with morbidity and mortality related to endothelial barrier dysfunction. PMID- 25838988 TI - Estimating Vertex Measures in Social Networks by Sampling Completions of RDS Trees. AB - This paper presents a new method for obtaining network properties from incomplete data sets. Problems associated with missing data represent well-known stumbling blocks in Social Network Analysis. The method of "estimating connectivity from spanning tree completions" (ECSTC) is specifically designed to address situations where only spanning tree(s) of a network are known, such as those obtained through respondent driven sampling (RDS). Using repeated random completions derived from degree information, this method forgoes the usual step of trying to obtain final edge or vertex rosters, and instead aims to estimate network-centric properties of vertices probabilistically from the spanning trees themselves. In this paper, we discuss the problem of missing data and describe the protocols of our completion method, and finally the results of an experiment where ECSTC was used to estimate graph dependent vertex properties from spanning trees sampled from a graph whose characteristics were known ahead of time. The results show that ECSTC methods hold more promise for obtaining network-centric properties of individuals from a limited set of data than researchers may have previously assumed. Such an approach represents a break with past strategies of working with missing data which have mainly sought means to complete the graph, rather than ECSTC's approach, which is to estimate network properties themselves without deciding on the final edge set. PMID- 25838986 TI - IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis. AB - As previous studies suggested that IL-9 may control intestinal barrier function, we tested the role of IL-9 in experimental T cell-mediated colitis induced by the hapten reagent 2,4,6-trinitrobenzenesulfonic acid (TNBS). The deficiency of IL-9 suppressed TNBS-induced colitis and led to lower numbers of PU.1 expressing T cells in the lamia propria, suggesting a regulatory role for Th9 cells in the experimental TNBS colitis model. Since IL-9 is known to functionally alter intestinal barrier function in colonic inflammation, we assessed the expression of tight junction molecules in intestinal epithelial cells of TNBS-inflamed mice. Therefore we made real-time PCR analyses for tight junction molecules in the inflamed colon from wild-type and IL-9 KO mice, immunofluorescent stainings and investigated the expression of junctional proteins directly in intestinal epithelial cells of TNBS-inflamed mice by Western blot studies. The results demonstrated that sealing proteins like occludin were up regulated in the colon of inflamed IL-9 KO mice. In contrast, the tight junction protein Claudin1 showed lower expression levels when IL-9 is absent. Surprisingly, the pore-forming molecule Claudin2 revealed equal expression in TNBS-treated wild-type and IL-9 deficient animals. These results illustrate the pleiotropic functions of IL-9 in changing intestinal permeability in experimental colitis. Thus, modulation of IL 9 function emerges as a new approach for regulating barrier function in intestinal inflammation. PMID- 25838989 TI - Early Life Metabolism of Bisphenol A: A Systematic Review of the Literature. AB - When a comprehensive report on BPA was published in 2008, few data were available to assess the extent to which known poor glucuronidation capacity impacts BPA internal dose in infants and young children. In this paper, evidence that has emerged since the 2008 report is summarized, including: 1) human biomarker studies in children aged 0-5 years; 2) animal studies of neonatal toxicokinetics; and 3) physically based pharmacokinetic (PBPK) models. To address limitations in these studies, we recommend more human biomonitoring studies in children aged 0-5 years in which unmetabolized (free) BPA and BPA metabolites are separately quantified and detailed quality-control data are reported, investigation of metabolic differences between humans and animal species used for the study of BPA metabolism, and enzyme ontogeny studies, which along with biomonitoring studies would reduce uncertainty in PBPK models of early-life BPA metabolism. PMID- 25838987 TI - Control of vascular permeability by adhesion molecules. AB - Vascular permeability is a vital function of the circulatory system that is regulated in large part by the limited flux of solutes, water, and cells through the endothelial cell layer. One major pathway through this barrier is via the inter-endothelial junction, which is driven by the regulation of cadherin-based adhesions. The endothelium also forms attachments with surrounding proteins and cells via 2 classes of adhesion molecules, the integrins and IgCAMs. Integrins and IgCAMs propagate activation of multiple downstream signals that potentially impact cadherin adhesion. Here we discuss the known contributions of integrin and IgCAM signaling to the regulation of cadherin adhesion stability, endothelial barrier function, and vascular permeability. Emphasis is placed on known and prospective crosstalk signaling mechanisms between integrins, the IgCAMs- ICAM-1 and PECAM-1, and inter-endothelial cadherin adhesions, as potential strategic signaling nodes for multipartite regulation of cadherin adhesion. PMID- 25838985 TI - Roles and regulation of the mucus barrier in the gut. AB - The gastrointestinal tract is coated by a thick layer of mucus that forms the front line of innate host defense. Mucus consists of high molecular weight glycoproteins called mucins that are synthesized and secreted by goblet cells and functions primarily to lubricate the epithelium and protect it from damage by noxious substances. Recent studies have also suggested the involvement of goblet cells and mucins in complex immune functions such as antigen presentation and tolerance. Under normal physiological conditions, goblet cells continually produce mucins to replenish and maintain the mucus barrier; however, goblet cell function can be disrupted by various factors that can affect the integrity of the mucus barrier. Some of these factors such as microbes, microbial toxins and cytokines can stimulate or inhibit mucin production and secretion, alter the chemical composition of mucins or degrade the mucus layer. This can lead to a compromised mucus barrier and subsequently to various pathological conditions like chronic inflammatory diseases. Insight into how these factors modulate the mucus barrier in the gut is necessary in order to develop strategies to combat these disorders. PMID- 25838990 TI - Joint GWAS Analysis: Comparing similar GWAS at different genomic resolutions identifies novel pathway associations with six complex diseases. AB - We show here that combining two existing genome wide association studies (GWAS) yields additional biologically relevant information, beyond that obtained by either GWAS separately. We propose Joint GWAS Analysis, a method that compares a pair of GWAS for similarity among the top SNP associations, top genes identified, gene functional clusters, and top biological pathways. We show that Joint GWAS Analysis identifies additional enriched biological pathways that would be missed by traditional Single-GWAS analysis. Furthermore, we examine the similarities of six complex genetic disorders at the SNP-level, gene-level, gene-cluster-level, and pathway-level. We make concrete hypotheses regarding novel pathway associations for several complex disorders considered, based on the results of Joint GWAS Analysis. Together, these results demonstrate that common complex disorders share substantially more genomic architecture than has been previously realized and that the meta-analysis of GWAS needs not be limited to GWAS of the same phenotype to be informative. PMID- 25838991 TI - Development of floating chitosan-xanthan beads for oral controlled release of glipizide. AB - INTRODUCTION: The aim of the present work was to develop controlled release, floating and mucoadhesive beads of glipizide by using the polyionic complexation technique. Plasma half-life of glipizide being 2-4 h was selected for development of controlled release dosage form. METHODS: Formulation batches were designed by employing chitosan as cationic and xanthan gum as anionic polymers. In vitro drug release was evaluated for the period of 24 h in phosphate buffer pH 7.4. RESULTS: Sustained release of drug was observed in all formulation batches with % drug release ranging from 87.50% to 100.67%, no significant effect on the drug release was observed after varying chitosan to xanthan gum ratio. Encapsulation efficiency was found to be in the range of 79.48 +/- 1.10-94.48 +/- 1.52. In vitro bioadhesion studies showed that beads had satisfactory bioadhesive strength ranging from 67.11% +/- 1.73% to 93.12% +/- 1.56%. Buoyancy studies revealed that beads possess comparable floating capacity in the gastric fluids. Swelling kinetics was carried in pH 1.2 and 7.4 buffers. Significant difference (P < 0.05) in swelling kinetics was observed. Drug to polymer interaction was analyzed by Fourier transform infrared spectroscopy and differential scanning calorimetry studies. Scanning electron microscopy studies revealed that formed beads were discrete with rough and wrinkled surfaces. CONCLUSIONS: In conclusion, beads were successfully formed by employing chitosan and xanthan gum and showed to possess sustained release effect. Beads also showed pH dependent swelling kinetics, this property can also be applied for the drugs which are susceptible to the acidic environment in the stomach, and comparable bioadhesive and floating properties were also observed. PMID- 25838992 TI - Design and development and evaluation of candesartan cilexetil liquid filling formulations. AB - Most of the currently available drugs are having poor water solubility and suffer from low oral bioavailability. One of the most promising approaches to deliver such insoluble drugs is by dissolving it in lipids, liquids or semi-solids to formulate new products.[1] Candesartan meets the requirement of high potency but it is poorly absorbed when administered as tablets. Therefore the prodrug Candesartan cilexitil is developed.[2] Two piece hard gelatin liquid filling capsules are one of the most logical approaches when choosing the best dosage form to deliver these new liquid formulations.[1] Liquid filled formulations were prepared by employing different cosolvents and surfactants. The formulation containing SLS-2%, PVP- 17.5%, PEG-15%, and PG-53% exhibited desire solubility, rheological property and found to be stable in hard gelatin capsules. PMID- 25838993 TI - Effect of the moist-heat sterilization on fabricated nanoscale solid lipid particles containing rasagiline mesylate. AB - BACKGROUND: Nanoscale solid lipid particles of rasagiline mesylate (RM) were fabricated by microemulsion technique. The nanoscale particle must be sterile for intravenous administration, and several approaches are available for sterilization. However, the selection of sterilization technique for the fabricated RM loaded nanoscale solid lipid particles mainly depends on the nature of the drug that needs to be encapsulated and release pattern of the polymer. MATERIALS AND METHODS: We have preferred moist heat sterilization, as it is the most convenient and the composition of the carrier and incorporated drug should remain unchanged and the incorporated drug should not leak out of the drug carrier. The physical and chemical stability of RM loaded nanoscale solid lipid particles investigated during sterilization and to determine the average mean particle size, polydispersity index, zeta potential (ZP), transmission electron microscopy (TEM), entrapment efficiency (EE), and drug content after autoclaving. RESULT: There were no significant changes in the average mean particle size, polydispersity index, ZP, TEM, EE, and drug content of RM loaded nanoscale solid lipid particles after autoclaving (121 degrees C for 20 min [15 lbs]). CONCLUSION: These observations suggest that the moist heat sterilization by autoclaving is the most suitable method for nanoscale solid lipid formulations. PMID- 25838994 TI - Formulation and characterization of sustained release dosage form of moisture sensitive drug. AB - OBJECTIVE: The purpose of this study was to prepare sustained release tablet of moisture sensitive drug like Ranitidine Hydrochloride for treatment of gastroesophageal reflux disease along with the improvement of moisture stability to get better therapeutic efficacy. MATERIALS AND METHODS: Pan coating technique was used for coating of the tablet. Film coating was done using Eudragit RLPO and Eugragit EPO as coating polymer. 3(2) full factorial design was applied for optimization purpose, and 9 runs were conducted. In that Eudragit RLPO and Eudragit EPO taken as an independent variables and moisture gain and Cummulative Drug Release (CDR) were taken as dependent variables. Drug and excipient compatibility was done using differential scanning calorimetry and Fourier transform infrared spectroscopy study. The tablet was evaluated for precompression parameter and all postcompression parameter. Stability study was carried out at room temperature (30 degrees C +/- 2 degrees C/65% +/- 5% relative humidity). Final formulation was compared with marketed formulation RANTEC 300. RESULT: Tablets were passing out all precompression parameter along with postcompression parameter. Stability study shows that the parameter such as hardness, friability, and dissolution are in the range. Hence, there is no significant change shown after stability study. Our final formulation was compared with marketed formulation RANTEC 300 and result demonstrates that our final formulation have less moisture gain and give release up to 12 h. CONCLUSION: The result of present study demonstrates that final formulation has less moisture gain and getting desired CDR for sustained release of drug. On the basis of all study, it was concluded that the tablet was coated by combination of Eudragit RLPO 10% and Eudragit EPO 10% give better result. This formation provided promising approach for the drug release up to 12 h for moisture sensitive drug like ranitidine hydrochloride. PMID- 25838995 TI - Formulation of rizatriptan benzoate fast dissolving buccal films by emulsion evaporation technique. AB - AIM: The present study deals with the formulation of fast dissolving films of Rizatriptan benzoate that is used for the treatment of Migraine. The concept of fast-dissolving drug delivery emerged from the desire to provide patient with more conventional means of taking their medication. MATERIALS AND METHODS: In the present research work, various trials were carried out using film forming agents such as maltodextrin, gum karaya and xanthan gum to prepare an ideal film. Emulsion evaporation method was used for the preparation of films. The prepared films were evaluated for weight uniformity, drug content, film thickness, folding endurance, dispersion test and curling. The in vitro dissolution studies were carried out using simulated salivary fluid (pH 6.8 phosphate buffer). RESULTS: About 97% of the drug was found to be released from the film within 10 min that is a desirable character for fast absorption. The drug excipient interaction studies carried out by differential scanning calorimetry analysis and Fourier transform infrared studies revealed that there were no major interactions between the drugs and excipients used for the preparation of films. CONCLUSION: Fast dissolving films of Rizatriptan benzoate prepared by emulsion evaporation technique were found to be suitable for eliciting better therapeutic effect in the treatment of migraine. PMID- 25838996 TI - Chronomodulated drug delivery system of urapidil for the treatment of hypertension. AB - INTRODUCTION: Hypertension is a disease which shows circadian rhythm in the pattern of two peaks, one in the evening at about 7pm and other in the early morning between 4 am to 8 am. Conventional therapies are incapable to target those time points when actually the symptoms get worsened. To achieve drug release at two time points, chronomodulated delivery system may offer greater benefits. MATERIALS AND METHODS: The chronomodulated system comprised of dual approach; immediate release granules (IRG) and pulsatile release mini-tablets (PRM) filled in the hard gelatin capsule. The mini-tablets were coated using Eudragit S-100 which provided the lag time. To achieve the desired release, various parameters like coating duration and coat thickness were studied. The immediate release granules were evaluated for micromeritical properties and drug release, while mini-tablets were evaluated for various parameters such as hardness, thickness, friability, weight variation, drug content, and disintegration time and in-vitro drug release. Compatibility of drug-excipient was checked by fourier transform infrared spectroscopy and Differential scanning calorimetry studies and pellets morphology was done by Scanning electron microscopy studies. RESULTS: The in-vitro release profile suggested that immediate release granules gives drug release within 20 min at the time of evening attack while the programmed pulsatile release was achieved from coated mini-tablets after a lag time of 9hrs, which was consistent with the demand of drug during early morning hour attack. Pellets found to be spherical in shape with smooth surface. Moreover compatibility studies illustrated no deleterious reaction between drug and polymers used in the study. CONCLUSIONS: The dual approach of developed chronomodulated formulation found to be satisfactory in the treatment of hypertension. PMID- 25838997 TI - Solubility enhancement studies on lurasidone hydrochloride using mixed hydrotropy. AB - Low aqueous solubility is a major problem faced during formulation development of new drug molecules. Lurasidone HCl (LRD) is an antipsychotic agent specially used in the treatments of schizophrenia and is a good example of the problems associated with low aqueous solubility. Lurasidone is practically insoluble in water, has poor bioavailability and slow onset of action and therefore cannot be given in emergency clinical situations like schizophrenia. Hence, purpose of this research was to provide a fast dissolving oral dosage form of Lurasidone. This dosage form can provide quick onset of action by using the concept of mixed hydrotropy. Initially, solubility of LRD was determined individually in nicotinamide, sodium citrate, urea and sodium benzoate at concentration of 10, 20, 30 and 40% w/v solutions using purified water as a solvent. Highest solubility was obtained in 40% sodium benzoate solution. In order to decrease the individual hydrotrope concentration mixed hydrotropic agents were used. Highest solubility was obtained in 15:20:5 ratio of Nicotinamide + sodium benzoate + sodium citrate. This optimized combination was utilized in the preparation of solid dispersions by using distilled water as a solvent. Solid dispersions were evaluated for X-ray diffraction, differential scanning calorimetry and Fourier transform infrared to show no drug-hydrotropes interaction has occurred. This solid dispersion was compressed to form fast dissolving tablets. Dissolution studies of prepared tablets were done using USP Type II apparatus. The batch L3 tablets show 88% cumulative drug release within 14 min and in vitro dispersion time was 32 min. It was concluded that the concept of mixed hydrotropic solid dispersion is novel, safe and cost-effective technique for enhancing the bioavailability of poorly water-soluble drugs. The miraculous enhancement in solubility and bioavailability of Lurasidone is clear indication of the potential of mixed hydrotropy to be used in future for other poorly water-soluble drugs in which low bioavailability is a major concern. PMID- 25838998 TI - Clinical use of Insulin Degludec: Practical Experience and Pragmatic Suggestions. AB - Insulin degludec (IDeg) is an ultralong acting basal insulin. IDeg has unique pharmacokinetic and pharmacodynamic properties which allow once a daily dosage, at any time of the day. Its use is associated with a significantly lower risk of hypoglycemia. This review discusses the pragmatic use of IDeg, based on available evidence. A complete search of all nine original research papers (BEGIN(r) clinical trial program) pertaining to IDeg, listed in PubMed, was made to prepare this article. PMID- 25838999 TI - Statin Intolerance Because of Myalgia, Myositis, Myopathy, or Myonecrosis Can in Most Cases be Safely Resolved by Vitamin D Supplementation. AB - BACKGROUND: Low serum vitamin D can cause myalgia, myositis, myopathy, and myonecrosis. Statin-induced myalgia is a major and common cause of statin intolerance. Low serum vitamin D and statins, additively or synergistically, cause myalgia, myositis, myopathy, and/or myonecrosis. Statin-induced myalgia in vitamin D deficient patients can often be resolved by vitamin D supplementation, normalizing serum vitamin D levels. AIMS: In 74 men and 72 women (age 59 +/- 14 years) intolerant to >=2 statins because of myalgia, myositis, myopathy, or myonecrosis and found to have low (<32 ng/mL) serum vitamin D, we prospectively assessed whether vitamin D supplementation (vitamin D2: 50,000-100,000 units/week) to normalize serum vitamin D would allow successful rechallenge therapy with statins. MATERIALS AND METHODS: Follow-up evaluation on vitamin D supplementation was done on 134 patients at 6 months (median 5.3), 103 patients at 12 months (median 12.2), and 82 patients at 24 months (median 24). RESULTS: Median entry serum vitamin D (22 ng/mL, 23 ng/mL, and 23 ng/mL) rose at 6 months, 12 months, and 24 months follow-up to 53 ng/mL, 53 ng/mL, and 55 ng/mL, respectively, (P < .0001 for all) on vitamin D therapy (50,000-100,000 units/week). On vitamin D supplementation, serum vitamin D normalized at 6 months, 12 months, and 24 months follow-up in 90%, 86%, and 91% of the patients, respectively. On rechallenge with statins while on vitamin D supplementation, median low-density lipoprotein cholesterol (LDLC) fell from the study entry (167 mg/dL, 164 mg/dL, and 158 mg/dL) to 90 mg/dL, 91 mg/dL, and 84 mg/dL, respectively, (P < .0001 for all). On follow-up at median 6 months, 12 months, and 24 months on statins and vitamin D, 88%, 91%, and 95% of the previously statin-intolerant patients, respectively, were free of myalgia, myositis, myopathy, and/or myonecrosis. CONCLUSIONS: Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis associated with low serum vitamin D can be safely resolved by vitamin D supplementation (50,000-100,000 units /week) in most cases (88-95%). PMID- 25839000 TI - Nicotine Dependence, Physical Activity, and Sedentary Behavior among Adult Smokers. AB - BACKGROUND: Research has previously demonstrated an inverse association between smoking status and physical activity; however, few studies have examined the association between nicotine dependence and physical activity or sedentary behavior. AIM: This study examined the association between nicotine dependence and accelerometer-determined physical activity and sedentary behavior. MATERIALS AND METHODS: Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) were used. A total of 851 adult (>=20 years) smokers wore an accelerometer for >=4 days and completed the Fagerstrom Test for Nicotine Dependence scale. Regression models were used to examine the association between nicotine dependence and physical activity/sedentary behavior. RESULTS: After adjusting for age, gender, race-ethnicity, poverty level, hypertension, emphysema, bronchitis, body mass index (BMI), cotinine, and accelerometer wear time, smokers 50 + years of age with greater nicotine dependence engaged in more sedentary behavior (beta = 11.4, P = 0.02) and less light-intensity physical activity (beta = -9.6, P = 0.03) and moderate-to-vigorous physical activity (MVPA; beta = -0.14, P = 0.003) than their less nicotine dependent counterparts. CONCLUSION: Older adults who are more nicotine dependent engage in less physical activity (both MVPA and light-intensity) and more sedentary behavior than their less nicotine dependent counterparts. PMID- 25839001 TI - Antidepressant-like activity of flunarizine in modified tail suspension test in rats. AB - BACKGROUND: Flunarizine, a Ca(2+) channel blocker, crosses blood brain barrier (BBB), antagonizes calcium influx and interferes with neurotransmitter system. Flunarizine 20 mg/kg exhibited significant antidepressant activity in our previous study using forced swim test (FST) in mice, which was contradictory to the findings of other authors. Hence, the present study was designed to strengthen the results of our previous study, using the modified tail suspension test (TST) in rats. AIM: Aim of this study was to evaluate the antidepressant activity of flunarizine versus standard antidepressant drug fluoxetine in modified TST in rats. MATERIALS AND METHODS: The study approved by Institutional Animal Ethics Committee was conducted using 24 adult albino rats (n = 6 in each group). Antidepressant effect of normal saline (0.1 ml/100 g), fluoxetine (10 mg/kg, intraperitoneally (ip)), and flunarizine (2 and 10 mg/kg, ip) was evaluated by using modified TST in rats. Thirty minutes after administration of all test drugs the duration of immobility was recorded for a period of 5 min in all rats by using modified TST. The data was analyzed by Student's t-test and one way analysis of variance (ANOVA) and P < 0.05 was considered significant. RESULTS: Mean duration of immobility was significantly reduced in fluoxetine and flunarizine (10 mg/kg, ip) group as compared to the normal saline, that is, 160.33, 175.17, and 226.83 s, respectively (P < 0.05). Decrease in immobility with flunarizine (10 mg/kg, ip) was statistically significant compared with normal saline, but was not found to be significant when compared to fluoxetine (P > 0.05). Also, currently used human dose of flunarizine when extrapolated to rats (i. e., 2 mg/kg, ip) failed to show significant antidepressant effect in modified TST in rats. CONCLUSION: The results of the present study indicate antidepressant like activity of flunarizine. PMID- 25839002 TI - Factors associated with the uptake of cervical cancer screening among women in portland, Jamaica. AB - BACKGROUND: Cervical cancer is the second most common cancer among women worldwide and is the leading cause of deaths in developing countries. Despite the strong evidence that cervical cancer screening results in decreased mortality from this disease, the uptake for cervical screening among Jamaican women remains low. AIMS: This study was carried out to identify factors associated with Jamaican women's decisions to screen for cervical cancer. MATERIALS AND METHODS: Cross-sectional descriptive study of 403 women aged 19 years and older from Portland, Jamaica. An interviewer-administered questionnaire assessed the women's cervical cancer screening history, as well as their knowledge, attitudes, and practices regarding the disease and screening. RESULTS: Of the 403 women interviewed, 66% had a Papanicolaou (Pap) smear and only 16% had a Pap test within the past year. Significant predicators of uptake of screening were being married, age, parity, discussing cancer with health provider, perception of consequences of not having a Pap smear, and knowing a person with cervical cancer. Women who did not know where to go for a Pap smear were 85% less likely to have been screened (prevalence odds ratio (POR): 0.15, 95% confidence interval (CI): 0.04, 0.52). CONCLUSIONS: This study showed suboptimal uptake of cervical cancer screening among Jamaican women. Multipronged approaches are needed to address barriers to screening, as well as identify and support conditions that encourage women's use of reproductive health services, thereby reducing incidence and mortality rates from cervical cancer. PMID- 25839003 TI - Left ventricular aneurysm and ventricular tachycardia as initial presentation of cardiac sarcoidosis. AB - CONTEXT: Cardiac sarcoidosis (CS) is a rare, potentially fatal disease. It has a wide range of clinical presentations that range from asymptomatic electrocardiogram changes to sudden cardiac death. Ventricular aneurysms and ventricular tachycardia are seen late in the disease, and are rarely the presenting manifestation of the disease. Diagnosis of CS is challenging and often missed or delayed. CASE REPORT: We report a 35-year-old patient who presented with sustained ventricular tachycardia and ST-elevation on electrocardiogram. Cardiac catheterization showed normal coronaries and left ventricular aneurysm. Subsequent 2D-echocardiography showed an infiltrative disease pattern. Cardiac MRI was done and showed late gadolinium enhancement in the septum, apex and lateral wall. The patient was diagnosed with cardiac sarcoidosis and treated with immune suppression and antiarrhythmic agent. In addition underwent AICD implantation. CONCLUSION: Our case highlights the importance of suspecting cardiac sarcoidosis in young patients presenting with electrocardiogram changes, and present an atypical presentation of this disease. PMID- 25839004 TI - Thyrotoxic periodic paralysis in long standing graves' disease: an unusual presentation with normokalemia. AB - CONTEXT: Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of hyperthyroidism that is underdiagnosed and frequently missed. It is relatively common in Asian men with Graves' disease. TPP attacks are frequently associated with hypokalemia. CASE REPORT: Here we report a non-Asian female patient with Graves' disease, who presented with flaccid paralysis associated with an episode of subacute thyroiditis (SAT). Interestingly, she was found to have low normal potassium levels in the serum during the initial attack despite which she continues to require low dose potassium supplementation to prevent recurrent TPP attacks. Unique features in our patient include her gender, ethnicity, time lag between initial diagnosis of Graves' disease, and the development of TPP and borderline low potassium levels, with the continuous need for prophylactic potassium supplementation. CONCLUSION: It is important to be aware of this complication of hyperthyroidism that has a dramatic yet variable presentation, but is readily amenable to therapy. PMID- 25839005 TI - Rhabdomyolysis secondary to influenza a infection: a case report and review of the literature. AB - CONTEXT: Rhabdomyolysis is a serious clinical syndrome that results from damage to skeletal muscles. Common causes include drugs, crush injuries, seizures, heat, exertion, and infection. Viral infections, particularly Influenza A, have been recognized as a cause of rhabdomyolysis. CASE REPORT: Our report describes a 58 year-old male who presented with viral pneumonia secondary to Influenza A virus infection. His hospital course was complicated by acute renal failure secondary to rhabdomyolysis, which was attributed to an overwhelming viremia. We discuss the differential diagnosis of rhabdomyolysis and review the literature for cases of Influenza A-related rhabdomyolysis. We also discuss the proposed mechanisms for the condition. CONCLUSION: The scope of clinical manifestations of Influenza A infection extends beyond pulmonary syndromes. Rhabdomyolysis is being increasingly recognized as a complication of Influenza A infection with considerable morbidity and mortality. PMID- 25839006 TI - Hereditary hemorrhagic telangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder, which affects various internal organs and has a tendency for bleeding. It has a classic triad of mucocutaneous telangiectasias, recurrent hemorrhages and positive familial history of first-degree relative. Epistaxis or gastrointestinal telangiectasia can be fatal in a small number of cases. CASE REPORT: A 44-year-old woman came with complaints of recurrent episodes of hematemesis and epistaxis. Patient had a family history of similar complaints. Patient underwent esophagogastroduodenoscopy (EGD), which revealed telangiectasia in the stomach. Imaging of the abdomen showed features suggestive of arteriovenous shunting. CONCLUSION: HHT can remain undiagnosed for a long time, and is rarely being reported in the literature with management needing a multidisciplinary approach with early inputs from a gastroenterologist. PMID- 25839007 TI - Laparoscopic Cholecystectomy under Epidural Anesthesia: A Feasibility Study. PMID- 25839008 TI - The changing face of acute myeloid leukemia therapeutics in the elderly population. PMID- 25839009 TI - What is the way forward for unresectable oral cavity cancers among Indian patients? PMID- 25839010 TI - Role of low dose cytarabine in elderly patients with acute myeloid leukemia: An experience. AB - PURPOSE: To highlight the acceptable results seen after use of low dose cytarabine in elderly patients of acute myeloid leukemia (AML) with comorbidities. MATERIALS AND METHODS: This was a prospective study carried on 30 newly diagnosed patients of AML over 60 years of age who were unfit for standard treatment regimens. We did not use azacytidine and decitabine in our patients because these therapeutic modalities being extremely costly and our patient affordability being poor. After taking patient consent and institutional ethical clearance these patients were treated with 20 mg/m(2) cytarabine subcutaneously in two divided doses 12 h apart for 4 days every week for 4 weeks which constituted a cycle before disease, re-assessment was done. A repeat cycle was administered where ever needed and after attainment of remission, we continued low dose cytarabine for 2 days/week as maintenance after complete or partial response was documented. RESULTS: In our study, we found that around 20% of patients achieved complete remission and 30% partial remission. The remission rates were definitely influenced by counts at presentation, performance at presentation, comorbidities, underlying myelodysplastic syndrome and baseline cytogenetics. CONCLUSION: Low dose cytarabine is effective treatment option for elderly patients with AML when standard treatment options are not warranted. PMID- 25839011 TI - Open-label observational study to assess the efficacy and safety of aprepitant for chemotherapy-induced nausea and vomiting prophylaxis in Indian patients receiving chemotherapy with highly emetogenic chemotherapy/moderately emetogenic chemotherapy regimens. AB - CONTEXT: Currently, there is limited data on the prevention of chemotherapy induced nausea and vomiting (CINV) in Indian population with aprepitant containing regimens. AIMS: The aim was to assess the Efficacy and Safety of Aprepitant for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy/moderately emetogenic chemotherapy (HEC/MEC) regimens. SETTINGS AND DESIGN: Investigator initiated, multicentric, open-label, prospective, noncomparative, observational trial. SUBJECTS AND METHODS: Triple drug regimen with aprepitant, palonosetron, and dexamethasaone administration was assessed for the prevention of CINV during acute, delayed, and the overall phase (OP) for HEC/MEC Regimens. The primary endpoint was complete response (CR; no emesis and no use of rescue medication) and the key secondary endpoint was the complete control (CC; no emesis, no rescue medication and no more than mild nausea) during the OP. STATISTICAL ANALYSIS USED: Perprotocol efficacy was analyzed for the first cycle with results represented in terms of CR/CC rates using descriptive statistics. RESULTS: Seventy-five patients were included in the study with median age of 49.7 years and 89.7% being females. The CR rate (OP) for patients administered HEC or MEC regimens during the first cycle were 92% and 90.9%, respectively. Similarly, the CC rates (OP) were 75% and 90% for these regimens, respectively. 7 (9.2%) patients reported adverse drug reactions that were mild and transient with no reports of any serious adverse events. CONCLUSIONS: Use of aprepitant containing regimen for patients receiving HEC/MEC regimen resulted in significantly high CR and CC response rates, which further consolidate its potential role to improve patient quality of life and compliance to disease management. PMID- 25839012 TI - Simultaneous integrated boost with intensity modulated radiation therapy in brain oligometastases: A feasible technique for developing countries. AB - INTRODUCTION: To analyze the pattern of brain metastasis (BM), and to use intensity modulated radiation therapy (IMRT) for target dose escalation in cases with <=3 metastatic lesions (oligometastases). MATERIALS AND METHODS: Thirty-two consecutive cases of BM treated during September 2009 to August 2012 were analyzed retrospectively. RESULTS: The study comprised 13 males (40.62%) and 19 females (59.37%). Thirteen (40%) patients presented with disseminated intracranial metastases, while 19 (60%) had <=3 foci. In 25 cases (78%), the primary was located either in the breast (14 cases) or lung (11 cases). The 13 patients with disseminated intracranial metastases received whole brain radiation therapy to a dose of 30 Gy/10-12 daily fractions (Group A) while the 19 cases with <=3 lesions received an additional dose of 6-10 Gy to gross lesions using a simultaneous integrated boost (SIB) with IMRT thus receiving a total dose of 36 40 Gy/12-15 fractions (Group B). Overall survival (OS) for the breast primary was 6.3 and lung primary was 5.3 months, respectively. The mean OS for breast cases in Group B was higher (9.5 months) as compared to Group A cases (1.9 months) and was statistically significant (P = 0.0056). Similarly, primary lung cancer cases in Group B showed a mean OS of 8.75 months versus 2.6 months for Group A cases (P = 0.213). CONCLUSIONS: IMRT is a safe and effective technique in cases with oligometastases for dose escalation in the form of SIB. PMID- 25839013 TI - Impact of changing trends of treatment on outcome of cerebral gliosarcoma: A tertiary care centre experience. AB - AIM: To assess clinicopathological features and outcomes in patients of primary gliosarcoma with changing trends of treatment. MATERIALS AND METHODS: Medical records were reviewed and data collected on primary gliosarcoma over a 5-year period (2009-2013) from the departmental case files. RESULTS: A total 27 patients were included in this study. The median age of presentation was 54 years. There was a slight male preponderance, with male to female ratio of 1.25:1. The most common location of the tumor was temporal lobe (44.4%). Gross total resection was possible in 19 cases, near total excision was done in five cases, and only partial excision with decompression in three cases. Of the 27 patients, 80.8% patients received post-operative radical external beam radiotherapy of 60 Gy/30#/6 weeks. Concurrent and adjuvant temozolomide was used in 42.3% cases, depending on affordability and tolerance. Median overall survival was 9 months. On subgroup analysis, median overall survival in the radiotherapy plus temozolomide group was 10 months as compared to 9 months in the radiotherapy alone group; however, this was not statistically significant.(P = 0.244). CONCLUSION: Treating Gliosarcoma is a major therapeutic challenge for a clinician because of its poor prognosis, aggressive clinical behavior, rarity, and limited clinical experience. With surgery and concurrent chemoradiation, we were able to achieve a median overall survival of 9 months. Addition of temozolomide has shown a better trend in survival though it is not statistically significant. PMID- 25839014 TI - Addition of magnetic resonance imaging to computed tomography-based three dimensional conformal radiotherapy planning for postoperative treatment of astrocytomas: Changes in tumor volume and isocenter shift. AB - INTRODUCTION: Postoperative radiotherapy is the current gold standard treatment in astrocytomas. Computed tomography (CT)-based radiotherapy planning leads to either missing of the tumor volume or underdosing. The aim of this prospective study was to study the changes in tumor volume on addition of magnetic resonance imaging (MRI) to CT-based three-dimensional radiotherapy treatment planning of astrocytomas. MATERIALS AND METHODS: Twenty-five consecutive patients of astrocytoma (WHO grades I-IV) for postoperative three-dimensional conformal radiotherapy were included in this prospective study. Postoperative tumor volumes were contoured on CT-based images and recontoured on CT-MRI images after automated MRI co-registration on treatment planning system Eclipse 8.9.15 as per ICRU-50 report. Tumor volumes were compared with each other. RESULT: The MRI based mean and median tumor volume was 24.24 cc +/- 13.489 and 18.72 cc (range 5.6-46.48 cc), respectively, while for CT it was 19.4 cc +/- 11.218 and 16.24 cc (range: 5.1-38.72 cc), respectively. The mean and median isocenter shift between CT and MRI was 4.05 mm and 4.39 mm (range 0.92-6.32 mm), respectively. There is a linear relationship between MRI and CT volume with a good correlation coefficient of R (2) = 0.989, and MRI-based tumor volume was 1.208 times as compared to CT volume. Statistical analysis using paired sample t-test for the difference in CT and MRI tumor volume was highly significant (P < 0.001). CONCLUSION: Addition of MRI to the CT-based three-dimensional radiation treatment planning reduces the chances of geographical miss or tumor under dosing. Thus, MRI should be an integral part of three-dimensional planning of astrocytomas. PMID- 25839015 TI - Cancer related fatigue: A ubiquitous problem yet so under reported, under recognized and under treated. AB - BACKGROUND: Cancer related fatigue (CRF) is a problem that is highly under reported, under recognized and thus, under treated. About 80% of patients receiving chemotherapy/radiotherapy experience CRF, making it the most common side effect of cancer treatment. Functional assessment of chronic illness therapy fatigue (FACIT-F) version-4 is a 13 item questionnaire that has been used to measure the level of fatigue of cancer patients during their daily activities over the past 7 days. MATERIALS AND METHODS: 92 patients of age 18 years and above attending the oncology Out Patient Department (OPD) of a regional cancer center were recruited in this study and were given FACIT-F questionnaire. The relevant sociodemographic parameters were obtained from the medical records of the patients. The internal consistency of the 13 items was measured using the Cronbach's alpha. RESULTS: The Cronbach alpha coefficient for FACIT-F scale in our study was found to be 0.74. Kendall's coefficient of concordance was estimated to be 0.080. The correlation between Eastern Cooperative Oncology Group (ECOG) performance status and mean score of FACIT-F was studied, Pearson correlation coefficient was estimated to be 0.271 (P = 0.009). CONCLUSIONS: FACIT F is a brief, simple, easy to administer and patient friendly tool to measure the fatigue in last 7 days. CRF should be given adequate attention from the beginning of the treatment to improve the quality of life of cancer patients. PMID- 25839016 TI - Denominators: An attempt to adjust for cancer incidence and mortality rates and its role in cancer registries. AB - Cancer is an important public health burden in India and around the Globe. Incident cases of cancer are reported continuously, and trends in incidence rates vary among five yearly age group. In India National census is carried out after every 10 years since 1951, the latest census is carried out in 2011. As Incident cases of cancer are reported continuously for 5 year age group and estimation of rates and trends for a given year of interest fall in-between two census period population estimation of five yearly age group, which serves as Denominator sense importance. Denominator serves as the most essential part of any cancer registry program as it used for calculation of various rates for five yearly age group such as age-standardized rate, crude rate, truncated rate, cumulative risk etc., Calculated by different registries and Individual Researchers, Government organizations, etc. Currently most of the registries used individual exponential growth rate and differential distribution method to estimate the growth rate. However, it is found that the calculated rates and risk be suffering from bias most of the time since some method over and underestimate the growth rate while some does not able to maintain consistency. Here, an attempt is made to adjust the world standard population with two census period to estimate the five yearly age group for a given year of interest of a geographical region falls in-between two census period. It is also shown here that how the proposed model "age adjusted population growth model" maintain the overall growth as in exponential growth model and difference distribution method also maintains the estimated growth rate is as found in difference distribution method. Further, it is tried to highlight the points how these method overcomes the problems compared with other methods that are currently used by registries. PMID- 25839017 TI - Immunohistochemical detection of axillary lymph node micrometastases in node negative breast cancer patients using cytokeratin and epithelial membrane antigen. AB - BACKGROUND AND OBJECTIVE: The study was conducted to detect occult metastases in lymph node negative breast cancer patients using cytokeratin (CK) and epithelial membrane antigen (EMA) immunohistochemistry (IHC) and correlate this with primary tumor size and grade. MATERIALS AND METHODS: A total of 32 cases including 12 prospective and 20 retrospective cases of axillary lymph node negative breast cancer were studied. CK and EMA IHC were performed to detect micrometastases. RESULTS: Axillary lymph node metastases were detected in 18.75% of previously node negative cases using CK and EMA IHC. CK was found to be more sensitive for detection of metastases compared to EMA. A highly significant correlation was observed between tumor grade and axillary lymph node metastases detected by CK and EMA. However, no significant correlation was found between tumor size and axillary lymph node metastases detected by IHC. CONCLUSION: In the present study, there was an increase of 18.75% in the occult metastases detection rate using CK and EMA. To conclude, IHC detection of occult metastases should be done using CK in all axillary node negative cases, especially in T1 and T2 stage tumors. PMID- 25839018 TI - Cytological grading of breast carcinoma on fine needle aspirates and its relation with histological grading. AB - BACKGROUND: Grading of breast carcinoma on fine needle aspiration cytology (FNAC) is beneficial for selecting patients for neoadjuvant chemotherapy. AIMS: To grade the breast carcinoma on FNAC using Robinson grading system and to assess the concordance of cytological grading (CG) with histological grading (HG) using Elston-Ellis modification of Scarff-Bloom-Richardson grading system. MATERIALS AND METHODS: The study was conducted for 1-year, comprising of 50 female patients attending outpatient departments (OPD) as well as admitted in various surgical wards of a teaching hospital, diagnosed as breast carcinoma. FNAC smears were stained with May-Grunwald-Giemsa and Papanicolaou (Pap) stains and CG was done using Robinson system on Pap stained smears. The results were compared with HG system after resection of tumors. RESULTS: Of 50 cases, 14 (28%) cases were graded as grade I, 24 (48%) grade II, and 12 (24%) grade III by CG, whereas 9 (18%), 28 (56%) and 13 (26%) cases were graded as grade I, II and III by HG. The result showed overall 72% concordance of CG with HG, with grade II and grade III showing highest degree of concordance (83.33%), which is comparable to previous studies. Kappa measurement showed a higher degree of agreement in high-grade tumors compared with low-grade tumors (0.73 in grade III, 0.53 in grade II and 0.39 in grade I). CONCLUSION: Cytological grading is comparable to HG in majority of cases. Because neoadjuvant chemotherapy is becoming increasingly popular as primary treatment modality of breast cancer, CG could be a useful parameter in selecting the mode of therapy and predicting tumor behavior. PMID- 25839019 TI - Role of FNAC in Hepatic lesions: Risk of track metastases. AB - BACKGROUND: Liver is one of the most common site of metastases in patients with malignancy and the evaluation of space occupying lesions (SOL) of liver in patients with malignancy is important. Its important to differentiate benign from malignant to take necessary decisions. MATERIALS AND METHODS: We have performed a retrospective analysis of liver SOLs for which fine needle aspiration cytology (FNAC) was done in the year 2011. Risks and benefits associated with FNAC were evaluated. RESULTS: We analyzed 755 patients who underwent FNAC of which 524 patients had secondary metastases to liver, 148 patients had primary hepatocellular carcinoma, 14 cases were benign neoplasms and 53 were nonneoplastic conditions. Histological correlation with FNAC was available in 112 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 93%, 90.9%, 98.9%, 58.8%, and 92.8%, respectively. Though there were no incidence of bleeding, two patients developed track metastases following FNAC. One was a case of Hepatocellular carcinoma and the other a case of metastatic breast cancer. CONCLUSION: FNAC was very much useful in our setup where most of the patients could not afford for Computer tomography (CT) scan and was useful in counseling them especially in patients with advanced malignancy where no active cancer directed therapy is required. PMID- 25839020 TI - Novel formulation of cytarabine and daunorubicin: A new hope in AML treatment. AB - Acute myeloid leukemia (AML) treatment has always been a challenge to the treating physician. Continuous efforts are being made to improve treatment outcomes in AML. CPX-351 is a pharmacologic advancement in this direction. It is a liposomal fixed drug combination of cytarabine and daunorubicin. Early studies indicate that it will play a big role in AML treatment. This is a short review about this drug. PMID- 25839021 TI - Giant solitary trichoepithelioma. AB - Adnexal tumors like giant solitary trichoepitheliomas are uncommon to most of us to permit a ready familiarity with them. Information regarding the genesis, clinical profile, behavior, and management options for this tumor is limited. There are 18 cases reported in the world literature till date. This review attempts to provide insight to this rare tumor. Our search included indexed literature from Pubmed, Directory of Open Access Journals, Health Inter Network Access to Research Initiative and Google databases in addition to standard dermatology texts. Giant solitary trichoepithelioma is a rare trichogenic tumor with potential for local recurrence. It has predilection for the older age, but may present at any age including at birth. It has close resemblance to basal cell carcinoma and other skin adnexal tumors - clinically, cytologically, and histologically. CD10, CD 34, PHLDA1 but not p75NTR are useful adjunct markers. Surgical excision is the standard treatment. Recurrence and possible transformation into BCC cautions follow up at regular intervals. PMID- 25839022 TI - Laparoscopic management of sigmoidorectal intussusception caused by sigmoid carcinoma. PMID- 25839023 TI - Subcutaneous implantation of metastatic carcinoma: An unpredicted event following endoscopic parathroidectomy for adenoma. PMID- 25839024 TI - Unusual etiology of secondary thyrotoxicosis and its presentation. PMID- 25839025 TI - A retrospective analysis of occupational exposure to pesticides as a possible risk factor for non-melanoma skin cancers. PMID- 25839027 TI - Epidemiological research on cancers by cancer registries: A view point. PMID- 25839026 TI - Spontaneous rupture of renal cell carcinoma: A series of three cases. PMID- 25839028 TI - Oncocytic adenoma of thyroid with papillary architecture: A diagnostic dilemma. PMID- 25839029 TI - Gastric and colonic metastasis from cancer cervix: An unusual progression with an uncommon cause of mortality. PMID- 25839030 TI - A novel role of centrin in flagellar motility: stabilizing an inner-arm dynein motor in the flagellar axoneme. AB - Centrin is an evolutionarily conserved EF-hand calcium-binding protein found in the centriole of animals and the basal body of flagellated organisms. It was originally discovered in the flagellated unicellular green alga Chlamydomonas reinhardtii, where it associates with flagellum-associated structures and regulates basal body duplication and flagellar motility. Centrin constitutes a light chain of three inner-arm dynein complexes in the flagellar axoneme in Chlamydomonas, and presumably regulates the activity of the inner-arm dynein for flagellar motility. In the ciliated organism Tetrahymena, centrin also associates with the inner-arm dynein and appears to regulate the microtubule sliding velocity of the inner-arm dynein. Using Trypanosoma brucei as the model organism, we discovered that centrin maintains the stability of an inner-arm dynein in the flagellar axoneme [Wei et al., (2014) Nat. Commun 5: 4060]. T. brucei expresses five centrins, three of which, TbCentrin1, 2, and 4, associate with the flagellar basal body, but no centrin was found to regulate cell motility. We found that TbCentrin3 associates tightly with the flagellum and that RNAi of TbCentrin3 compromised cell motility. Biochemical approaches further showed that TbCentrin3 interacts with TbIAD5-1, an inner-arm dynein in the flagellar axoneme. Knockdown of TbIAD5-1 also caused defective cell motility. Strikingly, depletion of TbCentrin3 or depletion of TbIAD5-1 resulted in disassembly of the complex from the axoneme and subsequent degradation of the complex in the cytosol. Our findings identified a novel role of TbCentrin3 in cell motility by stabilizing TbIAD5-1 in the axoneme, which likely is well conserved in other flagellated and ciliated organisms, such as Chlamydomonas and Tetrahymena where centrin is also known to associate with inner-arm dyneins. PMID- 25839031 TI - Improving the thermostability and optimal temperature of a lipase from the hyperthermophilic archaeon Pyrococcus furiosus by covalent immobilization. AB - A recombinant thermostable lipase (Pf2001Delta60) from the hyperthermophilic Archaeon Pyrococcus furiosus (PFUL) was immobilized by hydrophobic interaction on octyl-agarose (octyl PFUL) and by covalent bond on aldehyde activated-agarose in the presence of DTT at pH = 7.0 (one-point covalent attachment) (glyoxyl-DTT PFUL) and on glyoxyl-agarose at pH 10.2 (multipoint covalent attachment) (glyoxyl PFUL). The enzyme's properties, such as optimal temperature and pH, thermostability, and selectivity, were improved by covalent immobilization. The highest enzyme stability at 70 degrees C for 48 h incubation was achieved for glyoxyl PFUL (around 82% of residual activity), whereas glyoxyl-DTT PFUL maintained around 69% activity, followed by octyl PFUL (27% remaining activity). Immobilization on glyoxyl-agarose improved the optimal temperature to 90 degrees C, while the optimal temperature of octyl PFUL was 70 degrees C. Also, very significant changes in activity with different substrates were found. In general, the covalent bond derivatives were more active than octyl PFUL. The E value also depended substantially on the derivative and the conditions used. It was observed that the reaction of glyoxyl-DTT PFUL using methyl mandelate as a substrate at pH 7 presented the best results for enantioselectivity (E = 22) and enantiomeric excess (ee (%) = 91). PMID- 25839032 TI - Wu-tou decoction inhibits chronic inflammatory pain in mice: participation of TRPV1 and TRPA1 ion channels. AB - Wu-tou decoction (WTD) is a classic traditional Chinese medicine formula and has been used effectively to treat joint diseases clinically. Previous reports indicated that WTD possesses anti-inflammatory activity; however, its actions on pain have not been clarified. Here, we investigated the antinociceptive activity of WTD in CFA-induced mice, and its possible mechanism of the action associated with transient receptor potential (TRP) ion channels was also explored. Our results showed that 1.58, 3.15, and 6.30 g/kg WTD significantly attenuated mechanical, cold, and heat hypersensitivities. Moreover, WTD effectively inhibited spontaneous nociceptive responses to intraplantar injections of capsaicin and cinnamaldehyde, respectively. WTD also effectively suppressed jumping and wet-dog-shake behaviors to intraperitoneal injection of icilin. Additionally, WTD significantly reduced protein expression of TRPV1 and TRPA1 in dorsal root ganglia and skins of injured paw. Collectively, our data demonstrate firstly that WTD exerts antinociceptive activity in inflammatory conditions by attenuating mechanical, cold, and heat hypersensitivities. This antinociceptive effect may result in part from inhibiting the activities of TRPV1, TRPA1, and TRPM8, and the suppression of TRPV1 and TRPA1 protein by WTD was also highly effective. These findings suggest that WTD might be an attractive and suitable therapeutic agent for the management of chronic inflammatory pain. PMID- 25839033 TI - Impact on human health of microorganisms present in fermented dairy products: an overview. AB - Fermented dairy products provide nutrients in our diet, some of which are produced by the action of microorganisms during fermentation. These products can be populated by a diverse microbiota that impacts the organoleptic and physicochemical characteristics foods as well as human health. Acidification is carried out by starter lactic acid bacteria (LAB) whereas other LAB, moulds, and yeasts become dominant during ripening and contribute to the development of aroma and texture in dairy products. Probiotics are generally part of the nonstarter microbiota, and their use has been extended in recent years. Fermented dairy products can contain beneficial compounds, which are produced by the metabolic activity of their microbiota (vitamins, conjugated linoleic acid, bioactive peptides, and gamma-aminobutyric acid, among others). Some microorganisms can also release toxic compounds, the most notorious being biogenic amines and aflatoxins. Though generally considered safe, fermented dairy products can be contaminated by pathogens. If proliferation occurs during manufacture or storage, they can cause sporadic cases or outbreaks of disease. This paper provides an overview on the current state of different aspects of the research on microorganisms present in dairy products in the light of their positive or negative impact on human health. PMID- 25839034 TI - The interplay between synaptic activity and neuroligin function in the CNS. AB - Neuroligins (NLs) are postsynaptic transmembrane cell-adhesion proteins that play a key role in the regulation of excitatory and inhibitory synapses. Previous in vitro and in vivo studies have suggested that NLs contribute to synapse formation and synaptic transmission. Consistent with their localization, NL1 and NL3 selectively affect excitatory synapses, whereas NL2 specifically affects inhibitory synapses. Deletions or mutations in NL genes have been found in patients with autism spectrum disorders or mental retardations, and mice harboring the reported NL deletions or mutations exhibit autism-related behaviors and synapse dysfunction. Conversely, synaptic activity can regulate the phosphorylation, expression, and cleavage of NLs, which, in turn, can influence synaptic activity. Thus, in clinical research, identifying the relationship between NLs and synapse function is critical. In this review, we primarily discuss how NLs and synaptic activity influence each other. PMID- 25839035 TI - Assessment of the body composition and parameters of the cardiovascular risk in juvenile idiopathic arthritis. AB - The study was aimed to evaluate cardiovascular risk parameters, body mass index (BMI) centiles for sex and age, and body fat percentage using the electric bioimpedance method in children with juvenile idiopathic arthritis (JIA). 30 children with JIA participated in the study. A control group included 20 children. Patients were well matched for the age and sex. The body mass and body fat percentage were determined using the segmental body composition analyser; the BMI centiles were determined. All patients had the following parameters determined: lipid profile, hsCRP, homocysteine, and IL-6. The intima media thickness (IMT) was measured. Patients with JIA had significantly lower body weight, BMI, and the BMI centile compared to the control group. The IL-6 levels were significantly higher in patients with JIA compared to the control group. There were no differences between two groups with regard to the lipid profile, % content of the fat tissue, homocysteine levels, hsCRP, and IMT. Further studies are necessary to search for reasons for lower BMI and BMI centile in children with JIA and to attempt to answer the question of whether lower BMI increases the cardiovascular risk in these patients, similarly as in patients with rheumatoid arthritis (RA). PMID- 25839036 TI - Investigation of the vitamin D receptor polymorphisms in acromegaly patients. AB - OBJECTIVE: The genetic structural alterations in the majority of somatotroph adenomas are not clarified and the search for novel candidate genes is still a challenge. We aimed to investigate possible associations between vitamin D receptor (VDR) polymorphisms and acromegaly. DESIGN, PATIENTS, AND METHODS: 52 acromegaly patients (mean age 45.7 +/- 1.9 years) and 83 controls (mean age 43.1 +/- 2.6 years) were recruited to the study. VDR polymorphism was determined by polymerase chain reaction-based restriction fragment length polymorphism methods. RESULTS: The distribution of VDR genotypes showed a significant difference in the frequencies of VDR FokI genotypes between patients and controls (P = 0.034). VDR FokI ff genotype was significantly decreased in acromegaly patients (P = 0.035) and carriers of FokI Ff genotype had a 1.5-fold increased risk for acromegaly (OR: 1.5, 95% CI: 1.07-2.1; P = 0.020). IGF1 levels after treatment were significantly higher in patients carrying the Ff genotype compared to carrying ff genotype (P = 0.0049). 25(OH)D3 levels were significantly lower in acromegaly patients (P < 0.001). CONCLUSIONS: Our study suggests that VDR FokI genotypes might affect the development of acromegaly and VDR polymorphisms may play a role in the course of acromegaly as a consequence of altering hormonal status. PMID- 25839037 TI - Dexamethasone enhanced functional recovery after sciatic nerve crush injury in rats. AB - Dexamethasone is currently used for the treatment of peripheral nerve injury, but its mechanisms of action are not completely understood. Inflammation/immune response at the site of nerve lesion is known to be an essential trigger of the pathological changes that have a critical impact on nerve repair and regeneration. In this study, we observed the effects of various doses of dexamethasone on the functional recovery after sciatic nerve crush injury in a rat model. Motor functional recovery was monitored by walking track analysis and gastrocnemius muscle mass ratio. The myelinated axon number was counted by morphometric analysis. Rats administered dexamethasone by local intramuscular injection had a higher nerve function index value, increased gastrocnemius muscle mass ratio, reduced Wallerian degeneration severity, and enhanced regenerated myelinated nerve fibers. Immunohistochemical analysis was performed for CD3 expression, which is a marker for T-cell activation, and infiltration in the sciatic nerve. Dexamethasone-injected rats had fewer CD3-positive cells compared to controls. Furthermore, we found increased expression of GAP-43, which is a factor associated with development and plasticity of the nervous system, in rat nerves receiving dexamethasone. These results provide strong evidence that dexamethasone enhances sciatic nerve regeneration and function recovery in a rat model of sciatic nerve injury through immunosuppressive and potential neurotrophic effects. PMID- 25839038 TI - Cooperative regulation of substrate stiffness and extracellular matrix proteins in skin wound healing of axolotls. AB - Urodele amphibians (Ambystoma mexicanum), unique among vertebrates, can regenerate appendages and other body parts entirely and functionally through a scar-free healing process. The wound epithelium covering the amputated or damaged site forms early and is essential for initiating the subsequent regenerative steps. However, the molecular mechanism through which the wound reepithelializes during regeneration remains unclear. In this study, we developed an in vitro culture system that mimics an in vivo wound healing process; the biomechanical properties in the system were precisely defined and manipulated. Skin explants that were cultured on 2 to 50 kPa collagen-coated substrates rapidly reepithelialized within 10 to 15 h; however, in harder (1 GPa) and other extracellular matrices (tenascin-, fibronectin-, and laminin-coated environments), the wound epithelium moved slowly. Furthermore, the reepithelialization rate of skin explants from metamorphic axolotls cultured on a polystyrene plate (1 GPa) increased substantially. These findings afford new insights and can facilitate investigating wound epithelium formation during early regeneration using biochemical and mechanical techniques. PMID- 25839039 TI - Cognitive-motor interference in multiple sclerosis: a systematic review of evidence, correlates, and consequences. AB - Individuals with multiple sclerosis (MS) regularly exhibit deficits in motor and cognitive function. Recent evidence suggests that these impairments are compounded when motor and cognitive task are performed simultaneously such as walking while talking. The changes incurred during simultaneous performance of motor and cognitive tasks are a result of cognitive-motor interference (CMI) and operationalized as dual task costs (DTC). Recently in MS, research has been conducted to understand and analyze the impact of CMI. The purpose of this paper was to review the current literature related to the evidence, correlates, and consequences of CMI in MS. Relevant literature was collected from the results of a PubMed search for terms including "Cognitive-motor interference" or "Cognitive motor interaction" or "Dual task" and "multiple sclerosis." Overall, 20 papers were included for review which focused on CMI during balance and walking tasks. The finding that there is a lack of evidence pertaining to changes in the cognitive domain as well as to the specific consequences of CMI in MS was noted. Future work should aim to fill these gaps and ultimately investigate the usefulness of targeted interventions in reducing the deleterious effects of CMI in individuals with MS. PMID- 25839040 TI - Folated synperonic-cholesteryl hemisuccinate polymeric micelles for the targeted delivery of docetaxel in melanoma. AB - The objective of this study was the synthesis of folic acid- (FA-) targeted polymeric micelles of Synperonic PE/F 127-cholesteryl hemisuccinate (PF127-Chol) for specific delivery of docetaxel (DTX). Targeted or nontargeted micelles loaded with DTX were prepared via dialysis method. The effects of processing variables on the physicochemical properties of targeted micelles were evaluated using a full factorial design. After the optimization of the polymer/drug ratio, the organic solvent type used for the preparation of the micelles, and the temperature of dialyzing medium, the in vitro cytotoxicity and cellular uptake of the optimized micelles were studied on B16F10 melanoma cells by flow cytometry and fluorescent microscopy. The anticancer efficacy of DTX-loaded FA-PF127-Chol was evaluated in mice bearing melanoma tumor. Optimized targeted micelles had the particle size of 171.3 nm, zeta potential of -7.8 mV, PDI of 0.325, and a high encapsulation efficiency that released the drug within 144 h. The MTT assay indicated that targeted micelles carrying DTX were significantly more cytotoxic, had higher cellular uptake, and reduced the tumor volume significantly more than the nontargeted micelles and the free drug. FA-PF127-Chol could be, therefore, a promising biomaterial for tumors overexpressing folate receptors. PMID- 25839042 TI - Conventional and unconventional use of lasers in skin disorders. PMID- 25839041 TI - Synthesis and characterization of biodegradable polyurethane for hypopharyngeal tissue engineering. AB - Biodegradable crosslinked polyurethane (cPU) was synthesized using polyethylene glycol (PEG), L-lactide (L-LA), and hexamethylene diisocyanate (HDI), with iron acetylacetonate (Fe(acac)3) as the catalyst and PEG as the extender. Chemical components of the obtained polymers were characterized by FTIR spectroscopy, (1)H NMR spectra, and Gel Permeation Chromatography (GPC). The thermodynamic properties, mechanical behaviors, surface hydrophilicity, degradability, and cytotoxicity were tested via differential scanning calorimetry (DSC), tensile tests, contact angle measurements, and cell culture. The results show that the synthesized cPU possessed good flexibility with quite low glass transition temperature (T g , -22 degrees C) and good wettability. Water uptake measured as high as 229.7 +/- 18.7%. These properties make cPU a good candidate material for engineering soft tissues such as the hypopharynx. In vitro and in vivo tests showed that cPU has the ability to support the growth of human hypopharyngeal fibroblasts and angiogenesis was observed around cPU after it was implanted subcutaneously in SD rats. PMID- 25839044 TI - Biomedical insights of human genetic diversity in complex diseases. PMID- 25839043 TI - Shengmai injection improved doxorubicin-induced cardiomyopathy by alleviating myocardial endoplasmic reticulum stress and caspase-12 dependent apoptosis. AB - BACKGROUND: Apoptosis plays vital roles in the progression of doxorubicin-induced cardiomyopathy (DOX-CM). Endoplasmic reticulum stress (ER stress) could induce specific apoptosis by caspase-12 dependent pathway. Shengmai Injection (SMI), a famous Traditional Chinese Medicine, could alleviate the heart damage via inhibiting myocardial apoptosis. However, it is unknown whether SMI can alleviate ER stress and its specific apoptosis in the setting of DOX-CM. OBJECTIVE: To explore the effects of SMI on heart function, myocardial ER stress, and apoptosis of DOX-CM rats. METHODS: Rats with DOX-CM were treated by SMI. Heart function was assessed by echocardiography and brain natriuretic peptide. Myocardial apoptosis was detected by TUNEL assay. ER stress was assessed by detecting the expressions of GRP78 and caspase-12. RESULTS: At the end of eight-week, compared to control, significant heart dysfunction happened in DOX group. The ratio of apoptotic cardiomyocytes and the expressions of GRP78 and caspase-12 increased significantly (P < 0.05). Compared to DOX group, the apoptotic ratio and the expressions of GRP78 and caspase-12 significantly decreased in DOX + SMI group (P < 0.05), accompanied with improved heart function. CONCLUSION: SMI could alleviate myocardial ER stress and caspase-12 dependent apoptosis, which subsequently helped to improve the heart function of rats with DOX-CM. PMID- 25839045 TI - Vaccines and therapies for biodefence agents. PMID- 25839046 TI - Inducing gene expression by targeting promoter sequences using small activating RNAs. AB - Vector-based systems comprised of exogenous nucleic acid sequences remain the standard for ectopic expression of a particular gene. Such systems offer robust overexpression, but have inherent drawbacks such as the tedious process of construction, excluding sequences (e.g. introns and untranslated regions) important for gene function and potential insertional mutagenesis of host genome associated with the use of viral vectors. We and others have recently reported that short double-stranded RNAs (dsRNAs) can induce endogenous gene expression by targeting promoter sequences in a phenomenon referred to as RNA activation (RNAa) and such dsRNAs are termed small activating RNAs (saRNAs). To date, RNAa has been successfully utilized to induce the expression of different genes such as tumor suppressor genes. Here, we describe a detailed protocol for target selection and dsRNA design with associated experiments to facilitate RNAa in cultured cells. This technique may be applied to selectively activate endogenous gene expression for studying gene function, interrogating molecular pathways and reprogramming cell fate. PMID- 25839048 TI - Effect of Threading Dislocations on the Quality Factor of InGaN/GaN Microdisk Cavities. AB - In spite of the theoretical advantages associated with nitride microcavities, the quality factors of devices with embedded indium gallium nitride (InGaN) or gallium nitride (GaN) optical emitters still remain low. In this work we identify threading dislocations (TDs) as a major limitation to the fabrication of high quality factor devices in the nitrides. We report on the use of cathodoluminescence (CL) to identify individual TD positions within microdisk lasers containing either InGaN quantum wells or quantum dots. Using CL to accurately count the number, and map the position, of dislocations within several individual cavities, we have found a clear correlation between the density of defects in the high-field region of a microdisk and its corresponding quality factor (Q). We discuss possible mechanisms associated with defects, photon scattering, and absorption, which could be responsible for degraded device performance. PMID- 25839047 TI - Oncolytic Poxviruses. AB - Current standard treatments of cancer can prolong survival of many cancer patients but usually do not effectively cure the disease. Oncolytic virotherapy is an emerging therapeutic for the treatment of cancer that exploits replication competent viruses to selectively infect and destroy cancerous cells while sparing normal cells and tissues. Clinical and/or preclinical studies on oncolytic viruses have revealed that the candidate viruses being tested in trials are remarkably safe and offer potential for treating many classes of currently incurable cancers. Among these candidates are vaccinia and myxoma viruses, which belong to the family Poxviridae and possess promising oncolytic features. This article describes poxviruses that are being developed for oncolytic virotherapy and summarizes the outcomes of both clinical and preclinical studies. Additionally, studies demonstrating superior efficacy when poxvirus oncolytic virotherapy is combined with conventional therapies are described. PMID- 25839049 TI - Excitonic AND Logic Gates on DNA Brick Nanobreadboards. AB - A promising application of DNA self-assembly is the fabrication of chromophore based excitonic devices. DNA brick assembly is a compelling method for creating programmable nanobreadboards on which chromophores may be rapidly and easily repositioned to prototype new excitonic devices, optimize device operation, and induce reversible switching. Using DNA nanobreadboards, we have demonstrated each of these functions through the construction and operation of two different excitonic AND logic gates. The modularity and high chromophore density achievable via this brick-based approach provide a viable path toward developing information processing and storage systems. PMID- 25839050 TI - Does Marijuana Use Contribute to Intimate Partner Aggression? A Brief Review and Directions for Future Research. AB - Marijuana users are more likely to perpetrate intimate partner aggression (IPA) than non-users, yet the mechanism responsible for this association is unknown. Recent studies considering the association between episodes of marijuana use and episodes of IPA have failed to find evidence consistent with an acute effect of marijuana. Research gaps are highlighted and a heuristic model of marijuana's potential effects on IPA is presented. Research priorities include consideration of mediating mechanisms, moderating variables at the individual and couple level, and examination of acute effects of marijuana using daily report and EMA designs. PMID- 25839051 TI - Association study between novel CYP26 polymorphisms and the risk of betel quid related malignant oral disorders. AB - BQ chewing may produce significant amounts of reactive oxygen species (ROS), resulting in oral mucosa damage, and ROS may be metabolized by CYP26 families. Because the CYP26 polymorphisms associated with malignant oral disorders are not well known, we conducted an association study on the associations between the single nucleotide polymorphisms (SNP) of CYP26 families and the risks of malignant oral disorders. BQ chewers with the CYP26A1 rs4411227 C/C+C/G genotype and C allele showed an increased risk of oral and pharyngeal cancer (adjusted odds ratio (aOR) = 2.30 and 1.93, respectively). The CYP26B1 rs3768647 G allele may be associated with oral and pharyngeal cancer (aOR = 3.12) and OPMDs (aOR = 2.23). Subjects with the rs9309462 CT genotype and C allele had an increased risk of oral and pharyngeal cancer (aOR = 9.24 and 8.86, respectively) and OPMDs (aOR = 8.17 and 7.87, respectively). The analysis of joint effects between the CYP26A1 rs4411227 and CYP26B1 rs3768647/rs9309462 polymorphisms revealed statistical significance (aOR = 29.91 and 10.03, respectively). Additionally, we observed a significant mRNA expression of CY26A1 and CYP26B1 in cancerous tissues compared with adjacent noncancerous tissues. Our findings suggest that novel CYP26 polymorphisms are associated with an increased risk of malignant oral disorders, particularly among BQ chewers. PMID- 25839052 TI - Impact of pneumococcal conjugate vaccine on pediatric tympanostomy tube insertion in partial immunized population. AB - OBJECTIVE: To investigate the impact of seven-valent pneumococcal conjugate vaccine on tube insertions in a partial immunized pediatric population. STUDY DESIGN: Retrospective ecological study. METHODS: This study used Taiwan National Health Insurance Research Database for the period 2000-2009. Every child under 17 years old who received tubes during this 10-year period was identified and analyzed. The tube insertion rates in different age groups and the risk to receive tubes in different birth cohorts before and after the release of the vaccine in 2005 were compared. RESULTS: The tube insertion rates for children under 17 years of age ranged from 21.6 to 31.9 for 100,000 persons/year. The tube insertion rate of children under 2 years old decreased significantly after 2005 in period effect analysis (beta = -0.074, P < 0.05, and the negative beta value means a downward trend) and increased in children 2 to 9 years old throughout the study period (positive beta values which mean upward trends, P < 0.05). The rate of tube insertion was lower in 2004-2005 and 2006-2007 birth cohorts than that of 2002-2003 birth cohort (RR = 0.90 and 0.21, 95% CI 0.83-0.97 and 0.19-0.23, resp.). CONCLUSION: The seven-valent pneumococcal conjugate vaccine may reduce the risk of tube insertion for children of later birth cohorts. The vaccine may have the protective effect on tube insertions in a partial immunized pediatric population. PMID- 25839053 TI - Evaluation of Cinnamomum osmophloeum Kanehira extracts on tyrosinase suppressor, wound repair promoter, and antioxidant. AB - Cinnamomum osmophloeum Kanehira belongs to the Lauraceae family of Taiwan's endemic plants. In this study, C. osmophloeum Kanehira extract has shown inhibition of tyrosinase activity on B16-F10 cellular system first. Whether extracts inhibited mushroom tyrosinase activity was tested, and a considerable inhibition of mushroom tyrosinase activity by in vitro assays was presented. Animal experiments of C. osmophloeum Kanehira were carried out by observing animal wound repair, and the extracts had greater wound healing power than the vehicle control group (petroleum jelly with 8% DMSO, w/v). In addition, the antioxidant capacity of C. osmophloeum Kanehira extracts in vitro was evaluated. We measured C. osmophloeum Kanehira extract's free radical scavenging capability, metal chelating, and reduction power, such as biochemical activity analysis. The results showed that a high concentration of C. osmophloeum Kanehira extract had a significant scavenging capability of free radical, a minor effect of chelating ability, and moderate reducing power. Further exploration of the possible physiological mechanisms and the ingredient components of skincare product for skin-whitening, wound repair, or antioxidative agents are to be done. PMID- 25839054 TI - Indoxyl sulfate-induced oxidative stress, mitochondrial dysfunction, and impaired biogenesis are partly protected by vitamin C and N-acetylcysteine. AB - Indoxyl sulfate (IS) contributes to oxidative stress and endothelial dysfunction in chronic kidney disease patients. However, the role of mitochondria in IS induced oxidative stress is not very clear. In this study, we examined whether mitochondria play a pivotal role in modulating the effects of antioxidants during IS treatment. In the context of human umbilical vein endothelial cells, we found that IS had a dose-dependent antiproliferative effect. In addition, we used flow cytometry to demonstrate that the level of reactive oxygen species increased in a dose-dependent manner after treatment with IS. High doses of IS also corresponded to increased mitochondrial depolarization and decreased mitochondrial DNA copy number and mitochondrial mass. However, these effects could be reversed by the addition of antioxidants, namely, vitamin C and N-acetylcysteine. Thus, our results suggest that IS-induced oxidative stress and antiproliferative effect can be attributed to mitochondrial dysfunction and impaired biogenesis and that these processes can be protected by treatment with antioxidants. PMID- 25839055 TI - Measuring psychological trauma in the workplace: psychometric properties of the Italian version of the psychological injury risk indicator-a cross-sectional study. AB - BACKGROUND: The aim of this study was to cross-culturally adapt the Psychological Injury Risk Indicator (PIRI) and to validate its psychometric properties. METHODS: Workers from 24 small companies were invited to self-complete the PIRI before undergoing their routine medical examination at the workplace. All participants (841 out of 845, 99.6%) were also asked to report occupational injuries and episodes of violence that had occurred at the workplace in the previous 12 months and were given the General Health Questionnaire (GHQ12) to complete. RESULTS: Exploratory factor analysis revealed a 4-factor structure, "sleep problems," "recovery failure," "posttraumatic stress symptoms," and "chronic fatigue," which were the same subscales observed in the original version. The internal consistency was excellent (alpha = 0.932). ROC curve analysis revealed that the PIRI was much more efficient than GHQ12 in diagnosing workers who had suffered trauma (workplace violence or injury) in the previous year, as it revealed an area under the curve (AUC) of 0.679 (95% CI: 0.625-0.734) for the PIRI, while for the GHQ12 the AUC was 0.551 (not significant). CONCLUSIONS: This study, performed on a large population of workers, provides evidence of the validity of the Italian version of the PIRI. PMID- 25839056 TI - Discovery of specific inhibitors for intestinal E. coli beta-glucuronidase through in silico virtual screening. AB - Glucuronidation is a major metabolism process of detoxification for carcinogens, 4-(methylnitrosamino)-1-(3-pyridy)-1-butanone (NNK) and 1,2-dimethylhydrazine (DMH), of reactive oxygen species (ROS). However, intestinal E. coli beta glucuronidase (ebetaG) has been considered pivotal to colorectal carcinogenesis. Specific inhibition of ebetaG may prevent reactivating the glucuronide-carcinogen and protect the intestine from ROS-mediated carcinogenesis. In order to develop specific ebetaG inhibitors, we found that 59 candidate compounds obtained from the initial virtual screening had high inhibition specificity against ebetaG but not human betaG. In particular, we found that compounds 7145 and 4041 with naphthalenylidene-benzenesulfonamide (NYBS) are highly effective and selective to inhibit ebetaG activity. Compound 4041 (IC50 = 2.8 MUM) shows a higher inhibiting ability than compound 7145 (IC50 = 31.6 MUM) against ebetaG. Furthermore, the molecular docking analysis indicates that compound 4041 has two hydrophobic contacts to residues L361 and I363 in the bacterial loop, but 7145 has one contact to L361. Only compound 4041 can bind to key residue (E413) at active site of ebetaG via hydrogen-bonding interactions. These novel NYBS-based ebetaG specific inhibitors may provide as novel candidate compounds, which specifically inhibit ebetaG to reduce ebetaG-based carcinogenesis and intestinal injury. PMID- 25839058 TI - Role of Cellular Magnesium in Human Diseases. AB - Magnesium is required for many of the major organs to function and plays a crucial role in human and mammalian physiology. Magnesium is essential for the structure of bones and teeth, acts as a cofactor for more than 300 enzymes in the body, including binding to ATP for kinase reactions, and affects permeability of excitable membranes and neuromuscular transmission. Despite these essential roles, much is still unknown about magnesium physiology and homeostasis. Currently, nutritionists believe that the general population intakes insufficient magnesium daily through the diet. The effects of magnesium deficiency are, for the most part undetected, and simple, widespread assessments of magnesium intake remain unavailable for humans. Many of the patients admitted to hospitals or medical care facilities are unaware of their low magnesium levels. Moreover, because magnesium is predominantly an intracellular cation (>99%), serum magnesium levels remain a poor predictor of tissue magnesium content and availability. This review will discuss the effects of magnesium deficiency in various pathologies affecting the human population. The underlying causes for magnesium depletion in major physiological systems will be examined along with the involved signaling pathways and the main roles of magnesium homeostasis. Where possible (e.g. alcoholism), the implications of administering supplemental magnesium will be discussed. Ultimately, this review will advocate for the necessity of identifying easy and reproducible methods to assess serum and cellular magnesium levels and to identify magnesium deficiency in order to alleviate related pathological conditions. PMID- 25839057 TI - Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling. AB - The beating heart exhibits remarkable contractile fidelity over a lifetime, which reflects the tight coupling of electrical, chemical, and mechanical elements within the sarcomere, the elementary contractile unit. On a beat-to-beat basis, calcium is released from the ends of the sarcomere and must diffuse toward the sarcomere center to fully activate the myosin- and actin-based contractile proteins. The resultant spatial and temporal gradient in free calcium across the sarcomere should lead to nonuniform and inefficient activation of contraction. We show that myosin-binding protein C (MyBP-C), through its positioning on the myosin thick filaments, corrects this nonuniformity in calcium activation by exquisitely sensitizing the contractile apparatus to calcium in a manner that precisely counterbalances the calcium gradient. Thus, the presence and correct localization of MyBP-C within the sarcomere is critically important for normal cardiac function, and any disturbance of MyBP-C localization or function will contribute to the consequent cardiac pathologies. PMID- 25839059 TI - Use of atropine-diphenoxylate compared with hyoscyamine to decrease rates of irinotecan-related cholinergic syndrome. AB - BACKGROUND: Cholinergic syndrome is a well established acute adverse reaction associated with irinotecan. Cholinergic side effects can be ameliorated or prevented with anticholinergic agents. To date, no formal studies have compared atropine-diphenoxylate and hyoscyamine as premedications for prophylaxis of the cholinergic syndrome with irinotecan infusion. OBJECTIVES: To compare the incidence of cholinergic syndrome with irinotecan using atropine-diphenoxylate or hyoscyamine as premedication. METHODS: We conducted a retrospective, single center, nonrandomized, cohort study of adult patients treated with atropine diphenoxylate or hyoscyamine as premedication before receiving irinotecan. For all irinotecan infusions, intravenous atropine was administered for patients experiencing any cholinergic reaction. RESULTS: A total of 532 irinotecan cycles (354 cycles for atropine-diphenoxylate group; 178 cycles for hyoscyamine group) were analyzed in 80 patients. Overall incidence of cholinergic syndrome did not differ between atropine-diphenoxylate (8.2%) and hyoscyamine (9.0%) groups (P = .76). The incidence of cholinergic syndrome after the Lrst cycle of irinotecan was similar between the 2 arms, atropine-diphenoxylate (14.6%) and hyoscyamine (10.7%), with P = .74. The most common cholinergic symptoms documented were abdominal pain or cramping, and diarrhea. LIMITATIONS: This study was subjected to vulnerabilities to bias and random error because of its observational retrospective design and small number of participants. CONCLUSIONS: Lack of difference in the incidence of cholinergic syndrome observed in irinotecan treated patients suggests atropinediphenoxylate and hyoscyamine may both be effective prophylactic options. The findings support the need for a larger, randomized study to assess and compare these agents with other potential premedications such as scopolamine and atropine in prevention of irinotecan related cholinergic syndrome. PMID- 25839060 TI - Rectal cancer management in elderly patients: experience of a single Portuguese institution. AB - BACKGROUND: The incidence of rectal cancer increases with age, and older patients are more likely to have other chronic conditions that can affect outcome and tolerability of treatment. OBJECTIVE: The incidence of rectal cancer increases with age, and older patients are more likely to have other chronic conditions that can affect outcome and tolerability of treatment. METHODS: 59 patients aged 75 years and older with stage II-III rectal cancer who were treated during a 3 year period were included in the study. Comorbidities were assessed using the Charlson Comorbidity Index (CCI) and the patients were divided into 2 groups based on their CCI scores: Fit (score of 0-1 points) and Vulnerable (score of greater than or = 2). Primary endpoint was survival at 1 and 3 years. RESULTS: The sample included 43 patients (72.9%) in the Fit group and 16 patients (27.1%) in the Vulnerable group. The most common comorbidities were myocardial infarction, diabetes, and chronic lung disease. One-year survival the same between the groups (P = .330), but 3-year survival was lower in the Vulnerable group patients (83.7% vs 56.3%, respectively; P = .040). The rates of neoadjuvant chemo- and radiotherapy use and low anterior resection performance were the same between the groups. Colostomy closure was achieved more frequently in the Fit group compared with the Vulnerable group (83.3% vs 55.6%; P = .083). There was no difference in mean disease-free survival, grade 3-4 toxicity, and dose reduction between the groups. CONCLUSIONS: Comorbidity assessment should always be included in standard oncological management of elderly patients. Fit patients can be managed with standard treatment and may bene|t from a conventional, more aggressive approach in their therapy. PMID- 25839061 TI - Impact of a telehealth intervention on quality of life and symptom distress in patients with head and neck cancer. AB - BACKGROUND: Patients undergoing treatment for head and neck cancer commonly experience signi?cant changes in quality of life (QoL) and levels of symptom distress. It is not known if a telehealth intervention would mitigate these changes. OBJECTIVE: To evaluate the impact of a telehealth intervention on QoL and symptom burden in patients undergoing initial treatment for head and neck cancers. METHODS: A randomized clinical trial comparing the impact on QoL and symptom distress of telehealth intervention and standard care was conducted with 80 patients (45 treatment, 35 control) who had been diagnosed with head or neck cancer and were receiving 1 or more treatment modalities. Treatment group participants responded daily to symptom management algorithms using a simple telehealth messaging device. QoL was evaluated by the Functional Assessment of Cancer Therapy-Head and Neck Scale (FACTHN) and symptom burden by the Memorial Symptom Assessment Scale (MSAS). Control group participants completed assessments while they received routine care. RESULTS: In the posttreatment phase, the telehealth participants had signi?cantly better scores than the controls for physical well-being (20.6 vs 17.0, P = .02) and trial outcome index (59.9 vs. 50.2, P = .04) on the FACT-HN, and total scores on the MSAS (0.9 vs. 1.2, P = .04). LIMITATIONS: The moderate sample size of 80 patients limits the power to measure more subtle impacts of the intervention. CONCLUSIONS: Using telehealth to provide support to patients with head and neck cancer during the acute phase of treatment improved some aspects of posttreatment QoL and symptom burden. PMID- 25839062 TI - Beneficial effects of animal-assisted visits on quality of life during multimodal radiation-chemotherapy regimens. AB - BACKGROUND: Animal-assisted visits (AAVs) are commonplace in cancer centers, but there is little evidence of their usefulness. OBJECTIVE: To test the efficacy of AAVs in improving the quality of life in patients with head and neck cancer receiving combined chemotherapy-radiation therapy. METHODS: 42 patients consented to daily AAVs during the time they received therapy for head and neck cancer. The Functional Assessment of Cancer Therapy-General Scale (FACT-G) was administered at baseline, week 3, and week 7 (at the end of therapy), and the Satisfaction With The AAV Intervention instrument, an 18-item scale adapted from the Pet Attitude Scale. RESULTS: 37 patients completed at least baseline and 1 follow-up assessment for a single group analysis of change over time. Means for Fact-G subscales showed significant declines in Physical Well-Being (PWB, P < .001) and Functional Well-Being (FWB, P = .003). In contrast, Social Well-Being increased (SWB, P = .03). Controlling for declines in PWB at each time point, increases in Emotional Well-Being (EWB) were also significant (P = .004). LIMITATIONS: Scheduling and patient preference prevented conducting a randomized trial. CONCLUSION: FACT-G analysis showed significant increase in SWB and EWB despite high symptom burden and clinically evident and expected declines in PWB and FWB. Mean scores for satisfaction related to psychological symptoms, liking animals/pets, and contact with animals were consistently higher than neutral score or Unsure (all, P < .001). Satisfaction related to physical symptoms was not significantly different from neutral. Though self-selected for an affinity to pets, patients endorsed a high level of satisfaction, which supports the usefulness of this intervention. PMID- 25839063 TI - Radiation exposure from diagnostic procedures in patients with newly diagnosed breast cancer. AB - Radiation exposure is associated with an increased risk of secondary cancers. Knowing the approximate radiation exposure from diagnostic procedures in the ?rst year after a breast cancer diagnosis could help educate patients and allow physicians to monitor them more closely for potential risks. PMID- 25839065 TI - Pore collapse and regrowth in silicon electrodes for rechargeable batteries. AB - Structure and composition of an 11 nm thick amorphous silicon (a-Si) thin film anode, capped with 4 nm of alumina are measured, in operando, by neutron reflectivity (NR) and electrochemical impedance spectroscopy in a lithium half cell. NR data are analyzed to quantify the a-Si thickness and composition at various states of charge over six cycles. The a-Si anode expands and contracts upon lithiation and delithiation, respectively, while maintaining its integrity and low interfacial roughness (<=1.6 nm) throughout the cycling. The apparently non-linear expansion of the a-Si layer volume versus lithium content agrees with previous thin-film a-Si anode studies. However, a proposed pore collapse and regrowth (PCRG) mechanism establishes that the solid domains in the porous LixSi film expand linearly with Li content at 8.48 cm(3) mol(-1) Li, similar to crystalline Si. In the PCRG model, porosity is first consumed by expansion of solid domains upon lithiation, after which the film as a whole expands. Porosity is reestablished at 5-28% upon delithiation. Data show that the alumina protective layer on the a-Si film functions as an effective artificial solid electrolyte interphase (SEI), maintaining its structural integrity, low interfacial roughness, and relatively small transport resistance. No additional spontaneously-formed SEI is observed in this study. PMID- 25839064 TI - Tetrapeptide unfolding dynamics followed by core-level spectroscopy: a first principles approach. AB - In this work we demonstrate that core level analysis is a powerful tool for disentangling the dynamics of a model polypeptide undergoing conformational changes in solution and disulphide bond formation. In particular, we present computer simulations within both initial and final state approximations of 1s sulphur core level shifts (S1s CLS) of the CYFC (cysteine-phenylalanine-tyrosine cysteine) tetrapeptide for different folding configurations. Using increasing levels of accuracy, from Hartree-Fock and density functional theory to configuration interaction via a multiscale algorithm capable of reducing drastically the computational cost of electronic structure calculations, we find that distinct peptide arrangements present S1s CLS sizeably different (in excess of 0.5 eV) with respect to the reference disulfide bridge state. This approach, leading to experimentally detectable signals, may represent an alternative to other established spectroscopic techniques. PMID- 25839066 TI - Coalescence of water films on carbon-based substrates: the role of the interfacial properties and anisotropic surface topography. AB - Molecular dynamics (MD) simulations are carried out to study the coalescence of identical adjacent and nonadjacent water films on graphene (G), vertically or horizontally stacked carbon nanotube arrays (VCNTA and HCNTA respectively). We highlight the key importance of carbon-based substrates in the growth of the liquid bridge connecting the two water films. This simulation provides reliable evidence to confirm a linear increase of the liquid bridge height, which is sensitive to the surface properties and the geometric structure. In the case of nonadjacent water films, the meniscus liquid bridge occurs solely on the VCNTA, which is attributed to the spreading of water films driven by the capillary force. Our results provide an available method to tune the coalescence of adjacent or nonadjacent films with alteration of topographically patterned surfaces, which has important implications in the design of condensation, ink-jet printing and drop manipulation on a substrate. PMID- 25839067 TI - Controlled decoration of the surface with macromolecules: polymerization on a self-assembled monolayer (SAM). AB - Polymer functionalized surfaces are important components of various sensors, solar cells and molecular electronic devices. In this context, the use of self assembled monolayer (SAM) formation and subsequent reactions on the surface have attracted a lot of interest due to its stability, reliability and excellent control over orientation of functional groups. The chemical reactions to be employed on a SAM must ensure an effective functional group conversion while the reaction conditions must be mild enough to retain the structural integrity. This synthetic constraint has no universal solution; specific strategies such as "graft from", "graft to", "graft through" or "direct" immobilization approaches are employed depending on the nature of the substrate, polymer and its area of applications. We have reviewed current developments in the methodology of immobilization of a polymer in the first part of the article. Special emphasis has been given to the merits and demerits of certain methods. Another issue concerns the utility - demonstrated or perceived - of conjugated or non conjugated macromolecules anchored on a functionally decorated SAM in the areas of material science and biotechnology. In the last part of the review article, we looked at the collective research efforts towards SAM-based polymer devices and identified major pointers of progress (236 references). PMID- 25839069 TI - Mechanical properties of amyloid-like fibrils defined by secondary structures. AB - Amyloid and amyloid-like fibrils represent a generic class of highly ordered nanostructures that are implicated in some of the most fatal neurodegenerative diseases. On the other hand, amyloids, by possessing outstanding mechanical robustness, have also been successfully employed as functional biomaterials. For these reasons, physical and chemical factors driving fibril self-assembly and morphology are extensively studied - among these parameters, the secondary structures and the pH have been revealed to be crucial, since a variation in pH changes the fibril morphology and net chirality during protein aggregation. It is important to quantify the mechanical properties of these fibrils in order to help the design of effective strategies for treating diseases related to the presence of amyloid fibrils. In this work, we show that by changing pH the mechanical properties of amyloid-like fibrils vary as well. In particular, we reveal that these mechanical properties are strongly related to the content of secondary structures. We analysed and estimated the Young's modulus (E) by comparing the persistence length (Lp) - measured from the observation of TEM images by using statistical mechanics arguments - with the mechanical information provided by peak force quantitative nanomechanical property mapping (PF-QNM). The secondary structure content and the chirality are investigated by means of synchrotron radiation circular dichroism (SR-CD). Results arising from this study could be fruitfully used as a protocol to investigate other medical or engineering relevant peptide fibrils. PMID- 25839070 TI - Peri-tunnel bone loss: does it affect early tendon graft to bone tunnel healing after ACL reconstruction? AB - PURPOSE: The clinical relevance and mechanisms of local bone loss early post anterior cruciate ligament (ACL) reconstruction remain unclear. The early spatial and temporal changes of peri-tunnel bone, its molecular mechanisms and its relationships with graft-bone tunnel healing were investigated in a 12-week-old rat model. METHODS: At various times, the reconstructed ACL complex was harvested for vivaCT imaging, biomechanical test, histology and immunohistochemical staining of CD68+ cells (a monocyte-macrophage lineage marker), MMP1 and MMP13. RESULTS: The peri-tunnel bone resorbed simultaneously with improvement of graft bone tunnel healing. There were 30.1 +/- 17.4, 46.8 +/- 10.5 and 81.5 +/- 12.3 % loss of peri-tunnel BMD as well as 43.2 +/- 21.7, 78.7 +/- 8.5 and 92.4 +/- 17.7 % loss of peri-tunnel bone volume/total volume (BV/TV) at week 6 at the distal femur, epiphysis and metaphysis of tibia, respectively. MMP1, MMP13 and CD68+ cells were expressed at the graft-bone tunnel interface and peri-tunnel bone and increased with time post-reconstruction at the tibia. The ultimate load and stiffness of the healing complex positively correlated with tibial tunnel bone formation and negatively correlated with tibial peri-tunnel bone. Tunnel BV/TV at the tibial metaphysis and epiphysis showed the highest correlation with ultimate load (rho = 0.591; p = 0.001) and stiffness (rho = 0.427; p = 0.026) of the complex, respectively. CONCLUSION: There was time-dependent loss of peri-tunnel bone early post-reconstruction, with the greatest loss occurring at the tibial metaphysis. This was consistent with high expression of MMP1, MMP13 and CD68+ cells at the graft-bone tunnel interface and the peri-tunnel region. The significant loss of peri-tunnel bone, though not critically affecting early tunnel healing, suggested the need to protect the knee joint early post reconstruction. PMID- 25839068 TI - Systems biology of the microvasculature. AB - The vascular network carries blood throughout the body, delivering oxygen to tissues and providing a pathway for communication between distant organs. The network is hierarchical and structured, but also dynamic, especially at the smaller scales. Remodeling of the microvasculature occurs in response to local changes in oxygen, gene expression, cell-cell communication, and chemical and mechanical stimuli from the microenvironment. These local changes occur as a result of physiological processes such as growth and exercise, as well as acute and chronic diseases including stroke, cancer, and diabetes, and pharmacological intervention. While the vasculature is an important therapeutic target in many diseases, drugs designed to inhibit vascular growth have achieved only limited success, and no drug has yet been approved to promote therapeutic vascular remodeling. This highlights the challenges involved in identifying appropriate therapeutic targets in a system as complex as the vasculature. Systems biology approaches provide a means to bridge current understanding of the vascular system, from detailed signaling dynamics measured in vitro and pre-clinical animal models of vascular disease, to a more complete picture of vascular regulation in vivo. This will translate to an improved ability to identify multi component biomarkers for diagnosis, prognosis, and monitoring of therapy that are easy to measure in vivo, as well as better drug targets for specific disease states. In this review, we summarize systems biology approaches that have advanced our understanding of vascular function and dysfunction in vivo, with a focus on computational modeling. PMID- 25839071 TI - Arthroscopic partial anterior synovectomy of the knee on patients with haemophilia. AB - PURPOSE: This study assessed the results of two-portal knee arthroscopic synovectomy in terms of bleeding recurrence, knee function, quality of life (QOL), and radiographic staging in a prospective case series of patients with haemophilia. METHODS: Nine knees from eight patients (median age 16.1 years; range 9.6-25 years) with haemophilia and recurrent knee haemarthrosis were prospectively evaluated. Yearly recurrence of bleeding was evaluated once a year for 5 years postoperatively. Range of motion (ROM) and radiographic staging, as well as results of the short form (SF)-36 and subjective knee form of the International Knee Documentation Committee (IKDC) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaires, were evaluated before surgery and at the end of follow-up. RESULTS: Mean bleeding recurrence was significantly reduced during the 5-year follow-up period. Questionnaire results showed significant improvements (IKDC P = 0.015, WOMAC P = 0.011, and SF-36 P = 0.023), whereas ROM was not significantly affected. Arthropathy progressed from Arnold-Hilgartner radiographic stage III to stage IV (P = 0.0082). CONCLUSIONS: Two-portal knee arthroscopic synovectomy was effective at reducing bleeding recurrence and improving knee function and QOL in patients with haemophilia, but did not interrupt the progression of radiographic changes. PMID- 25839072 TI - Reliability of the imaging software in the preoperative planning of the open wedge high tibial osteotomy. AB - PURPOSE: The purpose of this study was to verify a recently developed picture archiving and communications system-photoshop method by comparing reliabilities between real-size paper template and the PACS-photoshop methods in preoperative planning of open-wedge high tibial osteotomy. METHODS: A prospective case series was conducted, including patients with medial osteoarthritis undergoing open wedge high tibial osteotomy. In the preoperative planning, the picture-archiving and communications system-photoshop method and real-size paper template method were used simultaneously in all patients. Preoperative hip-knee-ankle angle, height, and angle of the osteotomy were evaluated. The reliability of this newly devised method was evaluated, and the consistency between the two methods was also evaluated using intra-class correlation coefficient. RESULTS: Using the picture-archiving and communications system-photoshop method, the mean correction angle and height of osteotomy gap of rater-1 were 11.7 degrees +/- 3.6 degrees and 10.7 +/- 3.6 mm, respectively. The mean correction angle and height of osteotomy gap of rater-2 were 12.0 +/- 2.6 and 10.8 +/- 3.6, respectively. The inter- and intra-rater reliabilities of the correction angle were 0.956 ~ 0.979 and 0.980 ~ 0.992, respectively. The inter- and intra-rater reliabilities of the height of the osteotomy gap were 0.968 ~ 0.985 and 0.971 ~ 0.994, respectively (p < 0.001). Using the real-size paper template method, the correction angle and height of the osteotomy gap were 11.5 degrees +/- 3.4 degrees and 10.9 +/- 3.8 mm, respectively. Using the picture-archiving and communications system-photoshop method, mean values of the correction angle and height of the osteotomy gap were 11.9 degrees +/- 3.6 degrees and 10.8 +/- 3.6 mm, respectively. Consistency between the two methods by comparing the means of the correction angle and the height of the osteotomy gap were 0.985 and 0.985, respectively (p < 0.001). CONCLUSIONS: Use of the picture-archiving and communications system-photoshop method enables direct measurement of the height of the osteotomy gap with high reliability. PMID- 25839073 TI - Reconstruction of distal biceps tendon ruptures with a cortical button. AB - PURPOSE: Reconstruction of the ruptured distal biceps tendon is best done with a cortical button technique according to recent biomechanical studies. However, clinical outcome studies that evaluate the cortical button reconstruction technique are scarce. The purpose of this study was to evaluate the results of a cortical button reconstruction technique in patients with a traumatic distal biceps tendon rupture. METHODS: Twenty-two patients with 24 traumatic distal biceps tendon ruptures underwent surgical treatment. Reconstructions were done using the Endobutton or Toggle Loc. Postoperative evaluation consisted of ROM, strength, stability, neurological status and standard radiographs in AP view and lateral direction. The Mayo Elbow Performance Index (MEPI) and quick Disabilities of Arm, Shoulder and Hand (qDASH) questionnaires were also obtained. RESULTS: At a median follow-up of 22 months, the mean strength for flexion was 100 % (SD 21.3) and for supination 97 % (SD 7.8), compared to the contralateral side. There were complications in 8 patients (36 %), and heterotopic ossifications were seen on radiographs in 23 % of patients. Heterotopic ossifications were symptomatic in one patient. CONCLUSIONS: The results after distal biceps tendon refixation with a cortical button were good according to ROM, MEPI and qDASH scores and strength. However, this procedure was accompanied with complications; in particular, the formation of heterotopic ossifications was frequently seen, though clinically relevant in only one patient. PMID- 25839075 TI - [Reflections on the audit Czech surgical departments]. PMID- 25839074 TI - Dengue fever in returning travellers. PMID- 25839076 TI - Authorship: Dynamic duos. PMID- 25839077 TI - [The discussion of sections Czech Surgical Society]. PMID- 25839078 TI - DSM-5 SUD diagnoses: changes, reactions, remaining open questions. PMID- 25839079 TI - Expression of RXR, EcR, E75 and VtG mRNA levels in the hepatopancreas and ovary of the freshwater edible crab, Oziothelphusa senex senex (Fabricius, 1798) during different vitellogenic stages. AB - The objective of the present study was to investigate the expression profile of retinoid X receptor (RXR), ecdysone receptor (EcR) and ecdysone inducible gene (E75) in the hepatopancreas and ovary of Oziothelphusa senex senex during different vitellogenic stages. RXR, EcR and E75 complementary DNAs (cDNAs) were isolated from the ovaries, while vitellogenin (VtG) cDNA was isolated from the hepatopancreas of vitellogenic female crab. Deduced amino acid sequence of the messenger RNAs (mRNAs) of RXR, EcR and E75 showed more than 80% identity with their respective mRNAs of other brachyurans. VtG mRNA was not detected in the ovary throughout vitellogenic stages. RXR and EcR were significantly increased in the ovaries during vitellogenic stage I. The levels of EcR, E75 and VtG in the hepatopancreas elevated significantly during vitellogenic stages I and II, whereas the levels of RXR elevated only in vitellogenic stage I. During vitellogenic stage III, the levels of RXR, EcR and VtG in the hepatopancreas were significantly decreased. Immunoprecipitation analysis revealed the presence of VtG in the haemolymph, hepatopancreas and ovary extracts from the females but absent in haemolymph and hepatopancreas extract of males. It can be inferred that RXR, EcR and E75 are involved in the regulation of synthesis of VtG in hepatopancreas, whereas in ovary, it is hypothesized that they play an important role in the uptake of VtG from the haemolymph, probably by regulating the levels of vitellogenin receptor. These are the first data showing an association between the expression levels of RXR, EcR and E75 and vitellogenesis and provide an alternative molecular intervention mechanism to the traditional eyestalk ablation to induce vitellogenesis and ovarian maturation in crustaceans. PMID- 25839080 TI - Non-target effects of clothianidin on monarch butterflies. AB - Monarch butterflies (Danaus plexippus) frequently consume milkweed in and near agroecosystems and consequently may be exposed to pesticides like neonicotinoids. We conducted a dose response study to determine lethal and sublethal doses of clothianidin using a 36-h exposure scenario. We then quantified clothianidin levels found in milkweed leaves adjacent to maize fields. Toxicity assays revealed LC10, LC50, and LC90 values of 7.72, 15.63, and 30.70 ppb, respectively. Sublethal effects (larval size) were observed at 1 ppb. Contaminated milkweed plants had an average of 1.14+/-0.10 ppb clothianidin, with a maximum of 4 ppb in a single plant. This research suggests that clothianidin could function as a stressor to monarch populations. PMID- 25839081 TI - New biomarkers for drug-induced liver injury: are they really better? What do they diagnose? PMID- 25839082 TI - Maximizing the reactivity of phenolic and aminic radical-trapping antioxidants: just add nitrogen! AB - Hydrocarbon autoxidation, the archetype free radical chain reaction, challenges the longevity of both living organisms and petroleum-derived products. The most important strategy in slowing this process is via the intervention of radical trapping antioxidants (RTAs), which are abundant in nature and included as additives to almost every petroleum-derived product as well as several other commercial products. Accordingly, a longstanding objective of many academic and industrial scientists has been the design and development of novel RTAs that can outperform natural and industrial standards, such as alpha-tocopherol, the most biologically active form of vitamin E, and dialkylated diphenylamines, respectively. Some time ago we recognized that attempts to maximize the reactivity of phenolic RTAs had largely failed because substitution of the phenolic ring with electron-donating groups to weaken the O-H bond and accelerate the rate of H atom transfer to radicals leads to compounds that are unstable in air. We surmised that incorporating nitrogen into the phenolic ring would render them more stable to one-electron oxidation, enabling their substitution with strong electron-donating groups. Guided by computational chemistry, we demonstrated that replacing the phenyl ring in very electron-rich phenols with either 3-pyridyl or 5-pyrimidyl rings leads to phenolic-like RTAs with good air stability and great reactivity. In fact, rate constants determined for the reactions of some compounds with peroxyl radicals were almost 2 orders of magnitude greater than those for alpha-tocopherol and implied that the reactions proceeded without an enthalpic barrier. Following extensive thermochemical and kinetic characterization, we took our studies of these compounds to more physiologically relevant media, such as lipid bilayers and human low density lipoproteins, where the heterocyclic analogues of vitamin E shone, displaying unparalleled abilities to inhibit lipid peroxidation and prompting their current investigation in animal models of degenerative disease. Moreover, we carried out studies of these compounds in several industrially relevant contexts and in particular demonstrated that they could be used synergistically with less reactive, less expensive, phenolic RTAs. More recently, our attention has turned to the application of these ideas to maximizing the reactivity of diarylamine RTAs that are common in additives to petroleum-derived products, such as lubricating oils, transmission and hydraulic fluids, and rubber. In doing so, we have developed the most reactive diarylamines ever reported. The 3-pyridyl- and 5 pyrimidyl-containing diarylamines are easily accessed using Pd- and/or Cu catalyzed cross-coupling reactions, and display an ideal compromise between reactivity and stability. The most reactive compounds are characterized by rate constants for reactions with peroxyl radicals that are independent of temperature, implying that-as for the most reactive heterocyclic phenols-these reactions proceed without an enthalpic barrier. Unprecedented reactivity was also observed when hydrocarbon autoxidations were carried out at elevated temperatures, real-world conditions where diarylamines are uniquely effective because of a catalytic RTA activity that makes use of the hydrocarbon substrate as a sacrificial reductant. Our studies to date suggest that heterocyclic diarylamines have real potential to increase the longevity of petroleum-derived products in a variety of applications where diphenylamines are currently used. PMID- 25839083 TI - Reduced plasma-induced damage to near-surface nitrogen-vacancy centers in diamond. AB - Understanding plasma etch damage on near-surface nitrogen vacancy (NV) centers in diamond is essential for preserving NV emission in photonic structures and magnetometry systems. We have developed a methodology to compare the optical properties of ensemble NV centers initially 70 nm from the surface brought closer to the surface through etching with O2 plasmas in three different reactors. We employ a conventional reactive ion etcher, a barrel etcher, and a downstream etcher. We find that, irrespective of the etcher used, NV luminescence dims steadily as NVs are brought closer to the surface due to optical and surface effects. When NVs are less than 40 nm from the surface, differences in damage from the three different plasma processes affect the NV emission intensity in different ways. Diamond that is etched using the conventional etching method shows a greatly reduced NV luminescence, whereas NVs 15 nm from the surface still survive when the diamond is etched in the downstream reactor. As a result, downstream etching provides a possible alternative method for low damage etching of diamond for preservation of near surface NV properties. PMID- 25839084 TI - A facile peroxo-precursor synthesis method and structure evolution of large specific surface area mesoporous BaSnO3. AB - In this paper, we propose a facile and efficient strategy for synthesizing mesoporous BaSnO3 with a surface area as large as 67 m(2)/g using a peroxo precursor decomposition procedure. As far as we know, this is the largest surface area reported in literature for BaSnO3 materials and may have a potential to greatly promote the technological applications of this kind of functional material in the area of chemical sensors, NOx storage, and dye-sensitized solar cells. The structure evolution of the mesoporous BaSnO3 from the precursor was followed using a series of techniques. Infrared analysis indicates large amount of protons and peroxo ligands are contained in the peroxo-precursor. Although the crystal structure of the precursor appears cubic according to the analysis of X ray diffraction data, Raman and Mossbauer spectroscopy results show that the Sn atom is offset from the center of [SnO6] octahedron. After calcination at different temperatures, the precursor gradually transforms into BaSnO3 by release of water and oxygen, and the distortion degree of [SnO6] octahedral decreases. However, a number of oxygen vacancies are generated in the calcined samples, which are further confirmed by the physical property measurement system, and they would lower the local symmetry to some content. The concentration of the oxygen vacancies reduces simultaneously as the calcination temperature increases, and their contributions to the total heat capacity of the sample are calculated based on theoretical analysis of heat capacity data in the temperature region below 10 K. PMID- 25839085 TI - Large scale anomalous patterns of muscovite mica discovered by atomic force microscopy. AB - Muscovite mica is a widely used substrate because of its flatness. The large scale anomalous patterns of muscovite have been discovered by atomic force microscopy (AFM). These patterns distribute around the defects of the muscovite surface. By using different imaging modes and analyzing functions of AFM, these extraordinary patterns are thoroughly characterized, and it was revealed that some selected regularly aligned patterns mimic 2-D orthorhombic crystal systems surrounding the regular structure. However, such patterned nanostructures have no effects on the template-assisted self-assembly (or epitaxial growth) of a disease related peptide GAV-9. PMID- 25839086 TI - Dual Mechanism Conceptual Model for Cr Isotope Fractionation during Reduction by Zerovalent Iron under Saturated Flow Conditions. AB - Chromium isotope analysis is rapidly becoming a valuable complementary tool for tracking Cr(VI) treatment in groundwater. Evaluation of various treatment materials has demonstrated that the degree of isotope fractionation is a function of the reaction mechanism, where reduction of Cr(VI) to Cr(III) induces the largest fractionation. However, it has also been observed that uniform flow conditions can contribute complexity to isotope measurements. Here, laboratory batch and column experiments were conducted to assess Cr isotope fractionation during Cr(VI) reduction by zerovalent iron under both static and saturated flow conditions. Isotope measurements were accompanied by traditional aqueous geochemical measurements (pH, Eh, concentrations) and solid-phase analysis by scanning electron microscopy and X-ray absorption spectroscopy. Increasing delta(53)Cr values were associated with decreasing Cr(VI) concentrations, which indicates reduction; solid-phase analysis showed an accumulation of Cr(III) on the iron. Reactive transport modeling implemented a dual mechanism approach to simulate the fractionation observed in the experiments. The faster heterogeneous reaction pathway was associated with minimal fractionation (epsilon=-0.20/00), while the slower homogeneous pathway exhibited a greater degree of fractionation (epsilon=-0.90/00 for the batch experiment, and epsilon=-1.50/00 for the column experiment). PMID- 25839087 TI - Space reconstruction by primary visual cortex activity: a parallel, non computational mechanism of object representation. AB - The current view posits that objects, despite changes in appearance, are uniquely encoded by 'expert' cells. This view is untenable. First, even if cell ensemble responses are invariant and unique, we are consciously aware of all of the objects' details. Second, in addition to detail preservation, data show that the current hypothesis fails to account for uniqueness and invariance. I present an alternative view whereby objects' representation and recognition are based on parallel representation of space by primary visual cortex (V1) responses. Information necessary for invariance and other attributes is handled in series by other cortical areas through integration, interpolation, and hierarchical convergence. The parallel and serial mechanisms combine to enable our flexible space perception. Only in this alternative view is conscious perception consistent with the underlying architecture. PMID- 25839088 TI - Association of Physical Fitness With Fibromyalgia Severity in Women: The al Andalus Project. AB - OBJECTIVES: To assess the association between physical fitness and fibromyalgia (FM) severity in women with FM as well as to assess whether different fitness components present an independent relation with FM severity. DESIGN: Population based cross-sectional study. SETTING: University facilities and FM associations. PARTICIPANTS: Women with FM (N=444). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FM severity was assessed with the Revised Fibromyalgia Impact Questionnaire (FIQR). Aerobic fitness (6-min walk test), muscle strength (handgrip, chair stand, and arm curl tests), flexibility (chair sit and reach and back scratch tests), and motor agility (8 foot Up and Go test) were measured with the Senior Fitness Test battery and digital dynamometry. A standardized composite score (hereafter "global fitness profile") was calculated and divided into quintiles. RESULTS: Overall, physical fitness was significantly associated with the FIQR total and subscale scores, regardless of the fitness test used (all P<.05). The 6-minute walk and back-scratch tests were independently associated with the FIQR total score (R(2)=.88; both P<.005). The group with the highest global fitness profile had 16% lower FM severity than did the group with the lowest global fitness profile (P<.001). CONCLUSIONS: Our results suggest that higher physical fitness is consistently associated with lower FM severity in women with FM. Aerobic fitness and flexibility present independent associations with FM severity. However, the FIQR variability explained by these fitness tests was rather low (<10%), and further research on the potential disagreement between performance-based physical fitness and different self-reported outcomes in women with FM is warranted. PMID- 25839089 TI - Immediate Effects of Therapeutic Ultrasound on Quadriceps Spinal Reflex Excitability in Patients With Knee Injury. AB - OBJECTIVE: To investigate the effects of nonthermal therapeutic ultrasound on quadriceps spinal reflex excitability in patients with knee joint injury. DESIGN: Double-blind, randomized controlled laboratory study with a pretest posttest design. SETTING: University laboratory. PARTICIPANTS: Recreationally active volunteers with a self-reported history of diagnosed intra-articular knee joint injury and documented quadriceps dysfunction (N=30). INTERVENTIONS: A nonthermal ultrasound, or sham, treatment was applied to the anteromedial knee. MAIN OUTCOME MEASURES: Hoffmann reflex measurements were recorded at baseline, immediately postintervention, and 20 minutes post-intervention. The peak Hoffmann reflex amplitude was normalized by the peak motor response (H/M ratio) measured from the vastus medialis using surface electromyography as an estimate of quadriceps motorneuron pool excitability. A repeated-measures analysis of variance was used for comparisons. RESULTS: A significant group-by-time interaction was observed for mean (P=.016) and change (P=.044) in H/M ratio. The ultrasound group demonstrated significantly higher mean (P=.015) and change (P=.028) in H/M ratio 20 minutes postintervention than did the sham ultrasound group. CONCLUSIONS: Quadriceps motoneuron pool excitability was facilitated 20 minutes after a nonthermal therapeutic ultrasound treatment, and not a sham treatment. These data provide supporting evidence of the contribution of peripheral receptors in modulation of the arthrogenic response in patients with persistent quadriceps dysfunction. Future research in this area should attempt to identify optimal treatment parameters and translate them to clinical outcomes. PMID- 25839090 TI - Development of a new family of chiral auxiliaries. AB - A new family of chiral auxiliaries designed on a conformationally restricted version of (-)-8-phenylmenthol has been developed. Both enantiomers are available from an inexpensive synthesis conducted on multigram scale. A first application has showed comparable diastereoselectivity between the novel auxiliary and (-)-8 phenylmenthol. PMID- 25839091 TI - IGFBP-3/transferrin/transferrin receptor 1 complexes as principal mediators of IGFBP-3 delivery to colon cells in non-cancer and cancer tissues. AB - PURPOSE: The aim of this work was to study the involvement of IGFBP-3/Tf complexes in the pathology of colorectal carcinoma (CRC), quantify them, investigate their relation to iron concentration and binding to transferrin receptor (TfR) in colon tissue (non-cancer and cancer), and to assess the priority of this pathway for internalization of IGFBP-3. METHODS: The presence of IGFBP-3/Tf complexes was analyzed in sera from healthy persons and patients with CRC, and in colon tissue by immunoblotting. Complexes were immunoprecipitated, quantified by immunoassay and structurally characterized by immunoblotting, lectin blotting and mass spectrometry. Complexes which interacted with colon cells were immunoprecipitated with anti-TfR1 antibody and studied. Colon tissue slides were subjected to immunohistochemical analysis. RESULTS: The concentration of IGFBP-3/Tf complexes was three times lower in patients with CRC. They were increasingly carbonylated, sialylated, contained more Galbeta4GlcNAc units, expressed altered charge density and increased affinity for metal ions. Immunoprecipitation experiments revealed more TfR1 on membranes than in cytosol of colon cells, also more in cancer than non-cancer tissue. TfR1 on membranes were less occupied with IGFBP-3/Tf complexes than in cytosol. Immunofluorescent staining indicated a remarkable degree of co-localization of IGFBP-3 and TfR1, evenly distributed in non-cancer tissue and both evenly and cell surface concentrated in cancer tissue. CONCLUSIONS: Increased expression of TfR1 on colon cell membranes in patients with CRC compensates for the reduced extracellular availability of IGFBP-3/Tf and TfR1 is the principal binding partner of extracellular IGFBP-3. IGFBP-3/Tf complexes in patients with CRC exhibit increased affinity for iron ions. PMID- 25839093 TI - Distribution of the cytoskeletal protein, Nestin, in acute leukemia. AB - Nestin is a neuroepithelial stem cell marker that is expressed in some types of tumor cells. Recent reports suggest that Nestin may be closely related to malignant cell proliferation and migration. Acute leukemia (AL) is characterized by a lack of differentiation, which results in uncontrolled proliferation in the bone marrow and accumulation of immature cells. The expression and function of Nestin in AL is unclear. We investigated Nestin immunohistochemical patterns of 87 patients that included 47 cases of acute myeloid leukemia (AML) and 40 cases of acute lymphoblastic leukemia (ALL), and 20 patients in complete remission (CR) from AML or ALL. We also investigated the clinico-pathological features of 87 cases of AL and their CR and overall survival (OS). Nestin was expressed in leukemic blasts and mature granulocytic cells in most cases (39/47) of AML. Conversely, Nestin was expressed in mature granulocytic cells in fewer cases (6/40) of ALL, but not in blasts. Nestin expression appeared in leukemic blasts of AML, but not ALL. Nestin expression in AML blast cells was not associated with CR or OS. We provide evidence that Nestin is expressed in AL and might be a useful immunohistochemical marker for identifying AML and ALL. PMID- 25839092 TI - Temporal and spatial rearrangements of a repetitive element array on C57BL/6J mouse genome. AB - Repetitive elements (REs) make up the vast majority of the mammalian genomes. We identified species-specific genomic libraries of RE arrays. The non-random configurations of RE arrays suggest their functions. We tested whether RE arrays undergo age- and tissue/cell-specific rearrangements. An RE array of C57BL/6J mice, containing tandem repeats of a mosaic of transposable REs, was selected to examine rearrangements in different ages and tissues. There were marked changes in the array configuration in the genomes of the skin and brain in all mice of six weeks and older, whereas the heart and liver had alterations at 29weeks. The temporal variations were confirmed by identifying putative rearrangement junctions. Temporal and spatial rearrangements of certain RE arrays may contribute to the acquired characteristics of the genome information system. PMID- 25839094 TI - The control of short-term feed intake by metabolic oxidation in late-pregnant and early lactating dairy cows exposed to high ambient temperatures. AB - The objective of the present study was to integrate the dynamics of feed intake and metabolic oxidation in late pregnant and early lactating Holstein cows under heat stress conditions. On day 21 before parturition and again on day 20 after parturition, seven Holstein cows were kept for 7days at thermoneutral (TN) conditions (15 degrees C; temperature-humidity-index (THI)=60) followed by a 7day heat stress (HS) period at 28 degrees C (THI=76). On the last day of each temperature condition, gas exchange, feed intake and water intake were recorded every 6min in a respiration chamber. Pre- and post-partum cows responded to HS by decreasing feed intake. The reduction in feed intake in pre-partum cows was achieved through decreased meal size, meal duration, eating rate and daily eating time with no change in meal frequency, while post-partum cows kept under HS conditions showed variable responses in feeding behavior. In both pre- and post partum cows exposed to heat stress, daily and resting metabolic heat production decreased while the periprandial respiratory quotient (RQ) increased. The prolonged time between meal and the postprandial minimum in fat oxidation and the postprandial RQ maximum, respectively, revealed that HS as compared to TN early lactating cows have slower postprandial fat oxidation, longer feed digestion, and thereby showing a shift from fat to glucose utilization. PMID- 25839095 TI - Cocaine exposure alters dopaminergic modulation of prefronto-accumbens transmission. AB - In the nucleus accumbens (NAc), dopamine transmission modulates glutamatergic input from the prefrontal cortex (PFC). This neuromodulatory action of dopamine can be disrupted by repeated exposure to psychostimulants such as cocaine. However, it is unclear whether this modulation depends on the precise timing of transmission at the same medium spiny neurons (MSNs) and if so, then whether this timing related modulation is also influenced by cocaine experience. Here, combining cocaine self-administration and in vivo extracellular recordings in anesthetized rats, we show that dopamine efflux in the NAc evoked by electrically stimulating the ventral tegmental area (VTA) exerted timing-dependent regulation of the excitatory accumbens response to stimulation of the medial prefrontal cortex (mPFC), and also that this modulation was blunted following prolonged abstinence from cocaine self-administration. These data indicate that dopaminergic timing-dependent dysregulation of mPFC-NAc glutamatergic transmission is implicated in cocaine addiction and might contribute to vulnerability to drug relapse after prolonged abstinence. PMID- 25839096 TI - Diverse development and higher sensitivity of the circadian clocks to changes in maternal-feeding regime in a rat model of cardio-metabolic disease. AB - Spontaneously hypertensive rats (SHR) develop cardiovascular and metabolic pathology in adulthood when their circadian system exhibits significant aberrances compared with healthy control rats. This study was aimed to elucidate how the SHR circadian system develops during ontogenesis and to assess its sensitivity to changes in maternal-feeding regime. Analysis of ontogenesis of clock gene expression rhythms in the suprachiasmatic nuclei, liver and colon revealed significant differences in SHR compared with Wistar rats. In the suprachiasmatic nuclei of the hypothalamus (SCN) and liver, the development of a high-amplitude expression rhythm selectively for Bmal1 was delayed compared with Wistar rat. The atypical development of the SHR circadian clocks during postnatal ontogenesis might arise from differences in maternal behavior between SHR and Wistar rats that were detected soon after delivery. It may also arise from higher sensitivity of the circadian clocks in the SHR SCN, liver and colon to maternal behavior related to changes in the feeding regime because in contrast to Wistar rat, the SHR SCN and peripheral clocks during the prenatal period and the hepatic clock during the early postnatal period were phase shifted due to exposure of mothers to a restricted feeding regime. The maternal restricted feeding regime shifted the clocks despite the fact that the mothers were maintained under the light/dark cycle. Our findings of the diverse development and higher sensitivity of the developing circadian system of SHR to maternal cues might result from previously demonstrated differences in the SHR circadian genotype and may potentially contribute to cardiovascular and metabolic diseases, which the animal model spontaneously develops. PMID- 25839097 TI - Hippocampus: From memory to epilepsy, and back.... PMID- 25839101 TI - A plain view of poor health in a land of plenty. AB - This article provides a clear description of U.S. health spending that is on a steep upward trajectory, and U.S. health outcomes on a downward trajectory, as compared to other nations. The article is written to inform social workers and other health professionals, who observe the poor health of their clients in a high-resource nation, while the nation banters about health care reform. This report presents international and national health resource and outcome comparisons, with implications for sustainable support for U.S population health and national capabilities. PMID- 25839102 TI - Delocalized hole domains in Guanine-rich DNA oligonucleotides. AB - Differential pulse voltammetries of guanine-rich single- and double-stranded oligonucleotides containing up to six consecutive guanines are reported. The observed progressive lowering of the first voltammetric peak potential as the number of adjacent guanines increases unambiguously points toward the establishment of delocalized hole domains; the hole stabilization energy is ca. 0.1 eV per GG step, significantly lower than that observed for AA steps. PMID- 25839098 TI - Systems Pharmacology Links GPCRs with Retinal Degenerative Disorders. AB - In most biological systems, second messengers and their key regulatory and effector proteins form links between multiple cellular signaling pathways. Such signaling nodes can integrate the deleterious effects of genetic aberrations, environmental stressors, or both in complex diseases, leading to cell death by various mechanisms. Here we present a systems (network) pharmacology approach that, together with transcriptomics analyses, was used to identify different G protein-coupled receptors that experimentally protected against cellular stress and death caused by linked signaling mechanisms. We describe the application of this concept to degenerative and diabetic retinopathies in appropriate mouse models as an example. Systems pharmacology also provides an attractive framework for devising strategies to combat complex diseases by using (repurposing) US Food and Drug Administration-approved pharmacological agents. PMID- 25839103 TI - HIV specific responses induced in nonhuman primates with ANRS HIV-Lipo-5 vaccine combined with rMVA-HIV prime or boost immunizations. AB - We evaluated the immunogenicity of a prime/boost vaccine strategy combining 5 lipopeptides (HIV-Lipo-5) and a recombinant modified vaccinia virus Ankara (rMVA HIV) in cynomolgus macaques. Both of these vaccine components deliver HIV LAI Gag, Pol, and Nef antigens. Systemic and local safety was excellent in all groups. Immunization with HIV-Lipo-5 alone induced significant serum anti-HIV antibody titers which were not modified by rMVA-HIV immunization. However, induction of T-cell responses, as measured by IFNgamma and IL-2 producing cells upon short-term stimulation with HIV peptide pools, required combined immunization with rMVA-HIV. Responses were preferentially observed against Gag antigen. Interestingly, HIV-Lipo-5 efficiently primed HIV induced T-cell responses upon the injection of rMVA-HIV, which may help to reduce the required number of vector injections. Our results provide a rationale for the use of a strategy involving HIV-Lipo-5 priming followed by rMVA-HIV booster immunization as a prophylactic or therapeutic vaccine approach against HIV infection and AIDS. PMID- 25839105 TI - Varicella in Europe-A review of the epidemiology and experience with vaccination. AB - There is no consensus as regards the European varicella immunisation policy; some countries have introduced varicella vaccination in their routine childhood immunisation programs whereas others have decided against or are debating. With the aim of providing an overview of the epidemiology of varicella in Europe and addressing the different strategies and the experiences so far, we performed a review of epidemiological studies done in Europe from 2004 to 2014. Varicella is mainly a disease of childhood, but sero-epidemiological studies show regional differences in the proportion of susceptible adults. Hospitalisation due to varicella is not common, but complications and hospitalisation mainly affect previously healthy children, which underlines the importance of not dismissing varicella as a disease of little importance. The experience with universal vaccination in Europe shows that vaccination leads to a rapid reduction of disease incidence. Vaccine effectiveness is high and a protective herd effect is obtained. Experience with vaccination in Europe has not been long enough, though, to draw conclusions on benefits and drawbacks with vaccination as well as the capacity for national programs in Europe to maintain a sufficiently high coverage to prevent a change in age group distribution to older children and young adults or on the impact that varicella immunisation may have on the epidemiology of shingles. PMID- 25839104 TI - Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine. AB - There is an urgent need for improvements in vaccine delivery technologies. This is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. Microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. Here, we aimed to investigate immunity induced by the recombinant simian adenovirus-vectored vaccine ChAd63.ME-TRAP; currently undergoing clinical assessment as a candidate malaria vaccine, when delivered percutaneously by silicon microneedle arrays. In mice, we demonstrate that microneedle-mediated delivery of ChAd63.ME-TRAP induced similar numbers of transgene-specific CD8(+) T cells compared to intradermal (ID) administration with needle-and-syringe, following a single immunisation and after a ChAd63/MVA heterologous prime-boost schedule. When mice immunised with ChAd63/MVA were challenged with live Plasmodium berghei sporozoites, microneedle-mediated ChAd63.ME-TRAP priming demonstrated equivalent protective efficacy as did ID immunisation. Furthermore, responses following ChAd63/MVA immunisation correlated with a specific design parameter of the array used ('total array volume'). The level of transgene expression at the immunisation site and skin-draining lymph node (dLN) was also linked to total array volume. These findings have implications for defining silicon microneedle array design for use with live, vectored vaccines. PMID- 25839106 TI - Integrating -Omics: Systems Biology as Explored Through C. elegans Research. AB - -Omics data have become indispensable to systems biology, which aims to describe the full complexity of functional cells, tissues, organs and organisms. Generating vast amounts of data via such methods, researchers have invested in ways of handling and interpreting these. From the large volumes of -omics data that have been gathered over the years, it is clear that the information derived from one -ome is usually far from complete. Now, individual techniques and methods for integration are maturing to the point that researchers can focus on network-based integration rather than simply interpreting single -ome studies. This review evaluates the application of integrated -omics approaches with a focus on Caenorhabditis elegans studies, intending to direct researchers in this field to useful databases and inspiring examples. PMID- 25839107 TI - A potential compensatory role for endogenous striatal tyrosine hydroxylase positive neurons in a nonhuman primate model of Parkinson's disease. AB - The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4 phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages. PMID- 25839108 TI - Mutations of SCN4A gene cause different diseases: 2 case reports and literature review. AB - SCN4A encodes the Nav1.4 channel and mutations in SCN4A lead to different ionic channelopathies. In this study, one sporadic individual of periodic paralysis, one paramyotonia family and 200 normal healthy controls are enrolled. Genomic DNA was extracted from peripheral blood leukocytes, followed by polymerase chain reaction and DNA sequencing of candidate genes, including SCN4A and CACNA1S. As a result, heterozygous mutations c.2024G>A (R675Q) and c.1333G>A (V445M) of gene SCN4A were identified in the hypokalemic periodic paralysis patient and the paramyotonia congenita family respectively. Both mutations were not detected in healthy controls. Compared with reported cases, patients with mutation R675Q usually do not present hypokalemic periodic paralysis but hyperkalemic or normokalemic periodic paralysis. The mutation V445M was first reported in Chinese patients with nondystrophic myotonias. In addition, we carried out literature review by summarizing clinical features of the 2 mutations and establish the genotype-phenotype correlations to provide guidance for diagnosis. PMID- 25839109 TI - Multimodal processing of emotional information in 9-month-old infants I: emotional faces and voices. AB - Making sense of emotions manifesting in human voice is an important social skill which is influenced by emotions in other modalities, such as that of the corresponding face. Although processing emotional information from voices and faces simultaneously has been studied in adults, little is known about the neural mechanisms underlying the development of this ability in infancy. Here we investigated multimodal processing of fearful and happy face/voice pairs using event-related potential (ERP) measures in a group of 84 9-month-olds. Infants were presented with emotional vocalisations (fearful/happy) preceded by the same or a different facial expression (fearful/happy). The ERP data revealed that the processing of emotional information appearing in human voice was modulated by the emotional expression appearing on the corresponding face: Infants responded with larger auditory ERPs after fearful compared to happy facial primes. This finding suggests that infants dedicate more processing capacities to potentially threatening than to non-threatening stimuli. PMID- 25839110 TI - Multimodal processing of emotional information in 9-month-old infants II: prenatal exposure to maternal anxiety. AB - The ability to read emotional expressions from human face and voice is an important skill in our day-to-day interactions with others. How this ability develops may be influenced by atypical experiences early in life. Here, we investigated multimodal processing of fearful and happy face/voice pairs in 9 month-olds prenatally exposed to maternal anxiety, using event-related potentials (ERPs). Infants were presented with emotional vocalisations (happy/fearful) preceded by emotional facial expressions (happy/fearful). The results revealed larger P350 amplitudes in response to fearful vocalisations when infants had been exposed to higher levels of anxiety, regardless of the type of visual prime, which may indicate increased attention to fearful vocalisations. A trend for a positive association between P150 amplitudes and maternal anxiety scores during pregnancy may suggest these infants are more easily aroused by and extract features more thoroughly from fearful vocalisations as well. These findings are compatible with the hypothesis that prenatal exposure to maternal anxiety is related to more extensive processing of fear-related stimuli. PMID- 25839111 TI - Early repolarization patterns associated with increased arrhythmic risk are common in young non-Caucasian Australian males and not influenced by athletic status. AB - BACKGROUND: Early repolarization (ER) with a horizontal ST segment (ST-h) and high-amplitude J waves in the inferior leads is associated with an increased risk of cardiac arrhythmic death. The effect of ethnicity and athletic status on this increased-risk ER pattern has not been established. Aboriginal Australian/Torres Strait Islander and Pacific Islander/Maori (non-Caucasian [non-C]) subjects are well represented in Australian sport; however, the patterns and prevalence of ER in these populations are unknown. OBJECTIVE: The purpose of this study was to assess the prevalence and effect of athletic activity on ER patterns in young non C and Caucasian (C) subjects. METHODS: Twelve-lead ECGs of 726 male athletes (23.8% non-C) and 170 male controls (45.9% non-C) aged 16-40 years were analyzed for the presence of ER, defined as J-point elevation (J wave, QRS slur, or discrete ST elevation) >=0.1 mV in >=2 inferior (II, III, aVF) or lateral (I, aVL,V4-V6) leads. ST morphology was coded as horizontal (ST-h) or ascending (ST a). "Increased-risk ER" was defined as inferior ER with ST-h and J waves >2 mV. RESULTS: Regardless of athletic status, ER and increased-risk ER were more prevalent in non-C than in C subjects (53.8% vs 32% and 7.6% vs 1.2%, respectively, P <.0001). Whereas lower heart rate, larger QRS voltage, and shorter QRS duration were predictors of ER, non-C ethnicity was the only independent predictor of increased-risk ER (odds ratio 17.621, 95% confidence interval 4.98-62.346, P < .0001). CONCLUSION: ER patterns associated with increased arrhythmic risk are more common in young non-C than C subjects and were not influenced by athletic status. The long-term clinical significance of ER in these populations is yet to be determined. PMID- 25839112 TI - Letter to the Editor--Extraction of nonfunctional leads at the time of device upgrade: Still unproven benefit compared to abandoning leads. PMID- 25839113 TI - Wearable cardioverter-defibrillator for prevention of sudden cardiac death after infected implantable cardioverter-defibrillator removal: A cost-effectiveness evaluation. AB - BACKGROUND: Prevention of sudden cardiac arrest (SCA) after removal of an infected implantable cardioverter-defibrillator (ICD) is a challenging clinical dilemma. The cost-effectiveness of the wearable cardioverter-defibrillator (WCD) in this setting remains uncertain. OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of the WCD with discharge home, discharge to a skilled nursing facility, or inpatient monitoring for the prevention of SCA after infected ICD removal. METHODS: A decision model was developed to compare the cost effectiveness of use of the WCD to several different strategies for patients who undergo ICD removal. One-way and 2-way sensitivity analyses were performed to account for uncertainties. RESULTS: In the base-case analysis, the incremental cost-effectiveness of the WCD strategy was $20,300 per life-year (LY) or $26,436 per quality-adjusted life-year (QALY) compared to discharge home without a WCD. Discharge to a skilled nursing facility and in-hospital monitoring resulted in higher costs and worse clinical outcomes. The incremental cost-effectiveness ratio was as low as $15,392/QALY if the WCD successfully terminated 95% of SCA events and exceeded the $50,000/QALY willingness-to-pay threshold if the efficacy was <69%.The WCD strategy remained cost-effective, assuming 5.6% 2-month SCA risk, as long as the time to reimplantation was at least 2 weeks. CONCLUSION: The WCD likely is cost-effective in protecting patients against SCA after infected ICD removal while waiting for ICD reimplantation compared to keeping patients in the hospital or discharging them home or to a skilled nursing facility. PMID- 25839114 TI - Overcoming reporting challenges: How to display, summarize, and model late reintervention outcomes, follow-up, and vital status information after surgery for atrial fibrillation. AB - BACKGROUND: Postsurgical late reinterventions for atrial fibrillation (AF) include cardioversions (CV) or catheter ablations (CA). Commonly used methods for reporting and modeling the frequency and timing of CA or CV have well-known shortcomings. OBJECTIVE: The purpose of this study was to present intuitive and robust methods to visualize, summarize, and model late reinterventions type/timing and vital status simultaneously. METHODS: We present (1) the SMART plot (Summary of Mortality And Outcomes Reported Over Time); (2) the reintervention mean cumulative function (MCF); and (3) the proportional means model and the proportional rates model. We illustrate these methods in 3 groups: patients age <=60 years, 60-75 years (reference), and >75 years who underwent surgical AF ablation. RESULTS: Patients age >75 years had a significantly lower MCF of CVs (hazard ratio [HR] 0.50, P <.001). MCF for CAs was not significantly lower for patients age >75 years (HR 0.57, P = .13). For combined reinterventions (CV or CA), the age group >75 years had a significantly lower MCF (HR 0.51, P <.001). There were no significant differences in late CV or CA reintervention patterns for patients age <=60 years. CONCLUSION: The methods presented provide a comprehensive framework for displaying, summarizing, and modeling repeated late reinterventions after surgical AF ablation. Other areas of application are described, further emphasizing the potential for immediate use. PMID- 25839116 TI - Cytotoxicity of medicinal plants of the West-Canadian Gwich'in Native Americans towards sensitive and multidrug-resistant cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicine of the Native Americans has a long tradition of medicinal plants, which also influenced modern oncology. For instance, podophyllotoxin the active ingredient of Podophyllum peltatum L. (Berberidaceae) used by Native Americans to treat warts led to the development of etoposide and teniposide. In the present investigation, we studied 10 medicinal plants used by the Gwich'in First Nation of West-Canada, which have been used against diverse diseases including cancer. MATERIAL AND METHODS: Sensitive and multidrug-resistant (MDR) tumor cell lines expressing various ATP-binding cassette (ABC) transporters (P-glycoprotein/ABCB1/MDR1, MRP1/ABCC1, or BCRP/ABCG2) have been used. Cytotoxicity was determined by the resazurin assay. RESULTS: Arctium minus Bernh. (Asteraceae). Lysichiton americanus Hulten & St. John (Araceae), and Maianthemum dilatatum (Alph.Wood) A.Nelson & J.F.Macbr.(Asparagaceae) were cytotoxic with IC50 values ranging from 2.40 to 86.35 ug/mL. The MDR cell lines did not exert cross-resistance to these extracts. CONCLUSION: As these medicinal plants of the West-Canadian Gwich'in First Nation were not involved in classical drug resistance mechanisms and might therefore be valuable to bypass anticancer drug resistance in refractory tumors. PMID- 25839115 TI - In vitro and in vivo anti-inflammatory activity of Phyllanthus acidus methanolic extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Phyllanthus acidus (L.) Skeels (Phyllanthaceae) has traditionally been used to treat gastric trouble, rheumatism, bronchitis, asthma, respiratory disorders, and hepatitis. Despite this widespread use, the pharmacological activities of this plant and their molecular mechanisms are poorly understood. Therefore, we evaluated the immunopharmacological activities of the methanolic extract of the aerial parts of this plant (Pa-ME) and validated its pharmacological targets. MATERIALS AND METHODS: Lipopolysaccharide (LPS) treated macrophages, an HCl/EtOH-induced gastritis model, and an acetic acid injected capillary permeability mouse model were employed to evaluate the anti inflammatory activity of Pa-ME. Potentially active anti-inflammatory components of this extract were identified by HPLC. The molecular mechanisms of the anti inflammatory activity were studied by kinase assays, reporter gene assays, immunoprecipitation analysis, and overexpression of target enzymes. RESULTS: Pa ME suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) and prevented morphological changes in LPS-treated RAW264.7 cells. Moreover, both HCl/EtOH-induced gastric damage and acetic acid-triggered vascular permeability were restored by orally administered Pa-ME. Furthermore, this extract downregulated the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and reduced the nuclear levels of NF-kappaB. Signalling events upstream of NF-kappaB translocation, such as phosphorylation of Src and Syk and formation of Src/Syk signalling complexes, were also inhibited by Pa-ME. The enzymatic activities of Src and Syk were also suppressed by Pa-ME. Moreover, Src-induced and Syk-induced luciferase activity and p85/Akt phosphorylation were also inhibited by Pa-ME. Of the identified flavonoids, kaempferol and quercetin were revealed as partially active anti-inflammatory components in Pa-ME. CONCLUSION: Pa-ME exerts anti-inflammatory activity in vitro and in vivo by suppressing Src, Syk, and their downstream transcription factor, NF-kappaB. PMID- 25839117 TI - Modulatory effect of Senecio brasiliensis (Spreng) Less. in a murine model of inflammation induced by carrageenan into the pleural cavity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senecio brasiliensis (Spreng) Less (S. brasiliensis), known as "Flor-das-almas", "Margaridinha" or "Maria mole", is used in folk medicine as an anti-inflammatory and to treat gastric ulcers and stomach pain. While the Senecio genus has been widely studied for its pharmacological activities to support its use in traditional medicine, few studies focus on the anti-inflammatory activities of the species. AIM OF THE STUDY: To investigate the anti-inflammatory activities of S. brasiliensis, a specie native to Brazil, using a murine model of pleurisy induced by carrageenan. MATERIAL AND METHODS: The flowers of S. brasiliensis were air-dried for 3 days and subjected to ethanol (96%) extraction for 7 days to obtain the crude extract (CE). The CE was subjected to acid-base extraction to obtain the alkaloid fraction (AF). The hexane (HEX), dichloromethane (DCM) and ethyl acetate (EtOAc) fractions were obtained by extracting from CE with different solvents. The alkaloids senecionine (Sen), integerrimine (Int) and senecionine N-oxide were obtained from AF by chromatographic fractionation and a mixture of 1,4-, 3,4-, 3,5- and 4,5 dicaffeoylquinic acids (DCQs) were obtained from the EtOAc fraction. The isolated alkaloids were identified through spectroscopic analysis of IR, NMR and LC-MS coupled with electrospray ionization mass spectrometry (ESI-MS), and the dicaffeoylquinic acids through the hierarchical key method. Swiss mice were used in the in vivo experiments. We evaluated the effect of the CE, its derived fractions (AF, HEX, DCM and EtOAc), and the isolated compounds (Sen, Int, N-oxide senecionine, and DCQs) on: leukocyte migration, exudate concentrations, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities, and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleukin 17A levels in the fluid leakage from the pleural cavity using a mouse model of pleurisy induced by carrageenan. The effects of the isolated compounds, Sen, Int, N-oxide senecionine and DCQs, were also analyzed for their ability to inhibit p65 phosphorylation (p-p65) in the nuclear factor-kappa B (NF-kappaB) pathway in the lung tissue. MPO and ADA were analyzed by colorimetric assays, and the cytokines and protein p65 levels were determined using an enzyme immunoassay (EIA). RESULTS: The CE, its EtOAc and AF fractions, and its isolated compounds (Sen, Int and DCQs), significantly reduced leukocyte migration (P < 0.05), MPO and ADA activities (P < 0.01), and TNF-alpha (P < 0.05), and IL-17A levels (P < 0.01). The CE, the EtOAc and AF fractions, and the DCQs also decreased IL-1beta levels (P < 0.01). The isolated compounds, Sen, Int and the DCQs, inhibited p65 phosphorylation (NF-kappaB) (P < 0.05). CONCLUSION: This study demonstrated that S. brasiliensis has important anti-inflammatory properties that are capable of inhibiting activated leukocytes by decreasing neutrophil migration. This effect may be attributed to the inhibition of pro-inflammatory cytokines and the reduction of the NF-kappaB pathway. The compounds Sen, Int, and DCQs may be responsible for the anti-inflammatory actions of S. brasiliensis. PMID- 25839118 TI - Effects of the aqueous extract of Pimpinella anisum L. seeds on exploratory activity and emotional behavior in rats using the open field and elevated plus maze tests. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pimpinella anisum L. is considered one of the first plants used for medicinal purposes. Pharmacological actions of the plant on the central nervous system have been proven but previous analyses have focused on anticonvulsant and neuroprotective actions. In traditional medicine worldwide, the use of Pimpinella is commonly recommended as a tranquilizer, although no scientific information supporting this use is available. Therefore, it was decided to investigate the central actions of the plant to observe behavioral responses, with an emphasis on the emotional component. AIM OF STUDY: To investigate the effects of the aqueous extract of Pimpinella seeds on exploratory activity and emotional behavior in rats using the open field and elevated plus maze tests. MATERIALS AND METHODS: Seeds of Pimpinella were extracted with distilled water, concentrated and freeze-dried yielding the aqueous extract(AE). Rats were divided into four groups: control(water 5 mL/kg, p.o.) and AE 0.5, 1.0 and 2.0 g/kg, p.o. Individual observations were performed in an open field and the parameters locomotor activity, rearing, grooming and defecation were recorded. In elevated plus maze test, rats were divided into four groups: control(water 5 mL/kg, p.o.) and AE 0.5, 1.0 and 2.0 g/kg, p.o. The parameters arm entries, total time spent in open and closed arms; and total number of arrivals at the end of an open or closed arm were recorded for each rat. RESULTS: Among the parameters assessed with the open field test, only rearing was reduced in the AE 0.5 g/kg group. When AE 1.0 g/kg was administered, only the initiation of exploratory activity was delayed, without impairing the animals' general activity. The highest dose of AE (2.0 g/kg) induced a reduction in the animals' habituation during the open field test within the same session, as evidenced by the maintenance of high levels of peripheral locomotion and rearing throughout the test. On the elevated plus maze test, no alterations were observed in the responses of the animals relative to controls for all doses tested. CONCLUSION: These results failed to support anxiety-related central action of the aqueous extract of Pimpinella seeds, invalidating popular beliefs regarding a tranquilizing effect. However, a habituation-related central action of the extract was demonstrated, suggesting action of bioactive compounds on central learning-related areas. The characterization of effects that may interfere with cognitive processes reinforces caution regarding indiscriminate consumption of the plant, especially in individuals with deficits, such as Alzheimer's Disease patients. PMID- 25839119 TI - Glycosmis pentaphylla (Retz.) DC arrests cell cycle and induces apoptosis via caspase-3/7 activation in breast cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Glycosmis pentaphylla (Retz.) DC belonging to the family Rutaceae has been traditionally used for the treatment of rheumatism, anaemia, jaundice, skin diseases, bronchitis etc. The plant is traditionally considered as anti-cancer medicine and used by the healers of Bangladesh to treat all types of cancers. Perhaps the key to many of its medicinal applications is its inherent anti-inflammatory property. AIM OF THE STUDY: The present study is aimed at evaluating the effect of various fractions of G. pentaphylla (Retz.) DC leaves on the cell cycle and apoptosis of breast cancer cells viz. MCF-7 and MDA MB-231. MATERIALS AND METHODS: Various extracts and fractions of the leaves of G. pentaphylla (Retz.) DC were studied for their cytotoxicity with the help of Sulforhodamine B assay, in MCF-7, MDA-MB-231 and Vero cell lines. The most active fractions were studied for their effect on the cell cycle of MCF-7 and MDA-MB-231 cells. Apoptotic studies were done using Hoechst staining, DNA fragmentation, Annexin V staining and caspase-3/7 activation assay in breast cancer cells. HPLC and HPTLC profiling of the active fractions were done. RESULTS: HPTLC and HPLC profiling revealed the presence of lupeol, chrysin, quercetin, beta-sitosterol and kaempferol as components in active fractions. Lupeol and chrysin are being reported in this plant for the first time. The studies showed that the selected fractions possess cell cycle inhibitory and apoptosis inducing effect on both MCF 7 and MDA-MB-231 cells. Apoptotic effect of the fractions on MCF-7 and MDA-MB-231 cells may be through the mitochondrial pathway by the activation of caspase-3/7. PMID- 25839120 TI - An overview of thin film nitinol endovascular devices. AB - Thin film nitinol has unique mechanical properties (e.g., superelasticity), excellent biocompatibility, and ultra-smooth surface, as well as shape memory behavior. All these features along with its low-profile physical dimension (i.e., a few micrometers thick) make this material an ideal candidate in developing low profile medical devices (e.g., endovascular devices). Thin film nitinol-based devices can be collapsed and inserted in remarkably smaller diameter catheters for a wide range of catheter-based procedures; therefore, it can be easily delivered through highly tortuous or narrow vascular system. A high-quality thin film nitinol can be fabricated by vacuum sputter deposition technique. Micromachining techniques were used to create micro patterns on the thin film nitinol to provide fenestrations for nutrition and oxygen transport and to increase the device's flexibility for the devices used as thin film nitinol covered stent. In addition, a new surface treatment method has been developed for improving the hemocompatibility of thin film nitinol when it is used as a graft material in endovascular devices. Both in vitro and in vivo test data demonstrated a superior hemocompatibility of the thin film nitinol when compared with commercially available endovascular graft materials such as ePTFE or Dacron polyester. Promising features like these have motivated the development of thin film nitinol as a novel biomaterial for creating endovascular devices such as stent grafts, neurovascular flow diverters, and heart valves. This review focuses on thin film nitinol fabrication processes, mechanical and biological properties of the material, as well as current and potential thin film nitinol medical applications. PMID- 25839121 TI - Multidimensional characterisation of biomechanical structures by combining Atomic Force Microscopy and Focused Ion Beam: A study of the rat whisker. AB - Understanding the heterogeneity of biological structures, particularly at the micro/nano scale can offer insights valuable for multidisciplinary research in tissue engineering and biomimicry designs. Here we propose to combine nanocharacterisation tools, particularly Focused Ion Beam (FIB) and Atomic Force Microscopy (AFM) for three dimensional mapping of mechanical modulus and chemical signatures. The prototype platform is applied to image and investigate the fundamental mechanics of the rat face whiskers, a high-acuity sensor used to gain detailed information about the world. Grazing angle FIB milling was first applied to expose the interior cross section of the rat whisker sample, followed by a "lift-out" method to retrieve and position the target sample for further analyses. AFM force spectroscopy measurements revealed a non-uniform pattern of elastic modulus across the cross section, with a range from 0.8GPa to 13.5GPa. The highest elastic modulus was found at the outer cuticle region of the whisker, and values gradually decreased towards the interior cortex and medulla regions. Elemental mapping with EDS confirmed that the interior of the rat whisker is dominated by C, O, N, S, Cl and K, with a significant change of elemental distribution close to the exterior cuticle region. Based on these data, a novel comprehensive three dimensional (3D) elastic modulus model was constructed, and stress distributions under realistic conditions were investigated with Finite Element Analysis (FEA). The simulations could well account for the passive whisker deflections, with calculated resonant frequency as well as force deflection for the whiskers being in good agreement with reported experimental data. Limitations and further applications are discussed for the proposed FIB/AFM approach, which holds good promise as a unique platform to gain insights on various heterogeneous biomaterials and biomechanical systems. PMID- 25839122 TI - Surface charge tunability as a powerful strategy to control electrostatic interaction for high efficiency silencing, using tailored oligopeptide-modified poly(beta-amino ester)s (PBAEs). AB - Here we present an extended family of pBAEs that incorporate terminal oligopeptide moieties synthesized from both positive and negative amino acids. Polymer formulations of mixtures of negative and positive oligopeptide-modified pBAEs are capable of condensing siRNA into discrete nanoparticles. We have demonstrated that efficient delivery of nucleic acids in a cell-type dependent manner can be achieved by careful control of the pBAE formulation. In addition, our approach of adding differently charged oligopeptides to the termini of poly(beta-amino ester)s is of great interest for the design of tailored complexes having specific features, such as tuneable zeta potential. We anticipate that this surface charge tunability may be a powerful strategy to control unwanted electrostatic interactions, while preserving high silencing efficiency and reduced toxicity. PMID- 25839123 TI - Surface tailoring for selective endothelialization and platelet inhibition via a combination of SI-ATRP and click chemistry using Cys-Ala-Gly-peptide. AB - Surface tailoring is an attractive approach to enhancing selective endothelialization, which is a prerequisite for current vascular prosthesis applications. Here, we modified polycarbonate urethane (PCU) surface with both poly(ethylene glycol) and Cys-Ala-Gly-peptide (CAG) for the purpose of creating a hydrophilic surface with targeting adhesion of endothelial cells (ECs). In the first step, PCU-film surface was grafted with poly(ethylene glycol) methacrylate (PEGMA) to covalently tether hydrophilic polymer brushes via surface initiated atom transfer radical polymerization (SI-ATRP), followed by grafting of an active monomer pentafluorophenyl methacrylate (PFMA) by a second ATRP. The postpolymerization modification of the terminal reactive groups with allyl amine molecules created pendant allyl groups, which were subsequently functionalized with cysteine terminated CAG-peptide via photo-initiated thiol-ene click chemistry. The functionalized surfaces were characterized by water contact angle and XPS analysis. The growth and proliferation of human ECs or human umbilical arterial smooth muscle cells on the functionalized surfaces were investigated for 1, 3 and 7 day/s. The results indicated that these peptide functionalized surfaces exhibited enhanced EC adhesion, growth and proliferation. Furthermore, they suppressed platelet adhesion in contact with platelet-rich plasma for 2h. Therefore, these surfaces with EC targeting ligand could be an effective anti thrombogenic platform for vascular tissue engineering application. PMID- 25839124 TI - Cytocompatible in situ forming chitosan/hyaluronan hydrogels via a metal-free click chemistry for soft tissue engineering. AB - Injectable hydrogels are important cell scaffolding materials for tissue engineering and regenerative medicine. Here, we report a new class of biocompatible and biodegradable polysaccharide hydrogels derived from chitosan and hyaluronan via a metal-free click chemistry, without the addition of copper catalyst. For the metal-free click reaction, chitosan and hyaluronan were modified with oxanorbornadiene (OB) and 11-azido-3,6,9-trioxaundecan-1-amine (AA), respectively. The gelation is attributed to the triazole ring formation between OB and azido groups of polysaccharide derivatives. The molecular structures were verified by FT-IR spectroscopy and elemental analysis, giving substitution degrees of 58% and 47% for chitosan-OB and hyaluronan-AA, respectively. The in vitro gelation, morphologies, equilibrium swelling, compressive modulus and degradation of the composite hydrogels were examined. The potential of the metal-free hydrogel as a cell scaffold was demonstrated by encapsulation of human adipose-derived stem cells (ASCs) within the gel matrix in vitro. Cell culture showed that this metal-free hydrogel could support survival and proliferation of ASCs. A preliminary in vivo study demonstrated the usefulness of the hydrogel as an injectable scaffold for adipose tissue engineering. These characteristics provide a potential opportunity to use the metal-free click chemistry in preparation of biocompatible hydrogels for soft tissue engineering applications. PMID- 25839125 TI - Targeting and liposomal drug delivery to CD40L expressing T cells for treatment of autoimmune diseases. AB - CD40L is considered as an important target for the treatment of autoimmune diseases. There have been many efforts devoted to the development of antibodies and other molecules to disrupt CD40/CD40L interaction for therapeutic benefits. In this study, we designed a CD40L specific peptide ligand - A25 based on CD40L crystal structure and molecular docking studies. Its binding affinity and specificity to CD40L were confirmed by Surface Plasmon Resonance (SPR) measurements. The peptide A25 was then conjugated on the surface of liposomes and shown to be able to mediate specific liposomal drug delivery to CD40L+ cells. Loaded with the cytostatic drug methotrexate (MTX), the A25 modified liposome could significantly reduce the CD40L+ cell ratios in the experimental autoimmune encephalomyelitis (EAE) mice, resulting in great improvement in clinical scores. Since CD40L+ cells are involved in the pathological development of many auto immune diseases, A25 conjugated drug targeting systems may be useful for developing therapies that are more efficacies and with less side effects. PMID- 25839126 TI - Efficient peptide recovery from secreted recombinant MHC-I molecules expressed via mRNA transfection. AB - Most current methods for identifying peptides that are bound to a distinct MHC-I product in a given cell sample utilize detergent solubilization of membrane proteins followed by immunoaffinity purification. Since detergent traces and cell debris hamper subsequent peptide analysis, exceedingly large cell samples are often required. To avoid the use of detergents, truncated MHC-I heavy chains have recently been expressed by stable DNA transfection or retroviral transduction, resulting in the secretion of soluble MHC-I complexes to the growth medium. The electroporation of in vitro-transcribed mRNA achieves remarkable efficacy and uniformity of gene expression in numerous cell types, exhibiting exceedingly fast kinetics. We reasoned that mRNA transfection offers a simple, fast and widely applicable alternative to current gene delivery protocols for expressing secreted MHC-I products in cells of interest. To test this assumption we used mRNA to express soluble derivatives of HLA-A2 in the human AF10 B cell myeloma and 624mel melanoma and H-2K(d) in the mouse SP2/0 B cell myeloma. The level of MHC-I complexes secreted by these cells peaked within less than 24h post-transfection and they could be affinity-purified directly from the culture medium in considerably greater yields when compared to nonionic detergent lysates on a cell to-cell basis. Mass-spectrometry analysis of eluted peptides revealed larger pools in the secreted material than in lysates with substantial overlap in composition. Our results introduce mRNA transfection as a powerful tool for determining the cell's MHC-I peptidome, which can be potentially applied to a broad range of cell types. PMID- 25839128 TI - Characterization and clinical relevance of circulating CD4+CD28- T cells in Graves' disease. AB - During autoimmune disease the fraction of CD4+CD28- T cells in the peripheral blood of has been found to be elevated. In the present study, peripheral blood was collected from 61 patients with Graves' disease (GD) and 30 healthy control participants. Serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4) and thyrotropin receptor autoantibody (TRAb) were measured and peripheral blood mononuclear cell (PBMC) surface expression of CD4 and CD28 molecules was detected by flow cytometry. CD4+CD28- cells were sorted from six patients undergoing subtotal thyroidectomy and cultured ex vivo. The influence of TSH pretreated thyroid follicular cells on CD4+CD28- cell proliferation was evaluated using the agonist CD40 mAb 5C11, the blocking CD40L mAb 4F1 or B7-1 mAb 4E5 in 3H-TdR assays. Our data showed that the fraction of CD4+CD28- T cells was higher in GD patients than healthy donors (10.21%+/-8.56% vs. 2.33%+/-1.94%; P<0.001), and further elevated in 24 of 61 patients with Graves' ophthalmopathy (GO) (7.00+/-6.57% vs. 15.21+/-8.96%; P<0.001). A higher proportion of CD4+CD28- cells was detected in patients with degree II or III goiter than those with degree I goiter (11.53+/-9.18% vs. 6.11+/ 3.97%; P<0.05 and 14.50+/-10.41% vs. 6.11+/-3.97%; P<0.01). The percentage of CD4+CD28- T cells correlated positively with serum levels of FT3 (r=0.354, P<0.01) and TRAb (r=0.304, P<0.05), but did not correlate with serum FT4 or TSH. Ex vivo, 5C11 enhanced proliferation of CD4+CD28+ cells (P<0.05), but did not influence the proliferation of CD4+CD28- cells. 4F1 inhibited the proliferation of both CD4+CD28+ (P<0.05) and CD4+CD28- (P<0.01) cells, and 4E5 inhibited proliferation of CD4+CD28+ cells (P<0.05). The elevation in circulating CD4+CD28- cells in GD patients correlates with disease severity and maybe plays an important role in the pathogenesis of GD. PMID- 25839127 TI - Anti-diabetic actions of carbon monoxide-releasing molecule (CORM)-A1: Immunomodulation and regeneration of islet beta cells. AB - We have recently shown that carbon monoxide releasing molecule (CORM)-A1 prevents type 1 diabetes induced in C57BL/6 mice with multiple low doses of streptozotocin (MLDS) by shifting the Th1/Th17/M1 balance towards a Th2/M2 response. In the present work we tested the hypothesis that CORM-A1 might influence regulatory arm of the immune response, as well as beta cell regeneration. CORM-A1 (2 mg/kg/day) was administered for 10 days to mice induced with MLDS and/or depleted of low dose cyclophosphamide (CY)-sensitive FoxP3+ T regulatory (Treg) cells. Besides monitoring hyperglycaemia, ex vivo analysis of spleen, pancreatic lymph nodes (PLN) and pancreas was performed at the end of treatment. In CORM-A1-treated MLDS induced mice the improvement of hyperglycaemia was observed only without depletion of CY-sensitive FoxP3+ Treg cells. This was accompanied by decreased levels of interleukin (IL)-12, IL-2 and early activation marker CD25 in the spleen and PLN and increased transforming growth factor (TGF)-beta, resulting in reduced lymphocyte proliferation in both organs. In parallel, decreased transcript levels of IL-2, but increased mRNA expression of TGF-beta, accompanied with up-regulation of Ki-67 protein expression was observed within pancreas. Together, the data suggested that besides the immunomodulatory potential, CORM-A1 probably induces beta cell regeneration. PMID- 25839129 TI - Characteristic Features of the Interictal EEG Background in 2 Patients With Malignant Migrating Partial Epilepsy in Infancy. AB - PURPOSE: To describe chronological electrographic features of the interictal EEG background observed in two patients with malignant migrating partial epilepsy in infancy from neonatal to early infantile period. METHODS: EEGs of two patients who fulfilled diagnostic criteria for malignant migrating partial epilepsy in infancy were acquired over the period of 6 months to monitor treatment efficacy and characterize seizures and other paroxysmal events. RESULTS: Both patients followed a similar sequential pattern. A distinctive evolution from a dysmature term neonatal EEG pattern to an asynchronous suppression burst pattern was observed before the interictal background becoming continuous. CONCLUSIONS: Physicians providing care to infants with intractable epilepsy and burst suppression EEG pattern should be alert to the possibility of malignant migrating partial epilepsy in infancy. An earlier diagnosis of malignant migrating partial epilepsy in infancy would help to guide diagnostic workup including genetic testing. PMID- 25839130 TI - Effects of ropivacaine, bupivacaine and sufentanil in colon and pancreatic cancer cells in vitro. AB - The perioperative period is supposed to be a vulnerable period for cancer progression. Results of clinical studies indicate that the use of regional anesthesia can influence and improve oncological outcome of cancer patients. Uncontrolled cell proliferation and resistance to apoptotic cell death are important characteristics of solid tumors. The aim of this study was to investigate the effects of the clinically used local anesthetics ropivacaine or bupivacaine and the opioid analgesic sufentanil on cell proliferation, cell cycle distribution and apoptosis of colon (HT 29 and SW 480) and pancreatic (PaTu 8988t and PANC 1) cancer cell lines in vitro. Cell proliferation was measured by Cell Proliferation ELISA BrdU Assay. Apoptosis was analyzed by annexin V staining and cell cycle distribution was detected by flow cytometry. Ropivacaine, bupivacaine and sufentanil did not change apoptosis rate and cell cycle distribution in clinically concentration. Only high concentrations of ropivacaine or bupivacaine revealed antiproliferative potency. Protective effects of epidural anesthesia observed in clinical studies seem not to be based on direct effects of these drugs on cancer cells. PMID- 25839134 TI - Stress-Strain Measurements in Vitrified Arteries Permeated With Synthetic Ice Modulators. AB - This study measures the Young's modulus in vitrified blood vessels below the glass transition temperature in conditions relevant to cryogenic storage and focuses on the cryoprotective agents (CPAs) cocktail DP6 mixed with synthetic ice modulators (SIMs). Small steplike strain changes were observed during the loading without affecting the bulk behavior, suggesting microfracture occurrences resembling previous observation on microfracture formation under compression in crystallized blood vessels. Young's modulus was measured to be 0.92-3.01 GPa, with no clear indication of SIM dependency on the Young's modulus. Instead, the range of values is attributed to variations between specimens of the same species. PMID- 25839135 TI - Novel substrate specificities of two lacto-N-biosidases towards beta-linked galacto-N-biose-containing oligosaccharides of globo H, Gb5, and GA1. AB - We describe the novel substrate specificities of two independently evolved lacto N-biosidases (LnbX and LnbB) towards the sugar chains of globo- and ganglio series glycosphingolipids. LnbX, a non-classified member of the glycoside hydrolase family, isolated from Bifidobacterium longum subsp. longum, was shown to liberate galacto-N-biose (GNB: Galbeta1-3GalNAc) and 2'-fucosyl GNB (a type-4 trisaccharide) from Gb5 pentasaccharide and globo H hexasaccharide, respectively. LnbB, a member of the glycoside hydrolase family 20 isolated from Bifidobacterium bifidum, was shown to release GNB from Gb5 and GA1 oligosaccharides. This is the first report describing enzymatic release of beta-linked GNB from natural substrates. These unique activities may play a role in modulating the microbial composition in the gut ecosystem, and may serve as new tools for elucidating the functions of sugar chains of glycosphingolipids. PMID- 25839136 TI - Synthesis, conformational study, glycosidase inhibitory activity and molecular docking studies of dihydroxylated 4- and 5-amino-iminosugars. AB - An efficient methodology for the synthesis of new amino iminosugars 6a, 7a and 8, starting from D-glucose, is reported. The conformational study using (1)H NMR data showed that the amino iminosugar 6a exists in the (2)C5 while; the 7a and 8 exist in the (5)C2 conformation. The inhibition activities with different glycosidases showed that 6a and 7a are poor glycosidase inhibitors. However, amino iminosugar 8 showed selective inhibition against the beta-galactosidase (IC50 = 43 MUM, Ki = 153 MUM). These results are substantiated by the molecular docking studies. PMID- 25839137 TI - Biomarkers in volunteers exposed to mobile phone radiation. AB - For some time it has been investigated whether low-intensity non-thermal microwave radiation from mobile phones adversely affects the mammalian blood brain barrier (BBB). All such studies except one have been either in vitro or experimental animal studies. The one carried out on humans showed a statistically significant increase in serum transthyretin (TTR) 60 min after finishing of a 30 min microwave exposure session. The aim of the present study was to follow up on the finding of the previous one using a better study design. Using biomarkers analyzed in blood serum before and after the exposure this single blinded randomized counterbalanced study, including 24 healthy subjects aged 18-30 years that all underwent three exposure conditions (SAR(10G)=2 W/kg, SAR(10G)=0.2 W/kg, sham), tested whether microwaves from an 890-MHz phone-like signal give acute effects on the integrity of brain-shielding barriers. Over time, statistically significant variations were found for two of the three biomarkers (TTR; beta trace protein); however, no such difference was found between the different exposure conditions nor was there any interaction between exposure condition and time of blood sampling. In conclusion this study failed to show any acute clinically or statistically significant effect of short term microwave exposure on the serum levels of S100beta, TTR and beta-trace protein with a follow up limited to two hours. The study was hampered by the fact that all study persons were regular wireless phone users and thus not naive as to microwave exposure. PMID- 25839147 TI - Sensorimotor event-related desynchronization represents the excitability of human spinal motoneurons. AB - Amplitudes of mu and beta (7-26Hz) oscillations measured by electroencephalography over the sensorimotor areas are suppressed during motor imagery as well as during voluntary movements. This phenomenon is referred to as event-related desynchronization (ERD) and is known to reflect motor cortical excitability. The increased motor cortical excitability associated with ERD during hand motor imagery would induce a descending cortical volley to spinal motoneurons, resulting in facilitation of spinal motoneuronal excitability. Therefore, in the present study, we tested the association of ERD during motor imagery with the excitability of spinal motoneurons in 15 healthy participants. Spinal excitability was tested using the F-wave recorded from the right abductor pollicis brevis muscle. The F-wave results from antidromic activation of spinal motoneurons and is induced by peripheral nerve stimulation. Participants performed 5s of motor imagery of right thumb abduction following 7s of rest. The right median nerve was stimulated at wrist level when the ERD magnitude of the contralateral hand sensorimotor area exceeded predetermined thresholds during motor imagery. The results showed ERD magnitude during hand motor imagery was associated with an increase in F-wave persistence, but not with the response average of F-wave amplitude or F-wave latency. These findings suggest that the ERD magnitude may be a biomarker representing increases in the excitability of both cortical and spinal levels. PMID- 25839146 TI - Cochlear ablation effects on amino acid levels in the chinchilla cochlear nucleus. AB - Inner ear damage can lead to hearing disorders, including tinnitus, hyperacusis, and hearing loss. We measured the effects of severe inner ear damage, produced by cochlear ablation, on the levels and distributions of amino acids in the first brain center of the auditory system, the cochlear nucleus. Measurements were also made for its projection pathways and the superior olivary nuclei. Cochlear ablation produces complete degeneration of the auditory nerve, which provides a baseline for interpreting the effects of partial damage to the inner ear, such as that from ototoxic drugs or intense sound. Amino acids play a critical role in neural function, including neurotransmission, neuromodulation, cellular metabolism, and protein construction. They include major neurotransmitters of the brain - glutamate, glycine, and gamma-aminobutyrate (GABA) - as well as others closely related to their metabolism and/or functions - aspartate, glutamine, and taurine. Since the effects of inner ear damage develop over time, we measured the changes in amino acid levels at various survival times after cochlear ablation. Glutamate and aspartate levels decreased by 2weeks in the ipsilateral ventral cochlear nucleus and deep layer of the dorsal cochlear nucleus, with the largest decreases in the posteroventral cochlear nucleus (PVCN): 66% for glutamate and 63% for aspartate. Aspartate levels also decreased in the lateral part of the ipsilateral trapezoid body, by as much as 50%, suggesting a transneuronal effect. GABA and glycine levels showed some bilateral decreases, especially in the PVCN. These results may represent the state of amino acid metabolism in the cochlear nucleus of humans after removal of eighth nerve tumors, which may adversely result in destruction of the auditory nerve. Measurement of chemical changes following inner ear damage may increase understanding of the pathogenesis of hearing impairments and enable improvements in their diagnosis and treatment. PMID- 25839148 TI - Juxtapositions between the somatostatinergic and growth hormone-releasing hormone (GHRH) neurons in the human hypothalamus. AB - Somatostatin is a 14-28 amino acid peptide that is located not only in the gastrointestinal system but also in multiple sites of the human brain. The inhibitory effect of somatostatin on the growth hormone (GH) secretion of the pituitary gland is a well-established phenomenon. There is a general consensus that somatostatin is released into the hypophysial portal blood and modulates GH secretion by hormonal action. In the present study, we explored the possibility that in addition to the hormonal route, somatostatin may also influence GH secretion via influencing the growth hormone-releasing hormone (GHRH) secretion by direct contacts that may be functional synapses. Since the verification of these putative synapses by electron microscopy is virtually impossible in humans due to the long post mortem time, in order to reveal the putative somatostatinergic-GHRH juxtapositions, light microscopic double-label immunohistochemistry was utilized. By examining the slides with high magnification, we observed that the vast majority of the GHRH perikarya received contacting somatostatinergic axonal varicosities in the arcuate nucleus. In contrast, GHRH axonal varicosities rarely contacted somatostatinergic perikarya. The morphology and the abundance of somatostatin to GHRH juxtapositions indicate that these associations are functional synapses, and they represent, at least partially, the morphological substrate of the somatostatin-influenced GHRH secretion. Thus, in addition to influencing the GH secretion directly via the hypophysial portal system, somatostatin may also modulate GH release from the anterior pituitary by regulating the hypothalamic GHRH secretion via direct contacts. The rare GHRH to somatostatin juxtapositions indicate that the negative feedback effect of GH targets the somatostatinergic system directly and not via the GHRH system. PMID- 25839149 TI - The antidepressant fluoxetine protects the hippocampus from brain damage in experimental pneumococcal meningitis. AB - BACKGROUND: High mortality and morbidity rates are observed in patients with bacterial meningitis (BM) and urge for new adjuvant treatments in addition to standard antibiotic therapies. In BM the hippocampal dentate gyrus is injured by apoptosis while in cortical areas ischemic necrosis occurs. Experimental therapies aimed at reducing the inflammatory response and brain damage have successfully been evaluated in animal models of BM. Fluoxetine (FLX) is an anti depressant of the selective serotonin reuptake inhibitors (SSRI) and was previously shown to be neuroprotective in vitro and in vivo. We therefore assessed the neuroprotective effect of FLX in experimental pneumococcal meningitis. METHODS: Infant rats were infected intracisternally with live Streptococcus pneumoniae. Intraperitoneal treatment with FLX (10mgkg(-1)d(-1)) or an equal volume of NaCl was initiated 15min later. 18, 27, and 42h after infection, the animals were clinically (weight, clinical score, mortality) evaluated and subject to a cisternal puncture and inflammatory parameters (i.e., cyto-/chemokines, myeloperoxidase activity, matrix metalloproteinase concentrations) were measured in cerebrospinal fluid (CSF) samples. At 42h after infection, animals were sacrificed and the brains collected for histomorphometrical analysis of brain damage. RESULTS: A significant lower number of animals treated with FLX showed relevant hippocampal apoptosis when compared to littermates (9/19 animals vs 18/23, P=0.038). A trend for less damage in cortical areas was observed in FLX-treated animals compared to controls (13/19 vs 13/23, P=ns). Clinical and inflammatory parameters were not affected by FLX treatment. CONCLUSION: A significant neuroprotective effect of FLX on the hippocampus was observed in acute pneumococcal meningitis in infant rats. PMID- 25839150 TI - Electrophysiological characterization of activation state-dependent Ca(v)2 channel antagonist TROX-1 in spinal nerve injured rats. AB - Prialt, a synthetic version of Ca(v)2.2 antagonist omega-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury. PMID- 25839152 TI - Echocardiography and three-dimensional printing: sound ideas to touch a heart. PMID- 25839151 TI - Poisonous birds: A timely review. AB - Until very recently, toxicity was not considered a trait observed in birds, but works published in the last two decades started to shed light on this subject. Poisonous birds are rare (or little studied), and comprise Pitohui and Ifrita birds from Papua New Guinea, the European quail, the Spoor-winged goose, the Hoopees, the North American Ruffed grouse, the Bronzewings, and the Red warbler. A hundred more species are considered unpalatable or malodorous to humans and other animals. The present review intends to present the current understanding of bird toxicity, possibly pointing to an ignored research field. Whenever possible, biochemical characteristics of these poisons and their effects on humans and other animals are discussed, along with historical aspects of poison discovery and evolutionary hypothesis regarding their function. PMID- 25839153 TI - Comments on the assessment of biventricular function in children after tetralogy of fallot repair. PMID- 25839154 TI - Echocardiography educational products for all generations. PMID- 25839155 TI - ASE 2015: Boston is wicked awesome! PMID- 25839156 TI - Cardiac ultrasound and extracorporeal life support: the two go together. PMID- 25839157 TI - An investigation of the dosimetric and kinetic properties of sand using ESR and TL techniques. AB - In this research, the general dosimetric and kinetic properties of sand from a beach in southern Turkey were investigated using electron spin resonance (ESR) and thermoluminescence (TL) techniques. The ESR dose response curve presents linear behaviour in the dose range of 250-1000 Gy followed by sublinear behaviour in the dose range of 2-8 kGy. Kinetic behaviors and activation energy of the free radical were also calculated using the data obtained from annealing studies performed at four different temperatures (220, 240, 260 and 280 degrees C). The activation energy value was calculated as 1.47 eV. The long-term fading of the ESR signal at room temperature turned out to be best described by a second-order kinetic decay function. The presence of measurable ESR signal intensity even after a storage period of 90 days was considered as providing an opportunity in the dose estimation of irradiated sand sample. Although the TL glow curve of the natural (unirradiated) sand sample only has a single broad peak at 317 degrees C, the glow curve of the irradiated sample has four glow peaks located at ~115 degrees C, ~156 degrees C, ~231 degrees C and ~308 degrees C and their intensity tends to be increased with absorbed dose.Tmax-Tstop and glow curve fitting results showed that presence of at least five peaks located at ~116 degrees C, 149 degrees C, 228 degrees C, 306 degrees C and 360 degrees C. This result suggests that the apparently single glow peak D may consist of two or more overlapping glow peaks. According to the thermal fading of the sand sample at room temperature, the TL signal intensities (23 degrees C and 308 degrees C) were found to be quite large after 30 days of storage this allows a more accurate measurement of the glow peak intensity. The additive dose method, variable heating rate method (VHRM), Tmax-Tstop and glow curve fitting method were used to number of peaks, dosimetric properties and kinetic parameters. This study shows that ESR and TL techniques could be successfully used to investigate the kinetics and dosimetric properties of sand sample. Furthermore, the results in this study plus the previous work done by the authors suggest that sand could, by using the ESR and TL techniques, be a suitable material for alternative dose measurement. PMID- 25839158 TI - A mutation in the NADH-dehydrogenase subunit 2 suppresses fibroblast aging. AB - Mutations of mitochondrial (mt)DNA cause a variety of human diseases and are implicated in premature aging syndromes. Here we investigated a single nucleotide exchange (leucine to methionine) at position nt4738 in the mitochondrial NADH dehydrogenase subunit 2 (Nd2) gene of the respiratory chain. Primary fibroblasts derived from the conplastic mouse strain C57BL/6J-mtALR/LTJ with mutant enzyme, possessed high enzyme activity and ATP production and low ROS production. Furthermore, Nd2-mutant fibroblasts expressed lower senescence markers. Transcriptome analysis revealed that the members of the p38MAPK pathway were significantly downregulated in Nd2-mutant mice. In agreement, inhibition of p38MAPK with SB203580 enhanced proliferation and reduced cytokine secretion in fibroblasts. In Nd2-mutant mouse skin, the amount of Ki67-positive cells was significantly higher than in control skin. The higher amount of Ki67-positive cells and the thicker epidermis in Nd2-mutant mice strongly supported the in vitro data. In conclusion, Nd2 is a mitochondrial gene, involved in age-related signaling pathways. PMID- 25839159 TI - Translation initiation complex eIF4F is a therapeutic target for dual mTOR kinase inhibitors in non-Hodgkin lymphoma. AB - Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients. PMID- 25839160 TI - Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism. AB - Cancer cells exhibit characteristic changes in their metabolism with efforts being made to address them therapeutically. However, targeting metabolic enzymes as such is a major challenge due to their essentiality for normal proliferating cells. The most successful pharmaceutical targets are G protein-coupled receptors (GPCRs), with more than 40% of all currently available drugs acting through them.We show that, a family of metabolite-sensing GPCRs, the Hydroxycarboxylic acid receptor family (HCAs), is crucial for breast cancer cells to control their metabolism and proliferation.We found HCA1 and HCA3 mRNA expression were significantly increased in breast cancer patient samples and detectable in primary human breast cancer patient cells. Furthermore, siRNA mediated knock-down of HCA3 induced considerable breast cancer cell death as did knock-down of HCA1, although to a lesser extent. Liquid Chromatography Mass Spectrometry based analyses of breast cancer cell medium revealed a role for HCA3 in controlling intracellular lipid/fatty acid metabolism. The presence of etomoxir or perhexiline, both inhibitors of fatty acid beta-oxidation rescues breast cancer cells with knocked-down HCA3 from cell death.Our data encourages the development of drugs acting on cancer-specific metabolite-sensing GPCRs as novel anti proliferative agents for cancer therapy. PMID- 25839161 TI - Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis. AB - Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN gamma-expressing T-bet/RORgammat double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-alpha and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC. PMID- 25839162 TI - TMEM16A overexpression contributes to tumor invasion and poor prognosis of human gastric cancer through TGF-beta signaling. AB - TMEM16A is a newly identified calcium activated chloride channel, and has been reported to be overexpressed by various solid malignant cancers to promote proliferation and invasion, yet little is known about its role in gastric cancer(GC). Therefore, we investigated the role of TMEM16A in GC and its clinical significance by a retrospective analysis of 367 GC patients, and in vitro study was performed for validation and underlying molecular mechanism.TMEM16A was significantly upregulated and amplified in GC tissues, and its overexpression was positively correlated with disease stage, negatively with patient survival and identified as an independent prognostic factor for patient outcome. A negative correlation between TMEM16A and E-cadherin was found in 367 GC specimens. TMEM16A silencing significantly decreased calcium activated chloride currents, impaired TGF-beta secretion, reduced E-cadherin expression, and inhibited the migration and invasion without affecting proliferation of GC cells (AGS and BGC-823). Supplement of TGF-beta reverted the effects of TMEM16A silencing on E-cadherin expression, cell migration and invasion.In conclusion, TMEM16A promotes invasion and metastasis in GC, and might be a novel prognostic biomarker and potential therapeutic target in the treatment of GC. PMID- 25839163 TI - The hypoxia-related microRNA miR-199a-3p displays tumor suppressor functions in ovarian carcinoma. AB - During the dissemination of ovarian cancer cells, the cells float in the peritoneal cavity without access to a vascular supply and so are exposed to hypoxic conditions, which may cause the ovarian cancer cells to acquire a more aggressive and malignant phenotype. In this study, we screened microRNAs (miRNAs) to identify those that displayed altered expression patterns under hypoxic conditions and then analyzed their functional roles in ovarian cancer progression. miRNA PCR arrays performed on cells from 2 ovarian cancer cell lines (CaOV3 and RMUG-S) revealed miR-199a-3p as one of the miRNAs that are downregulated under hypoxia. In silico analyses indicated that MET is one of the target genes for miR-199a-3p; subsequently, miR-199a-3p expression was found to be inversely correlated with c-Met expression in ovarian cancer. Transfection of precursor miR-199a-3p into ovarian cancer cells reduced c-Met expression and inhibited the phosphorylation of c-Met, extracellular signal-regulated kinase, and AKT; in addition, proliferation, adhesion, and invasiveness were inhibited. Moreover, overexpression of miR-199a-3p in cancer cells significantly suppressed peritoneal dissemination in a xenograft model. In summary, the hypoxia-related microRNA miR-199a-3p drastically inhibits ovarian cancer progression through the downregulation of c-Met expression. Therefore, miR-199a-3p is a potential target for treating ovarian cancer dissemination. PMID- 25839164 TI - A novel role for drebrin in regulating progranulin bioactivity in bladder cancer. AB - We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer. PMID- 25839166 TI - Evolution for exogenous octanoic acid tolerance improves carboxylic acid production and membrane integrity. AB - Carboxylic acids are an attractive biorenewable chemical, but as with many biorenewables, their toxicity to microbial biocatalysts limits their fermentative production. While it is generally accepted that membrane damage is the main mechanism of fatty acid toxicity, previous metabolic engineering efforts that increased membrane integrity did not enable increased carboxylic acid production. Here we used an evolutionary approach to improve tolerance to exogenous octanoic acid, with the goal of learning design strategies from this evolved strain. This evolution of an Escherichia coli MG1655 derivative at neutral pH in minimal media produced a strain with increased tolerance not only to octanoic acid, but also to hexanoic acid, decanoic acid, n-butanol and isobutanol. This evolved strain also produced carboxylic acids at a 5-fold higher titer than its parent strain when expressing the Anaerococcus tetradius thioesterase. While it has been previously suggested that intracellular acidification may contribute to carboxylic acid toxicity, we saw no evidence that the evolved strain has increased resistance to this acidification. Characterization of the evolved strain membrane showed that it had significantly altered membrane polarization (fluidity), integrity (leakage) and composition relative to its parent. The changes in membrane composition included a significant increase in average lipid length in a variety of growth conditions, including 30 degrees C, 42 degrees C, carboxylic acid challenge and ethanol challenge. The evolved strain has a more dynamic membrane composition, showing both a larger number of significant changes and larger fold changes in the relative abundance of membrane lipids. These results highlight the importance of the cell membrane in increasing microbial tolerance and production of biorenewable fuels and chemicals. PMID- 25839165 TI - Down-regulation of ARNT promotes cancer metastasis by activating the fibronectin/integrin beta1/FAK axis. AB - The aryl hydrocarbon receptor nuclear translocator (ARNT) is broadly involved in regulating tumorigenesis by inducing genes that are involved in tumor growth and angiogenesis. Tumorigenesis usually involves normoxic conditions. However, the role of ARNT in tumor metastasis during normoxia remains unclear. Here, we demonstrate that ARNT protein levels were decreased in late-stage human colorectal cancer using immunohistochemical analysis. Down-regulation of ARNT protein promoted cancer cell migration and invasion, which was mediated by activation of the fibronectin/integrin beta1/FAK signaling axis. In addition, the enhancement of migration and invasion in ANRT knockdown cells was blocked when ARNT was restored in the cells. In xenografts in severe combined immunodeficiency mice, tumor growth was significantly inhibited in the ARNT-knockdown condition. However, the tail-vein injection animal model revealed that the depletion of ARNT induced metastatic lung colonies was further enhanced when ARNT expression was recovered post-injection. Interestingly, chemotherapeutic drugs inhibited ARNT expression and promoted the invasion of residual tumor cells. These results suggest that ARNT may play a positive role during tumor growth (either in early stage tumor growth or in organ metastases), but plays a negative role in tumor migration and invasion. Therefore, the efficiency of ARNT-targeted therapy during different cancer stages should be carefully evaluated. PMID- 25839167 TI - Global exponential periodicity and stability of discrete-time complex-valued recurrent neural networks with time-delays. AB - In recent years, complex-valued recurrent neural networks have been developed and analysed in-depth in view of that they have good modelling performance for some applications involving complex-valued elements. In implementing continuous-time dynamical systems for simulation or computational purposes, it is quite necessary to utilize a discrete-time model which is an analogue of the continuous-time system. In this paper, we analyse a discrete-time complex-valued recurrent neural network model and obtain the sufficient conditions on its global exponential periodicity and exponential stability. Simulation results of several numerical examples are delineated to illustrate the theoretical results and an application on associative memory is also given. PMID- 25839168 TI - A new delay-independent condition for global robust stability of neural networks with time delays. AB - This paper studies the problem of robust stability of dynamical neural networks with discrete time delays under the assumptions that the network parameters of the neural system are uncertain and norm-bounded, and the activation functions are slope-bounded. By employing the results of Lyapunov stability theory and matrix theory, new sufficient conditions for the existence, uniqueness and global asymptotic stability of the equilibrium point for delayed neural networks are presented. The results reported in this paper can be easily tested by checking some special properties of symmetric matrices associated with the parameter uncertainties of neural networks. We also present a numerical example to show the effectiveness of the proposed theoretical results. PMID- 25839170 TI - Reply: Evidence-Based Medicine: Unilateral Cleft Lip and Nose Repair. PMID- 25839169 TI - Small circular single stranded DNA viral genomes in unexplained cases of human encephalitis, diarrhea, and in untreated sewage. AB - Viruses with small circular ssDNA genomes encoding a replication initiator protein can infect a wide range of eukaryotic organisms ranging from mammals to fungi. The genomes of two such viruses, a cyclovirus (CyCV-SL) and gemycircularvirus (GemyCV-SL) were detected by deep sequencing of the cerebrospinal fluids of Sri Lankan patients with unexplained encephalitis. One and three out of 201 CSF samples (1.5%) from unexplained encephalitis patients tested by PCR were CyCV-SL and GemyCV-SL DNA positive respectively. Nucleotide similarity searches of pre-existing metagenomics datasets revealed closely related genomes in feces from unexplained cases of diarrhea from Nicaragua and Brazil and in untreated sewage from Nepal. Whether the tropism of the cyclovirus and gemycircularvirus reported here include humans or other cellular sources in or on the human body remains to be determined. PMID- 25839172 TI - Laser Resurfacing at the Time of Rhytidectomy. AB - BACKGROUND: Laser resurfacing with simultaneous rhytidectomy has been used to augment aesthetic results and decrease overall patient recuperative time, yet presents a potential dual insult to the microvasculature supply of facial skin flaps. This study describes the authors' experience with rhytidectomy and simultaneous laser resurfacing. METHODS: Between May of 1999 and January of 2013, 85 face lifts with concomitant erbium laser resurfacing were reviewed retrospectively. Seven procedures were excluded for incomplete charting. Patient demographics, treatment zone, concomitant procedures, and secondary/tertiary face lifts were analyzed for associations with postoperative complications attributable to laser resurfacing. RESULTS: No complications were reported in the perioral resurfacing group. There was one instance of delayed wound healing and prolonged erythema in the full face group, and one instance of moderate hyperpigmentation in the central face group. No instances of hypopigmentation or flap necrosis attributable to laser resurfacing were noted. The overall complication rate was 3.8 percent. There was a statistically significant difference when comparing the number of complications between the facial laser resurfacing zones (p = 0.037). When analyzing zone of laser resurfacing as an independent risk factor for complications, no significant association was derived, but full face zone resurfacing approached statistical significance (p = 0.063). CONCLUSIONS: Although a significant difference in the number of complications between treatment groups existed, the authors were not able to definitively attribute this solely to the extent of laser resurfacing. Simultaneous laser resurfacing and rhytidectomy can be performed safely in select patients using ablative mode only over the undermined flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25839173 TI - Donor-Site Hernia Repair in Abdominal Flap Breast Reconstruction: A Population Based Cohort Study of 7929 Patients. AB - BACKGROUND: The authors investigated hernia repair rates following pedicled transverse rectus abdominis myocutaneous (TRAM), free TRAM, and deep inferior epigastric perforator (DIEP) flap breast reconstruction in English National Health Service hospitals. METHODS: Women diagnosed with breast cancer who underwent pedicled TRAM, free TRAM, or DIEP flap breast reconstruction procedures in English National Health Service hospitals between April of 2006 and March of 2012 were identified using the Hospital Episode Statistics database. Women who underwent mastectomy without reconstruction acted as controls, and hernia repair rates were calculated for all four groups. Multiple Cox regression was performed to estimate the relative risk of hernia repair among the reconstruction groups, adjusted for age, obesity, previous abdominal surgery, reconstruction year, and bilateral flap harvest. RESULTS: Between 2006 and 2012, 7929 women had a DIEP or TRAM flap breast reconstruction. The overall hernia repair rate within 3 years was 2.45 percent after abdominal flap breast reconstruction, and 0.28 percent among the 15,679 women who had mastectomy only. Mean time to hernia repair following an abdominal flap harvest was 17.7 months. Compared with DIEP flaps, free and pedicled TRAM flap procedures were associated with adjusted hazard ratios of 1.81 (95 percent CI, 1.24 to 2.64) and 2.89 (95 percent CI, 1.91 to 4.37), respectively. The only independent risk factor for hernia repair was age older than 60 years (p = 0.039). CONCLUSIONS: Abdominally based autologous breast reconstruction carries a small risk of subsequent donor-site hernia repair. The rates herein can be used to inform patients and to assess quality of care across service providers. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 25839174 TI - Evidence-Based Medicine: Unilateral Cleft Lip and Nose Repair. PMID- 25839175 TI - The protective role of (-)-epigallocatechin-3-gallate in thrombin-induced neuronal cell apoptosis and JNK-MAPK activation. AB - (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenolic component of green tea, has anti-inflammatory and antioxidant properties and provides neuroprotection against central nervous system diseases. Yet, it is not known whether EGCG may be neuroprotective against intracerebral hemorrhage. In this study, we used a simplified in-vitro model of thrombin neurotoxicity to test whether EGCG provides neuroprotection against thrombin-associated toxicity. Exposure of primary cortical neurons to thrombin (100 U/ml) caused dose-dependent and time-dependent cytotoxicity. Cell Counting Kit 8 and lactate dehydrogenase were used to monitor cell viability after exposure of neurons to thrombin or EGCG and after EGCG pretreatment. Flow cytometric analysis and western blotting demonstrated that thrombin-induced neuron degeneration occurs through apoptosis. A concentration of 25 MUM EGCG significantly abolished thrombin-induced toxicity and prevented apoptosis by suppressing c-Jun-N-terminal kinase (JNK) phosphorylation, and the JNK inhibitor SP600125 reduced thrombin-induced caspase 3 activation and apoptosis. These data suggest that EGCG may have protective effects against thrombin-induced neuroapoptosis by inhibiting the activation of JNK, leading to caspase 3 cleavage. EGCG is a novel candidate neuroprotective agent against intracerebral hemorrhage-induced neurotoxicity. PMID- 25839176 TI - Requirement of AMPK activation for neuronal metabolic-enhancing effects of antidepressant paroxetine. AB - Reduced glucose metabolism has been implicated as a pathophysiology of depressive disorder. Normalization of such impaired neurometabolism has been related to the therapeutic actions of antidepressant medication. However, the molecular mechanism underlying the neurometabolic actions of antidepressants has not been fully understood. Given that AMP-activated protein kinase (AMPK) is a master switch for energy homeostasis, we aimed to determine whether selective serotonin reuptake inhibitor paroxetine enhances energy metabolism by activating AMPK in neuroblastoma cells. We found that paroxetine dose dependently increased mitochondrial biogenesis, which involves the AMPK-peroxisome proliferator activated receptor-gamma coactivator-1alpha pathway. In addition, paroxetine induced AMPK activation increases glucose uptake and ATP production. These neurometabolic effects of paroxetine were suppressed by cotreatment with compound C (CC), an AMPK inhibitor. These findings suggest a possibility that modulation of the AMPK pathway might be a previously unrecognized mechanism underlying the neurometabolic action of antidepressants. Further study is warranted to examine the region-specific and time-specific effects of AMPK modulation by antidepressants on mood-related behaviors. PMID- 25839177 TI - Noradrenaline concentrations in the hypothalamus of anoestrus ewes following the ram-induced luteinizing hormone release. AB - Sheep are seasonal breeders, but exposure of anoestrus ewes to rams results in a rapid increase in luteinizing hormone (LH) secretion, eventually leading to surge in LH. Although LH secretion is known to be under the control of many neurotransmitters, noradrenaline (NA) is of particular importance for the LH surge in induced ovulators, although little is known about its role in LH secretion induced by males in spontaneous ovulators. To address this question, anoestrus ewes fitted with guide-tubes in the medial preoptic area (MPOA) or the ventromedial hypothalamus were subjected to microdialysis and blood sampling every 15 min for an hour before and 2 h after exposure to rams, and the concentrations of LH, monoamine and amino acid transmitters were measured. In ewes implanted in the posterior MPOA that responded to the ram by an increase in LH pulses, NA concentrations changed after exposure to the ram (P<0.018) and were higher at 15 (P<0.054) and 45 min (P<0.03) after male introduction than before. By contrast, no change in NA could be detected in ewes implanted in the same region, but not responding to the ram, or in those showing increased LH pulsatility, but implanted in the anterior MPOA or in the ventromedial hypothalamus. No changes were observed in other neurotransmitters or when the ewes were exposed to male odour alone. These results suggest that NA release in the posterior MPOA is selectively involved in the triggering of LH secretion by rams in anoestrus ewes. PMID- 25839178 TI - Transport of three veterinary antimicrobials from feedlot pens via simulated rainfall runoff. AB - Veterinary antimicrobials are introduced to wider environments by manure application to agricultural fields or through leaching or runoff from manure storage areas (feedlots, stockpiles, windrows, lagoons). Detected in manure, manure-treated soils, and surface and ground water near intensive cattle feeding operations, there is a concern that environmental contamination by these chemicals may promote the development of antimicrobial resistance in bacteria. Surface runoff and leaching appear to be major transport pathways by which veterinary antimicrobials eventually contaminate surface and ground water, respectively. A study was conducted to investigate the transport of three veterinary antimicrobials (chlortetracycline, sulfamethazine, tylosin), commonly used in beef cattle production, in simulated rainfall runoff from feedlot pens. Mean concentrations of veterinary antimicrobials were 1.4 to 3.5 times higher in surface material from bedding vs. non-bedding pen areas. Runoff rates and volumetric runoff coefficients were similar across all treatments but both were significantly higher from non-bedding (0.53Lmin(-1); 0.27) than bedding areas (0.40Lmin(-1); 0.19). In keeping with concentrations in pen surface material, mean concentrations of veterinary antimicrobials were 1.4 to 2.5 times higher in runoff generated from bedding vs. non-bedding pen areas. Water solubility and sorption coefficient of antimicrobials played a role in their transport in runoff. Estimated amounts of chlortetracycline, sulfamethazine, and tylosin that could potentially be transported to the feedlot catch basin during a one in 100 year precipitation event were 1.3 to 3.6ghead(-1), 1.9ghead(-1), and 0.2ghead( 1), respectively. This study demonstrates the magnitude of veterinary antimicrobial transport in feedlot pen runoff and supports the necessity of catch basins for runoff containment within feedlots. PMID- 25839179 TI - Active moss biomonitoring for extensive screening of urban air pollution: Magnetic and chemical analyses. AB - In this study, active magnetic biomonitoring of moss for particulate air pollution and an assessment of heavy metals and polycyclic aromatic hydrocarbons (PAHs) were performed for the entire metropolitan area of Belgrade. Two mosses, Sphagnum girgensohnii (a species of the most recommended biomonitoring moss genus) and Hypnum cupressiforme (a common moss in the study area), were used. During the summer of 2013, moss bags were exposed at 153 sampling sites, forming a dense network of sites. A type II regression model was applied to test the interchangeable use of the two moss species. Significantly higher levels of all measured pollutants were recorded by S. girgensohnii in comparison with H. cupressiforme. Based on the results, the mosses could not be interchangeably used in urban areas, except for the biomonitoring of Cu. Nevertheless, according to the relative accumulation factors obtained for both moss species, similar city zones related to high, moderate and low levels of air pollution were distinguished. Moreover, new pollution hotspots, omitted by regulatory monitoring, were identified. The results demonstrate that moss magnetic analysis represents an effective first step for obtaining an overview of particulate air pollution before more expensive chemical analyses. Active moss biomonitoring could be applied as a pragmatic approach for optimizing the representativeness of regulatory monitoring networks. PMID- 25839180 TI - A Perioperative Evaluation of Respiratory Mechanics Using the Forced Oscillation Technique. AB - BACKGROUND: The forced oscillation technique is a new approach for assessing perioperative respiratory function. METHODS: This study enrolled 40 patients undergoing general anesthesia: 20 for >=2 hours and 20 for <2 hours. Respiratory parameters were measured the day before and after surgery using forced oscillation during normal tidal breathing. RESULTS: Respiratory resistance at 5 Hz (P = 0.029 with the Student t test with unequal variances and P = 0.033 with analysis of covariance) changed significantly in the patients who underwent procedures for which they were anesthetized for >2 hours. CONCLUSIONS: The forced oscillation technique is a clinical tool that can be used to assess the effects of perioperative ventilation strategies on respiratory mechanics. PMID- 25839181 TI - Prior Podcast Experience Moderates Improvement in Electroencephalography Evaluation After Educational Podcast Module. AB - BACKGROUND: There is continued interest in using technology to enhance medical education and the variables that may affect its success. METHODS: Anesthesiology residents and fourth-year medical students participated in an electroencephalography (EEG) educational video podcast module. A 25-item evaluation tool was administered before any EEG education was provided (baseline), and the podcast was then viewed. Another 25-item evaluation tool was administered after podcast viewing (after podcast). Ten EEG interpretations were completed with a neurophysiologist with an additional 25-item evaluation tool administered after the interpretations (after 10 EEG interpretations). Participants were surveyed concerning technology and podcasting experience before the educational module and their responses to the podcast educational model. Multiple analyses were performed (1) to evaluate differences in improvement in EEG evaluation scores between the podcast module and the standard didactics (control group); and (2) to evaluate potential moderation by technology and the podcast experience on the change in mean EEG evaluation scores from after the podcast module to after 10 EEG interpretations. RESULTS: A total of 21 anesthesiology residents and 12 fourth-year medical students participated. Scores on the 25-item evaluation tool increased with each evaluation time (P <= 0.001). Moderation analyses revealed that individuals with more podcast experience (>=4 previous podcasts) had greater increases in scores after a podcast and 10 EEG interpretations compared with individuals with less experience (<=3 previous podcasts) (P = 0.027). Furthermore, compared with a control group with similar baseline characteristics that received only standard didactics without a podcast, those in the podcast group had greater increases in mean EEG evaluation scores between baseline and after 10 EEG interpretations. CONCLUSIONS: In reviewing the improvement in EEG evaluation after a podcast education module, those with more podcast experience achieved greater gains in EEG evaluation scores. For EEG education, those receiving the podcast education module showed greater increases in scores compared with those receiving didactic teaching without podcasting, as measured by change in a mean EEG evaluation scores. PMID- 25839183 TI - Toxicity of two imidazolium ionic liquids, [bmim][BF4] and [omim][BF4], to standard aquatic test organisms: Role of acetone in the induced toxicity. AB - The main goal of this study was to investigate the toxicity of the imidazolium based ionic liquids (ILs), [bmim][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and [omim][BF4] (1-octyl-3-methylimidazolium tetrafluoroborate), in battery of standard aquatic toxicity test organisms. Specifically, exposure of the algae Scenedesmus rubescens, crustaceans Thamnocephalus platyurus and Artemia franciscana, rotifers Brachionus calyciflorus and Brachionus plicatilis and bivalve Mytilus galloprovincialis to different concentrations of [bmim][BF4], [omim][BF4] and/or a binary mixture of [bmim][BF4]-[omim][BF4] (1:1) with or without acetone (carrier solvent), revealed that solvent can differentially mediate ILs' toxic profile. Acetone's ability to differentially affect ILs' cation's alkyl chain length, as well as the hydrolysis of [BF4(-)] anions was evident. Given that the toxic potency of the tested ILs seemed to be equal or even higher (in some cases) than those of conventional organic solvents, the present study revealed that the characterization of imidazolium-based ILs as "green solvents" should not be generalized, at least in case of their natural occurrence in mixtures with organic solvents, such as acetone. PMID- 25839182 TI - Mechanistic Modeling of the Effects of Acidosis on Thrombin Generation. AB - BACKGROUND: Acidosis, a frequent complication of trauma and complex surgery, results from tissue hypoperfusion and IV resuscitation with acidic fluids. While acidosis is known to inhibit the function of distinct enzymatic reactions, its cumulative effect on the blood coagulation system is not fully understood. Here, we use computational modeling to test the hypothesis that acidosis delays and reduces the amount of thrombin generation in human blood plasma. Moreover, we investigate the sensitivity of different thrombin generation parameters to acidosis, both at the individual and population level. METHODS: We used a kinetic model to simulate and analyze the generation of thrombin and thrombin antithrombin complexes (TAT), which were the end points of this study. Large groups of temporal thrombin and TAT trajectories were simulated and used to calculate quantitative parameters, such as clotting time (CT), thrombin peak time, maximum slope of the thrombin curve, thrombin peak height, area under the thrombin trajectory (AUC), and prothrombin time. The resulting samples of parameter values at different pH levels were compared to assess the acidosis induced effects. To investigate intersubject variability, we parameterized the computational model using the data on clotting factor composition for 472 subjects from the Leiden Thrombophilia Study. To compare acidosis-induced relative parameter changes in individual ("virtual") subjects, we estimated the probabilities of relative change patterns by counting the pattern occurrences in our virtual subjects. Distribution overlaps for thrombin generation parameters at distinct pH levels were quantified using the Bhattacharyya coefficient. RESULTS: Acidosis in the range of pH 6.9 to 7.3 progressively increased CT, thrombin peak time, AUC, and prothrombin time, while decreasing maximum slope of the thrombin curve and thrombin peak height (P < 10). Acidosis delayed the onset and decreased the amount of TAT generation (P < 10). As a measure of intrasubject variability, maximum slope of the thrombin curve and CT displayed the largest and second largest acidosis-induced relative changes, and AUC displayed the smallest relative changes among all thrombin generation parameters in our virtual subject group (1-sided 95% lower confidence limit on the fraction of subjects displaying the patterns, 0.99). As a measure of intersubject variability, the overlaps between the maximum slope of the thrombin curve distributions at acidotic pH levels with the maximum slope of the thrombin curve distribution at physiological pH level systematically exceeded analogous distribution overlaps for CT, thrombin peak time, and prothrombin time. CONCLUSIONS: Acidosis affected all quantitative parameters of thrombin and TAT generation. While maximum slope of the thrombin curve showed the highest sensitivity to acidosis at the individual-subject level, it may be outperformed by CT, thrombin peak time, and prothrombin time as an indicator of acidosis at the subject-group level. PMID- 25839184 TI - Trichoderma inoculation augments grain amino acids and mineral nutrients by modulating arsenic speciation and accumulation in chickpea (Cicer arietinum L.). AB - Trichoderma reesei is an industrially important fungi which also imparts stress tolerance and plant growth promotion in various crops. Arsenic (As) contamination of field soils is one of the challenging problems in agriculture, posing potential threats for both human health and the environment. Plants in association with microbes are a liable method to improve metal tolerance and enhance crop productivity. Chickpea (Cicer arietinum L.), is an important grain legume providing cheap source of protein in semi-arid regions including As affected areas. In this study we report the role of T. reesei NBRI 0716 (NBRI 0716) in supporting chickpea growth and improving soil quality in As simulated conditions. NBRI 0716 modulated the As speciation and its availability to improve grain yield and quality (amino acids and mineral content) in chickpea (C. arietinum L.) plants grown in As spiked soil (100 mg As kg(-1) soil). Arsenic accumulation and speciation results indicate that arsenate [As(V)] was the dominant species in chickpea seeds and rhizosphere soil. The Trichoderma reduced total grain inorganic As (Asi) by 66% and enhanced dimethylarsonic acid (DMA) and monomethylarsinic acid (MMA) content of seed and rhizosphere soil. The results indicate a probable role of NBRI 0716 in As methylation as the possible mechanism for maneuvering As stress in chickpea. Analysis of functional diversity using carbon source utilization (Biolog) showed significant difference in diversity and evenness indices among the soil microbial rhizosphere communities. Microbial diversity loss caused by As were prevented in the presence of Trichoderma NBRI 0716. PMID- 25839185 TI - Development and evaluation of dexamethasone nanomicelles with potential for treating posterior uveitis after topical application. AB - PURPOSE: This study aims at the development and preliminary evaluation of dexamethasone nanomicelles for treating posterior uveitis. Nanomicelles were formulated using polyoxyl 40 stearate (P40S) and polysorbate 80 (P80), which are approved by the FDA for ocular use. METHODS: Dexamethasone nanomicelles were prepared and characterized for critical micellar concentration, solubility of dexamethasone, particle size, surface charge, morphology, in vitro drug release, clarity, stability, filtration efficiency, and sterility. Ocular tolerance and the tissue drug distribution of dexamethasone were assessed in rabbits after single and multiple topical administration. RESULTS: Dexamethasone nanomicelles (0.1% w/v) were successfully developed and characterized with an optimized composition of P40S/P80=7/3 by weight. The mean diameter of blank and drug-loaded nanomicelles was 13.3+/-0.4 and 14.5+/-0.4 nm, respectively. Transmission electron microscopy images revealed the spherical structure of nanomicelles. Nanomicelles were found to be stable with respect to clarity, size and drug content at 4 degrees C and 25 degrees C for up to 6 months. No irritation or redness was observed in the treated eyes as compared with the untreated control rabbit eyes. Therapeutic concentrations of dexamethasone were observed in the retina and choroid after single and multiple topical application in rabbits. CONCLUSION: In conclusion, the nanomicelles of P40S and P80 could efficiently solubilize 0.1% dexamethasone in their cores. The results also indicate that mixed nanomicelles could be utilized as a potential delivery system for delivering dexamethasone to treat the back of the eye diseases such as posterior uveitis after topical application. PMID- 25839187 TI - Vodka vs. Fortified Wine in Russia: Retrospective View. PMID- 25839188 TI - Out of the Water: Origin and Diversification of the LBD Gene Family. AB - LBD (lateral organ boundaries domain) genes are essential to the developmental programs of many fundamental plant organs and function in some of the basic metabolic pathways of plants. However, our historical perspective on the roles of LBD genes during plant evolution has, heretofore, been fragmentary. Here, we show that the LBD gene family underwent an initial radiation that established five gene lineages in the ancestral genome of most charophyte algae and land plants. By inference, the LBD gene family originated after the emergence of the green plants (Viridiplantae), but prior to the diversification of most extant streptophytes. After this initial radiation, we find limited instances of gene family diversification in land plants until successive rounds of expansion in the ancestors of seed plants and flowering plants. The most dynamic phases of LBD gene evolution, therefore, trace to the aquatic ancestors of embryophytes followed by relatively recent lineage-specific expansions on land. PMID- 25839189 TI - Proof of concept studies exploring the safety and functional activity of human parthenogenetic-derived neural stem cells for the treatment of Parkinson's disease. AB - Recent studies indicate that human pluripotent stem cell (PSC)-based therapies hold great promise in Parkinson's disease (PD). Clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD. However, the source of fetal tissue grafts is limited and ethically controversial. Human parthenogenetic stem cells offer a good alternative because they are derived from unfertilized oocytes without destroying viable human embryos and can be used to generate an unlimited supply of neural stem cells for transplantation. Here we evaluate for the first time the safety and engraftment of human parthenogenetic stem cell-derived neural stem cells (hpNSCs) in two animal models: 6-hydroxydopamine (6-OHDA)-lesioned rodents and 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates (NHPs). In both rodents and nonhuman primates, we observed successful engraftment and higher dopamine levels in hpNSC-transplanted animals compared to vehicle control animals, without any adverse events. These results indicate that hpNSCs are safe, well tolerated, and could potentially be a source for cell-based therapies in PD. PMID- 25839190 TI - Obesity-Associated Inflammatory Cytokines and Prostaglandin E2 Stimulate Glucose Transporter mRNA Expression and Glucose Uptake in Primary Human Adipose Stromal Cells. AB - Obesity is associated with chronic low-grade inflammation. This occurs largely as a result of the infiltration of immune cells within the obese adipose, which produce a number of inflammatory factors, including interleukin-6 (IL-6), IL 1beta, tumor necrosis factor-alpha (TNFalpha), and prostaglandin E(2) (PGE(2)). These factors have previously been shown to affect insulin-mediated glucose uptake in differentiated adipocytes. However, the insulin-independent effect of inflammation on adipocyte precursors, the adipose stromal cells, has not been explored. This study therefore aimed to examine the effect of obesity-associated inflammatory factors on the expression of insulin-independent glucose transporters (GLUT1 and GLUT3) and on the uptake of glucose within adipose stromal cells. Primary human subcutaneous adipose stromal cells were isolated from abdominoplasty, and the effect of inflammatory cytokines (IL-6, IL-1beta, and TNFalpha) and PGE(2) on GLUT mRNA expression and glucose transport was assessed using real-time polymerase chain reaction and radiolabeled deoxyglucose uptake assays, respectively. Results demonstrate that all four inflammatory mediators caused a dose-dependent increase in GLUT1 mRNA expression and glucose uptake. GLUT3 mRNA expression was also upregulated by IL-6 (0.5 ng/mL), TNFalpha (0.1 and 10 ng/mL), and PGE(2) (0.1 MUM). Overall, these results demonstrate that obesity-associated inflammation increases insulin-independent glucose transporter expression and glucose uptake in undifferentiated adipose stromal cells. PMID- 25839191 TI - Aerobic Oxidation of Cyclohexane on Catalysts Based on Twinned and Single-Crystal Au75Pd25 Bimetallic Nanocrystals. AB - Bimetallic Au75Pd25 nanocrystals with shapes of icosahedron and octahedron were synthesized by adding different amounts of iodide ions, and were employed as catalysts for solvent-free aerobic oxidation of cyclohexane. Although both icosahedrons and octahedrons were bounded by {111} facets, the turnover frequency number of Au75Pd25 icosahedrons reached 15,106 h(-1), almost three times as high as that of Au75Pd25 octahedrons. The conversion of cyclohexane reached 28.1% after 48 h using Au75Pd25 icosahedrons, with the selectivity of 84.3% to cyclohexanone. Density functional theory calculations along with X-ray photoelectron spectroscopy examinations reveal that the excellent catalytic performance of AuPd icosahedrons could be ascribed to twin-induced strain and highly negative charge density of Au atoms on the surface. PMID- 25839192 TI - Fluorescence signaling of hydrogen sulfide in broad pH range using a copper complex based on BINOL-benzimidazole ligands. AB - A weakly fluorescent complex derived from a binaphthol-benzimidazole ligand was designed and synthesized for hydrogen sulfide at different pH conditions. It was demonstrated that the probe showed the same reactivity to various hydrogen sulfide species in a broad range of pH values to generate highly fluorescent product through a displacement reaction mechanism, whereas the product's fluorescence spectrum exhibited a hypsochromic shift of ~73 nm (2393 cm(-1)) as pH increased from neutral to basic, which can be used for distinguishing the various species of hydrogen sulfide. This turn-on fluorescence probe was highly selective and sensitive to hydrogen sulfide with a detection limit of 0.11 MUM. It was then applied for evaluating the total content of sulfide (including hydrogen sulfide, hydrosulfide, and sulfide) as well as for the visual detection of gaseous H2S in air using a simple test paper strip. PMID- 25839193 TI - Dynamics of rhenium photocatalysts revealed through ultrafast multidimensional spectroscopy. AB - Rhenium catalysts have shown promise to promote carbon neutrality by reducing a prominent greenhouse gas, CO2, to CO and other starting materials. Much research has focused on identifying intermediates in the photocatalysis mechanism as well as time scales of relevant ultrafast processes. Recent studies have implemented multidimensional spectroscopies to characterize the catalyst's ultrafast dynamics as it undergoes the many steps of its photocycle. Two-dimensional infrared (2D IR) spectroscopy is a powerful method to obtain molecular structure information while extracting time scales of dynamical processes with ultrafast resolution. Many observables result from 2D-IR experiments including vibrational lifetimes, intramolecular redistribution time scales, and, unique to 2D-IR, spectral diffusion, which is highly sensitive to solute-solvent interactions and motional dynamics. Spectral diffusion, a measure of how long a vibrational mode takes to sample its frequency space due to multiple solvent configurations, has various contributing factors. Properties of the solvent, the solute's structural flexibility, and electronic properties, as well as interactions between the solvent and solute, complicate identifying the origin of the spectral diffusion. With carefully chosen experiments, however, the source of the spectral diffusion can be unveiled. Within the context of a considerable body of previous work, here we discuss the spectral diffusion of several rhenium catalysts at multiple stages in the catalysis. These studies were performed in multiple polar liquids to aid in discovering the contributions of the solvent. We also performed electronic ground state 2D-IR and electronic excited state transient-2D-IR experiments to observe how spectral diffusion changes upon electronic excitation. Our results indicate that with the original Lehn catalyst in THF, relative to the ground state, the spectral diffusion slows by a factor of 3 in the equilibrated triplet metal-to-ligand charge transfer state. We attribute this slowdown to a decrease in dielectric friction as well as an increase in molecular flexibility. It is possible to partially simulate the charge transfer by altering the electron density moderately by adding electron donating or withdrawing substituents symmetrically to the bipyridine ligand. We find that unlike the significant electronic structure change induced by MLCT, such small substituent effects do not influence the spectral diffusion. A solvent study in THF, DMSO, and CH3CN found there to be an explicit solvent dependence that we can correlate to the solvent donicity, which is a measure of its nucleophilicity. Future studies focused on the solvent effects on spectral diffusion in the crucial photoinitiated state can illuminate the role the solvent plays in the catalysis. PMID- 25839194 TI - Hollow V2O5 Nanoassemblies for High-Performance Room-Temperature Hydrogen Sensors. AB - Nanostructured oxides with characteristic morphologies are essential building blocks for high-performance gas-sensing devices. We describe the high-yield fabrication of a series of functionalized V2O5 nanoassemblies through a facile polyol approach with specific varieties of polyvinylpyrrolidone. The synthesized V2O5 nanoassemblies consisting of tiny one-dimensional nanoblocks with the absence of any extrinsic catalysts exhibit distinct hemispherical or spherical hollow morphologies and operate as room-temperature hydrogen sensors with remarkable sensitivities and responses. PMID- 25839195 TI - Immunoexpression of tenascin as a predictor of the malignancy potential of oral leukoplakia associated with a tobacco habit. AB - Oral leukoplakia is a morphological alteration of tissue that is an early indicator for malignancy. Tenascin (TN) is a large hexameric extracellular matrix (ECM) protein with anti-adhesive properties that fosters cell migration during development, wound healing and tissue remodeling; it is present in small amounts in adult tissues. Overexpression of TN in a pathological condition may be either a cause or a consequence of the disease. We evaluated the efficacy of TN for early prediction of tobacco-associated oral cancers. We studied retrospectively 95 cases of oral leukoplakia, including mild, moderate and severe cases, using immunohistochemistry for TN. We evaluated the intensity, area and pattern of TN expression. Greater intensity and area of TN expression was observed in mild and severe dysplasia than in moderate dysplasia. Most cases showed a reticular pattern of expression, especially in mild and moderate dysplasia; a fibrillar pattern was more evident in severe dysplasia. We also observed homogeneous expression pattern in some cases. TN is a marker for dysplastic changes in epithelium and its expression may be helpful for predicting the malignancy potential of tobacco-associated oral leukoplakia. PMID- 25839196 TI - Saving lives by building bridges between user needs and clean cooking technology. PMID- 25839197 TI - Behavior change communication: a key ingredient for advancing clean cooking. PMID- 25839198 TI - Quantitative stove use and ventilation guidance for behavior change strategies. AB - Achieving World Health Organization air quality targets and aspirational fuel savings targets through clean cooking solutions will require high usage rates of high-performing products and low usage rates of traditional stoves. Catalyzing this shift is challenging as fuel and stove use practices associated with new technologies generally differ from those used with traditional technologies. Accompanying this shift with ventilation improvements can help further reduce exposure to emissions of health damaging pollutants. Behavior change strategies will be central to these efforts to move users to new technologies and minimize exposure to emissions. In this article, the authors show how behavior change can be linked to quantitative guidance on stove usage, household ventilation rates, and performance. The guidance provided here can help behavior change efforts in the household energy sector set and achieve quantitative goals for usage and ventilation rates. PMID- 25839199 TI - Advocate program for healthy traditional houses, Ume Kbubu, in a Timor community: preserving traditional behavior and promoting improved health outcomes. AB - Families in the Timor society of Indonesia have customarily used traditional houses, called Ume Kbubu, for confinement practices of a newborn baby and the mother during the first 40 days after birth. The practice, known as Sei (smoke) tradition, involves retaining heat, which is believed to foster healing, inside the house by continuously burning a wood burning stove. Exacerbated by inadequate ventilation in the traditional house, this practice results in poor indoor air quality and negatively affects the health of the mother and baby. Preliminary findings from a baseline study conducted in 2009 identified high levels of indoor air pollution in Ume Kbubu where mothers practiced the Sei tradition. Many respondents expressed that they suffered from respiratory health problems during the practice. On the basis of those results, a follow-up study was conducted in 2011 to develop and test a communication-focused behavior change intervention that would foster conversion of traditional houses into healthy Ume Kbubu and promote changes to traditional practices for better health outcomes. The study suggests that redesigning an Ume Kbubu house could promote better air quality inside the house and involving the community in the health intervention program led to positive changes in the Sei practice (i.e., decreasing the Sei period's length from 40 days to 4 days on average and attempting to reduce household air pollution). The study resulted in several recommendations in relation to sustained transformation to improve health behaviors. PMID- 25839200 TI - Understanding consumer preference and willingness to pay for improved cookstoves in Bangladesh. AB - The USAID/WASHplus project conducted a comprehensive assessment to understand consumer needs and preferences as they relate to increasing the uptake and consistent, exclusive, and correct use of improved cookstoves (ICSs) in Bangladesh. The assessment included household ICS trials, fuel and stove use monitoring, and consumers' perceived value of and willingness to pay for ICSs. Results showed that cooks appreciated and liked the ICS, but that no models met consumer needs sufficiently to replace traditional stoves. Initially, many preferred ICSs over traditional stoves, but this preference decreased over the 3 week trial period. Complaints and suggestions for improvement fell into two general categories: those that can be addressed through fairly simple modifications to the stove design, and those more appropriately addressed through point-of-purchase consumer education and follow-up from service agents or health outreach workers. Most households using the ICS realized fuel use reductions, although these were lower than expected, partly because of continued parallel traditional stove use. When given the option to purchase the stoves at market value, only one of 105 households did so; however, a separate assessment showed that 80% of participants (12 of 15 households) preferred to keep the stove rather than receive a cash buyout at market value. This indicates that users value the ICS when acquisition barriers are removed and highlights the need for better financing options. PMID- 25839201 TI - Piloting improved cookstoves in India. AB - Despite the potential of improved cookstoves to reduce the adverse environmental and health impacts of solid fuel use, their adoption and use remains low. Social marketing-with its focus on the marketing mix of promotion, product, price, and place-offers a useful way to understand household behaviors and design campaigns to change biomass fuel use. We report on a series of pilots across 3 Indian states that use different combinations of the marketing mix. We find sales varying from 0% to 60%. Behavior change promotion that combined door-to-door personalized demonstrations with information pamphlets was effective. When given a choice amongst products, households strongly preferred an electric stove over improved biomass-burning options. Among different stove attributes, reduced cooking time was considered most valuable by those adopting a new stove. Households clearly identified price as a significant barrier to adoption, while provision of discounts (e.g., rebates given if households used the stove) or payments in installments were related to higher purchase. Place-based factors such as remoteness and nongovernmental organization operations significantly affected the ability to supply and convince households to buy and use improved cookstoves. Collectively, these pilots point to the importance of continued and extensive testing of messages, pricing models, and different stove types before scale-up. Thus, we caution that a one-size-fits-all approach will not boost improved cookstove adoption. PMID- 25839202 TI - Use of behavior change techniques in clean cooking interventions: a review of the evidence and scorecard of effectiveness. AB - Despite decades of effort, around 2.8 billion people still rely on solid fuels to meet domestic energy needs. There is robust evidence this causes premature death and chronic disease, as well as wider economic, social, and environmental problems. Behavior change interventions are effective to reduce exposure to harm such as household air pollution, including those using health communications approaches. This article reports the findings of a project that reviewed the effectiveness of behavior change approaches in cleaner cooking interventions in resource-poor settings. The authors synthesized evidence of the use of behavior change techniques, along the cleaner cooking value chain, to bring positive health, economic, and environmental impacts. Forty-eight articles met the inclusion criteria, which documented 55 interventions carried out in 20 countries. The groupings of behavior change techniques most frequently used were shaping knowledge (n = 47), rewards and threats (n = 35), social support (n = 35), and comparisons (n = 16). A scorecard of behavior change effectiveness was developed to analyze a selection of case study interventions. Behavior change techniques have been used effectively as part of multilevel programs. Cooking demonstrations, the right product, and understanding of the barriers and benefits along the value chain have all played a role. Often absent are theories and models of behavior change adapted to the target audience and local context. Robust research methods are needed to track and evaluate behavior change and impact, not just technology disseminated. Behavior change approaches could then play a more prominent role as the "special sauce" in cleaner cooking interventions in resource poor settings. PMID- 25839203 TI - Does peer use influence adoption of efficient cookstoves? Evidence from a randomized controlled trial in Uganda. AB - The authors examined the effect of peer usage on consumer demand for efficient cookstoves with a randomized controlled trial in rural Uganda. The authors tested whether the neighbors of buyers who ordered and received a stove are more likely to purchase an efficient cookstove than the neighbors of buyers who ordered but have not yet received a stove. The authors found that neighbors of buyers who have experience with the stove are not detectably more likely to purchase a stove than neighbors of buyers who have not yet received their stove. The authors found evidence of peer effects in opinions about efficient cookstoves. Knowing that a prominent member of the community has the efficient stove predicts 17-22 percentage points higher odds of strongly favoring the stove. However, this more favorable opinion seemingly has no effect on purchase decisions. PMID- 25839204 TI - Agency-based empowerment training enhances sales capacity of female energy entrepreneurs in Kenya. AB - Globally, women's involvement in clean cooking value chains has been minimal. This is partly because of the multiple challenges faced by women that impede their capacity to effectively engage in the energy sector. To better discern gender-specific differences in involvement in the energy sector, the authors conducted a randomized trial in Kenya to compare sales performance of newly trained male and female improved cookstove entrepreneurs and to test the effects of an agency-based empowerment training on business activity. A total of 257 entrepreneurs completed either a 4-day entrepreneurial training (control) or a 4 day empowerment training (intervention) and were followed for nearly 8 months documenting business activity and sales. The empowerment training led to more than doubling of sales for both genders. In addition, participants in the intervention group were significantly more likely to demonstrate business commitment over time and nearly three times more likely to be higher sellers (relative risk = 2.7, 95% CI [1.4, 5.4]), controlling for gender and rural/urban locale. Women outsold men by a margin of nearly 3 to 1 and were more likely to continue to pursue leads despite limited sales. Nonactive participants (those selling 1 improved cookstove or less) were a larger percentage of the control group (72%) than the intervention group (50%), and more men were nonactive participants (65% of men) compared with women (56% of women).These data show that women can serve as active improved cookstove entrepreneurs in both urban and rural settings and that targeted agency-based empowerment training can significantly increase women's capacity to engage effectively within the improved cookstove value chain. PMID- 25839205 TI - Factors influencing the acquisition and correct and consistent use of the top-lit updraft cookstove in Uganda. AB - This study looked at the effects of select behavior change interventions on the purchase and the correct and consistent use of a locally fabricated top-lit updraft (TLUD) stove in Uganda. Behavior change interventions included training of community sales agents and village health team volunteers on household air pollution and correct use, referral of interested community members to sales agents, community cooking demonstrations, information flyers, and direct sales of TLUDs and processed wood. Qualitative and quantitative research methods shaped interventions and were used to understand attitudes and practices related to TLUD stove acquisition and use. Results showed that TLUDs were appreciated because they use wood efficiently, cook quickly, reduce smoke, and produce charcoal. However, the substantial purchase price barrier, combined with the cost of processed wood, effectively eliminated the cost savings from its significant fuel efficiency. This made it difficult for the TLUD to be a meaningful part of most households' cooking practices. PMID- 25839206 TI - The role of mixed methods in improved cookstove research. AB - The challenge of promoting access to clean and efficient household energy for cooking and heating is a critical issue facing low- and middle-income countries today. Along with clean fuels, improved cookstoves (ICSs) continue to play an important part in efforts to reduce the 4 million annual premature deaths attributed to household air pollution. Although a range of ICSs are available, there is little empirical evidence on appropriate behavior change approaches to inform adoption and sustained used at scale. Specifically, evaluations using either quantitative or qualitative methods provide an incomplete picture of the challenges in facilitating ICS adoption. This article examines how studies that use the strengths of both these approaches can offer important insights into behavior change in relation to ICS uptake and scale-up. Epistemological approaches, study design frameworks, methods of data collection, analytical approaches, and issues of validity and reliability in the context of mixed methods ICS research are examined, and the article presents an example study design from an evaluation study in Kenya incorporating a nested approach and a convergent case oriented design. The authors discuss the benefits and methodological challenges of mixed-methods approaches in the context of researching behavior change and ICS use recognizing that such methods represent relatively uncharted territory. The authors propose that more published examples are needed to provide frameworks for other researchers seeking to apply mixed methods in this context and suggest a comprehensive research agenda is required that incorporates integrated mixed-methods approaches, to provide best evidence for future scale-up. PMID- 25839207 TI - Integrating behavior change theory and measures into health-based cookstove interventions: a proposed epidemiologic research agenda. PMID- 25839208 TI - Validation of an innovative method, based on tilt sensing, for the assessment of activity and body position. AB - Since there is less movement during sleep than during wake, the recording of body movements by actigraphy has been used to indirectly evaluate the sleep-wake cycle. In general, most actigraphic devices are placed on the wrist and their measures are based on acceleration detection. Here, we propose an alternative way of measuring actigraphy at the level of the arm for joint evaluation of activity and body position. This method analyzes the tilt of three axes, scoring activity as the cumulative change of degrees per minute with respect to the previous sampling, and measuring arm tilt for the body position inference. In this study, subjects (N = 13) went about their daily routine for 7 days, kept daily sleep logs, wore three ambulatory monitoring devices and collected sequential saliva samples during evenings for the measurement of dim light melatonin onset (DLMO). These devices measured motor activity (arm activity, AA) and body position (P) using the tilt sensing of the arm, with acceleration (wrist acceleration, WA) and skin temperature at wrist level (WT). Cosinor, Fourier and non-parametric rhythmic analyses were performed for the different variables, and the results were compared by the ANOVA test. Linear correlations were also performed between actimetry methods (AA and WA) and WT. The AA and WA suitability for circadian phase prediction and for evaluating the sleep-wake cycle was assessed by comparison with the DLMO and sleep logs, respectively. All correlations between rhythmic parameters obtained from AA and WA were highly significant. Only parameters related to activity levels, such as mesor, RA (relative amplitude), VL5 and VM10 (value for the 5 and 10 consecutive hours of minimum and maximum activity, respectively) showed significant differences between AA and WA records. However, when a correlation analysis was performed on the phase markers acrophase, mid-time for the 10 consecutive hours of highest (M10) and mid-time for the five consecutive hours of lowest activity (L5) with DLMO, all of them showed a significant correlation for AA (R = 0.607, p = 0.028; R = 0.582, p = 0.037; R = 0.620, p = 0.031, respectively), while for WA, only acrophase did (R = 0.621, p = 0.031). Regarding sleep detection, WA showed higher specificity than AA (0.95 +/- 0.01 versus 0.86 +/- 0.02), while the agreement rate and sensitivity were higher for AA (0.76 +/- 0.02 versus 0.66 +/- 0.02 and 0.71 +/- 0.03 versus 0.53 +/- 0.03, respectively). Cohen's kappa coefficient also presented the highest values for AA (0.49 +/- 0.04) and AP (0.64 +/- 0.04), followed by WT (0.45 +/- 0.06) and WA (0.37 +/- 0.04). The findings demonstrate that this alternative actigraphy method (AA), based on tilt sensing of the arm, can be used to reliably evaluate the activity and sleep-wake rhythm, since it presents a higher agreement rate and sensitivity for detecting sleep, at the same time allows the detection of body position and improves circadian phase assessment compared to the classical actigraphic method based on wrist acceleration. PMID- 25839209 TI - Integrating tunable anion exchange with reverse osmosis for enhanced recovery during inland brackish water desalination. AB - For inland brackish water desalination by reverse osmosis or RO, concentrate or reject disposal poses a major challenge. However, enhanced recovery and consequent reduction in the reject volume using RO processes is limited by the solubility of ions present in the feedwater. One of the most common and stubborn precipitate formed during desalination is calcium sulfate. Reducing or eliminating the presence of sulfate would allow the process to operate at higher recoveries without threat to membrane scaling. In this research, this goal is accomplished by using an appropriate mixture of self-regenerating anion exchange resins that selectively remove and replace sulfate by chloride prior to the RO unit. Most importantly, the mixed bed of anion exchange resins is self regenerated with the reject brine from the RO process, thus requiring no addition of external chemicals. The current work demonstrates the reversibility of the hybrid ion exchange and RO (HIX-RO) process with 80% recovery for a brackish water composition representative of groundwater in San Joaquin Valley in California containing approximately 5200 mg/L of total dissolved solids or TDS. Consequently, the reject volume can be reduced by 50% without the threat of sulfate scaling and use of antiscaling chemicals can be eliminated altogether. By appropriately designing or tuning the mixed bed of anion exchange resins, the process can be extended to nearly any composition of brackish water for enhanced recovery and consequent reduction in the reject volume. PMID- 25839210 TI - Dissociation of equimolar mixtures of aqueous carboxylic acids in ionic liquids: role of specific interactions. AB - Hammett acidity function observes the effect of protonation/deprotonation on the optical density/absorbance of spectrophotometric indicator. In this work, the Hammett acidity, H0, of equimolar mixtures of aqueous HCOOH, CH3COOH, and CH3CH2COOH was measured in 1-methylimidazolium-, 1-methylpyrrolidinium-, and 1 methylpiperidinium-based protic ionic liquids (PILs) and 1-butyl-3 methylimidazolium-based aprotic ionic liquid (AIL) with formate (HCOO(-)) anion. Higher H0 values were observed for the equimolar mixtures of aqueous carboxylic acids in protic ionic liquids compared with those of the aprotic ionic liquid because of the involvement of the stronger specific interactions between the conjugate acid of ionic liquid and conjugate base of carboxylic acids as suggested by the hard-soft acid base (HSAB) theory. The different H0 values for the equimolar mixtures of aqueous carboxylic acids in protic and aprotic ionic liquids were noted to depend on the activation energy of proton transfer (Ea,H(+)). The higher activation energy of proton transfer was obtained in AIL, indicating lower ability to form specific interactions with solute than that of PILs. Thermodynamic parameters determined by the "indicator overlapping method" further confirmed the involvement of the secondary interactions in the dissociation of carboxylic acids. On the basis of the thermodynamic parameter values, the potential of different ionic liquids in the dissociation of carboxylic acids was observed to depend on the hydrogen bond donor acidity (alpha) and hydrogen bond acceptor basicity (beta), characteristics of specific interactions. PMID- 25839211 TI - The discovery of a novel route to highly substituted alpha-tropolones enables expedient entry to the core of the gukulenins. AB - A simple and general method for the synthesis of highly substituted alpha tropolone ethers that allows rapid access to the bis(tropolone) core of the antiproliferative metabolites (-)-gukulenins A and F (3, 4) is described. The reaction proceeds by thermolytic opening of gem-dibromobicyclo[4.1.0]heptane intermediates, which are readily accessed from simple starting materials. Mechanistic studies suggest the reaction proceeds via an autocatalytic process mediated by methyl hypobromite. This synthetic sequence allows access to a broad array of highly substituted alpha-tropolones. PMID- 25839212 TI - Addition to chabazite: stable cation-exchanger in hyper alkaline concrete pore water. PMID- 25839213 TI - Effects of diet quality on vulnerability to mild subchronic social defeat stress in mice. AB - OBJECTIVES: The chronic social defeat stress (CSDS) mouse model is a potentially useful system for understanding stress responses to social environments. We previously developed a mouse model of subchronic and mild social defeat stress (sCSDS) that exhibits increased body weight gain and food intake following polydipsia-like features. sCSDS mice also show avoidance behavior in a social interaction test. In this study, we examined the effects of diet quality on susceptibility to sCSDS by feeding these mice semi- and non-purified diets. METHODS: Male C57BL/6J (B6; n = 82) mice were exposed to sCSDS using male ICR mice. The B6 mice were divided into four test groups: semi-purified pellet diet + sCSDS, non-purified pellet diet + sCSDS, semi-purified diet + control (no sCSDS), and non-purified diet + control. RESULTS: Although increased body weight, and food and water intake following sCSDS exposure were consistently observed in the groups that were fed semi- and non-purified diets, social avoidance behavior was influenced by food type (i.e., sCSDS mice fed semi-purified diet showed the greatest social avoidance behavior). In addition, the rates of stress susceptibility were estimated at 73.9 and 34.8% in sCSDS mice fed semi-purified and non-purified diets, respectively (P < 0.05). For comparison, the susceptible like phenotype rates were estimated at 12.5 and 8.3% in healthy control mice fed semi-purified and non-purified diets, respectively. DISCUSSION: These results suggest that diet quality affects the vulnerability of mice to social defeat stress. PMID- 25839214 TI - The Impact of Social Support and Attachment Style on Quality of Life and Readiness to Change in a Sample of Individuals Receiving Medication-Assisted Treatment for Opioid Dependence. AB - BACKGROUND: A basic principle within the addictions treatment field is that social support is a vital ingredient in the recovery process. This study examines the nature of social support in a sample of opioid-dependent men and women who are currently being treated in a medication-assisted treatment program (methadone). This research examines the types of social support behaviors that the opioid-dependent individuals consider helpful and explores whether attachment style (i.e., secure, ambivalent, or anxious attachment) was a determining factor in whether social support was perceived as helpful. The dependent variables included readiness to change addictive behaviors and abstinence from other mood altering drugs. METHODS: Participants (N = 159) completed a demographic questionnaire, the Significant Others Scale, the Experiences in Close Relationships Scale, the Multidimensional Scale of Perceived Social Support Assessment, the Readiness to Change Scale, and an Attachment Style Questionnaire. The demographic questionnaire included subjective ratings of self-improvement. RESULTS: Social support predicted perceived improvement in all of the areas examined (e.g., health, family/social relationships) and abstinence; however, attachment style did not predict improvement or with readiness to change. CONCLUSIONS: Social support is an important factor in one's recovery from substance use disorders. Yet attachment style (i.e., anxious, avoidant, or secure) did not predict abstinence or overall improvement in functioning. PMID- 25839215 TI - Letter from the editor. PMID- 25839217 TI - Biodegradable polymeric microsphere-based vaccines and their applications in infectious diseases. AB - Vaccination, which provides effective, safe infectious disease protection, is among the most important recent public health and immunological achievements. However, infectious disease remains the leading cause of death in developing countries because several vaccines require repeated administrations and children are often incompletely immunized. Microsphere-based systems, providing controlled release delivery, can obviate the need for repeat immunizations. Here, we review the function of sustained and pulsatile release of biodegradable polymeric microspheres in parenteral and mucosal single-dose vaccine administration. We also review the active-targeting function of polymeric particles. With their shield and co-delivery functions, polymeric particles are applied to develop single-dose and mucosally administered vaccines as well as to improve subunit vaccines. Because polymeric particles are easily surface-modified, they have been recently used in vaccine development for cancers and many infectious diseases without effective vaccines (e.g., human immunodeficiency virus infection). These polymeric particle functions yield important vaccine carriers and multiple benefits. PMID- 25839218 TI - Letter to the editor: Fatal varicella due to the vaccine-strain varicella-zoster virus. PMID- 25839219 TI - Successful therapy with bevacizumab in a case of hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT), genetic disorder manifested by uncontrolled multisystem angiogenesis with epistaxis, gastrointestinal bleeding, iron-deficiency anaemia, and arteriovenous malformations (AVM) is often related with increased levels of vascular endothelial growth factor (VEGF). Bevacizumab, a VEGF inhibitor, reduces epistaxis, telangiectasias, and iron-deficiency anaemia. A case of a female patient with HHT and chronic gastrointestinal bleeding is presented. The patient required iron supplementation and multiple blood transfusions. Bevacizumab brought marked symptomatic improvement and allowed for transfusion-independence. It is intended to apply for approval of the indications for bevacizumab administration in HHT as the 'orphan drug'. PMID- 25839220 TI - Type I interferon related genes are common genes on the early stage after vaccination by meta-analysis of microarray data. AB - The objective of this study was to find common immune mechanism across different kinds of vaccines. A meta-analysis of microarray datasets was performed using publicly available microarray Gene Expression Omnibus (GEO) and Array Express data sets of vaccination records. Seven studies (out of 35) were selected for this meta-analysis. A total of 447 chips (145 pre-vaccination and 302 post vaccination) were included. Significance analysis of microarrays (SAM) program was used for screening differentially expressed genes (DEGs). Functional pathway enrichment for the DEGs was conducted in DAVID Gene Ontology (GO) database. Twenty DEGs were identified, of which 10 up-regulated genes involved immune response. Six of which were type I interferon (IFN) related genes, including LY6E, MX1, OAS3, IFI44L, IFI6 and IFITM3. Ten down-regulated genes mainly mediated negative regulation of cell proliferation and cell motion. Results of a subgroup analysis showed that although the kinds of genes varied widely between days 3 and 7 post vaccination, the pathways between them are basically the same, such as immune response and response to viruses, etc. For an independent verification of these 6 type I IFN related genes, peripheral blood mononuclear cells (PBMCs) were collected at baseline and day 3 after the vaccination from 8 Enterovirus 71(EV71) vaccinees and were assayed by RT-PCR. Results showed that the 6 DEGs were also upregulated in EV71 vaccinees. In summary, meta-analysis methods were used to explore the immune mechanism of vaccines and results indicated that the type I IFN related genes and corresponding pathways were common in early immune responses for different kinds of vaccines. PMID- 25839221 TI - A multi-head intradermal electroporation device allows for tailored and increased dose DNA vaccine delivery to the skin. AB - The identification of an effective and tolerable delivery method is a necessity for the success of DNA vaccines in the clinic. This article describes the development and validation of a multi-headed intradermal electroporation device which would be applicable for delivering multiple DNA vaccine plasmids simultaneously but spatially separated. Reporter gene plasmids expressing green and red fluorescent proteins were used to demonstrate the impact of spatial separation on DNA delivery to increase the number of transfected cells and avoid interference through visible expression patterns. To investigate the impact of plasmid interference on immunogenicity, a disease target was investigated where issues with multi-valent vaccines had been previously described. DNA-based Hantaan and Puumala virus vaccines were delivered separately or as a combination and the effect of multi-valence was determined by appropriate assays. While a negative impact was observed for both antigenic vaccines when delivered together, these effects were mitigated when the vaccine was delivered using the multi-head device. We also demonstrate how the multi-head device facilitates higher dose delivery to the skin resulting in improved immune responses. This new multi-head platform device is an efficient, tolerable and non-invasive method to deliver multiple plasmid DNA constructs simultaneously allowing the tailoring of delivery sites for combination vaccines. Additionally, this device would allow the delivery of multi-plasmid vaccine formulations without risk of impacted immune responses through interference. Such a low-cost, easy to use device platform for the delivery of multi-agent DNA vaccines would have direct applications by the military and healthcare sectors for mass vaccination purposes. PMID- 25839222 TI - In silico design of a DNA-based HIV-1 multi-epitope vaccine for Chinese populations. AB - The development of an HIV-1 vaccine that is capable of inducing effective and broadly cross-reactive humoral and cellular immune responses remains a challenging task because of the extensive diversity of HIV-1, the difference of virus subtypes (clades) in different geographical regions, and the polymorphism of human leukocyte antigens (HLA). We performed an in silico design of 3 DNA vaccines, designated pJW4303-MEG1, pJW4303-MEG2 and pJW4303-MEG3, encoding multi epitopes that are highly conserved within the HIV-1 subtypes most prevalent in China and can be recognized through HLA alleles dominant in China. The pJW4303 MEG1-encoded protein consisted of one Th epitope in Env, and one, 2, and 6 epitopes in Pol, Env, and Gag proteins, respectively, with a GGGS linker sequence between epitopes. The pJW4303-MEG2-encoded protein contained similar epitopes in a different order, but with the same linker as pJW4303-MEG1. The pJW4303-MEG3 encoded protein contained the same epitopes in the same order as that of pJW4303 MEG2, but with a different linker sequence (AAY). To evaluate immunogenicity, mice were immunized intramuscularly with these DNA vaccines. Both pJW4303-MEG1 and pJW4303-MEG2 vaccines induced equally potent humoral and cellular immune responses in the vaccinated mice, while pJW4303-MEG3 did not induce immune responses. These results indicate that both epitope and linker sequences are important in designing effective epitope-based vaccines against HIV-1 and other viruses. PMID- 25839224 TI - Conformational stability and intramolecular hydrogen bonding in 1,2-ethanediol and 1,4-butanediol. AB - The gas-phase infrared spectra of 1,2-ED and 1,4-BD have been recorded at three different temperatures using a multipass gas cell of 6 m optical path length. DFT calculation has also been carried out using 6-311++G** and aug-cc-pVDZ basis sets to look for the existence of intramolecular hydrogen bonding in them from the red shift and infrared absorption intensity enhancement of the bonded O-H band compared to that of the free O-H band. Equilibrium population analysis with 10 conformers of 1,2-ED and 1,4-BD at experimental temperatures were carried out for the reconstruction of the observed vibrational spectra at that temperature using standard statistical relationships. The most abundant conformer at experimental temperatures was identified. In 1,2-ED a red shift of 45 cm(-1) in the intramolecularly interacting O-H stretching vibrational band position and no significant intensity enhancement compared to that of the free O-H have been observed. On the contrary, in one of the hydrogen-bonded conformers of 1,4-BD, a 124 cm(-1) red shift in the O-H stretching frequency and a 8.5 times intensity enhancement for the "bonded" O-H compared to that of the "free" O-H is seen. On the basis of this comparative study, we have concluded that strong intramolecular hydrogen bonding exists in 1,4-BD. But there appears to be weak intramolecular hydrogen bonding in 1,2-ED at temperatures of 303, 313, and 323 K in the gas phase. We have found that most stable hydrogen-bonded conformers of 1,4-BD are less populated than some of the non-hydrogen-bonded conformers. Even for the 1,4 BD, the relative population of the g'GG'Gt conformer, which has a strong intramolecular hydrogen bond, is less than what is predicted. Perhaps the intramolecular hydrogen bond plays a less significant role in the relative stability of the various conformers than what has been predicted from calculations and prevails in the literature. PMID- 25839223 TI - Quantitative proteomics using ultralow flow capillary electrophoresis-mass spectrometry. AB - In this work, we evaluate the incorporation of an ultralow flow interface for coupling capillary electrophoresis (CE) and mass spectrometry (MS), in combination with reversed-phase high-pressure liquid chromatography (HPLC) fractionation as an alternate workflow for quantitative proteomics. Proteins, extracted from a SILAC (stable isotope labeling by amino acids in cell culture) labeled and an unlabeled yeast strain were mixed and digested enzymatically in solution. The resulting peptides were fractionated using RP-HPLC and analyzed by CE-MS yielding a total of 28 538 quantified peptides that correspond to 3 272 quantified proteins. CE-MS analysis was performed using a neutral capillary coating, providing the highest separation efficiency at ultralow flow conditions (<10 nL/min). Moreover, we were able to demonstrate that CE-MS is a powerful method for the identification of low-abundance modified peptides within the same sample. Without any further enrichment strategies, we succeeded in quantifying 1 371 phosphopeptides present in the CE-MS data set and found 49 phosphopeptides to be differentially regulated in the two yeast strains. Including acetylation, phosphorylation, deamidation, and oxidized forms, a total of 8 106 modified peptides could be identified in addition to 33 854 unique peptide sequences found. The work presented here shows the first quantitative proteomics approach that combines SILAC labeling with CE-MS analysis. PMID- 25839225 TI - Wide-scale quantitative phosphoproteomic analysis reveals that cold treatment of T cells closely mimics soluble antibody stimulation. AB - The activation of T lymphocytes through antigen-mediated T cell receptor (TCR) clustering is vital in regulating the adaptive immune response. Although T cell receptor signaling has been extensively studied, the fundamental mechanisms for signal initiation are not fully understood. Reduced temperatures have initiated some of the hallmarks of TCR signaling, such as increased phosphorylation and activation on ERK and calcium release from the endoplasmic reticulum, as well as coalesced the T cell membrane microdomains. The precise mechanism of the TCR signaling initiation due to temperature change remains obscure. One critical question is whether the signaling initiated by the cold treatment of T cells differs from the signaling initiated by the cross-linking of the T cell receptor. To address this uncertainty, we performed a wide-scale, quantitative mass spectrometry-based phosphoproteomic analysis on T cells stimulated either by temperature shifts or through the cross-linking of the TCR. Careful statistical comparisons between the two stimulations revealed a striking level of identity among the subset of 339 sites that changed significantly with both stimulations. This study demonstrates for the first time, in unprecedented detail, that T cell cold treatment was sufficient to initiate signaling patterns that were nearly identical to those of soluble antibody stimulation, shedding new light on the mechanism of activation of these critically important immune cells. PMID- 25839226 TI - Effects of heating temperature and duration by gold nanorod mediated plasmonic photothermal therapy on copolymer accumulation in tumor tissue. AB - Previously, water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been used with gold nanorod (GNR) mediated plasmonic photothermal therapy (PPTT) to induce hyperthermia (43 degrees C for 10 min) and have been shown to improve delivery of hydrophobic drugs to treat cancer. However, it was unknown how altering the heating parameters (temperature and duration) of PPTT would affect HPMA copolymer accumulation and retention. This study aimed to investigate how changes in heating parameters, or thermal dose, would change polymer accumulation profiles with PPTT. It was observed that temperatures of either 40, 43, 46, or 49 degrees C at durations of 10 or 30 min had significant effects on HPMA copolymer accumulation. Mild temperatures led to transient enhancement in accumulation, but more severe temperatures led to tissue and vascular damage, creating slowed dynamics of inflow and outflow of the polymers from the tumor tissue. PMID- 25839227 TI - "We Haven't Got a Prayer" (Or Much of Anything Else for That Matter). PMID- 25839228 TI - Roles of kinins in the nervous system. AB - The kallikrein-kinin system (KKS) is an endogenous pathway involved in many biological processes. Although primarily related to blood pressure control and inflammation, its activation goes beyond these effects. Neurogenesis and neuroprotection might be stimulated by bradykinin being of great interest for clinical applications following brain injury. This peptide is also an important player in spinal cord injury pathophysiology and recovery, in which bradykinin receptor blockers represent substantial therapeutic potential. Here, we highlight the participation of kinin receptors and especially bradykinin in mediating ischemia pathophysiology in the central and peripheral nervous systems. Moreover, we explore the recent advances on mechanistic and therapeutic targets for biological, pathological, and neural repair processes involving kinins. PMID- 25839229 TI - Interferon-gamma Decreases Nuclear Localization of Pdx-1 and Triggers beta-Cell Dysfunction in Chronic Pancreatitis. AB - Interferon-gamma (IFN-gamma) is shown to play a major role in beta-cell dysfunction in chronic pancreatitis (CP). However, the underlying mechanisms are to be elucidated. The present study was conducted to determine the role of IFN gamma subverting insulin gene expression in CP. Pancreatic tissues from control (n=15) and CP patients (n=30) were analyzed for nuclear localization of pancreatic and duodenal homeobox transcription factor (Pdx-1) after ascertaining their diabetic status. By immunofluorescence and western blot analysis, the influence of IFN-gamma, anti-inflammatory cytokine (interleukin-10), and anti-IFN gamma agent epigallocatechin-3-gallate (EGCG) on nuclear localization of Pdx-1was examined in the islets isolated from resected normal pancreatic tissue. Nuclear localization of Pdx-1 was 20.25+/-2.19 in the islets of diabetic CP patients and 31.44+/-2.09 in nondiabetic CP patients as compared with controls (60.45+/-5.11) and the corresponding distribution of Pdx-1 protein in the nuclear compartment was also decreased. Exposure of normal islets to IFN-gamma revealed decreased nuclear localization of Pdx-1. Pretreatment with polyphenolic compound EGCG restored the nuclear localization of Pdx-1. These results suggest that IFN-gamma induced beta-cell dysfunction is mediated through decreased nuclear localization of Pdx-1. PMID- 25839230 TI - Influence of magnetic domain walls and magnetic field on the thermal conductivity of magnetic nanowires. AB - We investigated the influence of magnetic domain walls and magnetic fields on the thermal conductivity of suspended magnetic nanowires. The thermal conductivity of the nanowires was obtained using steady-state Joule heating to measure the change in resistance caused by spontaneous heating. The results showed that the thermal conductivity coefficients of straight and wavy magnetic nanowires decreased with an increase in the magnetic domain wall number, implying that the scattering between magnons and domain walls hindered the heat transport process. In addition, we proved that the magnetic field considerably reduced the thermal conductivity of a magnetic nanowire. The influence of magnetic domain walls and magnetic fields on the thermal conductivity of polycrystalline magnetic nanowires can be attributed to the scattering of long-wavelength spin waves mediated by intergrain exchange coupling. PMID- 25839231 TI - Thrombospondin-1 (TSP1)-producing B cells restore antigen (Ag)-specific immune tolerance in an allergic environment. AB - Restoration of the antigen (Ag)-specific immune tolerance in an allergic environment is refractory. B cells are involved in immune regulation. Whether B cells facilitate the generation of Ag-specific immune tolerance in an allergic environment requires further investigation. This paper aims to elucidate the mechanism by which B cells restore the Ag-specific immune tolerance in an allergic environment. In this study, a B cell-deficient mouse model was created by injecting an anti-CD20 antibody. The frequency of tolerogenic dendritic cell (TolDC) was assessed by flow cytometry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The expression of thrombospondin-1 (TSP1) was assessed by quantitative real-time RT-PCR, Western blotting, and methylation specific PCR. The results showed that B cells were required in the generation of the TGF-beta-producing TolDCs in mice. B cell-derived TSP1 converted the latent TGF-beta to the active TGF-beta in DCs, which generated TGF-beta-producing TolDCs. Exposure to IL-13 inhibited the expression of TSP1 in B cells by enhancing the TSP1 gene DNA methylation. Treating food allergy mice with Ag specific immunotherapy and IL-13 antagonists restored the generation of TolDCs and enhanced the effect of specific immunotherapy. In conclusion, B cells play a critical role in the restoration of specific immune tolerance in an allergic environment. Blocking IL-13 in an allergic environment facilitated the generation of TolDCs and enhanced the therapeutic effect of immunotherapy. PMID- 25839232 TI - Expression of Non-acetylatable H2A.Z in Myoblast Cells Blocks Myoblast Differentiation through Disruption of MyoD Expression. AB - H2A.Z is a histone H2A variant that is essential for viability in Tetrahymena and Drosophila and also during embryonic development of mice. Although implicated in diverse cellular processes, including transcriptional regulation, chromosome segregation, and heterochromatin formation, its essential function in cells remains unknown. Cellular differentiation is part of the developmental process of multicellular organisms. To elucidate the roles of H2A.Z and H2A.Z acetylation in cellular differentiation, we examined the effects of expressing wild type (WT) or a non-acetylatable form of H2A.Z in the growth and differentiation of the myoblast C2C12 cell line. Ectopic expression of wild type or mutant H2A.Z resulted in distinct phenotypes in the differentiation of the C2C12 cells and the formation of myotubes. Most strikingly, expression of the H2A.Z non-acetylatable mutant (H2A.Z-Ac-mut) resulted in a complete block of myoblast differentiation. We determined that this phenotype is caused by a loss of MyoD expression in the Ac-mut-expressing cells prior to and after induction of differentiation. Moreover, chromatin accessibility assays showed that the promoter region of MyoD is less accessible in the differentiation-defective cells. Altogether, these new findings show that expression of the Ac-mut form of H2A.Z resulted in a dominant phenotype that blocked differentiation due to chromatin changes at the MyoD promoter. PMID- 25839233 TI - Defining a two-pronged structural model for PB1 (Phox/Bem1p) domain interaction in plant auxin responses. AB - Phox/Bem1p (PB1) domains are universal structural modules that use surfaces of different charge for protein-protein association. In plants, PB1-mediated interactions of auxin response factors (ARF) and auxin/indole 3-acetic acid inducible proteins regulate transcriptional events modulated by the phytohormone auxin. Here we investigate the thermodynamic and structural basis for Arabidopsis thaliana ARF7 PB1 domain self-interaction. Isothermal titration calorimetry and NMR experiments indicate that key residues on both the basic and acidic faces of the PB1 domain contribute to and organize coordinately to stabilize protein protein interactions. Calorimetric analysis of ARF7PB1 site-directed mutants defines a two-pronged electrostatic interaction. The canonical PB1 interaction between a lysine and a cluster of acidic residues provides one prong with an arginine and a second cluster of acidic residues defining the other prong. Evolutionary conservation of this core recognition feature and other co-varying interface sequences allows for versatile PB1-mediated interactions in auxin signaling. PMID- 25839234 TI - Basophil-associated OX40 ligand participates in the initiation of Th2 responses during airway inflammation. AB - Asthma is characterized by increased airway submucosal infiltration of T helper (Th) cells and myeloid cells that co-conspire to sustain a chronic inflammation. While recent studies have demonstrated that the myeloid basophils promote Th2 cells in response to various types of allergens, the underlying mechanisms are poorly understood. Here, we found for the first time that in a mouse model of allergic asthma basophils highly expressed OX40 ligand (OX40L) after activation. Interestingly, blockade of OX40-OX40L interaction suppressed basophils-primed Th2 cell differentiation in vitro and ameliorated ovalbumin (OVA)-induced allergic eosinophilic inflammation mediated by Th2 activation. In accordance, the adoptive transfer of basophils derived from mediastinal lymph nodes (MLN) of OVA-immunized mice triggered a robust Th2 response and eosinophilic inflammation in wild-type mice but largely muted in OX40(-/-) mice and mice receiving OX40L-blocked basophils. Taken together, our results reveal a critical role of OX40L presented by the activated basophils to initiate Th2 responses in an allergic asthma model, implicating OX40-OX40L signaling as a potential therapeutic target in the treatment of allergic airway inflammation. PMID- 25839236 TI - Reactivity of Cys4 zinc finger domains with gold(III) complexes: insights into the formation of "gold fingers". AB - Gold(I) complexes such as auranofin or aurothiomalate have been used as therapeutic agents for the treatment of rheumatoid arthritis for several decades. Several gold(I) and gold(III) complexes have also shown in vitro anticancer properties against human cancer cell lines, including cell lines resistant to cisplatin. Because of the thiophilicity of gold, cysteine-containing proteins appear as likely targets for gold complexes. Among them, zinc finger proteins have attracted attention and, recently, gold(I) and gold(III) complexes have been shown to inhibit poly(adenosine diphosphate ribose)polymerase-1 (PARP-1), which is an essential protein involved in DNA repair and in cancer resistance to chemotherapies. In this Article, we characterize the reactivity of the gold(III) complex [Au(III)(terpy)Cl]Cl2 (Auterpy) with a model of Zn(Cys)4 "zinc ribbon" zinc finger by a combination of absorption spectroscopy, circular dichroism, mass spectrometry, high-performance liquid chromatography analysis, and X-ray absorption spectroscopy. We show that the Zn(Cys)4 site of Zn.LZR is rapidly oxidized by Auterpy to form a disulfide bond. The Zn(2+) ion is released, and the two remaining cysteines coordinate the Au(+) ion that is produced during the redox reaction. Subsequent oxidation of these cysteines can take place in conditions of excess gold(III) complex. In the presence of excess free thiols mimicking the presence of glutathione in cells, mixing of the zinc finger model and gold(III) complex yields a different product: complex (Au(I))2.LZR with two Au(+) ions bound to cysteines is formed. Thus, on the basis of detailed speciation and kinetic measurements, we demonstrate herein that the destruction of Zn(Cys)4 zinc fingers by gold(III) complexes to achieve the formation of "gold fingers" is worth consideration, either directly or mediated by reducing agents. PMID- 25839235 TI - Expression of Ceramide Synthase 6 Transcriptionally Activates Acid Ceramidase in a c-Jun N-terminal Kinase (JNK)-dependent Manner. AB - A family of six ceramide synthases with distinct but overlapping substrate specificities is responsible for generation of ceramides with acyl chains ranging from ~14-26 carbons. Ceramide synthase 6 (CerS6) preferentially generates C14- and C16-ceramides, and we have previously shown that down-regulation of this enzyme decreases apoptotic susceptibility. In this study, we further evaluated how increased CerS6 expression impacts sphingolipid composition and metabolism. Overexpression of CerS6 in HT29 colon cancer cells resulted in increased apoptotic susceptibility and preferential generation of C16-ceramide, which occurred at the expense of very long chain, saturated ceramides. These changes were also reflected in sphingomyelin composition. HT-CerS6 cells had increased intracellular levels of sphingosine, which is generated by ceramidases upon hydrolysis of ceramide. qRT-PCR analysis revealed that only expression of acid ceramidase (ASAH1) was increased. The increase in acid ceramidase was confirmed by expression and activity analyses. Pharmacological inhibition of JNK (SP600125) or curcumin reduced transcriptional up-regulation of acid ceramidase. Using an acid ceramidase promoter driven luciferase reporter plasmid, we demonstrated that CerS1 has no effect on transcriptional activation of acid ceramidase and that CerS2 slightly but significantly decreased the luciferase signal. Similar to CerS6, overexpression of CerS3-5 resulted in an ~2-fold increase in luciferase reporter gene activity. Exogenous ceramide failed to induce reporter activity, while a CerS inhibitor and a catalytically inactive mutant of CerS6 failed to reduce it. Taken together, these results suggest that increased expression of CerS6 can mediate transcriptional activation of acid ceramidase in a JNK dependent manner that is independent of CerS6 activity. PMID- 25839237 TI - Optically Tunable Chiral Plasmonic Guest-Host Cellulose Films Weaved with Long range Ordered Silver Nanowires. AB - Plasmonic materials with large chiroptical activity at visible wavelength have attracted considerable attention due to their potential applications in metamaterials. Here we demonstrate a novel guest-host chiral nematic liquid crystal film composed of bulk self-co-assembly of the dispersed plasmonic silver nanowires (AgNWs) and cellulose nanocrystals (CNCs). The AgNWs-CNCs composite films show strong plasmonic optical activities, that are dependent on the chiral photonic properties of the CNCs host medium and orientation of the guest AgNWs. Tunable chiral distribution of the aligned anisotropic AgNWs with long-range order is obtained through the CNCs liquid crystal mediated realignment. The chiral plasmonic optical activity of the AgNWs-CNCs composite films can be tuned by changing the interparticle electrostatic repulsion between the CNCs nanorods and AgNWs. We also observe an electromagnetic energy transfer phenomena among the plasmonic bands of AgNWs, due to the modulation of the photonic band gap of the CNCs host matrix. This facile approach for fabricating chiral macrostructured plasmonic materials with optically tunable property is of interest for a variety of advanced optics applications. PMID- 25839238 TI - Possible salivary and serum biomarkers for oral lichen planus. AB - There are few reports concerning the potential for clinical application of oxidative stress (OS) and collagen degradation markers in oral lichen planus (OLP) patients. We investigated the possibility of using some disease-related biomarkers in saliva and serum of OLP patients. Our study included 30 patients with OLP and 30 controls. We evaluated serum and salivary OS biomarkers including 8-OHdG, MDA, uric acid, TAC and GPx. We also investigated collagen degradation markers such as CTX I and MMP-8. We found significantly increased salivary levels of MMP-8 and CTX I in the OLP group compared to controls and significant differences between the OLP and control groups in serum and saliva for 8-OHdG, MDA (significantly increased), uric acid, TAC and GPx (significantly reduced). Currently there are no criteria for evaluating which OLP patients have a greater risk of malignant transformation. In addition to clinical surveillance, the serum and salivary biomarkers that we evaluated may be useful biomarkers for monitoring OLP patients in the future. PMID- 25839239 TI - Membrane-based osmotic heat engine with organic solvent for enhanced power generation from low-grade heat. AB - We present a hybrid osmotic heat engine (OHE) system that uses draw solutions with an organic solvent for enhanced thermal separation efficiency. The hybrid OHE system produces sustainable energy by combining pressure-retarded osmosis (PRO) as a power generation stage and membrane distillation (MD) utilizing low grade heat as a separation stage. While previous OHE systems employed aqueous electrolyte draw solutions, using methanol as a solvent is advantageous because methanol is highly volatile and has a lower heat capacity and enthalpy of vaporization than water. Hence, the thermal separation efficiency of a draw solution with methanol would be higher than that of an aqueous draw solution. In this study, we evaluated the performance of LiCl-methanol as a potential draw solution for a PRO-MD hybrid OHE system. The membrane transport properties as well as performance with LiCl-methanol draw solution were evaluated using thin film composite (TFC) PRO membranes and compared to the results obtained with a LiCl-water draw solution. Experimental PRO methanol flux and maximum projected power density of 47.1 L m(-2) h(-1) and 72.1 W m(-2), respectively, were achieved with a 3 M LiCl-methanol draw solution. The overall efficiency of the hybrid OHE system was modeled by coupling the mass and energy flows between the thermal separation (MD) and power generation (PRO) stages under conditions with and without heat recovery. The modeling results demonstrate higher OHE energy efficiency with the LiCl-methanol draw solution compared to that with the LiCl water draw solution under practical operating conditions (i.e., heat recovery<90%). We discuss the implications of the results for converting low grade heat to power. PMID- 25839240 TI - Pursuit-and-Evasion Reaction-Diffusion Waves in Microreactors with Tailored Geometry. AB - Out-of-equilibrium chemical systems may self-organize into structures displaying spatiotemporal order, such as traveling waves and Turing patterns. Because of its predictable chemistry, DNA has recently appeared as an interesting candidate to engineer these spatiotemporal structures. However, in addition to the intrinsic chemical parameters, initial and boundary conditions have a major impact on the final structure. Here we take advantage of microfluidics to design controlled reactors and investigate pursuit-and-evasion chemical waves generated by a DNA based reaction network with Predator-Prey dynamics. We first propose two complementary microfabrication strategies to either control the initial condition or the two-dimensional geometry of the reactor where the waves develop. We subsequently use them to investigate the effect of curvature in wave propagation. We finally show that DNA-based waves can compute the optimal path within a maze. We thus suggest that coupling configurable microfluidics to programmable DNA based dissipative reaction networks is a powerful route to investigate spatiotemporal order formation in chemistry. PMID- 25839241 TI - Sadness. PMID- 25839242 TI - Gender based violence and women's health-the global view. PMID- 25839243 TI - A rare case of neonatal cryptococcal meningitis in an HIV-unexposed 2-day-old infant: the youngest to date? AB - Cryptococcal meningitis is uncommon in children, particularly in infants. A 2-day old boy was admitted with signs suggestive of meningitis. Lumbar puncture confirmed meningitis and cryptococcal infection (cryptococcal antigen and Indian ink stain-positive). His mother was HIV-negative. This is thought to be the youngest case of cryptococcal meningitis to be reported. Cryptococcal infection should be considered in children of all ages with meningitis where there is possible immunodeficiency or failure to respond to initial treatment with antibiotics. PMID- 25839244 TI - Berezinskii-Kosterlitz-Thouless phase transition in 2D spin-orbit-coupled Fulde Ferrell superfluids. AB - The experimental observation of traditional Zeeman-field induced Fulde-Ferrell Larkin-Ovchinnikov (FFLO) superfluids has been hindered by various challenges, in particular, the requirement of low dimensional systems. In 2D, finite temperature phase fluctuations lead to an extremely small Berezinskii-Kosterlitz-Thouless (BKT) transition temperature for FFLO superfluids, raising serious concerns regarding their experimental observability. Recently, it was shown that FFLO superfluids can be realized using a Rashba spin-orbit coupled Fermi gas subject to Zeeman fields, which may also support topological excitations such as Majorana fermions in 2D. Here we address the finite temperature BKT transition issue in this system, which may exhibit gapped, gapless, topological, and gapless topological FF phases. We find a large BKT transition temperature due to large effective superfluid densities, making it possible to observe 2D FF superfluids at finite temperature. In addition, we show that gapless FF superfluids can be stable due to their positive superfluid densities. These findings pave the way for the experimental observation of 2D gapped and gapless FF superfluids and their associated topological excitations at finite temperature. PMID- 25839245 TI - Finite-temperature free fermions and the Kardar-Parisi-Zhang equation at finite time. AB - We consider the system of N one-dimensional free fermions confined by a harmonic well V(x)=momega(2)x(2)/2 at finite inverse temperature beta=1/T. The average density of fermions rho(N)(x,T) at position x is derived. For N?1 and beta~O(1/N), rho(N)(x,T) is given by a scaling function interpolating between a Gaussian at high temperature, for beta?1/N, and the Wigner semicircle law at low temperature, for beta?N(-1). In the latter regime, we unveil a scaling limit, for betahomega=bN(-1/3), where the fluctuations close to the edge of the support, at x~+/-?[2hN/(momega)], are described by a limiting kernel K(b)(ff)(s,s') that depends continuously on b and is a generalization of the Airy kernel, found in the Gaussian unitary ensemble of random matrices. Remarkably, exactly the same kernel K(b)(ff)(s,s') arises in the exact solution of the Kardar-Parisi-Zhang equation in 1+1 dimensions at finite time t, with the correspondence t=b(3). PMID- 25839246 TI - Spin-imbalanced quasi-two-dimensional Fermi gases. AB - We measure the density profiles for a Fermi gas of (6)Li containing N(1) spin-up atoms and N(2) spin-down atoms, confined in a quasi-two-dimensional geometry. The spatial profiles are measured as a function of spin imbalance N(2)/N(1) and interaction strength, which is controlled by means of a collisional (Feshbach) resonance. The measured cloud radii and central densities are in disagreement with mean-field Bardeen-Cooper-Schrieffer theory for a true two-dimensional system. We find that the data for normal-fluid mixtures are reasonably well fit by a simple two-dimensional polaron model of the free energy. Not predicted by the model is a phase transition to a spin-balanced central core, which is observed above a critical value of N(2)/N(1). Our observations provide important benchmarks for predictions of the phase structure of quasi-two-dimensional Fermi gases. PMID- 25839247 TI - Microwave experiments simulating quantum search and directed transport in artificial graphene. AB - A series of quantum search algorithms have been proposed recently providing an algebraic speedup compared to classical search algorithms from N to ?N, where N is the number of items in the search space. In particular, devising searches on regular lattices has become popular in extending Grover's original algorithm to spatial searching. Working in a tight-binding setup, it could be demonstrated, theoretically, that a search is possible in the physically relevant dimensions 2 and 3 if the lattice spectrum possesses Dirac points. We present here a proof of principle experiment implementing wave search algorithms and directed wave transport in a graphene lattice arrangement. The idea is based on bringing localized search states into resonance with an extended lattice state in an energy region of low spectral density-namely, at or near the Dirac point. The experiment is implemented using classical waves in a microwave setup containing weakly coupled dielectric resonators placed in a honeycomb arrangement, i.e., artificial graphene. Furthermore, we investigate the scaling behavior experimentally using linear chains. PMID- 25839248 TI - Heralded quantum gates with integrated error detection in optical cavities. AB - We propose and analyze heralded quantum gates between qubits in optical cavities. They employ an auxiliary qubit to report if a successful gate occurred. In this manner, the errors, which would have corrupted a deterministic gate, are converted into a nonunity probability of success: once successful, the gate has a much higher fidelity than a similar deterministic gate. Specifically, we describe that a heralded, near-deterministic controlled phase gate (CZ gate) with the conditional error arbitrarily close to zero and the success probability that approaches unity as the cooperativity of the system, C, becomes large. Furthermore, we describe an extension to near-deterministic N-qubit Toffoli gate with a favorable error scaling. These gates can be directly employed in quantum repeater networks to facilitate near-ideal entanglement swapping, thus greatly speeding up the entanglement distribution. PMID- 25839249 TI - Connectivity is a poor indicator of fast quantum search. AB - A randomly walking quantum particle evolving by Schrodinger's equation searches on d-dimensional cubic lattices in O(?N) time when d>=5, and with progressively slower runtime as d decreases. This suggests that graph connectivity (including vertex, edge, algebraic, and normalized algebraic connectivities) is an indicator of fast quantum search, a belief supported by fast quantum search on complete graphs, strongly regular graphs, and hypercubes, all of which are highly connected. In this Letter, we show this intuition to be false by giving two examples of graphs for which the opposite holds true: one with low connectivity but fast search, and one with high connectivity but slow search. The second example is a novel two-stage quantum walk algorithm in which the walking rate must be adjusted to yield high search probability. PMID- 25839250 TI - Entanglement-based machine learning on a quantum computer. AB - Machine learning, a branch of artificial intelligence, learns from previous experience to optimize performance, which is ubiquitous in various fields such as computer sciences, financial analysis, robotics, and bioinformatics. A challenge is that machine learning with the rapidly growing "big data" could become intractable for classical computers. Recently, quantum machine learning algorithms [Lloyd, Mohseni, and Rebentrost, arXiv.1307.0411] were proposed which could offer an exponential speedup over classical algorithms. Here, we report the first experimental entanglement-based classification of two-, four-, and eight dimensional vectors to different clusters using a small-scale photonic quantum computer, which are then used to implement supervised and unsupervised machine learning. The results demonstrate the working principle of using quantum computers to manipulate and classify high-dimensional vectors, the core mathematical routine in machine learning. The method can, in principle, be scaled to larger numbers of qubits, and may provide a new route to accelerate machine learning. PMID- 25839251 TI - Information transmission without energy exchange. AB - We show that it is possible to use a massless field in the vacuum to communicate in such a way that the signal travels arbitrarily slower than the speed of light and such that no energy is transmitted from the sender to the receiver. Instead, the receiver has to supply a signal-dependent amount of work to switch his detector on and off. This type of communication is related to Casimir-like interactions, and it is made possible by dimension-and curvature-dependent subtleties of Huygens' principle. PMID- 25839252 TI - Entanglement-enhanced sensing in a lossy and noisy environment. AB - Nonclassical states are essential for optics-based quantum information processing, but their fragility limits their utility for practical scenarios in which loss and noise inevitably degrade, if not destroy, nonclassicality. Exploiting nonclassical states in quantum metrology yields sensitivity advantages over all classical schemes delivering the same energy per measurement interval to the sample being probed. These enhancements, almost without exception, are severely diminished by quantum decoherence. Here, we experimentally demonstrate an entanglement-enhanced sensing system that is resilient to quantum decoherence. We employ entanglement to realize a 20% signal-to-noise ratio improvement over the optimum classical scheme in an entanglement-breaking environment plagued by 14 dB of loss and a noise background 75 dB stronger than the returned probe light. Our result suggests that advantageous quantum-sensing technology could be developed for practical situations. PMID- 25839253 TI - Exact mapping of the stochastic field theory for Manna sandpiles to interfaces in random media. AB - We show that the stochastic field theory for directed percolation in the presence of an additional conservation law [the conserved directed-percolation (C-DP) class] can be mapped exactly to the continuum theory for the depinning of an elastic interface in short-range correlated quenched disorder. Along one line of the parameters commonly studied, this mapping leads to the simplest overdamped dynamics. Away from this line, an additional memory term arises in the interface dynamics; we argue that this does not change the universality class. Since C-DP is believed to describe the Manna class of self-organized criticality, this shows that Manna stochastic sandpiles and disordered elastic interfaces (i.e., the quenched Edwards-Wilkinson model) share the same universal large-scale behavior. PMID- 25839254 TI - Hyperuniformity of critical absorbing states. AB - The properties of the absorbing states of nonequilibrium models belonging to the conserved directed percolation universality class are studied. We find that, at the critical point, the absorbing states are hyperuniform, exhibiting anomalously small density fluctuations. The exponent characterizing the fluctuations is measured numerically, a scaling relation to other known exponents is suggested, and a new correlation length relating to this ordering is proposed. These results may have relevance to photonic band-gap materials. PMID- 25839255 TI - Radiation from a collapsing object is manifestly unitary. AB - The process of gravitational collapse excites the fields propagating in the background geometry and gives rise to thermal radiation. We demonstrate by explicit calculations that the density matrix corresponding to such radiation actually describes a pure state. While Hawking's leading order density matrix contains only the diagonal terms, we calculate the off-diagonal correlation terms. These correlations start very small, but then grow in time. The cumulative effect is that the correlations become comparable to the leading order terms and significantly modify the density matrix. While the trace of the Hawking's density matrix squared goes from unity to zero during the evolution, the trace of the total density matrix squared remains unity at all times and all frequencies. This implies that the process of radiation from a collapsing object is unitary. PMID- 25839257 TI - String theory of the Regge intercept. AB - Using the Polchinski-Strominger effective string theory in the covariant gauge, we compute the mass of a rotating string in D dimensions with large angular momenta J, in one or two planes, in fixed ratio, up to and including first subleading order in the large J expansion. This constitutes a first-principles calculation of the value for the order-J(0) contribution to the mass squared of a meson on the leading Regge trajectory in planar QCD with bosonic quarks. For open strings with Neumann boundary conditions, and for closed strings in D>=5, the order-J(0) term in the mass squared is exactly calculated by the semiclassical approximation. This term in the expansion is universal and independent of the details of the theory, assuming only D-dimensional Poincare invariance and the absence of other infinite-range excitations on the string world volume, beyond the Nambu-Goldstone bosons. PMID- 25839258 TI - Entanglement entropy in Galilean conformal field theories and flat holography. AB - We present the analytical calculation of entanglement entropy for a class of two dimensional field theories governed by the symmetries of the Galilean conformal algebra, thus providing a rare example of such an exact computation. These field theories are the putative holographic duals to theories of gravity in three dimensional asymptotically flat spacetimes. We provide a check of our field theory answers by an analysis of geodesics. We also exploit the Chern-Simons formulation of three-dimensional gravity and adapt recent proposals of calculating entanglement entropy by Wilson lines in this context to find an independent confirmation of our results from holography. PMID- 25839259 TI - Entanglement entropy of electromagnetic edge modes. AB - The vacuum entanglement entropy of Maxwell theory, when evaluated by standard methods, contains an unexpected term with no known statistical interpretation. We resolve this two-decades old puzzle by showing that this term is the entanglement entropy of edge modes: classical solutions determined by the electric field normal to the entangling surface. We explain how the heat kernel regularization applied to this term leads to the negative divergent expression found by Kabat. This calculation also resolves a recent puzzle concerning the logarithmic divergences of gauge fields in 3+1 dimensions. PMID- 25839260 TI - Enhanced Higgs boson to tau(+)tau(-) search with deep learning. AB - The Higgs boson is thought to provide the interaction that imparts mass to the fundamental fermions, but while measurements at the Large Hadron Collider (LHC) are consistent with this hypothesis, current analysis techniques lack the statistical power to cross the traditional 5sigma significance barrier without more data. Deep learning techniques have the potential to increase the statistical power of this analysis by automatically learning complex, high-level data representations. In this work, deep neural networks are used to detect the decay of the Higgs boson to a pair of tau leptons. A Bayesian optimization algorithm is used to tune the network architecture and training algorithm hyperparameters, resulting in a deep network of eight nonlinear processing layers that improves upon the performance of shallow classifiers even without the use of features specifically engineered by physicists for this application. The improvement in discovery significance is equivalent to an increase in the accumulated data set of 25%. PMID- 25839256 TI - First direct limits on lightly ionizing particles with electric charge less than e/6. AB - While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200. PMID- 25839261 TI - Chiral symmetry breaking in QCD with two light flavors. AB - A distinctive feature of the presence of spontaneous chiral symmetry breaking in QCD is the condensation of low modes of the Dirac operator near the origin. The rate of condensation must be equal to the slope of M(pi)(2)F(pi)(2)/2 with respect to the quark mass m in the chiral limit, where M(pi) and F(pi) are the mass and the decay constant of the Nambu-Goldstone bosons. We compute the spectral density of the (Hermitian) Dirac operator, the quark mass, the pseudoscalar meson mass, and decay constant by numerical simulations of lattice QCD with two light degenerate Wilson quarks. We use lattices generated by the Coordinated Lattice Simulation (CLS) group at three values of the lattice spacing in the range 0.05-0.08 fm, and for several quark masses corresponding to pseudoscalar mesons masses down to 190 MeV. Thanks to this coverage of parameters space, we can extrapolate all quantities to the chiral and continuum limits with confidence. The results show that the low quark modes do condense in the continuum as expected by the Banks-Casher mechanism, and the rate of condensation agrees with the Gell-Mann-Oakes-Renner relation. For the renormalization-group invariant ratios we obtain [Sigma(RGI)](1/3)/F=2.77(2)(4) and Lambda(MS)/F=3.6(2), which correspond to [Sigma(MS)(2 GeV)](1/3)=263(3)(4) MeV and F=85.8(7)(20) MeV if F(K) is used to set the scale by supplementing the theory with a quenched strange quark. PMID- 25839262 TI - Elliptic flow and nuclear modification factor in ultrarelativistic heavy-ion collisions within a partonic transport model. AB - The quark gluon plasma produced in ultrarelativistic heavy-ion collisions exhibits remarkable features. It behaves like a nearly perfect liquid with a small shear viscosity to entropy density ratio and leads to the quenching of highly energetic particles. We show that both effects can be understood for the first time within one common framework. Employing the parton cascade Boltzmann approach to multiparton scatterings, the microscopic interactions and the space time evolution of the quark gluon plasma are calculated by solving the relativistic Boltzmann equation. Based on cross sections obtained from perturbative QCD with explicitly taking the running coupling into account, we calculate the nuclear modification factor and elliptic flow in ultrarelativistic heavy-ion collisions. With only one single parameter associated with coherence effects of medium-induced gluon radiation, the experimental data of both observables can be understood on a microscopic level. Furthermore, we show that perturbative QCD interactions with a running coupling lead to a sufficiently small shear viscosity to entropy density ratio of the quark gluon plasma, which provides a microscopic explanation for the observations stated by hydrodynamic calculations. PMID- 25839264 TI - Identification of a previously unobserved dissociative ionization pathway in time resolved photospectroscopy of the deuterium molecule. AB - A femtosecond vacuum ultraviolet (VUV) pulse with high spectral resolution (<200 meV) is selected from the laser-driven high order harmonics. This ultrafast VUV pulse is synchronized with an infrared (IR) laser pulse to study dissociative ionization in deuterium molecules. At a VUV photon energy of 16.95 eV, a previously unobserved bond-breaking pathway is found in which the dissociation direction does not follow the IR polarization. We interpret it as corresponding to molecules predissociating into two separated atoms, one of which is photoionized by the following IR pulse. A time resolved study allows us to determine the lifetime of the intermediate predissociation process to be about 1 ps. Additionally, the dissociative ionization pathways show high sensitivity to the VUV photon energy. As the VUV photon energy is blueshifted to 17.45 eV, the more familiar bond-softening channel is opened to compete with the newly discovered pathway. The interpretation of different pathways is supported by the energy sharing between the electron and nuclei. PMID- 25839265 TI - Coherent excitation transfer in a spin chain of three Rydberg atoms. AB - We study coherent excitation hopping in a spin chain realized using highly excited individually addressable Rydberg atoms. The dynamics are fully described in terms of an XY spin Hamiltonian with a long range resonant dipole-dipole coupling that scales as the inverse third power of the lattice spacing, C(3)/R(3). The experimental data demonstrate the importance of next neighbor interactions which are manifest as revivals in the excitation dynamics. The results suggest that arrays of Rydberg atoms are ideally suited to large scale, high-fidelity quantum simulation of spin dynamics. PMID- 25839263 TI - Measurements of double-polarized compton scattering asymmetries and extraction of the proton spin polarizabilities. AB - The spin polarizabilities of the nucleon describe how the spin of the nucleon responds to an incident polarized photon. The most model-independent way to extract the nucleon spin polarizabilities is through polarized Compton scattering. Double-polarized Compton scattering asymmetries on the proton were measured in the Delta(1232) region using circularly polarized incident photons and a transversely polarized proton target at the Mainz Microtron. Fits to asymmetry data were performed using a dispersion model calculation and a baryon chiral perturbation theory calculation, and a separation of all four proton spin polarizabilities in the multipole basis was achieved. The analysis based on a dispersion model calculation yields gamma(E1E1)=-3.5+/-1.2, gamma(M1M1)=3.16+/ 0.85, gamma(E1M2)=-0.7+/-1.2, and gamma(M1E2)=1.99+/-0.29, in units of 10(-4) fm(4). PMID- 25839266 TI - Sensitivity of ultracold atoms to quantized flux in a superconducting ring. AB - We report on the magnetic trapping of an ultracold ensemble of (87)Rb atoms close to a superconducting ring prepared in different states of quantized magnetic flux. The niobium ring of 10 MUm radius is prepared in a flux state n Phi(0), where Phi(0)=h/2e is the flux quantum and n varying between +/-6. An atomic cloud of 250 nK temperature is positioned with a harmonic magnetic trapping potential at ~18 MUm distance below the ring. The inhomogeneous magnetic field of the supercurrent in the ring contributes to the magnetic trapping potential of the cloud. The induced deformation of the magnetic trap impacts the shape of the cloud, the number of trapped atoms, as well as the center-of-mass oscillation frequency of Bose-Einstein condensates. When the field applied during cooldown of the chip is varied, the change of these properties shows discrete steps that quantitatively match flux quantization. PMID- 25839267 TI - Proposal for an optomechanical microwave sensor at the subphoton level. AB - Because of their low energy content, microwave signals at the single-photon level are extremely challenging to measure. Guided by recent progress in single-photon optomechanics and hybrid optomechanical systems, we propose a multimode optomechanical transducer that can detect intensities significantly below the single-photon level via adiabatic transfer of the microwave signal to the optical frequency domain where the measurement is then performed. The influence of intrinsic quantum and thermal fluctuations is also discussed. PMID- 25839268 TI - Master-slave locking of optomechanical oscillators over a long distance. AB - Frequency locking and other phenomena emerging from nonlinear interactions between mechanical oscillators are of scientific and technological importance. However, existing schemes to observe such behavior are not scalable over distance. We demonstrate a scheme to couple two independent mechanical oscillators, separated in frequency by 80 kHz and situated far from each other (3.2 km), via light. Using light as the coupling medium enables this scheme to have low loss and be extended over long distances. This scheme is reversible and can be generalized for arbitrary network configurations. PMID- 25839269 TI - Nearly deterministic bell measurement for multiphoton qubits and its application to quantum information processing. AB - We propose a Bell-measurement scheme by employing a logical qubit in Greenberger Horne-Zeilinger entanglement with an arbitrary number of photons. Remarkably, the success probability of the Bell measurement as well as teleportation of the Greenberger-Horne-Zeilinger entanglement can be made arbitrarily high using only linear optics elements and photon on-off measurements as the number of photons increases. Our scheme outperforms previous proposals using single-photon qubits when comparing the success probabilities in terms of the average photon usages. It has another important advantage for experimental feasibility in that it does not require photon-number-resolving measurements. Our proposal provides an alternative candidate for all-optical quantum information processing. PMID- 25839270 TI - Multipartite entangled spatial modes of ultracold atoms generated and controlled by quantum measurement. AB - We show that the effect of measurement backaction results in the generation of multiple many-body spatial modes of ultracold atoms trapped in an optical lattice, when scattered light is detected. The multipartite mode entanglement properties and their nontrivial spatial overlap can be varied by tuning the optical geometry in a single setup. This can be used to engineer quantum states and dynamics of matter fields. We provide examples of multimode generalizations of parametric down-conversion, Dicke, and other states; investigate the entanglement properties of such states; and show how they can be transformed into a class of generalized squeezed states. Furthermore, we propose how these modes can be used to detect and measure entanglement in quantum gases. PMID- 25839271 TI - Adiabatic soliton laser. AB - The key to generating stable optical pulses is mastery of nonlinear light dynamics in laser resonators. Modern techniques to control the buildup of laser pulses are based on nonlinear science and include classical solitons, dissipative solitons, parabolic pulses (similaritons) and various modifications and blending of these methods. Fiber lasers offer remarkable opportunities to apply one dimensional nonlinear science models for the design and optimization of very practical laser systems. Here, we propose a new concept of a laser based on the adiabatic amplification of a soliton pulse in the cavity-the adiabatic soliton laser. The adiabatic change of the soliton parameters during evolution in the resonator relaxes the restriction on the pulse energy inherent in traditional soliton lasers. Theoretical analysis is confirmed by extensive numerical modeling. PMID- 25839272 TI - Isotropically polarized speckle patterns. AB - The polarization of the light scattered by an optically dense and random solution of dielectric nanoparticles shows peculiar properties when the scatterers exhibit strong electric and magnetic polarizabilities. While the distribution of the scattering intensity in these systems shows the typical irregular speckle patterns, the helicity of the incident light can be fully conserved when the electric and magnetic polarizabilities of the scatterers are equal. We show that the multiple scattering of helical beams by a random dispersion of "dual" dipolar nanospheres leads to a speckle pattern exhibiting a perfect isotropic constant polarization, a situation that could be useful in coherent control of light as well as in lasing in random media. PMID- 25839273 TI - Topological acoustics. AB - The manipulation of acoustic wave propagation in fluids has numerous applications, including some in everyday life. Acoustic technologies frequently develop in tandem with optics, using shared concepts such as waveguiding and metamedia. It is thus noteworthy that an entirely novel class of electromagnetic waves, known as "topological edge states," has recently been demonstrated. These are inspired by the electronic edge states occurring in topological insulators, and possess a striking and technologically promising property: the ability to travel in a single direction along a surface without backscattering, regardless of the existence of defects or disorder. Here, we develop an analogous theory of topological fluid acoustics, and propose a scheme for realizing topological edge states in an acoustic structure containing circulating fluids. The phenomenon of disorder-free one-way sound propagation, which does not occur in ordinary acoustic devices, may have novel applications for acoustic isolators, modulators, and transducers. PMID- 25839274 TI - Thermal boundary layer equation for turbulent Rayleigh-Benard convection. AB - We report a new thermal boundary layer equation for turbulent Rayleigh-Benard convection for Prandtl number Pr>1 that takes into account the effect of turbulent fluctuations. These fluctuations are neglected in existing equations, which are based on steady-state and laminar assumptions. Using this new equation, we derive analytically the mean temperature profiles in two limits: (a) Pr?1 and (b) Pr?1. These two theoretical predictions are in excellent agreement with the results of our direct numerical simulations for Pr=4.38 (water) and Pr=2547.9 (glycerol), respectively. PMID- 25839275 TI - Experimental verification of overlimiting current by surface conduction and electro-osmotic flow in microchannels. AB - Direct evidence is provided for the transition from surface conduction (SC) to electro-osmotic flow (EOF) above a critical channel depth (d) of a nanofluidic device. The dependence of the overlimiting conductance (OLC) on d is consistent with theoretical predictions, scaling as d(-1) for SC and d(4/5) for EOF with a minimum around d=8 MUm. The propagation of transient deionization shocks is also visualized, revealing complex patterns of EOF vortices and unstable convection with increasing d. This unified picture of surface-driven OLC can guide further advances in electrokinetic theory, as well as engineering applications of ion concentration polarization in microfluidics and porous media. PMID- 25839276 TI - Equilibrium electroconvective instability. AB - Since its prediction 15 years ago, hydrodynamic instability in concentration polarization at a charge-selective interface has been attributed to nonequilibrium electro-osmosis related to the extended space charge which develops at the limiting current. This attribution had a double basis. On the one hand, it has been recognized that neither equilibrium electro-osmosis nor bulk electroconvection can yield instability for a perfectly charge-selective solid. On the other hand, it has been shown that nonequilibrium electro-osmosis can. The first theoretical studies in which electro-osmotic instability was predicted and analyzed employed the assumption of perfect charge selectivity for the sake of simplicity and so did the subsequent studies of various time-dependent and nonlinear features of electro-osmotic instability. In this Letter, we show that relaxing the assumption of perfect charge selectivity (tantamount to fixing the electrochemical potential of counterions in the solid) allows for the equilibrium electroconvective instability. In addition, we suggest a simple experimental test for determining the true, either equilibrium or nonequilibrium, origin of instability in concentration polarization. PMID- 25839277 TI - Nodal analysis of nonlinear behavior of the instability at a fluid interface. AB - In interface instabilities, deformations first grow exponentially, then enter a nonlinear regime affecting amplitude and symmetry. Most extant studies have focused on amplitude alone. Here, we study a 2D Rayleigh-Taylor instability for an initial sinusoidal deformation, analyzing its amplitude and asymmetry over time. For the latter, we define a metric based on the zero crossings of the interface. We develop a weakly nonlinear model and compare it to experimental data. It shows that our asymmetry metric complements the amplitude for an improved description of the instabilities' nonlinear phases. PMID- 25839278 TI - Resolving the paradox of oceanic large-scale balance and small-scale mixing. AB - A puzzle of oceanic dynamics is the contrast between the observed geostrophic balance, involving gravity, pressure gradient, and Coriolis forces, and the necessary turbulent transport: in the former case, energy flows to large scales, leading to spectral condensation, whereas in the latter, it is transferred to small scales, where dissipation prevails. The known bidirectional constant-flux energy cascade maintaining both geostrophic balance and mixing tends towards flux equilibration as turbulence strengthens, contradicting models and recent observations which find a dominant large-scale flux. Analyzing a large ensemble of high-resolution direct numerical simulations of the Boussinesq equations in the presence of rotation and no salinity, we show that the ratio of the dual energy flux to large and to small scales agrees with observations, and we predict that it scales with the inverse of the Froude and Rossby numbers when stratification is (realistically) stronger than rotation. Furthermore, we show that the kinetic and potential energies separately undergo a bidirectional transfer to larger and smaller scales. Altogether, this allows for small-scale mixing which drives the global oceanic circulation and will thus potentially lead to more accurate modeling of climate dynamics. PMID- 25839279 TI - Collapse of surface nanobubbles. AB - Surface attached nanobubbles populate surfaces submerged in water. These nanobubbles have a much larger contact angle and longer lifetime than predicted by classical theory. Moreover, it is difficult to distinguish them from hydrophobic droplets, e.g., polymeric contamination, using standard atomic force microscopy. Here, we report fast dynamics of a three phase contact line moving over surface nanobubbles, polymeric droplets, and hydrophobic particles. The dynamics is distinct: across polymeric droplets the contact line quickly jumps and hydrophobic particles pin the contact line, while surface nanobubbles rapidly shrink once merging with the contact line, suggesting a method to differentiate nanoscopic gaseous, liquid, and solid structures. Although the collapse process of surface nanobubbles occurs within a few milliseconds, we show that it is dominated by microscopic dynamics rather than bulk hydrodynamics. PMID- 25839280 TI - Multiple transitions in rotating turbulent Rayleigh-Benard convection. AB - Sometimes it is thought that sharp transitions between potentially different turbulent states should be washed out by the prevailing intense fluctuations and short coherence lengths and times. Contrary to this expectation, we found a sequence of such transitions in turbulent rotating Rayleigh-Benard convection as the rotation rate was increased. This phenomenon was observed in cylindrical samples with aspect ratios (diameter/height) Gamma=1.00 and 0.50. It became most prominent at very large Rayleigh numbers up to 2*10(12), where the fluctuations are extremely vigorous, and was manifested most clearly for Gamma=1.00. It was found in the heat transport as well as in the temperature gradient near the sample center. We conjecture that the transitions are between different large scale structures which involve changes of symmetry and thus cannot be gradual [L. Landau, Zh. Eksp. Teor. Fiz. 7, 19 (1937); L. D. Landau, Phys. Z. Sowjetunion 11, 26 (1937); L. D. Landau, in Collected Papers of L. D. Landau, (Oxford University Press, Oxford, 1965), pp. 193-216]. PMID- 25839281 TI - Demonstration of nonlinear-energy-spread compensation in relativistic electron bunches with corrugated structures. AB - High quality electron beams with flat distributions in both energy and current are critical for many accelerator-based scientific facilities such as free electron lasers and MeV ultrafast electron diffraction and microscopes. In this Letter, we report on using corrugated structures to compensate for the beam nonlinear energy chirp imprinted by the curvature of the radio-frequency field, leading to a significant reduction in beam energy spread. By using a pair of corrugated structures with orthogonal orientations, we show that the quadrupole wakefields, which, otherwise, increase beam emittance, can be effectively canceled. This work also extends the applications of corrugated structures to the low beam charge (a few pC) and low beam energy (a few MeV) regime and may have a strong impact in many accelerator-based facilities. PMID- 25839282 TI - Terahertz acoustics in hot dense laser plasmas. AB - We present a hitherto unobserved facet of hydrodynamics, namely the generation of an ultrahigh frequency acoustic disturbance in the terahertz frequency range, whose origins are purely hydrodynamic in nature. The disturbance is caused by differential flow velocities down a density gradient in a plasma created by a 30 fs, 800 nm high-intensity laser (~5*10(16) W/cm(2)). The picosecond scale observations enable us to capture these high frequency oscillations (1.9+/-0.6 THz) which are generated as a consequence of the rapid heating of the medium by the laser. Adoption of two complementary techniques, namely pump-probe reflectometry and pump-probe Doppler spectrometry provides unambiguous identification of this terahertz acoustic disturbance. Hydrodynamic simulations well reproduce the observations, offering insight into this process. PMID- 25839283 TI - Effective critical electric field for runaway-electron generation. AB - In this Letter we investigate factors that influence the effective critical electric field for runaway-electron generation in plasmas. We present numerical solutions of the kinetic equation and discuss the implications for the threshold electric field. We show that the effective electric field necessary for significant runaway-electron formation often is higher than previously calculated due to both (1) extremely strong dependence of primary generation on temperature and (2) synchrotron radiation losses. We also address the effective critical field in the context of a transition from runaway growth to decay. We find agreement with recent experiments, but show that the observation of an elevated effective critical field can mainly be attributed to changes in the momentum space distribution of runaways, and only to a lesser extent to a de facto change in the critical field. PMID- 25839284 TI - Generalized magnetofluid connections in relativistic magnetohydrodynamics. AB - The concept of magnetic connections is extended to nonideal relativistic magnetohydrodynamical plasmas. Adopting a general set of equations for relativistic magnetohydrodynamics including thermal-inertial, thermal electromotive, Hall, and current-inertia effects, we derive a new covariant connection equation showing the existence of generalized magnetofluid connections that are preserved during the dissipationless plasma dynamics. These connections are intimately linked to a general antisymmetric tensor that unifies the electromagnetic and fluid fields, allowing the extension of the magnetic connection notion to a much broader concept. PMID- 25839285 TI - Observing chiral superfluid order by matter-wave interference. AB - The breaking of time-reversal symmetry via the spontaneous formation of chiral order is ubiquitous in nature. Here, we present an unambiguous demonstration of this phenomenon for atoms Bose-Einstein condensed in the second Bloch band of an optical lattice. As a key tool, we use a matter-wave interference technique, which lets us directly observe the phase properties of the superfluid order parameter and allows us to reconstruct the spatial geometry of certain low-energy excitations, associated with the formation of domains of different chirality. Our work marks a new era of optical lattices where orbital degrees of freedom play an essential role for the formation of exotic quantum matter, similarly as in electronic systems. PMID- 25839286 TI - Polaronic atom-trimer continuity in three-component Fermi gases. AB - Recently it has been proposed that three-component Fermi gases may exhibit a new type of crossover physics in which an unpaired Fermi sea of atoms smoothly evolves into that of trimers in addition to the ordinary BCS-BEC crossover of condensed pairs. Here we study its corresponding polaron problem in which a single impurity atom of one component interacts with condensed pairs of the other two components with equal populations. By developing a variational approach in the vicinity of a narrow Feshbach resonance, we show that the impurity atom smoothly changes its character from atom to trimer with increasing the attraction and eventually there is a sharp transition to dimer. The emergent polaronic atom trimer continuity can be probed in ultracold atoms experiments by measuring the impurity spectral function. Our novel crossover wave function properly incorporating the polaronic atom-trimer continuity will provide a useful basis to further investigate the phase diagram of three-component Fermi gases in more general situations. PMID- 25839287 TI - Element-specific X-ray phase tomography of 3D structures at the nanoscale. AB - Recent advances in fabrication techniques to create mesoscopic 3D structures have led to significant developments in a variety of fields including biology, photonics, and magnetism. Further progress in these areas benefits from their full quantitative and structural characterization. We present resonant ptychographic tomography, combining quantitative hard x-ray phase imaging and resonant elastic scattering to achieve ab initio element-specific 3D characterization of a cobalt-coated artificial buckyball polymer scaffold at the nanoscale. By performing ptychographic x-ray tomography at and far from the Co K edge, we are able to locate and quantify the Co layer in our sample to a 3D spatial resolution of 25 nm. With a quantitative determination of the electron density we can determine that the Co layer is oxidized, which is confirmed with microfluorescence experiments. PMID- 25839288 TI - Breaking of symmetry in graphene growth on metal substrates. AB - In graphene growth, island symmetry can become lower than the intrinsic symmetries of both graphene and the substrate. First-principles calculations and Monte Carlo modeling explain the shapes observed in our experiments and earlier studies for various metal surface symmetries. For equilibrium shape, edge energy variations deltaE manifest in distorted hexagons with different ground-state edge structures. In growth or nucleation, energy variation enters exponentially as ~e(deltaE/k(B)T), strongly amplifying the symmetry breaking, up to completely changing the shapes to triangular, ribbonlike, or rhombic. PMID- 25839289 TI - Hydrogen-induced rupture of strained Si?O bonds in amorphous silicon dioxide. AB - Using ab initio modeling we demonstrate that H atoms can break strained Si?O bonds in continuous amorphous silicon dioxide (a-SiO(2)) networks, resulting in a new defect consisting of a threefold-coordinated Si atom with an unpaired electron facing a hydroxyl group, adding to the density of dangling bond defects, such as E' centers. The energy barriers to form this defect from interstitial H atoms range between 0.5 and 1.3 eV. This discovery of unexpected reactivity of atomic hydrogen may have significant implications for our understanding of processes in silica glass and nanoscaled silica, e.g., in porous low-permittivity insulators, and strained variants of a-SiO(2). PMID- 25839290 TI - Fragmentation of fractal random structures. AB - We analyze the fragmentation behavior of random clusters on the lattice under a process where bonds between neighboring sites are successively broken. Modeling such structures by configurations of a generalized Potts or random-cluster model allows us to discuss a wide range of systems with fractal properties including trees as well as dense clusters. We present exact results for the densities of fragmenting edges and the distribution of fragment sizes for critical clusters in two dimensions. Dynamical fragmentation with a size cutoff leads to broad distributions of fragment sizes. The resulting power laws are shown to encode characteristic fingerprints of the fragmented objects. PMID- 25839291 TI - Emergent rhombus tilings from molecular interactions with M-fold rotational symmetry. AB - We show that model molecules with particular rotational symmetries can self assemble into network structures equivalent to rhombus tilings. This assembly happens in an emergent way, in the sense that molecules spontaneously select irregular fourfold local coordination from a larger set of possible local binding geometries. The existence of such networks can be rationalized by simple geometrical arguments, but the same arguments do not guarantee a network's spontaneous self-assembly. This class of structures must in certain regimes of parameter space be able to reconfigure into networks equivalent to triangular tilings. PMID- 25839292 TI - Significant reduction of lattice thermal conductivity by the electron-phonon interaction in silicon with high carrier concentrations: a first-principles study. AB - The electron-phonon interaction is well known to create major resistance to electron transport in metals and semiconductors, whereas fewer studies are directed to its effect on phonon transport, especially in semiconductors. We calculate the phonon lifetimes due to scattering with electrons (or holes), combine them with the intrinsic lifetimes due to the anharmonic phonon-phonon interaction, all from first principles, and evaluate the effect of the electron phonon interaction on the lattice thermal conductivity of silicon. Unexpectedly, we find a significant reduction of the lattice thermal conductivity at room temperature as the carrier concentration goes above 10(19) cm(-3) (the reduction reaches up to 45% in p-type silicon at around 10(21) cm(-3)), a range of great technological relevance to thermoelectric materials. PMID- 25839293 TI - Nature of long-range order in stripe-forming systems with long-range repulsive interactions. AB - We study two dimensional stripe forming systems with competing repulsive interactions decaying as r(-alpha). We derive an effective Hamiltonian with a short-range part and a generalized dipolar interaction which depends on the exponent alpha. An approximate map of this model to a known XY model with dipolar interactions allows us to conclude that, for alpha<2 long-range orientational order of stripes can exist in two dimensions, and establish the universality class of the models. When alpha>=2 no long-range order is possible, but a phase transition in the Kosterlitz-Thouless universality class is still present. These two different critical scenarios should be observed in experimentally relevant two dimensional systems like electronic liquids (alpha=1) and dipolar magnetic films (alpha=3). Results from Langevin simulations of Coulomb and dipolar systems give support to the theoretical results. PMID- 25839294 TI - Modifying the interlayer interaction in layered materials with an intense IR laser. AB - We propose a transient interlayer compression in two-dimensional compound materials by using an intense IR laser resonant with the out-of-plane optical phonon mode (A(2u) mode). As a test case, we studied bilayer hexagonal boron nitride (h-BN), which is one of the compound layered materials. Excited state molecular dynamics calculations using time-dependent density functional theory show an 11.3% transient interlayer contraction of h-BN due to an interlayer dipole-dipole attraction of the laser-pumped A(2u) mode. These results are applicable to other layered compound materials. Such layered materials are a good material for nanospace chemistry, e.g., intercalating molecules and acting with them, and IR irradiation to contract the interlayer distance could provide a new route for chemical reactions under pressure. The duration of the contraction is at least 1 ps in the current simulation, which is observable by high-speed electron-beam diffraction measurements. PMID- 25839295 TI - Polariton Z topological insulator. AB - We demonstrate that honeycomb arrays of microcavity pillars behave as an optical frequency two-dimensional photonic topological insulator. We show that the interplay between the photonic spin-orbit coupling natively present in this system and the Zeeman splitting of exciton polaritons in external magnetic fields leads to the opening of a nontrivial gap characterized by a C=+/-2 set of band Chern numbers and to the formation of topologically protected one-way edge states. PMID- 25839296 TI - Effects of low-energy excitations on spectral properties at higher binding energy: the metal-insulator transition of VO(2). AB - The effects of electron interaction on spectral properties can be understood in terms of coupling between excitations. In transition-metal oxides, the spectral function close to the Fermi level and low-energy excitations between d states have attracted particular attention. In this work we focus on photoemission spectra of vanadium dioxide over a wide (10 eV) range of binding energies. We show that there are clear signatures of the metal-insulator transition over the whole range due to a cross coupling of the delocalized s and p states with low energy excitations between the localized d states. This coupling can be understood by advanced calculations based on many-body perturbation theory in the GW approximation. We also advocate the fact that tuning the photon energy up to the hard-x-ray range can help to distinguish fingerprints of correlation from pure band-structure effects. PMID- 25839297 TI - Exciton versus free carrier photogeneration in organometal trihalide perovskites probed by broadband ultrafast polarization memory dynamics. AB - We studied the ultrafast transient response of photoexcitations in two hybrid organic-inorganic perovskite films used for high efficiency photovoltaic cells, namely, CH(3)NH(3)PbI(3) and CH(3)NH(3)PbI(1.1)Br(1.9) using polarized broadband pump-probe spectroscopy in the spectral range of 0.3-2.7 eV with 300 fs time resolution. For CH(3)NH(3)PbI(3) with above-gap excitation we found both photogenerated carriers and excitons, but only carriers are photogenerated with below-gap excitation. In contrast, mainly excitons are photogenerated in CH(3)NH(3)PbI(1.1)Br(1.9). Surprisingly, we also discovered in CH(3)NH(3)PbI(3), but not in CH(3)NH(3)PbI(1.1)Br(1.9), transient photoinduced polarization memory for both excitons and photocarriers, which is also reflected in the steady state photoluminescence. From the polarization memory dynamics we obtained the excitons diffusion constant in CH(3)NH(3)PbI(3), D~0.01 cm(2) s(-1). PMID- 25839298 TI - Real-space calculation of the conductivity tensor for disordered topological matter. AB - We describe an efficient numerical approach to calculate the longitudinal and transverse Kubo conductivities of large systems using Bastin's formulation. We expand the Green's functions in terms of Chebyshev polynomials and compute the conductivity tensor for any temperature and chemical potential in a single step. To illustrate the power and generality of the approach, we calculate the conductivity tensor for the quantum Hall effect in disordered graphene and analyze the effect of the disorder in a Chern insulator in Haldane's model on a honeycomb lattice. PMID- 25839299 TI - Topological Kondo effect in transport through a superconducting wire with multiple Majorana end states. AB - We investigate a system of multiple Majorana states at the end of a topological superconducting wire coupled to a normal lead. For a minimum of three Majorana fermions at the interface, we find nontrivial renormalization physics. Interface tunneling processes can be classified in terms of spin-1/2 and spin-3/2 irreducible representations of the SU(2) group. We show that the renormalization of the tunneling amplitudes belonging to different representations is completely different in that one type is suppressed, whereas the other is enhanced, depending on the sign of the Kondo-type interaction coupling. This results in distinct temperature dependencies of the tunneling current through the interface and different spin polarizations of this current. PMID- 25839300 TI - Coherent terahertz control of vertical transport in semiconductor heterostructures. AB - Coherent-control protocols are introduced to selectively transport electrons, excitons, or pure two-particle correlations through semiconductor interfaces. The scheme is tested in a double-quantum-well structure where a sequence of terahertz pulses is applied to induce the vertical excitation transfer between the wells. Using a microscopic theory, it is shown that efficient and highly selective transfer can be realized even in the presence of the unavoidable scattering and dephasing processes. PMID- 25839301 TI - Topological spinon semimetals and gapless boundary states in three dimensions. AB - Recently, there has been much effort in understanding topological phases of matter with gapless bulk excitations, which are characterized by topological invariants and protected intrinsic boundary states. Here we show that topological semimetals of Majorana fermions arise in exactly solvable Kitaev spin models on a series of three-dimensional lattices. The ground states of these models are quantum spin liquids with gapless nodal spectra of bulk Majorana fermion excitations. It is shown that these phases are topologically stable as long as certain discrete symmetries are protected. The corresponding topological indices and the gapless boundary states are explicitly computed to support these results. In contrast to previous studies of noninteracting systems, the phases discussed in this work are novel examples of gapless topological phases in interacting spin systems. PMID- 25839302 TI - Pressure induced superconductivity on the border of magnetic order in MnP. AB - We report the discovery of superconductivity on the border of long-range magnetic order in the itinerant-electron helimagnet MnP via the application of high pressure. Superconductivity with T(sc)~1 K emerges and exists merely near the critical pressure P(c)~8 GPa, where the long-range magnetic order just vanishes. The present finding makes MnP the first Mn-based superconductor. The close proximity of superconductivity to a magnetic instability suggests an unconventional pairing mechanism. Moreover, the detailed analysis of the normal state transport properties evidenced non-Fermi-liquid behavior and the dramatic enhancement of the quasiparticle effective mass near P(c) associated with the magnetic quantum fluctuations. PMID- 25839303 TI - Detection of an unconventional superconducting phase in the vicinity of the strong first-order magnetic transition in CrAs using (75)As-nuclear quadrupole resonance. AB - Pressure-induced superconductivity was recently discovered in the binary helimagnet CrAs. We report the results of measurements of nuclear quadrupole resonance for CrAs under pressure. In the vicinity of the critical pressure P(c) between the helimagnetic (HM) and paramagnetic (PM) phases, a phase separation is observed. The large internal field remaining in the phase-separated HM state indicates that the HM phase disappears through a strong first-order transition. This indicates the absence of a quantum critical point in CrAs; however, the nuclear spin-lattice relaxation rate 1/T(1) reveals that substantial magnetic fluctuations are present in the PM state. The absence of a coherence effect in 1/T(1) in the superconducting state provides evidence that CrAs is the first Cr based unconventional superconductor. PMID- 25839304 TI - Linear magnetoresistance caused by mobility fluctuations in n-doped Cd(3)As(2). AB - Cd(3)As(2) is a candidate three-dimensional Dirac semimetal which has exceedingly high mobility and nonsaturating linear magnetoresistance that may be relevant for future practical applications. We report magnetotransport and tunnel diode oscillation measurements on Cd(3)As(2), in magnetic fields up to 65 T and temperatures between 1.5 and 300 K. We find that the nonsaturating linear magnetoresistance persists up to 65 T and it is likely caused by disorder effects, as it scales with the high mobility rather than directly linked to Fermi surface changes even when approaching the quantum limit. From the observed quantum oscillations, we determine the bulk three-dimensional Fermi surface having signatures of Dirac behavior with a nontrivial Berry phase shift, very light effective quasiparticle masses, and clear deviations from the band structure predictions. In very high fields we also detect signatures of large Zeeman spin splitting (g~16). PMID- 25839305 TI - Spin crossover in ferropericlase from first-principles molecular dynamics. AB - Ferropericlase, (Mg,Fe)O, is the second-most abundant mineral of Earth's lower mantle. With increasing pressure, the Fe ions in the material begin to collapse from a magnetic to nonmagnetic spin state. We present a finite-temperature first principles phase diagram of this spin crossover, finding a broad pressure range with coexisting magnetic and nonmagnetic ions due to favorable enthalpy of mixing of the two. Furthermore, we find the electrical conductivity of the mineral to reach semimetallic values inside Earth. PMID- 25839306 TI - Many-body localization in imperfectly isolated quantum systems. AB - We use numerical exact diagonalization to analyze which aspects of the many-body localization phenomenon survive in an imperfectly isolated setting, when the system of interest is weakly coupled to a thermalizing environment. We show that widely used diagnostics (such as many-body level statistics and expectation values in exact eigenstates) cease to show signatures of many-body localization above a critical coupling that is exponentially small in the size of the environment. However, we also identify alternative diagnostics for many-body localization, in the spectral functions of local operators. Diagnostics include a discrete spectrum and a hierarchy of energy gaps, including a universal gap at zero frequency. These alternative diagnostics are shown to be robust, and continue to show signatures of many-body localization as long as the coupling to the bath is weaker than the characteristic energy scales in the system. We also examine how these signatures disappear when the coupling to the environment becomes larger than the characteristic energy scales of the system. PMID- 25839307 TI - Evidence for room temperature electric polarization in RMn(2)O(5) multiferroics. AB - It is established that the multiferroics RMn(2)O(5) crystallize in the centrosymmetric Pbam space group and that the magnetically induced electric polarization appearing at low temperature is accompanied by a symmetry breaking. However, both our present x-ray study-performed on compounds with R=Pr,Nd,Gd,Tb, and Dy-and first-principles calculations unambiguously rule out this picture. Based on structural refinements, geometry optimization, and physical arguments, we demonstrate in this Letter that the actual space group is likely to be Pm. This turns out to be of crucial importance for RMn(2)O(5) multiferroics since Pm is not centrosymmetric. Ferroelectricity is thus already present at room temperature, and its enhancement at low temperature is a spin-enhanced process. This result is also supported by direct observation of optical second harmonic generation. This fundamental result calls into question the actual theoretical approaches that describe the magnetoelectric coupling in this multiferroic family. PMID- 25839308 TI - Submillisecond hyperpolarization of nuclear spins in silicon. AB - In this Letter, we devise a fast and effective nuclear spin hyperpolarization scheme, which is, in principle, magnetic field independent. We use this scheme to experimentally demonstrate polarizations of up to 66% for phosphorus donor nuclear spins in bulk silicon, which are created within less than 100 MUs in a magnetic field of 0.35 T at a temperature of 5 K. The polarization scheme is based on a spin-dependent recombination process via weakly coupled spin pairs, for which the recombination time constant strongly depends on the relative orientation of the two spins. We further use this scheme to measure the nuclear spin relaxation time and find a value of ~100 ms under illumination, in good agreement with the value calculated for nuclear spin flips induced by repeated ionization and deionization processes. PMID- 25839309 TI - Magnetic origin of giant magnetoelectricity in doped Y-type hexaferrite Ba(0.5)Sr(1.5)Zn(2)(Fe(1-x)Al(x))(12)O(22). AB - We investigated site-specific magnetic behaviors of multiferroic Ba(0.5)Sr(1.5)Zn(2)(Fe(1-x)Al(x))(12)O(22) using Fe L(2,3)-edge x-ray magnetic circular dichroism. The Al dopants mostly replace the Fe(3+) ions at octahedral (O(h)) sites, which contribute unquenched angular momenta through off-centering displacements. This replacement greatly reduces the magnetic anisotropy energy to change the magnetic order from a helical to a heliconical type with enhanced magnetoelectric susceptibility (alpha(ME)). The tetrahedral (T(d)) Fe sites exhibit magnetic hysteresis distinguishable from that of the O(h) sites, especially at low magnetic fields. These results provide essential clues for the heliconical order with a giant alpha(ME) and multibit memory effects in the Al doped Y-type hexaferrite. PMID- 25839310 TI - Forming a cube from a sphere with tetratic order. AB - Composed of square particles, the tetratic phase is characterized by a fourfold symmetry with quasi-long-range orientational order but no translational order. We construct the elastic free energy for tetratics and find a closed form solution for +/-1/4 disclinations in planar geometry. Applying the same covariant formalism to a sphere, we show analytically that within the one elastic constant approximation eight +1/4 disclinations favor positions defining the vertices of a cube. The interplay between defect-defect interactions and bending energy results in a flattening of the sphere towards superspheroids with the symmetry of a cube. PMID- 25839311 TI - Optical tracking of anomalous diffusion kinetics in polymer microspheres. AB - In this Letter we propose the use of whispering gallery mode resonance tracking as a label-free optical means to monitor diffusion kinetics in glassy polymer microspheres. Approximate solutions to the governing diffusion equations are derived for the case of slow relaxation and small Stefan number. Transduction of physical changes in the polymer, including formation of a rubbery layer, swelling, and dissolution, into detectable resonance shifts are described using a perturbative approach. Concrete examples of poly(methyl methacrylate) and polystyrene spheres in water are considered. PMID- 25839312 TI - Highly nonlinear wave propagation in elastic woodpile periodic structures. AB - In the present work, we experimentally implement, numerically compute with, and theoretically analyze a configuration in the form of a single column woodpile periodic structure. Our main finding is that a Hertzian, locally resonant, woodpile lattice offers a test bed for the formation of genuinely traveling waves composed of a strongly localized solitary wave on top of a small amplitude oscillatory tail. This type of wave, called a nanopteron, is not only motivated theoretically and numerically, but is also visualized experimentally by means of a laser Doppler vibrometer. This system can also be useful for manipulating stress waves at will, for example, to achieve strong attenuation and modulation of high-amplitude impacts without relying on damping in the system. PMID- 25839313 TI - Perceptrons with Hebbian learning based on wave ensembles in spatially patterned potentials. AB - A general scheme to realize a perceptron for hardware neural networks is presented, where multiple interconnections are achieved by a superposition of Schrodinger waves. Spatially patterned potentials process information by coupling different points of reciprocal space. The necessary potential shape is obtained from the Hebbian learning rule, either through exact calculation or construction from a superposition of known optical inputs. This allows implementation in a wide range of compact optical systems, including (1) any nonlinear optical system, (2) optical systems patterned by optical lithography, and (3) exciton polariton systems with phonon or nuclear spin interactions. PMID- 25839314 TI - Electrohydrodynamics near hydrophobic surfaces. AB - We show that an electro-osmotic flow near the slippery hydrophobic surface depends strongly on the mobility of surface charges, which are balanced by counterions of the electrostatic diffuse layer. For a hydrophobic surface with immobile charges, the fluid transport is considerably amplified by the existence of a hydrodynamic slippage. In contrast, near the hydrophobic surface with mobile adsorbed charges, it is also controlled by an additional electric force, which increases the shear stress at the slipping interface. To account for this, we formulate electrohydrodynamic boundary conditions at the slipping interface, which should be applied to quantify electro-osmotic flows instead of hydrodynamic boundary conditions. Our theoretical predictions are fully supported by dissipative particle dynamics simulations with explicit charges. These results lead to a new interpretation of zeta potential of hydrophobic surfaces. PMID- 25839315 TI - Confinement effects of ion tracks in ultrathin polymer films. AB - We show direct experimental evidence that radiation effects produced by single MeV heavy ions on a polymer surface are weakened when the length of the ion track in the material is confined into layers of a few tens of nanometers. Deviation from the bulk (thick film) behavior of ion-induced craters starts at a critical thickness as large as ~40 nm, due to suppression of long-range additive effects of excited atoms along the track. Good agreement was found between the experimental results, molecular dynamic simulations, and an analytical model. PMID- 25839316 TI - Refraction of scroll-wave filaments at the boundary between two reaction diffusion media. AB - We explore the shape and the dynamics of scroll-wave filaments in excitable media with an abruptly changing diffusion tensor, important for cardiac applications. We show that, similar to a beam of light, the filament refracts at the boundary separating domains with different diffusion. We derive the laws of filament refraction and test their validity in computational experiments. We discovered that at small angles to the interface, the filament can become unstable and develop oscillations. The nature of the observed instabilities, as well as overall theoretical and experimental significance of the findings, is discussed. PMID- 25839317 TI - Comment on "How the result of a single coin toss can turn out to be 100 heads". PMID- 25839318 TI - Ferrie and Combes reply. PMID- 25839319 TI - Total anatomical laparoscopic liver resection of segment 4 (S4), extended S4, and subsegments S4a and S4b for hepatocellular carcinoma. AB - BACKGROUND: When a tumor is located in segment 4 (S4), it is preferable to perform only limited resection of S4, even in laparoscopic surgery. Here we describe anatomical laparoscopic S4, subdivision of S4 (S4a and S4b), and extended S4 segmentectomy for hepatocellular carcinoma (HCC), using the Glissonian pedicle transection method for each, and evaluate the feasibility of laparoscopic liver resection (LLR) for tumors located in S4. PATIENTS AND METHODS: Among 417 patients who underwent LLR for malignant tumors between March 2003 and February 2014, we performed retrospective analysis of the clinical and perioperative outcomes of 10 patients who underwent anatomical liver resection for tumors located in the S4 area of the liver. RESULTS: Total laparoscopic anatomic liver resection (S4, extended S4, and S4a and S4b segmentectomies) were performed in 10 patients. There was no open conversion or postoperative mortality. The mean operation time was 316.5 minutes (range, 175-460 minutes), and mean estimated blood loss was 592 mL (range, 100-1600 mL). An intraoperative transfusion was necessary in 2 (20%) of the 10 patients. All patients had negative resection margins. Three patients (30%) had postoperative complications (intraabdominal fluid collection). The mean postoperative hospital stay was 7.7 days (range, 3-13 days). The median follow-up period was 18 months. Intrahepatic recurrence occurred in 2 (20%) of the 10 patients, which was managed by radiofrequency ablation with transarterial chemoembolization in 1 patient and by transarterial chemoembolization alone in the other patient. CONCLUSIONS: Total laparoscopic anatomical S4, extended S4, or S4a or S4b segmentectomy is a feasible procedure for HCC. The Glissonian pedicle transection method is an effective technique for rapid and safe control and subdivision of the S4 pedicle that facilitates anatomical laparoscopic S4, extended S4, and S4a and S4b segmentectomy. PMID- 25839320 TI - Membrane surface-enhanced Raman spectroscopy for sensitive detection of molecular behavior of lipid assemblies. AB - The dynamic properties of phospholipid (PL) membranes (phase state and phase transition) play crucial roles in biological systems. However, highly sensitive, direct analytical methods that shed light on the nature of lipids and their assemblies have not been developed to date. Here, we describe the analysis of PL modified Au nanoparticles (Au@PL) using membrane surface-enhanced Raman spectroscopy (MSERS) and report the properties of the self-assembled PL membranes on the Au nanoparticle. The Raman intensity per PL concentration increased by 50 170 times with Au@PL, as compared to large unilamellar vesicles (LUVs) at the same PL concentration. The phase state and phase transition temperature of the PL membrane of Au@PL were investigated by analyzing the Raman peak ratio (R = I2882/I2930). The enhancement at 714 cm(-1) (EF(714)) varied with the hydrocarbon chain length of the PLs and the assembled degree of Au@PLs. In calculation, the EF(714),assembled was estimated to be 111-142 when the distance between AuNPs was 7.0-7.5 nm, which was correlated to the speculative enhancement factor, suggesting that the assembly of the Au@PLs contributed to the MSERS. PMID- 25839321 TI - Analysis of the Constraint Joint Loading in the Thumb During Pipetting. AB - Dynamic loading on articular joints is essential for the evaluation of the risk of the articulation degeneration associated with occupational activities. In the current study, we analyzed the dynamic constraint loading for the thumb during pipetting. The constraint loading is considered as the loading that has to be carried by the connective tissues of the joints (i.e., the cartilage layer and the ligaments) to maintain the kinematic constraints of the system. The joint loadings are solved using a classic free-body approach, using the external loading and muscle forces, which were obtained in an inverse dynamic approach combined with an optimization procedure in anybody. The constraint forces in the thumb joint obtained in the current study are compared with those obtained in the pinch and grasp tests in a previous study (Cooney and Chao, 1977, "Biomechanical Analysis of Static Forces in the Thumb During Hand Function," J. Bone Joint Surg. Am., 59(1), pp. 27-36). The maximal compression force during pipetting is approximately 83% and 60% greater than those obtained in the tip pinch and key pinch, respectively, while substantially smaller than that obtained during grasping. The maximal lateral shear force is approximately six times, 32 times, and 90% greater than those obtained in the tip pinch, key pinch, and grasp, respectively. The maximal dorsal shear force during pipetting is approximately 3.2 and 1.4 times greater than those obtained in the tip pinch and key pinch, respectively, while substantially smaller than that obtained during grasping. Our analysis indicated that the thumb joints are subjected to repetitive, intensive loading during pipetting, compared to other daily activities. PMID- 25839322 TI - Conformational Analysis and Electronic Interactions of Some 4'-Substituted-2 ethylthio-phenylacetates. AB - The conformational analysis of various 4'-substituted-2-ethylthio-phenylacetate compounds bearing the substituents NO2 (1), Cl (2), H (3), Me (4), and OMe (5) was performed using infrared (IR) spectroscopic analysis of the carbonyl stretching band (nuCO) supported by B3LYP/6-31G(d,p), NBO, QTAIM, and SM5.42R calculations for compounds 1, 3, and 5. The IR spectra in n-hexane indicate the presence of three components, whose intensities decrease upon increasing frequency. In solvents with high permittivity, while the low intensity component at higher frequency disappears, the relative intensity of the component at the intermediate frequency changes with respect to the lower frequency component with differing trends for the various derivatives. It can be observed that the intensity does not vary for compounds 1 and 2, which bear an electron-withdrawing substituent at 4', while it increases in intensity for compounds 3-5. The computational results predict the presence of three gauche conformers, defined by the orientation of the C-S bond with respect to the carbonyl group, whose intensities and nuCO frequencies are in agreement with the experimental results. In solvents with increasing permittivity, the SM5.42R solvation model results reproduce the experimental trend observed for the two components in the low frequency region, while it overestimates the amount of the higher frequency conformer. NBO analysis suggests that all the conformers are stabilized to the same extent in the gauche conformation via sigmaC-S -> pi*CO and piCO -> sigma*C S orbital interactions. The different stability can be attributed to the geometrical arrangement of the C(O)-CH2-S-CH2-CH3 moiety, which assumes a six membered chair-like geometry in the g1 conformer, a six-membered twisted-chair like geometry in the g2 conformer, and a seven-membered chair-like ring in the g3 conformer. Quantum theory of atoms in molecules (QTAIM) indicates that the ring geometries were formed and stabilized from short contacts between the oppositely charged carbonyl oxygen and the methylene/methyl hydrogen atoms, which interact through unusual intramolecular electrostatic hydrogen bonding that satisfies the Popelier criteria. PMID- 25839323 TI - Probing the extracellular access channel of the Na,K-ATPase. AB - When the Na,K-ATPase pumps at each turnover two K(+) ions into the cytoplasm, this translocation consists of several reaction steps. First, the ions diffuse consecutively from the extracellular phase through an access pathway to the binding sites where they are coordinated. In the next step, the enzyme is dephosphorylated and the ions are occluded inside the membrane domain. The subsequent transition to the E1 conformation produces a deocclusion of the binding sites to the cytoplasmic side of the membrane and allows in the last steps ion dissociation and diffusion to the aqueous phase. The interaction and competition of K(+) with various quaternary organic ammonium ions have been used to gain insight into the molecular mechanism of the ion binding process from the extracellular side in the P-E2 conformation of the enzyme. Using the electrochromic styryl dye RH421, evidence has been obtained that the access pathway consists of a wide and water-filled funnel-like part that is accessible also for bulky cations such as the benzyltriethylammonium ion, and a narrow part that permits passage only of small cations such as K(+) and NH4(+) in a distinct electrogenic way. Benzyltriethylammonium ions inhibit K(+) binding in a competitive manner that can be explained by a stopper-like function at the interface between the wide and narrow parts of the access pathway. In contrast to other quaternary organic ammonium ions, benzyltriethylammonium ions show a specific binding to the ion pump in a position inside the access pathway where it blocks effectively the access to the binding sites. PMID- 25839325 TI - Synthesis of the spirastrellolide A, B/C spiroketal: enabling solutions for problematic Au(I)-catalyzed spiroketalizations. AB - A synthesis of the spirastrellolide A, B/C-ring monounsaturated spiroketal is reported. The key step relies on a Au-catalyzed spiroketalization of a propargyl triol employing an acetonide as a regioselectivity regulator. Through observation and analysis, a set of conditions has been developed that facilitates the use of a mixture of diastereomeric substrates, obviating the need to control the stereochemistry of the propargyl stereocenter and enabling a convenient retrosynthetic disconnection. The key reaction proceeds in 80% yield in 1 min at ambient temperature with the Me3PAuCl/AgOTf catalyst system. These conditions should be widely applicable for new synthetic endeavors as they appear to overcome all issues with the Au-catalyzed spiroketalization. PMID- 25839324 TI - The expression of P2X7 receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas. AB - In order to use endothelial progenitor cells (EPCs) as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas, how to enhance proliferation and targeting ability of transplanted EPCs is a high priority. Here, we confirmed, for the first time, the expression of P2X7 receptors in rat spleen-derived EPCs. Activation of P2X7 receptors in EPCs by BzATP promoted cells proliferation and migration, rather than apoptosis. In vivo, the homing of transplanted EPCs after long-term suppression of P2X7 receptors by persistent BBG stimulation was evaluated by MRI, immunohistochemistry and flow cytometry. Compared to the group without BBG treatment, less transplanted EPCs homed to gliomas in the group with BBG treatment, especially integrated into the vessels containing tumor-derived endothelial cells in gliomas. Moreover, western blot showed that CXCL1 expression was downregulated in gliomas with BBG treatment, which meant P2X7 receptors suppression inhibited the homing of EPCs to gliomas through down-regulation of CXCLl expression. Further, effects of P2X7 receptors on C6 glioma cells or gliomas were evaluated at the same dose of BzATP or BBG used in EPCs experiments in vitro and in vivo. MTT assay and MRI revealed that P2X7 receptors exerted no significant promoting effect on C6 glioma cells proliferation, gliomas growth and angiogenesis. Taken together, our findings imply the possibility of promoting proliferation and targeting ability of transplanted EPCs to brain gliomas in vivo through P2X7 receptors, which may provide new perspectives on application of EPCs as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas. PMID- 25839326 TI - Jean Lindenmann: from viral interference to interferon and beyond (1924-2015). PMID- 25839327 TI - Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability. AB - Innervation of the gut is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomous defects in enteric neuronal cell differentiation, proliferation, migration, or survival. Rare, high penetrance coding variants and common, low-penetrance non-coding variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret proto-oncogene (RET). We used a genome-wide association (220 trios) and replication (429 trios) study to reveal a second non-coding variant distal to RET and a non-coding allele on chromosome 7 within the class 3 Semaphorin gene cluster. Analysis in Ret wild-type and Ret-null mice demonstrates specific expression of Sema3a, Sema3c, and Sema3d in the enteric nervous system (ENS). In zebrafish embryos, sema3 knockdowns show reduction of migratory ENS precursors with complete ablation under conjoint ret loss of function. Seven candidate receptors of Sema3 proteins are also expressed within the mouse ENS and their expression is also lost in the ENS of Ret-null embryos. Sequencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein structure modeling and functional analyses identified five disease-associated alleles with loss-of-function defects in semaphorin dimerization and binding to their cognate neuropilin and plexin receptors. Thus, semaphorin 3C/3D signaling is an evolutionarily conserved regulator of ENS development whose dys-regulation is a cause of enteric aganglionosis. PMID- 25839330 TI - Identification of the sigma70-Dependent Promoter Controlling Expression of the ansPAB Operon of the Nitrogen-Fixing Bacterium Rhizobium etli. AB - The aim of the present work was to examine the putative promoter region of the operon ansPAB and to determine the general elements required for the regulation of transcriptional activity. The transcriptional start site of the ansPAB promoter was determined by using highresolution S1-nuclease mapping. Sequence analysis of this region showed -10 and -35 elements, which were consistent with consensus sequences for R. etli promoters that are recognized by the major form of RNA polymerase containing the sigma(70) transcription factor. Mutation studies affecting several regions located upstream of the transcriptional start site confirmed the importance of these elements on transcriptional expression. PMID- 25839329 TI - De novo mutations in SIK1 cause a spectrum of developmental epilepsies. AB - Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy. PMID- 25839331 TI - Evaluation of Glucose Dehydrogenase and Pyrroloquinoline Quinine (pqq) Mutagenesis that Renders Functional Inadequacies in Host Plants. AB - The rhizospheric zone abutting plant roots usually clutches a wealth of microbes. In the recent past, enormous genetic resources have been excavated with potential applications in host plant interaction and ancillary aspects. Two Pseudomonas strains were isolated and identified through 16S rRNA and rpoD sequence analyses as P. fluorescens QAU67 and P. putida QAU90. Initial biochemical characterization and their root-colonizing traits indicated their potential role in plant growth promotion. Such aerobic systems, involved in gluconic acid production and phosphate solubilization, essentially require the pyrroloquinoline quinine (PQQ)- dependent glucose dehydrogenase (GDH) in the genome. The PCR screening and amplification of GDH and PQQ and subsequent induction of mutagenesis characterized their possible role as antioxidants as well as in growth promotion, as probed in vitro in lettuce and in vivo in rice, bean, and tomato plants. The results showed significant differences (p < or = 0.05) in parameters of plant height, fresh weight, and dry weight, etc., deciphering a clear and in fact complementary role of GDH and PQQ in plant growth promotion. Our study not only provides direct evidence of the in vivo role of GDH and PQQ in host plants but also reveals their functional inadequacy in the event of mutation at either of these loci. PMID- 25839328 TI - Genomic analyses reveal mutational signatures and frequently altered genes in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets. PMID- 25839332 TI - Gut Microbiota Community and Its Assembly Associated with Age and Diet in Chinese Centenarians. AB - Increasing evidence suggests that gut microbiota underpin the development of health and longevity. However, our understanding of what influences the composition of this community of the longevous has not been adequately described. Therefore, illumina sequencing analysis was performed on the gut microbiota of centenarians (aged 100-108 years; RC) and younger elderlies (aged 85-99 years; RE) living in Bama County, Guangxi, China and the elderlies (aged 80-92 years; CE) living in Nanning City, Guangxi, China. In addition, their diet was monitored using a semiquantitative dietary questionary (FFQ 23). The results revealed the abundance of Roseburia and Escherichia was significantly greater, whereas that of Lactobacillus, Faecalibacterium, Parabacteroides, Butyricimonas, Coprococcus, Megamonas, Mitsuokella, Sutterella, and Akkermansia was significantly less in centenarians at the genus level. Both clustering analysis and UniFraq distance analysis showed structural segregation with age and diet among the three populations. Using partial least square discriminate analysis and redundancy analysis, we identified 33 and 34 operational taxonomic units (OTUs) as key OTUs that were significantly associated with age and diet, respectively. Age-related OTUs were characterized as Ruminococcaceae, Clostridiaceae, and Lachnospiraceae, and the former two were increased in the centenarians; diet-related OTUs were classified as Bacteroidales, Lachnospiraceae, and Ruminococcaceae. The former two were deceased, whereas the later one was increased, in the high-fiber diet. The age and high-fiber diet were concomitant with changes in the gut microbiota of centenarians, suggesting that age and high-fiber diet can establish a new structurally balanced architecture of gut microbiota that may benefit the health of centenarians. PMID- 25839333 TI - Immune Regulatory Effect of Newly Isolated Lactobacillus delbrueckii from Indian Traditional Yogurt. AB - Lactic acid bacteria (LAB) are microorganisms that are believed to provide health benefits. Here, we isolated LAB from Indian fermented foods, such as traditional Yogurt and Dosa. LAB from Yogurt most significantly induced TNF-alpha and IL 1beta production, whereas LAB from Dosa induced mild cytokine production. After 16S rRNA gene sequencing and phylogenetic analysis, a Yogurt-borne lactic acid bacterium was identified and classified as Lactobacillus delbrueckii subsp. bulgaricus, and it was renamed L. delbrueckii K552 for the further studies. Our data suggest that the newly isolated L. delbrueckii can be used for the treatment of immune deficiency disorders. PMID- 25839334 TI - Attitudes Toward Telemedicine in Urban, Rural, and Highly Rural Communities. AB - INTRODUCTION: The rate of telemedicine adoption using interactive video between patient and provider has not met expectations. Technology, regulations, and physician buy-in are cited reasons, but patient acceptance has not received much consideration. We examine attitudes regarding telemedicine to better understand the subjective definitions of its acceptability and utility that shape patients' willingness to use telemedicine. MATERIALS AND METHODS: Using the Montana Health Matters study (a random, statewide survey [n=3,512]), we use latent class analysis to identify groups with similar patterns of attitudes toward telemedicine followed by multinomial logistic regression to estimate predictors of group membership. RESULTS: Although only 5% are amenable to telemedicine regardless of circumstance, 23% would be comfortable if it could be convenient, whereas 29% would be situationally amenable but uncomfortable using telemedicine. Still, a substantial percentage (43%) is unequivocally averse to telemedicine despite the inconvenience of in-person visits. Educational attainment, prior Internet use, and rural residence are main predictors that increase the likelihood of being in an amenable group. CONCLUSIONS: From the patient's perspective, the advantages of reduced travel and convenience are recognized, but questions remain about the equivalence to physician visits. Many people are averse to telemedicine, indicating a perceived incompatibility with patient needs. Only 1.7% of the respondents reported using telemedicine in the previous year; about half were veterans. Hence, few have used telemedicine, and key innovation adoption criteria-trialability and observability-are low. Increased attention to public awareness in the adoption process is needed to increase willingness to embrace telemedicine as a convenient way to obtain quality healthcare services. PMID- 25839336 TI - Solution phase synthesis of indium gallium phosphide alloy nanowires. AB - The tunable physical and electronic structure of III-V semiconductor alloys renders them uniquely useful for a variety of applications, including biological imaging, transistors, and solar energy conversion. However, their fabrication typically requires complex gas phase instrumentation or growth from high temperature melts, which consequently limits their prospects for widespread implementation. Furthermore, the need for lattice matched growth substrates in many cases confines the composition of the materials to a narrow range that can be epitaxially grown. In this work, we present a solution phase synthesis for indium gallium phosphide (In(x)Ga(1-x)P) alloy nanowires, whose indium/gallium ratio, and consequently, physical and electronic structure, can be tuned across the entire x = 0 to x = 1 composition range. We demonstrate the evolution of structural and optical properties of the nanowires, notably the direct to indirect band gap transition, as the composition is varied from InP to GaP. Our scalable, low-temperature synthesis affords compositional, structural, and electronic tunability and can provide a route for realization of broader In(x)Ga(1-x)P applications. PMID- 25839335 TI - Reductant and sequence effects on the morphology and catalytic activity of peptide-capped Au nanoparticles. AB - The use of peptides as capping ligands for materials synthesis has been widely explored. The ambient conditions of bio-inspired syntheses using molecules such as peptides represent an attractive route for controlling the morphology and activity of nanomaterials. Although various reductants can be used in such syntheses, no comprehensive comparison of the same bio-based ligand with different reductants has been reported. In this contribution, peptides AuBP1, AuBP2, and Pd4 are used in the synthesis of Au nanoparticles. The reductant strength is varied by using three different reducing agents: NaBH4, hydrazine, and ascorbic acid. These changes in reductant produce significant morphological differences in the final particles. The weakest reductant, ascorbic acid, yields large, globular nanoparticles with rough surfaces, whereas the strongest reductant, NaBH4, yields small, spherical, smooth nanomaterials. Studies of 4 nitrophenol reduction using the Au nanoparticles as catalysts reveal a decrease in activation energy for the large, globular, rough materials relative to the small, spherical, smooth materials. These studies demonstrate that modifying the reductant is a simple way to control the activity of peptide-capped nanoparticles. PMID- 25839337 TI - Positive symptoms are associated with clinicians' global impression in treatment resistant schizophrenia. AB - Previous investigations on the relationship between global rating measures and symptoms have not considered the additional role of functioning. In this naturalistic study, we examined the relationship between symptom domains and functioning on Clinical Global Impression scales for severity (CGI-S) and improvement (CGI-I) in a sample of patients with schizophrenia assessed to be treatment resistant. Participants were patients with a diagnosis of schizophrenia or schizoaffective disorder who failed 2 prior antipsychotic trials and were considered candidates for clozapine. They were assessed on the 18-item Brief Psychiatric rating Scale (BPRS), Social Occupational Functioning Assessment Scale (SOFAS), and CGI-S at baseline. A subset of patients was followed up at 6 weeks after initiation of clozapine and assessed on the CGI-I. The independent effects of symptom domains and functioning on the CGI scales were examined via multivariate regression models. Brief Psychiatric rating Scale positive factor (P < 0.001) and SOFAS (P < 0.001) scores were significant determinants of CGI-S at baseline. Multivariate models suggested that relative change measures had a better fit for the CGI-I compared to absolute change measures (R = 0.72 vs R = 0.61, respectively). Improvements in BPRS positive (P < 0.001) and affect (P = 0.002) factors and SOFAS (P = 0.030) scores were significant determinants of CGI I. Ratings of 1 and 2 on the CGI-I corresponded to a mean relative change in the BPRS total of 65% and 41%, respectively. Positive symptoms were a key determinant of clinicians' impression of severity and improvement in this study. Although psychosocial functioning played a large part in determining severity, it was not as significant in the assessment of improvement. PMID- 25839338 TI - Effects of Shakuyaku-Kanzo-to on Extrapyramidal Symptoms During Antipsychotic Treatment: A Randomized, Open-Label Study. AB - Extrapyramidal symptoms (EPS) are common adverse effects of antipsychotic treatment. This study examined the effects of the traditional Japanese herbal medicine (kampo) shakuyaku-kanzo-to on EPS during antipsychotic treatment. Twenty two Japanese patients with psychiatric disorders who had developed EPS during antipsychotic treatment were randomly allocated to receive either shakuyaku-kanzo to (7.5 g/d) or biperiden (3 mg/d) for 2 weeks. Extrapyramidal symptoms were evaluated using the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) and the Barnes Akathisia Rating Scale. Plasma levels of the monoamine metabolite homovanillic acid and serum prolactin levels were measured to investigate the mechanisms of action of shakuyaku-kanzo-to. Twenty of the 22 patients completed the study (10 patients in the shakuyaku-kanzo-to group and 10 patients in the biperiden group). There was a time effect on the Drug-Induced Extrapyramidal Symptom Scale total score (P < 0.01), suggesting that both shakuyaku-kanzo-to and biperiden decreased EPS. Notably, there was a time * drug interaction in dystonia, suggesting that shakuyaku-kanzo-to had a greater effect on dystonia compared with biperiden. No significant changes were observed in plasma homovanillic acid or serum prolactin levels after 2 weeks of treatment in either group. The effects of shakuyaku-kanzo-to on abnormal muscle tonus and dopamine D2 receptors may have contributed to improve EPS. These results suggest that shakuyaku-kanzo-to may be useful in decreasing EPS, especially dystonia, in patients undergoing treatment with antipsychotic agents. PMID- 25839339 TI - Management of cystic or predominantly cystic thyroid nodules: role of simple aspiration of internal fluid. AB - PURPOSE: The purpose of this study is to evaluate the efficacy of simple aspiration of cystic thyroid nodules by comparing with control groups to exclude the occurrence of spontaneous regression by the definition of current guidelines of American Thyroid Association. MATERIALS AND METHODS: 217 nodules from 210 patients with cystic thyroid nodules (cystic portion >50%) were included. Nodules were classified into three groups as follows: Group 1, observation only; Group 2, fine needle aspiration (FNA) without aspiration of internal fluid; and Group 3, FNA after aspiration of internal fluid. Significant nodule size change was defined as a difference in the largest diameter of 20%, as seen on the last follow-up ultrasound (US) compared to the initial US. RESULTS: Demographic characteristics did not show significant differences among the three groups except for the patient age (p = 0.039). Mean nodule size significantly decreased only in group 3 (p = 0.005). Significant nodule size reductions were observed in 22.0% (13/59) in group 1, 25.7% (28/109) in group 2, and 40.8% (20/49) in group 3, respectively. CONCLUSIONS: Aspiration of internal fluid should be considered as the first-line procedure for both the diagnosis and treatment of cystic or predominantly cystic thyroid nodules. PMID- 25839340 TI - Magic angle spinning NMR of proteins: high-frequency dynamic nuclear polarization and (1)H detection. AB - Magic angle spinning (MAS) NMR studies of amyloid and membrane proteins and large macromolecular complexes are an important new approach to structural biology. However, the applicability of these experiments, which are based on (13)C- and (15)N-detected spectra, would be enhanced if the sensitivity were improved. Here we discuss two advances that address this problem: high-frequency dynamic nuclear polarization (DNP) and (1)H-detected MAS techniques. DNP is a sensitivity enhancement technique that transfers the high polarization of exogenous unpaired electrons to nuclear spins via microwave irradiation of electron-nuclear transitions. DNP boosts NMR signal intensities by factors of 10(2) to 10(3), thereby overcoming NMR's inherent low sensitivity. Alternatively, it permits structural investigations at the nanomolar scale. In addition, (1)H detection is feasible primarily because of the development of MAS rotors that spin at frequencies of 40 to 60 kHz or higher and the preparation of extensively (2)H labeled proteins. PMID- 25839341 TI - ATP synthase. AB - Oxygenic photosynthesis is the principal converter of sunlight into chemical energy. Cyanobacteria and plants provide aerobic life with oxygen, food, fuel, fibers, and platform chemicals. Four multisubunit membrane proteins are involved: photosystem I (PSI), photosystem II (PSII), cytochrome b6f (cyt b6f), and ATP synthase (FOF1). ATP synthase is likewise a key enzyme of cell respiration. Over three billion years, the basic machinery of oxygenic photosynthesis and respiration has been perfected to minimize wasteful reactions. The proton-driven ATP synthase is embedded in a proton tight-coupling membrane. It is composed of two rotary motors/generators, FO and F1, which do not slip against each other. The proton-driven FO and the ATP-synthesizing F1 are coupled via elastic torque transmission. Elastic transmission decouples the two motors in kinetic detail but keeps them perfectly coupled in thermodynamic equilibrium and (time-averaged) under steady turnover. Elastic transmission enables operation with different gear ratios in different organisms. PMID- 25839342 TI - Corneal Wavefront Aberrations After Primary and Recurrent Pterygium Surgery. AB - PURPOSE: To evaluate the effect of primary and recurrent pterygium surgery on corneal wavefront aberrations. METHODS: This prospective and interventional study included the 47 eyes of 47 patients with primary pterygium (primary group) and 41 eyes of 41 patients with recurrent pterygium (recurrent group). All patients underwent pterygium excision with conjunctival autograft transplantation. Corneal wavefront aberrations were measured using Sirius corneal topography and aberrometry system (Costruzione Strumenti Oftalmici, Florence, Italy) before surgery and at 3 and 12 months after surgery. The main outcome measures were root mean square values of total wavefront error (WFE), higher-order aberrations (HOAs), coma, trefoil, and spherical aberrations. RESULTS: Corneal wavefront aberrations were not significantly different between the primary and recurrent groups at baseline (P>0.05). Total WFE, HOA, trefoil, and coma decreased significantly in both primary and recurrent groups at postoperative 3 and 12 months compared with preoperative measurements (P<0.05). The mean spherical aberration was not significantly changed at 3 and 12 months compared with preoperative measurements (P>0.05). Total WFE, HOA, trefoil, and coma were significantly higher in the recurrent group than in the primary group at postoperative 3 and 12 months (P<0.05). CONCLUSIONS: Pterygium surgery can significantly reduce corneal wavefront aberrations, including total WFE, HOA, trefoil, and coma in eyes with primary or recurrent pterygium. However, postoperative corneal aberrations were higher in the recurrent group than in the primary group. PMID- 25839343 TI - One-Year Clinical Outcomes of a Two-Step Surgical Management for Keratoconus Topography-Guided Photorefractive Keratectomy/Cross-Linking After Intrastromal Corneal Ring Implantation. AB - PURPOSE: To present the results of same-day topography-guided photorefractive keratectomy (TG-PRK) and corneal collagen cross-linking (CXL) after intrastromal corneal ring (ISCR) implantation in patients with keratoconus. METHODS: Thirty three patients (41 eyes) aged between 19 and 45 years were included in this prospective study. All patients underwent a femtosecond laser-enabled (Intralase FS; Abbott Medical Optics, Inc.) placement of intracorneal ring segments (Kerarings; Mediphacos, Brazil). Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and keratometry readings remained stable for 6 months. Same-day PRK and CXL was subsequently performed in all patients. RESULTS: After 12 months of completion of the procedure, mean UDVA in log of minimal angle of resolution was significantly improved (0.74+/-0.54-0.10+/-0.16); CDVA did not improve significantly but 85% of eyes maintained or gained multiple lines of CDVA; mean refraction spherical equivalent improved (from -3.03+/-1.98 to -0.04+/-0.99 D), all keratometry readings were significantly reduced, from preoperative values, but coma did not vary significantly from preoperative values. Central corneal thickness and corneal thickness at the thinnest point were significantly (P<0.0001) reduced from 519.76+/-29.33 and 501.87+/-31.50 preoperatively to 464.71+/-36.79 and 436.55+/-47.42 postoperatively, respectively. Safety and efficacy indices were 0.97 and 0.88, respectively. From 6 months up until more than 1 year of follow-up, further significant improvement was observed only for UDVA (P<0.0001). CONCLUSIONS: Same-day combined TG-PRK and CXL after ISCR implantation is a safe and effective option for improving visual acuity and visual function, and it halts the progression of the keratoconus. The improvements recorded after 6 months of follow-up were maintained or improved upon 1 year after the procedure. PMID- 25839344 TI - Axial Length Measurement: PalmScan Versus IOLMaster. AB - OBJECTIVE: To compare axial length measurements taken on the handheld Micro Medical Devices (MMD) PalmScan with those taken with the Carl Zeiss Meditec IOLMaster. METHODS: Sixty subjects had IOLMaster performed by a single operator to measure axial length in both eyes. Subjects then had axial length measurements taken by a different single operator with the MMD device. Each operator was masked to the other's results. Independent statistical analysis was performed to compare results. RESULTS: Sixty subjects had both eyes measured with each device for a total of 120 eyes. Subjects were categorized into 1 of 3 groups with 20 subjects each, 40 eyes in each group. Subjects in group A were wearers of overnight corneal reshaping, group B were soft lens wearers, and group C were noncontact lens wearers. Overall, the measures of axial length from IOLMaster and MMD were highly correlated (correlation = 0.93, P < 0.001, n = 120). Similarly, measures within each group between the 2 methods were highly correlated: group A (correlation = 0.94, P < 0.0001, n = 40), group B (correlation = 0.90, P < 0.0001, n = 40), and group C (correlation = 0.98, P < 0.001, n = 40). Results were highly correlated between the two devices. Data scatter plots and Bland Altman plots were generated, showing that although there was good agreement between the methods, the MMD almost always measured the axial length smaller than the IOLMaster (median difference = 0.21 mm, mean difference +/- SD = 0.26 +/- 0.42 mm). CONCLUSIONS: The MMD is a convenient, reliable, and portable device to measure axial length. It can be used to monitor axial length in patients over time. PMID- 25839345 TI - Comparison of Validated Polymerase Chain Reaction and Culture Isolation for the Routine Detection of Acanthamoeba From Ocular Samples. AB - PURPOSE: Acanthamoeba keratitis should be definitively diagnosed for appropriate therapy. Our institution has validated polymerase chain reaction (PCR) as a routine diagnostic test to detect Acanthamoeba DNA from ocular samples. We compared PCR with culture isolation for detecting Acanthamoeba from ocular samples. METHODS: The microbiology records of patients that had specimens submitted (May 2012 to January 2014) for laboratory testing for Acanthamoeba keratitis were reviewed for (1) Acanthamoeba culture isolation, (2) Acanthamoeba DNA detection by PCR, and (3) non-Acanthamoeba culture results. For Acanthamoeba isolation, corneal samples were planted on nonnutrient agar overlaid with Enterobacter aerogenes. Validated PCR (May 2012) for Acanthamoeba DNA was processed at the Division of Molecular Diagnostics, UPMC, Pittsburgh, PA. Additional cultures were obtained for bacteria, fungus, and virus (i.e., herpes simplex virus) using standard techniques. RESULTS: Culture isolation and PCR were processed on 125 patients with a differential diagnosis of Acanthamoeba keratitis. Of these, 104 (83.2%) were culture negative, PCR negative; 14 (11.2%) were culture positive, PCR positive; 4 (3.2%) were culture negative, PCR positive; and, 3 (2.4%) were culture positive, PCR negative. Culture and PCR were statistically equivalent for detecting Acanthamoeba from ocular samples (P=1.0, McNemar's test). Nineteen of the culture-negative, PCR-negative corneal samples (18.3%) were positive for other pathogens such as bacteria, fungus, and virus. CONCLUSIONS: There is no clear advantage of PCR over culture isolation for detecting Acanthamoeba in ocular specimens. Other pathogens such as bacteria, fungus, and virus must still be considered in severe persistent keratitis. Polymerase chain reaction seems to be a complementary test for the clinical support of Acanthamoeba keratitis. PMID- 25839346 TI - Corneal Biomechanical Properties in Rheumatoid Arthritis. AB - PURPOSE: To investigate the variations in biomechanical properties of the cornea in rheumatoid arthritis (RA) patients. METHODS: A total of 53 RA patients, and 25 healthy individuals (control group) were enrolled. Rheumatoid arthritis patients were classified as in active phase (group 1; n=24) or in remission phase (group 2; n=29). Corneal biomechanical parameters including corneal hysteresis (CH), corneal resistance factor (CRF), corneal compensated intraocular pressure (IOPcc), and Goldmann-correlated IOP (IOPg) were measured with the Reichert Ocular Response Analyzer. Topographical measurements, including central corneal thickness (CCT), anterior chamber depth, iridocorneal angle, and corneal volume were measured using a Sirius corneal topographer. RESULTS: The mean CH was 9.43+/ 1.17 mm Hg in group 1, 9.42+/-1.84 mm Hg in group 2, and 10.47+/-1.68 mm Hg in the control group (P=0.03). The mean IOPcc was 17.85+/-3.2 mm Hg in group 1, 17.95+/-3.49 mm Hg in group 2, and 15.36+/-3.11 mm Hg in the control group (P=0.008). The CH showed a significant positive correlation with CRF (P=0.000, r=0.809) and CCT (P=0.000, r=0.461), and a significant negative correlation with IOPcc (P=0.000, r=-0.469). CONCLUSIONS: Decrease in the mean CH measurements indicates that ultrastructural changes in the cornea may occur in the active phase, and these changes persist in the remission period. In addition, IOPcc is significantly affected by the corneal biomechanical properties. In RA patients, it is important to control the corneal parameters and IOP measurements against the irreversible changes on the optic nerve. PMID- 25839347 TI - Vessel Sampling and Blood Flow Velocity Distribution With Vessel Diameter for Characterizing the Human Bulbar Conjunctival Microvasculature. AB - PURPOSE: This study determined (1) how many vessels (i.e., the vessel sampling) are needed to reliably characterize the bulbar conjunctival microvasculature and (2) if characteristic information can be obtained from the distribution histogram of the blood flow velocity and vessel diameter. METHODS: Functional slitlamp biomicroscope was used to image hundreds of venules per subject. The bulbar conjunctiva in five healthy human subjects was imaged on six different locations in the temporal bulbar conjunctiva. The histograms of the diameter and velocity were plotted to examine whether the distribution was normal. Standard errors were calculated from the standard deviation and vessel sample size. The ratio of the standard error of the mean over the population mean was used to determine the sample size cutoff. The velocity was plotted as a function of the vessel diameter to display the distribution of the diameter and velocity. RESULTS: The results showed that the sampling size was approximately 15 vessels, which generated a standard error equivalent to 15% of the population mean from the total vessel population. The distributions of the diameter and velocity were not only unimodal, but also somewhat positively skewed and not normal. The blood flow velocity was related to the vessel diameter (r=0.23, P<0.05). CONCLUSIONS: This was the first study to determine the sampling size of the vessels and the distribution histogram of the blood flow velocity and vessel diameter, which may lead to a better understanding of the human microvascular system of the bulbar conjunctiva. PMID- 25839348 TI - Prominent Decrease of Tear Meniscus Height With Contact Lens Wear and Efficacy of Eye Drop Instillation. AB - OBJECTIVE: To investigate the change in tear meniscus height (TMH) before and after wearing soft contact lenses (CLs) of different water contents (WCs) and the influence of eye drop instillation on TMH during CL wear. METHODS: Tear meniscus heights were measured using anterior segment optical coherence tomography in 20 normal subjects wearing a high-WC CL (WC, 69%) in 1 eye and a low-WC CL (WC, 24%) in the other. Tear meniscus height change after eye drop instillation with 3% diquafosol ophthalmic solution or saline with CL wear was evaluated at 5, 15, 30, and 60 min after instillation. RESULTS: A significant decrease in TMH was observed after lens insertions of both CLs. Tear meniscus height was significantly decreased with high-WC CL wear compared with that with low-WC CL wear. With high-WC CL wear, TMH increased significantly (P<0.001) at 5 min after the instillation of 3% diquafosol ophthalmic solution compared with the baseline values and then returned to the pre-instillation level. No significant TMH changes were found with the instillation of either eye drop (diquafosol or saline) with low-WC CL wear. CONCLUSIONS: Tear meniscus height decreased with CL wear, especially with high-WC CL wear. Significant increases in TMH were observed at 5 min after the instillation of diquafosol ophthalmic solution with high-WC CL wear. The increases in TMH after diquafosol instillation tended to be greater than those after saline instillation at least for 30 min with both high-WC and low-WC CLs. PMID- 25839349 TI - Evaluating the influence of perceived pain control on patient satisfaction in a hospital setting. AB - The authors evaluated whether a patient's perceived pain control influenced the relationships between four attributes (nursing, physician, staff, and environment) and patient satisfaction. Multiple linear regression analyses were conducted to examine overall satisfaction and intention to recommend, controlling for race, gender, age, and education. The authors found that no matter the level of pain control, nursing was always the most influential attribute in patient satisfaction. The influence of the other attributes varied, depending on the patients' pain control. Hospital managers may improve patient satisfaction by focusing on pain management nursing care. PMID- 25839350 TI - Utility of Head CT Scan for Acute Inpatient Delirium. AB - Delirium is a common occurrence in hospitalized patients, especially in the geriatric age group. Data was retrospectively reviewed for patients who developed delirium during hospitalization. Acute intracranial changes on imaging were noted only in four patients (11%) and all had preimaging clinical symptoms and signs, which warranted imaging. Imaging should be considered only in the presence of head injury, fall, history of anticoagulation, focal neurological signs, fever, and raised intracranial pressure. Development of more clear guidelines will result in decreased ordering of unnecessary neuroimaging, substantial cost savings, and less radiation exposure for patients. PMID- 25839351 TI - The Impact of Patient-to-Patient Interaction in Health Facility Waiting Rooms on Their Perception of Health Professionals. AB - Patients have to wait in waiting rooms prior to seeing the physician. But there are few studies that demonstrate what they are actually doing in the waiting room. This exploratory study was designed to investigate the types of discussions that patients in the waiting room typically engage in with other patients and how the conversations affected their opinion on general reputation of the clinic, injections/blocks as treatment procedures, waiting time, time spent with the caregiver, overall patient satisfaction, and the pain medication usage policy. The study demonstrates that patient interaction in the waiting room has a positive effect on patient opinion of the pain clinic and the caregivers. PMID- 25839352 TI - Kinetics of Substrate Biodegradation under the Cumulative Effects of Bioavailability and Self-Inhibition. AB - Microbial degradation is an important process in many environments controlling for instance the cycling of nutrients or the biodegradation of contaminants. At high substrate concentrations toxic effects may inhibit the degradation process. Bioavailability limitations of a degradable substrate can therefore either improve the overall dynamics of degradation by softening the contaminant toxicity effects to microorganisms, or slow down the biodegradation by reducing the microbial access to the substrate. Many studies on biodegradation kinetics of a self-inhibitive substrate have mainly focused on physiological responses of the bacteria to substrate concentration levels without considering the substrate bioavailability limitations rising from different geophysical and geochemical dynamics at pore-scale. In this regard, the role of bioavailability effects on the kinetics of self-inhibiting substrates is poorly understood. In this study, we theoretically analyze this role and assess the interactions between self inhibition and mass transfer-limitations using analytical/numerical solutions, and show the findings practical relevance for a simple model scenario. Although individually self-inhibition and mass-transfer limitations negatively impact biodegradation, their combined effect may enhance biodegradation rates above a concentration threshold. To our knowledge, this is the first theoretical study describing the cumulative effects of the two mechanisms together. PMID- 25839353 TI - The influence of cholesterol on membrane protein structure, function, and dynamics studied by molecular dynamics simulations. AB - The plasma membrane, which encapsulates human cells, is composed of a complex mixture of lipids and embedded proteins. Emerging knowledge points towards the lipids as having a regulating role in protein function. Furthermore, insight from protein crystallography has revealed several different types of lipids intimately bound to membrane proteins and peptides, hereby possibly pointing to a site of action for the observed regulation. Cholesterol is among the lipid membrane constituents most often observed to be co-crystallized with membrane proteins, and the cholesterol levels in cell membranes have been found to play an essential role in health and disease. Remarkably little is known about the mechanism of lipid regulation of membrane protein function in health as well as in disease. Herein, we review molecular dynamics simulation studies aimed at investigating the effect of cholesterol on membrane protein and peptide properties. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25839354 TI - Mixing of oxidized and bilayer phospholipids. AB - Composition and phase dependence of the mixing of 1,2-Dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), and 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), with the oxidized phospholipid, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) were investigated by characterizing the aggregation states of DPPC/PGPC and DOPC/PGPC using a fluorescence quenching assay, dynamic light scattering, and time-resolved fluorescence quenching in the temperature range 5-60 degrees C. PGPC forms 3.5nm radii micelles of aggregation number 33. In the gel phase, DPPC and PGPC fuse to form mixed vesicles for PGPC molar fraction, XPGPC<=0.3 and coexisting vesicles and micelles at higher XPGPC. Data suggest that liquid phase DPPC at 50 degrees C forms mixed vesicles with segregated or hemi fused DPPC and PGPC for XPGPC<=0.3. At 60 degrees C, DPPC and PGPC do not mix, but form coexisting vesicles and micelles. DOPC and PGPC do not mix in any proportion in the liquid phase. Two dissimilar aggregates of the sizes of vesicles and PGPC micelles were observed for all XPGPC for T>=22 degrees C. DOPC-PGPC and DPPC-PGPC mixing is non-ideal for XPGPC>0.3 in both gel and fluid phases resulting in exclusion of PGPC from the bilayer. Formation of mixed vesicles is favored in the gel phase but not in the liquid phase for XPGPC<=0.3. For XPGPC<=0.3, aggregation states change progressively from mixed vesicles in the gel phase to component segregated mixed vesicles in the liquid phase close to the chain melting transition temperature to separated coexisting vesicles and micelles at higher temperatures. PMID- 25839355 TI - Phylogenetic conservation of protein-lipid motifs in pentameric ligand-gated ion channels. AB - Using the crosstalk between the nicotinic acetylcholine receptor (nAChR) and its lipid microenvironment as a paradigm, this short overview analyzes the occurrence of structural motifs which appear not only to be conserved within the nAChR family and contemporary eukaryotic members of the pentameric ligand-gated ion channel (pLGIC) superfamily, but also extend to prokaryotic homologues found in bacteria. The evolutionarily conserved design is manifested in: 1) the concentric three-ring architecture of the transmembrane region, 2) the occurrence in this region of distinct lipid consensus motifs in prokaryotic and eukaryotic pLGIC and 3) the key participation of the outer TM4 ring in conveying the influence of the lipid membrane environment to the middle TM1-TM3 ring and this, in turn, to the inner TM2 channel-lining ring, which determines the ion selectivity of the channel. The preservation of these constant structural-functional features throughout such a long phylogenetic span likely points to the successful gain-of function conferred by their early acquisition. This article is part of a Special Issue entitled: Lipid-protein interactions. PMID- 25839356 TI - Structure-function relationships in histidine-rich antimicrobial peptides from Atlantic cod. AB - Gad-1 and Gad-2 are antimicrobial peptide (AMP) sequences encoded by paralogous genes. They are rich in histidine, which suggests that their activity might be pH dependent. We examined their structure-function relationships with a view to learning how to improve AMP therapeutic ratios. Activity assays with Gram negative bacteria and cancer cell lines demonstrate that Gad-2 is substantially more active at slightly acidic pH than it is at neutral pH. By contrast, the activity of Gad-1 at lower pH is similar to its activity at pH7. Circular dichroism spectra indicate that the greater functional plasticity of Gad-2 correlates with a greater structural plasticity; Gad-2's percent helicity varies dramatically with altered pH and lipid environment. Interestingly, Gad-2's highest levels of helicity do not correspond to the conditions where it is most active. High resolution solution NMR structures were determined in SDS micelles at pH5, conditions that induce an intermediate level of helicity in the peptides. Gad-1 is more helical than Gad-2, with both peptides exhibiting the greatest helical tendencies in their central region and lowest helicity in their N termini. The high resolution structures suggest that maximum activity relies on the appropriate balance between an N-terminal region with mixed hydrophobic/hydrophilic structure features and an amphipathic central and C terminal region. Taken together with previous studies, our results suggest that to improve the therapeutic ratio of AMPs, consideration should be given to including sequential histidine-pairs, keeping the overall charge of the peptide modest, and retaining a degree of structural plasticity and imperfect amphipathicity. PMID- 25839357 TI - Challenging AQP4 druggability for NMO-IgG antibody binding using molecular dynamics and molecular interaction fields. AB - Neuromyelitis optica (NMO) is a multiple sclerosis-like immunopathology disease affecting optic nerves and the spinal cord. Its pathological hallmark is the deposition of a typical immunoglobulin, called NMO-IgG, against the water channel Aquaporin-4 (AQP4). Preventing NMO-IgG binding would represent a valuable molecular strategy for a focused NMO therapy. The recent observation that aspartate in position 69 (D69) is determinant for the formation of NMO-IgG epitopes prompted us to carry out intensive Molecular Dynamics (MD) studies on a number of single-point AQP4 mutants. Here, we report a domino effect originating from the point mutation at position 69: we find that the side chain of T62 is reoriented far from its expected position leaning on the lumen of the pore. More importantly, the strength of the H-bond interaction between L53 and T56, at the basis of the loop A, is substantially weakened. These events represent important pieces of a clear-cut mechanistic rationale behind the failure of the NMO-IgG binding, while the water channel function as well as the propensity to aggregate into OAPs remains unaltered. The molecular interaction fields (MIF)-based analysis of cavities complemented MD findings indicating a putative binding site comprising the same residues determining epitope reorganization. In this respect, docking studies unveiled an intriguing perspective to address the future design of small drug-like compounds against NMO. In agreement with recent experimental observations, the present study is the first computational attempt to elucidate NMO-IgG binding at the molecular level, as well as a first effort toward a less elusive AQP4 druggability. PMID- 25839358 TI - Osmotic compression of anisotropic proteins: interaction properties and associated structures in wheat gliadin dispersions. AB - In this Article, we investigated the interaction properties of wheat gliadins, properties that are at the basis of their functionality in wheat grain and in food matrixes. We established the equation of state of our isolate by osmotic compression and characterized the concentration-induced structural transitions, from the secondary structure of proteins to the rheological properties. We evidenced three thermodynamical regimes corresponding to several structuring regimes. First, for Phi < 0.03, gliadins behave as repulsive colloids, with a positive second virial coefficient, arising presumably from their surface charge density and/or their steric repulsion. No intermolecular interaction was detected by FT-IR, suggesting that proteins form a stable dispersion. In the second regime, the system becomes more easily compressible, i.e., less repulsive and/or more attractive. It is associated with the disappearance of beta-sheet intramolecular structures of the proteins in favor of random coils/alpha-helix and intermolecular beta-sheet interactions. This coincides with the appearance of elasticity and the increase of the apparent viscosity. Finally, in the last regime, for Phi > 0.16, FT-IR spectra show that proteins are strongly interacting via intermolecular interactions. A correlation peak develops in SAXS, revealing a global order in the dispersion. Interestingly, the osmotic pressure applied to extract the solvent is higher than expected from a hard-sphere-like protein and we highlighted a liquid-like state at very high concentration (>450 g L(-1)) which is in contrast with most proteins that form gel or glass at such concentration. In the discussion, we questioned the existence of supramolecular assemblies and the role of the solvation that would lead to this specific behavior. PMID- 25839360 TI - [Impulse for prevention]. PMID- 25839359 TI - Streptococcus oralis cerebral abscess following monkey bite in a 2-month-old infant. AB - Although cerebral abscesses caused by animal bites have been reported, they are extremely rare in infants and have not been described following monkey bite. A 55 day-old male infant presented with a multi-loculated Streptococcus oralis cerebral abscess following a monkey bite on the scalp. There was a clinical response to antibiotic therapy and repeated surgical aspiration followed by a ventriculoperitoneal shunt. This is the first report of a patient with a brain abscess following a monkey bite. PMID- 25839361 TI - [Quality analyses of the development of preterm infants: results of the Lower Saxonian preterm infant follow-up project and a comparison group of term infants]. AB - Based on perinatal and neonatal quality assurance programmes, a follow-up project for the high-risk group of extremely preterm infants, unparalleled in Germany, was initiated in the federal state of Lower Saxony in 2004. Here we describe the new approach of examining a comparison group of term infants, which, for the first time, allows a valid interpretation of the collection of area-wide long term outcome data on preterm children. The prospective long-term outcome project investigates the medical care situation for children born at less than 28 weeks of gestation up to school age. Based on the information obtained about the children's development the quality of health care will be optimised. A standardised examining concept with established development tests at defined follow-up intervals (at the age of 6 months, 2, 5 and 10 years) is used. At the age of five years 75 % of the examined premature children exhibited impairments. In order to better assess remarkable results, a comparison group of term infants (n=305) selected by a matched-pairs method was examined at the age of five using an analogous concept in kindergartens in Lower Saxony. The results were compared with the first two age cohorts of the follow-up-project (n=226) and quality analyses performed. As expected, significant differences have been found in the children's motor, cognitive and linguistic development between the preterm and term infants examined. This fact draws attention to the importance of early support for the majority of extremely premature infants. Feedback on the results given to the medical staff involved allows for the implementation of best practices and quality improvements. Identifying potential for improvement in everyday health care will help to develop specific optimisation measures. PMID- 25839362 TI - [Comparative effectiveness and safety of screening and counselling interventions conducted by non-physicians and physicians: a systematic review]. AB - BACKGROUND: Current forecasts project a future shortage of physicians which might compromise the quality of health care if not addressed adequately by health policy decisions. One proposed measure is to shift selected tasks and responsibilities from physicians to other medical staff, a strategy that has proven successful in some areas (e. g., chronic disease management). To date, no studies have systematically and objectively assessed whether the application of a similar strategy to screening and counselling in preventive medicine compromises patients' health outcomes and experiences. METHODS: A systematic search was conducted in MEDLINE, the Cochrane Library, CINAHL, and EMBASE (January 2000 - June 2014). We dually reviewed articles and assessed the risk of bias. RESULTS: 3,315 citations were identified and five relevant articles located. Overall, the available evidence indicated that there were no substantial differences in benefits and harms of screening (colon cancer screening, sexual transmitted diseases, and mammography) and counselling (genetic breast cancer risk) between non-physicians and physicians. The quality of evidence, however, is very low for most comparisons. Reported statistically significant differences for some outcomes need to be viewed cautiously. CONCLUSION: Shifting tasks from physicians to other medical staff for screening and counselling could be a viable strategy to address the shortage of practicing physicians. Adequate training by a physician, however, is a prerequisite for the safe and beneficial screening and counselling conducted by non-physicians. PMID- 25839363 TI - [Development of patient education materials for the "German Prostate Cancer Trial PREFERE"]. AB - The German prostate cancer study PREFERE (www.prefere.de) started in January 2014. It is the first randomised controlled and preference-based trial to investigate all four options available for the treatment of organ-confined prostate cancer. According to the "Interdisciplinary evidence-based S3 guideline for the early detection, diagnosis and treatment of the different stages of prostate cancer" [1], these options include: radical prostatectomy, external radiotherapy, brachytherapy and active surveillance. In the context of PREFERE preference-based means that potential study participants who do not agree to being randomised into all four treatment arms can maximally refuse two treatment arms. This poses a big challenge to the patient education strategy employed and the information material it requires. In order to inform patients in the context of the PREFERE trial patient education materials (patient leaflet and video) had to be designed that provide patients with balanced and guideline-based information about the disease and the treatment options available, about the need for randomisation and, in particular, about the PREFERE trial and support their individual preference finding and shared decision making for participating in the trial. An iterative structured approach was used to develop the information materials on the basis of a previous literature search. Six focus groups with a total of 40 participants from three different self-help groups, affected men that do not belong to a self-help group, healthy men as well as experts, the members of the steering committee of the PREFERE trial and a focus group consisting of 18 male and female urologists were involved in the development and testing of both the patient information leaflet and the patient video. Both the patient information leaflet and the video supporting preference finding and decision making for participating in the PREFERE trial were tested for understandability and suitability by using a questionnaire and conducting a comprehensive discussion. The results of these lay evaluations have been included in the final revision. Also, a communication resource for physicians has been created comprising all the essential aspects of the PREFERE patient education materials. A short course conducted all over Germany will focus on the process of patient teaching as well as patient education materials. Whether and to what extent the decision for participating in the PREFERE trial has actually been influenced 1) by what the treating physicians communicated to the patient and 2) by the patient education materials used is one of the subjects of a quality of life survey that will be conducted following treatment or - in the case of the active surveillance option - after randomisation during the PREFERE trial. PMID- 25839365 TI - [Viewpoint: "Next please" - comments on indication determination in clinical medicine]. PMID- 25839364 TI - [Evidence-based health promotion and prevention in settings: which types of study designs are needed?]. AB - Health promotion and health prevention are cornerstones of public health. In Germany, a draft health prevention law was rejected in 2013, partly because it almost exclusively focused on measures at the individual level. Many health promotion and prevention measures, by contrast, (also) address the societal level and the environment, but there are few robust studies on their effectiveness, not least because of a lack of resources, the complexity of the measures, or randomisation problems. For example, regulations that protect non-smokers from smoke are subject to political processes where the majority of decision-makers would decline consent for randomisation. In a workshop at the 15(th) Annual Meeting of the German Network for Evidence-based Medicine (DNEbM) two case studies on controlled before-and-after studies (CBA) and interrupted time series (ITS) were developed by the audience as possible alternatives to randomised controlled trials for the evaluation of health promotion and health prevention programmes. The suggestions made by the audience were compared to the study designs chosen in published studies, and the strengths and weaknesses of the different study designs were discussed. The wide array of suggestions for effectiveness studies illustrated the potential of evidence-based health promotion and prevention, but also the specific challenges to be faced. PMID- 25839366 TI - [Improved stoves for reducing cardiovascular and respiratory tract diseases in developing countries - which factors enable or prevent implementation?]. PMID- 25839367 TI - [Comment on the article by Rehfuess, Eva et al. (2014): Enablers and barriers to large-scale uptake of improved solid fuel stoves: a systematic review. Environmental Health Perspectives. Vol. 122, No. 2. ]. PMID- 25839368 TI - [Incomplete dental caries restoration: a systematic review and meta-analysis]. PMID- 25839369 TI - [Comment on the practical relevance of the David Sackett Award 2014 excellent work "Incomplete removal of caries: A systematic review and meta-analysis" by Falk Schwendicke]. PMID- 25839370 TI - Short communication: final year students' deficits in physical examination skills performance in Germany. AB - BACKGROUND: The physical examination of patients is an important diagnostic competence, but little is known about the examination skills of final-year medical students. AIMS: To investigate physical examination skills of final-year medical students. METHODS: In a cross-sectional study, 40 final-year students were asked to perform a detailed physical examination on standardized patients. Their performances were video-recorded and rated by independent video assessors. RESULTS: Video ratings showed a mean success rate of 40.1 % (SD 8.2). As regards accompanying doctor-patient communication, final-year students achieved a mean of no more than 36.7 % (SD 8.9) in the appropriate use of the corresponding communication items. CONCLUSIONS: Our study revealed severe deficits among final year medical students in performing a detailed physical examination on a standardized patient. Thus, physical examination skills training should aim to improve these deficits while also paying attention to communicative aspects. PMID- 25839371 TI - [jeder-fehler-zaehlt.de: Content of and prospective benefits from a critical incident reporting and learning system (CIRS) for primary care]. AB - Critical incident reporting and learning systems (CIRS) have been recommended as an instrument to promote patient safety for a long time. However, both their scientific value and their actual impact have been disputed. The nationwide German CIRS for primary care has been in operation since September 2004. Incident reports are available online, and the question is how to make use of this large database to promote patient safety. A descriptive analysis of the content was performed, classifying, in particular, types of error and contributing factors. Its usage is presented for the period from 2004 to 2013 where a total of 483 complete reports have been recorded. Their severity ranges from 35.6 % with no tangible harm to patients to 14.6 % with important harm (or errors contributing to mortality). The majority of them (74.2 %) were process errors, compared to 25.8 % knowledge/skills errors. The main areas involved were treatment/medication (54.2 %) and diagnosis/tests (16.4 %). The results of the analysis of the CIRS cannot be used as an epidemiological data source. And yet they will generate hypotheses for further research in the field of patient safety. Moreover, they will enable practice teams to make themselves familiar with and learn from critical incident analysis. In spite of the specific difficulties in ambulatory care, CIRS should be promoted in this sector to enable learning. Participation in CIRS can be increased by enhanced feedback. PMID- 25839372 TI - [Subgroups in the early benefit assessment of pharmaceuticals: a methodical review]. AB - Benefit assessments according to Sect. 35a of the Social Code Book V are frequently divided into subsets of populations. This division of therapeutic indications is evident in almost every other of the completed appraisals by the Federal Joint Committee (G-BA). The subsets can be deduced from the wording of the approved therapeutic indication (subpopulations) or from potential effect modification (subgroups). Methodological challenges are illustrated on the basis of current scientific knowledge of how to tackle subgroups. Practical assessment examples are used to explain the methods implemented by IQWiG and the G-BA and reveal major problem areas concerning subgroup analyses, subpopulations as well as mismatches between the requirements of early benefit assessment and approval. Overall, it appears there is a need for establishing a more comprehensive discussion regarding the validity of subgroup analyses and their associated limitations. PMID- 25839373 TI - [Medicine and economics - a perspective from Switzerland]. PMID- 25839374 TI - Carry-over of self-regulation for physical activity to self-regulating eating in women with morbid obesity. AB - Poor outcomes from behavioral treatments of severe obesity have led to a dependence on invasive medical interventions, including surgery for morbidly obese individuals. Improved methods to self-regulate eating will be required to reduce obesity. The use of self-regulation methods for completing physical activity may carry over to increased self-regulation for eating through improved feelings of competence (self-efficacy) and mood. The study recruited women (Meanage = 43 years) with morbid obesity (MeanBMI = 44 kg/m(2)) to participate in 26 weeks of cognitive-behavioral support of physical activity paired with either nutrition education (n = 51) or cognitive-behavioral nutrition (n = 51) methods. Data collected were from 2011 and 2012. Significant improvements in self regulation for physical activity, self-regulation for eating, overall mood, and self-efficacy for eating, with greater improvement in self-regulation for eating, were observed in the cognitive-behavioral nutrition group. Changes in mood and self-efficacy for eating significantly mediated the relationship between changes in self-regulation for physical activity and self-regulation for eating. When subscales of overall mood and self-efficacy were entered into separate regression equations as mediators, the only significant mediators were vigor, and controlling eating when socially pressured and when increased cues to overeat were present. PMID- 25839376 TI - Stability of Cerebral Aneurysms After Stent-Assisted Coil Embolization: A Propensity Score-Matched Analysis. AB - BACKGROUND: The availability of stents has widened the indications of endovascular intervention for cerebral aneurysms. OBJECTIVE: To elucidate the effect of stents on radiologic outcomes and to analyze the risk factors for aneurysmal recanalization via propensity score matching. METHODS: From the 735 aneurysms treated with coil embolization with stents (n = 187) and without stents (n = 548) between 2009 and 2011, 157 propensity score-matched case pairs were selected. The recanalization rates and relevant risk factors were analyzed. The mean follow-up interval was 24.1 +/- 11.3 months (range, 6-48 months) and 22.9 +/ 11.4 months (range, 6-56 months) in the stent and nonstent groups, respectively (P = .388). RESULTS: The stent group demonstrated lower recanalization rates than the nonstent group during both the 6-month (1.9% vs 10.2%, P = .004) and the final follow-up periods (8.3% vs 18.5%, P = .005). The multivariate analysis identified the following significant factors for recanalization: the use of stents (hazard ratio, 0.40; 95% confidence interval, 0.21-0.76, P = .005), larger aneurysm size (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31, P < .001), and initially incomplete occlusion (hazard ratio, 2.39; 95% confidence interval, 1.28-4.43, P = .006). The incidence of permanent neurological complication tended to be higher in the stent group than in the nonstent group (3.2% vs 0%, P = .063). CONCLUSION: In this propensity score-matched analysis, stent implantation reduced the overall recanalization of the coiled cerebral aneurysms. However, the use of stents should be carefully decided upon. PMID- 25839377 TI - Smoking and Intracranial Aneurysm Morphology. AB - BACKGROUND: Smoking is a well-known independent risk factor for both aneurysm formation and rupture. There is mounting evidence that aneurysm morphology beyond size can have a significant role in aneurysm formation and rupture risk by its effects on aneurysmal hemodynamics. OBJECTIVE: To study the variation in aneurysm morphology between smokers and nonsmokers and delineate how changes in these factors might affect aneurysm formation and rupture. METHODS: We generated 3 dimensional models of aneurysms and their surrounding vasculature by analyzing preoperative computed tomography angiograms with Slicer software. We then examined the association between smoking status and intrinsic, transitional, and extrinsic aspects of aneurysm morphology in both univariate and multivariate statistical analyses. RESULTS: From 2005 to 2013, 199 cerebral aneurysms in never smokers and current smokers were evaluated/treated at a single institution with available computed tomography angiograms (102 in never smokers and 97 in current smokers). Multivariate analysis of current smokers vs never smokers demonstrated that aneurysms in current smokers were significantly associated with multiple aneurysms (odds ratio [OR]: 2.15, P = .03), larger daughter vessel diameters (OR: 3.13, P = .01), larger size ratio (OR: 1.78, P = .01), and location at the basilar apex (OR: 6.26, P = .02). CONCLUSION: The differences in aneurysm morphology between smoking and nonsmoking patient populations may elucidate the effects of smoking on aneurysm formation and eventual rupture. We identified several aspects of aneurysm morphology significantly associated with smoking status that may provide the morphological basis for how smoking leads to increased aneurysm rupture. PMID- 25839383 TI - Update on Urological Management of Spina Bifida from Prenatal Diagnosis to Adulthood. AB - PURPOSE: We review the current literature regarding urological management of spina bifida from prenatal diagnosis to adulthood. MATERIALS AND METHODS: We searched MEDLINE((r)), EMBASE((r)) and PubMed((r)) for English articles published through December 2014 using search terms "spina bifida," "spinal dysraphism" and "bladder." Based on review of titles and abstracts, 437 of 1,869 articles were identified as addressing topics related to open spina bifida in pediatric patients, or long-term or quality of life outcomes in adults with spina bifida. We summarize this literature to inform clinical guidelines and create a framework for disease management. RESULTS: The birth prevalence of spina bifida in the United States has recently plateaued at approximately 30 per 100,000. With improved management more individuals are surviving to adulthood, with an economic impact of $319,000 during the lifetime of an individual with spina bifida. Recent advances in prenatal surgery have demonstrated that prenatal closure of spina bifida is possible. To assess safety and efficacy, the National Institutes of Health sponsored Management of Myelomeningocele Study was undertaken, in which subjects were randomized to prenatal or postnatal closure. Until the urological results of this trial are published, the impact of prenatal intervention on future bladder function remains unclear. Controversy continues regarding the optimal use and timing of urodynamic studies, and the indications for initiation of clean intermittent catheterization and anticholinergics in infants and children. Many favor expectant management, while others argue for a more proactive approach. Based on the current literature, both approaches appear to protect the child from renal injury, although delayed intervention may increase rates of bladder augmentation. The current literature regarding this topic is difficult to interpret and compare due to heterogeneity of patient populations, variable outcome measures and lack of reporting of quality of life outcomes. Surgical intervention is indicated for those at risk for renal deterioration and/or is considered for children who fail to achieve satisfactory continence with medical management. Traditionally surgery concentrates on the bladder and bladder neck, and creation of catheterizable channels. For those with a hostile bladder, enterocystoplasty remains the gold standard for bladder augmentation, although use of bowel for augmentation remains suboptimal due to secondary complications, including increased risk of infections, metabolic abnormalities, neoplastic transformation and risk of life threatening perforation. Recent advances in tissue engineering technology may provide an alternative to traditional augmentation. However, recent results from phase II trials using current techniques to augment the bladder with engineered bladder tissue are disappointing. Catheterizable channels to the bladder and ascending colon further facilitate continence measures and promote independent care. While surgical reconstruction is clearly successful in improving continence, recent outcome studies have questioned the true impact of this type of surgery on quality of life. With improved survival transitional care issues, including health related independence, sexual health needs and development of a support system, are increasingly important. Transitional care remains a significant issue for which few public health measures are being quantitatively evaluated. CONCLUSIONS: Despite consensus regarding early urological involvement in the care of patients with spina bifida, controversy remains regarding optimal management. Major reconstructive urological surgeries still have a major role in the management of these cases to protect the upper urinary tract and to achieve continence. However, future studies are needed to better clarify the true impact on quality of life that these interventions have on patients and their families. Transition of urological care to adulthood remains a major avenue for improvement in disease management. PMID- 25839382 TI - Intravesical Liposomal Tacrolimus Protects against Radiation Cystitis Induced by 3-Beam Targeted Bladder Radiation. AB - PURPOSE: We primarily determined whether the small animal radiation research platform could create a rat radiation cystitis model via targeted bladder irradiation (phase I). The response to treating early phase radiation cystitis in rats with transurethral catheter instillation of liposomal tacrolimus was also examined (phase II). MATERIALS AND METHODS: In phase I 16 adult female Sprague Dawley(r) rats were used. Metabolic urination patterns were analyzed before and after exposure to 20, 30 or 40 Gy radiation. In phase II irradiated rats were randomly assigned to receive a single instillation of saline or liposomal tacrolimus. RESULTS: The 40 Gy radiation dose induced statistically significant reductions in the intermicturition interval compared to the lower radiation doses. By approximately 20 minutes 40 Gy radiation caused a significant decrease in the mean intermicturition interval (p < 0.0001). Histological analysis revealed degenerative epithelial changes and urothelial swelling with evidence of pseudocarcinomatous epithelial hyperplasia. Therefore, 40 Gy were chosen for the phase II efficacy study. There was no measurable change in total voided urine volume after irradiation, or after liposomal tacrolimus or saline instillation. Liposomal tacrolimus significantly increased the post-irradiation intermicturition interval by approximately 30 minutes back to baseline (p < 0.001). CONCLUSIONS: The radiation cystitis rat model showed a dose dependent decrease in the intermicturition interval without inducing short-term skin or gastrointestinal damage. This study demonstrates that liposomal tacrolimus may be a promising new intravesical therapy for the rare, serious condition of radiation cystitis. PMID- 25839384 TI - Minilaparoscopic versus standard laparoscopic hysterectomy for uteri >= 16 weeks of gestation: surgical outcomes, postoperative quality of life, and cosmesis. AB - OBJECTIVE: Hysterectomy for enlarged uteri is a surgical challenge. Our aim was to compare perioperative outcomes, cosmesis, and postoperative quality of life following laparoscopic hysterectomy for large uteri using minilaparoscopic 3-mm versus conventional laparoscopic 5-mm instruments. SUBJECTS AND METHODS: We prospectively enrolled women with a uterus between 16 and 20 weeks of gestation at the preoperative examination. These patients underwent laparoscopic procedures using either 3-mm (minilaparoscopy group) or 5-mm (standard laparoscopy group) instruments. Five months after surgery, patients were called back to fill out the validated Italian translation of the Short Form 12-item Health Survey. Data about the cosmetic outcome of the procedure were also collected, using a Numeric Rating Scale (NRS) from 0 to 10. RESULTS: Seventy-eight women were included (27 in the 3 mm and 51 in the 5-mm groups). Perioperative characteristics were comparable between groups. The median uterus weight was 575 (range, 440-1050) g and 550 (400 1000) g in the 3-mm and 5-mm groups, respectively. No minilaparoscopic procedure was converted to standard 5-mm or to an open approach. One (2%) conversion to open abdominal surgery was needed in the conventional laparoscopy group. A better subjective cosmetic outcome was found in the 3-mm (NRS, 9.7 +/- 0.4) versus the 5 mm (NRS, 8.9 +/- 1.2) group (P=.01). Postoperative quality of life was comparable between groups. CONCLUSIONS: Minilaparoscopic hysterectomy is feasible, even in the case of an enlarged-size uterus. Moreover, it is associated with a better cosmetic outcome, compared with conventional laparoscopy. PMID- 25839385 TI - Adjacent Segment Disease After Posterior Lumbar Interbody Fusion: Based on Cases With a Minimum of 10 Years of Follow-up. AB - STUDY DESIGN: Retrospective case-controlled study. OBJECTIVE: To investigate the incidence of adjacent segment degeneration (ASD) and the associated risk factors during a period of at least 10 years after posterior lumbar interbody fusion (PLIF). SUMMARY OF BACKGROUND DATA: ASD is a problematic sequelae after spinal fusion surgery. Few long-term follow-up studies have investigated ASD after PLIF; thus, magnetic resonance imaging (MRI) data available for the evaluation of postoperative changes associated with ASD are limited. METHOD: One hundred one patients were retrospectively enrolled. The minimum follow-up was 10 years after surgery. Preoperative and postoperative (2, 5, and 10 yr after surgery) Radiographs and MRI images were evaluated. Disc height, vertebral slip, and intervertebral angle were examined on radiographical images. Disc degeneration and spinal stenosis on MRI images were evaluated. Risk factors for developing early-onset radiographical ASD were evaluated using a multivariate logistic regression analysis. RESULT: The degenerative changes in disc height, vertebral slip, and intervertebral angle on radiographs 10 years after surgery were found in 12, 36, and 17 cases, respectively, at the cranial-adjacent level and in 3, 6, and 11 cases, respectively, at the caudal-adjacent level. Increased disc degeneration and spinal stenosis worsening were observed in 62 and 68 cases, respectively, at the cranial-adjacent level and in 25 and 12 cases, respectively, at the caudal-adjacent level on MRI 10 years after surgery. Ten patients (9.9%) required reoperation, and 80% of revision surgeries were performed more than 5 years after the initial surgery. High pelvic incidence was a risk factor for developing early-onset radiographical ASD. CONCLUSION: The majority of the reoperations for ASD were performed more than 5 years after the initial lumbar fusion surgery, although the progression of radiographical ASD began in the early postoperative period. A high degree of pelvic incidence was a risk factor for developing early-onset radiographical ASD. Obtaining appropriate lumbar lordosis in PLIF is important for preventing ASD. LEVEL OF EVIDENCE: 4. PMID- 25839386 TI - Sagittal Thoracic and Lumbar Spine Profiles in Upright Standing and Lying Prone Positions Among Healthy Subjects: Influence of Various Biometric Features. AB - STUDY DESIGN: A prospective study was performed on the assessment of both thoracic and lumbar spine sagittal profiles (from C7 to S1). OBJECTIVE: To propose a new noninvasive method for measuring the spine curvatures in standing and lying prone positions and to analyze their relationship with various biometric characteristics. SUMMARY OF BACKGROUND DATA: Modifications of spine curvatures (i.e. lordosis or kyphosis) are of importance in the development of spinal disorders. Studies have emphasized the development of new devices to measure the spine sagittal profiles using a noninvasive and low-cost method. To date, it has not been applied for analyzing both lumbar and thoracic alterations for various positioning. METHODS: Seventy-five healthy subjects (mean 22.6 +/- 4.3 yr) were recruited to participate in this study. Thoracic and lumbar sagittal profiles were assessed in standing and lying prone positions using a 3D digitizer. In addition, several biometric data were collected including maximal trunk isometric strength for flexion and extension movement. Statistical analysis consisted in data comparisons of spine profiles and a multivariate analysis including biometric features, to classify individuals considering low within- and high between-variability. RESULT: Kyphosis and lordosis angles decreased significantly from standing to lying prone position by an average of 13.4 degrees and 16.6 degrees , respectively. Multivariate analysis showed a sample clustering of 3 homogenous subgroups. The first group displayed larger lordosis and flexibility, and had low data values for height, weight, and strength. The second group had lower values than the overall trend of the whole sample, whereas the third group had larger score values for the torques, height, weight, waist, body mass index, and kyphosis angle but a reduced flexibility. CONCLUSION: The present results demonstrate a significant effect of the positioning on both thoracic and lumbar spine sagittal profiles and highlight the use of cluster analysis to categorize subgroups after biometric characteristics including curvature measurement. LEVEL OF EVIDENCE: N/A. PMID- 25839387 TI - Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis. AB - STUDY DESIGN: Review. OBJECTIVE: To formally introduce "degenerative cervical myelopathy" (DCM) as the overarching term to describe the various degenerative conditions of the cervical spine that cause myelopathy. Herein, the epidemiology, pathogenesis, and genetics of conditions falling under this hypernym are carefully described. SUMMARY OF BACKGROUND DATA: Nontraumatic, degenerative forms of cervical myelopathy represent the commonest cause of spinal cord impairment in adults and include cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, and degenerative disc disease. Unfortunately, there is neither a specific term nor a specific diagnostic International Classification of Diseases, Tenth Revision code to describe this collection of clinical entities. This has resulted in the inconsistent use of diagnostic terms when referring to patients with myelopathy due to degenerative disease of the cervical spine. METHODS: Narrative review. RESULTS: The incidence and prevalence of myelopathy due to degeneration of the spine are estimated at a minimum of 41 and 605 per million in North America, respectively. Incidence of cervical spondylotic myelopathy-related hospitalizations has been estimated at 4.04/100,000 person-years, and surgical rates seem to be rising. Pathophysiologically, myelopathy results from static compression, spinal malalignment leading to altered cord tension and vascular supply, and dynamic injury mechanisms. Occupational hazards, including transportation of goods by weight bearing on top of the head, and other risk factors may accelerate DCM development. Potential genetic factors include those related to MMP-2 and collagen IX for degenerative disc disease, and collagen VI and XI for ossification of the posterior longitudinal ligament. In addition, congenital anomalies including spinal stenosis, Down syndrome, and Klippel-Feil syndrome may predispose to the development of DCM. CONCLUSION: Although DCMs can present as separate diagnostic entities, they are highly interrelated, frequently manifest concomitantly, present similarly from a clinical standpoint, and seem to be in part a response to compensate and improve stability due to progressive age and wear of the cervical spine. The use of the term "degenerative cervical myelopathy" is advocated. LEVEL OF EVIDENCE: 5. PMID- 25839388 TI - What Patient Characteristics Could Potentially Affect Patient Satisfaction Scores During Spine Clinic? AB - STUDY DESIGN: Prospective study. OBJECTIVE: Assess which patient factors are associated with patient satisfaction scores in the outpatient spine clinic setting. SUMMARY OF BACKGROUND DATA: Patient satisfaction has become an important component of quality assessments, and thereby pay-for-performance metrics, made by government, hospitals, and insurance providers. METHODS: During a 7-month period, 200 patients were contacted via phone within 3 weeks of a new patient encounter with 1 of 11 spine providers. A standardized patient satisfaction phone survey consisting of 25 questions, answered using a 1-10 scale, was then administered. Patient demographics, medical/social history, and previous treatment were prospectively recorded. Potential associations between these patient factors and 3 outcomes of interest were investigated: (1) provider satisfaction, (2) overall clinic visit satisfaction, and (3) overall quality of care during clinic visit. RESULTS: Younger age, less formal education, and smoking were associated with diminished provider satisfaction, overall clinic visit satisfaction, and perceived overall quality of care (P <= 0.0001). Male patients were significantly less satisfied with their clinic visit compared with females (P = 0.029). Those treated under a worker's compensation claim were significantly less satisfied with their provider and overall quality of care (P <= 0.02). Marital status, working status, mental health history, travel distance, pain characteristics, previous treatments, and current narcotic use were not significant determinants of patient satisfaction (P > 0.05). CONCLUSION: This study found that those patients who were younger, with less formal education, and active smokers had lower patient satisfaction scores. Because patient satisfaction is increasingly being used in assessments of quality of care, it is essential that these factors be considered when evaluating a given provider's practice. This information is important to providers by helping guide individualized patient interactions while in clinic, as well as, the various agencies collecting satisfaction scores allowing them to account for potential sampling bias. LEVEL OF EVIDENCE: 1. PMID- 25839389 TI - Part 3: Developing Methods of In Vivo MRI Measurement of Spinal Cord Displacement in the Thoracolumbar Region of Asymptomatic Subjects With Unilateral and Bilateral Straight Leg Raise Tests. AB - STUDY DESIGN: Controlled radiological study. OBJECTIVE: Verify (1) whether conus medullaris displacement varies with the range of hip flexion and (2) whether the acquired data support the "principle of linear dependence." SUMMARY OF BACKGROUND DATA: We have previously quantified normal displacement of the conus with unilateral and bilateral straight leg raise (SLR) and have described the "principle of linear dependence." However, we have since effected methodological advances that have produced data that surpass previous studies. METHODS: Ten asymptomatic volunteers were scanned with a 1.5-T magnetic resonance scanner using T2-weighted spc 3-dimensional scanning sequences and a device that permits greater ranges of SLR. Displacement of the conus medullaris during the unilateral and bilateral SLRs was quantified reliably with a randomized procedure. RESULTS: Pearson correlations were higher than 0.99 for both intra- and interobserver reliability and the observed power was 1 for each tested maneuver. The conus displaced caudally in the spinal canal by 3.54 +/- 0.87 mm (MU +/- SD) with unilateral (P <= 0.001) and 7.42 +/- 2.09 mm with bilateral SLR (P <= 0.001). CONCLUSION: To the authors' knowledge, these are the first data on noninvasive, in vivo, normative measurement of spinal cord displacement with the SLR test at 60 degrees of hip flexion. Conus medullaris displacement increased with hip flexion angle, while maintaining the relationship between magnitude of conus displacement and number of nerve roots involved into the movement, supporting the "principle of linear dependence." The use of T2-weighted spc 3-dimensional sequence allows for better reliability testing, which is important for future clinical utility. LEVEL OF EVIDENCE: 5. PMID- 25839390 TI - Experimental integrative muscular movement technique enhances cervical range of motion in patients with chronic neck pain: a pilot study. AB - INTRODUCTION: Neck pain presents a tremendous physical and financial burden. This study compared the efficacy of the complementary and alternative medical treatments of integrative muscular movement technique (IMMT) and Swedish massage on neck pain in women of occupation age, the largest demographic group with neck pain. METHODS: A total of 38 women were assigned to IMMT (n=28) or Swedish massage (n=10) in a blinded manner. Both groups received eight 30-minute treatments over 4 weeks. Cervical range of motion (ROM) in flexion, extension, sidebending, and rotation was measured before and after treatment. Each patient's pain was assessed by using an analogue pain scale of 0-10. RESULTS: Compared with the Swedish massage group, patients receiving IMMT experienced a significant increase in ROM in cervical flexion (p<0.001), extension (p<0.001), sidebending (p<0.05), and rotation (p<0.001). Absolute change in pain for IMMT was -1.75 units compared with -0.3 units for Swedish massage (p<0.05). CONCLUSION: Patients receiving the IMMT demonstrated significantly improved cervical ROM in every movement measured compared with Swedish massage. Inclusion of the IMMT in a treatment regimen for chronic neck pain may lead to decreased pain and increased cervical ROM. These positive effects of the IMMT intervention may have a role in enhancing functional outcomes in patients with neck pain. PMID- 25839391 TI - Complement C3 mediated targeting of liposomes to granulocytic myeloid derived suppressor cells. AB - In cancer patients, granulocytic myeloid derived suppressor cells (G-MDSCs) expand in number, infiltrating tumor and lymphatic tissues where they suppress an anti-tumor immune response. We report here the development of a liposomal drug delivery system that selectively targets G-MDSCs. The liposomes form a disulfide bond with activated complement C3 after intravenous injection and are taken up by G-MDSCs, which express the receptor for activated C3. In vitro experiments utilizing serum from a C3 knockout mouse demonstrate that G-MDSCs take up these liposomes in a C3-dependent manner. After systemic administration to tumor bearing mice, liposomes were incorporated by 22% of G-MDSCs in the blood and were also present in a percentage of G-MDSCs in the tumor (11%), spleen (22%), liver (35%) and lungs (26%). This liposomal system offers a versatile means of targeted drug delivery to G-MDSCs and could be an important tool for restoring anti-tumor immunity in cancer patients. FROM THE CLINICAL EDITOR: It has been shown that the presence of granulocytic myeloid derived suppressor cells (G-MDSCs) in cancer patients suppress the tumor immune response of T cells. Many drugs can be used to reverse this process. In this article, the authors describe the development of a liposomal drug delivery system for targeted drug delivery to G- MDSCs. This system may prove to be useful adjunct in immunotherapy in the fight against cancers. PMID- 25839392 TI - Nanoformulation of antiretroviral drugs enhances their penetration across the blood brain barrier in mice. AB - Eradication of virus by sanctuary sites is a main goal in HIV management. The central nervous system (CNS) is a classic model of sanctuary where viral replication occurs despite a complete viral suppression in peripheral blood. In recent years, nanotechnologies have provided a great promise in the eradication of HIV from the CNS. We hereby demonstrate for the first time that the structurally complex antiretroviral drug enfuvirtide (Enf), which normally is unable to penetrate the cerebrospinal fluid, is allowed to cross the blood brain barrier (BBB) in mice by conjugation with a nanoconstruct. Iron oxide nanoparticles coated with an amphiphilic polymer increase Enf translocation across the BBB in both in vitro and in vivo models. The mechanism involves the uptake of nanoconjugated-Enf in the endothelial cells, the nanocomplex dissociation and the release of the peptide, which is eventually excreted by the cells in the brain parenchyma. FROM THE CLINICAL EDITOR: Despite the success of cocktail therapy of antiretroviral drugs, the complete eradication of HIV remains elusive, due to existence of viral sanctuary sites. The authors showed in this study that an antiretroviral drug complexed with iron oxide nanoparticles and coated with PMA amphiphilic polymer crosses the blood brain barrier. Furthermore, there was significant anti-viral activity. The results would aid further drug designs to eradicate HIV. PMID- 25839393 TI - Cluster analysis of quantitative parametric maps from DCE-MRI: application in evaluating heterogeneity of tumor response to antiangiogenic treatment. AB - PURPOSE: The objective of this study was to compare a clustering approach to conventional analysis methods for assessing changes in pharmacokinetic parameters obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during antiangiogenic treatment in a breast cancer model. MATERIALS AND METHODS: BALB/c mice bearing established transplantable her2+ tumors were treated with a DNA-based antiangiogenic vaccine or with an empty plasmid (untreated group). DCE MRI was carried out by administering a dose of 0.05 mmol/kg of Gadocoletic acid trisodium salt, a Gd-based blood pool contrast agent (CA) at 1T. Changes in pharmacokinetic estimates (K(trans) and vp) in a nine-day interval were compared between treated and untreated groups on a voxel-by-voxel analysis. The tumor response to therapy was assessed by a clustering approach and compared with conventional summary statistics, with sub-regions analysis and with histogram analysis. RESULTS: Both the K(trans) and vp estimates, following blood-pool CA injection, showed marked and spatial heterogeneous changes with antiangiogenic treatment. Averaged values for the whole tumor region, as well as from the rim/core sub-regions analysis were unable to assess the antiangiogenic response. Histogram analysis resulted in significant changes only in the vp estimates (p<0.05). The proposed clustering approach depicted marked changes in both the K(trans) and vp estimates, with significant spatial heterogeneity in vp maps in response to treatment (p<0.05), provided that DCE-MRI data are properly clustered in three or four sub-regions. CONCLUSIONS: This study demonstrated the value of cluster analysis applied to pharmacokinetic DCE-MRI parametric maps for assessing tumor response to antiangiogenic therapy. PMID- 25839394 TI - A rapid approach for quantitative magnetization transfer imaging in thigh muscles using the pulsed saturation method. AB - Quantitative magnetization transfer (qMT) imaging in skeletal muscle may be confounded by intramuscular adipose components, low signal-to-noise ratios (SNRs), and voluntary and involuntary motion artifacts. Collectively, these issues could create bias and error in parameter fitting. In this study, technical considerations related to these factors were systematically investigated, and solutions were proposed. First, numerical simulations indicate that the presence of an additional fat component significantly underestimates the pool size ratio (F). Therefore, fat-signal suppression (or water-selective excitation) is recommended for qMT imaging of skeletal muscle. Second, to minimize the effect of motion and muscle contraction artifacts in datasets collected with a conventional 14-point sampling scheme, a rapid two-parameter model was adapted from previous studies in the brain and spinal cord. The consecutive pair of sampling points with highest accuracy and precision for estimating F was determined with numerical simulations. Its performance with respect to SNR and incorrect parameter assumptions was systematically evaluated. QMT data fitting was performed in healthy control subjects and polymyositis patients, using both the two- and five-parameter models. The experimental results were consistent with the predictions from the numerical simulations. These data support the use of the two parameter modeling approach for qMT imaging of skeletal muscle as a means to reduce total imaging time and/or permit additional signal averaging. PMID- 25839395 TI - A new biodegradable and biocompatible gadolinium (III) -polymer for liver magnetic resonance imaging contrast agent. AB - A new biodegradable and biocompatible gadolinium (III) -copolymer (ACL-A2-DOTA Gd) has been developed as a potential liver magnetic resonance imaging (MRI) contrast agent. ACL-A2-DOTA-Gd consisted of a poly (aspartic acid-co-leucine) unit bound with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid gadolinium (Gd-DOTA) via the linkage of ethylenediamine. In vitro, the biodegradable experiment and cytotoxicity assay showed the biodegradability and biocompatibility of this gadolinium-polymer. ACL-A2-DOTA-Gd presented an increase in relaxivity of 2.4 times than the clinical Gd-DOTA. In vivo, gadolinium (III) copolymer was mainly accumulated in the liver, and it could be excreted via the renal and hepatobiliary mechanism. The average enhancement of ACL-A2-DOTA-Gd (60.71+/-5.93%, 50-80 min) in liver was 2.62-fold greater than that of Gd-DOTA (23.16+/-3.55%, 10-30 min). ACL-A2-DOTA-Gd could be as a potential liver MRI contrast agent with a long time-window. PMID- 25839396 TI - Attenuation of Cell Death in Injured Cortex After Post-Traumatic Brain Injury Moderate Hypothermia: Possible Involvement of Autophagy Pathway. AB - OBJECTIVE: Multiple mechanisms participated in the cell death after fluid percussion traumatic brain injury (TBI). In the present study, we evaluated the effect on cell death in the injured cortex after fluid percussion TBI and investigated a possible role of autophagy. METHODS: TBI model was induced by a fluid percussion TBI device. Moderate hypothermia (32 degrees C) was achieved by partial immersion in a water bath (0 degrees C) under general anesthesia for 4 hours. All rats were killed at 6 or 24 hours after TBI. RESULTS: Cleaved caspase 3 evaluated with Western blotting and terminal deoxynucleotidyl transferase mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling-positive cells in injured cortex were significantly increased 6 hours after fluid percussion TBI and were further up-regulated 24 hours after TBI, dramatic up-regulation of Beclin-1 and protein light chain-3 expression levels was also observed. Further up-regulation of biomarkers of autophagy, attenuation of caspase 3 up-regulation and reduction of cell death was observed after 4 hours of hypothermia. Immunofluorescence analysis for cell localization demonstrated that protein light chain-3- and Beclin-1-positive cells included neurons and glial cells in the injured cortex after TBI and hypothermic treatment. By ultrastructural observation, autolysosomes in injured cortex were significantly increased at 6 and 24 hours after TBI and were further up-regulated after TBI hypothermic treatment. CONCLUSIONS: These data suggest that hypothermic treatment could attenuate TBI-induced cell death in this fluid percussion TBI model, possibly through activation of autophagy pathway. PMID- 25839397 TI - Delayed Diagnosis of Enhancing Posterior Fossa Tumors Mimicking the Tela Choroidea of the Fourth Ventricle. AB - BACKGROUND: Posterior fossa brain tumors are common in children. Symptoms typically develop when the tumors have reached sufficient size to cause compression of adjacent neural structures or cause obstructive hydrocephalus. Many tumors in this region originate from the tela choroidea and choroid plexus of the fourth ventricle. Enhancement of the fourth ventricular tela choroidea and choroid plexus is uncommon in children, and when such enhancement is present, it may represent early tumor growth. METHODS: A 5-year-old girl with a history of congenital nystagmus, for whom initial work-up was reported as negative, presented again several years later with headache, nausea, and vomiting. She was found to have a large posterior fossa lesion on repeat neuroimaging that was retrospectively seen on the first neuroimaging scan as prominent enhancement in the region of the fourth ventricular choroid plexus. The second patient presented with congenital nystagmus and a lingual tremor and was found to have a slowly growing lesion situated in the fourth ventricle. Initial imaging was read as nodularly enhancing tela choroidea, but subsequent scans revealed enlargement of the lesion. RESULTS: The first patient underwent gross total resection, and neuropathology was consistent with an atypical teratoid rhabdoid tumor. The patient has done well with postoperative adjuvant therapies. In the second patient, resection of the lesion revealed ependymoma; the patient has done well after adjuvant radiation therapy. CONCLUSIONS: Pediatric patients who have enhancing tela choroidea or choroid plexus without an obvious mass lesion of the fourth ventricle may harbor early tumors. Surveillance imaging in these patients may be warranted given the aggressive nature of certain posterior fossa tumors in children. Failure to recognize abnormal enhancement patterns in this region may lead to delayed diagnosis. PMID- 25839398 TI - Transfusion Frequency of Red Blood Cells, Fresh Frozen Plasma, and Platelets During Ruptured Cerebral Aneurysm Surgery. AB - BACKGROUND: The use of blood products after subarachnoid hemorrhage (SAH) is common, but not without controversy. The optimal hemoglobin level in patients with SAH is unknown, and data on perioperative need for red blood cell (RBC), fresh frozen plasma (FFP), or platelet transfusions are limited. We studied perioperative administration of RBCs, FFP, and platelets and the impact of red blood cell transfusions (RBCTs) on outcome in patients undergoing surgery for ruptured a cerebral arterial aneurysm. METHODS: A retrospective analysis was performed of 488 patients with aneurysmal SAH during the years 2006-2009 at Helsinki University Central Hospital. Patients who received RBC, FFP, or platelet concentrates perioperatively were compared with a cohort of patients from the Helsinki database of aneurysmal SAH who did not receive transfusions. A multiple regression model was created to identify factors related to transfusion and outcome. RESULTS: RBC, FFP, or platelet concentrates were given in 7.6% (37 of 488), 3.1% (15 of 488), and 1.2% (6 of 488) of patients intraoperatively and in 3.5% (17 of 486), 1.6% (8 of 488), and 0.9% (4 of 488) of patients postoperatively. Of 37 intraoperative RBCTs, 26 were related to intraoperative rupture of the aneurysm. Intraoperative RBCTs were associated with lower preoperative hemoglobin concentration, higher World Federation of Neurosurgical Societies classification, and intraoperative rupture of an aneurysm. In multivariate analysis, intraoperative RBCT (odds ratio = 5.13, 95% confidence interval = 1.53-17.15), worse World Federation of Neurosurgical Societies classification and Fisher grade (odds ratio = 1.97, confidence interval = 1.64 2.36 and odds ratio = 1.89, confidence interval = 1.23-2.92, respectively), and increasing age (odds ratio = 1.07, confidence interval = 1.04-1.10) independently increased the risk of poor neurologic outcome at 3 months. CONCLUSIONS: Transfusion frequencies of RBCs, FFP, and platelets were relatively low. Intraoperative RBCT was strongly related to intraoperative rupture of the aneurysm in patients with poor-grade SAH. The observed association between poor outcome and RBCT in patients with SAH warrants further study. PMID- 25839399 TI - Optimal Timing of Whole-Brain Radiation Therapy Following Craniotomy for Cerebral Malignancies. AB - BACKGROUND: For patients with cerebral metastases that are limited in number, surgical resection followed by whole-brain radiation therapy is the standard of care. In addition, for high-grade gliomas, maximal surgical resection followed by local radiotherapy is considered the optimal treatment. Radiation is known to impair wound healing, including healing of surgical incisions. Radiotherapy shortly after surgical resection would be expected to minimize the opportunity for tumor regrowth or progression. Owing to these competing interests, the purpose of this study was to shed light on the optimal timing of radiotherapy after surgical resection of brain metastasis or high-grade gliomas. METHODS: A review of the literature was conducted on the following topics: radiation and wound healing, corticosteroid use and wound healing, radiotherapy for tumor control for cerebral metastases and high-grade gliomas, and whole-brain radiation therapy or focal radiotherapy after craniotomy with focus on the timing of radiotherapy after surgery. RESULTS: In animal models, wound integrity and healing was less impaired by radiotherapy administered 1 week after surgery. In humans, this timing would be expected to be significantly longer, on the order of several weeks. CONCLUSIONS: Given the limited literature, insufficient conclusions can be drawn. However, animal data suggest a period of at least 1 week (but it is likely several weeks in humans) is necessary for reconstitution of wound strength before initiation of radiation therapy. A randomized prospective study is recommended to understand better the effect of the timing of radiation therapy following surgical intervention for brain metastasis or high grade gliomas. PMID- 25839400 TI - Six Walls of the Cavernous Sinus Identified by Sectioned Images and Three Dimensional Models: Anatomic Report. AB - BACKGROUND: For the diagnosis and surgical treatment of diseases around the cavernous sinus (CS), radiologists should achieve complete mastery of the sectional anatomy of the CS, and neurosurgeons need to understand the stereoscopic orientation of the CS and circumjacent structures. However, despite the complicated structure of the CS, the current educational resources for its sectional and stereoscopic anatomy are insufficient. Another problem is that the definition of CS walls varies for each researcher. The purpose of this study is to redefine the walls of the CS and to provide related educational materials. METHODS: Previous studies on the shape of the CS were analyzed. Sectioned images of a cadaver were prepared at 0.1-mm intervals to be made into three-dimensional (3D) models of the CS and neighboring structures. RESULTS: Based on other studies, the shape of the CS was redefined as a hexahedron, consisting of 6 walls, and was illustrated as a schematic figure. Scientific exactitude of the hexahedron was proven through matching the points with the actual structures on the sectioned images and 3D models that were made in this study. CONCLUSIONS: The combination of the hexahedron theory, the sectioned images, and the 3D models in this study will enhance the efficiency of studying CS anatomy. The educational resources of this study can be obtained free of charge by medical students, radiologists, and neurosurgeons requiring knowledge of CS anatomy. PMID- 25839401 TI - Risk Factors for Infective Complications with Long-Term Subdural Electrode Implantation in Patients with Medically Intractable Partial Epilepsy. AB - OBJECTIVE: To evaluate infective complications with intracranial electroencephalography (EEG) recording so as to lessen them. METHODS: A database of intracranial monitoring cases with subdural electrodes at Kyoto University Hospital between May 1992 and March 2012 was retrospectively reviewed. RESULTS: This analysis included 46 EEG monitoring sessions. Infective complications related to intracranial electrodes occurred in 4 monitoring sessions (8.7%; 3 male patients). Causative agents were identified as Staphylococcus aureus in 3 monitoring sessions and Staphylococcus epidermidis in 1 session. In univariate analysis, the season of monitoring was identified as the sole significant risk factor. More infective complications occurred when monitoring occurred in autumn. More infective complications tended to occur in patients who had implantation in the right side or discontinuation of intravenously administered prophylactic antibiotics, although these factors were not statistically significant. Age, sex, duration of monitoring, number of electrodes, and pathologic diagnosis did not seem to be associated with an increased risk of infective complications. Infective complications had no significant influence on seizure outcome. CONCLUSIONS: Invasive EEG monitoring during autumn might be a risk factor in terms of infective complications. S aureus was a common pathogen. PMID- 25839405 TI - Hepatocyte senescence explains conjugated bilirubinaemia in chronic liver failure. PMID- 25839407 TI - Reduced mortality due to phlebotomy in moderately iron-loaded HFE haemochromatosis? The need for clinical trials. PMID- 25839406 TI - Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV)-infected patients with a history of injection drug use have low rates of initiation and completion of interferon based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy. METHODS: This was a phase II, multicenter, open-label, single-arm study in treatment-naive or peginterferon/ribavirin treatment experienced HCV genotype 1-infected patients on methadone or buprenorphine+/ naloxone. Patients received 12weeks of co-formulated ombitasvir/paritaprevir/ritonavir (25mg/150mg/100mg once daily) and dasabuvir (250mg twice daily)+weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment. RESULTS: Thirty-eight non cirrhotic patients on chronic methadone (n=19) or buprenorphine (n=19) were enrolled. A total of 37 patients (97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dl. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required. CONCLUSIONS: The interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin for 12weeks was well tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use. PMID- 25839408 TI - Wip1 knockout inhibits the proliferation and enhances the migration of bone marrow mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs), a unique population of multipotent adult progenitor cells originally found in bone marrow (BM), are extremely useful for multifunctional therapeutic approaches. However, the growth arrest and premature senescence of MSCs in vitro prevent the in-depth characterization of these cells. In addition, the regulatory factors involved in MSCs migration remain largely unknown. Given that protein phosphorylation is associated with the processes of MSCs proliferation and migration, we focused on wild-type p53-inducible phosphatase-1 (Wip1), a well-studied modulator of phosphorylation, in this study. Our results showed that Wip1 knockout significantly inhibited MSCs proliferation and induced G2-phase cell-cycle arrest by reducing cyclinB1 expression. Compared with WT-MSCs, Wip1(-/-) MSCs displayed premature growth arrest after six passages in culture. Transwell and scratch assays revealed that Wip1(-/-) MSCs migrate more effectively than WT-MSCs. Moreover, the enhanced migratory response of Wip1( /-) MSCs may be attributed to increases in the induction of Rac1-GTP activity, the pAKT/AKT ratio, the rearrangement of filamentous-actin (f-actin), and filopodia formation. Based on these results, we then examined the effect of treatment with a PI3K/AKT and Rac1 inhibitor, both of which impaired the migratory activity of MSCs. Therefore, we propose that the PI3K/AKT/Rac1 signaling axis mediates the Wip1 knockout-induced migration of MSCs. Our findings indicate that the principal function of Wip1 in MSCs transformation is the maintenance of proliferative capacity. Nevertheless, knocking out Wip1 increases the migratory capacity of MSCs. This dual effect of Wip1 provides the potential for purposeful routing of MSCs. PMID- 25839410 TI - High speed structured illumination microscopy in optically thick samples. AB - Structured illumination microscopy (SIM) allows imaging of fluorescently labelled biological samples with a spatial resolution improved by a factor of approximately two compared to traditional optical microscopy techniques. The cost of this resolution improvement is the need to capture a number of raw images of the sample to reconstruct a single SIM image, increasing sample light exposure and limiting the ability of the technique to capture dynamic processes. In this paper we describe image acquisition and reconstruction techniques that allow fast super-resolution imaging within optically thick specimens. By exploiting overlaps between SIM information passbands we are able to generate optically sectioned, super-resolution images from an image sequence acquired in a single focal plane. We consider how single plane super-resolution images may be obtained using 2D and 3D SIM illumination patterns, and compare the resulting images to those obtained using conventional 2D SIM reconstruction methods. By combining a single plane reconstruction algorithm with hardware for high-speed switching between illumination patterns and rapid acquisition of fluorescence images, we demonstrate high speed super-resolution imaging inside biological organisms. PMID- 25839409 TI - A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor. AB - The PI3K-AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC. PMID- 25839411 TI - Identification and rapid diagnosis of the pathogen responsible for haemorrhagic disease of the gill of Allogynogenetic crucian carp. AB - In recent years, an epizootic causing severe mortality among Allogynogenetic crucian carp (ACC), designated as haemorrhagic disease of ACC gill, occurred in Yancheng city of Jiangsu province of China. Obvious haemorrhage in the gills of moribund fish and a mortality rate of 100% were observed when ACCs were artificially infected with liver homogenate from diseased fish. A herpes-like virus, with enveloped virions ranged from 170 to 220 nm in diameter, could be observed in the tissues of challenged ACCs by examination with electron microscopy. Specific products representing the polymerase and helicase genes of Cyprinid herpesvirus-2 (CyHV-2) could be amplified from the challenged fish, suggesting that the haemorrhagic disease of ACC gill was caused by infection with CyHV-2. To rapidly diagnose CyHV-2-infected fish, an easy and effective detection assay with loop-mediated isothermal amplification (LAMP) was established. The LAMP assay was more sensitive than conventional PCR and the limit of detection was approximately 100 copies of target DNA. With this LAMP assay, CyHV-2 could be detected in some asymptomatic ACCs from the epidemic area and in eggs from the diseased ACCs, suggesting that CyHV-2 could infect ACCs latently and that the virus may be passed onto offspring by vertical transmission. PMID- 25839412 TI - Nanomechanical testing technique for millimeter-sized and smaller molecular crystals. AB - Large crystals are used as a control for the development of a mounting and nanoindentation testing technique for millimeter-sized and smaller molecular crystals. Indentation techniques causing either only elastic or elastic-plastic deformation produce similar results in assessing elastic modulus, however, the elastic indents are susceptible to surface angle and roughness effects necessitating larger sample sizes for similar confidence bounds. Elastic-plastic indentations give the most accurate results and could be used to determine the different elastic constants for anisotropic materials by indenting different crystal faces, but not by rotating the indenter about its axis and indenting the same face in a different location. The hardness of small and large crystals is similar, suggesting that defect content probed in this study is similar, and that small crystals can be compared directly to larger ones. The Young's modulus and hardness of the model test material, griseofulvin, are given for the first time to be 11.5GPa and 0.4GPa respectively. PMID- 25839413 TI - Self-nanoemulsifying drug delivery systems as novel approach for pDNA drug delivery. AB - It was the aim of this study to investigate a novel strategy for oral gene delivery utilizing a self-nanoemulsifying drug delivery system (SNEDDS). After hydrophobic ion pairing a plasmid was incorporated into SNEDDS. The mean droplet size of resulting nanoemulsions was determined to be between 45.8 and 47.5 nm. A concentration dependent cytotoxicity of the formulations was found on HEK-293 cells via MTT assay. Degradation studies via DNase I showed that incorporation into SNEDDS led to significantly, up to 8-fold prolonged resistant time against enzymatic digestion compared to naked pDNA and pDNA-lipid complexes. Transfection studies carried out revealed a significantly improved transfection compared to naked pDNA. Further, no decrease in transfection efficiency compared to transfection using Lipofectin((r)) transfection reagent was observed. PMID- 25839414 TI - Curcumin delivery from poly(acrylic acid-co-methyl methacrylate) hollow microparticles prevents dopamine-induced toxicity in rat brain synaptosomes. AB - The potential of poly(methyl methacrylate-co-acrylic acid) (PMMA-AA) copolymers to form hollow particles and their further formulation as curcumin delivery system have been explored. The particles were functionalized by crosslinking the acrylic acid groups via bis-amide formation with either cystamine (CYS) or 3,3' dithiodipropionic acid dihydrazide (DTP) which simultaneously incorporated reversibility due to the presence of disulfide bonds within the crosslinker. Optical micrographs showed the formation of spherical hollow microparticles with a size ranging from 1 to 7 MUm. Curcumin was loaded by incubation of its ethanol solution with aqueous dispersions of the cross-linked particles and subsequent evaporation of the ethanol. Higher loading was observed in the microparticles with higher content of hydrophobic PMMA units indicating its influence upon the loading of hydrophobic molecules such as curcumin. The in vitro release studies in a phosphate buffer showed no initial burst effect and sustained release of curcumin that correlated with the swelling of the particles under these conditions. The capacity of encapsulated and free curcumin to protect rat brain synaptosomes against dopamine-induced neurotoxicity was examined. The encapsulated curcumin showed greater protective effects in rat brain synaptosomes as measured by synaptosomal viability and increased intracellular levels of glutathione. PMID- 25839415 TI - Adenosine conjugated lipidic nanoparticles for enhanced tumor targeting. AB - Delivering chemotherapeutics by nanoparticles into tumor is impeded majorly by two factors: nonspecific targeting and inefficient penetration. Targeted delivery of anti-cancer agents solely to tumor cells introduces a smart strategy because it enhances the therapeutic index compared with untargeted drugs. The present study was performed to investigate the efficiency of adenosine (ADN) to target solid lipid nanoparticles (SLN) to over expressing adenosine receptor cell lines such as human breast cancer and prostate cancer (MCF-7 and DU-145 cells), respectively. SLN were prepared by emulsification and solvent evaporation process using docetaxel (DTX) as drug and were characterized by various techniques like dynamic light scattering, differential scanning calorimeter and transmission electron microscopy. DTX loaded SLNs were surface modified with ADN, an adenosine receptors ligand using carbodiimide coupling. Conjugation was confirmed using infrared spectroscopy and quantified using phenol-sulfuric acid method. Conjugated SLN were shown to have sustained drug release as compared to unconjugated nanoparticles and drug suspension. Compared with free DTX and unconjugated SLN, ADN conjugated SLN showed significantly higher cytotoxicity of loaded DTX, as evidenced by in vitro cell experiments. The IC50 was 0.41 MUg/ml for native DTX, 0.30 MUg/ml for unconjugated SLN formulation, and 0.09 MUg/ml for ADN conjugated SLN formulation in MCF-7 cell lines. Whereas, in DU-145, there was 2 fold change in IC50 of ADN-SLN as compared to DTX. IC50 was found to be 0.44 MUg/ml for free DTX, 0.39 MUg/ml for unconjugated SLN and 0.22 MUg/ml for ADN SLN. Annexin assay and cell cycle analysis assay further substantiated the cell cytotoxicity. Fluorescent cell uptake and competitive ligand-receptor binding assay corroborated the receptor mediated endocytosis pathway indicated role of adenosine receptors in internalization of conjugated particles. Pharmacokinetic studies of lipidic formulations depicted significant improvement in pharmacokinetic parameters than marketed formulation. ADN conjugated SLN proved to be an efficient drug delivery vehicle. Hence, ADN can be used as a potential ligand to target breast and prostate cancer. PMID- 25839416 TI - Ibuprofen-in-cyclodextrin-in-W/O/W emulsion - Improving the initial and long-term encapsulation efficiency of a model active ingredient. AB - A challenge in formulating water-in-oil-in-water (W/O/W) emulsions is the uncontrolled release of the encapsulated compound prior to application. Pharmaceuticals and nutraceuticals usually have amphipathic nature, which may contribute to leakage of the active ingredient. In the present study, cyclodextrins (CyDs) were used to impart a change in the relative polarity and size of a model compound (ibuprofen) by the formation of inclusion complexes. Various inclusion complexes (2-hydroxypropyl (HP)-beta-CyD-, alpha-CyD- and gamma CyD-ibuprofen) were prepared and presented within W/O/W emulsions, and the initial and long-term encapsulation efficiency was investigated. HP-beta-CyD ibuprofen provided the highest encapsulation of ibuprofen in comparison to a W/O/W emulsion with unassociated ibuprofen confined within the inner water phase, with a four-fold increase in the encapsulation efficiency. An improved, although lower, encapsulation efficiency was obtained for the inclusion complex gamma-CyD ibuprofen in comparison to HP-beta-CyD-ibuprofen, whereas alpha-CyD-ibuprofen had a similar encapsulation efficiency to that of unassociated ibuprofen. The lower encapsulation efficiency of ibuprofen in combination with alpha-CyD and gamma-CyD was attributed to a lower association constant for the gamma-CyD-ibuprofen inclusion complex and the ability of alpha-CyD to form inclusion complexes with fatty acids. For the W/O/W emulsion prepared with HP-beta-CyD-ibuprofen, the highest encapsulation of ibuprofen was obtained at hyper- and iso-osmotic conditions and by using an excess molar ratio of CyD to ibuprofen. In the last part of the study, it was suggested that the chemical modification of the HP-beta CyD molecule did not influence the encapsulation of ibuprofen, as a similar encapsulation efficiency was obtained for an inclusion complex prepared with mono 1-glucose-beta-CyD. PMID- 25839417 TI - Continuous twin screw melt granulation of glyceryl behenate: Development of controlled release tramadol hydrochloride tablets for improved safety. AB - Interest in granulation processes using twin screw extrusion machines is rapidly growing. The primary objectives of this study were to develop a continuous granulation process for direct production of granules using this technique with glyceryl behenate as a binder, evaluate the properties of the resulting granules and develop controlled release tablets containing tramadol HCl. In addition, the granulation mechanism was probed and the polymorphic form of the lipid and drug release rate were evaluated on stability. Granules were prepared using a Leistritz NANO16 twin screw extruder operated without a constricting die. The solid state of the granules were characterized by differential scanning calorimetry and X-ray diffraction. Formulated tablets were studied in 0.1N HCl containing 0-40% ethanol to investigate propensity for alcohol induced dose dumping. The extrusion barrel temperature profile and feed rate were determined to be the primary factors influencing the particle size distribution. Granules were formed by a combination immersion/distribution mechanism, did not require subsequent milling, and were observed to contain desirable polymorphic forms of glyceryl behenate. Drug release from tablets was complete and controlled over 16 h and the tablets were determined to be resistant to alcohol induced dose dumping. The drug release rate from the tablets was found to be stable at 40 degrees C and 75% relative humidity for the duration of a 3 month study. PMID- 25839418 TI - Electrophoretic mobility as a tool to separate immune adjuvant saponins from Quillaja saponaria Molina. AB - Quillaja saponins are used as adjuvants in animal vaccines but their application in human vaccination is still under investigation. Isolation and characterization of adjuvant saponins is very tedious. Furthermore, standardization of Quillaja saponins is critical pertaining to its application in humans. In this study, a convenient method based on agarose gel electrophoresis was developed for the separation of Quillaja saponins. Six different commercial Quillaja saponins were segregated by size/charge into numerous fractions. Each of the fractions was characterized by ESI-TOF-MS spectroscopy and thin layer chromatography. Real-time impedance-based monitoring and red blood cell lysis assay were used to evaluate cytotoxicity and hemolytic activities respectively. Two specific regions in the agarose gel (delimited by specific relative electrophoretic mobility values) were identified and characterized by exclusive migration of acylated saponins known to possess immune adjuvant properties (0.18-0.58), and cytotoxic and hemolytic saponins (0.18-0.94). In vivo experiments in mice with the isolated fractions for evaluation of adjuvant activity also correlated with the relative electrophoretic mobility. In addition to the separation of specific Quillaja saponins with adjuvant effects as a pre-purification step to HPLC, agarose gel electrophoresis stands out as a new method for rapid screening, separation and quality control of saponins. PMID- 25839419 TI - Kinetically stable propofol emulsions with reduced free drug concentration for intravenous delivery. AB - PURPOSE: Intravenous injections of propofol emulsions are accompanied by pain likely due to the interaction of the dissolved drug with endothelial cells of the vasculature. It is commonly hypothesized that reducing the aqueous phase concentration of propofol could reduce pain. METHODS: To minimize the propofol concentration in the aqueous phase, we developed stable oil-in-water emulsions with excipient oil mixtures that have an increased partition coefficient for propofol. We then explored the emulsion stability by measuring size distributions after extended durations of shelf storage and also after freeze-thaw cycling. The effects of oil type, surfactant and salt concentration on emulsion stability were also explored. RESULTS: Small chain oils like ethyl butyrate exhibit high drug partitioning but poor stability, while larger molecules such as soybean oil exhibit lower partitioning but excellent emulsion stability. Emulsions with mixtures of soybean oil and ethyl butyrate are stable for longer than a year, resistant to freeze-thaw cycling, and reduce aqueous drug concentrations of propofol twofold compared to pure soybean oil emulsions. CONCLUSIONS: Oil-in water emulsions of propofol formulated with mixtures of ethyl butyrate and soybean oil are kinetically stable and significantly reduce the aqueous phase drug concentration making them promising candidates for future propofol therapies. PMID- 25839420 TI - Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability. AB - DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature. PMID- 25839421 TI - A comparative analysis of vertical and horizontal fixation disparity in sentence reading. AB - Humans have two, frontally placed eyes and during reading oculomotor and sensory processes are needed to combine the two inputs into a unified percept of the text. Generally, slight vergence errors, i.e., fixation disparities, occur but do not cause double vision since disparate retinal inputs fall into Panum's fusional area, that is, a range of disparity wherein sensory fusion of the two retinal images is achieved. In this study, we report benchmark data with respect to the mean magnitude and range of vertical compared to horizontal fixation disparities for natural reading. Our data clearly fit to an elliptical pattern of Panum's fusional area that corresponds with theoretical estimates. Furthermore, when we examined disparity-driven vergence adjustments during fixations by comparing monocular with binocular reading conditions, we found that only horizontal fixation disparities increased significantly under conditions of monocular stimulation. Also, no significant vertical fine-tuning (vergence adjustment) was observed for vergence eye movements during reading fixations. Thus, horizontal and vertical fixation disparities and vergence adjustments during reading showed quite different characteristics, and this dissociation is directly related to the functional role of vergence adjustments: vertical fusion - and vertical vergence subserve the maintenance of a single percept and stereopsis by keeping the eyes in register and allowing for horizontal fusional processes to successfully operate over a vertically aligned input. A reliable and stable vertical alignment is, thus, a pre-requisite over which horizontal fusional responses (and depth perception) can work most efficiently - even in a task like reading. PMID- 25839422 TI - Locality-constrained Subcluster Representation Ensemble for lung image classification. AB - In this paper, we propose a new Locality-constrained Subcluster Representation Ensemble (LSRE) model, to classify high-resolution computed tomography (HRCT) images of interstitial lung diseases (ILDs). Medical images normally exhibit large intra-class variation and inter-class ambiguity in the feature space. Modelling of feature space separation between different classes is thus problematic and this affects the classification performance. Our LSRE model tackles this issue in an ensemble classification construct. The image set is first partitioned into subclusters based on spectral clustering with approximation-based affinity matrix. Basis representations of the test image are then generated with sparse approximation from the subclusters. These basis representations are finally fused with approximation- and distribution-based weights to classify the test image. Our experimental results on a large HRCT database show good performance improvement over existing popular classifiers. PMID- 25839423 TI - Improving label-free quantitative proteomics strategies by distributing shared peptides and stabilizing variance. AB - In a previous study, we demonstrated that spectral counts-based label-free proteomic quantitation could be improved by distributing peptides shared between multiple proteins. Here, we compare four quantitative proteomic approaches, namely, the normalized spectral abundance factor (NSAF), the normalized area abundance factor (NAAF), normalized parent ion intensity abundance factor (NIAF), and the normalized fragment ion intensity abundance factor (NFAF). We demonstrate that label-free proteomic quantitation methods based on chromatographic peak area (NAAF), parent ion intensity in MS1 (NIAF), and fragment ion intensity (NFAF) are also improved when shared peptides are distributed on the basis of peptides unique to each isoform. To stabilize the variance inherent to label-free proteomic quantitation data sets, we use cyclic-locally weighted scatter plot smoothing (LOWESS) and linear regression normalization (LRN). Again, all four methods are improved when cyclic-LOWESS and LRN are applied to reduce variation. Finally, we demonstrate that absolute quantitative values may be derived from label-free parameters such as spectral counts, chromatographic peak area, and ion intensity when using spiked-in proteins of known amounts to generate standard curves. PMID- 25839424 TI - Root architecture and morphometric analysis of Arabidopsis thaliana grown in Cd/Cu/Zn-gradient agar dishes: A new screening technique for studying plant response to metals. AB - A new screening strategy using Petri dishes with a gradient of distances between germinating seeds and a metal-contaminated medium was used for studying alterations in root architecture and morphology of Arabidopsis thaliana treated with cadmium, copper and zinc at sub-toxic concentrations. Metal concentrations in the dishes were determined by anodic stripping voltammetry on digested agar samples collected along the gradient, and kriging statistical interpolation method was performed. After two weeks, all agar dishes were scanned at high resolution and the root systems analyzed. In the presence of all the three metals, primary root length did not significantly change compared to controls, excepting for zinc applied alone (+45% of controls). In metal-treated seedlings, root system total length increased due to the higher number of lateral roots. The seedlings closer to the agar sectors including metals showed a marked curvature and a higher root branching in comparison to those further away from the metals. This behavior, together with an observed increase in root diameter in metal treated seedlings could be interpreted as compensatory growth, and a thicker roots could act as a barrier to protect root from the metals. We therefore propose that the remodeling of the root architecture in response to metals could be a pollution 'escaping strategy' aimed at seeking metal-free patches. PMID- 25839425 TI - Autocrine activity of cysteinyl leukotrienes in human vascular endothelial cells: Signaling through the CysLT2 receptor. AB - We evaluated the autocrine activities of cysteinyl leukotrienes (cysteinyl-LTs) in HUVEC and studied the signaling and the pharmacological profile of the CysLT2 receptor (CysLT2R) expressed by ECs, finally assessing the role of the CysLT2R in permeability alterations in a model of isolated brain. Cysteinyl-LTs and their precursor LTA4 contracted HUVEC and increased permeability to macromolecules, increasing the formation of stress fibers through the phosphorylation of myosin light-chain (MLC) following Rho and PKC activation. Accordingly, in an organ model of cerebral vasculature with an intact intima, neutrophils challenge leaded to significant formation of cysteinyl-LTs and edema. Pretreatment with a selective CysLT2R antagonist prevented cytoskeleton rearrangement and HUVEC contraction, along with edema formation in the brain preparation, while leaving the synthesis of cysteinyl-LTs unaffected. We also demonstrate here that the CysLT1R antagonist zafirlukast, pranlukast, pobilukast and iralukast also possess CysLT2R antagonistic activity, which could help in reconsidering previous data on the role of cysteinyl-LTs in the cardiovascular system. The results obtained are further supporting a potential role for CysLT2R in cardiovascular disease. PMID- 25839426 TI - Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists. AB - Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal beta-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes. PMID- 25839427 TI - Quantification of in vitro mesenchymal stem cell invasion into tumor spheroids using selective plane illumination microscopy. AB - Mesenchymal stem cell (MSC) homing and integration into tumors are under evaluation for clinical application. This approach requires the identification of conditions for optimal tumor invasion. We describe a tool for the in vitro comparison of parameters influencing invasion. Human MSC added to experimental tumor spheroids variably migrates toward the center of the structure. To determine MSC distribution inside the three-dimensional specimen, spatial analysis was performed using selective plane illumination microscopy. A standardized method to quantify and compare the invasion potential of variably treated MSC into experimental tumor environments allows efficient screening for optimizing conditions. PMID- 25839428 TI - Cylindrical diffuser axial detection profile is dependent on fiber design. AB - The axial emission and detection profiles of 1- and 2-cm cylindrical diffusing fibers based on concentration gradients of scatterers were measured. Based on these measurements, we describe a method for determination of the scatterer concentration gradient within the diffusers. Using a Monte Carlo model incorporating these concentrations, detection was simulated and found to agree with measurements. The measured and simulated detection profiles for these diffusers were found to be drastically different from those previously measured in an alternative diffuser design incorporating an end reflector. When using cylindrical diffusers as detection fibers, it is, therefore, important to understand the design of the fiber and characterize the detection behavior. PMID- 25839429 TI - Make them, break them, and catch them: studying rare ubiquitin chains. AB - Two studies in this issue, Kristariyanto et al. (2015) and Michel et al. (2015), describe innovative ways to produce large quantities of atypical K29 and K33 ubiquitin chains and report structures and mechanisms of chain-specific recognition. PMID- 25839431 TI - Caging the elephant: selective autophagy tackles giant intracellular protein crystals. AB - In this issue of Molecular Cell, Tsutsui et al. (2015) show that in vivo protein crystallization may come in handy not only when solving the structure of a protein, but also when studying molecular mechanisms of selective autophagy. PMID- 25839430 TI - gammaHV68 vGAT: a viral pseudoenzyme pimping for PAMPs. AB - In this issue, He et al. (2015) show how herpes virus usurps a cellular metabolic enzyme to induce RIG-I deamidation and RNA-independent activation, likely to better prevent further innate immune responses. PMID- 25839432 TI - Hsp90: breaking the symmetry. AB - Hsp90 chaperones receive much attention due to their role in cancer and other pathological conditions, and a tremendous effort of many laboratories has contributed in the past decades to considerable progress in the understanding of their functions. Hsp90 chaperones exist as dimers and, with the help of cochaperones, promote the folding of numerous client proteins. Although the original view of these interactions suggested that these dimeric complexes were symmetrical, it is now clear that many features are asymmetrical. In this review we discuss several recent advances that highlight how asymmetric interactions with cochaperones as well as asymmetric posttranslational modifications provide mechanisms to regulate client interactions and the progression through Hsp90's chaperone cycle. PMID- 25839433 TI - Adult sigmoidorectal intussusception related to colonic lipoma: A rare case report with an atypical presentation. AB - INTRODUCTION: Adult intussusception is rare. Lipoma is the second most common benign tumor of the colon and most common to cause colonic intussusception in adults, but rare. PRESENTATION OF CASE: A 35-years-old male presented with a history of intermittent abdominal pain and bright red rectal bleeding, with symptoms waxing and waning for one month. On physical examination, the abdomen was distended with tenderness over the periumbilical, suprapubic, and left lower quadrant regions with guarding. CT demonstrated colo-colonic intussusception of the sigmoid colon with a 2.3cm*2.6cm intra-mural lipoma of the rectosigmoid region. The patient underwent an exploratory laparotomy with partial reduction of the intussusception, sigmoid colon resection and end colostomy. Histopathology confirmed a 2.5cm sub-mucosal lipoma without evidence of malignancy. DISCUSSION: Sixty-sixty five percent of cases with intussusception of the large bowel in adults are related to a malignant etiology and most cases of sigmoidorectal intussusception reported in the literature are secondary to underlying malignancy. Colo-colic intussusception is the most common type of intussusception in adults. The incidence of lipomas of the large intestine is reported to range from 0.035% to 4.4%. Ninety percent of colonic lipomas are submuscosal and are mostly located in the right hemicolon. Only 25% of patients with colonic lipoma develop symptoms. Colonic lipomas of the rectosigmoid region represent a very rare occurrence and subsequent etiology for sigmoidorectal intussusceptions in adults. CONCLUSION: Colonic lipoma should be considered in the differential diagnosis of adults with intussusception, with reduction and resection leading to excellent results. PMID- 25839434 TI - Kidney transplantation in a patient with absent right common iliac artery and congenital renal abnormalities. AB - INTRODUCTION: Congenital atresia of the common and external iliac arteries is a rare vascular anomaly that may be associated with congenital renal or genitourinary malformations. In ESRD patients, its presence may pose potential problems during renal transplantation. CASE PRESENTATION: We report a rare case of kidney transplantation in a patient with VACTERL syndrome who was found to have absent right common and external iliac arteries during pre-operative imaging. Vascular supply to the right lower limb is derived from an anomalous branch from the left internal iliac artery which takes on a convoluted course across the pelvis. Kidney transplantation was performed successfully with implantation performed on the left side. DISCUSSION: Isolated cases of congenital iliac artery atresia have been described in association with urological abnormalities but no clear association has yet been established. However, we feel that it may be useful to perform routine angiographic evaluation for ESRD patients with congenital genitourinary abnormalities being planned for kidney transplantation. While most cases of congenital iliac artery anomalies are symptomatic with claudication, some remain asymptomatic with normal physical examination findings. There is some evidence in literature suggesting the usefulness of routine pre-operative CT in a selective group of patients. CONCLUSION: Kidney transplantation in such cases is safe and we recommend routine pre-operative imaging of patients known to have congenital genitourniary abnormalities. The kidney should be implanted heterotopically to the contralateral side of the vascular anomaly and care must be taken to preserve vascular supply to the lower limbs. PMID- 25839435 TI - Expert tibia nail for subtrochanteric femoral fracture to prevent thermal injury. AB - INTRODUCTION: Subtrochanteric femoral fractures are relatively uncommon, accounting for 7-15% of all hip fractures and treatment of these fractures are considered challenge for orthopaedic surgeons. Although several treatment options are reported with up to 90% of satisfactory results, the choice of the appropriate implant is still a matter of debate. Some authors reported thermal injury after reaming for intramedullary nail fixation in patients with narrow medullary canal. PRESENTATION OF CASE: A 21-year-old female patient was admitted to our hospital because of right subtrochanteric femoral fracture. The narrowest diameter of medullary canal of her femur was about 7mm but she refused open reduction and internal fixation with plate due to large scar formation. We used expert tibia nail instead of femoral intramedullary nail to prevent thermal injury. DISCUSSION: Subtrochanteric femoral fractures are difficult to treat because of their biomechanical and anatomical characteristics. Although several implants are reported for the surgical treatment of these fractures, intramedullary nails have been advocated due to their biological and biomechanical advantages. However, under certain circumstances with associated injury or anatomic difference we might consider another treatment options. CONCLUSION: Expert tibia nail may be considered one of the treatment options for subtrochanteric femoral fracture with narrow medullary canal. We also emphasize the importance of preoperative evaluation of the medullary canal size for these risky fractures. PMID- 25839436 TI - Aromatase inhibitor (anastrozole) affects growth of endometrioma cells in culture. AB - OBJECTIVE: To study the effects of aromatase inhibitor (anastrozole) on the growth and estradiol secretion of endometrioma cells in culture. DESIGN: Endometrioma cells are grown in vitro until maximum growth before used in this study. This was done in the research laboratory for tissue culture, in an academic hospital. INTERVENTIONS: Testosterone at a concentration of 10 MUg/mL was added as a substrate for the intracellular aromatase. In addition, aromatase inhibitor was added at a concentration of 200 and 300 MUg/mL. The effect on cell growth and estradiol secretion is evaluated using Student's t-test. RESULTS: The use of testosterone increased estradiol secretion by endometrioma cells in culture. The use of aromatase inhibitor significantly inhibited the growth of endometrioma cells, and estradiol secretion. CONCLUSION: Aromatase inhibitor (anastrozole) may be an effective treatment for endometriosis due to inhibition of cellular aromatase. PMID- 25839437 TI - Colposcopy training and assessment across the member countries of the European Federation for Colposcopy. AB - OBJECTIVES: Colposcopy training and assessment is not uniform across Europe with individual countries determining their own required standards and regulations. In light of the significant changes in colposcopic practice that have occurred over the past decade and the expansion of the European Federation for Colposcopy (EFC) membership, a study was conducted firstly, to assess the current requirements for training in each of the member countries and secondly, to review an EFC-approved core training curriculum for colposcopy. STUDY DESIGN: A questionnaire survey of the EFC representatives from all member countries investigating their country's current practices/requirements with regard to training, assessment and accreditation for colposcopy. A two-round Delphi consultation with representation from the full, associate and three potential member countries was conducted using a 5-point Likert scale for scoring opinions. The results were analysed with respect to each country's population size and World Bank economic classification. RESULTS: For the questionnaire survey, responses were received from 31/34 countries invited to participate. Training programmes were reported to be in place in 21 of the 31 countries but only 17 of the 21 countries had a committee overseeing the training programme. An assessment was part of the training programme in 20 countries with multiple choice questions and portfolios the most common assessment tools. Countries with a population size less than 2 million have a statistically significant lower probability of having a structured training/assessment programme, 1/5 compared to 20/26 for a populations greater than 2 million, p=0.013. For the Delphi study, responses were received from 34/39 countries invited to participate. Of the 51 competencies previously identified only 2 did not receive full support: 'perform bacterial swabs' and 'provide data to national body'. There was no significant difference in the responses given by member, associate member or potential member countries. CONCLUSIONS: There is considerable variation in colposcopy training and assessment across Europe. This study has enabled consensus opinion with the EFC on the contents of an EFC core curriculum. The revised curriculum has a mandate from the EFC member countries to be implemented across Europe as the standard for colposcopic training. PMID- 25839438 TI - Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation. AB - The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 = 40 MUM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 * PT value of 8.7 MUM. PMID- 25839439 TI - IL-12 augments antitumor responses to cycled chemotherapy. AB - Loss of antitumor response to repeated chemotherapy is a major cause of treatment failure in cancer patients. The development of acquired drug resistance is thought to come primarily from changes in tumor cells, and not host response to the tumor. Our recent study shows that antitumor immunity is activated and contributes significantly to the efficacy of chemotherapy. In this study of mouse tumor models, we demonstrate that loss of antitumor response during multiple cycles of chemotherapy is associated with a lack of immune activation, and not intrinsic tumor cell drug resistance. More importantly, we show that adding interleukin-12 (IL-12) to cycled chemotherapy maintains and even increases antitumor immune response in both immunogenic and nonimmunogenic murine tumors and significantly prolongs survival. In some instances, larger tumor burdens that relapse following an initial cycle of cyclophosphamide and IL-12 are eradicated by subsequent cycles of the same treatment at the same doses. Further analysis demonstrates that the initial cycle of the combined therapy increases antitumor immunity of the host. In other mice when tumors are not eradicated by the current cycle of therapy, it serves as a starting point for the subsequent cycles of treatment to generate higher levels of antitumor immunity and greater antitumor response. These results show that the status of host antitumor immunity is a critical factor affecting antitumor efficacy during repeated administration of chemotherapy. Further, IL-12 augments the antitumor immune response under such conditions. PMID- 25839440 TI - Efficient nontoxic delivery of PD-L1 and PD-L2 siRNA into dendritic cell vaccines using the cationic lipid SAINT-18. AB - Dendritic cell (DC)-based vaccination is an appealing strategy to boost graft versus-tumor immunity after allogeneic stem cell transplantation (allo-SCT), and thereby prevent or counteract tumor recurrence. By exploiting minor histocompatibility antigens (MiHA) presented on hematopoietic cells, donor CD8 T cell immunity can be selectively targeted to patient's hematological tumor cells without the risk of inducing graft-versus-host disease. Previously, we demonstrated that silencing RNA (siRNA) of programmed death-ligand 1 (PD-L1) and PD-L2 on DCs markedly augments the expansion and function of MiHA-specific CD8 T cells. However, previously applied methods based on electroporation or lipid nanoparticles were either incompatible with target antigen mRNA delivery or required complex manufacturing compliant to Good Manufacturing Practice. Here, we investigated whether transfection using lipoplexes composed of PD-L1 and PD-L2 siRNAs plus SAINT-18:DOPE (ie, SAINT-RED) is an effective and feasible clinical grade method in DC vaccine manufacturing. We observed that a single siRNA/SAINT RED transfection resulted in efficient and long-term knockdown of the PD-1 ligands without affecting DC maturation or viability. Furthermore, we demonstrated that SAINT-RED can be heat sterilized without loss of function, facilitating its use in aseptic DC vaccine production. Finally, we showed that the established transfection method can be combined with target antigen mRNA or peptide loading to efficiently stimulate MiHA-specific T-cell expansion and cytokine production. Together, these findings indicate that the developed PD-L siRNA/SAINT-RED transfection protocol in combination with MiHA mRNA or peptide loading can be applied in the generation of clinical-grade DC vaccines to boost antitumor immunity after allo-SCT. PMID- 25839441 TI - Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors. AB - Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-alpha, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor alpha/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38 carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy. PMID- 25839443 TI - Effect of Methanol Addition on the Resistivity and Morphology of PEDOT:PSS Layers on Top of Carbon Nanotubes for Use as Flexible Electrodes. AB - Overcoating carbon nanotube (CNT) films on flexible poly(ethylene terephthalate) (PET) foils with poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) layers reduces the surface roughness, which is interesting for use in organic electronics. Adding methanol to the PEDOT: PSS aqueous solution used for spin coating of the PEDOT: PSS layer improves the wetting behavior of the CNT/PET surface. Samples with different volume fractions of methanol (0, 33, 50, 67, and 75 vol %) are compared with respect to the transmission, horizontal, and vertical resistivity. With grazing-incidence small-angle X-ray scattering, the film morphologies are probed, which is challenging because of the substrate flexibility. At 50 vol %, methanol optimum conditions are achieved with the resistivity close to that of the bare CNT/PET substrates because of the best contact between the PEDOT: PSS film and CNT surface. At lower methanol ratios, the PEDOT: PSS films cannot adapt the CNT morphology, and at higher methanol ratios, they rupture into domains and no continuous PEDOT: PSS layers are formed. PMID- 25839442 TI - Delayed dermatologic hypersensitivity reaction secondary to ipilimumab. AB - The treatment of melanoma has long favored the use of immunologic agents. Ipilimumab is a monoclonal antibody used to enhance the immune response. This therapy is associated with a variety of adverse reactions including skin reactions. Although dermatologic toxicities associated with the use of ipilimumab are common, delayed hypersensitivity reactions related to the drug have yet to be identified. This report is believed to be the first case of a delayed, severe dermatologic drug-related reaction secondary to ipilimumab. This case highlights the potential for severe toxicity for long periods after administration of ipilimumab. PMID- 25839444 TI - Prophylactic lithium alleviates splenectomy-induced cognitive dysfunction possibly by inhibiting hippocampal TLR4 activation in aged rats. AB - Though the pathogenesis of postoperative cognitive dysfunction (POCD) remains unclear, evidence is accumulating for a pivotal role of neuroinflammation in the disease process. Advanced age and severe surgical trauma are two main risk factors for POCD. Lithium, a neuroprotective agent, can alleviate peripheral surgery-induced memory impairment in aged rats. The results of in vivo and in vitro experiments also showed that toll like receptor 4 (TLR4) was associated with the occurrence and development of neuroinflammation and POCD. So we hypothesized that inhibition of TLR4 signaling in the hippocampus maybe involved in the protective effects of prophylactic lithium on the occurrence of inflammation and POCD. In the present study, we incubated BV-2 microglia with 1MUg/ml lipopolysaccharide (LPS) to mimic neuroinflammation in vitro. We found that pretreatment with 10mM of lithium or 100nM of TLR4 siRNA could inhibit the tumor necrosis factor (TNF)-alpha and TLR4 mRNA expression induced by LPS in BV-2 microglia. Furthermore, combination of prophylactic lithium and TLR4 siRNA even decreased their mRNA expression to the baseline levels, which showed that TLR4 signaling may be vital in protective effects of prophylactic lithium on neuroinflammation. So we further undergone the in vivo experiment. Then, we firstly demonstrated that prophylactic 2mM/kg of lithium alleviated splenectomy induced cognitive impairments, decreased splenectomy-associated systemic, central, and hippocampal TNF-alpha and interleukin (IL)-1beta expression and reduced the increase of CD11b(+) area in hippocampal CA1 region caused by the surgery. Then, we also found that splenectomy merely increased hippocampal TLR2 and TLR4 mRNA levels in aged rats. At last, we confirmed that prophylactic lithium reduced the increased levels of hippocampal TLR4/NF-kappaB induced by splenectomy. Taken together, these results demonstrate that TLR4 signaling inactivation may contribute to the protective effects of prophylactic lithium on the occurrence of POCD by inhibiting systemic inflammation and especially neuroinflammation. PMID- 25839620 TI - Comparison of Three Isoelectronic Multiple-Well Reaction Systems: OH + CH2O, OH + CH2CH2, and OH + CH2NH. AB - Methylenimine (CH2NH) has been predicted to be a product of the atmospheric photo oxidation of methylamine, but its atmospheric reactions have not been measured. In this paper, we report potential energy surfaces (PESs) and rate constants for OH + CH2NH and its isoelectronic analogues OH + CH2O and OH + CH2CH2, which are more fully understood. The PESs were computed using the BHandHLYP/aug-cc-pVTZ and CCSD(T)/aug-cc-pVTZ levels of theory. Canonical variational transition state theory and Rice-Ramsperger-Kassel-Marcus and master equation modeling were used to calculate temperature- and pressure-dependent rate constants, with particular emphasis on the OH + reactant entrance channels and the effects of prereactive complexes. The computed results are in reasonable agreement with experimental data where they can be compared and also with the results of previous theoretical calculations. The results show that to some extent OH radicals both add to the carbon center double bond in CH2NH and abstract methylene hydrogen atoms, as in the OH + CH2O and OH + CH2CH2 reactions, respectively, but the dominant pathway is abstraction of the hydrogen from N-H. The computed rate constants are suitable for both atmospheric and combustion modeling. PMID- 25839621 TI - Complete blood cell count risk score as a predictor of in-hospital mortality and morbidity among patients undergoing cardiac surgery with cardiopulmonary bypass. PMID- 25839622 TI - Can treatment with beta blockers trigger episodes of atrial fibrillation in healthy patients? PMID- 25839623 TI - Glycoprotein IIb/IIIa inhibitors improve mortality after aspiration thrombectomy in patients with ST-segment elevation myocardial infarction. PMID- 25839624 TI - Lack of mitral valve leaflet coaptation in a case of non-compaction cardiomyopathy. PMID- 25839626 TI - An IVUS image report of coronary spasm induced by biodegradable-polymer drug eluting stent. PMID- 25839625 TI - The relevance of estrogen/estrogen receptor system on the gender difference in cardiovascular risk. AB - It has been reported that the incidence of thrombotic events can display a gender disparity. In particular, a lower thrombotic risk has been described in female gender. The mechanisms underlying this disparity are still poorly understood. Of great interest is the hypothesis that hormones, estrogen in particular, could play a key role. In fact, the possibility that some hormonal factors could protect women from thrombotic events appears well documented in literature. For instance, several studies aimed at the analysis of the impact of estrogen and estrogen receptors in thrombogenesis claim for the implication of these hormones either in megakaryocyte differentiation or, more intriguingly, directly affecting platelet integrity and function. In consideration of the absence of the nucleus, platelet susceptibility appears quite striking and probably due to the non nuclear estrogen receptor function. In this review we briefly summarize our knowledge as concerns the role of estrogen and estrogen receptors in determining megakaryocyte/platelet functions and thrombogenicity. PMID- 25839627 TI - QT-correction formulae and arrhythmogenic risk in female patients with anorexia nervosa. PMID- 25839628 TI - Myocarditis is an essential feature rather than an exclusion criterion for takotsubo syndrome: Case report. PMID- 25839629 TI - Incidence of ventricular arrhythmias during World Cup football 2014 in patients with implantable cardioverter defibrillator. PMID- 25839630 TI - Progressive aortic dissection following RCA instent angioplasty. PMID- 25839631 TI - The impact of a strategy of image-guided left ventricular lead placement during cardiac resynchronization therapy on health care utilization. PMID- 25839633 TI - Late recovery in peripartum cardiomyopathy. PMID- 25839632 TI - Effects of hemolysis on the diagnostic accuracy of cardiac troponin I for the diagnosis of myocardial infarction. PMID- 25839634 TI - Acute coronary syndrome and scombroid syndrome. PMID- 25839635 TI - Cytokine storm after cessation of tocilizumab in a patient with refractory Takayasu arteritis. PMID- 25839636 TI - Heart murmur and dysrhythmia are associated with accidents leading to poor mental health and cognition: Scottish Health Survey, 2013. PMID- 25839637 TI - Fractional flow-guided management in patients with acute coronary syndromes: A systematic review and meta-analysis. PMID- 25839638 TI - Noninvasive vagus nerve stimulation: A novel promising modulator for cardiac autonomic nerve system dysfunction. PMID- 25839639 TI - Benefit of implantable cardioverter-defibrillator therapy after generator replacement in patients with Brugada syndrome. AB - BACKGROUND: An implantable cardioverter-defibrillator (ICD) is the only proven effective therapeutic strategy for patients with Brugada syndrome (BS). However, it is controversial whether the device should be replaced even in patients who had never experienced appropriate ICD therapy until the time of generator replacement. METHODS AND RESULTS: This was a nationwide, multicenter retrospective study that enrolled patients who were diagnosed with BS and had an ICD implantation between January 1998 and April 2014. Appropriate ICD therapies administered for ventricular tachyarrhythmia were evaluated during follow-up. A total of 117 patients (age 43 +/- 12 years, male 115 [98.3%]) were enrolled, and the mean follow-up duration was 6.0 +/- 4.1 years. Thirty-seven (31.6%) patients had experienced appropriate ICD therapy during follow-up. Of all patients, 46 underwent replacement of the device. After the first generator replacement, the incidence of appropriate ICD therapy remained as high as 65.2% in patients who previously experienced appropriate ICD therapy before generator replacement. In 30 patients who did not experience any cardiac events until the first generator change, two (8.7%) had an episode of appropriate ICD therapy afterwards. CONCLUSIONS: No episode of ICD therapy before generator replacement could not guarantee a safe clinical course. ICD generator replacement should be considered even in patients without ICD therapy before. PMID- 25839640 TI - Meta-analysis of risk of stroke and thrombo-embolism with rivaroxaban versus vitamin K antagonists in ablation and cardioversion of atrial fibrillation. AB - BACKGROUND: Anticoagulation in cardioversion and ablation of atrial fibrillation is imperative for reducing thrombo-embolic events. Ample information is available about the use of warfarin and vitamin K antagonists (VKA) but few trials examine safety and efficacy of rivaroxaban in these procedures. We aim to explore the hypothesis that rivaroxaban causes equal thrombo-embolic and bleeding events when used in atrial fibrillation patients undergoing ablation or cardioversion compared to VKA. METHODS: We searched the online databases as well as conference abstracts till December 2014 for studies comparing rivaroxaban with VKA in atrial fibrillation patients undergoing catheter ablation or cardioversion. We report events as Odds ratio using random effects model except when event rates were less than 1% we used Peto Odds Ratio. RESULTS: A total of 8872 atrial fibrillation patients in 15 studies undergoing either catheter ablation or cardioversion were included in this analysis. There were significantly lower stroke events with rivaroxaban compared with VKA (Peto Odds Ratio (POR) 0.33, 95% confidence interval (CI) [0.11, 0.95]; P=0.04), and significantly less thrombo-embolic events with rivaroxaban compared with VKA (POR 0.46, 95% CI [0.21, 0.97]; P=0.04). Major and minor bleeding were equal with rivaroxaban versus VKA (Odds Ratio (OR) 0.92, 95% CI [0.62, 1.36]; P=0.68) and (OR 0.81,95% CI [0.58, 1.11]; P=0.19) respectively. CONCLUSION: The use of rivaroxaban in ablation and cardioversion of atrial fibrillation may be associated with decreased risk of stroke and thromboembolism with equal bleeding risk compared to VKA. PMID- 25839641 TI - Impact of prolonged dual antiplatelet therapy after acute myocardial infarction on 5-year mortality in the FAST-MI 2005 registry. AB - BACKGROUND: We document dual antiplatelet therapy (DAPT) use from discharge to 4 years after acute myocardial infarction (AMI), and investigate whether prolonged DAPT (beyond 1 year) is related to 5-year mortality. METHODS: The French Registry of Acute ST-elevation or non-ST-elevation Myocardial Infarction (FAST-MI 2005) included 3670 patients with AMI in 223 French centres. We identified predictors of DAPT (aspirin+clopidogrel) beyond 1 and 2 years, and relation with all-cause 5 year mortality. RESULTS: Among 3319 (96%) patients with discharge data, 2432 (73%) had DAPT, 582 (17%) single antiplatelet therapy (SAPT), and 305 (9%) no antiplatelet treatment. DAPT decreased from 75% at 1 year to 29% at 4 years, with a corresponding increase in SAPT (p<0.05 for trend). Patients with DAPT were more often male, treated with a drug-eluting stent (DES), and without oral anticoagulants. Independent predictors at 1 year of prolonged DAPT were age<75 years, in-hospital bleeding, history of MI, use of DES, discharge use of beta blockers or statins and no chronic anticoagulation. Predictors at 2 years were age<75 years, male gender, previous MI, diabetes, DES implantation, no chronic oral anticoagulation. By multivariate analysis, there was no difference in 5-year mortality between those on SAPT vs DAPT at 1 year. DAPT at 2 years was also not significantly related to 5-year mortality (Hazard Ratio 1.3, 95% CI [0.9; 1.8], p=0.21). CONCLUSION: Prolonged DAPT in selected AMI patients, observed in 47% at 1 year and 21% at 2 years, had no impact on 5-year mortality. These findings do not support the use of DAPT beyond 1 year after an initial ACS. PMID- 25839642 TI - Deinstitutionalization of American public hospitals for the mentally ill before and after the introduction of antipsychotic medications. AB - Deinstitutionalization following the introduction of antipsychotic medications in 1954 has received much attention as a major narrative in psychiatry. Little attention has been given, however, to deinstitutionalization before 1954. Using United States census data on discharge and readmission rates of US mental hospitals from 1935 to 1964, this article analyzes deinstitutionalization using an interrupted time-series model, with particular attention to the statistical significance of trends before and after the advent of antipsychotics. Discharge rates significantly increased in the period before antipsychotics, indicating that deinstitutionalization began before 1954, although readmissions during that same period increased at the same rate as discharges. A reasonable inference is that patients discharged in the pre-antipsychotic period were unable to live independently outside the hospital. After 1954, both discharges and readmissions increased significantly, but due to a continuing increase in admissions, no significant decrease in mental hospital populations occurred during the seven year period after 1954. The decline began in 1961 and coincided with changes in federal policy. The fate of mental patients discharged from hospitals during this second period of deinstitutionalization is examined. The central conclusions are (1) the overall reduction in the population of mental hospitals did not coincide with the 1954 introduction of antipsychotic medications, and (2) deinstitutionalization before and after drugs has been met with inadequate community-based care. PMID- 25839643 TI - The psychiatry of light. AB - Bright light therapy and the broader realm of chronotherapy remain underappreciated and underutilized, despite their empirical support. Efficacy extends beyond seasonal affective disorder and includes nonseasonal depression and sleep disorders, with emerging evidence for a role in treating attention deficit/hyperactivity disorder, delirium, and dementia. A practical overview is offered, including key aspects of underlying biology, indications for treatment, parameters of treatment, adverse effects, and transformation of our relationship to light and darkness in contemporary life. PMID- 25839644 TI - Introduction. PMID- 25839645 TI - Summary and epilogue. PMID- 25839646 TI - Cyclosporine A prevents ex vivo PCO formation through induction of autophagy mediated cell death. AB - The purpose of this study was to determine the Cyclosporine A (CsA) dose and minimum drug delivery time needed to prevent posterior capsule opacification (PCO) in an ex vivo canine model and evaluate the mechanism of CsA-induced cell death. Canine lens epithelial cells (LEC) were treated with CsA and changes in cell migration, proliferation, and density were monitored over time. CsA-treated LEC underwent transmission electron microscopy (TEM), immunofluorescence, and immunoblotting in the presence or absence of autophagy inhibitors to evaluate the mechanism of cell death. Lens capsules were harvested from canine cadaver eyes for an ex vivo model of PCO. Lens capsules were treated with CsA for 1, 2, 3, 4, 5, 6, or 7 days, and subsequently maintained in culture for a total of 28 days in the absence of drug. CsA reduced LEC viability in a dose dependent manner. Morphologically, CsA-treated LEC were swollen, had intact nuclei, lacked peripheral chromatin condensation, and demonstrated prominent vacuolization; TEM revealed autophagosomes. LC3-II protein expression and acridine orange fluorescence increased in CsA-treated cells. A small non-significant induction of cleaved caspase-3 was observed in CsA-treated LEC. Lens capsules treated with 5, 6, or 7 days of 10 MUg/mL CsA showed a significant decrease in ex vivo PCO formation; 6 days of drug delivery prevented PCO. This study finds that morphologic changes, formation of acidic vesicles, and increased expression of LC3-II supports the hypothesis that CsA mediates LEC death via autophagy; this is a novel finding in the lens. Induction of CsA-induced apoptosis was minimal. Six days of intracapsular CsA drug delivery prevented ex vivo PCO formation. PMID- 25839647 TI - Biotransformation and Degradation of the Insensitive Munitions Compound, 3-Nitro 1,2,4-triazol-5-one, by Soil Bacterial Communities. AB - Insensitive munitions (IM) are a new class of explosives that are increasingly being adopted by the military. The ability of soil microbial communities to degrade IMs is relatively unknown. In this study, microbial communities from a wide range of soils were tested in microcosms for their ability to degrade the IM, 3-nitro-1,2,4-triazol-5-one (NTO). All seven soil inocula tested were able to readily reduce NTO to 3-amino-1,2,4-triazol-5-one (ATO) via 3-hydroxyamino-1,2,4 triazol-5-one (HTO), under anaerobic conditions with H2 as an electron donor. Numerous other electron donors were shown to be suitable for NTO-reducing bacteria. The addition of a small amount of yeast extract (10 mg/L) was critical to diminish lag times and increased the biotransformation rate of NTO in nearly all cases indicating yeast extract provided important nutrients for NTO-reducing bacteria. The main biotransformation product, ATO, was degradable only in aerobic conditions, as evidenced by a rise in the inorganic nitrogen species nitrite and nitrate, indicative of nitrogen-mineralization. NTO was nonbiodegradable in aerobic microcosms with all soil inocula. PMID- 25839648 TI - Effect of hierarchy legitimacy on low status group members' attributions for ingroup and outgroup failures. AB - Previous research has shown that people have a tendency to explain successes and failures in ways that favor their ingroups relative to outgroups. However, there has been a dearth of research examining whether social-contextual factors such as group status and hierarchy legitimacy moderate such intergroup attributions. Participants in this study were assigned to a low status group, and perceived hierarchy legitimacy was then experimentally manipulated; the extent to which ingroup versus outgroup failures were attributed to several causes was measured. When low status was considered illegitimate, ingroup failure was attributed to external causes (task difficulty, bad luck) more so than outgroup failure. Implications and directions for future research examining consequences and mediating processes are discussed. PMID- 25839649 TI - Isoflurane induced cognitive impairment in aged rats through hippocampal calcineurin/NFAT signaling. AB - Calcineurin (CaN) over-activation constrains synaptic plasticity and memory formation. Upon CaN activation, NFAT imports into the nucleus and guides its downstream genes, which also affect neuronal and synaptic function. Aberrant CaN/NFAT signaling involves in neurotoxicity and cognitive impairment in neurological disorders such as Alzheimer's disease, but its role in postoperative cognitive dysfunction (POCD) remains uninvestigated. Inhaled anesthetic isoflurane facilitates the development of POCD, and the present study investigated the role of CaN/NFAT signaling in isoflurane induced cognitive impairment of aged rats, and the therapeutic effects of CaN inhibitor cyclosporine A (CsA). The results indicated that hippocampal CaN activity increased and peaked at 6 h after isoflurane exposure, and NFAT, especially NFATc4, imported into the nucleus following CaN activation. Furthermore, phamacological inhibition of CaN by CsA markedly attenuated isoflurane induced aberrant CaN/NFATc4 signaling in the hippocampus, and rescued relevant spatial learning and memory impairment of aged rats. Overall, the study suggests hippocampal CaN/NFAT signaling as the upstream mechanism of isoflurane induced cognitive impairment, and provides potential therapeutic target and possible treatment methods for POCD. PMID- 25839650 TI - TNF-alpha knockdown alleviates palmitate-induced insulin resistance in C2C12 skeletal muscle cells. AB - Insulin resistance is a cardinal feature of Type 2 Diabetes (T2D), which accompanied by lipid accumulation and TNF-alpha overexpression in skeletal muscle. The role of TNF-alpha in palmitate-induced insulin resistance remained to be elucidated. Here, we assessed effects of TNF-alpha knockdown on the components of insulin signaling pathway (IRS-1 and Akt) in palmitate-induced insulin resistant C2C12 skeletal muscle cells. To reduce TNF-alpha expression, C2C12 cells were transduced with TNF-alpha-shRNA lentiviral particles. Afterwards, the protein expression of TNF-alpha, IRS-1, and Akt, as well as phosphorylation levels of IRS-1 and Akt were evaluated by western blot. We also measured insulin stimulated glucose uptake in the presence and absence of palmitate. TNF-alpha protein expression in C2C12 cells significantly increased by treatment with 0.75 mM palmitate (P < 0.05). In TNF-alpha knockdown cells, the protein expression level of TNF-alpha was significantly decreased by almost 70% (P < 0.01) compared with the control cells. Our results also revealed that, in control cells, palmitate treatment significantly reduced the insulin-induced phosphorylations of IRS-1 (Tyr632) and Akt (Ser473) by 60% and 66% (P < 0.01), respectively. Interestingly, these phosphorylations, even in the presence of palmitate, were not significantly reduced in TNF-alpha knockdown cells with respect to the untreated control cells (P > 0.05). Furthermore, palmitate significantly reduced insulin-dependent glucose uptake in control cells, however, it was not able to reduce insulin-stimulated glucose uptake in TNF-alpha knockdown cells in comparison with the untreated control cells (P < 0.01). These findings indicated that TNF-alpha down-regulation maintains insulin sensitivity, even in the presence of palmitate, therefore, TNF-alpha inhibition could be a good strategy for the treatment of palmitate-induced insulin resistance. PMID- 25839651 TI - Crystal structure of CagL from Helicobacter pylori K74 strain. AB - Helicobacter pylori (Hp) CagL is a component of the type IV secretion system (T4SS) and interacts with integrin in host cells through its flexible RGD domain to translocate CagA. Differences in CagL amino acid polymorphisms between Western and East-Asian Hps are correlated with clinical outcome. CagL of East-Asian clinical Hp isolate K74 (CagL(K74)) contains multiple residue variations upstream of RGD motif and has different integrin binding affinities compared to those of CagL from Western Hp 26695. Here, we report the crystal structure of CagL(K74). The structure displayed a six-helix bundle including two short alpha-helices, and the RGD motif was found in the long rigid alpha2 helix flanked by the conserved protease-sensitive and RGD-helper sequences, as observed in CagL(26695). However, two additional salt bridges were found between the helices compared with the CagL(26695) structure, suggesting that the putative flexible region harboring the RGD motif may be more stable in this CagL variant. PMID- 25839652 TI - Apoptosis related protein 3 is a lysosomal membrane protein. AB - Apoptosis Related Protein 3 (APR3) is an important protein which is involved in retinoic acid-induced apoptosis, osteoblast differentiation and cervical squamous cell carcinoma progression. Although it was predicted to be a trans-membrane protein, its cellular localization is not clear. In this study, we analyzed APR3 with bioinformatic tools and found that APR3 contains a potential signal peptide, a transmembrane region and 3 N-glycosylation sites, all of which are characteristics of lysosomal proteins. Western blot with isolated lysosomes demonstrated that APR3 was mainly present in lysosomes, specially in the lysosomal membrane fraction, but not in endoplasmic reticulum. Concomitantly, double immunofluorescence confirmed that APR3 co-localized with lysosomal membrane protein, LAMP1, as well as lysosomal specific marker, Lyso-Tracker Red. Moreover, we showed that APR3 was highly expressed in the lung, liver, spleen, kidney and adipose tissue, but expressed at the low level in the heart, pancreas, stomach and intestine. Interestingly, APR3 expression was elevated in multiple hepatocellular carcinoma cell lines comparing to normal liver cells. Collectively, our results proved that APR3 is a novel lysosomal membrane protein and shed light on its possible functions. PMID- 25839653 TI - Crystal structure of human POP1 and its distinct structural feature for PYD domain. AB - Inflammatory caspases, such as caspase-1, which is critical for the innate immune response, are activated upon the formation of a molecular complex called the inflammasome. The inflammasome is composed of three proteins, the Nod-like receptor (NLRP, NLRC or AIM2), apoptosis associated speck-loke protein containing a caspase-recruitment domain (ASC), and caspase-1. ASC is an adaptor molecule that contains an N-terminal PYD domain and a C-terminal CARD domain for interaction with other proteins. Upon activation, the N-terminal PYD of ASC homotypically interacts with the PYD domain of the Nod-like receptor, while its C terminal CARD homotypically interacts with the CARD domain of caspase-1. PYD only protein 1 (POP1) negatively regulates inflammatory response by blocking the formation of the inflammasome. POP1 directly binds to ASC via a PYD:PYD interaction, thereby preventing ASC recruitment to Nod-like receptor NLRPs. POP1 mediated regulation of inflammation is of great biological importance. Here, we report the crystal structure of human POP1 and speculate about the inhibitory mechanism of POP1-mediated inflammasome formation based on the current structure. PMID- 25839654 TI - B-cell translocation gene 2 promotes hepatic hepcidin production via induction of Yin Yang 1. AB - Hepcidin is a peptide hormone secreted in the liver and plays a key role in maintaining iron homeostasis. Here, we demonstrate that B-cell translocation gene 2 (BTG2) is a key player in hepatic hepcidin regulation via induction of Yin Yang 1 (YY1). Hepatic hepcidin gene expression significantly enhanced by fasting states and glucagon exposure led to induction of gluconeogenic gene expression, and elevated serum hepcidin production in mice. Notably, overexpression of BTG2 using adenoviral system (Ad-BTG2) significantly elevated serum hepcidin levels via a significant induction of YY1 gene transcription. Immunoprecipitation studies demonstrated that BTG2 physically interacted with YY1 and recruited on the hepcidin gene promoter. Finally, ablation of hepatic BTG2 gene by gene silencing markedly attenuated the elevation of serum hepcidin production along with YY1 and hepcidin mRNA expression in fasting state. Likewise, forskolin (FSK) stimulated hepcidin promoter activity was dramatically disrupted by endogenous BTG2 knockdown. Overall, our current study provides a novel molecular mechanism of BTG2-mediated induction of hepcidin gene expression, thereby contributing to a better understanding of the hepatic hepcidin production involved in iron homeostasis. PMID- 25839655 TI - P2Y purinergic receptor-regulated insulin secretion is mediated by a cAMP/Epac/Kv channel pathway. AB - Enhancement of insulin secretion is a major therapeutic approach for type 2 diabetes (T2D). Activation of P2Y purinergic receptor (P2YR) causes potentiation of insulin secretion in a glucose-dependent manner, making it a promising therapeutic target for T2D. Here we show that activation of P2YR to potentiate insulin secretion is mediated by adenylyl cyclase/cyclic AMP (cAMP) and the downstream effector, exchange protein directly activated by cAMP (Epac), leading to inhibition of voltage-dependent potassium (Kv) channels. P2YR-mediated Kv channel inhibition results in prolongation of action potential duration, and in turn elevates intracellular Ca(2+) level and insulin secretion. Taken together, the data indicate that cAMP/Epac/Kv channel pathway mediates P2YR-regulated insulin secretion, which may have important therapeutic implications for T2D. PMID- 25839656 TI - Metabolic signatures of renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is characterized by the constitutive up regulation of the hypoxia inducible factor-1. One of its target enzymes, pyruvate dehydrogenase (PDH) kinase 1 (PDHK1) showed increased protein expression in tumor as compared to patient-matched normal tissues. PDHK1 phosphorylated and inhibited PDH whose enzymatic activity was severely diminished, depriving the TCA cycle of acetylCoA. We and others have shown a decrease in the protein expressions of all respiratory complexes alluding to a compromise in oxidative phosphorylation (OXPHOS). On the contrary, we found that key parameters of OXPHOS, namely ATP biosynthesis and membrane potential were consistently measurable in mitochondria isolated from ccRCC tumor tissues. Interestingly, an endogenous mitochondrial membrane potential (MMP) was evident when ADP was added to mitochondria isolated from ccRCC but not in normal tissues. In addition, the MMP elicited in the presence of ADP by respiratory substrates namely malate/glutamate, succinate, alpha-ketoglutarate and isocitrate was invariably higher in ccRCC. Two additional hallmarks of ccRCC include a loss of uncoupling protein (UCP)-2 and an increase in UCP-3. Based on our data, we proposed that inhibition of UCP3 by ADP could contribute to the endogenous MMP observed in ccRCC and other cancer cells. PMID- 25839657 TI - Endogenous ROS levels are increased in replicative senescence in human bone marrow mesenchymal stromal cells. AB - Cellular senescence is characterized by functional decline induced by cumulative damage to DNA, proteins, lipids, and carbohydrates. Previous studies have reported that replicative senescence is caused by excessive amounts of reactive oxygen species (ROS) produced as a result of aerobic energy metabolism. In this study, we established human bone marrow mesenchymal stromal cells (hBM-MSCs) in replicative senescence after culture over a long term to investigate the relationship between ROS levels and stem cell potential and to determine whether differentiation potential can be restored by antioxidant treatment. Intracellular ROS levels were increased in hBM-MSCs; this was accompanied by a decrease in the expression of the antioxidant enzymes catalase and superoxide dismutase (SOD)1 and 2 and of phosphorylated forkhead box O1 (p-FOXO1) as well as an increase in the expression of p53 and p16, along with a reduction in differentiation potential. When the antioxidant ascorbic acid was used to eliminate excess ROS, the levels of antioxidant enzymes (catalase, SOD1 and 2, p-FOXO1, and p53) were partly restored. Moreover, differentiation into adipocytes and osteocytes was higher in hBM-MSCs treated with ascorbic acid than in the untreated control cells. These results suggest that the decline in differentiation potential caused by increased endogenous ROS production during in vitro expansion can be reversed by treatment with antioxidants such as ascorbic acid. PMID- 25839658 TI - Crystal structure of GnsA from Escherichia coli. AB - Escherichia Coli GnsA is a regulator of phosphatidylethanolamine synthesis and functions as a suppressor of both a secG null mutation and fabA6 mutations. GnsA may also be a toxin with the cognate antitoxin YmcE. Here we report the crystal structure of GnsA to 1.8 A. GnsA forms a V shaped hairpin structure that is tightly associated into a homodimer. Our comprehensive structural study suggests that GnsA is structurally similar to an outer membrane protein, suggesting a function of protein binding. PMID- 25839659 TI - Na(+)-Ca(2+) exchanger targeting miR-132 prevents apoptosis of cardiomyocytes under hypoxic condition by suppressing Ca(2+) overload. AB - During ischemia-reperfusion (IR) injury of the heart, Ca(2+) overload occurs, leading to cardiomyocyte dysfunction and eventual cell death by apoptosis. Since preventing Ca(2+) overload during IR injury has been reported to protect cardiomyocytes, interrupting Ca(2+) signaling cascades leading to Ca(2+) overload may exert protective effect on cardiomyocytes under hypoxic condition. One of the key regulators of the intracellular Ca(2+) level during IR injury is Na(+)-Ca(2+) exchanger 1 (NCX1), whose down-regulation during IR injury conferred protection of heart. In the present study, we examined whether down-regulation of NCX1 using exogenous microRNA ameliorates apoptosis of cardiomyocytes under hypoxic condition. Here, we identified miR-132 as a novel microRNA targeting the NCX1, whose expression increased during hypoxia. Delivery of miR-132 suppressed the increase of intracellular Ca(2+) in cardiomyocytes under hypoxia, and the expressions of apoptotic molecules, such as Bax, cytochrome C, and caspase 3, and the number of apoptotic cells were also decreased by exogenous miR-132 treatment. These results suggest the potential of miR-132 as an effective therapeutic agent against IR damage to heart by preventing Ca(2+) overload during hypoxic condition and warrant further studies to validate its anti-apoptotic effect in vivo. PMID- 25839660 TI - New insights into the posttranslational regulation of human cytosolic thioredoxin by S-palmitoylation. AB - High level of palmitate is associated with metabolic disorders. We recently showed that enhanced level of S-palmitoylated cytosolic thioredoxin (Trx1) in mouse liver was new characteristic feature of insulin resistance. However, our understanding of the effect of S-palmitoylation on Trx1 is limited, and the tissue specificity of Trx1 S-palmitoylation is unclear. Here we show that S palmitoylation also occurs at Cys73 of Trx1 in living endothelial cells, and the level of S-palmitoylated Trx1 undergoes regulation by insulin signaling. Trx1 prefers thiol-thioester exchange with palmitoyl-CoA to acetyl-CoA. S palmitoylation alters conformation or secondary structure of Trx1, as well as decreases the ability of Trx1 to transfer electrons from thioredoxin reductase to S-nitrosylated protein-tyrosine phosphatase 1B and S-nitroso-glutathione. Our results demonstrate that S-palmitoylation is an important post-translational modification of human Trx1. PMID- 25839661 TI - Heparinase I-specific disaccharide unit of heparin is a key structure but insufficient for exerting anti-prion activity in prion-infected cells. AB - Glycosaminoglycans reportedly play important roles in prion formation, but because of their structural complexity, the chemical structures affecting prion formation have not been fully evaluated. Here, we compared two types of low molecular weight heparins and found that heparinase I-sensitive structures influenced anti-prion activity in prion-infected cells. Surface plasmon resonance analyses showed significant binding of a representative heparinase I substrate disaccharide unit, GlcNS6S-IdoA2S, to recombinant prion protein (PrP) fragments, such as full-length PrP23-231 and N-terminal domain PrP23-89, but not to PrP89 230. This binding was competitively inhibited by heparin or pentosan polysulfate, but not by Cu(2+). These PrP binding profiles of the disaccharide unit are consistent with those previously reported for heparin. However, synthetic compounds comprising disaccharide unit alone or its multimers exhibited no anti prion activity in prion-infected cells. Consequently, the findings suggest that the heparin disaccharide unit that binds to the N-terminal region of PrP is a key structure, but it is insufficient for exerting anti-prion activity. PMID- 25839662 TI - Fenofibrate suppressed proliferation and migration of human neuroblastoma cells via oxidative stress dependent of TXNIP upregulation. AB - There are no appropriate drugs for metastatic neuroblastoma (NB), which is the most common extra-cranial solid tumor for childhood. Thioredoxin binding protein (TXNIP), the endogenous inhibitor of ROS elimination, has been identified as a tumor suppressor in various solid tumors. It reported that fenofibrate exerts anti-tumor effects in several human cancer cell lines. However, its detail mechanisms remain unclear. The present study assessed the effects of fenofibrate on NB cells and investigated TXNIP role in its anti-tumor mechanisms. We used MTT assay to detect cells proliferation, starch wound test to investigate cells migration, H2DCF-DA to detect intracellular ROS, siRNA to interfere TXNIP and peroxisome proliferator-androgen receptor-alpha (PPAR-alpha) expression, western blot to determine protein levels, flow cytometry to analyze apoptosis. Fenofibrate suppressed proliferation and migration of NB cells, remarkably increased intracellular ROS, upregulated TXNIP expression, promoted cell apoptosis. Furthermore, inhibition of TXNIP expression attenuated anti-tumor effects of fenofibrate, while inhibition of PPAR-alpha had no influences. Our results indicated the anti-tumor role of fenofibrate on NB cells by exacerbating oxidative stress and inducing apoptosis was dependent on the upregulation of TXNIP. PMID- 25839663 TI - Introduction. PMID- 25839664 TI - Cancer stem cells: the promise and the potential. AB - Despite the advancement of treatment modalities, many cancer patients experience tumor recurrence and metastasis at regional or distant sites. Evolving understanding of tumor biology has led to the hypothesis that tumors may possess a stem cell-like subpopulation known as cancer stem cells (CSCs) that may be involved in driving tumor propagation and pathogenesis. Like normal stem cells (NSCs), CSCs can be identified by markers such as CD133, CD44, and ALDH. CSCs have the ability to self-renew and differentiate into different tumor components through stemness pathways, such as Wnt, TGF-beta, STAT, and Hippo-YAP/TAZ, among others. In NSCs, stemness pathways are strictly regulated and control many important biologic processes, including embryogenesis and intestinal crypt cellular regulation. In contrast, stemness pathways in CSCs are significantly dysregulated. Combining current drugs with the targeting of these stemness pathways may significantly improve patient prognosis. The aim of this supplement is to update clinicians on the accumulated evidence characterizing the role of CSCs in tumor initiation, heterogeneity, therapy resistance, and recurrence and metastasis, and the potential for effectively treating patients. PMID- 25839665 TI - A LCMT1-PME-1 methylation equilibrium controls mitotic spindle size. AB - Leucine carboxyl methyltransferase-1 (LCMT1) and protein phosphatase methylesterase-1 (PME-1) are essential enzymes that regulate the methylation of the protein phosphatase 2A catalytic subunit (PP2AC). LCMT1 and PME-1 have been linked to the regulation of cell growth and proliferation, but the underlying mechanisms have remained elusive. We show here an important role for an LCMT1-PME 1 methylation equilibrium in controlling mitotic spindle size. Depletion of LCMT1 or overexpression of PME-1 led to long spindles. In contrast, depletion of PME-1, pharmacological inhibition of PME-1 or overexpression of LCMT1 led to short spindles. Furthermore, perturbation of the LCMT1-PME-1 methylation equilibrium led to mitotic arrest, spindle assembly checkpoint activation, defective cell divisions, induction of apoptosis and reduced cell viability. Thus, we propose that the LCMT1-PME-1 methylation equilibrium is critical for regulating mitotic spindle size and thereby proper cell division. PMID- 25839669 TI - Outcome of ruptured abdominal aortic aneurysm repair: impact of aortic morphology. PMID- 25839670 TI - Exercise and the heart: the good, the bad, and the ugly. AB - The benefits of exercise are irrefutable. Individuals engaging in regular exercise have a favourable cardiovascular risk profile for coronary artery disease and reduce their risk of myocardial infarction by 50%. Exercise promotes longevity of life, reduces the risk of some malignancies, retards the onset of dementia, and is as considered an antidepressant. Most of these benefits are attributable to moderate exercise, whereas athletes perform way beyond the recommended levels of physical activity and constantly push back the frontiers of human endurance. The cardiovascular adaptation for generating a large and sustained increase in cardiac output during prolonged exercise includes a 10-20% increase in cardiac dimensions. In rare instances, these physiological increases in cardiac size overlap with morphologically mild expressions of the primary cardiomyopathies and resolving the diagnostic dilemma can be challenging. Intense exercise may infrequently trigger arrhythmogenic sudden cardiac death in an athlete harbouring asymptomatic cardiac disease. In parallel with the extraordinary athletic milieu of physical performances previously considered unachievable, there is emerging data indicating that long-standing vigorous exercise may be associated with adverse electrical and structural remodelling in otherwise normal hearts. Finally, in the current era of celebrity athletes and lucrative sport contracts, several athletes have succumbed to using performance enhancing agents for success which are detrimental to cardiac health. This article discusses the issues abovementioned, which can be broadly classified as the good, bad, and ugly aspects of sports cardiology. PMID- 25839672 TI - Telemedicine Spending by Medicare: A Snapshot from 2012. AB - BACKGROUND: Medicare has been one of the principal payers for healthcare services delivered via telemedicine to rural beneficiaries since 1997. Early projections of the cost of covering telemedicine for Medicare beneficiaries made legislators cautious to take on such a large obligation, but subsequent reports showed actual expenditures to be far below early estimates. As interest in expanding Medicare's coverage for services delivered via telemedicine grows, further examination of the extent of telemedicine use within the Medicare program and the costs associated with this use is warranted. MATERIALS AND METHODS: Medicare claims data from 2012 were examined. All valid claims associated with a Current Procedural Terminology code and modifier indicative of delivery via telemedicine were extracted and linked to the state of origin using carrier codes. Claims were summarized by clinical procedure code, medical specialty, and state. Expenditures were also calculated on a per member per month basis by state to compare the relative penetration of telemedicine among states. RESULTS: Total Medicare telemedicine-related expenditures in 2012 were found to be a little over $5 million, 65.2% of the total allowed telemedicine-related charges of $7.7 million. This figure represents an expenditure of approximately $0.09 annually per Medicare enrollee, or about three-quarters of a penny per member per month. Wide variation was found among states in telemedicine use. Mental health services and service providers accounted for nearly 70% of total telemedicine-related professional fees, and originating site facility fee claims accounted for only 28% of the total number of paid claims. CONCLUSIONS: Medicare spending on telemedicine is largely for mental health services and represents only a tiny fraction of overall Medicare spending. Adoption of telehealth is driven by multiple factors beyond need and rurality. PMID- 25839671 TI - No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study. AB - BACKGROUND: In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. PATIENTS AND METHODS: Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, postmastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. RESULTS: The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. CONCLUSION: Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved. PMID- 25839673 TI - Pakistan and the Millennium Development Goals for Maternal and Child Health: progress and the way forward. AB - The world has made substantial progress in reducing maternal and child mortality, but many countries are projected to fall short of achieving their Millennium Development Goals (MDGs) 4 and 5 targets. The major objective of this paper is to examine progress in Pakistan in reducing maternal and child mortality and malnutrition over the last two decades. Data from recent national and international surveys suggest that Pakistan lags behind on all of its MDGs related to maternal and child health and, for some indicators especially related to nutrition, the situation has worsened from the baseline of 1990. Progress in addressing key social determinants such as poverty, female education and empowerment has also been slow and unregulated population growth has further compromised progress. There is a need to integrate the various different sectors and programmes to achieve the desired results effectively and efficiently as many of the determinants and influencing factors are outside the health sector. Pakistan has to accelerate improvement of access to maternal health services, particularly contraception, emergency obstetric care and skilled birth attendance; the need to improve maternal and child nutrition cannot be over emphasised. PMID- 25839674 TI - Expression and purification of the natively disordered and redox sensitive metal binding regions of Mycobacterium tuberculosis protein kinase G. AB - Mycobacterium tuberculosis protein kinase G (PknG) is secreted into host macrophages to block lysosomal degradation. The catalytic domain (~147-405) is C terminally flanked by a tetratricopeptide repeat domain (TPRD). The preceding rubredoxin-like metal-binding motif (RD, ~74-147) mediates PknG redox regulation. The N-terminal ~75 residues were predicted to show no regulatory secondary structure (NORS) and harbor the only site (T63) phosphorylated in vivo. Deletions or mutations in the NORS or the redox-sensitive RD significantly decrease the survival function. Here, we show that the RD appears only to be present in the folded, metal-bound state if ZnCl2 is added upon induction of protein expression in minimal medium. Since factor Xa cleaves at the end of its recognition site (IEGR), a modified expression plasmid for PknG1-147 was obtained by mutating the N-terminal thrombin to a factor Xa recognition site. This allows preparing PknG1 147 with its native N-terminus. We further present a fast approach to generate expression plasmids for only the NORS or the RD by site-directed mutagenesis of the expression plasmid for His-tagged PknG1-147. An expression plasmid for PknG1 75 was obtained by introducing a stop codon at position 76 and one for PknG74-174 by introducing a factor Xa recognition site before position 74. SDS-PAGE analysis shows that all fragments are highly expressed in E. coli and can be purified to high purity. Thereby, the established preparation protocols pave the route for the NMR structural characterization of PknG regulation by its N-terminal regions, which is demonstrated by the recorded initial (1)H-(15)N-HSQC spectra. PMID- 25839675 TI - Topographic Characterization of Cu-Ni NPs @ a-C:H Films by AFM and Multifractal Analysis. AB - In the present work three-dimensional (3-D) surface topography of Cu-Ni nanoparticles in hydrogenated amorphous carbon (Cu-Ni NPs @ a-C:H) with constant thickness of Cu and three thicknesses of Ni prepared by RF-Plasma Enhanced Chemical Vapor Deposition (RF-PECVD) system were investigated. The thin films of Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni deposited by radio frequency (RF)-sputtering and RF-PECVD systems, were characterized. To determine the mass thickness and atomic structure of the films, the Rutherford backscattering spectroscopy (RBS) spectra was applied. The absorption spectra were applied to study localized surface plasmon resonance (LSPR) peaks of Cu-Ni NPs (observed around 608 nm in visible spectra), which is widened and shifted to lower wavelengths as the thickness of Ni over layer increases, and their changes are also evaluated by the 3-D surface topography. These nanostructures were investigated over square areas of 1 MUm * 1 MUm using atomic force microscopy (AFM) and multifractal analysis. Topographic characterization of surface samples (in amplitude, spatial distribution, and pattern of surface characteristics) highlighted 3-D surfaces with multifractal features which can be quantitatively estimated by the multifractal measures. The 3-D surface topography Cu-Ni NPs @ a-C:H with constant thickness of Cu and three thicknesses of Ni prepared by RF-PECVD system can be characterized using the multifractal geometry in correlation with the surface statistical parameters. PMID- 25839676 TI - A novel approach to determine post mortem interval using neutron radiography. AB - One of the most difficult challenges in forensic research is to objectively determine the post-mortem interval (PMI). The accuracy of PMI is critical for determining the timeline of events surrounding a death. Most PMI techniques rely on gross morphological changes of cadavers that are highly sensitive to taphonomic factors. Recent studies have demonstrated that even exhumed individuals exposed to the same environmental conditions with similar PMIs can present different stages of decomposition. After death, tissue undergoes sequential changes consisting of organic and inorganic phase variations, as well as a gradual reduction of tissue water content. Hydrogen (H) is the primary contributor to neutron radiography (NR) contrast in biological specimens because (1) it is the most abundant element in biological tissues and (2) its nucleus scatters thermal and cold neutrons more strongly than any other atomic nucleus. These contrast differences can be advantageous in a forensic context to determine small changes in hydrogen concentrations. Neutron radiography of decaying canine tissues was performed to evaluate the PMI by measuring the changes in H content. In this study, dog cadavers were used as a model for human cadavers. Canine tissues and cadavers were exposed to controlled (laboratory settings, at the University of Tennessee, College of Veterinary Medicine) and uncontrolled (University of Tennessee Anthropology Research Facility) environmental conditions, respectively. Neutron radiographs were supplemented with photographs and histology data to assess the decompositional stages of cadavers. Results demonstrated that the increase in neutron transmission likely corresponded to a decrease in hydrogen content in the tissue, which was correlated with the decay time of the tissue. Tissues depleted in hydrogen were brighter in the neutron transmission radiographs of skeletal muscles, lung, and bone, under controlled conditions. Over a period of 10 days, changes in neutron transmission through lung and muscle were found to be higher than bone by 8.3%, 7.0%, and 2.0%, respectively. Results measured during uncontrolled conditions were more difficult to assess and further studies are necessary. In conclusion, neutron radiography may be used to detect changes in hydrogen abundance that can be correlated with the post-mortem interval. PMID- 25839677 TI - Predicting the origin of soil evidence: High throughput eukaryote sequencing and MIR spectroscopy applied to a crime scene scenario. AB - Soil can serve as powerful trace evidence in forensic casework, because it is highly individualistic and can be characterised using a number of techniques. Complex soil matrixes can support a vast number of organisms that can provide a site-specific signal for use in forensic soil discrimination. Previous DNA fingerprinting techniques rely on variations in fragment length to distinguish between soil profiles and focus solely on microbial communities. However, the recent development of high throughput sequencing (HTS) has the potential to provide a more detailed picture of the soil community by accessing non-culturable microorganisms and by identifying specific bacteria, fungi, and plants within soil. To demonstrate the application of HTS to forensic soil analysis, 18S ribosomal RNA profiles of six forensic mock crime scene samples were compared to those collected from seven reference locations across South Australia. Our results demonstrate the utility of non-bacterial DNA to discriminate between different sites, and were able to link a soil to a particular location. In addition, HTS complemented traditional Mid Infrared (MIR) spectroscopy soil profiling, but was able to provide statistically stronger discriminatory power at a finer scale. Through the design of an experimental case scenario, we highlight the considerations and potential limitations of this method in forensic casework. We show that HTS analysis of soil eukaryotes was robust to environmental variation, e.g. rainfall and temperature, transfer effects, storage effects and spatial variation. In addition, this study utilises novel analytical methodologies to interpret results for investigative purposes and provides prediction statistics to support soil DNA analysis for evidential stages of a case. PMID- 25839678 TI - What a validation strategy means for the quantitation of cocaine and heroin? AB - A method of separation by gas chromatography with a flame ionisation detector was developed for quantifying cocaine and heroin in powders seized by law enforcement. The method was validated by studying parameters of calibration, trueness, precision based on trueness error (or systematic bias) and random error. Total error, which is the combination of these errors, verified its adequacy with the objectives fixed by the analyst. Accuracy profile proved to be an efficient decision tool for that purpose. Results obtained with weighted regression model were analysed and allowed to conclude that the method enables quantitation of heroin and cocaine in powders on 2-100% concentration (w/w) range with acceptance limits fixed at 10% and a risk at 5%. The possible sources of uncertainty were evaluated and measurement of their contribution was integrated. The combined standard uncertainty and expanded uncertainty were determined. PMID- 25839679 TI - Toolmark variability and quality depending on the fundamental parameters: Angle of attack, toolmark depth and substrate material. AB - The traditional way of visual toolmark comparison includes subjective judgments. Automated methods using computers are a possibility to render a comparison more objective, but they require the statistical properties, like the similarity and variability, of toolmarks to be determined quantitatively. Several parameters, that play a role during toolmark creation, are statistically analyzed in this article. We determined the same toolmark and the different toolmark similarity as well as variability of known matching toolmarks created in wax and compared the results with the similarity and variability of known non-matching toolmarks. In addition we studied the influence of the substrate materials wax and lead and the angle of attack on toolmark similarity and variability. Furthermore, we present an approach to determine toolmark quality, defined as how well structural details are preserved in the toolmark, to assist toolmark examiners in deciding, which structural details are reliable in a mark. We studied the influence of the substrate material, the angle of attack and the depth of a toolmark on the quality. The results show that for known matching toolmarks, the variability is very low within a toolmark and between toolmarks in wax, given that the parameters angle of attack and depth are held constant. Geometrical details are reliably represented down to 10-50MUm and toolmark similarity is clearly higher than known non-matching similarities. The comparison of wax and lead shows that wax is a good alternative as a substrate material for experimental toolmarks, capable of reliably representing structural details down to 10-25MUm. For finer details, lead is a better choice but might alter the original state of a tool. With increasing angle of attack, toolmark variability increases and toolmark quality decreases. Therefore it is advantageous to push the tool instead of pulling during toolmark creation for angles of attack above ~45 degrees . The quality also decreases with increasing toolmark depth, but only up to ~300MUm. Therefore toolmarks should be created as shallow as possible in the substrate material. PMID- 25839680 TI - Colorectal neoplasia pathways: state of the art. AB - Colorectal cancer (CRC) is a heterogeneous disease and each CRC possesses a unique molecular tumor profile. The main pathways of oncogenesis are the chromosomal instability, microsatellite instability and serrated neoplasia pathway. Sessile serrated adenomas/polyps (SSA/Ps) may be the precursor lesions of CRC arising via the serrated neoplasia pathway. This has led to a paradigm shift because all SSA/Ps should be detected and resected during colonoscopy. The ability to accurately detect and resect only those polyps with a malignant potential could result in safer and cost-effective practice. Optimization of the endoscopic classification systems is however needed to implement targeted prevention methods. PMID- 25839681 TI - Advances in bowel preparation for colonoscopy. AB - Precolonoscopy bowel preparation is adequate to identify lesions larger than 5 mm about 70% to 75% of the time, but the opportunity for further improvement exists. The use of high-quality formulations with established efficacy rates of 90% or greater, identification of patients who are at increased risk of an inadequate preparation, as well as patient education and motivation to be invested in the process further improves the success of cleansing. Endoscopists should strive to achieve an adequate bowel preparation in 85% or more of patients. High-quality colonoscopy requires high-quality bowel cleansing. PMID- 25839682 TI - Techniques and technologies to maximize mucosal exposure. AB - Performing high-quality colonoscopy is one of the important goals of gastroenterology practices and requires achieving a high level of bowel cleansing, performing good and safe polypectomy, and detecting all polyps present in the colon. This article summarizes currently available techniques and technologies to maximize mucosal visualization. Several maneuvers can be applied during insertion and withdrawal of the colonoscope to optimize mucosal visualization and decrease the number of missed polyps. Newly developed technologies support the endoscopist in the detection of polyps. Each technique is reviewed, with emphasis on the impact on colorectal polyp detection. PMID- 25839683 TI - Water-aided colonoscopy. AB - The successful intubation of the cecum during screening or surveillance colonoscopy is vital to ensure complete mucosal inspection of the colon on withdrawal. Even when performed by an experienced endoscopist, colonoscope insertion can sometimes be challenging. Water-aided colonoscopy can be used to assist the endoscopist in navigating colons with anatomies that may be challenging owing to severe angulation or redundancy. Water-assisted colonoscopy involves the infusion of water without air and subsequent suctioning during insertion (exchange) or withdrawal (immersion or infusion). This review discusses the technique, effectiveness, safety of water-assisted colonoscopy as well as the application in sedationless endscopy. PMID- 25839684 TI - Electronic imaging to enhance lesion detection at colonoscopy. AB - Adenoma removal prevents colorectal cancer (CRC) development. Lower adenoma detection rates correlate with increased postcolonoscopy CRC. Chromoendoscopy it is not practical for routine use. It was hoped that electronic imaging techniques would offer effective alternatives to improve detection; however, meta-analyses in average-risk patients indicate no benefit. Narrow band imaging may be of benefit for high-risk surveillance. Combining electronic imaging techniques with molecular imaging probes may highlight dysplasia at a molecular level. In future colonoscopy is likely to rely on sensitive and specific, labeled molecular probes detected by electronic endoscopic imaging to enhance detection and reduce miss rates for premalignant lesions. PMID- 25839686 TI - Tools for polyp histology prediction. AB - Although removal of adenomatous polyps has been shown to decrease the risk of colon cancer, distal hyperplastic polyps are thought to not have malignant potential. Most polyps detected during colonoscopy are diminutive (<= 5 mm) and rarely harbor advanced histology, such as high-grade dysplasia or cancer. Therefore, predicting histology in real-time during colonoscopy can potentially decrease the enormous expenditure that ensues from universal histopathologic evaluation of polyps, and several novel imaging technologies have been developed and tested over the past decade for this purpose. Of these different technologies, electronic chromoendoscopy seems to strike a fair balance between accuracy, feasibility, and cost. PMID- 25839685 TI - Chromocolonoscopy. AB - Chromoendoscopy techniques improve the visualization of mucosal structures. This article reviews and summarizes key studies addressing the impact of chromoendoscopy on colonic neoplasia detection and differentiation of neoplastic from non-neoplastic polyps in average and high-risk populations, including patients with colonic inflammatory bowel disease (IBD). In this context, there are convincing data that chromoendoscopy differentiates neoplastic from non neoplastic polyps in average-risk populations with high accuracy. Moreover, dye based chromoendoscopy improves neoplasia detection in colonic IBD surveillance. PMID- 25839687 TI - New paradigms in polypectomy: resect and discard, diagnose and disregard. AB - Polypectomy at colonoscopy has been shown to reduce the subsequent risk of colorectal cancer. With the advent of national screening programs, the number of colonoscopies performed has increased worldwide. In addition, the recent drive for quality improvement combined with advances in colonoscopic technology has resulted in increased numbers of polyps detected, resected, and sent for histopathology leading to spiraling costs associated with the procedure. Being able to diagnose small polyps in vivo (optical diagnosis) would allow for adenomas to be resected and discarded without the need to retrieve them or send them for formal histopathology. PMID- 25839688 TI - Advanced polypectomy and resection techniques. AB - Most colorectal cancer arises from adenomatous polyps. This gradual process may be interrupted by screening and treatment using colonoscopy and polypectomy. Advances in imaging platforms have led to classification systems that facilitate prediction of histologic type and both stratification for and prediction of the risk of invasion. Endoscopic treatment should be the standard of care even for extensive advanced mucosal neoplasm. Technique selection is influenced by lesion features, location, patient factors, and local expertise. Postprocedural complications are more common following advanced resection and endoscopists should be familiar with risk factors, early detection methods, and management. PMID- 25839689 TI - Management of polypectomy complications. AB - The 2 most significant complications of colonoscopy with polypectomy are bleeding and perforation. Incidence rates for bleeding (0.1%-0.6%) and perforation (0.7% 0.9%) are generally low. Recognition of pertinent risk factors helps to prevent these complications, which can be grouped into patient-related, polyp-related, and technique/device-related factors. Endoscopists should be equipped to manage bleeding and perforation. Currently available devices and techniques are reviewed to achieve hemostasis and close colon perforations. PMID- 25839690 TI - Colonic strictures: dilation and stents. AB - Colonic strictures, both benign and malignant, are commonly encountered in clinical practice. Benign strictures are most commonly treated by balloon dilation and less frequently with stents. Balloon dilation can help forestall or obviate surgery in some patients. Colonic strictures of malignant etiology generally need to be managed by stents and/or surgery. This article reviews endoscopic approaches to the management of colonic strictures. PMID- 25839691 TI - Colonoscopy quality assessment. AB - Colonoscopy is the cornerstone of colorectal cancer screening programs. There is significant variability in the quality of colonoscopy between endoscopists. Colonoscopy quality assessment tracks various metrics to improve the effectiveness of colonoscopy, aiming at reducing the incidence and mortality from colorectal cancer. Adenoma detection rate is the prime metric, because it is associated with the risk of interval cancer. Implementing processes to measure and improve the adenoma detection rate is essential to improve the quality of colonoscopy. PMID- 25839692 TI - Colon capsule endoscopy. AB - Colon capsule endoscopy (CCE) is a minimally invasive technique specifically designed to explore the colon without sedation and air insufflation. CCE may overcome some of the limitations of colonoscopy. Second-generation CCE (CCE-2) was proved accurate in detecting colonic neoplastic lesions when used in average risk individuals. The evidence to date supports the use of CCE-2 in cases of colonoscopy failure, in patients unwilling to undergo colonoscopy, and when colonoscopy is contraindicated. Other potential applications, such as colorectal cancer screening or diagnostic surveillance of inflammatory bowel disease, require clarification. PMID- 25839693 TI - The big picture: does colonoscopy work? AB - Colonoscopy for average-risk colorectal cancer screening has transformed the practice of gastrointestinal medicine in the United States. However, although the dominant screening strategy, its use is not supported by randomized controlled trials. Observational data do support a protective effect of colonoscopy and polypectomy on colorectal cancer incidence and mortality, but the level of protection in the proximal colon is variable and operator-dependent. Colonoscopy by high-level detectors remains highly effective, and ongoing quality improvement initiatives should consider regulatory factors that motivate changes in physician behavior. PMID- 25839694 TI - Modern colonoscopy continues to evolve and improve. PMID- 25839695 TI - Advances in colonoscopy. PMID- 25839696 TI - Celebrating 50 years of NPs. PMID- 25839697 TI - Prevention of Alzheimer disease: The roles of nutrition and primary care. AB - Risk factors for developing Alzheimer disease include hypercholesterolemia, hypertension, obesity, and diabetes. Due to lack of effective treatments for Alzheimer disease, nutrition and primary prevention becomes important. PMID- 25839698 TI - Grief & depression at the end of life. AB - People may experience grief and depression with serious illness at the end of life or as a loved one who survives. While grief is a normal reaction to loss, complicated grief and depression are not. Accurate diagnosis, treatment, and referral are essential clinical tools for practitioners managing this population. PMID- 25839699 TI - Detection of EML4-ALK fusion gene in Chinese non-small cell lung cancer by using a sensitive quantitative real-time reverse transcriptase PCR technique. AB - Anaplastic lymphoma kinase (ALK) rearrangement is present in approximately 5% of lung adenocarcinoma. Clinical trials on ALK inhibitor phase I to III have shown an interesting disease control rate and acceptable tolerability in ALK rearrangement patients. In clinical application, the precise diagnostic strategy for identifying ALK rearrangements remains to be determined. In this study, ALK rearrangement was screened by using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), direct sequencing, 2 fluorescence in situ hybridization (FISH) assays, and immunohistochemistry in 173 lung adenocarcinomas. We identified 18 cases (10.4%) with EML4-ALK fusion-positive by qRT-PCR, and all were positive for EML4-ALK fusion gene validated by direct sequencing. The result was consistent with that of other methods. Furthermore, of the 18 EML4-ALK fusion-positive cases, 16 (9.2%) were positive by using EML4-ALK fusion probe FISH, and 15 (8.7%) were positive by using ALK break-apart probe FISH and immunohistochemistry staining. Of the 18 ALK fusion-positive lung adenocarcinomas, 8 cases (44.4%) were histologically diagnosed as subtypes of cribriform adenocarcinoma, 7 cases (38.9%) as cribriform adenocarcinoma mixed with papillary and/or mucinous pattern, 2 cases (11.1%) as papillary adenocarcinoma, and 1 case (5.6%) as mucinous adenocarcinoma. In the present study, the ALK rearrangement frequency detected by qRT-PCR in Chinese NSCLC patients was higher than that in the western populations. QRT-PCR is a rapid, sensitive technology that could be used as a screening tool for identifying EML4 ALK fusion-positive NSCLC patients who would be sensitive for receiving ALK inhibitor therapy. PMID- 25839700 TI - Hybrid Capture 2 is as effective as PCR testing for high-risk human papillomavirus in head and neck cancers. AB - High-risk human papillomavirus (HPV) infection is a common cause of oropharyngeal squamous cell carcinoma, especially in young male nonsmokers. Accurately diagnosing HPV-associated oral cancers is important, because they have a better prognosis and may be treated differently than smoking-related oral carcinomas. Various methods have been validated to test for high-risk HPV in cervical tissue samples, and they are in routine clinical use to detect dysplasia before it progresses to invasive disease. Similarly, future screening for HPV-mediated oropharyngeal dysplasia may identify patients before it progresses. Our objective was to compare 4 of these methods in a retrospective series of 87 oral and oropharyngeal squamous cell carcinomas that had archived fresh-frozen and paraffin-embedded tissue for evaluation. Patient age, sex, smoking history, and tumor location were also recorded. DNA prepared from fresh-frozen tissue was tested for HPV genotypes by multiplex polymerase chain reaction analysis, and high-risk HPV screening was carried out using Hybrid Capture 2 and Cervista. Histologic sections were immunostained for p16. HPV-positive outcome was defined as agreement between at least 2 of the 3 genetic tests and used for chi analysis and calculations of diagnostic predictive value. As expected, high-risk HPV positive oral cancers were most common in the tonsil and base of the tongue (oropharynx) of younger male (55 vs. 65 y) (P=0.0002) nonsmokers (P=0.01). Most positive cases were HPV16 (33/36, 92%). Hybrid Capture 2 and Cervista were as sensitive as polymerase chain reaction and had fewer false positives than p16 immunohistochemical staining. PMID- 25839701 TI - Primary mucinous adenocarcinoma of the epididymis: report of a rare case with molecular genetic characterization including mutation analysis of the TP53 gene. AB - We report a case of primary epididymal mucinous adenocarcinoma in a 60-year-old man who presented with a scrotal mass and subsequently developed pulmonary metastases. On immunohistochemistry the tumor was positive for villin and CK20 and negative for CK7, CDX2, and thyroid transcription factor-1. Molecular genetic analysis revealed an uncommon mutation; 249: AGG ->ATG in the TP53 gene, which has not been previously described in association with a primary epididymal adenocarcinoma. Mutational analysis showed KRAS, BRAF, and VHL to be wild-type. No microsatellite instability was found. PMID- 25839702 TI - Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer. AB - DNA methyltransferases (DNMTs) is a key epigenetic enzyme for pharmacological manipulation and is employed in cancer reprogramming. During past few years multiple strategies have been implemented to excavate epigenetic compounds targeting DNMTs. In light of the emerging concept of chemoinformatics, molecular docking and simulation studies have been employed to accelerate the development of DNMT inhibitors. Among the DNMT inhibitors known till date, epigallocathechin 3-gallate (EGCG) was identified to be effective in reducing DNMT activity. However, the broad spectrum of EGCG to other diseases and variable target enzymes offers some limitations. In view of this, 32 EGCG analogues were screened at S Adnosyl-L-homocysteine (SAH) binding pocket of DNMTs and procyanidin B2-3, 3'-di O-gallate (procyanidin B2) was obtained as potent inhibitor having medicinally relevant chemical space. Further, in vitro analysis demonstrates the efficiency of procyanidin B2 in attenuating DNMT activity at IC50 of 6.88+/-0.647 MUM and subsequently enhancing the expression of DNMT target genes, E-cadherin, Maspin and BRCA1. Moreover, the toxic property of procyanidin B2 towards triple negative breast cancer cells to normal cells offers platform for pre-clinical trial and an insight to the treatment of cancer. PMID- 25839704 TI - Lung Cancer Prognosis in Elderly Solid Organ Transplant Recipients. AB - BACKGROUND: Treatment-related immunosuppression in organ transplant recipients has been linked to increased incidence and risk of progression for several malignancies. Using a population-based cancer cohort, we evaluated whether organ transplantation was associated with worse prognosis in elderly patients with non small cell lung cancer (NSCLC). METHODS: Using the Surveillance, Epidemiology, and End Results Registry linked to Medicare claims, we identified 597 patients aged 65 years or older with NSCLC who had received organ transplants (kidney, liver, heart, or lung) before cancer diagnosis. These cases were compared to 114,410 untransplanted NSCLC patients. We compared overall survival (OS) by transplant status using Kaplan-Meier methods and Cox regression. To account for an increased risk of non-lung cancer death (competing risks) in transplant recipients, we used conditional probability function (CPF) analyses. Multiple CPF regression was used to evaluate lung cancer prognosis in organ transplant recipients while adjusting for confounders. RESULTS: Transplant recipients presented with earlier stage lung cancer (P = 0.002) and were more likely to have squamous cell carcinoma (P = 0.02). Cox regression analyses showed that having received a non-lung organ transplant was associated with poorer OS (P < 0.05), whereas lung transplantation was associated with no difference in prognosis. After accounting for competing risks of death using CPF regression, no differences in cancer-specific survival were noted between non-lung transplant recipients and nontransplant patients. CONCLUSIONS: Non-lung solid organ transplant recipients who developed NSCLC had worse OS than nontransplant recipients due to competing risks of death. Lung cancer-specific survival analyses suggest that NSCLC tumor behavior may be similar in these 2 groups. PMID- 25839705 TI - C1q Binding Activity of De Novo Donor-specific HLA Antibodies in Renal Transplant Recipients With and Without Antibody-mediated Rejection. AB - BACKGROUND: Complement fixation by donor-specific HLA antibodies (DSA) is a primary mechanism for antibody-mediated damage of organ allografts. Using a recently developed kit that measures C1q binding to distinguish complement fixing and nonfixing antibodies, studies showed that C1q + DSAs have a higher risk of rejection and graft loss compared to C1q-DSA. The objective of this study was to assess the ability of the C1q-binding assay to identify clinically significant de novo DSA in renal transplant recipients and to define the properties of DSA that confer C1q binding ability. METHODS: The DSA-positive sera from 34 kidney recipients, 19 with biopsy-proven antibody-mediated rejection (AMR) + and 15 who were AMR-, were assayed in C1q-binding assays (C1q Screen; One Lambda, Inc. Canoga Park, CA). The correlation between C1q-binding activity, presence of AMR, DSA mean fluorescence intensity (MFI) values, and immunoglobulin G isotype was determined. RESULTS: Fifty-three percent (10/19) of sera from AMR+ patients had C1q + DSA, whereas only 13% (2/15) of sera from AMR- patients contained C1q + DSA. C1q + DSA exhibited significantly higher MFI values regardless of whether they were from AMR+ or AMR- patients (16,118 +/- 6698 vs 6429 +/- 4003; P < 0.0001). C1q + DSA converted to C1q - when diluted to a comparable MFI level as the C1q - DSA from AMR- patients, and some C1q - antibodies converted to C1q + when concentrated to MFI levels comparable to those observed for AMR+/C1q + sera. CONCLUSIONS: The C1q binding activity by de novo DSA in patients with AMR largely reflects differences in antibody strength. The C1q assay does not appear to distinguish functionally distinct DSA with clinical significance. PMID- 25839707 TI - Variation in Cost and Quality in Kidney Transplantation. AB - BACKGROUND: Bending the cost curve in medical expenses is a high national priority. The relationship between cost and kidney allograft failure has not been fully investigated in the United States. METHODS: Using Medicare claims from the United States Renal Data System, we determined costs for all adults with Medicare coverage who underwent kidney transplant January 1, 2007, to June 30, 2009. We compared relative cost (observed/expected payment) for year 1 after transplantation for all transplant centers, adjusting for recipient, donor, and transplant characteristics, region, and local wage index. Using program-specific reports from the Scientific Registry of Transplant Recipients, we correlated relative cost with observed/expected allograft failure between centers, excluding small centers. RESULTS: Among 19,603 transplants at 166 centers, mean observed cost per patient per center was $65,366 (interquartile range, $55,094-$71,624). Mean relative cost was 0.99 (+/- 0.20); mean observed/expected allograft failure was 1.03 (+/- 0.46). Overall, there was no correlation between relative cost and observed/expected allograft failure (r = 0.096, P = 0.22). Comparing centers with higher than expected costs and allograft failure rates (lower performing) and centers with lower than expected costs and failure rates (higher-performing) showed differences in donor and recipient characteristics. As these characteristics were accounted for in the adjusted cost and allograft failure models, they are unlikely to explain the differences between higher- and lower performing centers. CONCLUSIONS: Further investigations are needed to determine specific cost-effective practices of higher- and lower-performing centers to reduce costs and incidence of allograft failure. PMID- 25839706 TI - Interleukin-10 From Marginal Zone Precursor B-Cell Subset Is Required for Costimulatory Blockade-Induced Transplantation Tolerance. AB - BACKGROUND: Blocking CD40-CD40L costimulatory signals induces transplantation tolerance. Although B-cell depletion prevents alloantibody formation, nonhumoral functions of B cells in tolerance have not been well characterized. We investigated whether specific subsets of B cell or B cell-derived interleukin (IL)-10 contribute to tolerance. METHODS: Wild type C57BL/6, or B cell-specific interleukin (IL)-10 (CD19-Cre::IL-10) mice, received vascularized BALB/c cardiac allografts. BALB/c donor-specific splenocyte transfusion and anti-CD40L monoclonal antibody were used as tolerogen. B cells were depleted with antimouse CD20 monoclonal antibody. Various B-cell subsets were purified and characterized by flow cytometry, reverse transcription polymerase chain reaction, and adoptive transfer. RESULTS: B-cell depletion prevented costimulatory blockade-induced allogeneic tolerance. Costimulatory blockade increased IL-10 in marginal zone precursor (MZP) B cells, but not other subsets. In particular, costimulatory blockade did not change other previously defined regulatory B-cell subsets (Breg), including CD5CD1d Breg or expression of TIM1 or TIM4 on these Breg or other Breg cell subsets. Costimulatory blockade also induced IL-21R expression in MZP B cells, and IL-21R MZP B cells expressed even more IL-10. B-cell depletion or IL-10 deficiency in B cells prevented tolerance in a cardiac allograft model, resulting in rapid acute cardiac allograft rejection. Adoptive transfer of wild type MZP B cells but not other subsets to B cell-specific IL-10 deficient mice prevented graft rejection. CONCLUSIONS: CD40 costimulatory blockade induces MZP B cell IL-10 which is necessary for tolerance. These observations have implications for understanding tolerance induction and how B cell depletion may prevent tolerance. PMID- 25839708 TI - Detecting the humoral alloimmune response: we need more than serum antibody screening. AB - Whereas many techniques exist to detect HLA antibodies in the sera of immunized individuals, assays to detect and quantify HLA-specific B cells are only just emerging. The need for such assays is becoming clear, as in some patients, HLA specific memory B cells have been shown to be present in the absence of the accompanying serum HLA antibodies. Because HLA-specific B cells in the peripheral blood of immunized individuals are present at only a very low frequency, assays with high sensitivity are required. In this review, we discuss the currently available methods to detect and/or quantify HLA-specific B cells, as well as their promises and limitations. We also discuss scenarios in which quantification of HLA-specific B cells may be of additional value, besides classical serum HLA antibody detection. PMID- 25839709 TI - The Role of Specifically Tailored Communication Training Among Factors Influencing Consent for Cornea Donation Requested Via Telephone. AB - BACKGROUND: Consent for cornea donation from non-heart-beating donors is often requested by means of telephone interviews with relatives of the deceased. The purpose of this study was to identify the effect of specifically tailored interviewer communications training among other factors related to obtaining consent. METHODS: A retrospective analysis of consent requests made by the Aachen Cornea Bank was performed. Interviews were conducted via telephone by 26 ophthalmic residents or fellows in accordance with German and European laws and guidelines. Multiple logistic regression was used to identify factors related to the consent. Results were expressed as odds ratios (OR), 95% confidence interval (95% CI), and Wald P value. RESULTS: In 1694 interviews, the overall consent rate was 50.12%. Multivariate analysis identified 4 significant factors associated with the donation decision. Completion of a specific communication training seminar increased odds of consent by 1.533 (95% CI, 1.250-1.880; P < 0.0001). The individual interviewer had an impact on the OR of up to 1.255 (95% CI, 1.113 1.417; P = 0.0002). The odds for consent were inversely correlated with the clinical experience of the interviewer (OR, 0.884; 95% CI, 0.831-0.938; P < 0.0001). The consulted family member was 0.894 times less likely to grant consent for donation with each increase in degree of blood relation (95% CI, 0.849-0.940; P < 0.0001). CONCLUSIONS: A telephone interview is effective for obtaining consent for cornea donation. The consent decision may be associated with factors relating to the interviewer as well as the consulted family member. Specific training for cornea bank staff may increase the odds of obtaining consent. PMID- 25839710 TI - From Mean Fluorescence Intensity to C1q-Binding: The Saga of Anti-HLA Donor specific Antibodies. PMID- 25839711 TI - Chemokines in the melanoma metastasis biomarkers portrait. AB - Skin tumorigenesis is linked to inflammatory chemokines accumulation that can induce cancer-associated immune-suppression. Deregulation of the CXCR4/CXCL12 axis was reported in melanoma tumorigenesis while also linked to BRAF mutation. Some chemokine-receptor patterns can direct the organ-specific metastasis. CXCL10 can help to prognosticate high-risk patients as it is a chemokine that differentiated patients with vs. metastasis free ones. Besides serum/plasma, chemokine identification in the cerebrospinal fluid of melanoma patients can indicate brain metastasis. Interplay between suppressed and elevated chemokines in cerebrospinal fluid can pinpoint an aggressive melanoma brain metastasis. Chemokines are gaining rapid momentum in the biomarker discovery domain aiding melanoma prognosis and high-risk patients' stratification. PMID- 25839712 TI - Transition-metal-free tandem radical thiocyanooxygenation of olefinic amides: a new route to SCN-containing heterocycles. AB - A novel transition-metal-free tandem radical thiocyanooxygenation of olefinic amides with potassium thiocyanate has been developed under mild conditions. This method allows a reliable and practical access to diverse SCN-containing heterocycles bearing a wide range of functional groups in good to excellent yields. Furthermore, this tandem reaction provides a simple method for the construction of C-O and C-S bonds in one step. PMID- 25839713 TI - Menstrual pain and quality of life in women with primary dysmenorrhea: Rationale, design, and interventions of a randomized controlled trial of effects of a treadmill-based exercise intervention. AB - Dysmenorrhea in the absence of pelvic abnormality is termed primary dysmenorrhea (PD). The health burden and social and economic costs of PD are high as it is reported to be the leading cause of recurrent absenteeism from school or work in adolescent girls and young adults. The belief that exercise works for relieving symptoms in women with PD is based on anecdotal evidence and non-experimental studies. There is very limited evidence from randomized controlled trials (RCTs) to support the use of exercise to reduce the intensity of menstrual pain. The objective of this study is to evaluate the effectiveness of exercise to reduce intensity of pain and improve quality of life in women with PD. We describe the study design of a single-blind (assessor), prospective, two-arm RCT, and the participant characteristics of the 70 women recruited in the age-group 18 to 43 years. The primary outcome of the study is pain intensity. The secondary outcomes of the study are quality of life, functional limitation, sleep, global improvement with treatment, and protocol adherence. The outcomes assessments are done at first menstrual period (baseline, Week 0), 2nd menstrual period (Week 4) and at two additional time points (Week 16 and Week 28) during the trial. The results of the study will provide physiotherapists, medical practitioners, and researchers as well as the women who have PD with new insights, knowledge, and evidence about the use of exercise to manage pain in women with PD. PMID- 25839714 TI - Can exploring natural recovery from substance misuse in psychosis assist with treatment? A review of current research. AB - Substance misuse in people with psychosis presents significant problems, but trials of treatments to address it show little sustained advantage over control conditions. An examination of mechanisms underpinning unassisted improvements may assist in the refinement of comorbidity treatments. This study reviewed existing research on natural recovery from substance misuse in people with psychosis. To address this issue, a systematic search identified only 7 articles that fulfilled the criteria. Their results suggest that people with psychosis report similar reasons to change as do non-psychotic groups, although they did not clarify whether the relative frequencies or priority orders were the same. Differences involved issues relating to the disorder and the functional problems faced by this group: receipt of treatment for mental health difficulties, worsening of mental health difficulties, and homelessness. The current research on reasons for change in people with psychosis is sparse and has significant limitations, and as yet it offers little inspiration for new treatments. A more fertile source may prove to be a detailed investigation of successful substance control strategies that are used in self-management by this group. PMID- 25839715 TI - Do signals of a hand-held TETRA transmitter affect cognitive performance, well being, mood or somatic complaints in healthy young men? Results of a randomized double-blind cross-over provocation study. AB - BACKGROUND: TETRA (terrestrial trunked radio) is a digital radio communication standard, which has been implemented in several European countries and is used by public executives, transportation services, and by private companies. Studies on possible impacts on the users' health considering different exposure conditions are missing. OBJECTIVES: To investigate possible acute effects of electromagnetic fields (EMF) of two different levels of TETRA hand-held transmitter signals on cognitive function and well-being in healthy young males. METHODS: In the present double-blind cross-over study possible effects of short-term (2.5h) EMF exposure of handset-like signals of TETRA (385 MHz) were studied in 30 healthy male participants (mean+/-SD: 25.4+/-2.6 years). Individuals were tested on nine study days, on which they were exposed to three different exposure conditions (Sham, TETRA 1.5 W/kg and TETRA 6.0 W/kg) in a randomly assigned and balanced order. Participants were tested in the afternoon at a fixed timeframe. RESULTS: Attention remained unchanged in two out of three tasks. In the working memory significant changes were observed in two out of four subtasks. Significant results were found in 5 out of 35 tested parameters, four of them led to an improvement in performance. Mood, well-being and subjective somatic complaints were not affected by TETRA exposure. CONCLUSIONS: The results of the present study do not indicate a negative impact of a short-term EMF-effect of TETRA on cognitive function and well-being in healthy young men. PMID- 25839717 TI - Eelco F.M. Wijdicks, MD, PhD. PMID- 25839718 TI - The clinical determination of brain death: rational and reliable. PMID- 25839716 TI - Genome-wide association study of plasma levels of polychlorinated biphenyls disclose an association with the CYP2B6 gene in a population-based sample. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) are a group of man-made environmental pollutants which accumulate in humans with adverse health effects. To date, very little effort has been devoted to the study of the metabolism of PCBs on a genome-wide level. OBJECTIVES: Here, we conducted a genome-wide association study (GWAS) to identify genomic regions involved in the metabolism of PCBs. METHODS: Plasma levels of 16 PCBs ascertained in a cohort of elderly individuals from Sweden (n=1016) were measured using gas chromatography-high resolution mass spectrophotometry (GC-HRMS). DNA samples were genotyped on the Infinium Omni Express bead microarray, and imputed up to reference panels from the 1000 Genomes Project. Association testing was performed in a linear regression framework under an additive model. RESULTS: Plasma levels of PCB-99 demonstrated genome-wide significant association with single nucleotide polymorphisms (SNPs) mapping to chromosome 19q13.2. The SNP with the strongest association was rs8109848 (p=3.7*10(-13)), mapping to an intronic region of CYP2B6. Moreover, when all PCBs were conditioned on PCB-99, further signals were revealed for PCBs -74, -105 and -118, mapping to the same genomic region. The lead SNPs were rs8109848 (p=3.8*10(-12)) for PCB-118, rs4802104 (p=1.4*10(-9)) for PCB-74 and rs4803413 (p=2.5*10(-9)) for PCB-105, all of which map to CYP2B6. CONCLUSIONS: In our study, we found plasma levels of four lower-chlorinated PCBs to be significantly associated with the genetic region mapping to the CYP2B6 locus. These findings show that CYP2B6 is of importance for the metabolism of PCBs in humans, and may help to identify individuals who may be susceptible to PCB toxicity. PMID- 25839719 TI - Brain death guidelines explained. AB - Brain death is diagnosed in the minority of patients with acute severe brain injury. Guidelines have been developed in many countries in the world and physicians usually work through a set of criteria. The clinical evaluation starts with determination of futility of any medical or surgical intervention and an unmistakable certainty that the underlying diagnosis is correct. The actual neurologic evaluation in a patient suspected of being brain dead requires 25 tests and verifications. Brain death determination demands perfect diagnostic accuracy and thus requires skill and expertise. The overriding principle is simple: establish cause, exclude confounders, determine futility of interventions, examine brainstem reflexes, and test for apnea. In this review, the author revisits the American Academy of Neurology guidelines, and examines the details behind the guidelines. The 2010 guidelines have eliminated unnecessary tests and observation delays, and maintain a principle of simplicity. PMID- 25839720 TI - Pediatric brain death determination. AB - Clinical guidelines for the determination of brain death in children were first published in 1987. These guidelines were revised in 2011 under the auspices of the Society of Critical Care Medicine, the American Academy of Pediatrics, and the Child Neurology Society, and provide the minimum standards that must be satisfied before brain death can be declared in infants and children. After achieving physiologic stability and exclusion of confounders, two examinations including apnea testing separated by an observation period (24 hours for term newborns up to 30 days of age, and 12 hours for infants and children from 31 days up to 18 years) are required to establish brain death. Apnea testing should demonstrate a final arterial PaCO2 20 mm Hg above the baseline and >= 60 mm Hg with no respiratory effort during the testing period. Ancillary studies (electroencephalogram and radionuclide cerebral blood flow) are not required to establish brain death and are not a substitute for the neurologic examination. The committee concluded that ancillary studies may be used (1) when components of the examination or apnea testing cannot be completed, (2) if uncertainty about components of the neurologic examination exists, (3) if a medication effect may be present, or (4) to reduce the interexamination observation period. When ancillary studies are used, a second clinical examination and apnea test should still be performed and components that can be completed must remain consistent with brain death. PMID- 25839721 TI - Ancillary testing in brain death. AB - Despite worldwide acceptance of the concept of brain death, there is marked variability in the use of ancillary testing. In most countries, ancillary tests are used primarily when confounding factors interfere with reliable completion of a clinical assessment, or physiologic instability precludes performance of an apnea test. Alternatively, in some countries, confirmatory ancillary tests are routinely required before brain death can be diagnosed. Ancillary tests assess brain function (e.g., electroencephalography) or blood flow (e.g., cerebral angiography). Evaluation of blood flow is affected less by confounding clinical factors and is now preferred in most jurisdictions. With angiographic techniques, a significant proportion of patients meeting clinical criteria for brain death have some opacification of proximal intracranial arteries. Consequently, the sensitivity of angiography is strongly influenced by the particular criteria that are used to define intracranial circulatory arrest. Lack of enhancement of the great cerebral and internal cerebral veins has the highest sensitivity. Worldwide experience with newer tests, such as computed tomography and magnetic resonance angiography, is growing. Radionuclide imaging has the advantage of not requiring use of potentially nephrotoxic contrast material. Transcranial Doppler ultrasonography can be brought to the bedside to demonstrate lack of brain blood flow. The specificity of imaging techniques in the detection of intracranial circulatory arrest has not been as well studied as their sensitivity. PMID- 25839722 TI - Brain death: the European perspective. AB - Some of the seminal steps toward the recognition and definition of brain death were European. There is a general consensus on both the medical concept of brain death in Europe as well as the minimum fundamental clinical standards that are required for its diagnosis-the absence of consciousness, brainstem reflexes, and the ability to breathe in the absence of reversible or confounding conditions. Two aspects of brain death determination are addressed in this article. The authors analyze how brain death is diagnosed across Europe, identifying both the similarities and differences that exist between countries (the latter mainly concerning ancillary tests, timing, and the number of physicians involved in the brain death determination). In addition, they describe the very considerable variations in when brain death determinations are made between and within individual European countries, and propose that they are due to differences in the end-of-life care practices in patients with irreversible brain injuries, medical attitudes, and organ donation practices. Although legislation is available to standardize the brain death diagnosis process in most individual European countries, there are still disparities across Europe as a whole. The current variation in practice makes a continental consensus for the definition of brain death imperative. PMID- 25839723 TI - Brain death: the United kingdom perspective. AB - The United Kingdom (UK) has incorporated a brainstem formulation into its brain death criteria since the first guidelines were published in 1976. A clinical diagnosis incorporating three sequential but interdependent steps is sufficient for the determination of brain death in the UK. There must be no doubt that the patient's comatose condition is due to irreversible brain damage of known etiology, and potentially reversible causes of coma and apnea, such as drug effects, metabolic or endocrine disturbances, or hypothermia, must be excluded. A clinical examination of brainstem reflexes and an apnea test is then undertaken. Confirmatory tests are not required in the UK, but may be useful to reduce any element of uncertainty or minimize the period of observation prior to the diagnosis of brainstem death if the preconditions for clinical testing are not met, or if a comprehensive neurologic examination is not possible. Brainstem death must be diagnosed by two doctors who must be present at each of the two sets of clinical tests that are required to determine death. Although death is not confirmed until the second test has been completed, the legal time of death is when the first test confirms the absence of brainstem reflexes. PMID- 25839724 TI - Brain death: the Asian perspective. AB - Asia is the largest and most populous continent in the world with people from many diverse ethnic groups, religions and government systems. The authors surveyed 14 countries accounting for the majority of Asia's population and found that, although the concept of brain death is widely accepted, there is wide variability in the criteria for certification. Although most Asian countries have adopted the "whole-brain" concept of brain death, most countries with past colonial links to the United Kingdom follow the UK "brainstem" concept of brain death. Despite this difference, most countries require only neurologic testing of irreversible coma and absent brainstem reflexes as criteria for certification of brain death. Variability exists in the number of personnel required, qualifications of certifying doctors, need for repeat examination, minimum time interval between examinations, and requirement for and choice of confirmatory tests. PMID- 25839725 TI - Uniformity in brain death criteria. AB - Despite well-described international variabilities in brain death practices, de facto there already exists a minimum international clinical standard for the diagnosis of brain death. This remains rooted in the Harvard criteria and based on the characteristics of a permanently nonfunctioning brain. Medicine is evolving toward a single unified determination of death based on the cessation of brain function subsequent to catastrophic brain injury or circulatory arrest. Clarity in lexicon could be established, including movement toward functional definitions and away from anatomically based terms such as cardiac and brain death that erroneously imply death of the organ. The cessation of clinical functions of the brain that will not resume is determined by the absence of capacity for consciousness, centrally mediated motor responses, brainstem reflexes, and capacity to breathe. A known proximate cause and the absence of confounding or reversible conditions must be confirmed. Regional medical, legal, cultural, religious, or socioeconomic factors may require testing beyond this minimal clinical standard. PMID- 25839726 TI - Families and brain death. AB - It is necessary to support the family of a patient with a progressively worsening severe acute brain injury, and to do this with the utmost understanding of their ultimate hopelessness. Any conversation starts with an explanation of the catastrophic nature of the illness, but also with establishing the point of no return. When brainstem reflexes are lost and the patient has become apneic, family members should be appropriately informed. In contrast to circulatory death, the relatives of such a patient do not see a deceased person in the traditional sense, and even the neurologic progression may not have been obvious to family members. The conversation about brain death with the close relatives is therefore different, and is more detailed than a conversation about cardiopulmonary death. In this review, a six-phase approach of communication with the relatives is proposed. Insightful snippets of personal conversations with family members are included. Communicating with family members also necessarily involves a discussion on the potential suitability for organ donation. Some suggestions on how to approach reluctant family members to accept death of their loved one are included. PMID- 25839727 TI - Brain death: legal obligations and the courts. AB - Brain death, or death determined by neurologic criteria, has been legally adopted in all U.S. states for decades. Despite its long-established history, a lack of clear understanding has led to disputes requiring a legal forum for resolution. Recently, physicians and hospitals across the country have been impacted by a growing number of disputes about brain death. The authors offer clinicians a historical perspective on the evolution of brain death as a legal cause of death in the United States. They then review the more common legal categories of disputes encountered, including representative court cases for each. This overview provides physicians with a general legal perspective on brain death so they may better appreciate the pertinent issues if and when later confronted. PMID- 25839728 TI - Simulation training in brain death determination. AB - Skill in the determination of brain death is traditionally acquired during training in an apprenticeship model. Brain death is not frequently determined, and thus exposure to the techniques used is marginal. Brain death is therefore ideally suited for competency-based education models such as simulation. Simulation can ensure that all trainees have direct experience in brain death determination irrespective of their specialty, program design, or institutional protocol. In this review, the authors discuss the advantages and barriers to simulation and how to develop simulation scenarios for instruction in the determination of brain death. Future research should focus on validation of brain death simulation methods and assessment tools as well as the impact of simulation on performance in clinical practice. PMID- 25839729 TI - Resting respiratory sinus arrhythmia is related to longer hospitalization in mood disordered repetitive suicide attempters. AB - OBJECTIVES: Our aims were (1) to measure respiratory sinus arrhythmia (RSA), a high-frequency spectrum component of heart rate variability (HRV) in mood disordered suicide attempters and (2) to investigate the relationship of RSA to symptoms and length of hospitalization. METHODS: Forty-nine female repetitive suicide attempters with depressive disorder or bipolar disorder were recruited in a general hospital setting. Manic or psychotic patients were excluded. Resting RSA values were calculated from electrocardiogram data, and severity of clinical presentation shortly after admission and length of hospital stay were assessed. RESULTS: RSA was positively associated with a higher Beck Scale for Suicidal Ideation score (r = 0.33 P = 0.019). Stepwise multiple regression analysis showed a significant correlation between RSA and hospitalization length after adjusting other variables (beta coefficient = 3.00; P = 0.030). Patients with a higher resting RSA had more prolonged hospitalizations (hospitalization beyond 30 days) after controlling for other variables (odds ratio = 5.08, P = 0.017). CONCLUSIONS: Interaction between the environment and the autonomic nervous system is complex. Further and more comprehensive research is needed. PMID- 25839731 TI - The effects of TV unhealthy food brand placement on children. Its separate and joint effect with advertising. AB - This paper examines the effect of unhealthy food brand placement on children across different age groups (9, 12 and 15 year-old children). Results show that both brand awareness, and the behavioral disposition (toward junk food and McDonald's) increased when children were exposed to this marketing technique (in comparison with the control group). In the case of age, older groups (12-15) performed better in brand awareness, but scored lower in behavioral disposition than the 9-year-old group. Moreover, the joint use of advertising and placement (synergy) increased the effect of these communication tactics on children. Results are discussed in terms of previous results of the studies providing evidence of the influence of promotional tools of junk food on children. PMID- 25839732 TI - Adaptation and validation of the Spanish version of the Clinical Impairment Assessment Questionnaire. AB - The Clinical Impairment Assessment (CIA) assesses psychosocial impairment secondary to an eating disorder. The aim of this study was to create and validate a Spanish-language version of the CIA. Using a forward-backward translation methodology, we translated the CIA into Spanish and evaluated its psychometric characteristics in a clinical sample of 178 ED patients. Cronbach's alpha values, confirmatory factor analysis (CFA), and correlations between the CIA and the Eating Attitudes Test-12 and the Health-Related Quality of Life in ED-short form questionnaires evaluated the reliability, construct validity, and convergent validity, respectively. Known-groups validity was also studied comparing the CIA according to different groups; responsiveness was assessed by means of effect sizes. Data revealed a three-factor structure similar to that of the original CIA. Cronbach alpha coefficient of 0.91 for the total CIA score supported its internal consistency and correlations with other instruments demonstrated convergent validity. The total CIA score and factor scores also significantly discriminated between employment status, evidencing known-groups validity. Responsiveness parameters showed moderate changes for patients with restrictive eating disorders. These findings suggest that the CIA can be reliably and validly used in Spain in a number of different clinical contexts, by researchers and clinicians alike. PMID- 25839733 TI - Evolution, the loss of diversity and the role of trade-offs. AB - We investigate how the loss of previously evolved diversity in host resistance to disease is dependent on the complexity of the underlying evolutionary trade-off. Working within the adaptive dynamics framework, using graphical tools (pairwise invasion plots, PIPs; trait evolution plots, TEPs) and algebraic analysis we consider polynomial trade-offs of increasing degree. Our focus is on the evolutionary trajectory of the dimorphic population after it has been attracted to an evolutionary branching point. We show that for sufficiently complex trade offs (here, polynomials of degree three or higher) the resulting invasion boundaries can form closed 'oval' areas of invadability and strategy coexistence. If no attracting singular strategies exist within this region, then the population is destined to evolve outside of the region of coexistence, resulting in the loss of one strain. In particular, the loss of diversity in this model always occurs in such a way that the remaining strain is not attracted back to the branching point but to an extreme of the trade-off, meaning the diversity is lost forever. We also show similar results for a non-polynomial but complex trade off, and for a different eco-evolutionary model. Our work further highlights the importance of trade-offs to evolutionary behaviour. PMID- 25839730 TI - Differences in Evolution of HIV-1 Subtype C Reverse Transcriptase Between Children and Adults Likely Explained by Maturity of Cytotoxic T-Lymphocyte Responses. AB - In this study HIV-1 subtype C-infected adults demonstrated higher purifying selection on their viral populations in reverse transcriptase (RT) than infected children. This difference is likely explained by more mature cytotoxic T lymphocyte responses in adults, which may have implications for the development of drug resistance in the RT region. PMID- 25839734 TI - Benzouracil-coumarin-arene conjugates as inhibiting agents for chikungunya virus. AB - Chikungunya virus (CHIKV) is an arbovirus that was first recognized in an epidemic form in East Africa in 1952-1953. The virus is primarily transmitted through mosquitoes and the resulting disease, chikungunya fever, is found in nearly 40 countries. Neither an effective vaccine nor a specific antiviral drug exists for treatments of chikungunya fever. Thus 22 new conjugated compounds of uracil-coumarin-arene were designed and synthesized as potential inhibiting agents. Their chemical structures were determined unambiguously by spectroscopic methods, including single-crystal X-ray diffraction crystallography. The three units in these conjugates were connected by specially designed -SCH2- and -OSO2- joints. Five of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC50 = 10.2-19.1 MUM) and showed low toxicity (CC50 = 75.2-178 MUM). The selective index values were 8.8-11.5 for three conjugates. By analysis of the data from the anti-viral assays, the structure-activity relationship is derived on the basis of the nature of the uracil, the functional groups attached to the arene, and the joints between the ring units. PMID- 25839735 TI - Music Therapy is Associated With Family Perception of More Spiritual Support and Decreased Breathing Problems in Cancer Patients Receiving Hospice Care. AB - CONTEXT: Music therapy is a common discretionary service offered within hospice; however, there are critical gaps in understanding the effects of music therapy on hospice quality indicators, such as family satisfaction with care. OBJECTIVES: The purpose of this study was to examine whether music therapy affected family perception of patients' symptoms and family satisfaction with hospice care. METHODS: This was a retrospective, cross-sectional analysis of electronic medical records from 10,534 cancer patients cared for between 2006 and 2010 by a large national hospice. Logistic regression was used to estimate the effect of music therapy using propensity scores to adjust for non-random assignment. RESULTS: Overall, those receiving music therapy had higher odds of being female, having longer lengths of stay, and receiving more services other than music therapy, and lower odds of being married/partnered or receiving home care. Family satisfaction data were available for 1495 (14%) and were more likely available if the patient received music therapy (16% vs. 12%, P < 0.01). There were no differences in patient pain, anxiety, or overall satisfaction with care between those receiving music therapy vs. those not. Patients who received music therapy were more likely to report discussions about spirituality (odds ratio [OR] = 1.59, P = 0.01), had marginally less trouble breathing (OR = 0.77, P = 0.06), and were marginally more likely to receive the right amount of spiritual support (OR = 1.59, P = 0.06). CONCLUSION: Music therapy was associated with perceptions of meaningful spiritual support and less trouble breathing. The results provide preliminary data for a prospective trial to optimize music therapy interventions for integration into clinical practice. PMID- 25839736 TI - Pediatric Small Bowel Crohn Disease: Correlation of US and MR Enterography. AB - Small bowel Crohn disease is commonly diagnosed during the pediatric period, and recent investigations show that its incidence is increasing in this age group. Diagnosis and follow-up of this condition are commonly based on a combination of patient history and physical examination, disease activity surveys, laboratory assessment, and endoscopy with biopsy, but imaging also plays a central role. Ultrasonography (US) is an underutilized well-tolerated imaging modality for screening and follow-up of small bowel Crohn disease in children and adolescents. US has numerous advantages over computed tomographic (CT) enterography and magnetic resonance (MR) enterography, including low cost and no required use of oral or intravenous contrast material. US also has the potential to provide images with higher spatial resolution than those obtained at CT enterography and MR enterography, allows faster examination than does MR enterography, does not involve ionizing radiation, and does not require sedation or general anesthesia. US accurately depicts small bowel and mesenteric changes related to pediatric Crohn disease, and US findings show a high correlation with MR imaging findings in this patient population. PMID- 25839738 TI - Invited commentary: metrics and value in radiology and the role of the patient. PMID- 25839737 TI - Metrics for Radiologists in the Era of Value-based Health Care Delivery. AB - Accelerated by the Patient Protection and Affordable Care Act of 2010, health care delivery in the United States is poised to move from a model that rewards the volume of services provided to one that rewards the value provided by such services. Radiology department operations are currently managed by an array of metrics that assess various departmental missions, but many of these metrics do not measure value. Regulators and other stakeholders also influence what metrics are used to assess medical imaging. Metrics such as the Physician Quality Reporting System are increasingly being linked to financial penalties. In addition, metrics assessing radiology's contribution to cost or outcomes are currently lacking. In fact, radiology is widely viewed as a contributor to health care costs without an adequate understanding of its contribution to downstream cost savings or improvement in patient outcomes. The new value-based system of health care delivery and reimbursement will measure a provider's contribution to reducing costs and improving patient outcomes with the intention of making reimbursement commensurate with adherence to these metrics. The authors describe existing metrics and their application to the practice of radiology, discuss the so-called value equation, and suggest possible metrics that will be useful for demonstrating the value of radiologists' services to their patients. PMID- 25839739 TI - Initial kidney graft resistance index and the long-term cardiovascular mortality in transplanted patients: a paired grafts analysis. AB - BACKGROUND: Cardiovascular complications remain the most frequent cause of death in kidney transplant recipients. We analysed the prognostic value of early measured resistance index (RI) in the aspect of long-term cardiovascular mortality. In order to eliminate potential donor-related confounders, we analysed the mortality of recipients, transplanted with organs procured from the same donor, in whom the initial RI values substantially differed. METHODS: Doppler sonography was performed in 725 consecutive kidney graft recipients early after transplantation. We identified 133 pairs (266 patients) who received their kidney grafts from the same donor and their initial RI values differed by >0.1. RESULTS: During 109 +/- 37 months of follow-up after transplantation, 84 patients lost their graft and 29 died, 14 of them due to cardiovascular causes. Two groups of paired patients with higher RI and lower RI did not differ significantly with respect to their age, BMI, HLA mismatch and cold ischaemia time. There were more patients with diabetes in the higher RI group (14.3 versus 6.8%). Survival analysis revealed a higher mortality for cardiovascular (8.3 versus 2.3%, P = 0.02) and all causes (14.3 versus 7.5%, P = 0.06) among patients with higher initial RI values. In the Cox regression model, not including age, a higher RI value was a strong predictor of cardiovascular death (HR = 4.88), independent of previous cardiovascular episodes (HR = 6.78). Both these variables lost its significance as a predictors after inclusion of age in the regression model. CONCLUSION: Increased intrarenal resistance index in the early posttransplant period may help to identify the recipients with increased cardiovascular risk. PMID- 25839740 TI - Disparities in treatment rates of paediatric end-stage renal disease across Europe: insights from the ESPN/ERA-EDTA registry. AB - BACKGROUND: Considerable disparities exist in the provision of paediatric renal replacement therapy (RRT) across Europe. This study aims to determine whether these disparities arise from geographical differences in the occurrence of renal disease, or whether country-level access-to-care factors may be responsible. METHODS: Incidence was defined as the number of new patients aged 0-14 years starting RRT per year, between 2007 and 2011, per million children (pmc), and was extracted from the ESPN/ERA-EDTA registry database for 35 European countries. Country-level indicators on macroeconomics, perinatal care and physical access to treatment were collected through an online survey and from the World Bank database. The estimated effect is presented per 1SD increase for each indicator. RESULTS: The incidence of paediatric RRT in Europe was 5.4 cases pmc. Incidence decreased from Western to Eastern Europe (-1.91 pmc/1321 km, P < 0.0001), and increased from Southern to Northern Europe (0.93 pmc/838 km, P = 0.002). Regional differences in the occurrence of specific renal diseases were marginal. Higher RRT treatment rates were found in wealthier countries (2.47 pmc/?10 378 GDP per capita, P < 0.0001), among those that tend to spend more on healthcare (1.45 pmc/1.7% public health expenditure, P < 0.0001), and among countries where patients pay less out-of-pocket for healthcare (-1.29 pmc/11.7% out-of-pocket health expenditure, P < 0.0001). Country neonatal mortality was inversely related with incidence in the youngest patients (ages 0-4, -1.1 pmc/2.1 deaths per 1000 births, P = 0.10). Countries with a higher incidence had a lower average age at RRT start, which was fully explained by country GDP per capita. CONCLUSIONS: Inequalities exist in the provision of paediatric RRT throughout Europe, most of which are explained by differences in country macroeconomics, which limit the provision of treatment particularly in the youngest patients. This poses a challenge for healthcare policy makers in their aim to ensure universal and equal access to high-quality healthcare services across Europe. PMID- 25839741 TI - Phospholipase A2 receptor and sarcoidosis-associated membranous nephropathy. AB - Of the glomerulonephritis associated with sarcoidosis, membranous nephropathy (MN) is the most prevalent. Coincidence or a causal relationship between these two diseases is unclear. Here, we present for the first time a high prevalence of PLA2R-related MN among patients with MN associated with active sarcoidosis. Our results suggest some causal link between sarcoidosis and PLA2R-related MN. Detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. This important observation can affect treatment decision in these patients. PMID- 25839743 TI - Supramolecular approach to new inkjet printing inks. AB - Electronically complementary, low molecular weight polymers that self-assemble through tunable pi-pi stacking interactions to form extended supramolecular polymer networks have been developed for inkjet printing applications and successfully deposited using three different printing techniques. Sequential overprinting of the complementary components results in supramolecular network formation through complexation of pi-electron rich pyrenyl or perylenyl chain ends in one component with pi-electron deficient naphthalene diimide residues in a chain-folding polyimide. The complementary pi-pi stacked polymer blends generate strongly colored materials as a result of charge-transfer absorption bands in the visible spectrum, potentially negating the need for pigments or dyes in the ink formulation. Indeed, the final color of the deposited material can be tailored by varying the end-groups of the pi-electron rich polymer component. Piezoelectric printing techniques were employed in a proof of concept study to allow characterization of the materials deposited, and a thermal inkjet printer adapted with imaging software enabled in situ analysis of the ink drops as they formed and of their physical properties. Finally, continuous inkjet printing allowed greater volumes of material to be deposited, on a variety of different substrate surfaces, and demonstrated the utility and versatility of this novel type of ink for industrial applications. PMID- 25839742 TI - Multigenerational and transgenerational inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine. AB - Familial inheritance of drug abuse is composed of both genetic and environmental factors. Additionally, epigenetic transgenerational inheritance may provide a means by which parental drug use can influence several generations of offspring. Recent evidence suggests that parental drug exposure produces behavioral, biochemical, and neuroanatomical changes in future generations. The focus of this review is to discuss these multigenerational and transgenerational phenotypes in the offspring of animals exposed to drugs of abuse. Specifically, changes found following the administration of alcohol, opioids, cocaine, marijuana, and nicotine will be discussed. In addition, epigenetic modifications to the genome following administration of these drugs will be detailed as well as their potential for transmission to the next generation. PMID- 25839744 TI - A group decision-making tool for the application of membrane technologies in different water reuse scenarios. AB - A global challenge of increasing concern is diminishing fresh water resources. A growing practice in many communities to supplement diminishing fresh water availability has been the reuse of water. Novel methods of treating polluted waters, such as membrane assisted technologies, have recently been developed and successfully implemented in many places. Given the diversity of membrane assisted technologies available, the current challenge is how to select a reliable alternative among numerous technologies for appropriate water reuse. In this research, a fuzzy logic based multi-criteria, group decision making tool has been developed. This tool has been employed in the selection of appropriate membrane treatment technologies for several non-potable and potable reuse scenarios. Robust criteria, covering technical, environmental, economic and socio-cultural aspects, were selected, while 10 different membrane assisted technologies were assessed in the tool. The results show this approach capable of facilitating systematic and rigorous analysis in the comparison and selection of membrane assisted technologies for advanced wastewater treatment and reuse. PMID- 25839745 TI - Removal of arsenic from simulation wastewater using nano-iron/oyster shell composites. AB - In this paper, a nano-iron/oyster shell composite (NI/OS) was firstly prepared by an in-situ synthesis method to explore an efficient treatment technology for arsenic (As) contaminated wastewater. The micromorphologies and composition of the composite were characterized using field emission scanning electron microscopy and Fourier transform infrared spectroscopy. The effects of the preparation parameters, as well as the treatment conditions, on the removal of As(III) were also investigated. The characterization results showed that iron nanoparticles with a diameter of 60 nm were introduced into the composite by an in-situ reduction method. The physicochemical properties of the iron nanoparticles, such as diameter and aggregation, were influenced by the iron source more than the choice of reductant and temperature in the synthesis process, and these properties were closely related to the treatment performance of the composite. Under the suitable reaction conditions of a pH value of 6.8, a temperature of 20 degrees C, and an initial concentration of As(III) of 1.8 mg/L, As(III) was almost completely removed from the simulation wastewater. PMID- 25839746 TI - Why is the Diagnostic and Statistical Manual of Mental Disorders so hard to revise? Path-dependence and "lock-in" in classification. AB - The latest edition of the Diagnostic and Statistical Manual of Mental Disorders, the D.S.M.-5, was published in May 2013. In the lead up to publication, radical changes to the classification were anticipated; there was widespread dissatisfaction with the previous edition and it was accepted that a "paradigm shift" might be required. In the end, however, and despite huge efforts at revision, the published D.S.M.-5 differs far less than originally envisaged from its predecessor. This paper considers why it is that revising the D.S.M. has become so difficult. The D.S.M. is such an important classification that this question is worth asking in its own right. The case of the D.S.M. can also serve as a study for considering stasis in classification more broadly; why and how can classifications become resistant to change? I suggest that classifications like the D.S.M. can be thought of as forming part of the infrastructure of science, and have much in common with material infrastructure. In particular, as with material technologies, it is possible for "path dependent" development to cause a sub-optimal classification to become "locked in" and hard to replace. PMID- 25839748 TI - Photoreactivation of Escherichia coli is impaired at high growth temperatures. AB - Photolyase repairs UV-induced lesions in DNA using light energy, which is the principle of photoreactivation. Active photolyase contains the two-electron reduced flavin cofactor. We observed that photoreactivation of Escherichia coli was impaired at growth temperatures ?37 degrees C, and growth in this temperature range also resulted in decreased photolyase protein levels in the cells. However, the levels of phr transcripts (encoding photolyase) were almost unchanged at the various growth temperatures. A lacZ-reporter under transcriptional control of the phr promoter showed no temperature-dependent expression. However, a translational reporter consisting of the photolyase N-terminal alpha/beta domain-LacZ fusion protein exhibited lower beta-galactosidase activity at high growth temperatures (37-42 degrees C). These results indicated that the change in photolyase levels at different growth temperatures is post-transcriptional in nature. Limited proteolysis identified several susceptible cleavage sites in E. coli photolyase. In vitro differential scanning calorimetry and activity assays revealed that denaturation of active photolyase occurs at temperatures ?37 degrees C, while apo photolyase unfolds at temperatures ?25 degrees C. Evidence from temperature-shift experiments also implies that active photolyase is protected from thermal unfolding and proteolysis in vivo, even at 42 degrees C. These results suggest that thermal unfolding and proteolysis of newly synthesized apo-photolyase, but not active photolyase, is responsible for the impaired photoreactivation at high growth temperatures (37-42 degrees C). PMID- 25839747 TI - Air Pollution and Lung Function in Dutch Children: A Comparison of Exposure Estimates and Associations Based on Land Use Regression and Dispersion Exposure Modeling Approaches. AB - BACKGROUND: There is limited knowledge about the extent to which estimates of air pollution effects on health are affected by the choice for a specific exposure model. OBJECTIVES: We aimed to evaluate the correlation between long-term air pollution exposure estimates using two commonly used exposure modeling techniques [dispersion and land use regression (LUR) models] and, in addition, to compare the estimates of the association between long-term exposure to air pollution and lung function in children using these exposure modeling techniques. METHODS: We used data of 1,058 participants of a Dutch birth cohort study with measured forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) measurements at 8 years of age. For each child, annual average outdoor air pollution exposure [nitrogen dioxide (NO2), mass concentration of particulate matter with diameters <= 2.5 and <= 10 MUm (PM2.5, PM10), and PM2.5 soot] was estimated for the current addresses of the participants by a dispersion and a LUR model. Associations between exposures to air pollution and lung function parameters were estimated using linear regression analysis with confounder adjustment. RESULTS: Correlations between LUR- and dispersion-modeled pollution concentrations were high for NO2, PM2.5, and PM2.5 soot (R = 0.86-0.90) but low for PM10 (R = 0.57). Associations with lung function were similar for air pollutant exposures estimated using LUR and dispersion modeling, except for associations of PM2.5 with FEV1 and FVC, which were stronger but less precise for exposures based on LUR compared with dispersion model. CONCLUSIONS: Predictions from LUR and dispersion models correlated very well for PM2.5, NO2, and PM2.5 soot but not for PM10. Health effect estimates did not depend on the type of model used to estimate exposure in a population of Dutch children. PMID- 25839749 TI - Characterization of interaction of calf thymus DNA with gefitinib: spectroscopic methods and molecular docking. AB - The binding interaction of gefitinib with calf thymus DNA (ct-DNA) under the simulated physiological pH condition was studied employing UV absorption, fluorescence, circular dichroism (CD), viscosity measurement and molecular docking methods. The experimental results revealed that gefitinib preferred to bind to the minor groove of ct-DNA with the binding constant (Kb) of 1.29 * 10(4)Lmol(-1) at 298K. Base on the signs and magnitudes of the enthalpy change (DeltaH(0)=-60.4 kJ mol(-1)) and entropy change (DeltaS(0)=-124.7 J mol(-1)K(-1)) in the binding process and the results of molecular docking, it can be concluded that the main interaction forces between gefitinib and ct-DNA in the binding process were van der Waals force and hydrogen bonding interaction. The results of CD experiments revealed that gefitinib did not disturb native B-conformation of ct-DNA. And, the significant change in the conformation of gefitinib in gefitinib ct-DNA complex was observed from the molecular docking results and the change was close relation with the structure of B-DNA fragments, indicating that the flexibility of gefitinib molecule also plays an important role in the formation of the stable gefitinib-ct-DNA complex. PMID- 25839750 TI - Long-term under-masculinization in male rabbits due to maternal stress is reversed by prenatal administration of testosterone. AB - It is well established that in mammals prenatal exposure to exogenous testosterone has a masculinizing effect on female morphology and behavior. Fewer studies, however, have been conducted in males on this subject, and the results are controversial. In the present study, we investigated the long-term effect of administering extra prenatal testosterone (testosterone proprionate; TP) on adult male domestic rabbits' morphology and behavior using two different control groups, non-treated and vehicle injected mothers. Unexpectedly, administering the vehicle alone had a clear under-masculinizing effect on all morphological and behavioral measures; lower body mass, smaller anogenital distance and smaller chin glands, lower chin-marking activity and greater timidity. Administration of TP counteracted this effect in a dose-dependent manner such that animals exposed to the highest dose prenatally showed values on the morphological and behavioral measures equivalent to but not greater than the non-treated control group. We conclude (1) that additional testosterone beyond what male fetuses produce in utero does not result in increased masculinization, and thus, that male fetuses are less susceptible prenatally to hormonal effects than females, and (2) that presumably stress-related effects of administering the vehicle alone resulted in under-masculinization, which could be recovered by the prenatal administration of TP. These results may partly account for the contradictory findings of previous studies, and indicate the importance of including both non-treated and sham- (vehicle) treated controls in future experiments. PMID- 25839751 TI - Parasites and personality in periwinkles (Littorina littorea): Infection status is associated with mean-level boldness but not repeatability. AB - We demonstrate the presence of animal personality in an inter-tidal gastropod, Littorina littorea, both in a sample of individuals infected by the trematode Cryptocotyle lingua and in an uninfected sample. On average infected individuals behaved more cautiously than individuals free of infection, but the parasite did not affect repeatability. Although the parasite is not associated with greater diversity of behaviour amongst infected individuals, infection might be associated with state-dependent personality differences between infected and non infected individuals. PMID- 25839752 TI - Evolutionary history and adaptive significance of the polymorphic Pan I in migratory and stationary populations of Atlantic cod (Gadus morhua). AB - The synaptophysin (SYP) family comprises integral membrane proteins involved in vesicle-trafficking events, but the physiological function of several members has been enigmatic for decades. The presynaptic SYP protein controls neurotransmitter release, while SYP-like 2 (SYPL2) contributes to maintain normal Ca(2+)-signaling in the skeletal muscles. The polymorphic pantophysin (Pan I) of Atlantic cod shows strong genetic divergence between stationary and migratory populations, which seem to be adapted to local environmental conditions. We have investigated the functional involvement of Pan I in the different ecotypes by analyzing the 1) phylogeny, 2) spatio-temporal gene expression, 3) structure-function relationship of the Pan I(A) and I(B) protein variants, and 4) linkage to rhodopsin (rho) recently proposed to be associated with different light sensitivities in Icelandic populations of Atlantic cod. We searched for SYP family genes in phylogenetic key species and identified a single syp-related gene in three invertebrate chordates, while four members, Syp, Sypl1, Sypl2 and synaptoporin (Synpr), were found in tetrapods, Comoran coelacanth and spotted gar. Teleost fish were shown to possess duplicated syp, sypl2 and synpr genes of which the sypl2b paralog is identical to Pan I. The ubiquitously expressed cod Pan I codes for a tetra-spanning membrane protein possessing five amino acid substitutions in the first intravesicular loop, but only minor structural differences were shown between the allelic variants. Despite sizable genomic distance (>2.5 Mb) between Pan I and rho, highly significant linkage disequilibrium was found by genotyping shallow and deep water juvenile settlers predominated by the Pan I(A)-rho(A) and Pan I(B)-rho(B) haplotypes, respectively. However, the predicted rhodopsin protein showed no amino acid changes, while multiple polymorphic sites in the upstream region might affect the gene expression and pigment levels in stationary and migratory cod. Alternatively, other strongly linked genes might be responsible for the sharp settling stratification of juveniles and the different vertical behavior patterns of adult Atlantic cod. PMID- 25839753 TI - Draft genome sequence of Clostridium sulfidigenes 113A isolated from sub-seafloor sediments associated with methane hydrate deposits. AB - Clostridium sulfidigenes 113A is a strictly anaerobic, rod shaped, gram positive bacterium isolated from sub-seafloor sediments associated with methane hydrates. Here, we report the first draft genome of C. sulfidigenes strain 113A, which comprises 3,717,420 bp in 96 contigs with the G+C content of 30.1%. A total of 3148 protein coding sequences were predicted. The genome annotation revealed that 113A could play an important role in biogeochemical cycles and have potential biotechnological applications such as production of organic acids and butanol. PMID- 25839758 TI - Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry. AB - The cohort of 17,200 female Swedish hemangioma patients, who had been exposed to ionizing radiation because of skin hemangioma, was analyzed for breast cancer incidence with descriptive excess relative risk models and mechanistic models of carcinogenesis. The dosimetry system has recently been updated, leading to substantially reduced doses for the most highly exposed part of the Stockholm cohort. The follow-up includes persons until December 2009 with 877 breast cancer cases. All models agree on the risk estimates. The excess relative and excess absolute risk at the age of 50 years are 0.48 Gy(-1) (95% CI 0.28; 0.69) and 10.4 (10(4)PYR Gy)(-1) (95% CI 6.1; 14.4) (95% CI 6.1; 14.4), respectively. These risk estimates are about a factor of 2 higher than previous analyses of this cohort as a consequence of the re-evaluation of the dosimetry system. Explicit models incorporating effects of genomic instability were developed and applied to the hemangioma cohort. It was found that a radiation-induced transition towards genomic instability was highly significant. The models indicate that the main effect of radiation-induced genomic instability is to increase the rate of transition of non-initiated cells to initiated cells with a proliferative advantage. The magnitude of such an acceleration cannot be inferred from epidemiological data alone, but must be complemented by radiobiological measurements. PMID- 25839759 TI - The effect of low dose ionizing radiation on homeostasis and functional integrity in an organotypic human skin model. AB - Outside the protection of Earth's atmosphere, astronauts are exposed to low doses of high linear energy transfer (LET) radiation. Future NASA plans for deep space missions or a permanent settlement on the moon are limited by the health risks associated with space radiation exposures. There is a paucity of direct epidemiological data for low dose exposures to space radiation-relevant high LET ions. Health risk models are used to estimate the risk for such exposures, though these models are based on high dose experiments. There is increasing evidence, however, that low and high dose exposures result in different signaling events at the molecular level, and may involve different response mechanisms. Further, despite their low abundance, high LET particles have been identified as the major contributor to health risk during manned space flight. The human skin is exposed in every external radiation scenario, making it an ideal epithelial tissue model in which to study radiation induced effects. Here, we exposed an in vitro three dimensional (3-D) human organotypic skin tissue model to low doses of high LET oxygen (O), silicon (Si) and iron (Fe) ions. We measured proliferation and differentiation profiles in the skin tissue and examined the integrity of the skin's barrier function. We discuss the role of secondary particles in changing the proportion of cells receiving a radiation dose, emphasizing the possible impact on radiation-induced health issues in astronauts. PMID- 25839760 TI - Conservation of CFTR codon frequency through primates suggests synonymous mutations could have a functional effect. AB - Cystic fibrosis is an inherited chronic disease that affects the lungs and digestive system, with a prevalence of about 1:3000 people. Cystic fibrosis is caused by mutations in CFTR gene, which lead to a defective function of the chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Up-to-date, more than 1900 mutations have been reported in CFTR. However for an important proportion of them, their functional effects and the relation to disease are still not understood. Many of these mutations are silent (or synonymous), namely they do not alter the encoded amino acid. These synonymous mutations have been considered as neutral to protein function. However, more recent evidence in bacterial and human proteins has put this concept under revision. With the aim of understanding possible functional effects of synonymous mutations in CFTR, we analyzed human and primates CFTR codon usage and divergence patterns. We report the presence of regions enriched in rare and frequent codons. This spatial pattern of codon preferences is conserved in primates, but this cannot be explained by sequence conservation alone. In sum, the results presented herein suggest a functional implication of these regions of the gene that may be maintained by purifying selection acting to preserve a particular codon usage pattern along the sequence. Overall these results support the idea that several synonymous mutations in CFTR may have functional importance, and could be involved in the disease. PMID- 25839761 TI - Chronic exposure to morphine decreases the expression of EAAT3 via opioid receptors in hippocampal neurons. AB - Alterations in glutamate transporter expression are closely related to opiate addition behavior, but the role of opioid receptors is unclear. In this study, we used primary cultures of hippocampal neurons from neonatal rats to study the effects of chronic exposure to morphine on excitatory amino acid transporter 3 (EAAT3) expression and the roles of u opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) in the morphine-dependent alterations in EAAT3 expression. The results showed that the EAAT3 protein and mRNA expression levels decreased significantly after chronic exposure to morphine (10MUmol/L) for 48h, whereas the concentration of extracellular glutamate increased. In addition, we found that both the MOR inhibitor CTOP and the DOR inhibitor naltrindole could reverse the decreased expression of EAAT3 after exposure to morphine, whereas the MOR activator DAMGO and the DOR activator DPDPE significantly decreased EAAT3 expression. The KOR inhibitor had no effect on the expression of EAAT3, whereas its activator increased EAAT3 expression. These results suggest that the down-regulation of morphine-dependent EAAT3 expression in primary rat hippocampal cultures may be mediated by MOR and DOR and that KOR may not contribute significantly to this effect. PMID- 25839762 TI - Neurophysiological correlates of cognitive flexibility and feedback processing in violent juvenile offenders. AB - The persistence of aggressive criminal behavior is recurrently observed in offenders despite being previously advised on the negative consequences of their actions. One possible explanation for the continuation of aggressive behaviors could be that they are the consequence of either possible deficits in cognitive flexibility (set-shifting) or in altered feedback processing. Event-related brain potentials (ERPs) were used to investigate both processes in non-psychopathic violent juvenile offenders. A modified version of the Wisconsin Card Sorting Test (WCST) was used to disentangle the ERP components associated with cognitive set switching processes (P3) from feedback processing (Frontal-Related Negativity, FRN; P3). The results showed a reduction in the amplitude of the P3 component for the presentation of switch informative signals, related to set-switching processes, in the offender group. Interestingly, a larger amplitude of the P3 related to feedback processing as well as the FRN was observed in this population, probably indicating increased reliance on external feedback processing. At the behavioral level, the offender group presented a larger amount of issues with failures in implementing the new sorting rule. This behavioral pattern could be related to deficits in the ability to switch to another behavior and an altered pattern in processing the feedback information related to the precision of their performance. These observations highlight the possible role of cognitive set-switching and reward sensibility in the maintenance of harmful behaviors in juvenile offenders. PMID- 25839763 TI - The Application of Neuromuscular Electrical Stimulation Training in Various Non neurologic Patient Populations: A Narrative Review. AB - In the last 2 decades, neuromuscular electrical stimulation has been used increasingly in deconditioned patients with the aim of increasing muscle force. Much basic research has been conducted in the area of increasing a muscle's fatigue resistance by neuromuscular electrical stimulation but similarly thorough research with regard to increasing maximal force is missing. Insufficient clinical and basic knowledge exists on the selection of stimulation parameters that will optimize muscle hypertrophy and gains in muscle force. For volitional training, established stimuli for muscle hypertrophy (which more or less parallels maximal muscle force) are muscle tension, metabolic stress, and muscle damage. The present review summarizes findings from clinical and basic research in terms of muscle mechanical as well as acute and chronic physiologic effects of different stimulation protocols, explains the role of the various stimulation parameters in determining the effect of NMES training protocols, and gives clinical recommendations for the choice of stimulation parameters for different patient populations with different training goals, such as increasing muscle force, mass, endurance, or energy consumption. We limit this review to non neurologic patients, because training goals of neurologic patients are specific to their functional deficits. PMID- 25839764 TI - Association between serum uric acid and nonalcoholic fatty liver disease in the US population. AB - BACKGROUND/PURPOSE: Studies conducted in Eastern Asia suggest that serum uric acid (SUA) level is highly related to nonalcoholic fatty liver disease (NAFLD). However, limited information is available in the USA. Our objective was to determine the association between NAFLD and SUA levels in the USA and to determine if this is independent of age, sex, and components of metabolic syndrome (MetS). METHODS: We analyzed 5370 men and women aged 20-74 years from the Third National Health and Nutrition Examination Survey (NHANES III) (1988 1994) in the USA. We calculated the prevalence and odds ratio (OR) of NAFLD and elevated liver enzymes by SUA and sex-specific quintiles of SUA, adjusting for multiple factors. RESULTS: The prevalence of NAFLD was higher in participants with higher SUA levels (10.9%, 9.6%, 15.9%, 21.8% and 33.1%, respectively, from the second to the fifth sex-specific quintile of uric acid). After adjustment, individuals with hyperuricemia were more likely to have NAFLD (OR: 1.4, 95% CI: 1.1-1.9). Similarly, the adjusted odds of NAFLD were increasingly higher from the second to the fifth quintile of SUA (ORs: 0.8, 1.2, 1.5 and 1.7, respectively; p < 0.01) as compared to the lowest quintile. Finally, individuals with hyperuricemia were more likely to have elevated liver enzymes (aspartate aminotransferase or alanine aminotransferase) (adjusted OR: 1.8, 95% CI: 1.1 2.7). CONCLUSION: NAFLD and SUA levels were strongly and independently associated in this nationally representative sample of men and women after adjustment for multiple factors. PMID- 25839765 TI - A study of 65 patients with acquired hemophilia A in Taiwan. AB - BACKGROUND/PURPOSE: Acquired hemophilia A (AHA) is a rare disorder that has not been comprehensively reported in the Chinese population. Treatment-related fatal sepsis (TRS), other than hemorrhage, is the leading cause of death in patients with AHA. However, researchers have not systematically evaluated salient parameters, to determine their association with the risk of TRS in this rare disorder. This study reports the salient features of AHA in Chinese patients and presents possible factors associated with TRS. METHODS: Sixty-five Chinese patients with AHA, including 42 men and 23 women, were studied retrospectively. RESULTS: The median age was 64 years (range = 18-94 years). The features, laboratory findings, and outcomes of various therapies designed to arrest acute bleeding and eliminate autoantibodies against the factor VIII coagulant protein (VIIIi) were comparable to those previously reported. The complete response (CR) rate was 60%, and the median time to CR was 16 weeks. Ten patients (15%) died of bleeding related to FVIIIi by the end of the median follow-up period of 115 months. The estimated 1- and 5-year hemorrhage-related mortality rates were 15% and 22%, respectively. The absence of CR to therapy was the only independent factor associated with shorter survival. The rate of TRS was 20%, and the use of a rituximab-based (Rb) regimen (odds ratio = 8.0, 95% CI, 1.1-68.2) and platelet < 1.5 * 10(11)/L at diagnosis (odds ratio = 38.5, 95% CI, 1.3-1107.6) were the two significantly independent factors associated with TRS. CONCLUSION: The salient features of AHA and treatment outcomes of the patients in this study are similar to those of other patients. Two independent factors (the use of a Rb regimen and platelet < 1.5 * 10(11)/L) were significantly associated with TRS. PMID- 25839766 TI - Attenuating systemic inflammatory markers in simulated high-altitude exposure by heat shock protein 70-mediated hypobaric hypoxia preconditioning in rats. AB - BACKGROUND/PURPOSE: The primary goal of this study was to test whether high altitude exposure (HAE: 0.9% O(2) at 0.47 ATA for 24 hours) was capable of increasing the systemic inflammatory markers as well as the toxic organ injury indicators in rats, with a secondary goal to test whether preinduction of heat shock protein (HSP) 70 by hypobaric hypoxia preconditioning (HHP: 18.3% O(2) at 0.66 ATA for 5 h/day on 5 days consecutively for 2 weeks) attenuated the proposed increased serum levels of both the systemic inflammatory markers and the toxic organ injury indicators. METHODS: Rats were assigned to: (1) non-HHP (21% O(2) at 1.0 ATA)+non-HAE (21% O(2) at 1.0 ATA) group; (2) non-HHP+HAE group; (3) HHP+non HAE group; (4) HHP+HAE group; and (5) HHP+HSP70 antibodies (Ab)+HAE group. For the HSP70Ab group, a neutralizing HSP70Ab was injected intravenously at 24 hours prior to HAE. All the physiological and biochemical parameters were obtained at the end of HAE or the equivalent time period of non-HAE. Blood samples were obtained for determination of both the systemic inflammatory markers (e.g., serum tumor necrosis factor-alpha, interleukin-1beta, E-selectin, intercellular adhesion molecule-1, and liver myeloperoxidase activity) and the toxic organ injury indicators (e.g., nitric oxide metabolites, 2,3-dihydroxybenzoic acid, and lactate dehydrogenase). RESULTS: HHP, in addition to inducing overexpression of tissue HSP70, significantly attenuated the HAE-induced hypotension, bradycardia, hypoxia, acidosis, and increased tissue levels of both the systemic inflammatory markers and the toxic organ injury indicators. The beneficial effects of HHP in inducing tissue overexpression of HSP70 as well as in preventing the HAE-induced increased levels of the systemic inflammatory markers and the toxic organ injury indicators could be significantly reduced by HSP70Ab preconditioning. CONCLUSION: These results suggest that HHP may downgrade both the systemic inflammatory markers and the toxic organ injury indicators in HAE by upregulating tissue HSP70. PMID- 25839767 TI - Effect of dentin bonding agent diffusing through dentin slices on the reactive oxygen species production and apoptosis of pulpal cells. AB - BACKGROUND/PURPOSE: Dentin bonding agents (DBAs) are cytotoxic to dental pulp cells. This study aimed to evaluate the effects of three DBAs (Optibond Solo Plus, Op; Clearfil SE Bond, SE; and Xeno III, Xe) after diffusion through 0.2-mm or 0.5-mm dentin slices on reactive oxygen species (ROS) production and apoptosis in dental pulp cells. METHODS: The amounts of DBAs diffusing through 0.2-mm or 0.5-mm dentin slices were quantified using a UV-Vis spectrophotometer. The effects of diffused DBAs on ROS production and viability of dental pulp cells were investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay on Days 1 and 2. Flow cytometric analysis and double staining of treated dental pulp cells with Annexin V-fluorescein isothiocyanate (V-FITC) and propidium iodide (PI) were performed on Day 2. RESULTS: Xe showed greatest diffusion through dentin slices after 8-hour period, followed by SE and Op. Dental pulp cells produced a lesser amount of ROS, when treated with DBAs diffusing through a 0.5-mm dentin slice than through a 0.2-mm dentin slice for the same period of time. A small proportion of cells were TUNEL-positive after treatment with any of the three diffused DBAs. Annexin V-FITC/PI staining identified apoptotic cells; cell survival was higher in those cells treated with DBAs diffusing through a 0.5-mm dentin slice than through a 0.2-mm dentin slice. CONCLUSION: The three DBAs after diffusion through 0.2- or 0.5-mm dentin slice still exhibit cytotoxicity to dental pulp cells. However, the 0.5-mm dentin slice is found to be a better barrier than the 0.2-mm dentin slice to protect dental pulp cells from DBA-induced cytotoxicity. PMID- 25839768 TI - Chemokine MCP1/CCL2 and RANTES/CCL5 gene polymorphisms influence Henoch-Schonlein purpura susceptibility and severity. AB - BACKGROUND/PURPOSE: Henoch-Schonlein purpura (HSP) is the most common small vessel vasculitis in children. It is considered to be an IgA-containing immune complex-mediated disease. Chemokines are small secreted proteins that attract leukocytes during inflammation. Our aim was to determine the serum levels of chemokines and investigate the association of chemokine gene polymorphisms with childhood HSP. METHODS: Serum levels of chemokines (interleukin-8/CXCL8, MCP 1/CCL2, RANTES/CCL5, MIG/CXCL9, and IP-10/CXCL10) were determined using cytometric beads arrays. We investigated the association of three single nucleotide polymorphisms (SNPs) MCP1/CCL2 -2518C/T, RANTES/CCL5 -403C/T, and RANTES/CCL5 -28C/G with HSP in 85 HSP patients and 136 healthy controls. RESULTS: Five serum chemokine levels were significantly elevated in patients with the acute stage of HSP compared to the normal controls (p < 0.05). MCP1/CCL2 -2518 TT genotype and T allele were associated with the risk for HSP with OR (95% CI) 3.32 (1.45-7.59) and 1.78 (1.20-2.64), respectively. The RANTES/CCL5 -28 GG genotype was associated with a significantly lower percentage of corticosteroid usage and lower corticosteroid accumulative dose in HSP patients. RANTES/CCL5 -403 TC and TT genotype were significantly associated with renal manifestations with an OR (95% CI) of 4.33 (1.44-12.99), adjusted for sex and age and the other two SNP genotypes. CONCLUSION: Our results support the fact that chemokines play important roles in the pathogenesis of HSP. MCP1/CCL2 gene polymorphisms were associated with susceptibility for HSP. RANTES/CCL5 gene polymorphisms may be related to disease severity and HSP nephritis. PMID- 25839769 TI - B cells and immunoglobulin in ABO-incompatible renal transplant patients receiving rituximab and double filtration plasmapheresis. AB - BACKGROUND/PURPOSE: The effect of rituximab on B cell and immunoglobulin production after therapeutic apheresis has not been studied in ABO-incompatible renal transplant patients. METHODS: Twenty consecutive ABO-incompatible renal transplant patients receiving rituximab induction and double filtration plasmapheresis were enrolled; one case was excluded because of repeated plasmapheresis and immunoglobulin therapy (Incompatible group). The B cell count of the Incompatible group was compared to another group of 18 ABO-compatible renal transplant patients who were operated on during the same period (Compatible group). In the Incompatible group, the total IgM, IgG, and IgG1-4 subclasses after transplantation were compared to those before desensitization. Tacrolimus, mycophenolate mofetil, and steroids were used for both groups. RESULTS: The B cell count of the Incompatible group was significantly lower than the Compatible group post-transplant from Month 1 to Month 11 only. The B cell count of the Compatible group also decreased for the first 6 months, suggesting that maintenance immunosuppressive agents suppress B cells. Total IgG and IgM levels after transplantation were significantly lower than before desensitization during the 24-month follow-up period. The post-transplant IgG3 level was significantly lower than before desensitization for only 3 months. CONCLUSION: With the aid of tacrolimus and mycophenolate mofetil, rituximab resulted in sustained suppression of B cell count and total IgG and IgM. Among the IgG subclasses, IgG3 was less sensitive to rituximab. PMID- 25839770 TI - Cord blood level of insulin-like growth factor-1 and IGF binding protein-3 in monochorionic twins. AB - BACKGROUND/PURPOSE: Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are known to modulate fetal growth but their role in intrauterine growth of monochorionic twins (MCT) has not been studied. METHODS: Cord venous blood was collected directly after birth. IGF-1 and IGFBP-3 in the cord venous blood were quantified by radioimmunoassay. Birth weights (BWs) were obtained electronically. Placentas were examined for chorionicity. RESULTS: Cord blood was collected in 37 pairs of MCT (15 pairs were males). BWs ranged from 564 to 3240 g, and gestational ages (GAs) were between 24 weeks and 39 weeks. There was a correlation between BW and cord venous blood IGFBP-3 concentration (r = 0.28, p = 0.015), but not between BW and cord venous blood IGF-1 level. There was no difference in IGF-1 between the heavier twins (30.8 +/- 61.8 ng/mL) and lighter twins (33.2 +/- 63.7 ng/mL), but a trend (p = 0.096) of higher IGFBP-3 level was demonstrated in heavier twins (3.14 +/- 1.23 MUg/mL) than in lighter twins (2.71 +/- 1.19 MUg/mL). The IGFBP-3 levels were higher (p = 0.042) in female twins (3.20 +/- 1.33 MUg/mL) than in male twins (2.64 +/- 1.04 MUg/mL). The IGF-1 level of the heavier twins correlated significantly to their lighter co-twin (r = 0.73, p < 0.001). CONCLUSION: Our data showed that cord venous blood IGF-1 level might be controlled mainly by genetic factors. IGFBP-3 might play an important role in fetal growth. PMID- 25839771 TI - May-Thurner syndrome: correlation between digital subtraction and computed tomography venography. AB - BACKGROUND/PURPOSE: Digital subtraction venography (DSV) and computed tomography venography (CTV) are both recommended for diagnosing May-Thurner syndrome. The literature contains little information on the correlation between these imaging tools. We performed a retrospective case-series study to investigate this correlation. METHODS: From August 2009 to August 2010, 42 patients with May Thurner syndrome (34 women, 8 men; mean age: 52.8 +/- 13.5 years) received DSV followed by CTV. The DSV was used to evaluate the degree of venous reflux, reflux start-up time, and flow time. By CTV, the ratio of cross-sectional area and the ratio of diameter between the narrowest region to that of the caudal part of the left common iliac vein were calculated. The correlation between these variables for DSV versus CTV was calculated using Spearman's rank correlation coefficients. RESULTS: In DSV evaluation of the extent of reflux, 19.0% of cases were classified as Grade 0, 11.9% as Grade I, 28.6% as Grade II, and 40.5% as Grade III. The mean +/- standard deviation flow times for these groups were 2.00 +/- 0.38 seconds, 1.75 +/- 0.29 seconds, 1.67 +/- 0.72 seconds, and 1.81 +/- 0.68 seconds, the mean time for total patients was 1.76 +/- 0.78 seconds. The reflux start-up times for Grades I-III were 2.00 +/- 1.00 seconds, 1.80 +/- 1.23 seconds, and 1.40 +/- 0.49 seconds, and the mean time was 1.6 +/- 0.8 seconds. In CTV, the mean area ratio and diameter ratio were 0.78 +/- 0.22 (range, 0.22-1.27) and 0.75 +/- 0.24 (range, 0.33-1.25). The reflux start-up time showed a positive correlation with the cross-sectional area ratio (r = 0.518; p = 0.002) and diameter ratio (r = 0.413; p = 0.019). CONCLUSION: The cross-sectional area ratio and diameter ratio in CTV correlate with the reflux start-up time in DSV. For May Thurner syndrome, both CTV and DSV provide essential information for diagnosis and evaluation of the disease. The positive correlation between anatomical and hemodynamic properties corresponds with the underlying pathophysiology. PMID- 25839772 TI - A case of pulmonary metastasis of giant cell tumor of bone presenting as pulmonary arteriovenous malformation. AB - Although giant-cell tumor (GCT) of the bone was originally classified as a benign tumor, metastasis has been reported. The radiographic features usually comprise parenchymal solitary or multiple nodules that are round-to-oval nodular opacities of homogeneous density in patients with GCT. However, the patient described in this case presented with a hypervascular mass with feeding vessels and hemothorax, which are common features of pulmonary arteriovenous malformation. To the best of our knowledge, cases of pulmonary metastases presenting as a pulmonary arteriovenous malformation have not been reported. Here, we report a case of giant-cell tumor of the bone that exhibited histologically benign pulmonary metastases and mimicked an arteriovenous malformation. PMID- 25839773 TI - BK virus as a potential oncovirus for bladder cancer in a renal transplant patient. AB - Renal transplant patients have high risk for bladder cancer. The reactivation of BK virus is common in renal transplant patients especially in the urinary tract. There was some evidence suggesting that the reactivation of BK virus (BKV) in renal transplant patients may associate with the development of bladder cancer. Here we demonstrated that a patient that had persistent elevated BKV viruria (urine BKV DNA concentration more than 10(11) copies/ml) after renal transplantation. Then, bladder cancer was found in 13 months after kidney transplantation. The urine BKV DNA concentration was detected by real-time PCR and the BKV DNA in the bladder tumor was detected by PCR. BKV DNA was found in the marginal and central part of the bladder tumor. After removal of the bladder cancer, the urine BKV viral load in this patients dropped dramatically to <10(2) copies/ml. However, the urine viral load had increased modestly to 10(6) copies/ml in 3 months after surgery. Since there is a close correlation between the urine BK viral load and the presence of bladder cancer, we suggested that there might be a causal relationship between the reactivation of BKV and the development of bladder cancer in renal transplant patient. PMID- 25839774 TI - Near-infrared light-responsive composite microneedles for on-demand transdermal drug delivery. AB - This study presents near-infrared (NIR) light-responsive polymer-nanostructure composite microneedles used for on-demand transdermal drug delivery. Silica coated lanthanum hexaboride (LaB6@SiO2) nanostructures were incorporated into polycaprolactone microneedles, serving as an NIR absorber. When the microneedles were irradiated with NIR light, light-to-heat transduction mediated by the LaB6@SiO2 nanostructures caused the microneedle melting at 50 degrees C. This increased the mobility of the polymer chains, enabling drug release from the matrix. Drug release from the microneedles was evaluated for four laser on/off cycles. In each cycle, the samples were irradiated until the temperature reached 50 degrees C for 3 min (laser on); the laser was then turned off for 30 min (laser off). The results showed that light-induced phase transition in the polymer triggered drug release from the melted microneedles. A stepwise drug release behavior was observed after multiple cycles of NIR light exposure. No notable drug leakage was found in the off state. This NIR-light-triggerable device exhibits excellent reproducibility, low off-state leakage, and noninvasive triggerability and, thus, represents an advance in transdermal delivery technology. PMID- 25839775 TI - Systematic Review: Sequential Rescue Therapy in Severe Ulcerative Colitis: Do the Benefits Outweigh the Risks? AB - BACKGROUND: The options for medical management of acute severe steroid-refractory ulcerative colitis (UC) are limited. Recent guidelines recommend against use of sequential rescue therapy in the setting of failed medical management with initial salvage therapy. A systematic review was conducted to assess outcomes of sequential rescue therapy with infliximab (IFX) and calcineurin inhibitors like cyclosporine (CsA) or tacrolimus (Tac) in patients with steroid-refractory UC. METHODS: A literature search identified studies that investigated treatment with IFX and CsA or Tac in acute severe UC. Outcomes of interest included short-term symptomatic response to treatment, rates of remission, adverse drug reactions, serious infections, mortality, and colectomy at 3 and 12 months. RESULTS: Overall, ten studies with 314 participants were eligible for inclusion. After sequential treatment, patients achieved short-term treatment response in 62.4% (95% confidence interval [CI], 57.0%-67.8%) of cases and remission in 38.9% (95% CI, 33.5%-44.3%). Colectomy rates were 28.3% (95% CI, 21.7%-34.5%) at 3 months and 42.3% (95% CI, 36.0%-48.6%) at 12 months. Adverse events were encountered by 23.0% (95% CI, 17.7%-28.3%) of patients, including serious infections in 6.7% (95% CI, 3.6%-9.8%) and mortality in 1% (95% CI, 0%-2.1%). CONCLUSIONS: The risk of sequential therapy in steroid-refractory UC seems lower than initially reported. Caution must be exercised however because of very low-quality evidence. In contrast to recent guidelines, the current analysis does not support a decision for or against use of sequential rescue therapy, which should only be performed at specialized referral centers familiar with the use of calcineurin inhibition. PMID- 25839776 TI - Out-of-pocket Cost Burden in Pediatric Inflammatory Bowel Disease: A Cross sectional Cohort Analysis. AB - BACKGROUND: Pediatric inflammatory bowel disease (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC), can result in significant morbidity requiring frequent health care utilization. Although it is known that the overall financial impact of pediatric IBD is significant, the direct out-of-pocket (OOP) cost burden on the parents of children with IBD has not been explored. We hypothesized that affected children with a more relapsing disease course and families in lower income strata, ineligible for need-based assistance programs, disparately absorb ongoing financial stress. METHODS: We completed a cross sectional analysis among parents of children with IBD residing in California using an online HIPAA-secure Qualtrics survey. Multicenter recruitment occurred between December 4, 2013 and September 18, 2014 at the point-of-care from site investigators, informational flyers distributed at regional CCFA conferences, and social media campaigns equally targeting Northern, Central, and Southern California. IBD-, patient-, and family-specific information were collected from the parents of pediatric patients with IBD patients younger than 18 years of age at time of study, carry a confirmed diagnosis of CD or UC, reside in and receive pediatric gastroenterology care in California, and do not have other chronic diseases requiring ongoing medical care. RESULTS: We collected 150 unique surveys from parents of children with IBD (67 CD; 83 UC). The median patient age was 14 years for both CD and UC, with an overall 3.7 years (SD 2.8 yr) difference between survey completion and time of IBD diagnosis. Annually, 63.6%, 28.6%, and 5.3% of families had an OOP cost burden >$500, >$1000, and >5000, respectively. Approximately one-third (36.0%) of patients had emergency department (ED) visits over the past year, with 59.2% of these patients spending >$500 on emergency department copays, including 11.1% who spent >$5000. Although 43.3% contributed <$500 on procedure and test costs, 20.0% spent >$2000 in the past year. Families with household income between $50,000 and $100,000 had a statistically significant probability (80.6%) of higher annual OOP costs than families with lower income <$50,000 (20.0%; P < 0.0001) or higher income >$100,000 (64.6%; P < 0.05). Multivariate analysis revealed that clinical variables associated with uncontrolled IBD states correlated to higher OOP cost burden. Annual OOP costs were more likely to be >$500 among patients who had increased spending on procedures and tests (odds ratio [OR], 5.63; 95% confidence interval [CI], 2.73 11.63), prednisone course required over the past year (OR, 3.19; 95% CI, 1.02 9.92), at least 1 emergency department visit for IBD symptoms (OR, 2.84; 95% CI, 1.33-6.06), at least 4 or more outpatient primary medical doctor visits for IBD symptoms (OR, 2.82; 95% CI, 1.40-5.68), and history of 4 or more lifetime hospitalizations for acute IBD care (OR, 2.60; 95% CI, 1.13-5.96). CONCLUSIONS: Previously undocumented, a high proportion of pediatric IBD families incur substantial OOP cost burden. Patients who are frequently in relapsing and uncontrolled IBD states require more acute care services and sustain higher OOP cost burden. Lower middle income parents of children with IBD ineligible for need based assistance may be particularly at risk for financial stress from OOP costs related to ongoing medical care. PMID- 25839777 TI - Killing of Escherichia coli by Crohn's Disease Monocyte-derived Macrophages and Its Enhancement by Hydroxychloroquine and Vitamin D. AB - BACKGROUND: Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly adherent and invasive Escherichia coli that replicate inside macrophage phagolysosomes. We compared CD and healthy control (HC) macrophages for their abilities to kill E. coli and generate neutrophil chemoattractants and also assessed the effects of hydroxychloroquine (HCQ) and vitamin D on killing of phagocytosed E. coli. METHODS: Peripheral blood monocyte-derived macrophages from CD and HC were compared for bacterial killing and generation of neutrophil chemoattractants in response to CD-derived E. coli. Escherichia coli replication was also assessed in the presence and absence of HCQ, alone and with antibiotics, and vitamin D. RESULTS: Monocyte-derived macrophages from patients with CD were similar to HC in allowing replication of phagocytosed CD-derived E. coli: HM605 {CD: N = 10, mean fold replication in 3 hr = 1.08 (95% confidence interval [CI], 0.39-1.78); HC: N = 9, 1.50 (95% CI, 1.02-1.97); P = 0.15} and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD = 2.55 [95% CI, 2.31-2.80]; HC = 2.65 [95% CI, 2.46 2.85], P = 0.42). HCQ and 1,25 OH2-vitamin D3 both caused dose-dependent inhibition of intramacrophage E. coli replication 3-hour postinfection; HCQ: 73.9% inhibition (P < 0.001) at 1 MUg/mL, accompanied by raised intraphagosomal pH, and 1,25 OH2-vitamin D3: 80.7% inhibition (P < 0.05) at 80 nM. HCQ had synergistic effects with doxycycline and ciprofloxacin. CONCLUSIONS: CD and HC macrophages perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics. PMID- 25839779 TI - Oxidation and Oxygenation of Carbonyl Ruthenium(II) Azuliporphyrin. AB - Chemical oxidation and oxygenation of carbonyl ruthenium(II) azuliporphyrin [Ru(TPAP)(CO)] were explored. [Ru(TPAP)(CO)] reacts with dioxygen giving carbonyl ruthenium(II) 21-oxyazuliporphyrin [Ru(TPAP-O)(CO)] revealing the activation the Ru-C bond inside azuliporphyrin coordination cavity. Solution and X-ray structural studies confirmed the tendency of [Ru(TPAP-O)(CO)] to form dimeric [Ru(TPAP-O)(CO)]2. The dimer adopts a head-to-tail structure with the azulenolate groups forming bridges from one macrocycle to the ruthenium(II) in the adjacent unit. One-electron oxidation of [Ru(TPAP)(CO)] gives the first pi-cation radical of metallocarbaporphyrinoid-[Ru(TPAP)(CO)](+*)-with extraordinary participation of the azulene unit in the spin delocalization. The most characteristic (1)H NMR features of the radical are large, sign-alternating isotropic shifts of resonances assigned to meso-aryl, azulene, and pyrrolic hydrogen atoms. The spin distribution determined by density functional theory confirmed the pi-cation radical electronic structure reproducing the diagnostic spectroscopic features including pi-delocalization at meso-aryl resonances and very characteristic sign alternation of contact shifts for an azulene moiety. PMID- 25839778 TI - Mechanism of anti-inflammatory effect of tricin, a flavonoid isolated from Njavara rice bran in LPS induced hPBMCs and carrageenan induced rats. AB - Njavara is an indigenous medicinal rice variety traditionally used in Ayurvedic system of medicine practiced in Kerala, India. Tricin is a bioflavonoid present in significantly higher levels in rice bran of Njavara. Present study attempted to identify the molecular target of tricin in TLR mediated signaling pathways by using lipopolysaccharide (LPS) induced human peripheral blood mononuclear cells (hPBMCs) and carrageenan induced paw edema in rats as experimental models. Tricin acted upstream in the activation of inflammation cascade by interfering with TLR4 activation, preferably by blocking the LPS induced activation of TLR4, MYD88 and TRIF proteins in hPBMCs. Subsequently, tricin significantly blocked the activation of downstream kinases like p38MAPK, JNK1/2 and IRF3. Thus the inhibitory effect of tricin on NF-kappaB and IRF3 together confirms the specific inhibition of both MYD88 dependent and TRIF dependent pathways. Tricin treatment also inhibited the pro-inflammatory effect of LPS by blocking the TLR4 signaling mediated activation of cytosolic phospholipase A2 (cPLA2), which is confirmed by specific inhibition of COX-2. Results demonstrated that in addition to NF-kappaB, tricin can prevent the activation of STAT proteins by significantly inhibiting the activation of both STAT1 and STAT3 via the down regulation of upstream phosphorylating enzymes like JAK1 and JAK2. The protective anti-inflammatory effect of tricin was also confirmed by in vivo experiments. Thus, this study provides strong evidence that tricin exerts its anti-inflammatory effect via a mechanism involving the TLR4/NF-kappaB/STAT signaling cascade. PMID- 25839780 TI - Signet ring cell adenocarcinoma and bilateral leptomeningeal involvement of optic nerve sheaths. AB - Signet ring cell adenocarcinoma has a propensity for leptomeningeal carcinomatosis, and although bilateral optic nerve involvement is rare, this may occur with or without obvious signs of diffuse leptomeningeal involvement. We describe a 41-year-old woman who presented with a brief history of simultaneous bilateral visual deterioration and a distended abdomen. Examination revealed bilateral no light perception vision and bilateral optic disc edema. Radiologic work-up showed large multiple pelvic masses involving the ovaries, multifocal boney deposits, and widespread central nervous system carcinomatosis, involving the optic nerves and the first, fifth, and eighth cranial nerves. Biopsy of an ovarian mass demonstrated islands of signet ring cells. Signet cell adenocarcinomatous infiltration of the leptomeningeal space should be considered in cases of bilateral simultaneous vision loss with signs suggestive of leptomeningeal infiltration of the optic nerve sheath. PMID- 25839781 TI - Isolation a new strain of Kocuria rosea capable of tolerating extreme conditions. AB - A new actinobacterial strain was isolated from Ab-e-Siah spring (dark water) taken from the Ramsar city in Iran, and subjected to several stress conditions investigation. The isolate, named MG2 strain, was Gram-positive, aerobic, diplococci or tetrad shaped, non-spore forming and non-motile. Phylogenetic analysis of the isolate using 16S rDNA sequence indicated that the organism matched best with the genus Kocuria and the highest sequence similarities (98.55%) being found with Kocuria rosea. The 16S rDNA sequence determined in this study has been deposited in the NCBI database with the accession no. JX534199, K. rosea strain MG2. The isolated strain was an alkaliphilic-mesophilic bacterium because the optimal growth was observed at pH 9.2 and temperature of 28 degrees C under aerobic condition. MG2 was a halotolerant strain and tolerated maximally to 15% NaCl concentraion. Viability analysis by flow cytometry indicated that this strain had highly resistance to UV-C radiation and moderately resistance to desiccation after 28 days. The viability of K. rosea strains MG2 and Deinococcus radiodurans R1 were determined D87 and D98 according to D index, respectively, by a dose radiation 25 J/cm (Appukuttan et al., 2006). Thus the UV resistance of strain MG2 was comparable with representative radiation resistant Deinococcus. Also MG2 was grown at 1-4% of H2O2 as an oxidant agent. This research is the first study on multiple extreme resistance of Kocuria rosea new strain (MG2) isolated in Iran. PMID- 25839783 TI - Recessions, healthy no more? AB - Over the 1976-2010 period, total mortality shifted from strongly procyclical to being weakly or unrelated to macroeconomic conditions. The association is likely to be poorly measured when using short (less than 15 year) analysis periods. Deaths from cardiovascular disease and transport accidents continue to be procyclical; however, countercyclical patterns have emerged for fatalities from cancer mortality and external causes. Among the latter, non-transport accidents, particularly accidental poisonings, play an important role. PMID- 25839784 TI - Effectiveness and Safety of Acute Care Telemedicine for Children with Regular and Special Healthcare Needs. AB - OBJECTIVE: To assess the hypothesis that effectiveness and safety of the Health-e Access telemedicine model for care of children with special healthcare needs (CSHCN) with acute illness equaled those for care of children in regular childcare and schools (CRS). MATERIALS AND METHODS: We examined healthcare use through insurance claims and telemedicine records spanning 5.7 and 7.3 years for CSHCN and CRS, respectively. Effectiveness was measured as telemedicine visit completion, duplication, and adverse events. Completed visits had diagnosis and management decisions made, and treatment implemented, based solely on telemedicine. Duplicating visits addressed related problems in-person following telemedicine visits within 1 or 3 days. An adverse event was defined as an emergency department visit following a telemedicine visit within 3 days for a problem probably related. RESULTS: Comparisons addressing these measures included 483 and 10,008 telemedicine visits by CSHCN and CRS, respectively. Claims files captured health services use for varying periods of time among 300 different CSHCN and among 1,950 different CRS. Among the 483 telemedicine visits initiated for CSHCN over their telemedicine observation period, 9 were not completed. The CSHCN completion rate of 98.1% equaled the 97.6% completion observed among CRS. Within 3 days, in-person visits duplicated 16.1% of telemedicine visits for both CSHCN and CRS. Within 1 day, in-person visits duplicated 5.3% and 8.9% of telemedicine visits for CSHCN and CRS, respectively. Adverse events following telemedicine visits included 0.3% of telemedicine visits for CSHCN and 0.5% for CRS. CONCLUSIONS: Observations support safety and effectiveness of Health-e Access telemedicine for both CSHCN and CRS. PMID- 25839785 TI - Phthisis bulbi: clinical and pathologic findings in retinoblastoma. AB - PURPOSE: Phthisis bulbi represents an ocular end-stage disease characterized by shrinkage and disorganization of the eye. We aim at identifying the pathologic changes of phthisis bulbi associated with retinoblastoma. DESIGN: Retrospective observational case series study. METHODS: 16 enucleated eyes were enrolled retrospectively between 2007 and 2012. Pathologic gross and microscopic findings were assessed. RESULTS: Cases showed grossly shrunken eyes with a mean volume of 4.3 cc. Sclera was markedly thickened in the majority of cases with mean of 2272.8 MU. Choroid showed an average thickness of 1029 MU. Necrosis, dystrophic calcification, ossification, gliosis, residual viable tumor was identified in many cases. Pathologic high risk factors were seen in three specimens. CONCLUSIONS: We conclude that retinoblastoma must be considered in the differential diagnosis of phthisis bulbi in the pediatric patients and active tumor was present in half of the patients. PMID- 25839782 TI - Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome. AB - We have previously revealed that exogenously added lithocholic bile acid (LCA) extends the chronological lifespan of the yeast Saccharomyces cerevisiae, accumulates in mitochondria and alters mitochondrial membrane lipidome. Here, we use quantitative mass spectrometry to show that LCA alters the age-related dynamics of changes in levels of many mitochondrial proteins, as well as numerous proteins in cellular locations outside of mitochondria. These proteins belong to 2 regulons, each modulated by a different mitochondrial dysfunction; we call them a partial mitochondrial dysfunction regulon and an oxidative stress regulon. We found that proteins constituting these regulons (1) can be divided into several "clusters", each of which denotes a distinct type of partial mitochondrial dysfunction that elicits a different signaling pathway mediated by a discrete set of transcription factors; (2) exhibit 3 different patterns of the age-related dynamics of changes in their cellular levels; and (3) are encoded by genes whose expression is regulated by the transcription factors Rtg1p/Rtg2p/Rtg3p, Sfp1p, Aft1p, Yap1p, Msn2p/Msn4p, Skn7p and Hog1p, each of which is essential for longevity extension by LCA. Our findings suggest that LCA-driven changes in mitochondrial lipidome alter mitochondrial proteome and functionality, thereby enabling mitochondria to operate as signaling organelles that orchestrate an establishment of an anti-aging transcriptional program for many longevity defining nuclear genes. Based on these findings, we propose a model for how such LCA-driven changes early and late in life of chronologically aging yeast cause a stepwise development of an anti-aging cellular pattern and its maintenance throughout lifespan. PMID- 25839786 TI - Probing the Interfacial Interaction in Layered-Carbon-Stabilized Iron Oxide Nanostructures: A Soft X-ray Spectroscopic Study. AB - We have stabilized the iron oxide nanoparticles (NPs) of various sizes on layered carbon materials (Fe-oxide/C) that show excellent catalytic performance. From the characterization of X-ray absorption spectroscopy (XAS), X-ray emission spectroscopy (XES), scanning transmission X-ray microscopy (STXM) and X-ray magnetic circular dichroism spectroscopy (XMCD), a strong interfacial interaction in the Fe-oxide/C hybrids has been observed between the small iron oxide NPs and layered carbon in contrast to the weak interaction in the large iron oxide NPs. The interfacial interaction between the NPs and layered carbon is found to link with the improved catalytic performance. In addition, the Fe L-edge XMCD spectra show that the large iron oxide NPs are mainly gamma-Fe2O3 with a strong ferromagnetic property, whereas the small iron oxide NPs with strong interfacial interaction are mainly alpha-Fe2O3 or amorphous Fe2O3 with a nonmagnetic property. The results strongly suggest that the interfacial interaction plays a key role for the catalytic performance, and the experimental findings may provide guidance toward rational design of high-performance catalysts. PMID- 25839787 TI - Synthesis and in vitro characterization of a novel S-protected thiolated alginate. AB - The object of this study was to synthesize and characterize a novel S-protected thiolated polymer with a high degree of modification. In this regard, an alginate cysteine and an alginate-cysteine-2-mercaptonicotinic acid conjugate were synthesized. To achieve a high coupling rate of the thiol group bearing ligand cysteine to the polymer, the carbohydrate was activated by an oxidative ring opening with sodium periodate followed by a reductive amination to bind the primary amino group of cysteine to resulting reactive aldehyde groups. The obtained thiolated polymer displayed 1561+/-130MUmol thiol groups per gram polymer. About one third of these thiol groups were S-protected by the implementation of a thiol bearing aromatic protection group via disulfide bond formation. Test tablets of both modified polymers showed improved stability against oxidation in aqueous environment compared to the unmodified alginate and exhibit higher water-uptake capacity. Rheological investigations revealed an increased viscosity of the S-protected thiolated polymer whereat the thiolated non S-protected polymer showed gelling properties after the addition of hydrogen peroxide. The mucoadhesive properties could be improved significantly for both derivatives and no alteration in biocompatibility tested on Caco-2 cell monolayer employing an MTT assay could be detected after modification. According to these results, both new derivatives seem promising for various applications. PMID- 25839788 TI - Electrochemical characterization of gelatinized starch dispersions: voltammetry and electrochemical impedance spectroscopy on platinum surface. AB - The electrochemical properties of gelatinized starch dispersions (GSD; 5% w/w) from different botanical sources were studied using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) tests over a platinum surface. The phenomenological modelling of EIS data using equivalent circuits indicated that after gelatinization the electrical resistance was determined mainly by the resistance of insoluble material (i.e., ghosts). Sonication of the GSD disrupted the ghost microstructure, and produced an increase in electrical conductivity by reducing the resistance of the insoluble material. The CV data showed three oxidation peaks at potentials where glucose solutions displayed oxidation waves. It is postulated that hydrolysis at the bulk and electrocatalyzed oxidation on the Pt-surface are reactions involved in the starch transformation. Starches peak intensity increased with the amylose content, suggesting that the amylose-rich matrix played an important role in the charge transfer in the electrolytic system. PMID- 25839789 TI - Physicochemical, digestibility and structural characteristics of starch isolated from banana cultivars. AB - Banana starches from diverse varieties (Macho, Morado, Valery and Enano Gigante) were studied in their physicochemical, structural and digestibility features. X ray diffraction indicated that the banana starches present a B-type crystallinity pattern, with slight difference in the crystallinity level. Macho and Enano Gigante starches showed the highest pasting temperatures (79 and 78 degrees C, respectively), whilst Valery and Morado varieties presented a slight breakdown and higher setback than the formers. Morado starch presented the highest solubility value and Valery starch the lowest one. The swelling pattern of the banana starches was in agreement with their pasting profile. All banana starches showed a shear-thinning profile. The resistant starch (RS) fraction was the main fraction in the uncooked banana starches. Morado variety showed the highest amount of slowly digestible starch (SDS) and the lowest RS content reported until now in banana starches. Banana starch cooked samples presented an important amount of SDS and RS. Molecular weight and gyration radius of the four banana starches ranged between 2.88-3.14*10(8)g/mol and 286-302nm, respectively. The chain-length distributions of banana amylopectin showed that B1 chains (DP 13-24) is the main fraction, and an important amount of long chains (DP>=37) are present. The information generated from this study can be useful to determine banana varieties for starch isolation with specific functionality. PMID- 25839790 TI - Protective effect of polysaccharides from Opuntia dillenii Haw. fruits on streptozotocin-induced diabetic rats. AB - In this study, a novel water-soluble polysaccharide fraction with molecular weight of 6479.1kDa was isolated from the fruits of Opuntia dillenii Haw., which consisted of rhamnose, xylose, mannose and glucose in the molar ratio of 14.99:1.14:1.00:6.47. The protective effect of O. dillenii Haw. fruits polysaccharide (ODFP) against oxidative damage in streptozotocin (STZ)-induced diabetic rats was investigated. The results showed that oral administration of ODFP significantly decreased food intake, water intake, urine production, organ weights and blood glucose level, and increased body weight in STZ-induced diabetic rats. ODFP also significantly increased the activities of SOD, GPx and CAT, and decreased malondialdehyde level in serum, liver, kidney, and pancreas in STZ-induced diabetic rats. Moreover, histopathological examination showed that ODFP could markedly improve the structure integrity of pancreatic islet tissue in STZ-induced diabetic rats. These results suggest that ODFP have hypoglycemic and antioxidant properties and can protect rats from STZ-induced oxidative damage. PMID- 25839791 TI - Antimicrobial and antioxidant surface modification of cellulose fibers using layer-by-layer deposition of chitosan and lignosulfonates. AB - To confer cellulose fibers antimicrobial and antioxidant activities, chitosan (CS)/lignosulfonates (LS) multilayers were constructed on fibers surfaces through layer-by-layer deposition technique. The formation of CS/LS multilayers on cellulose fibers surfaces was verified by X-ray photoelectron spectroscopy (XPS) and zeta potential measurement. The surface morphologies of CS/LS multilayers on fibers surfaces were observed by atomic force microscopy (AFM). The results showed that characteristic element (i.e. N and S element) content increased with increasing bilayers number, the surface LS content increased linearly as a function of bilayers. Zeta potential of modified fibers was inversed after deposition of each layer. AFM phase images indicated that the cellulose microfibrils on fibers surfaces were gradually covered by granular LS aggregate. The antimicrobial testing results demonstrated that CS/LS multilayers modified fibers with CS in the outermost layer exhibited higher antimicrobial activity against Escherichia coli. The antioxidant testing results showed that antioxidant activity of CS/LS multilayers modified fibers was better than that of original fibers under the same oxidation conditions. PMID- 25839792 TI - Self-assembly in aqueous solution of amphiphilic graft copolymers from oxidized carboxymethylcellulose. AB - A series of oxidized carboxymethylcellulose-graft-poly(ethylene glycol) dodecylamine (OCMC-g-PEG-DDA) was prepared by using an appositely prepared PEG with terminal amino groups and different amounts of DDA. The nanoaggregates formed in aqueous solution were characterized by surface tension measurements, fluorescence spectroscopy, dynamic light scattering (DLS) and scanning electron microscopies (SEM and TEM). The micelles showed narrow hydrodynamic size distributions and diameters varying from 163 to 193nm depending on the ratio of DDA to PEG chains. The DDA content in the graft copolymers also affected the core shell interfacial compactness. PMID- 25839793 TI - Cellulosic fibers with high aspect ratio from cornhusks via controlled swelling and alkaline penetration. AB - Cellulosic fibers with high aspect ratio have been firstly obtained from cornhusks via controlled swelling in organic solvent and simultaneous tetramethylammonium hydroxide (TMAOH) post treatment within restricted depth. Cornhusks, with around 42% cellulose content, are a copious and inexpensive source for natural fibers. However, cornhusk fibers at 20tex obtained via small molecule alkaline extraction were too coarse for textile applications. Continuous NaOH treatment would result in fine fibers but with length of about 0.5-1.5mm, too short for textile use. In this research, post treatment using TMAOH and under controlled swelling significantly reduced fineness of cornhusk fibers from 21.3+/ 2.88 to 5.72+/-0.21tex. Fiber length was reduced from 105.47+/-10.03 to47.2+/ 27.4mm. The cornhusk fibers had more oriented microstructures and cellulose content increased to 84.47%. Besides, cornhusk fibers had similar tenacity, longer elongation, and lower modulus compared to cotton and linen, which endowed them with durability and flexibility. PMID- 25839794 TI - Methylesterase behaviour is related to polysaccharide organisation in model systems mimicking cell walls. AB - Pectin gels and pectin-cellulose binary gels were used as cell wall-mimicking systems to investigate the diffusion ability of a fungal pectin methylesterase. Increasing content of cellulose in the gel appears to result: (i) in longer demethylated blocks thus favouring AaPME processivity, and (ii) in accelerated enzyme kinetics. To better understand this unexpected behaviour, a method was set up to investigate the gel porosity as a function of the cellulose content by following the passive diffusion of three pullulans having different hydrodynamic volumes. Like the enzyme, the pullulans diffused more efficiently in the gels containing the highest proportions of cellulose. Altogether, these results suggest that the gel settled differently during formation according to the respective proportions of the two polysaccharides. With cellulose present, a fraction of pectin would form close interactions with the microfibrils resulting in a larger volume accessible to diffusing molecules. This volume would be related to the cellulose concentration. PMID- 25839795 TI - Ultrasonic assisted cross-flow ultrafiltration of starch and cellulose nanocrystals suspensions: characterization at multi-scales. AB - This study investigates for the first time the behaviors of starch and cellulose nanocrystals (SNC and CNC) suspensions which are simultaneously subjected to pressure, shear flow and ultrasound (US) during cross-flow ultrafiltration. This multi-forces process was characterized from macro-scales to nano-scales, with a custom designed "SAXS Cross-Flow US-coupled Filtration Cell". In addition, rheological behaviors of SNC samples at different concentrations/temperatures have been investigated. In both cases (ultrafiltration of SNC and CNC suspensions), better performances were observed with US. The in-situ SAXS measurements revealed that for SNC suspensions, no structure change occurred at the length scales range from 10 to 60nm in this multi-forces process, while CNC particles exhibited an ordered arrangement within the concentrated layer during the same process. SNC particles accumulated on the membrane surface forming a "fragile" concentrated layer which was removed very quickly by subsequent applied US. In contrary, the CNC particles accumulation was very severe, the additional ultrasonic force led to a disruption but not a totally removal of the CNC concentrated layer. PMID- 25839796 TI - Mechanical and barrier properties of guar gum based nano-composite films. AB - Guar gum based nano-composite films were prepared using organically modified (cloisite 20A) and unmodified (nanofil 116) nanoclays. Effect of nanoclay incorporation on mechanical strength, water vapor barrier property, chromatic characteristics and opacity of films was evaluated. Nano-composites were characterized using X-ray scattering, FTIR and scanning electron microscopy. A nanoclay concentration dependent increase in mechanical strength and reduction in water vapor transmission rate was observed. Films containing nanofil 116 (2.5% w/w guar gum) and closite 20A (10% w/w guar gum) demonstrated a 102% and 41% higher tensile strength, respectively, as compared to the control. Lower tensile strength of cloisite 20A films as compared to nanofil 116 films was due to its incompatibility with guar gum. X-ray scattering analysis revealed that interstitial spacing between nanofil 116 and cloisite 20A sheets increased due to intercalation by guar gum polymer. This resulted in improved mechanical and barrier properties of nano-composites compared to control. PMID- 25839797 TI - Influence of substitution on the rheological properties and gelation of hydroxyethyl cellulose solution in NaOH-water solvent. AB - The rheological properties of hydroxyethyl cellulose (HEC) with a low molar substitution (MS) dissolved in 8wt% NaOH-water were studied as a function of solution temperature, polymer concentration and molar substitution. Special attention was paid to gelation kinetics. Similar to cellulose dissolved in alkali or ionic liquids, the intrinsic viscosity of HEC decreased with temperature increase, indicating a decrease of solvent thermodynamic quality. The gelation time of HEC solutions decreased exponentially with temperature but the kinetics is much slower than the gelation of microcrystalline cellulose solutions in the same solvent. Higher molar substitution leads to slower gelation. The small amount of introduced hydroxyethyl groups prevented cellulose aggregation thus increasing solution stability. PMID- 25839798 TI - A novel polysaccharide from mycelia of cultured Phellinus linteus displays antitumor activity through apoptosis. AB - Two novel polysaccharides termed PLPS-1 and PLPS-2 were isolated from mycelia of cultured Phellinus linteus by hot water extraction, purified by DEAE-52 cellulose and Sephadex G-100 column chromatography, and structurally characterized by FTIR and NMR spectroscopy, GC-MS, periodate oxidation/Smith degradation, and methylation analysis. The monosaccharide compositions of PLPS-1 (MW 2.5*10(5)Da) and PLPS-2 (MW 2.8*10(4)Da) were respectively Glc, Ara, Fuc, Gal, and Xyl in molar ratio 21.964:1.336:1.182:1:1, and Glc, Gal, Man, Ara, Fuc, Xyl in molar ratio 14.368:2.594:1.956:1.552:1.466:1; i.e., both were heteropolysaccharides. The backbone of PLPS-1 consisted primarily of repeating alpha-d-Glc(1->4)-alpha-d Glc(1->6) units, while that of PLPS-2 consisted of alpha-(1->3)-d-Glc and alpha (1->6)-d-Glc. The side branches were also different in their carbohydrate components. In in vitro antitumor assays, PLPS-1 displayed strong anti proliferative effect against S-180 sarcoma cells through apoptosis, whereas PLPS 2 had no such effect. The difference in antitumor activity between the two PLPS evidently results from their structural differences. PLPS-1 has potential as a novel anticancer agent. PMID- 25839799 TI - Structure characterization of an arabinogalactan from green tea and its anti diabetic effect. AB - A water-soluble polysaccharide, 7WA, with an average molecular mass of 7.1*10(4)Da, was isolated from the leaves of green tea. Monosaccharide composition analysis indicated that 7WA mainly contained Arabinose and Galactose in the molar ratio of 1.0:0.96. By using the methods of methylation analysis, partial hydrolysis, and NMR, 7WA was characterized to possess a backbone consisting of 1,3- and 1,6-linked galactopyranosyl residues, with branches attached to O-3 of 1,6-linked galactose residues, and O-4 and O-6 of 1,3-linked galactose residues. The results of glucose-stimulated insulin secretion (GSIS) showed that 7WA significantly augmented insulin secretion at high glucose level (25mM), however, such effect was not seen at low glucose level (5mM). The mechanism study results indicated 7WA, a type II arabinogalactan from Green Tea, enhances GSIS through cAMP-PKA pathway. PMID- 25839800 TI - Oligosaccharide-based block copolymers: metal-free thiol-maleimide click conjugation and self-assembly into nanoparticles. AB - Amphiphilic oligosaccharide-based block copolymers (OBCPs) are able to self assemble either into nanoparticles with biocompatible oligosaccharides corona in aqueous solution or in sub-nanopatterned thin-films originating from the high incompatibility between the different blocks. For these reasons, these biosourced OBCPs are valuable structures for applications in nanomedicine and nanoelectronics. Up to now, the synthesis of those OBCPs was obtained through grafting-onto method using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). However, complete removal of metal catalyst residues from the resultant copolymer chains is critical and hampers electronic and biomedical applications. In this study, we report an efficient and convenient metal-free click chemistry approach consisting in coupling thiol-containing oligosaccharide blocks to maleimide terminated polystyrenes. Upon self-assembly in water, spherical micelles of similar size than those obtained by Cu(I)-catalyzed azide-alkyne cycloaddition were formed as evidenced using dynamic light scattering and transmission electron microscopy techniques. PMID- 25839801 TI - Studies on the sulfation of cellulose alpha-lipoate and ability of the sulfated product to stabilize colloidal suspensions of gold nanoparticles. AB - A versatile method for the synthesis of cellulose alpha-lipoate with a low degree of substitution (DS) has been developed using N,N-dimethylacetamide (DMA)/LiCl as a solvent and N,N'-carbonyldiimidazole (CDI) as an esterification reagent. The cellulose alpha-lipoate with DS of alpha-lipoate groups of 0.26 was converted with sulfur trioxide-pyridine complex in dimethyl sulfoxide (DMSO) as solvent. The sulfation is accompanied by an unexpected partial oxidation of the disulfide moiety leading to the formation of the corresponding stereoisomers of S-oxides. The resulting mixture of water-soluble cellulose alpha- and beta-lipoate sulfate possesses a DS of sulfuric acid half ester groups of 1.78. This cellulose alpha/beta-lipoate sulfate derivative can be used as an effective stabilizer and solubilizer for the formation of colloidal suspensions of gold nanoparticles formed in situ in aqueous solution. PMID- 25839802 TI - Thermal degradation behavior of hypochlorite-oxidized starch nanocrystals under different oxidized levels. AB - The thermal degradation behavior of hypochlorite-oxidized starch nanocrystals (OSNCs) was evaluated in this study. Carbonyl and carboxyl groups in OSNCs increased from 0.006 and 0.091mmol/g to 0.033 and 0.129mmol/g, respectively, as the active chlorine concentration increased from 1% to 4% (w/w). Compared with starch nanocrystals (SNCs), the initial degradation temperature of OSNCs with 4% oxidization decreased from 273 degrees C to 253 degrees C. Two degradation processes were detected using differential thermal analysis. The activation energy of the low-temperature process increased with increasing oxidization level because of removal of sulfate esters and reduction of the decomposition products of H2O during oxidation. With increasing temperature, the H2O generating from decarboxylation and decomposition of the carboxyl groups may catalyze SNCs depolymerization, leading to decrease in the activation energy of the high temperature process. OSNCs (4% oxidized level) can be used in dry process below 253 degrees C to avoid degradation. PMID- 25839803 TI - Synthesis of bacterial cellulose using hot water extracted wood sugars. AB - Bacterial cellulose (BC), a type of nanopolymer produced by Acetobacter xylinum is a nanostructured material with unique properties and wide applicability. However, a standard medium used for the cultivation of BC, the Hestrin-Schramm medium, is expensive and prevents wide scale extension of BC applications. In this research, a relatively low-cost culture media was successfully developed from wood hot water extracts for the Acetobacter xylinus 23769 strain. Hot water extract (HWE) is a residual material originating from pulp mills and lignocellulosic biorefineries and consists of mainly monomeric sugars, organic acids and organics. The effects of different pH (5, 6, 7 and 8) and temperatures (26, 28 and 30 degrees C) were also examined in this research. There were no significant differences in the crystallinity and the recorded Ialpha fraction of cellulose produced between Hestrin-Schramm and the HWE medium. The maximum production of 0.15g/l of BC was obtained at a pH of 8 and temperature of 28 degrees C. Glucose and xylose in the HWE were the main nutrient sources utilized in all BC cultivations based on high-pressure liquid chromatography (HPLC) results. HWE was shown to be a suitable carbon source for BC production, and a process was established for BC production from lignocellulosic feedstocks without using any modification of the HWE. HWE is an abundant and relatively inexpensive forest by-product. Using HWE for BC production could reduce burdens on the environment and also, achieve the goal of large scale BC production at low cost without using added culture nutrients. PMID- 25839804 TI - Thermally generated radicals as indicators of the starch modification studied by EPR spectroscopy: a review. AB - The results compiled and discussed in the present review have been published by the research group of the Chemistry Faculty, Jagiellonian University or by other Authors, as given in References. Relatively stable and short-lived radicals generated thermally in starches of various botanic origin were used as indicators of the changes in the starch structure and properties occurring upon chemical and physical modifications. The number of radicals was determined by electron paramagnetic resonance (EPR) spectroscopy. Distribution of water and accessibility of different zones in the starch granule for reagents were tested by using paramagnetic Cu(2+) ions as a probe molecule. Relatively stable radicals generated in starch at 300 degrees C revealed protective properties against ionizing radiation. Thermally induced short-lived radicals exhibited sensitivity to the degree of the starch structure ordering. PMID- 25839805 TI - Characterization and immunomodulatory activity of rice hull polysaccharides. AB - Rice hulls (Oryza sativa) are high in carbohydrate content and have been utilized as dietary fiber. The immunomodulatory bioactivity of rice hull polysaccharides (RHPS) has rarely been reported. This study demonstrated the structural characteristics and immunomodulating of RHPS. The RHPS were fractioned using DEAE 650M column, producing one neutral and 3 acidic polysaccharide fractions. RHPS were examined using HPAEC-PAD, HP-SEC, NMR and GC-MS for structural characteristics. The results showed that RHPS consisted of arabinose, galactose, glucose, mannose, and xylose in ratios of 10:44.8:29.8:9.3:6.1 and comprised (1 >3)-Gal as backbone, and its average molecular weight was 77kDa. The presence of type II arabinogalactan (AGII) was confirmed through LM2-ELISA and Yariv gel diffusion showed the RHPS had AGII features. This study examined the immunomodulatory effects of orally administering RHPS in vivo. The RHPS increased the cytotoxicity of splenic natural killer cells, macrophage phagocytosis, and cytokine inductions. This is the first study to demonstrate the structural characteristics of an active polysaccharide from rice hulls and its immunopharmacological effects in vivo. PMID- 25839806 TI - A polysaccharide from Trametes robiniophila inhibits human osteosarcoma xenograft tumor growth in vivo. AB - In the present study, we isolated and purified one polysaccharide (TRP) from Trametes robiniophila, which had a backbone of 1,3,6- and 1,4-linked glucpyranosyl moieties, with 1-linked arabinofuranosyl and galactopyranosyl terminal at the O-3 position of 1,3,6-linked glucpyranosyl residues. TRP was further evaluated for its antitumor activity against xenografted U-2 OS osteosarcoma in BALB/c nude mice together with the possible mechanism of action. We found that oral administration of TRP significantly suppressed U-2 OS tumor growth in mice via the induction of apoptosis, as evidenced by the increased number of TUNEL-positive cells in tumor tissues. Moreover, TRP administration increased the levels of the proapoptotic Bax protein and decreased the level of the antiapoptotic Bcl-2 protein, thus resulting in a rise of Bax/Bcl-2 ratio. Furthermore, the protein expression of caspase-9, caspase-3 and cleaved PARP became evident in tumor tissues from mice following TRP treatment, but caspase-8 keep unchanged. Besides, overexpression of metadherin (MTDH) was attenuated in tumor tissues of TRP-fed mice. Taken together, these findings suggest that the TRP-induced apoptosis of tumor tissues is through a mitochondria-mediated intrinsic apoptotic pathway. PMID- 25839807 TI - Effect of acid hydrolysis on regenerated kenaf core membrane produced using aqueous alkaline-urea systems. AB - Bleached kenaf core pulps (BKC) were hydrolyzed in H2SO4 (0.5M) at different time (0min to 90min) at room temperature. After the hydrolysis process, the viscosity average molecular weight (Mn) for BKC sample has reduced from 14.5*10(4) to 2.55*10(4). The hydrolyzed BKC was then dissolved in NaOH:urea:water and in LiOH:urea:water mixed solvent at the ratio of 7:12:81 and 4.6:15:80.4, respectively. The increased in hydrolysis time has decreased Mn of cellulose leading to easy dissolution process. Higher porosity and transparency with lower crystallinity index (CrI) of regenerated membrane produced can be achieved as the Mn reduced. The properties of membrane were observed through FESEM, UV-vis spectrophotometer and XRD. This study has proven that acid hydrolysis has reduced the Mn of cellulose, thus, enhanced the properties of regenerated membrane produced with assisted by alkaline/urea system. PMID- 25839808 TI - Encapsulation of vitamin E: effect of physicochemical properties of wall material on retention and stability. AB - Spray drying technique was used to fabricate Vitamin E loaded nanocapsules using Octenyl Succinic Anhydride (OSA) modified starches as emulsifiers and wall materials. Several physicochemical properties of modified starches that are expected to influence emulsification capacity, retention and storage stability of Vitamin E in nanocapsules were investigated. High Degree of Substitution (DS), low Molecular Weight (Mw) and low interfacial tension improved emulsification properties while Oxygen Permeability (OP) and Water Vapor Permeability (WVP) affected the film forming properties. The degradation profile of Vitamin E fitted well with the Weibull model. Nanocapsules from OSA modified starches MS-A and MS B retained around 50% of Vitamin E after a period of 60 days at 4-35 degrees C. Reduced retention and short half-life (35 days) in nanocapsules fabricated using MS-C at 35 degrees C were attributed to autoxidation reaction occurred due to poor film forming capacity. These results indicated that low molecular weights OSA modified starches were effective at forming stable Vitamin E nanocapsules that could be used in drug and beverage applications. PMID- 25839809 TI - Effect of crystallinity and plasticizer on mechanical properties and tissue integration of starch-based materials from two botanical origins. AB - The application of starch-based materials for biomedical purposes has attracted significant interest due to their biocompatibility. The physical properties and crystal structure of materials based on potato starch (PS) and amylomaize starch (AMS) were studied under physiological conditions. PS plasticized with 20% glycerol presented the best mechanical properties with an elastic modulus of 1.6MPa and a weak swelling, remaining stable for 30 days. The in vitro cell viability of 3T3 cells after contact with extracts from PS and AMS with 20% glycerol is 72% and 80%, respectively. PS presented good tissue integration and no significant inflammation or foreign body response after 30 days intra-muscular implantation in a rat model, contrary to AMS. It was shown that glycerol plasticization favors a fast B-type crystallization of PS materials, enhancing their mechanical strength and durability, and making them a good candidate for bioresorbable and biocompatible materials for implantable medical devices. PMID- 25839810 TI - In silico properties characterization of water-soluble gamma-cyclodextrin bi capped C60 complex: free energy and geometrical insights for stability and solubility. AB - Cyclodextrin-related host-guest encapsulation is pivotal to modulate the solubility of C60, thereby promoting its potential therapeutic applications. Here we present a computational study on gamma-cyclodextrin bi-capped C60 complex, probing characteristics for all the possible stoichiometry in aqueous solution. The potential of mean force (PMF) delineating the association process was computed, while the geometrical features of corresponding thermodynamically favored stoichiometry are captured by molecular dynamics simulations, which provides insightful explanations to previous experimental and computational results. PMF partitioning indicates that intermolecular van der Waals dispersion forces are essential for molecular recognition and self-assembly, and the hydrogen-bonding interactions play a key role in dissolving the complex in water. PMID- 25839811 TI - Carbohydrate composition of peach palm (Bactris gasipaes Kunth) by-products flours. AB - The flours obtained from peach palm by-products are rich in dietary fiber (62 71%) and they can be used as food ingredients. The aim of this work was to investigate the carbohydrate composition of the flours processed from the residual parts (stem and median sheath) of a hearts-of-palm industry. The flours were fractionated, based on their solubility, whose monomeric compounds were determined. The fraction containing mostly cellulose (S5) was the most abundant (26-28%), followed by the sum of fractions (S2, 53, S4) extracted with alkaline solutions (21-22%). The S1 fraction contained the highest percentage of uronic acids, which characterizes the presence of pectin. Xylose and arabinose were found in high proportion in S2 and S3 fractions. The S4 and S5 fractions, rich in glucose, were the main portion of the cell wall material and correspond to the insoluble fraction of the dietary fiber. PMID- 25839812 TI - An evaluation system for characterization of polysaccharides from the fruiting body of Hericium erinaceus and identification of its commercial product. AB - An evaluation system including colorimetric assay with iodine and potassium iodide, HPSEC-MALLS-RID analysis, GC-MS analysis, and saccharide mapping based on PACE analysis was proposed for the identification and discrimination of commercial product of Hericium erinaceus based on the chemical characters of polysaccharides in H. erinaceus fruiting body collected from different regions of China. The results showed that the molecular weights, the compositional monosaccharides and the glycosidic linkages of polysaccharides in H. erinaceus collected from different regions of China were similar, respectively. However, polysaccharides in the widely consumed product of H. erinaceus in China were significantly different from those of H. erinaceus fruiting body. The implications from these results were found to be beneficial to improve the quality control of polysaccharides from the H. erinaceus fruiting body, and suggest that the proposed evaluation system could be used as a routine approach for the quality control of polysaccharides in other edible and medicinal mushrooms. PMID- 25839813 TI - Purified polysaccharides of Geoffroea spinosa barks have anticoagulant and antithrombotic activities devoid of hemorrhagic risks. AB - Polysaccharides were extracted from the barks of Geoffroea spinosa, purified using anion exchange chromatography and characterized by chemical and methylation analysis, complemented by infrared and NMR spectroscopies. These polysaccharides were tested for their anticoagulant, antithrombotic and antiplatelet activities and also for their effects on bleeding. Unfractionated polysaccharide contains low levels of protein and high levels of carbohydrate (including hexuronic acid). The purified polysaccharides (fractions FII and FIII) are composed of arabinose (Ara), rhamnose (Rha), hexuronic acid, small amounts of galactose, but no sulfate ester. They have highly complex structure, which was partially characterized. NMR and methylation analysis indicate that the polysaccharides have a core of alpha Rhap and branches of 5-linked alpha-Araf. Residues of 4-linked alpha-GalpA are also found in the structure. The unfractionated (TPL) and fraction FIII, but not fractions FI and FII, prolonged the activated partial thromboplastin time (aPTT). TPL, FII and FIII inhibited the platelet aggregation induced by ADP. More significantly, both unfractionated and purified fractions exhibited potent antithrombotic effect (31-60%) and the fractions did not modify the bleeding tendency. These plant polysaccharides could be alternative source of new anticoagulant, antiplatelet and antithrombotic compounds devoid of the undesirable risk of hemorrhage. PMID- 25839814 TI - Rheological and kinetic study of the ultrasonic degradation of xanthan gum in aqueous solution: effects of pyruvate group. AB - The influence of the pyruvate group on the efficiency of ultrasonic degradation of xanthan gum in aqueous solution has been studied. Blends of natural and pyruvate-free xanthan gums were ultrasonicated at 20 degrees C for up to 30min and evaluated for molecular-weight degradation by viscometry. Solutions of pure pyruvate-free xanthan exhibited the highest stability to degradation among all blend ratios studied. Removing the pyruvate group is believed to enable the molecular chains to adopt a more compact conformation, which renders the polymer less susceptible to ultrasonication. In addition, the effects of salt on ultrasonic degradation efficiency were studied by using 0.1, 10(-2), or 10(-4)M of NaCl or Na2SO4 in solution prior to ultrasonication. A degradation kinetics model was developed to quantify the degradation behavior. The absence of pyruvate groups renders the xanthan gum less sensitive to the influence of salt, and hence decreases the ultrasonic degradation efficiency. PMID- 25839815 TI - Electrical, structural, thermal and electrochemical properties of corn starch based biopolymer electrolytes. AB - Biopolymer electrolytes containing corn starch, lithium hexafluorophosphate (LiPF6) and ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate (BmImPF6) are prepared by solution casting technique. Temperature dependence ionic conductivity studies reveal Vogel-Tamman-Fulcher (VTF) relationship which is associated with free volume theory. Ionic liquid-based biopolymer electrolytes show lower glass transition temperature (Tg) than ionic liquid-free biopolymer electrolyte. X-ray diffraction (XRD) studies demonstrate higher amorphous region of ionic liquid-added biopolymer electrolytes. In addition, the potential stability window of the biopolymer electrolyte becomes wider and stable up to 2.9V. Conclusively, the fabricated electric double layer capacitor (EDLC) shows improved electrochemical performance upon addition of ionic liquid into the biopolymer electrolyte. The specific capacitance of EDLC based on ionic liquid added polymer electrolyte is relatively higher than that of ionic liquid-free polymer electrolyte as depicted in cyclic voltammogram. PMID- 25839816 TI - Production of cationic xylan-METAC copolymer as a flocculant for textile industry. AB - Xylan is a part of hemicelluloses of woody materials and can be converted to value-added products such as flocculants for the textile industry. To assess the production of flocculants from hemicelluloses of woody materials, xylan was selected as a model and rendered cationic via copolymerization. In this study, the copolymerization reaction of xylan and [2-(methacryloyloxy) ethyl] trimethylammonium chloride (METAC) was optimized. The optimum parameters were 3mol/mol METAC/xylose, 3h reaction time, 80 degrees C reaction temperature, pH 7 and 25g/L xylan concentration. The copolymer was characterized by a charge density analyzer, viscometer, gel permeation chromatography (GPC), light scattering instrument, Fourier transform infrared spectroscopy (FTIR) and an elemental analyzer. The application of the cationic xylan copolymer as a flocculant to decolorize the simulated reactive orange 16 azo-dye wastewater was evaluated. The results confirmed that, by having 160mg/L xylan-METAC concentration in the dye solution with the concentration of 100mg/L, 97.8% of dye could be removed. PMID- 25839817 TI - Effect of modified starch and nanoclay particles on biodegradability and mechanical properties of cross-linked poly lactic acid. AB - Mechanical properties and biodegradation of cross-linked poly(lactic acid) (PLA)/maleated thermoplastic starch (MTPS)/montmorillonite (MMT) nanocomposite were studied. Crosslinking was carried out by adding di-cumyl peroxide (DCP) in the presence of triallyl isocyanurate (TAIC) as coagent. At first, MTPS was prepared by grafting maleic anhydride (MA) to thermoplastic starch in internal mixer. Experimental design was performed by using Box-Behnken method at three variables: MTPS, nanoclay and TAIC at three levels. Results showed that increasing TAIC amount substantially increased the gel fraction, enhanced tensile strength, and caused a decrease in elongation at break. Biodegradation was prevented by increasing TAIC amount in nanocomposite. Increasing MTPS amount caused a slight increase in gel fraction and decreased the tensile strength of nanocomposite. Also, MTPS could increase the elongation at break of nanocomposite and improve the biodegradation. Nanoclay had no effect on the gel fraction, but it improved tensile strength. PMID- 25839818 TI - Preparation and characterization of carboxymethyl starch microgel with different crosslinking densities. AB - Microgels synthesized with different crosslinking densities were characterized by Fourier transform infrared (FT-IR) spectroscopy, thermogravimetry analysis (TGA), swelling, and rheological analyses. The lysozyme uptake capacity of these microgels was evaluated through the effects of lysozyme concentration, pH, and ionic strength. The microgel particle size mostly ranged within 25MUm to 45MUm. FT-IR analysis results suggested that sodium trimetaphosphate reacted with the hydroxyl groups of carboxymethyl starch (CMS), thereby forming ester linkages. TGA data indicated that crosslinking increased the thermal stability of CMS. Swelling degree increased with increasing pH before pH 5, and then remained almost constant. However, swelling degree decreased with increasing ionic strength and crosslinking density. The microgels behaved as viscoelastic solids because the storage modulus was higher than the loss modulus over the entire frequency range of dispersions with polymer concentrations of 3% (W/W) at 25 degrees C. The data for the uptake of lysozyme by microgels demonstrated that the protein uptake increased with increasing pH and lysozyme concentration, as well as with decreasing ionic strength and crosslinking density. The lysozyme microgels complex was identified by CLSM, and the distribution of lysozyme in microgels with low crosslinking density was rather homogeneous. PMID- 25839819 TI - Inter-laboratory evaluation of SEC-post-column calcofluor for determination of the weight-average molar mass of cereal beta-glucan. AB - Even though size exclusion chromatography (SEC) with post column addition of calcofluor (SEC-calcofluor) has been used for the determination of cereal beta glucan molar mass in foods for many years, there is a lack of systematic evaluation of the method. To address this issue a set of suitable beta-glucan standards were generated by preparative SEC and their molar mass characteristics were determined by analytical multi-detection SEC (refractive index (RI), light scattering). Each standard was then analysed by SEC-calcofluor at three different labs. As a direct comparison, the analyses were repeated with a RI detector. For SEC-calcofluor accurate measurements of weight average molar mass (Mw) can be made for beta-glucan populations within 10-500*10(3)g/mol. Above this molar mass threshold there is an increasing tendency for underestimation of Mw. Precipitation of some beta-glucan-calcofluor complexes may have delayed their transport into the detector. PMID- 25839820 TI - Structural features of dilute acid, steam exploded, and alkali pretreated mustard stalk and their impact on enzymatic hydrolysis. AB - To overcome the recalcitrant nature of biomass several pretreatment methodologies have been explored to make it amenable to enzymatic hydrolysis. These methodologies alter cell wall structure primarily by removing/altering hemicelluloses and lignin. In this work, alkali, dilute acid, steam explosion pretreatment are systematically studied for mustard stalk. To assess the structural variability after pretreatment, chemical analysis, surface area, crystallinity index, accessibility of cellulose, FT-IR and thermal analysis are conducted. Although the extent of enzymatic hydrolysis varies upon the methodologies used, nevertheless, cellulose conversion increases from <10% to 81% after pretreatment. Glucose yield at 2 and 72h are well correlated with surface area and maximum adsorption capacity. However, no such relationship is observed for xylose yield. Mass balance of the process is also studied. Dilute acid pretreatment is the best methodology in terms of maximum sugar yield at lower enzyme loading. PMID- 25839821 TI - Separation of monodisperse alginate nanoparticles and effect of particle size on transport of vitamin E. AB - Four batches of oleoyl alginate ester (OAE) nanoparticles with narrow size distribution were rapidly separated from the initial batch of nanoparticles by means of centrifugation at the relative centrifugal force (RCF) between 270*g and 6750*g after adjusting the zeta potential. The size of nanoparticles decreased with increasing speed of centrifugation, and the polydispersity of nanoparticles significantly decreased. As particle size increased the loading capacity also increased, while transport across Caco-2 cells and the cellular uptake of nanoparticles in jejunum decreased. Endocytosis of nanoparticles around 50nm/120nm, 420nm and 730nm occur mainly via clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis respectively. These results show that centrifugation could separate nanoparticles with appropriate zeta potential into different sizes and the transport and cellular uptake of OAE polysaccharide nanoparticles were size dependent. PMID- 25839822 TI - Performance evaluation of pectin as ecofriendly corrosion inhibitor for X60 pipeline steel in acid medium: experimental and theoretical approaches. AB - The corrosion inhibition effect of pectin (a biopolymer) for X60 pipeline steel in HCl medium was investigated using weight loss, electrochemical, water contact angle measurements, and scanning electron microscopy techniques. The results obtained show that pectin acts as a good corrosion inhibitor for X60 steel. Inhibition efficiency increased with increase in pectin concentration and temperature. Potentiodynamic polarization results reveal that pectin could be classified as a mixed-type corrosion inhibitor with predominant control of the cathodic reaction. The effective corrosion inhibition potential of pectin could be related to the adsorption of pectin molecules at the metal/solution interface which is found to accord with the Langmuir adsorption isotherm model and a protective film formation. Quantum chemical calculations provided insights into the active sites and reactivity parameters governing pectin activity as a good corrosion inhibitor for X60 steel. PMID- 25839823 TI - Dextrans produced by lactic acid bacteria exhibit antiviral and immunomodulatory activity against salmonid viruses. AB - Viral infections in the aquaculture of salmonids can lead to high mortality and substantial economic losses. Thus, there is industrial interest in new molecules active against these viruses. Here we describe the production, purification, and the physicochemical and structural characterization of high molecular weight dextrans synthesized by Lactobacillus sakei MN1 and Leuconostoc mesenteroides RTF10. The purified dextrans, and commercial dextrans with molecular weights ranging from 10 to 2000kDa, were assayed in infected BF-2 and EPC fish cell-line monolayers for antiviral activity. Only T2000 and dextrans from MN1 and RTF10 had significant antiviral activity. This was similar to results obtained against infectious pancreatic necrosis virus. However the dextran from MN1 showed ten fold higher activity against hematopoietic necrosis virus than T2000. In vivo assays using the MN1 polymer confirmed the in vitro results and revealed immunomodulatory activity. These results together with the high levels of dextran production (2gL(-1)) by Lb. sakei MN1, indicate the compounds potential utility as an antiviral agent in aquaculture. PMID- 25839824 TI - Preparation of cross-linked maize (Zea mays L.) starch in different reaction media. AB - Granular normal maize starch was reacted with sodium trimetaphosphate in deionized water ( [Formula: see text] ), aqueous sodium sulfate solution ( [Formula: see text] ), aqueous ethanol (MSethanol) or aqueous acetone (MSacetone) under otherwise identical reaction conditions. Analysis of the resultant starches by Rapid Visco Analysis (RVA) showed that the starch was cross-linked to a higher degree in aqueous ethanol or aqueous acetone than in water or sodium sulfate solution, and with minimal starch leaching. While MSacetone and MSethanol had incorporated similar levels of phosphorous, RVA analysis and microscopic analysis showed that MSacetone granules were more effectively stabilized by cross-linking than MSethanol granules. Cross-linking in aqueous acetone is believed to either contain the greater numbers of distarch monophosphate (versus monostarch monophosphate), or occur more intensively at the granule outer layers than that in aqueous ethanol and, at the same time, to account for the greater granular strength of MSethanol than that of MSacetone. PMID- 25839825 TI - Solid acid catalysts pretreatment and enzymatic hydrolysis of macroalgae cellulosic residue for the production of bioethanol. AB - The aim of this study is to investigate the technical feasibility of converting macroalgae cellulosic residue (MCR) into bioethanol. An attempt was made to present a novel, environmental friendly and economical pretreatment process that enhances enzymatic conversion of MCR to sugars using Dowex (TM) Dr-G8 as catalyst. The optimum yield of glucose reached 99.8% under the optimal condition for solid acid pretreatment (10%, w/v biomass loading, 4%, w/v catalyst loading, 30min, 120 degrees C) followed by enzymatic hydrolysis (45FPU/g of cellulase, 52CBU/g of beta-glucosidase, 50 degrees C, pH 4.8, 30h). The yield of sugar obtained was found more superior than conventional pretreatment process using H2SO4 and NaOH. Biomass loading for the subsequent simultaneous saccharification and fermentation (SSF) of the pretreated MCR was then optimized, giving an optimum bioethanol yield of 81.5%. The catalyst was separated and reused for six times, with only a slight drop in glucose yield. PMID- 25839826 TI - Modifications of Saccharomyces pastorianus cell wall polysaccharides with brewing process. AB - The cell wall polysaccharides of brewers spent yeast Saccharomyces pastorianus (BSY) and the inoculum yeast (IY) were studied in order to understand the changes induced by the brewing process. The hot water and alkali extractions performed solubilized mainly mannoproteins, more branched for BSY than those of IY. Also, (31)P solid state NMR showed that the BSY mannoproteins were 3 times more phosphorylated. By electron microscopy it was observed that the final residues of alkali sequential extraction until 4M KOH preserved the yeast three-dimensional structure. The final residues, composed mainly by glucans (92%), showed that the BSY, when compared with IY, contained higher amount of (1->4)-linked Glc (43% for BSY and 16% for IY) and lower (1->3)-linked Glc (17% for BSY and 42% for IY). The enzymatic treatment of final residue showed that both BSY and IY had (alpha1->4) linked Glc and (beta1->4)-linked Glc, in a 2:1 ratio, showing that S. pastorianus increases their cellulose-like linkages with the brewing process. PMID- 25839827 TI - Effect of calcium on solution and conformational characteristics of polysaccharide from seeds of Plantago asiatica L. AB - Polysaccharide from seeds of Plantago asiatica L. is rich in calcium, which is important for keeping viscous and weak gelling properties of the polysaccharide. However, few studies reported effect of calcium on solution and conformational characteristics of the polysaccharide. In this study, polysaccharide was prepared from seeds of P. asiatica L. and named as PLCP. PLCP was treated with EDTA to remove calcium ion to get PLCP-E. PLCP and PLCP-E were characterized by Ubbelohde capillary viscometer, light scattering and HPSEC with refractive index, light scattering and viscometric detectors. The results showed that PLCP had much higher intrinsic viscosity, hydrodynamic radius (Rh), radius of gyration (Rg) and molecular weight than that of PLCP-E when measured in the same solvent. PLCP and PLCP-E were in random coil conformation in aqueous solutions according to light scattering and HPSEC measurements. HPSEC data showed PLCP-E had lower intrinsic viscosity than that of PLCP with the same molecular weight. Persistence length of Lp was 2.5nm for PLCP and 2.3nm for PLCP-E, respectively. In conclusion, PLCP exhibited higher intrinsic viscosity and molecular weight, and stiffer conformation than that of PLCP-E, which could explain the reason of higher viscosity of PLCP. PMID- 25839828 TI - Development of wheat gluten/nanocellulose/titanium dioxide nanocomposites for active food packaging. AB - Bionanocomposites were developed by casting/evaporation of wheat gluten (WG), cellulose nanocrystals (CNC), and TiO2 nanoparticles. The effect of addition of different percentages of CNC, and TiO2 on tensile strength (TS), Young's modulus and water sensitivity was studied. A significant improvement in the studied properties is observed when 7.5% CNC and 0.6% TiO2 is added to WG. WG/CNC 7.5%/0.6% TiO2 blend suspension was chosen to coat commercial packaging unbleached kraft paper sheets via 1, 2 and 3 coating layers. A significant enhancement of 56% and 53% in breaking length and burst index, respectively, was achieved for 3 layers coated paper. The antimicrobial activity of the coated papers, against Saccharomyces cervisiae, Gram-negative bacteria Escherichia coli and Gram-positive bacteria Staphylococcus aureus, was investigated and expressed in terms of reduction % of surviving number (CFU) of the tested organisms. More than 98.5% reduction in CFU was observed against the organisms compared to TiO2 free coated paper. PMID- 25839829 TI - The marine bacteria Cobetia marina DSMZ 4741 synthesizes an unexpected K-antigen like exopolysaccharide. AB - We have studied the exopolysaccharide produced by Cobetia marina DSMZ 4741, a marine bacterium isolated from coastal seawater. This strain is able to produce a polysaccharide in presence of carbon sources as glucose, mannitol and alginate. The maximum production occurs in aerobic condition, during the end of the exponential phase. The polymer is a non-viscous, acidic heteropolysaccharide of 270kDa constituted of a repeating unit of: This kind of chemical structure is generally related to K-antigen polysaccharide of pathogenic Escherichia coli strains. This is the first time this type of EPS is described from a marine bacterium. Moreover the polysaccharide exhibits a pyruvate substitution on its 3 deoxy-d-manno-oct-2-ulosonic acid (KDO) residue never encountered before. The discovery of such an unexpected EPS with high biotechnological potential is a new incentive for a better exploration of bioactive marine resources. PMID- 25839830 TI - Colloidal Nanoparticle Interaction Transition during Solvent Evaporation Investigated by in-Situ Small-Angle X-ray Scattering. AB - In-situ scanning small-angle X-ray scattering (SAXS) experiments have been performed to probe the drying of a single suspended droplet of silica colloids. It has been demonstrated that the formation of a nanoparticle shell during drying can be confirmed just by measuring the temporal evolution of the spatial transmission profile across the drying droplet. The shrinkage of the droplet stops once the shell is formed. The temporal dependence of the shell thickness and droplet radius has been estimated by quantitative analysis of the functionality of the transmission profiles. It is revealed that the position of the correlation peak originating from interactions between silica nanoparticles evolves linearly during the initial stage of drying and exhibits sigmoidal growth behavior in later stages. The interaction between colloidal particles in different drying stages has been investigated. We provide experimental confirmation of the transition from repulsive interaction to a capillary-driven short-range attraction during shell formation. The present work demonstrates that in-situ scanning SAXS on a suspended droplet is an invaluable technique for monitoring the dynamic self-organization of colloids as it probes the drying of complex fluids without the interference of a substrate. PMID- 25839832 TI - Integrated experimental investigation and mathematical modeling of brackish water desalination and wastewater treatment in microbial desalination cells. AB - Desalination of brackish water can provide freshwater for potable use or non potable applications such as agricultural irrigation. Brackish water desalination is especially attractive to microbial desalination cells (MDCs) because of its low salinity, but this has not been well studied before. Herein, three brackish waters prepared according to the compositions of actual brackish water in three locations in Israel were examined with domestic wastewater as an electron source in a bench-scale MDC. All three brackish waters could be effectively desalinated with simultaneous wastewater treatment. The MDC achieved the highest salt removal rate of 1.2 g L(-1) d(-1) with an initial salinity of 5.9 g L(-1) and a hydraulic retention time (HRT) of 0.8 d. The desalinated brackish water could meet the irrigation standard of both salinity (450 mg L(-1) TDS) and the concentrations of major ionic species, given a sufficient HRT. The MDC also accomplished nearly 70% removal of organic compounds in wastewater with Coulombic efficiency varied between 5 and 10%. A previously developed MDC model was improved for brackish water desalination, and could well predict salinity variation and the concentrations of individual ions. The model also simulated a staged operation mode with improved desalination performance. This integrated experiment and mathematical modeling approach provides an effective method to understand the key factors in brackish water desalination by MDCs towards further system development. PMID- 25839831 TI - SubspaceEM: A fast maximum-a-posteriori algorithm for cryo-EM single particle reconstruction. AB - Single particle reconstruction methods based on the maximum-likelihood principle and the expectation-maximization (E-M) algorithm are popular because of their ability to produce high resolution structures. However, these algorithms are computationally very expensive, requiring a network of computational servers. To overcome this computational bottleneck, we propose a new mathematical framework for accelerating maximum-likelihood reconstructions. The speedup is by orders of magnitude and the proposed algorithm produces similar quality reconstructions compared to the standard maximum-likelihood formulation. Our approach uses subspace approximations of the cryo-electron microscopy (cryo-EM) data and projection images, greatly reducing the number of image transformations and comparisons that are computed. Experiments using simulated and actual cryo-EM data show that speedup in overall execution time compared to traditional maximum likelihood reconstruction reaches factors of over 300. PMID- 25839833 TI - The specific reactive surface area of granular zero-valent iron in metal contaminant removal: Column experiments and modelling. AB - A series of dynamic-flow kinetic experiments were conducted to assess the removal rates of aqueous Cu(2+) and Zn(2+) ions by zero-valent iron (ZVI), a promising material for inclusion in cold-climate remediation applications. The influence of experimental parameters on contaminant removal rates, including aqueous flow rate, operating temperature, and the concentrations of ZVI, salt and dissolved oxygen, was investigated. A mass transport model has been developed that accounts (i) aqueous-phase dispersion processes, (ii) film diffusion of contaminant ions to the reactive ZVI surface and (iii) the reactive removal mechanism itself. Regression to the experimental data indicated that when oxygen is present in the solution feed Cu(2+) and Zn(2+) removal processes were limited by film diffusion. In de-aerated solutions film diffusion still controls Cu(2+) removal but a first order surface reaction provides a better model for Zn(2+) kinetics. Using air as the equilibrium feed gas, the reactive proportion of the total surface area for contaminant removal was calculated to be 97% and 64% of the active spherically assumed geometric area associated with ZVI media for Cu(2+) and Zn(2+), respectively. Relative to a gas absorption area, determined in previous studies, the reactive proportion is less than 0.41% of the unreacted ZVI total surface area. These findings suggest that only part of the iron oxyhydroxide surface is reacting during ZVI based metal contaminant removal. PMID- 25839834 TI - Life cycle assessment of urban wastewater systems: Quantifying the relative contribution of sewer systems. AB - This study aims to propose a holistic, life cycle assessment (LCA) of urban wastewater systems (UWS) based on a comprehensive inventory including detailed construction and operation of sewer systems and wastewater treatment plants (WWTPs). For the first time, the inventory of sewers infrastructure construction includes piping materials and aggregates, manholes, connections, civil works and road rehabilitation. The operation stage comprises energy consumption in pumping stations together with air emissions of methane and hydrogen sulphide, and water emissions from sewer leaks. Using a real case study, this LCA aims to quantify the contributions of sewer systems to the total environmental impacts of the UWS. The results show that the construction of sewer infrastructures has an environmental impact (on half of the 18 studied impact categories) larger than both the construction and operation of the WWTP. This study highlights the importance of including the construction and operation of sewer systems in the environmental assessment of centralised versus decentralised options for UWS. PMID- 25839835 TI - Computational treatment of metalloproteins. AB - Metalloproteins present a considerable challenge for modeling, especially when the starting point is far from thermodynamic equilibrium. Examples include formidable problems such as metalloprotein folding and structure prediction upon metal addition, removal, or even just replacement; metalloenzyme design, where stabilization of a transition state of the catalyzed reaction in the specific binding pocket around the metal needs to be achieved; docking to metal-containing sites and design of metalloenzyme inhibitors. Even more conservative computations, such as elucidations of the mechanisms and energetics of the reaction catalyzed by natural metalloenzymes, are often nontrivial. The reason is the vast span of time and length scales over which these proteins operate, and thus the resultant difficulties in estimating their energies and free energies. It is required to perform extensive sampling, properly treat the electronic structure of the bound metal or metals, and seamlessly merge the required techniques to assess energies and entropies, or their changes, for the entire system. Additionally, the machinery needs to be computationally affordable. Although a great advancement has been made over the years, including some of the seminal works resulting in the 2013 Nobel Prize in chemistry, many aforementioned exciting applications remain far from reach. We review the methodology on the forefront of the field, including several promising methods developed in our lab that bring us closer to the desired modern goals. We further highlight their performance by a few examples of applications. PMID- 25839836 TI - Vortex imaging: new information gain from tracking cardiac energy loss. PMID- 25839837 TI - Functional studies of transcription factors involved in plant defenses in the genomics era. AB - Plant transcription factors (TFs) play roles in diverse biological processes including defense responses to pathogens. Here, we provide an overview of recent studies of plant TFs with regard to defense responses. TFs play roles in plant innate immunity by regulating genes related to pathogen-associated molecular pattern-triggered immunity, effector-triggered immunity, hormone signaling pathways and phytoalexin synthesis. Currently, genome-wide phylogenetic and transcriptomic analyses are as important as functional analyses in the study of plant TFs. The integration of genomics information with the knowledge obtained from functional studies provides new insights into the regulation of plant defense mechanisms as well as engineering crops with improved resistance to invading pathogens. PMID- 25839838 TI - The V Sign: Tenting of the Globe From a Vascular Malformation. PMID- 25839839 TI - Thin-film freeze-drying for lyophilization of vaccines. PMID- 25839840 TI - Editorial. PMID- 25839841 TI - Microcirculation in the foot is augmented by neuromuscular stimulation via the common peroneal nerve in different lower limb postures: a potential treatment for leg ulcers. AB - AIM: Aim of the study was to examine the effects of the gekoTM device (a portable electical nerve stimulator) on microcirculatory flow on the dorsum of the foot, and whether this is influenced by lower limb postures and application of a plaster cast. METHODS: This was a cross-sectional, healthy cohort, open label, physiological response study. In 10 healthy volunteers, aged 19 to 24 years, laser Doppler fluxmetry measurements were made on the dorsum of the foot in four postures: standing (weight bearing and non-weight bearing) and supine lying (with the lower limb horizontal and then elevated). Measurements of flux were made both at rest and during stimulation with the gekoTM device applied over the common peroneal nerve, at 1 Hz for 5 minutes in each posture. Repeat measurement were made after the application of a below knee plaster cast. Measures of flux were compared to basal levels assumed to be in supine with limb horizontal, with no cast and an inactive gekoTM device. RESULTS: The gekoTM device was effective in increasing microcirculation on the dorsum of the foot in all four postures (mean difference =141%, 95% CI 70%-212%, P=0.001). This effect was more pronounced than that of using a plaster alone (Mean increase in flux of 73%, 95% CI 22%-125%, P=0.01) or variances due to the hydrostatic effects of different postures (mean difference 17-27.6%, P>0.05). There was a 2 to 3 fold increase in flux when stimulation was delivered in combination with the plaster cast. CONCLUSION: Stimulation using the gekoTM device augments microcirculation in the foot. The response is greater in lying and non-weight bearing than weight bearing standing but the most striking effect is when stimulation is combined with a plaster cast. The gekoTM offers a potential means of promoting conditions favourable for wound healing, where treatment using compression may be contraindicated, such as arterial/mixed aetiology ulcers. PMID- 25839842 TI - New genetic variants of influenza A(H1N1)pdm09 detected in Cuba during 2011-2013. AB - Influenza A(H1N1)pdm09 virus has evolved continually since its emergence in 2009. For influenza virus strains, genetic changes occurring in HA1 domain of the hemagglutinin cause the emergence of new variants. The aim of our study is to establish genetic associations between 35 A(H1N1)pdm09 viruses circulating in Cuba in 2011-2012 and 2012-2013 seasons, and A/California/07/2009 strain recommended by WHO as the H1N1 component of the influenza vaccine. The phylogenetic analysis revealed the circulation of clades 3, 6A, 6B, 6C and 7. Mutations were detected in the antigenic site or in the receptor-binding domains of HA1 segment, including S174P, S179N, K180Q, S202T, S220T and R222K. Substitutions S174P, S179N, K180Q and R222K were detected in Cuban strains for the first time. PMID- 25839866 TI - International normalized ratio monitoring of vitamin K antagonist therapy: comparative performance of point-of-care and laboratory-derived testing. AB - The monitoring of warfarin therapy using the international normalized ratio (INR) has now moved outside the laboratory's control by use of point-of-care (POC) devices. Although this provides patients with the convenience of immediate results and clinical assessment, POC-INRs are often performed by nonlaboratory staff with little experience in quality control. The Royal College of Pathologists of Australasia Quality Assurance Program (RCPAQAP) Haematology has devised a POC-INR external quality assessment (EQA) program that is suitable for both laboratory and nonlaboratory operators (e.g., nurses) to perform INR testing with good accuracy and precision. A comparison of the performance of the POC versus the laboratory-derived INR testing over the past 8 years has shown that the variation in test results (expressed as coefficient of variation; CV) for laboratory INRs increases with more prolonged INR values, whereas CVs for the POC INR testing were generally lower, with a reduced dependency on INR values. In our program, the CoaguChek XS (Roche, Basel, Switzerland) showed the best performance among the POC devices. A comparative assessment with other EQA providers showed agreement and disparity with our data in terms of comparative CVs obtained between the laboratory and POC-INRs. The growth of the RCPAQAP POC-INR program from 29 to 360 in the past 12 years highlights the importance of providing suitable EQA for POC-INR staff who are unfamiliar with laboratory practice. This helps maintaining consistent results, which have important implications for the therapeutic management of patients on vitamin K antagonist therapy. PMID- 25839867 TI - Quality and safety issues of direct oral anticoagulants in the emergency department. AB - The direct oral anticoagulants (DOACs) are increasingly used in patients with atrial fibrillation and venous thromboembolism. The decision making of clinicians and especially emergency physicians for the appropriate management of patients taking DOACs entails a thorough understanding of pharmacologic profile, practical guidance on their usage, and management of bleeding and/or thrombotic events. The available evidence suggests that the bleeding complications observed in patients taking DOACs are less frequent and potentially less severe than those in patients taking vitamin K antagonists or heparins. This should be regarded as an advantage for emergency physicians, since it would decrease the admission rate of anticoagulated patients and probably require a less aggressive treatment in the emergency department (ED). The greatest challenge of DOACs is so far represented by the lack of clinically usable antidotes, since these (i.e., idarucizumab, andexanet alfa, and aripazine) are in different phases of development. A second major concern is the current lack of consensus about laboratory monitoring for these drugs. Although there is widespread perception that patients on DOACs do not require dose adjustment based on laboratory testing, in some selected clinical situations, laboratory testing may be taken into consideration in the ED. The type of laboratory diagnostics needed for emergency management should hence include tests that are promptly available, affordable to all stat laboratories, and cost effective. The aim of this article is to provide a personal overview on quality and safety issues of DOACs with an ED perspective. PMID- 25839868 TI - Biological and analytical variations of 16 parameters related to coagulation screening tests and the activity of coagulation factors. AB - To accurately estimate longitudinal changes in individuals, it is important to take into consideration the biological variability of the measurement. The few studies available on the biological variations of coagulation parameters are mostly outdated. We confirmed the published results using modern, fully automated methods. Furthermore, we added data for additional coagulation parameters. At 8:00 am, 12:00 pm, and 4:00 pm on days 1, 3, and 5, venous blood was collected from 31 healthy volunteers. A total of 16 parameters related to coagulation screening tests as well as the activity of coagulation factors were analyzed; these included prothrombin time, fibrinogen (Fbg), activated partial thromboplastin time, thrombin time, international normalized ratio, prothrombin time activity, activated partial thromboplastin time ratio, fibrin(-ogen) degradation products, as well as the activity of factor II, factor V, factor VII, factor VIII, factor IX, and factor X. All intraindividual coefficients of variation (CVI) values for the parameters of the screening tests (except Fbg) were less than 5%. Conversely, the CVI values for the activity of coagulation factors were all greater than 5%. In addition, we calculated the reference change value to determine whether a significant difference exists between two test results from the same individual. PMID- 25839869 TI - Rapid evaluation of fibrinogen levels using the CG02N whole blood coagulation analyzer. AB - Rapid evaluation of fibrinogen (Fbg) levels is essential for maintaining homeostasis in patients with massive bleeding during severe trauma and major surgery. This study evaluated the accuracy of fibrinogen levels measured by the CG02N whole blood coagulation analyzer (A&T Corporation, Kanagawa, Japan) using heparinized blood drawn for blood gas analysis (whole blood-Fbg). A total of 100 matched pairs of heparinized blood samples and citrated blood samples were simultaneously collected from patients in the intensive care unit. Whole blood Fbg results were compared with those of citrated plasma (standard-Fbg). The whole blood coagulation analyzer measured fibrinogen levels within 2 minutes. Strong correlations between standard-Fbg and whole blood-Fbg were observed (rho = 0.91, p < 0.001). Error grid analysis showed that 88% of the values were clinically acceptable, and 12% were in a range with possible effects on clinical decision making; none were in a clinically dangerous range without appropriate treatment. Using a fibrinogen cutoff value of 1.5 g/L for standard-Fbg, the area under the receiver operating characteristic curve of whole blood-Fbg was 0.980 (95% confidence interval 0.951-1.000, p < 0.001). The whole blood coagulation analyzer can rapidly measure fibrinogen levels in heparinized blood and could be useful in critical care settings where excessive bleeding is a concern. PMID- 25839870 TI - International survey on D-dimer test reporting: a call for standardization. AB - D-dimer is the biochemical gold standard for diagnosing a variety of thrombotic disorders, but result reporting is heterogeneous in clinical laboratories. A specific five-item questionnaire was developed to gain a clear picture of the current standardization of D-dimer test results. The questionnaire was opened online (December 24, 2014-February 10, 2015) on the platform "Google Drive (Google Inc., Mountain View; CA)," and widely disseminated worldwide by newsletters and alerts. A total of 409 responses were obtained during the period of data capture, the largest of which were from Italy (136; 33%), Australia (55; 22%), Croatia (29; 7%), Serbia (26; 6%), and the United States (21; 5%). Most respondents belonged to laboratories in general hospitals (208; 51%), followed by laboratories in university hospitals (104; 26%), and the private sector (94; 23%). The majority of respondents (i.e., 246; 60%) indicated the use of fibrinogen equivalent unit for expressing D-dimer results, with significant heterogeneities across countries and health care settings. The highest prevalence of laboratories indicated they were using "ng/mL" (139; 34%), followed by "mg/L" (136; 33%), and "ug/L" (73; 18%), with significant heterogeneity across countries but not among different health care settings. Expectedly, the vast majority of laboratories (379; 93%) declared to be using a fixed cutoff rather than an age adjusted threshold, with no significant heterogeneity across countries and health care settings. The results of this survey attest that at least 28 different combinations of measurement units are currently used to report D-dimer results worldwide, and this evidence underscores the urgent need for more effective international joined efforts aimed to promote a worldwide standardization of D dimer results reporting. PMID- 25839871 TI - The influence of herbal medicine on platelet function and coagulation: a narrative review. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide. Platelet activation and aggregation play a central role in hemostasis and thrombosis. Herbal medicines have been traditionally used in the management of CVD and can play a role in modifying CVD progression, particularly in platelet function, and have the potential of altering platelet function tests, as well as some coagulation parameters. Herbal medicines, such as feverfew, garlic, ginger, ginseng, motherwort, St John's wort, and willow bark, were found to reduce platelet aggregation. In vitro studies show promise in the reduction of platelet aggregation for Andrographis, feverfew, garlic, ginger, Ginkgo, ginseng, hawthorn, horse chestnut, and turmeric. In addition, cranberry, danshen, dong quai, Ginkgo, ginseng, green tea, and St John's wort were found to have potential interactions with warfarin. Furthermore, St John's wort interacted with clopidogrel and danshen with aspirin. Therefore, repeat testing of platelet function and coagulation studies, particularly for patients on warfarin therapy, may be required after exclusion of herbal medicines that could have possibly affected initial test results. PMID- 25839872 TI - Complex caring. PMID- 25839873 TI - Recognising metastatic spinal cord compression. AB - Metastatic spinal cord compression (MSCC) is a potentially life changing oncological emergency. Neurological function and quality of life can be preserved if patients receive an early diagnosis and rapid access to acute interventions to prevent or reduce nerve damage. Symptoms include developing spinal pain, numbness or weakness in arms or legs, or unexplained changes in bladder and bowel function. Community nurses are well placed to pick up on the 'red flag' symptoms of MSCC and ensure patients access prompt, timely investigations to minimise damage. PMID- 25839874 TI - Safe and effective catheterisation for patients in the community. AB - Approximately 450 000 people use long-term urinary catheters in the UK. Permanent catheters are used by 3% of the community population and occupy an estimated 4% of a district nurse's caseload in the UK. Catheterisation is defined as 'drainage or aspiration of the bladder or urinary reservoir' and can be intermittent or indwelling. Long-term indwelling catheterisation can be transurethral or suprapubic via the anterior abdominal wall. This article will discuss the safe and effective use of different forms of catheterisation for patients in the community setting. PMID- 25839875 TI - Sample evaluation of caseload complexity in a community health-care NHS trust. AB - People diagnosed with a multiple long-term conditions and those with profound and multiple learning disabilities are the most intensive users of health and social care. In addition, around 30% of patients with long-term physical conditions also have a mental health problem. The close relationship between mental and physical health is reflected in the high frequency with which illnesses of both kinds overlap in an age of multi-morbidity. This study demonstrates that those with comorbid mental health problems show poorer clinical outcomes, lower quality of life and reduced ability to manage physical symptoms effectively. This also affects their capacity to engage in treatment and make decisions, which affects not only their care and treatment but ultimately their quality of life. The NHS Call to Action demanded improvement in the service provided to support the needs of people with long-term conditions. The scale of the impact of comorbid mental health problems on costs and outcomes suggests that developing services that respond more effectively to these needs should be a priority. PMID- 25839876 TI - Patient Online: putting patients in the driving seat of their care. PMID- 25839877 TI - Enhancing undergraduate community placements: a critical review of current literature. AB - In the face of the UK-wide policy shift to increased home care, inspiring and enabling the next generation of community nurses is more urgent than ever. The quality of the pre-registration practice learning experience is highly influential on career choices at the point of qualification. Given that 50% of learning by pre-registration students takes place in practice, mentors have a crucial role to play in preparing the next generation of nurses to work in the community. This article discusses the findings of a systematic and critical literature review of pre-registration placements that was funded by the Queen's Nursing Institute Scotland. The review found that students' experiences of learning in community settings are variable, and perceptions of students and mentors are misaligned in terms of what a quality placement should look like. Although there is no clear definition of what constitutes a community placement and there is some underuse of learning environments in areas such as general practice nursing, there are also a number of examples of new and imaginative placements. While these innovations provide 'whole experience' placements, they are currently lacking robust evaluation, despite their potential usefulness on a larger scale. Mentors have the opportunity to provide students with a range of learning opportunities that increase preparedness for working in the community, allowing final year students in particular greater influence over their learning experience. Students undertaking community practice learning, where they have a managed level of autonomy, are more likely to feel confident to take on community nursing roles. PMID- 25839878 TI - Mental and physical long-term conditions in the UK: spanning the boundaries. AB - The dual combination of a physical long-term condition coupled with mental health illness can increase the complexities of effective patient care. Greater integration of services spanning the health and social care spectrum have the potential to reduce fragmentation, enhance communications and ultimately support patient care. This short article discusses the reasons for this being a worthwhile philosophy and the case for change. PMID- 25839879 TI - Understanding the Code: upholding dignity. AB - The Nursing and Midwifery Council, the statutory professional regulator for registered district nurses, has introduced a revised code of standards that came into effect on 31 March 2015. The Code makes clear that while district nurses can interpret the values and principles for use in community settings, the standards are not negotiable or discretionary. They must be applied, otherwise the district nurse's fitness to practice will be called into question. In the second of a series of articles analysing the legal implications of the Code on district nurse practice, the author considers the first standard, which requires district nurses to treat people as individuals and to uphold their dignity. PMID- 25839880 TI - Recognising hypothyroidism in the community: what can nurses and patients do? AB - Aysha Mendes discusses underactive thyroid and dispels commonly held myths that it is not serious and cannot be prevented-health professionals can play a vital role in the diagnosis, support and treatment of this misunderstood condition. PMID- 25839881 TI - Using complementary therapies in palliative care. PMID- 25839882 TI - Dying at the right time. PMID- 25839883 TI - Haplotype distribution in the class I sirtuin genes and their associations with ultrasound carcass traits in Qinchuan cattle (Bos taurus). AB - Class I sirtuin genes including SIRT1, SIRT2 and SIRT3, are members of the nicotinamide adenine dinucleotide (NAD)-dependent family of histone deacetylases, and play essential roles in senescence, metabolism, and apoptosis. This study was conducted to detect potential polymorphisms of the bovine class I sirtuin genes and explore their relationships with ultrasound carcass traits in Qinchuan cattle. Four non-coding mutations in the 3'UTR (SIRT1: g.25751A > C, SIRT1: g.25846A > G, SIRT2: g.19676G > A and SIRT3: g. 25702C > T) and three mutations in exons (SIRT2: g.4062C > T; SIRT2: g.4406C > T and SIRT3: g.25557A > G) were identified in 468 individuals of Qinchuan cattle. Chi-square tests showed that g.25751A > C, g.19676G > A, and g.25702C > T were in Hardy-Weinberg disequilibrium (chi(2) < chi0.05(2)). The statistical analyses indicated that six SNPs were significantly associated with the ultrasound carcass traits (P < 0.05) except g.4062C > T (SIRT2) (P > 0.05). These results indicate that the variations in the class I sirtuin genes and their corresponding genotypes may be considered as molecular markers for economic traits in cattle breeding. PMID- 25839884 TI - Physicochemical properties, fatty acid profile and sensory characteristics of sheep and goat meat sausages manufactured with different pork fat levels. AB - The effect of three pork backfat levels (0% vs. 10% vs. 30%) on chemical composition, fatty acid profile and sensory properties on sheep and goat meat sausages was studied. All physicochemical parameters were affected by the addition of pork backfat in both types of sausages. Sausages manufactured with 30% of pork backfat showed the lowest moisture and protein contents and the highest total fat content. The lower a(w) values in sausages manufactured with higher fat content while in pH happened the reverse situation. The addition of pork backfat modified the total fatty acid profile, prompting a significant drop in the relative percentages of C14:0, C16:0, C17:0, C17:1, C18:0 and TVA (trans vaccenic acid), together with a marked increase in oleic and linoleic acids. Finally, in goat sausages, the fat content significantly affected sensory parameters: taste, texture and overall acceptability (P<0.05). As expected, all physicochemical parameters were affected by the addition of pork backfat in both types of sausages. PMID- 25839885 TI - Post-mortem oxidative stability of three yak (Bos grunniens) muscles as influenced by animal age. AB - The influence of animal age and muscle source on the oxidative stability of yak steaks was examined. Longissimus thoracis (LT) muscles from yaks of different age groups (0.5, 1.5, 2.5, and 3.5 years), and three muscle sources of LT, Psoas major (PM), and Biceps femoris (BF) from yaks of 0.5, 1.5, and 2.5 years, were evaluated for metmyoglobin content, activity of antioxidant enzymes, and antioxidant capacity. Oxidative stability was influenced (P<0.05) by muscle source and animal age. LT steaks from 0.5, 1.5, and 2.5 year old yaks exhibited lower (P<0.05) metmyoglobin content than their PM and BF counterparts. Furthermore, LT steaks from 3.5 year old yaks demonstrated lower (P<0.05) metmyoglobin content and greater (P<0.05) activities of antioxidant enzymes than LT steaks from other age groups. These results indicated the necessity to develop muscle- and age-specific processing strategies to improve color and oxidative stability of yak meat. PMID- 25839887 TI - Acantholysis in Striate Keratoderma as a Clue to the Diagnosis of a Genetic Abnormality. PMID- 25839886 TI - Panniculitis With Necrotizing Granulomata in a Patient on BRAF Inhibitor (Dabrafenib) Therapy for Metastatic Melanoma. AB - There have been major developments in targeted therapeutics with the clinical development of selective BRAF inhibitors (BRAFi) for patients with metastatic BRAF V600E mutant melanoma. Objective response rate of almost 50% has been witnessed in BRAFi clinical trials. Frequent side effects range from squamoproliferative lesions, including hyperplasia, keratoacanthomas, and squamous cell carcinomas to second primary melanomas. We describe a 50-year-old Hispanic woman with BRAF V600E mutant metastatic melanoma who was treated with surgery, radiation therapy, interleukin-2, and was enrolled on a BRAFi (dabrafenib) trial. Two months after initiation, she developed multiple erythematous, indurated, tender subcutaneous nodules bilaterally on the anterior thighs, posterior arms, and left dorsal forearm without overlying epidermal change. Punch biopsy revealed panniculitis with necrotizing granulomata. Infectious and other causes for panniculitis were excluded. We believe the histology likely represents a reaction to BRAFi therapy based on the temporal relationship of its onset to initiation of BRAFi therapy and previously reported cases of neutrophilic panniculitis associated with BRAFi therapy. Panniculitis has been emerging as an important unusual side effect of BRAFi therapy. Our case illustrates a unique presentation of BRAFi-associated panniculitis demonstrating necrotizing granulomata. PMID- 25839888 TI - Clinicopathologic spectrum of cutaneous tuberculosis: a retrospective analysis of 165 Indians. AB - BACKGROUND: Although cutaneous tuberculosis (CTB) is well described, it is wise to periodically revisit the prevailing clinical and epidemiological features, of this somewhat uncommon entity in developed nations that is also usually neglected in national tuberculosis control programs in countries where tuberculosis is a major health problem, to maintain heightened awareness as the HIV pandemic runs its course. METHODS: Medical records of 165 cases of CTB, diagnosed from 2007 to 2010, were studied. The diagnosis in each was made on the basis of well-conceived and described criteria. All patients had earlier been immunized with Bacillus Calmette-Guerin soon after birth. Patients were evaluated by routine hematology, Mantoux test, screening for HIV status in addition to fine-needle aspiration cytology, and/or histopathology of the lesion. RESULTS: Of the 165 cases (94 males and 71 females, male:female ratio of 1.32:1; age range, 1-64), 85 were lupus vulgaris, 11 tuberculosis verrucosa cutis (paucibacillary), and 39 scrofuloderma (multibacillary). The remaining 17 were tuberculids comprising 24 lichen scrofulosorum, 3 papulonecrotic tuberculid, 2 erythema induratum, and 1 erythema nodosum, afflicting children and young adults (age range, 0-10; 21-30). Fine-needle aspiration cytology was diagnostic in 39 cases, histopathology in 117, and their combination in 9. Clinicopathologic correlation and response to antituberculosis treatment were additional diagnostic adjuncts. CONCLUSIONS: CTB has a varied clinical and morphological spectrum. Cytology and histopathology play a key role in its diagnosis. An additional adjunct is the clinical response to antituberculosis treatment. PMID- 25839889 TI - Targeting the adnexal epithelium: an unusual case of syringometaplasia in a patient on vemurafenib. AB - Cutaneous adverse events (cAEs) are reported in 90% of all patients on selective BRAF inhibitors and contribute significantly to patient morbidity. Two weeks after initiating vemurafenib for metastatic melanoma, our patient developed a pruritic eruption with numerous, 1-2 mm pink hyperkeratotic follicular papules over his trunk and upper extremities. A biopsy demonstrated squamous metaplasia of the eccrine ducts with irregular hyperplasia of hair follicles sparing the interfollicular epidermis. Diffuse adnexal metaplasia is a novel and unusual cutaneous response to vemurafenib. The patient was started on acitretin 10 mg daily with improvement of the eruption after 4 weeks. We report an unusual cAE of vemurafenib selectively targeting the adnexal epithelium with relative sparing of the interfollicular epidermis. Interval improvement was noted after 4 weeks of acitretin, which is an effective therapeutic option for patients with cAEs involving squamous hyperplasia secondary to vemurafenib. Our case illustrates the particular sensitivity of the adnexal epithelium for vemurafenib-induced dysfunction in proliferation and differentiation, providing the basis for common cAEs observed on this medication. PMID- 25839890 TI - Idiopathic Hypereosinophilic Syndrome With Cutaneous Manifestations and Flame Figures: A Spectrum of Eosinophilic Dermatoses Whose Features Overlap With Wells' Syndrome. AB - IMPORTANCE: Wells syndrome (WS) (eosinophilic cellulitis) is an uncommon eosinophilic dermatitis that has been rarely described in association with, but distinct from, hypereosinophilic syndrome (HES). OBSERVATIONS: We report a case of an eosinophilic dermatosis with flame figures in association with idiopathic HES, manifested by inflammatory myocarditis, asthma, and peripheral blood eosinophilia. CONCLUSIONS AND RELEVANCE: The diagnoses of WS and HES, rather than being distinct findings, may represent 2 entities on a spectrum of hypereosinophilic diseases. The diagnosis of WS should be made with caution and should prompt a thorough investigation that includes a work-up for a systemic eosinophilic disorder. PMID- 25839891 TI - Nevus Lipomatosus Cutaneous Superficialis With Perifollicular Fibromas. AB - Nevus lipomatosus cutaneous superficialis (NLCS) is a rare cutaneous hamartoma characterized by groups of mature fat cells in the dermis. The authors report a case of a dark-skinnned, 6-year-old, Brazilian girl with 1 lesion in the right upper chest, extending to the neck, since 1 year of age. The dermatological examination consisted of skin-colored and yellowish follicular papules, isolated and grouped into a papillomatous plaque. The biopsy revealed ectopic mature adipose tissue in the dermis, compatible with NLCS, perifollicular well circumscribed fibroblast and collagen proliferation, and decreased elastic fibers in the papillary and upper reticular dermis. The finding of perifollicular fibrosis in NLCS is not common, having been first described in 2003. The perifollicular fibrosis is characteristic of other rare hamartoma, the perifollicular fibroma, but is also present in fibrofolliculomas or trichodiscomas, angiofibromas, and fibrotic papules on the face of tuberous sclerosis and postinflammatory fibrosis. This case is very similar to the first described case of NLCS with perifollicular fibrosis, and the authors believe that this is the second case of this entity, but they propose to name it NCLS with perifollicular fibromas, which better describes the nature of this lesion. PMID- 25839892 TI - Extranodal Marginal Zone Lymphoma-like Presentations of Angioimmunoblastic T-Cell Lymphoma: A T-Cell Lymphoma Masquerading as a B-Cell Lymphoproliferative Disorder. AB - Angioimmunoblastic T-cell lymphoma (AITL) is the second most common type of peripheral T-cell lymphoma worldwide, and in some countries, it is the most common form. Clinically, AITL usually presents with systemic symptoms, diffuse lymphadenopathy, hepatosplenomegaly, and common laboratory abnormalities such as hypergammaglobulinemia. Rashes are seen in 50%-80% of patients. AITL derives from follicular T-helper cells (TFH), that express germinal center markers and produce hyperactivation of B-cells seen in AITL. Although the histological features of AITL in the skin could be similar to pathological findings present in lymph node biopsies, herein, we present 2 cases of AITL with histological and immunophenotypic features that were somewhat suggestive of extranodal marginal zone lymphoma. Caution is urged to exclude the possibility of a systemic T-cell lymphoma such as AITL in cutaneous and lymph node B-cell proliferations. PMID- 25839893 TI - "Low-Fat" Pseudoangiomatous Spindle Cell Lipoma: A Rare Variant With Loss of 13q14 Region. AB - Spindle cell and pleomorphic lipoma constitute a spectrum of lipomatous lesions with characteristic clinical, morphologic, immunohistochemical, and molecular features. Multiple variants have been previously described including vascular, fibrous, plexiform, and those with significantly less fat termed "low-fat" and "fat-free" by Folpe. Cytogenetically, spindle cell lipomas frequently display monoallelic loss of 13q14 region, an abnormality also found in cellular angiofibroma and mammary-type myofibroblastoma. Pseudoangiomatous spindle cell lipoma, originally described by Fletcher et al in 1994, is a rare variant within the spindle cell/pleomorphic lipoma spectrum, with less than 20 published cases. It consists of an admixture of spindle cells, "ropey" collagen, variable amounts of mature fat, and irregular, branching slit-like vascular spaces. The authors present a case of a 1-cm subcutaneous lesion excised from the neck of a 70-year old man with classic histologic and immunohistochemical features of "low-fat" pseudoangiomatous spindle cell lipoma. Fluorescence in situ hybridization demonstrated a loss of 13q14 region, a characteristic presumed cytogenetic finding of spindle cell lipoma, which has been previously unconfirmed in this variant. PMID- 25839894 TI - Forced swim test: What about females? AB - In preclinical studies screening for novel antidepressants, male and female animals should be used. However, in a widely used antidepressant test, the forced swim test (FST), sex differences between males and females are not consistent. These discrepancies may discourage the inclusion of females in FST studies. In order to overcome this problem and provide a detailed insight regarding the use of female animals in the FST, we designed the following experiment and we performed a thorough analysis of the relevant literature. Male and female Wistar adult rats were subjected to the FST and sertraline was used as an antidepressant in two doses (10 mg/kg and 40 mg/kg, 3 injections in 24 h). Rodents were subjected in the two FST sessions during all possible combinations of the estrous cycle stages. We found that females exhibited higher levels of immobility than males and this sex difference was alleviated following antidepressant treatment. Sertraline at both doses enhanced swimming in both sexes, but females appeared more responsive to lower sertraline doses regarding immobility levels. Surprisingly, the high sertraline dose enhanced climbing particularly in proestrous and diestrous. Marked sex differences were also observed in the frequency of head swinging, with females exhibiting lower counts than males. Conclusively, when screening for new antidepressants, it is recommended to use standard FST procedures and if possible to include females in all phases of the cycle. Using only one dose of an investigational drug in females in certain phases of the cycle could result to false negative results. PMID- 25839895 TI - Agonist and antagonist effects of cytisine in vivo. AB - Varenicline, the most successful smoking cessation aid, is a selective partial agonists at alpha4beta2* nicotinic receptors. Its efficacy is likely to be shared by other drugs with similar receptor action, including cytisine. The present study aimed to characterize behavioral effects of cytisine compared with nicotine using locomotor activity tests, intracranial self-stimulation of ventral tegmental area (discrete-trial threshold current intensity titration procedure), drug discrimination (0.6 mg/kg nicotine from vehicle), physical dependence (osmotic minipumps delivering 6 mg/kg/day of nicotine) and intravenous nicotine self-administration (0.01 mg/kg per infusion) in adult Wistar rats. Cytisine (1-3 mg/kg) partially substituted for nicotine and at the highest dose tended to antagonize nicotine's discriminative stimulus effects. Nicotine (0.05-0.4 mg/kg), but not cytisine (0.3-3 mg/kg), lowered ICSS thresholds and cytisine dose dependently reversed effects of nicotine. Nicotine (0.15-0.6 mg/kg), but not cytisine (0.3-3 mg/kg), stimulated locomotor activity and cytisine (3 mg/kg) fully reversed these effects of nicotine. Acute pretreatment with nicotine (0.15 0.6 mg/kg), but not cytisine (0.3-3 mg/kg), reinstated extinguished nicotine self administration. Continuous infusion of nicotine induced physical dependence, as indicated by reduced rates of food-reinforced responding induced by a challenge dose of mecamylamine. At the highest tested dose (3 mg/kg), cytisine tended to reduce response rates irrespective of whether the rats were continuously exposed to nicotine or saline. Cytisine behaves like a weak partial agonist, mimicking effects of nicotine to a limited degree. Although cytisine reversed several effects of nicotine, it seemed to have a reduced potential to produce withdrawal signs in nicotine-dependent subjects. PMID- 25839896 TI - Investigating ion channel conformational changes using voltage clamp fluorometry. AB - Ion channels are membrane proteins whose functions are governed by conformational changes. The widespread distribution of ion channels, coupled with their involvement in most physiological and pathological processes and their importance as therapeutic targets, renders the elucidation of these conformational mechanisms highly compelling from a drug discovery perspective. Thanks to recent advances in structural biology techniques, we now have high-resolution static molecular structures for members of the major ion channel families. However, major questions remain to be resolved about the conformational states that ion channels adopt during activation, drug modulation and desensitization. Patch clamp electrophysiology has long been used to define ion channel conformational states based on functional criteria. It achieves this by monitoring conformational changes at the channel gate and cannot detect conformational changes occurring in regions distant from the gate. Voltage clamp fluorometry involves labelling cysteines introduced into domains of interest with environmentally sensitive fluorophores and inferring structural rearrangements from voltage or ligand-induced fluorescence changes. Ion channel currents are monitored simultaneously to verify the conformational status. By defining real time conformational changes in domains distant from the gate, this technique provides unexpected new insights into ion channel structure and function. This review aims to summarise the methodology and highlight recent innovative applications of this powerful technique. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. PMID- 25839897 TI - Role of interleukin-1 receptor signaling in the behavioral effects of ethanol and benzodiazepines. AB - Gene expression studies identified the interleukin-1 receptor type I (IL-1R1) as part of a pathway associated with a genetic predisposition to high alcohol consumption, and lack of the endogenous IL-1 receptor antagonist (IL-1ra) strongly reduced ethanol intake in mice. Here, we compared ethanol-mediated behaviors in mice lacking Il1rn or Il1r1. Deletion of Il1rn (the gene encoding IL 1ra) increases sensitivity to the sedative/hypnotic effects of ethanol and flurazepam and reduces severity of acute ethanol withdrawal. Conversely, deletion of Il1r1 (the gene encoding the IL-1 receptor type I, IL-1R1) reduces sensitivity to the sedative effects of ethanol and flurazepam and increases the severity of acute ethanol withdrawal. The sedative effects of ketamine and pentobarbital were not altered in the knockout (KO) strains. Ethanol intake and preference were not changed in mice lacking Il1r1 in three different tests of ethanol consumption. Recovery from ethanol-induced motor incoordination was only altered in female mice lacking Il1r1. Mice lacking Il1rn (but not Il1r1) showed increased ethanol clearance and decreased ethanol-induced conditioned taste aversion. The increased ethanol- and flurazepam-induced sedation in Il1rn KO mice was decreased by administration of IL-1ra (Kineret), and pre-treatment with Kineret also restored the severity of acute ethanol withdrawal. Ethanol-induced sedation and withdrawal severity were changed in opposite directions in the null mutants, indicating that these responses are likely regulated by IL-1R1 signaling, whereas ethanol intake and preference do not appear to be solely regulated by this pathway. PMID- 25839898 TI - Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease. AB - Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively. PMID- 25839899 TI - The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. AB - The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy. PMID- 25839900 TI - Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla. AB - The endocannabinoid system (ECS) comprises the cannabinoid receptors CB1 and CB2 and their endogenous arachidonic acid-derived agonists 2-arachidonoyl glycerol and anandamide, which play important neuromodulatory roles. Recently, a novel class of negative allosteric CB1 receptor peptide ligands, hemopressin-like peptides derived from alpha hemoglobin, has been described, with yet unknown origin and function in the CNS. Using monoclonal antibodies we now identified the localization of RVD-hemopressin (pepcan-12) and N-terminally extended peptide endocannabinoids (pepcans) in the CNS and determined their neuronal origin. Immunohistochemical analyses in rodents revealed distinctive and specific staining in major groups of noradrenergic neurons, including the locus coeruleus (LC), A1, A5 and A7 neurons, which appear to be major sites of production/release in the CNS. No staining was detected in dopaminergic neurons. Peptidergic axons were seen throughout the brain (notably hippocampus and cerebral cortex) and spinal cord, indicative of anterograde axonal transport of pepcans. Intriguingly, the chromaffin cells in the adrenal medulla were also strongly stained for pepcans. We found specific co-expression of pepcans with galanin, both in the LC and adrenal gland. Using LC-MS/MS, pepcan-12 was only detected in non-perfused brain (~ 40 pmol/g), suggesting that in the CNS it is secreted and present in extracellular compartments. In adrenal glands, significantly more pepcan-12 (400 700 pmol/g) was measured in both non-perfused and perfused tissues. Thus, chromaffin cells may be a major production site of pepcan-12 found in blood. These data uncover important areas of peptide endocannabinoid occurrence with exclusive noradrenergic immunohistochemical staining, opening new doors to investigate their potential physiological function in the ECS. This article is part of the Special Issue entitled 'Fluorescent Tools in Neuropharmacology'. PMID- 25839901 TI - A prototypic modified risk tobacco product exhibits reduced effects on chemotaxis and transendothelial migration of monocytes compared with a reference cigarette. AB - Monocyte adhesion and migration to the subendothelial space represent critical steps in atherogenesis. Here, we investigated whether extracts from the aerosol of a prototypic modified risk tobacco product (pMRTP), based on heating rather than combusting tobacco, exhibited differential effects on the migratory behavior of monocytes compared with that from the reference cigarette, 3R4F. THP-1 cells, a monocytic cell line, and human coronary arterial endothelial cells (HCAECs) were used to investigate chemotaxis and transendothelial migration (TEM) of monocytes in conventional and impedance-based systems. THP-1 cells migrated through a monolayer of HCAECs in response to C-X-C motif ligand 12 (CXCL12), a chemokine involved in diverse cellular functions including chemotaxis and survival of stem cells. Treatment of THP-1 cells with extracts from 3R4F or pMRTP induced concentration-dependent increases in cytotoxicity (7-aminoactinomycin D), and inflammation (IL-8 and TNF-alpha). CXCL12-mediated chemotaxis and TEM were decreased in extract-treated THP-1 cells. Extracts from 3R4F were ~21 times more potent than those from pMRTP in all examined endpoints. Extracts from 3R4F and pMRTP induced concentration-dependent responses in assays of inflammation, cytotoxicity, chemotaxis, and TEM. Furthermore, our findings indicate that extracts from a pMRTP are significantly less cytotoxic and induce less inflammation than those from the reference cigarette, 3R4F. PMID- 25839902 TI - An exposure and health risk assessment of lead (Pb) in lipstick. AB - Lead (Pb) content in lipstick and other consumer products has become an increasing concern. In 2010, the United States Food and Drug Administration tested 400 lipstick samples and found a maximum Pb concentration of 7.19 ppm. To assess the safety of lipstick in adults that chronically apply lipstick as well as instances where children might incidentally ingest lipstick products, the United States Environmental Protection Agency's (US EPA) Adult Lead Model and Integrated Exposure Uptake Biokinetic Model for Lead in Children were used to determine the blood Pb concentrations of adults and children ingesting varying amounts of lipstick of different Pb concentrations. Modeled blood Pb concentrations were compared with oral ingestion guidelines and to the Centers for Disease Control and the US EPA's actionable blood Pb levels of 5 and 10 ug/dL. Background Pb exposure was the primary contributor to estimated blood Pb levels (BLLs) in children and adults, and Pb exposure from lipstick did not significantly increase estimated BLLs. These results suggest that the safety of consumer products and cosmetics should be assessed not only by the presence and amounts of hazardous contents, but also in conjunction with an assessment of estimated background exposures and comparison to health-based standards. PMID- 25839903 TI - Brown adipose tissue in humans. PMID- 25839904 TI - Risk of Neoplasia in Pediatric Patients Receiving Growth Hormone Therapy--A Report From the Pediatric Endocrine Society Drug and Therapeutics Committee. AB - CONTEXT: GH and IGF-1 have been shown to affect tumor growth in vitro and in some animal models. This report summarizes the available evidence on whether GH therapy in childhood is associated with an increased risk of neoplasia during treatment or after treatment is completed. EVIDENCE ACQUISITION: A PubMed search conducted through February 2014 retrieved original articles written in English addressing GH therapy and neoplasia risk. Subsequent searches were done to include additional relevant publications. EVIDENCE SYNTHESIS: In children without prior cancer or known risk factors for developing cancer, the clinical evidence does not affirm an association between GH therapy during childhood and neoplasia. GH therapy has not been reported to increase the risk for neoplasia in this population, although most of these data are derived from postmarketing surveillance studies lacking rigorous controls. In patients who are at higher risk for developing cancer, current evidence is insufficient to conclude whether or not GH further increases cancer risk. GH treatment of pediatric cancer survivors does not appear to increase the risk of recurrence but may increase their risk for subsequent primary neoplasms. CONCLUSIONS: In children without known risk factors for malignancy, GH therapy can be safely administered without concerns about an increased risk for neoplasia. GH use in children with medical diagnoses predisposing them to the development of malignancies should be critically analyzed on an individual basis, and if chosen, appropriate surveillance for malignancies should be undertaken. GH can be used to treat GH deficient childhood cancer survivors who are in remission with the understanding that GH therapy may increase their risk for second neoplasms. PMID- 25839905 TI - Light-driven, proton-controlled, catalytic aerobic C-H oxidation mediated by a Mn(III) porphyrinoid complex. AB - The visible light-driven, catalytic aerobic oxidation of benzylic C-H bonds was mediated by a Mn(III) corrolazine complex. To achieve catalytic turnovers, a strict selective requirement for the addition of protons was established. The resting state of the catalyst was unambiguously characterized by X-ray diffraction as [Mn(III)(H2O)(TBP8Cz(H))](+), in which a single, remote site on the ligand is protonated. If two remote sites are protonated, however, reactivity with O2 is shut down. Spectroscopic methods revealed that the related Mn(V)(O) complex is also protonated at the same remote site at -60 degrees C, but undergoes valence tautomerization upon warming. PMID- 25839906 TI - Inhibiting corticosterone synthesis during fear memory formation exacerbates cued fear extinction memory deficits within the single prolonged stress model. AB - Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial. PMID- 25839907 TI - The N-terminal acidic residue of the cytosolic helix 8 of an odorant receptor is responsible for different response dynamics via G-protein. AB - We previously observed highly rapid and robust response of murine olfactory receptor S6 (mOR-S6) with chimeric Galpha15_olf, compared to Galpha15. To identify residues responsible for this difference in response, mutations of the cytosolic helix 8 were analyzed in a heterologous functional expression system. The N-terminal hydrophobic core between helix 8 and TM1-2 of mOR-S6 is important for activation of both Galpha15_olf and Galpha15. Point mutation of a helix 8 N terminal acidic residue eliminated the differences in response dynamics via Galpha. This result suggests that an N-terminal acidic residue of helix 8 is responsible for rapid response via Galpha15_olf. PMID- 25839908 TI - Nevirapine loaded Poloxamer 407/Pluronic P123 mixed micelles: Optimization of formulation and in vitro evaluation. AB - An attempt has been made to develop polymeric mixed micelle delivery system using Poloxamer 407 and Pluronic P123 for the encapsulation of an antiretroviral drug, Nevirapine. The stability of formulated mixed micellar system at different ratios (1:2, 1:1 and 2:1) and standard thermodynamic parameters of micellization have been determined from the temperature dependence of the critical micelle concentration. The process of micellization of Poloxamer 407/Pluronic P 123 system has been found to be entropy dominant at low temperatures and enthalpy driven at high temperatures. The amity of the different components of mixed micelles has been explored using Fourier transform infrared spectroscopy, Differential scanning calorimeter and X-ray diffraction studies, which rule out the possibility of any interactions between the drug and excipients. Micropolarity measurements infer that the drug is solubilized in the inner core of mixed micelles. In addition, dialysis method has been employed to determine the entrapment efficiency of all the three formulations. The formulation at 1:1 ratio exhibits high entrapment efficiency along with sustained release of the drug. PMID- 25839909 TI - Land use change impacts on air quality and climate. PMID- 25839910 TI - Specialist surgery for ovarian cancer in England. AB - OBJECTIVE: The aim of this study is to evaluate the impact of the 1999 national recommendations for ovarian cancer surgery in England to be performed by specialist surgeons in specialist centres. METHODS: A retrospective analysis of English cancer registry records, Hospital Episode Statistics (HES) data for all English NHS providers and General Medical Council (GMC) sub-specialty accreditation, to consider changes to the annual proportion of ovarian cancer (ICD10 C56-C57) patients undergoing major gynaecological surgery in gynaecological cancer centres (GCCs) or by specialist gynaecological oncologists (GOs). RESULTS: From 2000 to 2009, 2428 consultants were responsible for surgery on 30,753 patients. There were significant increases in the proportions of patients undergoing surgery at GCCs (43% to 76%, P<0.001), by GMC accredited GOs (5% to 36%, P<0.001), and by high ovarian cancer caseload (>=18 cases) surgeons (22% to 56%, P<0.001). CONCLUSION: There have been increased centralisation and specialisation of surgery for ovarian cancer patients since the NHS Cancer Plan (2000) and there has also been improved survival. However, by 2009, many ovarian cancer patients were still not receiving specialist surgery; the majority of patients were not operated on by GMC accredited gynaecological oncologists and there was considerable regional variation. Systems of accreditation should be reviewed and trusts should ensure that HES data accurately records clinical activity. PMID- 25839911 TI - Delay in chemotherapy administration impacts survival in elderly patients with epithelial ovarian cancer. AB - OBJECTIVES: The objective of this study was to characterize chemotherapy treatment patterns in elderly patients with epithelial ovarian cancer (EOC) and their impact on overall survival (OS). METHODS: We identified patients age >=65years with stage II-IV EOC who underwent cytoreduction from 2003 to 2011. Relevant clinical variables were extracted and correlated with OS. Statistical analyses were performed using logistic regression, Kaplan-Meier methods, and multivariable Cox proportional hazard models. RESULTS: One hundred and eighty four patients were included in the analysis. The average age was 73years with American Society of Anesthesiology Physical Status Class 2 or 3. Approximately 78% underwent primary debulking surgery (PDS). OS for the entire cohort was 3.3years. One hundred and fifty-seven patients received adjuvant chemotherapy, of which 70% received initial platinum-based doublet therapy; 67.5% of patients were able to complete the intended six cycles of chemotherapy; of these, 34% experienced a dose reduction and 45% experienced one or more dose delays. Any dose delay was associated with a decrease in overall survival (p=0.02) and remained significant even after controlling for age, stage, and residual disease and number of chemotherapy cycles received (p=0.029). CONCLUSIONS: Elderly EOC patients frequently required chemotherapy dose reductions and delays in chemotherapy administration. Multivariate analysis confirmed that dose delays are an independent factor associated with decreased OS. PMID- 25839912 TI - Fluoroalkylative aryl migration of conjugated N-arylsulfonylated amides using easily accessible sodium di- and monofluoroalkanesulfinates. AB - Fluorinated sulfinate salts RfSO2Na (Rf = CF2H, CF2Ph, and CH2F) have been prepared via NaBH4-mediated reduction of the corresponding benzo[d]thiazol-2-yl sulfones, and their synthetic application as di- and monofluoroalkyl radical precursors is demonstrated in the silver-catalyzed cascade fluoroalkylation/aryl migration/SO2 extrusion of conjugated N-arylsulfonylated amides. PMID- 25839913 TI - Evaluation of Organizational Readiness in Clinical Settings for Social Supporting Evidence-Based Information Seeking Behavior after Introducing IT in a Developing Country. AB - The health sector of Iran has endeavored to encourage physicians and medical students to use research findings in their practice. Remarkable changes have occurred, including: holding computer skills courses, digital library workshops for physicians and students, and establishing websites in hospitals. The findings showed that a small number of the participants completely agreed that they were supported by supervisors and colleagues to use evidence-based information resources in their clinical decisions. Health care organizations in Iran need other organizational facilitators such as social influences, organizational support, leadership, strong organizational culture, and climate in order to implement evidence-based practice. PMID- 25839915 TI - Correction to Mechanism and functional implications of the heme-induced binding promiscuity of IgE. PMID- 25839914 TI - Prenatal and Childhood Traffic-Related Pollution Exposure and Childhood Cognition in the Project Viva Cohort (Massachusetts, USA). AB - BACKGROUND: Influences of prenatal and early-life exposures to air pollution on cognition are not well understood. OBJECTIVES: We examined associations of gestational and childhood exposure to traffic-related pollution with childhood cognition. METHODS: We studied 1,109 mother-child pairs in Project Viva, a prospective birth cohort study in eastern Massachusetts (USA). In mid-childhood (mean age, 8.0 years), we measured verbal and nonverbal intelligence, visual motor abilities, and visual memory. For periods in late pregnancy and childhood, we estimated spatially and temporally resolved black carbon (BC) and fine particulate matter (PM2.5) exposures, residential proximity to major roadways, and near-residence traffic density. We used linear regression models to examine associations of exposures with cognitive assessment scores, adjusted for potential confounders. RESULTS: Compared with children living >= 200 m from a major roadway at birth, those living < 50 m away had lower nonverbal IQ [-7.5 points; 95% confidence interval (CI): -13.1, -1.9], and somewhat lower verbal IQ (-3.8 points; 95% CI: -8.2, 0.6) and visual motor abilities (-5.3 points; 95% CI: -11.0, 0.4). Cross-sectional associations of major roadway proximity and cognition at mid-childhood were weaker. Prenatal and childhood exposure to traffic density and PM2.5 did not appear to be associated with poorer cognitive performance. Third-trimester and childhood BC exposures were associated with lower verbal IQ in minimally adjusted models; but after adjustment for socioeconomic covariates, associations were attenuated or reversed. CONCLUSIONS: Residential proximity to major roadways during gestation and early life may affect cognitive development. Influences of pollutants and socioeconomic conditions on cognition may be difficult to disentangle. PMID- 25839916 TI - Impact of specialist neurovascular care in subarachnoid haemorrhage. AB - BACKGROUND: The management of neurosurgical disorders has become increasingly specialised. The care of patients with subarachnoid haemorrhage (SAH) has generally been part of core neurosurgical practice, provided by general neurosurgeons whatever their specialist interest. The aim of this present study therefore is to ascertain if, and to what extent care provided by a dedicated neurovascular team (compared to care provided by a general neurosurgical team) change patient disposition in SAH. METHODS: This is a retrospective analysis of SAH patients, identified from a departmental database of a single neurosurgical centre. In 2008, the service was reorganised such that a neurovascular team cared for all SAH patients. We compared clinical outcome in people admitted prior to this service reorganisation (Period A, 2004-2007) with patients admitted afterwards (Period B, 2009-2011). Survival and recovery were assessed according to the Glasgow Outcome Scale (GOS). Multi-factorial logistic regression analysis was performed to determine the injury and age adjusted incidence of complications, odds of survival at discharge, discharge home, mortality, good recovery (GOS 5) and favourable outcome, by dichotomising GOS (GOS 4-5 vs. GOS 1 3) at 3 months. RESULTS: 1114 patients were included in the study. The mean age of patients presenting in Period A (n = 543) was younger [50 years (SD 13.5)] than those in Period B (n = 571) [53 years (SD 13)]. Patients admitted in Period B were more likely to present as poor grade (World Federation of Neurological surgeons (WFNS) grades 4 and 5) compared to Period A (26.5% vs. 21.3%). No statistical differences between the groups in the incidence of pre-operative re bleeding (3% vs. 5%) or rates of delayed cerebral ischaemia (16.1% vs. 16.1%) were observed. After adjustment for age, sex and injury severity, the odds of patient time to discharge, discharge home and good recovery (GOS 5) were 27% (p < 0.001), 45% (p = 0.001) and 93% (p < 0.001) higher respectively in Period B than Period A. CONCLUSIONS: The data presented here demonstrates that management of SAH by a dedicated neurovascular team improves the potential for patient recovery. PMID- 25839917 TI - Pseudobulbar palsy due to deep-brain stimulation of the thalamic ventral intermediate nuclei. PMID- 25839918 TI - Sensory abnormalities and masticatory function after microvascular decompression or balloon compression for trigeminal neuralgia compared with carbamazepine and healthy controls. AB - OBJECT: Idiopathic trigeminal neuralgia (iTN) is a neurological condition treated with pharmacotherapy or neurosurgery. There is a lack of comparative papers regarding the outcomes of neurosurgery in patients with iTN. The objective of this study was to investigate sensory thresholds and masticatory function in 78 patients with iTN who underwent microvascular decompression (MVD) or balloon compression (BC), and compare these treatments with carbamazepine and 30 untreated healthy controls. METHODS: The authors conducted a case-controlled longitudinal study. Patients were referred to 1 of 3 groups: MVD, BC, or carbamazepine. All patients were evaluated before and after treatment with a systematic protocol composed of a clinical orofacial questionnaire, Research Diagnostic Criteria for temporomandibular disorders, Helkimo indices, and a quantitative sensory-testing protocol (gustative, olfactory, cold, warm, touch, vibration, superficial, and deep pain thresholds). RESULTS: Both MVD and BC were effective at reducing pain intensity (p = 0.012) and carbamazepine doses (p < 0.001). Myofascial and articular complaints decreased in both groups (p < 0.001), but only the patients in the MVD group showed improvement in Helkimo indices (p < 0.003). Patients who underwent MVD also showed an increase in sweet (p = 0.014) and salty (p = 0.003) thresholds. The sour threshold decreased (p = 0.003) and cold and warm thresholds increased (p < 0.001) in patients after MVD and BC, but only the patients who underwent BC had an increase in touch threshold (p < 0.001). CONCLUSIONS: Microvascular decompression and BC resulted in a reduction in myofascial and jaw articular complaints, and the impact on masticatory function according to Helkimo indices was greater after BC than MVD. MVD resulted in more gustative alterations, and both procedures caused impairment in thermal thresholds (warm and cold). However, only BC also affected touch perception. The sensorial and motor deficits after BC need to be included as targets directly associated with the success of the surgery and need to be assessed and relieved as goals in the treatment of iTN. PMID- 25839919 TI - Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance. AB - OBJECT: Intravenous fluorescein sodium has been used during resection of high grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood. METHODS: The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation. RESULTS: The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell-specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI-guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI. CONCLUSIONS: Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions. PMID- 25839920 TI - Impact of body mass index on cerebellar tonsil position in healthy subjects and patients with Chiari malformation. AB - OBJECT: It is unclear if there is a relationship between Chiari malformation Type I (CM-I) and body mass index (BMI). The aim of this study was to identify the relationship between BMI and cerebellar tonsil position in a random sample of people. METHODS: Cerebellar tonsil position in 2400 subjects from a cohort of patients undergoing MRI was measured. Three hundred patients were randomly selected from each of 8 age groups (from 0 to 80 years). A subject was then excluded if he or she had a posterior fossa mass or previous posterior fossa decompression or if height and weight information within 1 year of MRI was not recorded in the electronic medical record. RESULTS: There were 1310 subjects (54.6%) with BMI records from within 1 year of the measured scan. Of these subjects, 534 (40.8%) were male and 776 (59.2%) were female. The average BMI of the group was 26.4 kg/m(2), and the average tonsil position was 0.87 mm above the level of the foramen magnum. There were 46 subjects (3.5%) with a tonsil position >= 5 mm below the level of the foramen magnum. In the group as a whole, there was no correlation (R(2) = 0.004) between BMI and cerebellar tonsil position. CONCLUSIONS: In this examination of 1310 subjects undergoing MRI for any reason, there was no relationship between BMI and the level of the cerebellar tonsils or the diagnosis of CM-I on imaging. PMID- 25839921 TI - Quantitative analysis of the Kawase versus the modified Dolenc-Kawase approach for middle cranial fossa lesions with variable anteroposterior extension. AB - OBJECT: The surgical corridor to the upper third of the clivus and ventral brainstem is hindered by critical neurovascular structures, such as the cavernous sinus, petrous apex, and tentorium. The traditional Kawase approach provides a 10 * 5-mm fenestration at the petrous apex of the temporal bone between the 5th cranial nerve and internal auditory canal. Due to interindividual variability, sometimes this area proves to be insufficient as a corridor to the posterior cranial fossa. The authors describe a modification to the technique of the extradural anterior petrosectomy consisting of additional transcavernous exploration and medial mobilization of the cisternal component of the trigeminal nerve. This approach is termed the modified Dolenc-Kawase (MDK) approach. METHODS: The authors describe a volumetric analysis of temporal bones with 3D laser scanning of dry and drilled bones for respective triangles and rhomboid areas, and they compare the difference of exposure with traditional versus modified approaches on cadaver dissection. Twelve dry temporal bones were laser scanned, and mesh-based volumetric analysis was done followed by drilling of the Kawase triangle and MDK rhomboid. Five cadaveric heads were drilled on alternate sides with both approaches for evaluation of the area exposed, surgical freedom, and angle of approach. RESULTS: The MDK approach provides an approximately 1.5 times larger area and 2.0 times greater volume of bone at the anterior petrous apex compared with the Kawase's approach. Cadaver dissection objectified the technical feasibility of the MDK approach, providing nearly 1.5-2 times larger fenestration with improved view and angulation to the posterior cranial fossa. Practical application in 6 patients with different lesions proves clinical applicability of the MDK approach. CONCLUSIONS: The larger fenestration at the petrous apex achieved with the MDK approach provides greater surgical freedom at the Dorello canal, gasserian ganglion, and prepontine area and better anteroposterior angulation than the traditional Kawase approach. Additional anterior clinoidectomy and transcavernous exposure helps in dealing with basilar artery aneurysms. PMID- 25839922 TI - Preservation of the nerves to the frontalis muscle during pterional craniotomy. AB - OBJECT: There continues to be confusion over how best to preserve the branches of the facial nerve to the frontalis muscle when elevating a frontotemporal (pterional) scalp flap. The object of this study was to examine the full course of the branches of the facial nerve that must be preserved to maintain innervation of the frontalis muscle during elevation of a frontotemporal scalp flap. METHODS: Dissection was performed to follow the temporal branches of facial nerves along their course in 5 adult, cadaveric heads (n = 10 extracranial facial nerves). RESULTS: Preserving the nerves to the frontalis muscle requires an understanding of the course of the nerves in 3 areas. The first area is on the outer surface of the temporalis muscle lateral to the superior temporal line (STL) where the interfascial or subfascial approaches are applied, the second is in the area medial to the STL where subpericranial dissection is needed, and the third is along the STL. Preserving the nerves crossing the STL requires an understanding of the complex fascial relationships at this line. It is important to preserve the nerves crossing the lateral and medial parts of the exposure, and the continuity of the nerves as they pass across the STL. Prior descriptions have focused largely on the area superficial to the temporalis muscle lateral to the STL. CONCLUSIONS: Using the interfascial-subpericranial flap and the subfascial subpericranial flap avoids opening the layer of loose areolar tissue between the temporal fascia and galea in the area lateral to the STL and between the galea and frontal pericranium in the area medial to the STL. It also preserves the continuity of the nerve crossing the STL. This technique allows for the preservation of the nerves to the frontalis muscle along their entire trajectory, from the uppermost part of the parotid gland to the frontalis muscle. PMID- 25839923 TI - The predictive value of magnetic resonance imaging in evaluating intracranial arteriovenous malformation obliteration after stereotactic radiosurgery. AB - OBJECT: The current gold standard for diagnosing arteriovenous malformation (AVM) and assessing its obliteration after stereotactic radiosurgery (SRS) is digital subtraction angiography (DSA). Recently, MRI and MR angiography (MRA) have become increasingly popular imaging modalities for the follow-up of patients with an AVM because of their convenient setup and noninvasiveness. In this study, the authors assessed the sensitivity and specificity of MRI/MRA in evaluating AVM nidus obliteration as assessed by DSA. METHODS: The authors study a consecutive series of 136 patients who underwent SRS between January 2000 and December 2012 and who underwent regular clinical examinations, several MRI studies, and at least 1 post SRS DSA follow- up evaluation at the University of Virginia. The average follow up time was 47.3 months (range 10.1-165.2 months). Two blinded observers were enrolled to interpret the results of MRI/MRA compared with those of DSA. The sensitivity, specificity, positive predictive value, and negative predictive value for the obliteration of AVM were reported. RESULTS: On the basis of DSA, 73 patients (53.7%) achieved final angiographic obliteration in a median of 28.8 months. The sensitivity (the probability of finding obliteration on MRI/MRA among those for whom complete obliteration was shown on DSA) was 84.9% for one observer (Observer 1) and 76.7% for the other (Observer 2). The specificity was 88.9% and 95.2%, respectively. The false-negative interpretations were significantly related to the presence of draining veins, perinidal edema on T2-weighted images, and the interval between the MRI/MRA and DSA studies. CONCLUSIONS: MRI/MRA predicted AVM obliteration after SRS in most patients and can be used in their follow-up. However, because the specificity of MRI/MRA is not perfect, DSA should still be performed to confirm AVM nidus obliteration after SRS. PMID- 25839924 TI - Preparedness of neurosurgery graduates for neuroendovascular fellowship: a national survey of fellowship programs. AB - OBJECT: Endovascular interventions have become an essential part of a neurosurgeon's practice. Whether endovascular procedures have been effectively integrated into residency curricula, however, remains uncertain. The purpose of this study was to assess the preparedness of US neurosurgery graduate trainees for neuroendovascular fellowship. METHODS: A multidomain, global assessment survey was sent to all directors/faculty of neuroendovascular fellowship programs involved in training of US neurosurgery graduates. Surveyees were asked to assess trainees as they entered fellowship. RESULTS: The response rate was 78% (25/32). Of respondent program directors, 38% reported that new fellows did not know the history and imaging of the patient and 50% were unable to formulate an appropriate treatment plan. As many as 79% of fellows were unfamiliar with endovascular devices and 75% were unfamiliar with angiographic equipment. Furthermore, 58% of fellows were unable to perform femoral access, 54% were unable to perform femoral closure, 79% were unable to catheterize a major vessel, 86% were unable to perform a 4-vessel angiogram, and 100% were unable to catheterize an aneurysm. Additionally, program directors reported that over 50% of fellows could not recognize neurovascular anatomy and 54% could not recognize/classify vascular abnormalities. There was an overall agreement that fellows demonstrated professionalism and interest in research and had good communication/clinical skills. CONCLUSIONS: The results of this study suggest potential gaps in the training of neurosurgery residents with regard to endovascular neurosurgery. In an era of minimally invasive therapies, changes in residency curricula may be needed to keep pace with the ever-changing field of neurosurgery. PMID- 25839926 TI - Endoscopic endonasal transsphenoidal surgery in elderly patients with pituitary adenomas. AB - OBJECT: With the increase in the average life expectancy, medical care of elderly patients with symptomatic pituitary adenoma (PA) will continue to grow. Little information exists in the literature about the surgical treatment of these patients. The aim of this study was to present the results of a single pituitary center in the surgical treatment of PAs in patients > 70 years of age. METHODS: In this retrospective study, 55 consecutive elderly patients (age >= 70 years) with nonfunctioning PAs underwent endoscopic transsphenoidal surgery at the General Hospital of Fortaleza, Brazil, between May 2000 and December 2012. The clinical and radiological results in this group were compared with 2 groups of younger patients: < 60 years (n = 289) and 60-69 years old (n = 30). RESULTS: Fifty-five patients >= 70 years of age (average age 72.5 years, range 70-84 years) underwent endoscopic surgery for treatment of PAs. The mean follow-up period was 50 months (range 12-144 months). The most common symptoms were visual impairment in 38 (69%) patients, headache in 16 (29%) patients, and complete ophthalmoplegia in 6 (10.9%). Elderly patients presented a higher incidence of ophthalmoplegia (p = 0.032) and a lower frequency of pituitary apoplexy before surgery (p < 0.05). Tumors with cavernous sinus invasion were treated surgically less frequently than in younger patients. Although patients with an American Society of Anesthesiologists score of 3 were more common in the elderly group (p < 0.05), no significant difference regarding surgical time, extent of resection, and hospitalization were observed. Elderly patients presented with more complications than patients < 60 years (32.7% vs 10%, p < 0.05). Complications observed in the elderly group included 5 CSF leaks (9%), 2 permanent diabetes insipidus cases (3.6%), 4 postoperative refractory hypertension cases (7.2%), 1 myocardial ischemia (1.8%), and 1 death (1.8%). Postoperative new anterior pituitary deficit was more common in the younger group (< 60 years old: 17.7%) than in the elderly (>= 70 years old: 12.7%); however, there was no statistical difference. CONCLUSIONS: Endoscopic transsphenoidal surgery for elderly patients with PAs may be associated with higher complication rates, especially secondary to early transitory complications, when compared with surgery performed in younger patients. Although the worst preoperative clinical status might be observed in this group, age alone is not associated with a worst final prognosis after endoscopic removal of nonfunctioning PAs. PMID- 25839925 TI - Utility of dynamic computed tomography angiography in the preoperative evaluation of skull base tumors. AB - OBJECT: The anatomical complexity of skull base tumors mandates detailed preoperative planning for safe resection. In particular, the location of critical vascular and bony structures can influence the surgical approach. Traditional methods, such as MRI, MR angiography and/or venography (MRA/MRV), CT angiography and/or venography (CTA/CTV), and digital subtraction angiography, each have their limitations. One alternative that combines the benefits of both detailed anatomy compatible with intraoperative image guidance and visualization of the vascular flow is the 320-detector row dynamic volume CTA/CTV. The authors investigated this technique's impact on the surgical approach used in a series of complex intracranial tumors. METHODS: All patients with complex intracranial tumors who had undergone preoperative dynamic CTA/CTV as well as MRI in the period from July 2010 to June 2012 were retrospectively reviewed. Those in whom only routine CTA/CTV sequences had been obtained were excluded. Clinical records, including imaging studies, operative reports, and hospital course, were reviewed. Ease in detecting specific major arterial and venous tributaries using dynamic CTA/CTV was graded for each case. Furthermore, 2 skull base neurosurgeons projected a desired surgical approach for each tumor based on MRI studies, independent of the CTA/CTV sequences. The projected approach was then compared with the ultimately chosen surgical approach to determine whether preoperative awareness of vasculature patterns altered the actual operative approach. RESULTS: Sixty-four patients were eligible for analysis. Dynamic CTA/CTV successfully demonstrated circle of Willis arteries, major draining sinuses, and deep internal venous drainage in all cases examined. The superior petrosal sinus, vein of Labbe, tentorial veins, and middle fossa veins were also identified in a majority of cases, which played an important role in preoperative planning. Visualization of critical vascular-especially venous-anatomy influenced the surgical approach in 39% (25 of 64) of the cases. CONCLUSIONS: Dynamic CTA/CTV has been applied to few neurosurgical disease pathologies to date. This noninvasive technology offers insight into vascular flow patterns as well as 3D anatomical relationships and provides thin-cut sequences for intraoperative navigation. The authors propose dynamic CTA as an addition to the preoperative planning for complex skull base tumors. PMID- 25839927 TI - Improvement in venous outflow following superior sagittal sinus decompression after a gunshot wound to the head: case report. AB - The most commonly described indications for surgical management of closed depressed skull fractures are hematoma evacuation and repair of extensive cosmetic deformity. Venous sinus injury, which occurs in a subset of depressed skull fractures, is not typically listed as an indication for surgical treatment due to the potential for major venous hemorrhage associated with surgery near these structures. However, if patients exhibit signs and symptoms of intracranial hypertension and radiographic findings demonstrate sinus compromise, surgical elevation of the depressed skull fragments is indicated. The authors present the case of a 25-year-old woman with a depressed skull fracture secondary to a gunshot wound with symptomatic compromise in venous outflow of the posterior one third of the superior sagittal sinus. The patient was treated with surgical decompression via bilateral craniectomy along with intracranial pressure-lowering medical therapy and had almost full resolution of her presenting symptoms with documented improvement in flow through the superior sagittal sinus. While the use of surgical treatment for these types of injuries is highly debated, the authors demonstrate here that safe, effective surgical management of these patients is possible and that surgical decompression should always be considered in the case of symptomatic venous sinus flow obstruction. PMID- 25839928 TI - Letter to the Editor: Predictors of outcome for gunshot wounds. PMID- 25839929 TI - Editorial: Qualitative research in brachial plexus injury. PMID- 25839930 TI - Medical treatment decision making after total avulsion brachial plexus injury: a qualitative study. AB - OBJECT: Complete avulsion traumatic brachial plexus injuries (BPIs) can be treated using nerve and musculoskeletal reconstruction procedures. However, these interventions are most viable within certain timeframes, and even then they cannot restore all lost function. Little is known about how patients make decisions regarding surgical treatment or what impediments they face during the decision-making process. Using qualitative methodology, the authors aimed to describe how and why patients elect to pursue or forego surgical reconstruction, identify the barriers precluding adequate information transfer, and determine whether these patients are satisfied with their treatment choices over time. METHODS: Twelve patients with total avulsion BPIs were interviewed according to a semi-structured guide. The interview transcripts were qualitatively analyzed using the systematic inductive techniques of grounded theory to identify key themes related to the decision-making process and long-term satisfaction with decisions. RESULTS: Four decision factors emerged from our analysis: desire to restore function, perceived value of functional gains, weighing the risks and costs of surgery, and having concomitant injuries. Lack of insurance coverage (4 patients), delayed diagnosis (3 patients), and insufficient information regarding treatment (4 patients) prevented patients from making informed decisions and accessing care. Three individuals, all of whom had decided against reconstruction, had regrets about their treatment choices. CONCLUSIONS: Patients with panplexus avulsion injuries are missing opportunities for reconstruction and often not considering the long-term outcomes of surgery. As more Americans gain health insurance coverage, it is very likely that the number of patients able to pursue reconstruction will increase. The authors recommend implementing clinical pathways to help patients meet critical points in care within the ideal timeframe and using a patient- and family-centered care approach combined with patient decision aids to foster shared decision making, increase access to information, and improve patient satisfaction with decisions. These measures could greatly benefit patients with BPI while reducing costs, improving efficiency, and generating better outcomes. PMID- 25839931 TI - Predictors of sinonasal quality of life and nasal morbidity after fully endoscopic transsphenoidal surgery. AB - OBJECT: Despite the increasing application of endoscopic transsphenoidal surgery for pituitary lesions, the prognostic factors that are associated with sinonasal quality of life (QOL) and nasal morbidity are not well understood. The authors examine the predictors of sinonasal QOL and nasal morbidity in patients undergoing fully endoscopic transsphenoidal surgery. METHODS: An exploratory post hoc analysis was conducted of patients who underwent endoscopic pituitary surgery and were enrolled in a prospective multicenter QOL study. End points of the study included patient-reported sinonasal QOL and objective nasal endoscopy findings. Multivariate models were developed to determine the patient and surgical factors that correlated with QOL at 2 weeks through 6 months after surgery. RESULTS: This study is a retrospective review of a subgroup of patients studied in the clinical trial "Rhinological Outcomes in Endonasal Pituitary Surgery" (clinical trial no. NCT01504399, clinicaltrials.gov ). Data from 100 patients who underwent fully endoscopic transsphenoidal surgery were included. Predictors of a lower postoperative sinonasal QOL at 2 weeks were use of nasal splints (p = 0.039) and female sex at the trend level (p = 0.061); at 3 months, predictors of lower QOL were the presence of sinusitis (p = 0.025), advancing age (p = 0.044), and use of absorbable nasal packing (p = 0.014). Health status (multidimensional QOL) was also predictive at 2 weeks (p = 0.001) and 3 months (p < 0.001) and was the only significant predictor of sinonasal QOL at 6 months (p < 0.001). A Kaplan-Meier analysis was performed to study time to resolution of nasal crusting, mucopurulence, and synechia as observed during nasal endoscopy after surgery. The mean time (+/- SEM) to absence of nasal crusting was 16.3 +/- 2.1 weeks, mucopurulence was 6.2 +/- 1.1 weeks, and synechia was 4.4 +/- 0.5 weeks. Use of absorbable nasal packing was associated with more severe mucopurulence. CONCLUSIONS: Sinonasal QOL following endoscopic pituitary surgery reaches a nadir at 2 weeks and recovers by 3 months postoperatively. Use of absorbable packing and nasal splints, while used in a minority of patients, negatively correlates with early sinonasal QOL. Sinonasal QOL and overall health status are well correlated in the postoperative period, suggesting the important influence of sinonasal QOL on the patient experience. PMID- 25839932 TI - Editorial: Turning fluorescence into black and white. PMID- 25839933 TI - CTNND2 deletion and intellectual disability. AB - Neurodevelopmental disorders are a group of diseases characterized by either structural or functional alterations. The clinical spectrum can vary from isolated intellectual disability to more complex syndromes. Molecular karyotyping can explain 14%-18% of cases due to the presence of large pathogenic CNVs. Moreover, small CNVs involving single genes might result in a monogenic disease. In this article we report two cases of intragenic CTNND2 deletion, detected by molecular karyotyping, in patients with isolated intellectual disability. PMID- 25839934 TI - dsRNA interference on expression of a RNA-dependent RNA polymerase gene of Bombyx mori cytoplasmic polyhedrosis virus. AB - Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) is one of the major viral pathogens in silkworm. Its infection often results in significant losses to sericulture. Studies have demonstrated that RNAi is one of the important anti viral mechanisms in organisms. In this study, three dsRNAs targeting the RNA dependent RNA polymerase (RDRP) gene of BmCPV were designed and synthesized with 2'-F modification to explore their interference effects on BmCPV replication in silkworm larvae. The results showed that injecting dsRNA in the dosage of 4-6 ng per mg body weight into the 5th instar larvae can interfere with the BmCPV-RDRP expression by 93% after virus infection and by 99.9% before virus infection. In addition, the expression of two viral structural protein genes (genome RNA segments 1 and 5) was also decreased with the decrease of RDRP expression, suggesting that RNAi interference of BmCPV-RDRP expression could affect viral replication. The study provides an effective method for investigating virus replication as well as the virus-host interactions in the silkworm larvae using dsRNA. PMID- 25839935 TI - CYP2C8 rs17110453 and EPHX2 rs751141 two-locus interaction increases susceptibility to ischemic stroke. AB - AIMS: Ischemic stroke (IS) is a multifactorial disease caused by a combination of environmental risk factors and genetic susceptibilities. However, few studies have assessed the effects of gene-gene interactions among cytochrome P450 (CYP) pathway genes on the risk of stroke. The present study investigated the association of seven variants of six CYP pathway genes with IS in a Chinese population. MAIN METHODS: A total of 396 patients with IS and 378 controls were genotyped for seven variants from six CYP pathway genes, including CYP2J2 rs10889160, CYP2C8 rs17110453, CYP2C8 rs1934980, CYP2C9 rs1799853, CYP2C9 rs1057910, and CYP3A5 rs776746, as well as epoxide hydrolase 2 (EPHX2) rs751141, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) methods. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. KEY FINDINGS: Single-gene variant analysis showed no significant differences in the genotype distributions of the seven variants between IS patients and healthy volunteers. However, GMDR analysis showed a significant gene-gene interaction between rs17110453 and rs751141, with scores of 10 and 9 for the cross-validation consistency and sign test, respectively (P=0.0167). A 1.86-fold increased risk for IS was detected in individuals carrying the genotypes of rs17110453CC and rs751141GG (adjusted for age, hypertension, and diabetes mellitus; 95% CI: 1.216 2.896, P=0.005). SIGNIFICANCE: The CYP2C8 rs17110453 and EPHX2 rs751141 two-locus interaction confers a significantly higher risk for IS. The combinational analysis used in this study may be helpful in the elucidation of genetic risk factors for common and complex diseases such as IS. PMID- 25839936 TI - Diabetes susceptibility in Mayas: Evidence for the involvement of polymorphisms in HHEX, HNF4alpha, KCNJ11, PPARgamma, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes. AB - Association of type 2 diabetes (T2D) with common variants in HHEX, HNF4alpha, KCNJ11, PPARgamma, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes have been reported, mainly in populations of European and Asian ancestry and to a lesser extent in Latin Americans. Thus, we aimed to investigate the contribution of rs1111875 (HHEX), rs1800961 (HNF4alpha), rs5219 (KCNJ11), rs1801282 (PPARgamma), rs10811661 (CDKN2A/2B), rs13266634 (SLC30A8), rs12779790 (CDC123/CAMK1D), rs7903146 (TCF7L2), rs9282541 (ABCA1) and rs13342692 (SLC16A11) polymorphisms in the genetic background of Maya population to associate their susceptibility to develop T2D. This is one of the first studies designed specifically to investigate the inherited component of T2D in the indigenous population of Mexico. SNPs were genotyped by allelic discrimination method in 575 unrelated Maya individuals. Two SNPs rs10811661 and rs928254 were significantly associated with T2D after adjusting for BMI; rs10811661 in a recessive and rs9282541 in a dominant model. Additionally, we found phenotypical alterations associated with genetic variants: HDL to rs9282541 and insulin to rs13342692. In conclusion, these findings support an association of genetic polymorphisms to develop T2D in Maya population. PMID- 25839937 TI - Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease. AB - Familial hypercholesterolemia (FH) is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is an autosomal dominant disease, caused by variants in Ldlr, ApoB or Pcsk9, which results in high levels of LDL-cholesterol (LDL-C) leading to early coronary heart disease. Sequencing whole genome for screening variants for FH are not suitable due to high cost. Hence, in this study we performed targeted customized sequencing of FH 12 genes (Ldlr, ApoB, Pcsk9, Abca1, Apoa2, Apoc3, Apon2, Arh, Ldlrap1, Apoc2, ApoE, and Lpl) that have been implicated in the homozygous phenotype of a proband pedigree to identify candidate variants by NGS Ion torrent PGM. Only three genes (Ldlr, ApoB, and Pcsk9) were found to be highly associated with FH based on the variant rate. The results showed that seven deleterious variants in Ldlr, ApoB, and Pcsk9 genes were pathological and were clinically significant based on predictions identified by SIFT and PolyPhen. Targeted customized sequencing is an efficient technique for screening variants among targeted FH genes. Final validation of seven deleterious variants conducted by capillary resulted to only one novel variant in Ldlr gene that was found in exon 14 (c.2026delG, p. Gly676fs). The variant found in Ldlr gene was a novel heterozygous variant derived from a male in the proband. PMID- 25839938 TI - Novel de novo nonsense mutation of the PHEX gene (p.Lys50Ter) in a Chinese patient with hypophosphatemic rickets. AB - X-linked hypophosphatemic rickets (XLHR), the most common form of inherited rickets, is a dominant disorder characterized by hypophosphatemia, abnormal bone mineralization, and short stature. Mutations in the PHEX gene are major causes of XLHR. Herein, we clinically characterized four unrelated families with hypophosphatemia, bone abnormalities, short stature, and dentin malformation. Mutational analysis of the PHEX gene using Sanger sequencing revealed three recurrent mutations (c.2197T>C, c.1646G>C, and c.2198G>A) and a de novo nonsense mutation (c.148A>T). The novel mutation was not found in any of the unaffected family members or in the 100 healthy controls and was predicted to produce a truncated protein (p.K50X), a truncated form of the PHEX protein caused by nonsense mutations has been frequently detected in XLHR individuals. Thus, our work indicated that the c.148A>T (p.K50X) mutation was the likely pathogenic mutation in individual III-2 in family 2, and that PHEX gene mutations were responsible for XLHR in these Chinese families. These findings expand the mutation spectrum of PHEX and may help us to understand the molecular basis of XLHR in order to facilitate genetic counseling. PMID- 25839939 TI - Genetic association of IL-6, TNF-alpha and SDF-1 polymorphisms with serum cytokine levels in diabetic foot ulcer. AB - The IL-6 -174G/C (rs1800795), TNF-alpha -308G/A (rs1800629) and -238G/A (rs361525) and SDF-1 801G/A (rs1801157) are well characterized SNPs which have previously been linked to various diabetic complications. However, the involvement of these SNPs in DFU remains poorly studied. In the present study we looked at the association of these SNPs with DFU (disease phenotype) and correlated it with the serum levels of cytokines (intermediate phenotype) along with other clinical risk factors of DFU (adiponectin, leptin and hsCRP). Genotyping was carried out in Normal glucose tolerance ((NGT)/Control=106), T2DM without DFU (T2DM=139), T2DM with neuropathy (DFU-DN=191) and T2DM with PVD (DFU PVD=79) subjects by PCR-RFLP and the serum cytokine levels were determined by ELISA. IL-6 -176 "C" allele conferred significant protection against T2DM but not against DFU. TNF-alpha -308 "A" allele (but not -238 SNP) conferred significant susceptibility towards both T2DM and DFU-DN. The SDF-1 "A" allele conferred significant protection against both DM and DFU-DN but not against DFU-PVD. Further, these alleles were shown to influence the serum cytokine/chemokine levels under diabetic conditions. Thus SNPs in cytokine/chemokine genes serve as valuable biomarkers for DFU. PMID- 25839940 TI - Genetic polymorphism of MTHFR C677T and premature coronary artery disease susceptibility: A meta-analysis. AB - The association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and premature coronary artery disease (PCAD) is controversial. To explore a more precise estimation of the association, a meta-analysis was conducted in the present study. The relevant studies were identified by searching PubMed, EMBASE, the Web of Science, Cochrane Collaboration Database, Chinese National Knowledge Infrastructure, Wanfang Database and China Biological Medicine up to November, 2014. The meta-analysis was performed by STATA 11. 21 studies with a total of 6912 subjects, including 2972 PCAD patients and 3940 controls. The pooled analysis showed that MTHFR C677T gene polymorphism was probably associated with PCAD (CT vs. CC: OR=1.13, 95% CI=1.01-1.27; dominant model: OR=1.16, 95% CI=1.04-1.29; recessive model: OR=1.19, 95% CI=1.00-1.40; allele analysis: OR=1.17, 95% CI=1.01-1.34). Subgroup analysis by plasma homocysteine concentration showed a significant association in the homocysteine >15MUmol/L subgroup (CT vs. CC: OR=1.44, 95% CI=1.10-1.88; TT vs. CC: OR=2.51, 95% CI=1.12 5.63; dominant model: OR=1.51, 95% CI=1.16-1.96; recessive model: OR=2.33, 95% CI=1.05-5.20; allele analysis: OR=1.48, 95% CI=1.18-1.87). Subgroup analysis by continent displayed a significant association among the Asian population (CT vs. CC: OR=1.51, 95% CI=1.23-1.86; TT vs. CC: OR=2.81, 95% CI=1.87-4.23; dominant model: OR=1.65, 95% CI=1.35-2.01; recessive model: OR=2.22, 95% CI=1.53-3.21; allele analysis: OR=1.61, 95% CI=1.37-1.89). The statistical stability and reliability was demonstrated by sensitivity analysis and publication bias outcomes. In conclusion, the meta-analysis suggests that MTHFR C677T gene polymorphism may be associated with PCAD. PMID- 25839941 TI - Class III beta-tubulin in normal and cancer tissues. AB - Microtubules are polymeric structures composed of tubulin subunits. Each subunit consists of a heterodimer of alpha- and beta-tubulin. At least seven beta-tubulin isotypes, or classes, have been identified in human cells, and constitutive isotype expression appears to be tissue specific. Class III beta-tubulin (betaIII tubulin) expression is normally confined to testes and tissues derived from neural cristae. However, its expression can be induced in other tissues, both normal and neoplastic, subjected to a toxic microenvironment characterized by hypoxia and poor nutrient supply. In this review, we will summarize the mechanisms underlying betaIII-tubulin constitutive and induced expression. We will also illustrate its capacity to serve as a biomarker of neural commitment in normal tissues and as a pure prognostic biomarker in cancer patients. PMID- 25839942 TI - Idiopathic membranous nephropathy in children in China. AB - Idiopathic membranous nephropathy (IMN), which was the result from non-SLE, non hepatitis B or C virus infection, is relatively rare in children. We collected 584 pediatric cases of renal biopsy specimens in children hospitalized in Xijing Hospital from Jan 2008 to Dec 2013. We found that IgA nephropathy (27.9%) and Henoch-Schonlein purpura (26.4%) are the most common etiology of pediatric kidney disease, followed by minimal change disease (10.4%). Surprisingly, the prevalence of IMN is very high (7.5%) in pediatric patients. Moreover, the prevalence of IMN is quickly increasing from 4.4% in 2009 to 9.1% in 2013. PMID- 25839943 TI - Impact of manufactured TiO2 nanoparticles on planktonic and sessile bacterial communities. AB - In the present study, we conducted a 2 week microcosm experiment with a natural freshwater bacterial community to assess the effects of titanium dioxide nanoparticles (TiO2-NPs) at various concentrations (0, 1, 10 and 100 mg/L) on planktonic and sessile bacteria under dark conditions. Results showed an increase of planktonic bacterial abundance at the highest TiO2-NP concentration, concomitant with a decrease from that of sessile bacteria. Bacterial assemblages were most affected by the 100 mg/L TiO2-NP exposure and overall diversity was found to be lower for planktonic bacteria and higher for sessile bacteria at this concentration. In both compartments, a 100 mg/L TiO2-NPs exposure induced a decrease in the ratio between the Betaproteobacteria and Bacteroidetes. For planktonic communities, a decrease of Comamonadaceae was observed concomitant with an increase of Oxalobacteraceae and Cytophagaceae (especially Emticicia). For sessile communities, results showed a strong decrease of Betaproteobacteria and particularly of Comamonadaceae. PMID- 25839944 TI - Spectroscopic and computational studies of cobalamin species with variable lower axial ligation: implications for the mechanism of Co-C bond activation by class I cobalamin-dependent isomerases. AB - 5'-deoxyadenosylcobalamin (coenzyme B12, AdoCbl) serves as the cofactor for several enzymes that play important roles in fermentation and catabolism. All of these enzymes initiate catalysis by promoting homolytic cleavage of the cofactor's Co-C bond in response to substrate binding to their active sites. Despite considerable research efforts, the role of the lower axial ligand in facilitating Co-C bond homolysis remains incompletely understood. In the present study, we characterized several derivatives of AdoCbl and its one-electron reduced form, Co(II)Cbl, by using electronic absorption and magnetic circular dichroism spectroscopies. To complement our experimental data, we performed computations on these species, as well as additional Co(II)Cbl analogues. The geometries of all species investigated were optimized using a quantum mechanics/molecular mechanics method, and the optimized geometries were used to compute absorption spectra with time-dependent density functional theory. Collectively, our results indicate that a reduction in the basicity of the lower axial ligand causes changes to the cofactor's electronic structure in the Co(II) state that replicate the effects seen upon binding of Co(II)Cbl to Class I isomerases, which replace the lower axial dimethylbenzimidazole ligand of AdoCbl with a protein-derived histidine (His) residue. Such a reduction of the basicity of the His ligand in the enzyme active site may be achieved through proton uptake by the catalytic triad of conserved residues, DXHXGXK, during Co-C bond homolysis. PMID- 25839945 TI - The leaderful nurse. PMID- 25839946 TI - Evaluating an accelerated nursing program: a dashboard for diversity. AB - Diversity is a topic of increasing attention in higher education and the nursing workforce. Experts have called for a nursing workforce that mirrors the population it serves. Students in nursing programs in the United States do not reflect our country's diverse population; therefore, much work is needed before that goal can be reached. Diversity cannot be successfully achieved in nursing education without inclusion and attention to quality. The Inclusive Excellence framework can be used by nurse educators to promote inclusion, diversity, and excellence. In this framework, excellence and diversity are linked in an intentional metric-driven process. Accelerated programs offer a possible venue to promote diversity, and one accelerated program is examined using a set of metrics and a dashboard approach commonly used in business settings. Several recommendations were made for future assessment, interventions, and monitoring. Nurse educators are called to examine and adopt a diversity dashboard in all nursing programs. PMID- 25839947 TI - Advancing diversity through inclusive excellence in nursing education. AB - Nurse leaders call for a more diverse nursing workforce, but too few address the concept of inclusion as a recruitment and retention strategy or as part of improving the academic learning milieu. This article addresses organizational considerations of diversity and inclusion as part of the agenda established by the Association of American Colleges and Universities for inclusive excellence, building on the idea that academic environments only become excellent when an inclusive climate is reached. Six organizational strategies to inclusion are presented from the authors' experiences, some structural and others behavioral: admissions processes, invisibility, absence of community, promotion and tenure, exclusion, and tokenism. A call for structural and behavioral adaptions within nursing education to advance an inclusive excellence agenda is presented. PMID- 25839948 TI - Beginning with the end in mind: cultivating minority nurse leaders. AB - In response to the need for increased racial and ethnic diversity in the nursing profession, the Duke University School of Nursing (DUSON) established the Making a Difference in Nursing II (MADIN II) Program. The aim of the MADIN II Program is to improve the diversity of the nursing workforce by expanding nursing education opportunities for economically disadvantaged underrepresented minority (URM) students to prepare for, enroll in, and graduate from the DUSON's Accelerated Bachelors of Science in Nursing program. Adapted from the highly successful Meyerhoff Scholarship Program model, the program is to cultivate URM nursing graduates with advanced knowledge and leadership skills who can address health disparities and positively influence health care issues currently plaguing underrepresented populations. The article discusses the MADIN II framework consisting of four unique components: recruitment of students, the Summer Socialization Nursing Preentry Program, the Continued Connectivity Program, and the Succeed to Excellence Program, providing a framework for other academic programs interested in cultivating a pipeline of minority nurse leaders. PMID- 25839949 TI - NEXus: evaluation of an innovative educational consortium for doctoral education in nursing. AB - The purpose of this article is to describe the evaluation of the Nursing Education Xchange (NEXus), a national consortium of doctor of philosophy in nursing (PhD) and doctor of nursing practice programs, administered by the Western Institute of Nursing, which offers courses on-line. An external evaluator surveyed and interviewed faculty and staff coordinators, students, and the Western Institute of Nursing Board Members about their experiences with NEXus. Overall, individuals' perceptions of the NEXus program were positive. Some challenges in registering at other universities were addressed. The program helped PhD in nursing students complete their programs of study on time. Expansion of the program was recommended to offer more opportunities for students to take courses with experts in their areas of interest. Challenges and successes are discussed to assist others contemplating a consortium approach. PMID- 25839950 TI - Integrating Million Hearts into nursing and interprofessional educational curricula and community settings: a key strategy for improving population health across the United States. AB - Million Hearts is a national initiative to prevent 1 million heart attacks and strokes by 2017 by screening and educating the public on the "ABCS" of cardiovascular health. Million Hearts is an innovative platform for educating nursing and health sciences students on the importance of population health and interprofessional teamwork. The National Interprofessional Education and Practice Consortium to Advance Million Hearts was created, and a free on-line educational module was developed to help health care professionals and health sciences faculty and students learn about the Million Hearts initiative, conduct community screenings, and refer people who screen positive to appropriate resources. After completion of the module, individuals receive certification as a Million Hearts Fellow. More than 2,500 individuals from 80 colleges across the United States have accessed the module. More than 20,000 people have been screened. The module and screenings have been incorporated into health sciences curricula and community activities. Academic institutions and health science professions partnering together as part of the National Interprofessional Education and Practice Consortium to Advance Million Hearts provide a unique opportunity to demonstrate the impact that a unified approach can have on improving population health through the use of screening, education, and prevention. PMID- 25839951 TI - A model for increasing appreciation, accessibility and application of research in nursing. AB - The confidence and engagement of nurses (and midwives) in research are an area for continued development. The Research Appreciation, Accessibility, and Application Model (RAAAM), developed in 2011, provides a framework for enhancing research activities by nurses within the clinical setting. Unlike other models, the RAAAM does not assume a preexisting capacity or knowledge of research; however, the model incorporates the multiple research activities that comprise a research culture. Although it is acknowledged that undertaking a research project is not for everyone, using evidence-based knowledge for practice development is essential and relates to all clinical staff. The RAAAM model presents four domains-research appreciation, research accessibility, research application, and research sustainability. Research appreciation is a first step in realizing the potential beneficial impact of research in practice. Relating these activities to identified key result areas that are drawn from key stakeholders completes the loop, ensuring sustainability of research activities and processes. The model presented here offers a practical and user-friendly approach for research enhancement in nursing using the platform of a clinical and academic partnership. PMID- 25839952 TI - Preparedness for clinical: evaluation of the core elements of the Clinical Immersion curriculum model. AB - The Clinical Immersion Model is an innovative baccalaureate nursing curriculum that has demonstrated successful outcomes over the past 10 years. For those intending to adopt the model, individual components in isolation may prove ineffective. This article describes three core components of the curriculum that form the foundation of preparation for the senior-year clinical immersion. Detailed student-centered outcomes evaluation of these critical components is shared. Results of a mixed-methods evaluation, including surveys and focus groups, are presented. Implications of this curricular evaluation and future directions are explored. PMID- 25839953 TI - Practical strategies for nursing education program evaluation. AB - Self-evaluation is required for institutions of higher learning and the nursing programs within them. The literature provides information on evaluation models and instruments, and descriptions of how specific nursing education programs are evaluated. However, there are few discussions in the nursing education literature of the practical aspects of nursing education program evaluation: how to get started, how to keep track of data, who to involve in data collection, and how to manage challenging criteria. This article discusses the importance of program evaluation in the academic setting and provides information on practical ways to organize the evaluation process and aggregate data, and strategies for gathering data from students, graduates, alumni, and employers of graduates. PMID- 25839954 TI - Using Carl Rogers' person-centered model to explain interpersonal relationships at a school of nursing. AB - Faculty members are viewed as nurturers within the academic setting and may be able to influence students' behaviors through the formation of positive interpersonal relationships. Faculty members' attributes that best facilitated positive interpersonal relationships according to Carl Rogers' Person-Centered Model was studied. Students (n = 192) enrolled in a 3-year undergraduate nursing program in urban Jamaica were randomly selected to participate in this descriptive cross-sectional study. A 38-item questionnaire on interpersonal relationships with nursing faculty and students' perceptions of their teachers was utilized to collect data. Factor analysis was used to create factors of realness, prizing, and empathetic understanding. Multiple linear regression analysis on the interaction of the 3 factors and interpersonal relationship scores was performed while controlling for nursing students' study year and age. One hundred sixty-five students (mean age: 23.18 +/- 4.51years; 99% female) responded. The regression model explained over 46% of the variance. Realness (beta = 0.50, P < .001) was the only significant predictor of the interpersonal relationship scores assigned by the nursing students. Of the total number of respondents, 99 students (60%) reported satisfaction with the interpersonal relationships shared with faculty. Nursing students' perception of faculty members' realness appeared to be the most significant attribute in fostering positive interpersonal relationships. PMID- 25839955 TI - The teaching-learning approach and critical thinking development: a qualitative exploration of Taiwanese nursing students. AB - Health care professionals are challenged by the complexities of the health care environment. This study uses a qualitative approach to explore how teaching strategy affects the development of critical thinking (CT) among Taiwanese baccalaureate-level nursing students. Data collected from 109 students' reflection reports were analyzed using content analysis. Three categories generated by the analysis were the teaching-learning strategy, enhancing CT, and transiting into a different learning style. The teaching-learning strategy consisted of concept mapping, question and answer, and real-life case studies. CT was enhanced alternately by self-directed learning, the realization of the gap between known and unknown, and connecting the gap between theoretical nursing knowledge and clinical practice. The study results emphasize participants' perceptions of becoming a critical thinker, turning into an active learner, and eventually achieving self-confidence. These learning effects invest the wisdom of teaching-learning with a far-reaching significance. PMID- 25839956 TI - The experience of informatics nurses in Taiwan. AB - Despite recent progress in information technology, health care institutions are constantly confronted with the need to adapt to the resulting new processes of information management and use. Facilitating an effective technology implementation requires dedication from informatics nurses (INs) to bridge the gap between clinical care and technology. The purpose of this study was to explore the working experiences of INs, and alternatives to assist the growth and development of the specialty. This qualitative study recruited 8 participants, and data were collected in 2009 by use of interview guides related to work roles, responsibilities, competencies, and challenges. The emerged themes included (a) diversified roles and functions, (b) vague job description, (c) no decision making authority, (d) indispensable management support, and (e) searching resources for work fulfillment. Findings indicate that for organizations where nursing informatics development is ongoing, the IN role should be clearly defined as a specialist with identified support resources and decision-making authority. Nursing informatics interest groups should further develop training and certification programs to validate the professional image of the role. Concepts of nursing informatics should be included seamlessly throughout the educational curricula and informatics competency-based courses designed to strengthen student's technology use and data management capabilities. PMID- 25839957 TI - Tissue inhibitor of metalloproteinase 2 inhibits activation of the beta-catenin signaling in melanoma cells. AB - The tissue inhibitor of metalloproteinase (TIMP) family, including TIMP-2, regulates the activity of multifunctional metalloproteinases in pathogenesis of melanoma. The Wnt/beta-catenin pathway is constitutively activated and plays a critical role in melanoma progression. However, the relationship between TIMP-2 expression and beta-catenin activity is still unclear. We hypothesize that TIMP-2 over expression inhibits the activation of the Wnt/beta-catenin pathway in melanoma cells. Protein expression, distribution, and transcriptional activity of beta-catenin were assayed in established stable melanoma cell lines: parental A2058 expressing, A2058 T2-1 over-expressing (T2-1), and A2058 T2R-7 under expressing (T2R-7) TIMP-2. Compared to T2-1 cells at the basal level, T2R-7 showed significantly lower amount protein and weaker immunofluorescence staining of beta-catenin. This regulation is through posttranslational level via ubiquitination. Functionally, proliferation and cell growth were lower in T2R-7 compared to A2058 and T2-1. Lithium treatment was used to mimics activation of the Wnt/beta-catenin pathway. In T2R-7 cells under-expressing TIMP2, lithium significantly increased total beta-catenin, nuclear beta-catenin, and its downstream protein phosphor-c-Myc (S62). Nuclear beta-catenin staining was enhanced in T2R-7. Beta-catenin transcriptional activity and cell proliferation were also increased significantly. Axins inhibit beta-catenin pathway via GSK-3 beta. We further found the ratio of p-GSK-3 beta (S9) to beta-catenin and protein levels of Axins were significantly lower, whereas downstream Wnt 11 was high in T2R-7 treated with lithium. Collectively, the high level of TIMP-2 protein inhibits the activation of the Wnt/beta-catenin pathway, thus suppressing proliferation. Insights in the molecular mechanisms of TIMP-2 may provide promising opportunities for anti-proliferative therapeutic intervention. PMID- 25839958 TI - Antisynthetase Syndrome: two case report and literature review. AB - Antissintetase Syndrome (ASS) is characterized by myositis, Raunaud's phenomenon, fever, intertitial lung disease, mechanic's hands and arthropathy associated with the presence of antibodies against tRNA synthetase, especially anti-Jo-1. This article aims to review the literature on ASS and report two cases where the first is a patient with polymyositis who developed subluxation on the proximal interphalangeal joint of bilateral first right finger after a few years of the disease, associated with pulmonary manifestations and positive anti-JO-1. In the second case, we present a patient with dermatomyositis, who developed a subluxation of the two first fingers, anti-Jo1 positive and chest CT changes, but without clinical evidence of pulmonary involvement. These cases reveal the importance of performing early diagnosis. The authors describe two cases of this rare syndrome, emphasizing the severity of interstitial lung disease and arthritis. PMID- 25839959 TI - Parvovirus B19 infection as a cause of acute myositis in an adult. AB - Parvovirus B19 infection is often asymptomatic, but clinical expressions may include transient aplastic crisis, erythema infectiosum, non-immune hydrops fetalis, and chronic red cell aplasia. This virus has also been associated with rheumatoid arthritis and other autoimmune connective tissue diseases; however, we could not identify any acute adult myositis case developed after a Parvovirus B19 infection in the literature. For this reason, we would like to present a rare case of acute myositis developed after Parvovirus B19 infection. In patients presenting with symptoms of fever, rash on the legs and myositis, viral infections such as Parvovirus B19 should be kept in mind. PMID- 25839960 TI - Humanized mice dually challenged with R5 and X4 HIV-1 show preferential R5 viremia and restricted X4 infection of CCR5(+)CD4(+) T cells. AB - CCR5-tropic (R5) immunodeficiency virus type 1 (HIV-1) strains are highly transmissible during the early stage of infection in humans, whereas CXCR4-tropic (X4) strains are less transmissible. This study aimed to explore the basis for early phase R5 and X4 HIV-1 infection in vivo by using humanized mice dually challenged with R5 HIV-1NLAD8-D harboring DsRed and X4 HIV-1(NL-E) harboring EGFP. Whereas R5 HIV-1 replicated well, X4 HIV-1 caused only transient viremia with variable kinetics; however, this was distinct from the low level but persistent viremia observed in mice challenged with X4 HIV-1 alone. Flow cytometric analysis of HIV-1-infected cells revealed that X4 HIV-1 infection of CCR5(+)CD4(+) T cells was significantly suppressed in the presence of R5 HIV-1. X4 HIV-1 was more cytopathic than R5 HIV-1; however, this was not the cause of restricted X4 HIV-1 infection because there were no significant differences in the mortality rates of CCR5(+) and CCR5(-) cells within the X4 HIV-1-infected cell populations. Taken together, these results suggest that restricted infection of CCR5(+)CD4(+) T cells by X4 HIV-1 (occurring via a still-to-be-identified mechanism) might contribute to the preferential transmission of R5 HIV-1 during the early phase of infection. PMID- 25839961 TI - Association Between Organization Culture, Health Status, and Presenteeism. AB - OBJECTIVE: The aim of this study was to examine relationships of organizational culture and health behaviors with presenteeism. METHOD: Data of a self-reported questionnaire were collected from 816 employees, who joined the study on a voluntary basis, in seven enterprises in northern Taiwan. RESULTS: Organizational culture and health behaviors were found to be significantly associated with presenteeism. After adjusting for confounding factors, the number of health complaints seemed to be more suitable than chronic diseases in predicting presenteeism. CONCLUSIONS: This study result implied that advantage could be taken of organizational culture and employees' health behaviors to reduce presenteeism in the workplace. PMID- 25839962 TI - Nanopore Analysis of Single-Stranded Binding Protein Interactions with DNA. AB - We study the binding of E. coli single-stranded binding protein (SSB) to single stranded DNA (ssDNA) using a solid-state nanopore assay. We find that saturated nucleoprotein complexes can be distinguished easily from free SSB, ssDNA, or double-stranded DNA individually and demonstrate that the high affinity of SSB for ssDNA can be exploited to achieve high-fidelity differentiation from duplex molecules in a mixture. We then study nucleoprotein filament formation by systematically varying the amount of SSB relative to ssDNA. We observe a concomitant shift in the mean amplitude of electrical events that is consistent with weakly cooperative binding. Finally, we compare circular and linearized ssDNA saturated with SSB and use the results to infer structural details of the nucleoprotein complex. PMID- 25839963 TI - Cleaning nanoelectrodes with air plasma. AB - Unlike macroscopic and micrometer-sized solid electrodes whose surface can be reproducibly cleaned by mechanical polishing, cleaning the nanoelectrode surface is challenging because of its small size and extreme fragility. Even very gentle polishing typically changes the nanoelectrode size and geometry, thus, complicating the replication of nanoelectrochemical experiments. In this letter, we show the possibility of cleaning nanoelectrode surfaces nondestructively by using an air plasma cleaner. The effects of plasma cleaning have been investigated by atomic force microscopy (AFM) imaging, voltammetry, and scanning electrochemical microscopy (SECM). A related issue, the removal of an insoluble organic film from the nanoelectrode by plasma cleaning, is also discussed. PMID- 25839968 TI - E-mail to Promote Colorectal Cancer Screening Within Social Networks: Acceptability and Content. AB - Effective techniques to encourage colorectal cancer screening in underscreened populations have included social support interventions and e-mail reminders from physicians. Personalized e-mail messages to promote colorectal cancer screening within social networks could be even more effective but have not been studied. The authors interviewed 387 e-mail users, aged 42-73 years in Georgia, Hawaii, and Massachusetts. Participants were asked to edit a sample message in which the sender shares a recent colonoscopy experience and urges the recipient to discuss colorectal cancer screening with a doctor. For those reporting willingness to send this message, changes to the message and suggested subject lines were recorded. Edited text was analyzed for content and concordance with original message. The majority of participants (74.4%) were willing to e-mail a modifiable message. Of those willing, 63.5% edited the message. Common edits included deletion (17.7%) or modification (17.4%) of a negatively framed sentence on colon cancer risks and addition or modification of personalizing words (15.6%). Few edits changed the meaning of the message (5.6%), and even fewer introduced factual inaccuracies (1.7%). Modifiable e-mail messages offer a way for screened individuals to promote colorectal cancer screening to social network members. The accuracy and effects of such messages should be further studied. PMID- 25839969 TI - A Janus Kinase in the JAK/STAT signaling pathway from Litopenaeus vannamei is involved in antiviral immune response. AB - The JAK/STAT signaling pathways are conserved in evolution and mediate diversity immune responses to virus infection. In the present study, a Janus kinase (designated as LvJAK) gene was cloned and characterized from Litopenaeus vannamei. LvJAK contained the characteristic JAK homology domain (JH domain) from JH1 to JH7 and showed 19% identity (34% similarity) and 21% identity (35% similarity) to Drosophila Hopscotch protein and Human JAK2 protein, respectively. The mRNA of LvJAK was highly expressed in hepatopancreas of L. vannamei and its expression level was prominently upregulated after the stimulation of Poly (I:C) and white spot syndrome virus (WSSV) challenges. There were 10 putative STAT binding motifs in the promoter region of LvJAK, and it could be regulated by LvJAK self or (and) LvSTAT, suggesting that LvJAK is the JAK/STAT pathway target gene and could function as a positive regulator to form a positive feedback loop. In addition, the silencing of LvJAK caused higher mortality rate and virus load, suggesting that LvJAK could play an important role in defense against WSSV. This is the first report about the complete set of JAK/STAT proteins in shrimp and the results provide the evidence of the positive feedback loop mediated by JAK protein present in the JAK/STAT pathway in invertebrates. PMID- 25839970 TI - Particle size and traffic of phagocytes between the turbot peritoneal cavity and lymphoid organs. AB - New adjuvants based on microparticles are being developed for use in fish vaccines. The size of the microparticles may affect the immune response generated, as the adjuvant can either be retained at the site of injection or transported to lymphoid organs. The objectives of this study were to evaluate the maximum size of particles that can be exported out of the cavity, to determine the phagocytosis kinetics and to establish the routes whereby particle-containing cells move from the peritoneal cavity after injection. Fish were injected intraperitoneally with fluorescent cyclodextrins or with fluorescent particles of different size (0.1-10 MUm). Phagocytes containing beads of size 4 MUm or larger did not reach lymphoid organs, although some were able to cross the peritoneal mesothelium. The number of free peritoneal neutrophils and macrophage-like cells containing beads peaked at 6 and 24 h respectively, and the numbers then decreased quickly, indicating migration of cells to the peritoneum or other body areas. Migration of cells containing beads mainly occurs through the visceral peritoneum. These cells were found on the latero-ventral surfaces of the peritoneal folds that connect the visceral organs. Except for some vascularised areas, the surfaces of liver, stomach and intestine were devoid of particle containing cells. Some cells containing beads were also found attached to the parietal peritoneum, although in lower numbers than in the visceral peritoneum. Such cells were also found in high numbers in the spleen and kidney 6 h post injection. Because cells containing phagocytosed material quickly become attached to the peritoneum or migrate to lymphoid organs, the immune response generated by a vaccine or by an inflammatory stimulus should probably be evaluated in attached cells as well as in free peritoneal cells. PMID- 25839971 TI - Effect of copper nanoparticles and copper sulphate on oxidation stress, cell apoptosis and immune responses in the intestines of juvenile Epinephelus coioides. AB - Copper nanoparticles (Cu-NPs) are widely used in various industrial and commercial applications, but little is known about their potential hazard in the intestines of marine teleosts. In this study we investigated the effects of Cu NPs and soluble Cu in the intestines of juvenile Epinephelus coioides. The fish were exposed in triplicate to control, 20 or 100 MUg Cu L(-1) as either copper sulphate (CuSO4) or Cu-NPs for 25 days. With an increase in Cu-NPs or CuSO4 dose, the concentration of malonaldehyde in the intestines significantly increased, whereas the activities of total superoxide dismutase and catalase as well as glutathione concentration decreased compared to the control. Statistical analysis of an apoptosis index of intestinal cells showed that general dose-dependent apoptosis was induced by Cu-NPs or CuSO4, with Cu-NPs inducing the significantly higher apoptosis index than CuSOv. Caspase-3 and caspase-9 activities were increased with an increase in Cu-NPs or CuSO4 dose, more so in the Cu-NPs than CuSO4 treatment. With an increase in Cu-NPs or CuSOv dose, succinate dehydrogenase and Na(+)-K(+)-ATPase activity and cytochrome c concentration in mitochondria decreased, accompanied by increased cytochrome c concentration in the cytosol. Concentration of heat shock proteins 70 and 90 in the intestines and expression of corresponding genes were enhanced with an increase in the Cu-NPs or CuSOv dose, but the concentrations and expressions of immunoglobulin M and lysozyme decreased (more in the Cu-NPs than CuSO4 treatment) compared to the control. Expression of interleukin-1beta and tumor necrosis factor-alpha showed a dose-dependent increase with the increased Cu-NPs or CuSO4 dose, with the highest expression found in the Cu-NPs treatment. In conclusion, Cu-NPs had similar toxic effects as CuSOv in the intestines of juvenile E. coioides, but toxicity of Cu NPs was more severe than that of CuSO4. PMID- 25839972 TI - Shear-Induced Precursor Relaxation-Dependent Growth Dynamics and Lamellar Orientation of beta-Crystals in beta-Nucleated Isotactic Polypropylene. AB - Although a shear flow field and beta-nucleating agents (beta-NAs) can separately induce the formation of beta-crystals in isotactic polypropylene (iPP) in an efficient manner, we previously encountered difficulty in obtaining abundant beta crystals when these two factors were applied due to the competitive growth of alpha- and beta-crystals. In the current study, to induce the formation of a high fraction of beta-crystals, a strategy that introduces a relaxation process after applying a shear flow field but before cooling to crystallize beta-nucleated iPP was proposed. Depending on the relaxation state of the shear-induced oriented precursors, abundant beta-crystals with a refined orientation morphology were indeed formed. The key to producing these crystals lay in the partially dissolved shear-induced oriented precursors as a result of the relaxation process's ability to generate beta-crystals by inducing the formation of needlelike beta-NAs. Therefore, the content of beta-crystals gradually increased with relaxation time, whereas the overall crystallization kinetics progressively decreased. Moreover, more time was required for the content of the beta-phase to increase to the (maximum) value observed in quiescent crystallization than for the effect of flow on crystallization kinetics to be completely eliminated. The c-axis of the oriented beta-lamellae was observed to be perpendicular, rather than parallel, to the fiber axis of the needlelike beta-NAs, as first evidenced by the unique small angle X-ray scattering patterns obtained. The significance of the relaxation process was manifested in regulating the content and morphology of oriented beta crystals in sheared, beta-nucleated iPP and thus in the structure and property manipulation of iPP. PMID- 25839973 TI - MOF-derived magnetic carbonaceous nanocomposite as a heterogeneous catalyst to activate oxone for decolorization of Rhodamine B in water. AB - Metal Organic Frameworks (MOFs) represents one of the most interesting and versatile materials nowadays. As interests to explore MOFs' functionality and potential continue to grow, using MOFs as a platform/template to develop other functional materials has received a great attention recently. Among these MOF derived materials, MOF-derived carbonaceous materials are particularly attractive owing to its simple preparation and dual characteristics from carbon and metals. Herein, we propose to prepare a cobalt-based magnetic carbonaceous nanocomposite (MCN) by one-step carbonization of the cobalt-containing MOF, ZIF-67. Because of cobalt oxide (i.e., Co3O4) in MCN, MCN not only exhibits magnetic controllability but also catalytic activity to activate Oxone. To investigate and optimize this MCN-activated Oxone process, the decolorization of a cationic dye, Rhodamine B (Rh.B) in water is selected as a model reaction. This MCN-activated Oxone process was found to be the most effective when the ratio of Oxone/MCN was 5/1. While the high temperatures significantly improved the decolorization efficiency, the high initial pH was unfavorable for the Rh.B decolorization by this catalytic Oxone process. UV irradiation and ultrasonication were both found to enhance this MCN activated Oxone process. The recyclability test revealed that MCN can be continuously used with constant and effective catalytic activity. These features enable MCN to be a promising and interesting catalyst for the wet chemical oxidation such as the Oxone oxidation process. PMID- 25839975 TI - Response to Letter to the Editor Re: Clinical Outcome Parameters for Necrotizing Otitis Externa. PMID- 25839974 TI - A case study on quantitative in vitro to in vivo extrapolation for environmental esters: Methyl-, propyl- and butylparaben. AB - Parabens have been reported as potential endocrine disrupters and are widely used in consumer projects including cosmetics, foods and pharmaceuticals. We report on the development of a PBPK model for methyl-, propyl-, and butylparaben. The model was parameterized through a combination of QSAR for tissue solubility and quantitative in vitro to in vivo extrapolation (IVIVE) for hydrolysis in portals of entry including intestine and skin as well as in the primary site of metabolism, the liver. Overall, the model provided very good agreement with published time-course data in blood and urine from controlled dosing studies in rat and human, and demonstrates the potential value of quantitative IVIVE in expanding the use of human biomonitoring data in safety assessment. An in vitro based cumulative margin of safety (MOS) was calculated by comparing the effective concentrations from an in vitro assay of estrogenicity to the free paraben concentrations predicted by the model to be associated with the 95th percentile urine concentrations reported in NHANES (2009-2010 collection period). The calculated MOS for adult females was 108, whereas the MOS for males was 444. PMID- 25839976 TI - Clinical Characteristics and Management of External Auditory Canal Squamous Cell Carcinoma in Post-Irradiated Nasopharyngeal Carcinoma Patients. AB - OBJECTIVE: To describe the clinical characteristics and management of patients with external auditory canal (EAC) squamous cell carcinoma (SCC) that arose after they received radiotherapy for nasopharyngeal carcinoma (NPC) and to compare them with primary EAC SCC patients. STUDY DESIGN: Retrospective clinical analysis. SETTING: Hospital. PATIENTS: Nine irradiated NPC patients who subsequently developed secondary EAC SCC and 41 primary EAC SCC patients at a single hospital. INTERVENTION: Clinical characteristics and management outcomes of patients were reviewed. MAIN OUTCOME MEASURES: Clinical manifestations, regions of tumor involvement, the pathological staging, cumulative overall survival rates, Kaplan Meier method, log rank test, and Mann-Whitney U test. RESULTS: The most common symptoms of both groups were otorrhea, otalgia, and hearing loss. The region most involved in both groups was the EAC. The proportions of early stage (T1,T2) tumors in the post-irradiated and primary EAC SCC group were 56 and 22%, respectively. The 6-month, 1-year, 2-year, and 3-year cumulative overall survival rates of the post-irradiated EAC SCC group were 100, 100, 89, and 89%, respectively. The incidence of radionecrosis was higher in the post-irradiation EAC SCC group than in the primary EAC SCC group. CONCLUSIONS: Post-irradiation EAC SCC has similar symptoms and invades similar regions as primary EAC SCC. The proportion of early stage tumors in the post-irradiated EAC SCC group was higher than that in the primary EAC SCC group. High incidence of radionecrosis was observed after the second course of radiotherapy. Aggressive surgical treatment is strongly recommended, but adjuvant radiotherapy for early stage EAC SCC should be provided cautiously. PMID- 25839977 TI - 3D Printed Pediatric Temporal Bone: A Novel Training Model. AB - OBJECTIVE: Temporal bone dissection is a fundamental element of otologic training. Cadaveric temporal bones (CTB) are the gold standard surgical training model; however, many institutions do not have ready access to them and their cost can be significant: $300 to $500. Furthermore, pediatric cadaveric temporal bones are not readily available. Our objective is to develop a pediatric temporal bone model. STUDY DESIGN: Temporal bone model. SETTING: Tertiary Children's Hospital. SUBJECTS: Pediatric patient model. METHODS: We describe the novel use of a 3D printer for the generation of a plaster training model from a pediatric high- resolution CT temporal bone scan of a normal pediatric temporal bone. RESULTS: Three models were produced and were evaluated. The models utilized multiple colors (white for bone, yellow for the facial nerve) and were of high quality. Two models were drilled as a proof of concept and found to be an acceptable facsimile of the patient's anatomy, rendering all necessary surgical landmarks accurately. The only negative comments pertaining to the 3D printed temporal bone as a training model were the lack of variation in hardness between cortical and cancellous bone, noting a tactile variation from cadaveric temporal bones. CONCLUSION: Our novel pediatric 3D temporal bone training model is a viable, low cost training option for previously inaccessible pediatric temporal bone training. Our hope is that, as 3D printers become commonplace, these models could be rapidly reproduced, allowing for trainees to print models of patients before performing surgery on the living patient. PMID- 25839978 TI - Pros and Cons of Round Window Vibroplasty in Open Cavities: Audiological, Surgical, and Quality of Life Outcomes. AB - OBJECTIVE: To evaluate the audiological, surgical, quality of life, and quality of sound outcomes in adults with open cavities implanted with the Vibrant Soundbridge (VSB) implant using round window (RW) vibroplasty approach. STUDY DESIGN: Retrospective study. SETTING: Otolaryngology department, tertiary referral hospital. SUBJECTS AND METHODS: Twelve adult patients with conductive or mixed hearing loss, all with previous middle ear surgery, underwent RW vibroplasty in an open cavity. Compound action potential thresholds were assessed during surgery. Surgical complications were recorded. Subjective benefit was evaluated using the Nijmegen Cochlear Implant Questionnaire (NCIQ), Glasgow Benefit Inventory (GBI), and Hearing Implant Sound Quality Index (HISQUI29) tests. RESULTS: Mean follow-up was 42 months (range 12-76). There was no significant change in bone conduction thresholds after surgery. Mean functional gain was 34.3 dB and speech discrimination score at 65 dB significantly improved from 14 to 83%. Extrusion of the wire link was the main surgical complication in four patients. All NCIQ domains improved after surgery. All patients had a positive overall GBI score (mean 35.0). Mean HISQUI29 score was 152.8, on average the quality of sound being defined as "very good." CONCLUSION: VSB is an effective method of hearing restoration for adults with open cavities suffering from conductive or mixed hearing loss. Intraoperative electrocochleography may be considered of significant help to check the coupling to the inner ear. The high rate of extrusion suggests that middle ear obliteration may be considered in these patients. PMID- 25839979 TI - Electrophysiological Detection of Intracochlear Scalar Changing Perimodiolar Cochlear Implant Electrodes: A Blinded Study. AB - OBJECTIVE: To investigate whether a previous established neural response telemetry (NRT) ratio corresponds with the scalar position of the CI electrode. STUDY DESIGN: Retrospective blinded controlled study. SETTING: Tertiary referral center. PATIENTS: The electrophysiological data sets of 85 patients with measured intraoperative NRTs were evaluated. All patients were implanted with the same CI system. Using a flat panel tomography system, the position of the electrode array was confirmed radiologically. INTERVENTIONS: The radiological results were blindly compared with the intraoperatively obtained electrophysiological data (NRT ratio) and statistically evaluated. In a second step, irregularities between the NRT ratios and the radiologically confirmed electrode positions were determined and the entire study material was investigated deeper. MAIN OUTCOME MEASURES: Correlation of the NRT ratio with the intracochlear position of the CI electrode. RESULTS: By electrophysiological evaluation only, 69 patients were detected without a scalar change at first. In 16 patients, a scalar change was probable. A significant correlation between the radiological results and the NRT ratios was found. Secondly, additional patient characteristics were identified which influences the electrode's position. Excluding those patients, the selectivity and specificity of the NRT ratio could be increased to a higher level. CONCLUSION: Evidenced by a blinded group of patients, we are able to show that the electrode array position within the cochlea could be predicted using the NRT ratio. PMID- 25839980 TI - Correlation of Electrophysiological Properties and Hearing Preservation in Cochlear Implant Patients. AB - OBJECTIVE: To monitor changes in cochlear function during cochlear implantation using electrocochleography (ECoG) and to correlate changes to postoperative hearing preservation. METHODS: ECoG responses to acoustic stimuli of 250, 500, and 1000 Hz were recorded during cochlear implantation. The recording electrode was placed on the promontory and stabilized to fix the position during cochlear implantation. Baseline recordings were obtained after completion of the posterior tympanotomy. Changes of the ongoing ECoG response at suprathreshold intensities were analyzed after full insertion of the cochlear implant electrode array. Audiometric tests were conducted before and 4 weeks after surgery and correlated with electrophysiological findings. RESULTS: Ninety-five percent (18/19) of cochlear implant subjects had measurable ECoG responses. Under unchanged conditions, recordings showed a high repeatability without significant differences between 2 recordings (p <= 0.01). Ninety-four percent (17/18) of subjects showed no relevant changes in ECoG recordings after insertion of the cochlear implant electrode array. One subject showed decreases in responses at all frequencies indicative of cochlear trauma. This was associated with a complete hearing loss 4 weeks after surgery compared with mean presurgical low frequency hearing of 78 dB HL. CONCLUSION: Extracochlear ECoG is a reliable tool to assess cochlear function during cochlear implantation. Moderate threshold shifts could be caused by postoperative mechanisms or minor cochlear trauma. Detectable changes in extracochlear ECoG recordings, indicating gross cochlear trauma, are probably predictive of complete loss of residual acoustic hearing. PMID- 25839981 TI - Normal Values for Cervical Vestibular-Evoked Myogenic Potentials. AB - OBJECTIVES: To assess the variability of normal values for cervical vestibular evoked myogenic potentials (cVEMP) testing and to provide guidance regarding which parameters should be reported for clinical practice. STUDY DESIGN: Forty eight normal subjects with no history of hearing loss or vestibular symptoms underwent cVEMP testing. Measurement parameters were tabulated and compared to other sets of cVEMP normal values in the literature. The literature was reviewed to assess the clinical significance of abnormal cVEMP results. The distributions of threshold and symmetry ratios for normal subjects were compared to the distributions of 90 patients who underwent cVEMP testing. SETTING: Tertiary academic center. RESULTS: Upper limits of 42% symmetry ratio and the range of 65 to 95 dB HL for threshold were established for our center.The quartile coefficients of dispersion were much less than 1.0 for all cVEMP parameters in the literature, suggesting that the variability in normal ranges across the literature is small. The distributions for threshold and symmetry ratio were similar between normal and patient groups. There is a lack of information in the literature regarding the impairment of function resulting from various degrees of abnormality of VEMP results. CONCLUSIONS: Normal values for cVEMP parameters are statistically consistent in the literature. The clinical significance of abnormal values has not been validated. For clinical purposes, cVEMP "thresholds" should be reported. Reporting of other parameters is optional. PMID- 25839982 TI - Otosclerosis Without Stapes Fixation. PMID- 25839983 TI - The psychological side of sport. PMID- 25839984 TI - Diversity of CRISPR loci and virulence genes in pathogenic Escherichia coli isolates from various sources. AB - Shiga toxin-producing Escherichia coli (STEC) strains, including those of O157:H7 and the "big six" serogroups (i.e., O26, O45, O103, O111, O121, and O145) are food-borne pathogens that pose a serious health threat to humans. Ruminants, especially cattle, are a major reservoir for O157 and non-O157 STEC. In the present study, 115 E. coli strains isolated from small and very small beef processing plants were screened for virulence genes (stx1, stx2, eae) using a multiplex polymerase chain reaction (PCR). Thirteen (11.3%) of the 115 isolates tested positive for stx1, stx2, or eae genes, but only 4 (3.5%) tested positive for either stx1 or stx2. A multiplex PCR reaction targeting eight O-serogroups (O26, O45, O103, O111, O113, O121, O145, O157) identified 12 isolates as O26, O103, O111, or O145, with E. coli O26 being the most predominant serogroup (61.5%). The thirteen isolates were further analyzed using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) subtyping. Consistent with previous studies, CRISPR alleles from strains of the same serogroup were similar in their spacer content and order, regardless of the isolation source. A completely different CRISPR allele was observed in one isolate ("7-J") which exhibited a different O-serogroup (O78). Our results confirmed previous findings that CRISPR loci are conserved among phylogenetically-related strains. In addition, 8 E. coli O26 isolates and a collection of 42 E. coli O26 isolates were screened for 12 enterohemorrhagic E. coli-specific genes. Seven genes (ECs848 Hypothetical Protein, ECs2226-Hypothetical Protein, ECs3857-nleB, ECs3858 Hypothetical Protein, ECs4552-escF, ECs4553-Hypothetical Protein, and ECs4557 sepL) were found in all 50 isolates. An additional 5 genes (ECs1322-ureA urease subunit gamma, ECs1323-ureB urease subunit beta, ECs1326-ureF, ECs1561 Hypothetical Protein, and ECs1568-Hypothetical Protein) were found to be highly prevalent in isolates from human sources, while lower in isolates from beef processing plants, cattle, and other sources. This finding indicates the possible role of these genes in virulence of human O26 strains. PMID- 25839985 TI - Thermoelectric Transport Properties of Fe-Enriched ZnO with High-Temperature Nanostructure Refinement. AB - Thermoelectric properties of Fe-doped ZnO materials are investigated and correlated with the phase and microstructural evolution. Both a ZnO solid solution phase and a ZnFe2O4 spinel phase are observed. Analysis was made of temperature measurements of Seebeck coefficients as combined with the law of mixture to estimate the Fermi level in the constituent phases, which are further correlated with the Fe solute concentration in ZnO lattices and the overall electrical conductivity. In addition, the thermoelectric figure of merit is found to increase with the actual Fe content in ZnO lattices, due to the reduced thermal conductivity by point defect scattering of phonons and enhanced electrical transport via electron doping. The maximum achievable power factor of Fe-doped ZnO material is found to be similar to that of the ZnO-In2O3 system. Another important finding of the present work is the significant nanostructure refinement in 18 month old FeO1.5-doped ZnO after high-temperature thermal treatment, leading to further reduced thermal conductivity, which is beneficial and promising for high-temperature thermoelectric performance. PMID- 25839986 TI - Quality and length of life, money and urethral stricture disease. AB - PURPOSE OF REVIEW: This article walks through some of the ideas behind patient reported outcome measurement and quality of life research against the backdrop of urethral stricture disease and conditions of the lower urinary tract more generally, why measurement matters at all, future areas for research and development and potential opportunities for misuse and manipulation. RECENT FINDINGS: It is the authors' opinion that only one published study has substantially advanced our understanding of the way men with urethral stricture disease manage this condition in the real world, and, in turn, the outcomes those men seek when they consent to surgery and its associated risks. There is, however, almost certainly greater acceptance now by reconstructive urologists of the utility of patient-reported outcome measures in audit; surgical performance evaluation; clinical research; and fair, logical and transparent healthcare resource allocation at a population level. This is evidenced by the recent proliferation of studies incorporating patient-reported outcomes, which appear today to be on parity at least with those that surgeons historically gave priority to. SUMMARY: The next frontier in urethral stricture disease outcomes research is a better understanding of the impact of this condition on men's daily lives. That level of insight is likely to be gained through a mixture of qualitative and quantitative research methods applied to collaborative research ventures with men with the condition who, as those that have the most to gain and lose, must be majority stakeholders in this process. PMID- 25839989 TI - Ivabradine: A Unique and Intriguing Medication for Treating Cardiovascular Disease. AB - There has been much research linking elevated resting heart rate to cardiovascular morbidity and mortality. Based on these findings, a lower resting heart rate would be of theoretical benefit in patients with cardiovascular disease. From a pathophysiologic perspective, a lower resting heart rate would be of particular benefit in patients with ischemic heart disease and/or heart failure. Although beta-blockers and nondihydropyridine calcium channel blockers are effective at lowering heart rate, they have many other pharmacologic effects that may not be desirable in some patients, such as negative inotropy. Ivabradine is a drug designed to lower heart rate without any other demonstrable pharmacologic effects; in other words, a pure heart rate-lowering drug. It functions by blocking the hyperpolarization-activated cyclic nucleotide gated channels (f-channels) specific for the sinoatrial node and disrupting If ion current flow. This effectively prolongs diastolic depolarization and slows firing in the sinoatrial node, which lowers heart rate. The effects of ivabradine are most pronounced at higher heart rates (use-dependence), which is important in minimizing the development of symptomatic bradycardia. Clinical trials have demonstrated ivabradine to be an effective antianginal drug both alone and in combination with beta-blocker therapy, although it has not been shown to produce a demonstrable effect on reducing major adverse cardiovascular events. In patients with heart failure, ivabradine has demonstrated many hemodynamic benefits, but its effect on clinical outcomes have been mixed and dependent on baseline heart rate, ie, the drug may be of benefit with higher baseline heart rates, but detrimental with low baseline heart rates. The adverse effects of ivabradine are not uncommon, but are rarely severe and include visual disturbances, bradycardia, and atrial fibrillation. Although ivabradine is a very interesting new agent, its variable benefits in large-scale clinical trials leave its exact place in therapy still somewhat nebulous. Unanswered questions include which patient populations would benefit most from this drug, and which concomitant medications would produce the best clinical outcomes when used with ivabradine. PMID- 25839988 TI - Low-temperature plasma treatment induces DNA damage leading to necrotic cell death in primary prostate epithelial cells. AB - BACKGROUND: In recent years, the rapidly advancing field of low-temperature atmospheric pressure plasmas has shown considerable promise for future translational biomedical applications, including cancer therapy, through the generation of reactive oxygen and nitrogen species. METHOD: The cytopathic effect of low-temperature plasma was first verified in two commonly used prostate cell lines: BPH-1 and PC-3 cells. The study was then extended to analyse the effects in paired normal and tumour (Gleason grade 7) prostate epithelial cells cultured directly from patient tissue. Hydrogen peroxide (H2O2) and staurosporine were used as controls throughout. RESULTS: Low-temperature plasma (LTP) exposure resulted in high levels of DNA damage, a reduction in cell viability, and colony forming ability. H2O2 formed in the culture medium was a likely facilitator of these effects. Necrosis and autophagy were recorded in primary cells, whereas cell lines exhibited apoptosis and necrosis. CONCLUSIONS: This study demonstrates that LTP treatment causes cytotoxic insult in primary prostate cells, leading to rapid necrotic cell death. It also highlights the need to study primary cultures in order to gain more realistic insight into patient response. PMID- 25839987 TI - Frequent MED12 mutations in phyllodes tumours of the breast. AB - BACKGROUND: Phyllodes tumours are rare fibroepithelial tumours of the breast, that include benign, borderline, and malignant lesions. Although the molecular basis of phyllodes tumours largely remains unknown, a recent exome study identified MED12 mutations as a sole recurrent genetic alteration in fibroadenoma, a common benign fibroepithelial tumour that shares some histological features with the phyllodes tumour. METHODS: Forty-six phyllodes tumours and 58 fibroadenomas of the breast were analysed for MED12 mutations by using Sanger sequencing. RESULTS: MED12 mutations were identified in 37 out of the 46 phyllodes tumours (80%). The prevalence of MED12 mutations was similar among benign (15/18, 83%), borderline (12/15, 80%), and malignant tumours (10/13, 77%). MED12 mutations were also identified in 36 of the 58 fibroadenomas (62%). The mutations were frequent among intracanalicular-type (24/32, 75%) and complex type lesions (4/6, 67%), but were significantly less common among the pericanalicular-type lesions (8/20, 40%). A microdissection-based analysis showed that MED12 mutations were confined to the stromal components in both phyllodes tumours and fibroadenomas. CONCLUSIONS: MED12 mutations were frequent among the phyllodes tumours of the breast, regardless of the tumour grade. Phyllodes tumours and fibroadenomas share, at least in part, a common genetic background. PMID- 25839990 TI - Reverse Remodeling in Systolic Heart Failure. AB - Left ventricular (LV) remodeling is the most common term used to describe the functional, structural, myocellular, and interstitial changes that occur in response to myocardial injury and/or chronic changes in myocardial loading conditions. Progression of LV remodeling over time in response to neurohormonal activation, increased wall stress, and inflammatory signaling pathways is associated with an increased risk of major morbidity and mortality. LV reverse remodeling describes the process by which an injured LV with a dilated spherical phenotype may return toward a normalization of ventricular structure and function, either spontaneously or in response to therapeutic interventions. LV reverse remodeling can occur in response to interventions that mitigate the source of myocardial injury, or that reduce or eliminate the neurohormonal and/or hemodynamic factors that contribute to the progression of the LV remodeling process. In this article, we review selected studies that demonstrate the LV reverse remodeling process in response to pharmacological, pacemaker device, and mechanical circulatory support device interventions. Future therapies targeting the physiological, neurohormonal, and/or molecular signaling pathways to effect reverse remodeling may further improve clinical outcomes in heart failure patients. PMID- 25839991 TI - Usefulness of platelet function tests to predict bleeding with antithrombotic medications. AB - The pharmacological inhibition of platelets has always been regarded as a double edged sword: the challenge of balancing the antithrombotic effect against the bleeding risk. Potent antiplatelet agents and novel oral anticoagulants, sometimes in combination, are increasingly used in the treatment of cardiovascular disease and for thromboprophylaxis in atrial fibrillation. Although such treatment has reduced the risk of thrombotic events, the potential for major bleeding has increased, and a technique to identify those at increased bleeding risk is greatly needed. Platelet function tests (PFTs), most frequently VerifyNow and also the vasodilator-stimulated phosphoprotein -phosphorylation assay, have been used to identify low on-treatment platelet reactivity, to identify individuals who may be at increased bleeding risk. Such results predict nuisance bleeding, but many individuals have low on-treatment platelet reactivity and yet do not exhibit major or even minor bleeding. Although PFTs may be useful in assessing populations, they do not allow identification of individual patients at risk of bleeding on either antiplatelet or novel oral anticoagulant therapy, nor do they allow the tailoring of such therapy to optimize the risk:benefit ratio. Thrombin plays a cardinal role in both arterial thrombus formation and hemostasis, yet most PFTs fail to assess the contribution of thrombin, because they employ anticoagulated blood. Techniques such as the calibrated automated thrombogram and the point-of-care global thrombosis test, performed on native blood, which measure endogenous thrombin potential, seem to show the most promise for profiling bleeding risk, as tests that most physiologically assess the effects of medications on thrombin. PMID- 25839992 TI - Strain Imaging: From Physiology to Practical Applications in Daily Practice. AB - Non-Doppler, 2-dimensional strain imaging is a new echocardiographic technique for obtaining strain and strain rate measurements, which serves as a major advancement in understanding myocardial deformation. It analyzes motion in ultrasound imaging by tracking speckles in 2 dimensions. There are a lot of data emerging with multiple applications of strain imaging in the clinical practice of echocardiography. As incorporation of strain imaging in daily practice has been challenging, we intend to systematically highlight the top 10 applications of speckle-tracking echocardiography, which every cardiologist should be aware of: chemotherapy cardiotoxicity, left ventricular assessment, cardiac amyloidosis, hypertrophic obstructive cardiomyopathy, right ventricular dysfunction, valvular heart diseases (aortic stenosis and mitral regurgitation), cardiac sarcoidosis, athlete heart, left atrial assessment, and cardiac dyssynchrony. PMID- 25839993 TI - Epigenetic Regulation in Heart Failure: Part I RNA. AB - Epigenetic regulatory mechanisms play key roles in cardiac development, differentiation, homeostasis, response to stress and injury and disease. Human heart failure epigenetic regulatory mechanisms have not been deciphered to date. This 2-part review distills the rapidly evolving research focused on human heart failure epigenetic regulatory mechanisms. Part I focuses on epigenetic regulatory mechanisms involving RNA, specifically the role of short, intermediate and long noncoding RNAs and endogenous competing RNA regulatory networks. Part II focuses on the epigenetic regulatory mechanisms involving DNA, including DNA methylation, histone modifications, and chromatin conformational changes. Part II concludes with 2 examples of well-studied integrated epigenetic regulatory mechanisms, the structural and functional roles of the mediator complex in regulating transcription, and the epigenetic networked "cross-talk" regulating atrial natriuretic peptide and brain natriuretic peptide promoter activation. PMID- 25839994 TI - Regulation of alpha-1 acid glycoprotein synthesis by porcine hepatocytes in monolayer culture. AB - Alpha-1 acid glycoprotein (AGP, orosomucoid, ORM-1) is a highly glycosylated mammalian acute-phase protein, which is synthesized primarily in the liver and represents the major serum protein in newborn pigs. Recent data have suggested that the pig is unique in that AGP is a negative acute-phase protein in this species, and its circulating concentration appears to be associated with growth rate. The purpose of the present study was to investigate the regulation of AGP synthesis in hepatocytes prepared from suckling piglets and to provide a framework to compare its regulation with that of haptoglobin (HP), a positive acute-phase protein. Hepatocytes were isolated from preweaned piglets and maintained in serum-free monolayer culture for up to 72 h. The influences of hormones, cytokines, and redox modifiers on the expression and secretion of AGP and HP were determined by relative polymerase chain reaction and by measuring the concentration of each protein secreted into culture medium. The messenger RNA abundance and/or secretion of AGP protein was enhanced by interleukin (IL)-17a, IL-1, and resveratrol and inhibited by tumor necrosis factor-alpha (TNF), oncostatin M, and thyroid hormone (P < 0.05). HP expression and synthesis were upregulated by oncostatin M, IL-6, and dexamethasone and downregulated by TNF (P < 0.01). The overall messenger RNA expression at 24 h was in agreement with the secreted protein patterns confirming that control of these proteins in hepatocytes is largely transcriptional. Moreover, these data support the consideration that AGP is a negative acute-phase reactant and appears to be regulated by cytokines (with the exception of TNF) and hormones primarily in a manner opposite to that of the positive acute-phase protein, HP. PMID- 25839995 TI - Seasonality of dizziness and vertigo in a tropical region. AB - Vertigo and dizziness are among the most common medical complaints in the emergency room, and are associated with a considerable personal and health care burden. Scarce and conflicting reports indicate those symptoms may present a seasonal distribution. This study aimed at investigating the existence of a seasonal distribution of vertigo/dizziness in a tropical region, and the correlations of these findings with climatic variables. The charts of all patients consecutively admitted between 2009 and 2012 in the emergency room of a Brazilian general hospital were reviewed. A total of 4920 cases containing these terms were sorted from a sample of 276,076 emergency records. Seasonality was assessed using Cosinor Analysis. Pearson's correlations were performed between the incidence of consultations, considering separately dizziness and vertigo and each of the predictor climatic variables of that index month. Significant seasonal patterns were observed for dizziness and vertigo in the emergency room. Vertigo was more frequent in late winter-spring, negatively correlating to humidity (r = -0.374; p = 0.013) and rainfall (r = -0.334; p = 0.020). Dizziness peaked on summer months, and positively correlated to average temperatures (r = 0.520; p < 0.001) and rainfall (r = 0.297; p = 0.040), but negatively to atmospheric pressure (r = -0.424; p = 0.003). The different seasonal patterns evidenced for dizziness and vertigo indicate possible distinct underlying mechanisms of how seasons may influence the occurrence of those symptoms. PMID- 25839996 TI - Determining the probiotic potential of cholesterol-reducing Lactobacillus and Weissella strains isolated from gherkins (fermented cucumber) and south Indian fermented koozh. AB - This study sought to evaluate the probiotic potential of lactic acid bacteria (LAB) isolated from traditionally fermented south Indian koozh and gherkin (cucumber). A total of 51 LAB strains were isolated, among which four were identified as Lactobacillus spp. and three as Weissella spp. The strains were screened for their probiotic potential. All isolated Lactobacillus and Weissella strains were capable of surviving under low pH and bile salt conditions. GI9 and FKI21 were able to survive at pH 2.0 and 0.50% bile salt for 3 h without losing their viability. All LAB strains exhibited inhibitory activity against tested pathogens and were able to deconjugate bile salt. Higher deconjugation was observed in the presence of sodium glycocholate (P < 0.05). Strain FKI21 showed maximum auto-aggregation (79%) and co-aggregation with Escherichia coli MTCC 1089 (68%). Exopolysaccharide production of LAB strains ranged from 68.39 to 127.12 mg/L (P < 0.05). Moreover, GI9 (58.08 MUg/ml) and FKI21 (56.25 MUg/ml) exhibited maximum cholesterol reduction with bile salts. 16S rRNA sequencing confirmed GI9 and FKI21 as Lactobacillus crispatus and Weissella koreensis, respectively. This is the first study to report isolation of W. koreensis FKI21 from fermented koozh and demonstrates its cholesterol-reducing potential. PMID- 25839997 TI - Development of potentiometric equipment for the identification of altered dry cured hams: A preliminary study. AB - Microbiological contamination in dry-cured ham can occur in the early stages of the process, a large number of microorganisms involved in spoilage can produce alterations in the product. These include non-common odours, which are detected at the end of the process by a procedure called "cala", consisting of a sharp instrument punctured in every ham; this is smelled by an expert taster, who classifies hams as good and altered hams. An electronic device would be suitable for this process given the large amount of hams. The present research aims to develop objective equipment based on the potentiometry technique that identifies altered hams. A probe was developed, containing silver, nickel and copper electrodes, and was employed to classify altered and unaltered hams prior to classification by a tester. The results shown lower Ag and higher Cu potential values for altered hams. The differences in potentiometric response reveal a classification model, although further studies are required to obtain a reliable classification model. PMID- 25839998 TI - Multiple low-affinity interactions support binding of human osteopontin to integrin alphaXbeta2. AB - Integrin alpha(X)beta(2) (also known as complement receptor 4, p150,95, or CD11c/CD18) is expressed in the cell membrane of myeloid leukocytes. alpha(X)beta(2) has been reported to bind a large number of structurally unrelated ligands, often with a shared molecular character in the presence of polyanionic stretches in poorly folded proteins or glucosaminoglycans. Nevertheless, it is unclear what chemical sources of polyanionicity enable the binding by alpha(X)beta(2). Osteopontin (OPN) is an intrinsically disordered protein, which facilitates phagocytosis via the integrin alpha(X)beta(2). Unlike for other integrins, neither the RGD nor the SVVYGLR motifs account for this binding, and the molecular basis of OPN binding by alpha(X)beta(2) remains uncharacterized. Here, we show that the monovalent interactions between the ligand-binding domain of alpha(X)beta(2) and OPN, its fragments, or caseins are weak, with dissociation constants higher than 10(-5)M but with high apparent stoichiometries. From comparison with cell adhesion studies, the discrimination between alpha(X)beta(2) ligands and non-ligands appears to rely on these apparent stoichiometries in a way, which involves glutamate rather than aspartate side chains. Surprisingly, the extensive, negatively charged phosphorylation of OPN is not contributing to alpha(X)beta(2) binding. Furthermore, synchrotron radiation circular spectroscopy excludes that the phosphorylation affects the general folding of OPN. Taken together, our quantitative analyses reveal a mode of ligand recognition by integrin alpha(X)beta(2), which seem to differ in principles considerably from other OPN receptors. PMID- 25839999 TI - The ABC of protein kinase conformations. AB - Due to their involvement in human diseases, protein kinases are an important therapeutic target class. Conformation is a key concept for understanding how functional activity, inhibition and sequence are linked. We assemble and annotate the mammalian structural kinome from the Protein Data Bank on the basis of a universal residue nomenclature. We identify a torsion angle around the Gly of the DFG-motif whose sharp distribution profile corresponds to three eclipsed conformations. This allows the definition a small set of clusters whose distribution shows a bias for the active conformation. A common rationale links the active and inactive state: stabilization of the active conformation, as well as inactivation by displacement of helix-alphaC or the DFG-motif is governed by the interaction between helix-alphaC and the DFG motif. In particular, the conformation of the DFG-motif is tightly correlated with the propensity of helix alphaC displacement. Our analysis reveals detailed mechanisms for the displacement of helix-alphaC and the DFG and improves our understanding of the role of individual residues. By pooling conformations from the whole structural kinome, the energetic contributions of sequence and extrinsic factors can be estimated in free energy analyses. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. PMID- 25840000 TI - Kinetic isotope effects in the characterization of catalysis by protein tyrosine phosphatases. AB - Although thermodynamically favorable, the uncatalyzed hydrolysis of phosphate monoesters is extraordinarily slow, making phosphatases among the most catalytically efficient enzymes known. Protein-tyrosine phosphatases (PTPs) are ubiquitous in biology, and kinetic isotope effects were one of the key mechanistic tools used to discern molecular details of their catalytic mechanism and the transition state for phosphoryl transfer. Later, the unique level of detail KIEs provided led to deeper questions about the potential role of protein motions in PTP catalysis. The recent discovery that such motions are responsible for different catalytic rates between PTPs arose from questions originating from KIE data showing that the transition states and chemical mechanisms are identical, combined with structural data demonstrating superimposable active sites. KIEs also reveal perturbations to the transition state as mutations are made to residues directly involved in chemistry, and to residues that affect protein motions essential for catalysis. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. PMID- 25840001 TI - WITHDRAWN: Lidocaine-prilocaine cream for analgesia during circumcision in newborn boys. PMID- 25840002 TI - Parenting and social competence in school: The role of preadolescents' personality traits. AB - In a study of 230 preadolescent students (mean age 11.3 years) from the wider area of Athens, Greece, the role of Big Five personality traits (i.e. Neuroticism, Conscientiousness, Openness to Experience, Agreeableness and Extraversion) in the relation between parenting dimensions (overprotection, emotional warmth, rejection, anxious rearing) and social competence in school was examined. Multiple sets of regression analyses were performed. Main effects of Conscientiousness and Openness to Experience were identified. Limited evidence for moderation and some support of gender-specific parenting was found. Agreeableness and Extraversion interacted with paternal overprotection, whereas Neuroticism interacted with maternal and paternal rejection in predicting social competence. Mean differences in gender and educational grade were reported. The relationship between environmental effects (such as parenting during early adolescence) and social adjustment in school is discussed in terms of the plasticity and malleability of the preadolescents' personality characteristics. PMID- 25840003 TI - Development of Methods for Determination of Aflatoxins. AB - Aflatoxins can cause damage to the health of humans and animals. Several institutions around the world have established regulations to limit the levels of aflatoxins in food, and numerous analytical methods have been extensively developed for aflatoxin determination. This review covers the currently used analytical methods for the determination of aflatoxins in different food matrices, which includes sampling and sample preparation, sample pretreatment methods including extraction methods and purification methods of aflatoxin extracts, separation and determination methods. Validation for analysis of aflatoxins and safety considerations and precautions when doing the experiments are also discussed. PMID- 25840004 TI - Placebo 'serotonin' increases heart rate variability in recovery from psychosocial stress. AB - OBJECTIVE: To investigate placebo effects on heart rate (HR) and heart rate variability (HRV) in recovery from a psychosocial stressor. METHODS: A healthy sample underwent two mental arithmetic stress tests in one experimental session. After undergoing the baseline test, participants were randomized into control or placebo groups. Prior to the second stress test, the placebo group received an intranasal dose of 'serotonin' (placebo) with the suggestion that it would enhance recovery. HR and HRV were assessed throughout procedures. RESULTS: There was an increase in vagally-mediated HRV in the placebo group. The change in HR did not differ between groups. CONCLUSIONS: Placebo suggestion can enhance autonomic recovery after psychosocial stress. Findings are consistent with the notion of top-down mechanisms of placebo effects, but further research would need to specifically examine the role of top-down regulatory pathways as possible mediators of placebo-induced changes in autonomic function. PMID- 25840005 TI - Non-linear model for compression tests on articular cartilage. AB - Hydrated soft tissues, such as articular cartilage, are often modeled as biphasic systems with individually incompressible solid and fluid phases, and biphasic models are employed to fit experimental data in order to determine the mechanical and hydraulic properties of the tissues. Two of the most common experimental setups are confined and unconfined compression. Analytical solutions exist for the unconfined case with the linear, isotropic, homogeneous model of articular cartilage, and for the confined case with the non-linear, isotropic, homogeneous model. The aim of this contribution is to provide an easily implementable numerical tool to determine a solution to the governing differential equations of (homogeneous and isotropic) unconfined and (inhomogeneous and isotropic) confined compression under large deformations. The large-deformation governing equations are reduced to equivalent diffusive equations, which are then solved by means of finite difference (FD) methods. The solution strategy proposed here could be used to generate benchmark tests for validating complex user-defined material models within finite element (FE) implementations, and for determining the tissue's mechanical and hydraulic properties from experimental data. PMID- 25840007 TI - The genetics of neuropsychiatric diseases: looking in and beyond the exome. AB - Next-generation sequencing, which allows genome-wide detection of rare and de novo mutations, is transforming neuropsychiatric disease genetics through identifying on an unprecedented scale genes and protein-coding mutations that confer risk. Although understanding how regulatory variants influence risk remains a challenge, we are likely transitioning into a phase of neuropsychiatric disease genetics in which the rate-limiting step may no longer be gene discovery. Instead, the future will concentrate more on the biological and clinical translation of the torrent of specific risk mutations identified through next generation sequencing. Here, we review the recent progress that resulted specifically from exome sequencing and emphasize the need for rigorous statistical evaluation of the expanding data sets, as well as expanded functional analysis of implicated proteins and mutations. Then, we introduce some of the expected opportunities and challenges investigators face when moving beyond the exome. Finally, we briefly highlight the challenge of deriving translational benefit from the progress in genetics. PMID- 25840006 TI - Neurological aspects of human glycosylation disorders. AB - This review presents principles of glycosylation, describes the relevant glycosylation pathways and their related disorders, and highlights some of the neurological aspects and issues that continue to challenge researchers. More than 100 rare human genetic disorders that result from deficiencies in the different glycosylation pathways are known today. Most of these disorders impact the central and/or peripheral nervous systems. Patients typically have developmental delays/intellectual disabilities, hypotonia, seizures, neuropathy, and metabolic abnormalities in multiple organ systems. Among these disorders there is great clinical diversity because all cell types differentially glycosylate proteins and lipids. The patients have hundreds of misglycosylated products, which afflict a myriad of processes, including cell signaling, cell-cell interaction, and cell migration. This vast complexity in glycan composition and function, along with the limited availability of analytic tools, has impeded the identification of key glycosylated molecules that cause pathologies. To date, few critical target proteins have been pinpointed. PMID- 25840009 TI - Visual guidance in control of grasping. AB - Humans and other primates possess a unique capacity to grasp and manipulate objects skillfully, a facility pervasive in everyday life that has undoubtedly contributed to the success of our species. When we reach and grasp an object, various cortical areas in the parietal and frontal lobes work together effortlessly to analyze object shape and position, transform this visual information into useful motor commands, and implement these motor representations to preshape the hand before contact with the object is made. In recent years, a growing number of studies have investigated the neural circuits underlying object grasping in both the visual and motor systems of the macaque monkey. The accumulated knowledge not only helps researchers understand how object grasping is implemented in the primate brain but may also contribute to the development of novel neural interfaces and neuroprosthetics. PMID- 25840010 TI - 5'-AMP-activated protein kinase alpha regulates stress granule biogenesis. AB - Stress granule (SG) assembly represents a conserved eukaryotic defense strategy against various insults. Although essential for the ability to cope with deleterious conditions, the signaling pathways controlling SG formation are not fully understood. The energy sensor AMP-activated protein kinase (AMPK) is critical for the cellular stress response. Human cells produce two AMPK catalytic alpha-subunits with not only partially overlapping, but also unique functions. Here, we provide direct support for structural and functional links between AMPK alpha isoforms and SGs. As such, several stressors promote SG association of AMPK alpha2, but not AMPK-alpha1. Multiple lines of evidence link AMPK activity to SG biogenesis. First, pharmacological kinase inhibition interfered with SG formation. Second, AMPK-alpha knockdown combined with in-depth quantitative SG analysis revealed isoform-specific changes of SG characteristics. Third, overexpression of mutant alpha-subunits further substantiated that AMPK regulates SG parameters. Finally, we identified the SG-nucleating protein G3BP1 as an AMPK alpha2 binding partner. This interaction is stimulated by stress and notably occurs in SGs. Collectively, our data define the master metabolic regulator AMPK as a novel SG constituent that also controls their biogenesis. PMID- 25840008 TI - Neurodegenerative diseases: expanding the prion concept. AB - The prion paradigm has emerged as a unifying molecular principle for the pathogenesis of many age-related neurodegenerative diseases. This paradigm holds that a fundamental cause of specific disorders is the misfolding and seeded aggregation of certain proteins. The concept arose from the discovery that devastating brain diseases called spongiform encephalopathies are transmissible to new hosts by agents consisting solely of a misfolded protein, now known as the prion protein. Accordingly, "prion" was defined as a "proteinaceous infectious particle." As the concept has expanded to include other diseases, many of which are not infectious by any conventional definition, the designation of prions as infectious agents has become problematic. We propose to define prions as "proteinaceous nucleating particles" to highlight the molecular action of the agents, lessen unwarranted apprehension about the transmissibility of noninfectious proteopathies, and promote the wider acceptance of this revolutionary paradigm by the biomedical community. PMID- 25840011 TI - Selective removal of mitochondria via mitophagy: distinct pathways for different mitochondrial stresses. AB - The efficient and selective elimination of damaged or excessive mitochondria in response to bioenergetic and environmental cues is critical for maintaining a healthy and appropriate population of mitochondria. Mitophagy is considered to be the central mechanism of mitochondrial quality and quantity control. Atg32, a mitophagy receptor in yeast, recruits mitochondria targeted for degradation into the isolation membrane via both direct and indirect interactions with Atg8. In mammals, different mitophagy effectors, including the mitophagy receptors NIX, BNIP3 and FUDNC1 and the PINK1/Parkin pathway, have been identified to participate in the selective clearance of mitochondria. One common feature of mitophagy receptors is that they harbor an LC3-interacting region (LIR) that interacts with LC3, thus promoting the sequestration of mitochondria into the isolation membrane. Additionally, both receptor- and Parkin/PINK1-mediated mitophagy have been found to be regulated by reversible phosphorylation. Here, we review the recent progress in the understanding of the molecular mechanisms involved in selective mitophagy at multiple levels. We also discuss different mitophagy receptors from an evolutionary perspective and highlight the specific functions of and possible cooperation between distinct mechanisms of mitophagy. PMID- 25840012 TI - Mild maternal stress disrupts associative learning and increases aggression in offspring. AB - Maternal stress has been shown to affect behaviour of offspring in a wide range of animals, but this evidence has come from studies that exposed gestating mothers to acute or severe stressors, such as restraint or exposure to synthetic stress hormones. Here we show that exposure of mothers to even a mild stressor reduces associative learning and increases aggression in offspring. Female guppies were exposed to routine husbandry procedures that produced only a minimal, non-significant, elevation of the stress hormone cortisol. In contrast to controls, offspring from mothers that experienced this mild stress failed to learn to associate a colour cue and food reward, and showed a greater amount of inter-individual variation in behaviour compared with control offspring. This mild stress also resulted in offspring that were more aggressive towards their own mirror image than controls. While it is possible that these results could represent the transmission of beneficial maternal characteristics to offspring born into unpredictable environments, the potential for mild maternal stress to affect offspring performance also has important implications for research into the trans-generational effects of stress. PMID- 25840013 TI - Poly(ionic liquids) functionalized polypyrrole/graphene oxide nanosheets for electrochemical sensor to detect dopamine in the presence of ascorbic acid. AB - Novel poly(ionic liquids) functionalized polypyrrole/graphene oxide nanosheets (PILs/PPy/GO) were prepared by the polymerization of 1-vinyl-3-ethylimidazole bromide (VEIB) on the surface of N-vinyl imidazolium modified PPy/GO nanosheets. Due to the synergistic effects of GO with well-defined lamellar structures, conductive PPy and biocompatible PILs, PILs/PPy/GO modified glassy carbon electrode (GCE) presented the excellent electrochemical catalytic activity towards dopamine (DA) with good stability, high sensitivity and wide linear range in the present of ascorbic acid (AA) with high concentration. PILs played an essential role for the simultaneous determination of DA and AA in a mixture, whose existence effectively improved the transmission mode of electrons and resulted in the different electrocatalytic performance towards the oxidation of DA and AA. It is indicated that PILs/PPy/GO nanosheets can act as a good steady and sensitive electrode material for the development of improved DA sensors. PMID- 25840014 TI - Theophylline detection in serum using a self-assembling RNA aptamer-based gold nanoparticle sensor. AB - Recently, DNA aptamer-gold nanoparticle (AuNP) conjugates have emerged as novel biosensing tools. Although RNA aptamers are more advantageous than DNA aptamers, their vulnerable nature during the construction of these conjugates restricts the development of RNA aptasensors. In this study, we developed an RNA aptamer-based AuNP sensor for the detection of theophylline in serum, combining the high binding affinity and selectivity of a theophylline RNA aptamer and the fluorescence quenching ability of AuNPs. In order to prevent nuclease degradation during the experimental process, the single strand of the theophylline RNA aptamer (33-mer) was split at the end loop region into two shorter halves, which were able to reassemble to form the theophylline-binding pocket. One fragment was linked to a DNA sequence that included a 15 thymine (T15) spacer and a polyadenine (polyA, A12) tail. The chimeric RNA/DNA oligonucleotide was attached to AuNPs within a few minutes via adsorption of the polyA tail. The other fragment was labeled with a fluorophore (Cy3). The two individual fragments self assembled in the presence of theophylline. Upon ligand binding, the fragments came into close proximity, resulting in fluorescence quenching. This sensor exhibited a low detection limit of 0.05 uM, with a linear dynamic range from 0.1 to 10 uM in serum. Moreover, the sensor did not recognize theophylline-related compounds (e.g., caffeine and theobromine), demonstrating its high selectivity. This strategy offers new possibilities for the application of RNA aptasensors in clinical settings. PMID- 25840015 TI - Ultrasensitive homogeneous electrochemical strategy for DNA methyltransferase activity assay based on autonomous exonuclease III-assisted isothermal cycling signal amplification. AB - DNA methylation catalyzed by methyltransferase (MTase) plays an important role in many biological processes, including gene transcription, genomic imprinting and cellular differentiation. Herein, a simple and novel homogeneous electrochemical strategy for ultrasensitive DNA MTase activity assay has been successfully developed, which is based on methylation-triggered exonuclease (Exo) III-assisted autonomous isothermal cycling signal amplification. A duplex DNA (P1-P2 hybrid) containing the methylation-responsive sequence is ingeniously designed. In the presence of DNA adenine methylation (Dam) methyltransferase (MTase), P1-P2 hybrid is methylated and subsequently recognized and cleaved by Dpn I endonuclease, which triggers the Exo III-catalyzed autonomous cycling cleavage processes. Therefore, a large amount of methylene blue-labeled mononucleotides are released, generating a significantly amplified electrochemical signal toward the Dam MTase activity assay. The directly measured detection limit down to 0.004 U/mL is obtained, which is one or two orders magnitude lower than that of the approaches reported in literature. Since this assay is carried out in homogeneous solution phase under isothermal condition and sophisticated probe immobilization processes are avoided, it is very simple and easy to implement. Due to its advantages of ultrahigh sensitivity, excellent selectivity and simple operation, the as proposed strategy has great potential in the applications in DNA methylation related clinical practices and biochemical researches. PMID- 25840016 TI - Shape-controlled ceria-reduced graphene oxide nanocomposites toward high sensitive in situ detection of nitric oxide. AB - Nitric oxide (NO) is an important signal molecule released by most cancer cells under drug stimulation or/and disease development but it is extremely challenging to in situ while real-time sensitively detect NO due to its large diffusivity, low concentration and fast decay. Herein, shape-controlled reduced graphene oxide nanocomposing with ceria (rGO-CeO2) was synthesized via hydrothermal reaction to construct a highly sensitive real-time sensing platform for NO detection. The crystal shape of CeO2 nanoparticles in rGO-CeO2 composites significantly affects the sensing performance of rGO-CeO2, of which the regular hexagonal nanocrystal CeO2 achieves the highest sensitivity (1676.06 mA cm(-2) M(-1)), a wide dynamic range (18.0 nM to 5.6 uM) and a low detection limit (9.6 nM). This attributes to a synergical effect from high catalytic activity of the specifically shaped CeO2 nanocrystal and good conductivity/high surface area of rGO. This work demonstrates a way by rationally compose individual merit components while well control the nanostructure for a superior synergistic effect to build a smart sensing platform, while offering a great application potential to sensitively real-time detect NO released from living cells for diagnosis or/and studies of complicated biological processes. PMID- 25840017 TI - An exonuclease-assisted amplification electrochemical aptasensor for Hg(2+) detection based on hybridization chain reaction. AB - In this work, a novel electrochemical aptasensor was developed for Hg(2+) detection based on exonuclease-assisted target recycling and hybridization chain reaction (HCR) dual signal amplification strategy. The presence of Hg(2+) induced the T-rich DNA partly folded into duplex-like structure via the Hg(2+) mediated T Hg(2+)-T base pairs, which triggered the activity of exonuclease III (Exo III). Exo III selectively digested the double-strand DNA containing multiple T-Hg(2+)-T base pairs from its 3'-end, the released Hg(2+) participated analyte recycle. With each digestion cycle, a digestion product named as help DNA was obtained, which acted as a linkage between the capture DNA and auxiliary DNA. The presence of help DNA and two auxiliary DNA collectively facilitated successful HCR process and formed long double-stranded DNA. [Ru(NH3)6](3+) was used as redox indicator, which electrostatically bound to the double strands and produced an electrochemical signal. Exo III-assisted target recycling and HCR dual amplification significantly improved the sensitivity for Hg(2+) with a detection limit of 0.12 pM (S/N=3). Furthermore, the proposed aptasensor had a promising potential for the application of Hg(2+) detection in real aquatic sample analysis. PMID- 25840018 TI - Enzyme-free and label-free fluorescence aptasensing strategy for highly sensitive detection of protein based on target-triggered hybridization chain reaction amplification. AB - Proteins are of great importance in medical and biological fields. In this paper, a novel fluorescent aptasensing strategy for protein assay has been developed based on target-triggered hybridization chain reaction (HCR) and graphene oxide (GO)-based selective fluorescence quenching. Three DNA probes, a helper DNA probe (HP), hairpin probe 1 (H1) and hairpin probe 2 (H2) are ingeniously designed. In the presence of the target, the aptamer sequences in HP recognize the target to form a target-aptamer complex, which causes the HP conformation change, and then triggers the chain-like assembly of H1 and H2 through the hybridization chain reaction, generating a long chain of HP leading complex of H1 and H2. At last the fluorescence indicator SYBR Green I (SG) binds with the long double strands of the HCR product through both intercalation and minor groove binding. When GO was added into the solutions after HCR, the free H1, H2 and SG would be closely adsorbed onto GO surface via pi-pi stacking. However, the HCR product cannot be adsorbed on GO surface, thereby the SG bound to HCR product gives a strong fluorescence signal dependent on the concentration of the target. With the use of platelet-derived growth factor BB (PDGF-BB) as the model analyte, this newly designed protocol provides a highly sensitive fluorescence detection of PDGF-BB with a limit of detection down to 1.25 pM, and also exhibit good selectivity and applicability in complex matrixes. Therefore, the proposed aptasensing strategy based on target-triggered hybridization chain reaction amplification should have wide applications in the diagnosis of genetic diseases due to its simplicity, low cost, and high sensitivity at extremely low target concentrations. PMID- 25840019 TI - DNAzyme switches for molecular computation and signal amplification. AB - We have created molecular switches that consist of nucleic-acid cleaving DNAzymes which are temporarily inactivated by hybridization with blocking oligonucleotides. The unique design of the switches offers significant advantages over existing methods. Firstly, the switches are activated by a nucleic acid cleaving enzyme which can be made to function only in the presence of a specific target analyte. This allows for their use as reporter elements which can be easily adapted for use in computational logical operations. Secondly, the activation of each switch produces an active nucleic acid-cleaving DNAzyme as an output and this allows the switches to be modularly coupled to one another so that the output of one switch functions as the input of another. In addition, the switches are scalable, so that a single input target can produce more than one active DNAzyme output. These features therefore create the means for amplification of signal, which confers significant potential for future biosensing applications where detection of low quantities of target biomarkers is required. PMID- 25840020 TI - Label-free luminescent detection of LMP1 gene deletion using an intermolecular G quadruplex-based switch-on probe. AB - We have synthesized a series of luminescent iridium(III) complexes and investigated their ability to act as luminescent split G-quadruplex probes. After screening, the iridium(III) complex 1 [Ir(2-phenylquinoline)2(3,4,7,8-tetramethyl 1,10-phenanthroline)]PF6 was validated as a highly-selective G-quadruplex probe and was utilized to construct a label-free intermolecular G-quadruplex-based assay for the selective and sensitive detection of LMP1 gene deletion. This "mix and-detect" assay is simple and selective, and could detect down to 10 nM of the target gene in aqueous solution with a linear range from 10 to 500 nM. We also investigated the performance of our split G-quadruplex-based sensing platform for LMP1 gene deletion in the presence of cellular debris, demonstrating the robustness of this sensing system in biological samples. Comparative assays were also performed using either organic dyes or labeled oligonucleotides as signal transducing agents. PMID- 25840021 TI - L-Cysteine capped Mn-doped ZnS quantum dots as a room temperature phosphorescence sensor for in-vitro binding assay of idarubicin and DNA. AB - L-cysteine capped Mn doped ZnS quantum dots/ Idarubicin (IDA) nanohybrids were used as novel room temperature phosphorescence (RTP) sensor to detect double stranded deoxyribonucleic acid (ds-DNA)/drug interaction. IDA, anthracycline derivative anticancer drug, was adsorbed on the surface of the QDs as an electron acceptor to quench the RTP emission. The RTP intensity of QDs was quenched quickly upon addition of quencher and the reaction reached equilibrium within 2 min. The quenching mechanism of phosphorescence of Mn-doped ZnS QDs by IDA is a combined dynamic and static quenching. The static and dynamic quenching constants were found as 1.1*10(5) M(-1) and 8.7*10(4) M(-1), respectively. The addition of ds-DNA caused formation of ds-DNA/IDA complex and recovered the RTP signal of Mn doped ZnS QDs, which allowed qualitative analysis. Under optimal conditions, RTP intensity of QDs/IDA nanohybrids increased linearly with the concentration of ds DNA from 1.2 to 6.0 uM. This method is simple, low cost and avoids from interferences. PMID- 25840022 TI - World Trade Center disaster and sensitization to subsequent life stress: A longitudinal study of disaster responders. AB - PURPOSE: The current study examined the role of World Trade Center (WTC) disaster exposure (hours spent working on the site, dust cloud exposure, and losing friend/loved one) in exacerbating the effects of post-disaster life stress on posttraumatic stress disorder (PTSD) symptoms and overall functioning among WTC responders. METHOD: Participants were 18,896 responders (8466 police officers and 10,430 non-traditional responders) participating in the WTC Health Program who completed an initial examination between July, 2002 and April, 2010 and were reassessed an average of two years later. RESULTS: Among police responders, there was a significant interaction, such that the effect of post-disaster life stress on later PTSD symptoms and overall functioning was stronger among police responders who had greater WTC disaster exposure (beta's=.029 and .054, respectively, for PTSD symptoms and overall functioning). This moderating effect was absent in non-traditional responders. Across both groups, post-disaster life stress also consistently was related to the dependent variables in a more robust manner than WTC exposure. DISCUSSION: The present findings suggest that WTC exposure may compound post-disaster life stress, thereby resulting in a more chronic course of PTSD symptoms and reduced functioning among police responders. PMID- 25840023 TI - Synthesis of 2-(hetero)aryl-5-(trimethylsilylethynyl)oxazoles from (hetero)arylacrylic acids. AB - A three-step method for the synthesis of 2-(hetero)aryl-5 (trimethylsilylethynyl)oxazoles is described. Easily accessible bis(trimethylsilyl)acetylene and acrylic acid derivatives are used as starting materials for the preparation of mono- and disubstituted 5-(trimethylsilyl)pent-1 en-4-yn-3-ones. Oxidative phthalimidoaziridination of these enynones provides the key 2-acyl-1-phthalimidoaziridines that are further utilized in the thermal expansion of the three-membered ring to furnish the target functionalizable oxazoles. PMID- 25840024 TI - Stressors, Coping Resources, and Depressive Symptoms among Rural American Indian Older Adults. AB - The purpose of this study was to examine the associations of physical health stressors and coping resources with depressive symptoms among American Indian older adults age 50 years or older. The study used a convenience sample of 227 rural American Indian older adults. A hierarchical multiple regression tested three sets of predictors on depressive symptoms: (a) sociodemographics, (b) physical health stressors (functional disability and chronic medical conditions), and (c) coping resources (social support and spirituality). Most participants reported little difficulty in performing daily activities (e.g., eating, dressing, traveling, and managing money), while presenting over two types of chronic medical conditions. Depressive symptoms were predicted by higher scores on perceived social support and lower scores on functional disability; women and those having no health insurance also had higher levels of depressive symptoms. Findings suggest that social work practitioners should engage family and community support, advocate for access to adequate health care, and attend to women's unique circumstances and needs when working with American Indian older adults. PMID- 25840025 TI - Photocatalytic degradation of an azo textile dye (C.I. Reactive Red 195 (3BF)) in aqueous solution over copper cobaltite nanocomposite coated on glass by Doctor Blade method. AB - The degradation of C.I. Reactive Red 195 (3BF) in aqueous solution using copper cobaltite nanocomposite coated on glass by Doctor Blade method was studied. Structural, optical and morphological properties of nanocomposite coatings were characterized by X-ray powder diffractometry (XRD), diffuse reflectance spectroscopy (DRS) and field emission scanning electron microscopy (FESEM). The nanoparticles exhibit a particle size of 31 nm, showing a good nanoscale crystalline morphology. The photocatalytic activity of copper cobaltite nanocomposite coated on glass was studied by performing the photocatalytic degradation of 3BF at different irradiation time. The effect of irradiation time on the degradation of 3BF was studied and the results showed that more than 85% of the 3BF was degraded in 45 min of irradiation. The pseudo-first-order kinetic models were used and the rate constants were evaluated with pseudo first order rate constants of 4.10 * 10(-2) min(-1). The main advantage of the photocatalyst coated on glass overcomes the difficulties in separation and recycle of photocatalyst suspensions. PMID- 25840027 TI - A vibrational spectroscopic study of the phosphate mineral vantasselite Al4(PO4)3(OH)3.9H2O. AB - We have studied the phosphate mineral vantasselite Al4(PO4)3(OH)3.9H2O using a combination of SEM with EDX and Raman and infrared spectroscopy. Qualitative chemical analysis shows Al, Fe and P. Raman bands at 1013 and 1027 cm(-1) are assigned to the PO4(3-)nu1 symmetric stretching mode. The observation of two bands suggests the non-equivalence of the phosphate units in the vantasselite structure. Raman bands at 1051, 1076 and 1090 cm(-1) are attributed to the PO4(3 )nu3 antisymmetric stretching vibration. A comparison is made with the spectroscopy of wardite. Strong infrared bands at 1044, 1078, 1092, 1112, 1133, 1180 and 1210 cm(-1) are attributed to the PO4(3-)nu3 antisymmetric stretching mode. Some of these bands may be due to deltaAl2OH deformation modes. Vibrational spectroscopy offers a mechanism for the study of the molecular structure of vantasselite. PMID- 25840026 TI - Rayleigh light scattering detection of three alpha1-adrenoceptor antagonists coupled with high performance liquid chromatograph. AB - Herein, a Rayleigh light-scattering (RLS) detection method combined with high performance liquid chromatograph (HPLC) without any post-column probe was developed for the separation and determination of three alpha1-adrenoceptor antagonists. The quantitative analysis is benefiting from RLS signal enhancement upon addition of methanol which induced molecular aggregation to form an hydrophobic interface between aggregates and water that produce a sort of superficial enhanced scattering effect. A good chromatographic separation among the compounds was achieved using a Gemini 5u C18 reversed phase column (250 mm * 4.6 mm; 4 MUm) with a mobile phase consisting of methanol and ammonium acetate formic acid buffer solution (25 mM; pH=3.0) at the flow rate of 0.7 mL min(-1). The RLS signal was monitored at lambdaex=lambdaem=354 nm. A limit of detection (LOD) of 0.065-0.70 MUg L(-1) was reached and a linear range was found between peak height and concentration in the range of 0.75-15 MUg L(-1) for doxazosin mesylate (DOX), 0.075-3.0 MUg L(-1) for prazosin hydrochloride (PRH), and 0.25-5 MUg L(-1) for terazosin hydrochloride (TEH), with linear regression coefficients all above 0.999. Recoveries from spiked urine samples were 88.4-99.0% which is within acceptable limits. The proposed method is convenient, reliable and sensitive which has been used successfully in human urine samples. PMID- 25840033 TI - Solutions to the primary care physician shortage. PMID- 25840032 TI - The Association of Prenatal Exposure to Perfluorinated Chemicals with Maternal Essential and Long-Chain Polyunsaturated Fatty Acids during Pregnancy and the Birth Weight of Their Offspring: The Hokkaido Study. AB - BACKGROUND: Fatty acids (FAs) are essential for fetal growth. Exposure to perfluorinated chemicals (PFCs) may disrupt FA homeostasis, but there are no epidemiological data regarding associations of PFCs and FA concentrations. OBJECTIVES: We estimated associations between perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) concentrations and maternal levels of FAs and triglyceride (TG) and birth size of the offspring. METHODS: We analyzed 306 mother-child pairs in this birth cohort between 2002 and 2005 in Japan. The prenatal PFOS and PFOA levels were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. Maternal blood levels of nine FAs and TG were measured by gas chromatography-mass spectrometry and TG E-Test Wako kits, respectively. Information on infants' birth size was obtained from participant medical records. RESULTS: The median PFOS and PFOA levels were 5.6 and 1.4 ng/mL, respectively. In the fully adjusted model, including maternal age, parity, annual household income, blood sampling period, alcohol consumption, and smoking during pregnancy, PFOS but not PFOA had a negative association with the levels of palmitic, palmitoleic, oleic, linoleic, alpha-linolenic, and arachidonic acids (p < 0.005) and TG (p-value = 0.016). Female infants weighed 186.6 g less with mothers whose PFOS levels were in the fourth quartile compared with the first quartile (95% CI: -363.4, -9.8). We observed no significant association between maternal levels of PFOS and birth weight of male infants. CONCLUSIONS: Our data suggest an inverse association between PFOS exposure and polyunsaturated FA levels in pregnant women. We also found a negative association between maternal PFOS levels and female birth weight. PMID- 25840034 TI - One-hour rule-in and rule-out of acute myocardial infarction using high sensitivity cardiac troponin I. AB - OBJECTIVE: We aimed to prospectively derive and validate a novel 1h-algorithm using high-sensitivity cardiac troponin I (hs-cTnI) for early rule-out and rule in of acute myocardial infarction. METHODS: We performed a prospective multicenter diagnostic study enrolling 1811 patients with suspected acute myocardial infarction. The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography, echocardiography, follow-up data, and serial measurements of hs-cTnT (but not hs-cTnI). The hs-cTnI 1h-algorithm, incorporating measurements performed at baseline and absolute changes within 1 hour, was derived in a randomly selected sample of 906 patients (derivation cohort), and then validated in the remaining 905 patients (validation cohort). RESULTS: Acute myocardial infarction was the final diagnosis in 18% of patients. After applying the hs-cTnI 1h algorithm developed in the derivation cohort to the validation cohort, 50.5% of patients could be classified as "rule-out," 19% as "rule-in," 30.5% as "observe." In the validation cohort, the negative predictive value for acute myocardial infarction in the "rule-out" zone was 99.6% (95% confidence interval, 98.4% 100%), and the positive predictive value for acute myocardial infarction in the "rule-in" zone was 73.9% (95% confidence interval, 66.7%-80.2%). Negative predictive value of the 1h-algorithm was higher compared with the classical dichotomous interpretation of hs-cTnI and to the standard of care combining hs cTnI with the electrocardiogram (both P < .001). Positive predictive value also was higher compared with the standard of care (P < .001). CONCLUSION: Using a simple algorithm incorporating baseline hs-cTnI values and the absolute change within the first hour allows safe rule-out as well as accurate rule-in of acute myocardial infarction in 70% of patients presenting with suspected acute myocardial infarction. PMID- 25840035 TI - Tailored, interactive text messages for enhancing weight loss among African American adults: the TRIMM randomized controlled trial. AB - BACKGROUND: Helping patients control obesity remains a clinical challenge for internists, and African Americans experience obesity rates higher than other racial/ethnic groups. PURPOSE: To investigate whether a behavioral theory-based mobile health intervention would enhance weight loss when added to standard care among overweight/obese African American adults. METHODS: A randomized controlled trial of 124 adults recruited from Baltimore-area African American churches. Participant follow-up ended March 2013. Participants were randomized to standard care (included one-on-one counseling sessions with a dietitian and a physician) or standard care plus daily tailored text messages for 6 months. Text messages were delivered in phases: preparation, reinforcement of participant-selected diet and exercise goals, reflection, goal integration, weight loss methods, and maintenance. There were follow-up visits at 3, 6, and 12 months. Primary outcome was weight change from baseline to end-intervention at 6 months. Secondary outcomes included weight change at 3 months, engagement, and satisfaction with the intervention. RESULTS: Sixty-three participants were randomized to the mobile health intervention and 61 to standard-care control. Weights were collected in window for 45 (36.3%) at 3 months and 51 (41.1%) at 6 months. Mean weight loss at 3 months was 2.5 kg greater in the intervention group compared with standard care (95% confidence interval [CI], -4.3 to -0.6; P < .001), and 3.4 kg greater (95% CI, -5.2 to -1.7; P = .001) at 6 months. Degree of engagement with messages was correlated with weight loss. CONCLUSIONS: While attrition was high, this study supports a tailored, interactive text-message intervention to enhance weight loss among obese African-American adults. PMID- 25840036 TI - An extraction process to recover vanadium from low-grade vanadium-bearing titanomagnetite. AB - An extraction process to recover vanadium from low-grade vanadium-bearing titanomagnetite was developed. In this study, a mixed solvent system of di(2 ethylhexyl) phosphate (D2EHPA) and tri-n-butyl phosphate (TBP) diluted with kerosene was used for the selective extraction of vanadium from a hydrochloric acid leaching solution that contained low vanadium concentration with high concentrations of iron and impurities of Ca, Mg, and Al. In the extraction process, the initial solution pH and the phase ratio had considerable functions in the extraction of vanadium from the hydrochloric acid leaching solution. Under optimal extraction conditions (i.e., 30-40 degrees C for 10min, 1:3 phase ratio (O/A), 20% D2EHPA concentration (v/v), and 0-0.8 initial solution pH), 99.4% vanadium and only 4.2% iron were extracted by the three-stage counter-current extraction process. In the stripping process with H2SO4 as the stripping agent and under optimal stripping conditions (i.e., 20% H2SO4 concentration, 5:1 phase ratio (O/A), 20min stripping time, and 40 degrees C stripping temperature), 99.6% vanadium and only 5.4% iron were stripped by the three-stage counter-current stripping process. The stripping solution contained 40.16g/LV2O5,0.691g/L Fe, 0.007g/L TiO2, 0.006g/L SiO2 and 0.247g/L CaO. A V2O5 product with a purity of 99.12% V2O5 and only 0.026% Fe was obtained after the oxidation, precipitation, and calcination processes. The total vanadium recovered from the hydrochloric acid leaching solution was 85.5%. PMID- 25840037 TI - Diagnostic Role of High-Sensitivity Cardiac Troponin T in Acute Myocardial Infarction and Cardiac Noncoronary Artery Disease. AB - BACKGROUND AND AIMS: Currently, the distinction between AMI and cardiac noncoronary artery disease (CNCD) remains a challenge in clinical practice. Our aim was to evaluate the diagnostic role of high-sensitivity cardiac troponin T (hs-cTnT) level at presentation and its change within the first hour to distinguish AMI from CNCD. METHODS: hs-cTnT was measured at presentation and after 1 h in 110 consecutive Chinese patients with symptoms suggestive of AMI within 12 h from symptom onset. Receiver-operating characteristics (ROC) analysis was used to estimate the diagnostic accuracy of hs-cTnT. RESULTS: Patients with AMI had higher presentation values of hs-cTnT and higher absolute changes in the first h than patients with CNCD. The diagnostic accuracy of hs-cTnT at presentation for the distinction between patients with AMI and CNCD as quantified by the area under the receiver-operating characteristics curve (AUC) was 0.88. The discriminatory power of Deltahs-cTnT 0-1 h was higher for absolute (AUC, 0.89; 95% CI, 0.83-0.94) compared to relative (AUC, 0.64; 95% CI, 0.60-0.73) changes. Combining presentation values of hs-cTnT at presentation with absolute changes in the first h increased the AUC to 0.93 (p < 0.001 for comparison with AUC of 0 h hs-cTnT). CONCLUSIONS: Overall, our results suggest that the combined use of presentation values of hs-cTnT and its absolute change in the first hour discriminates well between patients with AMI and CNCD, further confirming the role of hs-cTnT as a biomarker for the early diagnosis of AMI. PMID- 25840038 TI - Radiculopathy in the setting of lumbar nerve root compression due to an extradural intraforaminal lipoma: a report of 3 cases. AB - A true adult spinal lipoma is an exceedingly rare cause of lumbar compression neuropathy. Only 5 cases of true extradural intraforaminal lipomas have been documented in the medical literature. The diagnostic criteria and treatment guidelines for this specific lipoma have yet to be established. This report features 3 histologically confirmed cases of extradural intraforaminal spinal lipomas that recently presented to the authors' practice. In addition, the literature was surveyed to include the 5 previously reported cases of true adult extradural intraforaminal spinal lipomas. The consistency in presentation, response to surgical intervention, and postoperative recovery in these 8 cases supports surgical intervention at the time of diagnosis. The authors' findings support elevated clinical suspicion, efficient diagnosis based on MRI, and early surgical intervention for this rare pathological entity. All cases presented in this report were symptomatic and occurred in the absence of other significant pathologies such as general spinal epidural lipomatosis, intradural lesions, tethering, or severe degenerative stenosis or herniated discs. The clinical, neuroradiological, and histological findings characteristic of a true adult extradural intraforaminal lipoma are emphasized to differentiate this lesion from the more common etiologies for lumbar compression neuropathy. Heightened awareness and clinical suspicion for the focal, foraminal spinal lipoma as a cause of radiculopathy symptoms will enable more efficient diagnosis and treatment. PMID- 25840039 TI - Intranasal delivery of bone marrow stromal cells to spinal cord lesions. AB - OBJECT: The intranasal delivery of bone marrow stromal cells (BMSCs) or mesenchymal stem cells to the injured brains of rodents has been previously reported. In this study, the authors investigated whether BMSCs migrate to spinal cord lesions through an intranasal route and whether the administration affected functional recovery. METHODS: Forty Sprague-Dawley rats that were subjected to spinal cord injuries at the T7-8 level were divided into 5 groups (injured + intranasal BMSC-treated group, injured + intrathecal BMSC-treated group, injured only group, injured + intranasal vehicle-treated group, and injured + intrathecal vehicle-treated group). The Basso-Beattie-Bresnahan (BBB) scale was used to assess hind limb motor functional recovery for 2 or 4 weeks. Intralesionally migrated BMSCs were examined histologically and counted at 2 and 4 weeks. To evaluate the neuroprotective and trophic effects of BMSCs, the relative volume of the lesion cavity was measured at 4 weeks. In addition, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in the CSF were evaluated at 2 weeks. RESULTS: Intranasally administered BMSCs were confirmed within spinal cord sections at both 2 and 4 weeks. The highest number, which was detected in the intrathecal BMSC-treated group at 2 weeks, was significantly higher than that in all the other groups. The BBB score of the intranasal BMSC-treated group showed statistically significant improvements by 1 week compared with the control group. However, in the final BBB scores, there was a statistically significant difference only between the intrathecal BMSC-treated group and the control group. The cavity ratios in the BMSC-treated groups were smaller than those of the control groups, but the authors did not find any significant differences in the NGF and BDNF levels in the CSF among the treatment and control groups. CONCLUSIONS: BMSCs reached the injured spinal cord through the intranasal route and contributed to the recovery of hind limb motor function and lesion cavity reduction. However, the effects were not as significant as those seen in the intrathecal BMSC-treated group. PMID- 25840040 TI - Surgical and clinical efficacy of sacroiliac joint fusion: a systematic review of the literature. AB - OBJECT: The sacroiliac joint (SIJ) and surgical intervention for treating SIJ pain or dysfunction has been a topic of much debate in recent years. There has been a resurgence in the implication of this joint as the pain generator for many patients experiencing low-back pain, and new surgical methods are gaining popularity within both the orthopedic and neurosurgical fields. There is no universally accepted gold standard for diagnosing or surgically treating SIJ pain. The authors systematically reviewed studies on SIJ fusion in the neurosurgical and orthopedic literature to investigate whether sufficient evidence exists to support its use. METHODS: A literature search was performed using MEDLINE, Google Scholar, and OvidSP-Wolters Kluwer Health for all articles regarding SIJ fusion published from 2000 to 2014. Original, peer-reviewed, prospective or retrospective scientific papers with at least 2 patients were included in the study. Exclusion criteria included follow-up shorter than 1-year, nonsurgical treatment, inadequate clinical data as determined by 2 independent reviewers, non-English manuscripts, and nonhuman subjects. RESULTS: A total of 16 peer-reviewed journal articles met the inclusion criteria: 5 consecutive case series, 8 retrospective studies, and 3 prospective cohort studies. A total of 430 patients were included, of whom 131 underwent open surgery and 299 underwent minimally invasive surgery (MIS) for SIJ fusion. The mean duration of follow-up was 60 months for open surgery and 21 months for MIS. SIJ degeneration/arthrosis was the most common pathology among patients undergoing surgical intervention (present in 257 patients [59.8%]), followed by SIJ dysfunction (79 [18.4%]), postpartum instability (31 [7.2%]), posttraumatic (28 [6.5%]), idiopathic (25 [5.8%]), pathological fractures (6 [1.4%]), and HLA-B27+/rheumatoid arthritis (4 [0.9%]). Radiographically confirmed fusion rates were 20%-90% for open surgery and 13%-100% for MIS. Rates of excellent satisfaction, determined by pain reduction, function, and quality of life, ranged from 18% to 100% with a mean of 54% in open surgical cases. For MIS patients, excellent outcome, judged by patients' stated satisfaction with the surgery, ranged from 56% to 100% (mean 84%). The reoperation rate after open surgery ranged from 0% to 65% (mean 15%). Reoperation rate after MIS ranged from 0% to 17% (mean 6%). Major complication rates ranged from 5% to 20%, with 1 study that addressed safety reporting a 56% adverse event rate. CONCLUSIONS: Surgical intervention for SIJ pain is beneficial in a subset of patients. However, with the difficulty in accurate diagnosis and evidence for the efficacy of SIJ fusion itself lacking, serious consideration of the cause of pain and alternative treatments should be given before performing the operation. PMID- 25840041 TI - The influence of preoperative spinal sagittal balance on clinical outcomes after microendoscopic laminotomy in patients with lumbar spinal canal stenosis. AB - OBJECT: More information about the association between preoperative anterior translation of the C-7 plumb line and clinical outcomes after decompression surgery in patients with lumbar spinal canal stenosis (LSS) would help resolve problems for patients with sagittal imbalance. The authors evaluated whether preoperative sagittal alignment of the spine affects low-back pain and clinical outcomes after microendoscopic laminotomy. METHODS: This study was a retrospective review of prospectively collected surgical data. The study comprised 88 patients with LSS (47 men and 41 women) who ranged in age from 39 to 86 years (mean age 68.7 years). All patients had undergone microendoscopic laminotomy at Osaka City University Graduate School of Medicine from May 2008 through October 2012. The minimum duration of clinical and radiological follow-up was 6 months. All patients were evaluated by Japanese Orthopaedic Association (JOA) and visual analog scale (VAS) scores for low-back pain, leg pain, and leg numbness before and after surgery. The distance between the C-7 plumb line and the posterior corner of the sacrum (sagittal vertical axis [SVA]) was measured on lateral standing radiographs of the entire spine obtained before surgery. Radiological factors and clinical outcomes were compared between patients with a preoperative SVA >= 50 mm (forward-bending trunk [F] group) and patients with a preoperative SVA < 50 mm (control [C] group). A total of 35 patients were allocated to the F group (19 male and 16 female) and 53 to the C group (28 male and 25 female). RESULTS: The mean SVA was 81.0 mm for patients in the F group and 22.0 mm for those in the C group. At final follow-up evaluation, no significant differences between the groups were found for the JOA score improvement ratio (73.3% vs 77.1%) or the VAS score for leg numbness (23.6 vs 24.0 mm); the VAS score for low-back pain was significantly higher for those in the F group (21.1 mm) than for those in the C group (11.0 mm); and the VAS score for leg pain tended to be higher for those in the F group (18.9 +/- 29.1 mm) than for those in the C group (9.4 +/- 16.0 mm). CONCLUSIONS: Preoperative alignment of the spine in the sagittal plane did not affect JOA scores after microendoscopic laminotomy in patients with LSS. However, low-back pain was worse for patients with preoperative anterior translation of the C-7 plumb line than for those without. PMID- 25840042 TI - Unplanned reoperation after lumbopelvic fixation with S-2 alar-iliac screws or iliac bolts. AB - OBJECT: S-2 alar-iliac (S2AI) screws are an attractive alternative to conventional fixation with iliac bolts because they are lower profile, require less muscle dissection, and have greater pullout strength. Few studies, however, compare outcomes between these techniques. METHODS: The authors conducted a retrospective cohort study of consecutive adult patients at a single institution from December 2009 to March 2012 who underwent lumbopelvic fixation using S2AI screws or iliac bolts. Medical records were reviewed for patients with clinical failure, defined as an unplanned reoperation because of instrumentation failure and/or wound-related complications. Univariate, multivariate, and survival analyses were used to compare patients who required reoperation with those who did not. Method of pelvic fixation was the main predictor variable of interest, and the authors adjusted for potential confounding risk factors. RESULTS: Of the 60 patients included, 23 received S2AI screws. Seventeen patients (28%) underwent an osteotomy. The mean follow-up was 22 months. A Kaplan-Meier survival model was used to evaluate the time to reoperation from the initial placement of lumbopelvic instrumentation. The failure-free rate was 96.6% at 6 months, 87.0% at 1 year, and 73.5% at 2 years. Reoperation was more common in patients with iliac bolts than in those with S2AI screws (13 vs 2; p = 0.031). Univariate analysis identified potential risk factors for unplanned reoperation, including use of iliac bolts (p = 0.031), absence of L5-S1 interbody graft (p = 0.048), previous lumbar fusion (p = 0.034), and pathology other than degenerative disease or scoliosis (p = 0.034). After adjusting for other risk factors, multivariate analysis revealed that the use of S2AI screws (OR 8.1 [1.5-73.5]; p = 0.030) was the only independent predictor for preventing unplanned reoperation. CONCLUSIONS: Both S2AI screws and iliac bolts were effective at improving fusion rates at the lumbosacral junction. The use of S2AI screws, however, was independently associated with fewer unplanned reoperations for wound-related complications and instrumentation failures than the use of iliac bolts. PMID- 25840043 TI - DREAM: a webserver for the identification of editing sites in mature miRNAs using deep sequencing data. AB - DREAM: detecting RNA editing associated with microRNAs, is a webserver for the identification of mature microRNA editing events using deep sequencing data. Raw microRNA sequencing reads can be provided as input, the reads are aligned against the genome and custom scripts process the data, search for potential editing sites and assess the statistical significance of the findings. The output is a text file with the location and the statistical description of all the putative editing sites detected. PMID- 25840044 TI - Regulatory network inferred using expression data of small sample size: application and validation in erythroid system. AB - MOTIVATION: Modeling regulatory networks using expression data observed in a differentiation process may help identify context-specific interactions. The outcome of the current algorithms highly depends on the quality and quantity of a single time-course dataset, and the performance may be compromised for datasets with a limited number of samples. RESULTS: In this work, we report a multi-layer graphical model that is capable of leveraging many publicly available time-course datasets, as well as a cell lineage-specific data with small sample size, to model regulatory networks specific to a differentiation process. First, a collection of network inference methods are used to predict the regulatory relationships in individual public datasets. Then, the inferred directional relationships are weighted and integrated together by evaluating against the cell lineage-specific dataset. To test the accuracy of this algorithm, we collected a time-course RNA-Seq dataset during human erythropoiesis to infer regulatory relationships specific to this differentiation process. The resulting erythroid specific regulatory network reveals novel regulatory relationships activated in erythropoiesis, which were further validated by genome-wide TR4 binding studies using ChIP-seq. These erythropoiesis-specific regulatory relationships were not identifiable by single dataset-based methods or context-independent integrations. Analysis of the predicted targets reveals that they are all closely associated with hematopoietic lineage differentiation. PMID- 25840046 TI - Shell-Thickness Controlled Semiconductor-Metal Transition in Si-SiC Core-Shell Nanowires. AB - We study Si-SiC core-shell nanowires by means of electronic structure first principles calculations. We show that the strain induced by the growth of a lattice-mismatched SiC shell can drive a semiconductor-metal transition, which in the case of ultrathin Si cores is already observed for shells of more than one monolayer. Core-shell nanowires with thicker cores, however, remain semiconducting even when four SiC monolayers are grown, paving the way to versatile, biocompatible nanowire-based sensors. PMID- 25840045 TI - Three minimal sequences found in Ebola virus genomes and absent from human DNA. AB - MOTIVATION: Ebola virus causes high mortality hemorrhagic fevers, with more than 25 000 cases and 10 000 deaths in the current outbreak. Only experimental therapies are available, thus, novel diagnosis tools and druggable targets are needed. RESULTS: Analysis of Ebola virus genomes from the current outbreak reveals the presence of short DNA sequences that appear nowhere in the human genome. We identify the shortest such sequences with lengths between 12 and 14. Only three absent sequences of length 12 exist and they consistently appear at the same location on two of the Ebola virus proteins, in all Ebola virus genomes, but nowhere in the human genome. The alignment-free method used is able to identify pathogen-specific signatures for quick and precise action against infectious agents, of which the current Ebola virus outbreak provides a compelling example. PMID- 25840047 TI - The influence of institutional pressures on hospital electronic health record presence. AB - Electronic health records (EHR) are a promising form of health information technology that could help US hospitals improve on their quality of care and costs. During the study period explored (2005-2009), high expectations for EHR diffused across institutional stakeholders in the healthcare environment, which may have pressured hospitals to have EHR capabilities even in the presence of weak technical rationale for the technology. Using an extensive set of organizational theory-specific predictors, this study explored whether five factors - cause, constituents, content, context, and control - that reflect the nature of institutional pressures for EHR capabilities motivated hospitals to comply with these pressures. Using information from several national data bases, an ordered probit regression model was estimated. The resulting predicted probabilities of EHR capabilities from the empirical model's estimates were used to test the study's five hypotheses, of which three were supported. When the underlying cause, dependence on constituents, or influence of control were high and potential countervailing forces were low, hospitals were more likely to employ strategic responses that were compliant with the institutional pressures for EHR capabilities. In light of these pressures, hospitals may have acquiesced, by having comprehensive EHR capabilities, or compromised, by having intermediate EHR capabilities, in order to maintain legitimacy in their environment. The study underscores the importance of our assessment for theory and policy development, and provides suggestions for future research. PMID- 25840048 TI - Challenges to successful implementation of HIV and AIDS-related health policies in Cartagena, Colombia. AB - The Caribbean region presents the highest prevalence of HIV/AIDS worldwide after sub-Saharan Africa; leading to serious social, economic and health consequences at the local scale but also at the regional and global levels. In Colombia, a national plan to tackle the epidemic was formulated with little evidence that its implementation in the local context is effective. This study focused on Cartagena - one of Colombia's largest cities and an international touristic hub - that presents one of the highest HIV prevalences in the country, to investigate whether the national plan accounts for local specificities and what are the barriers to local implementation. Based on the Contextual Interaction Theory (CIT), this qualitative research relied upon 27 interviews and 13 life stories of local inhabitants and stakeholders, collected in a first fieldwork in 2006-2007. A follow-up data collection took place in 2013 with 10 participants: key policymakers and implementers, NGO representatives and local inhabitants. Barriers identified by the participants included: local population's understandings and beliefs on condom use; stigma and discrimination; lack of collaboration from the Church, the education sector and local politicians; corruption; high staff turnover; frequent changes in leadership; lack of economic and human resources; and barriers to health care access. The findings suggest that global influences also have an impact on the CIT framework (e.g. international organisations as a major financier in HIV prevention). The participants put forward several feasible solutions to implementation barriers. We discuss how several of the proposed solutions have been applied in other Latin American and Caribbean countries and yielded positive results. However, further research is needed to find possible ways of overcoming certain barriers identified by this study such as corruption, the lack of collaboration of the Church and barriers to health care access. PMID- 25840049 TI - Early onset schizophrenia: Gender analysis of genome-wide potential methylation. AB - INTRODUCTION: Methylation studies show that there are substantial gender differences in DNA methylation. On the other hand, in schizophrenia male gender is strongly associated with early onset. The primary aims of the current study are: 1) to identify CpG SNPs across the genome in schizophrenia patients; and 2) to investigate gender differences in potential methylation considering the CpG SNPs at locus, gene and chromosome levels. METHODS: In this pilot analysis, we have collected detailed clinical information and DNA samples from 16 schizophrenia patients, allowing us to calculate genome-wide potential methylation at genome level in ten males and six females. This cross-sectional DNA sample included subjects with a diagnosis of schizophrenia that were genotyped using the Illumina Omni 2.5 Quad. We applied a novel genetic association strategy, selecting only the CpG SNPs across the genome and analyzed under additive model, to detect gender differences. The mapping analysis was conducted using a specific bioinformatic tool that we have developed, which analyzes only the polymorphic CpG sites genome wide. The bioinformatic tool can detect the SNPs that are affecting the polymorphic CpG sites across the genome. RESULTS: In the SNP-wise analysis, the top autosomal SNP was rs12619000 with 50% potential methylation in males and 95% in females (p=0.000008). In the gene-wise analysis, the KCNG3 was significantly associated with higher potential methylation in males (p=0.0004). CONCLUSIONS: The overall results show no robust association between CpG SNPs and gender however the information of the SNP CpG potential methylation can be used for future methylation analysis. PMID- 25840050 TI - Squamous cell carcinoma antigen in hepatocellular carcinoma: Ready for the prime time? AB - Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the third cause of cancer deaths. The leading predisposing condition is represented by an underlying viral hepatitis, mainly sustained by hepatitis B and C viruses. Since the cumulative risk of developing HCC can be as high as 30-fold in patients with infectious cirrhosis, a timely diagnosis is necessary for establishing an appropriate treatment in these patients. The armamentarium of diagnostic and prognostic biomarkers in patients with HCC currently entails alpha fetoprotein (AFP) and a limited number of innovative biomarkers, among which squamous cell carcinoma antigen (SCCA) and its immune complexes are among the most widely investigated. The clinical data published so far and reviewed in this article seemingly suggest that neither total serum SSCA or its isoform 1 (i.e., SCCA1) may be ready for the prime time for management of patients with HCC. More interesting evidence has emerged from studies investigating the serum values of SCCA-IgM, since the diagnostic performance of this biomarker was found to be frequently superior to that of AFP and, even more importantly, the combination of SCCA-IgM and AFP was characterized by a much better sensitivity than either biomarker alone, with only a modest decrease of specificity. Larger studies are needed before these preliminary findings can be generalized, but the combined use of AFP and SCCA-IgM represents an appealing perspective in diagnosis and prognostication of HCC. PMID- 25840051 TI - Postnatal management of prenatally diagnosed biliary cystic malformation. AB - PURPOSE: Recent advances in ultrasonography have increased prenatal diagnosis of biliary atresia (BA) and choledochal cyst (CC). These conditions are not easy to distinguish before or just after birth. This study investigated diagnostic and therapeutic problems in prenatal diagnosis of BA and CC. METHODS: We retrospectively studied clinical characteristics and progression of hepatobiliary cysts in 10 patients (4 cases of BA, 6 cases of CC) from the time of diagnosis. Chronological changes in cyst size and gallbladder morphology were assessed and measured sequentially by ultrasonography. RESULTS: Three cases of BA were type I cyst and 1 case was type III-d. All cases of CC were type Ia. Cyst size decreased between birth and surgery in BA but increased in CC. The gallbladder appeared atrophic in BA. There was no significant difference in gestational age or cyst size at prenatal diagnosis, changes in cyst size between birth and surgery, and degree of liver fibrosis. CONCLUSIONS: BA should be suspected if cyst size decreases before and after birth and the gallbladder atrophies after birth. Cholangiography is the only reliable method to differentiate BA from CC. Neonatal surgery is indicated for CC with icterus and liver dysfunction. PMID- 25840052 TI - Therapeutic step-up strategy for management of hereditary pancreatitis in children. AB - BACKGROUND/PURPOSE: Various different regimes exist for the treatment of hereditary pancreatitis in childhood. Here, we propose a therapeutic pathway with emphasis on endoscopic and surgical procedures. METHODS: From 2006 to 2013, 12 patients with a diagnosis of hereditary pancreatitis were prospectively included in a therapeutic step-up schema. The treatment outcome was evaluated and correlated to aetiological factors and pathoanatomic findings. RESULTS: After diagnostic work-up (laboratory data, ultrasound examination, magnetic resonance cholangiopancreatography and genetic testing), all 12 patients underwent early endoscopic retrograde cholangiopancreatography (ERCP), which was successfully performed in ten children. Obstructive pancreatitis was found in eight children, and required sphincterotomy, dilation and stenting for 12 months. In two children with unsuccessful ERCP, open surgical drainage procedures were performed. After a mean follow-up of 32 months all children are free of recurrence of pancreatitis without any impairment of everyday activities. CONCLUSIONS: For children with hereditary pancreatitis, a therapeutic step plan with early ERCP and open surgical drainage procedures in case of impossible or insufficient endoscopic treatment prevents recurring pancreatitis and offers a normal quality of life without any major complications. PMID- 25840053 TI - Favorable outcomes in high-risk congenital pulmonary airway malformations treated with multiple courses of maternal betamethasone. AB - BACKGROUND/PURPOSE: Congenital pulmonary airway malformations (CPAMs) are rare congenital lung lesions often diagnosed by prenatal ultrasound. High-risk cases can result in hydrops and prenatal or postnatal demise. Antenatal betamethasone has resulted in improved survival but it is unclear how to manage patients who do not respond to a single course. METHODS: We present a bi-institutional retrospective review of patients treated with multiple courses of prenatal steroids for high-risk CPAMs between 2007 and 2013. RESULTS: Nine patients met inclusion criteria. All but one either had an increased CPAM volume ratio (CVR) or number of fluid-containing compartments involved after a single course of antenatal betamethasone, prompting additional courses. Four patients stabilized, three improved and two progressed after the second course. The two cases with disease progression underwent an in utero resection. There were one in utero fetal demise and two deaths within the delivery room. Both fetuses that underwent a fetal resection died. All but one mother who delivered a viable fetus had complications of pregnancy. CONCLUSIONS: Multiple courses of antenatal betamethasone for high-risk fetal CPAMs often result in favorable short-term outcomes without the need for open fetal resection. Pregnancy complications are common and women within this cohort should be monitored closely. PMID- 25840054 TI - Management of laryngomalacia in children with congenital syndrome: the role of supraglottoplasty. AB - BACKGROUND/IMPORTANCE: Supraglottoplasty is the surgical procedure of choice for severe laryngomalacia and has shown to be successful in most cases; however, patients with medical comorbidities present a higher rate of failure. To date, the best management of laryngomalacia in children with congenital syndrome remains unclear. PURPOSE: To study the outcome of supraglottoplasty in children with severe laryngomalacia, and to analyze the management and outcome in infants with a congenital syndrome. METHODS: Retrospective medical records review from January 2003 to October 2012 of all patients who underwent laser supraglottoplasty for severe laryngomalacia at the University Children's Hospital Zurich, Switzerland. RESULTS: Thirty-one patients were included; median age at time of surgery was 3.5 months. Three patients (10%) had a genetically proven congenital syndrome with associated neurologic anomalies. Overall success rate was 87%. Failures were observed in four (13%) of 31 cases; including all three patients presenting a congenital syndrome. CONCLUSIONS: Supraglottoplasty is an effective and safe treatment for laryngomalacia in otherwise healthy children. Signs of a possible underlying predominant neurologic origin and discrepancy between the clinical presentation and the endoscopic findings have to be taken into account, as in children with congenital syndrome with neurologic anomalies the risk of failure is higher. PMID- 25840055 TI - Improved mortality rate for congenital diaphragmatic hernia in the modern era of management: 15 year experience in a single institution. AB - BACKGROUND/PURPOSE: Mortality rates with congenital diaphragmatic hernia (CDH) have remained at approximately 30% for the last 2 decades. Therapies targeting pulmonary hypertension (PHTN) have not been systematically studied in this population, but are increasingly used. We hypothesized that incremental changes in treatments for PHTN have improved mortality for CDH infants. METHODS: Prospective data from 1998 to 2013 on all liveborn CDH patients treated at our institution were retrospectively analyzed. Based on management of PHTN, 4 eras were identified for comparison. Logistic and linear regression were used to compare characteristics. The primary outcome of death prior to discharge was analyzed by multivariable Cox regression modeling. RESULTS: The study included 192 infants who met inclusion criteria. Length of stay increased, whereas rates of primary repair decreased, suggesting a sicker cohort in the most recent eras. Analysis of mortality across 4 eras showed no difference. By post-hoc analysis, ECMO availability was associated with mortality reduction for eras 3-4 versus 1-2 (HR=0.27, p<0.001). CONCLUSIONS: Improved survival at our institution may be related to recent introduction of ECMO and more aggressive approaches to pulmonary hypertension. Further systematic studies of these PHTN therapies in this specific population are warranted. PMID- 25840056 TI - Mediastinoscopic extended thymectomy for pediatric patients with myasthenia gravis. AB - BACKGROUND: Extended thymectomy is indicated for children with myasthenia gravis (MG) when drug-resistance or dependence is seen. We have employed a technique for mediastinoscopic extended thymectomy (MET) on children with MG. METHOD: A total of 14 children underwent MET at Kanagawa Children's Medical Center between 2005 and 2013. A mediastinal operation field was made by a V-shaped hook infrasternally to extirpate the thymus with adipose tissue around the thymus. RESULTS: The operation time and the amount of blood loss were 182+/-44 minutes and 34+/-43 ml, respectively. Postoperative complications, in the form of transient paralysis of the right recurrent nerve, occurred in 2 patients. The median length of postoperative hospital stay was 4.5 days. After MET, 6 patients achieved complete remission and 7 patients achieved steroid dose reduction, but no improvement was seen in 1 patient. CONCLUSIONS: This procedure offers the advantage of good surgical access for dissection around the bilateral phrenic nerves in extended total thymectomy, while achieving good cosmetic results. PMID- 25840057 TI - Defective upper gastrointestinal function after repair of combined esophageal and duodenal atresia. AB - BACKGROUND: Both esophageal atresia (EA) and duodenal atresia (DA) involve deficient anti-reflux barrier, poor esophageal function and eventually, duodenogastric reflux. This study aims at examining the upper gastrointestinal functional status in a cohort of patients with both EA and DA. METHODS: A retrospective survey of patients treated for EA and DA between 1965 and 2012 was conducted. Clinical charts, office visits, imaging, upper gastrointestinal endoscopy and esophageal pH metry/impedance were used to assess the long-term condition of the esophagus, the presence of gastroesophageal reflux disease (GERD) and/or the need for fundoplication. RESULTS: Twenty out of 581 patients treated for EA had associated DA. Ten/twenty children survived; 1 had primary esophageal replacement. With a median follow-up of 9 years, 8/9 had complicated outcomes and 5 still suffered digestive ailments: 2 GER; 1 eosinophilic esophagitis; 1 nodular gastritis, and 1 wrap herniation. A total of 10 procedures were performed: 8 fundoplications, 1 esophagogastric dissociation and 1 replacement with colon. DISCUSSION: The association of EA with DA involves a poor upper digestive function with high risks of GERD and fundoplication failure. The lifelong synergistic play of esophageal, gastric and duodenal dysfunctions in these patients prompts long-term follow-up, and eventually active treatment. PMID- 25840058 TI - A two-center comparative study of gastric pull-up and jejunal interposition for long gap esophageal atresia. AB - PURPOSE: When restoration of the anatomical continuity in case of long gap esophageal atresia (LGEA) is not feasible, esophageal replacement surgery becomes mandatory. The aim of this paper is to critically compare the experience of two tertiary referral centers in The Netherlands performing either gastric pull-up (GPU) or jejunal interposition (JI). METHODS: Retrospective chart review of all the patients with LGEA who underwent GPU in the University Medical Center Groningen and JI in the University Medical Center Utrecht. Main endpoints were short term morbidity, mortality and long term functional outcome (digestive functioning and growth). Descriptive analyses conducted using Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables. RESULTS: Nine children underwent GPU and 15 JI. Median age (years) at last follow up was fourteen (GPU) and eight (JI). One patient died, 10 years after JI. No grafts were lost. Perioperative anastomotic complications were reported more often after JI (73% vs. 22%, p=0.03). However reintervention rate was the same in both groups (33%). Among long term outcomes, functional obstruction was not registered after GPU, while it was recorded in 46% after JI (p=0.02). No other significant differences were found apart from some tendencies concerning full oral nutrition and gastroesophageal reflux (GPU>JI). CONCLUSION: Comparative data from this study reveal no mortality but significant morbidity in both groups. No graft was lost. Although not statistically different as a result of small patient numbers, clinically important differences regarding gastrointestinal system were noted. Growth should be monitored closely in both groups. PMID- 25840059 TI - Cognitive and behavioral characteristics of children with caustic ingestion. AB - BACKGROUND/AIM: Children with attention-deficit/hyperactivity disorder (AD/HD) have risk taking behavior and are more prone to sustaining injury. It is aimed to evaluate the cognitive and behavioral characteristics of children with caustic ingestion. PATIENTS AND METHODS: Ninety two children with a history of nonsuicidal caustic ingestion (CI, n=46) and healthy subjects (HS, n=46) admitted to pediatric surgery department were enrolled into the study. Patients in groups were evaluated for age, sex, number of siblings and educational status of the parents. Before filling the questionnaires, the children were undergone flexible endoscopy and treated accordingly. Conners Parents Rating Scale-revised long form (CPRS-R:L), validated for Turkish Children, was used to evaluate the cognitive and behavioral characteristics of children. Parents rate their child's behavior with a four-point Likert scale. Subscales of CPRS-R:L including cognitive problems/inattention (CG/I), hyperactivity (H), attention deficit hyperactivity disorder index (AD/HD-I), Conners' Global Index-discomfort-impulsivity (CGI-DI), DSM-IV-symptom subscale-inattention (DSMIV, SS-I), DSM-IV-symptom subscale hyperactivity-impulsivity (DSM-IV, SS-HI), DSMIV-symptom subscale-total score (DSM-IV SS-T) were used to determine the severity of the AD/HD symptom. Demographic features and cognitive/behavioral characteristics of children with caustic ingestion were compared with healthy subjects. RESULTS: The median age of the patients was 4 (2-14 years) in both CI and HS groups. Female male ratio was 13:33 in CI and 12:34 in HS. Sixty seven percent of patients were preschool children (younger than 5 years of age) in both CI and HS groups. There was no difference between groups for number of siblings (p>0.05). Parents of HS group had higher educational status than parents in CI (p<0.05). When subscale scores of CPRS-R:L compared between CI and HS groups, CI group had higher CGI-DI scores than HS (p<0.05). Children younger than five years of age had higher scores of H, emotional instability and total CG/I in CI than HS group (p<0.05). CONCLUSION: Children with caustic ingestion had impulsiveness behavior when compared to healthy children. In addition to impulsivity, hyperactivity can be also assessed as a risk factor for caustic ingestion in children younger than 5years of age. We suggest that association between AD/HD behavior and risk of sustaining injuries was also confirmed for caustic ingestion in children. PMID- 25840060 TI - Evaluation of the expression of I-FABP and L-FABP in a necrotizing enterocolitis model after the use of Lactobacillus acidophilus. AB - BACKGROUND/PURPOSE: Necrotizing enterocolitis (NEC) is a severe intestinal disease that primarily affects premature babies, leading to high mortality and morbidity. Probiotics represent an important alternative prophylaxis for NEC but its mechanism of action is poorly understood. Moreover, intestinal and liver-type fatty acid-binding proteins (I-FABP and L-FABP) may be utilized because markers of intestinal injury, including NEC. We aimed to evaluate the protection induced by the Lactobacillus acidophilus on the intestines of newborn rats submitted to experimental NEC using I-FABP and L-FABP as biomarkers. METHODS: Sprague-Dawley newborn rats were divided into three groups: (1) C (control)-breast-fed; (2) NEC subjected to NEC protocol and (3) NECP-NEC+probiotic. Morphometric, intestinal lesion, immunohistochemistry and Western blotting analysis were performed. Statistical significant differences were considered when p<0.05. RESULTS: Intestinal weight was lower in NEC and NECP compared to C (p<0.05). Intestinal injury was lower in NECP compared to NEC. Prophylactic probiotic recovered mucosa and muscular layers' thickness to C levels (p<0.05). I-FABP and L-FABP expressions in NECP showed intermediate values between C and NEC. CONCLUSION: L. acidophilus had a protective effect on the development of NEC and FABPs could demonstrate the degree of tissular damage of the intestine. PMID- 25840061 TI - Long-term physiologic and oncologic outcomes of inferior vena cava thrombosis in pediatric malignant abdominal tumors. AB - BACKGROUND: The long-term physiologic and oncologic outcomes of treatment for inferior vena cava (IVC) thrombosis in children with malignant abdominal tumors are unclear. METHODS: We conducted a retrospective review of children with malignant IVC tumor thrombosis treated at our institution between January 1996 and December 2011. Extent of tumor thrombus was classified using the Hinman system. Disease stage, management, and oncologic and physiologic outcomes and complications were evaluated. RESULTS: We identified 15 patients (median age, 4.7 years): 12 with Wilms tumor, 2 with hepatoblastoma, and 1 with adrenocortical carcinoma. Neoadjuvant chemotherapy changed Hinman levels in 2 (13%) patients. IVC thrombus resection was complete in 6 (40%) patients, partial in 7 (47%) patients, and not performed in 1 (6.7%) patient. On follow-up imaging, 8 (53%) patients' IVCs were patent, 6 (40%) had residual thrombus, and 1 (6.7%) was surgically interrupted. Three (20%) patients had perioperative complications, and 2 (13%) experienced transient effects related to IVC occlusion. CONCLUSIONS: Surgical management of tumor thrombus in the vena cava of children with solid abdominal tumors is challenging. Evidence on which to base strong treatment recommendations is lacking. Few long-term physiologic complications were observed. PMID- 25840062 TI - Complication risks associated with lower versus upper extremity peripherally inserted central venous catheters in neonates with gastroschisis. AB - PURPOSE: To compare the complication rates of lower extremity (LE) and upper extremity (UE) peripherally inserted central catheters (PICCs) in neonates with gastroschisis. METHODS: In this retrospective comparative study, neonates with gastroschisis admitted to a level IIId NICU between 2004 and 2013 were identified. Catheter dwell time and complication rates (infiltration, phlebitis, occlusion, migration, infection and thrombosis) between the initial UE and LE PICCs were compared. RESULTS: Forty (31%) and eighty-nine (69%) neonates with gastroschisis had their initial PICCs placed from their LE and UE, respectively. Complication rates were significantly higher when PICCs were inserted from LE, especially during silo-reduction and within 5 days after abdominal closure (LE: 20% vs. UE: 3.4%, p<0.01). LE PICCs were 5.0 times more likely to have complications than UE PICCs (OR 95% CI: 1.2-21.5) during this time period. In particular LE PICCs had significantly higher rates of infiltration (LE: 11.5% vs. UE: 1.4%; p=0.025) and phlebitis (LE: 11.5% vs. UE: 0%; p<0.01) in patients who underwent silo-reduction. CONCLUSION: LE PICCs are associated with significantly increased risks of infiltration and phlebitis in neonates with gastroschisis during silo-reduction and within 5 days after abdominal closure. PMID- 25840064 TI - Pancreatitis and portal vein thrombosis in children: the chicken or the egg causality dilemma. AB - BACKGROUND: The association of pancreatitis and portal vein thrombosis (PVT) is extremely rare in children. We report on 3 cases which suggest that there may be a causal relation between the two. METHODS: Clinical characteristics and evolution of 3 children with this particular condition were analyzed retrospectively. In this group of patients, the strategy consisted in opting for early surgical decompression of the portal hypertension, which was followed by a favorable outcome, not only in terms of complications related to the portal hypertension but also of a contemporaneous spontaneous regression of the concurrent pancreatic disease, in absence of any other specific management of the latter problem. RESULTS AND CONCLUSIONS: Combined PVT and pancreatitis is exceptional in children. Although this series is small, it provides insight and some evidence that the pancreatic disease might be secondary to the cavernomatous transformation of the regional venous system. More interestingly, it suggests that the appropriate management strategy should be to rapidly relieve portal hypertension after resolution of the acute phase of pancreatitis. PMID- 25840063 TI - The degree of spleen stiffness measured on acoustic radiation force impulse elastography predicts the severity of portal hypertension in patients with biliary atresia after portoenterostomy. AB - BACKGROUND/PURPOSE: Acoustic radiation focus impulse (ARFI) elastography is a new method for assessing the degree of tissue stiffness. We herein evaluated the degree of spleen stiffness (SS) using ARFI elastography in patients with biliary atresia (BA) after Kasai portoenterostomy (KPE). METHODS: We retrospectively collected the liver stiffness (LS) and SS values on ARFI elastography from 43 patients undergoing KPE between September 2010 and November 2013. We analyzed the correlations between these values and variables related to the severity of liver dysfunction and portal hypertension (PHT). The data were expressed as the standard deviation score (z-score) relative to the previously reported normal values for the patient's age. RESULTS: The SS value was significantly associated with the spleen diameter and development of collateral vessels, in comparison to the LS value. Interestingly, there was a significant correlation between SS value and the portal vein (PV) diameter. Thirty patients (69.8%) consequently underwent LT; these patients showed higher SS values and smaller PV diameters than the patients monitored without LT. CONCLUSIONS: The degree of SS measured on ARFI elastography can be used to predict the severity of PHT in BA patients after KPE. PMID- 25840065 TI - The risk of volvulus in abdominal wall defects. AB - BACKGROUND: Congenital abdominal wall defects are associated with abnormal intestinal rotation and fixation. A Ladd's procedure is not routinely performed in these patients; it is believed intestinal fixation is provided by adhesions that develop post-repair of the defects. However, patients with omphalocele may not have adequately protective postoperative adhesions because of difference in the inflammatory state of the bowel wall and in repair strategy. The aim of this study is to describe the occurrence of midgut volvulus in patients with gastroschisis or omphalocele. METHODS: A retrospective chart review was performed for all patients managed in a single institution born between 1/1/2000 and 12/31/2008 with a diagnosis of gastroschisis or omphalocele. Patient charts were reviewed through 12/31/2012 for occurrence of midgut volvulus or need for second laparotomy. RESULTS: Of the 206 patients identified with abdominal wall defects, 142 patients (69%) had gastroschisis and 64 patients (31%) had omphalocele. Patients' follow up ranged from 4 years to 13 years. The median gestational age was 36 weeks (26-41 weeks) and the median birth weight was 2.42 kg (0.8-4.87 kg). None of the patients with gastroschisis developed midgut volvulus, however two patients (3%) with omphalocele developed midgut volvulus. CONCLUSIONS: No patients with gastroschisis developed midgut volvulus. Therefore, the current practice of not routinely performing a Ladd's procedure is a safe approach during surgical repair of gastroschisis. The two cases of volvulus in patients with omphalocele may be related to less bowel fixation. It is necessary to examine current practice in regards to the need for assessing the risk of volvulus during omphalocele closure and counseling of these patients. This assessment may be achieved via routine examination of the width of the small bowel mesenteric base, whenever feasible; however, the sample size is relatively small to draw any definitive conclusions. PMID- 25840066 TI - Proposal of intestinal tissue engineering combined with Bianchi's procedure. AB - AIM: The aim of this study is to examine the feasibility of the small intestinal submucosa (SIS) when the longitudinal staples during Bianchi's procedure are replaced with SIS graft. METHODS: The mesentery of the bowel was separated based on the bifurcated vessels in five beagles. A 2*7-cm longitudinal half of the bowel was excised and the defect was repaired using SIS with similar blood supply in Bianchi's operation. Six months later, intestinal motility in the SIS-grafted area was recorded. Tissue preparations were obtained from the reorganized area. An organ bath technique with electrical field stimulation was applied. Both the native small intestine and grafted area were morphologically investigated using immunohistochemistry. MAIN RESULTS: All dogs survived and thrived with no anastomotic leakage. Isoperistaltic migrating contractility during fasting was observed through the grafted segment including the reorganized area. The SIS reorganized tissue contracted in response to an acetylcholine agonist and electrical field stimulation. The mucosa was covered with normal epithelium. Reorganization of neural and smooth muscle cells was observed. CONCLUSIONS: SIS has the potential for use as a scaffold that promotes the formation of a physical and physiological neointestine. Our present proposal approaches a novel surgical treatment in patients with short bowel syndrome. PMID- 25840067 TI - Evaluation of a water-soluble contrast agent for the conservative management of adhesive small bowel obstruction in pediatric patients. AB - BACKGROUND/PURPOSE: The diagnostic and therapeutic benefits of a commercial water soluble contrast agent (Gastrografin) in pediatric patients with adhesive small bowel obstruction (ASBO) are controversial. The aim of this study was to assess the therapeutic value of Gastrografin in the management of ASBO in children after unsuccessful conservative treatment. METHODS: Medical records from patients with uncomplicated ASBO managed at Cathay General Hospital, Taipei, Taiwan between January 1996 and December 2011 were retrospectively reviewed. All children <=18 years of age with clinical evidence of ASBO were managed conservative treatment, unless there was suspicion of strangulation. Patients who did not improve after 48 hours of conservative treatment were administered Gastrografin. RESULTS: Twenty-four patients with 33 episodes of ASBO were analyzed. Of those, there were 19 episodes of ASBO that failed to respond to the initial conservative management, and 16 (84%) responded well to Gastrografin administration thereby abrogating the need for surgical intervention. There were neither complications nor mortality that could be attributed to the use of Gastrografin. CONCLUSION: This preliminary study suggested that the use of a water-soluble contrast agent in ASBO is safe in children and useful for managing ASBO, particularly in reducing the need for surgery when conservative treatment fails. However, larger prospective studies would be needed to confirm these results. PMID- 25840068 TI - A comparison of two quality measurement tools in pediatric surgery--the American College of Surgeons National Surgical Quality Improvement Program-Pediatric versus the Agency for Healthcare Research and Quality Pediatric Quality Indicators. AB - BACKGROUND/PURPOSE: Identifying quality in pediatric surgery can be difficult given the low frequency of postoperative complications. We compared postoperative events following pediatric surgical procedures at a single institution identified by ACS-NSQIP Pediatric (ACS NSQIP-P) methodology and AHRQ Pediatric Quality Indicators (AHRQ PDIs), an administrative tool. METHODS: AHRQ PDI algorithms were run on inpatient hospital discharge abstracts for 1257 children in the 2010 to 2013 ACS NSQIP-P at our institution. Four events-pulmonary complications, postoperative sepsis, wound dehiscence and bleeding-were matched between ACS NSQIP-P and AHRQ PDI. RESULTS: Events were identified by ACS NSQIP-P in 7.9% of children and by AHRQ PDI in 8.0%. The four matched events were identified in 5.5% and 3.7%, respectively. Specificities of AHRQ PDI ranged from 97% to 100% and sensitivities from 0 to 2%. The largest discrepancy was in bleeding, where AHRQ PDI captured 1 of the 54 events identified by ACS NSQIP-P. None of the 41 pulmonary, sepsis, and wound dehiscence events identified by AHRQ PDI were clinically relevant according to ACS NSQIP-P. CONCLUSIONS: Adverse events following pediatric surgery are infrequent; thus, additional measures of quality to supplement postoperative adverse events are needed. AHRQ PDIs are inadequate for assessing quality in pediatric surgery. PMID- 25840069 TI - Effects of sphingosylphosphorylcholine against oxidative stress and acute lung injury induced by pulmonary contusion in rats. AB - BACKGROUND/PURPOSE: The goal of this study was to evaluate effects of exogenous sphingosylphosphorylcholine (SPC) administration on acute lung injury induced by pulmonary contusion in rats. METHODS: Eight animals were included in each of the following five groups: control, contusion, contusion phosphate-buffered solution (PBS), contusion SPC 2, contusion SPC 10. SPC was administered 3 days at a daily two different doses of 2 MUm/ml and 10 MUm/ml intraperitoneally. The severity of lung injury was determined by the neutrophil activation and histological and immunohistochemical changes in the lung. Malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) were determined to evaluate the oxidative status in the lung tissue. RESULTS: Treatment with 2 MUM SPC inhibited the increase in lung MDA and NO levels significantly and also attenuated the depletion of SOD, GPx, and GSH in the lung injury induced by pulmonary contusion. These data were supported by histopathological findings. The inducible nitric oxide synthase (iNOS) positive cells and apoptotic cells in the lung tissue were observed to be reduced with the 2 MUM SPC treatment. But, the 10 MUM SPC treatment did not provide similar effects. CONCLUSIONS: In conclusion, these findings suggested that 2 MUM SPC can attenuate lung damage in pulmonary contusion by prevention of oxidative stress, inflammatory process and apoptosis. All these findings suggest that low dose SPC may be a promising new therapeutic agent for acute lung injury. PMID- 25840070 TI - Utility of admission serum lactate in pediatric trauma. AB - BACKGROUND/PURPOSE: Serum lactate measurement has a predictive value in adult trauma. To date, there has been no prospective analysis of the predictive value of admission serum lactate in pediatric trauma. METHODS: Admission serum lactate was prospectively measured over a two year period on all children under age 15 years who met trauma alert criteria at an urban Level 1 trauma center. Elevated serum lactate (>2.0 mmol/L) was correlated with Injury Severity Scores (ISS), injury types, and hospital outcomes. RESULTS: A total of 277 injured children with admission lactate measurements were evaluated. Patients with elevated lactate had higher mean ISS than those with normal lactate (12.8 vs. 5.1, p<0.01), and increased need for intubation, major procedures and ICU admission. Elevated lactate was associated with low specificity (54.4%), moderate sensitivity (86.7%) and high negative predictive value (94.5%) for detecting injury (ISS>15). Lactate measurements over 4.7 mmol/L were highly specific (95.8%) for injury. CONCLUSIONS: Elevated admission venous lactate level is associated with injury and outcomes, but lacks adequate sensitivity and specificity. Lactate over 4.7 mmol/L is strongly suggestive of severe injury, while lactate below 2.0 mmol/L is reassuring for not having injury. Lactates between 2.0 and 4.7 mmol/L remain indeterminate in predictive potential for injury or outcomes. PMID- 25840071 TI - Beyond morbidity and mortality: the social and legal outcomes of non-accidental trauma. AB - BACKGROUND: Abusive head trauma (AHT) is a significant cause of morbidity and mortality in the pediatric population. We aimed to assess the social and legal outcomes of AHT and determine if the rates of successful prosecution have changed over recent years. METHODS: We utilized the trauma database at a single institution to identify all cases of AHT during two time periods: 1996-2001 and 2006-2010 then collected data from the Child Advocacy and Protection Team database. We characterized the social and legal outcomes and compared them between the two cohorts. RESULTS: A total of 254 patients (120 historic and 134 modern cohort) were included. Mortality rate was 19.7% and did not differ between the two cohorts. Thirty-seven percent of patients were discharged to foster care, this rate did not change across the two time periods. Suspected perpetrators pled guilty or were found guilty in only 74 cases (29%). However, when a case involved a fatality, perpetrators pled or were found guilty more often than in cases of a non-fatality (50 vs. 21.5%; p=0.0001). CONCLUSIONS: AHT results in fatality in approximately 1 in 5 cases, perpetrators are identified and found guilty in only 29% of the cases. Trauma surgeons need to be strong advocates for these vulnerable patients and actively participate in legal proceedings. PMID- 25840072 TI - Incidence and risk factors of burn injuries among infants, Finland 1990-2010. AB - BACKGROUND: Our aim was to study the incidence, mechanisms, treatment, and risk factors of burn injuries in infants younger than 1 year. METHODS: Data on burn injured infants during 1990-2011 in Finland came from the National Hospital Discharge Register (NHDR). Information on birth and maternal-related factors came from the Finnish Medical Birth Register, and data on fatal injuries from the Cause of Death Register of Finland. RESULTS: This study included 1842 children, female to male 1:1.5. The annual overall incidence of inhospital and outpatient admissions increased during the study period (p<0.05). Major risk factors were male gender, parity, and the mother's socioeconomic status and young age. The most common causes were scalds and contact burns. Severity of the injury increased along with increasing age, and children aged 9-12 months had the highest prevalence of surgical treatment. CONCLUSIONS: Burn injury incidence in children under 1 year has increased during recent decades in Finland. First-born 9- to 12-month-old boys of young mothers of low socioeconomic status are at higher risk of burn injuries. Preventative work needs strengthening to reduce infant burn injuries. PMID- 25840073 TI - Management of challenging congenital melanocytic nevi: outcomes study of serial excision. AB - BACKGROUND: Large congenital melanocytic nevi (CMN) cause significant deformity and are at risk for malignant degeneration. Techniques used to remove difficult CMN include serial excision, skin grafting, or tissue expansion. Some authors prefer skin grafting or tissue expansion if several stages would be required to serially resect the CMN. The purpose of this study was to determine the efficacy of serial excision for CMN requiring >=3 procedures. METHODS: Medical records and clinical images of patients with CMN treated between 2007 and 2013 were reviewed. Inclusion criteria were: (1) lesions that required >=3 serial excisions to remove and (2) CMN that could have been treated reasonably with skin grafting or tissue expansion. Patient age, gender, location of the lesion, size of the CMN, number of serial excisions, and complications were recorded. RESULTS: The study included 21 patients. Lesions were located on the lower extremity (38.1%), head/neck (33.3%), upper extremity (14.3%), or trunk (14.3%). Nevus size was 2.2%+/-1.2% total body surface area. The age during the first operation was 4.3 years (range 3 months to 15 years). The number of excisions was 3.5+/-0.7, spaced 8.2+/-4.3 months apart. Partial suture line dehiscence occurred after 2/72 operations and seroma resulted after 1/72 operations; there were no infections. CONCLUSION: Challenging CMN amenable to serial excision can be removed effectively and safely using this technique. Children are left with a favorable linear scar, do not have donor or recipient site morbidity from skin grafting, and are not subjected to potential tissue expander complications and injections required for expansion. PMID- 25840074 TI - Development of a locomotor rating scale for testing motor function in sheep. AB - BACKGROUND/PURPOSE: Research to cure paralysis associated with myelomeningocele (MMC) is ongoing using the fetal sheep model of MMC. Despite decades of research using this model, no standardized motor function assessment exists. The purpose of this study is to develop a sensitive and reliable locomotor scale for assessing the functional status of sheep. METHODS: Twenty lambs were used to develop and validate the locomotor scale. Lambs (n=15) underwent a surgically created MMC defect at gestational age (GA) 75 days, followed by repair with various methods at GA 100. One lamb underwent a sham operation (n=1). Normal lambs (n=4) served as controls. All lambs were born via spontaneous vaginal delivery, and motor function was assessed for 24 hours. A locomotor rating scale was developed based on behavioral observations of lambs. Inter-rater reliability testing was performed to determine if the scale could be reliably applied by different raters. RESULTS: Observations led to the definition of 7 categories of locomotor recovery. A scoring system was developed to rank these categories. The scale captured a wide variety of neurologic outcomes. Inter-rater reliability revealed minimal variability between examiners (average standard deviation +/ 0.431). The average score for all raters was within 1 point of the consensus score 100% of the time. CONCLUSIONS: The sheep locomotor rating scale is capable of capturing subtle differences in neurologic function with minimal inter-rater variability. We propose a standardized rating scale for neurologic outcomes and believe this is a critical component for assessing the validity of experimental treatments to cure paralysis in MMC. PMID- 25840075 TI - Pelvic floor in females with anorectal malformations--findings on perineal ultrasonography and aspects of delivery mode. AB - BACKGROUND: Advice on the mode of delivery to females born with anorectal malformation (ARM) is needed. The primary aim was to evaluate the anatomy of the pelvic floor muscles in females with ARM operated with posterior sagittal anorectal plasty (PSARP). The second aim was to correlate the extent of muscle defects to the bowel symptoms. METHODS: This interventional study with perineal 4D/3D ultrasonography describes the smooth muscles in the intestinal wall (neo IAS), external sphincter, levators and anal canal using a muscle score (0-6 worst). The bowel symptoms were prospectively registered with Krickenbeck criteria score (0-7 worst). RESULTS: Forty females with different subtypes of ARM, median age 13 (4-21), were followed up regarding bowel symptoms. Seventeen were examined with ultrasonography. Bowel symptoms were similar for those examined with ultrasonography and those not, median score 5 and 3 (1-7) respectively, (p=0.223, Fisher's exact test). All the females had at least one muscular defect. There was no significant correlation between muscle defects and bowel symptoms (p=0.094, Spearman's correlation). CONCLUSION: Females with ARM have considerable defects in the pelvic floor without any significant correlation to bowel symptoms. All women with ARM would benefit from individualized predelivery evaluations and caesarian section should be considered. PMID- 25840076 TI - Evaluation of transcutaneous electrical posterior tibial nerve stimulation for the treatment of fecal and urinary leaks in children: preliminary results. AB - OBJECTIVE: To examine the effectiveness of posterior tibial nerve stimulation (PTNS) for the treatment of fecal and urinary incontinence in children with malformations of the bowel or neurological pathologies. INTRODUCTION: Treatment of fecal and urinary leaks, in cases of congenital malformations remains a challenge. Recent studies in adults have shown the effectiveness of PTNS. METHOD: Eight children: 4 with anorectal malformations, 3 with neurological causes (1 medullary lipoma, 1 Arnold Chiari malformation, 1 sacrococcygeal teratoma) and 1 with Hirschsprung's disease presenting with serious anal incontinence, despite extensive bowel management during at least 2 years, were treated with PTNS. Six children had associated urinary leaks. Jorge-Wexner score for defecation and Schurch score for urine were used before treatment and after the second and sixth months of stimulation. RESULTS: After six months, five patients had no more fecal leakage, two patients were improved and one did not respond. Five out of the 6 patients with urinary leaks were continent at 6 months. CONCLUSION: PTNS is a noninvasive technique and painless modality which seems to be effective for the treatment of fecal and urinary leaks in children even with congenital digestive pathologies or neurological malformations. These results will be confirmed in a prospective study. PMID- 25840077 TI - One stage operation through modified posterior sagittal approach preserving the sphincter intact for anal agenesis with rectovestibular fistula. AB - PURPOSE: To describe the surgical technique and outcomes of an one stage operation through modified posterior sagittal approach (PSAP) preserving the sphincter intact for anal agenesia with rectovestibula fistula. PATIENTS AND METHODS: 57 patients suffering from anal agenesis with rectovestibular fistula were operated by a one-stage operation through a modified PSAP preserving the external sphincter intact from 2002 to 2010. The operation was performed in one stage through a posterior sagittal approach with three modifications: The external sphincter complex was not opened on the posterior side, the dissection was carried out outside the rectal pouch, the rectal pouch was not tapered and was pulled through the center of the external sphincter identified by muscle stimulator. RESULTS: Patients age varied from 3 days to 30 days (mean: 21+/-9 days). The mean operative time was 57+/-8 min (range, 35-90 min). There were no intraoperative complications. There were no intraoperative or postoperative deaths. There were no early postoperative complications. Follow up from 40 months to 140 was obtained in 52 (91.2%) patients. Constipation has seen in 3 patient, 46 patients (88.5%) had 1-2 defecations per day, 2 patients (3.85%) had 3-4 defecations per day, 1 patients (1.9%) had more than 4 defecations, and 3 patients(5.8%) had one defecation every 2-3 days. Rectal mucosal prolapse occurred in 7 patients who required a second operation. CONCLUSION: One stage operation through modified PSAP is feasible, is safe and provides good continence outcomes for anal agenesis with rectovestibular fistula. PMID- 25840078 TI - Correlating surgical and pathological diagnoses in pediatric appendicitis. AB - BACKGROUND: The stratification of appendicitis into simple and complex variants has far-reaching implications. While the operative diagnosis made by the surgeon dictates clinical management, the pathologic diagnosis often differs and is frequently used for coding and reimbursement. The purpose of this study was to examine discrepancies between the operative and pathologic diagnoses with subsequent correlation to clinical outcomes. METHODS: Patients with acute appendicitis from July 2011 to July 2012 were identified. Diagnoses included simple (normal, acute, and suppurative) and complex (gangrenous and perforated). We evaluated the inter-rater reliability between pathologic and operative diagnoses in the five appendicitis categories. Clinical outcomes of deep and superficial surgical site infections were evaluated according to the pathologic and surgical diagnosis. RESULTS: During the study period, we identified 1166 patients with acute appendicitis. The surgeon and pathologist agreed on the specific diagnosis (acute, suppurative, gangrenous, perforated, normal) in 48% of patients (kappa 0.289, 95% CI 0.259-0.324, p=0.001). Agreement on disease severity (simple vs. complex) improved to 82%. The operative diagnosis more accurately predicted infectious complications than the pathologic diagnoses. CONCLUSION: Significant discordance exists between surgical and pathologic diagnoses. While the relevance of this discordance to clinical outcomes is still not clear, a potential for incorrect hospital coding and subsequent reimbursement exists. Future quality improvement projects should focus on standardizing the surgical and pathologic diagnoses. PMID- 25840080 TI - Surgical approach to intussusception in older children: influence of lead points. AB - BACKGROUND: The likelihood of a lead point as the cause of ileocolic intussusception increases as children get older. This study looks at whether a different management strategy should be employed in older patients. METHODS: 7 year multi-institutional retrospective study of intussusception in patients aged <12 years. RESULTS: Ileocolic intussusception with complete data was found in 153 patients: 109 0-2 years, 34 3-5 years, and 10 6-12 years, respectively. Bloody stools occurred in 42/143 of 0-5 years and 0/10 of 6-12 years, p<0.001. Combined hydrostatic and/or surgical reduction was successful in 113/143 0-5 year olds vs 5/10 6-12 year olds, p<0.001. Enemas were safe but reduced only 1 patient over age 5. Resections were required in 29 patients (15 idiopathic, 14 lead points). Lead points were found in 4/109 children under 3 years, in 5/34 aged 3-5 years and 5/10 aged 6-12 years (p=0.04 vs 3-5 years and p <0.001 vs 0-5 years). Lead points consisted of 7 Meckel's diverticula and 7 others. CONCLUSION: Children older than 5 years are much more likely to have a pathologic lead point and early surgical intervention should be considered. In this study, enema reduction was safe but minimally beneficial in this age group. PMID- 25840079 TI - Use and accuracy of diagnostic imaging in the evaluation of pediatric appendicitis. AB - BACKGROUND: There are safety concerns about the use of radiation-based imaging (computed tomography [CT]) to diagnose appendicitis in children. Factors associated with CT use remain to be determined. METHODS: For patients <=18 years old undergoing appendectomy, we evaluated diagnostic imaging performed, patient characteristics, hospital type, and imaging/pathology concordance (2008-2012) using data from Washington State's Surgical Care and Outcomes Assessment Program. RESULTS: Among 2538 children, 99.7% underwent pre-operative imaging. 52.7% had a CT scan as their first study. After adjustment, age >10 years (OR 2.9 (95% CI 2.2 4.0), Hispanic ethnicity (OR 1.7, 95% CI 1.5-1.9), and being obese (OR 1.7, 95% CI 1.4-2.1) were associated with CT use first. Evaluation at a non-children's hospital was associated with higher odds of CT use (OR 7.9, 95% CI 7.5-8.4). Ultrasound concordance with pathology was higher for males (72.3 vs. 66.4%, p=.03), in perforated appendicitis (75.9 vs. 67.5%, p=.009), and at children's hospitals compared to general adult hospitals (77.3 vs. 62.2%, p<.001). CT use has decreased yearly statewide. CONCLUSIONS: Over 50% of children with appendicitis had radiation-based imaging. Understanding factors associated with CT use should allow for more specific QI interventions to reduce radiation exposure. Site of care remains a significant factor in radiation exposure for children. PMID- 25840081 TI - Early diagnosis of testicular torsion in rats by measuring plasma d-dimer levels: comparative study with epididymitis. AB - PURPOSE: To evaluate the differential diagnosis of testicular torsion and acute epididymo-orchitis by measuring the acute increase in plasma d-dimer levels in an experimental rat model. METHODS: Thirty male Wistar rats were randomly divided into 5 groups, 1--sham operated group (acute term; 4 hours), 2--early torsion group (acute term; 4 hours), 3--late torsion group (long-term; 72 hours), 4- control of epididymitis group (vehicle injected; 0.1 ml physiologic saline injected into the left ductus deferens) (long term; 72 hours), 5--epididymitis group (0.1 ml Escherichia coli injected into the left ductus deferens), (n=6 for each group). RESULTS: Serum d-dimer levels were significantly higher compared with the sham operated group with early torsion (p=0.002). This elevation remained mildly in the late torsion group compared with the control group (p<0.001), but there was no difference between 4 and 72 hours of the testis torsions (p=0.794). On the other hand, d-dimer levels were significantly higher in the torsion groups compared to the epididymitis group (p=0.042). CONCLUSIONS: The present study demonstrated that testicular damage that occurs following testicular torsion shows a higher increase in d-dimer levels than epididymitis, suggesting that d-dimer level can be used as a diagnostic marker of testicular torsion. PMID- 25840082 TI - Advantages of tubeless mini-percutaneous nephrolithotomy in the treatment of preschool children under 3 years old. AB - BACKGROUND/PURPOSE: Tubeless mini-percutaneous nephrolithotomy (MPCNL) for treating renal calculi was introduced in response to concerns over the use of adult nephrolithotomy apparatus in small children. However, it is unclear whether tubeless mini-PCNL (MPCNL) is of any benefit in the treatment of children. This study therefore aimed to assess the possible benefits of MPCNL, as compared to standard PCNL, in preschool children. METHODS: Seventy-eight preschool children under 3 years with renal calculi were randomized into two groups (PCNL and MPCNL). Operative time, hemoglobin decrease, blood transfusion rate, postoperative complications and length of hospital stay in the two groups were statistically compared. RESULTS: Recovery time was significantly shorter for patients receiving MPCNL than those treated with standard PCNL (4.6 versus 7.7 days, P<0.05). CONCLUSIONS: Treating preschool children with tubeless percutaneous nephrolithotomy has advantages over standard PCNL, including faster recovery and shorter hospital stay. PMID- 25840083 TI - Quality assessment of economic evaluation studies in pediatric surgery: a systematic review. AB - PURPOSE: To assess economic evaluation studies (EES) in pediatric surgery and to identify potential factors associated with high-quality studies. METHODS: A systematic review of the literature using PubMed and Cochrane databases was conducted to identify EES in pediatric surgery published between 1 June 1993 and 30 June 2013. Assessment criteria are derived from the Drummond checklist. A high quality study was defined as a Drummond score >=7. Logistic regression analysis was used to determine factors associated with high quality studies. RESULTS: 119 studies were included. 43.7% (n=52) of studies were full EES. Cost-effectiveness analysis was the most frequent (61.5%) type of full EES. Only 31.6% of studies had a Drummond score >=7 and 73% of these were full EES. The factors associated with high quality were identification of costs (OR: 14.08; 95% CI: 3.38-100; p<0.001), estimation of utility value (OR: 8.13; 95% CI: 2.02-43.47; p=0.005) and study funding (OR: 3.50; 95% CI: 1.27-10.10; p=0.02). CONCLUSION: This review shows that the number and the quality of EES are low despite the increasing number of studies published in recent years. In the current context of budget constraints, our results should encourage pediatric surgeons to focus more on EES. PMID- 25840084 TI - The classification based on intrahepatic portal system for congenital portosystemic shunts. AB - BACKGROUND/PURPOSE: Liver transplantation was previously indicated as a curative operation for congenital absence of portal vein. Recent advances in radiological interventional techniques can precisely visualize the architecture of the intrahepatic portal system (IHPS). Therefore, the therapeutic approach for congenital portosystemic shunt (CPS) needs to be reevaluated from a viewpoint of radiological appearances. The aim of this study was to propose the IHPS classification which could explain the pathophysiological characteristics and play a complementary role of a therapeutic approach and management for CPS. METHODS: Nineteen patients with CPS were retrospectively reviewed. The median age at diagnosis was 6.8 years old. Eighteen of these patients underwent angiography with a shunt occlusion test and were classified based of the severity of the hypoplasia of IHPS. RESULTS: The eighteen cases who could undergo the shunt occlusion test were classified into mild (n=7), moderate (n=6) and severe types (n=5) according to the IHPS classification. The IHPS classification correlated with the portal venous pressure under shunt occlusion, the histopathological findings, postoperative portal venous flow and liver regeneration. Shunt closure resulted in dramatic improvement in the laboratory data and subclinical encephalopathy. Two patients with the severe type suffered from sepsis associated with portal hypertension after treatment, and from the portal flow steal phenomenon because of the development of unexpected collateral vessels. The patients with the severe type had a high risk of postoperative complications after shunt closure in one step, even if the PVP was relatively low during the shunt occlusion test. CONCLUSION: The IHPS could be visualized by the shunt occlusion test. The IHPS classification reflected the clinicopathological features of CPS, and was useful to determine the therapeutic approach and management for CPS. PMID- 25840085 TI - 46XX cloacal exstrophy patients. PMID- 25840086 TI - Open Stomata 1 Kinase is Essential for Yeast Elicitor-Induced Stomatal Closure in Arabidopsis. AB - We recently demonstrated that yeast elicitor (YEL)-induced stomatal closure requires a Ca(2+)-dependent kinase, CPK6. A Ca(2+)-independent kinase, Open Stomata 1 (OST1), is involved in stomatal closure induced by various stimuli including ABA. In the present study, we investigated the role of OST1 in YEL induced stomatal closure in Arabidopsis using a knock-out mutant, ost1-3, and a kinase-deficient mutant, ost1-2. YEL did not induce stomatal closure or activation of guard cell S-type anion channels in the ost1 mutants unlike in wild type plants. However, YEL did not increase OST1 kinase activity in wild-type guard cells. The YEL-induced stomatal closure and activation of S-type anion channels were also impaired in a gain-of-function mutant of a clade A type 2C protein phosphatase (ABA INSENSITIVE 1), abi1-1C. In the ost1 mutants like in the wild type, YEL induced H2O2 accumulation, activation of non-selective Ca(2+) permeable cation (ICa) channels and transient elevations in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in guard cells. These results suggest that OST1 kinase is essential for stomatal closure and activation of S-type anion channels induced by YEL and that OST1 is not involved in H2O2 accumulation, ICa channel activation or [Ca(2+)]cyt elevations in guard cells induced by YEL. PMID- 25840087 TI - Mutations in Plastidial 5-Aminolevulinic Acid Biosynthesis Genes Suppress a Pleiotropic Defect in Shoot Development of a Mitochondrial GABA Shunt Mutant in Arabidopsis. AB - Plant developmental processes are co-ordinated with the status of cell metabolism, not only in mitochondria but also in plastids. In Arabidopsis thaliana, succinic semialdehyde (SSA), a GABA shunt metabolite, links the specific mitochondrial metabolic pathway to shoot development. To understand the mechanism of SSA-mediated development, we isolated a succinic semialdehyde dehydrogenase (ssadh) suppressor mutant, affected in its ability to catalyze SSA to succinic acid. We found that pleiotropic developmental phenotypes of ssadh are suppressed by a mutation in GLUTAMATE-1-SEMIALDEHYDE 2, 1-AMINOMUTASE 2 (GSA2), which encodes a plastidial enzyme converting glutatamate-1-semialdehyde to 5 aminolevulinic acid (5-ALA). In addition, a mutation in either HEMA1 or GSA1, two other enzymes for 5-ALA synthesis, also suppressed ssadh fully and partially, respectively. Furthermore, exogenous application of 5-ALA and SSA disturbed leaf development. These results suggest that metabolism in both mitochondria and plastids affect shoot development. PMID- 25840088 TI - Complementation of Seed Maturation Phenotypes by Ectopic Expression of ABSCISIC ACID INSENSITIVE3, FUSCA3 and LEAFY COTYLEDON2 in Arabidopsis. AB - ABSCISIC ACID INSENSITIVE3 (ABI3), FUSCA3 (FUS3) and LEAFY COTYLEDON2 (LEC2), collectively the AFL, are master regulators of seed maturation processes. This study examined the role of AFL in the production of seed reserves in Arabidopsis. Quantification of seed reserves and cytological observations of afl mutant embryos show that protein and lipid but not starch reserves are spatially regulated by AFL. Although AFL contribute to a common regulation of reserves, ABI3 exerts a quantitatively greater control over storage protein content whereas FUS3 controls lipid content to a greater extent. Although ABI3 controls the reserve content throughout the embryo, LEC2 and FUS3 regulate reserves in distinct embryonic territories. By analyzing the ability of an individual ectopically expressed AFL to suppress afl phenotypes genetically, we show that conserved domains common to each component of the AFL are sufficient for the initiation of storage product synthesis and the establishment of embryo morphology. This confirms redundancy among the AFL and indicates a threshold necessary for function within the AFL pool. Since no individual AFL was able to suppress the tolerance to desiccation, mid- and late-maturation programs were uncoupled. PMID- 25840089 TI - Inhibition of peroxisome fission, but not mitochondrial fission, increases yeast chronological lifespan. AB - Mitochondria are key players in aging and cell death. It has been suggested that mitochondrial fragmentation, mediated by the Dnm1/Fis1 organelle fission machinery, stimulates aging and cell death. This was based on the observation that Saccharomyces cerevisiae Deltadnm1 and Deltafis1 mutants show an enhanced lifespan and increased resistance to cell death inducers. However, the Dnm1/Fis1 fission machinery is also required for peroxisome division. Here we analyzed the significance of peroxisome fission in yeast chronological lifespan, using yeast strains in which fission of mitochondria was selectively blocked. Our data indicate that the lifespan extension caused by deletion of FIS1 is mainly due to a defect in peroxisome fission and not caused by a block in mitochondrial fragmentation. These observations are underlined by our observation that deletion of FIS1 does not lead to lifespan extension in yeast peroxisome deficient mutant cells. PMID- 25840090 TI - A global perspective on the epidemiology of pulmonary hypertension. AB - The epidemiology of pulmonary hypertension (PH) is not fully determined worldwide but is believed to vary in different regions of the world, with differences determined by genetic, geographic, environmental, and socioeconomic factors, as well as sex-related practices and inequities in access to health care. This article reviews the global epidemiology of PH, with emphasis on the prevalence, causes, forms, and underlying factors in the developing world. Left ventricular heart disease is the most common cause worldwide, but the main contributors in developing countries are chronic infectious diseases, hypertensive heart disease, cardiomyopathy, and rheumatic heart disease. Despite data suggesting a high prevalence in Sub-Saharan Africa, the available literature is very limited. International registries like the Pan African Pulmonary Hypertension Cohort are essential to provide information about the causes, comorbidities, and diagnostic classification, therapeutic management, and the natural course of PH worldwide. Moreover, there is a need to track diagnostic and management practices and challenges to identify the gaps and gradients between different regions of the world. The information gained will pinpoint areas for improvement, aiming at bridging the current divide between low-income and high-income countries. PMID- 25840091 TI - An evidence-based approach to screening and diagnosis of pulmonary hypertension. AB - Pulmonary hypertension (PH) continues to be a devastating disease, with a poor prognosis and high mortality rate if not treated early. Unfortunately, most patients are still diagnosed late in the course of the disease. Therefore, it is crucial to have a low threshold for suspecting PH and to refer patients early to specialized centres for diagnostic workup and management. In this article we focus on updated evidence-based screening and diagnosis in adults, based on the fifth World Symposium on Pulmonary Hypertension in 2013. The updated hemodynamic definition of PH includes a pulmonary vascular resistance > 3 Wood units. A new component to the hemodynamic definition of PH has been proposed in left heart disease, based on a diastolic pulmonary gradient (diastolic pulmonary arterial pressure - mean pulmonary artery wedge pressure), > 7 mm Hg. The term "borderline PH" for mean pulmonary artery pressures 21-24 mm Hg is discouraged, with emphasis on its significance for careful follow-up in high-risk patients, especially in systemic sclerosis. Annual pulmonary arterial hypertension (PAH) screening with a 2-step algorithm is recommended in asymptomatic systemic sclerosis patients. An updated simplified PH diagnostic algorithm approach is proposed. Genetic testing reveals mutations in bone morphogenic protein receptor type II in 70% of familial PAH, and is useful for screening asymptomatic family members. Important associated conditions that should be considered include thyroid disease, left heart disease, toxic causes, lung diseases (including pulmonary thromboembolism), hemolytic anemia, and human immunodeficiency virus infection. Biomarkers have been identified that correlate with PAH severity and mortality and are useful in follow-up. PMID- 25840093 TI - Pathophysiology and clinical relevance of pulmonary remodelling in pulmonary hypertension due to left heart diseases. AB - Pulmonary hypertension (PH) in left heart disease, classified as group II, is the most common form of PH that occurs in approximately 60% of cases of reduced and preserved left ventricular ejection fraction. Although relatively much is known about hemodynamic stages (passive or reactive) and their consequences on the right ventricle (RV) there is no consensus on the best hemodynamic definition of group II PH. In addition, the main pathways that lead to lung capillary injury and impaired biology of small artery remodelling processes are largely unknown. Typical lung manifestations of an increased pulmonary pressure and progressive RV pulmonary circulation uncoupling are an abnormal alveolar capillary gas diffusion, impaired lung mechanics (restriction), and exercise ventilation inefficiency. Of several classes of pulmonary vasodilators currently clinically available, oral phosphodiesterase 5 inhibition, because of its strong selectivity for targeting the cyclic guanosine monophosphate pathway in the pulmonary circulation, is increasingly emerging as an attractive opportunity to reach hemodynamic benefits, reverse capillary injury, and RV remodelling, and improve functional capacity. Guanylate cyclase stimulators offer an additional intriguing opportunity but the lack of selectivity and systemic effects might preclude some of the anticipated benefits on the pulmonary circulation. Future trials will determine whether new routes of pharmacologic strategy aimed at targeting lung structural and vascular remodelling might affect morbidity and mortality in left heart disease populations. We believe that this therapeutic goal rather than a pure hemodynamic effect might ultimately emerge as an important challenge for the clinician. PMID- 25840094 TI - Pulmonary hypertension secondary to heart failure with preserved ejection fraction. AB - Pulmonary hypertension (PH) secondary to heart failure with preserved ejection fraction (HFpEF) is an increasingly recognized cause of PH due to an emerging epidemic of HFpEF. The mechanisms underlying the pathogenesis of PH in HFpEF are not well established, but the presence of PH and right ventricular dysfunction in HFpEF is associated with worse prognosis. Currently, it is unclear whether PH is just a marker of underlying disease severity or whether it could be a target of treatment in HFpEF. Although PH-HFpEF and pulmonary arterial hypertension share several clinical characteristics, the evidence supporting the use of pulmonary arterial hypertension-specific therapies in PH-HFpEF is limited. Here, we review the disease classification, epidemiology, proposed pathophysiology, and treatments for PH-HFpEF. Our limited understanding highlights an urgent need for more research to elucidate the pathogenesis of PH in HFpEF and to develop novel therapies for this challenging syndrome. PMID- 25840092 TI - Right ventricular adaptation and failure in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of beta-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit. PMID- 25840095 TI - Multimodality imaging in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a pathophysiological condition defined as an increase in mean pulmonary artery pressure of >= 25 mm Hg at rest. Although right heart catheterization remains an essential step in the diagnostic algorithm particularly for pulmonary arterial hypertension-noninvasive multimodality imaging plays an important role in defining the cause, assessing outcome, monitoring the efficacy of specific therapeutic interventions, and detecting the preclinical stage of disease. We review the role of multimodality imaging in the evaluation of PH-including echocardiography, chest computed tomography, cardiovascular magnetic resonance imaging, and nuclear imaging-the choice of which depends on individual patient-based indications provided by the clinical team in accordance with current guidelines, also taking into account institutional expertise, patient safety and convenience, and repeatability. Recent advances in cardiac imaging (3-dimensional echocardiography and strain imaging, tissue characterization, and 18F-fluorodeoxyglucose positron emission tomography) may provide new insights into the pathophysiological characteristics of the right heart-pulmonary circulation unit. PMID- 25840096 TI - Current treatment approaches to pulmonary arterial hypertension. AB - Because of the complexities of the disease, early recognition and referral of patients with pulmonary arterial hypertension (PAH) to an expert centre is critically important. Advances in our understanding of the pathogenesis of PAH have translated into novel treatment strategies and pharmacotherapies. A supervised rehabilitation program, psychosocial support, and referral to palliative care might lead to improvements in exercise capacity and quality of life. At present the current medical treatments include prostanoids (parenteral, oral, and inhaled), endothelin antagonists, and agents that increase nitric oxide bioavailability. Although these agents all cause pulmonary vasodilation, they have been shown to improve outcome in patients who do not demonstrate an acute vasodilatory response. This suggests that they might also alter the abnormal proliferative vasculopathy that characterizes PAH. These agents have variably led to improvements in exercise capacity, symptoms, hemodynamics, and markers of right ventricular dysfunction. Adopting the principles of a goal-directed approach, most practitioners (and guidelines) advocate sequentially adding treatments until patients achieve a satisfactory clinical response. Emerging data suggest that upfront combination therapy might be superior to monotherapy. For patients who fail to achieve a satisfactory clinical response, parenteral prostanoids remain the medical treatment of choice. Early referral for evaluation of lung transplantation should be considered for patients who continue to demonstrate poor prognostic features or who require advanced medical treatments. PMID- 25840097 TI - Novel technologies and devices for monitoring and treating pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature associated with significant morbidity and mortality. Despite significant advances in the past 2 decades with the development of pharmacological therapies to target key molecular pathways of PAH, there remains an ongoing need for novel technologies and devices for diagnosis, monitoring, and treatment to improve PAH outcomes. The advent of sophisticated imaging tools, including cardiac magnetic resonance imaging, positron emission tomography, and speckle tracking echocardiography, offer novel opportunities for advanced, noninvasive assessment of right ventricular function, the most powerful predictor of death in patients with PAH. Noninvasive cardiac output monitors and implantable hemodynamic sensors are among the additional promising novel technologies that might offer daily access to hemodynamic data to influence clinical decision-making and potentially improve outcomes. Percutaneous interventional therapeutics might offer a nonpharmacological treatment option in select patients with PAH, ranging from the percutaneous creation of right to left shunts, pulmonary artery denervation, and right ventricular pacing. Finally, mechanical circulatory support with durable ventricular assist devices offers hope to one day provide a realistic strategy to treat life-threatening right ventricular failure in PAH. Future clinical trials and carefully designed prospective observational studies will be needed to evaluate the full potential of many of these novel devices and technologies for monitoring and treating PAH. PMID- 25840098 TI - Emerging therapies and future directions in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a complex obliterative vascular disease. It remains deadly despite an explosion of basic research over the past 20 years that identified myriads of potential therapeutic targets, few of which have been translated into early phase trials. Despite the agreement over the past decade that its pathogenesis is based on an antiapoptotic and proproliferative environment within the pulmonary arterial wall, and not vasoconstriction, all the currently approved therapies were developed and tested in PAH because of their vasodilatory properties. Numerous potential therapies identified in preclinical research fail to be translated in clinical research. Here we discuss 7 concepts that might help address the "translational gap" in PAH. These include: a need to approach the "pulmonary arteries-right ventricle unit" comprehensively and develop right ventricle-specific therapies for heart failure; the metabolic and inflammatory theories of PAH that put many "diverse" abnormalities under 1 mechanistic roof, allowing the identification of more effective targets and biomarkers; the realization that PAH might be a systemic disease with primary abnormalities in extrapulmonary tissues including the right ventricle, skeletal muscle, immune system, and perhaps bone marrow, shifting our focus toward more systemic targets; the realization that many heritable components of PAH have an epigenetic basis that can be therapeutically targeted; and novel approaches like cell therapy or devices that can potentially improve access to transplanted organs. This progress marks the entrance into a new and exciting stage in our understanding and ability to fight this mysterious deadly disease. PMID- 25840099 TI - Is exercise good for the right ventricle? Concepts for health and disease. AB - There is substantial evidence supporting the prescription of exercise training in patients with left-sided heart disease, but data on the effects of exercise are far more limited for conditions that primarily affect the right ventricle. There is evolving evidence that right ventricular (RV) function is of critical importance to circulatory function during exercise. Even in healthy individuals with normal pulmonary vascular function, the hemodynamic load on the right ventricle increases relatively more during exercise than that of the left ventricle, and this disproportionate load is far greater in patients with pulmonary hypertension. Exercise-induced increases in pulmonary artery pressures can exceed RV contractile reserve (so-called arterioventricular uncoupling), resulting in attenuated cardiac output and exercise intolerance. In this review, we explore the spectrum of RV reserve-from transient RV dysfunction observed in athletes after extreme bouts of intense endurance exercise to RV failure with minimal exertion in patients with advanced pulmonary hypertension. Recent advances and novel approaches to echocardiographic and cardiac magnetic resonance imaging have provided more accurate means of assessing the right ventricle and pulmonary circulation during exercise such that quantification of exercise reserve may provide a valuable means of assessing prognosis and response to therapies. We discuss the potential benefits and risks of exercise training in both health and disease while recognizing the need for prospective studies that assess the long-term efficacy and safety of exercise interventions in patients with pulmonary vascular and RV pathologic conditions. PMID- 25840100 TI - When to refer a patient with chronic thromboembolic pulmonary hypertension for pulmonary endarterectomy. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is much more frequent than previously estimated, potentially occurring with an incidence of several thousand cases per year in Canada. Refinements in the surgical technique of pulmonary endarterectomy, the development of medical therapy and, more recently, the introduction of balloon pulmonary angioplasty have provided an increasing array of therapeutic options for this disease. CTEPH is related to the presence of chronic thromboembolic disease and the development of a secondary vasculopathy that leads to worsening pulmonary hypertension despite adequate anticoagulation, emphasizing the importance of early diagnosis and appropriate referral to achieve optimal therapeutic results. It is increasingly recognized that patients with CTEPH can present with acute on chronic pulmonary emboli. Recognition of the underlying chronic disease at the time of the acute presentation is important to ensure that these patients are adequately managed and followed with ventilation perfusion scan and echocardiogram after their initial diagnosis of acute pulmonary emboli. Chronic thromboembolic disease should be suspected in the presence of idiopathic and/or recurrent pulmonary emboli, larger perfusion defects, longer times between symptom onset and diagnosis, a systolic pulmonary artery pressure > 50 mm Hg on echocardiogram and the presence of organized mural thrombi, mosaic parenchymal perfusion, and/or arterial web or bands on the computed tomography scan. Pulmonary endarterectomy is the treatment of choice for CTEPH. The surgery leads to major long-term clinical improvement and is curative in a large proportion of patients with resolution of the pulmonary hypertension. PMID- 25840103 TI - When to offer genetic testing for pulmonary arterial hypertension. AB - Genetic testing is poised to play a greater role in the diagnosis and management of pulmonary arterial hypertension (PAH). Physicians who manage PAH should know the heritable PAH phenotypes, inheritance patterns, and responsible genes. They also should know indications, potential risks and benefits, and the issues surrounding genetic counselling and testing for patients with PAH. PMID- 25840102 TI - Right ventricular function and right-heart echocardiographic response to therapy predict long-term outcome in patients with pulmonary hypertension. AB - BACKGROUND: Right ventricular (RV) dysfunction in pulmonary hypertension (PH) is linked to adverse outcomes, but this response is considered heterogeneous because it can be associated with multiple factors. METHODS: RV function of 51 PH patients was calculated by averaging peak speckle-tracking longitudinal strain from RV free-wall (RV-free), and the cutoff for RV dysfunction was predefined as RV-free <= 19%. Right-sided heart remodelling was assessed in terms of RV end systolic area (RVESA) and right atrial (RA) area (RA-area). Midterm reverse remodelling was defined as a relative decrease in RVESA (DeltaRVESA) and RA-area (DeltaRA-area) of at least 15% at 5.7 +/- 4.0 months after introduction of pulmonary artery hypertension-specific drugs. Long-term outcome was tracked for 3.0 +/- 2.0 years. RESULTS: Patients with midterm RV and RA reverse remodelling showed more favourable long-term outcomes than those without (P = 0.01, P = 0.047, respectively). Sequential Cox models showed that a model based on hemodynamic parameters (chi(2) = 0.3) was improved by the addition of RV-free (chi(2) = 6.4; P = 0.01), and further improved by addition of DeltaRVESA and DeltaRA-area (chi(2) = 28.2; P < 0.001). Furthermore, preservation of baseline RV function and midterm reverse remodelling in right-sided heart was associated with an optimal outcome: a survival rate of 100%. In contrast, absence of midterm reverse remodelling in the right-sided heart of patients with impaired baseline RV function was associated with significantly worse outcome with a survival rate of 33% (P = 0.01). CONCLUSIONS: RV function and echocardiographic right-heart reverse remodelling with therapy improves the prediction of long-term outcomes for PH patients over standard hemodynamic indices. PMID- 25840101 TI - Advanced imaging tools rather than hemodynamics should be the primary approach for diagnosing, following, and managing pulmonary arterial hypertension. AB - Pulmonary hypertension (PH) is currently defined based on invasive measurements: a resting pulmonary artery pressure >= 25 mm Hg. For pulmonary arterial hypertension, a pulmonary arterial wedge pressure <= 15 mm Hg and pulmonary vascular resistance > 3 Wood units are also required. Thus, right heart catheterization is inevitable at present. However, the diagnosis, follow-up, and management of PH by noninvasive techniques is progressing. Significant advances have been achieved in the imaging of pulmonary vascular disease and the right ventricle. We review the current sensitivities and specificities of noninvasive imaging of PH and discuss its role and future potential to replace hemodynamics as the primary approach to screening, diagnosing, and following/managing PH. PMID- 25840104 TI - Pulmonary hypertension due to fibrosing mediastinitis treated successfully with stenting of pulmonary vein stenoses. AB - We describe a patient with fibrosing mediastinitis after childhood histoplasmosis who presented with severe pulmonary hypertension secondary to pulmonary vein stenoses. Stenting of 2 stenosed pulmonary veins via a transseptal approach resulted in an immediate decrease in systolic pulmonary artery pressure from 90 to 68 mm Hg and improvement in dyspnea and cardiac index, which was sustained at 6 months. This case highlights the importance of routinely assessing the pulmonary veins during workup for pulmonary hypertension. PMID- 25840105 TI - Purification and functional characterization of mucosal IgA from vaccinated and SIV-infected rhesus macaques. AB - Vaccine-induced mucosal antibodies are often evaluated using small volumes of secretory fluids. However, fecal matter containing mucosal IgA is abundant. We purified fecal IgA from five SIV-vaccinated and five SIV-infected rhesus macaques by sequential affinity chromatography. The purified IgA was dimeric by native PAGE, contained secretory component, and was analogous to IgA in colostrum and vaginal fluid by western blot. IgA from one infected and four vaccinated animals neutralized H9-derived SIV(mac)251 with IC(50)s as low as 1 MUg/mL. Purified IgAs inhibited transcytosis and exhibited phagocytic activity, the latter significantly correlated with SIV(mac)251 Env-specific IgA in the purified samples. Among different affinity resins, peptide M was optimal compared to jacalin, anti-monkey IgA and SSL7 for IgA purification, as confirmed using tandem peptide M/anti-monkey IgA columns. Fecal IgA provided material sufficient for several assays relevant to protective efficacy, and was shown to be multifunctional. Our approach is potentially applicable to human clinical studies. PMID- 25840107 TI - Two homologous carboxylesterase genes from Locusta migratoria with different tissue expression patterns and roles in insecticide detoxification. AB - Carboxylesterases (CarEs) play a crucial role in detoxification of xenobiotics and resistance to insecticides in insects. In this study, two cDNAs of CarE genes (LmCesA4 and LmCesA5) were sequenced from the migratory locust, Locusta migratoria. The cDNAs of LmCesA4 and LmCesA5 putatively encoded 538 and 470 amino acid residues, respectively. The deduced amino acid sequences of the two CarE genes showed 45.0% identities, possessed highly conserved catalytic triads (Ser Glu-His), and clustered in phylogenetic analysis. These results suggest that they are homologous genes. Both CarE genes were expressed throughout the developmental stages. However, LmCesA4 was predominately expressed in the midgut (including the gastric caeca) and fat bodies, whereas LmCesA5 was mainly expressed in the gastric caeca. The in situ hybridization results showed that the transcripts of the two genes were localized in apical and basal regions of the columnar cells in the gastric caeca. Gene silencing followed by insecticide bioassay increased the mortalities of deltamethrin-, malathion-, and carbaryl-treated locusts by 29.5%, 31.0% and 20.4%, respectively, after the locusts were injected with LmCesA4 double-stranded RNA (dsRNA). In contrast, the injection of LmCesA5 dsRNA did not significantly increase the susceptibility of the locusts to any of these insecticides. These results suggest that these genes not only show different tissue expression patterns but also play different roles in insecticide detoxification. PMID- 25840106 TI - The intestinal microbiome and skeletal fitness: Connecting bugs and bones. AB - Recent advances have dramatically increased our understanding of how organ systems interact. This has been especially true for immunology and bone biology, where the term "osteoimmunology" was coined to capture this relationship. The importance of the microbiome to the immune system has also emerged as a driver of health and disease. It makes sense therefore to ask the question: how does the intestinal microbiome influence bone biology and does dysbiosis promote bone disease? Surprisingly, few studies have analyzed this connection. A broader interpretation of this question reveals many mechanisms whereby the microbiome may affect bone cells. These include effects of the microbiome on immune cells, including myeloid progenitors and Th17 cells, as well as steroid hormones, fatty acids, serotonin and vitamin D. As mechanistic interactions of the microbiome and skeletal system are revealed within and without the immune system, novel strategies to optimize skeletal fitness may emerge. PMID- 25840109 TI - Exploring cognitive factors in pain persistence behavior: some methodological and theoretical considerations-a commentary on a study by Andrews et al. PMID- 25840108 TI - A Wnt5a signaling pathway in the pathogenesis of HIV-1 gp120-induced pain. AB - Pathological pain is one of the most common neurological complications in patients with HIV-1/AIDS. However, the pathogenic process is unclear. Our recent studies show that Wnt5a is upregulated in the spinal cord dorsal horn (SDH) of the patients with HIV who develop pain and that HIV-1 gp120, a potential causal factor of the HIV-associated pain, rapidly upregulates Wnt5a in the mouse SDH. Using a mouse model, we show here that a specific Wnt5a antagonist, Box-5, attenuated gp120-induced mechanical allodynia. Conversely, a Wnt5a agonist, Foxy5, facilitated the allodynia. To elucidate the molecular mechanism by which Wnt5a regulates gp120-induced allodynia, we tested the role of the JNK/TNF-alpha pathway. We observed that the JNK-specific inhibitor SP600125 blocked either gp120- or Foxy5-induced allodynia. Similarly, the TNF-alpha-specific antagonist Enbrel also reversed either gp120- or Foxy5-induced allodynia. These data suggest that JNK and TNF-alpha mediate the biological effects of Wnt5a in regulating gp120-induced allodynia. To investigate the cellular mechanism, we performed extracellular single-unit recording from SDH neurons in anesthetized mice. Both Box-5 and SP600125 negated gp120-induced potentiation of SDH neuron spiking evoked by mechanical stimulation of the hind paw. Furthermore, while Foxy5 potentiated spike frequency of SDH neurons, either SP600125 or Enbrel blocked the potentiation. The data indicate that Wnt5a potentiates the activity of SDH neurons through the JNK-TNF-alpha pathway. Collectively, our findings suggest that Wnt5a regulates the pathogenesis of gp120-induced pain, likely by sensitizing pain-processing SDH neurons through JNK/TNF-alpha signaling. PMID- 25840115 TI - Establishment of a new pain catastrophizing baseline after pediatric major surgery? PMID- 25840116 TI - Structure of Multiresponsive Brush-Decorated Nanoparticles: A Combined Electrokinetic, DLS, and SANS Study. AB - Particles consisting of a glassy poly(methyl methacrylate) core (ca. 40 nm in radius) decorated with a poly(N-isopropylacrylamide) anionic corona are synthesized using either methacrylic acid (MA) or acrylic acid (AA) as reactive comonomers in the shell. The different reactivity ratios of MA and AA toward N isopropylacrylamide originates p(MA-N) and p(N-AA) particles with carboxylate charges supposedly located, preferentially, in the close vicinity of the core and at the shell periphery, respectively. The corresponding swelling features of these nanoparticles are addressed over a broad range of pH values (4 to 7.5), NaNO3 concentrations (3 to 200 mM), and temperatures (15 to 45 degrees C) by dynamic light scattering (DLS) and small angle neutron scattering (SANS). DLS shows that the swelling of the particle shells increases their thickness from ~10 to 90 nm with decreasing temperature, ionic strength, or increasing pH, with the effect being more pronounced for p(N-AA) whose lower critical solution temperature is shifted to higher values compared to that of p(MA-N). Potentiometric titration and electrokinetic results further reflect the easier dissociation of carboxyl groups in p(N-AA) and a marked heterogeneous interfacial swelling of the latter with decreasing solution salt content. The DLS response of both particles is attributed to the multiresponsive nature of a peripheral dilute shell, while SANS only probes the presence of a quasi-solvent-free dense polymer layer, condensed on the core surface. The thickness of that layer slightly increases from ~6 to 9.5 nm with increasing temperature from 15 to 45 degrees C (at 15 mM NaNO3 and pH 5) due to the collapse of the outer dilute shell layer. Overall, results evidence a nonideal brush behavior of p(MA-N) and p(N-AA) and their microphase segregated shell structure, which supports some of the conclusions recently formulated from approximate self-consistent mean-field computations. PMID- 25840118 TI - BIL&GIN: A neuroimaging, cognitive, behavioral, and genetic database for the study of human brain lateralization. AB - We report on a database, named BIL&GIN, designed for investigating the cognitive, behavioral, genetic, and brain morphological/functional correlates of hemispheric specialization. The database contains records from a sample of 453 adult participants enriched in left-handers (45%, N=205) as compared to the general population. For each subject, socio-demographic data, hand and eye laterality, family handedness, and cognitive abilities in the language, motor, visuo-spatial, and numerical domains have been recorded. T1-MRI and DTI data were also acquired, as well as resting-state functional MRI. Task-evoked functional MRI was performed in a sub-sample of 303 subjects (157 left-handers) using a customized functional battery of 16 cognitive tasks exploring the same three cognitive domains. Performances at the tasks executed in the magnet as well as post-acquisition debriefing were recorded. A saliva sample was obtained from the subjects of this sub-sample from which DNA was extracted. The BIL&GIN contains results of imaging data processing for each subject, namely maps of tissue (GM, WM, CSF) probability, cortical thickness, cortical surface, and diffusion parameters as well as regional values of these phenotypes for regions of both AAL and FreeSurfer parcellations. For the subjects who underwent FMRI, individual SPM contrast maps for each of the 8 runs were also calculated and included in the database, as well as corresponding BOLD variations in ROIs of the AAL and AICHA atlases, and Wilke's hemispheric functional lateralization index. The BIL&GIN data sharing is based on a collaborative model. PMID- 25840119 TI - Phytotoxicity of cobalt ions on the duckweed Lemna minor - Morphology, ion uptake, and starch accumulation. AB - Cobalt (Co2+) inhibits vegetative growth of Lemna minor gradually from 1 MUM to 100 MUM. Fronds accumulated up to 21 mg Co2+ g(-1) dry weight at 10 MUM external Co2+ indicating hyperaccumulation. Interestingly, accumulation of Co2+ did not decrease the iron (Fe) content in fronds, highlighting L. minor as a suitable system for studying effects of Co2+ undisturbed by Fe deficiency symptoms unlike most other plants. Digital image analysis revealed the size distribution of fronds after Co2+ treatment and also a reduction in pigmentation of newly formed daughter fronds unlike the mother fronds during the 7-day treatment. Neither chlorophyll nor photosystem II fluorescence changed significantly during the initial 4d, indicating effective photosynthesis. During the later phase of the 7 day treatment, however, chlorophyll content and photosynthetic efficiency decreased in the Co2+-treated daughter fronds, indicating that Co2+ inhibits the biosynthesis of chlorophyll rather than leading to the destruction of pre existing pigment molecules. In addition, during the first 4d of Co2+ treatment starch accumulated in the fronds and led to the transition of chloroplasts to chloro-amyloplasts and amylo-chloroplasts, while starch levels strongly decreased thereafter. PMID- 25840117 TI - The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth. AB - The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale study of child development that combines neuroimaging, diverse clinical and cognitive phenotypes, and genomics. Data from this rich resource is now publicly available through the Database of Genotypes and Phenotypes (dbGaP). Here we focus on the data from the PNC that is available through dbGaP and describe how users can access this data, which is evolving to be a significant resource for the broader neuroscience community for studies of normal and abnormal neurodevelopment. PMID- 25840120 TI - Description of mutual interactions between silicon and phosphorus in Andisols by mathematical and mechanistic models. AB - The Freundlich model and the Constant Capacitance Model (CCM) were used to describe silicon (Si) and phosphorus (P) sorption, both individually and for binary P-Si systems, on two Andisols with different chemical properties: Freire soil (FS) and Piedras Negras soil (PNS). Silicon sorption kinetics were examined through the Elovich equation, revealing that the initial sorption rate was 16 times greater in PNS. The Freundlich equation provides a good fit to the sorption data for both Andisols. When compared with FS, larger Si sorption capacity and lower Si affinity for the surface sites were observed in PNS; nevertheless, Si sorption decreased in both soils as P sorption increased. Slight reductions in P sorption capacity due to the presence of Si were found, whereas there was no apparent effect on P bonding intensity. The CCM was able to describe Si adsorption, and potentiometric titrations support that Si seems to be specifically sorbed mainly onto sites of negative charge. Comparable log KSiint values were obtained for both soils, indicating that Si was bound on similar sites. Phosphorus sorption was well described by the CCM, and log KPint denoted strong interactions of P with the surface sites. For binary systems, log KPint did not vary with increasing Si concentration; comparatively, log KSiint scarcely decreased with increasing P concentration in PNS, but a 28% reduction was found in FS at the highest initial P concentration. PMID- 25840121 TI - A new water absorbable mechanical Epidermal skin equivalent: the combination of hydrophobic PDMS and hydrophilic PVA hydrogel. AB - Research on human skin interactions with healthcare and lifestyle products is a topic continuously attracting scientific studies over the past years. It is possible to evaluate skin mechanical properties based on human or animal experimentation, yet in addition to possible ethical issues, these samples are hard to obtain, expensive and give rise to highly variable results. Therefore, the design of a skin equivalent is essential. This paper describes the design and characterization of a new Epidermal Skin Equivalent (ESE). The material resembles the properties of epidermis and is a first approach to mimic the mechanical properties of the human skin structure, variable with the length scale. The ESE is based on a mixture of Polydimethyl Siloxane (PDMS) and Polyvinyl Alcohol (PVA) hydrogel cross-linked with Glutaraldehyde (GA). It was chemically characterized by XPS and FTIR measurements and its cross section was observed by macroscopy and cryoSEM. Confocal Microscope analysis on the surface of the ESE showed an arithmetic roughness (Ra) between 14-16 MUm and contact angle (CA) values between 50-60 degrees , both of which are close to the values of in vivo human skins reported in the literature. The Equilibrium Water Content (ECW) was around 33.8% and Thermo Gravimetric Analysis (TGA) confirmed the composition of the ESE samples. Moreover, the mechanical performance was determined by indentation tests and Dynamo Thermo Mechanical Analysis (DTMA) shear measurements. The indentation results were in good agreement with that of the target epidermis reported in the literature with an elastic modulus between 0.1-1.5 MPa and it showed dependency on the water content. According to the DTMA measurements, the ESE exhibits a viscoelastic behavior, with a shear modulus between 1-2.5MPa variable with temperature, frequency and the hydration of the samples. PMID- 25840122 TI - Functionalization of strongly interacting magnetic nanocubes with (thermo)responsive coating and their application in hyperthermia and heat triggered drug delivery. AB - Herein, we prepare nanohybrids by incorporating iron oxide nanocubes (cubic IONPs) within a thermoresponsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR), but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermoresponsive shell is composed of poly(N-isopropylacrylamide-co-polyethylene glycolmethyl ether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 degrees C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 degrees C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes. PMID- 25840123 TI - New biomimetic barrier PermeapadTM for efficient investigation of passive permeability of drugs. AB - In this work the suitability of a newly invented physical patch comprising a biomimetic barrier (named PermeapadTM) for drug permeability tests has been investigated. Exemplars of PermeapadTM were adapted to Franz diffusion cells and apparent permeability (Papp) of a series of drugs were measured and compared with calculated partition coefficients (logPcal) of the investigated drugs as well as literature reference values obtained from Parallel Artificial Membrane Permeation Assay (PAMPA) and the cellular based method Caco-2. Moreover, tightness of the barrier to hydrophilic marker's permeation, resistance of these barriers to proton permeation (pH changes) and shelf-life functionality were also investigated. Comparison with the published data indicated a good correlation between the permeability values measured and partition coefficients (logPcal). Moreover, a good correlation between the permeabilities measured with the new barrier and well-established in vitro permeability methods (PAMPA and Caco-2 respectively) was found for both highly absorbed and poorly permeable compounds. PermeapadTM also proved to maintain high integrity over time and in different pH environments. In conclusion, PermeapadTM as an innovative barrier appears to be a promising tool for fast, cost effective and reliable screening of drugs and chemical entities' passive permeability. PMID- 25840125 TI - Biomimetic PVPA in vitro model for estimation of the intestinal drug permeability using fasted and fed state simulated intestinal fluids. AB - A prerequisite for successful oral drug therapy is the drug's ability to cross the gastrointestinal barrier. Considering the increasing number of new chemical entities in modern drug discovery, reliable and fast in vitro models are required for early and efficient prediction of intestinal permeability. To mimic the intestinal environment, use of biorelevant media may provide valuable information on in vivo drug permeation. The present study aims at improving the novel biomimetic phospholipid vesicle-based permeation assay's (PVPAbiomimetic) biorelevance by investigating the applicability of the biorelevant media; fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF). The FaSSIF and FeSSIF's influence on the permeability of the model drugs acyclovir, indomethacin, griseofulvin and nadolol was then assessed. The barriers' robustness in terms of storage stability was also evaluated. The barriers were found to maintain their integrity in presence of FaSSIF and FeSSIF. The model drugs showed changes in permeability in presence of the different simulated intestinal fluids that were in agreement with previous reports. Moreover, the barrier showed improved storage stability by maintaining its integrity for 6months. Altogether, this study moves the PVPAbiomimetic an important step towards a better in vitro permeability model for use in drug development. PMID- 25840124 TI - Aromatic hydroxylation of salicylic acid and aspirin by human cytochromes P450. AB - Aspirin (acetylsalicylic acid) is a well-known and widely-used analgesic. It is rapidly deacetylated to salicylic acid, which forms two hippuric acids salicyluric acid and gentisuric acid-and two glucuronides. The oxidation of aspirin and salicylic acid has been reported with human liver microsomes, but data on individual cytochromes P450 involved in oxidation is lacking. In this study we monitored oxidation of these compounds by human liver microsomes and cytochrome P450 (P450) using UPLC with fluorescence detection. Microsomal oxidation of salicylic acid was much faster than aspirin. The two oxidation products were 2,5-dihydroxybenzoic acid (gentisic acid, documented by its UV and mass spectrum) and 2,3-dihydroxybenzoic acid. Formation of neither product was inhibited by desferrioxamine, suggesting a lack of contribution of oxygen radicals under these conditions. Although more liphophilic, aspirin was oxidized less efficiently, primarily to the 2,5-dihydroxy product. Recombinant human P450s 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 all catalyzed the 5-hydroxylation of salicylic acid. Inhibitor studies with human liver microsomes indicated that all six of the previously mentioned P450s could contribute to both the 5- and 3-hydroxylation of salicylic acid and that P450s 2A6 and 2B6 have contributions to 5-hydroxylation. Inhibitor studies indicated that the major human P450 involved in both 3- and 5 hydroxylation of salicylic acid is P450 2E1. PMID- 25840126 TI - Celebrating National Nurses Week 2015. PMID- 25840127 TI - Why are we prolonging QT interval monitoring? AB - BACKGROUND: At present, monitoring of the QT interval (QTI) is not a standard practice in the medical intensive care unit setting, where many drugs that prolong the QTI are administered. This literature review looked at the current research for evidence-based standards to support QTI monitoring of patients with risk factors for QTI prolongation, which can result in life-threatening arrhythmias such as torsade de pointes. OBJECTIVE/AIM: The objective of this article is to establish the existence of evidence-based standards for monitoring of the QTI and to raise awareness in the nursing profession of the need for such monitoring among patients who are at high risk for prolonged QTI. METHOD: To determine whether published standards for QTI monitoring exist, a search was conducted of the bibliographic databases CINAHL, EBSCOhost, Medline, PubMed, Google Scholar, and the Cochrane Library for the years 2013 and 2014. Also, a survey was conducted to determine whether practice standards for QTI monitoring are being implemented at 4 major hospitals in the Memphis area, including a level 1 trauma center. RESULTS: The database search established the existence of published guidelines that support the need for QTI monitoring. Results of the hospital survey indicated that direct care nurses were not aware of the need to identify high-risk patients, drugs with the potential to prolong QTI that were being administered to their patients, or evidence-based standards for QTI monitoring. DISCUSSION: Review of the research literature underscored the need for QTI monitoring among high-risk patients, that is, those with genetic conditions that predispose them to QTI prolongation, those with existing cardiac conditions being treated with antiarrhythmic medications, or those who are prescribed any new medication classified as high risk on the basis of clinical research. This need is especially crucial in intensive care unit settings, where many antiarrhythmic medications are administered. PMID- 25840128 TI - Proper skin preparation and electrode placement decreases alarms on a telemetry unit. AB - BACKGROUND: An estimated 85% to 99% of electrocardiographic (ECG) alarms are false, leading to alarm fatigue, which is associated with increased risk of death among hospitalized patients. OBJECTIVE: The aim of this study was to examine the effect of proper skin preparation and electrode placement on frequency of ECG alarms on a telemetry unit. METHOD: A prospective descriptive design was used to test the effect of proper skin preparation and ECG electrode placement. Purposive sampling of patients (n = 15) admitted to a telemetry hospital in a suburban Veterans Affairs Medical Center was used. Alarms were counted for 24 hours after admission, electrodes were replaced using proper technique, and alarms were counted for 24 hours after electrode change. Bootstrapping was used to double the sample size for analysis. RESULTS: Electrocardiographic alarms decreased significantly (P < .05) after proper skin preparation and electrode placement (95% confidence interval, 1.273-82.327). DISCUSSION: Proper skin preparation and ECG electrode placement reduced alarms. Reducing alarm frequency is vital to decreasing alarm fatigue and increasing patient safety. PMID- 25840129 TI - Conflict management styles among Iranian critical care nursing staff: a cross sectional study. AB - BACKGROUND: Conflict among nurses has been recognized as an extremely important issue within health care settings throughout the world. Identifying the conflict management style would be a key strategy for conflict management. OBJECTIVE: The aim of this study was to evaluate the prevalence of conflict management styles and its related factors among Iranian critical care nursing staff. METHODS: In a descriptive cross-sectional study, a total of 149 critical care nurses who worked in the critical care units of 4 teaching hospitals in Sari (Iran) were evaluated. A 2-part self-reported questionnaire including personal information and Rahim Organizational Conflict Inventory II was used for data collection. RESULTS: Although Iranian critical care nurses used all 5 conflict management styles to manage conflict with their peers, the collaborating style was the most prevalent conflict management style used by them, followed by compromising, accommodating, avoiding, and competing. Male gender was a predictor for both compromising and competing styles, whereas position and shift time were significant predictors for compromising and competing styles, respectively. DISCUSSION: Based on the results of this study, nurse managers need to take these factors into account in designing programs to help nurses constructively manage unavoidable conflicts in health care setting. PMID- 25840130 TI - A personal reflection: going above and beyond for a patient in his last moments. AB - Death is common in the intensive care unit. Some patients are surrounded by family; others, with only nurses and physicians by their side. This article describes the experience of a critical care nurse caring for a patient in his last hours and in the hours after his death. These extraordinary measures left her with a sense of peace and pride in being an intensive care unit nurse. PMID- 25840132 TI - The process of death imminence awareness by family members of patients in adult critical care. AB - BACKGROUND: A focus on cost-effective quality end-of-life care remains a high priority in adult critical care given an aging population, high prevalence of death, and aggressive technologies used to extend or sustain life in this setting. METHOD: A Glaserian grounded theory design was used to conduct this retrospective study to yield a substantive middle-range theory. The data source was semistructured interviews with 14 family members of decedents who died 6 to 60 months prior to the study. OBJECTIVE: The purpose of this study was to generate a theory on how family members of patients in adult critical care come to realize that their loved one is dying. RESULTS: The Process of Death Imminence Awareness by Family Members of Patients in Adult Critical Care middle-range theory contained 6 phases: (1) patient's near-death awareness, (2) dying right in front of me, (3) turning points in the patient's condition, (4) no longer the person I once knew, (5) doing right by them, and (6) time to let go. Patient's near-death awareness preceded all other phases, if communicated by the decedent with their family. Then, family members iteratively moved through all the other key phases in the process until a time to let go became evident. DISCUSSION: This substantive middle-range theory will guide nursing education, practice, and research aimed at providing quality and cost-effective end-of-life care in adult critical care. PMID- 25840134 TI - The process of transformation experienced by the patients, their families, and nurses during critical illness in the intensive care unit: perspective from a phenomenological study. AB - BACKGROUND: There are no studies in the literature that explore and describe the concept of transformation from the perspective of patients, family members, and nurses during critical illness in the intensive care unit (ICU). OBJECTIVES: The purpose of this article is to explore and describe the concept of transformation among patients, their families, and nurses during critical illness in the ICU. METHODS: The concept "transformation" is a theme illuminated from a qualitative phenomenological study conducted in the ICU in 2010. Fifteen participants were interviewed until data saturation was achieved. van Manen's holistic, selective, and detailed line-by-line approach was used to analyze the data until themes emerged. RESULTS: Processes of transformation related to ICU experience during critical illness were noted among the patients, family members, and nurses and presented in the following descriptors: (a) patients: a "wake-up call," "the longest days of my life," and "thankful to be alive"; (b) family members: "the experience made me emotionally empowered," and "the experience strengthened my faith"; (c) nurses: "the experience made me grow as a person," "the experience made me more enthusiastic for learning," and "realization that good care equals family satisfaction thus own personal satisfaction." DISCUSSION: The concept of transformation from the perspective of a triad of patients, their families, and nurses may be noted in other conditions other than critical illness; thus, replicating studies with different populations and settings is needed. PMID- 25840138 TI - Embracing technology to strengthen care and enhance human connection. PMID- 25840137 TI - Cardiac monitoring: Hospital-wide education and staff competence. AB - BACKGROUND: The numbers of patients in acute care hospitals who require cardiac monitoring are increasing. Unpredictable fluctuations in patient flow may result in shortages of telemetry beds for patients who need this level of care. OBJECTIVE: The aims of this study were to design and implement cardiac monitoring education for all medical-surgical nursing staff in a level I trauma center. METHODS: This is a descriptive, quantitative performance improvement study. A multidisciplinary implementation plan was developed with biomedical engineering and physical facilities coordinating structural changes and nursing coordinating education and clinical competency. The nursing educational plans included a dysrhythmia course and testing, a clinically based competency, and a statistical analysis of the dysrhythmia test. The impact of this project was evaluated looking at areas transitioned, telemetry beds available, cardiac dysrhythmia education workshops, and dysrhythmia test results. RESULTS: The implementation of cardiac monitoring was completed over 2 years. Monitored medical-surgical beds increased from 132 to 282 beds. The nursing education expanded hospital-wide to clinical areas requesting standardization of nursing practice. CONCLUSIONS: In addition to expanding the number of monitored beds and decompression of critical care beds, benefits included increased level of staff competence, standardization of cardiac monitoring practices throughout the facility, and validation of the cardiac dysrhythmia test. PMID- 25840139 TI - The factor structure of posttraumatic stress disorder symptoms among Rwandans exposed to the 1994 genocide: A confirmatory factor analytic study using the PCL C. AB - The factor structure of posttraumatic stress disorder (PTSD) symptoms in Euro American populations has been extensively studied, but confirmatory factor analytic studies from non-Western societies are lacking. Alternative models of DSM-IV symptoms were tested among Rwandan adults (N=465) who experienced trauma during the 1994 genocide. A cluster random survey was conducted with interviews held in Rwandan households. PTSD was assessed with the Posttraumatic Stress Disorder Checklist-Civilian version. Competing models were the DSM-IV, emotional numbing, dysphoria, aroused intrusion, and dysphoric arousal models. Results showed that the emotional numbing, dysphoria, and dysphoric arousal models had almost identical, good fit indices and fit the data significantly better than the other models. The emotional numbing and dysphoric arousal models also exhibited good construct validity. Results suggest that the latent structure of PTSD symptoms in Rwanda are comparable to that found in Euro-American samples, thereby lending further support to the cross-cultural validity of the construct. PMID- 25840140 TI - Social problem solving strategies and posttraumatic stress disorder in the aftermath of intimate partner violence. AB - Social factors are often associated with the development or maintenance of posttraumatic stress disorder (PTSD) in the aftermath of interpersonal traumas. However, social problem solving strategies have received little attention. The current study explored the role of social problem solving styles (i.e., rational approaches, impulsive/careless strategies, or avoidance strategies) as intermediary variables between abuse exposure and PTSD severity among intimate partner violence survivors. Avoidance problem solving served as an intermediating variable for the relationship between three types of abuse and PTSD severity. Rational and impulsive/careless strategies were not associated with abuse exposure. These findings extend the current understanding of social problem solving among interpersonal trauma survivors and are consistent with more general avoidance coping research. Future research might examine whether avoidance problem solving tends to evolve in the aftermath of trauma or whether it represents a longstanding risk factor for PTSD development. PMID- 25840141 TI - In vivo fluorescence navigation of gastric and upper gastrointestinal tumors by 5 aminolevulinic acid mediated photodynamic diagnosis with a laser-equipped video image endoscope. AB - OBJECTIVE: Photodynamic diagnosis (PDD) is an imaging technology that is based on the fundamental biological features of cancer cells. Five-aminolevulinic acid (ALA), a precursor of photosensitizing protoporphyrin IX (PpIX) has been applied. In fact, ALA-mediated PDD provides good visualization for certain tumors. However, there have been few studies on clinical application of PDD for gastrointestinal (GI) cancers. This study was aimed to investigate the feasibility of ALA-mediated PDD for navigation of upper GI tumors. MATERIALS AND METHODS: Using a newly developed endoscope equipped with a blue laser light excitation, ALA-mediated PDD was conducted in 27 lesions from 23 patients with upper GI tumors including 2 Barrett's intramucosal cancers. ALA solution was given orally 3h before PDD. All the adenocarcinomas came under clinical stage I, and the tumors were resected endoscopic submucosal dissection and/or laparoscopic surgery. Red fluorescence signal and intensity was assessed as for clinicopathological features of the cases. RESULTS: The laser-based endoscopy could detect upper GI tumors as red fluorescent navigation (PDD-positive) in 23 of the 27 lesions. All but one intestinal typed tumors in histopathology were significantly PDD-positive, whereas each signet ring cell carcinoma was PDD negative. There was a significant difference in tumor size between the PDD positive and -negative tumors. The elevated lesions emitted significantly more intense fluorescence. CONCLUSIONS: Fluorescence navigation by ALA-mediated PDD provided sufficient detection of upper GI tumors in particular for the intestinal typed tumors. Thus, ALA-PDD using the blue laser-equipped endoscope offers a promising diagnostic tool. PMID- 25840142 TI - Cardiopulmonary resuscitation of pregnant women. PMID- 25840143 TI - To ventilate or not to ventilate? That is the question--again. PMID- 25840144 TI - Sensitivity of quantitative traits to mutational effects and number of loci. AB - When models of quantitative genetic variation are built from population genetic first principles, several assumptions are often made. One of the most important assumptions is that traits are controlled by many genes of small effect. This leads to a prediction of a Gaussian trait distribution in the population, via the Central Limit Theorem. Since these biological assumptions are often unknown or untrue, we characterized how finite numbers of loci or large mutational effects can impact the sampling distribution of a quantitative trait. To do so, we developed a neutral coalescent-based framework, allowing us to gain a detailed understanding of how number of loci and the underlying mutational model impacts the distribution of a quantitative trait. Through both analytical theory and simulation we found the normality assumption was highly sensitive to the details of the mutational process, with the greatest discrepancies arising when the number of loci was small or the mutational kernel was heavy-tailed. In particular, skewed mutational effects will produce skewed trait distributions and fat-tailed mutational kernels result in multimodal sampling distributions, even for traits controlled by a large number of loci. Since selection models and robust neutral models may produce qualitatively similar sampling distributions, we advise extra caution should be taken when interpreting model-based results for poorly understood systems of quantitative traits. PMID- 25840145 TI - Molecular biology of thermosensory transduction in C. elegans. AB - As the environmental temperature prominently influences diverse biological aspects of the animals, thermosensation and the subsequent information processing in the nervous system has attracted much attention in biology. Thermotaxis in the nematode Caenorhabditis elegans is an ideal behavioral paradigm by which to address the molecular mechanism underlying thermosensory transduction. Molecular genetic analysis in combination with other physiological and behavioral studies revealed that sensation of ambient temperature is mediated mainly by cyclic guanosine monophosphate (cGMP) signaling in thermosensory neurons. The information of the previously perceived temperature is also stored within the thermosensory neurons, and the consequence of the comparison between the past and the present temperature is conveyed to the downstream interneurons to further regulate the motor-circuits that encode the locomotion. PMID- 25840146 TI - Replacement of specific markers for apoptosis and necrosis by nuclear morphology for affordable cytometry. AB - OBJECTIVE: The objective of the present study was to employ high throughput image analysis to detect necrosis and apoptosis. Specific markers were replaced by morphological parameters of cells and nuclei. METHOD: Fresh blood was taken from a healthy female and given a treatment to induce cell necrosis and apoptosis. Afterward, the samples were stained with AnnexinV-FITC, DRAQ5 and DAPI. Slides were made and analyzed using the cytometer iCys. Pictures were scanned. The analyzed sample consisted of 73 sets of images of DAPI, DRAQ5 and AnnexinV-FITC, respectively. For image analysis and subsequent statistical processing, the CellProfiler and CellProfilerAnalyst were used. Each sample was analyzed twice. The first analysis was conducted using the markers (DAPI, DRAQ5 and Annexin) for an unequivocal identification and subsequent count of necrotic, apoptotic and live cells (gold standard). Thereafter, a second analysis was performed for the nuclear morphology and texture (morphometric analysis). After the machine learning process was completed, the software calculated the quantity of cells in each of the three groups. A comparison between the result of the gold standard and the morphometric analysis was performed using linear regression and a Bland Altman test. RESULTS: The linear regression between the two compared analyses was r(2)=0.57 for apoptosis, r(2)=0.84 for necrosis and r(2)=0.79 for living cells. CONCLUSION: It may be concluded that it is possible to replace specific markers against morphology without losing the reproducible high-throughput character of a cytometric analysis. PMID- 25840147 TI - High throughput multiplex-PCR for direct detection and diagnosis of dermatophyte species, Candida albicans and Candida parapsilosis in clinical specimen. AB - We have developed and validated a multiplex-PCR method for detection of dermatophyte spp., Candida albicans and parapsilosis for routine diagnostics. Our m-PCR showed excellent concordance with culture results in 475 clinical samples. Through the rapid diagnosis by our m-PCR, clinicians are able to initiate adequate antimycotic therapy much earlier. PMID- 25840148 TI - Controlled drug release from cross-linked kappa-carrageenan/hyaluronic acid membranes. AB - In this work, hydrogel membrane composed of; kappa carrageenan (kappaC) and hyaluronic acid (HA) crosslinked with epichlorohydrine is produced. The optimum condition has been established based on their water absorption properties. Tensile strength (TS) and elongation (E%) for the formed films are evaluated. The obtained films were characterized by FTIR, scanning electron microscopy (SEM) and thermal analysis. All membranes were loaded with l-carnosine as a drug model. The swelling properties and kinetics of the release of the model drug from the crosslinked hydrogel membrane were monitored in buffer medium at 37 degrees C. The equilibrium swelling of films showed fair dependency on the high presence of HA in the hydrogel. Moreover, the cumulative release profile increased significantly and ranged from 28% to 93%, as HA increases. SEM explored that, the porosity increased by increasing HA content; consequently, drug release into the pores and channels of the membranes is facilitated. In addition, water uptake % increased as well. A slight change in TS occurred by increasing the HA% to kappaC, while the highest value of strain for kappaC membrane was 498.38% by using 3% HA. The thermal stability of the kappaC/HA was higher than that of HA. PMID- 25840149 TI - Click chemistry modification of natural keratin fibers for sustained shrink resist performance. AB - This paper introduces a novel chemical treatment for achieving sustained shrink resist performance on natural keratin fibers. The new treatment involves the controlled reduction of keratin in the cuticle region of the fiber, and the application of a water soluble diacrylate, namely glycerol 1,3-diglycerolate diacrylate (GDA), on the reduced keratin substrate. The acrylate groups of the GDA react with cysteine residues in the reduced keratin through thiol-ene click reactions at room temperature, leading to GDA grafting and the formation of GDA crosslinks in the keratin structure. The modified substrates were characterized by infrared spectroscopy and scanning electron microscopy, and assessed for its shrink-resistance and wet burst strength. This chemical modification has shown to alter the fiber surface morphology and hydrophilicity, resulting in substantially improved shrink-resistance with good fiber strength retention. Possible shrink resistance mechanisms were also discussed. PMID- 25840150 TI - Bioconversion of crude glycerol to polyhydroxyalkanoate by Bacillus thuringiensis under non-limiting nitrogen conditions. AB - Glycerol has emerged as a cheap waste material due to blooming biodiesel manufacturing units worldwide. The need is to exploit the crude glycerol (CG) to produce useful products such as polyhydroxyalkanoate (PHA). Bacillus thuringiensis EGU45 was found to produce 1.5-3.5 gP HA L(-1) from feed containing 1-10% CG (vv(-1)) and nutrient broth (NB, 125 mL) without any acclimatization. B. thuringiensis EGU45 could produce PHA at the rate of 1.54-1.83 g L(-1), from 1% CG (vv(-1)) on media having high nitrogen contents: (i) NB, (ii) NB+0.5% NH4Cl (wv(-1)), and (iii) peptone+yeast extract+0.5% NH4Cl (wv(-1)). B. thuringiensis EGU45 was able to produce co-polymer of P(3HB-co-3HV) with 13.4% 3HV content on high N containing feed supplemented with propionic acid. This is the first report demonstrating the abilities of B. thuringiensis to convert CG into PHA co-polymer under non-limiting N conditions. PMID- 25840151 TI - Preparation and characterization of thermoplastic starches and their blends with poly(lactic acid). AB - Two different thermoplastic starches (TPS), namely maleic anhydride grafted starch (MA-g-starch) and epoxidized cardanol grafted starch (Epicard-g-starch), were successfully prepared by chemical modification without the addition of any plasticizer. The structure and properties were characterized by nuclear magnetic resonance (NMR), X-ray diffraction (XRD), hot press testing, scanning electron microscopy (SEM) and contact angle meter, respectively. Results from XRD showed that the highly crystalline structure of native starch was destroyed after modification. Continuous phase was obtained from both of the chemically modified starches after hot pressing at 130 degrees C, indicating that they have good thermoplasticity. Subsequently, they were melt-blended with PLA. It was found that the Epicard-g-starch had a much finer dispersed phase size than MA-g-starch in PLA matrix due to its better hydrophobicity. As a result, the mechanical properties of PLA/Epicard-g-starch blend were superior to those of PLA/MA-g starch blend. PMID- 25840152 TI - Antioxidant studies of chitosan nanoparticles containing naringenin and their cytotoxicity effects in lung cancer cells. AB - Chitosan based nano carrier systems have been widely explored owing to its reliability and simpler synthesis route. In the current study, chitosan (CS) encapsulated naringenin (NAR) nanoparticles (CS-NPs/NAR) were synthesized by ionic gelation method mediated by tripolyphosphate (TPP) as a cross-linker and characterized by DLS, SEM, Zeta potential, FT-IR and EDS analyses. The encapsulation efficiency of CS-NPs/NAR was determined by Folin-Ciocalteau (FC) and high performance liquid chromatography (HPLC) techniques. The native CS-NPs were found to be sized at 53.2 nm, while an increase in the size to 407.47 nm was observed upon loading with NAR. The encapsulation efficiency of CS-NPs/NAR was identified to be ~70% by FC method and ~80% by HPLC method, respectively. The release of NAR from CS-NPs/NAR in simulated gastric fluid was found to be ~15% and remaining 85% of NAR was entrapped in CS-NPs/NAR. Furthermore, the free radical scavenging ability of CS-NPs/NAR was studied by Nitrate scavenging, 2, 2 diphenyl-2-picryl hydrazyl hydrate and hydroxyl radical scavenging assays. The free radical scavenging activity was significantly higher in CS-NPs/NAR. MTT based cytotoxic analysis also depicted the non-toxic nature of CS-NPs/NAR towards normal fibroblast 3T3 cells, while cytotoxic effects were noticed against A549 lung cancer cells. Hence, the current investigations showed the superiority of chitosan encapsulated NAR over free NAR and suggested an efficient system for delivering NAR with antioxidant and anticancer activities. PMID- 25840153 TI - Spatial Variation and Land Use Regression Modeling of the Oxidative Potential of Fine Particles. AB - BACKGROUND: Oxidative potential (OP) has been suggested to be a more health relevant metric than particulate matter (PM) mass. Land use regression (LUR) models can estimate long-term exposure to air pollution in epidemiological studies, but few have been developed for OP. OBJECTIVES: We aimed to characterize the spatial contrasts of two OP methods and to develop and evaluate LUR models to assess long-term exposure to the OP of PM2.5. METHODS: Three 2-week PM2.5 samples were collected at 10 regional background, 12 urban background, and 18 street sites spread over the Netherlands/Belgium in 1 year and analyzed for OP using electron spin resonance (OP(ESR)) and dithiothreitol (OP(DTT)). LUR models were developed using temporally adjusted annual averages and a range of land-use and traffic-related GIS variables. RESULTS: Street/urban background site ratio was 1.2 for OP(DTT) and 1.4 for OP(ESR), whereas regional/urban background ratio was 0.8 for both. OP(ESR) correlated moderately with OP(DTT) (R2 = 0.35). The LUR models included estimated regional background OP, local traffic, and large-scale urbanity with explained variance (R2) of 0.60 for OP(DTT) and 0.67 for OP(ESR). OP(DTT) and OP(ESR) model predictions were moderately correlated (R2 = 0.44). OP model predictions were moderately to highly correlated with predictions from a previously published PM2.5 model (R2 = 0.37-0.52), and highly correlated with predictions from previously published models of traffic components (R2 > 0.50). CONCLUSION: LUR models explained a large fraction of the spatial variation of the two OP metrics. The moderate correlations among the predictions of OP(DTT), OP(ESR), and PM2.5 models offer the potential to investigate which metric is the strongest predictor of health effects. CITATION: Yang A, Wang M, Eeftens M, Beelen R, Dons E, Leseman DL, Brunekreef B, Cassee FR, Janssen NA, Hoek G. 2015. Spatial variation and land use regression modeling of the oxidative potential of fine particles. Environ Health Perspect 123:1187-1192; http://dx.doi.org/10.1289/ehp.1408916. PMID- 25840270 TI - Synthesis of folic acid functionalized redox-responsive magnetic proteinous microcapsules for targeted drug delivery. AB - Folic acid (FA) functionalized magnetic bovine serum albumin (BSA) microcapsules (FA-MBMCs) were prepared by a facile sonochemical method, in which FA molecule was immobilized onto the outer walls of microcapsules as a targeting ligand and oleic acid (OA) modifying Fe3O4 magnetic nanoparticles (OA-Fe3O4 MNPs) were wrapped into the microcapsules. The obtained FA-MBMCs possessed a nice spherical morphology with the mean size of 1.4 MUm. FA-MBMCs also showed an excellent magnetic and molecular dual-targeted property. Besides, the reductant-triggered diffusion of coumarin 6 suggested superior drug controlled release of FA-MBMCs. PMID- 25840271 TI - Disseminated intravascular coagulation in pregnancy: insights in pathophysiology, diagnosis and management. AB - Disseminated intravascular coagulation (DIC) is a life-threatening situation that can arise from a variety of obstetrical and nonobstetrical causes. Obstetrical DIC has been associated with a series of pregnancy complications including the following: (1) acute peripartum hemorrhage (uterine atony, cervical and vaginal lacerations, and uterine rupture); (2) placental abruption; (3) preeclampsia/eclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome; (4) retained stillbirth; (5) septic abortion and intrauterine infection; (6) amniotic fluid embolism; and (7) acute fatty liver of pregnancy. Prompt diagnosis and understanding of the underlying mechanisms of disease leading to this complication in essential for a favorable outcome. In recent years, novel diagnostic scores and treatment modalities along with bedside point of-care tests were developed and may assist the clinician in the diagnosis and management of DIC. Team work and prompt treatment are essential for the successful management of patients with DIC. PMID- 25840273 TI - A slow-release system of bacterial cellulose gel and nanoparticles for hydrophobic active ingredients. AB - A combination of bacterial cellulose (BC) gel and amphiphilic block copolymer nanoparticles was investigated as a drug delivery system (DDS) for hydrophobic active ingredients. Poly(ethylene oxide)-b-poly(caprolactone) (PEO-b-PCL) and retinol were used as the block copolymer and hydrophobic active ingredient, respectively. The BC gel was capable of incorporating copolymer nanoparticles and releasing them in an acetic acid-sodium acetate buffer solution (pH 5.2) at 37 degrees C. The percentage of released copolymer reached a maximum value of approximately 60% after 6h and remained constant after 24h. The percentage of retinol released from the copolymer-containing BC gel reached a maximum value at 4h. These results show that the combination of BC gel and nanoparticles is a slow release system that may be useful in the cosmetic and biomedical fields for skin treatment and preparation. PMID- 25840272 TI - Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient derived xenograft mouse model study. AB - OBJECTIVE: Uterine leiomyomas represent a common gynecologic problem with no satisfactory long-term medical treatment. The purpose of this study is to examine the effects of simvastatin on uterine leiomyoma, both in vitro and in vivo. STUDY DESIGN: This is a laboratory-based experimental study. For in vitro studies, we used human and rat leiomyoma cells. For in vivo studies, we used immunodeficient mice supplemented with estrogen/progesterone pellets xenografted with human leiomyoma tissue explant. RESULTS: For in vitro studies, cells were treated with different concentrations of simvastatin for 48 hours. Simvastatin induced dose dependent apoptosis in leiomyoma cells as measured by a fluorometric caspase-3 activity assay, and inhibited proliferation as demonstrated by an (3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay (both were significant at 5 and 10 MUM). In addition, simvastatin decreased Akt signaling pathway phosphorylation as examined using Western blot analysis. For in vivo studies, animals were treated for 28 days with simvastatin (20 MUg/gm body weight/day) vs vehicle control. The treatment inhibited tumor growth as measured weekly using calipers and/ or ultrasound (P < .01). Finally, simvastatin decreased expression of the proliferation marker Ki67 in xenograft tumor tissue as examined by immunohistochemistry (P = .02). CONCLUSION: Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required. PMID- 25840274 TI - In vitro and in vivo evaluation of APRPG-modified angiogenic vessel targeting micelles for anticancer therapy. AB - The study was aimed to evaluate the antitumor potential of the Ala-Pro-Arg-Pro Gly (APRPG)-modified angiogenic vessel targeting drug delivery system using paclitaxel (PTX) as a model drug. In this study, an angiogenesis homing peptide APRPG was conjugated to the amphipathic copolymer PLGA-PEG and the synthesized copolymer APRPG-PEG-PLGA was used to prepare PTX encapsulated micelles (APRPG-PEG Mic). The micelles were uniform spherical and exhibited a unimodal particle size distribution and a slight negative zeta-potential. The in vitro drug release result demonstrated a significant sustained release property of APRPG-PEG-Mic. Compared to Taxol((r)) and Cont-PEG-Mic, APRPG-PEG-Mic showed a stronger cytotoxicity against two cancerous cell lines. In the cell uptake studies, the APRPG-modified micelles enhanced intracellular fluorescent intensity in EA.hy926 cells. The biodistribution study revealed the accumulation of APRPG-PEG-Mic in tumor tissues as a result of passive accumulation and active targeting. In comparison with Taxol((r)) and Cont-PEG-Mic, APRPG-PEG-Mic reduced the tumor volume more significantly and prolonged the survival time of tumor-bearing mice, indicating a higher antitumor efficacy and lower systematic side effects of APRPG PEG-Mic. The results indicated that APRPG-modified micelles could be an efficient target-delivery method to angiogenic vessels and a highly promising therapeutic system in anticancer therapy. PMID- 25840275 TI - Use of ultrasound-targeted microbubble destruction to transfect IGF-1 cDNA to enhance the regeneration of rat wounded Achilles tendon in vivo. AB - The purpose of this study was to determine whether using ultrasound-targeted microbubble destruction (UTMD) to transfect rat wounded Achilles tendon with insulin-like growth factor-1 (IGF-1) cDNA would enhance tissue regeneration. Forty rats with injured Achilles tendons were transfected with IGF-1 cDNA and divided into: (1) control group, (2) plasmid-only group, (3) plasmid+ultrasound group and (4) plasmid+microbubbles+ultrasound group. The IGF-1 cDNA expression of the Achilles tendons was evaluated by histological adhesion finding, quantitative real-time reverse transcription PCR examination and biomechanical test. The adhesion scores in group 4 were lowest at weeks 2 and 8 (P<0.05). The IGF-1 expression in the Achilles tendons was highest in group 4 at weeks 2 and 8 (P<0.05). Compared with those of other three groups, the granulation tissues and inflammatory-cell infiltration were lighter in group 4 at week 2, and the scars on the tendons in group 4 were less evident at week 8. The messenger RNA (mRNA) of IGF-1 of group 4 was upregulated at weeks 2 and 8 (P<0.01). Groups 4 and 3 showed a greater maximum load, stiffness and ultimate stress (P<0.05). Maximum load, stiffness and ultimate stress of healing Achilles tendons in group 4 were highest at weeks 2 and 8 (P<0.05). PMID- 25840276 TI - Commentary on "Plasma polyunsaturated fatty acids and periodontal recovery in Taiwanese with periodontitis: A significant relationship". PMID- 25840277 TI - DNA alterations and effects on growth and reproduction in Daphnia magna during chronic exposure to gamma radiation over three successive generations. AB - This study examined chronic effects of external Cs-137 gamma radiation on Daphnia magna exposed over three successive generations (F0, F1 and F2) to environmentally relevant dose rates (ranging from 0.007 to 35.4 mGy h(-1)). Investigated endpoints included survival, growth, reproduction and DNA alterations quantified using random-amplified polymorphic DNA polymerase chain reaction (RAPD-PCR). Results demonstrated that radiation effects on survival, growth and reproduction increased in severity from generation F0 to generation F2. Mortality after 21 days at 35.4 mGy h(-1) increased from 20% in F0 to 30% in F2. Growth was affected by a slight reduction in maximum length at 35.4 mGy h(-1) in F0 and by reductions of 5 and 13% in growth rate, respectively, at 4.70 and 35.4 mGy h(-1) in F2. Reproduction was affected by a reduction of 19% in 21 day fecundity at 35.4 mGy h(-1) in F0 and by a delay of 1.9 days in brood release as low as 0.070 mGy h(-1) in F2. In parallel, DNA alterations became significant at decreasing dose rates over the course of F0 (from 4.70 mGy h(-1) at hatching to 0.007 mGy h(-1) after ~21 days) and from F0 to F2 (0.070 mGy h(-1) at hatching to 0.007 mGy h(-1) after ~21 days), demonstrating their rapid accumulation in F0 daphnids and their transmission to offspring generations. Transiently more efficient DNA repair leading to some recovery at the organism level was suggested in F1, with no effect on survival, a slight reduction of 12% in 21 day-fecundity at 35.4 mGy h(-1) and DNA alterations significant at highest dose rates only. The study improved our understanding of long term responses to low doses of radiation at the molecular and organismic levels in a non-human species for a better radioprotection of aquatic ecosystems. PMID- 25840278 TI - Prevalence and intensity of pathologies induced by the toxic dinoflagellate, Heterocapsa circularisquama, in the Mediterranean mussel, Mytilus galloprovincialis. AB - The harmful dinoflagellate, Heterocapsa circularisquama, has been causing mass mortalities of bivalve molluscs in Japan, at relatively low cell densities. Although several studies have been conducted to determine the toxicity mechanisms, the specific cause of death is still unclear. In a previous study, in our laboratory, it was shown that H. circularisquama (10(3) cells ml(-1)) caused extensive cytotoxicity in the gills of short-neck clams, Ruditapes philippinarum. In the present study, Mediterranean mussels, Mytilus galloprovincialis, were exposed to H. circularisquama at four cell densities (5, 50, 500, 10(3) cells ml( 1)), three temperatures (15, 20, and 25 degrees C), and three exposure durations (3, 24, and 48 h), and the pathologies in nine organs (gills, labial palps, mantle, hepatopancreas, stomach, intestines, exhalant siphon, adductor muscles, and foot) were assessed. Foot, adductor muscles, and exhalent siphons of mussels were not affected; however, 16 inflammatory (hemocytic infiltration and aggregation, diapedesis, hyperplasia, hypertrophy, edema, melanization, and firbrosis) and degenerative (thrombus, thrombosed edema, cilia matting and exfoliation, epithelial desquamation, atrophy, and necrosis) pathologies were identified in the gills, labial palps, mantle, hepatopancreas, stomach, and intestines. The total prevalence and total intensity of pathology in each individual mussel, and the prevalence and intensity of pathology in each organ increased significantly with increased cell density, exposure duration, and temperature. The prevalence of pathology was the highest in gills, followed by the prevalence in labial palps, mantle, stomach, and intestines. Pathology was least prevalent in the hepatopancreas. The intensity of pathology was the highest in the gills, followed by the labial palps and mantle, the stomach and intestines, and the hepatopancreas. This detailed quantitative histopathological study demonstrates that exposure to H. circularisquama induces a broad cytotoxic effect in six vital organs, even at low density (5 cells ml(-1)) and low temperature (15 degrees C), but not in muscular organs. Combining cell density, time, and duration of exposure, the organ most affected by the harmful alga was the gill, followed by the labial palps and mantle, the stomach and intestines, and the hepatopancreas. The results of this pathological analysis show that exposure to H. ciruclarisquama severely affects the gills, the labial palps, and mantle thereby interfering with particle clearance and sorting, cleansing, and respiration, but also affects the stomach, intestines, and hepatopancreas, altering the digestive processes and possibly detoxification pathways, if mussels are able to detoxify the toxins of H. circularisquama. In the most severe cases, bivalves would most likely have died as a result of combined severe alterations of the vital functions, failure of tissue repair, and moderate to heavy hemorrhaging in both the external organs and the digestive organs concomitantly with light to moderate alterations in the detoxifying processes. PMID- 25840279 TI - Desflurane increased the activity of excitatory amino-acid carrier 1 (EAAC1) expressed in Xenopus oocytes. AB - Desflurane is a volatile anaesthetic agent with neuroprotective properties. Excitatory amino-acid carrier 1 (EAAC1) may be neuroprotective by taking up glutamate and cysteine. Therefore, the effects of desflurane on EAAC1 activity were investigated in this study. EAAC1 was expressed in Xenopus laevis oocytes. Two-electrode voltage-clamping technique was used to record membrane currents upon exposure to l-glutamate (30 MUM) in the presence or absence of desflurane (0.4, 1.0, 2.0, 2.6, or 3.2mM). Currents were also measured in oocytes pre exposed to a protein kinase C (PKC) activator (50 nM phorbol-12-myristate-13 acetate, PMA), PKC inhibitors (1 MUM staurosporine or 50 MUM chelerythrine), or phosphatidylinositol-3-kinase (PI3K) inhibitors (5 MUM wortmannin or 10 MUM LY294002). Desflurane significantly increased EAAC1 activity. The EC50 of desflurane for increasing the EAAC1 response was 0.75 mM. A kinetic study showed that desflurane significantly increased the Vmax but had no effect on the Km of the EAAC1 response for glutamate. Treatment of oocytes with desflurane plus PMA significantly increased the transporter currents compared to the control, but did not further increase the response compared to either agent alone. Staurosporine attenuated desflurane-enhanced transporter currents without decreasing the basal activity; chelerythrine did not decrease either. In addition, pretreatment of oocytes with two PI3K inhibitors (wortmannin or LY294002) significantly reduced desflurane-enhanced EAAC1 activity without decreasing basal activity. Our results suggest that desflurane increases EAAC1 activity via PKC or PI3K. This enhanced EAAC1 activity may be a mechanism for the neuroprotective effect of desflurane. PMID- 25840280 TI - Effects of Icariin on insulin resistance via the activation of AMPK pathway in C2C12 mouse muscle cells. AB - Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes (T2D). In this study, we investigated the effect of icariin on insulin resistance in C2C12 mouse skeletal muscle cells. C2C12 myoblasts were differentiated into myotubes for five days, then treated with icariin (50 and 100uM) or metformin (1mM) in the presence of 100nM insulin for 24h. Adiponectin production was measured in culture media by ELISA, and AMP-activated protein kinase (AMPK)/insulin signaling pathway activation was assessed by the western blot analysis. Icariin significantly increased adiponectin production in C2C12 myotubes. Moreover, icariin markedly promoted the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). Icariin up-regulated the expression of phosphatidylinositol 3-kinase (PI3K) and the phosphorylation of insulin receptor substrate-1 (IRS-1) in C2C12 myotubes. These results suggest that icariin has therapeutic potential for the treatment of T2D via the regulation of insulin resistance in skeletal muscle. PMID- 25840281 TI - Epigallocatechin-3-gallate attenuates lipopolysaccharide-induced mastitis in rats via suppressing MAPK mediated inflammatory responses and oxidative stress. AB - Green tea (Camellia sinensis) is an extremely popular beverage worldwide. Epigallocatechin-3-gallate (EGCG) is one of the major catechins isolated from green tea and contributes to its beneficial therapeutic functions including antioxidant, anti-inflammatory and anti-cancer effects. However, the effect of EGCG on mastitis is not yet known. This study was to investigate the protective potential of EGCG against mastitis in rats. The rat mastitis model was induced by injecting lipopolysaccharide (LPS) into the duct of mammary gland. The mammary gland was collected after the experimental period. The levels of mammary oxidative stress and inflammatory responses were assessed by measuring the local activities of antioxidant enzymes and the levels of inflammatory cytokines. The mammary expressions of mitogen-activated protein kinases (MAPKs), nuclear factor kappaB-p65 (NFkappaB-p65) and hypoxia-inducible factor-1alpha (HIF-1alpha) were evaluated by western blot analysis. It was found that EGCG obviously normalized LPS-induced low activities of antioxidant enzymes as well as decreased the high levels of inflammatory cytokines. Additionally, EGCG inhibited the mammary over expression of MAPKs, NFkappaB-p65 and HIF-1alpha. These results indicated that EGCG was able to attenuate LPS-induced mastitis in rats by suppressing MAPK related oxidative stress and inflammatory responses. PMID- 25840282 TI - Rheumatoid arthritis: Biological therapy other than anti-TNF. AB - Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage. The introduction of biologic agents has made it possible to induce remission in many patients and inhibit joint damage. Activated T cells in RA patients proliferate and stimulate the production of pro-inflammatory cytokines including tumor necrosis factor (TNF) and interleukin 6 that play important roles in RA pathogenesis. The most widely used biologic agents indicated for RA inhibit the activity of TNF. However, newly developed biologic drugs targeting different pathways are now currently part of the therapeutic options to induce remission in patients with RA. The present review focuses on biologic agents directed at molecular targets different from TNF and addresses the possible advantages of these drugs. PMID- 25840283 TI - Authors' reply. PMID- 25840284 TI - Outcome of contemporary acute coronary syndrome complicated by ventricular tachyarrhythmias. AB - AIM: To evaluate the incidence and prognostic implications of ventricular tachyarrhythmias (VTAs) complicating acute myocardial infarction (MI). METHODS AND RESULTS: We evaluated 7669 MI patients [ST elevation (n = 3573) and non-ST elevation acute coronary syndrome (ACS) (n = 4096)] from the Acute Coronary Syndrome Israeli Survey for the incidence of VTA. Ventricular tachyarrhythmia occurred in 3.8% of patients [2.1% early (<= 48 h) and 1.7% late (>48 h) VTA]. In hospital mortality rates were higher for patients with VTA when compared with patients with no VTA (P < 0.001). Consistent with these findings, multivariable analysis demonstrated that early and late VTAs were associated with increased risk of in-hospital death [hazard ratio (HR) = 3.84; 95% confidence interval (CI) 1.77-6.78, P < 0.001, and HR = 8.23; 95% CI 4.84-13.98, P < 0.001, respectively]. In contrast, post-discharge outcomes demonstrated that only late VTA was independently associated with a significant increased risk of 30-day mortality (HR = 5.17; 95% CI 1.54-17.27, P = 0.007) with a trend towards an increased 1 year mortality risk (HR = 1.69; 95% CI 0.79-3.62, P = 0.17). The long-term risk associated with in-hospital VTA was driven by sustained ventricular tachycardia (VT) (HR = 3.28; 95% CI 1.92-5.60, P < 0.001) but not ventricular fibrillation (HR = 1.27; 95% CI 0.65-2.49, P = 0.47). CONCLUSIONS: Our findings suggest that in patients with ACS, both early and late VTAs are associated with an increased risk of in-hospital mortality. However, only late VTA, mostly sustained VT, is associated with long-term adverse outcome. PMID- 25840285 TI - Epicardial only mapping and ablation of ventricular tachycardia: a case series. AB - AIMS: Ventricular tachycardia (VT) ablation for ventricular arrhythmias is a validated approach, typically performed endocardially, or combined with an epicardial approach if endocardial ablation failed or in case of non-ischaemic cardiomyopathy. We report our experience with epicardial only procedure in a subset of patients with incessant VT or VT storm. METHODS AND RESULTS: This was a single centre retrospective study. Between 2011 and 2014, all patients referred for VT ablation were reviewed at CHU Bordeaux. All patients with an epicardial only (anterior percutaneous approach) mapping and ablation procedure were included. In total, 296 patients underwent a VT ablation and 4 (all male, 70 +/- 7 years, 27 +/- 11% left ventricular ejection fraction) of them underwent an epicardial only procedure: two ischaemic patients had an endocardial left ventricular thrombus and incessant VT. One patient post-myocarditis had a failed a previous endocardial procedure without local abnormal ventricular activity (LAVA). The fourth patient had a dilated cardiomyopathy and a complicated epicardial puncture followed by mild continuous bleeding (200 mL) precluding anticoagulation associated with left ventricular endocardial access. Local abnormal ventricular activity elimination was verified only epicardially in all and obtained in two patients and non-inducibility was tested and achieved in the two patients without thrombus. No further complications occurred. After a mean follow-up of 21 +/- 12 months, one patient (25%) had recurrence of VT and no patient death was observed. CONCLUSION: Epicardial only ablation seems feasible and effective and useful in a limited subset of patients with incessant VT. However, endpoints are more difficult to evaluate and long-term follow-up is needed. PMID- 25840286 TI - Implantable cardioverter-defibrillators and subsequent cancer risk: a nationwide population-based cohort study. AB - AIMS: Despite increasing use of implantable cardioverter-defibrillators (ICDs) and reports linking selected bio-implants with cancer, the cancer risk associated with implanted ICDs remains unknown. The objective of our study was to examine cancer risk among ICD recipients. METHODS AND RESULTS: We conducted a population based cohort study using medical registries covering the entire Danish population. We identified all first-time ICD recipients during the period of 2000 11 and determined their subsequent cancer incidence. Standardized incidence ratios (SIRs) were computed by comparing observed cancer incidence in the ICD cohort with expected cancer incidence based on national incidence rates according to age, sex, and year of diagnosis. A total of 6723 ICD recipients were followed for up to 12 years (median 2.8 years) and contributed a total of 23 254 person years of follow-up. Compared with the general population, ICD recipients had a slightly elevated overall risk of cancer [SIR = 1.1 (95% confidence interval (CI): 1.0-1.2)]. This was driven by the cancer risk among patients with ischaemic heart disease (IHD) [SIR = 1.1 (95% CI: 1.0-1.3)], which, as expected, was particularly elevated for tobacco-related cancers [SIR = 1.4 (95% CI: 1.2-1.6)]. Importantly, ICD recipients without IHD were not at increased cancer risk [SIR = 1.0 (95% CI: 0.8-1.3)]. CONCLUSION: This nationwide population-based cohort study with up to 12-year follow-up did not indicate a causal relation between ICD implantation and cancer. However, more follow-up data are needed to entirely rule out risks for individual cancer types. PMID- 25840287 TI - Comment on the article by Barra et al. entitled 'Implantable cardioverter defibrillators in the elderly: rationale and specific age-related considerations'. PMID- 25840288 TI - Better outcome of ablation for sustained outflow-tract ventricular tachycardia when tachycardia is inducible. AB - AIMS: In patients presenting with spontaneous sustained ventricular tachycardia (VT) from the outflow-tract region without overt structural heart disease ablation may target premature ventricular contractions (PVCs) when VT is not inducible. We aimed to determine whether inducibility of VT affects ablation outcome. METHODS AND RESULTS: Data from 54 patients (31 men; age, 52 +/- 13 years) without overt structural heart disease who underwent catheter ablation for symptomatic sustained VT originating from the right- or left-ventricular outflow region, including the great vessels. A single morphology of sustained VT was inducible in 18 (33%, SM group) patients, and 11 (20%) had multiple VT morphologies (MM group). VT was not inducible in 25 (46%) patients (VTni group). After ablation, VT was inducible in none of the SM group and in two (17%) patients in the MM group. In the VTni group, ablation targeted PVCs and 12 (48%) patients had some remaining PVCs after ablation. During follow-up (21 +/- 19 months), VT recurred in 46% of VTni group, 40% of MM inducible group, and 6% of the SM inducible group (P = 0.004). Analysis of PVC morphology in the VTi group further supported the limitations of targeting PVCs in this population. CONCLUSION: Absence of inducible VT and multiple VT morphologies are not uncommon in patients with documented sustained outflow-tract VT without overt structural heart disease. Inducible VT is associated with better outcomes, suggesting that attempts to induce VT to guide ablation are important in this population. PMID- 25840290 TI - Patients with congenital heart disease: how to determine the eligibility for implantation of a subcutaneous implantable defibrillator? PMID- 25840289 TI - Comparison between radiofrequency with contact force-sensing and second generation cryoballoon for paroxysmal atrial fibrillation catheter ablation: a multicentre European evaluation. AB - AIMS: Whether pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF) using contact force (CF)-guided radiofrequency (RF) or second-generation cryoballoon (CB) present similar efficacy and safety remains uncertain. METHODS AND RESULTS: We performed a multicentre study comparing procedural safety and arrhythmia recurrence after standardized PVI catheter ablation for PAF using CF guided RF ablation (Thermocool((r)) SmartTouchTM, Biosense Webster; or TacticathTM, St Jude Medical) (CF group) with second-generation CB ablation (Arctic Front AdvanceTM, Medtronic) (CB group). Overall, 376 patients (mean age 59.8 +/- 10.4 years, 280 males) were enrolled in 4 centres: 198 in CF group and 178 in CB group. Procedure was shorter for CB group than for CF group (109.6 +/- 40 vs. 122.5 +/- 40.7 min, P = 0.003), but fluoroscopy duration and X-ray exposure were not statistically different (P = 0.1 and P = 0.22, respectively). Overall complication rate was similar in both groups: 14 (7.1%) in the CF group vs. 13 (7.3%) in the CB group (P = 0.93). However, transient right phrenic nerve palsy occurred only in CB group (10 patients, 5.6%; P = 0.001 vs. CF group) and severe non-lethal complications (embolic event, tamponade, or oesophageal injury) occurred only in CF group (5 patients, 2.5%; P = 0.03 vs. CB group). No periprocedural death occurred in either group. Single-procedure freedom from any atrial arrhythmias at 18 months post-ablation was comparable in CF group and CB group (76 vs. 73.3%, respectively, log rank P = 0.63). CONCLUSION: Pulmonary vein isolation using CF-guided RF and second-generation CB leads to comparable single procedure arrhythmia-free survival at up to 18 months with similar overall complication rate. PMID- 25840291 TI - Ectasia risk: a multifactorial conundrum. PMID- 25840292 TI - Norman S. Jaffe, MD: the American pioneer. PMID- 25840293 TI - Femtodelineation to enhance safety in posterior polar cataracts. AB - We describe the technique of femtodelineation for posterior polar cataracts. In this technique, the femtosecond laser is used with a cylindrical pattern of lens division to create multiple cylinders within the lens, which results in sharply demarcated layers. The number, size, and depth of the cylinders can be controlled by the surgeon using the live anterior segment optical coherence tomography view. The multiple layers act as mechanical cushions that protect each layer as it is removed. Because of its sharp demarcation, the last epinuclear layer can be easily stripped using a combination of the phaco probe and bimanual irrigation/aspiration. This approach eliminates the need for any type of hydro procedure in posterior polar cataracts. It reduces posterior capsule rupture rates and enhances safety in posterior polar cataract emulsification. FINANCIAL DISCLOSURE: Dr. A.R. Vasavada receives research support from Alcon Laboratories, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25840294 TI - Glued intraocular lens scaffolding for Soemmerring ring removal in aphakia with posterior capsule defect. AB - We describe using the glued intraocular lens (IOL) scaffolding technique to remove Soemmerring ring during secondary IOL implantation in aphakic eyes with associated posterior capsule defect following previous pediatric cataract surgery. Vitrectomy is performed, and the remnants of the posterior capsule are removed from the visual axis. A 3-piece foldable IOL is injected below the Soemmerring ring, and glued transscleral haptic fixation of the IOL is performed. The Soemmerring ring is dislodged from the periphery with a Sinskey hook and brought into the center of the pupil over the surface of the IOL optic, where it is emulsified with the phacoemulsification probe. The optic of the preplaced IOL acts as a scaffold and prevents dislodgement of Soemmerring ring material into the vitreous cavity during emulsification. Placement of a secondary IOL can be successfully accomplished in selected patients. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840295 TI - Assessment of intraoperative complications in intumescent cataract surgery using 2 ophthalmic viscosurgical devices and trypan blue staining. AB - PURPOSE: To evaluate intraoperative complications during capsulorhexis and phacoemulsification in intumescent white cataracts using 2 ophthalmic viscosurgical device (OVD) techniques. SETTING: Ruhr University Eye Clinic, Bochum, Germany. DESIGN: Case series. METHODS: Patients with eyes with intumescent white cataract were recruited and placed in 2 groups. After capsule staining using trypan blue, a central indentation of the anterior lens capsule was created in the eyes in Group 1 using a medium-viscosity OVD (Healon 1.0%) and in the eyes in Group 2 using both medium-viscosity (1.0%) and high-viscosity (2.3%) OVDs. Then a continuous curvilinear capsulorhexis (CCC) was performed. The outcomes measured were the horizontal and vertical diameters of the CCC, the deviation from the target diameter, and intraoperative complications. RESULTS: In Group 1 (21 eyes), deviation from the target CCC diameter occurred in 12 eyes (10 oversized, 2 undersized), and in Group 2 (20 eyes) deviation occurred in 6 eyes (4 oversized, 2 undersized). In Group 1, capsule tears appeared in 2 eyes and in 1 eye, the procedure had to be converted to extracapsular cataract extraction with anterior vitrectomy. In Group 2, there were no capsule tears. CONCLUSION: Using 2 different OVDs and placing the high-viscosity OVD centrally led to safe indentation of the anterior lens capsule and reduced the risk for CCC enlargement and capsule tear during surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840296 TI - Clinical study of pain sensation during phacoemulsification with and without cryoanalgesia. AB - PURPOSE: To compare the analgesic efficacy of 2 types of anesthetic techniques topical and topical associated with cryoanalgesia-during cataract surgery. SETTING: Department of Ophthalmology, University of Sao Paulo, Ribeirao Preto, Brazil. DESIGN: Prospective randomized study. METHODS: Patients with symmetrical bilateral cataract had phacoemulsification with the use of an intraocular irrigation solution at room temperature in 1 eye and a cold (4 degrees C) solution in the contralateral eye (Group 2). The pain related to the procedure was assessed using a visual analog scale ranging from 0 to 100, with 0 representing no pain and 100 the worst pain. In addition, endothelial cell loss, the change in corneal thickness, and visual acuity were evaluated 30 days +/- 2 (SD) after each surgery. The surgery duration, total irrigation volume, phacoemulsification time, and ultrasound power used were analyzed. RESULTS: The study enrolled 25 patients (50 eyes). There was no statistically significant difference in the mean pain score between Group 1 (26.0 +/- 3.7) and Group 2 (21.3 +/- 3.6) (P = .2016, paired t test). No significant difference was found in the mean corneal endothelial cell loss (Group 1: 10.0% +/- 0.4%; Group 2: 9.9% +/ 0.3%; P = .7576), corneal thickness increase (Group 1: 1.5 +/- 1.0 MUm; Group 2: 1.4 +/- 0.9 MUm; P = .9340), or visual acuity gain (Group 1: 0.54 +/- 0.06 logMAR; Group 2: 0.55 +/- 0.09 logMAR; P = .8208). CONCLUSION: There is no difference in the intensity of pain during phacoemulsification with the use of topical anesthesia or topical anesthesia associated with cryoanalgesia. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840298 TI - Comparison of 2 femtosecond lasers for flap creation in myopic laser in situ keratomileusis: one-year results. AB - PURPOSE: To compare laser in situ keratomileusis (LASIK) outcomes between 2 femtosecond lasers for flap creation in the treatment of myopia up to 1 year. SETTING: University eye clinic. DESIGN: Prospective randomized eye-to-eye study. METHODS: Consecutive myopic patients were treated with wavefront-guided LASIK. One eye had a flap created by the Intralase FS 60 kHz femtosecond laser, and the fellow eye was treated with the Intralase iFS 150 kHz femtosecond laser. Eyes were randomized according to ocular dominance. Evaluations included measurement of uncorrected distance visual acuity (UDVA), corrected distance visual acuity, contrast sensitivity and wavefront aberrometry. RESULTS: The study enrolled 122 eyes of 61 patients. The mean preoperative spherical equivalent refraction was 4.62 diopters (D) +/- 2.32 (SD) and -4.66 +/- 2.30 D in the 150 kHz group and 60 kHz group, respectively. Patients preferred the 150 kHz laser to the 60 kHz laser intraoperatively (52.5% versus 26.2%) (P = .005). One week postoperatively, UDVA was 20/16 or better in 85.2% in the 150 kHz group and 70.5% in the 60 kHz group; the difference was statistically significant (P < .05). At 12 months, there were no significant differences in refractive outcomes or higher-order aberrations between the 2 groups. CONCLUSIONS: Flap creation with the 150 kHz system and the 60 kHz system resulted in excellent LASIK outcomes. Intraoperatively, patients preferred the 150 kHz system, which yielded better UDVA in the early postoperative period. There were no significant differences at 1 year between the 2 laser systems. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 25840297 TI - Comparison of 1-day versus 1-hour application of topical neomycin/polymyxin-B before cataract surgery. AB - PURPOSE: To compare the efficacy of 2 prophylaxis regimens before cataract surgery using topical antibiotics (1 hour before surgery versus the day before), both with povidone-iodine, with regard to reducing the preoperative conjunctival bacterial load. SETTING: Tertiary ophthalmic referral center, Munich, Germany. DESIGN: Prospective comparative case series. METHODS: Eyes were treated with topical antibiotics and their conjunctival sac flush irrigated using 10 mL of povidone-iodine 1.0%. All eyes were randomized to receive either 4 applications of topical 3500 IU/mL neomycin sulfate/6000 IU/mL polymyxin-B sulfate within 1 hour preoperatively (Group 1) or on the day before surgery (Group 2). Conjunctival specimens were obtained at 4 timepoints: T0C untreated fellow eye (control), T0 surgery eye (after antibiotic prophylaxis but before povidone iodine irrigation), T1 after povidone-iodine, and T2 at the conclusion of surgery. All specimens were inoculated onto blood and chocolate-blood agar and into thioglycollate broth. RESULTS: One hundred thirty-three eyes of 133 consecutive patients were included (Group 1, 64 eyes; Group 2, 69 eyes). The antibiotic regimens were equally effective in reducing the aerobic and microaerophilic conjunctival flora (Group 1, P=.028; Group 2, P=.000), but had no significant effect on anaerobic bacteria (Group 1, P=.201; Group 2, P=.117). Flush irrigation of the conjunctival sac using 10.0 mL povidone-iodine 1.0% significantly decreased the conjunctival bacterial load in both groups. CONCLUSION: Topical neomycin/polymyxin-B was equally effective in reducing the conjunctival bacterial load whether given 1 day or 1 hour before surgery. The greatest effect was achieved by irrigating the conjunctival sac using povidone iodine. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840299 TI - Analgesic effect of preoperative topical nonsteroidal antiinflammatory drugs on postoperative pain after laser-assisted subepithelial keratectomy. AB - PURPOSE: To assess the effect of preoperative topical nonsteroidal antiinflammatory drugs (NSAIDs) on postoperative pain after laser-assisted subepithelial keratectomy (LASEK) and to investigate their mechanism. SETTING: Severance Eye Hospital and Saeyan Eye Clinic, Seoul, South Korea. DESIGN: Prospective randomized clinical trial. METHODS: Participants in 2 related studies were assessed. Study 1 comprised patients scheduled for bilateral LASEK (Group 1) who were randomized to receive an NSAID in 1 eye and a placebo in the fellow eye 30, 20, and 10 minutes before LASEK. Postoperative pain, glare, tearing, and irritation were assessed using a visual analog scale. Study 2 comprised healthy subjects (Group 2) who were randomly divided into subgroups. The participants in these subgroups were randomized to receive ketorolac tromethamine 0.5% in 1 eye and placebo (ofloxacin 0.3%) in the fellow eye (Group 2A), proparacaine hydrochloride 0.5% in 1 eye and placebo in the fellow eye (Group 2B), or ketorolac tromethamine 0.5% in 1 eye and placebo in the fellow eye, followed 10 minutes later by 1 drop of proparacaine hydrochloride 0.5% in both eyes (Group 2C). In all 3 groups, corneal sensitivity was measured after 1, 2, and 6 hours. RESULTS: The mean postoperative pain score in the NSAID-pretreated eye was statistically significantly lower than in the placebo-pretreated eye 6, 12, and 24 hours postoperatively (P < .05). The mean corneal sensitivity was statistically significantly lower in the NSAID-treated eye than in the placebo treated eye at 1 and 2 hours in Groups 2A and 2C (P < .05). CONCLUSION: Preoperative administration of topical NSAIDs before LASEK effectively reduces postoperative pain. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840300 TI - Neutralization method for detecting the incidence of color perception changes after cataract surgery. AB - PURPOSE: To evaluate and compare the incidence of cyanopsia using the neutralization method in eyes in which clear or yellow intraocular lenses (IOLs) were implanted. SETTING: Miyata Eye Clinic, Hiroshima, Japan. DESIGN: Retrospective comparative study. METHODS: Patients who had cataract surgery with the implantation of a monofocal IOL were enrolled in the study. Group 1 had implantation of a clear IOL (Acrysof SA60AT, Sensar AR40e, N4-18B). Group 2 had implantation of a yellow IOL (AF-1 YA60BB, AN-6). A control group comprised healthy patients. The detection and degree of cyanopsia were evaluated using white gradation cards (1 white [W] and 5 white gradation cards with increasing intensity of yellow tint [Y1, Y2, Y3, Y4, and Y5]) (neutralization method). RESULTS: The study comprised 57 patients in Group 1, 96 in Group 2, and 41 in the control group. All patients in the control group selected the W, Y1, or Y2 cards as white. Cyanopsia was then defined as the perception of Y3, Y4, and Y5 as white. One month postoperatively, cyanopsia occurred significantly more frequently in Group 1 than in Group 2 (14.5% versus 4.9%) (P = .049). There was no significant difference at 3 months (9.1% versus 5.2%) (P > .05). In Group 1, cyanopsia was more frequent in eyes with monocular IOL implantation than in eyes with binocular IOL implantation (22.2% versus 2.7%; P = .035). CONCLUSION: The incidence of cyanopsia evaluated with the neutralization method was higher with clear IOLs than with yellow IOLs. In monocular implantation, yellow IOLs are recommended to avoid cyanopsia. FINANCIAL DISCLOSURE: The author has no financial or proprietary interest in any material or method mentioned. PMID- 25840301 TI - Measurement and use of postoperative anterior chamber depth of fellow eye in refractive outcomes. AB - PURPOSE: To compare refractive outcomes using fellow-eye postoperative anterior chamber depth (ACD) in intraocular lens (IOL) power calculations with outcomes obtained without fellow-eye data and to assess postoperative ACD stability. SETTING: Johns Hopkins University, Baltimore, Maryland, USA. DESIGN: Consecutive case series. METHODS: The main outcome measures were the optimized median absolute error (MedAE) and ACD at postoperative day 1 and postoperative month 1 measured by optical biometry. A program using the Olsen IOL power formula predicted the postoperative ACD and refractive outcomes and calculated theoretical refractive outcomes of inputting fellow-eye ACD at postoperative day 1 and postoperative month 1. Theoretical results were subtracted from the observed manifest refraction and then optimized. Calculations were repeated for the other eye. RESULTS: In 102 paired eyes, the MedAE was 0.32 diopter (D) (interquartile range, 25% to 75%; range 0.12 to 0.54 D) for Olsen (without fellow eye data), 0.33 D (range 0.20 to 0.57 D) using fellow-eye postoperative day 1 ACD, and 0.28 D (range 0.13 to 0.51 D) using fellow-eye postoperative month 1 ACD, with a significant difference between the latter 2 MedAE values (P < .0005). In eyes with an Olsen absolute error greater than 0.50 D, use of either ACD in the fellow eye resulted in a smaller MedAE (P <= .01). The ACD shallowed by a mean of 148 MUm +/- 13 (SD). CONCLUSIONS: Use of the fellow-eye postoperative month 1 ACD predicted refractive outcomes better than postoperative day 1 ACD. In eyes with a larger Olsen absolute error, use of either postoperative ACD from the fellow eye would have yielded better results. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840302 TI - Influence of corneal asphericity on the refractive outcome of intraocular lens implantation in cataract surgery. AB - PURPOSE: To evaluate the possible influence of anterior corneal surface asphericity on the refractive outcomes in eyes having intraocular lens (IOL) implantation after cataract surgery. SETTING: Fondazione G.B. Bietti IRCCS, Rome, Italy. DESIGN: Retrospective comparative case series. METHODS: Intraocular lens power was calculated using the Haigis, Hoffer Q, Holladay 1, and SRK/T formulas. Asphericity (Q-value) was measured at 8.0 mm with a Placido-disk corneal topographer (Keratron), a rotating Scheimpflug camera (Pentacam), and a rotating Scheimpflug camera combined with Placido-disk corneal topography (Sirius). The relationship between the error in refraction prediction (ie, difference between expected refraction and refraction measured 1 month after surgery) and the Q value was assessed by linear regression. RESULTS: The same IOL model (Acrysof SA60AT) was implanted in 115 eyes of 115 consecutive patients. Regression analysis showed a statistically significant relationship between the error in refraction prediction and the Q-value with all formulas and all devices. In all cases, a more negative Q-value (prolate cornea) was associated with a myopic outcome, whereas a more positive Q-value (oblate cornea) was associated with a hyperopic outcome. The highest coefficient of determination was detected between the Hoffer Q formula and the Placido-disk corneal topographer (R(2) = 0.2630), for which the error in refraction prediction (y) was related to the Q-value (x) according to the formula y = -0.2641 + 1.4589 * x. CONCLUSION: Corneal asphericity influences the refractive outcomes of IOL implantation and should be taken into consideration when using third-generation IOL power formulas. FINANCIAL DISCLOSURE: Dr. Hoffer receives book royalties from Slack, Inc., Thorofare, New Jersey, and formula royalties from all manufacturers using the Hoffer Q formula. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 25840304 TI - Prevalence of cataract after collagen copolymer phakic intraocular lens implantation for myopia, hyperopia, and astigmatism. AB - PURPOSE: To evaluate the prevalence of cataract after Implantable Collamer Lens phakic intraocular lens (pIOL) implantation with different models at different ages and for different refractive powers. SETTING: Fernandez-Vega Ophthalmological Institute, Oviedo, Spain. DESIGN: Retrospective nonrandomized clinical study. METHODS: The pIOL (models V4, V4b, or V4c) was implanted in all cases. RESULTS: The study included 3420 eyes (1898 patients). The mean patient age at surgery was 31.2 years +/- 6.4 (SD) (range 18 to 50 years) and the mean spherical refractive error, -7.27 +/- 5.24 diopters (D) (range -26.5 to 12.5 D). Twenty-one eyes (0.61%) of 15 patients had pIOL explantation (all model V4) because cataract developed. The mean age of the patients who had explantation was 39.43 +/- 4.57 years; 7 were younger than 40 years, and 8 were 40 years or older. The mean spherical equivalent was -10.1 +/- 5.41 D; 3 eyes had a pIOL power less than -10.50 D, 4 eyes between -10.50 D and -13.50 D, and 14 higher than -13.50 D. The mean time between pIOL implantation and cataract surgery was 4.2 +/- 1.8 years. No eye with implantation of the latest models (V4b and V4c) developed cataract. The mean vault distance in eyes that developed cataracts was 103 +/- 69 MUm. CONCLUSIONS: The incidence of cataract was low after pIOL implantation at the 6-year follow-up. The rate of cataract was higher in older patients and in those with high refractive errors. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840303 TI - Vector analysis of astigmatism correction after toric intraocular lens implantation. AB - PURPOSE: To determine astigmatic changes by vector analysis and postoperative refractive and visual outcomes after implantation of the monofocal aspheric bitoric AT Torbi 709M toric intraocular lens (IOL). SETTING: Three centers in Salzburg, Austria, and Alicante and San Sebastian, Spain. DESIGN: Prospective interventional case series. METHODS: Preoperative and postoperative visual acuity, subjective and objective refractions, and corneal radii using a topographer were examined in all patients. All patients had postoperative examinations within the first week and at 6 to 12 weeks. Astigmatic changes were evaluated using the Alpins vector method based on 3 fundamental vectors as follows: target induced astigmatism (TIA), surgically induced astigmatism (SIA), and difference vector. The various relationships between these 3 vectors were calculated, providing an extensive description of the astigmatic correction achieved. RESULTS: Eighty-eight eyes (71 patients) were included. Postoperatively, refractive cylinder was reduced significantly (P < .001), concurrent with visual improvement. The mean magnitude of the SIA vector (2.54 diopters [D] +/- 1.21 [SD]) was slightly higher than the mean magnitude of the TIA vector (2.37 +/- 1.15 D) at the last follow-up. The mean difference vector was 0.46 +/- 0.46 D, the mean magnitude of error was 0.16 +/- 0.46 D, and the mean correction index was 1.09 +/- 0.21, all indicating minimal overcorrection at 3 months that remained stable during the follow-up. CONCLUSION: Implantation of the toric IOL was safe and effective for the treatment of eyes with cataract in combination with preexisting regular corneal astigmatism over a short-term follow up. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840305 TI - Repeatability of topographic and aberrometric measurements at different accommodative states using a combined topographer and open-view aberrometer. AB - PURPOSE: To evaluate the repeatability of corneal first-surface aberrations and aberrometric measurements of a combined aberrometer-topographer (iTrace Visual Function Analyzer) for 5 accommodative stimuli. SETTING: Department of Ophthalmology, Goethe-University, Frankfurt, Germany. DESIGN: Prospective case series. METHODS: Eyes of young adults with low to moderate myopia or hyperopia were examined in 2 measurement series comprising 3 corneal topography measurements and wavefront measurements focusing on targets at 5 distances (0.4, 0.5, 0.6, 1.0, and 4.0 m). Repeatability was analyzed using the standard deviation (SD) within 6 measurements and the coefficient of repeatability (CoR) by Bland-Altman analysis of the means of the 2 measurement series. RESULTS: Fifty eyes (50 subjects) were evaluated. The lowest calculated mean SD/CoR measurements using the aberrometer function at 5 target distances were 0.07 MUm/0.14 MUm for total ocular aberrations root mean square (RMS), 0.07 MUm/0.16 MUm for lower order aberrations (LOAs) RMS, 0.03 MUm/0.66 MUm for higher-order aberrations (HOAs) RMS, 0.10 diopter (D)/0.22 D for sphere, 0.08 D/0.13 D for cylinder, and 0.09 D/0.21 D for the spherical equivalent (SE). Repeatability of the total RMS, LOAs RMS, sphere, and SE measurements improved with increasing target distance (P < .01 for aberrometric values; P < .03 for refractive values). Measurement reproducibility using the corneal topographer showed mean SDs/CoRs of 0.19 MUm/0.41 MUm for total RMS, 0.19 MUm/0.39 MUm for LOAs RMS, and 0.08 MUm/0.23 MUm for HOAs RMS. CONCLUSION: The aberrometer showed satisfactory results for measurement repeatability at all target distances and declining repeatability with increasing accommodation effort. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840306 TI - Corneal epithelial thickness mapping using Fourier-domain optical coherence tomography for detection of form fruste keratoconus. AB - PURPOSE: To determine whether optical coherence tomography (OCT) epithelial mapping can improve the detection of form fruste keratoconus. SETTING: French National Eye Hospital, Paris 6 Pierre & Marie Curie University, Paris, France. DESIGN: Retrospective comparative study. METHODS: Eyes with normal corneas, form fruste keratoconus, moderate keratoconus, or severe keratoconus were assessed using Fourier-domain OCT (RTVue 5.5), scanning-slit corneal topography (Orbscan IIz), and rotating Scheimpflug camera (Pentacam Comprehensive Eye Scanner). Several parameters provided by the software or derived from elevation maps, OCT pachymetric maps, and OCT epithelium parameters were evaluated and compared between the 4 groups. RESULTS: The study involved 145 eyes. There were no significant differences in the keratometry (K) value, inferior-superior value, keratoconus index, central K index, and topographic keratoconus classification indices between the form fruste keratoconus group and the control group (P > .05). Form fruste keratoconic corneas had less epithelial thickness in the thinnest corneal zone than normal corneas, and greater epithelial thickness in the thinnest corneal zone than keratoconic corneas (P < .005). The epithelial thickness in the thinnest corneal zone in form fruste corneas was located inferiorly (P < .005) and corresponded with the zone of minimum epithelial thickness and maximum posterior elevation (P < .005). The receiver operating characteristic curve analysis showed good overall predictive accuracy of the epithelial thickness in the thinnest corneal zone, with a 52 MUm threshold value for discriminating form fruste keratoconic corneas from normal corneas. CONCLUSIONS: The epithelial thickness in the thinnest corneal zone and its location provided by the OCT epithelial mapping might be useful for the early diagnosis of form fruste keratoconus. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840307 TI - Femtosecond laser-assisted pediatric cataract surgery: Bochum formula. AB - PURPOSE: To assess capsulotomy enlargement after femtosecond laser treatment in pediatric cataract surgery and to assess the possible relationship to the patient's age. SETTING: Ruhr University Eye Hospital, Bochum, Germany. DESIGN: Prospective case series. METHODS: Anterior and posterior laser capsulotomies were performed in cases of pediatric cataract. The Pearson correlation coefficient (r) was used to evaluate the relationship between the programmed capsulotomy diameter and the achieved capsulotomy diameter. Linear bivalent regression analysis was used to describe the extent to which the capsulotomy enlargement factor was age dependent. RESULTS: Twenty-two eyes of 18 children were included in the trial. The mean age was 9.2 years +/- 6.08 (SD) (range 0.17 to 18.0 years). The enlargement factors of the capsulotomies showed a highly significant negative correlation with patient age (r = -0.863; P < .001). In particular, younger children had a distinct deviation from the target diameter. Using linear bivalent regression analysis, an age-depending correction formula was developed. CONCLUSION: The Bochum formula for pediatric laser capsulotomies helped minimize the age-dependent deviation from the targeted diameter. Anterior and posterior laser capsulotomies in children were safe to perform. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840308 TI - Reshaping procedures for the surgical management of corneal ectasia. AB - Corneal ectasia is a progressive, degenerative, and noninflammatory thinning disorder of the cornea. Recently developed corneal reshaping techniques have expanded the treatment armamentarium available to the corneal specialist by offering effective nontransplant options. This review summarizes the current evidence base for corneal collagen crosslinking, topography-guided photorefractive keratectomy, and intrastromal corneal ring segment implantation for the treatment of corneal ectasia by analyzing the data published between the years 2000 and 2014. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 25840309 TI - Explanted multifocal intraocular lenses. AB - We report 2 cases in which single-piece multifocal acrylic intraocular lenses (IOLs) were explanted because of complications related to the presence of glistenings in the bulk of the IOL optic. In both cases, the patients complained about blurry or hazy vision. In vivo slitlamp examinations prior to IOL explantation confirmed the presence of severe glistenings in the IOL optic in 1 case and moderate glistenings in the second case. In the first case, the symptoms resolved and both corrected and uncorrected distance visual acuities improved by 4 lines following IOL exchange with a monofocal IOL. In the second case, the visual symptoms persisted with a hard contact lens. Symptoms resolved following an exchange with a monofocal IOL that was free of glistenings. These findings indicate that straylight caused by IOLs with glistenings may be clinically significant in cases in which multifocal IOLs are implanted and patients require optimized retinal sensitivity. FINANCIAL DISCLOSURE: Mr. van der Mooren, Ms. Langeslag, and Dr. Piers are employees of Abbott Medical Optics, Inc. Drs. Steinert and Tyson are consultants to Abbott Medical Optics Inc. PMID- 25840310 TI - Clinical usefulness of best-fit toric ellipsoid reference body in ectatic and crosslinked corneas. PMID- 25840311 TI - Primary reverse optic capture with implantation of capsular tension ring to prevent pseudophakic negative dysphotopsia. PMID- 25840312 TI - Predisposing factors for intraocular lens dislocation treated by pars plana vitrectomy: Involvement of atopic dermatitis. PMID- 25840313 TI - Corneal surgical problem: April consultation #1. PMID- 25840314 TI - April consultation #2. PMID- 25840315 TI - April consultation #3. PMID- 25840316 TI - April consultation #4. PMID- 25840317 TI - April consultation #5. PMID- 25840318 TI - April consultation #6. PMID- 25840319 TI - Refractive lenticule extraction. PMID- 25840320 TI - Prophylaxis of bacterial pseudophakic endophthalmitis: myth of cross-reactivity between penicillin and cefuroxime. PMID- 25840321 TI - Reply: To PMID 25465213. PMID- 25840322 TI - Pseudophakic endophthalmitis and the validity of different prophylactic regimens. PMID- 25840323 TI - Reply: To PMID 25532634. PMID- 25840324 TI - Incidence of postoperative endophthalmitis with the use of povidone-iodine. PMID- 25840325 TI - Reply: To PMID 25532634. PMID- 25840326 TI - Prevalence of glaucoma and cataract morphology in congenital rubella syndrome. PMID- 25840327 TI - Reply: To PMID 25465688. PMID- 25840328 TI - Femtosecond laser-assisted capsulorhexis: anterior capsule tags and tears. PMID- 25840329 TI - Reply: To PMID 25466483. PMID- 25840330 TI - The Mediating Role of Acceptance in Multidisciplinary Cognitive-Behavioral Therapy for Chronic Pain. AB - Cognitive-behavioral therapy (CBT) is the most frequently delivered psychological intervention for adults with chronic pain. The treatment yields modest effect sizes, and the mechanisms of action remain understudied and unclear. Efforts are needed to identify treatment mediators that could be used to refine CBT and improve outcomes. The primary aim of this study was to investigate whether pain related acceptance, from the psychological flexibility model, mediates changes in outcome over time in a CBT-based treatment program. This includes comparing how this variable relates to 3 other variables posited as potential mediators in standard CBT: life control, affective distress, and social support. Participants attended a 5-week outpatient multidisciplinary program with self-report data collected at assessment, posttreatment, and 12-month follow-up. Multilevel structural equation modeling was used to test for mediation in relation to 3 outcomes: pain interference, pain intensity, and depression. Results indicate that effect sizes for the treatment were within the ranges reported in the CBT for pain literature. Pain-related acceptance was not related to pain intensity, which is in line with past empirical evidence and the treatment objectives in acceptance and commitment therapy. Otherwise, pain-related acceptance was the strongest mediator across the different indices of outcome. Accumulated results like these suggest that acceptance of pain may be a general mechanism by which CBT-based treatments achieve improvements in functioning. More specific targeting of pain-related acceptance in treatment may lead to further improvements in outcome. PERSPECTIVE: Potential mediators of outcome in a CBT-based treatment for adult chronic pain were investigated using multilevel structural equation modeling. The results highlight the role of pain-related acceptance as an important treatment process even when not explicitly targeted during treatment. These data may help clinicians and researchers better understand processes of change and improve the choice and development of treatment methods. PMID- 25840331 TI - Brain alterations and neurocognitive dysfunction in patients with complex regional pain syndrome. AB - Few studies have examined the involvement of specific subregions of the prefrontal cortex in complex regional pain syndrome (CRPS). We analyzed cortical thickness to identify morphologic differences in local brain structures between patients with CRPS and healthy control subjects (HCs). Furthermore, we evaluated the correlation between cortical thickness and neurocognitive function. Cortical thickness was measured in 25 patients with CRPS and 25 HCs using the FreeSurfer method. Pain severity and psychiatric symptoms were assessed using the Short Form McGill Pain Questionnaire and the Beck Depression and Anxiety Inventories, respectively. Neurocognitive function was assessed via the Wisconsin Card Sorting Test and the stop-signal task. The right dorsolateral prefrontal cortex and left ventromedial prefrontal cortex were significantly thinner in CRPS patients than in HCs. CRPS patients made more perseveration errors on the Wisconsin Card Sorting Test and had longer stop-signal task reaction times than HCs. Although the Beck Depression Inventory and the Beck Anxiety Inventory differ significantly between the groups, they were not correlated with cortical thickness. Our study suggests that the pathophysiology of CRPS may be related to reduced cortical thickness in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex. The structural alterations in dorsolateral prefrontal cortex may explain executive dysfunction and disinhibited pain perception in CRPS. PERSPECTIVE: The present study reports decreased cortical thickness in the prefrontal cortex and neurocognitive dysfunctions in patients with CRPS. These findings may contribute to the understanding of pain-related impairments in cognitive function and could help explain the symptoms or progression of CRPS. PMID- 25840332 TI - What's in an Outgroup? The Impact of Outgroup Choice on the Phylogenetic Position of Thalattosuchia (Crocodylomorpha) and the Origin of Crocodyliformes. AB - Outgroup sampling is a central issue in phylogenetic analysis. However, good justification is rarely given for outgroup selection in published analyses. Recent advances in our understanding of archosaur phylogeny suggest that many previous studies of crocodylomorph and crocodyliform relationships have rooted trees on outgroup taxa that are only very distantly related to the ingroup (e.g., Gracilisuchus stipanicicorum), or might actually belong within the ingroup. Thalattosuchia, a group of Mesozoic marine crocodylomorphs, has a controversial phylogenetic position--they are recovered as either the sister group to Crocodyliformes, in a basal position within Crocodyliformes, or nested high in the crocodyliform tree. Thalattosuchians lack several crocodyliform apomorphies, but share several character states with derived long-snouted forms with a similar ecological habit, suggesting their derived position may be the result of convergent evolution. Several of these "shared" characters may result from ambiguously worded character state definitions--structures that are superficially similar but anatomically different in detail are identically coded. A new analysis of crocodylomorphs with increased outgroup sampling recovers Thalattosuchia as the sister group to Crocodyliformes, distantly related to long snouted crocodyliforms. I also demonstrate that expanding the outgroup sampling of previously published matrices results in the recovery of thalattosuchians as sister to Crocodyliformes. The exclusion of thalattosuchians from Crocodyliformes has numerous implications for large-scale evolutionary trends within the group, including extensive convergence in the evolution of the secondary palate characteristic of the group. These results demonstrate the importance of careful outgroup sampling and character construction, and their profound effect on the position of labile clades. PMID- 25840334 TI - Hematopoietic Cell Transplantation Using Reduced-Intensity Conditioning Is Successful in Children with Hematologic Cytopenias of Genetic Origin. AB - Genetically derived hematologic cytopenias are a rare heterogeneous group of disorders. Allogeneic hematopoietic cell transplantation (HCT) is curative but offset by organ toxicities from the preparative regimen, graft rejection, graft versus-host disease (GVHD), or mortality. Because of these possibilities, consideration of HCT can be delayed, especially in the unrelated donor setting. We report a prospective multicenter trial of reduced-intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan and HCT in 11 children with marrow failure of genetic origin (excluding Fanconi anemia) using the best available donor source (82% from unrelated donors). The median age at transplantation was 23 months (range, 2 months to 14 years). The median times to neutrophil (>500 * 10(6)/L) and platelet (>50 * 10(9)/L) engraftment were 13 (range, 12 to 24) and 30 (range, 7 to 55) days, respectively. The day +100 probability of grade II to IV acute GVHD and the 1-year probability of limited and extensive GVHD were 9% and 27%, respectively. The probability of 5-year overall and event-free survival was 82%; 9 patients were alive with normal blood counts at last follow-up and all were successfully off systemic immunosuppression. In patients with genetically derived severe hematologic cytopenias, allogeneic HCT with this RIC regimen was successful in achieving a cure. This experience supports consideration of HCT early in such patients even in the absence of suitable related donors. PMID- 25840335 TI - The Sequence of Cyclophosphamide and Myeloablative Total Body Irradiation in Hematopoietic Cell Transplantation for Patients with Acute Leukemia. AB - Limited clinical data are available to assess whether the sequencing of cyclophosphamide (Cy) and total body irradiation (TBI) changes outcomes. We evaluated the sequence in 1769 (CyTBI, n = 948; TBICy, n = 821) recipients of related or unrelated hematopoietic cell transplantation who received TBI (1200 to 1500 cGY) for acute leukemia from 2003 to 2010. The 2 cohorts were comparable for median age, performance score, type of leukemia, first complete remission, Philadelphia chromosome-positive acute lymphoblastic leukemia, HLA-matched siblings, stem cell source, antithymocyte globulin use, TBI dose, and type of graft-versus-host disease (GVHD) prophylaxis. The sequence of TBI did not significantly affect transplantation-related mortality (24% versus 23% at 3 years, P = .67; relative risk, 1.01; P = .91), leukemia relapse (27% versus 29% at 3 years, P = .34; relative risk, .89, P = .18), leukemia-free survival (49% versus 48% at 3 years, P = .27; relative risk, .93; P = .29), chronic GVHD (45% versus 47% at 1 year, P = .39; relative risk, .9; P = .11), or overall survival (53% versus 52% at 3 years, P = .62; relative risk, .96; P = .57) for CyTBI and TBICy, respectively. Corresponding cumulative incidences of sinusoidal obstruction syndrome were 4% and 6% at 100 days (P = .08), respectively. This study demonstrates that the sequence of Cy and TBI does not impact transplantation outcomes and complications in patients with acute leukemia undergoing hematopoietic cell transplantation with myeloablative conditioning. PMID- 25840336 TI - Hematologic Recovery after Pretransplant Chemotherapy Does Not Influence Survival after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients. AB - Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT. PMID- 25840337 TI - National Survey of Hematopoietic Cell Transplantation Center Personnel, Infrastructure, and Models of Care Delivery. AB - Hematopoietic cell transplantation (HCT) is a complex procedure that requires availability of adequate infrastructure, personnel, and resources at transplantation centers. We conducted a national survey of transplantation centers in the United States to obtain data on their personnel, infrastructure, and care delivery models. A 42-item web-based survey was administered to medical directors of transplantation centers in the United States that reported any allogeneic HCT to the Center for International Blood and Marrow Transplant Research in 2011. The response rate for the survey was 79% for adult programs (85 of 108 centers) and 82% for pediatric programs (54 of 66 centers). For describing results, we categorized centers into groups with similar volumes based on 2010 total HCT activity (adult centers, 9 categories; pediatric centers, 6 categories). We observed considerable variation in available resources, infrastructure, personnel, and care delivery models among adult and pediatric transplantation centers. Characteristics varied substantially among centers with comparable transplantation volumes. Transplantation centers may find these data helpful in assessing their present capacity and use them to evaluate potential resource needs for personnel, infrastructure, and care delivery and in planning for growth. PMID- 25840338 TI - Age and Modified European LeukemiaNet Classification to Predict Transplant Outcomes: An Integrated Approach for Acute Myelogenous Leukemia Patients Undergoing Allogeneic Stem Cell Transplantation. AB - We evaluated the prognostic significance of a modified European LeukemiaNet (ELN) classification for patients with acute myelogenous leukemia (AML) undergoing hematopoietic stem cell transplantation (HSCT) while in first complete remission (CR1). We analyzed 464 AML patients with matched related (n = 211, 45.5%), matched unrelated (n = 176, 37.9%), and mismatched donors (n = 77, 16.6%). Patients were classified into 4 modified ELN risk groups (favorable, intermediate I, intermediate-II, and adverse) separately for 354 patients age < 60 years and 110 patients age >= 60 years. In this modified version of ELN classification, patients with normal cytogenetic were classified by FLT3-ITD mutational status: favorable risk if FLT3-ITDwild and intermediate-I if FLT3-ITDmut. The best outcomes occurred in the ELN favorable and intermediate-II groups in younger AML patients and in the favorable and intermediate-I groups in older AML patients. Older AML patients had worse transplant outcomes within each modified ELN risk group except intermediate-I when compared with younger patients; leukemia-free survival at 3 years was 67.8% versus 49.8% in favorable, 53.4% versus 50.7% in intermediate-I, 65.7% versus 20.2% in intermediate-II, and 44.6% versus 23.8% in adverse group younger and older patients, respectively. Among lesion-specific abnormalities, del5q/-5 and abnl(17p) had the worse transplant outcomes, with 3 year leukemia-free survival rates of 18.4% and 20% in younger CR1 patients. In conclusion, the modified ELN prognostic classification developed for chemotherapy outcomes also identifies prognostic groups for HSCT, which is useful for a selection of patients for post-transplant strategies to improve outcomes. PMID- 25840339 TI - Epidemiology, management, and outcome of invasive fungal disease in patients undergoing hematopoietic stem cell transplantation in China: a multicenter prospective observational study. AB - The China Assessment of Antifungal Therapy in Hematological Disease study, the first large-scale observational study of invasive fungal disease (IFD) in China, enrolled 1401 patients undergoing hematopoietic stem cell transplantation (HSCT) (75.2% allogeneic and 24.8% autologous) at 31 hospitals across China. The overall incidence of proven or probable IFD was 7.7% (108 of 1401); another 266 cases (19.0%) were possible IFD. After allogeneic or autologous HSCT, the incidence of proven/probable IFD was 8.9% (94 of 1053) and 4.0% (14 of 348), respectively. Some cases (14 of 108) developed during conditioning before transplantation. The cumulative incidence of proven/probable IFD increased steeply in the first month after transplantation and after 6 months, the incidence was significantly higher in allogeneic than it was in autologous transplant recipients (9.2% versus 3.5%; P = .001) and when stem cells were derived from cord blood or bone marrow and peripheral blood (P = .02 versus other sources). Independent risk factors for proven/probable IFD in allogeneic HSCT were diabetes, HLA-matched unrelated donor, prolonged severe neutropenia (absolute neutrophil count > 500/mm(3) for >14 days), and immunosuppressants (odds ratio, 2.0 to 3.4 for all). Antifungal prophylaxis was independently protective (P = .01). Previous IFD and prolonged severe neutropenia were significant independent risk factors among autologous transplantation patients (P < .01, P = .04, respectively). In total, 1175 (83.9%) patients received antifungal prophylaxis (91.6% triazoles) and 514 (36.7%) were treated in the hospital with therapeutic antifungals (89.1% triazoles; median 27 days). Empirical, pre-emptive, and targeted antifungals were used in 82.3%, 13.6%, and 4.1% of cases, respectively. Overall mortality (13.4%; 188 deaths) was markedly higher in patients with proven (5 of 16; 31.3%), probable (20 of 92; 21.7%), or possible (61 of 266; 22.9%) IFD; allogeneic (171 of 1053; 16.2%) rather than autologous (17 of 348; 4.9%) HSCT and was significantly higher in patients receiving pre-emptive (18.6%) rather than empirical (6.1%) or targeted (9.5%) antifungal therapy (P = .002). Improvements in the selection and timing of prophylactic antifungals would be welcome. Health care providers should remain alert to the increased risk of IFD and associated mortality in allogeneic HSCT recipients and the ongoing risk of IFD even after discharge from the hospital. PMID- 25840340 TI - Human exposure to toxic metals via contaminated dust: Bio-accumulation trends and their potential risk estimation. AB - We assessed the levels of potentially toxic trace metals, Zinc (Zn), Lead (Pb), Manganese (Mn), Copper (Cu), Nickel (Ni), Chromium (Cr), Cobalt (Co), and Cadmium (Cd), in dust, hair, nail and serum, sampled in rural, urban and industrial areas of Punjab, Pakistan. Trace metals occurrence in all samples, in descending order, was: Zn, Pb, Mn, Cu, Cr, Ni, Co, Cd. The samples from the urban areas showed significantly higher concentration of toxic trace metals (Zn, Ni, Cr, Co, Mn, and Cd) than those from industrial (which conversely had higher levels of Pb and Cu), and than samples from rural areas. Bioaccumulation patterns showed that dust exposure is one of the major routes into human body for Cd, Pb, Co, Mn and Cr, while the burden of Zn, Cu, and Ni can be more linked to dietary sources. The concentrations of trace metals in the samples from Punjab were comparable and/or higher than those reported worldwide. In many cases, the levels of Zn, Cr, Pb, Ni and Cd in hair and nail were beyond the ATSDR threshold guideline values that may cause some serious health effects. Hazard Index (HI) calculated for trace metal concentrations in the human population of Punjab points particularly to health risks from Cd (for children in urban and industrial areas) and from Pb (for all sub-groups). PMID- 25840341 TI - Sublethal effects of imidacloprid on interactions in a tritrophic system of non target species. AB - Imidacloprid is one of the most used insecticides worldwide, but is highly toxic to non-target arthropods. Effects of sublethal imidacloprid intoxication can potentially propagate in food webs, yet little is known about the impact on non target populations and communities. We investigated short-term sublethal toxicity of imidacloprid in a tritrophic model system of wild strawberry Fragaria vesca, wood cricket Nemobius sylvestris and nursery web spider Pisaura mirabilis. Strawberries were treated two times with 0mg (control), 1mg (low rate) and 10mg (high rate) of Confidor(r) WG 70 and crickets were allowed to feed on them. In four lab experiments, we quantified the impact of imidacloprid on leaf damage, growth, behaviour and survival of crickets. The high imidacloprid rate reduced feeding, mass gain, thorax growth and mobility in crickets compared to the control, while mortality was similarly low in all treatments. The low rate reduced mass gain only. Cricket survival of spider predation was higher in the low rate treatment than in the control. Overall, herbivory and predation were reduced at sublethal imidacloprid rates in a non-target organism, three-level food chain, which demonstrates possible propagation of sublethal effects through trophic interactions. PMID- 25840342 TI - Completion of a worldwide reference panel of samples for an ancestry informative Indel assay. AB - The use of ancestry informative markers (AIMs) in forensic analysis is of considerable utility since ancestry inference can progress an investigation when no identification has been made of DNA from the crime-scene. Short-amplicon markers, including insertion deletion polymorphisms, are particularly useful in forensic analysis due to their mutational stability, capacity to amplify degraded samples and straightforward amplification technique. In this study we report the completion of H952 HGDP-CEPH panel genotyping with a set of 46 AIM-Indels. The study adds Central South Asian and Middle Eastern population data, allowing a comparison of patterns of variation in Eurasia for these markers, in order to enhance their use in forensic analyses, particularly when combined with sets of ancestry informative SNPs. Ancestry analysis using principal component analysis and Bayesian methods indicates that a proportion of classification error occurs with European-Middle East population comparisons, but the 46 AIM-Indels have the capability to differentiate six major population groups when European-Central South Asian comparisons are made. These findings have relevance for forensic ancestry analyses in countries where South Asians form much of the demographic profile, including the UK, USA and South Africa. A novel third allele detected in MID-548 was characterized - despite a low frequency in the HGDP-CEPH panel samples, it appears confined to Central South Asian populations, increasing the ability to differentiate this population group. The H952 data set was implemented in a new open access SPSmart frequency browser - forInDel: Forensic Indel browser. PMID- 25840343 TI - Plant aldo-keto reductases (AKRs) as multi-tasking soldiers involved in diverse plant metabolic processes and stress defense: A structure-function update. AB - The aldo-keto reductase (AKR) superfamily comprises of a large number of primarily monomeric protein members, which reduce a broad spectrum of substrates ranging from simple sugars to potentially toxic aldehydes. Plant AKRs can be broadly categorized into four important functional groups, which highlight their roles in diverse plant metabolic reactions including reactive aldehyde detoxification, biosynthesis of osmolytes, secondary metabolism and membrane transport. Further, multiple overlapping functional aspects of plant AKRs including biotic and abiotic stress defense, production of commercially important secondary metabolites, iron acquisition from soil, plant-microbe interactions etc. are discussed as subcategories within respective major groups. Owing to the broad substrate specificity and multiple stress tolerance of the well characterized AKR4C9 from Arabidopsis thaliana, protein sequences of all the homologues of AKR4C9 (A9-like proteins) from forty different plant species (Phytozome database) were analyzed. The analysis revealed that all A9-like proteins possess strictly conserved key catalytic residues (D-47, Y-52 and K-81) and belong to the pfam00248 and cl00470 AKR superfamilies. Based on structural homology of the three flexible loops of AKR4C9 (Loop A, B and C) responsible for broad substrate specificity, A9-like proteins found in Brassica rapa, Phaseolus vulgaris, Cucumis sativus, Populus trichocarpa and Solanum lycopersicum were predicted to have a similar range of substrate specificity. Thus, plant AKRs can be considered as potential breeding targets for developing stress tolerant varieties in the future. The present review provides a consolidated update on the current research status of plant AKRs with an emphasis on important functional aspects as well as their potential future prospects and an insight into the overall structure-function relationships of A9-like proteins. PMID- 25840344 TI - In vitro 3-D model based on extending time of culture for studying chronological epidermis aging. AB - Skin aging is a complex phenomenon in which several mechanisms operate simultaneously. Among them, intrinsic aging is a time-dependent process, which leads to gradual skin changes affecting its structure and function such as thinning down of both epidermal and dermal compartments and a flattening and fragility of the dermo-epidermal junction. Today, several approaches have been proposed for the generation of aged skin in vitro, including skin explants from aged donors and three-dimensional skin equivalent treated by aging-inducing chemical compounds or engineered with human cells isolated from aged donors. The aim of this study was to develop and validate a new in vitro model of aging based on skin equivalent demonstrating the same phenotypic changes that were observed in chronological aging. By using prolonged culture as a proxy for cellular aging, we extended to 120 days the culture time of a skin equivalent model based on collagen-glycosaminoglycan-chitosan porous polymer and engineered with human skin cells from photo-protected sites of young donors. Morphological, immunohistological and ultrastructural analysis at different time points of the culture allowed characterizing the phenotypic changes observed in our model in comparison to samples of non photo-exposed normal human skin from different ages. We firstly confirmed that long-term cultured skin equivalents are still morphologically consistent and functionally active even after 120 days of culture. However, similar to in vivo chronological skin aging a significant decrease of the epidermis thickness as well as the number of keratinocyte expressing proliferation marker Ki67 are observed in extended culture time skin equivalent. Epidermal differentiation markers loricrin, filaggrin, involucrin and transglutaminase, also strongly decreased. Ultrastructural analysis of basement membrane showed typical features of aged skin such as duplication of lamina densa and alterations of hemidesmosomes. Moreover, the expression of hyaluronan and its surface receptor CD44 drastically decreased as observed during chronological skin aging. Finally, we found that the level of p16INK4A expression significantly increased supporting cellular senescence process associated to our model. To conclude, the major morphological and ultrastructural epidermal modifications observed in both our extended culture skin equivalent model and skin biopsies from old donors validate the relevance of our model for studying chronological aging, understanding and elucidating age-related modifications of basic skin biological processes. In addition, our model provides a unique tool for identifying new targeted molecules intended at improving the appearance of aging skin. PMID- 25840346 TI - Is this your (paediatric patient's) brain on (anaesthetic) drugs?: The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans. PMID- 25840345 TI - Deletion of ADAMTS5 does not affect aggrecan or versican degradation but promotes glucose uptake and proteoglycan synthesis in murine adipose derived stromal cells. AB - ADAMTS5 (TS5), a member of the aggrecanase clade (TS1, 4, 5, 8, 9, 15) of ADAMTS proteases, has been considered largely responsible for the proteolysis of the hyalectans, aggrecan (Acan) and versican (Vcan), in vivo. However, we have reported that ts5-knockout (KO) mice show joint protection after injury due to inhibition of synovial scarring and enhanced Acan deposition. Also, KO mice have an impaired wound healing phenotype in skin and tendons which is associated with Acan/Vcan-rich deposits at the wound sites. Moreover, the Acan and Vcan deposited was aggrecanase-cleaved, even in the absence of TS5. In this study, we have used adipose-derived stromal cell (ADSC) and epiphyseal chondrocyte cultures from wild type and KO mice to further study the role of TS5 in Acan and Vcan turnover. We have confirmed with both cell types that the aggrecanase-mediated degradation of these hyalectans is not due to TS5, but an aggrecanase which primarily cleaves them before they are secreted. We also provide data which suggests that TS5 protein functions to suppress glucose uptake in ADSCs and thereby inhibits the synthesis, and promotes the intracellular degradation of Acan and Vcan by an ADAMTS other than TS5. We propose that this apparently non-proteolytic role of TS5 explains its anti-chondrogenic and pro-fibrotic effects in murine models of wound repair. A possible role for TS5 in an endocytotic process, involving competitive interactions between TS5, LRP1 and GLUT4 is discussed. PMID- 25840347 TI - Bispectral index aware or minimum alveolar concentration aware?: Alerting thresholds for prevention of awareness. PMID- 25840349 TI - MYB Transcription Factors as Regulators of Phenylpropanoid Metabolism in Plants. AB - Phenylpropanoid-derived compounds represent a diverse family of secondary metabolites that originate from phenylalanine. These compounds have roles in plant growth and development, and in defense against biotic and abiotic stress. Many of these compounds are also beneficial to human health and welfare. V-myb myeloblastosis viral oncogene homolog (MYB) proteins belong to a large family of transcription factors and are key regulators of the synthesis of phenylpropanoid derived compounds. This review summarizes the current understanding of MYB proteins and their roles in the regulation of phenylpropanoid metabolism in plants. PMID- 25840350 TI - The Cedar Project: Residential transience and HIV vulnerability among young Aboriginal people who use drugs. AB - Aboriginal homelessness is considered to be a result of historic dispossession of traditional territories and forced displacement from community structures. Using data collected from 2005-2010 from the Cedar Project, a cohort of young Aboriginal people who use drugs in two Canadian cities, we examined how residential transience shapes HIV vulnerability. At baseline, 48 of 260 participants (18.5%) reported sleeping in six or more places ('highly transient') in the past six months. Generalized linear mixed models identified associations between high transience and sex and drug related HIV vulnerabilities. Transience was independently associated with sex work (AOR:3.52, 95%CI:2.06, 6.05); sexual assault (AOR:2.48, 95%CI:1.26, 4.86); injection drug use (AOR:4.54, 95%CI:2.71, 7.61); daily cocaine injection (AOR:2.16, 95%CI:1.26, 3.72); and public injection (AOR:2.87, 95%CI:1.65, 5.00). After stratification, transience and sexual vulnerability remained significantly associated among women but not men. Ensuring that young Aboriginal people have access to safe spaces to live, work, and inject must include policies addressing residential transience as well as the absence of a roof and walls. PMID- 25840351 TI - Changes in the perceived neighborhood environment in relation to changes in physical activity: A longitudinal study from childhood into adolescence. AB - The aim was to investigate how physical activity and the perceived neighborhood environment in children change when they enter adolescence. Also the relation between changes in the perceived environment and changes in children's physical activity was investigated. In total, 321 children and one of their parents filled out a physical activity questionnaire and the NEWS-Y at two time points (last grade of elementary school and 2 years later). Children also wore an activity monitor. Changes in children's physical activity were dependent on the physical activity domain. Only less than half of children's perceived neighborhood factors changed and about half of the parental perceived neighborhood factors changed. Most of these factors changed towards higher activity friendliness. Changes in the perceived environment were only limitedly related to changes in children's physical activity. PMID- 25840352 TI - Is local alcohol outlet density related to alcohol-related morbidity and mortality in Scottish cities? AB - Alcohol consumption may be influenced by the local alcohol retailing environment. This study is the first to examine neighbourhood alcohol outlet availability (on- and off-sales outlets) and alcohol-related health outcomes in Scotland. Alcohol related hospitalisations and deaths were significantly higher in neighbourhoods with higher outlet densities, and off-sales outlets were more important than on sales outlets. The relationships held for most age groups, including those under the legal minimum drinking age, although were not significant for the youngest legal drinkers (18-25 years). Alcohol-related deaths and hospitalisations were higher in more income-deprived neighbourhoods, and the gradient in deaths (but not hospitalisations) was marginally larger in neighbourhoods with higher off sales outlet densities. Efforts to reduce alcohol-related harm should consider the potentially important role of the alcohol retail environment. PMID- 25840353 TI - The role of neighborhoods in shaping perceived norms: An exploration of neighborhood disorder and norms among injection drug users in Baltimore, MD. AB - A large literature suggests that social norms contribute to HIV and substance use related behaviors. Less attention has been given to neighborhood factors that may contribute to the development of norms about risky behaviors. We examined the cross-sectional associations between perceptions of one's neighborhood and norms of perceived prevalence of, and peer support for sex exchange and risky injection behaviors. The sample consisted of 719 people who reported injecting heroin and cocaine and did not move in the past 6 months in Baltimore, MD. Living in a neighborhood with disorder was associated with believing that others exchanged sex, practiced risky injection behaviors (descriptive norms) and approved of risky injection behavior (injunctive norms). PMID- 25840355 TI - Micellization parameters (number average, aggregation number and critical micellar concentration) of bile salt 3 and 7 ethylidene derivatives: Role of the steroidal skeleton II. AB - BACKGROUND: Bile salts are steroidal biosurfactants. Micellar systems of bile salts are not only important for solubilization of cholesterol, but they also interact with certain drugs thus changing their bioavailability. METHODS: The number-average aggregation numbers (n-) are determined using the Moroi-Matsuoka Sugioka thermodynamic method. Critical micellar concentrations were determined by spectrofluorometric method using pyren and by surface tension measurements. RESULTS: Micelles of ethylidene derivatives possess the following values for n-: 7-Eth-D (n-=11 (50 mM)-n-=14.8 (100 mM)); 12-Ox-7-Eth-L (n-~8.8, without concentration dependence) and 7,12-diOx-3-Eth-Ch (n-~2.9, without concentration dependence). In the planes n--ln k and ln CMC-ln k derivative 7-Eth-D is outlier in respect to hydrophobic linear congeneric groups. CONCLUSION: Gibbs energy of formation for 7-Eth-D anion micelles in addition to the Gibbs energy of hydrophobic interactions consists excess Gibbs energy (GE) from hydrogen bond formation between building blocks of micelles. Gibbs energy of formation for 7,12 diOx-3-Eth-Ch and 12-Ox-7-Eth-L anion micelle is determined by the Gibbs energy of hydrophobic interactions. Relative increase in hydrophobicity and aggregation number for ethylidene derivatives is larger when ethylidene group is introduced from the C7 lateral side of steroidal skeleton then it is when ethylidene group is on C3 carbon. GENERAL SIGNIFICANCE: Position of outlier towards hydrophobic congeneric groups from n--ln k and ln CMC-ln k planes indicates the existence of excess Gibbs energy (GE) which is not of hydrophobic nature (formation of hydrogen bonds). For the bile salt micelles to have GE (formation of secondary micelles) it is necessary that steroidal skeleton possesses C3-alpha-(e)-OH and C12-alpha-(a)-OH groups. PMID- 25840356 TI - NiO nanoparticles induce apoptosis through repressing SIRT1 in human bronchial epithelial cells. AB - With application of nano-sized nickel-containing particles (Nano-Ni) expanding, the health concerns about their adverse effects on the pulmonary system are increasing. However, the mechanisms for the pulmonary toxicity of these materials remain unclear. In the present study, we focused on the impacts of NiO nanoparticles (NiONPs) on sirtuin1 (SIRT1), a NAD-dependent deacetylase, and investigated whether SIRT1 was involved in NiONPs-induced apoptosis. Although the NiONPs tended to agglomerate in fluid medium, they still entered into the human bronchial epithelial cells (BEAS-2B) and released Ni(2+) inside the cells. NiONPs at doses of 5, 10, and 20MUg/cm(2) inhibited the cell viability. NiONPs' produced cytotoxicity was demonstrated through an apoptotic process, indicated by increased numbers of Annexin V positive cells and caspase-3 activation. The expression of SIRT1 was markedly down-regulated by the NiONPs, accompanied by the hyperacetylation of p53 (tumor protein 53) and overexpression of Bax (Bcl-2 associated X protein). However, overexpression of SIRT1 through resveratrol treatment or transfection clearly attenuated the NiONPs-induced apoptosis and activation of p53 and Bax. Our results suggest that the repression of SIRT1 may underlie the NiONPs-induced apoptosis via p53 hyperacetylation and subsequent Bax activation. Because SIRT1 participates in multiple biologic processes by deacetylation of dozens of substrates, this knowledge of the impact of NiONPs on SIRT1 may lead to an improved understanding of the toxic mechanisms of Nano-Ni and provide a molecular target to antagonize Nano-Ni toxicity. PMID- 25840357 TI - Hemispheric asymmetry in the influence of language on visual perception. AB - Many studies have shown that language can affect visual perception; however, our understanding of the neural basis of linguistic influence is inadequate. This can be investigated by examining the hemispheric asymmetry of linguistic influence. The left and right hemispheres are dominant in close and distant semantic processing, respectively. In this study, we investigated whether the hemispheric asymmetry of semantic processing led to hemispheric asymmetry for concept priming on the detection of objects degraded by continuous flash suppression. We combined a priming paradigm with the divided visual field paradigm and used continuous flash suppression, which renders objects invisible. The results indicated that the hemispheric asymmetry of semantic processing led to a right lateralization in the influence of more abstract concepts on visual perception. The lateralization of brain connectomes may be the underlying neural basis of this effect. PMID- 25840358 TI - The influence of vertical motor responses on explicit and incidental processing of power words. AB - There is increasing evidence demonstrating that power judgment is affected by vertical information. Such interaction between vertical space and power (i.e., response facilitation under space-power congruent conditions) is generally elicited in paradigms that require participants to explicitly evaluate the power of the presented words. The current research explored the possibility that explicit evaluative processing is not a prerequisite for the emergence of this effect. Here we compared the influence of vertical information on a standard explicit power evaluation task with influence on a task that linked power with stimuli in a more incidental manner, requiring participants to report whether the words represented people or animals or the font of the words. The results revealed that although the effect is more modest, the interaction between responses and power is also evident in an incidental task. Furthermore, we also found that explicit semantic processing is a prerequisite to ensure such an effect. PMID- 25840354 TI - Therapeutic potential of alpha-crystallin. AB - BACKGROUND: The findings that alpha-crystallins are multi-functional proteins with diverse biological functions have generated considerable interest in understanding their role in health and disease. Recent studies have shown that chaperone peptides of alpha-crystallin could be delivered into cultured cells and in experimental animals with beneficial effects against protein aggregation, oxidation, inflammation and apoptosis. SCOPE OF REVIEW: In this review, we will summarize the latest developments on the therapeutic potential of alpha crystallins and their functional peptides. MAJOR CONCLUSIONS: alpha-Crystallins and their functional peptides have shown significant favorable effects against several diseases. Their targeted delivery to tissues would be of great therapeutic benefit. However, alpha-crystallins can also function as disease causing proteins. These seemingly contradictory functions must be carefully considered prior to their therapeutic use. GENERAL SIGNIFICANCE: alphaA and alphaB-Crystallin are members of the small heat shock protein family. These proteins exhibit molecular chaperone and anti-apoptotic activities. The core crystallin domain within these proteins is largely responsible for these prosperities. Recent studies have identified peptides within the crystallin domain of both alpha- and alphaB-crystallins with remarkable chaperone and anti apoptotic activities. Administration of alpha-crystallin or their functional peptides has shown substantial inhibition of pathologies in several diseases. However, alpha-crystallins have been shown to promote disease-causing pathways. These two sides of the proteins are discussed in this review. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID- 25840359 TI - An illustrated heuristic prototype facilitates scientific inventive problem solving: A functional magnetic resonance imaging study. AB - Many scientific inventions (SI) throughout history were inspired by heuristic prototypes (HPs). For instance, an event or piece of knowledge similar to displaced water from a tub inspired Archimedes' principle. However, the neural mechanisms underlying this insightful problem solving are not very clear. Thus, the present study explored the neural correlates used to solve SI problems facilitated by HPs. Each HP had two versions: a literal description with an illustration (LDI) and a literal description with no illustration (LDNI). Thirty two participants were divided randomly into these two groups. Blood oxygenation level-dependent fMRI contrasts between LDI and LDNI groups were measured. Greater activity in the right middle occipital gyrus (RMOG, BA19), right precentral gyrus (RPCG, BA4), and left middle frontal gyrus (LMFG, BA46) were found within the LDI group as compared to the LDNI group. We discuss these results in terms cognitive functions within these regions related to problem solving and memory retrieval. PMID- 25840360 TI - Influencing the occurrence of mind wandering while reading. AB - The current concerns hypothesis suggests that directing attention towards unfulfilled plans of the individual prior to a task would result in more off-task thoughts (or mind wandering). In this experiment, participants were asked to read a scientific text and self-report instances of mind wandering by indicating when they were experiencing task-unrelated thoughts (TUTs) or task-related interferences (TRIs). Prior to reading, participants in the individual plans experimental condition were asked to reflect upon their short-term plans by making a "to do" list while participants in a control condition were asked to make a list of the components of an automobile. In support of the current concerns hypothesis, directing attention towards the short-term plans resulted in significantly more TUTs, but not TRIs. Furthermore, participants in the individual plans condition had significantly lower scores on an assessment of reading comprehension, and this relationship was mediated by the frequency of TUTs. PMID- 25840361 TI - Influence of reaction conditions on the composition of liquid products from two stage catalytic hydrothermal processing of lignin. AB - The influence of reaction conditions on the composition of liquid products during two-stage hydrothermal conversion of alkali lignin has been investigated in a batch reactor. Reactions were carried out in the presence of formic acid (FA) and Pt/Al2O3 catalyst. The two different sets of reaction conditions involved alternative reaction times of 1h and 5h at 265 degrees C and 350 degrees C, respectively. These provided different contributions to reaction severity, which affected the compositions of liquid products. Yields of liquid products reached up to 40wt% (on lignin feed basis) in the presence of FA under the less severe reaction condition. With 5h reaction time at 350 degrees C, alkylphenols, alkylguaiacols and hydrocarbons were the dominant liquid products. However, with 5h reaction time at 265 degrees C, phenol and methanol became dominant. The two stage hydrothermal process led to improved lignin conversion, with the potential to manipulate the liquid product range. PMID- 25840362 TI - Tensor decomposition of EEG signals: a brief review. AB - Electroencephalography (EEG) is one fundamental tool for functional brain imaging. EEG signals tend to be represented by a vector or a matrix to facilitate data processing and analysis with generally understood methodologies like time series analysis, spectral analysis and matrix decomposition. Indeed, EEG signals are often naturally born with more than two modes of time and space, and they can be denoted by a multi-way array called as tensor. This review summarizes the current progress of tensor decomposition of EEG signals with three aspects. The first is about the existing modes and tensors of EEG signals. Second, two fundamental tensor decomposition models, canonical polyadic decomposition (CPD, it is also called parallel factor analysis-PARAFAC) and Tucker decomposition, are introduced and compared. Moreover, the applications of the two models for EEG signals are addressed. Particularly, the determination of the number of components for each mode is discussed. Finally, the N-way partial least square and higher-order partial least square are described for a potential trend to process and analyze brain signals of two modalities simultaneously. PMID- 25840363 TI - Laser system refinements to reduce variability in infarct size in the rat photothrombotic stroke model. AB - BACKGROUND: The rat photothrombotic stroke model can induce brain infarcts with reasonable biological variability. Nevertheless, we observed unexplained high inter-individual variability despite using a rigorous protocol. Of the three major determinants of infarct volume, photosensitive dye concentration and illumination period were strictly controlled, whereas undetected fluctuation in laser power output was suspected to account for the variability. NEW METHOD: The frequently utilized Diode Pumped Solid State (DPSS) lasers emitting 532 nm (green) light can exhibit fluctuations in output power due to temperature and input power alterations. The polarization properties of the Nd:YAG and Nd:YVO4 crystals commonly used in these lasers are another potential source of fluctuation, since one means of controlling output power uses a polarizer with a variable transmission axis. Thus, the properties of DPSS lasers and the relationship between power output and infarct size were explored. RESULTS: DPSS laser beam intensity showed considerable variation. Either a polarizer or a variable neutral density filter allowed adjustment of a polarized laser beam to the desired intensity. When the beam was unpolarized, the experimenter was restricted to using a variable neutral density filter. COMPARISON WITH EXISTING METHOD(S): Our refined approach includes continuous monitoring of DPSS laser intensity via beam sampling using a pellicle beamsplitter and photodiode sensor. This guarantees the desired beam intensity at the targeted brain area during stroke induction, with the intensity controlled either through a polarizer or variable neutral density filter. CONCLUSIONS: Continuous monitoring and control of laser beam intensity is critical for ensuring consistent infarct size. PMID- 25840364 TI - Use of radiolabeled antagonist assays for assessing agonism at D2 and D3 dopamine receptors: comparison with functional GTPgammaS assays. AB - BACKGROUND: Cell-based drug screening assays are essential tools for drug discovery and development targeting G protein-coupled receptors, which include dopamine D3 receptors. D3 is notorious for its poor coupling to G protein in most heterologous cell lines, and therefore D3 agonist-stimulated binding of [(35)S]GTPgammaS to G protein cannot be observed in many "non-functional" D3 expressing cell lines. NEW METHOD: The present work explores the use of an alternate method for assessing agonist activity, consisting of measuring the difference in agonist competition between [(3)H]spiperone bound to low-affinity states of the receptor and that with radioligand bound to high-affinity states (GTP shift assay). COMPARISON WITH EXISTING METHOD: The current study describes the determination of GTP shifts in [(3)H]spiperone binding assays for the assessment of agonists' potencies (at D2 and D3) and efficacies (at D3). Compared with GTPgamma(35)S binding assays, the new method removes the cumbersome need of functional D3 cell lines and limited project duration due to short half-life of isotope (35)S. CONCLUSION: The new method allows the estimation of potency (D2 and D3) and efficacy (D3) at the level of receptor and G protein activation in a simple fashion from shifts in monophasic-inhibition curves. Moreover, it does not require [(35)S]GTPgammaS binding assays with functional D3 cells. This method will have wide applicability for D3-selective agonist screening. It may also be useful for other GPCRs circumventing the need for functional assays and offering the ability to detect agonist activity regardless of the particular signaling pathway. PMID- 25840366 TI - Immunosensor for trace penicillin G detection in milk based on supported bilayer lipid membrane modified with gold nanoparticles. AB - In this work, we developed an immunosensor for electrochemical detection of penicillin G at trace level. The biosensor was fabricated by immobilizing anti penicillin G in a supported bilayer lipid membrane (s-BLM) modified with gold nanoparticles, and the modified electrodes were characterized by the scanning electron microscope (SEM), cyclic voltammetry and electrochemical impedance spectroscopy. The biosensor was able to detect penicillin G with a linear correlation ranging from 3.34*10(-3)ng/L to 3.34*10(3)ng/L and a detection limit of 2.7*10(-4)ng/L, much lower than the maximum residue limit (MRL) of penicillin G in milk (4ppb, equal to 4*10(3)ng/L) set out by the European Union. The mean coefficient variation (CV) of the intra-assays and the inter-assays were 5.4% and 7.7%, respectively. In addition, the concentration of penicillin G in milk samples determined by this biosensor was in good agreement with that determined by high performance liquid chromatography (HPLC) assay. PMID- 25840367 TI - Study of the immunogenicity of hepatitis B surface antigen synthesized in transgenic potato plants with increased biosafety. AB - Oral immunogenicity of the hepatitis B surface antigen (HBsAg) synthesized in the tubers of marker-free potato plants has been demonstrated. Experiments were performed in the two groups of outbred NMRI mice. At the beginning of investigations, the mice of experimental group were fed the tubers of transgenic potato synthesizing the HBsAg three times. The mice of control group were fed nontransgenic potato. Intraperitoneal injection of the commercial vaccine against hepatitis B (0.5MUg/mouse) was made on day 71 of the experiment. Enzyme-linked immunoassay (ELISA) of the serum of immunized animals showed an increase in the level of HBsAg antibodies significantly above the protective value, which was maintained for 1 year after the immunization. In 1 year, the experimental group of mice underwent additional oral immunization with HBsAg-containing potato tubers. As a result, the level of antibodies against the HBsAg increased and remained at a high protective level for several months. The findings show the possibility of using transgenic plants as a substance for obtaining a safe edible vaccine against hepatitis B. PMID- 25840365 TI - Validation of a method to assess ADHD-related impulsivity in animal models. AB - BACKGROUND: Response inhibition capacity (RIC), the ability to withhold instrumentally reinforced responses, is compromised in ADHD. Most standard methods for assessing RIC in rodents potentially confound motivational, motor, learning, and inhibitory processes, lack sensitivity to pharmacological treatment, and have unknown reliability. NEW METHOD: The fixed minimum interval (FMI) schedule of reinforcement and its associated analytical techniques are designed to dissociate inhibitory processes from incentive-motivational and timing processes. This study is aimed at validating the FMI as a method for assessing RIC in animal models. FMI performance was compared across different withholding requirements (0.5, 3, 6 and 21s), deprivation levels, reinforcement rates, and reinforcer magnitudes. RESULTS AND COMPARISON WITH EXISTING METHODS: Motivational manipulations differentially affected estimates of incentive motivation but not the FMI-derived index of RIC, theta. Changes in the withholding requirement influenced timed IRTs in a manner consistent with extant timing theories. Individual estimates of RIC were resilient to prolonged changes in motivation but not to changes in FMI schedule. Results indicate that the FMI schedule is not vulnerable to the same limitations associated with existing methods for assessing RIC. CONCLUSIONS: These results support the use of the FMI schedule and associated analytic techniques as tools for assessing RIC in animal models. PMID- 25840368 TI - Amitotic chromosome loss predicts distinct patterns of senescence and non senescence in ciliates. AB - Over time and repeated asexual divisions, many ciliate species display the characteristics of senescence, reduced fecundity and increased mortality. Their only path to recovery is sexual conjugation or autogamy. While more traditional models of cellular aging have been proposed, one of the most accepted explanations relies on the faulty mechanism by which ciliates duplicate their somatic nucleus, a process referred to as amitosis. Amitosis involves the random segregation of chromosomes with no consideration for homology. Over subsequent divisions, chromosome copy numbers will fluctuate until an entire chromosome is lost, resulting in death. Via simulations of this process, we find that senescence and death via chromosome loss is not the only possible result of amitosis. Random chromosome loss is less damaging to populations than previously thought, and strict adherence to the model predicts that Paramecium tetraurelia would not senesce. A combination of the reciprocal nature of amitosis and lethal selection against low-copy number chromosomes is responsible for this startling prediction. Additionally, our results provide an alternate explanation to recent evidence for selection on chromosome copy number in Tetrahymena thermophila and peculiar patterns of senescence in Tetrahymena pyriformis. PMID- 25840371 TI - Diffraction contrast imaging using virtual apertures. AB - Two methods on how to obtain the full diffraction information from a sample region and the associated reconstruction of images or diffraction patterns using virtual apertures are demonstrated. In a STEM-based approach, diffraction patterns are recorded for each beam position using a small probe convergence angle. Similarly, a tilt series of TEM dark-field images is acquired. The resulting datasets allow the reconstruction of either electron diffraction patterns, or bright-, dark- or annular dark-field images using virtual apertures. The experimental procedures of both methods are presented in the paper and are applied to a precipitation strengthened and creep deformed ferritic alloy with a complex microstructure. The reconstructed virtual images are compared with conventional TEM images. The major advantage is that arbitrarily shaped virtual apertures generated with image processing software can be designed without facing any physical limitations. In addition, any virtual detector that is specifically designed according to the underlying crystal structure can be created to optimize image contrast. PMID- 25840372 TI - A complete comparison of simulated electron diffraction patterns using different parameterizations of the electron scattering factors. AB - The steadily improving experimental possibilities in instrumental resolution as in sensitivity and quantization of the data recording put increasingly higher demands on the precision of the scattering factors, which are the key ingredients for electron diffraction or high-resolution imaging simulation. In the present study, we will systematically investigate the accuracy of fitting of the main parameterizations of the electron scattering factor for the calculation of electron diffraction intensities. It is shown that the main parameterizations of the electron scattering factor are consistent to calculate electron diffraction intensities for thin specimens and low angle scattering. Parameterizations of the electron scattering factor with the correct asymptotic behavior (Lobato and Dyck [5], Kirkland [4], and Weickenmeier and Kohl [2]) produce similar results for both the undisplaced lattice model and the frozen phonon model, except for certain thicknesses and reflections. PMID- 25840370 TI - The cis conformation of proline leads to weaker binding of a p53 peptide to MDM2 compared to trans. AB - The cis and trans conformations of the Xaa-Pro (Xaa: any amino acid) peptide bond are thermodynamically stable while other peptide bonds strongly prefer trans. The effect of proline cis-trans isomerization on protein binding has not been thoroughly investigated. In this study, computer simulations were used to calculate the absolute binding affinity for a p53 peptide (residues 17-29) to MDM2 for both cis and trans isomers of the p53 proline in position 27. Results show that the cis isomer of p53(17-29) binds more weakly to MDM2 than the trans isomer, and that this is primarily due to the difference in the free energy cost associated with the loss of conformational entropy of p53(17-29) when it binds to MDM2. The population of cis p53(17-29) was estimated to be 0.8% of the total population in the bound state. The stronger binding of trans p53(17-29) to MDM2 compared to cis may leave a minimal level of p53 available to respond to cellular stress. This study demonstrates that it is feasible to estimate the absolute binding affinity for an intrinsically disordered protein fragment binding to an ordered protein that are in good agreement with experimental results. PMID- 25840373 TI - Frequency-place map for electrical stimulation in cochlear implants: Change over time. AB - The relationship between the place of electrical stimulation from a cochlear implant and the corresponding perceived pitch remains uncertain. Previous studies have estimated what the pitch corresponding to a particular location should be. However, perceptual verification is difficult because a subject needs both a cochlear implant and sufficient residual hearing to reliably compare electric and acoustic pitches. Additional complications can arise from the possibility that the pitch corresponding to an electrode may change as the auditory system adapts to a sound processor. In the following experiment, five subjects with normal or near-to-normal hearing in one ear and a cochlear implant with a long electrode array in the other ear were studied. Pitch matches were made between single electrode pulse trains and acoustic tones before activation of the speech processor to gain an estimate of the pitch provided by electrical stimulation at a given insertion angle without the influence of exposure to a sound processor. The pitch matches were repeated after 1, 3, 6, and 12 months of experience with the sound processor to evaluate the effect of adaptation over time. Pre activation pitch matches were lower than would be estimated by a spiral ganglion pitch map. Deviations were largest for stimulation below 240 degrees degrees and smallest above 480 degrees . With experience, pitch matches shifted towards the frequency-to-electrode allocation. However, no statistically significant pitch shifts were observed over time. The likely explanation for the lack of pitch change is that the frequency-to-electrode allocations for the long electrode arrays were already similar to the pre-activation pitch matches. Minimal place pitch shifts over time suggest a minimal amount of perceptual remapping needed for the integration of electric and acoustic stimuli, which may contribute to shorter times to asymptotic performance. PMID- 25840374 TI - 40 years and counting. PMID- 25840375 TI - Response to "fostering early breast cancer detection: faith community nurses reaching at-risk populations". PMID- 25840377 TI - What matters to the patient is what really matters: ?quality in oncology nursing. AB - Reflecting on the 40th anniversary of the Oncology Nursing Society led me to recall my own 30-plus years in nursing and how, as a new graduate nurse, almost all oncology care was delivered in the inpatient setting. In my first few years of practice, I mixed my patients' chemotherapy in a medicine room without a ventilated hood and administered those medications without personal protective equipment or the independent RN double checks that have become standard to safe practice today. Through advances in science, tools are now in place to test and make changes, measure impact, and sustain improvements over time. Through advancements in nursing science and oncology research, the ability to treat and cure many cancers and to manage the symptoms and side effects of treatment has improved. Those improvements extend survival; enhance quality of life; and keep patients, staff, and practice environments safer than ever before. In addition, the human side of care has advanced with respect to the quality of interactions with patients and families. Some call this the art of nursing. I call it the essence of our practice. Increasingly, nurses are able to name specific interventions, measure impact, and document outcomes of this so-called art. It is to this human side of our practice that I dedicate this column.?. PMID- 25840376 TI - Cancer-related fatigue: scientific progress has been made in 40 years. AB - Cancer-related fatigue (CRF) is a distressing, persistent symptom that is experienced by survivors during and after treatment. Unsurprisingly, many early CRF studies were conducted by nurses. These studies included a look at patients receiving localized radiation treatment (Haylock & Hart, 1979); an exploration of fatigue as a conceptual approach to a clinical problem (Aistars, 1987); the development of a nursing theory focused on fatigue mechanisms (Piper, Lindsey, & Dodd, 1987); an examination of fatigue mechanisms (St Pierre, Kasper, & Lindsey, 1992), as well as of fatigue in advanced cancer (Bruera & MacDonald, 1988) and in non-small cell lung cancer (Sarna, 1993); and a description of fatigue and potential nursing interventions (Nail & King, 1987). Winningham et al. (1994) wrote a state-of-the-science article about fatigue in the cancer experience for the Oncology Nursing Forum, and Mock et al. (1997) was one of the first to conduct an exercise study regarding the effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer. Nurse scholars from the 1970s-2000s were pivotal in advancing the science of fatigue in various cancers and have provided a scientific foundation for those four decades. ?. PMID- 25840378 TI - Success is not final: onward to the future ?of evidence-based practice. AB - The Oncology Nursing Society (ONS) is celebrating its 40th anniversary, so it seems only fitting that this column focuses on how evidence-based practice (EBP) has evolved for oncology nurses and ONS during the past 40 years. EBP has been around for a very long time. In the famous Notes on Nursing published in 1860, Florence Nightingale noted that, "The most important practical lesson that can be given to nurses is to teach them what to observe-how to observe-what symptoms can indicate improvement-what the reverse-which are important-which are of none" (p. 5). This quote seems pertinent given that a large part of what oncology nurses do is related to the management of symptoms, either from cancer or its treatment (e.g., chemotherapy, radiation). In addition, during the past 10-15 years, nurses have been immersed in providing symptom management interventions that are based on evidence, not just in hearsay or ritual. ?. PMID- 25840379 TI - The evolution of the electronic health record. AB - Medical record documentation of patient data has evolved during the past several years. Early patient medical records included brief, written case history reports maintained for teaching purposes. One such document obtained is a text from Egypt of 48 case reports that includes injuries, fractures, wounds, dislocations, and tumors that date back to 1600 BC. This document was written on papyrus text and acquired by Edwin Smith, an Egyptologist, in 1862 (Atta, 1999; Gillum, 2013). Case reports served as the patient record for many years, used only intermittently by physicians. By the 1880s, concerns regarding medical records as legal documents for insurance and malpractice cases encouraged administrators of hospitals to supervise record content (Gillum, 2013). By 1898, the patient record came to the bedside, moving from retrospective documentation to cases reported in actual time. Medical records resembled more of the present-day record with family history, patient habits, previous illnesses, present illness, physical examination, admission urine, blood analysis, progress notes, discharge diagnosis, and instructions (Gillum, 2013). ?. PMID- 25840380 TI - Learning from disaster: ?patient safety and the role of oncology nurses. AB - When the Oncology Nursing Society (ONS) was almost exactly half its present age, in November 1994, a Boston Globe health columnist named Betsy Lehman was admitted to the Dana-Farber Cancer Institute in Boston, Massachusetts, to receive an investigational regimen for breast cancer. Her treatment ended in disaster. In one of the most notorious patient safety failures of modern times, Lehman was given severe overdoses of cyclophosphamide during a four-day period. On each of those four days, nurses, physicians, and pharmacists at Dana-Farber failed to notice that Lehman was receiving doses four times greater than the intended amount (Aspden, Wolcott, Bootman, & Cronenwett, 2007). Lehman died of cyclophosphamide toxicity on December 3, 1994.?. PMID- 25840381 TI - A culture of avoidance: voices from inside ethically difficult clinical situations. AB - BACKGROUND: Healthcare providers experience many ethical challenges while caring for and making treatment decisions with patients and their families. OBJECTIVES: The purpose of this ethnographic study was to examine the challenges and circumstances that surround ethically difficult situations in oncology practice. METHODS: The authors conducted six focus groups with 30 oncology nurses in the United States and interviewed 12 key informants, such as clinical ethicists, oncologists, and nurse administrators. FINDINGS: The authors found that many healthcare providers remain silent about ethical concerns until a precipitating crisis occurs and ethical questions can no longer be avoided. Patients, families, nurses, and physicians tended to delay or defer conversations about prognosis and end-of-life treatment options. Individual, interactional, and system-level factors perpetuated the culture of avoidance. These included the intellectual and emotional toll of addressing ethics, differences in moral perspectives, fear of harming relationships, lack of continuity in care, emphasis on efficiency, and lack of shared decision making. This information is critical for any proactive and system-level effort aimed at mitigating ethical conflicts and their frequent companions-moral distress and burnout. PMID- 25840382 TI - Selection of optimal tobacco cessation medication treatment in patients with cancer. AB - BACKGROUND: Tobacco use is responsible for almost half a million deaths per year in the United States, and it accounts for one-third of all cancer deaths. Limited data concerning tobacco treatment among patients with cancer are available. In addition, these patients often have complicated medical histories and are taking multiple medications. No clear, published procedures exist to help the healthcare provider select the proper medication for tobacco cessation in that context. OBJECTIVES: This article describes the screening process established within the Tobacco Treatment Program (TTP) at the University of Texas MD Anderson Cancer Center to minimize the risk of prescribing a contraindicated tobacco cessation medication to patients with cancer. The screening process developed and used by the TTP is presented as a viable model for selecting appropriate tobacco cessation medications for patients with cancer. METHODS: The electronic medical record of each patient who uses tobacco is carefully reviewed once he or she is scheduled for a consultation. A summary is produced with a standardized template and used later as a template for the medical provider evaluation. Precautions are put in place with consideration of the characteristics of each of the tobacco cessation medications (e.g., mechanism of action, route of administration, interactions with other medications, possible side effects, contraindications). Since 2006, the TTP has had more than 4,000 new patients and more than 39,000 follow-up visits. FINDINGS: Because each patient with cancer has unique medical, psychological, and social circumstances, the process of selecting the optimal tobacco cessation medication needs to be individualized. Oncology healthcare providers should follow some form of screening to tailor a medication plan to each patient. PMID- 25840383 TI - When do I get my brain back? Breast cancer survivors' experiences of cognitive problems. AB - BACKGROUND: Many survivors report troubling cognitive problems that can persist long after active treatment and seriously affect their quality of life, particularly in terms of employment. OBJECTIVES: The purpose of this study was to explore survivors' perceptions of their cognitive functioning. METHODS: Ten female breast cancer survivors receiving treatment in a community oncology setting participated in interviews or a focus group. FINDINGS: Six major themes were derived from the analysis. PMID- 25840384 TI - An integrative review of subjective and objective measures of sleep disturbances in breast cancer survivors. AB - BACKGROUND: Sleep disturbances are recognized as a side effect of cancer treatment, affecting physiological and psychological functioning. Sleep disturbances can persist through treatment and survivorship, and are increasingly prevalent among breast cancer survivors (BCSs). OBJECTIVES: The purpose of this review is to summarize current research on subjective and objective measures of sleep disturbances, the association between subjective and objective measures, and interventions used to manage sleep disturbances among BCSs after the completion of treatment. METHODS: Articles published from 2003-2013 were retrieved using PubMed, Web of Science, and ScienceDirect. Key search terms included breast cancer, sleep actigraphy, and sleep disturbances. Articles assessing sleep subjectively and objectively in the post-treatment period were included. FINDINGS: Twelve studies met the inclusion criteria. PMID- 25840385 TI - Promoting adherence to skin care practices among patients receiving radiation therapy. AB - BACKGROUND: The effects of radiation on the skin are particularly troublesome for patients and can result in impaired quality of life and an inability to perform activities of daily living. Skin care during radiation therapy is needed to prevent and treat radiation dermatitis. Patient adherence to prescribed skin care protocols is paramount to an optimal outcome but not always monitored closely. OBJECTIVES: The focus of this study was to optimize patient adherence to the Oncology Nursing Society's Putting Evidence Into Practice recommendations for skin care during radiation therapy. METHODS: A multidimensional approach was used to enhance adherence to the skin care protocol. Outcomes measured included adherence, patient satisfaction, and skin condition. FINDINGS: Five interacting dimensions affect adherence. PMID- 25840386 TI - Awareness of symptoms and risk factors of ovarian cancer in a population of women and healthcare providers. AB - BACKGROUND: Awareness of ovarian cancer among women and healthcare providers is understudied. An early awareness of ovarian cancer may lead to early detection and treatment of ovarian cancer. OBJECTIVES: The purpose of this study was to determine the level of that awareness among a sample of women and providers. METHODS: Written surveys were developed by the authors based on available literature and were administered to women (n = 857) and healthcare providers (n = 188) attending or volunteering at a community health fair. Chi-square tests for independence and z tests were used for analysis. FINDINGS: Healthcare providers were significantly more likely to identify the symptoms and risk factors for ovarian cancer. Forty percent of women reported being at least slightly familiar with the symptoms of ovarian cancer. Women who were familiar with symptoms were significantly more likely to identify symptoms and risk factors correctly and to report symptoms immediately to a provider. Identification of symptoms among healthcare providers ranged from 59%-93%. Identification of ovarian cancer symptoms and risk factors is poor among women, and knowledge deficits are present in providers. Increasing familiarity and awareness could lead to improvements in early diagnosis. PMID- 25840387 TI - Addressing physical activity needs of survivors by developing a community-based exercise program: LIVESTRONG(r) at the YMCA. AB - BACKGROUND: Although methods of cancer detection and treatment have improved, the side effects of treatment can cause profound debilitation that may linger years after treatment ends. Exercise during and after cancer treatment is safe, and it minimizes many of the deleterious physical and emotional side effects. With this evidence in mind, the LIVESTRONG Foundation and the YMCA of the USA collaborated to develop a community-based physical activity program for survivors, LIVESTRONG(r) at the YMCA. OBJECTIVES: This article provides in-depth information about the development of the LIVESTRONG at the YMCA program and its subsequent spread to meet the physical activity needs of survivors across the country. METHODS: Participating YMCAs engage in regular data collection efforts to track progress on organizational change and program delivery. These efforts include a staff evaluation survey, functional assessment of participants, patient-reported health status assessment, and patient program evaluation. FINDINGS: From the time of its development, the LIVESTRONG at the YMCA program has served more than 29,000 survivors and trained more than 2,200 LIVESTRONG at the YMCA instructors. A national survey of more than 1,600 program participants demonstrates positive outcomes on health and well-being, as well as intent to continue exercising after the program's end. PMID- 25840388 TI - Misattributed paternity in hematopoietic stem cell transplantation: the role of the healthcare provider. AB - BACKGROUND: With emerging technologies and genetic advancements in the field of oncology, ethical controversies and questions on how to approach them will continue to grow. Advancements in the field of hematopoietic stem cell transplantation have led to increased testing of transplantation recipients' children and parents as potential donors related to an increase in the use of haploidentical transplantations. This testing opens the door for an increased incidence of misattributed paternity findings. OBJECTIVES: This article attempts to address the ethical conflicts and provide potential solutions to assist in the transition from individual-focused care to family-focused care. METHODS: The principlist approach was used. FINDINGS: Healthcare providers should be educated on methods of incidental finding disclosure and how to provide adequate support for those individuals. PMID- 25840389 TI - Oncology nursing essentials: then and now. AB - Forty years ago, in 1975, if you were a practicing clinical oncology nurse, you may have been working in an inpatient setting, acting as a primary care nurse during your 8- to 10-hour shift, and caring for patients with lymphoma or leukemia who were receiving multiple-day infusion treatment. These patients, most of whom were receiving a variation of standard chemotherapy regimens, were treated as inpatients because they were or would be very sick, based on their reaction to chemotherapy and their need for urgent symptom management. ?. PMID- 25840390 TI - Roles played by advanced practitioners in oncology: ?present status and future outlook. AB - The 40th anniversary of the Oncology Nursing Society is the perfect time to reflect on the role that advanced practitioners in oncology (APOs) play in the care of patients with cancer. APOs have become an important part of cancer care. This group of professionals practicing in various settings includes physician assistants (PAs), clinical nurse specialists (CNSs), and nurse practitioners (NPs). Areas of practice include inpatient and outpatient settings, emergency departments, surgical centers, and community health clinics (Leonard & Grossman, 2015), as well as academia and pharmaceutical companies. In practice, APOs typically assume a wide range of roles that can involve direct patient care, education (of patients and in a professional capacity), administration, consulting, and research. APOs often take on more than one of these roles. ?. PMID- 25840392 TI - Acupuncture for menopausal hot flashes. PMID- 25840391 TI - Celebrating ONS's 40th anniversary and its commitment ?to cultural competency, diversity, and inclusiveness. AB - Today, we all have been taught that cultural competence is a valuable tool in providing patient-centered care. However, this concept was not considered a standard of oncology nursing practice when the Oncology Nursing Society (ONS) began. It was not regarded as a critical component of patient safety, satisfaction, or quality care. In fact, in the 1970s, the importance of providing culturally competent care was virtually nonexistent in our nation's government policies, regulatory standards, academic curriculum, or professional practice. ?. PMID- 25840393 TI - The obituary and the oncology nurse. PMID- 25840394 TI - Level of adherence to an extravasation protocol over 10 years in a tertiary care hospital. AB - BACKGROUND: Extravasation of chemotherapy is an undesirable complication related to the administration of antineoplastic therapy. Establishing the real incidence is difficult. Because of the importance of a quick intervention after an extravasation, every hospital should have an extravasation protocol. OBJECTIVES: The purpose of this study was to determine the degree of observance of an extravasation protocol by nursing staff and to determine extravasation incidence. METHODS: This descriptive, longitudinal, retrospective study was set in a tertiary-level hospital. The researchers reviewed 117 extravasation notification forms received by the pharmacy department during a 10-year period. Nursing actuation, particularly observance of the extravasation protocol, was analyzed. FINDINGS: Protocol adherence was 89%. Twelve deviations from the protocol in the application of recommended measures were detected. An antidote was used in 41 patients, and temperature measures were applied in 14 cases. Ninety-nine patients had at least one episode of reported follow-up. No cases of necrosis or skin ulcers were described, except by one patient, who developed a delayed skin ulcer to vinorelbine. Drugs most frequently reported were etoposide, carboplatin, and paclitaxel. Nursing staff should be continuously trained in extravasation protocol because a rapid actuation can prevent skin lesions. PMID- 25840395 TI - Nursing management of patients with castration-resistant prostate cancer undergoing radium-223 dichloride treatment. AB - BACKGROUND: Radium-223 dichloride, or radium-223, is a first-in-class alpha emitter that selectively targets bone metastases with high-energy, short-range alpha particles and is approved for the treatment of patients with castration resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Nurses are essential in educating patients about radium-223. OBJECTIVES: This article provides oncology nurses with information from the randomized phase III Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, as well as important handling, administration, and safety details unique to radium-223. METHODS: Data from the ALSYMPCA trial and related published information on radium-223 were reviewed. FINDINGS: Radium-223 is the only alpha-emitting radiopharmaceutical that has been shown to improve overall survival in patients with CRPC, as demonstrated in the ALSYMPCA trial. In addition, radium-223 delays time to first symptomatic skeletal event, and it is well tolerated with a low incidence of myelosuppression and gastrointestinal adverse events. Delivered on an outpatient basis, radium-223 requires universal precautions for handling and administration. Because of the potential for additive myelosuppression, the concomitant use of radium-223 with chemotherapy, other systemic radioisotopes, or hemibody external radiation therapy is not recommended. PMID- 25840396 TI - Equivalence of temperature measurement methods in the adult hematology/oncology population. AB - BACKGROUND: Neutropenic patients often become febrile and require frequent temperature monitoring. Monitoring core body temperature is considered the gold standard for accuracy. Taking oral temperature is the recommended noninvasive practice when core body temperature cannot be obtained; however, neutropenic patients often, for various reasons, are unable to tolerate an oral probe. OBJECTIVES: The purpose of this article is to determine the equivalence of temperatures taken via temporal artery, axillary, and oral methods, and to determine the best alternative to the oral method in the adult hematology/oncology population. METHODS: A repeated measures equivalence design was used. A convenience sample of 40 data sets (N = 33 inpatients) was tested on a hematology/oncology inpatient unit in a National Cancer Institute-designated comprehensive cancer center in the southeastern United States. A Latin squares design was employed with three possible sequences of measurement. Demographic data were analyzed using descriptive statistics, and equivalence was tested using the two one-sided tests method. Acceptance criterion for difference between methods was set at 0.2 degrees F from the oral method. FINDINGS: The temporal method is a potential noninvasive alternative to the oral method for the adult hematology/oncology population. PMID- 25840397 TI - Authentic caring occasions for patients in hairy cell leukemia clinical trials. AB - BACKGROUND: Rare diseases present challenges for patients, healthcare providers, and researchers. Rare disease communities exist for collaboration, dissemination of information, and to promote support for all community members. Patients with a rare disease desire to be supported through a rare disease community. Hairy cell leukemia (HCL) is a rare adult B-cell lymphocytic cancer that currently has no cure. OBJECTIVES: Patients with relapsed or refractory HCL may need to consider participation in a clinical trial. The research nurse can initiate a planned caring occasion based on Watson's Theory of Human Caring. The purpose of the planned caring occasion for patients with HCL in clinical trials is to establish authentic intentional caring encounters between the research nurse and patients and meaningful caring encounters between patients. OBSERVATIONS: Relapsed or refractory patients enrolled in an HCL clinical trial identify the trial as a microcommunity and the research nurse as an advocate and liaison. Patients seek support, empowerment, and the opportunity to connect with other patients with HCL. The planned caring occasion has the potential to provide a healing environment and facilitate shared experiences of living with HCL. The potential outcome for patients is strengthened holistic wellness. PMID- 25840398 TI - Trans-splicing group I intron targeting hepatitis C virus IRES mediates cell death upon viral infection in Huh7.5 cells. AB - The HCV-IRES sequence is vital for both protein translation and genome replication and serves as a potential target for anti-HCV therapy. We constructed a series of anti-HCV group I introns (alphaHCV-GrpIs) to attack conserved target sites within the HCV IRES. These alphaHCV-GrpIs were designed to mediate a trans splicing reaction that replaces the viral RNA genome downstream of the 5' splice site with a 3' exon that encodes an apoptosis-inducing gene. Pro-active forms of the apoptosis inducing genes BID, Caspase 3, Caspase 8, or tBax were modified by incorporation of the HCV NS5A/5B cleavage sequence in place of their respective endogenous cleavage sites to ensure that only HCV infected cells would undergo apoptosis following splicing and expression. Huh7.5 cells transfected with each intron were challenged at MOI 0.1 with HCV-Jc1FLAG2 which expresses a Gaussia Luciferase (GLuc) marker. Virus-containing supernatants were then assayed for GLuc expression as a measure of viral replication inhibition. Cellular extracts were analyzed for the presence of correct splice products by RT-PCR and DNA sequencing. We also measured levels of Caspase 3 activity as a means of quantifying apoptotic cell death. Each of these alphaHCV-GrpI introns was able to correctly splice their 3' apoptotic exons onto the virus RNA genome at the targeted Uracil, and resulted in greater than 80% suppression of the GLuc marker. A more pronounced suppression effect was observed with TCID50 virus titrations, which demonstrated that these alphaHCV-GrpIs were able to suppress viral replication by more than 2 logs, or greater than 99%. Robust activation of the apoptotic factor within the challenged cells was evidenced by a significant increase of Caspase 3 activity upon viral infection compared to non-challenged cells. This novel genetic intervention tool may prove beneficial in certain HCV subjects. PMID- 25840399 TI - Spine surgery and malpractice liability in the United States. AB - BACKGROUND CONTEXT: The correlation of negative outcomes with aggressiveness of malpractice liability has been questioned in the literature. PURPOSE: The aim of this study was to investigate the association of malpractice liability with unfavorable outcomes and hospitalization charges in spine surgery. STUDY DESIGN/SETTING: This was a retrospective cohort study. PATIENT SAMPLE: The sample included a total of 709,951 patients undergoing spine surgery who were registered in the Nationwide Inpatient Sample (NIS) database from 2005 to 2010. OUTCOME MEASURES: The outcome measures were state-level mortality, length of stay (LOS), and hospitalization charges after spinal surgery. METHODS: We performed a retrospective cohort study involving patients who underwent spine surgery from 2005 to 2010 and were registered in NIS. We used data from the National Practitioner Data Bank from 2005 to 2010 to create measures of volume and size of malpractice claim payments. Their association of the latter with the outcome measures was investigated. RESULTS: During the study period, there were 707,951 patients (mean age, 54.4 years, with 49.7% females) who underwent spine surgery and were registered in NIS. In a multivariable regression model, higher number of claims per 100 physicians in a state was associated with increased hospitalization charges (beta=0.14; 95% confidence interval [CI], 0.13-0.14) and LOS (beta=0.041; 95% CI, 0.036-0.047). On the contrary, there was no association with mortality (odds ratio [OR], 0.99; 95% CI, 0.87-1.12). Larger magnitude of awarded claims was associated with increased hospitalization charges (beta=0.08; 95% CI, 0.075-0.09) and LOS (beta=0.02; 95% CI, 0.016-0.031). On the contrary, there was no association with mortality (OR, 0.95; 95% CI, 0.82-1.11). CONCLUSIONS: In the present national study, aggressive malpractice environment was not correlated with mortality but was associated with higher hospitalization charges after spine surgery. Further research is needed to identify ways to regulate the malpractice system to address these disparities. PMID- 25840400 TI - Hemodynamic effects of standard versus larger-capacity intraaortic balloon counterpulsation pumps. AB - OBJECTIVE: Several recent trials have examined the clinical utility of intraaortic balloon counterpulsation pumps (IABPs) in cardiogenic shock and acute coronary syndromes. More recently, a larger-capacity 50 cc IABP was introduced into practice. No data comparing the hemodynamic effects of the 40 cc vs 50 cc IABP exist. Our aim was to explore the hemodynamic effects of the 50 cc IABP in real-world clinical practice. METHODS: Demographic, hemodynamic, and laboratory data were retrospectively examined in 26 consecutive subjects treated with a 50 cc IABP and compared with 26 patients receiving a 40 cc IABP between 2012 and 2013. IABP tracings were analyzed within 24 hours of implantation in all patients. Pulmonary artery catheter data were available before and after IABP implantation in 20 subjects. RESULTS: Baseline demographics, including body surface area, were similar between groups. Compared with the 40 cc IABP group, 50 cc IABP recipients showed higher augmented diastolic blood pressure, greater systolic unloading, and a larger reduction in pulmonary capillary occlusion pressure (PCOP). Percent diastolic augmentation was higher among 50 cc IABP recipients. Only 58% of subjects achieved <10 mm Hg of systolic unloading in the 40 cc group compared with 27% in the 50 cc group. For both the 40 cc and 50 cc IABPs, the magnitude of systolic unloading correlated inversely with PCOP and directly with the magnitude of diastolic augmentation. CONCLUSION: In real-world practice, greater systolic unloading and diastolic augmentation were observed among 50 cc vs 40 cc IABP recipients. Future trials evaluating the clinical utility of the 50 cc IABP are required. PMID- 25840401 TI - Differential hemodynamic profile of high-capacity intraaortic balloon pumps: new promise for an antiquated technology? PMID- 25840402 TI - First optical coherence tomography follow-up of coronary bifurcation lesions treated by drug-eluting balloons. AB - BACKGROUND: A strategy of percutaneous bifurcation intervention with provisional bare-metal stent (BMS) implantation followed by drug-eluting balloon (DEB) treatment represents a valuable opportunity in patients not compliant with long duration dual-antiplatelet therapy. We used optical coherence tomography (OCT) to assess coronary bifurcation lesions treated by BMS and DEB, and secondarily, to better explore the association between stent geometry and tissue coverage. METHODS: Twelve patients underwent frequency-domain OCT 6 months after undergoing percutaneous bifurcation intervention with BMS implantation followed by kissing DEB. The same type of BMS was correspondingly implanted in silicone bifurcation models and scanned by microcomputed tomography. RESULTS: Overall, a total 2914 struts were analyzed, revealing 0.6% malapposed struts and 3.1% uncovered struts, with neointimal thickness of covered struts measured at 0.19 +/- 0.13 mm. Findings were homogeneous among patients with the exception of one outlier who presented a significant distortion of the stent geometry, suggesting proximal cell rewiring prior to kissing DEB, as supported by the microcomputed tomography model. This pattern was not present in the other cases, which showed struts optimally apposed and nicely scaffolding the side-branch ostium. CONCLUSION: This is the first study describing the effects of DEB in percutaneous bifurcation interventions according to OCT parameters. The results show that a strategy of kissing DEB following BMS is associated with low neointimal thickness and high rate of covered stent struts. Moreover, these results appear to be dependent on the quality of bifurcation intervention, with distal cell rewiring more favorable than proximal cell rewiring. PMID- 25840403 TI - Comparison of fluoro and cine coronary angiography: balancing acceptable outcomes with a reduction in radiation dose. AB - Use of last fluoro hold (LFH) mode in fluoroscopy, which enables the last live image to be saved and displayed, could reduce radiation during percutaneous coronary intervention when compared with cine mode. No previous study compared coronary angiography radiation doses and image quality between LFH and conventional cine mode techniques. METHODS: We compared cumulative dose-area product (DAP), cumulative air kerma, fluoroscopy time, contrast use, interobserver variability of visual assessment between LFH angiography, and conventional cine angiography techniques. Forty-six patients were prospectively enrolled into the LFH group and 82 patients into the cine angiography group according to operator decision. RESULTS: Mean cumulative DAP was higher in the cine group vs the LFH group (50058.98 +/- 53542.71 mGy*cm2 vs 11349.2 +/- 8796.46 mGy*cm2; P<.001). Mean fluoroscopy times were higher in the cine group vs the LFH group (3.87 +/- 5.08 minutes vs 1.66 +/- 1.51 minutes; P<.01). Mean contrast use was higher in the cine group vs the LFH group (112.07 +/- 43.79 cc vs 88.15 +/- 23.84 cc; P<.001). Mean value of Crombach's alpha was not statistically different between visual estimates of three operators between cine and LFH angiography groups (0.66680 +/- 0.19309 vs 0.54193 +/- 0.31046; P=.20). CONCLUSION: Radiation doses, contrast use, and fluoroscopy times are lower in fluoroscopic LFH angiography vs cine angiography. Interclass variability of visual stenosis estimation between three operators was not different between cine and LFH groups. Fluoroscopic LFH images conventionally have inferior diagnostic quality when compared with cine coronary angiography, but with new angiographic systems with improved LFH image quality, these images may be adequate for diagnostic coronary angiography. PMID- 25840404 TI - The association between the extent of coronary artery disease and major bleeding events after percutaneous coronary intervention: from the ACUITY trial. AB - OBJECTIVE: We sought to evaluate the relation between the extent of coronary artery disease (CAD) and bleeding risk in patients undergoing percutaneous coronary intervention (PCI) for non-ST segment elevation acute coronary syndrome (NSTEACS). BACKGROUND: Patients with severe CAD undergoing PCI for NSTEACS are at high risk for recurrent adverse events. Hemorrhagic events after PCI are associated with high rates of morbidity and mortality. Despite sharing many common risk factors, the relationship between the extent of CAD and bleeding after PCI remains understudied. METHODS: The SYNTAX score (SS) was used to quantify the extent and severity of CAD. We stratified 2627 patients from the ACUITY PCI cohort into SS groups based on score tertiles from the ACUITY trial (<7, 7-12, and >12). Thirty-day major bleeding rates were determined for each group. RESULTS: When stratified by ACUITY tertiles, 30-day major bleeding rates were significantly greater in the highest SS tertile (>12) than in the intermediate and lowest tertiles (P<.01). By multivariable analysis, the SS (by augmentation of 1 point) remained independently associated with 30-day major bleeding (hazard ratio = 1.03; 95% confidence interval, 1.01-1.04; P<.01). CONCLUSION: The results of this large-scale study suggest that in addition to its previously described association with adverse ischemic events, the extent of CAD, as assessed by the SS, was independently associated with major bleeding after PCI for NSTEACS. PMID- 25840405 TI - Clinical outcomes of patients with critical limb ischemia who undergo routine coronary angiography and subsequent percutaneous coronary intervention. AB - BACKGROUND: Critical limb ischemia (CLI) is associated with a high risk of cardiovascular ischemic events. We assessed the strategy of routine coronary angiography and subsequent coronary revascularization, if clinically indicated, in patients with CLI who underwent percutaneous transluminal angioplasty (PTA). METHODS: Of a total 286 consecutive CLI patients treated by PTA, 252 patients who underwent coronary angiography before or after PTA were enrolled. Coronary artery disease (CAD) was defined as angiographic stenosis >=50% and significant CAD as >=70% stenosis. RESULTS: Of the 252 patients with CLI who underwent coronary angiography, a total of 167 patients (66.3%) had CAD and 85 patients (33.7%) did not have CAD. Patients in the CAD group were older, had a higher prevalence of diabetes and cerebrovascular disease, and had a lower mean ejection fraction. In the CAD group, of the 145 patients with significant CAD, percutaneous coronary intervention (PCI) was performed in 114 patients (78.6%). At 1 year, the CAD and non-CAD groups had no statistically significant differences in mortality (7.1% vs 4.7%; P=.45), myocardial infarction (1.1% vs 0%; P=.31), and PCI (4.7% vs 1.1%; P=.31). These outcomes were similar after the adjustment of baseline confounders. At 1 year, the CAD and non-CAD groups had similar rates of repeat PTA (16.7% vs 17.6%; P=.86), target lesion revascularization (13.7% vs 14.1%; P=.94), and amputation (19.1% vs 16.4%; P=.60). CONCLUSION: A strategy of routine coronary angiography and coronary revascularization may be a reasonable treatment option for these patients who have high risk for severe CAD. A randomized trial is needed to determine if this is the preferred strategy for CLI patients. PMID- 25840406 TI - Forearm arterial anatomy and flow characteristics: a prospective observational study. AB - BACKGROUND: Morphometric data on Caucasian radial and ulnar arteries are limited, with no data on flow interdependence in the forearm arterial circuit. METHODS: A total of 250 upper extremities in 125 patients were evaluated. Ultrasonography was performed and radial and ulnar artery lumen diameters were measured. Ulnar artery (UA) was compressed at the level of the wrist, and flow parameters in radial artery (RA) were recorded using duplex Doppler ultrasound. RESULTS: Radial and ulnar artery diameters were comparable at the level of the distal forearm (RA = 2.03 +/- 0.28 mm, UA = 2.07 +/- 0.27 mm; P=.14). There was no significant difference in radial or ulnar artery diameter between the dominant upper extremity and the non-dominant upper extremity. Upon compression of the ulnar artery, radial artery velocity-time integral (VTI) increased from 8.4 +/- 3.8 cm to 12.8 +/- 5.5 cm, which was statistically significant (P<.001). There was a significant inverse correlation between radial artery diameter and the magnitude of increase in radial VTI observed with UA compression (r2 = 0.106; P<.001). CONCLUSION: RA diameter at the level of the distal forearm is comparable to UA. RA-VTI and likely flow significantly increase by compression of the UA. The smaller the radial artery, the larger the increase in radial artery flow with ulnar compression. PMID- 25840407 TI - The clinical implications of balloon rupture during cardiovascular interventions. AB - Balloon rupture is an infrequent complication of cardiac catheterization that can lead to vessel injury. We report 6 cases that highlight the potential consequences of balloon rupture, including perforation, dissection, balloon entrapment, and distal embolization, and discuss prevention and treatment strategies. PMID- 25840408 TI - Transcatheter closure of five atrial septal communications in the presence of severe pulmonary arterial hypertension and severe left ventricular non compliance. AB - Closure of congenital atrial communications in the presence of either severe pulmonary arterial hypertension (PAH) with pulmonary-to-systemic (right-to-left) shunting, or severe left ventricular (LV) non-compliance with left-to-right shunting is often considered prohibitive. Thus, the recognition of durable reversibility of these physiologic conditions is crucial. We describe a hemodynamic conundrum in a patient with five septal communications in whom the coexistence of unmasked bidirectional physiologic shunting, severe PAH, and worsening left-sided overload dissuaded initial closure. We report our strategy for hemodynamic evaluation and successful closure of all defects. PMID- 25840409 TI - Rotational atherectomy in the era of cost containment. PMID- 25840411 TI - Occurrence, profiles, and ecological risks of polybrominated diphenyl ethers (PBDEs) in river sediments of Shanghai, China. AB - Fifty-two PBDE congeners in river sediments from Shanghai were analyzed in the present study. The concentrations of Sigma51PBDEs (defined as the sum of 51 BDE congeners except BDE209) and BDE209 ranged from 0.231 to 119 ng g(-1) and from nd to 189 ng g(-1), respectively. The most abundant BDE congeners in surface sediments were BDE118, 207, 208, 99, 49, 75, 47, 71 and 209, with median values of 1.67, 1.81, 1.83, 1.87, 1.98, 2.52, 2.73, 4.62 and 45.7 ng g(-1) dw, respectively. The concentrations of Sigma52PBDEs were significantly correlated with total organic carbon (TOC) content in sediments (p < 0.05). Weak correlations between all PBDE homologues and TOC (r < 0.32) suggest that TOC had a little influence on sediment PBDE transport and distribution patterns in river sediments of Shanghai. Correspondence analysis (CA) showed that PBDEs in sediments in the studied area originated from commercial BDE formulations, combustion emission sources, and debromination of highly brominated PBDEs by aerobic/anaerobic microbes or sunlight. Risk assessment based on risk quotients (RQ) showed that PBDEs in all river sediments collected from Shanghai posed a high potential ecological risk (RQ > 1) to the sediment dwelling organisms, and pentaBDE, decaBDE and tetraBDE were the major ecological risk drivers. PMID- 25840412 TI - High-level Gpr56 expression is dispensable for the maintenance and function of hematopoietic stem and progenitor cells in mice. AB - Blood formation by hematopoietic stem cells (HSCs) is regulated by a still incompletely defined network of general and HSC-specific regulators. In this study, we analyzed the role of G-protein coupled receptor 56 (Gpr56) as a candidate HSC regulator based on its differential expression in quiescent relative to proliferating HSCs and its common targeting by core HSC regulators. Detailed expression analysis revealed that Gpr56 is abundantly expressed by HSPCs during definitive hematopoiesis in the embryo and in the adult bone marrow, but its levels are reduced substantially as HSPCs differentiate. However, despite enriched expression in HSPCs, Gpr56-deficiency did not impair HSPC maintenance or function during steady-state or myeloablative stress-induced hematopoiesis. Gpr56 deficient HSCs also responded normally to physiological and pharmacological mobilization signals, despite the reported role of this GPCR as a regulator of cell adhesion and migration in neuronal cells. Moreover, Gpr56-deficient bone marrow engrafted with equivalent efficiency as wild-type HSCs in primary recipients; however, their reconstituting ability was reduced when subjected to serial transplantation. These data indicate that although GPR56 is abundantly and selectively expressed by primitive HSPCs, its high level expression is largely dispensable for steady-state and regenerative hematopoiesis. PMID- 25840413 TI - Development of a protein marker panel for characterization of human induced pluripotent stem cells (hiPSCs) using global quantitative proteome analysis. AB - The emergence of new methods for reprogramming of adult somatic cells into induced pluripotent stem cells (iPSC) led to the development of new approaches in drug discovery and regenerative medicine. Investigation of the molecular mechanisms underlying the self-renewal, expansion and differentiation of human iPSC (hiPSC) should lead to improvements in the manufacture of safe and reliable cell therapy products. The goal of our study was qualitative and quantitative proteomic characterizations of hiPSC by means of electrospray ionization (ESI) MS(e) and MALDI-TOF/TOF mass spectrometry (MS). Proteomes of hiPSCs of different somatic origins: fibroblasts and peripheral blood CD34(+) cells, reprogrammed by the same technique, were compared with the original somatic cells and hESC. Quantitative proteomic comparison revealed approximately 220 proteins commonly up regulated in all three pluripotent stem cell lines compared to the primary cells. Expression of 21 proteins previously reported as pluripotency markers was up regulated in both hiPSCs (8 were confirmed by Western blot). A number of novel candidate marker proteins with the highest fold-change difference between hiPSCs/hESC and somatic cells discovered by MS were confirmed by Western blot. A panel of 22 candidate marker proteins of hiPSC was developed and expression of these proteins was confirmed in 8 additional hiPSC lines. PMID- 25840414 TI - Multiple layers of chimerism in a single-stranded DNA virus discovered by deep sequencing. AB - Viruses with single-stranded (ss) DNA genomes infect hosts in all three domains of life and include many medically, ecologically, and economically important pathogens. Recently, a new group of ssDNA viruses with chimeric genomes has been discovered through viral metagenomics. These chimeric viruses combine capsid protein genes and replicative protein genes that, respectively, appear to have been inherited from viruses with positive-strand RNA genomes, such as tombusviruses, and ssDNA genomes, such as circoviruses, nanoviruses or geminiviruses. Here, we describe the genome sequence of a new representative of this virus group and reveal an additional layer of chimerism among ssDNA viruses. We show that not only do these viruses encompass genes for capsid proteins and replicative proteins that have distinct evolutionary histories, but also the replicative genes themselves are chimeras of functional domains inherited from viruses of different families. Our results underscore the importance of horizontal gene transfer in the evolution of ssDNA viruses and the role of genetic recombination in the emergence of novel virus groups. PMID- 25840415 TI - Recent positive selection has acted on genes encoding proteins with more interactions within the whole human interactome. AB - Genes vary in their likelihood to undergo adaptive evolution. The genomic factors that determine adaptability, however, remain poorly understood. Genes function in the context of molecular networks, with some occupying more important positions than others and thus being likely to be under stronger selective pressures. However, how positive selection distributes across the different parts of molecular networks is still not fully understood. Here, we inferred positive selection using comparative genomics and population genetics approaches through the comparison of 10 mammalian and 270 human genomes, respectively. In agreement with previous results, we found that genes with lower network centralities are more likely to evolve under positive selection (as inferred from divergence data). Surprisingly, polymorphism data yield results in the opposite direction than divergence data: Genes with higher centralities are more likely to have been targeted by recent positive selection during recent human evolution. Our results indicate that the relationship between centrality and the impact of adaptive evolution highly depends on the mode of positive selection and/or the evolutionary time-scale. PMID- 25840416 TI - Plastid genome-based phylogeny pinpointed the origin of the green-colored plastid in the dinoflagellate Lepidodinium chlorophorum. AB - Unlike many other photosynthetic dinoflagellates, whose plastids contain a characteristic carotenoid peridinin, members of the genus Lepidodinium are the only known dinoflagellate species possessing green alga-derived plastids. However, the precise origin of Lepidodinium plastids has hitherto remained uncertain. In this study, we completely sequenced the plastid genome of Lepidodinium chlorophorum NIES-1868. Our phylogenetic analyses of 52 plastid encoded proteins unite L. chlorophorum exclusively with a pedinophyte, Pedinomonas minor, indicating that the green-colored plastids in Lepidodinium spp. were derived from an endosymbiotic pedinophyte or a green alga closely related to pedinophytes. Our genome comparison incorporating the origin of the Lepidodinium plastids strongly suggests that the endosymbiont plastid genome acquired by the ancestral Lepidodinium species has lost genes encoding proteins involved in metabolism and biosynthesis, protein/metabolite transport, and plastid division during the endosymbiosis. We further discuss the commonalities and idiosyncrasies in genome evolution between the L. chlorophorum plastid and other plastids acquired through endosymbiosis of eukaryotic photoautotrophs. PMID- 25840417 TI - Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses. AB - The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine phosphorylation and co-internalization with the IGF-IR. Significantly, DDR1 was critical for IGF-IR endocytosis and trafficking into early endosomes, IGF-IR protein expression and IGF-I intracellular signaling and biological effects, including cell proliferation, migration and colony formation. These biological responses were inhibited by DDR1 silencing and enhanced by DDR1 overexpression.Experiments in mouse fibroblasts co-transfected with the human IGF IR and DDR1 gave similar results and indicated that, in the absence of IGF-IR, collagen-dependent phosphorylation of DDR1 is impaired.These results demonstrate a critical role of DDR1 in the regulation of IGF-IR action, and identify DDR1 as a novel important target for breast cancers that overexpress IGF-IR. PMID- 25840418 TI - NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib. AB - There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and lestaurtinib have been developed to block TrkA kinase signaling, but no clinical trial has fully demonstrated their therapeutic efficacy. Therapeutic failures are likely due to the existence of intrinsic signaling pathways in cancer cells that impede or bypass the effects of TrkA tyrosine kinase inhibitors. To verify this hypothesis, we combined different approaches including mass spectrometry proteomics, co-immunoprecipitation and proximity ligation assays. We found that NGF treatment induced CD44 binding to TrkA at the plasma membrane and subsequent activation of the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion. The NGF-induced CD44 signaling was independent of TrkA kinase activity. Moreover, both TrkA tyrosine kinase inhibition with lestaurtinib and CD44 silencing with siRNA inhibited cell growth in vitro as well as tumor development in mouse xenograft model; combined treatment significantly enhanced the antineoplastic effects of either treatment alone. Altogether, our results demonstrate that NGF-induced tyrosine kinase independent TrkA signaling through CD44 was sufficient to maintain tumor aggressiveness. Our findings provide an alternative mechanism of cancer resistance to lestaurtinib and indicate that dual inhibition of CD44 and TrkA tyrosine kinase activity may represent a novel therapeutic strategy. PMID- 25840419 TI - MiR-195 suppresses non-small cell lung cancer by targeting CHEK1. AB - MiR-195 suppresses tumor growth and is associated with better survival outcomes in several malignancies including non-small cell lung cancer (NSCLC). Our previous study showed high miR-195 plasma levels associated with favorable overall survival of non-smoking women with lung adenocarcinoma. To further elucidate role of miR-195 in NSCLC, we conducted in vitro experiment as well as clinical studies in a cohort of 299 NSCLC samples. We demonstrated that miR-195 expression was lower in tumor tissues and was associated with poor survival outcome. Overexpression of miR-195 suppressed tumor cell growth, migration and invasion. We discovered that CHEK1 was a direct target of miR-195, which decreased CHEK1 expression in lung cancer cells. High expression of CHEK1 in lung tumors was associated with poor overall survival. Our results suggest that miR 195 suppresses NSCLC and predicts lung cancer prognosis. PMID- 25840420 TI - Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study. AB - Although it has been shown that polymorphisms in one-carbon metabolism (OCM) pathway are associated with gastric cancer (GC), their interactions and contributions for patients' survival are elusive. In this study, we investigated the effects of polymorphisms and their interactions on the survival of GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR 677C > T, 1298A > C), Methionine synthase reductase (MTRR 66A > G), Methionine synthase (MTR 2756A > G), and Thymidylate synthase (TS 3'-UTR ins6 > del6, 5'-UTR 2R > 3R). We recruited 919 GC patients from 1998 to 2006. The Kaplan-Meier plots, Cox regression analyses and the log-rank tests were carried out in this study. MTHFR 1298CC genotype showed protective effect (HR = 0.444, 95% CI = 0.210-0.940). MTRR 66 GA + GG genotypes decreased the risk of death (HR = 0.793, 95% CI = 0.651 0.967) in general, and in subgroups with more pronounced diffuse type, greater depth of invasion (T2/T3/T4), higher level lymph node metastasis (N1/N2/N3), advanced TNM stages (II/III level) and 5-Fu treatment. However, the improved survival disappeared when GC patients simultaneously had MTR 2756 GA + GG genotypes (HR = 1.063, 95% CI = 0.750-1.507). Although MTRR 66GA genotype was not associated with the survival of GC patients, patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609-0.981). MTHFR 1298 CA + CC combined with TS 5-UTR 2R3R + 3R3R genotypes (HR = 0.536, 95% CI = 0.315-0.913) also increased patient survival rates. Our results suggest that the MTRR 66A > G and MTHFR 1298A > C polymorphisms may be useful prognostic biomarkers for GC patients. PMID- 25840421 TI - Dual targeting of microtubule and topoisomerase II by alpha-carboline derivative YCH337 for tumor proliferation and growth inhibition. AB - Both microtubule and topoisomerase II (Top2) are important anticancer targets and their respective inhibitors are widely used in combination for cancer therapy. However, some combinations could be mutually antagonistic and drug resistance further limits their therapeutic efficacy. Here we report YCH337, a novel alpha carboline derivative that targets both microtubule and Top2, eliciting tumor proliferation and growth inhibition and overcoming drug resistance. YCH337 inhibited microtubule polymerization by binding to the colchicine site and subsequently led to mitotic arrest. It also suppressed Top2 and caused DNA double strand breaks. It disrupted microtubule more potently than Top2. YCH337 induced reversible mitotic arrest at low concentrations but persistent DNA damage. YCH337 caused intrinsic and extrinsic apoptosis and decreased MCL-1, cIAP1 and XIAP proteins. In this aspect, YCH337 behaved differently from the combination of vincristine and etoposide. YCH337 inhibited proliferation of tumor cells with an averaged IC50 of 0.3 MUM. It significantly suppressed the growth of HT-29 xenografts in nude mice too. Importantly, YCH337 nearly equally killed different mechanism-mediated resistant tumor cells and corresponding parent cells. Together with the novelty of its chemical structure, YCH337 could serve as a promising lead for drug development and a prototype for a dual microtubule/Top2 targeting strategy for cancer therapy. PMID- 25840422 TI - The Attentional Fields of Visual Search in Simultanagnosia and Healthy Individuals: How Object and Space Attention Interact. AB - Simultanagnosia is a deficit in which patients are unable to perceive multiple objects simultaneously. To date, it remains disputed whether this deficit results from disrupted object or space perception. We asked both healthy participants as well as a patient with simultanagnosia to perform different visual search tasks of variable difficulty. We also modulated the number of objects (target and distracters) presented. For healthy participants, we found that each visual search task was performed with a specific "attentional field" depending on the difficulty of visual object processing but not on the number of objects falling within this "working space." This was demonstrated by measuring the cost in reaction times using different gaze-contingent visible window sizes. We found that bilateral damage to the superior parietal lobule impairs the spatial integration of separable features (within-object processing), shrinking the attentional field in which a target can be detected, but causing no deficit in processing multiple objects per se. PMID- 25840423 TI - Intracortical Posterior Cingulate Myelin Content Relates to Error Processing: Results from T1- and T2-Weighted MRI Myelin Mapping and Electrophysiology in Healthy Adults. AB - Myelin content of the cerebral cortex likely impacts cognitive functioning, but this notion has scarcely been investigated in vivo in humans. Here we tested for a relationship between intracortical myelin and a direct measure of neural activity in the form of the electrophysiological response error-related negativity (ERN). Using magnetic resonance imaging, myelin mapping was performed in 81 healthy adults aged 40-60 years by means of a T1- and T2-weighted (T1w/T2w) signal intensity ratio approach. Error trials on a version of the Eriksen flanker task triggered the ERN, a negative deflection of the event-related potential reflecting performance monitoring. Compelling evidence from neuroimaging, lesion, and source localization studies indicates that the ERN stems from the cingulate cortex. Vertex-wise analyses across the cingulate demonstrated that increased amplitude of the ERN was related to higher levels of intracortical myelin in the left posterior cingulate cortex. The association was independent of general ability level and subjacent white matter myelin. The results fit the notion that degree of myelin within the posterior cingulate cortex as measured by T1w/T2w signal intensity plays a role in error processing and cognitive control through the relationship with neural activity as measured by ERN amplitude, potentially by facilitating local neural synchronization. PMID- 25840424 TI - Dynamics of Ionic Shifts in Cortical Spreading Depression. AB - Cortical spreading depression is a slowly propagating wave of near-complete depolarization of brain cells followed by temporary suppression of neuronal activity. Accumulating evidence indicates that cortical spreading depression underlies the migraine aura and that similar waves promote tissue damage in stroke, trauma, and hemorrhage. Cortical spreading depression is characterized by neuronal swelling, profound elevation of extracellular potassium and glutamate, multiphasic blood flow changes, and drop in tissue oxygen tension. The slow speed of the cortical spreading depression wave implies that it is mediated by diffusion of a chemical substance, yet the identity of this substance and the pathway it follows are unknown. Intercellular spread between gap junction-coupled neurons or glial cells and interstitial diffusion of K(+) or glutamate have been proposed. Here we use extracellular direct current potential recordings, K(+) sensitive microelectrodes, and 2-photon imaging with ultrasensitive Ca(2+) and glutamate fluorescent probes to elucidate the spatiotemporal dynamics of ionic shifts associated with the propagation of cortical spreading depression in the visual cortex of adult living mice. Our data argue against intercellular spread of Ca(2+) carrying the cortical spreading depression wavefront and are in favor of interstitial K(+) diffusion, rather than glutamate diffusion, as the leading event in cortical spreading depression. PMID- 25840427 TI - On the coffee theory of disease. PMID- 25840426 TI - Hospital costs during the first 5 years of life for multiples compared with singletons born after IVF or ICSI. AB - STUDY QUESTION: Do in vitro fertilization (IVF) multiples generate higher hospital costs than IVF singletons, from birth up to age 5? SUMMARY ANSWER: Hospital costs from birth up to age 5 were significantly higher among IVF/ICSI multiple children compared with IVF/ICSI singletons; however, when excluding the costs incurred during the birth admission period, hospital costs of multiples and singletons were comparable. WHAT IS KNOWN ALREADY: Concern has risen over the long-term outcome of children born after IVF. The increased incidence of multiple births in IVF as a result of double-embryo transfer predisposes children to a poorer neonatal outcome such as preterm birth and low birthweight. As a consequence, IVF multiples require more medical care. Costs and consequences of poorer neonatal outcomes in multiples may also exist later in life. STUDY DESIGN, SIZE, DURATION: All 5497 children born from IVF in 2003-2005, whose parents received IVF or ICSI treatment in one of five participating Dutch IVF centers, served as a basis for a retrospective cohort study. Based on gestational age, birthweight, Apgar and congenital malformation, children were assigned to one of three risk strata (low-, moderate- or high-risk). PARTICIPANTS/MATERIALS, SETTING, METHODS: To enhance the efficiency of the data collection, 816 multiples and 584 singletons were selected for 5-year follow-up based on stratified (risk) sampling. Parental informed consent was received of 322 multiples and 293 singletons. Individual-level hospital resource use data (hospitalization, outpatient visits and medical procedures) were retrieved from hospital information systems and patient charts for 302 multiples and 278 singletons. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of hospitalization (OR 4.9, 95% CI 3.3 7.0), outpatient visits (OR 2.6, 95% CI 1.8-3.6) and medical procedures (OR 1.7, 95% CI 1.2-2.2) was higher for multiples compared with singletons. The average hospital costs amounted to ?10 018 and ?2093 during the birth admission period (P < 0.001), ?1131 and ?696 after the birth admission period to the first birthday (not significant (n.s.)) and ?1084 and ?938 from the second to the fifth life year (n.s.) for multiples and singletons, respectively. Hospital costs from birth up to age 5 were 3.3-fold higher for multiples compared with singletons (P < 0.001). Among multiples and singletons, respectively, 90.8 and 76.2% of the total hospital costs were caused by hospital admission days and 8.9 and 25.2% of the total hospital costs during the first 5 years of life occurred after the first year of life. LIMITATIONS, REASONS FOR CAUTION: Resource use and costs outside the hospital were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the increased use of healthcare resources by IVF/ICSI multiples compared with IVF/ICSI singletons. Single-embryo transfer may result in substantial savings, particularly in the birth admission period. These savings need to be compared with the extra costs of additional embryo transfers needed to achieve a successful pregnancy. Besides costs, health outcomes of children born after single-embryo transfer should be compared with those born after double-embryo transfer. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 25840425 TI - Cognitive Correlates of Basal Forebrain Atrophy and Associated Cortical Hypometabolism in Mild Cognitive Impairment. AB - Degeneration of basal forebrain (BF) cholinergic nuclei is associated with cognitive decline, and this effect is believed to be mediated by neuronal dysfunction in the denervated cortical areas. MRI-based measurements of BF atrophy are increasingly being used as in vivo surrogate markers for cholinergic degeneration, but the functional implications of reductions in BF volume are not well understood. We used high-resolution MRI, fluorodeoxyglucose-positron emission tomography (PET), and neuropsychological test data of 132 subjects with mild cognitive impairment (MCI) and 177 cognitively normal controls to determine associations between BF atrophy, cortical hypometabolism, and cognitive deficits. BF atrophy in MCI correlated with both impaired memory function and attentional control deficits, whereas hippocampus volume was more specifically associated with memory deficits. BF atrophy was also associated with widespread cortical hypometabolism, and path analytic models indicated that hypometabolism in domain specific cortical networks mediated the association between BF volume and cognitive dysfunction. The presence of cortical amyloid pathology, as assessed using AV45-PET, did not significantly interact with the observed associations. These data underline the potential of multimodal imaging markers to study structure-function-cognition relationships in the living human brain and provide important in vivo evidence for an involvement of the human BF in cortical activity and cognitive function. PMID- 25840428 TI - Insulin action in women with polycystic ovary syndrome and its relation to gestational diabetes. AB - STUDY QUESTION: How does insulin action change during pregnancy in women with polycystic ovary syndrome (PCOS) who develop gestational diabetes (GDM) compared with women with PCOS who do not? SUMMARY ANSWER: Women with PCOS who develop GDM already show disturbed insulin action early in pregnancy. WHAT IS KNOWN ALREADY: Pregnant women with PCOS are at increased risk of developing GDM compared with women without PCOS. STUDY DESIGN, SIZE, DURATION: This study represents a post hoc analysis of a subgroup of pregnant women with PCOS participating in a multicentre prospective cohort study. A total of 72 women were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included before conception and followed during pregnancy. Insulin, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), sex hormone-binding globulin (SHBG) and testosterone were analysed at three different time points in women who developed GDM and women who did not. MAIN RESULTS AND THE ROLE OF CHANCE: Seventy-two pregnant women with PCOS were included of which 22 (31%) women developed GDM. Both insulin levels and HOMA-IR were significantly higher at each sampling point in women with PCOS who developed GDM. SHBG levels were significantly lower before conception and in the second trimester compared with women who did not develop GDM. Testosterone concentrations were significantly lower before conception in women who developed GDM. After adjusting for BMI, waist circumference and waist/hip ratio, the differences in insulin, HOMA-IR, SHBG and testosterone levels remained largely the same. LIMITATIONS, REASONS FOR CAUTION: Selection bias cannot be excluded since only women from one centre with a complete blood sampling set were included in this study. WIDER IMPLICATIONS OF THE FINDINGS: The knowledge that women with PCOS who develop GDM already have a disturbed insulin action early in pregnancy is likely to be useful in considering the pathophysiology processes underlying this disorder in this specific group of women. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Child Health research programme of the University Medical Centre Utrecht. M.A.d.W., A.J.G., S.M.V.-V., A.F. and M.P.H.K. have no conflicts of interest to disclose. M.J.C.E. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. The authors declare complete independence from funders. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov, number NCT00821379. PMID- 25840429 TI - Sublingual versus vaginal misoprostol for cervical dilatation 1 or 3 h prior to surgical abortion: a double-blinded RCT. AB - STUDY QUESTION: Can sublingual administration of misoprostol 1 h prior to vacuum aspiration be more effective than vaginal administration and as effective as either route three 3 h prior to surgery? SUMMARY ANSWER: Sublingually administered misoprostol is superior to vaginally administered misoprostol when given 1 h pre operatively, and it is as effective as after a three 3 h priming interval with either route of administration. WHAT IS KNOWN ALREADY: Misoprostol reduces complications and morbidity when used for cervical priming prior to surgical dilatation and vacuum aspiration in first trimester pregnancy. Despite the widespread use and extensive studies, the optimal route of administration of misoprostol before surgical abortion remains to be defined. The optimal priming interval after vaginal and sublingual administration of 400 mcg misoprostol has been reported to be 3 h. A longer interval will not improve dilatation but will increase the risk for bleeding and expulsion of the uterine contents before surgical evacuation. The pharmacokinetic properties of misoprostol indicate that sublingual compared with vaginal administration of misoprostol may result in a more rapid cervical priming effect. STUDY DESIGN, SIZE, DURATION: Women were randomized to four treatment groups and received 400 mcg misoprostol sublingually, or vaginally, 1 or 3 h prior to surgery. The study was a double blinded RCT with regard to route of misoprostol administration but not the timing interval. The primary outcome was baseline cervical dilatation after misoprostol priming. The study was conducted between June 2007 and March 2014 and 184 women aged 18 years or older were recruited. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were recruited among nulliparous women undergoing elective surgical first trimester abortion. Exclusion criteria were any contraindication for misoprostol, untreated genital infection, previous history of surgery to the cervix, or abnormal pregnancy. Gestational age was established by endovaginal ultrasound examination. The trial was conducted in a university hospital outpatient clinic. The allocated medication (misoprostol and placebo) was self-administered 1 h or 3 h prior to surgery. All women received 2 tablets of 200 mcg misoprostol and 2 identical looking placebo tablets. Prophylactic pain medication, 100 mg oral diclofenac, was administered at the time of misoprostol. Side effects were recorded immediately before surgery and women were asked which administration route of administration they found most convenient and which they would have preferred. The exact priming time (from misoprostol administration to initiation of dilatation) and signs of bleeding prior to dilatation were recorded. Vacuum aspiration was performed under general anaesthesia according to clinical routine. Dilatation was performed using tapered Pratt-dilatators and the resistance of the cervix was assessed objectively using a tonometer. All surgery was performed by two investigators, experienced in using the tonometer. The cumulative force required to dilate the cervix was calculated by adding the peak force needed for each dilatator up to 9.7 mm. The time needed for surgery including cervical dilatation and vacuum aspiration, was recorded. Intra-operative blood loss was measured and any surgical complications noted. MAIN RESULTS AND THE ROLE OF CHANCE: Six women were excluded retrospectively from the analysis. Multivariate analysis of the primary outcome baseline dilatation showed a significant influence on route of administration (P = 0.034, 95% confidence interval (CI) 2.202, -0.086) as well as the interaction variable between route of administration and total priming time (P = 0.042, 95% CI 0.00, 0.016), with the vaginal route becoming more effective with longer priming time. These factors also had a significant influence on the peak force (administration route P = 0.042, 95% CI 0.221, 12.427, interaction P = 0.049, 95% CI -0.089, 0.000) and cumulative force (administration route P = 0.023, 95% CI 3.142, 40.877, interaction P = 0.026, 95% CI -0.293, -0.019) used for dilatation. The total priming time had a significant influence on bleeding before surgery, with more women bleeding the longer the total priming time (P = 0.003, 95% CI 2.203, 49.706). For abdominal pain before surgery there was a significant influence of administration route (P = < 0.001 95% CI 0.028, 0.235) and the interaction variable between administration route and priming time (P = 0.003, 95% CI 2.005, 30.757) with more women in the sublingual group experiencing abdominal pain the longer the priming time. The groups did not differ regarding duration of surgery, amount of bleeding and rate of side effects, such as nausea and shivering. Women in our study preferred vaginal treatment, as they disliked the taste of the misoprostol tablets. Vaginal treatment was also perceived as quicker to administer (P = 0.0001). LIMITATIONS, REASONS FOR CAUTION: The cervical tissue has viscoelastic properties, i.e. tissue resistance to mechanical dilatation depends also on the rate at which dilatation is performed. The ideal measurement of dilatation force should therefore also record the rate and time of dilatation. To ensure comparability, only nulliparous women without prior cervical surgery were recruited. In addition, time of dilatation was recorded and did not differ between the groups, and it is therefore assumed that dilatation took place at approximately the same rate. A limitation is that the study was conducted over a long time period because there was only one tonometer, decreasing numbers of surgical abortions and the fact that the main author was on a rotation schedule. In addition, the study was not powered to detect differences in side effects. WIDER IMPLICATIONS OF FINDINGS: Priming with misoprostol is recommended prior to surgical abortion. The priming interval of misoprostol may be reduced to 1 h after sublingual administration but not after vaginal administration. The results of the present study will increase choice and flexibility in cervical priming. STUDY FUNDING/COMPETING INTERESTS: The Swedish research council (521-2009-2605), Swedish Council for Working Life and Social Research (1404/08), Stockholm County Council and Karolinska Institutet (ALF 2009-2012). All authors declare that they have no conflicts of interest. TRIAL REGISTRATION NUMBER: www.clincaltrials.gov, NCT 01933360. PMID- 25840430 TI - A Multifunctional Mutagenesis System for Analysis of Gene Function in Zebrafish. AB - Since the sequencing of the human reference genome, many human disease-related genes have been discovered. However, understanding the functions of all the genes in the genome remains a challenge. The biological activities of these genes are usually investigated in model organisms such as mice and zebrafish. Large-scale mutagenesis screens to generate disruptive mutations are useful for identifying and understanding the activities of genes. Here, we report a multifunctional mutagenesis system in zebrafish using the maize Ds transposon. Integration of the Ds transposable element containing an mCherry reporter for protein trap events and an EGFP reporter for enhancer trap events produced a collection of transgenic lines marking distinct cell and tissue types, and mutagenized genes in the zebrafish genome by trapping and prematurely terminating endogenous protein coding sequences. We obtained 642 zebrafish lines with dynamic reporter gene expression. The characterized fish lines with specific expression patterns will be made available through the European Zebrafish Resource Center (EZRC), and a database of reporter expression is available online (http://fishtrap.warwick.ac.uk/). Our approach complements other efforts using zebrafish to facilitate functional genomic studies in this model of human development and disease. PMID- 25840431 TI - Novel Genes Critical for Hypoxic Preconditioning in Zebrafish Are Regulators of Insulin and Glucose Metabolism. AB - Severe hypoxia is a common cause of major brain, heart, and kidney injury in adults, children, and newborns. However, mild hypoxia can be protective against later, more severe hypoxia exposure via "hypoxic preconditioning," a phenomenon that is not yet fully understood. Accordingly, we have established and optimized an embryonic zebrafish model to study hypoxic preconditioning. Using a functional genomic approach, we used this zebrafish model to identify and validate five novel hypoxia-protective genes, including irs2, crtc3, and camk2g2, which have been previously implicated in metabolic regulation. These results extend our understanding of the mechanisms of hypoxic preconditioning and affirm the discovery potential of this novel vertebrate hypoxic stress model. PMID- 25840433 TI - Simultaneous Determination of 10 Adulterants in Antihypertensive Functional Foods Using Multi-Walled Carbon Nanotubes-Dispersive Solid-Phase Extraction Coupled with High Performance Liquid Chromatography. AB - Consumption of functional foods based on extracts from selected herbs to alleviate hypertension is an increasingly common practice in China. Adulteration of these foods with pharmaceuticals can significantly impact a consumer's health. To control the quality of the functional foods effectively, a method for the simultaneous determination of 10 common adulterants including chlortalidone, hydrochlorothiazide, indapamide, metoprolol, nifedipine, nimodipine, nitrendipine, reserpine, triamterene and valsartan in antihypertensive functional foods was developed. The target chemicals in samples were ultrasonically extracted with acetonitrile, and then cleaned-up with multi-walled carbon natotubes-dispersive solid-phase extraction. Finally, the analytes were separated with a C18 column using binary mobile phases consisting of acetonitrile and 0.03 mol/L KH2PO4 solutions (pH 3.0). The flow rate of the mobile phase was 0.80 mL/min, and the column temperature was 35 degrees C. The detection wavelength was set at 220 nm. The limits of detection and quantification of the method ranged from 0.014 to 0.053 and 0.047 to 0.178 MUg/mL, respectively. The recoveries of the method were in the range of 80.1-98.1% with relative standard deviations <9.53%. The method was successfully applied to the determination of the target chemicals in real samples and simulated samples, and respirine was detected in one tonic wine sample with a concentration of 56.8 +/- 1.2 mg/L. PMID- 25840432 TI - The Drosophila melanogaster Mutants apblot and apXasta Affect an Essential apterous Wing Enhancer. AB - The selector gene apterous (ap) plays a key role during the development of the Drosophila melanogaster wing because it governs the establishment of the dorsal ventral (D-V) compartment boundary. The D-V compartment boundary is known to serve as an important signaling center that is essential for the growth of the wing. The role of Ap and its downstream effectors have been studied extensively. However, very little is known about the transcriptional regulation of ap during wing disc development. In this study, we present a first characterization of an essential wing-specific ap enhancer. First, we defined an 874-bp fragment about 10 kb upstream of the ap transcription start that faithfully recapitulates the expression pattern of ap in the wing imaginal disc. Analysis of deletions in the ap locus covering this element demonstrated that it is essential for proper regulation of ap and formation of the wing. Moreover, we showed that the mutations ap(blot) and ap(Xasta) directly affect the integrity of this enhancer, leading to characteristic wing phenotypes. Furthermore, we engineered an in situ rescue system at the endogenous ap gene locus, allowing us to investigate the role of enhancer fragments in their native environment. Using this system, we were able to demonstrate that the essential wing enhancer alone is not sufficient for normal wing development. The in situ rescue system will allow us to characterize the ap regulatory sequences in great detail at the endogenous locus. PMID- 25840434 TI - Structure and function of the tricuspid and bicuspid regurgitant aortic valve: an echocardiographic study. AB - OBJECTIVES: The emerging new treatment options for aortic valve disease call for more sophisticated diagnostics. We aimed to describe the echocardiographic pathophysiology and characteristics of the purely regurgitant aortic valve in detail. METHODS: Twenty-nine men, with chronic aortic regurgitation without concomitant heart disease referred for aortic valve intervention, underwent 2D transoesophageal echocardiographic (TEE) examination prior to surgery according to a previously published matrix. Measurements of the aortic valve apparatus in long and short axis view were made in systole and diastole and analysed off-line. The aortic valves were grouped as tricuspid (TAV) or bicuspid (BAV), and classified by regurgitation mechanism. RESULTS: Twenty-four examinations were eligible for analysis of which 13 presented TAV and 11 BAV. The regurgitation mechanism was classified as dilatation of the aorta in 6 cases, as prolapse in 11 cases and as poor cusp tissue quality or quantity in 7 cases. The ventriculo aortic junction (VAJ) and valve opening were closely related (TAV r = 0.5, BAV r = 0.73) but no correlation was found between the VAJ and the maximal sinus diameter (maxSiD) or the sinotubular junction (STJ). However, the STJ and maxSiD were significantly related (TAV vs BAV: systole r = 0.9, r = 0.8; diastole r = 0.9, r = 0.7), forming an entity. The conjoined BAV cusps were shorter than the anterior cusps when closed (P = 0.002); the inter-commissural distances of the cusps in the BAV group were significantly different (P = 0.001 resp. 0.03) in both systole and diastole. CONCLUSIONS: The VAJ was independent of other aortic dimensions and should thereby be considered as a separate entity with influence on valve opening. The detailed 2D TEE measurements of this study add further important information to our knowledge about the function and echocardiographic anatomy of the pathological aortic valve and root either as a stand-alone examination or as a benchmark and complement to 3D echocardiography. This may have an impact on decisions regarding repairability of the native aortic valve. PMID- 25840435 TI - Effectiveness of alcohol media literacy programmes: a systematic literature review. AB - Alcohol media literacy is an emerging field that aims to address the link between exposure to alcohol advertising and subsequent expectancies and behaviours for children and adolescents. The design, rigour and results of alcohol media literacy programmes vary considerably, resulting in a number of unanswered questions about effectiveness. To provide insight into some of these questions, a systematic literature review of alcohol media literacy studies was conducted. The review was guided by the following research question: What considerations are needed to develop an effective school-based alcohol media literacy programme? On the basis of a critical synthesis of 10 interventions (published in the period 1997 to May 2014), our findings provide a comprehensive understanding of the descriptive, methodological and outcome characteristics of this small body of significant research. The review provides considerations for future alcohol media literacy programmes, including the need for an interactive pedagogical approach within the naturalistic school setting, implementation fidelity and a holistic approach to programme evaluation, a means for maintaining relevance, consideration of gender differences, relevance for an international audience and use of follow-up and longitudinal data. PMID- 25840436 TI - Does an evidence-based healthy relationships program for 9th graders show similar effects for 7th and 8th graders? Results from 57 schools randomized to intervention. AB - Integrating social and emotional learning (SEL) programming throughout curricula to support the development of healthy behaviors and prevent violence is critical for a comprehensive approach to school health. This study used a post-test comparison design to evaluate a healthy relationships program for eighth grade students that applies a SEL approach. The program was adapted from the Fourth R, an evidence-based program for ninth graders, but matches the curriculum and developmental context for eighth graders. Surveys were collected post intervention from 1012 students within 57 schools randomized to intervention or control conditions. Multivariate multilevel analysis accounted for the nested nature of students within schools. There were significant group differences on three of four outcomes following intervention, including improved knowledge about violence, critical thinking around the impact of violence, and identification of more successful coping strategies. There was no group difference on general acceptance of violence. Overall, students learned relevant information and strategies and were able to apply that knowledge to demonstrate critical thinking, suggesting that adapting an evidence-based approach for use with younger students provided similar benefits. These findings build a case for 2 years of consecutive evidence-based healthy relationships programming in grades 8 and 9, consistent with best practice guidelines. PMID- 25840437 TI - Lack of IL-17 signaling decreases liver fibrosis in murine schistosomiasis japonica. AB - Accumulating evidence has identified the profibrogenic properties of IL-17A in organ fibrosis. However, the role of IL-17A signal in liver fibrosis induced by Schistosoma japonicum infection remains unclear. In this study, we investigated liver fibrosis in wild-type (WT) and IL-17RA(-/-) mice upon S. japonicum infection. Hepatic IL-17A, IL-17C, IL-17E (IL-25), IL-17F, IL-17RA, IL-17RB and IL-17RC transcript levels were determined by RT-PCR. IL-17A(+) cells were analyzed by flow cytometry and confocal microscopy among granuloma cells. Immunostaining of IL-17R was performed on liver sections. Collagen deposition was assessed by Van Gieson's staining. IL-17A, IL-17C, IL-17E, IL-17F, IL-17RA and IL 17RC mRNA levels were dramatically increased in fibrotic livers. Among granuloma cells, CD3(+) and CD3(-) lymphocytes, neutrophils and macrophages were found to express IL-17A. Compared to WT, IL-17RA(-/-) mice displayed attenuated granulomatous inflammation, liver fibrosis, improved liver function and high survival. Meanwhile, alpha-smooth muscle actin staining and the expression of fibrogenic genes (transforming growth factor beta, IL-13 and collagen-I) as well as IL-17A-induced proinflammatory mediators (IL-1beta, IL-6, tumor necrosis factor alpha, CXCL1 and CXCL2) and proteinases (MMP3 and TIMP1) involved in fibrosis were markedly reduced in IL-17RA(-/-) mice. In addition, Th2 cytokines IL-4 and IL-17E (IL-25) were also decreased in IL-17RA(-/-) mice. These results indicated that IL-17A signal contributes to the pathogenesis of liver fibrosis in murine schistosomiasis. This effect was induced possibly by activating hepatic stellate cells and stimulating the release of proinflammatory cytokines and chemokines. Furthermore, the Th2 response was also enhanced by IL-17A signals. Our data demonstrate that IL-17A may serve as a promising target for antifibrotic therapy. PMID- 25840438 TI - Enterococcus faecalis lipoteichoic acid suppresses Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced IL-8 expression in human periodontal ligament cells. AB - Periodontitis is caused by multi-bacterial infection and Aggregatibacter actinomycetemcomitans and Enterococcus faecalis are closely associated with inflammatory periodontal diseases. Although lipopolysaccharide (LPS) of A. actinomycetemcomitans (Aa.LPS) and lipoteichoic acid of E. faecalis (Ef.LTA) are considered to be major virulence factors evoking inflammatory responses, their combinatorial effect on the induction of chemokines has not been investigated. In this study, we investigated the interaction between Aa.LPS and Ef.LTA on IL-8 expression in human periodontal ligament (PDL) cells. Aa.LPS, but not Ef.LTA, substantially induced IL-8 expression at the protein and mRNA levels. Interestingly, Ef.LTA suppressed Aa.LPS-induced IL-8 expression without affecting the binding of Aa.LPS to Toll-like receptor (TLR) 4. Ef.LTA reduced Aa.LPS induced phosphorylation of mitogen-activated protein kinases, including ERK, JNK and p38 kinase. Furthermore, Ef.LTA inhibited the Aa.LPS-induced transcriptional activities of the activating protein 1, CCAAT/enhancer-binding protein and nuclear factor-kappa B transcription factors, all of which are known to regulate IL-8 gene expression. Ef.LTA augmented the expression of IL-1 receptor-associated kinase-M (IRAK-M), a negative regulator of TLR intracellular signaling pathways, in the presence of Aa.LPS at both the mRNA and protein levels. Small interfering RNA silencing IRAK-M reversed the attenuation of Aa.LPS-induced IL-8 expression by Ef.LTA. Collectively, these results suggest that Ef.LTA down-regulates Aa.LPS induced IL-8 expression in human PDL cells through up-regulation of the negative regulator IRAK-M. PMID- 25840439 TI - Validation of a high-power, time-resolved, near-infrared spectroscopy system for measurement of superficial and deep muscle deoxygenation during exercise. AB - Near-infrared assessment of skeletal muscle is restricted to superficial tissues due to power limitations of spectroscopic systems. We reasoned that understanding of muscle deoxygenation may be improved by simultaneously interrogating deeper tissues. To achieve this, we modified a high-power (~8 mW), time-resolved, near infrared spectroscopy system to increase depth penetration. Precision was first validated using a homogenous optical phantom over a range of inter-optode spacings (OS). Coefficients of variation from 10 measurements were minimal (0.5 1.9%) for absorption (MUa), reduced scattering, simulated total hemoglobin, and simulated O2 saturation. Second, a dual-layer phantom was constructed to assess depth sensitivity, and the thickness of the superficial layer was varied. With a superficial layer thickness of 1, 2, 3, and 4 cm (MUa = 0.149 cm(-1)), the proportional contribution of the deep layer (MUa = 0.250 cm(-1)) to total MUa was 80.1, 26.9, 3.7, and 0.0%, respectively (at 6-cm OS), validating penetration to ~3 cm. Implementation of an additional superficial phantom to simulate adipose tissue further reduced depth sensitivity. Finally, superficial and deep muscle spectroscopy was performed in six participants during heavy-intensity cycle exercise. Compared with the superficial rectus femoris, peak deoxygenation of the deep rectus femoris (including the superficial intermedius in some) was not significantly different (deoxyhemoglobin and deoxymyoglobin concentration: 81.3 +/- 20.8 vs. 78.3 +/- 13.6 MUM, P > 0.05), but deoxygenation kinetics were significantly slower (mean response time: 37 +/- 10 vs. 65 +/- 9 s, P <= 0.05). These data validate a high-power, time-resolved, near-infrared spectroscopy system with large OS for measuring the deoxygenation of deep tissues and reveal temporal and spatial disparities in muscle deoxygenation responses to exercise. PMID- 25840440 TI - Analysis of codeine positivity in urine of pain management patients. AB - The opioids codeine and morphine have legitimate uses in managing chronic pain conditions, but they are frequently abused. Patients prescribed opioids submit urine samples for medication compliance monitoring, and the interpretation of the results is complex. The purpose of this study was to evaluate the percentage of codeine- and morphine-positive urine drug tests that result from morphine use only, with the positive codeine result arising from low levels of codeine present in pharmaceutical formulations of morphine. This study included 80 urine samples which tested positive for codeine and morphine after pre-analytical hydrolysis and analysis by gas chromatography-mass spectrometry. Quantitative results were correlated with patient prescription information and immunoassay results to classify patients into one of four categories: heroin users (50%), codeine users (34%), codeine and morphine users (5%), and morphine users (11%). The percentage of codeine-positive resulting from morphine use was higher than previous estimates. Urine from patients prescribed morphine only was found to contain codeine at <1% of the morphine concentration, a ratio that was also observed in patients who used heroin. Careful analysis of urine drug testing results, including assessing the ratio of codeine to morphine (C/M), can help providers determine if patients are compliant with their pain management regimens. PMID- 25840441 TI - Pathogenic Role of Human Herpesvirus 6B Infection in Mesial Temporal Lobe Epilepsy. AB - BACKGROUND: Human herpesvirus 6B (HHV-6B) is the causative agent for exanthem subitum. HHV-6B was associated with mesial temporal sclerosis (MTS), leading to mesial temporal lobe epilepsy (MTLE). In this study, we sought to elucidate the pathogenic role of HHV-6B in patients with MTLE. METHODS: Seventy-five intractable MTLE patients, including 52 MTS patients and 23 non-MTS patients, were enrolled in this study. Resected hippocampus, amygdala, and mixed samples of amygdala and uncus samples were examined by real-time polymerase chain reaction (PCR) and reverse-transcriptase PCR to detect viral DNA and messenger RNA (mRNA), respectively. Host gene expressions, including neural markers, were measured using the TaqMan Gene Expression Assay. RESULTS: Detection of HHV-6 DNA was higher in MTS patients than non-MTS patients (median/interquartile range: 19.1/0 89.2 vs 0.0/0.0-0.0 copies/ug DNA; P = .004). HHV-6B viral DNA was determined in 12/27 HHV-6 DNA-positive samples, and no HHV-6B mRNA were detected in all samples. In MTS patients, expression of monocyte chemotactic protein-1 (P = .029) and glial fibrillary acidic protein (P = .043) were significantly higher in the amygdala samples with HHV-6 DNA than those without viral DNA. CONCLUSIONS: This study suggests that HHV-6B may play an important role in the pathogenesis of MTS via modification of host gene expression. PMID- 25840442 TI - Human Herpesvirus 6 as a Viral Trigger in Mesial Temporal Lobe Epilepsy. PMID- 25840444 TI - Docetaxel for platinum-refractory advanced thymic carcinoma. AB - OBJECTIVE: Thymic carcinoma is a rare mediastinal neoplasm. While platinum-based chemotherapy has been reported to be effective for advanced thymic carcinoma in a first-line setting, little information is available regarding the benefits of salvage chemotherapy for platinum-refractory thymic carcinoma. This study assessed the efficacy and safety profiles of docetaxel monotherapy for platinum refractory thymic carcinoma. METHODS: A total of 13 thymic carcinoma patients treated with docetaxel monotherapy in a second- or later-line setting between January 2003 and April 2014 were retrospectively reviewed. The median age was 61 years (range, 41-75 years). RESULTS: The overall response rate and disease control rate were 31% [95% confidence interval (CI), 6-56%] and 77% (95% CI, 54 100%), respectively. The median progression-free survival and overall survival after docetaxel monotherapy were 5.5 months (95% CI, 2.3-6.5 months) and 24.0 months (95% CI, 9.4-31.2 months), respectively. The most common Grade >=3 toxicity was neutropenia (62%). No incidents of febrile neutropenia and no treatment-related deaths were recorded. CONCLUSIONS: This retrospective analysis demonstrated that docetaxel was active against platinum-refractory thymic carcinoma with acceptable toxicities. Docetaxel monotherapy might be a promising therapeutic option for patients with platinum-refractory thymic carcinoma. PMID- 25840443 TI - Comparative Analysis of Host Cell Entry of Ebola Virus From Sierra Leone, 2014, and Zaire, 1976. AB - The ongoing Ebola virus (EBOV) disease (EVD) epidemic in Western Africa is the largest EVD outbreak recorded to date and requires the rapid development and deployment of antiviral measures. The viral glycoprotein (GP) facilitates host cell entry and, jointly with cellular interaction partners, constitutes a potential target for antiviral intervention. However, it is unknown whether the GPs of the currently and previously circulating EBOVs use the same mechanisms for cellular entry and are thus susceptible to inhibition by the same antivirals and cellular defenses. Here, we show that the GPs of the EBOVs circulating in 1976 and 2014 transduce the same spectrum of target cells, use the same cellular factors for host cell entry, and are comparably susceptible to blockade by antiviral interferon-induced transmembrane proteins and neutralizing antibody KZ52. Thus, the viruses responsible for the ongoing EVD epidemic should be fully susceptible to established antiviral strategies targeting GP and cellular entry factors. PMID- 25840445 TI - Topical Review: Eosinophilic Esophagitis in Children: Implications for Health Related Quality of Life and Potential Avenues for Future Research. AB - OBJECTIVE: To characterize the health-related quality of life (HRQoL) of children with eosinophilic esophagitis (EoE) as well as generate novel hypotheses for future research in this pediatric population. METHOD: A literature review was completed using PubMed and the keywords below. RESULTS: Research has shown that for children with EoE and their parents, symptom experiences and recommended treatments can have a negative impact on HRQoL. However, studies have yet to adequately address mechanisms that may help explain why this is. Areas of interest include sleep quality and disturbances, the experience of pain, and the presence of internalizing symptoms, all of which have the potential to uniquely and synergistically impact HRQoL. CONCLUSION: With greater understanding of the associations among sleep, pain, internalizing symptoms, and HRQoL in children with EoE may come enhanced therapies that substantially improve the quality of their health care. PMID- 25840446 TI - Childhood Cancer in Context: Sociodemographic Factors, Stress, and Psychological Distress Among Mothers and Children. AB - OBJECTIVE: To examine associations between sociodemographic factors (single parenthood, family income, education level, race), stress, and psychological distress among pediatric cancer patients and their mothers. METHODS: Participants completed measures assessing sociodemographic variables, depressive symptoms, posttraumatic stress symptoms, general stress, and cancer-related stress within the first year of the child's (ages 5-17 years) cancer diagnosis or relapse. Mothers (N = 318) provided self-reports and parent report of their children; children aged 10-17 years (N = 151) completed self-reports. RESULTS: Each sociodemographic variable demonstrated unique associations with mothers' and children's stress and distress in bivariate analyses. A cumulative sociodemographic risk measure was positively correlated with all stress and distress variables. In regression analyses predicting mothers' and children's distress, independent and cumulative sociodemographic measures were no longer significant when accounting for levels of stress. CONCLUSIONS: Findings highlight the need to consider the ecological context of pediatric cancer, particularly the impact of sociodemographic disadvantage on stress and distress in this population. PMID- 25840447 TI - Distinct Influences of Anxiety and Pain Catastrophizing on Functional Outcomes in Children and Adolescents With Chronic Pain. AB - OBJECTIVES: Examine whether anxiety and pain catastrophizing are distinct constructs in relation to functional outcomes in pediatric chronic pain, and whether they differentially predict functional outcomes based on age. METHODS: In all, 725 youth (191 children, 534 adolescents) with chronic pain completed measures of pain characteristics, anxiety, pain catastrophizing, functional disability, and health-related quality of life (HRQOL). Structural equation modeling was used to examine interrelationships. RESULTS: Anxiety and pain catastrophizing were distinct. For both children and adolescents, pain catastrophizing predicted pain, functional disability, and HRQOL, and was a stronger predictor of pain intensity. For children, anxiety predicted HRQOL, and pain catastrophizing was a stronger predictor of functional disability. For adolescents, anxiety predicted functional disability and HRQOL, and anxiety was a stronger predictor of HRQOL. CONCLUSIONS: There were age-related differences regarding whether anxiety or pain catastrophizing more strongly predicted specific functional outcomes. Assessment and intervention efforts should emphasize both anxiety and pain catastrophizing. PMID- 25840448 TI - Measuring Health-Related Quality of Life With the Parental Opinions of Pediatric Constipation Questionnaire. AB - OBJECTIVES: The purpose of this study was to develop a caregiver-completed constipation condition-specific health-related quality of life (HRQL) instrument. METHODS: 410 caregivers of children aged 2-18 years completed the Parental Opinions of Pediatric Constipation (POOPC), the PedsQL Generic Core Scales, PedQL Family Impact Module, Pediatric Symptom Checklist, the Functional Disability Inventory, the Pediatric Inventory for Parents, and a demographic questionnaire. Exploratory and confirmatory factor analyses were conducted to assess the psychometric properties of the POOPC. RESULTS: Analyses yielded four factors called Parental Burden/Distress, Family Conflict, Difficulties with the Medical Team, and Worry about Social Impact that reflect problems in HRQL secondary to constipation and soiling, which were generally more strongly correlated with similar measures relative to a general measure of youth's psychosocial functioning. CONCLUSION: The POOPC is a psychometrically sound measure, which may be useful to clinicians and researchers identifying domains of treatment needs for children and their families. PMID- 25840450 TI - Teaching versus enforcing game rules in preschoolers' peer interactions. AB - Children use normative language in two key contexts: when teaching others and when enforcing social norms. We presented pairs of 3- and 5-year-old peers (N=192) with a sorting game in two experimental conditions (in addition to a third baseline condition). In the teaching condition, one child was knowledgeable, whereas the other child was ignorant and so in need of instruction. In the enforcement condition, children learned conflicting rules so that each child was making mistakes from the other's point of view. When teaching rules to an ignorant partner, both age groups used generic normative language ("Bunnies go here"). When enforcing rules on a rule-breaking partner, 3-year-olds used normative utterances that were not generic and aimed at correcting individual behavior ("No, this goes there"), whereas 5-year-olds again used generic normative language, perhaps because they discerned that instruction was needed in this case as well. Young children normatively correct peers differently depending on their assessment of what their wayward partners need to bring them back into line. PMID- 25840449 TI - Ionizing radiation induces immediate protein acetylation changes in human cardiac microvascular endothelial cells. AB - Reversible lysine acetylation is a highly regulated post-translational protein modification that is known to regulate several signaling pathways. However, little is known about the radiation-induced changes in the acetylome. In this study, we analyzed the acute post-translational acetylation changes in primary human cardiac microvascular endothelial cells 4 h after a gamma radiation dose of 2 Gy. The acetylated peptides were enriched using anti-acetyl conjugated agarose beads. A total of 54 proteins were found to be altered in their acetylation status, 23 of which were deacetylated and 31 acetylated. Pathway analyses showed three protein categories particularly affected by radiation-induced changes in the acetylation status: the proteins involved in the translation process, the proteins of stress response, and mitochondrial proteins. The activation of the canonical and non-canonical Wnt signaling pathways affecting actin cytoskeleton signaling and cell cycle progression was predicted. The protein expression levels of two nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, sirtuin 1 and sirtuin 3, were significantly but transiently upregulated 4 but not 24 h after irradiation. The status of the p53 protein, a target of sirtuin 1, was found to be rapidly stabilized by acetylation after radiation exposure. These findings indicate that post-translational modification of proteins by acetylation and deacetylation is essentially affecting the radiation response of the endothelium. PMID- 25840451 TI - [Breast cancer classification is evolving]. AB - Diagnostic strategy of breast cancer has changed enormously during the last thirty years. To classical obligatory morphological data on the macroscopical and microscopical levels are now added imunocytochemistry, which is capable of detecting therapeutic targets such hormonal receptors and HER2 (Human Epidermal growth factor Receptor2), and molecular biology, which yields the molecular profile of tumors and their multigenic properties. By leaning on up-to-date classifications (TNM system and UICC grades), the pathologist is able to evaluate not only diagnostic but also pronostic criteria, leading to personalized and predictive treatments. PMID- 25840452 TI - [Circadian clock and non-visual functions: the role of light in humans]. AB - Hormonal secretion, cognitive performance, motor activity, metabolic processes, the sleep wake cycle and, most recently shown, cell division and ADN repair show a 24 h rhythmicity that is driven by the circadian timing system (the biological clock). Their appropriate activity over the 24 h requires appropriate entrainment of the circadian clock, which is achieved through the synchronizing effects of ocular light exposure. The activation of melanopsin-expressing ganglion cells in the retina depends on timing, quality, intensity, and history of light exposure. Inappropriate lighting leads to inappropriate synchronization of the clock, and activation of non-visual functions (mood, wakefulness, cognition, etc.). In turn, a deficit of circadian entrainment to the 24 h is responsible for alterations of a large number of functions, and leads to altered sleep, wake, mood, neurobehavioral processes and cell division, but also to pathologies. The crucial role of the circadian clock and the nature of the non-visual functions activated by light give rise to the concept that light is a biological need fundamental to health. Without an appropriate light hygiene, the clock receives an odd tempo, and it is cacophony! PMID- 25840453 TI - [Circadian clocks and energy metabolism in rodents]. AB - Circadian rhythmicity is an important component of physiological processes which provides them with a 24-hour temporal organization and adjustment to cyclical changes in the environment. Circadian rhythms are controlled by a network of endogenous clocks, comprising the main clock in the suprachiasmatic nuclei of the hypothalamus and many secondary clocks in the brain and peripheral tissues. All aspects of energy metabolism, from food intake to intracellular signaling pathways, are strongly influenced by circadian rhythmicity. In turn, meal timing is an efficient synchronizer (time-giver) to set the phase of the peripheral clocks, while the suprachiasmatic clock is synchronized by ambient light. In certain nutritional conditions (i.e., low- or high-calory diets), metabolic factors remaining to be identified modulate the functioning of the suprachiasmatic clock. Animal models of obesity and diabetes show circadian alterations. Conversely, when circadian rhythmicity is disturbed, either due to genetically defective circadian clocks, or to circadian desynchronization (chronic light exposure or repeated meals at odd times of the cycle), lipid and glucose metabolism is deregulated. The metabolic impact of circadian desynchronization justifies the development of preventive or therapeutic strategies that could rely, among others, on dietary interventions combining timed meals and specific composition. PMID- 25840454 TI - [Clock and molecular genetics in Drosophila]. AB - Most living organisms possess a circadian clock (24 h period) which allows them to adapt to environmental conditions. Numerous studies in Drosophila allowed to discover various key clock genes, such as period and timeless. The powerful tools of drosophila genetics have shown that the molecular clock relies on negative feedback loops that generate oscillations of the clock genes mRNA. A delay between the accumulation of mRNAs and proteins is required for the feedback loop. It is generated by post-translational modifications as phosphorylations and ubiquitinations, which control protein stability and determine the period of their oscillations. Clock cells are present in brain as well as in multiple peripheric tissues where they run autonomously. The synchronisation of clock cells by light relies on cryptochrome in both brain and peripheral tissues. In the brain, synchronisation also involves the eye photoreceptors. The clock that drives sleep-wake rhythms is controlled by different groups of neurons in the brain. Each group has a distinct function in the generation of the behavioral rhythm and this function is modulated by environmental conditions. PMID- 25840455 TI - [Is the biological clock central to the aging process? Studies in a non-human primate]. AB - The ability of organisms to adapt to their environment during aging is altered. Age-related disorders in Human include disturbances of biological rhythms, especially sleep-wake rhythms alterations, and perturbations of body temperature and hormone secretion. The alteration of biological rhythms with age leads to major health consequences, particularly due to the alteration of sleep-wake rhythms that causes a strong alteration of the general condition. The study of these changes is therefore a major health issue and requires the use of appropriate animal models such as the grey mouse lemur (Microcebus murinus), a small Madagascar primate with very pronounced biological rhythms. PMID- 25840456 TI - [Connecting isolated congenital asplenia to the ribosome]. AB - Isolated congenital asplenia is characterized by the absence of a spleen at birth without any other developmental defect. Isolated congenital asplenia is a rare and life-threatening disease that predisposes patients to severe bacterial infections. The first and main genetic etiology of isolated congenital asplenia was discovered in 2013. Mutations in the gene RPSA, which encodes ribosomal protein SA, cause more than half of the cases of isolated congenital asplenia. These disease-causing mutations lead to haploinsufficiency of RPSA. Haploinsufficiency of genes encoding other ribosomal proteins have been reported to cause other developmental defects in humans, and in model organisms like the fly or the mouse. About half of the patients with Diamond-Blackfan anemia, which is a well-characterized ribosomopathy, present developmental defects such as craniofacial defects, cardiac defects or thumb abnormalities. The mechanism of pathogenesis linking mutations in ribosomal proteins, which are highly and ubiquitously expressed, to specific developmental defects remains to be elucidated. One hypothesis is that the ribosome, and ribosomal proteins in particular, regulate the expression of specific genes during development. PMID- 25840457 TI - [TRAF4, a multifaceted protein involved in carcinoma progression]. AB - Eukaryotic epithelial cells form a sheet of contiguous cells, called epithelium, by means of the establishment of well-developed junctional complexes. These junctional complexes ensure the cell cohesion in the tissue and separate the plasma membrane into an apical and a basolateral compartment. This apicobasal polarity, which is crucial for both the architecture and the function of epithelia, is mainly maintained by tight junctions (TJS). Indeed, TJS weakening or loss disrupts the integrity of the epithelium, a process participating to the formation and progression of carcinomas. It has recently been shown that TRAF4, a protein dynamically localized in TJS and commonly overexpressed in carcinomas, plays a variety of functions in tumor progression. Here, we review recent data implicating TRAF4 in carcinogenesis. First, the conserved TRAF proteins family will be presented, and then the molecular mechanism addressing TRAF4 to TJS which involves lipid binding by the TRAF domain will be described. The various roles of TRAF4 in carcinogenesis will be discussed. Finally, we will highlight the ability of all TRAF proteins to bind lipids and discuss its potential functional relevance. PMID- 25840458 TI - [How does the apicomplexan parasite Theileria control host cell identity?]. AB - Infectious agents, like bacteria or virus, are responsible for a large number of pathologies in mammals. Microbes have developed mechanisms for interacting with host cell pathways and hijacking cellular machinery to change the phenotypic state. In this review, we focus on an interesting apicomplexan parasite called Theileria. Infection by the tick-transmitted T. annulata parasite causes Tropical Theileriosis in North Africa and Asia, and the related T. parva parasite causes East Coast Fever in Sub-Saharan Africa. This parasite is the only eukaryote known to induce the transformation of its mammalian host cells. Indeed, T. annulata and T. parva infect bovine leukocytes leading to transforming phenotypes, which partially mirror human lymphoma pathologies. Theileria infection causes hyperproliferation, invasiveness and escape from apoptosis, presumably through the manipulation of host cellular pathways. Several host-signaling mechanisms have been implicated. Here we describe the mechanisms involved in parasite induced transformation phenotypes. PMID- 25840459 TI - Development of a Diastereoselective Phosphorylation of a Complex Nucleoside via Dynamic Kinetic Resolution. AB - The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a ~7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1). PMID- 25840460 TI - A Heterogeneous Renal Mass and Arm Pain in a 38-Year-old African American Female. PMID- 25840461 TI - Which tyrosine-kinase inhibitor to use first in chronic phase chronic myelogenous leukemia? AB - INTRODUCTION: Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder distinctly characterized by the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. The resulting translocation leads to the development of the BCR-ABL1 oncogene, a constitutively active fusion protein, which leads to uncontrolled cell proliferation and reduced apoptosis and has a clear association with driving the malignant activity of CML cells. AREAS COVERED: Given that the BCR-ABL1 oncogene is a known key cause of CML, it has led to the development of numerous small molecule tyrosine-kinase inhibitors (TKIs), which target the specific oncogene mutation in CML. Presently, there are three FDA-approved TKI agents, imatinib, dasatinib and nilotinib, for the treatment of frontline CML. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents. EXPERT OPINION: Imatinib, dasatinib and nilotinib are all effective at yielding hematological, molecular and cytogenetic responses in patients with newly diagnosed CML. Frontline therapy may depend on physician experience, patient age and ability to tolerate therapy, and with the lack of data comparing all three agents alongside each other, imatinib, dasatinib, or nilotinib may all be suitable frontline choices. PMID- 25840462 TI - Amyloid biomarkers in Alzheimer's disease. AB - Aggregation of amyloid-beta (Abeta) into oligomers, fibrils, and plaques is central in the molecular pathogenesis of Alzheimer's disease (AD), and is the main focus of AD drug development. Biomarkers to monitor Abeta metabolism and aggregation directly in patients are important for further detailed study of the involvement of Abeta in disease pathogenesis and to monitor the biochemical effect of drugs targeting Abeta in clinical trials. Furthermore, if anti-Abeta disease-modifying drugs prove to be effective clinically, amyloid biomarkers will be of special value in the clinic to identify patients with brain amyloid deposition at risk for progression to AD dementia, to enable initiation of treatment before neurodegeneration is too severe, and to monitor drug effects on Abeta metabolism or pathology to guide dosage. Two types of amyloid biomarker have been developed: Abeta-binding ligands for use in positron emission tomography (PET) and assays to measure Abeta42 in cerebrospinal fluid (CSF). In this review, we present the rationales behind these biomarkers and compare their ability to measure Abeta plaque load in the brain. We also review possible shortcomings and the need of standardization of both biomarkers, as well as their implementation in the clinic. PMID- 25840463 TI - [Heptopulmonary syndrome]. AB - Hepatopulmonary syndrome is characterized by the presence of liver disease, pulmonary vascular dilatations, and arterial hypoxemia. It is usually associated with cirrhosis of any origin, but has been described in other liver diseases, both acute and chronic, and not always associated with portal hypertension. The gold standard method to detect pulmonary vascular dilations is contrast enhancement echocardiography with saline and is essential for the diagnosis of hepatopulmonary syndrome. These dilatations reflect changes in the pulmonary microvasculature (vasodilatation, intravascular monocyte accumulation, and angiogenesis) and induce a ventilation/perfusion mismatch, or even true intrapulmonary shunts, which eventually trigger hypoxemia. This syndrome worsens patients' prognosis and impairs their quality of life and may lead to the need for liver transplantation, which is the only effective and definitive treatment. In this article, we review the etiological, pathophysiological, clinical and therapeutic features of this syndrome. PMID- 25840464 TI - [Development, implementation, and analysis of a "collaborative decision-making for reasonable care" document in pediatric palliative care]. AB - INTRODUCTION: In France, a legal framework and guidelines state that decisions to limit treatments (DLT) require a collaborative decision meeting and a transcription of decisions in the patient's file. The do-not-attempt resuscitation order involves the same decision-making process for children in palliative care. To fulfill the law's requirements and encourage communication within the teams, the Resource Team in Pediatric Palliative Care in Aquitaine created a document shared by all children's hospital units, tracing the decision making process. This study analyzed the decision-making process, quality of information transmission, and most particularly the relevance of this new "collaborative decision-making for reasonable care" card. MATERIAL AND METHODS: Retrospective study evaluating the implementation of a traceable document relating the DLT process. All the data sheets collected between January and December 2013 were analyzed. RESULTS: A total of 58 data sheets were completed between January and December 2013. We chose to collect the most relevant data to evaluate the relevance of the items to be completed and the transmission of the document, to draw up the patients' profile, and the contents of discussions with families. Of the 58 children for whom DLT was discussed, 41 data sheets were drawn up in the pediatric intensive care unit, seven in the oncology and hematology unit, five in the neonatology unit, four in the neurology unit, and one in the pneumology unit. For 30 children, one sheet was created, for 11 children, two sheets and for two children, three sheets were filled out. Thirty nine decisions were made for withholding lifesaving treatment, 11 withdrawing treatment, and for five children, no limitation was set. Nine children survived after DLT. Of the 58 data sheets, only 31 discussions with families were related to the content of the data sheet. Of the 14 children transferred out of the unit with a completed data sheet, it was transmitted to the new unit for 11 children (79%). DISCUSSION: The number of data sheets collected in 1 year shows the value of this document. The participation of several pediatric specialities' referents in its creation, then its progressive presentation in the children's hospital units, were essential steps in introducing and establishing its use. Items describing the situation, management proposals, and adaptation of the children's supportive care were completed in the majority of cases. They correspond to a clinical description, the object of the discussion, and the daily caregiver's practices, respectively. On the other hand, discussions with families were related to the card's contents in only 53% of the cases. This can be explained by the time required to complete the DLT process. It is difficult for referring doctors to systematically, faithfully, and objectively transcribe discussions with parents. Although this process has been used for a long time in intensive care units, this document made possible an indispensable formalisation in the decision-making process. In other pediatric specialities, the sheet allowed introducing the palliative approach and was a starter and a tool for reflection on the do-not-attempt-resuscitation order, thus suggesting the need for anticipation in these situations. CONCLUSION: With the implementation of this new document, the DLT, data transmission, and continuity of care conditions were improved in the children's hospital units. Sharing this sheet with all professionals in charge of these children would support homogeneity and quality of management and care for children and their parents. PMID- 25840465 TI - [Lemierre syndrome revealed by torticollis]. AB - Classical Lemierre syndrome is a rare and severe disease with thrombosis of the internal jugular vein and metastatic infections. We report on a case of Lemierre like syndrome secondary to mastoiditis, with a favorable outcome, in a healthy infant presenting with torticollis. Early diagnosis and treatment with antibiotics are necessary to decrease mortality. PMID- 25840466 TI - [Ethics in pediatric emergencies: Care access, communication, and confidentiality]. AB - Children suffer most from today's increasing precariousness. In France, access to care is available for all children through various structures and existing measures. The support for foreign children is overseen by specific legislation often unfamiliar to caregivers. Pediatric emergencies, their location, organization, actors, and patient flow are a particular environment that is not always suitable to communication and may lead to situations of abuse. Communication should not be forgotten because of the urgency of the situation. The place of the child in the dialogue is often forgotten. Considering the triangular relationship, listening to the child and involving the parents in care are the basis for a good therapeutic alliance. Privacy and medical confidentiality in pediatric emergencies are governed by law. However, changes in treatments and medical practices along with the variety of actors involved imply both individual and collective limitations, to the detriment of medical confidentiality. PMID- 25840467 TI - Rumination: Cognitive consequences of training to inhibit the negative. AB - BACKGROUND AND OBJECTIVES: To explore cognitive factors in ruminative thinking, we assessed the effect of a single-session of inhibition training on subsequent biases in attention and interpretation. METHODS: We randomly assigned participants to either inhibit or attend to negative stimuli. Inhibition was assessed by using assessment trials embedded throughout the training, and interpretation bias was assessed following the training. RESULTS: Trait rumination moderated training effects on both measures. Low ruminators in the inhibition-training condition maintained their level of inhibition of negative stimuli, but those in the attention-training condition showed a non-significant trend for decreased inhibition. Participants also showed a transfer-congruent tendency in interpretation bias, with reduced bias by those trained to inhibit negative stimuli, compared to those trained to attend to negative stimuli. In contrast, high ruminators in the inhibition training condition showed a training incongruent decrease in inhibition of negative stimuli, but no change in inhibition when trained to attend to negative stimuli. No effects of the training on interpretation bias were observed among high ruminators. Finally, the training did not affect subsequent measures of mood or state rumination, even when trait rumination scores were taken into account. LIMITATIONS: This study used a single session of inhibition training rather than a multi-session training, and this may explain the null effects among high ruminators. CONCLUSIONS: Findings highlight the critical role that trait rumination plays in moderating the effect of inhibition training. Our results suggest that inhibition training may provide an effective technique to change inhibition bias and later interpretation bias. PMID- 25840468 TI - [Cerebral venous thrombosis after spinal anesthesia: case report]. AB - INTRODUCTION: Cerebral venous thrombosis (CVT) is a rare, but serious complication after spinal anesthesia. It is often related to the presence of predisposing factors, such as pregnancy, puerperium, oral contraceptive use, and malignancies. Headache is the most common symptom. We describe a case of a patient who underwent spinal anesthesia who had postoperative headache complicated with CVT. CASE REPORT: Male patient, 30 years old, ASA 1, who underwent uneventful arthroscopic knee surgery under spinal anesthesia. Forty eight hours after the procedure, the patient showed frontal, orthostatic headache that improved when positioned supine. Diagnosis of sinusitis was made in the general emergency room, and he received symptomatic medication. In subsequent days, the headache worsened with holocranial location and with little improvement in the supine position. The patient presented with left hemiplegia followed by tonic-clonic seizures. He underwent magnetic resonance venography; diagnosed with CVT. Analysis of procoagulant factors identified the presence of lupus anticoagulant antibody. The patient received anticonvulsants and anticoagulants and was discharged eight days without sequelae. DISCUSSION: Any patient presenting with postural headache after spinal anesthesia, which intensifies after a plateau, loses its orthostatic characteristic or become too long, should undergo imaging tests to rule out more serious complications, such as CVT. The loss of cerebrospinal fluid leads to dilation and venous stasis that, coupled with the traction caused by the upright position, can lead to TVC in some patients with prothrombotic conditions. PMID- 25840469 TI - Genetic and pathological characteristics of Cryptococcus gattii and Cryptococcus neoformans var. neoformans from meningoencephalitis in autochthonous goats and mouflons, Sardinia, Italy. AB - In this study, we examined in Sardinia the brain of 555 autochthonous sheep, 50 goats, and 4 mouflons which were found affected by neurological signs. We found 6 goats and one mouflon with meningoencephalitis caused by Cryptococcus sp. There was no evidence of cryptococcal infections in any of the examined sheep. MLST genotyping on Cryptococcus sp. isolates identified Cryptococcus gatti genotype AFLP4/VGI and Cryptococcus neoformans var. neoformans genotype AFLP2/VNIV. Phylogenetically, all Cryptococcus gattii isolates fell within the autochthonous animal, human and environmental Mediterranean isolate cluster, forming a distinct branch along with environmental strains from Alicante, in the southern Mediterranean coast of Spain. PMID- 25840470 TI - Genomic characterisation of the feline sarcoid-associated papillomavirus and proposed classification as Bos taurus papillomavirus type 14. AB - Feline sarcoids are rare mesenchymal neoplasms of domestic and exotic cats. Previous studies have consistently detected short DNA sequences from a papillomavirus (PV), designated feline sarcoid-associated papillomavirus (FeSarPV), in these neoplasms. The FeSarPV sequence has never been detected in any non-sarcoid sample from cats but has been amplified from the skin of cattle suggesting that feline sarcoids are caused by cross-species infection by a bovine papillomavirus (BPV). The aim of the present study was to determine the genome of the PV that contains the FeSarPV sequence. Using the circular nature of PV DNA, four specifically designed 'outward facing' primers were used to amplify two approximately 4,000 bp DNA segments from a feline sarcoid. The two PCR products were sequenced using next generation sequencing and the full genome of the PV, consisting 7,966 bp, was assembled and analysed. Phylogenetic analysis revealed the PV was closely related to the species 4 delta BPVs-1, -2, and -13, but distantly related to any carnivoran PV genus. These results are consistent with feline sarcoids being caused by a BPV type and we propose a classification of BPV 14 for this novel PV. Initial analysis suggests that, like other delta BPVs, the BPV-14 E5 protein could cause mesenchymal proliferation by binding to the platelet derived growth factor beta receptor. Interestingly BPV-14 has not been detected in any equine sarcoid suggesting that BPV-14 has a host range that is limited to bovids and felids. PMID- 25840471 TI - Mast cells promote malaria infection? AB - PURPOSE: Malaria remains the most deadly human parasitic disease, mostly because of the mosquito-born protozoan parasite Plasmodium falciparum with ~627,000 deaths reported in 2012. Unfortunately, there is resistance to most drugs, and successful vaccines are still not developed. The role of the immune system is critical but poorly understood. METHODS: One specific publication that reported a new way through which the immune system may promote malaria pathogenesis is discussed. FINDINGS: Kenyan children with mild and severe malaria had increased plasma levels of the Flt3 ligand, a soluble cytokine released from the surface of mast cells (MCs). A positive correlation was found between disease severity and frequencies of circulating BDCA3(+) dendritic cells. These human equivalents of the rodent CD8(+) T cells migrate to tissues with a heavy parasite load and cause damage primarily through cytolysis. IMPLICATIONS: Malaria parasites may promote malaria pathogenesis by triggering MCs, which expand a unique class of dendritic cells with the subsequent activation of pathogenic CD8(+) T cells. However, MCs may have additional regulatory functions. Selective inhibition of MC activation may serve as an adjuvant treatment. PMID- 25840472 TI - Ultrastructural study of spermatogenesis and sperm in the African medicinal leech Hirudo troctina Johnson, 1816 (Annelida, Hirudinida). AB - This paper presents the process of spermatogenesis in the leech Hirudo troctina Johnson, 1816 using light, fluorescent and transmission electron microscopy. At the onset of spermatogenesis in testes, the pear-shaped spermatogonia divide mitotically without full cytokinesis and as a result isogenic groups are formed (clusters, clones) with 2, 4, 8, 16, 32, 64, 128 spermatogonia and, finally, 256 primary spermatocytes occur. The final meiotic divisions of spermatocytes give rise to clones with 1024 spermatids. There are hundreds of developing germ-line clones in each testis. In each clone, the male germ cells divide in full synchrony and they are in the same phase of spermatogenesis. During complex spermiogenesis each spermatid becomes a filiform spermatozoon with a helicoid nucleus, which is characterized by the presence of a long acrosome with two regions - anterior and posterior, which are followed by a helicoid nucleus, a midpiece with only one mitochondrion and a long flagellum. Our results were compared to those on other clitellate annelids that have been studied to date, especially to sperm formation in Hirudo medicinalis Linnaeus, 1785. Only minor differences were found in the length and the diameter of different organelles and the number of spermatids in germ-line clones. PMID- 25840473 TI - The hidden biology of sponges and ctenophores. AB - Animal evolution is often presented as a march toward complexity, with different living animal groups each representing grades of organization that arose through the progressive acquisition of complex traits. There are now many reasons to reject this classical hypothesis. Not only is it incompatible with recent phylogenetic analyses, but it is also an artifact of 'hidden biology', that is, blind spots to complex traits in non-model species. A new hypothesis of animal evolution, where many complex traits have been repeatedly gained and lost, is emerging. As we discuss here, key details of this new model hinge on a better understanding of the Porifera and Ctenophora, which have each been hypothesized to be sister to all other animals, but are poorly studied and often misrepresented. PMID- 25840475 TI - Spin resolved bandstructure imaging with a high resolution momentum microscope. AB - We present a spin resolving "momentum microscope" for the high resolution imaging of the momentum distribution of photoelectrons. Measurements of the band structure of a Au(111) single crystal surface demonstrate an energy resolution of DeltaE=12 meV and a momentum resolution of Deltak?=0.0049 A(-1), measured at the line-width of the spin-orbit split Shockley surface state. The relative accuracy of the k? measurement in the order of 10(-4) A(-1) reveals a deviation from the ideal two-dimensional free electron gas model of the Shockley surface state, manifested in a threefold radial symmetry. Spin resolution in the full momentum image is obtained by an imaging spin-filter based on low-energy electron diffraction at a Au passivated Ir(100) single crystal. Using working points at 10.5 eV and 11.5 eV scattering energy with a completely reversed asymmetry of +/ 60% we demonstrate the efficient mapping of the spin texture of the Au(111) surface state. PMID- 25840474 TI - Magnetic resonance imaging-measured bone marrow adipose tissue area is inversely related to cortical bone area in children and adolescents aged 5-18 years. AB - Previous studies have shown an inverse correlation between bone marrow adipose tissue and bone mineral density in cancellous bone; however, such relationships in cortical bone are less studied, especially in children. A total of 185 healthy children and adolescents (76 females and 109 males, aged 5-18 years) were included in this study. Right femoral bone marrow adipose tissue area (BMA), right femoral cortical bone area (CBA), subcutaneous adipose tissue, visceral adipose tissue, and skeletal muscle were accessed by whole-body magnetic resonance imaging. In regression analysis with CBA as the dependent variable and BMA as the independent variable, BMA negatively contributed to CBA after adjusting for weight and total body fat or subcutaneous adipose tissue, visceral adipose tissue, and skeletal muscle (beta = -0.201 to -0.272, p < 0.001). These results suggest an inverse relationship between BMA and CBA in children and adolescents after adjustment of body weight or body composition. The data support the hypothesis that a competitive relationship exists between bone and marrow fat in cortical bone and is consistent with a similar finding in cancellous bone in previous studies. Future research is needed to clarify the role of marrow fat in childhood fractures that are related to cortical bone quality. PMID- 25840476 TI - Differentiation of Breast Lesions by Use of HyperSPACE: Hyper-Spectral Analysis for Characterization in Echography. AB - Early diagnosis represents the cornerstone in breast cancer control. Ultrasound is still a valid tool because of its low invasiveness, reduced costs and reduced risk of harm, but better exploitation of its potential is necessary to extract information on tissue features. The proposed method, HyperSPACE (hyper-spectral analysis for characterization in echography), which processes the ultrasonic radiofrequency signal in an N-dimension spectral hyperspace to define several characteristic parameters of the tissue under investigation, was used with the aim of differentiating two types of breast lesion: infiltrating ductal carcinoma and fibroadenoma. The analyzed data set consisted of 2000 radiofrequency frames related to 200 sections of pathologic breast nodules: 104 infiltrating ductal carcinomas and 96 fibroadenomas. The algorithm was trained on single radiofrequency frames related to 50 sections (26 carcinomas, 24 fibroadenomas) to recognize the two pathologies considered, and all the radiofrequency frames related to the other 150 sections were classified, yielding a sensitivity of 92.2%, specificity of 93%, positive predictive value of 93.2% and negative predictive value of 91%. The results were compared with those of RULES (radiofrequency ultrasonic local estimators), a processing method set developed by our group and used by other researchers in clinical and laboratory environments. PMID- 25840477 TI - Comparing Carotid and Brachial Artery Stiffness: A First Step Toward Mechanical Mapping of the Arterial Tree. AB - Arterial stiffness is a predictor of cardiovascular mortality. It increases with age and is accelerated by hypertension and other cardiovascular risk factors. In addition to the disease state, arterial stiffness increases from the proximal to the distal arterial compartments. Concurrent assessment of various vessels from the same subjects is unavailable in the literature. The aim of this work was to quantify an intrinsic mechanical feature, namely, wall stiffness, of the common carotid artery (CCA) and brachial artery (BA). CCAs and BAs of healthy adolescents were investigated. Cine loops of CCA and BA B-mode data were digitally recorded at the same clinical examination, and arterial elastic moduli were estimated off-line with our proprietary non-invasive Imaging-based BioMarker (ImBioMark) algorithm. The 11 study subjects were 14.4 +/- 1.2 years old, with normal body habitus and blood pressures 112.3 +/- 10.6/63.6 +/- 5.7 mm Hg. BAs had a higher elastic modulus than CCAs (arterial elastic moduli: 129.73 +/- 25.67 kPa vs. 49.55 +/- 14.75 kPa, p < 0.001). There was a positive correlation between the BA and CCA (slope = 0.36, intercept = 111.62 kPa, R(2) = 0.045). This article documents, for the first time, a correlation between the CCA and BA of the same subject, under the same conditions. We previously reported preliminary data for the aorta and documented the effect of aging on the CCA; we now intend to study the femoral artery as well and include age stratification to pursue our investigations. The results reported here can be seen as the first step toward mechanical mapping of the arterial tree. PMID- 25840478 TI - Utility and cost analysis of radiographs taken 2 weeks following plate fixation of distal radius fractures. AB - PURPOSE: To evaluate the utility of radiographs taken 2 weeks following plate fixation of distal radius fractures. METHODS: A retrospective review of patients requiring operative fixation of distal radius fractures was performed with the objective of determining the utility of a 2-week postoperative radiograph in patient management. RESULTS: Three out of 268 (1%) patients had loss of fixation noted radiographically at the 2-week visit that resulted in a reoperation. There was no statistically significant difference in radial inclination, radial height, or volar tilt measured at 2 weeks, 6 weeks, or final follow-up. The average cost of a series of wrist radiographs was $85 with no additional radiology reading fees. CONCLUSIONS: Routine 2-week postoperative radiographs of operatively treated distal radius fractures rarely resulted in a change in patient management; however, they may have added unnecessary cost to the patient and health care system. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analysis IV. PMID- 25840479 TI - Two versus 3 lag screws for fixation of long oblique proximal phalanx fractures of the fingers: a cadaver study. AB - PURPOSE: To compare 2- versus 3-screw fixation for oblique fractures of the proximal phalanx in a cadaver model that simulates active finger motion. METHODS: We experimentally cut the proximal phalanges of the index, middle, and ring fingers of 9 cadaveric hands. Five fingers were assigned to a control group with no fixation, and 22 were fixed with either 2 or 3 lag screws. One digit was excluded because of iatrogenic fracture during preparation. The fingers were fitted with a differential variable reluctance transducer that measured maximum interfragment displacement while the fingers were subjected to 2,000 full flexion and extension cycles to simulate a 6-week active motion protocol. RESULTS: Analysis of variance revealed a significant difference between the control group and both the 2- and the 3-screw group. The 2- and 3-screw group average displacements were not significantly different. Both of these groups were equivalent with a power of 90%. CONCLUSIONS: Biomechanical stability during simulated active motion protocol did not differ in simulated proximal phalanx fractures treated with 2 lag screws or 3. CLINICAL RELEVANCE: Fracture fixation using 2 screws may be more cost and time effective and, therefore, more attractive to the surgeon, even when 3 screws can be placed. Furthermore, surgeons may consider using 2 screws rather than resorting to plate fixation when 3-screw fixation is not possible for these types of fractures. PMID- 25840480 TI - Randomized comparison of volar locking plates and intramedullary nails for unstable distal radius fractures. AB - PURPOSE: To compare minimally invasive intramedullary nails (IMN) and volar locking plates (VLP) for the treatment of unstable distal radius fractures by evaluating postoperative subjective, radiographic, and functional outcomes. The hypothesis was that IMN patients would have less pain and required less pain medication in the early postoperative period and returned to work earlier than VLP patients. METHODS: Sixty patients with closed, displaced, unstable, extra articular, metaphyseal fractures of the distal radius were randomized to receive a VLP or an IMN for internal fixation. Functional outcomes (Quick Disabilities of the Arm, Shoulder, and Hand, Michigan Hand Questionnaire), radiographic measurements (ulnar variance, radial height, inclination, and volar tilt), and range of motion were assessed until final follow-up at 2 years after surgery. Narcotic pain medication use was documented for 5 weeks following surgery. RESULTS: There were 2 groups of 30 patients with IMN (mean age, 55 +/- 14 y) or VLP (mean age, 55 +/- 16 y) with similar demographics and comorbidities. Patients with IMN regained extension earlier but had similar range of motion to patients with VLP at final follow-up. There was similar improvement in Michigan Hand Questionnaire, Quick Disabilities of the Arm, Shoulder, and Hand, and strength between groups. Five weeks after surgery, fewer IMN patients required narcotic pain medication (13%) than VLP patients (33%). Radiographic outcomes were similar at final follow-up. There were 3 failures with IMN versus 1 failure with VLP. All 10 employed patients with IMN returned to previous work compared with 10 of the 12 employed patients with VLP. Time to return to work was similar for both groups. CONCLUSIONS: In a cohort of similar patients, IMN and VLP provided comparable improvement in functional and radiographic outcomes. Patients with IMN required less narcotic pain medication after surgery than VLP patients. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 25840481 TI - The Nevada Rural Ozone Initiative (NVROI): Insights to understanding air pollution in complex terrain. AB - The Nevada Rural Ozone Initiative (NVROI) was established to better understand O3 concentrations in the Western United States (US). The major working hypothesis for development of the sampling network was that the sources of O3 to Nevada are regional and global. Within the framework of this overarching hypothesis, we specifically address two conceptual meteorological hypotheses: (1) The high elevation, complex terrain, and deep convective mixing that characterize Nevada, make this state ideally located to intercept polluted parcels of air transported into the US from the free troposphere; and (2) site specific terrain features will influence O3 concentrations observed at surface sites. Here, the impact of complex terrain and site location on observations are discussed. Data collected in Nevada at 6 sites (1385 to 2082 m above sea level (asl)) are compared with that collected at high elevation sites in Yosemite National Park and the White Mountains, California. Average daily maximum 1-hour concentrations of O3 during the first year of the NVROI ranged from 58 to 69 ppbv (spring), 53 to 62 ppbv (summer), 44 to 49 ppbv (fall), and 37 to 45 ppbv (winter). These were similar to those measured at 3 sites in Yosemite National Park (2022 to 3031 m asl), and at 4 sites in the White Mountains (1237 to 4342 m asl) (58 to 67 ppbv (summer) and 47 to 58 ppbv (fall)). Results show, that in complex terrain, collection of data should occur at high and low elevation sites to capture surface impacts, and site location with respect to topography should be considered. Additionally, concentrations measured are above the threshold reported for causing a reduction in growth and visible injury for plants (40 ppbv), and sustained exposure at high elevation locations in the Western USA may be detrimental for ecosystems. PMID- 25840482 TI - Quantifying faecal indicator organism hydrological transfer pathways and phases in agricultural catchments. AB - Faecal indicator organisms (FIOs) can impact on water quality and pose a health and environmental risk. The transfer of FIOs, such as Escherichia coli (E. coli), from land to water is driven by hydrological connectivity and may follow the same flowpaths as nutrients, from agricultural and human sources. This study investigated E. coli transfer in two catchment areas with high source and transport pressures. These pressures were: organic phosphorus (P) loading; human settlement; conduits and fissures in a grassland karst area; and clay rich and impermeable soils in a mixed arable area. The occurrence of E. coli and its transport pathways, along with the pathways of nutrients, were studied using a combination of targeted FIO sampling, during different hydrological phases and events, and high resolution nutrient analysis. The quick flow component in both catchments was found to be a more potent vector for E. coli, and was coincident with the total P flowpaths using a P Loadograph Recession Analysis (LRA). The karst grassland catchment was found to be a transport limited system and the mixed arable catchment a source limited system. Hence, despite the grassland catchment being a potentially higher FIO source, the E. coli loads leaving the catchment were low compared to the mixed arable catchment. E. coli load whole event comparisons also indicated that the grassland karst transfers tended to be much lower on falling phases of runoff, while the arable catchment, over greywacke and mudstone geology, showed little change between the phases. Furthermore, the arable catchment showed asymptotic decline of sustained E. coli loads towards low flows, which may be indicative of chronic point sources. These results indicate the dominance of transport mechanisms over source mechanisms for mass E. coli loads and also chronic loads during low flow. These will be important considerations for risk assessment and mitigation. PMID- 25840483 TI - Association of longitudinal fractional exhaled nitric oxide measurements with asthma control in atopic children. AB - OBJECTIVES: We sought to determine whether longitudinal measurements of FeNO are informative for future loss of asthma control in children with atopic asthma. METHODS: One hundred seventy-eight patients aged 8-16 years with atopic asthma were enrolled. FeNO and lung functions were serially monitored 10 times or more over 2 years when subjects were not receiving controller medications. After completion of monitoring, 1-year observation on the occurrence of loss of asthma control was performed and associations of loss of asthma control with spirometric and FeNO measurements were analyzed. RESULTS: Loss of asthma control occurred during observation periods in 110 (76%) of 145 patients who completed the study. Of all monitored parameters including airway reactivity, the highest FeNO of serial measurements (H-FeNO) (adjusted odds ratio (aOR), 1.21; 95% CI, 1.08-1.36) and the rate of FeNO levels higher than 21 ppb (R21FeNO) (aOR, 1.06; 95% CI, 1.01 1.11) were the only independent predictors of upcoming control loss in the multiple logistic regression analysis. In receiver-operator characteristic curve analysis, H-FeNO > 37 ppb and R21FeNO > 20% demonstrated 91% and 88% sensitivity for a future loss of asthma control at the cost of low specificity (60% and 65%, respectively). In contrast, H-FeNO > 47 ppb and R21FeNO > 41% gave 96% and 88% specificity, but these sacrificed sensitivity to 70% and 72%, respectively. CONCLUSIONS: Our data show that both amount and frequency of a FeNO increase during longitudinal monitoring are helpful in predicting asthma control status. PMID- 25840484 TI - Low interleukin (IL)-18 levels in sputum supernatants of patients with severe refractory asthma. AB - BACKGROUND: Severe refractory asthma (SRA) is characterized by persistent asthma symptoms, amplified airway inflammation despite treatment with high dose inhaled steroids and increased airway bacterial colonization. Interleukin (IL)-18 is a pleiotropic pro-inflammatory cytokine that modulates airway inflammation. Furthermore, as a product of the inflammasome, IL-18 is involved in host defence against viral and bacterial stimuli by modulating the immune response. OBJECTIVE: To determine IL-18 levels in sputum supernatants of patients with asthma and to investigate whether underlying severity affects its levels. Furthermore, possible associations with atopy and mediators and cells involved in the inflammatory process of the airways were examined. METHODS: Forty-five patients with mild intermittent asthma (21 smokers) and 18 patients with SRA in stable state were studied. All subjects underwent lung function tests, skin prick tests, and sputum induction for cell count identification. IL-18 and ECP levels were measured in sputum supernatants. Furthermore, sputum samples were examined for the commonest respiratory pathogens and viruses by real time polymerase chain reaction (RT PCR). RESULTS: Patients with SRA had significantly lower IL-18 levels in sputum supernatants compared to mild asthmatics (p < 0.001). Twelve out of eighteen patients with SRA were colonized by viruses and/or bacterial pathogens. IL-18 levels correlated with the percentage of macrophages (r = 0.635, p = 0.026) and inversely correlated with the percentage of neutrophils in sputum (r = -0.715, p = 0.009). No correlations were found between IL-18, ECP and the percentage of eosinophils in the sputum of SRA. CONCLUSIONS: In SRA IL-18 is possibly involved in chronic airway inflammation through an eosinophil independent pathway. The decreased levels of IL-18 in SRA support the hypothesis of deregulated inflammasome activation, justifying the susceptibility of these patients for bacterial colonization or infection. PMID- 25840485 TI - The relationship between trauma center volume and in-hospital outcomes. AB - BACKGROUND: Increases in hospital volume are positively associated with improved surgical outcomes. However, in the trauma setting, studies have reported conflicting findings in regard to volume's effect on in-hospital mortality. This study investigates whether complications, failure-to-rescue (FTR), and mortality are influenced by trauma centers' average annual volume. METHODS: We performed a retrospective cohort study that analyzed patient records included in the National Trauma Data Bank from years 2008-2010. We calculated risk-adjusted complication, FTR, and mortality rates for centers treating different volumes of patients. We also performed multilevel logistic regression modeling to examine the probability that patients treated at trauma centers with higher annual volumes would experience complication, FTR, and mortality while controlling for injury severity, type of injury, mechanism of trauma, age, gender, race, number of comorbidities, head injury, hypotension, and hospital clustering. Hospital characteristics including designation level, academic status, nonprofit status, safety-net status, and region were incorporated into the model. RESULTS: Risk adjusted complication, FTR, and mortality rates differed significantly across hospital volume quintiles. Regression analyses indicated that higher hospital volumes were significantly associated with a decreased likelihood of mortality for individual patient but not for complication or FTR. CONCLUSIONS: Our findings suggest that higher trauma center volume is associated with improved mortality outcomes. However, the relationship between volume and FTR is more complex. Future research should address the question of determining optimal volume levels that lead to high provider experience, efficient resource usage, and low unintended consequences or outcomes. PMID- 25840486 TI - Evaluation and comparison of the effect of hypothermia and ozone on ischemia reperfusion injury of skeletal muscle in rats. AB - BACKGROUND: Tourniquet-induced ischemia-reperfusion, which affects local and distant organs, is very common in orthopedic surgery. Hypothermia is used in traumatic tissue during ischemic period commonly. Ozone (O3) has been recommended as a novel therapeutic agent in various medical conditions. The objective of the study was to evaluate and compare the effect of hypothermia (H) and O3 on ischemia-reperfusion injury of skeletal muscle in rats by measuring oxidative parameters and inducible nitric oxide synthase (iNOS) levels. MATERIALS AND METHODS: Eighteen rats (Wistar albino) were separated into five groups randomly (sham, IR, IR + H, IR + O3, IR + H + O3; n = 6). The lower right extremity of all rats was subjected to 2 h of ischemia and 22 h of reperfusion clamping the common iliac artery and using the rubber-band technique at the level of the lesser trochanter under general anesthesia. Two hours of hypothermia were applied during the first 2 h of reperfusion in two groups. O3 was applied in two groups. All rats were sacrificed after the IR period with high dose of anesthesia. The tibialis anterior muscle and blood were saved. Levels of superoxide dismutase, glutathione peroxidase, MDA, NOx, and interleukin-1beta were measured in the muscle. Creatinine kinase, lactate dehydrogenase, aspartate aminotransferase, urea, creatinine, and electrolytes were measured in serum. Immunohistochemical iNOS staining was performed on muscle samples. RESULTS: The levels of MDA, NOx, and interleukin-1beta in muscle were raised in the IR group compared with those in the sham group. The same parameters were lower in the groups of IR + H, IR + O3, and IR + H + O3 compared with those in the IR group. Superoxide dismutase and glutathione peroxidase activities in muscle were lower in the IR group compared with those in the sham group; however, same parameters were higher in the groups of IR + H, IR + O3, and IR + H + O3 compared with those in the IR group. Score and intensity of iNOS staining in skeletal muscle in the IR group was increased compared with that in the sham group and decreased in the groups of IR + H, IR + O3, and IR + H + O3 compared with that in the IR group. Levels of creatinine kinase, aspartate aminotransferase, and K in the three treatment groups decreased compared with those in the IR group. CONCLUSIONS: These findings showed that hypothermia, which has more affect, and O3 decreased the tourniquet-induced IR injury in the rat's muscle-skeletal system by reducing the levels of oxidative and nitrosative stress parameters and enhancing antioxidant enzymes. Hypothermia and O3 had no synergistic effect. Hypothermic reperfusion and O3 preconditioning might be beneficial in skeletal muscle IR injury-associated tourniquet. PMID- 25840487 TI - Comparing surgical infections in National Surgical Quality Improvement Project and an Institutional Database. AB - BACKGROUND: Surgical quality improvement requires accurate tracking and benchmarking of postoperative adverse events. We track surgical site infections (SSIs) with two systems; our in-house surgical secondary events (SSE) database and the National Surgical Quality Improvement Project (NSQIP). The SSE database, a modification of the Clavien-Dindo classification, categorizes SSIs by their anatomic site, whereas NSQIP categorizes by their level. Our aim was to directly compare these different definitions. MATERIALS AND METHODS: NSQIP and the SSE database entries for all surgeries performed in 2011 and 2012 were compared. To match NSQIP definitions, and while blinded to NSQIP results, entries in the SSE database were categorized as either incisional (superficial or deep) or organ space infections. These categorizations were compared with NSQIP records; agreement was assessed with Cohen kappa. RESULTS: The 5028 patients in our cohort had a 6.5% SSI in the SSE database and a 4% rate in NSQIP, with an overall agreement of 95% (kappa = 0.48, P < 0.0001). The rates of categorized infections were similarly well matched; incisional rates of 4.1% and 2.7% for the SSE database and NSQIP and organ space rates of 2.6% and 1.5%. Overall agreements were 96% (kappa = 0.36, P < 0.0001) and 98% (kappa = 0.55, P < 0.0001), respectively. Over 80% of cases recorded by the SSE database but not NSQIP did not meet NSQIP criteria. CONCLUSIONS: The SSE database is an accurate, real-time record of postoperative SSIs. Institutional databases that capture all surgical cases can be used in conjunction with NSQIP with excellent concordance. PMID- 25840488 TI - Design of vessel ligation simulator for deliberate practice. AB - BACKGROUND: Surgical residents develop technical skills at variable rates, often based on random chance of cases encountered. One such skill is tying secure knots without exerting excessive force. This study describes the design of a simulator using a force sensor to measure instantaneous forces exerted on a blood vessel analog during vessel ligation and the development of expert-derived performance goals. MATERIALS AND METHODS: Vessel ligations were performed on Silastic tubing at an offset from a Vernier Force Sensor. Nine experts (surgical faculty and senior residents) and 10 novices (junior residents) were recruited to each perform 10 vessel ligations (two square knots each) with two-handed and one handed techniques. Internal consistency for the series of vessel ligations was tested with Cronbach alpha. Maximum forces exerted by novices and experts were compared using Student t-test. RESULTS: Internal consistency across the 10 ligations on the simulator was excellent (Cronbach alpha = 0.91). The expert group on average exerted a significantly lower maximum force when compared with novices while performing two-handed (0.76 +/- 0.39 N versus 1.12 +/- 0.49 N, P < 0.01) and one-handed (0.84 +/- 0.32 N versus 1.36 +/- 0.44 N, P < 0.01) vessel ligations. CONCLUSIONS: Although the expert group performed vessel ligations with significantly lower peak force than the novice group, there were novices who performed at the expert level. This is consistent with the conceptual framework of milestones and suggests that the skill of gentle knot-tying can be measured and develops at different chronologic levels of training in different individuals. This simulator can be used as part of a deliberate practice curriculum with instantaneous visual feedback. PMID- 25840489 TI - Intestinal alkaline phosphatase to treat necrotizing enterocolitis. AB - BACKGROUND: Intestinal alkaline phosphatase (IAP) activity is decreased in necrotizing enterocolitis (NEC), and IAP supplementation prevents NEC development. It is not known if IAP given after NEC onset can reverse the course of the disease. We hypothesized that enteral IAP given after NEC induction would not reverse intestinal injury. MATERIALS AND METHODS: NEC was induced in Sprague Dawley pups by delivery preterm followed by formula feedings with lipopolysaccharide (LPS) and hypoxia exposure and continued up to 4 d. IAP was added to feeds on day 2 until being sacrificed on day 4. NEC severity was scored based on hematoxylin and eosin-stained terminal ileum sections, and AP activity was measured using a colorimetric assay. IAP and interleukin-6 expression were measured using real time polymerase chain reaction. RESULTS: NEC pups' alkaline phosphatase (AP) activity was decreased to 0.18 U/mg compared with controls of 0.57 U/mg (P < 0.01). Discontinuation of LPS and hypoxia after 2 d increased AP activity to 0.36 U/mg (P < 0.01). IAP supplementation in matched groups did not impact total AP activity or expression. Discontinuing LPS and hypoxia after NEC onset improved intestinal injury scores to 1.14 compared with continued stressors, score 2.25 (P < 0.01). IAP supplementation decreased interleukin-6 expression two-fold (P < 0.05), though did not reverse NEC intestinal damage (P = 0.5). CONCLUSIONS: This is the first work to demonstrate that removing the source of NEC improves intestinal damage and increases AP activity. When used as a rescue treatment, IAP decreased intestinal inflammation though did not impact injury making it likely that IAP is best used preventatively to those neonates at risk. PMID- 25840490 TI - Targeted approaches to childhood cancer: progress in drug discovery and development. AB - INTRODUCTION: Cancer is a leading cause of death in childhood. Encouraging progress has been made in the treatment of childhood malignancies, but there is an unmet need for new drugs to improve survival and reduce treatment-associated toxicities. Drug development in paediatric oncology has specific requirements with regard to the patient population and the regulatory background and presents several unique challenges that need addressing. AREAS COVERED: This review discusses the current framework of paediatric oncology drug development and some of the specific challenges in pre-clinical and clinical research. The authors discuss the recent developments in the targeting of various signalling pathways. These pathways represent a selection of targets that have been identified by pre clinical and clinical investigators to be highly relevant in paediatric malignancies. EXPERT OPINION: The development of targeted agents in paediatric oncology must be driven by knowledge of tumour biology. Predictive and pharmacodynamic biomarkers should be incorporated within paediatric early clinical trials wherever possible. Faster dose-escalation, limited numbers of cohorts and novel adaptive designs can help to make paediatric early clinical trials more efficient. Close collaboration between academic/clinical researchers, the pharmaceutical industry, regulatory bodies and parent groups are crucial in overcoming the challenges associated with paediatric oncology drug development. PMID- 25840491 TI - Flexor tendon injuries in children: Rehabilitative options and confounding factors. AB - Research pertaining to the rehabilitation of children with flexor tendon injuries is less prevalent than that in the adult population, and most authors agree that immobilization protocols comprise a safe and efficacious choice. This article presents suggested protocols and correlated literature regarding the outcomes of immobilization, early passive motion, and early active motion in the pediatric population. Confounding factors which influence rehabilitative choices, both personal and environmental, are also presented. PMID- 25840492 TI - Upper extremity function: What's posture got to do with it? AB - This perspective paper reviews the linkage between developing postural control and upper extremity function. We suggest updated principles for guiding clinical practice, based on current views from motor learning, motor development, and motor control research. Using three clinical examples, we illustrate principles focusing on the use of variability, the importance of errors in learning movement, task specific exploration and practice, and the critical timing necessary to build skill of the upper extremity in a variety of postures. These principles differ from historic approaches in therapeutic exercise, which treated posture as a separate system and a precursor for extremity skill building. We maintain that current movement science supports the tight interaction of posture and upper extremity function through developmental time and in real time, such that one system cannot be considered separate from the other. Specific suggestions for clinical practice flow from the guiding principles outlined in this paper. PMID- 25840494 TI - Common medial elbow injuries in the adolescent athlete. AB - Recently there has been increased year-round sports participation among children and adolescents with limited to no rest periods. This has led to increases in pediatric repetitive stress injuries, once considered a rarity. Whether in the throwing athlete or in the athlete that experiences repetitive axial loading; increased medial tension and overload syndromes can lead to stress reactions and fractures. This occurs in the developing athlete due to the bone being weaker than the surrounding tendons and ligaments. The medial elbow is a high stress area and is susceptible to many conditions including apophysitis , avulsion fractures and ulnar collateral ligament disruption. Valgus stress can cause injury to the medial elbow which can lead to increased lateral compression, Panner's disease and osteochondral lesions of the capitellum and olecranon. The purpose of this manuscript is to review common elbow disorders in the adolescent population, outline management and highlight important features of rehabilitation. PMID- 25840493 TI - Clinical assessment of the infant and child following perinatal brachial plexus injury. AB - STUDY DESIGN: Literature review. INTRODUCTION: After perinatal brachial plexus injury (PBPI), clinicians play an important role in injury classification as well as the assessment of recovery and secondary conditions. Early assessment guides the initial plan of care and influences follow-up and long-term outcome. PURPOSE: To review methods used to assess, classify and monitor the extent and influence of PBPI with an emphasis on guidelines for clinicians. METHODS: We use The International Classification of Functioning, Disability, and Health (ICF) model to provide a guide to assessment after PBPI for rehabilitation clinicians. DISCUSSION: With information gained from targeted assessments, clinicians can design interventions to increase the opportunities infants and children have for optimal recovery and to attain skills that allow participation in areas of interest. PMID- 25840495 TI - NOD1 and NOD2 control the invasiveness of trophoblast cells via the MAPK/p38 signaling pathway in human first-trimester pregnancy. AB - INTRODUCTION: Nucleotide binding and oligomerization leucine-rich repeats (NLR) are recognized as members of pattern-recognition receptors that play important roles in host innate immune defenses. In this study, we have investigated the expression and regulation of nucleotide-binding oligomerization domains 1 and 2 (NOD1 and NOD2) on the invasiveness of primary human trophoblasts during the first trimester of pregnancy. METHODS: The expression of NOD1 and NOD2 by human first rimester villi from recurrent spontaneous abortion (RSA) patients and normal pregnancy was analyzed by immunochemistry, western blot and real-time RT PCR, respectively. The effects of ligands on the regulation of their receptors and invasiveness of trophoblasts were examined. The ELISA was used to measure the secretion of matrix matallopeptidase-9 (MMP9) and matrix matallopeptidase-2 (MMP2) by trophoblasts. We also investigated the signaling pathways involved in invasion of trophoblasts. RESULTS: The higher NOD1 and NOD2 were observed in villi from patients who experienced RSA compared with those who experienced a normal pregnancy. The ligands can up-regulate the expression of their receptors. After activation, NOD1 and NOD2 inhibited the invasion of trophoblast cells by decreasing MMP9 but not MMP2. After the activation of NOD1 and NOD2, the mitogen activated protein kinase (MAPK)/p38 pathway was activated time dependently. Blocking this pathway with a specific inhibitor (SB203580) attenuated NOD1-and NOD2-regulated trophoblast invasions. DISCUSSION: These results suggest that abnormal elevated NOD1 and NOD2 expression in villi relate to pregnancy outcomes. Further, activation of NOD1 and NOD2 could have a bearing on our understanding of the invasive ability of trophoblasts. PMID- 25840496 TI - [Is smoking a chronic disease? No]. PMID- 25840497 TI - Different postprandial lipid metabolism and insulin resistance between non diabetic patients with and without coronary artery disease. AB - BACKGROUND: Postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis. Diabetes mellitus (DM) has an impact on lipid metabolism, however, little is known about the relationship between the postprandial lipid and glucose metabolism in normoglycemic patients with coronary artery disease (CAD). METHODS: To compare the postprandial lipid and glucose metabolism in normoglycemic patients with and without CAD, a total of 36 normoglycemic patients: 19 patients with stable CAD (CAD group, age 60.2+/-11.3 years) and 17 patients without CAD (Non-CAD group, age 60.4+/-9.6 years) were loaded with a high-fat and high-glucose test meal, and the changes in serum level of the lipid and glucose parameters were monitored before and 0, 2, 4, and 6h later. RESULTS: In the Non-CAD group, postprandial serum levels of triglycerides (TG) and remnant-like particle cholesterol increased significantly and reached peak levels at the 4th hour and decreased significantly at the 6th hour of observation, whereas those levels in CAD group kept rising during 6h of observation. Although there was no significant difference in the area under the curves (AUCs) for the postprandial plasma glucose levels between CAD and Non-CAD group, the AUCs for the postprandial plasma insulin and C-peptide levels were significantly higher in the CAD group than in the Non-CAD group. The AUCs for postprandial TG levels showed good correlation with those for postprandial plasma insulin and C-peptide levels (insulin: r=0.455, p<0.005; C-peptide: r=0.462, p<0.05). CONCLUSIONS: These findings suggest that postprandial hyperlipidemia and hyperinsulinemia may have a close relationship in CAD patients without DM and might play an important role in the development of atherosclerosis even before the onset of diabetes. PMID- 25840498 TI - Contemplating the etiology of chronic urticaria and the implications of current guidelines. PMID- 25840499 TI - Factors associated with high short-acting beta2-agonist use in urban children with asthma. AB - BACKGROUND: One goal of guideline-based asthma therapy is minimal use of short acting beta2 agonist (SABA) medications. Inner-city children with asthma are known to have high SABA use. OBJECTIVE: To examine factors associated with high SABA use in inner-city children with asthma. METHODS: One hundred inner-city children with persistent asthma were enrolled into a randomized controlled trial of an emergency department (ED) and home intervention. All children underwent serologic allergen specific IgE and salivary cotinine testing at the ED enrollment visit. Pharmacy records for the past 12 months were obtained. Number of SABA fills during the past 12 months was categorized into low- to moderate- vs high-use groups. SABA groups were compared by the number of symptom days and nights, allergen sensitization, and exposures. Regression models were used to predict high SABA use. RESULTS: Mean number of SABA fills over 12 months was 3.12. Unadjusted bivariate analysis showed that high SABA users were more than 5 times more likely to have an asthma hospitalization, almost 3 times more likely to have an asthma intensive care unit admission, and more than 3 times more likely to have prior specialty asthma care or positive cockroach sensitization than low to moderate SABA users. In the final regression model, for every additional inhaled corticosteroid fill, a child was 1.4 times more likely and a child with positive cockroach sensitization was almost 7 times more likely to have high SABA use when controlling for prior intensive care unit admission, receipt of specialty care, child age, and income. CONCLUSION: Providers should closely monitor SABA and controller medication use, allergen sensitization, and exposures in children with persistent asthma. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT01981564. PMID- 25840500 TI - The role of arbuscular mycorrhizas in reducing soil nutrient loss. AB - Substantial amounts of nutrients are lost from soils via leaching and as gaseous emissions. These losses can be environmentally damaging and expensive in terms of lost agricultural production. Plants have evolved many traits to optimize nutrient acquisition, including the formation of arbuscular mycorrhizas (AM), associations of plant roots with fungi that acquire soil nutrients. There is emerging evidence that AM have the ability to reduce nutrient loss from soils by enlarging the nutrient interception zone and preventing nutrient loss after rain induced leaching events. Until recently, this important ecosystem service of AM had been largely overlooked. Here we review the role of AM in reducing nutrient loss and conclude that this role cannot be ignored if we are to increase global food production in an environmentally sustainable manner. PMID- 25840501 TI - Cost analysis of in-home telerehabilitation for post-knee arthroplasty. AB - BACKGROUND: Rehabilitation provided through home visits is part of the continuum of care after discharge from hospital following total knee arthroplasty (TKA). As demands for rehabilitation at home are growing and becoming more difficult to meet, in-home telerehabilitation has been proposed as an alternate service delivery method. However, there is a need for robust data concerning both the effectiveness and the cost of dispensing in-home telerehabilitation. OBJECTIVE: The objective of this study was to document, analyze, and compare real costs of two service delivery methods: in-home telerehabilitation and conventional home visits. METHODS: The economic analysis was conducted as part of a multicenter randomized controlled trial (RCT) on telerehabilitation for TKA, and involved data from 197 patients, post-TKA. Twice a week for 8 weeks, participants received supervised physiotherapy via two delivery methods, depending on their study group allocation: in-home telerehabilitation (TELE) and home-visit rehabilitation (VISIT). Patients were recruited from eight hospitals in the province of Quebec, Canada. The TELE group intervention was delivered by videoconferencing over high speed Internet. The VISIT group received the same intervention at home. Costs related to the delivery of the two services (TELE and VISIT) were calculated. Student's t tests were used to compare costs per treatment between the two groups. To take distance into account, the two treatment groups were compared within distance strata using two-way analyses of variance (ANOVAs). RESULTS: The mean cost of a single session was Can $93.08 for the VISIT group (SD $35.70) and $80.99 for the TELE group (SD $26.60). When comparing both groups, real total cost analysis showed a cost differential in favor of the TELE group (TELE minus VISIT: -$263, 95% CI -$382 to -$143). However, when the patient's home was located less than 30 km round-trip from the health care center, the difference in costs between TELE and VISIT treatments was not significant (P=.25, .26, and .11 for the <10, 10-19, and 20-29 km strata, respectively). The cost of TELE treatments was lower than VISIT treatments when the distance was 30 km or more (30-49 km: $81<$103, P=.002; >=50 km: $90<$152, P<.001). CONCLUSIONS: To our knowledge, this is the first study of the actual costs of in-home telerehabilitation covering all subcosts of telerehabilitation and distance between the health care center and the patient's home. The cost for a single session of in-home telerehabilitation compared to conventional home-visit rehabilitation was lower or about the same, depending on the distance between the patient's home and health care center. Under the controlled conditions of an RCT, a favorable cost differential was observed when the patient was more than 30 km from the provider. Stakeholders and program planners can use these data to guide decisions regarding introducing telerehabilitation as a new service in their clinic. TRIAL REGISTRATION: International Standard Registered Clinical Study Number (ISRCTN): 66285945; http://www.isrctn.com/ISRCTN66285945 (Archived by WebCite at http://www.webcitation.org/6WlT2nuX4). PMID- 25840502 TI - A new technique of totally laparoscopic resection with natural orifice specimen extraction (NOSE) for large rectal adenoma. AB - There is no consensus about the best technique to use for the surgical treatment for large rectal adenomas. The advent of laparoscopic surgery has led to the development of several new methods for the treatment of gastrointestinal tumors. This study was designed to introduce an innovative technique of totally laparoscopic resection with natural orifice specimen extraction (NOSE) for large rectal adenomas and to assess the feasibility and safety of the technique. Between February 2011 and January 2014, we performed totally laparoscopic resection with NOSE on 18 patients with a large rectal adenoma. This new technique was successful in all 18 patients. The average size of the adenoma was 4.2 cm. Mean operation time was 108.4 min, and mean intraoperative blood loss was 36.6 ml. The mean time to passing of the first flatus was 2.3 days, and the mean postoperative hospital stay was 7.2 days. Only one patient needed analgesics after the operation. All patients were able to walk within the first 2 days. There were no cases of morbidity and recurrence. Totally laparoscopic resection with NOSE appears to be suitable for selected patients with a large adenoma located in mid- or low rectum. PMID- 25840503 TI - Effect of moderate- versus high-intensity exercise on vascular function, biomarkers and quality of life in heart transplant recipients: A randomized, crossover trial. AB - BACKGROUND: Growing evidence in long-term treatment of heart transplant (HTx) recipients indicates effects of high-intensity interval training (HIIT) on several parameters, including oxygen uptake, vascular function and psychological distress. In this study we compare the effect of HIIT vs continued moderate training (CON) on vascular function, biomarkers and health-related quality of life (HRQoL) in HTx recipients. METHODS: A randomized, controlled crossover trial of stable HTx recipients >12 months after transplantation was done on patients with 12 weeks of HIIT or 12 weeks of CON, followed by a 5-month washout and crossover. Outcomes included endothelial function, arterial stiffness, biomarkers, HRQoL and markers of anxiety and depression. RESULTS: Sixteen HTx recipients (mean age 52 years, 75% male) completed the study. HIIT increased VO(2peak) more than CON (between-group difference, p < 0.001). The physical component score of the 36-item Short Form (SF-36) was increased significantly in HIIT patients (p = 0.02) and borderline increased in CON patients (p = 0.07), whereas there was no significant effect of exercise on the mental component. Depression score decreased significantly in HIIT patients (p = 0.04) with no change in CON patients (p = 0.75), whereas anxiety score decreased significantly in both HIIT (p < 0.01) and CON (p < 0.05) patients. There were no between-group differences in any of the measures (all p > 0.05). Arterial stiffness and biomarkers were not changed, nor did endothelial function change after HIIT (p = 0.08) or CON (p = 0.68). CONCLUSIONS: HIIT and CON are both well tolerated and induce similar improvements in physical components of HRQoL and in markers of anxiety. Effects of either training modality on vascular function and biomarkers could not be confirmed. PMID- 25840504 TI - Gene expression profiling to study racial differences after heart transplantation. AB - BACKGROUND: The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. METHODS: We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. RESULTS: In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. CONCLUSIONS: African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups. PMID- 25840505 TI - Management of children with dilated cardiomyopathy in The Netherlands: Implications of a low early transplantation rate. AB - BACKGROUND: The policy for listing and transplant for children with dilated cardiomyopathy (DCM) in The Netherlands has been conservative because of low donor availability. The effects of this policy on outcome are reported. METHODS: This was a multicenter, nationwide study performed in 148 children with DCM. The primary outcome was death or heart transplant. RESULTS: Overall, 43 patients (29%) died or were transplanted. Within 1 year of diagnosis, 21 patients died, and only 4 underwent transplantation (3 on mechanical circulatory support). The 1 year survival was 85% (95% confidence interval [CI] = 79-91), and 5-year survival was 84% (95% CI = 78-90). Transplantation-free survival at 1 year was 82% (95% CI = 75-88) and at 5 years was 72% (95% CI = 64-80). Within 1 year of diagnosis, with death as the main end-point (21 of 25, 84%), intensive care unit admission (hazard ratio = 2.6, p = 0.05) and mechanical circulatory support (hazard ratio = 3.2, p = 0.03) were risk factors (multivariable Cox analysis); inotropic support was longer in patients reaching an end-point. At >1 year after diagnosis, with transplantation as the main end-point (15 of 18, 83%), age >6 years (hazard ratio = 6.1, p = 0.02) was a risk factor. There were 56 (38%) children who recovered, 50% within 1 year of diagnosis. Recovery was associated with younger age; was similar in patients with myocarditis (43%) and idiopathic disease (41%); and was similar in patients initially admitted to the intensive care unit, admitted to the ward, or treated as outpatients. CONCLUSIONS: The transplantation rate in our cohort in the first year was low, with 1-year and 5-year survival rates similar to other cohorts. Our results suggest that a conservative approach to list children for transplantation early after presentation may be justifiable except for patients with prolonged intensive care unit or mechanical circulatory support. PMID- 25840506 TI - Circulating microRNA as a biomarker for recovery in pediatric dilated cardiomyopathy. AB - BACKGROUND: MicroRNAs (miRNAs) are short regulatory RNAs that control gene expression through interacting with the 3'UTR of target messenger RNAs. The purpose of this study was to determine if circulating miRNAs are useful biomarkers of outcome in children with dilated cardiomyopathy (DCM). METHODS: An array for 754 miRNAs and real time polymerase chain reaction confirmation of select miRNAs were performed. Serum from 55 children <18 years old with DCM was analyzed. Samples were drawn from all patients with DCM when undergoing heart transplant evaluation and/or at the time of transplantation. Patients with DCM were categorized based on when their blood was drawn (Pre-Transplant or Transplant) and outcome (Transplant/died or Recovered). RESULTS: Two miRNAs were significantly up-regulated (hsa-miR-155 and hsa-miR-636) and 2 miRNAs were down regulated (hsa-miR-646 and hsa-miR-639) in patients with DCM who were transplanted or died compared with patients with DCM who recovered their ventricular function. Receiver operator curves, performed for differences in any 1 of these 4 differentially regulated miRNAs in patients who were transplanted or died compared with patients who recovered, resulted in an area under the receiver operating characteristic curve of 0.875 for the Pre-Transplant blood draw time point and an area under the receiver operating characteristic curve of 0.93 for the day of Transplant time point. CONCLUSIONS: We identified specific miRNAs that are differentially regulated between children with DCM who need a transplant compared with children with DCM who recover. A unique biomarker signature of miRNAs that are specific to children with DCM who have the potential to recover would be valuable in risk stratification of this challenging patient population. PMID- 25840507 TI - Design of a novel prosthetic socket: assessment of the thermal performance. AB - Prosthetic liners and sockets insulate the residual limb, causing excessive sweating and concomitant skin maceration. When coupled with atypical loading conditions, further dermatologic problems can arise. This can significantly reduce the quality of life of an amputee patient. Improving the design of the prosthetic socket has been proposed as a means of reestablishing a normal thermal environment around the residual limb. In this study, a prosthetic socket was modified by incorporating a helical cooling channel within the socket wall using additive manufacturing techniques. Two sockets were modeled: a control socket, and a modified socket containing a 0.48 cm diameter cooling channel. Computer simulations and bench-top testing were used to assess the design's ability to create a greater temperature differential across the socket wall. A greater temperature drop across the socket wall suggested that the socket could provide cooling benefits to the residual limb by allowing for heat to be drawn away from the limb. The temperature difference across the socket wall was calculated for both sockets in each aspect of the study. Both socket type (p=0.002) and location on the socket (p=0.014) were statistically significant factors affecting the temperature difference between inner and outer socket walls. Compared with the control socket, the modified socket containing a helical cooling channel exhibited greater temperature differences across its wall of 11.1 degrees C and 6.4 degrees C in the computer simulations and bench-top testing, respectively. This finding suggested that socket modifications, such as the cooling channel presented, could provide a beneficial cooling effect to an amputee patient's residual limb. PMID- 25840508 TI - A novel resting form of the trinuclear copper center in the double mutant of a multicopper oxidase, CueO, Cys500Ser/Glu506Ala. AB - A multicopper oxidase, CueO was doubly mutated at its type I copper ligand, Cys500 and an acidic amino acid residue located in the proton transfer pathway, Glu506, to Ser and Ala, respectively. Cys500Ser/Glu506Ala was mainly in a novel resting form to afford the absorption band at ca. 400 nm and an EPR signal with a highly anisotropic character derived from type III copper. However, Cys500Ser/Glu506Ala gave the same reaction intermediate (peroxide intermediate) as that from Cys500Ser and Cys500Ser/Glu506Gln. PMID- 25840509 TI - Editorial overview: Folding and binding: Old concepts, new ideas, novel insights. PMID- 25840510 TI - Cribriform adenocarcinoma of the minor salivary glands arising in the epiglottis- a previously undocumented occurrence. AB - A 39-year-old female was referred to her local Ear, Nose, and Throat department with tonsillar hypertrophy. During intubation for a tonsillectomy, a mass was also noted on the epiglottis. Histopathologic examination showed this mass to be a cribriform adenocarcinoma of the minor salivary glands (CAMSG). As far as the authors are aware, a CAMSG has never been documented in the larynx. PMID- 25840511 TI - Salivary gland lesions: recent advances and evolving concepts. AB - Recently, there have been significant developments in our understanding of salivary gland pathology, and new entities, such as mammary analogue secretory carcinoma, have been described. Attempts are being made to identify effective therapeutic agents for salivary duct carcinomas by using molecular diagnostic techniques. Concepts such as high-grade transformation have been described, which not only influence macroscopic and microscopic evaluation of a specimen but, given the high incidence of metastases and morbidity, also carry significant treatment implications. Specific chromosomal translocations, which can be detected by fluorescent in situ hybridization, can augment diagnostic accuracy and carry prognostic implications. The landscape of benign salivary gland lesions is changing with better understanding of chronic sclerosing sialadenitis related to IgG4. This multiorgan inflammatory condition may primarily present as a salivary gland lesion and clinically and radiologically mimic a salivary gland malignancy. Histology and immunohistochemistry play a critical role in its accurate diagnosis. The purpose of this article is to review these changes, with an emphasis on their effect on patient management. Given their diagnostic, prognostic, and therapeutic implications, it is critical that surgeons, oncologists, pathologists, and those involved in caring for patients with salivary gland tumors are aware of these changes while considering management options. PMID- 25840512 TI - Fracture of mandibular condyle-to open or not to open: an attempt to settle the controversy. AB - OBJECTIVE: To compare the outcome of the open method versus the closed method of treatment for mandibular condylar fracture. STUDY DESIGN: Fifty patients with fractures of the mandibular condylar processes were evaluated. All fractures were displaced, with a degree of deviation between the condylar fragment and the ascending ramus of 10 to 45 degrees (mediolaterally). The patients were randomly divided into two groups, with group 1 receiving open reduction internal fixation and group 2 receiving closed reduction. The follow-up was done over the period of 6 months. RESULTS: Statistically significant improvement was seen in group 1 compared with group 2 in terms of anatomic reduction of the condyle, shortening of the ascending ramus, occlusal status, and deviation on mouth opening. CONCLUSIONS: A statistically significant difference was seen in the patients treated with the open method, with improved temporomandibular joint functions and fewer short- and long-term complications compared with those treated with the closed method. PMID- 25840513 TI - Oral aspects in celiac disease children: clinical and dental enamel chemical evaluation. AB - OBJECTIVE: The aim of this study was to evaluate the oral manifestations of celiac disease (CD), the chemical composition of dental enamel, and the occurrence of CD in children with dental enamel defects (DEDs). STUDY DESIGN: In the study, 52 children with CD and 52 controls were examined for DEDs, recurrent aphthous stomatitis (RAS), dental caries experience, and salivary parameters. In addition, 10 exfoliated primary enamel molars from each group were analyzed by energy dispersive x-ray spectroscopy and Fourier transform infrared spectroscopy. Fifty children with DEDs were submitted to CD diagnosis. RESULTS: Among the children with CD, a higher prevalence of DEDs (P = .00001) and RAS (P = .0052), lower caries experience (P = .0024), and reduction of salivary flow (P = .0060) were observed. Dental enamel from the children with CD demonstrated a lower calcium-to-phosphorus ratio (P = .0136), but no difference in the carbonate-to phosphate ratio (P = .5862) was observed. In the multivariate analysis, CD was a protective factor for caries (OR = 0.74) and a risk factor for RAS (OR3.23). CONCLUSIONS: The children with CD presented with more RAS, DEDs, reduction of salivary flow, and chemical alterations in the enamel. PMID- 25840514 TI - Direct immunofluorescence testing results in cases of premalignant and malignant oral lesions. AB - OBJECTIVES: Oral premalignant and malignant lesions may mimic oral lichen planus (OLP) clinically and microscopically. OLP often shows basement membrane fibrinogen positivity on direct immunofluorescence testing (DIF). This study examined fibrinogen positivity in oral premalignant lesions and squamous cell carcinoma. STUDY DESIGN: The University of Florida Oral Pathology Biopsy Service records were searched for the years 2003 to 2013 for oral premalignant lesions and squamous cell carcinoma with concurrent DIF testing. Demographic, clinical, and DIF or histologic information was collected and analyzed. RESULTS: Sixty eight fibrinogen positive lesions were identified within a total of 164 cases. Low-grade dysplasia and premalignant verrucous lesions made up the majority of the fibrinogen positive lesions (combined n = 43; 63.2%), and the most common locations in positive cases were the buccal mucosa, tongue, and gingiva. A lichenoid distribution of the inflammatory infiltrate significantly predicted fibrinogen positivity (P < .0005). CONCLUSIONS: Fibrinogen positivity may be seen in premalignant and malignant oral lesions increasing the risk of misdiagnosis. PMID- 25840515 TI - [Use of French version of Ureteral Stent Symptom Questionnaire for tolerance evaluation of ureteral double J-stent]. AB - OBJECTIVES: To evaluate the quality of life of the holders of a ureteral double J stent (US) using the USSQ questionnaire (Ureteral Stent Symptom Questionnaire), validated in French in 2010. METHODS: Between January 2009 and December 2011, 249 patients underwent flexible ureteroscopy for urolithiais in our service. Among them, 160 received a US in perioperative, and they were sent self-questionnaire USSQ-FR retrospectively. The questionnaire includes 38 questions, concerning the perioperative period with US, and 4 weeks after its removal, grouped into 6 sections: urinary symptoms, pain, general health, professional resounding, sexual resounding, and other problems. A subgroup analysis was performed, comparing US used in emergency and planned US, active patients or retired, male or female. Statistical analysis used the Chi(2) test for paired data, the Fisher exact test and the Kruskal Wallis test. RESULTS: Of the 157 questionnaires sent (two patients who died, one mentally retarded), we obtained 80 responses. Quality of life appears to be significantly altered in all areas explored by the questionnaire. Urinary symptoms: 26.9 versus 19.9 score (P<0.0001), pain: 16.1 versus 10.7 (P=0.003), general health: 13.9 versus 9.1 (P<0.0001), professional practice: 6.1 versus 3.6 (P=0.0002), female: 3.3 versus 1.8 (P=0.001). There was no significant difference if the US was placed in emergency or programmatically, if patients were professionally active or retired. In addition, women had a significantly impaired quality of life compared to men for urinary symptoms, general health and professional practice. CONCLUSION: US are responsible for a significant impairment of quality of life for patients. The validated, self administered, USSQ-FR questionnaire is a reliable tool for this evaluation. LEVEL OF EVIDENCE: 5. PMID- 25840516 TI - Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction. AB - Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. PMID- 25840517 TI - Stress Factors Contributing to Depression Among Latino Migrant Farmworkers in Nebraska. AB - Migrant farmworkers represent a structurally vulnerable population coming to rural communities to work, but often are economically disadvantaged and socially isolated. Based on survey data from 200 migrant farmworkers in rural Nebraska in 2013, this study seeks to identify and categorize major stressors that have contributed to depression among farmworkers. Over 30% of respondents were identified to have high stress levels as indicated by the Migrant Farmworker Stress Inventory (MFWSI). The MFWSI was categorized into eight domains: economics and logistics; acculturation and social isolation; relationship with partner; health; entertainment; concerns for children; and substance use by others. Nearly half (45.8%) of respondents were depressed. Correlations between the principal component scores of the eight stressor domains and the cumulative depression score were significant for the domains: (1) economics and logistics and (2) health (r = 0.22, p < 0.01). Findings highlight the importance of improving economic and living conditions as well as addressing social and cultural needs by creating more welcoming receiving communities. PMID- 25840518 TI - Probability distributions for multimeric systems. AB - We propose a fast and accurate method of obtaining the equilibrium mono-modal joint probability distributions for multimeric systems. The method necessitates only two assumptions: the copy number of all species of molecule may be treated as continuous; and, the probability density functions (pdf) are well-approximated by multivariate skew normal distributions (MSND). Starting from the master equation, we convert the problem into a set of equations for the statistical moments which are then expressed in terms of the parameters intrinsic to the MSND. Using an optimization package on Mathematica, we minimize a Euclidian distance function comprising of a sum of the squared difference between the left and the right hand sides of these equations. Comparison of results obtained via our method with those rendered by the Gillespie algorithm demonstrates our method to be highly accurate as well as efficient. PMID- 25840519 TI - Slow-fast stochastic diffusion dynamics and quasi-stationarity for diploid populations with varying size. AB - We are interested in the long-time behavior of a diploid population with sexual reproduction and randomly varying population size, characterized by its genotype composition at one bi-allelic locus. The population is modeled by a 3-dimensional birth-and-death process with competition, weak cooperation and Mendelian reproduction. This stochastic process is indexed by a scaling parameter K that goes to infinity, following a large population assumption. When the individual birth and natural death rates are of order K, the sequence of stochastic processes indexed by K converges toward a new slow-fast dynamics with variable population size. We indeed prove the convergence toward 0 of a fast variable giving the deviation of the population from quasi Hardy-Weinberg equilibrium, while the sequence of slow variables giving the respective numbers of occurrences of each allele converges toward a 2-dimensional diffusion process that reaches (0,0) almost surely in finite time. The population size and the proportion of a given allele converge toward a Wright-Fisher diffusion with stochastically varying population size and diploid selection. We insist on differences between haploid and diploid populations due to population size stochastic variability. Using a non trivial change of variables, we study the absorption of this diffusion and its long time behavior conditioned on non-extinction. In particular we prove that this diffusion starting from any non-trivial state and conditioned on not hitting (0,0) admits a unique quasi-stationary distribution. We give numerical approximations of this quasi-stationary behavior in three biologically relevant cases: neutrality, overdominance, and separate niches. PMID- 25840520 TI - Feasibility of high-flow nasal cannula oxygen therapy for acute respiratory failure in patients with hematologic malignancies: A retrospective single-center study. AB - PURPOSE: This study investigated the feasibility of high-flow nasal cannula (HFNC) oxygen therapy for acute respiratory failure in adult patients with hematologic malignancies. MATERIALS AND METHODS: We identified 45 acute respiratory failure patients with hematologic malignancies who received HFNC therapy between March 2012 and June 2014 at Seoul St Mary's Hospital. Their medical records were reviewed retrospectively to identify useful prognostic factors for successful treatment. RESULTS: Of the 45 patients, 15 (33.3%) successfully recovered, and 30 were changed to invasive ventilation due to failed HFNC treatment. The etiologies of acute respiratory failure were bacterial pneumonia (57.8%), Pneumocystis jirovecii pneumonia (17.8%), pulmonary edema (8.9%), and bronchiolitis obliterans organizing pneumonia (8.9%). The overall mortality rate was 62.2%. The HFNC treatment success rate was significantly different between the survivors and nonsurvivors. To evaluate risk factors for HFNC treatment failure, differences between the HFNC treatment success and failure groups were compared. There were no significant differences in the severity of underlying medical conditions. The percentage of bacterial pneumonia was significantly higher in the HFNC treatment failure group compared with the success group (73.3% vs 26.7%; P = .004). CONCLUSIONS: High-flow nasal cannula offers an interesting alternative to invasive ventilation in acute respiratory failure patients with hematologic malignancies. However, attention must be paid to the appropriate choice of HFNC settings such as oxygen flow. PMID- 25840521 TI - Progress Monitoring in an Integrated Health Care System: Tracking Behavioral Health Vital Signs. AB - Progress monitoring implementation in an integrated health care system is a complex process that must address factors such as measurement, technology, delivery system care processes, patient needs and provider requirements. This article will describe how one organization faced these challenges by identifying the key decision points (choice of measure, process for completing rating scale, interface with electronic medical record and clinician engagement) critical to implementation. Qualitative and quantitative data will be presented describing customer and stakeholder satisfaction with the mental health progress monitoring tool (MHPMT) as well as organizational performance with key measurement targets. PMID- 25840522 TI - Swiss ball enhances lumbar multifidus activity in chronic low back pain: A letter to the editor. PMID- 25840524 TI - Simplified technique for making a straight subciliary incision. PMID- 25840523 TI - Modified auricular cartilage sling for paralytic ectropion. AB - OBJECTIVE: To evaluate the outcomes of a modified auricular cartilage sling for paralytic ectropion. METHODS: We treated 17 eyelids of 17 patients (average 67 years old) with an auricular cartilage sling between 2004 and 2012. All patients had paralytic ectropion with lower eyelid ptosis. Cartilage was harvested via an incision just inside the anterior rim of the helix. Skin incisions were made at the subciliary, medial and lateral canthal regions. The auricular cartilage graft was sutured to the medial canthal tendon medially, lateral orbital rim laterally, inferior tarsus superiorly, and lower eyelid retractors inferiorly. Average follow-up period was 40 months (range 16-60 months). RESULTS: The median L-MRD (mm) was improved from 8.4 preoperatively (interquartile range 7.5-8.9) to 5.2 postoperatively (4.8-5.3). The median lagophthalmos (mm) was improved from 5.8 preoperatively (4.7-7.0) to 2.2 postoperatively (1.6-2.6). 16 patients had corneal exposure preoperatively and this resolved completely in 12 patients. All patients experienced good anatomical and functional results with relief of their preoperative pain/discomfort symptoms without complications. No patients required reoperation and none experienced infection, exposure of the cartilage graft, or recurrence of lower eyelid malpositions. Postoperatively, all lower eyelids moved downward with down-gaze. The auricular scar left no significant cosmetic deformity. CONCLUSIONS: The modified auricular cartilage sling with 4 point fixation for paralytic ectropion appears to maintain normal eyelid mobility with down-gaze and avoids the problem of lower eyelid fixation. PMID- 25840525 TI - A randomized 'N-of-1' single blinded clinical trial of barbed dermal sutures vs. smooth sutures in elective plastic surgery shows differences in scar appearance two-years post-operatively. AB - BACKGROUND: Barbed sutures have unidirectional circumferential shallow barbs, which distribute tension throughout the wound and close wound securely without the need to tie knots. OBJECTIVES: We compare two different methods of wound closure in elective plastic surgical cases: barbed 3/0 V-LocTM180 suture and smooth 3/0 MaxonTM sutures, both polyglyconate monofilament synthetic absorbable sutures. We assessed the aesthetic long-term results with a minimum two year follow up. METHODS: This is a prospective, randomized controlled study with internal control. A single surgeon performed all cases. Patients who underwent elective operations that involved long wound closure were enrolled in the study. Each patient acted as their own internal control with half their wound being sutured with 3/0 V-LocTM180 barbed suture and the other half with smooth 3/0 MaxonTM deep dermal sutures and then a subcuticular skin closure. In both groups, the superficial fascial system was closed with 1 Vicryl interrupted sutures on both sides. Long-term cosmesis was evaluated using the modified Hollander cosmesis score by review of standardized postoperative photographs by 9 blinded plastic surgeons and specialist registrars. RESULTS: The study reports on 33 female patients. The time taken for wound closure was significantly reduced using the barbed suture (p < 0.001). There was no difference in the complication ratio in either group. Two-year aesthetic outcome was significantly superior when using the barbed suture (p = 0.0075). CONCLUSION: Barbed sutures closure of long wounds is faster and produces a better long-term aesthetic outcome than smooth sutures. PMID- 25840526 TI - Vitamin B12 Deficiency in Infants. AB - OBJECTIVE: To determine different clinical presentations of vitamin B12 deficiency in infants. METHODS: Infants at the age of 1-20 mo admitted to infancy clinic of authors' hospital between January 2011-2013 with various clinical presentations due to vitamin B12 deficiency were included in the study. Hospital records of all the patients were evaluated by means of history, physical, laboratory, imaging examinations and treatment. The diagnosis was based on a nutritional history of mothers and infants, clinical findings, hematological evaluation, and low level of serum vitamin B12. RESULTS: A total of 20 patients with a mean age of 6.65 +/- 4.5 mo were included in the study. The weight and height were below the third percentile in four patients. The most common symptoms of the patients were; infections in 30 %, pallor in 25 %, hypotonia and neuro developmental delay in 25 %, refusal to solid food or to suck in 20 %, failure to thrive in 15 %, fatigue in 10 %. Twenty-five percent of patients had neurologic signs and symptoms. Anemia was found in 16/20 (80 %) patients. Three (15 %) patients had leukopenia, 7 (35 %) had neutropenia, 2 (10 %) patients had thrombocytopenia. All of the mothers had vitamin B12 deficiency. All of the patients were fed with breast milk. Cyanocobalamin was administered to all the patients and mothers. After the treatment, clinical and laboratory findings of all the patients improved. CONCLUSIONS: Vitamin B12 deficiency should be considered in the differential diagnosis of some hematological, neurological, and gastrointestinal disturbances of infants. PMID- 25840527 TI - Local pain during transcranial magnetic stimulation induced by ferromagnetic pigments in commonly used cosmetics. PMID- 25840528 TI - Effects of age and task difficulty on ERP responses to novel sounds presented during a speech-perception-in-noise test. AB - OBJECTIVE: Event-related potentials (ERPs) to task-irrelevant novel sounds have been shown to increase in amplitude with increasing task difficulty and might therefore reflect listening effort. Here we investigated whether this effect is similar in two groups of younger and older listeners with normal hearing. METHODS: Novel sounds were presented during a speech-perception-in noise test and task difficulty was adjusted decreasing the signal-to-noise ratio (SNR) relative to the individual 50% correct speech recognition SNR (easy +10 dB, medium +2dB, hard 0 dB). RESULTS: Amplitudes of the Novelty P3 and a late positive potential (LPP) were significantly larger in younger compared to older participants. Novelty P3 amplitude increased with increasing task difficulty in both age groups, but the effect was more robust in younger listeners. By contrast, LPP amplitude increases were observed only in older listeners. CONCLUSIONS: Novelty P3 and LPP were found to be differently affected by task difficulty in the two age groups indicating sustained and more effortful processing under challenging listening conditions in older listeners. SIGNIFICANCE: These results confirmed the potential use of novel sounds during an auditory task as an indirect measure of listening effort in younger and older listeners, but the different focus on Novelty P3 and LPP should be taken into account. PMID- 25840529 TI - Value of Cardiac Troponin and sPESI in Treatment of Pulmonary Thromboembolism at Outpatient Setting. AB - BACKGROUND: Currently, guidelines do not recommend any standard approach for treatment of pulmonary thromboembolism (PTE) at outpatient setting. We investigated the efficacy and safety of a 90-day anticoagulant treatment of outpatients diagnosed with PTE who had negative troponin levels and low-risk simplified pulmonary embolism severity index (sPESI) at presentation. METHODS: This prospective cohort study included a total of 206 patients with objectively confirmed acute symptomatic PTE. Any troponin negative (cTn-) and low sPESI patients (as classified Group-1) were treated in outpatient setting. The primary endpoint was all-cause mortality during the first 90 days, and the secondary endpoint included non-fatal symptomatic recurrent PTE or non-fatal major bleeding. Presence of cancer was excluded from sPESI score. RESULTS: Fifty-two of 206 patients were eligible for had Group-1, and 31 were treated at outpatients settings. The 90-day all-cause mortality rate was 3.2 % among patients who received outpatient treatment. Otherwise cTn+ and high-risk sPESI 90-day mortality rate was 43.7 %. No difference was found in terms of secondary endpoints between the patients who received outpatient treatment and those who received inpatient treatment in Group-1 (p = NS). In our study, cancer was present in 16 (51.6 %) of the 31 outpatients. CONCLUSION: We observed that patients with acute PTE, low-risk sPESI, and negative troponin levels can be safely treated in the outpatient settings. Also the presence of cancer alone does not necessitate hospitalization. PMID- 25840530 TI - Management of 1- to 2-cm Carcinoid Tumors of the Appendix: Using the National Cancer Data Base to Address Controversies in General Surgery. AB - BACKGROUND: The management of 1- to 2-cm appendiceal carcinoid tumors remains controversial. Here we use the National Cancer Data Base (NCDB) to compare long term outcomes for patients treated via resection of the primary tumor alone vs right hemicolectomy (RHC). STUDY DESIGN: The 1998 to 2011 NCDB User File was queried to identify patients with 1- to 2-cm appendiceal carcinoids. Patients were stratified by surgical technique: resection of the primary tumor alone vs RHC with regional lymphadenectomy. Multivariable logistic regression was used to compare short-term outcomes. Survival was estimated using the Kaplan-Meier method with comparisons based on the log-rank test. RESULTS: A total of 916 patients were identified, including 42% managed with primary resection and 58% with RHC. Patients who underwent RHC had slightly larger tumors and higher-stage tumors; otherwise, there were no baseline differences between groups. The rates of positive margins were similar (5.5% vs 4.5%; p = 0.60). Among all patients, 1- and 5-year survival were 98.1% and 88.7% vs 96.7% and 87.4% (p = 0.52) for those managed via primary resection vs RHC, respectively. Among patients with moderate/high-grade/anaplastic carcinoids, 1- and 5-year survival were 93.3% and 72.0% vs 92.3% and 71.9%, respectively (p = 0.78). After adjustment with Cox proportional hazards modeling, we confirmed that there was no survival benefit for patients undergoing RHC (hazard ratio = 1.14; p = 0.72). CONCLUSIONS: For 1- to 2-cm appendiceal carcinoids, formal resection of the right colon does not appear to improve survival, even for higher-grade tumors. Our findings suggest that resection of the primary tumor alone is adequate for all carcinoids <2 cm. PMID- 25840531 TI - Laparoscopic pancreaticoduodenectomy should not be routine for resection of periampullary tumors. AB - BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) is a difficult procedure that has become increasingly popular. Nevertheless, comparative data on outcomes remain limited. Our aim was to compare the outcomes of LPD and open pancreaticoduodenectomy (OPD). STUDY DESIGN: Between April 2011 and April 2014, 46 LPD were performed and compared with 46 OPD, which theoretically can be done by the laparoscopic approach. Patients were also matched for demographic data, associated comorbidities, and underlying disease. Patient demographics and perioperative and postoperative outcomes were studied from our single center prospective database. RESULTS: Lower BMI (23 vs 27 kg/m(2), p < 0.001) and a soft pancreas (57% vs 47%, p = 0.38) were observed in patients with LPD, but there were no differences in associated comorbidities or underlying disease. Surgery lasted longer in the LPD group (342 vs 264 minutes, p < 0.001). One death occurred in the LPD group (2.1% vs 0%, p = 0.28) and severe morbidity was higher (28% vs 20%, p = 0.32) in LPD due to grade C pancreatic fistula (PF) (24% vs 6%, p = 0.007), bleeding (24% vs 7%, p = 0.02), and revision surgery (24% vs 11%, p = 0.09). Pathologic examination for malignant diseases did not identify any differences between the LPD and OPD as far as size (2.51 vs 2.82 cm, p = 0.27), number of harvested (20 vs 23, p = 0.62) or invaded (2.4 vs 2, p = 0.22) lymph nodes, or R0 resection (80% vs 80%; p = 1). Hospital stays were similar (25 vs 23 days, p = 0.59). There was no difference in outcomes between approaches in patients at a lower risk of PF. CONCLUSIONS: This study found that LPD is associated with higher morbidity, mainly due to more severe PF. Laparoscopic pancreaticoduodenectomy should be considered only in the subgroup of patients with a low risk of PF. PMID- 25840532 TI - Feasibility and impact of an evidence-based program for gastric bypass surgery. AB - BACKGROUND: Health care in the United States is expensive and quality is variable. The aim of this study was to investigate whether our integrated health system, composed of academic hospitals, a practice plan, and a managed care payer, could reliably implement an evidence-based program for gastric bypass surgery. A secondary aim was to evaluate the impact of the program on clinical outcomes. STUDY DESIGN: A standardized program for delivery of clinical best practice elements for patients undergoing initial open or laparoscopic Roux-en-Y gastric bypass was implemented in 2008. Best-practice elements were embedded into the workflow. The best-practice elements were refined after reviewing failures observed during the early implementation period. The study period was divided into 3 groups: group alpha = year preceding program implementation (control), group beta = first year of implementation (unreliable), and group Omega = 2nd to 4th years of implementation (reliable). Outcomes data were collected for all patients who had undergone Roux-en-Y gastric bypass between May 2008 and April 2012 and were compared with a control group from the preceding year using multiple logistic regression analysis. RESULTS: Two thousand and sixty-one patients were studied, with no significant demographic differences between study groups. Best-practice elements delivery was 40% in group beta, but was >90% for group Omega (p < 0.001). Length of stay for group alpha was 3.5 days and improved to 2.2 days (p < 0.001) for group Omega. Complications and readmission rates improved considerably with reliable delivery of best-practice elements. CONCLUSIONS: Standardization of evidence-based care delivery for Roux-en-Y gastric bypass was feasible and reliable delivery of this pathway improved clinical outcomes. PMID- 25840533 TI - A decade of excellent outcomes after surgical intervention in 538 patients with thoracic outlet syndrome. AB - BACKGROUND: Our aim was to evaluate the outcomes of patients who underwent first rib resection (FRR) for all 3 forms of thoracic outlet syndrome (TOS) during a period of 10 years. STUDY DESIGN: Patients treated with FRR from August 2003 through July 2013 were retrospectively reviewed using a prospectively maintained database. RESULTS: Five hundred and thirty-eight patients underwent 594 FRRs for indications of neurogenic (n = 308 [52%]), venous (n = 261 [44%]), and arterial (n = 25 [4%]) TOS. Fifty-six (9.4%) patients had bilateral FRR. Fifty-two (8.8%) patients had cervical ribs. Three hundred and ninety-eight (67%) FRRs were performed on female patients, with a mean age of 33 years (range 10 to 71 years). Three hundred and forty (57%) were right-sided procedures. Seventy-five children (aged 18 years or younger) underwent FRRs; 25 during the first 5 years and 50 during the second 5 years. When comparing the second 5-year period with the first 5-year period, more patients had venous TOS (48% vs 37%; p < 0.02); fewer patients had neurogenic TOS (48% vs 58%; p < 0.05), and improved or fully resolved symptoms increased from 93% to 96%. Complications included 2 vein injuries, 2 hemothoraces, 4 hematomas, 138 pneumothoraces (23%), and 8 (1.3%) wound infections. Mean length of stay was 1 day. CONCLUSIONS: Excellent results were seen in this surgical series of neurogenic, venous, and arterial TOS due to appropriate selection of neurogenic patients, use of a standard protocol for venous patients, and expedient intervention in arterial patients. There is an increasing role for surgical intervention in children. PMID- 25840534 TI - Quality of Care Delivered Before vs After a Quality-Improvement Intervention for Acute Geriatric Trauma. AB - BACKGROUND: Older trauma-injury patients had improved recovery after we implemented routine geriatric consultation for patients aged 65 years and older admitted to the trauma service of a Level I academic trauma center. The intervention aimed to improve quality of geriatric care. However, the specific care processes that improved are unknown. STUDY DESIGN: We conducted a prospective observation comparing medical care after (December 2007 to November 2009) vs before (December 2006 to November 2007) implementation of the geriatric consult-based intervention. To measure quality of care (QOC), we used 33 previously validated care-process quality indicators (QIs) from the Assessing the Care of Vulnerable Elders (ACOVE) study, measured by review of medical records for 76 geriatric consult (GC) vs 71 control group patients. As prespecified subgroup analyses, we aggregated QIs by type: geriatric (eg, delirium screening) vs nongeriatric condition-based care (eg, thrombosis prophylaxis) and compared QI scores by type of care. Last, we aggregated QI scores into overall, geriatric, and nongeriatric QOC scores for each patient (number of QIs passed/number of QIs eligible), and compared patient-level QOC for the GC vs control group, adjusting for age, sex, ethnicity, comorbidity, and injury severity. RESULTS: Sixty-three percent of the GC patients vs 11% of the control group patients received a geriatric consultation. We evaluated 2,505 QIs overall (1,664 geriatric type and 841 nongeriatric QIs). In general, fewer geriatric-type QIs were passed than nongeriatric QIs (71% vs 81%; p < 0.001). We provided better overall QOC to the GC (77%) than control group patients (73%; p < 0.05). However, the difference was not statistically significant after multivariable adjustment (p = 0.08). We improved geriatric QOC for the GC (74%) compared with the control group (68%; p < 0.01), a difference that was significant after multivariable adjustment (p = 0.01). CONCLUSIONS: Geriatricians and surgeons can collaboratively improve geriatric QOC for older trauma patients. PMID- 25840535 TI - Sealing pancreaticojejunostomy in combination with duct parenchyma to mucosa seromuscular one-layer anastomosis: a novel technique to prevent pancreatic fistula after pancreaticoduodenectomy. PMID- 25840536 TI - Impact of National Cancer Institute Comprehensive Cancer Centers on ovarian cancer treatment and survival. AB - BACKGROUND: The regional impact of care at a National Cancer Institute Comprehensive Cancer Center (NCI-CCC) on adherence to National Comprehensive Cancer Network (NCCN) ovarian cancer treatment guidelines and survival is unclear. STUDY DESIGN: We performed a retrospective population-based study of consecutive patients diagnosed with epithelial ovarian cancer between January 1, 1996 and December 31, 2006 in southern California. Patients were stratified according to care at an NCI-CCC (n = 5), non-NCI high-volume hospital (>= 10 cases/year, HVH, n = 29), or low-volume hospital (<10 cases/year, LVH, n = 158). Multivariable logistic regression and Cox-proportional hazards models were used to examine the effect of NCI-CCC status on treatment guideline adherence and ovarian cancer-specific survival. RESULTS: A total of 9,933 patients were identified (stage I, 22.8%; stage II, 7.9%; stage III, 45.1%; stage IV, 24.2%), and 8.1% of patients were treated at NCI-CCCs. Overall, 35.7% of patients received NCCN guideline adherent care, and NCI-CCC status (odds ratio [OR] 1.00) was an independent predictor of adherence to treatment guidelines compared with HVHs (OR 0.83, 95% CI 0.70 to 0.99) and LVHs (OR 0.56, 95% CI 0.47 to 0.67). The median ovarian cancer-specific survivals according to hospital type were: NCI-CCC 77.9 (95% CI 61.4 to 92.9) months, HVH 51.9 (95% CI 49.2 to 55.7) months, and LVH 43.4 (95% CI 39.9 to 47.2) months (p < 0.0001). National Cancer Institute Comprehensive Cancer Center status (hazard ratio [HR] 1.00) was a statistically significant and independent predictor of improved survival compared with HVH (HR 1.18, 95% CI 1.04 to 1.33) and LVH (HR 1.30, 95% CI 1.15 to 1.47). CONCLUSIONS: National Cancer Institute Comprehensive Cancer Center status is an independent predictor of adherence to ovarian cancer treatment guidelines and improved ovarian cancer-specific survival. These data validate NCI-CCC status as a structural health care characteristic correlated with superior ovarian cancer quality measure performance. Increased access to NCI-CCCs through regional concentration of care may be a mechanism to improve clinical outcomes. PMID- 25840537 TI - Pre-trauma center red blood cell transfusion is associated with improved early outcomes in air medical trauma patients. AB - BACKGROUND: Hemorrhage is the leading cause of survivable death in trauma and resuscitation strategies including early RBC transfusion have reduced this. Pre trauma center (PTC) RBC transfusion is growing and preliminary evidence suggests improved outcomes. The study objective was to evaluate the association of PTC RBC transfusion with outcomes in air medical trauma patients. STUDY DESIGN: We conducted a retrospective cohort study of trauma patients transported by helicopter to a Level I trauma center from 2007 to 2012. Patients receiving PTC RBC transfusion were matched to control patients (receiving no PTC RBC transfusion during transport) in a 1:2 ratio using a propensity score based on prehospital variables. Conditional logistic regression and mixed-effects linear regression were used to determine the association of PTC RBC transfusion with outcomes. Subgroup analysis was performed for scene transport patients. RESULTS: Two-hundred and forty treatment patients were matched to 480 control patients receiving no PTC RBC transfusion. Pre-trauma center RBC transfusion was associated with increased odds of 24-hour survival (adjusted odds ratio [AOR] = 4.92; 95% CI, 1.51-16.04; p = 0.01), lower odds of shock (AOR = 0.28; 95% CI, 0.09-0.85; p = 0.03), and lower 24-hour RBC requirement (Coefficient -3.6 RBC units; 95% CI, -7.0 to -0.2; p = 0.04). Among matched scene patients, PTC RBC was also associated with increased odds of 24-hour survival (AOR = 6.31; 95% CI, 1.88 21.14; p < 0.01), lower odds of shock (AOR = 0.24; 95% CI, 0.07-0.80; p = 0.02), and lower 24-hour RBC requirement (Coefficient -4.5 RBC units; 95% CI, -8.3 to 0.7; p = 0.02). CONCLUSIONS: Pre-trauma center RBC was associated with an increased probability of 24-hour survival, decreased risk of shock, and lower 24 hour RBC requirement. Pre-trauma center RBC appears beneficial in severely injured air medical trauma patients and prospective study is warranted as PTC RBC transfusion becomes more readily available. PMID- 25840539 TI - Trans-thoracic minimally invasive liver resection guided by augmented reality. PMID- 25840538 TI - Plasma is the physiologic buffer of tissue plasminogen activator-mediated fibrinolysis: rationale for plasma-first resuscitation after life-threatening hemorrhage. AB - BACKGROUND: Prehospital resuscitation with crystalloid exacerbates fibrinolysis, which is associated with high mortality. We hypothesized that plasma compared with crystalloid resuscitation prevents hyperfibrinolysis in a tissue plasminogen activator (tPA)-rich environment via preservation of proteins essential for regulation of fibrinolysis. STUDY DESIGN: Healthy individuals donated blood, which was assayed using a native (nonactivated) thrombelastography (TEG). Whole blood was mixed with normal saline (NS) or platelet poor plasma (PPP) at progressive dilutions. Tissue plasminogen activator was added to promote a fibrinolytic environment. In a separate experiment, PPP was run through a 100 kDa filter and liquid remaining on top of the filter (TFP) and below the filter (BFP) was obtained. Whole blood was diluted by 50% with TFP, BFP, and NS and assayed with a tPA TEG challenge. The TFP and BFP were assayed for protein concentration and protein composition. RESULTS: Normal saline and PPP dilution of whole blood without tPA did not affect clot lysis at 30 minutes (LY30) (NS Spearman's rho 0.300, p = 0.186 and PPP 0.294, p = 0.288). When tPA was added, NS dilution of whole blood increased LY30 in a percentage-dependent manner (0.844, p < 0.001), but did not significantly increase with PPP dilution (0.270, p = 0.202). The difference in LY30 from whole blood to diluted whole blood with PPP (mean change, -1.05, 95% CI, -9.42 to 7.33) was similar with TFP (1.23, 95% CI, -5.20 to 7.66, p = 0.992). However, both BFP (37.65, 95% CI 24.47 to 50.82, p = 0.001) and NS (47.36, 95% CI 34.3 to 60.45, p < 0.001) showed large increases in fibrinolysis compared with PPP. CONCLUSIONS: Crystalloid and plasma dilution of whole blood does not increase fibrinolysis. However, NS dilution of whole blood increases susceptibility to tPA-mediated fibrinolysis. Plasma resuscitation, simulated by plasma dilution of whole blood, attenuates increased susceptibility to tPA mediated fibrinolysis. The benefits of plasma resuscitation are mediated through preservation of plasma proteins. PMID- 25840540 TI - Hospital Resource Use with Donation after Cardiac Death Allografts in Liver Transplantation: A Matched Controlled Analysis from 2007 to 2011. AB - BACKGROUND: Although donation after cardiac death (DCD) liver allografts have been used to expand the donor pool, concerns exist regarding primary nonfunction and biliary complications. Our aim was to compare resource use and outcomes of DCD allografts with donation after brain death (DBD) liver allografts. STUDY DESIGN: Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 11,856 patients who underwent deceased donor liver transplantation (LT) from 2007 to 2011. Patients were divided into 2 cohorts based on type of allograft (DCD vs DBD). Matched pair analysis (n = 613 in each group) was used to compare outcomes of the 2 donor types. RESULTS: Donation after cardiac death allografts comprised 5.2% (n = 613) of all LTs in the studied cohort; DCD allograft recipients were healthier and had lower median Model of End-Stage Liver Disease (MELD) score (17 vs 19; p < 0.0001). Post LT, there was no significant difference in length of stay, perioperative mortality, and discharge to home rates. However, DCD allografts were associated with higher direct cost ($110,414 vs $99,543; p < 0.0001) and 30-day readmission rates (46.4% vs 37.1%; p < 0.0001). Matched analysis revealed that DCD allografts were associated with higher direct cost, readmission rates, and inferior graft survival. CONCLUSIONS: While confirming the previous reports of inferior graft survival associated with DCD allografts, this is the first national report to show increased financial and resource use associated with DCD compared with DBD allografts in a matched recipient cohort. PMID- 25840542 TI - Single purse-string duct to mucosa pancreaticogastrostomy: a safe, easy, and useful technique after pancreaticoduodenectomy. PMID- 25840541 TI - GNAS and KRAS Mutations Define Separate Progression Pathways in Intraductal Papillary Mucinous Neoplasm-Associated Carcinoma. AB - BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are being increasingly recognized as important precursors to pancreatic adenocarcinoma. Elucidation of the genetic changes underlying IPMN carcinogenesis may improve the diagnosis and management of IPMN. We sought to determine whether different histologic subtypes of IPMN would exhibit different frequencies of specific genetic mutations. STUDY DESIGN: Patients with resected IPMN-associated invasive carcinoma (IPMN-INV) between 1997 and 2012 were reviewed. Areas of carcinoma, high-grade dysplasia, and low-grade dysplasia were micro-dissected from each pathologic specimen. Targeted, massively parallel sequencing was then performed on a panel of 275 genes (including KRAS, GNAS, and RNF43). RESULTS: Thirty-eight patients with resected IPMN-INV and sufficient tissue for micro-dissection were identified. Median follow-up was 2.6 years. Mutations in GNAS were more prevalent in colloid-type IPMN-INV than tubular-type IPMN-INV (89% vs 32% respectively; p = 0.0003). Conversely, KRAS mutations were more prevalent in tubular-type than colloid-type IPMN-INV (89% vs 52%, respectively; p = 0.01). For noninvasive IPMN subtypes, GNAS mutations were more prevalent in intestinal (74%) compared with pancreatobiliary (31%) and gastric (50%) subtypes (p = 0.02). The presence of these mutations did not vary according to the degree of dysplasia (GNAS: invasive 61%, high-grade 59%, low-grade 53%; KRAS: invasive 71%, high-grade 62%, low-grade 74%), suggesting that mutations in these genes occur early in IPMN carcinogenesis. CONCLUSIONS: Colloid carcinoma associated with IPMN and its intestinal-type preinvasive precursor are associated with high frequencies of GNAS mutations. The mutation profile of tubular carcinoma resembles that of conventional pancreatic adenocarcinoma. Preoperative determination of mutational status may assist with clinical treatment decisions. PMID- 25840543 TI - RETRACTED: How does high-concentration supplemental perioperative oxygen influence surgical outcomes after thyroid surgery? A prospective, randomized, double-blind, controlled, monocentric trial. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Editor-in-Chief. An independent statistical analysis based on the summary data tables and statistical results reported in the article confirmed that the statistical results are incorrect and the data do not support the conclusions of the article. PMID- 25840544 TI - Venous Thromboembolism after Breast Reconstruction in Patients Undergoing Breast Surgery: An American College of Surgeons NSQIP Analysis. AB - BACKGROUND: Given the grave consequences of venous thromboembolic (VTE) events, we examined the impact of breast reconstruction on VTE incidence in patients undergoing breast operations and, secondarily, assess the risk factors associated with VTE. STUDY DESIGN: Patients undergoing breast operations were identified in the 2007 to 2011 American College of Surgeons NSQIP database. The patients were divided into the following treatment categories: lumpectomy, mastectomy, mastectomy with reconstruction, and reconstruction. Missing data were imputed and propensity score weighting was used to balance confounders in each group. Venous thromboembolism incidence was compared across the groups and risk factors for VTE were analyzed using stepwise multivariate logistic regression. RESULTS: Overall, 68,285 patients were identified. The global incidence of VTE was 0.27%. The incidence of VTE was highest in the reconstruction and mastectomy with reconstruction groups (0.41% and 0.52% compared with 0.13% in the lumpectomy and 0.29% in the mastectomy groups; p < 0.0001). Independent risk factors for VTE included operation in the 30 days preceding breast surgery (0.56% vs 0.26% for none; p = 0.002), higher BMI (p < 0.0001), increased operative time (p < 0.0001), increased length of hospital stay (p < 0.0001), and oddly, nonsmoking status (0.29% vs 0.14% for smokers; p = 0.012). CONCLUSIONS: Breast reconstruction, higher BMI, increased operative time, operation within 30 days preceding breast surgery, and nonsmoking status are independent risk factors for VTE. The association of lower VTE rates with smoking is counterintuitive and might represent more aggressive VTE prophylaxis in this patient population. Additional investigation is warranted to understand this relationship. PMID- 25840545 TI - Assessing the Quality of Graduate Surgical Training Programs: Perception vs Reality. PMID- 25840546 TI - Nipple-sparing mastectomy: an alternative technique for large ptotic breasts. PMID- 25840547 TI - Fistulojejunostomy for refractory post-traumatic biliary fistula in an austere environment: an unusual, time-honored procedure. PMID- 25840548 TI - Superior mesenteric artery-first approach in radical antegrade modular pancreatosplenectomy for borderline resectable pancreatic cancer: a technique to obtain negative tangential margins. PMID- 25840549 TI - Oncocytic-type intraductal papillary mucinous neoplasms: a unique malignant pancreatic tumor with good long-term prognosis. AB - BACKGROUND: The different epithelial phenotypes of intraductal papillary mucinous neoplasms (IPMNs) are predictors of tumor biology and post-surgical outcomes. Oncocytic-type IPMN (O-IPMN) seems to have a unique natural history, but not much information is available because of its rarity. We sought to describe the characteristics of a cohort of patients resected for O-IPMNs, focusing on their long-term outcomes after surgery. STUDY DESIGN: We conducted a retrospective review of the demographics, clinical presentation, pathology, and survival of a cohort of patients resected for IPMN between 1990 and 2013, comparing O-IPMN with other IPMN subtypes. RESULTS: Eighteen of 400 patients (4.5%) who underwent resection for IPMN had the oncocytic subtype. Compared with other IPMN patients, those with O-IPMNs were more likely to be male (72% vs 45%; p = 0.02) and to have main pancreatic duct involvement (72% vs 42%; p = 0.01). Oncocytic IPMNs occurred in asymptomatic individuals in 67% of cases. They had either invasive carcinoma (61%) or high-grade dysplasia (39%), and the proportions in other epithelial subtypes were 19% and 21%, respectively (p < 0.001). After resection, the 10-year recurrence rate for O-IPMNs was 46%. Recurrences occurred up to 11 years after the initial resection and a completion total pancreatectomy was performed in 4 patients. At a median follow-up of 7 years, no patients with O-IPMN had died from the disease. CONCLUSIONS: Oncocytic IPMN is a unique tumor subtype that occurs mostly in the main pancreatic duct and is malignant. Recurrences after resection are not uncommon and can occur more than 10 years after the initial resection. Reoperations for recurrent O-IPMN are often feasible and have excellent results in terms of survival. PMID- 25840551 TI - Erratum to: Liver stiffness measurement by acoustic radiation force impulse is useful in predicting the presence of esophageal varices or high-risk esophageal varices among patients with HCV-related cirrhosis. PMID- 25840550 TI - Leukocyte telomere length and left ventricular function after acute ST-elevation myocardial infarction: data from the glycometabolic intervention as adjunct to primary coronary intervention in ST elevation myocardial infarction (GIPS-III) trial. AB - BACKGROUND: Telomere length has been associated with coronary artery disease and heart failure. We studied whether leukocyte telomere length is associated with left ventricular ejection fraction (LVEF) after ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Leukocyte telomere length (LTL) was determined using the monochrome multiplex quantitative PCR method in 353 patients participating in the glycometabolic intervention as adjunct to primary percutaneous coronary intervention in STEMI III trial. LVEF was assessed by magnetic resonance imaging. The mean age of patients was 58.9 +/- 11.6 years, 75 % were male. In age- and gender-adjusted models, LTL at baseline was significantly associated with age (beta +/- standard error; -0.33 +/- 0.01; P < 0.01), gender (0.15 +/- 0.03; P < 0.01), TIMI flow pre-PCI (0.05 +/- 0.03; P < 0.01), TIMI flow post-PCI (0.03 +/- 0.04; P < 0.01), myocardial blush grade ( 0.05 +/- 0.07; P < 0.01), serum glucose levels (-0.11 +/- 0.01; P = 0.03), and total leukocyte count (-0.11 +/- 0.01; P = 0.04). At 4 months after STEMI, LVEF was well preserved (54.1 +/- 8.4 %) and was not associated with baseline LTL (P = 0.95). Baseline LTL was associated with n-terminal pro-brain natriuretic peptide (NT-proBNP) at 4 months (-0.14 +/- 0.01; P = 0.02), albeit not independent for age and gender. CONCLUSION: Our study does not support a role for LTL as a causal factor related to left ventricular ejection fraction after STEMI. PMID- 25840552 TI - Understanding Adolescent Nonresponsiveness to Text Messages: Lessons from the DepoText Trial. AB - Urban adolescents face economic, social, and behavioral challenges in adhering to long-term contraceptive use. Use of text messaging reminders has the potential to increase adherence to family planning appointments and to educate patients about safe sexual health practices; however, nonresponsiveness to messages is difficult to interpret and may jeopardize programmatic success. We aimed to understand why adolescent girls enrolled in a randomized, controlled pilot trial (DepoText) designed to increase attendance at family planning visits were periodically nonresponsive to text messages through conducting structured interviews with participants whose text reply rates were less than 100 % during the trial period. Qualitative and quantitative data were collected and classified using descriptive data analysis. Reasons for nonresponsiveness, barriers to continuous cell phone coverage, cell phone plan characteristics, and attitudes toward the DepoText program were the primary endpoints of interest. Most participants (78%) attributed instances of nonresponsiveness to being away from the phone or due to a personal conflict such as school or work. Service interruption due to bill nonpayment (44%), phone loss (28%), and cell phone number change (28%) were significant barriers to continuous coverage during the trial period, and many respondents indicated that the downturn in the economy made it more difficult to maintain their cell phone plan. Almost a third reported having to choose between cell phone and other payments, but the vast majority (88%) considered their cell phone a "need" rather than a "want." Participants universally expressed satisfaction with the text messaging program and reported feeling more connected to the clinic (96%) through the messages serving as reminders (64%), encouragement to assume personal responsibility for their health care (12%), and enhanced personal connection with the clinic staff (4%). Our study suggests that a text messaging program can be used in an urban clinical setting to communicate with adolescent girls about family planning services. While economic barriers to continuous cell phone coverage do exist, adolescents indicate that the text message reminder system can be a valuable tool for enhancing clinic connectedness and promoting autonomy in care-seeking behavior. PMID- 25840553 TI - Tuberculosis DALY-Gap: Spatial and Quantitative Comparison of Disease Burden Across Urban Slum and Non-slum Census Tracts. AB - To quantitatively assess disease burden due to tuberculosis between populations residing in and outside of urban informal settlements in Rio de Janeiro, Brazil, we compared disability-adjusted life years (DALYs), or "DALY-gap." Using the 2010 Brazilian census definition of informal settlements as aglomerados subnormais (AGSN), we allocated tuberculosis (TB) DALYs to AGSN vs non-AGSN census tracts based on geocoded addresses of TB cases reported to the Brazilian Information System for Notifiable Diseases in 2005 and 2010. DALYs were calculated based on the 2010 Global Burden of Disease methodology. DALY-gap was calculated as the difference between age-adjusted DALYs/100,000 population between AGSN and non AGSN. Total TB DALY in Rio in 2010 was 16,731 (266 DALYs/100,000). DALYs were higher in AGSN census tracts (306 vs 236 DALYs/100,000), yielding a DALY-gap of 70 DALYs/100,000. Attributable DALY fraction for living in an AGSN was 25.4%. DALY-gap was highest for males 40-59 years of age (501 DALYs/100,000) and in census tracts with <60% electricity (12,327 DALYs/100,000). DALY-gap comparison revealed spatial and quantitative differences in TB burden between slum vs non slum census tracts that were not apparent using traditional measures of incidence and mortality. This metric could be applied to compare TB burden or burden for other diseases in mega-cities with large informal settlements for more targeted resource allocation and evaluation of intervention programs. PMID- 25840554 TI - Sepsis in standard care: patients' characteristics, effectiveness of antimicrobial therapy and patient outcome--a cohort study. AB - PURPOSE: Fast diagnosis and initiation of appropriate antibiotic therapy is pivotal for the survival of sepsis patients. However, most studies on suspected sepsis patients are conducted in the intensive care unit or in the emergency room setting, neglecting the standard care setting. This study evaluated sepsis risk factors, microbiological accurateness of the initial empiric antimicrobial therapy and its effect on hospital mortality in standard care patients. METHODS: In this prospective observational cohort study, patients with clinically suspected sepsis meeting two or more SIRS criteria were screened on standard care wards. After hospital discharge, occurrence of an infection was assessed according to standardized criteria, and empirical antibiotic therapy was evaluated using antibiograms of recognized pathogens by expert review. RESULTS: Of the 2384 screened patients, 298 fulfilled two or more SIRS criteria. Among these were 28.2 % SIRS patients without infection, 46.3 % non-bacteremic/fungemic sepsis patients and 25.5 % bacteremic/fungemic sepsis patients. Occurrence of a malignant disease and chills were associated with a higher risk of patients having bacteremic/fungemic sepsis, whereas other described risk factors remained insignificant. In total, 91.1 % of suspected sepsis patients received empirical antimicrobial therapy, but 41.1 % of bacteremic sepsis patients received inappropriate therapy. Non-surviving bacteremic sepsis patients received a higher proportion of inappropriate therapy than those who survived (p = 0.022). CONCLUSIONS: A significant proportion of bacteremic sepsis patients receive inappropriate empiric antimicrobial therapy. Our results indicate that rapid availability of microbiological results is vital, since inappropriate antimicrobial therapy tended to increase the hospital mortality of sepsis patients. PMID- 25840556 TI - Light-concentrating plasmonic Au superstructures with significantly visible-light enhanced catalytic performance. AB - Noble metals are well-known for their surface plasmon resonance effect that enables strong light absorption typically in the visible regions for gold and silver. However, unlike semiconductors, noble metals are commonly considered incapable of catalyzing reactions via photogenerated electron-hole pairs due to their continuous energy band structures. So far, photonically activated catalytic system based on pure noble metal nanostructures has seldom been reported. Here, we report the development of three different novel plasmonic Au superstructures comprised of Au nanoparticles, multiple-twinned nanoparticles and nanoworms assembling on the surfaces of SiO2 nanospheres respectively via a well-designed synthetic strategy. It is found that these novel Au superstructures show enhanced broadband visible-light absorption due to the plasmon resonance coupling within the superstructures, and thus can effectively focus the energy of photon fluxes to generate much more excited hot electrons and holes for promoting catalytic reactions. Accordingly, these Au superstructures exhibit significantly visible light-enhanced catalytic efficiency (up to ~264% enhancement) for the commercial reaction of p-nitrophenol reduction. PMID- 25840555 TI - Effect of Early Use of Covered Self-Expandable Endoscopic Stent on the Treatment of Postoperative Stapler Line Leaks. AB - BACKGROUND: Postoperative leaks are a dreaded complication after bariatric surgery (BS). Its treatment is based on nutritional support and sepsis control by antibiotics, collections drainage and/or prosthesis, and/or surgery. OBJECTIVES: The aim of this study is to report our experience with coated self-expandable endoscopic stents (SEES) for leaks treatment. SETTING: This study was performed in a University Hospital, (censored). METHODS: We performed a retrospective analysis of our BS database from January 2007 to December 2013. All patients with leak after BS treated with SEES were included. RESULTS: We identified 29 patients; 17 (59%) were women, with median age of 37 (19-65) years, and preoperative body mass index of 40 (28.7-56-6) kg/m(2). Nineteen (65.5%) patients had a sleeve gastrectomy and 10 (34.5%) a Roux-en-Y gastric bypass. All patients had a leak in the stapler line. Median time from surgery to leak diagnosis was 7 (1-51) days, and SEES were installed 8 (0-104) days after diagnosis. Twenty-one (72%) patients also had abdominal exploration. Median length of SEES use was 60 (1-299) days. Patients who had SEES as primary treatment (with or without simultaneous reoperation) had a shorter leak closure time (50 [6-112] vs 109 [60 352] days; p = 0.008). Twenty-eight (96.5%) patients successfully achieved leak closure with SEES. There were 16 migrations in 10 (34%) patients, 1 (3%) stent fracture, 1 opening of the blind end of alimentary limb (3%), and 5 patients (17%) required a second stent due to leak persistence. CONCLUSIONS: SEES is a feasible, safe, and effective management of post BS leaks, although patients may also require prosthesis revision and abdominal exploration. Primary SEES placement is associated with a shorter leak resolution time. PMID- 25840557 TI - Explaining variation across grantees in breast and cervical cancer screening proportions in the NBCCEDP. AB - PURPOSE: There is substantial variation across the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) grantees in terms of the proportion of the eligible population served by the grantees each year (hereafter referred to as the screening proportion). In this paper, we assess program- and state-level factors to better understand the reason for this variation in breast and cervical cancer screening proportions across the NBCCEDP grantees. METHODS: We constructed a longitudinal data set, consisting of data from NBCCEDP grantees for each of the three study years (program-years 2006-2007, 2008-2009, and 2009-2010). We performed multivariate analysis to explain the variation in breast and cervical cancer screening proportions across the grantees. The program-level factors studied were the total federal funds received, average cost of screening women by grantee, and the overall organizational structure. The state-level variables included were urban versus rural mix, access to care, and the size of the eligible population. RESULTS: Of the 48 grantees included in the study, those that serve larger populations, as measured by the size of the population and the percentage of women eligible for services, had lower screening proportions. Higher average cost of service delivery was also associated with lower screening proportions. In addition, grantees whose populations were more concentrated in urban areas had lower screening proportions. CONCLUSIONS: Overall, the average cost of screening, the overall size of the population eligible, and the concentration of population in urban areas all had a negative relationship to the proportion of eligible women screened by NBCCEDP grantees. PMID- 25840558 TI - Trends in initial management of prostate cancer in New Hampshire. AB - PURPOSE: Prostate cancer management strategies are evolving with increased understanding of the disease. Specifically, there is emerging evidence that "low risk" cancer is best treated with observation, while localized "high-risk" cancer requires aggressive curative therapy. In this study, we evaluated trends in management of prostate cancer in New Hampshire to determine adherence to evidence based practice. METHODS: From the New Hampshire State Cancer Registry, cases of clinically localized prostate cancer diagnosed in 2004-2011 were identified and classified according to D'Amico criteria. Initial treatment modality was recorded as surgery, radiation therapy, expectant management, or hormone therapy. Temporal trends were assessed by Chi-square for trend. RESULTS: Of 6,203 clinically localized prostate cancers meeting inclusion criteria, 34, 30, and 28% were low-, intermediate-, and high-risk disease, respectively. For low-risk disease, use of expectant management (17-42%, p < 0.001) and surgery (29-39%, p < 0.001) increased, while use of radiation therapy decreased (49-19 %, p < 0.001). For intermediate-risk disease, use of surgery increased (24-50%, p < 0.001), while radiation decreased (58-34%, p < 0.001). Hormonal therapy alone was rarely used for low- and intermediate-risk disease. For high-risk patients, surgery increased (38-47%, p = 0.003) and radiation decreased (41-38%, p = 0.026), while hormonal therapy and expectant management remained stable. DISCUSSION: There are encouraging trends in the management of clinically localized prostate cancer in New Hampshire, including less aggressive treatment of low-risk cancer and increasing surgical treatment of high-risk disease. PMID- 25840559 TI - Association analysis of genes involved in maize (Zea mays L.) root development with seedling and agronomic traits under contrasting nitrogen levels. AB - A better understanding of the genetic control of root development might allow one to develop lines with root systems with the potential to adapt to soils with limited nutrient availability. For this purpose, an association study (AS) panel consisting of 74 diverse set of inbred maize lines were screened for seedling root traits and adult plant root traits under two contrasting nitrogen (N) levels (low and high N). Allele re-sequencing of RTCL, RTH3, RUM1, and RUL1 genes related to root development was carried out for AS panel lines. Association analysis was carried out between individual polymorphisms, and both seedling and adult plant traits, while controlling for spurious associations due to population structure and kinship relations. Based on the SNPs identified in RTCL, RTH3, RUM1, and RUL1, lines within the AS panel were grouped into 16, 9, 22, and 7 haplotypes, respectively. Association analysis revealed several polymorphisms within root genes putatively associated with the variability in seedling root and adult plant traits development under contrasting N levels. The highest number of significantly associated SNPs with seedling root traits were found in RTCL (19 SNPs) followed by RUM1 (4 SNPs) and in case of RTH3 and RUL1, two and three SNPs, respectively, were significantly associated with root traits. RTCL and RTH3 were also found to be associated with grain yield. Thus considerable allelic diversity is present within the candidate genes studied and can be utilized to develop functional markers that allow identification of maize lines with improved root architecture and yield under N stress conditions. PMID- 25840560 TI - Readmission After Pancreaticoduodenectomy: The Influence of the Volume Effect Beyond Mortality. AB - BACKGROUND: As increased focus is placed on quality of care in surgery, readmission is an increasingly important metric by which hospital and surgeon quality is measured. For complex pancreatic surgery, we hypothesized that increased pancreaticoduodenectomy (PD) volume may mitigate readmission rates. METHODS: The University Healthsystems Consortium database was queried for all patients (n = 9805) undergoing PD from 2009 to 2011. Hospitals were stratified into quintiles based on number of cases performed annually. Univariate and multivariate logistic regression analyses were performed to identify factors associated with 30-day readmission. RESULTS: The 30-day readmission rate for patients undergoing PD was 19.1 %. Stratified by volume, hospitals performing the highest two quintiles of PDs annually (>=56 cases) had a significantly lower unadjusted readmission rate than those hospitals performing the lowest quintile (n <= 23 cases; 16.7 and 18.0 % vs. 20.9 %, p < 0.05). On univariate analysis, readmitted patients tended to have higher severity of illness (p < 0.01) and longer index admission (10 vs. 9 days, p < 0.01). Age and insurance status had no significant association with readmission. Multivariate analysis demonstrated that higher severity of illness (odds ratio [OR] 1.36, 95 % confidence interval [CI] 1.04-1.77, p = 0.02), discharge to rehab (OR 1.41, 95 % CI 1.19-1.66, p < 0.001), and surgery at the lowest volume hospitals (OR 1.28, 95 % CI 1.08-1.51, p = 0.004) were factors independently associated with readmission. CONCLUSIONS: Lower hospital volume is a significant risk factor for readmission after PD. To minimize the excess resource utilization that accompanies readmission, patients undergoing complex oncologic pancreatic surgery should be directed to hospitals most experienced in caring for this patient population. PMID- 25840561 TI - Decreased Survival Rates of Older-Aged Patients with Melanoma: Biological Differences or Undertreatment? PMID- 25840562 TI - Respiratory Motion, Anterior Heart Displacement and Heart Dosimetry: Comparison Between Prone (Pr) and Supine (Su) Whole Breast Irradiation. AB - To analyze respiratory motion of surgical clips, chest wall (CW) and the anterior displacement of the heart and its impact on heart dosimetry between prone (Pr) and supine (Su) positions during whole breast radiotherapy after breast conserving surgery. Sixteen patients underwent 4D-CT for radiotherapy planning in Pr and Su positions. Maximum inhale and maximum exhale phases were analyzed. Mean 3D vectorial displacements +/- standard deviations (SD) of the surgical clips were measured. Volumetric changes of the CW were recorded and compared. Cardiac displacement was assessed by a volume between the inner surface of CW and the myocardium of the heart (CW/H-V). For left-sided cases, comparative dosimetry was performed in each position simulating no- (Pr-noC, Su-noC) versus daily correction protocols (Pr-C, Su-C). The movements of 81 surgical clips were analyzed. Prone positioning significantly reduced both the mean 3D vectorial displacements (1.1 +/- 0.6 (Pr) vs. 2.0 +/- 0.9 mm (Su), p < 0.01) and their variability (0.3 +/- 0.2 vs. 0.5 +/- 0.3 mm, p = 0.01). Respiration-induced volumetric changes of CW were also significantly lower in Pr (2.3 +/- 4.9 vs. 9.6 +/- 7.1 cm(3), p < 0.01). The CW/H-V was significantly smaller in Pr than in Su (39.9 +/- 14.6 vs. 64.3 +/- 28.2 cm(3), p < 0.01). Besides identical target coverage heart, left-anterior-descending coronary artery (LADCA) and ipsilateral lung dose parameters were lowered with Pr-C compared to Pr-noC, Su-C and Su-noC. Prone position significantly reduced respiration-related surgical clip movements, their variability as well as CW movements. Significant anterior heart displacement was observed in Pr. Prone position with daily online correction could maximize the heart and LADCA protection. PMID- 25840564 TI - Measuring the solid-phase fractionation of lead in urban and rural soils using a combination of geochemical survey data and chemical extractions. AB - The study used 276 urban soils and 447 rural soils collected from in and around the UK town of Northampton and focussed on the fractionation of Pb. The Pb fractionation obtained from total element data was compared to the fractionation of Pb in a subset of 10 urban soils obtained using a sequential extraction method. The fractionation of the Pb from the total element data and from the sequential extractions was estimated using a self-modelling mixture resolution statistical model. The bioaccessibility of Pb in a subset of 50 of the urban soils, as measured using the unified BARGE method, was shown to be quantitatively linked with Pb fractionation from both the total element and the sequential extraction data. Three intrinsic soil components from the regional total element data model and one physico-chemical component from the sequential extraction data model were identified as the sources of bioaccessible Pb. The source of bioaccessible Pb in both rural and urban soils was tentatively identified as a fine-grained pyromorphite mineral. PMID- 25840563 TI - [Puumala hantavirus infection in Isere: Geographic extension of this zoonosis in France]. PMID- 25840565 TI - Chemical composition of groundwater and relative mortality for cardiovascular diseases in the Slovak Republic. AB - The study deals with the analysis of relationship between chemical composition of the groundwater/drinking water and the data on relative mortality for cardiovascular diseases (ReI) in the Slovak Republic. Primary data consist of the Slovak national database of groundwater analyses (20,339 chemical analyses, 34 chemical elements/compounds) and data on ReI collected for the 10-year period (1994-2003). The chemical and health data were unified in the same form and expressed as the mean values for each of 2883 municipalities within the Slovak Republic for further analysis. Artificial neural network was used as mathematic method for model data analysis. The most significant chemical elements having influence on ReI were identified together with their limit values (maximal acceptable, minimal necessary and optimal). Based on the results of calculations, made through the neural networks, the following ten chemical elements/parameters in the groundwater were defined as the most significant for ReI: Ca + Mg (mmol l( 1)), Ca, Mg, TDS, Cl, HCO3, SO4, NO3, SiO2 and PO4. The obtained results document the highest relationship between ReI and the groundwater contents of Ca + Mg (mmol l(-1)), Ca and Mg. Following limit values were set for the most significant groundwater chemicals/parameters: Ca + Mg 4.4-7.6 mmol l(-1), Ca > 89.4 mg l(-1) and Mg 42-78.1 mg l(-1). At these concentration ranges, the relative mortality for cardiovascular diseases in the Slovak Republic reaches the lowest levels. These limit values are about twice higher in comparison with the current Slovak valid guideline values for the drinking water. PMID- 25840566 TI - Mismatch discrimination in fluorescent in situ hybridization using different types of nucleic acids. AB - In the past few years, several researchers have focused their attention on nucleic acid mimics due to the increasing necessity of developing a more robust recognition of DNA or RNA sequences. Fluorescence in situ hybridization (FISH) is an example of a method where the use of these novel nucleic acid monomers might be crucial to the success of the analysis. To achieve the expected accuracy in detection, FISH probes should have high binding affinity towards their complementary strands and discriminate effectively the noncomplementary strands. In this study, we investigate the effect of different chemical modifications in fluorescent probes on their ability to successfully detect the complementary target and discriminate the mismatched base pairs by FISH. To our knowledge, this paper presents the first study where this analysis is performed with different types of FISH probes directly in biological targets, Helicobacter pylori and Helicobacter acinonychis. This is also the first study where unlocked nucleic acids (UNA) were used as chemistry modification in oligonucleotides for FISH methodologies. The effectiveness in detecting the specific target and in mismatch discrimination appears to be improved using locked nucleic acids (LNA)/2'-O methyl RNA (2'OMe) or peptide nucleic acid (PNA) in comparison to LNA/DNA, LNA/UNA, or DNA probes. Further, the use of LNA modifications together with 2'OMe monomers allowed the use of shorter fluorescent probes and increased the range of hybridization temperatures at which FISH would work. PMID- 25840567 TI - High glucose microenvironments inhibit the proliferation and migration of bone mesenchymal stem cells by activating GSK3beta. AB - Diabetes mellitus involves metabolic changes that can impair bone repair. Bone mesenchymal stem cells (BMSCs) play an important role in bone regeneration. However, the bone regeneration ability of BMSCs is inhibited in high glucose microenvironments. It can be speculated that this effect is due to changes in BMSCs' proliferation and migration ability, because the recruitment of factors with an adequate number of MSCs and the microenvironment around the site of bone injury are required for effective bone repair. Recent genetic evidence has shown that the Cyclin D1 and the CXC receptor 4 (CXCR-4) play important roles in the proliferation and migration of BMSCs. In this study we determined the specific role of glycogen synthase kinase-3beta (GSK3beta) in the proliferation and migration of BMSCs in high glucose microenvironments. The proliferation and migration ability of BMSCs were suppressed under high glucose conditions. We showed that high glucose activates GSK3beta but suppresses CXCR-4, beta-catenin, LEF-1, and cyclin D1. Inhibition of GSK3beta by LiCl led to increased levels of beta-catenin, LEF-1, cyclin D1, and CXCR-4 expression. Our data indicate that GSK3beta plays an important role in regulating the proliferation and migration of BMSCs by inhibiting cyclin D1 and CXCR-4 under high glucose conditions. PMID- 25840569 TI - A simple graphical quantitative analysis of ultrasonography images to decide when to perform fine needle aspiration biopsy in diagnosing malignancy in solid thyroid nodules? A two centres prospective study. AB - OBJECTIVE: Since the prevalence of thyroid nodules is high and ultrasonography (USG)-guided fine-needle aspiration biopsy (FNAB) as a diagnostic means cannot be performed in all cases, we aimed to evaluate the feasibility and applicability of simple graphical analysis of USG two-dimensional images, to identify patients with suspicious thyroid nodules who would benefit from FNAB. SUBJECTS AND METHODS: We studied prospectively 211 consecutive patients with thyroid nodules: 122 from the University Clinical Centre (UCC) of Maribor and 89 from the University Medical Centre (UMC) of Ljubljana who underwent USGguided FNAB from January 2011 to October 2013. The cytology report was categorized as benign or suspicious/malignant. Blind to cytology reports, we later performed graphical analysis of USG images using ImageJ (version 1.48r) which is a public domain Java image processing and analysis programme. We compared the average gray value and standard deviation (SD) of the gray values used to generate the mean gray within the selection, with cytology reports. RESULTS: According to cytology reports, 24 thyroid nodules were suspicious/malignant (14/10) and 187 benign. Graphical analysis of USG images performed with ImageJ demonstrated significantly higher values of SD of the gray values used to generate the mean gray value in suspicious/malignant thyroid nodules as compared to unsuspicious nodules in both UCC Maribor and in UMC Ljubljana (P<0.001 and P=0.002, respectively). A higher value of the SD of gray value used to generate the mean gray value meant variation or dispersion from the average value and was correlated by the presence of micro-calcifications. By applying a cut-off level of the quotient between the SD value of an examined thyroid nodule and the SD value of normal/reference thyroid tissue of 1.20, we found that 21/24 nodules were classified as true positive and 114/187 as true negative. CONCLUSION: Our results showed that our graphical quantitative analysis of USG images had a negative predictive value of more than 90% and was able to suggest which thyroid nodules were potentially malignant and needed further investigation. PMID- 25840568 TI - O-GlcNAc modification is essential for the regulation of autophagy in Drosophila melanogaster. AB - O-GlcNAcylation is a dynamic post-translational modification that takes place on ser/thr residues of nucleocytoplasmic proteins. O-GlcNAcylation regulates almost all cellular events as a nutrient sensor, a transcriptional and translational regulator, and a disease-related factor. Although the role of O-GlcNAcylation in insulin signaling and metabolism are well established, the relationship between O GlcNAcylation and autophagy is largely unknown. Here, we manipulated O GlcNAcylation in Drosophila and found that it regulates autophagy through Akt/dFOXO signaling. We demonstrate that O-GlcNAcylation and the levels of O GlcNAc transferase (OGT) are increased during starvation. Furthermore, Atg proteins and autolysosomes are increased in OGT-reduced flies without fasting. Atg proteins and autophagosomes are reduced in OGT-overexpressing flies. Our results suggest that not only autophagy gene expression but also autophagic structures are regulated by OGT through Akt and dFOXO. These data imply that O GlcNAcylation is important in modulating autophagy as well as insulin signaling in Drosophila. PMID- 25840570 TI - Diagnosis of high-risk patients with multivessel coronary artery disease by combined cardiac gated SPET imaging and coronary calcium score. AB - OBJECTIVE: The added value of coronary artery calcium (CAC) to SPET for identification of multivessel CAD has not been studied yet. The aim of this original study was to investigate CAC as an adjunct to gated single photon emission tomography (GSPET) in the detection of multivessel coronary artery disease (CAD). SUBJECTS AND METHODS: The study group consisted of 164 prospectively recruited patients without known CAD-123 (75%) men and 60 (37%) women, having diabetes type II, renal insufficiency, left ventricular dilatation and other cardiac problems (arrhythmia, necessity of pharmacological stress test, etc.). The mean age of these patients was 61+/-12 years (range 34-85 years). All these patients underwent GSPET imaging, CAC score measurement, and coronary angiography. The percentage of ischaemic myocardium, stress and rest left ventricular ejection fraction (LVEF), and transient ischaemic dilation (TID) ratio were measured. RESULTS: Patients with multivessel CAD had more frequently reversible defects in multiple territories, severe ischaemia >=10% of the left ventricle, stress worsening of the LVEF >=5%, TID ratio >=1.17, and CAC score >1000. In the detection of multivessel CAD, the sensitivity of combined assessment of perfusion, function, and CAC (i.e., multiple and/or >=10% ischaemia, and/or worsening of the LVEF >=5%, and/or TID ratio >=1.17, and/or CAC score >1000) was significantly higher than the sensitivity of perfusion alone or perfusion and function alone (81% vs. 55% and 65%, respectively, P<0.05). Sensitivity of only CAC was low (41%). CONCLUSION: Sensitivity of combined assessment of myocardial perfusion, function, and CAC was significantly higher than sensitivity of perfusion alone or perfusion and function alone, suggesting better identification of high-risk patients with CAD. PMID- 25840571 TI - Can (18)F-FDG PET/CT scan change treatment planning and be prognostic in recurrent colorectal carcinoma? A prospective and follow-up study. AB - OBJECTIVE: To prospectively study whether in patients with resected primary colorectal cancer fluorine- 18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) examination could diagnose the stage, specify treatment procedure and be prognostic. SUBJECTS AND METHODS: This prospective study included 75 patients with resected primary colorectal adenocarcinoma referred for (18)F-FDG PET/CT to the National PET Center, at the Clinical Center of Serbia, Belgrade, from January 2010 to May 2013. Findings of (18)F-FDG PET/CT were compared to findings of subsequent histopathological examinations or with results of clinical and imaging follow-up. Patients were followed after PET/CT examination for a mean follow-up time of 16.7+/-5.9 months. RESULTS: In the detection of recurrent disease (18)F-FDG PET/CT showed overall sensitivity, specificity, PPV, NPV and accuracy of 96.6%, 82.4%, 94.9%, 87.5% and 93.3%, respectively. In the detection of stages I and II sensitivity, specificity and accuracy of (18)F-FDG PET/CT were: 88%, 96.6% and 94.7%, respectively, and in the detection of stages III and IV sensitivity, specificity and accuracy were 94.9%, 87.5% and 93.3%, respectively. These findings prevented or changed intended surgical treatment in 12/32 cases. Univariate and multivariate Cox proportional regression analyses revealed that metastatic recurrence (stages III and IV) was the only and independent prognostic factor of disease progression during follow-up (P=0.012 and P=0.023, respectively). Although, survival seemed better in patients with local recurrence compared to metastatic recurrent disease, this difference did not reach significance (Log-rank test; P=0.324). In addition, progression-free survival time was significantly longer in patients in whom (18)F-FDG PET/CT scan led to treatment changes (Log-rank test; P=0.037). CONCLUSION: (18)F-FDG PET/CT was sensitive and accurate for the detection and staging of local and metastatic recurrent colorectal carcinoma, with higher specificity in the detection of local recurrences. The (18)F-FDG PET/CT scan induced treatment changes in 30/75 patients, including 12/32 patients in which surgical treatment was previously planned, and progression free survival time was significantly longer in these patients. PMID- 25840572 TI - Clinical issues regarding misclassification by Dixon based PET/MR attenuation correction. AB - OBJECTIVE: The Dixon sequence is acquired for attenuation correction (AC) of positron emission tomography (PET) data in integrated PET/magnetic resonance (MR). However it sometimes misclassifies soft tissue and fat in MU-map. In the present study, we investigated factors related to this misclassification and their clinical impacts. SUBJECT AND METHODS: Forty-eight oncological patients (19 males and 29 females, mean age: 59+/-11 years old) underwent a single fluorine-18 fluorodeoxyglucose ((18)F-FDG) injection/dualimaging protocol on PET/computed tomography (CT) and subsequently PET/MR. Patients were assigned to either of two groups; group A with a misclassification in at least one bed position or group B with a correctly classified MU-map. We compared body mass index (BMI), lean body mass, fasting duration, volume of hydration and age between group A and group B. In addition, we analyzed the impact of PET quantification using standard uptake ratio (SUR) defined as uptake in volume of interest/uptake in thigh muscle. The Dixon-AC SUR was compared with CT-AC SUR in misclassified bed positions and correctly classified bed positions. All patients were scanned in four bed positions by PET/MR. Ten patients were assigned to group A; six showed misclassification in a bed position (5 in head and 1 in abdomen), three patients in 3 bed positions (head-thorax-abdomen), and one patient in partial bed position in neck. RESULTS: Misclassification was observed in 21% of 48 patients. Group A and group B showed no statistically significant differences in BMI, lean body mass, fasting duration or age, however the volume of hydration in group A (245mL) was smaller than in group B (452.6mL) (P=0.027). In group A, we analyzed Dixon-AC SUR/CT-AC SUR ratios in 16 misclassified and 24 correctly classified regions, and ratios in these regions were significant different 0.80 and 0.93, respectively (P=0.046). CONCLUSION: Because no corrective method has been devised after a scan, we recommend that Dixon images with MU-maps should be checked before interpreting PET/MR images and emphasize the importance of hydration, pre examination. Misclassification errors do not change the presence of (18)F-FDG uptake but can have significant impacts on PET quantification in affected bed positions. PMID- 25840573 TI - Fluorine-18-fluoroethylcholine PET/CT in the detection of prostate cancer: a South African experience. AB - OBJECTIVE: Imaging with fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has, until recently provided disappointing results with low sensitivity ranging from 31%-64% in patients with well-differentiated prostate cancer (PC) at all prostatic specific antigen (PSA) levels while fluorine-18-fluoroethylcholine ((18)F-FECh) PET/CT showed about 85% sensitivity in restaging patients after relapse. We present our experience of the sensitivity of (18)F-FECh PET/CT in the early stages of PC. SUBJECT AND METHODS: Fifty patients were prospectively recruited and imaged, of which 40 fulfilled all inclusion criteria. Our patients had an average age of 65.5 years. Fifteen patients were referred for initial staging, with the remaining 25 referred for restaging and all patients had histologically confirmed adenocarcinoma. Patients were imaged by (18)F-FECh PET/CT. Findings were evaluated qualitatively and quantitatively and compared to the results of histology, PSA, Gleason score and bone scintigraphy. The prostate SUVmax was also used. RESULTS: Thirty-one patients demonstrated abnormal pelvic- and or extra- pelvic findings on (18)F FECh PET/CT, which was consistent with malignant or metastatic involvement. The prostate SUVmax could not be used to predict the presence or absence of metastatic disease. CONCLUSION: Findings of this paper suggest that (18)F-FECh PET/CT in 30/40 cases (estimated as 75%) was helpful in the initial staging, restaging and lymph node detection of patients with PC. The SUVmax was not helpful. We diagnosed more PC cases in our African-American patients as compared to the Caucasian patients. PMID- 25840574 TI - A probabilistic assessment of the diagnosis of paraganglioma/pheochromocytoma based on clinical criteria and biochemical/imaging findings. AB - Paragangliomas (PGL) and pheochromocytomas (P) are rare neural-crest-derived neoplasms. Very recently guidelines on diagnosis and treatment of PGL/P have been presented by the US Endocrine Society. In the following overview we assessed the implementation of these guidelines with probabilistic reasoning (calculating with Fagan nomograms the post-test probability of PGL/P for a given pre-test probability). CONCLUSION: Biochemical evaluation of PGL/P showed excellent diagnostic characteristics with post-test probabilities that are very different from the pre-test probabilities, thus a positive biochemical test is usually indicative of disease whereas a negative one usually rules out disease. The post test probabilities of anatomical and functional imaging modalities (i.e. in nuclear medicine) were different from the pre-test probabilities but to a lesser degree than the biochemical tests; furthermore in biochemically-proven PGL/P a negative imaging modality is not useful, while a positive one may indicate only one of multiple foci of metastatic/extra-adrenal disease. Thus, regarding imaging modalities, they should be combined in order to get the most of their characteristics for the localization of PGL/P. PMID- 25840575 TI - Correlative bone imaging in a case of Schnitzler's syndrome and brief review of the literature. AB - Schnitzler's syndrome is a rare disease characterized by a monoclonal IgM (or IgG) paraprotein, a nonpruritic urticarial skin rash, and 2 (or 3) of the following: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It responds well to treatment with the interleukine-1-inhibitor anakinra. We report the bone scintigraphy and MRI findings in a 45 years old man with this syndrome and compare them with data from the literature. CONCLUSION: None of the imaging findings are specific, but they lead to a differential diagnosis including infiltrative diseases (e.g. systemic mastocytosis or Erdheim-Chester disease) and dysplastic diseases (e.g. melorheostosis, Camurati-Engelmann disease or van Buchem disease). The bone scintigraphy pattern may be very suggestive of the correct diagnosis and of bone involvement in this syndrome. PMID- 25840576 TI - Gastric Schwannoma mimicking malignant gastrointestinal stromal tumor and misdiagnosed by (18)F-FDG PET/CT. AB - Gastric Schwannoma is a rare benign mesenchymal tumor that accounts for only 0.2% of all gastric tumors. The current study presents a case of gastric Schwannoma misdiagnosed as malignant gastrointestinal stromal tumor (GIST) by esophagogastroduodenoscopy, endoscopic ultrasonography, and contrast-enhanced or not enhanced and (18)F-FDG PET/CT imaging. PMID- 25840577 TI - Antiplatelet and Statin Use in US Patients With Coronary Artery Disease Categorized by Race/Ethnicity and Gender, 2003 to 2012. AB - Antiplatelets and statins are efficacious for preventing future cardiovascular events in patients with coronary heart disease. Disparity in cardiovascular outcomes exists by race/ethnicity and gender; however, few studies have explored potential disparities in long-term antiplatelet and statin use by race/ethnicity and gender. We conducted a repeated cross-sectional analysis using the nationally representative Medical Expenditure Panel Survey from 2003 to 2012. The sample consisted of 14,334 men and women >29 years with coronary heart disease. We identified antiplatelet and statin use, medical conditions, and sociodemographic characteristics. Rates of use did not change for statins or the combination of statins and antiplatelets from 2003 to 2012 but decreased for antiplatelets (p = 0.015). Of the total sample, 70.9% (95% confidence interval [CI] 69.7 to 72.1) reported use of antiplatelets, 52.5% (95% CI 51.1 to 53.8) reported statin use, and 43.1% (95% CI 41.8 to 44.4) reported the combination. Use of antiplatelets and statins were associated with one another (odds ratio 3.22; 95% CI 2.87 to 3.62). From 2009 to 2012, black and Hispanic men along with all race/ethnicities of women were less likely to report use of statins, antiplatelets, and the combination of the 2 compared with white men, even after controlling for sociodemographics. Changing the definition of a medication use, inclusion of cardiovascular risk factors, or the inclusion of warfarin in the antiplatelet category did not substantially change the results. Future practice and policy goals should focus on increasing the number of high-risk patients on appropriate preventative medications while focusing particular attention on decreasing the identified disparity. PMID- 25840578 TI - Prevalence and outcomes of patients receiving implantable cardioverter defibrillators for primary prevention not based on guidelines. AB - Implantable cardioverter-defibrillator (ICD) implantation outside practice guidelines remains contentious, particularly during the mandated waiting periods in patients with recent cardiac events. We assessed the prevalence and outcomes of non-guideline-based (NGB) ICD implantations in a tertiary academic medical center, with a specific focus on adjudication of arrhythmia events. All patients who underwent initial primary prevention ICD implantation at our institution from 2004 to 2012 were categorized as having received guideline-based (GB) or NGB implants and were retrospectively assessed for first episode of appropriate ICD therapy and total mortality. Of 807 patients, 137 (17.0%) received NGB implants. During a median follow-up of 2.9 years, patients with NGB implants had similar times to first appropriate ICD therapy (median time to event 1.94 vs 2.17 years in patients with GB implants, p = 0.20). After multivariable analysis, patients with NGB implants remained at higher risk for death (hazard ratio 1.54, 95% confidence interval 1.1 to 2.2, p = 0.03) but not appropriate ICD therapy (hazard ratio 0.83, 95% confidence interval 0.5 to 1.3, p = 0.51). Furthermore, only 1 of 125 patients who underwent implant within the 40-day waiting period after myocardial infarction or 3-month waiting period after revascularization or cardiomyopathy diagnosis received an appropriate therapy within this period. In conclusion, few patients received NGB ICD implants in our academic medical center. Although these patients have similar long-term risk of receiving appropriate ICD therapy compared with patients with GB implants, this risk is very low during the waiting periods mandated by clinical practice guidelines. These results suggest that there is little need to rush into implanting ICDs during these waiting periods. PMID- 25840579 TI - Meta-Analysis of Randomized Controlled Trials Comparing Multivessel Versus Culprit-Only Revascularization for Patients With ST-Segment Elevation Myocardial Infarction and Multivessel Disease Undergoing Primary Percutaneous Coronary Intervention. AB - Current guidelines recommend against revascularization of the noninfarct artery during the index percutaneous coronary intervention (PCI) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI). This was based largely on observational studies with few data coming from randomized controlled trials (RCTs). Recently, several small-to-moderate sized RCTs have provided data, suggesting that a multivessel revascularization approach may be appropriate. We performed a meta-analysis of RCTs comparing multivessel percutaneous coronary intervention (MV PCI) versus culprit vessel-only revascularization (COR) during primary PCI in patients with STEMI and multivessel coronary disease (MVCD). We searched Medline, PubMed, and Scopus databases for RCTs comparing MV PCI versus COR in patients with STEMI and MVCD. The incidence of all-cause death, cardiac death, recurrent myocardial infarction, and revascularization during follow-up were extracted. Four RCTs fit our primary selection criteria. Among these, 566 patients underwent MV PCI (either at the time of the primary PCI or as a staged procedure) and 478 patients underwent COR. During long-term follow-up (range 1 to 2.5 years), combined data indicated a significant reduction in all-cause mortality (relative risk [RR] 0.57, 95% confidence interval [CI] 0.36 to 0.92, p = 0.02) and in cardiac death (RR 0.38, 95% CI 0.20 to 0.73, p = 0.004) with MV PCI. In addition, there was a significantly lower risk of recurrent myocardial infarction (RR 0.41, 95% CI 0.23 to 0.75; p = 0.004) and future revascularization (RR 0.37, 95% CI 0.27 to 0.52; p <0.00001). In conclusion, from the RCT data, MV PCI appears to improve outcomes in patients with STEMI and MVCD. PMID- 25840580 TI - Carperitide and atrial fibrillation after coronary bypass grafting: the Nihon University working group study of low-dose HANP infusion therapy during cardiac surgery trial for postoperative atrial fibrillation. AB - BACKGROUND: Occurrence of atrial fibrillation after cardiac surgery is associated with long-term mortality. We investigated whether infusion of human atrial natriuretic peptide (carperitide) could prevent postoperative atrial fibrillation. METHODS AND RESULTS: A total of 668 patients who underwent isolated coronary artery bypass grafting were randomized to receive infusion of carperitide or physiological saline from the initiation of cardiopulmonary bypass. Patients were monitored continuously for 1 week after surgery to detect atrial fibrillation. The risk factors were investigated by Cox proportional hazard model. Postoperative atrial fibrillation occurred in 41 of 335 patients (12.2%) from the carperitide group versus 110 of 333 patients (32.7%) from the placebo group (P<0.0001). Postoperative levels of angiotensin-II, aldosterone, creatine kinase MB isoenzyme, human heart fatty acid-binding protein, and brain natriuretic peptide were all significantly lower in the carperitide group. The risk factors for postoperative atrial fibrillation by the Cox proportional hazard model were an age >=70 years, emergency surgery, preoperative aldosterone level >150 ng/mL, preoperative nonuse of angiotensin receptor antagonists, preoperative use of calcium antagonists, postoperative nonuse of beta-blockers, postoperative nonuse of aldosterone blockers, and nonuse of carperitide. CONCLUSIONS: Perioperative carperitide infusion reduced the occurrence of postoperative atrial fibrillation. Accordingly, carperitide could be a useful option for preventing postoperative atrial fibrillation. CLINICAL TRIAL REGISTRATION: -URL: http://www.umin.ac.jp. Unique Identifier: UMIN000003958. PMID- 25840581 TI - Associations of Alterations in Pulsatile Arterial Load With Left Ventricular Longitudinal Strain. AB - BACKGROUND: Increased arterial stiffness leads to increased pulsatile load on the heart. We investigated associations of components of pulsatile load with a measure of left ventricular (LV) systolic function-global longitudinal strain (GLS), in a community-based cohort ascertained based on family history of hypertension. METHODS: Arterial tonometry and echocardiography with speckle tracking were performed in 520 adults with normal LV ejection fraction (EF) (age 67+/-9 years, 70% hypertensive) to quantify measures of pulsatile load (characteristic aortic impedance (Zc), total arterial compliance (TAC), and augmentation index (AI)) and GLS. The associations of log-Zc, log-TAC, and AI with GLS were assessed using sex-specific z-scores for each measure of arterial load. RESULTS: In univariable analyses, higher Zc was associated with worse GLS (less negative) and higher TAC and AI were associated with better GLS (all P < 0.001). In a multivariable model including age, sex, heart rate (HR), LVEF, mean arterial load (systemic vascular resistance), and measures of pulsatile load, Zc remained associated with GLS (beta = 0.28, P < 0.001), while the associations of TAC and AI were no longer significant (P > 0.5). Additional adjustment for cardiovascular risk factors and history of coronary heart disease and stroke did not attenuate the association of Zc with GLS; Zc, sex, HR, LVEF remained associated with GLS after stepwise elimination (all P < 0.001). CONCLUSIONS: Greater proximal aortic stiffness, as manifested by a higher Zc, is independently associated with worse LV longitudinal function. PMID- 25840582 TI - Oral Infections, Metabolic Inflammation, Genetics, and Cardiometabolic Diseases. AB - Although several epidemiologic studies reported plausible and potentially causal associations between oral infections and cardiometabolic diseases (CMDs), controversy still lingers. This might be due to unrecognized confounding from metabolic inflammation and genetics, both of which alter the immune responses of the host. Low-grade inflammation termed metainflammation is the hallmark of obesity, insulin resistance, type 2 diabetes, and CMDs. According to the common soil theory, the continuum of obesity to CMDs is the same pathology at different time points, and early metainflammations, such as hyperglycemia and obesity, display many adverse cardiometabolic characteristics. Consequently, adipose tissue is now considered a dynamic endocrine organ that expresses many proinflammatory cytokines such as TNF-alpha, IL-6, plasminogen activator inhibitor 1, and IL-1beta. In metainflammation, IL-1beta and reactive oxygen species are generated, and IL-1beta is a pivotal molecule in the pathogenesis of CMDs. Note that the same cytokines expressed in metainflammation are also reported in oral infections. In metabolic inflammation and oral infections, the innate immune system is activated through pattern recognition receptors-which include transmembrane receptors such as toll-like receptors (TLRs), cytosolic receptors such as nucleotide-binding oligomerization domain-like receptors, and multiprotein complexes called inflammasome. In general, TLR-2s are presumed to recognize lipoteichoic acid of Gram-positive microbes-and TLR-4s, lipopolysaccharide of Gram-negative microbes-while nucleotide-binding oligomerization domain-like receptors detect both Gram-positive and Gram-negative peptidoglycans on the bacterial cell walls. However, a high-fat diet activates TLR-2s, and obesity activates TLR-4s and induces spontaneous increases in serum lipopolysaccharide levels (metabolic endotoxemia). Moreover, genetics controls lipid-related transcriptome and the differentiation of monocyte and macrophages. Additionally, genetics influences CMDs, and this creates a confounding relationship among oral infections, metainflammation, and genetics. Therefore, future studies must elucidate whether oral infections can increase the risk of CMDs independent of the aforementioned confounding factors. PMID- 25840583 TI - CD30 Downregulation, MMAE Resistance, and MDR1 Upregulation Are All Associated with Resistance to Brentuximab Vedotin. AB - Brentuximab vedotin (BV) is an antibody-drug conjugate that specifically delivers the potent cytotoxic drug monomethyl auristatin E (MMAE) to CD30-positive cells. BV is FDA approved for treatment of relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV-resistant disease. We selected for BV-resistant Hodgkin lymphoma (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (Hodgkin lymphoma) exposure to BV. We confirmed drug resistance by MTS assay and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV resistant cells. In addition, tissue biopsy samples from 10 Hodgkin lymphoma and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the Hodgkin lymphoma cell line, demonstrated downregulated CD30 expression compared with the parental cell line. In contrast, the Hodgkin lymphoma cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared with the parental line. For both Hodgkin lymphoma and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One Hodgkin lymphoma patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for Hodgkin lymphoma both in vitro and in patients. PMID- 25840584 TI - Inhibition of Homologous Recombination and Promotion of Mutagenic Repair of DNA Double-Strand Breaks Underpins Arabinoside-Nucleoside Analogue Radiosensitization. AB - In concurrent chemoradiotherapy, drugs are used to sensitize tumors to ionizing radiation. Although a spectrum of indications for simultaneous treatment with drugs and radiation has been defined, the molecular mechanisms underpinning tumor radiosensitization remain incompletely characterized for several such combinations. Here, we investigate the mechanisms of radiosensitization by the arabinoside nucleoside analogue 9-beta-D-arabinofuranosyladenine (araA) placing particular emphasis on the repair of DNA double-strand breaks (DSB), and compare the results to those obtained with fludarabine (F-araA) and cytarabine (araC). Postirradiation treatment with araA strongly sensitizes cells to ionizing radiation, but leaves unchanged DSB repair by NHEJ in logarithmically growing cells, in sorted G1 or G2 phase populations, as well as in cells in the plateau phase of growth. Notably, araA strongly inhibits DSB repair by homologous recombination (HRR), as assessed by scoring ionizing radiation-induced RAD51 foci, and in functional assays using integrated reporter constructs. Cells compromised in HRR by RNAi-mediated transient knockdown of RAD51 show markedly reduced radiosensitization after treatment with araA. Remarkably, mutagenic DSB repair compensates for HRR inhibition in araA-treated cells. Compared with araA, F-araA and araC are only modestly radiosensitizing under the conditions examined. We propose that the radiosensitizing potential of nucleoside analogues is linked to their ability to inhibit HRR and concomitantly promote the error-prone processing of DSBs. Our observations pave the way to treatment strategies harnessing the selective inhibitory potential of nucleoside analogues and the development of novel compounds specifically utilizing HRR inhibition as a means of tumor cell radiosensitization. PMID- 25840585 TI - Effect of the probiotic bacterium Lactobacillus reuteri on white spot lesion development in orthodontic patients. AB - BACKGROUND/OBJECTIVES: The purpose of the study is to evaluate the effect of daily intake of lozenges containing probiotic bacteria on white spot lesion (WSL) formation as well as on salivary lactobacilli (LB) and mutans streptococci (MS) counts, in patients undergoing orthodontic treatment with fixed appliances. MATERIALS/METHODS: A randomized double-blind placebo-controlled study design with two parallel arms was employed. Patients (n = 85, mean age 15.9 years) with maxillary braces on at least eight anterior teeth and a remaining treatment period of 7-24 months were finally enrolled and randomly allocated to a test or placebo group. Subjects in the test group were instructed to take one probiotic lozenge containing two strains of Lactobacillus reuteri once daily. An identical lozenge without active bacteria was used in the placebo group. Dental plaque, WSL, and salivary MS and LB levels were recorded at baseline and immediately after debonding. RESULTS: The groups were balanced at baseline. The mean duration of the intervention was 17 months and the total dropout rate was 10 per cent. There were no differences in the incidence of WSL between the groups at debonding. The patients had generally a neglected oral hygiene, both at baseline and at the follow-up. The levels of salivary LB were significantly reduced in both groups (P < 0.05) at the time of debonding compared with baseline, while no alterations of the MS counts were unveiled. LIMITATIONS: WSL were scored from photos that may not fully mirror the clinical situation. Chair-side tests estimate the counts of selected bacteria in saliva and do not reflect the entire microbiota. The invention was implemented approximately 6 months after the onset of the fixed appliances and some lesions may have been present at bonding. CONCLUSIONS/CLINICAL IMPLICATIONS: Daily intake of probiotic lozenges did not seem to affect the development of WSL during orthodontic treatment with fixed appliances. PMID- 25840586 TI - Meta-analysis and systematic review of the number of non-syndromic congenitally missing permanent teeth per affected individual and its influencing factors. AB - BACKGROUND AND PURPOSE: Dental aplasia (or hypodontia) is a frequent and challenging anomaly and thus of interest to many dental fields. Although the number of missing teeth (NMT) in each person is a major clinical determinant of treatment need, there is no meta-analysis on this subject. Therefore, we aimed to investigate the relevant literature, including epidemiological studies and research on dental/orthodontic patients. METHODS: Among 50 reports, the effects of ethnicities, regions, sample sizes/types, subjects' minimum ages, journals' scientific credit, publication year, and gender composition of samples on the number of missing permanent teeth (except the third molars) per person were statistically analysed (alpha = 0.05, 0.025, 0.01). LIMITATIONS: The inclusion of small studies and second-hand information might reduce the reliability. Nevertheless, these strategies increased the meta-sample size and favoured the generalisability. Moreover, data weighting was carried out to account for the effect of study sizes/precisions. RESULTS: The NMT per affected person was 1.675 [95% confidence interval (CI) = 1.621-1.728], 1.987 (95% CI = 1.949-2.024), and 1.893 (95% CI = 1.864-1.923), in randomly selected subjects, dental/orthodontic patients, and both groups combined, respectively. The effects of ethnicities (P > 0.9), continents (P > 0.3), and time (adjusting for the population type, P = 0.7) were not significant. Dental/orthodontic patients exhibited a significantly greater NMT compared to randomly selected subjects (P < 0.012). Larger samples (P = 0.000) and enrolling younger individuals (P = 0.000) might inflate the observed NMT per person. CONCLUSIONS: Time, ethnic backgrounds, and continents seem unlikely influencing factors. Subjects younger than 13 years should be excluded. Larger samples should be investigated by more observers. PMID- 25840588 TI - Correction for Moller, Mitochondrial metabolism is regulated by thioredoxin. PMID- 25840589 TI - Correction for Paytan et al., Methane transport from the active layer to lakes in the Arctic using Toolik Lake, Alaska, as a case study. PMID- 25840587 TI - Shape variation and covariation of upper and lower dental arches of an orthodontic population. AB - OBJECTIVES: This study aimed to quantify the patterns of shape variability and the extent and patterns of shape covariation between the upper and lower dental arch in an orthodontic population. METHODS: Dental casts of 133 white subjects (61 males, 72 females; ages 10.6-26.6) were scanned and digitized in three dimensions. Landmarks were placed on the incisal margins and on the cusps of canines, premolars, and molars. Geometric morphometric methods were applied (Procrustes superimposition and principal component analysis). Sexual dimorphism and allometry were evaluated with permutation tests and age-size and age-shape correlations were computed. Two-block partial least squares analysis was used to assess covariation of shape. RESULTS: The first four principal components represented shape patterns that are often encountered and recognized in clinical practice, accounting for 6-31 per cent of total variance. No shape sexual dimorphism was found, nevertheless, there was statistically significant size difference between males and females. Allometry was statistically significant, but low (upper: R(2) = 0.0528, P < 0.000, lower: R (2) = 0.0587, P < 0.000). Age and shape were weakly correlated (upper: R(2) = 0.0370, P = 0.0001, lower: R (2) = 0.0587, P = 0.0046). Upper and lower arches covaried significantly (RV coefficient: 33 per cent). The main pattern of covariation between the dental arches was arch width (80 per cent of total covariance); the second component related the maxillary canine vertical position to the mandibular canine labiolingual position (11 per cent of total covariance). LIMITATIONS: Results may not be applicable to the general population. Age range was wide and age-related findings are limited by the cross-sectional design. Aetiology of malocclusion was also not considered. CONCLUSIONS: Covariation patterns showed that the dental arches were integrated in width and depth. Integration in the vertical dimension was weak, mainly restricted to maxillary canine position. PMID- 25840590 TI - Telomere dysfunction causes alveolar stem cell failure. AB - Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial. PMID- 25840592 TI - The application of engineered liver tissues for novel drug discovery. AB - INTRODUCTION: Drug-induced liver injury remains a major cause of drug attrition. Furthermore, novel drugs are being developed for treating liver diseases. However, differences between animals and humans in liver pathways necessitate the use of human-relevant liver models to complement live animal testing during preclinical drug development. Microfabrication tools and synthetic biomaterials now allow for the creation of tissue subunits that display more physiologically relevant and long-term liver functions than possible with declining monolayers. AREAS COVERED: The authors discuss acellular enzyme platforms, two-dimensional micropatterned co-cultures, three-dimensional spheroidal cultures, microfluidic perfusion, liver slices and humanized rodent models. They also present the use of cell lines, primary liver cells and induced pluripotent stem cell-derived human hepatocyte-like cells in the creation of cell-based models and discuss in silico approaches that allow integration and modeling of the datasets from these models. Finally, the authors describe the application of liver models for the discovery of novel therapeutics for liver diseases. EXPERT OPINION: Engineered liver models with varying levels of in vivo-like complexities provide investigators with the opportunity to develop assays with sufficient complexity and required throughput. Control over cell-cell interactions and co-culture with stromal cells in both two dimension and three dimension are critical for enabling stable liver models. The validation of liver models with diverse sets of compounds for different applications, coupled with an analysis of cost:benefit ratio, is important for model adoption for routine screening. Ultimately, engineered liver models could significantly reduce drug development costs and enable the development of more efficacious and safer therapeutics for liver diseases. PMID- 25840591 TI - The potential of technology-based psychological interventions for anorexia and bulimia nervosa: a systematic review and recommendations for future research. AB - BACKGROUND: Previous studies have shown an unmet need in the treatment of eating disorders. In the last decade, interest in technology-based interventions (TBIs) (including computer- and Internet-based interventions [CBIs] or mobile interventions) for providing evidence-based therapies to individuals with different mental disorders has increased. OBJECTIVE: The aim of this review was to systematically evaluate the potential of TBIs in the field of eating disorders, namely for anorexia nervosa (AN) and bulimia nervosa (BN), for both prevention and treatment, and also for carers of eating disorder patients. METHODS: A systematic literature search was conducted using Medline and PsycINFO. Bibliographies of retrieved articles were also reviewed without date or study type restrictions. RESULTS: Forty studies resulting in 45 publications reporting outcomes fulfilled the inclusion criteria: 22 randomized controlled trials, 2 controlled studies, and 16 uncontrolled studies. In total, 3646 patients were included. Overall, the studies provided evidence for the efficacy of guided CBIs, especially for BN patients and for compliant patients. Furthermore, videoconferencing also appeared to be a promising approach. Evaluation results of Internet-based prevention of eating disorders and Internet-based programs for carers of eating disorder patients were also encouraging. Finally, there was preliminary evidence for the efficacy of mobile interventions. CONCLUSIONS: TBIs may be an additional way of delivering evidence-based treatments to eating disorder patients and their use is likely to increase in the near future. TBIs may also be considered for the prevention of eating disorders and to support carers of eating disorder patients. Areas of future research and important issues such as guidance, therapeutic alliance, and dissemination are discussed. PMID- 25840593 TI - Are big potassium-type Ca(2+)-activated potassium channels a viable target for the treatment of epilepsy? AB - INTRODUCTION: BK (big potassium) channels are Ca(2+)-activated K(+) channels widely expressed in mammalian cells. They are extensively distributed in the CNS, the most abundant level being found in brain areas largely involved in epilepsy, namely cortex, hippocampus, piriform cortex, and other limbic structures. BK channels control action potential shape/duration, thereby regulating membrane excitability and Ca(2+) signaling. AREAS COVERED: The potassium channel superfamily represents a rich source of potential targets for therapeutic intervention in epilepsy. Some studies have identified alterations in BK channel function, therefore, supporting the development of drugs acting on these channels for epilepsy treatment. EXPERT OPINION: The actual sketch is intriguing and controversial, since mechanisms altering the physiological role of BK channels leading to either a loss- or gain-of-function have both been linked to seizure onset. Not many studies have been performed to unravel the efficacy of drugs acting on these channels as potential antiepileptics; however, paradoxically, efficacy has been demonstrated for both BK channel openers and blockers. Furthermore, their potential usefulness in preventing epileptogenesis has not been investigated at all. Substantial data on risks and benefits of modulating these channels are urgently needed to draw a definitive conclusion on whether BK channels are a viable future target for the treatment of epilepsy. PMID- 25840594 TI - Identifying sequential substrate binding at the single-molecule level by enzyme mechanical stabilization. AB - Enzyme-substrate binding is a dynamic process intimately coupled to protein structural changes, which in turn changes the unfolding energy landscape. By the use of single-molecule force spectroscopy (SMFS), we characterize the open-to closed conformational transition experienced by the hyperthermophilic adenine diphosphate (ADP)-dependent glucokinase from Thermococcus litoralis triggered by the sequential binding of substrates. In the absence of substrates, the mechanical unfolding of TlGK shows an intermediate 1, which is stabilized in the presence of Mg.ADP(-), the first substrate to bind to the enzyme. However, in the presence of this substrate, an additional unfolding event is observed, intermediate 1*. Finally, in the presence of both substrates, the unfolding force of intermediates 1 and 1* increases as a consequence of the domain closure. These results show that SMFS can be used as a powerful experimental tool to investigate binding mechanisms of different enzymes with more than one ligand, expanding the repertoire of protocols traditionally used in enzymology. PMID- 25840595 TI - Socio-cultural and service delivery dimensions of maternal mortality in rural central India: a qualitative exploration using a human rights lens. AB - BACKGROUND: Despite the avoidable nature of maternal mortality, unacceptably high numbers of maternal deaths occur in developing countries. Considering its preventability, maternal mortality is being increasingly recognised as a human rights issue. Integration of a human rights perspective in maternal health programmes could contribute positively in eliminating avertable maternal deaths. This study was conducted to explore socio-cultural and service delivery-related dimensions of maternal deaths in rural central India using a human rights lens. DESIGN: Social autopsies were conducted for 22 maternal deaths during 2011 in Khargone district in central India. The data were analysed using thematic analysis. The factors associated with maternal deaths were classified by using the 'three delays' framework and were examined by using a human rights lens. RESULTS: All 22 women tried to access medical assistance, but various factors delayed their access to appropriate care. The underestimation of the severity of complications by family members, gender inequity, and perceptions of low-quality delivery services delayed decisions to seek care. Transportation problems and care seeking at multiple facilities delayed reaching appropriate health facilities. Negligence by health staff and unavailability of blood and emergency obstetric care services delayed receiving adequate care after reaching a health facility. CONCLUSIONS: The study highlighted various socio-cultural and service delivery-related factors which are violating women's human rights and resulting in maternal deaths in rural central India. This study highlights that, despite the health system's conscious effort to improve maternal health, normative elements of a human rights approach to maternal health (i.e. availability, accessibility, acceptability, and quality of maternal health services) were not upheld. The data and analysis suggest that the deceased women and their relatives were unable to claim their entitlements and that the duty bearers were not successful in meeting their obligations. Based on the findings of our study, we conclude that to prevent maternal deaths, further concentrated efforts are required for better community education, women's empowerment, and health systems strengthening to provide appropriate and timely services, including emergency obstetric care, with good quality. PMID- 25840596 TI - Developing a healthy web-based cookbook for pediatric cancer patients and survivors: rationale and methods. AB - BACKGROUND: Obesity has been a growing problem among children and adolescents in the United States for a number of decades. Childhood cancer survivors (CCS) are more susceptible to the downstream health consequences of obesity such as cardiovascular disease, endocrine issues, and risk of cancer recurrence due to late effects of treatment and suboptimal dietary and physical activity habits. OBJECTIVE: The objective of this study was to document the development of a Web based cookbook of healthy recipes and nutrition resources to help enable pediatric cancer patients and survivors to lead healthier lifestyles. METHODS: The Web-based cookbook, named "@TheTable", was created by a committee of researchers, a registered dietitian, patients and family members, a hospital chef, and community advisors and donors. Recipes were collected from several sources including recipe contests and social media. We incorporated advice from current patients, parents, and CCS. RESULTS: Over 400 recipes, searchable by several categories and with accompanying nutritional information, are currently available on the website. In addition to healthy recipes, social media functionality and cooking videos are integrated into the website. The website also features nutrition information resources including nutrition and cooking tip sheets available on several subjects. CONCLUSIONS: The "@TheTable" website is a unique resource for promoting healthy lifestyles spanning pediatric oncology prevention, treatment, and survivorship. Through evaluations of the website's current and future use, as well as incorporation into interventions designed to promote energy balance, we will continue to adapt and build this unique resource to serve cancer patients, survivors, and the general public. PMID- 25840597 TI - Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. AB - We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16. PMID- 25840598 TI - Sequential combination of gemcitabine, vinorelbine, pegylated liposomal doxorubicin and brentuximab as a bridge regimen to transplant in relapsed or refractory Hodgkin lymphoma. PMID- 25840599 TI - Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease. AB - Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (>= 1 year post transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed. PMID- 25840600 TI - Impact of maintenance therapy on subsequent treatment in patients with newly diagnosed multiple myeloma: use of "progression-free survival 2" as a clinical trial end-point. PMID- 25840601 TI - Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis. AB - Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the "bad seed in bad soil" hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis. PMID- 25840603 TI - What does it take to be a successful pediatric surgeon-scientist? AB - BACKGROUND: The factors that contribute to success as a pediatric surgeon scientist are not well defined. The purpose of this study is to define a group of NIH-funded pediatric surgeons, assess their academic productivity, and elucidate factors that have contributed to their success. METHODS: Pediatric surgeons were queried in the NIH report database to determine NIH funding awarded. Academic productivity was then assessed. An online survey was then targeted to NIH-funded pediatric surgeons. RESULTS: Since 1988, 83 pediatric surgeon-investigators have received major NIH funding. Currently, there are 37 pediatric surgeons with 43 NIH-sponsored awards. The mean h-index of this group of pediatric surgeons was 18 +/- 1.1, mean number of publications (since 2001) was 21 +/- 2.1, and both increase commensurate with academic rank. In response to the survey, 81% engaged in research during their surgical residency, and 48% were mentored by a pediatric surgeon-scientist. More than 60% of respondents had significant protected time and financial support. Factors felt to be most significant for academic success included mentorship, perseverance, and protected time. CONCLUSIONS: Mentorship, perseverance, institutional commitment to protected research time, and financial support are considered to be important to facilitate the successes of pediatric surgeon-scientists. These results will be useful to aspiring pediatric surgeon scientists and departments wishing to develop a robust research program. PMID- 25840602 TI - Targeting the Ataxia Telangiectasia Mutated-null phenotype in chronic lymphocytic leukemia with pro-oxidants. AB - Inactivation of the Ataxia Telangiectasia Mutated gene in chronic lymphocytic leukemia results in resistance to p53-dependent apoptosis and inferior responses to treatment with DNA damaging agents. Hence, p53-independent strategies are required to target Ataxia Telangiectasia Mutated-deficient chronic lymphocytic leukemia. As Ataxia Telangiectasia Mutated has been implicated in redox homeostasis, we investigated the effect of the Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia genotype on cellular responses to oxidative stress with a view to therapeutic targeting. We found that in comparison to Ataxia Telangiectasia Mutated-wild type chronic lymphocytic leukemia, pro-oxidant treatment of Ataxia Telangiectasia Mutated-null cells led to reduced binding of NF-E2 p45-related factor-2 to antioxidant response elements and thus decreased expression of target genes. Furthermore, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia cells contained lower levels of antioxidants and elevated mitochondrial reactive oxygen species. Consequently, Ataxia Telangiectasia Mutated-null chronic lymphocytic leukemia, but not tumors with 11q deletion or TP53 mutations, exhibited differentially increased sensitivity to pro oxidants both in vitro and in vivo. We found that cell death was mediated by a p53- and caspase-independent mechanism associated with apoptosis inducing factor activity. Together, these data suggest that defective redox-homeostasis represents an attractive therapeutic target for Ataxia Telangiectasia Mutated null chronic lymphocytic leukemia. PMID- 25840604 TI - Management of spontaneous pneumomediastinum in children. AB - PURPOSE: We characterize the outcomes of pediatric spontaneous pneumomediastinum in the largest series to date and propose a management pathway. METHODS: All patients at our institution with ICD-9 code 518.1 confirmed to have isolated radiographic findings of spontaneous pneumomediastinum between January 2003 and February 2014 were retrospectively reviewed for admission, intensive care unit (ICU) stay, complications, and outcome. RESULTS: We identified 96 children with 99 episodes, median age 14.1 years (IQR: 8.7-16.4). Primary symptoms were chest pain, cough, and dyspnea. Most were hospitalized (n=91, 91.9%), with 20 (20.2%) admitted to ICU. Median lengths of stay (LOS) were 1 day (IQR: 1-2) for non-ICU admissions and 3 days (IQR: 2-3) for ICU admissions. The surgical service discharged non-ICU patients 0.94 days earlier than medical services (95% CI 0.38 1.50, p=0.0014). Asthma affected neither LOS nor ICU admission rates. Follow-up imaging, when obtained (n=81, 81.8%), did not alter management. Recurrences occurred in three asthmatics, all after one year. Each was rehospitalized and discharged uneventfully. No patient developed pneumomediastinum-related complications (e.g., pneumothorax, pneumopericardium, or mediastinitis). CONCLUSION: Spontaneous pneumomediastinum without associated comorbidities can be managed with expectant outpatient observation without further imaging. Children with asthma should be treated independent of spontaneous pneumomediastinum. PMID- 25840605 TI - Designing drugs that combat kidney damage. AB - INTRODUCTION: Kidney disease remains one of the last worldwide frontiers in the field of non-communicable human disease. From 1990 to 2013, chronic kidney disease (CKD) was the top non-communicable cause of death with a greatest increase in global years of life lost while mortality of acute kidney injury (AKI) still hovers around 50%. This reflects the paucity (for CKD) or lack of (for AKI) therapeutic approaches beyond replacing renal function. Understanding what the barriers are and what potential pathways may facilitate the design of new drugs to combat kidney disease is a key public health priority. AREAS COVERED: The authors discuss the hurdles and opportunities for future drug development for kidney disease in light of experience accumulated with drugs that made it to clinical trials. EXPERT OPINION: Inflammation, cell death and fibrosis are key therapeutic targets to combat kidney damage. While the specific targeting of drugs to kidney cells would be desirable, the technology is only working at the preclinical stage and with mixed success. Nanomedicines hold promise in this respect. Most drugs undergoing clinical trials for kidney disease have been repurposed from other indications. Currently, the chemokine receptor inhibitor CCX140 holds promise for CKD and the p53 inhibitor QPI-1002 for AKI. PMID- 25840606 TI - Controlling differentiation of adipose-derived stem cells using combinatorial graphene hybrid-pattern arrays. AB - Control of stem cell fate by modulating biophysical cues (e.g., micropatterns, nanopatterns, elasticity and porosity of the substrates) has emerged as an attractive approach in stem cell-based research. Here, we report a method for fabricating combinatorial patterns of graphene oxide (GO) to effectively control the differentiation of human adipose-derived mesenchymal stem cells (hADMSCs). In particular, GO line patterns were highly effective for modulating the morphology of hADMSCs, resulting in enhanced differentiation of hADMSCs into osteoblasts. Moreover, by generating GO grid patterns, we demonstrate the highly efficient conversion of mesodermal stem cells to ectodermal neuronal cells (conversion efficiency = 30%), due to the ability of the grid patterns to mimic interconnected/elongated neuronal networks. This work provides an early demonstration of developing combinatorial graphene hybrid-pattern arrays for the control of stem cell differentiation, which can potentially lead to more effective stem cell-based treatment of incurable diseases/disorders. PMID- 25840607 TI - A pilot study of a new method of cognitive stimulation using abacus arithmetic in healthy and cognitively impaired elderly subjects. AB - BACKGROUND: This study explores the applicability of a cognitive stimulation method based on abacus arithmetic in elderly people with and without cognitive impairment. METHODS: This observational and prospective pilot study was performed in 2 hospitals. The study assessed the applicability of a programme of arithmetic training developed for use in the elderly population. The primary endpoint was an evaluation of the stimulation programme, in terms of usability, satisfaction, and participation, in healthy elderly controls and elderly patients with mild cognitive impairment or Alzheimer disease. Secondary endpoints were family satisfaction, caregiver burden, and the behaviour and cognition of patients. RESULTS: Usability, satisfaction, and degree of participation were high. The Mini Mental State Examination showed significant changes (23.1+/-4.8 before the intervention vs 24.9+/-4.2 afterwards, P=.002); there were no changes on the Trail Making Test parts A and B, Yesavage Geriatric Depression scale, and Zarit caregiver burden scale. CONCLUSIONS: The study suggests that cognitive stimulation with abacus arithmetic may be used in elderly people with and without cognitive impairment. Further studies will be needed to evaluate the efficacy of this kind of programmes. PMID- 25840608 TI - Magnitude of negative impact of preoperative heart failure on mortality during aortic valve replacement in the medicare population. AB - BACKGROUND: In patients with severe aortic stenosis, the development of heart failure (HF) prior to aortic valve replacement (AVR) is associated with worse prognosis. We sought to quantify the effect of progressive HF on mortality during AVR in the Medicare population over a 10-year period. METHODS: Medicare beneficiaries 65 or greater years of age who underwent primary isolated AVR from 2000 through 2009 were included (n = 114,135). Logistic regression and Cox proportional hazards were used to model adjusted operative mortality (OM) and long-term survival, according to the presence of preoperative HF and its duration (<= 3 vs > 3 months). RESULTS: The incidence of preoperative comorbidities was high, and it was higher in patients with preoperative HF, compared with those without. Preoperative HF dramatically increased adjusted OM, odds ratio (OR) 1.57 (95% confidence interval [CI], 1.48 to 1.67). Preoperative HF greater than 3 months conferred a significant increase in adjusted OM compared with HF 3 months or less, OR 1.43 (95% CI, 1.32 to 1.55). Similarly, preoperative HF increased the likelihood of long-term mortality by 50%, hazard ratio (HR) 1.48 (95% CI, 1.45 to 1.51). Long-term mortality was higher for patients with longer duration of preoperative HF as compared with those without preoperative HF, HR 1.81 (95% CI, 1.75 to 1.87) and compared with patients with HF 3 months or less, HR 1.26 (95% CI, 1.23 to 1.30). CONCLUSIONS: The magnitude of the negative impact of preoperative HF on operative mortality and long-term survival of elderly patients undergoing primary isolated AVR is significant with 50% increased likelihood of adverse outcome. Duration of preoperative HF is also significantly related to mortality. These data support AVR in the elderly prior to the development of HF. PMID- 25840609 TI - Involved Node, Site, Field and Residual Volume Radiotherapy for Lymphoma: A Comparison of Organ at Risk Dosimetry and Second Malignancy Risks. AB - AIMS: Recent radiotherapy guidelines for lymphoma have included involved site radiotherapy (ISRT), involved node radiotherapy (INRT) and irradiation of residual volume after full-course chemotherapy. In the absence of late toxicity data, we aim to compare organ at risk (OAR) dose-metrics and calculated second malignancy risks. MATERIALS AND METHODS: Fifteen consecutive patients who had received mediastinal radiotherapy were included. Four radiotherapy plans were generated for each patient using a parallel pair photon technique: (i) involved field radiotherapy (IFRT), (ii) ISRT, (iii) INRT, (iv) residual post-chemotherapy volume. The radiotherapy dose was 30 Gy in 15 fractions. The OARs evaluated were: breasts, lungs, thyroid, heart, oesophagus. Relative and absolute second malignancy rates were estimated using the concept of organ equivalent dose. Significance was defined as P < 0.005. RESULTS: Compared with ISRT, IFRT significantly increased doses to lung, thyroid, heart and oesophagus, whereas INRT and residual volume techniques significantly reduced doses to all OARs. The relative risks of second cancers were significantly higher with IFRT compared with ISRT for lung, breast and thyroid; INRT and residual volume resulted in significantly lower relative risks compared with ISRT for lung, breast and thyroid. The median excess absolute risks of second cancers were consistently lowest for the residual technique and highest for IFRT in terms of thyroid, lung and breast cancers. The risk of oesophageal cancer was similar for all four techniques. Overall, the absolute risk of second cancers was very similar for ISRT and INRT. CONCLUSIONS: Decreasing treatment volumes from IFRT to ISRT, INRT or residual volume reduces radiation exposure to OARs. Second malignancy modelling suggests that this reduction in treatment volumes will lead to a reduction in absolute excess second malignancy. Little difference was observed in second malignancy risks between ISRT and INRT, supporting the use of ISRT in the absence of a pre-chemotherapy positron emission tomography scan in the radiotherapy treatment position. PMID- 25840610 TI - Generation of a Nkx2.2(Cre) knock-in mouse line: Analysis of cell lineages in the central nervous system. AB - A Nkx2.2(cre) knock-in mutant mouse line was generated that on the appropriate reporter strain enables cell fate analysis of the Nkx2.2 cell lineage in the central nervous system and elsewhere. We here demonstrate that Nkx2.2 lineage marked cells reside in the ventral p3 region along the entire length of the CNS and also in pancreas of mouse embryos. Nkx2.2(+) progenitor cells develop into V3 interneurons in spinal cord and generate the branchio-visceral motor nuclei of cranial nerves in hindbrain. Nkx2.2(+) cells in hindbrain also form serotonergic neurons and oligodendrocytes during later developmental stages. In mouse mutants lacking Nkx2.2 protein the neuronal progenitor cells in spinal cord are transformed to the distinct fate of somatic motor neurons including their axonal projections that exit the CNS ventrally and no longer cross the midline at the commissure. These data identify Nkx2.2 as key regulator to determine neuronal subtypes in the p3 domain of the central nervous system. PMID- 25840611 TI - Genotypic characterization of initial acquisition of Streptococcus mutans in American Indian children. AB - BACKGROUND: Severe-early childhood caries (S-ECC) is one of the most common infectious diseases in children and is prevalent in lower socio-economic populations. American Indian children suffer from the highest levels of S-ECC in the United States. Members of the mutans streptococci, Streptococcus mutans, in particular, are key etiologic agents in the development of caries. Children typically acquire S. mutans from their mothers and early acquisition is often associated with higher levels of tooth decay. METHODS: We have conducted a 5-year birth cohort study with a Northern Plains Tribe to determine the temporality and fidelity of S. mutans transmission from mother to child in addition to the genotypic diversity of S. mutans in this community. Plaque samples were collected from 239 mother/child dyads at regular intervals from birth to 36 months and S. mutans were isolated and genotyped by arbitrarily primed-polymerase chain reaction (AP-PCR). RESULTS: Here we present preliminary findings from a subset of the cohort. The focus for this paper is on initial acquisition events in the children. We identified 17 unique genotypes in 711 S. mutans isolates in our subset of 40 children, 40 mothers and 14 primary caregivers. Twelve of these genotypes were identified in more than one individual. S. mutans colonization occurred by 16 months in 57.5% of the children and early colonization was associated with higher decayed, missing and filled surface (DMFS) scores (p=0.0007). Children colonized by S. mutans shared a common genotype with their mothers 47.8% of the time. While multiple genotypes were common in adults, only 10% of children harbored multiple genotypes. CONCLUSION: These children acquire S. mutans at an earlier age than the originally described 'window of infectivity' and often, but not exclusively, from their mothers. Early acquisition is associated with both the caries status of the children and the mothers. PMID- 25840613 TI - Comments on "Human health risk assessment of pharmaceuticals and personal care products in plant tissue due to biosolids and manure amendments, and wastewater irrigation". PMID- 25840612 TI - Outer membrane vesicles - offensive weapons or good Samaritans? AB - Outer membrane vesicles (OMVs) from Gram-negative bacteria were first considered as artifacts and were followed with disbelief and bad reputation. Later, their existence was accepted and they became characterized as bacterial bombs, virulence bullets, and even decoys. Today, we know that OMVs also can be involved in cell-cell signaling/communication and be mediators of immune regulation and cause disease protection. Furthermore, OMVs represent a distinct bacterial secretion pathway selecting and protecting their cargo, and they can even be good Samaritans providing nutrients to the gut microbiota maintaining commensal homeostasis beneficial to the host. The versatility in functions of these nanostructures is remarkable and includes both defense and offense. The broad spectrum of usability does not stop with that, as it now seems that OMVs can be used as vaccines and adjuvants or vehicles engineered for drug treatment of emerging and new diseases not only caused by bacteria but also by virus. They may even represent new ways of selective drug treatment. PMID- 25840614 TI - Exogenous melatonin does not improve the freezability of Blanca Andaluza goat semen over exposure to two months of short days. AB - This paper compares the effects of exposure to exogenous melatonin (MEL), short days (SD, 8h of light) and long days (LD, 16 h of light), on reproductive activity, sperm motility and other reproductive variables, in Blanca Andaluza bucks. Fourteen males were spilt into two groups of seven animals (G1 and G2). They were subjected to five alternations of 2 months of LD followed by 2 months of SD or MEL before the experimental period of three consecutive intervals of: (1) 2 months of SD (G1, N=7) or MEL (G2, N=7); (2) 2 months of LD (G1+G2, N=14); and (3) 2 months of SD (G2, N=7) or MEL (G1, N=7). Plasma testosterone concentration, live weight, testicular weight and fresh semen quality were determined weekly. Semen was also cooled and frozen-thawed every fortnight, and the same quality variables measured as for fresh sperm. When the bucks were under LD treatment, the testosterone concentration was lower than when under MEL or SD treatment (P<0.01); values for the semen concentration and total number of sperm per ejaculate were also higher (P<0.001). No differences were observed between the MEL and SD treatments in terms of fresh, cooled or frozen-thawed sperm quality. Only some quality variables on fresh semen were improved by MEL and SD treatment (P<0.05). In conclusion the results of the present experiment showed that MEL improved the fresh semen motility variables, but this did not improve the motility of frozen-thawed sperm over that recorded for either SD or LD treatment. PMID- 25840615 TI - Severe vaso-occlusive chorioretinopathy in a patient with catastrophic antiphospholipid antibody syndrome secondary to systemic lupus erythematosus. PMID- 25840616 TI - [Laffer-Ascher syndrome: a case report]. PMID- 25840617 TI - Tolerability of intracameral cefuroxime during cataract surgery in case of penicillin allergy. AB - INTRODUCTION: Since the results of the ESCRS study in 2007 and then the AFSSAPS recommendations of 2011, postoperative endophthalmitis prophylaxis in cataract surgery has evolved toward intracameral cefuroxime. Penicillin allergy is frequent and is not considered as a contra-indication to cefuroxime injection, but cross-reactions do exist. The goal of this study was to assess the tolerability of intracameral cefuroxime in patients with a penicillin allergy. MATERIALS AND METHODS: In this monocentric open prospective study, adult patients undergoing cataract surgery and declaring themselves penicillin-allergic were included. A subcutaneous test of cefuroxime was performed preoperatively. If negative, patients received the intracameral injection of cefuroxime at the conclusion of the surgical procedure. The primary assessment criteria, evaluated on the day after the surgery, was the occurrence of allergic reactions. RESULTS: Forty-eight eyes of 40 patients, 72 +/- 8 years old, were included. Forty-three skin tests were performed: 1 was positive and one was unreliable. Thirty-six patients were examined in our center the day after the surgery: 2 presented a conjunctival allergic reaction. No severe anaphylactic reaction was reported. DISCUSSION: Of our patients, 95.3% declaring a penicillin allergy had a negative pre-operative cefuroxime test. According to literature, 80 to 90% of presumed penicillin allergic patients would not actually be allergic to cefuroxime. In our population, we reported 2 benign conjunctival cross-reactions. CONCLUSION: Intracameral cefuroxime injection during cataract surgery seems well-tolerated in penicillin-allergic patients with a negative preoperative skin test. PMID- 25840618 TI - [Management of a choroidal neovascular membrane with aflibercept in a patient with a rare, autosomal dominant late-onset retinal degeneration: case report]. PMID- 25840619 TI - The National Centre for Oncological Hadrontherapy (CNAO): Status and perspectives. AB - The National Centre for Oncological Hadrontherapy (CNAO, sited in Pavia, Italy) completed at the end of 2013 the clinical trial phase achieving the CE label from the notified body of the Italian Health Ministry and obtained the authorisation to treat patients within the national health system. Nowadays more than 400 patients completed the treatments, two thirds of them with carbon ions, and recently started the treatment of pathologies located within moving organs. For the first time in the world carbon ions delivered with active scanning, coupled with breathing synchronisation and rescanning modalities have been applied to treat patients affected by tumours of the liver and by pancreatic cancers. The path to reach the final CE label required a wide-ranging experimental activity that went through dosimetry measurements of the hadron beams, in-vitro and in vivo radiobiology essays and treatments of 150 patients, all enrolled in one of the 23 clinical trials approved by the Ethical Committee of CNAO and then authorized by the Italian Ministry of Health. The results of the trials were very positive in terms of safety and reliability of the procedures. The follow-up period is still short, but preliminary good results are observed in particular in terms of limited toxicity, that on the whole is less than expected. The paper gives a status report on the experimental phase that completed the CE certification process and then outlines the ongoing activities with also indications on the future trends and the most interesting R&D programmes pursued at CNAO. PMID- 25840620 TI - A Monte Carlo software bench for simulation of spectral k-edge CT imaging: Initial results. AB - PURPOSE: Spectral Computed Tomography (SCT) systems equipped with photon counting detectors (PCD) are clinically desired, since such systems provide not only additional diagnostic information but also radiation dose reductions by a factor of two or more. The current unavailability of clinical PCDs makes a simulation of such systems necessary. METHODS: In this paper, we present a Monte Carlo-based simulation of a SCT equipped with a PCD. The aim of this development is to facilitate research on potential clinical applications. Our MC simulator takes into account scattering interactions within the scanned object and has the ability to simulate scans with and without scatter and a wide variety of imaging parameters. To demonstrate the usefulness of such a MC simulator for development of SCT applications, a phantom with contrast targets covering a wide range of clinically significant iodine concentrations is simulated. With those simulations the impact of scatter and exposure on image quality and material decomposition results is investigated. RESULTS: Our results illustrate that scatter radiation plays a significant role in visual as well as quantitative results. Scatter radiation can reduce the accuracy of contrast agent concentration by up to 15%. CONCLUSIONS: We present a reliable and robust software bench for simulation of SCTs equipped with PCDs. PMID- 25840621 TI - Immunogenicity and protective efficacy of an Eimeria vaccine candidate based on Eimeria tenella immune mapped protein 1 and chicken CD40 ligand. AB - The CD40 ligand (CD40L) has shown potential as a powerful immunological adjuvant in various studies. Here, the efficacy of a chimeric subunit vaccine, consisting of Eimeria tenella immune mapped protein 1 (EtIMP1) and chicken CD40L, was evaluated against E. tenella infection. The recombinant EtIMP1-CD40L was purified from E. coli over-expressing this protein. Chickens were vaccinated with EtIMP1 CD40L without adjuvant or EtIMP1 with Freund's adjuvant. Immunization of chickens with EtIMP1-CD40L fusion protein resulted in stronger IFN-gamma secretion and IgA response than that with only recombinant EtIMP1 with Freund's adjuvant. The clinical effect (cecal lesions, body weights gain, and oocysts shedding) of the EtIMP1-CD40L without adjuvant was also better than that of the EtIMP1 with adjuvant, as evidenced by the difference between the two groups in the oocyst output of E. tenella-challenged chickens. The results suggest that the EtIMP1 CD40L fusion protein can be used as an effective immunogen in the development of subunit vaccines against Eimeria infection. PMID- 25840622 TI - The influence of childbirth experiences on women's postpartum traumatic stress symptoms: A comparison between Israeli Jewish and Arab women. AB - BACKGROUND: childbirth is a positive experience for most women yet some women express distress after birth. Traumatic experience can sometimes cause post traumatic stress disorder (PTSD) in relation to childbirth. Prevalence of traumatic birth experience and PTSD after childbirth differs between cultures. OBJECTIVES: to examine the subjective recall of childbirth experiences and PTSD symptoms of Israeli Jewish and Arab women; to examine comparatively the prevalence of PTSD symptoms six to eight weeks after childbirth and to establish the factors that predict PTSD symptoms. METHODS: a prospective study was conducted in a region characterised by wide variations in ethnocultural groups. The study was comprised of two time points: Time 1 (T1) interviews were conducted at the bedside of the women in the maternity ward of each hospital 24-48 hours after childbirth. Time 2 (T2), all 171 women participating in T1 were interviewed by phone six to eight weeks after childbirth. FINDINGS: 34 women (19.9%) reported their labour as traumatic 24-48 hours after birth (T1), and six to eight weeks later (T2) 67 women (39.2%) assessed their experience as traumatic. More Arab women (69.6%) than Jewish women (56.5%) had a positive memory of childbirth, but this difference only approached statistical significance (p=.09). Results showed rather low frequencies of PTSD symptoms, and no ethnic difference. PTSD symptoms were significantly and positively predicted by subjective recollection of childbirth experience (Time 2). PTSD symptoms were higher for women who did not have a vaginal birth, and more women with PTSD symptoms were not breast feeding. CONCLUSIONS: we found more similarities than differences between Arab and Jewish women's experience of their births and no differences between them on the prevalence of PTSD symptoms after birth. The results suggest that non-vaginal birth (instrumental or caesarean section) and negative recollection of the childbirth experience are important factors related to the development of PTSD symptoms after birth, and that women with PTSD symptoms are less likely to breast feed. PMID- 25840623 TI - Lower urinary tract symptoms in men: refocus on your patients. PMID- 25840624 TI - Pediatric systemic lupus erythematosus presenting with coronary arteritis: A case series and review of the literature. AB - OBJECTIVE: Pediatric-onset systemic lupus erythematosus (pSLE) is typically more aggressive in presentation than adult-onset lupus. Presenting manifestations of lupus in children and adults involve similar organ systems, with renal and neuropsychiatric involvement more common in pSLE. Cardiac manifestations are similar in the 2 groups, with pericarditis accounting for the majority of cardiac lupus at presentation. There are no reports to our knowledge of coronary arteritis as a presenting feature of pSLE. METHODS: This is a retrospective case series describing 4 pediatric lupus patients who presented with prominent coronary artery dilatation and a review of the literature regarding coronary artery involvement in lupus. RESULTS: Coronary arteritis appears to be a more common feature of pSLE than previously thought. Based on our experience, coronary artery changes tend to resolve once the SLE is treated. CONCLUSIONS: Early recognition of this disease manifestation may guide therapy and result in improved long-term cardiovascular outcomes. PMID- 25840625 TI - [Clinical and biological features of patients with essential thrombocythaemia according to their mutational status JAK2 or CALR: Single-center study of 40 patients and review of the literature]. AB - BACKGROUND: Somatic mutations in the calreticulin gene (CALR) were recently described in essential thrombocythemia (ET) and primary myelofibrosis with non mutated JAK2 or MPL. The aim of this single-center study was to compare the clinical and biological features of ET patients according to their mutational status. METHODS: We included 40 patients with ET followed in hematology consultation. The JAK2 V617F mutation was assessed by quantitative PCR. For the detection of CALR mutations, we performed a PCR amplification of CALR exon 9 followed by direct sequencing. RESULTS: Among 40 study patients, 23 (57.5%) harbored V617F JAK2, 12 of the 17 patients without JAK2 mutation harbored CALR, no patient expressed MPL mutation and 5 were negative for all three mutations. Five types of mutations were identified with predominance of 52bp deletion and 5bp insertion (7/12 and 2/12 respectively). The incidence of thrombotic events at diagnosis was significantly higher in JAK2 mutated patients (P<0.05). Biologically, patients with CALR mutation had significantly higher platelet count (P<0.01) and significantly lower hemoglobin level (P<0.05) than those with V617F JAK2 mutation. CONCLUSION: JAK2 and CALR mutation screening in ET has a diagnostic value. Each mutation displays a distinct phenotype with uncertain impact on long-term outcome. PMID- 25840626 TI - Anaphylaxis, asthma and supplementary medicines, looking from West to East. PMID- 25840627 TI - Effects of inactivated influenza vaccine on respiratory illnesses and asthma related events in children with mild persistent asthma in Asia. AB - BACKGROUND: Acute asthmatic exacerbation and readmission may be associated with severe influenza infection and asthmatic children are a priority group for influenza vaccination. To date, our study is the first to evaluate the outcome of the influenza vaccine in asthmatic Asian children. OBJECTIVE: To analyze the outcomes of inactivated influenza vaccine in children with mild persistent asthma METHODS: A cross sectional non-randomized study was performed on 93 mild persistent asthmatic children who attended the Pediatric Allergy clinic between June 2012 in Chiang Rai Hospital and August 2013. Forty eight patients were immunized with 2 doses of inactivated influenza vaccine at one month interval. Respiratory illnesses and asthma-related events were compared between the immunized and the un-immunized groups. RESULTS: The two study groups had similar demographic and clinical characteristic except with regards to eczema, including asthma controllers and skin prick testing results. One year after the vaccine was administered, the immunized group had significantly reduced acute respiratory tract illnesses, asthma exacerbations, ER visits, bronchodilator usage and systemic steroid administrations. Hospitalizations (p < 0.001) and their duration (p < 0.034) were also reduced in the immunized group. CONCLUSIONS: Immunization of inactivated influenza vaccine in children with mild persistent asthma decreased respiratory illnesses and asthma-related events. PMID- 25840628 TI - What clinical factors are associated with biphasic anaphylaxis in Thai adult patients? AB - BACKGROUND: Anaphylaxis is an emergency condition and may be fatal. Approximately 20% of patients with anaphylaxis may develop recurrent episodes of anaphylaxis within 72 hours or biphasic anaphylaxis. The severity of biphasic anaphylaxis can be either more or less severe than the first episode. Knowledge of factors associated with biphasic anaphylaxis in particular in Asian populations is still limited. OBJECTIVES: To study predictors for biphasic anaphylaxis in Thai patients at the Emergency Department (ED). METHODS: All consecutive patients diagnosed as anaphylaxis at the ED, Ramathibodi Hospital, Mahidol University, Bangkok were enrolled. The study was prospectively conducted from January to December 2011. Patients were divided into two groups; uniphasic and biphasic anaphylaxis. Multivariate logistic regression was used to identify factors associated with biphasic anaphylaxis. RESULTS: During the study period, there were 63 patients diagnosed with anaphylaxis at the ED. Of those, 16 patients were excluded due to or treatment of anaphylaxis, concomitant medications or pre hospital treatment. In total, there were 47 patients remaining in the study, including 10 patients with biphasic anaphylaxis (21.28%). The clinical characteristics of the uniphasic and biphasic anaphylaxis groups were comparable. In multivariate logistic regression analyses, only respiratory rate and abdominal pain were significantly associated with biphasic anaphylaxis. The adjusted ORs (95% CI) of both factors were 0.653 (0.457, 0.932) and 15.429 (1.395, 170.690), respectively. CONCLUSION: Reduced respiratory rate and the presence of abdominal pain were two significant factors associated with biphasic anaphylaxis. PMID- 25840629 TI - Survey of asthma management in Thailand - the asthma insight and management study. AB - BACKGROUND: Previous Thai surveys of asthma care have shown suboptimal management and poor control. Since then several editions of the Thailand National Asthma Guidelines have been distributed to help improve asthma control. A new survey was undertaken to see if any improvement in care had occurred. It examined patients' insights, attitudes and perceptions about their asthma and its treatment. METHODS: Asthma patients (>12 years) were randomly selected and participated in face-to-face interviews. Patients answered 53 questions exploring general health, diagnosis, symptoms, exacerbations, patient burden, disease management, treatment and attitudes. The Global Initiative for Asthma guidelines were used to assess asthma control. RESULTS: Data were obtained from 400 asthma patients from 8,177 screened households. This showed that 36% had had exacerbations in the previous year, 17% had been hospitalized and 35% had had an unscheduled emergency visit to hospital or a doctor's office or clinic. Work or school was missed by 44% due to asthma while a similar number had had an asthma episode that made them feel their life was in danger. Only 8% had good asthma control. Patients had low expectations with respect to asthma treatment and their understanding of how to use therapies was poor. Forty-four percent of participants reported day-time symptoms and about one-third (34%) of adults and adolescents in the survey reported night-time symptoms at least once a week in the previous 4 weeks. Asthma patients in Thailand rated their average productivity when asthma was at its worst at 48%, on a scale of 0 to 100%, which equates to a 36% decline in productivity. Rescue medication during the previous four weeks had been used by 44% of asthma patients while 54% had used a controller medication. Pill controller medication is the most used form among those reporting controller medication use (67%), whereas 57% reported taking an inhaler. Oral steroids had been used in the previous 12 months by 40% of patients with the average number for 3 day or longer at 24 times, while the median was about 4 times. CONCLUSIONS: Asthma had a profound impact on patients' wellbeing, despite the availability of effective treatments and evidence-based management guidelines. A large proportion of asthma patients overestimate their asthma control and have inappropriate concepts about asthma treatment. Gaining better insight into patient's attitudes about self-care is critical to improve asthma management. PMID- 25840630 TI - Evaluation of asthma control by inhaled corticosteroids in general practice in Thailand. AB - BACKGROUND: Inhaled corticosteroid (ICS) is the main treatment of asthma but the clinical data of its efficacy is limited. This study aimed to evaluate the therapeutic efficacy of ICS alone or combined with controllers other than LABA for persistent asthma in Thailand. METHODS: This cross-sectional study involved 1,206 patients with persistent asthma and was conducted at 38 hospitals across Thailand between May and November, 2009. Patients were enrolled if they were >12 years old, had persistent asthma, receiving ICS with/without controllers other than long-acting beta2-agonists (LABA) for at least 3 months, and smoked <10 packs-year. RESULTS: Of 1,206 patients, 78.4% were females, age 49.4 +/- 13.8 years old, 89.3% were nonsmokers, the median duration of illness was 11 years, the median duration of ICS treatment was 20.4 months, and the mean dose of ICS was 738 +/- 258 microgram per day. The top three medications prescribed in combination to ICS were short-acting beta2- agonist inhalers, theophylline, and short-acting beta2- agonist tablets. The mean Asthma Control Test (ACT) score was 19.2 +/- 4.4. The percentage of successful asthma control (ACT >= 20) was 53.5% (95% CI: 50.7 to 56.3). The rate per patient per year of emergency room visits and all urgent health care visits were 0.98 and 1.28. CONCLUSIONS: In clinical practice, patients using ICS alone or combined with theophylline or short-acting b2 agonists had a low percentage of asthma control and a high number of urgent care visits. ICS either alone or combined with theophylline or short-acting b2 agonists is not sufficient. PMID- 25840631 TI - Immunomodulatory properties of Tamm-Horsfall glycoprotein (THP) and uromodulin. AB - BACKGROUND: Tamm-Horsfall glycoprotein (THP) and uromodulin are the most abundant glycoproteins in non-pregnant women's/men's and pregnant women's urine, respectively. However, the bioactivities of these glycoproteins are still unclear. OBJECTIVE: To evaluate the immunomodulatory properties of THP and uromodulin on human peripheral blood mononuclear cells (PBMC) METHODS: THP and uromodulin isolated with diatomaceous earth filtration were subjected to several bioassays, such as MTS viability assay, immunophenotyping and cytokine analysis. RESULTS: MTS viability assay and immunophenotyping analysis showed that uromodulin has greater inhibitory activities in suppressing PBMC viability and the percentage of CD4+ T helper cells and CD8+ cytotoxic T cells, compared to that of THP. In cytokine analysis, THP tended to induce pro-inflammatory cytokines such as IL-1beta, TNF and Th1 cytokine IFN-gamma; while uromodulin only induced IL-1beta and suppressed both Th1 cytokine IFN-gamma and Th2 cytokine IL 10. CONCLUSION: These results demonstrate that uromodulin has greater immunosuppressive activities and lower inductive property in relation to activation of immune cells, which provides a more tolerant environment for the developing fetus. PMID- 25840632 TI - Effect of diethylcarbamazine citrate and omega-3 fatty acids on trimellitic anhydride-induced rat skin allergy. AB - BACKGROUND: Diethylcarbamazine citrate (DEC) is the drug most widely used in the treatment of lymphatic filariasis. Omega-3 fatty acids (omega-3 FAs) are essential polyunsaturated fatty acids and commonly found in marine oils. Both have been applied in treatment of inflammatory diseases but anti-allergic effects should be investigated. OBJECTIVE: The present study was performed to test the effect of both DEC and omega -3 FAs on Trimellitic anhydride (TMA) - induced rat skin allergy. METHODS: In vivo experiment was executed in white albino rats using 100 and 600 mg/ Kg body weight of DEC and omega-3 FAs, respectively in treatment. Ear thickness of sensitized rats to TMA was monitored after challenge. Blood eosinophilia was determined using differential leukocyte count while the appearance of mast cells, eosinophils and collagen fibers in skin tissue were investigated using specific stains. Colorimetric assay of NO was performed in homogenized ears, while expression of inducible nitric oxide synthase (iNOS) was detected using immunohistochemistry. RESULTS: Ear thickness showed a significant (p < 0.05) reduction in both of DEC and omega-3 FAs treated groups. Blood eosinophilia and skin eosinophils were significantly (p < 0.001) decreased by DEC and ?-3 FAs, while the decrease of skin mast cells was only significant (p < 0.01) when omega-3 FAs applied. The expression of iNOS and intensity of stained collagen fibers were decreased obviously by omega-3 FAs but less by DEC treatment. Histopathological observations were more normal in omega-3 FAs than DEC treated groups. CONCLUSION: omega-3 FAs was more potent antiallergic substance against TMA-induced dermatitis than DEC. PMID- 25840633 TI - Zingiber cassumunar ROXb. and its active constituent inhibit MMP-9 direct activation by house dust mite allergens and MMP-9 expression in PMA-stimulated human airway epithelial cells. AB - BACKGROUND: House dust mite (HDM) induced matrix metalloproteinase (MMP)-9 plays a role in asthma. Zingiber cassumunar Roxb. (Phlai in Thai) has been used in folk medicine for asthma treatment. OBJECTIVE: We investigated effects of Phlai and its constituent (E)-4-(3',4'-dimethoxyphenyl)but-3-en-1-ol (compound D) on the cleavage of pro- MMP-9 by HDM. The effects of these compounds on phorbol 12 myristate 13-acetate (PMA)- induced MMP-9 gene and protein expression in airway epithelial cells (NCI-H292) were also investigated. METHODS: Pro-MMP-9 was directly activated in vitro with HDM in the presence or absence of the ethanolic extracts of Phlai or compound D for 1 hour. The amount of activated MMP-9 was determined using gelatin zymography. To study the cellular response of Phlai, NCI H292 cells were pretreated with crude Phlai extracts or compound D for 2 hours, and then the cells were stimulated with PMA for 48 hours. The mRNA RT-PCR and Western blotting, respectively. MMP-9 activity was determined by gelatin zymography. RESULTS: Crude Phlai extracts (0.25 - 2.0 mg/ml) and compound D (0.5 4.0 mg/ml) inhibited pro- MMP-9 cleavage by HDM. Furthermore, crude Phlai extracts (100 mg/ml) and compound D, at concentrations of 50 and 100 mg/ml, attenuated the PMA-induced MMP-9 gene and expression in NCI-H292 cells. These compound also suppressed MMP-9 release from PMA-induced NCI-H292 cells. CONCLUSION: The crude ethanolic extract of Z. cassumunar and its active constituent compound D inhibited the cleavage of pro-MMP-9 by HDM. They also inhibited PMA-induced MMP-9 gene and protein synthesis in human airway epithelial cells. PMID- 25840634 TI - In vitro cytokine changes after pediatric liver transplantation. AB - BACKGROUND: Patients with chronic liver disease have been shown to have impaired immune statuses. Liver transplantation (LT) is the standard treatment for end stage liver disease patients and immunosuppressive drugs are commonly used to prevent graft rejection. There is an increasing evidence of de novo food allergies post LT. OBJECTIVE: To investigate the cytokine response of peripheral blood mononuclear cells (PBMCs) of pediatric LT recipients before and six months after transplantation. METHOD: PBMCs collected before and six months after LT were stimulated with phytohemagglutinin (PHA), beta-lactoglobulin (BLG), tacrolimus (Tac), dexamethasone (Dex), and a combination of BLG and Dex (B+D), BLG and Tac (B+T), BLG and Tac plus Dex (B+T+D). Culture supernatants were measured for IL-5, IFN-gamma and IL-10. Blood for liver function tests, complete blood counts, total IgE and specific IgE (sIgE) to cow's milk were recorded. RESULTS: A total of five pediatric LT recipients were enrolled in the study. There were no food allergy cases. Total IgE and sIgE to cow's milk decreased significantly after LT. After transplantation, there was a significant increase in IL-5, IFN-gamma and IL-10 in culture supernatants of PHA-stimulated PBMCs. Among different stimulations in post transplantation's PBMCs, the level of IL-5 significantly increased in B+D was suppressed with the combination of B+T+D. The level of IL-10 significantly increased in all conditions containing BLG both before and after transplantation. CONCLUSION: There was an improvement of the in vitro-cytokine responses after liver transplantations. Immunosuppressive drugs used in post transplantation had an effect on the cytokine responses. PMID- 25840635 TI - Plasma adipokine levels in Thais. AB - OBJECTIVE: To assess three plasma adipokines that might act as biomarkers useful in determining persons exposed to asbestos. METHOD: Sixty subjects were included in the study, 30 male workers from factories manufacturing cement products using chrysotile asbestos, and 30 volunteer controls comprising 15 men and 15 women. Fasting venous blood specimens were submitted for blood chemistry examination and analysis of plasma levels of three adipokines, i.e. adipsin, adiponectin and resistin. RESULTS: (1) Compared with non-obese subjects, the adiponectin levels were lower in obese subjects, resistin levels were higher, and hemoglobin concentrations were lower. (2) Adipsin levels in the workers were significantly higher than in the controls (p < 0.005), and this difference was not related to body fat. (3) There were no statistically significant differences in adiponectin, resistin, and adipsin levels between the male and female controls. (4) Adiponectin in the male controls was significantly higher than that in the male workers (p <0.05). (5) Female controls had significantly higher percentages of body fat (p < 0.0005) and resistin (p < 0.02) levels than male controls and male workers. (6) A significant negative correlation existed between resistin and hemoglobin levels levels (r= -0.336, p < 0.01). (7) Overall adipsin levels among male workers were significantly higher than among control subjects (p < 0.005); the six workers in whom asbestos bodies (AB) were detected did not have significantly higher levels of adipsin than those of workers without AB having been detected. CONCLUSIONS: Although the findings apparently showed higher adipsin levels in the workers, its value as a biomarker for asbestos exposure requires confirmation from studies on a larger group of subjects. PMID- 25840636 TI - Jackfruit anaphylaxis in a latex allergic patient. AB - Several fruits have been reported to crossreact with latex antigen in latex allergy patients but little is known regarding tropical fruits in particular. Here we report the case of a 34-year old nurse who developed anaphylaxis following the ingestion of dried jackfruit (Artocarpus heterophyllus). The patient had a history of chronic eczema on both hands resulting from a regular wear of latex gloves. She and her family also had a history of atopy (allergic rhinitis and/or atopic dermatitis). The results of skin prick tests were positive for jackfruit, latex glove, kiwi and papaya, but the test was negative for banana. While we are reporting the first case of jackfruit anaphylaxis, further research needs to be conducted to identify the mechanisms underlying it. In particular, in-vitro studies need to be designed to understand if the anaphylaxis we describe is due to a cross reactivity between latex and jackfruit or a coincidence of allergy to these 2 antigens. PMID- 25840637 TI - A longitudinal study of the Friedreich Ataxia Impact Scale. AB - BACKGROUND: Quality of life in Friedreich ataxia (FRDA) has been explored using various generic health status measurement tools, most commonly the Short Form Health Survey Version 2 (SF-36v2). The tool did not address many specific issues related to disease impact in people with FRDA. The Friedreich Ataxia Impact Scale (FAIS) was developed to examine clinically relevant areas in FRDA. The aims of the current study were to assess the relationship between the FAIS and clinical characteristics of FRDA, as well as to determine the responsiveness of the FAIS to change over one and two years. METHODS: One hundred and four individuals with FRDA, homozygous for the GAA expansion in intron 1 of FXN, completed the FAIS at baseline. Seventy individuals completed the FAIS again 12 months later and 49 completed the FAIS at 24 months. Clinical parameters and neurologic scales (Friedreich Ataxia Rating Scale (FARS)) were also recorded. RESULTS: The total FARS score, onset age and disease duration correlated significantly with FAIS subscales measuring symptoms and physical functioning. The physical and mental summary measures of the SF-36 V2 also correlated well with the FAIS subscales. Speech was the only subscale that demonstrated significant change over one and two years. CONCLUSIONS: The FAIS provides valuable insight into the perspective of individuals with FRDA on their health status, and is an important measure of morbidity. It has, however, limited responsiveness to change and its use in intervention studies is questionable. PMID- 25840638 TI - NaCl-elicited, vacuolar Ca(2+) release facilitates prolonged cytosolic Ca(2+) signaling in the salt response of Populus euphratica cells. AB - High environmental salt elicits an increase in cytosolic Ca(2+) ([Ca(2+)]cyt) in plants, which is generated by extracellular Ca(2+) influx and Ca(2+) release from intracellular stores, such as vacuole and endoplasmic reticulum. This study aimed to determine the physiological mechanisms underlying Ca(2+) release from vacuoles and its role in ionic homeostasis in Populus euphratica. In vivo Ca(2+) imaging showed that NaCl treatment induced a rapid elevation in [Ca(2+)]cyt, which was accompanied by a subsequent release of vacuolar Ca(2+). In cell cultures, NaCl altered intracellular Ca(2+) mobilization was abolished by antagonists of inositol (1, 4, 5) trisphosphate (IP3) and cyclic adenosine diphosphate ribose (cADPR) signaling pathways, but not by slow vacuolar (SV) channel blockers. Furthermore, the NaCl-induced vacuolar Ca(2+) release was dependent on extracellular ATP, extracellular Ca(2+) influx, H2O2, and NO. In vitro Ca(2+) flux recordings confirmed that IP3, cADPR, and Ca(2+) induced substantial Ca(2+) efflux from intact vacuoles, but this vacuolar Ca(2+) flux did not directly respond to ATP, H2O2, or NO. Moreover, the IP3/cADPR-mediated vacuolar Ca(2+) release enhanced the expression of salt-responsive genes that regulated a wide range of cellular processes required for ion homeostasis, including cytosolic K(+) maintenance, Na(+) and Cl(-) exclusion across the plasma membrane, and Na(+)/H(+) and Cl(-)/H(+) exchanges across the vacuolar membrane. PMID- 25840639 TI - Pressure Overload Creates Right Ventricular Diastolic Dysfunction in a Mouse Model: Assessment by Echocardiography. AB - BACKGROUND: Noninvasive diagnostic tools for right ventricular (RV) dysfunction measurements are increasingly being used, although their association with the pathologic mechanisms of dysfunction is poorly understood. Although investigations have focused mainly on RV systolic function, RV diastolic function remains mostly neglected. The aim of this study was to test which echocardiographic parameters best reflect RV diastolic function in mice. METHODS: Pulmonary artery banding (PAB) was used to induce RV pressure overload in mice. Transthoracic echocardiography and invasive hemodynamic measurements were performed after 3 weeks in PAB and sham-operated mice. Subsequently, the hearts were investigated by histology and analyzed for gene expression. RESULTS: PAB induced pressure overload (RV systolic pressure PAB 52.6 +/- 11.8 mm Hg vs sham 27.0 +/- 2.7 mm Hg) resulted in RV hypertrophy and remodeling, as reflected by increased Fulton index (PAB 0.37 +/- 0.05 vs sham 0.25 +/- 0.02, P = .001). Masson's trichrome staining revealed increased interstitial fibrosis (PAB 12.25 +/- 3.12% vs sham 3.97 +/- 1.58%, P = .002). This was associated with significant systolic RV dysfunction as demonstrated by reduced contractility index and diastolic dysfunction as demonstrated by end-diastolic pressure (PAB 2.66 +/- 0.83 mm Hg vs sham 1.49 +/- 0.50 mm Hg, P < .001) and tau (PAB 40.0 +/- 16.1 msec vs sham 13.0 +/- 3.5 msec, P < .001). Messenger ribonucleic acid expression of beta-myosin heavy chain, atrial and brain natriuretic peptides, collagen family members was elevated, and the sarco/endoplasmic reticulum Ca(2+)-ATPase was decreased. Echocardiography revealed significant increases in RV free wall thickness and isovolumic relaxation time and a decrease in left ventricular eccentricity index, E', and tricuspid annular plane systolic excursion. Isovolumic relaxation time and E' were significantly correlated with end diastolic pressure (rs = 0.511 and -0.451) and tau (rs = 0.739 and -0.445, respectively). Moreover, E' was negatively correlated with the degree of RV fibrosis (rs = -0.717). CONCLUSIONS: Within 3 weeks, PAB causes pressure overload induced RV hypertrophy and remodeling with compensated systolic and diastolic dysfunction in mice. RV free wall thickness, tricuspid annular plane systolic excursion, E', E/E' ratio, and isovolumic relaxation time appear to be the most reliable echocardiographic parameters for the assessment of RV dysfunction. PMID- 25840640 TI - Usefulness of Speckle-Tracking Imaging for Right Ventricular Assessment after Acute Myocardial Infarction: A Magnetic Resonance Imaging/Echocardiographic Comparison within the Relation between Aldosterone and Cardiac Remodeling after Myocardial Infarction Study. AB - BACKGROUND: Right ventricular (RV) dysfunction after acute myocardial infarction (AMI) is frequent and associated with poor prognosis. The complex anatomy of the right ventricle makes its echocardiographic assessment challenging. Quantification of RV deformation by speckle-tracking echocardiography is a widely available and reproducible technique that readily provides an integrated analysis of all segments of the right ventricle. The aim of this study was to investigate the accuracy of conventional echocardiographic parameters and speckle-tracking echocardiographic strain parameters in assessing RV function after AMI, in comparison with cardiac magnetic resonance imaging (CMR). METHODS: A total of 135 patients admitted for AMI (73 anterior, 62 inferior) were prospectively studied. Right ventricular function was assessed by echocardiography and CMR within 2 to 4 days of hospital admission. Right ventricular dysfunction was defined as CMR RV ejection fraction < 50%. Right ventricular global peak longitudinal systolic strain (GLPSS) was calculated by averaging the strain values of the septal, lateral, and inferior walls. RESULTS: Right ventricular dysfunction was documented in 20 patients. Right ventricular GLPSS was the best echographic correlate of CMR RV ejection fraction (r = -0.459, P < .0001) and possessed good diagnostic value for RV dysfunction (area under the receiver operating characteristic curve [AUROC], 0.724; 95% CI, 0.590-0.857), which was comparable with that of RV fractional area change (AUROC, 0.756; 95% CI, 0.647-0.866). In patients with inferior myocardial infarctions, the AUROCs for RV GLPSS (0.822) and inferolateral strain (0.877) were greater than that observed for RV fractional area change (0.760) Other conventional echocardiographic parameters performed poorly (all AUROCs < 0.700). CONCLUSIONS: After AMI, RV GLPSS is the best correlate of CMR RV ejection fraction. In patients with inferior AMIs, RV GLPSS displays even higher diagnostic value than conventional echocardiographic parameters. PMID- 25840641 TI - IL-9 induces IL-8 production via STIM1 activation and ERK phosphorylation in epidermal keratinocytes: A plausible mechanism of IL-9R in atopic dermatitis. AB - BACKGROUND: IL-9 and its receptor play important roles in the pathogenesis of asthma. Its role in atopic dermatitis (AD) was examined in just a few studies, including nucleotide polymorphisms, increased transcriptional levels of IL-9 and IL-9R in diseased skin, and an association of blood IL-9 levels with clinical severity. OBJECTIVE: Little was known about the pathophysiological regulation of IL-9/IL-9R in AD skin. We asked whether IL-9R was expressed in epidermal keratinocytes; if so, what the functional outcome, cytokine production, and signaling pathway of IL-9/IL-9R in keratinocytes are. METHODS: We measured and compared the expression of IL-9R in skin from AD patients and controls by immunofluorescence. We also performed in vitro studies on the IL-9-treated primary keratinocytes, including flow cytometry for IL-9R expressions, Western blotting for mTOR, S6K, ERK, p38, and STAT3 activations, ELISA for cytokine levels, and immunofluorescence for STIM1. RESULTS: We found that IL-9R was indeed expressed in keratinocytes but not in fibroblasts. Its expression in keratinocytes was enhanced by IL-4 but not by TGF-beta1. IL-9 induced a moderate production of IL-8 but not CXCL16, CCL22, TSLP, nor IL-33. IL-9 induced formation of STIM1-puncta. IL-9 induced ERK phosphorylation both dose- and time dependently, but not mTOR, S6K, p38, or STAT3. Pretreatment with U0126 (ERK inhibitor) but not rapamycin (mTOR inhibitor) abrogated the IL-9-mediated IL-8 production. Blockage of STIM1 with BTP2 or SKF96265 abrogated ERK phosphorylation and IL-8 production induced by IL-9. CONCLUSION: This study represents the first to show the regulation of the IL-9-STIM1-ERK-IL-8 axis in keratinocyte, and how the axis might play an important role in the pathophysiology of AD. PMID- 25840642 TI - Prognostic value of troponin I and NT-proBNP concentrations in patients after in hospital cardiac arrest. AB - OBJECTIVES: Cardiac arrest (CA) is a complex event with a dismal survival rate. The aim of this study was to determine whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels measured on admission and serial cardiac troponin I determination in patients with in-hospital cardiac arrest (IHCA) are predictive of 30-day mortality. METHODS: Out of 9877 patients hospitalized in the cardiac intensive care unit during the study, we enrolled consecutive patients experiencing cardiac arrest within 12 hours of admission. Baseline characteristics, information about circumstances of CA and cardiopulmonary resuscitation, and initial biochemical parameters were retrospectively collected. RESULTS: A total of 106 patients (61 male, age 71.4+/-12.6 years) were enrolled. Thirty-four (32.1%) had a history of myocardial infarction, and 13 (12.3%) a history of stroke. Total 30-day mortality was 60.4%. Deceased patients were older (73.7+/-11.9 vs. 67.8+/-13.0 years; p=0.01) and had lower systolic (89.4+/-37.0 vs. 115.0+/-24.0 mmHg; p=0.0001) and diastolic (53.6+/-24.8 vs. 66.1+/-15.0 mmHg; p=0.008) blood pressure on admission. Shockable initial rhythm was more often noted in the survivor group (54.8% vs. 28.1%; p=0.01). Deceased patients had higher median NT-proBNP levels (9590.0 [25-75% interquartile range (IQR), 5640.0 26450.0] vs. 3190.0 [25-75% IQR, 973.8-5362.5] pg/ml; p=0.02) on admission. There were no differences in the first two troponin I measurements, but values were higher on the third measurement in non-survivors (98.2 [25-75% IQR, 76.4-175.8] vs. 18.7 [25-75% IQR, 5.2-50.6]; p=0.009). CONCLUSIONS: The survival rate of patients after in-hospital CA is poor. Deceased patients have higher NT-proBNP levels on admission, along with higher troponin I concentrations on the third measurement. Those biomarkers are useful in predicting 30-day mortality in IHCA patients. PMID- 25840643 TI - Noninvasive anatomical and functional assessment of coronary artery disease. AB - INTRODUCTION AND OBJECTIVE: In suspected coronary artery disease (CAD), invasive coronary angiography (ICA) is traditionally the diagnostic tool of choice. However, patients often have no significant disease. Moreover, assessment of fractional flow reserve (FFR) has been shown to have prognostic implications. Recently, coronary computed tomography angiography (CTA) and cardiac magnetic resonance (CMR) myocardial perfusion imaging (CMR-Perf) have gained increasing attention through their accurate anatomical and functional assessment, respectively. We studied the added value of integrating these tests (CT+CMRint) in the diagnosis of CAD, with FFR as the reference standard. METHODS: We included 101 patients consecutively referred for outpatient assessment of CAD who underwent CTA and CMR-Perf prior to ICA with FFR assessment. Lesions were considered positive by CT+CMRint only if positive in the two tests alone. The mean follow-up was 2.9+/-0.6 years. RESULTS: All patients completed the study protocol without adverse effects. Forty-four patients had CAD by FFR. CTA had excellent sensitivity and negative predictive value (100%) but, as expected, its specificity and positive predictive value were lower (61% and 67%, respectively). Diagnostic accuracy by FFR was 78% for CTA, 88% for CMR-Perf and 92% for CT+CMRint. Regarding diagnostic accuracy, CT+CMRint showed statistically significant superiority (AUC=0.917, 95% CI 0.845-0.963) compared with CTA (AUC=0.807, 95% CI 0.716-0.879, p=0.0057) or CMR-Perf (AUC=0.882, 95% CI 0.802 0.938, p=0.0398) alone. Regarding prediction of revascularization, the integrated protocol maintained its superior performance. CONCLUSIONS: CT+CMRint showed superior diagnostic accuracy and could thus lead to a considerable reduction in invasive procedures for CAD diagnosis, with less risk and greater patient comfort. PMID- 25840644 TI - Comparison between diabetic and non-diabetic patients after successful percutaneous coronary intervention for chronic total occlusions in the drug eluting stent era. AB - OBJECTIVE: Diabetes mellitus and chronic total occlusions are associated with unfavorable outcome after percutaneous coronary intervention. We sought to assess the clinical and angiographic outcomes of diabetic and non-diabetic patients who underwent successful percutaneous revascularization of chronic total occlusions with drug-eluting stents. METHODS: Baseline clinical and angiographic characteristics, procedural details, nine-month angiographic follow-up and clinical events at 12 months were compared between 75 diabetic and 132 non diabetic patients included in a clinical trial that randomized successful recanalization of chronic total occlusions to receive sirolimus- or everolimus eluting stents. RESULTS: In both diabetic and non-diabetic groups there was a favorable non-significantly different angiographic result at nine months, with low in-stent late loss (0.14+/-0.60 mm vs. 0.25+/-0.68 mm, p=0.305) and rates of binary restenosis (4.0% vs. 10.6%, p=0.180) and reocclusion (0.0% vs. 2.3%, p=0.334). During follow-up similar survival from death (97.3+/-1.9% vs. 99.2+/ 0.8%, log-rank p=0.273), acute myocardial infarction (100.0+/-0.0% vs. 97.7+/ 1.3%, log-rank p=0.192), target vessel revascularization (88.7+/-3.8% vs. 88.2+/ 2.9%, log-rank p=0.899) and stent thrombosis (100.0+/-0.0% vs. 97.7+/-1.3%, log rank p=0.192) was observed. Furthermore, the presence of more diffuse peripheral and coronary artery disease and higher frequency of calcified lesions in diabetic patients did not lead to significant differences in the approach (20.0% vs. 25.0% radial approach, p=0.413), strategy (6.7% vs. 3.8% retrograde strategy, p=0.353), total stent length (48.1+/-24.6 mm vs. 49.2+/-23.9 mm, p=0758) or contrast volume (261.3+/-116.4 ml vs. 297.4+/-135.9 ml, p=0.109) required for revascularization. CONCLUSIONS: In the drug-eluting stent era, diabetic and non-diabetic patients have comparable favorable clinical and angiographic outcomes after successful percutaneous revascularization of chronic total occlusions. PMID- 25840645 TI - Anatomical and functional assessment of coronary artery disease: The search for the perfect protocol. PMID- 25840646 TI - Late device embolization in a persistent mitral paravalvular leak. AB - An 83-year-old man with severe organic mitral regurgitation underwent mitral valve surgery with implantation of a biologic prosthesis. Four months later he presented with hemolytic anemia and heart failure due to severe paravalvular regurgitation. Since the patient refused surgery, the paravalvular leak was closed percutaneously using two Amplatzer devices, with angiographic and clinical success. Two months after the intervention he developed heart failure again and embolization of one of the devices was documented, with significant worsening of paravalvular regurgitation. A redo percutaneous closure was attempted but although initially promising, was ultimately unsuccessful as heart failure symptoms and hemolytic anemia persisted. Surgical correction was the final solution for this case. This is the second case of late device embolization reported in the literature and highlights the importance of careful long-term follow-up of such patients, as late complications, although rare, may occur. PMID- 25840647 TI - Transient apical dyskinesia with a pacemaker: Electrocardiographic features. AB - Transient apical dyskinesia syndromes present features similar to acute coronary syndromes, but with normal coronary arteries and rapid complete resolution of wall motion alterations. We report the case of a 73-year-old woman who was admitted to hospital because of typical chest pain at rest after her brother's death. She had had a pacemaker implanted in 2001. Troponin levels were elevated and apical hypokinesia was shown by ventriculography and echocardiography, with normal coronary arteries. Evolving ECG alterations were observed in spite of the continued pacing rhythm. All these alterations were fully resolved after discharge. This case shows that, even in the presence of a pacemaker, evolving ECG alterations can be observed in Takotsubo syndrome. PMID- 25840649 TI - Critical particle sizes for the engulfment of nanoparticles by membranes and vesicles with bilayer asymmetry. AB - The adhesion and engulfment of nanoparticles by biomembranes is essential for many processes such as biomedical imaging, drug delivery, nanotoxicity, and viral infection. Many studies have shown that both surface chemistry, which determines the adhesive strength of the membrane-particle interactions, and particle size represent key parameters for these processes. Here, we show that the asymmetry between the two leaflets of a bilayer membrane provides another key parameter for the engulfment of nanoparticles. The asymmetric membrane prefers to curve in a certain manner as quantitatively described by its spontaneous curvature. We derive two general relationships between particle size, adhesive strength, and spontaneous curvature that determine the instabilities of (i) the nonadhering or free state and (ii) the completely engulfed state of the particle. For model membranes such as lipid or polymer bilayers with a uniform composition, the two relationships lead to two critical particle sizes that determine four distinct engulfment regimes, both for the endocytic and for the exocytic engulfment process. For strong adhesion, the critical particle sizes are on the order of 10 nm, while they are on the order of 1000 nm for weak or ultraweak adhesion. Our theoretical results are therefore accessible to both experimental studies and computer simulations of model membranes. In order to address the more complex process of receptor-mediated endocytosis, we take the adhesion-induced segregation of membrane components into account and consider bound and unbound membrane segments that differ in their spontaneous curvatures. To model protein coats as formed during clathrin-dependent endocytosis, we focus on the case in which the bound membrane segments have a large spontaneous curvature compared to the unbound ones. We derive explicit expressions for the engulfment rate and the uptake of nanoparticles, which both depend on the particle size in a nonmonotonic manner, and provide a quantitative fit to experimental data for clathrin dependent endocytosis of gold nanoparticles. PMID- 25840648 TI - The Polycystic Ovary Morphology-Polycystic Ovary Syndrome Spectrum. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common cause of chronic hyperandrogenic anovulation. Two-thirds of PCOS patients have functionally typical PCOS, with typical functional ovarian hyperandrogenism manifest as 17 hydroxyprogesterone hyper-responsiveness to gonadotropin stimulation. Most, but not all, of the remainder have atypical functional ovarian hyperandrogenism. Many asymptomatic volunteers with polycystic ovary morphology (PCOM) have similar abnormalities. OBJECTIVE: The objective of this paper is to review the relationship of biochemical ovarian function to the clinical spectrum observed in PCOS and in normal volunteers with PCOM. FINDINGS: Adolescents and adults with PCOS are similar clinically and biochemically. Ninety-five percent of functionally typical PCOS have classic PCOS, ie, hyperandrogenic anovulation with PCOM. In addition to having more severe hyperandrogenism and a greater prevalence of PCOM than other PCOS, they have a significantly greater prevalence of glucose intolerance although insulin resistance is similarly reduced. Half of normal variant PCOM have PCOS-related steroidogenic dysfunction, which suggests a PCOS carrier state. CONCLUSIONS: There is a spectrum of ovarian androgenic dysfunction that ranges from subclinical hyperandrogenemia in some normal-variant PCOM to severe ovarian hyperandrogenism in most classic PCOS. A minority of mild PCOS cases do not fall on this spectrum of ovarian androgenic dysfunction, but rather seem to have obesity as the basis of their hyperandrogenism, or, less often, isolated adrenal androgenic dysfunction. Half of normal-variant PCOM also do not fall on the PCOS spectrum, and some of these seem to have excessive folliculogenesis as a variant that may confer mild prolongation of the reproductive lifespan. Improved understanding of PCOM in young women is needed. PMID- 25840650 TI - Neoadjuvant chemotherapy in gynaecological cancers - Implications for staging. AB - The management of advanced gynaecological cancers remains a therapeutic challenge. Neoadjuvant chemotherapy has been used to reduce tumour size, thus facilitating subsequent local treatment in the form of surgery or radiation. For advanced epithelial ovarian cancer, data from several non-randomized and one randomized studies indicate that neoadjuvant chemotherapy followed by interval debulking surgery is a reasonable approach in patients deemed inoperable. Such an approach results in optimum debulking (no visible tumour) in approximately 40% of the patients with reduced operative morbidity. Overall and progression free survival is comparable to the group treated with primary debulking surgery followed by chemotherapy. Neoadjuvant chemotherapy followed by surgery is associated with improved survival for women with stage IB2-IIA cervix cancer. There is a resurgence of interest for using short-course neoadjuvant chemotherapy prior to concurrent chemo-radiation. Currently, this is being tested in randomized trials. PMID- 25840651 TI - The evolution of face processing networks. AB - Recent studies in marmosets, macaques, and humans have begun to show commonalities and differences in the evolution of face processing networks. Despite differences in brain size and gyrification across species, myelination and motion may be key anatomical and functional features contributing to the surprising similarity of face networks across species. PMID- 25840652 TI - The evolution of cognition in natural populations. AB - Individual differences in cognitive abilities have been described in a range of species, but do they impact survival or reproduction? Several recent studies report links between putative cognitive and reproductive traits in avian systems. Whether or when selection should occur in the wild is becoming an exciting avenue of research. PMID- 25840653 TI - Primitive Neuroectodermal Tumor of the Kidney: A Case Report. PMID- 25840654 TI - Comparison of diagnostic accuracy of plain film radiographs between original film and smartphone capture: a pilot study. AB - The use of mobile devices for medical image capture has become increasingly popular given the widespread use of smartphone cameras. Prior studies have generally compared mobile phone capture images to digitized images. However, many underserved and rural areas without picture archiving and communication systems (PACS) still depend greatly on the use of film radiographs. Additionally, there is a scarcity of specialty-trained or formally licensed radiologists in many of these regions. Subsequently, there is great potential for the use of smartphone capture of plain radiograph films which would allow for increased access to economical and efficient consultation from board-certified radiologists abroad. The present study addresses the ability to diagnose a subset of radiographic findings identified on both the original film radiograph and the captured camera phone image. PMID- 25840655 TI - Treatment of Hypertension in Patients With Coronary Artery Disease: A Scientific Statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. PMID- 25840656 TI - New approaches for improving outcomes in breast cancer in Europe. AB - Considerable progress has been made in breast cancer treatment in Europe over the past three decades, yet survival rates for metastatic disease remain poor, underlining the need for further advances. While the use of predictive biomarkers for response to systemic therapy could improve drug development efficiency, progress in identifying such markers has been slow. The currently inadequate classification of breast cancer subtypes is a further challenge. Improved understanding of the molecular pathology of the disease has led to the identification of new targets for drug treatment, and evolving classifications should reflect these developments. Further ongoing challenges include difficulties in finding optimal combinations and sequences of systemic therapies, circumventing multidrug resistance and intra-tumor heterogeneity, problems associated with fragmentation in clinical trials and translational research efforts. Adoption of some of the strategies identified in this article may lead to further improvements in outcomes for patients with the disease. PMID- 25840657 TI - [Elderly patients and radiotherapy: A short review]. AB - The ageing of French population imposes to radiotherapists the challenge to treat older patients and to adjust their treatment. Unthinkable 30 years ago, radiation therapy concerns nowadays patients aged more than 90 years old. Oncogeriatric scales have been improved those last years without necessarily making sure that the right treatment is given to the right patient: if oncogeriatric scales use influences the final therapeutic decision, it does not define new target volumes, new doses, or new fractionation protocols. Except for some organs, there is not, for the moment, any consensus concerning geriatric population adapted treatments. This makes any therapeutic decision difficult. The present review has for objective to realise a report of the studies about favorable and unfavorable effects of radiation therapy amongst aged (>70 years old) or very aged (>90years old) population. PMID- 25840658 TI - A derivatization strategy for the detection and identification of volatile trialkylphosphites using liquid chromatography-online solid phase extraction and offline nuclear magnetic resonance spectroscopy. AB - We demonstrate herein the application of selective derivatization method that converts volatile and labile trialkylphosphites (TAPs) into virtually non volatile, thermally stable, and UV absorbing derivatives. After simple sample preparation, purification/enrichment of the derivatives was achieved by using high performance liquid chromatography (HPLC) coupled to on-line post column solid phase extraction (SPE) system. These derivatives were subjected to (31)P{(1)H} NMR and 1D-selTOCSY experiments. Conclusive identification was achieved on the basis of their HPLC retention time and NMR spectral signatures ( [Formula: see text] , (n)JH-H, and (3)JP-H). This method was tested for the unambiguous identification of a mixture containing low concentrations (~10MUgmL( 1)) of trimethylphosphite (TMP), triethylphosphite (TEP), triisopropylphosphite (TIP), and tributylphosphite (TBP) along with a high concentration of irrelevant background chemicals. It offered a high dynamic range and good detection limit and recovery (>75%) without the need for special NMR probe heads or exotic NMR experiments. PMID- 25840659 TI - Determination of high-intensity sweeteners in river water and wastewater by solid phase extraction and liquid chromatography-tandem mass spectrometry. AB - High-intensity sweeteners have been suggested as potential organic contaminants due to their widespread use in food, drugs and sanitary products. As a consequence, they are introduced into the environment by different pathways, affecting aquatic life. In this study, a method based on solid-phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) has been developed and validated for the determination of eight sweeteners (saccharin, cyclamate, aspartame, acesulfame, neohesperidin dihydrochalcone, sucralose, stevioside and glycyrrhizic acid) in river water and wastewater. To get the maximum recoveries in SPE, several commercial sorbents were tested and Oasis HLB gave the best results, with recoveries higher than 41% for all of the compounds in the different matrices. Method limits of detection were in the range of 0.001 0.04MUg/L in river water and 0.01-0.5MUg/L in influent and effluent wastewater. Method reproducibility between days (n=5) was below 15% for all compounds. The method was applied to the determination of sweeteners in various river waters and wastewaters in Catalonia. Cyclamate, aspartame, neohesperidin dihydrochalcone, acesulfame and sucralose were found in river water, with the two last compounds being present at the highest values (1.62MUg/L for acesulfame and 3.57MUg/L for sucralose). In influent and effluent wastewater, all of the compounds were found at concentration levels ranging from 0.05 to 155MUg/L except for stevioside and neohesperidin dihydrochalcone, which were not detected. PMID- 25840660 TI - Fabrication of aluminum terephthalate metal-organic framework incorporated polymer monolith for the microextraction of non-steroidal anti-inflammatory drugs in water and urine samples. AB - Polymer monolith microextraction (PMME) based on capillary monolithic column is an effective and useful technique to preconcentrate trace analytes from environmental and biological samples. Here, we report the fabrication of a novel aluminum terephthalate metal-organic framework (MIL-53(Al)) incorporated capillary monolithic column via in situ polymerization for the PMME of non steroidal anti-inflammatory drugs (NSAIDs) (ketoprofen, fenbufen and ibuprofen) in water and urine samples. The fabricated MIL-53(Al) incorporated monolith was characterized by X-ray powder diffractometry, scanning electron microscopy, Fourier transform infrared spectrometry, and nitrogen adsorption experiment. The MIL-53(Al) incorporated monolith gave larger surface area than the neat polymer monolith. A 2-cm long MIL-53(Al) incorporated capillary monolith was applied for PMME coupled with high-performance liquid chromatography for the determination of the NSAIDs. Potential factors affecting the PMME were studied in detail. Under the optimized conditions, the developed method gave the enhancement factors of 46 51, the linear range of 0.40-200MUgL(-1), the detection limits (S/N=3) of 0.12 0.24MUgL(-1), and the quantification limits (S/N=10) of 0.40-0.85MUgL(-1). The recoveries for spiked NSAIDs (20MUgL(-1)) in water and urine samples were in the range of 77.3-104%. Besides, the MIL-53(Al) incorporated monolith was stable enough for 120 extraction cycles without significant loss of extraction efficiency. The developed method was successfully applied to the determination of NSAIDs in water and urine samples. PMID- 25840661 TI - Quantitation of various indolinyl caged glutamates as their o-phthalaldehyde derivatives by high performance liquid chromatography coupled with tandem spectroscopic detections: derivatization, stoichiometry and stability studies. AB - Quantification, stability and unique spectroscopic properties of indolinyl-caged glutamates (ICGs), with the o-phthalaldehyde-3-mercaptopropionic acid (OPA-MPA) reagent, were described, at first. As new principle to the field, reactivity and stoichiometry of variously substituted OPA-MPA derivatized ICGs, such as 4 methoxy-7-nitroindolinyl-(MNI-Glu), 4-methoxy-5,7-dinitroindolinyl-(DNI-Glu), 2 dimethylamino-propoxy and dimethylamino-isobutoxy alternatives (2DMA-1PO-DNI-Glu, 1DMA-2P-DNI-Glu and 3DMA-1iBU-DNI-Glu), was demonstrated. Derivatives' stability was determined using high performance liquid chromatography (HPLC) applying simultaneous photodiode array (DAD) and fluorescence (Fl) detections, while their structural identity was confirmed by HPLC-time of flight mass spectrometry (HPLC TOF-MS). The SH-additive of the reagents was also varied. ICGs react unequivocally, with one OPA-SH-group molecule, in the molar ratios of ([OPA-SH additive]/[ICG]=1/1, resulting in species with the characteristic isoindole spectral property (EEx/EEm=337/454nm; lambdamax=337nm). ICGs' isoindole derivatives, due to their sandwich structure, are manifesting the pi-pi-stacking phenomenon: they fail to show fluorescence. ICGs' stability decreased in the order of MNI-Glu, 2DMA-1PO/1DMA-2PO, 3DMA-1iBU and DNI-Glu, correspondingly, resulting in increasing order of free glutamic acid (GA), as their decomposition product. GA and ICGs were determined as their OPA/MPA derivatives while uncaged species (MNI, DNI and its substituted alternatives) in their initial forms. The practical utility of the method was confirmed analyzing ICGs and their decomposition products, simultaneously. Quantifications' reliability and reproducibility were characterized with the relative standard deviation percentages of responses (RSDs%): for GA 0.41-12 RSD% for ICGs 0.057-7.0 RSD% were obtained. Stability properties of variously substituted, recently introduced ICGs, prepared in laboratories of Institute of Experimental Medicine, were defined. PMID- 25840662 TI - Facile modification of multi-walled carbon nanotubes-polymeric ionic liquids coated solid-phase microextraction fibers by on-fiber anion exchange. AB - In situ anion exchange has been proved to be an efficient method for facile modification of polymeric ionic liquids (PILs)-based stationary phases. In this work, an on-fiber anion exchange process was utilized to tune the extraction performance of a multi-walled carbon nanotubes (MWCNTs)-poly(1-vinyl-3 octylimidazolium bromide) (poly(VOIm(+)Br(-)))-coated solid-phase microextraction (SPME) fiber. MWCNTs were first coated onto the stainless steel wire through a layer-by-layer fabrication method and then the PILs were coated onto the MWCNTs physically. Anion of the MWCNTs-poly(VOIm(+)Br(-)) fiber was changed into bis(triflroromethanesulfonyl)imide (NTf2(-)) and 2-naphthalene-sulfonate (NapSO3( )) by on-fiber anion exchange. Coupled to gas chromatography, the MWCNTs poly(VOIm(+)Br(-)) fiber showed acceptable extraction efficiency for hydrophilic and hydrogen-bonding-donating alcohols, with limits of detection (LODs) in the range of 0.005-0.05MUgmL(-1); after the anion exchange with NTf2(-), the obtained MWCNTs-poly(VOIm(+)NTf2(-)) fiber brought wide linear ranges for hydrophobic n alkanes with correlation coefficient (R) ranging from 0.994 to 0.997; aromatic property of the fiber was enhanced by aromatic NapSO3(-) anions to get sufficient extraction capacity for phthalate esters and halogenated aromatic hydrocarbons. The MWCNTs-poly(VOIm(+)NapSO3(-)) fiber was finally applied to determine several halogenated aromatic hydrocarbons in groundwater of industrial park. PMID- 25840663 TI - The high-performance liquid chromatography/multistage electrospray mass spectrometric investigation and extraction optimization of beech (Fagus sylvatica L.) bark polyphenols. AB - The aim of the present work was the high-performance liquid chromatographic separation and multistage mass spectrometric characterization of the polyphenolic compounds of beech bark, as well as the extraction optimization of the identified compounds. Beech is a common and widely used material in the wood industry, yet its bark is regarded as a by-product. Using appropriate extraction methods these compounds could be extracted and utilized in the future. Different extraction methods (stirring, sonication, microwave assisted extraction) using different solvents (water, methanol:water 80:20 v/v, ethanol:water 80:20 v/v) and time/temperature schedules have been compared basing on total phenol contents (Folin-Ciocalteu) and MRM peak areas of the identified compounds to investigate optimum extraction efficiency. Altogether 37 compounds, including (+)-catechin, ( )-epicatechin, quercetin-O-hexoside, taxifolin-O-hexosides (3), taxifolin-O pentosides (4), B-type (6) and C-type (6) procyanidins, syringic acid- and coumaric acid-di-O-glycosides, coniferyl alcohol- and sinapyl alcohol-glycosides, as well as other unknown compounds with defined [M-H](-) m/z values and MS/MS spectra have been tentatively identified. The choice of the method, solvent system and time/temperature parameters favors the extraction of different types of compounds. Pure water can extract compounds as efficiently as mixtures containing organic solvents under high-pressure and high temperature conditions. This supports the implementation of green extraction methods in the future. Extraction times that are too long and high temperatures can result in the decrease of the concentrations. Future investigations will focus on the evaluation of the antioxidant capacity and utilization possibilities of the prepared extracts. PMID- 25840664 TI - Effect of bore fluid composition on microstructure and performance of a microporous hollow fibre membrane as a cation-exchange substrate. AB - Micro-capillary film (MCF) membranes are effective platforms for bioseparations and viable alternatives to established packed bed and membrane substrates at the analytical and preparative chromatography scales. Single hollow fibre (HF) MCF membranes with varied microstructures were produced in order to evaluate the effect of the bore fluid composition used during hollow fibre extrusion on their structure and performance as cation-exchange adsorbers. Hollow fibres were fabricated from ethylene-vinyl alcohol (EVOH) copolymer through solution extrusion followed by nonsolvent induced phase separation (NIPS) using bore fluids of differing composition (100wt.% N-methyl-2-pyrrolidone (NMP), 100wt.% glycerol, 100wt.% water). All HFs displayed highly microporous and mesoporous microstructures, with distinct regions of pore size <1MUm, 5-15MUm and up to 50MUm in diameter, depending upon proximity to the bore fluid. Scanning electron microscopy (SEM) revealed skins of pore size <1MUm at the inner surface of HFs produced with water and glycerol, while NMP bore fluid resulted in a skinless inner HF surface. The HFs were modified for chromatography by functionalising the polymer surface hydroxyl groups with sulphonic acid (SP) groups to produce cation exchange adsorbers. The maximum binding capacities of the HFs were determined by frontal analysis using lysozyme solutions (0.05-100mgml(-1)) for a flow rate of 1.0mlmin(-1). The NMP-HF-SP module displayed the largest maximum lysozyme binding capacity of all the fibres produced (40.3mg lysozyme/ml adsorbent volume), a nearly 2-fold increase over the glycerol and 10-fold increase over the water variants at the same sample flow rate. The importance of NMP as a bore fluid to hollow fibre membrane performance as a result of inner surface porosity was established with a view to applying this parameter for the optimisation of multi capillary MCF performance in future studies. PMID- 25840665 TI - Using electronic monitoring devices to measure inhaler adherence: a practical guide for clinicians. AB - Use of electronic monitoring devices (EMDs) for inhalers is growing rapidly because of their ability to provide objective and detailed adherence data to support clinical decision making. There is increasing potential for the use of EMDs in clinical settings, especially as cost-effectiveness is realized and device costs reduce. However, it is important for clinicians to know about the attributes of different EMDs so that they can select the right device for their patients and understand the factors that affect the reliability and accuracy of the data EMDs record. This article gives information on where to obtain EMDs, describes device specifications, and highlights useful features for the clinician and the patient, including user feedback data. We discuss the benefits and potential drawbacks of data collected by EMDs and provide device users with a set of tools to optimize the use of EMDs in clinical settings, such as advice on how to carry out brief EMD checks to ensure data quality and device reliability. New EMDs on the market require pretesting before use by patients. We provide information on how to carry out EMD pretesting in the clinic and patients' homes, which can be carried out by health professionals or in collaboration with researchers or manufacturers. Strategies for interpreting and managing common device malfunctions are also discussed. PMID- 25840666 TI - Triticum monococcum in patients with celiac disease: a phase II open study on safety of prolonged daily administration. AB - BACKGROUND AND AIMS: To assess safety of prolonged daily administration of Triticum monococcum (Tm) using clinical, serological and histological criteria. Tm is an ancient wheat suitable for production of palatable baked goods that contains gluten devoid of strongly immunostimulatory epitopes and potentially safe for celiac disease (CD) patients as suggested by in vitro and ex vivo studies. METHODS: Protocol involved 60-day administration of 100 g/day Tm water biscuits to CD patients in remission on gluten-free diet. Symptoms Gastrointestinal Symptom Rating Scale questionnaire (GSRS) and CD-related serology were assessed at time (T) 0, T30 and T60 days, and duodenal biopsy was obtained at T0 and T60. RESULTS: Eight patients (F/M: 6/2, median age 26) were enrolled. One patient was excluded at T0 because of positive serology, and two patients dropped out because of symptoms recurrence. In the five patients completing the study, there was no difference in GSRS score at T0 to T60. All patients had Marsh II lesion at T0, four had Marsh III and one had recurrence of dermatitis herpetiformis at T60. CD-related antibodies converted from negative to positive at T60 in three patients. CONCLUSIONS: Our study shows that Tm is toxic for CD patients as judged on histological and serological criteria, but it was well tolerated by the majority of patients, suggesting that Tm is not a safe cereal for celiacs, but that it may be of value for patients with gluten sensitivity or for prevention of CD. PMID- 25840668 TI - Response to letter commenting on "Outcome of localised blastemal-type Wilms tumour patients treated according to intensified treatment in the SIOP WT 2001 protocol, a report of the SIOP Renal Tumour Study Group (SIOP-RTSG)". PMID- 25840667 TI - Adaptive response activated by dietary cis9, trans11 conjugated linoleic acid prevents distinct signs of gliadin-induced enteropathy in mice. AB - PURPOSE: The beneficial effects of conjugated linoleic acid (CLA) mixture (cis9, trans11, c9; trans10, cis12, t10) against gliadin-induced toxicity in HLA-DQ8 transgenic mice (DQ8) have been associated with improved duodenal cytoprotective mechanisms [nuclear factor-E2-related factor-2, Nrf2; acylpeptide hydrolase (APEH)/proteasome]. The present study was aimed at investigating the ability of individual CLA isomers to improve the efficacy of these defensive mechanisms and to protect against duodenal injury caused by the combined administration of gliadin and indomethacin (GI). METHODS: Gluten-mediated enteropathy was induced in DQ8 mice by three intra-gastric administration of gliadin (20 mg kg(-1)/bw) and indomethacin (15 mg L(-1)) in drinking water for 10 days (GI). C9 or t10 CLA (520 mg kg(-1)/bw/day) were orally administered for 2 weeks. Pro-oxidant and toxic effects associated with GI treatment, anti-oxidant/detoxifying ability of c9 or t10-CLA and the protective effect induced by c9 pre-treatment (c9 + GI) were evaluated in DQ8 mice duodenum by combining enzymatic, immunoblotting, histological evaluation and quantitative real-time PCR assays. RESULTS: GI treatment produces the time-dependent decline of the considered detoxifying mechanisms thus leading to pro-apoptotic and pro-oxidant effects. APEH/proteasome pathway was not markedly affected by individual CLA isomers, but duodenal redox status and activity/mRNA levels of Nrf2-activated enzymes were significantly improved by c9 administration. c9 pre-treatment protects against GI-mediated accumulation of oxidative stress markers, and histological examination reveals the increase of goblet cells number in mouse duodenum but induces only a partial recovery of APEH/proteasome activity. CONCLUSIONS: The activation of and adaptive response by low doses of c9 supplementation prevents distinct signs of gliadin induced enteropathy in DQ8 mice. PMID- 25840669 TI - The power of phase II end-points for different possible mechanisms of action of an experimental treatment. AB - BACKGROUND: The high failure rate in phase III oncology trials is partly because the signal obtained from phase II trials is often weak. Several papers have considered the appropriateness of various phase II end-points for individual trials, but there has not been a systematic comparison using simulated data to determine which end-point should be used in which situation. METHODS: In this paper we carry out simulation studies to compare the power of several Response Evaluation Criteria in Solid Tumours (RECIST) response-based end-points for one arm and two-arm trials, together with progression-free survival (PFS) and testing the tumour-shrinkage directly for two-arm trials. We consider six scenarios: (1) short-term cytotoxic therapy; (2) continuous cytotoxic therapy; (3+4) cytostatic therapy; (5+6) delayed tumour-shrinkage effect (seen in some immunotherapies). We also consider measurement error in the assessment of tumour size. RESULTS: Measurement error affects the type-I error rate and power of single-arm trials, and the power of two-arm trials. Generally no single end-point performed well in all scenarios. Best observed response rate, PFS and directly testing the tumour shrinkages performed best for a number of scenarios. PFS performed very poorly when the effect of the treatment was short-lived. In scenario 6, where the delay in effect was long, no end-point performed well. CONCLUSIONS: A clinician setting up a phase II trial should consider the likely mechanism of action the drug will have and choose an end-point that provides high power for that scenario. Testing the difference in tumour-shrinkage is often powerful. Alternative end-points are required for therapies with a long delayed effect. PMID- 25840671 TI - Morphological Decomposition in Japanese De-adjectival Nominals: Masked and Overt Priming Evidence. AB - Whether morpheme-based processing extends to relatively unproductive derived words remains a matter of debate. Although whole-word storage and access has been proposed for some derived words, such as Japanese de-adjectival nominals with the unproductive (-mi) suffix (e.g., Hagiwara et al. in Language 75:739-763, 1999), Clahsen and Ikemoto (Ment Lex 7:147-182, 2012) found masked priming from de adjectival nominals with productive (-sa) and unproductive (-mi) suffixes to their adjectivally-inflected base morpheme. Using masked and unmasked priming, we examine whether adjectivally-inflected base morpheme primes facilitate the processing of Japanese de-adjectival nominal targets with a productive or unproductive affix, including an orthographic-overlap condition and semantic relatedness measure that Clahsen and Ikemoto (2012) did not include. Our results replicate and extend Clahsen and Ikemoto (2012), revealing significant, statistically-equivalent morphological priming effects for -sa and -mi affixed targets, independent of orthographic and semantic relatednesss, suggesting that the processing of derived words with the unproductive -mi affix makes recourse to morpheme-level representations. PMID- 25840670 TI - Predictors of long-term diabetes remission after metabolic surgery. AB - BACKGROUND DATA: Bariatric/metabolic surgery has been proposed for the treatment of inadequately controlled type 2 diabetes mellitus (T2DM) in obese patients. However, prediction on successful long-term remission of T2DM after metabolic surgery has not been clearly studied. Our objectives were to evaluate rates of long-term remission of T2DM after metabolic surgery and determine the independent predictors of remission. METHODS: Outcomes of 157 patients who underwent metabolic surgery between 2006 and 2009 and who had complete 5-year follow-up data were assessed. Prolonged complete remission was defined as glycated hemoglobin (HbA1c) less than 6 % without diabetes medication up to 5 years. Predictors of prolonged remission studies included patient characteristics such as glucose level, HbA1c, body weight, waist circumference, blood pressure, total cholesterol, LDL, triglyceride, uric acid, AST, alanine transaminase (ALT), albumin, insulin, C-peptide, iron, calcium, complete blood cell count, the ABCD score (a multidimensional grading system composed of age, body mass index (BMI), C-peptide levels, and duration of T2DM), and postoperative weight loss. RESULTS: At 5 years after surgery, the weight loss was 27.1 % and the mean BMI decreased from 39.8 to 28.8 kg/m(2). The mean HbA1c decreased from 8.3 to 6.0 %. A significant number of patients had improvement in their glycemic control, including 97 (71.3 %) patients who had complete remission (HbA1c < 6.0 %), 27 (19.9 %) partial remission (HbA1c < 6.5 %), and 12 (8.8 %) improved condition (HbA1c < 7 %). In univariate analysis, patients with prolonged T2DM remission after surgery were younger and heavier; had a wider waist, higher C-peptide, shorter duration of T2DM, higher liver enzyme, higher insulin resistance, higher C-peptide level, and higher white blood cell count; were taking smaller insulin dosage; had higher ABCD score; and had greater weight loss than those without remission. Multivariate logistical regression analyses showed that the ABCD score and weight loss were the only predictors of remission after metabolic surgery. CONCLUSIONS: Metabolic surgery is a treatment option for patients with obesity and T2DM. Baseline ABCD score and weight loss have a major influence on outcome. PMID- 25840672 TI - Cognitive and behavioral symptoms in Parkinson's disease patients with the G2019S and R1441G mutations of the LRRK2 gene. AB - OBJECTIVE: To compare the cognitive and psychiatric status of patients with Parkinson's disease related to the G2019S and the R1441G mutations of the LRRK2 gene (LRRK2-PD) and idiopathic Parkinson's disease (iPD) patients. METHODS: We examined cognition and psychiatric symptoms in 27 patients with LRRK2-PD (12 G2019S and 15 R1441G) and 27 iPD patients. RESULTS: The groups were similar in age, education, disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale (UPDRS) II-IV; however, the LRRK2-PD showed less impairment on UPDRS-I (2.0 +/- 1.7 vs. 4.2 +/- 2.8, p = 0.003). The LRRK2-PD presented less frequent subjective cognitive complaints (18.5% vs. 63.0%, p = 0.002), and mild cognitive impairment or dementia (25.9% vs. 59.2%, p = 0.027). They also showed less impairment on scales for general cognition (Mattis dementia rating scale 131.2 +/- 10.9 vs. 119 +/- 24.0, p = 0.022), episodic verbal memory (Rey's auditory verbal learning test, immediate recall 39.2 +/- 9.5 vs. 27.6 +/- 12.8 p < 0.001, delayed recall 7.2 +/- 3.7 vs. 4.7 +/- 4.0 p = 0.022), and the Neuropsychiatric Inventory (9.7 +/- 9.2 vs. 20.5 +/- 14.3, p = 0.004, significant differences for apathy and hallucinations). The LRRK2-PD subjects were less frequently treated with antipsychotic medication (0% vs. 25.9%, p = 0.010). There were no significant differences between G2019S and R1441G mutation carriers. CONCLUSIONS: Mutations of the LRRK2 gene might cause PD associated with less cognitive and neuropsychiatric impairment as compared to iPD. PMID- 25840673 TI - Limited correlations between clinician-based and patient-based measures of essential tremor severity. AB - INTRODUCTION: We investigated the relation between changes in clinician-based and patient-based measures of tremor severity, within the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) and Visual Analogue Scale (VAS) in essential tremor patients. METHODS: Thirty-seven patients were assessed twice: on- and off-medication. Clinician-based, objective TRS assessments, consisting of part A (postures/movements) and part B (tremor-inducing tasks) were conducted by a blinded assessor using video-tapes. Patients completed TRS part C (limitations in activities of daily life) and indicated subjective tremor severity using VAS. RESULTS: Patients' total TRS and VAS scores improved on-medication (both p < 0.001). Mean improvement was 6.3 (sd 5.4) points on the total TRS and 2.3 (sd 2.3) points on the VAS score. Within the TRS, we found moderate correlations between changes in clinician-based TRS-B and patient-based TRS-C scores (rho = 0.387, p = 0.011), but not between changes in clinician-based TRS-A and TRS-C scores (rho = 0.128, p = 0.232). Moreover, changes in subjective VAS scores correlated with changes in total TRS (rho = 0.422, p = 0.007), changes in TRS-C scores (rho = 0.367, p = 0.015) and, more weakly, with changes in TRS-B scores (rho = 0.281, p = 0.049), but again: not with changes in TRS-A scores (rho = 0.008, p = 0.482). DISCUSSION: We found no correlation between changes in clinician-based TRS-A, and patient-based measures TRS-C or VAS scores, and a weak correlation between clinician-based TRS-B and VAS scores. The limited correlations between changes in clinician-based and patient-based measures of tremor severity suggest that the different scales measure different aspects of tremor severity and support the additional use of subjective patient-based assessments in clinical practice and clinical trials. PMID- 25840674 TI - Vascular responses of the extremities to transdermal application of vasoactive agents in Caucasian and African descent individuals. AB - PURPOSE: Individuals of African descent (AFD) are more susceptible to non freezing cold injury than Caucasians (CAU) which may be due, in part, to differences in the control of skin blood flow. We investigated the skin blood flow responses to transdermal application of vasoactive agents. METHODS: Twenty four young males (12 CAU and 12 AFD) undertook three tests in which iontophoresis was used to apply acetylcholine (ACh 1 w/v %), sodium nitroprusside (SNP 0.01 w/v %) and noradrenaline (NA 0.5 mM) to the skin. The skin sites tested were: volar forearm, non-glabrous finger and toe, and glabrous finger (pad) and toe (pad). RESULTS: In response to SNP on the forearm, AFD had less vasodilatation for a given current application than CAU (P = 0.027-0.004). ACh evoked less vasodilatation in AFD for a given application current in the non-glabrous finger and toe compared with CAU (P = 0.043-0.014) with a lower maximum vasodilatation in the non-glabrous finger (median [interquartile], AFD n = 11, 41[234] %, CAU n = 12, 351[451] %, P = 0.011) and non-glabrous toe (median [interquartile], AFD n = 9, 116[318] %, CAU n = 12, 484[720] %, P = 0.018). ACh and SNP did not elicit vasodilatation in the glabrous skin sites of either group. There were no ethnic differences in response to NA. CONCLUSION: AFD have an attenuated endothelium dependent vasodilatation in non-glabrous sites of the fingers and toes compared with CAU. This may contribute to lower skin temperature following cold exposure and the increased risk of cold injuries experienced by AFD. PMID- 25840675 TI - Fault ride-through enhancement using an enhanced field oriented control technique for converters of grid connected DFIG and STATCOM for different types of faults. AB - With increase in electric power demand, transmission lines were forced to operate close to its full load and due to the drastic change in weather conditions, thermal limit is increasing and the system is operating with less security margin. To meet the increased power demand, a doubly fed induction generator (DFIG) based wind generation system is a better alternative. For improving power flow capability and increasing security STATCOM can be adopted. As per modern grid rules, DFIG needs to operate without losing synchronism called low voltage ride through (LVRT) during severe grid faults. Hence, an enhanced field oriented control technique (EFOC) was adopted in Rotor Side Converter of DFIG converter to improve power flow transfer and to improve dynamic and transient stability. A STATCOM is coordinated to the system for obtaining much better stability and enhanced operation during grid fault. For the EFOC technique, rotor flux reference changes its value from synchronous speed to zero during fault for injecting current at the rotor slip frequency. In this process DC-Offset component of flux is controlled, decomposition during symmetric and asymmetric faults. The offset decomposition of flux will be oscillatory in a conventional field oriented control, whereas in EFOC it was aimed to damp quickly. This paper mitigates voltage and limits surge currents to enhance the operation of DFIG during symmetrical and asymmetrical faults. The system performance with different types of faults like single line to ground, double line to ground and triple line to ground was applied and compared without and with a STATCOM occurring at the point of common coupling with fault resistance of a very small value at 0.001Omega. PMID- 25840676 TI - Suspension force control of bearingless permanent magnet slice motor based on flux linkage identification. AB - The control accuracy and dynamic performance of suspension force are confined in the traditional bearingless permanent magnet slice motor (BPMSM) control strategies because the suspension force control is indirectly achieved by adopting a closed loop of displacement only. Besides, the phase information in suspension force control relies on accurate measurement of rotor position, making the control system more complex. In this paper, a new suspension force control strategy with displacement and radial suspension force double closed loops is proposed, the flux linkage of motor windings is identified based on voltage current model and the flexibility of motor control can be improved greatly. Simulation and experimental results show that the proposed suspension force control strategy is effective to realize the stable operation of the BPMSM. PMID- 25840677 TI - Depressive Symptoms, Cardiac Anxiety, and Fear of Body Sensations in Patients with Non-Cardiac Chest Pain, and Their Relation to Healthcare-Seeking Behavior: A Cross-Sectional Study. AB - BACKGROUND: Patients with non-cardiac chest pain (NCCP) suffer from recurrent chest pain and make substantial use of healthcare resources. OBJECTIVE: To explore the prevalence of depressive symptoms, cardiac anxiety, and fear of body sensations in patients discharged with a NCCP diagnosis; and to describe how depressive symptoms, cardiac anxiety, and fear of body sensations are related to each other and to healthcare-seeking behavior. METHODS: Cross-sectional design. Data were collected between late October 2013 and early January 2014 in 552 patients with NCCP from four hospitals in southeast Sweden, using the Patient Health Questionnaire-9, Cardiac Anxiety Questionnaire, and Body Sensations Questionnaire. RESULTS: About 26 % (n = 141) of the study participants reported at least moderate depressive symptoms, 42 % (n = 229) reported at least moderate cardiac anxiety, and 62 % (n = 337) reported some degree of fear of body sensations. We found strong positive relationships between depressive symptoms and cardiac anxiety (r s = 0.49; P < 0.01), depressive symptoms and fear of body sensations (r s = 0.50; P < 0.01), and cardiac anxiety and fear of body sensations (r s = 0.56; P < 0.01). About 60 % of the participants sought care because of chest pain once, 26 % two or three times, and the rest more than three times. In a multivariable regression analysis, and after adjustment for multimorbidity, cardiac anxiety was the only variable independently associated with healthcare-seeking behavior. CONCLUSION: Patients with NCCP and many healthcare consultations had high levels of depressive symptoms and cardiac anxiety, and moderate levels of fear of body sensations. Cardiac anxiety had the strongest relationship with healthcare-seeking behavior and may therefore be an important target for intervention to alleviate suffering and to reduce healthcare use and costs. PMID- 25840678 TI - Missed nursing care and predicting factors in the Italian medical care setting. AB - Missed nursing care (MNC), such as nursing care omitted or delayed, has not been measured in the Italian context where several cost containment interventions affect the care offered in medical units. The aim of the study is to identify the amount, type, and reasons for MNC in the Italian medical care setting and to explore the factors that affect the occurrence of MNC. A 3-month longitudinal survey was carried out followed by a cross-sectional study design in 12 north eastern acute medical units. A total of 314 nursing staff members were involved. Multivariate logistic regression was performed to identify the predictors of MNC. Patient ambulation (91.4 %), turning the patient every 2 h (74.2 %), and right timing in administering medications (64.6 %) were the most perceived MNC. Among the most frequent reasons were the unexpected rise in patient volume or critical conditions (95.2 %), inadequate numbers of staff (94.9 %), and large numbers of admissions/discharges (93.3 %). The R (2) 33.2 % of the variance in MNC were explained by a full-time position (OR 4.743, 95 % CI 1.146-19.629), communication tensions between Registered Nurses and Nurses' Aides (OR 1.601, 95 % CI 1.020 2.515), the amount of experience in medical unit (OR 1.564, 95 % CI 1.021-2.397), and the amount of daily care offered by Nurses' Aides (1.039, 95 % CI 1.011 1.067). A substantial amount of basic and clinically relevant nursing interventions was perceived to be missed, and this may lead to an increase in negative outcomes for patients admitted to a medical unit. Appropriate standards of nursing care should be adopted urgently in medical units aiming to protect frail patients. PMID- 25840679 TI - Pros and cons of new oral anticoagulants in the treatment of venous thromboembolism in patients with cancer. AB - Patients with cancer account for 20 % of cases of venous thromboembolism (VTE). Cancer patients are at increased risk for VTE during the entire course of their disease, also in absence of traditional VTE risk factors. Furthermore, patients with VTE and cancer have an estimated risk of bleeding of 15-20 % per year while on anticoagulant treatment. For these reasons, treatment of acute VTE in patients with cancer remains a clinical challenge. In clinical studies, which included about 27,000 patients, new oral anticoagulants (NOACs) have been shown to be as effective and safe as conventional anticoagulation (heparin given with and followed by vitamin K antagonists) for the treatment of VTE. In these studies, 1227 patients with active cancer were enrolled. Preliminary results of subgroup analyses and meta-analyses of randomized clinical trials suggest that NOACs could represent an alternative to conventional anticoagulation in patients with active cancer. Further "ad hoc" studies evaluating the clinical benefit of treatment with NOACs in patients with VTE and cancer are needed. PMID- 25840680 TI - Mycobacterium tuberculosis effectors interfering host apoptosis signaling. AB - Tuberculosis remains a serious human public health concern. The coevolution between its pathogen Mycobacterium tuberculosis and human host complicated the way to prevent and cure TB. Apoptosis plays subtle role in this interaction. The pathogen endeavors to manipulate the apoptosis via diverse effectors targeting key signaling nodes. In this paper, we summarized the effectors pathogen used to subvert the apoptosis, such as LpqH, ESAT-6/CFP-10, LAMs. The interplay between different forms of cell deaths, such as apoptosis, autophagy, necrosis, is also discussed with a focus on the modes of action of effectors, and implications for better TB control. PMID- 25840681 TI - Functional Exposed Amino Acids of BauA as Potential Immunogen Against Acinetobacter baumannii. AB - Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram negative bacilli to control and treat. One of the major challenges that the pathogenic bacteria face in their host is the scarcity of freely available iron. To survive under such conditions, bacteria express new proteins on their outer membrane and also secrete iron chelators called siderophores. Antibodies directed against these proteins associated with iron uptake exert a bacteriostatic or bactericidal effect against A. baumanii in vitro, by blocking siderophore mediated iron uptake pathways. Attempts should be made to discover peptides that could mimic protein epitopes and possess the same immunogenicity as the whole protein. Subsequently, theoretical methods for epitope prediction have been developed leading to synthesis of such peptides that are important for development of immunodiagnostic tests and vaccines. The present study was designed to in silico resolving the major obstacles in the control or in prevention of the diseases caused by A. baumannii. We exploited bioinformatic tools to better understand and characterize the Baumannii acinetobactin utilization structure of A. baumannii and select appropriate regions as effective B cell epitopes. In conclusion, amino acids 26-191 of cork domain and 321-635 of part of the barrel domain including L4-L9, were selected as vaccine candidates. These two regions contain functional exposed amino acids with higher score of B cell epitopes properties. Majority of amino acids are hydrophilic, flexible, accessible, and favorable for B cells from secondary structure point of view. PMID- 25840682 TI - T follicular helper cells have distinct modes of migration and molecular signatures in naive and memory immune responses. AB - B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169(+) subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen. PMID- 25840684 TI - Erratum to: Parent Training in Autism Spectrum Disorder: What's in a Name? PMID- 25840683 TI - Clinical Evaluation of PET Image Quality as a Function of Acquisition Time in a New TOF-PET/MRI Compared to TOF-PET/CT--Initial Results. AB - PURPOSE: The purpose of this study was to compare only the performance of the PET component between a TOF-PET/CT (henceforth noted as PET/CT) scanner and an integrated TOF-PET/MRI (henceforth noted as PET/MRI) scanner concerning image quality parameters and quantification in terms of standardized uptake value (SUV) as a function of acquisition time (a surrogate of dose). The CT and MR image quality were not assessed, and that is beyond the scope of this study. PROCEDURES: Five brain and five whole-body patients were included in the study. The PET/CT scan was used as a reference and the PET/MRI acquisition time was consecutively adjusted, taking into account the decay between the scans in order to expose both systems to the same amount of the emitted signal. The acquisition times were then retrospectively reduced to assess the performance of the PET/MRI for lower count rates. Image quality, image sharpness, artifacts, and noise were evaluated. SUV measurements were taken in the liver and in the white matter to compare quantification. RESULTS: Quantitative evaluation showed strong correlation between PET/CT and PET/MRI brain SUVs. Liver correlation was good, however, with lower uptake estimation in PET/MRI, partially justified by bio redistribution. The clinical evaluation showed that PET/MRI offers higher image quality and sharpness with lower levels of noise and artifacts compared to PET/CT with reduced acquisition times for whole-body scans while for brain scans there is no significant difference. CONCLUSION: The TOF-PET/MRI showed higher image quality compared to TOF-PET/CT as tested with reduced imaging times. However, this result accounts mainly for body imaging, while no significant differences were found in brain imaging. PMID- 25840685 TI - A systematic review of the cost-effectiveness of non-surgical obesity interventions in men. AB - BACKGROUND: Increasing obesity related health conditions have a substantial burden on population health and healthcare spending. Obesity may have a sex specific impact on disease development, men and women may respond differently to interventions, and there may be sex-specific differences to the cost effectiveness of interventions to address obesity. There is no clear indication of cost-effective treatments for men. METHODS: This systematic review summarises the literature reporting the cost-effectiveness of non-surgical weight-management interventions for men. Studies were quality assessed against a checklist for appraising decision modelling studies. RESULTS: Although none of the included studies explicitly set out to determine the cost-effectiveness of treatment for men, seven studies reported results for subgroups of men. Interventions were grouped into lifestyle interventions (five studies) and Orlistat (two studies). The retrieved studies showed promising evidence of cost-effectiveness, especially when interventions were targeted at high-risk groups, such as those with impaired glucose tolerance. There appears to be some sex-specific elements to cost effectiveness, however, there were no clear trends or indications of what may be contributing to this. CONCLUSION: The economic evidence was highly uncertain, and limited by variable methodological quality of the included studies. It was therefore not possible to draw strong conclusions on cost-effectiveness. Future studies are required to demonstrate the cost-effectiveness of interventions specifically targeted towards weight loss for men. PMID- 25840686 TI - Protective roles of N-benzylcinnamide on cortex and hippocampus of aged rat brains. AB - Brain aging has been associated with oxidative stress leading to inflammation and apoptosis. The protective effects and underlying mechanisms of N-benzylcinnamide (PT-3), purified from Piper submultinerve, on brains of 90-week-old Wistar rats were investigated following daily intraperitoneal injection with 1.5 mg of PT 3/kg of body weight for 15 days. PT-3 treatment improved spatial learning and memory of aged rats and caused significant changes in brain frontal cortex, hippocampus, and temporal cortex in parameters associated with oxidative stress (decreased reactive oxygen species production and iNOS and nNOS levels), inflammation (reduced levels of IL-1beta and IL-6), apoptosis (reduced levels of Bax and activated caspase-3, and elevated level of Bcl-2), and signaling pathways related to inflammation and apoptosis (decreased amounts of phospho-JNK and -p38, increased phospho-Akt level and no change in phospho-ERK1/2 content) compared to controls. PT-3 treatment also inhibited aged rat brain AChE activity. These results suggest that PT-3 with its intrinsic antioxidant and AChE inhibitory properties has therapeutic potential in ameliorating, in part, age-associated damages to the brain. PMID- 25840687 TI - Neurophysiological mechanisms underlying sex- and maturation-related variation in pheromone responses in honey bees (Apis mellifera). AB - In the honey bee (Apis mellifera), social organization is primarily mediated by pheromones. Queen-produced 9-oxo-2-decenoic acid (9-ODA) functions as both a social and sex pheromone, eliciting attraction in both female workers and male drones, but also affecting other critical aspects of worker physiology and behavior. These effects are also maturation related, as younger workers and sexually mature drones are most receptive to 9-ODA. While changes in the peripheral nervous system drive sex-related differences in sensitivity to 9-ODA, the mechanisms driving maturation-related shifts in receptivity to 9-ODA remain unknown. Here, we investigate the hypothesis that changes at the peripheral nervous system may be mediating plastic responses to 9-ODA by characterizing expression levels of AmOR11 (the olfactory receptor tuned to 9-ODA) and electrophysiological responses to 9-ODA. We find that receptor expression correlates significantly with behavioral receptivity to 9-ODA, with nurses and sexually mature drones exhibiting higher levels of expression than foragers and immature drones, respectively. Electrophysiological responses to 9-ODA were not found to correlate with behavioral receptivity or receptor expression, however. Thus, while receptor expression at the periphery exhibits a level of plasticity that correlates with behavior, the mechanisms driving maturation-dependent responsiveness to 9-ODA appear to function primarily in the central nervous system. PMID- 25840688 TI - Genetic dissimilarity between primary colorectal carcinomas and their lymph node metastases: ploidy, p53, bcl-2, and c-myc expression--a pilot study. AB - The current paradigm of metastasis proposes that rare cells within primary tumors acquire metastatic capability via sequential mutations, suggesting that metastases are genetically dissimilar from their primary tumors. This study investigated the changes in the level of expression of a well-defined panel of cell proliferation, differentiation, and apoptosis markers between the primary colorectal cancer (CRC) and the corresponding synchronous lymph node (LN) metastasis from the same patients. DNA flow cytometry and immunostaining of p53, bcl-2, and c-myc were carried out on 36 cases of CRC radical resection specimens with their corresponding LN metastases. There was very low probability that the histological patterns of primary tumors and LN metastases are independent (p < 0.001). Metastatic tumors were significantly more diffusely positive for p53 than the primary tumors (p < 0.001). Conversely, primary tumors were significantly more diffusely positive for c-myc than metastatic tumors (p = 0.011). No significant difference was found between the LNs and the primary tumors in bcl-2 positivity (p = 0.538) and DNA aneuploidy (p = 0.35), with a tendency towards negative bcl-2 and less aneuploidy in LN metastases than primary tumors. In conclusion, LN metastatic colorectal carcinomas have a tendency of being less differentiated, with a higher incidence of diffuse p53 staining, lower incidence of bcl-2 staining, and less aneuploidy in comparison to their primary counterparts suggesting a more aggressive biological behavior, which could indicate the necessity for more aggressive adjuvant therapy. PMID- 25840689 TI - Role of pancreatic stellate cells and periostin in pancreatic cancer progression. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and one of the five most lethal malignancies characterized by prominent desmoplastic reaction. Accumulating evidences indicate that tumor desmoplasia plays a pivotal role in PDAC progression, and it has been largely ignored until recent times. It has now been unequivocally shown that pancreatic stellate cells (PSCs) are the principal effector cells responsible for stroma production. Periostin, also known as osteoblast-specific factor 2, is a secretory protein and originally identified as an osteoblast-specific factor that expressed in periosteum. Periostin is exclusively produced by activated PSCs, and periostin overexpression presents in various malignant tumors and closely relates with disease progression. In addition, periostin has been suggested to stimulate pancreatic cancer cells proliferation and enhance their resistance to serum starvation and hypoxia. Therefore, the interplay between cancer cells and stromal cells plays a vital role in PDAC development. However, the function of periostin in pancreatic cancer development is controversial. This review summarizes existing knowledge about the role of PSCs in cancer stroma production, the interaction between PSCs and pancreatic cancer cells, tumor angiogenesis, and hypoxic microenvironment, with particular focus on the expression and function as well as signaling pathways of periostin in PDAC cells and PSCs. PMID- 25840691 TI - Using platelet-rich plasma to treat jumper's knees: Exploring the effect of a second closely-timed infiltration. AB - OBJECTIVES: Some clinical series have evaluated the effect of platelet-rich plasma (PRP) in the treatment of proximal patellar tendinopathy. Although it is possible that a single infiltrative administration may prove to be an effective treatment for this indication, most of the existing studies evaluated the effects of two or three successive infiltrations. The aim of this study was to evaluate whether two infiltrations of PRP proves more effective than a single treatment. DESIGN: Prospective, randomized and comparative study of level 2. METHODS: Twenty patients suffering from chronic proximal patellar tendinopathy were enrolled into the study and split into two randomized groups (one or two infiltrations of PRP, respectively). The 3-month follow-up evaluation consisted of VAS, IKDC and VISA-P scores, along with algometer, isokinetic and ultrasounds evaluations. After 1 year, subjects were contacted to define their functional evolution. RESULTS: The concentration of the PRP used for each infiltration was similar in both groups, and contained no red or white cells. Results revealed no difference in treatment efficacy between the groups. CONCLUSIONS: The comparison between one or two infiltrations of PRP did not reveal any difference between the two groups at short to mid term. A second closely-timed infiltration of PRP to treat proximal patellar tendinopathies is not necessary to improve the efficacy of this treatment in the short term. PMID- 25840690 TI - miR-30 overexpression promotes glioma stem cells by regulating Jak/STAT3 signaling pathway. AB - Malignant glioma is the most common intracranial tumor with poor prognosis. It is well believed that glioma stem cells (GSCs) are responsible for the initiation and progression of glioma. Janus kinase/signal transducer and activator of transcription (Jak/STAT3) pathway plays a key role in the functions of GSCs. However, the regulatory mechanism of Jak/STAT3 pathway has not been completely elucidated. This study employed multidisciplinary approaches to investigate the upstream regulators of Jak/STAT3 signaling in GSCs. miR-30 was found to be overexpressed in the GSCs derived from U-87 MG and primary glioma cells, compared with non-stem-cell-like glioma cells and normal cells. Downregulation of miR-30 was able to suppress Jak/STAT3 pathway and reduce the tumorigenecity of GSCs. miR 30 decreased the expression of suppressor of cytokine signaling 3 (SOCS3) expression by targeting 3'UTR of its mRNA. The silencing of SOCS3 abolished the effect of miR-30 downregulation on GSCs. Collectively, there is a regulatory pathway consisting of miR-30, SOCS3, and Jak/STAT3 in GSCs, and targeting this pathway may be a promising strategy to treat glioma. PMID- 25840692 TI - Adjuvant immunotherapy for cancer: the next step. PMID- 25840694 TI - New guidelines for hypertension control in cardiac patients - lower may not be better. PMID- 25840693 TI - Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. AB - BACKGROUND: Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence. METHODS: We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis <=1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov, number NCT00636168. FINDINGS: Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2.74 years (IQR 2.28-3.22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26.1 months (95% CI 19.3-39.3) in the ipilimumab group versus 17.1 months (95% CI 13.4-21.6) in the placebo group (hazard ratio 0.75; 95% CI 0.64 0.90; p=0.0013); 3-year recurrence-free survival was 46.5% (95% CI 41.5-51.3) in the ipilimumab group versus 34.8% (30.1-39.5) in the placebo group. The most common grade 3-4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 [16%] vs four [<1%] in the placebo group), hepatic (50 [11%] vs one [<1%]), and endocrine (40 [8%] vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 [39%] during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barre syndrome. INTERPRETATION: Adjuvant ipilimumab significantly improved recurrence free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. FUNDING: Bristol-Myers Squibb. PMID- 25840695 TI - Treatment of hypertension in patients with coronary artery disease: A scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. PMID- 25840696 TI - Can species traits predict the susceptibility of riverine fish to water resource development? An Australian case study. AB - Water resource developments alter riverine environments by disrupting longitudinal connectivity, transforming lotic habitats, and modifying in-stream hydraulic conditions. Effective management of anthropogenic disturbances therefore requires an understanding of the range of potential ecosystem effects and the inherent traits symptomatic of elevated vulnerability to disturbance. Using 42 riverine fish native to South Eastern Australia as a case study, we quantified six morphological, behavioral, and life-history traits to classify species into groups reflecting potential differences in their response to ecosystem changes as a result of water resource development. Classification analysis identified five strategies based on fish life-history dispersal requirements, climbing potential, and habitat preference. These strategies in turn highlight the potential species at risk from the separate impacts of water resource development and inform management decisions to mitigate those risks. Swimming ability did not contribute to distinguishing species into functional groups, likely due to methodological inconsistencies in quantifying swimming performance that may ultimately hinder the ability of fish passage facilities to function within the physical capabilities of species at risk of habitat fragmentation. This study improves our ability to predict the performance of groups of species at risk from the multiple environmental changes imposed by humans and goes beyond broad-scale dispersal requirements as a predictor of individual species response. PMID- 25840697 TI - Vegetation in Bangalore's Slums: Composition, Species Distribution, Density, Diversity, and History. AB - There is widespread acknowledgement of the need for biodiversity and greening to be part of urban sustainability efforts. Yet we know little about greenery in the context of urban poverty, particularly in slums, which constitute a significant challenge for inclusive development in many rapidly growing cities. We assessed the composition, density, diversity, and species distribution of vegetation in 44 slums of Bangalore, India, comparing these to published studies on vegetation diversity in other land-use categories. Most trees were native to the region, as compared to other land-use categories such as parks and streets which are dominated by introduced species. Of the most frequently encountered tree species, Moringa oleifera and Cocos nucifera are important for food, while Ficus religiosa plays a critical cultural and religious role. Tree density and diversity were much lower in slums compared to richer residential neighborhoods. There are also differences in species preferences, with most plant (herb, shrub and vines) species in slums having economic, food, medicinal, or cultural use, while the species planted in richer residential areas are largely ornamental. Historic development has had an impact on species distribution, with older slums having larger sized tree species, while recent slums were dominated by smaller sized tree species with greater economic and food use. Extensive focus on planting trees and plant species with utility value is required in these congested neighborhoods, to provide livelihood support. PMID- 25840698 TI - The role and value of conservation agency research. AB - Governments charge their conservation agencies to safeguard biodiversity through protected areas and threat mitigation. Increasingly, conservation management and policy need to be supported by rigorous evidence provided by science. As such, institutional arrangements should consider and enable effective scientific research and information dissemination. What role can in-house agency research play in responding to this challenge? We examined the research capabilities of three conservation agencies from Australia, South Africa, and United States. Seven indicators were used to characterize the reliability and relevance of agency research. We found similarities among agencies in their patterns of peer reviewed publication, cultures of research collaboration, and tendencies to align research with organizational objectives. Among the many and diverse activities that constitute the role of a contemporary agency researcher, we emphasize two key research dimensions: reliability, achieved through peer-reviewed research output, and relevance, achieved through active stakeholder engagement. Amid increasingly challenging realities for conservation of ecosystems, agency science functions are vital to providing the evidence base required for effective management and policy development. PMID- 25840699 TI - Using Flow-Ecology Relationships to Evaluate Ecosystem Service Trade-Offs and Complementarities in the Nation's Largest River Swamp. AB - Large river systems are inextricably linked with social systems; consequently, management decisions must be made within a given ecological, social, and political framework that often defies objective, technical resolution. Understanding flow-ecology relationships in rivers is necessary to assess potential impacts of management decisions, but translating complex flow-ecology relationships into stakeholder-relevant information remains a struggle. The concept of ecosystem services provides a bridge between flow-ecology relationships and stakeholder-relevant data. Flow-ecology relationships were used to explore complementary and trade-off relationships among 12 ecosystem services and related variables in the Atchafalaya River Basin, Louisiana. Results from Indicators of Hydrologic Alteration were reduced to four management-relevant hydrologic variables using principal components analysis. Multiple regression was used to determine flow-ecology relationships and Pearson correlation coefficients, along with regression results, were used to determine complementary and trade-off relationships among ecosystem services and related variables that were induced by flow. Seven ecosystem service variables had significant flow ecology relationships for at least one hydrologic variable (R (2) = 0.19-0.64). River transportation and blue crab (Callinectes sapidus) landings exhibited a complementary relationship mediated by flow; whereas transportation and crawfish landings, crawfish landings and crappie (Pomoxis spp.) abundance, and blue crab landings and blue catfish (Ictalurus furcatus) abundance exhibited trade-off relationships. Other trade-off and complementary relationships among ecosystem services and related variables, however, were not related to flow. These results give insight into potential conflicts among stakeholders, can reduce the dimensions of management decisions, and provide initial hypotheses for experimental flow modifications. PMID- 25840700 TI - The effects of recreation experience, environmental attitude, and biospheric value on the environmentally responsible behavior of nature-based tourists. AB - The scientific understanding of the recreation experience and the environmentally responsible behavior of nature-based tourists is limited. This study examines the relationship among the recreation experience, environmental attitude, biospheric value, and the general and site-specific environmentally responsible behavior of nature-based tourists in Taomi, Liuqiu Island, and Aowanda and Najenshan in Taiwan. A total of 1342 usable questionnaires were collected for this study. The empirical results indicate that the recreation experience influences biospheric value and environmental attitude; subsequently, it then indirectly influences the general and site-specific environmentally responsible behavior of nature-based tourists. Our theoretical behavioral model elucidates previously proposed but unexamined behavioral models among nature-based tourists, and it offers a theoretical framework for researchers, decision makers, managers, and tourists in the field of nature-based tourism. We conclude that when an individual participates in nature-based tourism as described here, these recreation experiences strengthen their environmental attitude and biospheric value, and consequently increase their engagement in both general and site-specific environmentally responsible behaviors. PMID- 25840701 TI - A case of pseudoseizures precipitated by anticonvulsant toxicity. AB - We report a case of induction of pseudoseizures by anticonvulsant toxicity in a patient with underlying seizure disorder, hence supporting the argument of an organic subtype of pseudoseizure. PMID- 25840702 TI - An unusual case of bilateral vestibulopathy, chronic subjective dizziness and spondyloarthropathy. AB - OBJECTIVE: Vertigo and dizziness are two common symptoms seen in everyday practice. However, in some cases, making a diagnosis can be challenging. This case report shows the relevance of a careful psychiatric history, which led to the diagnosis of chronic subjective dizziness associated with bilateral peripheral vestibulopathy. METHODS: A case of a 33-year-old lady with multiple episodes of vertigo attack after a minor head injury is reported. RESULTS: A comprehensive audiometric and vestibular evaluation reviewed bilateral peripheral vestibulopathy. The frequency of the vertigo attacks decreased after treatment with betahisdine, but the patient still experienced chronic dizziness. Interestingly, when she developed spondyloarthropathy (SpA) 2 years later, both the vertigo and dizziness disappeared. When the patient went into clinical remission for SpA, she once again felt the vertigo and dizziness. The symptoms were initially thought to be part of the autoimmune disease. However, a course of oral prednisolone was ineffective. She was later diagnosed with agoraphobia without panic attack and chronic subjective dizziness, and was successfully treated with a course of benzodiazepine. CONCLUSION: The case presented demonstrates the importance of a biopsychosocial approach to patient management as vertigo and dizziness are often accompanied by psychological problems that must not be overlooked. PMID- 25840703 TI - Reversibility of trapped air on chest computed tomography in cystic fibrosis patients. AB - PURPOSE: To investigate changes in trapped air volume and distribution over time and compare computed tomography (CT) with pulmonary function tests for determining trapped air. METHODS: Thirty children contributed two CTs and pulmonary function tests over 2 years. Localized changes in trapped air on CT were assessed using image analysis software, by deforming the CT at timepoint 2 to match timepoint 1, and measuring the volume of stable (TAstable), disappeared (TAdisappeared) and new (TAnew) trapped air as a proportion of total lung volume. We used the difference between total lung capacity measured by plethysmography and helium dilution, residual volume to total lung capacity ratio, forced expiratory flow at 75% of vital capacity, and maximum mid-expiratory flow as pulmonary function test markers of trapped air. Statistical analysis included Wilcoxon's signed rank test and Spearman correlation coefficients. RESULTS: Median (range) age at baseline was 11.9 (5-17) years. Median (range) of trapped air was 9.5 (2-33)% at timepoint 1 and 9.0 (0-25)% at timepoint 2 (p=0.49). Median (range) TAstable, TAdisappeared and TAnew were respectively 3.0 (0-12)%, 5.0 (1-22)% and 7.0 (0-20)%. Trapped air on CT correlated statistically significantly with all pulmonary function measures (p<0.01), other than residual volume to total lung capacity ratio (p=0.37). CONCLUSION: Trapped air on CT did not significantly progress over 2 years, may have a substantial stable component, and is significantly correlated with pulmonary function markers. PMID- 25840704 TI - Erratum to: Synthesis and crystal structure of new heterocyles derived from saccharin and uracil carrying 1,2,4-oxadiazolylmethyl group. PMID- 25840705 TI - Synthetic Strategies in Molecular Imprinting. AB - This chapter introduces the basic principle and the synthetic aspects of molecular imprinting. First, the use of a molecular template to guide the location of functional groups inside molecularly imprinted cavities is explained. Three different mechanisms that ensure a molecular template associates with functional monomers or the imprinted polymers, that is, through reversible covalent, noncovalent, and sacrificial covalent bonds, are then described. The main focus is put on noncovalent molecular imprinting using free radical polymerization. The merits of using classical radical polymerization and more sophisticated, controlled radical polymerization are analyzed. After these synthetic chemistry aspects, the chapter continues to discuss the different polymerization processes that can be used to prepare well-defined polymer monoliths, microspheres, and nanoparticles. New top-down processing techniques that produce micro- and nanopatterns of imprinted polymers are also reviewed. The chapter finishes with a brief introduction to using imprinted polymers as building blocks to construct new functional materials and devices, which we consider as one important direction for further development. PMID- 25840706 TI - [Recommendations for respiratory support in the newborn (iii). Surfactant and nitric oxide]. AB - The recommendations included in this document will be part a series of updated reviews of the literature on respiratory support in the newborn infant. These recommendations are structured into twelve modules, and in this work module 7 is presented. Each module is the result of a consensus process including all members of the Surfactant and Respiratory Group of the Spanish Society of Neonatology. They represent a summary of the published papers on each specific topic, and of the clinical experience of each one of the members of the group. PMID- 25840707 TI - [Cytomegalovirus screening in less than 1500 g premature newborns. National Congenital Cytomegalovirus Disease Registry Scientific committee]. PMID- 25840708 TI - [Use of sugars and sweeteners in children's diets. Recommendations of the Nutrition Committee of the Spanish Paediatric Association]. AB - The term "sweetener" refers to a food additive that imparts a sweet flavour and usually provides no or very low energy. It is used to sweeten foods, medicines and food supplements with no nutritional purposes. For years, no-calorie sweeteners have been used as substitutes for all or part of the sugar content in foods and beverages. In recent decades its consumption has risen to prevent tooth decay, or as an aid in weight control, obesity and diabetes and, in general, to achieve an optimal energy balance. However, consumption of sugary or sweetened food and soft drinks is high, making this situation of special interest in calorie intake and in the poor behavioural pattern of eating habits in children. In addition, questions remain among consumers about the risks to health associated with their use, whether they are artificial or natural. The "artificial sweeteners" are the group of greatest interest in research in order to demonstrate their safety and to provide firm data on their possible therapeutic effects. The aim of the present document is to increase information for paediatricians on the characteristics of different sweeteners, and to advise on the choice of sweeteners, based on their properties. PMID- 25840709 TI - Is your cough getting better? PMID- 25840710 TI - Mold allergens in respiratory allergy: from structure to therapy. AB - Allergic reactions to fungi were described 300 years ago, but the importance of allergy to fungi has been underestimated for a long time. Allergens from fungi mainly cause respiratory and skin symptoms in sensitized patients. In this review, we will focus on fungi and fungal allergens involved in respiratory forms of allergy, such as allergic rhinitis and asthma. Fungi can act as indoor and outdoor respiratory allergen sources, and depending on climate conditions, the rates of sensitization in individuals attending allergy clinics range from 5% to 20%. Due to the poor quality of natural fungal allergen extracts, diagnosis of fungal allergy is hampered, and allergen-specific immunotherapy is rarely given. Several factors are responsible for the poor quality of natural fungal extracts, among which the influence of culture conditions on allergen contents. However, molecular cloning techniques have allowed us to isolate DNAs coding for fungal allergens and to produce a continuously growing panel of recombinant allergens for the diagnosis of fungal allergy. Moreover, technologies are now available for the preparation of recombinant and synthetic fungal allergen derivatives which can be used to develop safe vaccines for the treatment of fungal allergy. PMID- 25840711 TI - Interactions between innate immunity genes and early-life risk factors in allergic rhinitis. AB - PURPOSE: Allergic rhinitis (AR) is a common chronic disease. Many factors could affect the development of AR. We investigated early-life factors, such as delivery mode, feeding method, and use of antibiotics during infancy, which could affect the development of AR. In addition, how interactions between these factors and innate gene polymorphisms influence the development of AR was investigated. METHODS: A cross-sectional study of 1,828 children aged 9-12 years was conducted. Three early-life factors and AR were assessed by a questionnaire. Skin prick tests were done. Polymorphisms of TLR4 (rs1927911) and CD14 (rs2569190) were genotyped. RESULTS: Use of antibiotics during infancy increased the risk of AR (aOR [95% CI] 1.511 [1.222-2.037]) and atopic AR (aOR [95% CI], 1.565 [1.078 2.272]). There were synergistic interactions between caesarean delivery, formula feeding, and use of antibiotics in the rate of atopic AR (aOR [95% CI], 3.038 [1.256-7.347]). Additional analyses revealed that the risk for the development of AR or atopic AR subjects with the TLR4 CC genotype were highest when all the 3 early-life factors were present (aOR [95% CI], 5.127 [1.265-20.780] for AR; 6.078 [1.499-24.649] for atopic AR). In addition, the risk for the development of AR or atopic AR in subjects with the CD14 TT genotype were highest when all the 3 early life factors were present (aOR [95% CI], 5.960 [1.421-15.002] for AR; 6.714 [1.440-31.312] for atopic AR). CONCLUSIONS: Delivery mode, feeding method, and use of antibiotics during infancy appeared to have synergistic interactions in the development of AR. Gene-environment interactions between polymorphism of innate genes and early- life risk factors might affect the development of AR. PMID- 25840712 TI - Detection and investigation of temporal clusters of congenital anomaly in Europe: seven years of experience of the EUROCAT surveillance system. AB - Detection and investigation of congenital anomaly clusters is one part of surveillance to detect new or changing teratogenic exposures in the population. The EUROCAT (European Surveillance of Congenital Anomalies) cluster monitoring system and results are described here. Monitoring was conducted annually from 2007 to 2013 for 18 registries covering an annual birth population up to 0.5 million births. For each registry and 72 anomaly subgroups, the scan "moving window" technique was used to detect clusters in time occurring within the last 2 years based on estimated date of conception. Registries conducted preliminary investigations using a standardised protocol to determine whether there was cause for concern, and expert review was used at key points. 165 clusters were detected, a rate of 3.4% of all 4823 cluster tests performed over 7 years, more than expected by chance. Preliminary investigations of 126 new clusters confirmed that 35% were an unusual aggregation of cases, while 56% were explained by data quality or diagnostic issues, and 9% were not investigated. For confirmed clusters, the registries' course of action was continuing monitoring. Three confirmed clusters continued to grow in size for a limited period in subsequent monitoring. This system is best suited to early detection of exposures which are sudden, widespread and/or highly teratogenic, and was reassuring in demonstrating an absence of a sustained exposure of this type. Such proactive monitoring can be run efficiently without overwhelming the surveillance system with false positives, and serves an additional purpose of data quality control. PMID- 25840713 TI - An examination of motor unit number index in adults with cerebral palsy. AB - Spinal motor neuron loss may be a factor contributing to weakness in central disorders. The aim of this study was to assess whether motor unit numbers are reduced in the hand musculature of adults with cerebral palsy (CP) using the motor unit number index (MUNIX) technique. In this prospective, case-control study, 10 adults with CP were matched with healthy controls. MUNIX was computed using area and power of voluntary surface hypothenar electromyographic (EMG) signals and the compound muscle action potential (CMAP) recorded with ulnar nerve stimulation. The motor unit size index (MUSIX) was calculated based on maximum CMAP amplitude and MUNIX value. Gross Motor Function Classification Scale (GMFCS) and Manual Abilities Classification Scale (MACS) levels were rated for CP subjects. MUNIX was significantly lower for CP participants (Mean 167.8 vs. 214.4, p=.022). MUNIX values did not correlate with GMFCS or MACS. MUSIX values were higher, though not significantly, for CP subjects (p=.11). MUSIX increased with increasing MACS levels (r(2)=.4017, p=.049). Thus, motor unit numbers in ulnar hand muscles may be decreased with CP. MUSIX values are associated with greater hand impairment. Therefore, peripheral motor unit loss as a component of the weakness found with CP deserves further evaluation. PMID- 25840714 TI - Hospital infection control units: staffing, costs, and priorities. AB - BACKGROUND: This article describes infection prevention and control professionals' (ICPs') staffing levels, patient outcomes, and costs associated with the provision of infection prevention and control services in Australian hospitals. A secondary objective was to determine the priorities for infection control units. METHODS: A cross-sectional study design was used. Infection control units in Australian public and private hospitals completed a Web-based anonymous survey. Data collected included details about the respondent; hospital demographics; details and services of the infection control unit; and a description of infection prevention and control-related outputs, patient outcomes, and infection control priorities. RESULTS: Forty-nine surveys were undertaken, accounting for 152 Australian hospitals. The mean number of ICPs was 0.66 per 100 overnight beds (95% confidence interval, 0.55-0.77). Privately funded hospitals have significantly fewer ICPs per 100 overnight beds compared with publicly funded hospitals (P < .01). Staffing costs for nursing staff in infection control units in this study totaled $16,364,392 (mean, $380,566). Infection control units managing smaller hospitals (<270 beds) identified the need for increased access to infectious diseases or microbiology support. CONCLUSION: This study provides valuable information to support future decisions by funders, hospital administrators, and ICPs on service delivery models for infection prevention and control. Further, it is the first to provide estimates of the resourcing and cost of staffing infection control in hospitals at a national level. PMID- 25840715 TI - Catheter-associated urinary tract infection: Role of the setting of catheter insertion. AB - BACKGROUND: This study aimed to describe the epidemiology of catheter-associated urinary tract infections (CAUTIs) in patients admitted to a surgical ward in Central Italy and to analyze the associated risk factors. METHODS: An active surveillance program for CAUTI was carried out in patients catheterized for at least 48 hours. Place of catheter insertion (operating room, hospital ward, cystoscopy room, emergency care unit), indication for catheterization and its duration, among other risk factors were monitored until discharge. Antibiotic resistance profiles of isolates were analyzed. RESULTS: There were 641 catheterized patients monitored for CAUTI onset. Of these, 40 (6.2%) developed a CAUTI (rates were 15.1/1,000 catheter days, 95% confidence interval [CI], 11.9 22.6; 8.7/1,000 patient days, 95% CI, 6.9-13.1). Patients with CAUTI were older (P < .05) and their durations of hospitalization and catheterization were both longer compared with those who were not affected (P < .05). Catheterization >4 days (odds ratio [OR] = 8.21; 95% CI, 3.79-17.73; P < .05) and place of catheter insertion different from the operating room (OR = 7.9; 95% CI, 2.83-22.08; P < .05, for catheters placed in the ward) were associated with CAUTI. Among the micro-organisms isolated in CAUTIs, the most common were Pseudomonas aeruginosa (41.5%), Klebsiella pneumoniae (19.5%), and Escherichia coli (12.2%); 82.5% of them were resistant to different classes of antibiotics. CONCLUSION: These results highlight the role played by the setting of catheter insertion in CAUTIs onset, therefore reflecting the importance of hand hygiene and proper aseptic insertion techniques as crucial determinants in CAUTIs prevention. PMID- 25840716 TI - A computer-based automated reminder increases the percentage of urinary catheters justified by an order and increases urinary catheter discontinuation orders. AB - Use of an automated reminder for an order to continue or to discontinue a urinary catheter resulted in a significant increase in the percentage of urinary catheters justified by an order and the percentage of urinary catheter discontinuation orders increased. This is an essential first step toward reducing inappropriate urinary catheter use. PMID- 25840717 TI - An electronic surveillance tool for catheter-associated urinary tract infection in intensive care units. AB - BACKGROUND: Traditional methods of surveillance of catheter-associated urinary tract infections (CAUTIs) are error-prone and resource-intensive. To resolve these issues, we developed a highly sensitive electronic surveillance tool. OBJECTIVE: To develop an electronic surveillance tool for CAUTIs and assess its performance. METHODS: The study was conducted at a 947-bed tertiary care center. Patients included adults aged >=18 years admitted to an intensive care unit between January 10 and June 30, 2012, with an indwelling urinary catheter during their admission. We identified CAUTIs using 4 methods: traditional surveillance (TS) (ie, manual chart review by ICPs), an electronic surveillance (ES) tool, augmented electronic surveillance (AES) (ie, ES with chart review on a subset of cases), and reference standard (RS) (ie, a subset of CAUTIs originally ascertained by TS or ES, confirmed by review). We assessed performance characteristics to RS for reviewed cases. RESULTS: We identified 417 candidate CAUTIs in 308 patients; 175 (42.0%) of these candidate CAUTIs were selected for review, yielding 32 confirmed CAUTIs in 22 patients (RS). Compared with RS, the sensitivities of TS, ES, and AES were 43.8% (95% confidence interval [CI], 26.4% 62.3%), 100.0% (95% CI, 89.1%-100.0%), and 100.0% (95% CI, 89.1%-100.0%). Specificities were 82.5% (95% CI, 75.3%-88.4%), 2.8% (95% CI, 0.8%-7.0%), and 100.0% (95% CI, 97.5%-100.0%). CONCLUSIONS: Electronic CAUTI surveillance offers a streamlined approach to improve reliability and resource burden of surveillance. PMID- 25840718 TI - Repeated carotid endarterectomy versus carotid artery stenting for patients with carotid restenosis after carotid endarterectomy: Systematic review and meta analysis. AB - PURPOSE: Carotid restenosis (CRS) after carotid endarterectomy (CEA) is an issue that cannot be ignored. This study was undertaken to compare the outcomes of repeated CEA (redo CEA) and carotid artery stenting (CAS) for CRS after CEA. METHODS: We performed a systematic analysis using the search terms "CEA restenosis," "carotid restenosis," or "CEA recurrent stenosis" in the MEDLINE, EMBASE, PubMed, and Cochrane Library databases. After applying the inclusion criteria, all available data were summarized to evaluate the effects of redo CEA and CAS for patients with CRS after prior CEA. RESULTS: Fifty articles (9 comparative studies and 41 noncomparative studies) involving 4,399 patients were included. No differences were observed in the 30-day perioperative mortality, stroke and transient ischemic attack rates in the comparative studies (P > .05) and the noncomparative studies (P > .05). Patients undergoing redo CEA suffered more cranial nerve injuries (CNIs) than those undergoing CAS (P < .05), but most of these cases recovered within 3 months. Patients treated with redo CEA exhibited similar myocardial infarction (MI) rates to those treated with CAS in the comparative studies (P = .53), but the rate was higher in the noncomparative studies (P < .01). However, a nonsignificant difference was noted in freedom from stroke at 36 months in the comparative studies (P = .47) and at 12 months in the noncomparative studies (P = .89). The risk of restenosis was greater in the CAS patients than in the redo CEA patients (P < .05 for comparative and noncomparative studies). CONCLUSION: Both redo CEA and CAS are safe and feasible for CRS after CEA. Although the incidences of CNI and MI were increased in the redo CEA group, most of the CNI cases were reversible. Patients treated with CAS were more likely to develop restenosis than those treated with redo CEA over long term follow-up. PMID- 25840719 TI - Undergraduate nursing students' attitudes toward mental health nursing. AB - OBJECTIVES: The purpose of this study was to describe undergraduate nursing students' attitudes toward mental health nursing and how these attitudes influenced their professional career choices in mental health nursing. DESIGN: A descriptive, online survey was utilized to examine students' perceptions of mental health nursing. A total of 229 junior and senior nursing students were recruited from eight nursing colleges in Midwestern United States to participate in this survey. RESULTS: Students of different ages, genders, ethnicities, and nursing programs did not report significantly different perceptions of: (a) knowledge of mental illness; (b) negative stereotypes; (c) interest in mental health nursing as a future career; and (d), and beliefs that psychiatric nurses provide a valuable contribution to consumers and the community. Negative stereotypes were significantly different between students who had mental health nursing preparation either in class (p=0.0147) or in clinical practice (p=0.0018) and students who had not. There were significant differences in anxiety about mental illness between students who had classes on mental health nursing (p=.0005), clinical experience (p=0.0035), and work experience in the mental health field (p=0.0012). Significant differences in an interest in a future career in mental health nursing emerged between students with and without prior mental health experience and between students with and without an interest in an externship program with p-values of 0.0012 and <0.0001, respectively. CONCLUSIONS: The more exposure that students have to mental health nursing through clinical experiences, theory classes, and previous work in the field, the more prepared they feel about caring for persons with mental health issues. PMID- 25840720 TI - Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan. AB - BACKGROUND: The long-term outcome of X-linked hyper-IgM syndrome (XHIM) caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We sought to determine the clinical features and factors affecting outcomes in patients with XHIM. METHODS: We enrolled and retrospectively analyzed data from 56 Japanese patients with XHIM, including 29 patients who received HSCT. RESULTS: The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2%). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P = .0231). Moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15). CONCLUSION: On the basis of these results, we concluded that HSCT improved the outcomes of patients with XHIM and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years. PMID- 25840721 TI - Rhinovirus-induced bronchiolitis: Lack of association between virus genomic load and short-term outcomes. PMID- 25840723 TI - Chronic rhinosinusitis is rare but bothersome in adolescents from a Swedish population-based cohort. PMID- 25840722 TI - RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications. AB - BACKGROUND: Genomic profiling of lesional and nonlesional skin of patients with atopic dermatitis (AD) using microarrays has led to increased understanding of AD and identification of novel therapeutic targets. However, the limitations of microarrays might decrease detection of AD genes. These limitations might be lessened with next-generation RNA sequencing (RNA-seq). OBJECTIVE: We sought to define the lesional AD transcriptome using RNA-seq and compare it using microarrays performed on the same cohort. METHODS: RNA-seq and microarrays were performed to identify differentially expressed genes (criteria: fold change, >= 2.0; false discovery rate <= 0.05) in lesional versus nonlesional skin from 18 patients with moderate-to-severe AD, with real-time PCR (RT-PCR) and immunohistochemistry used for validation. RESULTS: Both platforms showed robust disease transcriptomes and correlated well with RT-PCR. The common AD transcriptome identified by using both techniques contained 217 genes, including inflammatory (S100A8/A9/A12, CXCL1, and 2'-5'-oligoadenylate synthetase-like [OASL]) and barrier (MKi67, keratin 16 [K16], and claudin 8 [CLDN8]) AD-related genes. Although fold change estimates determined by using RNA-seq showed somewhat better agreement with RT-PCR (intraclass correlation coefficient, 0.57 and 0.70 for microarrays and RNA-seq vs RT-PCR, respectively), bias was not eliminated. Among genes uniquely identified by using RNA-seq were triggering receptor expressed on myeloid cells 1 (TREM-1) signaling (eg, CCL2, CCL3, and single immunoglobulin domain IL1R1 related [SIGIRR]) and IL-36 isoform genes. TREM-1 is a surface receptor implicated in innate and adaptive immunity that amplifies infection-related inflammation. CONCLUSIONS: This is the first report of a lesional AD phenotype using RNA-seq and the first direct comparison between platforms in this disease. Both platforms robustly characterize the AD transcriptome. Through RNA-seq, we unraveled novel disease pathology, including increased expression of the novel TREM-1 pathway and the IL-36 cytokine in patients with AD. PMID- 25840724 TI - Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease. AB - BACKGROUND: Epithelial barrier dysfunction is thought to play a role in many mucosal diseases, including asthma, chronic rhinosinusitis (CRS), and eosinophilic esophagitis. OBJECTIVE: The objective of this study was to investigate the role of oncostatin M (OSM) in epithelial barrier dysfunction in human mucosal disease. METHODS: OSM expression was measured in tissue extracts, nasal secretions, and bronchoalveolar lavage fluid. The effects of OSM stimulation on barrier function of normal human bronchial epithelial cells and nasal epithelial cells cultured at the air-liquid interface were assessed by using transepithelial electrical resistance and fluorescein isothiocyanate dextran flux. Dual-color immunofluorescence was used to evaluate the integrity of tight junction structures in cultured epithelial cells. RESULTS: Analysis of samples from patients with CRS showed that OSM mRNA and protein levels were highly increased in nasal polyps compared with those seen in control uncinate tissue (P < .05). OSM levels were also increased in bronchoalveolar lavage fluid of allergic asthmatic patients after segmental allergen challenge and in esophageal biopsy specimens from patients with eosinophilic esophagitis. OSM stimulation of air-liquid interface cultures resulted in reduced barrier function, as measured by decreased transepithelial electrical resistance and increased fluorescein isothiocyanate-dextran flux (P < .05). Alterations in barrier function by OSM were reversible, and the viability of epithelial cells was unaffected. OSM levels in lysates of nasal polyps and uncinate tissue positively correlated with levels of alpha2-macroglobulin, a marker of epithelial leak, in localized nasal secretions (r = 0.4855, P < .05). CONCLUSIONS: These results suggest that OSM might play a role in epithelial barrier dysfunction in patients with CRS and other mucosal diseases. PMID- 25840725 TI - Systematic neonatal screening for severe combined immunodeficiency and severe T cell lymphopenia: Analysis of cost-effectiveness based on French real field data. AB - BACKGROUND: The inclusion of severe combined immunodeficiency (SCID) in a Europe wide screening program is currently debated. OBJECTIVE: In making a case for inclusion in the French newborn screening program, we explored the costs incurred and potentially saved by early management of SCID. METHODS: For test costs, a microcosting study documented the resources used in a laboratory piloting a newborn screening test on Guthrie cards using the T-cell receptor excision circle quantification method. For treatment costs, patients with SCID admitted to the national reference center for primary immunodeficiency in France between 2006 and 2010 were included. Costs of admission were estimated from actual national production costs. We estimated the costs for patients who underwent early versus delayed hematopoietic stem cell transplantation (HSCT; age, <=3 vs. >3 months, respectively). RESULTS: The unit cost of the test varied between ?4.69 and ?6.79 for 33,800 samples per year, depending on equipment use and saturation. Of the 30 patients included, 27 underwent HSCT after age 3 months. At 1 year after HSCT, 10 of these had died, and all 3 patients undergoing early transplantation survived. The medical costs for HSCT after 3 months were ?195,776 (interquartile range, ?165,884-?257,160) versus ?86,179 (range, ?59,014-?272,577) when performed before 3 months of age. In patients undergoing late transplantation, active infection contributed to high cost and poor outcome. CONCLUSION: Early detection of SCID could reduce the cost of treatment by ?50,000-100,000 per case. Assuming a ?5 unit cost per test, the incidence required to break even is 1:20,000; however, if the survival advantage of HSCT before 3 months is confirmed, universal screening is likely to be cost-effective. PMID- 25840726 TI - A scientist during wartime: Richard Goldschmidt's internment in the U.S.A. during the First World War. PMID- 25840727 TI - Efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in black/African American patients with type 2 diabetes: Pooled analysis from eight Phase III trials. AB - BACKGROUND: The prevalence of type 2 diabetes in black/African Americans from North and South America is high; yet data evaluating antidiabetic agents in this population is scarce. To address this gap, we pooled data from the clinical development program for linagliptin. METHODS: A retrospective pooled analysis of eight completed randomized, placebo-controlled Phase III trials of linagliptin identified 336 patients with type 2 diabetes who self-identified their ethnicity as black or African American. Participants received linagliptin (n = 173, 5 mg/day) or placebo (n = 163) as monotherapy, or as add-on to other antidiabetic agents, including insulin. The primary end point was the change in glycated hemoglobin (HbA1c) from baseline to week 18 or 24. RESULTS: The placebo-adjusted mean change (95% confidence interval [CI]) in HbA1c from baseline was -0.69% ( 0.92 to -0.46; p < 0.0001) at week 18 (eight trials), and -0.64% (-0.90 to -0.39; p < 0.0001) at week 24 (six trials). The placebo-adjusted mean change (95% CI) in fasting plasma glucose from baseline was -11.7 mg/dL (-23.1 to -0.3; p = 0.0446) at week 18 and -14.7 mg/dL (-25.7 to -3.8; p = 0.0087) at week 24. Incidence of investigator-defined hypoglycemia was similar between the two groups (linagliptin, 12.1%; placebo, 11.7%). Overall, the safety profile of linagliptin in this patient group was comparable to that of placebo, with comparable incidence of adverse events; linagliptin was weight-neutral in this patient population. CONCLUSION: Linagliptin provided clinically significant improvements in glycemic control without increased risk of hypoglycemia and without weight gain, representing a useful type 2 diabetes therapy option for the black/African American population. PMID- 25840728 TI - Comparative proteomic analysis of gamma-aminobutyric acid responses in hypoxia treated and untreated melon roots. AB - Hypoxia is one of the main environmental stresses that accounts for decreasing crop yield. To further investigate the mechanisms whereby exogenous GABA alleviates hypoxia injury to melon seedlings, a comparative proteomic analysis was performed using roots subjected to normal aeration and hypoxia conditions with or without GABA (5mM). The results indicated that protein spots on gels after hypoxia and hypoxia+GABA treatment were significantly changed. Three "matched sets" were analyzed from four treatments, and 13 protein spots with large significant differences in expression were identified by MALDI-TOF/TOF mass spectrometry. Exogenous GABA treatment enhanced the expression of protein in cytosolic phosphoglycerate kinase 1, exaA2 gene product, dnaJ and myb-like DNA binding domain-containing proteins, as well as elongation factor-1 alpha and hypothetical proteins in hypoxia-induced roots. However, the hypoxia+GABA treated roots had a significantly lower expression of proteins including malate dehydrogenase, nucleoside diphosphate kinase, disease resistance-like protein, disulfide isomerase, actin, ferrodoxin NADP oxidoreductase, glutathione transferase, netting associated peroxidase. This paper describes the effect of GABA on melon plants under hypoxia-induced stress using proteomics, and supports the alleviating function of GABA in melon plants grown under hypoxic conditions. PMID- 25840729 TI - Squamous cell carcinoma with aggressive subclinical extension: 5-year retrospective review of diagnostic predictors. AB - BACKGROUND: Squamous cell carcinoma with aggressive subclinical extension (SCC ASE) is a tumor whose extensive spread becomes revealed during surgery or pathologic review, particularly during Mohs micrographic surgery. Limited clinical awareness of these lesions may result in unanticipated longer surgical times and larger postoperative defects. SCC-ASE-associated clinical risk factors are not well studied. OBJECTIVE: We sought to evaluate the incidence of and risk factors associated with SCC-ASE. METHODS: We conducted a retrospective analysis of SCC treated with Mohs micrographic surgery between 2007 and 2012 at a single academic surgical center. SCC-ASE was defined as a lesion requiring at least 3 Mohs stages with a final surgical margin of >=1 cm. RESULTS: Of 954 cases studied, 31% were SCC-ASE. In multivariable analysis, sex (P = .001), history of previous nonmelanoma skin cancer (P < .001), Fitzpatrick skin types II and III (P = .004 and <.001, respectively), immunosuppression related to solid organ transplant (P < .001), and cigarette use (P < .001) were significant predictors of SCC-ASE. LIMITATIONS: Single academic center selection bias, not-controlled for sun exposure differences, no information on medication regimens of solid organ transplant patients, and a small sample size are all limitations of our study. CONCLUSION: Easily attainable demographic factors, especially immunosuppressed status and cigarette use, can help predict the occurrence of SCC ASE and thereby optimize surgical planning and patient preparedness. PMID- 25840730 TI - Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: A systematic review and meta-analysis. AB - BACKGROUND: There is controversy regarding a potential increased risk of lymphoma in patients with atopic dermatitis (AD). OBJECTIVE: To assess the risk of lymphoma and the role of topical treatments in patients with AD. METHODS: A systematic literature search and a separate meta-analysis were performed on case control and cohort studies. RESULTS: Of the 3979 articles retrieved, 24 references met the inclusion criteria. In cohort studies, the risk of lymphoma was slightly increased, with a relative risk (RR) of 1.43 (95% confidence interval [CI], 1.12-1.81). In case control studies, no significant increased risk of lymphoma was found, with an odds ratio (OR) of 1.18 (95% CI, 0.94-1.47). Severity of AD was a significant risk factor. Highly potent topical steroids were associated with an increased risk of lymphoma. For topical calcineurin inhibitors (TCIs), a significant association between tacrolimus and mostly skin lymphoma was found in 1 study. LIMITATIONS: Confusion between severe AD and cutaneous T-cell lymphoma may account for part of the increased risk of lymphoma in patients with AD. CONCLUSION: This systematic literature review shows a slightly increased risk of lymphoma in patients with AD. Severity of AD appears to be a significant risk factor. The role of topical steroids and TCIs is unlikely to be significant. PMID- 25840731 TI - Umbilical and periumbilical dermatoses. AB - The umbilicus may be the site of congenital and acquired malformations and may harbor clinical clues to the diagnosis of potentially fatal inherited disorders, primary skin conditions, and a variety of infectious diseases. Both benign and malignant tumors may involve the umbilicus, and some are unique to this site. Finally, cutaneous signs localized to this anatomic location may be found in diverse systemic diseases. PMID- 25840732 TI - [Nomadic plastic surgery: 1 NGO, 10 years, 30 missions]. AB - This publication presents the results of 10 years of nomadic plastic surgery missions by a small French non-governmental organization: Interplast France/surgery without borders (www.Interplast-France.net). This NGO is specialized in reconstructive surgery in challenging conditions and works in developing countries. We present a view of 10 years of missions carried out between 2003 and 2013. This experience covers a uniform period both by the objectives proposed and the regularity of missions observed. This work shows the way surgical missions take place and the methodology used. We carried out 30 missions. We made more than 4000 consultations and we operated 1500 patients. Interventions are divided into one quarter cleft, one quarter tumors, one quarter burn injuries and one quarter of various diseases such as noma and Buruli ulcer. We show some adaptations such as autonomy during missions, the adjustment guidance in relation to this new environment and the integration of local traditions in our therapeutic action. We offer practical notions on the surgical procedures and some reflections on the societal level. This work aims primarily to pay tribute to all the invisible actors in this long chain of humanity, and thanks to the simple intervention of men, a patient can have the same medical treatment whether he is in an industrial country or in some isolated place on this earth. PMID- 25840733 TI - The rise and fall of the world's first fat tax. AB - In 2011, Denmark introduced the world's first tax on saturated fat, but only 15 months later the fat tax was abolished. The aim of this article is to investigate the political processes surrounding the implementation and rapid abolition of the fat tax. Our findings suggest that industry and trade associations were heavily involved in the political process of formulating the fat tax. Industry representatives used certain tactics to oppose the fat tax: threatening lawsuits, predicting welfare losses, casting doubt on evidence, diverting focus and requesting postponement. After the fat tax was implemented, the food industry continued their opposition through intensified lobbyism and juridical actions at EU level. However, other factors seem to have contributed to the fall of the fat tax. The tax received criticism for being poorly designed and gradually lost popularity among health professionals, politicians and the public. In the end, the fat tax was abolished for financial reasons. This study demonstrates how politicians considered the fat tax as a funding source rather than a public health initiative, which resulted in significant shortcomings. Furthermore, we demonstrate that the massive influence by industry stakeholders was not balanced with inputs from public health professionals, who should assume a more proactive role in policy-making. PMID- 25840734 TI - Modified Mostardi approach with ultra-high-molecular-weight polyethylene tape for total hip arthroplasty provides a good rate of union of osteotomized fragments. AB - BACKGROUND: A lateral approach is common in total hip arthroplasty because of the good exposure it provides and its low complication rates. However, a drawback of the procedure is that the abductor mechanism is damaged when the tendinous insertion of the abductor muscle is split. Here, we describe a wafer technique using ultra-high-molecular-weight polyethylene tape for promising reattachment of the abductor mechanism. METHODS: We retrospectively evaluated 120 consecutive primary total hip arthroplasties performed using a modified Mostardi approach, which involved reattaching the trochanter using either a braided polyester suture (polyester suture group, n = 60) or ultra-high-molecular-weight polyethylene tape (UHMWPE tape group, n = 60). The osteotomized fragment was reattached by inducing bone-to-bone contact using 3-mm-wide tapes that were precisely tied with a double loop sliding knot in conjunction with a cable gun tensioner. The abductor strength and radiographic union rate were postoperatively assessed at 4 weeks and 6 months, respectively. RESULTS: A statistically significant lower incidence of nonunion and cutout was observed in the UHMWPE group (0 and 5.0 %, respectively) compared to the polyester suture group (8.3 and 15 %, respectively). No differences in abductor strength either preoperatively or at 4 weeks postoperatively were observed between the groups. In radiographically healed patients, abductor strength at 4 weeks post-surgery exceeded preoperative strength. The recovery rate of hip abductor strength was 109.9 +/- 34.3 % in union patients and 92.9 +/- 23.3 % in nonunion patients, which was statistically significant. The mean Japanese Orthopedic Association hip scores improved from 48.6 to 86.8 in union patients and from 50.3 to 85.9 in nonunion patients at 1 year postoperatively; however, this difference was not significant. CONCLUSIONS: The modified Mostardi approach using ultra-high molecular weight polyethylene tape can promote successful union of the osteotomized fragment. PMID- 25840735 TI - Reverse logistics network for municipal solid waste management: The inclusion of waste pickers as a Brazilian legal requirement. AB - This study proposes a reverse logistics network involved in the management of municipal solid waste (MSW) to solve the challenge of economically managing these wastes considering the recent legal requirements of the Brazilian Waste Management Policy. The feasibility of the allocation of MSW material recovery facilities (MRF) as intermediate points between the generators of these wastes and the options for reuse and disposal was evaluated, as well as the participation of associations and cooperatives of waste pickers. This network was mathematically modelled and validated through a scenario analysis of the municipality of Sao Mateus, which makes the location model more complete and applicable in practice. The mathematical model allows the determination of the number of facilities required for the reverse logistics network, their location, capacities, and product flows between these facilities. The fixed costs of installation and operation of the proposed MRF were balanced with the reduction of transport costs, allowing the inclusion of waste pickers to the reverse logistics network. The main contribution of this study lies in the proposition of a reverse logistics network for MSW simultaneously involving legal, environmental, economic and social criteria, which is a very complex goal. This study can guide practices in other countries that have realities similar to those in Brazil of accelerated urbanisation without adequate planning for solid waste management, added to the strong presence of waste pickers that, through the characteristic of social vulnerability, must be included in the system. In addition to the theoretical contribution to the reverse logistics network problem, this study aids in decision-making for public managers who have limited technical and administrative capacities for the management of solid wastes. PMID- 25840736 TI - Converting the organic fraction of solid waste from the city of Abu Dhabi to valuable products via dark fermentation--Economic and energy assessment. AB - Landfilling the organic fraction of municipal solid waste (OFMSW) leads to greenhouse gas emissions and loss of valuable resources. Sustainable and cost efficient solutions need to be developed to solve this problem. This study evaluates the feasibility of using dark fermentation (DF) to convert the OFMSW to volatile fatty acids (VFAs), fertilizer and H2. The VFAs in the DF effluent can be used directly as substrate for subsequent bioprocesses or purified from the effluent for industrial use. DF of the OFMSW in Abu Dhabi will be economically sustainable once VFA purification can be accomplished on large scale for less than 15USD/m(3)(effluent). With a VFA minimum selling price of 330 USD/tCOD, DF provides a competitive carbon source to sugar. Furthermore, DF is likely to use less energy than conventional processes that produce VFAs, fertilizer and H2. This makes DF of OFMSW a promising waste treatment technology and biorefinery platform. PMID- 25840737 TI - Co-digestion of pig slaughterhouse waste with sewage sludge. AB - Slaughterhouse wastes (SHW) are potentially very attractive substrates for biogas production. However, mono-digestion of these wastes creates great technological problems associated with the inhibitory effects of ammonia and fatty acids on methanogens as well as with the foaming in the digesters. In the following study, the co-digestion of slaughterhouse wastes with sewage sludge (SS) was undertaken. Batch and semi-continuous experiments were performed at 35 degrees C with municipal sewage sludge and pig SHW composed of meat tissue, intestines, bristles and post-flotation sludge. In batch assays, meat tissue and intestinal wastes gave the highest methane productions of 976 and 826 dm(3)/kg VS, respectively, whereas the methane yield from the sludge was only 370 dm(3)/kg VS. The co digestion of sewage sludge with 50% SHW (weight basis) provided the methane yield exceeding 600 dm(3)/kg VS, which was more than twice as high as the methane production from sewage sludge alone. However, when the loading rate exceeded 4 kg VS/m(3) d, a slight inhibition of methanogenesis was observed, without affecting the digester stability. The experiments showed that the co-digestion of sewage sludge with large amount of slaughterhouse wastes is feasible, and the enhanced methane production does not affect the digester stability. PMID- 25840738 TI - [Should beta blockers remain as first-line therapy in the treatment of patients with atrial fibrillation and heart failure?]. PMID- 25840739 TI - [Mortality among the sulphonylureas]. PMID- 25840740 TI - Lithium might be associated with better decision-making performance in euthymic bipolar patients. AB - Bipolar disorder is associated with impaired decision-making. Little is known about how treatment, especially lithium, influences decision-making abilities in bipolar patients when euthymic. We aimed at testing for an association between lithium medication and decision-making performance in remitted bipolar patients. Decision-making was measured using the Iowa Gambling Task in 3 groups of subjects: 34 and 56 euthymic outpatients with bipolar disorder, treated with lithium (monotherapy and lithium combined with anticonvulsant or antipsychotic) and without lithium (anticonvulsant, antipsychotic and combination treatment), respectively, and 152 matched healthy controls. Performance was compared between the 3 groups. In the 90 euthymic patients, the relationship between different sociodemographic and clinical variables and decision-making was assessed by stepwise multivariate regression analysis. Euthymic patients with lithium (p=0.007) and healthy controls (p=0.001) selected significantly more cards from the safe decks than euthymic patients without lithium, with no significant difference between euthymic patients with lithium and healthy controls (p=0.9). In the 90 euthymic patients, the stepwise linear multivariate regression revealed that decision-making was significantly predicted (p<0.001) by lithium dose, level of education and no family history of bipolar disorder (all p<=0.01). Because medication was not randomized, it was not possible to discriminate the effect of different medications. Lithium medication might be associated with better decision-making in remitted bipolar patients. A randomized trial is required to test for the hypothesis that lithium, but not other mood stabilizers, may specifically improve decision-making abilities in bipolar disorder. PMID- 25840742 TI - Dopaminergic modulation of the trade-off between probability and time in economic decision-making. AB - Studies on animals and humans have demonstrated the importance of dopamine in modulating decision-making processes. In this work, we have tested dopaminergic modulation of economic decision-making and its neural correlates by administering either placebo or metoclopramide, a dopamine D2-receptor antagonist, to healthy subjects, during a functional MRI study. The decision-making task combined probability and time delay with a fixed monetary reward. For individual behavioral characterization, we used the Probability Time Trade-off (PTT) economic model, which integrates the traditional trade-offs of reward magnitude time and reward magnitude-probability into a single measurement, thereby quantifying the subjective value of a delayed and probabilistic outcome. A regression analysis between BOLD signal and the PTT model index permitted to identify the neural substrate encoding the subjective reward-value. Behaviorally, medication reduced the rate of temporal discounting over probability, reflected in medicated subjects being more prone to postpone the reward in order to increase the outcome probability. In addition, medicated subjects showed less activity during the task in the postcentral gyrus as well as frontomedian areas, whereas there were no differences in the ventromedial orbitofrontal cortex (VMOFC) between groups when coding the subjective value. The present study demonstrates by means of behavior and imaging that dopamine modulation alters the probability-time trade-off in human economic decision-making. PMID- 25840741 TI - BDNF-TRKB signaling system of the dorsal periaqueductal gray matter is implicated in the panicolytic-like effect of antidepressant drugs. AB - A wealth of evidence implicates the BDNF-TRKB system in the therapeutic effects of antidepressant drugs (ADs) on mood disorders. However, little is known about the involvement of this system in the panicolytic property also exerted by these compounds. In the present study we evaluated the participation of the BDNF-TRKB system of the dorsal periaqueductal gray matter (DPAG), a core structure involved in the pathophysiology of panic disorder, in AD-induced panicolytic-like effects in rats. The results showed that short- (3 days) or long-term (21 days) systemic treatment with the tricyclic ADs imipramine, clomipramine or desipramine increased BDNF levels in the DPAG. Only longterm treatment with the selective serotonin reuptake inhibitor fluoxetine was able to increase BDNF levels in this structure. After 21-day treatment, fluoxetine and the three tricyclic ADs used also increased BDNF concentration in the hippocampus, a key area implicated in their mood-related actions. Neither in the DPAG nor hippocampus did long-term treatment with the standard anxiolytics diazepam, clonazepam or buspirone affect BDNF levels. Imipramine, both after short and long-term administration, and fluoxetine under the latter regimen, raised the levels of phosphorylated TRKB in the DPAG. Short-term treatment with imipramine or BDNF microinjection inhibited escape expression in rats exposed to the elevated T maze, considered as a panicolytic-like effect. This anti-escape effect was attenuated by the intra-DPAG administration of the TRK receptor antagonist k252a. Altogether, our data suggests that facilitation of the BDNF-TRKB system in the DPAG is implicated in the panicolytic effect of ADs. PMID- 25840744 TI - Evaluation of the toxicology, pharmacokinetics, and local tolerance of recombinant factor IX Fc fusion protein in animals. AB - INTRODUCTION: Recombinant factor IX Fc fusion protein (rFIXFc) is a recombinant coagulation factor composed of a single molecule of recombinant factor IX (rFIX) covalently fused to the Fc domain of human immunoglobulin G1 (IgG1) with no intervening sequence. An extensive nonclinical program was performed to support the clinical development of rFIXFc for treatment of people with hemophilia B. MATERIALS AND METHODS: Repeat-dose toxicology studies of rFIXFc were performed in 2 relevant species: Sprague Dawley rats (4-week study) and cynomolgus monkeys (5- and 27-week studies). Assessments included in-life observations, electrocardiograms (monkeys only), laboratory evaluations (including hematology and blood chemistry), postmortem analyses, local tolerance, and pharmacokinetics (PK). Allometric scaling was performed with PK data from multiple species, including humans. Local tolerance (single-dose study) and thrombogenic potential (Wessler stasis model) of rFIXFc were tested in New Zealand White rabbits. RESULTS: There were no significant local or systemic toxicity findings in the repeat-dose studies. Allometric scaling data suggested that animal rFIXFc PK results are predictive of human PK parameters. There were no findings from the local tolerance study in rabbits; thrombogenic activity was less than that elicited by rFIX and a prothrombin complex concentrate, and similar to vehicle control. CONCLUSIONS: rFIXFc was well tolerated in toxicology studies and demonstrated a low thrombogenic potential. These results are consistent with phase 1/2a and phase 3 clinical studies of rFIXFc in people with hemophilia B. PMID- 25840743 TI - Thalidomide and multiple myeloma serum synergistically induce a hemostatic imbalance in endothelial cells in vitro. AB - BACKGROUND: Thalidomide (Thal) treatment of patients with multiple myeloma (MM) is associated with vascular thrombosis, but the underlying mechanism is unknown. OBJECTIVES: To evaluate the hypothesis that Thal, dexamethasone (Dex) and MM serum perturb the hemostatic balance on human umbilical vein endothelial cells (HUVECs). METHODS: Drugs with or without the serum of MM patients or healthy controls were incubated with HUVECs. Analyses of phosphatidylserine (PS), tissue factor (TF), endothelial protein C receptor (EPCR) and thrombomodulin (TM) were performed using flow cytometry. The production of thrombin and activated protein C (APC) were measured by chromogenic assay. The roles of IL-6 and TNFalpha in regulating these indicators were also investigated. RESULTS: We found that Thal or Dex alone could not increase TF and PS expression in HUVECs. However, when pretreated with MM serum, their expression was significantly increased by either Thal or Dex. Concurrent changes were also detected in thrombin generation. In contrast, Thal and Dex had a direct inhibitory effect on the expression of EPCR and TM, and this inhibitory effect was especially significant when MM serum was added. The generation of APC paralleled the expression of EPCR and TM. All of the above outcomes were reversed to a variable extent by anti-IL-6R and anti-TNFalpha antibodies. CONCLUSIONS: These findings suggest Thal may act as a procoagulant by altering the balance between procoagulant and anticoagulant proteins on the surface of HUVECs, thereby contributing to thrombogenesis. MM serum plays a synergistic role in this process. PMID- 25840745 TI - Stabilizing effect of biochar on soil extracellular enzymes after a denaturing stress. AB - Stabilizing extracellular enzymes may maintain enzymatic activity while protecting enzymes from proteolysis and denaturation. A study determined whether a fast pyrolysis hardwood biochar (CQuestTM) would reduce evaporative losses, subsequently stabilizing soil extracellular enzymes and prohibiting potential enzymatic activity loss following a denaturing stress (microwaving). Soil was incubated in the presence of biochar (0%, 1%, 2%, 5%, or 10% by wt.) for 36 days and then exposed to microwave energies (0, 400, 800, 1600, or 3200 J g(-1) soil). Soil enzymes (beta-glucosidase, beta-d-cellobiosidase, N-acetyl-beta glucosaminidase, phosphatase, leucine aminopeptidase, beta-xylosidase) were analyzed by fluorescence-based assays. Biochar amendment reduced leucine aminopeptidase and beta-xylosidase potential activity after the incubation period and prior to stress exposure. The 10% biochar rate reduced soil water loss at the lowest stress level (400 J microwave energy g(-1) soil). Enzyme stabilization was demonstrated for beta-xylosidase; intermediate biochar application rates prevented a complete loss of this enzyme's potential activity after soil was exposed to 400 (1% biochar treatment) or 1600 (5% biochar treatment) J microwave energy g(-1) soil. Remaining enzyme potential activities were not affected by biochar, and activities decreased with increasing stress levels. We concluded that biochar has the potential to reduce evaporative soil water losses and stabilize certain extracellular enzymes where activity is maintained after a denaturing stress; this effect was biochar rate and enzyme dependent. While biochar may reduce the potential activity of certain soil extracellular enzymes, this phenomenon was not universal as the majority of enzymes assayed in this study were unaffected by exposure to biochar. PMID- 25840746 TI - Waist-to-hip ratio as an indicator of atherosclerosis among women at risk. PMID- 25840747 TI - Discrepancies between bone marrow histopathology and clinical phenotype in BCR ABL1-negative myeloproliferative neoplasms associated with splanchnic vein thrombosis. AB - We examined a consecutive series of 29 patients with myeloproliferative neoplasms (MPNs) associated with splanchnic vein thrombosis (SVT) in order to evaluate their bone marrow morphology and identify possible associations between histological findings and clinical features. Eleven patients showed the morphological features of polycythemia vera (PV), 11 of primary myelofibrosis (PMF) and six of essential thrombocythemia (ET). Molecular analyses identified the JAK2 V617F mutation in 27 patients; one of the JAK2-negative patients carried the MPL W515K mutation, the other was "triple-negative" (no JAK2, MPL or CALR mutation). On the basis of the WHO classification, three patients were classified as having PV, 11 as having PMF, and two as having ET; the remaining 13 cases fell into the MPN-unclassifiable category as there were discrepancies between their morphological and clinical features. In conclusion, our findings suggest that bone marrow histology should always be considered a key component of the diagnostic algorithm in patients with SVT, but that it is not enough to distinguish the different entities. This is particularly important because diagnoses of PV, PMF or ET have very different prognoses and obviously imply different therapies. It is therefore necessary to adopt a comprehensive approach that considers morphological, clinical and molecular data. PMID- 25840748 TI - High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the Western world. Autophagy is a highly conserved process in eukaryotic cells. In CLL autophagy is involved in mediating the effect of chemotherapy but the role of autophagy in CLL pathogenesis remains unknown. In the present study, we used real-time RT-PCR to analyze expression of the PIK3C3, PIK3R4, and BECN1 genes. These genes encode the components of the PI3K core complex, which is central to initiation of autophagy. A consecutive series of 149 well-characterized CLL cases from Region of Southern Denmark were included in the study. All three genes were observed to be independent markers of prognosis in CLL with high expression being associated with more aggressive disease. With this clear association with outcome in CLL, these genes thereby represent promising candidates for future functional studies on the role of autophagy in CLL, and they may further represent targets of treatment. PMID- 25840749 TI - Early emerging nicotine dependence symptoms in adolescence predict daily smoking in young adulthood. AB - PURPOSE: The present study evaluated the predictive validity of individual early emerging nicotine dependence symptoms in adolescence on smoking behavior in young adulthood. METHODS: A total of 492 adolescents who, at baseline, had not smoked more than 100 cigarettes in their lifetime and 123 adolescents who smoked more than 100 cigarettes lifetime, and who participated in the 6-year follow-up assessment were included in the present analyses. Predictive validity of 10 nicotine dependence items administered at baseline was evaluated at the 6 year follow-up when the sample had entered young adulthood (mean age=21.6). RESULTS: Among adolescents who had smoked fewer than 100 cigarettes, experiencing higher levels of overall nicotine dependence as well as individual symptoms at baseline longitudinally predicted an increase in risk for daily smoking in young adulthood, after controlling for baseline smoking and other tobacco use. For adolescents who had smoked more than 100 cigarettes at baseline, level of nicotine dependence and individual symptom endorsement did not predict smoking behavior in young adulthood. CONCLUSIONS: These findings add to accumulating evidence that early emerging dependence symptoms reported at low levels of smoking exposure signal a greater propensity for continued smoking behavior. Screening for these early emerging symptoms among novice adolescent smokers represents an important and unused tool in tobacco control efforts aimed at preventing the development of chronic smoking patterns. PMID- 25840751 TI - Natalizumab in spinal multiple sclerosis in a daily clinical setting. AB - OBJECTIVE: We aimed to investigate the influence of natalizumab (NTZ) treatment on multiple sclerosis course in patients with and without spinal involvement. METHODS: Annualized relapse rate (ARR), disability progression and occurrence of new brain and spinal T2 lesions (N2TL) in 68 spinal (S-P) versus 68 non-spinal matched patients (NS-P) were retrospectively collected and compared between before (2 years) and after NTZ treatment using multivariate regression models. RESULTS: Mean duration of NTZ treatment was 31.3 +/- 16.3 months in S-P and 32.1 +/- 15.1 months in N-SP (p = 0.56). The mean ARR after NTZ treatment was similarly reduced in both S-P (0.07 +/- 0.19) and N-SP (0.07 +/- 0.16) (p < 0.001 for both). Disability progression after NTZ start was similarly low in S-P and NS P. However, when compared to before NTZ start, disability progression was significantly reduced in S-P (p = 0.017), but not in NS-P (p = 0.68). This was largely mediated by a higher disability progression before NTZ start in S-P than N-SP. The risk of developing N2TL during NTZ was not different between S-P and NS P (p = 0.10). CONCLUSIONS: NTZ similarly reduced the occurrence of relapses and NT2L in S-P and NS-P, whereas the effect on disability progression was particularly evident in the presence of spinal involvement. NTZ appears to be a treatment of high efficacy in both S-P and NS-P. PMID- 25840750 TI - Denial in methamphetamine users: Associations with cognition and functional connectivity in brain. AB - BACKGROUND: Despite harmful consequences of drug addiction, it is common for individuals with substance use disorders to deny having problems with drugs. Emerging evidence suggests that some drug users lack insight into their behavior due to neurocognitive dysfunction, but little research has examined potential neurocognitive contributions to denial. METHODS: This study explored the relationship between denial, cognitive performance and functional connectivity in brain. The participants were 58 non-treatment-seeking, methamphetamine-dependent participants who completed the URICA precontemplation scale, a self-report measure of denial of drug problems warranting change, as well as a cognitive test battery. A subset of participants (N = 21) had functional MRI scans assessing resting-state functional connectivity. Given literature indicating roles of the rostral anterior cingulate (rACC), anterior insula and precuneus in self awareness, relationships between denial and resting-state connectivity were tested using seeds placed in these regions. RESULTS: The results revealed a negative relationship between denial and an overall cognitive battery score (p = 0.001), the effect being driven particularly by performance on tests of memory and executive function. Denial was negatively associated with strength of connectivity between the rACC and regions of the frontal lobe (precentral gyri, left ventromedial prefrontal cortex, left orbitofrontal cortex), limbic system (left amygdala, left hippocampus and left parahippocampal gyrus), occipital lobes and cerebellum; and between the precuneus and the midbrain and cerebellum. Anterior insula connectivity was unrelated to denial. CONCLUSIONS: These findings suggest that denial by methamphetamine users is linked with a cognitive and neural phenotype that may impede the development of insight into their behavior. PMID- 25840752 TI - Average effect estimates remain similar as evidence evolves from single trials to high-quality bodies of evidence: a meta-epidemiologic study. AB - OBJECTIVES: The objective of our study was to use a diverse sample of medical interventions to assess empirically whether first trials rendered substantially different treatment effect estimates than reliable, high-quality bodies of evidence. STUDY DESIGN AND SETTING: We used a meta-epidemiologic study design using 100 randomly selected bodies of evidence from Cochrane reports that had been graded as high quality of evidence. To determine the concordance of effect estimates between first and subsequent trials, we applied both quantitative and qualitative approaches. For quantitative assessment, we used Lin's concordance correlation and calculated z-scores; to determine the magnitude of differences of treatment effects, we calculated standardized mean differences (SMDs) and ratios of relative risks. We determined qualitative concordance based on a two-tiered approach incorporating changes in statistical significance and magnitude of effect. RESULTS: First trials both overestimated and underestimated the true treatment effects in no discernible pattern. Nevertheless, depending on the definition of concordance, effect estimates of first trials were concordant with pooled subsequent studies in at least 33% but up to 50% of comparisons. The pooled magnitude of change as bodies of evidence advanced from single trials to high-quality bodies of evidence was 0.16 SMD [95% confidence interval (CI): 0.12, 0.21]. In 80% of comparisons, the difference in effect estimates was smaller than 0.5 SMDs. In first trials with large treatment effects (>0.5 SMD), however, estimates of effect substantially changed as new evidence accrued (mean change 0.68 SMD; 95% CI: 0.50, 0.86). CONCLUSION: Results of first trials often change, but the magnitude of change, on average, is small. Exceptions are first trials that present large treatment effects, which often dissipate as new evidence accrues. PMID- 25840753 TI - Porcine aortic surgical model to study isolated intraspinal collateralization. PMID- 25840754 TI - Investigation of hemodynamics in an in vitro system simulating left ventricular support through the right subclavian artery using 4-dimensional flow magnetic resonance imaging. AB - OBJECTIVES: Left ventricular assist devices are an important treatment option for patients with heart failure alter the hemodynamics in the heart and great vessels. Because in vivo magnetic resonance studies of patients with ventricular assist devices are not possible, in vitro models represent an important tool to investigate flow alterations caused by these systems. By using an in vitro magnetic resonance-compatible model that mimics physiologic conditions as close as possible, this work investigated the flow characteristics using 4-dimensional flow-sensitive magnetic resonance imaging of a left ventricular assist device with outflow via the right subclavian artery as commonly used in cardiothoracic surgery in the recent past. METHODS: An in vitro model was developed consisting of an aorta with its supra-aortic branches connected to a left ventricular assist device simulating the pulsatile flow of the native failing heart. A second left ventricular assist device supplied the aorta with continuous flow via the right subclavian artery. Four-dimensional flow-sensitive magnetic resonance imaging was performed for different flow rates of the left ventricular assist device simulating the native heart and the left ventricular assist device providing the continuous flow. Flow characteristics were qualitatively and quantitatively evaluated in the entire vessel system. RESULTS: Flow characteristics inside the aorta and its upper branching vessels revealed that the right subclavian artery and the right carotid artery were solely supported by the continuous-flow left ventricular assist device for all flow rates. The flow rates in the brain supplying arteries are only marginally affected by different operating conditions. The qualitative analysis revealed only minor effects on the flow characteristics, such as weakly pronounced vortex flow caused by the retrograde flow via the brachiocephalic artery. CONCLUSIONS: The results indicate that, despite the massive alterations in natural hemodynamics due to the retrograde flow via the right subclavian and brachiocephalic arteries, there are no drastic consequences on the flow in the brain-feeding arteries and the flow characteristics in the ascending and descending aortas. It may be beneficial to adjust the operating condition of the left ventricular assist device to the residual function of the failing heart. PMID- 25840755 TI - Graft flow assessment using a transit time flow meter in fractional flow reserve guided coronary artery bypass surgery. AB - OBJECTIVE: To evaluate the relationship between preoperative severity of coronary stenosis occurring with fractional flow reserve (FFR), and the intraoperative bypass graft flow pattern. METHODS: In all, 72 patients were enrolled in this retrospective study. The FFR value of the left anterior descending artery was evaluated, and data on "in situ" bypass grafting from the internal thoracic artery to the left anterior descending artery were assessed. Patients were divided into 3 groups according to preoperative FFR values (Group S: FFR < 0.70; group M: 0.70 <= FFR < 0.75; and group N: FFR >= 0.75). RESULTS: In groups S, M, and N, respectively, mean graft flow was 24.7 +/- 10.6 mL/minute, 19.2 +/- 14.0 mL/minute, and 16.0 +/- 9.7 mL mL/minute; pulsatility index was 2.35 +/- 0.6, 3.02 +/- 1.1, and 5.51 +/- 8.20; and number of patients with systolic reverse flow was 3 (6.8%), 5 (35.7%), and 4 (28.6%). Significant differences were observed in graft flow (P = .009), pulsatility index (P = .038), and proportion of systolic reverse flow (P = .023) among the 3 groups. In all patients, graft patency was confirmed with intraoperative fluorescence imaging; postoperative graft patency was confirmed with multislice computed tomography or coronary angiography in 69 patients (follow-up interval: 213 days). Early graft failure occurred in 1 patient. CONCLUSIONS: As coronary stenosis severity increased, graft flow increased, pulsatility index decreased, and proportion of patients with systolic reverse flow increased. In mild coronary artery stenosis, the chance of flow competition between the native coronary artery and the bypass graft increased. PMID- 25840757 TI - Discussion. PMID- 25840756 TI - Importance of excision repair cross-complementation group 1 and ribonucleotide reductase M1 as prognostic biomarkers in malignant pleural mesothelioma treated with platinum-based induction chemotherapy followed by surgery. AB - OBJECTIVES: Survival and response to platinum-based induction chemotherapy are heterogeneous among patients with malignant pleural mesothelioma. The aim of the present study was to assess the prognostic role of DNA repair markers, such as excision repair cross-complementation group 1 and ribonucleotide reductase M1, in multimodally treated patients with malignant pleural mesothelioma. METHODS: Tumor tissue of a malignant pleural mesothelioma cohort (n = 107) treated with platinum/gemcitabine (n = 46) or platinum/pemetrexed (n = 61) induction chemotherapy followed by extrapleural pneumonectomy was assembled on a tissue microarray. Immunohistochemical expression of excision repair cross complementation group 1 (nuclear) and ribonucleotide reductase M1 (nuclear and cytoplasmic) was assessed for its prognostic impact (association with overall survival or freedom from recurrence). RESULTS: Patients with high nuclear ribonucleotide reductase M1 expression before chemotherapy showed significantly longer freedom from recurrence (P = .03). When specifically analyzed in the subgroup of patients receiving platinum/gemcitabine followed by extrapleural pneumonectomy, high nuclear ribonucleotide reductase M1 was associated with prolonged freedom from recurrence (P = .03) and overall survival (P = .02). Low excision repair cross-complementation group 1 expression in prechemotherapy tumor tissues was associated with significantly longer freedom from recurrence (P = .04). Nuclear ribonucleotide reductase M1 and excision repair cross complementation group 1 were independent prognosticators of freedom from recurrence in addition to pT stage in multivariate analysis. CONCLUSIONS: In the present study, nuclear ribonucleotide reductase M1 and excision repair cross complementation group 1 expression were identified as independent prognosticators for freedom from recurrence of malignant pleural mesothelioma in patients undergoing induction chemotherapy followed by extrapleural pneumonectomy. PMID- 25840758 TI - Another link between aortopathy and congenital anomaly? PMID- 25840759 TI - Ankle Fractures and Modality of Hospital Transport at a Single Level 1 Trauma Center: Does Transport by Helicopter or Ground Ambulance Influence the Incidence of Complications? AB - In an era of concern over the rising cost of health care, cost-effectiveness of auxiliary services merits careful evaluation. We compared costs and benefits of Helicopter Emergency Medical Service (HEMS) with Ground Emergency Medical Service (GEMS) in patients with an isolated ankle fracture. A medical record review was conducted for patients with an isolated ankle fracture who had been transported to a level 1 trauma center by either HEMS or GEMS from January 1, 2000 to December 31, 2010. We abstracted demographic data, fracture grade, complications, and transportation mode. Transportation costs were obtained by examining medical center financial records. A total of 303 patients was included in the analysis. Of 87 (28.71%) HEMS patients, 53 (60.92%) had sustained closed injuries and 34 (39.08%) had open injuries. Of the 216 (71.29%) GEMS patients, 156 (72.22%) had closed injuries and 60 (27.78%) had open injuries. No significant difference was seen between the groups regarding the percentage of patients with open fractures or the grade of the open fracture (p = .07). No significant difference in the rate of complications was found between the 2 groups (p = 18). The mean baseline cost to transport a patient via HEMS was $10,220 + a $108/mile surcharge, whereas the mean transport cost using GEMS was $976 per patient + $16/mile. Because the HEMS mode of emergency transport did not significantly improve patient outcomes, health systems should reconsider the use of HEMS for patients with isolated ankle fractures. PMID- 25840760 TI - Cross-Sectional and Longitudinal Associations Between Anemia and Frailty in Older Australian Men: The Concord Health and Aging in Men Project. AB - BACKGROUND: Anemia and frailty are both common in older people and are associated with adverse health outcomes. There have been some cross-sectional studies of anemia and frailty but no longitudinal studies. The objectives of this study were to examine cross-sectional and longitudinal associations between anemia and frailty in older Australian men. METHODS: A total of 1666 men aged 70 years and older from the Concord Health and Aging in Men Project were assessed at baseline (2005-2007), 1314 men came for the 2-year follow-up between 2007 and 2009, and of those, 917 men returned for the 5-year follow-up between 2012 and 2013. The main outcome measurement was frailty, assessed using the Cardiovascular Health Study method. Anemia was defined as a hemoglobin levels <13.0 g/dL. Covariates included age, income, body mass index, measures of health, estimated glomerular filtration rate, and inflammatory markers (white cell count and albumin). RESULTS: The prevalence of anemia was 14.6% at baseline, 16.2% at 2-year follow-up, and 19.4% at 5-year follow-up. Prevalence of frailty was 9.1% at baseline and 9.7 % at both 2- and 5-year follow-up. Among men aged 70-74 at baseline, prevalence of frailty was 4.5%, but at 5-year follow-up the prevalence was 9.0%. There were significant cross-sectional associations between anemia and frailty in unadjusted [odds ratio, [OR 5.03 (95% confidence interval, CI 3.50, 7.25, P < .0001)] and in fully adjusted analysis [OR 2.90 (95% CI 1.87, 4.51, P < .0001)]. Generalized estimating equations time-lag models were used to examine the longitudinal associations between repeated measurements of hemoglobin and frailty. There were significant associations between measurements of anemia and frailty in unadjusted [OR 2.51 (95% CI 1.58, 4.00, P < .0001] and in fully adjusted analysis (OR 1.80, 95% CI 1.14, 2.85, P = .01). CONCLUSIONS: Anemia was associated with frailty in both cross-sectional and longitudinal analyses, and anemia precedes frailty in men who were nonfrail at baseline. Low hemoglobin levels among patients may alert clinicians to the increased risk of frailty. PMID- 25840761 TI - Clinical burden, quality of care, organizational context: different lenses to optimize care for older people. PMID- 25840762 TI - Focus on multiple system atrophy. Introduction. PMID- 25840763 TI - Spatial dynamics of TRAIL death receptors in cancer cells. AB - TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in cancer cells without harming most normal cells. Currently, multiple clinical trials are underway to evaluate the antitumor activity of recombinant human TRAIL (rhTRAIL) and agonistic antibodies that target death receptors (DRs) 4 or 5. It is encouraging that these products have shown a tolerated safety profile in early phase studies. However, their therapeutic potential is likely limited by the emergence of tumor drug resistance phenomena. Increasing evidence indicates that TRAIL DRs are deficient on the plasma membrane of some cancer cells despite their total protein expression. Notably, the lack of surface DR4/DR5 is sufficient to render cancers resistant to TRAIL-induced apoptosis, regardless of the status of other apoptosis signaling components. The current review highlights recent findings on the dynamic expression of TRAIL death receptors, including the regulatory roles of endocytosis, autophagy, and Ras GTPase-mediated signaling events. This information could aid in the identification of novel predictive biomarkers of tumor response as well as the development of combinational drugs to overcome or bypass tumor drug resistance to TRAIL receptor-targeted therapies. PMID- 25840764 TI - [Clinical recommendations for sport practice in diabetic patients (RECORD Guide). Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN)]. AB - Sporting activity is becoming a common practice in patients with diabetes mellitus (DM). This situation requires both a preliminary medical assessment and a wide range of changes in treatment which have scarcely been addressed in medical literature. OBJECTIVE: To prepare a clinical guideline on the medical approach to patients with diabetes who practice sport regularly. METHODS: An expert panel from the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN) reviewed the most relevant literature in each of the sections. Based both on this review and on data from the experience of a number of athletes with DM, a number of recommendations were agreed within each section. Finally, the Working Group and representatives of the SEEN jointly discussed all these recommendations. CONCLUSION: The guideline provides recommendations ranging from medical assessment before patients with DM start to practice sport to actions during and after physical activity. Recommendations are also given on aspects such as the impact of sport on blood glucose control, training schemes, or special risk situations. PMID- 25840765 TI - Fate, activity, and impact of ingested bacteria within the human gut microbiota. AB - The human gut contains a highly diverse microbial community that is essentially an open ecosystem, despite being deeply embedded within the human body. Food associated fermentative bacteria, including probiotics, are major sources of ingested bacteria that may temporarily complement resident microbial communities, thus forming part of our transient microbiome. Here, we review data on the fate and activity of ingested bacteria and, in particular, lactobacilli and bifidobacteria in the gastrointestinal (GI) tract and their impact on the composition and metabolism of the gut microbiome with a focus on data from clinical studies. In addition, we discuss the mechanisms involved and the potential impact on the host's health. PMID- 25840767 TI - Nebulized fentanyl vs intravenous morphine for ED patients with acute abdominal pain: a randomized double-blinded, placebo-controlled clinical trial. AB - OBJECTIVES: Patients with acute abdominal pain commonly present to emergency departments. The safe and effective relief of discomfort is a concern to patients and physicians. Intravenous opioids are the traditional method used to provide pain relief in this setting, but intravenous access is time consuming and not always achievable. Alternative methods of pain control may therefore be necessary for the acute management of painful conditions without adding to the overall physical or psychological discomfort. The purpose of this study was to evaluate the feasibility of nebulized fentanyl (NF) in the alleviation of acute and undifferentiated abdominal pain. We also sought to compare NF with intravenous morphine (IVM) and to assess patient and provider satisfaction with NF. Nebulized fentanyl (2 MUg/kg) was compared to IVM (0.1 mg/kg) at 10, 20, 30, and 40 minutes; and patient and physician satisfaction was recorded. The NF group experienced more rapid pain relief and more sustained and clinically significant pain relief over the 40-minute study interval. There were no adverse effects noted in the NF group. Both patient and physician satisfaction scores were higher in the NF group. Fentanyl citrate at a dose of 2 MUg/kg through a breath-actuated nebulizer appears to be a feasible and safe alternative to IVM (0.1 mg/kg) in the treatment of acute abdominal pain. PMID- 25840766 TI - The changing face of asthma and its relation with microbes. AB - During the past 50 years, the prevalence of asthma has increased and this has coincided with our changing relation with microorganisms. Asthma is a complex disease associated with local tissue inflammation of the airway that is determined by environmental, immunological, and host genetic factors. In a subgroup of sufferers, respiratory infections are associated with the development of chronic disease and more frequent inflammatory exacerbations. Recent studies suggest that these infections are polymicrobial in nature. Furthermore, there is increasing evidence that the recently discovered asthma airway microbiota may play a critical role in pathophysiological processes associated with the disease. Here, we discuss the current data regarding a possible role for infection in chronic asthma with a particular focus on the role bacteria may play. We discuss recent advances that are beginning to elucidate the complex relations between the microbiota and the immune response in asthma patients. We also highlight the clinical implications of these recent findings in regards to the development of novel therapeutic strategies. PMID- 25840768 TI - Myocarditis mimicking acute coronary syndrome: the role of cardiac magnetic resonance imaging and immunoglobulin therapy. PMID- 25840769 TI - Better brave than big. PMID- 25840770 TI - Incidence, risk factors, and treatment outcome of symptomatic osteonecrosis in Taiwanese children with acute lymphoblastic leukemia: a retrospective cohort study of 245 patients in a single institution. AB - Osteonecrosis (ON) is a potentially disabling complication encountered in children who receive chemotherapy for acute lymphoblastic leukemia (ALL). Considering the possible effect of ethnic difference on the clinical features of symptomatic ON in pediatric ALL, we retrospectively evaluated 245 children with ALL who were treated at Chang Gung Memorial Hospital, Linkou, between 2002 and 2011. Six (2.4 %) patients developed symptomatic ON in a total of 17 sites during the follow-up period. Diagnosis of ON was confirmed by X-ray in seven, magnetic resonance imaging in two, and bone scan in three patients. The estimated cumulative incidence of symptomatic ON in newly diagnosed ALL was 3.4 % at 8 years. Four patients received ON-directed surgical interventions, including total hip replacement in three and arthroplasty in one. The incidence of ON was significantly higher among girls (P = 0.03), patients >10 years old (P = 2.2 * 10(-4)), and patients who had received more intensive chemotherapy regimen (P = 0.02). These results indicate that the incidence and risk factors in our institute were similar to those observed in Western countries. Future studies surveying the impact on the quality of life of childhood ALL survivors in Taiwan are warranted. PMID- 25840771 TI - The IgE-dependent pathway in allergic transfusion reactions: involvement of donor blood allergens other than plasma proteins. AB - On transfusion, several plasma proteins can cause anaphylaxis in patients deficient in the corresponding plasma proteins. However, little is known about other allergens, which are encountered much more infrequently. Although it has been speculated that an allergen-independent pathway underlying allergic transfusion reactions (ATRs) is elicited by biological response modifiers accumulated in blood components during storage, the exact mechanisms remain unresolved. Furthermore, it is difficult even to determine whether ATRs are induced via allergen-dependent or allergen-independent pathways. To distinguish these two pathways in ATR cases, we established a basophil activation test, in which the basophil-activating ability of supernatants of residual transfused blood of ATR cases to whole blood basophils was assessed in the presence or absence of dasatinib, an inhibitor of IgE-mediated basophil activation. Three of 37 supernatants from the platelet concentrates with ATRs activated panel blood basophils in the absence, but not in the presence, of dasatinib. The basophil activation was inhibited by treatment of anti-fish collagen I MoAb in one case, suggesting that the involvement of fish allergens may have been present in donor plasma. We concluded that unknown non-plasma proteins, some of which had epitopes similar to fish antigens, in blood component may be involved in ATRs via an allergen/IgE-dependent pathway. PMID- 25840772 TI - High body mass index did not result in poor outcome in Taiwanese children with acute myeloid leukemia: a single-institution experience. AB - Overweight/obese patients with acute myeloid leukemia (AML) are reported as experiencing inferior outcomes and greater numbers of treatment-related complications. We retrospectively studied 58 children with newly diagnosed AML who received chemotherapy at Chang Gung Memorial Hospital between January 2003 and December 2011. Patients enrolled were considered overweight if body mass index (BMI) was >=85th percentile. Fifteen of 58 (25.9 %) patients were judged overweight by this criterion. Patients diagnosed in the last third of this period (2009-2011) had a higher average BMI (P = 0.06). The rates of documented infection in overweight patients and non-overweight patients were not significantly different (53.3 vs. 62.8 %). The 5-year event-free survival (EFS) of overweight patients was superior to that of non-overweight patients (78.8 vs. 55.4 %). Patients (n = 11) who received hematopoietic stem cell transplantation (HSCT) in first remission (CR1) had a significantly higher 5-year EFS (87.5 vs. 55.2 %, P = 0.04). Among 47 children who did not receive HSCT in CR1, 10 (21.3 %) were overweight. The 5-year EFS of overweight patients was consistently superior to that for non-overweight patients (70.0 vs. 51.2 %). In conclusion, overweight/obese children with AML did not experience poor outcomes in the present study. PMID- 25840773 TI - Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction. AB - Dickkopf-3 (DKK3) is a secreted glycoprotein of the Dickkopf family (DKK1-4) that modulates Wnt signalling. DKK3 has been reported to regulate cell development, proliferation, apoptosis, and immune response. However, the functional role of DKK3 in cardiac remodelling after myocardial infarction (MI) has not yet been elucidated. This study aimed to explore the functional significance of DKK3 in the regulation of post-MI remodelling and its underlying mechanisms. MI was induced by surgical left anterior descending coronary artery ligation in transgenic mice expressing cardiac-specific DKK3 and DKK3 knockout (KO) mice as well as their non-transgenic and DKK3(+/+) littermates. Our results demonstrated that after MI, mice with DKK3 deficiency had increased mortality, greater infarct size, and exacerbated left ventricular (LV) dysfunction. Significantly, at 1 week post-MI, the hearts of DKK3-KO mice exhibited increased apoptosis, inflammation, and LV remodelling compared with the hearts of their DKK3(+/+) littermates. Conversely, DKK3 overexpression led to the opposite phenotype after infarction. Similar results were observed in cultured neonatal rat cardiomyocytes exposed to hypoxia in vitro. Mechanistically, DKK3 promotes cardioprotection by interrupting the ASK1-JNK/p38 signalling cascades. In conclusion, our results indicate that DKK3 protects against the development of MI-induced cardiac remodelling via negative regulation of the ASK1-JNK/p38 signalling pathway. Thus, our study suggests that DKK3 may represent a potential therapeutic target for the treatment of heart failure after MI. PMID- 25840774 TI - MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-kappaB activation and suppressing inflammation-associated microRNA expression. AB - MCP-1-induced protein (MCPIP, also known as ZC3H12A) has recently been uncovered to act as a negative regulator of inflammation. Expression of MCPIP was elevated in the ventricular myocardium of patients with ischemic heart failure. However, the role of MCPIP in the development of post-infarct cardiac inflammation and remodeling is unknown. The objective of the present study was to investigate whether MCPIP exerts an inhibitory effect on the cardiac inflammatory response and adverse remodeling after myocardial infarction (MI). Mice with cardiomyocyte specific expression of MCPIP and their wild-type littermates (FVB/N) were subjected to permanent ligation of left coronary artery. The levels of MCPIP were significantly increased in the ischemic myocardium and sustained for 4 weeks after MI. Acute infarct size was comparable between groups. However, constitutive overexpression of MCPIP in the murine heart resulted in improved survival rate, decreased cardiac hypertrophy, less of fibrosis and scar formation, and better cardiac performance at 28 days after MI, along with a markedly reduced monocytic cell infiltration, less cytokine expression, decreased caspase-3/7 activities and apoptotic cell death compared to the wild-type hearts. Cardiomyocyte-specific expression of MCPIP also attenuated activation of cardiac NF-kappaB signaling and expression of inflammation-associated microRNAs (miR-126, -146a, -155, and -199a) when compared with the post-infarct wild-type hearts. In vitro, MCPIP expression suppressed hypoxia-induced NF-kappaB-luciferase activity in cardiomyocytes. In conclusion, MCPIP expression in the ischemic myocardium protects against adverse cardiac remodeling and dysfunction following MI by modulation of local myocardial inflammation, possibly through mitigating NF-kappaB signaling and suppressing inflammation-associated microRNA expression. PMID- 25840775 TI - Modeling full-scale osmotic membrane bioreactor systems with high sludge retention and low salt concentration factor for wastewater reclamation. AB - A full-scale model was developed to find optimal design parameters for osmotic membrane bioreactor (OMBR) and reverse osmosis (RO) hybrid system for wastewater reclamation. The model simulates salt accumulation, draw solution dilution and water flux in OMBR with sludge concentrator for high retention and low salt concentration factor. The full-scale OMBR simulation results reveal that flat sheet module with spacers exhibits slightly higher flux than hollow-fiber; forward osmosis (FO) membrane with high water permeability, low salt permeability, and low resistance to salt diffusion shows high water flux; an optimal water recovery around 50% ensures high flux and no adverse effect on microbial activity; and FO membrane cost decreases and RO energy consumption and product water concentration increases at higher DS flow rates and concentrations. The simulated FO water flux and RO energy consumption ranges from 3.03 to 13.76LMH and 0.35 to 1.39kWh/m(3), respectively. PMID- 25840776 TI - [Current situation and perspectives of proton therapy]. AB - Proton beam therapy is indicated as a treatment for some rare tumours and paediatric tumours because the technique allows a good local control with minimal toxicity; the growing number of centres that use proton beam therapy is associated with an increase of dosimetric and clinical data for other malignant tumours as well. This paper reviews potential indications of proton beam therapy. A systematic review on Medline was performed with the following keywords proton beam therapy, cancer, heavy particle, charged particle. No phase III trial has been published using proton beam therapy in comparison with the best photon therapy, but numerous retrospective and dosimetric studies have revealed an advantage of proton beam therapy compared to photons, above all in tumours next to parallel organs at risk (thoracic and abdominal tumours). This could be accompanied with a better safety profile and/or a better tumoural control; numerous phase 0, I, II, III and IV studies are ongoing to examine these hypotheses in more common cancers. Use of proton beam therapy is growing for common cancers within clinical trials but some indications could be applied sooner since in silico analysis showed major advantages with this technique. PMID- 25840778 TI - Using the StarT Back Tool: Does timing of stratification matter - In response to Peter Kent and Alice Kongsted. PMID- 25840777 TI - Peer Group Similarity in Perceptions of Pubertal Timing. AB - Self-report measures of perceived pubertal timing correspond only weakly with clinical measures of "objective" physical development. Peer and school contexts shape adolescents' self-perceptions of pubertal timing. The current study examined associations between perceived pubertal timing and the pubertal timing reported by nominated friends and schoolmates. Participants included 2817 adolescents (Mage = 16.6; 49 % female; 16 % Black; 20 % Hispanic) from the National Longitudinal Study of Adolescent Health. Three measures of pubertal timing were included: age-standardized ratings of body changes, comparisons of development relative to peers (relative timing), and, in females, age at menarche. It was hypothesized that relative timing, which explicitly asks adolescents to compare themselves to their peers, would be related to the age standardized pubertal timing of nominated friends and schoolmates. Surprisingly, there were no associations between relative timing and age-standardized pubertal timing reported by peers, suggesting that pubertal self-perceptions do not fluctuate in response to the average level of development in a friend group. Instead, males were similar to nominated friends and schoolmates in age standardized ratings of body changes, and females were similar to nominated friends in relative timing, controlling for race, ethnicity, and age. Different self-report measures of pubertal timing index different underlying constructs, and the social processes that influence adolescents' perceptions of pubertal maturation may differ between genders. PMID- 25840779 TI - Cost-Effectiveness of Decision Support Strategies in Acute Bronchitis. AB - BACKGROUND: A recent clinical trial suggests that printed (PDS) and computer decision support (CDS) interventions are safe and effective in reducing antibiotic use in acute bronchitis relative to usual care (UC). OBJECTIVE: Our aim was to evaluate the cost-effectiveness of decision support interventions in reducing antibiotic use in acute bronchitis. DESIGN: We conducted a clinical trial-based cost-effectiveness analysis comparing UC, PDS and CDS for management of acute bronchitis. We assumed a societal perspective, 5-year program duration and 30-day time horizon. PATIENTS: The U.S. population aged 13-64 years presenting with acute bronchitis in the ambulatory setting. INTERVENTIONS: Printed and computer decision support interventions relative to usual care. MAIN MEASURES: Cost per antibiotic prescription safely avoided. KEY RESULTS: In the base case, PDS dominated UC and CDS, with lesser total costs (PDS: $2,574, UC: $2,768, CDS: $2,805) and fewer antibiotic prescriptions (PDS: 3.79, UC: 4.60, CDS: 3.95) per patient over 5 years. In one-way sensitivity analyses, PDS dominated UC across all parameter values, except when antibiotics reduced work loss by >= 1.9 days or the probability of hospitalization within 30 days was >= 0.9 % in PDS (base case: 0.2 %) or <= 0.4 % in UC (base case: 1.0 %). The dominance of PDS over CDS was sensitive both to probability of hospitalization and plausible variation in the adjusted odds of antibiotic use in both strategies. CONCLUSIONS: A PDS strategy to reduce antibiotic use in acute bronchitis is less costly and more effective than both UC and CDS strategies, although results were sensitive to variation in probability of hospitalization and the adjusted odds of antibiotic use. This simple, low-cost, safe, and effective intervention would be an economically reasonable component of a multi component approach to address antibiotic overuse in acute bronchitis. PMID- 25840780 TI - Using the Knowledge Base of Health Services Research to Redefine Health Care Systems. AB - This Perspective discusses 12 key facts derived from 50 years of health services research and argues that this knowledge base can stimulate innovative thinking about how to make health care systems safer, more efficient, more cost effective, and more patient centered, even as they respond to the needs of diverse communities. PMID- 25840781 TI - Comparison of anterior approach versus posterior approach for the treatment of multilevel cervical spondylotic myelopathy. AB - PURPOSE: The purpose of this study is to evaluate the clinical outcomes, complications, and surgical trauma between anterior and posterior approaches for the treatment of multilevel cervical spondylotic myelopathy (CSM). STUDY DESIGN: Systematic review and meta-analysis. METHODS: Randomized controlled trials or non randomized controlled trials published up to November 2014 that compared the clinical effectiveness of anterior and posterior surgical approaches for the treatment of multilevel CSM were acquired by a comprehensive search in four electronic databases (PubMed, EMBASE, Cochrane Controlled Trial Register and MEDLINE). Exclusion criteria were non-controlled studies, combined anterior and posterior surgery and cervical myelopathy caused by ossification of the posterior longitudinal ligament. The main end points included: recovery rate; Japanese Orthopedic Association (JOA) score; complication rate; reoperation rate; blood loss; operation time and length of stay. RESULTS: A total of ten studies were included in the meta-analysis; none of which were randomized controlled trials. All of the selected studies were of high quality as indicated by the Newcastle Ottawa scale. In six studies involving 467 patients, there was no significant difference in the preoperative JOA score between the anterior surgery group and the posterior group [P > 0.05, WMD -0.00 (-0.50, 0.50)]. In four studies involving 268 patients, the postoperative JOA score was significantly higher in the anterior surgery group compared with the posterior surgery group [P < 0.05, WMD 0.79 (0.16, 1.42)]. In five studies involving 420 patients, there was no statistically significant difference in recovery rate between the anterior and posterior surgery groups [P > 0.05, WMD 2.73 (-8.69, 14.15)]. In nine studies involving 804 patients, the postoperative complication rate was significantly higher in the anterior surgery group compared with the posterior surgery group [P = 0.009, OR 1.65 (1.13, 2.39)]. In five studies involving 294 patients, the reoperation rate was significantly higher in the anterior surgery group compared with the posterior surgery group [P = 0.0001, OR 8.67 (2.85, 26.34)]. In the four studies involving 252 patients, the intraoperative blood loss and operation time was significantly higher in the anterior surgery group compared with the posterior surgery group [P < 0.05, WMD -40.25 (-76.96, -3.53) and P < 0.00001, WMD 61.3 (52.33, 70.28)]. In the three studies involving 192 patients, the length of stay was significantly lower in the anterior surgery group compared with the posterior surgery group [P < 0.00001, WMD -1.07 (-2.23, -1.17)]. CONCLUSIONS: In summary, our meta-analysis suggested that a definitive conclusion could not be reached regarding which surgical approach is more effective for the treatment of multilevel CSM. Although anterior approach was associated with better postoperative neural function than posterior approach in the treatment of multilevel CSM, there was no apparent difference in the neural function recovery rate between the two approaches. Higher rates of surgery-related complication and reoperation should be taken into consideration when anterior approach is used for patients with multilevel CSM. PMID- 25840782 TI - Surgery and survival outcomes of 30 patients with neurological deficit due to clear cell renal cell carcinoma spinal metastases. AB - PURPOSE: The aim of this study was to provide some useful insights into the clinical and imaging presentations, treatment and prognostic factors in patients with neurological deficit caused by clear cell renal cell carcinoma (CCRCC) spinal metastases for the sake of designing individualized therapeutic plans for such patients. METHODS: A total of 30 patients with neurological deficit due to CCRCC spinal metastases who received surgery in our department were identified during an 8-year period from 2003 to 2012 and used for discussion of treatment options for CCRCC spinal metastases on the basis of literature review and our own experience. RESULTS: Univariate analysis showed that age (<=45 years/>45 years), visceral metastasis, Tomita score (3-5/6-8), Tokuhashi score (4-9/10-12) and radiotherapy were suggested as the potential prognostic factors. However, the multivariate Cox regression model showed that only Tokuhashi score was an independent prognostic factor. CONCLUSIONS: Tokuhashi score 10 or more is a favorable prognostic factor of CCRCC spinal metastasis. PMID- 25840783 TI - Implications of different patterns of "double-layer sign" in cervical ossification of the posterior longitudinal ligament. AB - PURPOSE: To make a preliminary classification of double-layer sign according to the morphological characteristics of the ossified and central hypodense mass and clarify implications of different patterns of "double-layer sign". METHODS: The 268 patients of cervical ossification of the posterior longitudinal ligament (OPLL) who underwent anterior corpectomy were retrospectively analyzed from January 2009 to January 2014. All these patients were performed cervical plain X rays, CT and MRI. The double-layer sign was observed on axial bone window of CT images. According to the morphological characteristics of the ossified and central hypodense mass, this sign was classified into three types: type A was crescent shape, type B was short-straight shape and type C was long-straight shape. Type A was named when the central hypodense mass traced an arc and the OPLL is much more extensive than the dural ossification (DO). It belonged to type B when the central hypodense mass traced a short-straight line, less than or equal to half of the base width of the vertebrae. The OPLL may be extensive or equal to the DO. Type C was defined when it was more than half of the base width, presenting with a long-straight line and DO is much more extensive than OPLL. Intraoperative findings including dural mater ossification and adhesion, postoperative CSF leakage and outcome were all studied. Two spinal surgeons with rich experiences read the CT images according to this classification method and verified its consistency. RESULTS: Ninety-two patients were found in association with DO during the anterior decompression procedure, meanwhile the double-layer sign could be seen on axial bone window of CT imaging. In these 92 patients, there were 51 patients presenting with type A, and the ossified mass was completely resected with ossified dura mater reserved. Only two patients presented with dural defect and postoperative CSF leakage. Thirty-five patients was classified as type B, of which six accompanied by CSF leakage. All the other six patients of type C presented with CSF leakage after operation. There was a significant correlation between the occurence of CSF leakage and pattern of double-layer sign, but not gender, age, duration of symptoms, extent of OPLL and occupying rate. The Kappa value between the two surgeons was 0.82, showing a good consistency of the method. CONCLUSIONS: OPLL patients with double-layer sign of type C is almost inevitably followed by CSF leakage after anterior decompression. For type A and B, occurrence of CSF leakage is not as high as we thought before. Pattern of double-layer sign should be a considered factor when anterior or posterior approach is chosen. PMID- 25840785 TI - Meningioma of the external auditory canal. PMID- 25840784 TI - Predictors of clinical outcome following lumbar disc surgery: the value of historical, physical examination, and muscle function variables. AB - PURPOSE: Explore the relationships between preoperative findings and clinical outcome following lumbar disc surgery, and investigate the prognostic value of physical examination findings after accounting for information acquired from the clinical history. METHODS: We recruited 55 adult patients scheduled for first time, single-level lumbar discectomy. Participants underwent a standardized preoperative evaluation including real-time ultrasound imaging assessment of lumbar multifidus function, and an 8-week postoperative rehabilitation programme. Clinical outcome was defined by change in disability, and leg and low back pain (LBP) intensity at 10 weeks. Linear regression models were used to identify univariate and multivariate predictors of outcome. RESULTS: Univariate predictors of better outcome varied depending on the outcome measure. Clinical history predictors included a greater proportion of leg pain to LBP, pain medication use, greater time to surgery, and no history of previous physical or injection therapy. Physical examination predictors were a positive straight or cross straight leg raise test, diminished lower extremity strength, sensation or reflexes, and the presence of postural abnormality or pain peripheralization. Preoperative pain peripheralization remained a significant predictor of improved disability (p = 0.04) and LBP (p = 0.02) after accounting for information from the clinical history. Preoperative lumbar multifidus function was not associated with clinical outcome. CONCLUSIONS: Information gleaned from the clinical history and physical examination helps to identify patients more likely to succeed with lumbar disc surgery. While this study helps to inform clinical practice, additional research confirming these results is required prior to confident clinical implementation. PMID- 25840786 TI - Effects of Tongue Strength Training and Detraining on Tongue Pressures in Healthy Adults. AB - This study examined the effect of tongue strengthening training and long-term detraining on tongue tip pressure, tongue base pressure, and tongue pressure during effortful swallowing. Ten young healthy volunteers (21-35 years) were participated in this study. Participants received 8-week tongue strengthening exercise 3 days a week with each session lasting 30 min. Measurement of tongue pressure and tongue strengthening exercise were administrated using Iowa Oral Performance Instrument (IOPI). Training intensity was applied at 60 and 80% of maximal tongue pressure for the first week and the remainder, respectively. Following completion of 8-week training, 28 weeks of detraining period was continued. Training increased tongue tip pressure, tongue base pressure, and tongue pressure during effortful swallowing above pre-training values (p < 0.05). After 28-week detraining, all tongue variables were significantly lower than after 8-week training (p < 0.05) but remained significantly higher than pre training levels (p < 0.05). These findings demonstrate that high-intensity tongue strengthening exercise can improve tongue pressures. However, training effects were diminished gradually during detraining period. Thus, maintenance programs after strengthening exercise would be required for prolonging training effects. PMID- 25840787 TI - Reliability for Identification of a Select Set of Temporal and Physiologic Features of Infant Swallows. AB - There is little reported evidence regarding the reliability of temporal and physiologic features of infant swallowing from videofluoroscopic swallowing studies (VFSS). The purpose of this retrospective study was to determine a reliable set of temporal and physiologic features from infant swallowing that can be measured from analysis of VFSS. Temporal and physiologic features for testing were determined from review of previously reported features of infant VFSS in the literature. Two novel analysts underwent three training sessions to learn and practice visual recognition of the proposed features. The two analysts then assessed 25 swallows from 10 total subjects' VFSS. To establish inter- and intra rater reliability, calculation of Pearson's r was used for features that met criteria for parametric analysis and Spearman's rank correlation coefficient was used for the non-continuous features. Percent agreement was used to report on the reliability of the dichotomous features due to insufficient variability for Spearman's rho analyses. Fifteen of the 16 tested features were found to have acceptable inter- and intra-rater reliability measures, with each analyst achieving a correlation of 0.75 or higher. This project identifies 15 variables that can be reliably measured from infant VFSS. This information can be used to assist with determination of normal versus abnormal swallow features and in developing and testing therapeutic strategies for infants with dysphagia. PMID- 25840788 TI - Effects of Strengthening Exercises on Swallowing Musculature and Function in Senior Healthy Subjects: a Prospective Effectiveness and Feasibility Study. AB - Head and neck cancer (HNC) patients may develop dysphagia due to muscle atrophy and fibrosis following chemoradiotherapy. Strengthening of the swallowing muscles through therapeutic exercise is potentially effective for improving swallowing function. We hypothesize that a customized Swallow Exercise Aid (SEA), developed for isometric and isokinetic strengthening exercises (against resistance), can help to functionally strengthen the suprahyoid musculature, which in turn can improve swallowing function. An effectiveness/feasibility study was carried out with ten senior healthy volunteers, who performed exercises 3 times per day for 6 weeks. Exercises included chin tuck against resistance (CTAR), jaw opening against resistance (JOAR), and effortful swallow exercises with the SEA. Multidimensional assessment consisted of measurements of maximum chin tuck and jaw opening strength, maximum tongue strength/endurance, suprahyoid muscle volume, hyoid bone displacement, swallowing transport times, occurrence of laryngeal penetration/aspiration and/or contrast residue, maximum mouth opening, feasibility/compliance (questionnaires), and subjective swallowing complaints (SWAL-QOL). After 6-weeks exercise, mean chin tuck strength, jaw opening strength, anterior tongue strength, suprahyoid muscle volume, and maximum mouth opening significantly increased (p < .05). Feasibility and compliance (median 86 %, range 48-100 %) of the SEA exercises were good. This prospective effectiveness/feasibility study on the effects of CTAR/JOAR isometric and isokinetic strengthening exercises on swallowing musculature and function shows that senior healthy subjects are able to significantly increase swallowing muscle strength and volume after a 6-week training period. These positive results warrant further investigation of effectiveness and feasibility of these SEA exercises in HNC patients with dysphagia. PMID- 25840789 TI - Distal femoral fractures: The need to review the standard of care. AB - BACKGROUND: Hip fracture care has evolved, largely due to standardisation of practice, measurement of outcomes and the introduction of the Best Practice Tariff, leading to the sustained improvements documented by the National Hip Fracture Database (NHFD). The treatment of distal femoral fractures in this population has not had the same emphasis. This study defines the epidemiology, current practice and outcomes of distal femoral fractures in four English centres. PATIENTS AND METHODS: 105 patients aged 50 years or greater with a distal femoral fracture, presenting to four UK major trauma centres between October 2010 and September 2011 were identified. Data was collected using an adapted NHFD data collection tool via retrospective case note and radiograph review. Local ethics approval was obtained. RESULTS: Mean age was 77 years (range 50-99), with 86% female. 95% of injuries were sustained from a low energy mechanism, and 72% were classified as either 33-A1 or 33-C1. The mean Parker mobility score and Barthel Independence Index were 5.37 (0-9) and 75.5 (0-100) respectively. Operative management was performed in 84%, and 86% had their surgery within 36 h. Three quarters were fixed with a peri-articuar locking plate. There was no consensus on post operative rehabilitation, but no excess of complications in the centres where weight bearing as tolerated was the standard. 45% were seen by an orthogeriatrician during their admission. Mean length of stay was 29 days. Mortality at 30 days, 6 months, and 1 year was 7%, 16% and 18% respectively. DISCUSSION: This study demonstrates that the distal femoral and hip fracture populations are similar, and highlights the current disparity in their management. The metrics and standards of care currently applied to hip fractures should be applied to the treatment of distal femoral fractures. Optimal operative treatment and rehabilitation remains unclear, and is in need of further research. PMID- 25840790 TI - Accuracy of targeted wire guided tube thoracostomy in comparison to classical surgical chest tube placement - A clinical study. AB - BACKGROUND: Chest tube malfunction, after the tube thoracostomy, is often the result of an inappropriate chest tube tip position. The aim of this study was to analyse the precision of chest tube placement using the targeted wire guide technique (TWG technique) with curve dilator and to compare it to the classical surgical technique (CS technique). MATERIALS AND METHODS: In this clinical study 80 patients with an indication for thoracic drainage, due to pneumothorax or pleural effusion were included. Experimental group contained 39 patients whose chest tube was placed using the TWG technique. The control group contained 41 patients whose chest tube was placed using the CS technique. RESULTS: The comparison of the outcomes of the two techniques applied suggests that the TWG technique was significantly more successful in achieving adequate (precise) chest tube placement, irrespective of patient diagnosis (TWG vs. CS in all patients, 78.4% vs. 36.6%, p<0.001). In the pleural effusion group, TWG and CS had success rates of 78.2% and 37.5% (p=0.005), respectively, while in pneumothorax group, TWG and CS had success rates of 78.6% and 35.3% (p=0.029), respectively. CONCLUSIONS: Using a curved dilator and the TWG technique for the thoracic drainage procedure we found statistically significant advantage to the TWG technique in comparison to the CS technique (78% vs. 37%) regarding precise chest tube placement within the pleural cavity. Introducing the materials and technique used in this clinical trial into clinical practice may improve the quality of thoracic drainage, including residual volume of air and/or fluid, poor functioning of the chest tube, and, as a consequence of both, prolonged hospitalisation. PMID- 25840791 TI - Wnt signaling regulation of stem-like properties in human lung adenocarcinoma cell lines. AB - The refractory pulmonary adenocarcinoma is characterized by its metastasis and resistance to cytotoxic agents. While the underlying molecular mechanism is unclear, the property of chemoresistance may mainly lie in the presence of highly resistant cancer stem cells. We examined the function of Wnt/beta-catenin signaling in maintaining cancer stem cells (CSCs) in lung adenocarcinoma. Lentivirus-mediated knockdown of beta-catenin expression accelerated cell cycle. Subsequently, beta-catenin knockdown PC9 cells improve the sensitivity to chemotherapy. Further focusing on Wnt signal by administrating PP and EGFR-TKIs as Wnt antagonists can decrease metastasis and induce apoptosis. Collectively, these results indicate that Wnt signaling pathway plays an essential role in maintaining highly resistant CSCs, regulation of cell cycle, metastasis and apoptosis in lung adenocarcinoma. PMID- 25840792 TI - CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells. AB - Alterations in the expression of C-C chemokine receptor type 5 (CCR5 or CD195) have been correlated with disease progression in different cancers. Recently, a few investigations have reported the blockage of this receptor by an antagonist (maraviroc) and its antineoplastic effects on tumor cell growth. However, little is known about the mechanistic reasons behind these antineoplastic effects of CCR5 blockage by maraviroc. In this study, we blocked the CCR5 receptor by maraviroc in SW480 and SW620 colorectal cancer cells to study the resulting changes in biological properties and related pathways. This blockage induced significantly reduced proliferation and a profound arrest in G1 phase of the cell cycle. Concomitantly, maraviroc caused significant signs of apoptosis at morphological level. Significant modulation of multiple apoptosis-relevant genes was also noticed at mRNA levels. In addition, we found remarkable increases in cleaved caspases at protein level. These modulations led us to propose a signaling pathway for the observed apoptotic effects. In conclusion, blocking the CCR5 by maraviroc induces significant cytotoxic and apoptotic effects in colorectal cancer cells. Thus, maraviroc can be considered a model compound, which may foster the development of further CCR5 antagonists to be used for the treatment of colorectal cancer. PMID- 25840793 TI - Does segmental body composition differ in women with Prader-Willi syndrome compared to women with essential obesity? AB - BACKGROUND: Subjects with Prader-Willi syndrome (PWS) have a higher fat mass and a lower fat-free mass compared to subjects with essential obesity. However, few data are presently available on the segmental body composition (BC) of PWS subjects. AIM: To evaluate whether women with PWS and women with essential obesity, matched for age and percent body fat, differ in segmental fat distribution and surrogate markers of cardiometabolic disease (CMD). SUBJECTS AND METHODS: 35 women with PWS and 50 women with essential obesity were matched for age and percent body fat using coarsened exact matching. BC was measured by dual energy X-ray absorptiometry. Oral glucose tolerance testing and measurements of cholesterol, triglycerides, C-reactive protein, and blood pressure were performed. Comparisons between PWS and obese women were performed using generalized linear models. RESULTS: Trunk fat was lower in PWS than in obese women on both absolute [-7.3 (95% confidence interval -9.4 to -5.2) kg] and relative [-4.1 (-6.9 to -1.4)% of body fat] grounds. PWS and obese women had similar surrogate markers of CMD, with the exception of HDL-cholesterol, which was higher in PWS women. CONCLUSION: Trunk fat is lower in obese women with PWS than in those with essential obesity. Surrogate markers of CMD are, however, mostly similar in the two groups. PMID- 25840794 TI - Pregnancy outcome in women treated with methimazole or propylthiouracil during pregnancy. AB - PURPOSE: Control of thyroid function in hyperthyroid women during pregnancy is based on antithyroid drugs (ATD) [propylthiouracil (PTU) and methimazole (MMI)]. While a teratogenic effect has been suggested for MMI and, more recently, for PTU, a clear demonstration is still lacking. Aim of this study was to assess the safety of ATD during pregnancy. METHODS: A total of 379 pregnancies were retrospectively recruited in eight Italian Departments of Endocrinology and divided in five groups: (1) MMI-treated and euthyroid throughout pregnancy (n = 89); (2) MMI-treated and hyperthyroid on at least two occasions (n = 35); (3) PTU treated women and euthyroid throughout pregnancy (n = 32); (4) PTU-treated women and hyperthyroid on at least two occasions (n = 20); and (5) non-ATD-treated (n = 203). Data on maternal thyroid function, miscarriages, type of delivery, neonatal weight, length and TSH, perinatal complications and congenital malformation were analyzed. RESULTS: The gestational age at delivery, the rate of vaginal delivery, neonatal weight, length and neonatal TSH did not significantly differ among groups. In all groups, the rates of spontaneous miscarriage and of major congenital malformations were not higher than in the general population. No newborns were born with a phenotype similar to those described in the "MMI embryopathy". CONCLUSIONS: While a clear demonstration of a teratogenic effect of MMI is currently lacking, it seems reasonable to follow the current guidelines and advice for PTU treatment in hyperthyroid women during the first trimester of pregnancy. Further, large and prospective worldwide studies will be needed to fully clarify the issue of ATD safety during pregnancy. PMID- 25840796 TI - Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents. AB - Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3', with various targeted substitutions to understand the structure-activity relationships. Inhibitor synthesis was accomplished by first obtaining the appropriate dipeptide precursors with common structural components. The pyrrolidine moiety introduced interesting rotamers in a number of synthesized molecules, which was confirmed using high-temperature (1)H NMR spectroscopy. Among the synthesized compounds, 61, 62, and 66 inhibited falcipain-2 activity with inhibition constants (Ki) of 1.8 +/- 1.1, 0.2 +/- 0.1 and 7.0 +/- 2.3 MUM, respectively. A group of molecules with a pyrrolidine moiety at the T2 position (68, 70, 71, 72, and 73) also potently inhibited falcipain-2 activity (Ki=0.4 +/- 0.1, 2.5 +/- 0.5, 3.3 +/- 1.1, 7.5 +/- 1.9, and 4.6 +/- 0.7 MUM, respectively). Overall, compound 74 exhibited potent anti-parasitic activity (IC50=0.9 +/- 0.1 MUM), corresponding with its inhibitory activity against falcipain-2, with a Ki of 1.1 +/- 0.1 MUM. Compounds 62 and 67 inhibited the growth of the drug resistant parasite Dd2 with better efficacy, and compound 74 exhibited a 7- to 12 fold higher potency against Dd2 and MCamp isolates, than the laboratory strain (3D7). These data suggest that this novel series of compounds should be further investigated as potential antimalarial agents. PMID- 25840795 TI - Synthesis, crystal structures, and urease inhibition of an acetohydroxamate coordinated oxovanadium(V) complex derived from N'-(3-bromo-2-hydroxybenzylidene) 4-methoxybenzohydrazide. AB - A new benzohydrazone compound N'-(3-bromo-2-hydroxybenzylidene)-4 methoxybenzohydrazide (H2L) was prepared. Reaction of H2L and acetohydroxamic acid (HAHA) with VO(acac)2 in methanol gave the complex [VOL(AHA)]. Both H2L and the oxovanadium complex were characterized by elemental analysis, IR, UV-vis and (1)H NMR spectra, and single crystal X-ray diffraction. H2L was also characterized by high-resolution mass spectrum. Thermal analysis of the oxovanadium complex was carried out. The benzohydrazone ligand, in its dianionic form, coordinates to V atom through the phenolate oxygen, imino nitrogen and enolate oxygen. The acetohydroxamic acid coordinates to V atom through the carbonyl oxygen and deprotonated hydroxyl oxygen. The V atom is in octahedral coordination. H2L, HAHA and the oxovanadium complex were tested for their urease inhibitory activities. The percent inhibition at concentration of 100 MUmol.L(-1) on Helicobacter pylori urease is 78% for the oxovanadium complex. The IC50 value for the complex is 36.5 MUmol.L(-1). Molecular docking study was performed to study the inhibition. PMID- 25840797 TI - Reversible chemical dimerizer-induced recovery of PIP2 levels moves clathrin to the plasma membrane. AB - Chemical dimerizers are powerful non-invasive tools for bringing molecules together inside intact cells. We recently introduced a rapidly reversible chemical dimerizer system which enables transient translocation of enzymes to and from the plasma membrane (PM). Here we have applied this system to transiently activate phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown at the PM via translocation of phosphoinositide 5-phosphatase (5Ptase). We found that the PIP2 sensor phospholipase C-delta PH domain (PLCdelta-PH) is released from the PM upon addition of the reversible chemical dimerizer rCD1. By outcompeting rCD1, rapid release of the 5Ptase from the PM is followed by PIP2 recovery. This permits the observation of the PIP2-dependent clathrin assembly at the PM. PMID- 25840798 TI - Design of a selenylsulfide-bridged EGFR dimerization arm mimic. AB - The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this beta-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable beta loop peptides for disruption of protein-protein interactions. PMID- 25840799 TI - Female Condom Use and Adoption Among Men and Women in a General Low-Income Urban U.S. Population. AB - HIV prevention is increasingly focused on antiretroviral treatment of infected or uninfected persons. However, barrier methods like male condoms (MC) and female condoms (FC) remain necessary to achieve broad reductions in HIV and other sexually transmitted infections (STI). Evidence grows suggesting that removal of basic obstacles could result in greater FC use and reduced unprotected sex in the general population. We conducted four annual cross-sectional surveys (2009-2012) of urban residents (N = 1614) in low-income neighborhoods of a northeastern U.S. city where prevalence of HIV and other STIs is high. Findings indicate slow FC uptake but also heterosexual men's willingness to use them. Factors associated with men's and women's FC use included positive FC attitudes, network exposure, and peer influences and norms. These results suggest that men can be supporters of FC, and reinforce the need for targeted efforts to increase FC use in both men and women for HIV/STI prevention. PMID- 25840800 TI - Minimally invasive mitral valve surgery through right mini-thoracotomy: recommendations for good exposure, stable cardiopulmonary bypass, and secure myocardial protection. AB - An apparent advantage of minimally invasive mitral surgery through right mini thoracotomy is cosmetic appearance. Possible advantages of this procedure are a shorter ventilation time, shorter hospital stay, and less blood transfusion. With regard to hard endpoints, such as operative mortality, freedom from reoperation, or cardiac death, this method is reportedly equivalent, but not superior, to the standard median sternotomy technique. However, perfusion-related complications (e.g., stroke, vascular damage, and limb ischemia) tend to occur more frequently in minimally invasive technique than with the standard technique. In addition, valve repair through a small thoracotomy is technically demanding. Therefore, screening out patients who are not appropriate for performing minimally invasive surgery is the first step. Vascular disease and inadequate anatomy can be evaluated with contrast-enhanced computed tomography. Peripheral cannulation should be carefully performed, using transesophageal echocardiography guidance. Preoperative detailed planning of the valve repair process is desirable because every step is time-consuming in minimally invasive surgery. Three-dimensional echocardiography is a powerful tool for this purpose. For satisfactory exposure and detailed observation of the valve, a special left atrial retractor and high definition endoscope are useful. Valve repair can be performed in minimally invasive surgery as long as cardiopulmonary bypass is stable and bloodless exposure of the valve is obtained. PMID- 25840801 TI - Midterm Re-interventions and Survival After Endovascular Versus Open Repair for Ruptured Abdominal Aortic Aneurysm. AB - OBJECTIVE: To compare the midterm re-intervention and survival rates after EVAR and OR for ruptured abdominal aortic aneurysms (RAAA). METHODS: Observational cohort study including all consecutive RAAA patients between 2004 and 2011 in 10 hospitals in the Amsterdam ambulance region. The primary end point was re interventions within 5 years of the primary intervention. The secondary end point was death. The outcomes were estimated by survival analyses, compared using the logrank test, and subsequently adjusted for possible confounders using Cox proportional hazard models. Re-interventions were estimated in all patients and in patients who survived their hospital stay. RESULTS: Of 467 patients with a RAAA, 73 were treated by EVAR and 394 by OR. Five years after the primary intervention, the rates of freedom from re-intervention were 55% for EVAR (26/73, 95% CI: 41-69%) and 60% for OR (130/394, 95% CI: 55-66%) (p = .96). After adjustment for age, sex, comorbidity, and pre-operative hemodynamic stability, the risk of re-intervention was similar (HR 1.01, 95% CI: 0.65-1.55). The survival rates were 36% for EVAR (45/73, 95% CI: 24-47%) and 38% for OR (235/394, 95% CI: 33-43%) (p = .83). In 297 patients who survived their hospital stay, the rates of freedom from re-intervention were 66% for EVAR (15/54, 95% CI: 52-81%) and 90% for OR (20/243, 95% CI: 86-95%) (p < .01). After adjustment for age and sex, the risk of re-intervention was higher after EVAR (HR 0.27, 95% CI: 0.14 0.52). CONCLUSIONS: Five years after the primary intervention, endovascular and open repair for ruptured abdominal aortic aneurysm resulted in similar re intervention and survival rates. However, in patients who survived their hospital stay the re-intervention rate was higher for EVAR than for OR. PMID- 25840802 TI - Blood Warming and Hemolysis: A Systematic Review With Meta-Analysis. AB - The use of fluid warmers during blood transfusion is recommended to avoid inducing hypothermia and its harmful effects. Fluid warmers offered by manufacturers can reach temperatures of 43 degrees C. However, the recommendations of national regulatory organizations do not clearly indicate the maximum heating temperature in relation to the risk of hemolysis. To fill this gap, we conducted a systematic review of the literature with meta-analysis. To match clinical practice, this review was limited to fluid warmers that used contact heating; thus, studies that used radiofrequency or microwave heating were excluded. Twenty-four observational studies were included, 17 of which were the subject of a meta-analysis. A preliminary descriptive analysis indicated that multiple factors can influence the level of hemolysis during blood heating with a liquid warmer, including blood age, anticoagulant type, duration of exposure to heat, stirring the blood during heating, and various elements of the circuit through which blood flows (eg, type of infusion pump with pressure and flow, type of microfilter, and type of tubing). Moreover, the duration between sampling and hemolysis assay was a source of heterogeneity among studies, as were the initial free hemoglobin levels in the various experiments. In general, the increase generated by each of these factors other than temperature appears to have been limited except for blood age, which is an important parameter of hemolysis, the length of exposure to heat, and, in some studies, the type of infusion pump used. Regarding the meta-analysis, at temperatures at or less than 43 degrees C and even up to 45-46 degrees C, it appears that blood heating is safe and causes hemolysis only in clinically negligible proportions. PMID- 25840803 TI - TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction. AB - RATIONALE: Optimal outcome after myocardial infarction (MI) depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI. OBJECTIVE: In this study, we examined the role of triggering receptor expressed on myeloid cells-1(TREM-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response. METHODS AND RESULTS: After infarction, TREM-1 expression is upregulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacological inhibition using a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and monocyte chemoattractant protein-1 production, thus reducing classical monocytes mobilization to the heart. It also improves left ventricular function and survival in mice (n=20-22 per group). During both permanent and transient myocardial ischemia, Trem-1 blockade also ameliorates cardiac function and limits ventricular remodeling as assessed by fluorodeoxyglucose-positron emission tomographic imaging and conductance catheter studies (n=9-18 per group). The soluble form of TREM-1 (sTREM-1), a marker of TREM-1 activation, is detectable in the plasma of patients having an acute MI (n=1015), and its concentration is an independent predictor of death. CONCLUSIONS: These data suggest that TREM-1 could constitute a new therapeutic target during acute MI. PMID- 25840804 TI - Circulating Lp-PLA2 activity correlates with oxidative stress and cytokines in overweight/obese postmenopausal women not using hormone replacement therapy. AB - Controversy remains regarding whether there is an association between circulating lipoprotein-associated phospholipase A2 (Lp-PLA2), cytokines, and oxidative stress in healthy postmenopausal women. We investigated the influence of age on Lp-PLA2 activity in postmenopausal women not using hormone therapy and the relationship of Lp-PLA2 enzyme activity to serum cytokine levels and oxidative stress indices. Normal weight (n = 1284) and overweight/obese (n = 707) postmenopausal women not using hormone therapy were categorized into five age groups: 50-54, 55-59, 60-64, 65-69, and 70-89 years. Overweight-obese women showed higher plasma Lp-PLA2 activity, urinary 8-epi-prostaglandin F2alpha (8-epi PGF2alpha), serum interleukin (IL)-6, and smaller LDL particles than normal weight women after adjusting for age, years postmenopause, smoking, drinking, blood pressure, glucose, insulin, lipid profiles, BMI, and waist circumference. Overweight/obese women 70-89 years old showed higher Lp-PLA2 activity than those aged 50-54 years, whereas no significant difference in Lp-PLA2 activity existed across normal-weight female age groups. Overweight/obese women aged >= 65 years showed higher Lp-PLA2, oxidized LDL (ox-LDL), IL-6, and 8-epi-PGF2alpha than age matched normal-weight controls. Overweight/obese women aged >= 70 years had higher ox-LDL levels than those aged 50-59, and overweight/obese women aged 65-89 showed higher IL-6 and 8-epi-PGF2alpha. There were strong positive correlations between Lp-PLA2 and ox-LDL (r = 0.385, P < 0.001), Lp-PLA2 and IL-6 (r = 0.293, P < 0.001), and ox-LDL and IL-6 (r = 0.303, P < 0.001) in overweight/obese women; however, these relationships were weak in normal-weight women. These results suggest that aging and obesity-related oxidative and inflammatory mediators are associated with Lp-PLA2 activity in overweight/obese postmenopausal women not using hormone therapy. PMID- 25840805 TI - Local Injection of Lenti-BDNF at the Lesion Site Promotes M2 Macrophage Polarization and Inhibits Inflammatory Response After Spinal Cord Injury in Mice. AB - There is much evidence to suggest that brain-derived neurotrophic factor (BDNF) is a prominent candidate in promoting neuroprotection, axonal regeneration, and synaptic plasticity following spinal cord injury (SCI). Although some evidence indicates that BDNF has potent anti-oxidative effects and may be involved in the regulation of the immune response, the effects of BDNF in the inflammatory response during the course of secondary damage after SCI is still unclear. The present study was designed to investigate the effects of BDNF with a special focus on their effect on macrophage polarization after SCI. Adult C57 mice underwent T10 spinal cord clip compression injury and received lenti-BDNF vector injections at the epicenter of the lesion site. Four days later, total BDNF levels were greatly increased in animals that received lenti-BDNF injections. Confocal imaging showed that more than 80 % of the lenti-virus infected cells were CD11b-positive macrophages. In addition, the expression of arginase-1 and CD206 (associated with M2 macrophage phenotype) significantly increased in the animals that received lenti-BDNF injections compared with those that received lenti-EGFP injections. On the contrary, the expression of CD16/32 and inducible nitric oxide synthase (M1 phenotype marker) was down-regulated as demonstrated using flow cytometry and immunohistochemistry. Furthermore, the production of interleukin 1beta and tumor necrosis factor alpha was significantly reduced whereas the levels of interleukin 10 and interleukin 13 were elevated in subjects that received lenti-BDNF vector injections. The time course of functional recovery revealed that gradual recovery was observed in the subacute phase in lenti-BDNF group, little improvement was observed in lenti-EGFP group. At the axonal level, significant retraction of the CST axons were observed in lenti-EGFP injected animals relative to lenti-BDNF group by biotinylated dextran amine tracing. In addition, compared to lenti-BDNF group markedly demyelination was observed in the lenti-EGFP group using luxol fast blue staining. In conclusion, we found that BDNF could promote the shift of M1 to M2 phenotype and ameliorate the inflammatory microenvironment. Furthermore, the roles of BDNF in immunity modulation may enhance neuroprotective effects and partially contribute to the locomotor functional recovery after SCI. PMID- 25840806 TI - The time is now: revisiting the case for the 3-year radiology residency. PMID- 25840807 TI - Timing of menarche related to carotid artery intima-media thickness in black and white young adult women: the Bogalusa Heart Study. AB - PURPOSE: The early onset of menarche is related to the adulthood risk of cardiovascular (CV) disease. This study examines the relation of early onset of menarche to carotid artery intima-media thickness (IMT), which is a surrogate marker of CV disease, among asymptomatic young adult women in a black-white community. METHODS: A cohort of 461 women (31% black, 69% white) aged 24 to 43 years (mean of 35.6 years) were participants in the Bogalusa Heart Study. The age at menarche was retrospectively collected. In addition to CV risk factor variable measurements B-mode ultrasound images of the far walls of carotid artery segments were obtained. The multivariate linear regression model along with mediating effect by Sobel test was applied to analyze menarcheal age effect on carotid artery IMT, adjusting for covariates. RESULTS: Waist to height ratio was significantly greater (P = .01) in early menarcheal age (<11 years) versus menarcheal age (>=11 years) in both black and white women. Homeostasis model assessment of insulin resistance (HOMA-IR) was significantly greater (P = .01) in early menarcheal age (<11 years) versus menarcheal age (>=11 years) in white women and also similar direction in black women. Internal carotid artery IMT was the same in early menarcheal age (<11 years) versus menarcheal age (>=11 years) in white women but higher (P = .02) in black women. Given as previously mentioned these different associations, the mediation analysis by race was performed. The effect of early menarcheal age (<11 years) versus menarcheal age (>=11 years) was mediated by waist to height ratio and HOMA-IR in white women after adjusting for parental education and age. The mediating effect of waist to height ratio (Sobel test = -2.26 and P = .02) and HOMA-IR (Sobel test = -1.85 and P = .06) on internal carotid artery IMT was noted in white women. The direct effect of early menarcheal age (<11 years) versus menarcheal age (>=11 years) on internal carotid artery IMT (beta = -0.150, P = .01) was observed in black women. CONCLUSIONS: The observed deleterious effect of early onset of menarche on carotid artery IMT in asymptomatic black and white younger adult women has biological, social, and public health implications. PMID- 25840808 TI - Antiatherogenic and antitumoral properties of Opuntia cladodes: inhibition of low density lipoprotein oxidation by vascular cells, and protection against the cytotoxicity of lipid oxidation product 4-hydroxynonenal in a colorectal cancer cellular model. AB - Opuntia species have been used for thousands of years as a folk medicine in the treatment of diseases. However, the components and protective mechanisms are still unclear. We make the hypothesis that Opuntia species may protect the development of oxidative stress-associated diseases, such as atherosclerosis or colon cancer, via their antioxidant properties. We investigated the protective effect of Opuntia cladode powder against the oxidation of low-density lipoprotein (LDL) evoked by vascular endothelial cells, an important risk factor for atherosclerosis development, and the toxicity of 4-hydroxynonenal (a major lipid peroxidation product) on normal (Apc +/+) and preneoplastic (Apc min/+) immortalized epithelial colon cells. Various Opuntia species classified according to their degree of domestication, from the wildest (Opuntia streptacantha, Opuntia hyptiacantha, Opuntia megacantha), medium (Opuntia albicarpa), to the most domesticated (Opuntia ficus-indica) were tested. Cladode powders prepared from these Opuntia species significantly inhibited LDL oxidation induced by incubation with murine endothelial cells and the subsequent foam cell formation of RAW 264.7 murine macrophages and cytotoxicity on murine endothelial cells. Moreover, Opuntia cladode powder blocked the promotion of colon cancer development on an in vitro model of colonocytes. It may be noted that the phenolic acid and flavonoids content, the antioxidant capacity, and the protective effect were relatively similar in all the cladode powders from wild (O. streptacantha) and domesticated Opuntia. Altogether, these data confirm the therapeutic potential of Opuntia cladodes in diseases associated with oxidative stress. PMID- 25840809 TI - MicroRNA208 family in cardiovascular diseases: therapeutic implication and potential biomarker. AB - Cardiovascular disease remains to be a severe and yet unsolved health problem that has become a leading threat to human health. It is urgent to explore early diagnostic biomarker and innovative therapeutic strategy to prevent the progression of cardiovascular diseases. MicroRNAs (miRNAs) are conserved endogenous, non-coding small RNAs that are essential modulators of gene expression by inhibiting translation or promoting degradation of messenger RNAs (mRNAs). A large range of functions has been attributed to miRNAs, such as cell proliferation, differentiation, apoptosis, and invasion. So far, miRNAs have shown characteristic changes in expression during the process of cardiovascular disease that may act as potential biomarkers. A series of studies have clearly discovered that the miR-208 family is closely associated with the development of cardiac diseases, such as myocardial hypertrophy, cardiac fibrosis, myocardial infarction, arrhythmia, and heart failure. In this review, we will highlight novel insights into miR-208 family functions and discuss it as potential biomarker and therapeutic target in cardiovascular diseases. PMID- 25840810 TI - Photocross-Linked Peptide-Protein Complexes Analysis: A Comparative Study of CID and ETD Fragmentation Modes. AB - Protein-protein interactions are among the keys to organizing cellular processes in space and time. One of the only direct ways to identify such interactions in their cellular environment is to covalently bond the interacting partners to fix the interaction. Photocross-linking in living cells is thus a very promising technique. The feasibility of in cellulo photocross-linking reactions has been shown and mass spectrometry is a tool of choice to analyze photocross-linked proteins. However, the interpretation of the MS and MS/MS spectra of photocross linked peptides remains one of the most important bottlenecks of the method and still limits its potential for large-scale applications (interactomics). Fundamental studies are still necessary to understand and characterize the fragmentation behavior of photocross-linked peptides. Here, we report the successful identification of the interaction sites in a well-characterized model of in vitro interaction between a protein and a peptide. We describe in detail the fragmentation pattern of these photocross-linked species in order to identify trends that could be generalized. In particular, we compare CID and ETD fragmentation modes (and HCD in a lesser extent), demonstrating the complementarity of both methods and the advantage of ETD for the analysis of photocross-linked species. The information should help further development of dedicated software to properly score MS/MS spectra of photocross-linked species. PMID- 25840811 TI - Glycopeptide Site Heterogeneity and Structural Diversity Determined by Combined Lectin Affinity Chromatography/IMS/CID/MS Techniques. AB - Glycopeptides from a tryptic digest of chicken ovomucoid were enriched using a simplified lectin affinity chromatography (LAC) platform, and characterized by high-resolution mass spectrometry (MS) as well as ion mobility spectrometry (IMS) MS. The LAC platform effectively enriched the glycoproteome, from which a total of 117 glycopeptides containing 27 glycan forms were identified for this protein. IMS-MS analysis revealed a high degree of glycopeptide site heterogeneity. Comparison of the IMS distributions of the glycopeptides from different charge states reveals that higher charge states allow more structures to be resolved. Presumably the repulsive interactions between charged sites lead to more open configurations, which are more readily separated compared with the more compact, lower charge state forms of the same groups of species. Combining IMS with collision induced dissociation (CID) made it possible to determine the presence of isomeric glycans and to reconstruct their IMS profiles. This study illustrates a workflow involving hybrid techniques for determining glycopeptide site heterogeneity and evaluating structural diversity of glycans and glycopeptides. PMID- 25840812 TI - Influence of Desorption Conditions on Analyte Sensitivity and Internal Energy in Discrete Tissue or Whole Body Imaging by IR-MALDESI. AB - Analyte signal in a laser desorption/postionization scheme such as infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) is strongly coupled to the degree of overlap between the desorbed plume of neutral material from a sample and an orthogonal electrospray. In this work, we systematically examine the effect of desorption conditions on IR-MALDESI response to pharmaceutical drugs and endogenous lipids in biological tissue using a design of experiments approach. Optimized desorption conditions have then been used to conduct an untargeted lipidomic analysis of whole body sagittal sections of neonate mouse. IR-MALDESI response to a wide range of lipid classes has been demonstrated, with enhanced lipid coverage received by varying the laser wavelength used for mass spectrometry imaging (MSI). Targeted MS(2) imaging (MS(2)I) of an analyte, cocaine, deposited beneath whole body sections allowed determination of tissue-specific ion response factors, and CID fragments of cocaine were monitored to comment on wavelength-dependent internal energy deposition based on the "survival yield" method. PMID- 25840813 TI - Imaging MALDI MS of Dosed Brain Tissues Utilizing an Alternative Analyte Pre extraction Approach. AB - Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry has been adopted in the pharmaceutical industry as a useful tool to detect xenobiotic distribution within tissues. A unique sample preparation approach for MALDI imaging has been described here for the extraction and detection of cobimetinib and clozapine, which were previously undetectable in mouse and rat brain using a single matrix application step. Employing a combination of a buffer wash and a cyclohexane pre-extraction step prior to standard matrix application, the xenobiotics were successfully extracted and detected with an 8 to 20-fold gain in sensitivity. This alternative approach for sample preparation could serve as an advantageous option when encountering difficult to detect analytes. PMID- 25840815 TI - Patient radiation dose reduction using an X-ray imaging noise reduction technology for cardiac angiography and intervention. AB - Coronary angiography and intervention can expose patients to high radiation dose. This retrospective study quantifies the patient dose reduction due to the introduction of a novel X-ray imaging noise reduction technology using advanced real-time image noise reduction algorithms and optimized acquisition chain for fluoroscopy and exposure in interventional cardiology. Patient, procedure and radiation dose data were retrospectively collected in the period August 2012 August 2013 for 883 patients treated with the image noise reduction technology (referred as "new system"). The same data were collected for 1083 patients in the period April 2011-July 2012 with a system using state-of-the-art image processing and reference acquisition chain (referred as "reference system"). Procedures were divided into diagnostic (CAG) and intervention (PCI). Acquisition parameters such as fluoroscopy time, volume of contrast medium, number of exposure images and number of stored fluoroscopy images were collected to classify procedure complexity. The procedural dose reduction was investigated separately for three main cardiologists. The new system provides significant dose reduction compared to the reference system. Median DAP values decreased for all procedures (p < 0.0001) from 172.7 to 59.4 Gy cm(2), for CAG from 155.1 to 52.0 Gy cm(2) and for PCI from 229.0 to 85.8 Gy cm(2) with reduction quantified at 66, 66 and 63 %, respectively. Based on median values, the dose reduction for all procedures was 68, 60 and 67 % for cardiologists 1, 2 and 3, respectively. The X-ray imaging technology combining advanced real-time image noise reduction algorithms and anatomy-specific optimized fluoroscopy and cine acquisition chain provides 66 % patient dose reduction in interventional cardiology. PMID- 25840816 TI - Safety and efficacy of single-agent bendamustine after failure of brentuximab vedotin in patients with relapsed or refractory hodgkin's lymphoma: experience with 27 patients. AB - BACKGROUND: The optimal treatment of patients with heavily pretreated Hodgkin's lymphoma is controversial. Brentuximab vedotin is an active single agent in this context. Also, bendamustine can be regarded as a safe and effective alternative for patients with relapse after autologous transplantation and as an interesting cytoreductive strategy before allogeneic transplantation. PATIENTS AND METHODS: An observational, multicenter, retrospective study is reported of single-agent bendamustine in 27 heavily pretreated patients with relapsed or refractory Hodgkin's lymphoma, who had all received brentuximab vedotin as their last treatment and who showed disease progression, refractory disease, or early relapse. The primary study endpoint was the objective response rate, and the secondary endpoint was the safety of the bendamustine regimen. RESULTS: The overall response rate was 55.5%, with 10 of 27 patients (37.0%) obtaining a complete response. In comparison, the overall response rate previously observed with brentuximab vedotin in the same subset of patients was much lower (18.5%). Among the 10 patients with a complete response after bendamustine, only 1 had had a complete response to brentuximab, with 2 having a partial response and 7 stable or progressive disease. With a median duration of response of 8 months, all these patients had maintained a continuous response at the last follow-up examination. The treatment was well tolerated, with rather infrequent adverse events and transient and manageable toxicities. CONCLUSION: Albeit with the limits of an observational retrospective study, these data indicate that bendamustine shows its efficacy in patients already treated with brentuximab vedotin, regardless of their previously obtained response and without any significant toxicity. PMID- 25840817 TI - A systematic review of randomised controlled trials examining the effectiveness of breast and cervical cancer screening interventions for ethnic minority women. AB - PURPOSE: To examine the effect that breast and/or cervical cancer screening programmes for ethnic minority women have on their knowledge of and beliefs about breast or cervical cancer and screening, and on their screening intentions and uptake rates. Recommendations are also made for the format and content of such programmes, based on existing evidence. METHODS: A comprehensive literature search was carried out both manually and by means of five electronic databases. The findings are summarised and synthesised in narrative fashion. RESULTS: The ten RCTs included here were conducted among ethnic minority women in the United States or Canada, where breast or cervical cancer screening programmes have led to improvements in screening intentions, knowledge of cervical cancer and pap test uptake. The Breast Cancer Screening Belief Scale and self-reporting were the methods commonly used to measure outcomes. The shared characteristics of both countries' programmes were that they were theory- and language-based, the instruction took place in a community setting, the materials were culturally relevant, the content highlighted key messages about breast or cervical cancer and screening measures, and there were multiple intervention strategies. CONCLUSION: Breast or cervical cancer screening programmes in Western countries have demonstrated improvements in knowledge of the disease, screening intentions and pap test uptake, although evidence on the effectiveness of the interventions has been limited. The common characteristics of programmes are identified, but a comprehensive model is still needed to link these characteristics with other factors and mediators influencing outcomes. PMID- 25840819 TI - Achalasia: A to Z. PMID- 25840818 TI - Prognostic communication in cancer: A critical interpretive synthesis of the literature. AB - PURPOSE: For patients with cancer, providing appropriate information about prognosis or chances of recurrent disease remains a difficult area of practice. Much research has suggested that patients want to be given all available information, although the realities of attempting to do this are complex and may be perceived by some as uncaring. A review of recent literature was undertaken to explore the process of disclosure, patient experience and preferences for information regarding prognosis or risk of recurrence. METHODS: A systematic approach was taken to searching electronic databases for relevant literature from 2004 to June 2014. Primary research from a range of methodological approaches was included and critical interpretive synthesis was employed to explore themes and identify gaps in the evidence. RESULTS: Twenty papers were identified as appropriate. They were diverse in objectives and patient groups. Themes identified included: the nature of prognostic information, patient need for prognostic information, patient need to maintain hope, balancing hope and realism, patient factors, disease factors and clinician factors. A thematic framework was developed. CONCLUSIONS: Patients often struggle to fully understand complex prognostic information. They value help in making sense of this information and generally want information that supports hope. Working with patients to understand and manage the uncertainty of their situation may be particularly valuable. Further research is needed to fully understand the process of prognostic information giving and what information patients want regarding recurrence risk. Research should be aimed at identifying strategies helpful to patients in managing uncertainty inherent in their situation. PMID- 25840821 TI - International Association of Trauma and Surgical Intensive Care Symposium: Penetrating Trauma. Update on Penetrating Trauma. PMID- 25840820 TI - Preoperative Imaging Features are Associated with Surgical Complications Following Carotid Body Tumor Resection. AB - BACKGROUND: Surgical resection remains the treatment of choice for carotid body tumors (CBTs). Although perioperative complications such as carotid artery injury and neurological deficits occur infrequently, they can be devastating. The aim of this study was to evaluate whether clinical factors or preoperative imaging findings can accurately predict perioperative complications. METHODS: Twenty CBTs were resected from 19 patients. Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) of the neck were used to measure the degree of circumferential involvement of the CBT to the internal carotid artery (ICA), carotid artery narrowing, tumor length, tumor volume, and the distance from the tip of the C2 dens to the superior aspect of the CBT (dens-CBT). Operative reports and Shamblin classification (I-III) of each tumor were independently reviewed. Preoperative imaging features were compared to perioperative cranial nerve injury (CNI), rates of carotid artery injury, and major carotid artery repairs, as well as Shamblin classifications>=II. RESULTS: CNI was associated with a high-lying CBT (dens-CBT=1.8 vs. 2.9 cm, p<0.01). All four patients with CNI had a dens-CBT of <3 cm. Neither tumor length and tumor volume nor the involvement of the ICA (>=180 degrees as measured by CT or MRI) was associated with CNI, carotid artery injury, major carotid artery repair, or Shamblin II or III classification. No carotid artery narrowing was observed in any of the cases. CONCLUSIONS: Preoperative measurement of the dens-CBT is helpful in identifying CBTs at risk for CNI after surgical resection. PMID- 25840822 TI - Unusual spinal tuberculosis in an Avar Age skeleton (Csongrad-Felgyo, Urmos tanya, Hungary): A morphological and biomolecular study. AB - The paleopathological analysis of a well-preserved young adult female skeleton from the AD 7-8th century (Avar Age) in Hungary revealed multiple lytic lesions in all of the thoracic and lumbar vertebral bodies. The lesions were characterized by smooth marginal zones and space-occupying mass appearance. The considerable loss of spongy bone in the thoracolumbar vertebrae resulted in angular deformity and fusion, characteristic of the healing stage of TB. Osteolytic lesions were also observed on the vertebral processes, ribs and sternum. On the endocranial surface, abnormal blood vessel impressions were revealed, indicating some kind of meningitis. The X-ray and CT analysis of the affected bones detected abnormal structures and cystic zones of destruction. The lesions were however not always bordered by areas of increased density, which is typical in cystic TB. Vertebral remains were also subjected to biomolecular analysis in two different laboratories, which attested the presence of Mycobacterium tuberculosis complex (MTBC) DNA and supported the paleopathological diagnosis of TB. Spoligotyping analysis confirmed the presence of MTBC DNA and more specifically an infection caused by bacteria belonging to the M. tuberculosis lineage. This case study provides new data for the paleoepidemiology of TB in this geographical area and historical period, and draws attention to the great variability of TB lesions in the human skeleton. PMID- 25840823 TI - Construction of a multicolor GeneScan analytical system to detect clonal rearrangements of immunoglobulin and T cell receptor genes in canine lymphoid tumors. AB - Polymerase chain reaction (PCR) amplification to detect immunoglobulin heavy chain (IgH) and T cell receptor gamma-chain (TCRgamma) gene rearrangements has recently become widely used as part of the diagnostic strategy for lymphoid tumors in dogs. In this study, we constructed a multicolor GeneScan analytical system to improve the sensitivity and resolution of the clonality analysis of antigen receptor gene rearrangements in dogs. We used 7 reactions per sample, with 2 PCR conditions, to amplify IgH/TCRgamma and control genes. By using multicolor-labeled primers, these 7 PCR products could be combined into 3 tubes before capillary electrophoresis. Clonal rearrangement of the IgH/TCRgamma genes was detected in 93.3% of dogs with multicentric lymphoma and 84.6% of dogs with gastrointestinal lymphoma. Detection sensitivity of the clonally expanded cells in the background of normal peripheral blood mononuclear cells was 1-10%. The multicolor GeneScan analytical system developed here may prove to be helpful for the diagnosis of lymphoid tumors in dogs. PMID- 25840824 TI - Effect of monochloramine treatment on the microbial ecology of Legionella and associated bacterial populations in a hospital hot water system. AB - Opportunistic pathogens, including Legionella spp. and non-tuberculous mycobacteria, can thrive in building hot water systems despite municipal and traditional on-site chlorine disinfection. Monochloramine is a relatively new approach to on-site disinfection, but the microbiological impact of on-site chloramine use has not been well studied. We hypothesized that comparison of the microbial ecology associated with monochloramine treatment versus no on-site treatment would yield highly dissimilar bacterial communities. Hot water samples were collected monthly from 7 locations for three months from two buildings in a Pennsylvania hospital complex supplied with common municipal water: (1) a hospital administrative building (no on-site treatment) and (2) an adjacent acute care hospital treated on-site with monochloramine to control Legionella spp. Water samples were subjected to DNA extraction, rRNA PCR, and 454 pyrosequencing. Stark differences in the microbiome of the chloraminated water and the control were observed. Bacteria in the treated samples were primarily Sphingomonadales and Limnohabitans, whereas Flexibacter and Planctomycetaceae predominated in untreated control samples. Serendipitously, one sampling month coincided with dysfunction of the on-site disinfection system that resulted in a Legionella bloom detected by sequencing and culture. This study also demonstrates the potential utility of high-throughput DNA sequencing to monitor microbial ecology in water systems. PMID- 25840825 TI - Moderate DNA damage promotes metabolic flux into PPP via PKM2 Y-105 phosphorylation: a feature that favours cancer cells. AB - Pyruvate kinase M2, an important metabolic enzyme, promotes aerobic glycolysis (Warburg effect) to facilitate cancer cell proliferation. Unravelling the status of this important glycolytic pathway enzyme under sub-lethal doses of etoposide, a commonly used anti-proliferative genotoxic drug to induce mild/moderate DNA damage in HeLa cells as a model system and discern its effect on: PKM2 expression, phosphorylation, dimer: tetramer ratio, activity and associated effects, was pertinent. Protein expression and phosphorylation of PKM2 from HeLa cells was estimated using Western blotting. Same protein lysate was also used to estimate total pyruvate kinase activity and the total dimer: tetramer content evaluated using glycerol gradient ultra-centrifugation. Intracellular PEP was estimated manually using standard curve; while NADPH was assessed by NADPH estimation kit. Unpaired t test and two-way-ANOVA was used for statistical analysis. A relative decrease in PKM2 expression and a subsequent dose and time dependent increase in Y105-phosphorylation were observed. A concomitant increase in PKM2 dimer content and Y105-phosphorylation responsible for reduced PKM2 activity promoted PEP accumulation and NADPH production, representing increased metabolic flux into PPP, a feature that favours cancer cells. It was apparent that the sub-lethal doses of etoposide induced inadequate damage to DNA in cancer cells in culture promoted pro-survival conditions due to Y105-phosphorylation of PKM2, its stable dimerization and inactivation, a unique association not known earlier, indicating what might happen in tumour revivals or recurrences. PMID- 25840826 TI - Pre-operative Predictive Factors of Post-operative Pain in Patients With Hip or Knee Arthroplasty: A Systematic Review. AB - OBJECTIVE: To analyze pre-surgical predictive factors of post-surgical pain in patients undergoing hip or knee arthoplasty. METHODS: A systematic literature review was performed. We defined a sensitive strategy on Medline, Embase and Cochrane Library up to May 2013. The inclusion criteria were: patients undertaking knee and/or hip arthroplasty, adults with moderate or severe pain (>=4 on a Visual Analog Scale) in whom predictive factors of post-surgical pain were evaluated before surgery. Systematic reviews, meta-analyses, controlled trials and observational studies were selected. We excluded animals and basic science articles, reviews of prosthesis, prosthesis due to fractures, patients with rheumatic diseases or studies with mixed population in which disaggregated data was not possible to obtain. RESULTS: A total 37 articles of moderate quality were selected. The articles included representative patients undergoing a knee or hip arthroplasty in our country; most of them were aged 60 years or above, with osteoarthritis, and with a high rate of obesity and comorbidities. We found great variability regarding the type of studies and predictive factors. There was a strong association between post-surgical pain and the following pre-surgical factors: female gender, low socio-economic status, higher pain, comorbidities, low back pain, poor functional status, and psychological factors (depression, anxiety or catastrophic pain). CONCLUSIONS: There are pre-surgical factors that might influence post-surgical pain in patients undergoing a knee or hip arthroplasty. Therefore, they should be taken into account when considering an arthroplasty. PMID- 25840827 TI - Exercise outcomes in prevalent users of stimulant medications. AB - BACKGROUND: To compare users of stimulant medications with matched nonusers on exercise outcomes during a maximal treadmill exercise test. METHODS: A cross sectional study of a community-based cohort comparing propensity-score-matched stimulant medication users (n = 245) and nonusers (n = 735) who underwent a maximal treadmill exercise test in the Cooper Center Longitudinal Study cohort from January 1, 1995 to December 31, 2013. Main Outcomes were peak systolic blood pressure (SBP), average rise in SBP, peak heart rate (HR), and estimated VO2max during exercise. A linear mixed model analysis was used to evaluate the effect of stimulant exposure on each of the exercise outcomes. In a sensitivity analysis, users were compared against nonusers for risk of chronotropic incompetence. Analyses were adjusted for relevant covariates and multiple testing. RESULTS: Peak HR during exercise was significantly lower in stimulant medication users (least square mean estimate 170.2 beats/minute) compared to nonusers (174.4 beats/minute; p < 0.0001). Moreover, stimulant medication users had an increased risk of chronotropic incompetence compared to nonusers (adjusted odds ratio 3.28, 95% confidence interval 1.70 to 6.34, p = 0.0008). No significant differences were observed in the outcomes of peak SBP, average SBP rise, and estimated VO2max between matched groups. CONCLUSIONS: Stimulant medication use was associated with a significant decrease in peak HR and an increased risk of chronotropic incompetence. Further investigation is required to understand the clinical significance of chronotropic incompetence in stimulant medication users. Concerns that stimulant medication use may increase peak SBP and average SBP during exercise were not supported by this study. PMID- 25840828 TI - Multiple epigenetic factors predict the attention deficit/hyperactivity disorder among the Chinese Han children. AB - Attention deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. Despite its prevalence, the critical factors involved in its development remain to be identified. It was recently suggested that epigenetic mechanisms probably contribute to the etiology of ADHD. The present study was designed to examine the associations of epigenetic markers with ADHD among Chinese Han children, aiming to establish the prediction model for this syndrome from the epigenetic perspective. We conducted a pair-matching case control study, and the ADHD children were systematically evaluated via structured diagnostic interviews, including caregiver interviews, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised criteria (DSM-IV R). The expression levels of risk genes DAT1, DRD4, DRD5, as well as their promoter methylation, were determined respectively, followed by the expression profiles of histone-modifying genes p300, MYST4, HDAC1, MeCP2. The multivariate logistic regressions were performed to establish ADHD prediction models. All of the seven genes tested were identified as risk factors for ADHD. The methylation of one critical CpG site located upstream of DRD4 was shown to affect its transcription, suggesting a role in ADHD's development. Aberrant DNA methylation and histone acetylation were indicated in ADHD patients. In addition, a prediction model was established using the combination of p300, MYST4 and HDAC1, with the accuracy of 0.9338. This is, to our knowledge, the first study to clearly demonstrate the associations between epigenetic markers and ADHD, shedding light on the preliminary diagnosis and etiological studies of this widespread disorder. PMID- 25840829 TI - Long-term healthcare cost reduction with Intensive Short-term Dynamic Psychotherapy in a tertiary psychiatric service. AB - OBJECTIVE: To evaluate whether a mixed population of patients treated with Intensive Short-term Dynamic Psychotherapy (ISTDP) would exhibit reduced healthcare costs in long-term follow-up. METHODS: A quasi-experimental design was employed in which data on pre- and post-treatment healthcare cost were compared for all ISTDP cases treated in a tertiary care service over a nine year period. Observed cost changes were compared with those of a control group of patients referred but never treated. Physician and hospital costs were compared to treatment cost estimates and normal population cost figures. RESULTS: 1082 patients were included; 890 treated cases for a broad range of somatic and psychiatric disorders and 192 controls. The treatment averaged 7.3 sessions and measures of symptoms and interpersonal problems significantly improved. The average cost reduction per treated case was $12,628 over 3 follow-up years: this compared favorably with the estimated treatment cost of $708 per patient. Significant differences were seen between groups for follow-up hospital costs. CONCLUSIONS: ISTDP in this setting appears to facilitate reductions in healthcare costs, supporting the notion that brief dynamic psychotherapy provided in a tertiary setting can be beneficial to health care systems overall. CLINICALTRIALS. GOV IDENTIFIER NUMBER: NCT01924715. PMID- 25840830 TI - miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome. AB - Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome-c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (~50%). Neutrophils increased transiently on day 3 RI in the collateral dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (~75%) while increasing Bax/Bax dimers, cytochrome-c release, and caspase activation (~70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (~60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21 dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation. PMID- 25840831 TI - Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice. AB - We tested the hypothesis that aortic perivascular adipose tissue (PVAT) from young low-density lipoprotein receptor-deficient (LDLr(-/-)) mice promotes aortic stiffness and remodeling, which would be mediated by greater PVAT-derived IL-6 secretion. Arterial stiffness was assessed by aortic pulse wave velocity and with ex vivo intrinsic mechanical properties testing in young (4-6 mo old) wild-type (WT) and LDLr(-/-) chow-fed mice. Compared with WT mice, LDLr(-/-) mice had increased aortic pulse wave velocity (407 +/- 18 vs. 353 +/- 13 cm/s) and intrinsic mechanical stiffness (5,308 +/- 623 vs. 3,355 +/- 330 kPa) that was associated with greater aortic protein expression of collagen type I and advanced glycation end products (all P < 0.05 vs. WT mice). Aortic segments from LDLr(-/-) compared with WT mice cultured in the presence of PVAT had greater intrinsic mechanical stiffness (6,092 +/- 480 vs. 3,710 +/- 316 kPa), and this was reversed in LDLr(-/-) mouse arteries cultured without PVAT (3,473 +/- 577 kPa, both P < 0.05). Collagen type I and advanced glycation end products were increased in LDLr(-/-) mouse arteries cultured with PVAT (P < 0.05 vs. WT mouse arteries), which was attenuated when arteries were cultured in the absence of PVAT (P < 0.05). PVAT from LDLr(-/-) mice secreted larger amounts of IL-6 (3.4 +/- 0.1 vs. 2.3 +/- 0.7 ng/ml, P < 0.05), and IL-6 neutralizing antibody decreased intrinsic mechanical stiffness in LDLr(-/-) aortic segments cultured with PVAT (P < 0.05). Collectively, these data provide evidence for a role of PVAT-derived IL-6 in the pathogenesis of aortic stiffness and remodeling in chow-fed LDLr(-/-) mice. PMID- 25840832 TI - Improved Specificity of Gene Electrotransfer to Skin Using pDNA Under the Control of Collagen Tissue-Specific Promoter. AB - In order to ensure safe, efficient and controlled gene delivery to skin, the improvement of delivery methods together with proper design of DNA is required. Non-viral delivery methods, such as gene electrotransfer, and the design of tissue-specific promoters are promising tools to ensure the safety of gene delivery to the skin. In the scope of our study, we evaluated a novel skin specific plasmid DNA with collagen (COL) promoter, delivered to skin cells and skin tissue by gene electrotransfer. In vitro, we determined the specificity of the COL promoter in fibroblast cells. The specific expression under the control of COL promoter was obtained for the reporter gene DsRed as well as for therapeutic gene encoding cytokine IL-12. In vivo, the plasmid with COL promoter encoding the reporter gene DsRed was efficiently transfected to mouse skin. It resulted in the notable and controlled manner, however, in lower and shorter expression, compared to that obtained with ubiquitous promoter. The concentration of the IL-12 in the skin after the in vivo transfection of plasmid with COL promoter was in the same range as after the treatment in control conditions (injection of distilled water followed by the application of electric pulses). Furthermore, this gene delivery was local, restricted to the skin, without any evident systemic shedding of IL-12. Such specific targeting of skin cells, observed with tissue-specific COL promoter, would improve the effectiveness and safety of cutaneous gene therapies and DNA vaccines. PMID- 25840833 TI - Gene Electrotransfer of Canine Interleukin 12 into Canine Melanoma Cell Lines. AB - A gene electrotransfer (GET) of interleukin 12 (IL-12) had already given good results when treating tumors in human and veterinary clinical trials. So far, plasmids used in veterinary clinical studies encoded a human or a feline IL-12 and an ampicillin resistance gene, which is not recommended by the regulatory agencies to be used in clinical trials. Therefore, the aim of the current study was to construct the plasmid encoding a canine IL-12 with kanamycin antibiotic resistance gene that could be used in veterinary clinical oncology. The validation of the newly constructed plasmid was carried out on canine malignant melanoma cells, which have not been used in GET studies so far, and on human malignant melanoma cells. Canine and human malignant melanoma cell lines were transfected with plasmid encoding enhanced green fluorescence protein at different pulse parameter conditions to determine the transfection efficiency and cell survival. The IL-12 expression of the most suitable conditions for GET of the plasmid encoding canine IL-12 was determined at mRNA level by the qRT-PCR and at protein level with the ELISpot assay. The obtained results showed that the newly constructed plasmid encoding canine IL-12 had similar or even higher expression capacity than the plasmid encoding human IL-12. Therefore, it represents a promising therapeutic plasmid for further IL-12 gene therapy in clinical studies for spontaneous canine tumors. Additionally, it also meets the main regulatory agencies' (FDA and EMA) criteria. PMID- 25840834 TI - Space: The Final Frontier for IR. AB - A manned mission to Mars requires advanced on-board medical capabilities to address medical incidents that may arise during long-duration interplanetary spaceflight. As this role does not exactly match that of any single specialty, the ideal choice of physician is not immediately obvious. In this work, we review the considerable challenges of providing medical care in the austere conditions of interplanetary space travel and explain why an interventional radiologist may be well-equipped to deliver diagnostic and therapeutic care within these severely constrained conditions. PMID- 25840835 TI - Percutaneous Cryoablation of Clinical T2 (> 7 cm) Renal Masses: Technical Considerations, Complications, and Short-Term Outcomes. AB - PURPOSE: To determine the technical success, safety, and preliminary clinical outcome of percutaneous cryoablation of large (> 7 cm) renal masses. MATERIALS AND METHODS: Twelve patients underwent percutaneous cryoablation for treatment of renal tumors measuring greater than 7 cm (clinical stage II, T2aN0M0) between 2004 and 2013. Median patient age was 75 years (range, 46-84 y), median Charlson comorbidity index was 5 (range, 4-9), and median maximal tumor diameter was 8.4 cm (range, 7.2-9.7 cm). Seven of the 12 patients underwent superselective intraarterial tumor embolization before cryoablation. Technical success, procedural complications, renal function, and oncologic and survival outcomes were evaluated for each patient. RESULTS: All cryoablation procedures were technically successful in a single treatment session, with no mortalities at 30 days. Two patients (17%) experienced major complications related to postprocedural hemorrhage. Median change in estimated glomerular filtration rate within 7 days following cryoablation treatment was 11 mL/min (range, 7-14 mL/min). One patient with baseline stage IV chronic kidney disease and a major bleeding complication required temporary dialysis in the periprocedural period. In 11 patients (92%) who had follow-up beyond 3 months after the procedure (mean, 19 mo; range, 4-49 mo), recurrence-free survival and overall survival rates at 2 years were 100% and 91%, respectively. CONCLUSIONS: Percutaneous cryoablation of large (> 7 cm) renal masses was technically successful, with effective preliminary clinical outcomes. However, major complications are more common with cryoablation of stage T2 tumors than is typically encountered with treatment of smaller stage T1 tumors. PMID- 25840836 TI - Radiofrequency ablation for neuroendocrine liver metastases: a systematic review. AB - To determine the efficacy of radiofrequency (RF) ablation in neuroendocrine tumor (NET) liver metastases. A systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eight studies were included (N = 301). Twenty-six percent of RF ablation procedures were percutaneous (n = 156), with the remainder conducted at surgery. Forty-eight percent of patients had a concomitant liver resection. Fifty-four percent of patients presented with symptoms, with 92% reporting symptom improvement following RF ablation (alone or in combination with surgery). The median duration of symptom improvement was 14-27 months. However, recurrence was common (63% 87%). RF ablation can provide symptomatic relief in NET liver metastases alone or in combination with surgery. PMID- 25840837 TI - Age-related microstructural differences quantified using myelin water imaging and advanced diffusion MRI. AB - Age-related microstructural differences have been detected using diffusion tensor imaging (DTI). Although DTI is sensitive to the effects of aging, it is not specific to any underlying biological mechanism, including demyelination. Combining multiexponential T2 relaxation (MET2) and multishell diffusion MRI (dMRI) techniques may elucidate such processes. Multishell dMRI and MET2 data were acquired from 59 healthy participants aged 17-70 years. Whole-brain and regional age-associated correlations of measures related to multiple dMRI models (DTI, diffusion kurtosis imaging [DKI], neurite orientation dispersion and density imaging [NODDI]) and myelin-sensitive MET2 metrics were assessed. DTI and NODDI revealed widespread increases in isotropic diffusivity with increasing age. In frontal white matter, fractional anisotropy linearly decreased with age, paralleled by increased "neurite" dispersion and no difference in myelin water fraction. DKI measures and neurite density correlated well with myelin water fraction and intracellular and extracellular water fraction. DTI estimates remain among the most sensitive markers for age-related alterations in white matter. NODDI, DKI, and MET2 indicate that the initial decrease in frontal fractional anisotropy may be due to increased axonal dispersion rather than demyelination. PMID- 25840838 TI - Early life lipid profile and metabolic programming in very young children. AB - BACKGROUND AND AIMS: Lipid derangements during early postnatal life may induce stable epigenetic changes and alter metabolic programming. We investigated associations between serum lipid profiles in very young children and DNA methylation of tumor necrosis factor-alpha (TNFalpha) and leptin (LEP). Secondly, we explored if the maternal serum lipid profile modifies DNA methylation in the child. METHODS AND RESULTS: In 120 healthy children at 17 months of age, DNA methylation of TNFalpha and LEP was measured in DNA derived from whole blood. Linear mixed models were used to calculate exposure-specific differences and associations. Total cholesterol in children was associated with decreased methylation of TNFalpha (-5.8%, p = 0.036), and HDL-cholesterol was associated with decreased methylation of both TNFalpha (-6.9%, p = 0.013) and LEP (-3.4%, p = 0.021). Additional adjustment for gestational age at birth, birth weight, sex, breastfeeding and educational level attenuated the effects, TNFalpha (-6.1%, p = 0.058) and LEP (-3.1%, p = 0.041). In mothers, HDL-cholesterol only was associated with decreased methylation of TNFalpha in the child (-8.7%, p = 0.001). CONCLUSION: Our data support the developmental origin of health and disease hypothesis by showing that total cholesterol and HDL-cholesterol levels in very young children are associated with epigenetic metabolic programming, which may affect their vulnerability for developing cardiovascular diseases in later life. PMID- 25840839 TI - Femtosecond laser will be the standard method for cataract extraction ten years from now. AB - The femtosecond laser is a new and developing technology for cataract surgery. This technology is approved for the capulotomy, primary incisions, astigmatic incisions, and lens fragmentation. The femtosecond laser has the potential to offer significant advantages over current phacoemulification and will be the standard method of cataract extraction in ten years. PMID- 25840840 TI - Systematic review of the impact of HbA1c on outcomes following surgery in patients with diabetes mellitus. AB - BACKGROUND & AIMS: Diabetes is a significant risk factor for surgical complications and also increases the prevalence of comorbidities, thereby increasing surgical risk. The aim of this systematic review was to establish the relationship between long-term preoperative glycemic control as measured by HbA1c and postoperative complications. METHODS: A systematic search was conducted to source articles published between 1980 and 2014 pertinent to the review. Full text articles were included if they met the pre-determined criteria as determined by two reviewers. Studies reporting the impact of preoperative HbA1c levels on postoperative outcomes in all disciplines of surgery were included. RESULTS: Twenty studies, including a total of 19,514 patients with diabetes mellitus from a range of surgical specialties, were suitable for inclusion. Preoperative glycemic control did not have a bearing on 30-day mortality. There were no significant differences in the incidence of stroke, venous thromboembolic disease, hospital readmission and ITU length of stay based on glycemic control. The majority of studies suggested no link between preoperative HbA1c levels and acute kidney injury or need for postoperative dialysis, dysrhythmia, infection not related to the surgical site and total hospital length of stay. The literature was highly variable with regards to myocardial events, surgical site infection and reoperation rates. CONCLUSIONS: Elevated preoperative HbA1c was not definitively associated with increased postoperative morbidity or mortality in patients with diabetes mellitus. The studies included in this review were relatively heterogeneous, predominantly retrospective, and often contained small patient numbers, suggesting that good quality evidence is necessary. PMID- 25840841 TI - Natural influence of season on follicular, luteal, and endocrinological turnover in Indian crossbred cows. AB - The study was aimed at investigating the effect of seasonal changes on follicular and luteal dynamics in vivo in normally cycling crossbred cows during summer and winter months of the year. Six healthy regularly cycling Jersey crossbred nonlactating pluriparous cows were used for the study. Follicular and luteal developmental pattern was studied every other day throughout the estrous cycle by scanning the ovaries during two periods of a year viz., hot season (April to June; n = 16) and cold season (December to February; n = 12). Plasma progesterone (P4) concentrations were measured on Days 0 (estrus), 6, and 12 of the estrous cycle. Among the 12 cycles studied during the cold season, 11 (91.7%) had three waves and one had two waves. Of 16 cycles studied during the hot season, eight (50%) had two waves, four (25%) had three waves, and the remaining four cycles had single (n = 2) and four waves (n = 2). High P4 concentrations during the midcycle would have suppressed the dominant follicle of the second follicular wave and induced the emergence of the third wave during the cold season. The first follicular wave (wave I) of the cycle emerged much earlier (Day 0.5 +/- 0.3) during the cold season than that in the hot season (Day 1.7 +/- 0.4). The ovulatory wave emerged significantly earlier during the hot season (Day 11.5 +/- 1.3) than in the cold season (Day 14.8 +/- 0.4), and hence, the growth phase of ovulatory follicle significantly increased during the former season (11.0 +/- 1.4 days) than the latter (5.8 +/- 0.2 days). The ovulatory follicle attained a significantly larger diameter (12.8 +/- 0.8 mm) to express the estrus during the hot season when compared to the cold season (11.3 +/- 0.4 mm), which might be indicative of alterations in steroidogenic activity within the follicular microenvironment. During the midphase of the cycle, a period critical for embryonic sustenance, the P4 level was significantly reduced in the hot months indicating suppression of luteal activity during hot period of the year. Thus, it could be concluded that increased incidence of two follicular waves associated with a prolonged growth phase of the ovulatory follicle, and altered luteal endocrine activity during the hot season might be associated with decreased fertility in crossbred cattle. PMID- 25840842 TI - Measurement of visceral fat on preoperative computed tomography predicts complications after sigmoid colectomy for diverticular disease. AB - BACKGROUND: Visceral and subcutaneous abdominal fat parameters have been associated with worse surgical outcomes in colorectal cancer but have not been investigated in diverticulitis. METHODS: Volumetric fat parameters were measured on preoperative computed tomography scans from 211 diverticulitis patients. Primary outcome was a serious postoperative complication (Clavien-Dindo grades 2 4). Variables including age, disease duration, American Society of Anesthesiology score, ostomy, immunosuppression, body mass index, and volumetric fat parameters were examined. SPSS was used for statistics. RESULTS: The serious postoperative complication rate was 12.7%. On univariate analysis, several factors including older age (P = .0001), ostomy creation (P = .02), higher visceral fat (VF, P = .01), emergent surgery (P = .05), and higher American Society of Anesthesiology score (P = .05) were associated with complications. On multivariate regression analysis, only VF was independently associated with complications. CONCLUSIONS: Diverticulitis patients with high VF are more likely to develop complications after sigmoidectomy. VF measurement may potentially be used as a tool to assist in surgical decision making and prediction of outcomes. PMID- 25840843 TI - Effect of in ovo injection of threonine on Mucin2 gene expression and digestive enzyme activity in Japanese quail (Coturnix japonica). AB - A total of 540 Japanese quail eggs were assigned to 9 treatments of 4 replicates to investigate the effect of in ovo injection of threonine (THR) on mucin2 (MUC2) mRNA expression and digestive enzyme activity. Treatments were (non-injected) eggs and those in ovo injected with saline (0.05 or 0.1 ml) with or without THR (5 mg/ml) in two sites (in or under the air sac). On hatch day, 0.05 ml in ovo injected (under the air sac: TUAS) hatchlings were divided into three groups based on NRC recommendations for THR, while all 0.1 ml in ovo injected chicks were removed due to low hatchability. The remaining treatments received the NRC recommended diet until day 10 post-hatch. Treatments had no effect on protease and amylase activities, while TUAS increased MUC2 gene expression. In conclusion, the in ovo injection of THR increased MUC2 gene expression but had no effect on enzyme activity. PMID- 25840844 TI - A generic methodology for the optimisation of sewer systems using stochastic programming and self-optimizing control. AB - The design of sewer system control is a complex task given the large size of the sewer networks, the transient dynamics of the water flow and the stochastic nature of rainfall. This contribution presents a generic methodology for the design of a self-optimising controller in sewer systems. Such controller is aimed at keeping the system close to the optimal performance, thanks to an optimal selection of controlled variables. The definition of an optimal performance was carried out by a two-stage optimisation (stochastic and deterministic) to take into account both the overflow during the current rain event as well as the expected overflow given the probability of a future rain event. The methodology is successfully applied to design an optimising control strategy for a subcatchment area in Copenhagen. The results are promising and expected to contribute to the advance of the operation and control problem of sewer systems. PMID- 25840845 TI - Global emergency medicine journal club: a social media discussion about the Age Adjusted D-Dimer Cutoff Levels To Rule Out Pulmonary Embolism trial. AB - STUDY OBJECTIVE: Annals of Emergency Medicine collaborated with an educational Web site, Academic Life in Emergency Medicine (ALiEM), to host an online discussion session featuring the 2014 Journal of the American Medical Association publication on the Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism (ADJUST-PE) trial by Righini et al. The objective is to describe a 14 day (August 25 to September 7, 2014) worldwide academic dialogue among clinicians in regard to 4 preselected questions about the age-adjusted D-dimer cutoff to detect pulmonary embolism. METHODS: Five online facilitators hosted the multimodal discussion on the ALiEM Web site, Twitter, and Google Hangout. Comments across the social media platforms were curated for this report, as framed by the 4 preselected questions, and engagement was tracked through various Web analytic tools. RESULTS: Blog and Twitter comments, as well as video expert commentary involving the ADJUST-PE trial, are summarized. The dialogue resulted in 1,169 page views from 391 cities in 52 countries on the ALiEM Web site, 502,485 Twitter impressions, and 159 views of the video interview with experts. A postdiscussion summary on the Journal Jam podcast resulted in 3,962 downloads in its first week of publication during September 16 to 23, 2014. CONCLUSION: Common themes that arose in the multimodal discussions included the heterogeneity of practices, D-dimer assays, provider knowledge about these assays, and prevalence rates in different areas of the world. This educational approach using social media technologies demonstrates a free, asynchronous means to engage a worldwide audience in scholarly discourse. PMID- 25840846 TI - Emergency Medicine and Critical Care Blogs and Podcasts: Establishing an International Consensus on Quality. AB - STUDY OBJECTIVE: This study identified the most important quality indicators for online educational resources such as blogs and podcasts. METHODS: A modified Delphi process that included 2 iterative surveys was used to build expert consensus on a previously defined list of 151 quality indicators divided into 3 themes: credibility, content, and design. Aggregate social media indicators were used to identify an expert population of editors from a defined list of emergency medicine and critical care blogs and podcasts. Survey 1 consisted of the quality indicators and a 7-point Likert scale. The mean score for each quality indicator was included in survey 2, which asked participants whether to "include" or "not include" each quality indicator. The cut point for consensus was defined at greater than 70% "include." RESULTS: Eighty-three percent (20/24) of bloggers and 90.9% (20/22) of podcasters completed survey 1 and 90% (18/20) of bloggers and podcasters completed survey 2. The 70% inclusion criteria were met by 44 and 80 quality indicators for bloggers and podcasters, respectively. Post hoc, a 90% cutoff was used to identify a list of 14 and 26 quality indicators for bloggers and podcasters, respectively. CONCLUSION: The relative importance of quality indicators for emergency medicine blogs and podcasts was determined. This will be helpful for resource producers trying to improve their blogs or podcasts and for learners, educators, and academic leaders assessing their quality. These results will inform broader validation studies and attempts to develop user-friendly assessment instruments for these resources. PMID- 25840847 TI - Brain motion and volume transmission: Keeping the interstice flowing. AB - Human brain undergoes two different kinds of movements: subtle pulsatile ones associated with the cardiac cycle and others of a greater magnitude related to breathing activity. These motions constitute a pumping force for the circulation of cerebrospinal fluid (CSF). Moreover, brain motion (BM) plays a fundamental role as a driving force for the interstitial and CSF flow of tracers. We hypothesize that BM is more than a mere consequence of cardiac and respiratory activities; that it would be part of a fundamental physiological mechanism by propelling the interstitial flow of messengers, a mechanism also known as 'non synaptic transmission' or 'volume transmission' (VT). Intracranial hypertension (ICH), a frequent complication of severe head trauma, is related to brain stiffness. Under this circumstance, not only brain perfusion could be at risk, but BM could be engaged as well. Decompressive craniectomy, presently indicated to reduce ICH refractory to medical treatment, could play a role in helping BM and VT. Once brain swelling is overcome, the closure of the cranial bone defect would ensure the recovery of the spatial and temporal patterns of BM. We discuss evidence supportive of the necessary role of a minimal and sequential BM for an adequate VT. PMID- 25840849 TI - Disseminated histoplasmosis caused by Histoplasma capsulatum var. duboisii in a non-HIV patient in Burkina Faso: Case report. AB - Histoplasmosis is a fungal infection due to Histoplasma capsulatum. The African form of this mycosis, caused by Histoplasma capsulatum var. duboisii, remains rare. We report a case of disseminated African histoplasmosis with skin, lymph nodes, bones and viscera localizations. The 22-year-old patient was HIV seronegative and was considered immunocompetent. The presence of Histoplasma capsulatum var duboisii in ulcerations and a nodule pus aspiration was confirmed by direct microscopic examination and by culture. The medical treatment was based on fluconazole. Even though a regression of the symptoms was observed, the patient died. In disseminated African histoplasmosis, an early laboratory diagnosis must be carried out for accurate treatment. PMID- 25840850 TI - A multiplex PCR method for detection of Aspergillus spp. and Mycobacterium tuberculosis in BAL specimens. AB - OBJECTIVE: The aim of this study was the detection of Aspergillus species and Mycobacterium tuberculosis together in bronchoalveolar lavage (BAL) using of multiplex PCR. MATERIAL AND METHODS: In this study, from September 2012 until June 2013, 100 bronchoalveolar lavage (BAL) specimens were collected from patients suspected of tuberculosis (TB). After the direct and culture test, multiplex PCR were utilized in order to diagnose Aspergillus species and M. tuberculosis. Phenol-chloroform manual method was used in order to extract DNA from these microorganisms. Aspergillus specific primers, M. tuberculosis designed primers and beta actin primers were used for multiplex PCR. RESULTS: In this study, by multiplex PCR method, Aspergillus species were identified in 12 samples (12%), positive samples in direct and culture test were respectively 11% and 10%. Sensitivity and specificity of this method in comparison to direct test were respectively 100% and 98.8%, also sensitivity and specificity of this method in comparison to culture test were respectively 100% and 97.7%. In this assay, M. tuberculosis was identified in 8 samples (8%). Mycobacterium-positive samples in molecular method, direct and culture test were respectively 6%, 5% and 7%. Sensitivity and specificity of PCR method in comparison to direct test were 80% and 97.8% also sensitivity and specificity of this method in comparison to culture test was 71.4% and 98.9%. CONCLUSION: In the present study, multiplex PCR method had higher sensitivity than direct and culture test in order to identify and detect Aspergillus, also this method had lower sensitivity for identification of M. tuberculosis, suggesting that the method of DNA extraction was not suitable. PMID- 25840848 TI - Telomere length variation: A potential new telomere biomarker for lung cancer risk. AB - OBJECTIVES: In this report the associations between telomere length variation (TLV), mean telomere length in blood lymphocytes and lung cancer risk were examined. MATERIALS AND METHODS: The study design is case-control. Cases (N=191) were patients newly diagnosed with histologically confirmed non-small cell lung cancer. Controls (N=207) were healthy individuals recruited from the same counties as cases and matched to cases on age and gender. Telomere fluorescent in situ hybridization was used to measure telomere features using short-term cultured blood lymphocytes. Logistic regression was used to estimate the strength of association between telomere features and lung cancer risk. RESULTS: Telomere length variation across all chromosomal ends was significantly associated with lung cancer risk; adjusted odds ratios 4.67 [95% confidence interval (CI): 1.46 14.9] and 0.46 (95% CI: 0.25-0.84) for younger (age<=60) and older (age>60) individuals, respectively. TLV and mean telomere length jointly affected lung cancer risk: when comparing individuals with short telomere length and high TLV to those with long telomere length and low TLV, adjusted odd ratios were 8.21 (95% CI: 1.71-39.5) and 0.33 (95% CI: 0.15-0.72) for younger and older individuals, respectively. CONCLUSIONS: TLV in blood lymphocytes is significantly associated with lung cancer risk and the associations were modulated by age. TLV in combination with mean telomere length might be useful in identifying high risk population for lung cancer computerized tomography screening. PMID- 25840851 TI - When you can't see the wood for the trees. Mucor circinelloides: A rare case of primary cutaneous zygomycosis. AB - A patient with refractory diffuse lymphoma treated for pulmonary invasive aspergillosis developed a concomitant primary cutaneous mucormycosis. The mucormycete was identified by sequencing as Mucor circinelloides. This case confirms the importance of a rapid pathogen diagnosis in immunocompromised patients and the usefulness of molecular methods for identification of rare fungal species. PMID- 25840852 TI - The prevalence of umbilical and epigastric hernia repair: a nationwide epidemiologic study. AB - PURPOSE: Umbilical and epigastric hernia repair are common surgical procedures; however, the nationwide gender and age-specific prevalence of these repairs is unknown, and this knowledge could form the basis for new studies. METHODS: A nationwide register-based study covering all people living in Denmark on December 31st, 2010 was performed. Within this population all umbilical and epigastric hernia repairs from January 1st, 2006 to December 31st, 2010 were identified using data from the Danish National Hospital Register, and 5-year prevalence estimates were calculated. RESULTS: The study population covered 5,639,885 persons (49 % males). A total of 10,107 patients (68 % males) were operated for an umbilical hernia and 2412 patients (55 % males) were operated for an epigastric hernia. The age-specific 5-year prevalence differed for both hernia types. The highest 5-year prevalence of umbilical hernia repairs was seen in males aged 60-70 years with a 5-year prevalence of 0.53 % (95 % CI 0.51-0.56 %) and the highest age-specific 5-year prevalence of epigastric hernia repair was seen in 40-50 year females with a 5-year prevalence of 0.086 % (95 % CI 0.077 0.095 %). CONCLUSION: The gender and age-specific 5-year prevalence of umbilical and epigastric hernia repair differed in a nationwide population. PMID- 25840853 TI - Cell salvage for vaginal delivery - is it time we considered it? PMID- 25840854 TI - Desultory propriospinal myoclonus after epidural analgesia in a healthy parturient. PMID- 25840855 TI - Obstetric anaesthesia 2015: torquay. PMID- 25840856 TI - Coagulopathy and placental abruption: changing management with ROTEM-guided fibrinogen concentrate therapy. PMID- 25840858 TI - Clinical application of platelet-rich fibrin as the sole grafting material in maxillary sinus augmentation. PMID- 25840857 TI - The 100-genomes strains, an S. cerevisiae resource that illuminates its natural phenotypic and genotypic variation and emergence as an opportunistic pathogen. AB - Saccharomyces cerevisiae, a well-established model for species as diverse as humans and pathogenic fungi, is more recently a model for population and quantitative genetics. S. cerevisiae is found in multiple environments-one of which is the human body-as an opportunistic pathogen. To aid in the understanding of the S. cerevisiae population and quantitative genetics, as well as its emergence as an opportunistic pathogen, we sequenced, de novo assembled, and extensively manually edited and annotated the genomes of 93 S. cerevisiae strains from multiple geographic and environmental origins, including many clinical origin strains. These 93 S. cerevisiae strains, the genomes of which are near reference quality, together with seven previously sequenced strains, constitute a novel genetic resource, the "100-genomes" strains. Our sequencing coverage, high quality assemblies, and annotation provide unprecedented opportunities for detailed interrogation of complex genomic loci, examples of which we demonstrate. We found most phenotypic variation to be quantitative and identified population, genotype, and phenotype associations. Importantly, we identified clinical origin associations. For example, we found that an introgressed PDR5 was present exclusively in clinical origin mosaic group strains; that the mosaic group was significantly enriched for clinical origin strains; and that clinical origin strains were much more copper resistant, suggesting that copper resistance contributes to fitness in the human host. The 100-genomes strains are a novel, multipurpose resource to advance the study of S. cerevisiae population genetics, quantitative genetics, and the emergence of an opportunistic pathogen. PMID- 25840859 TI - A geometric morphometric analysis of hominin lower molars: Evolutionary implications and overview of postcanine dental variation. AB - Lower molars have been extensively studied in the context of hominin evolution using classic and geometric morphometric analyses, 2D and 3D approaches, evaluations of the external (outer enamel surface) and internal anatomy (dentine, pulp chamber, and radicular canals), and studies of the crown and root variation. In this study, we present a 2D geometric morphometric analysis of the crown anatomy of lower first, second, and third molars of a broad sample of hominins, including Pliocene and Lower, Middle, and Upper Pleistocene species coming from Africa, Asia, and Europe. We show that shape variability increases from first to second and third molars. While first molars tend to retain a relatively stable 5 cusped conformation throughout the hominin fossil record, second and third molars show marked distal reductions in later Homo species. This trend to distal reduction is similar to that observed in previous studies of premolars and upper second and third molars, and points to a correlated reduction of distal areas across the whole postcanine dentition. Results on lower molar variation, as well as on other postcanine teeth, show certain trends in European Pleistocene populations from the Atapuerca sites. Middle Pleistocene hominins from Sima de los Huesos show Neanderthal affinities and strong dental reduction, especially in the most distal molars. The degree of dental reduction in this population is stronger than that observed in classic Neanderthals. Homo antecessor hominins from Gran Dolina-TD6 have primitive lower teeth that contrast with their more derived upper teeth. The evolutionary implications of these dental affinities are discussed in light of recent paleogenetic studies. PMID- 25840860 TI - Minimally invasive corticotomy in orthodontics: a new technique using a CAD/CAM surgical template. AB - Accelerating orthodontic tooth movement is a topical issue. Despite the different techniques described in the literature, the corticotomy is the only effective and safe means of accelerating orthodontic tooth movement. Although effective, the corticotomy presents significant postoperative discomfort. The aggressive nature of these particular methods, related to the elevation of mucoperiosteal flaps and to the length of the surgery, has resulted in reluctance to proceed with this technique among both patients and the dental community. To overcome the disadvantages of the corticotomy, this technical note describes an innovative, minimally invasive, flapless procedure combining piezoelectric surgical cortical micro-incisions with the use of a 3D Printed CAD/CAM surgical guide. PMID- 25840861 TI - In vitro biomechanical comparison of six different fixation methods following 5 mm sagittal split advancement osteotomies. AB - The sagittal split ramus osteotomy (SSRO) is a surgical technique used widely to treat many congenital and acquired mandibular discrepancies. Stabilization of the osteotomy site and the potential for skeletal relapse after the procedure are still major problems. The aim of this study was to compare the mechanical stability of six methods of rigid fixation in SSRO using a biomechanical test model. Sixty polyurethane replicas of human hemimandibles were divided into six groups. In group I, the osteotomies were fixed with two four-hole titanium miniplates; in group II, with one four-hole miniplate; in group III, with one four-hole miniplate+a bicortical screw; in group IV, with a grid miniplate; in group V, with a four-hole locking miniplate; and in group VI, with a six-hole miniplate. A linear load in the premolar region was applied to the hemimandibles. The resistance forces (N) needed to displace the distal segment by 1, 3, and 5mm were recorded and the data transmitted from the load cell to a computer. One-way analysis of variance with Tukey's post hoc test was performed to compare the means between groups. For the three displacement conditions, there was a strong tendency for the 2.0-mm plate+screw and the grid plate to have higher values. PMID- 25840862 TI - Epidemiological and statistical considerations for interpreting and communicating oncology clinical trials. AB - The use of randomised controlled trials (RCTs) in veterinary oncological research and practice is increasing as is the number of relevant scientific publications. While clear guidelines exist for the reporting of RCTs, a thorough understanding of statistical and epidemiological concepts is required in order to accurately interpret and then impart the results of such trials, and to make balanced decisions regarding the uptake of published findings. This review presents the most important epidemiological and statistical considerations that are needed in order to interpret and communicate with confidence the results of oncology clinical trials. PMID- 25840863 TI - Genetics of bovine abomasal displacement. AB - Displacement of the abomasum (DA) is a common inherited condition in Holstein cows. This article reviews the genetics of DA including risk factors, genetic parameters and molecular genetic results. Breeds other than Holsteins affected by DA include Guernseys, Jerseys, Brown Swiss, Ayrshires and Simmental-Red Holsteins. In most DA cases, left displacements of the abomasum (LDA) are seen. Lactation incidence rates are higher for DA in first lactation Holsteins compared to later lactations. For Holstein cows, heritability estimates for DA are between 0.03 and 0.53. Genetic correlation estimates among DA and milk production traits range from positive to negative. Genome-wide significant genomic regions associated with LDA are located on bovine chromosomes (BTA) 1, 3, 11, 20 and 23. Motilin-associated single nucleotide polymorphisms on BTA23 exhibit a functional relationship with LDA. Pathways for deposition of calcium, insulin-dependent diabetes mellitus and synaptic transmission are significantly related to LDA in Holsteins. Deciphering the DA-associated genomic regions and genes may be an important step in the quest to understand the underlying disease-causing mechanisms and in unravelling mutations with a causal relationship to DA. PMID- 25840864 TI - [Facilitators and barriers for older people to take part in fall prevention programs: A review of literature]. AB - BACKGROUND: Falling is the leading cause of accidental death after 65. Fall prevention programs are effective, but they involve few seniors. This article reviewed the literature on facilitators and barriers to participate in such programs. METHODS: A literature review was conducted to identify documents in English, German and French published between 1990 and May 2012. Medline database, PsychInfo, Psychological and behavioral sciences and Francis were systematically searched, as were the bibliographies and some journals of public health, gerontology and social sciences. Of 462 documents found, 19 were selected and analyzed. RESULTS: Of the 19 articles selected, 12 were on qualitative studies and 7 on literature reviews. Among the barriers to participation in falls prevention programs, documents highlighted the perception of fall as an inevitable event, the inadequate timing of prevention intervention and material difficulties. Conversely, being referred to prevention intervention by a professional, being convinced by the social benefits of interventions and the adequacy of interventions to the needs of beneficiaries were factors facilitating the participation and compliance of the elderly. CONCLUSION: This literature review identified three major issues to consider when implementing sustainable and acceptable fall prevention programs: choice of the referring agent, and social representations of falling. PMID- 25840865 TI - Attitudes towards euthanasia among Greek intensive care unit physicians and nurses. AB - OBJECTIVES: To investigate the attitudes of Greek intensive care unit (ICU) medical and nursing staff towards euthanasia. BACKGROUND: ICU physicians and nurses deal with end-of-life dilemmas on a daily basis. Therefore, the exploration of their stances on euthanasia is worthwhile. METHODS: This was a descriptive quantitative study conducted in three ICUs in Athens. The convenience sample included 39 physicians and 107 nurses. RESULTS: Of respondents, 52% defined euthanasia inaccurately, as withholding or withdrawal of treatment, while 15% ranked limitation of life-support among the several forms of euthanasia, together with active shortening of the dying process and physician - assisted suicide. Only one third of participants defined euthanasia correctly. While 59% of doctors and 64% of nurses support the legalization of active euthanasia, just 28% and 26% of them, respectively, agree with it ethically. CONCLUSIONS: Confusion prevails among Greek ICU physicians and nurses regarding the definition of euthanasia. The majority of staff disagrees with active euthanasia, but upholds its legalization. PMID- 25840866 TI - Spatial and seasonal characteristics of dissolved heavy metals in the east and west Guangdong coastal waters, South China. AB - Heavy metal concentrations and physicochemical parameters in seawater were measured in Guangdong coastal waters, South China. Results showed that the concentrations and distribution of heavy metals varied spatially and seasonally. Generally, heavy metal concentrations in the east regions were higher than in the west. Concentrations of Pb, Zn, Cd and Cr in wet seasons were generally higher than in dry seasons owing to the seasonal differences of the river discharge, rainfall and seawater intrusion. Principal component (PC) analysis showed that PC1, PC2 and PC3 in the east were correlated to Pb+Cr+Zn+Cd, As+Cd and Cu, respectively, and they were correlated to Pb+Cr, Zn+Cu+Cd and As+Cu, respectively, in the west. That was maybe due to the differences of local heavy metal sources. The anthropogenic activities contributed more to the main sources of heavy metals, and contamination factors indicated that Zn and Pb pollution was serious in study area. PMID- 25840867 TI - Distributions and sources of volatile chlorocarbons and bromocarbons in the Yellow Sea and East China Sea. AB - Six volatile halogenated organic compounds (VHOC), namely, chloroform, carbon tetrachloride, trichloroethylene, bromodichloromethane, dibromochloromethane, and bromoform, were studied in the Yellow Sea and East China Sea from April to May, 2009. The spatial variability of these VHOC was influenced by various factors, including anthropogenic inputs, biogenic production and complicated hydrographic features such as Changjiang Diluted Water, Yellow Sea Cold Water Mass, and Kuroshio Current. Diurnal study results showed that factors such as solar irradiation, biological activity, and tide affected the abundance of these VHOC. Correlation analyses revealed that bromodichloromethane was positively correlated with chlorophyll a in surface seawater. Principal component analysis suggested that chlorinated compounds like carbon tetrachloride originated from anthropogenic sources whereas brominated compounds such as bromodichloromethane originated from biogenic sources. Sources of other chlorinated and brominated compounds may not be governed by biological processes in the marine environment. PMID- 25840868 TI - Trophic implications and faunal resilience following one-off and successive disturbances to an Amphibolis griffithii seagrass system. AB - Disturbances in seagrass systems often lead to considerable loss of seagrass fauna. We examined the capacity for seagrass fauna, across multiple trophic levels, to recover from disturbances, using empirical and modelling techniques. Model outputs, using Ecosim with Ecopath (EwE), were consistent with the results of field investigations, highlighting the models robustness. Modelled outcomes suggest second and third order consumers are likely to be negatively effected by disturbances in the seagrass canopy. Particularly piscivores, which once disturbed, appear unlikely to recover following severe declines in primary productivity. EwE also revealed the complex interaction between the duration and intensity of disturbances on seagrass fauna, which may differentially affect higher order consumers. Further, modelling predicted a variable capacity of higher order consumers to recover from successive disturbances, suggesting taxa with comparatively fast reproductive cycles and short generation terms would be more resilient than taxa with comparatively long generation terms and slow reproductive cycles. PMID- 25840870 TI - Relative bioavailability and toxicity of fuel oils leaking from World War II shipwrecks. AB - The Norwegian Authorities have classified 30 WWII shipwrecks to have a considerable potential for pollution to the environment, based on the location and condition of the wreck and the types and amount of fuel. Oil thus far has been removed from eight of these shipwrecks. The water accommodated fractions of oils from two British wrecks and two German wrecks have been studied with special emphasis on chemistry and biological effects (algae growth (Skeletonema costatum) and copepod mortality (Calanus finmarchicus)). Chemical analyses were also performed on three additional German wreck oils. The results from these studies show that the coal based oils from German WWII shipwrecks have higher toxicity to marine organisms than the mineral oils from the British shipwrecks. The potential for higher impact on the marine environment of coal based oils has resulted in an altering of the priority list for oil recovery from WWII wrecks by the authorities. PMID- 25840869 TI - A predictive model for microbial counts on beaches where intertidal sand is the primary source. AB - Human health protection at recreational beaches requires accurate and timely information on microbiological conditions to issue advisories. The objective of this study was to develop a new numerical mass balance model for enterococci levels on nonpoint source beaches. The significant advantage of this model is its easy implementation, and it provides a detailed description of the cross-shore distribution of enterococci that is useful for beach management purposes. The performance of the balance model was evaluated by comparing predicted exceedances of a beach advisory threshold value to field data, and to a traditional regression model. Both the balance model and regression equation predicted approximately 70% the advisories correctly at the knee depth and over 90% at the waist depth. The balance model has the advantage over the regression equation in its ability to simulate spatiotemporal variations of microbial levels, and it is recommended for making more informed management decisions. PMID- 25840871 TI - The nutrient, total petroleum hydrocarbon and heavy metal contents in the seawater of Bohai Bay, China: Temporal-spatial variations, sources, pollution statuses, and ecological risks. AB - Seawater samples collected between 2007 and 2012 were determined the concentrations of nutrient (DIN and DIP), total petroleum hydrocarbon (TPH), and six different heavy metals (As, Cu, Zn, Pb, Cd and Hg). The DIN, DIP, TPH, Pb, and Cd concentrations decreased from 2007 to 2009 or 2010 and increased after 2010. However, the Hg and Cu concentrations increased from 2007 to 2012. In contrast, the As and Zn gradually decreased during the study period. All of the pollutant concentrations gradually decreased from the shoreline to the offshore sites. PCA result showed that urban and port areas, agriculture, and atmospheric deposition were the main sources of pollutants in the bay. Although most of the pollutants were present at concentrations bellow the highest seawater quality standards in China, eutrophication was a risk in Bohai Bay. In addition, DIN was the main pollutant and was responsible for the eutrophication risk in Bohai Bay. PMID- 25840872 TI - Preoperative Mapping in Unicompartmental Knee Arthroplasty Using Computed Tomography Scans Is Associated with Radiation Exposure and Carries High Cost. AB - Robotic-assisted knee arthroplasty with some systems requires the use of computed tomography (CT) scans. The associated radiation dose has not been studied. The effective dose (ED, mSv) of radiation was calculated for 236 preoperative CT scans used for planning of robotic assisted surgery. The mean ED was 4.8+/-3.0 mSv. There was a 3-fold difference in ED between institutions. One or more additional CT scans were obtained in 25% of patients, amounting to a cumulative ED per patient up to 103 mSv. Preoperative CT is a disadvantage of some robotic assisted knee arthroplasty systems due to additional cost and radiation exposure. Newer image-free robotic technologies are an alternative to CT-dependent surgery if accuracy and safety are not compromised. PMID- 25840874 TI - Diagnostic delay in Crohn's disease is associated with increased rate of abdominal surgery: A retrospective study in Chinese patients. AB - BACKGROUND: Diagnostic delay of Crohn's disease presents a challenge, and may increase the abdominal surgery rate. There have been no reports regarding diagnostic delay in Chinese patients. AIMS: We aimed to evaluate the impact of diagnostic delay on outcomes of Chinese Crohn's disease patients, and identify potential risk factors for the delay. METHODS: Altogether, 343 Crohn's disease patients from our hospital were retrospectively included. We assessed the effects of diagnostic delay on the outcomes, and identified the underlying risk factors. RESULTS: Diagnostic interval was defined as the interval between the first symptoms and the diagnosis of Crohn's disease. Diagnostic delay was defined according to the time interval in which the 76th to 100th percentiles of patients were diagnosed. The rates of subsequent surgery for diagnostic-delay and non diagnostic-delay patients were 84.7% and 62.4%, respectively (odds ratio=1.108, P<0.0001). We found statistical differences between the two groups regarding age >40 years at diagnosis (35.3% versus 18.2%, P=0.004), basic educational level (48.2% versus 30.6%, P=0.005), and no family history of Crohn's disease (0 versus 1.6%, P=0.045). CONCLUSIONS: Diagnostic delay of Crohn's disease was significantly associated with increased rates of intestinal surgery. Risk factors for diagnostic delay were age >40 years at diagnosis, basic educational level, and no family history of Crohn's disease. PMID- 25840873 TI - Comparative metabolic profiling reveals the key role of amino acids metabolism in the rapamycin overproduction by Streptomyces hygroscopicus. AB - Rapamycin is an important natural macrolide antibiotic with antifungal, immunosuppressive and anticancer activity produced by Streptomyces hygroscopicus. In this study, a mutant strain obtained by ultraviolet mutagenesis displayed higher rapamycin production capacity compared to the wild-type S. hygroscopicus ATCC 29253. To gain insights into the mechanism of rapamycin overproduction, comparative metabolic profiling between the wild-type and mutant strain was performed. A total of 86 metabolites were identified by gas chromatography-mass spectrometry. Pattern recognition methods, including principal component analysis, partial least squares and partial least squares discriminant analysis, were employed to determine the key biomarkers. The results showed that 22 potential biomarkers were closely associated with the increase of rapamycin production and the tremendous metabolic difference was observed between the two strains. Furthermore, metabolic pathway analysis revealed that amino acids metabolism played an important role in the synthesis of rapamycin, especially lysine, valine, tryptophan, isoleucine, glutamate, arginine and ornithine. The inadequate supply of amino acids, or namely "nitrogen starvation" occurred in the mutant strain. Subsequently, the exogenous addition of amino acids into the fermentation medium of the mutant strain confirmed the above conclusion, and rapamycin production of the mutant strain increased to 426.7 mg/L after adding lysine, approximately 5.8-fold of that in the wild-type strain. Finally, the results of real-time PCR and enzyme activity assays demonstrated that dihydrodipicolinate synthase involved with lysine metabolism played vital role in the biosynthesis of rapamycin. These findings will provide a theoretical basis for further improving production of rapamycin. PMID- 25840875 TI - Target Controlled Infusion for non-anaesthesiologist propofol sedation during gastrointestinal endoscopy: The first double blind randomized controlled trial. AB - BACKGROUND: Target Controlled Infusion is a sophisticated tool for providing optimal sedation regimen avoiding under or oversedation in gastrointestinal endoscopy. AIMS: To compare standard moderate sedation vs. non-anaesthesiologist administered propofol sedation during gastrointestinal endoscopy. METHODS: Randomized controlled trial of 70 consecutive colonoscopies and 70 consecutive esophagogastroduodenoscopies (EGD). Standard group (n=70), received fentanyl (1 MUg/kg)+midazolam (0.03-0.04 mg/kg) or midazolam only; propofol group (n=70), received fentanyl (1 MUg/kg)+propofol Target Controlled Infusion (1.2-1.6 MUg/ml) or propofol Target Controlled Infusion only. Discharge time, endoscopist satisfaction and patient satisfaction were recorded in all endoscopies. RESULTS: Colonoscopy: discharge time was significantly shorter in the propofol than the standard group (1.1 +/- 0.3 vs. 5 +/- 10.2 min, respectively; P=0.03). Endoscopist satisfaction was significantly higher (98.3 +/- 11.4/100 vs. 87.2+/ 12/100; P=0.001); patient satisfaction was significantly higher (95 +/- 9.3/100 vs. 85.5 +/- 14.4/100; P=0.002) in the propofol compared to the standard group. EGD: discharge time was not significantly different in the propofol and standard groups (1.1 +/- 0.7 vs. 3.9 +/- 9.2 min, respectively; P=0.146). Endoscopist satisfaction was significantly higher (92.7 +/- 14.3/100 vs. 82.8 +/- 21.2/100; P=0.03); patient satisfaction was significantly higher (93.8 +/- 18.2/100 vs. 76.5 +/- 25.2/100; P=0.003). In the propofol group 94.3% of patients vs. 71.4% of patients in standard group asked to receive the same sedation in the future (P=0.021). CONCLUSION: Target Controlled Infusion is a promising method for non anaesthesiologist-administered propofol sedation. PMID- 25840876 TI - Secondary sclerosing cholangitis in patients with drug-induced liver injury. AB - BACKGROUND: Secondary sclerosing cholangitis has clinical features similar to primary sclerosing cholangitis but originates from a known pathological entity. Secondary sclerosing cholangitis has not been investigated in patients with drug induced liver injury. METHODS: Overall 102 patients diagnosed with drug-induced liver injury were identified and magnetic resonance cholangiopancreatography images of 25 patients were reviewed. RESULTS: Ten patients (all females) out of 102 had confirmed features of secondary sclerosing cholangitis on biliary imaging. Overall 70% of patients with sclerosing cholangitis had jaundice vs. 25% without sclerosing cholangitis (p<0.01). All sclerosing cholangitis patients had cholestatic/mixed type of liver injury and compared with patients with cholestatic/mixed liver injury without confirmed abnormal MRCP (n=52), they also had more frequently jaundice, 70% vs. 23% (p=0.0065), higher peak alkaline phosphatase 551 (352-716) vs. 329 (202-543) (p=0.055) and longer time to resolution of liver injury 152 days (123-353) vs. 62 days (36-91) than patients without confirmed sclerosing cholangitis (p<0.0009). CONCLUSIONS: Our results indicate that drugs can lead to bile duct injury visualized on imaging. This should be a part of the differential diagnoses of secondary sclerosing cholangitis. These patients were more likely to present with jaundice and longer recovery of liver injury than other patients with cholestatic/mixed type of drug induced liver injury. PMID- 25840877 TI - Extreme volume expansion of a vestibular schwannoma due to intratumoral hemorrhage after gamma knife radiosurgery. AB - A 48-year-old man with right hemi-facial palsy and cerebellar ataxia was referred to our hospital. Three years and 10 months earlier he had undergone gamma knife radiosurgery (GKRS) at the referring hospital for an 18 mm right vestibular schwannoma. Slight tumor enlargement had been observed on MRI performed at the referring hospital 3 years after the GKRS. On close follow-up after another 6 months an MRI showed an obvious enlargement of the tumor. An MRI on admission revealed an iso-intense mass lesion measuring 36 mm in maximum diameter at the right cerebellopontine angle. A two stage surgery was conducted using a retrosigmoid approach because bleeding from the tumor wall was difficult to control intraoperatively during the first operation. At the second operation, the majority of the tumor capsule had converted to necrotic tissue. A large hematoma cavity was present inside the tumor capsule which explained the rapid increase in size over a short period of time. Near total removal was achieved. Histopathological examination revealed massive intratumoral hemorrhage within a typical vestibular schwannoma with no malignancy. The complication of intratumoral hemorrhage is very rare and the utility of stereotactic radiation surgery/therapy, including GKRS, for vestibular schwannoma is well known. However, we must emphasize that careful follow-up is still required, even after several years. PMID- 25840878 TI - Clinical outcome and complications of gamma knife radiosurgery for intracranial arteriovenous malformations. AB - We sought to evaluate the outcome of intracranial arteriovenous malformation (AVM) treated with gamma knife radiosurgery (GKRS) (Elekta, Stockholm, Sweden) as a primary treatment as well as an adjunct therapy. GKRS has emerged as an important treatment option for intracranial AVM. However, the long term outcome of GKRS on AVM is not well understood. We performed a retrospective review of 85 patients with AVM from 2000-2012 who received GKRS. Out of 85 patients, 13 had undergone prior embolization. The study population was monitored clinically and radiographically after GKRS treatment. Outcome following GKRS for intracranial AVM showed significant variations in nidus obliteration (obliteration in 67 [79%] patients and increase of nidus size on MRI in 18 [21%] patients). The median time to nidus obliteration was 31 months. Overall two (2.3%) patients had intracranial bleeding and the annual bleeding risk was 1.6% after GKRS. Predictive factors for obliteration of the nidus in patients with AVM were low AVM score, Spetzler Martin grade I-III and female sex. Seventeen (20%) and one (1.17%) patients underwent repeat GKRS and resection, respectively, after initial GKRS, due to increased size of the nidus and GKRS related cyst formation. Thus, GKRS offers a high obliteration rate of AVM, low risk of intracranial bleeding and neurological morbidity, both as primary modality and as an adjunctive treatment. Therefore, GKRS is an effective treatment option for new patients with AVM as well as an adjuvant therapy in patients with recurrent AVM. PMID- 25840879 TI - A predictive coding framework for rapid neural dynamics during sentence-level language comprehension. AB - There is a growing literature investigating the relationship between oscillatory neural dynamics measured using electroencephalography (EEG) and/or magnetoencephalography (MEG), and sentence-level language comprehension. Recent proposals have suggested a strong link between predictive coding accounts of the hierarchical flow of information in the brain, and oscillatory neural dynamics in the beta and gamma frequency ranges. We propose that findings relating beta and gamma oscillations to sentence-level language comprehension might be unified under such a predictive coding account. Our suggestion is that oscillatory activity in the beta frequency range may reflect both the active maintenance of the current network configuration responsible for representing the sentence-level meaning under construction, and the top-down propagation of predictions to hierarchically lower processing levels based on that representation. In addition, we suggest that oscillatory activity in the low and middle gamma range reflect the matching of top-down predictions with bottom-up linguistic input, while evoked high gamma might reflect the propagation of bottom-up prediction errors to higher levels of the processing hierarchy. We also discuss some of the implications of this predictive coding framework, and we outline ideas for how these might be tested experimentally. PMID- 25840880 TI - Adolescent Electronic Cigarette Use: Associations With Conventional Cigarette and Hookah Smoking. AB - INTRODUCTION: The emerging trends and rapid growth of electronic cigarettes (e cigarettes) among adolescents are being monitored closely. The trends are critical as policy to prevent uptake among adolescents is considered. The purpose of this study is to describe the prevalence of e-cigarette use and potential correlates for use. Associations between e-cigarettes, cigarettes, and hookah are assessed. METHODS: This study used data from the 2013 Florida Youth Tobacco Survey. Prevalence estimates were calculated in 2014 and differences were determined based on CIs. Adjusted logistic regression models were used to identify correlates of e-cigarette use among participants based on demographic and other tobacco products used. RESULTS: There were no sex differences in middle school, whereas male high school students reported higher use than their female counterparts. Cigarette smoking and hookah use were significantly associated with ever and current e-cigarette use among both middle and high school students. CONCLUSIONS: Although e-cigarettes are being assessed as a potential replacement product for traditional tobacco, evidence from this study indicates the possibility of multiple product use among adolescents. E-cigarettes are not only associated with traditional cigarettes, but also with hookahs, a similar emerging product that offer tobacco flavors that may appeal to adolescents. Notably, many e-cigarette users also reported no cigarette or hookah use. PMID- 25840881 TI - A vascular lesion mimicking a primitive brain tumour in a patient examined by (18)F-choline PET/CT and MRI. PMID- 25840882 TI - Classification and Epidemiology of Mammary Tumours in Pet Rabbits (Oryctolagus cuniculus). AB - Mammary tumours are common in pet rabbits; however, published studies are predominantly derived from laboratory and meat rabbits. This study reports basic data on type and location of 119 separate tumours from 109 pet rabbits. The animals were aged 2-14 years (mean 5.5 years) and all 90 rabbits of known gender were female. Cranial and caudal mammary glands were affected equally. The majority of lesions (n = 105) were classified as carcinomas with 32 tubular, 16 papillary, 12 tubulopapillary, 11 solid, nine adenosquamous, nine comedo type, five complex, four ductal, three cribriform, three anaplastic and one spindle cell carcinoma. Twelve percent of the lesions were benign, with eight intraductal papillary adenomas, three simple tubular adenomas and one complex adenoma. One non-neoplastic lesion was found in the form of cystic duct ectasia. PMID- 25840883 TI - A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion. AB - Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion. PMID- 25840884 TI - Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference. AB - On September 16 and 17, 2014, the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI) inaugurated their Conference on Evolving Product Quality. The Conference is conceived as an annual forum in which scientists from regulatory agencies, industry, and academia may exchange viewpoints and work together to advance pharmaceutical quality. This Conference Summary Report highlights key topics of this conference, including (1) risk-based approaches to pharmaceutical development, manufacturing, regulatory assessment, and post-approval changes; (2) FDA-proposed quality metrics for products, facilities, and quality management systems; (3) performance-based quality assessment and clinically relevant specifications; (4) recent developments and implementation of continuous manufacturing processes, question-based review, and European Medicines Agency (EMA)-FDA pilot for Quality-by-Design (QbD) applications; and (5) breakthrough therapies, biosimilars, and international harmonization, focusing on ICH M7 and Q3D guidelines. The second FDA/PQRI conference on advancing product quality is planned for October 5-7, 2015. PMID- 25840886 TI - Discovery of 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide analogs as new RORC modulators. AB - Structure-based and pharmacophore-based virtual screening in combination with combinatorial chemistry and X-ray crystallography led to the discovery of a new class of benzothiadiazole dioxide analogs with functional activity as RORC inverse agonists. The early RORC SAR compound 14 exhibited RORC inhibition in a cell based reporter gene assay of 5.7 MUM and bound to RORC with an affinity of 1.6 MUM in a fluorescence polarization assay displacing a ligand binding site probe. Crystallography confirmed the binding mode of the compound in the ligand binding domain displaying the engagement of a novel sub pocket close to Ser404. Subsequent optimization yielded compounds with enhanced RORC inverse agonist activity. The most active compound 19 showed an IC50 of 440 nM in a human PBMC assay. PMID- 25840885 TI - Multidrug Resistance Proteins (MRPs) and Cancer Therapy. AB - The ATP-binding cassette (ABC) transporters are members of a protein superfamily that are known to translocate various substrates across membranes, including metabolic products, lipids and sterols, and xenobiotic drugs. Multidrug resistance proteins (MRPs) belong to the subfamily C in the ABC transporter superfamily. MRPs have been implicated in mediating multidrug resistance by actively extruding chemotherapeutic substrates. Moreover, some MRPs are known to be essential in physiological excretory or regulatory pathways. The importance of MRPs in cancer therapy is also implied by their clinical insights. Modulating the function of MRPs to re-sensitize chemotherapeutic agents in cancer therapy shows great promise in cancer therapy; thus, multiple MRP inhibitors have been developed recently. This review article summarizes the structure, distribution, and physiological as well as pharmacological function of MRP1-MRP9 in cancer chemotherapy. Several novel modulators targeting MRPs in cancer therapy are also discussed. PMID- 25840887 TI - Fracture reduction with positive medial cortical support: a key element in stability reconstruction for the unstable pertrochanteric hip fractures. AB - PURPOSE: To introduce the concept of fracture reduction with positive medial cortical support and its clinical and radiological correlation in geriatric unstable pertrochanteric fractures. METHODS: A retrospective analysis of 127 patients (32 men and 95 women, with mean age 78.7 years) with AO/OTA 31A2.2 and 2.3 hip fractures treated with cephalomedullary nail (PFNA-II or Gamma-3) between July 2010 and June 2013 was performed. They were classified into three groups according the grade of medial cortical support in postoperative fracture reduction (positive, neutral, and negative). The positive cortex support was defined that the medial cortex of the head-neck fragment displaced and located a little bit superomedially to the medial cortex of the shaft. If the neck cortex is located laterally to the shaft, it is negative with no cortical buttress, and if the two cortices contact smoothly, it is in neutral position. The demographic baseline, postoperative radiographic femoral neck-shaft angle and neck length, rehabilitation progress and functional recovery scores of each group were recorded and compared. RESULTS: There were 89 cases (70 %) in positive, 26 in neutral, and 12 in negative support. No statistical differences were found between the three groups among patient age, sex ratio, prefracture score of activity of daily living, walking ability score, ASA physical risk score, number of medical comorbidities, osteoporosis Singh index, fracture reduction quality (Garden alignments), and the position of lag screw or helical blade in femoral head (TAD). In follow-up, patients in positive medial cortical support reduction group had the least loss in neck-shaft angle and neck length, and got ground walking much earlier than negative reduction group, with good functional outcomes and less hip-thigh pain presence. CONCLUSION: Fracture reduction with nonanatomic positive medial cortical support allows limited sliding of the head-neck fragment to contact with the femur shaft and achieve secondary stability, providing a good mechanical environment for fracture healing. PMID- 25840888 TI - Effect of microRNA-203 on tumor growth in human hypopharyngeal squamous cell carcinoma. AB - MicroRNAs (MiRNAs) have been recognized to regulate cancer initiation and progression in carcinogenesis as either oncogenes or tumor suppressor genes, but their role in hypopharyngeal cancer development is not clearly defined. To determine whether miRNA-203 can promote tumor growth in human hypopharyngeal squamous cell carcinoma, we conducted experiments on the functional study of miRNA-203 and identification of miRNA-203 regulated target genes in hypopharyngeal cancer cells. We found that cell proliferation and cell colony forming increased more in the miRNA-203 up-regulated cancer cells than in the negative control cancer cells. Up-regulation of miRNA-203 accelerated cell cycle progression in hypopharyngeal cancer cells. TP63 and B3GNT5 mRNAs were identified and validated as targets of miRNA-203. However, transwell assay and wound scratch assay showed that miRNA-203 did not involve in invasion and metastasis in hypopharyngeal cancer cells. According to the results, we conclude that miRNA-203 can promote tumor growth in human hypopharyngeal squamous cell carcinoma. These results provide the convincing evidence for the first time that up-regulation of miRNA-203 contributes to the malignancy of hypopharyngeal squamous cell carcinoma, possibly through down-regulating TP63 and B3GNT5. PMID- 25840889 TI - Antibody responses of Chlamydophila pneumoniae pneumonia: Why is the diagnosis of C. pneumoniae pneumonia difficult? AB - The ELNAS Plate Chlamydophila pneumoniae commercial test kit for the detection of anti-C. pneumoniae-specific immunoglobulin M (IgM), IgA and IgG antibodies has become available in Japan recently. To determine the optimum serum collection point for the ELNAS plate in the diagnosis of C. pneumoniae pneumonia, we analyzed the kinetics of the antibody response in patients with laboratory confirmed C. pneumoniae pneumonia. We enrolled five C. pneumoniae pneumonia cases and collected sera from patients for several months. The kinetics of the IgM and IgG antibody responses were similar among the five patients. Significant increases in IgM and IgG antibody titer between paired sera were observed in all patients. IgM antibodies appeared approximately 2-3 weeks after the onset of illness, reached a peak after 4-5 weeks, and were generally undetectable after 3 5 months. IgG antibodies developed slowly for the first 30 days and reached a plateau approximately 3-4 months after the onset of illness. The kinetics of IgA antibody responses were different among the five patients, and significant increases in IgA antibody titer between paired sera were observed in only two patients. Although the sample size was small, the best serum collection time seemed to be approximately 3-6 weeks after onset of illness when using a single serum sample for the detection of IgM antibodies. Paired sera samples should be obtained at least 4 weeks apart. IgA antibody analysis using ELNAS may not be a useful marker for acute C. pneumoniae pneumonia. PMID- 25840891 TI - The influence of resin cements on the final color of ceramic veneers. AB - PURPOSE: To evaluate the effect of three brands of resin cement on the final color of ceramic veneers. METHODS: 50 disk-shaped ceramic specimens (IPS e.Max, 0.6mm*8.0mm diameter) and disk-shaped composite resin background specimens (4.0mm*8.0mm diameter) were prepared and divided into 10 groups (n=5). These paired specimens were bonded using ten shades of resin cement (Variolink Veneer, shades LV-3, LV-2, MV, HV+2, HV+3; Panavia F, shades light and brown; and RelyXTM Veneer, shades WO, TR, A3). A spectrophotometer (VITA Easyshade) was used to measure the color parameters (CIE L*a*b* values) of the paired disks before and after cementation. The color differences (DeltaE values) after cementation were calculated and statistically analyzed by the One-way ANOVA (at the significant level p<0.05). RESULTS: The color parameters of the ceramic disks were measured in terms of the increase in L* value, and the decrease in Cab(*) value after bonding with the resin cement. The DeltaE values of ceramic disks after cementation ranged from 1.38 to 7.16. The DeltaE values were more than 3.3 when the ceramic disks were cemented with resin cements in shade HV+3 (4.90) and shade WO (7.16). One-way ANOVA of DeltaE values revealed significant differences in the resin cement shades. CONCLUSIONS: Resin cements can affect the final color of ceramic veneer restorations, and the extent of this effect varies according to the resin cement shades. PMID- 25840890 TI - Building a bridge to recovery: the pathophysiology of LVAD-induced reverse modeling in heart failure. AB - Heart failure mainly caused by ischemic or dilated cardiomyopathy is a life threatening disorder worldwide. The previous work in cardiac surgery has led to many excellent surgical techniques for treating cardiac diseases, and these procedures are now able to prolong the human lifespan. However, surgical treatment for end-stage heart failure has been under-explored, although left ventricular assist device (LVAD) implantation and heart transplantation are options to treat the condition. LVAD can provide powerful circulatory support for end-stage heart failure patients and improve the survival and quality of life after implantation compared with the existing medical counterparts. Moreover, LVADs play a crucial role in the "bridge to transplantation", "bridge to recovery" and recently have served as "destination therapy". The structural and molecular changes that improve the cardiac function after LVAD implantation are called "reverse remodeling", which means that patients who have received a LVAD can be weaned from the LVAD with restoration of their cardiac function. This strategy is a desirable alternative to heart transplantation in terms of both the patient quality of life and due to the organ shortage. The mechanism of this bridge to recovery is interesting, and is different from other treatments for heart failure. Bridge to recovery therapy is one of the options in regenerative therapy which only a surgeon can provide. In this review, we pathophysiologically analyze the reverse remodeling phenomenon induced by LVAD and comment about the clinical evidence with regard to its impact on the bridge to recovery. PMID- 25840892 TI - Laparoscopic adhesiolysis for acute small bowel obstruction: systematic review and pooled analysis. AB - BACKGROUND: Adhesional small bowel obstruction (SBO) occurs in 14-17% of patients within 2 years of open colorectal or general surgery. The aim of this pooled analysis is to compare the safety and efficacy of laparoscopic versus open treatment of SBO. METHODS: An electronic search of Embase, Medline, Web of Science, and Cochrane databases was performed. Weighted mean differences (WMDs) were calculated for the effect size of laparoscopic surgery on continuous variables, and pooled odds ratios (PORs) were calculated for discrete variables. RESULTS: There were eleven non-randomized comparative studies included this review. Laparoscopic surgery was associated with a significant reduction in mortality (POR = 0.31; 95% CI 0.16-0.61; P = 0.0008), overall morbidity (POR = 0.34; 95 % CI 0.27-0.78; P < 0.0001), pneumonia (POR = 0.31; 95% CI 0.20-0.49; P < 0.0001), wound infection (POR = 0.29; 95% CI 0.12-0.70; P = 0.005), and length of hospital stay (WMD = -7.11; 95 % CI -8.47 to -5.75; P < 0.0001). The rates of bowel injury and reoperation were not significantly different between the two groups. Operative time was significantly longer in the laparoscopic group (WMD = 72.31; 95% CI 60.96-83.67; P < 0.0001). CONCLUSION: Laparoscopic surgery for treatment of adhesional SBO improves clinical outcomes and can be performed safely in selected cases with similar rates of bowel injury and reoperation to open surgery. Large scale randomized controlled trials are needed to validate the findings of this pooled analysis of non-randomized data. PMID- 25840893 TI - Natural orifice translumenal endoscopic surgery (NOTES): emerging trends and specifications for a virtual simulator. AB - INTRODUCTION AND STUDY AIM: A virtual translumenal endoscopic surgical trainer (VTEST) is being developed to accelerate the development of natural orifice translumenal endoscopic surgery (NOTES) procedures and devices in a safe and risk free environment. For a rapidly developing field such as NOTES, a needs analysis must be conducted regularly to discover emerging research trends and areas of potential high impact for a virtual simulator. This paper presents a survey-based study which follows a similar study conducted by this group in 2011 (Sankaranarayanan et al. in Surg Endosc 27:1607-1616, 2013). METHODS: A 32-point questionnaire was distributed at the 2012 Natural Orifice Surgery Consortium for Assessment and Research annual meeting. These data were subsequently augmented by an identical online survey, targeted at the members of the American Society for Gastrointestinal Endoscopy and the Society of American Gastrointestinal and Endoscopic Surgeons, and analyzed. RESULTS: Twenty-eight NOTES experts participated in the 2012 study. Cholecystectomy (CE) procedure remained the most commonly performed NOTES technique, with 18 positive responses (64%). In contrast to 2011, the popularity of the NOTES appendectomy (AE) was significantly lower, with only 2 (7%) instances (CE vs. AE, p < 0.001), while the number of peroral endoscopic myotomy (POEM, PE) cases had increased significantly, with 11 (39%) positive responses, respectively (PE vs. AE, p = 0.013). Strong preference toward hybrid rather than pure NOTES techniques (82 vs. 11%, p < 0.001) was also expressed. Other responses were similar to those in the 2011 study, with the VTESTTM utility in developing and testing new techniques and instruments ranked particularly high. CONCLUSION: Based on the results of this study, a decision was made to focus exclusively on the transvaginal hybrid NOTES cholecystectomy procedure, including both rigid and flexible scope techniques. The importance of developing a virtual NOTES simulator was reaffirmed, with POEM identified as a promising candidate for future simulator development. PMID- 25840894 TI - Two-stage optical system for colorectal polyp assessments. AB - BACKGROUND AND AIMS: Macroscopic real-time evaluations of the histopathology and degree of invasion of colorectal polyps help to select the most suitable endoscopic treatment method. Dual-focus (DF) narrow-band imaging (NBI) is a new imaging enhancement system that uses digital and optical methods to enhance the view of blood vessels on mucosal surfaces. However, the superiority of this technique over standard imaging techniques has not been previously reported. The aim of this study was to determine whether the two-stage optical systems in a new generation of endoscopes will increase the diagnostic accuracy of colorectal polyp recognition. METHODS: The study included 270 patients, and 386 colorectal polyps were diagnosed and removed. The polyps were assessed with white light and NBI using one- and two-stage optical systems, respectively. After being classified according to the Kudo pit pattern schemes, the polyps were removed and histopathologically verified. RESULTS: Regarding non-neoplastic lesions (Kudo I and II), no difference was observed in the recognition of polyps when using the NBI-DF function. We observed improved accuracy in the preliminary diagnoses of Kudo IIIL lesions (from 87.16 to 90.09%, p < 0.05) and Kudo IIIS lesions (from 87.29 to 92.79%, p < 0.01). NBI-DF also increased the accuracy of preliminary diagnoses of Kudo IV lesions (from 88.24 to 94.12%, p < 0.01). The Kudo V pit patterns were also more distinct with NBI-DF imaging, increasing the diagnostic accuracy from 91.67 to 100%. CONCLUSIONS: Using a two-stage optical system with electronic colorization of the mucosa increased diagnostic accuracy for differentiating colorectal polyps with neoplastic potential. PMID- 25840895 TI - The new robotic TELELAP ALF-X in gynecological surgery: single-center experience. AB - BACKGROUND: To evaluate the safety and feasibility of the new robotic TELELAP ALF X platform in a heterogeneous series of gynecological procedures. METHODS: Between September 2013 and May 2014, 146 patients were enrolled in this Phase II study trial. Patients with presumed benign or borderline adnexal disease, and benign and early stage malignant uterine disease were prospectively included. RESULTS: Median age was 52 years (range 19-79 years), and median BMI was 23.7 (range 17.3-34.0 kg/m(2)). Sixty-two patients (32.5%) underwent mono/bilateral salpingo-oophorectomy or cyst removal (Group A), four patients (2.7%) myomectomy (Group B), 46 patients (31.5%) total hysterectomy (Group C), and 34 (23.3%) endometrial cancer staging (Group D). Median docking time was 7 min (range 3-36). Median OT was 35 min (range 17-145) in the Group A, 40 min (range 10-50) in the Group B, 133 min (range 58-320) in the Group C, and 160 min (range 69-290) in the Group D. Reduction in OT over the study period for hysterectomy (p < 0.001) and adnexal surgery (p < 0.002) was observed. We registered two laparoscopic conversion (3.2%) in the Group A and two (4.3 %) in the Group C. In the Group D, we showed one (2.9%) laparoscopic and two (5.8%) laparotomic conversions. One patient (2.17%) in the Group C was readmitted in the early postoperative period for severe vaginal bleeding. CONCLUSIONS: We report the first series of a novel robotic approach for the treatment of various gynecological conditions. When performed by experienced minimally invasive surgeons, TELELAP ALF-X is feasible and safe. Further studies are mandatory to define the benefits, advantages, and costs of this new robotic approach with respect to others minimally invasive approaches. PMID- 25840896 TI - Three-dimensional versus two-dimensional vision in laparoscopy: a systematic review. AB - BACKGROUND: Laparoscopic surgery is widely used, and results in accelerated patient recovery time and hospital stay were compared with laparotomy. However, laparoscopic surgery is more challenging compared with open surgery, in part because surgeons must operate in a three-dimensional (3D) space through a two dimensional (2D) projection on a monitor, which results in loss of depth perception. To counter this problem, 3D imaging for laparoscopy was developed. A systematic review of the literature was performed to assess the effect of 3D laparoscopy. METHODS: A systematic search of the literature was conducted to identify randomized controlled trials that compared 3D with 2D laparoscopy. The search was accomplished in accordance with the PRISMA guidelines using the PubMed, EMBASE, and The Cochrane Library electronic databases. No language or year of publication restrictions was applied. Data extracted were cohort size and characteristics, skill trained or operation performed, instrument used, outcome measures, and conclusions. Two independent authors performed the search and data extraction. RESULTS: Three hundred and forty articles were screened for eligibility, and 31 RCTs were included in the review. Three trials were carried out in a clinical setting, and 28 trials used a simulated setting. Time was used as an outcome measure in all of the trials, and number of errors was used in 19 out of 31 trials. Twenty-two out of 31 trials (71%) showed a reduction in performance time, and 12 out of 19 (63%) showed a significant reduction in error when using 3D compared to 2D. CONCLUSIONS: Overall, 3D laparoscopy appears to improve speed and reduce the number of performance errors when compared to 2D laparoscopy. Most studies to date assessed 3D laparoscopy in simulated settings, and the impact of 3D laparoscopy on clinical outcomes has yet to be examined. PMID- 25840897 TI - Nonradiation ERCP with endoscopic biliary sphincterotomy plus papillary balloon dilation for the treatment of choledocholithiasis during pregnancy. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is currently the treatment of choice for symptomatic choledocholithiasis in pregnant patients. We aimed to present our experience with pregnant patients who underwent nonradiation ERCP and to evaluate the safety and efficacy of a new technique. METHODS: A retrospective analysis of nonradiation ERCP in 22 pregnant patients with symptomatic choledocholithiasis between January 2002 and December 2013 was performed. The bile aspiration technique with wire-guided sphincterotome was used to confirm selective biliary cannulation. Transpapillary pancreatic septotomy was performed in cases with difficult biliary cannulation (n = 3). After endoscopic biliary sphincterotomy, endoscopic papillary balloon dilation was performed with a 6- or 8-mm dilation balloon in all patients to reduce the risk of recurrent cholangitis because of residual or additional stones. Stones were extracted by balloon sweeping after dilation. All patients were followed for 6 months after the ERCP procedure. RESULTS: Biliary cannulation was achieved in all patients. Endoscopic papillary balloon dilation was performed with a 6-mm balloon in 17 patients and an 8-mm balloon in five patients. The stones were extracted in 18 of the 22 patients by balloon sweeping, but no stones were extracted in the remaining four patients. There were two cases of mild post-ERCP pancreatitis. All patients delivered at term, and none experienced recurrence of choledocholithiasis and/or cholangitis during the 6-month follow-up. CONCLUSIONS: Endoscopic biliary sphincterotomy plus endoscopic papillary balloon dilation in nonradiation ERCP is a safe and effective treatment method for symptomatic choledocholithiasis during pregnancy. PMID- 25840898 TI - A nurse-led case management program on home exercise training for hemodialysis patients: A randomized controlled trial. AB - BACKGROUND: Patients on maintenance hemodialysis suffer from diminished physical health. Directly supervised exercise programs have been shown to be effective at improving physical function and optimizing well-being. However, nurses seldom include an exercise intervention in the care plan for hemodialysis patients. OBJECTIVES: The purpose of this study was to examine the effects of a 12-week nurse-led case management program on home exercise training for hemodialysis patients. DESIGN: The study was a randomized, two-parallel group trial. SETTINGS: Hemodialysis units in two tertiary hospitals in Nanjing, mainland China. PARTICIPANTS: One hundred and thirteen adult patients who have been in stable condition while on dialysis treatment for more than 3 months were recruited and randomly assigned to either the study group (n=57) or the control group (n=56). METHODS: Both groups underwent a brief weekly in-center exercise training session before their dialysis sessions for the first 6 weeks. The study group received additional nurse case management weekly for the first 6 weeks and biweekly for the following 6 weeks. The intervention was to facilitate patients in performing regular exercise at home. Outcome measures, including gait speed, 10-repetition sit-to-stand performance, and quality of life were collected at baseline, and at 6 and 12 weeks into the program. RESULTS: The results revealed that patients in the study group demonstrated greater increases in normal gait speed [F(1,111)=4.42, p=0.038] than the control group. For the study group, a mean increase of 12.02 (+/-3.03)centimeters/second from baseline to week 12 was found. With regard to the fast gait speed, there was a marginally significant between group effect [F(1,111)=3.93, p=0.050]. The study group showed a mean improvement of 11.08 (+/-3.32)cm/s, from baseline to week 12. Patients from both groups showed improvements in their 10-repetition sit-to-stand performance. The between group differences approached significance [F(1,111)=3.92, p=0.050], with the study group showed greater improvement than the control group. The time taken by the patients in the study group to complete the 10-STS test increased by 5.75 (+/ 3.88)s from baseline to week 12. Significant improvements in quality of life across three time points were found only in the study group. CONCLUSIONS: Home exercise using a nurse-led case management approach is practical and effective in improving the physical function and self-perceived health of stable hemodialysis patients. PMID- 25840899 TI - Language barriers and patient safety risks in hospital care. A mixed methods study. AB - INTRODUCTION: A language barrier has been shown to be a threat for quality of hospital care. International studies highlighted a lack of adequate noticing, reporting, and bridging of a language barrier. However, studies on the link between language proficiency and patient safety are scarce, especially in Europe. The present study investigates patient safety risks due to language barriers during hospitalization, and the way language barriers are detected, reported, and bridged in Dutch hospital care. METHODS: We combined quantitative and qualitative methods in a sample of 576 ethnic minority patients who were hospitalized on 30 wards within four urban hospitals. The nursing and medical records of 17 hospital admissions of patients with language barriers were qualitatively analyzed, and complemented by 12 in-depth interviews with care providers and patients and/or their relatives to identify patient safety risks during hospitalization. The medical records of all 576 patients were screened for language barrier reports. The results were compared to patients' self-reported Dutch language proficiency. The policies of wards regarding bridging language barriers were compared with the reported use of interpreters in the medical records. RESULTS: Situations in hospital care where a language barrier threatened patient safety included daily nursing tasks (i.e. medication administration, pain management, fluid balance management) and patient-physician interaction concerning diagnosis, risk communication and acute situations. In 30% of the patients that reported a low Dutch proficiency, no language barrier was documented in the patient record. Relatives of patients often functioned as interpreter for them and professional interpreters were hardly used. DISCUSSION: The present study showed a wide variety of risky situations in hospital care for patients with language barriers. These risks can be reduced by adequately bridging the language barrier, which, in the first place, demands adequate detecting and reporting of a language barrier. This is currently not sufficiently done in most Dutch hospitals. Moreover, new solutions to bridge language barriers are needed for situations such as routine safety checks performed by nurses, in which a professional or even informal interpreter is not feasible. PMID- 25840900 TI - Computing Expected Value of Partial Sample Information from Probabilistic Sensitivity Analysis Using Linear Regression Metamodeling. AB - Decision makers often desire both guidance on the most cost-effective interventions given current knowledge and also the value of collecting additional information to improve the decisions made (i.e., from value of information [VOI] analysis). Unfortunately, VOI analysis remains underused due to the conceptual, mathematical, and computational challenges of implementing Bayesian decision theoretic approaches in models of sufficient complexity for real-world decision making. In this study, we propose a novel practical approach for conducting VOI analysis using a combination of probabilistic sensitivity analysis, linear regression metamodeling, and unit normal loss integral function--a parametric approach to VOI analysis. We adopt a linear approximation and leverage a fundamental assumption of VOI analysis, which requires that all sources of prior uncertainties be accurately specified. We provide examples of the approach and show that the assumptions we make do not induce substantial bias but greatly reduce the computational time needed to perform VOI analysis. Our approach avoids the need to analytically solve or approximate joint Bayesian updating, requires only one set of probabilistic sensitivity analysis simulations, and can be applied in models with correlated input parameters. PMID- 25840901 TI - Mapping between 6 Multiattribute Utility Instruments. AB - BACKGROUND: Cost-utility analyses commonly employ a multiattribute utility (MAU) instrument to estimate the health state utilities, which are needed to calculate quality-adjusted life years. Different MAU instruments predict significantly different utilities, which makes comparison of results from different evaluation studies problematical. AIM: This article presents mapping functions ("crosswalks") from 6 MAU instruments (EQ-5D-5L, SF-6D, Health Utilities Index 3 [HUI 3], 15D, Quality of Well-Being [QWB], and Assessment of Quality of Life 8D [AQoL-8D]) to each of the other 5 instruments in the study: a total of 30 mapping functions. METHODS: Data were obtained from a multi-instrument comparison survey of the public and patients in 7 disease areas conducted in 6 countries (Australia, Canada, Germany, Norway, United Kingdom, and United States). The 8022 respondents were administered each of the 6 study instruments. Mapping equations between each instrument pair were estimated using 4 econometric techniques: ordinary least squares, generalized linear model, censored least absolute deviations, and, for the first time, a robust MM-estimator. RESULTS: Goodness-of fit indicators for each of the results are within the range of published studies. Transformations reduced discrepancies between predicted utilities. Incremental utilities, which determine the value of quality-related health benefits, are almost perfectly aligned at the sample means. CONCLUSION: Transformations presented here align the measurement scales of MAU instruments. Their use will increase confidence in the comparability of evaluation studies, which have employed different MAU instruments. PMID- 25840902 TI - Predicting the EQ-5D-3L Preference Index from the SF-12 Health Survey in a National US Sample: A Finite Mixture Approach. AB - BACKGROUND: . When data on preferences are not available, analysts rely on condition-specific or generic measures of health status like the SF-12 for predicting or mapping preferences. Such prediction is challenging because of the characteristics of preference data, which are bounded, have multiple modes, and have a large proportion of observations clustered at values of 1. METHODS: . We developed a finite mixture model for cross-sectional data that maps the SF-12 to the EQ-5D-3L preference index. Our model characterizes the observed EQ-5D-3L index as a mixture of 3 distributions: a degenerate distribution with mass at values indicating perfect health and 2 censored (Tobit) normal distributions. Using estimation and validation samples derived from the Medical Expenditure Panel Survey 2000 dataset, we compared the prediction performance of these mixture models to that of 2 previously proposed methods: ordinary least squares regression (OLS) and two-part models. RESULTS: . Finite mixture models in which predictions are based on classification outperform two-part models and OLS regression based on mean absolute error, with substantial improvement for samples with fewer respondents in good health. The potential for misclassification is reflected on larger root mean square errors. Moreover, mixture models underperform around the center of the observed distribution. CONCLUSIONS: . Finite mixtures offer a flexible modeling approach that can take into account idiosyncratic characteristics of the distribution of preferences. The use of mixture models allows researchers to obtain estimates of health utilities when only summary scores from the SF-12 and a limited number of demographic characteristics are available. Mixture models are particularly useful when the target sample does not have a large proportion of individuals in good health. PMID- 25840903 TI - Value of Information: We've Got Speed, What More Do We Need? PMID- 25840904 TI - A Randomized Trial Examining Three Strategies for Supporting Health Insurance Decisions among the Uninsured. AB - BACKGROUND: The Affordable Care Act allows uninsured individuals to select health insurance from numerous private plans, a challenging decision-making process. This study examined the effectiveness of strategies to support health insurance decisions among the uninsured. METHODS: Participants (N = 343) from urban, suburban, and rural areas were randomized to 1 of 3 conditions: 1) a plain language table; 2) a visual condition where participants chose what information to view and in what order; and 3) a narrative condition. We administered measures assessing knowledge (true/false responses about key features of health insurance), confidence in choices (uncertainty subscale of the Decisional Conflict Scale), satisfaction (items from the Health Information National Trends Survey), preferences for insurance features (measured on a Likert scale from not at all important to very important), and plan choice. RESULTS: Although we did not find significant differences in knowledge, confidence in choice, or satisfaction across condition, participants across conditions made value consistent choices, selecting plans that aligned with their preferences for key insurance features. In addition, those with adequate health literacy skills as measured by the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM SF) had higher knowledge overall ([Formula: see text] = 6.1 v. 4.8, P < 0.001) and preferred the plain language table to the visual (P = 0.04) and visual to narrative (P = 0.0002) conditions, while those with inadequate health literacy skills showed no preference for study condition. A similar pattern was seen for those with higher subjective numeracy skills and higher versus lower education with regard to health insurance knowledge. Individuals with higher income felt less confident in their choices ([Formula: see text] = 28.7 v. 10.0, where higher numbers indicate less confidence/more uncertainty; P = 0.004). CONCLUSIONS: Those developing materials about the health insurance marketplace to support health insurance decisions might consider starting with plain language tables, presenting health insurance terminology in context, and organizing information according to ways the uninsured might use and value insurance features. Individuals with limited health literacy and numeracy skills and those with lower education face unique challenges selecting health insurance and weighing tradeoffs between cost and coverage. PMID- 25840905 TI - Immobilization of Bioactive Protein A from Staphylococcus aureus (SpA) on the Surface of Bacillus subtilis Spores. AB - Protein A from Staphylococcus aureus (SpA) is a 40-60 kDa cell-wall component, composed of five homologous immunoglobulin (Ig)-binding domains folded into a three-helix bundle. Each of these five domains is able to bind Igs from many different mammalian species. Recombinant SpA is widely used as a component of diagnostic kits for the detection and purification of IgGs from serum or other biological fluids. In this study, purified SpA was adsorbed and covalently linked to Bacillus subtilis spores. Spores are extremely stable cell forms and are considered as an attractive platform to display heterologous proteins. A sample containing about 36 MUg of SpA was covalently immobilized on the surface of 4 * 10(10) spores. Spore-bound SpA retained its IgG-binding activity, even after seven consecutive binding and washing steps, suggesting that it can be recycled and utilized several times. FACS analysis revealed that spores with covalently attached SpA had significantly improved fluorescence intensities when compared to those of spores with adsorbed SpA, suggesting that the covalent approach is more efficient than sole adsorption regarding protein attachment to the spore surface. PMID- 25840906 TI - NMR studies of membrane proteins. PMID- 25840907 TI - Survey of expert opinions and related recommendations regarding bridging therapy using hypomethylating agents followed by allogeneic transplantation for high-risk MDS. AB - According to current guidelines on therapeutic strategies for myelodysplastic syndrome (MDS), cytoreductive therapies before allogeneic stem cell transplantation (SCT) are not widely recommended for patients with high-risk MDS or refractory anemia with excess blasts (RAEB) who are eligible for allogeneic SCT because of controversial evidence on the role of such therapies. Yet, while treatment with hypomethylating agents (HMAs) has a critical limitation in eradicating MDS clones, the use of HMA treatment as a bridge to allogeneic SCT has become a focus with the hope of improving the SCT outcome based on the chance of achieving complete remission or reducing the blast percentage safely and effectively before allogeneic SCT. However, a consensus needs to be established on the use of HMAs as a bridging therapy for high-risk MDS or RAEB. Thus, the Korean AML/MDS working party group surveyed 34 Korean MDS experts on their bridging therapies for high-risk MDS. Accordingly, this paper presents the survey questionnaire and resulting data, along with a summary of the consensus and related recommendations regarding strategies using HMA treatment and allogeneic SCT based on reported studies and the current survey results. PMID- 25840908 TI - New Ceratocystis species from Eucalyptus and Cunninghamia in South China. AB - During routine surveys for possible fungal pathogens in the rapidly expanding plantations of Eucalyptus and Cunninghamia lanceolata in China, numerous isolates of unknown species in the genus Ceratocystis (Microascales) were obtained from tree wounds. In this study we identified the Ceratocystis isolates from Eucalyptus and Cunninghamia in the GuangDong, GuangXi, FuJian and HaiNan Provinces of South China based on morphology and through comparisons of DNA sequence data for the ITS, partial beta-tubulin and TEF-1alpha gene regions. Morphological and DNA sequence comparisons revealed two previously unknown species residing in the Indo-Pacific Clade. These are described here as Ceratocystis cercfabiensis sp. nov. and Ceratocystis collisensis sp. nov. Isolates of Ceratocystis cercfabiensis showed intragenomic variation in their ITS sequences and four strains were selected for cloning of the ITS gene region. Twelve ITS haplotypes were obtained from 17 clones selected for sequencing, differing in up to seven base positions and representing two separate phylogenetic groups. This is the first evidence of multiple ITS types in isolates of Ceratocystis residing in the Indo-Pacific Clade. Caution should thus be exercised when using the ITS gene region as a barcoding marker for Ceratocystis species in this clade. This study also represents the first record of a species of Ceratocystis from Cunninghamia. PMID- 25840909 TI - Bone transport through an induced membrane in the management of tibial bone defects resulting from chronic osteomyelitis. AB - Wide resection of infected bone improves the odds of achieving remission of infection in patients with chronic osteomyelitis. Aggressive debridement is followed by the creation of large bone defects. The use of antibiotic-impregnated PMMA spacers, as a customized dead space management tool, has grown in popularity. In addition to certain biological advantages, the spacer offers a therapeutic benefit by serving as a vehicle for delivery of local adjuvant antibiotics. In this study, we investigate the efficacy of physician-directed antibiotic-impregnated PMMA spacers in achieving remission of chronic tibial osteomyelitis. This retrospective case series involves eight patients with chronic osteomyelitis of the tibial diaphysis managed with bone transport through an induced membrane using circular external fixation. All patients were treated according to a standardized treatment protocol. A review of the anatomical nature of the disease, the physiological status of the host and the outcome of treatment in terms of remission of infection, time to union and the complications that occurred was carried out. Seven patients, with a mean bone defect of 7 cm (range 5-8 cm), were included in the study. At a mean follow-up of 28 months (range 18 45 months), clinical eradication of osteomyelitis was achieved in all patients without the need for further reoperation. The mean total external fixation time was 77 weeks (range 52-104 weeks), which equated to a mean external fixation index of 81 days/cm (range 45-107). Failure of the skeletal reconstruction occurred in one patient who was not prepared to continue with further reconstructive surgery and requested amputation. Four major and four minor complications occurred. The temporary insertion of antibiotic-impregnated PMMA appears to be a useful dead space management technique in the treatment of post infective tibial bone defects. Although the technique does not appear to offer an advantage in terms of the external fixation index, it may serve as a useful adjunct in order to achieve resolution of infection. PMID- 25840910 TI - Hypothermia Evidence, Afterdrop, and Guidelines. PMID- 25840911 TI - Macrophage epoxygenase determines a profibrotic transcriptome signature. AB - Epoxygenases belong to the cytochrome P450 family. They generate epoxyeicosatrienoic acids, which are known to have anti-inflammatory effects, but little is known about their role in macrophage function. By high-throughput sequencing of RNA in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (ortholog of human CYP2J2) resulted in reduced epoxyeicosatrienoic acid synthesis. Cyp2j4(-/-) macrophages have relatively increased peroxisome proliferator-activated receptor-gamma levels and show a profibrotic transcriptome, displaying overexpression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4(-/-) rats show upregulation of type I collagen following unilateral ureter obstruction of the kidney, and quantitative proteomics analysis (liquid chromatography-tandem mass spectrometry) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a profibrotic macrophage transcriptome that could have implications in various inflammatory conditions, depending on macrophage function. PMID- 25840912 TI - In Vivo Suppression of Heat Shock Protein (HSP)27 and HSP70 Accelerates DMBA Induced Skin Carcinogenesis by Inducing Antigenic Unresponsiveness to the Initiating Carcinogenic Chemical. AB - Heat shock proteins (HSPs) are constitutively expressed in murine skin. HSP27 is present in the epidermis, and HSP70 can be found in both the epidermis and dermis. The purpose of this study was to investigate the role of these proteins in cutaneous chemical carcinogenesis and to determine whether their effects on cell-mediated immune function were a contributing factor. In vivo inhibition of HSP27 and HSP70 produced a reduction in the T cell-mediated immune response to 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene in C3H/HeN mice and resulted in a state of Ag-specific tolerance. When mice were pretreated with anti HSP27 and anti-HSP70 Abs in vivo prior to subjecting them to a standard two-stage DMBA/12-O-tetradecanoylphorbol-13-acetate cutaneous carcinogenesis protocol, the percentage of mice with tumors was much greater (p < 0.05) in anti-HSP27- and HSP70-pretreated animals compared with mice pretreated with control Ab. Similar results were obtained when the data were evaluated as the cumulative number of tumors per group. Mice pretreated with HSP27 and HSP70 Abs developed more H-ras mutations and fewer DMBA-specific cytotoxic T lymphocytes. These findings indicate that in mice HSP27 and HSP70 play a key role in the induction of cell mediated immunity to carcinogenic polyaromatic hydrocarbons. Bolstering the immune response to carcinogenic polyaromatic hydrocarbons may be an effective method for prevention of the tumors that they produce. PMID- 25840913 TI - mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo. AB - The mammalian/mechanistic target of rapamycin (mTOR) is a key integrative kinase that functions in two independent complexes, mTOR complex (mTORC) 1 and mTORC2. In contrast to the well-defined role of mTORC1 in dendritic cells (DC), little is known about the function of mTORC2. In this study, to our knowledge, we demonstrate for the first time an enhanced ability of mTORC2-deficient myeloid DC to stimulate and polarize allogeneic T cells. We show that activated bone marrow derived DC from conditional Rictor(-/-) mice exhibit lower coinhibitory B7-H1 molecule expression independently of the stimulus and enhanced IL-6, TNF-alpha, IL-12p70, and IL-23 production following TLR4 ligation. Accordingly, TLR4 activated Rictor(-/-) DC display augmented allogeneic T cell stimulatory ability, expanding IFN-gamma(+) and IL-17(+), but not IL-10(+) or CD4(+)Foxp3(+) regulatory T cells in vitro. A similar DC profile was obtained by stimulating Dectin-1 (C-type lectin family member) on Rictor(-/-) DC. Using novel CD11c specific Rictor(-/-) mice, we confirm the alloreactive Th1 and Th17 cell polarizing ability of endogenous mTORC2-deficient DC after TLR4 ligation in vivo. Furthermore, we demonstrate that proinflammatory cytokines produced by Rictor(-/ ) DC after LPS stimulation are key in promoting Th1/Th17 responses. These data establish that mTORC2 activity restrains conventional DC proinflammatory capacity and their ability to polarize T cells following TLR and non-TLR stimulation. Our findings provide new insight into the role of mTORC2 in regulating DC function and may have implications for emerging therapeutic strategies that target mTOR in cancer, infectious diseases, and transplantation. PMID- 25840914 TI - Herpes simplex virus type 2-infected dendritic cells produce TNF-alpha, which enhances CCR5 expression and stimulates HIV production from adjacent infected cells. AB - Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2 infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1-DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-alpha was by far the most prominent cytokine in the supernatant and also within HSV-2-infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF alpha (and low levels of IFN-beta). Neutralizing Ab to TNF-alpha and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions. PMID- 25840915 TI - Pattern recognition receptor-initiated innate antiviral responses in mouse epididymal epithelial cells. AB - Viral infections of the epididymis may impair male fertility and spread sexually transmitted pathogens. The innate antiviral immune responses in the epididymis have yet to be intensively investigated. This study found that mouse epididymal epithelial cells (EECs) constitutively express several viral sensors, including TLR3, retinoic acid-inducible gene I, and DNA-dependent activator of IFN regulatory factors. Other DNA sensors, including p204 and cGMP-AMP synthase, can be induced by transfection of synthetic HSV genomic DNA (HSV60). TLR3 and retinoic acid-inducible gene I in EECs can be activated by their common agonist, polyinosinic-polycytidylic acid [poly(I:C)]. The signaling pathway of DNA sensors can be initiated by HSV60. Both poly(I:C) and HSV60 induced the expression of type 1 IFNs and various antiviral proteins, including IFN-stimulated gene 15, 2',5'-oligoadenylate synthetase, and myxovirus resistance 1. Poly(I:C), but not HSV60, also dramatically induced the expression of major proinflammatory cytokines, including TNF-alpha and MCP-1, in EECs. In vivo assay confirmed that the local injection of poly(I:C) or HSV60 induced the innate antiviral responses in EECs. This study provided novel insights into the mechanisms underlying the innate antiviral responses in the mouse epididymis. PMID- 25840916 TI - Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (IV): phenanthroindolizidine alkaloids from Tylophora tanakae leaves. AB - Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T lymphocytes caused by human T-cell lymphotropic virus type 1 (HTLV-1). There are an estimated 5 million to 20 million HTLV-1-infected individuals worldwide; their lifetime risk of developing ATL is 3-5 %, and high HTLV-1 proviral loads have been shown to be an independent risk factor. Although conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to ATL patients, the prognosis is often poor. In previous studies, we screened 459 extracts from 344 plants to isolate components exhibiting antiproliferative activity against HTLV-1-infected T-cell lines (MT-1 and MT-2). In our continuing search for potential anti-HTLV-1 natural products, 15 extracts of Asclepiadaceae plants were further tested against MT-1 and MT-2 cells. The MeOH extract of aerial parts of Tylophora tanakae showed antiproliferative activity. Activity-guided fractionation resulted in the isolation of 6 phenanthroindolizidine alkaloids (including a new compound), and we examined their antiproliferative activity against MT-1 and MT-2 cells. The EC50 value of some of the alkaloids was in the low nanomolar range, comparable to that of the clinically used antineoplastic drug doxorubicin. Structure-activity relationship analyses suggested that a 14beta-hydroxy moiety is essential for activity against HTLV-1-infected T cells. In contrast, the presence of a 2-methoxy moiety, a 7 methoxy moiety, or an N-oxide moiety appears to reduce the potency of the antiproliferative activity against HTLV-1-infected T cells. PMID- 25840917 TI - Sinomenine and magnoflorine, major constituents of Sinomeni caulis et rhizoma, show potent protective effects against membrane damage induced by lysophosphatidylcholine in rat erythrocytes. AB - The effects of the water extract of Sinomeni Caulis et Rhizoma (SCR-WE) and its major constituents, sinomenine (SIN) and magnoflorine (MAG), on moderate hemolysis induced by lysophosphatidylcholine (LPC) were investigated in rat erythrocytes and compared with the anti-hemolytic effects of lidocaine (LID) and propranolol (PRO) as reference drugs. LPC caused hemolysis at concentrations above the critical micelle concentration (CMC), and the concentration of LPC producing moderate hemolysis (60 %) was approximately 10 MUM. SCR-WE at 1 ng/mL 100 MUg/mL significantly inhibited the hemolysis induced by LPC. SIN and MAG attenuated LPC-induced hemolysis in a concentration-dependent manner from very low to high concentrations (1 nM-100 MUM and 10 nM-100 MUM, respectively). In contrast, the inhibiting effects of LID and PRO on LPC-induced hemolysis were observed at higher concentrations (1-100 MUM) but not at lower concentrations (1 100 nM). Neither SIN nor MAG affected micelle formation of LPC, nor, at concentrations of 1 nM-1 MUM, did they attenuate the hemolysis induced by osmotic imbalance (hypotonic hemolysis). Similarly, SCR-WE also did not modify micelle formation or hypotonic hemolysis, except at the highest concentration. These results suggest that SIN and MAG potently protect the erythrocyte membrane from LPC-induced damage and contribute to the beneficial action of SCR-WE. The protective effects of SIN and MAG are mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance. PMID- 25840918 TI - The Inappropriate Prescription of Oral Proton Pump Inhibitors in the Hospital Setting: A Prospective Cross-Sectional Study. AB - Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal tract disorders. Their efficacy and perceived safety have led to widespread prescription. This is not without effect, in terms of adverse events and resource utilization. AIM: To prospectively assess oral PPI prescription in hospitalized patients. METHODS: PPI prescription in consecutive hospitalized patients was assessed. Indication and dose were assessed by patient interview and medical record review. Comparisons with current published prescribing guidelines were made. RESULTS: Four hundred and forty-seven patients were included. 57.5 % were prescribed PPIs. 26.8 % prescriptions were for inappropriate or unclear indications. 68.4 % were on higher doses than guidelines recommended, of which 41.6 % could have undergone dose reduction, and 26.5 % discontinued. In a multivariate analysis, age, gender, and length of stay had no association with PPI prescription. Although aspirin use was appropriately associated with PPI prescription (RR: 1.8, 95 % CI 1.127-3.69; p < 0.05), the PPI was often given at higher than recommended doses (p < 0.001). This may reflect older age and multiple risk factors in this subset. Surgical patients commenced more PPIs and at higher dosages (p < 0.001). Omeprazole and lansoprazole were most often inappropriately prescribed (p < 0.01, p < 0.001, respectively). CONCLUSION: Inappropriate PPI therapy is still a problem in hospitals, though it appears to be at a lower level compared with previous studies. Awareness of evidence-based guidelines and targeted medicine reconciliation strategies are essential for cost effective and safe use of these medications. PMID- 25840919 TI - Vitamin D Deficiency Adds an Element of Risk to Insulin Resistance in Colorectal Neoplasms. AB - BACKGROUND: Both insulin resistance (IR) and vitamin D deficiency (VitDdef) have been suggested as risk factors for colorectal neoplasms (CRNs). However, the associations between the two with regard to CRNs are unclear. AIMS: To determine whether IR is a risk factor for CRNs and whether VitDdef confers an additive risk of CRNs. METHODS: Colonoscopy-naive asymptomatic women undergoing a routine health screening program were analyzed. IR was defined as homeostatic model assessment of IR >3 and VitDdef set as <20 ng/mL. Multivariable logistic regression was performed between women with and without CRNs, matched for age and body mass index, to investigate associations with CRNs in IR, VitDdef, and VitDdef combined with IR. RESULTS: We analyzed 216 women with CRNs and 216 without CRNs. A significant association was found between IR and CRNs (OR 1.838, 95 % CI 1.029-3.285, P = 0.040) but not with VitDdef. IR conferred a higher risk in advanced CRNs (OR 3.244, 95 % CI 1.588-6.631, P = 0.001) than CRNs. When VitDdef was combined with IR, risks of both CRNs and advanced CRNs increased (OR 2.131, 95 % CI 1.077-4.216, P = 0.030 and OR 4.438, 95 % CI 2.058-9.571, P < 0.001, respectively). CONCLUSIONS: IR increases the risk of CRNs, and a combination of IR and VitDdef further increases this risk. As both VitDdef and IR are modifiable risk factors, such associations may have important clinical implications in the prevention of CRNs. PMID- 25840921 TI - Systemic Analysis of Predictive Biomarkers for Recurrence in Colorectal Cancer Patients Treated with Curative Surgery. AB - BACKGROUND: Preoperative serum systemic inflammatory response (SIR) in patients with colorectal cancer (CRC) has been reported to be a predictive biomarker of early recurrence. The molecular status of CRC, including microsatellite instability (MSI), BRAF and KRAS mutations, and tumor-infiltrating lymphocytes (TILs), has also been associated with recurrence in CRC patients treated with curative surgery. AIM: We investigated the impacts of SIR status, TILs, and MSI on recurrence in curative CRC patients. METHODS: In this retrospective study, we enrolled 157 patients with stage I-III CRC undergoing curative surgery, for whom preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and C-reactive protein (CRP) data were available as indicators of SIR status. Molecular status was evaluated by counting TILs as the numbers of intratumoral Foxp3- and CD8-positive T cells by immunohistochemistry. MSI status was determined using five mononucleotide repeat microsatellite markers. RESULTS: Kaplan-Meier analysis of SIR indicators revealed that higher CRP, NLR, and PLR were associated with significantly poorer disease-free survival (DFS). Low levels of infiltrating CD8-positive T cells in CRC tissue was a significant predictor of poor DFS. Multivariate analysis showed that few infiltrating CD8-positive T cells and high serum CRP levels were independent predictive factors for recurrence. Furthermore, the combination of high CRP and few infiltrating CD8-positive T cells increased the predictive accuracy in these patients. CONCLUSIONS: The results of this study suggest that both CRP levels in preoperative serum and CD8 T cells in CRC tissue are useful biomarkers for predicting early relapse in CRC patients treated with curative surgery. PMID- 25840922 TI - Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the USA. Existing data on the relationship between OSA and NAFLD are conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort, we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. METHODS: Two hundred and thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5 % macrovesicular steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. RESULTS: Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 vs. 37.7 U/L, P = 0.0007; AST 31.7 vs. 20.5 U/L, P = 0.0007). OSA was associated with the presence of NASH, and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P = 0.03 OR 2.01; 95 %, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score, and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. CONCLUSIONS: OSA is associated with elevated aminotransferase levels, the presence of NASH, and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH. PMID- 25840923 TI - Foods provoking and alleviating symptoms in gastroparesis: patient experiences. AB - BACKGROUND: Nutritional counseling for gastroparesis focuses on reduction of meal size, fiber, and fat to control symptoms. The tolerance of gastroparesis patients for particular foods is largely anecdotal. The aim of this study was to identify and characterize foods provoking or alleviating gastroparesis symptoms. METHODS: Gastroparesis patients completed: (1) Demographic Questionnaire; (2) Patient Assessment of Upper GI Symptoms; (3) Food Toleration and Aversion survey asking patients about experiences when eating certain foods utilizing a scale from -3 (greatly worsening symptoms) to +3 (greatly improving symptoms). Descriptive qualities (acidic, fatty, spicy, roughage-based, bitter, salty, bland, and sweet) were assigned to foods. RESULTS: Forty-five gastroparesis patients participated (39 idiopathic gastroparesis). Foods worsening symptoms included: orange juice, fried chicken, cabbage, oranges, sausage, pizza, peppers, onions, tomato juice, lettuce, coffee, salsa, broccoli, bacon, and roast beef. Saltine crackers, jello, and graham crackers moderately improved symptoms. Twelve additional foods were tolerated by patients (not provoking symptoms): ginger ale, gluten-free foods, tea, sweet potatoes, pretzels, white fish, clear soup, salmon, potatoes, white rice, popsicles, and applesauce. Foods provoking symptoms were generally fatty, acidic, spicy, and roughage-based. The foods shown to be tolerable were generally bland, sweet, salty, and starchy. CONCLUSIONS: This study identified specific foods that worsen as well as foods that may help alleviate symptoms of gastroparesis. Foods that provoked symptoms differed in quality from foods that alleviated symptoms or were tolerable. The results of this study illustrate specific examples of foods that aggravate or improve symptoms and provide suggestions for a gastroparesis diet. PMID- 25840920 TI - Molecular Alterations of Colorectal Cancer with Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer (CRC). The risk of CRC begins to increase 8 or 10 years after the diagnosis of IBD. This type of cancer is called colitis associated CRC (CA-CRC). The molecular pathogenesis of inflammatory epithelium might play a critical role in the development of CA-CRC. Genetic alterations detected in CA-CRC such as genetic mutations, microsatellite instability, and DNA hypermethylation are also recognized in sporadic CRC; however, there are differences in the timing and frequency of molecular events between CA-CRC and sporadic CRC. Interaction between gene-environmental factors, including inflammation, lifestyle, psychological stress, and prior appendectomy, might be associated with the etiopathology of IBD. The mucosal inflammatory mediators, such as oxidant stress, free radicals, and chemokines, may cause the genetic alterations. Understanding the molecular mechanisms of CA-CRC might be important to develop clinical efficacies for patients with IBD. This review discusses the molecular characteristics of CA-CRC, especially ulcerative colitis-associated CRC, including clinical features, signaling pathways, and interactions between genetic alterations and environment involved in inflammatory carcinogenesis. PMID- 25840924 TI - Recurrent abdominal pain in a patient with Down syndrome. PMID- 25840926 TI - Removal of an embedded, migrated plastic biliary stent with the use of cholangioscopy. PMID- 25840925 TI - Determination and establishment of discriminating concentrations of malathion, coumaphos, fenvalerate and fipronil for monitoring acaricide resistance in ticks infesting animals. AB - Discriminating concentrations (DCs) of malathion, coumaphos, fenvalerate and fipronil were determined to monitor acaricide resistance in field conditions. The LC99 values with 95% confidence interval for malathion, coumaphos, fenvalerate and fipronil were 5126.8 (5011.5-5240.7), 131.0 (120.4-142.5), 2257.5 (2198.1 2318.4) and 6.2 (5.87-6.55), respectively. The narrow confidence intervals in LC50 and LC99 of adult immersion test (AIT) and larval packet test (LPT) affirming the homogeneity of IVRI-I line. Variation in LPT based LC50 and LC99 values of malathion (55.9ppm) and coumpahos (28.4ppm) compared to those obtained in AIT indicating that larvae were more susceptible to these chemicals. The DCs for malathion, coumaphos, fenvalerate and fipronil against adults were determined as 10253.6, 262.0, 4515.0 and 12.4ppm while against larvae the values were 111.8, 56.8, 4014.0 and 9.6ppm, respectively. The working efficiency of DCs was successfully tested in field tick isolates. Establishment of country specific DCs of commonly used insecticides for monitoring of resistance in field ticks is emphasized for establishing tick control strategies. PMID- 25840927 TI - Double-balloon enteroscopy in Crohn's disease: findings and impact on management in a multicenter retrospective study. AB - BACKGROUND: Double-balloon enteroscopy (DBE) is effective in visualizing the small bowel to perform biopsy sampling and interventions. Few studies have evaluated the utility of DBE in patients with known or suspected Crohn's disease (CD). OBJECTIVE: To evaluate the use of DBE in the diagnosis and impact on patient management in known and suspected CD and to compare capsule endoscopy (CE) with DBE findings. DESIGN: Retrospective study from August 2004 to August 2009 of DBE procedures. SETTING: Five academic, tertiary U.S. centers. PATIENTS: Patients with known or suspected CD. MAIN OUTCOME MEASURES: Diagnostic yield, impact on patient management, and comparison of DBE to CE findings in patients with known and suspected CD. RESULTS: We analyzed 98 DBE procedures performed in 81 patients (38 with known CD and 43 with suspected CD). For patients with CD, common indications were abdominal pain and bleeding/anemia. The diagnostic yield was 87% (33/38 patients). The impact on subsequent management decisions was 82% (31/38). Common indications for DBE in patients with suspected CD were abnormal CE or other imaging. The diagnostic yield was 79% (34/43 patients). The impact on subsequent management decisions was 77% (33/43). In 17% of patients (14/81), DBE failed to reach the target lesion. There was 1 perforation, 3 strictures dilated, and 1 of 2 retained capsules recovered. When CE was followed by DBE, 46% of lesions were confirmed on DBE. LIMITATIONS: Retrospective analysis, imperfect criterion standard. CONCLUSIONS: DBE is an effective technique for assessment of the small bowel in known and suspected CD and affects management. Failure to reach target areas with DBE is not uncommon, and perforations can occur. There is poor correlation between CE and DBE. PMID- 25840928 TI - Investigating endoscopic features of sessile serrated adenomas/polyps by using narrow-band imaging with optical magnification. AB - BACKGROUND: A sessile serrated adenoma/polyp (SSA/P) is a common type of colorectal polyp that possesses malignant potential. Although narrow-band imaging (NBI) can easily differentiate neoplastic lesions from hyperplastic polyps (HPs), SSA/Ps can be a challenge to distinguish from HPs. OBJECTIVE: To investigate specific endoscopic features of SSA/Ps by using NBI with optical magnification. DESIGN: Retrospective study. SETTING: Single high-volume referral center. PATIENTS: A total of 289 patients with histopathologically proven SSA/Ps or HPs obtained from colonoscopic polypectomy. INTERVENTION: Endoscopic images obtained by using NBI with optical magnification of 242 lesions (124 HPs, 118 SSA/Ps) removed between January 2010 and December 2012 were independently evaluated by 2 experienced endoscopists. Three external experienced endoscopists systematically validated the diagnostic accuracies by using 40 lesions (21 HPs and 19 SSA/Ps) removed between January and March 2013. MAIN OUTCOME MEASUREMENTS: Specific endoscopic features of SSA/Ps by using 5 potential characteristics: dilated and branching vessels (DBVs), irregular dark spots, a regular network pattern, a disorganized network pattern, and a dense pattern. RESULTS: Multivariate analysis demonstrated that DBV had a 2.3-fold odds ratio (95% confidence interval, 0.96 5.69) among SSA/Ps compared with HPs (sensitivity, 56%; specificity, 75%; accuracy, 65%). Interobserver and intraobserver agreement indicated almost perfect agreement for DBVs in both the evaluation and validation studies. When DBVs, proximal location, and tumor size (>=10 mm) were combined, the positive predictive value was 92% and the area under the curve was 0.783 in the receiver operating characteristics by using the validation group. LIMITATIONS: Retrospective study. CONCLUSIONS: The current study suggests that a DBV is a potentially unique endoscopic feature of a colorectal SSA/P. PMID- 25840929 TI - Gestational weight gain and perinatal outcomes of subgroups of Asian-American women, Texas, 2009. AB - BACKGROUND: Asian-American subgroups are heterogeneous, but few studies had addressed differences on gestational weight gain (GWG) and perinatal outcomes related to GWG among this growing and diverse population. The purposes of this study were to examine whether Asian-American women are at higher risk of inadequate or excessive GWG and adverse perinatal outcomes than non-Hispanic White (NH-White) women, and to compare those risks among Asian-American subgroups. METHODS: This retrospective study included all singleton births to NH Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnam, and NH-White women documented in 2009 Texas birth certificate data (N = 150,674). Data were analyzed using the chi(2) test, t test, multinomial logistic regression, and binary logistic regression. Chinese women were the reference group in the comparisons among Asian subgroups. FINDINGS: Asian women had a higher risk of inadequate GWG and gestational diabetes mellitus (GDM) than NH-White women. No difference in the odds of excessive GWG was found among Asian subgroups, although Japanese women had the highest risk of inadequate GWG. After adjusting for confounders, Korean women had the lowest risk of GDM (adjusted odds ratio [AOR], 0.49), whereas Filipino women and Asian Indian had the highest risks of gestational hypertension (AOR, 2.01 and 1.61), cesarean birth (AOR, 1.44 and 1.39), and low birth weight (AOR, 1.94 and 2.51) compared with Chinese women. CONCLUSIONS: These results support the heterogeneity of GWG and perinatal outcomes among Asian-American subgroups. The risks of adverse perinatal outcomes should be carefully evaluated separately among Asian-American subpopulations. PMID- 25840930 TI - The Impact of Neighborhood Environment, Social Support, and Avoidance Coping on Depressive Symptoms of Pregnant African-American Women. AB - BACKGROUND: Although depressive symptoms during pregnancy have been related to negative maternal and child health outcomes such as preterm birth, low birth weight infants, postpartum depression, and maladaptive mother-infant interactions, studies on the impact of neighborhood environment on depressive symptoms in pregnant women are limited. Pregnant women residing in disadvantaged neighborhoods reported higher levels of depressive symptoms and lower levels of social support. No researchers have examined the relationship between neighborhood environment and avoidance coping in pregnant women. Guided by the Ecological model and Lazarus and Folkman's transactional model of stress and coping, we examined whether social support and avoidance coping mediated associations between the neighborhood environment and depressive symptoms in pregnant African-American women. METHODS: Pregnant African-American women (n = 95) from a medical center in Chicago completed the instruments twice during pregnancy between 15 and 25 weeks and between 25 and 37 weeks. The self administered instruments measured perceived neighborhood environment, social support, avoidance coping, and depressive symptoms using items from existing scales. Objective measures of the neighborhood environment were derived using geographic information systems. FINDINGS: Perceived neighborhood environment, social support, avoidance coping, and depressive symptoms were correlated significantly in the expected directions. Objective physical disorder and crime were negatively related to social support. Social support at time 1 (20 +/- 2.6 weeks) mediated associations between the perceived neighborhood environment at time 1 and depressive symptoms at time 2 (29 +/- 2.7 weeks). An increase in avoidance coping between times 1 and 2 also mediated the effects of perceived neighborhood environment at time 1 on depressive symptoms at time 2. CONCLUSION: Pregnant African-American women's negative perceptions of their neighborhoods in the second trimester were related to higher levels of depressive symptoms in the third trimester. If these results are replicable in prospective studies with larger sample sizes, intervention strategies could be implemented at the individual level to support pregnant women in their ability to cope with adverse neighborhood conditions and ultimately improve their mental health. PMID- 25840931 TI - Cervical Cancer Screening and Sexual Risky Behaviors among a Population of Hispanic Origin. AB - OBJECTIVE: To assess the prevalence of cervical cancer screening through Papanicolaou (Pap) test utilization and its association with sexual behaviors among a population-based sample of Hispanic women in Puerto Rico (PR). METHODS: This study was a secondary data analysis of the database of a cross-sectional study of HPV infection in PR (2010-2013; n = 554 women). Pap test utilization (past 3 years) was self-reported and sexual risky behavior was defined as an index that considered the following sexual behaviors: early age of sexual debut (<=16 years), 11 or more lifetime sexual partners, and 2 or more sexual partners in the last year. Multivariable logistic regression was used to estimate the magnitude of the association between sexual risk behavior and Pap test utilization, after adjusting for socioeconomic and lifestyles characteristics. RESULTS: The overall prevalence of Pap test utilization was 78.0%. Pap test screening varied with sexual behavior, with women with none or one risky sexual behavior having higher odds of Pap test utilization in the past 3 years (odds ratio [OR], 1.74; 95% CI, 1.03-2.93) compared with those with two or three risky sexual behaviors. This difference remained marginally significant (p < .10) after adjusting for age, educational attainment, smoking status and STI history (OR, 1.72; 95% CI, 0.96-3.08). CONCLUSIONS: The prevalence of cervical cancer screening in this population (78%) is still below Healthy People 2020 recommendations (93%). Also, women with risky sexual behaviors are less likely to have been screened. Efforts to promote cervical screening programs should focus on these high-risk women as a method for cervical cancer prevention and control. PMID- 25840932 TI - Introduction to Special Issue: At the Precipice of Quality Health Care: The Role of the Toxicologist in Enhancing Patient and Medication Safety : At the Precipice of Quality Health Care: The Role of the Toxicologist in Enhancing Patient and Medication Safety. Venue: 2014 North American Congress of Clinical Toxicology. ACMT Pre-Meeting Symposium, New Orleans, LA. PMID- 25840933 TI - The Institute for Safe Medication Practices and Poison Control Centers: Collaborating to Prevent Medication Errors and Unintentional Poisonings. AB - This article provides an overview on the Institute for Safe Medication Practices (ISMP), the only independent nonprofit organization in the USA devoted to the prevention of medication errors. ISMP developed the national Medication Errors Reporting Program (MERP) and investigates and analyzes errors in order to formulate recommendations to prevent further occurrences. ISMP works closely with the US Food and Drug Administration (FDA), drug manufacturers, professional organizations, and others to promote changes in package design, practice standards, and healthcare practitioner and consumer education. By collaborating with ISMP to share and disseminate information, Poison Control centers, emergency departments, and toxicologists can help decrease unintentional and accidental poisonings. PMID- 25840934 TI - Mania as a presenting clinical feature of subacute sclerosing panencephalitis. PMID- 25840936 TI - Enhanced and Updated American Heart Association Heart-Check Front-of-Package Symbol: Efforts to Help Consumers Identify Healthier Food Choices. PMID- 25840935 TI - Survey on the management of anorectal malformations (ARM) in European pediatric surgical centers of excellence. AB - PURPOSE: Various management strategies for anorectal malformations (ARM) have been proposed. The aim of this study was to assess the current management in centers of excellence in Europe. METHODS: An online survey on the pre- and post operative concepts, surgical techniques, and the management of complications was sent to the representative experts of 28 selected European centers of pediatric surgery with special expertise in the treatment of ARM. RESULTS: The survey was completed by 25 experts from 14 countries. To assess the level of the rectal pouch in newborns 60% of participants perform a prone cross-table X-ray and 52% ultrasound. If an ostomy is required, 84% create divided Pena stomas. Primary repair in the newborn period is performed in females with rectoperineal (92%), rectovestibular (60%), and no fistula (32%), and in males with rectoperineal (92%), rectourinary (17%) and no fistula (38%). For 68 % of surgeons, the PSARP is the preferred surgical approach for "low" malformations. Laparoscopically assisted pull-throughs are routinely performed by 48% of experts for ARM with bladderneck and 28% for rectoprostatic fistula. 88% perform postoperative dilations. CONCLUSIONS: The management of ARM in Europe is very heterogeneous. High-quality clinical studies are needed to provide scientific evidence for the optimal treatment strategies. PMID- 25840937 TI - Dietary Research to Reduce Children's Oral Health Disparities: An Exploratory Cross-Sectional Analysis of Socioeconomic Status, Food Insecurity, and Fast-Food Consumption. AB - BACKGROUND: Tooth decay is the most common childhood disease and it disproportionately affects low-income children. The dietary risk factors associated with socioeconomic status (SES), such as food insecurity and fast-food consumption, are poorly understood. OBJECTIVE: To better understand how upstream social factors are related to dietary behaviors by testing the hypothesis that food insecurity mediates the SES-fast-food consumption relationship. DESIGN: A 36 item survey was administered to caregivers of children younger than age 18 years (n=212). The predictor variable was SES, measured by whether the child was insured by Medicaid (no/yes). Food insecurity, the potential dietary mediator, was measured using the six-item US Department of Agriculture Household Food Security Survey (food secure/food insecure without hunger/food insecure with hunger). The outcome variable was whether the household reported eating at a fast food restaurant >=2 times a week (no/yes). We used logistic structural equation and mediation models to test our hypothesis. RESULTS: About 63% of children were classified as low SES. Thirty percent of caregivers reported food insecurity (with or without hunger) and 18.6% of households consumed fast food >=2 times per week. Lower SES was significantly associated with food insecurity (odds ratio [OR] 3.03, 95% CI 1.51 to 6.04; P=0.002), but SES was not related to fast-food consumption (OR 1.94, 95% CI 0.86 to 4.36; P=0.11). Food insecurity was not associated with fast-food consumption (OR 1.76, 95% CI 0.86 to 3.62; P=0.12). The mediation analyses suggest food insecurity does not mediate the relationship between SES and fast-food consumption. However, there are important potential differences in fast-food consumption by SES and food insecurity status. CONCLUSIONS: Future dietary research focusing on tooth decay prevention in vulnerable children may need to account for the differential effects of SES on food insecurity and dietary behaviors like fast-food consumption. Studies are needed to further elucidate the mechanisms linking SES, dietary behaviors, and tooth decay in children. PMID- 25840938 TI - At-risk and underserved: a proposed role for nutrition in the adult trajectory of autism. PMID- 25840939 TI - A Prospective Study of the Physiological and Neurobehavioral Effects of Ramadan Fasting in Preteen and Teenage Boys. AB - BACKGROUND: Intermittent fasting during the month of Ramadan, although not obligatory, is commonly practiced by Muslim children. OBJECTIVE: Our aim was to describe the effects of Ramadan fasting on various physiological and neurobehavioral measures in preteen and teenaged boys. DESIGN: We conduced a prospective cohort study during Ramadan, observed from August 9 to September 11, 2010. PARTICIPANTS: Eighteen healthy Muslim boys (mean age+/-standard deviation 12.6+/-1.5 years) were recruited and assessed before, during (1st and 4th weeks), and after Ramadan. Subjects were classified as preteens (aged 9 to 12 years) or teens (aged 13 to 15 years). INTERVENTION: On each clinic visit, participants completed a match-to-sample test, a spatial planning and working memory task, and a working memory capacity test using the Cambridge Neuropsychological Test Automated Battery. Participants were also assessed for their sleep patterns, daily energy expenditure, and dietary intake. Body composition was determined using a dual-energy x-ray scan. Complete blood count, lipid profile analysis, and iron indices were conducted. MAIN OUTCOME MEASURES: We measured morphologic, metabolic, and neurobehavioral parameters. STATISTICAL ANALYSES: A linear mixed model was used to assess changes in outcome measures. Post hoc pairwise comparisons were performed as necessary with Bonferroni adjustment. RESULTS: Within 1 week of fasting, there was a drop in body fat only in preteens (P=0.001). Reported fat (P=0.004) and protein intake (P=0.037) was higher during Ramadan, but energy expenditure did not change. By the end of Ramadan, there was a significant reduction in hemoglobin (mean+/-standard error -0.48+/-0.4 mmol/L) and serum iron (-25.7+/-31.8 MUg/dL [-4.6+/-5.7 MUmol/L]) levels. During week 4, total sleep duration decreased by 1.8 hours. At week 4, performance on the spatial planning and working memory task and working memory capacity test increased significantly (P=0.002), while match-to-sample test performance declined in preteens only (P=0.045). CONCLUSIONS: Ramadan fasting was associated with significant changes in body composition, dietary intake, and sleep patterns. Reductions in attention and iron indices were observed in preteens only. PMID- 25840940 TI - Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions. AB - Initially used as an alternative hematopoietic stem cell source for patients without a human leukocyte antigen-matched bone marrow or peripheral blood stem cell donor, unrelated cord blood (UCB) is now the preferred donor source when hematopoietic stem cell transplantation (HSCT) is used to treat patients with lysosomal storage disorders (LSD). Without transplantation, these patients have serious progressive multi-system deterioration and premature death. UCB transplantation favorably alters the natural history of these diseases and prolongs survival. It primarily works through cellular enzyme replacement by healthy engrafted donor cells providing a continuous endogenous supply of enzyme throughout the body and, thorough engraftment of donor-derived microgial cells, in the central nervous system. HSCT in LSD, the majority performed in patients with mucopolysaccharidoses and leukodystrophies, is associated with remarkably high rates of engraftment and survival. Importantly, recipients of UCB, as compared with other donor sources, more often achieve full-donor chimerism and normalization of enzyme levels, which has been associated with superior long-term clinical prognosis. Additionally, UCB units are readily available, reducing time to transplantation and thereby providing access to transplant at young ages, another highly important predictor for long-term neuro-developmental function. For these reasons, UCB grafts are nowadays considered to be the optimal graft source for HSCT in patients with LSD. PMID- 25840941 TI - Aberrant pancreatic ductal organisation: a case report. AB - Anomalous pancreatic ductal system has always enthralled the anatomists, surgeons, gastroenterologists and radiologists alike. With the growing use of MRCP, ERCP and endoscopic and surgical procedures, the knowledge of anatomical aberrations of pancreaticobiliary tract becomes extremely important. Moreover, the anomalous pancreatic duct morphology may be responsible for atypical gastrointestinal complains. We report an exceptionally rare case of two accessory ventral pancreatic ducts opening separately into the common bile duct proximal to the hepato pancreatic ampulla. Concomitant occurrence of an ectopic major duodenal papilla, 3.8 cm distal to the pyloric end of stomach was also seen. Moreover, the accessory pancreatic duct and the minor duodenal papilla were absent. Clinical implications and embryological description of these rare anomalies are discussed. Awareness of such rare morphological variants can go a long way in assisting effective patient management. PMID- 25840942 TI - The Hypoglycemic Risk of Glyburide (Glibenclamide) Compared with Modified-Release Gliclazide. AB - OBJECTIVES: The risk for hypoglycemia when taking glyburide compared with modified-release gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release gliclazide. METHODS: In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days. RESULTS: The baseline characteristics between matched groups were similar. Initiating glyburide vs. gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p<0.0001). Similar findings were noted when glyburide vs. gliclazide was initiated in the presence of metformin (110 patients of 8038 taking glyburide [1.37%] vs. 19 patients of 8038 taking gliclazide [0.24%], absolute risk increase 1.13% [95% CI 0.86% to 1.40%], number needed to harm 77 [71 to 116], odds ratio 6.06 [95% CI 3.68 to 9.97], p<0.0001). CONCLUSIONS: Glyburide was associated with a higher risk for hypoglycemia than modified-release gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release gliclazide as a safer alternative. PMID- 25840943 TI - The combination of DPP-4 inhibitors versus sulfonylureas with metformin after failure of first-line treatment in the risk for major cardiovascular events and death. AB - OBJECTIVE: To determine whether the combination of dipeptidyl-peptidase 4 (DPP-4) inhibitors vs. sulfonylureas with metformin after failure of first-line treatment is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction and stroke) and for all-cause mortality. METHOD: Using the UK Clinical Practice Research Datalink, a cohort of patients newly treated with metformin or sulfonylurea monotherapy between January 1, 1988, and December 31, 2011, was identified and was followed until December 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to compare the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination so as to study the risk for a composite endpoint consisting of myocardial infarction, stroke and all-cause mortality. The models were adjusted for high-dimensional propensity score deciles. RESULTS: The cohort consisted of 11,807 patients that included 2286 on a DPP-4 inhibitor metformin combination and 9521 on a sulfonylurea-metformin combination. The crude incidence rates (95% CIs) of the composite endpoint were 1.2% (0.8% to 1.7%) and 2.2% (1.9% to 2.5%) per year for the DPP-4 inhibitor-metformin and sulfonylurea metformin combinations, respectively. In the high-dimensional propensity score adjusted model, the use of the DPP-4 inhibitor-metformin combination was associated with a 38% decreased risk for the composite endpoint (adjusted HR: 0.62; 95% CI 0.40 to 0.98), compared with the sulfonylurea-metformin combination. CONCLUSIONS: The use of a DPP-4 inhibitor combination with metformin, compared with a sulfonylurea-metformin combination, was associated with decreased risks for major cardiovascular events and all-cause mortality. PMID- 25840944 TI - Monitoring blood glucose control: what does the future hold? PMID- 25840945 TI - School performance and wellbeing of children with CI in different communicative educational environments. AB - OBJECTIVES: This study aimed to evaluate the long term effects of CI on auditory, language, educational and social-emotional development of deaf children in different educational-communicative settings. METHODS: The outcomes of 58 children with profound hearing loss and normal non-verbal cognition, after 60 months of CI use have been analyzed. At testing the children were enrolled in three different educational settings; in mainstream education, where spoken language is used or in hard-of-hearing education where sign supported spoken language is used and in bilingual deaf education, with Sign Language of the Netherlands and Sign Supported Dutch. Children were assessed on auditory speech perception, receptive language, educational attainment and wellbeing. RESULTS: Auditory speech perception of children with CI in mainstream education enable them to acquire language and educational levels that are comparable to those of their normal hearing peers. Although the children in mainstream and hard-of hearing settings show similar speech perception abilities, language development in children in hard-of-hearing settings lags significantly behind. Speech perception, language and educational attainments of children in deaf education remained extremely poor. Furthermore more children in mainstream and hard-of hearing environments are resilient than in deaf educational settings. Regression analyses showed an important influence of educational setting. CONCLUSIONS: Children with CI who are placed in early intervention environments that facilitate auditory development are able to achieve good auditory speech perception, language and educational levels on the long term. Most parents of these children report no social-emotional concerns. PMID- 25840946 TI - Unilateral common cavity deformity: Recurrent meningitis due to insufficient newborn hearing screening. AB - Insufficient newborn hearing screening may leave the other ear with undetected hearing loss. Subsequently, the missed pathology behind the impairment may have potential risk for severe infections. We describe a case of recurrent Streptococcus pneumoniae meningitis in an infant with unilateral common cavity deformity. The diagnosis of the deaf left ear was delayed due to insufficient newborn hearing screening and not until the second meningitis the pathology behind the deafness was confirmed. Subtotal petrosectomy was performed unsuccessfully and resulted in another meningitis. We highlight the importance of proper newborn hearing screening and surgical technique to treat cochlear malformations. PMID- 25840947 TI - Recent applications of microchip electrophoresis to biomedical analysis. AB - Many separation methods have been developed for biomedical analysis, including chromatographic (e.g. high performance liquid chromatography (HPLC) and gas chromatography (GC)) and electrophoretic methods (e.g. gel electrophoresis and capillary electrophoresis (CE)). Among these techniques, CE provides advantages in terms of high separation efficiency, simplicity, low sample and solvent volume consumption, short analysis time and applicability to a wide range of biomedically important substances. Microchip electrophoresis (ME) is a miniaturized platform of CE and is now considered as a simpler and more convenient alternative, which has demonstrated potential in analytical chemistry. High-throughput, cost-effective and portable analysis systems can be developed using ME. The current review describes different separation modes and detectors that have been employed in ME to analyze various classes of biomedical analytes (e.g. pharmaceuticals and related substances, nucleic acids, amino acids, peptides, proteins, antibodies and antigens, carbohydrates, cells, cell components and lysates). Recent applications (during 2010-2014) in these areas are presented in tables and some significant findings are highlighted. PMID- 25840948 TI - Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model. AB - PURPOSE: To assess the antiangiogenic effect of bumetanide with dynamic contrast enhanced (DCE)-MRI and a biodegradable macromolecular MRI contrast agent. METHODS: A new polydisulfide containing macrocyclic gadolinium (Gd(III)) chelates, poly([(Gd-DOTA)-DETA]-co-DTBP) (GODP), was synthesized as a safe biodegradable macromolecular MRI contrast agent for DCE-MRI. Nude mice bearing flank HT29 colon cancer xenografts were then treated daily with either bumetanide or saline for a total of 3 weeks. DCE-MRI was performed before and after the treatment weekly. The DCE-MRI data were analyzed using the adiabiatic approximation to the tissue homogeneity (AATH) model to assess the change of tumor vascularity in response to the treatment. Immunohistochemistry (IHC) and western blot were performed to study tumor angiogenic biomarkers and hypoxia. RESULTS: DCE-MRI with GODP revealed that bumetanide reduced vascular permeability and plasma volume fraction by a significantly greater extent than the saline control therapy after 3 weeks of therapy. These changes were verified by the significant decline of CD31 and VEGF expression in the bumetanide treatment group. Despite a significant regression in vascularity, the tumors remained highly proliferative. Overexpression of the transcription factor HIF-1alpha in response to elevated hypoxia is thought to be the driving force behind the uninterrupted tumor expansion. CONCLUSION: This study demonstrated the effectiveness of DCE-MRI with GODP in detecting vascular changes following the administration of bumetanide. Bumetanide has the potential to curtail growth of the tumor vasculature and can be employed in future therapeutic strategies. PMID- 25840950 TI - Somatization among ethnic minorities and immigrants: Why does it matter to Consultation Liaison Psychiatry? PMID- 25840949 TI - Design and Development of Bioceramic Based Functionalized PLGA Nanoparticles of Risedronate for Bone Targeting: In-vitro Characterization and Pharmacodynamic Evaluation. AB - PURPOSE: Bioceramic(Hydroxyapatite) based Poly(D,L-lactide-co-glycolide) (PLGA) and polyethylene glycol (PEG) nanoparticles of Risedronate was prepared by dialysis method for bone-targeting. METHODS: Risedronate, a targeting moiety that has a strong affinity for bone, was conjugated to PLGA via carbodiimide chemistry. Mono-methoxy PEG(mPEG)-PLGA block polymers were synthesized and used to impart surface hydrophilicity to nanoparticles to avoid its uptake by reticuloendothelial system (RES). The structure of prepared di block copolymers were characterized by FT-IR and NMR spectrometry. Risedronate was adsorbed on the surface of hydroxyapatite (RIS-HA) and it was conjugated with different ratios of mPEG-PLGA. The formation of surface-modified PLGA nanoparticle prepared with various ratios of risedronate as well as hydroxyapatite and mPEG was confirmed by (1)H NMR and FT-IR spectrometry. RESULTS: Size and % entrapment of the prepared nanoparticle was found to be 79.3 +/- 2.3 nm and 93 +/- 3.1%. Transmission electron microscopy (TEM) revealed that mPEG-PLGA-RIS-HA nanoparticles possess smooth and uniform surface. Pharmacodynamic study was performed on Dexamethasone (DEX) induced osteoporotic model. The effect of various formulations (mPEG-PLGA RIS, mPEG-PLGA-RIS-HA and RISOFOS tablet) on bone was studied by Volume bone density (VBD) and by histopathological evaluation. Interestingly mPEG-PLGA-RIS HA, showed a significant enhancement in bone micro-architecture when compared with other formulations. CONCLUSIONS: The results strongly implicated that mPEG PLGA-RIS-HA has a therapeutic benefits over risedronate sodium monotherapy for the treatment of osteoporosis in a rat model. PMID- 25840951 TI - Psychological and interactional characteristics of patients with somatoform disorders: Validation of the Somatic Symptoms Experiences Questionnaire (SSEQ) in a clinical psychosomatic population. AB - OBJECTIVE: The new DSM-5 Somatic Symptom Disorder (SSD) emphasizes the importance of psychological processes related to somatic symptoms in patients with somatoform disorders. To address this, the Somatic Symptoms Experiences Questionnaire (SSEQ), the first self-report scale that assesses a broad range of psychological and interactional characteristics relevant to patients with a somatoform disorder or SSD, was developed. This prospective study was conducted to validate the SSEQ. METHODS: The 15-item SSEQ was administered along with a battery of self-report questionnaires to psychosomatic inpatients. Patients were assessed with the Structured Clinical Interview for DSM-IV to confirm a somatoform, depressive, or anxiety disorder. Confirmatory factor analyses, tests of internal consistency and tests of validity were performed. RESULTS: Patients (n=262) with a mean age of 43.4 years, 60.3% women, were included in the analyses. The previously observed four-factor model was replicated and internal consistency was good (Cronbach's alpha=.90). Patients with a somatoform disorder had significantly higher scores on the SSEQ (t=4.24, p<.001) than patients with a depressive/anxiety disorder. Construct validity was shown by high correlations with other instruments measuring related constructs. Hierarchical multiple regression analyses showed that the questionnaire predicted health-related quality of life. Sensitivity to change was shown by significantly higher effect sizes of the SSEQ change scores for improved patients than for patients without improvement. CONCLUSION: The SSEQ appears to be a reliable, valid, and efficient instrument to assess a broad range of psychological and interactional features related to the experience of somatic symptoms. PMID- 25840952 TI - Left Ventricular Geometry on Transthoracic Echocardiogram and Prognosis after Lacunar Stroke: The SPS3 Trial. AB - BACKGROUND: The spectrum, prevalence, and prognostic implications of abnormal left ventricular geometry (LVG) in patients with lacunar stroke are unknown. We examined the spectrum of LVG and its relationship with vascular risk factors and outcomes after lacunar stroke. METHODS: LVG was determined with transthoracic echocardiography for 1961 patients with magnetic resonance imaging-verified recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes trial. Multivariable logistic regression and Cox proportional hazards models were used to identify characteristics independently associated with LVG and to estimate risk from abnormal LVG for recurrent stroke and death. RESULTS: Abnormal LVG was present in 77%. Hispanic (odds ratio [OR], 1.4; 95% confidence interval, 1.1-1.8) or black (OR, 2.0; 1.3-2.9) race-ethnicity, diabetes (OR, 1.3; 1.0-1.7), hypertension, impaired renal function (OR, 1.8; 1.2 2.5), intracranial stenosis (OR, 1.5; 1.1-2.1), and abnormal left ventricular function (OR, 2.0; 1.4-3.0) were independently associated with abnormal LVG. Subjects with abnormal LVG also more frequently had advanced manifestations of small-vessel disease specifically previous subcortical infarcts and white matter hyperintensities. After adjusting for assigned treatments, clinical risk factors, and advanced manifestations of small-vessel disease, subjects with abnormal LVG remained at increased risk of stroke recurrence (hazard ratio, 1.5; confidence interval, 1.0-2.4). There was no interaction between LVG and assigned antiplatelet or blood pressure target. Abnormal LVG was not associated with mortality. CONCLUSIONS: LVG consistent with chronic hypertensive changes was highly prevalent and correlated with neuroradiologic manifestations of small vessel disease in lacunar stroke patients. These results support the constructs that both cerebral small-vessel disease and LVG represent end-organ consequences of chronic hypertension. PMID- 25840953 TI - Effect of CREST Findings on Carotid Revascularization Practice in the United States. AB - BACKGROUND: We sought to measure the impact of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) findings on clinical practice by studying trends in carotid artery stenting (CAS) and carotid endarterectomy (CEA) utilization before and after publication of CREST in a large US multihospital database. METHODS: The Premier Perspective Database was used to identify inpatient CEA and CAS procedures performed from January 2006 to March 2013. Patients were subclassified by age (<70/>=70 years) and presentation (symptomatic/asymptomatic). CEA and CAS volumes were compared before and after the publication of CREST (July 2010) using an interrupted time series model. RESULTS: A total of 121,157 CEA and 18,503 CAS procedures performed at 445 medical centers were identified. There was no significant change observed in the overall number of CEA procedures performed after CREST publication relative to the pre-existing trend (P = .08); however, there was a significant increase in the overall number of CAS procedures performed (delta of 40 cases, P = .0179) in patients aged younger than 70 years (delta of 24 cases, P = .0008), 70 years or older (delta of 25 cases, P = .0047), and asymptomatic patients (delta of 39 cases, P = .0159). The overall percentage of CEA procedures performed in relation to all revascularization procedures was significantly lower after CREST publication overall (delta, -1.5%; P = .041) for patients aged younger than 70 years (delta, -2.4%; P < .0001) and asymptomatic patients (delta, -1.5%; P = .035). CONCLUSIONS: In this large sample of US hospitals, performance of CAS significantly increased after the publication of the CREST study. PMID- 25840954 TI - Varicella-zoster vasculitis presenting with cerebellar hemorrhage. AB - BACKGROUND: Varicella zoster virus (VZV) is known as one of the rare, but important, causes of both ischemic and hemorrhagic stroke. Most previously reported VZV-related hemorrhagic stroke and cerebral vasculitis are associated with anterior circulation because VZV spreads from trigeminal ganglia to the anterior circulation of Willis. The present study presents a patient with cerebellar hemorrhage, who was diagnosed with VZV encephalitis and vasculitis of the posterior inferior cerebellar artery. CASE REPORT: A 75-year-old man with stupor was admitted to our hospital. Computed tomography revealed right intracerebellar hemorrhage, and magnetic resonance imaging revealed multiple high intense signals throughout the brainstem and temporal lobe on fluid attenuation inversion recovery, suggestive of encephalitis. Cerebral angiography revealed stenosis of left posterior inferior cerebellar artery. Based on cerebrospinal fluid analysis, including anti-VZV IgG antibody and VZV DNA polymerase chain reaction, the patient was diagnosed with VZV encephalitis, vasculitis, and cerebellar hemorrhage. CONCLUSIONS: Both cerebral vasculitis and hemorrhagic stroke due to VZV can occur in the vertebrobasilar system. VZV may enter the central nervous system not only from trigeminal ganglia but also from other pathways. We should be aware that a VZV infection could cause cerebral vasculitis and hemorrhagic stroke in the vertebrobasilar system and in anterior circulation. PMID- 25840955 TI - [Apnea test in brain death. Is it safe to perform with CPAP using conventional respirators?]. PMID- 25840956 TI - Partitioning of Aromatic Constituents into Water from Jet Fuels. AB - A comprehensive study of the most commonly used jet fuels (i.e., Jet A-1 and JP 8) was performed to properly assess potential contamination of the subsurface environment from a leaking underground storage tank occurred in an airport. The objectives of this study were to evaluate the concentration ranges of the major components in the water-soluble fraction of jet fuels and to estimate the jet fuel-water partition coefficients (K fw) for target compounds using partitioning experiments and a polyparameter linear free-energy relationship (PP-LFER) approach. The average molecular weight of Jet A-1 and JP-8 was estimated to be 161 and 147 g/mole, respectively. The density of Jet A-1 and JP-8 was measured to be 786 and 780 g/L, respectively. The distribution of nonpolar target compounds between the fuel and water phases was described using a two-phase liquid-liquid equilibrium model. Models were derived using Raoult's law convention for the activity coefficients and the liquid solubility. The observed inverse, log-log linear dependence of the K fw values on the aqueous solubility were well predicted by assuming jet fuel to be an ideal solvent mixture. The experimental partition coefficients were generally well reproduced by PP-LFER. PMID- 25840957 TI - Reply To: Citation Distortions in the Literature on the Serotonin-Transporter Linked Polymorphic Region and Amygdala Activation. PMID- 25840958 TI - A comparison of the potential health risk of aluminum and heavy metals in tea leaves and tea infusion of commercially available green tea in Jiangxi, China. AB - Heavy metals and Al in tea products are of increasing concern. In this study, contents of Al, Cd, Co, Cr, Cu, Ni, and Pb in commercially available green tea and its infusions were measured by ICP-MS and ICP-AES. Both target hazard quotient (THQ) and hazard index (HI) were employed to assess the potential health risk of studied metals in tea leaves and infusions to drinkers. Results showed that the average contents of Al, Cd, Co, Cr, Cu, Ni, and Pb in tea leaves were 487.57, 0.055, 0.29, 1.63, 17.04, 7.71, and 0.92 mg/kg, respectively. Except for Cu, metal contents were within their maximum limits (1, 5, 30, and 5 mg/kg for Cd, Cr, Cu, and Pb, respectively) of current standards for tea products. Concentrations of metals in tea infusions were all below their maximum limits (0.2, 0.005, 0.05, 1.0, 0.02, and 0.01 mg/L for Al, Cd, Cr(VI), Cu, Ni, and Pb, respectively) for drinking water, and decreased with the increase of infusion times. Pb, Cd, Cu, and Al mainly remained in tea leaves. The THQ from 2.33 * 10( 5) to 1.47 * 10(-1) and HI from1.41 * 10(-2) to 3.45 * 10(-1) values in tea infusions were all less than 1, suggesting that consumption of tea infusions would not cause significant health risks for consumers. More attention should be paid to monitor Co content in green tea. Both THQ and HI values decreased with the increase of infusion times. Results of this study suggest that tea drinkers should discard the first tea infusion and drink the following infusions. PMID- 25840959 TI - Lectin microarray technology identifies specific lectins related to lymph node metastasis of advanced gastric cancer. AB - BACKGROUND: Although various molecular profiling technologies have the potential to predict specific tumor phenotypes, the comprehensive profiling of lectin-bound glycans in human cancer tissues has not yet been achieved. METHODS: We examined 242 advanced gastric cancer (AGC) patients without or with lymph node metastasis N0 (n = 62) or N+ (n = 180)-by lectin microarray, and identified the specific lectins highly associated with AGC phenotypes. RESULTS: In seven gastric cancer cell lines, in contrast to expressed-in-cancer lectins, not-expressed-in-cancer (NEC) lectins were tentatively designated by lectin microarray. Binding signals of the specific lectins were robustly reduced in AGC patients with N+ status as compared with those with N0 status. The receiver operating characteristic curve determined the optimal cutoff value to differentiate N0 status from N+ status, and subsequent profiling of NEC lectins identified Vicia villosa agglutinin (VVA) association with the significant other lectins involved in lymph node metastasis. VVA reaction was clearly found on cancer cells, suggesting that it may result from carcinoma-stroma interaction in primary AGC, because VVA is an NEC lectin. Most intriguingly, VVA reaction was remarkably attenuated in the tumor cells of the metastatic lymph nodes, even if it was recognized in primary AGC. In AGC, histological type was strongly associated with soybean agglutinin and Bauhinia purpurea lectin, whereas p53 mutation was the best correlated with Griffonia simplicifolia lectin II. CONCLUSIONS: Lectin microarrays can be used to very accurately quantify the reaction of glycans with tumor tissues, and such profiles may represent the specific phenotypes, including N+ status, histological type, or p53 mutation of AGC. PMID- 25840960 TI - Molecular cloning and immune responsive expression of LGP2 gene, a pivotal member of the RLR gene family from Muscovy duck Cairina moschata. AB - Laboratory of genetics and physiology 2 (LGP2) is an important intracellular receptor that recognizes viral RNAs in innate immunity. In this study, a novel LGP2 cDNA was identified from the spleen of a Muscovy duck (Cairina moschata). The deduced amino acid sequence of Muscovy duck LGP2 (MDLGP2) consisted of 675 amino acid residues. The peptide contained two main structure domains: six important motifs, including a DExD/H box for RNA helicase activity in the RNA helicase region located at the N-terminal region, and two Zn2+-binding regions with an RNA-binding loop in the C-terminus regulatory domain (CTD). The MdLGP2 mRNA was ubiquitously expressed in the tested tissues, with high expression levels in glandular stomach, colon, ileum, crop, and caecum tissues, and low expression levels in the brain, skin, and heart. The mRNA expression of MdLGP2 was significantly upregulated in the brain, spleen, and lungs of ducks in the early stages of postinfection with H5N1 highly pathogenic avian influenza virus (HPAIV). These results suggested that MdLGP2 was involved in the early stages of antiviral innate immune response in ducks after infection with H5N1 HPAIV. However, whether it plays a positive or negative regulatory role in the host antiviral response requires further investigation. PMID- 25840961 TI - Temporal expression and DNA hypomethylation profile of CD30 in Marek's disease virus-infected chicken spleens. AB - Marek's disease (MD) is a viral neoplastic disease of chickens caused by Marek's disease virus (MDV), which is serious threat to worldwide poultry industry. Our previous studies showed that the CD30 gene was hypomethylated in MD lymphoma. In this study, we further analyzed differential expression patterns and methylation levels of the CD30 gene between MDV-infected and noninfected spleens at 4, 7, 14, 21, and 28 d postinfection (dpi). The results showed that the expression of CD30 in MDV-infected spleens was significantly lower than that in noninfected spleens at 4 dpi. The expression of CD30 did not present significant difference between MDV-infected and noninfected spleens at 7 and 14 dpi. However, an increased expression of CD30 was presented in MDV-infected spleens at both 21 and 28 dpi. Simultaneously, CD30 showed a lower DNA methylation level in MDV-infected spleens at 14, 21, and 28 dpi. The results indicated that CD30 gene was involved in the whole process of MD tumorigenesis and upregulated expression of CD30 in MDV infected spleens might be attributed to the hypomethylation of promoter of CD30 gene. PMID- 25840962 TI - Characterization of Clostridium perfringens isolates obtained from 2010 to 2012 from chickens with necrotic enteritis in Korea. AB - Clostridium perfringens produces diverse virulent toxins that cause necrotic enteritis in poultry, resulting in a great negative impact on the poultry industry. To study the characteristics of C. perfringens in chickens, we isolated 88 strains from chickens (1 strain per flock) with necrotic enteritis. The isolated bacterial strains were screened for toxin type and antimicrobial susceptibility. Necropsy of 17 chickens that died from necrotic enteritis revealed that their intestines were dilated with inflammatory exudates and characterized by mucosal necrosis. All the isolated strains were identified as toxin type A using multiplex PCR for toxin typing. We found that the rate of netB positive strains isolated from dead chickens was significantly higher (8 of 17) than the rate among healthy chickens (2 of 50). We performed antimicrobial susceptibility test with 20 selected antimicrobial agents using the disk diffusion test and found that 30 tested strains were completely resistant to 5 antibiotics and partially resistant to 6 antibiotics whereas all the strains were susceptible to 9 antimicrobial agents. Using pulsed-field gel electrophoresis analysis, the 17 strains were divided into 13 genetic clusters showing high genetic diversity. In conclusion, C. perfringens strains isolated from Korean poultry showed a high resistance to antimicrobial drugs and high genetic diversity, suggesting that continuous monitoring is essential to prevent outbreaks of necrotic enteritis in chickens. PMID- 25840964 TI - Class 1 and class 2 integrons in avian pathogenic Escherichia coli from poultry in Italy. AB - The aim of this study was to investigate the occurrence of class 1 and 2 integrons in avian pathogenic Escherichia coli (APEC) from poultry in northern Italy. Strains were tested for phenotypic resistance to aminoglycosides and sulphonamides, and the association between the presence of integrons and the resistance to these antimicrobials was evaluated. A total of 299 isolates (158 from turkeys, 110 from broilers, and 31 from layer hens) were collected from 200 industrial farms. Antimicrobial susceptibility test by the disk diffusion method was performed in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. All strains were screened for the presence of class 1 and 2 integrons by PCR and sequencing. About 55% of APEC contained integrons (class 1, 49.8%; class 2, 10.4%). Different variants of the aadA (5 variants) and the dfrA (4 variants) genes, encoding for streptomycin and trimethoprim resistance respectively, were detected in integron-positive isolates. Less common gene cassettes, such as sat, estX, and orfF, were also identified. Fifteen and 4 gene cassette arrays were found among class 1 and 2 integrons, respectively. High levels of resistance were observed for triple sulphonamides (79.3%), streptomycin (67.2%), and sulfamethoxazole combined with trimethoprim (62.2%), whereas resistance against gentamycin (16.7%), kanamycin (14.7%), and apramycin 3.0%) was low. Integron positivity was significantly higher in isolates phenotypically resistant to aminoglycosides (63.6% vs. 37.8%, P<0.001) and sulfonamides (64.1% vs. 21.1%, P<0.001) than in susceptible ones. Integron-borne aminoglycoside and sulfonamide resistance in APEC represents a concern for the poultry industry in Italy, since they are among the most commonly used antimicrobials in poultry therapy. PMID- 25840963 TI - Prevalence and effects of mycotoxins on poultry health and performance, and recent development in mycotoxin counteracting strategies. AB - Extensive research over the last couple of decades has made it obvious that mycotoxins are commonly prevalent in majority of feed ingredients. A worldwide mycotoxin survey in 2013 revealed 81% of around 3,000 grain and feed samples analyzed had at least 1 mycotoxin, which was higher than the 10-year average (from 2004 to 2013) of 76% in a total of 25,944 samples. The considerable increase in the number of positive samples in 2013 may be due to the improvements in detection methods and their sensitivity. The recently developed liquid chromatography coupled to (tandem) mass spectrometry allows the inclusion of a high number of analytes and is the most selective, sensitive, and accurate of all the mycotoxin analytical methods. Mycotoxins can affect the animals either individually or additively in the presence of more than 1 mycotoxin, and may affect various organs such as gastrointestinal tract, liver, and immune system, essentially resulting in reduced productivity of the birds and mortality in extreme cases. While the use of mycotoxin binding agents has been a commonly used counteracting strategy, considering the great diversity in the chemical structures of mycotoxins, it is very obvious that there is no single method that can be used to deactivate mycotoxins in feed. Therefore, different strategies have to be combined in order to specifically target individual mycotoxins without impacting the quality of feed. Enzymatic or microbial detoxification, referred to as "biotransformation" or "biodetoxification," utilizes microorganisms or purified enzymes thereof to catabolize the entire mycotoxin or transform or cleave it to less or non-toxic compounds. However, the awareness on the prevalence of mycotoxins, available modern techniques to analyze them, the effects of mycotoxicoses, and the recent developments in the ways to safely eliminate the mycotoxins from the feed are very minimal among the producers. This symposium review paper comprehensively discusses the above mentioned aspects. PMID- 25840965 TI - Inclusion levels of sweet potato root meal in the diet of broilers I. Effect on performance, organ weights, and carcass quality. AB - The amount of corn available for animal and poultry feed has been unpredictable in recent years due to the increased use of corn for ethanol production. As a consequence, there has been an increase in the price of feed, chicken, and chicken products. Researchers are exploring alternative feed sources to substitute for corn in poultry ration. This study evaluated the performance and carcass quality of broilers fed diets containing sweet potato root meal (SPRM). After a complete nutrient analysis of the SPRM, diets were formulated where 0, 10, 20, and 30% of corn was substituted with SPRM. The study utilized 360 1-d-old Cornish X Rock male broiler chickens randomly assigned to one of 4 treatments; 0%, 10%, 20%, and 30% SPRM. Body weights and feed intake (FI) were monitored weekly for 7 wk. Birds were slaughtered on d 50 and FI, BW gain, ADG, ADFI, abdominal fat, dressing percentage, and organ weights measured. White (breast) and dark (leg and thigh) meat were evaluated for nutrient content (protein, moisture, fat, and ash). Results showed birds fed 20% SPRM had lower (P<0.03) final BW, BW gain and ADG than those fed the 30% SPRM diet. There were no differences in FI and ADFI among treatments. Feed conversion ratio was lowest (P<0.02) in birds fed 10, 20, and 30% SPRM than the control. There were no differences in dressing percentage among treatments. Abdominal fat was highest (P<0.05) in birds fed 30% SPRM. Organ weights were similar across treatments except for gizzard which weighed highest (P<0.05) in the control. For white meat; moisture, protein, fat, and ash were similar across treatments. For dark meat, moisture (P<0.004) and fat (P<0.03) were highest in the control, while protein and ash were similar among treatments. Birds fed the SPRM diets compared well with those fed the control for both performance and nutrient content of meat. PMID- 25840966 TI - Nutritional effects of egg shell membrane supplements on chicken performance and immunity. AB - Eggshell membranes (ESM) contain a variety of proteins and peptides which help in the development of embryo and provide protection to it. Many of the peptides and proteins associated with ESM have antimicrobial, immune-modulatory, and adjuvant properties. We hypothesized that the membrane byproducts from egg, provided as posthatch nutritional supplements to chickens, may improve their performance and immunity. To explore its effect, we fed 3 groups of broiler chicks with feed containing 0, 0.2, and 0.4% ESM from d 1 posthatch through 14 d and regular feed thereafter. The birds were individually weighed at the onset of the study and at weekly intervals until the termination at third wk when they were bled and euthanized. The relative weights of liver, spleen, bursa, and heart, hematology profiles, and clinical chemistry variables including serum IgM, IgG, and corticosterone concentrations were measured. The chickens in the ESM treated groups showed a statistically significant increase in BW with no impact on relative organ weights. Compared with controls, the WBC and lymphocyte percentage increased in chickens fed 0.4% ESM whereas the monocyte percentage decreased at both levels of ESM. Except for the serum protein which increased in ESM fed birds no other metabolic clinical chemistry variables showed any significant change. Both IgM and IgG(Y) levels were elevated and corticosterone levels reduced in chickens fed ESM supplemented diets. Our results suggest that ESM supplements during the early phases of growth may improve immunity and stress variables, and enhance their growth performance without any detrimental effect on other physiological parameters. PMID- 25840967 TI - Bacterial enteritis in ostrich (Struthio Camelus) chicks in the Western Cape Province, South Africa. AB - Ostrich (Struthio camelus) chicks less than 3 mo age are observed to experience a high mortality rate that is often associated with enteritis. This study was undertaken to investigate the infectious bacteria implicated in ostrich chick enteritis. Postmortems were performed on 122 ostrich chicks aged from 1 d to 3 mo and intestinal samples were subjected to bacterial culture. Bacterial isolates were typed by PCR and serotyping. Escherichia coli (E. coli; 49%) was the most frequently isolated from the samples followed by Clostridium perfringens (C. perfringens; 20%), Enterococcus spp. (16%), and Salmonella spp. (7%). Of the E. coli, 39% were categorized as enteropathogenic E. coli, 4% enterotoxigenic E. coli, and no enterohaemorrhagic E. coli were found. The majority (93%) of C. perfringens was Type A and only 7% was Type E. C. perfringens Types B through D were not present. The netB gene that encodes NetB toxin was identified from 16% of the C. perfringens isolated. All the C. perfringens Type E harbored the netB gene and just 10% of the C. perfringens Type A had this gene. Three Salmonella serotypes were identified: Salmonella Muenchen (S. Muenchen; 80%), S. Hayindongo (13%), and S. Othmarschen (7%). The indication is that the cause of enteritis in ostrich chicks is bacterial-involving: enteropathogenic E. coli and enterotoxigenic E. coli; C. perfringens Types A and E (with the possible influence of netB gene); and S. Muenchen, S. Hayindongo, and S. Othmarschen. PMID- 25840968 TI - Sialyltransferases with enhanced legionaminic acid transferase activity for the preparation of analogs of sialoglycoconjugates. AB - Legionaminic acids (Leg) are bacterial analogs of neuraminic acid, with the same stereochemistry but different substituents at C5, C7 and C9. Hence they may be incorporated into useful analogs of sialoglycoconjugates, and we previously reported two sialyltransferases that could utilize cytidine monophosphate (CMP) Leg5Ac7Ac for preparation of Leg glycoconjugates, which were resistant to sialidases [Watson DC, Leclerc S, Wakarchuk WW, Young NM. 2011. Enzymatic synthesis and properties of glycoconjugates with legionaminic acid as a replacement for neuraminic acid. Glycobiology. 21:99-108.]. These were the porcine ST3Gal1 and Pasteurella multocida sialyltransferases. We now report two additional sialyltransferases with superior Leg-transferase properties to the previous two. These are (i) a truncated form of a Photobacterium alpha2,6 sialyltransferase with an Ala-Met mutation in its active site, and (ii) an alpha2,3-sialyltransferase from Neisseria meningitidis MC58 with a higher transferase activity than the P. multocida enzyme, with either CMP-Neu5Ac or CMP Leg5Ac7Ac as the donor. These enzymes will enable the production of useful Leg5Ac7Ac glycoconjugate derivatives with either alpha2,6 or alpha2,3 linkages and unique biological properties. PMID- 25840969 TI - A Novel Anti-CD22 Anthracycline-Based Antibody-Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs. AB - PURPOSE: We are interested in identifying mechanisms of resistance to the current generation of antibody-drug conjugates (ADC) and developing ADCs that can overcome this resistance. EXPERIMENTAL DESIGN: Pinatuzumab vedotin (anti-CD22-vc MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22 NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE based ADCs. RESULTS: We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE-based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines. CONCLUSIONS: These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates. PMID- 25840970 TI - Global Transcriptional Changes Following Statin Treatment in Breast Cancer. AB - BACKGROUND: Statins purportedly exert antitumoral effects, but the underlying mechanisms are currently not fully elucidated. The aim of this study was to explore potential statin-induced effects on global gene expression profiles in primary breast cancer. EXPERIMENTAL DESIGN: This window-of-opportunity phase II trial enrolled 50 newly diagnosed breast cancer patients prescribed atorvastatin (80 mg/day) for 2 weeks presurgically. Pre- and posttreatment tumor samples were analyzed using Significance Analysis of Microarrays (SAM) to identify differentially expressed genes. Similarly, SAM and gene ontology analyses were applied to gene expression data derived from atorvastatin-treated breast cancer cell lines (MCF7, BT474, SKBR3, and MDAMB231) comparing treated and untreated cells. The Systematic Motif Analysis Retrieval Tool (SMART) was used to identify enriched transcription factor-binding sites. Literature Vector Analysis (LitVAn) identified gene module functionality, and pathway analysis was performed using GeneGo Pathways Software (MetaCore; https://portal.genego.com/). RESULTS: Comparative analysis of gene expression profiles in paired clinical samples revealed 407 significantly differentially expressed genes (FDR = 0); 32 upregulated and 375 downregulated genes. Restricted filtration (fold change >=1.49) resulted in 21 upregulated and 46 downregulated genes. Significantly upregulated genes included DUSP1, RHOB1, GADD45B, and RGS1. Pooled results from gene ontology, LitVAn and SMART analyses identified statin-induced effects on the apoptotic and MAPK pathways among others. Comparative analyses of gene expression profiles in breast cancer cell lines showed significant upregulation of the mevalonate and proapoptotic pathways following atorvastatin treatment. CONCLUSIONS: We report potential statin-induced changes in global tumor gene expression profiles, indicating MAPK pathway inhibition and proapoptotic events. PMID- 25840971 TI - Biological Activities of RUNX1 Mutants Predict Secondary Acute Leukemia Transformation from Chronic Myelomonocytic Leukemia and Myelodysplastic Syndromes. AB - PURPOSE: Transcription factor RUNX1 is essential for normal hematopoiesis. High mutation frequencies of RUNX1 gene in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) have been described, whereas the biologic significances of the mutations were not investigated. Here, we aimed to correlate the biologic activities of the RUNX1 mutants with the clinical outcomes of patients. EXPERIMENTAL DESIGN: We examined the mutational status of RUNX1 in 143 MDS and 84 CMML patients. Then, we studied the DNA and CBFbeta binding abilities of all the RUNX1 mutants identified by using electrophoretic mobility shift assay and co-immunoprecipitation assay, and also determined their activities on target C-FMS gene induction by Western blotting and luciferase reporter assay. Using luciferase reporter assay, the relative biologic activities of each RUNX1 mutant could be quantified and correlated with the patient outcomes by statistical analyses. RESULTS: We observed that most RUNX1 mutants had reduced abilities in DNA binding, CBFbeta heterodimerization, and C-FMS gene induction. The relative biologic activities of RUNX1 mutants were grouped into high- and low-activity mutations. Correlation of the activities of RUNX1 mutants with the clinical outcomes revealed that patients harboring lower activities of RUNX1 mutants had a higher risk and shorter time to secondary acute myeloid leukemia transformation in MDS and CMML. In multivariate analysis, low RUNX1 activity remained an independent predictor for secondary acute myeloid leukemia-free survival in MDS patients. CONCLUSIONS: The biologic activity rather than the mutational status of RUNX1 might be an indicator in predicting outcome of patients with MDS and CMML. PMID- 25840972 TI - Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma. AB - PURPOSE: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma. PATIENTS AND METHODS: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed. RESULTS: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade >=3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage >=50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival >=6 months. CONCLUSIONS: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development. PMID- 25840973 TI - Claudin-4 SPECT Imaging Allows Detection of Aplastic Lesions in a Mouse Model of Breast Cancer. AB - The expression of claudin-4, a protein involved in tight junction complexes, is widely dysregulated in epithelial malignancies. Claudin-4 is overexpressed in several premalignant precursor lesions, including those of cancers of the breast, pancreas, and prostate, and is associated with poor survival. A noncytotoxic C terminal fragment of Clostridium perfringens enterotoxin (cCPE) is a natural ligand for claudin-4. Here, we demonstrate whole-body quantitative SPECT imaging of preneoplastic breast cancer tissue using (111)In-labeled cCPE. METHODS: cCPE.GST or GST (GST is glutathione S-transferase) was conjugated to the metal ion chelator benzyl-diethylenetriaminepentaacetic acid to allow (111)In radiolabeling. The affinity of radiolabeled cCPE.GST for claudin-4 was confirmed using claudin-4-expressing MDA-MB-468 and SQ20b cells, compared with claudin-4 negative HT1080 cells. In vivo SPECT imaging was performed using athymic mice bearing MDA-MB-468 or HT1080 xenografts and using genetically modified BALB/neuT mice, which spontaneously develop claudin-4-expressing breast cancer lesions. RESULTS: The uptake of (111)In-cCPE.GST in claudin-4-positive MDA-MB-468 xenograft tumors in athymic mice was significantly higher than in (111)In-GST or claudin-4-negative HT1080 tumors (6.72 +/- 0.18 vs. 3.88 +/- 1.00 vs. 2.36 +/- 1.25 percentage injected dose per gram [%ID/g]; P < 0.0001). No other significant differences were observed in any of the examined organs. BALB/neuT mice, expressing rat neuT under mmtv promotor control, spontaneously developed tumorous lesions within their mammary fat pads over the course of 130 d. Overt mammary tumors were claudin-4-positive, and (111)In-cCPE.GST uptake was 3.2 +/- 0.70 %ID/g, significantly higher than (111)In-GST (1.00 +/- 0.60 %ID/g; P < 0.05). Mammary fat pads in mice aged 80 d bore claudin-4-positive aplastic lesions and accumulated (111)In-cCPE.GST (3.17 +/- 0.51 %ID/g) but not (111)In-GST (0.99 +/- 0.39 %ID/g; P < 0.001). CONCLUSION: Taken together, (111)In-cCPE.GST targets claudin-4 expression in frank tumors and preneoplastic tissue, and cCPE imaging may be used as an early detection tool for breast, prostate, and pancreatic cancer. PMID- 25840975 TI - 99mTc-NTP 15-5 Imaging for Cartilage Involvement in Experimental Rheumatoid Arthritis: Comparison with Routinely Used Molecular Imaging Methods and Sensitivity to Chronic Nonsteroidal Antiinflammatory Drug Treatment. AB - This study determined, using the intraarticular complete Freund adjuvant arthritis mice model, whether the radiotracer (99m)Tc-N-(triethylammonium)-3 propyl-[15]ane-N5 ((99m)Tc-NTP 15-5) targeting proteoglycans has a pathophysiologic validity for in vivo imaging of rheumatoid arthritis (RA) and its response to chronic nonsteroidal antiinflammatory drugs. METHODS: We investigated the time course of cartilage remodeling by (99m)Tc-NTP 15-5 scintigraphy, bone damages by (99m)Tc-hydroxymethylene diphosphonate imaging, inflammation by (18)F-FDG PET, and joint proteoglycan content and pain behavior in animals, without and with meloxicam treatment. Paw circumference, thermal pain behavior, and histology as well as proteoglycan content of the whole joint were determined. RESULTS: (99m)Tc-NTP 15-5 showed specific tracer accumulation within RA joints, with a significant increase in scintigraphic ratio observed in RA versus shams from day 3 to day 28. (18)F-FDG evidenced uptake in RA joints from day 15 to day 29. Animals treated with meloxicam (5 mg/kg) exhibited a dose dependent decrease in both (99m)Tc-NTP 15-5 and (18)F-FDG uptake ratios versus saline-treated animals. (99m)Tc-hydroxymethylene diphosphonate bone scans were only positive at day 14 in RA versus shams, with a significant effect of meloxicam. An increase in proteoglycans of RA joint and thermal pain behavior were observed and were dose-dependently reduced by meloxicam. CONCLUSION: These experimental results bring data in favor of the (99m)Tc-NTP 15-5 radiotracer for assessing, in vivo, cartilage remodeling in RA that could be used to monitor therapy. PMID- 25840974 TI - Cerenkov Luminescence Imaging for Radiation Dose Calculation of a 90Y-Labeled Gastrin-Releasing Peptide Receptor Antagonist. AB - (90)Y has been used to label various new therapeutic radiopharmaceuticals. However, measuring the radiation dose delivered by (90)Y is challenging because of the absence of suitable gamma emissions and its low abundance of positron emissions. For the treatment of prostate cancer, radiolabeled gastrin-releasing peptide receptor (GRPr) antagonists have yielded promising results in mouse models. In this study, we evaluated whether Cerenkov luminescence imaging (CLI) could be used to determine radiation doses of a (90)Y-labeled GRPr antagonist in nude mice. METHODS: Mice bearing subcutaneous prostate cancer xenografts were injected with 0.74-18.5 MBq of the (90)Y-labeled GRPr antagonist DOTA-AR and underwent in vivo and ex vivo CLI at 1-48 h after injection. After imaging, animals were sacrificed, their tumors and organs were harvested, and the activity concentration was measured by liquid scintillation counting. In a second set of experiments, Cerenkov photon counts for tumor and kidney on in vivo CLI were converted to activity concentrations using conversion factors determined from the first set of experiments. RESULTS: (90)Y-DOTA-AR concentration in the 3 tumor models ranged from 0.5% to 4.8% of the injected activity per gram at 1 h after injection and decreased to 0.05%-0.15 injected activity per gram by 48 h after injection. A positive correlation was found between tumor activity concentrations and in vivo CLI signal (r(2) = 0.94). A similar correlation was found for the renal activity concentration and in vivo Cerenkov luminescence (r(2) = 0.98). Other organs were not distinctly visualized on the in vivo images, but ex vivo CLI was also correlated with the radioactivity concentration (r(2) = 0.35-0.94). Using the time-activity curves from the second experiment, we calculated radiation doses to tumor and kidney of 0.33 +/- 0.12 (range, 0.21-0.66) and 0.06 +/- 0.01 (range, 0.05-0.08) Gy/MBq, respectively. CONCLUSION: CLI is a promising, low-cost modality to measure individual radiation doses of (90)Y-labeled compounds noninvasively. The use of Cerenkov imaging is expected to facilitate the development and comparison of (90)Y-labeled compounds for targeted radiotherapy. PMID- 25840976 TI - Flow-Dependent Uptake of 123I-CMICE-013, a Novel SPECT Perfusion Agent, Compared with Standard Tracers. AB - Rotenone derivatives have shown promise in myocardial perfusion imaging (MPI). CMICE-013 is a novel (123)I-labeled rotenone derivative developed for SPECT MPI. The objective of this study was to assess the image quality of CMICE-013 and compare its uptake with tetrofosmin, sestamibi, and (201)Tl in vivo in a porcine model of stress-induced myocardial ischemia. METHODS: Microspheres were injected simultaneously with the radiotracer injections at rest and stress to measure blood flow. Mimicking a 1-d tetrofosmin protocol, stress imaging used 3 times as much activity and occurred 1 h after the rest injection. SPECT images were obtained at both rest and stress. After imaging, the heart was sectioned into 44 50 pieces. In each heart sample, the tracer uptake was measured in a gamma counter. The images were aligned, and the decay-corrected ratio of the signals at rest and stress was used to separate the well-counter signal into rest and stress components. The uptake at rest and stress was compared with microsphere flow measurements. RESULTS: The CMICE-013 images showed good contrast between the heart and surrounding organs, with heart-to-liver and heart-to-lung uptake ratios similar to those of the standard tracers. Uptake of CMICE-013 was 1.5% of the injected dose at rest and increased more rapidly with increased blood flow than did the standard SPECT tracers. The percentage injected dose of CMICE-013 taken up by the heart was greater (P < 0.05) than (201)Tl, tetrofosmin, or sestamibi at flows greater than 1.5 mL/min/g. CONCLUSION: CMICE-013 is a promising new SPECT MPI agent. PMID- 25840978 TI - Semiquantitative Analysis of the Biodistribution of the Combined 18F-NaF and 18F FDG Administration for PET/CT Imaging. AB - In this study, we evaluated the biodistribution of the (18)F(-)/(18)F-FDG administration, compared with separate (18)F-NaF and (18)F-FDG administrations. We also estimated the interaction of (18)F-NaF and (18)F-FDG in the (18)F( )/(18)F-FDG administration by semiquantitative analysis. METHODS: We retrospectively analyzed the data of 49 patients (39 men, 10 women; mean age +/- SD, 59.3 +/- 15.2 y) who underwent separate (18)F-FDG PET/CT and (18)F-NaF PET/CT scans as well as (18)F(-)/(18)F-FDG PET/CT sequentially. The most common primary diagnosis was prostate cancer (n = 28), followed by sarcoma (n = 9) and breast cancer (n = 6). The mean standardized uptake values (SUVs) were recorded for 18 organs in all patients, and maximum SUV and mean SUV were recorded for all the identified malignant lesions. We also estimated the (18)F(-)/(18)F-FDG uptake as the sum of (18)F-FDG uptake and adjusted (18)F-NaF uptake based on the ratio of (18)F-NaF injected dose in (18)F(-)/(18)F-FDG PET/CT. Lastly, we compared the results to explore the interaction of (18)F-FDG and (18)F-NaF uptake in the (18)F(-)/(18)F-FDG scan. RESULTS: The (18)F(-)/(18)F-FDG uptake in the cerebral cortex, cerebellum, parotid grand, myocardium, and bowel mostly reflected the (18)F-FDG uptake, whereas the uptake in the other analyzed structures was influenced by both the (18)F-FDG and the (18)F-NaF uptake. The (18)F(-)/(18)F-FDG uptake in extraskeletal lesions showed no significant difference when compared with the uptake from the separate (18)F-FDG scan. The (18)F(-)/(18)F-FDG uptake in skeletal lesions reflected mostly the (18)F-NaF uptake. The tumor-to background ratio of (18)F(-)/(18)F-FDG in extraskeletal lesions showed no significant difference when compared with that from (18)F-FDG alone (P = 0.73). For skeletal lesions, the tumor-to-background ratio of (18)F(-)/(18)F-FDG was lower than that from (18)F-NaF alone (P < 0.001); however, this difference did not result in missed skeletal lesions on the (18)F(-)/(18)F-FDG scan. CONCLUSION: The understanding of the biodistribution of radiopharmaceuticals and the lesion uptake of the (18)F(-)/(18)F-FDG scan as well as the variations compared with the uptake on the separate (18)F-FDG PET/CT and (18)F-NaF PET/CT are valuable for more in-depth evaluation of the combined scanning technique. PMID- 25840979 TI - Methods of CT Dose Estimation in Whole-Body 18F-FDG PET/CT. AB - We evaluated the effective dose (ED) of the CT component of whole-body PET/CT using software dedicated to CT dose estimation and from dose-length product (DLP) values to establish practical methods of ED estimation. METHODS: Eighty adult patients who underwent (18)F-FDG whole-body PET/CT were divided into groups A and B, each consisting of 20 men and 20 women. In group A, ED of the CT component was calculated using CT-Expo for 6 anatomic regions separately, and whole-body ED was obtained by summing the regional EDs (CT-Expo method). DLP was calculated for each of the 6 regions and multiplied by a corresponding conversion factor described in International Commission on Radiological Protection publication 102 to obtain the ED for each region (regional DLP method). Whole-body ED was also calculated as the product of a whole-body DLP value provided by the scanner automatically and a conversion factor (simple DLP method). Moreover, the ED/DLP values were calculated using whole-body ED estimated by the CT-Expo method and the scanner-derived DLP, to optimize the conversion factor. In group B, the optimized conversion factor was applied for the estimation of ED by the simple DLP method. RESULTS: In group A, the regional DLP method allowed an accurate estimation of mean whole-body ED as a result of counterbalance of mild overestimation in men and mild underestimation in women, regarding the CT-Expo method as a standard. The simple DLP method using a conversion factor for the trunk (0.015 mSv/mGy/cm) caused overestimation. On the basis of the ED/DLP values in group A, a modified conversion factor of 0.013 mSv/mGy/cm and sex-specific conversion factors of 0.012 and 0.014 mSv/mGy/cm for men and women, respectively, were determined. In group B, the use of the modified conversion factor improved accuracy, and the use of sex-specific conversion factors eliminated sex-dependent residual errors. CONCLUSION: ED of the CT component of whole-body PET/CT can be assessed by multiplying the scanner-derived DLP by a conversion factor optimized for whole-body PET/CT. PMID- 25840980 TI - Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort? AB - Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects. To translate the findings of neuroinflammation studies to the entire population, it is crucial to establish the influence of TSPO genotypes on AD. Here, we investigated whether different TSPO genotypes influence cognitive function, amyloid load, and disease progression over time. METHODS: We evaluated 798 subjects (225 control, 388 with mild cognitive impairment [MCI], and 185 with AD) from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during follow-up. All subjects were screened for TSPO genotype and underwent detailed clinical and neuropsychologic assessments yearly for 4 y. Of the 798 subjects, 255 also had T1- and T2-weighted MR imaging and amyloid PET with (11)C Pittsburgh compound B or (18)F-florbetapir. RESULTS: We demonstrated that all TSPO binding groups (HAB, MAB, and LAB) have same level of amyloid load in AD and MCI subjects. We also demonstrated that the prevalence is 50.3% for HAB, 41.2% for MAB, and 8.5% for LAB, without a statistical difference among the AD, MCI, and control groups. During longitudinal follow-up, the mean change in neuropsychometric test scores on the Mini-Mental State Examination, the cognitive and modified Alzheimer Disease Assessment Scales (ADASs), and the Geriatric Depression Scale over time were similar in AD and MCI subjects among the 3 TSPO binding groups. Analysis of the covariates showed that diagnostic group (control, MCI, AD), apolipoprotein E4 status, and sex had a significant effect on decline on the modified Alzheimer Disease Assessment Scale (>3 points of the scale), but age and TSPO genotype did not. CONCLUSION: This study suggests that information obtained from evaluating a subgroup of AD or MCI subject using second-generation TSPO tracers can be translated to the entire AD and MCI population. Thus, we can study fewer AD subjects in evaluating new antineuroinflammatory and antimicroglial agents in intervention studies and in observational studies evaluating the role of neuroinflammation. PMID- 25840981 TI - PET of c-Met in Cancer with 64Cu-Labeled Hepatocyte Growth Factor. AB - The hepatocyte growth factor (HGF) and its receptor, c-Met, are actively involved in tumor progression and metastasis and are closely associated with a poor prognostic outcome for cancer patients. Thus, the development of PET agents that can assess c-Met expression would be extremely useful for diagnosing cancer and subsequently monitoring response to c-Met-targeted therapies. Here, we report the characterization of recombinant human HGF (rh-HGF) as a PET tracer for detection of c-Met expression in vivo. METHODS: rh-HGF was expressed in human embryonic kidney 293 cells and purified by nickel-nitrilotriacetic acid affinity chromatography. The concentrated rh-HGF was conjugated to 2-S-(4 isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid and labeled with (64)Cu. c-Met binding evaluation by flow cytometry was performed on both U87MG and MDA-MB-231 cell lines, which have a high level and a low level, respectively, of c-Met. PET imaging and biodistribution studies were performed on nude mice bearing U87MG and MDA-MB-231 xenografted tumors. RESULTS: The rh-HGF expression yield was 150-200 MUg of protein per 5 * 10(6) cells after a 48-h transfection, with purity of approximately 85%-90%. Flow cytometry examination confirmed that rh-HGF had a strong and specific capacity to bind to c-Met. After (64)Cu labeling, PET imaging revealed specific and prominent uptake of (64)Cu NOTA-rh-HGF in c-Met-positive U87MG tumors (percentage injected dose per gram, 6.8 +/- 1.8 at 9 h after injection) and significantly lower uptake in c-Met negative MDA-MB-231 tumors (percentage injected dose per gram, 1.8 +/- 0.6 at 9 h after injection). The fact that sonication-denatured rh-HGF had significantly lower uptake in U87MG tumors, along with histology analysis, confirmed the c-Met specificity of (64)Cu-NOTA-rh-HGF. CONCLUSION: This study provided initial evidence that (64)Cu-NOTA-rh-HGF visualizes c-Met expression in vivo, an application that may prove useful for c-Met-targeted cancer therapy. PMID- 25840982 TI - Rho kinase inhibitors block melanoma cell migration and inhibit metastasis. AB - There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both "amoeboid-like" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis. PMID- 25840983 TI - Effective Eradication of Glioblastoma Stem Cells by Local Application of an AC133/CD133-Specific T-cell-Engaging Antibody and CD8 T Cells. AB - Cancer stem cells (CSC) drive tumorigenesis and contribute to genotoxic therapy resistance, diffuse infiltrative invasion, and immunosuppression, which are key factors for the incurability of glioblastoma multiforme (GBM). The AC133 epitope of CD133 is an important CSC marker for GBM and other tumor entities. Here, we report the development and preclinical evaluation of a recombinant AC133*CD3 bispecific antibody (bsAb) that redirects human polyclonal T cells to AC133(+) GBM stem cells (GBM-SC), inducing their strong targeted lysis. This novel bsAb prevented the outgrowth of AC133-positive subcutaneous GBM xenografts. Moreover, upon intracerebral infusion along with the local application of human CD8(+) T cells, it exhibited potent activity in prophylactic and treatment models of orthotopic GBM-SC-derived invasive brain tumors. In contrast, normal hematopoietic stem cells, some of which are AC133-positive, were virtually unaffected at bsAb concentrations effective against GBM-SCs and retained their colony-forming abilities. In conclusion, our data demonstrate the high activity of this new bsAb against patient-derived AC133-positive GBM-SCs in models of local therapy of highly invasive GBM. PMID- 25840984 TI - Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression. AB - Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBR(hi)). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBR(hi) population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy. PMID- 25840985 TI - Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. AB - The management of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to lack of an efficient therapy and development of chemoresistance to the current standard therapy, gemcitabine. Recent studies implicate the intimate reciprocal interactions between epithelia and underlying stroma due to paracrine Sonic hedgehog (SHH) signaling in producing desmoplasia and chemoresistance in PDAC. Herein, we report for the first time that a nonsteroidal drug, ormeloxifene, has potent anticancer properties and depletes tumor-associated stromal tissue by inhibiting the SHH signaling pathway in PDAC. We found that ormeloxifene inhibited cell proliferation and induced death in PDAC cells, which provoked us to investigate the combinatorial effects of ormeloxifene with gemcitabine at the molecular level. Ormeloxifene caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets such as Gli-1, SMO, PTCH1/2, NF-kappaB, p-AKT, and cyclin D1. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice. Furthermore, ormeloxifene depleted tumor-associated stroma in xenograft tumor tissues by inhibiting the SHH cellular signaling pathway and mouse/human collagen I expression. Xenograft tumors treated with ormeloxifene in combination with gemcitabine restored the tumor-suppressor miR-132 and inhibited stromal cell infiltration into the tumor tissues. In addition, invasiveness of tumor cells cocultivated with TGFbeta-stimulated human pancreatic stromal cells was effectively inhibited by ormeloxifene treatment alone or in combination with gemcitabine. We propose that ormeloxifene has high therapeutic index and in a combination therapy with gemcitabine, it possesses great promise as a treatment of choice for PDAC/pancreatic cancer. PMID- 25840986 TI - Using SRM-MS to quantify nuclear protein abundance differences between adipose tissue depots of insulin-resistant mice. AB - Insulin resistance (IR) underlies metabolic disease. Visceral, but not subcutaneous, white adipose tissue (WAT) has been linked to the development of IR, potentially due to differences in regulatory protein abundance. Here we investigate how protein levels are changed in IR in different WAT depots by developing a targeted proteomics approach to quantitatively compare the abundance of 42 nuclear proteins in subcutaneous and visceral WAT from a commonly used insulin-resistant mouse model, Lepr(db/db), and from C57BL/6J control mice. The most differentially expressed proteins were important in adipogenesis, as confirmed by siRNA-mediated depletion experiments, suggesting a defect in adipogenesis in visceral, but not subcutaneous, insulin-resistant WAT. Furthermore, differentiation of visceral, but not subcutaneous, insulin-resistant stromal vascular cells (SVCs) was impaired. In an in vitro approach to understand the cause of this impaired differentiation, we compared insulin-resistant visceral SVCs to preadipocyte cell culture models made insulin resistant by different stimuli. The insulin-resistant visceral SVC protein abundance profile correlated most with preadipocyte cell culture cells treated with both palmitate and TNFalpha. Together, our study introduces a method to simultaneously measure and quantitatively compare nuclear protein expression patterns in primary adipose tissue and adipocyte cell cultures, which we show can reveal relationships between differentiation and disease states of different adipocyte tissue types. PMID- 25840987 TI - Gender differences in responses to moral dilemmas: a process dissociation analysis. AB - The principle of deontology states that the morality of an action depends on its consistency with moral norms; the principle of utilitarianism implies that the morality of an action depends on its consequences. Previous research suggests that deontological judgments are shaped by affective processes, whereas utilitarian judgments are guided by cognitive processes. The current research used process dissociation (PD) to independently assess deontological and utilitarian inclinations in women and men. A meta-analytic re-analysis of 40 studies with 6,100 participants indicated that men showed a stronger preference for utilitarian over deontological judgments than women when the two principles implied conflicting decisions (d = 0.52). PD further revealed that women exhibited stronger deontological inclinations than men (d = 0.57), while men exhibited only slightly stronger utilitarian inclinations than women (d = 0.10). The findings suggest that gender differences in moral dilemma judgments are due to differences in affective responses to harm rather than cognitive evaluations of outcomes. PMID- 25840988 TI - In good company: managing interpersonal resources that support self-regulation. AB - Effective self-regulation could involve not only managing internal resources for goal pursuit but also the often-fleeting interpersonal resources that can support goal attainment. In five studies, we test whether people who are effective self regulators tend to position themselves in social environments that best afford self-regulatory success. Results indicated individual differences in self regulatory effectiveness predict stronger preferences to spend time with, collaborate with, and be informed by others who were (a) high in self-control or self-regulation themselves or (b) instrumental to one's goal pursuit. These preferences for supportive social environments appeared to be both targeted and strategic. Together, the findings suggest that effective self-regulation may involve positioning oneself in social environments that support goal pursuit and increase one's chances of success. PMID- 25840991 TI - High-resolution assessment of copy number variation. PMID- 25840992 TI - Fisetin, a dietary flavonoid, induces apoptosis of cancer cells by inhibiting HSF1 activity through blocking its binding to the hsp70 promoter. AB - Heat shock factor 1 (HSF1) is a transcription factor for heat shock proteins (HSPs) expression that enhances the survival of cancer cells exposed to various stresses. HSF1 knockout suppresses carcinogen-induced cancer induction in mice. Therefore, HSF1 is a promising therapeutic and chemopreventive target. We performed cell-based screening with a natural compound collection and identified fisetin, a dietary flavonoid, as a HSF1 inhibitor. Fisetin abolished heat shock induced luciferase activity with an IC50 of 14 MUM in HCT-116 cancer cells. The treatment of HCT-116 with fisetin inhibited proliferation with a GI50 of 23 MUM. When the cells were exposed to heat shock in the presence of fisetin, the induction of HSF1 target proteins, such as HSP70, HSP27 and BAG3 (Bcl-2 associated athanogene domain 3), were inhibited. HSP70/BAG3 complexes protect cancer cells from apoptosis by stabilizing anti-apoptotic Bcl-2 family proteins. The downregulation of HSP70/BAG3 by fisetin significantly reduced the amounts of Bcl-2, Bcl-xL and Mcl-1 proteins, subsequently inducing apoptotic cell death. Chromatin immunoprecipitation assays showed that fisetin inhibited HSF1 activity by blocking the binding of HSF1 to the hsp70 promoter. Intraperitoneal treatment of nude mice with fisetin at 30mg/kg resulted in a 35.7% (P < 0.001) inhibition of tumor growth. PMID- 25840993 TI - The histone H3 lysine-27 demethylase Jmjd3 plays a critical role in specific regulation of Th17 cell differentiation. AB - Interleukin (IL) 17-producing T helper (Th17) cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases, such as multiple sclerosis, psoriasis, and ulcerative colitis. Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently, the participation of epigenetic modifications in the differentiation process has yet to be elucidated. We demonstrated here that histone H3 lysine-27 (H3K27) demethylation, predominantly mediated by the H3K27 demethylase Jmjd3, crucially regulated Th17 cell differentiation. Activation of naive CD4(+) T cells immediately induced high expression of Jmjd3. Genetic depletion of Jmjd3 in CD4(+) T cells specifically impaired Th17 cell differentiation both in vitro and in vivo. Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficient CD4(+) T cells. Importantly, Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro. At the molecular level, Jmjd3 directly bound to and reduced the level of H3K27 trimethylation (me3) at the genomic sites of Rorc, which encodes the master Th17 transcription factor Rorgammat, and Th17 cytokine genes such as Il17, Il17f, and Il22. Therefore, our studies established a critical role of Jmjd3-mediated H3K27 demethylation in Th17 cell differentiation and suggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses. PMID- 25840994 TI - Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia. AB - Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor beta aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, beta aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia. PMID- 25840996 TI - STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 protein-induced acute lung inflammation. AB - Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 protein-induced acute lung inflammation. PMID- 25840995 TI - TGF-beta-induced IL-6 prevents development of acute lung injury in influenza A virus-infected F508del CFTR-heterozygous mice. AB - As the eighth leading cause of annual mortality in the USA, influenza A viruses are a major public health concern. In 20% of patients, severe influenza progresses to acute lung injury (ALI). However, pathophysiological mechanisms underlying ALI development are poorly defined. We reported that, unlike wild-type (WT) C57BL/6 controls, influenza A virus-infected mice that are heterozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (HETs) did not develop ALI. This effect was associated with higher IL-6 and alveolar macrophages (AMs) at 6 days postinfection (d.p.i.) in HET bronchoalveolar lavage fluid (BALF). In the present study, we found that HET AMs were an important source of IL-6 at 6 d.p.i. Infection also induced TGF-beta production by HET but not WT mice at 2 d.p.i. TGF-beta neutralization at 2 d.p.i. (TGF-N) significantly reduced BALF IL-6 in HETs at 6 d.p.i. Neither TGF-N nor IL 6 neutralization at 4 d.p.i. (IL-6-N) altered postinfection weight loss or viral replication in either mouse strain. However, both treatments increased influenza A virus-induced hypoxemia, pulmonary edema, and lung dysfunction in HETs to WT levels at 6 d.p.i. TGF-N and IL-6-N did not affect BALF AM and neutrophil numbers but attenuated the CXCL-1/keratinocyte chemokine response in both strains and reduced IFN-gamma production in WT mice. Finally, bone marrow transfer experiments showed that HET stromal and myeloid cells are both required for protection from ALI in HETs. These findings indicate that TGF-beta-dependent production of IL-6 by AMs later in infection prevents ALI development in influenza A virus-infected HET mice. PMID- 25840997 TI - Nrf2 regulates PU.1 expression and activity in the alveolar macrophage. AB - Alveolar macrophage (AM) immune function depends on the activation of the transcription factor PU.1 by granulocyte macrophage colony-stimulating factor. We have determined that chronic alcohol ingestion dampens PU.1 signaling via an unknown zinc-dependent mechanism; specifically, although PU.1 is not known to be a zinc-dependent transcription factor, zinc treatment reversed alcohol-mediated dampening of PU.1 signaling. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a zinc-dependent basic leucine zipper protein essential for antioxidant defenses, is also impaired by chronic alcohol ingestion and enhanced by zinc treatment. We hypothesized that the response of PU.1 to zinc treatment may result from the action of Nrf2 on PU.1. We first performed Nrf2/PU.1 protein coimmunoprecipitation on a rat AM cell line (NR8383) and found no evidence of protein-protein interactions. We then found evidence of increased Nrf2 binding to the PU.1 promoter region by chromatin immunoprecipitation. We next activated Nrf2 using either sulforaphane or an overexpression vector and inhibited Nrf2 with silencing RNA to determine whether Nrf2 could actively regulate PU.1. Nrf2 activation increased protein expression of both factors as well as gene expression of their respective downstream effectors, NAD(P)H dehydrogenase[quinone] 1 (NQO1) and cluster of differentiation antigen-14 (CD14). In contrast, Nrf2 silencing decreased the expression of both proteins, as well as gene expression of their effectors. Activating and inhibiting Nrf2 in primary rat AMs resulted in similar effects. Taken together, these findings suggest that Nrf2 regulates the expression and activity of PU.1 and that antioxidant response and immune activation are coordinately regulated within the AM. PMID- 25840998 TI - Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients. AB - Alterations in extracellular matrix (ECM) have been implicated in the pathophysiology of pulmonary hypertension. Here, we have undertaken a compartment specific study to elucidate the expression profile of collagens and their processing enzymes in donor and idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries. Predominant intimal, but also medial and perivascular, remodeling and reduced lumen diameter were detected in IPAH pulmonary arteries. Two-photon microscopy demonstrated accumulation of collagen fibers. Quantification of collagen in pulmonary arteries revealed collagen accumulation mainly in the intima of IPAH pulmonary arteries compared with donors. Laser capture-microdissected pulmonary artery profiles (intima+media and perivascular tissue) were analyzed by real-time PCR for ECM gene expression. In the intima+media of IPAH vessels, collagens (COL4A5, COL14A1, and COL18A1), matrix metalloproteinase (MMP) 19, and a disintegrin and metalloprotease (ADAM) 33 were higher expressed, whereas MMP10, ADAM17, TIMP1, and TIMP3 were less abundant. Localization of COLXVIII, its cleavage product endostatin, and MMP10, ADAM33, and TIMP1 was confirmed in pulmonary arteries by immunohistochemistry. ELISA for collagen XVIII/endostatin demonstrated significantly elevated plasma levels in IPAH patients compared with donors, whereas circulating MMP10, ADAM33, and TIMP1 levels were similar between the two groups. Endostatin levels were correlated with pulmonary arterial wedge pressure, and established prognostic markers of IPAH, right atrial pressure, cardiac index, 6-min walking distance, NH2-terminal pro-brain natriuretic peptide, and uric acid. Expression of unstudied collagens, MMPs, ADAMs, and TIMPs were found to be significantly altered in IPAH intima+media. Elevated levels of circulating collagen XVIII/endostatin are associated with markers of a poor prognosis. PMID- 25841000 TI - Review and Summary of Research on the Embodied Effects of Expansive (vs. Contractive) Nonverbal Displays. PMID- 25840999 TI - Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF alpha. AB - Innate airway hyperresponsiveness (AHR) and augmented responses to ozone, an asthma trigger, are characteristics of obese mice. Systemic inflammation, a condition of increased circulating concentrations of inflammatory moieties, occurs in obesity. We hypothesized that TNF-alpha, via its effects as a master effector of this systemic inflammation, regulates innate AHR and augmented responses to ozone in obese mice. Therefore, we examined pulmonary inflammation and airway responsiveness in unexposed or ozone-exposed (2 ppm for 3 h) lean wild type and obese Cpe(fat) mice that were TNF-alpha sufficient or deficient. Cpe(fat) mice lack carboxypeptidase E, which regulates satiety. Compared with wild type, Cpe(fat) mice had elevated serum IL-17A, G-CSF, KC, MCP-1, IL-9, MIG, and leptin, indicating systemic inflammation. Despite reductions in most of these moieties in TNF-alpha-deficient vs. -sufficient Cpe(fat) mice, we observed no substantial difference in airway responsiveness in these two groups of mice. Ozone-induced increases in bronchoalveolar lavage (BAL) neutrophils and macrophages were lower, but ozone-induced AHR and increases in BAL hyaluronan, osteopontin, IL-13, and protein carbonyls, a marker of oxidative stress, were augmented in TNF-alpha-deficient vs. -sufficient Cpe(fat) mice. Our data indicate that TNF-alpha has an important role in promoting the systemic inflammation but not the innate AHR of obesity, suggesting that the systemic inflammation of obesity is not the major driver of this AHR. TNF-alpha is required for the augmented effects of acute ozone exposure on pulmonary inflammatory cell recruitment in obese mice, whereas TNF-alpha protects against ozone-induced AHR in obese mice, possibly by suppressing ozone-induced oxidative stress. PMID- 25841001 TI - Development of a Job-Exposure Matrix (AsbJEM) to Estimate Occupational Exposure to Asbestos in Australia. AB - INTRODUCTION: Occupational exposure data on asbestos are limited and poorly integrated in Australia so that estimates of disease risk and attribution of disease causation are usually calculated from data that are not specific for local conditions. OBJECTIVE: To develop a job-exposure matrix (AsbJEM) to estimate occupational asbestos exposure levels in Australia, making optimal use of the available exposure data. METHODS: A dossier of all available exposure data in Australia and information on industry practices and controls was provided to an expert panel consisting of three local industrial hygienists with thorough knowledge of local and international work practices. The expert panel estimated asbestos exposures for combinations of occupation, industry, and time period. Intensity and frequency grades were estimated to enable the calculation of annual exposure levels for each occupation-industry combination for each time period. Two indicators of asbestos exposure intensity (mode and peak) were used to account for different patterns of exposure between occupations. Additionally, the probable type of asbestos fibre was determined for each situation. RESULTS: Asbestos exposures were estimated for 537 combinations of 224 occupations and 60 industries for four time periods (1943-1966; 1967-1986; 1987-2003; >=2004). Workers in the asbestos manufacturing, shipyard, and insulation industries were estimated to have had the highest average exposures. Up until 1986, 46 occupation industry combinations were estimated to have had exposures exceeding the current Australian exposure standard of 0.1 f ml(-1). Over 90% of exposed occupations were considered to have had exposure to a mixture of asbestos varieties including crocidolite. CONCLUSION: The AsbJEM provides empirically based quantified estimates of asbestos exposure levels for Australian jobs since 1943. This exposure assessment application will contribute to improved understanding and prediction of asbestos-related diseases and attribution of disease causation. PMID- 25841002 TI - Chloride-Inducible Expression Vector for Delivery of Antimicrobial Peptides Targeting Antibiotic-Resistant Enterococcus faecium. AB - Antibiotic-resistant enterococcal infections are a major concern in hospitals where patients with compromised immunity are readily infected. Enterococcus faecium bacteria are of particular interest as these pathogens account for over 80% of vancomycin-resistant enterococcal infections. Antimicrobial peptides (AMPs) produced at the site of infection by engineered bacteria may offer a potential alternative to traditional antibiotics for the treatment of resistant bacteria such as E. faecium. For this mode of delivery to be effective, it is essential to identify a suitable protein expression system that can be used in the desired delivery bacterium. In this study, we describe a promising chloride inducible promoter and its application in the bacterial delivery of AMPs from Lactococcus lactis to reduce counts of E. faecium bacteria in vitro. Reporter gene studies show that at chloride concentrations found within the human intestines, the chloride-inducible promoter exhibits high levels of protein expression compared to those of the commonly used nisin-inducible promoter. These results indicate that this system is powerful and would not require the exogenous administration of an inducer molecule. In its application for AMP production against E. faecium in vitro, L. lactis producing AMPs under the chloride promoter rapidly decreased E. faecium counts by nearly 10,000-fold. As an extension of this application, we also demonstrate the potential in using this type of delivery system in combination with traditional antibiotics to slow the development of resistance. Collectively, this study shows the promise of using a chloride-inducible promoter for the bacterial delivery of AMPs in the body for the treatment of vancomycin-resistant enterococci (VRE) and other antibiotic resistant bacteria. PMID- 25841003 TI - Nisin H Is a New Nisin Variant Produced by the Gut-Derived Strain Streptococcus hyointestinalis DPC6484. AB - Accumulating evidence suggests that bacteriocin production represents a probiotic trait for intestinal strains to promote dominance, fight infection, and even signal the immune system. In this respect, in a previous study, we isolated from the porcine intestine a strain of Streptococcus hyointestinalis DPC6484 that displays antimicrobial activity against a wide range of Gram-positive bacteria and produces a bacteriocin with a mass of 3,453 Da. Interestingly, the strain was also found to be immune to a nisin-producing strain. Genome sequencing revealed the genetic determinants responsible for a novel version of nisin, designated nisin H, consisting of the nshABTCPRKGEF genes, with transposases encoded between nshP and nshR and between nshK and nshG. A similar gene cluster is also found in S. hyointestinalis LMG14581. Notably, the cluster lacks an equivalent of the nisin immunity gene, nisI. Nisin H is proposed to have the same structure as the prototypical nisin A but differs at 5 amino acid positions-Ile1Phe (i.e., at position 1, nisin A has Ile while nisin H has Phe), Leu6Met, Gly18Dhb (threonine dehydrated to dehydrobutyrine), Met21Tyr, and His31Lys--and appears to represent an intermediate between the lactococcal nisin A and the streptococcal nisin U variant of nisin. Purified nisin H inhibits a wide range of Gram-positive bacteria, including staphylococci, streptococci, Listeria spp., bacilli, and enterococci. It represents the first example of a natural nisin variant produced by an intestinal isolate of streptococcal origin. PMID- 25841004 TI - Distinct circular single-stranded DNA viruses exist in different soil types. AB - The potential dependence of virus populations on soil types was examined by electron microscopy, and the total abundance of virus particles in four soil types was similar to that previously observed in soil samples. The four soil types examined differed in the relative abundances of four morphological groups of viruses. Machair, a unique type of coastal soil in western Scotland and Ireland, differed from the others tested in having a higher proportion of tailed bacteriophages. The other soils examined contained predominantly spherical and thin filamentous virus particles, but the Machair soil had a more even distribution of the virus types. As the first step in looking at differences in populations in detail, virus sequences from Machair and brown earth (agricultural pasture) soils were examined by metagenomic sequencing after enriching for circular Rep-encoding single-stranded DNA (ssDNA) (CRESS-DNA) virus genomes. Sequences from the family Microviridae (icosahedral viruses mainly infecting bacteria) of CRESS-DNA viruses were predominant in both soils. Phylogenetic analysis of Microviridae major coat protein sequences from the Machair viruses showed that they spanned most of the diversity of the subfamily Gokushovirinae, whose members mainly infect obligate intracellular parasites. The brown earth soil had a higher proportion of sequences that matched the morphologically similar family Circoviridae in BLAST searches. However, analysis of putative replicase proteins that were similar to those of viruses in the Circoviridae showed that they are a novel clade of Circoviridae-related CRESS-DNA viruses distinct from known Circoviridae genera. Different soils have substantially different taxonomic biodiversities even within ssDNA viruses, which may be driven by physicochemical factors. PMID- 25841005 TI - Public Health Investigation of Two Outbreaks of Shiga Toxin-Producing Escherichia coli O157 Associated with Consumption of Watercress. AB - An increase in the number of cases of Shiga toxin-producing Escherichia coli (STEC) O157 phage type 2 (PT2) in England in September 2013 was epidemiologically linked to watercress consumption. Whole-genome sequencing (WGS) identified a phylogenetically related cluster of 22 cases (outbreak 1). The isolates comprising this cluster were not closely related to any other United Kingdom strain in the Public Health England WGS database, suggesting a possible imported source. A second outbreak of STEC O157 PT2 (outbreak 2) was identified epidemiologically following the detection of outbreak 1. Isolates associated with outbreak 2 were phylogenetically distinct from those in outbreak 1. Epidemiologically unrelated isolates on the same branch as the outbreak 2 cluster included those from human cases in England with domestically acquired infection and United Kingdom domestic cattle. Environmental sampling using PCR resulted in the isolation of STEC O157 PT2 from irrigation water at one implicated watercress farm, and WGS showed this isolate belonged to the same phylogenetic cluster as outbreak 2 isolates. Cattle were in close proximity to the watercress bed and were potentially the source of the second outbreak. Transfer of STEC from the field to the watercress bed may have occurred through wildlife entering the watercress farm or via runoff water. During this complex outbreak investigation, epidemiological studies, comprehensive testing of environmental samples, and the use of novel molecular methods proved invaluable in demonstrating that two simultaneous outbreaks of STEC O157 PT2 were both linked to the consumption of watercress but were associated with different sources of contamination. PMID- 25841006 TI - Interactions between Human Norovirus Surrogates and Acanthamoeba spp. AB - Human noroviruses (HuNoVs) are the most common cause of food-borne disease outbreaks, as well as virus-related waterborne disease outbreaks in the United States. Here, we hypothesize that common free-living amoebae (FLA)-ubiquitous in the environment, known to interact with pathogens, and frequently isolated from water and fresh produce-could potentially act as reservoirs of HuNoV and facilitate the environmental transmission of HuNoVs. To investigate FLA as reservoirs for HuNoV, the interactions between two Acanthamoeba species, A. castellanii and A. polyphaga, as well as two HuNoV surrogates, murine norovirus type 1 (MNV-1) and feline calicivirus (FCV), were evaluated. The results showed that after 1 h of amoeba-virus incubation at 25 degrees C, 490 and 337 PFU of MNV 1/ml were recovered from A. castellanii and A. polyphaga, respectively, while only few or no FCVs were detected. In addition, prolonged interaction of MNV-1 with amoebae was investigated for a period of 8 days, and MNV-1 was demonstrated to remain stable at around 200 PFU/ml from day 2 to day 8 after virus inoculation in A. castellanii. Moreover, after a complete amoeba life cycle (i.e., encystment and excystment), infectious viruses could still be detected. To determine the location of virus associated with amoebae, immunofluorescence experiments were performed and showed MNV-1 transitioning from the amoeba surface to inside the amoeba over a 24-h period. These results are significant to the understanding of how HuNoVs may interact with other microorganisms in the environment in order to aid in its persistence and survival, as well as potential transmission in water and to vulnerable food products such as fresh produce. PMID- 25841007 TI - Two-Component-System Histidine Kinases Involved in Growth of Listeria monocytogenes EGD-e at Low Temperatures. AB - Two-component systems (TCSs) aid bacteria in adapting to a wide variety of stress conditions. While the role of TCS response regulators in the cold tolerance of the psychrotrophic foodborne pathogen Listeria monocytogenes has been demonstrated previously, no comprehensive studies showing the role of TCS histidine kinases of L. monocytogenes at low temperature have been performed. We compared the expression levels of each histidine kinase-encoding gene of L. monocytogenes EGD-e in logarithmic growth phase at 3 degrees C and 37 degrees C, as well as the expression levels 30 min, 3 h, and 7 h after cold shock at 5 degrees C and preceding cold shock (at 37 degrees C). We constructed a deletion mutation in each TCS histidine kinase gene, monitored the growth of the EGD-e wild-type and mutant strains at 3 degrees C and 37 degrees C, and measured the minimum growth temperature of each strain. Two genes, yycG and lisK, proved significant in regard to induced relative expression levels under cold conditions and cold-sensitive mutant phenotypes. Moreover, the DeltaresE mutant showed a lower growth rate than that of wild-type EGD-e at 3 degrees C. Eleven other genes showed upregulated gene expression but revealed no cold-sensitive phenotypes. The results show that the histidine kinases encoded by yycG and lisK are important for the growth and adaptation of L. monocytogenes EGD-e at low temperature. PMID- 25841008 TI - Differential Metabolism of Exopolysaccharides from Probiotic Lactobacilli by the Human Gut Symbiont Bacteroides thetaiotaomicron. AB - Probiotic microorganisms are ingested as food or supplements and impart positive health benefits to consumers. Previous studies have indicated that probiotics transiently reside in the gastrointestinal tract and, in addition to modulating commensal species diversity, increase the expression of genes for carbohydrate metabolism in resident commensal bacterial species. In this study, it is demonstrated that the human gut commensal species Bacteroides thetaiotaomicron efficiently metabolizes fructan exopolysaccharide (EPS) synthesized by probiotic Lactobacillus reuteri strain 121 while only partially degrading reuteran and isomalto/malto-polysaccharide (IMMP) alpha-glucan EPS polymers. B. thetaiotaomicron metabolized these EPS molecules via the activation of enzymes and transport systems encoded by dedicated polysaccharide utilization loci specific for beta-fructans and alpha-glucans. Reduced metabolism of reuteran and IMMP alpha-glucan EPS molecules may be due to reduced substrate binding by components of the starch utilization system (sus). This study reveals that microbial EPS substrates activate genes for carbohydrate metabolism in B. thetaiotaomicron and suggests that microbially derived carbohydrates provide a carbohydrate-rich reservoir for B. thetaiotaomicron nutrient acquisition in the gastrointestinal tract. PMID- 25841009 TI - The impact of gamma radiation on sediment microbial processes. AB - Microbial communities have the potential to control the biogeochemical fate of some radionuclides in contaminated land scenarios or in the vicinity of a geological repository for radioactive waste. However, there have been few studies of ionizing radiation effects on microbial communities in sediment systems. Here, acetate and lactate amended sediment microcosms irradiated with gamma radiation at 0.5 or 30 Gy h(-1) for 8 weeks all displayed NO3 (-) and Fe(III) reduction, although the rate of Fe(III) reduction was decreased in 30-Gy h(-1) treatments. These systems were dominated by fermentation processes. Pyrosequencing indicated that the 30-Gy h(-1) treatment resulted in a community dominated by two Clostridial species. In systems containing no added electron donor, irradiation at either dose rate did not restrict NO3 (-), Fe(III), or SO4 (2-) reduction. Rather, Fe(III) reduction was stimulated in the 0.5-Gy h(-1)-treated systems. In irradiated systems, there was a relative increase in the proportion of bacteria capable of Fe(III) reduction, with Geothrix fermentans and Geobacter sp. identified in the 0.5-Gy h(-1) and 30-Gy h(-1) treatments, respectively. These results indicate that biogeochemical processes will likely not be restricted by dose rates in such environments, and electron accepting processes may even be stimulated by radiation. PMID- 25841010 TI - Development and Application of a Blastocystis Subtype-Specific PCR Assay Reveals that Mixed-Subtype Infections Are Common in a Healthy Human Population. AB - The human gut is host to a diversity of microorganisms, including the single celled microbial eukaryote Blastocystis. Research has shown that most carriers host a single Blastocystis subtype (ST), which is unusual given the considerable within-host species diversity observed for other microbial genera in this ecosystem. However, our limited knowledge of both the incidence and biological significance of Blastocystis diversity within hosts (i.e., so-called mixed infections) is likely due to problems with existing methodologies. Here, we developed and applied Blastocystis ST-specific PCRs for the investigation of the most common subtypes of Blastocystis (ST1 to ST4) to a healthy human cohort (n = 50). We detected mixed infections in 22% of the cases, all of which had been identified as single-ST infections in a previous study using state-of-the-art methods. Our results show that certain STs occur predominantly as either single (ST3 and 4) or mixed (ST1) infections, which may reflect inter alia transient colonization patterns and/or cooperative or competitive interactions between different STs. Comparative analyses with other primers that have been used extensively for ST-specific analysis found them unsuitable for detection of mixed and, in some cases, single-ST infections. Collectively, our data shed new light on the diversity of Blastocystis within and between human hosts. Moreover, the development of these PCR assays will facilitate future work on the molecular epidemiology and significance of mixed infections in groups of interest, including health and disease cohorts, and also help identify sources of Blastocystis transmission to humans, including identifying potential animal and environmental reservoirs. PMID- 25841011 TI - A Novel Binary Mixture of Helicoverpa armigera Single Nucleopolyhedrovirus Genotypic Variants Has Improved Insecticidal Characteristics for Control of Cotton Bollworms. AB - The genotypic diversity of two Spanish isolates of Helicoverpa armigera single nucleopolyhedrovirus (HearSNPV) was evaluated with the aim of identifying mixtures of genotypes with improved insecticidal characteristics for control of the cotton bollworm. Two genotypic variants, HearSP1A and HearSP1B, were cloned in vitro from the most pathogenic wild-type isolate of the Iberian Peninsula, HearSNPV-SP1 (HearSP1-wt). Similarly, six genotypic variants (HearLB1 to -6) were obtained by endpoint dilution from larvae collected from cotton crops in southern Spain that died from virus disease during laboratory rearing. Variants differed significantly in their insecticidal properties, pathogenicity, speed of kill, and occlusion body (OB) production (OBs/larva). HearSP1B was ~3-fold more pathogenic than HearSP1-wt and the other variants. HearLB1, HearLB2, HeaLB5, and HearLB6 were the fastest-killing variants. Moreover, although highly virulent, HearLB1, HearLB4, and HearLB5 produced more OBs/larva than did the other variants. The co occluded HearSP1B:LB6 mixture at a 1:1 proportion was 1.7- to 2.8-fold more pathogenic than any single variant and other mixtures tested and also killed larvae as fast as the most virulent genotypes. Serial passage resulted in modified proportions of the component variants of the HearSP1B:LB6 co-occluded mixture, suggesting that transmissibility could be further improved by this process. We conclude that the improved insecticidal phenotype of the HearSP1B:LB6 co-occluded mixture underlines the utility of the genotypic variant dissection and reassociation approach for the development of effective virus-based insecticides. PMID- 25841012 TI - sigma54-Dependent Response to Nitrogen Limitation and Virulence in Burkholderia cenocepacia Strain H111. AB - Members of the genus Burkholderia are versatile bacteria capable of colonizing highly diverse environmental niches. In this study, we investigated the global response of the opportunistic pathogen Burkholderia cenocepacia H111 to nitrogen limitation at the transcript and protein expression levels. In addition to a classical response to nitrogen starvation, including the activation of glutamine synthetase, PII proteins, and the two-component regulatory system NtrBC, B. cenocepacia H111 also upregulated polyhydroxybutyrate (PHB) accumulation and exopolysaccharide (EPS) production in response to nitrogen shortage. A search for consensus sequences in promoter regions of nitrogen-responsive genes identified a sigma(54) consensus sequence. The mapping of the sigma(54) regulon as well as the characterization of a sigma(54) mutant suggests an important role of sigma(54) not only in control of nitrogen metabolism but also in the virulence of this organism. PMID- 25841013 TI - Anoxic Conditions Promote Species-Specific Mutualism between Gut Microbes In Silico. AB - The human gut is inhabited by thousands of microbial species, most of which are still uncharacterized. Gut microbes have adapted to each other's presence as well as to the host and engage in complex cross feeding. Constraint-based modeling has been successfully applied to predicting microbe-microbe interactions, such as commensalism, mutualism, and competition. Here, we apply a constraint-based approach to model pairwise interactions between 11 representative gut microbes. Microbe-microbe interactions were computationally modeled in conjunction with human small intestinal enterocytes, and the microbe pairs were subjected to three diets with various levels of carbohydrate, fat, and protein in normoxic or anoxic environments. Each microbe engaged in species-specific commensal, parasitic, mutualistic, or competitive interactions. For instance, Streptococcus thermophilus efficiently outcompeted microbes with which it was paired, in agreement with the domination of streptococci in the small intestinal microbiota. Under anoxic conditions, the probiotic organism Lactobacillus plantarum displayed mutualistic behavior toward six other species, which, surprisingly, were almost entirely abolished under normoxic conditions. This finding suggests that the anoxic conditions in the large intestine drive mutualistic cross feeding, leading to the evolvement of an ecosystem more complex than that of the small intestinal microbiota. Moreover, we predict that the presence of the small intestinal enterocyte induces competition over host-derived nutrients. The presented framework can readily be expanded to a larger gut microbial community. This modeling approach will be of great value for subsequent studies aiming to predict conditions favoring desirable microbes or suppressing pathogens. PMID- 25841014 TI - Next-generation pyrosequencing analysis of microbial biofilm communities on granular activated carbon in treatment of oil sands process-affected water. AB - The development of biodegradation treatment processes for oil sands process affected water (OSPW) has been progressing in recent years with the promising potential of biofilm reactors. Previously, the granular activated carbon (GAC) biofilm process was successfully employed for treatment of a large variety of recalcitrant organic compounds in domestic and industrial wastewaters. In this study, GAC biofilm microbial development and degradation efficiency were investigated for OSPW treatment by monitoring the biofilm growth on the GAC surface in raw and ozonated OSPW in batch bioreactors. The GAC biofilm community was characterized using a next-generation 16S rRNA gene pyrosequencing technique that revealed that the phylum Proteobacteria was dominant in both OSPW and biofilms, with further in-depth analysis showing higher abundances of Alpha- and Gammaproteobacteria sequences. Interestingly, many known polyaromatic hydrocarbon degraders, namely, Burkholderiales, Pseudomonadales, Bdellovibrionales, and Sphingomonadales, were observed in the GAC biofilm. Ozonation decreased the microbial diversity in planktonic OSPW but increased the microbial diversity in the GAC biofilms. Quantitative real-time PCR revealed similar bacterial gene copy numbers (>10(9) gene copies/g of GAC) for both raw and ozonated OSPW GAC biofilms. The observed rates of removal of naphthenic acids (NAs) over the 2-day experiments for the GAC biofilm treatments of raw and ozonated OSPW were 31% and 66%, respectively. Overall, a relatively low ozone dose (30 mg of O3/liter utilized) combined with GAC biofilm treatment significantly increased NA removal rates. The treatment of OSPW in bioreactors using GAC biofilms is a promising technology for the reduction of recalcitrant OSPW organic compounds. PMID- 25841015 TI - Functional Analysis of Two l-Arabinose Transporters from Filamentous Fungi Reveals Promising Characteristics for Improved Pentose Utilization in Saccharomyces cerevisiae. AB - Limited uptake is one of the bottlenecks for l-arabinose fermentation from lignocellulosic hydrolysates in engineered Saccharomyces cerevisiae. This study characterized two novel l-arabinose transporters, LAT-1 from Neurospora crassa and MtLAT-1 from Myceliophthora thermophila. Although the two proteins share high identity (about 83%), they display different substrate specificities. Sugar transport assays using the S. cerevisiae strain EBY.VW4000 indicated that LAT-1 accepts a broad substrate spectrum. In contrast, MtLAT-1 appeared much more specific for l-arabinose. Determination of the kinetic properties of both transporters revealed that the Km values of LAT-1 and MtLAT-1 for l-arabinose were 58.12 +/- 4.06 mM and 29.39 +/- 3.60 mM, respectively, with corresponding Vmax values of 116.7 +/- 3.0 mmol/h/g dry cell weight (DCW) and 10.29 +/- 0.35 mmol/h/g DCW, respectively. In addition, both transporters were found to use a proton-coupled symport mechanism and showed only partial inhibition by d-glucose during l-arabinose uptake. Moreover, LAT-1 and MtLAT-1 were expressed in the S. cerevisiae strain BSW2AP containing an l-arabinose metabolic pathway. Both recombinant strains exhibited much faster l-arabinose utilization, greater biomass accumulation, and higher ethanol production than the control strain. In conclusion, because of higher maximum velocities and reduced inhibition by d glucose, the genes for the two characterized transporters are promising targets for improved l-arabinose utilization and fermentation in S. cerevisiae. PMID- 25841016 TI - Enhancing the Detection of Giardia duodenalis Cysts in Foods by Inertial Microfluidic Separation. AB - The sensitivity and specificity of current Giardia cyst detection methods for foods are largely determined by the effectiveness of the elution, separation, and concentration methods used. The aim of these methods is to produce a final suspension with an adequate concentration of Giardia cysts for detection and a low concentration of interfering food debris. In the present study, a microfluidic device, which makes use of inertial separation, was designed and fabricated for the separation of Giardia cysts. A cyclical pumping platform and protocol was developed to concentrate 10-ml suspensions down to less than 1 ml. Tests involving Giardia duodenalis cysts and 1.90-MUm microbeads in pure suspensions demonstrated the specificity of the microfluidic chip for cysts over smaller nonspecific particles. As the suspension cycled through the chip, a large number of beads were removed (70%) and the majority of the cysts were concentrated (82%). Subsequently, the microfluidic inertial separation chip was integrated into a method for the detection of G. duodenalis cysts from lettuce samples. The method greatly reduced the concentration of background debris in the final suspensions (10-fold reduction) in comparison to that obtained by a conventional method. The method also recovered an average of 68.4% of cysts from 25-g lettuce samples and had a limit of detection (LOD) of 38 cysts. While the recovery of cysts by inertial separation was slightly lower, and the LOD slightly higher, than with the conventional method, the sample analysis time was greatly reduced, as there were far fewer background food particles interfering with the detection of cysts by immunofluorescence microscopy. PMID- 25841017 TI - Bactericidal Compounds Controlling Growth of the Plant Pathogen Pseudomonas syringae pv. actinidiae, Which Forms Biofilms Composed of a Novel Exopolysaccharide. AB - Pseudomonas syringae pv. actinidiae is the major cause of bacterial canker and is a severe threat to kiwifruit production worldwide. Many aspects of the disease caused by P. syringae pv. actinidiae, such as the pathogenicity-relevant formation of a biofilm composed of extracellular polymeric substances (EPSs), are still unknown. Here, a highly virulent strain of P. syringae pv. actinidiae, NZ V 13, was studied with respect to biofilm formation and architecture using a flow cell system combined with confocal laser scanning microscopy. The biofilm formed by P. syringae pv. actinidiae NZ V-13 was heterogeneous, consisting of a thin cellular base layer 5 MUm thick and microcolonies with irregular structures. The major component of the EPSs produced by P. syringae pv. actinidiae NZ V-13 bacteria was isolated and identified to be an exopolysaccharide. Extensive compositional and structural analysis showed that rhamnose, fucose, and glucose were the major constituents, present at a ratio of 5:1.5:2. Experimental evidence that P. syringae pv. actinidiae NZ V-13 produces two polysaccharides, a branched alpha-d-rhamnan with side chains of terminal alpha-d-Fucf and an alpha-d-1,4 linked glucan, was obtained. The susceptibility of the cells in biofilms to kasugamycin and chlorine dioxide was assessed. About 64 and 73% of P. syringae pv. actinidiae NZ V-13 cells in biofilms were killed when kasugamycin and chlorine dioxide were used at 5 and 10 ppm, respectively. Kasugamycin inhibited the attachment of P. syringae pv. actinidiae NZ V-13 to solid surfaces at concentrations of 80 and 100 ppm. Kasugamycin was bacteriostatic against P. syringae pv. actinidiae NZ V-13 growth in the planktonic mode, with the MIC being 40 to 60 ppm and a bactericidal effect being found at 100 ppm. Here we studied the formation, architecture, and composition of P. syringae pv. actinidiae biofilms as well as used the biofilm as a model to assess the efficacies of bactericidal compounds. PMID- 25841018 TI - Evaluation of Lactococcus lactis Isolates from Nondairy Sources with Potential Dairy Applications Reveals Extensive Phenotype-Genotype Disparity and Implications for a Revised Species. AB - Lactococcus lactis is predominantly associated with dairy fermentations, but evidence suggests that the domesticated organism originated from a plant niche. L. lactis possesses an unusual taxonomic structure whereby strain phenotypes and genotypes often do not correlate, which in turn has led to confusion in L. lactis classification. A bank of L. lactis strains was isolated from various nondairy niches (grass, vegetables, and bovine rumen) and was further characterized on the basis of key technological traits, including growth in milk and key enzyme activities. Phenotypic analysis revealed all strains from nondairy sources to possess an L. lactis subsp. lactis phenotype (lactis phenotype); however, seven of these strains possessed an L. lactis subsp. cremoris genotype (cremoris genotype), determined by two separate PCR assays. Multilocus sequence typing (MLST) showed that strains with lactis and cremoris genotypes clustered together regardless of habitat, but it highlighted the increased diversity that exists among "wild" strains. Calculation of average nucleotide identity (ANI) and tetranucleotide frequency correlation coefficients (TETRA), using the JSpecies software tool, revealed that L. lactis subsp. cremoris and L. lactis subsp. lactis differ in ANI values by ~14%, below the threshold set for species circumscription. Further analysis of strain TIFN3 and strains from nonindustrial backgrounds revealed TETRA values of <0.99 in addition to ANI values of <95%, implicating that these two groups are separate species. These findings suggest the requirement for a revision of L. lactis taxonomy. PMID- 25841019 TI - Eaf1 Links the NuA4 Histone Acetyltransferase Complex to Htz1 Incorporation and Regulation of Purine Biosynthesis. AB - Proper modulation of promoter chromatin architecture is crucial for gene regulation in order to precisely and efficiently orchestrate various cellular activities. Previous studies have identified the stimulatory effect of the histone-modifying complex NuA4 on the incorporation of the histone variant H2A.Z (Htz1) at the PHO5 promoter (A. Auger, L. Galarneau, M. Altaf, A. Nourani, Y. Doyon, R. T. Utley, D. Cronier, S. Allard, and J. Cote, Mol Cell Biol 28:2257 2270, 2008, http://dx.doi.org/10.1128/MCB.01755-07). In vitro studies with a reconstituted system also indicated an intriguing cross talk between NuA4 and the H2A.Z-loading complex, SWR-C (M. Altaf, A. Auger, J. Monnet-Saksouk, J. Brodeur, S. Piquet, M. Cramet, N. Bouchard, N. Lacoste, R. T. Utley, L. Gaudreau, J. Cote, J Biol Chem 285:15966-15977, 2010, http://dx.doi.org/10.1074/jbc.M110.117069). In this work, we investigated the role of the NuA4 scaffold subunit Eaf1 in global gene expression and genome-wide incorporation of Htz1. We found that loss of Eaf1 affects Htz1 levels mostly at the promoters that are normally highly enriched in the histone variant. Analysis of eaf1 mutant cells by expression array unveiled a relationship between NuA4 and the gene network implicated in the purine biosynthesis pathway, as EAF1 deletion cripples induction of several ADE genes. NuA4 directly interacts with Bas1 activation domain, a key transcription factor of adenine genes. Chromatin immunoprecipitation (ChIP) experiments demonstrate that nucleosomes on the inactive ADE17 promoter are acetylated already by NuA4 and enriched in Htz1. Upon derepression, these poised nucleosomes respond rapidly to activate ADE gene expression in a mechanism likely reminiscent of the PHO5 promoter, leading to nucleosome disassembly. These detailed molecular events depict a specific case of cross talk between NuA4-dependent acetylation and incorporation of histone variant Htz1, presetting the chromatin structure over ADE promoters for subsequent chromatin remodeling and activated transcription. PMID- 25841020 TI - Aspergillus nidulans Ambient pH Signaling Does Not Require Endocytosis. AB - Aspergillus nidulans (Pal) ambient pH signaling takes place in cortical structures containing components of the ESCRT pathway, which are hijacked by the alkaline pH-activated, ubiquitin-modified version of the arrestin-like protein PalF and taken to the plasma membrane. There, ESCRTs scaffold the assembly of dedicated Pal proteins acting downstream. The molecular details of this pathway, which results in the two-step proteolytic processing of the transcription factor PacC, have received considerable attention due to the key role that it plays in fungal pathogenicity. While current evidence strongly indicates that the pH signaling role of ESCRT complexes is limited to plasma membrane-associated structures where PacC proteolysis would take place, the localization of the PalB protease, which almost certainly catalyzes the first and only pH-regulated proteolytic step, had not been investigated. In view of ESCRT participation, this formally leaves open the possibility that PalB activation requires endocytic internalization. As endocytosis is essential for hyphal growth, nonlethal endocytic mutations are predicted to cause an incomplete block. We used a SynA internalization assay to measure the extent to which any given mutation prevents endocytosis. We show that none of the tested mutations impairing endocytosis to different degrees, including slaB1, conditionally causing a complete block, have any effect on the activation of the pathway. We further show that PalB, like PalA and PalC, localizes to cortical structures in an alkaline pH-dependent manner. Therefore, signaling through the Pal pathway does not involve endocytosis. PMID- 25841021 TI - Cryptococcus strains with different pathogenic potentials have diverse protein secretomes. AB - Secreted proteins are the frontline between the host and pathogen. In mammalian hosts, secreted proteins enable invasive infection and can modulate the host immune response. Cryptococcosis, caused by pathogenic Cryptococcus species, begins when inhaled infectious propagules establish to produce pulmonary infection, which, if not resolved, can disseminate to the central nervous system to cause meningoencephalitis. Strains of Cryptococcus species differ in their capacity to cause disease, and the mechanisms underlying this are not well understood. To investigate the role of secreted proteins in disease, we determined the secretome for three genome strains of Cryptococcus species, including a hypovirulent and a hypervirulent strain of C. gattii and a virulent strain of C. neoformans. Sixty-seven unique proteins were identified, with different numbers and types of proteins secreted by each strain. The secretomes of the virulent strains were largely limited to proteolytic and hydrolytic enzymes, while the hypovirulent strain had a diverse secretome, including non conventionally secreted canonical cytosolic and immunogenic proteins that have been implicated in virulence. The hypovirulent strain cannot establish pulmonary infection in a mouse model, but strains of this genotype have caused human meningitis. To directly test brain infection, we used intracranial inoculation and found that the hypovirulent strain was substantially more invasive than its hypervirulent counterpart. We suggest that immunogenic proteins secreted by this strain invoke a host response that limits pulmonary infection but that there can be invasive growth and damage if infection reaches the brain. Given their known role in virulence, it is possible that non-conventionally secreted proteins mediate this process. PMID- 25841022 TI - Diversification of Paralogous alpha-Isopropylmalate Synthases by Modulation of Feedback Control and Hetero-Oligomerization in Saccharomyces cerevisiae. AB - Production of alpha-isopropylmalate (alpha-IPM) is critical for leucine biosynthesis and for the global control of metabolism. The budding yeast Saccharomyces cerevisiae has two paralogous genes, LEU4 and LEU9, that encode alpha-IPM synthase (alpha-IPMS) isozymes. Little is known about the biochemical differences between these two alpha-IPMS isoenzymes. Here, we show that the Leu4 homodimer is a leucine-sensitive isoform, while the Leu9 homodimer is resistant to such feedback inhibition. The leu4Delta mutant, which expresses only the feedback-resistant Leu9 homodimer, grows slowly with either glucose or ethanol and accumulates elevated pools of leucine; this phenotype is alleviated by the addition of leucine. Transformation of the leu4Delta mutant with a centromeric plasmid carrying LEU4 restored the wild-type phenotype. Bimolecular fluorescent complementation analysis showed that Leu4-Leu9 heterodimeric isozymes are formed in vivo. Purification and kinetic analysis showed that the hetero-oligomeric isozyme has a distinct leucine sensitivity behavior. Determination of alpha-IPMS activity in ethanol-grown cultures showed that alpha-IPM biosynthesis and growth under these respiratory conditions depend on the feedback-sensitive Leu4 homodimer. We conclude that retention and further diversification of two yeast alpha-IPMSs have resulted in a specific regulatory system that controls the leucine-alpha-IPM biosynthetic pathway by selective feedback sensitivity of homomeric and heterodimeric isoforms. PMID- 25841023 TI - Comment: Muscle strength at age 18 and Parkinson disease among Swedish men from a nationwide cohort. PMID- 25841024 TI - GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia. AB - OBJECTIVES: In a large family of Algerian origin, we aimed to identify the genetic mutation segregating with simultaneous presence of adult-onset, paucisymptomatic, slowly progressive, cerebellar ataxia in 7 adults and congenital ataxia in 1 child, and then to assess the involvement of GRID2 mutations in 144 patients with congenital cerebellar ataxia. METHODS: We used a combined approach of linkage analysis and whole-exome sequencing in one family, and a targeted gene panel sequencing approach in 144 congenital ataxias. RESULTS: In the large family with spinocerebellar ataxia, we identified a missense mutation (c.1966C>G/p.Leu656Val) in the GRID2 gene, in a heterozygous state in adults, and in a homozygous state in one child with congenital ataxia, compatible with a semidominant transmission pattern. In 144 patients affected with congenital ataxia, we identified 2 missense de novo GRID2 mutations in 2 children (c.1960G>A/p.Ala654Thr, c.1961C>A/p.Ala654Asp). They affect the same amino acid as the previously described Lurcher mutation in mice; the variant in the large family concerns a nearby amino acid. CONCLUSIONS: In humans, GRID2 had only been involved in ataxia through complete loss-of-function mutations due to exon deletions. We report the first point mutations in this gene, with putative gain of-function mechanisms, and a semidominant transmission as was observed in the Lurcher mice model. Of note, cerebellar ataxia is the core phenotype, but with variable severity ranging from very mild adult-onset to congenital-onset ataxias linked to both the heterozygous and homozygous state of the variant, and the position of the mutation. PMID- 25841027 TI - Does the presence of aura inform us regarding migraine severity and response to treatment? PMID- 25841025 TI - Prevalence and factors associated with convulsive status epilepticus in Africans with epilepsy. AB - OBJECTIVE: We conducted a community survey to estimate the prevalence and describe the features, risk factors, and consequences of convulsive status epilepticus (CSE) among people with active convulsive epilepsy (ACE) identified in a multisite survey in Africa. METHODS: We obtained clinical histories of CSE and neurologic examination data among 1,196 people with ACE identified from a population of 379,166 people in 3 sites: Agincourt, South Africa; Iganga-Mayuge, Uganda; and Kilifi, Kenya. We performed serologic assessment for the presence of antibodies to parasitic infections and HIV and determined adherence to antiepileptic drugs. Consequences of CSE were assessed using a questionnaire. Logistic regression was used to identify risk factors. RESULTS: The adjusted prevalence of CSE in ACE among the general population across the 3 sites was 2.3 per 1,000, and differed with site (p < 0.0001). Over half (55%) of CSE occurred in febrile illnesses and focal seizures were present in 61%. Risk factors for CSE in ACE were neurologic impairments, acute encephalopathy, previous hospitalization, and presence of antibody titers to falciparum malaria and HIV; these differed across sites. Burns (15%), lack of education (49%), being single (77%), and unemployment (78%) were common in CSE; these differed across the 3 sites. Nine percent with and 10% without CSE died. CONCLUSIONS: CSE is common in people with ACE in Africa; most occurs with febrile illnesses, is untreated, and has focal features suggesting preventable risk factors. Effective prevention and the management of infections and neurologic impairments may reduce the burden of CSE in ACE. PMID- 25841026 TI - Challenges and opportunities in designing clinical trials for neuromyelitis optica. AB - Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end. PMID- 25841028 TI - RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. AB - OBJECTIVE: To identify the genetic cause in 2 Belgian families with autosomal recessive Huntington-like disorder (HDL). METHODS: Homozygosity mapping and whole exome sequencing in a consanguineous family as well as Sanger sequencing of the candidate gene in an independent family with HDL followed by genotype-phenotype correlation studies. RESULTS: We identified a homozygous mutation in the gene RNF216 p.(Gly456Glu) within a shared 4.8-Mb homozygous region at 7p22.3 in 2 affected siblings of a consanguineous HDL family. In an independent family, 2 siblings with HDL were compound heterozygous for mutations in RNF216 p.(Gln302*) and p.(Tyr539Cys). Chorea, behavioral problems, and severe dementia were the core clinical signs in all patients. Brain imaging consistently showed white matter lesions. Low gonadotropin serum levels and cerebellar atrophy could be demonstrated in the index family. CONCLUSIONS: Mutations in RNF216 have recently been found in families with Gordon Holmes syndrome, a condition defined by hypogonadotropic hypogonadism and cerebellar ataxia. The mode of inheritance was proposed to be oligogenic for most families. We describe novel RNF216 mutations causing an HDL phenotype with pure monogenic recessive inheritance. Subclinical serum evidence of hypogonadotropic hypogonadism links this disorder to Gordon Holmes syndrome. Our study thus challenges the oligogenic inheritance model and emphasizes chorea as an essential clinical feature in RNF216-mediated neurodegeneration. PMID- 25841029 TI - Quality of life in pediatric epilepsy: Considerations for measurement and use. PMID- 25841030 TI - Somatotopic fascicular organization of the human sciatic nerve demonstrated by MR neurography. AB - OBJECTIVES: To investigate whether the human sciatic nerve might have a consistent somatotopic organization according to proximal fascicle input by spinal nerves. METHODS: Twelve patients (55.3 +/- 15.5 years) with confirmed lesions of either the L5 or S1 spinal nerve root underwent magnetic resonance neurography of sciatic nerve fascicles including thigh and knee levels (T2 weighted sequence with fat saturation, repetition time/echo time 7,552/52 milliseconds, voxel size 0.27 * 0.27 * 3.0 mm(3)). Twenty healthy subjects and 12 additional patients with an established diagnosis of peripheral polyneuropathy served as 2 separate age- and sex-matched control groups. Two blinded readers assessed patients and controls for presence of distinct lesion patterns. Spatial maps of normalized T2 signal were rendered after segmentation and coregistration of sciatic nerve voxels to detect fascicle lesion patterns. RESULTS: A clear somatotopic distribution of nerve fascicles was observed on cross-sections along the entire course of the sciatic nerve and was distinct between patients with L5 and those with S1 lesions. Fascicles emerging from L5 were ordered in anterolateral positions within sciatic nerve cross-sections, while fascicles emerging from S1 appeared posteromedially. Visual assessment discriminated these somatotopic lesions in all cases from both healthy and polyneuropathy controls. CONCLUSION: A distinct pattern of somatotopy was identified within the sciatic nerve according to proximal fascicle input by L5 and S1 spinal nerves. Knowledge of human nerve somatotopy may have clinically useful implications in imaging aided diagnosis of neuropathies. PMID- 25841031 TI - Children's perspective of quality of life in epilepsy. AB - OBJECTIVE: To study child mental health, parental support, and social support of children with epilepsy as these relate to quality of life (QOL) using child self report, seizure-related variables, and estimated verbal intelligence based on receptive vocabulary. METHODS: A cross-sectional structural equation model of baseline data from the QUALITE cohort study, which includes 6 Canadian child epilepsy ambulatory programs. A sample of 3,481 children were screened for the following eligibility: 8 to 14 years of age, with active or medication-managed epilepsy. Of 894 eligible children, 506 agreed to participate, of whom 26 were then excluded because of an inability to self-report based on a standard cutoff score of receptive vocabulary lower than 70. The primary outcome of child reported QOL was measured using the Child Epilepsy QOL Questionnaire. RESULTS: From the child's perspective, epilepsy-specific QOL is strongly related to their mental health and social support but not to their seizures. Specifically, child mental health and peer support exhibit direct associations with QOL; parental support has both direct and indirect associations with QOL (via child mental health); estimated verbal intelligence exerts its strongest association with QOL through mental health; and seizure status exhibits a weak relationship to QOL only through mental health. CONCLUSIONS: Among children with epilepsy aged 8 to 14 years, mental health and social support should be areas of focus in the assessment of QOL. Controlling seizures is insufficient care for influencing the child's perception of their life. PMID- 25841032 TI - Reduced efficacy of sumatriptan in migraine with aura vs without aura. AB - OBJECTIVE: To determine whether acute migraine treatment outcome is different in migraine with aura compared with migraine without aura. METHODS: We examined pooled outcome data for sumatriptan treatment of migraine with and without aura from the sumatriptan/naratriptan aggregate patient database. We also examined similar outcome data for inhaled dihydroergotamine (DHE) from a single, large randomized controlled study. RESULTS: The pooled pain-free rates 2 hours postdose for sumatriptan 100 mg were significantly higher in patients treating attacks without aura (32%) compared with the group who treated attacks with aura (24%) (p < 0.001). The relative risk for pain freedom 2 hours postdose for attacks without aura was 1.33 (95% confidence interval: 1.16-1.54). The number needed to treat for 2 hours of pain freedom was 4.4 for attacks without aura and 6.2 for attacks with aura. For the clinical trial of DHE, the 2-hour pain-free rates did not differ between patients treating attacks without aura (29.4%) compared with those who treated attacks with aura (27.2%; p = 0.65). The relative risk for pain freedom 2 hours postdose for attacks without aura vs with aura was 1.08 (95% confidence interval: 0.77-1.53). The number needed to treat for 2 hours pain free was 5.8 for attacks without aura and 5.0 for attacks with aura. CONCLUSION: This post hoc analysis of pooled data from multiple randomized trials indicates that sumatriptan is less effective as acute therapy for migraine attacks with aura compared with attacks without aura. In the single study of inhaled DHE, the treatment had similar efficacy for migraine attacks with and without aura. Different responses of migraine with vs without aura to acute therapies may provide insight into underlying migraine mechanisms and influence the choice of acute therapies for different types of migraine attacks. PMID- 25841033 TI - Low muscle strength in late adolescence and Parkinson disease later in life. AB - OBJECTIVE: To evaluate maximal isometric muscle force at 18 years of age in relation to Parkinson disease (PD) later in life. METHODS: The cohort consisted of 1,317,713 men who had their muscle strength measured during conscription (1969 1996). Associations between participants' muscle strength at conscription and PD diagnoses, also in their parents, were examined using multivariate statistical models. RESULTS: After adjustment for confounders, the lowest compared to the highest fifth of handgrip strength (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.79), elbow flexion strength (HR 1.34, 95% CI 1.02-1.76), but not knee extension strength (HR 1.24, 95% CI 0.94-1.62) was associated with an increased risk of PD during follow-up. Furthermore, men whose parents were diagnosed with PD had reduced handgrip (fathers: mean difference [MD] -5.7 N [95% CI -7.3 to -4.0]; mothers: MD -5.0 N [95% CI -7.0 to -2.9]) and elbow flexion (fathers: MD -4.3 N [95% CI -5.7 to -2.9]; mothers: MD -3.9 N [95% CI -5.7 to 2.2]) strength, but not knee extension strength (fathers: MD -1.1 N [95% CI -2.9 to 0.8]; mothers: MD -0.7 N [95% CI -3.1 to 1.6]), than those with no such familial history. CONCLUSIONS: Maximal upper extremity voluntary muscle force was reduced in late adolescence in men diagnosed with PD 30 years later. The findings suggest the presence of subclinical motor deficits 3 decades before the clinical onset of PD. PMID- 25841034 TI - Perinatal and childhood risk factors for early-onset type 1 diabetes: a population-based case-control study in Taiwan. AB - BACKGROUND: Certain factors originating from the perinatal and childhood periods are suspected of contributing to the recent increasing trend of childhood type 1 diabetes (T1D) incidence. This study sought to investigate the relationships between various perinatal and childhood risk factors and T1D incidence in young children (<10 years). METHODS: We used a nested case-control design based on 1,478,573 live births born in 2000-05 in Taiwan. Cases were 632 incident cases of T1D between 2000 and 2008. Ten matched controls for each case were randomly selected. Information on various perinatal risk factors was also identified from claim data. Multiple conditional logistic regression was employed to estimate odds ratio (OR) and 95 confidence interval (CI) of T1D. RESULTS: Childhood infection was significantly associated with an increased risk of T1D (OR = 1.46, 95% CI = 1.23-1.73). Increased risk of T1D was also noted in children born to younger mothers (<25 years) (OR = 1.94, 95% CI = 1.34-2.81), older fathers (>30 years) (OR = 1.56 (95% CI = 1.16-2.10) to 1.57 (95% CI = 1.19-2.05), mothers with Caesarean section (CS) (OR = 2.35, 95% CI = 1.52-3.64), and mothers with gestational diabetes mellitus (OR = 4.36, 95% CI = 2.76-7.77). Fathers with T1D (OR = 7.36, 95% CI = 1.02-57.21) or type 2 diabetes (OR = 1.54, 95% CI = 1.04 2.26) were observed to substantially increase the risk of offspring T1D. CONCLUSIONS: Certain modifiable perinatal factors such as infection and CS may predispose incidence of T1D in young children. PMID- 25841035 TI - Spatial variation of male alcohol-related mortality in Belarus and Lithuania. AB - BACKGROUND: Numerous studies have addressed the problem of hazardous alcohol consumption, alcohol-related causes of death and their relationship to persisting excess male mortality in the countries of the former USSR. Yet relatively little is known about the geographical patterns of alcohol-related mortality within these countries and the cross-border continuities of such patterns. This study aims at identifying the spatial distribution and the cross-border patterns of adult male mortality from alcohol poisonings and liver cirrhosis in Belarus and Lithuania. METHODS: We use cause-specific mortality data for 2003-2007. We employ spatial econometric techniques to detect 'hot spots' of alcohol-related mortality across the combined territory of the two countries. RESULTS: Specific patterns associated with extremely high rates of mortality from alcohol poisoning can be observed in Belarus, particularly in the areas bordering Russia and Lithuania. Meanwhile, patterns of alcohol-induced liver disease dominate in Lithuania, and continue across the border from eastern Lithuania into north-western Belarus. CONCLUSIONS: The districts located along the Belarusian-Lithuanian border appear to be especially problematic, as they suffer from an enormous burden of alcohol consumption. The situation is particularly severe on the Belarusian side, where there are extremely high levels of mortality from both alcohol poisoning and liver cirrhosis. These areas should be considered primary targets for antialcohol policies. PMID- 25841036 TI - The Transcriptional Regulator BBX19 Promotes Hypocotyl Growth by Facilitating COP1-Mediated EARLY FLOWERING3 Degradation in Arabidopsis. AB - Hypocotyl elongation is a highly coordinated physiological response regulated by myriad internal and external cues. Here, we show that BBX19, a transcriptional regulator with two B-box motifs, is a positive regulator of growth; diminished BBX19 expression by RNA interference reduces hypocotyl length, and its constitutive expression promotes growth. This function of BBX19 is dependent on the E3 ubiquitin ligase CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), EARLY FLOWERING3 (ELF3), and PHYTOCHROME-INTERACTING FACTOR4 (PIF4) and PIF5. BBX19 is nucleus colocalized and interacts physically with COP1 and ELF3, a component of the evening complex that represses the expression of PIF4 and PIF5. Moreover, ELF3 protein abundance inversely correlates with BBX19 expression levels in a COP1 dependent manner. By contrast, PIF expression, coinciding with the initiation of hypocotyl growth in the early evening, is positively correlated with the BBX19 transcript abundance. These results collectively establish BBX19 as an adaptor that binds to and recruits ELF3 for degradation by COP1 and, as such, dynamically gates the formation of the evening complex, resulting in derepression of PIF4/5. This finding refines our perspective on how plants grow by providing a molecular link between COP1, ELF3, and PIF4/5 as an underlying mechanism of photomorphogenic development in Arabidopsis thaliana. PMID- 25841037 TI - Ethylene responses in rice roots and coleoptiles are differentially regulated by a carotenoid isomerase-mediated abscisic acid pathway. AB - Ethylene and abscisic acid (ABA) act synergistically or antagonistically to regulate plant growth and development. ABA is derived from the carotenoid biosynthesis pathway. Here, we analyzed the interplay among ethylene, carotenoid biogenesis, and ABA in rice (Oryza sativa) using the rice ethylene response mutant mhz5, which displays a reduced ethylene response in roots but an enhanced ethylene response in coleoptiles. We found that MHZ5 encodes a carotenoid isomerase and that the mutation in mhz5 blocks carotenoid biosynthesis, reduces ABA accumulation, and promotes ethylene production in etiolated seedlings. ABA can largely rescue the ethylene response of the mhz5 mutant. Ethylene induces MHZ5 expression, the production of neoxanthin, an ABA biosynthesis precursor, and ABA accumulation in roots. MHZ5 overexpression results in enhanced ethylene sensitivity in roots and reduced ethylene sensitivity in coleoptiles. Mutation or overexpression of MHZ5 also alters the expression of ethylene-responsive genes. Genetic studies revealed that the MHZ5-mediated ABA pathway acts downstream of ethylene signaling to inhibit root growth. The MHZ5-mediated ABA pathway likely acts upstream but negatively regulates ethylene signaling to control coleoptile growth. Our study reveals novel interactions among ethylene, carotenogenesis, and ABA and provides insight into improvements in agronomic traits and adaptive growth through the manipulation of these pathways in rice. PMID- 25841038 TI - Suppression of Arbuscule Degeneration in Medicago truncatula phosphate transporter4 Mutants is Dependent on the Ammonium Transporter 2 Family Protein AMT2;3. AB - During arbuscular mycorrhizal (AM) symbiosis, the plant gains access to phosphate (Pi) and nitrogen delivered by its fungal symbiont. Transfer of mineral nutrients occurs at the interface between branched hyphae called arbuscules and root cortical cells. In Medicago truncatula, a Pi transporter, PT4, is required for symbiotic Pi transport, and in pt4, symbiotic Pi transport fails, arbuscules degenerate prematurely, and the symbiosis is not maintained. Premature arbuscule degeneration (PAD) is suppressed when pt4 mutants are nitrogen-deprived, possibly the result of compensation by PT8, a second AM-induced Pi transporter. However, PAD is also suppressed in nitrogen-starved pt4 pt8 double mutants, negating this hypothesis and furthermore indicating that in this condition, neither of these symbiotic Pi transporters is required for symbiosis. In M. truncatula, three AMT2 family ammonium transporters are induced during AM symbiosis. To test the hypothesis that suppression of PAD involves AMT2 transporters, we analyzed double and triple Pi and ammonium transporter mutants. ATM2;3 but not AMT2;4 was required for suppression of PAD in pt4, while AMT2;4, but not AMT2;3, complemented growth of a yeast ammonium transporter mutant. In summary, arbuscule life span is influenced by PT4 and ATM2;3, and their relative importance varies with the nitrogen status of the plant. PMID- 25841040 TI - Development of a retrospective/fortuitous accident dosimetry service based on OSL of mobile phones. AB - Work is presented on the development of a retrospective/fortuitous accident dosimetry service using optically stimulated luminescence of resistors found in mobile phones to determine the doses of radiation to members of the public following a radiological accident or terrorist incident. The system is described and discussed in terms of its likely accuracy in a real incident. PMID- 25841039 TI - Axillary Meristem Formation in Rice Requires the WUSCHEL Ortholog TILLERS ABSENT1. AB - Axillary shoot formation is a key determinant of plant architecture. Formation of the axillary shoot is regulated by initiation of the axillary meristem or outgrowth of the axillary bud. Here, we show that rice (Oryza sativa) TILLERS ABSENT1 (TAB1; also known as Os WUS), an ortholog of Arabidopsis thaliana WUS, is required to initiate axillary meristem development. We found that formation of the axillary meristem in rice proceeds via a transient state, which we term the premeristem, characterized by the expression of OSH1, a marker of indeterminate cells in the shoot apical meristem. In the tab1-1 (wus-1) mutant, however, formation of the axillary meristem is arrested at various stages of the premeristem zone, and OSH1 expression is highly reduced. TAB1/WUS is expressed in the premeristem zone, where it shows a partially overlapping pattern with OSH1. It is likely, therefore, that TAB1 plays an important role in maintaining the premeristem zone and in promoting the formation of the axillary meristem by promoting OSH1 expression. Temporal expression patterns of WUSCHEL-RELATED HOMEOBOX4 (WOX4) indicate that WOX4 is likely to regulate meristem maintenance instead of TAB1 after establishment of the axillary meristem. Lastly, we show that the prophyll, the first leaf in the secondary axis, is formed from the premeristem zone and not from the axillary meristem. PMID- 25841042 TI - The Quality of Life Burden Associated With Voice Disorders in Sjogren's Syndrome. AB - OBJECTIVES: This study examined quality of life burden of voice disorders in Sjogren's syndrome (SS). METHODS: Patients with SS (n = 101) completed interviews involving patient-reported histories of voice disorders, specific voice symptoms, SS disease severity, the Voice-Related Quality of Life (V-RQOL), and the general health-related quality of life Short Form 36 (SF-36) questionnaires. Relationships among voice symptoms, disease severity, and quality-of-life measures were examined and compared with patient-reported voice disorders. RESULTS: Significant correlations were observed among voice symptoms, disease severity, V-RQOL, SF-36, and patient-reported voice disorders (P < .05). Patients with SS who reported a voice disorder experienced a greater burden on general quality of life as compared with those without voice disorders. Specific voice symptoms significantly correlated with reduced SF-36 scores included frequent throat-clearing, throat soreness, difficulty projecting, and vocal discomfort. Despite the added burden of a voice disorder on quality of life in SS, voice related treatment seeking was low (15.8%). However, the majority of patients who received voice treatment reported voice improvement. CONCLUSIONS: Individuals with SS frequently experience voice disorders and specific voice-related symptoms that are associated with reduced quality of life. These findings have important implications for voice referral practices and voice disorder symptom management in this population. PMID- 25841041 TI - Dose Equivalents for Second-Generation Antipsychotic Drugs: The Classical Mean Dose Method. AB - BACKGROUND: The concept of dose equivalence is important for many purposes. The classical approach published by Davis in 1974 subsequently dominated textbooks for several decades. It was based on the assumption that the mean doses found in flexible-dose trials reflect the average optimum dose which can be used for the calculation of dose equivalence. We are the first to apply the method to second generation antipsychotics. METHODS: We searched for randomized, double-blind, flexible-dose trials in acutely ill patients with schizophrenia that examined 13 oral second-generation antipsychotics, haloperidol, and chlorpromazine (last search June 2014). We calculated the mean doses of each drug weighted by sample size and divided them by the weighted mean olanzapine dose to obtain olanzapine equivalents. RESULTS: We included 75 studies with 16 555 participants. The doses equivalent to 1 mg/d olanzapine were: amisulpride 38.3 mg/d, aripiprazole 1.4 mg/d, asenapine 0.9 mg/d, chlorpromazine 38.9 mg/d, clozapine 30.6 mg/d, haloperidol 0.7 mg/d, quetiapine 32.3mg/d, risperidone 0.4 mg/d, sertindole 1.1 mg/d, ziprasidone 7.9 mg/d, zotepine 13.2 mg/d. For iloperidone, lurasidone, and paliperidone no data were available. CONCLUSIONS: The classical mean dose method is not reliant on the limited availability of fixed-dose data at the lower end of the effective dose range, which is the major limitation of "minimum effective dose methods" and "dose-response curve methods." In contrast, the mean doses found by the current approach may have in part depended on the dose ranges chosen for the original trials. Ultimate conclusions on dose equivalence of antipsychotics will need to be based on a review of various methods. PMID- 25841043 TI - Community-Engaged Public Health Research to Inform Hospital Campus Planning in a Low Socioeconomic Status Urban Neighborhood. AB - OBJECTIVE: To compare sociodemographic and motivational factors for healthcare use and identify desirable health-promoting resources among groups in a low socioeconomic status (SES) community in Chicago, IL. BACKGROUND: Disparities in health services and outcomes are well established in low SES urban neighborhoods in the United States and many factors beyond service availability and quality impact community health. Yet there is no clear process for engaging communities in building resources to improve population-level health in such locales. METHODS: A hospital building project led to a partnership of public health researchers, architects, and planners who conducted community-engaged research. We collected resident data and compared factors for healthcare use and choice and likelihood of engaging new health-promoting services. RESULTS: Neighborhood areas were strongly associated with ethnic groupings, and there were differences between groups in healthcare choice and service needs, such as, proximity to home was more important to Latinos than African Americans in choice of healthcare facility ( p adj = .001). Latinos expressed higher likelihood to use a fitness facility ( p adj = .001). Despite differences in vehicle ownership, >75% of all respondents indicated that nearby public transportation was important in choosing healthcare. CONCLUSION: Knowledge of community needs and heterogeneity is essential to decision makers of facility and community development plans. Partnerships between public health, urban planning, architecture, and local constituents should be cultivated toward focus on reducing health disparities. Further work to integrate community perspectives through the planning and design process and to evaluate the long-term impact of such efforts is needed. PMID- 25841044 TI - Efficacy of mechanical insufflation-exsufflation in extubating unweanable subjects with restrictive pulmonary disorders. PMID- 25841045 TI - What is the potential role of transcutaneous carbon dioxide in guiding acute noninvasive ventilation? PMID- 25841046 TI - A look at the diversity in management of respiratory failure in amyotrophic lateral sclerosis. PMID- 25841047 TI - Mechanical ventilation for the treatment of severe excessive dynamic airway collapse. PMID- 25841048 TI - Excessive dynamic airway collapse in the critical care setting. PMID- 25841050 TI - Correction for Kim et al., development of an adenovirus-based respiratory syncytial virus vaccine: preclinical evaluation of efficacy, immunogenicity, and enhanced disease in a cotton rat model. PMID- 25841051 TI - Correction for McGuire et al., diverse recombinant HIV-1 Envs fail to activate B cells expressing the germline B cell receptors of the broadly neutralizing anti HIV-1 antibodies PG9 and 447-52D. PMID- 25841053 TI - MALDI-TOF typing highlights geographical and fluconazole resistance clusters in Candida glabrata. AB - Utilizing matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectra for Candida glabrata typing would be a cost-effective and easy-to use alternative to classical DNA-based typing methods. This study aimed to use MALDI-TOF for the typing of C. glabrata clinical isolates from various geographical origins and test its capacity to differentiate between fluconazole sensitive and -resistant strains.Both microsatellite length polymorphism (MLP) and MALDI-TOF mass spectra of 58 C. glabrata isolates originating from Marseilles (France) and Tunis (Tunisia) as well as collection strains from diverse geographic origins were analyzed. The same analysis was conducted on a subset of C. glabrata isolates that were either susceptible (MIC <= 8 mg/l) or resistant (MIC >= 64 mg/l) to fluconazole.According to the seminal results, both MALDI-TOF and MLP classifications could highlight C. glabrata population structures associated with either geographical dispersal barriers (p < 10(-5)) or the selection of antifungal drug resistance traits (<10(-5)).In conclusion, MALDI-TOF geographical clustering was congruent with MPL genotyping and highlighted a significant population genetic structure according to fluconazole susceptibility in C. glabrata. Furthermore, although MALDI-TOF and MLP resulted in distinct classifications, MALDI-TOF also classified the isolates with respect to their fluconazole susceptibility profile. Further prospective studies are required to evaluate the capacity of MALDI-TOF typing to investigate C. glabrata infection outbreaks and predict the antifungal susceptibility profile of clinical laboratory isolates. PMID- 25841054 TI - Inhibitory effects of antimicrobial agents against Fusarium species. AB - We investigated the inhibitory effects of antibacterial, biocidal, and antifungal agents against Fusarium spp. Seven Fusarium spp: four F. falciforme (Fusarium solani species complex), one Fusarium spp, one Fusarium spp. (Fusarium incarnatum equiseti species complex), and one F. napiforme (Gibberella fujikuroi species complex), isolated from eyes with fungal keratitis were used in this study. Their susceptibility to antibacterial agents: flomoxef, imipenem, gatifloxacin, levofloxacin, moxifloxacin, gentamicin, tobramycin, and Tobracin(r) (contained 3,000 MUg/ml of tobramycin and 25 MUg/ml of benzalkonium chloride (BAK), a biocidal agent: BAK, and antifungal agents: amphotericin B, pimaricin (natamycin), fluconazole, itraconazole, miconazole, voriconazole, and micafungin, was determined by broth microdilution tests. The half-maximal inhibitory concentration (IC50), 100% inhibitory concentration (IC100), and minimum inhibitory concentration (MIC) against the Fusarium isolates were determined. BAK had the highest activity against the Fusarium spp. except for the antifungal agents. Three fluoroquinolones and two aminoglycosides had inhibitory effects against the Fusarium spp. at relatively high concentrations. Tobracin(r) had a higher inhibitory effect against Fusarium spp. than tobramycin alone. Amphotericin B had the highest inhibitory effect against the Fusarium spp, although it had different degrees of activity against each isolate. Our findings showed that fluoroquinolones, aminoglycosides, and BAK had some degree of inhibitory effect against the seven Fusarium isolates, although these agents had considerably lower effect than amphotericin B. However, the inhibitory effects of amphotericin B against the Fusarium spp. varied for the different isolates. Further studies for more effective medications against Fusarium, such as different combinations of antibacterial, biocidal, and antifungal agents are needed. PMID- 25841055 TI - Scedo-Select III: a new semi-selective culture medium for detection of the Scedosporium apiospermum species complex. AB - The Scedosporium apiospermum complex is responsible for a large variety of infections in human. Members of this complex have become emerging fungal pathogens with an increasing occurrence in patients with underlying conditions such as immunosuppression or cystic fibrosis. A better knowledge of these fungi and of the sources of contamination of the patients is required and more accurate detection methods from the environment are needed. In this context, a highly selective culture medium was developed in the present study. Thus, various aliphatic, cyclic, or aromatic compounds were tested as the sole carbon source, in combination with some inorganic nitrogen sources and fungicides. The best results were obtained with 4-hydroxy-benzoate combined with ammonium sulfate and the fungicides dichloran and benomyl. This new culture medium called Scedo-Select III was shown to support growth of all species of the S. apiospermum complex. Subsequently, this new culture medium was evaluated successfully on water and soil samples, exhibiting higher sensitivity and selectivity than the previously described SceSel+ culture medium. Therefore, this easy-to-prepare and synthetic semi-selective culture medium may be useful to clarify the ecology of these fungi and to identify their reservoirs in patients' environment. PMID- 25841056 TI - Morphology and its underlying genetic regulation impact the interaction between Cryptococcus neoformans and its hosts. AB - Cryptococcus neoformans is a fungus that causes the majority of fatal cryptococcal meningitis cases worldwide. This pathogen is capable of assuming different morphotypes: yeast, pseudohypha, and hypha. The yeast form is the most common cell type observed clinically. The hyphal and pseudohyphal forms are rarely observed in the clinical setting and are considered attenuated in virulence. However, as a ubiquitous environmental pathogen, Cryptococcus interacts with various organisms, and it is known to be parasitic to different hosts. Capitalizing on recent discoveries, morphogenesis regulators were manipulated to examine the impact of cell shape on the cryptococcal interaction with three different host systems: the soil amoeba Acanthamoeba castellanii (a protist), the greater wax moth Galleria mellonella (an insect), and the murine macrophage cell line J774A.1 (mammalian cells). The regulation of Ace2 and morphogenesis (RAM) pathway is a highly conserved pathway among eukaryotes that regulates cytokinesis. Disruption of any of five RAM components in Cryptococcus renders cells constitutively in the pseudohyphal form. The transcription factor Znf2 is the master activator of the yeast to hyphal transition. Deletion of ZNF2 locks cells in the yeast form, while overexpression of this regulator drives hyphal growth. Genetic epistasis analyses indicate that the RAM and the Znf2 pathways regulate distinct aspects of cryptococcal morphogenesis and independently of each other. These investigations using the Cryptococcus RAM and ZNF2 mutants indicate that cell shape, cell size, and likely cell surface properties weigh differently on the outcome of cryptococcal interactions with different hosts. Thus, certain traits evolved in Cryptococcus that are beneficial within one host might be detrimental when a different host is encountered. PMID- 25841057 TI - Cholesterol anchored arabinogalactan for asialoglycoprotein receptor targeting: synthesis, characterization, and proof of concept of hepatospecific delivery. AB - Asialoglycoprotein receptors (ASGPR) are hepatocyte bound receptors, which exhibit receptor mediated endocytosis (RME) for galactose specific moieties. Arabinogalactan (AG), a liver specific high galactose containing branched polysaccharide was hydrophobized using cholesterol (CHOL) as a lipid anchor via a two step reaction process to yield the novel polysaccharide lipid conjugated ligand (CHOL-AL-AG). CHOL-AL-AG was characterized by Fourier transform infra red (FTIR) spectroscopy, (1)H and (13)C nuclear magnetic spectroscopy (NMR), size exclusion chromatography (SEC) and differential scanning calorimetry (DSC). Conventional liposomes (CL) and surface modified liposomes (SML) containing CHOL AL-AG were prepared using reverse phase evaporation technique. Effect of CHOL-AL AG concentration on particle size and zeta potential of SML was evaluated. Surface morphology of CL and SML was studied using cryo-transmission electron microscopy (cryo-TEM). In vitro binding affinity of SML and CL was evaluated using Ricinus communis agglutinin (RCA) assay. Cellular uptake of SML and CL was determined on ASGPR expressing HepG2 cell lines by confocal laser scanning microscopy technique (CLSM). FTIR spectra revealed bands at 1736 cm(-1) and 1664 cm(-1) corresponding to ester and carbamate functional groups, respectively. Signals at delta 0.5-2.5 corresponding to the cholestene ring and delta 3-5.5 corresponding to the carbohydrate backbone were observed in (1)H NMR spectrum of the product. CHOL-AL-AG possessed a mean average molecular weight of 27 KDa as determined by size exclusion chromatography. An endothermic peak at 207 degrees C was observed in the DSC thermogram of CHOL-AL-AG, which was not observed in thermograms of reactants and intermediate product. Synthesized CHOL-AL-AG was successfully incorporated in liposomes to yield SML. Both CL and SML possessed a mean particle size of ~ 200 nm with polydispersity index of ~ 0.25. The zeta potential of CLs was observed to be -17 mV whereas zeta potential of SMLs varied from -18 to -22 mV. RCA assay revealed enhanced binding of SML compared to CL confirming presence of galactose on surface of SML. CLSM studies demonstrated enhanced cellular uptake of SMLs compared to CL by HepG2 cells post 3 h administration indicating enhanced uptake by the ASGPR. Thus surface modified liposomes specific to target heptocytes demonstrate a promising approach for targeted drug delivery in liver cancer therapeutics. PMID- 25841058 TI - Novel family GH3 beta-glucosidases or beta-xylosidases of unknown function found in various animal groups, including birds and reptiles. AB - Proteins from the glycoside hydrolase family 3 (GH3) are important bacterial, fungal and plant enzymes involved in cell wall remodeling, energy metabolism and pathogen defense but no animal GH3 proteins have been reported so far. In presented work we use the in silico approach to describe putative GH3 proteins of animals. Based on tertiary structure modeling, domain organization and transcriptomics data analysis, presence of catalytic and substrate binding residues and evolutionary relationship inference, we assume that there is a monophyletic group of GH3 enzymes (probably beta-xylosidases) found in various animal taxa with possible role in development. PMID- 25841059 TI - Solubilization of octane in cationic surfactant-anionic polymer complexes: effect of polymer concentration and temperature. AB - Polymers may alter the ability of oppositely charged surfactant micelles to solubilize hydrophobic molecules depending on surfactant-polymer interactions. This study was conducted to investigate the effects of polymer concentration and temperature on the solubilization thermodynamics of an octane oil-in-water emulsion in mixtures of an anionic polymer (carboxymethyl cellulose) and cationic cetyltrimethylammonium bromide (CTAB) surfactant micelles using isothermal titration calorimetry (ITC). Results showed that the CTAB binding capacity of carboxymethyl cellulose increased with increasing temperature from 301 to 323 K, and correspondingly the thermodynamic behavior of octane solubilization in CTAB micelles, either in the absence or presence of polymer, was found to depend on temperature. The addition of carboxymethyl cellulose caused the solubilization in CTAB micelles to be less endothermic, and increased the solubilization capacity. Based on the phase separation model, the solubilization was suggested to be mainly driven by enthalpy gains. Results suggest that increasing concentrations of the anionic polymer gave rise to a larger Gibbs energy decrease and a larger unfavorable entropy increase for octane solubilization in cationic surfactant micelles. PMID- 25841060 TI - Manganese chlorins immobilized on silica as oxidation reaction catalysts. AB - Synthetic strategies that comply with the principles of green chemistry represent a challenge: they will enable chemists to conduct reactions that maximize the yield of products with commercial interest while minimizing by-products formation. The search for catalysts that promote the selective oxidation of organic compounds under mild and environmentally friendly conditions constitutes one of the most important quests of organic chemistry. In this context, metalloporphyrins and analogues are excellent catalysts for oxidative transformations under mild conditions. In fact, their reduced derivatives chlorins are also able to catalyze organic compounds oxidation effectively, although they have been still little explored. In this study, we synthesized two chlorins through porphyrin cycloaddition reactions with 1.3-dipoles and prepared the corresponding manganese chlorins (MnCHL) using adequate manganese(II) salts. These MnCHL were posteriorly immobilized on silica by following the sol-gel process and the resulting solids were characterized by powder X-ray diffraction (PXRD), UVVIS spectroscopy, FTIR, XPS, and EDS. The catalytic activity of the immobilized MnCHL was investigated in the oxidation of cyclooctene, cyclohexene and cyclohexane and the results were compared with the ones obtained under homogeneous conditions. PMID- 25841061 TI - Immobilization of laccase in a sponge-like hydrogel for enhanced durability in enzymatic degradation of dye pollutants. AB - A highly stable and efficient biocatalyst was fabricated by encapsulating Trametes versicolor laccase within a chitosan grafted polyacrylamide hydrogel (denoted as Lac-PAM-CTS). Scanning electron microscopy and nitrogen adsorption desorption tests demonstrated that channels of diameter of 10-20 MUm were regularly distributed throughout the sponge-like Lac-PAM-CTS. Besides, there were massive mesopores and macropores in the lamellar walls of the hydrogel. Such a network structure reduced the diffusion resistance of the hydrogel to the target substrates. The recovered activity of the obtained Lac-PAM-CTS was 40.8%. As compared to free laccase, the Lac-PAM-CTS showed enhanced thermal and chemical stability. The positive surface charge of the Lac-PAM-CTS endowed it with a pre enrichment effect in the treatment of anionic dyes. In a continuous six-cycle batch decoloration of Malachite Green, the Lac-PAM-CTS showed much better durability than the free laccase. The results here suggest that sponge-like hydrogel is a good supporting matrix for laccase. PMID- 25841062 TI - Intercalation of a block co-polymer in kaolinite. AB - Intercalates of kaolinite/Polyethylene-block-poly (ethylene glycol) were successfully prepared by melt intercalation of the polymer with a kaolinite: dimethyl sulfoxide pre-intercalate. Powder X-ray diffraction gives an 11.05 A d spacing which remains after washing the material with water. Thermal gravimetric analysis and nuclear magnetic resonance confirm the presence of the polymer in the prepared material. Perturbation of the kaolinite hydroxyl stretch and the polymer's CH2 bending modes in the materials' infrared spectrum suggest strong interaction between the aluminol clay sheet and the ethylene glycol units in the polymer. Dipolar dephasing studies show both polymer blocks experience a significant loss in mobility in the prepared material, indicative of intercalation. The presence of highly hydrophobic polyethylene inside kaolinite is expected to drastically modify the nature of the interlayer space, and could be of interest for applications where retention or sequestration of hydrophobic species is required. PMID- 25841063 TI - Adverse effects of bisphenol A on water louse (Asellus aquaticus). AB - Experiments were performed to study the effects of short and long-term exposure to bisphenol A (BPA) on a freshwater crustacean isopod Asellus aquaticus (L.). Two life stages of isopods were exposed to a range of BPA concentrations, from aqueous and two dietary sources, in the form of with BPA spiked conditioned alder leaf (Alnus glutinosa) discs, or spiked formulated sediment, to determine the relative importance of each source of exposure on the uptake of this contaminant. Several lethal and sublethal endpoints were evaluated in this study to measure the potential effects of BPA on A. aquaticus, including mortality, growth and feeding rate inhibition, mobility inhibition, de-pigmentation and molting disturbances. They signify a correlation to BPA levels and a difference in BPA uptake efficiency from different uptake sources. Results of acute exposure to BPA show a greater sensitivity of test systems using juvenile specimens with a 96 h LC50 of 8.6 mg L(-1) BPA in water medium and a 96 h LC50 of 13.5 mg L(-1) BPA in sediment. In comparison, adult isopods show a 96 h LC50 of 25.1 mg L(-1) BPA in water medium and a 96 h LC50 of 65.1 mg L(-1) BPA in sediment. Observed endpoints of chronic exposures suggest the alder leave discs to be the most efficient uptake source of BPA, in contrast to uptake from water or heterogeneous sediment. Significant (p<0.05) growth inhibition, with a 21d NOEC of 0.5/2.5 mg L(-1) (for juvenile/adult organisms), and feeding rate inhibition, with a 21d NOEC of 0.5/1.0 mg L(-1) (for juvenile/adult organisms), were proven to be the most sensitive toxicity endpoints. An even more sensitive effect turned out to be molting frequency, which was significantly reduced; a 21d NOEC was 1.0 mg L(-1) of BPA for adult organisms and an even lower 21d NOEC of 0.05 mg L(-1) of BPA for juveniles. The observed endpoints are recorded at very low, non-toxic exposure concentrations, indicating that BPA acts as an endocrine disrupting compound, as well as a toxic substance. We also determined the importance of the direct dietary uptake of the pollutants, significant for juveniles as well as adult animals. PMID- 25841064 TI - Effects of land use intensity on the natural attenuation capacity of urban soils in Beijing, China. AB - Urban soils are major sinks that provide the services of attenuating and detoxifying environmental pollutants. This significant ecosystem service of urban soil can be evaluated by the natural attenuation capacity (NAC). In this research, we develop a method to calculate the natural pollutant attenuation capacity of urban soils on the basis of 5 chemical and physical measurements. By selecting municipal parks soils for reference, we assessed the spatial and temporal changes of NAC in Beijing city soils under influences of rapid urbanization. Results indicated that NAC was increasingly impacted by land use in the order: parks=.9). A one factor solution was identified for two of the measures (DHQ, DMQ-A) and a two factor solution accounting for over 70% of the score variance was identified for the third measure. The two factors assessed situations that may be avoided while driving because of the "external" (e.g., weather-related) or "internal" (e.g., passenger-related) driving environments, respectively. The findings suggest that the interpretation of an overall summated scale score, or single-item interpretations, may not be appropriate. Instead, driving self-regulation may be a multifaceted construct comprised of distinct dimensions that have not been identified previously but can be reliably measured. These data have implications for our understanding of driving self-regulation by older adults and the way in which this behavior is measured. PMID- 25841081 TI - Towards structural and functional characterization of photosynthetic and mitochondrial supercomplexes. AB - Bioenergetic reactions in chloroplasts and mitochondria are catalyzed by large multi-subunit membrane proteins. About two decades ago it became clear that several of these large membrane proteins further associate into supercomplexes and since then a number of new ones have been described. In this review we focus on supercomplexes involved in light harvesting and electron transfer in the primary reactions of oxygenic photosynthesis and on the mitochondrial supercomplexes that catalyze electron transfer and ATP synthesis in oxidative phosphorylation. Functional and structural aspects are overviewed. In addition, several relevant technical aspects are discussed, including membrane solubilization with suitable detergents and methods of purification. Some open questions are addressed, such as the lack of high-resolution structures, the outstanding gaps in the knowledge about supercomplexes involved in cyclic electron transport in photosynthesis and the unusual mitochondrial protein complexes of protists and in particular of ciliates. PMID- 25841082 TI - Signal analysis and classification methods for the calcium transient data of stem cell-derived cardiomyocytes. AB - Calcium cycling is crucial in the excitation-contraction coupling of cardiomyocytes, and therefore has a key role in cardiac functionality. Cardiac disorders and different drugs alter the calcium transients of cardiomyocytes and can cause serious dysfunction of the heart. New insights into this biochemical phenomena can be achieved by studying and analyzing calcium transients. Calcium transients of spontaneously beating human induced pluripotent stem cell-derived cardiomyocytes were recorded for a data set of 280 signals. Our objective was to develop and program procedures: (1) to automatically detect cycling peaks from signals and to classify the peaks of signals as either normal or abnormal, and (2) on the basis of the preceding peak detection results, to classify the entire signals into either a normal class or an abnormal class. We obtained a classification accuracy of approximately 80% compared to class decisions made separately by an experienced researcher, which is promising for the further development of an automatic classification approach. Automated classification software would be beneficial in the future for analyzing cardiomyocyte functionality on a large scale when screening for the adverse cardiac effects of new potential compounds, and also in future clinical applications. PMID- 25841083 TI - Transportation and kinetic analysis of Mo(VI) ions through a MDLM system containing TNOA as carrier. AB - In this report, Mo(VI) ions are transported from an aqueous donor phase into an aqueous acceptor phase by a newly designed method called as multi dropped liquid membrane (MDLM) system prepared by dissolving TNOA as carrier in kerosene. During the extraction of Mo(VI) ions by the liquid membrane system; 100ppm Mo(VI) solutions as donor phase, buffer solution(pH:9.5) and Na2CO3 in different concentrations as acceptor phase and TNOA diluted by kerosen as organic phase are used.In our experimental work, the effect of temperature by using buffer solution and Na2CO3 in the acceptor phase and effect of concentration of acceptor phase on the extraction of Mo(VI) ions were investigated. Appropriate conditions for Mo(VI) transportation were as follows: pH of donor phase is 2.00, concentration of TNOA is 0.005M, 1.00M Na2CO3 as acceptor phase, and flux rate is 50mL/min. Besides, Mo(VI) ion transportation is consecutive first order irreversible reaction and the transportation of Mo(VI) ions is diffusion controlled process. The kinetic parameters (k1, k2, Rm(max), tmax, Jd(max), Ja(max)) were calculated for the interface reactions assuming two consecutive, irreversible first-order reactions. PMID- 25841084 TI - Effects of feed solution chemistry on low pressure reverse osmosis filtration of cesium and strontium. AB - The objective of this study was to identify the removal mechanisms of radionuclides by reverse osmosis (RO) membranes under conditions relevant to full scale water treatment. For this purpose, the effects of feed solution chemistry on the removal of Cs and Sr by a low pressure RO system was investigated by systematically varying membrane surface charge, ionic composition, and organic matter concentrations. The results showed that the effects of solution chemistry on the filtration of Cs and Sr were related to their hydrated ionic radius, resulting in the predominance of the Donnan's effect and electrostatic interactions, respectively. Consequently, the rejection of Cs increased more pronouncedly than Sr with the increases of feed concentration. Due to the Donnan's effect, different anions decreased the rejection of Cs to different extents in accordance to the order of anions' radii as SO4(2-)>Cl(-)>NO3(-)>F(-). The variations in Sr rejection were influenced by the electrostatic interactions between Sr(2+) and the membrane. In addition, humic acid (HA) lowered the rejection of Cs and caused significant membrane flux decline, but did not change the rejection of Sr. Sr also aggravated HA fouling of the membrane. PMID- 25841085 TI - Abatement of fluorinated compounds using a 2.45GHz microwave plasma torch with a reverse vortex plasma reactor. AB - Abatement of fluorinated compounds (FCs) used in semiconductor and display industries has received an attention due to the increasingly stricter regulation on their emission. We have developed a 2.45GHz microwave plasma torch with reverse vortex reactor (RVR). In order to design a reverse vortex plasma reactor, we calculated a volume fraction and temperature distribution of discharge gas and waste gas in RVR by ANSYS CFX of computational fluid dynamics (CFD) simulation code. Abatement experiments have been performed with respect to SF6, NF3 by varying plasma power and N2 flow rates, and FCs concentration. Detailed experiments were conducted on the abatement of NF3 and SF6 in terms of destruction and removal efficiency (DRE) using Fourier transform infrared (FTIR). The DRE of 99.9% for NF3 was achieved without an additive gas at the N2 flow rate of 150 liter per minute (L/min) by applying a microwave power of 6kW with RVR. Also, a DRE of SF6 was 99.99% at the N2 flow rate of 60 L/min using an applied microwave power of 6kW. The performance of reverse vortex reactor increased about 43% of NF3 and 29% of SF6 abatements results definition by decomposition energy per liter more than conventional vortex reactor. PMID- 25841086 TI - DFT and two-dimensional correlation analysis methods for evaluating the Pu(3+) Pu(4+) electronic transition of plutonium-doped zircon. AB - Understanding how plutonium (Pu) doping affects the crystalline zircon structure is very important for risk management. However, so far, there have been only a very limited number of reports of the quantitative simulation of the effects of the Pu charge and concentration on the phase transition. In this study, we used density functional theory (DFT), virtual crystal approximation (VCA), and two dimensional correlation analysis (2D-CA) techniques to calculate the origins of the structural and electronic transitions of Zr1-cPucSiO4 over a wide range of Pu doping concentrations (c=0-10mol%). The calculations indicated that the low angular-momentum Pu-fxy-shell electron excites an inner-shell O-2s(2) orbital to create an oxygen defect (VO-s) below c=2.8mol%. This oxygen defect then captures a low-angular-momentum Zr-5p(6)5s(2) electron to form an sp hybrid orbital, which exhibits a stable phase structure. When c>2.8mol%, each accumulated VO-p defect captures a high-angular-momentum Zr-4dz electron and two Si-pz electrons to create delocalized Si(4+)->Si(2+) charge disproportionation. Therefore, we suggest that the optimal amount of Pu cannot exceed 7.5mol% because of the formation of a mixture of ZrO8 polyhedral and SiO4 tetrahedral phases with the orientation (10-1). This study offers new perspective on the development of highly stable zircon-based solid solution materials. PMID- 25841087 TI - The epidemiology and progression time from transient to permanent psychiatric disorders of substance-induced psychosis in Taiwan. AB - INTRODUCTION: Substance-induced psychosis (SIP), including alcohol-induced psychotic disorder (AIPD) and substance-induced psychotic disorder (SIPD), is gradually increasing in importance in clinical practice. However, few studies have investigated the epidemiology and progression time from transient to permanent psychiatric disorders for AIPD and SIPD patients. METHODS: We utilized the National Health Insurance Research Database (NHIRD) to investigate the incidence and prevalence of AIPD and SIPD in Taiwan and determined the timing of AIPD or SIPD followed by the development of persistent psychotic conditions. RESULTS: The average incidence and prevalence were 1.97 and 2.94 per 100,000 person-years for AIPD, 3.09 and 5.67 per 100,000 person-years for SIPD in Taiwan. Moreover, 10.9% to 24.3% of subjects with either AIPD or SIPD had a change in diagnosis to either schizophrenia or affective disorder, and ~50% of patients had a psychotic or affective transformation in their first year after AIPD and SIPD diagnoses. The mean progression time of psychotic or affective transformation was 1.9 to 2.7 years. CONCLUSIONS: SIP is a predictive factor for persistent psychotic and affective transformation, and a three-year follow-up may be an optimal clinical practice to prevent psychotic or affective transformation in 60% of patients. PMID- 25841088 TI - Prevalence and predictors of hookah use in US Air Force military recruits. AB - INTRODUCTION: Hookah use has gained recent popularity among U.S. youth. The current study describes the characteristics and correlates associated with hookah use in late adolescent and young adult US Air Force (USAF) recruits. METHODS: Data were obtained from a cross-sectional questionnaire of USAF personnel in Technical Training School at Joint Base San Antonio (N=10,997). Response rate was 78%. Logistic regression was used to analyze the associations between hookah use, demographic variables, other tobacco and nicotine containing product (TNCP) use, and the social environment. RESULTS: The prevalence of ever hookah use was 28%; at least monthly hookah use was 10%. Increased hookah use was positively associated with Hispanic ethnicity (OR [odds ratio] 1.52; 95% CI: 1.25, 1.85), cigarette smoking (OR 4.05; CI: 3.41, 4.82) and smokeless tobacco use (OR 1.35; 95% CI: 1.07, 1.71). Hookah use was negatively associated with age (OR 0.84; 95% 0.71 to 1.00), living as married (OR 0.54; 95% CI: 0.40-0.72), African American (OR 0.53; 95% CI: 0.40, 0.69) and >=4-year degree (OR 0.54; 95% CI: 0.35, 0.82). Hookah use was highest among recruits who "many or almost all" of their friends smoked cigarettes (OR 2.43; 95% CI: 1.80, 3.30) and for those who reported willingness to try a tobacco product that claims to be safer than cigarettes (OR 3.16; 95% CI: 2.64, 3.77). CONCLUSIONS: Hookah use among military recruits is similar to the civilian population. A willingness to try TNCPs claiming to be safer than cigarettes may influence hookah use. Public health campaigns disseminating accurate information about hookah health risks may be needed to reduce hookah use among youth. PMID- 25841089 TI - Operant responding for alcohol following alcohol cue exposure in social drinkers. AB - INTRODUCTION: Cue reactivity paradigms have found that alcohol-related cues increase alcohol consumption in heavy drinkers and alcoholics. However, evidence of this relationship among non-alcohol dependent "social" drinkers is mixed, suggesting that individual differences must be considered when examining cue induced drinking behavior. One important individual difference factor that might contribute to cue-induced drinking in the laboratory is the amount of alcohol that participants typically drink during occasions outside the laboratory. That is, those who typically consume more alcohol per occasion could display greater cue-induced drinking than those who typically drink less. The present study examined this hypothesis in healthy, non-dependent beer drinkers. METHODS: The drinkers were exposed to either a series of beer images intended to prime their motivation to drink beer or to a series of non-alcoholic images of food items that served as a control condition. Following cue exposure, motivation to drink was measured by giving participants an opportunity to work for glasses of beer by performing an operant response task. RESULTS: Results indicated that drinkers exposed to alcohol cues displayed greater operant responding for alcohol and earned more drinks compared with those exposed to non-alcohol (i.e., food) cues. Moreover, individual differences in drinking habits predicted subjects' responding for alcohol following exposure to the alcohol cues, but not following exposure to food cues. CONCLUSIONS: The findings suggest that cue-induced drinking in non-dependent drinkers likely results in consumption levels commensurate with their typical consumption outside the laboratory, but not excessive consumption that is sometimes observed in alcohol-dependent samples. PMID- 25841090 TI - Fate of zinc and silver engineered nanoparticles in sewerage networks. AB - Engineered zinc oxide (ZnO) and silver (Ag) nanoparticles (NPs) used in consumer products are largely released into the environment through the wastewater stream. Limited information is available regarding the transformations they undergo during their transit through sewerage systems before reaching wastewater treatment plants. To address this knowledge gap, laboratory-scale systems fed with raw wastewater were used to evaluate the transformation of ZnO- and Ag-NPs within sewerage transfer networks. Two experimental systems were established and spiked with either Ag- and ZnO-NPs or with their dissolved salts, and the wastewater influent and effluent samples from both systems were thoroughly characterised. X-ray absorption spectroscopy (XAS) was used to assess the extent of the chemical transformation of both forms of Zn and Ag during transport through the model systems. The results indicated that both ZnO- and Ag-NPs underwent significant transformation during their transport through the sewerage network. Reduced sulphur species represented the most important endpoint for these NPs in the sewer with slight differences in terms of speciation; ZnO converted largely to Zn sulfide, while Ag was also sorbed to cysteine and histidine. Importantly, both ionic Ag and Ag-NPs formed secondary Ag sulfide nanoparticles in the sewerage network as revealed by TEM analysis. Ag-cysteine was also shown to be a major species in biofilms. These results were verified in the field using recently developed nanoparticle in situ deployment devices (nIDDs) which were exposed directly to sewerage network conditions by immersing them into a municipal wastewater network trunk sewer and then retrieving them for XAS analysis. PMID- 25841091 TI - Timing and communication of parietal cortex for visuomotor control. AB - In both monkeys and humans, motor cognition emerges from a parietal-frontal network containing discrete dominant domains of visual, eye and hand signals, where neurons are responsible for goal and effector selection. Within these domains, the combination of different inputs shape the tuning properties of neurons, while local and long cortico-cortical connections outline the architecture of the distributed network and determine the conduction time underlying eye-hand coordination, necessary for visually guided operations in the action space. The analysis of the communication timing between parietal and frontal nodes of the network helps understanding the sensorimotor cortical delays associated to different functions, such as online control of movement and eye hand coordination, and opens a new perspective to the study of the parieto frontal interactions. PMID- 25841092 TI - A lump in the heart. PMID- 25841093 TI - Neighbourhood disadvantage and individual adversities in adolescence and total alcohol consumption up to mid-life-Results from the Northern Swedish Cohort. AB - This study tests if neighbourhood socioeconomic disadvantage and family social and material adversities during adolescence are independently related to total alcohol consumption from adolescence through to mid-life. Self-reports from the Northern Swedish Cohort (effective sample=950) at ages 16, 18, 21, 30 and 42 was combined with register data on the socioeconomic composition of neighbourhoods at age 16. Total volume of alcohol consumed between age 16-42 was estimated based on the five survey waves, and self-reported social and material adversities were computed as composite variables. Neighbourhood socioeconomic disadvantage at age 16 was associated with alcohol consumption age 16-42 for men but not for women. Social adversities at age 16 were associated with alcohol consumption age 16-42 for both women and men, but material adversity or parental class was not. In conclusion, neighbourhood socioeconomic disadvantage in adolescence has a significant relationship with later alcohol consumption among men, even independently from individual factors. On family level, social factors but not socioeconomic factors in adolescence independently predict later alcohol consumption. PMID- 25841094 TI - Exploring the practice of patient centered care: The role of ethnography and reflexivity. AB - Patient centered care (PCC) is an essential dimension of healthcare systems' mission worldwide and is recognized as an important condition for ensuring the quality of care. Nonetheless, it is also acknowledged that various care providers perceive patient centeredness differently and that there remain several unanswered questions about the aspects of healthcare delivery that are linked to an actual achievement of PCC. In the paper, we categorize the current research on PCC into two streams ("dyadic" and "organizational") and we discuss the strengths and weaknesses of each. Despite their important contributions to healthcare services research, these approaches to PCC do not fully capture the network of practices and relationships constituting patients and providers' experiences within healthcare contexts. Therefore, we propose an alternative interpretation of PCC that integrates insights from "practice theories" and emphasizes the negotiated and local nature of patient centeredness, which is accomplished through the engagement of providers and patients in everyday care practices. To develop such interpretation, we propose a research approach combining ethnographic and reflexive methods. Ethnography can help achieve more nuanced descriptions of what PCC truly encapsulates in the care process by drawing attention to the social and material reality of healthcare contexts. Reflexivity can help disentangle and bring to surface the tacit knowledge spread in everyday care practices and transform it into actionable knowledge, a type of knowledge that may support services improvement toward PCC. We anticipate that such improvement is far from straightforward: an actual achievement of PCC may challenge the interests of different stakeholders and unsettle consolidated habits, hierarchies and power dynamics. This unsettlement, however, can also serve as a necessary condition for engaging in a participative process of internal development. We discuss the outcomes, limitations and benefits of our approach through a hospital case study. PMID- 25841095 TI - Characteristics and patterns of elective admissions to for-profit and not-for profit hospitals in France in 2009 and 2010. AB - In the mid 2000s, in an effort to increase competition among hospitals in France and thereby reduce hospital care costs - policymakers implemented a prospective payment system and created incentives to promote use of for-profit hospitals. But such policies might incentivize 'upcoding' to higher-reimbursed procedures or overuse of preference-sensitive elective procedures, either of which would offset anticipated cost savings. To explore either possibility, we examined the relative use and costs of admissions for ten common preference-sensitive elective surgical procedures to French not-for profit and for-profit sector hospitals in 2009 and 2010. For each admission type, we compared sector-specific hospitalization characteristics and mean per-admission reimbursement and sector-specific relative rates of lower- and higher-reimbursed procedures. We found that, despite having substantially fewer beds, for-profit hospitals captured a large portion of market for these procedures; further, for-profit admissions were shorter and less expensive, even after adjustment for patient demographics, hospital characteristics, and patterns of admission to different reimbursement categories. While French for-profit hospitals appear to provide more efficient care, we found coding inconsistencies across for-profit and not-for-profit hospitals that may suggest supplier-induced demand and upcoding in for-profit hospitals. Future work should examine sector-specific changes in relative use and billing practices of for elective surgeries, the degree to which these elective surgeries are justified in either sector, and whether outcomes differ according to sector used. PMID- 25841096 TI - The traditional healer in obstetric care: A persistent wasted opportunity in maternal health. AB - Traditional medical systems in low income countries remain the first line service of choice, particularly for rural communities. Although the role of traditional birth attendants (TBAs) is recognised in many primary health care systems in low income countries, other types of traditional practitioners have had less traction. We explored the role played by traditional healers in northern Ghana in managing pregnancy-related complications and examined their relevance to current initiatives to reduce maternal morbidity and mortality. A grounded theory qualitative approach was employed. Twenty focus group discussions were conducted with TBAs and 19 in-depth interviews with traditional healers with expertise in managing obstetric complications. Traditional healers are extensively consulted to manage obstetric complications within their communities. Their clientele includes families who for either reasons of access or traditional beliefs, will not use modern health care providers, or those who shop across multiple health systems. The traditional practitioners claim expertise in a range of complications that are related to witchcraft and other culturally defined syndromes; conditions for which modern health care providers are believed to lack expertise. Most healers expressed a willingness to work with the formal health services because they had unique knowledge, skills and the trust of the community. However this would require a stronger acknowledgement and integration within safe motherhood programs. PMID- 25841097 TI - The impact of economic, political and social globalization on overweight and obesity in the 56 low and middle income countries. AB - Anecdotal and descriptive evidence has led to the claim that globalization plays a major role in inducing overweight and obesity in developing countries, but robust quantitative evidence is scarce. We undertook extensive econometric analyses of several datasets, using a series of new proxies for different dimensions of globalization potentially affecting overweight in up to 887,000 women aged 15-49 living in 56 countries between 1991 and 2009. After controlling for relevant individual and country level factors, globalization as a whole is substantially and significantly associated with an increase in the individual propensity to be overweight among women. Surprisingly, political and social globalization dominate the influence of the economic dimension. Hence, more consideration needs to be given to the forms of governance required to shape a more health-oriented globalization process. PMID- 25841098 TI - Visualizing harm reduction: Methodological and ethical considerations. AB - The use of visual methods is becoming increasingly common and accepted in health research. This paper explores the opportunities and constraints of using photo based methods in the context of a community-based participatory research study on how to engage people living with HIV in conversations about a hospital's recently introduced harm reduction policy. Using a blended approach of photovoice and photo-elicited interviews, we provided participants (n = 16) with cameras and asked them to take a series of photos that "show how you feel about or have experienced harm reduction as a Casey House client." We reflect on methodological insights from the study to think through the process of doing photo-based work on a stigmatized topic in a small hospital setting by foregrounding: 1) how the act of taking photos assisted participants in visualizing connections between space, harm reduction, and substance use; 2) expectations of participation and navigating daily health realities; and 3) issues of confidentiality, anonymity and stigma in clinical settings. These reflections provide a case study on the importance of critically examining the process of engaging with photo-based methods. We conclude the paper by re-thinking issues of context and photo-based methods. Rather than viewing context as a neutral backdrop to apply a method, context should be viewed as an active force in shaping what can or cannot be done or produced within the space. Photo-based methods may offer an effective community-engagement strategy but may require modification for use in a clinical setting when working on a stigmatized topic with individuals with complex health care needs. Given the potential of visual methods as a community engagement strategy, research teams are advised to understand the entire process as a data collection opportunity so that these methods can be further explored in a variety of contexts. PMID- 25841099 TI - Rituximab for treating inhibitors in people with inherited severe hemophilia. AB - BACKGROUND: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. OBJECTIVES: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies.Date of last search: 27 January 2015. SELECTION CRITERIA: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. DATA COLLECTION AND ANALYSIS: No randomized controlled trials matching the selection criteria were eligible for inclusion. MAIN RESULTS: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence. PMID- 25841100 TI - Cross-species inhibition of dUTPase via the Staphylococcal Stl protein perturbs dNTP pool and colony formation in Mycobacterium. AB - Proteins responsible for the integrity of the genome are often used targets in drug therapies against various diseases. The inhibitors of these proteins are also important to study the pathways in genome integrity maintenance. A prominent example is Ugi, a well known cross-species inhibitor protein of the enzyme uracil DNA glycosylase, responsible for uracil excision from DNA. Here, we report that a Staphylococcus pathogenicity island repressor protein called StlSaPIbov1 (Stl) exhibits potent dUTPase inhibition in Mycobacteria. To our knowledge, this is the first indication of a cross-species inhibitor protein for any dUTPase. We demonstrate that the Staphylococcus aureus Stl and the Mycobacterium tuberculosis dUTPase form a stable complex and that in this complex, the enzymatic activity of dUTPase is strongly inhibited. We also found that the expression of the Stl protein in Mycobacterium smegmatis led to highly increased cellular dUTP levels in the mycobacterial cell, this effect being in agreement with its dUTPase inhibitory role. In addition, Stl expression in M. smegmatis drastically decreased colony forming ability, as well, indicating significant perturbation of the phenotype. Therefore, we propose that Stl can be considered to be a cross species dUTPase inhibitor and may be used as an important reagent in dUTPase inhibition experiments either in vitro/in situ or in vivo. PMID- 25841102 TI - Motor performance, postural stability and behaviour of non-disabled extremely preterm or extremely low birth weight children at four to five years of age. AB - BACKGROUND: Extremely preterm or extremely low birth weight (ELBW) children who are non-disabled and otherwise healthy are at risk of neurodevelopmental impairments. Further understanding of these impairments is needed before commencement of formal education to optimise participation levels at a critical time point for these children. AIMS: To explore motor co-ordination, postural stability, limb strength and behaviour of non-disabled four to five year old children with a history of extreme prematurity or ELBW. STUDY DESIGN: Prospective descriptive-cohort-study. SUBJECTS: 50 children born at less than 28 weeks gestation or who had a birth weight less than 1000g with minimal/mild motor impairments and no significant neurological/cognitive impairments. OUTCOME MEASURES: Movement Assessment Battery for Children second-edition (MABC-2), single leg stance test (SLS), lateral reach test, standing long jump test and Child Behaviour Checklist for preschool children (CBCL). RESULTS: The mean percentile rank of the extremely preterm or ELBW sample on MABC-2 was 31% (SD 23%). SLS right (mean +/- SD; 4.6 +/- 2.5s) and lateral reach to the right (10.0 +/- 3.9 cm) were slightly stronger than SLS left (4.4 +/- 3.3s) and lateral reach left (9.9 +/- 3.5 cm). The average for standing long jump was 71.6 cm (SD 21.0 cm). All participants were classified as 'normal' on CBCL syndrome scale scores, internalizing and externalizing syndrome T scores and total problem T score. CONCLUSIONS: This sample of non-disabled extremely preterm or ELBW children performed in the lower range of normal. These children continue to be at risk of impairments, therefore, ongoing monitoring and tailored intervention may optimise development. PMID- 25841101 TI - TDP1 promotes assembly of non-homologous end joining protein complexes on DNA. AB - The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. In tumor cells, the ability to repair DSBs predicts response to radiation and many cytotoxic anti-cancer drugs. DSB repair pathways include homologous recombination and non-homologous end joining (NHEJ). NHEJ is a template-independent mechanism, yet many NHEJ repair products carry limited genetic changes, which suggests that NHEJ includes mechanisms to minimize error. Proteins required for mammalian NHEJ include Ku70/80, the DNA-dependent protein kinase (DNA-PKcs), XLF/Cernunnos and the XRCC4:DNA ligase IV complex. NHEJ also utilizes accessory proteins that include DNA polymerases, nucleases, and other end-processing factors. In yeast, mutations of tyrosyl-DNA phosphodiesterase (TDP1) reduced NHEJ fidelity. TDP1 plays an important role in repair of topoisomerase-mediated DNA damage and 3'-blocking DNA lesions, and mutation of the human TDP1 gene results in an inherited human neuropathy termed SCAN1. We found that human TDP1 stimulated DNA binding by XLF and physically interacted with XLF to form TDP1:XLF:DNA complexes. TDP1:XLF interactions preferentially stimulated TDP1 activity on dsDNA as compared to ssDNA. TDP1 also promoted DNA binding by Ku70/80 and stimulated DNA-PK activity. Because Ku70/80 and XLF are the first factors recruited to the DSB at the onset of NHEJ, our data suggest a role for TDP1 during the early stages of mammalian NHEJ. PMID- 25841103 TI - C1-carbon sources for chemical and fuel production by microbial gas fermentation. AB - Fossil resources for production of fuels and chemicals are finite and fuel use contributes to greenhouse gas emissions and global warming. Thus, sustainable fuel supply, security, and prices necessitate the implementation of alternative routes to the production of chemicals and fuels. Much attention has been focussed on use of cellulosic material, particularly through microbial-based processes. However, this is still costly and proving challenging, as are catalytic routes to biofuels from whole biomass. An alternative strategy is to directly capture carbon before incorporation into lignocellulosic biomass. Autotrophic acetogenic, carboxidotrophic, and methanotrophic bacteria are able to capture carbon as CO, CO2, or CH4, respectively, and reuse that carbon in products that displace their fossil-derived counterparts. Thus, gas fermentation represents a versatile industrial platform for the sustainable production of commodity chemicals and fuels from diverse gas resources derived from industrial processes, coal, biomass, municipal solid waste (MSW), and extracted natural gas. PMID- 25841104 TI - A pilot open study of long term high dose creatine augmentation in patients with treatment resistant negative symptoms schizophrenia. AB - BACKGROUND: The effects of creatine on brain metabolism and the potential cognitive enhancing properties of this compound raise the possibility of developing a new augmentation therapeutic strategy in schizophrenia especially in patients demonstrating negative and cognitive symptomatology. METHODS: Seven inpatients with chronic schizophrenia presenting with treatment resistant negative symptoms were enrolled into exploratory treatment study with creatine monohydrate augmentation at a daily high-dose of 10 grams, administered for 6 months. Several clinical rating scales and a computerized cognitive assessment battery were applied. RESULTS: Creatine treatment mildly improved the schizophrenia symptomatology but there were no significant changes in cognitive functions. Several ward behaviors were also improved. Tardive parkinsonism improved numerically by above 40% in 4 out of 6 patients. CONCLUSION: This small, open design study of high dose creatine add-on for 6 months in chronic inpatients with schizophrenia demonstrated only mild positive effects on the patients' symptomatology and behavior and might have beneficial effect on tardive parkinsonism. PMID- 25841105 TI - Safety, tolerability and pharmacokinetics of open label sarcosine added on to anti-psychotic treatment in schizophrenia - preliminary study. AB - BACKGROUND: Hypofunction of NMDA receptor-mediated neurotransmission might play a critical role in schizophrenia. Sarcosine, N- methylglycine and inhibitor of the glycine transporter-1 (Gly-T1), has been suggested as a novel treatment for schizophrenia. METHODS: Open label sarcosine was added to 22 stabilized patients: 5 patients received 2 gm/d, and 17 received 4gm/d. Pharmacokinetics samples, clinical and cognitive parameters using PANSS, CGI and MCCB were collected for all patients. RESULTS: Significant improvement was observed after one week of treatment on PANSS sub-scale of 'positive symptoms' (Z= -2.68; P=0.007) and 'general psychopathology' (Z= -3.02; P=0.003), an improvement in PANSS total score and CGI-S showed a trend (Z= -2.72; P=0.06; Z=-2.69; P=0.08). Speed of processing (MCCB subscale) improved significantly (Z=-2.13; P=0.03). Sarcosine exhibited linear kinetics, with a Tmax and t1/2 of ~11/2- 21/2 hr and ~1hr, respectively. LIMITATIONS: This was a short period, open label pilot study with small sample size per dosage group. CONCLUSIONS: Sarcosine is a safe compound and might be efficacious in the treatment of schizophrenia. PMID- 25841106 TI - Long-term Follow-up of MDD Patients Who Respond to Deep rTMS: A Brief Report. AB - BACKGROUND: Deep transcranial magnetic stimulation (dTMS) is effective in treatment of Major Depressive Disorder (MDD), and in re-treatment in case of relapse. Our study evaluates the long-term durability of dTMS in MDD. METHOD: Seventeen patients that responded to dTMS treatment evaluated. Follow-up period was 9.3 months. Patients were considered as relapsed if: HDRS (Hamilton Depression Rating Scale) score was 16 points or more, in case of change in antidepressants, hospitalization due to exacerbation, referral to ECT. RESULTS: Six months after last treatment three patients relapsed (17.6%). During the follow-up of 9.3 months, nine relapsed. Relapse rate was 5.6 per 100 person months. Patients continued to improve in HDRS following the treatment. We have found number of treatment sessions, stimulation, age, age of depressive disorder onset, length of depressive episode prior to the first treatment, as well as number of depressive episodes to have no predictive value regarding propensity to relapse in these patients. LIMITATIONS: The study's main limitations are the relatively small sample size, patients differing in follow-up periods and the lack of a control group. CONCLUSION: Relapse rates after dTMS are comparable to pharmacotherapy and ECT. PMID- 25841107 TI - Suicides among persons with psychiatric hospitalizations. AB - BACKGROUND: Persons with severe mental disorders have higher suicide rates than the general population. Their risk profile needs to be fully explored to better guide suicide preventive efforts. Downsizing the number of beds in psychiatric hospitals and high bed turnover may also affect the suicide risk. OBJECTIVES: To investigate 1) Suicide rates among persons who were ever hospitalized in psychiatric facilities compared to the general population, 2) Associated sociodemographic and psychiatric factors, 3) Changes in rate over time, and 4) Timing of suicide deaths. METHODS: We linked the National Psychiatric Case Register (NPCR) with the national database on causes of death. Suicides in the years 1981-2009 were analyzed for the study group of Israelis aged 18 and over ever hospitalized (N= 158,800). ANALYSIS: Suicide rates were computed by age, gender, psychiatric diagnosis and year of death, as well as agestandardized rates and rate ratios (RR) for persons in the NPCR compared with those never hospitalized. The proportion of suicides committed by the ever hospitalized from all suicides in the population was calculated. Standardized mortality ratios (SMR) for suicide were computed for the ever hospitalized based on the total suicide rates of the population. A multivariate logistic model investigated risk factors associated with suicide in the ever-hospitalized population. RESULTS: The age-standardized suicide rate of Jews and Others with a psychiatric hospitalization was 17.6 times higher than that of the non-hospitalized (95% CI 16.7-18.6) and 29.7 times higher for Arabs (95% CI 23.4- 37.9). The rates were higher among females and younger persons. In the years 2007-2009, 30% of all suicides of Jews and Others were committed by persons who had been hospitalized in psychiatric facilities. The SMRs of Jews and Others, which increased at the beginning of the study period, fell steadily until 1995. In recent years they have been rising since 2000 and 2005 among females and males, respectively. One fifth (19%) of suicides of Jews and Others occurred before or on the discharge day, and another 6% and 7% within a week and between a week and a month after discharge, respectively. Logistic analysis showed significantly higher suicide risk for males, those who attempted suicide before hospitalization, persons under age 65 and Ethiopian immigrants. Suicide risk increased with number of hospitalizations. CONCLUSION: This study highlights the importance of suicide prevention interventions for persons both during their inpatient stay and who were expected to be followed up in community-based facilities. PMID- 25841108 TI - Validation of the Hebrew and Arabic Versions of the Outcome Questionnaire (OQ 45). AB - BACKGROUND: Measuring the progress of mental health treatment aids in assessment and monitoring of psychotherapeutic outcomes. The OQ-45 is a widely accepted measure of such outcomes. The aim of this study was to validate the Hebrew and Arabic versions of the OQ-45. METHOD: Data were collected from three samples: non patient university students (n=189), university mental health clinic patients (n=37), and outpatient mental health clinic patients (n=135). Subjects completed the OQ-45 as well as the BSI and PHQ-9 questionnaires. RESULTS: Test-retest and internal reliability, and concurrent and discriminative validity of both OQ-45 versions were satisfactory. Sensitivity of the Hebrew and Arabic versions was 0.70 and 0.80, respectively, and the specificity was 0.69and 0.93, respectively. Sensitivity-to-change was noted only for the Symptom Distress (SD) subscale. LIMITATIONS: Sensitivity-to-change was not demonstrated for the total OQ-45, possibly due to a too-short follow-up period. CONCLUSIONS: Adequate psychometric properties of the Hebrew and Arabic OQ-45 suggest that they can serve as useful measures of mental health treatment in Israel.Further research is necessary to confirm norms, cut-off scores and sensitivity-to-change using a larger representative population and diverse types of treatment over a longer period of time. PMID- 25841109 TI - Social Anxiety Disorder Comorbid with Schizophrenia: The Importance of Screening for This Under recognized and Under treated Condition. AB - BACKGROUND: While the presence of comorbid anxiety disorders such as obsessive compulsive disorder and panic disorder have been well described in schizophrenia, comorbid social anxiety disorder (SAD) has been less emphasized. The goal of this study was to examine the prevalence of SAD in our ambulatory population of patients with schizophrenia. METHODS: A group of 50 outpatients with schizophrenia randomly selected from our public mental health outpatient population was evaluated with the Structured Clinical Interview for DSM-IV (SCID) schizophrenia section, the Positive and Negative Syndrome Scale (PANSS), the Schizophrenia Quality of Life Scale (SQLS), the Liebowitz Social Anxiety Scale (LSAS) and the Global Assessment of Functioning Scale (GAF). After completion of assessments, a retrospective chart review was conducted on all study patients who met criteria for a diagnosis of SAD in order to determine how many of these patients had been previously given a diagnosis of SAD. RESULTS: Based on a cutoff score of 29/30 on the total LSAS score, 38% of our sample had a comorbid diagnosis of SAD. Compared to patients who did not suffer from comorbid SAD, patients with schizophrenia and comorbid SAD had lower ratings of quality of life, but similar GAF and PANSS scores. According to the results of the chart review, none of the affected patients had been previously diagnosed with SAD. CONCLUSIONS: According to the results of our study, SAD as a comorbid condition is highly prevalent in schizophrenia and may be under-detected in the outpatient mental health care setting. Furthermore, the presence of SAD may lead to a decreased quality of life for patients with schizophrenia. Further studies should evaluate whether the diagnosis and treatment of comorbid SAD would improve the treatment and quality of life of patients with schizophrenia. PMID- 25841110 TI - Dissociative Reality and Dissociative Being in Therapy for Post traumatic Patients. AB - Post traumatic patients experience a wide range of symptoms, some of them existential in nature which we term "dissociative being." Many varied psychotherapeutic approaches are available for the treatment of post traumatic patients. Nevertheless, in view of this disorder's complexity, therapists face shortcomings when employing each of these therapeutic interventions. In order to understand this, we posit the principle we call "dissociative reality" for the treatment of trauma survivors. Our proposed method "speaks the patient's own language," harnessing dissociative elements to help individuals recall, re-enact and integrate traumatic experiences, where words are insufficient, while still upholding reality. We believe that this may be seen as an effective part of the therapeutic dialogue, and suggest that therapists may consider supplementing this approach in their treatment "toolkit" for patients with post traumatic stress and other trauma related disorders, irrespective of their declared therapeutic approach. PMID- 25841111 TI - Cognitive appraisal and psychological distress among patients with irritable bowel syndrome. AB - BACKGROUND: Irritable Bowel Syndrome (IBS) is a debilitating condition that affects mainly the patient's mental health and quality of life. There is a gap in the literature regarding the relationship between cognitive appraisals and adjustment to physical and psychological aspects resulting from IBS. The aim of the current study was to explore the psycho-social factors that are associated with psychological distress among IBS patients and the contribution of cognitive appraisal to their adjustment. METHODS: One hundred and three patients diagnosed with Irritable Bowel Syndrome participated in the study. Each participant filled a battery of questionnaires targeting demographic and psycho-social factors. The study variables were analyzed via hierarchical regression along with supplementary analyses of multiple mediation tests of indirect effects. RESULTS: The findings showed that psychological distress and depressive symptoms among IBS patients are better predicted by their global positive illness cognition appraisal, specific illness cognition appraisal of helplessness, resilience and to a lesser extent by social support, perceived optimism, illness cognitions appraisals of acceptance and perceived benefit. Global positive illness cognition appraisal gives us a sum of positive and negative appraisals into one unified appraisal. CONCLUSIONS: Our findings highlight the salience of cognitive appraisal and resilience in IBS psychological adjustment. It seems that IBS patients might benefit from psycho-educational interventions designed to assist them in reducing their helplessness appraisal and increasing the appraisal of their ability to cope with the symptoms of their illness. PMID- 25841112 TI - Assessing fears of preschool children with nighttime fears by a parent version of the fear survey schedule for preschool children. AB - BACKGROUND: Although excessive fears are common in preschool children, validated assessment tools for this age are lacking. Our aim was to modify and provide preliminary evidence of the utility of a preschoolers' fear screening tool, a parent-reported Fear Survey Schedule for Preschool Children (FSS-PC). METHODS: 109 Israeli preschool children (aged 4-6 years) with chronic night time fears (NF) and 30 healthy children (controls) participated. The FSS-PC analysis included: 1) internal reliability, 2) correlations between FSS-PC scores and Child Behavior Checklist (CBCL) measures, 3) differences between NF and a comparison sample of FSS-PC scores, and 4) FSS-PC sensitivity in detecting change in NF following an intervention for NF. RESULTS: There were low-to-medium positive correlations between the FSS-PC scores and several internalizing scales of the CBCL measures. FSS-PC scores in the NF group were significantly higher than the control children's score. FSS-PC scores had adequate internal reliability and were also sensitive for detecting significant changes in fear levels following behavioral interventions. LIMITATIONS: Unique cultural and environmental circumstances and specific study group. CONCLUSIONS: This new version of the FSS-PC may provide clinicians with a novel and useful screening tool for early assessment of fear- and anxiety-related phenomena of preschool children. PMID- 25841113 TI - LSD-associated "Alice in Wonderland Syndrome"(AIWS): A Hallucinogen Persisting Perception Disorder (HPPD) Case Report. AB - A side effect associated with the use of LSD is the return of perceptual disturbances which anteriorly emerged during intoxication, despite absence of present use. Here we present the case of a patient with a previous history of sporadic and recreational cannabis, alcohol and LSD consumption who reported LSD associated "Alice in Wonderland Syndrome" (AIWS) or Todd's syndrome. AIWS is basically characterized by four frequent visual illusions: macropsia, micropsia, pelopsia and teleopsia. AIWS only appeared during LSD consumption and continued after LSD suspension, namely, Hallucinogen Persisting Perception Disorder (HPPD). This phenomenon did not cause a major functional impairment but provoked sufficient worry and concern due to its persistent continuation. The patient refused medical treatment and continued psychiatric follow-up. At the one year follow-up he reported complete remission. To the best of our knowledge this is the first reported case of AIWS which persist after LSD interruption (HPPD) in the professional literature. Reasons for this intriguing, benign, reversible and apparently harmless side effect are proposed. PMID- 25841114 TI - Lixiviation of natural radionuclides and heavy metals in tropical soils amended with phosphogypsum. AB - The main phosphate industries in Brazil are responsible for the annual production of 5.5 million tons of a residue (phosphogypsum), which is stored in stacks. The presence of radionuclides and metals puts restrictions on the use of phosphogypsum in agriculture. To assure a safe utilization, it is important to estimate the lixiviation of the radionuclides ((238)U, (226)Ra, (210)Pb, (210)Po, (232)Th and (228)Ra) and metals (As, Cd, Cr, Ni, Se, Hg and Pb) present in phosphogypsum. For this purpose, an experiment was carried out, in which columns filled with sandy and clay Brazilian typical soils mixed with phosphogypsum were percolated with water, to achieve a mild extraction of these elements. The results obtained for the concentration of the radionuclides and metals in the leachate were low; giving evidence that, even when these elements are present in the phosphogypsum, they do not contribute to an enhancement of their content in water. PMID- 25841115 TI - Effect of minerals on accumulation of Cs by fungus Saccaromyces cerevisiae. AB - The accumulation of Cs by unicellular fungus of Saccharomyces cerevisiae in the presence of minerals has been studied to elucidate the role of microorganisms in the migration of radioactive Cs in the environment. Two different types of experiments were employed: experiments using stable Cs to examine the effect of a carbon source on the accumulation of Cs, and accumulation experiments of radioactive Cs from agar medium containing (137)Cs and zeolite, vermiculite, phlogopite, smectite, mica, or illite as mineral supplements. In the former type of experiments, the Cs-accumulated cells were analyzed by scanning electron microscopy equipped with energy dispersive X-ray analysis (SEM-EDS). In the latter type, the radioactivity in the yeast cells was measured by an autoradiography technique. When a carbon source was present, higher amounts of Cs accumulated in the cells than in the resting condition without a carbon source. Analyses with SEM-EDS showed that no mineral formed on the cell surface. These results indicate that the yeast cells accumulate Cs by adsorption on the cell surface and intracellular accumulation. In the presence of minerals in the agar medium, the radioactivity in the yeast cells was in the order of mica > smectite, illite >> vermiculite, phlogopite, zeolite. This order is inversely correlated to the ratio of the concentration of radioactive Cs between the minerals and the medium solution. These results strongly suggest that the yeast accumulates radioactive Cs competitively with minerals. PMID- 25841116 TI - 2D ratiometric fluorescent pH sensor for tracking of cells proliferation and metabolism. AB - Extracellular pH plays a vital role no matter in physiological or pathological studies. In this work, a hydrogel, CD@Nile-FITC@Gel (Gel sensor), entrapping the ratiometric fluorescent probe CD@Nile-FITC was developed. The Gel sensor was successfully used for real-time extracellular pH monitoring. In the case of CD@Nile-FITC, pH-sensitive fluorescent dye fluorescein isothiocyanate (FITC) was chosen as the response signal for H(+) and Nile blue chloride (Nile) as the reference signal. The developed fluorescent probe exhibited high selectivity for pH over other metal ions and amino acids. Meanwhile, the carbon-dots-based inorganic-organic probe demonstrated excellent photostability against long-term light illumination. In order to study the extracellular pH change in processes of cell proliferation and metabolism, CD@Nile-FITC probe was entrapped in sodium alginate gel and consequently formed CD@Nile-FITC@Gel. The MTT assay showed low cytotoxicity of the Gel and the pH titration indicated that it could monitor the pH fluctuations linearly and rapidly within the pH range of 6.0-9.0, which is valuable for physiological pH determination. As expected, the real-time bioimaging of the probe was successfully achieved. PMID- 25841117 TI - Diagnostics on acute myocardial infarction: Cardiac troponin biomarkers. AB - Acute myocardial infarction or myocardial infarction (MI) is a major health problem, due to diminished flow of blood to the heart, leads to higher rates of mortality and morbidity. Data from World Health Organization (WHO) accounted 30% of global death annually and expected more than 23 million die annually by 2030. This fatal effects trigger the need of appropriate biomarkers for early diagnosis, thus countermeasure can be taken. At the moment, the most specific markers for cardiac injury are cardiac troponin I (cTnI) and cardiac troponin T (cTnT) which have been considered as 'gold standard'. Due to higher specificity, determination of the level of cardiac troponins became a predominant indicator for MI. Several ways of diagnostics have been formulated, which include enzyme linked immunosorbent assay, chemiluminescent, fluoro-immunoassays, electrical detections, surface plasmon resonance, and colorimetric protein assay. This review represents and elucidates the strategies, methods and detection levels involved in these diagnostics on cardiac superior biomarkers. The advancement, sensitivity, and limitations of each method are also discussed. In addition, it concludes with a discussion on the point-of care (POC) assay for a fast, accurate and ability of handling small sample measurement of cardiac biomarker. PMID- 25841118 TI - A novel ECL biosensor for beta-lactamase detection: Using RU(II) linked ampicillin complex as the recognition element. AB - In this work, Ru(phen)2(cpaphen)(2+) linked-ampicillin (Ru-Amp), as the novel specific recognition element, was proposed to construct a simple and sensitive electrogenerated chemiluminescence (ECL) biosensor for the determination of beta lactamase. Here, Ru-Amp complex acted not only as a novel specific recognition element for beta-lactamase but also as the ECL Luminescent reagent. Through electrostatic adsorption and the intermolecular pi-pi interactions, a large amount of Ru-Amp was immobilized to gold nanoparticles (TA@AuNPs) prepared by thiophenemalonic acid (TA) to obtain Ru-Amp/TA@AuNPs nanocomposites. The nanocomposites, which can produce very stable films exhibiting excellent ECL behaviors, were self-assembled on the CNTs-Nf modified glassy carbon electrode surface. The presence of the target beta-lactamase resulted in autonomous hydrolysis reaction of Amp, achievement of the efficient ECL emission and highly sensitive detection of beta-lactamase. The biosensor for beta-lactamase detection was developed with excellent sensitivity of a concentration variation from 50 pg mL(-1) to 100 ng mL(-1) with a low detection limit of 37 pg mL(-1). An ECL assay offers the proposed method opportunities for designing new Ru-based ECL luminophores for biosensing applications. PMID- 25841119 TI - Ultrasensitive electrochemical detection of microRNA-21 combining layered nanostructure of oxidized single-walled carbon nanotubes and nanodiamonds by hybridization chain reaction. AB - Measurement of microRNA (miRNA) levels in body fluids is a crucial tool for the early diagnosis and prognosis of cancers. In this study, we developed an electrochemical assay to detect miRNA-21 by fabricating the electrode with layer by-layer assembly of oxidized single-walled carbon nanotubes and nanodiamonds. Tetrahedron-structured probes with free-standing probe on the top served as receptors to hybridize with target miRNA directly. The probes were immobilized on the deposited gold nanoparticles through a well-established strong Au-S bond. The electrochemical signal was mainly derived from an ultrasensitive pattern by combining hybridization chain reaction with DNA-functionalized AuNPs, which provided DNAzyme to catalyze H2O2 reduction. Differential pulse voltammetry was applied to record the electrochemical signals, which was increased linearly with the target miRNA-21, and the linear detection range was 10 fM to 1.0 nM. The limit of detection reached 1.95 fM (S/N=3), and the proposed biosensor exhibited good reproducibility and stability, as well as high sensitivity. Hence, this biosensor has a promising potential in clinical application. PMID- 25841120 TI - Fabrication of plasmon length-based surface enhanced Raman scattering for multiplex detection on microfluidic device. AB - The length of bioreceptors plays an important role in signal enhancement of surface-enhanced Raman scattering (SERS) due to amplification of electromagnetic fields generated by the excitation of localized surface plasmons. Herein, intact antibodies (IgG) and Fab fragments conjugated onto gold nanostar were used to fabricate two kinds of immunosensors for measurement of their SERS signals. Using CA125 as the antigen and Rhodamine-6G (R6G)-conjugated immunogolds, a SERS immunosensor was self-assembled by antigen-antibody interaction. The results showed that the SERS signal from the Fab immunosensor was 2.4 times higher than that of the IgG immunosensor. Furthermore, increased hot-spots by silver atom deposition onto the IgG and Fab immunosensor showed 2.1 and 1.4 times higher signals than before enhancement, respectively. For application, based on the Fab immunosensor, a SERS-compatible microfluidic system was designed for multiplex assays to overcome the drawbacks of conventional assays. This system can measure biological specimens directly from bio fluids instead of using a complex microfluidic device containing separation and detection elements. Four approved biomarkers of breast cancer, including cancer antigen (CA125), HER2, epididymis protein (HE4), and Eotaxin-1, were detected from patient-mimicked serum with limits of 15 fM, 17 fM, 21 fM, and 6.5 fM, respectively. The results indicated that the lengths and geometry of the bioreceptors determined the intensity of SERS signal from the interface and cavity of the sandwich immunosensor. Silver atom deposition at the cavity of the immunosensor increased the SERS signal. Finally, the SERS immunosensor built-in microfluidic system improved the performance of multiplex diagnostics. PMID- 25841121 TI - Microfluidic enzymatic biosensing systems: A review. AB - Microfluidic biosensing systems with enzyme-based detection have been extensively studied in the last years owing to features such as high specificity, a broad range of analytes and a high degree of automation. This review gives an overview of the most important factors associated with these systems. In the first part, frequently used immobilization protocols such as physisorption and covalent bonding and detection techniques such as amperometry and fluorescence measurements are discussed with respect to effort, lifetime and measurement range. The Michaelis-Menten model describing the kinetics of enzymatic reactions, the role of redox mediators and the limitations of the linear measurement range of enzymatic sensors are introduced. Several possibilities of extending the linear measurement range in microfluidic systems such as diffusion-limiting membranes and the flow injection setup are presented. Regarding the integration of enzymes into microfluidic systems during the fabrication process, the constraints imposed by the biomolecules due to the limited usage of high temperatures and solvents are addressed. In the second part, the most common forms of enzyme integration into microfluidic systems, i.e. in channels and on electrodes, on microparticles, on paper and thread and as injected enzyme solutions, are reviewed, focusing on fabrication, applications and performance. PMID- 25841122 TI - Centenarians with acute coronary syndrome - Biological and not chronological age counts. PMID- 25841123 TI - Clinical outcome of transcatheter treatment of heart failure with preserved or mildly reduced ejection fraction using a novel implant. PMID- 25841124 TI - Role of mitochondrial fission and fusion in cardiomyocyte contractility. AB - BACKGROUND: Mitochondria constitute 30% of cell volume and are engaged in two dynamic processes called fission and fusion, regulated by Drp-1 (dynamin related protein) and mitofusin 2 (Mfn2). Previously, we showed that Drp-1 inhibition attenuates cardiovascular dysfunction following pressure overload in aortic banding model and myocardial infarction. As dynamic organelles, mitochondria are capable of changing their morphology in response to stress. However, whether such changes can alter their function and in turn cellular function is unknown. Further, a direct role of fission and fusion in cardiomyocyte contractility has not yet been studied. In this study, we hypothesize that disrupted fission and fusion balance by increased Drp-1 and decreased Mfn2 expression in cardiomyocytes affects their contractility through alterations in the calcium and potassium concentrations. METHODS: To verify this, we used freshly isolated ventricular myocytes from wild type mouse and transfected them with either siRNA to Drp-1 or Mfn2. Myocyte contractility studies were performed by IonOptix using a myopacer. Intracellular calcium and potassium measurements were done using flow cytometry. Immunocytochemistry (ICC) was done to evaluate live cell mitochondria and its membrane potential. Protein expression was done by western blot and immunocytochemistry. RESULTS: We found that silencing mitochondrial fission increased the myocyte contractility, while fusion inhibition decreased contractility with simultaneous changes in calcium and potassium. Also, we observed that increase in fission prompted decrease in Serca-2a and increase in cytochrome c leakage leading to mitophagy. CONCLUSION: Our results suggested that regulating mitochondrial fission and fusion have direct effects on overall cardiomyocyte contractility and thus function. PMID- 25841125 TI - Association between neutrophil to lymphocyte ratio and atrial fibrillation. PMID- 25841126 TI - Left ventricular thrombus in repaired Tetralogy of Fallot. PMID- 25841127 TI - Noncoding RNA in cardiac fibrosis. PMID- 25841128 TI - Recurrent takotsubo syndrome triggered by undiagnosed pheochromocytoma. PMID- 25841129 TI - Optical coherence tomography during carotid artery stenting: A new niche application? PMID- 25841130 TI - Angiographically invisible spontaneous coronary artery dissection: A ticking time bomb during coronary intervention. PMID- 25841131 TI - Estrogen resisted stress-induced cardiomyopathy through increasing the activity of beta2AR-Galphas signal pathway in female rats. AB - BACKGROUND: Stress-induced cardiomyopathy (SCM) is characterized by transient left ventricular systolic dysfunction. Over 90% of SCM patients are postmenopausal women, suggesting that the incidence of SCM is associated with low level of estrogen. Previous studies have shown that high levels of epinephrine (EPI) triggered SCM by switching beta2-adrenoceptor (beta2AR) coupling from Galphas to Galphai signaling pathway. This study examined whether estrogen protected myocardium against SCM through modulating the beta2AR-G proteins signal pathway. METHODS AND RESULTS: Female Sprague-Dawley (SD) rats were divided into sham operation (Sham) and ovariectomized (OVX) groups. Six weeks after ovariectomy, the plasma levels of EPI and norepinephrine significantly increased. Then they were injected with EPI to make SCM models. Lack of estrogen resulted in more serious cardiac dysfunction and higher cardiac troponin I (cTnI) concentration in acute EPI surge. Pretreatment with ICI118,551 abolished the discrepancy induced by ovariectomy. Pretreatment with clenbuterol aggravated the difference of left ventricular hemodynamics between Sham and OVX rats. Blocking Galphai abolished the cardiomyocyte contractile inhibition by high levels of EPI. Estrogen deficiency decreased the concentration of cAMP and the phosphorylation of PKA in OVX+EPI group. After EPI injection for 20 min, acute estrogen supplementation could increase the concentration of cAMP and the phosphorylation of PKA in OVX rats suffered EPI-induced injury. CONCLUSIONS: Our results showed that estrogen improved the inhibitory effects of myocardial contraction induced by high levels of EPI. Estrogen protected myocardium against SCM via increasing the activity of beta2AR-Galphas signal pathway and decreasing the concentration of catecholamine in plasma. PMID- 25841132 TI - Nesiritide is beneficial or harmful to patients with decompensated acute congestive heart failure. PMID- 25841133 TI - Comparison of low dose versus standard dose heparin for radial approach in elective coronary angiography? AB - OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of two doses of heparin, a low dose (2500 IU) and a standard dose (5000 IU) in patients who underwent transradial coronary angiography (TRCAG). METHODS: A total of 459 consecutive patients were included in the present study, 217 in the 2500-IU heparin group and 242 in the 5000-IU heparin group. Radial artery patency was evaluated one month after the TRCAG with Doppler ultrasonography. RESULTS: The RAO was observed in 15 (3.3%) patients. The RAO was significantly higher in 2500 IU heparin group than 5000 IU heparin group (5.5% vs 1.2% p=0.010, respectively). Female gender (Odds ratio (OR)=66.135, p=0.002, 95% confidence interval (CI)=4.584-954.131), sheath removal time (OR=1.496, p<0.001, 95% CI=1.254-1.784) and administration of 2500 IU heparin (OR=9.758, p=0.034, 95% CI=1.195-79.695) were the independent predictors of RAO in multivariate regression analysis. While the presence of hypertension was independently associated with radial artery patency in multivariate regression analysis (OR=0.022, p=0.005, 95% CI=0.002 0.307). CONCLUSION: The patients in the standard dose heparin group had lower RAO rates compared to low dose group in this study. This suggests that using the current technique, standard dose of heparin is still required for transradial diagnostic angiography. PMID- 25841134 TI - Estrogen-Related Receptor alpha (ERRalpha) is required for adaptive increases in PGC-1 isoform expression during electrically stimulated contraction of adult cardiomyocytes in sustained hypoxic conditions. AB - BACKGROUND AND OBJECTIVES: In adult myocardium, Estrogen-Related Receptor alpha (ERRalpha) programs energetic capacity of cardiomyocytes by regulating expression of target genes required for mitochondrial biogenesis, fatty acid metabolism and oxidative phosphorylation. Transcriptional activation by ERRalpha is dependent on the alpha or beta isoform of Peroxisome Proliferator-Activated Receptor gamma Coactivator-1 (PGC-1). This study utilized a model of continuously contracting adult cardiomyocytes to determine the effects of sustained oxygen reduction (hypoxia) on ERRalpha target gene expression. METHODS AND RESULTS: Adult feline cardiomyocytes in primary culture were electrically stimulated to contract at 1 Hz in either normoxia (21% O2) or hypoxia (0.5% O2). Compared to normoxia, hypoxia increased PGC-1alpha mRNA and PGC-1beta mRNA levels by 16-fold and 14 fold after 24h. ERRalpha mRNA levels were increased 3-fold by hypoxia over the same time period. Treatment of cardiomyocytes with XCT-790, an ERRalpha inverse agonist, caused knockdown of ERRalpha protein expression. The increases in PGC-1 mRNA levels in response to hypoxia were blocked by XCT-790 treatment, which indicates that expression of PGC-1 isoforms is dependent on ERRalpha activity. The products of two ERRalpha target genes required for energy metabolism, Cox6c mRNA and Fabp3 mRNA, increased by 4.5-fold and 3.5 fold after 24h of hypoxia as compared to normoxic controls. These increases were blocked by XCT-790 treatment of hypoxic cardiomyocytes with a concomitant decrease in ERRalpha expression. CONCLUSIONS: ERRalpha activity is required to increase expression of PGC-1 isoforms and downstream target genes as part of the adaptive response of contracting adult cardiomyocytes to sustained hypoxia. PMID- 25841135 TI - Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension: Challenges and future directions. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a common type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction of major pulmonary arteries and associated vascular remodeling in more distal vessels. The mainstay of CTEPH treatment is pulmonary endarterectomy (PEA), which has the potential to be curative but is possible in less than two thirds of cases. In inoperable patients and those with residual or recurrent CTEPH, medical therapy has been shown to be beneficial, albeit not curative. Balloon pulmonary angioplasty (BPA) is a percutaneous technique for the relief of chronic thromboembolic lesions, first reported over two decades ago. More recent case series have demonstrated that, as the technique is refined, results are improving. The potential indications for BPA are now expanding beyond inoperable CTEPH patients, with Shimura et al. demonstrating the aggressive nature of residual or recurrent CTEPH, treated successfully by BPA years after PEA. Major challenges lie ahead of BPA before it can take its place alongside PEA and medication in the treatment of CTEPH. PMID- 25841136 TI - A comparison of low versus standard heparin dose for prevention of forearm artery occlusion after 5 French coronary angiography. AB - BACKGROUND: Radial artery occlusion (RAO) remains the Achilles' heel of transradial coronary procedures. Standard over lower systemic anticoagulation levels are believed to reduce RAO rates but this is ill-supported by scientific evidence. We compared whether standard in comparison with less intensive anticoagulation was superior in preventing vessel closure. METHODS AND RESULTS: The two arms of this analysis included 731 pooled patients with the same inclusion and exclusion criteria. We assessed forearm arterial access site occlusion rate by unfractionated heparin (UFH) dose in an individual participant data meta-analysis of this randomized study and of consecutive eligible patients from our previous trial. We randomized 308 consecutive patients undergoing transradial coronary angiography with 5 French (5 Fr) catheters without need to crossover to receive 2500 or 5000 UFH units. The primary end-point was the ultrasonographically determined vessel occlusion rate. Incident RAOs in the randomized arm were 15.9% vs. 14%, in the low and standard UFH dose, respectively (p=0.7). Corresponding figures for forearm arterial occlusion rates in the pooled population were 13.0% vs. 9.9% (relative risk: 1.3, 95% confidence interval - CI: 0.88-1.98; p=0.2). Procedural and fluoroscopy duration was less than 15 and 3 min, respectively. The mean UFH dose difference was 3.52 (95% CI: -0.45 to 7.49) units per kilo body weight between occluded (n=84) and patent forearm arteries (n=647); (p=0.053). CONCLUSIONS: Incident forearm arterial occlusions were high despite using 5 Fr catheters for a short-lasting procedure. Systemic anticoagulation with standard over lower UFH dose did not reduce the frequency of RAOs after coronary angiography. PMID- 25841137 TI - Impact of left ventricular hypertrophy on impaired coronary microvascular dysfunction. PMID- 25841138 TI - Ethnic differences in the diurnal variation of symptom onset time for acute ST elevation myocardial infarction - An observational cohort study. PMID- 25841139 TI - Rosuvastatin and risk of acute pancreatitis in a population-based case-control study. AB - BACKGROUND/OBJECTIVES: Few data exist about the relationship between rosuvastatin use and acute pancreatitis. We tested a plausible hypothesis that rosuvastatin use might be associated with acute pancreatitis in Taiwan. METHODS: We designed a case-control study using a randomly sampled database of the Taiwan National Health Insurance Program. We identified 5728 subjects with the first episode of acute pancreatitis in 1998-2011 as the case group and we randomly selected 22,912 sex- and age-matched subjects without acute pancreatitis as the control group. Subjects who never received a rosuvastatin prescription were defined as never use of rosuvastatin. Subjects who at least received 1 prescription for rosuvastatin within 7 days before the date of diagnosing acute pancreatitis were defined as active use of rosuvastatin. Subjects who did not receive a prescription within 7 days but at least received 1 prescription for rosuvastatin >= 8 days before the date of diagnosing acute pancreatitis were defined as non-active use of rosuvastatin. Those at least receiving 1 prescription for other statins or non statin lipid-lowering drugs were excluded from this study. We estimated the odds ratio with 95% confidence interval for acute pancreatitis associated with rosuvastatin use by using the multivariable unconditional logistic regression model. RESULTS: The multivariable analysis disclosed that the adjusted odds ratio for acute pancreatitis in subjects with active use of rosuvastatin was 3.21 (95% confidence interval 1.70, 6.06). The adjusted odds ratio was 0.90 in subjects with non-active use of rosuvastatin (95% confidence interval 0.67, 1.19), without statistical significance. CONCLUSIONS: We observed active use of rosuvastatin to be associated with increased risk for acute pancreatitis. PMID- 25841140 TI - Endogenous vascular endothelial growth factor produces tonic facilitation of cardiac vagal baroreflex via fetal liver kinase-1 in medulla oblongata. PMID- 25841141 TI - Meta-analysis of major bleeding with uninterrupted warfarin compared to interrupted warfarin and heparin bridging in ablation of atrial fibrillation. PMID- 25841142 TI - In-stent restenosis after vertebral artery stenting. PMID- 25841143 TI - Contribution of ultrasound contrast in predicting conduction disturbances during percutaneous alcohol septal ablation. PMID- 25841144 TI - Unipolar voltage threshold of 5.0 mV is optimal to localize critical isthmuses in post-infarction patients presenting with ventricular tachycardia. AB - INTRODUCTION: Bipolar voltage mapping is useful to delineate post-infarct endocardial scar and guide ablation of ischemic VT. The role of unipolar mapping is not yet well defined. The aim of this study was to assess the correlation between electrophysiological findings in patients with ischemic VT and unipolar voltage maps using different cut-offs. METHODS: We included 10 patients (age 67 +/- 7 years, ejection fraction 33 +/- 10%) with ischemic cardiomyopathy undergoing catheter ablation for recurrent VT. Patients with right-sided VTs were excluded. In all patients a unipolar voltage map was constructed during right ventricular pacing. Ablation was performed guided by activation and entrainment mapping in hemodynamically stable VTs and by pace-mapping and abnormal (late/split/fractionated) potentials in unstable VTs. Subsequently, the unipolar voltage maps were analyzed off-line using cutoffs from 1.0 to 8.0 mV and correlated with the isthmus sites. RESULTS: A total of 17 sustained VTs were induced in the 10 patients and non-inducibility of the clinical VT was achieved in 90% of patients by endocardial ablation. The optimal cutoff was 5.0 mV. By using this value, the mean surface area of abnormal unipolar voltage was 43.8% and 95% of all VT isthmuses were located within the area of scar, as well as 81% of abnormal potentials. In addition, 71% of isthmuses were at less than 1cm from the scar border. CONCLUSION: Unipolar voltage mapping showed good correlation with areas of isthmuses and abnormal electrograms in patients with scar-related VT, with a cut-off of 5.0 mV allowing the best delineation of ablation targets. PMID- 25841145 TI - Morphine may enhance the cardioprotection induced by remote ischemic perconditioning. PMID- 25841146 TI - Omega-3 fatty acids do not suppress atrial fibrillation even in the "inflamed" heart. PMID- 25841147 TI - Predictors of mid-term functional tricuspid regurgitation after device closure of atrial septal defect in adults: Impact of pre-operative tricuspid valve remodeling. AB - BACKGROUND: Functional TR occurs in adults with congenital atrial septal defect (ASD) due to left-to-right inter-atrial shunting and enlarged right heart. The prevalence and the predictors of TR following ASD closure in adults remain unknown. Moreover, whether preoperative anatomical parameters of tricuspid valve related to TR after ASD closure is understudied. METHODS: Comprehensive transthoracic echocardiography was performed in 64 consecutive secundum ASD patients before and at 3 months after device closure. Tricuspid valve parameters [annulus diameter (TAD), tenting area, tenting height, distal tricuspid septal leaflet angle (TSLA)], right ventricular (RV) function, pulmonary arterial pressures and severity of TR were recorded. Post-closure TR was defined as PISA radius >= 6 mm at 3 months. RESULTS: The TR severity was reduced after ASD closure with post-closure TR in 31 patients (48%) at follow-up. TR patients had larger ventricles, more TR, greater TAD, and larger tenting area/height and TSLA but similar RV long-axis function and pulmonary pressures at baseline. Pre closure TAD [odds ratio (OR): 6.076, p=0.032] and TSLA (OR: 1.218, p=0.001) were the independent predictors for TR. A TAD >3.5 cm and a TSLA >30 degrees had sensitivity, specificity, and area under the curve of 97%, 76%, and 0.82 and 100%, 78%, and 0.84, respectively. Assessment of TSLA showed an incremental value over TAD for predicting TR after closure (chi(2)=21.3 vs. 9.9, p<0.001). CONCLUSION: Nearly half of adults had TR following device closure of ASD. It was related to the excessive pre-operative structural remodeling in tricuspid valve rather than changes in RV. PMID- 25841148 TI - Systematic review of percutaneous coronary intervention and transcatheter aortic valve implantation for concomitant aortic stenosis and coronary artery disease. PMID- 25841149 TI - Impaired cholesterol efflux capacity is related to increased carotid intima media thickness in patients with end-stage renal disease. PMID- 25841150 TI - Spectroscopic and ultrasonic investigations on structural characterization of borate glass specimen doped with transition metal ions. AB - The present work describes the glass samples of composition (x% V2O5-(80-x)% B2O3 20% Na2CO3) VBS glass system and (x%MnO2-(80-x)% B2O3-20% Na2CO3) in MBS glass system with mol% ranging from x=3, 6, 9, 12, 15 and 18 in steps of 3 mol% are prepared by melt quenching technique. For these prepared glass systems, sound velocity (longitudinal and shear velocities) and density have been measured. The sound velocity (longitudinal and shear) was measured by using pulse-echo technique at 5 MHz. The XRD study was carried to out to ascertain the amorphous nature of the glass specimen. Using these measured values, the elastic moduli, Poisson's ratio, Debye temperature, acoustic impedance and thermal expansion coefficient of the two glass systems were evaluated. The elastic and mechanical properties of the prepared glass systems are analyzed from ultrasonic study and the structural characterization from spectroscopic study. The effects due to the doping of transition metal ions with borate have been discussed. In the V2O5 doped glass system,(VBS glass system) the sound velocity, density and elastic moduli, steeply increases after 12 mol% comparatively with MnO2 doped glass system (VBS glass system). The present study critically observes the doping of V2O5 with borate enhances the strengthening of network linkage and hardening of the glassy network structure than MnO2. The IR spectral analysis reveals depolymerization of the borate network and conversion of BO3 or BO4 units with the formation of non-bridging oxygen. The FTIR spectral studies confirm the presence of various functional groups of the sample. FTIR spectrum of sample exhibits broad absorption bands indicating the wide distribution of borate structural units. The effect of Na2CO3, V2O5 and MnO2 contents on the structures of borate glass is evaluated from the FTIR spectra. The topological aspects of the prepared glass samples are exhaustively reported from SEM micrographs. PMID- 25841151 TI - Quantum chemical study on surface complex structures of phosphate on gibbsite. AB - Quantum mechanics calculations based on the density functional theory (DFT) were used to identify phosphate surface complexes on gibbsite at low and high pH. The different phosphate species were represented using the Al6(OH)18(H2O)6 cluster model considering four different geometries: monodentate mononuclear (Pmm), monodentate binuclear (Pmb), bidentate mononuclear (Pbm) and bidentate binuclear (Pbb). The corresponding adsorption reactions were modelled via ligand exchange between phosphate species and surface functional groups (hydroxyls and protonated hydroxyls at high and low pH, respectively). The theoretical results indicate that phosphate surface complexes are thermodynamically more favored at acid pH, in agreement with experimental evidences. The first step in these reactions, i.e., the generation of required aluminum vacant sites, was predicted to be particularly favorable when singly coordinated aquo groups are released. Stretching and bending vibrational frequencies associated with the different surface structures were calculated at both pH conditions. The corresponding values at low pH were found to be shifted to higher frequencies with respect to those ones at high pH. ATR-FTIR studies were also carried out. The resulting spectra are dominated by a strong band within the 800-840 cm(-1) interval due to P-OH stretching modes. The corresponding peak appearing around 820 cm(-1) at high pH is shifted to lower frequencies with respect to the position at low pH, a tendency well predicted by DFT calculations. PMID- 25841152 TI - Correlation between ionic radii of metal azodye complexes and electrical conductivity. AB - 5-(2,3-Dimethyl-1-phenylpyrazol-5-one azo)-2-thioxo-4-thiazolidinone (HL) and its metal complexes with copper(II) (1), cobalt(II) (2) and nickel(II) (3) are synthesized and characterized by physico-chemical techniques. The thermal properties of the ligand (HL) and its metal complexes (1-3) are discussed. The thermal activation energies of decomposition (Ea) of HL and its metal complexes with Cu(II), Co(II) and Ni(II) are found to be 48.76, 36.83, 30.59 and 40.45 kJ/mol, respectively. The frequency and temperature dependence of ac conductivity, dielectric constants for HL and its complexes (1-3) are investigated in the temperature range 300-356 K and frequency range 0.1-100 kHz. Both of the ac conductivity and the values of the thermal activation energy for conduction, as well as the dielectric properties of the complexes of HL are found to depend on the nature of the metallic ions. The values of the thermal activation energies of electrical conductivity decrease with increasing the value of test frequency. The small polarons tunneling (SPT) is the dominant conduction mechanism for the ligand (HL), while for complex (2) the overlapping large tunneling model (OLPT) is the dominant conduction mechanism. The correlated barrier hopping (CBH) is the dominant conduction mechanism for both of the complexes (1) and (3). PMID- 25841153 TI - FT-IR, FT-Raman, UV/Vis spectra and fluorescence imaging studies on 2 (bromoacetyl)benzo(b)furan by ab initio DFT calculations. AB - The vibrational and electronic properties of 2-(bromoacetyl)benzo(b)furan have been studied in the ground state using experimental techniques (FT-IR, FT-Raman and UV) and density functional theory (DFT) employing B3LYP exchange correlation with the 6-31G(d,p) basis set. The theoretically calculated optimized parameters, vibrational frequencies etc., were compared with the experimental values, which yield good agreement between the observed and calculated values. The complete assignments of fundamental modes were performed on the basis of the potential energy distribution (PED). UV-visible spectrum of the compound was recorded in the region 300-600 nm and compared with the theoretical spectrum obtained from SAC-CI calculations. A good agreement is observed between the experimental and theoretical spectra. Fluorescence microscopic imaging studies proved that the compound can be used as one of the potential light sources in the yellow region with suitable excitation. Further, the predicted electronic transitions between the MOs 47->64, 52->62, 56->65, 56->72, 56->77 of the compound show a strong line at 569.8 nm. PMID- 25841154 TI - Chondrosarcoma of a rib. AB - Chondrosarcoma of a rib is a very rare malignant tumor of the bone. Most patients were present with an enlarging painful anterior chest wall tumor. We present a case of an asymptomatic 29-years old female with a tumor size of 10cm*12cm on the left anterior chest wall involving the 8th rib. CT scan with intravenous contrast is the gold standard for radiological imaging and planning for surgery. Since chondrosarcoma is less sensitive to chemotherapy and radiotherapy, surgical treatment with extensive resection with a sufficient margin is considered first line treatment. PMID- 25841155 TI - Confirmation of immunoglobulin heavy chain rearrangement by polymerase chain reaction using surgically obtained, paraffin-embedded samples to diagnose primary palate mucosa-associated lymphoid tissue lymphoma: A case study. AB - INTRODUCTION: Intraoral mucosa-associated lymphoid tissue (MALT) lymphoma is a rare lymphoma that has a good prognosis if diagnosed correctly and treated in time. PRESENTATION OF CASE: A 64-year-old woman was referred to our department with asymptomatic swelling of the left hard palate. Computed tomography and magnetic resonance imaging revealed a mass in the left hard palate. We performed a pre-surgery biopsy; however, it was difficult to differentiate MALT lymphoma from other reactive lymphoproliferative disorders via gross or microscopic examination. Although the lesion was completely excised, histological findings did not allow a definitive diagnosis due to an absence of visible monoclonality. We then performed polymerase chain reaction (PCR) using DNA extracted from formalin-fixed, paraffin-embedded surgical samples. Capillary electrophoresis showed monoclonal peaks of immunoglobulin heavy chain gene rearrangement, thus facilitating a definitive diagnosis of MALT lymphoma. DISCUSSION: PCR technique is rapid, accurate, and enables a definitive diagnosis without relying on traditional histological or molecular diagnostic techniques, such as Southern blotting. CONCLUSION: We suggest that, if histological examination is ambiguous or fresh material is insufficient, PCR can be performed using paraffin-embedded materials to definitively diagnose low-grade lymphomas, such as MALT lymphoma. PMID- 25841156 TI - Postpneumonectomy syndrome in a newborn after esophageal atresia repair. AB - INTRODUCTION: Postpneumonectomy syndrome (PPS) is an ominous complication, caused by mediastinal shift following massive lung resection. PRESENTATION OF THE CASE: A neonate with oesophageal atresia and tracheo-oesophageal fistula developed acute respiratory distress shortly after surgery, despite mechanical ventilation. The patient was found to have an associated oesophageal right lung that collapsed after oesophageal atresia repair and a left pulmonary artery sling causing left main bronchus stenosis mimicking a postpneumonectomy syndrome. DISCUSSION: We will describe the diagnostic work-up and the therapeutic measures used both in the acute phase and as definitive treatment in this challenging case. CONCLUSIONS: Neonatologists and paediatric surgeons should be aware of this rare association that may cause acute life threatening and worsening of patient's clinical status. Prompt realignment of the mediastinum in the normal position is critical to obtain rapid improvement of the patient's clinical conditions. PMID- 25841157 TI - Normalization of chromium and cobalt values after femoral head replacement. AB - INTRODUCTION: Adverse reaction to metal debris (ARMD) can be caused by metal-on metal total hip arthoplasty. We treated a case of ARMD in a 61-year-old patient by limited prosthetic revision, replacing the metal head with a polyethylene one. PRESENTATION OF CASE: Two years after metal-on-metal total arthoplasty of the left hip, radiographic control showed osteolysis of the patient's greater trochanter. He underwent surgical curettage and the application of demineralized bone matrix. After a few months, blood Co and Cr increased, and at clinical evaluation, the patient had worsening paresthesias. He agreed to prosthetic revision after 14 months. DISCUSSION: During surgery, the acetabular cup and femoral stem appeared correctly osteointegrated; therefore, the cup was maintained, while the prosthetic femoral head was removed and replaced with a 50mm polyethylene head. CONCLUSION: Blood Cr and urinary Cr and Co decreased and normalized 3 months after surgery, and the patient no longer suffered paresthesias. Blood Co normalized 7 months after revision. Radiographic follow-up showed no change after 30 months post-operatively. We believe this case report could be a starting point for a future randomized clinical trial to test the efficacy of the procedure used compared with complete implant revision. PMID- 25841158 TI - Jejuno-ileal diverticulitis: Etiopathogenicity, diagnosis and management. AB - INTRODUCTION: Although diverticular disease of the duodenum and colon is frequent, the jejuno-ileal diverticulosis (JOD) is an uncommon entity. The perforation of the small bowel diverticula can be fatal due to the delay in diagnosis. PRESENTATION OF CASE: We report the case of a 79-year-old man presenting with generalized abdominal pain and altered bowel habits. Physical examination revealed a severe diffuse abdominal pain. A CT scan of the abdomen and pelvis with oral contrast showed thickening of the distal jejunal loop and thickening and infiltration of the mesenteric fat and the presence of free air in the mesentery suggesting a possible perforation adjacent to the diverticula. A midline laparotomy was performed. The jejunal diverticula were found along the mesenteric border. Forty centimeters of the jejunum were resected. Histopathology report confirmed the presence of multiple jejunual diverticula, and one of them was perforated. The patient tolerated the procedure and the postoperative period was uncomplicated. DISCUSSION: The prevalence of small intestinal diverticula ranges from 0.06% to 1.3%. The etiopathogenesis of JOD is unclear, although the current hypothesis focuses on abnormalities in the smooth muscle or myenteric plexus, on intestinal dyskinesis and on high intraluminal pressures. Diagnosis is often difficult and delayed because clinical symptoms are not specific and mainly imaging studies performs the diagnosis. CONCLUSION: Because of the relative rarity of acquired jejuno-ileal diverticulosis, the perforation of small bowel diverticulitis poses technical dilemmas. PMID- 25841159 TI - Small bowel obstruction caused by dried apple. AB - INTRODUCTION: Small bowel obstruction in a virgin abdomen is an uncommon surgical condition. While malignancy, inflammatory bowel disease and foreign body are the main reported causes, undigested food bezoar causing bowel obstruction is a rare entity. We report a case of small bowel obstruction secondary to dried preserved apple having re-expanded within the gastrointestinal tract. PRESENTATION OF CASE: A 69 year old male presented with severe abdominal distension, generalized abdominal tenderness and obstipation for 1 week. Small bowel obstruction (SBO) was confirmed on plain abdominal X-ray and CT imaging. An emergency explorative laparatomy identified a sausage-shaped intra-luminal foreign body obstructing the distal ileum. An enterotomy was performed which revealed a rehydrated, donut shaped piece of dried apple. DISCUSSION: Swallowed items that pass through the pylorus rarely cause obstruction as they are usually small enough to pass through the rest of the bowel without difficulty. We postulate that in our patient that the dried apple was originally small enough to pass through the pylorus. However during small bowel, its' highly absorbable nature resulted in an increase in size that prevented its' passage through the ileocecal valve. A simple in-vitro experiment discovered that dried apple has a potential to reabsorb fluid and expand up to 35% of its initial size within 72h. CONCLUSION: This report illustrates the potential for dried food substances to cause intra-luminal SBO after significant expansion with rehydration. PMID- 25841160 TI - Pathological fracture of the coronoid process secondary to medication-related osteonecrosis of the jaw (MRONJ). AB - INTRODUCTION: Medication-related osteonecrosis of the jaw (MRONJ) is a growing problem within the field of oral and maxillofacial surgery. It is defined as the presence of exposed necrotic alveolar bone that does not resolve over a period of 8 weeks in a patient taking bisphosphonates, who has not had radiotherapy to the jaw [1]. Since the first report in 2003 that highlighted the potential harm caused by MRONJ, many more patients have been diagnosed with the condition [2]. The growth in recent years is likely due to the more potent drugs delivered intravenously however there is some evidence that oral bisphosphonates given over longer periods of time can have similar effects. Bone exposure may occur spontaneously or most commonly occurs following an invasive dental procedure, as shown in the case below [3]. PRESENTATION OF CASE: This case report demonstrates the unpredictable nature of symptoms associated with medication related osteonecrosis and its management within the hospital environment. DISCUSSION: This case demonstrastes the unpredictable nature of MRONJ and how the disease can progress to cause significant morbidity. In this case extensive surgery was required to remove the necrotic fragments of bone with no guarnatee that the necrosis will stop spreading. CONCLUSION: It seems a matter of great importance that the lasting effects of MRONJ are known to general dental and medical practitioners alike. Nationally recognised evidence based guidelines are lacking and uniformity in the management of MRONJ is required amongst the speciality. PMID- 25841161 TI - Impact of real-time traffic characteristics on freeway crash occurrence: systematic review and meta-analysis. AB - The development of methods for real-time crash prediction as a function of current or recent traffic and roadway conditions is gaining increasing attention in the literature. Numerous studies have modeled the relationships between traffic characteristics and crash occurrence, and significant progress has been made. Given the accumulated evidence on this topic and the lack of an articulate summary of research status, challenges, and opportunities, there is an urgent need to scientifically review these studies and to synthesize the existing state of-the-art knowledge. This paper addresses this need by undertaking a systematic literature review to identify current knowledge, challenges, and opportunities, and then conducts a meta-analysis of existing studies to provide a summary impact of traffic characteristics on crash occurrence. Sensitivity analyses were conducted to assess quality, publication bias, and outlier bias of the various studies; and the time intervals used to measure traffic characteristics were also considered. As a result of this comprehensive and systematic review, issues in study designs, traffic and crash data, and model development and validation are discussed. Outcomes of this study are intended to provide researchers focused on real-time crash prediction with greater insight into the modeling of this important but extremely challenging safety issue. PMID- 25841162 TI - Dual antiplatelet therapy after acute coronary syndrome: a cardiologist-based optimal decision. PMID- 25841164 TI - Response to: 'Towards optimal cut-off trough levels of adalimumab and etanercept for a good therapeutic response in rheumatoid arthritis. Results of the INMUNOREMAR study' by Sanmarti et al. PMID- 25841163 TI - Return to sport after hip surgery for femoroacetabular impingement: a systematic review. AB - BACKGROUND: We aimed to appraise (1) the rate of return to sport of athletes after hip surgery for femoroacetabular impingement (FAI) and (2) some aspects that may influence the return to sport. METHODS: Four databases (EMBASE, PubMed, Web of Science, Cochrane Library) were searched until 21 October 2014. Studies evaluated return to sport of athletes who underwent hip surgery for the treatment of symptomatic FAI. A validated tool was used for quality evaluation of the studies. RESULTS: A total of 18 case series (level of evidence IV) with moderate to-high methodological quality were included. On average, 87% of athletes returned to sport after hip surgery for FAI and 82% returned to the same sport level as before the occurrence of the symptoms. Professional athletes seem to return to sport at a higher rate compared with recreational and collegiate athletes. Sport participation after hip arthroscopy tends to decrease for professional athletes at short-term and mid-term follow-ups. Diffuse hip osteoarthritis at the time of surgery may not allow athletes to return to sport. CONCLUSIONS: Most athletes return to sport after hip surgery for the treatment of symptomatic FAI. The level of competition, time of evaluation after hip surgery and presence of articular cartilage lesions at the time of surgery may influence return to sport. Future studies with higher levels of evidence should describe and evaluate return to sport protocols after hip surgery for FAI. PMID- 25841165 TI - Economic comparison of the monitoring programmes for bluetongue vectors in Austria and Switzerland. AB - With the bluetongue virus serotype 8 (BTV-8) outbreak in 2006, vector monitoring programmes (according to EU regulation 1266/2007) were implemented by European countries to obtain information on the spatial distribution of vectors and the vector-free period. This study investigates the vector monitoring programmes in Austria and Switzerland by performing a retrospective cost analysis for the period 2006-2010. Two types of costs were distinguished: costs financed directly via the national bluetongue programmes and costs contributed in-kind by the responsible institutions and agricultural holdings. The total net costs of the monitoring programme in Austria amounted to ?1,415,000, whereby in Switzerland the costs were valued at ?94,000. Both countries followed the legislation complying with requirements, but differed in regard to sampling frequency, number of trap sites and sampling strategy. Furthermore, the surface area of Austria is twice the area of Switzerland although the number of ruminants is almost the same in both countries. Thus, for comparison, the costs were normalised with regard to the sampling frequency and the number of trap sites. Resulting costs per trap sample comprised ?164 for Austria and ?48 for Switzerland. In both countries, around 50 per cent of the total costs can be attributed to payments in-kind. The benefit of this study is twofold: first, veterinary authorities may use the results to improve the economic efficiency of future vector monitoring programmes. Second, the analysis of the payment in-kind contribution is of great importance to public authorities as it makes the available resources visible and demonstrates how they have been used. PMID- 25841166 TI - Non-urgent accident and emergency department use as a socially shared custom: a qualitative study. AB - OBJECTIVE: We explored attitudes of non-urgent accident and emergency department (AED) patients in the middle-income healthcare setting Saint Vincent and the Grenadines (SVG) in the Caribbean to understand how and why they decide to seek emergency care and resist using primary care facilities. METHODS: In 2013, we conducted 12 semistructured interviews with a purposive sample of non-urgent AED users from a variety of social backgrounds. Verbatim transcripts were analysed with a grounded theory approach. RESULTS: In this study, we found, first, that participants automatically chose to visit the AED and described this as a locally shared custom. Second, the healthcare system in SVG reinforced this habitual use of the AED, for example, by health professionals routinely referring non-urgent cases to the AED. Third, there was also some deliberate use; patients took convenience and the systemic encouragement into account to determine that the AED was the most appropriate choice for healthcare. CONCLUSIONS: We conclude that the attitudes and habits of the Vincentian non-urgent patient are major determinants of their AED use and are intricately linked to local, socially shared practices of AED use. Findings show that health services research should reconsider rational choice behaviour models and further explore customs of health-seeking. PMID- 25841167 TI - Comparative Analysis of Principal Components Can be Misleading. AB - Most existing methods for modeling trait evolution are univariate, although researchers are often interested in investigating evolutionary patterns and processes across multiple traits. Principal components analysis (PCA) is commonly used to reduce the dimensionality of multivariate data so that univariate trait models can be fit to individual principal components. The problem with using standard PCA on phylogenetically structured data has been previously pointed out yet it continues to be widely used in the literature. Here we demonstrate precisely how using standard PCA can mislead inferences: The first few principal components of traits evolved under constant-rate multivariate Brownian motion will appear to have evolved via an "early burst" process. A phylogenetic PCA (pPCA) has been proprosed to alleviate these issues. However, when the true model of trait evolution deviates from the model assumed in the calculation of the pPCA axes, we find that the use of pPCA suffers from similar artifacts as standard PCA. We show that data sets with high effective dimensionality are particularly likely to lead to erroneous inferences. Ultimately, all of the problems we report stem from the same underlying issue--by considering only the first few principal components as univariate traits, we are effectively examining a biased sample of a multivariate pattern. These results highlight the need for truly multivariate phylogenetic comparative methods. As these methods are still being developed, we discuss potential alternative strategies for using and interpreting models fit to univariate axes of multivariate data. PMID- 25841168 TI - Leptomeningeal collateral vessels are a major risk factor for intracranial hemorrhage after carotid stenting in patients with carotid atherosclerotic plaque. AB - AIM: To evaluate the relationship between leptomeningeal collaterals and intracranial hemorrhage (ICH) after carotid artery stenting (CAS). METHODS: A retrospective study was undertaken of 228 patients (median age 75 years (range 44 90); 187 men and 41 women) who underwent CAS due to unilateral carotid atherosclerotic plaque from January 2009 to December 2013. Cerebral angiographic findings were classified into three patterns: type I, normal visualization of the anterior and middle cerebral arteries without leptomeningeal collaterals; type II, visualization of the middle cerebral artery only without leptomeningeal collaterals; and type III, visualization of leptomeningeal collateral flow. RESULTS: For all cerebral angiographic findings, 146 (64.0%) were type I, 61 (26.8%) were type II, and 21 (9.2%) were type III. Four patients (1.8%) died with fatal ICH after CAS and had type III angiographic findings (19%). The prevalence of ICH in patients with leptomeningeal collateral vessels was significantly higher than in patients without leptomeningeal collateral vessels (19% vs 0%, p<0.0001). The percentage of carotid stenosis in patients with ICH based on North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria was significantly higher than in patients without ICH (89.8+/-3.6% vs 72.8+/-12.8%, p=0.014). CONCLUSIONS: Leptomeningeal collateral vessels are a major risk factor for ICH after CAS in patients with carotid atherosclerotic plaque. PMID- 25841169 TI - Vascular geometry of the extracranial carotid arteries: an analysis of length, diameter, and tortuosity. AB - BACKGROUND: Stable access is essential for successful intracranial interventions. Quantifying variations in extracranial carotid arteries may help in the selection and development of access catheters. This study describes the vascular dimensions from the aortic arch to the skull base. METHODS: CT angiography analysis was performed on 100 patients. The lengths, diameters, and tortuosity of the common carotid artery (CCA) and internal carotid artery (ICA) were measured from the aortic arch to the skull base. RESULTS: The mean+/-SD length of the carotid artery from the aortic arch to the skull base was 22.2+/-2.2 cm for the right side and 20.8+/-1.9 cm for the left side (p<0.0001). The length of the right CCA was 13.6+/-1.2 cm and the length of the left CCA was 12.4+/-1.4 cm (p<0.0001). The length of the right ICA was 8.6+/-1.4 cm compared with 8.4+/-1.4 cm for the left ICA (p=0.3). The ICA length in men and women was 8.9+/-1.3 cm and 8.2+/-1.3 cm, respectively (p=0.0001), and the CCA length in men and women was 13.6+/-1.5 cm and 12.3+/-1.6 cm, respectively (p<0.0001). The lengths of the CCA and ICA in patients aged >=60 years were 13.3+/-1.7 cm and 8.9+/-1.5 cm, respectively compared with 12.8+/-1.7 cm and 8.2+/-1.1 cm, respectively, for patients aged <60 years (p=0.04 for CCA, p=0.0002 for ICA). Tortuosity of the CCA and ICA was 1.2+/ 0.2 and 1.3+/-0.1, respectively, in patients aged >=60 years compared with 1.1+/ 0.1 for both the ICA and CCA in patients aged <60 years (p<0.0001 for both). There was a consistent ratio of CCA/ICA length of 1.6+/-0.3 on the right and 1.5+/-0.3 on the left (p<0.0001). The arterial diameters did not show any significant difference. CONCLUSIONS: The distance from the aortic arch to the skull base is longer on the right than on the left side. Both the CCA and ICA are longer in men and in patients aged >=60 years. The tortuosity of both segments significantly increases with age. PMID- 25841170 TI - Successful endovascular treatment of three fusiform cerebral aneurysms with the Pipeline Embolization Device in a patient with dilating HIV vasculopathy. PMID- 25841171 TI - Serum nesfatin-1 is reduced in type 2 diabetes mellitus patients with peripheral arterial disease. AB - BACKGROUND: Nesfatin-1, recently identified as a satiety regulator, elicits an anti-atherosclerosis effect. Our study was designed to determine whether there is an association between serum nesfatin-1 and the development and severity of peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: This cross-sectional study included 355 T2DM patients (200 without PAD and 155 with PAD). RESULTS: T2DM patients with PAD exhibited marked lower serum nesfatin-1 concentrations than those without PAD. Multivariable logistic regression analysis indicated an inverse association of serum nesfatin-1 concentrations with the development of PAD in T2DM patients (OR 0.008, 95% CI 0.002 to 0.028; P<0.001). Simple linear regression analysis showed a marked correlation between serum nesfatin-1 concentrations and body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), C-reactive protein (CRP), and ankle-brachial index (ABI) in T2DM patients. By contrast, multivariable analysis showed only BMI and ABI as independent correlates of serum nesfatin-1. CONCLUSIONS: Our study shows an association of serum nesfatin-1 concentrations and the development and severity of PAD in T2DM patients. PMID- 25841172 TI - Exploring age differences in visual working memory capacity: is there a contribution of memory for configuration? AB - Recent research has shown marked developmental increases in the apparent capacity of working memory. This recent research is based largely on performance on tasks in which a visual array is to be retained briefly for comparison with a subsequent probe display. Here we examined a possible theoretical alternative (or supplement) to a developmental increase in working memory in which children could improve in the ability to combine items in an array to form a coherent configuration. Elementary school children and adults received, on each trial, an array of colored spots to be remembered. On some trials, we provided structure in the probe display to facilitate the formation of a mental representation in which a coherent configuration is encoded. This stimulus structure in the probe display helped younger children, and thus reduced the developmental trend, but only on trials in which the participants were held responsible for the locations of items in the array. We conclude that, in addition to the development of the ability to form precise spatial configurations from items, the evidence is consistent with the existence of an actual developmental increase in working memory capacity for objects in an array. PMID- 25841173 TI - Identification and expression analysis of two interleukin-23alpha (p19) isoforms, in rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar. AB - Interleukin (IL)-23 is a heterodimeric IL-12 family cytokine composed of a p19 alpha-chain, linked to a p40 beta-chain that is shared with IL-12. IL-23 is distinguished functionally from IL-12 by its ability to induce the production of IL-17, and differentiation of Th17 cells in mammals. Three isoforms of p40 (p40a, p40b and p40c) have been found in some 3R teleosts. Salmonids also possess three p40 isoforms (p40b1, p40b2 and p40c) although p40a is missing, and two copies (paralogues) of p40b are present that have presumably been retained following the 4R duplication in this fish lineage. Teleost p19 has been discovered recently in zebrafish, but to date there is limited information on expression and modulation of this molecule. In this report we have cloned two p19 paralogues (p19a and p19b) in salmonids, suggesting that a salmonid can possess six potential IL-23 isoforms. Whilst Atlantic salmon has two active p19 genes, the rainbow trout p19b gene may have been pseudogenized. The salmonid p19 translations share moderate identities (22.8-29.9%) to zebrafish and mammalian p19 molecules, but their identity was supported by structural features, a conserved 4 exon/3 intron gene organisation, and phylogenetic tree analysis. The active salmonid p19 genes are highly expressed in blood and gonad. Bacterial (Yersinia ruckeri) and viral infection in rainbow trout induces the expression of p19a, suggesting pathogen specific induction of IL-23 isoforms. Trout p19a expression was also induced by PAMPs (poly IC and peptidoglycan) and the proinflammatory cytokine IL-1beta in primary head kidney macrophages. These data may indicate diverse functional roles of trout IL-23 isoforms in regulating the immune response in fish. PMID- 25841174 TI - Functional roles and gene regulation of tumor necrosis factor receptor 1 in freshwater striped murrel. AB - In this study, a complete molecular characterization of tumor necrosis factor receptor 1 (TNFR1) which was identified from the constructed cDNA library of striped murrel Channa striatus (Cs) is reported. The CsTNFR1 encoded a type I membrane receptor protein that contains 399 amino acids including three cysteine rich domains (CRDs) at CRD1(41-46), CRD2(79-118) and CRD3(120-159) in the extracellular region and a putative TNF receptor-associated factor (TRAF) site at 245-253 and a death domain between 297 and 388 in the cytoplasmic region which is essential for induction of apoptosis. The predicted molecular mass of CsTNFR1 is 45kDa and its corresponding theoretical isoelectric point (pI) is 6.3. CsTNFR1 shared maximum identity with TNFR1 from olive flounder Paralichthys olivaceus (82%). Real-time PCR showed that CsTNFR1 gene was expressed most abundantly (P<0.05) in the head kidney. Further, CsTNFR1 mRNA transcription was studied after challenge with fungus Apanomyces invadans and bacteria Aeromonas hydrophila. The fungus injected murrels showed a highest expression at 48h, whereas bacteria injected murrels showed at 24h. The gene expression studies revealed that CsTNFR1 may be involved in innate immune process of murrels against pathogenic infections. The over-expressed and purified recombinant CsTNFR1 protein (rCsTNFR1) was subjected to TNF-alpha inhibition assay to confirm their specificity and activity against TNF-alpha which confirmed that the rCsTNFR1 inhibits the activity of TNF-alpha in a dose dependent manner where maximum inhibition (97%) was observed at 10,000 fold concentration of rCsTNFR1. In addition, the direct cytotoxic effect of rCsTNFR1 was analyzed against head kidney phagocyte. The results showed that the recombinant CsTNFR1 protein does not exhibit any significant cytotoxicity against head kidney phagocyte cells even at higher concentration (8MUg/ml). Moreover, the recombinant protein was analyzed for respiratory burst activity in the presence of two different ROS inducers, opsonized zymosan (fungal cell wall component) and phorbol 12-myristate 13 acetate (PMA). The findings showed that the C. striatus head kidney phagocyte exposed to purified recombinant CsTNFR1 protein alone do not produced any ROS. However, opsonized zymosan induced recombinant CsTNFR1 protein significantly (P<0.05) enhanced the ROS production on concentration basis which is revealed that the ROS production depends on the concentration of the recombinant CsTNFR1 protein. Overall, the study showed that the CsTNFR1 plays an important role in the pathogen-induced inflammatory process of striped murrel. PMID- 25841175 TI - Early adolescent temperament, parental monitoring, and substance use in Mexican origin adolescents. AB - Previous studies suggest that temperamental dispositions are associated with substance use. However, most research supporting this association has relied on European American samples (Stautz & Cooper, 2013). We addressed this gap by evaluating the prospective relations between 5th grade temperament and 9th grade substance use in a longitudinal sample of Mexican-origin youth (N = 674). Effortful control and trait aggressiveness predicted 9th grade substance use, intentions, and expectations, even after controlling for 5th grade substance use. Additionally, we found an interaction between temperament and parental monitoring such that monitoring is a protective factor for early substance use primarily for youth with temperamental tendencies associated with risk for substance use (e.g., low effortful control and aggression). Results add to the growing literature demonstrating that early manifestations of self-control are related to consequential life outcomes. PMID- 25841176 TI - Effect of prosthodontic planning on intercuspal occlusal contacts: comparison of digital and conventional planning. AB - BACKGROUND: Adequate occlusal contacts are critical for masticatory function. The aim of this study is to evaluate the intercuspal occlusal contacts following conventional and digital wax-ups. METHODS: Stone casts of 15 patients undergoing prosthodontic treatment were gathered. Each cast was duplicated twice, so that conventional and digital wax-ups could be performed. To assess the occlusion, the following variables were evaluated: contact number per tooth (CNT), contact area per tooth (CAT) and contact accuracy. Further, the impact of tooth location in the arch was assessed. RESULTS: The CNT and CAT after the wax-ups increased significantly following each wax-up, and this increase was more prominent for the posterior teeth than the anterior teeth. The conventional wax-up was associated with lower CNT than the digital wax-up, especially for the posterior teeth. On the other hand, the CAT was greater for the conventional wax-up than the digital wax-up for the anterior and posterior teeth. In terms of accuracy, the two wax ups showed greater discrepancies than the pre-treatment casts, however, the magnitude of discrepancy was greater for the digital wax-up. CONCLUSIONS: The two wax-ups improved the contact number and area. Despite the statistical variation between the wax-ups, the actual difference was minimal. Therefore, it could be speculated that the two wax-ups produced a similar outcome. PMID- 25841177 TI - The influence of cognitive control training on stress reactivity and rumination in response to a lab stressor and naturalistic stress. AB - Cognitive control impairments have been identified as an underlying mechanism for rumination, a key predictor of depression. Literature suggests that cognitive control training (CCT) targeting working memory functioning can increase effectiveness of existing antidepressant treatments to reduce rumination. However, it remains unclear whether CCT can also be implemented as a preventive intervention for depression, increasing resilience. For this purpose, at-risk undergraduate students (high trait ruminators) were allocated to a CCT or active control condition, consisting of 10 online training sessions. Working memory functioning was assessed preceding and following the training and reactivity to a lab stressor was assessed directly following training. Finally, at four weeks follow-up, brooding--the maladaptive form of rumination--was re-assessed in response to a naturalistic stressor (examination period). Although we did not find direct transfer effects of CCT on working memory functioning, increase in working memory functioning following CCT was related to post-training brooding and resilience levels. Moreover, participants receiving CCT demonstrated lower stress reactivity in the lab and a decrease in brooding following a naturalistic stressor at follow-up, indicating temporal stability of our findings. These findings suggest that CCT can be considered a promising preventive intervention to reduce stress reactivity and rumination. PMID- 25841178 TI - A histological and ultrastructural study of the skin of rainbow trout (Oncorhynchus mykiss) alevins exposed to different levels of ultraviolet B radiation. AB - The current study was conducted to evaluate the effects of UV-B radiation on survival rate and histopathological changes in the skin structure and ultrastructure in rainbow trout (Oncorhynchus mykiss) alevins. In laboratory dark conditions, newly hatched rainbow trout alevins were exposed to two different doses of UV-B radiation (high dose: HD: 94.83 MUW cm(-2)) and (low dose: LD: 68.75 MUW cm(-2)) for 9 days (time of exposure: 15 min per day), whereas specimens kept in darkness served as a control group. At the end of the experiment, alevins exposed to HD-UVB had the lowest survival rate (43.9 +/- 0.9%), whereas fish exposed to LD-UVB showed intermediate values (73.6 +/- 0.4%) with regard to the control group (91.2 +/- 0.2%). Light microscopic and scanning electron microscopic studies revealed necrosis, sunburned cells, epidermis lifting of the epidermis, reduced number of mucous cells, degeneration of mucous cells and destruction of pavement cell microridges in both UV-B exposed groups. Hemorrhage and inflation in the meningeal layer of the brain were also observed in 17% and 42% of fish exposed to LD- and HD-UVB, respectively. PMID- 25841179 TI - Acute phytotoxicity of seven metals alone and in mixture: Are Italian soil threshold concentrations suitable for plant protection? AB - Metals can pollute soils in both urban and rural areas with severe impacts on the health of humans, plants and animals living there. Information on metal toxicity is therefore important for ecotoxicology. This study investigated the phytotoxicity of different metals frequently found as pollutants in soils: arsenic, cadmium, chromium, lead, mercury, nickel and zinc. Cucumber (Cucumis sativus), sorghum (Sorghum saccharatum) and cress (Lepidium sativum) seeds were used as models for other plants used in human nutrition such as cereals, rice, fruits and vegetables. The 72-h germination rate and root elongations were selected as short-term ecotoxicological endpoints in seeds exposed to single metals and mixtures. Metals were spiked onto OECD standard soils in concentrations comparable to current Italian contamination threshold concentrations for residential and commercial soils. Arsenic, chromium, mercury and nickel were the most toxic metals in our experimental conditions, particularly to cress seeds (5.172, 152 and 255.4 mg/kg as 72 h IC50 for arsenic, mercury and nickel respectively). Italian limits were acceptable for plant protection only for exposure to each metal alone but not for the mixtures containing all the metals concentrations expected by their respective legislative threshold. The effects of the mixture were class-specific: trends were comparable in dicots but different in monocots. The response induced by the mixture at high concentrations differed from that theoretically obtainable by summing the effects of the individual metals. This might be due to partial antagonism of the metals in soil or to the formation of complexes between the metals, which reduce the bioavailability of the pollutants for plants. PMID- 25841180 TI - Neurokinin (NK)-1 receptor expression in monocytes from bipolar disorder patients: a pilot study. AB - BACKGROUND: Neurokinin 1 receptors (NK-1R) have been involved in several psychiatric disorders including major depression, but less is known for bipolar disorder (BD). METHOD: We compared NK-1R expression and Substance P (SP) ability to induce NF-kappaB activation in monocytes from BD patients and healthy donors (HD), also looking for the effects of tobacco smoke. After informed written consent, 20 euthymic BD patients, either bipolar type 1 (BDI) or type 2 (BDII), and 14 age-matched healthy donors (HD) were enrolled. NK-1R expression in monocytes was evaluated by Western blot and expressed as the ratio between NK-1R and Na(+)/K(+)-ATPase protein expressions. NF-kappaB activation was assessed by measuring the nuclear content of the p50 subunit (ELISA kit). RESULTS: NK-1R expression was significantly reduced (P<0.001) in monocytes from BD patients as compared to HD, with no major differences between BDI and BDII patients. Tobacco smoke enhanced NK-1R expression in HD, but not in BD patients. Un-stimulated monocytes from BD patients presented a constitutively higher (P<0.05) content of nuclear p50 subunit as compared to HD. SP and an NK-1R agonist induced NF-kappaB activation, with a higher effect in HD: this effect was receptor-mediated as it was abrogated by an NK-1R antagonist. LIMITATIONS: As a pilot study enrolling 20 BD patients, an obvious limitation is the sample size. CONCLUSIONS: Our results show the existence of a relevant alteration in NK-1R expression in BD patients and further suggest SP involvement in BD, so improving our understanding of the underlying mechanisms of this disease. PMID- 25841181 TI - Degradation and monitoring of acetamiprid, thiabendazole and their transformation products in an agro-food industry effluent during solar photo-Fenton treatment in a raceway pond reactor. AB - In this study, pesticides acetamiprid and thiabendazole and their transformation products (TPs), seven from each pesticide, were successfully monitored during solar photo-Fenton treatment in a real secondary effluent from an agro-food industry spiked with 100MUgL(-1) of each pesticide. To this end, a highly sensitive procedure was developed, based on liquid chromatography (LC) coupled to hybrid quadrupole-linear ion trap mass spectrometry (QqLIT-MS). In addition, finding low-cost and operational technology for the application of AOPs would then facilitate their use on a commercial level. Simple and extensive photoreactors such as raceway pond reactors (RPRs) are therefore proposed as an alternative for the application of solar photo-Fenton. Results showed that high degradation could be achieved in a complex water matrix (>99% TBZ and 91% ACTM in 240min) using a 120-L RPR pilot plant as novel technology. The analyses indicated that after the treatment only three TPs from ACTM were still present in the effluent, while the others had been removed. The study showed that the goal of either just removing the parent compounds, or going one step further and removing all the TPs, can significantly change the treatment time, which would affect process costs. PMID- 25841182 TI - Genetic algorithm based feature selection combined with dual classification for the automated detection of proliferative diabetic retinopathy. AB - Proliferative diabetic retinopathy (PDR) is a condition that carries a high risk of severe visual impairment. The hallmark of PDR is the growth of abnormal new vessels. In this paper, an automated method for the detection of new vessels from retinal images is presented. This method is based on a dual classification approach. Two vessel segmentation approaches are applied to create two separate binary vessel map which each hold vital information. Local morphology features are measured from each binary vessel map to produce two separate 4-D feature vectors. Independent classification is performed for each feature vector using a support vector machine (SVM) classifier. The system then combines these individual outcomes to produce a final decision. This is followed by the creation of additional features to generate 21-D feature vectors, which feed into a genetic algorithm based feature selection approach with the objective of finding feature subsets that improve the performance of the classification. Sensitivity and specificity results using a dataset of 60 images are 0.9138 and 0.9600, respectively, on a per patch basis and 1.000 and 0.975, respectively, on a per image basis. PMID- 25841183 TI - Urinary incontinence in spina bifida: Initial instrument validation. AB - The purpose of this study was to perform a psychometric assessment of the Incontinence Symptom Index-Pediatric (ISI-P) in a cohort of adolescents with spina bifida (SB) and neuropathic urinary incontinence (UI) to test its validity and reliability. The ISI-P, an 11-item instrument with domains for symptom severity and impairment, was self-administered by subjects 11-17 years old with SB and UI. Controls were 11-17 years old, with nephrolithiasis and no history of UI. Formal psychometric assessment included an evaluation of internal consistency, test re-test reliability and factor analysis. Of 78 study-eligible subjects we attempted to contact, 33 (66.7% female) with a median age of 13.1 years completed the ISI-P (42.3% response rate). 21 control patients also completed the ISI-P. Cronbach's alpha was 0.936 and 0.792 for the severity and bother factors respectively. The delta Chi-square test for the two-factor (vs. one-factor) model was significantly [chi(2)(89) = 107.823, p < 0.05] in favor of the former model with descriptive fit indices being excellent (e.g., comparative fit index = 0.969). Furthermore, category information analysis showed that all categories were associated with different threshold values, namely that each category contributed unique information for the measurement of the latent trait. In conclusion, the ISI-P has desirable psychometric properties for the measurement of UI symptom severity and impairment in adolescents with SB. PMID- 25841184 TI - Economic process to co-produce poly(epsilon-l-lysine) and poly(l-diaminopropionic acid) by a pH and dissolved oxygen control strategy. AB - This study tended to apply biorefinery of indigenous microbes to the fermentation of target-product generation through a novel control strategy. A novel strategy for co-producing two valuable homopoly(amino acid)s, poly(epsilon-l-lysine) (epsilon-PL) and poly(l-diaminopropionic acid) (PDAP), was developed by controlling pH and dissolved oxygen concentrations in Streptomyces albulus PD-1 fermentation. The production of epsilon-PL and PDAP got 29.4 and 9.6gL(-1), respectively, via fed-batch cultivation in a 5L bioreactor. What is more, the highest production yield (21.8%) of similar production systems was achieved by using this novel strategy. To consider the economic-feasibility, large-scale production in a 1t fermentor was also implemented, which would increase the gross profit of 54,243.5USD from one fed-batch bioprocess. This type of fermentation, which produces multiple commercial products from a unified process is attractive, because it will improve the utilization rate of raw materials, enhance production value and enrich product variety. PMID- 25841185 TI - Suppression of methanogenesis for hydrogen production in single-chamber microbial electrolysis cells using various antibiotics. AB - Methanogens can utilize the hydrogen produced in microbial electrolysis cells (MECs), thereby decreasing the hydrogen generation efficiency. However, various antibiotics have previously been shown to inhibit methanogenesis. In the present study antibiotics, including neomycin sulfate, 2-bromoethane sulfonate, 2 chloroethane sulfonate, 8-aza-hypoxanthine, were examined to determine if hydrogen production could be improved through inhibition of methanogenesis but not hydrogen production in MECs. 1.1mM neomycin sulfate inhibited both methane and hydrogen production while 2-chloroethane sulfonate (20mM), 2-bromoethane sulfonate (20mM), and 8-aza-hypoxanthine (3.6mM) can inhibited methane generation and with concurrent increases in hydrogen production. Our results indicated that adding select antibiotics to the mixed species community in MECs could be a suitable method to enhance hydrogen production efficiency. PMID- 25841186 TI - The influence of light intensity and photoperiod on duckweed biomass and starch accumulation for bioethanol production. AB - Duckweed has been considered as a valuable feedstock for bioethanol production due to its high biomass and starch production. To investigate the effects of light conditions on duckweed biomass and starch production, Lemna aequinoctialis 6000 was cultivated at different photoperiods (12:12, 16:8 and 24:0h) and light intensities (20, 50, 80, 110, 200 and 400MUmolm(-2)s(-1)). The results showed that the duckweed biomass and starch production was increased with increasing light intensity and photoperiod except at 200 and 400MUmolm(-2)s(-1). Considering the light cost, 110MUmolm(-2)s(-1) was optimum light condition for starch accumulation with the highest maximum growth rate, biomass and starch production of 8.90gm(-2)day(-1), 233.25gm(-2) and 98.70gm(-2), respectively. Moreover, the results suggested that high light induction was a promising method for duckweed starch accumulation. This study provides optimized light conditions for future industrial large-scale duckweed cultivation. PMID- 25841187 TI - Production of cellulosic ethanol from cotton processing residues after pretreatment with dilute sodium hydroxide and enzymatic hydrolysis. AB - In this study, production of cellulosic ethanol from two cotton processing residues was investigated after pretreatment with dilute sodium hydroxide. Pretreatment performance was investigated using a 2(2) factorial design and the highest glucan conversion was achieved at the most severe alkaline conditions (0.4g NaOH g(-1) of dry biomass and 120 degrees C), reaching 51.6% and 38.8% for cotton gin waste (CGW) and cotton gin dust (CGD), respectively. The susceptibility of pretreated substrates to enzymatic hydrolysis was also investigated and the best condition was achieved at the lowest total solids (5wt%) and the highest enzyme loading (85mg of Cellic CTec2 g(-1) of dry substrate). However, the highest concentration of fermentable sugars - 47.8 and 42.5gL(-1) for CGD and CGW, respectively - was obtained at 15wt% total solids using this same enzyme loading. Substrate hydrolysates had no inhibitory effects on the fermenting microorganism. PMID- 25841188 TI - In situ biodegradation of naphthenic acids in oil sands tailings pond water using indigenous algae-bacteria consortium. AB - In this study, the biodegradation of total acid-extractable organics (TAOs), commonly called naphthenic acids (NAs), was investigated. An indigenous microbial culture containing algae and bacteria was taken from the surface of a tailings pond and incubated over the course of 120days. The influence of light, oxygen and the presence of indigenous algae and bacteria, and a diatom (Navicula pelliculosa) on the TAO removal rate were elucidated. The highest biodegradation rate was observed with bacteria growth only (without light exposure) with a half life (t(1/2)) of 203days. The algae-bacteria consortium enhanced the detoxification process, however, bacterial biomass played the main role in toxicity reduction. Principal component analysis (PCA) conducted on FT-IR spectra, identified functional groups and bonds (representing potential markers for biotransformation of TAOs) as follows: hydroxyl, carboxyl and amide groups along with CH, arylH, arylOH and NH bonds. PMID- 25841189 TI - Evaluation of hydrogen production and internal resistance in forward osmosis membrane integrated microbial electrolysis cells. AB - In order to enhance hydrogen production by facilitated proton transport through a forward osmosis (FO) membrane, the FO membrane was integrated into microbial electrolysis cells (MECs). An improved hydrogen production rate was obtained in the FO-MEC (12.5+/-1.84*10(-3)m(3)H2/m(3)/d) compared to that of the cation exchange membrane (CEM) - MEC (4.42+/-0.04*10(-3)m(3)H2/m(3)/d) during batch tests (72h). After an internal resistance analysis, it was confirmed that the enhanced hydrogen production in FO-MEC was attributed to the smaller charge transfer resistance than in the CEM-MEC (90.3Omega and 133.4Omega respectively). The calculation of partial internal resistance concluded that the transport resistance can be substantially reduced by replacing a CEM with a FO membrane; decrease of the resistance from 0.069Omegam(2) to 5.99*10(-4)Omegam(2). PMID- 25841190 TI - Earlier biomarker or index for the identification between Takotsubo cardiomyopathy and acute myocardial infarction. PMID- 25841191 TI - Successful closure of a large secundum atrial septal defect via the transjugular approach after failed transfemoral approach. PMID- 25841192 TI - Effluent quality and reuse potential of domestic wastewater treated in a pilot scale hybrid constructed wetland system. AB - The study investigates treatment and reuse potential of domestic wastewater of a small community of about 30 people sequentially by anaerobic pretreatment followed by horizontal (HSSF-CW) and vertical (VSSF-CW) sub-surface flow constructed wetlands operated in series. The organic and suspended solids load to the hybrid wetland system was decreased by anaerobic pretreatment. HSSF-CW mainly removed organic matter and supported denitrification whereas VSSF-CW mainly obtained nitrification and phosphorus removal. Recirculation of the effluent increased particularly total nitrogen removal in the wetland system. The study involves evaluation of the whole system in terms of effluent quality. It was achieved on average >95% organic matter and >90% nitrogen removal in the hybrid constructed wetland system with anaerobic pretreatment at a specific wetland surface area of only about 1 m(2) per person. Average mass removal rates were 21.17 gCOD/m(2)day, 5.58 gBOD5/m(2)day, 2.78 gTKN/m(2)day, 1.35 gTN/m(2)day, 0.44 gTP/m(2)day and 5.21 gTSS/m(2)day throughout the total duration of the operation. Consequently, the effluent met the regulations for discharge limits for organic matter and suspended solids. COD and TN concentrations decreased to below 20 mg/L in the effluent. It was also shown that effluent of the system could be reused for irrigation if it is disinfected properly. PMID- 25841193 TI - Carbonaceous material obtained from exhausted coffee by an aqueous solution combustion process and used for cobalt (II) and cadmium (II) sorption. AB - New carbonaceous materials were obtained using a fast aqueous solution combustion process from mixtures of exhausted coffee, ammonium nitrate (oxidizer) and urea (fuel) heated at 600, 700, 800 or 900 degrees C. The resulting powders were effective adsorbents for removing Co(II) and Cd(II) from aqueous solutions. Exhausted coffee was also calcined at different temperatures and compared. The products were characterized, and the obtained carbons had BET specific surface areas of 114.27-390.85 m(2)/g and pore diameters of 4.19 to 2.44 nm when the temperature was increased from 600 to 800 degrees C. Cobalt and cadmium adsorption by the carbonaceous materials was correlated with the maximum adsorption capacities and specific surface areas of the materials. The method reported here is advantageous because it only required 5 min of reaction to improve the textural properties of carbon obtained from exhausted coffee, which play an important role in the material's cobalt and cadmium adsorption capacities. PMID- 25841194 TI - Effect of weathering transformations of coal combustion residuals on trace element mobility in view of the environmental safety and sustainability of their disposal and use. I. Hydrogeochemical processes controlling pH and phase stability. AB - Coal combustion residuals (CCRs) are one of the most abundant high-volume waste materials disposed in impoundments worldwide. Some methods of CCR recycling, e.g. their use as structural fill for low lying areas or as soil amendment, also expose this material to atmospheric conditions. Combustion processes result in concentration of trace elements in CCRs at about an order of magnitude compared to coal. In order to assess an effect of long-term weathering transformations of CCRs on trace element binding/release, a study has been carried out. It is based on the chemical composition of real pore solutions extracted from the most abundant primary alkaline Class F bituminous CCRs, 0 to >40 years old, sampled from the surface layer and vertical profiles at four different impoundments. In this part of the study, results of a hydrogeochemical simulation of the saturation state of real pore solutions with respect to mineral phases of CCRs with use of the PHREEQC program, related to actual pH values reflecting the full cycle of weathering transformations, have been discussed. This study is the first geochemical proof of the general trend towards a progressive acidification up to pH < 4 of primary alkaline CCRs due to release of protons during internal processes of formation of gibbsite and aluminosilicate minerals, buffered by carbonates at the alkaline - near-neutral stages, and followed by parallel dissolution and buffering by aluminosilicates at pH < 7 after carbonate depletion, to the level up to pH~3.5-4.0. The intrinsic geochemical changes have resulted in the different susceptibility of trace elements to release and associated changes in risk to the environment at consecutive stages of weathering. PMID- 25841195 TI - Cattle-derived microbial input to source water catchments: An experimental assessment of stream crossing modification. AB - The provision of safe drinking water is a global issue, and animal production is recognized as a significant potential origin of human infectious pathogenic microorganisms within source water catchments. On-farm management can be used to mitigate livestock-derived microbial pollution in source water catchments to reduce the risk of contamination to potable water supplies. We applied a modified Before-After Control Impact (BACI) design to test if restricting the access of livestock to direct contact with streams prevented longitudinal increases in the concentrations of faecal indicator bacteria and suspended solids. Significant longitudinal increases in pollutant concentrations were detected between upstream and downstream reaches of the control crossing, whereas such increases were not detected at the treatment crossing. Therefore, while the crossing upgrade was effective in preventing cattle-derived point source pollution by between 112 and 158%, diffuse source pollution to water supplies from livestock is not ameliorated by this intervention alone. Our findings indicate that stream crossings that prevent direct contact between livestock and waterways provide a simple method for reducing pollutant loads in source water catchments, which ultimately minimises the likelihood of pathogenic microorganisms passing through source water catchments and the drinking water supply system. The efficacy of the catchment as a primary barrier to pathogenic risks to drinking water supplies would be improved with the integration of management interventions that minimise direct contact between livestock and waterways, combined with the mitigation of diffuse sources of livestock-derived faecal matter from farmland runoff to the aquatic environment. PMID- 25841197 TI - Coumarin sharing the benzene ring with quinoline for quenching radicals and inhibiting DNA oxidation. AB - Fifteen 8-substituted-phenyl-6-ferrocenyl-4-methyl-2H-pyrano[3,2-g]quinolin-2 ones were synthesized via Povarov three-component reaction, in which the substituted aromatic aldehydes reacted with ferrocenylacetylene and 7-amino-4 methylcoumarin in the presence of Ce(OTf)3 as the catalyst. The obtained coumarin fused quinolines were applied to quench 2,2'-azinobis(3-ethylbenzothiazoline-6 sulfonate) cationic radical (ABTS(+)) and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH) and to inhibit 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation of DNA. It was found that the ferrocenyl group attaching to pyrano[3,2 g]quinolin-2-one scaffold can trap radicals and inhibit DNA oxidation even in the absence of phenolic hydroxyl group. The inhibitory effects on radicals and DNA oxidation can be further enhanced by the electron-donating groups such as p-(N,N dimethyl amino)phenyl, ferrocenyl, and furan-2-yl group at 8-position. Therefore, ferrocenyl-substituted pyrano[3,2-g]quinolin-2-one skeleton together with electron-donating groups became a novel structural style for antioxidants. PMID- 25841196 TI - Synthesis and pharmacological evaluation of novel bisindole derivatives bearing oximes moiety: identification of novel proapoptotic agents. AB - In an effort to develop potent anti-cancer chemopreventive agents, a novel series of bisindole derivatives bearing oxime moiety were synthesized. Structures of all compounds were characterized by NMR and HRMS. Anti-proliferative activities for all of these compounds were investigated by the method of MTT assay on 7 human cancer lines and the normal cell lines (HUVEC). Most of them showed a noteworthy anti-cancer activity in vitro, the half maximal inhibitory concentration (IC50) value is 4.31 MUM of 4e against T24. The results from Hoechst 33258 and acridine orange/propidium iodide staining as well as annexinV-FITC assays provided evidence for an apoptotic cell death. The further mechanisms of compound 4e induced apoptosis in T24 cells demonstrated that compound 4e induced the productions of ROS, and altered anti- and pro-apoptotic proteins, leading to mitochondrial dysfunction and activations of caspase-9 and caspase-3 for causing cell apoptosis. Moreover, the cell cycle analysis and western-blot analysis indicated that compound 4e effectively arrested T24 cells in G1 stage and possibly has an effect on cell cycle regulatory proteins particularly cyclin D1. PMID- 25841198 TI - Discovery of N-benzoxazol-5-yl-pyrazole-4-carboxamides as nanomolar SQR inhibitors. AB - Succinate-ubiquinone oxidoreductase (SQR, EC 1.3.5.1, complex II), an essential component of cellular respiratory chain and tricarboxylic acid (or Krebs) cycle, has been identified as one of the most significant targets for pharmaceutical and agrochemical. Herein, with the aim of discovery of new antibacterial lead structure, a series of N-benzoxazol-5-yl-pyrazole-4-carboxamides were designed, synthesized, and evaluated for their SQR inhibitory effects. Very promisingly, one candidate (Ki = 11 nM, porcine SQR) was successfully identified as the most potent synthetic SQR inhibitor so far. The further inhibitory kinetics studies revealed that the candidate is non-competitive with respect to the substrate cytochrome c and DCIP. Computational simulations revealed that the titled compounds have formed hydrogen bond with D_Y91 and B_W173 and the pyrazole ring formed cation-pi interaction with C_R46. In addition, in R(1) position, -CHF2 group has increased the binding affinity and decreased the entropy contribution, while -CF3 group displayed completely opposite effect when bound with SQR. The results of the present work showed that N-benzoxazol-5-yl-pyrazole-4-carboxamide is a new scaffold for discovery of SQR inhibitors and worth further study. PMID- 25841199 TI - Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents. AB - A series of novel ursolic acid (UA) derivatives modified at the C-3 and the C-28 positions were designed and synthesized in an attempt to develop potential antitumor agents. The in vitro cytotoxicity were evaluated against five cancer cell lines (MGC-803, HCT-116, T24, HepG2 and A549 cell lines) and a normal cell (HL-7702) by MTT assay. The screening results indicated that some of these target compounds displayed moderate to high levels of antiproliferative activities compared with ursolic acid and 5-fluorouracil (5-FU), and exhibited much lower cytotoxicity than 5-FU, indicating that the targeted compounds had selective and significant effect on the cell lines. The induction of apoptosis and affects on the cell cycle distribution of compound 6r were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which revealed that the antitumor activity of 6r was possibly achieved through the induction of cell apoptosis by G1 cell-cycle arrest. Western blot and qRT-PCR (quantitative real-time PCR) experiments demonstrated that compound 6r may induce apoptosis through both of intrinsic and extrinsic apoptosis pathway. PMID- 25841200 TI - Design, synthesis, in vitro antiproliferative evaluation, and kinase inhibitory effects of a new series of imidazo[2,1-b]thiazole derivatives. AB - Design and synthesis of a new series of 5,6-diarylimidazo[2,1-b]thiazole derivatives possessing terminal aryl sulfonamide moiety are described. Their in vitro antiproliferative activities against a panel of 57 human cancer cell lines of nine different cancer types were tested at the NCI. Compounds 8a, 8b, 8n, 8q, 8t, and 8u showed the highest mean % inhibition values over the 57 cell line panel at 10 MUM, and they were further tested in 5-dose testing mode to determine their IC50 values. Among the six compounds, compound 8u possessing terminal para hydroxybenzenesulfonamido moiety and ethylene linker showed the highest potency. It demonstrated superior potency than Sorafenib against eight different cell lines, and was equipotent to Sorafenib against COLO 205 colon cancer cell line. Its IC50 values over NCI-H460 non-small cell lung cancer cell line and MCF7 breast cancer cell line were 0.845 MUM and 0.476 MUM, respectively. Compounds 8a, 8b, 8q, 8t, and 8u showed high selectivity indices towards cancer cells over L132 normal lung cell line. Compound 8u showed potential inhibitory effects over the components of ERK pathway. Its IC50 value over V600E-B-RAF and C-RAF kinases were 39.9 nM and 19.0 nM, respectively. PMID- 25841201 TI - Synthesis, characterization and anticancer activity of gold(I) complexes that contain tri-tert-butylphosphine and dialkyl dithiocarbamate ligands. AB - Two new gold(I) complexes that contain tri-ter-butylphosphine and dialkyl dithiocarbamate ligands were synthesized and characterized by FTIR, NMR spectroscopy, Cyclic voltammetry, elemental analysis and X-ray diffraction. The in vitro cytotoxicity of both complexes was examined against A549 (lung cancer), MCF7 (breast cancer), and HeLa (cervical cancer) human cancer cell lines. Both complexes exhibit very strong in vitro cytotoxic effects against A549, MCF7 and HeLa cell lines. The screening of the cytotoxic activity based on IC50 data against the A549, MCF7, and HeLa lines shows that the synthesized gold(I) complexes are highly effective, particularly against HeLa cancer cell line. Based on IC50 data, the cytotoxic activity of both complexes is better than well-known commercial anticancer drug cisplatin against all the three cancer lines tested. PMID- 25841202 TI - Calcium-ion-modulated ceramic hydroxyapatite resin for the scalable purification of recombinant Adeno-Associated Virus serotype 9. AB - Column chromatography has been widely used as a scalable purification strategy for recombinant adeno-associated virus (rAAV) vectors. The rAAV1, 2, 4, 5, 6, 8 and 9 serotypes could be separated using affinity resins, ion exchange resins or other types of resins. Apatite resin has displayed outstanding performance in protein purification in the past 10 years, and ceramic hydroxyapatite (CHT) chromatography resin with a polyethylene glycol (PEG) modulation has recently been used for rAAV1 and rAAV9 vectors. This study reports the use of CHT chromatography modulated by calcium ions instead of PEG for rAAV9 purification. Calcium-ion-containing buffers effectively improve the inclusion of CHT as a capture resin, the resin-binding capacity and the yield. The optimum calcium ion concentration is 30ppm, and the optimum pH is 7.0. A frontal analysis indicated that the binding capacity of CHT at 2ml/min reaches 65.1mg total protein per ml of resin. A previously developed purification strategy consists of CHT followed by ANX anion exchange chromatography. The vector yield of this approach is approximately 70%, and a software analysis indicated a vector purity exceeding 98%. The residual host cell (HEK293) protein contents are 24.75+/-2.32ng and 67.21+/-2.10ng, and the Benzonase residue contents are 1.55+/-0.10pg and 1.95+/ 0.16ng per 10(13) vector genome copies (G.C.) separated by CHT/ANX and CsCl. In addition, CHT/ANX yields 798.44+/-50.10pg of plasmid DNA and 2.17+/-0.11ng of HEK293 DNA, while CsCl purification yields 840.27+/-76.14pg of plasmid DNA and 2.43+/-0.19 of HEK293 DNA. The two methods produce vectors with similar in vitro and in vivo potencies. The results indicated that the CHT/ANX method is suitable for the scalable purification of the rAAV9 vector. PMID- 25841203 TI - Development of a SPE-HPLC-MS/MS method for the determination of most prescribed pharmaceuticals and related metabolites in urban sewage samples. AB - Based on regional prescription data several pharmaceuticals with variable amounts of prescription and corresponding metabolites were selected and analyzed in influent and effluent samples of the sewage treatment plant (STP) in Dresden, Germany. Pharmaceuticals of the following most prescribed therapeutic groups were chosen: antibiotics, antifungals, anticonvulsants, antipsychotics, antidepressants, and cardiovascular active compounds like beta blockers and angiotensin-converting enzyme inhibitors. To analyze the selected compounds, a multi-target method was developed and applied to 24-h composite wastewater samples for three single days in May and June 2014. The method was based on a cleanup of a sample with a volume of 1mL using solid phase extraction followed by a high performance liquid chromatography coupled to a tandem mass spectrometer. Analytes were separated in a 15min chromatographic separation and quantified using 23 Internal Standards and a calibration curve in 40-fold diluted blank urine. The limit of quantification varied between 50 and 200ng/L and for all analytes good accuracy and precision as well as linearity for the calibration curve with the correlation coefficient R(2) higher than 0.99 was reached. A total of 41 and 40 of the selected 55 analytes were detected and quantified in the influent and effluent samples of the studied STP, respectively. Valsartan was the compound with the highest maximum concentration in influent (27.1MUg/L) and effluent (15.7MUg/L). Furthermore, analytes like bezafibrate, candesartan, carbamazepine, gabapentin, metoprolol, levetiracetam, pregabalin and telmisartan as well as the metabolite O-desmethyl venlafaxine were detectable in influent and effluent samples, respectively, with a concentration higher than 1MUg/L. PMID- 25841204 TI - The effects of sad prosody on hemispheric specialization for words processing. AB - This study examined the effect of sad prosody on hemispheric specialization for word processing using behavioral and electrophysiological measures. A dichotic listening task combining focused attention and signal-detection methods was conducted to evaluate the detection of a word spoken in neutral or sad prosody. An overall right ear advantage together with leftward lateralization in early (150-170 ms) and late (240-260 ms) processing stages was found for word detection, regardless of prosody. Furthermore, the early stage was most pronounced for words spoken in neutral prosody, showing greater negative activation over the left than the right hemisphere. In contrast, the later stage was most pronounced for words spoken with sad prosody, showing greater positive activation over the left than the right hemisphere. The findings suggest that sad prosody alone was not sufficient to modulate hemispheric asymmetry in word-level processing. We posit that lateralized effects of sad prosody on word processing are largely dependent on the psychoacoustic features of the stimuli as well as on task demands. PMID- 25841205 TI - Metabolic fate of cardiac glycosides and flavonoids upon fermentation of aqueous sea squill (Drimia maritima L.) extracts. AB - Sea squill (Drimia maritima L.) extracts have been used for centuries for the medical treatment of heart diseases. A procedure for the preparation of Drimia extracts applied for such purposes comprising a fermentation step is described in the German Homoeopathic Pharmacopoeia (GHP). However, little is known about the secondary metabolite profile of such extracts and the fate of these components upon processing and storage. Thus, in the present study sea squill extracts were monitored during fermentation and storage by HPLC-DAD-MS(n) and GC-MS to characterise and quantitate individual cardiac glycosides and phenolic compounds. For this purpose, a previously established HPLC method for the separation and quantitation of pharmacologically relevant cardiac glycosides (bufadienolides) was validated. Within 12 months of storage, total bufadienolide contents decreased by about 50%, which was attributed to microbial and plant enzyme activities. The metabolisation and degradation rates of individual bufadienolide glycosides significantly differed, which was attributed to differing structures of the aglycones. Further degradation of bufadienolide aglycones was also observed. Besides reactions well known from human metabolism studies, dehydration of individual compounds was monitored. Quantitatively predominating flavonoids were also metabolised throughout the fermentation process. The present study provides valuable information about the profile and stability of individual cardiac glycosides and phenolic compounds in fermented Drimia extracts prepared for medical applications, and expands the knowledge of cardiac glycoside conversion upon microbial fermentation. PMID- 25841207 TI - Cation transporters/channels in plants: Tools for nutrient biofortification. AB - Cation transporters/channels are key players in a wide range of physiological functions in plants, including cell signaling, osmoregulation, plant nutrition and metal tolerance. The recent identification of genes encoding some of these transport systems has allowed new studies toward further understanding of their integrated roles in plant. This review summarizes recent discoveries regarding the function and regulation of the multiple systems involved in cation transport in plant cells. The role of membrane transport in the uptake, distribution and accumulation of cations in plant tissues, cell types and subcellular compartments is described. We also discuss how the knowledge of inter- and intra-species variation in cation uptake, transport and accumulation as well as the molecular mechanisms responsible for these processes can be used to increase nutrient phytoavailability and nutrients accumulation in the edible tissues of plants. The main trends for future research in the field of biofortification are proposed. PMID- 25841208 TI - Recently fixed carbon allocation in strawberry plants and concurrent inorganic nitrogen uptake through arbuscular mycorrhizal fungi. AB - Most crop species form a symbiotic association with arbuscular mycorrhizal (AM) fungi, receiving plant photosynthate and exchanging nutrients from the soil. The plant carbon (C) allocation to AM fungi and the nitrogen feedback are rarely studied together. In this study, a dual (13)CO2 and (15)NH4(15)NO3 pulse labeling experiment was carried out to determine the allocation of recent photosynthates to mycorrhizal hyphae and the translocation of N absorbed by hyphae to strawberry plants. Plants were grown in pots in which a 50 MUm mesh net allowed the physical separation of the mycorrhizal hyphae from the roots in one portion of the pot. An inorganic source of (15)N was added to the hyphal compartment at the same time of the (13)CO2 pulse labeling. One and seven days after pulse labeling, the plants were destructively harvested and the amount of the recently fixed carbon (C) and of the absorbed N was determined. (13)C allocated to belowground organs such as roots and mycorrhizal hyphae accounted for an average of 10%, with 4.3% allocated to mycorrhizal hyphae within the first 24h after the pulse labeling. Mycorrhizae absorbed labeled inorganic nitrogen, of which almost 23% was retained in the fungal mycelium. The N uptake was linearly correlated with the (13)C fixed by the plants suggesting a positive correlation between a plant photosynthetic rate and the hyphal absorption capacity. PMID- 25841206 TI - Cell fate commitment during mammalian sex determination. AB - The gonads form bilaterally as bipotential organs that can develop as testes or ovaries. All secondary sex characteristics that we associate with 'maleness' or 'femaleness' depend on whether testes or ovaries form. The fate of the gonads depends on a cell fate decision that occurs in a somatic cell referred to as the 'supporting cell lineage'. Once supporting cell progenitors commit to Sertoli (male) or granulosa (female) fate, they propagate this decision to the other cells within the organ. In this review, we will describe what is known about the bipotential state of somatic and germ cell lineages in the gonad and the transcriptional and antagonistic signaling networks that lead to commitment, propagation, and maintenance of testis or ovary fate. PMID- 25841209 TI - Proteomic and biochemical responses of canola (Brassica napus L.) exposed to salinity stress and exogenous lipoic acid. AB - To evaluate the mitigating effects of exogenous lipoic acid (LA) on NaCl toxicity, proteomic, biochemical and physiological changes were investigated in the leaves of canola (Brassica napus L.) seedlings. Salinity stress decreased the growth parameters and contents of ascorbate (AsA) and glutathione (GSH), and increased the contents of malondialdehyde (MDA), proline, cysteine and the activities of antioxidant enzymes such as superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX). The foliar application of LA alleviated the toxic effects of salinity stress on canola seedlings and notably decreased MDA content and increased growth parameters, cysteine content, and activities of CAT and POD. In the proteomic analyses, total proteins from the leaves of control, LA, NaCl and NaCl+LA treated-seedlings were separated using two-dimensional gel electrophoresis (2-DE). A total of 28 proteins were differentially expressed. Of these, 21 proteins were successfully identified by MALDI-TOF/TOF MS. These proteins had functions related to photosynthesis, stress defense, energy metabolism, signal transduction, protein folding and stabilization indicating that LA might play important roles in salinity through the regulation of photosynthesis, stress defense and signal transduction related proteins. The proteomic findings have provided new insight to reveal the effect of LA on salinity stress for the first time. PMID- 25841210 TI - Unconscious attention modulates the silencing effect of top-down predictions. AB - The brain is considered to be proactive in that it continuously generates predictions about external environment stimuli. Recent Bayesian models of perception have demonstrated that prediction and attention operate synergistically to optimize stimulus processing. However, the relation between prediction and unconscious attention remains unclear given the relative neglect of unconscious attention in scholarly literatures. To investigate this issue, twenty participants (12 women) performed an orientation identification task in which a circular grating appeared either in the left or in the right visual field in a single 30-40min session, during which 64-channel EEG data were acquired. Behavioral results showed an unconscious-attended effect and a facilitated effect. Importantly, prediction-related P1 and N1 silencing effects were observed in the unconscious-attended condition, probably reflecting that unconscious attention improves the precision of top-down predictions at an early stage of processing, thereby increasing the synaptic gain of predictor neurons. Moreover, unlike the early ERP components, P3 revealed a reversed pattern of results, which displayed a silencing effect of prediction only in the unattended condition, suggesting that the influence of unconscious attention on the silencing effect may change over time. PMID- 25841211 TI - Benzonphenone-type UV filters in urine of Chinese young adults: Concentration, source and exposure. AB - Benzophenone (BP)-type UV filters are commonly used in our daily life. 2-hydroxy 4-methoxy benzophenone (BP-3), 4-hydroxy benzophenone (4-HBP), 2,4-dihydroxy benzophenone (BP-1), 2,2',4,4'-tetrahydroxy benzophenone (BP-2) and 2,2' dihydroxy-4-methoxy benzophenone (BP-8) were measured in urine samples from Chinese young adults. The results indicated that Chinese young adults were widely exposed to BP-3, BP-1, and 4-HBP, with the median concentrations of 0.55, 0.21, and 0.08 ng/mL, respectively. No significant difference was found between males and females, between urban and rural population. The correlations between urinary concentrations provided important indications for sources and metabolic pathways of target compounds. The estimated daily excretion doses of BP-3, 4-HBP, BP-1, BP 2 and BP-8 were 27.2, 2.24, 5.86, 0.76 and 0.30 ng/kg-bw/day, respectively. The ratio of exposure to excretion must be considered for the exposure assessment with chemicals based on urine measurement. This is the first nationwide study on BP-derivatives with young adults in China. PMID- 25841212 TI - Contaminants of legacy and emerging concern in terrestrial passerines from a nature reserve in South China: Residue levels and inter-species differences in the accumulation. AB - Knowledge is limited about the bioaccumulation of persistent halogenated compounds (PHCs) in terrestrial wildlife. Several PHCs, including dichlorodiphenyltrichloroethane (DDT) and its metabolites (designated as DDTs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), decabromodiphenylethane (DBDPE) and 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), and stable isotopes (delta(15)N and delta(13)C) were analyzed in the muscle of four terrestrial passerines, Parus major, Copsychus saularis, Pycnonotus sinensis and Pycnonotus jocosus, from a nature reserve in South China. P. major had the highest PHC concentrations, with median values of 1060, 401, 92, 25 and 0.3 ng/g lipid weight for DDTs, PCBs, PBDEs, DBDPE and BTBPE, respectively. Fractions of DDT in P. jocosus and PCBs 153, 118 and 180 in C. saularis were higher compared with the other species. The inter-species differences in PHC concentrations and profiles could be attributed to the differences in trophic level, diet, living habits and metabolic capacity among the birds. PMID- 25841213 TI - Chaotropicity: a key factor in product tolerance of biofuel-producing microorganisms. AB - Fermentation products can chaotropically disorder macromolecular systems and induce oxidative stress, thus inhibiting biofuel production. Recently, the chaotropic activities of ethanol, butanol and vanillin have been quantified (5.93, 37.4, 174kJ kg(-1)m(-1) respectively). Use of low temperatures and/or stabilizing (kosmotropic) substances, and other approaches, can reduce, neutralize or circumvent product-chaotropicity. However, there may be limits to the alcohol concentrations that cells can tolerate; e.g. for ethanol tolerance in the most robust Saccharomyces cerevisiae strains, these are close to both the solubility limit (<25%, w/v ethanol) and the water-activity limit of the most xerotolerant strains (0.880). Nevertheless, knowledge-based strategies to mitigate or neutralize chaotropicity could lead to major improvements in rates of product formation and yields, and also therefore in the economics of biofuel production. PMID- 25841214 TI - The intensive margin of technology adoption--Experimental evidence on improved cooking stoves in rural Senegal. AB - Today, almost 3 billion people in developing countries rely on biomass as primary cooking fuel, with profound negative implications for their well-being. Improved biomass cooking stoves are alleged to counteract these adverse effects. This paper evaluates take-up and impacts of low-cost improved stoves through a randomized controlled trial. The randomized stove is primarily designed to curb firewood consumption, but not smoke emissions. Nonetheless, we find considerable effects not only on firewood consumption, but also on smoke exposure and, consequently, smoke-related disease symptoms. The reduced smoke exposure results from behavioural changes in terms of increased outside cooking and a reduction in cooking time. We conclude that in order to assess the effectiveness of a technology-oriented intervention, it is critical to not only account for the incidence of technology adoption - the extensive margin - but also for the way the new technology is used - the intensive margin. PMID- 25841215 TI - Double-faceted mechanism of parvoviral oncosuppression. AB - The H-1 parvovirus (H-1PV) exerts oncosuppressive action that has two components: oncotoxicity and immunostimulation. While many human tumor cells, including conventional drug-resistant ones, can be killed by H-1PV, some fail to support progeny virus production, necessary for infection propagation in neoplastic tissues. This limitation can be overcome through forced selection of H-1PV variants capable of enhanced multiplication and spreading in human tumor cells. In the context of further developing H-1PV for use in cancer therapy, arming it with immunostimulatory CpG motifs under conditions preserving replication and oncolysis enhances its action as an anticancer vaccine adjuvant. A first clinical study of H-1PV treatment in glioma patients has yielded evidence of intratumoral synthesis of the viral oncotoxic protein NS1 and immune cell infiltration. PMID- 25841216 TI - The influence of low-temperature degradation and cyclic loading on the fracture resistance of monolithic zirconia molar crowns. AB - The present study analyzed the kinetics of low-temperature degradation (LTD) in zirconia, and evaluated the influence of LTD and cyclic loading on the fracture resistance of monolithic zirconia molar crowns. Bar-shaped zirconia specimens were divided into nine groups and autoclaved at 134 degrees C for 0-200h to induce LTD. The surface fraction and penetration depth of the monoclinic phase were examined using X-ray diffraction and scanning electron microscopy. Monolithic zirconia molar crowns were prepared for crown fracture testing. The crowns were autoclaved for 0-100h (n=6) and cemented to dies. Six crown-die samples that were not autoclaved and six samples that were autoclaved for 100h were subjected to cyclic loading with a load of 300N for 240,000 cycles. All samples were tested in a load-to-failure test. The monoclinic fraction on the surface increased with autoclaving time and reached a plateau after 50h. The depth of the monoclinic phase increased without reaching a plateau. The fracture load of the crowns significantly decreased from 5683N (SD: 342) to 3975N (SD: 194) after 100h of autoclaving. Cyclic loading did not significantly affect the fracture resistance of the crowns in all cases. Kinetic analysis showed no linear correlation between the surface fraction and depth of the monoclinic phase after 50h of autoclaving. Even though LTD increased the monoclinic phase, resulting in lower strength, the fracture resistance of the monolithic zirconia crowns was still sufficient to withstand the loading conditions in the molar regions. PMID- 25841217 TI - Comparison of disordered eating symptoms and emotion regulation difficulties between female college athletes and non-athletes. AB - The purpose of the study was to compare the prevalence of disordered eating between female college athletes and non-athletes and explore emotion regulation as a potential mediator of the link between participation in athletics and disordered eating symptoms. Data for this cross-sectional study came from 527 college students in a mid-western state of the USA in fall of 2013 (376 non athletes and 151 athletes). Disordered eating symptoms and emotion regulation were assessed utilizing the Eating Attitudes Test and the Difficulties with Emotion Regulation Scale in a survey-based format. The prevalence of disordered eating was higher in non-athletes (16.5%, vs. 6.6%; X(2)=62.8; p<.05). Non athletes reported more signs and symptoms of disordered eating than athletes (p<.01). A linear regression approach indicated a statistically significant indirect effect (0.63, CI95=0.18, 1.20) of athletic-status on disordered eating via emotion regulation; however, this effect did not reach practical significance. Our findings show that female athletes in our sample were somewhat protected from disordered eating compared to non-athletes, but the mechanism of this relationship is unclear. A further in-depth examination of other factors, such as self-esteem and body satisfaction, that may have contributed to this finding is warranted utilizing a large sample of female college students and athletes representing a variety of sports. PMID- 25841218 TI - Associations between aspects of friendship networks and dietary behavior in youth: Findings from a systematized review. AB - OBJECTIVE: To gather and synthesize current evidence on the associations between aspects of friendship networks (e.g., friends' dietary behavior, popularity) and an individual's dietary behavior among children and adolescents. METHODS: A systematic search of six scientific online databases was conducted in August 2013. Eligible studies included child or adolescent participants (aged 6 to 18years), a measure of each participant's friendship network, and a measure of habitual dietary behavior for both the participant and the participant's nominated friend(s). Data on study design, participant characteristics, friendship networks, dietary behavior, and study outcomes were abstracted. RESULTS: From a total of 9041 articles retrieved, seven studies were included in this review. Overall, friends' unhealthy food consumption was associated with an individual's unhealthy food consumption, and this association appeared to be stronger for boys compared with girls. More popular adolescents also tended to consume more unhealthy foods. Best friends' total energy intake was correlated with an individual's total energy intake. Similarities among friends' healthy food consumption, as well as daily breakfast consumption, were inconclusive. Longitudinal evidence showed that an individual's unhealthy food consumption tended to become similar to friends' unhealthy food consumption over time. CONCLUSIONS: Social network analysis in the adolescent dietary behavior literature is beginning to emerge. Results highlight friends' particular influence on unhealthy food consumption among adolescents. Focus on modeling healthy dietary behaviors among adolescent friendship group may help reduce unhealthy dietary behaviors and promote healthy weight status among youth. PMID- 25841219 TI - Response inhibition and sustained and attention in Heavy smokers versus non smokers. AB - BACKGROUND: Repeated nicotine administration induces neuro-adaptations associated with abnormal dopaminergic activity. These neuronal changes may contribute to impaired inhibitory control and attention deficit. However, it remains unclear whether smokers perform worse than non-smokers on tests that involve attention and control of impulsivity. The present study examined response inhibition and sustained attention capacities in a large sample of smokers and non-smokers. METHODS: Continuous Performance Test (CPT) and Go/ NoGo computerized tasks were used as a measure of response-inhibition ability and sustained attention. Threeway repeated measures analysis of covariance was used with response time, variability of response time, number of commission errors (inappropriate responses to stimuli) and number of omission errors (missed stimuli) as dependent measures. Main effects were: group (smokers and controls), condition (CPT and Go/NoGo), and block (in each condition); gender, education, and age were used as covariates. RESULTS AND CONCLUSIONS: Smokers, as compared to the control group, made more errors of commission in the Go/ NoGo task, reflecting impaired inhibition ability. However, we found no significant differences between the groups in our measure of sustained attention. Impaired response inhibition was found to co-occur with heavy smoking and therefore may be a potential target for the development of more effective cessation programs. PMID- 25841220 TI - The Prevalence of Alcohol, Substance and Cigarettes Exposure among Pregnant Women within a General Hospital and the Compliance to Brief Intervention for Exposure Reduction. AB - BACKGROUND: Compliance and impact of a time-limited brief intervention (BI) for reducing exposure to alcohol, psychoactive substances and nicotine among women admitted to the hospital during pregnancy were assessed. METHODS: Pregnant women (gestational week <=30) from a medical center pre-delivery, emergency and high risk units were interviewed about alcohol (AUDIT and TWEAK questionnaires), smoking (modified Fagerstrom) and psychoactive substance (modified ASI). All exposed women were invited to participate in a BI and underwent follow-up. Characteristics and rate of exposure were compared to a "standard-group" of non selected women who arrived to the hospital directly solely to give birth. RESULTS: Forty-six of the 108 study participants (42.6%) were exposed to smoking (85%), alcohol (41%), or drugs (39%), and 41 underwent the BI. Self-report of exposure was reduced significantly following BI but re-elevated post-delivery. Women belonging to the "standardgroup" were better educated, had lower lifetime rates of exposure, and gave birth to newborns with higher birth weights (3254.7+/ 506.9 g vs. 2650.8+/-785.6 g for the study group). CONCLUSION: Compliance of the exposed women to BI was high and contributed to exposure reduction during pregnancy but relapsed following delivery. PMID- 25841221 TI - Clinical Correlates of Alcohol Abuse among Adolescent Psychiatric Inpatients in Israel. AB - BACKGROUND: Recent epidemiological studies have reported a world-wide increase in the rates of alcohol use among adolescents. Research has shown a strong link between alcohol abuse and psychiatric disorders. This study explored the clinical and demographic correlates of adolescents with a history of alcohol abuse (AA) compared to adolescents with no history of alcohol abuse (NAA) among a group of adolescent psychiatric inpatients in Israel. METHOD: Two hundred and thirty-eight subjects were screened, all were patients consecutively admitted to an adolescent inpatient unit at a university-affiliated mental health center in Israel during a 4-year period RESULT: Patients in the AA group were more prone to have a history of suicide attempts and self-injury compared to patients in the NAA group. Prevalence of attentiondeficit disruptive behavior disorders was more common in the AA group, and these patients were more prone to have a history of criminal activity and drug use. Median length of hospitalization was greater in the NAA group. LIMITATIONS: Limitations concerning attribution of causality due to the cross-sectional nature of this study. CONCLUSION: Higher prevalence of criminal behavior, selfinjury and suicide attempts associated with alcohol abuse may be related to higher levels of impulsivity, indicated by higher prevalence of attention-deficit disruptive behavior disorders. Alcohol-related disorders should be carefully screened and addressed in adolescent psychiatric units and in consequent ambulatory treatment settings. PMID- 25841222 TI - Emerging issues in the relationship between adolescent substance use and suicidal behavior. AB - Adolescent suicidal behavior poses a major global public health concern as it is highly prevalent and associated with mortality and morbidity worldwide. Substanceuse disorders are also an issue of increasing concern among adolescents and have been shown to increase the risk for suicidal behaviors. In this review we address emerging issues in the relationship between adolescent substance use disorders and suicidal behaviors. We focus on common hazardous patterns of substance abuse such as binge drinking and poly-substance abuse and point out developing patterns of substance preferences as evidenced by the contemporary widespread use of synthetic cannabinoids. We address these issues in the context of vulnerable populations such as sexual-minority adolescents and youth with co occurring mental-disorder diagnoses. Finally, we relate to the present and future challenges presented by these issues to implement effective anti-suicidal treatment and prevention strategies in adolescents with substance use disorders. PMID- 25841223 TI - Cannabis Withdrawal - A New Diagnostic Category in DSM-5. AB - BACKGROUND: Cannabis withdrawal was not formally recognized by the DSM-IV classification but is listed, albeit without diagnostic criteria by ICD-10. The American Psychiatric Association recently has included cannabis withdrawal into DSM-5 classification as part of the "Substance-Related and Addictive Disorders" Section. However, many psychiatrists as well as other medical professionals have very little information, if at all, about the new diagnostic entity. METHOD: The information was obtained from PubMed (research words: Cannabis, THC, Hashish, Marijuana and Withdrawal). The different clinical symptoms of the phenomena as well as some pathophysiological mechanisms and treatment considerations were summarized and discussed. RESULTS AND CONCLUSIONS: A substantial amount of scientific data has been obtained in recent years concerning reliability, validity and clinical importance of cannabis withdrawal.The possible influence of cannabis withdrawal on the severity of major psychiatric disturbances is far from being understood and deserves further research. LIMITATIONS: The reviewed studies varied in sample size, design and methodology limiting clear conclusions. PMID- 25841224 TI - Synthetic Cannabis Substances (SPS) Use and Hallucinogen Persisting Perception Disorder (HPPD): Two Case Reports. AB - Hallucinogen Persistent Perceptual Disorder (HPPD) is a clinical syndrome characterized by the recurrence of distressing perceptual disturbances which previously emerged during primary hallucinogen intoxication, in the absence of recent use. Here we present two patients who developed HPPD following use of Synthetic Cannabis Substances (SCS), with no prior history of natural-occurring or synthetic hallucinogen use. Both cases had a prior history of cannabis dependence and current tobacco dependence. In both cases patients reported the presence of visual disturbances when smoking SCS and staring at stationary and moving objects. Both patients discontinued SCS use abruptly after suffering from a panic attack under the influence of SCS. Despite cessation of SCS, both patients continued to suffer from HPPD which was accompanied by significant anxiety. Following clonazepam treatment, both subjects reported significant improvement in symptoms and remained with a residual focal visual disturbance which was not accompanied by significant anxiety. To the best of our knowledge these are the first reports of HPPD following SCS use. In light of the increasing use of SCS, clinical psychiatrists should be aware of these perceptual side effects. PMID- 25841225 TI - Buprenorphine for opiate dependence: clinic based therapy in Israel. AB - BACKGROUND: Opioid dependency is characterized by repeated use of an opioid drug despite physical dependence, behavioral impairments and social dysfunction. Therapeutic approaches for the treatment of opioid dependence are total abstinence and opioid agonist maintenance treatment (OAMT). Opiate agonist maintenance therapy is administered using opioid replacement pharmacological agents, i.e., methadone or buprenorphine. Methadone acts as a full opiate agonist while buprenorphine acts as a partial agonist. Strict supervision is necessary when dispensing methadone, because overdose can be fatal. Buprenorphine associates with opioid receptors slowly but with high affinity, and dissociation from the receptor site is (pseudo) irreversible. It is safer than opioid full agonists such as methadone. METHODS: We probed the therapeutic efficacy of buprenorphine using a retrospective evaluation of numerical data in the first private buprenorphine clinic in Israel. Data was collected for all patients attending the clinic in December 2012. Our indicator for treatment success is retention in the program. RESULTS: During the years 2005-2012, 1,399 individuals approached the clinic; 1,224 (87.5%) of them attended the clinic at least twice; treatment adherence in this group was 66.5 % at the end of one year. CONCLUSIONS: The success rates of patients who are treated with buprenorphine and are able to eventually return to their families and re-enter the workforce is encouraging. Thus, the community based minimal intervention treatment model using buprenorphine for the treatment of opiate dependence is a viable treatment option in the war against opiate abuse. PMID- 25841226 TI - Benzodiazepine usage during 19.5 years in methadone maintenance treatment patients and its relation to long-term outcome. AB - BACKGROUND: Benzodiazepines (BDZs) abuse was found to cause diverse harmful effects among MMT patients. The current study evaluates prevalence rates of BDZ usage during 19.5 years in MMT, and its relation to patients' long-term retention in treatment. METHODS: All 787 opiate addicts who were ever admitted to the Adelson MMT clinic in Tel Aviv between 1993 and 2012 were studied. Observed and random urine results for BDZs usage were taken a few times every month. Positive for BDZ was defined in each month if at least one of the urines tested positive. Long-term retention was studied using Kaplan Meier analyses. RESULTS: BDZ prevalence among the MMT patients (ranged from 26 patients in 1994, and 300 to 350 since 2009) was about 35-40% in the last few years, with a "peak" of 61% followed by low rate of 25.4%. Followed up for up to 19.5 years, those who were negative to BDZ upon admission to MMT stayed longer in treatment (mean 8.5y, 95% Confidence Interval [CI] 7.6-9.4) than those who were positive to BDZ when admitted (mean 6.9y, 95% CI 6.2-7.7) (Kaplan Meier analyses p=0.01). CONCLUSION: BDZs abuse is highly prevalent among MMT patients. Abuse of BDZ on entry to treatment predicts worse MMT outcome. High and low rates of BDZ abuse may also be attributed to staff tolerance of this abuse; thus, we strongly recommend a strict attitude by staff in order to reduce patients' harm. PMID- 25841227 TI - Evaluating the clinical impact of involuntary admission to a specialized dual diagnosis ward. AB - BACKGROUND: We aimed to identify characteristics and outcomes of involuntary and voluntary admissions of dual-diagnosis patients in a single, large mental health center in Israel. METHODS: Using a retrospective chart review methodology, 24 patient records were reviewed spanning a period of five years; clinical and demographic variables of voluntary and involuntary admissions were compared. RESULTS: No significant differences were found in sociodemographic characteristics, admission diagnosis and length of hospitalization between the two types of admission. A smaller proportion of patients discharged from involuntary admissions were in remission compared to those discharged from voluntary admission. Nevertheless, involuntary admissions were associated with longer time to next hospitalization. LIMITATIONS: The data were based on a small number of patients in a single ward, thus the generalizability of the results is uncertain. CONCLUSIONS: The finding of the current study that involuntary admission leads to longer tenure in the community suggests that there may be clinical advantages to involuntary admissions for certain dual diagnosis patients. PMID- 25841228 TI - Flashbacks and HPPD: A Clinical-oriented Concise Review. AB - A unique characteristic of LSD, LSD-like and substances with hallucinogenic properties is the recurrence of some or all the hallucinogenic symptoms which had appeared during the intoxication after the immediate effects of the substance had worn off. This recurring syndrome, mainly visual, is not clearly understood. The terms Flashback and Hallucinogen Persisting Perception Disorder (HPPD) have been used interchangeably in the professional literature. We have observed at least two different recurrent syndromes, the first Flashback Type we refer to as HPPD I, a generally short-term, non-distressing, benign and reversible state accompanied by a pleasant affect. In contrast, the second HPPD Type we refer to as HPPD II, a generally long-term, distressing, pervasive, either slowly reversible or irreversible, non-benign state accompanied by an unpleasant affect. HPPD I and II appear to be part of a broad spectrum of non-psychopathological and psychopathological states reported by hallucinogen users. HPPD I and II may be clinically characterized by prodromal symptoms, onset, content of visual imagery, precipitators, frequency, duration and intensity of perceptual recurrences, severity, course, differential diagnosis, accompanying mood and affect, insight and remission. Pharmacological therapy with or without preceding or following co occurring psychiatric disorders have been shown to ameliorate this syndrome. A large variety of medications may be utilized to alleviate this condition, but with differential results suggesting several subtypes. The purpose of this manuscript is to provide a clinical-oriented, comprehensive and concise review to treating psychiatrists. PMID- 25841229 TI - A model for treating HCV hepatitis in patients receiving methadone maintenance therapy. AB - INTRODUCTION: Although hepatitis C virus (HCV) is associated with substance abuse, treatment of addicts is problematic. We report the results of a pilot scheme for treatment of HCV - infected substance abusers in a methadone maintenance center (MMC). METHODS: The treatment program was carried out at a single MMC. Patients were not using illicit drugs or alcohol and received regular treatment with methadone. The program consisted of 5 stages: 1. An explanatory lecture concerning HCV (50/114 attended). 2. 25 of the 50 presented for examination including HCV RNA, genotype and viral load. 3. HCV treatment with pegylated alfa-interferon-1b and ribavarin. 4. The MMC physician and staff aided the clients' medical compliance. 5. A hepatologist (SM) volunteered his services on the basis of one 3 hourly session every 4-6 weeks, in addition to open access telephone consultation with the MMC staff physician. RESULTS: 50 of 114 HCV seropositive clients attended the initial meeting , 25 (50%) were candidates for treatment, of whom 20 were treated. 10 had genotype 3 infection, 9 genotype 1 and 1 genotype 2. The sustained virological response (SVR) on an intention-to-treat basis was 8/20 (40%). DISCUSSION: We present a model for the successful treatment of chronic HCV hepatitis in patients receiving methadone. PMID- 25841230 TI - LSD Flashbacks - The Appearance of New Visual Imagery Not Experienced During Initial Intoxication: Two Case Reports. AB - A side effect associated with the use of synthetic hallucinogens such as lysergic acid diethylamide-(LSD) is the partial or total recurrence of perceptual disturbances which previously appeared during intoxication, despite absence of recent use. These are commonly referred to as "flashbacks" or Hallucinogen Persisting Perception Disorder (HPPD). Here we present two cases of patients with a prior history of LSD use who turned to psychiatric consultation following brief episodes of HPPD. Surprisingly, in both cases new visual imagery appeared during episodes of flashbacks which was not experienced during primary LSD use. Both subjects reported the ability to discern between LSD-associated visual disturbances and new visual imagery. This phenomenon did not cause functional impairment and in both cases caused gradual concern due to its persistence. Both patients refused medical treatment and continued psychiatric follow-up. At one year follow-up both patients reported almost complete spontaneous remission. To the best of our knowledge these are the first reported cases of LSD-related benign flashbacks in which new imagery is experienced. Reasons for this reversible and apparently harmless side effect are proposed. Conclusions from case reports should be taken with caution. PMID- 25841231 TI - Intercostal chest drain insertion by general physicians: attitudes, experience and implications for training, service and patient safety. AB - BACKGROUND: Intercostal chest drain (ICD) insertion is considered a core skill for the general physician. Recent guidelines have highlighted the risks of this procedure, while UK medical trainees have reported a concurrent decline in training opportunities and confidence in their procedural skills. OBJECTIVES: We explored clinicians' attitudes, experience and knowledge relating to pleural interventions and ICD insertion in order to determine what changes might be needed to maintain patient safety and quality of training. METHODS: Consultants and trainees delivering general medical services across five hospitals in England were invited to complete a questionnaire survey over a 5-week period in July and August 2014. RESULTS: 117 general physicians (32.4% of potential participants; comprising 31 consultants, 48 higher specialty trainees, 38 core trainees) responded. Respondents of all grades regarded ICD insertion as a core procedural skill. Respondents were asked to set a minimum requirement for achieving and maintaining independence at ICD insertion; however, only 25% of higher specialty trainees reported being able to attain this self-imposed standard. A knowledge gap was also revealed, with trainees managing clinical scenarios correctly in only 51% of cases. CONCLUSIONS: Given the disparity between clinical reality and what is expected of the physician-in-training, it is unclear whether ICD insertion can remain a core procedural skill for general physicians. Consideration should be given to how healthcare providers and training programmes might address issues relating to clinical experience and knowledge given the implications for patient safety and service provision. PMID- 25841232 TI - HFE gene mutation and oxidative damage biomarkers in patients with myelodysplastic syndromes and its relation to transfusional iron overload: an observational cross-sectional study. AB - OBJECTIVE: A relation between transfusional IOL (iron overload), HFE status and oxidative damage was evaluated. DESIGN, SETTING AND PARTICIPANTS: An observational cross-sectional study involving 87 healthy individuals and 78 patients with myelodysplastic syndromes (MDS) with and without IOL, seen at University Hospital of the Federal University of Ceara, Brazil, between May 2010 and September 2011. METHODS: IOL was defined using repeated measures of serum ferritin >=1000 ng/mL. Variations in the HFE gene were investigated using PCR/restriction fragment length polymorphism (RFLP). The biomarkers of oxidative stress (plasmatic malonaldehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD)) were determined by spectrophotometry. RESULTS: The HFE gene variations were identified in 24 patients (30.77%) and 5 volunteers (5.74%). The H63D variant was observed in 35% and the C282Y variant as heterozygous in 5% of patients with MDS with IOL. One patient showed double heterozygous variant (C282Y/H63D) and serum ferritin of 11,649 ng/mL. In patients without IOL, the H63D variant was detected in 29.34%. Serum MDA levels were highest in patients with MDS with IOL, with a significant difference when compared with patients without IOL and healthy volunteers, pointing to the relationship between IOL and oxidative stress. The GPx and SOD were also significantly higher in these patients, indicating that lipid peroxidation increase was followed by an increase in antioxidant capacity. Higher ferritin levels were observed in patients with HFE gene variation. 95.7% of patients with MDS with the presence of HFE gene variations had received more of 20 transfusions. CONCLUSIONS: We observed a significant increase in MDA levels in patients with MDS and IOL, suggesting an increased lipid peroxidation in these patients. The accumulation of MDA alters the organisation of membrane phospholipids, contributing to the process of cellular degeneration. Results show that excess iron intensifies the process of cell damage through oxidative stress. TRIAL REGISTRATION NUMBER: Local Ethics Committee (licence 150/2009). PMID- 25841234 TI - Recovery of photoreceptor inner and outer segment layer thickness after reattachment of rhegmatogenous retinal detachment. AB - AIMS: To evaluate the recovery of retinal function and the thicknesses of the photoreceptor inner (IS) and outer segment (OS) layers after a reattachment of a rhegmatogenous retinal detachment (RRD). METHODS: 49 eyes of 49 patients (mean age, 57.4+/-10.3 years) with successfully reattached RRD were retrospectively studied. Spectral-domain optical coherence tomography was used to obtain images of the foveal area, and the thicknesses of the IS and OS were measured before and 1, 3, 6 and 12 months after surgery. The thicknesses of the corresponding structures of the healthy fellow eye served as control. RESULTS: The thickness of the IS layer was 20.4+/-5.0 MUm and that of the OS layer was 34.4+/-9.7 at 1 month after surgery, which was significantly thinner than the IS (28.9+/-2.9) and OS (55.4+/-5.2) layers of the fellow eyes. The thicknesses gradually increased and were not significantly different from that in the fellow eye at 12 months (IS, 28.4+/-4.4 um and OS, 50.7+/-6.6 um). The IS and OS thicknesses at 1 month after surgery in eyes that had a decimal visual acuity of 1.0 at 6 months were significantly thicker than those in eyes that had a visual acuity of <1.0. CONCLUSIONS: The increase in the thicknesses of the IS and OS layers of the photoreceptors during the recovery phase of eyes with RRD indicates that the recovery process was slow and gradual. Quantitative analysis of the IS and OS thicknesses may be useful to follow the disease process. PMID- 25841233 TI - The Australian public's preferences for emergency care alternatives and the influence of the presenting context: a discrete choice experiment. AB - OBJECTIVES: The current study seeks to quantify the Australian public's preferences for emergency care alternatives and determine if preferences differ depending on presenting circumstances. SETTING: Increasing presentations to emergency departments have led to overcrowding, long waiting times and suboptimal health system performance. Accordingly, new service models involving the provision of care in alternative settings and delivered by other practitioners continue to be developed. PARTICIPANTS: A stratified sample of Australian adults (n=1838), 1382 from Queensland and 456 from South Australia, completed the survey. This included 951 females and 887 males from the 2045 people who met the screening criteria out of the 4354 people who accepted the survey invitation. INTERVENTIONS: A discrete choice experiment was used to elicit preferences in the context of one of four hypothetical scenarios: a possible concussion, a rash/asthma-related problem involving oneself or one's child and an anxiety related presentation. Mixed logit regression was used to analyse the dependent variable choice and identify the relative importance of care attributes and the propensity to access care in each context. RESULTS: Results indicated a preference for treatment by an emergency physician in hospital for possible concussion and treatment by a doctor in ambulatory settings for rash/asthma related and anxiety-related problems. Participants were consistently willing to wait longer before making trade-offs in the context of the rash/asthma-related scenario compared with when the same problem affected their child. Results suggest a clear preference for lower costs, shorter wait times and strong emphasis on quality care; however, significant preference heterogeneity was observed. CONCLUSIONS: This study has increased awareness that the public's emergency care choices will differ depending on the presenting context. It has further demonstrated the importance of service quality as a determinant of healthcare choices. The findings have also provided insights into the Australian public's reactions to emergency care reforms. PMID- 25841235 TI - Six-month changes in cytokine levels after intravitreal bevacizumab injection for diabetic macular oedema and macular oedema due to central retinal vein occlusion. AB - BACKGROUND/AIMS: This study evaluated the impact of intravitreal injection of bevacizumab (IVB) on the microenvironment of the eyes of diabetic macular oedema (DMO) and macular oedema due to central retinal vein occlusion (CRVO-MO) patients. METHODS: This study comprised 136 patients, including 51 patients in the DMO group, 70 in the CRVO-MO group and 15 in the control group, who were followed for 6 months after IVB. Angiogenic cytokines, inflammatory cytokines and growth factors concentrations in the aqueous humour were measured before and after IVB using suspension array technology. We compared the levels of cytokines among DMO patients, CRVO-MO patients and control patients. We compared the levels of cytokines among groups according to the interval between the first and second injections of bevacizumab and according to the number of injections received during the 6-month follow-up period. RESULTS: Significantly higher concentrations of vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), hepatocyte growth factor (HGF), interleukin 6 (IL-6), serum amyloid A (SAA) and monocyte chemoattractant protein-1 (MCP-1) were found in the aqueous humour of DMO and CRVO-MO patients compared with cataract patients. One month after IVB, the intraocular concentrations of VEGF were significantly decreased in the eyes of DMO (p=0.045) and CRVO-MO (p=0.002) patients compared with baseline. No other cytokine was significantly altered by bevacizumab therapy. CONCLUSIONS: Angiogenic, inflammatory and growth factors are involved in the development of DMO and CRVO-MO. In addition to VEGF, IVB did not cause significant differences in other inflammatory cytokines and growth factors in DMO and CRVO-MO patients. PMID- 25841236 TI - Perinatal paracetamol exposure in mice does not affect the development of allergic airways disease in early life. AB - BACKGROUND: Current data concerning maternal paracetamol intake during pregnancy, or intake during infancy and risk of wheezing or asthma in childhood is inconclusive based on epidemiological studies. We have investigated whether there is a causal link between maternal paracetamol intake during pregnancy and lactation and the development of house dust mite (HDM) induced allergic airways disease (AAD) in offspring using a neonatal mouse model. METHODS: Pregnant mice were administered paracetamol or saline by oral gavage from the day of mating throughout pregnancy and/or lactation. Subsequently, their pups were exposed to intranasal HDM or saline from day 3 of life for up to 6 weeks. Assessments of airway hyper-responsiveness, inflammation and remodelling were made at weaning (3 weeks) and 6 weeks of age. RESULTS: Maternal paracetamol exposure either during pregnancy and/or lactation did not affect development of AAD in offspring at weaning or at 6 weeks. There were no effects of maternal paracetamol at any time point on airway remodelling or IgE levels. CONCLUSIONS: Maternal paracetamol did not enhance HDM induced AAD in offspring. Our mechanistic data do not support the hypothesis that prenatal paracetamol exposure increases the risk of childhood asthma. PMID- 25841239 TI - Altered microbiota in microscopic colitis. PMID- 25841238 TI - Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. AB - OBJECTIVES: The tumour stroma/microenvironment not only provides structural support for tumour development, but more importantly it provides cues to cancer stem cells (CSCs) that regulate their self-renewal and metastatic potential. This is certainly true for pancreatic ductal adenocarcinomas (PDAC), where tumour associated fibroblasts, pancreatic stellate cells and immune cells create an abundant paracrine niche for CSCs via microenvironment-secreted factors. Thus understanding the role that tumour stroma cells play in PDAC development and CSC biology is of utmost importance. DESIGN: Microarray analyses, tumour microarray immunohistochemical assays, in vitro co-culture experiments, recombinant protein treatment approaches and in vivo intervention studies were performed to understand the role that the immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) plays in PDAC biology. RESULTS: We found that hCAP-18/LL 37 was strongly expressed in the stroma of advanced primary and secondary PDAC tumours and is secreted by immune cells of the stroma (eg, tumour-associated macrophages) in response to tumour growth factor-beta1 and particularly CSC secreted Nodal/ActivinA. Treatment of pancreatic CSCs with recombinant LL-37 increased pluripotency-associated gene expression, self-renewal, invasion and tumourigenicity via formyl peptide receptor 2 (FPR2)- and P2X purinoceptor 7 receptor (P2X7R)-dependent mechanisms, which could be reversed by inhibiting these receptors. Importantly, in a genetically engineered mouse model of K-Ras driven pancreatic tumourigenesis, we also showed that tumour formation was inhibited by either reconstituting these mice with bone marrow from cathelicidin related antimicrobial peptide (ie, murine homologue of hCAP-18/LL-37) knockout mice or by pharmacologically inhibiting FPR2 and P2X7R. CONCLUSIONS: Thus, hCAP 18/LL-37 represents a previously unrecognised PDAC microenvironment factor that plays a critical role in pancreatic CSC-mediated tumourigenesis. PMID- 25841240 TI - Stimulating hepatocyte renewal: a new paradigm for the treatment of severe alcoholic hepatitis unresponsive to corticosteroids? PMID- 25841237 TI - Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. AB - BACKGROUND: The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease (COPD) is unclear. The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists (LAMA), when combined with an inhaled corticosteroid (ICS) and a long acting beta2 agonist (LABA). METHODS: This randomised, blinded, placebo controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium (GLY) 50 ug, once-daily tiotropium (TIO) 18 ug or placebo (PLA), when combined with salmeterol/fluticasone propionate (SAL/FP) 50/500 ug twice daily. The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP on trough FEV1 after 12 weeks. An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone. RESULTS: 773 patients (mean FEV1 57.2% predicted) were randomised; 84.9% completed the trial. At week 12, GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP for trough FEV1: least square mean treatment difference (LSMdiff) -7 mL (SE 17.4) with a lower limit for non-inferiority of -60 mL. There was significant increase in week 12 trough FEV1 with GLY+SAL/FP versus PLA+SAL/FP (LSMdiff 101 mL, p<0.001). At 12 weeks, GLY+SAL/FP produced significant improvement in St George's Respiratory Questionnaire total score versus PLA+SAL/FP (LSMdiff -2.154, p=0.02). GLY+SAL/FP demonstrated significant rescue medication reduction versus PLA+SAL/FP (LSMdiff 0.72 puffs/day, p<0.001). Serious adverse events were similar for GLY+SAL/FP, TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8%, 8.5% and 5.8%, respectively. CONCLUSIONS: GLY+SAL/FP showed comparable improvements in lung function, health status and rescue medication to TIO+SAL/FP. Importantly, addition of GLY to SAL/FP demonstrated significant improvements in lung function, health status and rescue medication compared to SAL/FP. TRIAL REGISTRATION NUMBER: NCT01513460. PMID- 25841241 TI - Socioeconomic inequalities in smoking cessation in 11 European countries from 1987 to 2012. AB - BACKGROUND: During the 1990s, inequalities in smoking prevalence by socioeconomic status (SES) have widened in Europe. Since then, many tobacco control policies have been implemented. Yet, European overviews of recent trends in smoking inequalities are lacking. This paper aims to provide an overview of long-term trends of socioeconomic inequalities in smoking cessation in Europe. METHODS: We used data for 11 countries taken from Eurobarometer surveys from 1987 to 1995 and 2002-2012, with a total study sample of 63 737 respondents. We performed multilevel logistic regression to model associations of the quit ratio (proportion former smokers of ever smokers) with SES, measured by education and occupation separately, with adjustments for age, sex and time. RESULTS: We found a significant, positive association for education and occupation with the quit ratio. The strength of the association decreased slightly from 1987 to 1995 and increased again from 2002 to 2012. Inequalities increased between the two periods in most countries and decreased in only one country. While in 1987-1995, the quit ratio increased among all SES groups and most strongly among the low SES group, in 2002-2012 it increased only among the high-education group (OR=1.38, 95% CI 1.02 to 1.87), and non-manual occupation group (OR=1.59, 95% CI 1.19 to 2.12). CONCLUSIONS: Socioeconomic inequalities in smoking cessation rates have strongly increased since the 1990s and during the 2000s. This suggests that the tobacco control policies implemented during the 2000s have not been able to counter the trend in increasing inequalities. PMID- 25841242 TI - Brief interventions to prevent recurrence and alcohol-related problems in young adults admitted to the emergency ward following an alcohol-related event: a systematic review. AB - BACKGROUND: Brief interventions addressing harmful alcohol use in adults admitted to emergency wards have been shown to be effective. The evidence in relation to interventions aimed at adolescents is less conclusive. Young adults share developmental characteristics with adolescents, while receiving care in adult services. We conducted a systematic review to assess the effectiveness of interventions to reduce the recurrence of alcohol-related events and their consequences in young adults (18-24 years) admitted to an emergency ward following alcohol intoxication. METHODS: We followed PRISMA guidelines to conduct this review. We searched Medline, Embase, Cochrane and PsychINFO, until March 2014. We included randomised trials of brief interventions aimed at young adults admitted to an emergency ward following an alcohol-related event. Two investigators independently selected, analysed, rated and summarised the evidence from relevant studies. RESULTS: Four trials (n=618) were included, comparing a brief motivational interview with usual care (2 trials), personalised feedback or an educational brochure. In two studies, motivational interview was significantly associated with a reduction in alcohol-use while two studies showed no effect attributable to the intervention. Successful interventions were either delivered at a distance from the event or included booster sessions. Motivational interview favoured a reduction in alcohol-related problems in all but one study. Benefits were sustained over 12 months. CONCLUSIONS: The evidence is inconclusive, but the most effective interventions include at least one therapeutic contact several days after the event. Further research should provide more guidance about effective interventions in this age-group as well as about ways to favour delayed attendance for treatment. The potential role of parents or peers in supporting treatment also warrants further attention. PMID- 25841244 TI - Coronary artery bypass graft surgery provides clinically important quality-of life improvements over medical therapy in patients with ischaemic left ventricular dysfunction. PMID- 25841243 TI - Patterns and correlates of objectively measured free-living physical activity in adults in rural and urban Cameroon. AB - BACKGROUND: Urbanisation in sub-Saharan Africa is changing lifestyles and raising non-communicable disease burden. Understanding the underlying pattern of physical activity and its correlates may inform preventive interventions. We examined correlates of objectively-measured physical activity in rural and urban Cameroon. METHODS: Participants were 544 adults resident in rural (W-156, M-89) or urban (W 189, M-110) regions. Physical activity was measured using individually-calibrated combined heart rate and movement sensing over seven continuous days. Sociodemographic data were collected by self-report. Independent associations of sociodemographic correlates with physical activity energy expenditure (PAEE) or moderate-to-vigorous physical activity (MVPA) were analysed in multivariate regression models. RESULTS: Rural dwellers were significantly more active than their urban counterparts (PAEE: 58.0 vs 42.9 kJ/kg/day; MVPA: 107 vs 62 min/day; MVPA of 150 min/week in >10 min bouts: 62 vs 39%) and less sedentary (923 vs 1026 min/day); p<0.001. There was no significant seasonal difference (dry vs rainy) in activity in urban dwellers whereas in rural dwellers activity was higher during dry seasons compared to rainy seasons (p<0.001). Age, obesity and education showed significant inverse associations with activity. Urban dwellers who considered themselves adequately active were only as active as rural dwellers who thought they were not adequately active. CONCLUSIONS: This is the first study providing data on sociodemographic patterning of objectively-measured physical activity in rural and urban sub-Saharan Africa. Age, urban residence, obesity and higher educational level are important correlates of lower levels of physical activity. These suggest targets for public health interventions to improve physical activity in Cameroon. PMID- 25841245 TI - Impact of a GRADE-based medical question answering system on physician behaviour: a randomised controlled trial. AB - Physicians are frequently faced with questions related to their patients' care that they cannot answer. A vast number of randomised trials have tested a wide variety of behaviour-changing strategies designed to improve practitioners' evidence utilisation, but systematic reviews have concluded that the effects are generally small and inconsistent. We conducted a randomised controlled trial to determine whether a question identification and solving system, using structured evidence summaries with recommendations, would change physician's behavior related to the care of their hospitalised patients. The trial was conducted at the secondary level, internal medicine ward. Relevant clinical questions were the units of randomisation; 14 clinicians participated in the study. The question identification and answering system was carried out using evidence summaries with recommendations based on the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach stressing influence on clinician behaviour (decision/recommendation concordance). During 131 morning reports, 553 questions were identified (4.2 questions per meeting). 398 were excluded because they were not about diagnostic or therapeutic interventions or because their answers could not have impact on clinician behaviour, and 31 were excluded because of lack of time to answer them, leaving 124 included questions. The proportion of clinical decisions concordant with the proposed recommendations was 79%in the intervention arm and 44% in the control arm: relative risk 1.8 (95% CI 1.3 to 2.4), number of evidence summaries needed to change a care decision for one question raised was 3 (95% CI 2 to 6). A question identification and answering system was feasible, effectively performed and significantly influenced clinician behaviour related to the care of hospitalised patients, which suggests that interventions facilitating accessibility and interpretability of the best available evidence at the point of care have the potential to significantly impact on the quality of healthcare. PMID- 25841246 TI - The human papillomavirus vaccination is not associated with risk of multiple sclerosis or other demyelinating diseases. PMID- 25841247 TI - Prenatal and postnatal exposure to parental smoking increases odds of allergic diseases during childhood and adolescence. PMID- 25841248 TI - Ocular histoplasmosis syndrome. AB - Ocular histoplasmosis syndrome (OHS) is a chorioretinal disorder with a distinct fundus appearance that is commonly found in regions endemic for Histoplasma capsulatum. Choroidal neovascularization (CNV) secondary to OHS is considered one of the principal causes of central vision loss among young adults in endemic areas. Although there is no consensus regarding its pathogenesis, evidence points to Histoplasma capsulatum as the most probable etiology. Once considered an intractable hemorrhagic maculopathy, CNVs are now treatable. Extrafoveal CNVs are successfully treated with laser photocoagulation. Subfoveal and juxtafoveal CNVs are managed with anti-vascular endothelial growth factor therapy, photodynamic therapy, or a combination of both. Modern imaging technologies such as spectral domain optical coherence tomography have improved our diagnostic abilities, making it easier to monitor disease activity and CNV regression. We review the epidemiology, pathogenesis, clinical manifestations, differential diagnosis, and current treatment of this disease. PMID- 25841249 TI - Mechanisms of enhanced insulin secretion and sensitivity with n-3 unsaturated fatty acids. AB - The widespread acceptance that increased dietary n-3 polyunsaturated fatty acids (PUFAs), especially alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), improve health is based on extensive studies in animals, isolated cells and humans. Visceral adiposity is part of the metabolic syndrome, together with insulin resistance, dyslipidemia, hypertension and inflammation. Alleviation of metabolic syndrome requires normalization of insulin release and responses. This review assesses our current knowledge of the mechanisms that allow n-3 PUFAs to improve insulin secretion and sensitivity. EPA has been more extensively studied than either ALA or DHA. The complex actions of EPA include increased G-protein-receptor-mediated release of glucagon-like peptide 1 (GLP-1) from enteroendocrine L-cells in the intestine, up-regulation of the apelin pathway and down-regulation of other control pathways to promote insulin secretion by the pancreatic beta-cells, together with suppression of inflammatory responses to adipokines, inhibition of peroxisome proliferator activated receptor alpha actions and prevention of decreased insulin-like growth factor-1 secretion to improve peripheral insulin responses. The receptors involved and the mechanisms of action probably differ for ALA and DHA, with antiobesity effects predominating for ALA and anti-inflammatory effects for DHA. Modifying both GLP-1 release and the actions of adipokines by n-3 PUFAs could lead to additive improvements in both insulin secretion and sensitivity. PMID- 25841250 TI - White and dark kidney beans reduce colonic mucosal damage and inflammation in response to dextran sodium sulfate. AB - Common beans are a rich source of nondigestible fermentable components and phenolic compounds that have anti-inflammatory effects. We assessed the gut health-promoting potential of kidney beans in healthy mice and their ability to attenuate colonic inflammation following dextran sodium sulphate (DSS) exposure (via drinking water, 2% DSS w/v, 7 days). C57BL/6 mice were fed one of three isocaloric diets: basal diet control (BD), or BD supplemented with 20% cooked white (WK) or dark red kidney (DK) bean flour for 3 weeks. In healthy mice, anti inflammatory microbial-derived cecal short chain fatty acid (SCFA) levels (acetate, butyrate and propionate), colon crypt height and colonic Mucin 1 (MUC1) and Resistin-like Molecule beta (Relmbeta) mRNA expression all increased in WK- and DK-fed mice compared to BD, indicative of enhanced microbial activity, gut barrier integrity and antimicrobial defense response. During colitis, both bean diets reduced (a) disease severity, (b) colonic histological damage and (c) increased mRNA expression of antimicrobial and barrier integrity-promoting genes (Toll-like Receptor 4 (TLR4), MUC1-3, Relmbeta and Trefoil Factor 3 (TFF3)) and reduced proinflammatory mediator expression [interleukin (IL)-1beta, IL-6, interferon (IFN)gamma, tumor necrosis factor (TNF)alpha and monocyte chemoattractant protein-1], which correlated with reduced colon tissue protein levels. Further, bean diets exerted a systemic anti-inflammatory effect during colitis by reducing serum levels of IL-17A, IFNgamma, TNFalpha, IL-1beta and IL 6. In conclusion, both WK and DK bean-supplemented diets enhanced microbial derived SCFA metabolite production, gut barrier integrity and the microbial defensive response in the healthy colon, which supported an anti-inflammatory phenotype during colitis. Collectively, these data demonstrate a beneficial colon function priming effect of bean consumption that mitigates colitis severity. PMID- 25841252 TI - Leptin, adiposity, and mortality: results from the National Health and Nutrition Examination Survey III, 1988 to 1994. AB - OBJECTIVE: To determine whether leptin is related to all-cause and cardiovascular (CV) mortality in older adults. PATIENTS AND METHODS: Participants 60 years and older with plasma leptin level measurements from the National Health and Nutrition Examination Survey III (1988-1994) and mortality data linked to the National Death Index were included. We created sex-specific tertiles of leptin (men: 4.2-7.7 MUg/L; women: 11.5-21.4 MUg/L) to identify the effect of leptin on all-cause and CV mortality. We also determined whether leptin predicted mortality in patients with obesity. We classified obesity using 4 possible definitions: body mass index 30 kg/m(2) or greater; body fat 25% or more in men and 35% or more in women; waist circumference 102 cm or greater in men and 88 cm or greater in women; and waist-hip ratio 0.85 or higher in women and 0.95 or higher in men. Sex-specific proportional hazard models were used to assess the effect of leptin on all-cause and CV mortality. RESULTS: Of 1794 participants, 51.6% were women; the mean age was 70.3+/-0.4 years, and the follow-up period was 12.5 years with 994 deaths (469 were CV deaths). All-cause mortality in the highest leptin tertile was significant neither in men (hazard ratio [HR], 1.23; 95% CI, 0.93 1.63) nor in women (HR, 0.97; 95% CI, 0.68-1.40). CV mortality was the highest in the highest leptin tertile in men (HR, 1.69; 95% CI, 1.06-2.70) but not in women (HR, 1.21; 95% CI, 0.73-1.98). Evaluating the effect of leptin in subgroups of different obesity definitions, we found that high leptin levels as predict CV mortality in men as measured by waist circumference or body fat. CONCLUSION: Elevated leptin level is predictive of CV mortality only in men. Leptin may provide additional mortality discrimination in obese men. PMID- 25841251 TI - Digital health interventions for the prevention of cardiovascular disease: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the potential benefit of digital health interventions (DHIs) on cardiovascular disease (CVD) outcomes (CVD events, all-cause mortality, hospitalizations) and risk factors compared with non-DHIs. PATIENTS AND METHODS: We conducted a systematic search of PubMed, MEDLINE, EMBASE, Web of Science, Ovid, CINHAL, ERIC, PsychINFO, Cochrane, and Cochrane Central Register of Controlled Trials for articles published from January 1, 1990, through January 21, 2014. Included studies examined any element of DHI (telemedicine, Web-based strategies, e-mail, mobile phones, mobile applications, text messaging, and monitoring sensors) and CVD outcomes or risk factors. Two reviewers independently evaluated study quality utilizing a modified version of the Cochrane Collaboration risk assessment tool. Authors extracted CVD outcomes and risk factors for CVD such as weight, body mass index, blood pressure, and lipid levels from 51 full-text articles that met validity and inclusion criteria. RESULTS: Digital health interventions significantly reduced CVD outcomes (relative risk, 0.61; 95% CI, 0.46-0.80; P<.001; I(2)=22%). Concomitant reductions in weight ( 2.77 lb [95% CI, -4.49 to -1.05 lb]; P<.002; I(2)=97%) and body mass index (-0.17 kg/m(2) [95% CI, -0.32 kg/m(2) to -0.01 kg/m(2)]; P=.03; I(2)=97%) but not blood pressure (-1.18 mm Hg [95% CI, -2.93 mm Hg to 0.57 mm Hg]; P=.19; I(2)=100%) were found in these DHI trials compared with usual care. In the 6 studies reporting Framingham risk score, 10-year risk percentages were also significantly improved (-1.24%; 95% CI, -1.73% to -0.76%; P<.001; I(2)=94%). Results were limited by heterogeneity not fully explained by study population (primary or secondary prevention) or DHI modality. CONCLUSION: Overall, these aggregations of data provide evidence that DHIs can reduce CVD outcomes and have a positive impact on risk factors for CVD. PMID- 25841253 TI - The "delivery" of Adam: a medical interpretation of Michelangelo. AB - This article describes what we believe to be the key to interpreting the concept represented by Michelangelo's painting the Creation of Adam. This fresco, one of his most famous masterpieces, is situated in the heart of the Sistine Chapel and is viewed by millions of people every year. A man of many talents, Michelangelo's proficiency in anatomical dissection is reflected in his artwork. As such, analyses of hidden meanings in this fresco have been ascribed, including the concept of the "Brain-God." However, we see a postpartum uterus and adjacent anatomy, justifying our interpretation that Michelangelo was depicting something far more fundamental: the birth of mankind. PMID- 25841254 TI - Nonexercise activity thermogenesis in obesity management. AB - Obesity is linked to cardiovascular disease. The global increase in sedentary lifestyle is an important factor contributing to the rising prevalence of the obesity epidemic. Traditionally, counseling has focused on moderate- to vigorous intensity exercise, with disappointing results. Nonexercise activity thermogenesis (NEAT) is an important component of daily energy expenditure. It represents the common daily activities, such as fidgeting, walking, and standing. These high-effect NEAT movements could result in up to an extra 2000 kcal of expenditure per day beyond the basal metabolic rate, depending on body weight and level of activity. Implementing NEAT during leisure-time and occupational activities could be essential to maintaining a negative energy balance. NEAT can be applied by being upright, ambulating, and redesigning workplace and leisure time environments to promote NEAT. The benefits of NEAT include not only the extra calories expended but also the reduced occurrence of the metabolic syndrome, cardiovascular events, and all-cause mortality. We believe that to overcome the obesity epidemic and its adverse cardiovascular consequences, NEAT should be part of the current medical recommendations. The content of this review is based on a literature search of PubMed and the Google search engine between January 1, 1960, and October 1, 2014, using the search terms physical activity, obesity, energy expenditure, nonexercise activity thermogenesis, and NEAT. PMID- 25841255 TI - Optimizing bowel cleansing for colonoscopy. AB - Adequate bowel cleansing is essential for complete examination of the colon mucosa during colonoscopy. Suboptimal bowel preparation has potential adverse consequences, such as missed pathologic abnormalities, the need for repeated procedures, and increased procedure-related complications. Several factors can predict individuals at increased risk for inadequate bowel preparation. If predictors of inadequate bowel preparation are identified, then education should be intensified and a more aggressive bowel regimen recommended. On completion of this article, you should be able to (1) define the frequency of inadequate colon preparations, (2) identify predictors of poor bowel preparation, and (3) use a more aggressive bowel regimen when clinically indicated. PMID- 25841256 TI - 42-year-old man with asthma symptoms and recurrent bronchitis. PMID- 25841257 TI - Neuropathic pain: principles of diagnosis and treatment. AB - Neuropathic pain is caused by disease or injury of the nervous system and includes various chronic conditions that, together, affect up to 8% of the population. A substantial body of neuropathic pain research points to several important contributory mechanisms including aberrant ectopic activity in nociceptive nerves, peripheral and central sensitization, impaired inhibitory modulation, and pathological activation of microglia. Clinical evaluation of neuropathic pain requires a thorough history and physical examination to identify characteristic signs and symptoms. In many cases, other laboratory investigations and clinical neurophysiological testing may help identify the underlying etiology and guide treatment selection. Available treatments essentially provide only symptomatic relief and may include nonpharmacological, pharmacological, and interventional therapies. Most extensive evidence is available for pharmacological treatment, and currently recommended first-line treatments include antidepressants (tricyclic agents and serotonin-norepinephrine reuptake inhibitors) and anticonvulsants (gabapentin and pregabalin). Individualized multidisciplinary patient care is facilitated by careful consideration of pain related disability (eg, depression and occupational dysfunction) as well as patient education; repeat follow-up and strategic referral to appropriate medical/surgical subspecialties; and physical and psychological therapies. In the near future, continued preclinical and clinical research and development are expected to lead to further advancements in the diagnosis and treatment of neuropathic pain. PMID- 25841258 TI - Regenerative medicine in diabetes. AB - Diabetes is a common multisystem disease that results in hyperglycemia due to a relative or absolute insulin deficiency. Improved glycemic control decreases the risk of development and progression of microvascular and, to a lesser extent, macrovascular complications and prevents symptomatic hyperglycemia. However, complex treatment regimens aimed at improving glycemic control are associated with an increased incidence of hypoglycemia. On paper at least, cellular therapies arising from reprogramed stem cells or other somatic cell types would provide ideal therapy for diabetes and the prevention of its complications. This hypothesis has led to intensive efforts to grow beta cells from various sources. In this review, we provide an overview of beta-cell development as well as the efforts reported to date in terms of cellular therapy for diabetes. Engineering beta-cell replacement therapy requires an understanding of how beta cells respond to other metabolites such as amino acids, free fatty acids, and ketones. Indeed, efforts thus far have been characterized by an inability of cellular replacement products to adequately respond to metabolites that normally couple the metabolic state to beta-cell function and insulin secretion. Efforts to date intended to capitalize on current knowledge of islet cell development and stimulus-secretion coupling of the beta cell are encouraging but as yet of little clinical relevance. PMID- 25841259 TI - In reply-Maternal, paternal, and societal efforts are needed to "cure" childhood obesity. PMID- 25841260 TI - Maternal, paternal, and societal efforts are needed to "cure" childhood obesity. PMID- 25841261 TI - In reply-Early goal-directed therapy for severe sepsis. PMID- 25841262 TI - Early goal-directed therapy for severe sepsis. PMID- 25841263 TI - Metastatic breast cancer. PMID- 25841264 TI - 64-year-old woman with diarrhea and increased abdominal girth. PMID- 25841265 TI - John E. Walker-Nobel Prize in chemistry in 1997. PMID- 25841267 TI - Cluster headache and trigeminal autonomic cephalgias. PMID- 25841268 TI - [Cleft lip, alveolar and palate sequelae. Proposal of new alveolar score by the Alveolar Cleft Score (ACS) classification]. AB - INTRODUCTION: The management of cleft lip, alveolar and palate sequelae remains problematic today. To optimize it, we tried to establish a new clinical index for diagnostic and prognostic purposes. TECHNICAL NOTE: Seven tissue indicators, that we consider to be important in the management of alveolar sequelae, are listed by assigning them individual scores. The final score, obtained by adding together the individual scores, can take a low, high or maximum value. DISCUSSION: We propose a new classification (ACS: Alveolar Cleft Score) that guides the therapeutic team to a prognosis approach, in terms of the recommended surgical and prosthetic reconstruction, the type of medical care required, and the preventive and supportive therapy to establish. Current studies are often only based on a standard radiological evaluation of the alveolar bone height at the cleft site. However, the gingival, the osseous and the cellular areas bordering the alveolar cleft sequelae induce many clinical parameters, which should be reflected in the morphological diagnosis, to better direct the surgical indications and the future prosthetic requirements, and to best maintain successful long term aesthetic and functional results. PMID- 25841269 TI - [Combined approach of parotid lithiasis. A technical note]. AB - INTRODUCTION: Sialendoscopy, extracorporeal lithotripsy and transoral removal are the usual treatments for parotid lithiasis. These techniques cannot treat all the patients. In fact, removal of lithiasis bigger than the ductal diameter and situated in the middle or posterior third of the duct may fail with such techniques. For this reason the combined approach has been developed. Our technical note describes this procedure. TECHNICAL NOTE: Preoperative check-up needs an ultrasound or a CT scan of the parotid region. The procedure is conducted under general anesthesia. It begins with the localization of the lithiasis with help of the sialendoscope light visible through the skin. A face lift approach is performed giving access to the SMAS that is opened over the lithiasis and the transilluminated area. A window is opened on the duct and the lithiasis is removed. Proximal duct permeability is assessed with the sialendoscope. The different layers are sutured and a suction drainage is left in place. DISCUSSION: Combined approach is indicated in case of failure of conservative techniques. It provides good results in removal of lithiasis located in the posterior or middle thirds of the duct. Its morbidity is low. It can avoid performing a parotidectomy and lowers the risk of facial palsy. In case of failure, botulinum toxin injection may be indicated. PMID- 25841270 TI - Increased incidence of extrapancreatic neoplasms in patients with IPMN: Fact or fiction? A critical systematic review. AB - BACKGROUND: To identify potential associations between intraductal papillary mucinous neoplasm of the pancreas (IPMN) and extrapancreatic neoplasms (EPN), a systematic review of the literature has been performed. METHODS: A systematic search of Medline/Pubmed was performed according to the PRISMA guidelines for reporting systematic reviews and meta-analysis for the following search terms: "extrapancreatic", "non pancreatic", "additional pancreatic", "additional primary" and alternatively matched with "neoplasms/tumours/cancers/malignancies/lesions". The results obtained specifically for IPMN were examined one by one by two independent investigators for further data selection and extraction. RESULTS: Fifteen studies were identified to be suitable and included for systematic review. Fourteen reported an elevated risk for extrapancreatic malignancy, particularly gastric and colon cancer, while the largest and only prospective study did not find any association. Most studies were retrospective with a weak level of evidence that was not substantially enhanced even by a recent multicentre case series. CONCLUSIONS: The available data on this clinically relevant question remain inconclusive. Due to lacking evidence on extrapancreatic neoplasms in IPMN patients, only a standard surveillance can be advised. PMID- 25841271 TI - NEDDylation in liver cancer: The regulation of the RNA binding protein Hu antigen R. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer death. The current view of cancer progression and malignancy supports the notion that cancer cells must undergo through a post translational modification (PTM) regulation and a metabolic switch or reprogramming in order to progress in an unfriendly environment. NEDDylation is a post-translational modification of the proteins involved in several processes such as cell growth, viability and development. A ground-breaking knowledge on a new critical aspect of HCC research has been to identify that NEDDylation plays a role in HCC by regulating the liver oncogenic driver Hu antigen R (HuR). HuR is a RNA-binding protein that stabilizes target mRNAs involved in cell dedifferentiation, proliferation, and survival, all well-established hallmarks of cancer. And importantly, HuR levels were found to be highly representative in liver and colon cancer. These findings open a completely new area of research, exploring the impact that NEDDylation plays in liver diseases and paving the way for novel therapeutical approaches. PMID- 25841272 TI - Editorial. PMID- 25841273 TI - Guest editorial. PMID- 25841274 TI - Current image acquisition options in PET/MR. AB - Whole-body PET/MR hybrid imaging combines excellent soft tissue contrast and various functional imaging parameters provided by MR with high sensitivity and quantification of radiotracer uptake provided by PET. Although clinical evaluation now is under way, PET/MR demands for new technologies and innovative solutions, currently subject to interdisciplinary research. Attenuation correction (AC) of human soft tissues and of hardware components has to be MR based to maintain quantification of PET imaging as CT attenuation information is missing. MR-based AC is inherently associated with the following challenges: patient tissues are segmented into only few tissue classes, providing discrete attenuation coefficients; bone is substituted as soft tissue in MR-based AC; the limited field of view in MRI leads to truncations in body imaging and, consequently, in MR-based AC; and correct segmentation of lung tissue may be hampered by breathing artifacts. Use of time of flight during PET image acquisition and reconstruction, however, may improve the accuracy of AC. This article provides a status of current image acquisition options in PET/MR hybrid imaging. PMID- 25841275 TI - Future image acquisition trends for PET/MRI. AB - Hybrid PET/MRI scanners have become commercially available in the past years but are not yet widely distributed. The combination of a state-of-the-art PET with a state-of-the-art MRI scanner provides numerous potential advantages compared with the established PET/CT hybrid systems, namely, increased soft tissue contrast; functional information from MRI such as diffusion, perfusion, and blood oxygenation level-dependent techniques; true multiplanar data acquisition; and reduced radiation exposure. On the contrary, current PET/MRI technology is hampered by several shortcomings compared with PET/CT, the most important issues being how to use MR data for PET attenuation correction and the low sensitivity of MRI for small-scale pulmonary pathologies compared with high-resolution CT. Moreover, the optimal choice for hybrid PET/MRI acquisition protocols needs to be defined providing the highest possible degree of sensitivity and specificity within the constraints of the available measurement time. A multitude of new acquisition strategies of PET and MRI not only offer to overcome current obstacles of hybrid PET/MRI but also provide deeper insights into the pathophysiology of oncological, inflammatory, or degenerative diseases from the combination of molecular and functional imaging techniques. PMID- 25841277 TI - PET/MR in dementia and other neurodegenerative diseases. AB - The spectrum of neurodegenerative diseases covers the dementias, parkinsonian syndromes, Huntington disease, amyotrophic lateral sclerosis, and prion diseases. In these entities, brain MRI is often used in clinical routine to exclude other pathologies and to demonstrate specific atrophy patterns. [18F]FDG PET delivers early and sensitive readouts of neural tissue loss, and more specific PET tracers currently in use clinically target beta-amyloid plaques or dopaminergic deficiency. The recent integration of PET into MR technology offers a new chance to improve early and differential diagnosis of many neurodegenerative diseases. Initial evidence in the literature is available to support this notion. New emerging PET tracers, such as tracers that bind to tau or alpha-synuclein aggregates, as well as MR techniques, like diffusion-tensor imaging, resting state functional MRI, and arterial spin labeling, have the potential to broaden the diagnostic capabilities of combined PET/MRI to image dementias, Parkinson disease, and other neurodegenerative diseases. The ultimate goal is to establish combined PET/MRI as a first-line imaging technique to provide, in a one-stop-shop fashion with improved patient comfort, all biomarker information required to increase diagnostic confidence toward specific diagnoses. The technical challenge of accurate PET data attenuation correction within PET/MRI systems needs yet to be solved. Apart from the projected clinical routine applications, future research would need to answer the questions of whether combined brain PET/MRI is able to improve basic research of neurodegenerative diseases and antineurodegeneration drug testing. PMID- 25841276 TI - Motion correction options in PET/MRI. AB - Subject motion is unavoidable in clinical and research imaging studies. Breathing is the most important source of motion in whole-body PET and MRI studies, affecting not only thoracic organs but also those in the upper and even lower abdomen. The motion related to the pumping action of the heart is obviously relevant in high-resolution cardiac studies. These two sources of motion are periodic and predictable, at least to a first approximation, which means certain techniques can be used to control the motion (eg, by acquiring the data when the organ of interest is relatively at rest). Additionally, nonperiodic and unpredictable motion can also occur during the scan. One obvious limitation of methods relying on external devices (eg, respiratory bellows or the electrocardiogram signal to monitor the respiratory or cardiac cycle, respectively) to trigger or gate the data acquisition is that the complex motion of internal organs cannot be fully characterized. However, detailed information can be obtained using either the PET or MRI data (or both) allowing the more complete characterization of the motion field so that a motion model can be built. Such a model and the information derived from simple external devices can be used to minimize the effects of motion on the collected data. In the ideal case, all the events recorded during the PET scan would be used to generate a motion-free or corrected PET image. The detailed motion field can be used for this purpose by applying it to the PET data before, during, or after the image reconstruction. Integrating all these methods for motion control, characterization, and correction into a workflow that can be used for routine clinical studies is challenging but could potentially be extremely valuable given the improvement in image quality and reduction of motion-related image artifacts. PMID- 25841278 TI - PET/MRI of the heart. AB - Hybrid imaging devices including PET/CT and SPECT/CT have seen a great success in clinical routine, especially in the field of oncology. With the recent advent of PET/MRI scanners, expectations that PET/MRI would replicate that success were accordingly high. The combination of molecular imaging with a variety of very specific PET tracers and the high spatial resolution of MRI are expected to result in increased diagnostic accuracy or even in the creation of additional demands for hybrid imaging. However, as these systems have entered the market just recently, experience in the field of nuclear cardiology is limited and some applications still need to be validated. Owing to the profound technical differences between CT and MRI, which influences not only the estimation of the photon attenuation but also causes marked differences in the workflow, particularly in cardiovascular studies (such as the need for special personnel training and interaction between nuclear medicine specialists, radiologists, and physicists), the "familiarization phase" with this new technique also seems to be extended. However, the approach to study various conditions such as perfusion, viability, and atherosclerosis in a single imaging examination session using PET and MRI offers advantages. Although MRI allows for a detailed morphologic characterization of the studied tissue, PET adds the information on functional biological markers that are not (or at least not fully) measurable by MRI. Thus, this combined imaging approach will prove valuable in distinct cardiac diseases (such as myocarditis and cardiac sarcoidosis) and will offer vast research opportunities. PMID- 25841279 TI - PET/MR in cancers of the head and neck. AB - One early application of PET/MRI in clinical practice may be the imaging of head and neck cancers. This is because the morphologic imaging modalities, CT and MR, are recognized as similarly effective tools in cross-sectional oncological imaging of the head and neck. The addition of PET with FDG is believed to enhance the accuracy of both modalities to a similar degree. However, there are a few specific scenarios in head and neck cancer imaging where MR is thought to provide an edge over CT, including perineural spread of tumors and the infiltration of important anatomical landmarks, such as the prevertebral fascia and great vessel walls. Here, hybrid PET/MR might provide higher diagnostic certainty than PET/CT or a separate acquisition of PET/CT and MR. Another advantage of MR is the availability of several functional techniques. Although some of them might enhance the imaging of head and neck cancer with PET/MR, other functional techniques actually might prove dispensable in the presence of PET. In this overview, we discuss current trends and potential clinical applications of PET/MR in the imaging of head and neck cancers, including clinical protocols. We also discuss potential benefits of implementing functional MR techniques into hybrid PET/MRI of head and neck cancers. PMID- 25841280 TI - Normal saline instillation before endotracheal suctioning: "What does the evidence say? What do the nurses think?": Multimethod study. AB - PURPOSE: This study aimed to systematically review studies that investigated the effects of normal saline instillation before endotracheal suctioning and to determine the views of nurses concerning this procedure. METHODS: This study was carried out in 2 stages as a systematic review and a descriptive study. In the first stage, the Medline and CINAHL databases were searched. The second stage of the study consisted of a survey of 65 intensive care nurses. RESULTS: The systematic review identified 7 studies. Nearly all of the studies had a self controlled clinical trial design. Normal saline instillation before endotracheal suctioning was demonstrated to decrease patient oxygenation in most studies (P < .05). However, the impact of normal saline on hemodynamics and the incidence of ventilator-associated pneumonia remain unclear. Most nurses (87.7%) apply normal saline instillation. CONCLUSION: Although the effects of normal saline instillation on hemodynamics and pneumonia incidence remain controversial, this procedure significantly decreases the oxygenation. Therefore, the use of this procedure is not recommended. However, normal saline instillation is used frequently by nurses to manage thick and tenacious secretions in clinical practice. Additional studies are needed to determine the effectiveness of applications that may be alternatives to normal saline instillation in the management of these secretions. PMID- 25841281 TI - Foker process for the correction of long gap esophageal atresia: Primary treatment versus secondary treatment after prior esophageal surgery. AB - PURPOSE: The Foker process (FP) uses tension-induced growth for primary esophageal reconstruction in patients with long gap esophageal atresia (LGEA). It has been less well described in LGEA patients who have undergone prior esophageal reconstruction attempts. METHODS: All cases of LGEA treated at our institution from January 2005 to April 2014 were retrospectively reviewed. Patients who initially had esophageal surgery elsewhere were considered secondary FP cases. Demographics, esophageal evaluations, and complications were collected. Median time to esophageal anastomosis and full oral nutrition was estimated using the Kaplan-Meier method. Multivariate Cox-proportional hazards regression identified potential risk factors. RESULTS: Fifty-two patients were identified, including 27 primary versus 25 secondary FP patients. Median time to anastomosis was 14 days for primary and 35 days for secondary cases (p<0.001). Secondary cases (p=0.013) and number of thoracotomies (p<0.001) were identified as significant predictors for achieving anastomosis and the development of a leak. Predictors of progression to full oral feeding were primary FP cases (O.R.=17.0, 95% CI: 2.8 102, p<0.001) and patients with longer follow-up (O.R.=1.06/month, 95% CI: 1.01 1.11, p=0.005). CONCLUSIONS: The FP has been successful in repairing infants with primary LGEA, but the secondary LGEA patients proved to be more challenging to achieve a primary esophageal anastomosis. Early referral to a multidisciplinary esophageal center and a flexible approach to establish continuity in secondary patients is recommended. Given their complexity, larger studies are needed to evaluate long-term outcomes and discern optimal strategies for reconstruction. PMID- 25841282 TI - Prematurity and neonatal comorbidities as risk factors for nonaccidental trauma. AB - BACKGROUND: Parental, familial, and demographic risk factors for nonaccidental trauma (NAT) have been well-studied, but neonatal factors, such as comorbidities and prematurity have not. We assess the correlation of these factors with NAT. METHODS: A total of 234 cases of NAT and 287 cases of accidental trauma (AT) among children <1 year were identified in a trauma registry. Known risk factors for NAT, gestational age, and neonatal comorbidities were abstracted from medical records. Chi-square analysis and logistic regression evaluated the association of prematurity and comorbidities with NAT compared to AT with and without controlling for confounders. RESULTS: Children treated for NAT were younger than those treated for AT and were more likely to have younger parents with substance abuse issues. Prematurity, major comorbidities, and minor comorbidities were more common in those treated after NAT than after AT (24.8% vs 12.7%, p=0.0004; 25.6% vs 7.2%, p<0.0001, and 42.6% vs 29.3%, p=0.0014, respectively). After model adjustments for other risk factors, major comorbidity remained a significant risk factor for NAT compared to AT, with an adjusted odds ratio of 4.37 (p<0.0001). CONCLUSIONS: Among other risk factors, neonatal factors predict a child's risk for abuse. We have an opportunity for targeted preventive interventions among this at-risk population. PMID- 25841283 TI - The non-diagnostic ultrasound in appendicitis: is a non-visualized appendix the same as a negative study? AB - PURPOSE: The purpose of this retrospective study was to investigate outcomes in children who underwent a non-diagnostic ultrasound (US) evaluating for appendicitis and to identify predictors of a negative diagnosis. METHODS: An IRB approved retrospective chart review was performed on patients age 0-18, who underwent an abdominal US evaluating for acute appendicitis from 2004 through 2013. Clinical data and specified outcomes were recorded, and exams were categorized into non-diagnostic studies and further separated into studies where the appendix was non-visualized. RESULTS: Of the 1383 studies included for analysis, 876 were non-diagnostic for acute appendicitis (63.34%) with 777 specifically because the appendix was non-visualized. Seven hundred forty of the 876 non-diagnostic studies and 671 of the 777 non-visualized studies were ultimately considered true negatives, corresponding to a negative predictive value (NPV) of 84.47 and 86.36%, respectively. In patients with WBC <7.5*10(9)/L, the NPV of non-diagnostic and non-visualized studies increased to 97.12 and 98.86%, respectively. Patients with WBC <11.0*10(9)/L have similarly high NPVs of 95.59 and 96.99% (non-diagnostic and non-visualized). CONCLUSION: Based on the high NPV of a non-diagnostic US in children without leukocytosis, these patients may safely avoid further diagnostic imaging for the workup of suspected appendicitis. PMID- 25841284 TI - Strategic assessment of the availability of pediatric trauma care equipment, technology and supplies in Ghana. AB - BACKGROUND: This study aimed to assess the availability of pediatric trauma care items (i.e. equipment, supplies, technology) and factors contributing to deficiencies in Ghana. METHODS: Ten universal and 9 pediatric-sized items were selected from the World Health Organization's Guidelines for Essential Trauma Care. Direct inspection and structured interviews with administrative, clinical and biomedical engineering staff were used to assess item availability at 40 purposively sampled district, regional and tertiary hospitals in Ghana. RESULTS: Hospital assessments demonstrated marked deficiencies for a number of essential items (e.g. basic airway supplies, chest tubes, blood pressure cuffs, electrolyte determination, portable X-ray). Lack of pediatric-sized items resulting from equipment absence, lack of training, frequent stock-outs and technology breakage were common. Pediatric items were consistently less available than adult-sized items at each hospital level. CONCLUSION: This study identified several successes and problems with pediatric trauma care item availability in Ghana. Item availability could be improved, both affordably and reliably, by better organization and planning (e.g. regular assessment of demand and inventory, reliable financing for essential trauma care items). In addition, technology items were often broken. Developing local service and biomedical engineering capability was highlighted as a priority to avoid long periods of equipment breakage. PMID- 25841286 TI - Indoor Air Problems and Hoarseness in Children. AB - OBJECTIVES: A well-functioning voice is becoming increasingly important because voice-demanding professions are increasing. The largest proportion of voice disorders is caused by factors in the environment. Moisture damage is common and can initiate microbial growth and/or diffusion of chemicals from building materials. Indoor air problems due to moisture damage are associated with a number of health symptoms, for example, rhinitis, cough, and asthma symptoms. The purpose of this study was to investigate if children attending a day care center, preschool, or school with indoor air problems due to moisture damage were hoarse more often than the children in a control group. METHODS: Information was collected through electronic and paper questionnaires from the parents of 6- to 9 year-old children (n = 1857) attending 57 different day care centers, preschools, or schools with or without indoor air problems due to moisture damage. RESULTS: The results showed a significant correlation between the degree of indoor air problem due to moisture damage and the frequency of hoarseness. Significant predictors for the child being hoarse every week or more often were dry cough, phlegm cough, and nasal congestion. CONCLUSIONS: The results indicate that these symptoms and exposure to indoor air problems due to moisture damage should be included in voice anamnesis. Furthermore, efforts should be made to remediate indoor air problems due to moisture damage and to treat health symptoms. PMID- 25841285 TI - Area deprivation and the food environment over time: A repeated cross-sectional study on takeaway outlet density and supermarket presence in Norfolk, UK, 1990 2008. AB - Socioeconomic disparities in the food environment are known to exist but with little understanding of change over time. This study investigated the density of takeaway food outlets and presence of supermarkets in Norfolk, UK between 1990 and 2008. Data on food retail outlet locations were collected from telephone directories and aggregated within electoral wards. Supermarket presence was not associated with area deprivation over time. Takeaway food outlet density increased overall, and was significantly higher in more deprived areas at all time points; furthermore, socioeconomic disparities in takeaway food outlet density increased across the study period. These findings add to existing evidence and help assess the need for environmental interventions to reduce disparities in the prevalence of unhealthy food outlets. PMID- 25841287 TI - Vocal Assessment Before, After, and the Day After Opera Performance. AB - OBJECTIVE: To explore aerodynamic, acoustic, and laryngeal changes surrounding opera performance. STUDY DESIGN: Prospective preperformance, postperformance, and day after performance. METHODS: The laryngeal and vocal function of five male and five female classically trained singers was assessed immediately before, immediately after, and 1 day after an actual operatic performance. Phonatory threshold pressure was obtained. In addition, during a full-voice singing task, aerodynamic and acoustic measures included estimated subglottal pressure, airflow during voicing, laryngeal resistance, and sound pressure level (SPL). Expert listeners in the audience judged performers' voice quality at the beginning and the end of the performance. Laryngeal visualization was performed immediately before performance and the day after performance. RESULTS: Laryngeal stroboscopy revealed allergy symptoms with no change in vocal fold edges for all men. Women were less impacted by allergies. For all singers, perceptual judgments of expert listeners in the audience corresponded well with laryngeal findings. The men whose voices were perceived to be balanced and strong across the performance demonstrated increased airflow and reduced laryngeal resistance after performance. The two women who did not sing in church the morning after the performance demonstrated increased airflow and reduced laryngeal resistance. The two men who did sing in church the morning after the performance demonstrated noticeably reduced SPL and increased laryngeal resistance the day after performance. CONCLUSIONS: It appears most useful to describe the complexity of vocal performance with a variety of acoustic, aerodynamic, and perceptual measures. The findings further suggest that vocal rest the day after performance may facilitate recovery. PMID- 25841288 TI - Rapid and specific identification of Brucella abortus using the loop-mediated isothermal amplification (LAMP) assay. AB - A rapid and accurate diagnosis of brucellosis is required to reduce and prevent the spread of disease among animals and the risk of transfer to humans. In this study, a Brucella abortus-specific (Ba) LAMP assay was developed, that had six primers designed from the BruAb2_0168 region of chromosome I. The specificity of this LAMP assay was confirmed with Brucella reference strains, B. abortus vaccine strains, B. abortus isolates and phylogenetically or serologically related strains. The detection limit of target DNA was up to 20 fg/MUl within 60 min. The sensitivity of the new LAMP assay was equal to or slightly higher than other PCR based assays. Moreover, this Ba-LAMP assay could specifically amplify all B. abortus biovars compared to previous PCR assays. To our knowledge, this is the first report of specific detection of B. abortus using a LAMP assay. The Ba-LAMP assay can offer a rapid, sensitive and accurate diagnosis of bovine brucellosis in the field. PMID- 25841289 TI - Abnormal urinalysis results are common, regardless of specimen collection technique, in women without urinary tract infections. AB - BACKGROUND: Voided urinalysis to test for urinary tract infection (UTI) is prone to false-positive results for a number of reasons. Specimens are often collected at triage from women with any abdominal complaint, creating a low UTI prevalence population. Improper collection technique by the patient may affect the result. At least four indices, if positive, can indicate UTI. OBJECTIVE: We examine the impact of voided specimen collection technique on urinalysis indicators of UTI and on urine culture contamination in disease-free women. METHODS: In this crossover design, 40 menstrual-age female emergency department staff without UTI symptoms collected urine two ways: directly in a cup ("non-clean") and midstream clean catch ("ideal"). Samples underwent standard automated urinalysis and culture. Urinalysis indices and culture contamination were compared. RESULTS: The proportion of abnormal results from samples collected by "non-clean" vs. "ideal" technique, respectively, were: leukocyte esterase (>trace) 50%, 35% (95% confidence interval for difference -6% to 36%); nitrites (any) 2.5%, 2.5% (difference -2.5 to 2.5%); white blood cells (>5/high-powered field [HPF]) 50%, 27.5% (difference 4 to 41%); bacteria (any/HPF) 77.5%, 62.5%, (difference -7 to 37%); epithelial cells (>few) 65%, 30% (difference 13 to 56%); culture contamination (>1000 colony-forming units of commensal or >2 species) 77%, 63% (difference -5 to 35%). No urinalysis index was positively correlated with culture contamination. CONCLUSION: Contemporary automated urinalysis indices were often abnormal in a disease-free population of women, even using ideal collection technique. In clinical practice, such false-positive results could lead to false positive UTI diagnosis. Only urine nitrite showed a high specificity. Culture contamination was common regardless of collection technique and was not predicted by urinalysis results. PMID- 25841290 TI - Another Disease Re-emerges Due to Parental Shot Refusal: Case Report of a Fussy Infant with Blood in Stool. AB - BACKGROUND: Infants may present to the emergency department (ED) with vague complaints worrisome to parents and may initially appear well, despite serious underlying pathology. Whereas sepsis and nonaccidental trauma are high on most providers' diagnostic considerations, we report a case representative of a worrisome trend secondary to the refusal of parenteral vitamin K at birth leading to significant neurologic sequelae. CASE REPORT: A 10-week-old boy presented to the ED with gradual increase in fussiness for 2 weeks and new onset of blood flecks in the stool on the day of presentation. Careful physical examination revealed a pale-appearing infant, leading to diagnostic evaluation demonstrating profound anemia and intracranial bleeding. The patient was diagnosed with late onset vitamin K-deficient bleeding (VKDB) secondary to parental refusal of the vitamin K shot at birth. Why Should Emergency Physicians be Aware of This? Emergency Medicine providers need to add this serious treatable disease into their diagnostic consideration for fussy infants, infants with unexplained bruising or bleeding, or infants with new-onset seizures. Rapid identification of VKDB can lead to prompt treatment and halt the rapid progression of symptoms. Emergency Medicine providers should ask all parents if their infant received parenteral vitamin K in the newborn period, especially if they are exclusively breastfed or born out of the hospital. PMID- 25841291 TI - Hyperdense Basal Ganglia in Nonketotic Hyperglycemia. PMID- 25841292 TI - Hemodynamic study of TCPC using in vivo and in vitro 4D Flow MRI and numerical simulation. AB - INTRODUCTION: Altered total cavopulmonary connection (TCPC) hemodynamics can cause long-term complications. Patient-specific anatomy hinders generalized solutions. 4D Flow MRI allows in vivo assessment, but not predictions under varying conditions and surgical approaches. Computational fluid dynamics (CFD) improves understanding and explores varying physiological conditions. This study investigated a combination of 4D Flow MRI and CFD to assess TCPC hemodynamics, accompanied with in vitro measurements as CFD validation. 4D Flow MRI was performed in extracardiac and atriopulmonary TCPC subjects. Data was processed for visualization and quantification of velocity and flow. Three-dimensional (3D) geometries were generated from angiography scans and used for CFD and a physical model construction through additive manufacturing. These models were connected to a perfusion system, circulating water through the vena cavae and exiting through the pulmonary arteries at two flow rates. Models underwent 4D Flow MRI and image processing. CFD simulated the in vitro system, applying two different inlet conditions from in vitro 4D Flow MRI measurements; no-slip was implemented at rigid walls. Velocity and flow were obtained and analyzed. The three approaches showed similar velocities, increasing proportionally with high inflow. Atriopulmonary TCPC presented higher vorticity compared to extracardiac at both inflow rates. Increased inflow balanced flow distribution in both TCPC cases. Atriopulmonary IVC flow participated in atrium recirculation, contributing to RPA outflow; at baseline, IVC flow preferentially traveled through the LPA. The combination of patient-specific in vitro and CFD allows hemodynamic parameter control, impossible in vivo. Physical models serve as CFD verification and fine tuning tools. PMID- 25841294 TI - Mechanical properties and morphological analysis of the transitional zone between meniscal body and ligamentous meniscal attachments. AB - In recent years, an increasing number of studies reporting on meniscal root tears have been published. While the meniscus and its ligamentous meniscal attachments have been studied before, little is known about the transitional zone between these two structures. Therefore, the aim of this study was to mechanically and morphologically characterize the transitional zone between meniscus and its meniscal attachments. Dumbbell-shaped specimens were obtained from the transitional zone between meniscus and its meniscal attachments of 6 knee joints. Samples were divided into tibial and central layers of the anterior lateral (AL), anterior medial (AM), posterior lateral (PL) and posterior medial (PM) transitional region. Testing was performed to obtain the dissipated energy during hysteresis as well as the linear modulus (Elin), the maximum strain (epsilonmax), the maximum engineering stress (sigmamax,eng) and location of rupture during tensile test to failure. Two additional knee joints were used to investigate morphological differences between meniscus, transitional zone and meniscal attachments in 8um transverse slices. The central layer of the AL, AM and PL dissipated up to 48% less energy than the tibial layer. Elin was highest in the tibial layer of the PM with 107.4+/-61.1MPa and lowest in the central layer of the PL with 56.0+/-20.5MPa. The maximum strain was higher in the central layer than in the tibial layer at the AL, AM, and PL locations. The average sigmamax,eng was 12.7+/-9.9MPa over all location and layers. 78% of the samples ruptured during tensile test to failure in the transitional zone. The morphological evaluation showed a smooth transitional zone with a transitional curve which was either linear or bell-shaped. The strength found in the transitional zone was lower than in the meniscus and the meniscal attachments, which corresponds well to clinical findings. PMID- 25841293 TI - The mechanical role of the cervix in pregnancy. AB - Appropriate mechanical function of the uterine cervix is critical for maintaining a pregnancy to term so that the fetus can develop fully. At the end of pregnancy, however, the cervix must allow delivery, which requires it to markedly soften, shorten and dilate. There are multiple pathways to spontaneous preterm birth, the leading global cause of death in children less than 5 years old, but all culminate in premature cervical change, because that is the last step in the final common pathway to delivery. The mechanisms underlying premature cervical change in pregnancy are poorly understood, and therefore current clinical protocols to assess preterm birth risk are limited to surrogate markers of mechanical function, such as sonographically measured cervical length. This is what motivates us to study the cervix, for which we propose investigating clinical cervical function in parallel with a quantitative engineering evaluation of its structural function. We aspire to develop a common translational language, as well as generate a rigorous integrated clinical-engineering framework for assessing cervical mechanical function at the cellular to organ level. In this review, we embark on that challenge by describing the current landscape of clinical, biochemical, and engineering concepts associated with the mechanical function of the cervix during pregnancy. Our goal is to use this common platform to inspire novel approaches to delineate normal and abnormal cervical function in pregnancy. PMID- 25841295 TI - Effectiveness of microbubble removal in an airtrap with a free surface interface. AB - An end stage renal disease patient will undergo haemodialysis (HD) three or four times a week for four to five hours per session. Because of the chronic nature of the treatment, any minor imperfection in the extracorporeal system may become significant over time. Clinical studies have raised concerns relating to small microbubbles entering HD patients. These bubbles lead to further pathophysiological complications with the size of the bubble being a major factor. Microbubbles of different sizes can be generated throughout the extra corporeal HD circuit. It is important to understand the possibility of these bubbles passing through the air trap or successfully being removed which indicates the performance of the air trap, the only mechanics of removing air bubbles. Chronic exposure to various sizes of microbubbles was analysed in detail for haemodialysis patients. However, smaller microbubbles are shown to be able to pass our modelled air trap. While studies have reported the presence of bubbles before and after the air trap, because these bubbles are only counted and not tracked, the performance of the air trap for removing different bubble sizes is not understood. Here, the performance of the air trap in filtering bubbles and the possibility of different bubble sizes passing through the air trap with the presence of the free surface interface have been evaluated. The modelled air trap is shown to be ineffective for filtering small micro bubbles. PMID- 25841296 TI - Lens GABA receptors are a target of GABA-related agonists that mitigate experimental myopia. AB - Coordinated growth of eye tissues is required to achieve visual acuity. However, visual experience also guides this process. Experimental myopia can be produced by altering light entering the eye, but also by changing light/dark regimens. Drug discovery studies demonstrated that gamma-aminobutyric acid (GABA)-related agonists (e.g., baclofen) will mitigate experimental myopia, and are also drugs studied for their capacity to affect neurodevelopmental disorders that include Fragile X Syndrome and related autism spectrum disorders. GABA receptors thought to mediate these responses in the eye have been studied in the neural retina as well as the cornea and sclera which are both innervated tissues. In addition to neurons, lenses express GAD25/65/67 GABA metabolic enzymes and at least 13 GABA receptor subunits with developmental expression profiles that match neural development. Evidence that lens GABA receptors are expressed in a cell environment comparable to neurons is seen in the lens expression of AMPA and NMDA glutamate receptors together with an unexpectedly comprehensive array of associated signaling proteins that include post-synaptic-density 95 (PSD95), calcium calmodulin kinase IIalpha (CaMKIIalpha), Fragile X Syndrome mental retardation protein (FMRP), ephrin receptors, Ca(V)1.2, 1.3 channels, cyclin dependent kinase 5 (Cdk5), and neuronal C-src among others. Moreover, lens cells share fundamental molecular regulatory mechanisms that integrate the regulation and function of these genes at the DNA, RNA, and protein levels in neurons. GABA has trophic, growth promoting effects early in neuron development and later assumes its classic inhibitory role in the adult neural system. We hypothesize that the extensive parallels between GABA and glutamate receptor biology in lens and brain identifies the lens as a site of GABA agonist drug action affecting experimental myopia, acting through lens GABA receptors to similarly affect growth in both elongated cell types. PMID- 25841297 TI - Telomere length variability is related to symptoms and cognition in schizophrenia. PMID- 25841299 TI - Comparative investigation of the detective quantum efficiency of direct and indirect conversion detector technologies in dedicated breast CT. AB - PURPOSE: To investigate the dose saving potential of direct-converting CdTe photon-counting detector technology for dedicated breast CT. MATERIALS AND METHODS: We analyzed the modulation transfer function (MTF), the noise power spectrum (NPS) and the detective quantum efficiency (DQE) of two detector technologies, suitable for breast CT (BCT): a flat-panel energy-integrating detector with a 70 MUm and a 208 MUm thick gadolinium oxysulfide (GOS) and a 150 MUm thick cesium iodide (CsI) scintillator and a photon-counting detector with a 1000 MUm thick CdTe sensor. RESULTS: The measurements for GOS scintillator thicknesses of 70 MUm and 208 MUm delivered 10% pre-sampled MTF values of 6.6 mm( 1) and 3.2 mm(-1), and DQE(0) values of 23% and 61%. The 10% pre-sampled MTF value for the 150 MUm thick CsI scintillator 6.9 mm(-1), and the DQE(0) value was 49%. The CdTe sensor reached a 10% pre-sampled MTF value of 8.5 mm(-1) and a DQE(0) value of 85%. CONCLUSION: The photon-counting CdTe detector technology allows for significant dose reduction compared to the energy-integrating scintillation detector technology used in BCT today. Our comparative evaluation indicates that a high potential dose saving may be possible for BCT by using CdTe detectors, without loss of spatial resolution. PMID- 25841298 TI - Intensive care medicine and organ donation: exploring the last frontiers? AB - The main, universal problem for transplantation is organ scarcity. The gap between offer and demand grows wider every year and causes many patients in waiting list to die. In Spain, 90% of transplants are done with organs taken from patients deceased in brain death but this has a limited potential. In order to diminish organ shortage, alternative strategies such as donations from living donors, expanded criteria donors or donation after circulatory death, have been developed. Nevertheless, these types of donors also have their limitations and so are not able to satisfy current organ demand. It is necessary to reduce family denial and to raise donation in brain death thus generalizing, among other strategies, non-therapeutic elective ventilation. As intensive care doctors, cornerstone to the national donation programme, we must consolidate our commitment with society and organ transplantation. We must contribute with the values proper to our specialization and try to reach self-sufficiency by rising organ obtainment. PMID- 25841301 TI - Mr Ivor William Broomhead. PMID- 25841300 TI - Saxagliptin is similar in glycaemic variability more effective in metabolic control than acarbose in aged type 2 diabetes inadequately controlled with metformin. AB - This study compared the effects on glycaemic variability and glucose control between saxagliptin and acarbose as add-on therapies for aged T2DM inadequately controlled with metformin alone. The results showed that compared with acarbose metformin, saxagliptin-metformin was more effective in glucose control with similar glycaemic variability. PMID- 25841302 TI - Plastic surgery statistics: low cost/no cost methods for collecting, analyzing and interpreting visual data. PMID- 25841303 TI - A fatal poisoning involving 25C-NBOMe. AB - This paper reports on a fatal overdose case involving the potent hallucinogenic drug 25C-NBOMe (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2 methoxyphenyl)methyl]ethanamine). In the present case, a young male was hospitalized after the recreational use of this potent drug. He died at the hospital at approximately 12h after ingestion, with preceding signs of serotonin toxicity. Medico-legal autopsy was performed on the deceased, during which time peripheral whole blood, urine, vitreous humor, liver and gastric content samples were submitted for toxicological examination. Further, whole blood collected at the hospital at 2-4h following ingestion of the drug was analyzed. 25C-NBOMe and a demethylated and glucuronidated metabolite of 25C-NBOMe were identified in the urine and blood samples using ultra-performance liquid chromatography with high resolution time-of-flight mass spectrometry (UPLC-HRTOF-MS). Subsequently, 25C NBOMe was quantified in the peripheral whole blood (0.60MUg/kg), urine (2.93MUg/kg), vitreous humor (0.33MUg/kg), liver (0.82MUg/kg) and gastric content (0.32MUg total) samples collected during autopsy and in the ante-mortem whole blood (0.81MUg/kg) by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). The autopsy findings were consistent with acute poisoning. Based on the toxicological findings, the cause of death was determined to be a fatal overdose of 25C-NBOMe in combination with amphetamine intake. To our knowledge, the present paper reports the first quantification of 25C-NBOMe in biological specimens from a fatal intoxication case. PMID- 25841304 TI - Impact of nuclear factor erythroid-derived 2-like 2 and p62/sequestosome expression on prognosis of patients with gliomas. AB - The objective of the present study was to determine whether 2 proteins (nuclear erythroid 2-related factor 2 [Nrf2] and p62) can be used as the biomarkers for prognosis of gliomas. The glioma samples were from 75 glioma patients after surgery. The expression of Nrf2 and p62 in 75 samples was detected with immunohistochemical staining. The correlation between immunohistochemical results and clinicopathological parameters or prognosis was analyzed. The results indicated that high Nrf2 expression was detected in 61.3% of glioma tissue samples and was significantly correlated with age (P = .006), tumor grade (P = .002), and onset time (P = .019). The overall survival (OS) and disease-free survival (DFS) in patients with high Nrf2 expression were significantly shorter than those in patients with low Nrf2 expression (P < .001). High p62 expression was detected in 65.3% of glioma tissue samples, and p62 expression was correlated significantly with the tumor grade (P < .001) and 1-year survival (P = .024). OS and DFS in patients with high p62 expression were significantly shorter than those in patients with low p62 expression (P < .001). Spearman rank correlation test revealed a significant positive relation between Nrf2 and p62 expressions (r = 0.515, P < .001). Multivariate regression analysis showed that p62 expression and age were the significant independent prognostic factors for DFS (P < .05) and tumor grade and p62 expression were independent prognostic parameters for OS (P < .01 or P < .05). These findings indicated that p62 may be used as the prognostic biomarker in patients with gliomas. PMID- 25841305 TI - Transgelin: a potentially useful diagnostic marker differentially expressed in triple-negative and non-triple-negative breast cancers. AB - Triple negative (TN) (estrogen receptor [ER], progesterone receptor [PR] and HER2 ) are highly aggressive, rapidly growing, hormone-unresponsive tumors diagnosed at later stage that affect younger women with shorter overall survival. Most TN tumors are of the basal type. For the remainder, identification of target markers for effective treatment strategies remains a challenge. Transgelin (TGLN) is a 22 kd actin-binding protein of the calponin family. It is one of the earliest markers of smooth muscle differentiation. TGLN has been shown to have important biologic activities including regulating muscle fiber contractility, cell migration, and tumor suppression. We examined TGLN expression in the different molecular subtypes of breast cancer. TGLN expression was examined as a function of tumor size, grade, histologic type, lymph node status, patients' age and overall survival, ER, PR, HER2, and Ki-67 in 101 tumors that included 35 luminal A, 28 luminal B, 4 HER2, and 34 TN types. TGLN positivity (defined as 2+ or 3+) was associated with more aggressive tumors (10% of grade I/II tumors were TGLN+ versus 53% of grade III tumors; P < .001), high Ki-67 count, and low ER and PR expression (P < .001) but not with tumor size, age, or lymph node metastasis. TN (n = 34) tumors were 7.7 times more likely to be TGLN+ than non-TN (n = 67) tumors (77% versus 10%, respectively; P < .001). TGLN may be an excellent diagnostic marker of TN tumors and could be useful in stratification of patients. TGLN may also prove a potential target for future treatment strategies. PMID- 25841306 TI - Expression of LATS family proteins in ovarian tumors and its significance. AB - Epithelial ovarian cancer is composed of a diverse group of tumors that can be derived from the fallopian tube, endometrium, or ovary. In this study, we explored the expression levels of LATS family members in ovarian tumors using normal ovaries, fallopian tubes, and endometrium as controls. Immunohistochemistry studies of LATS1, LATS2, Pax8, and calretinin were performed on normal ovary, fallopian tube, normal endometrium, and ovarian tumor sections. Statistical analyses were conducted using the chi(2) test, Fisher exact test, or Kruskal-Wallis H test. Patient survival was analyzed using the Kaplan-Meier method. LATS1 was expressed in normal ovarian epithelia, endometrium, and fallopian tubes, whereas LATS2 expression was observed in the normal fallopian tubes and endometrium. High expressions of LATS1 and LATS2 in serous cystadenomas gradually decreased in borderline cystadenomas and carcinomas, respectively. However, an opposite expression pattern was observed in mucinous tumors. Low expressions of LATS1 and LATS2 were also detected in clear cell carcinoma. Both LATS1 and LATS2 expression levels significantly correlated with recurrence and stage; LATS1 levels were also related with tumor grades in serous carcinoma. However, univariate and multivariate Cox regression analyses revealed that high expression of LATS1 was associated with better prognosis in patients with serous carcinoma. Both LATS1 and LATS2 were not related with the clinical variables in mucinous and clear cell carcinoma. LATS1 expression levels might be a valuable survival indicator in ovarian serous carcinoma. PMID- 25841307 TI - Marking of tumor resection borders for improved radiation planning facilitates reduction of radiation dose to free flap reconstruction in head and neck cancer surgery. AB - Accurate localization of tumor resection borders is crucial for adjuvant radiotherapy. An improvement to adjuvant radiotherapy with the reduction of radiation doses to free flap reconstruction by virtual navigation procedures and titanium clips was evaluated. Thirty-three patients with oral cancer were prospectively included in the study. Following complete local excision of the primary tumor, resection borders were marked virtually using a navigation pointer and with titanium ligature clips. Postoperative delineation of tumor resection borders was examined. In five patients with microvascular free flap reconstruction a reduction of the radiation dose to the free flap reconstruction was achieved. The tumor resection borders in 30 patients were marked with titanium ligature clips. Surgical clip insertion was successful in 91%. We demonstrate a significant relationship between the reconstruction volume and the part of the target volume which will receive a reduced radiation dose. A cumulative dose of 60 Gy was administered to the target volume and a significant reduction of the administered radiation dose to the center of the flap could be demonstrated. We demonstrate an accurate delineation of the tumor resection margins. These improvements in tumor resection margin delineation allow for increased accuracy in adjuvant treatment and a reduction of radiation dose to the vascular free flap reconstruction. PMID- 25841308 TI - Measured symmetry of facial 3D shape and perceived facial symmetry and attractiveness before and after orthognathic surgery. AB - One aim of cranio-maxillo-facial surgery is to strive for an esthetical appearance. Do facial symmetry and attractiveness correlate? How are they affected by surgery? Within this study faces of patients with orthognathic surgery were captured and analyzed regarding their symmetry. A total of 25 faces of patients were measured three-dimensionally by an optical sensor using the fringe projection technique before and after orthognathic surgery. Based upon this data an asymmetry index was calculated for each case. In order to gather subjective ratings each face was presented to 100 independent test subjects in a 3D rotation sequence. Those were asked to rate the symmetry and the attractiveness of the faces. It was analyzed to what extend the ratings correlate with the measured asymmetry indices and whether pre- and post-surgical data differ. The measured asymmetry indices correlate significantly with the subjective ratings of both items. The measured symmetry as well as the rated symmetry and attractiveness increased on average after surgery. The increase of the ratings was even statistically significant. A larger enhancement of symmetry is achieved in pre-surgical strongly asymmetric faces than in rather symmetric faces. PMID- 25841309 TI - Unknown primary of the head and neck: A long-term follow-up. AB - BACKGROUND: A diagnosis of squamous cell carcinoma of an unknown primary (CUP) is a major burden for patients. Because the location of the primary tumor is unclear, patients remain fearful of recurrence, which aggravates the uncertain prognosis of the disease. This study evaluates factors associated with long-term recurrence-free and overall survival of patients with CUP of the head and neck. Additionally, patient survival rates are compared with those of patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 293 consecutive patients operated on between January 1999 and December 2009 with at least a 5-year follow-up (survival permitting), were evaluated retrospectively. RESULTS: Twenty-six patients with a CUP of the head and neck were identified. Patients with CUP had a low overall survival rate, comparable with that of patients with pN + HNSCC, and recurrent disease occurred with a similar likelihood as in patients with pN + HNSCC. The median recurrence-free survival in the CUP group was 28.5 months compared with 48 months in the whole of the HNSCC group. The median overall survival of the CUP group was 56 months versus 65 months for the HNSCC group. Extracapsular spread was the only independent prognostic factor for overall survival for CUP patients. CONCLUSION: Patients diagnosed with CUP syndrome have a poorer prognosis for overall survival compared with other HNSCC patients. Postoperative radiotherapy diminished disease recurrence and improved overall survival. Omission of postoperative radiotherapy resulted in a very high recurrence rate (75%) for CUP patients. Based on these results we suggest postoperative radiotherapy including the oral mucosa for all patients, regardless of histopathological results, possible favorable nodal disease, or favorable lymph node ratios. PMID- 25841310 TI - Application of biodegradable plates for treating pediatric mandibular fractures. AB - OBJECTIVE: We assessed the clinical results of a biodegradable plate system for the internal fixation of mandibular fractures in children, and observed the imaging features of fracture healing and bone changes around the biodegradable plates and screws during follow-up. PATIENTS AND METHODS: We enrolled 39 patients (22 male, 17 female, average age 4 years 10 months) with different mandibular fractures. We used 2.0-mm resorbable plates to repair the fractures. Postoperative follow-up ranged from 6 months to 5 years; average follow-up was 1 year 2 months. The outcome measures identified and assessed included facial symmetry, mouth opening, occlusal relationship, infection, nonunion, malunion, and plate dehiscence. RESULTS: We fixed 42 fractures with 43 resorbable plates; the fracture site of one patient (aged 11 years 3 months) was fixed with two plates. Two patients developed small fistulas at the intraoral incision 2 months after surgery; the fistulas healed after 1 month without special treatment. In the other patients, the incision healed well, there was facial symmetry, mouth opening was >35 mm, and occlusion was good. Follow-up computed tomography examination data were available for 20 cases, and revealed different degrees of radiolucency indicating that osteolysis had occurred. Radiolucency was observed around the resorbable plates 1 month after the surgery. The extent and depth of the radiolucent region were obvious within 1 year of surgery. In the second year, there were obvious repairs, with the bony defect areas becoming shallower. After 2 years, the bony defect areas had almost disappeared. CONCLUSION: Biodegradable fixation devices are safe and efficient for treating pediatric mandibular fractures. Osteolysis commonly follows biodegradable fixation of pediatric mandibular fractures, and has no adverse effect on fracture healing. PMID- 25841311 TI - Incidence of bisphosphonate-related osteonecrosis of the jaw in high-risk patients undergoing surgical tooth extraction. AB - As the most suitable approach for preventing bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients undergoing surgical tooth extraction is still under discussion, the present study evaluates the incidence of BRONJ after surgical tooth extraction using a standardized surgical protocol in combination with an adjuvant perioperative treatment setting in patients who are at high-risk for developing BRONJ. High-risk patients were defined as patients who received intravenous bisphosphonate (BP) due to a malignant disease. All teeth were removed using a standardized surgical protocol. The perioperative adjuvant treatment included intravenous antibiotic prophylaxis starting at least 24 h before surgery, a gastric feeding tube and mouth rinses with chlorhexidine (0.12%) three times a day. In the follow-up period patients were examined every 4 weeks for the development of BRONJ. Minimum follow-up was 12 weeks. In 61 patients a total number of 184 teeth were removed from 102 separate extraction sites. In eight patients (13.1%) BRONJ developed during the follow-up. A higher risk for developing BRONJ was found in patients where an additional osteotomy was necessary (21.4% vs. 8.0%; p = 0.0577), especially for an osteotomy of the mandible (33.3% vs. 7.3%; p = 0.0268). Parameters including duration of intravenous antibiotic prophylaxis, the use of a gastric feeding tube and the duration of intravenous BP therapy showed no statistical impact on the development of BRONJ. Furthermore, patients currently undergoing intravenous BP therapy showed no higher risk for BRONJ compared with patients who have paused or completed their intravenous BP therapy (p = 0.4232). This study presents a protocol for surgical tooth extraction in high-risk BP patients in combination with a perioperative adjuvant treatment setting, which reduced the risk for postoperative BRONJ to a minimum. However, the risk for BRONJ increases significantly if an additional osteotomy is necessary, especially in the mandible. PMID- 25841313 TI - Management of pancreatic mucinous cystic neoplasms: surgery or surveillance? PMID- 25841314 TI - Characterization of gait in female patients with moderate to severe hallux valgus deformity. AB - BACKGROUND: Hallux valgus is one of the most common forefoot problems in females. Studies have looked at gait alterations due to hallux valgus deformity, assessing temporal, kinematic or plantar pressure parameters individually. The present study, however, aims to assess all listed parameters at once and to isolate the most clinically relevant gait parameters for moderate to severe hallux valgus deformity with the intent of improving post-operative patient prognosis and rehabilitation. METHODS: The study included 26 feet with moderate to severe hallux valgus deformity and 30 feet with no sign of hallux valgus in female participants. Initially, weight bearing radiographs and foot and ankle clinical scores were assessed. Gait assessment was then performed utilizing pressure insoles (PEDAR) and inertial sensors (Physilog) and the two groups were compared using a non-parametric statistical hypothesis test (Wilcoxon rank sum, P<0.05). Furthermore, forward stepwise regression was used to reduce the number of gait parameters to the most clinically relevant and correlation of these parameters was assessed with the clinical score. FINDINGS: Overall, the results showed clear deterioration in several gait parameters in the hallux valgus group compared to controls and 9 gait parameters (effect size between 1.03 and 1.76) were successfully isolated to best describe the altered gait in hallux valgus deformity (r(2)=0.71) as well as showed good correlation with clinical scores. INTERPRETATION: Our results, and nine listed parameters, could serve as benchmark for characterization of hallux valgus and objective evaluation of treatment efficacy. PMID- 25841315 TI - [Bone marrow toxicity secondary to a primary Epstein-Barr infection in a patient with Crohn's disease on thiopurines treatment]. PMID- 25841316 TI - Effects of LEP, LEPR, ADIPOQ, MC4R and FTO polymorphisms on dyslipidemia in Korean patients with schizophrenia who are taking clozapine. PMID- 25841317 TI - Corneal Cross-linking as an Adjuvant Therapy in the Management of Recalcitrant Deep Stromal Fungal Keratitis: A Randomized Trial. AB - PURPOSE: To assess the efficacy of corneal cross-linking (CXL) as an adjuvant to appropriate antifungal therapy in nonresolving deep stromal fungal keratitis. DESIGN: Randomized clinical trial. METHODS: Eyes with culture-positive deep stromal fungal keratitis not responding to appropriate medical therapy for a period of 2 weeks were randomized to receive either adjuvant CXL or no additional treatment. Antifungal medical therapy was continued in both groups. The prespecified primary outcome was treatment failure at 6 weeks after enrollment, defined as perforation and/or increase in ulcer size by >=2 mm. RESULTS: The trial was stopped before full enrollment because of a marked difference in the rate of perforation between the 2 groups. Of the 13 cases enrolled in the study, 6 were randomized to the CXL group and 7 to the non-CXL group. Five eyes in the CXL group and 3 eyes in the non-CXL group experienced treatment failure by 6 weeks (P = .56). In a secondary analysis, the CXL group experienced more perforations than the non-CXL group (4 vs 0, respectively; P = .02). CONCLUSION: CXL used as adjuvant therapy for recalcitrant deep stromal fungal keratitis did not improve outcomes. PMID- 25841318 TI - Protective effects of protocatechuic acid on acute lung injury induced by lipopolysaccharide in mice via p38MAPK and NF-kappaB signal pathways. AB - The study aims to investigate the effects of protocatechuic acid (PCA) separated from Chinese herbs, on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. The mouse model was induced by intraperitoneal injection of LPS at the dose of 5mg/kg body weight. Three doses of PCA (30, 15, 5 mg/kg) were administered to mice with intraperitoneal injection one hour prior to LPS exposure. Six hours later after LPS administration, the effect of PCA on ALI mice was assessed via histopathological examination by HE staining, inflammatory cytokine production by ELISA assay and RT-PCR, p38MAPK and NF-kappaB activation by Western blot analysis. We found that PCA administration significantly ameliorated lung histopathological changes and decreased protein concentration in the bronchoalveolar lavage fluid. Furthermore, the overproduction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) was reduced by PCA. Additionally, PCA at the dose of 30 mg/kg could block the activation of p38MAPK and NF-kappaB signal pathways induced by LPS. In conclusion, our findings demonstrate that PCA possesses a protective effect on LPS-induced ALI in mice via suppression of p38MAPK and NF-kappaB signal pathways. Therefore, PCA may be useful in the therapy of lung inflammatory diseases, especially for ALI. PMID- 25841319 TI - Tetramethylpyrazine (TMP) exerts antitumor effects by inducing apoptosis and autophagy in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common types of liver cancers with high recurrence rate and mortality rate. Recent studies have indicated that tetramethylpyrazine (TMP), a purified chemical extracted from Ligusticum wallichii Franchat (ChuanXiong), possessed antitumor effects on HCC, but detailed mechanism remains unclear. Our study aims at investigating the antitumor effect of TMP on HCC and its underlying mechanism. We found that TMP inhibited cell proliferation of HepG2 cells in a dose-dependent way, and xenograft tumor models also indicated that high concentrations of TMP administration inhibited tumor growth. Next, flow cytometric analysis and transmission electron microscope images showed that TMP enhanced cell apoptosis in HepG2 cells, and western blot results showed that TMP promoted cleavage of caspase-3 and PARP in vitro and in vivo. We also found that TMP caused autophagy in HCC in vitro and in vivo. In order to examine the role of autophagy in TMP-induced apoptosis, 3-methyladenine (3-MA) was used to block the action of autophagy. Our data showed TMP-induced autophagy might be a pro-apoptosis process in HCC. Furthermore, the results of anti-oxidative enzymes and oxidation-sensitive fluorescent probe 2, 7 dichlorofluorescein diacetate (DCFH-DA) indicated that TMP induced ROS generation and inhibition of ROS diminished the anticancer function of TMP. In conclusion, our studies provide new insights into the mechanisms underlying the antitumor effect of TMP and suggest that TMP can be a novel therapeutic regimen for HCC. PMID- 25841320 TI - Trehalose decreases mutant SOD1 expression and alleviates motor deficiency in early but not end-stage amyotrophic lateral sclerosis in a SOD1-G93A mouse model. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder for which there is currently no effective treatment. Studies indicate that enhancing autophagy in mouse models of neurodegenerative disease can ameliorate the behavioral symptoms and pathological damage associated with the accumulation of pathological mutant proteins such as mutant superoxide dismutase (SOD1). This study investigated the effects of trehalose treatment on both early and end-stage disease in a transgenic mouse model of ALS via short-term (30 days after administration) and long-term (from 60 days after administration to death) trehalose treatment experiments. Sixty-day-old female SOD1-G93A transgenic mice were treated daily with 2% (w/v) trehalose in their drinking water for 30 days and monitored until they reached a neurological score of four, whereupon they were euthanized by cervical dislocation. Neurological, rotarod performance test and hanging wire test scores were recorded and body weight monitored. After death, the spinal cord was removed to assess the number of motor neurons and to measure the expression of mutant SOD1, LC3-II and p62. Trehalose significantly reduced the levels of mutant SOD1 and p62 and increased LC3-II in the spinal cords of 90-day-old SOD1-G93A transgenic mice. Furthermore, trehalose treatment significantly postponed disease onset, lengthened the time it took to reach a neurological score of 2 and preserved motor function; however, trehalose became less effective at delaying further disease progression as the disease progressed beyond a neurological score of 2 and it failed to extend the survival of SOD1 G93A transgenic mice. Additionally, independent of autophagy, trehalose consistently inhibited microgliosis and astrogliosis throughout the entire duration of the study. In conclusion, trehalose may be a useful add-on therapy in conjunction with other ALS treatment options to alleviate symptoms in early-stage ALS. PMID- 25841321 TI - Atomoxetine reverses locomotor hyperactivity, impaired novel object recognition, and prepulse inhibition impairment in mice lacking pituitary adenylate cyclase activating polypeptide. AB - Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed. PMID- 25841322 TI - Reductions of docosahexaenoic acid-containing phosphatidylcholine levels in the anterior horn of an ALS mouse model. AB - In this study, we analyzed the spatiotemporal alterations of phospholipid composition in the spinal cord of an amyotrophic lateral sclerosis (ALS) mouse model (G93A-mutated human superoxide dismutase 1 transgenic mice [SOD1(G93A) mice]) using imaging mass spectrometry (IMS), a powerful method to visualize spatial distributions of various types of molecules in situ. Using this technique, we deciphered the phospholipid distribution in the pre-symptomatic stage, early stage after disease onset, and terminal stages of disease in female SOD1(G93A) mouse spinal cords. These experiments revealed a significant decrease in levels of docosahexaenoic acid (DHA)-containing phosphatidylcholines (PCs), such as PC (diacyl-16:0/22:6), PC (diacyl-18:0/22:6), and PC (diacyl-18:1/22:6) in the L5 anterior horns of terminal stage (22-week-old) SOD1(G93A) mice. The reduction in PC (diacyl-16:0/22:6) level could be reflecting the loss of motor neurons themselves in the anterior horn of the spinal cord in ALS model mice. In contrast, other PCs, such as PC (diacyl-16:0/16:0), were observed specifically in the L5 dorsal horn gray matter, and their levels did not vary between ALS model mice and controls. Thus, our study showed a significant decrease in DHA containing PCs, but not other PCs, in the terminal stage of ALS in model mice, which is likely to be a reflection of neuronal loss in the anterior horns of the spinal cords. Given its enrichment in dorsal sensory regions, the preservation of PC (diacyl-16:0/16:0) may be the result of spinal sensory neurons being unaffected in ALS. Taken together, these findings suggest that ALS spinal cords show significant alterations in PC metabolism only at the terminal stage of the disease, and that these changes are confined to specific anatomical regions and cell types. PMID- 25841323 TI - Temporal dissociation between sodium depletion and sodium appetite appearance: Involvement of inhibitory and stimulatory signals. AB - Our aim was to analyze the participation of inhibitory and stimulatory signals in the temporal dissociation between sodium depletion (SD) induced by peritoneal dialysis (PD) and the appearance of sodium appetite (SA), particularly 2h after PD, when the rats are hypovolemic/natremic but SA is not evident. We investigated the effects of bilateral injections of the serotonin (5-HT) receptor antagonist, methysergide, into the lateral parabrachial nucleus (LPBN) on hypertonic NaCl and water intake 2h vs. 24h after PD. We also studied plasma renin activity (PRA) and aldosterone (ALDO) concentration 2h vs. 24h after PD. Additionally, we combined the analysis of brain Fos immunoreactivity (Fos-ir) with the detection of double immunoreactivity in 5HT and oxytocinergic (OT) cells 2h after PD. Bilateral LPBN injections of methysergide (4MUg/200nl at each site) increased NaCl intake when tested 2h after PD compared to controls. We found a significant increase in PRA and ALDO concentration after PD but no differences between 2 and 24h after PD. We also found for the first time a significant increase 2h after PD in the number of Fos-ir neurons in the brainstem nuclei that have been shown to be involved in the inhibition of SA. In summary, the results show that 5HT-mechanisms in the LPBN modulate sodium intake during the delay of SA when the renin angiotensin aldosterone system (RAAS) is increased. In addition, the activation of brainstem areas previously associated with the satiety phase of SA is in part responsible for the temporal dissociation between SD and behavioral arousal. PMID- 25841324 TI - Impact of Ambulatory Blood Pressure Monitoring on Control of Untreated, Undertreated, and Resistant Hypertension in Older People in Spain. AB - BACKGROUND AND OBJECTIVE: The impact of ambulatory blood pressure monitoring (ABPM) on hypertension control has not been fully assessed across the treatment spectrum in older community-living individuals and could have important implications; specifically, the number of untreated, undertreated, and treatment resistant uncontrolled hypertensives in need of or with unnecessary drug treatment could vary with respect to studies based on conventional blood pressure (BP) measured in clinical settings. DESIGN, SETTING, AND PARTICIPANTS: Cross sectional study conducted in 2012 among 1118 community-living individuals aged >=60 years in Spain. MEASUREMENTS: Three conventional BP measurements at participants' homes and 24-hour ABPM were performed under standardized conditions. Uncontrolled hypertension (mean of the last 2 conventional BP readings >=140/90 mm Hg) was considered undertreated if on 1 or 2 antihypertensive drugs, and apparently treatment-resistant if on >=3 drugs. White coat effect was defined as conventional BP >= 140/90 mm Hg and 24-hour BP <130/80 mm Hg. RESULTS: Of 720 hypertensive patients (mean age, 72.3 +/- 6.3 years; 51.3%, males), 64.4% had conventional BP >= 140/90 mm Hg, and from these 39.9% were untreated, 49.5% undertreated, and 10.6% apparently treatment-resistant. Among uncontrolled hypertensive patients, the white-coat effect was present in 52.4% of those untreated, in 53.5% of undertreated, and in 49% of apparent treatment-resistant. These white-coat results were similar or even higher across alternative BP thresholds. CONCLUSIONS: One-half of older uncontrolled hypertensive patients studied at home were actually controlled according to ABPM, regardless of treatment status. This suggests reconsideration of treatment needs in these numerous white-coat hypertensive patients, who probably do not need drug treatment initiation or intensification. PMID- 25841325 TI - Consensus-Derived Interventions to Reduce Acute Care Transfer (INTERACT) Compatible Order Sets for Common Conditions Associated with Potentially Avoidable Hospitalizations. PMID- 25841326 TI - Grading Frailty in Long-Term Care. PMID- 25841327 TI - Effects of an Oral Nutritional Supplementation Plus Physical Exercise Intervention on the Physical Function, Nutritional Status, and Quality of Life in Frail Institutionalized Older Adults: The ACTIVNES Study. AB - OBJECTIVES: The objective of this study was to assess the effects of a hyperproteic, hypercaloric oral nutritional supplement with prebiotic fiber, vitamin D, and calcium, plus a standardized physical intervention, in the functional status, strength, nutritional status, and quality of life of frail institutionalized older adults. DESIGN: Multicentric prospective observational study under usual clinical practice conditions. SETTING: Four nursing homes from Burgos (2), Albacete, and Madrid, Spain. PARTICIPANTS: Participants included 91 institutionalized older adults (age >=70), able to walk 50 m, and meeting at least 3 of the Fried frailty phenotype criteria. INTERVENTION: Daily intake of two 200-mL bottles of an oral nutritional supplement, each bottle containing 300 kcal, 20 g protein, 3 g fiber, 500 IU vitamin D, and 480 mg calcium, plus a standardized physical exercise training consisting of flexibility, balance, and strengthening exercises for arms and legs, 5 days per week. MEASUREMENTS: Short Physical Performance Battery (SPPB), Short-Form-Late-Life Function and Disability Instrument (SF-LLFDI) function subscale, handgrip strength, EuroQoL-5 Dimensions visual analogic scale (EQ5DVAS), weight, body mass index (BMI), and Short-Form Mini Nutritional Assessment (MNA-SF) at baseline and 6 and 12 weeks. RESULTS: Forty-eight participants (52.7%) improved at least 1 point in the SPPB at week 6, and 44 (48.4%) did so at week 12; 39 participants (42.9%) improved at least 2 points in the SF-LLFDI at week 6, and 46 (50.5%) at week 12. Participants improved their quality of life measured with the EQ5DVAS by 6% (95% confidence interval [CI] 3%-10%) at week 6, and by 5% (95% CI 0%-10%) at week 12. They also improved their nutritional status (weight gain, BMI increase, and higher MNA-SF scores at 6- and 12-week follow-up). This improvement was higher in participants with more frailty criteria, lower functional level, lower vitamin D levels, and poorer nutritional status. CONCLUSION: A 12-week intervention with oral nutritional supplementation plus physical exercise improves function, nutritional status, and quality of life in frail institutionalized older adults. PMID- 25841329 TI - Angioedema of the tongue with an unfamiliar final diagnosis. PMID- 25841328 TI - Building bridges across electronic health record systems through inferred phenotypic topics. AB - OBJECTIVE: Data in electronic health records (EHRs) is being increasingly leveraged for secondary uses, ranging from biomedical association studies to comparative effectiveness. To perform studies at scale and transfer knowledge from one institution to another in a meaningful way, we need to harmonize the phenotypes in such systems. Traditionally, this has been accomplished through expert specification of phenotypes via standardized terminologies, such as billing codes. However, this approach may be biased by the experience and expectations of the experts, as well as the vocabulary used to describe such patients. The goal of this work is to develop a data-driven strategy to (1) infer phenotypic topics within patient populations and (2) assess the degree to which such topics facilitate a mapping across populations in disparate healthcare systems. METHODS: We adapt a generative topic modeling strategy, based on latent Dirichlet allocation, to infer phenotypic topics. We utilize a variance analysis to assess the projection of a patient population from one healthcare system onto the topics learned from another system. The consistency of learned phenotypic topics was evaluated using (1) the similarity of topics, (2) the stability of a patient population across topics, and (3) the transferability of a topic across sites. We evaluated our approaches using four months of inpatient data from two geographically distinct healthcare systems: (1) Northwestern Memorial Hospital (NMH) and (2) Vanderbilt University Medical Center (VUMC). RESULTS: The method learned 25 phenotypic topics from each healthcare system. The average cosine similarity between matched topics across the two sites was 0.39, a remarkably high value given the very high dimensionality of the feature space. The average stability of VUMC and NMH patients across the topics of two sites was 0.988 and 0.812, respectively, as measured by the Pearson correlation coefficient. Also the VUMC and NMH topics have smaller variance of characterizing patient population of two sites than standard clinical terminologies (e.g., ICD9), suggesting they may be more reliably transferred across hospital systems. CONCLUSIONS: Phenotypic topics learned from EHR data can be more stable and transferable than billing codes for characterizing the general status of a patient population. This suggests that EHR-based research may be able to leverage such phenotypic topics as variables when pooling patient populations in predictive models. PMID- 25841330 TI - Correlations between basophil activation, allergen-specific IgE with outcome and severity of oral food challenges. AB - BACKGROUND: Double-blinded, placebo-controlled food challenges (DBPCFCs) remain the gold standard for diagnosing food allergies. Skin prick tests (SPTs) and allergen-specific IgE (sIgE) are routinely used in medical practice but are not sufficient to predict severity of clinical reactivity. OBJECTIVE: To compare the utility of SPT wheal diameter, sIgE, allergen-specific IgG4 (sIgG4), total IgE (tIgE), sIgE/sIgG4 and sIgE/tIgE ratios, peanut component-specific IgE, and basophil activation in predicting outcome and severity of reactions at DBPCFCs. METHODS: Sixty-seven subjects (12-45 years old) underwent DBPCFCs for peanut, tree nut, fish, shrimp, and/or sesame as part of screening for enrollment in a clinical trial. The SPT, sIgE, tIgE, sIgG4, and peanut component-specific IgE (if applicable) levels were measured. CD63 upregulation on basophils in response to in vitro allergen challenge was analyzed by flow cytometry. Correlations between these measurements and DBPCFC severity scores were analyzed. RESULTS: The SPT and sIgE showed a weak correlation with DBPCFC severity scores, but tIgE and sIgG4 did not. The sIgE/sIgG4 ratio differentiated between positive and negative reactions but did not correlate with DBPCFC severity scores. A low positive correlation was seen between DBPCFC severity score and Ara h 2 IgE, whereas a low negative correlation with Ara h 8 IgE was observed. Basophil activation was positively correlated with DBPCFC severity scores. Receiver operating characteristic curves showed basophil reactivity had the largest area under the curve at 0.904 and sIgE at 0.870. CONCLUSION: These results indicate that basophil activation testing can enhance discrimination between allergic and nonallergic individuals and could serve as an additional tool to predict clinical severity. PMID- 25841331 TI - Allergen of the month-annual wormwood. PMID- 25841332 TI - Regulation of the expression of renal drug transporters in KEAP1-knockdown human tubular cells. AB - The kidney secretes various xenobiotics through a well-established transport system. The transcription factor NF-E2-related factor 2 (NRF2) up-regulates a subset of genes encoding antioxidant and detoxification proteins. Kelch-like ECH associated protein 1 (KEAP1) down-regulates NRF2 by facilitating continuous degradation of NRF2 protein. Here, we investigated the role of NRF2 in the expression of renal drug transporters by using a stable KEAP1 knockdown renal tubular HK-2 cell line (shKEAP1). KEAP1 knockdown resulted in a significant increase in the expression of four renal transporters, namely, multidrug resistance protein 1 (MDR1; ABCB1), breast cancer resistance protein (BCRP; ABCG2), multidrug resistance-associated protein 2 (MRP2; ABCC2), and MRP3 (ABCC3). In western blot and immunocytochemical analyses, protein levels of these transporters were also significantly higher in the knockdown group. Consequently, shKEAP1 cells released more Hoechst 33342 fluorescent dye and doxorubicin, and they were more resistant to doxorubicin than the control cells. In addition, cisplatin resistance of shKEAP1 decreased upon co-incubation with a transporter inhibitor. Whereas, a short term incubation (24h) with sulforaphane did not show noticeable changes in the expression of transporter. Collectively, these results indicate that NRF2 regulates the expression of MDR1, BCRP, MRP2, and MRP3 in human tubular epithelial cells. Altered expression of these transporters affects drug secretion in these cells, which may result in the renal cellular damage upon exposure to nephrotoxic xenobiotics. PMID- 25841333 TI - Effects of climatic conditions on annual shoot length and tree-ring width of alpine dwarf pine Pinus pumila in central Japan. AB - This study compared the effects of climatic conditions on annual shoot length (ASL) and tree-ring width (TRW) of alpine dwarf pine Pinus pumila in central Japan, by using dendrochronological techniques. Chronologies of ASL (1951-2009) and TRW (1972-2009) were standardized to remove non-climatic signals, and correlation tests were done for non-standardized observed values and standardized indices with monthly temperatures and precipitation. Monthly mean temperatures from March to October, except for July, increased during 1951-2009; observed values and a standardized index of ASL increased during this period. For the rate of increase in ASL, the standardized index was lower than the observed values. However, these values of TRW showed no trends. The observed values and standardized index of TRW positively correlated with temperatures of the beginning of the growing season of the current year. The observed values of ASL positively correlated with temperatures during the growing season of the previous and current years. However, the standardized index of ASL positively correlated with only June temperatures of the previous and current years. The different results of ASL between observed values and standardized indices indicate that many significant correlations of observed values were attributable to increasing trends of temperature and ASL. This study suggests that standardized ASL of P. pumila tended to increase greater than TRW, that high temperatures at the beginning of the growing season increases ASL and TRW, and that analyzing observed values of ASL may overestimate the effects of temperature on ASL of P. pumila. PMID- 25841334 TI - Phytochrome-mediated regulation of cell division and growth during regeneration and sporeling development in the liverwort Marchantia polymorpha. AB - Light regulates various aspects of development throughout the life cycle of sessile land plants. Photoreceptors, such as the red (R) and far-red (FR) light receptors phytochromes, play pivotal roles in modulating developmental programs. Reflecting high developmental plasticity, plants can regenerate tissues, organs, and whole bodies from varieties of cells. Among land plants, bryophytes exhibit extraordinary competency of regeneration under hormone-free conditions. As an environmental factor, light plays critical roles in regeneration of bryophytes. However, how light regulates regeneration remains unknown. Here we show that using the liverwort Marchantia polymorpha, which contains a single phytochrome gene, the phytochrome regulates re-entry into the cell cycle and cell shape in newly regenerating tissues. Our morphological and cytological observations revealed that S-phase entry of G1-arrested epidermal cells around the midrib on the ventral surface of thallus explants was greatly retarded in the dark or under phytochrome-inactive R/FR cycle irradiation conditions, where, nevertheless, small, laterally narrow regenerants were eventually formed. Thus, consistent with earlier descriptions published over a century ago, light is not essential for, but exerts profound effects on regeneration in M. polymorpha. Ventral cells in regenerants grown under R/FR cycle conditions were longer and narrower than those under R cycle. Expression of a constitutively active mutant of M. polymorpha phytochrome allowed regeneration of well grown, widely expanded thalli even in the dark when sugar was supplied, further demonstrating that the phytochrome signal promotes cell proliferation, which is rate-limited by sucrose availability. Similar effects of R and FR irradiation on cell division and elongation were observed in sporelings as well. Thus, besides activation of photosynthesis, major roles of R in regeneration of M. polymorpha are to facilitate proliferation of rounder cells through the phytochrome by mechanisms that are likely to operate in the sporeling. PMID- 25841335 TI - Different visual exploration of tool-related gestures in left hemisphere brain damaged patients is associated with poor gestural imitation. AB - According to the direct matching hypothesis, perceived movements automatically activate existing motor components through matching of the perceived gesture and its execution. The aim of the present study was to test the direct matching hypothesis by assessing whether visual exploration behavior correlate with deficits in gestural imitation in left hemisphere damaged (LHD) patients. Eighteen LHD patients and twenty healthy control subjects took part in the study. Gesture imitation performance was measured by the test for upper limb apraxia (TULIA). Visual exploration behavior was measured by an infrared eye-tracking system. Short videos including forty gestures (20 meaningless and 20 communicative gestures) were presented. Cumulative fixation duration was measured in different regions of interest (ROIs), namely the face, the gesturing hand, the body, and the surrounding environment. Compared to healthy subjects, patients fixated significantly less the ROIs comprising the face and the gesturing hand during the exploration of emblematic and tool-related gestures. Moreover, visual exploration of tool-related gestures significantly correlated with tool-related imitation as measured by TULIA in LHD patients. Patients and controls did not differ in the visual exploration of meaningless gestures, and no significant relationships were found between visual exploration behavior and the imitation of emblematic and meaningless gestures in TULIA. The present study thus suggests that altered visual exploration may lead to disturbed imitation of tool related gestures, however not of emblematic and meaningless gestures. Consequently, our findings partially support the direct matching hypothesis. PMID- 25841336 TI - Dimerization model of the C-terminal RNA Recognition Motif of HuR. AB - Human antigen R (HuR) is a ubiquitous 32 kDa protein comprising three RNA Recognition Motifs (RRMs), whose main function is to bind Adenylate and uridylate Rich Elements (AREs) in 3' UnTranslated Regions (UTRs) of mRNAs. In addition to binding RNA molecules, the third domain (RRM3) is involved in HuR oligomerization and apoptotic signaling. The RRM3 monomer is able to dimerize, with its self binding affinity being dependent on ionic strength. Here we provide a deeper structural insight into the nature of the encounter complexes leading to the formation of RRM3 dimers by using Brownian Dynamics and Molecular Dynamics. Our computational data show that the initial unspecific encounter follows a downhill pathway until reaching an optimum conformation stabilized by hydrophobic interactions. PMID- 25841337 TI - miR-889 promotes proliferation of esophageal squamous cell carcinomas through DAB2IP. AB - MicroRNAs have been reported to play critical roles in various cancers, but there has been no study on the role of miR-889 in cancers. Here, we report that over expression of miR-889 leads to rapid proliferation of EC109 and EC9706 cells in vitro and in vivo by inducing cells into S-phase. Using bioinformatics methods, DAB2IP was further confirmed to be a direct target of miR-889. In addition, the expression of DAB2IP, which was negatively correlated with that of miR-889, was significantly associated with clinicopathological features of ESCC patients. In conclusion, miR-889 is an important regulator in ESCC and both miR-889 and DAB2IP may serve as promising biomarkers and therapeutic targets in patients with ESCC. PMID- 25841338 TI - Mitsugumin 56 (hedgehog acyltransferase-like) is a sarcoplasmic reticulum resident protein essential for postnatal muscle maturation. AB - Mitsugumin 56 (MG56), also known as the membrane-bound O-acyl-transferase family member hedgehog acyltransferase-like, was identified as a new sarcoplasmic reticulum component in striated muscle. Mg56-knockout mice grew normally for a week after birth, but shortly thereafter exhibited a suckling defect and died under starvation conditions. In the knockout skeletal muscle, regular contractile features were largely preserved, but sarcoplasmic reticulum elements swelled and further developed enormous vacuoles. In parallel, the unfolded protein response was severely activated in the knockout muscle, and presumably disrupted muscle development leading to the suckling failure. Therefore, MG56 seems essential for postnatal skeletal muscle maturation. PMID- 25841339 TI - Combined effect of microRNA, nutraceuticals and drug on pancreatic cancer cell lines. AB - AIM: We proposed to investigate the combination effect of microRNA, nutraceuticals and drug (MND), in two pancreatic cancer cell lines to assess the therapeutic potential. MATERIALS AND METHODS: MIA PaCa-2 and PANC-1 cells transfected with miR-101 or miR-24-2 were treated with Betulinic acid or Thymoquinone and gemcitabine independently and in combination and assessed for the extent of synergism in both experimental and control conditions, considering significance at the p value of <0.05. RESULTS: miR-101 or miR-24-2 over expressing cells when treated with lower than IC50 doses of the dietary compounds and drug showed a reduced (37-50%) viability in two cell lines with differential synergistic effect and the outcome for Pro-caspase3, Poly (ADP-ribose) polymerase (PARP) cleavage and PKM2 expression. CONCLUSION: Two independent microRNA backgrounds showed promise in therapeutic intervention of gemcitabine sensitive, MIA PaCa-2 and resistant, PANC-1 pancreatic cancer cells, in combination with dietary agents and drug. PMID- 25841341 TI - Taming molecular flexibility to tackle rare diseases. AB - Many mutations responsible of Fabry disease destabilize lysosomal alpha galactosidase, but retain the enzymatic activity. These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis. We demonstrate the effectiveness of molecular dynamics simulations to correlate the genotype to the severity of the disease. We studied the relation between protein flexibility and residual enzymatic activity of pathological missense mutants in the cell. We found that mutations occurring at flexible sites are likely to retain activity in vivo. The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases. PMID- 25841340 TI - Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates. AB - The Oxidative Stress Theory of Aging has had tremendous impact in research involving aging and age-associated diseases including those that affect the nervous system. With over half a century of accrued data showing both strong support for and against this theory, there is a need to critically evaluate the data acquired from common biomedical research models, and to also diversify the species used in studies involving this proximate theory. One approach is to follow Orgel's second axiom that "evolution is smarter than we are" and judiciously choose species that may have evolved to live with chronic or seasonal oxidative stressors. Vertebrates that have naturally evolved to live under extreme conditions (e.g., anoxia or hypoxia), as well as those that undergo daily or seasonal torpor encounter both decreased oxygen availability and subsequent reoxygenation, with concomitant increased oxidative stress. Due to its high metabolic activity, the brain may be particularly vulnerable to oxidative stress. Here, we focus on oxidative stress responses in the brains of certain mouse models as well as extremophilic vertebrates. Exploring the naturally evolved biological tools utilized to cope with seasonal or environmentally variable oxygen availability may yield key information pertinent for how to deal with oxidative stress and thereby mitigate its propagation of age-associated diseases. PMID- 25841342 TI - Human and tuberculosis co-evolution: An integrative view. AB - Tuberculosis (TB) ranks as the second cause of death from an infectious disease worldwide after HIV. Archaeogenetics and evolutionary scenario for the Mycobacterium tuberculosis complex (MTBC) are in favor of a long-term interaction between tuberculosis and humans, predating the Neolithic period, contrary to the traditional belief. If tuberculosis evolved as a human pathogen in Africa and has spread outside Africa about more than ten-thousand years ago, its life history traits have been shaped by the immune system. Numerous studies described a variety of human susceptibility factors to TB, suggesting that MTBC strains have evolved different ways to overcome this system. However, the results of these studies reveal some inconsistencies even within populations. The temporally varying history of epidemics and ever-varying genetic diversity of pathogens and strains could easily contribute to blur out signal of selection in our human genome. Palaeomicrobiology gives the opportunity to genotype ancient TB strains circulating in past populations. Accessing ancient human pathogens allows us to a better understanding of infectious agents over a longer time scale and confrontation with the dynamic of modern TB strains. Nevertheless, we have to consider tuberculosis as a multifactorial disorder in which environmental factors interact tightly with human and pathogen genetic. PMID- 25841343 TI - Genetic diversity of the Mycobacterium tuberculosis Beijing family in Brazil and Mozambique and relation with infectivity and induction of necrosis in THP-1 cells. AB - INTRODUCTION: The success of the Mycobacterium tuberculosis Beijing (MtbB) lineage in different geographical regions has been attributed to high transmission, increased virulence, drug resistance and rapid adaptation to the host. In some countries of secondary MtbB dispersion like South Africa and Peru, rising prevalence of the Beijing strains is registered. However, in neighboring countries to affected regions such as Mozambique and Brazil, respectively, the prevalence of these strains is still low and this could be due to biological particularities of the circulating MtbB strains and/or differentiated host susceptibility. OBJECTIVE: To characterize genetically and phenotypically MtbB strains isolated in Brazil (n = 8) and Mozambique (n = 17). METHODS: This is a descriptive study of genotypes of the MtbB isolates, determined by spoligotyping, MIRU-VNTR typing, analysis of the IS6110 copy number in the NTF region and screening for mutations in mutT2, mutT4, rpoB, katG and pks 15/1 genes. Virulence associated properties of the studied isolates were verified in the in vitro model of infection of human THP-1 cells. RESULTS: The genotypes defined by the 24VNTRs were distinct for all isolates included in this study and presented an HGDI of 0.997. The VNTR patterns with seven copies of MIRU26 and seven copies of QUB26, representative for the previously described MtbB genotype B0, dominant in Russia, were detected in 38.5% of the studied isolates. In addition, all isolates presented RD105 deletion and a 7 bp insertion in pks15/1 gene. Almost all tested strains belonged to the RD181 sublineage, with the exception of two strains from Mozambique of RD150 sublineage. Combined analysis of the NTF region integrity and mutations in mutT genes showed that 62.5% and 47% of isolates obtained in Brazil and Mozambique, respectively, were of the ancestral genotype. The virulence index of the ancient isolates, evaluated in the THP-1 cells, was significantly lower than that of the modern genotype group. CONCLUSIONS: These data demonstrate genotype particularities of the Beijing strains isolated in Brazil and Mozambique, two countries of low prevalence of the MtbB lineage in local Mtb populations. In contrast to the neighboring countries with high prevalence of the MtbB strains of modern sublineage, significant proportions of the isolates obtained in Brazil and Mozambique were presented by the strains of the ancient sublineage. Our data suggest that lower virulence of the ancient strains, compared with the modern strains, could be involved in the slow spread of the MtbB strains in some regions. PMID- 25841344 TI - beta-N-methylamino-L-alanine (BMAA) uptake by the animal model, Daphnia magna and subsequent oxidative stress. AB - beta-N-methylamino-l-alanine (BMAA), produced by cyanobacteria, is a neurotoxin implicated in Amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC). BMAA concentrations in cyanobacteria are lower than those thought to be necessary to result in neurological damage thus bioaccumulation or biomagnification is required to achieve concentrations able to cause neurodegeneration. Many cyanobacteria produce BMAA and uptake routes into the food web require examination. In this study we investigate the uptake of BMAA by adult phytoplanktivorus Daphnia magna via exposure to dissolved pure BMAA and BMAA containing cyanobacteria, as well as the subsequent oxidative stress response in the daphnia. Free BMAA and protein-associated BMAA were quantified by LC-MS/MS. Dissolved BMAA was taken up and was found as free BMAA in D. magna. No protein-associated BMAA was detected in D. magna after a 24-h exposure period. No BMAA was detectable in D. magna after exposure to BMAA containing cyanobacteria. BMAA inhibited the oxidative stress defence and biotransformation enzymes within 24-h exposure in the tested Daphnia and could therefore impair the oxidant status and the capability of detoxifying other substances in D. magna. PMID- 25841345 TI - Protective effects of bacterial osmoprotectant ectoine on bovine erythrocytes subjected to staphylococcal alpha-haemolysin. AB - Ectoine (ECT) is a bacterial compatible solute with documented protective action however no data are available on its effects on various cells against bacterial toxins. Therefore, we determined the in vitro influence of ECT on bovine erythrocytes subjected to staphylococcal alpha-haemolysin (HlyA). The cells exposed to HlyA alone showed a distinct haemolysis and reduced glutathione (GSH)/oxidised glutathione (GSSG) level, however the toxic effects were attenuated in the combinations of HlyA + ECT suggesting ECT-induced protection of erythrocytes from HlyA. PMID- 25841346 TI - The potential role of strontium ranelate in treating particle-induced osteolysis. AB - Ultra high molecular weight polyethylene (UHMWPE) wear-particle-induced osteolysis is one of the major issues affecting the long-term survival of total joint prostheses. Currently, there are no effective therapeutic options to prevent osteolysis from occurring. The aim of this study was to evaluate the role of strontium ranelate (SR) in reducing the risk of particle-induced osteolysis. Forty-eight C57BL/6J ultra-high molecular weight polyethylene (UHMWPE) particle induced murine calvarial osteolysis models were used. The mice were randomized into four groups as: sham (Group 1), UHMWPE particles (Group 2), and SR with UHMWPE particles (Group 3 and Group 4). Groups 1 to 3 were sacrificed at two weeks and group 4 was sacrificed at the fourth week. The skulls were then analyzed with a high-resolution micro-CT. Histological evaluation was then conducted and osteoclast numbers were analyzed for comparison. Based on the micro CT, percentage bone volume and trabecular thickness were found to be significantly higher in Group 4 than in Group 2 (p<0.001). Osteoclast numbers in SR treated groups (Group 3 and Group 4) were reduced when compared to groups that did not receive SR treatment (Group 2). These results indicated that SR treatment helps to increase bone volume percentage and trabecular thickness and also suppresses osteoclast proliferation. It is suggested that oral SR treatment could serve as an alternative therapy for preventing particle-induced osteolysis. PMID- 25841347 TI - Effect of tooth bleaching agents on protein content and mechanical properties of dental enamel. AB - This study investigated the effect of two bleaching agents, 16% carbamide peroxide (CP) and 35% hydrogen peroxide (HP), on the mechanical properties and protein content of human enamel from freshly extracted teeth. The protein components of control and treated enamel were extracted and examined on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Marked reduction of the protein matrix and random fragmentation of the enamel proteins after bleaching treatments was found. The mechanical properties were analyzed with Vickers indentations to characterize fracture toughness, and nanoindentation to establish enamel hardness, elastic modulus and creep deformation. Results indicate that the hardness and elastic modulus of enamel were significantly reduced after treatment with CP and HP. After bleaching, the creep deformation at maximum load increased and the recovery upon unloading reduced. Crack lengths of CP and HP treated enamel were increased, while fracture toughness decreased. Additionally, the microstructures of fractured and indented samples were examined with field emission gun scanning electron microscopy (FEG-SEM) showing distinct differences in the fracture surface morphology between pre- and post-bleached enamel. In conclusion, tooth bleaching agents can produce detrimental effects on the mechanical properties of enamel, possibly as a consequence of damaging or denaturing of its protein components. PMID- 25841348 TI - Tunicate-mimetic nanofibrous hydrogel adhesive with improved wet adhesion. AB - The main impediment to medical application of biomaterial-based adhesives is their poor wet adhesion strength due to hydration-induced softening and dissolution. To solve this problem, we mimicked the wound healing process found in tunicates, which use a nanofiber structure and pyrogallol group to heal any damage on its tunic under sea water. We fabricated a tunicate-mimetic hydrogel adhesive based on a chitin nanofiber/gallic acid (a pyrogallol acid) composite. The pyrogallol group-mediated cross-linking and the nanofibrous structures improved the dissolution resistance and cohesion strength of the hydrogel compared to the amorphous polymeric hydrogels in wet condition. The tunicate mimetic adhesives showed higher adhesion strength between fully hydrated skin tissues than did fibrin glue and mussel-mimetic adhesives. The tunicate mimetic hydrogels were produced at low cost from recyclable and abundant raw materials. This tunicate-mimetic adhesive system is an example of how natural materials can be engineered for biomedical applications. PMID- 25841349 TI - Effects of thyroid hormone status on metabolic pathways of arachidonic acid in mice and humans: A targeted metabolomic approach. AB - Symptoms of cardiovascular diseases are frequently found in patients with hypothyroidism and hyperthyroidism. However, it is unknown whether arachidonic acid metabolites, the potent mediators in cardiovascular system, are involved in cardiovascular disorders caused by hyperthyroidism and hypothyroidism. To answer this question, serum levels of arachidonic acid metabolites in human subjects with hypothyroidism, hyperthyroidism and mice with hypothyroidism or thyroid hormone treatment were determined by a mass spectrometry-based method. Over ten arachidonic acid metabolites belonging to three catalytic pathways: cyclooxygenases, lipoxygenases, and cytochrome P450, were quantified simultaneously and displayed characteristic profiles under different thyroid hormone status. The level of 20-hydroxyeicosatetraenoic acid, a cytochrome P450 metabolite, was positively correlated with thyroid hormone level and possibly contributed to the elevated blood pressured in hyperthyroidism. The increased prostanoid (PG) I2 and decreased PGE2 levels in hypothyroid patients might serve to alleviate atherosclerosis associated with dyslipidemia. The elevated level of thromboxane (TX) A2, as indicated by TXB2, in hyperthyroid patients and mice treated with thyroid hormone might bring about pulmonary hypertension frequently found in hyperthyroid patients. In conclusion, our prospective study revealed that arachidonic acid metabolites were differentially affected by thyroid hormone status. Certain metabolites may be involved in cardiovascular disorders associated with thyroid diseases. PMID- 25841350 TI - Different effects of lysophosphatidic acid on L-type calcium current in neonatal rat ventricular myocytes with and without H2O2 treatment. AB - L-type calcium current (I(Ca-L)) alterations are implicated in various cardiac diseases, and the lysophosphatidic acid (LPA) level increases in several ischemic heart diseases. We investigated the effects of LPA on I(Ca-L) in normal and H2O2 treated neonatal rat ventricular myocytes. LPA treatment (24h) increased the action potential duration (APD) and I(Ca-L) in normal ventricular myocytes, but it decreased these parameters in H2O2-treated myocytes. LPA increased the single channel open probability of L-type calcium channels in both normal and H2O2 treated myocytes. LPA activated calcineurin (CaN) and induced the cytoplasm-to nucleus translocation of nuclear factor of activated T-cells (NFAT) in H2O2 treated cardiomyocytes. In H2O2-treated cardiomyocytes, LPA decreased Ca(v)1.2 mRNA and protein expression levels at 4 and 8h, respectively. A CaN inhibitor (FK 506) prevented LPA-induced APD, I(Ca-L), and Ca(v)1.2 mRNA and protein down regulation. The LPA-induced I(Ca-L) increase in normal cardiomyocytes was CaN NFAT signaling-independent, and LPA did not affect Ca(v)1.2 mRNA or protein expression. In conclusion, LPA increases the I(Ca-L) in normal ventricular myocytes by increasing the single-channel open probability of L-type calcium channels, and LPA decreases I(Ca-L) in H2O2-treated cardiomyocytes via the CaN NFAT pathway. PMID- 25841351 TI - Promoter hypermethylation profiling of distant breast cancer metastases. AB - Promoter hypermethylation of tumor suppressor genes seems to be an early event in breast carcinogenesis and is potentially reversible. This makes methylation a possible therapeutic target, a marker for treatment response and/or a prognostic factor. Methylation status of 40 tumor suppressor genes was compared between 53 primary breast tumors and their corresponding metastases to brain, lung, liver, or skin. In paired analyses, a significant decrease in methylation values was seen in distant metastases compared to their primaries in 21/40 individual tumor suppressor genes. Furthermore, primary tumors that metastasized to the liver clustered together, in line with the finding that primary breast carcinomas that metastasized to the brain, skin, or lung, showed higher methylation values in up to 27.5 % of tumor suppressor genes than primary carcinomas that metastasized to the liver. Conversion in methylation status of several genes from the primary tumor to the metastasis had prognostic value, and methylation status of some genes in the metastases predicted survival after onset of metastases. Methylation levels for most of the analyzed tumor suppressor genes were lower in distant metastases compared to their primaries, pointing to the dynamic aspect of methylation of these tumor suppressor genes during cancer progression. Also, specific distant metastatic sites seem to show differences in methylation patterns, implying that hypermethylation profiles of the primaries may steer site specific metastatic spread. Lastly, methylation status of the metastases seems to have prognostic value. These promising findings warrant further validation in larger patient cohorts and more tumor suppressor genes. PMID- 25841352 TI - Pretransplant donor and recipient CTLA-4 mRNA and protein levels as a prognostic marker for aGvHD in allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory T cells' receptor essential for maintaining T cell homeostasis and immunotolerance. The role of the co-stimulatory pathway in development of aGvHD has been studied mostly in animal models. To the best of our knowledge, there are no published data on the role of CTLA-4 in pathogenesis of aGvHD after hematopoietic stem cell transplantation (HSCT) in humans. Therefore the aim of our study was to determine the association of CTLA-4 mRNA and proteins level in HSCT donor-recipient pairs, prior to and after HSCT, with aGvHD risk. METHODS: Total CTLA-4 mRNA level in 51 donor-recipient pairs prior to and 56 days after HSCT was determined using real time PCR techniques, while membrane (m) and cytoplasmic (c) CTLA-4 expression in CD3+ cells were measured by flow cytometry in 40 donor-recipient pairs at the same time points. RESULTS: We found an association between the risk of aGvHD and high pre-transplant CTLA-4 mRNA expression level both in recipients and in donors, stronger in recipients (OR=2.02, CI95% 1.39-3.01), and less pronounced in donors (OR=1.57, CI95% 1.18-2.0). Moreover, we showed that proportion of CD3+ cells positive for mCTLA-4 in recipients prior to HSCT positively correlated with increased risk of aGvHD (OR=1.175, CI95% 1.024-1.311, p=0.018). CONCLUSION: Our results indicate that both donor and recipient CTLA-4 mRNA as well as recipient membrane protein expression levels measured before transplantation may be considered as prognostic factors for aGvHD development. PMID- 25841353 TI - The effect of walking while typing on neck/shoulder patterns. AB - PURPOSE: This project aimed to quantify the effects of modifying computer work posture on neck/shoulder patterns during a prolonged typing task. METHOD: Twenty healthy participants completed a 90-min typing task while sitting or walking on a treadmill. Electromyography (EMG) was recorded from eight upper body muscles and laser Doppler flowmetry (LDF) from two upper body sites. Effects of Time and Posture were assessed for EMG amplitude (RMS), variability (CoV), normalized mutual information (NMI), LDF and upper limb discomfort. RESULTS: Upper limb discomfort was higher during sitting and increased with time, from 0.86 +/- 1.3 to 3.7 +/- 3.1 out of 10. Interaction effects showed that EMG amplitude decreased over time for the lumbar erector spinae (LES) (from 6.3 +/- 2.9 to 5.6 +/- 3.2 % MIVC) and wrist extensor (from 12.4 +/- 2.7 to 11.3 +/- 3.5 % MIVC) during walking, but increased during sitting. Anterior Deltoid EMG amplitude was 64 % lower during walking while External Oblique EMG amplitude (43 %) and Lower Trapezius EMG variability (65 %) were higher during walking. Interaction effects showed higher LES CoV during walking compared to sitting (p = 0.019) in the beginning but not at the end of the task, and higher neck/shoulder NMI (p = 0.050) towards the end of the task during sitting compared to walking. CONCLUSION: Results suggest that walking while performing computer work may be effective in inducing healthier muscular patterns, possibly explaining the lower level of discomfort compared to sitting. PMID- 25841354 TI - A near-isogenic line (NIL) collection in diploid strawberry and its use in the genetic analysis of morphologic, phenotypic and nutritional characters. AB - KEY MESSAGE: First near-isogenic line collection in diploid strawberry, a tool for morphologic, phenotypic and nutritional QTL analysis. Diploid strawberry (Fragaria vesca), with a small genome, has a high degree of synteny with the octoploid cultivated strawberry (F. * ananassa), so can be used as a simplified model for genetic analysis of the octoploid species. Agronomically interesting traits are usually inherited quantitatively and they need to be studied in large segregating progenies well characterized with molecular markers. Near-isogenic lines (NILs) are tools to dissect quantitative characters and identify some of their components as Mendelian traits. NILs are fixed homozygous lines that share the same genetic background from a recurrent parent with a single introgression region from a donor parent. Here, we developed the first NIL collection in Fragaria, with F. vesca cv. Reine des Vallees as the recurrent parent and F. bucharica as the donor parent. A collection of 39 NILs was identified using a set of single sequence repeat markers. The NILs had an average introgression of 32 cM (6 % of genome) and were phenotyped over several years in two locations. This collection segregates for agronomic characters, such as flowering, germination, fruit size and shape, and nutritional content. At least 16 QTLs for morphological and reproductive traits, such as round fruits and vegetative propagation, and seven for nutritional traits such as sugar composition and total polyphenol content, were identified. The NIL collection of F. vesca can significantly facilitate understanding of the genetics of many traits and provide insight into the more complex F. * ananassa genome. PMID- 25841355 TI - Quantification of sugars in breakfast cereals using capillary electrophoresis. AB - About 80% of the Australian population consumes breakfast cereal (BC) at least five days a week. With high prevalence rates of obesity and other diet-related diseases, improved methods for monitoring sugar levels in breakfast cereals would be useful in nutrition research. The heterogeneity of the complex matrix of BCs can make carbohydrate analysis challenging or necessitate tedious sample preparation leading to potential sugar loss or starch degradation into sugars. A recently established, simple and robust free solution capillary electrophoresis (CE) method was used in a new application to 13 BCs (in Australia) and compared with several established methods for quantification of carbohydrates. Carbohydrates identified in BCs by CE included sucrose, maltose, glucose and fructose. The CE method is simple requiring no sample preparation or derivatization and carbohydrates are detected by direct UV detection. CE was shown to be a more robust and accurate method for measuring carbohydrates than Fehling method, DNS (3,5-dinitrosalicylic acid) assay and HPLC (high performance liquid chromatography). PMID- 25841356 TI - Mammogram segmentation using maximal cell strength updation in cellular automata. AB - Breast cancer is the most frequently diagnosed type of cancer among women. Mammogram is one of the most effective tools for early detection of the breast cancer. Various computer-aided systems have been introduced to detect the breast cancer from mammogram images. In a computer-aided diagnosis system, detection and segmentation of breast masses from the background tissues is an important issue. In this paper, an automatic segmentation method is proposed to identify and segment the suspicious mass regions of mammogram using a modified transition rule named maximal cell strength updation in cellular automata (CA). In coarse-level segmentation, the proposed method performs an adaptive global thresholding based on the histogram peak analysis to obtain the rough region of interest. An automatic seed point selection is proposed using gray-level co-occurrence matrix based sum average feature in the coarse segmented image. Finally, the method utilizes CA with the identified initial seed point and the modified transition rule to segment the mass region. The proposed approach is evaluated over the dataset of 70 mammograms with mass from mini-MIAS database. Experimental results show that the proposed approach yields promising results to segment the mass region in the mammograms with the sensitivity of 92.25% and accuracy of 93.48%. PMID- 25841357 TI - Bioavailability of heavy metals in soils: definitions and practical implementation--a critical review. AB - Worldwide regulatory frameworks for the assessment and remediation of contaminated soils have moved towards a risk-based approach, taking contaminant bioavailability into consideration. However, there is much debate on the precise definition of bioavailability and on the standardization of methods for the measurement of bioavailability so that it can be reliably applied as a tool for risk assessment. Therefore, in this paper, we reviewed the existing definitions of heavy metal bioavailability in relation to plant uptake (phytoavailability), in order to better understand both the conceptual and operational aspects of bioavailability. The related concepts of specific and non-specific adsorption, as well as complex formation and organic ligand affinity were also intensively discussed to explain the variations of heavy metal solubility and mobility in soils. Further, the most frequently used methods to measure bioavailable metal soil fractions based on both chemical extractions and mechanistic geochemical models were reviewed. For relatively highly mobile metals (Cd, Ni, and Zn), a neutral salt solution such as 0.01 M CaCl2 or 1 M NH4NO3 was recommended, whereas a strong acid or chelating solution such as 0.43 M HNO3 or 0.05 M DTPA was recommended for strongly soil-adsorbed and less mobile metals (Cu, Cr, and Pb). While methods which assessed the free metal ion activity in the pore water such as DGT and DMT or WHAM/Model VI, NICA-Donnan model, and TBLM are advantageous for providing a more direct measure of bioavailability, few of these models have to date been properly validated. PMID- 25841358 TI - Core outcome domains for clinical trials in non-specific low back pain. AB - PURPOSE: Inconsistent reporting of outcomes in clinical trials of patients with non-specific low back pain (NSLBP) hinders comparison of findings and the reliability of systematic reviews. A core outcome set (COS) can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials. In 1998, Deyo et al. recommended a standardized set of outcomes for LBP clinical research. The aim of this study was to update these recommendations by determining which outcome domains should be included in a COS for clinical trials in NSLBP. METHODS: An International Steering Committee established the methodology to develop this COS. The OMERACT Filter 2.0 framework was used to draw a list of potential core domains that were presented in a Delphi study. Researchers, care providers and patients were invited to participate in three Delphi rounds and were asked to judge which domains were core. A priori criteria for consensus were established before each round and were analysed together with arguments provided by panellists on importance, overlap, aggregation and/or addition of potential core domains. The Steering Committee discussed the final results and made final decisions. RESULTS: A set of 280 experts was invited to participate in the Delphi; response rates in the three rounds were 52, 50 and 45%. Of 41 potential core domains presented in the first round, 13 had sufficient support to be presented for rating in the third round. Overall consensus was reached for the inclusion of three domains in this COS: 'physical functioning', 'pain intensity' and 'health-related quality of life'. Consensus on 'physical functioning' and 'pain intensity' was consistent across all stakeholders, 'health-related quality of life' was not supported by the patients, and all the other domains were not supported by two or more groups of stakeholders. Weighting all possible argumentations, the Steering Committee decided to include in the COS the three domains that reached overall consensus and the domain 'number of deaths'. CONCLUSIONS: The following outcome domains were included in this updated COS: 'physical functioning', 'pain intensity', 'health-related quality of life' and 'number of deaths'. The next step for the development of this COS will be to determine which measurement instruments best measure these domains. PMID- 25841359 TI - Reduction of cement leakage by sequential PMMA application in a vertebroplasty model. AB - PURPOSE: Leakage is the most common complication of percutaneous cement augmentation of the spine. The viscosity of the polymethylmethacrylate (PMMA) cement is strongly correlated with the likelihood of cement leakage. We hypothesized that cement leakage can be reduced by sequential cement injection in a vertebroplasty model. METHODS: A standardized vertebral body substitute model, consisting of aluminum oxide foams coated by acrylic cement with a preformed leakage path, simulating a ventral vein, was developed. Three injection techniques of 6 ml PMMA were assessed: injection in one single step (all-in-one), injection of 1 ml at the first and 5 ml at the second step with 1 min latency in between (two-step), and sequential injection of 0.5 ml with 1-min latency between the sequences (sequential). Standard PMMA vertebroplasty cement was used; each injection type was tested on ten vertebral body substitute models with two possible leakage paths per model. Leakage was assessed by radiographs using a zonal graduation: intraspongious = no leakage and extracortical = leakage. RESULTS: The leakage rate was significantly lower in the "sequential" technique (2/20 leakages) followed by "two-step" (15/20) and "all-in-one" (20/20) techniques (p < 0.001). The RR for a cement leakage was 10.0 times higher in the "all-in-one" compared to the "sequential" group (95 % confidence intervals 2.7 37.2; p < 0.001). CONCLUSIONS: The sequential cement injection is a simple approach to minimize the risk for leakage. Taking advantage of the temperature gradient between body and room temperature, it is possible to increase the cement viscosity inside the vertebra while keeping it low in the syringe. Using sequential injection of small cement volumes, further leakage paths are blocked before further injection of the low-viscosity cement. PMID- 25841360 TI - Affect of antidepressants on the in vitro differentiation of rat bone marrow mesenchymal stem cells into neuronal cells. AB - BACKGROUND: Bone marrow is a valuable source of mesenchymal stem cells (MSCs) that can be used in regenerative medicine. MSCs are able to differentiate into cells from all three germ layers under specific conditions. The aim of the current work was to study the differentiation of rat MSCs (rMSCs) into neuron like cells. NEW METHOD: We investigated how the antidepressants imipramine, desipramine, fluoxetine and tianeptine affect the differentiation of rMSCs. Furthermore, we present differentiation cocktails using a cortex astrocyte conditioned medium (CACM) separately or in conjunction with each of the antidepressants and investigated their additive effect on the efficiency of differentiation. We also observed how various differentiation conditions affect the number of primary dendrites and branching dendrites per cell. RESULTS: Gene expression for an early neuronal marker (beta-III-tubulin) and markers that are typical for adult neurons such as Th, Htr2A and Slc6a4 were observed. The Tubb3 and Htr2A gene expression were up-regulated, Th decreased slightly and Slc6a4 was down-regulated after differentiation We observed a two-fold higher percentage of beta-III-tubulin positive cells after treatment with antidepressants and two-fold increase of neuron-like cells after using CACM with imipramine or fluoxetine simultaneously. Differentiation using imipramine or in conjunction with CACM and desipramine or fluoxetine simultaneously increased the number of cell dendrites. COMPARISON WITH EXISTING METHODS: The results that were obtained are completely new and need further investigations in the nearest future. CONCLUSIONS: These results suggest that antidepressants improve differentiation efficiency of rMSCs and may be useful in the preparation of rMSCs for transplantation. Differentiation efficiency is higher after long-term exposure to antidepressants, than after a 24-h exposure. Nearly additive effect of CACM and imipramine or fluoxetine suggests a beneficial role of antidepressants after transplantation. PMID- 25841361 TI - Evaluation of three-dimensional printing for laparoscopic partial nephrectomy of renal tumors: a preliminary report. AB - OBJECTIVES: To investigate the impact of three-dimensional (3D) printing on the surgical planning, potential of training and patients' comprehension of minimally invasive surgery for renal tumors. METHODS: Patients of a T1N0M0 single renal tumor and indicated for laparoscopic partial nephrectomy were selected. CT data were sent for post-processing and output to the 3D printer to create kidney models with tumor. By presenting to experienced laparoscopic urologists and patients, respectively, the models' realism, effectiveness for surgical planning and training, and patients' comprehension of disease and procedure were evaluated with plotted questionnaires (10-point rating scales, 1-not at all useful/not at all realistic/poor, 10-very useful/very realistic/excellent). The size of resected tumors was compared with that on the models. RESULTS: Ten kidney models of such patients were fabricated successfully. The overall effectiveness in surgical planning and training (7.8 +/- 0.7-8.0 +/- 1.1), and realism (6.0 +/- 0.6-7.8 +/- 1.0) were reached by four invited urologists. Intraoperative correlation was advocated by the two performing urologists. Patients were fascinated with the demonstration of a tactile "diseased organ" (average >= 9.0). The size deviation was 3.4 +/- 1.3 mm. CONCLUSIONS: Generating kidney models of T1N0M0 tumors with 3D printing are feasible with refinements to be performed. Face and content validity was obtained when those models were presented to experienced urologists for making practical planning and training. Understandings of the disease and procedure from patients were well appreciated with this novel technology. PMID- 25841362 TI - Reply to: "Reduced mortality due to phlebotomy in moderately iron-loaded HFE Haemochromatosis? The need for clinical trials". PMID- 25841363 TI - Informed consent and Italian physicians: change course or abandon ship--from formal authorization to a culture of sharing. AB - In Italy in recent years, an exponential increase in the frequency of medical malpractice claims relating to the issue of informed consent has substantially altered not only medical ethics, but medical practice as well. Total or partial lack of consent has become the cornerstone of many malpractice lawsuits, and continues to be one of the primary cudgels against defendant physicians in Italian courtrooms. Physicians have responded to the rising number of claims with an increase in 'defensive medicine' and a prevailing preoccupation with the purely formal aspects of consent. The result is a plethora of consent forms, believed to be a guarantee of 'informed consent', as well as a growing reliance on informed consent as a shield against judicial action brought by the patient. Physicians 'inform' patients without really sharing information, often delegating the task of communication to other professionals who are not doctors. Italian judges always condemn the physician when information to the patient has been inadequate, thus leading insurance companies to consider the lack of valid informed consent as the total responsibility of the physician and/or the hospital. It is necessary to change tack, to remove this idea of consent which permeates the defensive culture of medical practice. Italian physicians need to be trained, first of all, to become aware that information and consent are two distinct processes, albeit closely connected. Valid communication (in which there is information and consent) demands a higher level of professionalism from physicians. PMID- 25841364 TI - Tough and highly stretchable polyacrylamide nanocomposite hydrogels with chitin nanocrystals. AB - Chitin nanocrystals (CNCs) that were 10-20 nm wide and 100-500 nm long were synthetized via acidolysis and characterized with various methods. To avoid the flocculation of CNCs in the initiator solution during acrylamide polymerization, chitosan was selected as a surface modifier. The chitosan-modified CNCs were employed as multifunctional crosslinkers for the polyacrylamide (PAAm) nanocomposite (NC) hydrogels. The NC gels were tough and stretchable; for example, the maximum tensile strength and the elongation at break of the NC gels were 90 kPa and 3070%, respectively. The dynamic shear modulus of the NC gels was also significantly higher than that of the PAAm. The NC gels were nearly free of residual strain after 2000% elongation. The microstructures of all NC gels were porous, with a pore size of 20-100 MUm. The maximum equilibrium swelling degree of the NC gels was 3800%. The improvement in the properties of the NC gels is attributed to the good dispersion of CNCs and the interfacial interactions in the composites. This work developed PAAm NC hydrogels with CNCs for application as absorbent or biomedical material due to the high mechanical properties, high absorb ability and good biocompatibility of CNCs and explored new applications for CNCs as well. PMID- 25841365 TI - EGCG prevents tryptophan oxidation of cataractous ocular lens human gamma crystallin in presence of H2O2. AB - Disruption of the short range order of proteins present in the ocular lens leads to cataract resulting in a loss of transparency. Human gamma-crystallin (HGC), a water soluble protein present in the lens is known to aggregate with aging. A modified form of HGC (HGC(c)) was isolated from cataractous human ocular lens extract and the number of Trp residues that undergo oxidation was determined. The extent of oxidized Trp (N-formyl kynurenine) in HGC due to cataract formation was determined, primarily using fluorescence spectroscopy. The ability of (-) epigallocatechin gallate (EGCG) to retain its antioxidant effect even in the presence of H2O2 was investigated. This was monitored by its ability to prevent the modification of intact Trp residues in HGC(c) isolated from cataractous human eye lens. Significant Trp fluorescence quenching occurs on interaction of the green tea component, EGCG with HGC(c) accompanied by a red shift. Docking studies were employed to substantiate the experimental results. As eye lens proteins are prone to oxidative stress it is essential that a clear understanding of the effects of the components generated in vivo vis-a-vis the antioxidant effects of natural polyphenols be obtained. PMID- 25841366 TI - Effect of the physicochemical properties of binary ionic liquids on lipase activity and stability. AB - In the present study, the lipase-catalyzed hydrolysis of p-nitrophenyl butyrate is used as a model reaction to determine the activity and stability of Candida rugosa lipase in binary ionic liquids (ILs). The binary ILs consist of hydrophobic 1-butyl-3-methylimidazolium hexafluorophosphate ([Bmim]PF6) and a small amount of hydrophilic 1-butyl-3-methylimidazolium nitrate ([Bmim]NO3) or 1 butyl-3-methylimidazolium trifluoromethanesulfonate ([Bmim]CF3SO3) or 1-butyl-3 methylimidazolium tetrafluoroborate ([Bmim]BF4). The activity and the stability of lipase are first correlated with the physicochemical properties of the binary ILs. In the three binary IL systems, both the hydrophilicity and the polarity of the systems increase with the increase of the content of hydrophilic ILs (HILs). At a fixed concentration of HIL, they vary in a descending order of [Bmim]PF6/[Bmim]NO3>[Bmim]PF6/[Bmim]CF3SO3>[Bmim]PF6/[Bmim]BF4. This order is in contrast with the order of the lipase conformation stability, i.e., the higher the polarity of ILs, the more unstable the lipase conformation. However, both the activity and the stability of lipase depend on the type and the content of the HIL in binary ILs, showing a complex dependency. Analysis shows that the catalytic performance of lipase in the binary ILs is affected not only by the direct influence of the ILs on lipase conformation, but also through their indirect influence on the physicochemical properties of water. The present study helps to explore binary IL mixtures suitable for lipase-based biocatalysis. PMID- 25841367 TI - Enhancing catalytic performance of laccase via immobilization on chitosan/CeO2 microspheres. AB - In this study, laccase from Trametes versicolor was immobilized onto chitosan/CeO2 microspheres (CCMS) by adsorption or covalent binding after activating the amine groups of chitosan with glutaraldehyde (GA). The results indicated that the laccase loading on chitosan/CeO2 microspheres was approximately 73 mg/g under the optimum conditions (pH 5.4, 6 h), and the activity recovery was 66.9%. In comparison with free laccase, the thermal and operational stabilities of the immobilized laccase were significantly improved. The catalytic activity of the immobilized laccase was also demonstrated by the decolorization of two reactive dyes (methyl red and orange II). The laccase immobilized on CCMS was very effective for the removal of textile dyes from an aqueous solution. The removal rates of methyl red and orange II by the immobilized laccase were 83.3% and 92.6%, respectively, which are much higher than that of free laccase (i.e., 49.0% and 67.1%, respectively). PMID- 25841368 TI - Chitosan/mangiferin particles for Cr(VI) reduction and removal. AB - In this work, chitosan/mangiferin particles (CMP) were prepared by spray-drying technique and characterized by SEM, DLS, FTIR, HPLC-UV and adsorption studies to investigate a possible application as a preventive material in cases of human and animal contamination with Cr(VI). CMP presented sizes ranging from nano to micrometers. Chitosan and mangiferin (MA) presence in the powder was confirmed by FTIR and MA quantification (136 MUg/mg) was performed using a calibration curve prepared by HPLC-UV. Adsorption capacity of Cr(VI) onto CMP was compared with chitosan and investigated in a batch system by considering the effects of various parameters like contact time, initial concentration of adsorbent and pH. Cr(VI) removal is pH dependent and it was found to be maximum at pH 5.0. The results showed that CMP has a potential application as a preventive material in cases of human or animal contamination with Cr(VI). PMID- 25841370 TI - Characterization of films based on chitosan lactate and its blends with oxidized starch and gelatin. AB - Minimal inhibitory concentration (MIC) of chitosan lactate (CHL) was tested against bacteria and phytopathogenic fungi. Then, the structural, physicochemical and antimicrobial properties of films based on CHL, oxidized potato starch (OPS), and gelatin (GEL) were investigated. With the exception of Rhizopus nigricans, CHL was effective against the target organisms. Gram-positive bacteria (Staphylococcus aureus and Bacillus cereus) were more sensitive to CHL than Gram negative bacteria (Pectobacterium carotovorum and Escherichia coli). Cryo-SEM images showed total miscibility between the polymers in the blends and the ATR FTIR spectra revealed that there was an interaction among the polymeric components. Pure CHL films displayed the highest moisture content (25.51%), water vapor permeability (48.78gmmm(-2)d(-1)kPa(-1)), and the lowest tensile and puncture strength (2.00 and 1.45MPa, respectively) among the studied films. CHL50/GEL50 films had lower permeability, higher mechanical strength, and lower elongation compared to CHL50/OPS50 films. Films obtained from CHL and CHL50/GEL50 were completely water-soluble and did not show sorbitol recrystallization. The incorporation of CHL into OPS and GEL films did not affect their transparency and improved UV-blocking capacity. CHL films were the only ones that exhibited antibacterial efficiency. Antifungal activities against Alternaria alternata and Monilinia fructigena were detected for CHL and CHL50/GEL50 films. PMID- 25841369 TI - Chemical modification of chitin with polypyrrole for the uptake of Pb(II) and Cd(II) ions. AB - This study described the possibility of using chemically modified chitin with polypyrrole (PPy-g-Ch) as an adsorbent for the removal of Pb(II) and Cd(II) ions from aqueous solution. The PPy-g-Ch was characterized using FTIR, SEM, EDX, XRD, TGA and DSC techniques. The influence of various parameters such as pH, dosage, co-ions, contact time and concentration on the removal of Pb(II) and Cd(II) ions was investigated. Among the various isotherm models studied, the Freundlich isotherm model fitted well to the equilibrium data. The magnitude of DeltaG(0), DeltaH(0) and DeltaS(0) indicated the feasibility, spontaneity and the endothermic nature of the adsorption process, respectively. The kinetic process followed the pseudo-second-order kinetic model. The applicability of the PPy-g-Ch has been tested for the removal of Pb(II) and Cd(II) ions from a real water sample spiked with Pb(II) and Cd(II) ions. PMID- 25841371 TI - Amidase, a cell wall hydrolase, elicits protective immunity against Staphylococcus aureus and S. epidermidis. AB - The morbidity and the mortality associated with Staphylococcus aureus and S. epidermidis infections have greatly increased due to the rapid emergence of highly virulent and antibiotic resistant strains. Development of a vaccine-based therapy is greatly desired. However, no staphylococcal vaccine is available till date. In this study, we have identified Major amidase (Atl-AM) as a prime candidate for future vaccine design against these pathogens. Atl-AM is a multi functional non-covalently cell wall associated protein which is involved in staphylococcal cell separation after cell division, host extracellular matrix adhesion and biofilm formation. Atl-AM is present on the surface of diverse S. aureus and S. epidermidis strains. When used in combination with Freund's adjuvant, Atl-AM generated a mixed Th1 and Th2 mediated immune response which is skewed more toward Th1; and showed increased production of opsonophagocytic IgG2a and IgG2b antibodies. Significant protective immune response was observed when vaccinated mice were challenged with S. aureus or S. epidermidis. Vaccination prevented the systemic dissemination of both organisms. Our results demonstrate the remarkable efficacy of Atl-AM as a vaccine candidate against both of these pathogens. PMID- 25841372 TI - Murein hydrolase activity of surface layer proteins from Lactobacillus acidophilus against Escherichia coli. AB - The aim of this study was to investigate the murein hydrolase activities of the surface layer proteins (SLPs) from two strains of Lactobacillus acidophilus using zymography. The influence of these hydrolase activities on Escherichia coli ATCC 43893 was also evaluated by analysing their growth curve, cell morphology and physiological state. After the incubation of E. coli with SLPs, growth was inhibited, the number of viable cells was significantly reduced, examination by transmission electron microscopy showed that the cell wall was damaged and flow cytometry results indicated that the majority of the cells were sublethally injured. All of these results suggested that the SLPs of both L. acidophilus strains possessed murein hydrolase activities that were sublethal to E. coli cells. PMID- 25841373 TI - Biosorption of palladium(II) from aqueous solution by grafting chitosan on persimmon tannin extract. AB - A low-cost and environmentally green biosorbent (PTCS) was prepared by grafting chitosan onto persimmon tannin extract and its potentiality for efficient adsorption of palladium ion (Pd(II)) from aqueous solution was evaluated. Various adsorption parameters such as pH, the initial Pd(II) concentration and temperature were investigated. The maximum adsorption capacity reached 330mg/g at 323K and pH 5.0 when the initial Pd(II) concentration was 100mg/L. The equilibrium adsorption data were satisfactorily fitted with Freundlich isotherm model and biosorption kinetics was found to be in good agreement with pseudo second-order kinetics model. Thermodynamic calculations indicated that the adsorption process was endothermic and spontaneous in nature because of the negative value of free energy change (DeltaG) and positive value of enthalpy change (DeltaH). The positive value of entropy change (DeltaS) revealed the increased randomness at the solid-liquid interface. FT-IR and XRD analysis verified that Pd(II) adsorption on PTCS was electrostatic interaction and redox reaction. Moreover, selective adsorption study revealed that the adsorbent exhibited good adsorption ability to Pd(II) in the mixture metal ions solutions. All these results indicated that the PTCS biosorbent could be used as a low-cost alternative for the adsorption of Pd(II) in waste-water treatment. PMID- 25841374 TI - alpha-Glucosidase inhibition by Tunisian Scabiosa arenaria Forssk. extracts. AB - Recent decades have witnessed a sharp increase in the incidence and prevalence of type 2 diabetes mellitus. One antidiabetic therapeutic approach is to reduce gastrointestinal glucose production and absorption through the inhibition of carbohydrate-digesting enzymes such as alpha-amylase and alpha-glucosidase. In this study, crude extracts and their corresponding fractions of flowers, fruits, (stems and leaves) and roots of the endemic North African plant Scabiosa arenaria Forssk. were screened for their ability of alpha-glucosidase inhibition. It was found that the fruits ethyl acetate (EtOAc), the fruits butanolic (n-BuOH) and the flowers ethyl acetate (EtOAc) fractions inhibited alpha-glucosidase in a non competitive manner with IC50 values of 0.11+/-0.09, 0.28+/-0.04 and 0.221+/ 0.01mg/ml, respectively. RP-HPLC analysis indicated that the major components of these active fractions are flavonoid aglycone, cinnamic acid and its derivatives. This result supports the conclusion that the three studied fractions could be a useful natural source for the development of a novel alpha-glucosidase inhibitory agent against diabetic complications. PMID- 25841375 TI - Structural elucidation of inhomogeneous lignins from bamboo. AB - A better understanding of the inhomogeneous molecular structure of lignin from bamboo is a prerequisite for promoting the "biorefinery" technologies of the bamboo feedstock. A mild and successive method for fractionating native lignin from bamboo species was proposed in the present study. The molecular structure and structural inhomogeneity of the isolated lignin polymers were comprehensively investigated by elemental analysis, carbohydrate analysis, state-of-the-art NMR and analytical pyrolysis techniques (quantitative (13)C NMR, (13)C-DEPT 135 NMR, 2D-HSQC NMR, (31)P NMR, and pyrolysis-GC-MS). The results showed that the proposed method is effective for extracting lignin from bamboo. NMR results showed that syringyl (S) was the predominant unit in bamboo lignin over guaiacyl (G) and p-hydroxyphenyl (H) units. In addition, the lignin was associated with p coumarates and ferulates via ester and ether bonds, respectively. Moreover, various substructures, such as beta-O-4, beta-beta, beta-5, beta-1, and alpha,beta-diaryl ether linkages, were identified and quantified by NMR techniques. Based on the results obtained, a proposed schematic diagram of structural heterogeneity of the lignin polymers extracted from the bamboo is presented. In short, well-defined inhomogeneous structures of native lignin from bamboo will facilitate further applications of bamboo in current biorefineries. PMID- 25841376 TI - Spectroscopy study and co-administration effect on the interaction of mycophenolic acid and human serum albumin. AB - Mycophenolic acid (MPA), an immunosuppressor, is always administered in combination with several drugs in clinical therapy, which may alter the binding of MPA to human serum albumin (HSA) and could influence its pharmacological activities. Thus, this study evaluated the interaction between HSA and MPA, as well as investigated the effect of co-administrated drugs on the MPA-protein binary system using fluorescence spectroscopy. Results revealed that MPA has a strong capability to quench the fluorescence of HSA, and the acting forces for the binding are hydrogen bonds and van der Waals forces. Competition on combined administration showed that balofloxacin significantly affects the MPA-HSA interaction, as reflected by the remarkable decrease in fluorescence intensity. Furthermore, cefminox sodium has competitive capability with MPA to some extent, whereas methyl prednisone and amlodipine besylate have a minor influence on the binary system. However, simvastatin has no appreciable effect on the MPA-HSA interaction. In addition, three-dimensional fluorescence spectra and circular dichroism spectroscopy, which were employed to determine the conformation, showed that the binding of MPA with HSA can induce conformation changes in HSA. PMID- 25841377 TI - Antifungal activity of chitooligosaccharides against the dermatophyte Trichophyton rubrum. AB - Antifungal activity against the dermatophytic fungus Trichophyton rubrum by a well-characterized chitooligosaccharides (COS) sample, hydrolyzed using a recombinant chitosanase, was investigated in vitro and in vivo. The minimum inhibitory concentration (MIC) of COS ranged between 0.25 and 0.50%, which was measured using a microdilution method. Analysis of inhibition rates using an agar diffusion method showed that treatment with 0.5% and 1% COS significantly suppressed T. rubrum cell growth (p<0.05 and p<0.01, respectively, in comparison with untreated control). Morphological changes and structural alterations of cells were observed by TEM. In vivo efficacy of COS in treatment of T. rubrum dermatophytosis was evaluated using a guinea pig model. Skin lesion scores revealed a strong, dose-dependent therapeutic effect of COS. The 5% COS group showed a reduction of skin lesions even greater than that of the positive control group treated with 1% fluconazole (FCZ). Histological analysis revealed no inflammation or tissue destruction in the groups treated with 5% COS or 1% FCZ. Hyperkeratosis was also observed, perhaps resulting from a defensive response of the tissue cells to COS. The findings indicate that COS has excellent potential for development of novel antifungal drugs for clinical treatment/remission of dermatophytoses. PMID- 25841378 TI - Purification, antioxidant and hepatoprotective activities of polysaccharide from Cissus pteroclada Hayata. AB - Polysaccharide of Cissus pteroclada Hayata (CPHP) was extracted and purified. Three major fractions (CPHP I, CPHP II-1 and CPHP II-2) from the CPHP were purified by column chromatography and investigated for their monosaccharide compositions, scavenging radical effects and hepatoprotective activities in vitro. The results showed that glucose and galactose were the main monosaccharides of three polysaccharide fractions, CPHP II-1 and CPHP II-2 were acidic polysaccharide fractions which contained glucuronic acid and galacturonic acid. Antioxidant activity determination suggested that CPHP I and CPHP II-1 had a higher scavenging effects on DPPH, superoxide radical, hydroxyl radical and ABTS radical. And the results of antioxidant test in vitro showed that CPHP II-2 could significantly increase (P<0.01) the activities of SOD and GSH-Px and decreased MDA level in human hepatocyte cell line (HL7702 cell), which indicating that CPHP II-2 possessed good hepatoprotective activity. PMID- 25841379 TI - Selective recognition of specific G-quadruplex vs. duplex DNA by a phenanthroline derivative. AB - A key problem in designing G-quadruplex ligand is how to discriminate quadruplex DNA specifically from other DNAs, searching ligands targeted at special G quadruplex structure with high selectivity is a major challenge. Herein, a phenanthrolin-dicarboxylate ester (PD) is proved to exhibit selectivity toward parallel and hybrid G-quadruplex structures with propeller and edge-wise loops, over duplex DNA and antiparallel quadruplex structure with diagonal loop. Such preferred binding of PD to these special G-quadruplex structures is possibly resulted from steric hindrance of: (1) the four substituent groups in PD molecule which prevent close interaction with duplex DNA and (2) the diagonal loop above the G-tetrads in antiparallel G-quadruplex which hinder face-to-face stacking of planar phenanthrolin ring to G-tetrads. In line with its stabilizing ability of G quadruplex, PD molecule exhibit a inhibitory ability telomerase activity, as well as the potent cytotoxic activity against several human cancer cell lines, which makes it an interesting anti-tumor drug lead. PMID- 25841380 TI - The interaction of amino acids, peptides, and proteins with DNA. AB - Amino acids that carry charges on their side groups can bind to double stranded DNA (dsDNA) and change the strength of the double helix. Measurement of the DNA melting temperature (Tm) confirmed that acidic amino acids (Glu, Asp) weaken the H-bonds between DNA strands, whereas basic amino acids (Arg, Lys) strengthen the interaction between the strands. A rank correlation exists between the amino acid isoelectric points and the observed changes in Tm. A similar dependence of the hyperchromic effect on the isoelectric point of a protein (pepsin, insulin, cortexin, and protamine) was observed for DNA-protein complexes at room temperature. Short peptides (KE, AEDG, and KEDP) containing a mixture of acidic and basic amino acid residues also affect Tm and the stability of the double helix. A model for binding Glu and Lys to dsDNA was explored by a docking simulation. The model shows that Glu, in an untwisted shape, binds to dsDNA in its major groove and disrupts three H-bonds between the strands, thereby destabilizing the double helix. Lys, in an untwisted shape, binds to the external side of the dsDNA and forms two bonds with O atoms of neighboring phosphodiester groups, thereby strengthening the DNA helix. PMID- 25841381 TI - Development of receptor-based inhibitory RNA aptamers for anthrax toxin neutralization. AB - Anthrax toxin excreted by Bacillus anthracis is the key causative agent of infectious anthrax disease. In the present study, we targeted the binding of PA to the ATR/TEM8 Von Willebrand factor type A (VWA) domain, which we cloned into Escherichia coli and purified to homogeneity under denaturing conditions. To develop an anthrax toxin inhibitor, we selected and identified short single strand RNA aptamers (approximately 30mer) consisting of different sequences of nucleic acids with a high binding affinity in the 100 nanomolar range against the recombinant ATR/TEM8 VWA domain using systematic evolution of ligands by exponential enrichment (SELEX). Five candidate aptamers were further characterized by several techniques including secondary structural analysis. The inhibitor efficiency (IC50) of one of the aptamers toward anthrax toxin was approximately 5MUM in macrophage RAW 264.7 cells, as determined from cytotoxicity analysis by MTT assay. We believe that the candidate aptamers should be useful for blocking the binding of PA to its receptor in order to neutralize anthrax toxin. PMID- 25841382 TI - Applications of chitosan powder with in situ synthesized nano ZnO particles as an antimicrobial agent. AB - ZnO nanoparticles are immobilized on the chitosan matrix by an in situ sol-gel conversion of precursor molecules in a single step. Three different composites are prepared by varying the concentration of sodium hydroxide with same quantity of chitosan and zinc acetate dihydrate. The composites were characterized by FTIR, UV-visible spectra, and XRD. The observed decrease in the band width corresponding to OH and NH2 group in the composites is ascribed to the reduction of hydrogen bond due to the presence of ZnO nanoparticles. The direct evidence of the immobilization of nano ZnO particles in the matrix was identified by SEM. The average particle size values obtained for the nanoparticles, using Debye-Scherrer equation from XRD, is in the range 10-18nm. Optical studies proved that all the three composites studied have the same band gap energy (3.28eV) in agreement with the reported values. We observed that the composites possess excellent antimicrobial activity against Gram negative bacteria Escherichia coli (E. coli) and Gram positive bacteria Staphylococcus aureus (S. aureus) than chitosan. Based on the above studies, the biocompatible, eco-friendly and low-cost composite powder could be applied in various fields as an antimicrobial agent. PMID- 25841383 TI - Explosive radiation or uninformative genes? Origin and early diversification of tachinid flies (Diptera: Tachinidae). AB - Molecular phylogenetic studies at all taxonomic levels often infer rapid radiation events based on short, poorly resolved internodes. While such rapid episodes of diversification are an important and widespread evolutionary phenomenon, much of this poor phylogenetic resolution may be attributed to the continuing widespread use of "traditional" markers (mitochondrial, ribosomal, and some nuclear protein-coding genes) that are often poorly suited to resolve difficult, higher-level phylogenetic problems. Here we reconstruct phylogenetic relationships among a representative set of taxa of the parasitoid fly family Tachinidae and related outgroups of the superfamily Oestroidea. The Tachinidae are one of the most species rich, yet evolutionarily recent families of Diptera, providing an ideal case study for examining the differential performance of loci in resolving phylogenetic relationships and the benefits of adding more loci to phylogenetic analyses. We assess the phylogenetic utility of nine genes including both traditional genes (e.g., CO1 mtDNA, 28S rDNA) and nuclear protein-coding genes newly developed for phylogenetic analysis. Our phylogenetic findings, based on a limited set of taxa, include: a close relationship between Tachinidae and the calliphorid subfamily Polleninae, monophyly of Tachinidae and the subfamilies Exoristinae and Dexiinae, subfamily groupings of Dexiinae+Phasiinae and Tachininae+Exoristinae, and robust phylogenetic placement of the somewhat enigmatic genera Strongygaster, Euthera, and Ceracia. In contrast to poor resolution and phylogenetic incongruence of "traditional genes," we find that a more selective set of highly informative genes is able to more precisely identify regions of the phylogeny that experienced rapid radiation of lineages, while more accurately depicting their phylogenetic context. Although much expanded taxon sampling is necessary to effectively assess the monophyly of and relationships among major tachinid lineages and their relatives, we show that a small number of well-chosen nuclear protein-coding genes can successfully resolve even difficult phylogenetic problems. PMID- 25841384 TI - The upcoming book, The Art and Science of Palliative Medicine, edited by Howard S. Smith and Julie G. Pilitsis. PMID- 25841385 TI - The PARAMOUNT trial in NSCLC: is the amount of benefit clinically meaningful? AB - The PARAMOUNT study recently updated for survival analysis, showed that continuous maintenance with pemetrexed (P) lead to a 3 months overall survival (OS) benefit in non-small cell lung cancer (NSCLC) patients not progressing after P-based induction chemotherapy. The conclusion are that, continuing P alone up to progression of disease, is better that stop chemotherapy after 4 cycles of cisplatinum/P doublet, at the expense of a slightly worst toxicity compared to placebo arm, and no worsening of quality of life. If the benefit in this population of performance status 0-1 (and nonsquamous histology) subjects, would have been the same with reintroduction of P (or with any active second line available) at the progression of disease, is a matter of debate. Appropriate randomized trials are ongoing and will answer to this question. PMID- 25841386 TI - Expectations as outcome of effectiveness for patients with metastatic lung cancer. AB - In patients that presented advanced or metastatic non-small-cell lung cancer (NSCLC), palliative treatments, as chemotherapy and radiation therapy (RT), play a central role to manage symptoms, prolong life, and improve quality of life (QoL). Although these treatments are not curative, our patients deserve different expectations regarding their effectiveness based on different variables, as communication skills, family support and psychological status. Expectations of effectiveness are related to communications between patients and physician that is the corner stone of "relationship" between patients and disease. In this article, we explore this interesting issue analysing the most interesting criticism. PMID- 25841387 TI - End of life care in lung cancer patients: not at life's end? AB - Metastatic lung cancer has a poor prognosis, with a mortality of more than 80% within one year. As chemo- and radiotherapy are both effective in the palliation of symptoms, the emphasis of management is often too much put on these therapies, inducing unrealistic expectations. Since the most important aspect of caring for patients with metastatic lung cancer is to optimize or restore their quality of life (QoL), we need to integrate standard oncologic therapy with early palliative care to achieve a better understanding of the disease by the patient and his caregivers. PMID- 25841388 TI - How many drugs in the maintenance setting for non-small-cell lung cancer? For what benefit? AB - Maintenance treatment has been used for several years inside clinical trials. Meta-analyses have been published. A new clinical trial (AVAPERL) has been recently published. Despite significant increase of progression-free survival (PFS), overall survival (OS) has not been changed with these strategies. Before a transfer into clinical practices and guidelines, new data on economic analyses (the cost effectiveness ratio was very high among specific studies) and quality of life are mandatory. PMID- 25841389 TI - The use of opioids at the end-of-life and the survival of Egyptian palliative care patients with advanced cancer. AB - BACKGROUND AND AIM: One of the barriers to cancer pain control and palliative care (PC) development is the misconception that the use of opioids may hasten death. This concern is exaggerated when higher doses of opioids are used at the end-of-life. The aim of this study was to investigate the relationship between survival and the dose of opioids used at the end-of-life of patients with advanced cancer in an Egyptian PC setting. METHODS: Retrospective review of the medical records of 123 patients with advanced cancer managed in an Egyptian cancer center-based palliative medicine unit (PMU). Patients were classified according to the last prescribed regular opioid dose expressed in milligrams of oral morphine equivalent (OME) per day (mg OME/24 h) into three groups: no opioid or low-dose group (<120 mg OME/24 h), intermediate-dose group (120-<300 mg OME/24 h) and high-dose group (>=300 mg OME/24 h). Survival was calculated from the date of first referral to the PMU to death. RESULTS: The median age of patients was 53 years, breast cancer was the most common diagnosis (18%) and the majority (68%) died at home. Opioids were prescribed for pain control in 94% of patients and were prescribed on regular basis in 89%. The mean last prescribed opioid dose for the whole group of patients was 167 (+/-170) mg OME/24 h and it was highest among patients with pleural mesothelioma [245 (+/-258) mg OME/24 h]. The last prescription included no opioids or low-dose opioids in 57 (46%) patients, intermediate-dose in 42 (34%) and high-dose in 24 (20%). The estimated median survival was 45 days for the no opioid/low-dose group, 75 days for the intermediate-dose group and 153 days for the high-dose group (P=0.031). CONCLUSIONS: The results suggest that the dose of opioids has no detrimental impact on the survival of patients with advanced cancer in an Egyptian PC setting. Further research is needed to overcome barriers to cancer pain control especially in settings with inadequate cancer pain control. PMID- 25841390 TI - Palliative care for patients with locally advanced and metastatic non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) often presents at an advanced stage and can result in a significant symptomatic burden. Many patients with advanced NSCLC experience symptoms that include pain, dyspnea, cough, decreased appetite, weight loss, and depression. Early initiation of palliative care for advanced or metastatic NSCLC can reduce symptoms, improve quality of life, and prolong survival. Palliative care interventions by an interdisciplinary team focus on patient and family and address physical symptoms, illness understanding, coping, and psychosocial and spiritual distress. The addition of systemic therapy to best supportive care can further improve quality of life and prolong survival. Thoracic external beam radiation therapy beam radiotherapy is well tolerated and can improve quality of life and relieve symptoms such as hemoptysis, pain, cough, and dyspnea. For central airway obstruction, external beam radiation therapy, endobronchial brachytherapy, Nd:YAG laser therapy, and photodynamic therapy can improve symptoms. Symptomatic lung metastases to the brain, adrenal glands, and liver or compressing or impinging the spinal cord or nerve roots can also result in patient symptoms and can be managed with medical and pharmacologic interventions, radiation therapy, surgery, ablative therapy, and systemic therapy. All healthcare providers treating patients with advanced or metastatic NSCLC should make palliative care a priority by assessing for pain, dyspnea, coping and psychosocial distress, and other symptoms at each patient encounter to reduce patient morbidity, improve quality of life, and potentially prolong survival. PMID- 25841391 TI - Opioid combination: rationale and possible clinical applications. AB - The aim of this review is to provide a potential benefit of an opioid combination at receptor sites, based on experimental data and preliminary clinical studies where a combination of opioids with different characteristics yielded greater analgesic activity with lesser adverse effects. The receptor activity, including intrinsic activity, endocytosis, and oligomerization, and the interaction on opioid receptors and between different opioid receptors or different sites are described. Finally, clinical observations of opioid combinations reported in literature regarding the possible benefits of such an approach are presented. PMID- 25841393 TI - Commentary on Alsirafy et al. The use of opioids at the end-of-life and the survival of Egyptian palliative care patients with advanced cancer. PMID- 25841392 TI - Bridging the communication gap between oncologists and patients receiving palliative therapies. AB - The discussion of prognosis is a regular component of oncology practice. When the prognosis is poor, the disclosure can be difficult for both patients and physicians alike. In a recent article by Chen et al., stage IIIB and IV lung cancer patients were surveyed on their beliefs about radiotherapy they were receiving. A significant proportion of patients expressed the belief that radiotherapy, which they were receiving purely with palliative intent, was likely to cure their cancer. Misunderstanding the goals of treatment can have important consequences with respect to informed decision-making and end-of-life planning. There are likely many factors contributing to this misunderstanding, both from the perspective of the patient as well as the physician. Discussing incurable disease in a clear, honest manner without taking away hope can be very challenging for the physician. Even when done well, patients often do not hear or completely understand the message. Focusing on active treatment may in fact perpetuate the patient's belief that they can be cured. In this article, some of the factors contributing to inaccurate beliefs are discussed. Awareness of the issue, and approaching the patient in a somewhat different manner when disclosing prognosis, may help patients to develop more appropriate beliefs about their disease and treatment. Ultimately the goal is for patients to make decisions that align with their beliefs and values, which can only be done if they have clear understanding of prognosis. PMID- 25841394 TI - The importance of surgical oncology in China: a view from across the ocean. PMID- 25841395 TI - Perspectives in drug development for cancer therapy in Asia. PMID- 25841396 TI - Clinical practice guidelines on cancer-related anemia (2012-2013 Edition). PMID- 25841397 TI - Risk of venous thromboembolism with the erythropoiesis-stimulating agents (ESAs) for the treatment of cancer-associated anemia: a meta-analysis of randomized control trials. AB - BACKGROUND: In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate the overall risk of venous thromboembolism (VTE) associated with the use of ESAs, a systematic review and meta-analysis of published randomized controlled trials (RCT) was performed. METHODS: The databases of PubMed and Web of Science were searched from January 1966 until December 2012 and abstracts presented at American Society of Clinical Oncology conferences held between January 2000 and December 2012 were searched to identify relevant clinical trials. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. RESULTS: Data from a total of 11,632 patients with cancer in 50 RCTs were identified and included for meta-analysis. Among those patients receiving ESAs, the summary incidences of all-grade VTE were 7.62%. Patients with cancer who received ESAs had increased VTE risks (482 events among 6,238 patients treated with ESA vs. 269 events among 5,394 control patients; RR=1.75; 95% CI, 1.49-2.05). The highest risk of VET was found in patients with ovarian and cervical cancer for 2.45 (1.12-5.33). CONCLUSIONS: The use of ESAs was significantly associated with an increased risk of developing VTE in cancer patients receiving this drug. The risks of VTE may vary with various tumor types. PMID- 25841398 TI - The latest meta-analysis on the use of erythritopoiesis-stimulating agents in chemotherapy induced anaemia brings new light on the safety. PMID- 25841399 TI - Intravenous iron for treating cancer-induced anemia: meeting an unmet need? PMID- 25841400 TI - Is it time for erythropoietin use in acute myeloid leukemia and allogeneic hematopoietic stem cell transplantation patients? PMID- 25841401 TI - Is it already time for combination treatment in lower risk MDS? PMID- 25841402 TI - Breakthrough in tracking tumor erythropoietin receptor expression. PMID- 25841403 TI - High-dose recombinant human erythropoietin for "low-risk" myelodysplastic patients: is more better? PMID- 25841404 TI - Erythropoietin and cancer - a poorly understood liaison! PMID- 25841405 TI - Sandra M. Swain: follow your passion at work. PMID- 25841406 TI - Charles M. Balch: specializing surgeons is going to be a trend. PMID- 25841407 TI - Claus-Henning Koehne: the awareness of K-Ras is a great progress in molecular targeted therapy. PMID- 25841408 TI - Rik J Scheper: European Regulations on cell therapy, going too far? PMID- 25841409 TI - The changing world of drug development. AB - Cancer drug development is undergoing a substantial shift nowadays. The underlying drivers are multi-factorial. On the one side, drug development is performed more rationally than ever, profiting from the scientific advances in molecular biology in general and the elucidation of the various "omes" from genome to metabolome in particular. On the other side, it is based on enormous technological progress, e.g., in the field of genome sequencing, and in that of adequate handling of the resulting plethora of data. The high attrition rate of oncologic drugs under development in the past and the pressure from the side of the payers make it necessary to find permanently new answers for and adaptations of the process of drug development. In this context, it is necessary to respect arguments and views from the various perspectives of all the relevant stakeholders. Together with a group of international experts from different perspectives of drug development, this special issue will illustrate the respective role of patients, laboratory, clinical trials, drug companies, regulatory bodies, and also the economic principle in drug development, aiming at facilitating drug research in the near future. PMID- 25841410 TI - The spectrum of clinical trials aiming at personalizing medicine. AB - All anticancer molecularly targeted agents on the market today have been approved with one or no companion diagnostic based on a specific genomic molecular alteration. These drugs have followed the same clinical development than chemotherapeutic agents and have been developed in selected tumor types and histologies. Now, some molecular alterations have been described across different tumor types, although with variable prevalence and functional impact. The latter raises the question of whether treatment decision should be mainly based on molecular biology, independently of tumor location and histology. This approach refers to what is commonly named personalized medicine and can today be addressed in clinical trials, since major advances in high throughput technologies allow depicting most druggable molecular alterations for an affordable cost in a timeframe that is compatible with clinical practice. Several studies have been initiated that aim at personalizing medicine in oncology. They include molecular screening programs, as well as personalized medicine trials that can be divided in two categories: (I) stratified clinical trials according to either molecular alterations or tumor types; and (II) algorithm-testing trials evaluating a treatment algorithm instead of drugs efficacy. Multiple challenges are associated with personalized medicine trials, but the main one remains our ability to predict drug efficacy based on molecular alterations. It is expected that taking into account several molecular alterations for the prediction of drug efficacy using systems biology approaches will improve patients' outcome. Bioinformatics research will be an important factor of future progression in this emerging field. PMID- 25841411 TI - Integrative oncology drug discovery accompanied by preclinical translational research as prerequisite for clinical development. AB - The molecular heterogeneity of cancer calls for individualized therapies to become the standard of care. It is now generally accepted that target-specific compounds require specific new development programs. But, even for new drugs with general mode of action (i.e., chemotherapy), tailored treatment approaches, such as specific schedules or combinations, have been shown to improve the therapeutic outcome. Therefore, the preclinical development of new therapeutic agents needs, next to the "classical pharmacodynamic studies", the implementation of integrative translational research (TR) as early as possible. New TR approaches, starting already at target identification and validation (TIV) will allow to defining the optimal patient population for clinical development, to tailor individual treatment of the tumor disease and to choose a rational basis among the manifold options for treatment combinations. We will discuss several examples from TR studies, which have initially been started to evaluate the molecular mode of action and to recognize mechanisms which can lead to resistance. Research was extended later to identify predictive response biomarkers and establish a rationale for combination with different therapies. A detailed gene expression analysis of lung cancer cells and apoptotic pathway interference studies in colon cancer cells provided insight in the molecular mechanisms of action. These new findings are correlated with results from other studies performed during the preclinical development program. We discuss pros and cons, successes and failures of our integrative preclinical development program and provide recommendations for future oncology projects. PMID- 25841412 TI - From genomic data analysis to drug development: a new generation of trials using molecular marker assessment in breast cance. AB - With the advent of molecular subtypes in breast cancer, the landscape of clinical trials and drug development is rapidly changing. Molecular screening identifies numerous mutations but actually druggable targets are few and far between. Thus, new clinical trial concepts are needed which are feasible in clinical practice and successful from the point of view of drug development. This article highlights the evolution of the sequencing technologies, the current molecular screening efforts and their impact on drug development as well as novel successful trial designs, focusing on the hormone receptor (HR) positive breast cancer patients. The range of mutations to identify in order to adapt the treatment to each patient and limit the resistance mechanisms is quite wide already, but theoretical or practical restriction may have to be considered to optimize the development of such adaptive combinations of targeted therapies. PMID- 25841413 TI - Functional and molecular imaging in cancer drug development. AB - Imaging biomarkers have a potential to identify key metabolic pathways that are up-regulated in cancer cells compared to normal cells. In early drug development, they can provide valuable information on the dissemination of the drug and estimate whether the drug reaches the target and, consequently, to determine the appropriate clinical benefit. The use of imaging as an early surrogate biomarker of response is also appealing, since it allows to tailor treatment regimens in individual patients. The aim of this review is to describe various imaging biomarkers covering most important cancer hallmarks such as cell death, proliferation, metabolism, vascularity, and hypoxia. We highlight the current status of using molecular imaging such as fluorodeoxyglucose (FDG), fluorothymidine (FLT), fluoromisonidazole (FMISO), and fluoroazomycin arabinoside (FAZA) positron emission tomography (PET) as well as advanced magnetic resonance imaging (MRI) techniques such as dynamic contrast enhancing (DCE) and diffusion weighted (DW)-MRI, and their potential roles in cancer drug development. PMID- 25841414 TI - New challenge of developing combined radio-drug therapy. AB - Combined modality treatment can be used to improve control of the local disease at the expense of increased toxicity. Several randomized trials have demonstrated that this combined modality therapy is better than radiotherapy alone or chemotherapy alone in the treatment of locally advanced diseases. Several new targets as well as potential new radio-sensitizers have been identified. To speed up the process of developing new combined modality treatments, good preclinical models for optimization of the ratio between efficacy and toxicity and a well established methodology within a network of advanced high-tech laboratories and clinical departments devoted to early phase trials, are mandatory. The Synergy of Targeted Agents and Radiation Therapy (STAR) platform of the European Organisation for Research and Treatment of Cancer (EORTC) is gathering these tools. PMID- 25841415 TI - The changing world of drug development: an academic research organization's perspective on the "Seven Wonders" of the future world of anticancer drug development. AB - Cancer poses a considerable economic burden to healthcare systems worldwide, so healthcare payers will only pay for "performance" in the future. It is likely that new "wonders" have emerged and as a scientific community we need to learn how we can make future cancer research more efficient. Biobanking and imaging platforms will allow full use of this wealth of data for defining and testing hypotheses before the launch of fewer, but ambitious, pivotal clinical studies targeting large therapeutic benefit. Clinical trials must be based on optimized trial designs with sound methodologies and high qualities. These multidisciplinary therapeutic strategies need to be in the new generation of patient treatment planning. In order to accelerate patient access to new treatments and techniques, better harmonized regulatory procedures and new forms of multi-stakeholder collaboration are needed in future drug development. PMID- 25841416 TI - The changing world of oncology drug development-A global pharmaceutical company's perspective. AB - Recent approvals for oncology drugs have seen an increasing proportion directed to specific genetic targets identified with an associated companion diagnostic test. In addition, there is a wave of drugs directed against immune 'checkpoints' which promise to transform the way cancer is treated in the next decade. We can increase the probability of success in drug development based on a thorough mechanistic understanding of how a target drug affects cancer biology and the specific biological and genotypic context in which it operates. This article compares and contrasts the discovery and development of gefitinib-the first EGFR tyrosine kinase inhibitor and AZD9291, an irreversible inhibitor of both sensitizing and resistant mutated EGFR. This demonstrates how the better understanding we now have of the genetic changes driving the cancer growth and the biochemical structure and function of the mutated proteins, has led to a much faster developmental path with higher likelihood of success in pivotal trials. An emerging trend in response to the challenge of the increasing segmentation of cancers based on their genetic makeup is the development of 'basket' studies which include one or more screening tests for multiple genetic aberrations and the direction of patients to one of several arms of a clinical trial based on the specific aberration in their tumor. In the face of both the wealth of genetic information about cancer and the challenges of drug development, collaboration across academia and industry is vital. There is great potential to benefit from more 'open innovation' to address some of these challenges and opportunities. Far from there being a decline in innovation in pharmaceutical development, I see that we are in one of the most exciting times in cancer drug development with innovation in every aspect of how we discover and develop new therapies. PMID- 25841417 TI - Medicine adaptive pathways to patients (MAPPs): using regulatory innovation to defeat Eroom's law. AB - Eroom's Law is, literally, Moore's law in reverse. The pharmaceutical sector invests $50 billion annually in research for new medicines but, "the number of new drugs approved per billion US dollars spent has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms". Pharmaceutical companies have invested enormous sums in new molecular entities (NME) in the areas of unmet medical need identified by the World Health Organization (WHO), but the approval rates from phase I are only 7% for cardiovascular disease, dropping to 4% for Alzheimer's disease. The increasing cost of research & development (R&D) is not only a factor of research management quality, but also indicative of an industry trying to address therapeutic areas that have incredibly complex biological mechanisms with budget-crushing failure rates. Medicine adaptive pathways to patients (MAPPs) build on the stratification breakthroughs of personalized medicine to facilitate new types of clinical trials that adapt to a given patient's response. At their core, MAPPs will have a limited commercial marketing authorization for a patient group who has access to new therapeutic agents while validating additional clinical endpoints at the same time. This gives MAPPs a theoretical ability to run trials that fulfil both the efficacy requirements for authorization and the effectiveness needs of national health technology assessments (HTA) simultaneously, providing patients with needed therapies in the most efficient timescale and trial size possible. In order to move science forward and meet these daunting medical challenges for patients, new collaborative approaches to testing the efficacy and effectiveness of new improved medicines such as MAPPs should be embraced by regulators in close partnership with patients, payers, and practitioners. To not do so puts the entire healthcare value chain, and the future health of patients, at risk. PMID- 25841418 TI - The changing world of cancer drug development: the regulatory bodies' perspective. AB - BACKGROUND: Although not a singular disease entity, advanced cancer continues to be a largely intractable disease and a high unmet medical need situation. Discovery of novel therapeutic modalities, including new drugs targeting cancer, is undoubtedly of major public health interest. METHODS: In this article, we discuss current trends in oncology drug development as these are ultimately reflected in regulatory drug approvals. RESULTS AND CONCLUSIONS: These include the shift to targeted therapies which hold the promise of personalized medicine, but also financial pressures, the call for adaptive licensing which places more emphasis on early access and post-authorization studies (patient registries, prospective interventional and observational studies) and real-life effectiveness studies, as well as the emergence of biosimilars in the oncology treatment armamentarium. PMID- 25841419 TI - The positioning of economic principles under the changing conditions of the novel drug developmental process in cancer. AB - Cancer is a major burden to the health care system, presently mainly in developed countries, but is rapidly becoming a problem of similar magnitude in developing countries. Cancer ranks number two or three measured in loss of "good years of life" in Europe. The direct cost of cancer are estimated to be around 50% of total health care costs and of these costs a major part is linked to cancer drugs. With the ongoing revolution in the understanding of cancer and the development of an increasing number of new, but often very costly drugs, the health care systems in all parts of the world need to have a systematic way of evaluating new cancer drugs. Health technology assessment (HTA) now plays a major role in many parts of Europe. HTA has its focus on determining the value of new innovations in order to balance allocation of health care resources in a fair and equal way. This paper reviews the HTA process in general and for cancer drugs specifically. The key findings are that cancer drugs must be evaluated in a similar way as other health care technologies. One must however take into account that cancer drugs are often approved with a high level of uncertainty. Thus, it is of key importance that not only clinical efficacy, i.e., effect in pivotal clinical trials, is taken into account, but that there is a great need for follow up studies so that post regulatory approval is able to properly measure population based effects [clinical effectiveness (CLE)]. PMID- 25841420 TI - And now for something completely different: drugs that work!-The patients' perspective. AB - The result of drug development so far is beyond expectations and also beyond what is possible. The reason for this is probably that the aim is not a better quality of life for the patient and her loved ones but profit. Working together with patients on an equal basis-and in the patients' best interest-will bring better drugs to the market that work and provide better quality of life and with less severe side effects. For the pharmaceutical companies that want to benefit patients, it will bring enough profit. Essential is that we are honest about our interests and respect the interest of one another. And go for the win-win situation instead of the compromise. We can also do better by doing research on combinations of new and existing drugs. This might be faster available for patients and also cheaper. The government can help by making the rules for drug development easier on safety. The cooperation with patients will still make things safe enough. The government has to support the patient advocacy groups financially to make them less dependent on the pharmaceutical companies. And finally, the patient advocacy groups can do a lot to make the patients, doctors, researchers, government and industry more cancer literate. PMID- 25841421 TI - Introduction to the inaugural issue of Annals of Palliative Medicine. PMID- 25841422 TI - Opioid-induced hyperalgesia method is a clinically relevant issue. PMID- 25841423 TI - The double cross of morphine: Stopping OIH in its tracks. PMID- 25841424 TI - Opioid-induced hyperalgesia: What to do when it occurs? PMID- 25841425 TI - Cancer pain management: What should be done to improve effectiveness? PMID- 25841426 TI - Opioid-induced hyperalgesia after rapid titration with intravenous morphine: Switching and re-titration to intravenous methadone. AB - BACKGROUND: Rapid titration with intravenous morphine (IV-MO) provides fast and efficient pain relief in cancer patients with severe-excruciating pain. However, some patients, after an initially favourable response, can develop an hyperexcitated state unrelieved or worsened by further dose increments. METHODS: Eighty-one patients admitted on emergency basis titrated with IV-MO were assessed. RESULTS: 12 patients were unsuccessfully titrated with IV-MO. Switching to intravenous methadone (IV-ME) and titrating the doses proved to be successfully. CONCLUSIONS: In escalating opioid doses rapidly a recognition of the development of hyperalgesia should be suspected. Increasing doses of opioids may stimulate rather than inhibiting the central nervous system, with complex mechanisms already recognized in experimental studies. Switching to IV-ME and titrating the doses could be taken into consideration to break this vicious circle before pain conditions worsen irreversibly. PMID- 25841427 TI - Painful boney metastases. AB - Treatments for painful osseous metastases may not only diminish pain, but also may improve quality of life and independence/mobility, and reduce skeletal morbidity, potential pathologic fractures, spinal cord compression, and other "skeletal-related events". Treatment strategies for painful osseous metastases include: Systemic analgesics, intrathecal analgesics, glucocorticoids, radiation (external beam radiation, radiopharmaceuticals), ablative techniques [radiofrequency ablation (RFA) and cryoablation], bisphosphonates, chemotherapeutic agents, inhibitors of RANKL-RANK interaction (e.g., denosumab), hormonal therapies, interventional techniques (e.g., kyphoplasty), and surgical approaches. The mechanisms underlying the development of bone metastases remain incompletely understood. A greater understanding of the pathophysiology of painful osseous metastases may lead to improved and more selective targeted analgesic therapy. Additionally, potential future therapeutic approaches to painful osseous metastases may revolutionize approaches to analgesia for this condition, leading to optimal outcomes with maximal pain relief and minimal adverse effects. PMID- 25841428 TI - Assessment and treatment of cancer pain: From Western to Eastern. AB - Satisfactory control of the cancer pain remains the single most important element in palliative care, as failure of pain relief is a major threat to the quality of life. Inadequate classification and assessment would unavoidably lead to inappropriate and impractical treatment of cancer pain, which has been a striking challenge in cancer clinical practice for the past several decades. While the cancer pain characteristics are influenced by physiological, psychological, pathological, cultural and even social factors, a comprehensive assessment and an individualized plan of care should be provided throughout the course of illness. This review attempted to describe the framework, illustrate the present evidence supporting current classification methodologies and assessment approaches, and demonstrate the advance in multidisciplinary interventions for cancer pain syndrome, including Western and Traditional Chinese medicine. PMID- 25841429 TI - Rapid onset opioids in palliative medicine. AB - Opioids are potent broad-spectrum analgesics useful to treat a variety of painful conditions. Opioids have been classified by many different categorizations (e.g. natural, semisynthetic, synthetic). One classification that may be useful in terms of selecting specific opioid agents is based on the pharmacokinetic characteristics of the various opioid formulations (e.g. longacting opioids, short-acting opioids, and rapid onset opioids). These various opioid agents appear to be useful to "match" specific types of pains. Rapid onset opioids appear especially well-suited to treat breakthrough pain and in particular, rapidonset breakthrough pain. This article will briefly review 5 rapid onset opioids that are FDA approved in the U.S. PMID- 25841430 TI - Advances in the use of opioids in treating neuropathic cancer pain. AB - Neuropathic cancer pain has been challenging for both physicians and patients. As opioids' positive analgesic effect has been confirmed by some randomized studies in recent years, they are gradually becoming a first line option for the treatment of neuropathic cancer pain. Researches and trials in this field mainly concentrate on the pathogenesis of the pain and the metabolism, excretion and potential analgesic mechanisms of different opioids. Selective use of opioids, which has a dual mechanism of action, may be helpful in controlling neuropathic cancer pain. This review summarizes the different properties and usages of a variety of opioids. PMID- 25841431 TI - Neuromodulation and palliative medicine. AB - The palliative care population is generally vulnerable to experiencing medication induced adverse effects and drug-drug interactions. Neuromodulation may offer particular advantages over systemic medications in this population. Although brain electrical stimulation has not been adequately trialed or in some cases even tried at all for management of a variety of symptoms, it is conceivable that in the future that it may be a potential therapeutic option in efforts to palliate various severe refractory symptoms. PMID- 25841432 TI - Palliative radiotherapy for painful bone metastases: short-course or long-course? AB - For patients of bony metastases, the survival time becomes much longer as the anti-tumor strategies developed. External beam radiotherapy is effective for pain relieving. The appropriate fractionation scheme for the most effective regimen of palliative radiotherapy to treat bone metastases is still in debate. This article reviews the prospective randomized trials comparing short-course or long-course regimens of palliative radiotherapy for painful bone metastases. PMID- 25841433 TI - Painful bone metastases - Can we do better? PMID- 25841434 TI - Denosumab will play an important role in patients with solid tumours and bone metastases. PMID- 25841435 TI - Early palliative care in patients with metastatic non-small cell lung cancer. PMID- 25841436 TI - Delivery outcomes and patterns of morbidity and mortality for neonatal admissions in five Kenyan hospitals. AB - A cross-sectional survey was conducted in neonatal and maternity units of five Kenyan district public hospitals. Data for 1 year were obtained: 3999 maternal and 1836 neonatal records plus tallies of maternal deaths, deliveries and stillbirths. There were 40 maternal deaths [maternal mortality ratio: 276 per 100 000 live births, 95% confidence interval (CI): 197-376]. Fresh stillbirths ranged from 11 to 43 per 1000 births. A fifth (19%, 263 of 1384, 95% CI: 11-30%) of the admitted neonates died. Compared with normal birth weight, odds of death were significantly higher in all of the low birth weight (LBW, <2500 g) categories, with the highest odds for the extremely LBW (<1000 g) category (odds ratio: 59, 95% CI: 21-158, p < 0.01). The observed maternal mortality, stillbirths and neonatal mortality call for implementation of the continuum of care approach to intervention delivery with particular emphasis on LBW babies. PMID- 25841437 TI - dbPSP: a curated database for protein phosphorylation sites in prokaryotes. AB - As one of the most important post-translational modifications, phosphorylation is highly involved in almost all of biological processes through temporally and spatially modifying substrate proteins. Recently, phosphorylation in prokaryotes attracted much attention for its critical roles in various cellular processes such as signal transduction. Thus, an integrative data resource of the prokaryotic phosphorylation will be useful for further analysis. In this study, we presented a curated database of phosphorylation sites in prokaryotes (dbPSP, Database URL: http://dbpsp.biocuckoo.org) for 96 prokaryotic organisms, which belong to 11 phyla in two domains including bacteria and archaea. From the scientific literature, we manually collected experimentally identified phosphorylation sites on seven types of residues, including serine, threonine, tyrosine, aspartic acid, histidine, cysteine and arginine. In total, the dbPSP database contains 7391 phosphorylation sites in 3750 prokaryotic proteins. With the dataset, the sequence preferences of the phosphorylation sites and functional annotations of the phosphoproteins were analyzed, while the results shows that there were obvious differences among the phosphorylation in bacteria, archaea and eukaryotes. All the phosphorylation sites were annotated with original references and other descriptions in the database, which could be easily accessed through user-friendly website interface including various search and browse options. Taken together, the dbPSP database provides a comprehensive data resource for further studies of protein phosphorylation in prokaryotes. Database URL: http://dbpsp.biocuckoo.org PMID- 25841440 TI - Carbon monoxide augments electrical signaling in cultured neural networks of hippocampal neurons partly through activation of BKCa channels. AB - Carbon monoxide (CO) is often viewed as a lethal gas in light of its capacity to prevent oxygen uptake in hemoglobin; however, it also functions to regulate a variety of proteins and physiological processes. Here we show that CO is an important chemical cue, to which neurons respond strongly, and this response is then integrated into neural network activity. In cultured mouse hippocampal neurons, CO enhanced synchronized spontaneous cytosolic Ca(2+) oscillations which arose from periodic action potentials through synaptic transmission. We used single-cell patch-clamp recording to investigate the neural network. Our results showed that the frequency of spontaneous and miniature post synaptic current was increased in neurons cultured for 14-18 days after addition of CO, with no change in current amplitude. BK channels have recently been demonstrated to be important in the action of CO. Our results showed that the effect of CO on neural network electrical activity was partly abolished after blocking the BK channels. Altogether, our results suggest that CO can influence neural network electrical activity and that BK channels participate in this regulation process. PMID- 25841438 TI - Generating a focused view of disease ontology cancer terms for pan-cancer data integration and analysis. AB - Bio-ontologies provide terminologies for the scientific community to describe biomedical entities in a standardized manner. There are multiple initiatives that are developing biomedical terminologies for the purpose of providing better annotation, data integration and mining capabilities. Terminology resources devised for multiple purposes inherently diverge in content and structure. A major issue of biomedical data integration is the development of overlapping terms, ambiguous classifications and inconsistencies represented across databases and publications. The disease ontology (DO) was developed over the past decade to address data integration, standardization and annotation issues for human disease data. We have established a DO cancer project to be a focused view of cancer terms within the DO. The DO cancer project mapped 386 cancer terms from the Catalogue of Somatic Mutations in Cancer (COSMIC), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium, Therapeutically Applicable Research to Generate Effective Treatments, Integrative Oncogenomics and the Early Detection Research Network into a cohesive set of 187 DO terms represented by 63 top-level DO cancer terms. For example, the COSMIC term 'kidney, NS, carcinoma, clear_cell_renal_cell_carcinoma' and TCGA term 'Kidney renal clear cell carcinoma' were both grouped to the term 'Disease Ontology Identification (DOID):4467 / renal clear cell carcinoma' which was mapped to the TopNodes_DOcancerslim term 'DOID:263 / kidney cancer'. Mapping of diverse cancer terms to DO and the use of top level terms (DO slims) will enable pan-cancer analysis across datasets generated from any of the cancer term sources where pan cancer means including or relating to all or multiple types of cancer. The terms can be browsed from the DO web site (http://www.disease-ontology.org) and downloaded from the DO's Apache Subversion or GitHub repositories. Database URL: http://www.disease-ontology.org PMID- 25841439 TI - Parthenolide inhibits LPS-induced inflammatory cytokines through the toll-like receptor 4 signal pathway in THP-1 cells. AB - Parthenolide (PTL) shows potent anti-inflammatory and anti-cancer activities. In the present study, the molecular mechanisms of PTL's activities were explored in lipopolysaccharide (LPS)-induced human leukemia monocytic THP-1 cells and human primary monocytes. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2 (4-sulfophenyl)-2H-tetrazolium salt (MTS) assay was used to analyze the effect of PTL on THP-1 cell viability. Enzyme-linked immunosorbent assay was used to determine the effect of PTL on LPS-induced inflammatory cytokine secretion. Flow cytometry and quantitative real-time polymerase chain reaction were used to assess the effect of PTL on LPS-induced toll-like receptor 4 (TLR4) expression. Phosphorylation levels of signaling molecules were determined by western blot analysis. Results showed that PTL <12.5 MUM did not significantly affect THP-1 cells viability. LPS treatment led to a marked up-regulation of interleukin (IL) 6, IL-1beta, IL-8, IL-12p40, tumor necrosis factor-alpha, IL-18, and NO in THP-1 cells. However, PTL inhibited the expression of these cytokines in a dose dependent manner, with IC50 values of 1.091-2.620 MUM. PTL blocked TLR4 expression with an IC50 value of 1.373 MUM as determined by the flow cytometry analysis, and this blocking effect was verified at both protein and mRNA levels. Up-regulation of phosphorylation levels of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, p38, nuclear factor kappaB (NF-kappaB) p65, and IkappaBalpha and up-regulation of expressions of other molecules (inducible nitric oxide synthase, TLR4, and TNF receptor-associated factor 6) induced by LPS were abolished by PTL in a dose-dependent manner. The anti-inflammatory mechanisms of PTL operate partly through the TLR4-mediated mitogen-activated protein kinase and NF-kappaB signaling pathways. Therefore, TLR4 may be a new target for anti-inflammation therapies. PMID- 25841441 TI - Calibration ruler for CW-EPR distance measurement using diradical molecule of rigid structure. AB - Many experimental factors and uncontrollable factors may introduce errors in the distance measurement by continuous wave electron paramagnetic resonance. To deal with this problem, several C60 nitroxide diradical adducts with rigid structure and definite molecular dimension were used as distance calibration rulers. Based on the improvement of distance calculation program via adding simulation programs of experimental spectra and dipolar broadening function, respectively, the distance calibration method was developed under different conditions such as different solvent, solution concentration, measuring temperature, and microwave power. As a result, stable distance calibration rulers were established within the range of 8-13 A. The distance calibration effect was evaluated resulting in a corresponding distance measurement precision of 0.84 A. The results suggested that the influence of non-dipolar spectral broadening factors could be overcome, and the established experimental and calculation methods were suitable to a wide range of situations. The developed method will ensure more accurate and objective distance measurement in biomacromolecular analysis. PMID- 25841442 TI - Thiazide-sensitive Na+-Cl- cotransporter: genetic polymorphisms and human diseases. AB - The thiazide-sensitive Na(+)-Cl(-) cotransporter (TSC) is responsible for the major sodium chloride reabsorption pathway, which is located in the apical membrane of the epithelial cells of the distal convoluted tubule. TSC is involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl(-) concentration below or above its electrochemical potential equilibrium. In addition, TSC serves as the target of thiazide-type diuretics that are the first line of therapy for the treatment of hypertension in the clinic, and its mutants are also reported to be associated with the hereditary disease, Gitelman's syndrome. This review aims to summarize the publications with regard to the TSC by focusing on the association between TSC mutants and human hypertension as well as Gitelman's syndrome. PMID- 25841443 TI - Can EGFR mutation status evolve with chemotherapy? PMID- 25841444 TI - EGFR mutation in lung cancer: tumor heterogeneity and the impact of chemotherapy. PMID- 25841445 TI - Drifting EGFR mutation. PMID- 25841446 TI - Molecular therapy for gastric cancer. AB - Several agents that target specific molecules have been investigated for the treatment of gastric cancer in many preclinical and clinical studies. Anti-HER2 antibody, when combined with classical cytotoxic agents, has been shown to confer a significant survival benefit in patients with HER2-positive gastric cancer. This is the only targeted drug that has been shown to be successful for the treatment of gastric cancer. We need to determine specific targets for regulating gastric cancer cells by translational research, develop precise diagnostic procedures for personalized medicine, and identify candidate drugs for gastric cancer. PMID- 25841447 TI - Current status and future direction of chemotherapy for pancreatic cancer. PMID- 25841448 TI - The B7-H1/PD-1 pathway in cancers associated with infections and inflammation: opportunities for therapeutic intervention. AB - Almost one fifth of malignancies worldwide and about one quarter in China are associated with viral or bacterial infections, mediating an inflammatory environment in the tumor. Hepatitis viruses (B and C), Epstein Barr Virus (EBV), and helicobacter pylori have been linked to liver, gastric, and nasopharyngeal cancer. The context of infection and chronic inflammation in these cancers may provide an opportunity for therapeutic intervention based on the role of immune checkpoint pathways, which are an important defense mechanism of many cancers against a tumor-directed immune response. Specifically, the expression of the inhibitory receptor PD-1 on the surface of activated T cells has been associated with T cell exhaustion in inflammatory and tumor environments. Furthermore, tumors have been found to over-express the PD-1 ligand B7-H1. Recent therapeutic successes with monoclonal antibodies directed against both B7-H1 and PD-1 in patients with advanced melanoma, renal cell cancer (RCC), and non-small cell cancer, along with the prominent role of this immune checkpoint axis in the inflammatory tumor context, suggest that B7-H1/PD-1 blockade may be particularly beneficial in cancers associated with infections and inflammation. PMID- 25841449 TI - Colorectal cancer screening: are stool and blood based tests good enough? AB - Colorectal cancer (CRC) is the third commonest cancer worldwide. As many CRC patients were identified at advanced stages, screening asymptomatic individuals has substantial clinical benefit. Most CRC arises through recognizable early stage. With the improved understanding of the biology of CRC and precancerous lesion, testing molecular aberrations in stool and blood promises novel screening approaches that are noninvasive, sensitive, and more affordable compared with traditional structural examinations. PMID- 25841450 TI - The future of clinical research in oncology: where are we heading to? AB - Despite considerable investment in oncological research, the rate of improvement in cancer treatments remains frustratingly slow and the attrition rate in anticancer drug development has reached exasperatingly high levels. New skills are required to expand upon platforms to integrate clinical, biological and imaging data in the decision making process so that we can control the attrition rate of new drugs and/or determine tumor molecular sub-entities which will ultimately benefit new therapeutic strategies. Furthermore, modern clinical trials will be unable to generate reliable and robust evidence if they are not quality assured. Decreasing the number of poorly designed clinical trials through stronger collaboration between industry and academia is a win-win situation and will reduce the current high attrition rate and minimize exposure of patients to ineffective investigational therapies. PMID- 25841451 TI - Paradigm of polyendocrine therapy in endocrine responsive breast cancer: the role of fulvestrant. PMID- 25841452 TI - Systemic treatment of cutaneous and mucosal melanoma. PMID- 25841453 TI - Melanoma adjuvant therapy. AB - The risk of recurrence and death after complete surgical resection of clinically detectable primary cutaneous melanoma ranges from low, intermediate to high risk depending on the stage of disease at diagnosis. This is defined by the depth, ulceration status and mitotic rate of the primary tumor, the presence of regional nodal disease or distant metastasis. For high-risk melanoma, adjuvant therapy aims at eradicating melanoma micrometastases in those patients that carry an unacceptable risk of mortality from melanoma recurrence. The ultimate goal of adjuvant therapy is to provide a potential cure before progression into advanced inoperable stages. After decades of randomized clinical trials, interferon-alpha alone has been shown to have a significant impact on relapse free survival and at high dosage on overall survival. These survival benefits were seen in comparison to observation (E1684 trial) and the ganglioside GMK vaccine (E1694 trial). Advances in our understanding of melanoma molecular biology and host immunology have given ways to novel targets and therapeutic agents that have demonstrated unprecedented results in the management of metastatic disease and currently are being tested in the adjuvant stetting where recent data support a significant clinical impact of adjuvant ipilimumab. Here, we review the standard of care melanoma adjuvant therapy along with the main completed, current and planned clinical trials. PMID- 25841454 TI - Treatment of BRAF-mutated advanced cutaneous melanoma. AB - The field of melanoma oncology has recently awakened with groundbreaking scientific advances and innovative therapeutic strategies. New groups of small molecule kinase inhibitors targeting the aberrant mitogen-activated protein kinase (MAPK) pathway activation mediating tumor growth and survival have revolutionized the therapeutic approach to advanced melanoma. BRAF and MEK inhibitors are the first groups of agents that improved all clinical efficacy endpoints, including response rate, progression-free survival (PFS) and overall survival (OS), in patients with BRAF-mutated advanced melanoma when compared with standard chemotherapy in randomized phase III studies. However, despite the impressive clinical responses in patients with BRAF mutant advanced melanoma, duration of response to MAPK pathway-targeted therapy remains limited, implicating rapid emergence of drug resistance. Diverse strategies to overcome tumor resistance to MAPK inhibitors, the focus of today's translational and clinical research, will further improve the clinical outcome for patients with BRAF-mutated advanced melanoma in the near future. PMID- 25841455 TI - BRAF, MEK and KIT inhibitors for melanoma: adverse events and their management. AB - The introduction of tyrosine kinase inhibitors for the treatment of malignant melanoma has led to unprecedented response rates with superior overall survival rates in patients with targetable kinase mutations. Even though targeted, the effects of these new therapies are not limited to the cancer cells and induce a wide array of different adverse events (AEs). Most toxicities are mild to moderate in severity and often only affect the skin, but quality of life of patients is still affected. To prevent dose reduction and/or interruption, a sound knowledge of potential AEs and their management is required. BRAF inhibitors should not be used in patients with known RAS-mutant tumour in the medical history. We review common AEs of BRAF, MEK and KIT inhibitors used for the treatment of malignant melanoma and their management. PMID- 25841456 TI - Checkpoint inhibitors in the treatment of cutaneous malignant melanoma. AB - Advanced malignant melanoma has historically been considered a uniformly lethal disease. Recent scientific strides have led to unprecedented understanding of both the molecular alterations and the mechanisms of immune evasion in this malignancy. The realization that an intense and dynamic interplay of stimulatory and inhibitory signals occurs in the "immune synapses" among T cells, tumor cells and dendritic cells, led to the development and subsequent clinical testing of agonist and antagonist monoclonal antibodies (mAb) that can modulate these signals. The resulting positive outcomes of the clinical trials utilizing CTLA-4, PD-1 and PD-L1 modulating drugs, has catapulted the field of immunotherapy into the realm of standard treatment. In this article we review the most important agents and clinical data feeding the ongoing paradigm change in the treatment of advanced melanoma. PMID- 25841457 TI - Toxicity of checkpoint inhibitors. AB - Immunologic checkpoint inhibitor is a new class of antineoplastic drugs which mechanism of action depends on the interaction with the immune system. The first in class was ipilimumab, anti-CTLA4, and soon the anti-PD1 (Programmed Death 1) and anti-PDL1 are expected to be available. Although the profile of adverse events is unique, they are predictable and, by complying with the guidelines available, the management of these drugs is safe in the great majority of patients. Here, it is provided a review of adverse events and their management. PMID- 25841458 TI - Algorithm for the management of metastatic cutaneous melanoma. AB - Over the last 4 years, various drugs have been approved for the treatment of metastatic cutaneous melanoma. Ipilimumab, an anti-CTLA-4 inhibitor that stimulates antitumor immunity, was the first agent to improve overall survival both in first line and in previously treated patients. Ipilimumab results in long term disease control in approximately 20% of the patients. Vemurafenib was the first BRAF inhibitor (BRAFi) approved and also resulted in improved overall survival compared with dacarbazine in patients with BRAF mutated metastatic melanoma. More recently, another BRAFi, dabrafenib, and a MEK inhibitor, trametinib, were approved either alone or in combination as they each showed significant antitumor activity relative to dacarbazine and the combination appeared superior to dabrafenib monotherapy. The major feature of such tumor targeted therapy is its high response rate (40-70%) and the rapidity of the responses, resulting in prompt clinical improvement. However, unlike immunotherapy, targeted therapy does not result in long-term treatment free survival. In this paper, we discuss how best to integrate the currently available treatment options including high-dose interleukin-2 (HD IL-2), systemic chemotherapy, ipilimumab and tumor targeted therapy in various clinical scenarios. PMID- 25841459 TI - Adjuvant therapy of mucosal melanoma. AB - Mucosal melanoma is a rare subtype of melanoma and associated with extremely poor prognosis. However, standard adjuvant therapy for mucosal melanoma has not been established. Some approaches have been studied to reduce the risk of recurrence in patients. These include adjuvant chemotherapy, immunotherapy, targeted therapy, and radiotherapy (RT). In this review we aim to summarize and evaluate the therapies in development. PMID- 25841460 TI - Genotyping of mucosal melanoma. AB - Mucosal melanoma is rare and associated with extremely poor prognosis. Mucosal melanoma has historically been refractory to traditional therapeutic approaches. Recently molecularly based targeted drugs show great success in melanoma. The success of these drug strategies can be partially attributed to the identification of the genetic alterations responsible for the development and progression of metastatic melanoma. This review will focus on genes involved in two major mucosal melanoma-related signaling pathways, the RAS/RAF/mitogen activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinases (PI3K)-AKT pathway, and detail the current understanding of their roles in melanoma progression. Additional mutations in key genes, such as KIT, GNAQ and MITF, in mucosal melanoma will also be introduced. Finally, an overview of the current targeted therapy landscape will be provided. PMID- 25841461 TI - Treatment of KIT-mutated metastatic mucosal melanoma. AB - Mucosal melanoma is a rare, aggressive histologic subtype of malignant melanoma, and prognosis for patients with metastatic mucosal melanoma is very poor. In general, conventional cytotoxic agents alone or in combination with immunologic drugs have limited clinical benefit. Advances in molecular analytic techniques have helped researchers discover genetic aberrations in KIT, a receptor tyrosine kinase, in nearly 40% of patients with mucosal melanoma. Preclinical studies have demonstrated that hot-spot mutations, mostly substitutions in exons 11 and 13, result in constitutive activation of KIT and its downstream signal transduction pathways, such as the MEK/ERK, PI3K/AKT and JAK/STAT pathways. KIT inhibitors, most notably imatinib, have shown promising clinical activity in KIT-mutant advanced melanoma, including mucosal melanoma, with clinical response rates exceeding 35% in patients with hot-spot mutations in exon 11 or 13 and/or a high mutant/wild-type allelic ratio. However, the duration of disease control is rather short in general, and treatment with KIT inhibitors as single agents is not optimal. Well-designed mechanistic studies aimed at assessing molecular differences between various KIT mutations or other aberrations and mechanisms of resistance are urgently needed to improve KIT-targeting therapy for melanoma. In addition, with availability of checkpoint inhibitors, such as anti-CTLA4 and/or anti-PD-1 antibodies, immunotherapies using those inhibitors alone or in combinations of such immunotherapies with KIT inhibitors may lead to more effective therapeutic regimens. This review discusses the rationale for KIT inhibitor therapy in patients with metastatic mucosal melanoma and the findings of preclinical and clinical studies of KIT inhibitors in this patient population. PMID- 25841462 TI - Chemotherapy, biochemotherapy and anti-VEGF therapy in metastatic mucosal melanoma. AB - Mucosal melanomas arise from melanocytes located at various mucosal membranes, which demonstrate a clear demographic and ethnic disparity. This subtype of melanoma has more aggressive course and poorer prognosis than other subsets of melanomas. Due to their rarity, there is no well-established protocol of staging and treatment of mucosal melanomas. Significant advances have been achieved in novel immunotherapeutic and specific targeted agents for metastatic melanomas. For mucosal melanoma patients especially without known gene mutation, anti angiogenic therapy combined with chemotherapy or other targeted drugs has shown promising efficacy, either as first- or second-line treatment. In some subset analysis, patients with mucosal melanoma, harboring wild type BRAF, might get more clinical and survival benefits than cutaneous ones. Therefore it is rational to further study these therapeutic strategies in the group of mucosal melanoma. Chemotherapy or biochemotherapy only showed limited efficacy without significant survival improvement, but larger sample size study is still required. Herein we presented a comprehensive review of chemotherapy/biochemotherapy and anti vascular endothelial growth factor (anti-VEGF) therapy in metastatic mucosal melanoma. PMID- 25841463 TI - Checkpoint inhibitors in treatment of metastatic mucosal melanoma. AB - Mucosal melanoma (MM) is rare and of extremely poor prognosis. Although significant progress has been made in developing new therapies for patients with metastatic melanoma arising from the cutaneous, knowledge about the effects of treatments for patients with MM is limited. In this review we aim to summarize and evaluate related trials. PMID- 25841464 TI - Treatment algorithm of metastatic mucosal melanoma. AB - Mucosal melanoma is usually considered as the most aggressive and treatment resistant subtype of melanoma. The unsatisfactory results of standard clinical therapies for metastatic melanoma highlight the needs for effective new therapeutic strategies. Recent successes in the development of new therapies for metastatic melanoma, such as inhibitors for mitogen-activated protein kinase (MAPK) pathway and blocking antibodies against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway, have yielded promising results, expanding the continually evolving landscape of therapeutic options for patients with this disease. In this chapter we review chemotherapies, immunotherapies, targeted therapies and angiogenesis therapies in metastatic mucosal melanoma and discuss their implications. PMID- 25841465 TI - Biomarker based clinical trial design. AB - The established molecular heterogeneity of human cancers and the subsequent stratification of conventional diagnostic categories require the development of new paradigms for the development of a reliable basis for predictive medicine. We review clinical trial designs for the development of new therapeutics and predictive biomarkers to inform their use. We cover designs for a wide range of settings. At one extreme is the development of a new drug with a single biomarker and strong biological evidence that marker negative patients are unlikely to benefit from the new drug. At the other extreme are phase III clinical trials involving both genome-wide discovery and internal validation of a predictive classifier that identifies the patients most likely and unlikely to benefit from the new drug. PMID- 25841466 TI - On independent data monitoring committees in oncology clinical trials. AB - BACKGROUND: An independent data safety monitoring committee (IDMC) that is established to monitor the safety of participants in a clinical trial has, as its primary purpose, the protection of participants in the trial and the maintenance of the integrity of the trial. The IDMC should operate under a clear charter, with expectations understood by all its members. The investigators and sponsors should trust their IDMCs and give the IDMC the tools that it needs to operate effectively. The need to separate the investigators of randomized clinical trials from ongoing data has become widely appreciated. Especially when the study in question is a so-called 'phase III', or confirmatory, trial, knowledge of ongoing results can subtly or explicitly affect the care of participants in the trial, the methods of data collection, and the recruitment of new participants into the trial. These changes, if data-driven, can induce bias and therefore affect the scientific integrity of the trial. Failure to monitor the ongoing data, however, may put patients at undesirable risk, especially if emerging data indicate an unknown adverse consequence of therapy. The use of IDMCs has increased perhaps in response to the growing sophistication of the community of clinical trialists, the US Food and Drug Administration (FDA) draft guidance on data monitoring committees, the US National Institutes of Health (NIH)'s current rules for data monitoring plans, and the Data Monitoring Committees: Lessons, Ethics, Statistics Study Group from the UK National Health Service (DAMOCLES) recommendations. METHODS: This article summarizes and describes the design and operations of IDMCs in oncology. RESULTS: IDMCs in oncology share many similarities with IDMCs in other disease areas, but the particular nature of cancer patients affects the operation of these committees. COMMENTS: IDMC are important in oncology clinical trials because of the severity of illness and the often toxic effects of treatments. PMID- 25841467 TI - What can we do in the journey of fighting cancer? PMID- 25841468 TI - Pathophysiology of nausea and vomiting in palliative medicine. AB - Nausea/vomiting remains a significant problem in medicine, especially in patients with chronic illnesses. The incidence and patient distress level from nausea and vomiting are underestimated by health care providers. A thorough patient evaluation followed by rational polypharmacy and a multimodal treatment approach may minimize the occurrence and intensity of nausea/vomiting. Utilizing new techniques (e.g., PET imaging of the CNS with novel radiotracers, functional Magnetic Resonance Imaging), clinicians could have a greater chance to elucidate which receptors may be contributing to an individual's experience of nausea and vomiting and the relative importance of each. Future research into assessing precise mechanisms of nausea and vomiting in particular patients may enable clinicians to design the most appropriate combinations of antiemetics in efforts to achieve the most effective therapy with the least side effects. Individually tailored antiemetic "cocktails," based on patient specific pathophysiology, may lead to optimal treatment outcomes. PMID- 25841469 TI - Postoperative nausea and vomiting. AB - Postoperative nausea and vomiting (PONV) remains a significant clinical issue that can detract from patients' quality of life in hospital/treatment facility, as well as in the days immediately postdischarge. In addition, PONV may increase perioperative costs, increase perioperative morbidity, increase postanesthesia care unit stay, prolong hospital stays, length of stay/delay discharge, delay the time that the patient can go back to work, and lead to readmissions. Despite the existence of multiple tools to stratify patients according to their risk of developing PONV and multiple PONV treatment guidelines, clinicians do not appear to systematically address the treatment and/or prophylaxis of PONV in a uniform fashion with both pharmacologic and nonpharmacologic strategies in attempts to minimize PONV occurrences. PMID- 25841470 TI - An overview of nausea/vomiting in palliative medicine. AB - Nausea, vomiting and retching are among the most distressing symptoms that palliative care may experience. This article presents a brief overview of various medical conditions/treatments that may lead to nausea/vomiting/retching as well as potential mechanisms/neurotransmitters/receptors that may be involved and thus may represent therapeutic targets for antiemetic treatments. PMID- 25841471 TI - 5-HT3 receptor antagonists for the treatment of nausea/vomiting. AB - It is well appreciated that a number of things (e.g., various insults, chemotherapeutic agents, radiation) may lead to the release of serotonin from the enterochromaffin of the gastrointestinal tract. Released serotonin may then bind to certain 5-HT3 receptors and promote nausea/vomiting. 5-HT3 receptor antagonists may ameliorate nausea/vomiting in a number of circumstances and have been utilized as important antiemetics for multiple conditions such as chemotherapy-induced nausea/vomiting (CINV), radiation-induced emesis (RIS), and postoperative nausea/vomiting (PONV). PMID- 25841472 TI - Opioid-induced nausea and vomiting. AB - Opioids are broad spectrum analgesics that are an integral part of the therapeutic armamentarium to combat pain in the palliative care population. Unfortunately, among the adverse effects of opioids that may be experienced along with analgesia is nausea, vomiting, and/or retching. Although it is conceivable that in the future; combination agents (opioids combined with agents which may nullify emetic effects) currently; nausea/vomiting remains a significant issue for certain patients. However, there exists potential current strategies that may be useful in efforts to diminish the frequency and/or intensity of opioid-induced nausea/ vomiting. PMID- 25841473 TI - Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting. AB - Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. The discovery of several NK1 receptor antagonists is a big revolution to dealt this problem. NK1 receptor antagonists prevent both acute and delayed chemotherapy induced nausea and vomiting (CINV). These agents act centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, these agents help improve patients' daily living and their ability to complete multiple cycles of chemotherapy. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed. PMID- 25841474 TI - Dopamine receptor antagonists. AB - Intractable nausea and/or vomiting is a serious and significant clinical dilemma that may greatly detract from quality of life. One of the first classes of antiemetic agents used as well as one of the commonest classes of antiemetic agents used is that of the dopamine receptor antagonists. Dopamine receptor antagonists are useful antiemetic agents, however, unfortunately, clinicians have on occasion resorted to switching from one dopamine receptor antagonist to another dopamine receptor antagonist when the initial dopamine receptor antagonist was ineffective rather than adding on a second antiemetic agent from a totally different class (e.g., 5-HT3 receptor antagonists, NK-1 receptor antagonists). PMID- 25841475 TI - Understanding vomiting from the perspective of traditional Chinese medicine. AB - Vomiting is a common clinical symptom in which the conditions associated with impaired homeostasis and qi flow ascend reversely within the stomach, resulting in the expulsion of the stomach's contents through the mouth. The stomach, located in the middle warmer (also known as Zhong Jiao), is primarily responsible for receiving and digesting food and liquid, and its qi typically flows downward. Various unfavorable conditions associated with the environment, food, mental health, or physiological stress can compromise the stomach, thereby leading to a loss of gastric homeostasis, which often triggers vomiting. However, regardless of external factors or internal weaknesses, the direct cause of vomiting is the loss of gastric homeostasis and the ascending qi flow. Traditional Chinese medicine (TCM) built its understanding of vomiting from the long-term accumulation of clinical observations and treatments, which were used to gradually improve and develop relevant theories, diagnoses, and treatments. This review paper presents vomiting from the nonaggressive perspective of TCM; specifically, we summarize TCM's unique insights with regard to vomiting across various aspects including its etiology, diagnosis, locations, relationships with other organs, dialectical treatment, and drug and medical characteristics. By revealing the abundance of TCM's theoretical and clinical knowledge concerning vomiting, we attempt to integrate Chinese and western medicines to treat it. In addition, the valuable knowledge that TCM provides with regard to vomiting certainly deserves better understanding to develop and improve modern medicine. PMID- 25841476 TI - Medication related nausea and vomiting in palliative medicine. AB - There are multiple potential states and/or symptoms that may occur in the palliative care population including: pain, nausea/vomiting, fatigue, anorexia, dyspnea, hiccups, cough, constipation, abdominal cramps/bloating, diarrhea, pruritis, depression/anxiety, dysphagia and sleep disturbances. Some of this may be the direct result of medications or drug-drug interactions from agents prescribed to treat the medical conditions that the patient has. Medication related nausea and vomiting (MRNV) is a significant problem in palliative medicine that is reasonably common likely due to the multiple medications that these patients are often taking. PMID- 25841477 TI - Pain intensity in cancer. PMID- 25841478 TI - Concept mapping in palliative medicine research. AB - Palliative care adopts a share care model that emphasizes the collaboration among patients, families, and health care providers. Different views and different priority of care are often reported. Concept mapping is a research methodology that can best obtain a big picture as well as a clustering of sub-themes that are identified by different parties involved in palliative care. Concept mapping adopts qualitative method to identify themes, and then uses quantitative techniques such as multidimensional scaling to create a map that shows the patterns of relationships between themes. The method draws the shared expertise of a studied group by constructing graphic models of an issue in palliative medicine examined by the group. This paper will introduce the approach of concept mapping and its use in palliative medicine research. Issues such as sample size calculation and validity and reliability will be discussed. PMID- 25841479 TI - Neuropathic pain in cancer. AB - Unrelieved neuropathic pain continues to be a substantial health problem in a cancer patient arises either due to disease itself or its treatment. Review of literature showed that neuropathic pain has high prevalence rate, greater severity and analgesic requirement with worse quality of life. Underreporting by patient and under treatment by physician is an important causative factor of indefinite persistence of neuropathic pain. Careful history taking, elaborated physical examination, patient's self report and diagnostic tools with high sensitivity and specificity are needed for accurate assessment of neuropathic pain. Neuropathic cancer pain is difficult to treat and also shows poor response to opioids so in this situation alternate a treatment strategy that also includes psycosocial and spiritual counseling with yoga and meditation exercises under the palliative care framework should be practiced. To find out the burden and estimation of resource generation of this widely recognized problem, accurate establishment of incidence, prevalence, severity, and effectiveness of treatment is quite mandatory. Complex phenomenon of neuropathic pain abolishes establishment of early diagnosis and accurate etiology of this symptom, emphasizes the need of sensitive and reliable clinical grading scale, international classification system and validated diagnostic tools that correspond with clinical assessment. Multiple studies towards this direction has been culminated and some are still going on, though the data and literature is very scant and require further research for the complete evaluation of neuropathic pain. PMID- 25841480 TI - Fentanyl for episodic dyspnoea in cancer patients. AB - Two different patterns of breathlessness have been identified: chronic or continuous breathlessness and breathlessness crisis (acute, incident, episodic, breakthrough breathlessness). Meta-analysis and systematic reviews prove that opioids are beneficial in either opioid-naive or -tolerant patients. However, data from two recent randomised controlled trials were not able to show the effectiveness of fentanyl for the relief of exertion-induced dyspnoea. PMID- 25841481 TI - End of life care in hematology: still a challenging concern. AB - The majority of patients with hematological malignancies (HM) may experience troublesome symptoms and complicating clinical syndromes throughout all phases of disease. Therefore, among the current concepts concerning the comprehensive management of hematological patients, palliative care should exert a more ever expanding role, in particular in the advanced phases of disease, as there are special clinical needs (such as blood transfusions and anti-infective treatments), presented by this peculiar category of cancer patients. However, reported experiences on advanced HM patients claimed a too intensive level of medical care during the last week of life for which the needs of future and collaborative researches in order to set a proper allocation of medical resources and the optimal end-of-life care in the hematologic setting are highly awaited. Indeed, the most important aspect of caring for these suffering patients is to ameliorate or restore their quality of life (QoL) though a highly humanized approach, whereas technological and pharmacological measures should be limited enough to control the symptoms burden and the several kinds of sufferance that may complicate the final phase of disease course. PMID- 25841482 TI - Lack of patient-reported outcomes assessment in phase III breast cancer studies: a missed opportunity for informed decision making. AB - A phase III study comparing capecitabine monotherapy to combination treatment with capecitabine and sunitinib in patients with metastatic breast cancer failed to demonstrate a benefit in terms of progression-free or overall survival. Both regimens were reasonably well tolerated with some differences noted in the specific toxicity profiles. However, the study failed to incorporate an assessment of patient-reported outcomes (PROs) such as self-reported pain, quality of life, or employment outcomes. This is a missed opportunity. If more clinical trials included such measures, they would provide valuable information to patients and clinicians choosing from a wide array of available and otherwise similarly effective systemic therapies for metastatic breast cancer. PMID- 25841483 TI - Haematology and palliative medicine: moving forward. AB - The documentation of details on the provision of medical care for haematology patients in the palliative care setting not only provides useful baseline information for clinical consideration and debate, but signals that the scholarship in this area has come of age. Previously the research literature predominantly centred on the question of whether palliative medicine could or should be integrated into the care of haematology patients. The assumption is now in the affirmative and the concern becomes how best to effectively achieve this end. PMID- 25841484 TI - Patient reported outcomes from LUX-Lung 3: first-line afatinib is superior to chemotherapy-would patients agree? AB - The LUX-Lung 3 trial was an important randomized phase 3 trial in patients with EGFR mutant advanced non-small cell lung cancer (NSCLC). Here, patients were randomized to either afatinib or cisplatin-pemetrexed and the primary endpoint of progression-free survival (PFS) was easily met (HR=0.58, P=0.001). This was the first large-scale trial of this type using a modern chemotherapy comparator, including Asian and non-Asian patients, central radiology review, and utilizing comprehensive patient-reported outcomes. Whilst efficacy for afatinib was markedly superior to chemotherapy, do the patient-reported outcomes reflect this superiority? The symptom control and quality of life (QoL) data from this trial has now been published. Analysis of these demonstrate clear superiority of afatinib over chemotherapy for delay in cough deterioration, and dyspnoea. Notably, given the toxicity profile of afatinib, these improvements translated into significant improvements in global health status, physical, role, and cognitive functioning. The clinical benefits for afatinib over cisplatin pemetrexed chemotherapy for EGFR mutation-positive advanced non-small cell lung patients seem overwhelming, and are clinically meaningful. These results are also consistent with QoL data from other trials of gefitinib/erlotinib, but much more robust, given the larger patient numbers. Would patients agree that afatinib is superior to chemotherapy? On the basis of data presented, the answer is probably "Yes". However, the key unanswered question remaining is "Which is the best EGFR tyrosine kinase inhibitor (TKI) to use up front?" and we will have to wait until ongoing trial data can help answer this. PMID- 25841485 TI - Acupuncture of the Five Shu Acupoints in spleen meridian to lower blood uric acid level. AB - BACKGROUND: Based on the principle of "spleen governing transportation and transformation", we have found that acupuncture of the Five Shu Acupoints in spleen meridian can remarkably lower the blood uric acid levels in patients with primary hyperuricemia. OBJECTIVE: To explore the clinical efficacy of the acupuncture of the Five Shu Acupoints in spleen meridian in reducing the blood uric acid level and its relevant mechanism. METHODS: A total of 32 patients with primary hyperuricemia were enrolled in this study. They were allowed to have free access to diets. The initial treatment for the concomitant diseases (but not including the therapy that might affect uric acid metabolism) was kept unchanged. The observation was formally initiated at 8:00 am on day 1. Acupuncture was not performed within the 48 hours, and only the 24-hour urine volume was recorded. The urine uric acid concentration and urinary creatinine concentration were measured from 25 to 48 hours. On the 46th hour, venous blood samples were collected to detect blood uric acid and creatinine concentrations. After the 48th hour, the patients received acupuncture of the Five Shu Acupoints in spleen meridian each morning. Once Qi was encountered, retain the needle for 30 min. The acupuncture was performed once daily for ten consecutive days. The 24-hour urine volume was recorded daily, and the fasting indicators were detected on the morning of the 11th day. RESULTS: After the acupuncture, the blood uric acid level significantly decreased in patients with increased production (overproduction) of uric acid, decreased excretion (underexcretion) of uric acid, and mixed type (all P<0.01). In the underexcretion type, the urine uric acid concentration significantly increased after the treatment (P<0.01). After the acupuncture, the fraction excretion of uric acid (FEUA) significantly increased in the underexcretion type and mixed type (P<0.01) and decreased in the overproduction type (P<0.01). After the acupuncture, the serum uric acid concentration decreased by 16.32-18.29% whereas the 24-hour urine volume increased by 24.22-29.32%. CONCLUSIONS: Acupuncture of the Five Shu Acupoints in spleen meridian can lower the blood uric acid levels by promoting uric acid excretion the and increasing urine volume. PMID- 25841486 TI - Exploring obstacles of administrating AIDS control and prevention strategies in Iran. AB - BACKGROUND & AIM: Executing a strategy is a complicate process that seeks to reach the best results for guarantee some achievements. To explore barriers related to executing diseases prevention and control, is crucial to resolve weakness and improve administration of therapeutic procedure. This study aims to explore obstacles of implementing acquired immune deficiency syndrome (AIDS) prevention and control strategies in Mazandaran province of Iran. MATERIALS AND METHODS: This cross sectional study was conducted during 2012. The samples included 130 managers, experts and employees of Mazandaran University of Medical science of Iran and the other organization and agencies participating in an AIDS national program. The data were analysed by the chi-square method through SPSS software. RESULTS: The results showed that among eight factors of obstacles of implementing strategy including educational, technological, cultural, communication, legal, political, organizational and economic factors, technology and political issues are recognized as obstacles. CONCLUSIONS: Technology as an inter-organizational factor and political factors as out-organizational factors, could affect the successful executing of AIDS control and prevention strategies, therefore the health care providers should pay more attention on these matters. PMID- 25841487 TI - Effectiveness of acupoint sticking therapy in common chronic diseases, with disease differentiation principle. AB - OBJECTIVE: To explore the effectiveness of acupoint sticking therapy (AST) in three common chronic diseases including respiratory diseases, digestive system diseases, and chronic pain according to the disease differentiation principle. METHODS: A total of 200 eligible patients with respiratory diseases, digestive diseases, or chronic pain were enrolled in this study. AST was applied based on their specific conditions. The treatment effectiveness was compared three months later. RESULTS: The overall positive response rate was 87.50%, with 54.00% overall rate of significant effectiveness. For the respiratory diseases, digestive diseases, and chronic pain, the overall response rate was 87.69%, 80.00%, and 93.33%, respectively (P>0.05), whereas the rate of significant effectiveness was 46.15%, 43.33%, and 69.33% (P<0.01). CONCLUSIONS: AST is effective for all these three common chronic diseases, particularly for the chronic pain. PMID- 25841488 TI - A Comprehensive Transcriptomic and Proteomic Analysis of Hydra Head Regeneration. AB - The cnidarian freshwater polyp Hydra sp. exhibits an unparalleled regeneration capacity in the animal kingdom. Using an integrative transcriptomic and stable isotope labeling by amino acids in cell culture proteomic/phosphoproteomic approach, we studied stem cell-based regeneration in Hydra polyps. As major contributors to head regeneration, we identified diverse signaling pathways adopted for the regeneration response as well as enriched novel genes. Our global analysis reveals two distinct molecular cascades: an early injury response and a subsequent, signaling driven patterning of the regenerating tissue. A key factor of the initial injury response is a general stabilization of proteins and a net upregulation of transcripts, which is followed by a subsequent activation cascade of signaling molecules including Wnts and transforming growth factor (TGF) beta related factors. We observed moderate overlap between the factors contributing to proteomic and transcriptomic responses suggesting a decoupled regulation between the transcriptional and translational levels. Our data also indicate that interstitial stem cells and their derivatives (e.g., neurons) have no major role in Hydra head regeneration. Remarkably, we found an enrichment of evolutionarily more recent genes in the early regeneration response, whereas conserved genes are more enriched in the late phase. In addition, genes specific to the early injury response were enriched in transposon insertions. Genetic dynamicity and taxon specific factors might therefore play a hitherto underestimated role in Hydra regeneration. PMID- 25841489 TI - Functional Pairing of Class B1 Ligand-GPCR in Cephalochordate Provides Evidence of the Origin of PTH and PACAP/Glucagon Receptor Family. AB - Several hypotheses have been proposed regarding the origin and evolution of the secretin family of peptides and receptors. However, identification of homologous ligand-receptor pairs in invertebrates and vertebrates is difficult because of the low levels of sequence identity between orthologs of distant species. In this study, five receptors structurally related to the vertebrate class B1 G protein coupled receptor (GPCR) family were characterized from amphioxus (Branchiostoma floridae). Phylogenetic analysis showed that they clustered with vertebrate parathyroid hormone receptors (PTHR) and pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon receptors. These PTHR-like receptors shared synteny with several PTH and PACAP/glucagon receptors identified in spotted gar, Xenopus, and human, indicating that amphioxus preserves the ancestral chordate genomic organization of these receptor subfamilies. According to recent data by Mirabeau and Joly, amphioxus also expresses putative peptide ligands including homologs of PTH (bfPTH1 and 2) and PACAP/GLUC-like peptides (bfPACAP/GLUCs) that may interact with these receptors. Functional analyses showed that bfPTH1 and bfPTH2 activated one of the amphioxus receptors (bf98C) whereas bfPACAP/GLUCs strongly interacted with bf95. In summary, our data confirm the presence of PTH and PACAP/GLUC ligand receptor pairs in amphioxus, demonstrating that functional homologs of vertebrate PTH and PACAP/glucagon GPCR subfamilies arose before the cephalochordate divergence from the ancestor of tunicates and vertebrates. PMID- 25841490 TI - A Robust ANOVA Approach to Estimating a Phylogeny from Multiple Genes. AB - In this article, we address the issue of estimating the phylogenetic tree based on sequence data across a set of genes. Recognizing that the individual gene trees may not all share the same evolutionary history due to lateral gene transfer or differences in rates of evolution for instance, we develop a robust algorithm for tree estimation based on pairwise distances computed gene by gene. A robust analysis of variance (ANOVA) is used to combine the distances across all genes giving a summary distance for all genes. The tree can then be constructed using any distance method such as BIONJ. Using the weights from the robust ANOVA, we can then identify the outlying genes and taxa for further examination. As the method is based on distances, computation is much faster than maximum likelihood on the concatenated genes. It is also very straightforward to carry out a bootstrap analysis using standard methods for regression models. We test our methods in a comprehensive simulation study and apply them to three data sets recently analyzed in the literature. PMID- 25841491 TI - Causes and management of early colorectal cancer. PMID- 25841492 TI - Practical genetics of colorectal cancer. AB - Hereditary colorectal cancer (CRC) is highly heterogeneous, both genotypically and phenotypically. The most frequently occurring hereditary colorectal cancer syndrome is Lynch syndrome, accounting for approximately 3% of the total colorectal cancer burden. Polyposis syndromes, such as familial adenomatous polyposis, account for a lesser percentage. Familial colorectal cancer, defined by family history, occurs in an estimated 20% of all colorectal cancer cases. With a worldwide annual colorectal cancer incidence of over one million, and annual mortality of over 600,000, hereditary and familial forms of colorectal cancer are a major public health problem. Lynch syndrome is attributable to DNA mismatch repair germline mutations, with the MSH2, MLH1, MSH6, and PMS2 genes being implicated. The characteristics of Lynch syndrome-associated colorectal tumors, including early age of onset and predilection to the proximal colon, mandate surveillance by colonoscopy beginning by age 20 to 25 and repeated every other year through age 40 and annually thereafter. Besides colorectal cancer, Lynch syndrome also predisposes to a litany of extracolonic cancers, foremost of which is endometrial cancer, followed by cancer of the ovary, stomach, renal pelvis and ureter, small bowel, hepatobiliary tract, pancreas, glioblastoma multiforme in the Turcot's variant, and sebaceous skin tumors in the Muir-Torre variant and, more recently identified, cancers of the breast and prostate. The most common polyposis syndrome is familial adenomatous polyposis, caused by mutations in the APC gene. Affected individuals have multiple colonic adenomas and, without treatment invariably develop colorectal cancer. Colonic surveillance with polypectomy may be pursued until the appearance of multiple colonic adenomas, at which time prophylactic colectomy should be considered. Extra intestinal manifestations include desmoid tumor, hepatoblastoma, thyroid carcinoma, and medulloblastoma. Other polyposis syndromes include the hamartomatous polyp syndromes, including juvenile polyposis syndrome, Peutz Jeghers syndrome, Cowden syndrome, and Bannayan-Ruvalcaba-Riley syndrome. PMID- 25841494 TI - Current surgical considerations for colorectal cancer. PMID- 25841493 TI - Prevention of colorectal cancer and dietary management. AB - OBJECTIVES: This systematic review focuses on dietary and lifestyle risk factors for colorectal cancer (CRC) prevention and chemoprevention among high-risk populations. METHODS AND MATERIALS: We searched PubMed for English-language articles about dietary components, lifestyle risk factors, and chemoprevention agents in relation to colorectal cancer and their references published from 1980 through 2013. We reviewed articles jointly for the most clinically important information, emphasizing randomized trials and meta-analyses where available. RESULTS: There is convincing evidence that intake of garlic, vitamin B6 and magnesium, active living, maintaining a healthy weight and waist, avoiding or reducing red meat, alcohol, and smoking, as well as hormone replacement therapy among women may significantly protect against developing colorectal cancer. There is less consistent evidence for fruit and vegetable intake (fiber and folate), fish and Omega-3 fatty acids, selenium, dairy, calcium and vitamin D. For high risk populations, aspirin have been shown to protect against the development of colonic adenomas and CRC, while a minimal effective dose remains unclear. CONCLUSIONS: Colorectal cancer can be prevented in general population through dietary and lifestyle interventions, and aspirin may be a good choice of chemoprevention agent among high risk individuals. PMID- 25841495 TI - Surgical treatment of colorectal liver metastases. AB - The incidence of colorectal cancer is rising in China. Since nearly 50% of these patients will ultimately develop liver metastases, an understanding of the surgical management of hepatic metastases is important. Surgical strategies for the management of liver metastases have evolved in recent years and now include adjunctive procedures such as portal vein embolization and radiofrequency ablation, which can help increase the number of patients eligible for potentially curative surgical management. In addition, innovations in treatment sequencing, including the use of peri-operative chemotherapy and the liver-first approach to the management of synchronous liver metastases have helped improve outcomes in these patients. Along with such changes in surgical management come new risks, such as chemotherapy-induced liver damage, with which the surgeon must be prepared to contend. PMID- 25841496 TI - Stage II colon cancer. AB - Colorectal cancer (CRC) is the third commonest cancer in the Western world. Approximately one-quarter of cases are classified as Stage II/Dukes' B, meaning that the disease has breached the bowel wall but not spread to draining lymph nodes or distant sites. Stage II colon cancer is a heterogeneous disease both biologically and in terms of outcome. Although pivotal data have confirmed the benefit of adjuvant 5-fluorouracil (FU) chemotherapy following resection of stage II tumours the absolute reduction in risk of recurrence is small - 3 to 4 percentage points - and so most patients treated fail to gain from therapy. In contrast to stage III disease, the addition of oxaliplatin to FU as adjuvant chemotherapy for stage II disease does not improve outcome. Much attention has focused on the identification of biomarkers that identify patients more or less likely to benefit from treatment. Recent data confirm that patients with T3 primary and tumour microsatellite instability (MSI) have excellent prognosis and do not require adjuvant chemotherapy. For patients with microsatellite-stable disease, a validated recurrence score based on gene expression provides greater prognostic information than conventional clinicopathological features alone and can be used to inform discussion on the benefits of adjuvant chemotherapy. PMID- 25841497 TI - Adjuvant therapy of stage III colon cancer. AB - The decision for adjuvant therapy of colon cancer by both physicians and patients requires many factors, including knowledge of the risk for recurrence (prognosis), the likelihood of significant clinical benefit (prediction), toxicity of treatment, comorbidities, and the patient's understanding and acceptance of both the relative and absolute benefit of therapy. To predict the risk of recurrence, clinicopathologic features have typically been used such as the number of positive and negative nodes, T stage, tumor differentiation, obstruction and lymphovascular invasion. More recent quantitative prognostic markers include microsatellite instability, with MSI-H conferring better prognosis. In addition, in combination with MSI, gene expression profiles have been developed which may be especially helpful in stage II disease, and in some low risk stage III patients to decide on whether they should receive combination chemotherapy, capecitabine or no adjuvant treatment. The standard treatment for most stage III patients is a combination of oxaliplatin with infusional and bolus 5-FU (FOLFOX) or with an oral agent such as capecitabine (XELOX), with equivalent results. Although irinotecan is active in advanced colorectal cancer, two trials of this drug with 5-FU failed to show improvement over the fluoropyrimidines alone. The antiangiogenic agent bevacizumab also failed to improve treatment compared to FOLFOX alone, as did the EGFR agent, cetuximab. Studies are currently underway to compare the standard 6 months of FOLFOX with 3 months of therapy, to reduce the risk of neurotoxocity associate with oxaliplatin, while maintaining treatment efficacy. PMID- 25841498 TI - Mining the ACCENT database: a review and update. AB - The database of the Adjuvant Colon Cancer End Points (ACCENT) Group was assembled to address questions in early stage colon cancer that could be best answered by information pooled across many similar trials. Today, the ACCENT database contains individual patient-level data from over 33,000 patients enrolled onto 25 adjuvant colon cancer trials conducted between 1977 and 2008. Since its flagship analysis of 3-year disease-free survival as a surrogate endpoint for 5-year overall survival in 2005, the ACCENT group has produced many noteworthy scientific findings addressing a variety of clinical questions, which we describe here. Additionally, we provide an overview of the history, collaboration, construction, principles, and future of the ACCENT database, as it has set a precedent for multi-trial database creation in other types of cancer. PMID- 25841499 TI - Future of therapy for rectal cancer. AB - Since 2004, the standard of care for patients with cT3 and/or N+ rectal cancer has been preoperative chemoradiation followed by surgery and postoperative adjuvant chemotherapy. A number of advances have occurred and are defining the future of rectal cancer therapy. Among these are short course radiation, the impact of postoperative adjuvant chemotherapy, selective radiation and selective surgery, and new chemoradiation regimens with novel agents. This review will examine these developments and assess their impact on the future therapy of rectal cancer. PMID- 25841500 TI - Current focus and future advances for Annals of Palliative Medicine. PMID- 25841501 TI - Physical methods in palliation. PMID- 25841502 TI - Self-expanding metallic stents and self-expanding plastic stents in the palliation of malignant oesophageal dysphagia. AB - Endoluminal stenting has revolutionised the practice of gastrointestinal endoscopy for many years. What started as rigid, inflexible, plastic stents have now evolved into flexible, easy-to-deploy self-expanding stents with a myriad of choices, including covered, partially covered and uncovered types. Many of these also come along with special features including anti-reflux, anti-migration and lasso for stent adjustment and retrieval. Numerous papers with meta-analyses and systemic reviews have without doubt confirmed the efficacy, safety and cost effectiveness of endoluminal stenting in the palliation of malignant obstruction of the oesophagus, stomach, duodenum, colon and the biliary tree. This paper will focus on the use of self-expanding plastic stents (SEPS) as well as self expanding metallic stents (SEMS) in the palliation of malignant oesophageal obstruction. PMID- 25841503 TI - CT image guided thermal ablation techniques for palliation of painful bone metastases. AB - BACKGROUND: Many different treatment methods have been used for pain palliation in patients with bone metastases. The ideal treatment has to be fast, safe, effective and tolerable for the patient. OBJECTIVE: To evaluate the efficacy and safety of computed tomography (CT)-guided radiofrequency ablation (RFA) or microwave ablation (MWA) as a minimal invasive method of pain palliation. MATERIALS AND METHODS: A total of forty-five patients with painful bone metastases were included in our study (median age 65.43; range, 36-90 years). Thirty patients were treated with RFA and fifteen with MWA, all under CT guidance. Lesion diameter was between 2 and 9 cm (mean +/- SD: 3.9+/-2.6 cm). Pain was assessed in all patients with the Brief Pain Inventory (BPI). All procedures were performed under conscious sedation. RFAs were performed with a RITA Model 1500(r) electrosurgical generator with a seven or a nine-array multitined electrode depending on the lesion's size. MWAs were done with AMICA GEM microwave generator 2,450 MHz connected to a 14- or 16-gauge coaxial antenna. Technically successful ablation was considered to be when lesions were treated according to protocol and completely covered. After each session a dual-phase spiral CT examination with intravenous contrast medium was performed in order to evaluate immediate response. Patients were hospitalised and observed for 24-hour monitoring. Post-ablation assessment with BPI score and report of the use of analgesics was performed with telephone interview one, four and eight weeks after the ablation. RESULTS: In both groups there was a significant and similar decrease in the mean past day BPI score for worst pain, for average pain and for pain interference during daily life in comparison to preprocedural symptoms (P<0.001, paired t-test), one, 4 and 8 weeks after treatment. There was also a marked decrease (3 out of 45 patients, 4 and 8 weeks after treatment) in the use of analgesics. Mean ablation time for MWA was 4.5 minutes, shorter than RFA's mean ablation time that was 9.5 minutes but with the same clinical result. CONCLUSIONS: RFA and MWA appear to be similarly effective for treatment of painful bone metastases. The main difference is that MWA achieves the same clinical result faster but in a more expensive way. PMID- 25841504 TI - Self-expandable metallic stent placement for palliation in gastric outlet obstruction. AB - Malignant gastric outlet obstruction (GOO) often has a markedly adverse impact on the quality of life (QOL) of patients. Procedures in affected patients should aim to reduce obstructive symptoms and enable oral ingestion. Surgical gastrojejunostomy (GJJ) has been performed as a conventional palliative procedure. Enteral stenting has been increasingly used as an alternative to surgical palliation because of its lower invasiveness. Enteral stents used for GOO are made of a metal alloy mesh in a cylindrical shape, and are termed self expandable metallic stent (SEMS). Of the two placement techniques, over-the-wire (OTW) and through-the-scope (TTS) deployment, TTS is easier and is now more frequently used. In general, the technical success rate is extremely high, at nearly 100%, and the clinical success rate is about 90%, but complications after placement can occur, most frequently late-developing stent dysfunction due to stent obstruction and migration. Biliary obstruction can occur concurrently with GOO, or before or after GOO, particularly in patients with pancreaticobiliary malignancies. Considering accessibility to the bile duct, biliary stenting should generally be conducted prior to enteral stenting. Transhepatic or transmural biliary stenting may be required if transpapillary stenting is not possible. Because enteral stenting is more commonly associated with late-developing stent dysfunction, it is better suited than GJJ for patients with a short life expectancy and poorer performance score. Chemotherapy may be beneficial in reducing the risk of stent obstruction, despite the possible risk of migration, particularly in patients with GOO due to gastric cancer. Many enteral stents with different structures are now commercially available, but the association between the design and mechanical properties of a stent and clinical outcomes is still poorly understood. Further, no consensus on the benefits of covered SEMS has yet been obtained. Further study to verify which types of SEMS are most suited for GOO is warranted. PMID- 25841505 TI - Advances in loco-regional palliation of unresectable cholangiocarcinomas. AB - Cholangiocarcinoma (CC) represents the second most common primary hepatic malignancy after hepatocellular carcinoma, accounting for 10% to 15% of primary liver tumors. Its prognosis is often poor due to its late presentation and its relative resistance to current chemotherapy and radiotherapy regimens. At the time of diagnosis, more than half of the patients are not candidates for surgical therapy due to either invasion of vascular structures or distant metastases. Therefore, for a large proportion of patients, palliation remains the only option for better quality of life and, in some circumstances, longer survival. The main goals of palliative interventions for CC are: restoration of the biliary drainage and resolution of pruritis caused by obstructive jaundice, improvement of the nutritional status and reduction of pain. During the last decades, novel therapies have been introduced to optimize the management of patients with unresectable CC. These therapies can be resource intensive and have some adverse effects; therefore patient selection is crucial. This article discusses the current options for palliation of CC. PMID- 25841506 TI - Thoracic reirradiation for lung cancer: a literature review and practical guide. AB - INTRODUCTION: Approximately half of all patients with lung cancer (LC) experience locoregional failure after initial treatment. Historically, thoracic reirradiation (ReRT) has been limited by toxicity concerns and lack of robust evidence. Our objective was to perform a systematic literature review regarding ReRT. METHODS: Search of the English-language literature related to best-practice thoracic ReRT (Medline and Embase) was performed. Clinical practice guidelines and consensus statements were also reviewed. Data was abstracted regarding patient, tumour and radiotherapy characteristics; response rate; overall survival (OS); and toxicity. In addition to descriptive analysis, Spearman's test explored relationships between RT dose and OS. RESULTS: A total of 379 patients (89% non small cell; 11% small cell LC) retreated with radical or palliative intent have been described by 13 publications (1982-2014). A total of 86% were symptomatic at the time of ReRT; rate of symptom improvement was 69%. Range of reported median survivals (MS) was 3-15 months. Median initial (59 Gy; range, 12-80 Gy), ReRT (36 Gy; range, 12-70 Gy) and combined dose (86 Gy; range, 58-120 Gy) significantly correlated with OS, with Spearman's rho values of 0.85 (P=0.002), 0.72 (P=0.006), and 0.88 (P=0.001) respectively. Toxicity after ReRT was reported in 17% (esophagitis) and 12% (pneumonitis), with RT complications contributing to 2% of deaths. CONCLUSIONS: Despite heterogeneity of patient cohorts, RT techniques and duration of follow-up, ReRT appears to be a feasible option for recurrent thoracic disease. Treatment guidelines derived from this data will guide clinical decision-making for both radical- and palliative-intent ReRT. PMID- 25841507 TI - Self-expanding metal stents in palliative malignant oesophageal dysplasia. AB - Oesophageal cancer is the sixth leading cause of cancer-related death worldwide. At the time of presentation, more than half of patients with oesophageal cancer have advanced disease not eligible for curative resection. Due to this, the treatment of oesophageal malignancy is usually palliative, with the main aim to relieve dysphagia, maintain nutritional intake and occlusion of tracheoesophageal fistulas. Palliative surgery offers the optimal alleviation for oesophageal obstruction symptoms such as dysphagia and vomiting. However, due to the poor prognosis, the short survival time, the significant morbidity and mortality rate for surgical intervention, this treatment option cannot be justified to less invasive non-surgical techniques such as oesophageal stenting. Oesophageal stenting has now become the treatment option of choice for palliative oesophageal malignancy. The previously used covered plastic stents were related with high migration rates and nowadays have been superseded by self-expandable metal stents (SEMS) which comparably have significantly lower migration rates, whilst at the same time provide safe, rapid and effective symptomatic relief. Herein, we present an up to date review of the current literature regarding malignant oesophageal stenting. In particular, the authors will detail important factors in patient selection, indications, contraindications, procedural steps, complications and stent design. PMID- 25841508 TI - Radiotherapy and radioembolization for liver metastases. AB - Liver metastases are a common source of cancer-related morbidity. While systemic palliative chemotherapy is an option for patients with significant metastatic disease burden, radiotherapy (RT) is a safe, well-tolerated local treatment that can offer durable tumor control and relief of symptoms. Innovations in RT delivery now allow for treatment of liver metastases in one to five sessions with high local control rates. There is a growing body of Phase I-II data supporting the use of such RT techniques, including stereotactic body radiotherapy (SBRT) and radioembolization for the treatment of liver metastases. While there are a variety of local therapies available to patients with liver metastases, RT should be strongly considered in patients with liver metastasis related pain or oligometastatic disease not amenable to surgery. We recommend a multidisciplinary approach when weighing the risks and benefits of the available local treatment modalities for each patient. PMID- 25841509 TI - External beam radiotherapy and bone metastases. AB - Management of bone metastasis is a multi-disciplinary effort that involves coordination between several medical specialties. External beam radiation therapy (EBRT) remains a powerful and efficient method of palliating pain and preventing skeletal complications from osseous metastasis. Various fractionation schemes, ranging from 8 Gy in a single dose to 30 Gy in 10 fractions, provide equivalent pain relief as demonstrated by dozens of randomized clinical trials. Toxicity profiles are well established and the treatment is generally well tolerated. Radiopharmaceuticals and high-dose, stereotactic radiation therapy are adjuncts to EBRT whose role is being elucidated through clinical trials. Multiple organizations have compiled guidelines and quality metrics to help refine the role of each modality in the management of painful osseous metastases. PMID- 25841510 TI - Persistent pain after breast cancer treatment. PMID- 25841511 TI - Brain metastases in HER2-positive breast cancer: challenges and opportunities. PMID- 25841512 TI - Brain metastases in HER2 positive breast cancer: the next hurdle. PMID- 25841514 TI - Psychometric evaluation of the Functional Assessment of Cancer Therapy-Breast Symptom Index. PMID- 25841513 TI - Primary systemic treatment of HER2-positive metastatic brain disease: profaning the sanctuary. PMID- 25841515 TI - Measure validation is an ongoing process: the Functional Assessment of Cancer Therapy-Breast Symptom Index as a case example. PMID- 25841516 TI - Breast cancer and sleep disturbance: more than simply a quality of life concern. PMID- 25841517 TI - Breakthrough expected in translational research of targeted therapy for small cell lung cancer. PMID- 25841518 TI - Measuring non-pharmacological caregiving. PMID- 25841519 TI - Ketamine and cancer pain - an inconvenient truth? PMID- 25841520 TI - Reflections on an international study of non-pharmacological caregiving activities at the end of life. PMID- 25841521 TI - Non-pharmacological dimensions of end of life care. PMID- 25841522 TI - Growth of palliative care programs - how are we doing? PMID- 25841523 TI - The value of multidiciplinary cancer care and research: the role of the surgeon as an oncologist and clinical investigator. PMID- 25841524 TI - Organizing a multidisciplinary clinic. AB - Multidisciplinary cancer care models have become increasingly more popular in recent years. This comprehensive approach to care delivery has evolved to address numerous medical and social aspects critical to all patients diagnosed with cancer. Because of the sheer number of specialists involved in the care trajectory of patients with cancer, multidisciplinary care models add significant value in facilitating communication between specialists and in coordinating care. Multidisciplinary models also allow for new and innovative therapies to be incorporated more quickly than is seen in single provider care. Two principal modes of multidisciplinary care have been described-the tumor board and the multidisciplinary clinic. While tumor boards are well established in oncology literature and practice, there is growing support favoring the use of multidisciplinary clinics, bringing providers together at the point of care. In this section, we describe recent data demonstrating the value of the multidisciplinary approach, with particular focus on the creation and potential benefits of a formal multidisciplinary clinic. PMID- 25841525 TI - The distinctive features of surgical oncology as a specialty: considerations for Chinese surgeons. AB - In China, as in the United States and other countries, cancer patients will increasingly receive more than one modality of treatment delivered by cancer physicians from different medical specialties (e.g., internal medicine and surgery). In the United States and in many other countries, the surgical specialization, known as "surgical oncology" has grown as an essential part of cancer care delivery in the United States, both in academic medical centers and in the majority of cancer centers and hospitals in the local community. At a broad level, one can define the roles and responsibilities of a surgical oncologist as follows: (I) an excellent surgeon who can safely manage cancer patients through complex operations and have the judgment to know what operations to select; (II) knows how to integrate surgical treatment as part of a multidisciplinary team, including the type and timing of surgery after pre operative systemic therapies and/or radiation therapies; (III) participates as an oncologist in the long-term disease-management of cancer patients; and (IV) participates in cancer clinical research and/or translational research. Perhaps the most compelling reason for surgical specializations is the evidence from multiple studies in the United States and Europe that "high volume" cancer centers and surgical specialists have better outcomes for treating complex or advanced cancers. It is important for all surgeons treating cancer patients to keep up to date with advances in oncology and be a partner with medical and radiation oncologists in providing contemporary multidisciplinary cancer care and to participate actively in cancer clinical trials where they are available. The uniqueness of our specialty is to function as both a surgeon and an oncologist in the management of the surgical patient with cancer. PMID- 25841526 TI - Training and certification of the surgical oncologist. AB - Surgical Oncology has evolved as a distinct subspecialty of General Surgery with a well-defined curriculum focused on surgical care of the cancer patient, specific areas of clinical and basic science research focus and specialty journals dedicated to the discipline. The Society of Surgical Oncology (SSO), originally formed as the James Ewing Society, has provided leadership in developing training programs in Surgical Oncology and for three decades has been involved in the approval and oversight of Surgical Oncology training programs. Over this time, Surgical Oncology Fellowship training has expanded and in 2013 there were 103 applicants for 56 fellowship positions in 21 programs. The basic tenants of Surgical Oncology training has remained devoted to the core principles of multidisciplinary care, surgical management of cancer patients and a focus on education in research, clinical trials, community outreach, patient advocacy and leadership in oncology. With the maturation of Surgical Oncology as a separate specialty, Surgical Oncology training programs are now accredited by the Accreditation Council on Graduate Medical Education (ACGME) and graduates of the programs will soon be offered subspecialty certification in Complex General Surgical Oncology (CGSO) by the American Board of Surgery, which has created a component Surgical Oncology Board (SOB). Similar expansion has occurred in other specialty areas including an expansion of Breast Fellowships, which are still being approved by the SSO. In the 2013 SSO Breast Oncology Match, there were 67 applicants for 54 positions in 39 Breast Fellowship programs. Continued advances in cancer biology and technology will challenge us to evolve training programs in Surgical Oncology to produce surgeons capable of advancing the multidisciplinary care of cancer patients. PMID- 25841527 TI - Clinical trials in lung cancer surgery and research cooperation. AB - BACKGROUND: With China having an increasingly huge burden of lung cancers, the number of Chinese studies was the second largest all over the world. METHODS: We used the advanced search option available on the ClinicalTrials.gov to review clinical trials regarding surgical issues. In the drop down menus, we chose "all studies" for recruitment status and "interventional" for study type and all trials reported until Aug, 2013 on the website were included. RESULTS: Clinical trials on lung cancer surgeries (658 records) mainly aim at surgical procedures and (neo)adjuvant clinical studies, among which phase III trials account for 15.5%. Only 34.9% (230 records) trials were completed, and 43 studies presented their results on ClinicalTrials.gov. The median time to completion (MTC) of phase III surgical procedure trials is 9.4 years. The MTCs of phase III neo-adjuvant and adjuvant trials have not been reached, but definitely are longer than 10 years. In comparison, the MTC of phase III trials in the first-line treatment are only 4.3 years. COMMENTS: We summarized the characteristics of these trials using real-world case examples. Our analyses reveal that it is critically needed for regulatory authorities, clinical trial sponsors, collaborative research groups, and academic institutions to work together to build up the infrastructure and research cooperation for clinical trials with a surgical component. In 2007, a national collaborative clinical research group, Chinese Thoracic Oncology Group (CTONG), was established. CTONG is a network of researchers, physicians and health-care professionals in public institutions throughout China and currently has a growing membership of 25 hospitals. A CTONG-sponsored trial (CTONG1104) is discussed to illustrate our experience in surgical clinical trials. In summary, it is imperative for investigators to collaborate in cooperative clinical trials in order to expedite applications of therapies from clinical researches to cancer treatment. Since cancer treatment is multidisciplinary, current surgical trials should have multiple treatment combinations while retaining a surgical focus, and be carried out systematically with the cooperation of extensive monitoring and coordinating systems. PMID- 25841528 TI - Analysis of cardiac adverse events following postmastectomy hypofractionated radiotherapy. AB - BACKGROUND: Cardiac complications following chest wall irradiation are inevitable. The effects of conventional radiotherapy (RT) delivering 50 Gy in 25 fractions +/- boost have been clearly demonstrated in a large number of trials. However, there are limited prospective studies demonstrating the impact of hypofractionated RT on normal cardiac tissues in post-mastectomy patients. Through this trial we tried to quantify the cardiac adverse events after post mastectomy hypofractionated RT. MATERIALS AND METHODS: Between June 2011 to June 2012, 61 female patients post-mastectomy were treated with either 40 Gy in 15 fractions or 42.5 Gy in 16 fractions. All patients had echocardiography (ECHO) done before start of RT, and then at three monthly intervals till last follow up. The Common Terminology Criteria (CTC) for Adverse Events v 3.0 was employed to evaluate early and late effects of RT. RESULTS: Median age of patients was 49 years. Average length and width of tangential portals were 19.5 cm * 1.5 cm, and 6.8 cm * 1.2 cm respectively. A total of 3.3% of the patients developed acute grade (Gr) 2 toxicity, while for late reactions, 8.2% and 6.6% had Gr 2 and Gr 3 adverse events respectively at a median follow up 20 months. CONCLUSIONS: Use of hypofractionated RT for chest wall irradiation post-mastectomy is safe with no clinically significant acute or late cardiac adverse event noted at a follow up of 2 years. PMID- 25841529 TI - Phase II design: history and evolution. AB - Historically, phase II trials in oncology generally had a single-arm design, constructed to distinguish between a tumor response rate felt to indicate a lack of promise (often 5%) and a rate that would indicate potential benefit (often 20%), with a one-sided type I error rate of 5% to 10% and a type II error rate of 10% to 20%. The dominant use of this design was based on the premise that an agent that could not produce a tumor response rate of 20% was not likely to produce a clinically meaningful overall survival (OS) or progression-free survival (PFS) benefit in subsequent phase III testing. Recent trends in oncology drug development have challenged this paradigm. Many phase II trials are now designed to assess the promise of a molecularly targeted agent, given either alone or in combination with another regimen. In many cases these agents are not anticipated to produce or improve tumor response rates; rather the desired outcome from their use is improved PFS or OS through means other than direct cell killing as evidenced by tumor shrinkage. In general, PFS is the preferred end point for such phase II trials, as it is more statistically efficient than OS (because it is substantially shorter and the treatment effect is not diluted by salvage treatment). However, in a situation with no effective salvage therapy and/or a disease with concerns regarding the timing of progression assessment, OS could be chosen as the endpoint. We have reviewed the history and evolution of the phase II trial over the past 50 years, in particular, in oncology trials. This review is not meant to be exhaustive, but rather to cover the primarily used designs in self-contained detail, in such a manner as to provide a primer for the young investigator and reminders for the more experienced. PMID- 25841530 TI - Adaptive clinical trial designs in oncology. AB - Adaptive designs have become popular in clinical trial and drug development. Unlike traditional trial designs, adaptive designs use accumulating data to modify the ongoing trial without undermining the integrity and validity of the trial. As a result, adaptive designs provide a flexible and effective way to conduct clinical trials. The designs have potential advantages of improving the study power, reducing sample size and total cost, treating more patients with more effective treatments, identifying efficacious drugs for specific subgroups of patients based on their biomarker profiles, and shortening the time for drug development. In this article, we review adaptive designs commonly used in clinical trials and investigate several aspects of the designs, including the dose-finding scheme, interim analysis, adaptive randomization, biomarker-guided randomization, and seamless designs. For illustration, we provide examples of real trials conducted with adaptive designs. We also discuss practical issues from the perspective of using adaptive designs in oncology trials. PMID- 25841531 TI - Professor Bruce D. Minsky: Advances in radiation oncology in 2014 ASTRO. PMID- 25841532 TI - Professor Hope S. Rugo: Reversing resistance and hormone therapy for metastatic breast cancer. PMID- 25841533 TI - Prof. Yi-Long Wu: Patients on the afatinib arm had a significantly better quality of life according to the data of LUX-Lung 6. PMID- 25841534 TI - Widespread use of pemetrexed in oncology: has it turned it into a new drug? PMID- 25841535 TI - Lipoma and liposarcoma of the larynx: case reports and literature review. AB - OBJECTIVE: Two cases of laryngeal lipomatous tumors are presented. Their diagnoses and management are discussed and contrasted. METHODS: Case report and literature review. RESULTS: Patient 1 is a 58 year old male presenting with five years of progressive shortness of breath, dysphagia, and globus sensation. Clinical exam and imaging study showed a 3.5 cm hypodense laryngeal mass, and he underwent transoral robotic-assisted surgery for complete excision. Final pathology revealed a well-differentiated liposarcoma. Patient 2 is a 79 year old female presenting with one year of non-progressive hoarseness and globus sensation. Clinical examination and imaging study revealed a 1.8 cm hypodense laryngeal mass. Transoral endoscopic complete excision of the submucosal mass was performed. Final pathology revealed benign spindle-cell lipoma. CONCLUSION: Liposarcoma and lipoma may present with similar symptomatology, clinical, and imaging findings. Pathology evaluation is of utmost importance for definitive diagnosis. Therefore, diagnosis and treatment of laryngeal lipomatous lesions are best accomplished with complete excision of the mass. PMID- 25841536 TI - Sudden hearing loss and Crohn disease: when Cogan syndrome must be suspected. AB - Cogan's syndrome is a rare systemic vasculitis of unknown origin. It is characterized by the presence of worsening audiovestibular and ocular symptoms that may manifest simultaneously or sequentially. No specific diagnostic laboratory tests or imaging studies exist. The diagnosis is clinical and should be established as early as possible so as to initiate prompt treatment with steroids and prevent rapid progression to deafness or blindness and potentially fatal systemic involvement. We report a case of association between Cogan's syndrome and ileal Crohn's disease which we believe deserves attention since, after an accurate review of the literature, we have found approximately 250 reports of patients with Cogan's syndrome, only 13 of whom with concurrent chronic inflammatory bowel disease; of these 13 cases, none experienced improvement after therapy. In the light of the good outcome obtained in our case, we proposed a valid treatment option with boluses of steroids, combined with early systemic immunosuppression and intra-tympanic steroid injections. PMID- 25841537 TI - Effectiveness of structured education on knowledge and health behaviors in patients with congenital heart disease. AB - OBJECTIVE: To investigate whether a single educational session increased the level of knowledge and changed the prevalence of health risk behaviors in young people with congenital heart disease (CHD). STUDY DESIGN: We conducted a longitudinal study of patients transferred to adult CHD care who received a single educational session (n = 201) at a tertiary care center. Their knowledge level and prevalence of health risk behaviors were assessed via the Leuven Knowledge Questionnaire CHD and the Health Behavior Scale CHD, respectively. A general linear model for longitudinal measurements was used to analyze the natural progression of patients' knowledge during a 27-month period and the effect of one educational session on outcomes. RESULTS: Participating in an educational session resulted in a small-to-moderate, but significant, increase in total knowledge level and better understanding of deterioration symptoms, and rationale and frequency of follow-up; however, it did not improve patients' health behaviors. CONCLUSIONS: This type of education did improve knowledge but did not improve the patients' tendency to engage in better health behaviors. Future studies should assess the effect of repetitive exposure to educational sessions dealing with CHD. PMID- 25841538 TI - Treatment of Attention Deficit/Hyperactivity Disorder among Children with Special Health Care Needs. AB - OBJECTIVES: To describe the parent-reported prevalence of treatments for attention deficit/hyperactivity disorder (ADHD) among a national sample of children with special health care needs (CSHCN), and assess the alignment of ADHD treatment with current American Academy of Pediatrics guidelines. STUDY DESIGN: Parent-reported data from the 2009-2010 National Survey of Children with Special Health Care Needs allowed for weighted national and state-based prevalence estimates of medication, behavioral therapy, and dietary supplement use for ADHD treatment among CSHCN aged 4-17 years with current ADHD. National estimates were compared across demographic groups, ADHD severity, and comorbidities. Medication treatment by drug class was described. RESULTS: Of CSHCN with current ADHD, 74.0% had received medication treatment in the past week, 44.0% had received behavioral therapy in the past year, and 10.2% used dietary supplements for ADHD in the past year. Overall, 87.3% had received past week medication treatment or past year behavioral therapy (both, 30.7%; neither, 12.7%). Among preschool-aged CSHCN with ADHD, 25.4% received medication treatment alone, 31.9% received behavioral therapy alone, 21.2% received both treatments, and 21.4% received neither treatment. Central nervous system stimulants were the most common medication class (84.8%) among CSHCN with ADHD, followed by the selective norepinephrine reuptake inhibitor atomoxetine (8.4%). CONCLUSION: These estimates provide a benchmark of clinical practice for the period directly preceding issuance of the American Academy of Pediatrics' 2011 ADHD guidelines. Most children with ADHD received medication treatment or behavioral therapy; just under one-third received both. Multimodal treatment was most common for CSHCN with severe ADHD and those with comorbidities. Approximately one-half of preschoolers received behavioral therapy, the recommended first-line treatment for this age group. PMID- 25841539 TI - Randomized, double-blind, placebo-controlled study of synbiotic yogurt effect on the health of children. AB - OBJECTIVE: To assess the effects of daily consumption of a synbiotic yogurt drink on the health, growth, and quality of life of healthy children 12-48 months of age in out-of-home child care. STUDY DESIGN: Healthy children attending child care centers were enrolled in a prospective, double-blind, placebo-controlled clinical trial. The intervention was a yogurt drink containing Streptococcus thermophilus, Lactobacillus bulgaricus, and Bifidobacterium animalis subspecies lactis (BB-12) (5 * 10(9) cfu/100 mL serving), and 1 g of inulin (synbiotic group) vs a similar nonsynbiotic-containing acidified milk drink (placebo group) once daily for 16 weeks. The end points were days of diarrhea, fever, vomiting, symptoms of upper respiratory tract infection, use of antibiotics, physician visits, child care absenteeism, parental work absenteeism, and quality of life (PedsQL 4.0; Mapi Research Trust, Lyon, France). RESULTS: Compared with placebo (n = 73), children receiving synbiotic (n = 76) had significantly fewer days of reported fever (1.85 vs 1.95, P < .05), significant improvement in social functioning (P < .035; pre-to-end intervention), and school functioning (P < .045; pre-to-mid intervention). More days with >= 3 loose/watery stools were reported in the synbiotic group (P < .05). CONCLUSIONS: Daily supplementation of children's diet with yogurt containing probiotic bacteria BB-12 and inulin significantly reduced days of fever and improved social and school functioning. The increased frequency of bowel movements may be explained by an accelerating effect of BB-12 and inulin on intestinal transit. Further research on the possible benefits of synbiotics on children's health is advised. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00653705. PMID- 25841540 TI - Necrotizing Enterocolitis and Central Line Associated Blood Stream Infection Are Predictors of Growth Outcomes in Infants with Short Bowel Syndrome. AB - OBJECTIVES: To describe the natural history of growth patterns and nutritional support in a cohort of infants with short bowel syndrome (SBS), and to characterize risk factors for suboptimal growth. STUDY DESIGN: A retrospective chart review of 51 infants with SBS followed by our intestinal rehabilitation program. Weight and length data were converted to age, sex, and gestational age standardized weight-for-age z-scores (WAZ) and length-for-age z-scores (LAZ). RESULTS: Median (IQR) age at enrollment was 8.3 (0.9-14.6) weeks, and follow-up duration was 10 (8-13) months, including both inpatient and outpatient visits. Both WAZ and LAZ followed a U-shaped curve, with median for newborns (WAZ = 0.28; LAZ = -0.41), a nadir at age 6 months (-2.38 and -2.18), and near recovery by age 1 year (-0.72 and -0.76). Using multivariable regression analysis, diagnosis of necrotizing enterocolitis was independently associated with significant decrements of WAZ (-0.76 +/- 0.32; P = .02) and LAZ (-1.24 +/- 0.32; P = .0001). >= 2 central line-associated bloodstream infections was also independently associated with decreases in WAZ (-0.95 +/- 0.33; P = .004) and LAZ (-0.86 +/- 0.32; P = .007). CONCLUSION: In a cohort of infants with SBS, we observed a unique pattern of somatic growth, with concomitant deceleration of both WAZ and LAZ and near recovery by 1 year. Inflammatory conditions (necrotizing enterocolitis and central line-associated bloodstream infections) represent potentially modifiable risk factors for suboptimal somatic growth. PMID- 25841541 TI - Bone Mineral Content as a Driver of Energy Expenditure in Prepubertal and Early Pubertal Boys. AB - OBJECTIVE: To examine the associations of bone and bone-secreted factors with measures of energy metabolism in prepubertal and early pubertal boys. STUDY DESIGN: Participants in this cross-sectional, observational study included 37 (69% black, 31% white) boys, aged 7-12 years (Tanner stage = 160 mg/dL [4.1 mmol/L]) were enrolled into a multicenter, 12-week, randomized, double-blind, placebo-controlled study. Following screening/drug washout and a 5-week single blind placebo-run-in with diet stabilization, subjects were randomized 2:1 to daily ezetimibe 10 mg (n = 93) or placebo (n = 45) for 12 weeks. Lipid-altering efficacy and safety were assessed in all treated patients. RESULTS: Overall, mean age was 8.3 years, 57% were girls, 80% were white, mean baseline LDL-C was 228 mg/dL (5.9 mmol/L), and 91% had HeFH. After 12 weeks, ezetimibe significantly reduced LDL-C by 27% after adjustment for placebo (P < .001) and produced significant reductions in total cholesterol (21%), nonhigh-density lipoprotein cholesterol (26%), and apolipoprotein B (20%) (P < .001 for all). LDL-C lowering response in sex, race, baseline lipids, and HeFH/nonFH subgroups was generally consistent with overall study results. Ezetimibe was well tolerated, with a safety profile similar to studies in older children, adolescents, and adults. CONCLUSIONS: Ezetimibe monotherapy produced clinically relevant reductions in LDL C and other key lipid variables in young children with primary HeFH or clinically important nonFH, with a favorable safety/tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00867165. PMID- 25841543 TI - Cerebral Palsy after Neonatal Encephalopathy: How Much Is Preventable? AB - OBJECTIVES: To determine the expected proportion of term cerebral palsy (CP) after neonatal encephalopathy (NE) that could theoretically be prevented by hypothermia and elucidate the perinatal factors associated with CP after NE in those who do not meet currently used clinical criteria required to qualify for hypothermia ("cooling criteria"). STUDY DESIGN: Using the Canadian CP Registry, we categorized children born at >= 36 weeks with birth weight >= 1800 g with CP after moderate or severe NE according to the presence or absence of cooling criteria. Maternal, perinatal, postnatal, and placental factors were compared between the 2 groups. A number needed to treat of 8 (95% CI 6-17) to prevent one case of CP was used for calculations. RESULTS: Among the 543 term-born children with CP, 155 (29%) had moderate or severe NE. Sixty-four of 155 (41%) met cooling criteria and 91 of 155 (59%) did not. Shoulder dystocia was more common in those who did not meet cooling criteria (OR 8.8; 95% CI 1.1-71.4). Low birth weights (20% of all singletons), small placentas (42%), and chorioamnionitis (13%) were common in both groups. CONCLUSIONS: The majority of children with CP after NE did not meet cooling criteria. An estimated 5.1% (95% CI 2.4%-6.9%) of term CP after NE may be theoretically prevented with hypothermia. Considering shoulder dystocia as an additional criterion may help recognize more neonates who could potentially benefit from cooling. In all cases, a better understanding of the antenatal processes underlying NE is essential in reducing the burden of CP. PMID- 25841544 TI - Physicians Failed to Write Flawless Prescriptions When Computerized Physician Order Entry System Crashed. AB - PURPOSE: Clinical care has become increasingly dependent on computerized physician order entry (CPOE) systems. No study has reported the adverse effect of CPOE on physicians' ability to handwrite prescriptions. This study took advantage of an extensive crash of the CPOE system at a large hospital to assess the completeness, legibility, and accuracy of physicians' handwritten prescriptions. METHODS: The CPOE system had operated at the outpatient department of an academic medical center in Taiwan since 1993. During an unintentional shutdown that lasted 3.5 hours in 2010, physicians were forced to write prescriptions manually. These handwritten prescriptions, together with clinical medical records, were later audited by clinical pharmacists with respect to 16 fields of the patient's, prescriber's, and drug data. FINDINGS: A total of 1418 prescriptions with 3805 drug items were handwritten by 114 to 1369 patients. Not a single prescription had all necessary fields filled in. Although the field of age was most frequently omitted (1282 [90.4%] of 1418 prescriptions) among the patient's data, the field of dosage form was most frequently omitted (3480 [91.5%] of 3805 items) among the drug data. In contrast, the scale of illegibility was rather small. The highest percentage reached only 1.5% (n = 57) in the field of drug frequency. Inaccuracies of strength, dose, and drug name were observed in 745 (19.6%), 517 (13.6%), and 435 (11.4%) prescribed drug items, respectively. IMPLICATIONS: The unintentional shutdown of a long-running CPOE system revealed that physicians fail to handwrite flawless prescriptions in the digital era. The contingency plans for computer disasters at health care facilities might include preparation of stand-alone e-prescribing software so that the service delay could be kept to the minimum. However, guidance on prescribing should remain an essential part of medical education. PMID- 25841545 TI - Effect of suppression of postpartum ovulation on endometrial inflammation in dairy cows. AB - The objective of this study was to investigate the effect of time of first postpartum ovulation on endometrial inflammation in dairy cows with and without uterine disease during the early puerperal period. Transvaginal follicular puncture (FP) was carried out to suppress postpartum ovulation and formation of a CL until Day 42. Fifty-three lactating Holstein Friesian cows were divided into four groups on the basis of presence (UD+) or absence (UD-) of uterine disease, which was defined as retained fetal membranes and/or metritis, and whether FP had (FP+) or had not been (FP-) carried out. This resulted in the following groups: UD-FP- (n = 15), UD-FP+ (n = 13), UD+FP- (n = 13), and UD+FP+ (n = 12). Cloprostenol was given on Days 55 to 60 postpartum, and GnRH was administered 2 days later for synchronization of ovulation. In the FP- groups, endometrial swab and biopsy samples were collected during the second estrus (approximately Day 40) and during the estrus after synchronization. In the FP+ groups, the same samples were collected during the first estrus (approximately Day 49) and during the estrus after synchronization. The prevalence of positive bacteriologic cultures of the endometrium was not affected by FP (P > 0.05). Histologic signs of endometritis were more severe in UD+FP- cows at second sampling than in UD+FP+ cows (P <= 0.05). Endometrial expression of IL1alpha (in UD- after first sampling and in UD+ after second sampling) and IL1beta (in UD- and UD+ after first sampling) was higher (P <= 0.05) in FP- cows than in FP+ cows. Regardless of group, cows with histopathologic evidence of endometritis had higher expression (P <= 0.05) of IL1alpha, IL1beta, IL6, and TNFalpha than cows without endometritis. In conclusion, suppression of early ovulation by transvaginal FP enhances clearance of uterine inflammation in postpartum cows. PMID- 25841546 TI - Assessing Option Grid(r) practicability and feasibility for facilitating shared decision making: An exploratory study. AB - OBJECTIVE: To assess the feasibility of Option Grids((r))for facilitating shared decision making (SDM) in simulated clinical consultations and explore clinicians' views on their practicability. METHODS: We used mixed methods approach to analyze clinical consultations using the Observer OPTION instrument and thematic analysis for follow-up interviews with clinicians. RESULTS: Clinicians achieved high scores on information sharing and low scores on preference elicitation and integration. Four themes were identified: (1) Barriers affect practicability of Option Grids((r)); (2) Option Grids((r)) facilitate the SDM process; (3) Clinicians are aware of the gaps in their practice of SDM; (4) Training and ongoing feedback on the optimal use of Option Grids((r)) are necessary. CONCLUSION: Use of Option Grids((r)) by clinicians with background knowledge in SDM did not facilitate optimal levels of competency on the SDM core concepts of preference elicitation and integration. Future research must evaluate the impact of training on the use of Option Grids((r)), and explore how best to help clinicians bridge the gap between knowledge and action. PRACTICE IMPLICATIONS: Clinicians proficiently imparting information in simulations struggled to elicit and integrate patient preferences - understanding this gap and developing strategies to close it are the next steps for implementing SDM into clinical practice. PMID- 25841547 TI - A 3-D enteroid-based model to study T-cell and epithelial cell interaction. AB - The constant interaction between intestinal epithelial cells (IECs) and intraepithelial lymphocytes (IELs) is thought to regulate mucosal barrier function and immune responses against invading pathogens. IELs represent a heterogeneous population of mostly activated and antigen-experienced T cells, but the biological function of IELs and their relationship with IECs is still poorly understood. Here, we describe a method to study T-cell-epithelial cell interactions using a recently established long-term intestinal "enteroid" culture system. This system allowed the study of peripheral T cell survival, proliferation, differentiation and behavior during long-term co-cultures with crypt-derived 3-D enteroids. Peripheral T cells activated in the presence of enteroids acquire several features of IELs, including morphology, membrane markers and movement in the epithelial layer. This co-culture system may facilitate the investigation of complex interactions between intestinal epithelial cells and immune cells, particularly allowing long term-cultures and studies targeting specific pathways in IEC or immune cell compartments. PMID- 25841548 TI - Anaphylaxis to food. AB - This article provides a clinically focused review of food-induced anaphylaxis that includes epidemiology, risk factors, allergens, diagnosis, and management. Currently, there is no treatment for food allergy. Dietary avoidance and emergency preparedness are the cornerstones of management. Effective and safe therapies to reduce the risk of serious food-induced reactions are urgently needed, as are reliable biomarkers to predict severity. PMID- 25841550 TI - Exercise-induced anaphylaxis. AB - Exercise-induced anaphylaxis is an uncommon disorder in which anaphylaxis occurs in response to physical exertion. Food-dependent exercise-induced anaphylaxis is a disorder with similar symptoms, although symptoms develop only if exercise takes place within a few hours of eating and, in most cases, only if a specific food is eaten. Management includes education about safe conditions for exercise, the importance of ceasing exercise immediately if symptoms develop, appropriate use of epinephrine, and, for patients with food-dependent exercise-induced anaphylaxis, avoidance of the culprit food for at least 4 hours before exercise. PMID- 25841549 TI - Anaphylaxis to the carbohydrate side chain alpha-gal. AB - In 2007, the monoclonal antibody cetuximab caused severe hypersensitivity reactions during the first infusion in a region of the southeastern United States. Investigation of pretreatment sera established that they contained immunoglobulin (Ig) E against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), which is present on the Fab of cetuximab. Alpha-gal is a blood group substance of nonprimate mammals. These IgE antibodies are also associated with delayed anaphylaxis to red meat (ie, to meat or organs of animals that carry this oligosaccharide). Evidence shows that the primary cause of these IgE antibodies is bites from the tick Amblyomma americanum or its larvae. PMID- 25841551 TI - Mast cell activation syndromes presenting as anaphylaxis. AB - Anaphylaxis results from severe systemic mast cell activation. In addition to IgE mediated and physical triggers, it may occur with a clonal mast cell disease and in an idiopathic fashion without clear provoking factors. Disorders of mast cell activation are classified into primary (clonal), secondary, and idiopathic. Mast cell activation syndrome (MCAS) is a multisystem disorder characterized by objective documentation of elevated mast cell mediators during attacks and a favorable response to antimediator therapy. It should be considered in the differential diagnosis of patients presenting with recurrent anaphylaxis without a clear cause. This article discusses the diagnosis of MCAS. PMID- 25841552 TI - Anaphylaxis to insect stings. AB - Anaphylaxis to insect stings has occurred in 3% of adults and can be fatal even on the first reaction. Large local reactions are more frequent but rarely dangerous. The chance of a systemic reaction to a sting is 5% to 10% in large local reactors and in children with mild (cutaneous) systemic reactions, and varies between 30% and 65% in adults with previous systemic reactions, depending on the severity of previous sting reactions. Baseline serum tryptase level is increased in many patients with sting anaphylaxis. Venom immunotherapy is 75% to 98% effective in preventing sting anaphylaxis. PMID- 25841553 TI - Anaphylaxis to drugs. AB - Drug-induced anaphylaxis is a common cause of anaphylaxis and a leading cause of fatal anaphylaxis. Antibiotics, radiocontrast, and nonsteroidal anti-inflammatory drugs are commonly implicated drugs. Vocal cord dysfunction can mimic anaphylaxis and is often overlooked. beta-Lactams are a common cause of anaphylaxis; however, skin testing and drug challenge can usually determine tolerability of other classes of beta-lactams. Nonionic contrast agents cause anaphylaxis less frequently than ionic contrast, and immunoglobulin E-mediated mechanisms may have a role in some of these reactions. Skin testing with radiocontrast may have a role in evaluating patients with anaphylaxis to nonionic contrast. PMID- 25841554 TI - Perioperative anaphylaxis: diagnosis, evaluation, and management. AB - Perioperative anaphylaxis can occur during or after surgery and can have life threatening consequences. As anesthesia protocols become more complex and incorporate multiple agents to regulate physiologic processes intraoperatively, perioperative anaphylaxis is becoming increasingly recognized. The allergist should obtain detailed records from the anesthesiologist in order to perform appropriate testing to identify the likely causative agents. Testing should ideally be performed 4 to 6 weeks after the reaction to account for a refractory period after mast cell activation. This article includes 2 cases of perioperative anaphylaxis and reviews the historical elements that must be considered after a reaction has occurred. PMID- 25841555 TI - Anaphylaxis to chemotherapy and monoclonal antibodies. AB - Hypersensitivity reactions are increasingly prevalent, although underrecognized and underreported. Platins induce immunoglobulin E-mediated sensitization; taxenes and some monoclonal antibodies can induce reactions at first exposure. Severe hypersensitivity can preclude first-line therapy. Tryptase level at the time of a reaction is a useful diagnostic tool. Skin testing provides a specific diagnosis. Newer tests are promising diagnostic tools to help identify patients at risk before first exposure. Safe management includes rapid drug desensitization. This review provides information regarding the scope of hypersensitivity and anaphylactic reactions induced by chemotherapy and biological drugs, as well as diagnosis, management, and treatment options. PMID- 25841556 TI - Idiopathic anaphylaxis. AB - Idiopathic anaphylaxis is a diagnosis of exclusion after other causes have been thoroughly evaluated and excluded. The pathogenesis of idiopathic anaphylaxis remains uncertain, although increased numbers of activated lymphocytes and circulating histamine-releasing factors have been implicated. Signs and symptoms of patients diagnosed with idiopathic anaphylaxis are indistinguishable from the manifestations of other forms of anaphylaxis. Treatment regimens are implemented based on the frequency and severity of patient symptoms and generally include the use of epinephrine autoinjectors, antihistamines, and steroids. The prognosis of idiopathic anaphylaxis is generally favorable with well-established treatment regimens and effective patient education. PMID- 25841557 TI - Recognition, treatment, and prevention of anaphylaxis. AB - Anaphylaxis is an acute and potentially lethal multisystem allergic reaction that occurs in a variety of clinical scenarios and is almost unavoidable. Immunologic reactions to medications, foods, and insect stings cause most episodes, but virtually any substance capable of inducing systemic degranulation of mast cells and basophils can produce anaphylaxis. All health care professionals must be able to recognize anaphylaxis promptly, be prepared to treat it appropriately, and be able to provide preventive recommendations. Similarly, at-risk individuals must be prepared to self-treat anaphylaxis promptly if prevention fails. PMID- 25841558 TI - Fatal and near-fatal anaphylaxis: factors that can worsen or contribute to fatal outcomes. AB - Anaphylaxis implies a risk of death even in patients whose prior episodes have been considered mild and managed easily. Anaphylaxis occurs in all age groups, from infants to the elderly, but most deaths occur in adults. Factors or circumstances associated with near-fatal or fatal anaphylaxis are reviewed from the following 10 perspectives: accidents and mishaps, adulterated products, age, allergens, atopy, comorbidities, Munchausen syndrome or contrived anaphylaxis, patient factors, route of administration, and treatment-related issues. There are no absolute contraindications to self-injectable epinephrine, and epinephrine can be administered for anaphylaxis to elderly patients or to those patients receiving beta-adrenergic blockers. PMID- 25841559 TI - Anaphylaxis. PMID- 25841560 TI - Therapeutic application of electrical stimulation and constraint induced movement therapy in perinatal brachial plexus injury: A case report. AB - Infants and children with perinatal brachial plexus injury (PBPI) have motion limitations in the shoulder, elbow, forearm and hand that are dependent on the level of injury and degree of recovery. The injury and subsequent recovery period occur during critical periods of central and spinal neural development placing infants and children at-risk for developmental disregard and disuse of the affected arm and hand. A case report outlines the therapy and surgical interventions provided in the first 2 years of life for a child with global PBPI and a positive Horner's sign. Electrical stimulation and constraint induced movement therapy provided sequentially were effective therapy interventions. Neurosurgery to repair the brachial plexus was performed at an optimal time period.(2) The Assisting Hand Assessment,(12) Modified Mallet(13) and Active Movement Scale(14) are effective outcome measures in PBPI and served as valuable guides for therapy intervention. Oxford Level of Evidence: 3b; Individual Case Control Study. PMID- 25841561 TI - Nicotinamide Mononucleotide Adenylyltransferase 1 Protects Neural Cells Against Ischemic Injury in Primary Cultured Neuronal Cells and Mouse Brain with Ischemic Stroke Through AMP-Activated Protein Kinase Activation. AB - Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) is a nicotinamide adenine dinucleotide biosynthetic enzyme. It has been shown to be neuroprotective against neonatal excitotoxicity-induced brain injury, but its role in ischemic stroke is unclear. In this study, the role of NMNAT1 in oxygen-glucose deprivation (OGD)-induced primary cultured neuronal cell injury and mouse middle cerebral artery occlusion-induced cerebral ischemic injury and its regulation on AMP-activated protein kinase (AMPK) activation were evaluated. The results showed that NMNAT1 overexpression reduced cell death and apoptosis both in vitro and in vivo. Conversely, NMNAT1 knockdown exacerbated cell death and apoptosis. Furthermore, NMNAT1 overexpression regulated neuron survival via AMPK activation, as NMNAT1 overexpression enhanced AMPK activity in OGD-treated cortical neurons, and AMPK inhibitor blocked LV-NMNAT1-induced neuroprotection in OGD-treated cortical neurons. In addition, NMNAT1 overexpression could reduce brain infarction size and improve behavioral outcomes in mice with ischemic stroke. These results suggested that up-regulation of NMNAT1 could induce neuroprotection against ischemic injury through AMPK activation and indicated that NMNAT1 is a potential therapeutic target for stroke. PMID- 25841562 TI - Neural responses to the mechanical characteristics of high velocity, low amplitude spinal manipulation: Effect of specific contact site. AB - BACKGROUND: Systematic investigations are needed identifying how variability in the biomechanical characteristics of spinal manipulation affects physiological responses. Such knowledge may inform future clinical practice and research study design. OBJECTIVE: To determine how contact site for high velocity, low amplitude spinal manipulation (HVLA-SM) affects sensory input to the central nervous system. DESIGN: HVLA-SM was applied to 4 specific anatomic locations using a no HVLA-SM control at each location randomized in an 8*8 Latin square design in an animal model. METHODS: Neural activity from muscle spindles in the multifidus and longissimus muscles were recorded from L6 dorsal rootlets in 16 anesthetized cats. A posterior to anterior HVLA-SM was applied through the intact skin overlying the L6 spinous process, lamina, inferior articular process and L7 spinous process. HVLA-SMs were preceded and followed by simulated spinal movement applied to the L6 vertebra. Change in mean instantaneous discharge frequency (DeltaMIF) was determined during the thrust and the simulated spinal movement. RESULTS: All contact sites increased L6 muscle spindle discharge during the thrust. Contact at all L6 sites significantly increased spindle discharge more than at the L7 site when recording at L6. There were no differences between L6 contact sites. For simulated movement, the L6 contact sites but not the L7 contact site significantly decreased L6 spindle responses to a change in vertebral position but not to movement to that position. CONCLUSIONS: This animal study showed that contact site for an HVLA-SM can have a significant effect on the magnitude of sensory input arising from muscle spindles in the back. PMID- 25841563 TI - Atlanto-axial facet displacement during rotational high-velocity low-amplitude thrust: An in vitro 3D kinematic analysis. AB - BACKGROUND: Very little is known about the kinematics of the upper cervical spine in particular during Manual Therapy techniques. In fact no data about displacement of the atlanto-axial joint during High-Velocity Low-Amplitude (HVLA) thrust are available. Knowing the precise kinematics of these vertebrae might allow a better comprehension of such important technique and possible vital structures involvement. METHODS: A Zebris CMS20 ultrasound-based motion tracking system was adopted. Twenty fresh human cervical specimens were used in this study. Facet joint displacements of C1 relative to C2 were analysed during three consecutive HVLA thrusts into rotation. Displacement during the thrust and the maximum displacement reached with the manoeuvre were analysed. RESULTS: Descriptive statistics showed a mean Norm displacement during the thrust of 0.5 mm (SD +/- 0.5). The maximum displacement, representing the overall facet movement from neutral to end-range position, indicated a Norm value of 6.0 mm (SD +/- 3.4). Heterogeneous displacement directions were found during the thrust. Intra and inter-rater reliability reached an insufficient reproducibility level. Considering the amount of displacement induced, no statistical significant differences between the registrations were shown. CONCLUSION: Displacement during the execution of HVLA thrust is unintentional, unpredictable and not reproducible. On the other hand and in accordance with other studies, the displacement induced with the present technique seems not to be able to endanger vital structure on the Spinal Cord and the Vertebral Artery. This study also adds to a better comprehension of the kinematic of the atlanto-axial segment during the performance of HVLA manipulation. PMID- 25841564 TI - Losing control over control conditions in knee osteoarthritis orthotic research. PMID- 25841565 TI - Two solid forms of tauroursodeoxycholic acid and the effects of milling and storage temperature on solid-state transformations. AB - Two phase-pure solid forms of tauroursodeoxycholic acid (TUDCA) were prepared and characterized by thermal analysis, vibrational spectroscopy, X-ray diffraction, solid-state nuclear magnetic resonance, and morphological analysis. All solid forms can be produced from solvents and also can be obtained by mechanically and non-mechanically activated polymorph conversion. Near-infrared (NIR) spectroscopy, in combination with chemometrical techniques, was used for the quantitative monitoring of the polymorph conversion of TUDCA in milling process and at different storage temperatures. The NIR spectra in the range of 7139-5488 cm(-1) were considered for multivariate analysis. Results demonstrated that the NIR multivariate chemometric model can predict the percentage of crystal and amorphous TUDCA with the correlation coefficient of 0.9998, root mean square error of calibration of 0.740%, root mean square error of prediction of 0.698%, and root mean square error of cross-validation of 1.49%. In the milling process of crystal TUDCA (Form I), a direct transformation from crystal to glass was observed in 4h. Moreover, the impact of different storage temperatures on the stability of amorphous TUDCA was investigated, and the rate of polymorph transformation was found to be accelerated with increasing temperature. PMID- 25841566 TI - Preparation and characterization of micronized ellagic acid using antisolvent precipitation for oral delivery. AB - In this work, poorly water soluble phytochemical ellagic acid (EA) was micronized to increase its solubility and thereby the bioavailability during antisolvent precipitation process using N-methyl pyrrolidone (NMP) as solvent and deionized water as antisolvent. The micronized EA (m-EA) freeze-dried powder was prepared by the subsequent lyophilization process. The effects of various experimental parameters on the mean particle size (MPS) of m-EA suspension (m-EAS) in the antisolvent precipitation process were investigated. MPS and production efficiency were taken into account comprehensively to obtain the optimum conditions of antisolvent precipitation. Under the optimum conditions, m-EA freeze-dried powder with a MPS of 429.2 +/- 7.6 nm was obtained. The physico chemical properties of m-EA freeze-dried powder were detected by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), liquid chromatography-tandem mass spectrometry (LC-MS/MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The results indicated m-EA kept the same chemical structure with raw EA, but the crystallinity was greatly reduced. Furthermore, a comparison of the 50% inhibition concentration (IC50) values revealed that m-EA was more effective than raw EA in scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Meanwhile, m EA also showed higher reducing power. Moreover, the residual amount of NMP was lower than the International Conference on Harmonization limit (530 ppm) for solvents. The dissolution rate of m-EA was approximately 2 times of raw EA. Moreover, the solubility of m-EA was about 6.5 times of raw EA. Meanwhile, the bioavailability of m-EA increased about 2 times compared with raw EA via oral administration. PMID- 25841567 TI - MPEG-DSPE polymeric micelle for translymphatic chemotherapy of lymph node metastasis. AB - Lymph node metastasis is one of the major pathways for tumor formation and it is difficult to deliver chemotherapeutics at therapeutic concentrations to lymph node metastasis. This study prepared methyl poly(ethylene glycol) distearoylphosphatidylethanolamine/doxorubicin (MPEG-DSPE/DOX) micelle for the treatment of lymph node metastasis. The MPEG-DSPE/DOX micelle prepared were of spherical morphology with a particle size of 20 +/- 5 nm. The uptake rates of DOX and MPEG-DSPE/DOX micelle by A375 cells were 51.2% and 88.7%, respectively. The phagocytosis rate of MPEG-DSPE/Rhodamine B micelle by RAW264.7 cells was 17.2 fold lower than for Rhodamine B alone. After subcutaneous injection, MPEG-DSPE micelle underwent lymphatic absorption and accumulated in popliteal lymph nodes. MPEG-DSPE/DOX micelle significantly alleviated damage to the subcutaneous tissue of the injection sites compared with DOX alone. We established a model of nude mice bearing lymph node metastasis of A375 cells. After subcutaneous injection, the weights of both the popliteal and iliac lymph nodes of the MPEG-DSPE/DOX micelle group were significantly lower than in the saline and DOX groups. MPEG DSPE/DOX micelle effectively killed the tumor cells in popliteal and iliac lymph nodes. In conclusion, MPEG-DSPE micelle is a promising drug delivery system for the treatment of lymph node metastasis. PMID- 25841568 TI - Development of fluorous lipid-based nanobubbles for efficiently containing perfluoropropane. AB - Nano-/microbubbles are expected not only to function as ultrasound contrast agents but also as ultrasound-triggered enhancers in gene and drug delivery. Notably, nanobubbles have the ability to pass through tumor vasculature and achieve passive tumor targeting. Thus, nanobubbles would be an attractive tool for use as ultrasound-mediated cancer theranostics. However, the amounts of gas carried by nanobubbles are generally lower than those carried by microbubbles because nanobubbles have inherently smaller volumes. In order to reduce the injection volume and to increase echogenicity, it is important to develop nanobubbles with higher gas content. In this study, we prepared 5 kinds of fluoro lipids and used these reagents as surfactants to generate "Bubble liposomes", that is, liposomes that encapsulate nanobubbles such that the lipids serve as stabilizers between the fluorous gas and water phases. Bubble liposome containing 1-stearoyl-2-(18,18-difluoro)stearoyl-sn-glycero-3-phosphocholine carried 2-fold higher amounts of C3F8 compared to unmodified Bubble liposome. The modified Bubble liposome also exhibited increased echogenicity by ultrasonography. These results demonstrated that the inclusion of fluoro-lipid is a promising tool for generating nanobubbles with increased efficiency of fluorous gas carrier. PMID- 25841569 TI - Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure. AB - Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture. PMID- 25841570 TI - Core-shell structured Fe3O4@TiO2-doxorubicin nanoparticles for targeted chemo sonodynamic therapy of cancer. AB - To facilitate targeting drug delivery and combined therapy, we develop titanium dioxide-encapsulated Fe3O4 nanoparticles (Fe3O4@TiO2 NPs). Titanium dioxide (TiO2), which is employed as a sonosensitizer for sonodynamic therapy (SDT), can also be used for the loading of doxorubicin (DOX). The fabricated Fe3O4@TiO2 NPs exhibit pH-dependent loading and release of doxorubicin (DOX) in vitro. After incubation with cancer cells, reactive oxygen species (ROS) are generated efficiently upon the irradiation of ultrasound. In the biodistribution experiments, extremely high in vivo tumor accumulation of Fe3O4@TiO2 NPs and long time retention effect are observed. Compared with chemotherapy or sonodynamic treatment alone, the combined therapy demonstrated a synergistic effect, resulting in stronger cytotoxicity and higher therapeutic efficacy. Thus, the constructed NPs are endowed with multifunctions which allow them to selectively deliver combinatorial therapeutic payload to tumor with enhanced therapeutic effectiveness and minimal side effects. PMID- 25841571 TI - Optimized mixed oils remarkably reduce the amount of surfactants in microemulsions without affecting oral bioavailability of ibuprofen by simultaneously enlarging microemulsion areas and enhancing drug solubility. AB - The toxicity and irritation associated with high amounts of surfactants restrict the extensive utilization of microemulsions. To address these shortcomings, employing mixed oils to enlarge microemulsion areas therefore reducing surfactant contents is a promising strategy. However, what kinds of mixed oils are more efficient in enlarging microemulsion areas still remains unclear. In this research, we found that the chain length and degree of unsaturation of oils play a key role in enlarging microemulsion areas. The combination of moderate chain saturated oil caprylic/capric triglyceride (GTCC) with long chain unsaturated oil glycerol trioleate significantly increased the microemulsion areas. Solubility of ibuprofen in the mixed oils was unexpectedly and remarkably increased (almost 300mg/mL) compared with that (around 100mg/mL) of the single oil (GTCC), which also resulted in greatly increased solubility of ibuprofen in mixed oils containing microemulsions. By optimizing the mixed oil formulation, the absolute amount of surfactant in drug-loaded microemulsions was reduced but increased drug oral bioavailability in rats was maintained. It could be concluded that the combined use of moderate chain oils and long chain unsaturated oils could not only acquire enlarged microemulsion areas but also enhanced drug solubility, therefore doubly reducing surfactant amount, which is extremely beneficial for developing safe microemulsions. PMID- 25841572 TI - Novel coprocessed excipients composed of lactose, HPMC, and PVPP for tableting and its application. AB - New coprocessed excipients composed of alpha-lactose monohydrate (a filler), HPMC E3 (a binder), and PVPP (a superdisintegrant) were developed by spray drying in this study to improve the tableting properties of lactose. Factors affecting the properties of the coprocessed excipients were investigated by a 3 * 3 * 2 factorial design. These factors include lactose grade (90 M, 200 M, and 450 M), percentage of HPMC (3.5%, 7.0%, and 10.5%), and percentage of PVPP (0% and 3.5%). The results show that the compactability of the excipients could be significantly improved by increasing either the percentage of HPMC or the primary particle size of lactose. The addition of 3.5% PVPP had little effect on the compactability, but significantly improved the disintegration ability. The developed coprocessed excipients have much lower yield pressures and much higher working efficiency during tableting compared to the main raw material (alpha-lactose monohydrate). These improvements are mainly attributed to the addition of HPMC and the proximately 30% amorphous lactose formed during process. Both HPMC and amorphous lactose were homogeneously distributed on the surface of the secondary particles, maximizing their effect. Furthermore, the low hygroscopicity and high glass transition temperature of HPMC led to a high yield. The drug loading capacity of the newly coprocessed excipients is also excellent. In summary, the tri-component coprocessed excipients investigated are promising and worthy of further development. PMID- 25841573 TI - A coal worker's pneumoconiosis diagnosed with endosonography. PMID- 25841574 TI - An unusual submucosal lesion. PMID- 25841576 TI - Is single-operator peroral cholangioscopy a useful tool for the diagnosis of indeterminate biliary lesion? A systematic review and meta-analysis. AB - BACKGROUND: Differentiating between malignant and benign biliary lesions is critical in clinical practice but is difficult. OBJECTIVE: To systematically evaluate the diagnostic performance of single-operator peroral cholangioscopy on indeterminate biliary lesions. DESIGN: A systematic review and meta-analysis. PATIENTS: Patients with indeterminate biliary lesions or equivocal ERCP findings. MAIN OUTCOME MEASUREMENTS: The diagnostic performance of single-operator peroral cholangioscopy on indeterminate biliary lesions. The area under the summary receiver-operating characteristic curve was used as the main indicator for the overall diagnostic performance of single-operator peroral cholangioscopy visual impression (VI) and SpyBite biopsy (SB). The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were also synthesized. RESULTS: A total of 8 studies met the inclusion criteria, involving 335 patients who had data on VI and 337 who had data on SB. The area under the curve values on the summary receiver-operating characteristic curve of single-operator peroral cholangioscopy VI and SB were 0.94 (95% confidence interval [CI], 0.92-0.96) and 0.93 (95% CI, 0.90-0.95) respectively. The combined sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 90% (95% CI, 73% 97%), 87% (95% CI, 76%-94%), 7.1 (95% CI, 3.8-13.3), 0.12 (95% CI, 0.04-0.33) for VI and 69% (95% CI, 57%-79%), 98% (95% CI, 92%-99%), 30.1 (95% CI, 8.5-106.9), and 0.32 (95% CI, 0.23-0.44) for SB, respectively. LIMITATIONS: Small number of included studies; comparison with ERCP could not be made. CONCLUSION: Single operator peroral cholangioscopy is a good tool for differentiating malignant and benign biliary lesions. VI is useful for detecting malignant lesion, whereas SB is better at confirming a malignant diagnosis, but VI is not perfect in excluding biliary cancer, nor is SB, and their negative results should be interpreted with caution. PMID- 25841575 TI - Sex and race and/or ethnicity differences in patients undergoing radiofrequency ablation for Barrett's esophagus: results from the U.S. RFA Registry. AB - BACKGROUND: Little is known about differences in Barrett's esophagus (BE) characteristics by sex and race and/or ethnicity or these differences in response to radiofrequency ablation (RFA). OBJECTIVE: We compared disease-specific characteristics, treatment efficacy, and safety outcomes by sex and race and/or ethnicity in patients treated with RFA for BE. DESIGN: The U.S. RFA patient registry is a multicenter collaboration reporting processes and outcomes of care for patients treated with RFA for BE. PATIENTS: Patients enrolled with BE. INTERVENTIONS: RFA. MAIN OUTCOME MEASUREMENTS: We assessed safety (stricture, bleeding, perforation, hospitalization), efficacy (complete eradication of intestinal metaplasia [CEIM]), complete eradication of dysplasia, and number of treatments to CEIM by sex and race and/or ethnicity. RESULTS: Among 5521 patients (4052 men; 5126 white, 137 Hispanic, 82 African American, 40 Asian, 136 heritage not identified), women were younger (60.0 vs 62.1 years) and had shorter BE segments (3.2 vs 4.4 cm) and less dysplasia (37% vs 57%) than did men. Women were almost twice as likely to stricture (odds ratio 1.7; 95% confidence interval, 1.2 2.3). Although white patients were predominantly male, about half of African Americans and Asians with BE were female. African Americans and Asians had less dysplasia than white patients. Asians and African Americans had more strictures than did white patients. There were no sex or race differences in efficacy. LIMITATIONS: Observational study with non-mandated paradigms, no central laboratory for reinterpretation of pathology. CONCLUSION: In the U.S. RFA patient registry, women had shorter BE segments and less-aggressive histology. The usual tendency toward BE in men was absent in African Americans and Asians. Posttreatment stricture was more common among women and Asians. RFA efficacy did not differ by sex or race. PMID- 25841577 TI - A prospective dual-center proof-of-principle study evaluating the incremental benefit of narrow-band imaging with a fixed zoom function in real-time prediction of polyp histology. Can we resect and discard? AB - BACKGROUND: Advancements in endoscopic technology have increased the ability to distinguish neoplastic polyps during colonoscopy. If a minimum accuracy can be achieved, then a resect-and-discard model can be implemented, although studies to date have demonstrated limited success, especially in the assessment of serrated polyps. OBJECTIVE: To perform a proof-of-principle study assessing the accuracy of narrow-band imaging with near focus in predicting polyp histology including serrated polyps and to determine whether the minimum requirements can be achieved for a resect-and-discard policy. DESIGN: Dual-center, prospective case series. SETTING: Two tertiary-care referral endoscopic centers in Australia. PATIENTS: Two hundred consecutive patients undergoing colonoscopy for routine indications were recruited. INTERVENTIONS: Any polyps identified were assessed by using standard white light followed by narrow-band imaging with near focus for Kudo pit patterns and modified Sano capillary patterns. Based on this assessment and the macroscopic appearance, the polyp histology was predicted and subsequently compared with histopathology results. MAIN OUTCOME MEASUREMENTS: Correlation in postpolypectomy surveillance intervals between endoscopic and pathologic assessments as well as negative predictive value for rectosigmoid hyperplastic polyps. RESULTS: There was a 96% agreement for surveillance intervals between endoscopic assessment and histology by using the American Society for Gastrointestinal Endoscopy guidelines. There was a 96% negative predictive value in assessing rectosigmoid hyperplastic polyps. LIMITATIONS: Because this was a proof-of-principle study, there was no control arm, and there were small numbers, especially in assessing subgroups. The results have limited generalizability with the training requirements for polyp recognition, with confidence to be determined. CONCLUSION: Narrow-band imaging with near focus can predict polyp histology (including serrated polyps) accurately in the hands of trained endoscopists. Further studies with larger numbers are required to further validate this practice. PMID- 25841578 TI - Prevalence, variability, and outcomes in portal hypertensive colopathy: a study in patients with cirrhosis and paired controls. AB - BACKGROUND: Management of portal hypertensive colopathy (PHC) has been challenged by controversial results in its prevalence and clinical relevance. OBJECTIVE: To describe the PHC prevalence and to evaluate the variability in diagnosis, the relation to severity of liver disease, and the incidence of severe outcomes. DESIGN: Cross-sectional study. SETTING: Endoscopic unit of a tertiary-care academic center in Rio de Janeiro, Brazil. PATIENTS: Patients with cirrhosis with portal hypertension and controls paired for age and sex. INTERVENTIONS: All patients were submitted to standard and image-enhanced colonoscopies, which were recorded in a coded video file and analyzed twice by a blinded endoscopist. MAIN OUTCOME MEASUREMENTS: The prevalence of PHC. RESULTS: A total of 51 patients with cirrhosis (55% male, mean age 59 years) and 51 healthy controls (43% male, mean age 61 years) were included. The top ranking colonoscopic findings were angiodysplasia-like lesions, nonspecific vascular pattern, red spots, and colorectal varices, all significantly more frequent in patients with cirrhosis compared with controls. PHC prevalence was 71% in patients with cirrhosis. For PHC, interobserver and intraobserver agreement (k values [standard error]) were 0.68 (0.09) and 0.63 (0.10), respectively. Intraobserver agreement for colonoscopic findings was satisfactory. PHC was not related to more severe liver disease or liver stiffness. Only 5 patients developed severe outcomes during follow-up. LIMITATIONS: The exclusion of patients with cirrhosis without esophageal varices and the absence of an interobserver agreement analysis by double-blinded endoscopists. CONCLUSION: PHC was highly prevalent in patients with cirrhosis, and its diagnostic agreement was satisfactory. PHC is not associated with relevant severe outcomes in a 12-month follow-up. PMID- 25841579 TI - When trainees reach competency in performing ERCP: a systematic review. AB - BACKGROUND AND AIMS: ERCP is an advanced endoscopic procedure that is technically more challenging and carries a higher risk of adverse events compared with standard endoscopy. A discrepancy currently exists among guidelines regarding the number of ERCPs that a trainee needs to complete before procedural competency should be assessed. Our aim was to assess the learning curve for performing ERCP. METHODS: Two authors independently searched MEDLINE (1946 to November 25, 2014) along with the gray literature to identify relevant citations. To warrant inclusion, citations were required to report successful trainee cannulation rate. Successful cannulation rate, set at a value of 80% or higher, was used as our baseline reference for competency. RESULTS: Nine studies, assessing 137 trainees and 17,100 ERCPs, were included in our analysis. Overall, competency was achieved among the included studies between 70 to 400 ERCPs. In the 2 studies that used pancreatic duct cannulation rate, competency was achieved by 70 to 160 ERCPs. Of the 5 studies that used selective duct cannulation rate, competency was achieved by 79 to 300 ERCPs. Finally, in the 4 studies that used common bile duct cannulation rate, 2 studies reached the reference competency threshold by 160 to 400 ERCPs. On further stratification, when assessing native papilla deep common bile duct cannulation, only 1 study reached the reference competency threshold by 350 to 400 ERCPs. CONCLUSIONS: Our findings suggest that as ERCP has evolved from a predominantly diagnostic to therapeutic procedure, procedural thresholds have risen well above North American training guidelines. Therefore, advanced endoscopy training programs need to reassess their current structure to ensure that procedural competency is being reached. PMID- 25841580 TI - Integrated diagnostic strategy for the invasion depth of early gastric cancer by conventional endoscopy and EUS. AB - BACKGROUND: Although conventional endoscopy (CE) and EUS are considered useful for predicting the invasion depth (T-staging) in early gastric cancer (EGC), no effective diagnostic strategy has been established. OBJECTIVE: To produce simple CE criteria and to elucidate an efficient diagnostic method by combining CE and EUS for accurate T-staging. DESIGN: Single-center retrospective analysis. SETTING: Academic university hospital. PATIENTS: Consecutive patients with EGC from April 2007 to March 2012 who underwent CE and EUS before treatment. INTERVENTIONS: Recorded endoscopic images were independently reviewed by 3 observers. The CE criteria for massive invasion were defined, and their utility and the additional value of EUS were assessed. MAIN OUTCOME MEASUREMENTS: The accuracy of CE based on the criteria and the accuracy of EUS. RESULTS: Two hundred thirty patients were enrolled: 195 with mucosal cancer or cancer in the submucosa less than 500 MUm from the muscularis mucosae and 35 with invasive cancers. Multivariate analysis of the CE findings by 1 observer revealed that an irregular surface and a submucosal tumor-like marginal elevation were significantly associated with massive invasion. The simple CE criteria, consisting of those 2 features, had an overall accuracy of 73% to 82% and no significant differences in the diagnostic yield compared with EUS in all observers. CE accurately revealed mucosal cancer, and EUS efficiently salvaged the lesions that were over-diagnosed by CE. With our strategy, which involved the CE criteria and the optimal use of EUS, the comprehensive accuracy exceeded 85% in each observer. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: We demonstrated a practical strategy for T-staging in EGC using simple CE criteria and EUS. PMID- 25841581 TI - Current knowledge of antibiotic prophylaxis guidelines regarding GI open-access endoscopic procedures is inadequate. AB - BACKGROUND: The American Heart Association (AHA) guidelines from 2007 and the American Society for Gastrointestinal Endoscopy (ASGE) guidelines from 2008 recommended against antibiotic prophylaxis before GI endoscopic procedures to prevent bacterial endocarditis. OBJECTIVE: To determine physician knowledge regarding these guidelines and to identify physician subgroups for which knowledge was suboptimal. DESIGN: A survey questionnaire was developed based on AHA and ASGE guidelines regarding antibiotics before endoscopy. Physicians were queried about 10 theoretical scenarios as to whether or not they would recommend before-procedure antibiotics. SETTING: The survey was administered at 3 academic medical centers. PARTICIPANTS: Attending physicians and trainees in primary care and subspecialties. INTERVENTIONS: Survey. MAIN OUTCOME MEASUREMENTS: Percentage of the survey questions answered correctly and predictors of correct response. RESULTS: The survey was administered to 941 participants of whom 12 declined to participate. Eighty percent (n=740/929) of participants completed the survey. The median number of correct answers was 70% (interquartile range [IQR] 50%-90%) and was similar at each institution (P=.6). A total of 7.3% (n=54) of respondents answered all questions correctly. There was no significant difference in correct responses between attending physicians and trainees or between study centers (median 7, IQR 5-9; P=.75). Gastroenterologists were more likely to answer questions correctly than other subspecialists or primary care physicians (P<.0001). On multivariate analysis, physician knowledge correlated directly with self-reported familiarity with guidelines (0.21; 95% confidence interval [CI], 0.08-0.34; P=.002) and specialty (0.56; 95% CI, 0.30-0.82; P<.001) and inversely with year of medical school graduation (0.22; 95% CI, 0.07-0.37; P=.005). LIMITATIONS: Survey study that used theoretical scenarios. CONCLUSION: Physician knowledge of guidelines regarding antibiotic use before endoscopy is suboptimal. Further interventions are needed to improve the knowledge of before-procedure guidelines. PMID- 25841582 TI - Splenic abscess: a rare adverse event of a benign penetrating gastric ulcer. PMID- 25841583 TI - Success of single-balloon enteroscopy in patients with surgically altered anatomy. AB - BACKGROUND: Single-balloon enteroscopy (SBE) was introduced in 2007 to diagnose and treat small-bowel disorders. No study to date has evaluated SBE in patients with surgically altered anatomy outside of ERCP. OBJECTIVE: To evaluate the efficacy, yield, and safety of SBE in patients with surgically altered anatomy. DESIGN: Retrospective study. SETTING: Tertiary-care academic medical center. PATIENTS: All patients with altered surgical anatomy who underwent SBE at the Medical University of South Carolina from July 2007 to September 2013. INTERVENTIONS: SBE. MAIN OUTCOME MEASUREMENTS: Diagnostic yield, therapeutic yield, technical success, and adverse events. RESULTS: A total of 48 patients met inclusion criteria. Mean age was 56 years (77% female). Eleven patients underwent single-balloon PEG placement, 8 single-balloon ERCP, 22 non-PEG/non-ERCP anterograde SBE, and 7 retrograde SBE. Previous surgeries included Roux-en-Y gastric bypass (n=26), small-intestine resection (n=6), colon resection (n=5), Whipple procedure (n=4), choledochojejunostomy (n=3), hepaticojejunostomy (n=1), Billroth I (n=1), Billroth II (n=1), and Puestow procedure (n=1). Procedural indications were PEG tube placement (n=11), choledocholithiasis (n=2), biliary stricture (n=2), obstructive jaundice (n=1), cholangitis (n=1), ampullary mass (n=1), sphincter of Oddi dysfunction (n=1), anemia and/or bleeding (n=15), abdominal pain (n=9), radiologic evidence of obstruction (n=3), and Peutz-Jeghers syndrome (n=2). The technical success rate was 73% in single-balloon PEG placement, 88% in single-balloon ERCP, 82% in other anterograde SBEs, and 86% in retrograde SBEs. No intraprocedural or postprocedural adverse events were observed. LIMITATIONS: Single center, retrospective study. CONCLUSION: SBE is safe and effective in patients with surgically altered anatomy. PMID- 25841584 TI - Pancreatic pseudotumor caused by toothpick ingestion. PMID- 25841585 TI - ERCP with per-oral pancreatoscopy-guided laser lithotripsy for calcific chronic pancreatitis: a multicenter U.S. experience. AB - BACKGROUND: In patients with chronic pancreatitis, laser lithotripsy (LL) permits stone fragmentation and removal during ERCP with some advantages over extracorporeal shock-wave lithotripsy (ESWL) and surgery. OBJECTIVES: To evaluate the technical success of LL in pancreatic duct (PD) stones. DESIGN: Retrospective cohort. SETTING: Four tertiary referral centers. PATIENTS: Patients undergoing endotherapy for PD stones. INTERVENTIONS: ERCP with per-oral pancreatoscopy (POP) guided LL. MAIN OUTCOME MEASUREMENT: Technical success was defined as complete stone clearance. RESULTS: Over 3 years, 28 patients (16 men, 51 years [mean age]) underwent a median of 1 (range, 1-4) POP-LL for PD stones. Baseline parameters included pain requiring hospitalization (n=19, 68%), opiate use (n=14, 50%), or weight loss (n=11, 39%). Before POP-LL, 22 of 28 patients (79%) had a median of 1 (range, 1-5) ERCP, 9 of 28 (32%) underwent a median of 2 (range, 1-3) ESWL sessions, and 5 underwent a median of 1 (range, 1-3) POP-guided electrohydraulic lithotripsy with failed (n=2) or partial (n=3) fragmentation. A median of 2 (range, 1-3) stones sized 15 mm (range, 4-32 mm) were identified in the head (n=9, 32%), neck (n=3, 11%), body (n=9, 32%), tail (n=1, 4%), or multiple sites (n=6, 21%). Technical success occurred in 22 patients (79%) with complete clearance. Partial clearance occurred in 3 (11%). Clinical success at a median of 13 (range, 1-25) months of follow-up was noted in 25 of 28 patients (89%) by improvement in pain (n=25), decreased narcotic use (n=25), or reduced hospitalizations (n=19). Mild adverse events occurred in 8 of 28 (29%). CONCLUSIONS: POP-LL is feasible at expert centers in patients with accessible stones. Although intensive endotherapy is required, most patients achieve stone clearance and clinical improvement. PMID- 25841586 TI - Do stage of disease, comorbidity or access to treatment explain socioeconomic differences in survival after ovarian cancer? - A cohort study among Danish women diagnosed 2005-2010. AB - AIMS: In order to reduce social inequality in cancer survival, knowledge is needed about where in the cancer trajectory disparities occur, and how social and health-related aspects may interact. We aimed to determine whether socioeconomic factors are related to cancer diagnosis stage, and whether socioeconomic disparities in survival after ovarian cancer can be explained by socioeconomic differences in cancer stage, comorbidity, treatment or lifestyle factors. METHODS: In the Danish Gynaecological Cancer Database we identified 2873 cases of ovarian cancer diagnosed between 2005 and 2010. From this data we retrieved information on prognostic factors, treatment information and lifestyle factors. Age, vital status, comorbidity, education, income and cohabitation status were ascertained from nationwide administrative registers. Associations were analyzed with logistic regression and Cox regression models. RESULTS: Educational level was weakly associated with cancer stage. Short education, lower income and living without a partner were related to poorer survival after ovarian cancer. Among women with early cancer stage, HR (95% CI) for death was 1.75 (1.20-2.54) in shorter compared to longer educated women. After adjustment for comorbid conditions, cancer stage, tumour histology, operation status and lifestyle factors, socioeconomic differences in survival persisted. CONCLUSIONS: Socioeconomic disparities in survival after ovarian cancer were to some extent, but not fully explained by differences in important prognostic factors, suggesting further investigations into this problem, however implying that socially less advantaged ovarian cancer patients should receive attention during cancer treatment and rehabilitation. PMID- 25841587 TI - Understanding type 2 diabetes: from genetics to epigenetics. AB - The known genetic variability (common DNA polymorphisms) does not account either for the current epidemics of type 2 diabetes or for the family transmission of this disorder. However, clinical, epidemiological and, more recently, experimental evidence indicates that environmental factors have an extraordinary impact on the natural history of type 2 diabetes. Some of these environmental hits are often shared in family groups and proved to be capable to induce epigenetic changes which alter the function of genes affecting major diabetes traits. Thus, epigenetic mechanisms may explain the environmental origin as well as the familial aggregation of type 2 diabetes much easier than common polymorphisms. In the murine model, exposure of parents to environmental hits known to cause epigenetic changes reprograms insulin sensitivity as well as beta cell function in the progeny, indicating that certain epigenetic changes can be transgenerationally transmitted. Studies from different laboratories revealed that, in humans, lifestyle intervention modulates the epigenome and reverts environmentally induced epigenetic modifications at specific target genes. Finally, specific human epigenotypes have been identified which predict adiposity and type 2 diabetes with much greater power than any polymorphism so far identified. These epigenotypes can be recognized in easily accessible white cells from peripheral blood, indicating that, in the future, epigenetic profiling may enable effective type 2 diabetes prediction. This review discusses recent evidence from the literature supporting the immediate need for further investigation to uncover the power of epigenetics in the prediction, prevention and treatment of type 2 diabetes. PMID- 25841588 TI - Eating disorders are frequent among type 2 diabetic patients and are associated with worse metabolic and psychological outcomes: results from a cross-sectional study in primary and secondary care settings. AB - AIMS: Data regarding the prevalence of eating disorders (ED) and their influence on clinical outcomes among patients with type 2 diabetes (T2DM) are scarce. Our aim is to investigate the frequency of positive screening for ED, specifically binge eating disorder (BED), in a T2DM sample and analyze whether there are any differences among T2DM subjects with a positive screening for ED or BED. METHODS: Three hundred and twenty subjects with T2DM were recruited randomly. All participants were evaluated for the presence of ED by completing the "Eating Attitudes Test-26" (EAT-26). In addition, the "Questionnaire of Eating and Weight Patterns-Revised" (QEWP-R) for the screening of BED was also implemented. Sociodemographic, clinical and biochemical parameters were also recorded. RESULTS: According to EAT-26, 14 % of subjects screened positive for ED. Regarding QEWP-R, 16 % had a positive screening for ED, with BED having a frequency of 12.2 %, being the most prevalent one. There was a positive correlation between the scores obtained with the EAT-26 and the Beck Depression Inventory (p = 0.0014). Patients with BED were younger (57.5 +/- 11.1 vs 63.3 +/- 10.3 years; p = 0.004), with a lesser T2DM duration (8.5 +/- 6.1 vs 12.1 +/- 9.6 years; p = 0.002). Weight and BMI among subjects with BED were greater (89.1 +/- 1.3 vs 82.4 +/- 16.7 kg; p = 0.04 and 39.4 +/- 10.3 vs 30.7 +/- 5.5 kg/m(2); p = 0.01). The frequency of subjects with one admission related to T2DM or any other condition during the last year was higher (10 vs 3 %; p = 0.04 and 33 vs 21 %; p = 0.01). CONCLUSIONS: ED among T2DM are frequent. Due to their deleterious effect on different metabolic and psychological outcomes, they should be diagnosed promptly, especially BED. PMID- 25841589 TI - Frequency of self-monitoring blood glucose and attainment of HbA1c target values. AB - AIMS: Test strips for self-monitoring of blood glucose (SMBG) represent in Argentina, around 50 % of diabetes treatment cost; the frequency of their use is closely associated with hyperglycemia treatment. However, the favorable impact of SMBG on attainment of HbA1c goal in different treatment conditions remains controversial. We therefore attempted to estimate the relationship between use of SMBG test strips and degree of attainment of metabolic control in an institution of our social security subsector (SSS) in which provision is fully covered and submitted to a regular audit system. METHODS: Observational retrospective study using information of 657 patients with T2DM (period 2009-2010) from the database of the Diabetes and Other Cardiovascular Risk Factors Program (DICARO) of one institution of our SSS. DICARO provides-with an audit system-100 % coverage for all drugs and keeps records of clinical, metabolic and treatment data from every patient. RESULTS: The average monthly test strips/patient used for SMBG increased as a function of treatment intensification: Monotherapy with oral antidiabetic drugs (OAD) < combined OAD therapy < insulin treatment. In every condition, the number was larger in people with target HbA1c levels. Test strips represented the larger percentage of total prescription cost. CONCLUSIONS: In our population, the type of hyperglycemia treatment was the main driver of test strip use for SMBG; in every condition tested, targeted HbA1c values were associated with greater strip use. Patient education and prescription audit may optimize its use and treatment outcomes. PMID- 25841590 TI - [Intensive care unit profesionals's knowledge about non invasive ventilation comparative analysis]. AB - AIMS: The literature highlights the lack of noninvasive ventilation (NIV) protocols and the variability of the knowledge of NIV between intensive care units (ICU) and hospitals, so we want to compare NIV nurses's Knowledge from 4 multipurpose ICU and one surgical ICU. METHODS: Multicenter, crosscutting, descriptive study in three university hospitals. The survey instrument was validated in a pilot test, and the calculated Kappa index was 0.9. Returning a completed survey is an indication of informed consent. Analysis by Chi square test. RESULTS: 117 responded (65%) nurses, 11+/-9.7 years of experience in ICU and 9.2+/-7.2 in use of NIV. One of the multipurpose ICU, was initiated NIV an average of 6 years later than the others (95% CI [3.3 to 8.6], P<.001). Only 23.1% of nurses would place a non-vented mask (with no exhalation port) by conventional ventilator, the rest any kind of face mask. 12.7% believed that the mask must be adjusted to the "2-finger" fit while 29% would seal the mask to the patient's face and cover the mask opening where air escapes to facilitate patient/ventilator synchronization. In the surgical ICU agitation identifies mostly as a complication of NIV compared with multipurpose UCIs (31.6% vs 1.8%, P<.001). 56.4% of nurses do not consider respiratory physiotherapy as nursing care, with no difference between units. CONCLUSIONS: Knowledge about types of interface is very dependent on the material of the unit. More training for complications of NIV as agitation and handling secretions it is necessary. PMID- 25841591 TI - Proteome evolution of wheat (Triticum aestivum L.) aleurone layer at fifteen stages of grain development. AB - The aleurone layer (AL) is the grain peripheral tissue; it is rich in micronutrients, vitamins, antioxidants, and essential amino acids. This highly nutritive part of the grain has been less studied partly because its isolation is so laborious. In the present study, the ALs of Triticum aestivum (variety Recital) were separated manually at 15 stages of grain development. A total of 327 proteins were identified using 2-DE LC-MS/MS. They were classified in six main groups and 26 sub-groups according to their biochemical function. Proteomic analysis revealed seven different profiles distributed among three main development stages: (i) early AL development, with proteins involved in intense metabolic activities in the growth and development of the cell wall compounds; (ii) the intermediate stage, characterized by oxidative stress and defense proteins (65%) linked with loss of water in peripheral layers during grain filling; and (iii) AL maturation, involving the production of amino acids and the control of reactive oxidative species to enable the accumulation and maturation of globulins within the AL. The present study provides the first insights into developing proteome in the AL. We describe the numerous AL enzymes involved in the accumulation of storage protein and in the protection of the endosperm over time. BIOLOGICAL SIGNIFICANCE: The hand dissection of wheat aleurone layer (AL) was carried in this study for the first time on fifteen developmental stages from cell differentiation to grain maturity. Three major phases were revealed over AL development: cell division activities, globulins storage, and grain protection. Enzymes related to metabolites and vitamins were abundantly expressed during the two first phases. In parallel to the progressive globulins accumulation, the final phase was characterized by key enzyme synthesis involved in energy production, amino-acids and antioxidant synthesis plus others to face hypoxia and dehydration of grain tissues. PMID- 25841592 TI - Feasibility of label-free phosphoproteomics and application to base-line signaling of colorectal cancer cell lines. AB - Robust phosphopeptide enrichment methods with minimal fractionation are required to profile signaling network analysis in cancer cell lines and tissues. We assessed performance of single-shot LC-MS/MS label-free phosphoproteomics using TiOx-based phosphopeptide enrichment and report phosphopeptide identification reproducibility (75.8%), depth of identification (6014-6150 phosphopeptides) and reproducibility of label-free quantification (CV 17.8%). Subsequently, we have profiled the baseline global phosphorylation of 8 colorectal cancer (CRC) cell lines representing different CRC prognostic subtypes. Global single-shot phosphoproteomics can distinguish CRC subtypes previously identified by transcriptomics and identifies signaling proteins and processes associated with the CCS3 poor prognosis subtype. Data are available via ProteomeXchange with identifiers PXD001546 and PXD001550. BIOLOGICAL SIGNIFICANCE: Label-free single shot phosphoproteomics is a mature workflow that can be used for global quantitative profiling of biological cell lines and tissues to map signaling networks in comparative analyses. Here we show the feasibility of label-free profiling of CRC cell lines at sample input levels compatible with clinical samples such as tumor biopsies. This article is part of a Special Issue entitled: HUPO 2014. PMID- 25841593 TI - Structural and functional screening in human induced-pluripotent stem cell derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types. AB - Safety pharmacology studies that evaluate new drug entities for potential cardiac liability remain a critical component of drug development. Current studies have shown that in vitro tests utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CM) may be beneficial for preclinical risk evaluation. We recently demonstrated that an in vitro multi-parameter test panel assessing overall cardiac health and function could accurately reflect the associated clinical cardiotoxicity of 4 FDA-approved targeted oncology agents using hiPS-CM. The present studies expand upon this initial observation to assess whether this in vitro screen could detect cardiotoxicity across multiple drug classes with known clinical cardiac risks. Thus, 24 drugs were examined for their effect on both structural (viability, reactive oxygen species generation, lipid formation, troponin secretion) and functional (beating activity) endpoints in hiPS-CM. Using this screen, the cardiac-safe drugs showed no effects on any of the tests in our panel. However, 16 of 18 compounds with known clinical cardiac risk showed drug induced changes in hiPS-CM by at least one method. Moreover, when taking into account the Cmax values, these 16 compounds could be further classified depending on whether the effects were structural, functional, or both. Overall, the most sensitive test assessed cardiac beating using the xCELLigence platform (88.9%) while the structural endpoints provided additional insight into the mechanism of cardiotoxicity for several drugs. These studies show that a multi-parameter approach examining both cardiac cell health and function in hiPS-CM provides a comprehensive and robust assessment that can aid in the determination of potential cardiac liability. PMID- 25841595 TI - Cervical cancer prevention: immunization and screening 2015. AB - Both primary and secondary prevention of cervical cancer are now available. Immunizations against human papillomavirus (HPV) types 16 and 18 have the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers. Screening guidelines were recently changed to recommend cotesting with cytology plus an HPV test. The addition of HPV testing increases the sensitivity and negative predictive value of screening over the Papanicolaou (Pap) test alone. PMID- 25841594 TI - Breast cancer screening: an evidence-based update. AB - Routine screening mammography is recommended by most groups issuing breast cancer screening guidelines, especially for women 50 years of age and older. However, both the potential benefits and risks of screening should be discussed with individual patients to allow for shared decision making regarding their participation in screening, age of commencement and conclusion, and interval of mammography screening. PMID- 25841596 TI - Oral contraception. AB - Oral contraception (OC) remains a popular noninvasive, readily reversible approach for pregnancy prevention and, largely off label, for control of acne, hirsutism, dysmenorrhea, irregular menstruation, menorrhagia, and other menstrual related symptoms. Many OC formulations exist, with generics offering lower cost and comparable efficacy. Certain medical conditions, including hypertension, migraine, breast cancer, and risk of venous thromboembolism (VTE), present contraindications. Blood pressure measurement is the only physical examination or testing needed before prescription. Although no OC is clearly superior to others, OCs containing the second-generation progestin levonorgestrel have been associated with lower VTE risk than those containing other progestins. PMID- 25841597 TI - Intrauterine devices and other forms of contraception: thinking outside the pack. AB - A variety of contraception options are available in addition to traditional combined oral contraceptive pills. Newer long-acting reversible contraceptive (LARC) methods such as intrauterine devices and subcutaneous implants are preferred because they do not depend on patient compliance. They are highly effective and appropriate for most women. Female and male sterilization are other effective but they are irreversible and require counseling to minimize regret. The contraceptive injection, patch, and ring do not require daily administration, but their typical efficacy rates are lower than LARC methods and similar to those for combined oral contraceptive pills. PMID- 25841598 TI - Menopause. AB - Women generally spend the last third of their lifetime in menopause, after their reproductive years have ended. During menopause, women experience a variety of predictable symptoms and conditions related to changes in sex hormone levels and aging. The menopausal transition precedes menopause by several years and is usually characterized by irregularity of the menstrual cycle and by hot flashes and night sweats. After menopause, genitourinary symptoms predominate, including vulvovaginal atrophy and dryness and lower urinary tract symptoms, including urinary frequency, urgency, and nocturia. Hormonal treatment is effective for vasomotor and genitourinary symptoms, but the understanding of its impact on cardiovascular disease, cognitive dysfunction, and depression continues to evolve. PMID- 25841599 TI - Cardiovascular risk factors and disease in women. AB - Coronary artery disease and stroke predominantly affect older women as opposed to younger women, but the risk factors that contribute to atherosclerotic cardiovascular disease risk often start in young women. Young women with polycystic ovary syndrome (PCOS), with migraine, and who use oral contraceptive pills (OCPs) have short-term increases in thrombotic complications that can result in coronary events or stroke. Attention should be focused on risk reduction in women of all ages. Screening for and discussing diabetes, hypertension, obesity, smoking, migraine, PCOS, and pregnancy complication history and discussing the pros and cons of hormone and statin medications are part of reducing cardiovascular risk for women. PMID- 25841600 TI - Common vaginal and vulvar disorders. AB - Vaginal and vulvar disorders are among the leading causes for women to visit a health care professional. Therefore, it is important to have a basic understanding of these diseases. Although rarely life threatening, these disorders can impact significantly a woman's sexual function and sense of well being. PMID- 25841601 TI - Prevalence and management of chronic hepatitis C virus infection in women. AB - Hepatitis C virus (HCV) is the most common blood-borne pathogen in the United States and is a leading cause of cirrhosis, need for liver transplantation, and liver-related mortality in women. Women should be offered testing if they fall in a high-risk group for exposure. Compared to men, women have higher rates of spontaneous HCV clearance after exposure and slower progression to cirrhosis but are more susceptible to liver damage from comorbid alcohol use. Premenopausal women with HCV should be counseled about the risks of antiviral treatment during pregnancy and the potential for vertical transmission of HCV to their offspring. PMID- 25841602 TI - Osteoporosis: screening, prevention, and management. AB - Osteoporosis is characterized by low bone mineral density (BMD) and abnormal bone architecture. Common fracture sites are vertebrae, proximal femur, and distal forearm. Osteoporosis is underdiagnosed and undertreated. All women 65 and older should be screened. Consider screening younger postmenopausal women with elevated risk. Osteoporosis is diagnosed based on T score or a fragility fracture. Women with osteoporosis or who have a 10-year risk of any major fracture of 20% or hip fracture of 3% should be evaluated for causes of low bone density and treated with an osteoporosis-specific medication, lifestyle interventions, and calcium and vitamin D intake. PMID- 25841603 TI - Female sexual dysfunction. AB - Female sexual dysfunction is a common patient concern. After providing an overview regarding the various types of female sexual dysfunction, we will focus on history taking and treatment options for desire, arousal, orgasm, and pain disorders. Testosterone therapy and management of selective serotonin reuptake inhibitor-associated sexual dysfunction are reviewed. Treatments for atrophic vaginitis are appraised. Patient cases lead the discussion, providing the reader with clinically relevant information. PMID- 25841604 TI - Intimate partner violence: prevalence, health consequences, and intervention. AB - Intimate partner violence (IPV) can be defined in many ways and encompasses many different types of physical and emotional abuse. IPV affects the health, safety, and quality of life for women, men, and children worldwide, regardless of race, sexual orientation, or socioeconomic status. The health effects include acute trauma; a wide range of physical and mental sequelae; and, for some, death. Because of the serious consequences of IPV, both the Centers for Disease Control and the World Health Organization identify IPV as a significant public health issue. PMID- 25841605 TI - Care of women veterans. AB - As more women have joined the US military, there has been a shift in the overall veteran population. Those who served in the US military, especially women, have undergone experiences that will impact their overall health and wellbeing. It is therefore critical for providers to better understand US military culture and be prepared on how to ask patients about their military experience. Health care providers need to be aware of the unique medical, psychiatric, and psychosocial needs of women veterans in order to best serve this patient population. PMID- 25841606 TI - Preconception care and reproductive planning in primary care. AB - Preconception care is designed to identify and reduce biomedical, behavioral, and social risks to the health of a woman or her baby before pregnancy occurs. Few women present requesting preconception care; however, 1 in 10 US women of childbearing age will become pregnant each year. As primary care physicians (PCPs) care for reproductive-aged women before, between, and after their pregnancies, they are ideally positioned to help women address health risks before conception, including optimizing chronic conditions, to prevent adverse pregnancy and longer-term health outcomes. PCPs can help women make informed decisions both about preparing for pregnancy and about using effective contraception when pregnancy is not desired. PMID- 25841607 TI - Women's health. PMID- 25841608 TI - Women's health. PMID- 25841609 TI - Which patients are less likely to improve during the first year after arthroscopic partial meniscectomy? A multivariate analysis of 201 patients with prospective follow-up. AB - PURPOSE: To determine which specific factors influence the improvements in function and pain at the first year following arthroscopic partial meniscectomy. METHODS: Between 2012 and 2013, patients who had arthroscopic partial meniscectomy were included (n = 201) and followed prospectively before surgery and at 12 months. Multivariable stepwise analysis included preoperative variables (age, gender, limb side, height, weight, body mass index, comorbidities, smoking, Tegner activity scale, Lysholm knee score, preceding injury and duration of preoperative symptoms) and arthroscopic findings (degree of cartilage lesions, medial or lateral meniscus involvement, type of meniscal tear and concomitant cruciate tear). The Lysholm clinical score at the last follow-up and the time interval for substantial pain relief was modelled as a function of the above predictor variables. RESULTS: At the last follow-up, the mean Lysholm score improved by 14.6 points (95 % CI 10.4-18.8, P < 0.001), from 68.0 +/- 16.1 to 82.6 +/- 19.6 points and 153 (76 %) patients declared they were satisfied to have had the operation. The mean time interval for substantial pain relief was 3.5 +/- 1.5 months. Females and patients with lower preoperative Lysholm score were correlated with lower post-operative Lysholm score, while females and patients with lateral meniscal tears (compared to medial meniscal tears) were correlated with longer recovery. CONCLUSIONS: Arthroscopic partial meniscectomy improved pain and function at the first year post-operatively. Female gender, lateral meniscal tear and less favourable preoperative function were relatively correlated to worse post-operative function and longer rehabilitation time. LEVEL OF EVIDENCE: IV. PMID- 25841610 TI - Minimizing thermal degradation in gas chromatographic quantitation of pentaerythritol tetranitrate. AB - An analytical method for establishing calibration curves for the quantitation of pentaerythriol tetranitrate (PETN) from sorbent-filled thermal desorption tubes by gas chromatography with electron capture detection (TDS-GC-ECD) was developed. As PETN has been demonstrated to thermally degrade under typical GC instrument conditions, peaks corresponding to both PETN degradants and molecular PETN are observed. The retention time corresponding to intact PETN was verified by high resolution mass spectrometry with a flowing atmospheric pressure afterglow (FAPA) ionization source, which enabled soft ionization of intact PETN eluting the GC and subsequent accurate-mass identification. The GC separation parameters were transferred to a conventional GC-ECD instrument where analytical method-induced PETN degradation was further characterized and minimized. A method calibration curve was established by direct liquid deposition of PETN standard solutions onto the glass frit at the head of sorbent-filled thermal desorption tubes. Two local, linear relationships between detector response and PETN concentration were observed, with a total dynamic range of 0.25-25ng. PMID- 25841611 TI - Dispersive liquid-liquid microextraction for the determination of new generation pesticides in soils by liquid chromatography and tandem mass spectrometry. AB - A sensitive method for the determination of five new generation pesticides (chlorantraniliprole, spirotetramat, spiromesifen, spirodiclofen and flubendiamide) in soil samples has been developed using liquid chromatography and tandem mass spectrometry (LC-MS(2)) with a triple-quadrupole in the multiple reaction monitoring mode. The target analytes are released from the solid matrix by single-phase extraction in acetonitrile (SLE), this organic phase being used as dispersant solvent in the dispersive liquid-liquid microextraction (DLLME) step. The different parameters affecting the extraction efficiency in DLLME were carefully studied, being 1.5mL of acetonitrile extract (disperser solvent), 125MUL carbon tetrachloride (extraction solvent) and 10mL aqueous solution, the selected conditions. The enriched organic phase was evaporated, reconstituted with 50MUL acetonitrile and injected into a liquid chromatograph with a mobile phase composed of acetonitrile and 0.1% (v/v) formic acid under gradient elution and a C8 stationary phase. Detection limits in the 0.0015-0.0090ngg(-1) range were obtained. Insecticide concentrations ranging from 0.03 to 197ngg(-1), depending on the compound, were found in the soil samples analysed. The recovery values obtained by SLE-DLLME-LC-ESI-MS(2) for three spiked soils at three concentration levels varied between 87 and 114%, with RSDs of between 5.5 and 14%. PMID- 25841612 TI - Fourier transform assisted deconvolution of skewed peaks in complex multi dimensional chromatograms. AB - Lower order peak moments of individual peaks in heavily fused peak clusters can be determined by fitting peak models to the experimental data. The success of such an approach depends on two main aspects: the generation of meaningful initial estimates on the number and position of the peaks, and the choice of a suitable peak model. For the detection of meaningful peaks in multi-dimensional chromatograms, a fast data scanning algorithm was combined with prior resolution enhancement through the reduction of column and system broadening effects with the help of two-dimensional fast Fourier transforms. To capture the shape of skewed peaks in multi-dimensional chromatograms a formalism for the accurate calculation of exponentially modified Gaussian peaks, one of the most popular models for skewed peaks, was extended for direct fitting of two-dimensional data. The method is demonstrated to successfully identify and deconvolute peaks hidden in strongly fused peak clusters. Incorporation of automatic analysis and reporting of the statistics of the fitted peak parameters and calculated properties allows to easily identify in which regions of the chromatograms additional resolution is required for robust quantification. PMID- 25841613 TI - Beyond experimental noise: Analyzing single-molecule data of heterogeneous systems: Comment on "Extracting physics of life at the molecular level: A review of single-molecule data analyses" by W. Colomb and S.K. Sarkar. PMID- 25841614 TI - Profiling of peripheral blood mononuclear cells does not accurately predict the bronchiolitis obliterans syndrome after lung transplantation. AB - After lung transplantation (LTx), circulating mononuclear cell composition and their subsets may be predictive for the bronchiolitis obliterans syndrome (BOS). We investigated the cellular composition in patients developing BOS, or not, by analyzing peripheral blood taken at multiple time points after transplantation. PBMCs of 11 BOS and 39 non-BOS patients were analyzed by FACS for monocytes, dendritic cells, NK-, NKT-, B- and T cells as well as B- and T cell subsets. Analysis of blood samples taken monthly during the first year post-LTx showed that circulating NK, NKT and dendritic cell percentages were not indicative of BOS development, whereas increases in T cells, monocytes and lowered fractions of B cells were related to BOS development. B- and T cell subset analysis at month 5 post-LTx indicated that IgM+IgD- memory B cells and central memory CD8+ T cells were decreased, whereas NKT cells were increased in BOS patients compared to non BOS patients. Prior to BOS diagnosis, the composition of specific mononuclear cells on a group level differs from patients remaining BOS free. However, given the overlap in percentages of cellular frequencies between the patient groups investigated, this analysis does not allow prediction or risk stratification for development of BOS in individual patients. PMID- 25841615 TI - Prevalence and characteristics of women reporting poor mental health during pregnancy: Findings from the 2010 French National Perinatal Survey. AB - BACKGROUND: Self-rated mental health is a useful indicator to examine the positive dimension of mental health and psychological well-being. The primary objective of this study was to estimate the prevalence of poor self-rated mental health during pregnancy in a nationally representative population in France. The second objective was to assess the sociodemographic and medical characteristics associated with this condition and with a health professional's consultation for psychological problems. METHODS: The study was based on the 2010 French National Perinatal Survey, which included all singleton live births in French maternity units during a 1-week period (n=14,326 women). Self-rated mental health was assessed using the following single-item question: "During your pregnancy, how did you feel from a psychological point of view: good - fairly good - rather poor - poor?" Women were also asked if they had visited a healthcare professional for psychological problems. They were interviewed between delivery and discharge to collect information on mental health, sociodemographic and medical characteristics, the context of their pregnancy, and their prenatal care. RESULTS: Of the women interviewed, 8.9% [95% CI, 8.5-9.5%] reported poor self rated mental health during pregnancy. Among them, 18.7% consulted a healthcare professional for psychological problems. Sociodemographic characteristics indicative of social disadvantage were associated with a higher-risk of poor self rated mental health, and a social gradient was observed. However, more favorable social characteristics were associated with consultation with a healthcare professional for these psychological difficulties. The reaction to the discovery of pregnancy and prenatal care differed significantly depending on self-rated mental health. Women with poor mental health had more complicated pregnancies. CONCLUSION: This study showed strong associations between many socially disadvantaged characteristics and a positive dimension of mental health. The findings suggest that well-being measures such as self-rated mental health should be routinely assessed during pregnancy so that women can be offered more appropriate support. PMID- 25841616 TI - The 6-OHDA mouse model of Parkinson's disease - Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions. AB - Unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway produce side-biased motor impairments that reflect the motor deficits seen in Parkinson's disease (PD). This toxin-induced model in the rat has been used widely, to evaluate possible therapeutic strategies, but has not been well established in mice. With the advancements in mouse stem cell research we believe the requirement for a mouse model is essential for the therapeutic potential of these and other mouse-derived cells to be efficiently assessed. This aim of this study focused on developing a mouse model of PD using the 129 P2/OLA Hsd mouse strain as this is widely used in the generation of mouse embryonic stem cells. Both unilateral 6-OHDA medial forebrain bundle (MFB) and striatal lesion protocols were compared, with mice analysed for appropriate drug-induced rotational bias. Results demonstrated that lesioned mice responded to d amphetamine with peak rotation dose at 5mg/kg and 10mg/kg for MFB and striatal lesions respectively. Apomorphine stimulation produced no significant rotational responses, at any dose, in either the MFB or striatal 6-OHDA lesioned mice. Analysis of dopamine neuron loss revealed that the MFB lesion was unreliable with little correlation between dopamine neuron loss and rotational asymmetry. Striatal lesions however were more reliable, with a strong correlation between dopamine neuron loss and rotational asymmetry. Functional recovery of d amphetamine-induced rotational bias was shown following transplantation of E13 mouse VM tissue into the lesioned striatum; confirming the validity of this mouse model. PMID- 25841617 TI - Memory boosts turn taking in evolutionary dilemma games. AB - Spontaneous turn taking phenomenon can be observed in many self-organized systems, and the mechanism is unclear. This paper tries to model it by evolutionary dilemma games with memory mechanism. Prisoner's dilemma, Snowdrift (including Leader and Hero) and Stag-hunt games are unified on an extended S-T plane. Agents play game with all the others and make decision by the last game histories. The experiments find that when agents remember last 2-step histories or more, a kind of cooperative turn taking (CAD) bursts at the area of Snowdrift game with restriction of S + T > 2R and S ? T, while the consistent strategy (DorC) gathers on the line of S + T > 2R and S = T. We also find that the system's fitness ratio greatly improved with 2-step memory. PMID- 25841618 TI - Cyclic supplementation of 5-MTHF is effective for the correction of hyperhomocysteinemia. AB - Folic acid supplementation is the mainstay treatment of hyperhomocysteinemia (HHcy). However, no recommendations are currently available in regard to the optimal replacement therapy. Therefore, this prospective study hypothesized that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5 methyltetrahydrofolate (5-MTHF) would reduce plasma levels of fasting total homocysteine (tHcy) in patients with mild/moderate HHcy. Patients with a new diagnosis of mild/moderate HHcy were evaluated for the methylenetetrahydrofolate reductase genotype and the presence of major features of metabolic syndrome. All enrolled subjects received a cyclic 5-MTHF oral supplementation and were reevaluated after each treatment cycle for a total of 2 years. In the 246 enrolled subjects, a significant reduction of tHcy levels occurred after the first cycle of treatment (from 31.6 +/- 13.6 to 14.4 +/- 5.77 MUmol/L, P < .001) and during the whole 2-year follow-up (from 31.6 +/- 13.6 to 12.18 +/- 3.03 MUmol/L, P < .001). The values of tHcy returned to reference range in 117 subjects (51.3%) after the first cycle and in 198 (86.8%) during the follow-up. The risk of failure in tHcy level normalization was increased in patients with metabolic syndrome (hazard ratio [HR], 3.49; 95% confidence interval [CI], 1.46 8.36), higher baseline tHcy levels (HR, 1.045; 95% CI, 1.018-1.073), or methylenetetrahydrofolate reductase homozygous mutation (HR, 6.59; 95% CI, 2.64 16.4). This study clearly shows that a cyclic schedule (1 month of therapy followed by 2 months of withdrawal) of 5-MTHF supplementation is able to significantly reduce tHcy levels in patients with mild/moderate HHcy. PMID- 25841619 TI - Reply. PMID- 25841620 TI - Current recommendations for the Japanese encephalitis vaccine. AB - Japanese encephalitis (JE) is a mosquito-borne flavivirus infection and an important cause of encephalitis in most of Asia and parts of the western Pacific. Most people infected with the JE virus (JEV) are asymptomatic or seemingly suffer from a nonspecific, flu-like illness; in others, JE can cause illness ranging from fever and headache to severe encephalitis. Although it can cause significant morbidity and mortality, JE is a vaccine-preventable disease, and vaccination programs have proven most effective in preventing and diminishing the burden of disease. Such JE vaccines have been available for decades with four types of JE vaccines-live attenuated SA14-14-2 vaccine, inactivated mouse brain-derived vaccine (JE-MB), inactivated Vero cell culture vaccine (JE-VC), and live attenuated chimeric vaccine (IMOJEV)-and are currently used in most countries. In some Asian countries such as Japan, China, Taiwan, Korea, and Thailand, immunization programs have been conducted for children and so the ongoing incidence of JE has declined considerably in recent decades. Until quite recently, the primary JE vaccine in use internationally has been the JE-MB, which is now commonly replaced by cell culture-based vaccines. PMID- 25841621 TI - Risk of Pathologic Upgrading or Locally Advanced Disease in Early Prostate Cancer Patients Based on Biopsy Gleason Score and PSA: A Population-Based Study of Modern Patients. AB - PURPOSE: Radiation oncologists rely on available clinical information (biopsy Gleason score and prostate-specific antigen [PSA]) to determine the optimal treatment regimen for each prostate cancer patient. Existing published nomograms correlating clinical to pathologic extent of disease were based on patients treated in the 1980s and 1990s at select academic institutions. We used the Surveillance, Epidemiology, and End Results (SEER) database to examine pathologic outcomes (Gleason score and cancer stage) in early prostate cancer patients based on biopsy Gleason score and PSA concentration. METHODS AND MATERIALS: This analysis included 25,858 patients whose cancer was diagnosed between 2010 and 2011, with biopsy Gleason scores of 6 to 7 and clinical stage T1 to T2 disease, who underwent radical prostatectomy. In subgroups based on biopsy Gleason score and PSA level, we report the proportion of patients with pathologically advanced disease (positive surgical margin or pT3-T4 disease) or whose Gleason score was upgraded. Logistic regression was used to examine factors associated with pathologic outcomes. RESULTS: For patients with biopsy Gleason score 6 cancers, 84% of those with PSA <10 ng/mL had surgical T2 disease with negative margins; this decreased to 61% in patients with PSA of 20 to 29.9 ng/mL. Gleason score upgrading was seen in 43% (PSA: <10 ng/mL) to 61% (PSA: 20-29.9 ng/mL) of biopsy Gleason 6 patients. Patients with biopsy Gleason 7 cancers had a one-third (Gleason 3 + 4; PSA: <10 ng/mL) to two-thirds (Gleason 4 + 3; PSA: 20-29.9 ng/mL) probability of having pathologically advanced disease. Gleason score upgrading was seen in 11% to 19% of patients with biopsy Gleason 4 + 3 cancers. Multivariable analysis showed that higher PSA and older age were associated with Gleason score upgrading and pathologically advanced disease. CONCLUSIONS: This is the first population-based study to examine pathologic extent of disease and pathologic Gleason score upgrading based on clinically available information in modern patients. These data inform the selection of radiation therapy strategies and an understanding of whether prostatectomy alone is likely to be curative for patients with early prostate cancers. PMID- 25841622 TI - Acupuncture-Like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Radiation-Induced Xerostomia: Results of RTOG 0537 Phase 3 Study. AB - PURPOSE AND OBJECTIVES: This report presents the analysis of the RTOG 0537 multicenter randomized study that compared acupuncture-like transcutaneous stimulation (ALTENS) with pilocarpine (PC) for relieving radiation-induced xerostomia. METHODS AND MATERIALS: Eligible patients were randomized to twice weekly 20-minute ALTENS sessions for 24 sessions during 12 weeks or PC (5 mg 3 times daily for 12 weeks). The primary endpoint was the change in the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) scores from baseline to 9 months from randomization (MFR). Secondary endpoints included basal and citric acid primed whole salivary production (WSP), ratios of positive responders (defined as patients with >=20% reduction in overall radiation-induced xerostomia symptom burden), and the presence of adverse events based on the Common Terminology Criteria for Adverse Events version 3. An intention-to-treat analysis was conducted. RESULTS: One hundred forty-eight patients were randomized. Only 96 patients completed the required XeQOLS and were evaluable at 9 MFR (representing merely 68.6% statistical power). Seventy-six patients were evaluable at 15 MFR. The median change in the overall XeQOLS in ALTENS and PC groups at 9 and 15 MFR were -0.53 and -0.27 (P=.45) and -0.6 and -0.47 (P=.21). The corresponding percentages of positive responders were 81% and 72% (P=.34) and 83% and 63% (P=.04). Changes in WSP were not significantly different between the groups. Grade 3 or less adverse events, mostly consisting of grade 1, developed in 20.8% of patients in the ALTENS group and in 61.6% of the PC group. CONCLUSIONS: The observed effect size was smaller than hypothesized, and statistical power was limited because only 96 of the recruited 148 patients were evaluable. The primary endpoint-the change in radiation-induced xerostomia symptom burden at 9 MFR-was not significantly different between the ALTENS and PC groups. There was significantly less toxicity in patients receiving ALTENS. PMID- 25841623 TI - Hypofractionated versus standard radiation therapy with or without temozolomide for older glioblastoma patients. AB - PURPOSE: Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ). METHODS AND MATERIALS: We conducted a retrospective analysis of patients >=65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis. RESULTS: Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P<.001) and had worse baseline performance status (P<.001) than those receiving SRT. On multivariate analysis, older age (adjusted hazard ratio [AHR]: 1.06; 95% confidence interval [CI]: 1.01-1.10, P=.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P=.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P=.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P=.03; HRT: AHR: 3.92; 95% CI: 1.44 10.60, P=.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P=.82). CONCLUSIONS: With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall survival for HRT and SRT with concurrent TMZ among elderly patients, suggesting the need for a randomized trial to compare these regimens directly. PMID- 25841624 TI - Long-term Results of the UCSF-LBNL Randomized Trial: Charged Particle With Helium Ion Versus Iodine-125 Plaque Therapy for Choroidal and Ciliary Body Melanoma. AB - PURPOSE: Relevant clinical data are needed given the increasing national interest in charged particle radiation therapy (CPT) programs. Here we report long-term outcomes from the only randomized, stratified trial comparing CPT with iodine-125 plaque therapy for choroidal and ciliary body melanoma. METHODS AND MATERIALS: From 1985 to 1991, 184 patients met eligibility criteria and were randomized to receive particle (86 patients) or plaque therapy (98 patients). Patients were stratified by tumor diameter, thickness, distance to disc/fovea, anterior extension, and visual acuity. Tumors close to the optic disc were included. Local tumor control, as well as eye preservation, metastases due to melanoma, and survival were evaluated. RESULTS: Median follow-up times for particle and plaque arm patients were 14.6 years and 12.3 years, respectively (P=.22), and for those alive at last follow-up, 18.5 and 16.5 years, respectively (P=.81). Local control (LC) for particle versus plaque treatment was 100% versus 84% at 5 years, and 98% versus 79% at 12 years, respectively (log rank: P=.0006). If patients with tumors close to the disc (<2 mm) were excluded, CPT still resulted in significantly improved LC: 100% versus 90% at 5 years and 98% versus 86% at 12 years, respectively (log rank: P=.048). Enucleation rate was lower after CPT: 11% versus 22% at 5 years and 17% versus 37% at 12 years, respectively (log rank: P=.01). Using Cox regression model, likelihood ratio test, treatment was the most important predictor of LC (P=.0002) and eye preservation (P=.01). CPT was a significant predictor of prolonged disease-free survival (log rank: P=.001). CONCLUSIONS: Particle therapy resulted in significantly improved local control, eye preservation, and disease-free survival as confirmed by long-term outcomes from the only randomized study available to date comparing radiation modalities in choroidal and ciliary body melanoma. PMID- 25841625 TI - Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer Tumors Greater Than 5 cm: Safety and Efficacy. AB - PURPOSE: The purpose of this study was to determine outcomes of patients with node-negative medically inoperable non-small cell lung cancer (NSCLC) whose primary tumors exceeded 5 cm and were treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: We surveyed our institutional prospective lung SBRT registry to identify treated patients with tumors >5 cm. Treatment outcomes for local control (LC), locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) were assessed by Kaplan-Meier estimates. Toxicities were graded according to Common Terminology Criteria for Adverse Events version 4. Mean pretreatment pulmonary function test values were compared to mean posttreatment values. RESULTS: From December 2003 to July 2014, 40 patients met study criteria. Median follow-up was 10.8 months (range: 0.4-70.3 months). Median age was 76 years (range: 56-90 years), median body mass index was 24.3 (range: 17.7-37.2), median Karnofsky performance score was 80 (range: 60 90), and median Charlson comorbidity index score was 2 (range: 0-5). Median forced expiratory volume in 1 second (FEV1) was 1.41 L (range: 0.47-3.67 L), and median diffusion capacity (DLCO) was 47% of predicted (range: 29%-80%). All patients were staged by fluorodeoxyglucose-positron emission tomography/computed tomography staging, and 47.5% underwent mediastinal staging by endobronchial ultrasonography. Median tumor size was 5.6 cm (range: 5.1-10 cm), median SBRT dose was 50 Gy (range: 30-60 Gy) in 5 fractions (range: 3-10 fractions). Eighteen month LC, LRC, DFS, and OS rates were 91.2%, 64.4%, 34.6%, and 59.7%, respectively. Distant failure was the predominant pattern of failure (32.5%). Three patients (7.5%) experienced grade 3 or higher toxicity. Mean posttreatment FEV1 was not significantly reduced (P=.51), but a statistically significant absolute 6.5% (P=.03) reduction in DLCO was observed. CONCLUSIONS: Lung SBRT for medically inoperable node-negative NSCLC with primary tumors larger than 5 cm is safe and provides excellent local control with limited toxicity. The predominant pattern of failure in this population was distant failure. PMID- 25841626 TI - The internal gene duplication and interrupted coding sequences in the MmpL genes of Mycobacterium tuberculosis: Towards understanding the multidrug transport in an evolutionary perspective. AB - The multidrug resistance has emerged as a major problem in the treatment of many of the infectious diseases. Tuberculosis (TB) is one of such disease caused by Mycobacterium tuberculosis. There is short term chemotherapy to treat the infection, but the main hurdle is the development of the resistance to antibiotics. This resistance is primarily due to the impermeable mycolic acid rich cell wall of the bacteria and other factors such as efflux of antibiotics from the bacterial cell. The MmpL (Mycobacterial Membrane Protein Large) proteins of mycobacteria are involved in the lipid transport and antibiotic efflux as indicated by the preliminary reports. We present here, comprehensive comparative sequence and structural analysis, which revealed topological signatures shared by the MmpL proteins and RND (Resistance Nodulation Division) multidrug efflux transporters. This provides evidence in support of the notion that they belong to the extended RND permeases superfamily. In silico modelled tertiary structures are in homology with an integral membrane component present in all of the RND efflux pumps. We document internal gene duplication and gene splitting events happened in the MmpL genes, which further elucidate the molecular functions of these putative transporters in an evolutionary perspective. PMID- 25841627 TI - The transcriptional programs of iNKT cells. AB - Invariant natural killer T (iNKT) cells are innate T cells that express a semi invariant T cell receptor (TCR) and recognize lipid antigens presented by CD1d molecules. As part of innate immunity, iNKT cells rapidly produce large amounts of cytokines after activation and regulate the function of innate and adaptive immune cells in antimicrobial immunity, tumor rejection and inflammatory diseases. Global transcriptional profiling has advanced our understanding of all aspects of iNKT cell biology. In this review, we discuss transcriptional analyses of iNKT cell development, functional subsets of iNKT cells, and global comparisons of iNKT cells to other innate and adaptive immune cells. Global transcriptional analysis revealed that iNKT cells have a transcriptional profile distinct from NK cells and MHC-restricted T cells, both during thymic development and in the periphery. The transcription factors EGR2 and PLZF (and microRNA like miR-150) are key regulators of the iNKT cell transcriptome during development. PLZF is one of several factors that control the homing and maintenance of organ specific iNKT cell populations. As in MHC-restricted T cells, specific transcription factors are characteristic of functional subsets of iNKT cells, such as the transcription factor T-bet in the NKT1 subset. Exciting future directions for global transcriptional analyses include iNKT cells in disease models, diverse NKT cells and human studies. PMID- 25841628 TI - Global transcriptional characterization of CD8+ T cell memory. AB - The differentiation of memory CD8T cells after acute infections comprises generation of functionally distinct populations that either have proliferative potential or display cytotoxic effector functions and that either recirculate into lymphoid tissues or remain tissue-resident. The development of these functionally distinct cell populations is dictated by defined signals from the microenvironment that result in a coordinated expression of a network of transcription factors, which determine the functionality of memory T cells. Distinct transcriptional regulation observed during chronic viral infection that results in generation of T cells that control viral replication in the absence of immunopathology suggests the existence of so far unappreciated functional adaptation of T cell function to the particular need during chronic infections to control infection and avoid immunopathology. Furthermore, the non-canonical generation of CD8T cell memory outside of lymphoid tissues in the liver in the absence of inflammation is correlated with a distinct transcriptional profile and indicates further complexity in the commensurate immune response to infectious pathogens that escape innate immunity. Taken together, distinct profiles of transcriptional regulation are linked to CD8T cells with different functions and provide important mechanistic insight into the continuous functional adaptation of CD8T cells to generate a commensurate immune response to infectious challenges. PMID- 25841629 TI - Diet-related determinants of childhood obesity in urban settings: a comparison between Shanghai and New York. AB - Over the past three decades, both Shanghai and New York City (NYC), have experienced dramatic rises in childhood obesity rates. Given the role that obesity plays in the aetiology of chronic diseases such as diabetes and heart disease, the elevated rates are a major concern. Despite differences in governance systems and cultures, Shanghai and NYC have experienced rapid industrialization, a growing population and a rise in income inequality. The prevalence of childhood obesity in Shanghai and NYC is greater than their respective national rate. However, the trajectory and development of this epidemic has differed between the cities. The distribution of obesity by race and ethnicity, socio-economic status, sex, and age differs markedly between the two cities. To reduce prevalence and inequities within this complex epidemic requires an understanding of the dynamic changes in living conditions among social groups in each city and the behaviours that are influenced by such changes. By comparing changes in the influences on dietary behaviours, such as food distribution, pricing, gender values, and media and marketing, this highlights opportunities for Shanghai, NYC, and other world cities with high or rising rates of childhood obesity to inform future program and policy initiatives. It reiterates the importance of a comprehensive and multilevel approach that includes action at the individual, family, community, municipal, national, and global levels. PMID- 25841630 TI - Distribution of the orexin-1 receptor (OX1R) in the mouse forebrain and rostral brainstem: A characterisation of OX1R-eGFP mice. AB - We have utilised a transgenic reporter mouse in which green fluorescent protein (GFP) expression is driven by the orexin-1 receptor (OX1R) promoter to systematically map the distribution of OX1R-expressing neurons throughout the mouse forebrain and rostral brainstem. GFP labelling was observed in perikarya and fibres in an extensive range of brain loci encompassing the olfactory and cerebral cortices, dorsal and ventral pallidum, hippocampus, amygdaloid regions, septal areas, thalamic nuclei, hypothalamic nuclei and several brainstem regions, consistent with previous studies of OX1R mRNA expression. This is the first study to systematically characterise the neuroanatomical distribution of OX1R in the OX1R-eGFP mouse, confirming its veracity as a faithful reporter of OX1R expression and utility for future studies assessing the role of OX1R in more complex behaviours. PMID- 25841631 TI - Keeping Blood Transfusion Safe From West Nile Virus: American Red Cross Experience, 2003 to 2012. AB - West Nile virus (WNV) appeared for the first time in the United States in 1999 and rapidly spread across the Western hemisphere within a few years causing hundreds of thousands of human infections and significant disease. In 2002, it was found to be transmissible by blood transfusion, and within less than a year, nucleic acid testing for WNV RNA was in place for all US donations. The American Red Cross (ARC) collects approximately 40% of blood donations in the United States and closely monitors the results of such testing and evaluates donors found to be reactive. This review describes the 10-year results of the ARC testing program during the period 2003 to 2012. Overall, more than 27 million donations were tested during the transmission periods with 1576 RNA-positive donations identified. The temporal and geographic distributions of the infected donors are described. Methods to initiate and discontinue periods of individual donation testing were developed and validated to maximize safety. The nature of WNV infection among donors was investigated, and the distribution of viral titers was defined and was found to be no greater than 720000 RNA copies per milliliter. The distribution of titers by time sequence of appearance of antibodies was determined. Donors who were identified as being in the earliest stages of infection were evaluated for the appearance of symptoms, and 26% developed at least 3 characteristic symptoms. The testing program has been successful in preventing transmission of WNV by transfusion, and only 1 of the 13 reported cases since the initiation of testing was attributable to the Red Cross; it was from a granulocyte product transfused before availability of the test result. PMID- 25841632 TI - [Detection of an intrapulmonary shunt in patients with liver cirrhosis through contrast-enhanced transcranial Doppler. A study of prevalence, pattern characterization, and diagnostic validity]. AB - INTRODUCTION: Intrapulmonary vascular dilatations (IPVD) are considered a complication of cirrhosis. The technique of choice for their diagnosis is contrast-enhanced echocardiography (CEE). The aim of this study was to determine the usefulness of contrast-enhanced transcranial Doppler (CETD) in the diagnosis of IPVD. METHOD: We consecutively included patients evaluated for liver transplantation. A cross-sectional study was conducted. The investigator interpreting CETD was blind to the results of the gold standard (CEE). The accuracy of the diagnostic test was evaluated through sensitivity, specificity, positive and negative predictive values, and likelihood ratio. RESULTS: CETD (n=43) showed a right-to-left shunt in 23 patients (62.2%): 4 early, 2 indeterminate and 17 late. Nineteen (51,4%) cases were classified as IPVD. With CEE (n=37), 10 procedures (27%) were negative for shunt, 27 (73%) were positive, and 21 (56.8%) were compatible with IPVD. Patients with and without IPVD showed no differences in age, sex, etiology, severity, or MELD score, independently of the diagnostic test. In the diagnostic validity study (n=37) of CETD versus CEE, the AUC for diagnostic yield was 0.813% (95%CI: 0.666-0.959; P=.001), sensitivity was 76.2% (95%CI: 54.9-89.4) and specificity was 90% (95%CI: 63.9-96.5). The positive likelihood ratio was 6.095. CONCLUSIONS: We found a high prevalence of IPVD in candidates for liver transplantation. When a late right-to-left shunt with recirculation is observed, CETD has a high probability of detecting IPVD, with few false-positive results. Because this technique has not previously been described in this indication, similar studies are needed for comparison. PMID- 25841634 TI - A massive cavitary lesion invading the chest wall. PMID- 25841633 TI - Predictors of postherpetic neuralgia in patients with herpes zoster: a pooled analysis of prospective cohort studies from North and Latin America and Asia. AB - OBJECTIVES: The most common complication of herpes zoster (HZ) is postherpetic neuralgia (PHN), a persistent pain that can substantially affect quality of life (QoL). This analysis aimed to evaluate predictors of PHN in HZ patients. METHODS: A pooled analysis of prospective cohort studies of HZ patients aged >= 50 years from North America (Canada), Latin America (Brazil, Mexico, and Argentina), and Asia (Taiwan, South Korea, and Thailand) was performed. Patients within 14 days of rash onset were included. The incidence of PHN was defined as a worst pain score of >= 3, persisting/appearing at >90 days after rash onset. Socio demographics, HZ disease characteristics, treatment, pain-related interference with activities of daily living, and health-related QoL were assessed. RESULTS: Of 702 patients with HZ, 148 (21.1%) developed PHN. Similar risks of PHN were observed across geographic regions. On multivariate analysis, older age, greater severity of pain at rash onset, employment status, walking problems at enrollment, and pain interference affecting social relationships were significantly associated with the development of PHN. CONCLUSIONS: In addition to older age and severe acute pain, this study suggests that impaired physical and social functioning from acute zoster pain may play a role in the development of PHN in this prospective cohort study of HZ patients from North and Latin America and Asia. PMID- 25841635 TI - Hemolytic-uremic syndrome with acute encephalopathy in a pregnant woman infected with epidemic enterohemorrhagic Escherichia coli: characteristic brain images and cytokine profiles. AB - A food-poisoning outbreak due to enterohemorrhagic Escherichia coli (EHEC) occurred in Toyama, Japan. The case of a 26-year-old pregnant woman with hemolytic-uremic syndrome who developed acute encephalopathy due to EHEC infection after eating raw meat is presented herein. On day 2 following admission, a cesarean section was performed because of a non-reassuring fetal status. Fecal bacterial culture confirmed an O111/O157 superinfection. Intensive care therapies including continuous hemodiafiltration and plasma exchange were performed. After the operation, the patient developed encephalopathy for which steroid pulse therapy was added. Her condition improved gradually and she was discharged 55 days after delivery. PMID- 25841636 TI - Soil-plant interaction monitoring: Small scale example of an apple orchard in Trentino, North-Eastern Italy. AB - Accurate monitoring and modeling of soil-plant systems are a key unresolved issue that currently limits the development of a comprehensive view of the interactions between soil and atmosphere, with a number of practical consequences including the difficulties in predicting climatic change patterns. This paper presents a case study where time-lapse minimal-invasive 3D micro-electrical tomography (ERT) is used to monitor rhizosphere eco-hydrological processes in an apple orchard in the Trentino region, Northern Italy. In particular we aimed at gaining a better understanding of the soil-vegetation water exchanges in the shallow critical zone, as part of a coordinated effort towards predicting climate-induced changes on the hydrology of Mediterranean basins (EU FP7 CLIMB project). The adopted strategy relied upon the installation of a 3D electrical tomography apparatus consisting of four mini-boreholes carrying 12 electrodes each plus 24 mini electrodes on the ground surface, arranged in order to image roughly a cubic meter of soil surrounding a single apple tree. The monitoring program was initially tested with repeated measurements over about one year. Subsequently, we performed three controlled irrigation tests under different conditions, in order to evaluate the water redistribution under variable root activities and climatic conditions. Laboratory calibration on soil samples allowed us to translate electrical resistivity variations into moisture content changes, supported also by in-situ TDR measurements. Richards equation modeling was used also to explain the monitoring evidence. The results clearly identified the effect of root water uptake and the corresponding subsoil region where active roots are present, but also marked the need to consider the effects of different water salinity in the water infiltration process. We also gained significant insight about the need to measure quantitatively the plant evapotranspiration in order to close the water balance and separate soil structure effects (primarily, hydraulic conductivity) from water dynamics induced by living plants. PMID- 25841637 TI - Auditory and visual localization accuracy in young children and adults. AB - OBJECTIVE: This study aimed to measure and compare sound and light source localization ability in young children and adults who have normal hearing and normal/corrected vision in order to determine the extent to which age, type of stimuli, and stimulus order affects sound localization accuracy. METHODS: Two experiments were conducted. The first involved a group of adults only. The second involved a group of 30 children aged 3 to 5 years. Testing occurred in a sound treated booth containing a semi-circular array of 15 loudspeakers set at 10 degrees intervals from -70 degrees to 70 degrees azimuth. Each loudspeaker had a tiny light bulb and a small picture fastened underneath. Seven of the loudspeakers were used to randomly test sound and light source identification. The sound stimulus was the word "baseball". The light stimulus was a flashing of a light bulb triggered by the digital signal of the word "baseball". Each participant was asked to face 0 degrees azimuth, and identify the location of the test stimulus upon presentation. Adults used a computer mouse to click on an icon; children responded by verbally naming or walking toward the picture underneath the corresponding loudspeaker or light. A mixed experimental design using repeated measures was used to determine the effect of age and stimulus type on localization accuracy in children and adults. A mixed experimental design was used to compare the effect of stimulus order (light first/last) and varying or fixed intensity sound on localization accuracy in children and adults. RESULTS: Localization accuracy was significantly better for light stimuli than sound stimuli for children and adults. Children, compared to adults, showed significantly greater localization errors for audition. Three-year-old children had significantly greater sound localization errors compared to 4- and 5-year olds. Adults performed better on the sound localization task when the light localization task occurred first. CONCLUSIONS: Young children can understand and attend to localization tasks, but show poorer localization accuracy than adults in sound localization. This may be a reflection of differences in sensory modality development and/or central processes in young children, compared to adults. PMID- 25841638 TI - Consider ultrasound first for imaging the female pelvis. AB - Ultrasound technology has evolved dramatically in recent years and now includes applications such as 3-dimensional volume imaging, real-time evaluation of pelvic organs (simultaneous with the physical examination), and Doppler blood flow mapping without the need for contrast, which makes ultrasound imaging unique for imaging the female pelvis. Among the many cross-sectional imaging techniques, we should use the most informative, less invasive, and less expensive modality to avoid radiation when possible. Hence, ultrasound imaging should be the first imaging modality used in women with pelvic symptoms. PMID- 25841639 TI - Identification of anti-HIV active dicaffeoylquinic- and tricaffeoylquinic acids in Helichrysum populifolium by NMR-based metabolomic guided fractionation. AB - South Africa being home to more than 35% of the world's Helichrysum species (c.a. 244) of which many are used in traditional medicine, is seen potentially as a significant resource in the search of new anti-HIV chemical entities. It was established that five of the 30 Helichrysum species selected for this study had significant anti-HIV activity ranging between 12 and 21 MUg/mL (IC50) by using an in-house developed DeCIPhR method on a full virus model. Subsequent toxicity tests also revealed little or no toxicity for these active extracts. With the use of NMR-based metabolomics, the search for common chemical characteristics within the plant extract was conducted, which resulted in specific chemical shift areas identified that could be linked to the anti-HIV activity of the extracts. The NMR chemical shifts associated with the activity were identified to be 2.56-3.08 ppm, 5.24-6.28 ppm, 6.44-7.04 ppm and 7.24-8.04 ppm. This activity profile was then used to guide the fractionation process by narrowing down and focusing the fractionation and purification processes to speed up the putative identification of five compounds with anti-HIV activity in the most active species, Helichrysum populifolium. The anti-HIV compounds identified for the first time from H. populifolium were three dicaffeoylquinic acid derivatives, i.e. 3,4 dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid and 4,5-dicaffeoylquinic acid as well as two tricaffeoylquinic acid derivatives i.e. 1,3,5-tricaffeoylquinic acid and either 5-malonyl-1,3,4-tricaffeoylquinic or 3-malonyl-1,4,5-tricaffeoylquinic acid, with the latter being identified for the first time in the genus. PMID- 25841640 TI - MBRRACE-UK: saving lives, improving mothers' care - implications for anaesthetists. AB - In December 2014, the latest UK Confidential Enquiry into Maternal Deaths report was published, covering the surveillance period from 2009 to 2012. This is the first report since a significant change in the organisational structure of the body responsible for surveillance and dissemination of reports. The Confidential Enquiry Reports are regarded as a gold standard worldwide and have contributed to quality improvement of maternity care both in the UK and elsewhere. This article aims to give obstetric anaesthetists an overview of the current report and highlight the pertinent implications for anaesthetic practice. PMID- 25841641 TI - Foodborne parasites from wildlife: how wild are they? AB - The majority of wild foods consumed by humans are sourced from intensively managed or semi-farmed populations. Management practices inevitably affect wildlife density and habitat characteristics, which are key elements in the transmission of parasites. We consider the risk of transmission of foodborne parasites to humans from wildlife maintained under natural or semi-natural conditions. A deeper understanding will be useful in counteracting foodborne parasites arising from the growing industry of novel and exotic foods. PMID- 25841642 TI - Both diabetes and fetuin-A are independently associated with increased risk of arterial stiffness. AB - BACKGROUND: Arterial stiffness is a functional assessment of vascular damage caused by cardiovascular disease (CVD) risk factors. Fetuin-A is associated with subclinical CVD and incident or fatal CVD, with some modification of its effect occurring with the presence of diabetes. We investigated the impact of different glycemic statuses and serum fetuin-A levels on arterial stiffness. METHODS: A total of 312 age- and sex-matched subjects with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed diabetes (NDD) were recruited. Serum fetuin-A levels were measured, and arterial stiffness was assessed by brachial-ankle pulse-wave velocity (baPWV). RESULTS: We found that the mean values of baPWV were 1533+/-338, 1518+/-353, 1589+/-307, and 1690+/-414 cm/s, and fetuin-A levels were 298+/-69, 313+/-67, 330+/-86, and 342+/-93 MUg/ml, in subjects with NGT, IFG, IGT, and NDD, respectively (both p<0.001, test for trend). NDD subjects had significantly higher baPWV and fetuin-A levels than those with NGT. Multiple linear regression analysis showed that age, fetuin-A, diabetes, hypertension, and hypertriglyceridemia are independently associated factors of baPWV after adjusting for cardiometabolic risk factors, HOMA-IR, and adiponectin. CONCLUSION: Both diabetes and fetuin-A levels are independently associated with arterial stiffness. Fetuin-A may further aggravate increased arterial stiffness in diabetes. PMID- 25841643 TI - MicroRNAs in cotton: an open world needs more exploration. AB - MAIN CONCLUSION: This paper reviews the progress and current problems in the field of cotton microRNAs. Cotton is not only one of the most important crops in terms of fiber usage and economic value, but also a model species for investigating cell wall and cellulose biosynthesis as well plant polyploidization. Compared with model plant species, such as Arabidopsis and rice, the research on cotton microRNAs (miRNAs) is lagging, although great progress has been made in the past decade. Since the first reports on identifying miRNAs in cotton in 2007, hundreds of miRNAs have been identified using an in silico comparative genome-based approach and direct cloning. Next-generation deep sequencing has opened the door for cotton miRNA research. In cotton, miRNAs are associated with many biological and metabolic processes, including fiber initiation and development, floral development, embryogenesis, and response to biotic and abiotic stresses. However, the majority of current research is focused on miRNA identification. Although several targets have been predicted using computational approaches and degradome sequencing, more functional studies should be performed in the next couple of years to elucidate the roles of miRNAs in cotton fiber development and response to different environmental stresses using transgenic technology. This paper reviews the history, identification, and function of cotton miRNAs as well as future directions for this research. PMID- 25841644 TI - Investigation into the misincorporation of norleucine into a recombinant protein vaccine candidate. AB - A high level of norleucine misincorporation was detected in a recombinant methionine-rich protein vaccine candidate expressed in E. coli K12. An investigation was conducted to evaluate a simple remediation strategy to reduce norleucine misincorporation and to determine if the phenomenon was either (a) due to the depletion of methionine during fermentation, (b) a result of the cultivation environment, or (c) a strain-specific effect. While supplementation with exogenous methionine improved product quality, the undesirable biosynthesis of non-standard amino acids such as norleucine and norvaline persisted. In contrast, non-standard amino acid biosynthesis was quickly minimized upon selection of an appropriate fed-batch process control strategy, fermentation medium, and nutrient feed. By expressing the same protein in E. coli BL21(DE3), it was determined that the biosynthesis of norleucine and norvaline, and the misincorporation of norleucine into the protein were primarily attributed to the use of E. coli K12 as the host for protein expression. PMID- 25841645 TI - Food concerns and support for environmental food policies and purchasing. AB - Consumer support for pro environmental food policies and food purchasing are important for the adoption of successful environmental policies. This paper examines consumers' views of food policy options as their predisposition to purchase pro environmental foods along with their likely demographic, educational and cognitive antecedents including food and environmental concerns and universalism values (relating to care for others and the environment). An online survey to assess these constructs was conducted among 2204 Australian adults in November 2011. The findings showed strong levels of support for both environmental food policies (50%-78% support) and pro environmental food purchasing (51%-69% intending to purchase pro environmental foods). Confirmatory factor analysis and structural equation modelling showed that different cognitive mediators exist along pathways between demographics and the two outcome variables. Support for food policy was positively related to food and environment concerns (std. Beta = 0.25), universalism (0.41), perceived control (0.07), and regulatory issues (0.64 but negatively with food security issues (-0.37). Environment purchasing intentions were positively linked to food and nutrition concerns (0.13), food and environment concerns (0.24), food safety concerns (0.19), food and animal welfare concerns (0.16), universalism (0.25), female gender (0.05), education (0.04), and perceived influence over the food system (0.17). In addition, health study in years 11 and 12 was positively related to the beginning of both of these pathways (0.07 for each). The results are discussed in relation to the opportunities that communications based on the mediating variables offer for the promotion of environmental food policies and purchasing. PMID- 25841646 TI - Impulsivity and overeating in children in the absence and presence of hunger. AB - Overweight children appear to be more responsive to environmental, hedonic cues and easily overeat in the current obesogenic environment. They are also found to overeat in the absence of hunger, and this overeating seems related to impulsivity: impulsive participants are more prone to external eating. However, some studies showed that impulsive adults are also more prone to hunger cues: impulsive participants overate especially when feeling hungry. This would mean impulsive people are more reactive to both external and internal cues. The overeating was limited to palatable high energy-dense foods: hunger made them fancy a snack. In the current study, we wanted to test the interaction between impulsivity, hunger and consumption of food type in children. Impulsivity was measured in 88 children between the ages of 7 and 9. Next, half of the participants performed a taste test before their own regular lunch and half of the participants immediately after their lunch. During the taste test, low, medium and high energy-dense food items were presented. Results showed that impulsive children ate more high energy-dense foods than low impulsive children, both before and after their lunch. No differences were found on low or medium energy-dense foods. Impulsive children therefore showed normal sensitivity for internal hunger and satiety cues, but abnormal response to high energy-dense foods. This might render them vulnerable to tasty temptation in the environment and to weight gain in their future. PMID- 25841647 TI - Making food labels social: The impact of colour of nutritional labels and injunctive norms on perceptions and choice of snack foods. AB - Recent studies report that using green labels to denote healthier foods, and red to denote less healthy foods increases consumption of green- and decreases consumption of red-labelled foods. Other symbols (e.g. emoticons conveying normative approval and disapproval) could also be used to signal the healthiness and/or acceptability of consuming such products. The present study tested the combined effects of using emoticons and colours on labels amongst a nationally representative sample of the UK population (n = 955). In a 3 (emoticon expression: smiling vs. frowning vs. no emoticon) * 3 (colour label: green vs. red vs. white) *2 (food option: chocolate bar vs. cereal bar) between-subjects experiment, participants rated the level of desirability, healthiness, tastiness, and calorific content of a snack bar they had been randomised to view. At the end they were further randomised to view one of nine possible combinations of colour and emoticon labels and asked to choose between a chocolate and a cereal bar. Regardless of label, participants rated the chocolate as tastier and more desirable when compared to the cereal bar, and the cereal bar as healthier than the chocolate bar. A series of interactions revealed that a frowning emoticon on a white background decreased perceptions of healthiness and tastiness of the cereal bar, but not the chocolate bar. In the explicit choice task selection was unaffected by label. Overall nutritional labels had limited effects on perceptions and no effects on choice of snack foods. Emoticon labels yielded stronger effects on perceptions of taste and healthiness of snacks than colour labels. Frowning emoticons may be more potent than smiling emoticons at influencing the perceived healthiness and tastiness of foods carrying health halos. PMID- 25841648 TI - A champion of organismal biology. PMID- 25841649 TI - Increased reports of measles in a low endemic region during a rubella outbreak in adult populations. AB - In 2013, a rubella outbreak was observed in Japan, Romania, and Poland. The outbreak in Japan was accompanied by an increase of measles reports, especially from a region where measles is highly controlled. This was attributed to the adult populations affected by this rubella outbreak, similarity of clinical signs between rubella and measles, sufficiently small impact of measles outbreaks from neighboring nations, and elimination levels of measles endemicity. Current and future concerns for measles control are discussed. PMID- 25841650 TI - Saving time and resources: observational research to support adoption of a hand hygiene promotion campaign. AB - Hand hygiene is the most effective way to prevent the spread of health care associated infections, but many facilities may not have the resources or expertise to develop their own hand hygiene promotion campaign. This observational study demonstrated that a campaign developed for 1 facility could successfully contribute to behavior change at another, unrelated facility. It serves as a model and evidence that health care facilities can successfully adopt hand hygiene promotion campaigns developed and validated at other facilities. PMID- 25841651 TI - Bridging with half-therapeutic dose enoxaparin in outpatients with left ventricular assist devices and sub-therapeutic international normalized ratios. PMID- 25841652 TI - Application of contrast media in post-mortem imaging (CT and MRI). AB - The application of contrast media in post-mortem radiology differs from clinical approaches in living patients. Post-mortem changes in the vascular system and the absence of blood flow lead to specific problems that have to be considered for the performance of post-mortem angiography. In addition, interpreting the images is challenging due to technique-related and post-mortem artefacts that have to be known and that are specific for each applied technique. Although the idea of injecting contrast media is old, classic methods are not simply transferable to modern radiological techniques in forensic medicine, as they are mostly dedicated to single-organ studies or applicable only shortly after death. With the introduction of modern imaging techniques, such as post-mortem computed tomography (PMCT) and post-mortem magnetic resonance (PMMR), to forensic death investigations, intensive research started to explore their advantages and limitations compared to conventional autopsy. PMCT has already become a routine investigation in several centres, and different techniques have been developed to better visualise the vascular system and organ parenchyma in PMCT. In contrast, the use of PMMR is still limited due to practical issues, and research is now starting in the field of PMMR angiography. This article gives an overview of the problems in post-mortem contrast media application, the various classic and modern techniques, and the issues to consider by using different media. PMID- 25841653 TI - Specific Alu elements involved in a significant percentage of copy number variations of the STK11 gene in patients with Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS) is a rare hereditary syndrome characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation and increased risk of cancer in multiple internal organs. PJS is preconditioned by the manifestation of mutations in the STK11 gene. The majority of detected STK11 changes are small scale mutations, however recent studies showed the significant contribution of medium-sized changes commonly known as copy number variations (CNVs). Here we present a novel 7001 bps deletion of STK11 gene fragment, in which we identified the presence of breakpoints (BPs) within the Alu elements. Comparative meta-analysis with the 80 other CNV cases from 12 publications describing STK11 mutations in patients with PJS revealed the participation of specific Alu elements in all deletions of exons 2-3 so far described. Moreover, we have shown their involvement in the two other CNVs, deletion of exon 2 and deletion of exon 1-3 respectively. Deletion of exons 2-3 of the STK11 gene may prove to be the most recurrent large rearrangement causing PJS. In addition, the sequences present in its BPs may be involved in a formation of a significant percentage of the remaining gene CNVs. This gives a new insight into the conditioning of this rare disease and enables improvements in PJS genetic diagnostics. PMID- 25841654 TI - How can we enhance cognitive bias modification techniques? The effects of prospective cognition. AB - BACKGROUND AND OBJECTIVES: Cognitive bias modification for interpretation, a computerized program which manipulates biased interpretations, has shown therapeutic promise, including evidence that negatively biased interpretations can be reduced, leading to corresponding improvements in symptoms. Cognitive bias modification for cognitive errors (CBM-errors) is a second generation CBM-I procedure which manipulates seven types of cognitive error and is especially relevant to depressive cognition. The aim of this study was to investigate whether the effects of the CBM-errors manipulation would be enhanced by adding a component facilitating prospective cognition to help embed and extend newly acquired interpretations. METHODS: A sample of 80 volunteers completed a single session experiment. With a pretraining-posttraining design, we compared the effects of enhanced CBM-errors (targeting cognitive errors plus prospective cognition) with standard CBM-errors (targeting cognitive errors without prospective cognition), on interpretations of new material and mood. RESULTS: Significant differences between enhanced and standard CBM-errors revealed that enhanced positive training was more effective at decreasing negative interpretations compared to the standard procedure. LIMITATIONS: Extending the current investigation to a sample dysphoria or depression is needed for an appropriate next step. CONCLUSION: The findings serve as 'a proof of principle' for the potential of prospective cognition to enhance the effects of CBM-errors and other similar CBM procedures. Further work to enhance the effectiveness of CBM procedures is needed. PMID- 25841655 TI - Wilms Tumor 1 rs16754 predicts favorable clinical outcomes for acute myeloid leukemia patients in South Chinese population. AB - The single nucleotide polymorphism (SNP) rs16754 in WT1 shows a clinical implication in Caucasus population. However, the results were not reproducible in different population cohorts. We evaluated the clinical significance of rs16754 for 205 de novo acute myeloid leukemia (AML) patients in South Chinese population, 188 healthy volunteers were recruited as healthy controls. WT1 mRNA expression was investigated in 81 pretreatment bone marrow specimens. WT1(GA/AA) patients showed better overall survival (OS, P=0.006) and relapse-free survival (RFS, P=0.025) as compared with WT1(GG) patients, and the favorable clinical outcomes were most prominent in older patients with superior OS (P=0.001) and RFS (P=0.003). In multivariable analysis, rs16754 was still associated with favorable OS (HR=1.533, P=0.042). The WT1(GG) patients showed significantly higher WT1 mRNA expression than the WT1(GA/AA) patients (P=0.01). In summary, WT1 rs16754 may serve as an independent biomarker in AML patients from South Chinese. PMID- 25841656 TI - Ageing of the vitreous: From acute onset floaters and flashes to retinal detachment. AB - Floaters and flashes are most commonly symptoms of age-related degenerative changes in the vitreous body and posterior vitreous detachment. The etiology and pathogenesis of floaters' formation is still not well understood. Patients with acute-onset floaters, flashes and defects in their visual field, represent a medical emergency with the need for same day referral to an ophthalmologist. Indirect ophthalmoscopy with scleral indentation is needed in order to find possible retinal break(s), on-time treatment and prevention of retinal detachment. The molecular and genetic pathogenesis, as well as the epidemiology of the ageing changes of the vitreous is summarized here, with view on the several treatment modalities in relation to their success rate and side-effects. PMID- 25841657 TI - A novel molluscan Fos gene with immune defense function identified in the Hong Kong oyster, Crassostrea hongkongensis. AB - The transcription factor Fos is a member of one of the best-studied AP-1 sub families and has been implicated in a wide variety of biological processes, including the regulation of apoptosis, immune responses and cytokine production. In this report, a novel mollusk Fos (referred to as ChFos) gene was cloned and characterized from the Hong Kong oyster, Crassostrea hongkongensis. The deduced ChFos protein sequence comprised 333 amino acids and shared significant homology with invertebrate homologs. Phylogenetic analysis revealed that ChFos clusters with Fos from Crassostrea gigas and Crassostrea ariakensis. Quantitative real time PCR analysis revealed that ChFos mRNA was broadly expressed in all tested tissues and during different stages of the oyster's embryonic and larval development. In addition, the expression of ChFos mRNA was significantly up regulated under challenge with microorganisms (Vibrio alginolyticus, Staphylococcus haemolyticus and Saccharomyces cerevisiae) and pathogen-associated molecular patterns (PAMPs: LPS, PGN and polyI:C). Moreover, fluorescence microscopy showed that ChFos protein is localized in the nucleus in HEK293T cells. Reporter assays suggested that ChFos may act as an efficient transcription activator in the regulation of AP-1-responsive gene expression through interaction with ChJun. Overall, this study presents the first experimental evidence of the presence and functional characteristics of Fos in mollusks, which reveals its involvement in host protection against immune challenge in the oyster. PMID- 25841658 TI - Is bronchoscopy necessary in the preoperative workup of a solitary pulmonary nodule? AB - OBJECTIVE: This study evaluated the role of conventional bronchoscopy in the preoperative workup of patients with solitary pulmonary nodules (SPNs). METHODS: Patients with SPNs of unknown origin were enrolled for preoperative bronchoscopy at our institution. Bronchoscopic findings were prospectively collected, and their impact on planned therapy was analyzed. RESULTS: A total of 1026 patients were included. Bronchoscopy identified unsuspected findings in 80 (7.8%) of them, with a total of 826 (80.5%) malignant nodules. Referent values for bronchoscopic detection of malignant SPNs were: accuracy, 24.3% (95% confidence interval [CI]: 21.7%-27.0%); sensitivity, 5.9% (95% CI: 4.5%-7.4%); specificity, 100%; and negative predictive value, 20.5% (95% CI: 18.0%-22.9%). Malignant bronchoscopic findings were more common in male patients (odds ratio [OR] = 2.1, 95% CI: 1.1 3.9, P = .021) and large nodules (OR = 2.3, 95% CI: 1.6-3.3, P < .001). Surgery was cancelled in 2 (0.2%) patients and modified in 36 (3.5%) patients because of bronchoscopic findings. In all, for 268 (26.1%) SPNs that presented with ground glass opacity, the bronchoscopy was unrevealing. CONCLUSIONS: In the preoperative evaluation of SPN, bronchoscopy is most likely to reveal malignancy in larger SPNs and in male patients. Bronchoscopy is not indicated in SPNs that present with ground-glass opacity on computed tomography scan. PMID- 25841659 TI - Paclitaxel-loaded expansile nanoparticles enhance chemotherapeutic drug delivery in mesothelioma 3-dimensional multicellular spheroids. AB - OBJECTIVES: Intraperitoneal administration of paclitaxel-loaded expansile nanoparticles (Pax-eNPs) significantly improves survival in an in vivo model of malignant mesothelioma compared with conventional drug delivery with the clinically utilized Cremophor EL/ethanol (C/E) excipient. However, in vitro monolayer cell culture experiments do not replicate this superior efficacy, suggesting Pax-eNPs utilize a unique mechanism of drug delivery. Using a mesothelioma spheroid model, we characterized the mechanisms of enhanced tumor cytotoxicity leveraged by Pax-eNPs. METHODS: Human malignant mesothelioma (MSTO 211H) spheroids were co-incubated for 24 hours with Oregon Green-conjugated paclitaxel dissolved in C/E or loaded into eNPs. Oregon Green-paclitaxel uptake was measured as Oregon Green intensity via confocal microscopy and kinetics of tumor cytotoxicity were assessed via propidium iodide staining. Pharmacologic endocytotic inhibitors were used to elucidate mechanisms of eNP uptake into spheroids. RESULTS: Increased drug penetration and a 38-fold higher intraspheroidal drug concentration were observed 24 hours after MSTO-211H spheroids were treated with Oregon Green-conjugated paclitaxel loaded into eNPs compared with Oregon Green-conjugated paclitaxel dissolved in C/E (P < .01). Macropinocytosis was the dominant endocytotic pathway of eNP uptake. Spheroids were more susceptible to paclitaxel when delivered via eNP, exhibiting more than twice the propidium iodine intensity compared with an equivalent paclitaxel-C/E dose. CONCLUSIONS: Compared with monolayer cell culture, the in vitro 3-D tumor spheroid model better reflects the superior in vivo efficacy of Pax-eNPs. Persistent tumor penetration and prolonged intratumoral release are unique mechanisms of Pax-eNP cytotoxicity. 3-D spheroid models are valuable tools for investigating cytotoxic mechanisms and nanoparticle-tumor interactions, particularly given the costs and limitations of in vivo animal studies. PMID- 25841661 TI - Alcohol dependence and physical comorbidity: Increased prevalence but reduced relevance of individual comorbidities for hospital-based mortality during a 12.5 year observation period in general hospital admissions in urban North-West England. AB - PURPOSE: Alcohol dependence (AD) is associated with an increase in physical comorbidities. The effects of these diseases on general hospital-based mortality are unclear. Consequently, we conducted a mortality study in which we investigated if the burden of physical comorbidities and their relevance on general hospital-based mortality differs between individuals with and without AD during a 12.5-year observation period in general hospital admissions. METHODS: During 1 January 2000 and 30 June 2012, 23,371 individuals with AD were admitted at least once to seven General Manchester Hospitals. Their physical comorbidities with a prevalence>=1% were compared to those of 233,710 randomly selected hospital controls, group-matched for age and gender (regardless of primary admission diagnosis or specialized treatments). Physical comorbidities that increased the risk of hospital-based mortality (but not outside of the hospital) during the observation period were identified using multiple logistic regression analyses. RESULTS: Hospital-based mortality rates were 20.4% in the AD sample and 8.3% in the control sample. Individuals with AD compared to controls had a higher burden of physical comorbidities, i.e. alcoholic liver and pancreatic diseases, diseases of the conducting airways, neurological and circulatory diseases, diseases of the upper gastrointestinal tract, renal diseases, cellulitis, iron deficiency anemia, fracture neck of femur, and peripheral vascular disease. In contrast, coronary heart related diseases, risk factors of cardiovascular disease, diverticular disease and cataracts were less frequent in individuals with AD than in controls. Thirty-two individual physical comorbidities contributed to the prediction of hospital-based mortality in univariate analyses in the AD sample; alcoholic liver disease (33.7%), hypertension (16.9%), chronic obstructive pulmonary disease (14.1%), and pneumonia (13.3%) were the most frequent diagnoses in deceased individuals with AD. Multiple forward logistic regression analysis, accounting for possible associations of diseases, identified twenty-three physical comorbidities contributing to hospital-based mortality in individuals with AD. However, all these comorbidities had an equal or even lower impact on hospital-based mortality than in the comparison sample. CONCLUSION: The excess of in-hospital deaths in general hospitals in individuals with AD is due to an increase of multiple physical comorbidities, even though individual diseases have an equal or even reduced impact on general hospital-based mortality in individuals with AD compared to controls. PMID- 25841662 TI - Failure to deactivate medial prefrontal cortex in people at high risk for psychosis. AB - Impaired working memory is a core feature of schizophrenia and is linked with altered engagement the lateral prefrontal cortex. Although altered PFC activation has been reported in people with increased risk of psychosis, at present it is not clear if this neurofunctional alteration differs between familial and clinical risk states and/or increases in line with the level of psychosis risk. We addressed this issue by using functional MRI and a working memory paradigm to study familial and clinical high-risk groups. We recruited 17 subjects at ultra high-risk (UHR) for psychosis, 10 non-affected siblings of patients with schizophrenia (familial high risk [FHR]) and 15 healthy controls. Subjects were scanned while performing the N-back working memory task. There was a relationship between the level of task-related deactivation in the medial PFC and precuneus and the level of psychosis risk, with deactivation weakest in the UHR group, greatest in healthy controls, and at an intermediate level in the FHR group. In the high-risk groups, activation in the precuneus was associated with the level of negative symptoms. These data suggest that increased vulnerability to psychosis is associated with a failure to deactivate in the medial PFC and precuneus during a working memory task, and appears to be most evident in subjects at clinical, as opposed to familial high risk. PMID- 25841663 TI - A functional SNP in MIR124-1, a brain expressed miRNA gene, is associated with aggressiveness in a Colombian sample. AB - BACKGROUND: Interpersonal violence and suicide are among the main causes of mortality and morbidity around the world. In several developing countries, such as Colombia, they are among the first five entities of public health concern. Aggressiveness is an important endophenotype for aggression and suicidal behavior, having a heritability of around 50%. Exploration of classical candidate genes, involved in serotoninergic and dopaminergic neurotransmission, has identified few consistent risk factors for aggressiveness. miRNAs are a novel class of molecules with a growing role in normal neural function and neuropsychiatric disorders; of special interest, miR-124 is a brain-specific miRNA that is key for neuronal plasticity. We evaluated the hypothesis that a functional polymorphism in MIR124-1 gene might be associated with aggressiveness in a Colombian sample. METHODS: The Spanish adaptation of the refined version of the Aggression Questionnaire and the abbreviated Barratt Impulsiveness Scale were applied to 170 young subjects. The functional SNP in MIR124-1 (rs531564) was genotyped by a TaqMan assay. RESULTS: We found a significant association between the MIR124-1 and aggressiveness in our sample, with G/G carriers having lower scores (P=0.01). This association seemed to be specific for aggressiveness, as it was not significant for impulsiveness. CONCLUSIONS: We showed for the first time the association of a functional polymorphism in MIR124-1 and aggressiveness. Known targets of miR-124 (such as BDNF and DRD4 genes) could explain the effect of this miRNA on behavior. A future analysis of additional novel functional polymorphisms in other brain expressed miRNAs could be useful for a deeper understanding of aggression in humans. PMID- 25841664 TI - The effects of the CACNA1C rs1006737 A/G on affective startle modulation in healthy males. AB - BACKGROUND: The CACNA1C rs1006737 risk A allele has been associated with affective psychoses and functional studies indicate that it is associated with increased hippocampal/amygdala activity during emotional face-processing. Here we studied the impact of the risk A allele on affective startle modulation. METHODS: Hundred and ninety-four healthy males stratified for their CACNA1C rs1006737 genotype (GG:111, GA:67, AA:16) were presented with 18 pleasant, 18 unpleasant and 18 neutral pictures with acoustic probes (104 dB) occurring during 12 pictures in each affective category. Baseline startle was assessed during blank screens. State mood was self-rated on arrival, pre- and post-test and the emotional valence and arousal of affective pictures at post-test. RESULTS: Relative to the other genotypes, risk A allele homozygotes presented with higher anxiety/negative affect at pre-test, reduced and exaggerated physiological responses to the pleasant and negative pictures respectively, negative affect with reduced arousal at post-test and rated the affective pictures as less arousing and inconsistently to their physiological responses (all P<0.05). Sustained contextual negative mood predicted reduced baseline and affective startle reactivity in the AA group. CONCLUSIONS: Healthy homozygous males for the risk A allele appear to have marked contextual sensitivity, affective reactivity akin to anxiety and depression and inefficient emotional appraisal. Our findings provide phenotypic detail of the CACNA1C AA genotype in non-symptomatic individuals, which suggest primary effects in emotional circuitry, consistent with previously documented alterations in hippocampal/amygdala processing. PMID- 25841665 TI - Coronary artery vasculitis: assessment with cardiac multi-detector computed tomography. AB - Coronary artery vasculitis is rare and comprises an array of inflammatory diseases. It often results in severe and life-threatening complications, including coronary artery aneurysm, coronary artery stenosis, intraluminal thrombosis, and microcirculation abnormalities. These may occur at a young age and are often silent in the early phases. Invasive coronary angiography is the gold standard for diagnosing coronary artery disease (CAD); however, multi detector computed tomography (MDCT) is now widely regarded as a powerful non invasive tool for the detection of CAD. It is important for clinicians to recognize the various CT findings associated with coronary artery vasculitis in order to promote accurate diagnosis and proper patient management. The purpose of this article is to present an overview of the conditions associated with coronary artery vasculitis, with an emphasis on etiology and cardiac MDCT diagnosis of CAD. Cardiac MDCT is clinically useful and can provide information for the accurate diagnosis and treatment of coronary vasculitis. PMID- 25841666 TI - Multiple sclerosis drugs: how much bang for the buck? PMID- 25841667 TI - Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator. AB - BACKGROUND: In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of L36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada. METHODS: In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective. FINDINGS: 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5.1 years (SD 1.4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75.8% [95% CI 71.4-80.2]; multilevel model, 60.0% [56.6-63.4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58.5% [95% CI 54.2-62.8]; multilevel model, 57.1% [53.0-61.2]). INTERPRETATION: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible. FUNDING: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme. PMID- 25841668 TI - Personalised care initiatives for diabetes care. PMID- 25841669 TI - Molecular modeling, simulation and virtual screening of MurD ligase protein from Salmonella typhimurium LT2. AB - The Mur enzymes of the peptidoglycan biosynthesis pathway constitute ideal targets for the design of new classes of antimicrobial inhibitors in Gram negative bacteria. We built a homology model of MurD of Salmonella typhimurium LT2 using MODELLER (9v12) software. 'The homology model was subjected to energy minimization by molecular dynamics (MD) simulation study with GROMACS software for a simulation time of 20 ns in water environment. The model was subjected for virtual screening study from the Zinc Database using Dockblaster software. Inhibition assay for the best inhibitor, 3-(amino methyl)-n-(4-methoxyphenyl) aniline, by flow cytometric analysis revealed the effective inhibition of peptidoglycan biosynthesis. Results from this study provide new insights for the molecular understanding and development of new antibacterial drugs against the pathogen. PMID- 25841670 TI - ADVAN-style analytical solutions for common pharmacokinetic models. AB - INTRODUCTION: The analytical solutions to compartmental pharmacokinetic models are well known, but have not been presented in a form that easily allows for complex dosing regimen and changes in covariate/parameter values that may occur at discrete times within and/or between dosing intervals. METHODS: Laplace transforms were used to derive ADVAN-style analytical solutions for 1, 2, and 3 compartment pharmacokinetic linear models of intravenous and first-order absorption drug administration. The equations calculate the change in drug amounts in each compartment of the model over a time interval (t; t = t2 - t1) accounting for any dose or covariate events acting in the time interval. The equations were coded in the R language and used to simulate the time-course of drug amounts in each compartment of the systems. The equations were validated against commercial software [NONMEM (Beal, Sheiner, Boeckmann, & Bauer, 2009)] output to assess their capability to handle both complex dosage regimens and the effect of changes in covariate/parameter values that may occur at discrete times within or between dosing intervals. RESULTS: For all tested pharmacokinetic models, the time-course of drug amounts using the ADVAN-style analytical solutions were identical to NONMEM outputs to at least four significant figures, confirming the validity of the presented equations. DISCUSSION: To our knowledge, this paper presents the ADVAN-style equations for common pharmacokinetic models in the literature for the first time. The presented ADVAN-style equations overcome obstacles to implementing the classical analytical solutions in software, and have speed advantages over solutions using differential equation solvers. The equations presented in this paper fill a gap in the pharmacokinetic literature, and it is expected that these equations will facilitate the investigation of useful open-source software for modelling pharmacokinetic data. PMID- 25841671 TI - Reassessment of Lhermitte's sign in multiple sclerosis. AB - The reliability and diagnostic value of Lhermitte's sign in multiple sclerosis (MS) has not been fully established. The purpose of this study was to determine the clinical, neurophysiological and neuroradiological correlations of Lhermitte's sign in a cohort of MS patients and reassess the relevance of this phenomenon in the clinical history of the disease. A prospective study of 694 patients with MS and 110 age-matched healthy adults was evaluated by a structured questionnaire that included basic demographic data, age of onset, clinical characteristics of the disease, and the inquiry of Lhermitte's sign. Cranial and spinal magnetic resonance imagings (MRI) and median and tibial somatosensory evoked potentials (SSEP) were performed at the same time. One hundred and twelve (16 %) patients were reported to have Lhermitte's sign; 582 (84 %) patients did not experience Lhermitte's sign during their disease duration (P < 0.026). No correlation was found between Lhermitte's sign and age, gender, EDSS, and disease duration; 88 % of patients with Lhermitte's sign had a demyelinating lesion on the cervical MRI. In negative Lhermitte's sign group, 64 % patients had a positive MRI. SSEP conductions were delayed in 92 % of patients with positive Lhermitte's sign and in 70 % of patients with negative Lhermitte's sign. Regarding the data, a significant correlation was found between MRI lesion and Lhermitte's sign (P < 0.001), and between SSEP abnormality and Lhermitte's sign as well (P < 0.001). This study underlines the relevance of this phenomenon with neuroradiological and neurophysiological abnormalities. PMID- 25841672 TI - Direct measurement of single-stranded DNA intermediates in mammalian cells by quantitative polymerase chain reaction. AB - Single-stranded DNA (ssDNA) intermediates are formed in multiple cellular processes, including DNA replication and recombination. Here, we describe a quantitative polymerase chain reaction (qPCR)-based assay to quantitate ssDNA intermediates, specifically the 3' ssDNA product of resection at specific DNA double-strand breaks induced by the AsiSI restriction enzyme in human cells. We protect the large mammalian genome from shearing by embedding the cells in low gelling-point agar during genomic DNA extraction and measure the levels of ssDNA intermediates by qPCR following restriction enzyme digestion. This assay is more quantitative and precise compared with existing immunofluorescence-based methods. PMID- 25841673 TI - A fast way to track functional OmpF reconstitution in liposomes: Escherichia coli total lipid extract. AB - A major requirement to perform structural studies with membrane proteins is to define efficient reconstitution protocols that ensure a high incorporation degree and protein directionality and topology that mimics its in vivo conditions. For this kind of studies, protein reconstitution in membrane systems via a detergent mediated pathway is usually successfully adopted because detergents are generally used in the initial isolation and purification of membrane proteins. This study reports OmpF reconstitution in preformed Escherichia coli liposomes followed by detection of its insertion by analyzing modifications on membrane structure by two different techniques: steady-state fluorescence anisotropy and dynamic light scattering. Another important issue is protein directionality. For OmpF, it is known that interaction with polyamines promotes channel blockage. In this work, the spermine-OmpF interaction was evaluated using surface plasmon resonance, and protein directionality was confirmed. PMID- 25841674 TI - Replacing beta-mercaptoethanol in RNA extractions. AB - RNA extractions are potentially compromised in terms of both yield and quality by ribonucleases (RNases). The pungent and toxic reducing agent beta-mercaptoethanol (beta-ME), therefore, is commonly added to the biospecimen's lysis buffer to aid in RNase deactivation. Using different tissue types (liver tissue, kidney tissue, and cell pellets), extraction kits (RNeasy Mini Kit, Illustra RNA Spin Mini Kit, and PureLink Mini Kit), RNA quality assays (RNA integrity numbers [RINs] and quantitative real-time polymerase chain reaction [qRT-PCR]), yield assessments, and in vitro functional RNase assays (RNaseAlert Kit), we demonstrate that beta ME should be replaced by the less toxic dithiothreitol (DTT) alternative. PMID- 25841676 TI - Expert consensus on the nutritional therapy for patients with malignancies. PMID- 25841675 TI - Combination of Paris and Vienna classifications may optimize follow-up of gastric epithelial neoplasia patients. AB - BACKGROUND: The aim of this study was to evaluate the efficiency of the combination of Paris and Vienna classifications in a follow-up study of gastric epithelial neoplasia (GEN) patients. MATERIAL AND METHODS: This study was conducted between January 2003 and September 2010, during which 170 biopsy-proven GEN patients were followed up by gastroenterologists and pathologists according to our follow-up regimen (modified Vienna classification). RESULTS: In total, 161 patients with low-grade neoplasia (LGN) and 9 patients with high-grade neoplasia (HGN) were randomly enrolled in our study. Eighteen patients with depressed appearance were observed, of which 9 patients had HGN and 9 patients had low grade dysplasia (LGD). Three patients with type 0-IIa were observed with low grade adenoma (LGA), and type 0-I was observed in 2 patients with LGN. Endoscopic or surgical treatments were performed to avoid potential malignancy or bleeding. Two patients with ulcer lesions, 2 patients with non-depressed type 0 appearance, and 3 patients without visible lesions were shown to have higher-grade lesions during follow-up. The misdiagnosis rate of forceps biopsy - 62.07% - was determined by comparing pre- and post-resection diagnoses of 29 patients. CONCLUSIONS: The combination of the Paris and Vienna classifications for GEN may optimize the follow-up routines for patients with suspicious precancerous lesions and may significantly improve the detection of early gastric cancer (EGC) while helping gastroenterologists select the best therapy option. PMID- 25841677 TI - The central role of nutritional therapy in cancer: the input of an experts committee of Chinese Society of Clinical Oncology. PMID- 25841678 TI - Targeted therapy in soft tissue sarcoma-a novel direction in therapeutics. AB - Inherent or acquired resistance to chemotherapy is a significant problem in the treatment of soft tissue sarcomas. Over the past decade, the discovery and characterization of aberrant signaling pathways and the identification of agents that can specifically target them has led to their introduction as novel treatment options in soft-tissue sarcomas (STS). Trials of monotherapy with targeted agents have shown results below expectations often because of activation of alternative signaling pathways. This review examines the potential for tactical combinations of these drugs to overcome this problem. PMID- 25841679 TI - Emerging therapies for pancreas neuroendocrine cancers. AB - Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors can be functional, i.e., hormone secreting tumors, e.g., insulinoma, gastrinoma or VIPoma, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNET's, usually present later either incidentally or due to tumor bulk symptoms. The recent WHO classification system in 2010 classified PNET's into different stages and grades depending on the mitotic activity and Ki-67 labeling index. PNET's have a broad range of prognoses depending on the histologic grade, differentiation and biologic behavior. Computerized tomographic scanning (CT), magnetic resonance imaging (MRI) and octreoscan are imaging tools used to diagnose PNET, in addition to a confirmatory tissue diagnosis with immunohistochemical stains, typically obtained by either cytologic or histologic assessment. Symptomatic advanced PNET's can be treated with a long-acting somatostatin analogue for those tumors with somatostatin receptor positivity and which may also have antiproliferative activity. Another treatment modality is peptide receptor radionucleotide therapy (PRRT) in somatostatin receptor-positive tumors, albeit as yet with limited availability in the United States. Systemic therapies with combination cytotoxic agents e.g., streptozocin, anthracyclines, and capecitabine and temozolomide, all have established activity in PNET's. Biologic agents targeting the VEGF and mTOR signaling pathways, e.g., sunitinib, bevacizumab or everolimus are becoming integrated as treatments for PNET's. Poorly differentiated, high grade PNETs with a very high mitotic rate are treated with platinum-based chemotherapy regimens similar to treatment paradigms for small cell carcinoma of the lung. For liver confined or predominant disease, strategies such as cytoreductive surgery, hepatic artery embolization or radioembolization are treatment modalities to effect locoregional tumor control. The next generation of studies in PNET will help define optimal sequencing strategies of available therapies and also will attempt to use biomarker-guided approaches to select therapies. PMID- 25841680 TI - Expert consensus on the nutritional therapy for patients with malignancies. PMID- 25841681 TI - A new rat model of prostate cancer. PMID- 25841682 TI - Locally advanced versus metastatic pancreatic cancer: two different diseases with two different treatment approaches? AB - The results of the SCALOP trial were reviewed and interpreted at the light of previous trials and of the more recent LAP-07 trial. In this latter trial the role of radiotherapy after an induction chmeotherapy has been questioned. Based on these findings data from the SCALOP trial loose most of their value. In fact, while it showed that capecitabine may be combined with radiotherapy more safely than gemcitabine and it could be a standard regimen as a consolidation regimen after an induction chemotherapy, the LAP-07 trial showed that radiotherapy in combination with chemotherapy does not add any valuable effect to chemotherapy alone. PMID- 25841683 TI - Managing clinical trial data-sharing databases: interview with Professor Daniel J. Sargent. PMID- 25841684 TI - Highlights in hepatocellular carcinoma. PMID- 25841685 TI - How far are we going in colorectal cancer? PMID- 25841686 TI - Statistics in Oncology Clinical Trials: a learning platform never to miss. PMID- 25841687 TI - The state of oncology in 2014 and the role of palliative care for advanced and metastatic malignancies. PMID- 25841688 TI - Multidisciplinary approaches to palliative oncology care. PMID- 25841689 TI - The global state of palliative care-progress and challenges in cancer care. AB - All persons have a right to palliative care during cancer treatment and at the end-of-life. The World Health Organization (WHO) defines palliative care as a medical specialty that addresses physical, psychological, social, legal, and spiritual domains of care by an interdisciplinary team of professional and lay health care providers. Widespread adoption of this universal definition will aid policy development and educational initiatives on a national level. The need for palliative care is expanding due to the aging of the world's population and the increase in the rate of cancer in both developed and developing countries. However, in one third of the world there is no access to palliative care for persons with serious or terminal illness. Palliative care improves symptoms, most frequently pain, and improves quality of life for patients and their families, especially in the terminal disease phase. Accessibility to palliative care services, adequately trained health care professionals, availability of essential medicines, and gaps in education vary greatly throughout the world. Pain management is an integral concept in the practice of palliative care; however, opioiphobia, insufficient supply of opioids, and regulatory restrictions contribute to undue suffering for millions. Ongoing advocacy efforts call for increased awareness, palliative care integration with cancer care, and public and professional education. Enacting necessary change will require the engagement of health ministries and the recognition of the unique needs and resources of each country. The aim of this review is to examine progress in palliative care development and explore some of the barriers influencing cancer care across the globe. PMID- 25841690 TI - A multidisciplinary approach in providing transitional care for patients with advanced cancer. AB - Patients living with a diagnosis of an advanced life-limiting malignancy often have concerns regarding symptom burden, physical and psychosocial impact on life, and questions surrounding end-of-life processes. Due to the complex care needs of patients with advanced life-limiting illness it is our experience that both a multidisciplinary and interdisciplinary approach to care can optimize the patient and family illness experience for this vulnerable population. Progressive metastatic illness often necessitates care in multiple settings including an ambulatory clinic, inpatient hospital ward, at home, and at an in-patient hospice or palliative care unit. Palliative care teams are typically composed of clinicians from various disciplines who work in multiple settings and can act as a link between community, ambulatory and in-patient care-settings. The team often includes physicians, advance practice nurses [nurse practitioners and clinical nurse specialists (CNSs)], nurses, social workers, chaplains, and other allied health clinicians. The result of this team approach, in collaboration with oncology providers, makes palliative care an ideal model for providing care through the many transitions that are inherent to patients living with advanced malignancy. PMID- 25841691 TI - Palliative care and advance care planning for patients with advanced malignancies. AB - Patients diagnosed with an advanced cancer frequently have a very limited life expectancy and need to understand their prognosis in order to make good choices about care. Advance care planning (ACP) is an important aspect of this care but can be especially difficult to address. Most patients and families prefer direct and honest communication, but they may interpret the information they are given in very different ways. In addition, oncologists strive to communicate honestly and sensitively, but often struggle with the best approach. Finally, standardization of ACP is challenging because patients have highly individualized values, traditions and social and family dynamics that guide their preferences. Palliative Care is a rapidly growing field that specializes in communication and patient-centered approaches to care. Treatment of patients with advanced or metastatic cancer should prioritize early discussions of ACP to ensure high quality end-of-life care. When available, this care should be delivered through careful integration with palliative care specialists. PMID- 25841692 TI - Spirituality, religion and palliative care. AB - As medical science has evolved, many conditions that once were thought to be "death sentences" have become chronic illness. In some ways, this makes death and dying more complicated, fraught with decisions about what care is appropriate and when to withhold or withdraw care. Studies have shown that most patients faced with life-threatening illness have spiritual needs that are not adequately addressed by their health care providers. The philosophy and practice of palliative care operates upon an understanding of whole person care, reflected in the muli-dimensional approach of the biopsychosocial model. One cannot provide whole-person care without giving consideration to the relevant spiritual needs held by patients with serious illness. As palliative care clinicians, we are uniquely positioned to work with teams/patients/families to explore the many variables that individuals and their families use as the guiding principles when making difficult decisions around end of life. While we are often consulted to manage physical symptoms, that is only part of our work. As we work on building relationships, both with our patients and their care team, we are often able to help facilitate communication that allows for mutually satisfactory goal setting. We are equipped to work with patients within their cultural contexts of which spirituality is a part. It is important to recognize the barriers to providing adequate spiritual care. The National Consensus Project has created clinical practice guidelines to provide a road map for the provision of quality palliative care. These guidelines delineate eight domains that are addressed through the provision of palliative care; the fifth domain gives attention to spiritual, religious and existential aspects of care. Guidelines recommend the use of standardized tools wherever possible to assess spiritual needs; referral to members of the interdisciplinary team who have specialized skills in addressing existential and spiritual concerns, and initiating contact and communication with community spiritual providers as requested by patients and their families. Palliative care providers are also called to be advocates for the spiritual and religious rituals of patients and families, especially at the time of death. PMID- 25841693 TI - Integrative and complementary therapies for patients with advanced cancer. AB - In integrative medicine, well-being is emphasized, and in palliative care, quality of life (QOL) is a similar concept or goal. Both can occur despite advanced cancer. Integrative medicine serves to combine the best of alternative, complementary and conventional therapies to optimize well-being and QOL, whether or not a person is at the end of their life. When integrative medicine is combined with palliative care modalities, the toolbox to provide symptom control and well-being or QOL is increased or broadened. Palliative care and integrative medicine are best provided early in the trajectory of illness such as cancer, and increase in amount as the illness progresses toward end of life. In cancer care, symptoms of the cancer, as well as symptoms produced by cancer therapies, are addressed with conventional and integrative therapies. Goals of care change as the disease progresses, and a patient's unique situation creates a different balance of integrative and conventional therapies. Integrative therapies such as music, aromatherapy, and massage might appeal to more patients than more specific, less common integrative therapies that might be more expensive, or seem more unusual such as Ayurvedic medicine and energy modalities. Each person may be drawn to different integrative modalities depending on factors such as cultural traditions, beliefs, lifestyle, internet information, advice from family and friends, books, etc. This review focuses on how integrative and complementary modalities can be included in comprehensive palliative care for patients with advanced malignancies. Nutrition and movement, often neglected in conventional treatment strategies, will also be included in the larger context of integrative and palliative modalities. Both conventional and integrative modalities in palliative care help patients live with empowerment, hope, and well-being no matter how long their lives last. A comprehensive review of all integrative and complementary therapies is impossible given the enormous diversity in this area. This review will concentrate on modalities such as nutrition, movement, music, aromatherapy, massage, select supplements, and acupuncture that have been researched in cancer survivors. Many of these modalities are quite effective for a number of symptoms in palliative care and have been studied in non-cancer populations. Resources for further study will also be included. PMID- 25841694 TI - Opioids, adjuvants, and interventional options for pain management of symptomatic metastases. AB - Cancer pain is a complex issue that unfortunately affects a majority of cancer patients, the assessment and treatment of which are equally essential in alleviating many facets of this pain. The objective of this section is to address the many facets of cancer pain: its assessment, management, and its varied treatment modalities. We will discuss characteristics of pain, essential aspects of the patient interview, and management using opioids, adjuvants, and interventional and invasive strategies as well as side effects of these techniques. Many of these modalities are used for palliation but may and should be used in cancer patients who experience side effects from both their cancer and their chemotherapeutics. PMID- 25841695 TI - Palliative radiotherapy for advanced malignancies in a changing oncologic landscape: guiding principles and practice implementation. AB - Radiotherapy can provide safe, cost-effective, efficient palliation of various symptoms of advanced cancer with minimal side effects. Radiotherapy can palliate pain related to bone metastases and growing visceral metastases or primary cancers, neurologic symptoms related to brain and spine metastases, other symptoms including cough and dyspnea from advanced cancers in the lung, bleeding from various internal and external tumors, and obstructive symptoms. Palliative radiotherapy should be offered in the context of a multidisciplinary oncology team including medical oncologists, palliative care clinicians and various surgical and interventional subspecialists. The prescription of radiotherapy should balance the convenience and fewer side effects associated with short, hypofractionated courses of radiotherapy with the potential greater durability associated with longer courses of radiotherapy in patients with more prolonged life expectancies. The judicious use of advanced techniques in radiotherapy, including intensity-modulated radiotherapy and stereotactic radiotherapy (SRT), may be warranted in select patients, and they can potentially improve symptom control and durability but are associated with increased technical and economic costs. PMID- 25841696 TI - Chemotherapy for advanced cancers. AB - The decision to treat with chemotherapy in advanced cancers is a complex process that requires oncologists to weigh the indications and benefits. Treatment of patients with advanced cancer is typically multidimensional and should ideally include oncologists in coordination with palliative care specialists. When the intent of chemotherapy for patients with advanced neoplasms is no longer curative, palliative care can and should be delivered simultaneously with antineoplastic agents. Often, chemotherapy for advanced cancers is delivered in an attempt to palliate symptoms, and therefore improve quality of life (QOL). The role of palliative chemotherapy should be continually reevaluated throughout the trajectory of the patient's illness. When chemotherapy is no longer controlling the disease or helping symptoms, the role of chemotherapy should be reconsidered. This review aims to provide a foundation for discussions about treatment of patients with advanced malignancies. PMID- 25841697 TI - Targeted therapy for lung cancer: present and future. AB - Recent advances in methods of genomic profiling have accelerated our understanding of the biology of oncologic diseases. Accumulating evidence suggests that both histology and molecular signature have prognostic and predictive value. Advances in molecular characterization of solid tumors have made individualized approaches feasible. Personalized chemotherapy and targeted biological therapy based on tumor's individual biologic and molecular profile can optimize efficacy while minimizing toxicity. Molecular testing for activating mutations is routinely performed for several disease subtypes, including non small cell lung cancer (NSCLC), breast cancer, melanoma and hematological malignancies including CML. For instance, alterations in the epidermal growth factor receptor (EGFR) domain and echinoderm microtubule associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK) translocation are routinely used to guide therapeutic decisions for advanced NSCLC. Several new treatments targeting EGFR family members, novel EML4-ALK inhibitors and MEK inhibitors are currently in clinical development. Availability of targeted therapies makes it easier to integrate early palliative and supportive care in the management of patients with advanced malignancies. This review summarizes recent advances in use of targeted therapy, with a focus on NSCLC and a special emphasis on investigational strategies for individualized treatment, especially in patients with metastatic disease. PMID- 25841698 TI - Anticipation in stuttering: A theoretical model of the nature of stutter prediction. AB - The fact that some people who stutter have the ability to anticipate a stuttering moment is essential for several theories of stuttering and important for maximum effectiveness of many currently used treatment techniques. The "anticipation effect," however, is poorly understood despite much investigation into this phenomenon. In the present paper, we combine (1) behavioral evidence from the stuttering-anticipation literature, (2) speech production models, and (3) models of error detection to propose a theoretical model of anticipation. Integrating evidence from theories such as Damasio's Somatic Marker Hypothesis, Levelt's Perceptual Monitoring Theory, Guenther's The Directions Into Velocities of Articulators (DIVA) model, Postma's Covert Repair Hypothesis, among others, our central thesis is that the anticipation of a stuttering moment occurs as an outcome of the interactions between previous learning experiences (i.e., learnt associations between stuttered utterances and any self-experienced or environmental consequence) and error monitoring. Possible neurological mechanisms involved in generating conscious anticipation are also discussed, along with directions for future research. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) describe historical theories that explain how PWS may learn to anticipate stuttering; (b) state some traditional sources of evidence of anticipation in stuttering; (c) describe how PWS may be sensitive to the detection of a stuttering; (d) state some of the neural correlates that may underlie anticipation in stuttering; and (e) describe some of the possible utilities of incorporating anticipation into stuttering interventions. PMID- 25841699 TI - Mitochondrial biology, targets, and drug delivery. AB - In recent years, mitochondrial medicine has emerged as a new discipline resting at the intersection of mitochondrial biology, pathology, and pharmaceutics. The central role of mitochondria in critical cellular processes such as metabolism and apoptosis has placed mitochondria at the forefront of cell science. Advances in mitochondrial biology have revealed that these organelles continually undergo fusion and fission while functioning independently and in complex cellular networks, establishing direct membrane contacts with each other and with other organelles. Understanding the diverse cellular functions of mitochondria has contributed to understanding mitochondrial dysfunction in disease states. Polyplasmy and heteroplasmy contribute to mitochondrial phenotypes and associated dysfunction. Residing at the center of cell biology, cellular functions, and disease pathology and being laden with receptors and targets, mitochondria are beacons for pharmaceutical modification. This review presents the current state of mitochondrial medicine with a focus on mitochondrial function, dysfunction, and common disease; mitochondrial receptors, targets, and substrates; and mitochondrial drug design and drug delivery with a focus on the application of nanotechnology to mitochondrial medicine. Mitochondrial medicine is at the precipice of clinical translation; the objective of this review is to aid in the advancement of mitochondrial medicine from infancy to application. PMID- 25841700 TI - Early versus late carotid artery stenting for symptomatic carotid stenosis. AB - INTRODUCTION: Early carotid revascularization (<= 14 days) is recommended for symptomatic carotid stenosis. Carotid artery stenting (CAS) has become an alternative to carotid endarterectomy (CEA); however, safety data on early CAS is controversial. The study aims to compare early versus late CAS, when CAS is performed as a first intention revascularization strategy. METHODS: A retrospective analysis of all symptomatic patients admitted to our stroke unit who underwent CAS was conducted. Patients were divided between two groups: patients who had undergone CAS within 14 days after symptoms and those who had undergone CAS later. Primary endpoints were ipsilateral ischemic stroke or ipsilateral parenchymal hemorrhage (iPH) at 30 days. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) at the 30-day and at the 12-month follow-up. RESULTS: One hundred twenty-seven consecutive patients were evaluated. Primary endpoints obtained in the early and late CAS groups were, respectively, ipsilateral stroke (2.0% vs. 2.6%, P = 1.00) and iPH (2.0% vs. 0.0%, P = 0.40). The rates of MACCE between the early and the late CAS groups were, respectively, (7.8% vs. 2.6%, P = 0.21) at the 30-day follow-up, and (12.2% vs. 10.5%, P = 0.77) at the 12-month follow-up. CONCLUSIONS: In this study, CAS seems to be safe when used as first intention revascularization treatment within 2 weeks of symptoms, if infarcted area is less than one third of the middle cerebral artery territory. Our results need to be confirmed by larger studies. PMID- 25841701 TI - Changes of the apparent diffusion coefficient in brain diffusion-weighted images due to subject positioning: A simulation study. AB - BACKGROUND AND PURPOSE: The purpose of this work was to investigate whether the cortical apparent diffusion coefficient (ADC) values derived from brain diffusion weighted images vary with changes in the position of the subject against a static magnetic field. MATERIALS AND METHODS: To focus on the variations in ADC due to the change of subject positioning, a simulation was performed using a digital brain phantom. The magnetic field inhomogeneities in the digital phantom were calculated for each subject position while changing the angle between the direction of the static field and the head of the digital phantom. The angle was changed from 0 to 40 degrees at 10-degree intervals. For each angle, the diffusion-weighted images were simulated based on magnetic resonance physics in which the magnetic field inhomogeneity was taken into account. The relative differences of average ADC values between the tilt angles were calculated to evaluate the variations in ADC. The Wilcoxon rank-sum test was used for comparisons of ADC values between the tilt angles for each cortical region. RESULTS: In the cortical regions distorted by magnetic field inhomogeneities, the average ADC values differed significantly according to the position of the subject (P < 0.05). The range of the relative differences in average ADC values in relation to the differences in subject positioning was approximately 1% to 12%. CONCLUSION: Our results suggest that subject positioning against a static field is one of the factors affecting the accuracy of cortical ADC measurements derived from brain diffusion-weighted images. PMID- 25841702 TI - New model of flap-gliding flight. AB - A new modelling approach is presented for describing flap-gliding flight in birds and the associated mechanical energy cost of travelling. The new approach is based on the difference in the drag characteristics between flapping and non flapping due to the drag increase caused by flapping. Thus, the possibility of a gliding flight phase, as it exists in flap-gliding flight, yields a performance advantage resulting from the decrease in the drag when compared with continuous flapping flight. Introducing an appropriate non-dimensionalization for the mathematical relations describing flap-gliding flight, results and findings of generally valid nature are derived. It is shown that there is an energy saving of flap-gliding flight in the entire speed range compared to continuous flapping flight. The energy saving reaches the highest level in the lower speed region. The travelling speed of flap-gliding flight is composed of the weighted average of the differing speeds in the flapping and gliding phases. Furthermore, the maximum range performance achievable with flap-gliding flight and the associated optimal travelling speed are determined. PMID- 25841704 TI - Extended-Release Naltrexone for Alcohol and Opioid Problems in Missouri Parolees and Probationers. AB - The purpose of this study was to compare the naturalistic outcomes of parolees and probationers with alcohol and/or opioid problems who were treated with extended-release naltrexone (XR-NTX) to those treated with other medication assisted therapies or psychosocial treatment only. Methods consisted of using intake and discharge data collected as part of SAMHSA's Treatment Episode Data Set (TEDS) assessments, controlling for group differences using propensity scores that were based on a range of intake variables. Results showed that patients receiving XR-NTX had longer durations of care (compared to oral naltrexone and psychosocial treatment only) and were more likely to become abstinent (compared to oral naltrexone, buprenorphine/naloxone, and psychosocial treatment only). Findings were similar for the total sample and those with opioid problems. These XR-NTX results were found in the absence of significant differences in rates of self-help participation. No differences were found in employment or arrests in this relatively short time frame. This study documents the real-world effectiveness study of current FDA-approved addiction medications in parolees/probationers and encourages the use of XR-NTX in such a criminal justice population. PMID- 25841703 TI - Treatment readiness, attitudes toward, and experiences with methadone and buprenorphine maintenance therapy among people who inject drugs in Malaysia. AB - BACKGROUND: Little is known about attitudes toward and experiences with opioid maintenance therapy (OMT) among people who inject drugs in Malaysia, a country where people who inject drugs comprise 1.3% of the adult population. METHODS: In 2010, 460 people who inject drugs in Greater Kuala Lumpur, Malaysia were surveyed to evaluate attitudes toward and experiences with OMT and treatment readiness. Attitudes towards OMT with both methadone and buprenorphine were assessed using an opinions scale. Multivariable linear regression was used to assess correlates of treatment readiness, measured with the 19-item Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). RESULTS: All 460 participants used opioids and nearly all (99.1%) met criteria for opioid dependence. Few had had previous experience with methadone (9.3%) or buprenorphine (12.6%) maintenance therapy, yet many had used methadone (55.2%) or buprenorphine (51.7%) outside of treatment settings. Fifteen percent had injected buprenorphine in the past month, and of the few that were currently receiving buprenorphine maintenance therapy, almost all were injecting it. The majority of subjects exhibited a moderate level of treatment readiness and a preference for methadone over buprenorphine. Those with low treatment readiness scores were more likely to have previous experience with compulsory drug detention centers (p<0.01), needle/syringe exchange programs (p<0.005), or be of Indian ethnicity (p<0.001). Past use of methadone (p<0.01), older age (p<0.001), higher stress symptom severity (p<0.001), and sharing of needles or syringes (p<0.05) were associated with higher treatment readiness scores. CONCLUSION: There are suboptimal levels of OMT experience among people who inject drugs that may be improved by addressing factors that influence patient attitudes. Those individuals with moderate treatment readiness may be targeted by brief motivational and cognitive interventions in primary care, prisons or OMT clinics aimed at improving entry into and retention in treatment. PMID- 25841705 TI - The Relationship Between Postpartum Depression and Perinatal Cigarette Smoking: An Analysis of PRAMS Data. AB - INTRODUCTION: This study examines the relationship between postpartum depression (PPD) and cigarette smoking from prior to pregnancy to postpartum. METHODS: The study sample consisted of 29,654 U.S. women who reported smoking in the 3months prior to pregnancy and for whom data on PPD were available from the Pregnancy Risk Assessment Monitoring System (PRAMS). Two sets of analyses were conducted. The first compared smoking at 2 time points (prior to pregnancy and postpartum) and the second at 3 time points (prior to pregnancy, during pregnancy, and postpartum). PPD was defined as responses of "often" or "always" to 2 questions: "Since your baby was born, how often have you felt down, depressed, or sad?" and "Since your new baby was born, how often have you had little interest or little pleasure in doing things?" RESULTS: Overall, 22% of the sample endorsed PPD symptoms. In the 2 time-point analysis, controlling for known confounders, participants whose smoking was reduced or unchanged postpartum were about 30% more likely to have PPD compared to those who quit (OR: 1.34; 95% CI=1.10-1.60, p=0.001; OR:1.32; 95% CI: 1.10-1.50, p<0.001 respectively). Participants who increased smoking postpartum were 80% more likely to have PPD compared those who quit (OR: 1.80; 95% CI: 1.50-2.30, p<0.001). In the 3 time-point analysis, participants who continued smoking at any level during pregnancy and postpartum had 1.48 times the odds of reporting PPD (95% CI: 1.26, 1.73) compared to those who quit during pregnancy and remained quit postpartum. Participants who quit during pregnancy but resumed postpartum had 1.28 times the odds of reporting PPD (95% CI: 1.06, 1.53) compared to those who quit during pregnancy and remained quit postpartum. CONCLUSION: Results suggest an association among women who smoke cigarettes prior to pregnancy between PPD and continued smoking during pregnancy and postpartum. PMID- 25841706 TI - Methods to select results to include in meta-analyses deserve more consideration in systematic reviews. AB - OBJECTIVES: To investigate how often systematic reviewers encounter multiple trial effect estimates that are available for inclusion in a particular meta analysis (multiplicity of results) and the methods they use to select effect estimates. STUDY DESIGN AND SETTING: We randomly sampled Cochrane and MEDLINE indexed non-Cochrane reviews published between January 2010 and January 2012. The first presented meta-analysis of an effect measure for a continuous outcome in each review was identified, and methods to select results to include in this meta analysis were extracted from review protocols and reviews. All effect estimates that were available for inclusion in the meta-analyses were extracted from trial reports. RESULTS: We examined 44 reviews. Multiplicity of results was common, occurring in 49% of trial reports (n = 210). Prespecification of decision rules to select results from multiple measurement scales and intervention/control groups (in multi-arm trials) was uncommon (19% and 14% of 21 review protocols, respectively). Overall, 70% of reviews included at least one randomized controlled trial with multiplicity of results, but this occurred less frequently in reviews with a protocol (risk difference, -25%; 95% confidence interval: -52%, 1%). CONCLUSION: Systematic reviewers are likely to encounter multiplicity of results in the included trials. We recommend that systematic reviewers always consider predefining methods to select results to include in meta-analyses. Methods focusing on selection of measurement scales and how to deal with multi arm trials would be most valuable. PMID- 25841708 TI - Chinese Clinical Oncology is now indexed by PubMed/MEDLINE: a big step forward. PMID- 25841709 TI - Lymphoma: looking from the present to the future. PMID- 25841707 TI - Sensitivity of neuroprogenitor cells to chemical-induced apoptosis using a multiplexed assay suitable for high-throughput screening. AB - High-throughput methods are useful for rapidly screening large numbers of chemicals for biological activity, including the perturbation of pathways that may lead to adverse cellular effects. In vitro assays for the key events of neurodevelopment, including apoptosis, may be used in a battery of tests for detecting chemicals that could result in developmental neurotoxicity. Apoptosis contributes to nervous system development by regulating the size of the neuroprogenitor cell pool, and the balance between cellular proliferation and apoptosis during neuroprogenitor cell proliferation helps to determine the size and shape of the nervous system. Therefore, chemicals that affect apoptosis during neuronal development can have deleterious effects on the developing brain. The present study examined the utility of a high-throughput assay to detect chemical-induced apoptosis in mouse or human neuroprogenitor cells, as well as differentiated human neurons derived from induced pluripotent stem cells. Apoptosis was assessed using an assay that measures enzymatic activity of caspase 3/7 in a rapid and cost efficient manner. The results show that all three commercially available models generated a robust source of proliferating neuroprogenitor cells, and that the assay was sensitive and reproducible when used in a multi-well plate format. There were differences in the response of rodent and human neuroprogenitor cells to a set of chemicals previously shown to induce apoptosis in vitro. Neuroprogenitor cells were more sensitive to chemical induced apoptosis than differentiated neurons, suggesting that neuroprogenitor cells are one of the cell models that should be considered for use in a developmental neurotoxicity screening battery. PMID- 25841710 TI - Pitfalls in the pathological diagnosis of lymphoma. AB - Since the publication of the 2008 World Health Organization classifications of lymphoma, additional immunohistochemical tests and other ancillary methods such as flow cytometry, cytogenetic and other molecular biology techniques, have been applied in routine clinical work. Due to the utilization of these methodologies, there has been great progress in the pathological diagnosis and classification of lymphomas in the mainland of China. Nonetheless, lymphoma pathology still remains very challenging in the field of diagnostic pathology. Ten percent of pathologist's annual consultation cases are lymphomas, thus reflecting the difficulty of this field. Here, we summarize the common misdiagnoses and pitfalls when dealing with lymphoma cases, the cause of the errors and strategies to avoid inaccurate diagnoses. PMID- 25841711 TI - PET/CT: appropriate application in lymphoma. AB - Positron emission tomography (PET) integrated with computed tomography (CT) (PET/CT) provides both metabolic and morphologic information, and becomes the most sensitive and specific imaging armamentarium in patients with non-Hodgkin lymphoma (NHL) and HL. This multimodality is being routinely used in staging, response assessment, and end-of-treatment evaluation for most lymphoma subtypes with convincing data. However, there are still controversial issues in the clinical management of patients with lymphoma. This comprehensive review addresses the latest information regarding the appropriate application of Fluorine 18 fluorodeoxyglucose ((18)F-FDG) PET/CT, discusses the current dilemma in the prognostic value of interim PET/CT, and tries to clarify questions existing in PET/CT-navigated application. PMID- 25841712 TI - Staging and response assessment in lymphomas: the new Lugano classification. AB - Staging and response criteria were initially developed for Hodgkin lymphoma (HL) over 60 years ago, but not until 1999 were response criteria published for non-HL (NHL). Revisions to these criteria for both NHL and HL were published in 2007 by an international working group, incorporating PET for response assessment, and were widely adopted. After years of experience with these criteria, a workshop including representatives of most major international lymphoma cooperative groups and cancer centers was held at the 11(th) International Conference on Malignant Lymphoma (ICML) in June, 2011 to determine what changes were needed. An Imaging Task Force was created to update the relevance of existing imaging for staging, reassess the role of interim PET-CT, standardize PET-CT reporting, and to evaluate the potential prognostic value of quantitative analyses using PET and CT. A clinical task force was charged with assessing the potential of PET-CT to modify initial staging. A subsequent workshop was help at ICML-12, June 2013. Conclusions included: PET-CT should now be used to stage FDG-avid lymphomas; for others, CT will define stage. Whereas Ann Arbor classification will still be used for disease localization, patients should be treated as limited disease [I (E), II (E)], or extensive disease [III-IV (E)], directed by prognostic and risk factors. Since symptom designation A and B are frequently neither recorded nor accurate, and are not prognostic in most widely used prognostic indices for HL or the various types of NHL, these designations need only be applied to the limited clinical situations where they impact treatment decisions (e.g., stage II HL). PET-CT can replace the bone marrow biopsy (BMBx) for HL. A positive PET of bone or bone marrow is adequate to designate advanced stage in DLBCL. However, BMBx can be considered in DLBCL with no PET evidence of BM involvement, if identification of discordant histology is relevant for patient management, or if the results would alter treatment. BMBx remains recommended for staging of other histologies, primarily if it will impact therapy. PET-CT will be used to assess response in FDG-avid histologies using the 5-point scale, and included in new PET based response criteria, but CT should be used in non-avid histologies. The definition of PD can be based on a single node, but must consider the potential for flare reactions seen early in treatment with newer targeted agents which can mimic disease progression. Routine surveillance scans are strongly discouraged, and the number of scans should be minimized in practice and in clinical trials, when not a direct study question. Hopefully, these recommendations will improve the conduct of clinical trials and patient management. PMID- 25841713 TI - Radiotherapy in early stage classical Hodgkin lymphoma: past, present and future. AB - For early stage classical Hodgkin lymphoma (HL), extended field irradiation (EFRT) alone has shown excellent results in low relapse rate and high long-term survival rate. With the patients achieving long-term survival, the risk of the RT related late complications was increased, such as secondary malignancies and heart infarctions. According to a series of studies, the combined modality therapy (CMT) as the first-line therapy has replaced the radiotherapy (RT) alone. The recommended regimens are 2 cycles of ABVD followed by involved field radiotherapy (IFRT) (20-30 Gy) for the favorable patients, and 4 cycles of ABVD followed by IFRT (30 Gy) for unfavorable patients. The involved nodular radiotherapy (INRT) has shown the potential to achieve satisfactory primary tumor control with lower RT-related toxicity than EFRT or IFRT in combined therapy. Some prospective randomized studies are going about chemotherapy (CT) plus INRT under the guidance of PET. It is not certain that whether CT alone has more benefits to cure limited HL. Appropriate application of new RT techniques can improve the radiation dose distribution in target fields and protect normal tissues from excess RT-related damage. PMID- 25841714 TI - Individualized management of follicular lymphoma. AB - Follicular lymphoma (FL) is the most common indolent non-hodgkin lymphoma. Most patients with FL are diagnosed with advanced disease and are considered incurable. The classical prognostic index in FL is the FL international prognostic index (FLIPI). The management of FL is mainly determined by histologic grading, clinical stage, and tumor burden. For patients with stage I and II disease, an involved-site radiation therapy (ISRT) is recommended and may be potentially curative approach with 60% to 80% of 10-year overall survival (OS) rates, while patients with stage III and IV should be treated with systemic therapy. The watchful waiting is still an option for patients without symptoms or/and low tumor burden. Induction of immuno-chemotherapy combined with consolidation of rituximab maintenance (MR) is standard care for patients with symptomatic disease or with high tumor burden when treatment indicated. The major indication for systemic therapy is including candidate for clinical trials, threatened end organ function, cytopenia secondary to lymphoma bulky disease and steady progress etc. at present time. Routine baseline and regular hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing is strongly recommended for all patients before the initiation of immuno-chemotherapy in order to minimize the risk of hepatitis B virus (HBV) reactivation which has been observed approximately 20% to 50% of patients with positive HBsAg and 3% to 45% of patients with positive HBcAb. Prophylactic antiviral treatment in patients who are HBsAg-positive or HBcAb-positive is indicated before immuno-chemotherapy. The management for elderly patients should be carefully selected to avoid overtreatment and severe toxicities. Individualized dose adjustment for chemotherapy and an adequate supportive treatment are essential for this special population. Novel agents such as lenalidomide, ibrutinib and idelalisib are promising. In conclusion, individualized management of FL remains challenging and role of new targeted agents need to be defined. PMID- 25841715 TI - Mantle cell lymphoma-management in evolution. AB - The management of mantle cell lymphoma (MCL) has been an area of rapid change in recent years. These changes have improved the prognosis for a disease that has had historically poor outcomes. There are several treatment options for the patient with newly diagnosed MCL, with younger, fit patients often receiving intensive treatment, while less intensive strategies have been used for older, less fit patients. The past few years has also seen the arrival of several novel agents used in the treatment of patients with relapsed/refractory (R/R) disease. These targeted therapies combine relatively high response rates with a favorable side-effect profile making them ideal agents for use in this patient population. PMID- 25841716 TI - Double hit diffuse large B-cell lymphomas: diagnostic and therapeutic challenges. AB - Although diffuse large B-cell lymphoma (DLBCL) is curable with standard chemoimmunotherapy, over 30% of patients with advanced stage disease experience refractory disease or progression. Recent studies suggest that rearrangement of the myc oncogene occurs in approximately 10% of patients with DLBCL, and confers a very poor prognosis, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double hit DLBCL". Using immunohistochemistry, up to 30% of patients have evidence of increased expression of myc, which occurs in both activated B-cell and germinal center type DLBCL. When bcl-2 is also positive by immunohistochemistry, prognosis is also poor. There are no randomized studies guiding treatment for patients with double hit DLBCL, but new datasets are emerging suggesting a possible role for dose-adjusted EPOCH infusional chemotherapy with rituximab. This review will conclude with a survey of novel agents which may be rationally incorporated into chemotherapy platforms for this high risk subset of DLBCL. PMID- 25841717 TI - Primary extranodal B-cell lymphoma: current concepts and treatment strategies. AB - Around 30% of all non-Hodgkin lymphoma (NHL) cases arise from extranodal sites. Often the primary extranodal presentation requires site-specific strategies either for diagnosis or therapy. However, several issues remain controversial such as the definition itself of primary extranodal lymphoma, and the most appropriate staging system to characterize the disease extent. Moreover, the specific presenting sites may have per se prognostic implications. The vast majority of the published reports on primary extranodal lymphomas are represented by single-institution retrospective studies. In most clinical trials the primary extranodal lymphomas are often included together with the nodal ones and only a few studies have investigated the peculiarity of extranodal lymphomas. This review summarizes the recent advances in B-cell extranodal lymphomas, addressing the critical points in the management of the more frequently involved sites. PMID- 25841719 TI - Extranodal natural killer/T cell lymphoma: we should and we can do more. AB - Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a rare disease, which is much more prevalent in Asia. With the advent of L-asparaginase-based regimen, the outcome of ENKL was improved obviously. Sequential chemotherapy and radiotherapy is the standard treatment for early-stage ENKL. However, the outcome of advanced-stage diseases is not satisfactory. Therefore, risk-stratification is needed for ENKL. The prognostic factors include IPI, KIPI, plasma EBV-DNA, and interim-PET/CT. However, these parameters are not validated in the era of L asparaginase. The role of high-dose chemotherapy and heamatopoietic stem cell transplantation require further investigation. PMID- 25841720 TI - Risk- and response-adapted strategies for the management of Hodgkin lymphoma. AB - Therapy for Hodgkin lymphoma (HL) is associated with excellent long-term survival rates, of 80% of more. Extended follow up has described late treatment-related toxicities, principally secondary malignancies, cardiovascular disease and infertility. Given the young age of many patients, there is a desire to offer a more personalised approach, correlated to individual tumour biology that enables treatment de-escalation in low risk patients to reduce toxicity, and treatment intensification in high risk patients to reduce treatment failure. Contemporary therapeutic strategies have involved risk assessment based on staging and clinical factors. The use of functional imaging with 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) as a predictive tool to identify early non-responders has been well validated and outperforms the risk stratifying International Prognostic Score (IPS). HL has particularly high FDG-avidity (97 100%), with FDG-PET scanning reflecting metabolic activity and acting as a surrogate biomarker for chemosensitivity. International consensus on the methods of reporting and interpreting FDG-PET scans has enabled their use to be standardised and reproducible. Given that primary therapy fails for 15-20% of patients, the use of combined FDG-PET and computerised tomography (FDG-PET/CT) to provide a response-adapted strategy to guide management is under investigation in numerous prospective clinical trials. They aim to determine whether early response scanning can be used to directly modulate subsequent therapy, through intensifying or abbreviating chemotherapy regimens and/or omitting radiotherapy. Integrated multi-modality imaging and advanced conformal planning techniques have led to the emergence of radiotherapy strategies such as involved-node radiation (INRT) that aim to optimise treatment volumes and maintain efficacy whilst lowering toxicity. Study groups have incorporated these modalities in trial designs to assess whether a PET-directed, individualised approach can become the new standard of care. PMID- 25841721 TI - New drugs for the treatment of non-Hodgkin lymphomas. AB - Non-Hodgkin lymphomas (NHL) are diverse diseases either of mature B-cell or T cell derivation. Despite being generally chemosensitive diseases, the last decade has focused on developing more targeted agents based on improved insights of underlying biology. The hope is that more targeted and biologically rational treatments will improve both the efficacy and toxicity profile of standard approaches, with the ultimate goal of improving clinical outcomes. Among the newest agents to be approved are inhibitors of B-cell receptor (BCR) and PI3K signaling; however, a number of other classes of agents such as selective inhibitors of nuclear export (SINE), inhibitors of immune regulation such as PD1 inhibitors, and small molecule inhibitors of apoptosis are on the horizon. In addition, growing clinical evidence supports continued and new applications for immunomodulatory agents, proteasome inhibitors and histone deacetylase inhibitors. Altogether, this is an exciting time for NHL, with a number of promising agents and early clinical data. The key path forward will be to better apply these new agents in a personalized way, which will hopefully constitute the next generation of trials. PMID- 25841718 TI - New approaches in primary central nervous system lymphoma. AB - Primary central nervous system lymphoma (PCNSL) has long been associated with an inferior prognosis compared to other aggressive non-Hodgkin's lymphomas (NHLs). However, during the past 10 years an accumulation of clinical experience has demonstrated that long-term progression-free survival (PFS) can be attained in a major proportion of PCNSL patients who receive dose-intensive consolidation chemotherapy and avoid whole brain radiotherapy. One recent approach that has reproducibly demonstrated efficacy for newly diagnosed PCNSL patients is an immunochemotherapy combination regimen used during induction that consists of methotrexate, temozolomide, and rituximab followed by consolidative infusional etoposide plus high-dose cytarabine (EA), administered in first complete remission (CR). Other high-dose chemotherapy-based consolidative regimens have shown efficacy as well. Our goal in this review is to update principles of diagnosis and management as well as data regarding the molecular pathogenesis of PCNSL, information that may constitute a basis for development of more effective therapies required to make additional advances in this phenotype of aggressive NHL. PMID- 25841722 TI - Professor Shukui Qin: patient reported outcomes in study of axitinib or sorafenib in Asian patients with metastatic renal cell carcinoma. PMID- 25841723 TI - Professor Jon Wigginton: where we are standing in immunotherapy. PMID- 25841724 TI - The lost Gemeinschaft: how people working with the elderly explain loneliness. AB - We conducted a qualitative interview study with people of different professions working with lonely elderly people. The rationale of the study was to examine how these respondents explain loneliness among the elderly. The present article focuses on the social explanations, i.e. explanations that identify causes of loneliness in the structure of modern society. We found that many of the social explanations given are aspects of a more encompassing and general pattern underlying all the reasoning about loneliness among the elderly. This pattern is the expression of two contrasting images of society which the classical sociologist Ferdinand Tonnies termed Gemeinschaft (community) and Gesellschaft (society). The former refers to traditional or small-size rural communities characterized by high degrees of social cohesion, integration, solidarity, proximity and familiarity, whereas the latter refers to functional differentiation, distance, individualization, exchanged-based social relations and anonymity. Loneliness among the elderly is explained by the lack of Gemeinschaft and its characteristics in contemporary society. This explanatory pattern goes hand in hand with a critical view of contemporary society and a nostalgic yearning for the lost communities of past societies, where inhabitants find their staked-out place and sense of belonging, and thus loneliness hardly seems to occur. We summarized this view under the label the "lost Gemeinschaft". PMID- 25841725 TI - Japan's long-term care policy for older people: the emergence of innovative "mobilisation" initiatives following the 2005 reforms. AB - Japan leads the global race for solutions to the increasing long-term care demand from an ageing population. Initial responses in 2000 saw the launch of the public Long-Term Care Insurance (LTCI) system which witnessed an unexpectedly substantial uptake - with doubts raised about financial viability and sustainability. The post-2005 LTCI reform led to the adoption of innovations - including the "mobilisation" of active, older volunteers to support their frailer peers. This strategy, within the wider government's "2025 Vision" to provide total care for the entire older population, sought to secure financial viability and sustainability. Drawing on qualitative in-depth interviews with 21 provider organisations this study will examine three "mobilisation" schemes and identify those factors contributing to overall strengths while acknowledging complexities, diversities and challenges the schemes encountered. Initial literature written by mobilisation proponents may have been overly optimistic: this study seeks to balance such views through providing an understanding and analysis of these mobilisation schemes' realities. The findings will provide insights and suggest more caution to policy-makers intending to promote such schemes - in both Japan and in countries considering doing so. Furthermore, more evaluation is required to obtain evidence to support financial feasibility and sustainability. PMID- 25841726 TI - Volunteering as reciprocity: beneficial and harmful effects of social policies to encourage contribution in older age. AB - Social policy applications of 'active ageing' ideals have recently focussed on volunteering as a beneficial and valuable contribution that older people can make to their communities. In this paper we draw attention to the positive and negative effects of a general imperative to contribute. Understanding the benefits of contribution in terms of the moral force of reciprocity recognises that older people do need and want to contribute to society and these contributions are beneficial for their sense of identity and wellbeing. However, older people vary greatly in their health, financial resources, and social networks and should not be seen as a homogenous group whose members must contribute in the same way. A policy focus on the imperative to contribute as a participating citizen can be oppressive and lead to withdrawal from social engagement by those who are the most in need of support to participate. Priorities for social and organisational policies must include support for the many ways older people are able to be involved in their communities and to provide structures necessary to support their preferences. A focus on individual responsibility for active engagement in society, which does not take account of individual circumstances or past contributions, can be harmful. PMID- 25841727 TI - "Careworkers don't have a voice:" epistemological violence in residential care for older people. AB - Drawing on feminist epistemologies, this paper attends to the way the reductionist assumptions have shaped the organization of nursing home carework in manners that are insufficient to the needs of relational care. This paper is informed by a study involving nine focus groups and a survey of Canadian residential care workers (141 RNs, 139 LPNs and 415 frontline careworkers). Four major themes were identified. Reductionist assumptions contributed to routinized, task-based approaches to care, resulting in what careworkers termed "assembly line care." Insufficient time and emphasis on the relational dimensions of care made it difficult to "treat residents as human beings." Accountability, enacted as counting and documenting, led to an "avalanche of paperwork" that took time away from care. Finally, hierarchies of knowledge contributed to systemic exclusions and the perception that "careworkers' don't have a voice." Careworkers reported distress as a result of the tensions between the organization of work and the needs of relational care. We theorize these findings as examples of "epistemological violence," a concept coined by Vandana Shiva (1988) to name the harm that results from the hegemony of reductionist assumptions. While not acting alone, we argue that reductionism has played an important role in shaping the context of care both at a policy and organizational level, and it continues to shape the solutions to problems in nursing home care in ways that pose challenges for careworkers. We conclude by suggesting that improving the quality of both work and care will require respecting the specificities of care and its unique epistemological and ontological nature. PMID- 25841728 TI - Staff members' negotiation of power in client engagement: analysis of practice within an Australian aged care service. AB - With increasing focus on client control and active client roles in aged care service provision, client engagement is highlighted as fundamental to contemporary care practice. Client engagement itself, however, is complex and is impacted by a range of issues including the relationships and power dynamics inherent in the care context. These dynamics do not simply reflect the roles that are available to or taken up by clients; just as important are the roles and positions that staff of aged care services are offered, and take up, in client engagement. This paper presents the findings of a study that explored client engagement practice within a large Australian service provider. Analysis of interview and focus group discussions addressed the ways in which staff were positioned - by both themselves and by clients - in terms of the roles that they hold within engagement practice and the power relations inherent within these. Analysis of power from the dominant policy perspective of choice and control, and the alternative perspective of an ethic of care suggests that power relations within the care context are dynamic, complex and involve on-going negotiation and regulation by clients and staff members in aged care. The use of these two contrasting perspectives reveals a more dynamic and complex understanding of power in care practice than dominant uni-dimensional approaches to critique suggest. PMID- 25841729 TI - The experiences of older mothers following the return of an adult child home. AB - CONTEXT: The present study examines the experience of co-residence of older mothers with their adult children who have returned home, as seen from the mothers' perspective. METHODS: The population of the study consisted of 14 women between the ages of 58 and 74, whose sons and daughters aged 30 to 40 had come to live with them. The study is a qualitative one, conducted on the basis of in depth, semi-structured interviews with the mothers. The data were analyzed using constant comparisons. FINDINGS: The analysis of the interviews yielded four main themes: a) the mother's perception of the parental role; b) the mother's perception of the returning son or daughter; c) the mother's perception of living together with the adult child; and d) the emotional ramifications arising from co residence. The differences among the mothers interviewed allowed for the distinction of three types: (1) the mother as rescuer (2) the ambivalent mother and (3) the involved mother. IMPLICATIONS: The study sheds light on this late stage of the mother-child relationship, points to the complexity of the phenomenon, and offers insights for professionals working with clients in such situations. PMID- 25841730 TI - Making sense of a changed physical body: why gender matters at end of life. AB - The bodily experience of patients near end of life has been presented within sociological literature as largely undifferentiated. The attempt of this paper is to overcome this gap by exploring how gender intersects with the loss of bodily autonomy experienced by hospice patients. The study was conducted in two in patient hospice units located near Lisbon, the capital of Portugal. A total of ten terminally ill patients were interviewed, along with twenty family members and twenty members of hospice staff. For the men in this study loss of bodily autonomy was a very dramatic experience as it contravened masculine norms. The women's reactions towards their loss of autonomy were less negative compared to those of men and they made a considerable effort to integrate the best as they could their physical condition. This reflected feminine traits. Findings suggested that the loss of bodily autonomy is gendered in the sense that men and women experience it in dissimilar ways. PMID- 25841731 TI - Sex and the (older) single girl: experiences of sex and dating in later life. AB - This study explored the sexual subjectivities of older Australian women. In this article we present findings from 15 qualitative interviews with Australian women aged 55-81 who were single at the time of interview. The majority of these women were single following divorce or separation, with a smaller number of women who were widowed or never in a long-term relationship. We found that these women's sexual desire and sexual activity were fluid and diverse across their life course. Although some participants desired a romantic or sexual relationship, they were also protective of their independence and reluctant to re-enter into a relationship in later life. Our findings indicate that these women's sexual subjectivities were shaped by dominant norms of ageing, sex, and gender. At the same time, older women are challenging and resisting these norms, and beginning to renegotiate sexuality in later life. PMID- 25841732 TI - Sweet old things: moral complexities in old age in Muriel Spark's Memento Mori. AB - Through the lens of Muriel Spark's dark comedic novel, Memento Mori, this paper explores questions of morality, mortality, and the moral choices and performances in old age and in the systems and places of care. Spark's elderly characters are complex moral actors - some virtuous and some decidedly not - who have been receiving mysterious phone calls telling them simply, "Remember you must die." We, the co-authors, are from two different disciplines, namely Renaissance and medieval literature, and social work and critical gerontology. Among the questions that interest us is the paradox of a master narrative that on the one hand exempts the old from moral criticism yet holds them to a higher moral standard - essentially positioning them as moral nonentities, and relieving the old, their caretakers, and society of moral responsibility. Another is the question of whether moral agency in old age has distinctive aspects, and whether consciousness of one's impending mortality effects moral reasoning and performance. In this paper we offer our individual readings of the ways the novel opens up conceptual space in aging theory, and conclude with our thoughts about what our collaboration suggests for continuing cross-disciplinary dialogue. PMID- 25841734 TI - Alexander Molassiotis: acupuncture, dramatic as it is. PMID- 25841733 TI - Incremental healthcare resource utilization and costs in US patients with Cushing's disease compared with diabetes mellitus and population controls. AB - PURPOSE: Resource utilization and costs in Cushing's disease (CD) patients have not been studied extensively. We compared CD patients with diabetes mellitus (DM) patients and population-based controls to characterize differences in utilization and costs. METHODS: Using 2008-2012 MarketScan(r) database, we identified three patient groups: (1) CD patients; (2) DM patients; and (3) population-based control patients without CD. DM and control patients were matched to CD patients by age, gender, region, and review year in a 2:1 ratio. Outcomes included annual healthcare resource utilization and costs. RESULTS: There were 1852 CD patients, 3704 DM patients and 3704 controls. Mean age was 42.9 years; 78.2 % were female. CD patients were hospitalized more frequently (19.3 %) than DM patients (11.0 %, p < .001) or controls (5.6 %, p < .001). CD patients visited the ED more frequently (25.4 %) than DM patients (21.1 %, p < .001) or controls (14.3 %, p < .001). CD patients had more office visits than DM patients (19.1 vs. 10.7, p < .001) or controls (7.1, p < .001). CD patients on average filled more prescriptions than DM patients (51.7 vs. 42.7, p < .001) or controls (20.5, p < .001). Mean total healthcare costs for CD patients were $26,269 versus $12,282 for DM patients (p < .001) and $5869 for controls (p < .001). CONCLUSIONS: CD patients had significantly higher annual rates of healthcare resource utilization compared to matched DM patients and population controls without CD. CD patient costs were double DM costs and quadruple control costs. This study puts into context the additional burdens of CD over DM, a common, chronic endocrine condition affecting multiple organ systems, and population controls. PMID- 25841735 TI - Using acupuncture as part of a comprehensive program in helping patients with breast cancer beyond fatigue. PMID- 25841736 TI - Guidance for prospective acupuncture treatment on cancer-related fatigue (CRF). PMID- 25841737 TI - Does the strength of evidence support recommending acupuncture to relieve cancer related fatigue? PMID- 25841738 TI - Demonstration wards for the standardized cancer pain management in China. PMID- 25841739 TI - Guidelines on cancer pain management (2011 Edition). PMID- 25841740 TI - The role of cryosurgery in palliative care for cancer. AB - Cryosurgery as one of the ablation methods is performed intraoperatively, laparoscopically or percutaneously, is especially adapted for ablation of prostate cancer, liver cancer, lung cancer, kidney cancer, breast cancer, benign fibroadenomas of breast, uterine tumors and neoplasms of soft tissue. Compared with other ablation methods (such as radiofrequency and microwave ablation), cryoablation has several advantages on therapeutic efficacy, imaging guidance and modality. PMID- 25841741 TI - Lapatinib as a therapeutic option in brain metastases from HER2+ breast cancer. PMID- 25841742 TI - Ketamine: to be or not to be. PMID- 25841743 TI - Relevance of ketamine in the management of cancer pain. PMID- 25841744 TI - Information and support: implications for developing palliative care programs. PMID- 25841745 TI - Assessing depression in cancer patients - a longitudinal comparison of three questionnaires. PMID- 25841746 TI - The implementation of palliative care: opening Pandora's box? PMID- 25841747 TI - Palliative radiotherapy in patients with metastatic non-small cell lung cancer. PMID- 25841748 TI - Genomic characterization of a turkey reovirus field strain by Next-Generation Sequencing. AB - The genome of a turkey arthritis reovirus (TARV) field strain (Reo/PA/Turkey/22342/13), isolated from a turkey flock in Pennsylvania (PA) in 2013, has been sequenced using Next-Generation Sequencing (NGS) on the Illumina MiSeq platform. The genome of the PA TARV field strain was 23,496bp in length with 10 dsRNA segments encoding 12 viral proteins. The lengths of the genomic segments ranged from 1192bp (S4) to 3959bp (L1). The 5' and 3' conserved terminal sequences of the PA TARV field strain were similar to the two Minnesota (MN) TARVs (MN9 and MN10) published recently and avian orthoreovirus (ARV) reference strains. Phylogenetic analysis of the nucleotide sequences of all 10 genome segments revealed that there was a low to significant nucleotide sequence divergence between the PA TARV field strain and reference TARV and ARV strains. Analysis of the PA TARV sequence indicates that this PA TARV field strain is a unique strain and is different from the TARV MN9 or MN10 in M2 segment genes and ARV S1133 vaccine strain. PMID- 25841749 TI - Reregulation of the Swedish pharmacy sector-A qualitative content analysis of the political rationale. AB - In 2009, a reregulation of the Swedish pharmacy sector took place, and a fundamental change in ownership and structure followed. The reregulation provides an opportunity to reveal the politicians' views on pharmacies. The aim of this study was to explore and analyze the political arguments for the reregulation of the Swedish pharmacy sector in 2009. The method used was a qualitative content analysis of written political documents regarding the reregulation. The primary rationales for the reregulation were better availability, efficiency, price pressure, and safe usage of medicines. During the preparatory work, the rationales of diversity on the market and entrepreneurship were added, while the original rationales of efficiency, price pressure, and better usage of medicines were abandoned. The reform can be seen as a typical New Public Management reform influenced by the notion that private actors are better equipped to perform public activities. The results point to that the reform was done almost solely in order to introduce private ownership in the pharmacy sector, and was not initiated in order to solve any general problems, or to enhance patient outcomes of medicine use. PMID- 25841750 TI - Transcriptional response to copper excess and identification of genes involved in heavy metal tolerance in the extremophilic microalga Chlamydomonas acidophila. AB - High concentrations of heavy metals are typical of acidic environments. Therefore, studies on acidophilic organisms in their natural environments improve our understanding on the evolution of heavy metal tolerance and detoxification in plants. Here we sequenced the transcriptome of the extremophilic microalga Chlamydomonas acidophila cultivated in control conditions and with 500 MUM of copper for 24 h. High-throughput 454 sequencing was followed by de novo transcriptome assembly. The reference transcriptome was annotated and genes related to heavy metal tolerance and abiotic stress were identified. Analyses of differentially expressed transcripts were used to detect genes involved in metabolic pathways related to abiotic stress tolerance, focusing on effects caused by increased levels of copper. Both transcriptomic data and observations from PAM fluorometry analysis suggested that the photosynthetic activity of C. acidophila is not adversely affected by addition of high amounts of copper. Up regulated transcripts include several transcripts related to photosynthesis and carbohydrate metabolism, transcripts coding for general stress response, and a transcript annotated as homologous to the oil-body-associated protein HOGP coding gene. The first de novo assembly of C. acidophila significantly increases transcriptomic data available on extremophiles and green algae and thus provides an important reference for further molecular genetic studies. The differences between differentially expressed transcripts detected in our study suggest that the response to heavy metal exposure in C. acidophila is different from other studied green algae. PMID- 25841751 TI - Desulfonatronum zhilinae sp. nov., a novel haloalkaliphilic sulfate-reducing bacterium from soda Lake Alginskoe, Trans-Baikal Region, Russia. AB - A novel haloalkaliphilic sulfate-reducing bacterium, designated Al915-01(T), was isolated from benthic sediments of the Lake Alginskoe, a soda lake located in the Trans-Baikal Region, Russia. Cells of the strain were Gram-stain negative, motile, non-spore-forming vibrion (0.4-0.5 * 1.2-2.3 um). Strain Al915-01(T) grew in the pH range from 8.0 to 10.5 (optimum pH 9.0) and required NaCl for growth (5 100 g l(-1) NaCl, optimum 40 g l(-1)). The bacterium grew at 10-40 degrees C (optimally at 36 degrees C) and used lactate, formate and pyruvate as electron donors in the presence of sulfate. It was able to reduce sulfate, sulfite, thiosulfate and nitrate with lactate as an electron donor. The isolate was able to grow lithoheterotrophically with sulfate and molecular hydrogen if acetate was added as a carbon source. The predominant fatty acids were anteisoC15:0, isoC17:1, C18:1omega7 and C16:1omega7. The G+C content in the DNA was 58.3 +/- 1 mol %. Analysis of the 16S rRNA gene sequence showed that the new bacterium belongs to the genus Desulfonatronum. The closest relatives were Desulfonatronum buryatense Ki5(T) (99.9 % similarity) and Desulfonatronum lacustre Z-7951(T) (99.2 % similarity). On the basis of the genotypic, phenotypic and phylogenetic characteristics, the isolate is proposed as a representative of a novel species Desulfonatronum zhilinae with the type strain Al915-01(T) (=VKM B-2744(T) = DSM 26338(T)). PMID- 25841752 TI - Racial Associations with Hemorrhagic Presentation in Cerebral Arteriovenous Malformations. AB - BACKGROUND: Studies focusing on hemorrhagic presentation of brain arteriovenous malformations (AVMs) have largely limited their analysis to angiographic features. We report the importance of race/ethnicity as a clinical factor associated with hemorrhagic AVM presentation in addition to previously reported angiographic features. METHODS: Data were prospectively and retrospectively collected on patients (N = 194) during the period 1993-2010 who presented with a single intracranial AVM, and baseline characteristics were compared for hemorrhagic presentation versus nonhemorrhagic presentation. Features that were statistically significant in univariate analysis or clinically significant were included in a multivariate analysis. RESULTS: The median age at presentation was 32 years; 37.2% of patients were male. Spetzler-Martin grades were I in 17.5%, II in 37.1%, III in 28.9%, IV in 14.9%, and V in 1.5%. Baseline characteristics that differed significantly between patients presenting with hemorrhage compared with patients without hemorrhage were the following: race (P < 0.01), AVM size (P < 0.01), <3 feeding arteries (P = 0.01), absence of middle cerebral artery supply to AVM (P < 0.01), and AVM location (P < 0.01). Multivariate analysis revealed nonwhite race (odds ratio [OR] = 3.09 [95% confidence interval (CI) = 1.52, 6.44], P < 0.01); smaller AVM size (OR = 0.65 [95% CI = 0.19, 0.86], P < 0.01); and nonfrontal lobar (OR = 2.61 [95% CI = 1.2, 5.59], P = 0.02), basal ganglia (OR = 6.20 [95% CI = 1.52, 26.26], P = 0.01), or brainstem locations (OR = 4.41 [95% CI = 1.38, 14.92], P = 0.01) as factors associated with hemorrhagic presentation of brain AVMs. CONCLUSIONS: To our knowledge, this is the first study demonstrating that race/ethnicity is significantly associated with hemorrhagic presentation of AVMs. We also confirmed previous observations that AVM size and location are associated with hemorrhagic presentation. PMID- 25841753 TI - To Remove or Not to Remove, that Is the Question? PMID- 25841754 TI - Risk Factors for Graft Infection After Cranioplasty in Patients with Large Hemicranial Bony Defects. AB - OBJECTIVE: To identify infection incidence and related risk factors in patients who underwent cranioplasty (CP) after unilateral decompressive craniectomy (DC). METHODS: CP after DC was performed in 45 patients from April 2011 through January 2012. The covariates studied were compared with occurrence versus nonoccurrence of infection. Univariate analysis was performed, followed by a multivariate analysis and development of independent logistic regression models with significance of 5%. RESULTS: Wound infections were observed in 24% of cases. Patients treated with polymethyl methacrylate flaps had a 31% rate of infection compared with 12% in patients treated with autologous flaps, but the difference was not statistically significant (P = 0.279). Increased risk of infection was associated with performing CP during the same period of hospitalization as DC (45% vs. 8%; P = 0.006), recent systemic infection (53% vs. 10%; P = 0.003), a Glasgow Outcome Scale score lower than 4 (48% vs. none; P < 0.001), motor deficit (42% vs. 5%; P = 0.011), and lower levels of hemoglobin (P < 0.001). Another risk factor for infection was an interval between DC and CP of 29-84 days compared with >168 days (P = 0.007). CONCLUSIONS: The incidence of wound infection was high. Risk factors included motor deficits, Glasgow Outcome Scale score <4, lower hemoglobin levels, recent systemic infections, interval between DC and CP of 29 84 days, and DC and CP performed during the same hospitalization. Performing CP during a different hospitalization may reduce the risk of graft infection because the hemoglobin level would be higher, and patients would be less dependent and free of recent infection. PMID- 25841755 TI - Anterior Transpetrosal Approach Combined with Partial Posterior Petrosectomy for Petroclival Meningiomas with Posterior Extension. AB - BACKGROUND: An anterior transpetrosal approach (ATPA) is suitable for treating upper petroclival lesions. However, the limit of the ATPA is reached when the tumor extends posterolaterally over the internal auditory canal (IAC) along the petrous edge. In such cases, ligation of the posterior part of the superior petrosal sinus (SPS) is necessary. To overcome this limitation, we combined the ATPA with a partial posterior petrosectomy in 8 patients who had petroclival meningiomas extending posterolaterally over the IAC. METHODS: We resected only the Trautmann triangle in addition to the Kawase triangle to secure the space to ligate the posterior portion of the SPS. Because the tympanic cavity and bony labyrinth of the ear were not exposed, we were able to preserve hearing function and lower the risk of cerebrospinal fluid leakage. Furthermore, this approach enables easy ligation of the SPS and the tentorium posterior to the tumor attachment. This combined technique also allows visualization of the petrosal vein, which is important for surgery of the posterior fossa. RESULTS: Total and near-total tumor removal was achieved in 6 patients (75%) with no permanent complications and no cerebrospinal fluid leakage. Postoperative hearing impairment was not found in any of the patients who underwent this surgery. CONCLUSIONS: The ATPA combined with partial posterior petrosectomy is an effective method for removal of complicated petroclival meningiomas that extend posterolaterally over the IAC along the petrous edge. PMID- 25841756 TI - The Road to Nonawaking Functional Mapping Combining High Gamma Activity with Corticocortical Evoked Potential. PMID- 25841757 TI - A Strange Case of Downward Displacement of a Deep Brain Stimulation Electrode 10 Years Following Implantation: The Gliding Movement of Snakes Theory. AB - BACKGROUND: Despite the best efforts to ensure stereotactic precision, deep brain stimulation (DBS) electrodes can wander from their intended position after implantation. We report a case of downward electrode migration 10 years following successful implantation in a patient with Parkinson disease. METHODS: A 53-year old man with Parkinson disease underwent bilateral implantation of DBS electrodes connected to a subclavicular 2-channel pulse generator. The generator was replaced 7 years later, and a computed tomography (CT) scan confirmed the correct position of both leads. The patient developed a gradual worsening affecting his right side 3 years later, 10 years after the original implantation. A CT scan revealed displacement of the left electrode inferiorly into the pons. The new CT scans and the CT scans obtained immediately after the implantation were merged within a stereotactic planning workstation (Brainlab). RESULTS: Comparing the CT scans, the distal end of the electrode was in the same position, the proximal tip being significantly more inferior. The size and configuration of the coiled portions of the electrode had not changed. At implantation, the length was 27.7 cm; after 10 years, the length was 30.6 cm. CONCLUSIONS: These data suggests that the electrode had been stretched into its new position rather than pushed. Clinicians evaluating patients with a delayed worsening should be aware of this rare event. PMID- 25841758 TI - [Guide dedicated to general practitioner for the management of lower urinary tract symptoms related to benign prostatic hyperplasia]. AB - OBJECTIVE: To establish a guide dedicated to general practitioner for the diagnosis, the follow-up, and the treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). METHOD: Guidelines already published for urologists were modified to make them relevant for general practitioners. The role of specialist's referral was defined. The whole content of the document was submitted to the formal consensus process in which urologists and general medicine teachers were involved. RESULTS: Initial assessment has several aims: making sure that LUTS are related to BPH, assessing bother related to LUTS, and checking for a possible complication. Initial assessment should include: medical history, physical examination with digital rectal examination, and urinalysis. Some other explorations such as frequency volume chart, serum PSA or creatinine, and ultrasonography of the urinary tract were found optional, meaning they are necessary only in specific situations. Referring to urologist is justified when LUTS might not be related to BPH (particularly when urgencies are predominant), or when a severe bladder outlet obstruction is suspected (severe symptoms, palpable bladder, post-voiding residual volume>100ml), or when a complication is assessed. Follow-up without treatment is justified for patients with no bothersome symptoms related to not complicated BPH. Several drugs are available for the treatment of bothersome symptoms related to BPH. Alpha-blockers and plants extracts might be offered as monotherapy. Five alpha reductase inhibitors might be offered to patients with LUTS related to a significant prostate hypertrophy (>40 ml) ; they might be given for a minimum duration of one year, alone or in association with alpha-blocker. The association of antimuscarinic and alpha-blocker might be used in patients with persistent storage LUTS in spite of alpha-blocker treatment. Phosphodiesterase 5 inhibitors might be offered to patients with erectile dysfunction associated with LUTS related to BPH. In case of complicated BPH, or when medical treatment is not efficacious or not tolerated, a surgical option should be discussed. CONCLUSION: The male lower urinary tract symptom committee of the French Urological Association and general practitioner present the first guide for the management of LUTS related to BPH dedicated to general practitioner. LEVEL OF EVIDENCE: 5. PMID- 25841759 TI - [Penile prosthesis: Systematic review of infectious complications]. AB - OBJECTIVES: In the absence of practice recommendations, it was realized a review of the literature to establish the epidemiological and bacteriological data, prevention of infection, therapeutic attitude according to the clinical situation as well as the future prospects about the infections of penile prostheses. METHODS: A systematic review of the scientific literature was realized by the base of Pubmed data (http://www.ncbi.nim.gov/pubmed/). The literature search was made between 1992 and 2014 using the keywords: penile prostheses, penile implant, infection. The article was developed according to the recommendations Preferred reporting items for systematic reviews and meta-analyses 2009 (Prisma). RESULTS: The analysis of 10 meta-analysis and series published in various expert centers allowed us to synthesize the care recommended at present. Coagulasse negative staphylococcus were germs most frequently persons in charge but variations are secondarily observed in the current practices. The physiopathological knowledge (biofilm and risk factors) allowed to develop the antibiotic antibioprophylaxis, the precautionary measures of the infection of the operating site, the design of prostheses antimicrobial-impregnated or antibiotic-dipped and meticulous surgical technique ("Wash-Out", "No Touch"). In case of real infection, it was recommended in the absence of contra-indication to realize immediate salvage procedure allowing to set up a new penile prostheses, so avoiding the penile fibrosis. CONCLUSION: All these measures have induced a decrease of the infection of penile implants significantly as well in case of primary implantation as of surgical revision. The future perspectives aim at preventing the infection by inhibition of the formation of the biofilm and by a more effective action of antibiotics about germs which it contains; or to use devices intrapenile "spacer" when the immediate salvage procedure is not feasible to facilitate the next implantation. PMID- 25841760 TI - Post-mortem assessment of the short and long-term effects of the trophic factor neurturin in patients with alpha-synucleinopathies. AB - Substantial interest persists for developing neurotrophic factors to treat neurodegenerative diseases. At the same time, significant progress has been made in implementing gene therapy as a means to provide long-term expression of bioactive neurotrophic factors to targeted sites in the brain. Nonetheless, to date, no double-blind clinical trial has achieved positive results on its primary endpoint despite robust benefits achieved in animal models. A major issue with advancing the field is the paucity of information regarding the expression and effects of neurotrophic factors in human neurodegenerative brain, relative to the well-characterized responses in animal models. To help fill this information void, we examined post-mortem brain tissue from four patients with nigrostriatal degeneration who had participated in clinical trials testing gene delivery of neurturin to the putamen of patients. Each had died of unrelated causes ranging from 1.5-to-3-months (2 Parkinson's disease patients), to 4+-years (1 Parkinson's disease and 1 multiple-system atrophy-parkinsonian type patient) following gene therapy. Quantitative and immunohistochemical evaluation of neurturin, alpha synuclein, tyrosine hydroxylase (TH) and an oligodendroglia marker (Olig 2) were performed in each brain. Comparable volumes-of-expression of neurturin were seen in the putamen in all cases (~15-22%; mean=18.5%). TH-signal in the putamen was extremely sparse in the shorter-term cases. A 6-fold increase was seen in longer term cases, but was far less than achieved in animal models of nigrostriatal degeneration with similar or even far less NRTN exposure. Less than 1% of substantia nigra (SN) neurons stained for neurturin in the shorter-term cases. A 15-fold increase was seen in the longer-term cases, but neurturin was still only detected in ~5% of nigral cells. These data provide unique insight into the functional status of advanced, chronic nigrostriatal degeneration in human brain and the response of these neurons to neurotrophic factor stimulation. They demonstrate mild but persistent expression of gene-mediated neurturin over 4 years, with an apparent, time-related amplification of its transport and biological effects, albeit quite weak, and provide unique information to help plan and design future trials. PMID- 25841762 TI - Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts. AB - The malaria parasite Plasmodium possesses a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is essential for parasite survival, and harbors several plant-like metabolic pathways including a type II fatty acid synthesis (FASII) pathway. The FASII pathway was discovered in 1998, and much of the early research in the field pursued it as a therapeutic drug target. These studies identified a range of compounds with activity against bloodstage parasites and led to the localization and characterization of most enzymes in the pathway. However, when genetic studies revealed FASII was dispensable in bloodstage parasites, it effectively discounted the pathway as a therapeutic drug target, and suggested these compounds instead interfered with other processes. Interest in FASII then shifted toward its disruption for malaria prophylaxis and vaccine development, with experiments in rodent malaria models identifying a crucial role for the pathway in the parasite's transition from the liver to the blood. Unexpectedly however, the human malaria parasite P. falciparum was recently found to differ from rodent models and require FASII for mosquito stage development. This requirement blocked the production of the FASII-deficient forms that might be used as a genetically attenuated parasite vaccine, suggesting the pathway was also unsuitable as a vaccine target. This review discusses how perception of FASII has changed over time, and presents key findings about each enzyme in the pathway to identify remaining questions and opportunities for malaria control. PMID- 25841763 TI - Assessing Differences Between Ancestral Recombination Graphs. AB - Ancestral recombination graphs (ARGs) represent the history of portions of a genome with recombination. Attempts to infer ARGs have been hampered by the lack of an ARG comparison metric which could be used to measure how well inference succeeded. We propose a simple ARG comparison framework based on averaging standard tree comparison measures across either all sites or variable sites only. Using simulated data, we show that this framework, instantiated with an appropriate tree comparison measure, can distinguish better from worse inferences of an ARG. PMID- 25841764 TI - Hemeoxygenase-1 maintains bone mass via attenuating a redox imbalance in osteoclast. AB - Heme oxygenase-1 (HO-1) has long been considered to be an endogenous antioxidant. However, the role of HO-1 is highly controversial in developing metabolic diseases. We hypothesized that HO-1 plays a role in maintaining bone mass by alleviating a redox imbalance. We investigated its role in bone remodeling. The absence of HO-1 in mice led to decreased bone mass with elevated activity and number of OCs, as well as higher serum levels of reactive oxygen species (ROS). HO-1, which is constitutively expressed at a high level in osteoclast (OC) precursors, was down-regulated during OC differentiation. HO-1 deficiency in bone marrow macrophages (BMM) in vitro resulted in increased numbers and activity of OCs due to enhanced receptor activator of nuclear factor-kappaB ligand (RANKL) signaling. This was associated with increased activation of nuclear factor-kappaB and of nuclear factor of activated T-cells, cytoplasmic 1 along with elevated levels of intracellular calcium and ROS. Decreased bone mass in the absence of HO 1 appears to be mainly due to increased osteoclastogenesis and bone resorption resulting from elevated RANKL signaling in OCs. Our data highlight the potential role of HO-1 in maintaining bone mass by negatively regulating OCs. PMID- 25841765 TI - Plasma membrane gp96 enhances invasion and metastatic potential of liver cancer via regulation of uPAR. AB - Targeted therapy is currently under intensive investigation due to the resistance of liver cancer to cytotoxic chemotherapies. Dissecting the molecular events that drive the progression of liver cancer and defining specific targets are urgently needed to develop efficient tailored therapies. Cell membrane gp96 (mgp96) has been implicated in tumor growth and malignancy. Here, we explored the functional and clinical relevance of mgp96 in liver cancer. We found that elevated mgp96 abundance was associated with tumor metastasis and recurrence in patients with primary liver tumors. Decreased KDELR1 levels in hepatoma cells contribute to cell membrane translocation of the normally ER-resident gp96. Urokinase-type plasminogen activator receptor (uPAR) was identified as a mgp96 client protein, and mgp96 stabilized uPAR protein. Our clinical results proved that elevated mgp96 abundance is positively correlated with uPAR expression levels in liver tumors. We further provided evidence that targeting mgp96 with siRNA or a specific mAb that blocked the mgp96-uPAR interaction led to inhibited cell growth, survival, and invasion in vitro, as well as the suppression of liver tumor growth and metastasis in vivo. mgp96 promotes liver cancer progression through increasing the protein stability and signaling of uPAR, and may be a new promising target for suppressing uPAR-mediated tumor growth and metastasis in liver cancer. PMID- 25841766 TI - Targeting Nrf2 in healthy and malignant ovarian epithelial cells: Protection versus promotion. AB - Risk factors indicate the importance of oxidative stress during ovarian carcinogenesis. To tolerate oxidative stress, cells activate the transcription factor Nrf2 (Nfe2l2), the master regulator of antioxidant and cytoprotective genes. Indeed, for most cancers, hyperactivity of Nrf2 is observed, and siRNA studies assigned Nrf2 as therapeutic target. However, the cancer-protective role of Nrf2 in healthy cells highlights the requirement for an adequate therapeutic window. We engineered artificial transcription factors to assess the role of Nrf2 in healthy (OSE-C2) and malignant ovarian cells (A2780). Successful NRF2 up- and downregulation correlated with decreased, respectively increased, sensitivity toward oxidative stress. Inhibition of NRF2 reduced the colony forming potential to the same extent in wild-type and BRCA1 knockdown A2780 cells. Only in BRCA1 knockdown A2780 cells, the effect of Nrf2 inhibition could be enhanced when combined with PARP inhibitors. Therefore, we propose that this combination therapy of PARP inhibitors and Nrf2 inhibition can further improve treatment efficacy specifically in BRCA1 mutant cancer cells without acquiring the side effects associated with previously studied Nrf2 inhibition combinations with either chemotherapy or radiation. Our findings stress the dual role of Nrf2 in carcinogenesis, while offering approaches to exploit Nrf2 as a potent therapeutic target in ovarian cancer. PMID- 25841767 TI - [Posttraumatic enophthalmos correction by bone graft: Why the unpredictable results?]. AB - PURPOSE OF THE STUDY: Posttraumatic enophthalmos cause complex cosmetic problems to fix. In order to get better results, we wanted to calculate the volume of parietal bone graft needed to be put in place, know where to place it in orbit and study soft tissues' participation. PATIENTS AND METHOD: In a retrospective study, we have calculated on scanner the volume of bone and soft tissue as well as the volume and the location of the graft. We have compared, between two groups ("good result" and "insufficient result"), graft volumes, taking into account differences in bone's volume between the healthy and the traumatized orbit. A comparison of the locations of the graft was also made. We were trying to find out if these factors were involved in the quality of the result. RESULTS: Twenty nine surgeries on 24 patients were analyzed. The average bone's volume of an orbit with enophthalmos was 24.76 cm(3) for 17.12 cm(3) of soft tissue. Retro lens distance was the most reliable measurement method of enophthalmos (P=0.001). There was a trend to a more substantial over-correction in the group "good result". A significant increase (P=0.0008) of soft tissue volumes in the traumatized orbit was found. CONCLUSION: This last result is surprising. Many authors believe that there is a scar retraction of soft tissues. But Kronish et al. showed an increase of the fat density and connective tissue. This, together with the assumption of a weathering of the ligament suspension of the globe, may affect our aesthetic results. MRI, ultrasound and anatomopathological studies would allow a better understanding of the fat, muscle and ligament pathophysiologies of an orbit with enophthalmos. PMID- 25841768 TI - [Comments on article "Scalp flap pedicled on posterior auricular artery. Anatomical study and clinical application"]. AB - The authors comment on the reliability of the scalp flap pedicled on auricular posterior artery, arguing with the conclusions of anatomic studies published in this issue and their little experience in reconstructing scalp defects by local flaps. PMID- 25841769 TI - Management of the spastic wrist and hand in cerebral palsy. AB - Research from the last 5 years on the pathophysiology and treatment of upper extremity sequelae of cerebral palsy (CP) is presented. The development of new treatments of CP-affected limbs, utilizing the brain's inherent neuroplasticity, remains an area of promising and active research. Functional magnetic resonance imaging scans have evaluated the role of neuroplasticity in adapting to the initial central nervous system insult. Children with CP appear to have greater recruitment of the ipsilateral brain for motor and sensory functions of the affected upper limb. Studies have also shown that constraint-induced movement therapy results in localized increase in gray matter volume of the sensorimotor cortex contralateral to the affected arm targeted during rehabilitation. Recent therapy interventions have emphasized the role of home therapy programs, the transient effects of splinting, and the promise of constraint-induced movement therapy and bimanual hand training. The use of motion laboratory analysis to characterize the movement pattern disturbances in children with CP continues to expand. Classification systems for CP upper limb continue to expand and improve their reliability, including use of the House Classification, the Manual Ability Classification System, and the Shriner's Hospital Upper Extremity Evaluation. Surgical outcomes have greater patients' satisfaction when they address functional limitations, also in addition to aesthetics, which may improve patients' self-esteem. Surgical techniques for elbow, wrist, fingers, and thumb continue to be refined. Research into each of these areas continues to expand our understanding of the nervous system insults that cause CP, how they may be modified, and how hand surgeons can continue to serve patients by improving their upper limb function and aesthetics. PMID- 25841770 TI - Eliciting health care priorities in developing countries: experimental evidence from Guatemala. AB - Although some methods for eliciting preferences to assist participatory priority setting in health care in developed countries are available, the same is not true for poor communities in developing countries whose preferences are neglected in health policy making. Existing methods grounded on self-interested, monetary valuations that may be inappropriate for developing country settings where community care is provided through 'social allocation' mechanisms. This paper proposes and examines an alternative methodology for eliciting preferences for health care programmes specifically catered for rural and less literate populations but which is still applicable in urban communities. Specifically, the method simulates a realistic collective budget allocation experiment, to be implemented in both rural and urban communities in Guatemala. We report evidence revealing that participatory budget-like experiments are incentive compatible mechanisms suitable for revealing collective preferences, while simultaneously having the advantage of involving communities in health care reform processes. PMID- 25841771 TI - Cardiovascular disease and impoverishment averted due to a salt reduction policy in South Africa: an extended cost-effectiveness analysis. AB - The South African Government recently set targets to reduce cardiovascular disease (CVD) by lowering salt consumption. We conducted an extended cost effectiveness analysis (ECEA) to model the potential health and economic impacts of this salt policy. We used surveys and epidemiologic studies to estimate reductions in CVD resulting from lower salt intake. We calculated the average out of-pocket (OOP) cost of CVD care, using facility fee schedules and drug prices. We estimated the reduction in OOP expenditures and government subsidies due to the policy. We estimated public and private sector costs of policy implementation. We estimated financial risk protection (FRP) from the policy as (1) cases of catastrophic health expenditure (CHE) averted or (2) cases of poverty averted. We also performed a sensitivity analysis. We found that the salt policy could reduce CVD deaths by 11%, with similar health gains across income quintiles. The policy could save households US$ 4.06 million (2012) in OOP expenditures (US$ 0.29 per capita) and save the government US$ 51.25 million in healthcare subsidies (US$ 2.52 per capita) each year. The cost to the government would be only US$ 0.01 per capita; hence, the policy would be cost saving. If the private sector food reformulation costs were passed on to consumers, food expenditures would increase by <0.2% across all income quintiles. Preventing CVD could avert 2400 cases of CHE or 2000 cases of poverty yearly. Our results were sensitive to baseline CVD mortality rates and the cost of treatment. We conclude that, in addition to health gains, population salt reduction can have positive economic impacts-substantially reducing OOP expenditures and providing FRP, particularly for the middle class. The policy could also provide large government savings on health care. PMID- 25841772 TI - Off-pump Bilateral Internal Thoracic Artery Grafting. AB - BACKGROUND: The long-term benefit of bilateral internal thoracic grafts (BITA) is well established. BITA grafting is often avoided in diabetic, female, obese, elderly and other high-risk patients because of concerns for deep sternal wound infection. The objective of this study is to analyse early results of our BITA grafting and to establish the safety of BITA use in all patients. METHODS: All cases of isolated consecutive unselected CABG were included in this retrospective study. BITA were used in-situ - one was used to graft left anterior descending artery and the other was used as inflow for a composite graft with radial artery. Dual inflow using in situ BITA grafting allows easy bailout by using an additional vein graft. RESULTS: BITA was used in 574 patients out of 602 (95.35%). Incidence of early death was 1.33% (8/602), stroke 0.5% (3/602), reoperation for bleeding 0.17% (1/602). Deep sternal wound infection was not seen in any patient but nine patients (1.5%) had superficial wound infection which healed with dressing. CONCLUSION: We have used BITA in 95% of our unselected, consecutive off-pump CABG patients without any major wound complications. Our limited experience has shown off-pump CABG using BITA grafting can be safely adopted routinely with excellent early result. PMID- 25841773 TI - Pulse-echo method cannot measure wave attenuation accurately. AB - A number of techniques with different degrees of accuracies have been devised for the measurement of acoustic wave attenuation in solids and liquids. Still, a wide variation is observed in the attenuation values in different materials reported in the literature. Present numerical study based on a 'propagating wave' model analysis clearly shows that the attenuation constant obtained from exponential fitting of the echo heights in pulse-echo method differs from the exact value of intrinsic attenuation in the medium, even in the ideal situation of plane wave propagation without diffraction, dispersion or scattering. PMID- 25841774 TI - Highly sensitive detection of cancer antigen human epidermal growth factor receptor 2 using novel chicken egg yolk immunoglobulin. AB - Human epidermal growth factor receptor 2 (HER2) is an important biomarker that plays a crucial role in therapeutic decision-making for breast cancer patients. Ensuring the accuracy and reproducibility of HER2 assays by enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry (IHC) requires high sensitive and specific antibodies. Immunoglobulin Y (IgY) is a kind of avian antibody usually isolated from chicken egg yolks. Generation and use of IgY is of increasing interest in a wide variety of applications within the life sciences. In this study, IgY antibodies against two different truncated proteins of the extracellular domain (ECD) of human HER2 were produced, their sensitivity and specificity were evaluated. Specific IgYs were produced by hens immunized with the ECD proteins of human HER2 in long-standing immunization response and were isolated from yolks with a purity of 90% by water dilution, salt precipitations and ultrafiltration. The anti-HER2 IgYs were analytically validated for specificity by ELISA, western blot, immunocytochemistry and IHC. The IgYs bound desired targets in cells and fixed tissues and showed high affinity to HER2. The results demonstrated the viability of detection of HER2 with IgYs and showed promise for the using of IgYs in strict clinical validation. PMID- 25841775 TI - [Protection of pregnancy in the Department of Health La Fe, Valencia, 2010 to 2013]. PMID- 25841776 TI - Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes. AB - Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in nonalcoholic fatty liver disease. alpha-Lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effects of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation, and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed a high-fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP, and increased the percentage of apoptotic cells. Cotreatment with LA prevented these effects. Similar results were found in mouse hepatocytes in which LA attenuated PA mediated activation of caspase 3 and reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production and endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Cotreatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, posttreatment with LA reversed the established damage induced by PA in hepatocytes, as well as preventing obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis. PMID- 25841777 TI - Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling. AB - The kidney is vulnerable to hypoxia, and substantial efforts have been made to ameliorate renal ischemic injury secondary to pathological conditions. Stimulation of the nitrate-nitrite-nitric oxide pathway is associated with renal and cardiovascular protection in disease models, but less is known about the vascular effects during renal ischemia. This study was aimed at investigating the vascular effects of nitrite in the kidney during normoxic and ischemic conditions. Using a multiwire myograph system, we assessed nitrite-mediated relaxation (10(-9)-10(-4)mol/L) in isolated and preconstricted renal interlobar arteries from C57BL/6 mice under normal conditions (pO2 13kPa; pH 7.4) and with low oxygen tension and low pH to mimic ischemia (pO2 3kPa; pH 6.6). Xanthine oxidoreductase expression was analyzed by quantitative PCR, and production of reactive nitrogen species was measured by DAF-FM DA fluorescence. During normoxia significant vasodilatation (15+/-3%) was observed only at the highest concentration of nitrite, which was dependent on NO-sGC-cGMP signaling. The vasodilatory responses to nitrite were greatly sensitized and enhanced during hypoxia with low pH, demonstrating significant dilatation (11+/-1%) already in the physiological range (10(-8)mol/L), with a maximum response of 27+/-2% at 10( 4) mol/L. In contrast to normoxia, and to that observed with a classical NO donor (DEA NONOate), this sensitization was independent of sGC-cGMP signaling. Moreover, inhibition of various enzymatic systems reported to reduce nitrite in other vascular beds, i.e., aldehyde oxidase (raloxifene), aldehyde dehydrogenase (cyanamide), and NO synthase (L-NAME), had no effect on the nitrite response. However, inhibition of xanthine oxidoreductase (XOR; febuxostat or allopurinol) abolished the sensitized response to nitrite during hypoxia and acidosis. In conclusion, in contrast to normoxia, nitrite exerted potent vasorelaxation during ischemic conditions already at physiological concentrations. This effect was dependent on functional XOR but independent of classical downstream signaling by sGC-cGMP. PMID- 25841778 TI - COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. AB - Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX 2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS. PMID- 25841779 TI - Transforming growth factor beta-interacting factor-induced malignant progression of hepatocellular carcinoma cells depends on superoxide production from Nox4. AB - Hepatocellular carcinoma (HCC) is one of the most deadly malignancies worldwide because of its high recurrence rate, high metastatic potential, and resistance to drugs. Elucidation of the mechanisms underlying malignancy in HCC is needed to improve diagnosis, therapy, and prognosis. Previously, we showed that transforming growth factor beta-interacting factor (TGIF) antagonizes arsenic trioxide-induced apoptosis of HepG2 cells and is associated with poor prognosis and progression of urothelial carcinoma in patients after radical nephroureterectomy. To determine whether TGIF plays a role in HCC tumorigenesis, we compared the expression of TGIF, its downstream targets, and reactive oxygen species levels between HCC HepG2 cells and the more invasive SK-Hep1 cells. Superoxide production, phosphorylation of c-Src(Y416) and AKT(S473), and expression of TGIF and NADPH oxidase (Nox) were higher in invasive SK-Hep1 cells than in HepG2 cells. TGIF-overexpressing HepG2 xenograft tumors markedly promoted tumor growth and metastasis to the lungs. Overexpression of TGIF in HepG2 cells increased superoxide production from Nox4, matrix metalloproteinase expression, invadopodia formation, and cellular migration/invasion ability. Conversely, knockdown of TGIF in SK-Hep1 cells attenuated these processes. Using gene knockdown and pharmacological inhibitors, we demonstrate that c-Src/AKT is the upstream signaling that regulates TGIF-induced Nox4 activation and subsequent superoxide production. Taken together, our results implicate TGIF as a potential biomarker for prognosis and target for clinical therapy in patients with advanced HCC. PMID- 25841780 TI - Sod1 gene ablation in adult mice leads to physiological changes at the neuromuscular junction similar to changes that occur in old wild-type mice. AB - Reactive oxygen species (ROS) are believed to be important mediators of muscle atrophy and weakness in aging and many degenerative conditions. However, the mechanisms and physiological processes specifically affected by elevated ROS in neuromuscular units that contribute to muscle weakness during aging are not well defined. Here we investigate the effects of chronic oxidative stress on neurotransmission and excitation-contraction (EC) coupling mechanisms in the levator auris longus (LAL) muscle from young (4-8 months) and old (22-28 months) wild-type mice and young adult Cu-Zn superoxide dismutase 1 knockout (Sod1(-/-)) mice. The frequency of spontaneous neurotransmitter release and the amplitude of evoked neurotransmitter release in young Sod1(-/-) and old wild-type LAL neuromuscular junctions were significantly reduced from the young wild-type values, and those declines were mirrored by decreases in synaptic vesicle pool size. Presynaptic cytosolic calcium concentration and mitochondrial calcium uptake amplitudes showed substantial increases in stimulated young Sod1(-/-) and old axon terminals. Surprisingly, LAL muscle fibers from old mice showed a greater excitability than fibers from either young wild-type or young Sod1(-/-) LAL. Both evoked excitatory junction potential (EJP) and spontaneous mini EJP amplitudes were considerably higher in LAL muscles from old mice than in fibers from young Sod1(-/-) LAL muscle. Despite a greater excitability, sarcoplasmic calcium influx in both old wild-type and young Sod1(-/-) LAL muscle fibers was significantly less. Sarcoplasmic reticulum calcium levels were also reduced in both old wild-type and young Sod1(-/-) mice, but the difference was not statistically significant in muscle fibers from old wild-type mice. The protein ratio of triad calcium channels RyR1/DHPR was not different in all groups. However, fibers from both young Sod1(-/-) and old mice had substantially elevated levels of protein carbonylation and S-nitrosylation modifications. Overall, our results suggest that young Sod1(-/-) recapitulate many neuromuscular and muscle fiber changes seen in old mice. We also conclude that muscle weakness in old mice might in part be driven by ROS-mediated EC uncoupling, while both EC uncoupling and reduced neurotransmitter release contribute to muscle weakness in Sod1(-/-) mice. PMID- 25841781 TI - Peroxynitrite-mediated glyoxalase I epigenetic inhibition drives apoptosis in airway epithelial cells exposed to crystalline silica via a novel mechanism involving argpyrimidine-modified Hsp70, JNK, and NF-kappaB. AB - Glyoxalase I (Glo1) is a cellular defense enzyme involved in the detoxification of methylglyoxal (MG), a cytotoxic by-product of glycolysis, and MG-derived advanced glycation end products (AGEs). Argpyrimidine (AP), one of the major AGEs coming from MG modification of protein arginines, is a proapoptotic agent. Crystalline silica is a well-known occupational health hazard, responsible for a relevant number of pulmonary diseases. Exposure of cells to crystalline silica results in a number of complex biological responses, including apoptosis. The present study was aimed at investigating whether, and through which mechanism, Glo1 was involved in Min-U-Sil 5 crystalline silica-induced apoptosis. Apoptosis, by TdT-mediated dUTP nick-end labeling assay, and transcript and protein levels or enzymatic activity, by quantitative real-time PCR, Western blot, and spectrophotometric methods, respectively, were evaluated in human bronchial BEAS 2B cells exposed or not (control) to crystalline silica and also in experiments with appropriate inhibitors. Reactive oxygen species were evaluated by coumarin-7 boronic acid or Amplex red hydrogen peroxide/peroxidase methods for peroxynitrite (ONOO(-)) or hydrogen peroxide (H2O2) measurements, respectively. Our results showed that Min-U-Sil 5 crystalline silica induced a dramatic ONOO(-)-mediated inhibition of Glo1, leading to AP-modified Hsp70 protein accumulation that, in a mechanism involving JNK and NF-kappaB, triggered an apoptotic mitochondrial pathway. Inhibition of Glo1 occurred at both functional and transcriptional levels, the latter occurring via ERK1/2 MAPK and miRNA 101 involvement. Taken together, our data demonstrate that Glo1 is involved in the Min-U-Sil 5 crystalline silica-induced BEAS-2B cell mitochondrial apoptotic pathway via a novel mechanism involving Hsp70, JNK, and NF-kappaB. Because maintenance of an intact respiratory epithelium is a critically important determinant of normal respiratory function, the knowledge of the mechanisms underlying its disruption may provide insight into the genesis, and possibly the prevention, of a number of pathological conditions commonly occurring in silica dust occupational exposure. PMID- 25841782 TI - Zinc and calcium modulate mitochondrial redox state and morphofunctional integrity. AB - Zinc and calcium have highly interwoven functions that are essential for cellular homeostasis. Here we first present a novel real-time flow cytometric technique to measure mitochondrial redox state and show it is modulated by zinc and calcium, individually and combined. We then assess the interactions of zinc and calcium on mitochondrial H2O2 production, membrane potential (DeltaPsim), morphological status, oxidative phosphorylation (OXPHOS), complex I activity, and structural integrity. Whereas zinc at low doses and both cations at high doses individually and combined promoted H2O2 production, the two cations individually did not alter mitochondrial redox state. However, when combined at low and high doses the two cations synergistically suppressed and promoted, respectively, mitochondrial shift to a more oxidized state. Surprisingly, the antioxidants vitamin E and N acetylcysteine showed pro-oxidant activity at low doses, whereas at high antioxidant doses NAC inhibited OXPHOS and dyscoupled mitochondria. Individually, zinc was more potent than calcium in inhibiting OXPHOS, whereas calcium more potently dissipated the DeltaPsim and altered mitochondrial volume and ultrastructure. The two cations synergistically inhibited OXPHOS but antagonistically dissipated DeltaPsim and altered mitochondrial volume and morphology. Overall, our study highlights the importance of zinc and calcium in mitochondrial redox regulation and functional integrity. Importantly, we uncovered previously unrecognized bidirectional interactions of zinc and calcium that reveal distinctive foci for modulating mitochondrial function in normal and disease states because they are potentially protective or damaging depending on conditions. PMID- 25841783 TI - Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich's ataxia. AB - Friedreich's ataxia is the most important recessive ataxia in the Caucasian population. Loss of frataxin expression affects the production of iron-sulfur clusters and, therefore, mitochondrial energy production. One of the pathological consequences is an increase of iron transport into the mitochondrial compartment leading to a toxic accumulation of reactive iron. However, the mechanism underlying this inappropriate mitochondrial iron accumulation is still unknown. Control and frataxin-deficient flies were fed with an iron diet in order to mimic an iron overload and used to assess various cellular as well as mitochondrial functions. We showed that frataxin-deficient flies were hypersensitive toward dietary iron and developed an iron-dependent decay of mitochondrial functions. In the fly model exhibiting only partial frataxin loss, we demonstrated that the inability to activate ferritin translation and the enhancement of mitochondrial iron uptake via mitoferrin upregulation were likely the key molecular events behind the iron-induced phenotype. Both defects were observed during the normal process of aging, confirming their importance in the progression of the pathology. In an effort to further assess the importance of these mechanisms, we carried out genetic interaction studies. We showed that mitoferrin downregulation improved many of the frataxin-deficient conditions, including nervous system degeneration, whereas mitoferrin overexpression exacerbated most of them. Taken together, this study demonstrates the crucial role of mitoferrin dysfunction in the etiology of Friedreich's ataxia and provides evidence that impairment of mitochondrial iron transport could be an effective treatment of the disease. PMID- 25841784 TI - Influence of vitamin C and vitamin E on redox signaling: Implications for exercise adaptations. AB - The exogenous antioxidants vitamin C (ascorbate) and vitamin E (alpha-tocopherol) often blunt favorable cell signaling responses to exercise, suggesting that redox signaling contributes to exercise adaptations. Current theories posit that this antioxidant paradigm interferes with redox signaling by attenuating exercise induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. The well-documented in vitro antioxidant actions of ascorbate and alpha-tocopherol and characterization of the type and source of the ROS/RNS produced during exercise theoretically enable identification of redox-dependent mechanisms responsible for the blunting of favorable cell signaling responses to exercise. This review aimed to apply this reasoning to determine how the aforementioned antioxidants might attenuate exercise-induced ROS/RNS production. The principal outcomes of this analysis are (1) neither antioxidant is likely to attenuate nitric oxide signaling either directly (reaction with nitric oxide) or indirectly (reaction with derivatives, e.g., peroxynitrite); (2) neither antioxidant reacts appreciably with hydrogen peroxide, a key effector of redox signaling; (3) ascorbate but not alpha-tocopherol has the capacity to attenuate exercise-induced superoxide generation; and (4) alternate mechanisms, namely pro oxidant side reactions and/or reduction of bioactive oxidized macromolecule adducts, are unlikely to interfere with exercise-induced redox signaling. Out of all the possibilities considered, ascorbate-mediated suppression of superoxide generation with attendant implications for hydrogen peroxide signaling is arguably the most cogent explanation for blunting of favorable cell signaling responses to exercise. However, this mechanism is dependent on ascorbate accumulating at sites rich in NADPH oxidases, principal contributors to contraction-mediated superoxide generation, and outcompeting nitric oxide and superoxide dismutase isoforms. The major conclusions of this review are: (1) direct evidence for interference of ascorbate and alpha-tocopherol with exercise induced ROS/RNS production is lacking; (2) theoretical analysis reveals that both antioxidants are unlikely to have a major impact on exercise-induced redox signaling; and (3) it is worth considering alternate redox-independent mechanisms. PMID- 25841785 TI - Reactivity of selenium-containing compounds with myeloperoxidase-derived chlorinating oxidants: Second-order rate constants and implications for biological damage. AB - Hypochlorous acid (HOCl) and N-chloramines are produced by myeloperoxidase (MPO) as part of the immune response to destroy invading pathogens. However, MPO also plays a detrimental role in inflammatory pathologies, including atherosclerosis, as inappropriate production of oxidants, including HOCl and N-chloramines, causes damage to host tissue. Low molecular mass thiol compounds, including glutathione (GSH) and methionine (Met), have demonstrated efficacy in scavenging MPO-derived oxidants, which prevents oxidative damage in vitro and ex vivo. Selenium species typically have greater reactivity toward oxidants compared to the analogous sulfur compounds, and are known to be efficient scavengers of HOCl and other hypohalous acids produced by MPO. In this study, we examined the efficacy of a number of sulfur and selenium compounds to scavenge a range of biologically relevant N-chloramines and oxidants produced by both isolated MPO and activated neutrophils and characterized the resulting selenium-derived oxidation products in each case. A dose-dependent decrease in the concentration of each N-chloramine was observed on addition of the sulfur compounds (cysteine, methionine) and selenium compounds (selenomethionine, methylselenocysteine, 1,4-anhydro-4-seleno L-talitol, 1,5-anhydro-5-selenogulitol) studied. In general, selenomethionine was the most reactive with N-chloramines (k2 0.8-3.4*10(3)M(-1) s(-1)) with 1,5 anhydro-5-selenogulitol and 1,4-anhydro-4-seleno-L-talitol (k2 1.1-6.8*10(2)M(-1) s(-1)) showing lower reactivity. This resulted in the formation of the respective selenoxides as the primary oxidation products. The selenium compounds demonstrated greater ability to remove protein N-chloramines compared to the analogous sulfur compounds. These reactions may have implications for preventing cellular damage in vivo, particularly under chronic inflammatory conditions. PMID- 25841786 TI - Long-term effects of prenatal stress and diazepam on D2 receptor expression in the nucleus accumbens of adult rats. AB - Early life stress during the gestational period alters specific neuronal circuits leading to behavioral alterations later in life. In the present study, we assessed the effects of prenatal stress and repeated benzodiazepine administration on dopamine receptor 2 expression in the nucleus accumbens of adult offspring. Our results show elevated Drd2 expression levels in the nucleus accumbens (NAcc) of prenatally stressed rats compared to control subjects, while repeated diazepam administration in adulthood down-regulated Drd2 expression and prevented the effect of prenatal stress. These observations suggest that prenatal stress may induce permanent alterations in the corticolimbic pathway implicated in drug-seeking behavior. PMID- 25841787 TI - 5-HT1B and other related serotonergic proteins are altered in APPswe mutation. AB - Serotonergic dysfunction is implicated in Alzheimer's disease (AD). In addition, reductions in brain of both monoamine synthesis and release have been reported. Serotonin 1B receptors (5-HT1B), along with serotonin transporter (SERT) are among the regulators of extracellular 5-HT levels. We investigated the effect of the familial AD APP (Amyloid precursor protein) K670N/M671L double mutation, APP Swedish mutation (APPswe), on the expression of 5-HT1B, SERT, MAOA, p11 and 5-HT and its metabolite 5-HIAA in SH-SY5Y human neuroblastoma cell line stably transfected with APPswe mutation. In addition, hippocampal expressions of 5-HT1B and SERT were assessed in wild type and transgenic mice expressing APPswe mutation (Tg2576) at different age groups. We found a reduction of 5-HT1B as well as SERT in both APPswe in vitro and ex vivo. P11 and 5HT were also reduced, whereas 5HT turnover and MAOA were increased. Our results indicate that APPswe induced decreased 5-HT1B expression and 5-HT release, as well as increased MAOA activity and 5-HT breakdown. Further studies to explore the detailed mechanism behind reduced 5-HT1B and SERT in AD and their clinical implications are needed. PMID- 25841788 TI - A bout of treadmill exercise increases matrix metalloproteinase-9 activity in the rat hippocampus. AB - Regular exercise induces a variety of structural changes in the hippocampus of rodents, although the underlying mechanisms remain obscure. Particularly, the possible involvement of molecules regulating the remodeling of the extracellular matrix (ECM) is under-studied. Matrix metalloproteinase-9 (MMP-9), an extracellular protease, plays a critical role in regulating neuronal plasticity by remodeling the ECM in the brain. The current study used gel zymography to examine for changes in the proteolytic activity of MMP-9 in the rat hippocampus following a bout of treadmill exercise at mild (10m/min) or moderate (25m/min) intensity. We found that MMP-9 activity was significantly increased at 12h after mild treadmill exercise. However, the activity of MMP-2 and the expression level of the tissue inhibitor of metalloproteinase-1 (TIMP-1) were unchanged following exercise. These findings suggest that exercise triggers MMP-9 activation in the hippocampus, which might be a new molecular mechanism of exercise-induced hippocampal plasticity. PMID- 25841789 TI - Hyperactivity and disruption of prepulse inhibition induced by NMDA infusion of the rat ventral hippocampus: Comparison of uni- and bilateral stimulation. AB - Numerous studies have demonstrated that NMDA stimulation of the rat ventral hippocampus induces hyperactivity and disruption of prepulse inhibition (PPI) and some reports have provided insights into the different neural substrates of these two effects. Bilateral or unilateral NMDA stimulation have been applied in these studies, but have never been compared directly. Thus, results of these studies can be related to each other only with reservations. Therefore - given the substantial interest in the behavioral effects of hippocampal overactivity and the neural substrates underlying PPI with respect to schizophrenia - the present experiments compared hyperactivity and PPI disruption following uni- or bilateral NMDA stimulation of the ventral hippocampus. Both bilateral and unilateral infusion of NMDA (0.5MUg/0.5MUl/side) induced hyperactivity in the open field and disrupted PPI. The major difference noted between unilateral and bilateral infusions was that the effects of bilateral infusions were stronger than those of the unilateral infusions. PMID- 25841790 TI - Irisin: A myokine with locomotor activity. AB - The mechanisms underlying alterations in brain functions in response to physical exercise are not fully understood. The present study examined the central effect of irisin, a 112 amino acid polypeptide hormone secreted from the skeletal muscle after exercise, on the locomotion in rats. Central administration of irisin significantly increased the locomotion. Relative to control animals treated with IgG Fc peptide, rats receiving irisin demonstrated a marked increase in total travel distance, ambulatory counts and time, and vertical counts and time. These changes were associated with a significant decrease in resting time. Central treatment of irisin also induced significant increases in oxygen consumption, carbon dioxide production and heat production, indicating an increase in metabolic activity. Our study suggests that physical activity may signal to the central nervous system to coordinate locomotion with metabolic activity via irisin. PMID- 25841791 TI - The effect of carmustine on Bergmann cells of the cerebellum. AB - Administration of the alkylating agent carmustine to pregnant mice induces hyperlocomotion in the offspring. Motor performance was evaluated by the rotarod task, which revealed that these animals have diminished Grab Frequency and a higher Performance Index, whereas Error of Latency and Latency to Fall were unaffected. Considering the recently revealed role of Bergmann cells of cerebellum in the control of motor activity, we used the transgenic mice GFAP-GFP to explore the impact of carmustine on the organization of these glial cells. Multiple examples of cell layer disorganization were detected; many soma of Bergmann cells were displaced to the external cell layer, and their processes were not well defined until young adulthood. In addition, the roof of the fourth ventricle was convoluted. These observations suggest that the exacerbated locomotion induced by carmustine may be due, in part, to the altered organization of the cell layers of cerebellum. PMID- 25841792 TI - Histidine decarboxylase knockout mice, a genetic model of Tourette syndrome, show repetitive grooming after induced fear. AB - Tics, such as are seen in Tourette syndrome (TS), are common and can cause profound morbidity, but they are poorly understood. Tics are potentiated by psychostimulants, stress, and sleep deprivation. Mutations in the gene histidine decarboxylase (Hdc) have been implicated as a rare genetic cause of TS, and Hdc knockout mice have been validated as a genetic model that recapitulates phenomenological and pathophysiological aspects of the disorder. Tic-like stereotypies in this model have not been observed at baseline but emerge after acute challenge with the psychostimulant d-amphetamine. We tested the ability of an acute stressor to stimulate stereotypies in this model, using tone fear conditioning. Hdc knockout mice acquired conditioned fear normally, as manifested by freezing during the presentation of a tone 48h after it had been paired with a shock. During the 30min following tone presentation, knockout mice showed increased grooming. Heterozygotes exhibited normal freezing and intermediate grooming. These data validate a new paradigm for the examination of tic-like stereotypies in animals without pharmacological challenge and enhance the face validity of the Hdc knockout mouse as a pathophysiologically grounded model of tic disorders. PMID- 25841793 TI - Markers related to the diagnosis and to the risk of abortion in bovine neosporosis. AB - Bovine neosporosis has emerged as a main cause of abortion in cattle worldwide. An important question to understand the disease is why not all infected cows abort. In the present review we summarize the knowledge on markers related to the diagnosis and more importantly to the risk of abortion in the infected cow. Markers considered herein include those based on specific antibodies, antibody titers and antibody subtypes, cellular immunological markers, hormones and other proteins related to gestation. The identification of parasite molecules that are specifically identified in the aborting cows might help to understand the mechanism of parasite-associated abortion and control the disease. PMID- 25841794 TI - Localised mitogenic activity in horses following infection with Streptococcus equi. AB - Streptococcus equi subspecies equi (S. equi) is the causative agent of strangles, a highly contagious upper respiratory disease of equids. Streptococcus equi produces superantigens (sAgs), which are thought to contribute to strangles pathogenicity through non-specific T-cell activation and pro-inflammatory response. Streptococcus equi infection induces abscesses in the lymph nodes of the head and neck. In some individuals, some abscess material remains into the guttural pouch and inspissates over time to form chondroids which can harbour live S. equi. The aim of this study was to determine the sites of sAg production during infection and therefore improve our understanding of their role. Abscess material, chondroids and serum collected from Equidae with signs of strangles were tested in mitogenic assays. Mitogenic sAg activity was only detected in abscess material and chondroids. Our data support the localised in vivo activity of sAg during both acute and carrier phases of S. equi infection. PMID- 25841795 TI - UCP1 and UCP2 expression in different subcutaneous and visceral adipose tissue deposits in 30 days old goat kids and effect of fatty acid enriched diets. AB - Beside its importance in the first hours of life, brown adipose tissue has also significant roles in the following stages of growth and in adults by regulating energy metabolism, but its identification in adult ruminants is still controversial. Quantitative PCR, followed by histological confirmation, was used to investigate UCP expression and brown and white adipocytes' distribution in 30 day-old goat kids. The influence of maternal diet enriched with either fish oil or stearic acid was investigated as well. Results showed the differential expression of both UCP1 and UCP2 genes between subcutaneous and visceral adipose tissues, suggesting a different thermogenic activity between the two macro areas. The maternal diet influenced neither UCP1 nor UCP2 gene expression. The presence of multilocular adipocytes in 1-month goat kids is remarkable, as suggests thermogenic activity in non-newborn animals. Further insights into characteristics and functions of adipose tissue in young and adult goats are worth exploring. PMID- 25841796 TI - Urinary cotinine levels and environmental tobacco smoke in mothers and children of Romania, Portugal and Poland within the European human biomonitoring pilot study. AB - The aim of this study was to explore data from the DEMOCOPHES study population for Romania, Portugal and Poland, in order to assess smoking patterns and the extent of ETS exposure and compare the national study samples with reference to the respective anti-smoking laws. The subset of the DEMOCOPHES study sample consisted of 360 children and their mothers (120 in each of the three countries - Romania (RO), Portugal (PT) and Poland (PL). Smoking was assessed using a detailed questionnaire for the participants, which addresses both active and passive smoking. This assessment uses exposure-relevant questionnaire data, in particular on the home environment and residence, socio-demographic characteristics, lifestyle such as nutrition, smoking behavior, other exposure relevant behavior and occupational history, as well as urinary cotinine and creatinine measurements. We performed general statistical analysis and innovative receiver operating characteristic (ROC) curve analyses. Smoking prevalence as evaluated by the questionnaire was generally high, and higher than official statistics, which suggests some under-reporting in the countries, particularly in Romania. Urinary cotinine levels provided biochemical confirmation of the high and similar smoking prevalence for the three countries. Concerning ETS exposure, Romania presented significantly higher levels, for children as well as for non smoking mothers, with Portugal showing significantly lower levels. Compared to non-smoking mothers, the children showed relatively higher ETS exposure levels in all three countries. The established country-specific optimal cut-off values in urinary cotinine to distinguish smokers from non-smokers vary more than those to discriminate ETS exposure extent in non-smoking mothers and children. Although different between countries, these values are a valuable output to monitor effectiveness of both national antismoking laws and educational programs in the three countries. The findings of this study point to the urgent need for stronger, more effective and well enforced smoke-free legislation in the three countries. PMID- 25841797 TI - Contralateral targeting of the corpus callosum in normal and pathological brain function. AB - The corpus callosum connects the two cortical hemispheres of the mammalian brain and is susceptible to structural defects during development, which often result in significant neuropsychological dysfunction. To date, such individuals have been studied primarily with regards to the integrity of the callosal tract at the midline. However, the mechanisms regulating the contralateral targeting of the corpus callosum, after midline crossing has occurred, are less well understood. Recent evidence suggests that defects in contralateral targeting can occur in isolation from midline-tract malformations, and may have significant functional implications. We propose that contralateral targeting is a crucially important and relatively under-investigated event in callosal development, and that defects in this process may constitute an undiagnosed phenotype in several neurological disorders. PMID- 25841798 TI - Idiosyncratic connectivity in autism: developmental and anatomical considerations. AB - Hahamy and colleagues demonstrate individualized alterations of functional connectivity in the brains of adults with autism, suggesting that previous characterizations of general under- or over-connectivity may be overly simplistic. Adopting a developmental perspective spanning both cortical and subcortical landscapes will further clarify the nature and extent of these atypicalities. PMID- 25841799 TI - The response of Paracoccidioides spp. to nitrosative stress. AB - Paracoccidioidomycosis (PCM) is an endemic disease in Latin America caused by species belonging to the genus Paracoccidioides. During infection, immune cells present a variety of defense mechanisms against pathogens. One of these defensive strategies is the production and release of nitric oxide (NO) and S-nitroso thiols (e.g., S-nitrosoglutathione, GSNO), which produce reactive nitrogen species (RNS). This results in damage to DNA and membranes, inhibition of respiration and inactivation of cellular enzymes. In response to nitrosative stress, human pathogenic fungi possess defense mechanisms to prevent the adverse effects of NO, which helps them survive during initial contact with the host immune system. To understand how Paracoccidioides spp. respond to nitrosative stress, we conducted this study to identify genes and proteins that might contribute to this response. The results of proteomic analysis demonstrated that nitrosative stress induced a reduction in the expression of proteins related to the mitochondrial electron transport chain. This hypothesis was supported by the reduced mitochondrial activity observed in the presence of GSNO. Additionally, lipids and branched chain amino acid metabolism enzymes were altered. The role played by enzymes acting in oxidative stress in the RNS response was remarkable. This interface among enzymes acting in both stress responses was confirmed by using a RNA approach to silence the ccp gene in Paracoccidioides. It was observed that mutants with low expression of the ccp gene were more sensitive to nitrosative stress. PMID- 25841801 TI - Subaxial cervical spine involvement in symptomatic rheumatoid arthritis patients: Comparison with cervical spondylosis. AB - OBJECTIVE: To investigate the frequency, location, characteristics, and clinical significance of subaxial involvement (below C1-C2) in a series of patients with rheumatoid arthritis (RA) and symptomatic involvement of the cervical spine. METHODS: A total of 41 patients with RA were examined via cervical spine magnetic resonance imaging (MRI). A comparative analysis of the incidence of the different types of subaxial lesions was performed between these patients and 41 age- and sex-matched patients with symptomatic cervical spondylosis. RESULTS: Stenosis of the spinal canal was found at the subaxial level in 85% of RA patients, and at the atlantoaxial level in 44%. Comparative analysis between these patients and the cervical spondylosis patients revealed significant differences in the types and frequencies of subaxial lesions. For both conditions, signs of discopathy and end-plate osteophytosis were the most common abnormalities observed on magnetic resonance imaging (MRI). However, in the RA patients these abnormalities coincided with subchondral bone and ligamentous acute inflammatory changes and with secondary destruction (vertebral instability) or repair (vertebral ankyloses). Only evidence of subaxial myelopathy was significantly associated with an increased risk of neurological dysfunction among the RA patients [Ranawat class II or III; P = 0.01; odds ratio (OR) = 11.43], although subaxial cord compression tended toward a significant association with the risk of neurological dysfunction (P = 0.06; OR = 3.95). CONCLUSION: Subaxial stenosis seems to be the consequence of both the inflammatory process and mechanical-degenerative changes. Despite its frequency, it was not usually related to the occurrence of myelopathy symptoms, not even in cases with MRI evidence of spinal cord compression. PMID- 25841800 TI - Filifactor alocis--a new emerging periodontal pathogen. AB - Filifactor alocis, a previously unrecognized Gram-positive anaerobic rod, is now considered a new emerging pathogen that may play a significant role in periodontal disease. F. alocis' unique characteristics and variations at the molecular level that may be responsible for the functional changes required to mediate the pathogenic process are discussed. PMID- 25841802 TI - Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab. AB - OBJECTIVE: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are systemic, necrotizing, small-vessel vasculitis associated with circulating anti-neutrophil cytoplasmic autoantibodies (ANCA), and thus called ANCA-associated vasculitides (AAV). The aim of the present study is to evaluate a potential role of interleukin (IL)-6 and its pathway in the pathogenesis of AAV and to review previous evidence of IL-6 in MPA and GPA. METHODS: Blood and histological samples from 10 untreated myeloperoxidase (MPO)-ANCA/proteinase 3 (PR3)-ANCA-positive patients with active AAV were studied. Serum levels of cytokines/chemokines were evaluated by means of a Bio-Plex Multiple Cytokine Assay. IL-6 production at sites of active vasculitis was assessed by means of both immunohistochemistry and in situ hybridization techniques. We also treated a patient with MPA who was resistant or allergic to conventional treatments with a 12-month course of the IL-6 inhibitor tocilizumab and followed him up for 24 additional months. We also reviewed all the published cases in the English literature of histologically confirmed MPA or GPA, in which elevated IL-6 serum levels or intralesional IL-6 expression were reported. RESULTS: IL-6 serum levels were significantly increased in patients with AAV as compared to controls (median = 51.96pg/mL; range: 34.11-84.30; versus 0.68pg/mL; range: 0.01-1.81; P < 0.005). Also, IL-6 was expressed and produced at sites of active vasculitis. Treatment with tocilizumab was able to induce a complete and sustained disease remission in a patient with severe multisystemic MPA, as well as normalization of circulating levels of IL-6-associated pro-inflammatory cytokines and chemokines. Previous evidence of IL-6 pathway activation in AAV is scarce. Increased serum levels of IL-6 were reported in seven clinical studies for a total of approximately 120 patients, mainly affected by GPA. CONCLUSION: The finding of an activated IL-6 pathway in patients with AAV, together with the observed effects of tocilizumab monotherapy, provides evidence for a possible central role of IL-6 in the pathogenesis of AAV and suggests its targeting as a potential treatment. PMID- 25841803 TI - 50th Anniversary Perspective on Groves LK. Carcinoma of the Esophagus-1965: evaluation of treatment. Ann Thorac Surg 1965;1:416-31. PMID- 25841804 TI - 50th Anniversary Landmark Commentary on Pearson FG, Andrews MJ. Detection and management of tracheal stenosis following cuffed tube tracheostomy. Ann Thorac Surg 1971;12:359-74. PMID- 25841805 TI - 50th Anniversary Landmark Commentary on Ross DN. The replacement of the aortic valve with biological tissue. Ann Thorac Surg 1968;5:383-92. PMID- 25841806 TI - 50th Anniversary Landmark Commentary on Gay WA. Potassium-induced cardioplegia. Ann Thorac Surg 1975;20:95-100. PMID- 25841807 TI - Invited commentary. PMID- 25841808 TI - Invited commentary. PMID- 25841809 TI - Invited commentary. PMID- 25841810 TI - Invited commentary. PMID- 25841811 TI - Invited commentary. PMID- 25841812 TI - Invited commentary. PMID- 25841813 TI - Invited commentary. PMID- 25841814 TI - Invited commentary. PMID- 25841815 TI - Invited commentary. PMID- 25841816 TI - Invited commentary. PMID- 25841817 TI - Invited commentary. PMID- 25841818 TI - Invited commentary. PMID- 25841819 TI - Invited commentary. PMID- 25841821 TI - Invited commentary. PMID- 25841820 TI - Development of off-pump mitral valve replacement in a porcine model. AB - PURPOSE: We describe our initial experience with on-bypass and off-bypass (off pump) mitral valve replacement with the modified version of our novel catheter based sutureless mitral valve (SMV) technology, which was developed to atraumatically anchor and seal in the mitral position. DESCRIPTION: The SMV is a self-expanding device consisting of a custom designed nitinol framework and a pericardial leaflet valve mechanism. For the current studies, our original device was modified (SMV2) to reduce the delivery profile and to allow for controlled deployment while still maintaining the key principles necessary for atraumatic anchoring and sealing in the mitral valve position. EVALUATION: Ten Yorkshire pigs underwent successful SMV2 device implantation through a left atriotomy (on pump, n = 6; off-pump, n = 4). Echocardiography and angiography revealed excellent left ventricular systolic function, no significant perivalvular leak, no mitral valve stenosis, no left ventricular outflow tract obstruction, and no aortic valve insufficiency. Postmortem examination demonstrated that the SMV2 devices were anchored securely. CONCLUSIONS: This study demonstrates the feasibility and short-term success of off-pump mitral valve replacement using a novel, catheter-based device in a porcine model. PMID- 25841822 TI - Cadaveric nerve allotransplantation in the treatment of persistent thoracic neuralgia. AB - When relief from neuralgia cannot be achieved with traditional methods, neurectomy may be considered to abate the stimulus, and primary opposition of the terminal nerve ending is recommended to prevent neuroma. Nerve repair with autograft is limited by autologous nerves available for large nerve defects. Cadaveric allografts provide an unlimited graft source without donor-site morbidities, but are rapidly rejected unless appropriate immunosuppression is achieved. An optimal treatment method for nerve allograft transplantation would minimize rejection while simultaneously permitting nerve regeneration. This report details a novel experience of nerve allograft transplantation using cadaveric nerve grafts to desensitize persistent postoperative thoracic neuralgia. PMID- 25841823 TI - Modified thoracoplasty using a breast implant to obliterate an infected pleural space: an alternative to traditional thoracoplasty. AB - Thoracoplasty is a technique used to obliterate residual intrapleural spaces after lung resection for infection or other causes. It involves multiple osteotomies on several ribs and then collapsing them into the space to be obliterated; however, this results in a distorted and asymmetrical chest wall. We report a case of a 34-year-old female with completely destroyed right upper lobe secondary to chronic Aspergillus infection. She underwent a completion right upper lobectomy and modified thoracoplasty with the use of a breast implant to obliterate the residual pleural space without any distortion of the chest wall, with an excellent outcome. PMID- 25841824 TI - Intrapulmonary gallstone. AB - An octogenarian presented to her primary care physician with hemoptysis and a disabling chronic cough that developed several months after a complicated partial cholecystectomy. During investigation, a biopsy sample showed a right lower lobe inflammatory mass containing bile pigment and abundant neutrophils. Thoracotomy performed approximately 18 months after symptom onset confirmed a right lower lobe lung abscess together with a large gallstone embedded at its center and a healed defect in the right hemidiaphragm. A wedge excision of this mass was performed. The patient made an excellent uncomplicated recovery from this rare complication of a gallbladder operation. PMID- 25841825 TI - Three-port thoracoscopic middle lobectomy in a patient after left pneumonectomy. AB - Lung lobectomy after contralateral pneumonectomy is a challenging procedure associated with high morbidity and mortality. To date, only limited evidence has been available, and adequate indication or surgical approach remain unclear. We herein report a successful case of thoracoscopic lobectomy in a single-lung patient. A 63-year-old man, who had a history of left pneumonectomy for lung cancer, was found to have an abnormal opacity in the right middle zone at a health checkup 13 years after the previous operation. This nodule was later diagnosed as squamous cell cancer (cT2N0M0, stage IB) and surgical resection was considered. Thoracoscopic middle lobectomy with D1 lymph node dissection was performed for this patient under selective ventilation of the right upper and lower lobes. Postoperative course was uneventful and he was discharged on postoperative day 7, requiring no oxygen. The patient is doing well with no evidence of recurrence for 5 years. Given the lower invasiveness, thoracoscopic lobectomy under the selective ventilation of residual lobes could be an option after contralateral pneumonectomy in selected patients. PMID- 25841826 TI - Pneumocephalus and chylothorax complicating vertebrectomy for lung cancer. AB - Pneumocephalus is a rare, but potentially fatal complication of thoracic surgery. We describe a case of successful management of pneumocephalus complicated by persistent chylothorax developing after en bloc partial vertebrectomy performed after induction chemoradiotherapy for lung cancer invading the spine. Surgical treatment should be considered for pneumocephalus complicated by any condition requiring persistent chest drainage. PMID- 25841827 TI - Long-term survival after pneumonectomy for primary pulmonary malignant melanoma. AB - As few as 30 cases of primary malignant melanoma of the lung have been reported in the literature. Many patients die within months of diagnosis; few published cases describe patients who survive long-term after treatment. We report a case of primary pulmonary malignant melanoma in a patient who remains disease-free 60 months after pneumonectomy. PMID- 25841828 TI - Endoluminal suturing of an anastomotic leak. AB - An anastomotic leak can be one of the most morbid and complex complications after esophagectomy. Typically, management can entail repair, stenting, or diversion. The leak complicates a patient's postoperative course and delays initiation of any adjuvant therapy. Novel minimally invasive tools created to expedite healing of the anastomotic leak may potentially limit additional procedures traditionally used to treat the leak. We present the case of a 49-year-old man who sustained an anastomotic leak 5 days after undergoing esophagectomy for cancer. He was initially managed with drainage, and when this failed, he was transferred to our hospital. An endoscopic suturing device was used to close the leak and pexy a partially covered self-expanding metal stent that was left in place for 2 weeks. At the end of 2 weeks, the leak healed and there was no stent migration. PMID- 25841829 TI - Delayed presentation of nitroprusside-induced cyanide toxicity. AB - Cyanide toxicity is a rare complication of sodium nitroprusside that can be difficult to diagnose in critically ill patients. We describe a case of cyanide toxicity after cardiac surgery that presented as lactic acidosis after discontinuation of nitroprusside. PMID- 25841830 TI - Late surgical explantation and aortic valve replacement after transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) in patients with bicuspid aortic valve disease is associated with higher rates of paravalvular aortic regurgitation, which may require subsequent surgical correction. We report a case of successful late surgical CoreValve explantation 1,389 days after TAVI in a patient with bicuspid aortic valve stenosis and McArdle's disease who developed severe paravalvular aortic regurgitation. We confirm that neoendothelialization and incorporation of the nitinol cage into the aortic wall had occurred at nearly 4 years postimplantation, although explantation with careful endarterectomy could still be performed without requiring simultaneous aortic root replacement. PMID- 25841831 TI - Resolution of heart block after surgical correction of failed transcatheter aortic valve implantation. AB - Surgical aortic valve replacement is the gold standard therapy for severe aortic stenosis but transcatheter aortic valve implantation (TAVI) is increasingly employed in "high-risk" patients. Atrioventricular block and aortic regurgitation are frequent complications of nitinol-based stented valves. We report a case of successful, but complex reoperative surgery 13 days after failed TAVI with iatrogenic aortic and mitral regurgitation and new-onset heart block. Removal of a CoreValve prosthesis (Medtronic Inc, Minneapolis, MN) with standard aortic valve replacement resulted in restoration of sinus rhythm and valvular competencies. PMID- 25841832 TI - Transcatheter mitral "valve-in-ring" implantation: a word of caution. AB - Transcatheter mitral valve-in-valve and valve-in-ring procedures have emerged as a potential alternative for patients with failed mitral bioprosthesis or mitral valve repair who are at very high or prohibitive surgical risk. However, transcatheter mitral valve-in-ring implantation (TMViRI) remains a challenging procedure, partially because of the oval shape of mitral rings, which may lead to prosthesis dysfunction when the ring is not able to adopt the circular shape of the transcatheter valve. We present a case of failed TMViRI in a dysfunctional mitral homograft. The potential factors leading to procedural failure are discussed. PMID- 25841833 TI - Intraoperative coronary artery dissection in fibromuscular dysplasia. AB - A 61-year-old woman with bicuspid aortic stenosis, an ascending aortic aneurysm, and a remote history of renal fibromuscular dysplasia underwent aortic root replacement complicated by extensive dissection of the left circumflex artery extending retrograde into the left anterior descending artery. This was managed by coronary artery bypass grafting, left ventricular support, and percutaneous coronary intervention for propagation of the dissection. This case highlights the prevalence, diagnosis, and management of intraoperative coronary dissection secondary to fibromuscular dysplasia. PMID- 25841834 TI - Reverse frozen elephant trunk procedure for rescue of a thoracic stent-graft in the false lumen. AB - Thoracic endovascular aortic repair (TEVAR) is now a common treatment for patients with descending aortic disease, including aortic dissection. As the indications for TEVAR have expanded, so has the complexity of complications. Retrograde aortic dissection may occur in 1% to 2% of patients after TEVAR. We present a patient who initially underwent TEVAR for a degenerative aneurysm followed by a proximal stent-graft extension for retrograde dissection that failed because of malposition within the false lumen. We performed a hybrid reverse frozen elephant trunk (RFET) operation as a salvage procedure for these complications. PMID- 25841835 TI - Thoracic endovascular aortic repair after iatrogenic aortic dissection and false lumen stent grafting. AB - Iatrogenic aortic dissections are a severe complication after thoracic endovascular aortic repair, and treatment guidelines do not exist. Herein, we report a patient who experienced an iatrogenic type B aortic dissection during elective thoracic endovascular aortic repair and suggest an interventional treatment option. PMID- 25841836 TI - Impaled aorta: a rare case of aortic perforation with a vertebral outgrowth. AB - We describe an unusual case of aortic perforation by a vertebral osteophyte, complicated by a mycotic pseudoaneurysm, in a patient who underwent successful repair. To our knowledge, no similar case has been reported previously. PMID- 25841837 TI - Bilateral thoracic impalement through mediastinum. PMID- 25841838 TI - Successful closure of postoperative esophagobronchial fistula with amplatzer vascular plug. PMID- 25841839 TI - Redo mitral valve replacement in patient with "coconut atrium". PMID- 25841840 TI - Successful endovascular treatment of a large azygos vein aneurysm with stent graft implantation. PMID- 25841841 TI - A 3-step therapeutic strategy for severe alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of lipoproteinaceous material in the terminal airways. Whole lung lavage (WLL) remains the gold standard treatment but may be particularly challenging in cases of severe hypoxemia. We present a 3-step strategy that was used in a patient with PAP-associated refractory hypoxemia and that combined venovenous extracorporeal membrane oxygenation (vvECMO), double-lumen orotracheal intubation, and bilateral multisegmental sequential lavage (MSL). The procedure was well tolerated and permitted weaning from the ventilator. PMID- 25841842 TI - Novel T-shaped linear-stapled intrathoracic esophagogastric anastomosis for minimally invasive Ivor Lewis esophagectomy. AB - We report a novel T-shaped linear-stapled intrathoracic esophagogastric anastomosis for minimally invasive Ivor Lewis esophagectomy. A unique feature of this technique is a "gastric pouch" that is preserved proximal to the gastric conduit and which serves as the stapler-firing pathway to protect the gastric conduit. The linear stapler is placed through an auxiliary port in the seventh intercostal space on the right posterior axillary line and fired along the longitudinal axis of the thorax, without being constrained by limited intrathoracic space. This technique, which has been performed in 8 patients, is efficient, reliable, and easy to perform. PMID- 25841843 TI - First beating-heart valve-sparing aortic root repair: a "corset" technique. AB - We present our preliminary experience with beating-heart aortic root remodeling using an external "corset," which we performed in 2 patients with aortic insufficiency and aortic root dilatation. Standard extracorporeal circulation (ECC) was used. After a meticulous dissection of the aortic root and ascending aorta, the bespoke vascular prosthesis was placed around the vessel to decrease its diameter and restore aortic valve function. Postoperative angiographic computed tomography (CT) showed a significant decrease in the diameter of the wrapped aorta. Echocardiography performed 12 months after the operation showed normal aortic valve function with trivial regurgitation and stable aortic diameter in both patients. PMID- 25841844 TI - Repair of unilateral absence of right pulmonary artery with contralateral pulmonary artery autograft interposition in an infant. AB - Unilateral absence of the pulmonary artery (PA) is a rare congenital abnormality. Although a traditional 2-stage approach with a preceding systemic-to-PA shunt followed by a definitive repair is mandatory in patients with absent extrapericardial pulmonary arteries, more creative solutions are necessary when 1 stage repair is concerned. We present a novel technique for repairing the absent intrapericardial right pulmonary artery (RPA) with a contralateral PA autograft segment interposition. We believe that this technique using solely autologous tissue is effective in patients in whom the intrapericardial segment of the PAs is absent. PMID- 25841845 TI - Management of esophageal small cell carcinoma. PMID- 25841846 TI - Combined heart-liver transplantation experience and improved organ utilization. PMID- 25841847 TI - Reply: To PMID 25069688. PMID- 25841848 TI - Mitral valve repair for ischemic mitral regurgitation: should we be targeting the papillary muscles?--letter 1. PMID- 25841849 TI - Mitral valve repair versus replacement for ischemic mitral regurgitation: controversy remains alive - letter 2. PMID- 25841850 TI - Reply: To PMID 24245543. PMID- 25841851 TI - Reply: To PMID 25087812. PMID- 25841852 TI - Anomalous aortic origin of the right coronary artery. PMID- 25841853 TI - Isolated unilateral absence of pulmonary artery: challenges in treatment. PMID- 25841854 TI - Esophagectomy for a rapidly progressing esophageal duplication cyst. AB - Esophageal duplication cysts are rare and frequently asymptomatic anomalies of the adult gastrointestinal tract that are often misdiagnosed in clinical practice. Identifying the unique features of esophageal duplication cysts is therefore important. We report a unique case of esophageal duplication cyst in a 52-year-old woman with rapidly progressing chest pain and dysphagia. The cyst was found to share, in part, a remarkably inflammatory and edematous inner lining with the esophagus. Enucleation was not feasible, and therefore, esophagectomy was performed. The only long-term side effect that occurred after 44 months of follow-up examinations was slight acid reflux esophagitis. PMID- 25841855 TI - An incidental pulmonary meningioma revealing an intracranial meningioma: primary or secondary lesion? AB - A 68-year-old man underwent a resection of the right middle lobe for a solitary lesion detected at computed tomography. The histologic result was suggestive for a pulmonary meningioma. Although the result of a preoperative brain computed tomography scan was negative, magnetic resonance imaging showed a skull-base meningioma. On the basis of the absence of symptoms, we decided to observe the intracranial meningioma. At 3 years of follow-up, the patient was free of recurrence and the cerebral lesion was stable. Primary pulmonary meningioma and benign meningioma metastasis share identical microscopic findings, and only a central nervous system radiologic study allows their distinction. The pulmonary lesion in our patient was classified as a meningioma metastasis. PMID- 25841856 TI - Invasive desmoplastic fibroblastoma in the chest wall. AB - Desmoplastic fibroblastoma is a rare soft tissue tumor. We present the case of a 61-year-old man with a growing chest wall tumor in the pleural cavity. After resection, the tumor was diagnosed as desmoplastic fibroblastoma. This is the first report of desmoplastic fibroblastoma occurring in the chest wall. Generally, desmoplastic fibroblastoma is considered as a benign and slow-growing tumor. However, the tumor in our patient grew very rapidly and invaded the adjacent lung, parietal pleura, and periosteum of the rib bone. We therefore describe this tumor as an "invasive" desmoplastic fibroblastoma. PMID- 25841857 TI - Symetis valve implantation in failing freestyle with close proximity between coronary Ostia and annulus. AB - Transcatheter treatment of patients with degenerated aortic valve stentless prosthesis and low proximal coronary ostia to the aortic annulus remain a challenge because of the elevated risk for coronary obstruction. Newer generation transcatheter aortic valve devices that engage and pull the aortic valve calcium towards the aortic annulus may be beneficial in these patients. We present a case of successful treatment of a degenerated tubular stentless prosthesis with low coronary ostia with a Symetis Acurate TA prosthesis. PMID- 25841858 TI - Periprocedural myocardial infarction resulting in a ventricular septal defect. AB - Although periprocedural myocardial infarction frequently occurs with the robustness of percutaneous coronary intervention, the prognosis of the periprocedural myocardial infarction has been known to be relatively good compared with that of spontaneous myocardial infarction. We present a patient with a postinfarction ventricular septal defect, with cardiogenic shock, that developed 7 days after a percutaneous coronary intervention. Emergency surgical repair combined with coronary artery bypass grafting saved the patient, without complications. PMID- 25841859 TI - Bridge to long-term mechanical circulatory support with a left ventricular assist device: novel use of transcatheter aortic valve replacement. AB - We describe the use of transcatheter aortic valve replacement to allow for bridging to a left ventricular assist device in a patient with end-stage heart failure, secondary to nonischemic cardiomyopathy and severe bioprosthetic aortic valve regurgitation. PMID- 25841860 TI - Left pulmonary artery originating from the right coronary artery in a patient with pulmonary atresia and ventricular septal defect. AB - We describe a patient with pulmonary atresia and ventricular septal defect in whom the left pulmonary artery was originating from the dilated right coronary artery. Successful division of the left pulmonary artery from the right coronary artery and the connection with the right ventricular outflow tract was carried out with closure of the end of the origin. The preoperative accurate diagnosis of this anomaly with ascending aortography is the most important in the surgical management of patients with pulmonary atresia and ventricular septal defect. PMID- 25841861 TI - Tracheobronchopathia osteochondroplastica: imaging and bronchoscopic findings. PMID- 25841862 TI - Anterior subcarinal node dissection on the left side using video thoracoscopy: an easier technique. AB - Lobectomy for lung carcinoma is usually associated with complete node dissection, but it is often difficult to perform using video thoracoscopy, especially on the left side. In this case, our team uses an anterior technique for subcarinal lymphadenectomy. After left lobectomy, we lift the bronchial stump by its anterior face to open and dissect the subcarinal space. Exposure is difficult using the more usual technique of posterior subcarinal lymphadenectomy, and the different techniques (often requiring retractors) remain complex because some vessels might be injured. We recommend using anterior lymphadenectomy, which should facilitate video thoracoscopy for lymphadenectomy on the left side. PMID- 25841863 TI - Integrated assessment of ivermectin pharmacokinetics, efficacy against resistant Haemonchus contortus and P-glycoprotein expression in lambs treated at three different dosage levels. AB - The main goals of the current work were: (a) to assess the ivermectin (IVM) systemic exposure and plasma disposition kinetics after its administration at the recommended dose, x5 and x10 doses to lambs, (b) to compare the clinical efficacy of the same IVM dosages in lambs infected with an IVM-resistant isolate of Haemonchus contortus, and (c) to assess the expression of the transporter protein P-glycoprotein (P-gp) in H. contortus recovered at 14 days after administration of the IVM dose regimens. There were two separated trials where IVM was administered either subcutaneously (SC, Experiment I) or intraruminally (IR, Experiment II). Each experiment involved twenty-four (24) lambs artificially infected with a highly resistant H. contortus isolate. Animals were allocated into 4 groups (n=6) and treated with IVM at either 0.2 (IVM x1), 1 (IVM x5) or 2mg/kg (IVM x10). Plasma samples were collected up to 12 days post-treatment and analysed by HPLC. An untreated-control Group was included to assess the comparative anthelmintic efficacy of the different treatments. The level of expression of Pgp in H. contortus specimens obtained from lambs both untreated and IR treated with the different IVM doses was quantified by real time PCR. Parametric and non-parametric tests were used to compare the statistical significance of the results (P<0.05). After the SC treatment, the IVM plasma area under the concentration-time curve (AUC0-LOQ) increased from 41.9 (IVM SCx1) up to 221 (IVM SCx5) and 287 (IVM SCx10)ng.day/mL and after the IR treatment from 20.8 (IVM IRx1) up to 121 (IVM IRx5) and 323 (IVM IRx10)ng.day/mL. Dose-adjusted AUC0-LOQ and Cmax were similar among doses, demonstrating dose proportionality for IVM after both SC and IR administration at the three different doses. The efficacies against resistant H. contortus after the SC treatment were 42% (IVM SC1), 75% (IVM SCx5) and 75% (IVM SCx10). However, the IR IVM treatment reached clinical efficacies ranging from 48% (IVM IRx1) up to 96% (IVM IRx5) and 98% (IVM IRx10). None of the IR IVM treatments increased the expression of P-gp in adult H. contortus at 14 days post-treatment compared to samples collected from the untreated control group. An enhanced parasite exposure of the drug at the abomasum may explain the improved efficacy against this recalcitrant H. contortus isolate observed only after the IR administration at 5- and 10-fold the IVM therapeutic dosage. PMID- 25841865 TI - Systems redesign: a quality improvement initiative at a tertiary-care veterans affairs medical Center. PMID- 25841864 TI - How Much Is That Head CT? Price Transparency and Variability in Radiology. AB - PURPOSE: To extend the investigation of price transparency and variability to medical imaging. METHODS: Eighteen upper-tier academic hospitals identified by U.S. News & World Report and 14 of the 100 largest private radiology practices in the country identified by the Radiology Business Journal were contacted by telephone between December 2013 and February 2014 to determine the cash price for a noncontrast head CT. The price for a noncontrast head CT was chosen to assess price transparency in medical imaging because it represents a standard imaging examination with minimal differences in quality. RESULTS: Fourteen upper-tier academic hospitals (78%) and 11 private practices (79%) were able to provide prices for a noncontrast head CT. There was no significant difference between the proportions of upper-tier academic hospitals and private practices that were able to provide prices for a noncontrast head CT (P = .96). The average total price for the upper-tier academic hospitals was $1,390.12 +/- $686.13, with the price ranging from $391.62 to $2,015. The average total price for the private practices was $681.60 +/- $563.58, with the total price ranging from $211 to $2,200. CONCLUSIONS: Prices for a noncontrast head CT study were readily available from the vast majority of upper-tier academic hospitals and private practices, although there was tremendous variation in the price estimates both within and between the upper-tier academic hospitals and private practices. Routine medical imaging thus appears to be more price transparent compared with other health care services. PMID- 25841866 TI - Morphological and clinical presentation of papillary thyroid carcinoma in children and adolescents of Belarus: the influence of radiation exposure and the source of irradiation. AB - OBJECTIVE: The aims were to analyse the features of papillary thyroid carcinoma in a large cohort of children and adolescents in Belarus and to study the influence of radiation exposure as well as the source of irradiation on the morphological and clinical presentations of tumours. DESIGN AND PATIENTS: The clinical and pathological features of 1086 young patients (age range=4 to 18 inclusive, followed up for >=18years) with papillary thyroid carcinoma diagnosed during the years 1990 to 2010 were reviewed. The patients were divided into three groups: "external radiation-related", "post-Chernobyl" (internal irradiation related) and "sporadic". Besides, patients from "post-Chernobyl" cohort (n=936) were further divided into the three equal subgroups according to the dates of surgery, which were corresponding to the early (4-9years), intermediate (10 12years) and long (14-18years) latency periods. RESULTS: Patients in the "external radiation-related" group often showed extra-thyroidal extension in tumours sized <=10mm (p=0.002). Distant metastases were more frequently (p=0.006) discovered in patients with papillary thyroid carcinoma in post-Chernobyl group (104 of 936, 11.1%) when compared to juveniles from other two groups. Lateral nodal disease and distant metastases were often noted in post-Chernobyl patients operated during the early and intermediate latency periods only. CONCLUSION: Young patients in Belarus with papillary thyroid carcinoma in the "post Chernobyl" group differed in many clinical and pathological parameters from those in the "sporadic" group. "External radiation related" papillary thyroid carcinomas were distinguished from other two groups of carcinoma in more advanced local spread and more aggressive behaviour of micro-carcinomas. PMID- 25841867 TI - The effect of the magnitude of the food deprivation motivating operation on free operant preference in mice. AB - A number of recent studies have demonstrated that organisms prefer stimuli correlated with food under high deprivation conditions over stimuli correlated with food under low deprivation conditions. The purpose of the present study was to extend the literature on this phenomenon by testing for preference under extinction conditions, testing for preference at baseline, employing a free operant preference test, and using mice as subjects. Our results appear to support the existing literature in that most subjects preferred a stimulus correlated with food under high deprivation conditions in the post-training preference test. We provide an analysis of this phenomenon based on the concept of the motivating operation (MO) and discuss how this analysis suggests a number of avenues for further research on this topic. PMID- 25841868 TI - Sickness absence and psychosocial job quality: an analysis from a longitudinal survey of working Australians, 2005-2012. AB - Sickness absence is associated with adverse health, organizational, and societal outcomes. Using data from a longitudinal cohort study of working Australians (the Household, Income and Labour Dynamics in Australia (HILDA) Survey), we examined the relationship between changes in individuals' overall psychosocial job quality and variation in sickness absence. The outcome variables were paid sickness absence (yes/no) and number of days of paid sickness absence in the past year (2005-2012). The main exposure variable was psychosocial job quality, measured using a psychosocial job quality index (levels of job control, demands and complexity, insecurity, and perceptions of unfair pay). Analysis was conducted using longitudinal fixed-effects logistic regression models and negative binomial regression models. There was a dose-response relationship between the number of psychosocial job stressors reported by an individual and the odds of paid sickness absence (1 adversity: odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.09, 1.45 (P = 0.002); 2 adversities: OR = 1.28, 95% CI: 1.09, 1.51 (P = 0.002); >=3 adversities: OR = 1.58, 95% CI: 1.29, 1.94 (P < 0.001)). The negative binomial regression models also indicated that respondents reported a greater number of days of sickness absence in response to worsening psychosocial job quality. These results suggest that workplace interventions aiming to improve the quality of work could help reduce sickness absence. PMID- 25841869 TI - Linking data from the Multiethnic Cohort Study to Medicare data: linkage results and application to chronic disease research. PMID- 25841871 TI - The eight-shaped heart: an incidental giant left ventricular pseudoaneurysm. PMID- 25841870 TI - Hearing impairment and cognitive decline: a pilot study conducted within the atherosclerosis risk in communities neurocognitive study. AB - Hearing impairment (HI) is prevalent, is modifiable, and has been associated with cognitive decline. We tested the hypothesis that audiometric HI measured in 2013 is associated with poorer cognitive function in 253 men and women from Washington County, Maryland (mean age = 76.9 years) in a pilot study carried out within the Atherosclerosis Risk in Communities Neurocognitive Study. Three cognitive tests were administered in 1990-1992, 1996-1998, and 2013, and a full neuropsychological battery was administered in 2013. Multivariable-adjusted differences in standardized cognitive scores (cross-sectional analysis) and trajectories of 20-year change (longitudinal analysis) were modeled using linear regression and generalized estimating equations, respectively. Hearing thresholds for pure tone frequencies of 0.5-4 kHz were averaged to obtain a pure tone average in the better-hearing ear. Hearing was categorized as follows: <=25 dB, no HI; 26-40 dB, mild HI; and >40 dB, moderate/severe HI. Comparing participants with moderate/severe HI to participants with no HI, 20-year rates of decline in memory and global function differed by -0.47 standard deviations (P = 0.02) and 0.29 standard deviations (P = 0.02), respectively. Estimated declines were greatest in participants who did not wear a hearing aid. These findings add to the limited literature on cognitive impairments associated with HI, and they support future research on whether HI treatment may reduce risk of cognitive decline. PMID- 25841872 TI - Genetic variation in the cholesterol transporter NPC1L1, ischaemic vascular disease, and gallstone disease. AB - AIMS: Ezetimibe reduces plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1 (NPC1L1), the transporter responsible for cholesterol uptake from the intestine into enterocytes and from the bile into hepatocytes. We tested the hypothesis that genetic variation in NPC1L1, mimicking the effect of ezetimibe, was associated with reduced risk of ischaemic vascular disease (IVD) and with increased risk of symptomatic gallstone disease. METHODS AND RESULTS: We included 67 385 individuals from the general population. Of these, 5255 and 3886 individuals developed IVD or symptomatic gallstone disease, respectively, during follow-up from 1977 to 2013. We genotyped four common NPC1L1 variants, previously associated with reduced LDL cholesterol levels, thus mimicking the effect of ezetimibe, and calculated a weighted genotype score. With increasing genotype score, LDL cholesterol decreased stepwise up to 3.5% (0.12 mmol/L) and total cholesterol up to 1.9% (0.11 mmol/L) (P-trend: 2 * 10(-12) and 2 * 10(-9)). The cumulative incidence by age of IVD decreased, while that of symptomatic gallstone disease increased as a function of increasing genotype score (P-trend: 0.005 and 0.01). Hazard ratios for genotype scores >= 5.0 vs. <2.0 were 0.82 (95% confidence interval: 0.70-0.95) for IVD and 1.22 (0.99-1.49) for gallstone disease (P-trend across genotype scores: 0.004 and 0.01). CONCLUSION: Genetic variation in NPC1L1 is associated with a reduction in risk of IVD, with a corresponding reduction in LDL cholesterol, but with a concomitant increased risk of gallstone disease. These data support the hypothesis that treatment with ezetimibe protects against IVD but raise the question whether long-term treatment increases the risk of gallstone disease. PMID- 25841873 TI - Supra-cardiac type (1a) total anomalous pulmonary venous return with right to left shunt atrial septal defect diagnosed by 320 slice CT. PMID- 25841874 TI - A plea for caution and more research in the 'experimental' use of ionophores in ICSI. PMID- 25841876 TI - Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB1-cannabinoid receptor in the ventral mesencephalon. AB - Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in gamma-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways. PMID- 25841875 TI - Activated matrix metalloproteinase-8 in saliva as diagnostic test for periodontal disease? A case-control study. AB - Untreated periodontal disease may influence general health. However, how may a physician, who is not trained in periodontal probing, detect untreated periodontitis? Activated matrix metalloproteinase-8 (aMMP-8) in saliva correlates with periodontal probing parameters. Thus, sensitivity and specificity of a chair side test for aMMP-8 to detect periodontitis were evaluated. Thirty cases [untreated chronic periodontitis (ChP); 15 generalized moderate and 15 generalized severe] and 30 controls [probing depths (PD) <=3 mm, vertical probing attachment level (PAL-V) <=2 mm at <30 % of sites) were examined periodontally (PD, PAL-V, bleeding on probing). Subsequently, the aMMP-8 test was performed. The test kit becomes positive with >=25 ng/ml aMMP-8 in the sample. The aMMP-8 test was positive in 87 % of ChP and in 40 % of controls. That corresponds to a sensitivity of 87 % and a specificity of 60 %. The sensitivity to detect generalized severe ChP was 93 % (60 % specificity). Backward stepwise logistic regression analysis to explain positive aMMP-8 tests identified exclusively ChP with an odds ratio of 9.8 (p < 0.001). Positive results of the aMMP-8 test significantly correlate with generalized ChP. The aMMP-8 test may be used by physicians to detect periodontitis in their patients. PMID- 25841877 TI - Translational research for Parkinson's disease: The value of pre-clinical primate models. AB - Animal models have been highly questioned for their ability to predict the efficacy of different therapeutic strategies for neurodegenerative diseases. The increasing number of phase I/II clinical trials that fail to proceed to further stages of drug development has discredited the pertinence of such investigations. However, critical analysis of the data has often revealed errors and partially explained the lack of efficacy, opening the way to a refinement in designing pre clinical studies. In parallel, many promising methods of drug delivery to the brain such as gene therapy or cell therapy have considerably advanced thanks to the clinical failures in the past 10 years. As methodological advances appear and knowledge becomes available, scientists will be faced with the choice of how to test new strategies or re-test old ones. With the hardening of social views and legislation regarding animal experimentation, there is increasing pressure to find alternative methods of assessment that predict efficacy (such as computational based models), or to perform efficacy trials directly in patients and only safety assays in animals. In this review we will focus on Parkinson's disease and on the impact of a body of data issued from NHP studies. We will attempt to critically examine the advantages and limitations of various approaches from the perspective of the animal model used to address specific questions. PMID- 25841878 TI - Antinociceptive action of diphenyl diselenide in the nociception induced by neonatal administration of monosodium glutamate in rats. AB - Monosodium glutamate (MSG) is a neuroexcitatory amino acid commonly used as flavoring of foods. MSG neonatal administration to animals leads to behavioral and physiological disorders in adulthood, including increased pain sensitivity. This study aimed to investigate the effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, on nociception induced by MSG. Newborn Wistar rats received 10 subcutaneous injections of MSG at a dose of 4.0g/kg or saline (once daily). At the 60th day of life, the rats were daily treated with (PhSe)2 (1mg/kg) or vehicle (canola oil) by the intragastric route for 7 days. The behavioral tests (locomotor activity, hot plate, tail-immersion and mechanical allodynia) were carried out. Ex vivo assays were performed in samples of hippocampus to determine Na(+), K(+)-ATPase and Ca(2+)-ATPase activities, cytokine levels and [(3)H]glutamate uptake. The results demonstrated that MSG increased nociception in the hot plate test and in the mechanical allodynia stimulated by Von-Frey hair but did not alter the tail immersion test. (PhSe)2 reversed all nociceptive behaviors altered by MSG. MSG caused an increase in Na(+),K(+)-ATPase and Ca(2+)-ATPase activities and in pro inflammatory cytokine levels and a decrease in the anti-inflammatory cytokine and in the [(3)H]glutamate uptake. (PhSe)2 was effective in reversing all alterations caused by MSG. The results indicate that (PhSe)2 had a potential antinociceptive and anti-inflammatory action in the MSG model. PMID- 25841879 TI - Fetal exposure to placental corticotropin-releasing hormone (pCRH) programs developmental trajectories. AB - The maternal endocrine stress system is profoundly altered during the course of human pregnancy. The human placenta expresses the genes for CRH as early as the seventh week of gestation and it is the expotential increase in placental CRH (pCRH) over the course of human gestation that is responsible for the greatest modification in the maternal stress system. The bi-directional placental release of hormones into the maternal and fetal compartments has profound influences for both. The influential Fetal Programming model predicted that early or fetal exposures to maternal signals of threat or adverse conditions have lifelong consequences for health outcomes. A basic assumption of this model was that developing organisms play a dynamic role in their own construction. Data are reviewed and new data are presented that elevated pCRH over the course of human gestation plays a fundamental role in the organization of the fetal nervous system, modifies birth phenotype (the timing of the onset of spontaneous labor and delivery), and influences developmental, temperamental and metabolic trajectories. Evidence for sex differences and conserved function across species is presented. Finally, a model is presented that proposes several pathways that pCRH can program risk for health and disease. PMID- 25841880 TI - Usefulness of administrative databases for risk adjustment of adverse events in surgical patients. AB - PURPOSE: The aim of this study was to assess the usefulness of clinical administrative databases for the development of risk adjustment in the assessment of adverse events in surgical patients. METHODS: The study was conducted at the Hospital of Navarra, a tertiary teaching hospital in northern Spain. We studied 1602 hospitalizations of surgical patients from 2008 to 2010. We analysed 40 comorbidity variables included in the National Surgical Quality Improvement (NSQIP) Program of the American College of Surgeons using 2 sources of information: The clinical and administrative database (CADB) and the data extracted from the complete clinical records (CR), which was considered the gold standard. Variables were catalogued according to compliance with the established criteria: sensitivity, positive predictive value and kappa coefficient >0.6. RESULTS: The average number of comorbidities per study participant was 1.6 using the CR and 0.95 based on CADB (p<.0001). Thirteen types of comorbidities (accounting for 8% of the comorbidities detected in the CR) were not identified when the CADB was the source of information. Five of the 27 remaining comorbidities complied with the 3 established criteria; 2 pathologies fulfilled 2 criteria, whereas 11 fulfilled 1, and 9 did not fulfil any criterion. CONCLUSION: CADB detected prevalent comorbidities such as comorbid hypertension and diabetes. However, the CABD did not provide enough information to assess the variables needed to perform the risk adjustment proposed by the NSQIP for the assessment of adverse events in surgical patients. PMID- 25841881 TI - A single German center experience with intermittent inotropes for patients on the high-urgent heart transplant waiting list. AB - AIM: Currently, more than 900 patients with end-stage heart failure are listed for heart transplantation in Germany. All patients on the Eurotransplant high urgent status (HU) have to be treated in intensive care units and have to be relisted every 8 weeks. Long-term continuous inotropes are associated with tachyphylaxia, arrhythmias and even increased mortality. In this retrospective analysis, we report our single center experience with HU patients treated with intermittent inotropes as a bridging therapy. METHODS AND RESULTS: 117 consecutive adult HU candidates were treated at our intensive care heart failure unit between 2008 and 2013, of whom 14 patients (12 %) were stabilized and delisted during follow-up. In the remaining 103 patients (age 42 +/- 15 years), different inotropes (dobutamine, milrinone, adrenaline, noradrenaline, levosimendan) were administered based on the patient's specific characteristics. After initial recompensation, patients were weaned from inotropes as soon as possible. Thereafter, intermittent inotropes (over 3-4 days) were given as a predefined weekly (until 2011) or 8 weekly regimen (from 2011 to 2013). In 57 % of these patients, additional regimen-independent inotropic support was necessary due to hemodynamic instabilities. Fourteen patients (14 %) needed a left- or biventricular assist device; 14 patients (14 %) died while waiting and 87 (84 %) received heart transplants after 87 +/- 91 days. Cumulative 3 and 12 months survival of all 103 patients was 75 and 67 %, respectively. CONCLUSION: Intermittent inotropes in HU patients are an adequate strategy as a bridge to transplant; the necessity for assist devices was low. These data provide the basis for a prospective multicenter trial of intermittent inotropes in patients on the HU waiting list. PMID- 25841882 TI - Sphingomonas paucimobilis bacteremia in an HIV and hepatitis C co-infected patient. AB - INTRODUCTION: Prompt diagnosis and treatment of blood stream infections in an immunocompromised host can result in a decrease in mortality with appropriate antibiotic coverage. Signs, symptoms, physical examination, cultures and sensitivity findings must be evaluated and interpreted together to accurately diagnose and manage the problem. CASE PRESENTATION: We present a case of Sphingomonas paucimobilis bacteremia in a patient with Human Immunodeficiency virus (HIV) and hepatitis C virus co-infection. CONCLUSION: To our knowledge, this is the first reported case of this organism in a patient with HIV co infected with chronic hepatitis C virus. PMID- 25841883 TI - The role of imaging in anoxic brain injury and brain death: a review of modalities with an Irish and international perspective. PMID- 25841884 TI - Brief Report: Use of Superheroes Social Skills to Promote Accurate Social Skill Use in Children with Autism Spectrum Disorder. AB - The current study evaluated the use of Superheroes Social Skills to promote accurate use of discrete social skills in training and generalization conditions in two children with autism spectrum disorder. Participants attended a twice weekly social skills training group over 5 weeks, with lessons targeting nonverbal, requesting, responding, and conversation skills. A multiple probe across social skills design, replicated across participants, was utilized to assess the effects of participation of the intervention on skill accuracy. Following introduction of the intervention, participants demonstrated abrupt improvements in skill accuracy in both training and generalization conditions. Additionally, parental reports of participant social functioning indicated improvements following participation in the intervention. Limitations and future directions are discussed. PMID- 25841885 TI - Differentiating physical discipline from abuse: Q findings from Chinese American mothers and pediatric nurses. AB - The perception and use of physical discipline (PD) is culture-based, and the differentiation between PD and abuse is subjective and complex. The purpose of this study was to understand how Chinese American mothers and one group of mandated reporters of child abuse (i.e. pediatric nurses) differentiate PD from abuse. Using Q-methodology, 3 viewpoints on PD and abuse differentiation were uncovered from a sample of 35 Chinese American mothers and 48 pediatric nurses. Although there was wide consensus on the most acceptable and most unacceptable parent discipline behaviors across the 3 views, the acceptability of punishments differed by their potential to inflict injury, pain, or incite fear and uncertainty. This was the first study to examine PD and abuse differentiation based on 5 definable domains of PD (i.e. specific behavior, intention, delivery, outcome, and pattern of use). Findings point to important nuances in how some mothers and nurses differentiate abuse from acceptable discipline, and the potential for using Q-methodology for exploring PD and abuse differentiations across diverse cultural, social, and professional groups. PMID- 25841886 TI - Completing the specificity swap: Single-stranded DNA recognition by F and R100 TraI relaxase domains. AB - During conjugative plasmid transfer, one plasmid strand is cleaved and transported to the recipient bacterium. For F and related plasmids, TraI contains the relaxase or nickase activity that cleaves the plasmid DNA strand. F TraI36, the F TraI relaxase domain, binds a single-stranded origin of transfer (oriT) DNA sequence with high affinity and sequence specificity. The TraI36 domain from plasmid R100 shares 91% amino acid sequence identity with F TraI36, but its oriT DNA binding site differs by two of eleven bases. Both proteins readily distinguish between F and R100 binding sites. In earlier work, two amino acid substitutions in the DNA binding cleft were shown to be sufficient to change the R100 TraI36 DNA-binding specificity to that of F TraI36. In contrast, three substitutions could make F TraI36 more "R100-like", but failed to completely alter the specificity. Here we identify one additional amino acid substitution that completes the specificity swap from F to R100. To our surprise, adding further substitutions from R100 to the F background were detrimental to binding instead of being neutral, indicating that their effects were influenced by their structural context. These results underscore the complex and subtle nature of DNA recognition by relaxases and have implications for the evolution of relaxase binding sites and oriT sequences. PMID- 25841887 TI - Enhancing the efficacy of electrolytic chlorination for ballast water treatment by adding carbon dioxide. AB - We examined the synergistic effects of CO2 injection on electro-chlorination in disinfection of plankton and bacteria in simulated ballast water. Chlorination was performed at dosages of 4 and 6ppm with and without CO2 injection on electro chlorination. Testing was performed in both seawater and brackish water quality as defined by IMO G8 guidelines. CO2 injection notably decreased from the control the number of Artemia franciscana, a brine shrimp, surviving during a 5-day post treatment incubation (1.8 and 2.3 log10 reduction in seawater and brackish water, respectively at 6ppm TRO+CO2) compared with water electro-chlorinated only (1.2 and 1.3 log10 reduction in seawater and brackish water, respectively at 6ppm TRO). The phytoplankton Tetraselmis suecica, was completely disinfected with no live cell found at >4ppm TRO with and without CO2 addition. The effects of CO2 addition on heterotrophic bacterial growth was not different from electro chlorination only. Total residual oxidant concentration (TRO) more rapidly declined in electro-chlorination of both marine and brackish waters compared to chlorine+CO2 treated waters, with significantly higher amount of TRO being left in waters treated with the CO2 addition. Total concentration of trihalomethanes (THMs) and haloacetic acids (HAAs) measured at day 0 in brackish water test were found to be 2- to 3-fold higher in 6ppm TRO+CO2-treated water than in 6ppm TRO treated water. The addition of CO2 to electro-chlorination may improve the efficiency of this sterilizing treatment of ballast water, yet the increased production of some disinfection byproducts needs further study. PMID- 25841888 TI - Sediment impacts on marine sponges. AB - Changes in sediment input to marine systems can influence benthic environments in many ways. Sponges are important components of benthic ecosystems world-wide and as sessile suspension feeders are likely to be impacted by changes in sediment levels. Despite this, little is known about how sponges respond to changes in settled and suspended sediment. Here we review the known impacts of sedimentation on sponges and their adaptive capabilities, whilst highlighting gaps in our understanding of sediment impacts on sponges. Although the literature clearly shows that sponges are influenced by sediment in a variety of ways, most studies confer that sponges are able to tolerate, and in some cases thrive, in sedimented environments. Critical gaps exist in our understanding of the physiological responses of sponges to sediment, adaptive mechanisms, tolerance limits, and the particularly the effect of sediment on early life history stages. PMID- 25841889 TI - Neurotrophic Activity of Cultured Cell Line U87 is Up-Regulated by Proline-Rich Polypeptide Complex and Its Constituent Nonapeptide. AB - Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor, as well as cytokines, for example, interleukin-6 (IL-6) play an important role in neuroprotection and in the control of the central nervous system (CNS) function. Reduced expression of neurotrophic factors can lead to dysregulation of neuron function and neuronal death. There is also evidence for mutual interactions between neurotrophins and IL-6. Therefore, the up-regulating the level of neuroprotective substances is one of the key manners to control the nervous system development and function. It can be a promising aim in the therapy of neurodegenerative disease in which the decreased level of neurotrophins is observed. In our recent studies, the role of proline-rich polypeptide complex (PRP) and its nonapeptide fragment (NP) in the regulation of neurotrophic activity in cultured astrocytes was shown. PRP and NP stimulate human astrocytoma cell line U87 to release the significant amounts of NGF to the extracellular space both in its precursor and mature form. We also provide the evidence that in NP-treated cells, the level of betaNGF mRNA was increased. NP-treated cells used in this study produced also increasing amounts of IL-6. This finding indicates that PRP and its nonapeptide fragment NP up-regulate neurotrophic activity of U87 cell line by increase of NGF synthesis and its release into the extracellular space. It was also shown that NP-dependent increased production of IL-6 can enhance the NGF activity. PMID- 25841890 TI - Effects of fluoxetine on the amygdala and the hippocampus after administration of a single prolonged stress to male Wistar rates: In vivo proton magnetic resonance spectroscopy findings. AB - Posttraumatic stress disorder (PTSD) is an anxiety- and memory-based disorder. The hippocampus and amygdala are key areas in mood regulation. Fluoxetine was found to improve the anxiety-related symptoms of PTSD patients. However, little work has directly examined the effects of fluoxetine on the hippocampus and the amygdala. In the present study, male Wistar rats received fluoxetine or vehicle after exposure to a single prolonged stress (SPS), an animal model of PTSD. In vivo proton magnetic resonance spectroscopy ((1)H-MRS) was performed -1, 1, 4, 7 and 14 days after SPS to examine the effects of fluoxetine on neurometabolite changes in amygdala, hippocampus and thalamus. SPS increased the N acetylaspartate (NAA)/creatine (Cr) and choline moieties (Cho)/Cr ratios in the bilateral amygdala on day 4, decreased the NAA/Cr ratio in the left hippocampus on day 1, and increased both ratios in the right hippocampus on day 14. But no significant change was found in the thalamus. Fluoxetine treatment corrected the SPS increases in the NAA/Cr and Cho/Cr levels in the amygdala on day 4 and in the hippocampus on day 14, but it failed to normalise SPS-associated decreases in NAA/Cr levels in the left hippocampus on day 1. These results suggested that metabolic abnormalities in the amygdala and the hippocampus were involved in SPS, and different effects of fluoxetine in correcting SPS-induced neurometabolite changes among the three areas. These findings have implications for fluoxetine treatment in PTSD. PMID- 25841892 TI - Outpatient treatment for neonates and young infants with clinically suspected severe infection. PMID- 25841891 TI - Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial. AB - BACKGROUND: Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. METHODS: We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. FINDINGS: Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). INTERPRETATION: Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable. PMID- 25841893 TI - The role of anaerobes in diabetic foot infections. AB - Diabetic foot infections (DFI) are a common cause of morbidity and, on occasion, even mortality. Infection can be either mono- or polymicrobial, with a wide variety of potential pathogens. Anaerobes may be involved, particularly in wounds that are deeper or more chronic, and are more frequently identified when using modern molecular techniques, such as 16s PCR and pyrosequencing. It remains unclear whether the presence of anaerobes in DFI leads to more severe manifestations, or if these organisms are largely colonizers associated with the presence of greater degrees of tissue ischemia and necrosis. Commonly used empiric antibiotic therapy for diabetic foot infections is generally broad spectrum and usually has activity against the most frequently identified anaerobes, such as Peptostreptococcus and Bacteroides species. Adequate surgical debridement and, when needed, foot revascularization may be at least as important as the choice of antibiotic to achieve a successful treatment outcome. PMID- 25841895 TI - A protein fold with multiple functions: Chlorite dismutase, HemQ and DyP-type peroxidase. PMID- 25841894 TI - Psychosine inhibits osteoclastogenesis and bone resorption via G protein-coupled receptor 65. AB - BACKGROUND: It was recently reported that G protein-coupled receptor 65 (GPR65) suppresses ovariectomy-induced bone loss. AIM: The present study investigated the role of the lysosphingolipid psychosine, a GPR65 ligand, on osteoclastic differentiation and bone resorption. METHODS: Osteoclasts were differentiated from mouse bone marrow macrophages. Tartrate-resistant acid phosphatase-positive multinucleated cells were considered to be osteoclasts, and the resorption area was measured by incubating the cells on dentine discs. The expression levels of osteoclast differentiation markers were assessed by qRT-PCR. GPR65 siRNA and its scrambled siRNA were transfected with lipofectamine. Intracellular cyclic adenosine monophosphate (cAMP) levels were assessed using a direct enzyme immunoassay. RESULTS: Psychosine inhibited osteoclastogenesis and in vitro bone resorption without any significant effect on the viability of pre-osteoclasts, decreased the expression of osteoclast differentiation markers significantly, and increased intracellular cAMP levels. The knockdown of GPR65 by its siRNA restored osteoclastogenesis and decreased cAMP levels in the presence of psychosine. CONCLUSION: Psychosine inhibits osteoclastogenesis by increasing intracellular cAMP levels via GPR65. PMID- 25841896 TI - Effects of a single glucocorticoid injection on propylene glycol-treated cows with clinical ketosis. AB - This study investigated the metabolic effects of glucocorticoids when administered to propylene glycol-treated cows with clinical ketosis. Clinical ketosis was defined by depressed feed intake and milk production, and a maximal score for acetoacetate in urine. All cows received 250 mL oral propylene glycol twice daily for 3 days and were randomly assigned to a single intramuscular injection with sterile isotonic saline solution (n = 14) or dexamethasone-21 isonicotinate (n = 17). Metabolic blood variables were monitored for 6 days and adipose tissue variables for 3 days. beta-Hydroxybutyrate (BHBA) concentrations in blood decreased in all cows during treatment, but were lower in glucocorticoid treated cows. Cows treated with glucocorticoids had higher plasma glucose and insulin concentrations, whereas concentrations of non-esterified fatty acids, 3 methylhistidine and growth hormone were unaffected. mRNA expression of hormone sensitive lipase, BHBA receptor and peroxisome proliferator-activated receptor type gamma in adipose tissue was not affected. This shows that lipolytic effects do not appear to be important in ketotic cows when glucocorticoids are combined with PG. Plasma 3-methyl histidine concentrations were similar in both groups, suggesting that glucocorticoids did not increase muscle breakdown and that the greater rise in plasma glucose in glucocorticoid-treated cows may not be due to increased supply of glucogenic amino acids from muscle. PMID- 25841897 TI - The effects of altered distances between obstacles on the jump kinematics and apparent joint angulations of large agility dogs. AB - Canine agility is a rapidly growing sport in the UK. However, there is a paucity of scientific research examining jump kinematics and associated health and welfare implications of the discipline. The aim of this research was to examine differences in jump kinematics and apparent joint angulation of large (>431 mm at the withers) agility dogs (n = 54), when the distance between hurdles was altered (3.6 m, 4 m and 5 m apart) and to determine how level of skill impacted upon jump kinematics. Significant differences were observed for both the take-off (P <0.001) and landing distances (P <0.001) between the 3.6 m, 4 m and 5 m distances. Further differences were observed when level of skill was controlled for; take-off (F[3,55] = 5.686, P = 0.002) and landing (F[3,55] = 7.552, P <0.001) distances differed at the 3.6 m distance, as did the take-off distance at the 4 m hurdle distance (F[3,50] = 6.168, P = 0.001). Take-off and landing speeds differed for hurdle distances (P <0.001) and level of skill (P <0.001). There were significant differences in apparent neck angle during take-off and landing (P <0.001), lumbar spine angles during take-off, bascule and landing (P <0.01), and in shoulder angles during the bascule phase (P <0.05). The results indicate that agility dogs alter their jumping patterns to accommodate the spacing between hurdles, which ultimately may impact long term health and welfare due to altered kinematics. PMID- 25841898 TI - Porcine epidemic diarrhea virus infection: Etiology, epidemiology, pathogenesis and immunoprophylaxis. AB - Porcine epidemic diarrhea virus (PEDV), a member of the genera Alphacoronavirus in the family Coronaviridae, causes acute diarrhea/vomiting, dehydration and high mortality in seronegative neonatal piglets. For the last three decades, PEDV infection has resulted in significant economic losses in the European and Asian pig industries, but in 2013-2014 the disease was also reported in the US, Canada and Mexico. The PED epidemic in the US, from April 2013 to the present, has led to the loss of more than 10% of the US pig population. The disappearance and re emergence of epidemic PED indicates that the virus is able to escape from current vaccination protocols, biosecurity and control systems. Endemic PED is a significant problem, which is exacerbated by the emergence (or potential importation) of multiple PEDV variants. Epidemic PEDV strains spread rapidly and cause a high number of pig deaths. These strains are highly enteropathogenic and acutely infect villous epithelial cells of the entire small and large intestines although the jejunum and ileum are the primary sites. PEDV infections cause acute, severe atrophic enteritis accompanied by viremia that leads to profound diarrhea and vomiting, followed by extensive dehydration, which is the major cause of death in nursing piglets. A comprehensive understanding of the pathogenic characteristics of epidemic or endemic PEDV strains is needed to prevent and control the disease in affected regions and to develop an effective vaccine. This review focuses on the etiology, epidemiology, disease mechanisms and pathogenesis as well as immunoprophylaxis against PEDV infection. PMID- 25841899 TI - The relationship between the Southern Oscillation Index, rainfall and the occurrence of canine tick paralysis, feline tick paralysis and canine parvovirus in Australia. AB - The aim of this study was to describe the association between climate, weather and the occurrence of canine tick paralysis, feline tick paralysis and canine parvovirus in Australia. The Southern Oscillation Index (SOI) and monthly average rainfall (mm) data were used as indices for climate and weather, respectively. Case data were extracted from a voluntary national companion animal disease surveillance resource. Climate and weather data were obtained from the Australian Government Bureau of Meteorology. During the 4-year study period (January 2010 December 2013), a total of 4742 canine parvovirus cases and 8417 tick paralysis cases were reported. No significant (P >= 0.05) correlations were found between the SOI and parvovirus, canine tick paralysis or feline tick paralysis. A significant (P < 0.05) positive cross-correlation was found between parvovirus occurrence and rainfall in the same month (0.28), and significant negative cross correlations (-0.26 to -0.36) between parvovirus occurrence and rainfall 4-6 months previously. Significant (P < 0.05) negative cross-correlations (-0.34 to 0.39) were found between canine tick paralysis occurrence and rainfall 1-3 months previously, and significant positive cross-correlations (0.29-0.47) between canine tick paralysis occurrence and rainfall 7-10 months previously. Significant positive cross-correlations (0.37-0.68) were found between cases of feline tick paralysis and rainfall 6-10 months previously. These findings may offer a useful tool for the management and prevention of tick paralysis and canine parvovirus, by providing an evidence base supporting the recommendations of veterinarians to clients thus reducing the impact of these diseases. PMID- 25841900 TI - Gene network and canonical pathway analysis in canine myxomatous mitral valve disease: a microarray study. AB - Myxomatous mitral valve disease (MMVD) is the single most common acquired heart disease of the dog and is particularly common in small pedigree breed dogs such as the Cavalier King Charles spaniel (CKCS). There are limited data on the mitral valve transcriptome and the aim of this study was to use the microarray technology in conjunction with bioinformatics platforms to analyse transcript changes in MMVD in CKCS compared to normal dogs (non-CKCS). Differentially expressed genes (n = 5397) were identified using cut-off settings of fold change, false discovery rate (FDR) and P <0.05. In total, 4002 genes were annotated to a specific transcript in the Affymetrix canine database, and after further filtering, 591 annotated canine genes were identified: 322 (55%) were up regulated and 269 (45%) were down-regulated. Canine microRNAs (cfa-miR; n = 59) were also identified. Gene ontology and network analysis platforms identified between six and 10 significantly different biological function clusters from which the following were selected as relevant to MMVD: inflammation, cell movement, cardiovascular development, extracellular matrix organisation and epithelial-to-mesenchymal (EMT) transition. Ingenuity Pathway Analysis identified three canonical pathways relevant to MMVD: caveolar-mediated endocytosis, remodelling of epithelial adherens junctions, and endothelin-1 signalling. Considering the biological relevance to MMVD, the gene families of importance with significant difference between groups included collagens, ADAMTS peptidases, proteoglycans, matrix metalloproteinases (MMPs) and their inhibitors, basement membrane components, cathepsin S, integrins, tight junction cell adhesion proteins, cadherins, other matrix-associated proteins, and members of the serotonin (5-HT)/transforming growth factor -beta signalling pathway. PMID- 25841901 TI - Understanding mechanisms of disease development: next generation pathology? PMID- 25841902 TI - Quality of life, heart rate, breathing, and pain: palliative care parameters and symptoms. PMID- 25841903 TI - Prospective evaluation of the quality of life of oral tongue cancer patients before and after the treatment. AB - BACKGROUND: This prospective study was to evaluate the changes in quality of life (QOL) after 12 months post treatment from their pre-treatment levels, using specific questionnaires of well-known acceptability, responsiveness, and validity, with special emphasis on domains such as chewing, swallowing, speech, psychological aspects (mood and anxiety) and pain. METHODS: This prospective analytical study included a total of 72 patients affected by oral tongue cancer (T1-2N0M0) who underwent treatment [wide local excision with selective + radiotherapy (RT)] from 2009 to 2012 at the Department of Oncosurgery and Otorhinolaryngology-Head and Neck Surgery, Sir Ganga Ram Hospital, New Delhi. RESULTS: A total of 39 (54.2%) patients were eligible for the study. Death occurred in 12 patients, four patients had disease recurrence and 17 patients lost to follow up. QOL in five domains was improved, there was significant improvement in pain scores [mean difference (-)17.94], overall activity of the patient was significantly improved (-13.46), recreational activities were also significantly improved (-8.33) and mental status of patient which included the mood and anxiety level were also significantly improved (-13.71 and -11.53) respectively. In seven domains which included the appearance of the patient (32.05), swallowing (16.41), chewing (24.35), speech (29.48), shoulder pain and discomfort (6.92), taste (35.12) and saliva production scores (20.51) were significantly worse. CONCLUSIONS: By our study we can strongly recommend that oral tongue cancers if diagnosed at early stages and without any neck node (T1 2N0M0) can be easily managed without compromising the QOL of the patients significantly. PMID- 25841904 TI - Predicting discharge of palliative care inpatients by measuring their heart rate variability. AB - OBJECTIVES: Home discharge after hospital admission to an inpatient palliative care unit (PCU) is a major challenge. Dysfunction of the autonomic nervous system is commonly observed in patients with advanced cancer in this setting. The aim of this prospective observational study was to determine whether the measurement of heart rate variability (HRV) by assessing parameters of the autonomic nervous system on a 24-h-ECG at the time of admission to the PCU was correlated with the likelihood of discharge. METHODS: Sixty hospitalized patients with advanced cancer of distinct origin, admitted to a PCU, were enrolled consecutively. The Karnofsky performance status scale (KPS) and the palliative performance scale (PPS) were obtained. HRV was measured over one day (20-24 hours) using a portable five-point ECG. The aim of the study was to compare HRV measurements in patients who could be discharged and those who died. The association of these variables with home discharge or death at the PCU was calculated. RESULTS: Discharge was achieved in 45% of patients while 55% of patients died. Median KPS and median PPS on admission were significantly higher in discharged patients than in those who died (P=0.001). Patients who were discharged tended to have a higher HRV, although the difference was not significant. CONCLUSIONS: KPS and PPS were significant predictors of the likelihood of discharge while HRV did not predict discharge. PMID- 25841905 TI - Safety evaluation of a potential ablation agent-hydrochloric acid in the rabbits' model. AB - AIM: To evaluate the safety of a potential ablation agent-hydrochloric acid (HCl), which may apply to treat hepatocellular carcinoma (HCC). METHODS: Eighty adult New Zealand rabbits were divided into five groups of equal size (n=16), i.e., untreated group, normal saline (NS) control group, 10% HCl group, 20% HCl group and 30% HCl group. Each group was divided into two subgroups: ten rabbits for two-week toxicology study at the time points of hours 0, 0.25, 0.5, 1, 3, 6 and days 2, 7, 14 and six rabbits for imaging and histopathology study at the time points of days 2, 7 and 14. In toxicology study we evaluated the safety of HCl from arterial blood gas status, hematology and hepatic and renal functions. In imaging and histopathology study, we observed the relationship between the sizes of lesion and the concentration of HCl, as well as extension of necrosis and concentration of HCl. In this study we also observed the microcosmic and macroscopic lesion that caused by HCl. RESULTS: In general condition, food, water consumption and body weight decreased notablely during the beginning of the experiment. In toxicology study, alanine aminotransferase, aspartate aminotransferase and lactic acid contents were higher in the 30% hydrochloric acid group than in other groups (P<0.005), all test items returned to normal on day 14. Imaging and histopathology study showed that 30% HCl caused larger lesion area than other HCl concentration and the necrosis that caused by HCl was complete. There was also a close relationship between the size of minor damaged area and HCl concentration. The 30% HCl caused larger minor damaged area than other HCl concentration. Because the damaged area was surrounded by a layer of fiber tissue, the lesion area became larger at days 7 and 14 time points. This study also demonstrated that the adjacent organs had no obvious damage, and all the damaged areas were limited in the liver. CONCLUSIONS: HCl is a safe ablation agent for local injection in the liver. HCl at a lower concentration is safer than at a higher concentration. PMID- 25841906 TI - Recent advances in the pharmacological management of acute and chronic pain. AB - This review focuses on newer medications for the treatment of pain as well as on new guidelines and indications for the use of established medications. With regard to classical analgesics, the use of non-opioids and opioids is reviewed. Here are relevant new data on the use of the old substance acetaminophen as well as on non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and the newer COX-2 selective agents, which continue to be misunderstood. Amongst the opioids the new compound tapentadol with a new mechanism of action is presented as well as a number of new opioid preparations aiming to increase speed of onset of effect and to reduce abuse and diversion. Many medications, which were not originally developed to treat pain, are now used as components of multimodal analgesia or in specific indications. Here are of relevance anticonvulsants such as pregabalin and gabapentin, which were initially used for neuropathic pain, but are now used successfully in a wide range of indications from postoperative pain to fibromyalgia. The reason for this increased range of indications is the realization of the relevance of central sensitization processes for all pain states. Similarly, the use of antidepressants and the old dissociative anesthetic ketamine is increasing for the same reasons. Calcitonin has also found some new indications in difficult to treat pain conditions, while the discussion on the role of cannabinoids in pain management continues, partially driven by political issues. For localized neuropathic pain, there is increasing interest in topical preparations such as lidocaine and capsaicin patches, in particular in view of their minimal systemic adverse effects. Overall, recent advances in the pharmacological management of pain are not so much the result of new 'miracle' drugs, but new preparations and new ways to use old drugs in a variety of settings, often as components of a multimodal approach to pain relief. PMID- 25841907 TI - Palliation of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is associated with a progressive course with a variable illness trajectory causing death either from respiratory failure or complications from its comorbities. Palliative care benefits patients throughout all stages of COPD, with a goal to manage patients' symptom burden which can reduce physical, psychological, and social complications. Dyspnea is the most common and distressing symptom patients with end stage COPD experience, which responds only partially to therapy and eventually becomes refractory to routine care. Palliative management goals aim at relieving refractory symptoms, improving function, and enhancing quality of life in patients with advanced illness and high symptom burden. Caregivers and informed patients can utilize palliative care resources to provide effective relief from refractory dyspnea and help patients maintain a dignified quality-of-life until the end of life. This review is focused on identifying current deficiencies in palliative care provided to patients with advanced COPD with attempts to overcome these. We hope to increase awareness of palliative care in advanced COPD to healthcare providers caring for this population of patients. PMID- 25841908 TI - Palliative radiotherapy: past, present and future-where do we go from here? AB - Radiotherapy is successful, time efficient, cost effective, and safe means to provide palliative relief for a variety of symptoms suffered by oncology patients. While the value of palliative radiotherapy has been understood for more than century, the radiation oncology specialty has only incompletely embraced its role in this setting. The optimization of palliative oncology requires accurate survival prognostication and a dedication to existing hypofractionated radiotherapy regimens that minimize toxicity and improve patient and caregiver convenience. The future of palliative radiotherapy demands more extensive treatment guidelines that explain the proper use of existing and novel technologies while remaining attentive to a growing population of cancer patients and a limited amount of resources with which to provide them care. PMID- 25841910 TI - Hepatocellular carcinoma: what is happening everywhere? PMID- 25841909 TI - The role of hypofractionated radiation in the management of non-osseous metastatic or uncontrolled local cancer. AB - Radiation therapy is often used to palliate symptoms caused by cancer. Short course, or "hypofractionated" palliative radiation therapy provides equivalent palliation in the setting of non-osseous metastasis or uncontrolled localized cancer while being more convenient and cost-effective than longer courses of radiation. Hypofractionated palliative radiation plays a role in the management of obstruction due to tumor, neurologic symptoms, pain caused by localized bulky disease, and bleeding in patients with primary tumors of the lung, head and neck, bladder, rectum, gynecologic malignancies, and metastasis to the liver, lung and brain. Hypofractionated palliative radiation is well tolerated with minimal and self-limited side effects. The side effects that do occur are generally limited to the body region treated and last from a few days to a few weeks. PMID- 25841911 TI - Viral hepatitis, non-alcoholic fatty liver disease and alcohol as risk factors for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common cancer worldwide, with significant increase in the incidence observed in the past two decades in the United States. Majority of cases of HCC are due to chronic viral hepatitis B and C infections; however non-alcoholic fatty liver disease, associated with obesity and diabetes emerges as an important risk factor for HCC, in particular in the developed countries. Here we will review viral characteristics associated with increased risk for development of HCC and role of antiviral therapy in decreasing risk of HCC in those with viral hepatitis and cirrhosis. Association of alcoholic cirrhosis and non-alcoholic fatty liver disease with liver cancer will be reviewed as well as possible measures to decrease the risk of HCC in these highly prevalent populations. PMID- 25841912 TI - A review of hepatocellular carcinoma (HCC) staging systems. AB - Accurately staging patients is essential to oncology practice. Cancer staging contributes to prognostication, guides management decisions, and informs clinical, epidemiologic, and health services research. In hepatocellular carcinoma (HCC), staging poses unique challenges due to the geographic and biological heterogeneity of the disease and lack of consensus on how to best classify patients. The features included in various HCC classifications systems have evolved over the last 50 years, but in general, need to account for both tumor characteristics as well as the burden of underlying liver disease.In this review, we discuss the Child-Turcotte-Pugh and Model for End-Stage Liver Disease, two practical systems that reflect the degree of hepatic dysfunction. We then describe several HCC staging systems, reviewing their development, and applicability to clinical practice, with a critical look at their validation. Finally, we look ahead to novel systems utilizing molecular markers. It is hoped this review will provide context regarding the use of current staging and scoring methods and a glimpse of what we can expect with future systems. PMID- 25841913 TI - Management of liver cirrhosis in patients with hepatocellular carcinoma. AB - Management of hepatocellular carcinoma (HCC) is challenging compared to other common malignancies because of the nature of the associated background of chronic liver dysfunction. Most of the patients with HCC have underlying cirrhosis. While progression of the tumor is a major contributor to mortality, cirrhosis and its complications often accounts for a significant portion of the morbidity and mortality seen in this group of patients. Severity of underlying liver disease and degree of decompensation predicts prognosis and dictates the tumor treatment options and responses. A multidisciplinary approach is considered the standard of care and paramount to optimal patient outcomes. This review provides information on the general management of cirrhosis, cirrhosis-related complications and commonly associated symptoms, mainly focusing when available on high-level evidence and guidelines. PMID- 25841914 TI - Hepatocellular carcinoma in the modern era: transplantation, ablation, open surgery or minimally invasive surgery? -A multidisciplinary personalized decision. AB - Hepatocellular carcinoma (HCC) is one of the few gastrointestinal cancers with increasing incidence and mortality worldwide. It arises most frequently in the setting of cirrhosis and presents heterogeneously with varying degrees of preserved liver function. Surgical resection and liver transplantation represent the cornerstones of curative treatment worldwide, whereas tumor ablation is being increasingly used for small tumors. A variety of different treatment algorithms have been developed, taking into consideration both the tumor stage as well as the liver reserve. Currently, many treatment modalities are continuously evolving. Transplantation criteria are expanding and even higher stage tumors become transplantable with neoadjuvant treatment. Surgical resection is being affected by the introduction of minimally invasive approaches. Ablation techniques are increasingly being used for small tumors. Combinations of different treatments are being introduced such as surgical resection followed by salvage transplantation. In this continuously changing field, the objectives of this review are to summarize the current curative surgical treatment options for patients with HCC, focusing on the controversial areas that multiple treatments might be applicable for the same patient, highlight the recent advances in minimally invasive surgery for HCC, and emphasize the need for a multidisciplinary approach and treatment plan tailored to the characteristics of each patient. PMID- 25841915 TI - Percutaneous therapies of hepatocellular carcinoma-an update. AB - Percutaneous image-guided tumor therapies have proved important in the treatment of patients with primary liver cancer. The therapeutic spectrum for the management of this patient group includes ablative techniques such as ethanol ablation and radiofrequency ablation for patients with early-stage disease as well as intra-arterial approaches such as radioembolization and transarterial chemoembolization for patients with intermediate and end-stage disease. The tremendous advantage of such therapies is the reduced systemic toxicity combined with efficient local tumor control. However, specific therapeutic algorithms continue to be highly unstandardized and depend on individual experience of the operator. In this review, we will describe the rationale behind several percutaneous techniques, focusing on intra-arterial therapies of hepatocellular carcinoma (HCC) and review the available clinical evidence. We will also discuss new developments such as the combination of intra-arterial therapies with new systemically applicable drugs. PMID- 25841916 TI - Systemic therapy for hepatocellular carcinoma. AB - The prognosis is poor for patients with advanced hepatocellular carcinoma (HCC). Sorafenib is the only accepted standard of care for advanced disease. The benefits of this agent are modest and the precise mechanism of antitumor activity in HCC is unknown. Since the approval of sorafenib, there has been intense investigation into strategies that block angiogenic pathways. Unfortunately, the results of three randomized phase III trials that compared newer anti-angiogenic treatments to sorafenib failed to demonstrate their superiority or non inferiority. Thus, there remains a critical need for both continued molecular characterization and aggressive drug development in hepatocellular carcinoma. PMID- 25841917 TI - Features and treatment options of Chinese hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. More than 53% of the total HCC patients in the world come from China. The absolute number of new Chinese HCC cases still keeps increasing and it remains a most dominant cancer burden in the next several decades. Compared to the HCC occurred in Europe and North America, Chinese HCC patients have their own special features in etiology, demographic features (risk factors, age of onset, gender distribution time trend of incidence), biological behavior, clinical manifestation, treatment strategy and prognosis. The success or failure of a series of clinical trials related with systemic therapy for advanced HCC can be partly attributed to those features of Chinese HCC. Thus it is suggested that new trials should be performed respectively for Chinese HCC patients from the Western population, like the success of sorafenib SHARP and ORIENTAL studies. The protocal design, organization and practice of trials in HCC of China should be made individually to avoid or reduce the possible heterogeneity of HCC populations and facilitate the personalized therapy of HCC. The present review discussed the features and treatment options of HCC in China that maybe help to understand the clinical course for Chinese patients with HCC. More importantly, the future strategies for clinical trials of Chinese HCC were emphasized. PMID- 25841918 TI - Status of hepatocellular carcinoma in South Korea. AB - In South Korea, liver cancer is the 4th most common cancer in men and 6th most common cancer in women. However, the incidences of liver cancer among Korean men and women have been declining from 1999 to 2010. The reason for the declining incidence appears secondary to decreased hepatitis B virus (HBV) infection, which is the leading risk factor for hepatocellular carcinoma (HCC), with successful implementation of HBV vaccination since 1983. Despite recent advances in the treatment of HCC, including liver transplantation (LT), radiofrequency ablation (RFA), transarterial embolization, and the use of molecularly targeted agents, many patients cannot be cured due to the advanced stage of HCC at the time of diagnosis in South Korea. While the 5-year survival rate of HCC patients in Korea is relatively lower than other cancers, it has been gradually increased from the early 1990s to the late 2000s. The reason for the improvement in 5-year survival rates is attributed that early detection of HCC becomes possible by well established surveillance program in high-risk populations for HCC in Korea. In Korea, national surveillance program for HCC was established in 2003, in which repeated applications of screening tests [serum alpha-fetoprotein (AFP) and liver ultrasound] at 6-month intervals have been recommended in patients at high risk for developing HCC, such as men and women older than 40 years of age with positive hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) or underlying liver cirrhosis. It is essential that the nationwide surveillance program for HCC should be effectively executed in high-risk patients for developing HCC. Optimal application of multidisciplinary team approach and active involvement in clinical studies with new agents in HCC patients are critically important not only for the management of advanced HCC patients but also for the improvement in natural history and therapeutic outcomes of HCC patients in the future. PMID- 25841919 TI - Current status of hepatocellular carcinoma in Japan. AB - Approximately 32,000 patients die of primary liver cancer each year in Japan. The annual number of deaths from primary liver cancer in Japan ranks second only to that in China in the world. In recent years, there has been a gradual trend towards decrease in the number of liver cancer patients from its peak in Japan, and this trend is expected to also continue in the future. The main reason for this decreasing trend was the establishment of screening of transfusion products for hepatitis B and hepatitis C viruses, which prevents transfusion-related transmission of the viral infection. Most patients with hepatocellular carcinoma (HCC) in Japan have underlying viral hepatitis, with hepatitis C accounting for about two-third of all the patients and hepatitis B accounting for about 15%. Regular screening of patients with viral hepatitis infection makes it possible to diagnose HCC early, and also enables effective loco-regional treatment, such as surgical resection, local ablative therapy and transcatheter arterial chemoembolization (TACE). However, HCC recurrence is encountered frequently even after these potentially effective treatments. After numerous loco-regional treatments for recurrent HCC, chemotherapy is administered for patients with highly advanced HCC. Among the modalities of chemotherapy, hepatic arterial infusion chemotherapy (HAIC) is employed more commonly than systemic chemotherapy, although no survival advantage has ever been demonstrated. Randomized controlled studies are currently under way to clarify the survival benefit of HAIC. Also, various novel systemic chemotherapeutic agents are currently under development in Japan, and further improvements in the treatment outcomes are expected. PMID- 25841921 TI - Status of hepatocellular carcinoma in Gulf region. AB - Hepatocellular carcinoma (HCC) has a unique geographic distribution that is likely to be determined by specific etiologic factors. There is a distinctive difference in sex and age related occurrence of disease. In the Gulf region, there are contradicting data on the prevalence and death rates due to HCC. In this review we highlight some aspects of HCC specific to the Gulf region. A retrospective analysis of 150 patient's data is presented, including demographic, epidemiological, aetiological disease status assessment with child Pugh criteria, modes of treatment and treatment related outcome. Hepatitis C virus (HCV) infection was the most common (45%) documented etiology, similar to Western European countries, followed by hepatitis B virus (HBV) infection in 27% of cases, alcoholic liver disease only in six patients (4%). Child-Pugh assessment was A in 33%, B in 37% and C in 30% of observed patients. Surgery (liver resection or transplantation) was performed in 12% and local ablation in 5% of cases. The others were treated by chemo-embolization in 17% and by systemic therapy with sorafenib in 13% of patients. Nearly half of the patients (53%) were in advanced stages and received palliative treatment. To improve the outcome of treatment in HCC patients in the Gulf region, an effective and strategic screening program must be implemented for early diagnosis and treatment to improve the outcome of this mostly fatal disease. PMID- 25841920 TI - Hepatocellular carcinoma in India. AB - Cancers of the liver are one of the commonest cancers that occur in the world, the commonest of which is the hepatocellular carcinoma (HCC). It is considered to be the 5th commonest cancer in the world. In the areas that are endemic for hepatitis B and C, it is extremely common. Unfortunately, India which is an endemic zone for hepatitis B, there has been no comprehensive analyzed data for HCC. Incidence of HCC in India occurs at two peaks, one at a young age between 40 to 55 years and another above 60 years. Eighty per cent of all HCCs occurring in India occur with cirrhosis of liver in the background and 60% of all these cases are hepatitis B positive carriers. Symptoms are reflective of late presentation with advanced disease. Surgery, the only curative modulus available, unfortunately is not possible in 95% of HCC patients. Majority of the patients are treated with palliative and supportive care and life spans are limited. Sorafenib is used in a small section of patients. Characterization of HCC with molecular sub-typing is the need of the hour. PMID- 25841922 TI - Risk factors for developing hepatocellular carcinoma in Egypt. AB - Hepatocellular carcinoma (HCC) is a common disorder worldwide and ranks 2nd and 6th most common cancer among men and women in Egypt. HCC has a rising incidence in Egypt mostly due to high prevalence of viral hepatitis and its complications. Proper management requires the interaction of multidisciplinary HCC clinic to choose the most appropriate plan. The different modalities of treatment include resection (surgery or transplantation), local ablation, chemoembolization, radioembolization and molecular targeted therapies. This paper summarizes both the environmental and host related risk factors of HCC in Egypt including well established risk factors such as hepatitis virus infection, aflatoxin, as well as possible risk factors. PMID- 25841923 TI - Status of hepatocellular cancer in Europe. AB - Hepatocellular cancer (HCC) accounts for 47,000 deaths per year in Europe and the incidence is expected to increase over the next 10-15 years. The highest incidence is found in Southern Europe, mainly attributable to chronic hepatitis C infection. The most widely used staging system used is the Barcelona-Clinic Liver Cancer (BCLC) classification according to which, 30-40% patients are suitable for potentially curative therapies including transplantation, resection or ablative therapy while the remainder are offered palliative therapy with transarterial therapy, systemic therapy or supportive care. Here we review the indications and outcomes of these interventions as applied to the European population. PMID- 25841924 TI - Current status of hepatocellular carcinoma in the United States. AB - Hepatocellular carcinoma (HCC) represents a challenging malignancy of worldwide importance and is the third most common cause of cancer-related death globally. While most of the burden of HCC is borne in Southeast Asia, particularly China, and sub-Saharan Africa, there have been several interesting trends of HCC in the United States in the past decades. First, the latest epidemiology trend has shown that the incidence rates for HCC in the United States have been rising. While most cancer related mortality is decreasing in the United States, deaths from HCC are increasing and at a rate faster than deaths from any other types of cancer. Second, early diagnosis of HCC continues to be challenging and most patients would present with unresectable disease. Third, the management of HCC is evolving with many new treatment modalities applied in clinical practice. In addition, multidisciplinary team efforts with increasing role of oncologists have emerged in the management of HCC in most centers in the United States. In this review, the author will highlight the key trends and current status of HCC in the United States. PMID- 25841925 TI - High symptom burden in children with cancer and high parental satisfaction: why the disconnect? PMID- 25841926 TI - Optimizing transcatheter therapies for hepatocellular carcinoma: invited editorial regarding "Roles played by chemolipiodolization and embolization in chemoembolization for hepatocellular carcinoma: single-blind, randomized trial". PMID- 25841927 TI - Quality of life and symptom prevalence in children with cancer in Lebanon: the perspective of parents. AB - In evaluating the outcomes of pediatric palliative care, health-care providers rely at times on the parents' input in evaluating children's quality of life and symptom experience. To date, the number of studies addressing the perspective of parents is scarce. Thus, the purpose of this study was to evaluate the quality of life, symptom prevalence and management, and the quality of palliative care provided to Lebanese children with cancer from their parents' perspectives. A convenience sample of 85 caregivers from the Children's Cancer Center of Lebanon was enrolled in the study over a 1-year period [2010-2011]. Using face- to-face interviews, the administered Arabic questionnaire was a combination of the Pediatric Quality of Life Inventory cancer module and the Memorial Symptom Assessment Scale (both parent's versions), and selected items from the Needs at End of life Screening Tool. The majority of the sample was recruited from the outpatient clinic; mean age of children was 12.5 years with the majority having leukemia. According to parents, children encountered health-related quality of life problems in the areas related to nausea, worry and treatment anxiety. The most common symptoms were feeling irritable, feeling nervous, lack of energy, lack of appetite, pain, and feeling sad. The most treated symptoms were found to be nausea, vomiting, cough, and pain with success rates ranging between 56.3% and 73.7%. According to the parents, cancer children had acceptable health-related quality of life. They experienced physical and psychological symptoms that were inadequately managed by the healthcare team. However, parents were highly satisfied with the provided quality of care by the center. The findings in this study highlight the importance of both physical and psychological symptom management among Lebanese children with cancer. PMID- 25841928 TI - Skin toxicity after palliative chemotherapy containing pegylated liposomal doxorubicin for ovarian cancer patients. AB - BACKGROUND: Skin toxicity in the course of anticancer treatment occurs in majority of patients and may substantially reduce quality of life. Pegylated liposomal doxorubicin (PLD) is an anthracyclines' derivative with reducing severity of cardiotoxicity and myelosuppression but with localized skin lesions on the palms and the soles (PPE). MATERIAL AND METHODS: The retrospective analysis included medical records of ovarian cancer patients who were treated with PLD due to disease progression after prior therapy. The impact of several factors on the risk and severity of PPE was analyzed. RESULTS: In analyzed group of ovarian cancer PPE occurred more often in patients who have previously received more than two chemotherapy lines, P=0.09. The risk of PPE increased with the number of chemotherapy cycles, P<0.001 and anemia, P=0.038. In 5% of pts dose reduction was necessary due to PPE. CONCLUSIONS: Skin toxicity may significantly limit the possibility to continue the treatment. Good communication with patients and their families, close cooperation with family doctors, palliative care and dermatologists is essential for prompt and effective treatment of skin toxicity. Early preventive actions make to alleviate the discomfort associated with skin complications. PMID- 25841929 TI - Assessing psychosocial distress: a pain audit at IRCH-AIIMS. AB - AIM: Recent work in palliative care has recognized that pain is a complex social, psychological, spiritual and psychological experience. In order to assess if each of these components is equally well addressed in clinical practice, we undertook a retrospective audit of psychosocial assessment procedures at the pain clinic at IRCH-AIIMS, New Delhi. METHODS: 686 pain assessment forms collected over 2011 were examined and analysed through SPPS. RESULTS: (I) While physical aspects of pain are recorded at almost 100% levels in the pain forms, psychosocial components of patient distress are found to be less adequately recorded; (II) The layout the assessment is slanted towards functional factors (such interference with daily activities and mobility), while non-functional symptoms are being recorded at relatively low levels (anxiety-1.2%, depression-4.4%). Prior studies in the same clinic as well as in the Indian psycho-oncology literature has shown that non-functional distress (such as anxiety and depression) are usually found at much higher rates of incidence (33-80%); (III) Analysis of the existing data revealed severe demographic vulnerabilities in our patient sample, an aspect that is recorded but not currently addressed as part of a psychosocial assessment. CONCLUSIONS: In light of these findings we surveyed 14 existing pain assessment tools, and chose two for incorporation into our existing pain practice. These tools were the Distress Inventory for Cancer-2 and the American Pain Society Patient Outcome Questionnaire. They were chosen for their balance between functional and non-functional symptoms, sensitivity to socioeconomic distress and ease of completion in the high volume public health scenario. PMID- 25841930 TI - Adverse reactions and their management in the treatment of malignant tumors using cytokine-induced killer cells. AB - OBJECTIVE: To identify the causes and the corresponding management of adverse reactions during the treatment of malignant tumors using cytokine-induced killer cells. METHODS: From January 2012 to December 2012, 441 patients received a total of 1,393 autologous cytokine-induced killer cell transfusion cycles in our department. The adverse reactions after the procedures were observed (assessed using the National Cancer Institute Common Toxicity version 2.0), and targeted care and health education were delivered by nurses. RESULTS: All treatment sessions were successfully completed, and the following adverse reactions were found: grade 1/3 fever in 1.36% (19/1,393) patients; grade 2/3 fever in 0.86% (12/1,393) patients; grade 2/3 chills in 0.65% (9/1,393) patients; and grade 1/3 dizziness in 0.29% (4/1,393) patients. CONCLUSIONS: After timely intervention of the adverse reactions, all patients were treated successfully. The best timing of the CIK cell therapy for cancer patients is when the tumor burden, or the number of tumor cells, reaches the minimal level after the end of surgery, chemotherapy and radiation therapy. PMID- 25841931 TI - The reimbursement system is not the dominant factor influencing reluctance to perform single-fraction radiotherapy for painful bone metastases. PMID- 25841932 TI - Radiotherapy in palliative treatment of metastatic NSCLC: not all one and the same. PMID- 25841933 TI - Helping patients articulate end-of-life wishes: a target for interprofessional participation. PMID- 25841934 TI - Promotion of case management with coordinated care for fatigued patients with advanced cancer. PMID- 25841935 TI - The generalizability paradox within palliative care clinical trials. AB - We are increasingly recognizing that personalized advanced and chronic illness care requires meticulous assessment and management of supportive care needs across the entire disease trajectory. This requires drawing clinical decisions from a research evidence base that is presumably generalizable to a heterogeneous patient population, often with poor performance status, multi-morbidity, and a large symptom distress profile. As sometimes this is not the case, how do we improve evidence generation that can be consistently applied to all patients with advanced disease? PMID- 25841936 TI - Commentary on children's palliative care. PMID- 25841938 TI - Optimization of brushless direct current motor design using an intelligent technique. AB - This paper presents a method for the optimal design of a slotless permanent magnet brushless DC (BLDC) motor with surface mounted magnets using an improved bee algorithm (IBA). The characteristics of the motor are expressed as functions of motor geometries. The objective function is a combination of losses, volume and cost to be minimized simultaneously. This method is based on the capability of swarm-based algorithms in finding the optimal solution. One sample case is used to illustrate the performance of the design approach and optimization technique. The IBA has a better performance and speed of convergence compared with bee algorithm (BA). Simulation results show that the proposed method has a very high/efficient performance. PMID- 25841939 TI - The recent views in treatment decision making for chronic kidney disease. PMID- 25841937 TI - Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'. AB - 'Autoantigen complementarity' is a theory proposing that the initiator of an autoimmune response is not necessarily the autoantigen or its molecular mimic, but may instead be a peptide that is 'antisense/complementary' to the autoantigen. We investigated whether such complementary proteins play a role in the immunopathogenesis of autoimmune glomerulonephritis. Experimental autoimmune glomerulonephritis, a model of anti-glomerular basement membrane (GBM) disease, can be induced in Wistar Kyoto (WKY) rats by immunization with the alpha3 chain of type IV collagen. In this study, WKY rats were immunized with a complementary alpha3 peptide (c-alpha3-Gly) comprised of amino acids that 'complement' the well characterized epitope on alpha3(IV)NC1, pCol(24-38). Within 8 weeks post immunization, these animals developed cresentic glomerulonephritis, similar to pCol(24-38)-immunized rats, while animals immunized with scrambled peptide were normal. Anti-idiotypic antibodies to epitopes from c-alpha3-Gly-immunized animals were shown to be specific for alpha3 protein, binding in a region containing sense pCol(24-38) sequence. Interestingly, anti-complementary alpha3 antibodies were identified in sera from patients with anti-GBM disease, suggesting a role for 'autoantigen complementarity' in immunopathogenesis of the human disease. This work supports the idea that autoimmune glomerulonephritis can be initiated through an immune response against a peptide that is anti-sense or complementary to the autoantigen. The implications of this discovery may be far reaching, and other autoimmune diseases could be due to responses to these once unsuspected 'complementary' antigens. PMID- 25841940 TI - Isolation and evaluation of dental pulp stem cells from teeth with advanced periodontal disease. AB - INTRODUCTION: Successful isolation of mesenchymal stem cells from waste tissues might be extremely promising for developing stem cell-based therapies. This study aimed to explore whether cells retrieved from teeth extracted due to advanced periodontal disease present mesenchymal stem cell-like properties. METHODS: Pulp cells were isolated from 15 intact molars and 15 teeth with advanced periodontal disease. Cell proliferation and markers of mesenchymal stem cells were evaluated. RESULTS: Based on the RT-PCR and agarose gel electrophoresis, nucleostemin, Oct-4 and jmj2c, but not Nanog, were expressed in undifferentiated mesenchymal stem cells of both groups. Interestingly, diseased pulp exhibited higher gene expressions although it was not statistically significant. The average percentage of BrdU positive cells in the diseased group (84.4%, n = 5) was significantly higher than that of the control group (65.4%, n = 5) (t-test, P = 0.001). CONCLUSION: Our results indicate the successful isolation of mesenchymal stem cells from the pulp tissue of hopeless periodontally involved teeth. PMID- 25841941 TI - Epithelial-myoepithelial carcinoma--review of clinicopathological and immunohistochemical features. AB - INTRODUCTION: Epithelial-myoepithelial carcinoma is a low-grade malignant salivary gland neoplasm with a biphasic cell population that encompasses around 1% of all salivary neoplasms. METHOD: We present different cases of epithelial myoepithelial carcinoma, with special emphasis on histopathology, differential diagnosis, relevant prognostic factors and follow-up. RESULT: This study included 8 patients who were diagnosed with epithelial-myoepithelial carcinoma and treated surgically including a follow-up period of at least 19 months. CONCLUSION: Clinical and histopathological characteristics of these rare tumors are extremely valuable for accurate diagnosis and further therapy planning. PMID- 25841942 TI - A comparative approach between heterologous prime-boost vaccination strategy and DNA vaccinations for rabies. AB - BACKGROUND AND AIM: Rabies is a widespread neurological zoonotic disease causing significant mortality rates, especially in developing countries. Although a vaccine for rabies is available, its production and scheduling are costly in such countries. Advances in recombinant DNA technology have made it a good candidate for an affordable vaccine. Among the proteins of rabies virus, the Glycoprotein (RVG) has been the major target for new vaccine development which plays the principal role in providing complete protection against RV challenge. The aim of this study is to produce recombinant RVG which could be a DNA vaccine candidate and to evaluate the efficiency of this construct in a prime-boost vaccination regimen, compared to commercial vaccine. METHODS: Cloning to pcDNA3.1(+) and expression of rabies virus glycoprotein gene in BSR cell line were performed followed by SDS-PAGE and Western blot analysis of the expressed glycoprotein. The resulting genetic construct was used as a DNA vaccine by injecting 80 ug of the plasmid to MNRI mice twice. Prime-Boost vaccination strategy was performed using 80 ug plasmid construct as prime dose and the second dose of an inactivated rabies virus vaccine. Production of rabies virus neutralizing antibody (RVNA) titers of the serum samples were determined by RFFIT. RESULTS: In comparisons between heterologous prime-boost vaccination strategy and DNA vaccinations, the potency of group D that received Prime-Boost vaccine with the second dose of pcDNA3.1(+)-Gp was enhanced significantly compared to the group C which had received pcDNA3.1(+)-Gp as first injection. CONCLUSION: In this study, RVGP expressing construct was used in a comparative approach between Prime-Boost vaccination strategy and DNA vaccination and compared with the standard method of rabies vaccination. It was concluded that this strategy could lead to induction of acceptable humoral immunity. PMID- 25841943 TI - Adverse cutaneous drug reactions--a clinico-demographic study in a tertiary care teaching hospital of the Kashmir Valley, India. AB - BACKGROUND: Adverse cutaneous drug reactions (ACDRs) are caused by a wide variety of agents. The aim was to study the incidence and clinico-demographic profile of ACDRs to identify any potential risk factors and compare the results with other studies. METHODS: A cross-sectional observational study was conducted over a period of one year from October 2012 to October 2013 in the outpatient department (OPD) of a tertiary care teaching hospital of the Kashmir valley in India and various ACDRs were recorded. RESULTS: The incidence of ACDRs was 0.16%. The mean age of patients was 39.36 +/- 16.77 years. The male: female ratio was 0.97:1. The most frequently reported cutaneous reactions were with antimicrobials (57.33%) followed by NSAIDs (21.33%) and antiepileptic drugs (17.33%). Less common groups involved were steroids, antipsychotics and bisphosphonates (1.33% each). Fixed drug eruptions (FDEs) were the commonest (45.33%) followed by maculopapular (17.33%), photoallergic (8%), erythema multiforme (6.66%), Stevens-Johnson syndrome (5.33%) and lichenoid eruptions (4%). Less common patterns were urticaria, Drug Reaction with Eosinophilia and systemic symptoms (DRESS syndrome) and acneform eruptions (2.66% each) followed by angioedema, acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis and toxic epidermal necrolysis (1.33% each). CONCLUSION: Physicians should have adequate knowledge of adverse drug reactions, especially of newer drugs which are increasing every year in order to minimize such events. PMID- 25841944 TI - Prevalence and comorbidity of depression, anxiety and obsessive compulsive disorders among Saudi secondary school girls, Taif Area, KSA. AB - BACKGROUND: Previous Saudi studies have shown the psychiatric comorbidity among adolescent girls. This article was done to assess the prevalence and comorbidity of psychiatric disorders among secondary school girls in Taif area. METHODS: A cross-sectional multistage cluster-sampling methodology was carried out on 1024 secondary school female students. Psychometric evaluation of students was carried out using the Beck depression inventory, Castello and Comery Anxiety scale and Obsessive - compulsive disorder scale. RESULTS: Out of the 1024 participants, 42.9%, 54.9%, and 23.1% had significant depression, anxiety and obsessive compulsive symptoms, respectively. In addition, 64.7% of them had symptoms of the three studied disorders. A highly significant positive correlation was found between depression score and both anxiety and OC symptoms scores and between anxiety score and OC symptoms score. CONCLUSIONS: There is a need for a national intervention program for promotion of adolescent mental health. The program should include screening of students using the psychometric scales. PMID- 25841945 TI - Potential impact of peer mentoring on treatment choice in patients with chronic kidney disease: a review. AB - Chronic kidney disease (CKD) and the resultant end stage renal disease (ESRD) are associated with significant mortality, morbidity, and cost for the individual patient and society. CKD is among the major contributors to years of life lost (YLL) due to premature mortality. Also, while the disability adjusted life years (DALY) for many conditions decreased between 1990 and 2010, the DALY for CKD has increased by 69%. In addition to the physical disability, CKD is associated with high prevalence (27.9%) of major depressive episodes, associated with limitations of employment, and a significant negative effect on quality of life (QOL). A major determinant of QOL is satisfaction with treatment choice. There is consensus among investigators that patients who are actively engaged in their own care experience improved health outcomes. The shared decision making (SDM) approach allows patients and providers the opportunity to work in partnership to make decisions that are congruent with the patient's values, preferences, and distinct situations. SDM has been associated with improved outcomes among patients with various chronic disease states. Mentoring, particularly by trained peers, has been used as an approach to enhance SDM in several chronic conditions, including cancer and cardiovascular disease. In this review, we will focus on care of patients with CKD as a model for the study of the impact of peer mentoring on SDM and choice of treatment for ESRD. PMID- 25841946 TI - The role of infectious mediators and gut microbiome in the pathogenesis of celiac disease. AB - Celiac disease (CD) is an immune disorder that is associated with gluten sensitivity in people who are genetically predisposed. In celiac disease, food containing gluten mounts inflammatory response that results in villous atrophy in small bowel and increased permeability. This disorder is not only related to complications in the small bowel, but also has association with manifestations outside the GI tract. Small bowel mucosal immunity, exposed to infectious agents, is affected by CD; therefore, it is likely that patients with untreated celiac disease are more susceptible to infectious diseases. It is possible that sensitivity to gluten increases in patients infected with infectious diseases, and consequently infection may trigger CD in susceptible individuals. It is likely that, due to reduced immunity following the loss of intestinal villi, viral, bacterial, and parasitic infections develop faster in celiac disease patients and systemic complication occur more frequently. In addition, increased permeability, changing the microbiota following the chronic inflammation of the small intestine and abnormal immunological reactions are associated with celiac disease. PubMed, Medline, Google scholar, SID, and Magiran were searched for full text articles published between 1999 and 2014 in Persian and English. The associated keywords were used, and papers, which described particularly the impact of infectious agents on celiac disease, were selected. In this review, we have focused on the role of infectious agents and gut microbiota in the pathogenesis of celiac disease. PMID- 25841947 TI - Treatment of bladder transitional cell carcinoma in children: a single center experience from China. AB - Transitional cell carcinoma of urinary bladder (TCCB) is an extreme rare entity in childhood. We aim to report our experience in treating this tumor. From 1980 to 2013, four patients (4 males, aged 11, 14, 15, and 17 years) were referred to our center with TCCB. The clinicopathological features, means of treatment, and prognostic outcomes were reviewed from the medical records. Of all the four patients, three presented with gross hematuria, whereas the other patient presented with dysuria. All patients were treated with transurethral resection alone, but one patient underwent postoperative multiple intravesical instillation of hydroxycamptothecin. Postoperative histological studies showed low-grade papillary urothelial carcinoma for all patients. No evidence of recurrence has been observed during the follow up. In childhood, TCCB which carries an excellent prognosis is low-grade and non-invasive. The general principle of therapy is transurethral resection. Bladder ultrasound is an efficient tool in the screening protocol, especially for low-grade TCCB patients. PMID- 25841948 TI - Simultaneous occurrence of two squamous cell carcinomas developing in a nevus sebaceous. AB - Nevus sebaceous (NS), also known as organoid nevus, is a congenital skin hamartoma involving pilosebaceous follicle, epidermis and adnexal structures, which usually occurs in the head and neck region. During the first stage, which is seen in infancy and childhood, the lesion remains static, but can subsequently grow during puberty to become more evident and verrucous or nodular. Depending on the location and extent, nevus sebaceous causes only a cosmetic problem during childhood; however, the development of benign and malignant neoplasms on the lesion is the most severe complication during adulthood. The association between nevus sebaceous and various benign and malignant cutaneous neoplasms is well documented. Basal cell carcinoma (BCC) is the most common malignant lesion, and syringocystadenoma papilliferum (SP) is the most common benign tumor associated with nevus sebaceous. Development of squamous cell carcinoma within NS is very rare. The literature contains only a few reports of simultaneous multiple malignant tumors developing on nevus sebaceous. We present a review of the literature and report the case of a 42-year-old female patient with two squamous cell carcinomas (SCC) simultaneously within a single NS. PMID- 25841949 TI - A rare case of aphallia with right kidney hypoplasia and left kidney dysplasia. AB - Aphallia or penile agenesis is an extremely rare congenital anomaly with an estimated incidence rate of 1 in 10 to 30 million births. We report a rare case of aphallia with right kidney hypoplasia and left kidney dysplasia in a 10-day old Iranian-Azeri male. The patient had creatinine rise and renal failure due to dysplastic left kidney and hypoplastic right kidney and expired on fifth day of admission. There were only six cases of renal malformation associated with aphallia in the literature review. Three of the cases were complicated by Potter sequence and one of them was accompanied by chronic renal failure. Our case had a unique presentation because of bilateral renal malformation and subsequent renal failure without the Potter sequence. PMID- 25841950 TI - Uterine primitive neuroectodermal tumor. AB - Primitive neuroectodermal tumors are fairly rare in uterus. A case of uterine body primitive neuroectodermal tumor in a 32-year-old Iranian woman is presented. The patient was admitted with abdominal pain and fever and underwent emergency exploratory surgery with total abdominal hysterectomy, bilateral salpingo oophorectomy, and pelvic lymph node dissection. Posterior wall of the uterus was necrotic and ruptured and a huge tumor disrupted the uterine body. The tumor was strongly positive for CD99, NSE, and chromogranin; No reaction was seen for CD10, CD45 and myogenin. To the best of our knowledge, this is the first report of an uterine body primitive neuroectodermal tumor and the second report of uterine primitive neuroectodermal tumor from Iran. PMID- 25841951 TI - Medical care of children during the golden age of Islamic medicine. AB - During the Sassanid Empire in Persia (226-652 AD), there was a renaissance of humanistic sciences, including medicine, in the city of Gondi-Shapur. When the Islamic center of power moved to Baghdad in about 750 AD, physicians of Gondi Shapur, including the dean of the medical school (a Nestorian Christian), gradually moved to Baghdad constructing hospitals and medical schools. Aided by the Persian and Nestorian Christians, the Islamic civilization ushered in what is considered to be the Golden Age of Islam from the 8th to 13th century AD. During this period, there were remarkable achievements in humanistic sciences including medicine by many physicians/authors whose medical textbooks were used for centuries in burgeoning medical schools in Europe. The medical texts written during the Golden Age of Islamic Medicine contain sections and chapters about the clinical conditions, diseases and medical care of children. It was during this era that the first treatise was written on the diseases of children and their care. This essay will describe, in brief, the writings about the conditions and diseases of children and their medical care, by three prominent Persian physicians of the Golden Age of Islamic Medicine: 1) Abubakr Muhammad Ibn Zakaria Razi, Rhazes (865-925 AD); 2) Ali ibn-al-Abbas al-Majusi or Haly Abbas (949-994 AD); and 3) Abu Ali al-Husayn ibn Abd Allah ibn Sina or Avicenna (980-1037 AD). PMID- 25841952 TI - The necessity of Improvement Statistical Management and Communication of identified suicides. PMID- 25841953 TI - Achalasia and pneumonia. PMID- 25841954 TI - Ebola worker's foot. PMID- 25841955 TI - Phase Transformation Behavior and Resistance to Bending and Cyclic Fatigue of ProTaper Gold and ProTaper Universal Instruments. AB - INTRODUCTION: The purpose of this study was to compare the flexibility and cyclic fatigue resistance of ProTaper Universal (PTU; Dentsply Tulsa Dental Specialities, Tulsa, OK) and ProTaper Gold (PTG; Dentsply Tulsa Dental Specialities, Tulsa, OK) instruments in relation to their phase transformation behavior. METHODS: Sizes S1, S2, F1, F2, and F3 of PTU and PTG instruments were subjected to rotational bending at a curvature of 40 degrees and a radius of 6 mm. The number of cycles to fracture (NCF) was recorded. The fracture surface of all fragments was examined with a scanning electron microscope. Flexibility was determined by 45 degrees bending tests according to the ISO 3630-1 specification. Unused and fractured instruments were examined by differential scanning calorimetry. RESULTS: PTG had a cyclic fatigue resistance superior to PTU in all sizes (P < .001). The NCF of the nickel-titanium files of sizes S1 and S2 was significantly higher than those of sizes F1 to F3 (P < .001). No significant difference in the NCF of PTU instruments was detected between F1 and F2. The fractured files of both PTU and PTG showed the typical fracture pattern of fatigue failure. The bending load values were significantly lower for PTG than for PTU (P < .05). The differential scanning calorimetry analyses showed that each segment of the PTG instruments had a higher austenite finish temperature (50.1 degrees C +/- 1.7 degrees C) than the PTU instruments (21.2 degrees C +/- 1.9 degrees C) (P < .001). PTG instruments had a 2-stage transformation behavior. There was no significant difference in the austenite finish between unused files and instruments subjected to the fatigue process. CONCLUSIONS: PTG files were significantly more flexible and resistant to fatigue than PTU files. PTG exhibited different phase transformation behavior than PTU, which may be attributed to the special heat treatment history of PTG instruments. PTG may be more suited for preparing canals with a more abrupt curvature. PMID- 25841956 TI - Quantitative Transportation Assessment in Simulated Curved Canals Prepared with an Adaptive Movement System. AB - INTRODUCTION: The aim of this study was to evaluate the ability of the Twisted File Adaptive (TF Adaptive; SybronEndo, Orange, CA) system in maintaining the original profile of root canal anatomy. The ProTaper Universal (Dentsply Maillefer, Ballaigues, Switzerland) and Twisted File (TF) (SybronEndo) systems were used as reference techniques for comparison. METHODS: Thirty simulated curved root canals manufactured in clear resin blocks were randomly assigned to 3 groups (n = 10) according to the instrumentation system: TF in rotary motion, TF in TF Adaptive motion, and ProTaper Universal. Color stereomicroscopic images from each block were taken exactly at the same position before and after instrumentation. All image processing and data analysis were performed with an open-source program (Fiji). Evaluation of canal transportation was obtained for 2 independent canal regions: straight and curved levels. Univariate analysis of variance and Tukey Honestly Significant Difference were used, and a cutoff for significance was set at alpha = 5%. RESULTS: Instrumentation systems significantly influenced canal transportation (P = .000). A significant interaction between instrumentation system and root canal level (P = .000) was also found as follows: at the straight part, TF and TF Adaptive systems produced similar canal transportation, which was significantly lower than for the ProTaper Universal system; at the curved part, TF resulted in the lowest canal transportation followed by TF Adaptive and ProTaper Universal systems. Canal transportation was higher at the curved canal parts (P = .00). CONCLUSIONS: The TF in rotary motion produced overall less canal transportation in the curved portion when compared with the others tested systems. The ProTaper Universal system showed the highest canal transportation. PMID- 25841957 TI - Outcome of Direct Pulp Capping with Mineral Trioxide Aggregate: A Prospective Study. AB - INTRODUCTION: The aim of this experimental study was to assess the outcome of direct pulp capping with mineral trioxide aggregate (MTA) after complete excavation of caries in permanent dentition with a 2-visit treatment protocol. METHODS: Sixty-four teeth with deep carious lesions were consecutively selected. The mean age of the patients was 36.1 +/- 15 years. An initial diagnosis of deep caries, with no irreversible pulp involvement, was made. Excavation of caries was performed under a rubber dam and operating microscope magnification. White MTA was applied, and a provisional restoration was placed. At the following appointment, positive sensibility testing and the MTA setting were confirmed. Bonded composite restorations were placed afterward. The patient was recalled at least 1 year after treatment for clinical and radiographic control. Outcome was described as success or failure. Success was defined as lack of complaints from the patient, positive reaction to cold testing, no sensitivity to percussion, and no widening of the periodontal ligament on the recall periapical radiograph. RESULTS: Forty-six teeth (77.9%) were recalled after 3.6 years (standard deviation = 1.1 years). The overall success rate was 91.3%. The success rate in occlusal caries was 100% and 89.7% in proximal caries (difference = 10.3%; 95% confidence interval [CI], 8.5-89.1). The success rate in initial caries was 94.7% and 88.9% in secondary caries (difference = 5.8%; 95% CI, -48.1 to 59.7). The success rate in patients younger than 40 years was 100% and 80% in patients aged 40 years or older (difference = 20%; 95% CI, 4.2-35.8). CONCLUSIONS: Direct pulp capping with MTA after pulp exposure during excavation of deep caries could maintain pulp vitality in permanent teeth when a 2-visit treatment protocol is observed. PMID- 25841958 TI - ProFile Vortex and Vortex Blue Nickel-Titanium Rotary Instruments after Clinical Use. AB - INTRODUCTION: The aim of this study was to analyze the incidence and mode of ProFile Vortex and Vortex Blue instrument defects after clinical use in a graduate endodontic program and to examine the impact of clinical use on the instruments' metallurgical properties. METHODS: A total of 330 ProFile Vortex and 1136 Vortex Blue instruments from the graduate program were collected after each had been used in 3 teeth. The incidence and type of instrument defects were analyzed. The lateral surfaces and fracture surfaces of the fractured files were examined by using scanning electron microscopy. Unused and used instruments were examined by full and partial differential scanning calorimetry. RESULTS: No fractures were observed in the 330 ProFile Vortex instruments, whereas 20 (6.1%) revealed bent or blunt defects. Only 2 of the 1136 Vortex Blue files fractured during clinical use. The cause of fracture was shear stress. The fractures occurred at the tip end of the spirals. Only 1.8% (21 of 1136) of the Vortex Blue files had blunt tips. Austenite-finish temperatures were very similar for unused and used ProFile Vortex files and were all greater than 50 degrees C. The austenite-finish temperatures of used and unused Vortex Blue files (38.5 degrees C) were lower than those in ProFile Vortex instruments (P < .001). However, the transformation behavior of Vortex Blue files had an obvious 2-stage transformation, martensite-to-R phase and R-to-austenite phase. The trends of differential scanning calorimetry plots of unused Vortex Blue instruments and clinically used instruments were very similar. CONCLUSIONS: The risk of ProFile Vortex and Vortex Blue instrument fracture is very low when instruments are discarded after clinical use in the graduate endodontic program. The Vortex Blue files have metallurgical behavior different from ProFile Vortex instruments. PMID- 25841959 TI - Effect of Buffered 4% Lidocaine on the Success of the Inferior Alveolar Nerve Block in Patients with Symptomatic Irreversible Pulpitis: A Prospective, Randomized, Double-blind Study. AB - INTRODUCTION: Medical studies have suggested that buffering local anesthetic may increase the ability to achieve anesthesia. The purpose of this study was to determine the effect of 4% buffered lidocaine on the anesthetic success of the inferior alveolar nerve (IAN) block in patients experiencing symptomatic irreversible pulpitis. METHODS: One hundred emergency patients diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth randomly received a conventional IAN block using either 2.8 mL 4% lidocaine with 1:100,000 epinephrine or 2.8 mL 4% lidocaine with 1:100,000 epinephrine buffered with sodium bicarbonate in a double-blind manner. For the buffered solution, each cartridge was buffered with 8.4% sodium bicarbonate using the OnPharma (Los Gatos, CA) system to produce a final concentration of 0.18 mEq/mL sodium bicarbonate. Fifteen minutes after administration of the IAN block, profound lip numbness was confirmed, and endodontic access was initiated. Success was defined as no or mild pain (<=54 mm on a 170-mm visual analog scale) on access or instrumentation of the root canal. RESULTS: The success rate for the IAN block was 32% for the buffered group and 40% for the nonbuffered group, with no significant difference (P = .4047) between the groups. Injection pain ratings for the IAN block were not significantly (P = .9080) different between the 2 formulations. CONCLUSIONS: For mandibular posterior teeth, a 4% buffered lidocaine formulation did not result in a statistically significant increase in the success rate or a decrease in injection pain of the IAN block in patients with symptomatic irreversible pulpitis. PMID- 25841960 TI - Effect of automatic cluster removers on milking efficiency and teat condition of Manchega ewes. AB - Milking operations represent more than 50% of the work on a dairy ewe farm. The implementation of automatic cluster removers (ACR) is gaining popularity, as it allows the operator to avoid manual cluster detachments, simplifying the milking routines. The aim of this study was to discover the effect on the milking of Manchega ewes over an entire lactation period by using this type of devices, set up with 2 different combinations of milk flow threshold (MF) and delay time (DT) and comparing them with the traditional method using manual cluster removal. During a 15-d pre-experimental period, the animals were milked without ACR and sampling was performed to select 108 ewes and distribute them into 3 groups of similar characteristics according to their parity, milk yield, milking duration, and mammary gland sanitary status. Later, each group was milked for a duration of 4 mo in 3 different conditions: 1 with manual cluster removal, the second setting the ACR at MF 150 g/min and DT 20 s, and the third setting the ACR at MF 200 g/min and DT 10 s. Samplings of milking fraction, milking duration, milk composition, mammary gland sanitary status, teat-end status, and vacuum level in the short milk tubes during milking were performed. The use of ACR limited the vacuum drops in the short milk tubes and the edema in the teat end after milking, although no reduction in the number of new cases of mastitis was observed and the milk composition did not change. Moreover, it was noted that the use of ACR set with MF 150 g/min and DT 20 s was more efficient than the manual cluster removal, as it obtained a similar amount of extracted milk but took less time. Conversely, the use of ACR set with MF 200 g/min and DT 10 s involved a higher reduction in individual milking duration and the milking duration of groups of animals but reduced milk extracted. PMID- 25841961 TI - Technical note: Comparison of radial immunodiffusion and ELISA for quantification of bovine immunoglobulin G in colostrum and plasma. AB - Historically, radial immunodiffusion (RID) has been the only method that directly measures IgG; however, recent studies have reported IgG concentrations in colostrum, milk, and plasma as measured using an ELISA. To our knowledge no comparison between RID and ELISA methods has been made for bovine colostrum or plasma. The objective of this study was to compare IgG concentrations measured by both methods in samples of bovine colostrum before and after heat treatment and bovine plasma. Concentration of IgG was quantified using a commercially available RID kit and a modified ELISA. Samples of bovine colostrum and plasma were collected from individual animals and colostrum was tested before and after heat treatment at 60 degrees C for 30 min. All samples were tested using both methods. Pearson correlation coefficients were determined for RID and ELISA values from unheated colostrum, heat-treated colostrum, and plasma samples. Mixed models were used to determine the effect of assay on IgG measurement in colostrum and plasma and effect of heat treatment on IgG concentration in colostrum. A weak correlation was found between ELISA and RID results in plasma and unheated colostrum. Concentration of IgG was significantly lower in all sample types when measured by ELISA compared to RID. Thus, direct comparison of ELISA and RID results is not recommended. Colostrum IgG concentration significantly decreased after heat treatment as measured by ELISA, but means were not different when measured by RID. Correlation plots between colostrum values measured before and after heat treatment indicated changes in the colostrum protein matrix due to heat affected RID and ELISA assays differently. This investigation compared RID and ELISA results, but no conclusions could be drawn as to the accuracy of either assay. PMID- 25841962 TI - Feed conversion efficiency in dairy cows: Repeatability, variation in digestion and metabolism of energy and nitrogen, and ruminal methanogens. AB - The objective was to study repeatability and sources of variation in feed conversion efficiency [FCE, milk kg/kg dry matter intake (DMI)] of lactating cows in mid to late lactation. Trials 1 and 2 used 16 cows (106 to 368 d in milk) grouped in 8 pairs of 1 high- and 1 low-FCE cow less than 16 d in milk apart. Trial 1 determined the repeatability of FCE during a 12-wk period. Trial 2 quantified the digestive and metabolic partitioning of energy and N with a 3-d total fecal and urine collection and measurement of CH4 and CO2 emission. Trial 3 studied selected ruminal methanogens in 2 pairs of cows fitted with rumen cannulas. Cows received a single diet including 28% corn silage, 27% alfalfa silage, 17% crude protein, and 28% neutral detergent fiber (dry matter basis). In trial 1, mean FCE remained repeatedly different and averaged 1.83 and 1.03 for high- and low-FCE cows, respectively. In trial 2, high-FCE cows consumed 21% more DMI, produced 98% more fat- and protein-corrected milk, excreted 42% less manure per kilogram of fat- and protein-corrected milk, but emitted the same daily amount of CH4 and CO2 compared with low-FCE cows. Percentage of gross energy intake lost in feces was higher (28.6 vs. 25.9%), but urinary (2.76 vs. 3.40%) and CH4 (5.23 vs. 6.99%) losses were lower in high- than low-FCE cows. Furthermore, high-FCE cows partitioned 15% more of gross energy intake toward net energy for maintenance, body gain, and lactation (37.5 vs. 32.6%) than low-FCE cows. Lower metabolic efficiency and greater heat loss in low-FCE cows might have been associated in part with greater energy demand for immune function related to subclinical mastitis, as somatic cell count was 3.8 fold greater in low- than high-FCE cows. As a percentage of N intake, high-FCE cows tended to have greater fecal N (32.4 vs. 30.3%) and had lower urinary N (32.2 vs. 41.7%) and greater milk N (30.3 vs. 19.1%) than low-FCE cows. In trial 3, Methanobrevibacter spp. strain AbM4 was less prevalent in ruminal content of high-FCE cows, which emitted less CH4 per unit of DMI and per unit of neutral detergent fiber digested than low-FCE cows. Thus lower digestive efficiency was more than compensated by greater metabolic efficiencies in high- compared with low-FCE cows. There was not a single factor, but rather a series of mechanisms involved in the observed differences in efficiency of energy utilization of the lactating cows in this study. PMID- 25841963 TI - Stall cleanliness and stall temperature of two different freestall bases. AB - The objective of this study was to describe the differences in freestall cleanliness and stall temperature between a barn with Dual Chamber Cow Waterbeds (DCCW; Advanced Comfort Technology, Reedsburg, WI) and a barn with rubber-filled mattresses at the University of Kentucky Coldstream Dairy Research Farm from January 18, 2012, to May 3, 2013. Stall cleanliness was measured twice weekly (n=134) by the same 2 observers using a 0.91 m*0.91 m wire grid containing 128 equally sized rectangles (10.16 cm*5.08 cm). This grid was centered at the rear portion of the stall; a rectangle that was visibly wet or had any amount of feces present was defined as a dirty rectangle. Weekly stall temperature (n=66) was measured by the same observer during a.m. milkings in the same predetermined stalls. Feces and wet sawdust were removed from the stalls before stall temperatures were acquired. Temperatures were obtained using a handheld thermometer at 30.48 cm above the stall base as determined via dual laser measurements. Stall temperature was measured on the front, middle, and back of the stall first with clean sawdust and then with the sawdust removed from the stall and wiped clean with a towel. Daily temperature-humidity index (THI) was calculated using Kentucky climate data calculated through the University of Kentucky College of Agriculture via a data logger, located 5.63 km from the Coldstream Dairy Farm. Stall cleanliness was not different between the DCCW barn (26.09+/-0.89 rectangles) and the rubber-filled mattress barn (23.70+/-0.89 rectangles). Mean THI throughout the study was 64.39+/-0.82. Stall temperature was different among THI categories. Temperature-humidity index categories 1 (coldest), 2, 3, and 4 (warmest) had THI ranges of 22.94 to 50.77, 50.77 to 64.88, 64.88 to 78.75, and 78.75 to 101.59, respectively. Stall temperatures ( degrees C; least squares means+/-SE) were 2.26+/-0.30, 8.86+/-0.30, 15.52+/-0.30, and 20.95+/-0.30 for THI categories 1 to 4, respectively. Stalls with rubber filled mattresses had a lower temperature ( degrees C) than DCCW with least squares means+/-SE of 10.52+/-0.21 degrees C and 13.29+/-0.21 degrees C, respectively. The DCCW were probably significantly warmer because water holds heat well. The DCCW may have more of a heat-insulating effect compared with rubber-filled mattresses. PMID- 25841964 TI - Methyl-coenzyme M reductase A as an indicator to estimate methane production from dairy cows. AB - The evaluation of greenhouse gas mitigation strategies requires the quantitative assessment of individual methane production. Because methane measurement in respiration chambers is highly accurate, but also comprises various disadvantages such as limited capacity and high costs, the establishment of an indicator for estimating methane production of individual ruminants would provide an alternative to direct methane measurement. Methyl-coenzyme M reductase is involved in methanogenesis and the subunit alpha of methyl-coenzyme M reductase is encoded by the mcrA gene of rumen archaea. We therefore examined the relationship between methane emissions of Holstein dairy cows measured in respiration chambers with 2 different diets (high- and medium-concentrate diet) and the mcrA DNA and mcrA cDNA abundance determined from corresponding rumen fluid samples. Whole-body methane production per kilogram of dry matter intake and mcrA DNA normalized to the abundance of the rrs gene coding for 16S rRNA correlated significantly when using qmcrA primers. Use of qmcrA primers also revealed linear correlation between mcrA DNA copy number and methane yield. Regression analyses based on normalized mcrA cDNA abundances revealed no significant linear correlation with methane production per kilogram of dry matter intake. Furthermore, the correlations between normalized mcrA DNA abundance and the rumen fluid concentration of acetic and isobutyric acid were positive, whereas the correlations with propionic and lactic acid were negative. These data suggest that the mcrA DNA approach based on qmcrA primers could potentially be a molecular proxy for methane yield after further refinement. PMID- 25841965 TI - Effect of sensor systems for cow management on milk production, somatic cell count, and reproduction. AB - To improve management on dairy herds, sensor systems have been developed that can measure physiological, behavioral, and production indicators on individual cows. It is not known whether using sensor systems also improves measures of health and production in dairy herds. The objective of this study was to investigate the effect of using sensor systems on measures of health and production in dairy herds. Data of 414 Dutch dairy farms with (n=152) and without (n=262) sensor systems were available. For these herds, information on milk production per cow, days to first service, first calving age, and somatic cell count (SCC) was provided for the years 2003 to 2013. Moreover, year of investment in sensor systems was available. For every farm year, we determined whether that year was before or after the year of investment in sensor systems on farms with an automatic milking system (AMS) or a conventional milking system (CMS), or whether it was a year on a farm that never invested in sensor systems. Separate statistical analyses were performed to determine the effect of sensor systems for mastitis detection (color, SCC, electrical conductivity, and lactate dehydrogenase sensors), estrus detection for dairy cows, estrus detection for young stock, and other sensor systems (weighing platform, rumination time sensor, fat and protein sensor, temperature sensor, milk temperature sensor, urea sensor, beta-hydroxybutyrate sensor, and other sensor systems). The AMS farms had a higher average SCC (by 12,000 cells/mL) after sensor investment, and CMS farms with a mastitis detection system had a lower average SCC (by 10,000 cells/mL) in the years after sensor investment. Having sensor systems was associated with a higher average production per cow on AMS farms, and with a lower average production per cow on CMS farms in the years after investment. The most likely reason for this lower milk production after investment was that on 96% of CMS farms, the sensor system investment occurred together with another major change at the farm, such as a new barn or a new milking system. Most likely, these other changes had led to a decrease in milk production that could not be compensated for by the use of sensor systems. Having estrus detection sensor systems did not improve reproduction performance. Labor reduction was an important reason for investing in sensor systems. Therefore, economic benefits from investments in sensor systems can be expected more from the reduction in labor costs than from improvements in measures of health and production in dairy herds. PMID- 25841966 TI - How imputation errors bias genomic predictions. AB - The objective of this study was to investigate in detail the biasing effects of imputation errors on genomic predictions. Direct genomic values (DGV) of 3,494 Brown Swiss selection candidates for 37 production and conformation traits were predicted using either their observed 50K genotypes or their 50K genotypes imputed from a mimicked 6K chip. Changes in DGV caused by imputation errors were shown to be systematic. The DGV of top animals were, on average, underestimated and that of bottom animals were, on average, overestimated when imputed genotypes were used instead of observed genotypes. This pattern might be explained by the fact that imputation algorithms will usually suggest the most frequent haplotype from the sample whenever a haplotype cannot be determined unambiguously. That was empirically shown to cause an advantage for the bottom animals and a disadvantage for the top animals. PMID- 25841967 TI - Optimization of reproductive management programs using lift chart analysis and cost-sensitive evaluation of classification errors. AB - The common practice on most commercial dairy farms is to inseminate all cows that are eligible for breeding, while ignoring (or absorbing) the costs associated with semen and labor directed toward low-fertility cows that are unlikely to conceive. Modern analytical methods, such as machine learning algorithms, can be applied to cow-specific explanatory variables for the purpose of computing probabilities of success or failure associated with upcoming insemination events. Lift chart analysis can identify subsets of high fertility cows that are likely to conceive and are therefore appropriate targets for insemination (e.g., with conventional artificial insemination semen or expensive sex-enhanced semen), as well as subsets of low-fertility cows that are unlikely to conceive and should therefore be passed over at that point in time. Although such a strategy might be economically viable, the management, environmental, and financial conditions on one farm might differ widely from conditions on the next, and hence the reproductive management recommendations derived from such a tool may be suboptimal for specific farms. When coupled with cost-sensitive evaluation of misclassified and correctly classified insemination events, the strategy can be a potentially powerful tool for optimizing the reproductive management of individual farms. In the present study, lift chart analysis and cost-sensitive evaluation were applied to a data set consisting of 54,806 insemination events of primiparous Holstein cows on 26 Wisconsin farms, as well as a data set with 17,197 insemination events of primiparous Holstein cows on 3 Wisconsin farms, where the latter had more detailed information regarding health events of individual cows. In the first data set, the gains in profit associated with limiting inseminations to subsets of 79 to 97% of the most fertile eligible cows ranged from $0.44 to $2.18 per eligible cow in a monthly breeding period, depending on days in milk at breeding and milk yield relative to contemporaries. In the second data set, the strategy of inseminating only a subset consisting of 59% of the most fertile cows conferred a gain in profit of $5.21 per eligible cow in a monthly breeding period. These results suggest that, when used with a powerful classification algorithm, lift chart analysis and cost-sensitive evaluation of correctly classified and misclassified insemination events can enhance the performance and profitability of reproductive management programs on commercial dairy farms. PMID- 25841968 TI - A functional study of proximal goat beta-casein promoter and intron 1 in immortalized goat mammary epithelial cells. AB - Goat beta-casein (CSN2) promoter has been extensively used to derive expression of recombinant therapeutic protein in transgenic goats; however, little direct evidence exists for signaling molecules and the cis-elements of goat CSN2 promoter in response to lactogenic hormone stimulation in goat mammary epithelial cells. Here, we use an immortalized caprine mammary epithelial cell line (CMC) to search for evidence of the above. Serial 5'-flanking regions deleted of promoter and intron 1 in goat CSN2 (-4,047 to +2,054) driven by firefly luciferase reporter gene were constructed and applied to measure promoter activity in CMC. The intron 1 region (+393 to +501) significantly decreased basal activity of the promoter. This finding contradicts other studies of the role of intron 1. The signal transducer and activator of transcription (STAT)5a played a significant role in activating promoter activity by prolactin stimulation. Hydrocortisone enhanced and prolonged the activity of STAT5a and promoter in CMC, but was independent of the glucocorticoid receptor response element. The minimum length of the CSN2 promoter segment in response to lactogenic stimulation was confirmed by 5' serial deletions. A cis-element located from -300 to -90 in proximal goat CSN2 promoter that is absent in bovine and human CSN2 promoter was newly identified. We demonstrated the presence of a STAT5a binding site (-102 to -82) and preservation of the guanosine nucleotide at position -90 based on responses to the presence of lactogenic hormone using internal deletions and point mutations of the predicted STAT5a binding site, and chromatin immunoprecipitation assay. Together, these findings demonstrate that the proximal -300 bp of goat CSN2 promoter containing the STAT5a binding site (-102 to -82) is the response element for lactogenic hormone stimulation. Additionally, intron 1 may be required for tissue or developmental stage-specific expression in mammary gland. The role of the far-distal regions of goat CSN2 promoter in high-level lactogenic hormone induction and specific expression require further examination. PMID- 25841969 TI - Effects of alfalfa hay and its physical form (chopped versus pelleted) on performance of Holstein calves. AB - Inclusion of forage and its physical form in starter may affect rumen development, average daily gain (ADG), and dry matter intake (DMI) of dairy calves. To evaluate the effects of forage and its physical form (chopped vs. pelleted) on growth of calves under a high milk feeding regimen, 32 Holstein calves (38.8+/-1.1kg) were assigned at birth to 1 of 3 treatments in a completely randomized block design. Dietary treatments (% of dry matter) were (1) 100% semi texturized starter (CON); (2) 90% semi-texturized starter + 10% chopped alfalfa hay (mean particle size=5.4mm) as a total mixed ration (TMR; CH); and (3) 90% semi-texturized starter + 10% pelleted alfalfa (mean=5.8mm) hay as a TMR (PH). Data were subjected to mixed model analysis with contrasts used to evaluate effect of forage inclusion. Calves were weaned at 76 d of age and the experiment finished 2 wk after weaning. Individual milk and solid feed consumption were recorded daily. Solid feed consumption and ADG increased as age increased (effect of week), but neither forage inclusion nor physical form of forage affected these variables pre- or postweaning. Plasma urea N was affected by treatments such that the CON group had a lower concentration than forage-fed groups. Forage inclusion, but not physical form, resulted in increased total protein in plasma. Although days with elevated rectal temperature, fecal score, and general appearance were not affected by dietary treatments, calves fed alfalfa hay during the first month of life had fewer days with respiratory issues, regardless of physical form of hay. We concluded that provision of forage does have some beneficial effects in calves fed large amounts of milk replacer, but pelleted alfalfa hay did not result in any improvement in calf performance or health. PMID- 25841970 TI - The effect of stocking rate on soil solution nitrate concentrations beneath a free-draining dairy production system in Ireland. AB - Economically viable and productive farming systems are required to meet the growing worldwide need for agricultural produce while at the same time reducing environmental impact. Within grazing systems of animal production, increasing concern exists as to the effect of intensive farming on potential N losses to ground and surface waters, which demands an appraisal of N flows within complete grass-based dairy farming systems. A 3-yr (2011 to 2013) whole-farm system study was conducted on a free-draining soil type that is highly susceptible to N loss under temperate maritime conditions. Soil solution concentrations of N from 3 spring-calving, grass-based systems designed to represent 3 alternative whole farm stocking rate (SR) treatments in a post-milk quota situation in the European Union were compared: low (2.51 cows/ha), medium (2.92 cows/ha), and high SR (3.28 cows/ha). Each SR had its own farmlet containing 18 paddocks and 23 cows. Nitrogen loss from each treatment was measured using ceramic cups installed to a depth of 1m to sample the soil water. The annual and monthly average nitrate, nitrite, ammonia, and total N concentrations in soil solution collected were analyzed for each year using a repeated measures analysis. Subsequently, and based on the biological data collated from each farm system treatment within each year, the efficiency of N use was evaluated using an N balance model. Based on similar N inputs, increasing SR resulted in increased grazing efficiency and milk production per hectare. Stocking rate had no significant effect on soil solution concentrations of nitrate, nitrite, ammonia, or total N (26.0, 0.2, 2.4, and 32.3 mg/L, respectively). An N balance model evaluation of each treatment incorporating input and output data indicated that the increased grass utilization and milk production per hectare at higher SR resulted in a reduction in N surplus and increased N use efficiency. The results highlight the possibility for the sustainable intensification of grass-based dairy systems and suggest that, at the same level of N inputs, increasing SR has little effect on N loss in pastoral systems with limited imported feed. These results suggest that greater emphasis should be attributed to increased grass production and utilization under grazing to further improve the environmental impact of grazing systems. PMID- 25841971 TI - Biofilm-producing ability and efficiency of sanitizing agents against Prototheca zopfii isolates from bovine subclinical mastitis. AB - The objectives of the present study were to evaluate (1) the capacity of the microalga Prototheca zopfii isolated from subclinical bovine mastitis cases to form biofilms; and (2) the resistance of these isolates to sanitizing agents. Ten isolates of P. zopfii from cows with subclinical mastitis (somatic cell count>200*10(3) cells/mL), distributed in 5 dairy farms, were evaluated for their capacity to form biofilms in polystyrene microplate assays and stainless steel coupons, at 25 degrees C and 37 degrees C+/-1 degrees C. Prototheca zopfii were isolated from milk samples via microbiological culture and analyzed by 18S rRNA gene sequencing. Biofilm formation on the coupons was observed by scanning electron microscopy. The resistance to sanitizing agents was assessed using the biofilm-forming P. zopfii isolates in stainless steel coupon assays, which were subjected to 3 sanitizers: peracetic acid, sodium hypochlorite, and iodine solution. To evaluate resistance to the sanitizers, the minimum inhibitory concentration (MIC) technique was performed using decreasing concentrations of the sanitizing agents (20, 10, 5, 2.5, 1.25, 0.625, 0.312, 0.156, 0.078, 0.039, and 0.019 g/L). After inoculating the isolates, all concentrations were evaluated at 3 distinct incubation periods (24, 48, and 72 h) to assess the effect of incubation time on the MIC. Using the polystyrene microplate assays, 1 isolate showed weak biofilm production, 5 moderate, and 4 strong, when incubated at 25 degrees C+/-1. For isolates incubated at 37 degrees C+/-1, 6 showed weak biofilm production and 4 moderate. All P. zopfii isolates (n=10) had the capacity to form biofilms on stainless steel coupons. The longer the incubation period of the P. zopfii isolates at different dilutions, the greater the concentrations of sanitizer needed to prevent growth of the microalgae under the tested conditions. We detected a significant effect of sanitizer and time of incubation (24, 48, and 72 h) on MIC values against P. zopfii isolates. The isolates were sensitive in vitro to peracetic acid (MIC90>=0.019 g/L), sodium hypochlorite (MIC90>=0.312 g/L), and iodine solution (MIC90>=0.625 g/L), after 24 h of incubation (where MIC90=concentration needed to inhibit 90% of isolates). Of the tested sanitizers, peracetic acid had the greatest efficiency against P. zopfii. We conclude that P. zopfii isolates are capable of biofilm production, which may contribute to their persistence in a milking and dairy environment. PMID- 25841972 TI - Probiotic potential of selected lactic acid bacteria strains isolated from Brazilian kefir grains. AB - A total of 34 lactic acid bacteria isolates from 4 different Brazilian kefir grains were identified and characterized among a group of 150 isolates, using the ability to tolerate acidic pH and resistance to bile salts as restrictive criteria for probiotic potential. All isolates were identified by amplified ribosomal DNA restriction analysis and 16S rDNA sequencing of representative amplicons. Eighteen isolates belonged to the species Leuconostoc mesenteroides, 11 to Lactococcus lactis (of which 8 belonged to subspecies cremoris and 3 to subspecies lactis), and 5 to Lactobacillus paracasei. To exclude replicates, a molecular typing analysis was performed by combining repetitive extragenic palindromic-PCR and random amplification of polymorphic DNA techniques. Considering a threshold of 90% similarity, 32 different strains were considered. All strains showed some antagonistic activity against 4 model food pathogens. In addition, 3 Lc. lactis strains and 1 Lb. paracasei produced bacteriocin-like inhibitory substances against at least 2 indicator organisms. Moreover, 1 Lc. lactis and 2 Lb. paracasei presented good total antioxidative activity. None of these strains showed undesirable enzymatic or hemolytic activities, while proving susceptible or intrinsically resistant to a series of clinically relevant antibiotics. The Lb. paracasei strain MRS59 showed a level of adhesion to human Caco-2 epithelial cells comparable with that observed for Lactobacillus rhamnosus GG. Taken together, these properties allow the MRS59 strain to be considered a promising probiotic candidate. PMID- 25841973 TI - Genetic parameters of ovarian and uterine reproductive traits in dairy cows. AB - The objective of the study was to estimate genetic parameters of detailed reproductive traits derived from ultrasound examination of the reproductive tract as well as their genetic correlations with traditional reproductive traits. A total of 226,141 calving and insemination records as well as 74,134 ultrasound records from Irish dairy cows were used. Traditional reproductive traits included postpartum interval to first service, conception, and next calving, as well as the interval from first to last service; number of inseminations, pregnancy rate to first service, pregnant within 42 d of the herd breeding season, and submission in the first 21 d of the herd breeding season were also available. Detailed reproductive traits included resumed cyclicity at the time of ultrasound examination, incidence of multiple ovulations, incidence of early postpartum ovulation, heat detection, ovarian cystic structures, embryo loss, and uterine score; the latter was a subjectively assessed on a scale of 1 (little fluid with normal uterine tone) to 4 (large quantity of fluid with a flaccid uterine tone). Variance (and covariance) components were estimated using repeatability animal linear mixed models. Heritability for all reproductive traits were generally low (0.001-0.05), with the exception of traits related to cyclicity postpartum, regardless if defined traditionally (0.07; calving to first service) or from ultrasound examination [resumed cyclicity at the time of examination (0.07) or early postpartum ovulation (0.10)]. The genetic correlations among the detailed reproductive traits were generally favorable. The exception was the genetic correlation (0.29) between resumed cyclicity and uterine score; superior genetic merit for cyclicity postpartum was associated with inferior uterine score. Superior genetic merit for most traditional reproductive traits was associated with superior genetic merit for resumed cyclicity (genetic correlations ranged from -0.59 to -0.36 and from 0.56 to 0.70) and uterine score (genetic correlations ranged from -0.47 to 0.32 and from 0.25 to 0.52). Genetic predisposition to an increased incidence of embryo loss was associated with both an inferior uterine score (0.24) and inferior genetic merit for traditional reproductive traits (genetic correlations ranged from -0.52 to -0.42 and from 0.33 to 0.80). The results from the present study indicate that selection based on traditional reproductive traits, such as calving interval or days open, resulted in improved genetic merit of all the detailed reproductive traits evaluated in this study. Additionally, greater accuracy of selection for calving interval is expected for a relatively small progeny group size when detailed reproductive traits are included in a multitrait genetic evaluation. PMID- 25841974 TI - Corneal angiography for guiding and evaluating fine-needle diathermy treatment of corneal neovascularization. AB - PURPOSE: To investigate the outcome of selective occlusion of the afferent vessel of corneal neovascular complexes (CoNVs), using angiographically guided fine needle diathermy (FND). DESIGN: Retrospective interventional case series. SUBJECTS: Patients with CoNV unresponsive to topical steroid therapy. METHODS: Visual acuity, color images, and fluorescein angiography and indocyanine green angiography were measured before and after FND with a minimum of 3 months of follow-up. The number of afferent vessels crossing the limbus, time to fluorescein leakage, area, and geometric properties of the CoNV were determined using an in-house automated program written in numerical computing language (MatLab R14; The MathWorks Inc., Natick, MA). The location of the afferent vessel was identified from the angiographic images and marked at the slit lamp using a needle to make a cut to the depth of the vessel. We then applied FND using an electrolysis needle. MAIN OUTCOME MEASURES: Area of CoNV. RESULTS: Thirty patients underwent FND for CoNV that had not responded to treatment with topical steroids. The CoNV was associated with previous microbial keratitis (n = 26), intrastromal corneal ring segments (n = 2), ectodermal dysplasia (n = 1), and corneal choristoma (n = 1). Duration of CoNV was >6 months in 23 patients (77%), between 3 and 6 months in 3 patients (10%), and <3 months in 5 patients (13%). The number of afferent vessels per CoNV ranged from 1 to 3, with a mean diameter of 40 MUm (standard deviation [SD], 10 MUm) and mean time to leakage from apical vessels was 44.22 seconds (minimum, 27.43 seconds; maximum, 63.59 seconds). The number of FND treatments that were required was 1 for 20 patients (66.6%), 2 for 8 patients (26.6%), and 3 for 2 patients (6.6%). After FND, the area of CoNV reduced by 1.80 mm(2) (SD, 1.40 mm(2)), from 2.42 (SD, 1.59) to 0.62 mm(2) (SD, 0.73 mm(2)) up to 12 weeks postoperatively (P < 0.01). CONCLUSIONS: The differentiation of afferent and efferent vessels using corneal angiography enables treatment to be selectively applied to the afferent vessels; there are usually 1 to 2 for each CoNV complex. PMID- 25841975 TI - Clinical features predictive of high-risk retinoblastoma in 403 Asian Indian patients: a case-control study. AB - PURPOSE: To identify the clinical features predictive of high-risk retinoblastoma on histopathology. DESIGN: Case-control study. PARTICIPANTS: A total of 145 cases with histopathologic high-risk features of retinoblastoma and 258 controls without high-risk features. METHODS: Enucleation and adjuvant chemotherapy. MAIN OUTCOME MEASURES: High-risk features on histopathology were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body infiltration, massive (>= 3 mm) choroidal invasion, postlaminar optic nerve invasion, invasion of optic nerve transection, combined nonmassive choroidal and prelaminar/laminar optic nerve invasion, or scleral/extrascleral infiltration. RESULTS: Of 403 patients who underwent primary enucleation for the treatment of retinoblastoma, 145 (36%) had high-risk features on histopathology (cases) and 258 (64%) had no high-risk features (controls). High-risk retinoblastoma occurred in 16% of (8/50) group D eyes and 39% of (137/353) group E eyes. The histopathologic high-risk features in these 145 patients included anterior chamber seeds (n = 25, 17%), iris infiltration (n = 12, 8%), ciliary body infiltration (n = 17, 12%), massive (>=3 mm) choroidal invasion (n = 69, 48%), postlaminar optic nerve invasion (n = 71, 49%), invasion of optic nerve transection (n = 3, 2%), combined choroidal and optic nerve invasion (n = 17, 12%), scleral infiltration (n = 20, 14%), and extrascleral involvement (n = 8, 6%). The mean number of high-risk features was 2 (median, 2; range, 1-7). The significant clinical features in cases versus controls included prolonged duration of symptoms of >6 months (21% vs. 7%; P < 0.001), poor visual acuity at presentation (74% vs. 64%; P = 0.05), buphthalmos (16% vs. 7%; P = 0.005), secondary glaucoma (47% vs. 15%; P < 0.001), iris neovascularization (46% vs. 22%; P < 0.001), ectropion uveae (39% vs. 14%; P < 0.001), and orbital cellulitis (3% vs. <1%; P = 0.05). On the basis of International Classification of Intraocular Retinoblastoma, group E tumor had a statistically significant higher incidence of high-risk retinoblastoma compared with controls (39% vs. 16%; P = 0.01). Multivariate analysis of clinical features at presentation that predicted high-risk features on histopathology included prolonged duration of symptoms of >6 months (P = 0.008) and secondary glaucoma (P = 0.021). CONCLUSIONS: In this study, the clinical features at presentation predictive of high-risk features on histopathology included prolonged duration of symptoms of >6 months and secondary glaucoma. Globe-preserving methods of treatment should be used with caution in patients with these features. PMID- 25841976 TI - Methods for characterizing the fate and effects of nano zerovalent iron during groundwater remediation. AB - The emplacement of nano zerovalent iron (nZVI) for groundwater remediation is usually monitored by common measurements such as pH, total iron content, and oxidation-reduction potential (ORP) by potentiometry. However, the interpretation of such measurements can be misleading because of the complex interactions between the target materials (e.g., suspensions of highly reactive and variably aggregated nanoparticles) and aquifer materials (sediments and groundwater), and multiple complications related to sampling and detection methods. This paper reviews current practice for both direct and indirect characterizations of nZVI during groundwater remediation and explores prospects for improving these methods and/or refining the interpretation of these measurements. To support our recommendations, results are presented based on laboratory batch and column studies of nZVI detection using chemical, electrochemical, and geophysical methods. Chemical redox probes appear to be a promising new method for specifically detecting nZVI, based on laboratory tests. The potentiometric and voltammetric detections of iron nanoparticles, using traditional stationary disc electrodes, rotating disc electrodes, and flow-through cell disc electrodes, provide insight for interpreting ORP measurements, which are affected by solution chemistry conditions and the interactions between iron nanoparticles and the electrode surface. The geophysical methods used for characterizing ZVI during groundwater remediation are reviewed and its application for nZVI detection is assessed with results of laboratory column experiments. PMID- 25841977 TI - Wine, alcohol and pills: What future for the French paradox? AB - The present review discusses the acquisitions obtained to date on the subject of wine consumption, health and cardiovascular protection. We distinguished the cardiovascular effects related to the consumption of wine and other alcoholic beverages focusing on non-alcoholic wine fraction: polyphenols and especially resveratrol. In the second part of the review we have addressed the issue of resveratrol bioavailability and the importance of wine matrix and phytocomplex highlighting the biological effects that can be obtained with nutraceuticals and resveratrol pills compared to the daily consumption of a glass of red wine. PMID- 25841978 TI - Factors associated with the quality of life of Korean COPD patients as measured by the EQ-5D. AB - PURPOSE: This study evaluated the health-related quality of life measured using the EuroQol five-dimension questionnaire (EQ-5D) and the degree of airway obstruction in a Korean population using Korea National Health and Nutritional Examination Survey (KNHANES IV-V, 2007-2010) data. METHODS: A cross-sectional analysis examined 2356 subjects (1178 COPD patients, 1178 control subjects) aged >=40 years and performed reliable spirometry as part of KNHANES IV-V. Baseline EQ 5D visual analog scale (VAS) and EQ-5D utility scores were obtained. A Tobit censored regression model was used to evaluate factors affecting EQ-5D in COPD patients. RESULTS: The EQ-5D VAS and EQ-5D utility scores were significantly different among the COPD severity groups (P < 0.05). The mean EQ-5D VAS scores for patients with mild, moderate, and severe COPD were 73.0 (SD 18.6), 70.8 (19.1), and 60.9 (23.4), respectively. The mean utility scores were 0.90 (0.14) for patients with mild COPD, 0.89 (0.14) for patients with moderate COPD, and 0.84 (0.15) for patients with severe COPD. Factors influencing the EQ-5D utility score in patients with COPD were age, gender, household income, education level, severe airflow obstruction, and comorbidities. CONCLUSIONS: The EQ-5D score could be a useful instrument for evaluating the quality of life of COPD patients in Korea. In Korean COPD patients, the main determinants of EQ-5D scores include older age, female gender, lower household income, lower education level, severe airflow obstruction, and many comorbid diseases. PMID- 25841979 TI - Measuring attachment to life in old age: the Portuguese version of the Positive Valuation of Life Scale (Positive VOL). AB - PURPOSE: This study aims to present the psychometric properties of the Portuguese version of the Positive Valuation of Life Scale (Lawton et al. in J Aging Ment Healt 13:3-31, 2001). METHOD: Sample included 207 community-dwelling elders (129 women; M Age = 77.2 years, SD = 7.5). The data collection included the translated and adapted Portuguese version of Positive Valuation of Life Scale, Life Satisfaction Index Z, Meaning in Life Questionnaire and Geriatric Depression Scale. RESULTS: From exploratory factor analysis, two factors emerged, existential beliefs and perceived control, explaining 49 % of the total variance. Both factors were positively related with meaning in life and life satisfaction and negatively related with depression (p < 0.05). The values obtained for internal consistency for the total scale and for each subscale were good (alpha > 0.75). CONCLUSION: The Portuguese version of Positive VOL Scale represents a reliable and valid measure to capture the subjective experience of attachment to one's life. The two-factor structure is an update to Lawton's previous work and in line with findings obtained in the USA (Dennis et al. in What is valuation of life for frail community-dwelling older adults: factor structure and criterion validity of the VOL, Thomas Jefferson University, Center for Applied Research on Aging and Health Research, 2005) and Japan (Nakagawa et al. in Shinrigaku Kenkyu 84:37-46, 2013). Future research is required to investigate VOL predictors and the potential changes toward the end of the life span. PMID- 25841981 TI - Enhanced amino acid utilization sustains growth of cells lacking Snf1/AMPK. AB - The metabolism of proliferating cells shows common features even in evolutionary distant organisms such as mammals and yeasts, for example the requirement for anabolic processes under tight control of signaling pathways. Analysis of the rewiring of metabolism, which occurs following the dysregulation of signaling pathways, provides new knowledge about the mechanisms underlying cell proliferation. The key energy regulator in yeast Snf1 and its mammalian ortholog AMPK have earlier been shown to have similar functions at glucose limited conditions and here we show that they also have analogies when grown with glucose excess. We show that loss of Snf1 in cells growing in 2% glucose induces an extensive transcriptional reprogramming, enhances glycolytic activity, fatty acid accumulation and reliance on amino acid utilization for growth. Strikingly, we demonstrate that Snf1/AMPK-deficient cells remodel their metabolism fueling mitochondria and show glucose and amino acids addiction, a typical hallmark of cancer cells. PMID- 25841980 TI - Trends in Breast Cancer Screening: Impact of U.S. Preventive Services Task Force Recommendations. AB - INTRODUCTION: Although there is general agreement among various guidelines on benefits of routine screening mammography, the age of screening initiation and the optimal frequency of the test remain controversial. In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended against routine breast cancer screening in women aged younger than 50 years. In this study, screening mammography guideline adherence among U.S. women is explored by examining patterns in rates of mammography age of initiation and utilization in years prior to and following the 2009 USPSTF guideline implementation. METHODS: U.S. population-based data from the 2007, 2008, 2010, and 2012 Behavioral Risk Factor Surveillance System surveys were used to measure the overall proportion and rate of change in the proportion of women who underwent screening mammography within the last year, by age and survey year. Data were accessed and analyzed in July 2014. RESULTS: Rates of mammography screening were lower in 2010 and 2012 compared with 2007 and 2008 (p<0.0001). The rate of screening initiation at age 40 years increased over time and was the highest in the years following USPSTF guideline changes (p=0.012). CONCLUSIONS: These data support no perceptible change in U.S. women's patterns of screening mammography age at initiation within 3 years of the USPSTF guideline revision. Whether this finding reflects a delayed effect of guideline revision in population trends or rather health provider practice and patient preference for more frequent screening is unclear and requires further investigation. PMID- 25841982 TI - Altered white matter in cocaine-dependent subjects with traumatic brain injury: A diffusion tensor imaging study. AB - BACKGROUND: Diffusion tensor imaging (DTI) is a useful technique for non invasively investigating the microstructural organization of white matter (WM), and the most consistent DTI finding regarding cocaine-related WM alterations is in the corpus callosum (CC). WM injury has also been observed in subjects with traumatic brain injury (TBI), including in the CC. METHODS: We used DTI to test if the WM microstructure is relatively more impaired in cocaine-dependent subjects who had suffered a mild TBI (mTBI). Fractional anisotropy (FA), which reflects the degree of alignment of cellular structures within fiber tracts and their structural integrity, was compared across cocaine-dependent subjects with mTBI (COCTBI group, n = 9), matched cocaine-dependent subjects without TBI (COC group, n = 12), and matched healthy controls (CTL group, n = 12). RESULTS: The COCTBI group had significantly lower FA in the genu, body, and splenium of CC, than the CTL group whenever the education was controlled or not. The COC group had significantly lower FA in the left and right anterior corona radiata than the CTL group only when the education was controlled. There was no significant difference in FA between the COC and COCTBI groups. CONCLUSION: Cocaine dependence (or mTBI) related WM impairments in the CC were not detectable in this small subject sample. The significant finding in the CC suggests that the concurrence of cocaine dependence and mTBI might result in more severe damage to the CC, which could even be detected in small sample size. PMID- 25841983 TI - Substance use and mental health disorders are linked to different forms of intimate partner violence victimisation. AB - BACKGROUND: Substance and mental health disorders convey significant health burdens and impair interpersonal relationships. We tested associations between comorbid substance and mental health disorders and different forms of intimate partner violence (IPV) experienced by young adults. METHOD: Mothers (n = 6703) were recruited during pregnancy to the longitudinal Mater-University of Queensland Study of Pregnancy. Mother/offspring dyads were followed up from birth to 21 years. Offspring with complete psychiatric data at 21 years who reported having had an intimate partnership were included (n = 1781). Participants' experiences of psychological, physical and severe combined IPV were assessed at 21 years using a summarised form of the Composite Abuse Scale. We used the Composite International Diagnostic Interview to obtain lifetime diagnoses of mental health and substance disorders. Multivariable logistic regression models of each IPV form were adjusted for individual, family and neighbourhood factors during adolescence, and for other forms of IPV. RESULTS: We have shown specific links between different forms of IPV experienced and individual substance and mental health disorders. Mental health disorders were related to all three forms of IPV, while alcohol disorders were linked to psychological IPV (ORAUD = 1.86; 1.21-2.86) and illicit substance disorders to physical IPV (ORSUD = 2.07; 1.25 3.43). The co-occurrence of related disorders was strongly linked to psychological and physical IPV. CONCLUSIONS: Intimate partner violence was experienced by both men and women. Substance and mental health disorders were associated with specific forms of IPV victimisation, suggesting that screening IPV clients and mental health/substance disorder patients for the converse problems may be important for intervention planning. PMID- 25841984 TI - Prevalence and experience of chronic pain in suburban drug injectors. AB - AIMS: To explore the relationship between chronic pain and characteristics, behaviors, and psychological status of suburban Connecticut injection drug users. METHODS: Cross-sectional study with quantitative interview and serological testing for HIV and hepatitis B and C in 456 individuals who injected drugs in the past month. Participants were dichotomized into those reporting current chronic pain of at least six months duration and all others. The interview covered (i) sociodemographics, (ii) injection drug use, (iii) interactions with drug treatment, criminal justice, and harm reduction, (iv) screening for alcohol use, chronic pain, anxiety, and depression, and (v) knowledge regarding HIV, hepatitis B (HBV) and C (HCV), and opioid overdose. Serological testing for HIV, HBV, and HCV was conducted. RESULTS: One-third (n = 143) reported chronic pain. These individuals differed significantly from those not reporting chronic pain on characteristics that included older age, lower educational achievement, and injection of pharmaceutical opioids. They also reported experiencing more psychological and family problems on the ASI and higher levels of depression and anxiety. Four of five individuals with chronic pain (n = 117) reported non medical opioid use prior to the onset of chronic pain. CONCLUSIONS: Chronic pain is common among drug injectors in our study population although it was unusual for chronic pain to have preceded non-medical opioid use. Psychological problems in injectors with co-occurring chronic pain are likely pose significant complications to successful treatment for substance abuse, pain, or infectious disease treatment. PMID- 25841985 TI - Hemodynamic monitoring of the critically ill neonate: An eye on the future. AB - By continuous assessment of dynamic changes in systemic and regional perfusion during transition to extrauterine life and beyond, comprehensive neonatal hemodynamic monitoring creates numerous opportunities for both clinical and research applications. In particular, it has the potential of providing additional details about physiologic interactions among the key hemodynamic factors regulating systemic blood flow and blood flow distribution along with the subtle changes that are frequently transient in nature and would not be detected without such systems in place. The data can then be applied for predictive mathematical modeling and validation of physiologically realistic computer models aiming to identify patient subgroups at higher risk for adverse outcomes and/or predicting the response to a particular perturbation or therapeutic intervention. Another emerging application that opens an entirely new era in hemodynamic research is the use of the physiometric data obtained by the monitoring and data acquisition systems in conjunction with genomic information. PMID- 25841986 TI - Consequences of dietary methyl donor supplements: Is more always better? AB - Epigenetic mechanisms are now recognized to play roles in disease etiology. Several diseases increasing in frequency are associated with altered DNA methylation. DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Increased intake of these compounds correlates with decreased neural tube defects, although this mechanism is not well understood. Consumption of these methyl donor pathway components has increased in recent years due to fortification of grains and high supplemental levels of these compounds (e.g. vitamins, energy drinks). Additionally, people with mutations in one of the enzymes that assists in the methyl donor pathway (5-MTHFR) are directed to consume higher amounts of methyl donors to compensate. Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects. Individualized medicine may be necessary to determine the appropriate amounts of methyl donors to be consumed, particularly in women of child bearing age. PMID- 25841988 TI - The protective effect of methylenetetrahydrofolate reductase C677T polymorphism against prostate cancer risk: Evidence from 23 case-control studies. AB - Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were considered to have some influence on both folate metabolism and cancer risk. Previous studies on the relation between MTHFR C677T polymorphism and prostate cancer (PCa) risk remained controversial. To derive a more precise estimation of the relationship, we carried out an update comprehensive meta-analysis to assess the associations of the MTHFR C677T polymorphism with the susceptibility of PCa. Twenty-three trials with a total of 24,024 participants on the MTHFR C677T polymorphism that met inclusion criteria were analyzed in the current study. Overall, no statistical relationship was found with any MTHFR C677T genetic model associated with susceptibility to PCa (TT versus CC, OR=0.83, 95% CI 0.68-1.02, P=0.07; CT versus CC, OR=0.95, 95% CI 0.85-1.07, P=0.43; Dominant, OR=0.93, 95% CI 0.83-1.03, P=0.17; Recessive, OR=0.84, 95% CI 0.70-1.02, P=0.09.). Nevertheless, subgroup analysis found a reduced PCa risk associated with polymorphism in Asian population (TT versus CC, CT versus CC, dominant and recessive model). Moreover, the protective effect of polymorphism against PCa risk was also shown upon hospital-based studies (TT versus CC, and recessive model). When benign prostate hyperplasia was chosen as controls, both TT versus CC and recessive model showed significant difference. In addition, the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference. Taken together, the existing evidence indicates the homozygote TT of MTHFR C677T should be viewed as a protective factor against PCa risk for clinical practice with the consideration of different gene background, study design as well as specific controls. PMID- 25841987 TI - Phosphorylation of epigenetic "readers, writers and erasers": Implications for developmental reprogramming and the epigenetic basis for health and disease. AB - Epigenetic reprogramming that occurs during critical periods of development can increase the susceptibility to many diseases in adulthood. Programming of the epigenome during development occurs via the activity of a variety of epigenetic modifiers, including "readers, writers and erasers" of histone methyl marks. Posttranslational modification of these programmers can alter their activity, resulting in global or gene-specific changes in histone methylation and gene transcription. This review summarizes what is currently known about phosphorylation of histone methyltransferases ("writers"), demethylases ("erasers") and effector proteins ("readers) that program the epigenome, and the impact of this posttranslational modification on their activity. Understanding how the activity of these epigenetic programmers is perturbed by environmental exposures via changes in phosphorylation is key to understanding mechanisms of developmental reprogramming and the epigenetic basis of health and disease. PMID- 25841989 TI - Gene cloning, characterization and expression and enzymatic activities related to trehalose metabolism during diapause of the onion maggot Delia antiqua (Diptera: Anthomyiidae). AB - Trehalose represents the main hemolymph sugar in many insects, and it functions in energy metabolism and protection in extreme environmental conditions. To gain an insight into trehalose functions in Delia antiqua diapausing pupae, genes encoding trehalose-6-phosphate synthase (TPS), trehalose-6-phosphatase (TPP) and trehalase (TRE) were identified and characterized. Analysis of the deduced amino acid sequences indicated that these genes were highly similar to each homolog from Diptera insects. Gene expressions and their enzyme activities were also investigated. The differential expressions of TPS and TPP shared very similar trends for summer and winter diapausing pupae. Their enzyme activities were consistent with the gene expressions. Trehalose concentrations in summer- and winter-diapausing pupae were lower at the initial phase (4.37-5.09MUg/mg) but increased gradually and peaked in the maintenance phase (10.59-14.36MUg/mg); the concentrations then declined in the quiescence phase. We speculated that a higher trehalose content during the maintenance stage may contribute to protein and/or biological membrane stabilization in winter or to desiccation resistance in the summertime. Diapause termination requires a decrease in the trehalose concentration to promote pupal-adult development. The glucose content also varied during the diapausing processes. Our results provide an overview of the differential expression levels of trehalose metabolic enzymes, confirming the important roles of trehalose in diapausing pupae of the onion maggot. Further work remains to explore its actual functions. PMID- 25841990 TI - Identification and expression patterns of extracellular matrix-associated genes fibropellin-ia and tenascin involved in regeneration of sea cucumber Apostichopus japonicus. AB - Sea cucumbers have a strong regenerative capacity. Many important genes involved in the molecular mechanism of regeneration and associated with intercellular signaling pathways of regeneration have been identified. The product of the fibropellin-ia gene forms a layer known as the apical lamina that surrounds the sea cucumber embryo throughout development. Meanwhile, the tenascin gene displays highly restricted and dynamic patterns of expression in the embryo and is expressed in the adult during normal processes such as wound healing, nerve regeneration and tissue involution. In this study, we cloned for the first time full-length cDNAs of fibropellin-ia (1390 bp, encoding a 199 amino acid protein) and tenascin (1366 bp, encoding a 179 amino acid protein) from Apostichopus japonicus (designated Aj-fnia and Aj-tenascin, respectively) using rapid amplification of cDNA ends. The structures and characteristics of these two genes were analyzed bioinformatically, and their expression patterns associated with extracellular matrix remodeling in regeneration of A. japonicus were investigated by real-time PCR and in situ hybridization (ISH). Expression levels of Aj-fnia and Aj-tenascin in the regeneration tissues were higher than those in normal tissues. The highest expression levels of Aj-fnia and Aj-tenascin were shown in the intestine and respiratory tree on the 15th and 20th days after sea cucumbers were eviscerated. In the body wall, the highest expression levels of Aj-fnia and Aj-tenascin occurred at 35 and 45 min during early regeneration and then emerged between 5 and 7 days again during late regeneration after the body wall was injured. ISH analysis revealed expression of these genes in the body wall, longitudinal muscle, intestine and respiratory tree. These findings suggest that Aj-fnia and Aj-tenascin are crucial genes that play important roles in the regeneration of the sea cucumber. PMID- 25841991 TI - Environmental and individual characteristics associated with depressive disorders and mental health care use. AB - PURPOSE: Few studies examined the relationship between neighborhood characteristics and both depressive disorders and the corresponding mental health care use. The aim of our study was to investigate neighborhood effects on depressive symptomatology, antidepressant consumption, and the consultation of psychiatrists. METHODS: Data from the French Residential Environment and Coronary heart Disease Study (n = 7290, 2007-2008, 30-79 years of age) were analyzed. Depressive symptomatology was cross-sectionally assessed. Health care reimbursement data allowed us to assess antidepressant consumption and psychiatric consultation prospectively more than 18 months. Multilevel logistic regression models were estimated. RESULTS: The risk of depressive symptoms increased with decreasing personal educational level and unemployment and slightly with decreasing neighborhood income. In a sample comprising participants with and without depressive symptoms, high individual and parental educational levels were both associated with the consultation of psychiatrists. In this sample, a low personal educational level increased the odds of consumption of antidepressants. No heterogeneity between neighborhoods was found for antidepressant consumption. However, the odds of consulting psychiatrists increased with median neighborhood income and with the density of psychiatrists, after adjustment for individual characteristics. Among depressive participants only, a particularly strong gradient in the consultation of psychiatrists was documented according to individual socioeconomic status. CONCLUSIONS: Future research on the relationships between the environments and depression should take into account health care use related to depression and consider the spatial accessibility to mental health services among other environmental factors. PMID- 25841992 TI - [Stereotactic body radiation radiotherapy for oligometastatic non-small cell lung cancer (NSCLC): A case report]. AB - Metastatic non-small cell lung cancer is associated with a poor prognosis, and palliative chemotherapy is the mainstay of treatment. However, long-time survival has been observed in oligometastatic patients treated with locally ablative therapies to all sites of metastatic disease. An 80-year-old man was diagnosed with an adenocarcinoma of the lung. The right upper lobe lesion was classified cT2aN0M0 and was treated with stereotactic body radiation therapy at the dose of 60Gy in eight fractions. A few months after, he successively presented with two brain metastases and one left adrenal metastasis, with a complete response on the primary tumor. The three secondary lesions were treated with stereotactic body radiation therapy alone. Thirty months after the diagnosis and 12months after metastases' apparition, primary and brain lesion kept controlled (complete response). Oligometastatic non-small cell lung cancer management is not clear. Locally ablative therapies such as stereotactic body radiation therapy, surgery and radiofrequency are efficient and should be considered. A phase III study should evaluate radical treatment strategies in such patients. PMID- 25841993 TI - Transcollation: lost in translation? PMID- 25841994 TI - Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha. AB - The signal transducer and activator of transcription 3 (STAT3) is a well described pro-oncogene found constitutively activated in several cancer types. Folates are B vitamins that, when taken up by cells through the Reduced Folate Carrier (RFC), are essential for normal cell growth and replication. Many cancer cells overexpress a glycophosphatidylinositol (GPI)-anchored Folate Receptor alpha (FRalpha). The function of FRalpha in cancer cells is still poorly described, and it has been suggested that transport of folate is not its primary function in these cells. We show here that folic acid and folinic acid can activate STAT3 through FRalpha in a Janus Kinase (JAK)-dependent manner, and we demonstrate that gp130 functions as a transducing receptor for this signalling. Moreover, folic acid can promote dose dependent cell proliferation in FRalpha positive HeLa cells, but not in FRalpha-negative HEK293 cells. After folic acid treatment of HeLa cells, up-regulation of the STAT3 responsive genes Cyclin A2 and Vascular Endothelial Growth Factor (VEGF) were verified by qRT-PCR. The identification of this FRalpha-STAT3 signal transduction pathway activated by folic and folinic acid contributes to the understanding of the involvement of folic acid in preventing neural tube defects as well as in tumour growth. Previously, the role of folates in these diseases has been attributed to their roles as one-carbon unit donors following endocytosis into the cell. Our finding that folic acid can activate STAT3 via FRalpha adds complexity to the established roles of B9 vitamins in cancer and neural tube defects. PMID- 25841996 TI - Emerging molecular networks common in ionizing radiation, immune and inflammatory responses by employing bioinformatics approaches. AB - Efficient radiation therapy is characterized by enhanced tumor cell killing involving the activation of the immune system (tumor immunogenicity) but at the same time minimizing chronic inflammation and radiation adverse effects in healthy tissue. The aim of this study was to identify gene products involved in immune and inflammatory responses upon exposure to ionizing radiation by using various bioinformatic tools. Ionizing radiation is known to elicit different effects at the level of cells and organism i.e. DNA Damage Response (DDR), DNA repair, apoptosis and, most importantly, systemic effects through the instigation of inflammatory 'danger' signals and innate immune response activation. Genes implicated both in radiation and immune/inflammatory responses were collected manually from the scientific literature with a combination of relevant keywords. The experimentally validated and literature-based results were inspected, and genes involved in radiation, immune and inflammatory response were pooled. This kind of analysis was performed for the first time, for both healthy and tumor tissues. In this way, a set of 24 genes common in all three different phenomena was identified. These genes were found to form a highly connected network. Useful conclusions are drawn regarding the potential application of these genes as markers of response to radiation for both healthy and tumor tissues through the modulation of immune and/or inflammatory mechanisms. PMID- 25841995 TI - PKA and actin play critical roles as downstream effectors in MRP4-mediated regulation of fibroblast migration. AB - Multidrug resistance protein 4 (MRP4), a member of the ATP binding cassette transporter family, functions as a plasma membrane exporter of cyclic nucleotides. Recently, we demonstrated that fibroblasts lacking the Mrp4 gene migrate faster and contain higher cyclic-nucleotide levels. Here, we show that cAMP accumulation and protein kinase A (PKA) activity are higher and polarized in Mrp4(-/-) fibroblasts, versus Mrp4(+/+) cells. MRP4-containing macromolecular complexes isolated from these fibroblasts contained several proteins, including actin, which play important roles in cell migration. We found that actin interacts with MRP4, predominantly at the plasma membrane, and an intact actin cytoskeleton is required to restrict MRP4 to specific microdomains of the plasma membrane. Our data further indicated that the enhanced accumulation of cAMP in Mrp4(-/-) fibroblasts facilitates cortical actin polymerization in a PKA dependent manner at the leading edge, which in turn increases the overall rate of cell migration to accelerate the process of wound healing. Disruption of actin polymerization or inhibition of PKA activity abolished the effect of MRP4 on cell migration. Together, our findings suggest a novel cAMP-dependent mechanism for MRP4-mediated regulation of fibroblast migration whereby PKA and actin play critical roles as downstream effectors. PMID- 25841997 TI - Preventing childhood scalds within the home: Overview of systematic reviews and a systematic review of primary studies. AB - OBJECTIVE: To synthesise and evaluate the evidence of the effectiveness of interventions to prevent scalds in children. METHODS: An overview of systematic reviews (SR) and a SR of primary studies were performed evaluating interventions to prevent scalds in children. A comprehensive literature search was conducted covering various resources up to October 2012. Experimental and controlled observational studies reporting scald injuries, safety practices and safety equipment use were included. RESULTS: Fourteen systematic reviews and 39 primary studies were included. There is little evidence that interventions are effective in reducing the incidence of scalds in children. More evidence was found that inventions are effective in promoting safe hot tap water temperature, especially when home safety education, home safety checks and discounted or free safety equipment including thermometers and thermostatic mixing valves were provided. No consistent evidence was found for the effectiveness of interventions on the safe handling of hot food or drinks nor improving kitchen safety practices. CONCLUSION: Education, home safety checks along with thermometers or thermostatic mixing valves should be promoted to reduce tap water scalds. Further research is needed to evaluate the effectiveness of interventions on scald injuries and to disentangle the effects of multifaceted interventions on scald injuries and safety practices. PMID- 25841998 TI - Risk factors for foot and mouth disease outbreaks in grazing beef cattle herds. AB - Foot and mouth disease (FMD) is considered one of the most important diseases of cattle. Recurrence of FMD outbreaks in Israel is common, even though routine vaccination of livestock is mandatory and control measures are applied during the outbreaks. Grazing beef herds are occasionally involved in these outbreaks and play an important role in disseminating the disease, due to the large efflux of animals from these herds to feedlots. Nevertheless, the risk factors for the occurrence of FMD among these herds have never been investigated. In 2011, Israel faced a large scale outbreak of serotype O FMD virus, which strongly affected beef cattle. We conducted a case-control study of 44 beef cattle herds grazing in the Golan Heights in order to determine the risk factors for FMDV infection. Data were analyzed using a generalized estimation equation (GEE) with a logit link function. Multivariable analysis was conducted for factors with p-value lower than 0.1 in the univariable analysis. The presence of calves under 6 months of age was found as a significant risk factor for FMDV infection in the univariable analysis (odds ratio (OR)=5.95, confidence intervals of 95% (CI95%)=1.59-22.29, p=0.008). This was also the only variable that remained statistically significant in the multivariable analysis. Herds in which more than 6 months between vaccination of adults and exposure had elapsed were in higher risk, albeit not statistically significant, for the occurrence of FMDV infection (OR=3.29, CI95%=0.83-12.99, p=0.089). The higher probability of infection in herds, which included young calves may be a result of their higher susceptibility due to administration of only one or no vaccine prior to the outbreak. The results of the study thus support increasing the frequency of vaccination of both cows and calves in grazing beef herds. Intensifying surveillance where young calves are abundant may also prove efficient for early detection of infected herds and for mitigating outbreaks of FMDV. PMID- 25841999 TI - Brucellosis and bovine tuberculosis prevalence in livestock from pastoralist communities adjacent to Awash National Park, Ethiopia. AB - This cross-sectional study investigated the prevalence of brucellosis and bovine tuberculosis (BTB) in local cattle and goat breeds of Oromo and Afar pastoralist communities living in two distinct parts around the Awash National Park. A questionnaire survey was carried out to assess information on husbandry, milk consumption habits, and on knowledge-attitude-practice regarding both diseases. Among a total of 771 animals from all sites tested by comparative intradermal tuberculin test (CIDT) none were BTB reactors with the >4mm cut-off. Using the >2mm cut-off, individual apparent prevalence was 0.9% (95%CI: 0.23-3.56%) in cattle and 0.7% (95%CI: 0.12-3.45%) in goats. Herd prevalence in Oromia and Afar sites was 0% and 66.7% respectively in goats and 16.7% and 50% in cattle. Among the 327 animals tested by enzyme linked immunoassay for brucellosis, 4.8% (95%CI: 1.2-17.1%) of cattle and 22.8% (95%CI: 5.98-29.5%) of goats were reactors. Highest individual prevalence of both diseases was found in Afar settlements with brucellosis being as high as 50%. Respondent ethnicity was the only risk factor for brucellosis positivity in goats in the univariable risk factor analysis. Knowledge about the diseases was poor. Raw goat milk was regularly consumed by women and children, putting them at risk for brucellosis. This study highlighted an increased prevalence gradient of BTB and brucellosis from West to East along the study sites with high brucellosis individual prevalence and abortion rates among Afar settlements in particular. PMID- 25842000 TI - How to reach the poor? Surveillance in low-income countries, lessons from experiences in Cambodia and Madagascar. AB - Surveillance of animal diseases in developing countries faces many constraints. Innovative tools and methods to enhance surveillance in remote and neglected areas should be defined, assessed and applied in close connection with local farmers, national stakeholders and international agencies. The authors performed a narrative synthesis of their own publications about surveillance in Madagascar and Cambodia. They analysed the data in light of their fieldwork experiences in the two countries' very challenging environments. The burden of animal and zoonotic diseases (e.g. avian influenza, African swine fever, Newcastle disease, Rift Valley fever) is huge in both countries which are among the poorest in the world. Being poor countries implies a lack of human and financial means to ensure effective surveillance of emerging and endemic diseases. Several recent projects have shown that new approaches can be proposed and tested in the field. Several advanced participatory approaches are promising and could be part of an innovative method for improving the dialogue among different actors in a surveillance system. Thus, participatory modelling, developed for natural resources management involving local stakeholders, could be applied to health management, including surveillance. Data transmission could benefit from the large mobile-phone coverage in these countries. Ecological studies and advances in the field of livestock surveillance should guide methods for enhancing wildlife monitoring and surveillance. Under the umbrella of the One Health paradigm, and in the framework of a risk-based surveillance concept, a combination of participatory methods and modern technologies could help to overcome the constraints present in low-income countries. These unconventional approaches should be merged in order to optimise surveillance of emerging and endemic diseases in challenging environments. PMID- 25842001 TI - Endoscopically assisted release of the superficial radial nerve. AB - INTRODUCTION: The feasibility of endoscopically assisted decompression of the superficial radial nerve at the midportion and distal forearm was assessed. SURGICAL TECHNIQUE: After a 3 cm longitudinal skin incision at the Tinel's sign at the forearm, the subcutaneous tissue is dissected until forearm fascia is detected. The fascia is opened cautiously under direct visualization and the superficial radial nerve is identified. Blunt forceps mobilize the subcutaneous tissue upon the fascia before the illuminated speculum is inserted. Then further dissection of the fascia is performed proximally using the Metzenbaum scissors. After further blunt tunneling by forceps the endoscope is introduced proximally in order to release the superficial radial nerve completely. Then the speculum is inserted distally to identify the nerve within the subcutaneous tissue. Then further visualization is facilitated using the endoscope. CONCLUSION: The endoscopically assisted release of the superficial radial nerve may be feasible in a safe and sufficient way. PMID- 25842002 TI - [Local analgesic effect of tramadol is not mediated by opioid receptors in early postoperative pain in rats]. AB - BACKGROUND AND OBJECTIVES: Tramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. METHODS: Young male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200MUg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. RESULTS: Plantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. CONCLUSIONS: Tramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors. PMID- 25842003 TI - [Comparison of interscalene brachial plexus block and intra-articular local anesthetic administration on postoperative pain management in arthroscopic shoulder surgery]. AB - BACKGROUND AND OBJECTIVES: In this study, the aim was to compare postoperative analgesia effects of the administration of ultrasound-guided interscalene brachial plexus block and intra-articular bupivacaine carried out with bupivacaine. METHODS: In the first group of patients 20mL 0.25% bupivacaine and ultrasound-guided interscalene brachial plexus block (ISPB) were applied, while 20mL 0.25% bupivacaine was given via intra-articular (IA) administration to the second group patients after surgery. Patients in the third group were considered the control group and no block was performed. Patient-controlled analgesia (PCA) with morphine was used in all three groups for postoperative analgesia. RESULTS: In the ISPB group, morphine consumption in the periods between 0-4, 6-12 and 12 24 postoperative hours and total consumption within 24h was lower than in the other two groups. Morphine consumption in the IA group was lower than in the control group in the period from 0 to 6h and the same was true for total morphine consumption in 24h. Postoperative VASr scores in the ISPB group were lower than both of the other groups in the first 2h and lower than the control group in the 4(th) and 6(th) hours (p<0.05). In the IA group, VASr and VASm scores in the 2(nd), 4(th) and 6(th) hours were lower than in the control group (p<0.05). CONCLUSION: Interscalene brachial plexus block was found to be more effective than intra-articular local anesthetic injection for postoperative analgesia. PMID- 25842004 TI - Case-based learning: What traditional curricula fail to teach. AB - BACKGROUND: Case-based learning seeks to contextualize learning and to enhance the transition of nurses to practice. This instructional approach is gaining widespread interest in nursing education since the unfolding process emulates the work environment. Case-based learning holds great promise to the development of professional skills. An assumption that was worth researching to determine what those skills are. OBJECTIVES: This study aimed at exploring perceptions of nursing students who had completed two undergraduate nursing courses using case based learning to be able to identify professional skills that may be gained by this instructional approach. DESIGN: The qualitative focus group research technique was used to explore the perceptions of 16 nursing students who used CBL in two adult health nursing courses in the junior year of an undergraduate nursing program in Beirut, Lebanon. The sample was divided into three groups of four to six students each. METHOD: Thematic analysis using cross-group analysis and inductive constant comparison. FINDINGS: The analyzed data converged on three learning practices that were developed by the case study approach: (a) recognizing the particulars of a clinical situation, (b) making sense of patient data and informing decisions, and (c) reflection. In-depth analysis of these practices helped unravel four professional attributes that form the tenets of case-based learning: (1) a salience of clinical knowledge, (2) multiple ways of thinking, (3) professional self-concept, and (4) professional caring. CONCLUSION: Since professional skills are developmental in nature, educational programs may play an active role in the skill acquisition process. In search of those ineffable skills, four professional attributes emerged from the study findings. Findings support concerns of higher education regarding the ability of the traditional curriculum to meet the expectations of employers at the workplace. PMID- 25842006 TI - Accelerated progression of white matter hyperintensities and subsequent risk of mortality: a 12-year follow-up study. AB - We examined the association of accelerated progression of white matter hyperintensities (WMH) with mortality outcomes in 534 older subjects at risk for cardiovascular disease. Using brain magnetic resonance imaging, volume of WMH was measured 2 times in an average of 33 months apart. After the second magnetic resonance imaging, occurrence of death was recorded during 12 years of follow-up. In multivariable analyses, each mL/y increase in global WMH was associated with 1.22-fold (95% confidence interval [CI], 1.09-1.37) higher risk of all-cause mortality, 1.29-fold (95% CI, 1.06-1.56) higher risk of cardiovascular mortality, and 1.20-fold (95% CI, 1.02-1.40) higher risk of noncardiovascular mortality. Each mL/y increase in periventricular WMH was associated with 1.22-fold (95% CI, 1.08-37) higher risk of all-cause mortality and 1.24-fold (95% CI, 1.06-1.44) higher risk of noncardiovascular mortality. Conversely, deep cortical WMH was only associated with cardiovascular mortality (1.92-fold, 95% CI, 1.12-3.30). Accelerated progression of WMH is linked with mortality risk in old age. Progression of periventricular WMH associates with noncardiovascular mortality, whereas progression of deep cortical WMH associates with cardiovascular mortality. PMID- 25842005 TI - The eHealth Enhanced Chronic Care Model: a theory derivation approach. AB - BACKGROUND: Chronic illnesses are significant to individuals and costly to society. When systematically implemented, the well-established and tested Chronic Care Model (CCM) is shown to improve health outcomes for people with chronic conditions. Since the development of the original CCM, tremendous information management, communication, and technology advancements have been established. An opportunity exists to improve the time-honored CCM with clinically efficacious eHealth tools. OBJECTIVE: The first goal of this paper was to review research on eHealth tools that support self-management of chronic disease using the CCM. The second goal was to present a revised model, the eHealth Enhanced Chronic Care Model (eCCM), to show how eHealth tools can be used to increase efficiency of how patients manage their own chronic illnesses. METHODS: Using Theory Derivation processes, we identified a "parent theory", the Chronic Care Model, and conducted a thorough review of the literature using CINAHL, Medline, OVID, EMBASE PsychINFO, Science Direct, as well as government reports, industry reports, legislation using search terms "CCM or Chronic Care Model" AND "eHealth" or the specific identified components of eHealth. Additionally, "Chronic Illness Self management support" AND "Technology" AND several identified eHealth tools were also used as search terms. We then used a review of the literature and specific components of the CCM to create the eCCM. RESULTS: We identified 260 papers at the intersection of technology, chronic disease self-management support, the CCM, and eHealth and organized a high-quality subset (n=95) using the components of CCM, self-management support, delivery system design, clinical decision support, and clinical information systems. In general, results showed that eHealth tools make important contributions to chronic care and the CCM but that the model requires modification in several key areas. Specifically, (1) eHealth education is critical for self-care, (2) eHealth support needs to be placed within the context of community and enhanced with the benefits of the eCommunity or virtual communities, and (3) a complete feedback loop is needed to assure productive technology-based interactions between the patient and provider. CONCLUSIONS: The revised model, eCCM, offers insight into the role of eHealth tools in self management support for people with chronic conditions. Additional research and testing of the eCCM are the logical next steps. PMID- 25842007 TI - Personalized microbial network inference via co-regularized spectral clustering. AB - We use Human Microbiome Project (HMP) cohort (Peterson et al., 2009) to infer personalized oral microbial networks of healthy individuals. To determine clustering of individuals with similar microbial profiles, co-regularized spectral clustering algorithm is applied to the dataset. For each cluster we discovered, we compute co-occurrence relationships among the microbial species that determine microbial network per cluster of individuals. The results of our study suggest that there are several differences in microbial interactions on personalized network level in healthy oral samples acquired from various niches. Based on the results of co-regularized spectral clustering we discover two groups of individuals with different topology of their microbial interaction network. The results of microbial network inference suggest that niche-wise interactions are different in these two groups. Our study shows that healthy individuals have different microbial clusters according to their oral microbiota. Such personalized microbial networks open a better understanding of the microbial ecology of healthy oral cavities and new possibilities for future targeted medication. The scripts written in scientific Python and in Matlab, which were used for network visualization, are provided for download on the website http://learning-machines.com/. PMID- 25842008 TI - Concomitant use of dronedarone with dabigatran in patients with atrial fibrillation in clinical practice. AB - INTRODUCTION: Dronedarone is a strong P-glycoprotein inhibitor with a potential to increase bioavailability of dabigatran. We sought to measure and report plasma concentrations of dabigatran in patients with atrial fibrillation (AF) on concomitant dronedarone treatment. MATERIALS AND METHODS: A cohort of 33 patients (mean age 64 years, 16 men) concomitantly treated with dabigatran at a dose of 110 mg twice a day (bid) and dronedarone at a dose of 400mg bid at the discretion of the patient's cardiologist were followed prospectively. RESULTS: Median trough plasma concentration of dabigatran at one week and one month after the concomitant treatment start was 102.0 (range 8-251) ng/ml and 84 (range 27-302) ng/ml respectively. Median treatment length was 13 (range 1-21) months. There was one major bleeding event (2,8% per patient-year) and no thrombotic events during a total of 35.5 patient-years. CONCLUSIONS: Median trough plasma concentration of dabigatran in our study was observed to be similar to median trough plasma concentration of dabigatran at a dose of 150 mg bid without concomitant dronedarone in earlier studies with low reported rate of bleeding and thrombosis. Since concomitant treatment offers potential benefits to patients with AF, larger future trials that might refute the current contraindication are warranted. PMID- 25842009 TI - Ultra-low iodine concentrations iso-attenuating with diagnostic 0.5M gadolinium in endovascular procedures to minimize the risk of contrast nephropathy: A phantom study. AB - PURPOSE: To establish the concentrations of iodine contrast media (I-CM) iso attenuating with 0.5M gadolinium contrast media (Gd-CM), regarded diagnostic in catheter angiography and vascular interventions in azotemic patients, at various X-ray tube potentials with correlation to skin radiation dose. MATERIALS AND METHOD: 20-mL syringes filled with 30, 40, 50, 70 and 90 mgI/mL, 0.5M Gd-CM and air were placed in a water-equivalent phantom and exposed at about 50, 60, 70, 80 and 90 kV in an X-ray angiographic system. Relative contrast between the contrast materials and the background phantom material was measured on a PACS workstation. Radiation entrance dose, measured with a dose meter and estimated from the dose area-product (DAP), was adjusted for radiation backscatter to simulate absorbed skin dose. RESULT: The iodine concentrations 30, 40, 50, 70 and 90 mg/mL resulted in the same relative contrast as 0.5M gadolinium at 53, 57, 62, 71 and 85 kVp, respectively. Air had lower relative contrast than all iodine concentrations at all kVp-settings except for 30 mgI/mL above 84 kVp. The measured skin radiation dose was less than 1 mGy per exposure at all kVp-settings, and around 25-30% lower than the dose estimations derived from the angiographic system's in-built DAP meter. CONCLUSION: Low-kilovoltage X-ray technique and ultra-low concentrations of I-CM iso-attenuating with 0.5M Gd-CM may be utilizable in peripheral arteriography and endovascular interventions, to minimize the total CM dose to avoid CIN in azotemic patients. PMID- 25842010 TI - Finding our roots and celebrating our shoots: Plant virology in Virology, 1955 1964. AB - To celebrate the sixtieth anniversary of Virology a survey is made of the plant viruses, virologists and their institutions, and tools and technology described in the first decade of plant virus publications in Virology. This was a period when plant viruses increasingly became tools of discovery as epistemic objects and plant virology became a discipline discrete from plant pathology and other life sciences. PMID- 25842011 TI - Radiologists adding value through the clinical practice of interventional radiology. PMID- 25842012 TI - Certainty. PMID- 25842013 TI - Pioneers of America. PMID- 25842014 TI - ACR Appropriateness Criteria indeterminate renal mass. AB - Renal masses are increasingly detected in asymptomatic individuals as incidental findings. An indeterminate renal mass is one that cannot be diagnosed confidently as benign or malignant at the time it is discovered. CT, ultrasonography, and MRI of renal masses with fast-scan techniques and intravenous (IV) contrast are the mainstays of evaluation. Dual-energy CT, contrast-enhanced ultrasonography, PET/CT, and percutaneous biopsy are all technologies that are gaining traction in the characterization of the indeterminate renal mass. In cases in which IV contrast cannot be used, whether because of IV contrast allergy or renal insufficiency, renal mass classification with CT is markedly limited. In the absence of IV contrast, ultrasonography, MRI, and biopsy have some advantages. Owing to the low malignant and metastatic potential of small renal cell carcinomas (<=4 cm in diameter), active surveillance is additionally emerging as a diagnostic strategy for patients who have high surgical risk or limited life expectancy. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and application by the panel of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 25842015 TI - Radiology order decision support: examination-indication appropriateness assessed using 2 electronic systems. AB - PURPOSE: The goal of the study was to determine the effects of guideline implementation strategy using 2 commercial radiology clinical decision support (CDS) systems. METHODS: The appropriateness and insurance dispositions of MRI and CT orders were evaluated using the Medicalis SmartReq and Nuance RadPort CDS systems during 2 different 3-month periods. Logistic regression was used to compare these outcomes between the 2 systems, after adjusting for patient-mix differences. RESULTS: Approximately 2,000 consecutive outpatient MRI and CT orders were evaluated over 2 periods of 3 months each. Medicalis scored 60% of exams as "indeterminate" (insufficient information) or "not validated" (no guidelines). Excluding these cases, Nuance scored significantly more exams as appropriate than did Medicalis (80% versus 51%, P < .001) and predicted insurance outcome significantly more often (76% versus 58%, P < .001). Only when the Medicalis "indeterminate" and "not validated" categories were combined with the high- or moderate-utility categories did the 2 CDS systems have similar performance. Overall, 19% of examinations with low-utility ratings were reimbursed. Conversely, 0.8% of examinations with high- or moderate-utility ratings were denied reimbursement. CONCLUSIONS: The chief difference between the 2 CDS systems, and the strongest influence on outcomes, was how exams without relevant guidelines or with insufficient information were handled. Nuance augmented published guidelines with clinical best practice; Medicalis requested additional information utilizing pop-up windows. Thus, guideline implementation choices contributed to decision making and outcomes. User interface, specifically, the number of screens and completeness of indication choices, controlled CDS interactions and, coupled with guidance implementation, influenced willingness to use the CDS system. PMID- 25842016 TI - Clinical imaging guidelines part 4: challenges in identifying, engaging and collaborating with stakeholders. AB - The effective development and use of clinical imaging guidelines requires an understanding of who the stakeholders are, what their interests in the process are, and what roles they should play. If the appropriate stakeholders are not engaged in the right roles, it is unlikely that clinical imaging guidelines will be successfully developed, relied on, and actually used. Some stakeholders are obvious: for the development of clinical imaging guidelines, both imagers and those who request examinations, such as general practitioners, internists, and medical specialists, must be involved. To gain acceptance, other relevant groups are stakeholders, including medical societies, other health care professionals, insurers, health IT experts and vendors, and patients. The role of stakeholders must be dictated by their specific interest. For some, involvement in the creation of guidelines is the right role. For others, such as regulators or insurers, reviews or invitations to comment are required, and for others, such as medical educators, it is probably sufficient to provide information and create awareness. Only through a careful consideration of who the stakeholders are and what are their interests are the successful development, acceptance, and use of clinical imaging guidelines likely to occur. Future efforts must focus on collaboration, particularly among groups that create clinical imaging guidelines and those that can support their use, and on regulatory roles and mandates. PMID- 25842017 TI - Role of the Quantitative Imaging Biomarker Alliance in optimizing CT for the evaluation of lung cancer screen-detected nodules. AB - The Quantitative Imaging Biomarker Alliance (QIBA) is a multidisciplinary consortium sponsored by the RSNA to define processes that enable the implementation and advancement of quantitative imaging methods described in a QIBA profile document that outlines the process to reliably and accurately measure imaging features. A QIBA profile includes factors such as technical (product-specific) standards, user activities, and relationship to a clinically meaningful metric, such as with nodule measurement in the course of CT screening for lung cancer. In this report, the authors describe how the QIBA approach is being applied to the measurement of small pulmonary nodules such as those found during low-dose CT-based lung cancer screening. All sources of variance with imaging measurement were defined for this process. Through a process of experimentation, literature review, and assembly of expert opinion, the strongest evidence was used to define how to best implement each step in the imaging acquisition and evaluation process. This systematic approach to implementing a quantitative imaging biomarker with standardized specifications for image acquisition and postprocessing for a specific quantitative measurement of a pulmonary nodule results in consistent performance characteristics of the measurement (eg, bias and variance). Implementation of the QIBA small nodule profile may allow more efficient and effective clinical management of the diagnostic workup of individuals found to have suspicious pulmonary nodules in the course of lung cancer screening evaluation. PMID- 25842018 TI - The imaging 3.0 informatics scorecard. AB - Imaging 3.0 is a radiology community initiative to empower radiologists to create and demonstrate value for their patients, referring physicians, and health systems. In image-guided health care, radiologists contribute to the entire health care process, well before and after the actual examination, and out to the point at which they guide clinical decisions and affect patient outcome. Because imaging is so pervasive, radiologists who adopt Imaging 3.0 concepts in their practice can help their health care systems provide consistently high-quality care at reduced cost. By doing this, radiologists become more valuable in the new health care setting. The authors describe how informatics is critical to embracing Imaging 3.0 and present a scorecard that can be used to gauge a radiology group's informatics resources and capabilities. PMID- 25842019 TI - The challenges in delivering the value chain. PMID- 25842020 TI - Are employers responsible for an employee's unauthorized review of a patient's confidential health information? PMID- 25842021 TI - Making quality improvement projects relevant to the 6 Institute of Medicine aims. PMID- 25842022 TI - Improving radiographic quality at a busy outpatient imaging center. PMID- 25842023 TI - The correct selection of pitch for optimal CT scanning: avoiding common misconceptions. PMID- 25842024 TI - Outcome of triple-tendon transfer, an Eden-Lange variant, to reconstruct trapezius paralysis. AB - BACKGROUND: This study describes the technique and evaluates the outcome of the triple-tendon (T3) transfer, an Eden-Lange variant, to the scapula to stabilize the scapulothoracic articulation in the treatment of symptomatic trapezius paralysis. METHODS: T3 transfers were performed in 22 patients with a history of persistent trapezius paralysis secondary to spinal accessory nerve injury. The indications for surgery included shoulder pain and weakness and limited range of motion of the shoulder. The T3 transfer included transfer of the levator scapulae to the lateral aspect of the spine of the scapula, the rhomboid minor to the spine of the scapula just medial to the levator scapulae insertion, and the rhomboid major to the medial spine of the scapula, including all muscles bony insertions. RESULTS: At an average follow-up of 35 months, winging was corrected in all patients, with improvement of shoulder asymmetry. All patients had significant improvement of pain (P < .01) and range of motion, including active shoulder abduction that improved from an average of 71 degrees preoperatively to 118 degrees postoperatively (P < .02) and shoulder flexion from an average of 102 degrees to 150 degrees (P < .01). There were also significant improvements in aggregate Constant Shoulder Score (P < .01), subjective shoulder value (P < .01), and Disabilities of the Arm, Shoulder and Hand score (P < .01). All patients were very satisfied with the outcome of surgery. CONCLUSION: This study shows that the T3 transfer is effective in stabilizing the scapulothoracic articulation and restoring the function of the trapezius, and thus, in improving pain and shoulder function in patients with symptomatic trapezius paralysis. PMID- 25842025 TI - Upper extremity blood flow changes in professional baseball pitchers between two consecutive seasons. AB - BACKGROUND: Because of the tremendous forces produced and the repetitive nature of baseball, players have shown various shoulder adaptations in strength and range of motion. However, no research has identified whether alterations occur in the blood flow to the dominant arm among competitive baseball players. METHODS: Twenty professional baseball pitchers and 16 position players participated. Measurements were taken on day 1 of 2 consecutive spring training seasons. Diagnostic ultrasound was used to measure blood flow of the throwing arm brachial artery. These measurements were taken in a standing position with the test arm resting at the participant's side and again with the test arm in a provocative shoulder position. Separate 1-way analyses of variance were conducted to compare blood flow between seasons (P < .05). RESULTS: In a resting position, the blood flow of the pitchers did not change from 1 year to the next (P = .48). However, blood flow of the pitchers in the provocative position significantly decreased after the first year (P = .009). The position players did not have any significant changes in blood flow for either arm position (P > .11). CONCLUSIONS: In a provocative shoulder position, the blood flow of pitchers significantly decreased after 1 competitive baseball season. These results indicate that after a competitive season, the blood flow to the upper extremity of pitchers may be compromised. PMID- 25842026 TI - Scapular allograft reconstruction after total scapulectomy: surgical technique and functional results. AB - HYPOTHESIS: Scapular allograft reconstruction after total scapulectomy preserving the rotator cuff muscles is an oncologically safe procedure and results in good functional outcome with a low complication rate. METHODS: The data of 6 patients who underwent scapular allograft reconstruction after a total scapulectomy for tumor resection were retrospectively reviewed. At least 1 of the rotator cuff muscles was preserved and the size-matched scapular allograft fixed to the residual host acromion with a plate and screws. The periscapular muscles and the residual joint capsule were sutured to the corresponding insertions of the allograft. RESULTS: The mean follow-up was 5.5 years (range, 24-175 months). In all patients, a wide surgical margin was achieved. The average functional scores were 20 points for the International Society of Limb Salvage score and 60 points for the American Shoulder and Elbow Surgeons score. Mean active shoulder flexion of 60 degrees (range, 30 degrees -90 degrees ) and mean active abduction of 62 degrees (range, 30 degrees -90 degrees ) were achieved. During the follow-up, 1 patient (16.6%) had a local recurrence and lung metastasis, whereas the remaining 5 patients (83.3%) were disease free. Two breakages of the osteosynthesis and 2 allograft fractures were observed, necessitating a revision surgery in 2 cases (33.3%). In this series, no infection, allograft resorption, or shoulder instability occurred. CONCLUSION: Allograft substitution of a completely removed scapula is an oncologically safe procedure, with good functional results, avoiding common complications in prosthetic replacements such as infection and dislocation of the shoulder joint. PMID- 25842027 TI - Five- to ten-year follow-up with a partially cemented all-polyethylene bone ingrowth glenoid component. AB - BACKGROUND: Although total shoulder arthroplasty has demonstrated better clinical outcomes than hemiarthroplasty, glenoid component loosening is a common complication. Recently, a novel partially cemented all-polyethylene fluted central peg bone-ingrowth component was introduced. METHODS: Forty-two consecutive total shoulder arthroplasties from 2003 to 2007 performed by a single surgeon were evaluated radiographically and clinically with American Shoulder and Elbow Surgeons (ASES) scores and range of motion. RESULTS: The average follow-up was 80 months (63-114); the average forward elevation improved from 107 degrees to 137 degrees , and external rotation improved from 30 degrees to 37 degrees at the latest follow-up. The average ASES score improved from 50 to 84. There was a strong correlation with the mean peripheral peg lucent line score (Lazarus score), which was 0.81, with the mean anchor peg lucent line score, which was 0.50 (P < .001). An analysis of polyethylene before and after cross-linking revealed a strong correlation between components with cross-linking and the Lazarus scores and the central fluted peg scores. Overall, there was 97% survivorship at 80 months. On radiographs, 81% of the central fluted pegs had complete incorporation with no lucent lines. These lucent lines correlated with lower ASES scores, suggesting that loosening of the glenoid decreases functional outcome. CONCLUSION: Care should be taken in preparing the central fluted peg as perforation of the vault can lead to central flute peg lucent line formation, whereas perforation of the peripheral pegs does not seem to negatively affect the outcome. PMID- 25842028 TI - Sleep quality and nocturnal pain in patients with shoulder disorders. AB - BACKGROUND: Nocturnal shoulder pain resulting in poor sleep quality is a common finding in patients with shoulder disease. The purpose of this paper was to describe and to compare the sleep quality, pain, and function in adult subjects who have been diagnosed with rotator cuff disorders, osteoarthritis, or adhesive capsulitis (AC). METHODS: Patients completed a clinical assessment and comprehensive questionnaire regarding their current medical health history, shoulder symptoms, and impact of their symptoms on activities of daily living and quality of sleep. RESULTS: The study analyzed 343 patients with an average age of 57.4 years. The mean Single Assessment Numeric Evaluation score for AC was 34%, which was significantly lower than the score for the subacromial impingement syndrome group of 53% (P = .007). The mean American Shoulder and Elbow Surgeons scale score for AC was 38, which was also significantly lower than the score for the subacromial impingement syndrome group of 51 (P = .007). There were no significant differences in pain, with mean scores ranging from 4.90 to 5.82 for diagnostic subgroups on a visual analog scale (P = .28). Sleep quality was significantly poorer in the AC group (P = .008), with a mean Pittsburgh Sleep Quality Index score of 12.07. Specific subcomponents of the Pittsburgh Sleep Quality Index that had a significant impact on sleep interruption included sleep quality, sleep duration, and habitual sleep efficiency in the AC group (P < .05). CONCLUSION: This study shows that whereas many patients with shoulder disease may have sleep-related issues, patients with adhesive capsulitis are particularly vulnerable to reduced sleep quality. PMID- 25842029 TI - Predictors of throwing velocity in youth and adolescent pitchers. AB - BACKGROUND: Shoulder and elbow injuries are a common cause of pain, dysfunction, and inability to play in overhead throwers. Pitch velocity plays an integral part in the etiology of these injuries; however, the demographic and biomechanical correlates with throwing velocity remain poorly understood. We hypothesized that pitchers with higher velocity would have shared demographic and kinematic characteristics. METHODS: Normal preseason youth and adolescent pitchers underwent dual-orthogonal high-speed video analysis while pitch velocity was collected with a radar gun. Demographic and pitching history data were also collected. Kinematic data and observational mechanics were recorded. Multivariate regression analysis was performed. RESULTS: A total of 420 pitchers were included, with a mean pitching velocity of 64 +/- 10 mph. After multivariate logistic regression analysis, the most important correlates with pitch velocity were age (P < .001; R(2) = 0.658), height (P < .001; R(2) = 0.076), separation of the hips and shoulders (P < .001; R(2) = 0.027), and stride length (P < .001; R(2) = 0.016); in combination, these 4 variables explained 78% of the variance in pitch velocity. Each year of age was associated with a mean 1.5 mph increase in velocity; each inch in height, with 1.2 mph; separation of the hips and shoulders, with 2.6 mph; and a 10% increase in stride length, with 1.9 mph. CONCLUSION: Pitch velocity is most strongly correlated with age, height, separation of the hips and shoulders, and stride length. PMID- 25842030 TI - Suture anchor fixation of displaced olecranon fractures in the elderly: a case series and surgical technique. AB - BACKGROUND: Olecranon fractures are common in elderly patients, causing significant morbidity and functional impairment. Traditional surgical treatments are often complicated by hardware failure and prominence, frequently requiring reoperation. To address these concerns, a suture anchor fixation technique was developed and clinically evaluated. METHODS: A consecutive series of elderly patients treated with this technique from 2006 to 2013 at a single institution were studied. All cases were surgically repaired with nonmetallic fully threaded suture anchors in a double-row fashion. Clinical outcome measures including the shortened Disabilities of the Arm, Shoulder, and Hand score, the Oxford Elbow Score, and the 12-Item Short Form Health Survey score were obtained. RESULTS: Eight female patients with Mayo IIA or IIB fractures were identified. The mean age of the patients at time of operation was 73.5 +/- 10.7 years (range, 59.3 88.8 years). The average time from injury to operation was 5.7 +/- 3.7 days. The average follow-up was 5.1 +/- 2.5 years (range, 0.8-7.4 years). Six patients were available for long-term follow-up; 1 patient had died, and 1 patient was unable to be contacted despite multiple attempts. There were no intraoperative complications or reoperations. All 8 patients healed uneventfully in an acceptable position without displacement. Postoperatively, the average Oxford Elbow Score was 47.17 +/- 2.04; the average shortened Disabilities of the Arm, Shoulder, and Hand score was 6.43 +/- 9.47; and the average 12-Item Short Form Health Survey scores were 49.02 +/- 16.59 and 55.38 +/- 4.05 for the physical and mental component scales, respectively. CONCLUSION: Suture anchor fixation of olecranon fractures in the elderly population provides excellent long-term radiographic and clinical outcomes without hardware complications associated with traditional fixation methods. PMID- 25842031 TI - Wear rates of retentive versus nonretentive reverse total shoulder arthroplasty liners in an in vitro wear simulation. AB - BACKGROUND: Although short-term outcomes of reverse total shoulder arthroplasty (rTSA) remain promising, the most commonly cited complication remains prosthetic instability. A retentive rTSA liner is commonly used to increase system constraint; however, no studies have evaluated the rate of polyethylene wear. Our hypothesis was that more constrained retentive liners would have higher wear rates than nonretentive liners. METHODS: Six nonretentive and six retentive rTSA non-cross-linked polyethylene liners were subjected to 4.5 million cycles of alternating cycles of abduction-adduction and flexion-extension motion loading profiles. The rTSA liners were assessed for gravimetric wear loss, 3-dimensional volumetric loss by novel micro-computed tomography analysis, and particulate wear debris analysis. RESULTS: Volumetric wear rates were significant at 7 specific time points (1.0, 2.0, 2.5, 3.25, 3.75, 4.0, and 4.5 million cycles) throughout testing between nonretentive and retentive liners; however, overall mean volumetric wear rate was not statistically significant (P = .076). Total volume loss between liner test groups was found to be significant starting after 3.5 million cycles of testing. Maximum and mean surface deviations were found to be larger for retentive liners vs. nonretentive liners by micro-computed tomography analysis across the entire articulation surface. DISCUSSION AND CONCLUSION: Retentive liners undergo significantly greater volume loss and greater surface deviation compared with nonretentive liners, most notably at later time points representing extended implantation times. Additional stability afforded by retentive liners should be balanced against the potential for increased wear and potential for subsequent polyethylene wear-induced aseptic loosening. PMID- 25842032 TI - Moving beyond standard procedures to assess spontaneous recognition memory. AB - This review will consider how spontaneous tasks have been applied alongside neuroscientific techniques to test complex forms of recognition memory for objects and their environmental features, e.g. the spatial location of an object or the context in which it is presented. We discuss studies that investigate the roles of the perirhinal cortex and the hippocampus in recognition memory using standard testing paradigms, and consider how these findings contribute to the ongoing debate about whether recognition memory is a single unitary process or multiple processes that can be dissociated anatomically and functionally. Due to the wide use of spontaneous tasks, the need for improved procedures that reduce animal use is acknowledged, with multiple trial paradigms discussed as a novel way of reducing variability and animal numbers in these tasks. The importance of improving translation of animal models to humans is highlighted, with emphasis on a shift away from relying on the phenomenological experience of human subjects. PMID- 25842033 TI - Patch clamp characterization of the effect of cardiolipin on MscS of E. coli. AB - The bacterial mechanosensitive channels MscS and MscL are gated by an increase in membrane tension when the bacterium experiences hypoosmotic shock. It has been well established that membrane lipids modulate the mechanosensitivity and gating behavior of these channels. The focus of this study is a negatively charged phospholipid, cardiolipin, which has been shown to localize at curved regions of the bacterial cell, including the poles and the septum, and to have a strong preference for binding to membrane proteins. Here we characterize the effect of cardiolipin on MscS, the mechanosensitive channel of small conductance, using patch-clamp electrophysiology. We compare the gating kinetics and mechanosensitivity of the channel in both azolectin and mixtures of pure lipids DOPE/DOPC liposomes with and without cardiolipin. In azolectin liposomes, the addition of 10 % cardiolipin abolishes hysteresis of MscS, but MscL remains largely unaffected, indicating that cardiolipin may stabilize the closed state of MscS. On the other hand, mixtures of DOPE/DOPC abolish the hysteresis gating of MscS even in the absence of cardiolipin, and the addition of cardiolipin increases the opening and closing thresholds of both MscS and MscL. In addition, we show that MscS gates more frequently when cardiolipin is present in both the azolectin and pure lipid systems; this dose-dependent effect ultimately destabilizes the open state of MscS and we consider the functional implications of this cardiolipin effect in the bacterial osmotic response. Our results show that cardiolipin modulates the mechanosensitivity and gating characteristics of MscS, indicating its important role in the physiology of bacterial cells. PMID- 25842034 TI - Downregulation of discoidin domain receptor 2 decreases tumor growth of hepatocellular carcinoma. AB - PURPOSE: Discoidin domain receptors (DDRs) have been identified as tyrosine kinase receptors for collagen, and the overexpression of DDR1 was correlated with hepatocellular carcinoma (HCC) progression in vitro. Little is known about DDR2 on HCC cells, and we investigated the expression and function of DDR2 in human HCC cells. METHODS: Expression of DDR2 in human HCC cell lines and patient HCC tissues was observed. The suppression of DDR2 by siRNA against DDR2 was performed in vitro and in vivo study. RESULTS: All of HCC cell lines expressed DDR2 mRNA, and all HCC tissues from the ten patients with HCC demonstrated DDR2 mRNA expression. Transfection of DDR2 siRNA significantly inhibits cell growth compared to cells with nontarget siRNA transfection in vitro (P < 0.001). In SNU182, Hep3B, and HeLa cell xenograft models, there was a significant difference in average tumor volumes after 12 days of the DDR2 siRNA injection (P < 0.05) in SNU182 xenograft mice. DDR2 siRNA injection decreased the mean tumor volume by 65.6 % compared to that of the control. The apoptosis analysis demonstrated that DDR2 siRNA treatment significantly increased apoptotic cells (P < 0.01). Cell migration (P < 0.05) and cell invasion (P < 0.01) were significantly decreased by DDR2 siRNA treatment. CONCLUSIONS: The inhibition of DDR2 by RNA interference suppressed in vivo and in vitro growth of human HCC cells. Our results may support that the use of DDR2 as a novel target of HCC treatment through control of tumor apoptosis, migration, and invasion. PMID- 25842035 TI - Assessment of the outcomes of the treatment of Cushing's disease in the hospitals of Castilla-La Mancha. AB - OBJECTIVE: Treatment of Cushing's disease poses interesting dilemmas in clinical practice. The aim of our study was to analyze the outcomes of the different treatments, the control and recurrence rates, and the complications derived from them. MATERIAL AND METHODS: Data were collected from the clinical records of 22 patients over 18 years of age (86.4% women). They had been diagnosed with Cushing's disease between 2000 and 2012, and were monitored at Complejo Hospitalario Universitario-Albacete, Hospital Virgen de la Salud-Toledo Hospital General Universitario de Ciudad Real, Hospital Virgen de la Luz-Cuenca, Hospital Nuestra Senora del Prado-Talavera de la Reina, and Complejo Hospitalario la Mancha Centro-Alcazar de San Juan. RESULTS: Surgery was the treatment of choice in all patients. Biochemical cure was achieved in 72.2% of patients. Nine patients developed in the early postoperative period diabetes insipidus, which became in 2 patients only. Surprisingly, 3 patients with normal postoperative neurohypophyseal function later developed permanent diabetes insipidus. New hormone deficiencies occurred in 7 patients. Seventeen patients received ketoconazole before surgery (5 of them after surgery also), and 70% of them achieved normal urinary free cortisol levels. Three patients also received radiotherapy, and all of them were cured after a median follow-up of 85.5 months; they developed no tumors or other complications. CONCLUSIONS: Our study reports the outcomes of management of Cushing's disease in non-reference centers for this disease, possibly giving a realistic picture of standard clinical practice for the condition in Spain. PMID- 25842036 TI - Diagnostic criteria for gestational diabetes: The debate goes on. PMID- 25842037 TI - Delftia deserti sp. nov., isolated from a desert soil sample. AB - A Gram-staining negative, short rod, motile, light brownish-pigmented bacterial strain, designated YIM Y792(T), was isolated from a soil sample taken from Turpan desert in Xinjiang Uyghur Autonomous Region, north-western China. Phylogenetic analysis indicated that strain YIM Y792(T) belongs to the genus Delftia. Strain YIM Y792(T) shared highest 16S rRNA gene sequence similarities with Delftia lacustris DSM 21246(T) (93.96 %), Delftia tsuruhatensis NBRC 16741(T) (93.74 %), and Delftia acidovorans NBRC 14950(T) (93.62 %). Growth of the strain YIM Y792(T) was found to occur at 20-45 degrees C (optimum at 30 degrees C), pH 6.0-9.0 (optimum at pH 7.0), and salinities of 0-3.0 % NaCl (optimum at 1.0 %). The new bacterium exhibits typical chemotaxonomic features of the genus Delftia with ubiqinone-8 (Q-8) as the predominant quinone and C16:0, Summed feature 3, Summed Feature 8 as major fatty acids (>10 %). The polar lipids were found to consist of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, glycolipid, two unidentified phospholipids and one unidentified lipid. The G+C content of the genomic DNA of strain YIM Y792(T) was found to be 70.3 mol%. The DNA-DNA relatedness values between strain YIM Y792(T) and D. lacustris DSM 21246(T), D. tsuruhatensis NBRC16741(T), D. acidovorans NBRC14950(T) were 35.5 +/ 2.0, 17.1 +/- 1.8, 26.2 +/- 2.0 %. Based on the phylogenetic, chemotaxonomic and phenotypic data presented here, we propose a novel species with the name Delftia desertisoli sp. nov. The type strain is YIM Y792(T) (=KCTC 42377(T) = JCM 30639(T)). PMID- 25842038 TI - Assessment of epiphytic yeast diversity in rice (Oryza sativa) phyllosphere in Thailand by a culture-independent approach. AB - The epiphytic yeast diversity in rice phyllosphere in Thailand was investigated by a culture-independent technique based on the RFLP pattern and the sequence of the D1/D2 domain of the large subunit rRNA gene. Forty-four samples of rice leaf were collected randomly from six provinces. The DNA was extracted from leaf washing samples and the D1/D2 domain was amplified using PCR technique. The PCR products were cloned and then screened by colony PCR. Of total 1121 clones, 451 clones (40.2 %) revealed the D1/D2 domain sequences closely related to sequences of yeasts in GenBank, and they were clustered into 45 operational taxonomic units (OTUs) at 99 % homology. Of total yeast related clones, 329 clones (72.9 %) were identified as nine known yeast species, which consisted of 314 clones (8 OTUs) in the phylum Basidiomycota including Bullera japonica, Pseudozyma antarctica, Pseudozyma aphidis, Sporobolomyces blumeae, Sporobolomyces carnicolor and Sporobolomyces oryzicola and 15 clones (6 OTUs) in the phylum Ascomycota including Metschnikowia koreensis, Meyerozyma guilliermondii and Wickerhamomyces anomalus. The D1/D2 sequences (122 clones) that could not be identified as known yeast species were closest to 3 and 14 species in Ascomycota and Basidiomycota, respectively, some of which may be new yeast species. The most predominant species detected was P. antarctica (42.6 %) followed by B. japonica (25.9 %) with 63.6 and 22.7 % frequency of occurrence, respectively. The results of OTU richness of each sampling location revealed that climate condition and sampling location could affect epiphytic yeast diversity in rice phyllosphere. PMID- 25842039 TI - The ipdC, hisC1 and hisC2 genes involved in indole-3-acetic production used as alternative phylogenetic markers in Azospirillum brasilense. AB - Plant growth-promoting bacteria of the genus Azospirillum are present in the rhizosphere and as endophytes of many crops. In this research we studied 40 Azospirillum strains isolated from different plants and geographic regions. They were first characterized by 16S rDNA restriction analysis, and their phylogenetic position was established by sequencing the genes 16S rDNA, ipdC, hisC1, and hisC2. The latter three genes are involved in the indole-3-pyruvic acid (IPyA) biosynthesis pathway of indole-3-acetic acid (IAA). Furthermore, the suitability of the 16S-23S rDNA intergenic spacer sequence (IGS) for the differentiation of closely related Azospirillum taxa and development of PCR protocols allows for specific detection of strains. The IGS-RFLP analysis enabled intraspecies differentiation, particularly of Azospirillum brasilense and Azospirillum lipoferum strains. Results demonstrated that the ipdC, hisC1, and hisC2 genes are highly conserved in all the assessed A. brasilense isolates, suggesting that these genes can be used as an alternative phylogenetic marker. In addition, IAA production determined by HPLC ranged from 0.17 to 98.2 MUg mg(-1) protein. Southern hybridization with the A. brasilense ipdC gene probe did not show, a hybridization signal with A. lipoferum, Azospirillum amazonense, Azospirillum halopreferans and Azospirillum irakense genomic DNA. This suggests that these species produce IAA by other pathways. Because IAA is mainly synthesized via the IPyA pathway in A. brasilense strains, a species that is used worldwide in agriculture, the identification of ipdC, hisC1, and hisC2 genes by PCR may be suitable for selecting exploitable strains. PMID- 25842041 TI - Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition. PMID- 25842040 TI - Kribbella qitaiheensis sp. nov., a novel actinomycete isolated from soil. AB - A novel nocardioform actinomycete, designated strain NEAU-GQTH2-3(T), was isolated from muddy soil collected from a stream in Qitaihe, Heilongjiang Province, northeast China and characterized using a polyphasic approach. Phylogenetic analysis based on the 16S rRNA gene sequence demonstrated that the organism should be assigned to the genus Kribbella and forms a clade with Kribbella catacumbae JCM 14968(T) (99.2 % sequence similarity), Kribbella koreensis JCM 10977(T) (99.1 %), Kribbella ginsengisoli JCM 16928(T) (98.6 %) and Kribbella sancticallisti JCM 14969(T) (98.4 %), although with low bootstrap support. Morphological and chemotaxonomic properties of the isolate are in agreement with the description of the genus Kribbella. Chemotaxonomic characteristics include LL-diaminopimelic acid in the cell-wall peptidoglycan; glucose and ribose as the characteristic whole-cell hydrolysates; diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol, a glycerolipid and an unidentified phospholipid as the predominant polar lipids; the major menaquinones MK-9(H4) and MK-9(H2); as well as iso-C15:0, iso-C16:0 and C17:1 omega7c being the predominant fatty acid components. Mycolic acids were not detected. Furthermore, the strain could be clearly distinguished by the combination of DNA-DNA hybridization results and some phenotypic characteristics from the closest phylogenetic relatives. Therefore, it is proposed that strain NEAU-GQTH2-3(T) represents a novel species of the genus Kribbella, for which the name Kribbella qitaiheensis sp. nov. is proposed. The type strain is NEAU-GQTH2-3(T) (=CGMCC 4.7215(T) =JCM 30343(T)). PMID- 25842042 TI - Development of pyruvate dehydrogenase kinase inhibitors in medicinal chemistry with particular emphasis as anticancer agents. AB - Many cancer cells demonstrate a high rate of glucose consumption via glycolysis to provide intermediates for macromolecule biosynthesis. To accomplish this metabolic change, the expression of pyruvate dehydrogenase kinases (PDKs) is rapidly increased in cancer cells. Inhibition of PDKs could promote the function of mitochondria by increasing the oxidative metabolism of pyruvate, resulting in the death of cancer cells. In this review, we provide an overview of the structural information available for PDKs and their connections to known therapeutic effects. We then describe the development of small molecule PDK inhibitors in medicinal chemistry with particular emphasis as anticancer agents. Finally, directions for further development of PDK inhibitors as potential anticancer agents are discussed. PMID- 25842043 TI - Postural- and respiratory-related activities of abdominal muscles during post exercise hyperventilation. AB - The present study focuses on the role of superficial abdominal muscles revealed by electromyographic recordings during the maintenance of a bipedal stance perturbed by post-exercise hyperventilation. Twelve healthy subjects performed six 30-s postural tests: one pre-exercise test while breathing quietly, then one test every minute for the 5 min immediately following a maximum-intensity, incremental cycling exercise test. Displacement of the centre of pressure in the sagittal plane was monitored over time. Myoelectric activities of the obliquus externus (OE), obliquus internus (OI) and rectus abdominis (RA) muscles were recorded by surface electromyography (EMG). Metabolic parameters were measured with a portable telemetric device. The change in ventilatory drive induced by exercise was accompanied by a significant increase in both postural sway parameters and EMG activities. For OE and OI, the increased EMG activities were prominent during expiration, whereas OI was silent during inspiration. OE and RA were activated during both expiration and inspiration. It is concluded that the compensation of respiratory disturbances of the erect posture appears to be less effective when minute ventilation increases. The patterns of muscle activity suggest that abdominal muscles are controlled differentially and that their functional coordination is dependent on the respiratory demand. PMID- 25842045 TI - Editor's Introduction on the Special Section "Spirituality in Adolescents: The Hub of Mental Health and Positive Development". PMID- 25842044 TI - Internet and Advertisement. AB - The Internet has revolutionized the way knowledge is currently produced, stored and disseminated. A few finger clicks on a keyboard can save time and many hours of search in libraries or shopping in stores. Online trademarks with an (e-) prefix such as e-library, e-business, e-health etc., are increasingly part of our daily professional vocabularies. However, the Internet has also produced multiple negative side effects, ranging from an unhealthy dependency to a dehumanization of human relationships. Fraudulent, unethical and scam practices are also flourishing through for example misleading online advertising methods. Some social and professional networks gather users' profiles for selling and advertising purposes, sometimes by making it technically difficult to unsubscribe. Here, I discuss some of these unethical aspects and propose some potential solutions to reduce them. PMID- 25842046 TI - Children of Few Words: Relations Among Selective Mutism, Behavioral Inhibition, and (Social) Anxiety Symptoms in 3- to 6-Year-Olds. AB - Children with selective mutism (SM) fail to speak in specific public situations (e.g., school), despite speaking normally in other situations (e.g., at home). The current study explored the phenomenon of SM in a sample of 57 non-clinical children aged 3-6 years. Children performed two speech tasks to assess their absolute amount of spoken words, while their parents completed questionnaires for measuring children's levels of SM, social anxiety and non-social anxiety symptoms as well as the temperament characteristic of behavioral inhibition. The results indicated that high levels of parent-reported SM were primarily associated with high levels of social anxiety symptoms. The number of spoken words was negatively related to behavioral inhibition: children with a more inhibited temperament used fewer words during the speech tasks. Future research is necessary to test whether the temperament characteristic of behavioral inhibition prompts children to speak less in novel social situations, and whether it is mainly social anxiety that turns this taciturnity into the psychopathology of SM. PMID- 25842047 TI - Staging for vulvar cancer. AB - Vulvar cancer has been staged by the International Federation of Gynaecology and Obstetrics (FIGO) since 1969, and the original staging system was based on clinical findings only. This system provided a very good spread of prognostic groupings. Because vulvar cancer is virtually always treated surgically, the status of the lymph nodes is the most important prognostic factor and this can only be determined with certainty by histological examination of resected lymph nodes, FIGO introduced a surgical staging system in 1988. This was modified in 1994 to include a category of microinvasive vulvar cancer (stage IA), because such patients have virtually no risk of lymph node metastases. This system did not give a reasonably even spread of prognostic groupings. In addition, patients with stage III disease were shown to be a heterogeneous group prognostically, and the number of positive nodes and the morphology of those nodes were not taken into account. A new surgical staging system for vulvar cancer was introduced by FIGO in 2009. Initial retrospective analyses have suggested that this new staging system has overcome the major deficiencies in the 1994 system. PMID- 25842048 TI - Erratum to: Growth Hormone Deficiency and Lysinuric Protein Intolerance: Case Report and Review of the Literature. AB - The first and last names of the authors were inadvertently reversed in the original version. PMID- 25842049 TI - Outcome of Patients with Immunoglobulin Light-Chain Amyloidosis with Lung, Liver, Gastrointestinal, Neurologic, and Soft Tissue Involvement after Autologous Hematopoietic Stem Cell Transplantation. AB - There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression free survival and overall survival (OS) were 36 and 73 months, respectively. Auto HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement. PMID- 25842050 TI - Impact of Additional Cytogenetic Abnormalities in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation. AB - The occurrence of additional cytogenetic abnormalities (ACAs) is common in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in the tyrosine kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case series of adults with Ph+ ALL who had undergone allogeneic hematopoietic cell transplantation (alloHCT) at City of Hope between 2003 and 2014. Among 130 adults with Ph+ ALL who had TKI therapy before alloHCT, 78 patients had available data on conventional cytogenetics at diagnosis and were eligible for outcomes analysis. ACAs were observed in 41 patients (53%). There were no statistically significant differences in median age, median initial WBC count, post-HCT TKI maintenance, or disease status at the time of transplant between the Ph-only and ACA cohorts; however, the Ph-only cohort had a higher rate of minimal residual disease positivity at the time of HCT. Three-year leukemia-free survival (79.8% versus 39.5%, P = .01) and 3-year overall survival (83% versus 45.6%, P = .02) were superior in the Ph-only cohort compared with the ACA cohort, respectively. Monosomy 7 was the most common additional aberration observed in our ACA cohort (n = 12). Thus, when TKI therapy and alloHCT are used as part of adult Ph+ ALL therapy, the presence of ACAs appears to have a significant deleterious effect on outcomes post-HCT. PMID- 25842051 TI - Effectiveness of conventional versus virtual reality-based balance exercises in vestibular rehabilitation for unilateral peripheral vestibular loss: results of a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of virtual reality-based balance exercises to conventional balance exercises during vestibular rehabilitation in patients with unilateral peripheral vestibular loss (UVL). DESIGN: Assessor blind, randomized controlled trial. SETTING: Two acute care university teaching hospitals. PARTICIPANTS: Patients with UVL (N=71) who had dizziness/vertigo, and gait and balance impairment. INTERVENTIONS: Patients with UVL were randomly assigned to receive 6 weeks of either conventional (n=36) or virtual reality based (n=35) balance exercises during vestibular rehabilitation. The virtual reality-based group received an off-the-shelf virtual reality gaming system for home exercise, and the conventional group received a foam balance mat. Treatment comprised weekly visits to a physiotherapist and a daily home exercise program. MAIN OUTCOME MEASURES: The primary outcome was self-preferred gait speed. Secondary outcomes included other gait parameters and tasks, Sensory Organization Test (SOT), dynamic visual acuity, Hospital Anxiety and Depression Scale, Vestibular Rehabilitation Benefits Questionnaire, and Activities Balance Confidence Questionnaire. The subjective experience of vestibular rehabilitation was measured with a questionnaire. RESULTS: Both groups improved, but there were no significant differences in gait speed between the groups postintervention (mean difference, -.03m/s; 95% confidence interval [CI], -.09 to .02m/s). There were also no significant differences between the groups in SOT scores (mean difference, .82%; 95% CI, -5.00% to 6.63%) or on any of the other secondary outcomes (P>.05). In both groups, adherence to exercise was high (~77%), but the virtual reality-based group reported significantly more enjoyment (P=.001), less difficulty with (P=.009) and less tiredness after (P=.03) balance exercises. At 6 months, there were no significant between-group differences in physical outcomes. CONCLUSIONS: Virtual reality-based balance exercises performed during vestibular rehabilitation were not superior to conventional balance exercises during vestibular rehabilitation but may provide a more enjoyable method of retraining balance after unilateral peripheral vestibular loss. PMID- 25842052 TI - Wechsler profiles in referred children with intellectual giftedness: Associations with trait-anxiety, emotional dysregulation, and heterogeneity of Piaget-like reasoning processes. AB - BACKGROUND/PURPOSE: It is common that intellectually gifted children (IQ >= 130) are referred to paediatric or child neuropsychiatry clinics for socio-emotional problems and/or school underachievement or maladjustment. Among them, those displaying developmental asynchrony - a heterogeneous developmental pattern reflected in a significant verbal-performance discrepancy (SVPD) on Wechsler's intelligence profile - are thought to be more emotionally and behaviourally impaired than others. Our purpose was to investigate this clinical dichotomy using a cognitive psychopathological approach. METHODS: Trait-anxiety and emotional dysregulation were investigated in two groups of referred gifted children (n = 107 and 136, respectively), a pilot-study of reasoning processes on extensive Piaget-like tasks was also performed in an additional small group (n = 12). RESULTS: Compared to those with a homogenous Wechsler profile, children with a SVPD exhibited: 1) a decreased prevalence of social preoccupation-anxiety (11.1% versus 27.4%; p < 0.05); 2) an increased prevalence of emotional dysregulation (58.7% versus 41.3%; p < 0.05); and 3) an increased prevalence of pathological cognitive disharmony on Piaget-like tasks (87.5% versus 0.0%; p < 0.05). CONCLUSION: The results support a clinical dichotomy of behaviourally impaired children with intellectual giftedness, with developmentally asynchronous ones exhibiting more severe psychopathological features. This suggests that developmental asynchrony matters when examining emotional and behavioural problems in gifted children and call for further investigation of this profile. PMID- 25842053 TI - Complications of mandibular distraction osteogenesis for acquired deformities: a systematic review of the literature. AB - A systematic review on complications in all forms of mandibular distraction osteogenesis (MDO) for acquired deformities was performed. Search terms expressing distraction osteogenesis were used in 'AND' combination with search terms comprising 'mandible' and terms for complication, failure, and morbidity. A search using PubMed (National Library of Medicine, NCBI), EMBASE, and the Cochrane Controlled Trials Register yielded 644 articles published between 1966 and mid October 2013. Three hundred and twenty-one eligible articles were screened in detail. Complications related to MDO in acquired deformities were reported in 105 clinical articles, involving 1332 patients. Treatments included alveolar distraction osteogenesis (ADO), mandibular lengthening, DO in bone grafts, and bi-/trifocal transport disc DO (TDDO) for segmental mandibular defects. A high incidence of complications was seen in MDO for acquired deformities (ADO 44.4%; residual group 43.9%). An index for classifying complications in MDO, based on the impact and further treatment or final results, was used. In the ADO group, soft tissue complications (8.0%), insufficient vector control (7.6%), temporary inferior alveolar nerve (IAN) neurosensory disturbances (6.5%), device-related problems (3.5%), mandible fractures (2.8%), insufficient bone formation (2.5%), and fracture of the transport disc (1.3%) were seen. In the residual group, temporary IAN neurosensory disturbances (13.4%), minor infection (5.3%), DO failure (4.0%), and device-related problems (3.8%) were reported. PMID- 25842054 TI - Predominance of B haplotype associated KIR genes in Tamil Speaking Dravidians. AB - Killer cell immunoglobulin like receptors (KIRs) are a group of activating (aKIRs) and inhibitory receptors (iKIRs) expressed on subsets of lymphoid cells. Their interaction with HLA class I molecules modulate the innate and adaptive immune response against infections and malignancies. KIR haplotypes varies in gene content and also at allelic level, thereby, distinguishing individuals and populations. Hence, the present study is aimed to determine the KIR gene diversity in Piramalai Kallar (PK) population of South India. The PK population shows diverged KIR gene frequencies and novel haplotypes than other South Indian populations. 52 different KIR gene profiles were identified and 18 of them were new in this population. In phylogenetic analysis the study population is positioned between African and Iranian population in the clade, which supports the South African ancestry of Indian population. PMID- 25842055 TI - Introducing a new manuscript format: Enabling access to immunogenomic population data with short population reports. PMID- 25842056 TI - Passenger lymphocyte syndrome in ABO and Rhesus D minor mismatched liver and kidney transplantation: A prospective analysis. AB - The increasing demand for solid organs has necessitated the use of ABO and Rhesus (Rh) D minor mismatched transplants. The passenger lymphocyte syndrome (PLS) occurs when donor lymphocytes produce antibodies that react with host red blood cell (RBC) antigens and result in hemolysis. Our aim was to evaluate prospectively the role of PLS in post transplant anemia and hemolysis in ABO and RhD minor mismatched recipients of liver and kidney grafts and to study the association of PLS with donor lymphocyte microchimerism. We examined 11 liver and 10 kidney recipients at Day +15 for anemia, markers of hemolysis, direct antiglobulin test and eluates, and serum RBC antibodies. Microchimerism was determined in peripheral blood lymphocytes by genotyping of simple sequence length polymorphisms encoding short tandem repeats. Immune hemolytic anemia and anti-recipient RBC antibodies were observed in 2 out of 11 liver (18.2%) and 2 out of 10 kidney (20%) transplants. RBC antibody specificity reflected the donor to recipient transplant, with anti-blood group B antibodies identified in 2 cases of O to B and 1 case of A to AB transplants while anti-D antibodies were detected in 1 case of RhD-negative to RhD-positive transplant. Donor microchimerism was found in only 1 patient. In conclusion, passenger lymphocyte mediated hemolysis is frequent in minor mismatched liver and kidney transplantation. Recognizing PLS as a potential cause of post transplant anemia may allow for early diagnosis and management to decrease the morbidity and mortality in some patients. PMID- 25842057 TI - The self-perceived identity of Spanish geriatric nurses: Comment on Carlson et al. (2014). PMID- 25842058 TI - Organizing the French response to the Ebola virus infection in West Africa - ethical considerations on information given to patients, their relatives, and healthcare professionals. PMID- 25842059 TI - Chinese Clinical Oncology: a new oncology journal for oncology physicians and researchers worldwide. PMID- 25842060 TI - Medical oncology in Asia. PMID- 25842061 TI - Advanced clinical trials for China. PMID- 25842062 TI - Serum Dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma. AB - We reviewed the tumor markers for hepatocellular carcinoma, with special reference to the roles of Dickkopf-1 and alpha-fetoprotein in hepatocellular carcinoma. PMID- 25842063 TI - Who will be the next rising star? -- Any hope to find a reliable biomarker for HCC? PMID- 25842064 TI - Vitamin E: potential therapeutical approach for prevention of liver cancer development. PMID- 25842065 TI - Vitamin intake and risk of liver cancer: potential for prevention? PMID- 25842066 TI - Vitamin E in prevention against hepatocellular carcinoma: right type, right dose and right population. PMID- 25842067 TI - Hepatocellular carcinoma: expanding the horizon. PMID- 25842068 TI - Guidelines on the diagnosis and treatment of primary liver cancer (2011 edition). PMID- 25842069 TI - Expert consensus on local ablation therapies for primary liver cancer. PMID- 25842071 TI - Current status of bevacizumab for advanced hepatocellular carcinoma. PMID- 25842070 TI - Expert consensus on the scheme of pathological diagnosis of primary liver cancer. PMID- 25842072 TI - Hepatocellular carcinoma: present and future. PMID- 25842073 TI - Guidelines for the management of hepatocellular carcinoma: still in need of standardization. PMID- 25842074 TI - Google-driven search for big data in autoimmune geoepidemiology: analysis of 394,827 patients with systemic autoimmune diseases. AB - Systemic autoimmune diseases (SADs) are a significant cause of morbidity and mortality worldwide, although their epidemiological profile varies significantly country by country. We explored the potential of the Google search engine to collect and merge large series (>1000 patients) of SADs reported in the Pubmed library, with the aim of obtaining a high-definition geoepidemiological picture of each disease. We collected data from 394,827 patients with SADs. Analysis showed a predominance of medical vs. administrative databases (74% vs. 26%), public health system vs. health insurance resources (88% vs. 12%) and patient based vs. population-based designs (82% vs. 18%). The most unbalanced gender ratio was found in primary Sjogren syndrome (pSS), with nearly 10 females affected per 1 male, followed by systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and antiphospholipid syndrome (APS) (ratio of nearly 5:1). Each disease predominantly affects a specific age group: children (Kawasaki disease, primary immunodeficiencies and Schonlein-Henoch disease), young people (SLE Behcet disease and sarcoidosis), middle-aged people (SSc, vasculitis and pSS) and the elderly (amyloidosis, polymyalgia rheumatica, and giant cell arteritis). We found significant differences in the geographical distribution of studies for each disease, and a higher frequency of the three SADs with available data (SLE, inflammatory myopathies and Kawasaki disease) in African-American patients. Using a "big data" approach enabled hitherto unseen connections in SADs to emerge. PMID- 25842075 TI - Differences of Intracranial Electrical Stimulation Thresholds in the Human Brain. AB - BACKGROUND: The thresholds of current intensities required to evoke a clinical response during intracranial electrical stimulation mapping vary. OBJECTIVE: We wanted to test if there is systematic variation of threshold currents between different brain areas. METHODS: Electrode contacts of depth electrodes in a series of patients undergoing presurgical evaluation for epilepsy surgery were stimulated. The brain regions we studied included the insular cortex, the pericentral cortex, and the intervening white matter. RESULTS: Current intensities that elicited clinical responses in central subcortical white matter tracts were significantly lower than those needed to evoke a clinical response in the cortex. CONCLUSION: We found systematic differences of threshold stimulation intensities between cortical and subcortical structures in the human brain. In addition to known neurophysiologic differences between white and grey matter, the systematic difference in stimulation thresholds may be due to the direction of the white matter tracts with respect to the electrode orientation and to inherent properties of specific brain regions. PMID- 25842076 TI - Aortic arch surgery after previous type A dissection repair: results up to 5 years. AB - OBJECTIVES: Open aortic arch surgery after type A dissection repair is challenging. We sought to review our surgical experience to analyse the causes and timing, establish the risk profile for this patient population, and better define outcomes. METHODS: From 2000 to 2014, we identified 55 patients who required aortic arch surgery after a previous type A dissection repair. Medical records were available for review including computerized tomographic angiograms, cerebral protection strategies and follow-up. RESULTS: The mean interval from previous type A dissection repair to aortic arch surgery was 5.7 +/- 5.4 years. At reoperation 36 patients (65%) had total arch replacement and 19 (35%) had hemiarch replacement. Indications for reoperations were: enlarging aneurysm in 27 (49%), impending rupture in 12 (22%), chronic dissection in 10 (18%) and aneurysms in 6 (11%). Arterial peripheral cannulation was used in 80% of patients. Selective antegrade cerebral perfusion was used in 35 patients (64%) and retrograde perfusion in 2 (4%). There were 3 perioperative deaths (5%) and 4 cases of permanent stroke (7%). Survival rates were 90, 85 and 77% at the 1-, 3- and 5-year follow-up, respectively. The 5-year survival rate was 10% lower than that of an age- and sex-matched population (P < 0.001). The only predictor of the follow-up mortality was older age (odds ratio: 1.07, 95% confidence interval: 1.02-1.13, P = 0.007). CONCLUSIONS: Aortic arch surgery after previous type A dissection repair can be performed with satisfactory early and mid-term results and acceptable risk of stroke. Cerebral perfusion strategies likely contribute to positive outcomes. Favourable mid-term survival justifies performing such difficult reoperations. PMID- 25842077 TI - Percutaneous closure of acquired Gerbode defect: management of a rare complication of cardiac surgery. AB - Although rare, acquired Gerbode defect (abnormal communication between left ventricle and right atrium) may result as a complication of myocardial infarction, endocarditis as well as aortic or mitral valve replacement resulting in resistant heart failure secondary to significant left to right shunting. We are reporting the case of a 50-year old lady with repeated aortic valve replacement presenting with resistant heart failure secondary to an acquired Gerbode defect. Management of this defect in these high-risk patients may be challenging and percutaneous closure, if feasible, may represent the best management option. PMID- 25842078 TI - Aortic cusp sizers to establish the functional classification of aortic insufficiency: algorithm and midterm outcome of operative repair. AB - OBJECTIVES: Wider adoption of aortic valve repair procedures is held up by the difficulty in recognizing the exact alterations that are responsible for aortic valve insufficiency. New aortic cusp sizers were developed to assist in aortic valve assessment in the operating theatre. Our objectives were to examine the efficacy of the aortic cusp sizers in establishing the functional classification of aortic valve insufficiency, and to report the midterm outcome in a group of patients who had undergone aortic valve repair guided by this device. METHODS: A prospective clinical study was performed involving 33 consecutive patients (18 males, age range: 8-74 years) with severe aortic valve insufficiency (mean severity: 3.4 +/- 0.5). The aortic cusp sizers were used as a template to identify existing cusp and root alterations. Consequently, the functional classification of aortic insufficiency was determined, and the appropriate techniques of aortic valve repair were implemented. RESULTS: Aortic valve repair was successful in all patients. Procedures performed were 37 functional aortic annulus corrections, 9 cusp free-edge plications, 2 cusp repairs with autologous pericardium, 9 replacements of the ascending aorta and 2 reimplantation procedures. At a mean follow-up time of 18.3 +/- 13.7 months, 1 patient underwent aortic valve replacement for recurrent aortic valve regurgitation, while aortic valve function remained stable in 32 patients, with aortic insufficiency <1+ in 27 (84.4%) patients and 1-1.5 in 5 (15.6%) patients, and no significant gradients across the aortic valves. CONCLUSIONS: The aortic cusp sizers are valuable in establishing the functional classification of aortic insufficiency, and can guide implementation of aortic valve repair techniques successfully. This approach is analogous to that accredited for the success and wide adoption of mitral valve repair techniques, and is likely to assist in increasing the percentage of aortic valves that are repaired when compared with current practice. PMID- 25842079 TI - Overview: biostatistician's role in oncology clinical trials-strive for sound, efficient and practical studies. PMID- 25842080 TI - The current design of oncology phase I clinical trials: progressing from algorithms to statistical models. AB - In this article we examine how phase I trial designs for anti-cancer agents have developed over the past few decades. We review the use of algorithmic, relatively non- statistical designs, and then describe nonparametric and parametric statistically-driven designs that have better operating characteristics than algorithmic designs. We then follow with a description of how the original parametric design, known as the continual reassessment method (CRM), has been generalized and expanded to create designs for many complex settings that occur in early-phase oncology trials. We conclude with a discussion of outstanding issues and controversies that continue to exist with phase I trial designs. PMID- 25842081 TI - Adaptive randomized phase II design for biomarker threshold selection and independent evaluation. AB - BACKGROUND: Frequently a biomarker capable of defining a patient population with enhanced response to an experimental agent is not fully validated with a known threshold at the start of a phase II trial. When such candidate predictive markers are evaluated and/or validated retrospectively, over-accrual of patients less likely to benefit from the regimen may result, leading to underpowered analyses or sub-optimal patient care. PURPOSE: We propose an adaptive randomized phase II study design incorporating prospective biomarker threshold identification (or non-identification), possible early futility stopping, potential mid-trial accrual restriction to marker-positive subjects, and final marker and treatment evaluation in the patient population identified as most likely to benefit. METHODS: An interim analysis is used to determine whether an initially unselected trial should stop early for futility, continue without a promising marker, or adapt accrual and resize (up to a pre-determined maximum) according to a promising biomarker. Final efficacy analyses are performed in the target population identified at the interim as most likely to benefit from the experimental regimen. Simulation studies demonstrate control of false-positive error rates, power, reduced average sample size, and other favorable aspects. RESULTS: The design performs well at identifying a truly predictive biomarker at interim analysis, and subsequently restricting accrual to patients most likely to benefit from the experimental treatment. Type I and type II error rates are adequately controlled by restricting the range of marker prevalence via the candidate thresholds, and by careful consideration of the timing of interim analysis. CONCLUSIONS: In situations where identification and validation of a naturally continuous biomarker are desired within a randomized phase II trial, the design presented herein offers a potential solution. PMID- 25842082 TI - Reducing late effects of radiotherapy in average risk medulloblastoma. AB - PURPOSE: To assess the efficacy and safety in average-risk pediatric medulloblastoma (MB) receiving tumor bed boost irradiation compared to a posterior fossa (PF) boost. PATIENTS AND METHODS: Thirty patients were enrolled in the study and divided evenly into two treatment arms of 15. Both arms received 23.4 Gy craniospinal irradiation (CS) and a 32.4 Gy boost. Patients in arm 1 were given PF boosts, and those in arm 2 were given boosts to the gross target volume (GTV). Weekly oncovin was given throughout all radiotherapy (RT). Eight cycles of adjuvant chemotherapy of CCNU, oncovin and platinol were given to all patients after RT. MRI, pure tone audiogram (PTA) and intelligence quotient (IQ) tests were performed before and after RT and every three months thereafter. RESULTS: There were significant differences in the sparing dose to the cochlea and brain stem as well as the volume of the normal brain receiving a 100% dose. There was a significant initial improvement of hearing function in patients given the target volume boost after RT, which was lost after chemotherapy. With a median follow up of 23 months, there was no difference in progression free survival or overall survival between the two arms. CONCLUSIONS: Irradiation of the tumor bed after 23.4 Gy craniospinal irradiation for average-risk MB results in similar disease control as a PF boost. Dosimetric sparing for the cochleae and normal tissue is evident in patients receiving tumor bed boosts. The hearing improvement and cognitive function preservation effects of the treatment need more follow up. PMID- 25842083 TI - EGFR-targeting therapy as an evolving concept: learning from nimotuzumab clinical development. AB - Epidermal growth factor receptor (EGFR)-targeted therapies have been extensively evaluated in the clinic for different tumor localizations and using different EGFR-targeting products, either registered or still in clinical development. Nonetheless, there still is a long way to go to optimize the clinical benefit from EGFR-targeted therapies. In this article we briefly discuss on current paradigms guiding the use of EGFR-targeting agents in the clinic, and on new emergent concepts. The discussion is largely based on experiences from the clinical development of the monoclonal antibody nimotuzumab, which has shown a quite particular clinical profile, characterized by a very low toxicity. In order to optimize the design of EGFR-targeting therapies, clinical researchers should take into account the interconnection between the EGFR pathway and other cellular pathways. Thus, clinical trials need to incorporate more translational research. PMID- 25842084 TI - Commentary on the clinical trial reported by: Tewari KS, Sill M, Long III HJ, et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group. J Clin Oncol 2013;(suppl; abstr 3). PMID- 25842085 TI - Commentary on "aTTom": long-term effects of continuing adjuvant Tamoxifen to 10 years. PMID- 25842086 TI - Comments on "Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: the phase III DECISION trial". PMID- 25842087 TI - Prof. Peter Yu: opportunities and challenges in big data era. PMID- 25842088 TI - Prof. Shukui Qin: strategy on liver cancer treatment for Asian population. PMID- 25842089 TI - Prof. Jean Armand: personalized medicine in France and the niche in future international cooperation. PMID- 25842090 TI - Usage of EGFR-TKI and WBRT in NSCLC patients with brain metastases. PMID- 25842091 TI - Efficacy of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer. AB - Treatment and control of brain metastases are important in patients with non small cell lung cancer (NSCLC). Whole brain radiation therapy (WBRT) has a major role in the management of brain metastasis. Recently, efficacy erlotinib plus concurrent WBRT for patients with brain metastases from NSCLC was reported. Herein, we discussed the results and commented the clinical matters in future. PMID- 25842092 TI - Treatment of brain metastases in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations: the role of EGFR tyrosine kinase inhibitors. PMID- 25842093 TI - Palliative concurrent chemoradiotherapy in locally advanced and metastatic esophageal cancer patients with dysphagia. AB - BACKGROUND & OBJECTIVE: Dysphagia is the most common and serious symptom in patients with esophageal cancer. Several management options have been developed to palliate dysphagia in unresectable and metastatic esophageal carcinoma patients. The aim of this prospective study was to evaluate the efficacy and toxicity of palliative chemoradiotherapy in locally advanced and metastatic esophageal cancer as regard improvement of dysphagia, primary tumor response and survival time. PATIENTS & METHODS: This prospective study was conducted on 25 patients with advanced and metastatic esophageal carcinoma. A radiation dose of 40 Gy/22 fractions was given concomitantly with chemotherapy, consisted of cisplatin 70 mg/m2 infusion on day 1, plus continuous infusion of 5-fluorouracil at 700 mg/m2 per day from day 1 to day 4. RESULTS: Dysphagia improved in 18 (72%) of the 25 patients. The median duration of dysphagia improvement was 5 months after treatment in these patients. Overall, treatment was well tolerated; acute haematologic toxicities were limited, with anaemia (80%) the commonest. The most common non-haematologic toxicity was esophagitis. There were no reports of grade IV toxicities. The activity of the concurrent chemoradiotherapy regimen was good, achieving incomplete response in 18 patients (72%), 5 patients showed stable disease (20%) and 2 patients showed progressive disease (8%). The median overall and progression free survival were 7 and 4 months, respectively. CONCLUSIONS: Our study showed that palliative concurrent chemo-radiotherapy is an effective and well tolerated treatment for dysphagia in patients with advanced and metastatic esophageal carcinoma. PMID- 25842094 TI - Changes in expression of cyclooxygenase-2 in the spinal dorsal horn after intrathecal p38MAPK inhibitor SB203580 on neuropathic pain in rats. AB - OBJECTIVE: To investigate the changes of cyclooxygenase-2 (COX-2) expression in the spinal cord dorsal horn after intrathecal a specific p38MAPK inhibitor SB203580 on neuropathic pain in rats induced by chronic constrictive injury (CCI) to the sciatic nerve. METHODS: Twenty-four male SD rats after intrathecal catheter placement were randomly divided into 4 groups: a sham group with sham surgery, the neuropathic pain model of a NS group, a DMSO group and an SB group were established by CCI to sciatic nerve. NS or DMSO or SB203580 was injected IT NS or 2% DMSO or SB203580 twice a day for 5 consecutive days starting at 6th day when the model of CCI was established. Mechanical stimuli were measured before the surgery and on 1st, 3rd, 5th, 7th, 9th, and 11th day after the surgery. Then all rats were sacrificed and the lumbar segment of spinal cord was removed to determine the COX-2 expression in the dorsal horn by immunocytochemistry. RESULTS: Day 1 to 11 after the surgery, the threshold to mechanical on the surgery side was significantly lower in the NS group and the DMSO group than in the sham group. Day 7 to 11 after the surgery, the threshold to mechanical on the surgery side was significantly lower in the SB group than in the NS group and the DMSO group. The expression of spinal COX-2 was higher in the NS group and the DMSO group than in the sham group, but lower in the SB group than in NS group and the DMSO group. PMID- 25842095 TI - Cryosurgery for colorectal liver metastases. AB - Cryosurgical ablation is mainly reserved for treatment of unresectable lesions for patients with colorectal liver metastases, including multiple tumors in the liver, tumors located at anatomical position that does not permit liver resection, patients with high risk for resection and patients who refuse liver resection. The techniques of cryosurgery include open cryosurgery, laparoscopic cryosurgery, and percutaneous cryoablation. Long-term follow-up study showed that cryosurgery is a safe and important option for a wide range of unresectable colorectal hepatic metastases and provides the potential for long-term survival. PMID- 25842096 TI - Traditional Chinese medicine in the treatment of symptoms in patients with advanced cancer. AB - Patients with advanced malignancies are often suffered from deficient vital qi, which is clinically presented as cancer-related pain, anorexia, nausea/vomiting, fatigue, fever, indigestion, and constipation, which severely lower the quality of life and even shorten the survival of these patients. Traditional Chinese medicine (TCM) has a long history and rich experiences in treating malignancies. In addition to surgery, radiotherapy, chemotherapy, and other modern therapies, the TCM-based treatment can dramatically alleviate the clinical symptoms and improve the quality of life. This article analyzes the TCM treatment for the cancer pain, nausea/vomiting and cancer-related fatigue in patients with advanced malignancies, and the TCM-based emotional care for these patients are also discussed. PMID- 25842097 TI - Welcome to join us in 2013 conferences-Annals of Palliative Medicine. PMID- 25842098 TI - Highlights in hepatocellular carcinoma. PMID- 25842099 TI - All-ceramic or metal-ceramic tooth-supported fixed dental prostheses (FDPs)? A systematic review of the survival and complication rates. Part I: Single crowns (SCs). AB - OBJECTIVE: To assess the 5-year survival of metal-ceramic and all-ceramic tooth supported single crowns (SCs) and to describe the incidence of biological, technical and esthetic complications. METHODS: Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials (CENTRAL) searches (2006-2013) were performed for clinical studies focusing on tooth-supported fixed dental prostheses (FDPs) with a mean follow-up of at least 3 years. This was complimented by an additional hand search and the inclusion of 34 studies from a previous systematic review [1,2]. Survival and complication rates were analyzed using robust Poisson's regression models to obtain summary estimates of 5-year proportions. RESULTS: Sixty-seven studies reporting on 4663 metal-ceramic and 9434 all-ceramic SCs fulfilled the inclusion criteria. Seventeen studies reported on metal-ceramic crowns, and 54 studies reported on all-ceramic crowns. Meta analysis of the included studies indicated an estimated survival rate of metal ceramic SCs of 94.7% (95% CI: 94.1-96.9%) after 5 years. This was similar to the estimated 5-year survival rate of leucit or lithium-disilicate reinforced glass ceramic SCs (96.6%; 95% CI: 94.9-96.7%), of glass infiltrated alumina SCs (94.6%; 95% CI: 92.7-96%) and densely sintered alumina and zirconia SCs (96%; 95% CI: 93.8-97.5%; 92.1%; 95% CI: 82.8-95.6%). In contrast, the 5-year survival rates of feldspathic/silica-based ceramic crowns were lower (p<0.001). When the outcomes in anterior and posterior regions were compared feldspathic/silica-based ceramic and zirconia crowns exhibited significantly lower survival rates in the posterior region (p<0.0001), the other crown types performed similarly. Densely sintered zirconia SCs were more frequently lost due to veneering ceramic fractures than metal-ceramic SCs (p<0.001), and had significantly more loss of retention (p<0.001). In total higher 5 year rates of framework fracture were reported for the all-ceramic SCs than for metal-ceramic SCs. CONCLUSIONS: Survival rates of most types of all-ceramic SCs were similar to those reported for metal-ceramic SCs, both in anterior and posterior regions. Weaker feldspathic/silica-based ceramics should be limited to applications in the anterior region. Zirconia-based SCs should not be considered as primary option due to their high incidence of technical problems. PMID- 25842100 TI - ECG screening for SCD in young adults: community volunteers can acquire higher quality ECGs than health professionals. AB - BACKGROUND AND PURPOSE: ECG screening of young athletes for risk of sudden cardiac death has grown in popularity throughout the world. The purpose of this study is to assess the technical error rate of ECGs acquired by appropriately trained community volunteers compared to that reported in the literature utilizing trained medical personnel. METHODS: This is a retrospective study analyzing consecutive ECGs acquired during 5 successive high school screenings at 3 separate schools in 2011. RESULTS: A total of 4477 consecutive ECGs were acquired and assessed for technical quality. The total rate of technically inadequate tracings was 0.34%. This is lower than that reported in outpatient clinics acquired by medically trained technicians (0.4%) and in ICUs acquired by nurses (4.8%). CONCLUSIONS: This study demonstrates that the ECG training program utilized by the YH4L program for community volunteers results in a technical error rate that is lower than reported in the literature. PMID- 25842101 TI - Apatite formation on calcined kaolin-white Portland cement geopolymer. AB - In this study, calcined kaolin-white Portland cement geopolymer was investigated for use as biomaterial. Sodium hydroxide and sodium silicate were used as activators. In vitro test was performed with simulated body fluid (SBF) for bioactivity characterization. The formation of hydroxyapatite bio-layer on the 28 day soaked samples surface was tested using SEM, EDS and XRD analyses. The results showed that the morphology of hydroxyapatite was affected by the source material composition, alkali concentration and curing temperature. The calcined kaolin-white Portland cement geopolymer with relatively high compressive strength could be fabricated for use as biomaterial. The mix with 50% white Portland cement and 50% calcined kaolin had 28-day compressive strength of 59.0MPa and the hydroxyapatite bio-layer on the 28-day soaked sample surface was clearly evident. PMID- 25842102 TI - Novel nanosized water soluble fluorescent micelles with embedded perylene diimide fluorophores for potential biomedical applications: cell permeability, localization and cytotoxicity. AB - Novel biocompatible water-soluble fluorescent micelles with embedded perylene diimides (PDI) for intracellular applications have been prepared by self assembling of amphiphilic poly(vinyl alcohol)-b-poly(acrylonitrile) (PVA-b-PAN) copolymers in the presence of synthesized fluorophores. Amphiphilic PVA-b-PAN copolymers were obtained by selective hydrolysis of well-defined poly(vinyl acetate)-b-poly(acrylonitrile) (PVAc-b-PAN) copolymer. The preparation of the novel fluorescence micelles consisting of PVA hydrophilic shell and PAN hydrophobic core with incorporated PDI fluorophores has been confirmed by DLS and TEM analysis. The cytotoxicity of the water-soluble fluorophores and their internalization into living cells depending on the micellar concentration have been tested. It was shown that they could successfully enter in living cells without destroying their morphology. The results obtained indicate that the novel water-soluble fluorescent micelles with embedded PDI fluorophores would be suitable for potential intracellular biomedical applications. PMID- 25842103 TI - Nanofibrous yet injectable polycaprolactone-collagen bone tissue scaffold with osteoprogenitor cells and controlled release of bone morphogenetic protein-2. AB - In this work, we developed a nanofibrous, yet injectable orthobiologic tissue scaffold that is capable of hosting osteoprogenitor cells and controlling kinetic release profile of the encapsulated pro-osteogenic factor without diminishing its bioactivity over 21days. This innovative injectable scaffold was synthesized by incorporating electrospun and subsequently O2 plasma-functionalized polycaprolactone (PCL) nanofibers within the collagen type-I solution along with MC3T3-E1 cells (pre-osteoblasts) and bone morphogenetic protein-2 (BMP2). Through changing the PCL nanofiber concentration within the injectable scaffolds, we were able to tailor the mechanical strength, protein retention capacity, bioactivity preservation, and osteoinductive potential of the scaffolds. The nanofibrous internal structure of the scaffold allowed us to use a low dose of BMP2 (200ng/ml) to achieve osteoblastic differentiation in in vitro culture. The osteogenesis capacity of the injectable scaffolds were evaluated though measuring MC3T3-E1 cell proliferation, ALP activity, matrix mineralization, and early- and late-osteoblast specific gene expression profiles over 21days. The results demonstrated that the nanofibrous injectable scaffold provides not only an osteoinductive environment for osteoprogenitor cells to differentiate, but also a suitable biomechanical and biochemical environment to act as a reservoir for osteogenic factors with controlled release profile. PMID- 25842104 TI - Carbodiimide cross-linking of amniotic membranes in the presence of amino acid bridges. AB - The purpose of this study was to investigate the carbodiimide cross-linking of amniotic membrane (AM) in the presence of amino acid bridges. The biological tissues were treated with glycine, lysine, or glutamic acid and chemically cross linked to examine the role of amino acid types in collagenous biomaterial processing. Results of zeta potential measurements showed that the use of uncharged, positively and negatively charged amino acids dictates the charge state of membrane surface. Tensile strength and water content measurements demonstrated that the addition of lysine molecules to the cross-linking system can increase the cross-linking efficiency and dehydration degree while the introduction of glutamic acid in the AM samples decreases the number of cross links per unit mass of chemically modified tissue collagen. The differences in the cross-linking density further determined the thermal and biological stability by differential scanning calorimetry and in vitro degradation tests. As demonstrated in matrix permeability studies, the improved formation of covalent cross-linkages imposed by lysine facilitated construction of stronger cross linking structures. In contrast, the added glycine molecules were insufficient to enhance the resistances of the proteinaceous matrices to thermal denaturation and enzymatic degradation. The cytocompatibility of these biological tissue membranes was evaluated by using human corneal epithelial cell cultures. Results of cell viability, metabolic activity, and pro-inflammatory gene expression level showed that the AM materials cross-linked with carbodiimide in the presence of different types of amino acids are well tolerated without evidence of detrimental effect on cell growth. In addition, the amino acid treated and carbodiimide cross-linked AM implants had good biocompatibility in the anterior chamber of the rabbit eye model. Our findings suggest that amino acid type is a very important engineering parameter to mediate carbodiimide cross-linking of AM collagen. PMID- 25842105 TI - Highly ordered Ni-Ti-O nanotubes for non-enzymatic glucose detection. AB - Anodization is used to fabricate Ni-Ti-O nanotube (NT) electrodes for non enzymatic glucose detection. The morphology, microstructure and composition of the materials are characterized by field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM) and X-ray photoelectron spectroscopy (XPS). Our results show amorphous and highly ordered NTs with diameter of 50nm, length of 800nm, and Ni/Ti ratio (at %) of 0.35 can be fabricated in ethylene glycol electrolyte supplemented with 0.2 wt.% NH4F and 0.5 vol.% H2O at 30 degrees C and 25V for 1h. Electrochemical experiments indicate that at an applied potential of 0.60V vs. Ag/AgCl, the electrode exhibits a linear response window for glucose concentrations from 0.002mM to 0.2mM with a response time of 10s, detection limit of 0.13MUM (S/N=3), and sensitivity of 83MUAmM(-1)cm(-2). The excellent performance of the electrode is attributed to its large specific area and fast electron transfer between the NT walls. The good electrochemical performance of the Ni-Ti-O NTs as well as their simple and low cost preparation method make the strategy promising in non-enzymatic glucose detection. PMID- 25842106 TI - Enhanced biocompatibility and wound healing properties of biodegradable polymer modified allyl 2-cyanoacrylate tissue adhesive. AB - As poly L-lactic acid (PLLA) is a polymer with good biocompatibility and biodegradability, we created a new tissue adhesive (TA), pre-polymerized allyl 2 cyanoacrylate (PACA) mixed with PLLA in an effort to improve biocompatibility and mechanical properties in healing dermal wound tissue. We determined optimal mixing ratios of PACA and PLLA based on their bond strengths and chemical structures analyzed by the thermal gravimetric analysis (TGA) and Fourier transform infrared (FT-IR) spectroscopy. In vitro biocompatibility of the PACA/PLLA was evaluated using direct- and indirect-contact methods according to the ISO-10993 cytotoxicity test for medical devices. The PACA/PLLA have similar or even better biocompatibility than those of commercially available cyanoacrylate (CA)-based TAs such as Dermabond(r) and Histoacryl(r). The PACA/PLLA were not different from those exposed to Dermabond(r) and Histoacryl(r) in Raman spectra when biochemical changes of protein and DNA/RNA underlying during cell death were compared utilizing Raman spectroscopy. Histological analysis revealed that incised dermal tissues of rats treated with PACA/PLLA showed less inflammatory signs and enhanced collagen formation compared to those treated with Dermabond(r) or Histoacryl(r). Of note, tissues treated with PACA/PLLA were stronger in the tensile strength compared to those treated with the commercially available TAs. Therefore, taking all the results into consideration, the PACA/PLLA we created might be a clinically useful TA for treating dermal wounds. PMID- 25842107 TI - Cysteine modified polyaniline films improve biocompatibility for two cell lines. AB - This work focuses on one of the most exciting application areas of conjugated conducting polymers, which is cell culture and tissue engineering. To improve the biocompatibility of conducting polymers we present an easy method that involves the modification of the polymer backbone using l-cysteine. In this publication, we show the synthesis of polyaniline (PANI) films supported onto Polyethylene terephthalate (PET) films, and modified using cysteine (PANI-Cys) in order to generate a biocompatible substrate for cell culture. The PANI-Cys films are characterized by Fourier Transform infrared and UV-visible spectroscopy. The changes in the hydrophilicity of the polymer films after and before the modification were tested using contact angle measurements. After modification the contact angle changes from 86 degrees +/-1 to 90 degrees +/-1, suggesting a more hydrophylic surface. The adhesion properties of LM2 and HaCaT cell lines on the surface of PANI-Cys films in comparison with tissue culture plastic (TCP) are studied. The PANI-Cys film shows better biocompatibility than PANI film for both cell lines. The cell morphologies on the TCP and PANI-Cys film were examined by florescence and Atomic Force Microscopy (AFM). Microscopic observations show normal cellular behavior when PANI-Cys is used as a substrate of both cell lines (HaCaT and LM2) as when they are cultured on TCP. The ability of these PANI-Cys films to support cell attachment and growth indicates their potential use as biocompatible surfaces and in tissue engineering. PMID- 25842108 TI - Crystalline hydroxyapatite coatings synthesized under hydrothermal conditions on modified titanium substrates. AB - Hydroxyapatite coatings were successfully produced on modified titanium substrates via hydrothermal synthesis in a Ca(EDTA)(2-) and (NH4)2HPO4 solution. The morphology of modified titanium substrates as well as hydroxyapatite coatings was studied using scanning electron microcopy and phase identification by X-ray diffraction, and Raman and FTIR spectroscopy. The results show that the nucleation and growth of hydroxyapatite needle-like crystals with hexagonal symmetry occurred only on titanium substrates both chemically and thermally treated. No hydroxyapatite phase was detected on only acid etched Ti metal. This finding demonstrates that only a particular titanium surface treatment can effectively induce the apatite nucleation under hydrothermal conditions. PMID- 25842109 TI - Molecular response of liver sinusoidal endothelial cells on hydrogels. AB - There is a high demand for the isolation of primary endothelial cells for biomaterial endotheliazation studies, tissue engineering, and artificial organ development. Further, biomarkers for monitoring the response of endothelial cells in biomaterials science are required. We systematically compared two strategies for isolating liver sinusoidal endothelial cells (LSEC) from mouse liver. We demonstrate that fluorescence-activated cell sorting results in a considerably higher purity (~97%) compared to magnetic-assisted cell sorting (~80%), but is associated with a lower yield and recovery rate. Cell repellent polyethylene glycol (PEG) substrates affected the morphology of primary LSEC in culture and significantly downregulated the intracellular adhesion molecule (ICAM) and upregulated the vascular cell adhesion molecule (VCAM). This molecular response could partially be reverted by further modification with arginylglycylaspartic acid (RGD). Thus, usage of PEGylated materials may reduce, while applying RGD may support endotheliazation of materials, and we could relate LSEC attachment to their expression of ICAM and VCAM mRNA, suggesting their usage as biomarkers for endothelialization. PMID- 25842110 TI - Crosslinked soy protein films and their application as ophthalmic drug delivery system. AB - In this research, the potential of soy protein (SPI) based-films as drug delivery devices for ocular therapy was developed. Hence, crosslinked films with a natural and non-cytotoxic crosslinking agent, genipin (Gen), coated with poly(lactic acid) (PLA), were prepared. Filmogenic solutions were loaded with timolol maleate (TM) as a model drug, to be used as drug delivery devices, a novel application for this material. The mechanical properties of the films were studied, observing that with the presence of PLA coating, more rigid materials with improved properties were obtained. Furthermore, the release behavior of TM was evaluated in aqueous medium, it being influenced by the degree of film crosslinking. Furthermore, it was determined that PLA coating decreased TM release rate compared to that of uncoated films. Similarly, this behavior was observed via indirect estimation of the release by assessing the hypotensive effectiveness of the films by in-vivo assays. Through intraocular pressure (IOP) determination tests in rabbits, it was demonstrated that, through the use of high crosslinked and coated films, a significant decrease in IOP could be achieved for prolonged time periods. These results suggest that the use of soy protein-based films as drug delivery systems is highly suitable. PMID- 25842111 TI - Biological properties of nanostructured Ti incorporated with Ca, P and Ag by electrochemical method. AB - TiO2 nanotube arrays were synthesized on Ti surface by anodic oxidation. The elements of Ca and P were simultaneously incorporated during nanotubes growth in SBF electrolyte, and then Ag was introduced to nanotube arrays by cathodic deposition, which endowed the good osseointegration and antibacterial property of Ti. The bioactivity of the Ti surface was evaluated by simulated body fluid soaking test. The biocompatibility was investigated by in vitro cell culture test. And the antibacterial effect against Staphylococcus aureus was examined by the bacterial counting method. The results showed that the incorporation of Ca, P and Ag elements had no significant influence on the formation of nanotube arrays on Ti surface during electrochemical treatment. Compared to the polished or nanotubular Ti surface, TiO2 nanotube arrays incorporated with Ca, P and Ag increased the formation of bone-like apatite in simulated body fluid, enhanced cell adhesion and proliferation, and inhibited the bacterial growth. Based on these results, it can be concluded that the nanostructured Ti incorporated with Ca, P and Ag by electrochemical method has promising applications as implant material. PMID- 25842112 TI - Analytical modeling of the thermomechanical behavior of ASTM F-1586 high nitrogen austenitic stainless steel used as a biomaterial under multipass deformation. AB - Precipitation-recrystallization interactions in ASTM F-1586 austenitic stainless steel were studied by means of hot torsion tests with multipass deformation under continuous cooling, simulating an industrial laminating process. Samples were deformed at 0.2 and 0.3 at a strain rate of 1.0s(-1), in a temperature range of 900 to 1200 degrees C and interpass times varying from 5 to 80s. The tests indicate that the stress level depends on deformation temperature and the slope of the equivalent mean stress (EMS) vs. 1/T presents two distinct behaviors, with a transition at around 1100 degrees C, the non-recrystallization temperature (Tnr). Below the Tnr, strain-induced precipitation of Z-phase (NbCrN) occurs in short interpass times (tpass<30s), inhibiting recrystallization and promoting stepwise stress build-up with strong recovery, which is responsible for increasing the Tnr. At interpass times longer than 30s, the coalescence and dissolution of precipitates promote a decrease in the Tnr and favor the formation of recrystallized grains. Based on this evidence, the physical simulation of controlled processing allows for a domain refined grain with better mechanical properties. PMID- 25842113 TI - Influence of the intramedullary nail preparation method on nail's mechanical properties and degradation rate. AB - When it comes to the treatment of long bone fractures, scientists are still investigating new materials for intramedullary nails and different manufacturing methods. Some of the most promising materials used in the field are resorbable polymers and their composites, especially since there is a wide range of potential manufacturing and processing methods. The aim of this work was to select the best manufacturing method and technological parameters to obtain multiphase, and multifunctional, biodegradable intramedullary nails. All composites were based on a poly(l-lactide) matrix. Either magnesium alloy wires or carbon and alginate fibres were introduced in order to reinforce the nails. The polylactide matrix was also modified with tricalcium phosphate and gentamicin sulfate. The composite nails were manufactured using three different methods: forming from solution, injection moulding and hot pressing. The effect of each method of manufacturing on mechanical properties and degradation rate of the nails was evaluated. The study showed that injection moulding provides higher uniformity and homogeneity of the particle-modified polylactide matrix, whereas hot pressing favours applying higher volume fractions of fibres and their better impregnation with the polymer matrix. Thus, it was concluded that the fabrication method should be individually selected dependently on the nail's desired phase composition. PMID- 25842114 TI - Pilot-scale synthesis and rheological assessment of poly(methyl methacrylate) polymers: perspectives for medical application. AB - This work presents the rheological assessment of poly(methyl methacrylate) (PMMA) polymers synthesized in a dedicated pilot-scale plant. This material is to be used for the construction of scaffolds via Rapid Prototyping (RP). The polymers were prepared to match the physical and biological properties required for medical applications. Differential Scanning Calorimetry (DSC) and Size Exclusion Chromatography (SEC) measurements verified that the synthesized polymers were atactic, amorphous and linear in chains. Rheological properties such as viscosity, storage and loss modulus, beyond the loss factor, and creep and recovery were measured in a plate-plate sensor within the viscoelastic linear region. The results showed the relevant influence of the molecular weight on the viscosity and elasticity of the material, and how, as the molecular weight increases, the viscoelastic properties are getting closer to those of human bone. This article demonstrates that by using the implemented methodology it is possible to synthesize a polymer, with properties comparable to commercially available PMMA. PMID- 25842115 TI - Surface modification of biomaterials based on high-molecular polylactic acid and their effect on inflammatory reactions of primary human monocyte-derived macrophages: perspective for personalized therapy. AB - Polylactic acid (PLA) based implants can cause inflammatory complications. Macrophages are key innate immune cells that control inflammation. To provide higher biocompatibility of PLA-based implants with local innate immune cells their surface properties have to be improved. In our study surface modification technique for high-molecular PLA (MW=1,646,600g/mol) based biomaterials was originally developed and successfully applied. Optimal modification conditions were determined. Treatment of PLA films with toluene/ethanol=3/7 mixture for 10min with subsequent exposure in 0.001M brilliant green dye (BGD) solution allows to entrap approximately 10(-9)mol/cm(2) model biomolecules. The modified PLA film surface was characterized by optical microscopy, SERS, FT-IR, UV and TG/DTA/DSC analysis. Tensile strain of modified films was determined as well. The effect of PLA films modified with BGD on the inflammatory reactions of primary human monocyte-derived macrophages was investigated. We developed in vitro test system by differentiating primary monocyte-derived macrophages on a coating material. Type 1 and type 2 inflammatory cytokines (TNFalpha, CCL18) secretion and histological biomarkers (CD206, stabilin-1) expression were analyzed by ELISA and confocal microscopy respectively. BGD-modified materials have improved thermal stability and good mechanical properties. However, BGD modifications induced additional donor-specific inflammatory reactions and suppressed tolerogenic phenotype of macrophages. Therefore, our test-system successfully demonstrated specific immunomodulatory effects of original and modified PLA-based biomaterials, and can be further applied for the examination of improved coatings for implants and identification of patient-specific reactions to implants. PMID- 25842116 TI - Quercetin-imprinted polymer for anthocyanin extraction from mangosteen pericarp. AB - Molecular imprinting is a facilitative technology for the production of artificial receptors possessing great endurance with high specificity toward target molecules of interest. The polymers are commonly applied for separation or analysis of substances of interest. In this study, we prepared molecularly imprinted polymers for the purpose of binding specifically to quercetin and related compounds. Quercetin was used as the template molecule, 4-vinylpyridine (4-VP) as the functional monomer, ethylene glycol dimethacrylate (EDMA) as the cross-linking monomer, azobisisobutyronitrile (AIBN) as the polymerization initiator and ethanol as the porogenic solvent. Such 4-VP-based imprinted polymer was found to bind the template molecule greater than that of the control polymer with an approximate 2 folds higher binding using 20mg of polymer in the optimal solvent, ethanol:water (4:1v/v). Quercetin-imprinted polymer (QIP) was found to bind well against its template; approximately 1mg/g polymer. In addition, QIP was applied to bind anthocyanin from the crude extract of mangosteen pericarp. The binding capacity of quercetin-MIP toward anthocyanin was approximately 0.875mg per gram of polymer. This result indicated that quercetin-MIP showed its specific binding to quercetin and related compound particularly anthocyanin. In conclusion, we have demonstrated the successful preparation and utilization of molecularly imprinted polymer for the specific recognition of quercetin as well as structurally related anthocyanins from the mangosteen pericarp with enhanced and robust performance. PMID- 25842117 TI - Effects of anodizing parameters and heat treatment on nanotopographical features, bioactivity, and cell culture response of additively manufactured porous titanium. AB - Anodizing could be used for bio-functionalization of the surfaces of titanium alloys. In this study, we use anodizing for creating nanotubes on the surface of porous titanium alloy bone substitutes manufactured using selective laser melting. Different sets of anodizing parameters (voltage: 10 or 20V anodizing time: 30min to 3h) are used for anodizing porous titanium structures that were later heat treated at 500 degrees C. The nanotopographical features are examined using electron microscopy while the bioactivity of anodized surfaces is measured using immersion tests in the simulated body fluid (SBF). Moreover, the effects of anodizing and heat treatment on the performance of one representative anodized porous titanium structures are evaluated using in vitro cell culture assays using human periosteum-derived cells (hPDCs). It has been shown that while anodizing with different anodizing parameters results in very different nanotopographical features, i.e. nanotubes in the range of 20 to 55nm, anodized surfaces have limited apatite-forming ability regardless of the applied anodizing parameters. The results of in vitro cell culture show that both anodizing, and thus generation of regular nanotopographical feature, and heat treatment improve the cell culture response of porous titanium. In particular, cell proliferation measured using metabolic activity and DNA content was improved for anodized and heat treated as well as for anodized but not heat-treated specimens. Heat treatment additionally improved the cell attachment of porous titanium surfaces and upregulated expression of osteogenic markers. Anodized but not heat-treated specimens showed some limited signs of upregulated expression of osteogenic markers. In conclusion, while varying the anodizing parameters creates different nanotube structure, it does not improve apatite-forming ability of porous titanium. However, both anodizing and heat treatment at 500 degrees C improve the cell culture response of porous titanium. PMID- 25842118 TI - Injectable hydrogels derived from phosphorylated alginic acid calcium complexes. AB - Phosphorylation of sodium alginate salt (NaAlg) was carried out using H3PO4/P2O5/Et3PO4 followed by acid-base reaction with Ca(OAc)2 to give phosphorylated alginic acid calcium complexes (CaPAlg), as a water dispersible alginic acid derivative. The modified alginate derivatives including phosphorylated alginic acid (PAlg) and CaPAlg were characterized by nuclear magnetic resonance spectroscopy for (1)H, and (31)P nuclei, high resolution inductively coupled plasma optical emission spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. CaPAlg hydrogels were prepared simply by mixing CaPAlg solution (2w/v%) with NaAlg solution (2w/v%) in various ratios (2:8, 4:6, 6:4, 8:2) of volume. No additional calcium salts such as CaSO4 or CaCl2 were added externally. The gelation was completed within about 3-40min indicating a high potential of hydrogel delivery by injection in vivo. Their mechanical properties were tested to be <=6.7kPa for compressive strength at break and about 8.4kPa/mm for elastic modulus. SEM analysis of the CaPAlg hydrogels showed highly porous morphology with interconnected pores of width in the range of 100-800MUm. Cell culture results showed that the injectable hydrogels exhibited comparable properties to the pure alginate hydrogel in terms of cytotoxicity and 3D encapsulation of cells for a short time period. The developed injectable hydrogels showed suitable physicochemical and mechanical properties for injection in vivo, and could therefore be beneficial for the field of soft tissue engineering. PMID- 25842119 TI - Microstructure and mechanical properties of Ti-Zr-Cr biomedical alloys. AB - The Ti-15Zr-xCr (0<=x<=10, wt.%) alloys were investigated to develop new biomedical materials. It was found that the phase constitutions and mechanical properties strongly depended on the Cr content. The Ti-15Zr alloy was comprised of alpha' phase and a small fraction of beta phase was detected with adding 1wt.% Cr. With addition of 5wt.% or more, the beta phase was completely retained. In addition, the omega phase was detected in the Ti-15Zr-5Cr alloy and Ti-15Zr-7Cr alloy which exhibited the highest compressive Young's modulus and the lowest ductility. On the other hand, all the Ti-15Zr-xCr alloys without omega phase exhibited high microhardness, high yield strength and superior ductility. Furthermore, the elastic energy of Ti-15Zr-10Cr alloy (5.89MJ/m(3)) with only beta phase and that of Ti-15Zr-3Cr alloy (4.04MJ/m(3)) with alpha' phase and small fraction of beta phase was higher than the elastic energy of c.p. Ti (1.25MJ/m(3)). This study demonstrated that Ti-15Zr-3Cr alloy and Ti-15Zr-10Cr alloy with superior mechanical properties are potential materials for biomedical applications. PMID- 25842120 TI - Impact and fracture analysis of fish scales from Arapaima gigas. AB - Fish scales from the Amazonian fish Arapaima gigas have been characterised to study their impact and fracture behaviour at three different environmental conditions. Scales were cut in two different directions to analyse the influence of the orientation of collagen layers. The energy absorbed during impact tests was measured for each sample and SEM images were taken after each test in order to analyse the failure mechanisms. The results showed that scales tested at cryogenic temperatures display fragile behaviour, while scales tested at room temperature did not fracture. Different failure mechanisms have been identified, analysed and compared with the failure modes that occur in bone. The impact energy obtained for fish scales was two to three times higher than the values reported for bone in the literature. PMID- 25842121 TI - TiO2 nanotube composite layers as delivery system for ZnO and Ag nanoparticles - an unexpected overdose effect decreasing their antibacterial efficacy. AB - Enhancement of biocompatibility and antibacterial properties of implant materials is potentially beneficial for their practical value. Therefore, the use of metallic and metallic oxide nanoparticles as antimicrobial coatings components which induce minimized antibacterial resistance receives currently particular attention. In this work, TiO2 nanotubes layers loaded with ZnO and Ag nanoparticles were designed for biomedical coatings and delivery systems and evaluated for antimicrobial activity. TiO2 nanotubes themselves exhibited considerable and diameter-dependent antibacterial activity against planktonic Staphylococcus epidermidis cells but favored bacterial adhesion. Loading of nanotubes with moderate amount of ZnO nanoparticles significantly diminished S. epidermidis cell adhesion and viability just after 1.5h contact with modified surfaces. However, an increase of loaded ZnO amount unexpectedly altered the structure of nanoparticle-nanolayer, caused partial closure of nanotube interior and significantly reduced ZnO solubility and antibacterial efficacy. Co deposition of Ag nanoparticles enhanced the antibacterial properties of synthesized coatings. However, the increase of ZnO quantity on Ag nanoparticles co-deposited surfaces favored the adhesion of bacterial cells. Thus, ZnO/Ag/TiO2 nanotube composite layers may be promising delivery systems for combating post operative infections in hard tissue replacement procedures. However, the amount of loaded antibacterial agents must be carefully balanced to avoid the overdose and reduced efficacy. PMID- 25842122 TI - Preparation of cellulose II and IIII films by allomorphic conversion of bacterial cellulose I pellicles. AB - The structural changes resulting from the conversion of native cellulose I (Cel I) into allomorphs II (Cel II) and IIII (Cel IIII) have usually been studied using powder samples from plant or algal cellulose. In this work, the conversion of Cel I into Cel II and Cel IIII was performed on bacterial cellulose films without any mechanical disruption. The surface texture of the films was observed by atomic force microscopy (AFM) and the morphology of the constituting cellulose ribbons, by transmission electron microscopy (TEM). The structural changes were characterized using solid-state NMR spectroscopy as well as X-ray and electron diffraction. The allomorphic change into Cel II and Cel IIII resulted in films with different crystallinity, roughness and hydrophobic/hydrophilicity surface and the films remained intact during all process of allomorphic conversion. PMID- 25842123 TI - PEGylation of novel hydroxyapatite/PEG/Ag nanocomposite particles to improve its antibacterial efficacy. AB - Hydroxyapatite (HAp) nanocomposite particles were prepared simply in the presence of polyethylene glycol (PEG) and fabricated with silver via a sol-gel route and the physico-chemical and biological properties of these materials were investigated. The objective of this study is to inspect the crystallinity and antibacterial activity of these composite materials. PEG has been used to greatly promote biocompatibility and biodegradability of HAp. Silver nanoparticles were used for improving its bactericidal efficacy while applying composites. Nano sized HAp composite particles with PEG and nano-silver was incorporated to increase the crystalline nature of the nanocomposite. The structure of nanocomposite particles was studied by XRD, FTIR, HR-SEM, EDS and TEM analyses. Silver nanoparticles loaded on the synthesized HAp-PEG showed a synergistic antibacterial effect against Gram-negative bacterium Escherichia coli (E. coli). The controlled release of Ag(+) ion from HAp-PEG-Ag nanocomposite has given good antibacterial efficacy evidenced by epi-fluorescence microscopy images during different hours. PMID- 25842124 TI - Carbon nanotube array inducing osteogenic differentiation of human mesenchymal stem cells. AB - Carbon nanotubes (CNTs) are a kind of nanomaterials which have been shown a promising application for biomedicine. There are a lot of studies to use CNTs to induce the differentiation of mesenchymal stem cells (MSCs). However, the cellular behavior of MSCs on the top layer of CNT array was still not well understood. In this study, we evaluated the morphology, the gene expressions of the osteogenic differentiation related markers, and the gene expressions of collagen type II (Col II, a marker of chondrogenesis), PPARgamma (a marker of adipogenesis) and scleraxis (SCX, a marker of tenogenesis) in human mesenchymal stem cells (hMSCs) cultured on multi-walled carbon nanotube (MWCNT) array. The effect of MWCNT array on the mineralization of hMSCs which were cultured in osteogenic differentiation medium (ODM) was further assayed. Our results showed that the hMSCs cultured on MWCNT array spread well, formed numerous spiral shaped cell colons and showed perinuclear morphology. Compared to hMSCs cultured on dish, the gene expression of osteocalcin (OCN) was increased while the gene expressions of collagen type II (Col II), PPARgamma and scleraxis (SCX) were decreased in hMSCs which were cultured on MWCNT array without any differentiation factors. Furthermore, compared with hMSCs on dish, the gene expressions of collagen type I (Col I), osteocalcin (OCN), osteopontin (OPN) and RUNX2, and the mineralization of hMSCs on MWCNT array were enhanced when they were cultured in osteogenic differentiation medium (ODM). Our results indicated that MWCNT array was able to promote the osteogenesis of hMSCs. PMID- 25842125 TI - Synthesis and properties of antifouling poly(CL-co-zDMAEMA) zwitterionic copolymer by one-step hybrid copolymerization. AB - A novel biocompatible and biodegradable copolymer was synthesized by one-step hybrid copolymerization of epsilon-caprolactone (CL) and 2-(N,N-dimethylamino) ethyl methacrylate (DMAEMA) employing (1-tert-butyl-4,4,4-tris(dimethylamino)-2,2 bis[tris(dimethylamino)phophoranylidenamino]-2Lambda5,Lambda5 catenadi(phosphazene) (t-BuP4) as a catalyst. The as-synthesized copolymer was betainizated resulting in a zwitterionic copolymer poly(CL-co-zDMAEMA) and the structure of the zwitterionic copolymer was confirmed by the FT-IR, NMR, and XPS measurements. The results of dynamic light scattering (DLS) show that this zwitterionic copolymer can self-assemble into stable micelles. The results of quartz crystal microbalance with dissipation (QCM-D) analysis and MTT measurement suggest that this zwitterionic copolymer possess better protein resistance and lower cell cytotoxicity in vitro in comparison with the cationic copolymer. The pyrene solubilization measurement of copolymers poly(CL-co-zDMAEMA) indicates an excellent pyrene solubilization capacity. These zwitterionic polymer micelles can release drugs in response to specific signals, such as temperature, pH, and enzymes and have a potential application in drug delivery and gene therapy due to their good antifouling, low cytotoxicity and high pyrene solubilization. PMID- 25842126 TI - Bioactive glass/hydroxyapatite composites: mechanical properties and biological evaluation. AB - Bioactive glass/hydroxyapatite composites for bone tissue repair and regeneration have been produced and discussed. The use of a recently developed glass, namely BG_Ca/Mix, with its low tendency to crystallize, allowed one to sinter the samples at a relatively low temperature thus avoiding several adverse effects usually reported in the literature, such as extensive crystallization of the glassy phase, hydroxyapatite (HA) decomposition and reaction between HA and glass. The mechanical properties of the composites with 80wt.% BG_Ca/Mix and 20wt.% HA are sensibly higher than those of Bioglass(r) 45S5 reference samples due to the presence of HA (mechanically stronger than the 45S5 glass) and to the thermal behaviour of the BG_Ca/Mix, which is able to favour the sintering process of the composites. Biocompatibility tests, performed with murine fibroblasts BALB/3T3 and osteocites MLO-Y4 throughout a multi-parametrical approach, allow one to look with optimism to the produced composites, since both the samples themselves and their extracts do not induce negative effects in cell viability and do not cause inhibition in cell growth. PMID- 25842127 TI - A modified milling system, using a bimodal distribution of highly resistant ceramics. Part 1. A natural hydroxyapatite study. AB - A careful combination of the main parameters controlling natural hydroxyapatite (NHA: Ca10(PO4)6(OH)2) production such as milling techniques, sintering temperature and holding time may lead to an interesting NHA based bio-ceramics without any foreign oxide additions. In this way, an original wet milling setup has been proposed to obtain sub-micron sized NHA powders. In order to avoid any possible NHA decomposition, a precise Ca/P ratio of NHA derived from animals was selected accordingly. Also, an alternative direct visual approach of the bone age classification was also proposed. A relative density of about 95% was obtained for powders sintered at 1300 degrees C for 2h. The best Vickers micro-hardness and 3 point bending strength values for these sintered samples, using this proposed milling system and without any additions, were 4.7+/-0.3GPa and 37MPa, respectively. Finally, a complete correlation between the powder microstructure and the final product properties has been established. PMID- 25842128 TI - Catalytic and biological activities of green silver nanoparticles synthesized from Plumeria alba (frangipani) flower extract. AB - Herein, we report the green synthesis of silver nanoparticles using Plumeria alba (frangipani) flower extract (FFE) and their biological applications. The formation of frangipani silver nanoparticles (FSNPs) was confirmed by UV-visible spectroscopy and characterized by DLS particle size analyzer, SEM/EDAX, FTIR, TGA/DSC and XRD. The synthesized spherical FSNPs were found to be 36.19nm in size as determined by DLS particle size analyzer. EDAX data and XRD pattern of FSNPs confirmed the presence and face-centered cubic (fcc) phase structure of silver. The bioactive groups C-C and C-N present in FFE were involved in the formation of FSNPs as identified by FTIR analysis. FSNPs exhibited powerful catalytic activity by reducing 4-nitrophenol to 4-aminophenol within 8min and the other organic dyes namely methylene blue and ethidium bromide were moderately degraded. Biological activities of FSNPs are evaluated by means of antioxidant, antibacterial and cytotoxic effect. Antioxidant potential of FSNPs was assessed by various in vitro assays in which they exhibited moderate antioxidant activity. The antibacterial effect of FSNPs was tested in two different pathogenic bacterial strains and their bacteriostatic effect was confirmed by growth kinetic study in Escherichia coli. The cytotoxic effect of FSNPs in COLO 205 was analyzed by MTT assay and the IC50 concentration was found at 5.5 and 4MUg/ml respectively after 24 and 48h of incubation. Cytotoxic effect of FSNPs in COLO 205 cells was associated with the loss of membrane integrity and chromatin condensation which might have played a crucial role in the induction of apoptosis as evidenced in AO/EB staining. PMID- 25842129 TI - Improved stress corrosion cracking resistance of a novel biodegradable EW62 magnesium alloy by rapid solidification, in simulated electrolytes. AB - The high corrosion rate of magnesium (Mg) and Mg-alloys precludes their widespread acceptance as implantable biomaterials. Here, we investigated the potential for rapid solidification (RS) to increase the stress corrosion cracking (SCC) resistance of a novel Mg alloy, Mg-6%Nd-2%Y-0.5%Zr (EW62), in comparison to its conventionally cast (CC) counterpart. RS ribbons were extrusion consolidated in order to generate bioimplant-relevant geometries for testing and practical use. Microstructural characteristics were examined by SEM. Corrosion rates were calculated based upon hydrogen evolution during immersion testing. The surface layer of the tested alloys was analyzed by X-ray photoelectron spectroscopy (XPS). Stress corrosion resistance was assessed by slow strain rate testing and fractography. The results indicate that the corrosion resistance of the RS alloy is significantly improved relative to the CC alloy due to a supersaturated Nd enrichment that increases the Nd2O3 content in the external oxide layer, as well as a more homogeneous structure and reduced grain size. These improvements contributed to the reduced formation of hydrogen gas and hydrogen embrittlement, which reduced the SCC sensitivity relative to the CC alloy. Therefore, EW62 in the form of a rapidly solidified extruded structure may serve as a biodegradable implant for biomedical applications. PMID- 25842130 TI - Surface modification of silk fibroin fibers with poly(methyl methacrylate) and poly(tributylsilyl methacrylate) via RAFT polymerization for marine antifouling applications. AB - In this study, silk fibroin surface containing hydroxyl and aminogroups was firstly modified using a polymerizable coupling agent 3-(trimethoxysilyl) propyl methacrylate (MPS), in order to induce vinyl groups onto the fiber surface. The reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization of methyl methacrylate (MMA) and tributylsilyl methacrylate (TBSiMA) through the immobilized vinyl bond on the silk fibroin surface in the presence of 2-cyanoprop 2-yl dithiobenzoate (CPDB) as chain-transfer agent and 2,2' azobis(isobutyronitrile) (AIBN) as initiator was conducted in toluene solution at 70 degrees C for 24h. The structure and properties of the modified fiber were characterized by Fourier Transform Infrared Spectroscopy, (13)C, (29)Si Nuclear Magnetic Resonance (NMR) spectroscopy, thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS), confirming the presence of the coupling molecule and the methacrylate groups onto the silk fibroin fiber surface. Molecular weight distributions were assessed by triple detection size exclusion chromatography (TD-SEC) in order to verify the livingness of the polymerization. PMID- 25842131 TI - In situ study of self-assembled nanocomposite films by spectral SPR sensor. AB - Spectral surface plasmon resonance (SPR) sensor with a time-resolved charge coupled device (CCD) detector is a powerful analytical tool for label-free detection of biomolecular interaction at the liquid/solid interface and for in situ study of molecular adsorption behavior. In this work, the layer-by-layer self-assembly processes for three nanocomposite films were monitored in real time using a broadband spectral SPR sensor with a large dynamic range. Kinetics studies suggest that cytochrome c (Cyt c) and deoxy ribonucleic acid (DNA) adsorptions obey the Langmuir-isotherm theory, while gold nanoparticle (GNP) adsorption follows the Diffusion-controlled model. Using poly(sodium 4 styrenesulfonate) (PSS) and poly(dimethyldiallylammonium chloride) (PDDA) as the positively charged agents, three kinds of multilayer films such as the PSS/Cyt c, GNP/Cyt c and PDDA/DNA binary nanocomposites were fabricated on the SPR chips by the electrostatic attraction based on self-assemble. The SPR response in terms of DeltalambdaR was measured to linear increase with increasing the number of layers for a six-bilayer PSS/Cyt c nanocomposite film, indicating that every PSS/Cyt c layer has equal mass coverage. In contrast, the nonlinear dependences of DeltalambdaR on the number of bilayers were observed for the GNP/Cyt c and PDDA/DNA nanocomposite multilayer films. PMID- 25842132 TI - Gene expression of human osteoblasts cells on chemically treated surfaces of Ti 6Al-4V-ELI. AB - Surface modifications of titanium alloys are useful methods to enhance the biological stability of intraosseous implants and to promote a well succeeded osseointegration in the early stages of implantation. This work aims to investigate the influence of chemically modified surfaces of Ti-6Al-4V-ELI (extra low interstitial) on the gene expression of human osteoblastic (HOb) cells. The surface treatments by acid etching or acid etching plus alkaline treatment were carried out to modify the topography, effective area, contact angle and chemical composition of the samples. The surface morphology was investigated using: scanning electron microscopy (SEM) and confocal laser-scanning microscope (CLSM). Roughness measurements and effective surface area were obtained using the CLSM. Surface composition was analysed by energy dispersive X-ray spectroscopy (EDX) and by X-Ray Diffraction (XRD). The expression levels of some bone related genes (ALPL, COL1A1, COL3A1, SPP1, RUNX2, and SPARC) were analysed using real-time Reverse Transcription Polymerase Chain Reaction (real-time RT-PCR). The results showed that all the chemical modifications studied in this work influenced the surface morphology, wettability, roughness, effective area and gene expression of human osteoblasts. Acid phosphoric combined to alkaline treatment presented a more accelerated gene expression after 7days while the only phosphoric etching or chloride etching combined to alkaline treatment presented more effective responses after 15days. PMID- 25842133 TI - Tautomerizable beta-ketonitrile copolymers for bone tissue engineering: Studies of biocompatibility and cytotoxicity. AB - beta-Ketonitrile tautomeric copolymers have demonstrated tunable hydrophilicity/hydrophobicity properties according to surrounding environment, and mechanical properties similar to those of human bone tissue. Both characteristic properties make them promising candidates as biomaterials for bone tissue engineering. Based on this knowledge we have designed two scaffolds based on beta-ketonitrile tautomeric copolymers which differ in chemical composition and surface morphology. Two of them were nanostructured, using an anodized aluminum oxide (AAO) template, and the other two obtained by solvent casting methodology. They were used to evaluate the effect of the composition and their structural modifications on the biocompatibility, cytotoxicity and degradation properties. Our results showed that the nanostructured scaffolds exhibited higher degradation rate by macrophages than casted scaffolds (6 and 2.5% of degradation for nanostructured and casted scaffolds, respectively), a degradation rate compatible with bone regeneration times. We also demonstrated that the beta ketonitrile tautomeric based scaffolds supported osteoblastic cell proliferation and differentiation without cytotoxic effects, suggesting that these biomaterials could be useful in the bone tissue engineering field. PMID- 25842134 TI - Engineering of a polymer layered bio-hybrid heart valve scaffold. AB - Current treatment strategy for end stage valve disease involves either valvular repair or replacement with homograft/mechanical/bioprosthetic valves. In cases of recurrent stenosis/ regurgitation, valve replacement is preferred choice of treatment over valvular repair. Currently available mechanical valves primarily provide durability whereas bioprosthetic valves have superior tissue compatibility but both lack remodelling and regenerative properties making their utility limited in paediatric patients. With advances in tissue engineering, attempts have been made to fabricate valves with regenerative potential using various polymers, decellularized tissues and hybrid scaffolds. To engineer an ideal heart valve, decellularized bovine pericardium extracellular matrix (DBPECM) is an attractive biocompatible scaffold but has weak mechanical properties and rapid degradation. However, DBPECM can be modified with synthetic polymers to enhance its mechanical properties. In this study, we developed a Bio Hybrid scaffold with non-cross linked DBPECM in its native structure coated with a layer of Polycaprolactone-Chitosan (PCL-CH) nanofibers that displayed superior mechanical properties. Surface and functional studies demonstrated integration of PCL-CH to the DBPECM with enhanced bio and hemocompatibility. This engineered Bio Hybrid scaffold exhibited most of the physical, biochemical and functional properties of the native valve that makes it an ideal scaffold for fabrication of cardiac valve with regenerative potential. PMID- 25842135 TI - Nacre-like calcium carbonate controlled by ionic liquid/graphene oxide composite template. AB - Nacre-like calcium carbonate nanostructures have been mediated by an ionic liquid (IL)-graphene oxide (GO) composite template. The resultant crystals were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray powder diffractometry (XRD). The results showed that either 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM]BF4) or graphene oxide can act as a soft template for calcium carbonate formation with unusual morphologies. Based on the time-dependent morphology changes of calcium carbonate particles, it is concluded that nacre-like calcium carbonate nanostructures can be formed gradually utilizing [BMIM]BF4/GO composite template. During the process of calcium carbonate formation, [BMIM]BF4 acted not only as solvents but also as morphology templates for the fabrication of calcium carbonate materials with nacre-like morphology. Based on the observations, the possible mechanisms were also discussed. PMID- 25842136 TI - Synthesis and cytotoxicity of azo nano-materials as new biosensors for L-Arginine determination. AB - Inspired from biological counterparts, chemical modification of azo derivatives with function groups may provide a highly efficient method to detect amino acid. Herein, we have designed and prepared a series of azo nano-materials involving NO2, -COOH, -SO3H and naphthyl group, which showed high response for Arginine (Arg) among normal twenty kinds of (Alanine, Valine, Leucine, Isoleucine, Methionine, Aspartic acid, Glutamic acid, Arginine, Glycine, Serine, Threonine, Asparagine, Phenylalanine, Histidine, Tryptophan, Proline, Lysine, Glutamine, Tyrosine and Cysteine). Furthermore, theoretical investigation further illustrated the possible binding mode in the host-guest interaction and the roles of molecular frontier orbitals in molecular interplay. In addition, nano-material 3 exhibited high binding ability for Arg and low cytotoxicity to KYSE450 cells over a concentration range of 5-50MUmol.L(-1) which may be used a biosensor for the Arg detection in vivo. PMID- 25842137 TI - Silk fibroin/sodium alginate fibrous hydrogels regulated hydroxyapatite crystal growth. AB - Use of organic templates for controlling the growth of inorganic crystals is one of the research topics in biomimetic field. In particular, oriented growth of hydroxyapatite (HAp) in organic fibrous matrix is provided a new view angle to study biomineralization of bone and its potential biomedical applications. The crystallization of HAp in fibrous hydrogels could mimic such biomineralization. In this paper, we report HAp nanorod crystal synthesized successfully by a biomimetic method using calcium chloride and ammonium dihydrogen phosphate as reagents in the presence of silk fibroin/sodium alginate (SF/SA) fibrous hydrogels. The effects of influence factors such as mineral times, pH, and temperature on controlling HAp nanorod crystals are discussed. The elongated HAp nanorods with rectangular column are grown with the increase of mineral times in biomimetic process. By changing pH, HAp nanorod crystals are obtained at alkaline condition in fibrous hydrogels. Moreover, compared to other temperatures, rod shaped HAp crystals were formed at 20 degrees C. The results imply this to be an effective method for preparing HAp crystals with controllable morphology for bone repair application. PMID- 25842138 TI - Structure-property relationships of iron-hydroxyapatite ceramic matrix nanocomposite fabricated using mechanosynthesis method. AB - Hydroxyapatite (HAp) is an attractive bioceramics due to its similar composition to bone mineral and its ability to promote bone-implant interaction. However, its low strength has limited its application as load bearing implants. This paper presented a work focusing on the improvement of HAp mechanical property by synthesizing iron (Fe)-reinforced bovine HAp nanocomposite powders via mechanosynthesis method. The synthesis process was performed using high energy milling at varied milling time (3, 6, 9, and 12h). The samples were characterized by X-ray diffraction (XRD), Fourier transform infrared (FT-IR), and scanning electron microscopy (SEM). Its mechanical properties were investigated by micro Vicker's hardness and compression tests. Results showed that milling time directly influenced the characteristics of the nanocomposite powders. Amorphous BHAp was formed after 9 and 12h milling in the presence of HPO4(2-) ions. Continuous milling has improved the crystallinity of Fe without changing the HAp lattice structure. The nanocomposite powders were found in spherical shape, agglomerated and dense after longer milling time. The hardness and Young's modulus of the nanocomposites were also increased at 69% and 66%, respectively, as the milling time was prolonged from 3 to 12h. Therefore, the improvement of the mechanical properties of nanocomposite was attributed to high Fe crystallinity and homogenous, dense structure produced by mechanosynthesis. PMID- 25842139 TI - Heat treatment mechanism and biodegradable characteristics of ZAX1330 Mg alloy. AB - Heat treatments are key processes in the development of biodegradable magnesium implants. The aim of this study is to investigate the factors of microstructures and metallurgical segregation on the functionality of biodegradable magnesium alloy. The solid solution heat treatment and strain induced melting activation heat treatment were employed to alter the microstructures of ZAX1330 alloy in this study. Heat treatments caused a significant change on grain size and distribution of secondary phases. The fine-grained microstructure enhanced the mechanical strength, corrosion resistance and achieved the lowest degradation rate in simulated body fluid solution. In coarse-grained microstructure systems, grain growth followed liquid phase formation. The corrosion rate increased due to a larger cathodic region. The status of micro-alloyed calcium (in solid solution or segregated) influenced the microstructural evolution mechanisms, mechanical strength, and degradation properties. A cytotoxicity test and a live/dead assay showed that ZAX1330 had good cytocompatibility, which varied with heat treatment, and no cell toxicity. The results suggest that heat treatment should be controlled precisely in order to improve the cytocompatibility of magnesium alloys for application in orthopedic implants. PMID- 25842140 TI - Hydroxyapatite-based materials of marine origin: a bioactivity and sintering study. AB - Single phase hydroxyapatite (HAp) and biphasic material hydroxyapatite/beta tricalcium phosphate (HAp/beta-TCP) were obtained from a marine source (Atlantic cod fish bones). Here we report a study on the biological properties of these materials, including cytotoxicity, bioactivity and haemocompatibility. Results showed that the materials are not cytotoxic, neither in their powder nor in pellet form; indeed growth of Saos-2 cells was comparable to that of commercial. The haemolysis rate was lower than 2%; hence the materials can be classified as non-haemolytic. Moreover, when immersed in Simulated Body Fluid (SBF), crystal formation was observed on the surface of both materials. The sintering behaviour of the samples was also studied; both powders showed very high sinterability (density higher than 95% of the theoretical value). Overall, these results confirm the suitability of these materials for biomedical applications. PMID- 25842141 TI - Layer-by-layer assembly of peptide based bioorganic-inorganic hybrid scaffolds and their interactions with osteoblastic MC3T3-E1 cells. AB - In this work we have developed a new family of biocomposite scaffolds for bone tissue regeneration by utilizing self-assembled fluorenylmethyloxycarbonyl protected Valyl-cetylamide (FVC) nanoassemblies as templates. To tailor the assemblies for enhanced osteoblast attachment and proliferation, we incorporated (a) Type I collagen, (b) a hydroxyapatite binding peptide sequence (EDPHNEVDGDK) derived from dentin sialophosphoprotein and (c) the osteoinductive bone morphogenetic protein-4 (BMP-4) to the templates by layer-by-layer assembly. The assemblies were then incubated with hydroxyapatite nanocrystals blended with varying mass percentages of TiO2 nanoparticles and coated with alginate to form three dimensional scaffolds for potential applications in bone tissue regeneration. The morphology was examined by TEM and SEM and the binding interactions were probed by FITR spectroscopy. The scaffolds were found to be non cytotoxic, adhered to mouse preosteoblast MC3T3-E1 cells and promoted osteogenic differentiation as indicated by the results obtained by alkaline phosphatase assay. Furthermore, they were found to be biodegradable and possessed inherent antibacterial capability. Thus, we have developed a new family of tissue engineered biocomposite scaffolds with potential applications in bone regeneration. PMID- 25842142 TI - Graded porous polyurethane foam: a potential scaffold for oro-maxillary bone regeneration. AB - Bone tissue engineering applications demand for biomaterials offering a substrate for cell adhesion, migration, and proliferation, while inferring suitable mechanical properties to the construct. In the present study, polyurethane (PU) foams were synthesized to develop a graded porous material-characterized by a dense shell and a porous core-for the treatment of oro-maxillary bone defects. Foam was synthesized via a one-pot reaction starting from a polyisocyanate and a biocompatible polyester diol, using water as a foaming agent. Different foaming conditions were examined, with the aim of creating a dense/porous functional graded material that would perform at the same time as an osteoconductive scaffold for bone defect regeneration and as a membrane-barrier to gingival tissue ingrowth. The obtained PU was characterized in terms of morphological and mechanical properties. Biocompatibility assessment was performed in combination with bone-marrow-derived human mesenchymal stromal cells (hBMSCs). Our findings confirm that the material is potentially suitable for guided bone regeneration applications. PMID- 25842143 TI - The structure and properties of the carbon non-wovens modified with bioactive nanoceramics for medical applications. AB - The paper presents the results of the manufacture of carbon fibers (CF) from polyacrylonitrile fiber precursor containing bioactive ceramic nanoparticles. In order to modify the precursor fibers two types of bio-glasses and wollastonite in the form of nanoparticles were used. The processing variables of the thermal conversion of polyacrylonitrile (PAN) precursor fibers into carbon fibers were determined using the FTIR method. The carbonization process of oxidized PAN fibers was carried out up to 1000 degrees C. The carbon fibers were characterized by a low ordered crystalline structure. The bioactivity tests of carbon fibers modified with a ceramic nanocomponent carried out in the artificial serum (SBF) revealed the apatite precipitation on the fibers' surfaces. PMID- 25842144 TI - Electrospun polyacrylonitrile nanofibers loaded with silver nanoparticles by silver mirror reaction. AB - The silver mirror reaction (SMR) method was selected in this paper to modify electrospun polyacrylonitrile (PAN) nanofibers, and these nanofibers loaded with silver nanoparticles showed excellent antibacterial properties. PAN nanofibers were first pretreated in AgNO3 aqueous solution before the SMR process so that the silver nanoparticles were distributed evenly on the outer surface of the nanofibers. The final PAN nanofibers were characterized by scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), transmission electron microscopy (TEM), TEM-selected area electron diffraction (SAED), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). SEM, TEM micrographs and SAED patterns confirmed homogeneous dispersion of the silver nanoparticles which were composed of monocrystals with diameters 20-30nm. EDS and XRD results showed that these monocrystals tended to form face-centered cubic single silver. TGA test indicated that the nanoparticles loaded on the nanofibers reached above 50wt.%. This material was also evaluated by the viable cell-counting method. The results indicated that PAN nanofibers loaded with silver nanoparticles exhibited excellent antimicrobial activities against gram-negative Escherichia coli (E. coli), gram-positive Staphylococcus aureus (S. aureus) and the fungus Monilia albicans. Thus, this material had many potential applications in biomedical fields. PMID- 25842145 TI - Anti-biofilm formation of a novel stainless steel against Staphylococcus aureus. AB - Staphylococcus aureus (S. aureus) is a bacterium frequently found proliferating on metal surfaces such as stainless steels used in healthcare and food processing facilities. Past research has shown that a novel Cu-bearing 304 type stainless steel (304CuSS) exhibits excellent antibacterial ability (i.e. against S. aureus) in a short time period (24h.). This work was dedicated to investigate the 304CuSS's inhibition ability towards the S. aureus biofilm formation for an extended period of 7days after incubation. It was found that the antibacterial rate of the 304CuSS against sessile bacterial cells reached over 99.9% in comparison with the 304SS. The thickness and sizes of the biofilms on the 304SS surfaces increased markedly with period of contact, and thus expected higher risk of bio-contamination, indicated by the changes of surface free energy between biofilm and the steel surfaces. The results demonstrated that the 304CuSS exhibited strong inhibition on the growth and adherence of the biofilms. The surface free energy of the 304CuSS after contact with sessile bacterial cells was much lower than that of the 304SS towards the same culture times. The continuously dissolved Cu(2+) ions well demonstrated the dissolution ability of Cu-rich precipitates after exposure to S. aureus solution, from 3.1ppm (2days) to 4.5ppm (7days). For this to occur, a hypothesis mechanism might be established for 304CuSS in which the Cu(2+) ions were released from Cu-rich phases that bond with extracellular polymeric substances (EPS) of the microorganisms. And these inhibited the activities of cell protein/enzymes and effectively prevented planktonic bacterial cells attaching to the 304CuSS metal surface. PMID- 25842146 TI - Nanostructured delivery system for Suberoylanilide hydroxamic acid against lung cancer cells. AB - With the objective to provide a potential approach for the treatment of lung cancer, nanotechnology based Suberoylanilide hydroxamic acid (SAHA)-loaded Poly d, l-lactide-co glycolide (PLGA) nanoparticles have been formulated using the nanoprecipitation technique. The acquired nanoparticles were characterized by various throughput techniques and the analyses showed the presence of smooth and spherical shaped SAHA-loaded PLGA nanoparticles, with an encapsulation efficiency of 44.8% and a particle size of 208nm. The compatibility between polymer and drug in the formulation was tested using FT-IR, Micro-Raman spectrum and DSC thermogram analyses, revealing a major interaction between the drug and polymer. The in vitro drug release from the SAHA-loaded PLGA nanoparticles was found to be biphasic with an initial burst followed by a sustained release for up to 50h. In experiments using the lung cancer cell line A549, SAHA-loaded PLGA nanoparticles demonstrated a superior antineoplastic activity over free SAHA. In conclusion, SAHA-loaded PLGA nanoparticles may be a useful novel approach for the treatment of lung cancer. PMID- 25842147 TI - [Editorial]. PMID- 25842148 TI - [Ocular involvement with Candida albicans: report of 2 cases]. AB - INTRODUCTION: Ocular involvement by Candida albicans is rare and may present as endogenous endophthalmitis or choroiditis. It occurs in the context of C. albicans septicemia, in the context of intensive care unit hospitalization or intravenous drug use. We report two cases referred to our department with different characteristics, background, diagnostic modalities and different courses. OBSERVATIONS: A 37-year-old woman, with a history of intravenous drug use, presented with C. albicans endophthalmitis. Intravenous combination antifungal therapy was begun, but vitrectomy and intravitreal amphotericin B were performed due to worsening of the endophthalmitis. The second case was a 53-year old man who was hospitalized in the intensive care unit for C. albicans septicemia with a left macular chorioretinitis. Intravenous antifungal therapy was initiated and allowed regression of the ocular lesion. DISCUSSION: Our cases illustrate both types of ophthalmic involvement by candidiasis requiring different treatments with well-described recommendations: in the case of endophthalmitis, the use of vitrectomy and intravitreal amphotericin B injection in association with intravenous antifungal treatment, whereas parenteral antifungal treatment is often sufficient in the case of chorioretinitis. CONCLUSION: Early detection, initiation of treatment and ophthalmologic monitoring are difficult but necessary in these populations non-compliant with follow-up or in intensive care units. The management of ocular candidiasis requires good collaboration between the ophthalmology, infectious diseases and intensive care unit departments. PMID- 25842149 TI - [Quantification of ocular dominance for better management of eye disease]. AB - INTRODUCTION: The dominant eye is defined as the one we unconsciously choose when we have to perform monocular tasks. In the field of clinical neuro-ophthalmology, it is well-established that ocular dominance plays a key role in several eye diseases. Furthermore, the accurate quantification of ocular dominance is crucial with regard to certain surgical techniques. However, classical preoperative tests cannot determine the amount of ocular dominance. MATERIALS AND METHODS: In order to obtain further insight into the phenomenon of ocular dominance, we study its influence at behavioral and neurophysiological levels (experiments 1 and 2). Based on these new data, we suggest a method to improve quantification of ocular dominance (experiment 3). RESULTS: We demonstrate that ocular dominance has an influence on hand movements and on interhemispheric transfer time. Moreover, we show that an analysis of the dynamics of saccades allows us to sort out participants with strong or weak ocular dominance. CONCLUSION: In conclusion, this better understanding of the phenomenon of ocular dominance, coupled with the analysis of saccadic dynamics, might, in the short or medium term, lead to the establishment of a quick and straightforward battery of tests allowing determination of the amount of ocular dominance for each patient. PMID- 25842150 TI - Tumor necrosis factor-alpha concentration in the aqueous humor of healthy and diseased dogs: a preliminary pilot study. AB - OBJECTIVES: To determine reference values of tumor necrosis factor-alpha (TNF alpha) concentrations in the aqueous humor of control dogs. To show whether these values are significantly different from those obtained in dogs affected with intraocular pathology: acute anterior uveitis (AAU) or chronic primary angle closure glaucoma (PACG). METHODS: Forty-four dogs were included in the study and were divided into two groups: a control group and a group with intraocular disease. Twenty-seven dogs (9 males and 18 females) were examined and found to be normal after a complete ophthalmological examination (control group), 7 (6 females and 1 male) presented with PACG, and 10 (7 females and 3 males) presented with AAU secondary to corneal perforation. One aqueous humor sample (volume >= 0.2 mL) was collected from one eye of all dogs. The aqueous TNF-alpha concentration was determined with an Elisa kit. RESULTS: TNF-alpha levels were detectable in all dogs. TNF-alpha levels were significantly higher in the group with intraocular disease compared to the normal control group (P=0.001). In the group with intraocular disease, TNF-alpha levels were significantly higher in the aqueous humor of the AAU group compared with the PACG group (P=0.001). CONCLUSIONS: In the dog, it is possible to measure the concentration of TNF-alpha in the aqueous humor. The level of TNF-alpha was significantly higher in the case of AAU. TNF-alpha is an interesting biomarker for longitudinal follow-up studies of comparative ophthalmology. PMID- 25842151 TI - [Comparison of two different surgical treatments of presbyopia for hyperopic patients over 55 years old: Presbylasik (Supracor) and Prelex (presbyopic lens exchange)]. AB - INTRODUCTION: The management of presbyopic patients is a medical, surgical and economic issue. We wondered which procedure, whether a Presbylasik technique called Regular Supracor or the intraocular surgery of clear lens replacement by a trifocal diffractive lens (presbyopic lens exchange [Prelex]), provided the best results (in visual acuity and satisfaction) for our hyperopic and presbyopic patients between 55 and 70. The aim of this study was to compare the safety and efficacy of the two techniques (at one week and three months) and to assess patients' quality of life. METHODS: This study is a retrospective monocentric clinical trial conducted between June 2011 and March 2014, on 21 hyperopic presbyopic patients (mean age 60.9 years), in the "hopital d'instruction des armees-Percy" (Clamart); 13 patients underwent the corneal treatment of Presbylasik (with the Intralase FS60 femtosecond laser [AMO, USA] and the Technolas 217P excimer laser [Technolas Perfect Vision, GmbH] following the Zyoptix Tissue-Saving algorithm adjusted with a nomogram and the Regular Supracor mode), and 8 patients underwent clear lens extraction (Prelex), through bimanual phacoemulsification and implantation of diffractive trifocal intraocular lenses (Finevision Micro F, PhysIOL(*)). RESULTS: Mean uncorrected binocular distance and near vision visual acuity in the Supracor group were respectively 0.03 (-0.2 0.1) LogMar and 0.23 (0.06-0.36) one week postoperatively and 0.031 (-0.2-0.1) and 0,166 (0.06-0.36) three months postoperatively. In the Prelex group, the mean uncorrected one week binocular VA was 0.025 (0-0.1) for distance vision and 0.165 (0.06-0.18) for near distance and the three months visual acuity was 0 (-0.1-0.1) and 0.105 (0.06-0.18) for distance and near vision. All Prelex patients were spectacle-free at all distances, whereas 4 Supracor patients required spectacles for near vision postoperatively. Seven of 11 patients in the Supracor group and 100% of the Prelex patients were completely satisfied. Both groups experienced halos, but patients reported more halos in the Prelex group (75%). One eye required intraocular lens exchange and four eyes (16.7%) required a new corneal procedure in the Supracor group. CONCLUSION: Both surgeries are safe and effective modalities in the management of hyperopic and presbyopic patients. However, the Prelex procedure seems to be more appropriate for patients over 55 years of age. PMID- 25842152 TI - Genome sequencing and analysis of an Escherichia coli phage vB_EcoM-ep3 with a novel lysin, Lysep3. AB - Bacteriophages represent one prospect for preventing and treating multi-drug resistant Escherichia coli. In this study, we have isolated a novel E. coli specific bacteriophage and characterised its biological properties. vB_EcoM-ep3 has a broad host range and was able to lyse 9 out of 15 clinical isolates of multi-drug-resistant pathogenic E. coli from chickens. The optimal multiplicity of infection for vB_EcoM-ep3 in host bacteria was 0.01. vB_EcoM-ep3 was thermostable at temperatures below 50 degrees C for up to 60 min. Electron microscopy demonstrated that vB_EcoM-ep3 belongs to Myoviridae. The vB_EcoM-ep3 genome contained 42,351 pairs of nucleotides with a GC content of 53.35 %. There were 52 predicted open reading frames that appeared to overlap and have a modular structure. Phylogenetic analysis indicates that the closest evolutionary relative to vB_EcoM-ep3 is the previously reported E. coli phage vB_EcoM_ECO1230-10. However, there was no homology between reported E. coli phage lysins and the vB_EcoM-ep3 lysin gene. Lysep3 was 58 % similar to the Pseudomonas phage PPpW-3 lysin despite showing no similarities at the gene sequence level. And Lysep3 has good lysis activity. PMID- 25842153 TI - Prevalence and evolution of scleroderma pattern at nailfold videocapillaroscopy in systemic sclerosis patients: Clinical and prognostic implications. AB - BACKGROUND: Microvascular involvement plays a decisive role in systemic sclerosis (SSc) pathogenesis occurring early in the course of the disease. Microangiopathy is responsible of important clinical manifestations, such as Raynaud's phenomenon, digital ulceration, and pulmonary arterial hypertension. Typical microvascular alterations, called scleroderma pattern, are detectable at nailfold capillaroscopy in a significant percentage of SSc patients; however its prevalence is highly variable in published studies. AIM: The aims of this study are to evaluate the prevalence and the evolution of scleroderma pattern in SSc patients and analyze their demographic, clinical and prognostic characteristics according to capillaroscopic features. METHODS: Two hundred and seventy-five SSc patients, underwent at least two nailfold videocapillaroscopy during follow-up, were retrospectively enrolled. RESULTS: A scleroderma pattern was observed in 80% of patients at baseline and 87.1% during follow-up, and it was significantly associated to digital ulcers, interstitial lung disease, reduction of diffusion lung of carbon monoxide <75%, teleangectasias and melanodermia, while sicca syndrome and arthralgias were associated to normal/nonspecific pattern. Digital ulcers, teleangectasias, sicca syndrome, and arthralgias remained independently associated with scleroderma pattern on multivariate analysis. In conclusion, the main clinical manifestation correlated with scleroderma pattern is the occurrence of digital ulcers, and their appearance is strictly correlated with the variation of capillaroscopic feature during the time. Further studies should confirm the association between SSc pattern and lung fibrosis. PMID- 25842154 TI - Children's Lung Health Improves With Reduced Air Pollution. PMID- 25842155 TI - Healthcare professionals' use of health clouds: Integrating technology acceptance and status quo bias perspectives. AB - PURPOSE: Cloud computing technology has recently been seen as an important milestone in medical informatics development. Despite its great potential, there are gaps in our understanding of how users evaluate change in relation to the health cloud and how they decide to resist it. Integrating technology acceptance and status quo bias perspectives, this study develops an integrated model to explain healthcare professionals' intention to use the health cloud service and their intention to resist it. METHODS: A field survey was conducted in Taiwan to collect data from healthcare professionals; a structural equation model was used to examine the data. A valid sample of 209 healthcare professionals was collected for data analysis. RESULTS: The results show that healthcare professionals' resistance to the use of the health cloud is the result of regret avoidance, inertia, perceived value, switching costs, and perceived threat. Attitude, subjective norm, and perceived behavior control are shown to have positive and direct effects on healthcare professionals' intention to use the health cloud. The results also indicate a significant negative effect in the relationship between healthcare professionals' intention and resistance to using the health cloud. CONCLUSION: Our study illustrates the importance of incorporating user resistance in technology acceptance studies in general and in health technology usage studies in particular. This study also identifies key factors for practitioners and hospitals to make adoption decisions in relation to the health cloud. Further, the study provides a useful reference for future studies in this subject field. PMID- 25842156 TI - Complete genome sequence of Streptomyces cyaneogriseus ssp. noncyanogenus, the thermotolerant producer of commercial antibiotics nemadectin. AB - Streptomyces cyaneogriseus ssp. noncyanogenus is thermotolerant bacterium producing commercially important nemadectin, a kind of macrolide antibiotics, which has been widely used as a biopesticide. Here, we report the complete genome sequence of S. cyaneogriseus ssp. noncyanogenus, which consists of one chromosome (7,762,396bp) with no plasmid. Genome sequence information contributes to understanding the biosynthesis of nemadectin better and provides the basis for analysis of its thermotolerance and biosynthetical potential. PMID- 25842157 TI - Extracellular bone matrix exhibits hardening elastoplasticity and more than double cortical strength: Evidence from homogeneous compression of non-tapered single micron-sized pillars welded to a rigid substrate. AB - We here report an improved experimental technique for the determination of Young's modulus and uniaxial strength of extracellular bone matrix at the single micrometer scale, giving direct access to the (homogeneous) deformation (or strain) states of the tested samples and to the corresponding mechanically recoverable energy, called potential or elastic energy. Therefore, a new protocol for Focused Ion Beam milling of prismatic non-tapered micropillars, and attaching them to a rigid substrate, was developed. Uniaxial strength turns out as at least twice that measured macroscopically, and respective ultimate stresses are preceded by hardening elastoplastic states, already at very low load levels. The unloading portion of quasi-static load-displacement curves revealed Young's modulus of 29GPa in bovine extracellular bone matrix. This value is impressively confirmed by the corresponding prediction of a multiscale mechanics model for bone, which has been comprehensively validated at various other observation scales, across tissues from the entire vertebrate animal kingdom. PMID- 25842158 TI - Extremity in surgeon volume: Korea may be the place to go if you want to be a decent gastric surgeon. PMID- 25842159 TI - Large B-cell lymphoma: is the future written in the blood? PMID- 25842160 TI - Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. AB - BACKGROUND: Diffuse large-B-cell lymphoma is curable, but when treatment fails, outcome is poor. Although imaging can help to identify patients at risk of treatment failure, they are often imprecise, and radiation exposure is a potential health risk. We aimed to assess whether circulating tumour DNA encoding the clonal immunoglobulin gene sequence could be detected in the serum of patients with diffuse large-B-cell lymphoma and used to predict clinical disease recurrence after frontline treatment. METHODS: We used next-generation DNA sequencing to retrospectively analyse cell-free circulating tumour DNA in patients assigned to one of three treatment protocols between May 8, 1993, and June 6, 2013. Eligible patients had diffuse large-B-cell lymphoma, no evidence of indolent lymphoma, and were previously untreated. We obtained serial serum samples and concurrent CT scans at specified times during most treatment cycles and up to 5 years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pretreatment specimens and serum circulating tumour DNA encoding the VDJ rearrangements was quantitated. FINDINGS: Tumour clonotypes were identified in pretreatment specimens from 126 patients who were followed up for a median of 11 years (IQR 6.8-14.2). Interim monitoring of circulating tumour DNA at the end of two treatment cycles in 108 patients showed a 5-year time to progression of 41.7% (95% CI 22.2-60.1) in patients with detectable circulating tumour DNA and 80.2% (69.6-87.3) in those without detectable circulating tumour DNA (p<0.0001). Detectable interim circulating tumour DNA had a positive predictive value of 62.5% (95% CI 40.6-81.2) and a negative predictive value of 79.8% (69.6-87.8). Surveillance monitoring of circulating tumour DNA was done in 107 patients who achieved complete remission. A Cox proportional hazards model showed that the hazard ratio for clinical disease progression was 228 (95% CI 51-1022) for patients who developed detectable circulating tumour DNA during surveillance compared with patients with undetectable circulating tumour DNA (p<0.0001). Surveillance circulating tumour DNA had a positive predictive value of 88.2% (95% CI 63.6-98.5) and a negative predictive value of 97.8% (92.2-99.7) and identified risk of recurrence at a median of 3.5 months (range 0-200) before evidence of clinical disease. INTERPRETATION: Surveillance circulating tumour DNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse. Interim circulating tumour DNA is a promising biomarker to identify patients at high risk of treatment failure. FUNDING: National Cancer Institute and Adaptive Biotechnologies. PMID- 25842161 TI - The anti-malarial chloroquine suppresses proliferation and overcomes cisplatin resistance of endometrial cancer cells via autophagy inhibition. AB - OBJECTIVE: The anti-malarial drug chloroquine (CQ) is also known as an autophagy inhibitor. Autophagy can promote tumor growth by fueling the necessary energy metabolism and inducing resistance to chemotherapy and/or irradiation in various human cancers. However, the role of autophagy in endometrial cancer has not yet been established. We investigated the anti-tumor effects and autophagy inhibition caused by CQ in endometrial cancer cells. METHODS: Cell proliferation and cell cycle were assessed in response to CQ in six endometrial cancer cell lines by using an MTT assay and/or flow cytometry. To assess the level of autophagy, western blotting and an immunofluorescence assay were used to measure LC3 expression. The effects of knockdown of either ATG5 or ATG7, both of which are indispensable for induction of autophagy, were assessed via an MTT assay. Sensitivity to CQ was compared between parental and cisplatin-resistant (CP-r) Ishikawa endometrial cancer cells. RESULTS: CQ suppressed proliferation in all six endometrial cancer cell lines in a dose-dependent manner, whereas it increased the population of apoptotic cells. Inhibition of autophagy via knockdown of either ATG5 or ATG7 decreased the sensitivity to CQ. Additionally, sensitivity to cisplatin was improved by knocking down ATG5 or ATG7. Finally, CP r Ishikawa cells, with a high basal level of autophagy, were more sensitive to CQ than parental Ishikawa cells. CONCLUSIONS: Our data suggest that autophagy is involved in endometrial tumor growth and cisplatin resistance. Furthermore, our data support a therapeutic role for CQ in endometrial cancer cells with upregulation of autophagy. PMID- 25842162 TI - Outcomes of pediatric and adolescent girls with malignant ovarian germ cell tumors. AB - OBJECTIVE: To analyze the oncologic and reproductive outcomes of pediatric and young adolescents with malignant ovarian germ cell tumors (MOGCTs). METHODS: Pediatric or young adolescent girls aged 16years or under with MOGCT were eligible for this study. RESULTS: Forty-two pediatric or adolescent girls with MOGCT met the inclusion criteria. The median age was 12years (range, 6-16years) and 29 patients were premenarchal. The most common histologic type was immature teratoma, and 30 patients (54.3%) had stage I MOGCT. All patients underwent fertility-sparing surgery, which was defined as the preservation of at least one adnexa and the uterus. No patient had residual disease after surgery. Thirteen patients had tumor spillage, two patients had a positive peritoneal cytology, and two patients had lymph node metastasis. After surgery, 31 patients received adjuvant chemotherapy with bleomyocin, etoposide, and cisplatin (BEP) (median, 4cycles; range, 1-6 cycles). After a median follow-up time of 93months (range, 22 217 months), six patients had a recurrence of the disease, and one patient died. The 5-year disease-free and overall survival rates were 85% and 97%, respectively. Among the surviving 41 patients, seven were premenarchal, 30 had regular menstruation, and three had irregular menstruation. No patient had premature ovarian failure. CONCLUSION: All patients received uniform treatment consisting of fertility-sparing complete cytoreductive surgery followed by BEP chemotherapy. Regardless of histologic type and FIGO stage, the oncologic outcomes were excellent and the reproductive outcomes were favorable. PMID- 25842163 TI - Detection failure rate of chest radiography for the identification of nursing and healthcare-associated pneumonia. AB - AIM: To clarify the detection failure rate of chest radiography for the identification of nursing and healthcare-associated pneumonia (NHCAP), we compared high-resolution computed tomography (HRCT) with chest radiography simultaneously for patients with clinical symptoms and signs leading to a suspicion of NHCAP. METHODS: We analyzed 208 NHCAP cases and compared them based on four groups defined using NHCAP criteria, patients who were: Group A) resident in an extended care facility or nursing home; Group B) discharged from a hospital within the preceding 90 days; Group C) receiving nursing care and had poor performance status; and Group D) receiving regular endovascular treatment. RESULTS: Chest radiography was inferior to HRCT for the identification of pneumonia (149 vs 208 cases, p < 0.0001). Among the designated NHCAP criteria, chest radiography identified pneumonia cases at a significantly lower frequency than HRCT in Group A (70 vs 97 cases, p = 0.0190) and Group C (86 vs 136 cases, p < 0.0001). The detection failure rate of chest radiography differed among NHCAP criteria; 27.8% in Group A, 26.5% in Group B, 36.7% in Group C and 5.8% in Group D. Cerebrovascular disease and poor functional status were significantly more frequent in patients in Groups A and C compared with those in Groups B and D. CONCLUSIONS: Physicians may underestimate pneumonia shadow in chest radiographs in patients with NHCAP, and the detection failure rate of chest radiography differed among NHCAP criteria. Poor functional status may correlate with the low accuracy of chest radiography in diagnosing pneumonia. PMID- 25842164 TI - The effect of uranium on bacterial viability and cell surface morphology using atomic force microscopy in the presence of bicarbonate ions. AB - Past disposal practices at nuclear production facilities have led to the release of liquid waste into the environment creating multiple radionuclide plumes. Microorganisms are known for the ability to interact with radionuclides and impact their mobility in soils and sediments. Gram-positive Arthrobacter sp. are one of the most common bacterial groups in soils and are found in large numbers in subsurface environments contaminated with radionuclides. This study experimentally analyzed changes on the bacteria surface at the nanoscale level after uranium exposure and evaluated the effect of aqueous bicarbonate ions on U(VI) toxicity of a low uranium-tolerant Arthrobacter oxydans strain G968 by investigating changes in adhesion forces and cell dimensions via atomic force microscopy (AFM). Experiments were extended to assess cell viability by the Live/Dead BacLight Bacterial Viability Kit (Molecular Probes) and quantitatively illustrate the effect of uranium exposure in the presence of varying concentrations of bicarbonate ions. AFM and viability studies showed that samples containing bicarbonate were able to withstand uranium toxicity and remained viable. Samples containing no bicarbonate exhibited deformed surfaces and a low height profile, which, in conjunction with viability studies, indicated that the cells were not viable. PMID- 25842165 TI - DNA damage checkpoint recovery and cancer development. AB - Cell cycle checkpoints were initially presumed to function as a regulator of cell cycle machinery in response to different genotoxic stresses, and later found to play an important role in the process of tumorigenesis by acting as a guard against DNA over-replication. As a counterpart of checkpoint activation, the checkpoint recovery machinery is working in opposition, aiming to reverse the checkpoint activation and resume the normal cell cycle. The DNA damage response (DDR) and oncogene induced senescence (OIS) are frequently found in precancerous lesions, and believed to constitute a barrier to tumorigenesis, however, the DDR and OIS have been observed to be diminished in advanced cancers of most tissue origins. These findings suggest that when progressing from pre-neoplastic lesions to cancer, DNA damage checkpoint barriers are overridden. How the DDR checkpoint is bypassed in this process remains largely unknown. Activated cytokine and growth factor-signaling pathways were very recently shown to suppress the DDR and to promote uncontrolled cell proliferation in the context of oncovirus infection. In recent decades, data from cell line and tumor models showed that a group of checkpoint recovery proteins function in promoting tumor progression; data from patient samples also showed overexpression of checkpoint recovery proteins in human cancer tissues and a correlation with patients' poor prognosis. In this review, the known cell cycle checkpoint recovery proteins and their roles in DNA damage checkpoint recovery are reviewed, as well as their implications in cancer development. This review also provides insight into the mechanism by which the DDR suppresses oncogene-driven tumorigenesis and tumor progression. PMID- 25842166 TI - Caveolin-1 is transcribed from a hypermethylated promoter to mediate colonocyte differentiation and apoptosis. AB - Caveolin-1(CAV1) is a tyrosine-phosphorylated scaffold protein of caveolae with multiple interacting partners. It functions both as an oncogene and a tumour suppressor depending upon the cellular contexts. In the early stage of colorectal cancers (CRC), CAV1 suppresses tumour progression, while over-expression of CAV1 reduced the tumourigenicity of colon carcinoma cells. In contrast, elevated level of CAV1 was reported in stage III CRC. To address this ambiguity, we studied the functional role and the regulation of CAV1 expression during colonocyte differentiation and apoptosis. Here, we reported for the first time that CAV1 expression was increased during colonocyte differentiation and mediated butyrate induced differentiation and apoptosis of HT29 cells. CAV1 expression was silenced by promoter hypermethylation in HT-29 cells and reactivated by prolonged histone hyperacetylation of the promoter upon treatment of the cells with butyrate. However, the methylation status was unaltered by butyrate. We for the first time showed that HDAC inhibitor-mediated transactivation of CAV1 was regulated by methylation density of the promoter. Our study further explains the underlying mechanisms of the anti-cancer property of butyrate in CRC. PMID- 25842167 TI - The c-Rel subunit of NF-kappaB is a crucial regulator of phenotype and motility of HaCaT keratinocytes. AB - The transcription factor NF-kappaB exerts key functions in epidermal homeostasis and carcinogenesis. Its c-Rel subunit is expressed in squamous cell carcinoma, and c-Rel down-regulation results in increased apoptosis, G2/M cell cycle delay with reduced proliferation and aberrant mitotic spindle formation. To further study the impact of c-Rel on essential keratinocyte features such as migration and epithelial morphology, c-Rel was down-regulated in HaCaT keratinocytes by a siRNA approach. This inhibition of c-Rel impaired the keratinocyte-typical clustered growth leading to a more scattered appearance of the cultures. The cells were more spindle-shaped and elongated, albeit without expression changes of markers characteristic for epithelial mesenchymal transition. In addition, wound healing-related migration and adhesion to type I collagen, fibronectin, laminin and vitronectin were significantly impaired. On the sub-cellular level, these functional features were not associated with quantitatively altered adhesion receptor or Rho-GTPase expression, but rather with a significantly reduced length of cell-matrix adhesion complexes and altered appearance of filamentous actin. Thus, our studies support a role for c-Rel in processes crucial for keratinocyte integrity and malignant transformation such as adhesion and migration. PMID- 25842168 TI - Beyond EGFR and ALK inhibition: unravelling and exploiting novel genetic alterations in advanced non small-cell lung cancer. AB - During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor receptor (EGFR) gene and of chromosomic rearrangements in the anaplastic-lymphoma kinase (ALK) proto-oncogene, have been the first well characterized genetic alterations with corresponding targeted agents to enter the clinical arena. Nevertheless, in the recent years a number of other oncogenic drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, as well as ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. The aim of this review is to provide comprehensive information on the novel therapeutic targets identified by recent preclinical evidence and to discuss developments in molecular treatments targeting these oncogenic drivers or actionable mutations beyond EGFR and ALK in advanced NSCLC. PMID- 25842169 TI - Current challenges and future perspectives of plant and agricultural biotechnology. AB - Advances in understanding plant biology, novel genetic resources, genome modification, and omics technologies generate new solutions for food security and novel biomaterials production under changing environmental conditions. New gene and germplasm candidates that are anticipated to lead to improved crop yields and other plant traits under stress have to pass long development phases based on trial and error using large-scale field evaluation. Therefore, quantitative, objective, and automated screening methods combined with decision-making algorithms are likely to have many advantages, enabling rapid screening of the most promising crop lines at an early stage followed by final mandatory field experiments. The combination of novel molecular tools, screening technologies, and economic evaluation should become the main goal of the plant biotechnological revolution in agriculture. PMID- 25842170 TI - [Reply to authors: "Epidemiological study about pain in Andalusian public hospitals"]. PMID- 25842171 TI - [Acute toxicity due to local anesthetics]. PMID- 25842172 TI - Morbidity after Total Gastrectomy: Analysis of 238 Patients. AB - BACKGROUND: Surgical quality improvement requires well-defined benchmarks and accurate reporting of postoperative adverse events, which have not been well defined for total gastrectomy. STUDY DESIGN: Detailed postoperative outcomes on 238 patients who underwent total gastrectomy with curative intent, from 2003 to 2012, were reviewed by a dedicated surgeon chart reviewer to establish 90-day patterns of adverse events. RESULTS: Of the 238 patients with stage I to III gastric adenocarcinoma who underwent curative-intent total gastrectomy, the median age was 66 years, and 68% were male. Median body mass index was 28 kg/m(2), and 68% of patients had at least 1 medical comorbidity. Forty-three percent of our patients received neoadjuvant chemotherapy, and 34% received postoperative adjuvant chemotherapy. Over the 90-day study period, 30-day mortality was 2.5% (6 of 238), and 90-day mortality was 2.9% (7 of 238). At least 1 postoperative adverse event was documented in 62% of patients, with 28% of patients experiencing a major adverse event requiring invasive intervention. The readmission rate was 20%. Anemia was the most common adverse event (20%), followed by wound complications (18%). The most common major adverse event was esophageal anastomotic leak, which required invasive intervention in 10% of patients. CONCLUSIONS: This analysis has defined comprehensive 90-day patterns in postoperative adverse events after total gastrectomy with curative intent in a Western population. This benchmark allows surgeons to measure, compare, and improve outcomes and informed consent for this surgical procedure. PMID- 25842173 TI - A rapid and miniaturized method for the selection of microbial phenol degraders using colourimetric microtitration. AB - A high-throughput method is described, consisting of a colourimetric microtitration for screening phenol-degrading microorganisms, using a mixture of 4-aminoantipyrine and potassium ferricyanide as the colour indicator. This contemporary study summarizes a new method to determine phenol-degrading bacteria isolated from different areas. The method was used for testing a total of 72 bacteria collected from the natural environment and five known strains obtained from diagnostic and research laboratories employing 200 mg/L phenol (the linear range saturation concentration). Depending on the change in colour indicator, the degradation profiles of 11 strains of bacteria are shown, of which seven strains were able to degrade more than 80 % of phenol within 6-8 h, while the other four strains took 12-24 h. Two of the environmentally isolated strains showed high efficiency of phenol degradation and were confirmed by the high-performance liquid chromatography analysis. These strains were identified by 16S rRNA sequencing as unique (Escherichia coli moh1 and Bacillus cereus moh2) and were deposited in the GenBank of NCBI. Two pathogenic strains (Uropathogenic E. coli and Salmonella sp.) were found to be the fast degraders of phenol, which is of medical concern, as phenol is generally used as a disinfectant in hospitals. This method can be used for the estimation and screening of phenol degraders in a single step, for its application in bioremediation as well as in hospitals for screening the phenol resistance of pathogens. PMID- 25842174 TI - Overexpression of Small Heat Shock Protein Enhances Heat- and Salt-Stress Tolerance of Bifidobacterium longum NCC2705. AB - Bifidobacteria are probiotics that are incorporated live into various dairy products. They confer health-promotive effects via gastrointestinal tract colonization. However, to provide their health-beneficial properties, they must battle the various abiotic stresses in that environment, such as bile salts, acids, oxygen, and heat. In this study, Bifidobacterium longum salt- and heat stress tolerance was enhanced by homologous overexpression of a small heat shock protein (sHsp). A positive contribution of overproduced sHsp to abiotic stress tolerance was observed when the bacterium was exposed to heat and salt stresses. Significantly higher survival of B. l ongum NCC2705 overexpressing sHsp was observed at 30 and 60 min into heat (55 degrees C) and salt (5 M NaCl) treatment, respectively. Thermotolerance analysis at 47 degrees C with sampling every 2 h also revealed the great potential tolerance of the engineered strain. Cell density and acid production rate increased for the sHsp-overexpressing strain after 8 and 10 h of both heat and salt stresses. In addition, tolerance to bile salts, low pH (3.5) and low temperature (4 degrees C) was also increased by homologous overexpression of the sHsp hsp20 in B. l ongum. Results revealed that hsp20 overexpression in B longum NCC2705 plays a positive cross-protective role in upregulating abiotic responses, ensuring the organism's tolerance to various stress conditions; therefore, sHsp-overexpressing B. l ongum is advised for fermented dairy foods and other probiotic product applications. PMID- 25842175 TI - Web 2.0 applications in medicine: trends and topics in the literature. AB - BACKGROUND: The World Wide Web has changed research habits, and these changes were further expanded when "Web 2.0" became popular in 2005. Bibliometrics is a helpful tool used for describing patterns of publication, for interpreting progression over time, and the geographical distribution of research in a given field. Few studies employing bibliometrics, however, have been carried out on the correlative nature of scientific literature and Web 2.0. OBJECTIVE: The aim of this bibliometric analysis was to provide an overview of Web 2.0 implications in the biomedical literature. The objectives were to assess the growth rate of literature, key journals, authors, and country contributions, and to evaluate whether the various Web 2.0 applications were expressed within this biomedical literature, and if so, how. METHODS: A specific query with keywords chosen to be representative of Web 2.0 applications was built for the PubMed database. Articles related to Web 2.0 were downloaded in Extensible Markup Language (XML) and were processed through developed hypertext preprocessor (PHP) scripts, then imported to Microsoft Excel 2010 for data processing. RESULTS: A total of 1347 articles were included in this study. The number of articles related to Web 2.0 has been increasing from 2002 to 2012 (average annual growth rate was 106.3% with a maximum of 333% in 2005). The United States was by far the predominant country for authors, with 514 articles (54.0%; 514/952). The second and third most productive countries were the United Kingdom and Australia, with 87 (9.1%; 87/952) and 44 articles (4.6%; 44/952), respectively. Distribution of number of articles per author showed that the core population of researchers working on Web 2.0 in the medical field could be estimated at approximately 75. In total, 614 journals were identified during this analysis. Using Bradford's law, 27 core journals were identified, among which three (Studies in Health Technology and Informatics, Journal of Medical Internet Research, and Nucleic Acids Research) produced more than 35 articles related to Web 2.0 over the period studied. A total of 274 words in the field of Web 2.0 were found after manual sorting of the 15,878 words appearing in title and abstract fields for articles. Word frequency analysis reveals "blog" as the most recurrent, followed by "wiki", "Web 2.0", "social media", "Facebook", "social networks", "blogger", "cloud computing", "Twitter", and "blogging". All categories of Web 2.0 applications were found, indicating the successful integration of Web 2.0 into the biomedical field. CONCLUSIONS: This study shows that the biomedical community is engaged in the use of Web 2.0 and confirms its high level of interest in these tools. Therefore, changes in the ways researchers use information seem to be far from over. PMID- 25842176 TI - The neuroprotective effect of lovastatin on MPP(+)-induced neurotoxicity is not mediated by PON2. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of the pigmented dopaminergic neurons in the substantia nigra pars compacta with subsequent striatal dopamine (DA) deficiency and increased lipid peroxidation. The etiology of the disease is still unclear and it is thought that PD may be caused by a combination of genetic and environmental factors. In the search of new pharmacological options, statins have been recognized for their potential application to treat PD, due to their antioxidant effect. The aim of this work is to contribute in the characterization of the neuroprotective effect of lovastatin in a model of PD induced by 1-methyl-4-phenylpyridinium (MPP(+)). Male Wistar rats (200-250 g) were randomly allocated into 4 groups and administered for 7 days with different pharmacological treatments. Lovastatin administration (5 mg/kg) diminished 40% of the apomorphine-induced circling behavior, prevented the striatal DA depletion and lipid peroxides formation by MPP(+) intrastriatal injection, as compared to the group of animals treated only with MPP(+). Lovastatin produced no change in paraoxonase-2 (PON2) activity. It is evident that lovastatin conferred neuroprotection against MPP(+)-induced protection but this effect was not associated with the induction of PON2 in the rat striatum. PMID- 25842177 TI - Rapid turnover of antimicrobial-type cysteine-rich protein genes in closely related Oryza genomes. AB - Defensive and reproductive protein genes undergo rapid evolution. Small, cysteine rich secreted peptides (CRPs) act as antimicrobial agents and function in plant intercellular signaling and are over-represented among reproductively expressed proteins. Because of their roles in defense, reproduction and development and their presence in multigene families, CRP variation can have major consequences for plant phenotypic and functional diversification. We surveyed the CRP genes of six closely related Oryza genomes comprising Oryza sativa ssp. japonica and ssp. indica, Oryza glaberrima and three accessions of Oryza rufipogon to observe patterns of evolution in these gene families and the effects of variation on their gene expression. These Oryza genomes, like other plant genomes, have accumulated large reservoirs of CRP sequences, comprising 26 groups totaling between 676 and 843 genes, in contrast to antimicrobial CRPs in animal genomes. Despite the close evolutionary relationships between the genomes, we observed rapid changes in number and structure among CRP gene families. Many CRP sequences are in gene clusters generated by local duplications, have undergone rapid turnover and are more likely to be silent or specifically expressed. By contrast, conserved CRP genes are more likely to be highly and broadly expressed. Variable CRP genes created by repeated duplication, gene modification and inactivation can gain new functions and expression patterns in newly evolved gene copies. For the CRP proteins, the process of gain/loss by deletion or duplication at gene clusters seems to be an important mechanism in evolution of the gene families, which also contributes to their expression evolution. PMID- 25842178 TI - Characterizations and expression analyses of NF-kappaB and Rel genes in the Yesso scallop (Patinopecten yessoensis) suggest specific response patterns against Gram negative infection in bivalves. AB - Rel/NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) genes are evolutionarily conserved and play a pivotal role in several physiological events. They have been extensively studied from various species, including both vertebrates and invertebrates. However, the Rel/NF-kappaB genes have not been systematically characterized in bivalves. In this study, we identified and characterized PyNF-kappaB and PyRel in the Yesso scallop (Patinopecten yessoensis). Phylogenetic and protein structural analyses were conducted to determine the identities and evolutionary relationships of Rel/NF kappaB genes in Yesso scallop. Compared with the Rel/NF-kappaB genes from vertebrate species, the PyNF-kappaB and PyRel are relatively conserved in their structural features, but there were no paralogs found in P. yessoensis or other invertebrates. To gain insights into the roles of Rel/NF-kappaB genes during the innate immune response in scallop, quantitative real-time PCR was used to investigate the expression profiles of these genes at different developmental stages, in healthy adult tissues and in the hemolymph after bacterial infection with Micrococcus luteus and Vibrio anguillarum. The real-time PCR results indicated the abundance of PyNF-kappaB in the first four embryonic stages, including oocytes, fertilized eggs, morulae and blastulae. By contrast, PyRel was abundantly expressed in blastulae, trochophores and D-shaped larvae. In adult scallops, PyNF-kappaB and PyRel were ubiquitously expressed in most healthy tissues and highly expressed in most of the immune related tissues. Both genes were significantly up-regulated during the acute phase (3 h) after infection with Gram-positive (M. luteus) and negative (V. anguillarum) bacteria, while the much higher expression level of PyNF-kappaB suggested the involvement of the extra immune deficiency (IMD)-like pathway against the Gram-negative bacterial infection. The complex pattern of Rel/NF-kappaB induced expression suggested that PyNF-kappaB and PyRel both have specific and cooperative roles in the acute immune responses to bacterial infection. PMID- 25842179 TI - Transcriptomic analysis and biomarkers (Rag1 and IgMU) for probing the immune system development in Pacific cod, Gadus macrocephalus. AB - Mortality (>90%) is a big concern in larval rearing facilities of Pacific cod, Gadus macrocephalus, limiting its culture presently still in the experimental stages. Understanding the immune system development of G. macrocephalus is crucial to optimize the aquaculture of this species, to improve the use of economic resources and to avoid abuse of antibiotics. For the transcriptome analysis, using an Illumina sequencing platform, 61,775,698 raw reads were acquired. After a de novo assembly, 77,561 unigenes were obtained. We have classified functionally these transcripts by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). 27 genes mainly related to hematopoietic or lymphoid organ development and somatic diversification of immune receptors have been reported for the first time in Pacific cod, and 14 Ig heavy chain (MU chain) locuses were assembled using Trinity. Based on our previous achievement, we have chosen Rag1 and IgMU as immune system development biomarkers. Full length cDNA of Rag1 and IgMU as biomarkers were obtained respectively using RACE PCR. Concerning Rag1, the deduced amino acid of Rag1 and protein immunodetection revealed a Rag1 isoform of 69 kDa, significantly different from other fish orthologs, such as Oncorhynchus mykiss (121 kDa). Phylogenetic analysis reveals a unique immune system for the Gadus genre, not exclusive for Atlantic cod, among vertebrates. Meanwhile, full length cDNA of IgMU included an ORF of 1710 bp and the deduced amino acid was composed of a leader peptide, a variable domain, CH1, CH2, Hinge, CH3, CH4 and C-terminus, which was in accordance with most teleost. Absolute quantification PCR revealed that significant expression of Rag1 appeared earlier than IgMU, 61 and 95 dph compared to 95 dph, respectively. Here we report the first transcriptomic analysis of G. macrocephalus as the starting point for genetic research on immune system development towards improving the Pacific cod aquaculture. PMID- 25842180 TI - Molecular characterization and functional analysis of a novel C-type lectin receptor-like gene from a teleost fish, Plecoglossus altivelis. AB - C-type lectin-like receptors (CLRs) are important pathogen pattern recognition molecules that recognize carbohydrate structures. However, the functions of these receptors in fish keep less known. In this study, we characterized a novel CLR from a teleost fish, Plecoglossus altivelis (ayu), tentatively named PaCD209L. The cDNA of PaCD209L is 1464 nucleotides (nts) in length, encoding a polypeptide of 281 amino acid residues with a calculated molecular weight of 31.5 kDa. Multiple alignment of the deduced amino acid sequences of PaCD209L and other related fish CLRs revealed that the PaCD209L sequence had typical characteristics of fish CLRs, but without Ca(2+)-binding sites. Sequence comparison and phylogenetic tree analysis showed that PaCD209L shared the highest amino acid identity (44%) with rainbow trout (Oncorhynchus mykiss) CD209 aE PaCD209L transcripts were detected in all of the tissues examined, mainly expressed in the brain and heart. Upon Vibrio anguillarum infection, PaCD209L transcripts were upregulated in all tested tissues and in monocytes/macrophages (MO/MPhi). We prepared recombinant PaCD209L (rPaCD209L) by prokaryotic expression and raised antiserum against PaCD209L. Western blot analysis revealed that native PaCD209L was glycosylated, and its protein expression significantly increased in ayu MO/MPhi upon V. anguillarum infection. In addition, rPaCD209L was able to bind Gram-positive and Gram-negative bacteria in the absence of Ca(2+). After PaCD209L was blocked by anti-PaCD209L IgG, the phagocytosis and bacterial killing activity of MO/MPhi significantly decreased. These results suggest that PaCD209L plays an important role in the regulation of MO/MPhi functions in ayu. PMID- 25842181 TI - Functional analysis of Pacific oyster (Crassostrea gigas) beta-thymosin: Focus on antimicrobial activity. AB - An antimicrobial peptide, ~5 kDa in size, was isolated and purified in its active form from the mantle of the Pacific oyster Crassostrea gigas by C18 reversed phase high-performance liquid chromatography. Matrix-assisted laser desorption ionisation time-of-flight analysis revealed 4656.4 Da of the purified and unreduced peptide. A comparison of the N-terminal amino acid sequence of oyster antimicrobial peptide with deduced amino acid sequences in our local expressed sequence tag (EST) database of C. gigas (unpublished data) revealed that the oyster antimicrobial peptide sequence entirely matched the deduced amino acid sequence of an EST clone (HM-8_A04), which was highly homologous with the beta thymosin of other species. The cDNA possessed a 126-bp open reading frame that encoded a protein of 41 amino acids. To confirm the antimicrobial activity of C. gigas beta-thymosin, we overexpressed a recombinant beta-thymosin (rcgTbeta) using a pET22 expression plasmid in an Escherichia coli system. The antimicrobial activity of rcgTbeta was evaluated and demonstrated using a bacterial growth inhibition test in both liquid and solid cultures. PMID- 25842182 TI - Ceftriaxone susceptibility of oxacillin-susceptible Staphylococcus aureus from patients with prosthetic joint infection. AB - Ceftriaxone is used to treat oxacillin-susceptible S. aureus (OSSA) prosthetic joint infection (PJI). Susceptibility of ceftriaxone against OSSA has been questioned. Ceftriaxone susceptibility was determined against 100 PJI OSSA isolates. Ceftriaxone MIC90/MIC50 were 8/4 and 4/3MUg/mL by broth microdilution and Etest, respectively. Ceftriaxone susceptibility is inferable by oxacillin susceptibility. PMID- 25842183 TI - Prevalence and characteristics of serrated lesions of the colorectum in Italy: A multicentre prospective cohort study. AB - BACKGROUND: Serrated lesions are recognized as important contributors to colorectal cancer incidence. We aimed to prospectively assess the prevalence of serrated lesions and identify potential predictors of these lesions during colonoscopy in an Italian population. METHODS: Prospective cross sectional study involving 8 endoscopy units from February 1st to July 31st 2012. RESULTS: Out of 2468 colonoscopies, 886 precancerous lesions were detected in 567 patients. Of these, 173 SELs were diagnosed in 148 patients (140 serrated/hyperplastic polyps and 33 serrated adenomas). Prevalence was 7% (173/2468). Serrated lesions accounted for 19.5% of all precancerous lesions. Serrated polyps were prevalent in the left colon (42.1%) and serrated adenomas in the proximal colon (54.5%). Independent clinical predictors of serrated lesions were patient age (OR 0.98 [0.97-1.00]) and post-polypectomy surveillance (OR 1.87 [1.24-2.82]). Endoscopic predictors were right colon location (OR 2.65 [1.63-4.30] vs. rectum; and 1.53 [1.03-2.26] vs. left colon), polypoid shape (OR 0.41 [027-0.64]) and size <6 mm (OR 0.49 [0.33-0.72] vs. 6-10 mm; and 0.14 [0.07-0.28] vs. >10 mm). There was no independent predictor of serrated adenoma. CONCLUSION: In our Italian study population, the prevalence of colorectal serrated lesions was 7%. Their diagnosis is associated with younger age and surveillance colonoscopy, right-sided colorectal location, non-polypoid shape and size <6 mm. PMID- 25842184 TI - General sale of non-prescription medicinal products: Comparing legislation in two European countries. AB - BACKGROUND: The number of non-prescription medicines (NPMs) available for self medication is increasing within the European Union (EU). This can enhance the autonomy of individuals but is also connected with risks. Under an existing EU Directive, Sweden has only recently deregulated and made NPMs available in non pharmacy outlets; The United Kingdom (UK) is a more established NPM market; both are guided by the same EU directives. OBJECTIVE: The aim of this study was to compare specific requirements under the legislation, rationales and outcomes regarding the sale of NPMs through non-pharmacy outlets between Sweden and the UK. METHOD: The main method was analysis of legislative text and policy documents, conducted in 2012. RESULTS: Both countries had specified medicines available to the public in non-pharmacy outlets, but with restrictions on different factors, e.g. placement and package size of the NPMs. The main rationales for legislation were quality and patient safety. NPMs for 51 ailments were available in the UK, compared to 35 in Sweden. CONCLUSION: Sweden had more extensive requirements, probably due to the market being more recently deregulated, while the UK represented a more mature market. There is a difference in the balance between confidence and control, as well as availability and safety when it comes to NPMs in non-pharmacy settings that needs to be further discussed. PMID- 25842185 TI - Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases. AB - Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery. PMID- 25842186 TI - BAFF blockade prevents anti-drug antibody formation in a mouse model of Pompe disease. AB - Antibodies formed against the therapeutic protein are a life-threatening complication that arises during enzyme replacement therapy for Pompe disease (acid alpha-glucosidase deficiency; GAA). To provide an effective alternative to current practices, we investigated the capacity of anti-B-cell activating factor (BAFF) as a novel drug candidate to prevent antibody formation in a Pompe disease mouse model. A BAFF-neutralizing antibody was administered prophylactically and with maintenance doses in association with enzyme replacement therapy using recombinant human GAA in Gaa(-/-) mice. BAFF blockade delayed antibody production and increased GAA activity within tissues with protection from anaphylaxis. Anti BAFF also resolved antibody formation during an immune response and precluded the maturation of antibody secreting cells from entering the bone marrow compartment. This treatment modality may therefore be a viable alternative for the clinical management of antibody formation for Pompe disease and has potential use against antibody formation in other protein replacement therapies. PMID- 25842187 TI - A combination dual-sized microparticle system modulates dendritic cells and prevents type 1 diabetes in prediabetic NOD mice. AB - We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-beta1 or GM-CSF. The combination of Vit D3/TGF-beta1 MPs confers an immature and LPS activation resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-beta1 and GM CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial based, MP vaccine system to successfully prevent autoimmune diabetes. PMID- 25842188 TI - Lactose hydrolysis by beta-galactosidase enzyme: optimization using response surface methodology. AB - In the present study, it was aimed to optimize the process of lactose hydrolysis using free and immobilized beta-galactosidase to produce glucose and galactose. Response surface methodology (RSM) by central composite design (CCD) was employed to optimize the degree of hydrolysis by varying three parameters, temperature (15 45 degrees C), solution pH (5-9) and beta-galactosidase enzyme concentration (2 8mg/mL) for free mode of analysis and sodium alginate concentration (2-4%), calcium chloride concentration (3-6%) and enzyme concentration (2-8mg/mL) for immobilized process. Based on plots and variance analysis, the optimum operational conditions for maximizing lactose hydrolysis were found to be temperature (35.5 degrees C), pH (6.7) and enzyme concentration (6.7mg/mL) in free mode and sodium alginate concentration (3%), calcium chloride concentration (5.9%) and enzyme concentration (5.2mg/mL) in immobilized mode. PMID- 25842189 TI - Regulation of RGS5 GAP activity by GPSM3. AB - Heterotrimeric G protein signaling is limited by intracellular proteins that impede the binding of or accelerate the hydrolysis of the activating nucleotide GTP, exemplified respectively by the G protein-signaling modifier (GPSM) and regulator of G protein-signaling (RGS) families of proteins. Little is known about how members of these groups of proteins might influence the impact of the other on G protein activity. In the present study, we have identified novel binding and functional interactions between GPSM3 (also known as activator of G protein-signaling 4 (AGS4) or G18) and RGS5, both of which were found to be expressed in primary rat aortic smooth muscle cell cultures. The binding of GPSM3 to RGS5 appears to be selective as no interactions were detected with other RGS proteins tested. In solution-based experiments, the addition of GPSM3 was found to enhance the ability of RGS5 to accelerate GTP hydrolysis by Galphai1 but not that of RGS4. In membrane-based assays utilizing M2 muscarinic receptor-activated Galphai1, GPSM3 decreased the rate of GTP hydrolysis in the presence of RGS4 but not RGS5, suggesting that the enhancement of RGS5 activity by GPSM3 is maintained under these conditions and/or that the binding of RGS5 to GPSM3 impedes its inhibitory effect on GTP turnover. Overall these findings show that it is possible for GPSM and RGS proteins to bind to one another to produce distinct regulatory effects on heterotrimeric G protein activity. PMID- 25842190 TI - Protective effects of N-acetylcysteine against hyperoxaluria induced mitochondrial dysfunction in male wistar rats. AB - The purpose of the present study was to evaluate the nephro-protective potential of N-acetylcysteine against hyperoxaluria-induced renal mitochondrial dysfunction in rats. Nine days dosing of 0.4 % ethylene glycol +1 % ammonium chloride, developed hyperoxaluria in male wistar rats which resulted in renal injury and dysfunction as supported by increased level of urinary lactate dehydrogenase, calcium, and decreased creatinine clearance. Mitochondrial oxidative strain in hyperoxaluric animals was evident by decreased levels of superoxide dismutase, glutathione peroxidase, glutathione reductase, reduced glutathione, and an increased lipid peroxidation. Declined activities of respiratory chain enzymes and tricarboxylic acid cycle enzymes showed mitochondrial dysfunction in hyperoxaluric animals. N-acetylcysteine (50 mg/kg, i.p.), by virtue of its -SH reviving power, was able to increase the glutathione levels and thus decrease the oxidative stress in renal mitochondria. Hence, mitochondrial damage is, evidently, an essential event in ethylene glycol-induced hyperoxaluria and N acetylcysteine presented itself as a safe and effective remedy in combating nephrolithiasis. PMID- 25842191 TI - 3 dimensional cell cultures: a comparison between manually and automatically produced alginate beads. AB - Cancer diseases are a common problem of the population caused by age and increased harmful environmental influences. Herein, new therapeutic strategies and compound screenings are necessary. The regular 2D cultivation has to be replaced by three dimensional cell culturing (3D) for better simulation of in vivo conditions. The 3D cultivation with alginate matrix is an appropriate method for encapsulate cells to form cancer constructs. The automated manufacturing of alginate beads might be an ultimate method for large-scaled manufacturing constructs similar to cancer tissue. The aim of this study was the integration of full automated systems for the production, cultivation and screening of 3D cell cultures. We compared the automated methods with the regular manual processes. Furthermore, we investigated the influence of antibiotics on these 3D cell culture systems. The alginate beads were formed by automated and manual procedures. The automated steps were processes by the Biomek((r)) Cell Workstation (celisca, Rostock, Germany). The proliferation and toxicity were manually and automatically evaluated at day 14 and 35 of cultivation. The results visualized an accumulation and expansion of cell aggregates over the period of incubation. However, the proliferation and toxicity were faintly and partly significantly decreased on day 35 compared to day 14. The comparison of the manual and automated methods displayed similar results. We conclude that the manual production process could be replaced by the automation. Using automation, 3D cell cultures can be produced in industrial scale and improve the drug development and screening to treat serious illnesses like cancer. PMID- 25842192 TI - Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia. AB - Reactivation of hepatitis B virus (HBV) following immunosuppressive therapy or hematopoietic stem cell transplantation is a potentially fatal complication that may occur even in patients with prior resolution of HBV infection. Dasatinib is a small-molecule inhibitor of the tyrosine kinases SRC and ABL that has been approved for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. Here, we report the first case of reactivation of resolved infection with the HBV immune escape mutant G145R in a CML patient receiving dasatinib. Although dasatinib is not recognized as an immunosuppressant, our observations suggest that dasatinib may enhance HBV replication and induce its reactivation in immunocompetent patients, that HBV escape mutants may contribute to the pathogenesis of HBV reactivation, and that close monitoring of HBV status is advisable in patients with current or resolved HBV infection. PMID- 25842193 TI - The effects of brain wave vibration on oxidative stress response and psychological symptoms. AB - OBJECTIVE: Brain Wave Vibration (BWV) training is a simple healing practice, a kind of Mind Body Training. This study was designed to investigate the psycho endocrine differences between BMV practitioners and naive controls. METHODS: The experimental group included 54 individuals who had participated in BWV. The control group included 58 subjects who had not participated in formal BWV. Levels of plasma NO, reactive oxygen species (ROS), and superoxide dismutase (SOD) were measured, and the modified form of the Stress Response Inventory (SRI-MF), the Positive Affect and Negative Affect Scale (PANAS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI) were administered. RESULTS: The BWV group demonstrated significantly higher plasma NO levels (p=0.003), and levels of ROS and SOD did not differ between the two groups. The BWV group showed lower scores in BDI (p=0.009), BAI (p=0.009) and stress level (p<0.001) and higher scores on positive affect (p=0.023) compared with the control group. NO levels were associated with increased positive affect (p = 0.024) only in BWV subjects. CONCLUSION: BWV may increase NO, a relaxation-related factor, possibly by improving emotional state. PMID- 25842194 TI - Validation of the Italian version of the Yale-Brown Obsessive Compulsive Scale Second Edition (Y-BOCS-II) in a clinical sample. AB - OBJECTIVE: The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) is the most widely accepted measure of obsessive-compulsive disorder (OCD) symptom severity. Recently, the scale has been revised into a second edition (Y-BOCS-II) in order to improve its measurement properties. The present study aimed to evaluate the psychometric properties of the Italian version of the Y-BOCS-II Severity Scale (SS) in a large clinical sample. METHOD: The original version of the Y-BOCS-II was translated into Italian, which involved forward and back-translation procedures. The Italian Y-BOCS-II-SS was administered to one hundred twenty-five treatment-seeking adults with OCD, together with the original Y-BOCS-SS and a battery of self-report measures assessing OCD symptom severity and depressive and anxious symptomology. The factor structure, internal consistency, temporal stability, and construct validity were investigated on the whole sample, while inter-rater and test-retest reliability were assessed on a subsample of participants. RESULTS: Factor analyses revealed a two-factor structure different from those of the original scale, comprising (1) symptom severity; and (2) interference from symptoms. Internal consistency, test-retest reliability over a 2-week period and inter-rater reliability were satisfactory. The Y-BOCS-II-SS also showed excellent construct validity (and better than the Y-BOCS-SS), with good convergent and discriminant validity when assessed against other OCD symptom measures and measures of depression, anxiety and worry. CONCLUSIONS: These findings suggest that the Italian version of the Y-BOCS-II-SS retains the adequate psychometric properties of the original and that it can be confidently used as an assessment tool of OCD symptoms in both clinical and research settings. PMID- 25842195 TI - Examining the associations between emotion regulation difficulties, anxiety, and eating disorder severity among inpatients with anorexia nervosa. AB - OBJECTIVE: There is growing interest in the role of emotion regulation in anorexia nervosa (AN). Although anxiety is also hypothesized to impact symptoms of AN, little is known about how emotion regulation, anxiety, and eating disorder symptoms interact in AN. In this study, we examined the associations between emotion regulation, anxiety, and eating disorder symptom severity in AN. METHODS: Questionnaires and interviews assessing emotion regulation difficulties, anxiety, eating disorder symptoms, and eating disorder-related clinical impairment were collected from group of underweight individuals with AN (n=59) at admission to inpatient treatment. Hierarchical linear regressions were used to examine the associations of emotion regulation difficulties, anxiety, and the interaction of these constructs with eating disorder symptoms and eating disorder-related clinical impairment. RESULTS: Emotion regulation difficulties were significantly positively associated with eating disorder symptoms and related clinical impairment only when anxiety levels were low and anxiety was significantly positively associated with eating disorder symptoms and related clinical impairment only when emotion regulation problems were not elevated. CONCLUSIONS: This study adds to a growing literature suggesting that emotion regulation deficits are associated with eating disorder symptoms in AN. Certain individuals with AN may especially benefit from a focus on developing emotion regulation skills in the acute stages of illness. PMID- 25842196 TI - [Profile and susceptibility to antibiotics in urinary tract infections in children and newborns from 2012 to 2013: Data from 1879 urine cultures]. AB - INTRODUCTION: We present recent data on the bacteriological profile and antibiotic susceptibility of uropathogenic bacteria isolated in children and newborns in our region over the past 2 years. MATERIALS AND METHODS: A retrospective study on the positive urine cultures from pediatric and neonatal populations during 2012-2013. Bacteria were identified using conventional methods. Susceptibility testing was performed and interpreted as recommended by the committee of the susceptibility of the French Society of Microbiology (CA SFM). RESULTS: We collected 1879 non-redundant bacteria with more than 73% Escherichia coli. Children and infants (mean age, 32 months [range, 1 month to 14 years]) accounted for 84% of the bacteria collected and newborns (mean age, 12 days [range, 1 day to 1 month]) 16%. A female predominance was observed in the pediatric population (M:F sex ratio, 3.2), whereas for the neonatal population, the proportions were almost identical in both sexes (M:F sex ratio, 1.1). Most of the positive urine cultures (n=1234) were from the community. Hospitalized patients (n=636) were divided into pediatric (60%) and neonatal units (40%). Five bacterial genera dominated the bacteriological profile: E. coli, Klebsiella sp., Proteus sp., Enterobacter sp., and Enterococcus. The susceptibility of the main BUP antibiotics used for treatment of frequent UTI showed the effectiveness of furadoine, imipenem, fosfomycin, and colistin. Amoxicillin kept constant activity against Enterococcus and Streptococcus agalactiae. The rates of resistance of Enterobacteriaceae to beta-lactam antibiotics were high, especially in the neonatal population. The production of extended-spectrum beta-lactamase (ESBL) was noted in 12.8% of pediatric Enterobacteria vs. 22.6% of the neonatal strains. For community Enterobacteriaceae, the activity of beta-lactam antibiotics was limited with 11.2% resistance to third-generation cephalosporins (C3G), including 8.6% ESBL production. CONCLUSION: The impact of widespread use of beta-lactam antibiotics in neonatal and pediatric environments is felt. Colistin, imipenem, and fosfomycin are the most frequently used antibiotics active against bacteria responsible for neonatal and pediatric UTI; however, they cannot be used as probabilistic treatment. Nitrofurans seem to be active antibiotics on UTI, but they present limits in their use in neonatal and pediatric populations. Their indication in case of pyelonephritis should be discussed. PMID- 25842197 TI - [Adenosine deaminase 1 deficiency, an inborn error of metabolism underlying a severe form of combined immunodeficiency]. AB - Severe combined immune deficiencies (SCIDs) are a heterogeneous group of severe cellular immunodeficiencies. Early diagnosis is essential to allow adapted care before life-threatening systemic infections or complications associated with live vaccines. Adenosine deaminase 1 deficiency (ADA1) is an inborn error of metabolism leading to severe lymphopenia and characteristic bone lesions. Herein, we present the typical case of a child in whom ADA SCID was diagnosed at 2 months of life, revealed by lung involvement and extreme lymphopenia. Immune restoration in terms of peripheral lymphocyte count with enzyme replacement therapy, namely pegylated bovine ADA, is satisfactory so far. The search for a compatible donor is underway. Correcting the genetic defect by gene transfer is also being considered. The phenotype of this very rare condition is described. A severe peripheral lymphopenia in a young child is a finding of utmost importance for the diagnosis of a primary cellular immunodeficiency. PMID- 25842198 TI - [Information for parents of children with sickle cell trait detected by neonatal screening: A 10-year experience]. PMID- 25842200 TI - The power of movement. PMID- 25842199 TI - [Acute tubulointerstitial nephritis following adenovirus and respiratory syncytial virus infection]. AB - Acute tubulointerstitial nephritis (TIN) is responsible for nearly 10% of acute renal failure (ARF) cases in children. It is mostly drug-induced, but in a few cases viruses are involved, probably by an indirect mechanism. An immune competent 13-month-old boy was admitted to the intensive care unit for severe ARF with anuria in a context of fever, cough, and rhinorrhea lasting 1 week. The kidney biopsy performed early brought out tubulointerstitial damage with mild infiltrate of lymphocytes, without any signs of necrosis. There were no virus inclusion bodies, no interstitial hemorrhage, and no glomerular or vascular damage. Other causes of TIN were excluded: there was no biological argument for an immunological, immune, or drug-induced cause. Adenovirus (ADV) and respiratory syncytial virus (RSV) were positive in respiratory multiplex polymerase chain reaction (PCR) in nasal aspirate but not in blood, urine, and renal tissue. The patient underwent dialysis for 10 days but the response to corticosteroid therapy was quickly observed within 48 h. The mechanism of TIN associated with virus infection is unknown. However, it may be immune-mediated to be able to link severe renal dysfunction and ADV and/or RSV invasion of the respiratory tract. PMID- 25842201 TI - Linear Extrapolation Results in Erroneous Overestimation of Plausible Stressor Related Yearly Weight Changes. PMID- 25842203 TI - The Pediatric Epilepsy Side Effects Questionnaire: Establishing clinically meaningful change. AB - The present study extends the utility of the Pediatric Epilepsy Side Effects Questionnaire (PESQ) by determining distribution-based minimally clinically important difference (MCID) scores. Participants (N=682) were youth (ages 2-25) with newly diagnosed and chronic epilepsy pooled from research and clinical data in the Comprehensive Epilepsy Center. Caregivers completed the PESQ. Demographic and medical data were extracted from medical chart reviews or via a questionnaire. The MCIDs, which are the standard errors of measurement for each scale, for the entire sample were as follows: Cognitive=4.66, Motor=4.67, Behavior=8.05, General Neurological=7.41, Weight=9.58, and Total Side Effects=3.25. Additionally, MCIDs for patients with new-onset (<12months) epilepsy on monotherapy, new-onset epilepsy on polytherapy, chronic epilepsy on monotherapy (>12months), and chronic epilepsy on polytherapy were calculated. Results from the present study extend the utility of the PESQ by providing clinicians and researchers an enhanced understanding about clinically meaningful changes in side effect profiles across the pediatric epilepsy spectrum. These data can inform clinical decision-making for clinicians and researchers. PMID- 25842204 TI - Cyclic lipopeptide iturin A structure-dependently induces defense response in Arabidopsis plants by activating SA and JA signaling pathways. AB - Iturin A is the most well studied antifungal cyclic lipopeptide produced by Bacillus species that are frequently utilized as biological control agents. Iturin A not only shows strong antifungal activity against phytopathogens but also induces defense response in plants, thereby reducing plant disease severity. Here we report the defense signaling pathways triggered by iturin A in Arabidopsis salicylic acid (SA) or jasmonic acid (JA)-insensitive mutants. Iturin A activated the transcription of defense genes PR1 and PDF1.2 through the SA and JA signaling pathways, respectively. The role of iturin A as an elicitor was dependent on the cyclization of the seven amino acids and/or the beta-hydroxy fatty acid chain. The iturin A derivative peptide, NH2-(L-Asn)-(D-Tyr)-(D-Asn)-(L Gln)-(L-Pro)-(D-Asn)-(L-Ser)-COOH, completely suppressed PR1 and PDF1.2 gene expression in wild Arabidopsis plants. The identification of target molecules binding to iturin A and its derivative peptide is expected to shed new light on defense response in plants through the SA and JA signaling pathways. PMID- 25842202 TI - Structural Plasticity of the Hippocampus and Amygdala Induced by Electroconvulsive Therapy in Major Depression. AB - BACKGROUND: Electroconvulsive therapy (ECT) elicits a rapid and robust clinical response in patients with refractory depression. Neuroimaging measurements of structural plasticity relating to and predictive of ECT response may point to the mechanisms underlying rapid antidepressant effects and establish biomarkers to inform other treatments. Here, we determine the effects of diagnosis and of ECT on global and local variations of hippocampal and amygdala structures in major depression and predictors of ECT-related clinical response. METHODS: Longitudinal changes in hippocampal and amygdala structures were examined in patients with major depression (N = 43, scanned three times: prior to ECT, after the second ECT session, and within 1 week of completing the ECT treatment series), referred for ECT as part of their standard clinical care. Cross-sectional comparisons with demographically similar controls (N = 32, scanned twice) established effects of diagnosis. RESULTS: Patients showed smaller hippocampal volumes than controls at baseline (p < .04). Both the hippocampal and the amygdala volumes increased with ECT (p < .001) and in relation to symptom improvement (p < .01). Hippocampal volume at baseline predicted subsequent clinical response (p < .05). Shape analysis revealed pronounced morphometric changes in the anterior hippocampus and basolateral and centromedial amygdala. All structural measurements remained stable across time in controls. CONCLUSIONS: ECT-induced neuroplasticity in the hippocampus and amygdala relates to improved clinical response and is pronounced in regions with prominent connections to ventromedial prefrontal cortex and other limbic structures. Smaller hippocampal volumes at baseline predict a more robust clinical response. Neurotrophic processes including neurogenesis shown in preclinical studies may underlie these structural changes. PMID- 25842205 TI - Aging accelerates memory extinction and impairs memory restoration in Drosophila. AB - Age-related memory impairment (AMI) is a phenomenon observed from invertebrates to human. Memory extinction is proposed to be an active inhibitory modification of memory, however, whether extinction is affected in aging animals remains to be elucidated. Employing a modified paradigm for studying memory extinction in fruit flies, we found that only the stable, but not the labile memory component was suppressed by extinction, thus effectively resulting in higher memory loss in aging flies. Strikingly, young flies were able to fully restore the stable memory component 3 h post extinction, while aging flies failed to do so. In conclusion, our findings reveal that both accelerated extinction and impaired restoration contribute to memory impairment in aging animals. PMID- 25842206 TI - Molecular characterization and hypoxia-induced upregulation of neuronal nitric oxide synthase in Atlantic croaker: Reversal by antioxidant and estrogen treatments. AB - Neuronal nitric oxide synthase (nNOS) catalyzes production of nitric oxide in vertebrate brains. Recent findings indicate that endothelial NOS and reactive oxygen species (ROS) are significantly increased during hypoxic stress and are modulated by antioxidants. However, the influence of antioxidants and steroids on nNOS upregulation by hypoxia is largely unknown. In this study, we characterized nNOS cDNA and examined the effects of hypoxia and antioxidant and steroid treatments on nNOS expression in Atlantic croaker hypothalamus. Hypoxia exposure (dissolved oxygen, DO: 1.7 mg/L for 2 and/or 4weeks) caused significant increases in hypothalamic nNOS mRNA, protein and its neuronal expression. Hypothalamic nNOS expression and superoxide radical (O2(.-), an index of ROS) production were increased by pharmacological treatment of fish exposed to normoxic conditions with N-ethylmaleimide, an alkene drug which covalently modifies sulfhydryl groups and inhibits aromatase activity. In contrast, treatments with Nomega-nitro-L arginine methyl ester, a competitive NOS-inhibitor, or vitamin E, an antioxidant, prevented the upregulation of O2(.-) production and nNOS expression in hypoxia exposed (DO: 1.7 mg/L for 4 weeks) fish. Moreover, treatment with 1,4,6 androstatrien-3,17-dione, an aromatase inhibitor, increased hypothalamic O2(.-) production and nNOS expression in normoxic control fish; whereas estradiol-17beta treatment significantly reduced O2(.-) production and nNOS expression in hypoxia exposed fish. Double-labeled immunohistochemical results showed that nNOS and aromatase proteins are co-expressed in the hypothalamus. Taken together, the results suggest that upregulation of nNOS and ROS in the croaker hypothalamus in response to hypoxia is influenced by antioxidant and overall estrogen status. PMID- 25842207 TI - A retrospective study of correlation of morphologic patterns, MIB1 proliferation index, and survival analysis in 134 cases of plasmacytoma. AB - Plasmacytoma classified into solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) is characterized by infiltrate of plasma cells of diverse maturity and by their monoclonal immunoglobulin products. Both SPB and EMP represent different groups of neoplasm in terms of location, tumor progression, and overall survival rate. There is a need for features that indicate likelihood of myeloma in patients with plasmacytoma without other manifestations. This study was an attempt to study the morphologic patterns of plasmacytoma (SPB and EMP), MIB1 proliferation index, and correlation of these with clinicopathologic features and survival of the patients. The study group comprised of 134 cases of plasmacytoma (88 SPB and 46 EMP) over duration of 8 years and were graded as per Bartl's histologic grading system. Commonest site was vertebral body in SPB (36%) and upper aerodigestive tract in EMP (48%). On serum electrophoresis, overall M band was detected in 41% cases. Both SPB and EMP on histology revealed similar morphologic features. MIB1 proliferation index ranged from less than 1% to 80%. It was slightly higher in EMP in comparison with SPB (P value = .002). Seventy percent of cases, which progressed to multiple myeloma (MM) showed MIB1 labeling index more than 10%; however, it was not statistically significant in predicting the disease progression. With the median follow-up of 19 months (range, 1-99 months), 10 SPB had disease progression of which 7 converted to MM, and 3 developed EMP, with a median interval of 21 months (range, 8-75 months) for the development of MM and 3 months (range, 3-9 months) for the progression to EMP. Five-year survival for EMP varied by site, with poorest survival in brain/central nervous system EMP as compared with EMP at other sites. To conclude, grade and MIB1 proliferation index help in predicting aggressive course in plasmacytoma. PMID- 25842208 TI - The 2011 West Nile disease outbreak in Sardinia region, Italy. AB - In 2011, strains of West Nile Virus (WNV) belonging to lineage 1 spread for the first time in Sardinia region (Italy). In contrast to previous WNV Italian incursion, the strains were found in Culex modestus and, more surprisingly, they were able to cause severe clinical signs in the affected birds. Based on the partial sequence of the NS3 encoding gene, the Sardinian WNV strains demonstrated a high similarity with the other WNV strains recently detected in the Mediterranean Basin. Nonetheless, the 2011 Sardinian sequences were grouped in a distinct sub-cluster. Both the NS3-249P and NS3-249T genotypes were detected in the Sardinian outbreaks confirming that the co-circulation of different genotypes in the affected population might be common for WNV as for many RNA viruses. No association, however, was observed between virulence and viral genotype. PMID- 25842209 TI - Orbivirus detection from Culicoides collected on African horse sickness outbreaks in Namibia. AB - African horse sickness (AHS), a non-contagious infectious disease caused by a RNA virus in the Orbivirus genus within the Reoviridae family affecting all equids, is endemic in sub-Saharan Africa. The virus is transmitted by some species of biting midges in the genus Culicoides (Diptera: Ceratopogonidae). In April 2011, 8 Culicoides collections were performed in 6 districts of 4 regions of the Republic of Namibia (Africa), all within a 400 km radious from the capital Windhoek. Six farms - Khomas (Windhoek and Steinhausen), Erongo (Karibib and Omaruru), Otjozondjupa (Okahandja), and Omaheke (Gobabis) involved in the AHS outbreaks, were sampled. Overall 194,211 Culicoides were collected and identified. Culicoides imicola was largely the most abundant species at all farms (99.4%). A total of 18,687 parous and gravid Culicoides females were assayed for AHS virus (AHSV) by real time RT-PCR. Of the 248 assayed pools, 227 consisted of C. imicola, 13 of Culicoides pycnostictus and 5 of Schultzei complex. Only 1 pool each of Culicoides nivosus, Culicoides leucostictus, and Culicoides tropicalis was assayed. Of the 248 pools examined by real time RT-PCR, 81 tested positive for AHSV, all consisting of C. imicola collected at Omaruru, resulting in a field vector infection rate of 0.91%. No viable AHSV could be isolated from 88 of the tested pools (n = 1,463). However, bluetongue virus (BTV) serotype-1 and 10 were isolated from 3 of these pools, each consisting of 100 C. imicola collected at Windhoek. The present study confirms the relative low infection prevalence in field collected Culicoides and the strict relationship between the high abundance of C. imicola and outbreaks of AHSV. PMID- 25842210 TI - A sero-survey of major infectious causes of abortion in small ruminants in Morocco. AB - A serological survey was conducted to estimate the seroprevalence of 5 major abortive infections in 13 sheep flocks and 10 goat herds in 2 regions of Morocco. A total of 308 from aborted females (202 ewes and 106 does) and 197 sera (97 ewes and 99 does), were tested for brucellosis, chlamydiosis, Q fever, toxoplasmosis, and for 9 major serovars of Leptospira. An average abortion rate of 12.10% was found in ewes and 10.26% in does. The serological analyses revealed the presence of all 5 abortive infections, both in sheep and in goats. Ten (43%) herds/flocks were positive to brucellosis, 21 (91%) to chlamydiosis, 17 (74%) to toxoplasmosis, 13 (57%) to Q fever, and 5 (22%) to leptospirosis. Leptospira spp. serovars Copenhageni and Grypothyphosa were found in a single sheep flock, while Tarassovi and Copenhageni were detected in 4 goat herds. Of the 23 investigated herds/flocks, 22 (96%) showed mixed infections. The findings of this study confirmed the possible involvement of the 5 selected abortive infections in abortion outbreaks occurring in the investigated regions. Further investigations are needed to better understand the aetiology of infectious abortions in herds and flocks within investigated regions. PMID- 25842211 TI - Phylogenetic analysis of the leader proteinase (Lpro) region of Indian foot and mouth disease serotype O isolates. AB - In this study, the nucleotide sequences of the complete leader proteinase (Lpro) region of 21 isolates of foot-and-mouth disease virus (FMDV) serotype O collected during various outbreaks in India were sequenced and compared with vaccine strains. The phylogenetic analysis of these Lpro sequences showed a difference in the clustering of the isolates based on the VP1 capsid coding region sequences. The comparison of amino acid sequences at the N terminus end of the Lpro region showed very high variability, although 2 conserved start codons (AUG) at 1st and 29th sites. Furthermore, all the amino acid residues that formed the active cleft site of the Lpro sequences of this study were conserved. These results suggest that Lpro sequences could also be used for phylogenetic comparison of FMDV isolates. PMID- 25842212 TI - Molecular characterization of canine parvovirus (CPV) infection in dogs in Turkey. AB - This study provides data about canine parvovirus (CPV) types circulating among dogs in Turkey. Sixty-five samples from dogs with and without clinical signs of parvovirus infection were collected between April 2009 and February 2010. The samples were subsequently tested for CPV using polymerase chain reaction (PCR). Twenty-five samples (38.4%) were positive; when positive samples were characterized by sequence analysis, results showed that both CPV-2a (17/25, 68%) and CPV-2b (8/25, 32%) strains are circulating among domestic dogs in Turkey. This is the first molecular characterization study of CPVs from dogs based on partial VP2 gene sequences in Turkey. PMID- 25842213 TI - The development of a four-way linking framework in Egypt: an example of the FAO, OIE and WHO joint activities to facilitate national risk assessment. AB - Cross-sectoral assessment of health risks arising or existing at the human-animal interface is crucial to identifying and implementing effective national disease control measures. This requires availability of information from 4 functional information 'streams' - epidemiological, laboratory, animal, and human health. The Food and Agriculture Organization of the United Nations (FAO)/ World Organisation for Animal Health (OIE)/ World Health Organization (WHO) Four-Way Linking (4WL) project promotes the establishing of a national-level joint framework for data sharing, risk assessment, and risk communication, in order to both improve communications within and among governmental public health and animal health influenza laboratories, epidemiology offices, national partners, with the aim of strengthening the national capacity to detect, report and assess risks arising from emerging influenza viruses. The project is currently being implemented in countries where H5N1 avian influenza is endemic and where human cases have been reported. The project is comprised of two main activities at country level: a 'review mission', which is the project launch in the country and has the objective to assess the existing situation; and a 'scenario based workshop', with the scope to bring together key national partners and build relationships among people working in the 4 information streams and to improve understanding of national strengths and gaps. During the workshop the delegates engaged in interactive sessions on basic risk assessment and devoted to specify the needs and roles of the 4 different streams. The participants work through a mock influenza outbreak scenario, which practically illustrates how risk assessment and communication of an emergency at the animal-human interface is more effective when there is linking of the 4 streams, collaboration, communication, and coordinated action. In 2010, Egypt was the first country where the project was successfully implemented, followed by Vietnam and Indonesia. PMID- 25842214 TI - Characterization of composting mixtures and compost of rabbit by-products to obtain a quality product and plant proposal for industrial production. AB - In this study we have observed the effects of using rabbit manure and slaughtering by-products in a composting process. Three piles of this material, 4700 kg each, with different amount and C/N ratio, have been investigated and experimental tests were carried out in an industrial horizontal axe reactor using a prototype of turning machine. The composting time lasted 85 days; 2 experimental cycles were conducted: one in Winter and one in Summer. In the Winter test, mesophilic reaction started only in the control mixture (animal manure + slaughtering by-products without straw). It is noteworthy that, the 3 investigated mixtures produced soil amendment by compost with good agronomical potential but with parameters close to the extreme limits of the law. In the Summer test, there was thermophilic fermentation in all mixtures and a better quality compost was obtained, meeting all the agronomic and legislative constraints. For each pile, we examined the progression of fermentation process and thus the plant limitations that did not allow a correct composting process. The results obtained in this study are useful for the development of appropriate mixtures, machines, and plants assuring continuance and reliability in the composting of the biomass coming from rabbit industry. PMID- 25842215 TI - Efficacy of nicarbazin (Ovistop(r)) in the containment and reduction of the populations of feral pigeons (Columba livia var. domestica) in the city of Genoa, Italy: a retrospective evaluation. AB - This study describes the results of a retrospective evaluation (8 years: 2005 2012) of the efficacy of the anti-fertility drug, Ovistop(r) nicarbazin (800 ppm) added to corn kernels used to feed non-migratory feral pigeon colonies, Columba livia var. domestica, in the city of Genoa, Italy. The observation interested 4 non-migratory feral pigeon colonies located into well-defined areas of the city of Genoa, Italy. Three of these colonies were treated for 12 months, with 10 g of drug (Ovistop(r)) provided per bird per day for 5 days each week; the other colony was treated in the same way but with a placebo (control station). Each colony and the relative area where the colony was located were both monitored with the same daily examination. Statistical analysis techniques were applied to the findings recorded - both descriptive (indices of central and dispersion trends) and comparative (one-way variance analysis). In the colonies treated with the drug, following an initial increase in the population ('magnet effect'), a reduction was observed over the following 4 years (-35% >x> -45%) and a further decrease (-65% >x> -70%) was observed over the subsequent 4 years (statistically significant one-way ANOVA p<0.01). This phenomenon was recorded across the board in the 3 treated stations, compared to the overall unstable trend observed for the control station. As no external or exceptional anthropic or natural factors were observed, it can be stated that, given the results observed, the drug seemed effective in reducing the treated bird populations. PMID- 25842216 TI - Molecular detection of Coxiella burnetii using an alternative loop-mediated isothermal amplification assay (LAMP). AB - Q fever, caused by Coxiella burnetii, is a worldwide zoonosis with important consequences for human and animal health. In livestock, the diagnosis, using direct and indirect techniques, is challenging even if to tackle coxiellosis in domesticated animals a rapid diagnosis is crucial. In the recent years, new molecular methods have been developed to overcome these issues. Several polymerase chain reaction (PCR) assays have been studied, but loop mediated isothermal amplification (LAMP) has not been fully developed. This new methodology is emerging due to simplicity and speed in diagnosis of microbial diseases. In this study, we design a new LAMP assay against C. burnetii targeting the com1 gene as an actual alternative to conventional PCR. The assay was specific to C. burnetii reactive with sensitivity comparable to standard PCR. The application of the com1 LAMP on 10 clinical samples from water buffalo, sheep, and goats, previously tested positive, confirmed the presence of C. burnetii. To our knowledge, this study is the first report of LAMP targeting C. burnetii in Europe and the results also suggest that it may be an useful and cost-effective tool for the clinical and epidemiological surveillance of Q Fever. PMID- 25842217 TI - Transcatheter closure of medium and large congenital coronary artery fistula using wire-maintaining technique. AB - BACKGROUND: For medium and large coronary artery fistula (CAF), the initially selected device sometimes has to be exchanged by reconstruction of track wire loop due to the complexity of CAF. OBJECTIVES: We sought to evaluate the feasibility and safety of transcatheter closure of medium and large CAF by using the wire-maintaining technique (WMT). METHODS: A total of 18 patients aged 15-56 years with congenital CAF underwent percutaneous transcatheter closure by WMT between April 2006 and October 2012. The immediate and long-term outcomes were evaluated. RESULTS: Of the 18 patients (11 females), 16 (88%) underwent successful transcatheter closure of fistula using WMT. The CAFs originated from the right coronary artery (67%), the left circumflex coronary artery (28%), and the left anterior descending coronary artery (5%). The drainage sites were the right ventricle (56%), right atrium (22%), left ventricle (11%), and coronary sinus (11%). The mean diameter of fistulas was 9.5+/-1.71mm and mean size of the devices was 13.6+/-3.03mm. An angiogram following device deployment showed complete occlusion in 11 patients, mild residual shunt in 2 patients, and trivial residual shunt in 3 patients. One patient had transient ST-T wave changes, and one patient had hemolysis after the procedure. Follow-up ranged from 1 month to 54 months (median 39 months). Echocardiogram showed trivial residual shunt in 3 patients at 6-month follow-up and in 1 patient at 12-month follow-up. Coronary artery thrombosis was observed in 1 patient by multislice computed tomography at 12-month follow-up. CONCLUSION: For those patients with medium and large complex fistula, transcatheter closure of CAF can be performed by using the wire maintaining technique. PMID- 25842218 TI - Opportunities and challenges in delivering influenza vaccine by microneedle patch. AB - INTRODUCTION: Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage. METHODS: To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self administration. RESULTS: All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming efficacy and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site. DISCUSSION AND CONCLUSIONS: Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for self-administration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace. PMID- 25842219 TI - M2e-immobilized gold nanoparticles as influenza A vaccine: Role of soluble M2e and longevity of protection. AB - Influenza virus causes seasonal epidemics and also poses a high risk for pandemics. To develop a broadly cross-protective influenza vaccine we have previously shown that a formulation consisting of the extracellular domain of M2 membrane protein (M2e) immobilized on gold nanoparticles (AuNPs) and soluble CpG as an adjuvant can elicit protective immunity against different influenza A subtypes. The vaccine formulation contains M2e that is immobilized on AuNPs, and an excess amount that is freely dissolved in solution, whose role in inducing protective immunity against virus infection is unclear. Using a mouse model, the current study shows that inclusion of excess soluble M2e antigen along with M2e immobilized on AuNPs is vital for inducing high levels of antibody response, and in providing complete protection against lethal influenza virus challenge. We also show that the vaccine induces long-lasting protection against mortality and morbidity upon lethal challenge with influenza A virus. PMID- 25842220 TI - Vagotomy reverses established allergen-induced airway hyperreactivity to methacholine in the mouse. AB - We evaluated the role of vagal reflexes in a mouse model of allergen-induced airway hyperreactivity. Mice were actively sensitized to ovalbumin then exposed to the allergen via inhalation. Prior to ovalbumin inhalation, mice also received intratracheally-instilled particulate matter in order to boost the allergic response. In control mice, methacholine (i.v.) caused a dose-dependent increase in respiratory tract resistance (RT) that only modestly decreased if the vagi were severed bilaterally just prior to the methacholine challenge. Sensitized and challenged mice, however, manifested an airway reactivity increase that was abolished by severing the vagi prior to methacholine challenge. In an innervated ex vivo mouse lung model, methacholine selectively evoked action potential discharge in a subset of distension-sensitive A-fibers. These data support the hypothesis that the major component of the increased airway reactivity in inflamed mice is due to a vagal reflex initiated by activation of afferent fibers, even in response to a direct (i.e., smooth muscle)-acting muscarinic agonist. PMID- 25842221 TI - Simplified antibiotic regimens compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with clinical signs of possible serious bacterial infection when referral is not possible: a randomised, open-label, equivalence trial. AB - BACKGROUND: WHO recommends hospital-based treatment for young infants aged 0-59 days with clinical signs of possible serious bacterial infection, but most families in resource-poor settings cannot accept referral. We aimed to assess whether use of simplified antibiotic regimens to treat young infants with clinical signs of severe infection was as efficacious as an injectable procaine benzylpenicillin-gentamicin combination for 7 days for situations in which hospital referral was not possible. METHODS: In a multisite open-label equivalence trial in DR Congo, Kenya, and Nigeria, community health workers visited all newborn babies at home, identifying and referring unwell young infants to a study nurse. We stratified young infants with clinical signs of severe infection whose parents did not accept referral to hospital by age (0-6 days and 7-59 days), and randomly assigned each individual within these strata to receive one of the four treatment regimens. Randomisation was stratified by age group of infants. An age-stratified randomisation scheme with block size of eight was computer-generated off-site at WHO. The outcome assessor was masked. We randomly allocated infants to receive injectable procaine benzylpenicillin gentamicin for 7 days (group A, reference group); injectable gentamicin and oral amoxicillin for 7 days (group B); injectable procaine benzylpenicillin-gentamicin for 2 days, then oral amoxicillin for 5 days (group C); or injectable gentamicin for 2 days and oral amoxicillin for 7 days (group D). Trained health professionals gave daily injections and the first dose of oral amoxicillin. Our primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event (including death), no improvement by day 4, or not cured by day 8. Independent outcome assessors, who did not know the infant's treatment regimen, assessed study outcomes on days 4, 8, 11, and 15. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044. FINDINGS: In Kenya and Nigeria, we started enrolment on April 4, 2011, and we enrolled the necessary number of young infants aged 7 days or older from Oct 17, 2011, to April 30, 2012. At these sites, we continued to enrol infants younger than 7 days until March 29, 2013. In DR Congo, we started enrolment on Sept 17, 2012, and continued until June 28, 2013. We randomly assigned 3564 young infants to either group A (n=894), group B (n=884), group C (n=896), or group D (n=890). We excluded 200 randomly assigned infants, who did not fulfil the predefined criteria of adherence to treatment and adequate follow up. In the per-protocol analysis, 828 infants were included in group A, 826 in group B, 862 in group C, and 848 in group D. 67 (8%) infants failed treatment in group A compared with 51 (6%) infants in group B (risk difference -1.9%, 95% CI 4.4 to 0.1), 65 (8%) in group C (-0.6%, -3.1 to 2.0), and 46 (5%) in group D ( 2.7%, -5.1 to 0.3). Treatment failure in groups B, C, and D was within the similarity margin compared with group A. During the 15 days after random allocation, 12 (1%) infants died in group A, compared with ten (1%) infants in group B, 20 (2%) infants in group C, and 11 (1%) infants in group D. An infant in group A had a serious adverse event other than death (injection abscess). INTERPRETATION: The three simplified regimens were as effective as injectable procaine benzylpenicillin-gentamicin for 7 days on an outpatient basis in young infants with clinical signs of severe infection, without signs of critical illness, and whose caregivers did not accept referral for hospital admission. FUNDING: Bill & Melinda Gates Foundation grant to WHO. PMID- 25842222 TI - Community management of neonatal infections. PMID- 25842223 TI - Oral amoxicillin compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with fast breathing when referral is not possible: a randomised, open-label, equivalence trial. AB - BACKGROUND: WHO recommends referral to hospital for possible serious bacterial infection in young infants aged 0-59 days. We aimed to assess whether oral amoxicillin treatment for fast breathing, in the absence of other signs, is as efficacious as the combination of injectable procaine benzylpenicillin gentamicin. METHODS: In a randomised, open-label, equivalence trial at five sites in DR Congo, Kenya, and Nigeria, community health workers followed up all births in the community, identified unwell young infants, and referred them to study nurses. We randomly assigned infants with fast breathing as a single sign of illness or possible serious bacterial infection, whose parents did not accept referral to hospital, to receive either injectable procaine benzylpenicillin gentamicin once per day or oral amoxicillin treatment twice per day for 7 days. A person who was off-site generated randomisation lists using computer software. Trained health professionals gave injections, but outcome assessors were masked to group allocations. The primary outcome was treatment failure by day 8 after enrolment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing on day 4, or recurrence up to day 8. The primary analysis was per protocol and we used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12610000286044. FINDINGS: From April 4, 2011, to March 29, 2013, we enrolled 2333 infants aged 0-59 days with fast breathing as the only sign of possible serious bacterial infection at the five study sites. We assigned 1170 infants to receive injectable procaine benzylpenicillin-gentamicin and 1163 infants to receive oral amoxicillin. In the per-protocol analysis, from which 137 infants were excluded, we included 1061 (91%) infants who fulfilled predefined criteria of adherence to treatment and adequate follow-up in the injectable procaine benzylpenicillin-gentamicin group and 1145 (98%) infants in the oral amoxicillin group. In the procaine benzylpenicillin-gentamicin group, 234 infants (22%) failed treatment, compared with 221 (19%) infants in the oral amoxicillin group (risk difference -2.6%, 95% CI -6.0 to 0.8). Four infants died within 15 days of follow-up in each group. We detected no drug-related serious adverse events. INTERPRETATION: Young infants with fast breathing alone can be effectively treated with oral amoxicillin on an outpatient basis when referral to a hospital is not possible. FUNDING: Bill & Melinda Gates Foundation grant to WHO. PMID- 25842226 TI - Editorial commentary revisited and the spin move refined. AB - First, editorial commentary: editorial commentary may be educational and may be controversial, but above all else, authors come first. Second, The Spin Move: The Spin Move is effective, cost-effective, and ubiquitous because, while many techniques are specific to a single joint, The Spin Move can be performed as a part of any arthroscopic and related procedure. However, like many advanced procedures, The Spin Move, when poorly executed, entails substantial risk. Preoperative planning is essential, and The Spin Move must be reviewed by inexperienced practitioners, in detailed text, figures tables, and video, at www.arthroscopytechniques.org. Practice makes perfect. PMID- 25842225 TI - Oral Debio1143 (AT406), an antagonist of inhibitor of apoptosis proteins, combined with daunorubicin and cytarabine in patients with poor-risk acute myeloid leukemia--results of a phase I dose-escalation study. AB - BACKGROUND: Treatment of acute myeloid leukemia (AML) remains difficult owing to the development of treatment resistance, which might be overcome through antagonists of inhibitors of apoptosis proteins (IAPs). PATIENTS AND METHODS: The present multicenter, open-label, dose-escalation study aimed to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Debio1143 (formerly AT-406), a new IAP antagonist, when given along with a standard "7 plus 3 regimen" of daunorubicin and cytarabine to poor-risk patients with AML during the induction cycle. Consecutive patient cohorts received once daily 100, 200, 300, or 400 mg of oral Debio1143 on treatment days 1 to 5. Blood samples were collected regularly until hematologic recovery or response was documented. Bone marrow samples were collected on days 0, 14, and 29 and PK and PD samples on days 1, 3, 5, 8, and 10 and 1, 2, and 8, respectively. RESULTS: Of the 29 enrolled patients, 23 completed the study. The most common adverse events of any grade deemed related to treatment were nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). Exposure exceeded dose proportionality, without accumulation over 5 days. Inhibition of cellular IAP1 was detectable in the CD34/CD117(+) cells and blasts. A total of 11 patients (38%) achieved complete remission, most in the 100-mg dose cohort. Of these, 6 (56%) developed a relapse within the study period. The patients with a response more frequently showed plasma increases of tumor necrosis factor-alpha and interleukin-8 after the first dose of Debio1143. CONCLUSION: Debio1143 <= 400 mg/d showed good tolerability in combination with daunorubicin and cytarabine. Additional studies in subsets of patients with AML are warranted. PMID- 25842227 TI - Authors' reply. PMID- 25842224 TI - Comparative investigation of the various determinants that influence the codon and amino acid usage patterns in the genus Bifidobacterium. AB - Various strains of the genus Bifidobacterium are crucial members of the human, animal and insect gut, associated with beneficial probiotic activities. An extensive analysis on codon and amino acid usage of the GC rich genus Bifidobacterium has been executed in the present study. Multivariate statistical analysis revealed a coupled effect of GC compositional constraint and natural selection for translational efficiency to be operative in producing the observed codon usage variations. Gene expression level was inferred to be the most crucial factor governing the codon usage patterns. Amino acid usage was found to be influenced significantly by hydrophobic and aromatic character of the encoded proteins. Gene expressivity and protein energetic cost also had considerable impact on the differential mode of amino acid usage. The genus was found to strictly obey the cost-minimization hypothesis as was reflected from the amino acid usage patterns of the potential highly expressed gene products. Evolutionary analysis revealed that the highly expressed genes were candidates to extreme evolutionary selection pressure and indicated a high degree of conservation at the proteomic level. Interestingly, the complimentary strands of replication appeared to evolve under similar evolutionary constraints which might be addressed as a consequence of absence of replicational selection and lack of strand-specific asymmetry among the members of the genus. Thus, the present endeavor confers considerable know-how pertaining to the codon and amino acid usage intricacies in Bifidobacterium and might prove handy for further scientific investigations associated with the concerned domain. PMID- 25842228 TI - Unspecific passive exercises in rotator cuff pathology: the need for comprehensive physical therapy. PMID- 25842229 TI - Platelet-rich plasma in arthroscopic rotator cuff repair. PMID- 25842230 TI - Authors' reply. PMID- 25842231 TI - Glenoid diameter is an inaccurate method for percent glenoid bone loss quantification: analysis and techniques for improved accuracy. AB - PURPOSE: To compare diameter-based glenoid bone loss quantification with a true geometric calculation for the area of a circular segment. METHODS: By use of Maxima 12.01.0 mathematics modeling software (Macysma, Boston, MA), the diameter based glenoid bone loss equation (% Bone loss = [Defect width (w)/Inferior glenoid circle diameter (D)] * 100%) was compared with a true geometric calculation for the area of a circular segment of the glenoid (Wolfram Research, Champaign, IL) rearranged in terms of w and D: Percent bone loss = (100/2pi) (2 * arccos [1 - 2 (w/D)] - sin {2 * arccos [1 - 2 (w/D)]}). Percent error was calculated by taking the difference between the diameter equation and the true geometric calculation at varying true glenoid defect widths (w) (0% to 50% of diameter). RESULTS: The commonly used diameter equation overestimated true glenoid bone loss at all values of w except at 0% and 50% of the diameter. The mean overestimation error was 3.9% +/- 1.9% (range, 0.0% to 5.8%), with the maximum error occurring when w was 20% of the diameter: At this value, w/D * 100% (diameter equation) predicts 20% bone loss when true bone loss is actually 14.2%. CONCLUSIONS: Diameter-based glenoid bone loss quantification overestimates true glenoid bone loss, with the maximum error occurring when theorized bone loss is 20%. To address situations for which a diameter-based bone loss quantification method must be performed or to improve the accuracy of surface-area calculations in previous diameter-based bone loss estimations, a corrective factor can be applied. Clinicians quantifying glenoid loss to make treatment decisions should be aware of the measurement methods used in the biomechanical studies on which they are basing their surgical decisions. CLINICAL RELEVANCE: Diameter-based glenoid bone loss quantification overestimates true glenoid bone loss, with the maximum error occurring when theorized bone loss is 20%, a commonly used threshold for bone grafting. PMID- 25842232 TI - ISAKOS knee committee: biologics in orthopaedics. PMID- 25842233 TI - Editorial commentary: healing requires scaffolds, growth factors, and cells. AB - Fracture biology healing requires scaffolds, growth factors, and cells. Biologics definitions are clarified in terms of osteoconductivity, osteoinductivity, and osteogenesis. PMID- 25842235 TI - Editorial commentary: autologous chondrocyte implantation versus microfracture. AB - Autologous chondrocyte implantation (ACI) shows greater durability, lower failure rates, and is effective for larger lesions, compared with microfracture. In addition, membrane-ACI (M-ACI) is technically simpler with fewer complications of cartilage hypertrophy than first-generation ACI using periosteum. However, second generation, M-ACI is not yet approved for general use in the United States. PMID- 25842234 TI - Editorial commentary: biologics of osteotomy of the proximal tibia. AB - Tri-calcium phosphate, calcium phosphate, hydroxyapatite/tri-calcium phosphate, or hydroxyapatite synthetic graft choices are associated with favorable outcomes for high tibial osteotomy, particularly in contrast to allograft. Smokers are at high risk of complications. PMID- 25842236 TI - Editorial commentary: osteoarticular transplant outcomes may deteriorate over time. AB - Osteoarticular (OA) transplant hyaline cartilage may deteriorate, and ultimately result in "fibrocartilage" at 2 years. Long-term OA transplant outcomes may be inferior to autologous chondrocyte transplantation, yet this conclusion is based on a single, prospective comparative study. The promise of an ideally conceived, tissue-engineered, OA transplantation graft remains distant. PMID- 25842237 TI - Editorial commentary: osteochondral allografts are an effective treatment for large osteochondral lesions. AB - Osteochondral (OC) allografts are an effective treatment for large OC lesions. OC allografts are hyaline. Allograft limitations and OC graft limitations are well known. Five year survivorship is similar to autologous chondrocyte implantation. PMID- 25842238 TI - Editorial commentary: scaffold-based cartilage treatments. AB - With or without cells, scaffold-based cartilage treatments show promising results. Clinical study focuses on autologous stem cells, but in vitro, basic science biologics research favors mesenchymal stem cells. MSCs vary by cell type and concentration, and may be expanded ex vivo. PMID- 25842239 TI - Editorial commentary: autologous platelet-rich plasma. AB - Autologous platelet-rich plasma (PRP) is promising for osteoarthritis pain and may effect cartilage repair. Platelets are growth factor factories. Commercially available PRP is heterogeneous. PMID- 25842240 TI - Editorial commentary: arthritis treatments for pain. AB - Arthritis treatment must be analyzed with regard to outcome. Pain is one important outcome measure. Pain relief is variable among individual patients; individually discerning, personalized, or precision medical indications for nonsurgical treatment of osteoarthritis must be more specifically determined. PMID- 25842241 TI - Highlighting clinical needs in Clostridium difficile infection: the views of European healthcare professionals at the front line. AB - BACKGROUND: Clostridium difficile infection (CDI) is the leading cause of infectious nosocomial diarrhoea in Europe. Despite increased focus, its incidence and severity are increasing in many European countries. AIM: We developed a series of consensus statements to identify unmet clinical needs in the recognition and management of CDI. METHODS: A consortium of European experts prepared a series of 29 statements representing their collective views on the diagnosis and management of CDI in Europe. The statements were grouped into the following six broad themes: diagnosis; definitions of severity; treatment failure, recurrence and its consequences; infection prevention and control interventions; education and antimicrobial stewardship; and National CDI clinical guidance and policy. These statements were reviewed using questionnaires by 1047 clinicians involved in managing CDI, who indicated their level of agreement with each statement. FINDINGS: Levels of agreement exceeded the 66% threshold for consensus for 27 out of 29 statements (93.1%), indicating strong support. Variance between countries and specialties was analysed and showed strong alignment with the overall consensus scores. CONCLUSION: Based on the consensus scores of the respondent group, recommendations are suggested for the further development of CDI services in order to reduce transmission and recurrence and to ensure that appropriate diagnosis and treatment strategies are applied across all healthcare settings. PMID- 25842243 TI - The nicotinic acetylcholine receptor: From molecular biology to cognition. PMID- 25842242 TI - Neurotensinergic augmentation of glutamate release at the perforant path-granule cell synapse in rat dentate gyrus: Roles of L-Type Ca2+ channels, calmodulin and myosin light-chain kinase. AB - Neurotensin (NT) serves as a neuromodulator in the brain where it is involved in modulating a variety of physiological functions including nociception, temperature, blood pressure and cognition, and many neurological diseases such as Alzheimer's disease, schizophrenia and Parkinson's disease. Whereas there is compelling evidence demonstrating that NT facilitates cognitive processes, the underlying cellular and molecular mechanisms have not been fully determined. Because the dentate gyrus expresses high densities of NT and NT receptors, we examined the effects of NT on the synaptic transmission at the synapse formed between the perforant path (PP) and granule cells (GC) in the rats. Our results demonstrate that NT persistently increased the amplitude of the AMPA receptor mediated EPSCs at the PP-GC synapse. NT-induced increases in AMPA EPSCs were mediated by presynaptic NTS1 receptors. NT reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that NT facilitates presynaptic glutamate release. NT increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle depletion. NT-mediated augmentation of glutamate release required the influx of Ca(2+) via L-type Ca(2+) channels and the functions of calmodulin and myosin light chain kinase. Our results provide a cellular and molecular mechanism to explain the roles of NT in the hippocampus. PMID- 25842244 TI - NH125 reduces the level of CPEB3, an RNA binding protein, to promote synaptic GluA2 expression. AB - Neuronal activity can alter the phosphorylation state of eukaryotic elongation factor 2 (eEF2) and thereby regulates protein synthesis. This is thought to be the underlying mechanism for a form of synaptic plasticity that involves changes in the expression of synaptic AMPA type glutamate receptors. Phosphorylation of eEF2 by Ca/calmodulin-dependent eEF2 kinase reduces the activity of eEF2, and this is prevented by a commonly used eEF2 kinase inhibitor, NH125. Here we show that 10 MUM NH125 increased the expression of synaptic GluA2-containing receptors in mouse cerebellar stellate cells and this was prevented by a protein synthesis inhibitor. However NH125 at 10 MUM also reduced the level of CPEB3, a protein that is known to bind to GluA2 mRNA and suppress GluA2 (also known as GluR2) synthesis. In contrast, a low concentration of NH125 lowered the peEF2 level, but did not alter CPEB3 expression and also failed to increase synaptic GluA2 receptors. A selective eEF2 kinase inhibitor, A-484954, decreased the level of peEF2, without changing the expression of CPEB3. This suggests that reducing peEF2 does not lead to a decrease in CPEB3 levels and is not sufficient to increase GluA2 synthesis. Thus NH125 at 10 MUM reduced the level of CPEB3, and promoted GluA2 translation via a mechanism independent of inhibition of eEF2 kinase. Therefore NH125 does not always alter protein synthesis via selective inhibition of eEF2 kinase and the effects of NH125 on translation of mRNAs should be interpreted with caution. PMID- 25842245 TI - Editorial. PMID- 25842246 TI - Neuropharmacology of light-induced locomotor activation. AB - Presentation of non-aversive light stimuli for several seconds was found to reliably induce locomotor activation and exploratory-like activity. Light-induced locomotor activity (LIA) can be considered a convenient simple model to study sensory-motor activation. LIA was previously shown to coincide with serotonergic and dopaminergic activation in specific cortical areas in freely moving and anesthetized animals. In the present study we explore the neuropharmacology of LIA using a receptor antagonist/agonist approach in rats. The non-selective 5-HT2 receptor antagonist ritanserin (1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. Selective antagonism of either the 5-HT2A-receptor by MDL 11,939 (0.1-0.4 mg/kg, i.p.), or the 5-HT2C-receptor by SDZ SER 082 (0.125-0.5 mg/kg, i.p.), alone or in combination, had no significant influence on LIA. Also the selective 5-HT1A receptor antagonist, WAY 100635 (0.4 mg/kg, i.p.) did not affect LIA. Neither did the preferential dopamine D2-receptor antagonist, haloperidol (0.025-0.1 mg/kg, i.p.) nor the D2/D3-receptor agonist, quinpirole (0.025-0.5 mg/kg, i.p.) affect the expression of LIA. However, blocking the glutamatergic NMDA-receptor with phencyclidine (PCP, 1.5-6 mg/kg, i.p.) dose-dependently reduced LIA. This effect was also observed with ketamine (10 mg/kg, i.p.). These findings suggest that serotonin and dopamine receptors abundantly expressed in the cortex do not mediate light-stimulus triggered locomotor activity. PCP and ketamine effects, however, suggest an important role of NMDA receptors in LIA. PMID- 25842247 TI - Effects of lorazepam and WAY-200070 in larval zebrafish light/dark choice test. AB - Zebrafish larvae spend more time in brightly illuminated area when placed in a light/dark testing environment. Here we report that the anxiolytic drugs lorazepam and diazepam increased the time larval fish spent in the dark compartment in the light/dark test. Lorazepam did not affect the visual induced optokinetic response of larval fish. Gene expression levels of c-fos and crh were significantly increased in the hypothalamus of fish larvae underwent light/dark choice behavior, whilst lorazepam treatment alleviated the increased c-fos and crh expressions. Furthermore, we found estrogen receptor beta gene expression level was increased in fish larvae underwent light/dark choice. We next examined effects of estrogen receptor modulators (estradiol, BPA, PHTPP, and WAY-200070) in the light/dark test. We identified WAY-200070, a highly selective ERbeta agonist significantly altered the light/dark choice behavior of zebrafish larvae. Further investigation showed WAY-200070 treatment caused a reduction of crh expression level in the hypothalamus, suggesting activation of ERbeta signaling attenuate the stress response. Interestingly, WAY-200070 treatment caused marked increase of c-fos expression in the habenula of fish larvae underwent behavior test. These results suggest WAY-200070 activation of ERbeta mediated signaling may regulate anxiety related behavior in zebrafish through modulation of neuronal activity in habenula. PMID- 25842248 TI - Mild to Moderate Hip OA: Joint Preservation or Total Hip Arthroplasty? AB - Treatment of structural hip disease such as FAI and acetabular dysplasia has increased dramatically over the past decade with the goal of preservation of the native hip joint. A number of patient and disease specific parameters including the amount of underlying hip osteoarthrosis can help predict success with joint preservation surgery. Total hip arthroplasty remains a very good option in young patients who are not ideal candidates for joint preservation surgery. Future developments will help to better identify ideal surgical candidates and improve understanding of the disease processes. PMID- 25842249 TI - Acetabular component navigation in lateral decubitus based on EOS imaging: A preliminary study of 13 cases. AB - INTRODUCTION: Acetabular component navigation classically requires palpation of the bone landmarks defining the anterior pelvic plane (APP) (anterior superior iliac spine [ASIS] and pubis), the recording of which is not very reliable when performed in lateral decubitus. The objectives of the current experimental study were: (1) to assess the clinical feasibility of NAVEOS navigation (based on EOS imaging) in lateral decubitus; and (2) to compare precision versus classical APP based navigation (NAVAPP). HYPOTHESIS: Iliac plane navigation using EOS is as reliable as APP navigation. PATIENTS AND METHODS: A continuous prospective series of 13 total hip replacements were implanted in lateral decubitus under APP-guided navigation (NAVAPP). Planning used preoperative EOS measurement. The ASIS, pubis and ipsilateral posterior superior iliac spine (PSIS) were located and exported to the navigator. Intra-operatively, NAVEOS landmarks (acetabular center, ASIS and PSIS on the operated side) were palpated. Postoperatively, cup inclination and anteversion with respect to the APP were measured on EOS imaging (SterEOS3D software). The SterEOS3D measurements were compared to those of the performed NAVAPP and simulated NAVEOS navigations. RESULTS: Three patients were excluded for technical reasons. In the remaining 10, inclination on NAVAPP and SterEOS3D differed by a median 4 degrees (range, 0-12 degrees ), and on NAVEOS versus SteEOS3D by 5 degrees (range, 2-10 degrees ); anteversion on NAVAPP and SterEOS3D differed by a median 4.5 degrees (range, 0-12 degrees ), and on NAVEOS versus SteEOS3D by 4 degrees (range, 0-14 degrees ). CONCLUSION: Precision was comparable between NAVEOS and classical navigation. NAVEOS simplifies cup navigation in lateral decubitus on initial acquisition. These results require validation on a larger sample. PMID- 25842250 TI - Body weight-associated differences in ovarian morphology in captive common marmoset (Callithrix jacchus). AB - In captivity, Callithrix jacchus (common marmoset) is on average heavier than their wild-living counterparts, and has a tendency to produce triplet litters rather than the normal twins. To provide initial basic information about possible weight-related differences among the ovaries, a morphometric study of follicular phase ovaries from 48 young adult marmosets has been carried out. Nearly 90% of these ovaries were found to contain some degree of luteal tissue composed of large and/or small cells. The luteal structures, follicles of all stages, and stroma were subjected to morphometric analysis, and these results were compared with body weight, circulating triglyceride, androstenedione, and total estrogens. Where only large luteal cells were present, the median body weight was the highest (only this group included animals over 500 g) compared with mixed, or only small luteal cells, or absence of luteal cells. Furthermore, in this group plasma triglycerides were significantly higher compared to other groups, suggesting possible role of triglycerides in promoting luteinisation. Plasma androstenedione was also a critical discriminating factor, and was elevated where large luteal cells were present even as a mixture with small cells suggesting the large luteal cells to be the likely major ovarian source of this hormone and its metabolites. Additionally, the ovaries with large luteal cells compared to those containing only small or no luteal cells, had lower primordial follicle reserve associated with high levels of atresia and luteinisation among growing non ovulatory follicles, indicating an accelerated activation, but at the same time a suboptimal environment for follicular growth. PMID- 25842251 TI - Spermatozoon ultrastructure and semen parameters of Brycon vermelha (Characiformes, Characidae). AB - This study analyzed semen parameters and the ultrastructure of spermatozoa of Brycon vermelha. The semen was white and viscous, with a mean volume of 5.0+/-2.6 mL/kg body weight and mean spermatozoon concentration of 4.3+/-0.8*10(10) spermatozoa/mL. The estimated motility rate was 90%, with 50% of spermatozoa motile at 35.0+/-0.1 s and 100% immotile by 46.5+/-0.1 s. The spermatozoon of B. vermelha had a distinct head, midpiece, and flagellum. The ovoid head measured 1.9+/-0.2 MUm by 1.3+/-0.1 MUm, with its volume almost completely occupied by the nucleus, and was enveloped by an irregular nuclear membrane, with no acrosome vesicle. The nuclear fossa held the centriole complex and the initial segment of flagellum. The midpiece was symmetrical and measured 1.3+/-0.3MUm. Mitochondria were scarce and restricted to the anterior region, while vesicles were absent. The posterior region of the midpiece was characterized by the absence of mitochondria and the presence of the cytoplasmic sheath. The flagellum, enclosed by the flagellar membrane, measured 29.6+/-3.4 MUm, and possessed an axial filament containing a 9+2 microtubule pattern. The spermatozoa of B. vermelha appeared similar in structure to those of fish that breed through external fertilization, thus classifying them as uniflagellate anacrosomal aquasperm, or Type 1 aquasperm. PMID- 25842253 TI - Oculopharyngeal muscular dystrophy: Clinical and neurophysiological features. PMID- 25842252 TI - The short-run causal effect of tumor detection and treatment on psychosocial well being, work, and income. AB - This paper estimates the short-run causal effect of tumor detection and treatment on psychosocial well-being, work and income. Tumor detection can be considered as a random event, so that we can compare individuals' average outcomes in the year of diagnosis with the year before. We argue for using panel data estimation techniques that enable us to control for observed and unobserved information intrinsic to the individual and time constants. We use data of a national representative panel in the Netherlands that includes health survey information and data on work, education, and income between 2007 and 2012. Our findings show differences in the psychosocial dysfunction of men and women in response to tumor detection and treatment. Women, not men, are decreasingly likely to participate in the labor force as a result of malignant tumor detection, while no significant effects are found on her personal or household income. We also demonstrate that fixed effects panel data models are superior to matching techniques. PMID- 25842254 TI - Epigenetics of T cells regulated by Polycomb/Trithorax molecules. AB - Epigenetics provides a bridge between genetic and environmental factors, and can change the transcriptional outcome of a gene without changing the genomic sequence. Allergies and autoimmune diseases are caused by both of these factors, and dynamic changes in epigenetic marks have been reported in T cells, which are key players in the pathogenesis of immune-mediated diseases. Advances in technology, including gene knockout systems and high-throughput sequencing, have significantly enhanced the understanding of the lifespan of T cells, including maturation, differentiation and memory formation. In this review, we focus on Polycomb and Trithorax proteins, well-characterized epigenetic modulators, and discuss their role in the epigenetic regulation of T cell differentiation and function. PMID- 25842255 TI - Detection and Pathologic Evaluation of Sentinel Lymph Nodes in the VX2 Tumor Model Using a Novel Ultrasound/Near-Infrared Dual-Modality Contrast Agent. AB - This study was conducted with the aim of developing a microbubble agent for near infrared (NIR) fluorescence and ultrasound dual-modality contrast microbubbles applicable to imaging of sentinel lymph nodes in the VX2 rabbit tumor model. Specific ligands of phosphatidylserine (PS) and Cy7 NIR fluorescent dyes with long emission wavelengths (750-900 nm) were conjugated to the surface of ultrasound contrast microbubbles (MBs), termed Cy7 PS MBs. Ultrasound lymphography and NIR fluorescence imaging were performed using subcutaneous injection of Cy7 PS MBs to visualize the sentinel lymph node. Sentinel lymph node detection rates using the patent blue method, ultrasound lymphography and NIR fluorescence imaging were 95%, 79% and 95%, respectively, and sensitivity was 87%, 74% and 92%, respectively. With 2-D ultrasound, the diagnostic sensitivity for detection of sentinel lymph node metastases was 60% and the specificity was 74%, whereas Cy7 PS MB-enhanced ultrasound had a sensitivity of 80% and a specificity of 87%. The results indicate that dual-modality Cy7 PS MBs combined with ultrasound lymphography and NIR fluorescence may be useful in the detection of normal and metastasized sentinel lymph nodes. PMID- 25842256 TI - A Simple Technique for Visualizing Ultrasound Fields Without Schlieren Optics. AB - A simple technique designed for visualization of ultrasound fields without Schlieren optics is introduced. An optical system of direct shadowgraphy with diverging light, which consists of a point light source and a shadow screen, constituted the basic system, but the screen was replaced by focusing optics: a camera that makes a virtual screen at its focus plane. The proposed technique visualizes displacement of light deflected by ultrasound, and the use of focusing optics enables flexible settings of the virtual screen position and optical magnification. Insufficient sensitivity of shadowgraphy was overcome by elimination of non-deflecting light using image subtraction of shadowgrams taken with and without ultrasound exposure. A 1-MHz focused transducer for ultrasound therapy and a 20-MHz miniature transducer for intravascular imaging were used for experiments, and alternate pressure change in short-pulsed ultrasound was visualized, indicating the usefulness of the proposed technique for evaluation of medical ultrasound fields. PMID- 25842257 TI - Reliability and Limits of Agreement of the Supraspinatus Muscle Anatomical Cross Sectional Area Assessment by Ultrasonography. AB - The purpose of this study was to evaluate the reliability and limits of agreement for assessment of the anatomical cross-sectional area (ACSA) of the supraspinatus muscle using B-mode ultrasonography. Sixteen participants were examined with two different protocols, on two different days. There were no statistically significant differences (p > 0.05) in ACSA values between days 1 and 2 or between protocols 1 and 2; the average intra-class correlation coefficient ranged from 0.93 to 0.96. The limits of agreement for supraspinatus ACSA were, in both protocols, about +/- 1 cm(2). Our findings revealed that both protocols had high reliability in distinguishing differences of about 1 cm(2) between groups or after interventions and that ultrasonography can be used for experimental designs in which the expected changes in ACSA would be higher than 14%. PMID- 25842258 TI - Alcohol use across the lifespan: An analysis of adolescent and aged rodents and humans. AB - Adolescence and old age are unique periods of the lifespan characterized by differential sensitivity to the effects of alcohol. Adolescents and the elderly appear to be more vulnerable to many of alcohol's physiological and behavioral effects compared to adults. The current review explores the differential effects of acute alcohol, predominantly in terms of motor function and cognition, in adolescent and aged humans and rodents. Adolescents are less sensitive to the sedative-hypnotic, anxiolytic, and motor-impairing effects of acute alcohol, but research results are less consistent as it relates to alcohol's effects on cognition. Specifically, previous research has shown adolescents to be more, less, and similarly sensitive to alcohol-induced cognitive deficits compared to adults. These equivocal findings suggest that learning acquisition may be differentially affected by ethanol compared to memory, or that ethanol-induced cognitive deficits are task-dependent. Older rodents appear to be particularly vulnerable to the motor- and cognitive-impairing effects of acute alcohol relative to younger adults. Given that alcohol consumption and abuse is prevalent throughout the lifespan, it is important to recognize age-related differences in response to acute and long-term alcohol. Unfortunately, diagnostic measures and treatment options for alcohol dependence are rarely dedicated to adolescent and aging populations. As discussed, although much scientific advancement has been made regarding the differential effects of alcohol between adolescents and adults, research with the aged is underrepresented. Future researchers should be aware that adolescents and the aged are uniquely affected by alcohol and should continue to investigate alcohol's effects at different stages of maturation. PMID- 25842259 TI - The relationship between liver function and liver parenchymal contrast enhancement on Gd-BOPTA-enhanced MR imaging in the hepatocyte phase. AB - OBJECTIVES: To investigate the relationships between liver function parameters and the degree of hepatic contrast enhancement on gadobenate dimeglumine (Gd BOPTA)-enhanced magnetic resonance (MR) imaging in the hepatocyte phase, as well as to clarify whether Gd-BOPTA-enhanced MR imaging in the hepatocyte phase could be used to evaluate liver function and liver function reserve. MATERIALS AND METHODS: In this study, 150 patients were classified into the following 4 groups: patients with normal liver function without liver cirrhosis (the NLF group) and cirrhosis patients with Child-Pugh Classes A, B, and C (the LCA, LCB, and LCC groups, respectively). The relative enhancement ratio (RE) of the liver parenchyma in the T1-vibe sequence was calculated from measurements of the signal intensity before (SI pre) and 90min after (SI post) the intravenous administration of Gd-BOPTA, using the following formula: RE=(SI post-SI pre)/SI pre. Statistical analysis was used to evaluate the relationship between the REs of the liver parenchyma and liver function parameters, as well as the different REs of the liver parenchyma among the NLF, LCA, LCB, and LCC groups. RESULTS: Increased REs of the hepatic parenchyma showed correlations with decreased serum levels of total bilirubin (r=-0.263, P<0.01) and prothrombin time (r=-0.24, P<0.01), and elevated serum levels of albumin (r=0.328, P<0.01) for all of the patients. The REs of the liver parenchyma were significantly higher for the NLF and LCA groups compared with the LCB (P<0.001) and LCC (P<0.001) groups, respectively. CONCLUSIONS: The intracellular uptake of Gd-BOPTA decreased with impaired liver function. Measurement of the degree of the liver parenchymal contrast enhancement on GD-BOPTA-enhanced MR imaging in the hepatocyte phase might be a non-invasive technique for assessing liver function and liver function reserve. PMID- 25842260 TI - The medical treatment of patients with Parkinson's disease receiving subthalamic neurostimulation. AB - INTRODUCTION: Deep brain stimulation of subthalamic nucleus (STN-DBS) for Parkinson's disease allows for a reduction in medication dosage. Changes in total levodopa equivalent daily dose (LEDD) have been frequently reported, there is little information about changes within the drug classes. METHODS: We retrospectively assessed the changes in antiparkinsonian drugs dosages in 150 patients from one center who had preoperative and postoperative evaluations at 6 months and 3 years. Two long term subgroups with postoperative follow-up till the 5th-6th year (n = 58) and 10th year (n = 15) were included. RESULTS: The major modifications in medication dosage occurred during the initial postoperative period. LEDD was reduced by 53.4% compared to baseline at 6 months and 47.9% at 3 years. Fifty six percent and 41.3% of the patients were on monotherapy, 9.3% on no medication at 6 months and 6.7% at 3 years post surgery. Patients on levodopa, or dopamine agonists showed similar reductions. At the 3rd year the oldest group of patients showed a significant decrease in dopamine agonists. The number of patients treated with amantadine was significantly reduced; however the number of patients treated with antidepressants was significantly increased over the first 3 years. Annual medication costs per patient were decreased after the DBS-STN implantation by 61.3% at 6 months and 55.4% at 3 years. CONCLUSION: STN-DBS allows for a reduction in the dosage of medication and the costs are similarly reduced. In this cohort different medication groups were reduced to a similar extent. Patients' demographic factors did not play a major role in the selection of treatment. PMID- 25842261 TI - Varying time-course of effects of high frequency stimulation of sub-regions of the globus pallidus in patients with parkinson's disease. AB - INTRODUCTION: Deep brain stimulation of the globus pallidus can be a highly effective treatment for patients with Parkinson's disease (PD), experiencing Levodopa-induced-dyskinesia (LID). Stimulation programming can focus simply on eliminating dyskinesia, or can also attempt to relieve the rigidity, tremor or akinesia of PD itself. METHODS: In this study, we explored whether additional benefit on the "off" symptoms and signs of PD, could be achieved in post operative PD patients with good LID control, by making further adjustment to existing stimulation parameters directed towards the more superior electrode contacts, located in the Globus Pallidus pars externa (GPe). RESULTS: Acutely, GPe-DBS led to clear improvement in the akinesia, rigidity and tremor of PD in the off-medication state compared with Globus Pallidus pars interna (GPi) DBS (p = 0.003), however this was accompanied by the development of off-medication dyskinesia. Combined GPi-GPe DBS allowed maintained improvement but without dyskinesia. Follow up of patients over the subsequent 6-12 weeks showed gradual loss of this initial improvement. Switching back to GPi-DBS alone provided greater improvement in off medication symptoms than had been observed using the same GPi-DBS setting, 6-12 weeks previously. CONCLUSIONS: Benefits on the off medication symptoms of PD obtained acutely with GPe-DBS are in general not sustained. Similarly, the effects of GPi-DBS on the off medication symptoms of PD, can evolve over short periods of time presumably as a result of changes in network-wide neuronal plasticity. These clinical observations provide further insight into DBS mechanism of action, and can also help inform optimal methods of GPi-DBS programming. PMID- 25842262 TI - Cardiac memory: The slippery slope twixt normalcy and pathology. AB - "Cardiac memory" is an altered repolarization phenotype resulting from prior cardiac rate, rhythm, and/or activation changes. The various types of memory depend on biophysical properties of cardiac ion channels, trafficking of those channels, and/or epigenetic changes in the genes determining the channels. The processes that engage the memory function presage changes in function that ultimately can lead to pathological remodeling. Hence--rather than completely benign--memory may be a warning of disease to come. This article considers the forms, the mechanisms, and the clinical expression of cardiac memory. PMID- 25842263 TI - Notch1 ligand signaling pathway activated in cervical cancer: poor prognosis with high-level JAG1/Notch1. AB - OBJECTIVE: Notch signalings are regulated multiple cellular processes during cancer progression. We aimed to investigate the significance and prognostic value of expression of Notch1 and JAG1 in cervical cancer to determine whether they could serve as prognostic predictors. METHODS/MATERIALS: The expression of Notch1/JAGD1 was investigated by real-time PCR, western blot assay and its association with overall survival of patients was analyzed by statistical analysis. RESULTS: Notch1 and JAGD1 expression level were significantly elevated in cervical cancer in comparison to normal specimens and other types of Notch receptors and ligands. It is also proved that Notch1 and JAGD1 expression were to be associated with cervical cancer invasion, lymph node metastasis, and FIGO system. In addition, survival analysis proved that elevated Notch1 and JAGD1 expression were associated with poor overall survival of patients (P = 0.01, P = 0.02 log-rank test), respectively. CONCLUSIONS: The present data proved the over expression of Notch1/JAGD1 and its association with tumor progression in human cervical cancer, which might be a potential valuable biomarker for cervical cancer and further studies need. PMID- 25842264 TI - Regulation of gene expression mediating indeterminate muscle growth in teleosts. AB - Teleosts are unique among vertebrates due to their indeterminate muscle growth, i.e., continued production of neonatal muscle fibers until death. However, the molecular mechanism(s) underlying this property is unknown. Here, we focused on the torafugu (Takifugu rubripes) myosin heavy chain gene, MYHM2528-1, which is specifically expressed in neonatal muscle fibers produced by indeterminate muscle growth. We examined the flanking region of MYHM2528-1 through an in vivo reporter assay using zebrafish (Danio rerio) and identified a 2100 bp 5'-flanking sequence that contained sufficient promoter activity to allow specific gene expression. The effects of enhanced promoter activity were observed at the outer region of the fast muscle and the dorsal edge of slow muscle in zebrafish larvae. At the juvenile stage, the promoter was specifically activated in small diameter muscle fibers scattered throughout fast muscle and in slow muscle near the septum separating slow and fast muscles. This spatio-temporal promoter activity overlapped with known myogenic zones involved in teleost indeterminate muscle growth. A deletion mutant analysis revealed that the -2100 to -600 bp 5'flanking sequence of MYHM2528-1 is essential for promoter activity. This region contains putative binding sites for several representative myogenesis-related transcription factors and nuclear factor of activated T-cell (NFAT), a transcription activator involved in regeneration of mammalian adult skeletal muscle. A significant reduction in the promoter activity of the MYHM2528-1 deletion constructs was observed in accordance with a reduction in the number of these binding sites, suggesting the involvement of specific transcription factors in indeterminate muscle growth. PMID- 25842265 TI - Authors' response: Understanding variation in disease risk. PMID- 25842266 TI - Commentary: Frailty and cancer. PMID- 25842267 TI - Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats. AB - Functional recovery after peripheral nerve injury and surgical repair declines with time and distance because the injured neurons without target contacts (chronic axotomy) progressively lose their regenerative capacity and chronically denervated Schwann cells (SCs) atrophy and fail to support axon regeneration. Findings that brief low frequency electrical stimulation (ES) accelerates axon outgrowth and muscle reinnervation after immediate nerve surgery in rats and human patients suggest that ES might improve regeneration after delayed nerve repair. To test this hypothesis, common peroneal (CP) neurons were chronically axotomized and/or tibial (TIB) SCs and ankle extensor muscles were chronically denervated by transection and ligation in rats. The CP and TIB nerves were cross sutured after three months and subjected to either sham or one hour 20Hz ES. Using retrograde tracing, we found that ES significantly increased the numbers of both motor and sensory neurons that regenerated their axons after a three month period of chronic CP axotomy and/or chronic TIB SC denervation. Muscle and motor unit forces recorded to determine the numbers of neurons that reinnervated gastrocnemius muscle demonstrated that ES significantly increased the numbers of motoneurons that reinnervated chronically denervated muscles. We conclude that electrical stimulation of chronically axotomized motor and sensory neurons is effective in accelerating axon outgrowth into chronically denervated nerve stumps and improving target reinnervation after delayed nerve repair. Possible mechanisms for the efficacy of ES in promoting axon regeneration and target reinnervation after delayed nerve repair include the upregulation of neurotrophic factors. PMID- 25842268 TI - Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal-prefrontal coherence. AB - Deep brain stimulation (DBS) of the subgenual cingulate gyrus (SCG) has been used to treat patients with treatment-resistant depression. As in humans, DBS applied to the ventromedial prefrontal cortex of rats induces antidepressant-like responses. Physiological interactions between structures that play a role in depression and antidepressant treatment are still unknown. The present study examined the effect of DBS on inter-region communication by measuring the coherence of local field potentials in the rat infralimbic cortex (IL; homologue of the SCG) and one of its major afferents, the ventral hippocampus (VH). Rats received daily IL DBS treatment (100 MUA, 90 MUs, 130 Hz; 8h/day). Recordings were conducted in unrestrained, behaving animals on the day before treatment, after 1 and 10 days of treatment, and 10 days stimulation offset. VH-IL coherence in the 2-4 Hz range was reduced in DBS-treated animals compared with shams after 10 days, but not after only 1 day of treatment. No effect of DBS was observed in the 6-10 Hz (theta) range, where coherence was generally high and could be further evoked with a loud auditory stimulus. Finally, coherence was not affected by fluoxetine (10mg/kg), suggesting that the effects of DBS were not likely mediated by increased serotonin levels. While these data support the hypothesis that DBS disrupts communication between regions important for expectation-based control of emotion, they also suggest that lasting physiological effects require many days of treatment and, furthermore, may be specific to lower-frequency patterns, the nature and scope of which await further investigation. PMID- 25842269 TI - Artificial milk-feeding women's views of their feeding choice in Ireland. AB - OBJECTIVE: despite the well-documented benefits of breast feeding to both mother and child, breast-feeding initiation rates in Ireland are the second lowest in Europe. This study set out to explore the views of women from low socio-economic groups in Ireland on their choice to feed their infants artificial milk, and to elicit factors that may encourage these women to breast feed in the future. DESIGN: a qualitative descriptive approach was used. METHODS: data were collected through recorded focus groups and individual interviews, using a semi-structured interview schedule. Data were transcribed verbatim. SETTING: interviews took place in two regions in the Republic of Ireland, north and south. PARTICIPANTS: a purposive sample was drawn from the population of 2572 women taking part in the Irish Infant Feeding Study who had never breast fed previously, had intended to, and had, fed this infant artificial milk and who had completed their education before they were 18 years of age. Two focus groups with two women in each were conducted and six women took part in individual interviews. ANALYSIS: constant comparative analysis was performed to construct the categories and concepts that led to the final themes. FINDINGS: these artificial milk-feeding women based their infant feeding decision on many social and experiential factors. The major influences on their decisions were: personal attitudes toward feeding methods, and external influences on infant feeding methods. Attitudes towards other women and feeding future infants reinforced a strong preference towards artificial milk feeding. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: it is apparent that a prevailing culture that is unreceptive to breast feeding and the lack of positive breast-feeding role models, contributed to a strong commitment to artificial milk feeding for these participants. Promotion of breast feeding must take account of the complex contexts in which women make decisions. Advice regarding breast feeding should take account of women's feelings and avoid undue pressure, while still promoting the benefits of breast feeding to women and their families. PMID- 25842270 TI - Which insights have we gained from the kindling and post-status epilepticus models? AB - Experimental animal epilepsy research got a big boost since the discovery that daily mild and short (seconds) tetanic stimulations in selected brain regions led to seizures with increasing duration and severity. This model that was developed by Goddard (1967) became known as the kindling model for epileptogenesis and has become a widely used model for temporal lobe epilepsy with complex partial seizures. During the late ninety-eighties the number of publications related to electrical kindling reached its maximum. However, since the kindling procedure is rather labor intensive and animals only develop spontaneous seizures (epilepsy) after hundreds of stimulations, research has shifted toward models in which the animals exhibit spontaneous seizures after a relatively short latent period. This led to post-status epilepticus (SE) models in which animals experience SE after injection of pharmacological compounds (e.g. kainate or pilocarpine) or via electrical stimulation of (limbic) brain regions. These post-SE models are the most widely used models in epilepsy research today. However, not all aspects of mesial temporal lobe epilepsy (MTLE) are reproduced and the widespread brain damage is often a caricature of the situation in the patient. Therefore, there is a need for models that can better replicate the disease. Kindling, although already a classic model, can still offer valid clues in this context. In this paper, we review different aspects of the kindling model with emphasis on experiments in the rat. Next, we review characteristic properties of the post-SE models and compare the neuropathological, electrophysiological and molecular differences between kindling and post-SE epilepsy models. Finally, we shortly discuss the advantages and disadvantages of these models. PMID- 25842271 TI - Remote monitoring improves outcome after ICD implantation: the clinical efficacy in the management of heart failure (EFFECT) study. AB - AIMS: Internet-based remote interrogation systems have been shown to reduce emergency department and in-office visits in patients with implantable cardioverter defibrillators (ICDs), resulting in increased efficiency for healthcare providers. Nonetheless, studies sized to demonstrate the impact of remote monitoring on patients' outcome have been lacking. METHODS AND RESULTS: The EFFECT study was a multicentre clinical trial aimed at measuring and comparing the outcome of ICD patients conventionally followed-up by means of in clinic visits (Standard arm) or by remote monitoring (Remote arm) in the clinical practice of 25 Italian centres. From 2011 to 2013, 987 consecutive patients were enrolled and followed up for at least 12 months. The primary endpoint was the rate of death and cardiovascular hospitalizations. Remote monitoring was adopted by 499 patients. Patients in the Standard and Remote arms did not differ significantly in terms of baseline clinical characteristics, except for a more frequent use of ICD with cardiac resynchronization therapy (CRT-D) in the Remote arm (48 vs. 36%, P < 0.001). One-year rates of the primary combined endpoint were 0.27 events/year for patients in the Standard arm and were 0.15 events/year for those in the Remote arm (incident rate ratio, 0.55; 95% CI, 0.41-0.73; P < 0.001). The endpoint rates in the Standard and Remote arms were 0.27 and 0.08 events/year, respectively, among CRT-D recipients (P < 0.001), and 0.28 vs. 0.21 among ICD patients (P = 0.094). The rates of in-office visits were 1.9 per year in the Standard arm and 1.7 per year in the Remote arm. CONCLUSION: Compared with the standard follow-up through in-office visits, remote monitoring is associated with reduced death and cardiovascular hospitalizations in patients with ICD in clinical practice. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ Identifier: NCT01723865. PMID- 25842272 TI - Three-dimensional atrial wall thickness maps to inform catheter ablation procedures for atrial fibrillation. AB - AIMS: Transmural lesion formation is critical to success in atrial fibrillation ablation and is dependent on left atrial wall thickness (LAWT). Pre- and peri procedural planning may benefit from LAWT measurements. METHODS AND RESULTS: To calculate the LAWT, the Laplace equation was solved over a finite element mesh of the left atrium derived from the segmented computed tomographic angiography (CTA) dataset. Local LAWT was then calculated from the length of field lines derived from the Laplace solution that spanned the wall from the endocardium or epicardium. The method was validated on an atrium phantom and retrospectively applied to 10 patients who underwent routine coronary CTA for standard clinical indications at our institute. The Laplace wall thickness algorithm was validated on the left atrium phantom. Wall thickness measurements had errors of <0.2 mm for thicknesses of 0.5-5.0 mm that are attributed to image resolution and segmentation artefacts. Left atrial wall thickness measurements were performed on 10 patients. Successful comprehensive LAWT maps were generated in all patients from the coronary CTA images. Mean LAWT measurements ranged from 0.6 to 1.0 mm and showed significant inter and intra patient variability. CONCLUSIONS: Left atrial wall thickness can be measured robustly and efficiently across the whole left atrium using a solution of the Laplace equation over a finite element mesh of the left atrium. Further studies are indicated to determine whether the integration of LAWT maps into pre-existing 3D anatomical mapping systems may provide important anatomical information for guiding radiofrequency ablation. PMID- 25842273 TI - Incessant ventricular tachycardia and concomitant recurrent left ventricular thrombus: to ablate or not to ablate? PMID- 25842274 TI - The risk of atrial fibrillation in the general male population: a lifetime follow up of 50-year-old men. AB - AIM: This study aimed to estimate the prevalence, incidence rate, and lifetime risk of developing atrial fibrillation (AF) in a population-based study of Swedish men. METHODS AND RESULTS: The study is a part of 'The Study of Men Born in 1913', which is a longitudinal prospective cohort study of 855 men born in 1913 and living in the city of Gothenburg in Sweden. They were followed from the age of 50 years until 98 years with repeated examinations and data from the Swedish National Hospital Discharge Register. A total of 185 (21.6%) men developed AF. The prevalence of AF increased from 0.4% at 50 years old, to 1.9% by 60 years old, to 4.6% by 70 years old, to 12.5% by 80 years old, and to 15.7% by 90 years old. The lifetime risk of developing AF was 22.5%. CONCLUSION: Atrial fibrillation is rare at the age of 50 in Swedish men, but it increases exponentially with age, markedly accelerating after 70 years old. In nonagenarians, one of five men has or has had AF. PMID- 25842275 TI - Inappropriate shocks by subcutaneous defibrillator in a patient with arrhythmogenic right ventricular cardiomyopathy: problem fixed. PMID- 25842276 TI - Novel SCN10A variants associated with Brugada syndrome. AB - AIMS: The expression of sodium channel Nav1.8 in cardiac nervous systems has been identified, and variants of SCN10A that encodes Nav1.8 contribute to the development of Brugada syndrome (BrS) by modifying the function of Nav1.5 or directly reducing the sodium current. The aim of this study was to identify the frequency of SCN10A mutations in Japanese patients with BrS and to compare the phenotypical differences between patients with BrS and those who have other BrS causative genes. METHODS AND RESULTS: This study involved 240 Japanese probands who were clinically suspected with BrS and were negative for mutations in major BrS-related genes. We screened for the SCN10A gene using a high-resolution melting method and direct sequencing. In addition, we compared the clinical characteristics among the probands with gene mutations in SCN10A, 6 probands with CACNA1C and 17 probands with SCN5A. We identified six SCN10A variant carriers (2.5%): W189R, R844H (in two unrelated probands), N1328K, R1380Q, and R1863Q. Five were male. Four were symptomatic: one died following sudden cardiopulmonary arrest at age 35, one suffered ventricular fibrillation, and two had recurrent syncope. Compared with BrS patients carrying SCN5A or CACNA1C mutations, although there were no significant differences among them, symptomatic patients in the SCN10A group tended to be older than those in the other gene groups. CONCLUSION: In six BrS probands who carried SCN10A variants, most experienced severe arrhythmic attacks. It is of clinical importance to screen SCN10A mutations in BrS, although the functional significance of these variants remains unclear. PMID- 25842277 TI - First We Have to Engage Them: A Mixed Methods Assessment of Low-Income Parents' Preferences for and Barriers to Receiving Child Health Promotion Information. AB - INTRODUCTION: The aim of this study is to understand low-income parents' preferences for and barriers to receiving child health promotion information. METHODS: A mixed-methods approach was used. Data were collected in an urban pediatric primary care setting serving predominantly low-income African American families. Parents (n = 190) of 3- to 8-year-old children completed a survey; a randomly selected subset participated in focus groups. RESULTS: The quantitative and qualitative samples differed with regard to whether they would like to get parenting information from their doctors. The most commonly cited obstacles to attending parenting classes were time (50.6%), work schedule (40.6%), transportation (37.7%), and own health (22.4%). DISCUSSION: New and creative methods are needed to promote child health and development that do not increase the burden associated with raising children in the context of limited resources. PMID- 25842278 TI - Implementation and Evaluation of a Unit-Based Discharge Coordinator to Improve the Patient Discharge Experience. AB - Hospitals are currently focusing on quality measure initiatives such as patient safety, satisfaction scores, and patient length of stay. Inefficient and ineffective discharge planning is often directly associated with long hospital stays and poor patient satisfaction with the overall discharge process. The purpose of this quality improvement initiative is to describe and address the implementation and evaluation of a unit-based discharge coordinator role on a general medicine pediatric unit at a tertiary care children's hospital. Improved outcomes, including an increase in patient satisfaction with the discharge process, decreased length of stay, and a decrease in patient safety net reports are demonstrated through implementation. A unit-based discharge coordinator can play an important part in enhancing the overall discharge experience for the patient and families by providing an effective and efficient approach to discharge, providing the patients and families with a feeling of preparedness. PMID- 25842279 TI - Trends in Major Lower Limb Amputation Related to Peripheral Arterial Disease in Hungary: A Nationwide Study (2004-2012). AB - OBJECTIVES: To assess the trends of peripheral arterial disease associated major lower limb amputation in Hungary over a 9 year period (2004-2012) in the whole Hungarian population. METHODS: This was a retrospective cohort study employing administrative health care data. Major amputations were identified in the entire Hungarian population during a 9 year period (2004-2012) using the health care administrative data. Direct standardization was used to eliminate the potential bias induced by the different age and sex structure of the compared populations. For external direct standardization, the ESP 2013 was chosen as reference. RESULTS: 76,798 lower limb amputations were performed. The number of major amputations was 38,200; these procedures affected 32,084 patients. According to case detection, 50.4% of the amputees were diabetic. The overall primary amputation rate was 71.5%. The annual crude and age adjusted major amputation rates exhibited no significant long-term pattern over the observation period. The major lower limb amputation incidence for the overall period was 42.3/10(5) in the total population and 317.9/10(5) in diabetic population. CONCLUSION: According to this whole population based study from Hungary, the incidence of lower limb major amputation is high with no change over the past 9 years. An explanation for this remains to be determined, as the traditional risk factors in Hungary do not account for it. The characteristics of major amputation (the rate of primary amputation, the ratio of below to above knee amputation and the age of the affected population) underline the importance of screening, early detection, improved vascular care and an optimal revascularization policy. Standardization and validation of amputation detection methods and reporting is essential. PMID- 25842280 TI - Editor's perspectives - April 2015. PMID- 25842281 TI - The long way to positive trials for mechanical thrombectomy in acute ischemic stroke. PMID- 25842282 TI - Patient engagement with a mobile web-based telemonitoring system for heart failure self-management: a pilot study. AB - BACKGROUND: Intensive remote monitoring programs for congestive heart failure have been successful in reducing costly readmissions, but may not be appropriate for all patients. There is an opportunity to leverage the increasing accessibility of mobile technologies and consumer-facing digital devices to empower patients in monitoring their own health outside of the hospital setting. The iGetBetter system, a secure Web- and telephone-based heart failure remote monitoring program, which leverages mobile technology and portable digital devices, offers a creative solution at lower cost. OBJECTIVE: The objective of this pilot study was to evaluate the feasibility of using the iGetBetter system for disease self-management in patients with heart failure. METHODS: This was a single-arm prospective study in which 21 ambulatory, adult heart failure patients used the intervention for heart failure self-management over a 90-day study period. Patients were instructed to take their weight, blood pressure, and heart rate measurements each morning using a WS-30 bluetooth weight scale, a self inflating blood pressure cuff (Withings LLC, Issy les Moulineaux, France), and an iPad Mini tablet computer (Apple Inc, Cupertino, CA, USA) equipped with cellular Internet connectivity to view their measurements on the Internet. Outcomes assessed included usability and satisfaction, engagement with the intervention, hospital resource utilization, and heart failure-related quality of life. Descriptive statistics were used to summarize data, and matched controls identified from the electronic medical record were used as comparison for evaluating hospitalizations. RESULTS: There were 20 participants (mean age 53 years) that completed the study. Almost all participants (19/20, 95%) reported feeling more connected to their health care team and more confident in performing care plan activities, and 18/20 (90%) felt better prepared to start discussions about their health with their doctor. Although heart failure-related quality of life improved from baseline, it was not statistically significant (P=.55). Over half of the participants had greater than 80% (72/90 days) weekly and overall engagement with the program, and 15% (3/20) used the interactive voice response telephone system exclusively for managing their care plan. Hospital utilization did not differ in the intervention group compared to the control group (planned hospitalizations P=.23, and unplanned hospitalizations P=.99). Intervention participants recorded shorter average length of hospital stay, but no significant differences were observed between intervention and control groups (P=.30). CONCLUSIONS: This pilot study demonstrated the feasibility of a low-intensive remote monitoring program leveraging commonly used mobile and portable consumer devices in augmenting care for a fairly young population of ambulatory patients with heart failure. Further prospective studies with a larger sample size and within more diverse patient populations is necessary to determine the effect of mobile-based remote monitoring programs such as the iGetBetter system on clinical outcomes in heart failure. PMID- 25842283 TI - Impact of prescription drug-monitoring program on controlled substance prescribing in the ED. AB - OBJECTIVE: In 2009, Florida initiated a statewide prescription drug-monitoring program (PDMP) to encourage safer prescribing of controlled substances and reduce drug abuse and diversion. Data supporting the utility of such programs in the emergency department (ED) is scarce. This study sought to determine the effect of PDMP data on controlled substance prescribing from the ED. METHODS: In this pre post study utilizing a historical control, pharmacists in the ED provided prescribers with a summary of the PDMP data for their patients. The number of controlled substances prescribed in the intervention group was compared with that prescribed in the historical control to determine if the intervention resulted in a change in the average number of controlled substance prescribed. RESULTS: Among the 710 patients evaluated, providing prescribers with PDMP data did not alter the average number of controlled substance per patient prescribed (0.23 controlled substances per patient in the historical control compared with 0.28 controlled substances per patient in the intervention group; 95% confidence interval [CI], -0.016 to 0.116; P = .125). All prescribers surveyed indicated that having PDMP data altered their controlled substance prescribing and felt more comfortable prescribing controlled substances. CONCLUSIONS: Although the results did not demonstrate a change in the average number of controlled substances prescribed when prescribers were provided with PDMP data, results from the survey indicate that prescribers felt the data altered their prescribing of controlled substances, and thus were more contented prescribing controlled substances. PMID- 25842284 TI - Evolution of the electrocardiogram QRS complexes voltage in scorpion envenomation induced Takotsubo syndrome. PMID- 25842285 TI - Accidental pediatric ingestions of medical marijuana: a 4-year poison center experience. PMID- 25842286 TI - Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma. PMID- 25842289 TI - Inter-subject neural code converter for visual image representation. AB - Brain activity patterns differ from person to person, even for an identical stimulus. In functional brain mapping studies, it is important to align brain activity patterns between subjects for group statistical analyses. While anatomical templates are widely used for inter-subject alignment in functional magnetic resonance imaging (fMRI) studies, they are not sufficient to identify the mapping between voxel-level functional responses representing specific mental contents. Recent work has suggested that statistical learning methods could be used to transform individual brain activity patterns into a common space while preserving representational contents. Here, we propose a flexible method for functional alignment, "neural code converter," which converts one subject's brain activity pattern into another's representing the same content. The neural code converter was designed to learn statistical relationships between fMRI activity patterns of paired subjects obtained while they saw an identical series of stimuli. It predicts the signal intensity of individual voxels of one subject from a pattern of multiple voxels of the other subject. To test this method, we used fMRI activity patterns measured while subjects observed visual images consisting of random and structured patches. We show that fMRI activity patterns for visual images not used for training the converter could be predicted from those of another subject where brain activity was recorded for the same stimuli. This confirms that visual images can be accurately reconstructed from the predicted activity patterns alone. Furthermore, we show that a classifier trained only on predicted fMRI activity patterns could accurately classify measured fMRI activity patterns. These results demonstrate that the neural code converter can translate neural codes between subjects while preserving contents related to visual images. While this method is useful for functional alignment and decoding, it may also provide a basis for brain-to-brain communication using the converted pattern for designing brain stimulation. PMID- 25842287 TI - Aberrant ORM (yeast)-like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice. AB - BACKGROUND: Asthma, a chronic inflammatory condition defined by episodic shortness of breath with expiratory wheezing and cough, is a serious health concern affecting more than 250 million persons. Genome-wide association studies have identified ORM (yeast)-like protein isoform 3 (ORMDL3) as a gene associated with susceptibility to asthma. Although its yeast ortholog is a negative regulator of de novo ceramide biosynthesis, how ORMDL3 contributes to asthma pathogenesis is not known. OBJECTIVES: We sought to decipher the molecular mechanism for the pathologic functions of ORMDL3 in asthma and the relationship to its evolutionarily conserved role in regulation of ceramide homeostasis. METHODS: We determined the relationship between expression of ORMDL3 and ceramide in epithelial and inflammatory cells and in asthma pathogenesis in mice. RESULTS: Although small increases in ORMDL3 expression decrease ceramide levels, remarkably, higher expression in lung epithelial cells and macrophages in vitro and in vivo increased ceramide production, which promoted chronic inflammation, airway hyperresponsiveness, and mucus production during house dust mite-induced allergic asthma. Moreover, nasal administration of the immunosuppressant drug FTY720/fingolimod reduced ORMDL3 expression and ceramide levels and mitigated airway inflammation and hyperreactivity and mucus hypersecretion in house dust mite-challenged mice. CONCLUSIONS: Our findings demonstrate that overexpression of ORMDL3 regulates ceramide homeostasis in cells in a complex manner and suggest that local FTY720 administration might be a useful therapeutic intervention for the control of allergic asthma. PMID- 25842290 TI - Combined MEG and EEG show reliable patterns of electromagnetic brain activity during natural viewing. AB - Naturalistic stimuli such as movies are increasingly used to engage cognitive and emotional processes during fMRI of brain hemodynamic activity. However, movies have been little utilized during magnetoencephalography (MEG) and EEG that directly measure population-level neuronal activity at a millisecond resolution. Here, subjects watched a 17-min segment from the movie Crash (Lionsgate Films, 2004) twice during simultaneous MEG/EEG recordings. Physiological noise components, including ocular and cardiac artifacts, were removed using the DRIFTER algorithm. Dynamic estimates of cortical activity were calculated using MRI-informed minimum-norm estimation. To improve the signal-to-noise ratio (SNR), principal component analyses (PCA) were employed to extract the prevailing temporal characteristics within each anatomical parcel of the Freesurfer Desikan Killiany cortical atlas. A variety of alternative inter-subject correlation (ISC) approaches were then utilized to investigate the reliability of inter-subject synchronization during natural viewing. In the first analysis, the ISCs of the time series of each anatomical region over the full time period across all subject pairs were calculated and averaged. In the second analysis, dynamic ISC (dISC) analysis, the correlation was calculated over a sliding window of 200 ms with 3.3 ms steps. Finally, in a between-run ISC analysis, the between-run correlation was calculated over the dynamic ISCs of the two different runs after the Fisher z-transformation. Overall, the most reliable activations occurred in occipital/inferior temporal visual and superior temporal auditory cortices as well as in the posterior cingulate, precuneus, pre- and post-central gyri, and right inferior and middle frontal gyri. Significant between-run ISCs were observed in superior temporal auditory cortices and inferior temporal visual cortices. Taken together, our results show that movies can be utilized as naturalistic stimuli in MEG/EEG similarly as in fMRI studies. PMID- 25842291 TI - Age differences in the brain mechanisms of good taste. AB - There is strong evidence demonstrating age-related differences in the acceptability of foods and beverages. To examine the neural foundations underlying these age-related differences in the acceptability of different flavors and foods, we performed an fMRI study to investigate brain and hedonic responses to orange juice, orange soda, and vegetable juice in three different age groups: Young (22), Middle (40) and Elderly (60 years). Orange juice and orange soda were found to be liked by all age groups, while vegetable juice was disliked by the Young, but liked by the Elderly. In the insular primary taste cortex, the activations to these stimuli were similar in the 3 age groups, indicating that the differences in liking for these stimuli between the 3 groups were not represented in this first stage of cortical taste processing. In the agranular insula (anterior to the insular primary taste cortex) where flavor is represented, the activations to the stimuli were similar in the Elderly, but in the Young the activations were larger to the vegetable juice than to the orange drinks; and the activations here were correlated with the unpleasantness of the stimuli. In the anterior midcingulate cortex, investigated as a site where the activations were correlated with the unpleasantness of the stimuli, there was again a greater activation to the vegetable than to the orange stimuli in the Young but not in the Elderly. In the amygdala (and orbitofrontal cortex), investigated as sites where the activations were correlated with the pleasantness of the stimuli, there was a smaller activation to the vegetable than to the orange stimuli in the Young but not in the Elderly. The Middle group was intermediate with respect to the separation of their activations to the stimuli in the brain areas that represent the pleasantness or unpleasantness of flavors. Thus age differences in the activations to different flavors can in some brain areas be related to, and probably cause, the differences in pleasantness of foods as they differ for people of different ages. This novel work provides a foundation for understanding the underlying neural bases for differences in food acceptability between age groups. PMID- 25842292 TI - Mental imagery of emotions: Electrophysiological evidence. AB - Affective stimuli such as emotional words, scenes or facial expressions elicit well-investigated emotional responses. For instance, two distinct event-related brain potentials (ERPs) have been reported in response to emotional facial expressions, the early posterior negativity (EPN), associated with enhanced attention and perception of affective stimuli, and a later centro-parietal positivity (LPP) that is taken to reflect evaluations of the intrinsic relevance of emotional stimuli. However, other rich sources of emotions that have as yet received little attention are internal mental events such as thoughts, memories and imagination. Here we investigated mental imagery of emotional facial expressions and its time course using ERPs. Participants viewed neutral familiar and unfamiliar faces, and were subsequently asked to imagine the faces with an emotional or neutral expression. Imagery was compared to visually perceiving the same faces with the different expressions. Early ERP modulations during imagery resemble the effects frequently reported for perceived emotional facial expressions, suggesting that common early processes are associated with emotion perception and imagination. A later posterior positivity was also found in the imagery condition, but with a different distribution than for perception. These findings underscore the similarity of the brain's responses to internally generated and external sources of emotions. PMID- 25842288 TI - PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity. AB - BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE expressing thymic epithelial cells. CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects. PMID- 25842293 TI - Modulation of prefrontal functioning in attention systems by NPSR1 gene variation. AB - Evidence has accumulated for a dysfunction of arousal and executive attention in anxiety. The neuropeptide S (NPS) system has been shown to play a pivotal role in the mediation of arousal and to be associated with anxiety/panic disorder. The present study aims at investigating the impact of functional neuropeptide S receptor (NPSR1) gene variation on neural attention patterns applying an imaging genetics approach. In an event-related functional magnetic resonance imaging (fMRI) setting, 47 healthy subjects (f=23) evenly pre-stratified for NPSR1 rs324981 A/T genotype were investigated for brain activation patterns while performing the Attention Network Task (ANT), simultaneously probing alerting and executive control functions. Anxiety sensitivity was ascertained by the Anxiety Sensitivity Index (ASI). In the alerting condition, NPSR1 TT homozygotes showed higher activations in the right prefrontal cortex and the locus coeruleus region as compared to A allele carriers. In the executive control condition, TT homozygotes displayed increased activations in fronto-parietal regions. Genotype driven activation differences in the prefrontal cortex correlated with anxiety sensitivity, in both the alerting and the executive control system. The present results for the first time suggest NPSR1 gene variation to be associated with alterations of prefrontal functioning in the attentional functions alerting and executive control partly modulated by anxiety sensitivity. These findings may aid in unraveling the neurobiological underpinnings of distorted arousal and attention in anxiety and thereby possibly in the biomarker-guided development of preventive/therapeutic strategies targeting attention processes in anxiety disorders. PMID- 25842295 TI - Isolating weather effects from seasonal activity patterns of a temperate North American Colubrid. AB - Forecasting the effects of climate change on threatened ecosystems and species will require an understanding of how weather influences processes that drive population dynamics. We have evaluated weather effects on activity patterns of western ratsnakes, a widespread predator of birds and small mammals in eastern North America. From 2010-2013 we radio-tracked 53 ratsnakes in the fragmented region of central Missouri. We relocated each snake 4* per week and used movement frequency as an index of activity. We used generalized linear mixed models within an information-theoretic approach to evaluate temporal and weather variables as potential predictors of snake activity. While snakes were generally sedentary, activity showed a linear response to relative humidity and a quadratic response to air temperature, peaking near 30 degrees C. Seasonal activity patterns differed between sexes and among years, but snakes were generally least active in mid-summer, regardless of weather. Our findings provide strong evidence that air temperature and relative humidity differentially affect activity patterns of an important predator and are the mechanism explaining increased nest predation rates with warmer temperatures. PMID- 25842294 TI - Human posterior parietal cortex mediates hand-specific planning. AB - The processes underlying action planning are fundamental to adaptive behavior and can be influenced by recent motor experience. Here, we used a novel fMRI Repetition Suppression (RS) design to test the hypotheses that action planning unfolds more efficiently for successive actions made with the same hand. More efficient processing was predicted to correspond with both faster response times (RTs) to initiate actions and reduced fMRI activity levels - RS. Consistent with these predictions, we detected faster RTs for actions made with the same hand and accompanying fMRI-RS within bilateral posterior parietal cortex and right lateralized parietal operculum. Within posterior parietal cortex, these RS effects were localized to intraparietal and superior parietal cortices. These same areas were more strongly activated for actions involving the contralateral hand. The findings provide compelling new evidence for the specification of action plans in hand-specific terms, and indicate that these processes are sensitive to recent motor history. Consistent with computational efficiency accounts of motor history effects, the findings are interpreted as evidence for comparatively more efficient processing underlying action planning when successive actions involve the same versus opposite hand. PMID- 25842296 TI - Cacti supply limited nutrients to a desert rodent community. AB - In the Sonoran Desert, cacti represent a potentially important source of nutrients and water for consumers. Columnar cacti, in particular, produce a large pulse of flowers and succulent fruit during hot summer months. The importance of cactus stems, flowers and fruit to the small mammal community has not been quantified. We exploited natural variation in the carbon isotope (delta(13)C) values of cacti (CAM) versus C3 plants to quantify the relative use of these resources by a diverse desert small mammal community. We also estimated trophic level by measuring nitrogen isotope (delta(15)N) values. We hypothesized that (H1) granivorous heteromyids (kangaroo rats, pocket mice) would exploit the summer pulse of seeds and pulp; (H2) folivorous and omnivorous cactus mice, wood rats, and ground squirrels would exploit cacti stems year-round and seeds when available; and (H3) kangaroo rats and pocket mice would shift from seeds to insects during hot dry months. We found that heteromyids made minimal use of seeds during the period of heavy seed rain. Of the cricetids, only the folivore Neotoma albigula made continuous but highly variable use of cacti resources (annual mean = 32%, range 0-81%), whereas the omnivore Peromyscus eremicus ignored cacti except during the summer, when it exploited seeds and/or fruit pulp (June-July mean = 39%, range 20-64%). We also found little evidence for a shift to greater consumption of insects by heteromyids during the hot dry months. Overall, use of cactus resources by the small mammal community is very limited and highly variable among species. PMID- 25842297 TI - Bark ecology of twigs vs. main stems: functional traits across eighty-five species of angiosperms. AB - Although produced by meristems that are continuous along the stem length, marked differences in bark morphology and in microenvironment would suggest that main stem and twig bark might differ ecologically. Here, we examined: (1) how closely associated main stem and twig bark traits were, (2) how these associations varied across sites, and (3) used these associations to infer functional and ecological differences between twig and main stem bark. We measured density, water content, photosynthesis presence/absence, total, outer, inner, and relative thicknesses of main stem and twig bark from 85 species of angiosperms from six sites of contrasting precipitation, temperature, and fire regimes. Density and water content did not differ between main stems and twigs across species and sites. Species with thicker twig bark had disproportionately thicker main stem bark in most sites, but the slope and degree of association varied. Disproportionately thicker main stem bark for a given twig bark thickness in most fire-prone sites suggested stem protection near the ground. The savanna had the opposite trend, suggesting that selection also favors twig protection in these fire-prone habitats. A weak main stem-twig bark thickness association was observed in non fire-prone sites. The near-ubiquity of photosynthesis in twigs highlighted its likely ecological importance; variation in this activity was predicted by outer bark thickness in main stems. It seems that the ecology of twig bark can be generalized to main stem bark, but not for functions depending on the amount of bark, such as protection, storage, or photosynthesis. PMID- 25842298 TI - Chemopreventive effects of aspirin at a glance. AB - Experimental, epidemiological, and clinical data from the last two decades have each supported the hypothesis that aspirin possesses anticancer properties, and that its use may also reduce the lifetime probability of developing or dying from a number of cancers. Aspirin's ability to act on multiple key metabolic and signaling pathways via inhibition of the cyclooxygenase (COX) enzyme, as well as through COX-independent mechanisms, makes it particularly relevant in the fight against cancer. A growing body of evidence indicates that aspirin may not only reduce cancer risk, but also prevent metastasis and angiogenesis while slowing the rate of mutation-inducing DNA damage. These emerging benefits of aspirin are offset to some extent by the known risks of treatment, such as cardiovascular events and gastrointestinal bleeding. However, it has been shown that pre treatment risk assessment of individual patients and the use of proton pump inhibitors or Helicobacter pylori eradication therapy concomitantly with aspirin treatment can reduce these potential risks. Thus, the significant benefits of aspirin treatment, coupled with recent data concerning its risks, may prove to tip the balance in favor of aspirin use in cancer prevention. PMID- 25842299 TI - Integrated fixed-biofilm activated sludge reactor as a powerful tool to enrich anammox biofilm and granular sludge. AB - A pilot-scale activated sludge bioreactor was filled with immobile carrier to treat high ammonium wastewater. Autotrophic nitrogen elimination occurred rapidly by inoculating nitrifying activated sludge and anammox biofilm. As the ammonium loading rate increased, nitrogen removal rate of 1.2kgNm(-3)d(-1) was obtained with the removal efficiency of 80%. Activated sludge diameter distribution profiles presented two peak values, indicating simultaneous existence of flocculent and granular sludge. Red granular sludge was observed in the reactor. Furthermore, the results of morphological and molecular analysis showed that the characteristics of granular sludge were similar to that of biofilm, while much different from the flocculent sludge. It was assumed granular sludge was formed through the continuous growth and detachment of anammox biofilm. The mechanism of granular sludge formation was discussed and the procedure model was proposed. According to the experimental results, the integrated fixed-biofilm activated sludge reactor provided an alternative to nitrogen removal based on anammox. PMID- 25842300 TI - Acrylamide in potato crisps prepared from 20 UK-grown varieties: effects of variety and tuber storage time. AB - Twenty varieties of field-grown potato were stored for 2 months and 6 months at 8 degrees C. Mean acrylamide contents in crisps prepared from all varieties at both storage times ranged from 131 MUg/kg in Verdi to 5360 MUg/kg in Pentland Dell. In contrast to previous studies, the longer storage period did not affect acrylamide formation significantly for most varieties, the exceptions being Innovator, where acrylamide formation increased, and Saturna, where it decreased. Four of the five varieties designated as suitable for crisping produced crisps with acrylamide levels below the European Commission indicative value of 1000 MUg/kg (Saturna, Lady Rosetta, Lady Claire, and Verdi); the exception was Hermes. Two varieties more often used for French fries, Markies and Fontane, also produced crisps with less than 1000 MUg/kg acrylamide. Correlations between acrylamide, its precursors and crisp colour are described, and the implications of the results for production of potato crisps are discussed. PMID- 25842301 TI - Selenium in commercial beer and losses in the brewing process from wheat to beer. AB - There is increasing interest in enhancing the micronutrient composition of cereals through fertilization. The aims of this study were (1) to determine the Se concentration of commercial beers retailing in the UK, and (2) to test if the transfer of Se, from biofortified grain to final beer product, is <10% under UK cultivation conditions, as seen previously under Mediterranean conditions. The Se concentration of 128 commercial beers was measured, using inductively coupled plasma-mass spectrometry (ICP-MS). The selenium content of commercial beers varied 6.5-fold, with beers originating from America having higher Se concentrations than those from Europe. Laboratory-scale brewing trials with isotopically-enriched (77)Se wheat, sampled from UK field-sites, showed that most (77)Se losses in the brewing process occurred during mashing (54%), with fermented beer containing ~ 10% of the (77)Se initially present in the wheat grain. Total N values in wort and malt were positively correlated with the (77)Se content of the wheat grain. PMID- 25842302 TI - Practical aspects in gas chromatography-mass spectrometry for the analysis of pesticide residues in exotic fruits. AB - The most relevant parameters of a multimode inlet were optimized to increase the injection volume up to 25 MUL using solvent vent mode in order to improve the sensitivity of the gas chromatography-mass spectrometry system. Consequently, the implementation of a concurrent backflushing was necessary to largely prevent the expected loss of performance derived from such matrix load out of a general purpose extraction (EN-15622-QuEChERS). Additionally, four mixtures of compounds used as analyte protectants were tested using spiked physalis to enhance the quality of signals. The chosen mixture remarkably improved sensitivity and yield better peak shapes, significantly more than others also tested. The analysis of pesticide residues in exotic fruits using instruments of limited selectivity is challenging since these complex matrices usually give notably dirty extracts. This scheme included an instrumental optimization and the addition of selected compounds that enabled to selectively reach limits of quantitation of 0.01 mg kg( 1) for most analytes. PMID- 25842303 TI - The effect of different cooking processes on stable C, N, and H isotopic compositions of beef. AB - The variability in the stable C, N, and H isotopic composition caused by different beef processing operations (boiling, frying, and roasting) was studied. The aim was to evaluate the stability of stable isotopic fingerprint information during the beef cooking process. The delta(13)C, delta(15)N, and delta(2)H values for raw, boiled, fried and roasted beef were measured, and the differences in the stable isotopic composition between raw and processed beef products were assessed. The results indicated that the delta(13)C and delta(15)N values in raw beef were not significantly different compared with processed beef, but the delta(2)H values were significantly higher in processed beef than in raw beef. In general, boiling, frying, and roasting had no significant effect on delta(13)C and delta(15)N values, but the delta(2)H value of processed beef increased. PMID- 25842304 TI - Fatty acids and oxidative stability of meat from lambs fed carob-containing diets. AB - Male Comisana lambs were individually stalled and, for 56 days, were fed concentrates with 60% barley (n = 8 lambs), or concentrates in which barley was partially replaced by 24% or 35% carob pulp (n = 9 lambs in each group). The intramuscular fatty acids were analyzed and the color stability, lipid and protein oxidation were measured in fresh meat overwrapped with polyvinyl chloride film at 0, 3 or 6 days of storage at 4 degrees C in the dark. Carob pulp increased the concentration of polyunsaturated fatty acids (PUFA) in muscle, including the rumenic acid (P < 0.01), and reduced the saturated fatty acids (P < 0.01) and the n-6/n-3 PUFA ratio (P = 0.01). The meat did not undergo extensive oxidative deterioration and the diet did not affect the oxidative stability parameters. Therefore, carob in lamb diet could increase PUFA in muscle without compromising meat oxidative stability. PMID- 25842305 TI - Quantification of adulterations in extra virgin flaxseed oil using MIR and PLS. AB - This paper proposes a new method for the quantitative analysis of soybean oil (SO) and sunflower oil (SFO) as adulterants in extra virgin flaxseed oil (EFO) by applying Mid Infrared Spectroscopy (MIR) associated with chemometric technique of Partial Least Squares (PLS). The PLS models were built in accordance with standard method ASTM E1655-05 and these showed good correlation between the reference values and those calculated using the PLS models with low error values, with R = 0.998 for SFO and R = 0.999 for SO in EFO. These models were validated analytically in accordance with Brazilian and international guidelines through the estimate of figures of merit parameters, thus showing an effective and feasible method to control the quality of extra virgin flaxseed oil. PMID- 25842306 TI - Volatile flavor compounds, total polyphenolic contents and antioxidant activities of a China gingko wine. AB - The volatile compounds in gingko wine, a novel functional wine, were extracted by head-space solid phase micro-extraction (SPME) and analyzed by gas chromatography mass spectrometry (GC-MS) coupled with odor activity value (OAV) and relative odor contribution (ROC) analyses. In addition, the total polyphenolic content of gingko wine was determined using the Folin-Ciocalteu reagent, and its antioxidant capacity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2' azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. Fifty-eight compounds were tentatively identified, including 13 esters, 10 alcohols, 11 acids, 12 carbonyl compounds, 2 lactones, 2 phenols, and 8 hydrocarbons. Ethyl hexanoate, ethyl pentanoate, nonanal, ethyl butyrate and ethyl heptanoate were the major contributors to the gingko wine aroma based on the results of OAV and ROC. The total phenols content of the gingko wine was 456 mg/L gallic acid equivalents, and its antioxidant capacity was higher than those of typical Chinese liquors analyzed in this paper. PMID- 25842307 TI - Selective methods for polyphenols and sulphur dioxide determination in wines. AB - A critical review to the methods recommended by international bodies and widely used in the winery industry and research studies was performed. A Laccase biosensor was applied to the selective determination of polyphenols in wines. The biosensor response was characterised and it responds mainly to o-diphenols which are the principal polyphenols responsible for the stability and sensory qualities of wines. The spectrophotometric method to determine free and total sulphur dioxide recommended for beers was applied directly to wines. A sampling of 14 red and white wines was performed and they were analysed for biosensor polyphenol index (IBP) and sulphur dioxide concentration (SO2). The antioxidant capacity by the ABTS(+) spectrophotometric method was also determined. A correlation study was performed to elucidate the influence of the polyphenols and SO2 on the wines stability. High correlations were found between IBP and antioxidant capacity and low correlation between SO2 and antioxidant capacity. To evaluate the benefits of wine drinking a new parameter (IBP/SO2) is proposed. PMID- 25842308 TI - In vitro digestion of short-dough biscuits enriched in proteins and/or fibres, using a multi-compartmental and dynamic system (1): viscosity measurement and prediction. AB - The effects of biscuit composition on the viscosity generated during digestion were investigated. A control biscuit, one with proteins, one with fibres, and one with both proteins and fibres were digested under the same conditions, using the TNO intestinal model (TIM-1). The TIM-1 is a multi-compartmental and dynamic in vitro system, simulating digestion in the upper tract (stomach and small intestine) of healthy adult humans. Digesta were collected at different times, in the different compartments of the TIM-1 (stomach, duodenum, jejunum and ileum) and viscosity was measured with a dynamic rheometer. Results showed a marked effect of biscuit composition on chyme viscosity. Highest viscosity was obtained with biscuits containing viscous soluble fibres, followed by those enriched in both proteins and fibres, then by protein-enriched and control biscuits. The viscosity was maintained throughout the gut up to the ileal compartment. A prediction of the evolution of the chyme viscosity in each compartment of the TIM 1 was built, based on model curves describing the evolution of the viscosity as a function of biscuit concentration, and on dilution factors measured by spectrophotometry on a blank digestion. PMID- 25842309 TI - Developing precipitation modes for preventing the calcium-oxalate contamination of sugar beet pectins. AB - Effects of precipitation modes on the co-precipitation of insoluble oxalates particles during the purification of sugar beet pectins (SBP) from the extract were investigated. It was observed that soluble oxalate ions formed insoluble oxalate salts with calcium and precipitated with pectins during ethanol precipitation as pH of the medium increased and the solvent changed from water to ethanol-water mixture. Comparison among the employed precipitation methods revealed that both the dialysis-ethanol-precipitation and metal precipitation effectively prevented the calcium-oxalate contamination of SBP. Emulsifying properties of DEPP, EPP and MPP were also studied. It was observed that DEPP performed better than the remainder with respect to emulsifying ability. Based on these results, we concluded that the dialysis-ethanolic-precipitation can be a suitable method for improving the purity as well as emulsifying properties of the resulting pectins. PMID- 25842310 TI - Homocapsaicin: it's NOT the 7-ene-9-methyl isomer. PMID- 25842311 TI - Optimisation of a simple and reliable label-free methodology for the relative quantitation of raw pork meat proteins. AB - Recent advances in proteomics have become an indispensable tool for a fast, precise and sensitive analysis of proteins in complex biological samples at both, qualitative and quantitative level. In this study, a label-free quantitative proteomic methodology has been optimised for the relative quantitation of proteins extracted from raw pork meat. So, after the separation of proteins by one-dimensional gel electrophoresis and trypsin digestion, their identification and quantitation have been done using nanoliquid chromatography coupled to a quadrupole/time-of-flight (Q/ToF) mass spectrometer. Relative quantitation has been based on the measurement of mass spectral peak intensities, which have been described that are correlated with protein abundances. The results obtained regarding linearity, robustness, repeatability and accuracy show that this procedure could be used as a fast, simple, and reliable method to quantify changes in protein abundance in meat samples. PMID- 25842312 TI - Determination of mycotoxins in pomegranate fruits and juices using a QuEChERS based method. AB - A rapid and accurate analytical method for the determination of three Alternaria mycotoxins (alternariol, alternariol monomethyl ether, and tentoxin) in pomegranate samples (fruits and juices) was developed and validated. The overall average recoveries ranged for 82.0-109.4% and the relative standard deviations were from 1.2% to 10.9%. The optimized and validated method was applied to detect the presence of the target mycotoxins in real samples (fruits and juices) purchased from Greek markets. Mycotoxins were not found in any of the analyzed samples. Also, artificially inoculated pomegranate fruits with six different Alternaria alternata species complex isolates, known to produce the target mycotoxins on pure cultures, were analyzed and alternariol concentrations found ranged from 0.3 to 50.5 MUg/g, alternariol monomethyl ether from 0.5 to 32.3 MUg/g, while tentoxin was not detected. The developed analytical method can be used for the routine monitoring of the major Alternaria mycotoxins in pomegranates. PMID- 25842313 TI - Thermal and spectroscopic studies of the antioxidant food additive propyl gallate. AB - Literature mentions propyl gallate (PG) as a non-toxic synthetic antioxidant that can be used as a food additive due to its high tolerance to heat. It is important to understand the thermal properties and to identify the decomposition products of this substance, since it has been reported to be thermally stable at temperatures as high as 300 degrees C. Simultaneous thermogravimetry differential thermal analysis (TG-DTA), differential scanning calorimetry photovisual (DSC-photovisual), coupled thermogravimetry-infrared spectroscopy (TG FTIR) analyses and spectroscopic techniques were used to study the food additive PG. The TG-DTA curves, which were performed with the aid of DSC-photovisual, provided information concerning the thermal stability and decomposition profiles of the compound. From the TG-FTIR coupled techniques, it was possible to identify n-propanol as a possible volatile compound released during the thermal decomposition of the antioxidant. A complete spectroscopic characterization in the ultraviolet, visible, near and middle infrared regions was performed in order to understand the spectroscopic properties of PG. PMID- 25842314 TI - Antioxidant activity of phenolic compounds added to a functional emulsion containing omega-3 fatty acids and plant sterol esters. AB - The effect of eleven compounds extracted from red propolis on the oxidative stability of a functional emulsion was evaluated. Emulsions prepared with Echium oil as omega 3 (omega-3 FA) source, containing 1.63 g/100mL of alpha-linolenic acid (ALA), 0.73 g/100 mL of stearidonic acid (SDA) and 0.65 g/100mL of plant sterol esters (PSE) were prepared without or with phenolic compounds (vanillic acid, caffeic acid, trans-cinnamic acid, 2,4-dihydroxycinnamic acid, p-coumaric acid, quercetin, trans-ferulic acid, trans,trans-farnesol, rutin, gallic acid or sinapic acid). tert-Butylhydroquinone and a mixture containing ascorbic acid and FeSO4 were applied as negative and positive controls of the oxidation. Hydroperoxide, thiobarbituric acid reactive substances (TBARS), malondialdehyde and phytosterol oxidation products (POPs) were evaluated as oxidative markers. Based on hydroperoxide and TBARS analysis, sinapic acid and rutin (200 ppm) showed the same antioxidant activity than TBHQ, representing a potential alternative as natural antioxidant to be applied in a functional emulsion containing omega-3 FA and PSE. PMID- 25842315 TI - New structural features of Acacia tortuosa gum exudate. AB - Acacia tortuosa produces a clear gum, very soluble in water. Previous reports showed that it was constituted by four fractions, one of them an arabinogalactan protein complex. The elucidation of the A. tortuosa gum structure by the combination of classical chemical methods, size exclusion chromatography and NMR spectroscopy, was the objective of this investigation. The data obtained show that the heteropolysaccharide is an arabinogalactan type II, highly ramified, with lateral chains at C-2 as well as at C-6 of the galactose 3-O residues; mono O-substituted galactoses were not detected. There are residues of mannose, the arabinose, pyranose predominantly, is terminal and 2-O-linked. The abundance of the 4-O-methyl-alpha-d-glucuronic acid was not previously reported. The proteic fraction is probably represented by an arabinogalactan-protein complex that binds poorly with beta-glucosyl Yariv reagent, and two glycoproteins. The NMR spectra suggest that the carbohydrate links to hydroxyproline through the galactose (galactosylation). PMID- 25842316 TI - Ethylene-dependent regulation of an alpha-L-arabinofuranosidase is associated to firmness loss in 'Gala' apples under long term cold storage. AB - Fruit texture changes impair the quality of apples submitted to long term storage, especially under cold. The changes are due to cell wall modifications during ripening and senescence and are associated to ethylene. We have investigated the activity of alpha-l-arabinofuranosidase, a glycosyl hydrolase acting on the side chains of pectin in the cell wall and middle lamella. The transcription of arabinofuranosidase coding sequences 1 and 3 was investigated in plant organs and in response to ethylene, employing hormone application and 1 methylcyclopropene. The transcription of arabinofuranosidase genes is not restricted to fruits, although upregulated by ripening and ethylene. Transcripts of the genes were detected under cold storage up to 180 days. Similarly, arabinofuranosidase activity increased with rising levels of ethylene and under cold storage. Levels of arabinofuranosidase3 transcripts were higher than those of arabinofuranosidase1, suggesting that the first is an important contributor to enzyme activity and texture changes during cold storage. PMID- 25842317 TI - Kinetics of protein and textural changes in Atlantic salmon under frozen storage. AB - Fish proteins are highly susceptible to changes during frozen storage, leading to modifications in protein solubility, functionality, and structure, which affect the rheological properties, which, in turn, contribute to changes in techno functional properties. Under frozen storage, these changes are the result of many physical and chemical modifications, especially structural and functional protein changes. The aim of this study was to evaluate and quantify protein and textural changes during frozen storage of Atlantic salmon (Salmo salar) fillets at four temperatures (268 K, 264 K, 260 K and 255 K). The Weibullian model was applied in order to understand the quality changes. Results for all frozen storage temperatures showed that total volatile basic nitrogen (TVB-N) did not reach the regulated limits (30-35 mg/100 g muscle), salt-soluble protein (SSP) decreased systematically and total nitrogen (TN) was constant. Hardness, adhesiveness, gumminess and chewiness levels decreased systematically at all temperatures, but cohesiveness and springiness values were relatively constant over time, at the same given temperature. A comparison between different temperatures showed an increase in the measurements observed. A kinetic analysis for TVBN, SSP, hardness, adhesiveness and chewiness, was performed. All quality indicators, except TVBN, showed reaction rates inversely proportional to the temperature, and fractional shape factors or orders of reaction. Using the Weibullian model, this study demonstrates that, in complex biological processes, quality indicators do not have an integer kinetic order and reaction rates are strongly temperature dependent. Thus, this kind of model can be used to improve understanding, prediction, and control of the frozen storage process. PMID- 25842318 TI - Variations in the accumulation, localization and rate of metabolization of selenium in mature Zea mays plants supplied with selenite or selenate. AB - Quantification of selenium bioavailability from foods is a key challenge following the discovery of the antioxidant role of this micronutrient in human health. This study presents the uptake, accumulation and rate of metabolization in mature Zea mays plants grown in hydroponic solution supplemented with selenate or selenite. Selenium content was lower in plants supplemented with selenate and accumulated mainly in the leaves compared with selenite-treated plants where the selenium was retained in the roots. Selenite-treated grains accumulated more selenium. Selenate was metabolized less than selenite in whole plants, but in grains selenium was present exclusively as organic selenium compounds. For humans, the bioavailability of organic selenium was evaluated at 90% compared with only 50% for inorganic forms. Our results show that the potential for selenium bioavailability is increased with selenite treatment. PMID- 25842319 TI - Rapid purification and characterization of angiotensin converting enzyme inhibitory peptides from lizard fish protein hydrolysates with magnetic affinity separation. AB - In this study, angiotensin converting enzyme (ACE) inhibitory peptides from lizard fish protein hydrolysate with neutral protease were purified through magnetic affinity separation. Magnetic agarose microsphere was prepared by reverse-phase microemulsion method, and its surface was modified with epoxy groups to immobilize ACE as a magnetic affinity medium (MAM-ACE) and then mixed with lizard fish ultrafiltration hydrolysate (<5 kDa). The MAM-ACE was recovered by a magnet. The bound peptides were released by 1M NaCl and further purified by reverse-phase high-performance liquid chromatography. The amino acid sequence of the peptide with the highest ACE inhibitory activity was identified as Gly-Met Lys-Cys-Ala-Phe, and its IC50 was 45.7 +/- 1.1 MUM. The result indicates that MAM ACE is a faster and more efficient method for purifying micro-bioactive peptides from food protein complex mixtures compared with ion exchange and gel chromatography. PMID- 25842320 TI - Comparative assessment of three cleanup procedures after QuEChERS extraction for determination of trichothecenes (type A and type B) in processed cereal-based baby foods by GC-MS. AB - A QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method was optimized and validated for the simultaneous extraction of 12 trichothecenes (type A and type B) from baby foods, followed by gas chromatography-mass spectrometry (GC-MS) analysis. Using this methodology, limits of detection and quantification ranging from 0.37 to 19.19 MUg/kg and 1.24 to 63.33 MUg/kg, respectively, were achieved. Mean recoveries between 44% and 135% were obtained and repeatability, expressed as relative standard deviation, was always lower than 29%. A comparison between the developed method and two alternative cleanup procedures (MultiSep and IAC- immunoaffinity columns) was performed, being the advantages and drawbacks of each one presented. The screening of nine commercially available cereal-based baby foods revealed the presence of 4 out of 12 studied trichothecenes: DON (deoxynivalenol), 15AcDON (15-acetyl-deoxynivalenol), T2-Tetrol and NEO (Neosolaniol). DON was the most commonly found, being detected in 4 samples in significant levels (29-270 MUg/kg), sometimes exceeding the maximum permitted level. 15AcDON, T2-Tetrol and NEO were found only in one sample each. PMID- 25842321 TI - Determination of irradiation dose and distinguishing between irradiated and non irradiated fish meat by real-time PCR. AB - In this study, the effects of gamma irradiation on the DNA of fish (Oncorhynchus mykiss) by real-time PCR were studied. Fish (O. mykiss) were exposed to radiation doses of 0.250, 0.500, 1, 3, 5, 7, and 9 kGy in a gamma cell. Primers were designed for regions with different lengths of both nuclear and mitochondrial DNA, and each primer was used to amplify the DNA from irradiated samples. The amplicon curves for mitochondrial and nuclear DNA, and the correlations among the curves, were obtained. The Ct values for a 519 bp region of the 18S RNA gene on nuclear DNA correlated appropriately. Radiation doses applied to the fillets were estimated using the standard curve data obtained from the correlation values, and the DNA damage caused by each dose was calculated. As a consequence, a molecular methodology to analyze irradiated fish meat qualitatively and also for the estimation of administered dose was developed. This method allowed analysis of irradiated fish, which had been stored for up to 3 months with a dose limit of approximately 0.5 kGy. PMID- 25842322 TI - Morphological, nutritional and chemical description of "Vatikiotiko", an onion local landrace from Greece. AB - "Vatikiotiko" is an onion local landrace from Greece with special quality features, such as strong and pungent taste and storability. In this study, we tried for the first time to describe this landrace and record its morphological traits and nutritional value in comparison with commercially cultivated genotypes ("Creamgold", "Red Cross F1" and "Sivan F1"). Nutritional value of "Vatikiotiko" was higher than commercial genotypes, whereas total sugars, fructose and glucose content were lower in "Vatikiotiko" and "Creamgold" onions. Fatty acids composed mostly from polyunsaturated fatty acids (linoleic and alpha-linolenic acid), whereas for "Vatikiotiko" saturated and monounsaturated fatty acids were detected in equal amounts (29.79% and 30.60%, respectively). "Vatikiotiko" and "Creamgold" had low antioxidant activity (DPPH radical scavenging activity), especially when comparing with "Sivan F1" and "Red Cross F1", whereas no flavonoids were detected in "Vatikiotiko". The overview of "Vatikiotiko" landrace supported its special character regarding its nutritional value (sugar content, mineral composition and fatty acids profile) and the necessity to revalorize and protect its traditional culture. The potential of introducing it as Protected Designation of Origin (PDO) or Protected Geographical Indication (PGI) product has also been discussed. PMID- 25842323 TI - Formation and reduction of 5-hydroxymethylfurfural at frying temperature in model system as a function of amino acid and sugar composition. AB - 5-Hydroxymethylfurfural (HMF) is formed during heat treatment of carbohydrate containing foods, especially in a deep-fat frying process. This study aimed to investigate the effect of amino acids on the formation and reduction of HMF from glucose, fructose and sucrose at frying temperature in model systems containing binary mixtures of an amino acid and a sugar in equal concentrations (0.3M). The results revealed that the formation of HMF from sugars accelerated in the presence of acidic amino acids (i.e. glutamic and aspartic acids). Conversely, the presence of basic amino acids (i.e. lysine, arginine and histidine) led to reduced concentrations of HMF to non-detectable levels in model systems. The results showed that both pH and heating time significantly affected the formation of HMF from fructose in the presence of glutamic acid. In this regard, a higher amount of HMF was formed at lower pH. PMID- 25842324 TI - Effect of water, metallic ions, fatty acid and temperature on oxidative stability of 1-octacosanol from sugarcane rind. AB - The chemical composition and selected physical parameters of crude 1-octacosanol (1-OC) extracted from sugarcane rind have been determined. GC-MS results exhibited that 1-OC sample was primarily composed of 1-OC (45.17%), 1-docosene (12.04%), 1-triacontanol (0.23%), 1-heneicosanol (0.33%), 1-tetracosanal (0.28%), campesterol (4.5%), stigmasterol (9.12%) and beta-sitosterol (8.23%). The linoleic acid had important effects on physical and chemical properties of 1-OC sample, as it notably changed the melting point and the onset oxidation temperature To of 1-OC sample from 83.75 +/- 0.35 degrees C to 63.25 +/- 0.35 degrees C and 245.64 +/- 2.04 degrees C to 160.03 +/- 0.01 degrees C, respectively. It was also proved that the oxidation reactions were significantly different at different temperature levels. 1-OC was stable up to 245.64 +/- 2.04 degrees C. However, when the temperature continued to rise, 1-OC and its oxidation products started to be oxidized. Therefore, attention should be paid to the quality of 1-OC during the preparation of food and to minimize the undesirable breakdown products. PMID- 25842325 TI - Rapid approach to identify the presence of Arabica and Robusta species in coffee using 1H NMR spectroscopy. AB - NMR spectroscopy was used to verify the presence of Arabica and Robusta species in coffee. Lipophilic extracts of authentic roasted and green coffees showed the presence of established markers for Robusta (16-O-methylcafestol (16-OMC)) and for Arabica (kahweol). The integration of the 16-OMC signal (delta 3.165 ppm) was used to estimate the amount of Robusta in coffee blends with an approximate limit of detection of 1-3%. The method was successfully applied for the analysis of 77 commercial coffee samples (coffee pods, coffee capsules, and coffee beans). Furthermore, principal component analysis (PCA) was applied to the spectra of lipophilic and aqueous extracts of 20 monovarietal authentic samples. Clusters of the two species were observed. NMR spectroscopy can be used as a rapid prescreening tool to discriminate Arabica and Robusta coffee species before the confirmation applying the official method. PMID- 25842326 TI - Effects of sub-lethal concentrations of thyme and oregano essential oils, carvacrol, thymol, citral and trans-2-hexenal on membrane fatty acid composition and volatile molecule profile of Listeria monocytogenes, Escherichia coli and Salmonella enteritidis. AB - The aim of this work was to investigate the modifications of cell membrane fatty acid composition and volatile molecule profiles of Listeria monocytogenes, Salmonella enteritidis, Escherichia coli, during growth in the presence of different sub-lethal concentrations of thyme and oregano essential oils as well as carvacrol, thymol, trans-2-hexenal and citral. The results evidenced that the tested molecules induced noticeable modifications of membrane fatty acid profiles and volatile compounds produced during the growth. Although specific differences in relation to the species considered were identified, the tested compounds induced a marked increase of some membrane associated fatty acids, particularly unsaturated fatty acids, trans-isomers, and specific released free fatty acids. These findings can contribute to the comprehension of the stress response mechanisms used by different pathogenic microorganisms often involved in food borne diseases in relation to the exposure to sub-lethal concentrations of natural antimicrobials. PMID- 25842327 TI - Ecdysteroids in Sida tuberculata R.E. Fries (Malvaceae): chemical composition by LC-ESI-MS and selective anti-Candida krusei activity. AB - Sida tuberculata is found in a region of South America and has traditionally been consumed as an infusion or tea. The chemical composition and antifungal activity of aqueous infusions from leaves and roots were investigated. LC-ESI-MS mass spectra were successfully obtained and used to identify four ecdysteroids: 20 hydroxyecdysone-3-O-beta-D-glycopyranoside, 20-hydroxyecdysone, 20 hydroxyecdysone-3-O-beta-D-xylose and a hydroxyecdysterone derivative. The in vitro antifungal activity was studied, and the minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) were established against Candida krusei isolates. The antibiofilm activity was evaluated by the determination of the biofilm removal efficiency in contaminated central venous catheter (CVC) coupons. The preparations exhibited antifungal activity against the species tested, with MICs ranging from 3.90 to 62.50 MUg/ml. The infusion removed the C. krusei biofilm after 90 min of exposure. The observed bioactivity and composition of ecdysteroids will contribute to the future development of antifungal substances for clinical use or as food additives. PMID- 25842328 TI - Application of muscadine grape (Vitis rotundifolia Michx.) pomace extract to reduce carcinogenic acrylamide. AB - Acrylamide is a byproduct of the Maillard reaction and is formed in a variety of heat-treated commercial starchy foods. It is known to be toxic and potentially carcinogenic to humans. Muscadine grape polyphenols and standard phenolic compounds were examined on the reduction of acrylamide in an equimolar asparagine/glucose chemical model, a potato chip model, and a simulated physiological system. Polyphenols were found to significantly reduce acrylamide in the chemical model, with reduced rates higher than 90% at 100 MUg/ml. In the potato chip model, grape polyphenols reduced the acrylamide level by 60.3% as concentration was increased to 0.1%. However, polyphenols exhibited no acrylamide reduction in the simulated physiological system. Results also indicated no significant correlation between the antioxidant activities of polyphenols and their acrylamide inhibition. This study demonstrated muscadine grape extract can mitigate acrylamide formation in the Maillard reaction, which provides a new value-added application for winery pomace waste. PMID- 25842329 TI - Singlet oxygen autoxidation of vegetable oils: evidences for lack of synergy between beta-carotene and tocopherols. AB - The synergy between beta-carotene and tocopherols--antioxidants protecting oils from oxidation, was analyzed in a model system. The model used stripped borage and evening primrose oils. A chlorophyll extract, beta-carotene and one of the tocopherols were added together or separately to the oils. Oil oxidation was initiated by singlet oxygen that was produced by chlorophylls irradiated with the use of a xenon lamp equipped with the cut-off 600 nm filter. Experiments were carried out at two mole ratios of tocopherols to beta-carotene, i.e. at 1:1 and 23:1. Analyses were performed using absorption and fluorescence spectra in the UV+Vis region. The results demonstrated an antagonistic action of the antioxidants. The protective effect of unsaturated fatty acids was significantly better in the case of beta-carotene compared to the tocopherols. Furthermore, tocopherols were less effective in protecting the oils in the presence of beta carotene than without it. PMID- 25842330 TI - Cooking behavior and starch digestibility of NUTRIOSE(r) (resistant starch) enriched noodles from sweet potato flour and starch. AB - The effect of a resistant starch source, NUTRIOSE(r) FB06 at 10%, 15% and 20% in sweet potato flour (SPF) and 5% and 10% in sweet potato starch (SPS) in reducing the starch digestibility and glycaemic index of noodles was investigated. While NUTRIOSE (10%) significantly reduced the cooking loss in SPF noodles, this was enhanced in SPS noodles and guar gum (GG) supplementation reduced CL of both noodles. In vitro starch digestibility (IVSD) was significantly reduced in test noodles compared to 73.6g glucose/100g starch in control SPF and 65.9 g in SPS noodles. Resistant starch (RS) was 54.96% for NUTRIOSE (15%)+GG (1%) fortified SPF noodles and 53.3% for NUTRIOSE (5%)+GG (0.5%) fortified SPS noodles, as against 33.8% and 40.68%, respectively in SPF and SPS controls. Lowest glycaemic index (54.58) and the highest sensory scores (4.23) were obtained for noodles with 15% NUTRIOSE+1% GG. PMID- 25842331 TI - The structure of infant formulas impacts their lipolysis, proteolysis and disintegration during in vitro gastric digestion. AB - Milk lipids supply most of the calories necessary for newborn growth in maternal milk or infant formulas. The chemical composition of infant formulas has been optimized but not the structure of the emulsion. There is still a major difference between the native emulsions of milk fat globules and processed submicronic emulsions in infant formulas. This difference may modify the kinetics of digestion of emulsions in newborns and influence lipid metabolism. To check this, semi-dynamic gastric in vitro digestions were conducted on three matrices: a standardized milk emulsion containing native milk fat globules referred to as minimally-processed emulsion and two processed model infant formulas (homogenized or homogenized/pasteurized). Gastric conditions mimicked those reported in newborns. The minimally-processed emulsion was lipolyzed and proteolyzed slower than processed formulas. The difference in initial structure persisted during digestion. The surface of the droplets was the key parameter to control gastric lipolysis kinetics, the pattern of released fatty acids and proteolysis by faster hydrolysis of adsorbed proteins. PMID- 25842332 TI - A reliable and reproducible method for the lipase assay in an AOT/isooctane reversed micellar system: modification of the copper-soap colorimetric method. AB - The copper-soap method, which is based on the absorbance of a fatty acid-copper complex at 715 nm, is a widely used colorimetric assay to determine the lipase activity in reversed micellar system. However, the absorbance of the bis(2 ethylhexyl) sodium sulfosuccinate (AOT)-copper complex prevents the use of an AOT/isooctane reversed micellar system. An extraction step was added to the original procedure to remove AOT and eliminate interference from the AOT-copper complex. Among the solvents tested, acetonitrile was determined to be the most suitable because it allows for the generation of a reproducible calibration curve with oleic acid that is independent of the AOT concentrations. Based on the validation data, the modified method, which does not experience interference from the AOT-copper complex, could be a useful method with enhanced accuracy and reproducibility for the lipase assay. PMID- 25842333 TI - Determination of creatinine, uric and ascorbic acid in bovine milk and orange juice by hydrophilic interaction HPLC. AB - Creatinine (Cr), uric (UA) and ascorbic acid (AA) are common constituents in human fluids. Their abnormal concentrations in human fluids are associated with various diseases. Thus, apart from the endogenous formation in human body, it is also important to examine their sources from food products. In this study, a rapid and accurate HILIC method was developed for simultaneous determination of Cr, UA and AA in bovine milk and orange juice. Milk samples were pretreated by protein precipitation, centrifugation and filtration, followed by HPLC separation and quantification using a Waters Spherisorb S5NH2 column. The developed method has been successfully applied to determine the concentration of UA, AA and Cr in milk and fruit juice samples. The milk samples tested were found to contain UA and creatinine in the concentration range of 24.1-86.0 and 5.07-11.2 MUg mL(-1), respectively. The orange juices contain AA over 212 MUg mL(-1). PMID- 25842334 TI - Validation of quantitative method for azoxystrobin residues in green beans and peas. AB - This study presents a method validation for extraction and quantitative analysis of azoxystrobin residues in green beans and peas using HPLC-UV and the results confirmed by GC-MS. The employed method involved initial extraction with acetonitrile after the addition of salts (magnesium sulfate and sodium chloride), followed by a cleanup step by activated neutral carbon. Validation parameters; linearity, matrix effect, LOQ, specificity, trueness and repeatability precision were attained. The spiking levels for the trueness and the precision experiments were (0.1, 0.5, 3 mg/kg). For HPLC-UV analysis, mean recoveries ranged between 83.69% to 91.58% and 81.99% to 107.85% for green beans and peas, respectively. For GC-MS analysis, mean recoveries ranged from 76.29% to 94.56% and 80.77% to 100.91% for green beans and peas, respectively. According to these results, the method has been proven to be efficient for extraction and determination of azoxystrobin residues in green beans and peas. PMID- 25842335 TI - GC-MS-olfactometric characterization of the most aroma-active components in a representative aromatic extract from Iranian saffron (Crocus sativus L.). AB - Aroma and aroma-active compounds of Iranian saffron (Crocus sativus L.) were analyzed by gas chromatography-mass spectrometry-olfactometry. The saffron aromatic extracts were obtained by four different extraction techniques including solvent-assisted flavour evaporation (SAFE), liquid-liquid extraction (LLE), solid phase extraction (SPE), and simultaneous distillation extraction (SDE) and compared to achieve a representative aromatic extract from saffron. According to sensory analysis, the aromatic extract obtained by SAFE was the most representative of saffron odour. A total of 28 aroma compounds were identified in saffron. Ketones were quantitatively the most dominant volatiles in saffron, followed by aldehydes and acids. Aroma extract dilution analysis (AEDA) was used for the determination of aroma-active compounds of saffron. A total of nine aroma active compounds were detected in the aromatic extract. On the basis of the flavour dilution (FD) factor, the most powerful aroma active compounds were safranal (FD = 512), 4-ketoisophorone (FD = 256) and dihydrooxophorone (FD = 128). PMID- 25842336 TI - Combined effects of reduced malaxation oxygen levels and storage time on extra virgin olive oil volatiles investigated by a novel chemometric approach. AB - Combined effects of oxygen level reduction in the malaxation headspace and storage time up to 6 months on the volatile composition of a monovarietal extra virgin olive oil (EVOO), obtained from cv. Carboncella olives, were investigated by applying a full factorial design approach (4 oxygen levels * 4 storage times) on EVOOs extracted on an industrial scale in two mills, equipped with "two-phase" and "three-phase" centrifugation systems, respectively. The outcoming data were analysed by the chemometric technique called ANOVA-simultaneous component analysis (ASCA). Both reduction of oxygen malaxation levels and storage time significantly affected the volatile profile of the extracted EVOOs. Reduction of oxygen malaxation levels hindered the formation of lipoxygenase derived volatiles (hexanal, 1-hexanol, (Z)-2-hexenal, (E)-2-hexen-1-ol, (Z)-2-penten-1-ol, 2,4 hexadienals), whereas prolonged storage times were associated with increased levels of autoxidation products (octane, hexanal, C10 hydrocarbons) and other compounds that could originate from exogenous microbial activity (1-octen-3-ol, 6 methyl-5-hepten-2-one, benzaldehyde, methyl salicylate). PMID- 25842337 TI - Effects of gluten-free breads, with varying functional supplements, on the biochemical parameters and antioxidant status of rat serum. AB - This paper examines the effects of gluten-free bread enriched with functional ingredients (milk powder, poppy, sunflower and pumpkin seeds, egg yolk, carum, hazel nuts and amaranth) on the morphological and biochemical parameters and antioxidant status of rats serum. Rats were provided test diets--gluten-free breads and water ad libitum. After 14 days, the animals were weighed and killed. A hazel nut-amaranth bread diet significantly increased the level of thrombocytes when compared to control bread. A mixed bread diet significantly decreased cholesterol levels in rats. All fortified breads decreased triglyceride levels and alanine transaminase activity and caused an increase in antiradical activity of the serum. In rats fed with poppy-milk bread, milk-seed bread and mixed bread, a marked decrease in superoxide dismutase activity was found. Enriched breads reduced the levels of triglyceride and improved the antiradical properties of serum, although the physiological relevance of this needs to be confirmed by human studies. PMID- 25842338 TI - Core-shell biopolymer nanoparticle delivery systems: synthesis and characterization of curcumin fortified zein-pectin nanoparticles. AB - Biopolymer core-shell nanoparticles were fabricated using a hydrophobic protein (zein) as the core and a hydrophilic polysaccharide (pectin) as the shell. Particles were prepared by coating cationic zein nanoparticles with anionic pectin molecules using electrostatic deposition (pH 4). The core-shell nanoparticles were fortified with curcumin (a hydrophobic bioactive molecule) at a high loading efficiency (>86%). The resulting nanoparticles were spherical, relatively small (diameter ~ 250 nm), and had a narrow size distribution (polydispersity index ~ 0.24). The encapsulated curcumin was in an amorphous (rather than crystalline form) as detected by differential scanning calorimetry (DSC). Fourier transform infrared (FTIR) and Raman spectra indicated that the encapsulated curcumin interacted with zein mainly through hydrophobic interactions. The nanoparticles were converted into a powdered form that had good water-dispersibility. These core-shell biopolymer nanoparticles could be useful for incorporating curcumin into functional foods and beverages, as well as dietary supplements and pharmaceutical products. PMID- 25842339 TI - Characterization of polyphenols, sugars, and other polar compounds in persimmon juices produced under different technologies and their assessment in terms of compositional variations. AB - Persimmon juice is emerging in the global juice market as a new wholesome commercial juice that could effectively complement a healthy diet, given the epidemiological evidence linking a diet rich in fruits and vegetables with reduced incidences of chronic diseases. However, little data are available on the persimmon-juice composition or on the effect of the technological treatment employed for its production. The present work performs a complete qualitative analytical characterization through high-performance liquid chromatography coupled to electrospray time-of-flight mass spectrometry (HPLC-DAD-ESI-TOF/MS) of the diverse persimmon juices produced under different technologies in a pilot plant (clarification, astringency removal, flash vacuum expansion, centrifugation and pasteurization) in order to evaluate the effect of the different production procedures on the polar chemical profile of persimmon juice. Persimmon-juice extracts have been found to be a source of sugars, protein derivatives, organic acids, vitamins, and polyphenols, including simple polyphenols (phenolic acids and flavonoids) and polymerized flavan-3-ols. A marked influence of processing on the composition of the juices has been noticed. Extracts 3 and 7 (undergoing the combinations of clarification and centrifugation, and astringency removal, centrifugation and pasteurization, respectively) contained more polyphenols, which may help reduce risk of chronic diseases. PMID- 25842340 TI - Physicochemical properties of tamarillo (Solanum betaceum Cav.) hydrocolloid fractions. AB - Tamarillo (Solanum betaceum Cav.) is an underutilised fruit in Malaysia. The fruit, however, contains good proportions of soluble fibre, protein, starch, anthocyanins and carotenoids. Amongst the fruits, only tamarillo mesocarp contains both polar (anthocyanins) and non-polar (carotenoids) pigments. The ability to retain both polar and non-polar pigments in the mesocarp could be related to the unique properties of its hydrocolloids. To understand the pigment hydrocolloid interaction in the fruit, information on the physicochemical characteristics of the hydrocolloids is required. Therefore, hydrocolloids from the anthocyanin-rich seed mucilage fraction of the tamarillo and its carotenoid rich pulp fraction were extracted and characterised. Water and 1% citric acid were used to extract the seed mucilage hydrocolloid while 72% ethanol and 20mM HEPES buffer were used for pulp hydrocolloid extraction. Seed mucilage hydrocolloid was primarily composed of arabinogalactan protein-associated pectin whereas pulp hydrocolloid was composed of hemicellulosic polysaccharides with some naturally interacting proteins and neutral polysaccharides. PMID- 25842342 TI - How does electron beam irradiation dose affect the chemical and antioxidant profiles of wild dried Amanita mushrooms? AB - As with all mushrooms, Amanita species demonstrates several conservation problems, due to a post-harvest life limited to a few days. Drying is one of the most commonly used methods in mushroom preservation. Food irradiation is another possible way to improve food quality and insure its security. Among the emerging irradiation technologies, electron beam irradiation has wide applications, allowing for high throughput, wide flexibility and potential, without any negative effect on the environment. The effects of different electron beam irradiation doses in Amanita genus, were assessed by measuring the changes produced on a wide variety of nutritional, chemical and antioxidant indicators. The evaluated profiles indicated differences between non-irradiated and irradiated samples, however a high similarity was observed among different doses. This finding advises that the highest assayed dose (10 kGy) be applied, ensuring a higher effectiveness from a decontamination and disinfestation perspective, without having any stronger effects than those observed by the lower doses. PMID- 25842341 TI - The content of Ca, Cu, Fe, Mg and Mn and antioxidant activity of green coffee brews. AB - A simple and fast method of the analysis of green coffee infusions was developed to measure total concentrations of Ca, Cu, Fe, Mg and Mn by high resolution continuum source flame atomic absorption spectrometry. The precision of the method was within 1-8%, while the accuracy was within -1% to 2%. The method was used to the analysis of infusions of twelve green coffees of different geographical origin. It was found that Ca and Mg were leached the easiest, i.e., on average 75% and 70%, respectively. As compared to the mug coffee preparation, the rate of the extraction of elements was increased when infusions were prepared using dripper or Turkish coffee preparation methods. Additionally, it was established that the antioxidant activity of green coffee infusions prepared using the mug coffee preparation was high, 75% on average, and positively correlated with the total content of phenolic compounds and the concentration of Ca in the brew. PMID- 25842343 TI - Identification and determination of 34 water-soluble synthetic dyes in foodstuff by high performance liquid chromatography-diode array detection-ion trap time-of flight tandem mass spectrometry. AB - An accurate method combining high performance liquid chromatography (HPLC) with diode array detection (DAD) and ion-trap time-of-flight mass spectrometry (IT TOF/MS) was developed for simultaneous identification and quantification of 34 water-soluble synthetic dyes in foodstuff. Fragmentation patterns of synthetic dyes were proposed based on IT-TOF/MS. The molecular ion [M+H](+) was not observed in the conventional single-stage mass spectra for most of synthetic dyes. The single-stage mass spectra of synthetic dyes all afforded the diagnostic ions [(M-nNa+nH)+H](+) or [(M-nNa+nH)-H](-) in the positive or negative mode. Doubly charged ions were the characteristic ions of azo dyes. An HPLC-DAD method was developed to analyze 34 synthetic dyes in foodstuffs. The limits of detection (LOD) for the dyes were 0.01-0.05 MUg/mL. The recoveries were between 76.1% and 105.0% with a RSD ranging from 1.4% to 6.4%. This method was successfully applied to analyzing the 34 water-soluble synthetic dyes in 21 commercial foods. PMID- 25842344 TI - Folate content and retention in commonly consumed vegetables in the South Pacific. AB - This paper reports the effect of boiling and frying on the retention of folate in commonly consumed Fijian vegetables (drumstick leaves, taro leaves, bele leaves, amaranth leaves, fern/ota, okra and French bean). The folate content was determined by microbiological assay (Lactobacillus casei rhamnosus) and tri enzyme (protease, alpha-amylase and chicken pancreas conjugase) extraction treatment. The folate loss varied among the vegetables from 10-64% on boiling while 1-36% on frying. The higher folate loss was observed during boiling. The folate content in the water derived after boiling different vegetables ranged from 11.9 +/- 0.5 to 61.6 +/- 2.5 MUg/100mL. The folate loss on boiling was accounted for in the cooking water. The predominant way of folate loss on boiling was leaching rather than thermal degradation which makes boiling the better choice of cooking the studied vegetables for folate intake, provided the cooking water is consumed together with the vegetables. PMID- 25842345 TI - Genetic and Environmental Influences on Adult Mental Health: Evidence for Gene Environment Interplay as a Function of Maternal and Paternal Discipline and Affection. AB - Researchers have long theorized that genetic influence on mental health may differ as a function of environmental risk factors. One likely moderator of genetic and environmental influences on psychopathological symptoms is parenting behavior, as phenotypic research shows that negative aspects of parent-child relationships are associated with greater likelihood of mental illness in adulthood. The current study examined whether levels of reported parental discipline and affection experienced in childhood act as a trigger, or buffer, for adult mental health problems. Results from a nationwide twin sample suggest level of father's discipline and affection, as reported by now-adult twins, moderated genetic and environmental influences on internalizing symptoms in adulthood, such that heritability was greatest at the highest levels of discipline and affection. Father's affection also moderated the etiological influences on alcohol use problems, with greater heritability at the lowest levels of affection. No moderating effect was found for mothers. Findings suggest relationships with fathers in childhood can have long-lasting effects on the etiological influences on adult mental health outcomes. PMID- 25842346 TI - The effect of sleep continuity on pain in adults with sickle cell disease. AB - This analysis examined the influence of quantifiable parameters of daily sleep continuity, primarily sleep duration and sleep fragmentation, on daily pain in adults with sickle cell disease. Seventy-five adults with sickle cell disease completed baseline psychosocial measures and daily morning (sleep) and evening (pain) diaries over a 3-month period. Mixed-effect modeling was used to examine daily between- and within-subjects effects of sleep continuity parameters on pain, as well as the synergistic effect of sleep fragmentation and sleep duration on pain. Results revealed that nights of shorter sleep duration and time in bed, increased fragmentation, and less efficient sleep (relative to one's own mean) were followed by days of greater pain severity. Further, the analgesic benefit of longer sleep duration was attenuated when sleep fragmentation was elevated. These results suggest that both the separate and combined effects of sleep duration and fragmentation should be considered in evaluating pain in adults with sickle cell disease. PERSPECTIVE: Subjective parameters of sleep continuity (eg, sleep duration, fragmentation, and efficiency) predict clinical pain in individuals with sickle cell disease. Additionally, sleep duration should not be considered in isolation, and its association with pain may be qualified by sleep fragmentation. Research and practice should include assessments of both when addressing pain severity. PMID- 25842348 TI - Coronary artery perforation in a patient with STEMI and a myocardial bridge: an increased risk for coronary artery perforation? AB - We present the case of a patient with ST-elevation myocardial infarction (STEMI) due to subtotal occlusion of the left anterior descending coronary artery caused by an atherosclerotic lesion and a myocardial bridge (MB). Stenting of the MB caused coronary artery perforation resulting in a fistula to the right ventricle that was closed by implantation of a PTFE-covered stent. Follow-up coronary angiography showed persistent shunting, which was sealed by inflation of a high pressure balloon over the site of extravasation guided by intravascular ultrasound. Additionally, we provide a short review of cases with coronary artery perforation after stenting of an MB. PMID- 25842347 TI - MU-Opioid Receptor Gene A118 G Variants and Persistent Pain Symptoms Among Men and Women Experiencing Motor Vehicle Collision. AB - The MU-opioid receptor 1 (OPRM1) binds endogenous opioids. Increasing evidence suggests that endogenous OPRM1 agonists released at the time of trauma may contribute to the development of posttraumatic musculoskeletal pain (MSP). In this prospective observational study, we evaluated the hypothesis that individuals with an AG or GG genotype at the OPRM1 A118 G allele, which results in a reduced response to opioids, would have less severe MSP 6 weeks after motor vehicle collision (MVC). Based on previous evidence, we hypothesized that this effect would be sex-dependent and most pronounced among women with substantial peritraumatic distress. European American men and women >= 18 years of age presenting to the emergency department after MVC and discharged to home after evaluation (N = 948) were enrolled. Assessments included genotyping and 6-week evaluation of overall MSP severity (0-10 numeric rating scale). In linear regression modeling, a significant A118 G Allele * Sex interaction was observed: an AG/GG genotype predicted reduced MSP severity among women with substantial peritraumatic distress (beta = -.925, P = .014) but not among all women. In contrast, men with an AG/GG genotype experienced increased MSP severity at 6 weeks (beta = .827, P = .019). Further studies are needed to understand the biologic mechanisms mediating observed sex differences in A118 G effects. PERSPECTIVE: These results suggest a sex-dependent mechanism by which an emotional response to trauma (distress) contributes to a biologic mechanism (endogenous opioid release) that increases MSP in the weeks after stress exposure. These results also support the hypothesis that endogenous opioids influence pain outcomes differently in men and women. PMID- 25842349 TI - Side-branch technique for difficult guidewire placement in coronary bifurcation lesion. AB - Despite tremendous advances in technology and skills, percutaneous coronary intervention (PCI) of bifurcation lesion (BL) remains a particular challenge for the interventionalist. During bifurcation PCI, safe guidewire placement in the main branch (MB) and the side branch (SB) is the first step for successful procedure. However, in certain cases, the complex pattern of vessel anatomy and the mix of plaque distribution may make target vessel wiring highly challenging. Therefore, specific techniques are required for solving this problem. Hereby, we describe a new use of side-branch technique for difficult guidewire placement in BL. PMID- 25842350 TI - The changing face of autism in Brazil. AB - At the end of 2012, after intensive lobbying by parent activist associations, a federal law recognized autism as a "disability for all legal purposes" in Brazil. Defining autism as a disability was more than a change of legal status to guarantee social benefits. It was also a political maneuver, orchestrated by parent associations, aimed to take the responsibility for treatment away from the public mental health network of services. This article examines the controversies that have set parent associations in direct antagonism with mental health professionals in the public health system. We draw from ethnographic data and theoretical discussions in the field of disability studies to situate these controversies within the context of a larger debate on the relationship between health, rights, and citizenship. We found similarities between the ethical and political goals of parent activists and mental health professionals in Brazil, but we argue that the main cause of dissent is the role that each of these social actors assigns to identity politics in their clinical and political projects. PMID- 25842351 TI - Erratum to: Writing Prozak Diaries in Tehran: Generational Anomie and Psychiatric Subjectivities. PMID- 25842353 TI - Erratum to: Anti-miR-362-3p Inhibits Migration and Invasion of Human Gastric Cancer Cells by Its Target CD82. PMID- 25842354 TI - Differential Expression of Ion Channels and Transporters During Hepatocellular Carcinoma Development. AB - BACKGROUND: Ion channels and transporters are potential markers and therapeutic targets for several cancers. However, their expression during hepatocellular carcinoma (HCC) development remains unclear. AIM: To investigate the mRNA expression of Na(+), K(+) and Ca(2+) channels and ABC transporters during rat HCC development, as well as Abcc3 protein in human liver biopsies. METHODS: Wistar rats were treated with diethylnitrosamine (DEN) and developed both cirrhosis (12 weeks of treatment) and either pre-neoplastic lesions (16 weeks of treatment) or multinodular HCC (16 weeks of treatment plus 2 weeks DEN-free). The mRNA expression of 12 ion channels and two ABC transporters was studied using real time RT-PCR. Tumor-containing or tumor-free liver sections were isolated by laser capture microdissection. Abcc3 protein expression was studied by immunohistochemistry in healthy, cirrhotic and HCC human biopsies. RESULTS: We observed expression changes in seven genes. Kcna3, Kcnn4, Kcnrg and Kcnj11 potassium channel mRNA expression reached peak values at the end of DEN treatment, while Scn2a1 sodium channel, Trpc6 calcium channel and Abcc3 transporter mRNA expression reached their highest levels in the presence of HCC (18 weeks). Whereas Kcnn4 and Scn2a1 channel expression was similar in non-tumor and tumor tissue, the Abcc3 transporter and Kcna3 potassium channels were preferentially overexpressed in the tumor sections. We observed differential Abcc3 protein subcellular localization and expression in human samples. CONCLUSIONS: The ion channel/transporter expression profile observed suggests that these genes are potential early markers or therapeutic targets of HCC. The differential localization of Abcc3 may be useful in the diagnosis of cirrhosis and HCC. PMID- 25842355 TI - Multi-Dimensional Gastrointestinal Symptom Severity Index: Validation of a Brief GI Symptom Assessment Tool. AB - Few instruments have been developed and validated for the evaluation of multi dimensional GI symptoms. The Gastrointestinal Symptoms Severity Index (GISSI), a multi-dimensional, self-report instrument, was designed as a brief measure of the frequency, severity, and bothersomeness of individual GI and pelvic floor/urogynecologic symptoms. AIM: To report the psychometric properties of the GISSI subscales, including factorial structure, validity, and internal consistency. METHODS: The GISSI included 32 items that assessed upper and lower GI symptoms and seven items related to pelvic floor/urogynecologic symptoms. A total of 934 patients presenting for upper and lower GI complaints completed the questionnaire between January 2013 and December 2013. The sample was randomly split into derivation (n = 466) and validation datasets (n = 468). A non-patient sample of 200 was collected separately. RESULTS: Exploratory factor analysis supported a six-factor model for the derivation sample that accounted for 69.3 % of the total variance. The six GI symptom clusters were labeled as constipation/difficult defecation (five items), abdominal pain/discomfort (four items), dyspepsia (four items), diarrhea/anal incontinence (four items), GERD/chest symptoms (four items), and nausea/vomiting (two items). Inclusion of additional items related to female pelvic floor/urogynecologic symptoms resulted in a separate factor. Confirmatory factor analysis of the validation dataset supported the a priori hypothesized six-factor measurement model (Chi (2)(428) = 1462.98; P < 0.001; GFI = .88; RMSEA = .051). CONCLUSION: The GISSI demonstrated good to excellent psychometric properties and provided multi-dimensional scaling of prominent GI symptom clusters. Further validation may provide an efficient, valid, and reliable measure of patient-reported clinical outcomes. PMID- 25842356 TI - Awareness of modifiable acute myocardial infarction risk factors has little impact on risk perception for heart attack among vulnerable patients. AB - BACKGROUND: Poor awareness of modifiable risks for acute myocardial infarction (AMI) may explain the reported weak relationship between patients' actual and perceived risk for AMI. OBJECTIVES: To assess the level of awareness of modifiable risks and perceived vulnerability for AMI among Jordanian patients, and to determine their independent association. METHODS: This was a cross sectional correlational study (N = 231). Perceived risk, awareness of risk factors and risk profile were collected by self-reports and medical chart review. RESULTS: Patients were mostly males (80%) and had a mean of 55.3 +/- 12.6 years for age. Perceived and actual AMI risks were not highly congruent even though patients had, on average, two modifiable risks and were knowledgeable of them. Awareness of risk factors independently explained 3.5% of the variance in perceived risk. CONCLUSIONS: The risk for developing AMI is underestimated among cardiac patients and it is only weakly linked with their awareness of AMI risk factors. PMID- 25842357 TI - Impacts of cardiac rehabilitation on ventricular repolarization indexes and ventricular arrhythmias in patients affected by coronary artery disease and type 2 diabetes. AB - BACKGROUND: The benefits of cardiac rehabilitation in diabetic patients are well recognized. We aimed to assess its impact on ventricular repolarization indexes and the occurrence of ventricular arrhythmias in patients with coronary artery disease (CAD) and diabetes type 2. METHODS: From January 2012 to August 2013, 122 consecutive patients [diabetics (n = 59) and non diabetics (n = 63)] were prospectively enrolled in an out-patient rehabilitation program. Clinical examination, 12-lead ECG, 24-Holter ECGs and maximal exercise testing were performed at the beginning and end of the rehabilitation program in all patients. RESULTS: Diabetic patients showed significant decreases of repolarization indexes: QTc (-6.4%; p = 0.006), QTc disp (-22.6%; p = 0.050) and JTc (-9.4%; p = 0.003). At the end of the rehabilitation program diabetic patients showed a higher decrease in ventricular arrhythmias according to Lown classes' grading in comparison to non diabetics (-1.05 +/- 0.84 vs -0.74 +/- 0.91; p = 0.048). Insulin therapy was associated with a lower decrease in Lown classes compared to oral anti-diabetics (-0.95 +/- 0.80 vs -1.61 +/- 0.84; p < 0.001). CONCLUSION: Cardiac rehabilitation provided an improvement in the majority of ventricular repolarization indexes in patients with diabetes type 2 and CAD, decreasing the frequency of ventricular arrhythmias, particularly in those not treated by insulin. PMID- 25842358 TI - Neutrophil count is the most important prognostic component of the differential white cell count in patients undergoing elective surgery for colorectal cancer. AB - BACKGROUND: Systemic inflammatory scoring systems such as the NLR have been reported to have prognostic value in many solid organ cancers. The aim of this study was to examine the relationships between the components of the white cell count (WCC) and survival in patients undergoing elective surgery for colorectal cancer. METHODS: Patients undergoing elective resection at a single center (1997 to 2008) were identified from a prospective database (n = 508). Patient demographics and preoperative laboratory measurements including the differential WCC and their association with cancer-specific survival (CSS) and overall survival were examined. RESULTS: There were 172 cancer deaths and 120 noncancer deaths. On Kaplan-Meier analysis of the whole cohort, age, Tumor, Nodal, and Metastasis stage, venous invasion, margin involvement, peritoneal involvement and tumor perforation, and white cell and neutrophil count (all P < .05) were associated with CSS. In those with node-negative colon cancer (n = 226), on multivariate analysis, age, venous invasion, modified Glasgow Prognostic Score, and neutrophil count (all P < .05) were independently associated with CSS. CONCLUSION: Of the components of a differential WCC, only the neutrophil count was independently associated with survival, particularly in node-negative colon cancer. PMID- 25842359 TI - Structure coefficients and strategy selection in multiplayer games. AB - Evolutionary processes based on two-player games such as the Prisoner's Dilemma or Snowdrift Game are abundant in evolutionary game theory. These processes, including those based on games with more than two strategies, have been studied extensively under the assumption that selection is weak. However, games involving more than two players have not received the same level of attention. To address this issue, and to relate two-player games to multiplayer games, we introduce a notion of reducibility for multiplayer games that captures what it means to break down a multiplayer game into a sequence of interactions with fewer players. We discuss the role of reducibility in structured populations, and we give examples of games that are irreducible in any population structure. Since the known conditions for strategy selection, otherwise known as [Formula: see text]-rules, have been established only for two-player games with multiple strategies and for multiplayer games with two strategies, we extend these rules to multiplayer games with many strategies to account for irreducible games that cannot be reduced to those simpler types of games. In particular, we show that the number of structure coefficients required for a symmetric game with [Formula: see text]-player interactions and [Formula: see text] strategies grows in [Formula: see text] like [Formula: see text]. Our results also cover a type of ecologically asymmetric game based on payoff values that are derived not only from the strategies of the players, but also from their spatial positions within the population. PMID- 25842360 TI - Design, synthesis, and biological evaluation of pyrimidine-2-carboxamide analogs: investigation for novel RAGE inhibitors with reduced hydrophobicity and toxicity. AB - This paper describes an investigation of novel RAGE inhibitors with improved drug like properties. To identify the improved drug-like RAGE inhibitor, we designed and synthesized pyrimidine-2-carboxamide analogs based on our previous work. Several potent analogs with improved hydrophilicity were identified by evaluation of RAGE inhibitory activity. In particular, one of the potent (diethylamino)ethoxymethoxy analogs did not exhibit undesired cytotoxicity in contrast with the parent RAGE inhibitors. PMID- 25842361 TI - Analysis of speed, curvature, planarity and frequency characteristics of heart vector movement to evaluate the electrophysiological substrate associated with ventricular tachycardia. AB - BACKGROUND: We developed a novel method of assessing ventricular conduction using the surface ECG. METHODS: Orthogonal ECGs of 81 healthy controls (age 39.0+/-14.2 y; 51.8% males; 94% white), were compared with iDower-transformed 12-lead ECGs (both 1000Hz), recorded in 8 patients with infarct-cardiomyopathy and sustained monomorphic ventricular tachycardia (VT) (age 68.0+/-7.8y, 37.5% male, mean LVEF 29+/-12%). Normalized speed at 10 QRS segments was calculated as the distance traveled by the heart vector along the QRS loop in three-dimensional space, divided by 1/10th of the QRS duration. Curvature was calculated as the magnitude of the derivative of the QRS loop tangent vector divided by speed. Planarity was calculated as the mean of the dihedral angles between 2 consecutive planes for all planes generated for the median beat. Orbital frequency (a scalar measure of rotation rate of the QRS vector) was calculated as a product of speed and curvature. RESULTS: Mixed regression analysis showed that speed was slower [6.6 (95%CI 4.4-8.9) vs. 24.6 (95%CI 11.5-37.7)uV/ms; P<0.0001]; orbital frequency was smaller [1.4 (95%CI 1.2-1.6) vs. 6.8 (95%CI 5.4-8.1)ms(-1); P<0.0001], and planarity was larger by 3.6 degrees (95%CI 1.4 degrees -5.8; P=0.002) in VT cases than in healthy controls. ROC AUC for orbital frequency was 0.940 (95%CI 0.935-0.944) across all frequencies and QRS segments. ROC AUC for planarity at 70 249Hz was 0.995 (95%CI 0.985-1.00). ROC AUC for speed at 70-79Hz was 0.979 (95%CI 0.969-0.989). CONCLUSION: This novel method reveals characteristic features of an abnormal electrophysiological substrate associated with VT. PMID- 25842362 TI - Histological features of peri-implant bone subjected to overload. AB - PURPOSE: The aim of this review has been to investigate the histological findings of bone structure surrounding implants subjected to excessive load. MATERIALS AND METHODS: Clinical and pre-clinical histological studies that observed overloaded intraoral implants were included. RESULTS: All included studies (n=15) were conducted on animals. Most of them failed to find pathological alteration in the microstructure of bone surrounding overloaded implants. Overload and infection alone may induce bone loss, but related lesions have different and peculiar features. CONCLUSIONS: The different histological features observed around implants subjected to overload or to ligature-induced peri-implantitis may indicate a specific pathogenetic mechanism for overload or infection-induced loss of osseointegration. The clinical significance of these findings should be confirmed in human studies. PMID- 25842363 TI - Design and synthesis of piperazine derivatives as a novel class of gamma secretase modulators that selectively lower Abeta42 production. AB - Novel piperazine derivatives as gamma-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Abeta42 production. Lead compound 3, with selective Abeta42-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Abeta42 in mice. PMID- 25842364 TI - Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs. AB - Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC50 1.4 +/- 1.3 MUM) and S1 (IC50 1.8 +/- 0.9 MUM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC50 15.8+/-3.7 MUM; p<0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells' sizes were also markedly increased and were obvious at 68 h of treatment with 1 MUM in HCT 116 (colon) and PC-3 (prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC50 values <10 MUM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean ICv values in the range 3.3-10.7 MUM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and beta-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents. PMID- 25842365 TI - Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors. AB - Nineteen new derivatives based on the structure of marine natural product tasiamide B were designed, synthesized, and evaluated for their inhibitory activity against BACE1, a potential therapeutic target for Alzheimer's disease. The hydrophobic substituents Val at P3 position, Leu at P1' position, Ala at P2' position, and Phe at P3' position were found to significantly affect the inhibition. Free carboxylic acid at C-terminus was also found to be important to the activity. In addition, the structure-activity relationships (SARs) were supported by molecular docking simulation. PMID- 25842367 TI - Overcoming Resistance Without the Risk of Reaction: Use of Afatinib and Panitumumab in Two Cases of Epidermal Growth Factor Receptor--Mutated Non--Small Cell Lung Cancer With T790M Mutations. PMID- 25842366 TI - Hepatocyte growth factor activator inhibitor type 1 maintains the assembly of keratin into desmosomes in keratinocytes by regulating protease-activated receptor 2-dependent p38 signaling. AB - Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol SPINT1) is a membrane-associated serine proteinase inhibitor abundantly expressed in epithelial tissues. Genetically engineered mouse models demonstrated that HAI 1 is critical for epidermal function, possibly through direct and indirect regulation of cell surface proteases, such as matriptase and prostasin. To obtain a better understanding of the role of HAI-1 in maintaining epidermal integrity, we performed ultrastructural analysis of Spint1-deleted mouse epidermis and organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, HaCaT. We found that the aggregation of tonofilaments to desmosomes was significantly reduced in HAI-1-deficient mouse epidermis with decreased desmosome number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated protein kinase was activated in response to HAI-1 insufficiency. Treatment of HAI 1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), because its silencing abrogated the enhanced activation of p38. Consequently, treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic culture. These results suggest that HAI-1 may have a critical role in maintaining normal keratinocyte morphology through regulation of PAR-2-dependent p38 mitogen activated protein kinase signaling. PMID- 25842368 TI - Mass spectrometric quantification of glucosylsphingosine in plasma and urine of type 1 Gaucher patients using an isotope standard. AB - Deficiency of glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Recently, we reported marked increases of deacylated GlcCer, named glucosylsphingosine (GlcSph), in plasma of GD patients. To improve quantification, [5-9] (13)C5-GlcSph was synthesised for use as internal standard with quantitative LC-ESI-MS/MS. The method was validated using plasma of 55 GD patients and 20 controls. Intra-assay variation was 1.8% and inter-assay variation was 4.9% for GlcSph (m/z 462.3). Plasma GlcSph levels with the old and new methods closely correlate (r=0.968, slope=1.038). Next, we analysed GlcSph in 24h urine samples of 30 GD patients prior to therapy. GlcSph was detected in the patient samples (median 1.20nM, range 0.11-8.92nM), but was below the limit of quantification in normal urine. Enzyme replacement therapy led to a decrease of urinary GlcSph of GD patients, coinciding with reductions in plasma GlcSph and markers of Gaucher cells (chitotriosidase and CCL18). In analogy to globotriaosylsphingsone in urine of Fabry disease patients, additional isoforms of GlcSph differing in structure of the sphingosine moiety were identified in GD urine samples. In conclusion, GlcSph can be sensitively detected by LC-ESI-MS/MS with an internal isotope standard. Abnormalities in urinary GlcSph are a hallmark of Gaucher disease allowing biochemical confirmation of diagnosis. PMID- 25842369 TI - Polymorphic variations influencing fetal hemoglobin levels: association study in beta-thalassemia carriers and in normal individuals of Portuguese origin. AB - Three major loci have been associated with HbF levels, including -158C/T (XmnI) at HBG2 promoter region, and several polymorphisms at BCL11A intron-2 and HBS1L MYB (HMIP) intergenic region. Mutations in the KLF1 gene were recently associated with increased HbF levels. This study aims to evaluate whether genetic variability at these loci influences HbF levels in beta-thalassemia carriers and in normal individuals of Portuguese origin. Sixty five beta-thalassemia carriers, HbF levels ranging from 0.2% to 9.5%, and 60 individuals with normal hematological parameters, HbF levels ranging from 0.2% to 7.4%, were selected for this study. In beta-thal carriers linear regression models revealed a strong statistical significant association for HBG2 (XmnI) rs7482144 (beta=0.455; P=5.858*10(-7)), and nominal significance for BCL11A rs766432 (beta=0.215; P=0.029) and HMIP rs9399137 (beta=0.209; P=0.011). In normal individuals, a case (HbF>2%; n=15) vs. control (HbF<1.7%; n=45) model, showed nominal significant associations for BCL11A SNPs rs11886868 (OR=4; P=0.001), rs766432 (OR=3.7; P=0.002) and rs7606173 (OR=0.36; P=0.032). KLF1 rs3817621 was not found associated with HbF levels. Our results suggest that in Portuguese beta-thal carriers the HBG2 XmnI polymorphism is strongly associated with HbF levels. In normal individuals, BCL11A polymorphisms, but not HMIP or HBG2 (XmnI) loci, are nominally associated with HbF expression. PMID- 25842370 TI - Severity of Brazilian sickle cell disease patients: severity scores and feasibility of the Bayesian network model use. AB - The integration of the several clinical and laboratory dimensions and the influence of each parameter on the sickle cell disease (SCD)-related mortality is useful for predicting the phenotype of an individual. This study evaluated the feasibility of the SCD severity calculator use to measure disease severity in Brazilian patients. The study group was composed of 500 SCD patients (440 HbSS and 60 HbSC) diagnosed by molecular biology. We observed a decrease in severity scores in 72 SCD patients assessed before and after the hydroxyurea (HU) use. Furthermore, the HU influenced the increase of mean corpuscular volume (MCV) and HbF concentration, and the decrease of leukocytes and total bilirubin. We found 180 (36.0%) patients with intermediate phenotype, 170 (34.0%) mild phenotype and 150 (30.0%) with severe phenotype. Patients with ages >40 years had higher mean score (0.778+/-0.177) than patients between 18 and 40 years (0.562+/-0.152) and patients between 5 and 17 years (0.322+/-0.145). We observe that there is a tendency of individuals with leg ulcers, avascular necrosis and cardiac complications with increasing age. Correlation analysis showed relations between severity scores with leukocytes, reticulocytes, bilirubin, lactate dehydrogenase, HbS, hemoglobin and hematocrit (p<0.05). Several comparisons involving age groups, SCD genotype and phenotypic classification had satisfactory results and this classification will be used for future studies involving genetic polymorphisms, response to treatment with HU and oxidative stress markers in SCD. PMID- 25842371 TI - Quantitative proteomic analysis of the brainstem following lethal sarin exposure. AB - The brainstem represents a major tissue area affected by sarin organophosphate poisoning due to its function in respiratory and cardiovascular control. While the acute toxic effects of sarin on brainstem-related responses are relatively unknown, other brain areas e.g., cortex or cerebellum, have been studied more extensively. The study objective was to analyze the guinea pig brainstem toxicology response following sarin (2*LD50) exposure by proteome pathway analysis to gain insight into the complex regulatory mechanisms that lead to impairment of respiratory and cardiovascular control. Guinea pig exposure to sarin resulted in the typical acute behavior/physiology outcomes with death between 15 and 25min. In addition, brain and blood acetylcholinesterase activity was significantly reduced in the presence of sarin to 95%, and 89%, respectively, of control values. Isobaric-tagged (iTRAQ) liquid chromatography tandem mass spectrometry (LC-MS/MS) identified 198 total proteins of which 23% were upregulated, and 18% were downregulated following sarin exposure. Direct gene ontology (GO) analysis revealed a sarin-specific broad-spectrum proteomic profile including glutamate-mediated excitotoxicity, calcium overload, energy depletion responses, and compensatory carbohydrate metabolism, increases in ROS defense, DNA damage and chromatin remodeling, HSP response, targeted protein degradation (ubiquitination) and cell death response. With regards to the sarin-dependent effect on respiration, our study supports the potential interference of sarin with CO2/H(+) sensitive chemoreceptor neurons of the brainstem retrotrapezoid nucleus (RTN) that send excitatory glutamergic projections to the respiratory centers. In conclusion, this study gives insight into the brainstem broad spectrum proteome following acute sarin exposure and the gained information will assist in the development of novel countermeasures. PMID- 25842372 TI - Neural correlates of taste and pleasantness evaluation in the metabolic syndrome. AB - Metabolic syndrome (MetS) is a constellation of cardiometabolic abnormalities that commonly occur together and increase risk for cardiovascular disease and type II diabetes. Having MetS, especially during middle-age, increases the risk for dementia in later life. Abdominal obesity is a central feature of MetS; therefore, increased efforts to prevent obesity and identify predictors of weight gain are of extreme importance. Altered processing of food reward in the brain of obese individuals has been suggested to be a possible mechanism related to overeating. We scanned fifteen healthy middle-aged controls (aged 44-54) and sixteen middle-aged adults with MetS after a fast (hungry) and after a preload (sated), while they rated the pleasantness of sucrose (sweet) and caffeine (bitter) solutions. Data were analyzed using voxelwise linear mixed-effects modeling, and a region of interest analysis to examine associations between hypothalamic activation to sweet taste and BMI during hunger and satiety. The results indicate that middle-aged individuals with MetS respond with significantly less brain activation than controls without MetS during pleasantness evaluation of sweet and bitter tastes in regions involved in sensory and higher-level taste processing. Participants with higher BMI had greater hypothalamic response during pleasantness evaluation of sucrose in the sated condition. Importantly, this study is the first to document differential brain circuitry in middle-aged adults with MetS, a population at risk for poor physical and cognitive outcomes. Future research aimed at better understanding relationships among MetS, obesity, and brain function is warranted to better conceptualize and develop interventions for overeating in these disorders. PMID- 25842373 TI - ERV enhances spatial learning and prevents the development of infarcts, accompanied by upregulated BDNF in the cortex. AB - PURPOSES: An anti-allergic and analgesic drug, "an extract derived from the inflamed cutaneous tissue of rabbits inoculated with vaccinia virus (ERV)", has been used in medical practice in Japan and some other countries. We examined the effect of ERV, prior to induction of ischemia, on the development of cerebral infarction, on learning and memory, or on brain-derived neurotrophic factor (BDNF) levels in C57BL/6J mice. METHODS: Following oral administration of ERV (the same in humans: *1) or vehicle, daily for three consecutive weeks, temporary focal ischemia was induced by the three vessel occlusion technique. In the other group of animals, after daily ERV (Low: *1; Med: *3, or High dose: *9) or vehicle administration for three weeks, we performed a quantitative assessment of spatial learning or intracerebral BDNF levels. RESULTS: The volumes of infarcted lesions, brain edema and the extent of the neurological deficits were significantly reduced in the ERV-treated group. ERV treatment also enhanced spatial learning, accompanied by upregulated BDNF in the cortex. CONCLUSIONS: Daily oral intake of ERV, at a clinically relevant dose, protects the brain from ischemic stroke, and also enhances the learning function in normal mice. As millions of people are currently taking the drug safely, and have been for many years in some cases, there is a need to test the inhibitory actions of the drug on progressive dementia encountered in humans with recurrent ischemic attacks or Alzheimer's disease. PMID- 25842374 TI - Production of poly(3-hydroxypropionate) and poly(3-hydroxybutyrate-co-3 hydroxypropionate) from glucose by engineering Escherichia coli. AB - Poly(3-hydroxypropionate) (P3HP) is the strongest family member of microbial polyhydroxyalkanoates (PHA) synthesized by bacteria grown on 1,3-propandiol or glycerol. In this study synthesis pathways of P3HP and its copolymer P3HB3HP of 3 hydroxybutyrate (3HB) and 3-hydroxypropionate (3HP) were assembled respectively to allow their synthesis from glucose, a more abundant carbon source. Recombinant Escherichia coli was constructed harboring the P3HP synthetic pathway consisting of heterologous genes encoding glycerol-3-phosphate dehydrogenase (gpd1), glycerol-3-P phosphatase (gpp2) from Saccharomyces cerevisiae that catalyzes formation of glycerol from glucose, and genes coding glycerol dehydratase (dhaB123) with its reactivating factors (gdrAB) from Klebsiella pneumoniae that transfer glycerol to 3-hydroxypropionaldehyde, as well as gene encoding propionaldehyde dehydrogenase (pdup) from Salmonella typhimurium which converts 3 hydroxypropionaldehyde to 3-hydroxypropionyl-CoA, together with the gene of PHA synthase (phaC) from Ralstonia eutropha which polymerizes 3-hydroxypropionyl-CoA into P3HP. When phaA and phaB from Ralstonia eutropha respectively encoding beta ketothiolase and acetoacetate reductase, were introduced into the above P3HP producing recombinant E. coli, copolymers poly(3-hydroxybutyrate-co-3 hydroxypropionate) (P3HB3HP) were synthesized from glucose as a sole carbon source. The above E. coli recombinants grown on glucose LB medium successfully produced 5g/L cell dry weight containing 18% P3HP and 42% P(3HB-co-84mol% 3HP), respectively, in 48h shake flask studies. PMID- 25842375 TI - Quinine for muscle cramps. AB - BACKGROUND: Muscle cramps can occur anywhere and for many reasons. Quinine has been used to treat cramps of all causes. However, controversy continues about its efficacy and safety. This review was first published in 2010 and searches were updated in 2014. OBJECTIVES: To assess the efficacy and safety of quinine-based agents in treating muscle cramps. SEARCH METHODS: On 27 October 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. We searched reference lists of articles up to 2014. We also searched for ongoing trials in November 2014. SELECTION CRITERIA: Randomised controlled trials of people of all ages with muscle cramps in any location and of any cause, treated with quinine or its derivatives. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials for inclusion, assessed risk of bias and extracted data. We contacted study authors for additional information. For comparisons including more than one trial, we assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). MAIN RESULTS: We identified 23 trials with a total of 1586 participants. Fifty-eight per cent of these participants were from five unpublished studies. Quinine was compared to placebo (20 trials, n = 1140), vitamin E (four trials, n = 543), a quinine-vitamin E combination (three trials, n = 510), a quinine theophylline combination (one trial, n = 77), and xylocaine injections into the gastrocnemius muscle (one trial, n = 24). The most commonly used quinine dosage was 300 mg/day (range 200 to 500 mg). We found no new trials for inclusion when searches were updated in 2014.The risk of bias in the trials varied considerably. All 23 trials claimed to be randomised, but only a minority described randomisation and allocation concealment adequately.Compared to placebo, quinine significantly reduced cramp number over two weeks by 28%, cramp intensity by 10%, and cramp days by 20%. Cramp duration was not significantly affected.A significantly greater number of people suffered minor adverse events on quinine than placebo (risk difference (RD) 3%, 95% confidence interval (CI) 0% to 6%), mainly gastrointestinal symptoms. Overdoses of quinine have been reported elsewhere to cause potentially fatal adverse effects, but in the included trials there was no significant difference in major adverse events compared with placebo (RD 0%, 95% CI -1% to 2%). One participant suffered from thrombocytopenia (0.12% risk) on quinine.A quinine-vitamin E combination, vitamin E alone, and xylocaine injections into gastrocnemius were not significantly different to quinine across all outcomes, including adverse effects. Based on a single trial comparison, quinine alone was significantly less effective than a quinine-theophylline combination but with no significant differences in adverse events. AUTHORS' CONCLUSIONS: There is low quality evidence that quinine (200 mg to 500 mg daily) significantly reduces cramp number and cramp days and moderate quality evidence that quinine reduces cramp intensity. There is moderate quality evidence that with use up to 60 days, the incidence of serious adverse events is not significantly greater than for placebo in the identified trials, but because serious adverse events can be rarely fatal, in some countries prescription of quinine is severely restricted.Evidence from single trials suggests that theophylline combined with quinine improves cramps more than quinine alone, and the effects of xylocaine injections into gastrocnemius are not significantly different to quinine across all outcomes. Low or moderate quality evidence shows no significant difference between quinine and vitamin E or quinine and quinine vitamin E mixture. Further research into these alternatives, as well other pharmacological and non-pharmacological treatments, is thus warranted.There is no evidence to judge optimal dosage or duration of quinine treatment. Further studies using different dosages and measurement of serum quinine levels will allow a therapeutic range to be defined for muscle cramp. Because serious adverse events are not common, large population studies are required to more accurately inform incidence. Longer lengths of follow-up in future trials will help determine the duration of action following cessation of quinine as well as long term adverse events. The search for new therapies, pharmacological and nonpharmacological, should continue and further trials should compare vitamin E, quinine-vitamin E combination, and quinine-theophylline mixture with quinine. PMID- 25842376 TI - Asbestos fibres in the lungs of an American mechanic who drilled, riveted, and ground brake linings: a case report and discussion. AB - In North America and Europe, the use of asbestos in friction products was discontinued before the end of the 20th century. In the developing world, the use of asbestos-containing friction products continues. In 2010, Cely-Garcia and colleagues (Cely-Garcia et al., 2012) sampled three brake repair shops located in Bogota, Colombia. Both asbestos and non-asbestos containing brake linings were sold separately or attached to a shoe. When brake linings are sold separated from the shoe, they must be manipulated to attach them to the shoe before installation. The process starts with the removal of the old brake shoe from the vehicle's brake drum. If the existing brake shoe is to be reused, the old lining needs to be removed and the old shoe must be ground to prepare it for a new lining. Riveting requires drilling holes in the linings and shoes and before installing rivets, the lining must be countersunk. The borders of the lining are bevelled. On some occasions, the entire exposed surface of the lining is ground to make it thinner. Once attached to the shoe, the edges of brake linings may extend beyond the shoe. In this case, it is necessary to cut or grind the edges to match the lining to the shoe before bevelling or grinding. The authors reported that 'the sampling results indicate that the brake mechanics sampled are exposed to extremely high asbestos concentrations (i.e. based on transmission electron microscopy counts), suggesting that this occupational group could be at excess risk of asbestos-related diseases'. PMID- 25842378 TI - Hoping Is Coping: A Guiding Theoretical Framework for Promoting Coping and Adjustment Following Pediatric Cancer Diagnosis. AB - OBJECTIVE: To determine the pattern of resilience and adjustment following pediatric cancer diagnosis and to evaluate hope as a mediator of adjustment. METHODS: 61 participants with pediatric cancer completed measures of hope, depression, anxiety, and quality of life (QoL) within 4 weeks of cancer diagnosis and every 3 months for 1 year. RESULTS: Participants showed high and increasing levels of hope and QoL, as well as low and decreasing levels of depression and anxiety. Linear mixed-effects regression analyses revealed changes in depression, anxiety, and hope to be significant predictors of changes in QoL. Changes in hope were found to partially mediate the effects of depression and anxiety on QoL. CONCLUSIONS: While a variety of interventions are efficacious for treating anxiety and depression, hope theory provides a framework for choosing interventions that may more globally promote children's ability to maintain good functioning, adjustment, well-being, and QoL following cancer diagnosis. PMID- 25842377 TI - Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity. AB - Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL(-/-) mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks. Profound increases of MG species in the MGL(-/-) mice compared with WT control mice were found. Weight gain over the 12 weeks was blunted in both diet groups. MGL(-/-) mice were leaner than WT mice at both baseline and after 12 weeks of LFD feeding. Circulating lipids were decreased in HFD-fed MGL(-/-) mice, as were the levels of several plasma peptides involved in glucose homeostasis and energy balance. Interestingly, MGL(-/-) mice had markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption. Overall, the results indicate that global MGL deletion leads to systemic changes that produce a leaner phenotype and an improved serum metabolic profile. PMID- 25842379 TI - Prevalence of and contributing factors for overweight and obesity among Montenegrin schoolchildren. AB - BACKGROUND: Newly emerging Western style economic systems provide new opportunities to study the prevalence and predictors of childhood obesity. We also provide for the first time a national study of childhood obesity using all three international anthropometric criteria. METHODS: The sample included 4097 Montenegrin children, 2076 boys (50.7%) and 2021 girls. Anthropometric measurements were performed in school. The questionnaire for parents included questions on 24 potential contributing factors for childhood obesity. Nutritional status was assessed according to World Health Organization, US Center for Disease Prevention and Control and International Obesity Task Force (IOTF) criteria. RESULTS: Overall percentage of Montenegrin children who are overweight or obese (IOTF) is 22.9% of which 5.3% are obese (7.0% boys vs. 3.5% girls). We found 10 factors to be independently associated with child obesity. Positive relations [odds ratio (95% confidence interval)] were found with maternal obesity [2.05 (1.68-2.51)], paternal obesity [1.67 (1.32-2.10)], paternal employment [1.40 (1.12-1.74)], maternal smoking [1.32 (1.08-1.61)], obesity at birth [1.33 (1.04 1.70)] and computer game playing [per hour--1.11 (1.00-1.24)]. Negative relations were found with female gender [0.64 (0.53-0.78)], the number of siblings [0.88 (0.78-0.98)], birth order [0.73 (0.64-0.83)] and age [0.92 (0.88-0.98)]. CONCLUSION: One out of four Montenegrin children is overweight, with two times more frequent obesity among boys compared with girls. Some previously salient predictors did not appear salient in this sample. To enable worldwide comparability, we propose the use of all three childhood obesity criteria in national studies. PMID- 25842380 TI - The effect of Greek herbal tea consumption on thyroid cancer: a case-control study. AB - BACKGROUND: Although in the last decade several studies have addressed the protective role of black and green tea on several diseases, including cancer, there are only few and controversial studies on the effect of tea on benign and malignant thyroid diseases. METHODS: An age and gender group matched case-control study conducted in Athens, Greece, was designed. 113 Greek patients with histologically confirmed thyroid cancer and 286 patients with benign thyroid diseases along with 138 healthy controls were interviewed with a pre-structured questionnaire in person by trained interviewers. RESULTS: An inverse association between chamomile tea consumption and benign/malignant thyroid diseases was found (P < 0.001). The odds of chamomile tea consumption, two to six times a week, after controlling for age, gender and BMI, were 0.30 (95% CI: 0.10-0.89) and 0.26 (95% CI: 0.12-0.5) for developing thyroid cancer and benign thyroid diseases, respectively when compared with not consumption. The duration of consumption was also inversely associated with the diseases. Thirty years of consumption significantly reduced the risk of thyroid cancer and benign thyroid diseases development by almost 80%. Similar, although weaker protective association, was found for sage and mountain tea. Adjustment for smoking, alcohol and coffee consumption did not alter the results. CONCLUSIONS: Our findings suggest for the first time that drinking herbal teas, especially chamomile, protects from thyroid cancer as well as other benign thyroid diseases. PMID- 25842381 TI - Are Spanish primary care professionals aware of patient safety? AB - BACKGROUND: Knowledge about safety culture improves patient safety (PS) in health care organizations. The first contact a patient has with health care occurs at the primary level. We conducted a survey to measure patient safety culture (PSC) among primary care professionals (PCPs) of health centres (HCs) in Spain and analyzed PS dimensions that influence PSC. METHODS: We used Agency for Healthcare Research and Quality (AHRQ) Medical Office Survey on Patient Safety Culture translated and validated into Spanish to conduct a cross-sectional anonymous postal survey. We randomly selected a sample of 8378 PCPs at 289 HCs operated by 17 Regional Health Services. Statistical analysis was performed on sociodemographic variables, survey items, PS dimensions and a patient safety synthetic index (PSSI), calculated as average score of the items per dimension, to identify potential predictors of PSC. We used AHRQ data to conduct international comparison. RESULTS: A total of 4344 PCPs completed the questionnaire. The response rate was 55.69%. Forty-two percent were general practitioners, 34.9% nurses, 18% administrative staff and 4.9% other professionals. The highest scoring dimension was 'PS and quality issues' 4.18 (4.1-4.20) 'Work pressure and pace' was the lowest scored dimension with 2.76 (2.74-2.79). Professionals over 55 years, with managerial responsibilities, women, nurses and administrative staff, had better PSSI scores. Professionals with more than 1500 patients and working for more than 11 years at primary care had lower PSSI scores. CONCLUSIONS: This is the first national study to measure PSC in primary care in Spain. Results may reflect on-going efforts to build a strong PSC. Further research into its association with safety outcomes and patients' perceptions is required. PMID- 25842382 TI - Increasing Melanoma Screening Among Hispanic/Latino Americans: A Community-Based Educational Intervention. AB - Melanoma incidence is increasing among Hispanics/Latinos in California. This community-based project reached out to a rural Hispanic/Latino community in North San Diego County to provide melanoma prevention and screening education. At a local community health fair, bilingual volunteer lay health workers led 10- to 15 minute-long information sessions on melanoma disease, risk factors, and skin self examination techniques. Pearson chi-square analyses of participants' (N = 34) responses to pre- and postintervention evaluation surveys indicate significant increases in knowledge, risk awareness, and self-efficacy for self-screening. The results revealed that Hispanics/Latinos in a low socioeconomic stratum might be at moderate to high risk for developing melanoma. Their low annual income, low level of education, occupational sun-exposure, and lack of access to health care are likely factors that deter at-risk Hispanics/Latinos from seeking health care. PMID- 25842383 TI - Individual, Social, and Environmental Correlates of Healthy and Unhealthy Eating. AB - BACKGROUND: Few studies use comprehensive ecological approaches considering multilevel factors to understand correlates of healthy (and unhealthy) dietary intake. The aim of this study was to examine the association between individual, social, and environmental factors on composite measures of healthy and unhealthy dietary intake in adults. METHOD: Participants (n = 565) of the Australian RESIDential Environments (RESIDE) project self-reported dietary intake, home food availability, and behavioral and perceived social and physical environmental influences on food choices. A geographic information system measured proximity of supermarkets from each participant's home. "Healthy" and "unhealthy" eating scores were computed based on adherence to dietary guidelines. Univariate and multivariate models were constructed using linear regression. RESULTS: After full adjustment, "healthy" eating (mean = 6.25, standard deviation [SD] = 1.95) was significantly associated with having confidence to prepare healthy meals (beta = 0.34; 95% confidence interval [CI] = [0.13, 0.55]); having more healthy (beta = 0.13; 95% CI = [0.09-0.16]) and fewer unhealthy (beta = -0.04; 95% CI = [-0.06, 0.02]) foods available at home; and having a supermarket within 800 meters of home (beta = 1.39; 95% CI = [0.37, 2.404]). "Unhealthy" eating (mean = 3.53, SD = 2.06) was associated with being male (beta = 0.39; 95% CI = [0.02, 0.75]), frequently eating takeaway (beta = 0.33; 95% CI = [0.21, 0.46]) and cafe or restaurant meals (beta = 0.20; 95% CI = [0.06, 0.33]) and having fewer healthy (beta = -0.07; 95% CI = [-0.10, -0.03]) and more unhealthy (beta = 0.09; 95% CI = [0.07, 0.10]) foods available within the home. CONCLUSION: Initiatives to improve adherence to dietary guidelines and reduce the consumption of unhealthy foods needs to be multifaceted; addressing individual factors and access to healthy food choices in both the home and neighborhood food environment. Ensuring proximity to local supermarkets, particularly in new suburban developments, appears to be an important strategy for facilitating healthy eating. PMID- 25842384 TI - Insights for Exercise Adherence From a Minimal Planning Intervention to Increase Physical Activity. AB - OBJECTIVE: To test the impact of a minimal, online planning intervention on physical activity in Australian office workers. METHOD: Employees were randomized to an implementation intention intervention (n = 124) or health information control group (n = 130). Measures of physical activity, past behavior, and motivation were taken at baseline and 6 weeks. RESULTS: Analysis revealed both groups increased weekly physical activity sessions (intervention M = 1.12, control M = 0.78) at follow-up, but no significant difference was found between groups. Because the sample consisted of experienced exercisers, secondary analyses investigated differential effects for those who had lapsed over the previous year (nonmaintainers) and those who had maintained their previous level of activity (maintainers). For nonmaintainers, both planning and information provision successfully changed behavior, but only planning significantly increased physical activity in maintainers over the study. CONCLUSION: Different minimal intervention approaches may be useful for preventing long-term relapse and assisting people to improve regular exercise routines. The practical and theoretical implications are discussed. PMID- 25842385 TI - Does Successful Weight Loss in an Internet-Based Worksite Weight Loss Program Improve Employee Presenteeism and Absenteeism? AB - Certain risk factors associated with overweight and obesity may lead to reduced productivity in the workforce (i.e., increased absenteeism and presenteeism). Participants in a large, Internet-based worksite weight loss intervention, who were present at follow-up (N = 1,030), completed a self-reported productivity measure (World Health Organization's Health and Work Performance Questionnaire) at baseline and postintervention. Twenty-two percent of the participants lost a clinically meaningful amount of weight (>=5% weight loss). There were no statistically significant (p < .05) relationships between weight change from baseline to 12 months and change scores of absolute or relative absenteeism or for absolute or relative presenteeism. Within a modestly successful Internet based, worksite weight loss intervention, weight loss did not improve self reported absenteeism or presenteeism. Further studies are needed to explore the sensitivity of the World Health Organization's Health and Work Performance Questionnaire and the long-term effects of weight loss on productivity. PMID- 25842386 TI - Racial/Ethnic Differences in Use of Health Care Services for Diabetes Management. AB - Research demonstrates consistent racial/ethnic disparities in access to and use of health care services for a variety of chronic conditions. Yet we know little about whether these disparities exist for use of health care services for diabetes management. Racial/ethnic minorities disproportionately suffer from diabetes, complications from diabetes, and diabetes-related mortality. Proper diabetes management can reduce the risk of complications and premature mortality. Using a large national data set (N = 37,705) of White, Black, Hispanic, Asian, and Native American U.S. adults aged 65 years and older who have been diagnosed with diabetes, we examine three specific types of health care provider (HCP) use for diabetes management: number of times seen by a health care professional for diabetes, number of times feet have been checked by a health care professional, and number of visits for a glycosylated hemoglobin check. We found that net of controls for a variety of demographic and socioeconomic characteristics, Blacks and Hispanics had significantly more visits to a HCP for their diabetes and significantly more glycosylated hemoglobin checks than Whites, and Blacks and Native Americans had significantly more HCP feet checks than Whites. Our results suggest that the reduced access to health care services traditionally found among racial/ethnic minorities does not hold for access to health care services for diabetes management, where racial/ethnic minority diabetics are actually more likely to use care than are White diabetics. Future research should examine whether higher use of health care services for diabetes among racial/ethnic minorities is due to greater disease severity among racial/ethnic minorities than among non-Hispanic Whites. PMID- 25842387 TI - Relationships Between Illicit Drug Use and Body Mass Index Among Adolescents. AB - Prior research has established associations between body mass index (BMI) and use of alcohol, tobacco, and marijuana. However, little research has been done investigating the relationship between other common illicit drugs and BMI trends. The present study investigated whether adolescents who reported using illicit drugs showed differences in BMI compared to peers who reported no drug use. There was a positive relationship between drug use and BMI as well as the number of drugs used and BMI. The results suggested that the positive relationship between the use of illicit drugs and BMI is largely due to smoking. Further research needs to ascertain whether smoking, illicit drug use, or both are among the first of many unhealthy behaviors that can subsequently lead to greater gains in BMI. Implications for health educators are discussed. PMID- 25842388 TI - Searching for the Kinkeepers: Historian Gender, Age, and Type 2 Diabetes Family History. AB - Kinkeepers facilitate family communication and may be key to family medical history collection and dissemination. Middle-aged women are frequently kinkeepers. Using type 2 diabetes (T2DM) as a model, we explored whether the predicted gender and age effects of kinkeeping can be extended to family medical historians. Through a U.S. telephone survey, nondiabetic Mexican Americans (n = 385), Blacks (n = 387), and Whites (n = 396) reported family histories of T2DM. Negative binomial regressions used age and gender to predict the number of affected relatives reported. Models were examined for the gender gap, parabolic age effect, and gender-by-age interaction predicted by kinkeeping. Results demonstrated support for gender and parabolic age effects but only among Whites. Kinkeeping may have application to the study of White family medical historians, but not Black or Mexican American historians, perhaps because of differences in family structure, salience of T2DM, and/or gender roles. PMID- 25842389 TI - Fruit and Vegetable Attitudes, Norms, and Intake in Low-Income Youth. AB - Fruit and vegetable (FV) attitudes and norms have been shown to influence intake in youth; yet research with low-income youth and studies supplementing self report with objective measures of intake are lacking. Cross-sectional survey data on self-rated FV intake, FV attitudes, and FV norms were collected in a sample of 116 youth attending a residential summer camp serving low-income families. FV intake also was estimated by direct observation. Differences between self-rated and observed FV intake, perceived and observed peer intake, and perceived and peer-reported attitudes toward eating FVs were assessed with paired samples t tests. The role of FV attitudes, descriptive norms (perceived peer FV intake), injunctive norms (perceived peer attitudes toward eating FVs), and actual norms (observed peer FV intake and peer-reported FV attitudes) in predicting FV intake also was examined with multiple regression analysis. Youth misperceived their own and their peers' FV intake (i.e., overestimated intake of fruit and underestimated intake of vegetables) and believed that peers held less favorable attitudes toward eating FVs than was the case. The models predicting self-rated intake were significant, accounting for 34% of the variance in fruit intake and 28% of the variance in vegetable intake. Attitudes and descriptive norms were positively associated with FV intake, and observed peer fruit intake was negatively associated with fruit intake. Findings suggest that in low-income youth, FV attitudes, descriptive norms, and normative peer behavior predict perceived but not actual intake. Youth may benefit from intervention to promote favorable FV attitudes and norms. A focus on descriptive norms holds promise for improving self-rated intake in this population. PMID- 25842391 TI - Evaluation of exome sequencing variation in undiagnosed ataxias. PMID- 25842392 TI - Reply: Evaluation of exome sequencing variation in undiagnosed ataxias. PMID- 25842390 TI - HS3ST2 expression is critical for the abnormal phosphorylation of tau in Alzheimer's disease-related tau pathology. AB - Heparan sulphate (glucosamine) 3-O-sulphotransferase 2 (HS3ST2, also known as 3OST2) is an enzyme predominantly expressed in neurons wherein it generates rare 3-O-sulphated domains of unknown functions in heparan sulphates. In Alzheimer's disease, heparan sulphates accumulate at the intracellular level in disease neurons where they co-localize with the neurofibrillary pathology, while they persist at the neuronal cell membrane in normal brain. However, it is unknown whether HS3ST2 and its 3-O-sulphated heparan sulphate products are involved in the mechanisms leading to the abnormal phosphorylation of tau in Alzheimer's disease and related tauopathies. Here, we first measured the transcript levels of all human heparan sulphate sulphotransferases in hippocampus of Alzheimer's disease (n = 8; 76.8 +/- 3.5 years old) and found increased expression of HS3ST2 (P < 0.001) compared with control brain (n = 8; 67.8 +/- 2.9 years old). Then, to investigate whether the membrane-associated 3-O-sulphated heparan sulphates translocate to the intracellular level under pathological conditions, we used two cell models of tauopathy in neuro-differentiated SH-SY5Y cells: a tau mutation dependent model in cells expressing human tau carrying the P301L mutation hTau(P301L), and a tau mutation-independent model in where tau hyperphosphorylation is induced by oxidative stress. Confocal microscopy, fluorescence resonance energy transfer, and western blot analyses showed that 3-O sulphated heparan sulphates can be internalized into cells where they interact with tau, promoting its abnormal phosphorylation, but not that of p38 or NF kappaB p65. We showed, in vitro, that the 3-O-sulphated heparan sulphates bind to tau, but not to GSK3B, protein kinase A or protein phosphatase 2, inducing its abnormal phosphorylation. Finally, we demonstrated in a zebrafish model of tauopathy expressing the hTau(P301L), that inhibiting hs3st2 (also known as 3ost2) expression results in a strong inhibition of the abnormally phosphorylated tau epitopes in brain and in spinal cord, leading to a complete recovery of motor neuronal axons length (n = 25; P < 0.005) and of the animal motor response to touching stimuli (n = 150; P < 0.005). Our findings indicate that HS3ST2 centrally participates to the molecular mechanisms leading the abnormal phosphorylation of tau. By interacting with tau at the intracellular level, the 3 O-sulphated heparan sulphates produced by HS3ST2 might act as molecular chaperones allowing the abnormal phosphorylation of tau. We propose HS3ST2 as a novel therapeutic target for Alzheimer's disease. PMID- 25842393 TI - The outline of a curriculum. PMID- 25842394 TI - Planning, requesting medicines and reporting for preventive chemotherapy. PMID- 25842395 TI - UNICEF and WHO meet to strengthen reporting of anthelminthic treatment for preschool children. PMID- 25842396 TI - Pain management prior to nasogastric tube placement: atomized lidocaine. AB - Nasogastric tube (NGT) insertion is often painful for patients of all ages. Randomized clinical trials in adult patients support the use of some form of topical lidocaine in reducing pain associated with NGT insertion. A review of pediatric evidence also confirms that NGT insertion is painful and provides guidance in determining lidocaine concentrations, dosages, and administration methods. The Iowa Model of Evidence-Based-Practice to Promote Quality Care provided the framework for development of a weight-based standard of practice (SOP) for administration of atomized lidocaine prior to NGT insertion for all patients. To facilitate usage, the orders for NGT placement and atomized lidocaine administration were linked in the electronic health record (EHR). Atomized lidocaine was administered via a patient-specific intranasal mucosal delivery device. Evaluation measures included pre- and post-implementation questionnaires which measured discomfort with NGT insertion in pediatric patients (0-10 scale; pre-implementation mean = 7.4; post-implementation mean = 6.5), monitoring utilization of atomized lidocaine via automated dispensing cabinet reports, soliciting comments from families and users, and monitoring institutional patient safety (incident) and adverse drug reaction reports. No patient safety or adverse drug reactions related to atomized lidocaine were identified post-implementation. Patients of all ages have benefited from administration of weight-based intranasal atomized lidocaine to decrease pain caused by NGT insertion. Ongoing safety evaluation and research is warranted since this is the first known report in the literature describing implementation of a weight-based dosing SOP. PMID- 25842397 TI - Vocal fold injection products. PMID- 25842398 TI - Being an older patient advocate: strategies for the non-geriatric nurse. PMID- 25842399 TI - [The alternative way of colorectal cancer developing. The histogenetic and molecular features of serrated lesions (review, continued)]. AB - The occurrence of colorectal cancer can be traced in two ways: from conventional adenomas with the APC-gene mutation (model Fearon-Vogelstein) and the "serrated way", that has a unique genetic profile and morphological characteristics at the early stages. These neoplasms are determined from 7 to 9%. The risk of developing cancer of them is 7.5-15%. Precursors of epithelial neoplasia are aberrant crypts foci. About 20% of colorectal cancer demonstrated the common defects in DNA methylation (CIMP-positive profile), mutations BRAF (KRAS)--oncogenes, microsatellite instability (MSI). The serrated lesions may have these mutations. Serrated polyposis syndrome has specific genetic changes associated with biallelic mutation MUTYH also. Risk of colorectal cancer is very high in this syndrome and is more than 50%. Often the synchronous or metachronous cancers presence. They are usually accompanied by MSI-H and represented serrated morphology too. Understanding epigenetic ways and molecular features of serrated lesions gives an knowledge of their clinical significance and provides the evidence for the treatment and monitoring of patients with this disease. This review is devoted to these issues. PMID- 25842400 TI - [Immune status estimation algorithm in irritable bowel syndrome patients with food intolerance]. AB - OBJECTIVE: To develop an algorithm for evaluation of the immune status in IBS patients with food intolerance. MATERIALS AND METHODS: 42 patients with IBS were observed. The diagnosis is based Rome III criteria. Determination of the concentration of serum allergen-IgG-antibodies to food allergens, IgG, IgA, IgM, IgE and immunoregulatory substances IL-5, TGF beta1, IL-10, IL-4 IL-2, IL-13 were determined by enzyme immunoassay. All the patients received rotational diet therapy based on immunoassay data in addition to medical treatment of the basis disease. The control group comprised 15 healthy individuals. RESULTS: Food intolerances basically to foods proteinaceous was diagnosed in 25 patients with IBS (59.5% of cases). The effectiveness of diet therapy was 68% (17 patients). Analysis of clinical and laboratory data revealed that the implementation of food intolerance in patients with IBS reducing the levels of IL-10 and TGFbeta1. An effective rotational diet of food intolerance in IBS patients had significantly (p < 0.05) increase IgA levels. CONCLUSION: Food intolerance in IBS patients characterized an increased synthesis of allergen-specific IgG antibodies, insufficient production of anti-inflammatory immunoregulatory substances IL-10 and TGFbeta1, and intact cytokines IL-2, - 4, - 5, - 13, IgG and IgM in serum. Efficiency rotary diet in patients with IBS is accompanied by positive clinical dynamics, increase levels of anti-inflammatory substances and serum IgA. PMID- 25842401 TI - [Elevated levels of circulating immune complexes -C3d and-C1q as a criterion for acute extraintestinal manifestations of ulcerative colitis]. AB - During ulcerative colitis in the exacerbation phase the high level of circulating immune complexes -C1q and -C3d (CIC-C1q and -C3d) was detected in 35.4% and 28.9% of patients respectively. This raise of CIC-C1q and -C3d level was accompanied by increase of clinical and endoscopic activity of ulcerative colitis (AC). In 45.4% of AC patients with extraintestinal onsets CIC-C3d was detected and only in 11.7% of patients CIC-C1q was found. These data confirm that activation of the humoral immunity accompanied by increase in formation of immune complexes is characteristic for AC patients with extraintestinal onsets. CIC emergence in serum of AC patients is considered as a prognostically unfavorable sign indicating that the disease may be accompanied by extraintestinal onsets. PMID- 25842402 TI - [Serum calprotectin as a marker for determining the activity of the inflammatory process and the effectiveness of therapy in inflammatory bowel disease]. AB - The increase in the concentration level of calprotectin in serum (ICP) in patients with inflammatory bowel disease (IBD) is closely associated with increased rates of acute phase of inflammation and combined with worsening of clinical and endoscopic disease activity. In the acute stage IBD concentration UPC hung on the degree of inflammatory activity, not localization. Test with the act is a highly sensitive method for assessing the degree of inflammatory activity and the effectiveness of therapy in IBD. After transplantation of mesenchymal stromal cells from bone marrow and standard therapy largely reduced levels SKP than selective immunosuppressive therapy with infliximab (INFL) in patients with IBD. PMID- 25842403 TI - [Colorectal neo- and dysplasia in acromegaly]. AB - Colorectal disorders can be not only an independent disease, but also manifestation of acromegaly--a neuroendocrine disease which is characterized by chronic pathological hypersecretion of the growth hormone (GH) and the increased concentration of insulino-like growth factor type 1 (IGF-1). In clinical recommendations on diagnosis and treatment of acromegaly, colonic polyps are marked as one of most pathognomonic manifestations of acromegaly. Prevalence of coloni polyps in acromegalic is 2,5-3 times higher than in the general population. Moreover, frequency of diverticula and dolichocolon is increased in patients with acromegaly compared with general population (in 3,6 and 12 times, accordingly). Colorectal cancer incidence with a tendency to more aggressive current is also increased (by 4,4 times). When these colonic diseases is diagnosed, especially in patients of young age, it is necessary to define the IGF 1 blood level as the first stage of acromegaly identification. If diagnosis of acromegaly is confirmed, gastroenterologist with endocrinologist together should direct treatment on correction of intestinal pathology as well as on achievement of the biochemical control over acromegaly. PMID- 25842404 TI - [Radiological diagnostics in Crohn's disease]. AB - The article presents modern methods of radiological small bowel imaging in Crohn's disease patients. The characteristic of each method was described, indicating the advantages and disadvantages, their specificity and sensitivity in the various forms of Crohn's disease. The sequence of use of radiological imaging methods in diagnostic algorithm was determined. The article is illustrated with a lot of own observations. PMID- 25842405 TI - [Anti-recurrent treatment of colon diverticulitis]. AB - The article presents the recent data of individual studies and meta-analyses of the frequency of relapses after one, two or more episodes of acute colon diverticulitis, lits different opinions about the predictors of the recurrent course of the disease. The bigger part of the article is devoted to the analysis of the results of different variants of anti-recurrent treatment of diverticulitis with the assessment of the effectiveness of therapy, with the conclusion that today the problem of the most effective method of treatment exists. PMID- 25842406 TI - [Normal values for high-resolution anorectal manometry in a healthy women: effects of age and maternity]. AB - BACKGROUND: High-resolution manometry (HRM) is increasingly used in the evaluation of anorectal disorders. However, the normal values of HRM have not been widely evaluated. Anorectal pressure patterns are known to be possibly influenced by maternity status in women, but the normal values of HRM in parous and non-parous asymptomatic women have not been studied. The aim of the present study was to evaluate, for the first time, the normal values HRM in asymptomatic parous and non-parous women. METHODS: Sixteen asymptomatic healthy females (age: 18-63 years) were enrolled into this study, and among them, 11 were parous women. HRM was performed using solid-state manometric assembly with 9 circumferential pressure sensors (MMS, Netherlands). Measurements of external and internal anal sphincter pressure at rest, during voluntary contraction and during rectal balloon distension were compared.. RESULTS: In asymptomatic parous women mean external anal sphincter resting pressure (69.9 +/- 13.2) was significantly lower then anal pressure (101.2 +/- 22.9) in healthy non-parous women. No differences were found between groups in internal sphincter pressure, voluntary contraction or during balloon distension. CONCLUSIONS: The found difference in resting external sphincter pressure between parous and non-parous women have to be taken in account when HRM is used for evaluation of functional defecatory disorders. Further studies for establishing of normal values of anorectal HRM in larger group of healthy controls are badly needed. PMID- 25842407 TI - [Non-steroidal anti-inflammatory drugs in the correction of experimental ulcerative colitis]. AB - Non-steroidal anti-inflammatory drugs influence the electromyogram of smooth muscle of ileum, the cecum and the ascending portion of the colon in rats during ulcerative colitis was investigated. It was shown that COX-2 inhibitors normalized the electromotor activity of ileo-ascendo complex, lowered infiltration of round cells in mucous-submucosal tissue and blood flow. PMID- 25842408 TI - [Adaptive changes of parietal cells of the fundal glands of the stomach after total colonectomy]. AB - The researchers are investigated in 32 white male, rats by means of electron microscopic methods and morphometric analysis. The sharp reduction acid produceds functions parietal hutches after total colonectomy, her (its) stability at early periods after operation are certainly conditioned inflammatory-distrofic change on the part of secretory membranes, and particularly mitochondria of the device. PMID- 25842409 TI - [Immunologic and oncological safety of autologous and allogenic mesenchymal bone marrow stromal cells]. AB - It is indubitable that autologous transplantation of mesenchymal stromal cells (MSCs) is the golden standard for cell therapy. But also it is still in interest to explore the possibilities of allogeneic MSCs transplantation, because of their special role in lymphopoiesis, particularly in the positive selection of T lymphocytes. PMID- 25842410 TI - [The superorganism concept in biology and medicine]. AB - The paper discusses the concept of the superorganism of man and his microbiota. A unique and little-known details regarding mutualistic relationship of the host and its microbiome are represented. The main metabolic effects of the gut microbiota of the intestine are described. The use of microbial metabolites as autoregulatory substances in experiments and in clinical practice is discussed. Authors propose an innovative concept of controlled microbiocenosis as a main goal and a priority task of the development of clinically effective probiotics and metabolite preparations (metabiotics). PMID- 25842411 TI - [Autonomic disorders in the patophysiology of irritable bowel syndrome]. AB - The article deals with results of researches autonomic disorders in patients with irritable bowel syndrome. It's maintained data various methods studies of state autonomic nervous system, role of autonomic disfunction in IBS pathogenesis mechanisms. PMID- 25842412 TI - [The development of severe methemoglobinemia in patients receiving "Almagel A"]. AB - This clinical case and the literature review show possible development of methemoglobinemia due to the use of local anesthetics, included in drugs for the gastrointestinal diseases treatment, in particular benzocaine, which is the methaemoglobin forming agent. These drugs are common and often taken by the patients themselves without any control. The aim of our paper is to draw the attention of physicians to the risk of the widely known drug administration which can be purchased without a prescription. PMID- 25842413 TI - [The 6th International Hepatology Congress "White Nights of Hepatology", Saint Petersburg, June 2014]. PMID- 25842414 TI - [Tobacco use: thank you Mrs Delaunay!]. PMID- 25842415 TI - [Therapeutic. Which therapeutic alternatives to antibiotics in the context of emerging bacterial resistance?]. PMID- 25842416 TI - [Does a slight overweight increase life expectancy?]. PMID- 25842417 TI - [Biotherapy targeting the immune system]. AB - The use of monoclonal antibody targeted therapy has changed the management of several diseases, including in hematology and immunology. The panel of the present available biotherapies allows a specific action at various stages of the immune response. Indeed, some of these molecules can target the naive T cell at the immunological synapse or the way of TH1, TH17 and regulatory T cell. Others may be more specific for the B cell and immunoglobulin. Some will even be active on both B and T cells. PMID- 25842418 TI - [Clostridium difficile colitis]. AB - C. difficile is a spore-forming anaerobic enteropathogen responsible for a wide range of clinical features ranging from mild uncomplicated diarrhoea to severe debilitating disease, toxic megacolon, or even perforation and sometimes death. Risk factors for C. difficile infection (CDI) include age > 65 years, previous hospitalization and recent antibiotic therapy. Main virulence factors of C. difficile are toxins A (TcdA) and B (TcdB). Since 2005, a new hypervirulent strain has emerged. This epidemic strain named 027/NAP/BI has been responsible for outbreaks worldwide, with increased mortality and severity. Antibiotic treatment of CDI is based on severity of the disease and relies on the use of oral metronidazole, vancomycin or fidaxomicin. Control of CDI needs an antimicrobial stewardship policy and the implementation of contact precautions for the infected patients. PMID- 25842419 TI - [Pachydermoperiostosis]. PMID- 25842420 TI - [Not Available]. PMID- 25842421 TI - [Not Available]. PMID- 25842422 TI - [Not Available]. PMID- 25842423 TI - [In Process Citation]. PMID- 25842424 TI - [How to put an emergency physician at less than 30 minutes of each French?]. PMID- 25842425 TI - [Organisation of emergency medicine in France]. AB - The French emergency medicine infrastructure (structures de medecine d'urgence) ensures patients care from the very location of the distress to the appropriate hospital department: medical care in the field, by hospital clinical teams (the services mobiles d'urgence et de reanimation [SMUR]), is a key characteristic of our medical emergency response system. Response to medical distress revolves around information about not only the location and characteristics of the medical need, but also the availability of adapted hospital services. Gathering and transmitting this information is the prerogative of the service d'aide medicale d'urgence (SAMU) and its telephone dispatch center (Centre 15). For patients coming directly to the hospital, the emergency room (ER), a former underfunded and neglected hospital service, has become a key point of access. The ER is now responsible, after providing immediate first line care, to guide the patient through the care system. As such they are equipped with short term hospitalization units designed to enable up to 24h patient observation before orientation. This ensemble, networked at the level of a health territory, ensures the quality, safety, and efficacy that the population is entitled to demand. PMID- 25842426 TI - [Helicopter transport in the management of emergencies]. PMID- 25842427 TI - [Improving emergency department organisation]. AB - Emergency departments use has been constantly increasing over the world. Overcrowding is defined as a situation which compromises patient safety because of delayed cares. This situation is often reached. Emergency departments have to continuously improve their organization to be able to ensure the same quality of care to a higher number of patients. Thus a good organization is essential: it doesn't always avoid overcrowding. The rest of the hospital has to be involved in this process to ensure efficiency. We examine the various interventions and procedures that can be found in medical literature for improving patients flow and management in emergency departments. PMID- 25842428 TI - [Paediatric emergencies; example of the management of winter epidemics]. AB - Every year, epidemics of viral bronchiolitis and gastroenteritis occur with a significant increase in the number of visits (by a factor 1.8) and hospitalisations that can over-exceed bed capacity leading to transfer sick children to other hospitals. This kind of hospital 'crisis' is not limited to paediatrics, big cities or western nations. It is a worldwide worrying problem. Because our hospital sits in the Northern districts of Paris where a large community of m.ncants lives in poverty, our number of visits is high (mean 250 per day), and winter epidemics further jeopardise the difficult equilibrium achieved between quality management and waiting times. Thus, we have taken various initiatives in terms of organisation of the paediatric emergency department and other wards, including a "fast track" clinic, the opening of beds dedicated to winter epidemics, the institution of a "bed manager" in order to more easily find a bed, and a larger use of home hospitalisations. Furthermore, we created a specific committee which may decide on various indicators of tension whether it is necessary to cancel programmed hospitalisations or surgery.in order to resolve the emergency crisis. This kind of organisation can serve as a model for other hospitals facing winter epidemics crises. PMID- 25842429 TI - [Lifelines of stroke]. PMID- 25842430 TI - [Lifelines of acute coronary syndrome]. PMID- 25842431 TI - [Lifelines of proximal femur fracture in the elderly]. PMID- 25842432 TI - [Disaster medicine]. AB - For over 30 years, the French hospital and pre-hospital medical teams are trained in disaster medicine. In fact, they are regularly confronted with the management of multiple casualties in accidents or even terrorist attacks, and more rarely to large-scale disasters. The intervention of physicians of the EMS system (SAMU SMUR) in the field allows an original healthcare organization: in an advanced medical post, the victims are triaged according to their severity and benefit if needed of initial resuscitation. SAMU medical regulating center then organize their transport and repartition in several hospitals put on alert. To cope with a mass casualty situation, the hospital also has a specific organization, the White Plan. This plan, initiated by the director, assisted by a medico-administrative cell crisis can mobilize all the resources of the institution. Personnel are recalled and the ability of emergency units is increased. Care, less urgent, other patients are postponed. There are many plans for responding to disasters. ORSEC plans of the ministry of Interior articulate with the ORSAN plans of the ministry of Health. This complementarity allows a global mobilization of public services in disasters or exceptional medical situations. PMID- 25842433 TI - [Management of a sanitary crisis]. PMID- 25842434 TI - [Forensic risk in emergency medicine]. AB - Activities in the emergency departments increase in all countries for many reasons: medical, social, economic, etc. In the same time, it is logical to observe an increase in claims; this is confirmed by the insurance companies. In this review, we describe the typology of claims according to the Reason model, also named Swiss cheese model. Thus weseparate the risk situations, the taking risk and the lack of information. When the three factors are associated, claims occur. Then it is easy to propose a method of prevention based on the compliance to the recommandations of good pratices written by the scientific societies. PMID- 25842435 TI - [To a new emergency medicine specialty]. PMID- 25842436 TI - [Risks of ionizing radiation]. PMID- 25842437 TI - [Risks associated to ionizing radiation from natural sources]. AB - This article presents an overview of current knowledge about natural sources of radiation exposure and potential associated health risks. Natural radioactivity constitutes the main source of exposure to ionizing radiation of the French and world population. Exposure is both external (telluric and cosmic rays) and internal (radon inhalation and ingestion of radionuclides from food and drinking water). It varies according to altitude, geology, and individual way of life (housing, food habits). Epidemiological studies demonstrated an excess risk of lung cancer associated to domestic radon exposure, ranking radon at the second place of known lung cancer risk factors after smoking. Data currently available do not allow concluding to risks associated to other natural sources of exposure to ionizing radiation. PMID- 25842438 TI - [Radon awareness and prevention in France]. PMID- 25842439 TI - [Diagnostic imaging and radiation hazards]. AB - For the last 20 years, the exposure of the population to medical radiation has been increased by 600%, mainly due to the extension of new imaging modalities such as CT or interventional radiology. The risk for radio-induced hazards is especially marked for children, because of the high sensivity of tissues to radiation especially during the first decade of the life. Two main ways allow to better control and reduce the mean effective dose per patient in diagnostic imaging: the introduction of recent technical improvement (i.e. low dose CT scans using iterative reconstruction algorithms, low dose technique for pediatric spine), and the substitution to non-radiating techniques such as ultrasound and MRI. The French National institute of Radioprotection and Nuclear Safety periodically publishes dose reference levels for conventional films and CT examinations, for both adults and pediatric patients. A close relationship between clinicians and radiologists remains essential for a better appreciation of the risk/benefit ratio of each individual examination using X-Rays. PMID- 25842440 TI - [Interventional radiology and radiation exposure hazard]. PMID- 25842441 TI - [Potential radiation hazard in nuclear medicine]. AB - Nuclear medicine uses unsealed radioisotopes. The potential radiation hazards depend on the amount of radioactivity administered and the type of radionucleide. Thus, radiation safety instructions will minimize radiation exposure and contamination as low as reasonably achievable. National nuclear safety authority requires rules, regulations and exposure limits for both patients and workers. Good practices and training staff contribute to optimize the radioprotection. PMID- 25842442 TI - [Risks related to radiation therapy]. AB - Radiotherapy is used for about 60% of cancer patients, in 2/3rd of the cases with a curative intent. If the frequent early secondary effects are transitory and with a limited impact, some late effects, even rare as cardiac troubles and secondary tumors, are now more important due to the increase of cure rate and due to the improvement of life expectancy of cured patients. Technologic improvements of the last decades reduced some of these risks, as the strengthening of human resources and the development of quality assurance procedures have contributed to reduce the risk of major accidents. PMID- 25842443 TI - [Risk of medical ionizing radiation during pregnancy]. PMID- 25842444 TI - [Occupational hazard related to ionizing radiation and surveillance of exposed people]. AB - In France, around 400,000 persons are occupationaly exposed to ionizing radiations especially in the field of medicine or industry (nuclear plant or other). Outside of accident the effective doses received are low and below the natural annual exposure dose in Paris (2,5 mSv). Epidemiological studies show that in the occupational environment the excess risk of cancexer leukemia related to ionizing radiations is negligible. Doctors performing interventional radiology if not taking safety measures may receive doses above 20 mSv responsible for lens opacity. In case of nuclear plant accident the emergency workers and liquidators may receive life-threatening whole body doses. In general industry accident may be responsible for high local dose and severe radiation necrosis which required a highly sophisticated treatment. Strict observance of radiation safety rules under the responsibility of the head of the company or institution must provide a safe professional environment. PMID- 25842445 TI - [Radiation-related health effects of major nuclear events]. AB - Three major nuclear events, the Hirosima and Nagasaki bombings and the Chernobyl and Fukushima catastrophes, have been selected to Illustrate the health consequences, observed or anticipated, of irradation of populations. Differences in doses and modalities of irradiation, with the combination of clinical epidemiology and dose estimates, recently revisited, allow for more accurate dose effect relationship models of the risks. However, extrapolation to the low-doses (< 0.1 Gy) or very low-doses of these models obtained with doses >= 0.2 Gy remains hazardous. PMID- 25842446 TI - [Iodide load: the antidote for the risk of thyroid irradiation in case of nuclear accident]. PMID- 25842447 TI - [Accreditation (certification) ... or not?]. PMID- 25842448 TI - [Managing a suspicion of stroke in the acute phase for a possible thrombolysis]. PMID- 25842449 TI - [Recent neurological deficit]. PMID- 25842450 TI - [Elevated serum creatinine]. PMID- 25842451 TI - [Sensitivities and mucocutaneous allergies in children and adults. Urticaria, atopic and contact dermatitis]. PMID- 25842452 TI - [Louis Desliens, unknown actor of the origins of modern cardiology]. PMID- 25842453 TI - In vitro effect of S. mutans biofilm on fluoride/MDPB-containing adhesive system bonded to caries-affected primary dentin. AB - PURPOSE: To evaluate the effect of storage in S. mutans culture or water on the durability of fluoride and MDPB-containing adhesive system on artificial caries affected primary dentin. METHODS: Dentin flat surfaces of primary molars were submitted to artificial caries development using S. mutans biofilm. CAPD cavities were restored with Adper Scotchbond Multi-Purpose (SBM) or Clearfil Protect Bond (CPB) and they were serially sectioned into sticks (1 mm2 cross-sectional area) and stored in S. mutans biofilm for 3 days, in deionized water for 3 months and afterwards subjected to microtensile bond strength (MUTBS) test. A control group was submitted to immediate TBS testing. Two-way ANOVA and Tukey's tests were used. Failure sites were observed by SEM and classified as cohesive (dentin or resin) and adhesive failures. RESULTS: The control group showed the highest MUTBS values (MPa) for both SBM (25.2 +/- 8.5) and CPB (15.6 +/- 6.1) adhesive systems. A significant decrease in MUTBS values after S. mutans biofilm and water storage was observed for SBM (18.7 +/- 5.7 and 17.4 +/- 4.1, respectively) and CPB (13.9 +/- 5.2 and 13.7 +/- 4.8, respectively), but no difference was found between them. The highest percentage of adhesive failure was observed for all groups. However, cohesive failure in dentin was observed in a higher percentage for SBM than CP. PMID- 25842454 TI - Indirect resin composite restorations bonded to dentin using self-adhesive resin cements applied with an electric current-assisted method. AB - PURPOSE: To evaluate the effects of an electric current-assisted application on the bond strength and interfacial morphology of self-adhesive resin cements bonded to dentin. METHODS: Indirect resin composite build-ups were luted to prepared dentin surfaces using two self-adhesive resin cements (RelyX Unicem and BisCem) and an ElectroBond device under 0, 20, or 40 MUA electrical current. All specimens were submitted to microtensile bond strength test and to interfacial SEM analysis. RESULTS: The electric current-assisted application induced no change (P > 0.05) on the overall bond strength, although RelyX Unicem showed significantly higher bond strength (P < 0.05) than BisCem. Similarly, no differences were observed in terms of interfacial integrity when using the electrical current applicator. PMID- 25842455 TI - Cytotoxicity of resin-based luting cements to pulp cells. AB - PURPOSE: To evaluate the cytotoxicity of components released from different types of luting cements to two cell lines obtained from pulp tissue. METHODS: Three types of luting cements were evaluated, distributed into the following groups: G1 -negative control (no treatment); G2--resin-modified glass-ionomer cement (Rely X Luting 2); G3--self-adhesive resin cement (Rely X U200); and G4--conventional resin cement (Rely X ARC). Standardized cylindrical specimens (14 mm diameter and 1 mm thick) prepared with the dental materials were immersed in culture medium (DMEM) for 24 hours to obtain the extracts (DMEM + components released from the cements). Then, the extracts were applied to cultured odontoblast-like MDPC-23 cells or human dental pulp cells (HDPCs). Finally, cell viability (MTT assay), cell death (Annexin/PI) (Kruskal-Wallis/Mann-Whitney; alpha = 5%) and cell morphology (SEM) were assessed. Cements' components in contact with cells (SEM/EDS) and pH of the extracts were also evaluated. RESULTS: The resin-modified glass-ionomer cement (G2) caused the most intense toxic effect to the two cell lines; the cell viability reduction was around 95.8% and 89.4% for MDPC-23 cells and HDPCs, respectively, which was statistically significantly different compared with that of the negative control group (G1). Also, a high quantity of particles leached from this ionomeric cement was found on the cells, which showed intense morphological alterations. In the G2 group, 100% necrosis was observed for both cell lines, and an acidic pH was detected on the extract. Conversely, Rely X U200 (G3) and Rely X ARC (G4), which presented low solubility and no alteration in pH, caused only slight cytotoxicity to the cultured cells. PMID- 25842456 TI - Restorations in abrasion/erosion cervical lesions: 8-year results of a triple blind randomized controlled trial. AB - PURPOSE: An equivalence randomized controlled trial within the subject was organized to evaluate the clinical long-term success of a new 2-step etch & rinse adhesive and a new nano-filled ormocer. METHODS: 50 subjects, 21 males and 29 females aged between 21 and 65, were randomized to receive 150 restorations, 100 with the new restorative material, 50 with the composite as control, placed in non-carious cervical lesions with the same bonding system. The main outcome measure was the cause of failure at 8 years. Randomization was number table generated, with allocation concealment by opaque sequentially numbered sealed and stapled envelopes. Subjects, examiner, and analyst were blinded to group assignment. Two interim analyses were performed. Data were analyzed by ANOVA and Cox test (P < 0.05). RESULTS: After 8 years, 40 subjects and 120 teeth were included in the analysis of the primary outcome. There were eight failures in the experimental group and four failures in the control group. The cumulative loss rate was 7% for both restorative materials, with the annual failure lower than 1%, without any statistically significant difference. There were two key elements of failure: the presence of sclerotic dentin and the relationship between lesion and gingival margin. PMID- 25842458 TI - Effect of the coating material on root dentin remineralization in vitro. AB - PURPOSE: A fluoride-releasing coating material containing surface pre-reacted glass-ionomer (S-PRG) filler has become commercially available. However, there has been no detailed investigation of its remineralization effects at various tooth surface regions. The remineralization effects of S-PRG filler-containing coating material at different sites of demineralized dentin surfaces in vitro were evaluated. METHODS: Baseline lesions were prepared on bovine root dentin surfaces by immersion in demineralization buffer and divided into four groups: (B)--baseline lesion; (P)--S-PRG filler-containing material; (V)--S-PRG filler free coating material as negative control; and (X)--resin-modified glass- ionomer as positive control. Material was applied to half the lesion surface, then P, V and X were remineralized in a gel system. Mineral profiles, integrated mineral loss (IML) and lesion depth (LD) at four regions, i.e. 1--exposed dentin surface adjacent to the material; 2--at a distance from the material; 3--beneath the material near to the edge; and 4--at a distance from the edge, were analyzed by transversal microradiography. Data were analyzed using ANOVA and Games-Howell test with alpha = 0.05. RESULTS: B showed typical artificial demineralized lesion. The IMLs of V, P and X at regions 1 and 2, and P and X at region 3 were significantly lower than that of B, however, those of V at region 3 and the other three groups at region 4 were not significantly different from that of B. At region 1, P and X showed significantly lower IMLs than V. At region 2, the IML of X showed significantly lower IML than V. There was no significant difference between P and X. The LD values of V, P and X at all regions were not significantly different from that of B. Fluoride, strontium and silicate ions released from the S-PRG filler would provide a favorable environment for remineralization of the demineralized dentin in P. PMID- 25842457 TI - Effectiveness of a desensitizing agent for topical and home use for dentin hypersensitivity: a randomized clinical trial. AB - PURPOSE: To evaluate the effectiveness of a desensitizing gel for topical and home use for the treatment of dentin hypersensitivity (DH) by means of a 3-arm parallel, randomized, double blind clinical trial. METHODS: 107 participants were allocated to three groups: placebo gel (PG), test gel (TG) (5% sodium fluoride, 5% potassium oxalate, 10% strontium chloride) and 2% sodium fluoride gel (FG). DH measurement was performed by a single blind examiner by means of the visual analog scale (VAS) after tactile (blunt tipped probe), thermal (air blast) and osmotic (water blast) stimulus at time intervals of baseline, 7, 15 and 30 days. RESULTS: The greatest reductions in DH were observed for the TG, with significant differences for FG in the thermal (Delta = -56 vs -30) and osmotic stimuli (Delta = -44 vs -18). Considering the percentage of participants with moderate/severe pain at 30 days, the TG demonstrated the lowest percentages, with significant differences in comparison with the other groups in thermal and osmotic stimuli. We can conclude that the test gel showed a greater reduction in DH than fluoride 2% and placebo gel, and maybe a treatment option for individuals with DH. PMID- 25842459 TI - Abrasive wear of enamel by bioactive glass-based toothpastes. AB - PURPOSE: To determine the abrasivity of a 45S5 bioactive glass based toothpaste on enamel as a function of the particle size and shape of the glass. METHODS: 45S5 glass was synthesized ground and sieved to give various particle sized fractions < 38, 38-63 and 63-110 microns. Two different grinding routes were used: percussion milling and ball milling. The glass powders were formulated into toothpastes and their tooth brush abrasivity measured according to BS EN ISO11609 methodology. RESULTS: Enamel loss increased with increasing particle size. The percussion milled powder exhibited particles that had sharp edges and the pastes were significantly more abrasive than the pastes made with round ball milled powders. One interesting observation made during the present study was that there was preferential wear of the enamel at the dentin-enamel junction (DEJ), particularly with the coarse particle sized pastes. PMID- 25842460 TI - Effect of mineral trioxide aggregate (MTA) pulpotomies in primary molars on their permanent tooth successors. AB - PURPOSE: To determine the long-term success rate of white MTA pulpotomies in primary teeth and its influence upon eruption and calcification of the permanent successor, as well as other key clinical and radiographic parameters. METHODS: A total of 138 molars from participants between 2-10 years of age were included. Clinical and radiographic parameters were monitored in the primary and/or permanent successor at 6, 12, 18, 24, 30, 36, 42, and 48 months or until eruption of the permanent successor, using the contralateral tooth as control. Chi-squared test and the Spearman correlation coefficient (r) were used to evaluate potential associations and distributions between radiographic/clinical parameters (P < 0.05; 95% CI). RESULTS: Clinical alterations were observed in 1.4% of the primary molars. Unfavorable radiographic pulp responses (furcation radiolucency, internal root resorption with perforation, or external root resorption) were observed in 6.5% of the cases. Dentin bridge formation in the roots was observed in a range as low as 71.2% to a maximum of 89.9% of the cases. The presence or absence of dentin bridge formation in any of the roots was not associated or correlated with the age of the patient (P > 0.05). Reparative dentin formation in any of the the root canals was recorded in 37.3 to a 68.1% of the canals (P > 0.05). The 50 permanent successors recorded after exfoliation of the treated molars showed no alterations in color, mineralization, structure or position, and no alterations in the timing of eruption were noted. PMID- 25842461 TI - A 6-month clinical investigation of custom tray application of peroxide gel with or without doxycycline as adjuncts to scaling and root planing for treatment of periodontitis. AB - PURPOSE: To evaluate the 6-month clinical effects of one scaling and root planing (SRP) procedure alone or combined with local administration of hydrogen peroxide gel (with or without inclusion of doxycycline for 2 weeks) using periodontal medicament carriers in the form of customized prescription trays for treatment of subjects with chronic periodontitis. METHODS: Using a randomized controlled design, 61 subjects with moderate to advanced periodontitis were assigned to three parallel treatment groups: 1) SRP combined with prescription-tray (Perio Tray) application of 1.7% hydrogen peroxide gel (Perio Gel) and, for the first 2 weeks, doxycycline, 2) SRP combined with prescription-tray application of peroxide gel, and 3) SRP alone. All subjects brushed twice daily with standard dentifrice and toothbrush for a 4-week acclimation phase, and continued this regimen throughout the 6-month treatment phase. Pocket probing depth (PPD) and bleeding index (BI) were assessed on natural and restored sites at baseline and after 2, 5, 13, and 26 weeks. SRP was performed 3 weeks after baseline. Clinical variables were compared by ANCOVA and paired t-tests after each treatment interval, analyzing natural and restored sites separately. RESULTS: 57 subjects completed the trial. Analysis of pockets > 5 mm at baseline showed that mean PPD for both test groups significantly decreased from baseline approximately 0.50 mm prior to SRP. Two weeks following SRP, mean PPD significantly decreased from baseline by > 0.90 mm for both test groups and 0.29 mm for the control. By 26 weeks, mean PPD decreased > 1.10 mm for both test groups compared to 0.38 mm for the SRP-only control (P < 0.001 for test versus control at all post-SRP comparisons). Analysis of pockets <= 5 mm at baseline showed the same relationship between groups (P < 0.001 for test versus control). Mean BI dropped significantly only for test groups before SRP, and the tray/peroxide-doxycycline group was significantly different from the control (P = 0.033). Two weeks post SRP, mean BI reductions for test groups were significantly greater than the control, and remained so for most comparisons. For restored sites, mean PPDs of both test groups were significantly better (P < 0.05) than the control for all post-baseline comparisons. PMID- 25842462 TI - Alveolar ridge augmentation with autogenous mental block harvested using ultrasonic bone surgery (USBS) and platelet rich plasma: a case report. AB - Predictable reconstruction of alveolar ridge defects can be obtained by using autogenous bone block. Ultrasonic bone surgery (USBS) is a fast, precise, and simple technique for block graft harvesting. It allows for a clean surgical field with no risk of injury to surrounding neurovascular structures. This article describes a case of horizontal alveolar ridge defect augmented with mental bone block harvested using USBS. The defect was overcorrected using bovine derived xenograft and platelet rich plasma, which is an autologous source of growth factors that helps in early graft consolidation. Platelet poor plasma (PPP) membrane was used for graft containment. After six months, on exposure, it was observed that the block graft was integrated with the alveolar ridge, resulting in increased ridge width. This was confirmed on dentascan and 3D reconstruction images. Implants were placed and restored with satisfactory aesthetic and functional outcome. PMID- 25842463 TI - The role of health behavior in preventing dental caries in resource-poor adults: a pilot intervention. AB - BACKGROUND: Dental caries is a highly prevalent, yet preventable disease that is commonly overlooked in the adult population. It is strongly related to health related behaviors and knowledge, and therefore, is potentially receptive to a behavioral health intervention. However, prevention strategies that target health behaviors in adults are fundamentally different from those in children, whom most current intervention strategies for dental caries target. This study attempts to pilot design, implement, and assess health behavior intervention tools for adults, in order to improve their oral health. OBJECTIVE: To increase knowledge about dental caries by 80% and increase positive self-reported oral hygiene behaviors by 80% in low-income adult participants at Interfaith Dental Clinic by piloting novel interventional and educational tools based on the Transtheoretical Model of Health Behavior. METHODS: A convenience sample of newly registered participants to the Interfaith Dental Clinic between August 2011 and May 2013, were interviewed on each participant's first appointment, exposed to the interventional tools, and subsequently interviewed at their next appointment. A control group, comprised of participants who had completed their caries care as deemed by the clinic and had not been exposed to the interventional tools, were also interviewed on their last appointment before graduating the clinic's program. RESULTS: A total of 112 participants were exposed to the intervention, and forty-two participants comprised the control group. Follow-up for the intervention group was 20.5% (n = 23). Knowledge about the cause of caries increased by 29.9%, and positive self-reported oral hygiene behaviors increased by 25.4%. A Wilcoxon rank sum test showed no significance between the interview scores of the post-intervention group and that of the control group (p = 0.18 for knowledge, p = 0.284 for behaviors). Qualitative results show the vast majority of participants blamed diet for cause of caries, that this participant population prioritized practical advice over factual education, and that flossing was perceived to be the largest barrier to proper oral care, citing pain, lack of time, and technique as common reasons. CONCLUSION: Educational tools based on current models of health behavior theory have the potential to improve participant knowledge and health behaviors, while also remaining low-cost and convenient for clinical use. PMID- 25842464 TI - Plaque reduction in school children using a disposable brush pre-pasted with xylitol toothpaste. AB - PREMISE: The epidemiological data from many countries indicates a global increase in dental caries in children and adults. The purpose of this study was to determine if children in a school setting would accept an after lunch brushing program and if such program would be effective in reducing plaque. STUDY SETTING: A small school of 300 students in Eastern Tennessee was selected to participate of which 200 elected to brush after lunch for 30 school days. Fifty-four students' anterior teeth were stained with a disclosing solution before, during and at the end of the study. The 54 students represented 4 students from each grade level, kindergarten through eighth grade MATERIALS: An ADA approved 27 tuft brush pre-pasted with a paste made with 49% by weight of xylitol was given to each child after lunch. The paste did not require water or the need to spit. A short, 4 minute, musical educational video on correct brushing was designed with the assistance of the mathematics teacher to be shown while the students brushed. RESULTS: The students, principal, and the staff readily accepted the concept and were very cooperative and appreciative. The reduction in plaque levels was dramatic. PMID- 25842465 TI - Management of traumatic tooth injuries in the dental office. AB - Dental trauma is sudden, unscheduled, and the dentist and staff must be adequately equipped to expeditiously and properly treat the patient to assure the best possible outcome. This paper reviews current dental trauma guidelines to provide the correct treatment protocol to ensure the best prognosis. The case report illustrates the technique of avulsion care, RCT care, and functional splinting in a successful manner. PMID- 25842466 TI - A simplified approach to implant restorations using innovative digital technology. AB - Digital impressions and CAM/CAD systems are currently burgeoning dental technologies. This article presents a case study describing the clinical protocol necessary to produce multiple crown restorations supported by dental implants. PMID- 25842467 TI - Dressing minor wounds: avant garde or tried and trusted? PMID- 25842468 TI - The value of historical vignettes. PMID- 25842469 TI - Rosemary oil vs minoxidil 2% for the treatment of androgenetic alopecia: a randomized comparative trial. AB - Rosmarinus officinalis L. is a medicinal plant with diverse activities including enhancement microcapillary perfusion. The present study aimed to investigate the clinical efficacy of rosemary oil in the treatment of androgenetic alopecia (AGA) and compare its effects with minoxidil 2%. Patients with AGA were randomly assigned to rosemary oil (n = 50) or minoxidil 2% (n = 50) for a period of 6 months. After a baseline visit, patients returned to the clinic for efficacy and safety evaluations every 3 months. A standardized professional microphotographic assessment of each volunteer was taken at the initial interview and after 3 and 6 months of the trial. No significant change was observed in the mean hair count at the 3-month endpoint, neither in the rosemary nor in the minoxidil group (P > .05). In contrast, both groups experienced a significant increase in hair count at the 6-month endpoint compared with the baseline and 3-month endpoint (P < .05). No significant difference was found between the study groups regarding hair count either at month 3 or month 6 (> .05). The frequencies of dry hair, greasy hair, and dandruff were not found to be significantly different from baseline at either month 3 or month 6 trial in the groups (P > .05). The frequency of scalp itching at the 3- and 6-month trial points was significantly higher compared with baseline in both groups (P < .05). Scalp itching, however, was more frequent in the minoxidil group at both assessed endpoints (P < .05). The findings of the present trial provided evidence with respect to the efficacy of rosemary oil in the treatment of AGA. PMID- 25842470 TI - Efficacy evaluation of a cosmetic slimming treatment for the waist and hips: a double-blind study. AB - The aim of this study was to evaluate by clinical and noninvasive instrumental evaluations the efficacy and tolerance of a cosmetic topical slimming treatment specific for light/moderate adipose pannicula at the level of the waist and hips. The protocol was performed as a double-blind active vs placebo trial in 110 volunteers for a period of 4 weeks, with an additional visit 4 weeks after the last product application. The following clinical/instrumental evaluation was performed during the visit: clinical assessment of hip-abdomen adipose pannicula, circumference measurements, ultrasonographic evaluation of adipose pannicula thickness, and plicometry. At the end of treatment, the slimming activity of the study product resulted in clinically different results than placebo, determined by a significant decrease in abdomen/hips circumferences and considerable reduction of abdomen/hips adipose pannicula thickness. The tolerability of the product was good and the enrolled volunteers expressed their full satisfaction with the studied product. PMID- 25842471 TI - The use of traditional Chinese medicine in some dermatologic diseases: Part I- Acne, psoriasis, and atopic dermatitis. AB - Traditional Chinese medicine (TCM) is increasingly being used in the Western world particularly in specialty areas such as gynecology, pediatrics, nutrition, and dermatology. TCM is an alternative method of therapy that proposes to treat symptoms that Western medicine is unable to manage by treating the underlying causes of disease. The authors provide a general overview of TCM remedies used in the treatment of various dermatologic disorders (acne, psoriasis, atopic dermatitis) for dermatologists interested in this unconventional therapeutic approach. PMID- 25842472 TI - Alopecia areata--Part I: Background . AB - Alopecia areata is a trichosis characterized by loss of hair, with the abrupt onset of round or oval, nonscarring, flat, single or multiple areas of alopecia lesions, which can coalesce. Several hypotheses have been raised to explain its etiology, with autoimmunity being accepted until today, along with genetic factors. PMID- 25842473 TI - Tavaborole 5% solution for onychomycosis. PMID- 25842474 TI - Infective endocarditis: of heart, head, and skin. PMID- 25842475 TI - Hoffman's drops: the technique of the concentrated neosalvarsan injection. PMID- 25842476 TI - The history of tuberous sclerosis complex: when skin gives a clue. PMID- 25842477 TI - Autologous fat transplantation for the treatment of linear scleroderma en coup de sabre. AB - Scleroderma en coup de sabre is a disfiguring disease for which only limited therapeutic options exist. Three cases of facial linear scleroderma treated with autologous fat transplantation with acceptable results are presented. Autologous fat transplantation was preferred to corrective surgery because of the extent of the lesions and absence of any associated facial distortion. Fat as a filler was chosen to reduce the risk of adverse effects. Adipocytes are suggested to have wider biological effects than other fillers and may offer more durable results. At least two transplantations were needed to evoke a significant effect. PMID- 25842478 TI - Battling mothers for measles. PMID- 25842479 TI - Pheochromocytoma presenting as acute non-ST elevation myocardial infarction following elective hysterectomy. AB - INTRODUCTION: Studies have shown patients with pheochromocytoma have a 14-fold higher rate of cardiovascular events than patients with essential hypertension. CASE PRESENTATION: A 47-year-old female was found to have elevated troponins and marked ST depression following elective hysterectomy. The patient underwent cardiac catheterization, and labile blood pressures with a narrow-complex tachycardia were noted during the procedure. No evidence of coronary artery disease or wall motion abnormality was found. After catheterization, the patient complained of abdominal pain with difficulty passing gas. CT abdomen/pelvis revealed a 4.3 x 5 cm left adrenal mass. Plasma metanephrines and 24-hour urine catecholamines suggested pheochromocytoma. She underwent left total adrenalectomy, and pathology confirmed pheochromocytoma. At 3-month follow-up, she was asymptomatic and required only one agent for blood pressure control. DISCUSSION: Suspecting pheochromocytoma in patients with an unexpected myocardialevent and labile hypertension can lead to prompt diagnosis and appropriate preoperative management as well as avoidance of unnecessary procedures. PMID- 25842480 TI - Pitfalls to avoid in treating the end-stage renal disease patient. PMID- 25842481 TI - How to eliminate the "perverse incentive" in medicine: health savings accounts. PMID- 25842482 TI - Physicians must continue to fight the good fights. PMID- 25842483 TI - Avoid the social networks: a mobile communication platform should provide a secure, efficient workflow. PMID- 25842484 TI - MS UR: an all-but-forgotten law pushed by MSMA dusted off as use of utilization review increases. PMID- 25842485 TI - [Bases of information hygiene: concepts and problems of innovations]. AB - The rising flow of information affects the health and affords ground for strengthening measures of hygienists. There is considered the place of information hygiene in preventive medicine. There are discussed physical and hygienic aspects of measurement and evaluation of information, there are considered some of their negative consequences. International and local regulations and guidance documents in this area are presented. In the light of the strategy of innovative development of Russia there are considered hygienic aspects of innovation and the improvement of hygienic standards. PMID- 25842486 TI - [Prevalence and transmission pathways of the pyloric Helicobacter infection. Transmission from person to person (literature review)]. AB - The purpose of review: analysis of the available in the literature data about the possible kinds and pathways of transmission of pyloric Helicobacter infection from person to person. Knowledge of these data is necessary for its prevention. Subjects--available literature, mainly English-language articles. There were separated two modes of transmission of Helicobacter pylori: vertical--the spread of infection from older to younger and horizontal--by contact between persons outside of the family. Basis statements. There is abundant evidence confirming the gastro-oral, oral-oral and fecal-oral transmission of H. pylori. To prevent the transmission of infection from person to person and the development of related diseases an essential measure is elibiotics. PMID- 25842487 TI - [Radio-ecological situation in the area of JSC "Priargunsky Production Mining and Chemical Association"]. AB - In order to assess the radioecological situation created in the area of the location of diversified uranium mining enterprise "Priargunsky Production Mining and Chemical Association" (PIMCU) there was investigated the radioactivity of a number of the compartments of environment, both at the industrial site and beyond it, as well as the volume activity of radon inside the ground and working premises. Radioecological situation in the vicinity of the uranium mines was performed in comparison with the background (fixed reference, control) district, where there is no uranium mining. Performed studies have shown the significant excess content of 226Ra, 232Th, 210Pb, 222Rn in soil, water open water bodies and local foods near uranium mines compared to areas outside the zone of influence of uranium mining that allows to make a conclusion about the significant technogenic pollution of local areas of the plant and adjoining territory. PMID- 25842488 TI - [Heterogeneity of microbial communities of surface waters on indices of antibiotic resistance of bacteria]. AB - Microorganisms isolated from reservoirs within urbanized areas, have acquired multiple antibiotic resistance, in this connection during the microbiological monitoring of water objects as an additional criterion of anthropogenic pollution it is worth to take into account indices of antibiotic resistance of bacteria. The study of heterogeneity of microbial communities of largest reservoirs in Eastern Siberia (Angara River and Lena) in terms of antibiotic resistance bacteria was performed from the positions of cluster structuredness. Opportunistic gram-negative bacteria and allochthonous representatives of microbiocenoses of the water bodies were established to be characterized by belonging to four clusters (antibiotic sensitive, mono-, moderately--and poly antibiotic resistant). At the same time the proportion of microorganisms belonging to different clusters, vary significantly both in terms of different water bodies, and in separate parts of the same body of water, being largely dependent on anthropogenic load on water. Thus, the heterogeneity of the microbial populations permits to present comparative quantitative assessment of reservoirs, as well as their portions, in terms of antibiotic resistance of microorganisms. The increment in the proportion of resistant strains reflects the sanitary and epidemiological importance of this property, because provides evidence of the contamination of water supplies by household sewage. PMID- 25842489 TI - [Current trends in the use of pesticides]. AB - The aim of this study--to identify the main trends in the use of pesticides at the present stage. Since 2004, in the Republic of Tatarstan, there is observed an increase of the discharge of pesticides, the list of drugs and cultivated area. The introduction of minimum tillage on technology was shown to have led to an increase in the share of herbicide to 86.2% and significantly changed their range. Glyphosate became the main active ingredient. PMID- 25842490 TI - [The formation of intestinal microbiocenosis in children in the industrial cities of Siberia]. AB - The purpose of this study was to investigate the features of the formation of intestinal microbiocenosis in children residing in the industrial cities of Siberia. The study included 168 healthy children. There is presented the medical and hygienic assessment of the examined area with bearing in mind the degree and specificity of the man-made pollution of the atmosphere. There were revealed distinctive features of formation of intestinal microecology, specific for the each of the examined groups (diversity of species of transient microorganisms, rated characteristics of opportunistic pathogens, "indicator" species). PMID- 25842491 TI - [Habitat and incidence of respiratory organs diseases in the Samara population]. AB - There was performed the assessment of habitat quality for Samara population. Risk factors for prevalence of respiratory diseases (pneumonia, allergic rhinitis, asthma) in children, teenagers and adults were revealed to be formaldehyde, phenol, hydrogen sulfide in the ambient, cadmium and copper in the soil. PMID- 25842492 TI - [hygienic assessment of the effectiveness of the implementation of the concept for the improvement the water supply of population in the south-east region of the Republic of Tatarstan]. AB - In the paper there is presented the hygienic evaluation of the implementation of the program aimed at the improvement of the water supply of the population in the oil-producing regions of the Republic of Tatarstan. As a result of the implementation of measures it managed to improve the quality of drinking water in terms of chemical harmlessness and to reduce the risk to public health. Currently following factors as quality of the water from water sources, the mismatch of sanitary protection zone to requirements of sanitary legislation and the failure of regime measures in its territory, water quality deterioration during transportation and the inadequacies in the laboratory control were shown to make the highest contribution to the disadvantage of centralized drinking water systems. PMID- 25842493 TI - [Evaluation of the migration of contaminants from building materials produced on the base of blast-furnace slags]. AB - There is experimentally established the change of the migratory activity of pollutants from building materials produced from blast furnace slag throughout their life cycle in the form of a nonlinear wave-like nature as there are appeared newly opened surfaces of a contact with aggressive waters in the process of gradual crushing of materials as a result of destructive mechanical effects on him and corrosive waters with varying pH values. There are established regularities of the migration activity ofpollutants (on the example of heavy metals) as directly dependent on the newly opening surface of the contact of the material with water having a various pH value. There is shown an expediency of introduction of alterations in the procedure for sanitary hygienic assessment of building materials with the addition of industrial waste (Methodical Instructions 2.1.674-97), allowing to take into account the migration of contaminants from them throughout the life cycle. PMID- 25842494 TI - [Results of monitoring of pollution by metallic impurities of environment of districts of anthropogenic impact in Georgia and methods to reduce their technogenic load]. AB - There was performed a comprehensive study of consistent pattern of the accumulation of toxic heavy metals in the natural environments of mentioned areas and there were developed methods and recommendations for improvement of their ecological status. The aim of the study--a performance of the study of pollution of natural environments by major mining regions of Georgia: Madneuli copper pyrite and barite-polymetallic deposit, Chiatura manganese deposit, Lukhumi arsenic deposits. In the process of the work, the special attention was paid to the consistent patterns of accumulation of heavy toxic contaminants in natural waters and soils, as well as to the development of methods and recommendations for their purification from impurities. At the same time there were used: field geochemical, and hydrogeochemical pedological methods, modern ultrasensitive analytical equipment, laboratory experiments for the identification of tools of water and soil purification from heavy metals etc. PMID- 25842495 TI - [On the problem of the study of the chemical air pollution with chlororganic hydrocarbons at productions of polyvinyl chloride and epichlorohydrin]. AB - Hygienic assessment of working conditions at the chemical productions of polyvinyl chloride (PVC) and epichlorohydrin (EPCH) in East Siberia has shown that the employees are exposed to the chlororganic hydrocarbons of hazard category 1-2, out of them there were found to be more toxical pollutants such as vinyl chloride, 1.2-dicloroethane in the production of polyvinyl chloride; allyl chloride and epichlorohydrin in the production of epichlorohydrin. Multistageness of the technological processes, the absence of the isolation of main stages of the technological processes as well as the heating microclimate contribute to the chemical pollution of the air environment. In spite of the significant improvement of the hygienic situation at the productions mentioned in the recent 10 years according to the chemical factor due to the introduction of the complex of curative measures, the working conditions of the employees still belonged to the harmful category. According to the content of the harmful chemical substances in the air of the working zone and the parameters of microclimate, the working conditions of the employees working at the production of epichlorohydrin and in the shop of vinyl chloride production must be qualified as the harmful ones of the first category of the hazard and danger (Class 3.1), in the production shop for PVC- as the harmful ones which correspond to the second category of the hazard and danger (Class 3.2). PMID- 25842496 TI - [To the issue on the optimization and regulation of microclimate in the subway trains and stations]. AB - There is presented an overview of currently existing regulatory framework governing the parameters of the microclimate in the salons of subway passenger cars and stations. Analysis of the normative documents indicated that they contain very incomplete, contradictory, often unfounded information about the parameters of microclimate parameters in salons of subway rolling stock. Also, there are no clear cut hygienically-sound requirements for the work of imposed on the rolling stock subway systems provide microclimate, including new systems for air conditioning and disinfection. PMID- 25842497 TI - [Functional state of the respiratory system in employees at the tantalum plant]. AB - Indices of pulmonary ventilation function in employees at the tantalum plant tended to decrease according to the length of service and type of performed technological operations. Physiological changes of the functional State of the respiratory system were accompanied by pulmonary ventilation disorders of mixed and obstructive types. Changes in indices of respiratory function at the level of distal and proximal airways, including the bronchial tree, wore compensatory adaptive character in response to the exposure of harmful factors of dust-gas mixture from the tantalum production. PMID- 25842498 TI - [Analysis of associations of polymorphic loci of a tumor suppressor gene TP53 with malignant neoplasms in glass fiber manufacturing workers]. AB - The purpose of the study was to determine the role of TP53 tumor suppressor gene polymorphisms in the occurrence of skin malignant neoplasms in glass fiber manufacturing workers. We carried out a comparative study of polymorphous loci Arg72Pro and dup16bp in TP53 gene in workers with skin cancer and hyperkeratosis (n = 68), occupied in continuous glass fiber manufacture, and in healthy workers (n = 52). The associations of both Pro and dup16 minor alleles of TP53 gene, and Arg/Pro-W/dup16 genotype combination with higher risks for skin oncologic diseases of occupational genesis have been revealed. PMID- 25842499 TI - [Health status, morbidity and injury rate in divers serving in the Kola North]. AB - The authors analyzed the health status of military personnel (males) of the Northern Fleet who did call-up military service (n = 420) and served on contract (n = 1370) in special diving positions in the Kola Arctic over the past few years. For the comparison of the rate of the decline of health level in different conditions of service the authors presented the averaged results of studies previously performed in the same period of time in the service personnel of coastal military units in the European North, troops from the surface ship crews and crew nuclear submarine. In the article there are considered the features of the primary disease and injury. Research and monitoring of causative-consecutive relationships between the features of military professional activity and the level and structure of primary morbidity rate allow to form the main directions of vocational rehabilitation for fleet specialists. PMID- 25842500 TI - [Comprehensive assessment of the health of students with different state of the musculoskeletal system]. AB - Priority health indices (the morbidity rate, the resistance status, the physical development, the orthopedic status, the level of bone mineralization, functional reserves of the body, health groups) in schoolchildren aged 7-18 years with a different state of the musculoskeletal system (MSS), learning in secondary schools were studied with the aim of the development of prevention programs. The high incidence of MSS diseases was determined to be combined with a high level of overall morbidity rate, on separate classes--with diseases of the nervous, endocrine, digestive systems, increasing with age ofthe student. Comprehensive assessment of health is much worse in schoolchildren with functional MSS diseases, as well as in girls. This demonstrates the need for careful monitoring of these children by experts in different fields, differentiated prescription, prevention and wellness programs throughout all the period of schooling. PMID- 25842501 TI - [On motivations of adolescents to promote a healthy lifestyle]. AB - There was studied the motivation of modern adolescents to promote healthy lifestyle. There were observed two arrays, including adolescent-schoolchildren aged 16-17 and 13-14 years in Moscow. The results showed that health occupied one of the first places among the positive motivations, being stable dominant in the period of 13-17 years. The real motivation for a healthy lifestyle coincides with the perspective and informed choice coincides with the life goals. In this, almost all of the identified negative motivation are "manageable", available to be modified or eliminated. PMID- 25842502 TI - [Regional features of the physical development of schoolchildren in the city of Ufa]. AB - There was studied the physical development of 4550 schoolchildren of the city of Ufa at the age from 8 to 16 years. Almost a third of the students was noted to have disharmonious physical development. The proportion of children with excess of body weight exceeds the proportion of underweight children in 2 times. Modern schoolchildren of middle and senior age groups were established to have higher indices of height and weight in comparison with peers at the end of twentieth century, and in younger schoolchildren the indices are higher than in their peers in 2004. PMID- 25842503 TI - [The features of the relationship of the indices of physical and sexual development of teenagers of the city of Chelyabinsk--the industrial center of South Ural]. AB - There was made a determination of the correlation relationships (CR) between indices of physical and sexual development (SD) of 1997 adolescents aged from 11 years 6 months to 17 years 5 months 29 days residing in the industrial center of the Southern Urals characterized by high levels of air pollution (API 7-13). Benzo(a)pyrene and formaldehyde contribute the greatest part to air pollution. The level of SD, time of appearance of secondary sexual characteristics was revealed to be interrelated with the pace of physical development of adolescents, regardless of the gender Children with an accelerated pace of physical development (macrosomatotype) are characterized by advancing sexual development and the earlier appearance of secondary sexual characteristics. Slow pace of physical development (microsomatotype) is characterized by SD retardation and the later appearance of secondary sexual characteristics. The degree of intensity of secondary sexual characteristics and such anthropometric indices as height, body mass are interrelated and have age and gender differences: the maximal CR for these indices is typical for boys aged from 13 to 16 years as for girls--of 13 and 14 years old. PMID- 25842504 TI - [Morbidity rate in students of lyceum and specialized educational institution]. AB - Comparative analysis of the morbidity rate of students was implemented on the basis of a special educational institution for students who are prone to crime and delinquency and for pupils of the lyceum-boarding school. The analysis showed that the state of health of the surveyed children was characterized by high indices of morbidity rates, the high occurrence of chronic diseases among students and the progressive decrease in the indices of the health. The highest morbidity rates were noted in classes of diseases of the nervous system, digestive system, circulatory system, diseases of the eye and adnexa, and musculoskeletal system. The higher level of incidence of different pathologies in students of the specialized secondary school gives evidence of the possibility of unfavorable prognosis for the future health of adolescents and can refer them to the risk group. PMID- 25842505 TI - [The levels of electrolytes and nitric oxide in saliva of students under mental emotional exertion]. AB - The influence of examination-induced psycho-emotional stress on students' hemodynamic parameters, nitric oxide (NO) level and electrolyte composition of saliva was investigated. Before examinations, the examinees with a sympathotonic response (75.0%) showed the increase of heart rate levels and blood pressure indices, the decline of salivary NO excretion that was retained within 24-hours after an exam. There was a significant negative correlation between the amount of NO and the values of blood pressure. The examinees with a parasympathetic response (25%) showed the elevated salivary NO level and lowered blood pressure indices in the pre- and post- examinational periods. Throughout the examination period the increased autonomic tone of the organism contributes to the changes of the electrolyte composition of saliva. In pre-examination period the examinees with sympathotonic response demonstrated a significant decrease of the concentration of Na+ in saliva, that persisted after exams also. Hyponatremia was associated with the increased K+ and decreased Na+/K+ ratio. Before exams the level of Na+ in the saliva of the students of the II group increased, at the same time concentration of K+ decreased. After the exam there was a reduction of Na+, which, however, did not reach the initial level. PMID- 25842506 TI - [The impact of social and psychological factors on the formation of health students during training in the higher educational institution]. AB - There was performed an assessment of anthropometric indices of physical development and functional parameters of the cardiovascular system, psychological and social status in 770 students of the higher educational institutions in the city ofSamara. There was revealed the presence of I-III degree obesity in 13.2% of young males and underweight in 19.1% of young females. Stress and disruption of the processes of the adaptation process were shown to be observed in 7.6% and 6.1% of students, respectively. There was found a tendency to hypertension in 12.6% of young males. Revealed changes are related to lifestyle of the modern student. The main factors for the improvement of the life quality is the duration of sleep and ultimate nutrition. Initially, the lower level of physical and functional capabilities is compensated by virtue of the correct organization of social and psychological factors and prevents possible deviations from the part of health. PMID- 25842507 TI - [Evaluation of the physical development and adaptation capacities of the body of schoolchildren in the Ulyanovsk region]. AB - The current environmental and socio-economic living conditions are major causes of the deterioration of the population health. The physical development of children and adolescents permits to evaluate fleeting changes in the population. There was performed the evaluation of the physical development of 1664 schoolchildren in the Ulyanovsk region. Features of the physical development, the state of autonomic tone and cardiac activity of children and adolescents residing in areas with the intense anthropogenic impact testify to the exertion of adaptation mechanisms under the influence of environmental factors. PMID- 25842508 TI - [Lifestyle of the students of specialized educational institutions and lyceum]. AB - The results of the survey indicate that students of the specialized educational institution have grown in less favorable conditions than lyceum students, they often brought up in single-parent (45% vs. 26%), large (34% vs. 14%) families, their parents are less likely to have higher education. Lifestyle of the parents of students of specialized educational institution is more "unhealthy" than in families of lyceum students: parents drink alcohol 1.8 times more frequently, the prevalence of smoking among mothers was 24 times more. Among students of the specialized educational institution one in five (21%) had the experience of tobacco smoking, among lyceum students--only every 25th (4.0%), alcohol use is common in 24% of pupils and 6% of lyceum students, 7.1% of students irregularly use drugs, among lyceum students there was no such children. Irrational mode of the day was more common among lyceum students: they less frequently rate their health as good (61% vs. 76%), had more complaints about their health, as well as more often experience a fatigue after training sessions (40% versus 26%) and difficulty in falling asleep. PMID- 25842509 TI - [Hygienic evaluation of the efficacy of the regional program of the modernization of school meals (on the example of Altai Krai)]. AB - With the use of the method for the analysis of the frequency of food intake there was studied the actual nutrition in adolescents at the age of 12-17 years (n = 257) who were the students of the urban and rural educational institutions (EI) of Altai Krai. The analysis of the menu-layout and assessment of nutritional status was performed with the use of clinical methods. The main group consisted of 125 adolescents from the EI with upgraded technological equipment of the nutrition unit, the comparison group--132 teenagers from EI with non-upgraded equipment of the nutrition department. The program of the modernization of school meals was implemented in several ways and included the reconstruction and technical re-equipment of school nutrition units on the base of modern technologies, delivery and introduction in accordance with the requirements of the school menu, differentiated by age groups with the use of food products aimed at the prevention of diseases caused by micronutrient deficiency. This led to the enlargement of the assortment of dishes, the increase of the coverage for catering students, improvement of the structure of student nutrition, the increased in the intake of a number of nutrients. Symptoms of skin lesions associated with insufficient provision of micronutrients in a core group of students occurred less common than in the comparison group (p < 0.01). PMID- 25842510 TI - [Interstitial endocrine apparatus of testes of experimental animals in conditions of chromium-benzene intoxication]. AB - With the use of histological, morphometric and statistical methods there was shown a gonadotropic effect of chromium, benzene and also their mixtures in male mice (CBA x C57Bl6) F1. The established structural changes in the testes of exposed animals showed the suppression of their germinative and endocrine functions. The response of Leydig cells in the chromium group expresses a development of the compensatory process in the relation with the destruction of seminiferous epithelium. PMID- 25842511 TI - [Effect of physical activity of varying intensity and hypodynamia on the morphological indices of the internal organs in the experiment]. AB - The influence of physical activity of varying intensity and hypodynamia on the morphological indices parameters of the internal organs of rats in the experiment was investigated. Animals were subjected to the forced swim test by Porsolt of varying duration and to immobilization. The intense exercise, as well as long term lack of exercise, were reveled to lead to the pronounced structural defects in the internal organs, while moderate exercise can be considered as the most favorable. PMID- 25842512 TI - [Crystallographic evaluation of structural changes in water]. AB - The study of the structural state of tap water that has been stored for two days in the packaging materials of various type and in different conditions, was performed with the use of crystallographic method for the investigation of liquids based on a special approach for dehydration of the drop, which is a fixed thin "slice" of the examines liquid. Most organized crystallographic pattern was shown to observe in a drop of water after treatment Bioptron lamp (content of liquid-crystal associates (LCA)--6.90 +/- 0.23), and stored in a silver vessel (content LCA--6.28 +/- 0.17), and the least organized, almost amorphous precipitate is formed in a drop of water stored in plastic containers (content LCA--2.92 +/- 0.15%). Basing on the obtained results, it can be concluded that the crystallographic method can be used for the identification of qualitative changes occurring in liquid water under the influence of various physical factors, for the identification of the rationality of the use of hereafter sophisticated quantitative techniques. PMID- 25842513 TI - [New methodological approach to hygienic audit of learning and upbringing environment for children in educational institutions]. AB - A methodical approach to the hygienic assessment of the educational environment in children's educational institutions was developed and tested for the objective determination of the level ofsanitary and epidemiological welfare and effective planning of preventive measures with bearing in mind environmental factors which have the most negative impact on children's health. PMID- 25842514 TI - [Methodical ware for the hygienic risk assessment of vanadium exposure to the children's health]. AB - In the article there is considered the complex of methodological approaches for the detection of vanadium in the air and biological substrates of the population for the practical use in the frameworks of public health monitoring in areas with localization of steel industry facilities. The developed complex of methods on the base of mass spectrometry with inductively coupled plasma (ICP-MS) allowed to perform the hygienic assessment of the quality of objects of the environment in the territory located in the zone of the impact of emissions of ferrovanadium production (the city of Tchusovoy of the Perm Krai). From the results of the study there was established the significant excess of the vanadium content in the ambient air of the studied area in relation to the control territory and to the reference concentration for chronic inhalation exposure (RfCxp) to 6.0 times. There was revealed a significant excess of vanadium content in the blood of children residing in the study area, with respect to the regional background levels (0.0001-0.00016 mg/dm3). Complex clinical laboratory and chemical analytical studies of biosubstrates of the children population allowed to substantiate the marker of the inhalation exposure (the vanadium content in the blood) and its reference level (0.0023 dm3). PMID- 25842515 TI - [Functional state of the visual analyzer in the conditions of the use of traditional and LED light sources]. AB - There was performed the experimental work on the study of the possibility of the application of LED lighting (LED light sources) in rail transport for traffic safety in related professions. Results of 4 series of studies involving 10 volunteers for the study and a comparative evaluation of the functional state of the visual analyzer, the general functional state and mental capacity under the performing the simulated operator activity in conditions of traditional light sources (incandescent, fluorescent lamp) and the new LED (LED lamp, LED panel) light sources have revealed changes in the negative direction. This was pronounced in a some decrease of functional stability to color discrimination between green and red cone signals, as well as an increase in response time in complex visual--motor response and significant reduction in readiness for emergency action of examinees. PMID- 25842516 TI - [Psychophysiological research of changes of the functional condition of the neuro psychic sphere of younger schoolchildren during the school day at luminescent and LED lighting in the classroom]. AB - The purpose of the study is to test the hypothesis that the LED lighting (LL) in training class does not have a negative impact on the change in the functional state of the neuro-psychiatric sphere in pupils by the end of the school day, if compared with traditional for schools fluorescent lighting (FL). With the help of specially matched methods for psychophysiological examination there was performed the testing of changes in the functional state of the neuro-psychiatric in pupils during the school day and there was made an analysis of these changes in dependence on the type of lighting the classroom. LL, if compared to FL, was established to lead to a significant weakening of the negative changes of functional lability of the visual analyzer, the power of excitation of the nervous system and cognitive functions, as well as to an increase in positive changes in psychomotorics. The data obtained allow us to recommend the use of LED lighting equipment in modern schools. PMID- 25842517 TI - Experience: we know it when we see it. PMID- 25842518 TI - Why experience matters: moving from words to action. AB - This article explores the nature of patient experience from the perspective of the language we use at a systemic level, discussing the range of terminology that has an impact on how we involve the voices of patients and families in health care today. The author explores the recent evolution in the language of patient experience, acknowledging the diversity of perspective while offering that there is an opportunity for alignment, and presents a model for integrating the constructs that frame excellence in patient experience. The author leaves us with a challenge: to continue the conversation and to find opportunities to elevate the impact of patient experience overall. PMID- 25842519 TI - Self-determination, end-of-life decisions, and the role of nurse practitioners. AB - Nurse practitioners should be aware that societal changes could lead to their being asked to actively assist terminally ill patients who wish to end their lives, as opposed to their current supportive role in palliative care. With physician staff shortages and the need for nurse practitioners to fill the gaps, end-of-life responsibilities could be placed in the hands of nurse practitioners, rather than being reserved for physicians alone (Sagon, 2013). End-of-life matters raise uncertainties about the nurse practitioner role because it differs state by state, relates to ethics, reflects the religious beliefs of those involved, and concerns the conflict of nurses simultaneously caring for their patients while advocating for their right to self-determination in choosing to end their lives. PMID- 25842520 TI - Transformation from within: a concept analysis of epiphany. AB - The aim of this article is to explore the concept of epiphany using a modified version of Walker and Avant's (2005) concept analysis procedures. This transformative experience produces behavior change that can impact wellness. The occurrence of epiphanies through analysis of historical figures, retrospective and qualitative studies, and literary works is described. Evidence suggests this phenomenon can be profound, liberating, and enduring. Nursing research has not considered the potential of epiphanies as a behavior change theory to improve health behaviors and wellness. PMID- 25842521 TI - Finding the research questions for care coordination of older adults. AB - With the growing number of older adults needing complex medical care, new models of care are needed to reduce unnecessary Medicare costs while helping older adults achieve their highest level of well-being. Advances in models for care coordination have occurred over the past 10 years, yet the research is not complete. Now is the time for nurses to examine the literature and identify research questions for future studies. This article identifies 2 research questions that will fill the gaps in the state of the science on how best to meet the needs of older adults with multiple chronic conditions. PMID- 25842522 TI - Primary nursing in a short-stay unit. AB - Primary nursing is a model of care delivery that has been shown to improve the quality of care provided to patients and enhance the nurse-patient relationship. Although there is considerable attention in the literature on Primary Nursing concerning inpatient hospital units, there has been no discussion of Primary Nursing in short-stay units. Our hospital aimed to introduce Primary Nursing into all the units including short-stay. Staff were educated about the role of the primary nurse using Koloroutis's (2004) Relationship-Based Care model, comprising three crucial relationships: care provider's relationship with patients and families, with self, and with colleagues. The primary nurse develops the plan of care for individual patients based on their therapeutic relationship, which is sustained for the patient's length of stay in the unit. PMID- 25842523 TI - To move health care to health caring: a conversation with Julie Kennedy Oehlert, DNP, RN. AB - The complex nature of health care requires a culture of interprofessionality that supports high-functioning interprofessional teams. Wolf and Prince (2014) wrote, "Culture is the foundation on which any healthcare encounter is delivered" (p. 3). It is therefore important for nursing to elevate thought leaders who can address the culture of health care organizations and how culture can be transformed. Julie Kennedy Oehlert is one of these leaders. PMID- 25842524 TI - Cognitive behavioral therapy in patients with sickle cell disease. AB - INTRODUCTION: Sickle cell disease (SCD) is an inherited autosomal recessive disorder. In the United States, most individuals with SCD are African Americans, withan incidence of 1 in 400 to 1 in 500 live births. SCD is a lifelong disorder with no known cure. BACKGROUND: SCD causes anemia, frequent painful episodes, and reduced life ex- pectancy. The most disturbing clinical problem associated with SCD is severe pain episodes, the most common reason for hospitalization. Pharmacological interventions have been the mainstream for treatment; however, psychological interventions such as cognitive behavioral therapy (CBT) may complement current medical treatment, lead- ing to better coping and overall improved quality of life. METHODS: In a quasi-experimental one-group pretest posttest study, 9 African American individuals with SCD completed 3 weekly educational sessions learning CBT methods. RESULTS: Participants demonstrated increased frequency of use of CBT methods post-intervention, including diverting attention, coping self-statements, and behavioral activities, leading to better pain control. However, quality of life and role limitation did not show significant improvement. DISCUSSION: CBT may be beneficial to those suffering from SCD when combined with conventional treatment options; however, there are still barriers to incorporating psychological interventions into practice. CONCLUSIONS: CBT shows promise for individuals with chronic conditions such as SCD, but more investigation into its efficacy is needed with larger sample sizes over longer periods of time. PMID- 25842525 TI - Joy, happiness, and humor in dementia care: a qualitative study. AB - People with advanced dementia can still enjoy life. Even if their language is impaired and they live in the moment, it should still be possible for them to live a life of pleasure and joy. A pilot study was conducted to learn more about these individuals' experiences, but because of the decline in their access to language, it was necessary to have others speak on their behalf. Analysis of findings was based on a hermeneutic approach inspired by Ricoeur (1981). Central findings were that all the interviewees emphasized humor and interacting with other people as a source of happiness. PMID- 25842526 TI - Using eHealth to improve health literacy among the patient population. AB - There is no denying the global influence of eHealth, in its various forms, on the health care system in the 21st Century. Health care professionals are often familiar with technological tools used to enhance health outcomes by assisting clinicians in meeting the needs of the patient population. In an age of social media, web-based information, and material available literally in an instant, it is crucial for nurses to use and proactively share their knowledge regarding accessing and finding credible sources of online health information with the patient population. By improving health literacy among consumers, self sufficiency and competence can be developed and promoted to improve health outcomes, placing the patient in a participatory starring role of managing and improving his or her overall well-being. PMID- 25842527 TI - A salon for students. AB - A Nursing Salon specifically for students and faculty of a baccalaureate school of nursing introduced the students to an opportunity to talk with nurses from all walks and all levels of nursing life. PMID- 25842528 TI - Ask "why" and don't be afraid to say "no". AB - The author of Questioning Protocol: How One Mom Dispensed Equal Doses of Humor; Humility, and Corporate Smarts to Help Her Family Navigate Their Health Care Crisis describes advocating for her chronically ill son in the hospital. The skills she gained working for 18 years as an engineer with General Electric empowered her to navigate the health care system effectively and find opportunities for process improvements. Best practices can be shared between companies, and the same is true for patients and loved ones. This adaptation of a passage from Questioning Protocol demonstrates a critical corporate survival skill: the confidence to say "No". PMID- 25842529 TI - Heavy metal accumulations in water, sediment, and some cyprinid species in Porsuk Stream (Turkey). AB - Porsuk Stream is one of Turkey's most important river systems and also one of the most important branches of the Sakarya River. It provides drinking and utility water for two Turkish cities (Kutahya and Eskisehir) with a total population of one million. In this study, water, sediment, and some tissues (liver, gill, and muscle) of five cyprinid fish species were collected seasonally (2010-2011) from eight stations on the Porsuk Stream, and the zinc (Zn), copper (Cu), chromium (Cr), manganese (Mn), nickel (Ni), lead (Pb), and arsenic (As) levels of collected samples were determined. The data observed were evaluated with national and international quality criteria. Based on the data observed, it was determined that the Porsuk Stream is affected by significant inorganic pollution from the Kutahya and Eskisehir Provinces. It was also determined that the Porsuk Dam Lake has an important cleaning capacity and that the water and sediment quality of the Porsuk Stream improves after the output of the dam lake. PMID- 25842530 TI - Experimental attempt at using Lecane inermis rotifers to control filamentous bacteria Eikelboom Type 0092 in activated sludge. AB - In laboratory experiments, the authors tested the efficacy of Lecane inermis rotifers in reducing the abundance of filamentous bacteria in activated sludge samples dominated by one filamentous bacterium, Eikelboom Type 0092. The experiment was conducted in three replicates and repeated three times at 1-month intervals. In all repetitions, rotifers were able to significantly reduce the density of bacterial filaments through predation. It was also shown that the influence of rotifers on filament abundance depends on the duration of grazing pressure. The data show that L. inermis, already reported to be effective in reducing the density of Microthrix parvicella, Nostocoida limicola, and Type 021N in activated sludge, can be equally helpful in limiting Type 0092, another troublesome filamentous bacterium found in low-loaded water resource recovery facilities. PMID- 25842531 TI - Quantitative microbial risk assessment for recreational exposure to water bodies in Philadelphia. AB - A quantitative microbial risk assessment was conducted to estimate risk of gastrointestinal (GI) illnesses associated with recreational exposure to Philadelphia waterways, under dry and wet weather conditions. Using maximum likelihood estimation, stochastic exposure models were generated for each exposure scenario and Monte Carlo techniques were applied to characterize uncertainty in final risk estimates. The dry-weather risk estimates were found significantly lower than those predicted for wet-weather conditions. Moreover, the predicted risk, calculated in proportion of the frequency of use, was elevated at 6 out of 10 sites (ranging from 9 to 52 illnesses/1000 users/day). Activities contributing most to the risk of GI illness at creeks were identified as wading and playing (81%), while fishing was the potential risk contributor (65%) at rivers. The quantitative measure of risk contribution from each type of water activity obtained from this study can be useful for policy makers in prioritizing the future interventions. PMID- 25842532 TI - Variability in the concentration of indicator bacteria in landfill leachate--a comparative study. AB - Leachate collected from the collection ponds of four landfill sites was investigated and compared for total coliforms and E. coli concentration as representatives of fecal pollution. Concentration of total coliforms and E. coli was comparable for leachate obtained from Kulim Landfill Site (KLS) and Ampang Landfill Site (ALS) with little variations. However, the level of indicator bacteria was significantly lower for Kuala Sepetang Landfill Site (KSLS), whereas Pulau Burung Landfill Site (PBLS) had the lowest concentration for both total coliforms and E. coli. Considering the landfills are currently operational, with the exception of ALS, the presence of indicator bacteria implies their inactivation prior to discharge. High concentration of indicator bacteria in ALS is attributed to the run-off entering the leachate pond. Greater concentration of ammonia and salinity level were partly responsible for lower concentration of indicator bacteria in leachate from KSLS and PBLS, indicating that salinty and ammonia could significantly affect the survival of indicator bacteria. PMID- 25842533 TI - Survival of biofilm-associated Legionella pneumophila exposed to various stressors. AB - Biofilm is crucial for the multiplication and survival of Legionella pneumophila. The survival after different stressors of biofilm-associated L. pneumophila was evaluated during 150 days in this study. Mixed biofilms were allowed to develop on coupons in a biofilm reactor, which was experimentally infected with L. pneumophila. A dose of 2 ppm of monochloramine was found ineffective to kill younger (60 days) biofilm-associated L. pneumophila, whereas shock treatment (500 and 1000 ppm) was found to be significantly successful, as expected. Also, short exposure to 60 degrees C was insufficient to kill all young L. pneumophila within biofilms. A significant amount of young L. pneumophila bacteria also resisted pH 11 and 3 molar salt solution. No significant change was observed after exposure to 4 degrees C, ultra pure water and pH 5. Interestingly, L. pneumophila bacteria in biofilm became more sensitive after 90 days. PMID- 25842534 TI - Application of a low cost ceramic filter to a membrane bioreactor for greywater treatment. AB - The performance of a low cost and simple ceramic filter to a membrane bioreactor (MBR) process was evaluated for greywater treatment. The ceramic filter was submerged in an acrylic cylindrical column bioreactor. Synthetic greywater (prepared by shampoo, dish cleaner and laundry detergent) was fed continuously into the reactor. The filter effluent was obtained by gravitational pressure. The average flux performance was observed to be 11.5 LMH with an average hydraulic retention time of 1.7 days. Complete biodegradation of surfactant (methylene blue active substance removal: 99-100%) as well as high organic removal performance (biochemical oxygen demand: 97-100% and total organic carbon: >88%) was obtained. The consistency of flux (11.5 LMH) indicated that the filter can be operated for a long time without fouling. The application of this simple ceramic filter would make MBR technology cost-effective in developing countries for greywater reclamation and reuse. PMID- 25842535 TI - Biological treatment of textile dyes by agar-agar immobilized consortium in a packed bed reactor. AB - The decolorization of Acid Maroon V was investigated using bacterial consortium EDPA containing Enterobacter dissolvens AGYP1 and Pseudomonas aeruginosa AGYP2 immobilized in different entrapment matrices. The consortium displayed 96% removal of dye (100 mg/l) within 6 h when immobilized in agar-agar. Under optimum concentrations of agar-agar (3.0% w/v) and cell biomass (0.9 g% w/v), the consortium displayed decolorization for 18 successive batches of Acid Maroon V and also decolorized 14 other different textile dyes. A packed bed reactor under batch mode showed 89% decolorization of dye after 56 repetitive cycles. Under continuous flow mode, maximum color removal was achieved with bed length of 36 cm, hydraulic retention time of 2.66 h, and dye concentration of 100 mg/l. Additionally, the reactor decolorized relatively higher concentrations (100-2000 mg/l) of dye. The synthetic dye wastewater containing five textile dyes was decolorized 92% with 62% COD reduction using an immobilized consortium. PMID- 25842536 TI - Energy balance affected by electrolyte recirculation and operating modes in microbial fuel cells. AB - Energy recovery and consumption in a microbial fuel cell (MFC) can be significantly affected by the operating conditions. This study investigated the effects of electrolyte recirculation and operation mode (continuous vs sequence batch reactor) on the energy balance in a tubular MFC. It was found that decreasing the anolyte recirculation also decreased the energy recovery. Because of the open environment of the cathode electrode, the catholyte recirculation consumed 10 to 50 times more energy than the anolyte recirculation, and resulted in negative energy balances despite the reduction of the anolyte recirculation. Reducing the catholyte recirculation to 20% led to a positive energy balance of 0.0288 kWh m(-3). The MFC operated as a sequence batch reactor generated less energy and had a lower energy balance than the one with continuous operation. Those results encourage the further development of MFC technology to achieve neutral or even positive energy output. PMID- 25842537 TI - Abiotic effects on effluent dissolved organic nitrogen along an estuarine transect. AB - Biological nutrient removal is a process commonly used in water resource recovery facilities to reduce dissolved inorganic nitrogen (DIN) concentrations in effluent; this process is less effective at removing all of the effluent dissolved organic nitrogen (EDON). The goal of this study was to investigate the fate of EDON after it undergoes the disinfection process and enters receiving waters. The authors quantified the abiotic effects of effluent exposure to sunlight, increased salinity, and a combination of the two factors. Effluent dissolved organic nitrogen showed significant breakdown during the disinfection process (UV and chlorine) and when exposed to sunlight and increasing salinity. Approximately 7% of the EDON was transformed to DIN and dissolved primary amines after exposure to 9 hours of sunlight and a salinity increase from 0 to 33. The production of DIN and primary amines should be taken into account when considering sources of labile nitrogen to aquatic ecosystems. PMID- 25842538 TI - Pilot demonstration of energy-efficient membrane bioreactor (MBR) using reciprocating submerged membrane. AB - Membrane bioreactor (MBR) is becoming popular for advanced wastewater treatment and water reuse. Air scouring to "shake" the membrane fibers is most suitable and applicable to maintain filtration without severe and rapidfouling. However, membrane fouling mitigating technologies are energy intensive. The goal of this research is to develop an alternative energy-saving MBR system to reduce energy consumption; a revolutionary system that will directly compete with air scouring technologies currently in the membrane water reuse market. The innovative MBR system, called reciprocation MBR (rMBR), prevents membrane fouling without the use of air scouring blowers. The mechanism featured is a mechanical reciprocating membrane frame that uses inertia to prevent fouling. Direct strong agitation of the fiber is also beneficial for the constant removal of solids built up on the membrane surface. The rMBR pilot consumes less energy than conventional coarse air scouring MBR systems. Specific energy consumption for membrane reciprocation for the pilot rMBR system was 0.072 kWh/m3 permeate produced at 40 LMH, which is 75% less than the conventional air scouring in an MBR system (0.29 kWh/m3). Reciprocation of the hollow-fiber membrane can overcome the hydrodynamic limitations of air scouring or cross-flow membrane systems with less energy consumption and/or higher energy efficiency. PMID- 25842539 TI - Impact of substrate feed patterns on solids reduction by the Cannibal process. AB - A biological solids reduction process that uses a side-stream anaerobic reactor (Cannibal process) was investigated to better understand why variations in solids reduction occur in field installations. Field observations indicated that single stage, high sludge age processes would frequently not provide a low solids yield. To study this, laboratory sequencing batch reactors were operated, one as a conventional activated sludge system and the other two with a side-stream anaerobic reactors. The control and one anaerobic side-stream system were operated with a 5-minute feed cycle to mimic a plug flow system. The other anaerobic side-stream system operated with a 4-hour feed cycle to simulate complete mix. The 5 minutes feed Cannibal system generated up to 80%. less biological solids than the control. The 4 hours feed Cannibal system produced less biological solids than the conventional activated sludge system but remained higher than for system with a 5-minute feed time. PMID- 25842540 TI - Conventional and advanced oxidation processes used in disinfection of treated urban wastewater. AB - The purpose of the current study is to compare the inactivation of Escherichia coli in wastewater effluents using conventional treatments (chlorination) and advanced oxidation processes (AOPs) such as UV irradiation, hydrogen peroxide (H2O2)/solar irradiation, and photo-Fenton processes. In addition, an analysis of the operational costs of each treatment is carried out taking into account the optimal dosages of chemicals used. Total inactivation of bacteria (7.5 log) was achieved by means of chlorination and UV irradiation. However, bacterial regrowth was observed 6 hours after the completion of UV treatment, obtaining a disinfection value around 3 to 4 log. On the other hand, the combination H2O2/solar irradiation achieved a maximum inactivation of E. coli of 3.30 +/- 0.35 log. The photo-Fenton reaction achieved a level of inactivation of 4.87 +/- 0.10 log. The order of disinfection, taking into account the reagent/cost ratio of each treatment, is as follows: chlorination > UV irradiation > photo-Fenton > H2O2/sunlight irradiation. PMID- 25842541 TI - Metamorphosis of vascular surgery and Hybrid operations rooms. PMID- 25842542 TI - Evaluation of antimicrobial activities of minocycline and rifampin-impregnated silicone surfaces in an in vitro urinary system model. AB - OBJECTIVE: To evaluate the antimicrobial activity in urinary catheters and silicones in antibiotic-coated prosthetic urinary systems in order to reduce morbidity and mortality caused by catheter-associated infection. METHODS: The study was initiated in 1993 at Houston, USA and continued in Turkey till 1996. A sterileplastic bag was used as kidney in the in vitro urinary system. Physiological renal jet streams (50 cc/h) were generated with an intravenous metric pump. The temperature was kept at body temperature. The bladder drainage was achieved at the physiological drainage period of 4-6 hours during the 72-hour experiment. Silicone surfaces coated with pure silicone and impregnated with Minocycline-Rifampin were exposed to the urine contaminated with the targeted bacteria in the in vitro urinary model for 72 hours. Antimicrobial activities occurring in the Eosin methylene blue and blood agar media in the infected silicones were assessed. RESULTS: Minocycline-Rifampin silicone surfaces exposed to the urine contaminated with Escherichia coli and Pseudomonas aeruginosa reported reproduction. No reproduction was observed in the culture of Minocycline Rifampin-impregnated silicone surfaces for Proteus mirabilis.The difference with the control group was regarded as statistically significant for Proteus mirabilis (p < 0.005). Minocycline-Rifampin-coated silicones were closely monitored only for Proteus mirabilis in the in vitro urinary medium. Although inhibition zones (< 10 mm) in the cultures were observed for Minocycline-Rifampin-coated silicones for Escherichia coli and Pseudomonas aeruginosa, but the microbial efficacy was not regarded sufficient. CONCLUSION: There is still need for evidence-based in vivo and in vitro studies where antimicrobial activity is evaluated on the surface of catheters. PMID- 25842543 TI - Clinical presentation and predictors of survival in patients with Budd Chiari syndrome: experience from a tertiary care hospital in Pakistan. AB - OBJECTIVE: To determine aetiology, clinical presentation and predictors of survival in Budd Chiari Syndrome patients. METHODS: The prospective observational study based on non-probability convenient sampling was conducted at the Sindh Institute of Urology and Transplantation (SIUT), Karachi, and comprised Budd Chiari Syndrome patients between January 2004 and December 2013. The patients were evaluated for onset of symptoms, causes, mode of presentation and predictors of survival. SPSS 20 was used for statistical analysis. RESULTS: Of the 25 patients, 16(64%) were males, and 16(64%) belonged to the paediatric age group. Overall age range was 2-50 years with a mean of 14.7 +/- 12.41 years. Presentation was chronic in 14(56%) patients, acute in 10(40%) and acute on chronic in 1(4%). Commonest morphological abnormality involved was hepatic veins alone in 14(56%). Probable aetiologies were hypercoagulable states in 21(84%) patients, infections in 2(8%) and malignancy in 1(4%). Among hypercoagulable states, protein C deficiency was the commonest, affecting 9 (36%) patients. Seven (28%) patients died; acute 4 (16%) and chronic 3 (12%). Causes of death included sepsis 4 (16%), fulminant hepatic failure 1 (4%), gastrointestinal bleeding 1 (4%), and bleeding from liver biopsy site 1 (4%). Poor survival was associated with bilirubin > 5 mg/dl (p < 0.031), serum alanine transaminase > 40 U/L (p < 0.005), serum albumin < 2.8 g/dl (p < 0.008), Child-Turcotte-Pugh score > 10 (p < 0.001) and absence of varices (p < 0.025). Cox regression analysis failed to show any significant independent predictors of survival. CONCLUSION: Budd Chiari Syndrome affected young patients more frequently and was associated with high mortality. The commonest aetiology was hypercoagulable state. Survival was poor in patients with decompensated liver disease and those with an acute clinical presentation. PMID- 25842544 TI - The influence of the lateral pharyngeal wall anatomy on snoring and sleep apnoea. AB - OBJECTIVES: To elucidate the variations of the lateral pharyngeal wall anatomy on physical examination and to assess the clinical importance of the examination of the lateral pharyngeal wall on the presence and severity of obstructive sleep apnoea syndrome. METHODS: The cross-sectional study was conducted at Ege University Medical School, Izmir, Turkey, between May 2010 and April 2011. The patients were divided into four equal groups: Group 1--snoring without apnoea (age 20-40); Group 2--snoring without apnoea (age 40-60); Group 3--apnoea hypopnoea index < 5/hr; Group 4: apnoea-hypopnoea index > 30/hr. Calibrated oropharynx pictures were taken. Distance between palatoglossal and palatopharyngeal arches, height of palatoglossal and palatopharyngeal arches, uvula width, uvula length and distance between tonsils were measured. SPSS 17 was used for statistical analysis. RESULTS: Of the 80 patients in the study, 44 (55%) were men. Mean distance between palatopharyngeal and palatoglossal arches were 1.55 +/- 0.34 cm and 2.70 +/- 0.43 cm respectively. Mean height of palatopharyngeal and palatoglossal arches were 0.60 +/- 0.21 cm and 1.37 +/- 0.36 cm respectively (p > 0.05). Mean uvula width and uvula length were 0.80 +/- 0.12cm and 1.25 +/- 0.27 cm respectively (p > 0.05). Mean distance between tonsils was 2.24 +/- 0.56 cm (p > 0.05). Distance between palatopharyngeal arches was significantly different between groups 3 and 4 (p < 0.05). CONCLUSIONS: Palatopharyngeal arch anatomy was found to be significantly associated with obstructive sleep apnoea syndrome severity, especially in patients with normal or small tonsil size. Patients with the palatopharyngeal arches, which narrow the oropharyngeal inlet more than the tonsils, should further be investigated with polysomnography. PMID- 25842545 TI - Prolidase activity and oxidative stress in patients with schizophrenia: a preliminary study. AB - OBJECTIVE: To determine whether serum prolidase levels are associated with the etiopathogenesis of schizophrenia. METHODS: The study was conducted at the psychiatry outpatient clinics of the University Hospitals of Recep Tayyip Erdogan and Afyonkocatepe in spring 2013. It comprised patients with schizophrenia who were consecutively recruited from the Psychiatry outpatient clinics of the hospital. An equal number of healthy individuals were recruited from the community. Each patient underwent a detailed diagnostic evaluation by psychiatry residents by using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV. Serum prolidase activity and oxidative parameters were measured in patient and control groups.The severity of psychotic symptoms was assessed using the positive and negative syndrome scale. SPSS 16 was used for statitistical analysis. RESULTS: There were 30 subjects in each group, with 18 (60%) females among the patients and 21 (70%) among the controls. Serum prolidase level was significantly higher in schizophrenia patients compared to the controls (p < 0.001). Total Oxidative Stress and Oxidative Stress Index parameters were found to be significantly different between the patients and the controls (p = 0.024 and p < 0.001). Serum prolidase level did not show any correlation with markers of oxidative stress in the patients. CONCLUSION: Prolidase activity, glutamate transmission and oxidative stress may be inter related in the etiopathogenesis of schizophrenia. PMID- 25842546 TI - Cigarette consumption habits and related factors among college students in Turkey: a logit model analysis. AB - OBJECTIVE: To investigate smoking habits, related factors and level of consciousness among college students in Turkey. METHODS: The study was conducted at Gaziosmanpasa University, Tokat, Turkey, in May 2013. Data was obtained through face-to-face questionnaires. It was tested using Binomial Logit Regression Model. In addition, students were asked to answer a five-score question group in order to determine the reflections and judgments of smoker students. RESULTS: Of the 253 students in the study, 125(49%) were males. Overall, there were 101 (40%) smokers. Smoking ban was found to lower cigarette smoking among the smokers (p < 0.0001). On the other hand, smoking habit of parents and friends, income levels and differences in places where they lived positively affected cigarette smoking (p < 0.05). CONCLUSION: Tobacco policies and precautions taken to lower tobacco use resulted in considerable decrease in cigarette consumption. PMID- 25842547 TI - Abuse among school going adolescents in three major cities of Pakistan: is it associated with school performances and mood disorders? AB - OBJECTIVE: To assess the proportion of various types of abuses and their association with school performances and psychological stress among adolescents from three major cities of Pakistan. METHODS: The cross-sectional school survey was conducted from March to September 2009, comprising adolescent students at six schools in Karachi, Lahore and Quetta. Data was collected using a self administered and pre-tested questionnaire by trained medical students. SPSS 16 was used for statistical analysis. RESULTS: Of the 414 subjects in the study, there were 223 (54%) boys and 191 (46%) girls with an overall mean age of 14.36 +/- 1.08 years. In all, 140 (33.7%) participants were physically abused and 236 (57%) participants were verbally abused in the preceding 12 months. Besides, 245 (59.2%) were involved in physical fight and 195 (47.1%) had suffered injury during the preceding year. There were 171 (41.4%) subjects having suffered bullying during the same period. Verbal abuse (p = 0.05), physical fight (p = 0.05) and bullying (p < 0.001) were significantly associated with poor school performances among adolescents. Physical abuse (p = 0.05), verbal abuse (p = 0.003), injury (p = 0.02) and bullying (p < 0.001) were significantly associated with psychological stress. CONCLUSION: Various types of abuse were quite prevalent in adolescents that were significantly associated with poor school performance and poor mental health. PMID- 25842548 TI - Evaluating success of curettage in the surgical treatment of endometrial polyps. AB - OBJECTIVES: To determine treatment efficacy of curettage on endometrial polyp. METHODS: The quasi-experimental pre-and-post study was conducted in 2011-12 at the gynaecology department of Imam Reza Hospital, Mashhad, Iran, and comprised patients who underwent hysteroscopy for endometrial polyp. Location, size, number and base condition of the polyps were recorded before the patient underwent curettage. Hysteroscopy was then performed and the condition of the remaining polyps was compared with initial findings. Also, the remaining polyps were resected. SPSS 13 was used for statistical analysis. RESULTS: There were 51 patients in the study with a mean age of 33.14 +/- 8.19 years (range: 23-59 years)Besides, there were 82 polyps; 38(46.3%) having a narrow base, and 44(53.7%) having a wide base. The mean polyp size was 2.39 +/- 2.63cm.After performing curettage, 23 (28.0%) polyps were removed completely, 39(47.6%) had size reduction, and 20(24.4%) had no change in size. Curettage could not significantly remove polyps (p < 0.001). Polyps smaller than 2cm were more likely to have been removed compared to the bigger ones (p = 0.003).Polyps with wide base were more significantly removed than those with narrow base (p < 0.001).Further, those with wide base and also smaller than 2 cm were removed more significantly than others (p < 0.001).The location of polyps had no effect on removal probability by curettage (p = 0.114). CONCLUSION: Curettage was not found to be a reliable method for endometrial polyp removal. If hysteroscopy is not accessible, the size of the polyp should be determined by vaginal sonograghy to estimate the probability of its removal by curettage. PMID- 25842549 TI - Opinion of Pakistani physiotherapists/students about anatomy as a subject and method of teaching anatomy: a cross sectional survey. AB - OBJECTIVE: To recognise and identify the importance of Anatomy as a subject for physiotherapists/students. METHODS: The cross-sectional descriptive study was conducted from January to October 2011 at Riphah International University, Lahore, and comprised physiotherapists registered with Pakistan Physical Therapy Association and students pursuing undergraduate physiotherapy studies at the University. A survey proforma consisting of six questions was used for data collection which was analysed using SPSS 17. RESULTS: Of the 500 questionnaires distributed among physiotherapists and students, 286(57.2%) were collected back duly filled. Overall, 280(97.9%) respondents said Anatomy was important in physical therapy, 179(62.58%) said Anatomy was a difficult subject to retain knowledge of, 155 (54.38%) were of the view that only Clinical Anatomy should be studied, 204 (71.32%) were in favour of performing dissection, 259 (90.55%) found that teaching videos were essential for the study of Anatomy, and 89 (31.11%) believed Anatomy could be memorised by multiple readings. CONCLUSION: Despite being a difficult subject, Anatomy is an essential subject for medical professionals. PMID- 25842550 TI - Features of retinopathy of prematurity in a tertiary care hospital in Lahore. AB - OBJECTIVE: To study the demographic and clinical features of Retinopathy of Prematurity in urban Punjab. METHODS: The cross-sectional study was performed at Hameed Latif Hospital, Lahore, from April 2010 to October 2013 and comprised neonates born with birth weight less than 2000 g, gestational age less than 37 weeks, or those who were considered high risk for Retinopathy of Prematurity. Variables recorded included history, birth weight, gestational age, oxygen supplementation, development of Retinopathy of Prematurity, and laser treatment. Data was analysed using SPSS 17. RESULTS: There were 285 neonates in the study with a mean birth weight of 1280.34 +/- 350.43 g and mean gestational age being 29.38 +/- 3.14 weeks. Overall, 167 (58.6%) received supplemental oxygen, 86(30.2%) were anaemic and 44 (15.4%) received blood transfusion. Besides, 47 (16.5%) premature babies were product of multiple gestation, 34 (11.9%) were having respiratory distress, 25 (8.8%) had sepsis and received intravenous antibiotics, 70(24.6%) developed Retinopathy of Prematurity, and 22 (7.7%) developed threshold disease and received laser treatment at mean gestational age of 32.11 +/- 2.53 weeks. CONCLUSION: Screening is key to preventing childhood blindness caused by Retinopathy of Prematurity. Prematurity, low birth weight and supplemental oxygen therapy are significant risk factors for the condition. PMID- 25842551 TI - Immune mechanisms in type-2 diabetic retinopathy. AB - OBJECTIVE: To enumerate CDR+CD25+ Treg cells and determine serum IL-6 and IL-17 in type 2 diabetes mellitus patients with retinopathy. METHODS: The case-control study was conducted at the Department of Immunology, University of Health Sciences, Lahore, from November 2009 to January 2012 and comprised diabetic patients and healthy controls who were divided into three groups. Group 1 had controls, while Group 2 had diabetic patients without retinopathy and Group 3 had diabetic patients with retinopathy. Flowcytometre and enzyme-linked immunosorbent assay were used for CD4+CD25+ Tregs and serum IL-6 and IL-17 respectively. SPSS 20 was used for statistical analysis. RESULTS: Of the 212 subjects in the study, 30(14%) were Group 1, 30(14%) in Group 2 and 152(72%) in Group 3.There were 25 (83%) women in Group 2 and 101 (66%) in Group 3 compared to 9 (30%) in Group 1. Higher mean age was in Group 3 (50.88 +/- 8.9 years) and Group 2 (49.46 +/- 9.94 years) compared to Group 1 (34.66 +/- 8.78 years) while longer mean disease duration was in Group 3 (10.51 +/- 5.24 years) than Group 2 (7.76 +/- 4.14 years). Highest median ratio of IL- 6 was in Group 1 (1468.62) (Q1-Q3: 1229.9 1543.35), followed by Group 2 (1455.32) (Q1-Q3:1214.22-158.9) and Group 3 (469.84) (Q1-Q3: 206.53-1231.33) whereas IL-17 was the highest in Group 1 (339.38) (QT-Q3: 159.89- 1174.93), followed by Group 3 (216.60) (Q1-Q3:141.87 410.25) and Group 2 (174.17) (Q1-Q3: 138.77-458.17). Higher percentage of Tregs was in Group 2 (3.07 +/- 0.43) followed by Group 1 (2.91 +/- 0.04) and Group 3 (2.88 +/- 0.38). Significant difference was observed in gender, age, disease duration, level of IL-6 and IL-17 (p < 0.05 each), while no difference was found in glycated haemoglobin, CD4+CD25+ and Tregs (p > 0.05 each). CONCLUSION: Age, gender and duration of diabetes contributed to diabetic retinopathy, while CD4+CD25+ T cells and Treg cells did not. Serum IL-6 and IL-17 were inversely associated with diabetic retinopathy. PMID- 25842552 TI - Acute and chronic impact of smoking on salivary and serum total antioxidant capacity. AB - OBJECTIVE: To investigate increased oxidative stress in saliva of smokers along with their serum. METHODS: The case-control study was conducted from September to December 2008 in the Department of Biochemistry of the Medical School, Kirikkale University, Kirikkale, Turkey. A blood sample and saliva samples before and after smoking were collected from the smokers, while blood and saliva samples were taken from the controls. All samples were taken concurrently. The samples were measured for total antioxidant capacity, total oxidant stress, oxidative stress index, malondialdehyde, nitric oxide and total sulfhydryl groups. Levels of superoxide dismutase and glutathione peroxidase were also measured on saliva samples. SPSS 13 was used for statistical analysis. RESULTS: Of the 54 subjects in the study, 27(50%) were smokers with a mean age of 28.4 +/- 5.42 years, and 27 (50%) were controls with a mean age of 29.7 +/- 8.03 years. Total oxidant stress, oxidative stress index, malondialdehyde and nitric oxide levels were found higher in the serum samples of smokers (p < 0.05), and the levels of total sulfhydryl groups in smokers were lower compared with the controls (p < 0.05). Among the smokers, salivary malondialdehyde levels were higher before and after smoking (p < 0.05), glutathione peroxidase levels were lower than the controls, and salivary nitric oxide levels after smoking were higher than both those of the control group and the levels before smoking (p < 0.05). CONCLUSION: Both acute and chronic increased oxidative conditions may be a significant sign of the destructive effects of smoking. The investigation of disorders in smokers concerning oxidative stress will be beneficial in terms of novel approaches and treatment modalities. PMID- 25842553 TI - Impact of rituximab and IPI on survival in diffuse large B cell lymphoma patients treated at a tertiary level cancer centre in Pakistan: a single-centre experience. AB - OBJECTIVE: To determine the impact of Rituximab and international prognostic index score on survival in diffuse large B-cell lymphoma patients. METHOD: The retrospective study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from January to May 2013 and comprised record of patients with diffuse large B-cell lymphoma who were treated from 2007 to 2010. Baseline international prognostic index score, stage at presentation were noted and the records were divided into two groups A and B on the basis of the type of chemotherapy. SPSS 19 was used for statistical analysis. RESULTS: Of the 93 patients in the study whose records were reviewed, 54(58%) were men. Overall median age was 43 years (range: 18-76). Stages at presentation were stage-I 14 (15.1%), stage-II 41 (44.1%), stage-III 20 (21.5%) and stage-lV 18 (19.4%). International prognostic index risk categorisation was low risk 59 (63.4%), low intermediate risk 23 (24.7%), high intermediate risk 10 (10.8%) and high risk 1 (1.1%). There were 31 (33%) patients in Group A and 62 (67%) in Group B. Median follow-up was 3.9 years (range: 1.2-6.1). Overall survival at 4 years was 66.4%; for Group A 65.3% and for Group B 66.7% (p < 0.4). On the basis of risk categories, overall survival was statistically significant (p < 0.001) between the groups. CONCLUSION: International prognostic index risk categorisation had statistically significant impact on survival. However, there was no evidence of a significant survival benefit between types of chemotherapy. Further controlled trials are needed in this regard. PMID- 25842554 TI - The effect of prenatal administration of valproic acid on the survivability and day of hatching of chick embryo. AB - OBJECTIVE: To assess the effects of prenatal administration of valproic acid on the survivability and day of hatching of chick embryo in comparison with age matched controls. METHODS: The experimental study was conducted at the Department of Anatomy, Regional Centre of College of Physicians and Surgeons Pakistan, Islamabad, from February 2010 to February 2011. Fertilised chicken eggs were divided into two groups, labelled as experimental group-A and control group-B. Group-A eggs were injected with valproic acid, incubated and hatched. Group-B eggs underwent sham treatment using normal saline. The fully hatched chicks were then evaluated for the day of hatching and survivability, on hatching or on day 22 of incubation whichever was earlier. Outcome was statistically compared with the controls using SPSS 10. RESULTS: The two groups had 30 eggs each. In Group-A 23 (76.66%) chicks hatched out, while there were 7 (23.33%) dead chicks. In Group B, 28 (93.33%) chicks hatched out and 2 (6.66%) were dead. Chicken embryos exposed to valproic acid in ovo showed increased mortality (p < 0.001) and delayed hatching (p < 0.001). CONCLUSION: Prenatal exposure of chick embryos to valproic acid decreased embryo survival and also delayed hatching compared to age matched controls. PMID- 25842555 TI - Acute renal failure in diabetes mellitus. AB - OBJECTIVE: To study the causes and outcome of Acute renal failure (ARF) in diabetes mellitus. METHODS: This prospective study was conducted at nephrology unit of SIUT Karachi, Pakistan from November 2012 to May 2013. All adult patients with known underlying diabetes presenting with suspected ARF were included in the study. The treatment options were conservative and dialysis. Renal biopsy was performed in selected patients. All patients were followed for a period of six weeks for outcome of renal failure i.e. recovery, dialysis dependency and death. RESULTS: A total of 95 patients with suspected ARF were enrolled during this period. We found sepsis as the single most common factor causing ARF in 66 (69.5%) patients and the most common focus of infection was found to be urinary tract in 47 (71.2%) patients. Other factors leading to ARF included volume depletion in 19 (20%), cardio renal in 13 (13.7%), acute glomerulonephritis in 3 (3.15%) and contrast exposure in 2 (2.1%) patients. In all 72 (75.8%) patients required dialysis, while 23 (24.2%) were managed conservatively. Eventually 62 (67.39%) patients recovered, 14 (15.21%) became dialysis dependent, and 16 (17.39%) died. Among those who expired, all underwent dialysis and sepsis was the leading cause of death in 13 (81.25%) patients. CONCLUSION: Infection, especially of urinary tract is the leading cause of ARF in Diabetics. Outcome is favourable in those who dot require dialysis. PMID- 25842557 TI - Visual inspection of cervix with acetic acid: a good alternative to pap smear for cervical cancer screening in resource-limited setting. AB - OBJECTIVE: To determine the diagnostic accuracy of visual inspection of cervix using 3% acetic acid as a screening test for early detection of cervical cancer taking histopathology as the gold standard. METHODS: The cross-sectional study was conducted at Civil Hospital Karachi from July 1 to December 31, 2012 and comprised all sexually active women aged 19-60 years. During speculum examination 3% acetic acid was applied over the cervix with the help of cotton swab. The observations were noted as positive or negative on visual inspection of the cervix after acetic acid application according to acetowhite changes. Colposcopy guided cervical biopsy was done in patients with positive or abnormal looking cervix. Colposcopic-directed biopsy was taken as the gold standard to assess visual inspection readings. SPSS 17 was used for statistical analysis. RESULTS: There were 500 subjects with a mean age of 35.74 +/- 9.64 years. Sensitivity, specifically, positive predicted value, negative predicted value of visual inspection of the cervix after acetic acid application was 93.5%, 95.8%, 76.3%, 99%, and the diagnostic accuracy was 95.6%. CONCLUSION: Visual inspection of the cervix after acetic acid application is an effective method of detecting pre invasive phase of cervical cancer and a good alternative to cytological screening for cervical cancer in resource-poor setting like Pakistan and can reduce maternal morbidity and mortality. PMID- 25842556 TI - A sample of paediatric residents' loneliness-anxiety-depression-burnout and job satisfaction with probable affecting factors. AB - OBJECTIVE: To assess levels of anxiety, depression, loneliness, burnout and job satisfaction among paediatric Residents, and how they influence each other. METHODS: The cross-sectional study was conducted at Necmettin Erbakan University, Meram, and Konya Meram Education and Research Hospital, Turkey from January to June 2011, and comprised paediatric Residents and their counterparts from other departments who formed the control group. While maintaining confidentiality, a questionnaire was used to collect data that had elements of the University of California, Los Angeles, Loneliness Scale, Hospital Anxiety and Depression Scale, Maslach Burnout Inventory and Minnesota Job Satisfaction Questionnaire. SPSS version 13 was used for statistical analysis. RESULTS: Overall there were 74 Residents in the study; 43 (58%) working with the paediatrics department, and 31 (42%) in the control group. Overall mean age was 27.60 +/- 2.25 years. Residents who were not satisfied with the city they were living in, with their professional career and who would not choose the same career given a second chance were feeling more lonely and had higher loneliness scores (p < 0.05). In contrast, anxiety among female Residents who were unsatisfied with their professional career and working conditions was significantly high (p < 0.05). Positive correlation was detected between the burnout levels of Residents and their anxiety, depression and loneliness scores (r = 0.74; r = 0.65; r = 0.36). In terms of intrinsic, extrinsic and total job satisfaction, there was an obvious negative correlation (r = -0.57; r = -0.54; r = -0.61). CONCLUSION: Working conditions and professional liability were the main factors affecting the Residents. Informed decision and career willingness may help them feel better. PMID- 25842558 TI - Higher frequency of methicillin resistant bacteria in children with familial mediterranean fever. AB - OBJECTIVE: To investigate resistant microorganisms in nasal mucosa of children with Familial Mediterranean Fever. METHODS: The study was conducted from March to May 2013 at Mustafa Kemal University, Turkey, and comprised children with Familial Mediterranean Fever and healthy controls. All subjects had no history of antibiotic or local and/or systemic steroid use within the preceding 2 weeks. Nasal swab samples were obtained from all the subjects. Strain identification was done by using standard methods. SPSS 13 was used for statistical analysis. RESULTS: Of the 151 subjects in the study, 73 (48.34%) were cases and 78 (51.65%) were controls. Among the cases, there were 26(35.6%) girls, while among the controls, there were 40(51.3%) girls (p=0.052). The mean age of the cases was 7.78 +/- 3.34 years (range: 3-15 years), while it was 8.15 +/- 2.71 years (range: 3-16) among the controls (p = 0.208). Methicillin-resistant coagulase-negative staphylococcus and methicillin-resistant staphylococcus aureus were isolated in both the groups. The growth rate of resistant bacteria was 63% (n = 46) in the cases, in the controls (p = 0.003; odds ratio [OR]: 2.7; 95% confidence interval [CI]: 1.4-5.2). Among the controls, history of hospitalisation increased the risk for the presence of resistant bacteria by 7.7 fold (OR: 7.7; 95% CI: 1.4-40.4). CONCLUSION: Higher rates of resistant bacteria showed that they were at risk of comorbidities related to antibiotic resistance. PMID- 25842559 TI - Analysis of surgical approaches for unstable thoracolumbar burst fracture: minimum of five year follow-up. AB - OBJECTIVES: To evaluate and compare the long-term outcome of unstable thoracolumbar burst fractures treated using anterior, posterior or combined anterior and posterior approaches. METHODS: The prospective randomised controlled study was conducted at the Tianjin 4th Centre Hospital, Tianjin, China, and comprised patients of unstable thoracolumbar burst fracture operated between July 2004 and July 2006 and followed up for five years. The patients were divided randomly into three groups of anterior, posterior and combined anterior and posterior approaches. Clinical data was analysed using SPSS 17. RESULTS: Of the 66 cases in the study, 45 (68.18%) were male and 21 (31.8%) were female, with overall age ranging from 19 to 69 years. There were 22 (33.3%) patients in the anterior group, 23 (35%) in the posterior group, and 21 (32%) in the combined anterior and posterior group. Comparison was made between two respective groups. The combined group was found to have the longest operation time (p < 0.02; p < 0.01, respectively), larger blood loss (p < 0.006; p < 0.005, respectively), longer hospital stay (p < 0.01; p < 0.003, respectively) and higher hospitalisation costs (p < 0.004; p < 0.001, respectively). The postoperative kyphotic angle was significantly smaller than preoperative one in all groups (p < 0.01; p < 0.02; p < 0.01). CONCLUSION: The anterior approach or combined anterior and posterior approach were better options in managing unstable thoracolumbar burst fracture, while the latter should be used only for the burst fracture with a significant posterior column injury. PMID- 25842560 TI - Charcot-Marie-Tooth type 1A disease from patient to laboratory. AB - Charcot-Marie-Tooth (CMT) disease is a well-known neural or spinal type of muscular atrophy. It is the most familiar disease within a group of conditions called Hereditary Motor and Sensory Neuropathies (HMSN). The disease was discovered by three scientists several years ago. Several genes are involved as the causative agents for the disease. Hundreds of causative mutations have been found and research work for the identification of a novel locus and for the treatment of CMT1A is going on. This review article was planned to gather information on CMT disease and updates on its treatment.National Center for Biotechnology Information (NCBI) and PubMed were searched for data retrieval. Molgen database, which is the exclusive site for CMT mutation, was the other source of articles. Different aspects of the CMT disease were compared.Advancements in the finding of the causative gene, discovery of the novel Loci are the current issues in this regard.CMT disease is incurable, but researchers are trying to get some benefits from different natural compounds and several therapeutic agents.Various groups are working on the treatment projects of CMT1A. Major step forward in CMT research was taken in 2004 when ascorbic acid was used for transgenic mice treatment. Gene therapy for constant neurotrophin-3 (NT- 3) delivery by secretion by muscle cells for the CMT1A is also one of the possible treatments under trial. PMID- 25842561 TI - Measles hectic in Pakistan; Upsurge versus the lurking vaccination. AB - Measles has claimed more lives than anticipated, as the outbreaks hit Pakistan severely in 2013 as compared to 2012. Claiming 350 lives through the year 2013, Measles became a headache for the health agencies, authorities and common people. The sudden appearance of the virus in different parts of the country both rural and urban at the same time can be linked to more than one cause. The notable being corruption in health system, poor health infrastructure, destabilized routine immunization, shortage in number of vaccinators, negligence among parents, and floods. As a consequence of these causative factors, the unclear picture of immunization coverage can be presumed as the ultimate etiology of outbreaks in such numbers. Therefore, there is an urgent need to draw out the actual data of immunisation coverage and focus on elimination of hurdles in the road to success in fully coverage with vaccines. PMID- 25842562 TI - Tubo-omental ectopic pregnancy. AB - Tubo-omental pregnancy is a very rare form of ectopic pregnancy. Here we present a case of tubo-omental pregnancy diagnosed at surgical exploration. A 26-year-old woman presented with abdominal discomfort, nausea and vomiting. There was ectopic pregnancy with viable foetus in the right adnexa and haemoperitonium. Laparotomy was performed and on exploration tubo-omental pregnancy was found attached to fimbria at one side and omentum at the other. Fimriaectomy and partial omentectomy was performed. The patient had a successful post-operative recovery. PMID- 25842563 TI - Pathognomonic symptom associated with lightning strike: Lichtenberg figure. AB - Lightning strikes especially occur during spring and summer months in the afternoons when there is heavy rain. In deaths resulting from lightning strike, there may either be no evidence on the dead person's clothes or body, or there may be burnt or torn patches on their clothes and lichtenberg figures specific to lightning strikes on their bodies. In such cases that also have a comorbid of cognitive dysfunction, since there is generally amnesia, having these figures during the physical examination has a valuable place in early diagnosis and quick treatment. This paper presents a case of lightning strike that was found to have Lichtenberg figures on the back and right leg after secondary examination. PMID- 25842564 TI - Tumour induced osteomalacia. AB - Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome usually presenting with bone pain, fracture of bones and muscle weakness. It is caused by high serum levels of fibroblast growth factor 23 (FGF- 23), which is a hormone regulating phosphate, and vitamin D. FGF-23 is secreted by several tumours, especially benign mesenchymal tumours which are very small and difficult to locate. There is a significant delay from onset of symptoms to the diagnosis of this entity dueto occult nature of this disease. We present a case of young male who presented with long history of progressively worsening muscular pain and weakness, rendering the patient confined to bed. Our aim of presenting this patient as a case report is to make physicians realise that any patient with unexplained muscular weakness and pain must undergo workup for TIO, including serum phosphate measurement, as this is a rare but potentially curable disease. PMID- 25842565 TI - Valentino appendix: a report of 3 cases. AB - We present three cases of young male patients with perforated duodenal ulcer that were diagnosed and treated as appendicitis with appendectomy. They presented with peritonitis and were treated accordingly. Because of the misdiagnosis, their hospital course was significantly prolonged. This morbidity could have been avoided by careful history-taking, examination and per-operative findings. PMID- 25842566 TI - Artificial sweeteners: safe or unsafe? AB - Artificial sweeteners or intense sweeteners are sugar substitutes that are used as an alternative to table sugar. They are many times sweeter than natural sugar and as they contain no calories, they may be used to control weight and obesity. Extensive scientific research has demonstrated the safety of the six low-calorie sweeteners currently approved for use in foods in the U.S. and Europe (stevia, acesulfame-K, aspartame, neotame, saccharin and sucralose), if taken in acceptable quantities daily. There is some ongoing debate over whether artificial sweetener usage poses a health threat .This review article aims to cover thehealth benefits, and risks, of consuming artificial sweeteners, and discusses natural sweeteners which can be used as alternatives. PMID- 25842567 TI - Radiography in primary care diabetes. AB - Diabetes mellitus is a relatively common disease, and a variety of plain radiographic changes are frequently encountered in diabetic patients. Primary care physicians should be able to recognize these common x-ray findings so that early treatment may be started, thereby preventing disease progression and decreasing patient morbidity. PMID- 25842568 TI - Growing prevalence of osteoporosis in Pakistan: call for action. PMID- 25842569 TI - Prevalence and correlates of poor oral hygiene among school attending 13-15 year adolescents in Morocco. PMID- 25842570 TI - Translational research versus promotional research; basic conflict in Iran. PMID- 25842572 TI - Enormity of urolithiasis in Sindh province. PMID- 25842571 TI - Frequency of comorbidities and risk factors among ischaemic heart disease patients in Karachi--perspective from three tertiary care hospitals. AB - OBJECTIVE: To evaluate comorbidities and risk factors among ischaemic heart disease patients. METHODS: The descriptive study was conducted at the cardiology wards of three hospitals in Karachi, and comprised and comprised data related to patients from September 5, 2013 to January 15, 2014. Data was analysed using SPSS 20. RESULTS: Out of 377 individuals, 238 (63.1%) were males and 139(36.9%) were females. Depression outnumbered all other comorbids 137(58%) in males and 103(74%) in females. It was followed by anxiety in 129 (54%) males and 90 (65%) females. In risk factors, high-cholesterol diet outnumbered all other risk factors 137 (58%) followed by stressful life 123 (52%) in males, while in females physical inactivity 91 (65%) and stressful life 91 (65%) both were leading risk factors. CONCLUSION: A variety of risk factors existed in ischaemic heart disease patients. Special attention should be paid to stressful lifestyle and high cholesterol, two of the most common risk factors in both genders. PMID- 25842573 TI - Medical students' perspective about factors motivating participation in small group discussions. AB - OBJECTIVE: To assess perceptions of medical students about the factors that may enhance motivation for learning through small group discussions. METHODS: The qualitative descriptive study was conducted in May, 2013, at Riphah International University, Islamabad, and comprised undergraduate medical students from the first to the fourth year who were given a questionnaire that sought their opinion about group characteristics, composition, expectations from the teachers, environment, additional tools and optimum time duration. The effects of granting extra marks for active participation, feedback and weightage of attendance in enhancing motivation in small group discussions were also explored. Common themes from within the responses were highlighted. RESULTS: Initially, 400 students were given the questionnaire, but complete responses were received from 290(72.5%). About the effective group size, 221(76.2%) suggested 12 or less students, while 153(52.75%) thought groups should be divided into subgroups according to the task, and 148(51.03%) were in favour of mixed gender composition of a group. A comfortable and air-conditioned environment was suggested as a motivating factor by 156(53.79%) students. Use of models, laptops and internet during the discussion was suggested by 97(33.44%) students, and 232(80%) suggested an hour or less as sufficient time. Grant of extra marks 209(72.06%), feedback 220(75.86%) and weightage of attendance 193(66.55%) were all considered positive motivating factors. Finally, 250(86.20%) were in favour of continuation of small group discussion as a learning tool. CONCLUSION: Most students thought a smaller size makes a small group discussion more effective, and that it should continue to be used as one of the learning modalities. PMID- 25842574 TI - Role of intraoperative ultrasound in achieving complete resection of intra-axial solid brain tumours. AB - OBJECTIVES: To determine the frequency of completeness of resection for intra axial solid brain tumours with the help of intra-operative ultrasound to detect residual brain tumour. METHODS: The cross-sectional study was conducted at the Department of Neurosurgery, Dow University of Health Sciences and Civil Hospital Karachi, from September 2009 to June 2010 and comprised patients with intra-axial solid brain lesion. During operation following standard craniotomy, multi-plane sonographic examination was performed using intra-operative ultrasound for tumour localisation and calculation of dimension, followed by tumour resection in the standard fashion. At the end of tumour resection ultrasound was again used for the detection of any residual tumour. Results of intra-operative ultrasound were compared with post-operative contrast magnetic resonance imaging. RESULTS: Of the 39 cases in which intra-operative ultrasound was performed, 32(82.1%) were males and 7(17.9%) were females, with an overall mean age of 42.6+/-19.7 years. Intra operative ultrasonography was able to localise and delineate the tumour in all 39 (100%) cases. It showed no residual tumour in 36 (92.3%) cases, but in 3(7.7%) cases residual tumour was detected. Post-operative contrast enhancing magnetic resonance imaging showed no residual tumour in 35(89.7%) cases and in 4(10.3%) cases residual tumour was detected. The frequency of completely resected intra axial solid brain tumour was 35(89.7%), while in 4(10.3%) cases incomplete resection was observed. CONCLUSION: The study concluded that intra-operative ultrasonography has an important role in achieving increased frequency of completely resected intra-axial solid brain tumours. PMID- 25842575 TI - Arthroplasty versus fusion for single-level cervical disc disease. AB - OBJECTIVE: To evaluate the effectiveness and safety of cervical arthroplasty and anterior cervical discectomy fusion methods. METHODS: The randomised clinical trial was conducted at the neurosurgical clinic of University of Harran, Turkey, between February 2009 and January 2010. The patients had single level disc disorder between C4-C7 levels. Before surgery, all of the patients had taken medical treatment with no improvement. Surgery was conducted with anterior approach, and disc prosthesis or polyetheretherketone cage for fusion were applied after patients were randomly divided into two groups. For preoperative and postoperative clinical evaluations Neck Disability Index and Visual Analogue Scale were used. Surgical results were evaluated according to Odom's criterion, and 'excellent' and 'good' results were accepted as successful. P<0.05 was taken as statistically significant. RESULTS: Of the 42 patients in the study, 23(54.76%) were treated with Anterior Cervical Discectomy and Fusion, and 19(45.23%) with Cervical Disc Arthroplasty. There were no statistical differences between postoperative mean Visual Analogue Scale score (p<0.86) and Neck Disability Index scores (p<0.11) in the two groups. Average decrease in lordosis angle was 1.2 degree in Arthroplasty group, while it was 1 degree in the Fusion group. Postoperative adjacent segment degeneration was not detected in either group. CONCLUSION: Anterior Cervical Discectomy and Fusion, and Cervical Disc Arthroplasty are safe and successful methods for the treatment of single level cervical disc disease. Although the latter is a relatively new technique performed with increased frequency, but its superiority is still uncertain. PMID- 25842576 TI - "Mentorship" a stride towards maintenance of medical student's well being. AB - OBJECTIVE: To evaluate the effectiveness of mentorship programme with respect to emotional wellness of medical students. METHODS: The cross-sectional questionnaire-based survey was carried out from March 2009 to February 2013 comprising first year medical students of five consecutive batches from two medical colleges. They were divided into two groups; Group A had non-mentored students from a medical college in Karachi, while Group B had mentored students of Bahria University Medical and Dental College, Karachi. Responses on aspects of emotional wellness was taken on a 4-point Likert scale; never, sometimes, mostly and always. Predictive Analysis Software version 18 was used for statistical analysis. RESULTS: Out of the 500 questionnaires distributed to each batch, 423(84.6%) were returned filled in Group A and 450(90%) in Groups B. Overall, 873(87.3%) responses were obtained. Group A had 275(65%) females whereas in Group B there were 275(61%) females. The mean age of the overall study population was 20+/-2 years. The scores of emotional wellness were better in Group A compared to Group B 21.36+/-4.54 vs. 20.54+/-4.340 (p<0.028). The feeling of being cheerful and helpful was valued by 212(50%) students of Group A and 180(40%) of Group B (p<0.008). The satisfaction of being needed by family members and recognising stresses of life was significant in Group A (p<0.0001 vs. p<0.014). Group B had low emotional wellness scores yet 369(82%) had never consulted psychologists and psychiatrists compared to 13(0.03%) of Group A (p<0.02). Help from family members was also acquired by non-mentored students (p<0.003). CONCLUSION: Emotional support provided by mentoring programme of Bahria University Medical and Dental College minimised the stress, limited consultation by psychologists or psychiatrists, and reduced reservations of parents and students of first year medical education. PMID- 25842577 TI - Idiopathic thrombocytopenic purpura in children: a 10 years experience at tertiary care hospital. AB - OBJECTIVE: To evaluate presenting features, treatment modalities and response to therapy in children with idiopathic thrombocytopenic purpura. METHODS: The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised clinical data, presenting demographics, clinical spectrum, management and outcome of children admitted with idiopathic thrombocytopenic purpura from 2001 to 2010. SPSS 20 was used for statistical analysis. RESULTS: Records of 95 children between 0-15 years in the period 2001 to 2010 were reviewed. The overall mean age at the time of presentation was 6.1+/-3.8 years. There were 45(47.3%) male and 50(52.7%) female cases. A total of 34(35.8%) patients had history of preceding illness. Regarding clinical presentations, bruises 81(85.3%), petechial rash 75(79%), epistaxis 23(24%) were common. Median platelet count at the time of presentation was 5,000 (Inter-quartile range: 4000 13,000). Spontaneous recovery was seen in 7(7.4%) children. Overall, 24(25.2%) patients received intravenous immunoglobulin G and only 19(20%) showed complete response. Besides, a total of 32(33.7%) patients did not respond and only 5(5.3%) developed chronic ailment. CONCLUSION: Bruises, petechial rash and epistaxis were the common presentations. Overall prognosis was good. PMID- 25842578 TI - The use of omega 3 on pregnancy outcomes: a single-center study. AB - OBJECTIVE: To investigate the rate of Omega 3 use in pregnant women and its effect on pregnancy outcome. METHODS: The study was conducted from January to April 2010 at Tamin Ejtemaee Hospital, Hamedan, Iran, and comprised women who were carrying 16 weeks of pregnancy and were referred to the study site. They were divided into 3 groups: those who did not consume fish in a month, those who consumed fish 1-3 times in the preceding month, and those who had it more than 3 times in the same period. Data was analysed using SPSS version 16. RESULTS: Of the 550 subjects initially approached, 20(3.6%) either declined to participate or were lost to follow-up. The final study sample, as such, comprised 530(96.4%) who were followed up until delivery. The overall mean age of the subjects was 27.98+/ 5.30 years. Of the total, 21(4%) were below 18 years, 467(88%) were between 18-35 years, and 42(8%) were over 35 years of age. Omega 3 consumption was significantly associated with neonate weight (p<0.03), pre-eclampsia (p<0.04) and pre-term labour (p<0.01). CONCLUSION: Increased consumption of omega 3 can prevent low birth weight, pre-term labour and pre-eclampsia. PMID- 25842579 TI - Mesterolone treatment of aging male syndrome improves lower urinary tract symptoms. AB - OBJECTIVE: To investigate the effects of mesterolone on prostate in patients treated for aging male syndrome. METHODS: The cross-sectional study was conducted from June to September, 2009, at endocrinology and metabolism department of Yuzuncu Yil University, Van, Turkey, andcomprised patients with symptoms of aging male syndrome and/or low testosterone. They were given mesterolone 50 mg/day per oral for two months. Aging Male Symptoms and International Prostate Symptom Score questionaires and prostate-related quality of life scores were completed and prostate ultrasonography (USG) was performed before and after the treatment. Total testosterone, free testosterone, gonadotropins, estradiol, prolactin, sex hormone binding globulin, as well as total and free prostate-specific antigen were also studied. RESULTS: Of the 34 patients in the study, 22(64.70%) had their prostate volume increased, while 12(35.29%) had it decreased. The change, however, was not statistically significant (p<0.098). Mesterolone significantly improved Aging Male Symptoms, International Prostate Symptom and prostate-related quality of life scores (p<0.001). These improvements though significant were independent of the changes in prostate volume. Total testosterone, sex-hormone binding globulin andestradiol decreased, while free testosterone showed no change (p<0.002, p<0.001, p<0.024, p<0.337). The fraction of free testosterone increased (p<0.001), while total and free prostate-specific antigen did not change (p<0.368 and p<0.841) CONCLUSION: Mesterolone proved to be a safe alternative in the treatment of Aging Male Syndrome. It also improved lower urinary tract symptoms and prostate-related quality of life. PMID- 25842580 TI - Use of bispectral index monitoring for determination of sedation depth in 50 patients undergoing cardioversion. AB - OBJECTIVES: To investigate the contribution of Bispectralindex monitoring on the amount of used anaesthetic substance and the quality of anaesthesia in patients with persistent atrial fibrillation who would undergo cardioversion. METHODS: The prospective, randomised, controlled clinical study was conducted at Akdeniz University, Antalya, Turkey from October 2010 to November 2011 Sedation was performed on 50 adult patients using midazolam and fentanyl. Patients were randomised to group 1 and 2. In group 1 cardioversion was performed when the BispectralIndex value was seen to have decreased to <80 and the Ramsay sedation score was 5-6. In Group 2, BispectralIndex monitor was blinded to the investigator, and cardioversion was performed when Ramsay sedation score was 5-6. In both groups, blood pressure, heart rate and Bispectral index values were recorded. Total anaesthetic amount, awareness and pain were also assessed. SPSS 13 was used for statistical analysis. RESULTS: Overall, 23(46%) patients were male and 27(54%) were female and there was no significant difference in the two groups in terms of age (p>0.05). No statistically significant difference was detected between the groups in terms of induction time, anaesthetic need and Bispectral Index values (p>0.05). In both groups, 2(8%) patients perceived pain and 2(8%) perceived the procedure. CONCLUSION: In the presence of anaesthetist in the team, Bispectral Index monitoring did not contribute to the determining of anaesthetic drug dosage and the depth and quality of anaesthesia in patients with persistent atrial fibrillation during cardioversion. PMID- 25842581 TI - Prevalence of albicans and non-albicans candiduria in a Malaysian medical centre. AB - OBJECTIVE: To determine the proportion of albicans and non-albicans candiduria in a hospital setting and to ascertain if fluconazole is still suitable as empirical antifungal therapy based on antifungal susceptibility patterns of Candida species. METHODS: The cross-sectional study was conducted between December 2010 and December 2011 at UKM Medical Centre, Kuala Lumpur, Malaysia and comprised 64 urine samples from patients who were either suspected or confirmed to have urinary tract infections. Yeasts were speciated using ID 32 C and subjected to antifungal susceptibility testing using Sensititre(r) YeastOne YO8. RESULTS: Candida albicans accounted for 38(59.4%) of the isolates, Candida tropicalis 18(28.1%), Candida glabrata 6(9.4%) and Candida parapsilosis 2(3.1%). Overall, the isolates were susceptible to both amphotericin B (MIC90 1 MUg/ml) and to 5 flucytosine (MIC90 0.25 MUg/ml), but susceptible-dose dependent towards fluconazole (MIC90 16 MUg/ml). Individually, Candida albicans was susceptible to fluconazole (MIC90 2 MUg/ml), amphotericin B (MIC90 0.5 MUg/ml) and 5-flucytosine (MIC90 0.25 MUg/ml). Candida tropicalis was also susceptible to fluconazole (MIC90 4 MUg/ml), amphotericin B (MIC90 1 MUg/ml) and 5-flucytosine (MIC90 0.125 MUg/ml). Candida glabrata was resistant to fluconazole (MIC90 64 MUg/ml), but susceptible to amphotericin B (MIC90 1 MUg/ml) and 5-flucytosine (MIC90 0.125 MUg/ml). Lastly, Candida parapsilosis was resistant to fluconazole (MIC90 256 MUg/ml), but susceptible to amphotericin B (MIC90 0.5 MUg/ml) and 5-flucytosine (MIC90 0.5 MUg/ml). CONCLUSION: The commonest yeast associated with candiduria at the study site was Candida albicans, and fluconazole can still be used for empirical therapy of candiduria. PMID- 25842582 TI - Spontaneous platelet recovery time in primary and secondary dengue infection in a tertiary care hospital. AB - OBJECTIVE: To determine the spontaneous platelet recovery time in primary and secondary dengue infection in a tertiary care hospital. METHOD: The cross sectional observational study was conducted at Abbasi Shaheed Hospital, Karachi, from July 2010 to January 2011, and comprised 138 seropositive patients with ages 13 years and above who fulfilled the World Health Organisation criteria of probable dengue infection, and presented with platelet count of <50,000/mm3 were enrolled. Serology was performed using rapid immunochromatographic assay and enzyme-linked immunosorbent assay with differential detection of immunoglobulin M and G. Spontaneous platelet recovery time (days) in both primary and secondary dengue infection was recorded. SPSS 20 was used for statistical analysis. RESULT: Of the total 138, patients, 38(27.5%) had primary infection and 100(72.5%) had secondary infection. Male-to-female ratio was 2.3:1. Among primary and secondary infections, platelet count on presentation was not significantly different (p<0.64). Mean spontaneous platelet recovery time was 3+/-2.6 days and 3+/-1.87 days in primary and secondary infection respectively. Higher platelet count at presentation was associated with early recovery time (p<0.033). Of 108(78%) patients who presented with platelet count of 20,000-<50,000/mm3, platelet count of 36(33.33%) rose to >50,000/mm3 within 2 days, and 62(57.4%) rose to >50,000 in 3-5 days. In primary and secondary dengue infections, no statistically significant difference was observed in spontaneous platelet recovery time ( =0.87). CONCLUSION: Platelet count at presentation and spontaneous platelet recovery time do not significantly differ in primary and secondary dengue infection. PMID- 25842583 TI - Determination of bacterial etiological agents, sensitivity pattern and clinical outcome of patients with bacterial endocarditis at Punjab Institute of Cardiology, Lahore. AB - OBJECTIVE: To determine the type of pathogens causing bacterial endocarditis, their in vitro drug susceptibility profile and the effect of empirical antibiotic therapy in endocarditis patients. METHODS: The prospective study was conducted at the Punjab Institute of Cardiology, Lahore, from January to November 2013. Blood samples of endocarditis patients in the 20-40 age group were collected and culture-positive patients were included in the study. Antibiotics given to patients as empirical therapy were noted. Antimicrobial susceptibility of the isolates against various antibiotics was determined in vitro by using Kirby Bauer disc diffusion technique. The results were interpreted as frequencies and percentages. RESULTS: Of the 110 endocarditis patients initially scanned, 60(54.5%) were culture-positive and represented the study sample. Of them, 31(51.7%) were men and 29(48.3%) were women. The combination of Benzyl Penicillin and Gentamicin was given to 11(18.3%) patients, while combination of Vancomycin and Gentamicin and Vancomycin alone was also given to 3(5%) and 6(10%) patients respectively. Overall, 53(88.3%) isolates were Gram-positive and 7(11.7%) were Gram-negative. Among Gram-positive isolates, 39(65%) were Methicillin-sensitive Staphylococcus aureus, 2(3.3%) were Methicillin-resistant Staphylococcus aureus and 12(20%) were Streptococcus species. Among the Gram-negative group, 5(8.4%) isolates were of Escherichia coli, 2(3.3%) were of Pseudomonas aeruginosa. In vitro antimicrobial susceptibility of Gram-positive revealed 100% susceptibility to Vancomycin. Pseudomonas aeruginosa showed 100% in vitro susceptibility to Ciprofloxacin, Ceftazidime, Piperacillin+Tazobactam and Tigecycline, while Escherichia coli showed 60% susceptibility to Amikacin and Co-Amoxiclav. CONCLUSION: The frequency of Gram-positive organisms causing endocarditis was high. Vancomycin in Gram-positive cases revealed better in vitro efficacy, while in Gram-negative cases, Ciprofloxacin, Ceftazidime, Piperacillin+Tazobactam, Tigecycline Amikacin and Co-Amoxiclav were more effective than other antibiotics. PMID- 25842584 TI - Elevated levels of ferritin and hs-CRP in type 2 diabetes. AB - OBJECTIVES: To measure the levels of high-sensitivity C-reactive protein and ferritin in blood and to assess their association with inflammation in people with Type 2 diabetes. METHOD: The case-control study was conducted between November 2012 to November 2013 at the Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre, Karachi, and comprised randomly selected patients and healthy controls. Fasting blood samples were analysed for blood glucose, insulin, high-sensitivity C-reactive protein and iron status. SPSS 19 was used for statistical analysis. RESULTS: Of the 210 subjects initially selected, 99(47%) were excluded owing to anaemia. The study population, as such, comprised 111(53%) with an overall mean age of 38.6+/-1.56 years and mean fasting blood sugar of 110.78+/-3.795 mg/dl. Group 1 had 44(39.6%) healthy controls while Group 2 had 67(60.3%) diabetic patients. Elevated levels of mean serum ferritin (233.11+/-43.84 ng/ml), insulin (29.94+/-2.19), homeostasis model of insulin resistance (10.23+/-0.89) and high-sensitivity C-reactive protein (5.29+/-0.80 mg/L) with low serum iron levels (1.07+/- 0.115 ?g/dl) were found in Group 2. There was positive correlation of homeostasis model of insulin resistance with fasting blood sugar (r=0.596; p<0.001), serum ferritin (r=0.306; p<0.008), insulin (r=0.866; p<0.001), and total iron-binding capacity (r=0.302; p<0.009). There was negative correlation with serum iron (r=-0.280; p<0.016) and transferrin saturation (r=-0.316; p<0.006). CONCLUSION: Elevated ferritin levels without evident iron overload may affect glucose homeostasis, leading to insulin resistance in conjunction with inflammatory changes as seen by elevated C reactive protein levels. PMID- 25842585 TI - Inpatient satisfaction at tertiary care public hospitals of a metropolitan city of Pakistan. AB - OBJECTIVE: To determine the satisfaction of in-patients towards quality of service provision and environment of public-sector hospitals. METHODS: The cross sectional study was conducted in four major public-sector hospitals of Karachi from December 2010 to February 2012. The questionnaire, besides the demographic details, also had 5-point Likert scale questions regarding satisfaction of patients with doctors, staff, administration and the hospital environment. SPSS 20 was used for statistical analysis and results were expressed as frequencies with percentages. RESULTS: Of the 710 subjects in the study, 475(67%) agreed that their doctors checked them with concentration and care. Staff was reported as being kind natured and well-mannered by 423(59.6%) and 451(63.5%) patients respectively. However, 414(58.3%) were not pleased with the sanitary condition of the hospital. Only 225(31.7%) got comfortable beds, while 498(70.14%) patients found bugs in beds. In terms of overall satisfaction 452(63.7%) were satisfied with the staff, 463(65.2%) with doctors, and 385(54.2%) with the hospital environment. CONCLUSION: Patients were relatively satisfied with the staff, but sanitary conditions and hospital environment were a concern for majority of the patients. PMID- 25842586 TI - Low-cost thermotherapy for cutaneous leishmaniasis in Sindh, Pakistan. AB - OBJECTIVE: To study the efficacy of a low-cost heating pack device used for thermotherapy in the treatment of cutaneous leishmaniasis. METHODS: The study was conducted at the Department of Dermatology, Civil Hospital Sukkur, Pakistan, from April 20, 2012, to January 3, 2013. Thermotherapy with Hand-Held Exothermic Crystallisation Therapy for cutaneous leishmaniasis was performed on each lesion of the participating subjects at an average initial temperature of 51.6 degrees C for 3 minutes daily for 7 days. Patients were followed regularly for 6 months after the therapy. SPSS 20 was used for statistical analysis. RESULTS: Even though all 27 patients completed 1 week of thermotherapy, only 23(85.2%) patients could be evaluated for full treatment response since 4(14.8%) were lost to complete follow-up. By the final 180-day evaluation, 19 (83%) patients had been cured. Applications were well tolerated with no side effects. CONCLUSION: The devise was a convenient, safe, non-toxic and effective treatment for cutaneous leishmaniasis at a fraction of the cost of standard antimonial treatment. Further studies are needed to certify its safety and efficacy as monotherapy for the condition. PMID- 25842587 TI - Community acquired pneumonia in Pakistan: an analysis on the literature published between 2003 and 2013. AB - This article reviews literature pertaining to community acquired pneumonia (CAP) in adults published over the last decade (2003-2013) and includes ten studies and one guideline document. The review was done to identify the trend in etiologies and antimicrobial susceptibilities in order to recognize the need to update treatment guidelines for CAP in adults. Except for one laboratory based study, no articles were published between 2003 and 2008. Thereafter, most of the studies are retrospective in nature and published with a time lag hence reducing the relevance of the data. Out of the ten studies, two were purely clinical and among those that presented microbiological data, sensitivities to antibiotics were demonstrated in five studies which too were mainly organism specific. Streptococcus pneumonia remains the most common etiology of CAP in adults. There is increased isolation of atypical organisms in mild to moderate CAP, possibly due to better detection techniques. Mortality related to CAP is on the rise and noted up to 51% in patients with severe disease. There is limited evidence to support increasing resistances of pathogens to antibiotics. Lack of updated data leaves Pakistan Chest Society guidelines 2010 for treatment of CAP applicable to date in its original form. However there is a need to conduct more comprehensive studies on CAP to help reduce morbidity and mortality associated with the disease. PMID- 25842588 TI - Number of Pakistani physicians working abroad; do we really need to know? AB - There are around 175,600 registered doctors in Pakistan, but limited data is available about Pakistani physicians pursuing medical careers abroad. Additionally, no data is reported about Pakistani physicians who leave the country to pursue medical career overseas, but end up in non-medical professions. We identified two groups of physicians leaving the country: those going abroad for postgraduate training and residency; and those doing so for better career incentives and monetary benefits and to avoid the deteriorating law and order situation and rising hostilities towards doctors in the last few years. Other factors contributing towards physician's migration include poor service structure and career prospects, lack of research funding, increased workload and stressful work environment. Optimal measures need to be taken so that the locally trained doctors can deliver their services where they are needed the most, instead of seeking overseas opportunities. Similarly, volume of expertise may be enhanced by promoting social accountability among Pakistani physicians working abroad and by creating comparable opportunities within the country. PMID- 25842589 TI - Importance of research and services among people who inject drugs in Pakistan. PMID- 25842590 TI - Huge congenital haemangioma of the tongue. AB - Haemangiomas, the most common type of benign vascular tumours, are rare in the oral cavity. Some of these lesions are congenital and show symptoms in late childhood or early adult life. A 32-years-old woman presented with a huge lesion on her tongue which caused dysphagia and dysphasia. She had first noticed the lesion when she was 6. Her obstructive symptoms started when she was 28 and, despite various medical treatments, the size of the lesion gradually increased. Magnetic resonance imaging revealed a 7 x 5 x 3 cm mass on the right side of the tongue. Because of severe functional and cosmetic problems, the lesion was excised with partial haemiglossectomy. Histopathological examination was consistent with intramuscular haemangioma. Haemangiomas are benign tumours with a benign course and are rarely seen on the tongue. They have clinical importance when localised in the oral cavity. Different treatment modalities exist, but in cases of large tumours, surgery may be the mainstay treatment. PMID- 25842591 TI - Pulmonary thromboembolism in a patient with active ulcerative colitis and lung abscess secondary to pulmonary infarction. AB - Crohn's disease and ulcerative colitis are inflammatory bowel diseases and they primarily involve intestines. Herein we report the case of a young man who, during a clinical recurrence of ulcerative colitis, presented with symptoms suggestive of a lung abscess. When the patient was re-evaluated because of unexplained shortness of breath, an area of infarction was detected that had led to the development of cavitation secondary to submassive embolism and foci of infection contained within. The patient was managed with subcutaneous heparin and he was asymptomatic during 2 months of follow-up. He completed six months of anti coagulation therapy and any recurrence was not detected during 3 months of post treatment follow-up. PMID- 25842592 TI - Microtubule inhibition therapy by colchicine in severe myocarditis especially caused by Epstein-Barr and cytomegalovirus co-infection during a two-year period: a novel therapeutic approach. AB - The co-infection of Epstein-Barr virus and Cytomegalovirus rarely gains multi pathogenicity and leads to viral myocarditis. Also, it may lead to progressive heart failure or sudden death. We present a case series of five patients who were monitored for the impact of low-dose colchicine therapy as adjunct to conventional heart failure therapy. Epstein-Barr virus, Cytomegalovirus and other viral antibodies were determined by enzyme-linked immunosorbent assay method. Adjuvant low-dose colchicine therapy (2x0.5 mg twice daily) was prescribed for addition to the conventional heart failure therapy of these patients and it wsa continued for two years. Ejection fractions of echocardiographic examinations in all patients were 21%, 18%, 25%, 20% and 21% before low-dose colchicine therapy. After two years of treatment, the values increased to 59%, 45%, 40%, 25% and 41%, respectively. The early implementation of low-dose colchicine in these patients seemed to have beneficial effects on overall survival. PMID- 25842593 TI - A novel method for repair of testis rupture after gunshot trauma: repair with Tutoplast processed pericardium. AB - Gunshot wound injury to the external genitalia is relatively uncommon. However, if a testis isaffected in such a case, early surgical exploration should be carried out. A 16-year-old boy presented with right testicular rupture. Tunica albugineal defect could not be closed primarily. We used a Tutoplast(r) processed bovine pericardium to repair the defect of tunica albuginea. At his 3-month follow-up visit, there was no complication. Doppler blood flow of testis was normal. In this case, preservation of testis tissue was obtained with early exploration and repair of the big tunica albugineal defect with Tutoplast(r) processed pericardium. PMID- 25842594 TI - Insulin initiation: the triage system. AB - Insulin is an effective glucose lowering agent and key component of effective diabetes management. However, prescription of insulin is faced with inertia as well as resistance. The barriers exists both at level of provider as well as patient. Here, we discuss a model, to overcome these barriers in a patient friendly and time effective way. PMID- 25842595 TI - My patient has had an intracerebral haemorrhage--how do I best control his blood pressure? PMID- 25842596 TI - Mast cell density, microvessel density and their role in renal cell carcinoma. PMID- 25842597 TI - Subjective well-being of nurses. PMID- 25842598 TI - Rheumatoid arthritis clinical features and management strategies at an urban tertiary facility in Pakistan. AB - OBJECTIVE: To determine the presentation patterns, biologically vulnerable patient groups and treatment strategies of rheumatoid arthritis. METHODS: The retrospective study was conducted at the Rheumatology Clinic of Liaquat National Hospital and Medical College, Karachi, and comprised data of rheumatology patients who presented between September 2006 and September 2012. After screening all the files, rheumatoid arthritis cases were identified. Data collection was done using a questionnaire that included patient demographics, co-morbidities, clinical manifestations and drug therapy. SPSS 13 was used for statistical analysis. RESULTS: Of the 2300 files screened, 500(21.7%) related to patients of rheumatoid arthritis. The mean age at presentation of these 500 patients was 41+/ 15 years. There were 367(73.4%) women and they presented at an earlier age compared to men (p<0.024). Erosions were present in 198(40%) patients on X-rays and 22(4.4%) had joint deformities. Seropositive rheumatoid arthritis was associated with higher erythrocyte sedimentation rate levels (p<0.014), but did not differ from seronegative rheumatoid arthritis in terms of Disease Activity Score-28 levels (p<0.21). CONCLUSIONS: The skewed gender distribution was likely an effect of rheumatoid arthritis biology rather than due to issues of healthcare accessibility. Seronegative RA is likely to present late though it is as destructive as the seropositive disease. PMID- 25842599 TI - Colonoscopic diagnosis of trichuris trichiura in a patient with pulmonary tuberculosis; there is more than what meets the eye. PMID- 25842600 TI - Personality changes in medical students: causes, consequences and proposed solutions. PMID- 25842601 TI - Looking forward. ACS program helps surgeons provide care for vulnerable population. PMID- 25842602 TI - Welcome to the 114th Congress: the implications for surgery. PMID- 25842603 TI - New resources from the College offer alternative approaches to medical liability reform. PMID- 25842604 TI - Report from the Past-Chair of the Board of Regents: Fostering innovation at the ACS through strategic planning. PMID- 25842605 TI - To Bangalore and back: resident leads software design effort at Indian heart hospital. PMID- 25842606 TI - Managing burnout: Seek outside help and foster a true work-life balance. PMID- 25842607 TI - Statement on medical liability reform. PMID- 25842608 TI - The ACS motto: What does it really mean? PMID- 25842609 TI - Setting standards of efficiency. PMID- 25842610 TI - Managing medication in ambulatory surgery centers. PMID- 25842611 TI - Affordable trauma care? PMID- 25842612 TI - Girma Tefera, MD, FACS, joins ACS staff as OGB Medical Director. PMID- 25842613 TI - M. Margaret Knudson, MD, FACS, new Medical Director of MHSSPACS. PMID- 25842614 TI - Murray F. Brennan, MD, FACS, named Knight Grand Companion of the New Zealand Order of Merit. PMID- 25842615 TI - Part 1. Assessment of carcinogenicity and biologic responses in rats after lifetime inhalation of new-technology diesel exhaust in the ACES bioassay. AB - The Health Effects Institute and its partners conceived and funded a program to characterize the emissions from heavy-duty diesel engines compliant with the 2007 and 2010 on-road emissions standards in the United States and to evaluate indicators of lung toxicity in rats and mice exposed repeatedly to 2007-compliant new-technology diesel exhaust (NTDE*). The a priori hypothesis of this Advanced Collaborative Emissions Study (ACES) was that 2007-compliant on-road diesel emissions "... will not cause an increase in tumor formation or substantial toxic effects in rats and mice at the highest concentration of exhaust that can be used ... although some biological effects may occur." This hypothesis was tested at the Lovelace Respiratory Research Institute (LRRI) by exposing rats by chronic inhalation as a carcinogenicity bioassay. Indicators of pulmonary toxicity in rats were measured after 1, 3, 12, 24, and 28-30 months of exposure. Similar indicators of pulmonary toxicity were measured in mice, as an interspecies comparison of the effects of subchronic exposure, after 1 and 3 months of exposure. A previous HEI report (Mauderly and McDonald 2012) described the operation of the engine and exposure systems and the characteristics of the exposure atmospheres during system commissioning. Another HEI report described the biologic responses in mice and rats after subchronic exposure to NTDE (McDonald et al. 2012). The primary motivation for the present chronic study was to evaluate the effects of NTDE in rats in the context of previous studies that had shown neoplastic lung lesions in rats exposed chronically to traditional technology diesel exhaust (TDE) (i.e., exhaust from diesel engines built before the 2007 U.S. requirements went into effect). The hypothesis was largely based on the marked reduction of diesel particulate matter (DPM) in NTDE compared with emissions from older diesel engine and fuel technologies, although other emissions were also reduced. The DPM component of TDE was considered the primary driver of lung tumorigenesis in rats exposed chronically to historical diesel emissions. Emissions from a 2007-compliant, 500-horsepower-class engine and after treatment system operated on a variable-duty cycle were used to generate the animal inhalation test atmospheres. Four groups were exposed to one of three concentrations (dilutions) of exhaust combined with crankcase emissions, or to clean air as a negative control. Dilutions of exhaust were set to yield average integrated concentrations of 4.2, 0.8, and 0.1 ppm nitrogen dioxide (NO2). Exposure atmospheres were analyzed by daily measurements of key effects of NTDE in the present study were generally consistent with those observed previously in rats exposed chronically to NO2 alone. This suggests that NO2 may have been the primary driver of the biologic responses to NTDE in the present study. There was little evidence of effects characteristic of rats exposed chronically to high concentrations of DPM in TDE, such as an extensive accumulation of DPM within alveolar macrophages and inflammation leading to neoplastic transformation of epithelia and lung tumors. components and periodic detailed physical-chemical characterizations. Exposures were conducted 16 hours/day (overnight, during the rats' most active period), 5 days/week. Responses to exposure were evaluated via hematology, serum chemistry, bronchoalveolar lavage (BAL), lung cell proliferation, histopathology, and pulmonary function. The exposures were accomplished as planned, with average integrated exposure concentrations within 20% of the target dilutions. The major components from exhaust were the gaseous inorganic compounds, nitrogen monoxide (NO), NO2, and carbon monoxide (CO). Minor components included low concentrations of DPM and volatile and semi-volatile organic compounds (VOCs and SVOCs). Among the more than 100 biologic response variables evaluated, the majority showed no significant difference from control as a result of exposure to NTDE. The major outcome of this study was the absence of pre-neoplastic lung lesions, primary lung neoplasia, or neoplasia of any type attributable to NTDE exposure. The lung lesions that did occur were minimal to mild, occurred only at the highest exposure level, and were characterized by an increased number and prominence of basophilic epithelial cells (considered reactive or regenerative) lining distal terminal bronchioles, alveolar ducts, and adjacent alveoli (termed in this report "Hyperplasia; Epithelial; Periacinar"), which often had a minimal increase in subjacent fibrous stroma (termed "Fibrosis; Interstitial; Periacinar"). Slight epithelial metaplastic change to a cuboidal morphology, often demonstrating cilia, was also noted in some animals (termed "Bronchiolization"). In addition to the epithelial proliferation, there was occasionally a subtle accumulation of pulmonary alveolar macrophages (termed "Accumulation; Macrophage") in affected areas. The findings in the lung progressed slightly from 3 to 12 months, without further progression between 12 months and the final sacrifice at 28 or 30 months. In addition to the histologic findings, there were biochemical changes in the lung tissue and lavage fluid that indicated mild inflammation and oxidative stress. Generally, these findings were observed only at the highest exposure level. There was also a mild progressive decrease in pulmonary function, which was more consistent in females than males. Limited nasal epithelial changes resulted from NTDE exposure, including increases in minor olfactory epithelial degeneration, hyperplasia, and/or metaplasia. Increases in these findings were present primarily at the highest exposure level, and their minor and variable nature renders their biologic significance uncertain. Overall, the findings of this study demonstrated markedly less severe biologic responses to NTDE than observed previously in rats exposed similarly to TDE. Further, the effects of NTDE in the present study were generally consistent with those observed previously in rats exposed chronically to NO2 alone. This suggests that NO2 may have been the primary driver of the biologic responses to NTDE in the present study. There was little evidence of effects characteristic of rats exposed chronically to high concentrations of DPM in TDE, such as an extensive accumulation of DPM within alveolar macrophages and inflammation leading to neoplastic transformation of epithelia and lung tumors. PMID- 25842616 TI - Part 2. Assessment of micronucleus formation in rats after chronic exposure to new-technology diesel exhaust in the ACES bioassay. AB - The formation of micronuclei (MN*) is a well-established endpoint in genetic toxicology; studies designed to examine MN formation in vivo have been conducted for decades. Conditions that cause double-strand breaks or disrupt the proper segregation of chromosomes during division result in increases in MN formation frequency. This endpoint is therefore commonly used in preclinical studies designed to assess the potential risks to humans of exposure to a myriad of chemical and physical agents, including inhaled diesel exhaust (DE). As part of the Advanced Collaborative Emissions Study (ACES) Phase 3B, which examined numerous additional toxicity endpoints associated with lifetime exposure to DE in a rodent model, this ancillary 24-month investigation examined the potential of inhaled DE to induce chromosome damage in chronically exposed rodents. The ACES design included exposure of both mice and rats to DE derived from heavy-duty engines that met U.S. Environmental Protection Agency (EPA) 2007 standards for diesel-exhaust emissions (new-technology diesel exhaust). The exposure conditions consisted of air (the control) and three dilutions of DE, resulting in four levels of exposure. At specific times, blood samples were collected, fixed, and shipped by the bioassay staff at Lovelace Respiratory Research Institute (LRRI) to Litron Laboratories (Rochester, NY) for further processing and analysis. In recent years, significant improvements have been made to MN scoring by using objective, automated methods such as flow cytometry, which allows the detection of micronucleated reticulocytes (MN-RET), micronucleated normochromatic erythrocytes (MN-NCE), and reticulocytes (RET) in peripheral blood samples from mice and rats. By using a simple staining procedure coupled with rapid and efficient analysis, many more cells can be examined in less time than was possible using traditional, microscopy-based MN assays. Thus, for each sample in the current study, 20,000 RET were scored for the presence of MN. In the chronic exposure (12 and 24 months) bioassay, blood samples were obtained from separate groups of exposed animals at specific time points throughout the course of the study. The automated method using flow cytometry has found widespread use in safety assessment and is supported by regulatory guidelines, including International Conference on Harmonisation (ICH) S2(R1) (2011). Statistical analyses included the use of analysis of variance (ANOVA) to compare the effects of sex, exposure condition, and duration, as well asthe interactions between them. Analyses of blood samples from rats combined data from our earlier 1- and 3 month exposure studies (Bemis et al. 2012) with data from our current 12- and 24 month exposure studies. Consistent with findings from the preliminary studies, no sex-based differences in MN frequency were observed in the rats. An initial examination of mean frequencies across the treatment groups and durations of exposure showed no evidence of treatment-related increases in MN at any of the time points studied. Further statistical analyses did not reveal any significant exposure-related effects. An examination of the potential genotoxic effects of DE is clearly valuable as part of a large-scale chronic exposure bioassay. The results described in this report provide a comprehensive examination of chronic exposure to DE in a rodent model. Our investigation of chromosomal damage also plays an important role in the context of ACES, which was designed to assess the safety of emissions from 2007-compliant diesel engines. PMID- 25842617 TI - Part 3. Assessment of genotoxicity and oxidative damage in rats after chronic exposure to new-technology diesel exhaust in the ACES bioassay. AB - In 2001, the U.S. Environmental Protection Agency (EPA*) and the California Air Resources Board (CARB) adopted new standards for diesel fuel and emissions from heavy-duty diesel engines. By 2007, diesel engines were required to meet these new standards for particulate matter (PM), with other standards to follow. Through a combination of advanced compression-ignition engine technology, development of exhaust aftertreatment systems, and reformulated fuels, stringent standards were introduced. Before the 2007 standards were put in place by the EPA, human health effects linked to diesel exhaust (DE) exposure had been associated with diesel-fuel solvent and combustion components. In earlier research, diesel engine exhaust components were, in turn, linked to increased mutagenicity in cultures of Salmonella typhimurium and mammalian cells (Tokiwa and Ohnishi 1986). In addition, DE was shown to increase both the incidence of tumors and the induction of 8-hydroxy-deoxyguanosine (8-OHdG) adducts in rodents (Ichinose et al. 1997) and total DNA adducts in rats (Bond et al. 1990). Furthermore, DE is composed of a complex mixture of polycyclic aromatic hydrocarbons (PAHs) and particulates. One such PAH, 3-nitrobenzanthrone (3-NBA), is also found in urban air. 3-NBA has been observed to induce micronucleus formation in the DNA of human hepatoma cells (Lamy et al. 2004). The current study is part of the Advanced Collaborative Emissions Study (ACES), a multidisciplinary program carried out by the Health Effects Institute and the Coordinating Research Council. Its purpose was to determine whether recent improvements in the engineering of heavy-duty diesel engines reduce the toxicity associated with exposure to DE components. To this end, we evaluated potential genotoxicity and induction of oxidative stress in bioassays of serum and tissues from Wistar Han rats chronically exposed--for up to 24 months--to DE from a 2007 compliant diesel engine (new-technology diesel exhaust, or NTDE). Genotoxicity was measured as DNA strand breaks in lung tissue, using an alkaline-modified comet assay. As a correlate of possible DNA damage evaluated in the comet assay, concentrations of the free DNA adduct 8-OHdG were evaluated in serum by a competitive enzyme-linked immunosorbent assay (ELISA). The 8-OHdG fragment found in the serum is a specific biomarker for the repair of oxidative DNA damage. In addition, an assay for thiobarbituric acid reactive substances (TBARS) was used to assess oxidative stress and damage in the form of lipid peroxidation in the hippocampus region of the brains of the DE-exposed animals. These endpoints were evaluated at 1, 3, 12, and 24 months of exposure to DE or to a control atmosphere (filtered air). At the concentrations of DE evaluated, there were no significant effects of exposure in male or female rats after 1, 3, 12, or 24 months in any measure of DNA damage in the comet assay (%DNA in tail, tail length, tail moment, or olive moment). The comparison of exposure groups versus control and the comparison of groups by sex for 1 and 3 months of exposure showed no significant differences in serum 8-OHdG concentrations (P > 0.05). The concentrations of 8 OHdG in all exposure groups at 3 months were higher than those in exposure groups at any other time point (P < 0.05). Looking at the levels of 8-OHdG in serum in the 12-month and 24-month groups, we saw a significant difference from control in the 12-month group at the mid and high levels (P < 0.05), as well as some other scattered changes. Sex differences were noted in the 12-month high-level group (P < 0.05). However, these differences did not follow an exposure-dependent pattern. All other comparisons were not significant (P > 0.05). Hippocampal concentrations of TBARs, measured as malondialdehyde (MDA), showed some small and scattered changes in groups exposed to different levels of DE and at different time points, but we did not consider these to be exposure-related. We concluded that exposure to DE in these rats did not produce any significant increase in oxidative damage to lipids or damage to DNA in the form of strand breaks. PMID- 25842618 TI - Part 4. Assessment of plasma markers and cardiovascular responses in rats after chronic exposure to new-technology diesel exhaust in the ACES bioassay. AB - Although epidemiologic and experimental studies suggest that chronic exposure to diesel exhaust (DE*) emissions causes adverse cardiovascular effects, neither the specific components of DE nor the mechanisms by which DE exposure could induce cardiovascular dysfunction and exacerbate cardiovascular disease (CVD) are known. Because advances in new technologies have resulted in cleaner fuels and decreased engine emissions, uncertainty about the relationship between DE exposure and human cardiovascular health effects has increased. To address this ever-changing baseline of DE emissions, as part of the larger Advanced Collaborative Emissions Study (ACES) bioassay studying the health effects of 2007-compliant diesel engine emissions (new-technology diesel exhaust), we examined whether plasma markers of vascular inflammation, thrombosis, cardiovascular aging, cardiac fibrosis, and aorta morphometry were changed over 24 months in an exposure-level-, sex-, or exposure-duration-dependent manner. Many plasma markers--several recognized as human CVD risk factors--were measured in the plasma of rats exposed for up to 24 months to filtered air (the control) or DE. Few changes in plasma markers resulted from 12 months of DE exposure, but significant exposure-level-dependent increases in soluble intercellular adhesion molecule 1 (sICAM-1) and interleukin 6 (IL-6) levels, as well as decreases in total and non-high-density-lipoprotein cholesterol (non-HDL) levels in plasma, were observed in female rats after 24 months of DE exposure. These effects were not observed in male rats, and no changes in cardiac fibrosis or aorta morphometry resulting from DE exposure were observed in either sex. Collectively, the significant changes may reflect an enhanced sensitivity of the female cardiovascular system to chronic DE exposure; however, this conclusion should be interpreted within both the context and limitations of the current study. PMID- 25842619 TI - [Retinopathy of pematurity prevention and risk factors assessment]. PMID- 25842620 TI - [Criticism of the gonioscopic classifications of the glaucoma: with particular reference to the classification issued by the European Glaucoma Society in 2008]. AB - PURPOSE: To critically analyze the gonioscopic classifications of glaucoma, especially of the classification issued by the European Glaucoma Society in 2008, in order to reveal its advantages and shortcomings. METHODS: The paper tries to determine the extent to which this classification is clear (being based on a coherent and consistently followed set of criteria), is comprehensive (framing all forms of glaucoma), helps to understand the sickness (using a logical framing system), and facilitates therapeutic decision making (offering direct therapeutic suggestions). RESULTS AND CONCLUSION: The paper shows that, compared with all the previous classifications, the 2008 European Glaucoma Society classification is one step ahead (in the way of classifying the group of secondary angle-closure glaucomas), two steps behind (in rejecting two useful categories of congenital glaucoma), and similar in several respects: that it is based on criticizable fundamental and secondary criteria that cannot cover all forms of sickness gathered at a particular crossing; that it uses several equally weighted criteria for one single crossing (division); that it frames one clinical entity in several clinical categories; that it does not reflect reality in some aspects; and that it does not offer direct therapeutic suggestions: after framing a case in a scheme built on the basis of gonioscopic observation, it requires a second stage of pathogenic analysis, so that the ophthalmologist is able to decide the correct treatment only in the third stage. This tortuous thinking pathway, with successive stages - that are not followed by all doctors, explains many of the erroneous therapeutic decisions. All these considerations justify the efforts to find a new classification, able to correct the abovementioned shortcomings. PMID- 25842621 TI - [Ocular hypertension in herpes simplex keratouveitis]. AB - The herpes simplex virus is one of the most common pathogens in humans, who are seropositive for the virus in 90% of the cases at the adult age. It determines reccurent infections in more than a third of the population and these infections depend on the immune response of the host. Ocular infections of newborns are due to the herpes simplex virus type 2, meanwhile type 1 is found predominantly at adults; almost all ocular structures can be affected. HSV-1 in the most frequent etiologic agent in infectious anterior uveitis (with the varicelo-zosterian virus) and it is responsible for 6-10% of all cases of anterior uveitis. More than half of the keratouveitides due to HSV will develop intraocular hypertension and open-angle secondary glaucoma, during reccurences and most of them will resolve after proper control of inflammation. PMID- 25842622 TI - [Issues and histopathologic correlations and imaging of complex coriocapilara - Bruch membrance - retinal pigment epithelium in age-related macular degeneration]. PMID- 25842623 TI - [Congenital aniridia]. AB - Aniridia is a rare congenital, hereditary, bilateral disease which is associated with various systemic and ocular defects. We present the case of a 61 year old patient who was admitted in the hospital of ophthalmology Cluj Napoca, for the symptoms caused by the ocular defects associated with aniridia. In this case, aniridia is autosomal dominant transmitted with incomplete penetrance and it is not accompanied by any systemic defects. The disease also affects three of her sons and two nephews of the patient. PMID- 25842624 TI - [Choroidal melanoma - evolution and prognosis]. AB - Choroidal melanoma is the most common primary intraocular malignant tumor. We present the case of a 62 year old patient who was diagnosed with intraocular tumor in his right eye, for about three years. Regarding the fact that the patient refused any kind of treatment during this period, we just had the opportunity to monitor this case. Finally, the diagnosis was choroidal melanoma, confirmed by the histopathological exam. PMID- 25842625 TI - [Importance of asferic treatment of intraocular lenses in contrast sensitivity of the human eye]. AB - PURPOSE OF THE STUDY: Clinical study which follows the influence of asphericity of intraocular lenses on an important parameter of quality of vision in operated cataract patients - contrast sensibility. MATERIAL AND METHODS: This is a pilot, prospective study with 131 eyes of 124 patients, which had cataract surgery by phacoemulsification between 2011-2012. All operations were done by the same surgeon. EXCLUSION CRITERIAS WERE: VA ( 0.7; postop refraction >0.75 D sf. or 0.75 D cyl, corneal diseases, optic nerv or retinal pathologies, atypical surgery, pupil diameter 3 mm. Postoperative control was done at six weeks and included : AV, optical correction, contrast sensibility testing, intraocular pressure, posterior pol exam. Contrast sensibility testing was done using a LCD device, in fotopic condition, CC-100 TOPCON. PRIMARY RESULTS: Contrast sensibility graphics were compared between spheric and aspheric lenses for Zeiss, AMO, Bausch&Lomb, Alcon. CONCLUSIONS: There were no statistically significant differences between aspherical lenses. Also, there were no differences for the same manufacturer between spherical and aspherical lenses. PMID- 25842626 TI - Why we use AT.Lisa multifocals? AB - In this paper, the authors try to motivate their preference for implanting AT.Lisa Multifocals from all other premium IOL's from the market. It is emphasized, through clinical examples, that their choice comes after a long experience with this type of mul- tifocals IOL's. We make a short presentation of this particular type of MIOL's with their good but also weak points and try to motivate our decision to change from other types. We present the steps that each patient has to follow in our clinic prior to surgery itself, stressing out the idea that the discussion with the patient is very important in taking a decision regarding the implantation of a Premium IOL. PMID- 25842627 TI - Recertifying the professional nurse anesthetist: a call for national dialogue. AB - In 2011 the National Board of Certification and Recertification for Nurse Anesthetists initiated a Continued Professional Certification program that strongly suggests the search for alternatives. This article presents a thoughtful critique of the proposed professional competency program as well as alternatives that could be considered in a revision of the current program. Options discussed include a Continuous Professional Development program, a Simulation-Based Model, and a Practice-Based Model. PMID- 25842628 TI - Five elements for consideration in the development of corneal abrasion avoidance protocols. PMID- 25842629 TI - Development of clinical sites. AB - Clinical experiences are vital to all types of healthcare educational programs. Supervised clinical experiences provide the opportunity for the learner to apply didactic knowledge and theory to real world situations and hone skills necessary for entry into practice. Nurse anesthesia programs utilize a wide variety of clinical sites to expose student registered nurse anesthetists to experiences that will prepare them clinically, academically and professionally to enter practice as a Certified Registered Nurse Anesthetist. This article describes the process of developing a clinical site. A thorough evaluation will determine the types of experiences meant to be offered at the site, the resources available to house and educate the students, and how to evaluate the effectiveness of the clinical site. Open communication between the clinical coordinator and the program director or designee is essential to ensure success of the clinical site. The Council on Accreditation of Nurse Anesthesia Educational Programs has resources available to guide those interested in becoming a clinical site, as well as for program administrators who seek to add new experiences to their programs. PMID- 25842630 TI - Difficult intubation resulting in surgical repair of esophageal and hypopharyngeal perforation. AB - Although rare, perilous injury of the aerodigestive tract due to traumatic endotracheal intubation can have devastating consequences for patient and provider. Resulting serious complications of injury may involve esophageal perforation, pneumomediastinum, mediastinitis, retropharyngeal abscess, vocal cord paralysis, arytenoids dislocation, and hypopharyngeal pseudodiverticulum. Morbidity, mortality, and legal and financial consequences can be enormous. Early identification and treatment of suspected injury will promote patient recovery and thwart life-threatening progression of injury. This case report presents a 70 year-old woman scheduled for an elective hip arthroplasty. Intraoperatively she was unable to be intubated, and her operation was canceled. In the post anesthesia care unit, the patient underwent an otolaryngology consultation and was admitted for observation of reactive airway edema. Pharyngoesophageal perforation was diagnosed several days later and required surgical repair. PMID- 25842631 TI - Primary cesarean delivery results in emergency hysterectomy due to placenta accreta: a case study. AB - Placenta accreta is a major cause of obstetric hemorrhage, a situation that remains the most significant cause of maternal morbidity and mortality worldwide. It is generally recognized that a previous cesarean delivery increases the risk of placenta accreta. However, the risk also increases with previous intrauterine procedures. In 2010, The Joint Commission released a sentinel event alert regarding the prevention of maternal death, which recommended the adoption of protocols to treat postpartum hemorrhage. This case study demonstrates the success of quickly initiating protocol interventions necessary to prevent disseminated intravascular coagulation and maternal mortality, while reviewing current literature on risk identification, management, and treatment of obstetric hemorrhage resulting from placenta accreta. PMID- 25842632 TI - Methods of identifying and managing the difficult airway in the pediatric population. AB - The goal of this literature review is to provide the anesthesia practitioner with the skill set to detect and prepare for a difficult pediatric airway. The authors have reviewed and compiled information on some of the most common conditions that can predispose pediatric patients to a difficulty airway, such as macroglossia, mandibular hypoplasia, micrognathia, cervical instability, limited cervical movement, maxillary and midfacial hypoplasia, and cleft palate. This article provides an overview of preoperative assessment techniques, normal pediatric airway anatomy, and respiratory physiology. An emphasis is placed on some common syndromes and their related anatomical abnormalities that can compromise the airway, as well as anesthetic approaches recommended to successfully secure a potentially difficult airway. PMID- 25842633 TI - Music in the operating room: is it a safety hazard? AB - Noise is a health hazard and a source of stress, and it impairs concentration and communication. Since 1960, hospital noise levels have risen around the world. Nowhere in the healthcare setting is noise more prevalent than in the operating room (OR). The genetic makeup of humans does not evolve at the rate of technology. Noise exposure, sensory overload, and the capacity to adapt without physical and psychological consequences are absent from the human condition. The World Health Organization has recognized environmental noise as harmful pollution that causesadverse effects on health. Although noise in the OR is unavoidable, music is a choice. The purpose of this literature review is to provide further insight into the ramifications of the presence of music in the OR, evaluate its appropriateness in relation to care and safety for the patient and staff, and provide information for future research. PMID- 25842634 TI - Alice Magaw: a model for evidence-based practice. AB - The model of evidence-based practice (EBP) of Alice Magaw places the practice of nurse anesthesia as an early pioneer in patient safety and is prophetic to the aims of the Institute of Medicine (IOM). In its 2001 report, Crossing the Quality Chasm, the IOM identified 6 aims essential to improving the delivery of care. These aims include safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity. Magaw used her vast expertise in anesthetic administration to develop protocols and a body of knowledge that could be used as a template for practitioners near and far. This early use of EBP principles places nurse anesthesia at the forefront of the model and the movement to provide high-quality care. Practitioners sought her practice model out as she demonstrated her techniques to visiting providers as well as through her published ideal anesthetics in the literature. She wrote, "Pioneers are noted for building upon a body of knowledge, establishing a model for continuous improvement, and exemplifying notable methods of research with subsequent documentation of their findings." Magaw exemplified the EBP model. PMID- 25842635 TI - Educational programs for students: what can China learn from the United States, the United Kingdom, and France? AB - Designed to explore a suitable way to develop nurse anesthetist education in China, this article introduces 3 educational models for nurse anesthesia education in 3 countries, which all are members of the International Federation of Nurse Anesthetists (IFNA). In addition, this article carries out the comparison from 4 areas: program admission requirements; structure and length; content; and delivery mode. Healthcare leaders in China can learn from the United States, France, and the United Kingdom regarding how to develop nurse anesthesia educational programs and how to design a standardized nurse anesthesia educational program, which is consistent with the national need. PMID- 25842636 TI - Surgical site infection and prevention guidelines: a primer for Certified Registered Nurse Anesthetists. AB - Each year 500,000 surgical site infections occur in the US. Surgical site infections are the second most common healthcare-associated infections resulting in readmissions, prolonged hospital stays, higher medical costs, and increased morbidity and mortality. Surgical site infections are preventable in most cases by following evidence-based guidelines for hand hygiene, administration of prophylactic antibiotics, and perioperative patient temperature management. As attention to issues of healthcare quality heightens, the demands for positive surgical patient outcomes are intensifying. The Certified Registered Nurse Anesthetist can provide transparent high-quality care by implementing evidence based guidelines for timely and appropriate antibiotic use, maintenance of normothermia, and hand washing. PMID- 25842637 TI - Sevoflurane cost comparisons questioned. PMID- 25842638 TI - Response. PMID- 25842639 TI - Objective Structured Clinical Examination as an educational initiative for summative simulation competency evaluation of first-year student registered nurse anesthetists' clinical skills. AB - The use of simulation to imitate real-life scenarios reaches back many centuries. In the last decade, the use of simulation in healthcare has gained acceptance as a valuable tool for teaching and learning technical and nontechnical skills in healthcare. The use of simulation technology has moved medical education from the standard of pen and paper examinations to the assessment of clinical competency before caring for patients. The old thinking of "see one, do one, teach one" is behind us as healthcare works to create a culture of safety that holds healthcare personnel accountable. A current use of testing clinical competence is the use of Objective Structured Clinical Examination (OSCE) by physician training programs. As a testing tool, the OSCE has great potential to assess the clinical competence of students before they enter the clinical setting. The nurse anesthesia program at the authors' university has moved toward creating a formal assessment to ensure clinical competence of their student registered nurse anesthetists. In this article, we describe the development and implementation of an OSCE to ensure clinical competence of first-year student registered nurse anesthetists before they begin their clinical training. PMID- 25842640 TI - Perioperative glucose monitoring and treatment of patients undergoing vascular surgery in a community hospital setting. AB - This article discusses the glucose monitoring and treatment practices of a small community hospital and aims to determine how these practices relate to postoperative complications in patients undergoing vascular surgery. Previous studies in patients undergoing cardiovascular surgery have demonstrated that glucose control directly affects outcomes, including length of stay and incidence of infection, stroke, renal failure, myocardial infarction, and readmissions within 30 days of the initial surgery. A retrospective analysis of 101 patients who underwent vascular surgery was performed. After informed consent was obtained, patient charts were reviewed. Perioperative blood glucose levels, frequency of monitoring, treatment practices, and postoperative complications were collected by review of both electronic and paper medical records. Twenty seven of the 101 patients had a blood glucose level greater than 140 mg/dL preoperatively. Intraoperative blood glucose levels were monitored for 8 patients. Nine patients had blood glucose levels treated during the perioperative period. The threshold for treatment of preoperative hyperglycemia was a blood glucose level of 236 mg/dL. Increased vigilance of perioperative blood glucose levels is needed so that appropriate interventions can be instituted and outcomes improved. Glucometers must be readily available to anesthesia providers so that intraoperative monitoring of blood glucose levels can occur. PMID- 25842641 TI - Anesthetic management and implications of pediatric patients with a diagnosis of anti-N-methyl-D-aspartate receptor encephalitis: two case reports. AB - This article discusses the anesthetic management and implications of 2 pediatric patients with a diagnosis of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Anti-NMDA receptor encephalitis has been described as an immune meditated syndrome that triggers the production of antibodies to the NMDA receptor: a site of action for many commonly used anesthetic agents. Symptoms of this disease can be autonomic, neurologic, and psychological in nature. This disease process can pose a challenge to the anesthesia provider during all stages of the anesthetic. Thus, the anesthesia provider must incorporate an understanding of the administered anesthetic agent's potential pharmacologic effect on the affected NMDA receptor when formulating the patient's anesthetic plan. PMID- 25842642 TI - Workplace incivility affecting CRNAs: a study of prevalence, severity, and consequences with proposed interventions. AB - Incivility in healthcare settings has potentially detrimental effects on healthcare providers and patient safety. This study examines the prevalence of incivility and the influence of workplace incivility on burnout among Certified Registered Nurse Anesthetists (CRNAs) in Michigan. It proposes interventions to prevent and manage incivility. The Nursing Incivility Scale and the Copenhagen Burnout Inventory were used to measure workplace incivility and professional burnout. Qualitative data were also collected to provide recommendations to address workplace incivility. The most notable sources of workplace incivility were general employee personnel or nonemployee individuals and physicians. A lesser prevalent source of incivility was other CRNA practitioners. The least prevalent source of incivility was CRNA supervisors. A statistically significant, direct relationship existed between workplace incivility and professional burnout. The only statistically significant factor contributing to professional burnout was experiencing workplace incivility, independent of other measured factors. The most notable recommendation was use of a zero tolerance policy for practice, regardless of title or role, in employment situations. Incivility is a major concern among CRNAs. PMID- 25842643 TI - Psychometric testing of the Pecka Grading Rubric for evaluating higher-order thinking in distance learning. AB - This article describes development of the Pecka Grading Rubric (PGR) as a strategy to facilitate and evaluate students' higher-order thinking in discussion boards. The purpose of this study was to describe psychometric properties of the PGR. Rubric reliability was pilot tested on a discussion board assignment used by 15 senior student registered nurse anesthetist enrolled in an Advanced Principles of Anesthesia course. Interrater and intrarater reliabilities were tested using an interclass correlation coefficient (ICC) to evaluate absolute agreement of scoring. Raters gave each category a score, scores of the categories were summed, and a total score was calculated for the entire rubric. Interrater (ICC = 0.939, P < .001) and intrarater (ICC = 0.902 to 0.994, P < .001) reliabilities were excellent for total point scores. A content validity index was used to evaluate content validity. Raters evaluated content validity of each cell of the PGR. The content validity index (0.8-1.0) was acceptable. Known-group validity was evaluated by comparing graduate student registered nurse anesthetists (N = 7) with undergraduate senior nursing students (N = 13). Beginning evidence indicates a valid and reliable instrument that measures higher-order thinking in the student registered nurse anesthetist. PMID- 25842644 TI - Securing the endotracheal tube with adhesive tape: an integrative literature review. AB - The practice of securing the endotracheal tube with adhesive tape appears to be benign. However, evidence-based research suggests it is a high-risk practice. Common elements for the taping practice include the tape, anesthesia gas machine, and anesthesia provider. Researchers have found that adhesive tape outside its original packaging became contaminated with pathogens. The bacteria found on the tape included Pseudomonas, Escherichia coli, Klebsiella, Enterobacter, coagulase positive staphylococci, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcal organisms. In addition, a patient does not need to have direct contact with the anesthesia gas machine for pathogen transmission to occur. Anesthesia providers were identified as the origin of bacterial transmission in 12% of cases, with pathogens on their hands 66% of the time. Unfortunately, anesthesia providers are often noncompliant with hand hygiene. They failed to practice hand hygiene 82% of the time. Last, the tape can drop to the floor and harbor pathogens despite cleaning 41.6% of the time; it is often retrieved and reused. All the common elements, independently and collectively, involve the tape and its potential to increase the patient's exposure to pathogens and the risk of infection. This literature review presents evidence based research regarding endotracheal tube taping practice to ensure patient safety. PMID- 25842645 TI - Medication administration in the operating room: new standards and recommendations. AB - Anesthesia is one of the few areas in healthcare with no secondary verification of medication administration, yet it also has the highest number of administered medications, most of which are high-alert medications. Anesthetists often prescribe, dispense, mix, relabel, administer, and document medications without secondary verification. To increase patient safety, vigilance is one of the basic principles of anesthesia delivery in addition to the other fundamentals of medication administration. The Anesthesia Patient Safety Foundation recommends implementing standardizations, barcode medication administration, and the use of prefilled or premixed syringes to assist in the safe delivery of anesthesia. It has been shown that adhering to the principles outlined by the Anesthesia Patient Safety Foundation reduces the number of adverse drug events and results in safer care of patients. PMID- 25842646 TI - Methodological weaknesses of block study make analyzing results very difficult. PMID- 25842647 TI - Author's reply. PMID- 25842648 TI - Serotonin syndrome: fentanyl and selective serotonin reuptake inhibitor interactions. AB - Serotonin syndrome is a rare but potentially fatal adverse drug reaction associated with increased serotonergic activity in the central nervous system. It is characterized by a triad of symptoms, which include altered mental status, neuromuscular hyperactivity, and autonomic instability or hyperactivity. Due to the potential of rapid onset, it is important for clinicians to recognize the signs and symptoms of serotonin syndrome. Serotonin syndrome symptoms may resemble other conditions. Although this article focuses on serotonin syndrome as a result of an adverse interaction of selective serotonin reuptake inhibitors (SSRI) and fentanyl, it is important for not only anesthesia professionals, but all clinicians--such as those in emergency medicine and critical care--to be aware of this syndrome and its management. This article discusses the clinical manifestations of the serotonin syndrome and highlights reported cases of serotonin syndrome specifically related to an interaction between SSRIs and fentanyl, a commonly used opioid in anesthesia practice. PMID- 25842649 TI - Anesthesia information management systems: imperatives for nurse anesthetists. AB - Informatics is a new science within healthcare and anesthesia that leverages computer technology to improve patient safety, the quality of care provided, and workload efficiency. In clinical anesthesia practice, appropriate application of informatics promotes data standardization and integrity, and supports clinical decision-making. This article describes current issues in anesthesia information management to support the critical need for Certified Registered Nurse Anesthetists (CRNAs) to influence functionality, adoption, and use of an anesthesia information management system. The use of informatics tools and concepts should enable CRNAs to enhance their bedside vigilance, align their practice with evidence-based clinical guidelines, and provide cost-effective care for patients and healthcare systems. PMID- 25842650 TI - Pharmacologic, physiologic, and psychological characteristics associated with emergence delirium in combat veterans. AB - The goal of this research was to investigate, through active-duty Army anesthesia providers, their perceptions on emergence delirium (ED) in US combat veterans. Specifically, the pharmacologic, physiologic, and psychological characteristics associated with ED. An online survey was sent to all active-duty Army anesthesia providers with a response rate of 34%. Results indicated that the providers overwhelmingly agreed that ED was related to type of anesthetic used (67.1%) with potent inhalational agents and ketamine ranking highest (88.6% and 63.6%, respectively). Providers also overwhelmingly considered both physiologic and psychological factors (86.8% and 97.1%, respectively) as producing ED in combat veterans. Young age (57.5%) and traumatic brain injury (54.2%) were believed to be the most likely physiologic factors, with posttraumatic stress disorder (88%) and anxiety (84.8%) rated highest for psychological factors related to ED. This study emphasizes the need to develop a prospective clinical database involving all military anesthesia providers that could collect demographic, pharmacologic, psychological, and physiologic information on all combat veterans undergoing anesthesia. This kind of longitudinal data would provide answers to many of the unanswered questions that we currently have regarding combat veterans and ED. PMID- 25842651 TI - Comparison of compliance of glove use among anesthesia providers: a prospective blinded observational study. AB - Compliance of using gloves in the operating room (OR) is still poor amongst anesthesia providers. The practice of using gloves amongst OR anesthesia providers (attending anesthesiologists, anesthesia nurses, and trainees) in a tertiary care center was observed over 8 months. Observations were made during intravenous (IV) cannulations, laryngeal mask airway (LMA)/endotracheal tube (ETT) introductions, and ETT extubation/LMA removals, without alerting anesthesia personnel. Ten observations were made from each of the procedures for every provider involved. 1,240 observations were made involving 8 attending anesthesiologists, 9 trainees, and 14 nurses. A Chi-square test showed significant difference of glove utilization rates between the groups during all 4 procedures. The highest compliance was observed in trainees (50%), followed by nurses (39.64%), and attending anesthesiologists (10.93%). All groups had their highest compliance levels during IV cannulation. Additionally, attending anesthesiologists had the lowest compliance levels during all individual procedures. Anesthesia nurses had the highest compliance during LMA removals (39.29%), whereas trainees showed the highest compliance in all other procedures. Glove usage by anesthesia providers during routine OR procedures continues to be low. Educational programs highlighting the hazards of noncompliance and strict departmental protocols may help to eliminate irregularities in the use of gloves. PMID- 25842652 TI - Anaphylactic reaction with avitene: a pediatric case report. AB - Anaphylaxis is an unanticipated severe allergic reaction that can occur during a surgical procedure. A patient is exposed to myriad foreign substances during surgery, such as anesthetic drugs, blood products, and surgical materials, including a commonly used hemostatic agent called Avitene Microfibrillar Collagen Hemostat. Anaphylaxis is the most severe immune-mediated reaction, and it generally occurs on reexposure to a specific antigen. This case report details a case of an acute anaphylactic reaction in a 10-year-old boy presumed to be from Avitene used during a routine ear, nose, and throat surgery. There will be a discussion of the mechanism and management of anaphylaxis as well as a brief overview of hemostasis and hemostatic agents. Education of anesthesia providers and the surgical team may enable early detection and management of anaphylactic reactions that may improve patient outcomes and save lives. PMID- 25842653 TI - A pilot study evaluating the perceptions of Certified Registered Nurse Anesthetists toward human patient simulation. AB - An evaluation was conducted of perceptions of practicing Certified Registered Nurse Anesthetists (CRNAs) toward use of simulation for initial certification, continuing education, and recertification. The hypothesis was that a 1-day simulation experience would improve their perceptions toward simulation use. The first phase developed content-valid questions to examine CRNAs' perceptions toward simulation. The second phase used these questions to survey practicing CRNAs in the District of Columbia, Maryland, and Virginia. During the third phase, 9 CRNAs were selected to complete a 1-day simulation experience and complete the perception questionnaire before and after the experience. Through content validity index calculations, 25 of 27 questions were retained for use in this study. A total of 378 CRNAs responded to the questionnaire. There was consensus that human patient simulation (HPS) is an important part of anesthesia provider training, and 85.7% strongly agreed, agreed, or somewhat agreed that HPS should be a required component for initial certification. Additionally, 52.9% of respondents agreed (somewhat agreed or strongly agreed) that continuing education units from HPS should be required for recertification. After the simulation, a significant (P < .05) positive change in level of agreement was noted for 13 of 25 questions, including questions related to initial training and recertification. PMID- 25842654 TI - Anesthesia and critical care ventilator modes: past, present, and future. AB - Mechanical ventilators have evolved from basic machines to complicated, electronic, microprocessing engines. Over the last 2 decades, ventilator capabilities and options for critical care and anesthesia ventilators have rapidly advanced. These advances in ventilator modalities--in conjunction with a better understanding of patient physiology and the effects of positive pressure ventilation on the body--have revolutionized the mechanical ventilation process. Clinicians today have a vast array of mechanical ventilator mode options designed to match the pulmonary needs of the critically ill and anesthetized patient. Modes of mechanical ventilation continue to be based on 1 of 2 variances: volume based or pressure-based. The wording describing the standard ventilatory modes on select present-day ventilators has changed, yet the basic principles of operation have not changed compared with older ventilators. Anesthesia providers need to understand these ventilator modes to best care for patients. This literature review encompasses a brief history of mechanical ventilation and current modes available for anesthesia and critical care ventilators, including definitions of each mode, definitions of the various descriptive labels given each mode, and techniques for optimizing and meeting the ventilator needs of the patient while avoiding complications in the surgical and critical care patient. PMID- 25842655 TI - [South Ural State Medical University on the 70th anniversary of foundation]. PMID- 25842656 TI - [The heterogeneity of genetic variants of Helicobacter pylori in patients with various acid-related diseases]. AB - THE PURPOSE OF THE STUDY: To study the genetic diversity of H. pylori in patients with chronic gastritis, peptic ulcer disease, chronic pancreatitis. MATERIALS AND METHODS: The study involved 490 patients with gastric ulcer, duodenal ulcer, chronic superficial gastritis, chronic atrophic gastritis, chronic pancreatitis. Diagnosis of H. pylori infection was carried out by the following methods: morphological, urea breath test serological (determining the concentration of IgG antibodies to H. pylori and immunoblotting) and by polymerase chain reaction. For genotyping of H. pylori using sets of primers with a mixture of CagA, VacA s1/ s2, VacA m1, VacA m2, IceA1, IceA2, BabA. To perform immunoblotting using Anti Helicobacter pylori EUROLINE-Western blot (IgG), based on the Western blot method using test strips with antigens separated by electrophoresis cell extract H. pylori. Statistical computer processing was performed using software packages Statistic for Windows 6.0. RESULTS: The virulent genotype of H. pylori was determined in 92% cases of duodenal ulcer. In chronic non-atrophic and atrophic gastritis virulent genotypes of H. pylori were not detected. In case of uncomplicated duodenal ulcer we revealed isolated (vacA m2) and combined (vacA s1/ s2) genotypes of H.pylori in 23% of cases, of them monogenotip VacAm2 (vacuolating-associated cytotoxin) was determined in 83%. In complicated duodenal ulcer the combined genotype of H. pylori (vacAs1/ s2; vacAs1/ s2 + vacAm1 + vacAm2; vacAs1/ s2 + vacAm2) and mixed genotype of H. pylori (vacAs1/ s2 + cagA, vacAs1/ s2 + iceA2, vacAm1 + cagA + iceA2) were determined in 77% of the samples. In cases of chronic pancreatitis the vacuolating cytotoxin VacA was detected in 35.7%, such as in the control group it was 81.8%. Genes encoding the production of urease (subunit A) were found in 85.7% of chronic pancreatitis patients, in the control group--54.5%. Genes encoding the synthesis of outer membrane proteins of H. pylori such as p26, p19, p17 were detected in 82.1% of patients with chronic pancreatitis, in patients of the control group--54.5%. H. pylori outer membrane proteins with molecular weights of 30 and 33kDa (p30 and p33) were detected in 85.7% of patients with chronic pancreatitis. CONCLUSION: The bacterium H. pylori, which is the main cause of acid diseases, realizes effect through its pathogenicity factors. Waste products of H. pylori have a direct damaging effect on the mucous membrane of the stomach and duodenum, contributing to the release of lysosomal enzymes, a number of cytokines. They are cause the development of inflammatory processes in the mucosa. Lipopolysaccharide of outer membrane of H. pylori cause immune response of the human body and the development of chronic inflammation at the system level. Set of pathogenicity factors of H. pylori determine the nature and severity of the pathological processes triggered by the bacterium at different levels of the microorganism. PMID- 25842657 TI - [Psychoemotional status and "adaptation diseases" at patients with the peptic ulcer in Ural Federal Territory]. AB - RESEARCH OBJECTIVE: To study the psycho-emotional status and prevalence of the coronary heart disease (CHD) and the idiopathic hypertensia (IH) at patients with the peptic ulcer of a stomach (PUS) and at patients with a peptic ulcer of a duodenum is (YaB DPK). MATERIALS AND METHODS: Examination of 226 patients with an exacerbation of a peptic ulcer was conducted. Patients were distributed in 3 groups of observation depending on localization of ulcerative process. At all surveyed questioning was carried out, data on heriditary burdeness, smoking, alcohol intake, existence of somatopathies were specified, clinic-morphological implications of a peptic ulcer were studied. RESULTS: Feeling of alarm was present at 109 (48.2%) patients with a peptic ulcer, from them at 92 (40.7%) the subclinical level of alarm is noted, and at 17 (7.5%) clinically expressed form is taped. At 39.3% of the examined patients the depression is defined, from them two thirds of patients had the subclinical level of a depression, and 13 people suffered from clinically expressed depression form. Communication of recurrence with a stress was noted at 86.0% of patients, professionally caused stress--at 44.4%. In our research at the time of the beginning of a disease prevalence of an ischemic heart disease among patients with an ulcer of a duodenum (DPK) made 18.2%. In group of patients with the combined localization of ulcerative defect in a stomach and in DPK which already had an ischemic heart disease before emergence of the second ulcerative defect there were 26.6% that statistically significantly doesn't differ. However that by the time of emergence of the combined lesion this category of patients made already 73.4% is indicative. In case of DPK ulcer prevalence of an ischemic heart disease increased from the moment of the beginning of a disease until carrying out research twice (to 36.4%), but patients with the combined ultserozny lesion nevertheless distinguished both larger initial prevalence of an ischemic heart disease, and more expressed its gain. At the time of the beginning of a disease of GB met in a group of persons with the isolated ulcerative defect authentically more often (36.4% against 18.7% in group of patients with the combined localization of an ulcer). At the time of carrying out research prevalence of GB among patients with DPK ulcer (47.7%) whereas in group of the combined lesion of a stomach and DPK of GB without ischemic heart disease there was only every fourth patient remained significant by 2,7 times (DI 1.2-6.3). The combination of associated diseases of an ischemic heart disease and GB at patients with the advent of an ulcer at the same time in a stomach and DPK practically always met at the persons abusing alcohol and tobacco smoking that in general enlarges risk of development of an ulcer of the second localization by 7,6 times CONCLUSION: At the peptic ulcer (PU) of any localization the previous stress conducting quite often to formation of alarm and a depression conducts to also education a stress--the induced conditions, for example, of an arterial hypertonia, and later--to an ischemic heart disease. As specific to every second patient with the combined form of a peptic ulcer of a stomach and a duodenum it is possible to consider a polisintropiya from such the comorbidity diseases as coronary heart disease and an idiopathic hypertensia. The combination of these associated diseases to alcohol intake and tobacco smoking progressively enlarges risk of development of a peptic ulcer of the combined localization by 7,6 times in comparison with the isolated duodenum canker. RESEARCH OBJECTIVE: To define influence of the comorbidity diseases and risk. PMID- 25842658 TI - [Clinical and immunological study of the relationship of the digestive system chronic diseases and atherosclerosis in the basin of the abdominal aorta in elderly patients]. AB - Paper describes clinical and immunological study about the relationship between chronic diseases of the digestive system and atherosclerosis in the basin of the abdominal aorta in patients of elderly and senile age. There were revealed the structural and clinical features of the gastrointestinal tract diseases, depending on the extent of atherosclerosis in the basin of the abdominal aorta. Evaluation of the immune status included the determination of lymphocyte subpopulation composition, the functional state of neutrophils and cytokine levels. It is found that the progression of atherosclerosis in the basin of the abdominal aorta in patients of elderly and senile age with chronic diseases of the digestive system was accompanied by the activation of pro-inflammatory mechanisms of the immune system and the accompanying intensification of oxidative stress. PMID- 25842659 TI - [Pathological features of coronary heart disease in patient of elderly and senile age depending on a blood flow condition in the abdominal aorta]. AB - AIM: To perform the analysis of correlation of clinical symptoms and laboratory sings in patients of elderly and senile age with coronary heart disease depending on a blood flow condition in the pool of abdominal aorta. MATERIAL AND METHODS: Longitudinal clinical research was conducted. The register was made by 132 patients of elderly and senile age with coronary heart disease being on treatment during the period since 2013-2014. RESULTS: Results of the research of correlation of clinical symptoms and indexes of lipidemia in patients of elderly and senile age with coronary heart disease depending on a blood flow condition in the pool of abdominal aorta are performed. CONCLUSION: Specific features of the cardiovascular pathology and a course of coronary heart disease in combination with atherosclerosis of the abdominal aorta and its visceral branches are revealed. PMID- 25842660 TI - [Association of structure-functional indices of the heart and psychoemotional factors in patients with duodenal ulcer]. AB - Peptic ulcer is a disease of the upper part of the psychosomatic continuum, that allows to consider it as a result of mental maladjustment. The cross-sectional study examined 62 men with newly diagnosed duodenal ulcer, the average age of the surveyed was 21.5 +/- 2.1 (M +/- s). Men suffering from duodenal ulcer have a significant correlation of structure-functional indices of heart and psychoemotional factors examined. According to the step by step regression to coping-strategies "flight- avoidance" in a lot of left ventricular myocardium and the indexed rate ranged between 62-77%. Our data allow us to propose that the left ventricular hypertrophy in patients with duodenal ulcer with the normal level of blood pressure is morphological and functional expression of adaptation in response to various stressors and exposure on the force. The nature of stress changes their biochemical, hormonal, functional support, essential for uncovering the mechanisms of influence of stress on the development and course of systemic diseases, develop psychosomatic approach to prevention of functional and organic psychosomatic disease. PMID- 25842661 TI - [The changes of microbiota and genetic polymorphism of cytokines in patients with irritable bowel syndrome]. AB - The aim of this study was to assess the presence or absence of association between the degree of changes in microbiota and gene polymorphism of cytokines IL 1Ra, IL-1b, TNFa, IL-4, IL-10 in patients with IBS. Materials and methods. The sample consisted of 81 patients, the diagnosis was verified according to the Rome criteria III. Polymorphism genotyping of IL-1Ra, IL-1b, IL-4, TNFalpha was carried out by PCR. Statistical processing: chi-square test, Fisher's exact test, odds ratio. The relationship between the heterozygous genotype G/A -308 TNFa and clinically relevant microbiological disorders in patients with irritable bowel syndrome was established. PMID- 25842662 TI - [Characteristics of eating behavior in overweight young people with biliary tract diseases among Bashkortostan population]. AB - The goal of the present research was to study the types of nutritional behavior disturbances in overweight patients with the pathology biliary tract. 132 patients with chronic noncalculous cholecystitis aged from 18 to 35 were examined. The comprehensive clinical examination was conducted and types of eating behavior disturbances with the help DEBQ test (Dutch Eating Behavior Questionnaire) were examined. It was discovered that disturbances of eating behavior are observed in 82,9 percent of normal weight patients, in 100 percent of overweight and in 93,3 percent of patients with obesity. Restraint and emotional eating are more often observed in obesity. External eating is more often observed in overweight and normal weight persons than that emotional eating. Rational eating is rarely observed in all groups of examined persons. PMID- 25842663 TI - [Prevalence of nonalcoholic fatty liver disease in young patients with abdominal obesity and hypertension]. AB - THE AIM: To estimate the incidence of nonalcoholic fatty liver disease and the factors of cardiovascular risk in young patients with abdominal obesity and hypertension compared to persons with isolated forms of these diseases. MATERIALS AND METHODS: Studied 127 patients aged 18-44 years with presence of abdominal obesity and/or hypertension. The factors of cardiovascular risk were evaluated. Laboratory examination included the determination of parameters of lipid metabolism, glucose and uric acid. The liver ultrasound was processed. In 61.3% of young patients with abdominal obesity and hypertension identified laboratory and instrumental signs of nonalcoholic fatty liver disease. In patients with abdominal obesity and hypertension were more prevalent family history of hypertension, smoking, dyslipidemia, mainly due to triglycerides, as well as higher levels of fasting glucose. PMID- 25842664 TI - [Evaluation of prognostic factors for the development of cholelithiasis in patients with metabolic syndrome]. AB - The aim of study to determine the leading clinical and immunological parameters, reflecting the high risk of development and progression of gallstone disease in patients with metabolic syndrome. MATERIALS AND METHODS: An assessment of clinical, biochemical and immunological parameters in 54 patients with gallstone disease associated with the metabolic syndrome and in comparison groups (31 with metabolic syndrome without gallstone disease and 29 with gallstone disease only) were made. For modeling the significant correlation and prediction of the effect of different combinations of factors on the risk of gallstone disease formation in patients with metabolic syndrome was used the multiple logistic regression analysis. RESULTS: In accordance with our results the main risk factors of gallstone formation in patients with metabolic syndrome are the age (P = 0.02), waist volume (P = 0.0002), the increase of serum concentration of GGTP (P = 0.00001), MMP-9 (P = 0.002) and TIMP-1 (P = 0.02). CONCLUSION: The results of our study have shown that in patients with metabolic syndrome was estimated the high risk of gallstone disease formation compared and the most significant factors of it formation are the patients age, waist volume and increase of serum concentration of GGTP, MMP-9 and TIMP-1. PMID- 25842665 TI - [Surgical treatment and different preoperative preparation of patients with malignant tumors of hepatopancreatoduodenal zone]. AB - Different tactical approaches present to optimize surgical treatment of patients with malignant tumors hepatopancreatoduodenal zone. This research based on diagnosis and results of treatment of tumors of this localization, which included 357 analyzed case histories of patients treated in the Chelyabinsk Regional Hospital from 2010 to 2014. During this study was considered the preoperative preparation of patients with malignant obstructive jaundice genesis, and was assessed its impact on the level of postoperative complications and mortality. Farther was found effectiveness of a two-stage surgical treatment of patients with obstructive jaundice malignant etiology for the reduction of postoperative mortality. The complication rate is significantly reduced radically operated patients with bilirubin level below 40 mmol/l, palliative - 80 mmol/l. Also were presented results of treatment of chronic pain. PMID- 25842666 TI - [The possibilities of modern prophylaxis of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP)]. AB - The paper presents the results of the 1778 performed ERCP on patients with benign bile duct occlusion. Father was given evaluation of the effectiveness of using ksifokam, and usage of preventive and therapeutic stenting of the main pancreatic duct in 31 patients. PMID- 25842667 TI - [Morphological changes of the esophagus in adenocarcinoma and squamous cell carcinoma]. AB - PURPOSE: To study the micro-topography of the abdominal wall of the esophagus and give it a quantitative characterization of tumor pathology of the esophagus. METHODS: The study was performed using morphological methods: 1 anatomical dissection; 2 gistotopographical method with coloring of gistotopogramms with hematoxylin-eosin and Van Gieson; 3 Morphometry of macro and microstructures of the esophagus. Operating studied material from 15 patients who over the tumor lesion was performed resection of the lower third of the esophagus and the upper part of the stomach. Operations were carried out on the basis of the thoracic department of the Orenburg Regional Clinical Oncology Center (ORCOC). RESULTS: This article describes the features of the morphological changes in the abdominal wall of the esophagus at its two forms of tumor lesions: in squamous cell carcinoma and in adenocarcinoma. For adenocarcinoma and squamous cell carcinoma is characterized by a different type of growth, a different degree of sprouting layers of the esophageal wall, different propensity to metastasize within the wall of the esophagus. Submucosa of the esophagus is the main layer in which there are significant changes in neoplastic lesions of the esophagus, both within tumor and in adjacent areas of the esophageal wall. CONCLUSION: The common involvement of submucosa of the abdominal esophagus in the pathological process in its malignant lesions (up to 5 cm in our study) should be considered when determining the upper limit of esophageal resection. PMID- 25842668 TI - [Colitis associated with C. difficile]. AB - Pseudomembranous colitis (PMC), is characterized by acute onset, severe diarrhea, hypovolemic shock, toxic expansion of colon perforation, thrombus syndrome and without treatment in some cases leading to death of the patient. The paper describes a clinical case of pseudomembranous colitis in patients 35 years that developed on the background of the massive antibiotic therapy. The diagnosis was made only at autopsy. This case is unique, and dictates the need to inform doctors of practical health care of the complications of antibiotic therapy, such as pseudomembranous colitis. PMID- 25842669 TI - [Modern surgical tactics in Crohn's disease]. AB - Surgical tactics of Crohn's disease (CD) treatment was elaborated on base of modern information analysis, concerning pathogenesis, peculiarities of clinical course, possibilities of diagnosis, experience in the disease treatment. The tactics provides a timely diagnosis of the disease, prognostication for the recurrence occurrence and postoperative complications, the indications and the method of surgery optimization. Application of the elaborated surgical tactics in CD in 121 patients have permitted to improve the objective estimation of the disease severity, to prognosticate complications, to optimize surgical indications, as well as a choice of the method of a conditionally-radical, restorational, reconstructive-restorational stages of operative intervention, to reduce the disease recurrences rate, postoperative complications, postoperative lethality. PMID- 25842670 TI - [Prognostication and prophylaxis of the adhesions recurrence postoperatively in patients suffering acute adhesive peritoneal disease complicated by ileus]. AB - The results of treatment of 92 patients, suffering an acute ileus, were analyzed. After urgent operative interventions for an acute ileus the recurrence have occurred in 19.6% patients. To reduce the operative intervention traumaticity the preference was given to local viscerolysis conduction. For the adhesions occurrence prophylaxis a barrier medicines were used, what have promoted the reduction of contents of a connective tissue metabolites, excluding oxyprolin, concentration of which have exceeded such in a control, what have guaranteed the risk lowering for postoperative adhesions occurrence. PMID- 25842672 TI - [Cholecystectomy as a simultant abdominal intervention in bariatric surgery]. AB - Necessity and validity of simultant interventions while doing restrictive bariatric operations were considered. There were analyzed the results of perioperative examination of 41 patients, in whom laparoscopic bariatric operation was performed, and 23--after simultant operations. There was established necessity for obligatory performance of simultant operations while presence of indices and according qualification of surgeons. PMID- 25842671 TI - [Prophylaxis and correction of inflammatory complications in peritonitis, depending on severity of enteral insufficiency]. AB - There were examined 54 patients, in whom peritonitis of various etiology was diagnosed. Clinical, biochemical, immunological and other investigations were conducted for estimation of the enteral insufficiency syndrome severity. Basing on the analysis of the data obtained and criterions of the patient common state there was determined the occurrence risk for inflammatory complications (IC). Complex of prophylactic and therapeutic measures for reduction of the IC rate was proposed. PMID- 25842673 TI - [Surgical treatment of chronic pancreatitis complicated by biliary hypertension]. AB - The results of 29 patients treatment, suffering chronic pancreatitis, complicated by biliary hypertension, in whom operative interventions in Department of Surgery of Regional Ivano-Frankivsk clinical hospital in 2009 - 2014 yrs, were analyzed. The drainage, resectional and combined interventions were performed. Direct intervention on pancreatic gland was not applied in 5 (17.2%) patients. Operation to Frey was performed in 7 (24.1%) patients, in 4--it was added by choledochojejunoanastomosis formation, longitudinal pancreatojejunostomy--in 13 (44.8%). In 4 (14.8%) patients while functional disorders of adjacent organs present a pancreaticoduodenal resection to Whipple was done. For biliary hypertension diagnosis (including the occult one) the method of intraoperative pressure measurement in common biliary duct (CBD) was proposed. The operation was added by biliodigestive anastomosis formation, using choledochoenterostomy to Roux method if while operations to Frey or Beger after intervention on pancreatic head with the intrapancreatic CBD freeing the intraductal pressure witnessed the biliary hypertension presence. In all the patients good and satisfactory results of operative treatment were noted. PMID- 25842674 TI - [Algorithm of tactics for nutritive support choice in operated patients]. AB - Algorithm of determination of energetic status for calculation of variants of nutritive support while performing operations in patients, depending on their functional state, was proposed, basing on literature data and results of own clinical investigations. PMID- 25842675 TI - [Peculiarities of application of a cell saver apparatus in neonathal cardiosurgery using artificial blood circulation]. AB - Elaborated and introduced into the practice method of the blood preservation, while correction of complex inborn heart failures (IHF) in a newborn babies, was proposed. It assumes application of system for intraoperative reinfusion of own erythrocytes with processing of residual perfusate and their reinfusion in a postperfusion period. Impact of the blood preservation on volume of a donor's blood components, hematological indices and methods of application of washed erythrocytes while correction of complex IHF in a newborn babies were presented. The method was applied in 47 newborn babies, to whom an arterial switch was performed for the main vessels transposition. PMID- 25842676 TI - [Evaluation of vascular bed before and after embolization of renal artery for renal cancer]. AB - Results of treatment of 120 patients, suffering nephro-cellular cancer, in the clinic were analyzed. In 60 of them radical nephrectomy was done, in 30- palliative angiographic occlusion of renal blood flow, in 30--the combined treatment in accordance to original method, using embolization of renal artery with further application of operative intervention. There was established, that performance of endovascular intervention and embolization of renal artery caused a renal blood flow inhibition: reduction of the contrasting coefficient of renal parenchyma and enhancement of period of maximal contrasting achievement. Such result have witnessed a sensitivity of the preoperative preparation method choosed, concerning changes in a renal blood flow parameters. PMID- 25842677 TI - [Thrombotic complications in severe forms of varicose disease: diagnosis, surgical treatment, using miniinvasive methods]. AB - Actual issues of surgical treatment of patients, suffering complications of varicose disease severe forms, are discussed. The causes of unsatisfactory results of treatment of patients, suffering varicothrombophlebitis, the main of which is the absence of common tactics of operative treatment and anticoagulant therapy, were analyzed. There were formatted the groups of patients, suffering severe forms of varicose disease of various localization of thrombotic process, a differentiated tactics of their surgical treatment was proposed. PMID- 25842678 TI - [Choice of fistulas optimal diameter while performance of thrombectomy from ileo femoral venous segment]. AB - The results of investigation of arterio-venous fistula (AVF) hemodynamics, depending on its diameter, were adduced. There were operated 98 patients for deep veins thrombosis (DVTH) of ileo-femoral segment, in 82 (83.7%) of them the extraction of a flotation thrombus with femoral vein ligation was performed, in 16 (16.3%)--thrombectomy from the ileo-femoral segment veins, in 14 (14.3%)--the intervention was added by formation of AVF. While AVF formation a lateral branches of femoral vein of a necessary diameter were applied. In all the patients AVF have closed spontaneously in terms from 3 to 10 weeks. While the accelerated blood flow presence in 1 (7.1%) patients a rethrombosis have occurred. Pulmonary thrombosis in operated patients did not occurr. Application of active surgical tactics in treatment of DVTH of ileo-femoral segment securely prophylacts the pulmonary thromboembolism, application of thrombectomy together with AVF formation of optimal diameter guarantees the essential reduction of the rethrombosis and complications occurrence rate. PMID- 25842679 TI - [Tactics of organ preserving interventions for splenic rupture]. AB - The results of treatment of 76 injured persons with splenic rupture were analysed. The methods of conserving surgery were elaborated, depending on the severity and localization of rupture, which permit to reduce complications rates and improve patient's quality of life. PMID- 25842681 TI - [Changes in clinical indices in patients in predisposition for pathological cicatrices formation]. AB - Prophylaxis of ocurrence of pathological cutaneous cicatrices is one of actual problems of plastic surgery of head and neck. Cicatricial changes of tissues, as a consequence of operative interventions and various damaging causes (mechanical, thermal and chemical impact, ionizing irradiation, deep destructive inflammation), were depicted. Propensity for formation of pathological cicatrices we consider as the organism state, in which cicatricial changes occur as an answer for minimal trauma or spontaneously. Detailed analysis of fundamental issues and periodical scientific publications witness the insufficient substantiation of this issue. PMID- 25842680 TI - [A magnet application for the splinters take out in the mine-explosion woundings]. AB - The methods of successful take out of metallic splinters from soft tissues with the help of magnet were depicted. Experience of the splinters take out, using small operative accesses or the wounding channell passage, was summarized. The method permits to determine precisely the splinter localization. The method application have promoted the reduction of the patient's stationary treatment duration and the comlications rate. PMID- 25842682 TI - [Pathogenetic substantiation of surgical treatment safety in early reproductive losses]. AB - Early loss of pregnancy is associated with high rate of chronic inflammatory processes of genital organs. While still and tubal pregnancy a multicomponent associations of microorganisms in genital ways are revealed, accordingly, in 66.7 and 48.9% women, morphological signs of inflammatory process--in 72.2 and 51.1%. Application of endoscopic methods of diagnosis and treatment of women in early loss of pregnancy is highly effective, permits to reveal comorbidities, to perform miniinvasive organ preserving interventions in necessary volume. Performance of complex anti-inflammatory treatment of women in early loss of pregnancy is substantiated with the objective to escape negative outcomes, and for improvement of immediate and late results of surgical treatment. PMID- 25842683 TI - [Comparative evaluation of mastoidoplasty results in application of various plastic materials]. AB - The results of surgical treatment of 62 patients, suffering chronic purulent middle otitis, were analyzed. The structure of mastoid processus and attic constitutes a base for choice of middle ear surgical sanation. Sanation operation with preservation or reconstruction of external acoustical meatus posterior wall was finished with combined mastoidoplasty using autobone, spongioid bone bioimplant Tutoplast or bioceramic material "Sintekost". Achievement of a steady sanating effect have promoted in late postoperative period a trustworthy lowering of the perception threshold of the bone--conducted sounds as on vocal, and also on high frequencies, while of the air--conducted sounds--on vocal frequencies. This permits in perspective to perform a hearing--improving operations with good functional result. PMID- 25842684 TI - [New approaches for determination of area of superficial functional and anatomic objects in pediatric anesthesiology and surgery]. AB - A hypothesis concerning expediency for application of a Bezye's curves in anesthesiology while solving the tasks of the images recognition of a functional part hyperalgesia and hemangioma. PMID- 25842685 TI - [Impact of abdominal cavity open EHF irradiation on activity of adhesive process in peritonitis]. AB - In experiment on 45 rats a purulent peritonitis was simulated. There was established, that on background of a standard therapy for peritonitis application of abdominal cavity open irradiation of extreme high frequency (EHF) have promoted rapid stabilization of the lipid metabolism indices and the blood coagulation system, the reduction of intensity of lipids peroxidal oxidation processes and severity of systemic inflammatory reaction. Under the influence of complex treatment the severity of adhesive process was reduced in 5.4 times, comparing with such in animals, to whom a standard treatment was conducted only. The revealed pathogenetic aspects of the adhesions formation witnesses the expediency to add EHF irradiation to complex therapy of peritonitis. PMID- 25842686 TI - [Simultant operative interventions in patients for the diseases of large bowel]. PMID- 25842687 TI - [Application of modern miniinvasive technologies in diagnosis and treatment of tubo-peritoneal infertility]. PMID- 25842688 TI - [Combined impairments of common hepatic duct and the branch of the right hepatic artery complicated by hemobilia]. PMID- 25842689 TI - [Method for video-assisted atypical lung resection]. PMID- 25842690 TI - Bringing to life the issues that matter. PMID- 25842691 TI - Is early intervention the most cost-effective way of helping children and troubled families? PMID- 25842692 TI - At a glance: respiratory tract infections in children. AB - Respiratory tract infections (RTIs) are one of the most common presentations to child health professionals. It is important that community practitioners are able to distinguish serious RTIs from those which can be managed in the community with advice and reassurance. Common respiratory symptoms include cough, wheeze, fever, tachypnoea and stridor. This paper aims to identify the common presentations of RTIs seen in children. A discussion on asthma with relevance to RTIs is also included. The red flag indicators and children from high risk groups should be identified while assessing a child with suspected RTI and an early referral to a medical professional should be initiated. Community practitioners should be able to reassure parents and educate them on signs of deterioration when the management of a child with RTI is considered appropriate in the community. PMID- 25842693 TI - Birthmarks in infants - cause for concern? PMID- 25842694 TI - Setting up an FNP programme in a London borough. PMID- 25842695 TI - Poor diabetes care costs lives. PMID- 25842696 TI - Bye bye bump! PMID- 25842697 TI - Legalizing pot--facts, fables and avoiding follies. PMID- 25842698 TI - Brian O. Foy selected to lead West Virginia State Medical Association. PMID- 25842699 TI - Acute calcific longus colli tendonitis. AB - Acute calcific longus colli tendonitis is an inflammatory response of the neck flexor musculature. Patients present with symptoms suggestive of a retropharyngeal abscess or meningitis. Adjunctive medical imaging is required to confirm the diagnosis and dispel other, more serious and life threatening, pathologies. We present a case of acute calcific longus colli tendonitis, and provide a discussion on the topic as to avoid unnecessary medical and surgical intervention because the entity can be easily confused with more severe diseases. PMID- 25842700 TI - Delayed fracture of fibular strut allograft following three-level anterior cervical corpectomy and fusion: a case report. AB - Strut allografts are used in cervical spine reconstruction following corpectomy. A stress fracture in the graft is a rare event. We explain a late stress fracture of an allograft following anterior cervical fusion. A 57-year-old male with a history of cervical myeloradiculopathy underwent a three-level anterior cervical corpectomy and allograft reconstruction from C3-C7. Fracture lucencies in the allograft were identified on flexion/extension radiographs 11 months post operatively. The patient reported no new pain, numbness, or weakness and denied any traumatic injury. Three years post-operatively, he was asymptomatic with no change in alignment or signs of failure of the instrumentation or strut graft. With a healed fibular strut allograft, a delayed stress fracture may be observed with a favorable outcome. PMID- 25842701 TI - Medical management of aortic coarctation is feasible & durable in selected patients: a case report & literature review. AB - Long-term survival in patients with complete aortic coarctation (AC) without surgical repair has not been well characterized and is rarely documented. We report a case of an 84 year old male with complete aortic coarctation with history of hypertension for more than 40 years. Since the diagnosis was made in early 1950's medical treatment to control hypertension was initiated as patient was deemed high risk for surgical intervention. He has survived to the age of 84 years with minimal medical problems. This report also reviews the few documented cases of prolonged survival in patients with aortic coarctation. This report demonstrates that prolonged survival is possible in patients with documented complete coarctation and awareness of this report may influence the decision to use medical treatment for selected elderly patients with high risk of mortality associated with surgical repair. PMID- 25842702 TI - Solid pseudopapillary tumor of the pancreas. AB - Solid pseudopapillary tumor is a rare tumor accounting for 1-2% of exocrine neoplasms involving the pancreas. This typically benign tumor is predominately found in young females of non-Caucasian descent between the second and fourth decades of life. Despite the reported increasing incidence of this neoplasm, many physicians are unfamiliar with this tumor, which may lead to uncertainty of diagnosis and treatment. While further delineating the clinical and imaging features of this tumor, we present two cases with review of the literature. PMID- 25842703 TI - Mentoring program that gives primary care providers (PCPs) direct access to clinical experts. PMID- 25842704 TI - State minority health. PMID- 25842705 TI - New legislature seeks to amend the MPLA. PMID- 25842706 TI - RHI students explore underground mines. PMID- 25842707 TI - The RACs are back: auditors to start performing complex reviews. AB - The Recovery Auditor program is cranking back up again after almost a year's hiatus, but despite the Centers for Medicare & Medicaid Services' plans to improve the program and issue new contracts, the audits will be conducted by the same auditors under the same rules. Auditors are likely to target short stays and other weak areas the Medicare Administrative Contractors identified during Probe and Educate, according to Elizabeth Lamkin, MHA, chief executive officer and partner in PACE Healthcare Consulting, LLC, based in Beaufort County, SC. CMS has not made any clarifications to the two-midnight rule, and auditors may begin auditing hospitals for compliance beginning April 1. The Outpatient Prospective Payment System (OPPS) final rule clarified the requirement for physician certification, saying that the order to admit must be signed by the treating physician and the justification for the admission, the expected length of stay, the treatment plan, and the discharge plan do not have to be a separate document but can be part of the history and physical. PMID- 25842708 TI - Changes in RA program are intended to reduce burden on providers. PMID- 25842709 TI - Game changer: HHS sets goals for basing payments on quality. AB - For the first time, theDepartment of Health and Human Services has set specific goals for basing Medicare fee-for-service payments on quality or value by the end of 2018. Commercial payers are expected to follow suit and develop their own programs for basing payment on quality or value. Since much of the data used in the Centers for Medicare & Medicaid Services quality-based programs is risk adjusted, complete and detailed documentation that represents all of the patients' conditions and services received is vital. The emphasis on care throughout the continuum means that case managers are going to have to communicate regularly with their counterparts in post-acute providers and make sure patients do well in the post-discharge setting. PMID- 25842710 TI - Tools improve communication with SNFs, reduce readmissions. AB - A case management team at UPMC Presbyterian Shadyside Hospital in Pittsburgh has developed an initiative to improve communication between the hospital and skilled nursing facilities in an effort to reduce readmissions. The team interviewed readmitted patients, analyzed trends in readmissions and what caused them, and researched readmission prevention tools. They developed a risk tool that assesses a variety of issues and use it to help identify patients who are at risk for readmission. The tool covers comorbidities, psychiatric issues, polypharmacy issues, emergency department visits and hospitalization, and other issues. They created a discharge checklist that lists the tasks that should be done for every skilled nursing discharge. PMID- 25842711 TI - Hospital cuts length of stay for babies in the NICU by four days. AB - An initiative in which the entire treatment team focuses on moving premature babies through the continuum has resulted in a drop of foul days in the average length of stay at Cedars-Sinai Medical Center's Neonatal Intensive Care Unit. The treatment team has daily rounds on every patient and a multidisciplinary early discharge team assesses every patientat the bedside to determine who is ready to go home and what is holding up the discharge, and to take action to move things along. The bedside nurses assess the babies several times a day for feeding readiness and to determine if they are ready to move along in the clinical protocol. The team gets parents involved in daily care and gives them hands-on experience so they won't be nervous about caring for the child at home. PMID- 25842712 TI - Health system, churches work together to support patients after discharge. PMID- 25842713 TI - Perioperative surgical home optimizes patient care, Part 1. PMID- 25842714 TI - Building the business case for a hybrid OR. PMID- 25842715 TI - Surgical patients warmed with forced air still experience hypothermia. PMID- 25842716 TI - First step taken in FDA-issued unique device identification system. PMID- 25842717 TI - Communication, collaboration, commitment are cornerstones of high reliability healthcare. PMID- 25842718 TI - Redefining staff roles and responsibilities can help reduce turnover time. PMID- 25842719 TI - Water: a critical ingredient for instrument cleaning and disinfection. PMID- 25842720 TI - Careful planning essential when expanding outpatient surgery repertoire. PMID- 25842721 TI - Chinese patent medicine for chronic obstructive pulmonary disease based on principles of tonifying Qi, promoting blood circulation by removing blood stasis, and resolving phlegm: a systematic review of randomized controlled trials. AB - OBJECTIVE: To assess the efficacy and safety of Chinese patent medicine (CPM) with the principle of tonifying Qi, promoting blood circulation by removing blood stasis, and resolving phlegm (TQ-PBC-RP) in the management of stable chronic obstructive pulmonary disease (COPD). METHODS: A systematic review of randomized controlled trials (RCTs) identified from electronic databases and print was conducted. RCTs testing CPMs with TQ-PBC-RP against any type of controlled intervention in patients with stable COPD and assessing clinically relevant outcomes were included. Methodological quality was evaluated with the risk of bias tool according to systematic review handbook 5.0.2. Quality of evidence was estimated by the rating approach developed by the Grading of Recommendations, Assessment, Development, and Evaluation Working Group. RESULTS: Thirteen eligible RCTs with 12 oral CPMs were tested. Significant differences between groups in favor of CPMs were not reported in all trials. Most trials included were deemed to be of low methodological quality with poor evidence quality. Because of large data heterogeneity, statistical pooling was not performed for all outcomes. CONCLUSION: The effectiveness of CPM in the treatment of stable COPD is not supported by evidence. Currently, evidence from RCTs is scarce and methodologically weak. Considering the popularity of CPMs among patients undergoing COPD, rigorously designed trials are warranted. PMID- 25842722 TI - Meta-analysis on integrative medicine for the treatment of malig- nant ascites: a comparative study. AB - OBJECTIVE: To compare the efficacy of integrated Chinese and Western Medicine with that of only Western Medicine for the treatment of malignant ascites. METHODS: All randomized controlled trials (January 2004 to March 2013) from the China National Knowledge Infrastructure Database, Chinese Biomedical Literature Database, and Wanfang Database were searched with keywords. Meta-analysis was conducted by combining the odds ratios of the individual studies. Review Manager 5.0 was used for the analysis. RESULTS: One thousand one hundred and fifty-six patients from 19 randomized controlled trails were included. Of them, 630 patients were treated with integrated Chinese and Western Medicine (the integrative group), and 526 patients were treated with Western Medicine alone (the control group). The Meta-analysis showed that the total effective rate was 78.73% in the integrated group, and 59.13% in the control group. The effective percentage was significantly higher in the integrative group than that of the control group [OR = 2.85, 95% CI (2.16, 3.74), P < 0.01]. CONCLUSION: The short term curative effect in the integrative group was better than that in the control group. Integrative medicine may be beneficial for malignant ascites. PMID- 25842723 TI - Effect of Huangshukuihua (Flos Abelmoschi Manihot) on diabetic nephropathy: a meta-analysis. AB - OBJECTIVE: To assess the efficacy of Huangshukuihua (Flos Abelmoschi Manihot) on diabetic nephropathy (DN). METHODS: Articles were retrieved from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure Database, Chinese Evidence-Based Medicine Database, and Wanfang Database. Two reviewers independently reviewed the article. Only randomized controlled trials were included and 27 were identified involving 2239 patients (1143 in the treatment group and 1096 in the control group). RESULTS: Huangshukuihua (Flos Abelmoschi Manihot) had a significant effect on renal function by improving blood urea nitrogen and serum creatinine, reducing urine protein (24-h urine protein, and urinary albumin excretion rate), and improving serum albumin level, compared with the control group. CONCLUSION: Our findings suggest that, although the bioactive ingredients and mechanism underlying renal protection are unknown, the role of Huangshukuihua (Flos Abelmoschi Manihot) in the treatment of DN deserves further investigation. PMID- 25842724 TI - Efficacy evaluation of summer acupoint application treatment on asthma patients: a two-year follow-up clinical study. AB - fill out a questionnaire evaluating asthma degree, exacerbation frequency, concomitant medications and self-satisfaction. The self-rate and doctor-report outcomes obtained in parallel were evaluated to assess the efficacy of SAAT. RESULTS: A total of 527 asthma patients were initially enrolled in this study, of which 97 elderly patients and those with more severe cases of asthma were lost to follow-up. Thus, a total of 430 patients were valid for analysis using self-rate data. Nevertheless, occasional negative returns were obtained; almost all of the outcomes were rated as "No change", "Moderate effective", or "Very effective". In addition, 80% of the patients were satisfied with this treatment. Moreover, 391 (91.4% ) patients were somewhat improved after SAAT in 2009, and further improvement was observed in 2010. After SAAT, the average asthma-degree score decreased from 5.3 in 2008 to 4 in 2009 and, subsequently to 3.5 in 2010. CONCLUSION: With pronounced patient satisfaction, SAAT can reduce the exacerbation severity and frequency, concomitant medications and asthma degree. Prolonging the treatment course might enhance the efficacy of SAAT. OBJECTIVE: To evaluate the self-efficacy and satisfaction of asthma patients subjected to summer acupoint application treatment (SAAT). METHODS: A two-year follow-up clinical study was conducted. Patients with asthma were treated by applying a herbal paste onto the Feishu (BL 13) and Fengmen (BL 12) acupoints on the three hottest days of summer, according to the traditional Chinese calendar, from 2008 to 2010. During a two-year follow-up, these patients were asked to PMID- 25842725 TI - 1H nuclear magnetic resonance-based metabolomic study on efficacy of Qingrehuatan decoction against abundant phlegm-heat syndrome in young adults with essential hypertension. AB - OBJECTIVE: To observe the influence of Qingrehuatan decoction (QRHT) on serum metabolic profile in young essential hypertension (YEH) patients with abundant phlegm-heat syndrome and provide a basis for treatment with the decoction. METHODS: Twelve male YEH patients were randomly selected and serum samples were collected for examination before and after 4 weeks of the treatment with QRHT. Twelve healthy males were randomly selected and their serum samples were collected as a control. All serum samples were detected using metabolomic technology with 1H nuclear magnetic resonance. Differences in metabolites were studied by principal component analysis and partial least squares-discriminate analysis, which produced scores and loadings plots. RESULTS: After 4 weeks of treatment, serum substances could be distinguished between the YEH patients with abundant phlegm-heat syndrome and the control patients. The specific serum endog- enous metabolites tended to improve after the treatment. QRHT can appropriately increase the levels of glucose, lactic acid, citric acid, high-density lipoprotein, phosphatidylcholine, glycerophosphate choline, hydroxybutyrate, alanine, and glutamate. QRHT could also decrease the levels of low-density lipoprotein/very low-density lipoprotein, lipids, N-acetyl glycoprotein, and O acetyl glycoprotein. CONCLUSION: QRHT can effectively ameliorate metabolic disorders in YEH Patients with abundant phlegm-heat syndrome. 1H NMR-based metabolomic technology can provide an objective basis for the treatment of YEH patients with abundant phlegm-heat syndrome using QRHT. PMID- 25842726 TI - Effect of stimulating acupoint Guanyuan (CV 4) on lower back pain by burning moxa heat for different time lengths: a randomized controlled clinical trial. AB - OBJECTIVE: To investigate the effect of different heat-stimulating time lengths on lower back pain. METHODS: Forty participants were randomly assigned to four groups of various heating time lengths. The short heating time length group (SL), moderate heating time length group (ML), and long heating time length group (LL) respectively received 15, 30, and 60 min of moxibustion therapy stimulating the acupoint Guanyuan (CV 4). The conventional acupuncture group (CA) received needle acupuncture treatment as a control group. The participants were treated continuously over a 2-week treatment period for a total of 10 sessions, with five sessions given per week. Participants were assessed weekly by blinded assessors,using the visual analogue scale (VAS) and Roland Morris Questionnaire (RMQ). RESULTS: The VAS and RMQ scores reduced in all four groups during treatment. There were significant differences in VAS scores (P < 0.01) and RMQ scores (P < 0.01) between before treatment and after 2 weeks of treatment in the LL group. After treatment, the LL group reported significantly lower VAS scores compared with the CA group, ML group, and SL group (P < 0.05). CONCLUSION: The long and moderate lengths of heat-stimulating time of 30 and 60 min may be more effective for relieving lower back pain than that of short stimulating time lengths. PMID- 25842727 TI - Integrated treatment for lower-limb stage II thromboangiitis obliterans by interventional therapy and oral administration of Chinese medicine: a randomized controlled clinical trial. AB - METHODS: Ninety lower-limb stage II or worse TAO patients were randomly divided into three groups: group A (30 cases) treated by intervention and oral administration of Chinese medicine; group B (30 cases) treated by intervention alone; and group C (30 cases) treated only with oral administration of Chinese medicine. Therapeutic effects were observed, including the cure rate; the recurrence rate after one month, three months, six months, nine months, and one year; the ankle brachial indexes; the incidence of complications; and the level of C-reactive protein and erythrocyte sedimentation rate. RESULTS: Group A had significantly better clinically curative effects, related indexes, and outcomes during the long-term follow-up survey, than that of groups B and C. CONCLUSION: Integrated treatment is more effective for treating lower-limb stage II or worse TAO. OBJECTIVE: To observe if integrated treatment is better than other therapies for lower-limb stage II thromboangiitis obliterans (TAO). PMID- 25842728 TI - Pattern characteristics in patients with primary liver cancer in different clinical stages. AB - OBJECTIVE: To explore the characteristics of primary liver cancer in terms of Traditional Chinese Medicine (TCM) by analyzing the variations of the patterns along with the clinical stages. METHODS: The patients who were hospitalized in the Changhai Hospital of Traditional Chinese Medicine dated from March 1999 to December 2008 were included in this retrospective study. The patients were grouped according to their cancer stages, and their patterns were judged and quantified according to the "Standard diagnosis and quantitative criteria of the common patterns in primary liver cancer" formulated by the Changhai Hospital of Traditional Chinese Medicine. Statistics methods included ANOVA and nonparametric test, among others. RESULTS: The data of the 398 newly diagnosed pa- tients showed that Qi Stagnation, Blood Stasis, and Dampness patterns were more frequent than the other basic patterns with relatively high scores; patterns of Liver Qi Stagnation, Liver Blood Stasis, and Dampness Heat were more than the other complex patterns and scored relatively high. Scores of Dampness and Liver Qi Stagnation patterns varied among the groups at different stages and the differences were statistically significant (P(Dnampness) = 0.002, P(Liver Qi Stagnation) = 0.020). The highest scores of Dampness pattern and Liver Qi Stagnation pattern corresponded with Stage IIIb, and Stage IIIa, respectively. Dampness pattern frequency was higher (P = 0.001) in the Stage IIIb group than in other groups. CONCLUSION: Pattern characteristics in patients with primary liver cancer of different clinical stages might manifest in the variations of the Dampness pattern along the process of the disease and the major pathogenic factor of primary liver cancer might be Dampness. PMID- 25842729 TI - Effect of Liuweibuqi capsule, a Chinese patent medicine, on the JAK1/STAT3 pathway and MMP9/TIMP1 in a chronic obstructive pulmonary disease rat model. AB - OBJECTIVE: To observe effect of Liuweibuqi Capsule, a Traditional Chinese Medicine (TCM), on the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and matrix metalloproteinases (MMPs) in a chronic obstructive pulmonary disease (COPD) rat model with lung deficiency in terms of TCM's pattern differentiation. METHODS: Rats were randomly divided into a normal group, model group, Liuweibuqi group, Jinshuibao group, and spleen aminopeptidase group (n=10). Aside from the normal group, all rats were exposed to smoke plus lipopolysaccharide tracheal instillation to establish the COPD model with lung deficiency. Models were established after 28 days and then the normal and model groups were given normal saline (0.09 g/kg), Liuweibuqi group was given Liuweibuqi capsule (0.35 g/kg), Jinshuibao group was given Jinshuibao capsules (0.495 g/kg), and the spleen group was given spleen aminopeptidase (0.33 mg/kg), once a day for 30 days. Changes in symptoms, signs, and lung histology were observed. Lung function was measured with a spirometer. Serum cytokines were detected using enzyme-linked immunosorbent assay, and changes in the JAK/STAT pathway, MMP-9, and MMPs inhibitor 1 (TIMP1) were detected by immunohistochemistry, RT-PCR, and western blotting, respectively. RESULTS: Compared with the normal group, lung tissue was damaged, and lung function was reduced in the model control group. Additionally, the levels of interleukin (IL) 1beta, gamma interferon (IFN-gamma), and IL-6 were higher, while IL-4 and IL-10 were lower in the model control group than those in the normal group. The expressions of JAK1, STAT3, p-STAT3, and MMP-9 mRNA and protein in lung tissue were higher, and TIMP1 mRNA and protein was lower in the model group compared with the normal group. After treatment, compared with the model group, the expression of inflammatory cytokines was lower in each treatment group, and expressions of JAK/STAT pathway, MMPs were lower. Compared with the positive control groups, the Jinshuibao and spleen aminopeptidase groups, lung function was better, and JAK1, STAT3, and p-STAT3 protein were lower and TIMP1 was higher in the Liuweibuqi group. CONCLUSION: Liuweibuqi capsules can improve the symptoms of COPD possibly by regulating the expression of the JAK1/STAT3 pathway and MMP9/TIMP1. PMID- 25842730 TI - Effect of allogeneic umbilical cord mesenchymal stem cell transplantation in a rat model of hepatic cirrhosis. AB - OBJECTIVE: To determine the effects of human umbilical cord mesenchymal stem cell (UCMSC) transplantation, alone or in combination with tanshinone IIA (Tan IIA) on hepatic cirrhosis in rats. METHODS: A rat model of cirrhosis was established. Rats were divided into control, UCMSC, and UCSMC plus Tan IIA groups. Rats in the UCMSC group were injected via the tail vein with 0.2 mL Dil-labeled UCMSC suspension. Intraperitoneal Tan IIA injections (20 mg/kg) were started on the day of UCMSC transplantation in the UCMSC plus Tan IIA group, and continued for 7 consecutive days thereafter. Rats were sacrificed 1 day, 3 days, 1 month, and 3 months after transplantation and the numbers of Dil-labeled UCMSCs colonizing the liver were determined. Albumin (ALB) and alanine aminotransferase (ALT) levels were measured in venous blood, and mRNA and protein expression levels of human ALB and cytokeratin (CK)-18 in liver tissues were determined by reverse transcription-polymerase chain reaction and western blotting, respectively. RESULTS: Serum ALT levels were significantly lower and serum ALB levels significantly higher in rats in the UCMSC group compared with the control group (P < 0.05). Hepatic CK-18 and ALB mRNA and protein expression levels increased after transplantation, and were significantly higher in the UCMSC plus Tan IIA group compared with the UCMSC group (P < 0.05). CONCLUSION: Human UCMSCs transplanted into rats with liver cirrhosis can grow and differentiate into hepatocyte-like cells resulting in improved liver function in vivo. Tan IIA further influenced transplantation outcomes. PMID- 25842731 TI - Qingnaoyizhi decoction suppresses the formation of glial fibrillary acidic protein-positive cells in cultured neural stem cells by inhibiting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. AB - OBJECTIVE: Inactivation of the Janus kinase 2 in treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD mediated neurogenesis. (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells (NSCs). Qingnaoyizhi decoction (QNYZD) has been used for the treatment of vascular dementia and has shown to improve synaptic remodeling. The aim of this study was to evaluate the effect of cerebrospinal fluid (CSF) containing QNYZD (CSF-QNYZD) on the differentiation of cultured NSCs and the involvement of the JAK2/STAT3 pathway. METHODS: The protein expression levels of glial fibrillary acidic protein (GFAP), tubulin, drosophila mothers against decapentaplegic protein (SMAD-1), STAT3, and phosphorylated-STAT3 were detected by western immunoblot analysis in the groups: control, CSF, JAK/STAT inhibitor (AG490), CSF-QNYZD, and CSF-XDZ (CSF-Xidezhen). The differentiation of NSCs was determined by immunofluorescence staining. The proliferation of NSCs was measured using the Cell Counting Kit-8 proliferation assay. RESULTS: Compared with the control group, CSF-QNYZD and AG490 significantly increased the number and expression of tubulin-positive cells, reduced the number and expression of GFAP positive cells, and down-regulated the expression of p-STAT3. However, CSF-QNYZD also decreased the expression of SMAD-1 and STAT3. CONCLUSION: Enhanced neuronal differentiation may be associated with the down-regulation of glial differentiation instead of promoting proliferation in treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis. PMID- 25842732 TI - Anti-tumor effect of the extract from qingyihuaji formula on pancreatic cancer by down-regulating Notch-4 and Jagged-1. AB - OBJECTIVE: To investigate, in terms of Notch signaling pathway, the effect on pancreatic cancer of the extract of an anti-tumor prescription--Qingyi-huaji formula (QYHJ)--from Traditional Chinese Medicine (TCM). METHODS: Nude mice were implanted subcutaneously with human pancreatic cancer cell line SW1990 and then randomly divided into four groups: Control, QYHJ extract, Gemcitabine, and Combination of QYHJ extract and gemcitabine. Treatments were given for 21 days and tumor growth was evaluated simultaneously. Then, expression of Notch receptors (Notch-1, Notch-2, Notch-3, and Notch-4) and their Jagged ligands (Jagged-1 and Jagged-2) in dissected tumor tissue were detected by real-time quantitative reverse transcription-polymerase chain reaction and Western blot. Finally, immunohistochemistry was performed to detect CD133, a marker of pancreatic cancer stem cells (CSCs), to evaluate the impact of QYHJ extract on pancreatic CSCs. RESULTS: QYHJ extract treatment effectively inhibited the tumor growth in nude mice. The expression of both Notch-4 and Jagged-1 were decreased significantly in QYHJ treatment groups (P < 0.05), while gemcitabine alone had no significant effect in down-regulating Jagged-1 (P > 0.05). No significant difference was observed in the ex- pression of Notch-1, Notch-2, Notch-3, and Jagged-2 between three treatment groups and control group (P > 0.05). Moreover, immunohistochemical analysis showed that the number of CD133 positive cells was significantly reduced by QYHJ treatment (P < 0.05), and the combined treatment was more effective than gemcitabine alone (P < 0.05). CONCLUSION: The role of the extract in pancreatic cancer treatment was associated with down-regulation of Notch-4 and Jagged-1 in Notch signaling pathway. The extract could enhance the antitumor activity of gemcitabine and was more effective than gemcitabine in regulating Notch signaling pathway to some extent. PMID- 25842733 TI - Daily administration times of canhuang tablet based on a pharmacodynamic/pharmacokinetic model in jaundiced rats. AB - OBJECTIVE: To study the daily administration times of Canhuang tablet (CHT) for treating jaundice in rats based on a pharmacodynamic/pharmacokinetic model. METHODS: Rats were modeled by 4% 1-Naphthylisothiocyanate (75 mg/kg, p.o.). After 48 h, CHT was given (p.o.) at 0.75 g/kg once a day, 0.375 g/kg twice a day, and 0.25 g/kg three times a day. Blood was collected from the orbital sinus at different intervals. Levels of liver enzymes and bilirubin were detected using these blood samples. Bile was collected and determined after the first administration of CHT. High-performance liquid chromatography was used to determine the concentration of berberine in bile simultaneously. Time-effect and time-dose curves were then obtained. RESULTS: Compared with rats taking CHT twice and three times a day, the total amount of bile within 10 h of rats taking CHT once a day were 1.32- and 1.47-fold higher, respectively. There was good consistency between the pharmacokinetics of berberine and the pharmacodynamics of the effect on liver enzymes and bilirubin in vivo. The pharmacokinetic analyses showed that rats administered CHT once daily maintained a higher concentration of berberine in bile for a longer period than rats administered CHT two- and three times daily. CONCLUSION: In jaundiced rats, taking CHT once a day is better than taking CHT twice or three times a day. These data may provide a reference for the clinical application of CHT. PMID- 25842734 TI - A combined dynamic inhalation device designed for moxa-smoking toxicity testing. AB - OBJECTIVE: To design a combined dynamic inhalation device for testing the toxicity induced by moxa smoking. METHODS: The new apparatus (Patent No. 201120101911.5) includes air renewal and recycling systems, a gas generating device, a gas control unit, and a device to measure and control temperature and humidity. Sprague-Dawley rats were tested for acute and sub-chronic toxicity after exposure to moxa-burning smoke. RESULTS: We found an LC50 of 1.2 x 10(4) mg/m3 in the acute toxicity assays. In sub-chronic toxicity tests the organ coefficients studied showed no significant differences within rats groups of the same gender after treatment with moxa smoke or a month of recovery. However, mean gray degree of lung 70 heat shock protein (HSP70) was significantly elevated in the high dose group in comparison with the low dose group (P < 0.05); mean gray degree, mean optical density, gross area of HSP70 in other organs and caspase-9 parameters showed no significant differences between groups. CONCLUSION: These results suggest that moxa smoke had no overt toxicity in rats. This work provides evidence and reference for the design of dynamic inhalation exposure systems. PMID- 25842735 TI - Postmarketing evaluation on the safety and effectiveness of deng-zhanxixin injection made from Dengzhanxixin (Herba Erigerontis Breviscapi). AB - OBJECTIVE: To assess the safety and effectiveness of Dengzhanxixin injection (DZI) extracted from Dengzhanxixin (Herba Erigerontis Breviscapi) and identify its potential risks. METHODS: A series of studies were conducted on the production process, quality standards, and pharmacology. Postmarketing clinical studies and literature reviews including adverse reactions (ADR) ,adverse events (ADE), case analysis and systematic reviews were also conducted. Data from the hospital information system and spontaneous reporting system were analyzed. RESULTS: The acute toxicity test indicated that the Lethal Dose 50 test ( LD 50) dosage was 250 times more than the clinical maximum daily dosage (6 mg/kg). In long-term toxicity tests, rats experienced renal tubular damage at 480 mg/kg. However, the dose of 120 mg/kg is safe and non-toxic, which is 40 times above the clinical daily maximum. Beagles had increased serum creatinine at 160 mg/kg. Ina prospective study, 15 962 cases experienced 16 ADR/ADE. The rate of ADR/ADE was 0.1002%. ADR symptoms included rash (16.00%), chills (16.00%), and fever (16.00%). CONCLUSION: There is significant evidence that DZI is safe and effective in a clinical setting. PMID- 25842736 TI - Medicinal properties of Peganum harmala L. in traditional Iranian medicine and modern phytotherapy: a review. AB - OBJECTIVE: To review the pharmacological activities of Peganum harmala L. (P. harmala, Nitrariaceae) in traditional Iranian medicine (TIM) and modern phytotherapy. METHODS: Opinions of TIM and modern phytotherapy about safety and acceptable dosage of this plant are discussed. Various medical properties of P. harmala were collected from important TIM references and added to scientific reports derived from modern medical databases like PubMed, Scirus, ScienceDirect and Scopus. RESULTS: The main medicinal part of the plant is the seed. In TIM resources, this plant possesses various Pharmacological activities such as carminative, galactagogue, diuretic, emmenagogue, antithrombotic and analgesic. In modern phytotherapy, P. harmala demonstrated numerous medicinal effects including cardiovascular, neurologic, antimicrobial, insecticidal, antineoplasmic, antiproliferative, gastrointestinal and antidiabetic effects. Adverse events such as neuro-sensorial symptoms, visual hallucination, bradycardia, hypotension, agitation, tremors, ataxia, abortion and vomiting cause people to use this plant cautiously. P. harmala is contraindicated during pregnancy, due to its abortive and mutagenic activities. Because of increasing the expression of CYP1A2, 2C19, and 3A4 and inhibition of monoamine oxidase, the pharmacokinetic parameters of drugs which are mainly metabolized by these enzymes may be affected by P. harmala. CONCLUSION: The medicinal properties declared for this plant in TIM are compared with those showed in modern phytotherapy. Some of the TIM properties were confirmed in modern phytotherapy like emetic and analgesic activities and some have not been evaluated in modern phytotherapy such as its therapeutic effects on paralysis, epilepsy and numbness. Finally, the current review provides the evidence for other researchers to use TIM properties of P. harmala as an efficacious natural drug. Further preclinical and clinical studies for adequate evaluating safety and therapeutic efficacy are recommended. PMID- 25842737 TI - A precise and accurate acupoint location obtained on the face using consistency matrix pointwise fusion method. AB - OBJECTIVE: To develop a more precise and accurate method, and identified a procedure to measure whether an acupoint had been correctly located. METHODS: On the face, we used an acupoint location from different acupuncture experts and obtained the most precise and accurate values of acupoint location based on the consistency information fusion algorithm, through a virtual simulation of the facial orientation coordinate system. RESULTS: Because of inconsistencies in each acupuncture expert's original data, the system error the general weight calculation. First, we corrected each expert of acupoint location system error itself, to obtain a rational quantification for each expert of acupuncture and moxibustion acupoint location consistent support degree, to obtain pointwise variable precision fusion results, to put every expert's acupuncture acupoint location fusion error enhanced to pointwise variable precision. Then, we more effectively used the measured characteristics of different acupuncture expert's acupoint location, to improve the measurement information utilization efficiency and acupuncture acupoint location precision and accuracy. CONCLUSION: Based on using the consistency matrix pointwise fusion method on the acupuncture experts' acupoint location values, each expert's acupoint location information could be calculated, and the most precise and accurate values of each expert's acupoint location could be obtained. PMID- 25842738 TI - Ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China. AB - OBJECTIVE: To explore the unique ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China. METHODS: Based on the natural life concept of "integration of universe and man", osteopathy in traditional Mongolian medicine in China uses the modern principles and methods of physiology, psychology, and biomechanics. Against this background, we explored the unique ideas, properties, and stan- dards of fracture repositioning in traditional Mongolian medicine. RESULTS: Fracture treatment with osteopathy in traditional Mongolian medicine in China is based on (a) the ideas of natural, sealed, self and dynamic repositioning of fractures; (b) the properties of structural continuity and functional completeness; (c) the standards of "integration of movement and stillness" and "force to force". CONCLUSION: The unique ideas, properties, and standards of fracture repositioning with osteopathy in traditional Mongolian medicine in China have resulted in the widespread use of such techniques and represents the future direction of the development of fracture repositioning. PMID- 25842739 TI - Epidemiological study of visual functions--refractive errors, macular degeneration and glaucoma in children in the Karst area of Opatija. AB - Authors of earlier studies examined the epidemiological characteristics of certain eye diseases: age-related macular degeneration (AMD), refractive errors and glaucoma in the area of Primorsho-goranska County (the island of Rab, Novi Vinodolshi and Delnice). It was found that the occurrence of AMD is most common on the island of Rab, followed by Novi Vinodolski and it is least common in Gorshi Kotar. This fact is associated with the intensity of solar radiation in the UV-A and UV-B fields. The highest percentage of the occurrence of glaucoma was also identified on the island of Rab. In comparison to this study, it was found that in the karst area of Opatija (Mune, Brgud, Zejane, Bresca, Zvonece, Pasjak, Sapjane and Zaluki) there is a very high incidence of glaucoma (27% suspected and 7% diagnosed glaucoma) within the indigenous population. Glaucoma does not appear among children whose parents migrated to the karst area of Opatija. Refractive errors are far less common among children of indigenous population than among the children whose parents migrated to this area. The occurrence ofAMD was not found in any child that was born and lives in this area, regardless of whether their parents are indigenous or not. This statement is very important because it confirms author's earlier statement which claims that at low exposure to solar UV-A and UV-B there is no occurrence of AMD. PMID- 25842740 TI - Discrepancy of whiteness and UV protection in wet state. AB - The incidence of skin cancer is increasing by epidemic proportions. Basal cell cancer remains the most common skin neoplasm, and simple excision is generally curative. On the other hand, aggressive local growth and metastasis are common features of malignant melanoma, which accounts for 75 percent of all deaths associated with skin cancer. In Croatia only, more than 20,000 new cases of skin cancer has been diagnosed in 2008 of which melanoma 286 new cases and 118 yearly deaths in men, and 275 new cases and 79 deaths in women population. The back sides in men and women, as well as the lower limbs in women, are the most common site for melanomas. The primary cause of skin cancer is believed to be a long exposure to solar ultraviolet (UV) radiation crossed with the amount of skin pigmentation in the population. There are indications that other parts of solar spectrum (e.g., blue light) might also have effects on skin and eyes. Most people think all clothing will protect them, but that's not the case. UV clothing can show UVprotection, but in the most cases it does not provide full sun screening properties. UV protection ability highly depends on large number of factors such are type of fiber, fabric surface and construction, type and concentration of dyestuff, fluorescent whitening agent (FWA), UV-B protective agents, as well as nanoparticles, if applied. For that reason, jeans and tightly woven fabrics offer a very good level of protection. However, on a hot summer day, those aren't the kinds of clothing people usually reach for. More often, when they are on the beach, they wear T-shirt, as well during the swimming in the sea, thinking that it will protect them. Therefore, in this paper the discrepancy of UVprotection in wet state was researched. For the purpose, FWA and UVabsorber were applied in wide concentration range to white cotton knit fabrics commonly used for T-shirts. Afterwards, the discrepancy in whiteness and UVprotection was research in distilled water as well as Adriatic Sea water. PMID- 25842741 TI - The importance of anatomical topography in nasolacrimal duct stenosis. AB - In our previous study the inclination of nasolacrimal canal in relation to Frankfurt horizontal plane has been analysed on 71 anatomically preparated human skulls by introducing the probe through canal. The results of that study showed that the alpha angle in the frontalplane was greater than 91 degrees in 27% of cases, i.e., nasolacrimal canals descend diverging in relation to the median plane and both probes are intersected on glabella. In 55% of cases, the alpha angle was less than 89 degrees and probes diverge on glabella, and in 18% of cases the canals were parallel to the median plane. In this study nasolacrimal ducts in patients were visualised with Omnipaque contrast that was injected with probe through the superior lacrimal punctum. Thereafter radiography was performed. These in vivo results confirm our previous results obtained on the skulls. Minimal individual variations of values of the angle were observed. These findings are very important inprobing of stenosis of nasolacrimal duct in infants, as the operator would not have to forcefully probe with rigid instrument through gentle infant nasolacrimal duct. Difficult and serious consequences for infants arise when directing the probe "via falsa" and that often happened in practice. The authors therefore suggest when using this old method ofprobing, that this "surgical" act should be performed with "soft" probe made of nylon or silver that is very pliable and does not lead to nasal or temporal rupture of the canal. PMID- 25842742 TI - Changes in the eyelids and conjunctiva caused by ultraviolet radiation. AB - The aim of this study was to show the frequency, sex and age distribution of eyelids skin tumor changes and degen erative changes of the conjunctiva for the period of three years (2011-2013) at the Department of Ophthalmology in Split. We analyzed the eyelids skin lesions in biopsy material at the Department of Pathology and the same were compared with the profession of the patients. In this period there were found 131 tumor changes of the eyelids. The most common tumor was the basal cell carcinoma (118) with the higher frequency in women. There were 10 squamous cell carcinomas with the equal representation among sexes and three melanomas. There were 79 female and 52 male patients. There were 299 pterygiums operated with the higher frequency in women (68.2%). Exposure to UV radiation, particulary UVB radiatiori is the most common causative factor for genetic abnormalities in cells and provoked factor in oncogenesis of skin tumors. In our research we found a correlation between changes in the eyelids and conjunctiva caused by UV radiation with the professional interest of the respondents. Due to high incidence of eyelids skin tumor changes in the population professionally exposed to UV radiation, medical professionals should be aware of the importance of the public education on the etiology of these tumors and the importance of the UVprotection. PMID- 25842743 TI - Contact lenses as the best conservative treatment of newly diagnosed keratoconus- epidemiological retrospective study. AB - Keratoconus is a progressive, non-inflammatory corneal ectasia characterized by thinning and weakening of the corneal stroma which results in its' protrusion. The onset is during puberty and progresses until the fourth decade of life. In earlier stages, good visual acuity can be provided with spectacles. With progression, contact lenses are considered to be a better therapy. Aim of this study was to determine if there is statistically significant difference between best corrected visual acuity (BCVA) obtained by spectacles and contact lenses in newly diagnosed keratoconus patients, as well as to determine which type of contact lenses provide better BCVA in keratoconus patients. We conducted a 5-year retrospective study of all 2891 patients attending our Contact Lens Department for the first time, searching for patients newly diagnosed with keratoconus. Data were obtained on gender, age, education level, treated eyes, corneal changes, keratoconus severity, BCVA with spectacles, contact lenses and best fitted contact lens type. All patients underwent standard ophthalmic exam, refractometry and keratometry have been done, followed by a spectacles correction and lens fitting. Wilcoxon signed rank test was used for statistical analysis. Results showed that of all 2891 patients examined for the first time, 137 patients (4.74%) have been newly diagnosed with heratoconus, there was male bias (72.26%), mean age 27.7 +/- 9.9 years. Most patients had high school education (51.11%), 3.70% had present corneal changes, 50.37% had mild heratoconus. Majority had keratoconus on both eyes (36.3%) or keratoconus of right eye (26.67%). There was a statistically significant difference (p<0.001) between the BCVA obtained with contact lenses (0.82 +/- 0.21 Snellen chart) rather than spectacles (0.37 +/- 0.27 Snellen chart). The best corrected visual acuity was achieved with rigid gas permeable (RGP) lenses in majority of kera- toconus eyes (51.85%), with semi-gas permeable (SGP) lenses in 43.39%, in 4.23% with polymethyl methacrylate (PMMA) lenses and with hard-soft gas permeable (GP) contact lenses in 0.53% of keratoconus eyes. We have showed that there is a statistically significant difference in BCVA achieved better with contact lenses than with spectacles. RGP lenses are most frequently used in conservative treatment of heratoconus, but SGP lenses were also shown to be a good option that gives equally satisfying final visual acuity with subjective comfortable feeling of contact lens wear. PMID- 25842744 TI - Prostate volume and urinary discomforts in elderly. AB - Occasional doubts about the real effect of the prostate volume on the urinary discomforts that elderly have been experiencing required additional assessment of these parameters. The aim of this study was to re-evaluate relationship between the urinary discomforts of the elderly and the prostate volume in comparison with age. Results of the group of 79 patients observed within one-year period were analyzed. In assessing their urinary discomforts the International Prostate Symptom Score (IPSS) was calculated, the ultrasound prostate volumetry was performed, and both of these parameters where compared with age. Statistical analysis of the results confirmed significant positive correlation between the prostate volume and age, positive correlation between IPSS and age, as well as between prostate volume and IPSS. PMID- 25842745 TI - Diagnostic accuracy of ultrasound T-staging of the urinary bladder cancer in comparison with histology in elderly patients. AB - Urinary bladder cancer (UBC) is dominantly the cancer of the elderly occurring primarily in the 6h, 7!h and 81h decade of life. The aim of this study was to evaluate diagnostic accuracy of ultrasound T-staging (UTS) of UBC in dhe group of elderly patients. In 152 elderly patients referred to transabdominal ultrasound examination in two different facilities (76 each) due to various symptoms (primarily painless gross or microscopic haematuria) UBC was diagnosed. Initial UTS at the moment of detection was performed and compared with final histological T-staging (HTS). A high level of conformity between UTS and HTS was detected. In a total of 152 patients with UBC there were 115 (75.66%) patients with complete match between the UTS and HTS, 24 (15.79%) patients with minimal variation within one stage, and 13 (8.55%) patients with one stage difference between the UTS and HTS. The best result was established for the stage T1, where the accuracy was 94.5%. In other stages the accuracy was between 84.9% and 91.8%. The Youden's index for all the stages was over 0.6. UTS has a high diagnostic accuracy, especially for stages T1 and T2. It is extremely useful tool in differentiating the superficial UBC from the muscle-invasive one, being of significant importance in planning the further treatment of elderly patients and having important role in choosing appropriate surgical approach. PMID- 25842746 TI - Transanal endoscopic microsurgery (TEM)--alternative or a method of choice in treating tumors of the rectum with appropriately selected patients? AB - TEM is an endoscopic method of operating tumors up to 18 cm of the anal verge. It enables procedures from a simple mucosectomy to en-block excisions of the whole thickness of the rectal wall. We present a study in which we evaluated surgical morbidity, mortality and recurrence rate of rectal tumors in patients treated with TEM from July 2007, up to the end of March 2014. In our Department 129 patients were treated by TEM and 123 of them (74 men and 49 women) had rectal tumors: 55 adenomas, 36 cancers in situ (Tis), 15 T1, 9 T2, 4 T3 (3 palliative, and 1 underwent salvage operation) and 4 T4 (all palliative) rectal cancers. 6/123 patients were treated with TEM after the finding of metachronic recurrences that emerged after previously performing major surgery. In 3/123 cases (2.44%) the resection margins were positive. The overall local recurrence rate was 19(15.45%)--adenoma 6/55(10.91%), Tis 4/36 (11.11%), T1 0/15 (0%), T2 4/9 (44.44%), T3 1/4 (25%), T4 4/4 (100%), respectively. In 2 patients the illness was subsequently disseminated, and in 7 patients it was widespread at the time of surgery. Nine (7.31%) patients died during follow-up due to disease dissemination. Minor com plications occurred in 24 patients (19.51%) whereas we had no major complications and no early postoperative mortality. The average postoperative hospital stay is 2.3 days. TEM is a safe and appropriate surgical treatment option for benign rectal tumors and for early-stage rectal carcinomas. TEM is also good as a palliative method, and it's useful for elderly and unfit patients. PMID- 25842747 TI - Can non-adhesive short stretch bandages change a life? AB - Venous stasis ulcers are common in patients who have a history of leg swelling, varicose veins, or a history of blood clots in either the superficial or the deep veins of their legs. The treatment is long and hard but the main aim of it is to create such an environment that allows skin to grow over an ulcer. Chronic wounds are a growing social, economical and health issue throughout the world. The purpose of this retrospective study was to establish detailed characterization of how effective a compression is in reducing the time of wound healing. A total of 176 patients with leg ulcers were included in our three years study. The measurements were taken based on the anamnesis, presenting clinical symptoms, digital photography at each dressing foam change, and, finally, wounds. During a 3 years period (2011-2013) a total of 176 patients (61 male and 115 female, 34.66% and 65.34% respectively) with different types of leg ulcers were treated at our Hospital. The average age is 68.94 years (male 68 years, female 70 years). We measured how long the patient had the wound before starting the treatment, and also how long the treatment lasted. This led us to the conclusion that compression therapy shortened the time of treatment by two thirds, compared to the usual therapy. Compression systems improve the healing of venous leg ulcers and should be used routinely regarding venous ulcers. PMID- 25842748 TI - Malignant neoplasms of breast and female genital organs (C50, C51-C58) in the Osijek-Baranja County, Croatia. AB - Breast cancer (C50) and neoplasms of female genital organs (C51-C58) represent one of the most frequent cancer groups among females in economically developed countries. The Institute of Public Health of the Osijek-Baranja County in collaboration with different county institutes provide updated information on the cancer occurrence and trends in the Osijek-Baranja County (OBC). The aim of this article is to provide information on the tendencies relating to these cancer groups in the OBC during the period from 2001 to 2009, which will be the first report on these cancer sites on a county level in Croatia. This article processes data on cancer incidence and mortality, appertaining age distribution, median age, cancer survival and length of stay in the county hospitals collected in period 1996-2010. In the OBC, the overall incidence rates of breast, cervix uteri, corpus uteri and ovary cancer were, using the EU standard population, 82.9, 13.0, 19.0 and 14.5/100,000, respectively, and are all characterized by a declining tendency in the second period except breast can- cer. The overall breast incidence rate resembles the Croatian average and way exceeds the corresponding Central and Eastern Europe incidence rates, but is still bellow the Northern Europe ones. Also, the overall mortality rates of breast, cervix uteri, corpus uteri and ovary cancer were 29.6, 5.0, 8.1 and 9.6/100,000, respectively, and are all featured by a increasing tendency. The cancer 5-year relative survival rate from breast, cervix uteri, corpus uteri and ovary cancer in period 2001-2005 amounted to 64.2%, 66.1%, 57.4% and 43.0%, respectively. The overall median ages at diagnosis of breast, cervix uteri, corpus uteri and ovary cancer totalled 61.9, 56.4, 66.4 and 60.8 years, respectively, while the median ages at death from these cancers were 68.7, 65.7, 70.3 and 67.6 years, respectively. During the entire 9-year period, the average length of stay in hospital due to breast, cervix uteri, corpus uteri and ovary cancer were 12.1, 14.8, 18.5 and 11.3 days, respectively. The length of stay in hospital decreased for all but for ovary cancer. Implementation and consolidation of women's awareness of these cancers and relating early diagnostic activities within the OBC population seem to be the most effective ways to reduce the appertaining risks and thus to encourage changes in the lifestyle. PMID- 25842749 TI - The effect of trombophilia on pregnancy outcome and IVF success. AB - Thrombophilia is a group of inherited and acquired coagulation disorders often associated with an increased risk of thrombosis. Over the last decade, inherited thrombophilia is often referred as a possible cause of recurrent miscarriages and in vitro fertilisation (IVF) failure. However, many studies in this area still give conflicting results, so the goal of our study was to determine the effect of thrombophilia on pregnancy outcome and success of IVF. The study included 38 patients with proven gene mutation for thrombophilia and 53patients without mutations. The studied parameters were age, duration of infertility, dose of gonadotropins, duration of stimulation, number of embryo transfer (ET), number of oocytes retrieved, the number of days to ET and the outcome in terms of delivery (full term or premature), ectopic pregnancy or abortion. There was no significant difference between two groups in the number of procedures performed, the number of twin pregnancies, abortions, twin miscarriages, ectopic pregnancies, births and the etiology of infertility. A statistically significant difference was found in the number of pregnancies (p=0.018) and in duration of infertility which was signifi- cantly longer in the group with thrombophilia (p<0.001). The number of abortions in homozygous PAI-1 was significantly more common (p=0.012). Procedures in natural cycle were significantly more frequent in group with thrombophila (p=0.011), so we recommend in patients with proven mutation first to start with procedures in the natural cycle, and only in case of failure to use the possibility of stimulating cycles. In conclusion, in patients on anticoagulant therapy a higher percentage of IVF failure has not been proven. Therefore, we strongly recommend the prophylactic use of low molecular weight heparin during pregnancy and screening for the most common mutations in our population, particularly in patients with a history of IVF failure and those with a long duration of infertility. PMID- 25842750 TI - Height, weight and body mass index by age and sex in children aged 4 to 6 years in Merida, Mexico, as compared to international references after normalization with LMS. AB - A cross-sectional study was done in 2006-2007 of 458 children (218 boys and 240 girls) aged 4 to 6 years (range 4.00 to 6.99 years) in Merida, Mexico. Height (cm) and body weight (kg) were measured to estimate growth; body mass index (BMI, kg/m2) was calculated to evaluate nutritional status. Results showed significant sex difference with respect to height, weight, and BMI. Increment of height and weight with age was observed. However, age difference in BMI was not consis- tent. Nutritional status was evaluated using International Obesity Task Force (IOTF) classification and BMI cut-off values showed notable rates of overweight (boys 14.41% and girls 17.75%) and obesity (boys 12.43% and girls 7.21%). Anthropometric data of height, weight, and BMI were normalized using LMS methodology and were compared with World Health Organization (WHO) growth reference data. Again, increment of height and weight with age was observed although those were lower in the present study for boys and girls than the corresponding WHO growth reference data. In contrast, mean BMI by age in the present results exceeded WHO reference data, especially above the 85th percentile. Assessment of nutritional status with reference to IOTF and WHO revealed similar trends. PMID- 25842751 TI - Treatment of congenital leg length discrepancies in children using an Ilizarov external fixator: a comparative study. AB - The purpose of this study was to evaluate the influence of intramedullary (IM) alignment used in combination with an Ilizarov external fixation on the healing index (HI) and lengthening index (LI) in the treatment of congenital leg length discrepancies (LLD). This study included 35patients aged from 3.5 to 19 (average age 10.73) who underwent thl egalisation procedure using an Ilizarov external fixator. We compared the duration of the external fixator application, LLD, HI and LI between two groups of children: children in Group I underwent limb lengthening by the conventional llizarov technique using an Ilizarov external fixator alone, and children in Group II underwent a combination of Ilizarov technique and intramedullary alignment with two Kirschner wires, introduced through two mini-incisions. We found significant differences between the two groups of patients for duration of external fixator application and HI. Patients with congeni- tal LLD treated with combined method of treatment had benefit from intramedullary alignment due to its better outcome. PMID- 25842752 TI - Virus etiology of schizophrenia: the characteristics of the "*Little Ice Age" and its consequences. AB - The data of the "Little Ice Age" (1500-1850) in Croatia and those which applied to human health were especially emphasized were analyzed. They are some which stand out like: importance of the sort of soil and relief, the influence of cutting down of woods and cattle-breeding and especially the war which lasted for 250 years in the territory of Croatia. The important interactions between those parameters were defined. The important correlations were also defined between freezing and long winters as well as wet springs and summers which caused starvation, malnutrition and the increase of infant mortality and also epidemics with enormous psychological stress among people in that period. The result was witch-hunting and burning (which was also advocated in the other parts of Europe) and they sometimes reached the levels of madness. Considering that such events were unknown in the earlier periods (in such proportions) and that (even today) the influence of the slow virus is emphasized in connection to the etiology of schizophrenia so why should't it be supposed that the "Litlle Ace Age" could be the cause of the larger prevalence of schizophrenia in the teritory of Croatia. PMID- 25842753 TI - Perception of stress, depression, hypertension and myocardial infarction as predictors of adherence to hypertension drug treatment. AB - This survey was performed to determine the relationship between the adherence to hypertension drug treatment and the perception of stress, depression, hypertension, and myocardial infarction. 300 patients with uncomplicated hyperten sion from Rijeka, Croatia, were included (131 women, 169 men, mean age 53.5 years). Adherence to hypertension drug treatment as criterion, and the perception of stress, depression hypertension and myocardial infarction as prediclors were determined by self-assessment. Collected data were analysed using factor analysis, regression analysis, Kolmogorov-Smirnov test, chi2-test and t-test. The statistical significance was set at a probability rate of less than 5% (p < 0.05). 45.09% of women (p=0.479), and 64.08% of men (p = 0.032) were motivated to take antihypertensives. 55.79% of women (p = 0.382) and 64.78% of men (p = 0.028) had sufficient knowledge about drug treatment of hypertension. The positive predictors of motivation for taking antihypertensives were physiological disturbances and perceived potency of hypertension and the negative were perceived helplessness in stress control and negative thoughts and emotions. The positive predictors of knowledge about taking antihypertensives were perceived helplessness in stress control, perceived potency of hypertension and myocardial infarction and the negative predictors were perceived self-efficacy in stress control, physiological disturbances and evaluation of hypertension. Both the motivation as well as the knowledge about taking antihypertensives should be improved, especially in women. The perception of stress, depression, hypertension and myocardial infarction can be used to predict adherence to hypertension drug treatment. PMID- 25842754 TI - Progression of conjunctival primary acquired melanosis (PAM) to widely spreaded malignant melanoma. AB - Primary acquired melanosis (PAM) is an acquired pigmentation of the conjunctival epithelium, a preinvasive pigmented lesion. When it is associated with cellular atypia it can lead to the developement of melanoma. We report a case report of malignant melanoma of the conjuntiva, which arrised from the conjuntival PAM. The disease was too extensive for ocular conservation, therefore exenteration was performed. This case highlights the need for regular follow-up of patients with melanocytic lesions of the ocular adnexa, and particular attention to the surgical technique, and careful follow-up to detect further disease activity. PMID- 25842755 TI - Vitiligo in Croatia: a case report. AB - Vitiligo is an acquired, chronic, multifactorial disorder which involves complex interactions between genetic risk factors and environmental triggers. It is characterized by scattered circumscribed depigmented macules and patches anywhere on the skin that result from loss of functional melanocytes. According to our statistical data, 1.6% of the general population in Croatia suffers from vitiligo, but varies based on region. It affects all age groups equally, with female patients being more affected (53.95%) than male patients, and no difference in severity of vitiligo. We present a case of a sudden onset of vitiligo vulgaris from a female patient in her twenties, treated at the Department of Dermatology and Venereology. Her 12-year-old brother simultaneously developed acrofacial vitiligo, six months after their mother died in a car accident. She has been previously diagnosed with type I diabetes and autoimmune endocrinopathies. The depigmented patches covered approximately 60% of her body, with Koebner response on trauma. Although no characteristic UV fluorescence was detected on the affected area, histopathological and immunohistochemical analyses revealed a complete loss of melanocytes, while Langerhans and dermal dendritic cells replaced the DOPA-positive melanocytes. TSH levels were elevated, and the ultrasound showed thyroid enlargement, which substantiated for a hypothyroidism therapy. Treatment by systemic corticosteroids for a 6 month period was successful in stabilizing the disease. PMID- 25842756 TI - Risk factors for subdural bleeding in elderly population. AB - In the elderly, a larger proportion of the intracranial bleeds is related to non traumatic causes or is caused by slight trauma--such that in a younger patient would not be expected to cause a bleed. In clinical practice, there is a prevailing impression that these bleeds, especially subdural hematomas of chronic and sub-chronic duration with or without acutization (evidence of "fresh" bleeding) are in many cases related directly to the use of anticoagulant therapy. A retrospective survey of medical documentation was performed for patients treated at the Neurosurgery Clinic of KBC Rijeka during the period of 2011 and 2012. Statistical analysis showed a significantly greater incidence of spontaneous SDH (subdural hematoma) in patients taking oral anticoagulation therapy (Fisher exact test, p < 0.01). In the article 3 typical cases of such patients are also presented. This survey confirmed the existence of a relationship between oral anticoagulant therapy and SDH, in particular the subgroup of "spontaneous" SDH. A larger study is planned. PMID- 25842757 TI - The role of negative pressure wound therapy in patients with kidney transplantation. AB - Kidney transplantation is the best treatment modality for patients with end-stage renal disease. Wound healing is impaired in these patients, and factors such as immunosuppression, older age and comorbidities have a negative impact on wound healing. Recently, negative pressure wound therapy has become an important wound management technique. We present two patients with wound healing issues in the early posttransplant period. In both patients, an imrnunosup- pressive treatment was administered, which included tacrolimus, mycophenolate mophetil and high-dose corticosteroids with anti-IL-2 induction therapy. Postoperatively, the wounds became inflamed with dehiscence. Negative pressure wound therapy was successfully applied to aid the wound healing. The treatment duration period was two weeks for one patient and three weeks for the other. After the treatment period, the wounds were significantly improved and were closed. After the secondary wound closures, the posttransplant course was uneventful in both patients. Presently, one and three years after the transplantations, both patients have well functioning kidneys. According to our limited experience, negative pressure wound therapy is a feasible and effective dehiscence wound treatment following kidney transplantation. PMID- 25842758 TI - Incarcerated diaphragmatic hernia--differential diagnoses. AB - The incarceration of diaphragmatic hernia is very rare. We present a case of a four-year-old girl who developed the incarceration of left-sided diaphragmatic hernia, who, until then, was completely asymptomatic. This incarceration of the hernia represented a surgical emergency presenting as obstructive ileus and a severe respiratory distress which developed from what appeared to be full health. During a brief pre-operative examination a number of differential diagnoses were suggested. Along with the laboratory blood analysis (complete blood count and acid-base balance) a plain thoracic and abdominal radiography was done (babygram). After that, through an inserted nasal-gastric tube, barium meal of the upper gastrointestinal tract was done, showing abdominal organs in the left half of the thorax and a significant shift of the mediastinum to the right. With an urgent upper medial laparotomy we accessed the abdominal cavity and made the correct diagnosis. An opening was shown in the rear part of the left hemi diaphragm with thickened and edematous edges, approx. 6 cm in diameter with incarcerated content. The incarcerated abdominal organs (stomach, transversal colon, small intestine and spleen) gradually moved into the abdominal cavity. The opening was closed with nonresorptive sutures (TiCron) size 2-0 with aprevious control and ventilated expansion of the well-developed left lung. In postoperative course the acid-base balance quickly recovered, as well as the general state of the patient and radiography showed a good expansion and lucency of the lung parenchyma and a return of the mediastinum into the middle part of the thorax. PMID- 25842759 TI - Less is more--possible option in the treatment of depression. AB - Depression is an illness of modern society, which affects population of different age. Etiological factors differ, and frustration factors as a cause of depression are multiplying. Each new episode presents difficulties, both for patients and psychiatrists. Despite the increasing number of antidepressants we use in treatment, it is sometimes hard to notice an efficient antidepressant in an optimal-efficient dose. In resistant cases we apply combinations of psychopharmacs, and the choice of the same depends on the leading symptoms. We will present the case of a 67-year-old patient where a depressive episode (in the terms of a reccurent major depressive disorder) lasts for one year. During this period she was treated as outpatient and inpatient with several antidepresants in combinations with other psychopharmacotherapeutical drugs. Despite regular treatment, mental state was worsening. Clinical presentation was indicating developing of dementia (behavior, cognition outges), which we excluded through diagnostic process. Psychopharmacological combinations (antidepresants, mood stabilizators, antypschotics, anxsiolotix) were not efficant. Progression of simptoms leads to rehospitalisation. In further treatmen, we followed the principle "Less is more" which resulted with an expected and satisfactory outcome. PMID- 25842760 TI - The wild boar attack--a case report of a wild boar inflicted injury and treatment. AB - Croatia is a relatively safe country in regards to wild animal attacks and trauma to humans, even though there are a few reported cases of wild animal attacks on humans almost every year. As a biodiversity hot-spot it is inhabited by a few wild animal species that are known to attack humans and cause serious, sometimes even fatal injuriCs to humans throughout the world, such as wolves, brown bears and wild boars. We present a case of a recent wild boar attack on a human--a hunter that occurred in central Croatia in the year 2012. The injured person was a part of a group of hunters involved in a drive hunt on wild boars. He sustained a 4 cm long laceration of the left knee by a wounded male wild boar. After the surgical and antibiotic treatment he recovered completely and without any complications. PMID- 25842761 TI - Comparison of 23 gauge and 25 gauge PPV in the treatment of epiretinal membranes and macular holes. AB - The aim of this study was to show the long term recovery after the operative procedure of pars plana vitrectomy (PPV) in patients with epiretinal membranes (ERM) and macular holes. We wanted to show if there is a difference in operative approach and results of 23 and 25 gauge PPV Twenty eight patients underwent to operative treatment of idiopatic ERM and macular holes grade III and IV In our study there was not a statistical significant difference in visual acuity (VA) between 23 gauge and 25 gauge operated patients, both ERM and macular holes. Although both approaches are good, morphological restitution do not always follow the functional recovery. PMID- 25842762 TI - Compliance among soft contact lens wearers. AB - Contact lens compliance is proven to be crucial for preventing lens wear-related complications because of the interdependence of the steps in lens care regime and their influence on lens system microbial contamination. Awareness of the patients' lens handling compliance as well as correct recognition of non compliant behaviours is the basis for creating more targeted strategies for patient education. The aim of this study was to investigate compliance among soft contact lens (SCL) wearers in different aspects of lens care handling and wearing habits. In our research 50 asymptomatic lens wearers filled out a questionnaire containing demographic data, lens type, hygiene and wearing habits, lenses and lens care system replacement schedule and self-evaluation of contact lens handling hygiene. We established criteria of compliance according to available manufacturer's recommendations, prior literature and our clinical experience. Only 2 (4%) of patients were fully compliant SCL wearers. The most common non compliant behaviours were insufficient lens solution soaking time (62%), followed by failure to daily exchange lens case solution and showering while wearing lenses. 44% of patients reported storing lenses in saline solution. Mean lens storage case replacement was 3.6 months, with up to 78% patients replacing lens case at least once in 3 months. Average grade in self evaluating level of compliance was very good (4 +/- 0.78) (from 1-poor level of hygiene to 5-great level of hygiene). Lens wearers who reported excessive daily lens wear and more than 10 years of lens wearing experience were also found to be less compliant with other lens system care procedures. (t = -2.99, df=47, p < 0.0045 and t = 2.33, df= 48, p < 0.024, respectively). Our study indicates that almost all patients had some degree of non-compliance in lens system maintenance steps. Most common non-compliant behaviours were the ones that are crucial for maintaining lens sterility and preventing infection. Despite the low objective compliance rate, self grading was relatively high. Therefore, these results indicate the need for patient education and encouragement of better lens wearing habits and all of the lens maintenance steps at each patient visit. PMID- 25842763 TI - Effect of the against the rule myopic astigmatism on the near vision of the elderly. AB - In the two groups of patients with myopic astigmatism the uncorrected near vision was tested after catatract surgery. Each group with 20 patients ages 60-80. All patients enrolled in study have uncorrected far vision 0.5 or better on Snellen tables. In the first group patients were with the rule after surgery myopic astigmatism (1-1.50 Diopter), and in the second group were patients with against the rule after surgery myopic astigmatism (1-1.50 Diopter). Patients in the second group with against the rule astigmatism achieved significantly (p<0.01) better uncorrected near vision. PMID- 25842764 TI - Surgical treatment of kidney cancer in elderly. AB - The aim of this study was to analyze our patients over the age of 70 suffering from kidney cancer that had undergone surgical treatment. During the 2000-2012 period 634 patients with kidney cancer were treated, 197 of whom were over the age of 70. In this group there were 117 (59.4%) men and 80 (40.6%) women. In most of these patients (156 patients--79.2%) the clear cell type of renal carcinoma was diagnosed. According to TNM classification the dominant stages were Tlb in 62 patients (31.8%) and T1a in 48 patients (24.6%). The most common grade was G2 (73 patients--37%). Radical nephrectomy was performed in 103 (52.3%) patients, simple nephrectomy in 86patients (43.7%), enucleation of the tumor and resection of the kidney in 6 (3.1%) patients, while in 2 patients the tumor was inoperable. Early postoperative compli cations developed in 21 (10.8%) patients. They included complications in distant organs in 11 (5.6%) patients and surgical complications in 10 (5.4%) patients. Five patients (2.6%) died during early postoperative period. Surgery is recommended treatment for elderly patients with kidney cancer with complications comparable with those in younger patients. PMID- 25842765 TI - Potential years of life lost due to premature mortality from cancer in Karlovac County (Croatia), 2006-2010. AB - The aim of this paper was to estimate cancer burden in the Karlovac County using potential years of life lost due to cancer and contribute to setting priorities in cancer control at the local level. Potential years of life lost (PYLL) is an important public health mortality indicator that goes into the category of social indicators and has a great role in the process of health care planning in defining priorities for the prevention of premature death. In this paper PYLL is defined as the number of years of life lost by persons who died in the age of 1 75. In the period 2006-2010 there were 4118 death in Karlovac County in the 1-75 age group which makes 48,204 potential years of life lost, where 33,856.5 (70.24%) PYLL referred to men, and 14,347.5 (29.76%) PYLL to women. Cancer was responsible for the largest proportion of premature death (33.17%), in which 62.90% of premature death referred to men and 37.10% to women. Lung cancer was the leading cause of premature death due to cancer for men (31.04% of PYLL due to cancer) and the breast cancer for women (17.95% PYLL due to cancer). In the observed period cancer caused the shortening of the average life span of 11.9 years, out of which the biggest loss was caused by melanoma (18.7 years). Population health measures based on PYLL are useful for measuring and monitoring the impact of local efforts to reduce premature mortality. PMID- 25842766 TI - Treatment of hardware infection after osteosynthesis of lower leg using negative pressure wound therapy and transforming powder dressing. AB - Fractures of the distal part of the lower leg are more common in everyday practice and traumatology. In young and active patients these injuries are mainly caused by high energy trauma. They are treated with external fixator in first step, and in second step, after sanation of the soft tissue, with open reduction and internal fixation (ORIF). It is very safe and effective method of treatment. Treatment of the infections that occur in the early postoperative period after open reduction and internal fixation represents a great problem and challenge for surgeons. It is widely accepted that the presence of deep infection can't be cured in the presence of hardware. However, removal of hardware in the presence of unhealed fractures significantly complicates sanation of infection and fracture itself We have decided to present a 35-years-old patient with a hardware infection with present chronic wound with hardware exposed eight months after the first operation and six months after second operation. The wound measured one centimeter in diameter with cell detritus and bad granulations tissue inside the wound. Hardwre was exposed in the depth of the wound.The secretion was minimal. Negative Pressure Wound Therapy (NPWT) was applicated after debridemet and lavage performed in ambulatory conditions. The starting therapy was continuously -125 mm Hg of vacuum. After five days of NPWT the defect was partially filled with granula- tion tissue. For another five days we continue with NPWT with the same values of-125 mm Hg pressure but in the inter- mitent mode. After that period we used transforming powder dressing for covering and protection of the wound with was filled with granulation tissue. Five days later, wound was completely healed with epithelisation. After four months of patient follow-up, we found the wound is completely repaired. The patient denies pain and has continued orderly flow of fracture healing, with no signs of infection. PMID- 25842767 TI - Influence of stressful life events on coping in psoriasis. AB - Outbreaks of psoriasis usually can be linked with traumatic life stress events. Stressful life events in response to psychosocial trigger have been reported to negatively affect the course of psoriasis and are regarded as preventable causes of morbidity. Aims of this study were to determine which coping strategies are mostly used in psoriatic patients and to determine if there is a difference in coping according genders, clinical stages and stress level. The result shows that denial, active coping, seeking emotional support, positive reframing and acceptance are most frequently used among psoriatic patients. In adaptive coping psoriatic patients Psoriasis Area and Severity Index (PASI) score was 16.24, in maladaptive coping psoriatic patients PASI score was 19.6. Difference between adaptive and maladaptive coping strategies in psoriatic patients according clinical stage measured by PASI score was not statistically significant. Psoriatic patients who had higher score of life stress events (461.57) measured by Life change units (LCU) used maladaptive coping statistically significant more then patients with lower life stress events score (284.71). The results point to the need of psoriatic patients to learn how to cope with stress, enabling them to change ways of coping. There is need for integrating psychological intervention into standard care protocol of chronic dermatologic disease as psoriasis. PMID- 25842768 TI - Impact of adolescents awareness on perception of sexually transmitted infections. AB - Sexually transmitted infections (STIs) are diseases transmitted by direct contact during sexual intercourse. Because of high incidence and possibility of development severe consequences on general and reproductive health, STIs are a major problem among young people in the world. Lack of information is one of the major risk factors for STI transmission. Most of young people (53.3%) had their first sexual intercourse at the age of 18 years, 67.7% of students have no knowledge about STI, 53.3% of students have already entered into sexual relations and 13% of them with more than 4partners. 31.1% of students who are sexually active was not examined by a gynecologist because of shame and fear. Most sexually active adolescents did not use contraceptives and they are not satisfied with the available information about STI. There is also continuing problem of teen pregnancy. The main goal of this research is to examine whether there is relationship between level of information and awareness of surveyed adolescents and their perception of sexually transmitted diseases. PMID- 25842769 TI - Photorejuvenation--topical photodynamic therapy as therapeutic opportunity for skin rejuvenation. AB - The intrinsic aging process of the skin in unavoidable and depends on the passage of time per se. Among harmful environmental factors that contribute to extrinsic aging, long-term effects of repeated exposure to ultraviolet radiation are the most significant and are referred to as photoaging. Photoaging is directly correlated to the quantity of UV rays received during the course of a lifetime. Topical photodynamic therapy is well-established procedure for the treatment of actinic keratoses, Bowen disease and basal cell carcinomas. Clinical experience has demonstrated that extensive treatment of actinic keratoses on sun-damaged skin also produces as a positive side effects significant improvement of the signs of skin aging. An improvement of lentigines, skin roughness, fine lines, increases in skin smoothness and improvement of actinic elastosis, skin colour and reduction of hyperpigmentation were seen. The reversible side effects of photodynamic therapy include pain, erythema, oedema, scaling and crusting, and sometimes in darker skin types post-inflammatory hyperpigmentation. Photodynamic therapy is promising approach for treatment ofphotoinduced skin aging and takes place between ablative and non-ablative methods for skin rejuvenation. Effective improvement of photoaged skin, the possibility of repeated treatments and imitated side effects makes photodynamic therapy a promising procedure for skin rejuvenation. PMID- 25842770 TI - Benefits of controlled ultraviolet radiation in the treatment of dermatological diseases. AB - Phototherapy is a second-line treatment modality for the most common dermatoses that is safe and effective. Most phototherapy regimens denote the use of ultraviolet (UV) radiation of different wavelengths in the management of several dermatoses. Currently, irradiations with broadband UVB (290-320 nm), narrowband UVB (311-313 nm), 308 nm excimer laser, UVA 1 (340-400 nm), UVA with psoralen (PUVA), and extracorporeal photochemotherapy (photopheresis) are being used. Beneficial effects of UV radiation are far from being completely understood. Dermatoses that may benefit from such approach are numerous, with psoriasis, parapsoriasis, atopic dermatitis, cutaneous T-cell lymphomas, morphea, and vitiligo vulgaris as main indications. UVB radiation primarily acts on cells at the epidermis and the epidermodermal junction, while UVA radiation affects epidermal and dermal components, especially blood vessels. UVradiation has im- mediate and delayed effects. Immediate effects are the formation of DNA photoproducts and DNA damage leading to apoptosis of heratinocytes, Langerhans cells, activated T-lymphocytes, neutrophils, macrophages, NK cells, fibroblasts, endothelial cells, and mast-cells, cell membrane damage by lipid peroxidation, and isomerization of chromophores such as urocanic acid. Delayed effects include synthesis of prostaglandins and cytokines that play important roles in immune suppression. Systemic and local immune suppression, alteration in cytokine expression (induction of interleukin-1 (IL-1) receptor antagonist, decrease in IL 2, increase in IL-IO, IL-15), and cell cycle arrest may all contribute to the suppression of disease activity. PUVA is a form of controlled and repeated induction of phototoxic reactions which uses UVA light to activate chemicals known as psoralens. The conjunction of psoralens with epidermal DNA inhibits DNA synthesis and causes cell apoptosis. PUVA also causes an alteration in the expression of cytokines and cytokine receptors. Psoralens interact with RNA, proteins and other cellular components and indirectly modify proteins and lipids via singlet oxygen-mediated reactions or by generating of free radicals. Psoralens and UV radiation also stimulate melanogenesis with variable effects in patients with vitiligo vulgaris. Extracorporealphotopheresis is treatment modality used in management of erythrodermic cutaneous T-cell lymphomas. It is very potent in induction of lymphocyte apoptosis. Despite the introduction of numerous potent bioengineered systemic medications in the field of dermatology, phototherapy remains established, and often preferred, option for the most common dermatoses. PMID- 25842771 TI - Neurosurgical procedure for treatment of traumatic subdural hematoma with severe brain injury: a single center matched-pair analysis. AB - Decompressive craniectomy (DC), an auxiliary neurosurgical invasive procedure, has been a part of the treatment regimen for severe brain injury (SBI). Today DC is the standard of care in patients with middle cerebral artery infarction. Our previous positive research results about effectiveness of DC procedure when applied to a specific group of SBIlpatients have made a solid base for a clinical evaluation of DC technique application to patients with isolated SBI with traumatic subdural hematoma (TSDH), despite controversies regarding clinical benefit of DC technique when applied to STBI patients. A matched-pair analysis has been performed to compare long-term clinical outcomes in patients with and without the DC technique applied. This study has encompassed 150 consecutive STBI patients with TSDH, aged between 18 and 82 years. One hundred patients had required application of DC procedure, while remaining 50 patients represented a matched control group in which the DCprocedure had not been applied. The control group match was conducted on the basis of epidemiological and potential prognostic factors, such as age, gender, DC surface area and Glasgow Coma Score (GCS). The main reason for occurrence of STBI with TSDH was traffic accidents, with sex ration 2:1 (male/female), while 2/3 of patients were aged between 26 and 40 years. Mortality rate of 18% had occurred in the group of patients in which DC procedure was applied early in the first 24 hours after the injury, while mortality rate of 54% had occurred in the group of patients in which DC procedure was applied later than 24 hours after the injury, in comparison to mortality rate of 35% that had occurred in the control matched group of patients. Also, better control of intracranial pressure (ICP) had occurred in patients in which a DC surface was made larger than 40ccm. In addition, less computed tomography (CT) scans were made as a follow up care procedure in patients in which DC procedure was performed and especially if DC procedure had been performed within 24 hours after the injury. However, regardless of many positive results that an early application of DC procedure has had on SBI patients with TSDH, an expected increase in immediate or delayed complications had occurred, for example we had recorded an increased number of encefalocele. Significantly better outcome of clinical recovery with less cases of morbidity and deaths had occurred in patients in which TSDH was removed with the DC technique within 24 hours after the time of injury and also if a DC surface had had size over 40 ccm, in compari- son to the group of patients that had TSDH removed with DC technique within longer period of time than 24 hours after the time of injury and also better than the control group. PMID- 25842772 TI - Periprosthetic infections after total hip and knee arthroplasty--a review. AB - Periprosthetic joint infections (PJI) in orthopedic surgery are considered to be very serious and dangerous complications of total joint arthroplasty. PJI becomes a long-lasting medical problem and a heavy burden on patient and his family. Patients with such a complication are a significant financial burden for the health care system. Recognizing this issue, investing in scientific research and simultaneously developing technologies in medicine are efforts taken to increase successfulness in preventing and treating PJI. Each year the number of total joint arthroplasties increases which entails a rise in the number of complications among which infections are the leading ones. Sometimes, in the worst case scenarios, infections can endanger patients' lives. New procedural algorithms and new diagnostic possibilities help us make accurate and early diagnoses of postoperative PJI with a great degree of certainty. These diagnostic methods include laboratory tests, imaging, histopathology and microbiological analyses. Treatment options depend on many factors which include the onset of symptoms, patients'general physical condition and type of pathogen. The approach to treating PJI is complex and it requires a multidisciplinary approach in order to ensure the most successful treatment possible. For adequate and successful treatment we need to take into account antibiotic therapy, one-stage or two-stage revision, Girdlestone operation, athrodesis and amputation. In this review we will try to sum up all relevant findings and suggest further steps in management of PJI. PMID- 25842773 TI - Endoscopic diagnostic of chronic pancreatitis. AB - Chronic pancreatitis is defined as a continuous inflammatory pancreatic disease, one characterized by irreversible morphological changes, often associates with pain and sometimes with the loss of endocrine and exocrine function. As a histological confirmation of chronic pancreatitis is often unavailable, the diagnosis is traditionally based on imaging methods such as computerized tomography (CT) or endoscopic retrograde cholangiopancreatography (ERCP), and recently magnetic resonance cholangiopancreatography (MRCP) as a noninvasive alternative to ERCP. Developments in the classification system of CP include the Marseille classification of 1963 which offered histopathologic criteria for CP, the Cambridge classification of 1984 which introduced imaging features of computed tomography (CT), transabdominal ultrasound (TUS) and endoscopic retrograde cholangiopancreatography (ERCP) for classification of CP as well as Rosemont classification system of 2007 which presented the endoscopic ultrasonography diagnosis of CP. Endoscopic ultra-sonography (EUS) was first introduced as a diagnostic method for evaluation of pancreatic disease in 1986. It has experienced significant improvements since then and allowed for an alternative approach in diagnosing patients with pancreatic diseases. In patients with suspected pancreatic masses EUS-guided fine needle aspiration (EUS-FNA) is the best method for obtaining tissue diagnosis and differentiating CP from pancreatic carcinoma. The recent studies indicate that EUS is the method of choice when compared with other imaging methods such as ERCP because it frequently provides more accurate diagnostics. The aim of this review is to discuss the findings in endoscopic diagnostics up to the present moment and to indicate advantages, limitations and possible complications along with the current recommendations in CP diagnostics. PMID- 25842774 TI - Nutrition in cancer patients. AB - Cachexia is defined as an unintended loss of stable weight exceeding 10%. Patients with advanced cachexia express anorexia, early satiety, severe weight loss, weakness, anemia, and edema. Anorexia represents the result of a failure of the usual appetite signals whereas cachexia is the debilitating state of involuntary weight loss. This syndrome, referred to as the cancer anorexia cachexia syndrome, (CACS) and usually consists of a combination of anorexia, tissue wasting, malnutrition, weight loss and loss of compensatory increase in feeding. CACS represents the result of a complex interaction between cancer growth and host response and is associated with a poor response to chemotherapy and with an increase in drug-related toxicity. In advanced cachexia (mostly in metastatic cancer and terminally disease) any interventions with nutritional suplements are ineffective. Therefore, nutritional support in the reversion of tumor cachexia and in the importance of maintaining patient weight, muscle mass, quality of life, has the exceptional importance, becouse good nutritional status of patients leads to the possibility of more aggressive and longer treatment and thus to longer survival. PMID- 25842775 TI - [Participation of the family in hospital-based palliative cancer care: perspective of nurses]. AB - The objective was to understand the perspective of nurses about the participation of the family in palliative cancer care and to analyze the nursing care strategies to meet their needs. Descriptive and qualitative research, conducted at the National Cancer Institute between January and March 2013, with 17 nurses. Elements of the Roy Adaptation Model were used for the interpretation of the data. Two categoriesemergedfrom the thematic analysis: perspective of nurses about the presence and valuation of family in the hospital; and appointing strategies to encourage family participation in care and meet their needs. This participation is essentialand represents a training opportunity for the purpose of homecare. Nurses create strategies to encourage it and seek to meet the needs. The results contribute to promote the family adaptation and integrity, in order to balance the dependent and independent behaviors, aimingfor quality of life and comfort. Further studies are neededdue to the challenges of the specialty. PMID- 25842776 TI - [Analysis of job satisfaction of the nursing staff of a primary health care unit]. AB - This was a cross-sectional, observational study conducted in an outpatient specialty district health unit in the city of Ribeirao Preto, in the southeastern Brazilian state of Sao Paulo, with the aim to analyze the job satisfaction of the nursing staff. Data were collected using the Index of Work Satisfaction (IWS), a validated instrument which was applied to 23 members of the nursing team in January 2012. Among the components of job satisfaction, participants considered Interaction to be most important, followed by Professional Status, Job Requirements, Organizational Policies, Remuneration and Autonomy. The combined mean Index of Work Satisfaction obtained was 8.29, corresponding to poor job satisfaction among the studied population, as most of the studies in the literature that used the same instrument had scores between 12 and 37. PMID- 25842777 TI - [Analysis of fall risk factors in adults within the first 48 hours of hospitalization]. AB - OBJECTIVE: To analyze fall risk factors in the first 48 hours of hospitalization and to associate them with the occurrence of falls. METHOD: Cohort study conducted at a hospital in Porto Alegre/RS, Brazil. A sample of 556 patients from an adult in-patient study population were evaluated within the first 48 hours of hospitalization for factors associated with falls, based on the Morse Fall Scale (MFS) and muscle strength, among others. RESULTS: Evidence showed that the classification of high-risk according to the MFS and, more specifically, the items history of falls, ambulatory aid, impaired gait and overestimation of walking ability, were associated with falls during hospitalization (p<=0.005). In addition to these risk factors, reduced muscle strength and visual deficit also contributed to the occurrence of this safety incident CONCLUSION: The analysis of fall risk factors in patients evaluated within 48 hours of hospitalization may contribute to minimizing these occurrences and preventing injury. PMID- 25842778 TI - [Poor self-rated health and associated factors among elderly urban residents]. AB - The purpose of this study was to examine the prevalence of bad self-rated health in the elderly and associated demographic and socioeconomic factors. This was an epidemiological, cross-sectional study. Data were collected through interviews using the BOAS (Brazil Old Age Schedule) questionnaire. The study included 573 elderly residents in the urban area of Cuiaba-MT, Brazil.The adopted measure of association was the prevalence ratio. For multivariate analysis, multiple Poisson regression was used. The prevalence of poor/very poor self-rated health was 30.9% and the associated factors were income, number of morbidities and urinary incontinence. The association of demographic and socioeconomic factors with poor/very poor self-rated health among the elderly in this study shows the need for assistance and policies that minimize the impact of these factors on the lives and health of the elderly. PMID- 25842779 TI - [Self-care among patients enrolled in a self-monitoring blood glucose program]. AB - This cross-sectional study checks specific self-care activities of patients with diabetes mellitus enrolled in a self-monitoring blood glucose program from August to December 2012 in two Primary Health Care units in the interior of Sao Paulo, Brazil.The sample was composed of 74 female and male individuals, aged 18 years old or older. The Summary of Diabetes Self-Care Activities Questionnaire was used. It contains six dimensions: general diet, specific diet, physical activity, blood glucose monitoring, foot care, medication usage, plus three items about smoking. Eight out of the 15 self-care activities were within desirable levels, namely: healthy diet, not eating sweets, blood glucose testing and as frequently as recommended, drying between toes after washing feet, and taking medications (three items).The results enabled the identification of gaps in specific self care activities among patients with diabetes mellitus. PMID- 25842780 TI - [Work ability in hospital housekeeping services and associated factors]. AB - This study aimed to measure the Work Ability Index of workers of a hospital housekeeping staff and identify the associated factors. Cross-sectional study conducted in 201 with 157 workers of the housekeeping staff of a university hospital in Rio Grande do Sul, Brazil. A questionnaire containing sociodemographic, labor and health variables and the Brazilian version of the Work Ability Index was used. As a result, 79.6% of the workers were classified as having good/great work capacity. Mild mental (31.8%) and musculoskeletal disorders (15.9%) were the most prevalent medical diagnoses. After some adjustments, the workers that did not have time for leisure showed a 2.67 times higher prevalence of having the work ability reduced (CI95%=1.23-5.82). The other variables lost their association with the outcome. Measures aimed at the maintenance of work ability and the practice of physical activity and training for postural care are indicated. PMID- 25842781 TI - [Organizational context and care management by nurses at emergency care units]. AB - The purpose of this study was to understand the meanings attributed to the organizational context and the role of nurses in care management at emergency care units.This study was based on qualitative research and the Grounded Theory methodological framework. Data were collected from September 2011 to June 2012 by means of semi-structured interviews with 20 participants from two emergency care units (UPA) in southern Brazil, divided into three sample groups. The context is marked by constraints that hinder communication and interaction between professionals and the search of assistance by patients with demands that are not resolved at other levels of care. This scenario highlights the performance of nurses in the managerial dimension of their work, who assume the responsibility for managing care and coordinating professional actions in favour of improved care practices. PMID- 25842782 TI - [Care as a commitment of all: a study in a rural settlement]. AB - This study aims to understand the perceptions of care of families living in a rural settlement in the northwestern area of Rio Grande do Sul. It is an ethnographical based qualitative field research, which has used the Observation Participation-Reflection Model for data collection, performed between February and March, 2011. The data analysis went through four steps: raw data collection and documentation, describers and indexes identification, contextual and current patterns analysis, and identification of research themes and relevant findings. The study has shown that, for the settlers who participated in the study, care is bound to their vision of world, meaning a commitment of everybody, under the collective and individual premise of improvement of their lives. It is concluded that Nursing needs to understand cultural behaviors in order to enable a congruent and holistic care. PMID- 25842783 TI - [The formation of nurses in residency programs in public and private intensive care units]. AB - This qualitative study aimed to acknowledge the importance of practice in public and private institutions in the training of nurses in residency programs. Data were collected at two hospitals between February and March 2013, through interviews. From their analysis the following categories emerged: experience of graduate nurses in residency programs in ICUs of public and private institutions and potential for learning in public and private institutions regarding the training of nurses. Differences were detected in the work process and in the profile of patients between the public and private fields, and dissociation between caring and management functions carried out by residents was demonstrated. It was concluded that the development of practices in public and private institutions provides different and complementary experiences which prepare residents for management and care activities, improve management and technical assistance skills, encourages the exercise of in-service education and, by means of surveys, the search for solutions to problems that emerge from daily work. PMID- 25842784 TI - [Nursing undergraduate education in relation to the death-dying process: perceptions in light of the complex thinking]. AB - The objective of this study was to perceive the death-dying process from the perspective of nursing students. This is an exploratory, descriptive and qualitative research study. Data were collected between June and July 2013, from three focus groups with six nursing students at a University Center located in the central region of Rio Grande do Sul, Brazil. The meetings were organized with an approach to increase discussions about the death-dying process from the perspective of the complex thinking. Data were analyzed by means of the Strategic Focal Analysis, and three categories were created: Death: a process of rupture or continuity?; Recognizing weaknesses in the undergraduate educational process; and Outlining strategies to broaden academic discussions. It is possible to conclude that the death/dying process is minimally discussed in undergraduate courses, and when it is discussed, it happens in a fragmented and disjunctive manner, without integrating it into the human living process. Descriptors: Death. Education, nursing. Attitude to death. PMID- 25842785 TI - [Spending with unnecessary complementary tests for hypertension and diabetes in health services]. AB - The aims of this study were to analyze unnecessary laboratory exams for patients with hypertension and diabetes and to check the expenditures involved.This is an exploratory-descriptive, cross-sectional study with a quantitative approach.We used data from medical records of 293 patients registered in primary units - the Family Health Center (NSF3); secondary: School Health Center (CSE); and tertiary: Hospital das Clinicas (HC) from 2006 to 2009 in a city in Southeastern Brazil. We identified a total of 9,522 laboratory tests, of which 5.97% were unnecessary. Of these, about 58% were requested by NSF3 and 42% by CSE. Results suggest there is a lack of integration among different levels of health care, which result in misallocation of resources and unnecessary spending. Descriptors: Health expenditures. Hypertension. Diabetes mellitus. Family health. Health services. PMID- 25842786 TI - [Social representations of HIV/AIDS among healthcare professionals in benchmark services]. AB - This study was based on exploratory research and a qualitative approach within the framework of the Social Representations Theory. It aims to capture the social representations of healthcare providers in relation to HIV/AIDS by describing their structure.The Free Evocations technique was applied on 86 professionals of HIV/AIDS benchmark services in Recife, Pernambuco, Brazil, from 2011 to 2013. Analysis using EVOC 2005 software showed that the possible central core is prejudice in a negative attitude dimension; in the contrast zone, chronic disease translates living with the disease. In the first periphery, treatment and disease in a clinical/biometric conception; in the second periphery, death has a imagistic and negative nature. Positive and negative elements were observed, allowing healthcare personnel to construct meaning attributed to the phenomenon and reflect on their practices. PMID- 25842787 TI - [Instruments of health literacy used in nursing studies with hypertensive elderly]. AB - This study aimed to analyze nursing research regarding the instruments used to evaluate health literacy in elderly hypertensive patients. This is an integrative literature review done in the databases LILACS, PubMed, CINAHL, Scopus, and Cochrane, in June 2013. The articles, electronically available, were selected for full-text review by nurses, who assessed health literacy of elderly with hypertension. Eight studies were selected for analysis and four different instruments were used in the research. The instruments were developed according to a methodology and they were all designed to evaluate the abilities of elderly regarding reading, numeracy, pronunciation and recognition of some health-related words. The nursing research analyzed in this study revealed the gaps in care related to measures aimed to increase patient's involvement in decision-making. Also, the instruments used for measuring health literacy showed limitations, and there is no gold standard test. PMID- 25842788 TI - [Health promotion of lesbian woman: nursing care]. AB - The aim of this study was to analyze national and international scientific literature on nursing care for lesbian women. An integrative approach was adopted to review studies from MEDLINE, LILACS, BDENF and SCOPUS databases and SciELO and Cochrane libraries using the keywords: female homosexuality, nursing care, health promotion and women's health. Studies published between 1990 and 2013 in English, Portuguese or Spanish were considered for analysis. After analyzing data, four international studies were selected, being that three were from the United States and one was from Canada. This study revealed a scarcity of Brazilian and international studies and the importance of increasing scientific literature on this topic. Descriptors: Homosexuality, female. Nursing care. Health promotion. Women's health. PMID- 25842789 TI - [Contextual analysis of gynaecological care provided to women with physical disability]. AB - This is a theoretical-reflective study that aimed to analyze the contexts associated with gynaecological care for women with physical disabilities. Discussion consisted of contextual analysis according to Hinds, Chaves and Cypress, leading to four interconnected layers: immediate, specific, general and metacontext. Analysis showed that gynaecological assistance to clients with physical disabilities is influenced by attitudinal, structural, financial and informational barriers. Other influential issues are social beliefs and stigmas and the persistence of a biomedical model, which is hegemonic in this type of assistance. Therefore, gynaecological care must be valued based on the holistic paradigm offered by a transdisciplinary team in orderto provide quality care to women with physical disabilities. PMID- 25842790 TI - Pregnancy outcomes of mothers with very advanced maternal age (40 years or more). AB - OBJECTIVE: To assess pregnancy outcomes in women at age of 40 years or more compared with those at age of 20 to 30 years. MATERIAL AND METHOD: The retrospective cohort study was conducted at Maternal Fetal Medicine Unit, Chiang Mai University, Thailand, to identify the delivery. All consecutive records between January 2002 and December 2012 were searched. Singleton pregnancies with maternal age of 20 years or older were recruitedfor study. The primary outcomes for comparison were the rates of various obstetric outcomes, such aspreterm birth, cesarean section, etc. RESULTS: During the study period, 797 women at age of 40 years or more and 18,802 women at age of between 20 and 30 years were recruited. Women in the study group had significantly higher rates of medical diseases, such as chronic hypertension or pregestational diabetes mellitus. Cesarean rate, preterm delivery, and fetal growth restriction were significantly higher in the study group. CONCLUSION: Maternal age of 40 years or more is associated with medical complications and more operative deliveries. Furthermore, very advanced maternal age is significantly associated with adverse perinatal outcomes such as abortion, preterm birth, and fetal growth restriction. This information may be useful for obstetric counseling. PMID- 25842791 TI - 24-Hour pad tests in Thai continent women. AB - BACKGROUND: Twenty-four hours pad test is a simple tool to establish the differential diagnosis between high amount of vaginal secretion and urinary incontinence, evaluate the severity, and assess the result after treatment in women with urinary incontinence problem. The normal value of 24-hour pad test has been studied in non-Thai population. However; this may be different based on race. Therefore, this value in Thai population is important. OBJECTIVE: Identify the normal value of 24-hour pad test in Thai continent women by accurately comparing pad's weight before and after use. The secondary objective was to identify the factor associating the amount of vulvo-vaginal secretion. MATERIAL AND METHOD: Continent women were screened to exclude urinary incontinence by urogenital distress inventory (UDI-6) questionnaire. Participants were requested to use pad test for 24 hours. During study period, participants were advised to do their routine as usual but avoid exercise and sexual intercourse. Participants were able to change the pads as needed and asked to put the used pad in airtight plastic bag, kept them in a sealed envelope, and sent them to the researcher at their earliest convenience. Once received, the pads were kept in airtight plastic bag and were weighed. Weights were recorded. RESULTS: Two hundred twenty continent women were eligible to participate in the present study to determine the normal value of 24-hour pad test as our reference value. The median of 24 hour pad test was found to be 1.8 g of which the 95 percentiles was 4.7 g. The high amount of vaginal secretion were affected by premenopausal status, hormonal contraceptive used, and duration after menopause less than 5 years, which these factors were associated with estrogen. CONCLUSION: The authors developed a normal value of the 24-hour pad test that could be used as reference or initial information for further evaluation and diagnosis of urinary incontinence in Thai women. PMID- 25842792 TI - Achievement of LDL-cholesterol goal with statins after an st segment elevation myocardial infarction. AB - BACKGROUND: In patients with very high cardiovascular risk, low-density lipoprotein cholesterol (LDL-C) less than 70 mg/dL or at least 50% reduction of LDL-C are recommended targets. High-dose atorvastatin has been shown to reduce death and ischemic events among patients with acute coronary syndrome. OBJECTIVE: To evaluate the proportion of STEMl patients that achieve LDL-C goal after hospital discharge from a real-world setting in Thailand To determine if the formulation of statin prescribed affected the LDL-C goal achievement. MATERIAL AND METHOD: The authors analyzed data from a cohort of patients with STEMI enrolled from June 1, 2008 through May 31, 2011. Patients who survived, were prescribed astatin on discharge and had LDL-C data at follow-up were analyzed. The formulation of statin was categorized as simvastatin or other statins (atorvastatin or rosuvastatin) group. RESULTS: Ninety-seven percent (n = 265 of 272) of patients were prescribed a statin at discharge. Of these, 216 patients had LDL-C data during a 3-month follow-up period, 75% were men, the mean age was 60.5 +/- 12.2 years old and the mean baseline LDL-C was 118.1 +/- 41.2 mg/dL. 73% (n = 157) of patients received simvastatin and 27% (n = 59) received other statins. At discharge, the median daily dose of simvastatin, atorvastatin and rosuvastatin were 20, 20 and 10 mg respectively. At follow-up, target LDL-C < 70 mg/dL or LDL-C reduction >= 50% was achieved in 30.1% (n = 65) of patients, 27.4% (n = 43) on simvastatin and 37.3% (n = 22) on other statins, (p = 0.158, simvastatin versus other statins). When stratified by the dose intensity of statin, a significantly greater proportion of patients on moderate to high intensity statin attained LDL-C goals than those on low intensity statin: (36.3% versus 24.3%, p = 0.038). CONCLUSION: Most patients with STEMI are prescribed statin therapy at discharge. Despite this, the target LDL-C is attained in a minority of the patients due to suboptimal statin dosing. The formulation of statin did not affect LDL-C goal attainment. High-dose statin therapy is underused in real-world clinical practice. These findings emphasize the opportunities to improve outcomes of STEMI patients with evidence-based therapies. PMID- 25842793 TI - Clinico-pathological correlation of severe tubulointerstitial fibrosis in glomerular diseases. AB - BACKGROUND: Renal histopathology is the best method available to assess chronicity ofglomerular diseases. However renal biopsy is an invasive procedure and is available only in medical schools or tertiary-care hospitals in Thailand. Clinical predictors that discriminate the chronicity index of renal pathology may be valuable for the best timing of biopsy. The authors conducted this study to identify the clinical parameters of severe fibrosis in glomerular diseases. MATERIAL AND METHOD: The authors retrospective analyzed all consecutive patients with glomerular diseases who underwent ultrasound-guided renal biopsy in Siriraj Hospital between 2008 and 2010. The patients were statified according to degree of tubulointerstitial fibrosis (IF) into mild to moderate group (IF < 50%) and severe group (IF >= 50%). Data of clinical and radiological parameters which relate to severe fibrosis were obtained. Formula for prediction of advanced IF was also developed by backward stepwise logistic regression analysis. The authors also validated the model by application to the patients who underwent kidney biopsy in our center between 2011 and 2012. RESULTS: Of a total 682 patients, 169 patients (24.8%) were classified as a severe IF group. In the multivariate model, higher serum creatinine, lower mean length of both kidneys and systolic blood pressure (SBP) of more than 140 mmHg were significantly related to severe IF All three factors were incorporated into apredictive model: e(x)/(1 +e(x)) while x = 1.3 + (0.6 x serum Cr in mg/dl)--(0.4 x mean length of both kidneys in cm)+(0.7 x 1 if SBP >= 140 mmHg or 0 if < 140 mmHg). The formula had AUROC of 0.82 and if calculated probability of fibrosis is higher than 0.37, it yields 90% specificity and 44% sensitivity for the prediction ofsevere fibrosis. When applied to 523 patients who underwent renal biopsy in 2011 and 2012, the sensitivity was 65.6% while specificity was 87.8%. CONCLUSION: High serum creatinine, presence of HT and decreased mean length of both kidneys are important clinical markers to predict renal fibrosis. The model constructed from these factors could be used in clinical practice for appropriate decision making. PMID- 25842794 TI - Hemodynamic effect of iloprost inhalation and oral sildenafil during acute vasoreactivity test in pulmonary arterial hypertension. AB - BACKGROUND: The vasoreactivity test is usually performed to identify pulmonary arterial hypertension (PAH) patients who may benefit from long-term calcium channel blocker (CCB). The first and most commonly used agent is intravenous epoprostenol. A few other agents such as intravenous adenosine and inhaled nitric oxide are also used. In Thailand, epoprostenol is not available and the others are costly. Therefore, inhaled iloprost or oral sildenafil may be alternatives to test vasoreactivity. OBJECTIVE: To evaluate the hemodynamic effect and response rate of inhaled iloprost and oral sildenafil during acute vasoreactivity test in PAH patients. MATERIAL AND METHOD: In this retrospective descriptive study, the authors recruited patients with idiopathic PAH (IPAH) or PAHassociated with connective tissue disease (PAH-CNT) seen at the Medicine department Siriraj Hospital between January 2005 and December 2011 for whom acute vasoreactivity test was indicated. All patients used 20 microgram of inhaled iloprost via Delphinus(r) nebulizer for the test. Hemodynamic parameters were recorded before and after iloprost administration. Eight of those patients subsequently had a repeated test using 100 mg of oral sildenafil. RESULTS: Fifteen patients had acute vasoreactivity testing. Eleven patients were IPAH and four were PAH-CNT Using ESC/ERS guidelines criteria for responsiveness to vasoreactivity test, the response rate was 13% (2 out of 15 patients) using inhaled iloprost. Hemodynamic change was seen as early as five minutes after the inhalation and the effect lasted up to 35 minutes. The response rate was 25% (2 out of 8 patients) using oral sildenafil. Hemodynamic change was seen as early as 30 minutes after sildenafil ingestion and lasted up to 480 minutes. CONCLUSION: Inhaled iloprost can be used for acute vasoreactivity test in Thailand. The hemodynamic parameters should be recorded immediately after iloprost inhalation. Oral sildenafil, however, is not a suitable agent for acute vasoreactivity test due to its extended effect. PMID- 25842795 TI - Pilot study of a non-return catheter valve for reducing catheter-associated urinary tract infections in critically ill patients. AB - OBJECTIVE: To determine the effectiveness of a non-return catheter valve vs. the standard urine bag for prevention of catheter-associated urinary tract infections (CAUTI) in critically ill patients. MATERIAL AND METHOD: This was a pilot, randomized, stratified, open-label controlled trial (ClinicalTrials.gov, number NCT01963013). Ninety-six critically illpatients requiring indwelling urinary catheter were assigned with either a non-return catheter valve or the standard urine bag. Symptoms and signs of CAUTI before and after enrollment for all patients were recorded. If CAUTI was suspected, urine for microbiological testing was collected The primary outcome was the incidence density rate of symptomatic CAUTI and bacteriurial presence. RESULTS: The 96 patients were randomized into two groups. Baseline patient characteristics were similar in both groups except for the sex distribution. The incidence rate ratio was 0.71 for symptomatic CAUTI in the non-return catheter valve group (95% CI 0.25-1.98, p-value = 0.51). The crude incidence rate ratio of bacteriuria in the non-return valve group was 0.66 (95% CI 0.3-1.46, p-value = 0.31). The sex-adjusted incidence rate ratio of bacteriuria in the non-return catheter valve group was 0.64 (95% CI 0.29-1.41, p value = 0.27). CONCLUSION: Using a non-return catheter valve might not prevent CA UTI among critically ill patients. PMID- 25842796 TI - Relationship between Cardio-Ankle Vascular Index (CAVI) and Obstructive Sleep Apnea (OSA). AB - BACKGROUND AND OBJECTIVE: A non-invasive test called Cardio-Ankle Vascular Index (CA VI) measures aortic stiffness, which is an early sign of atherosclerosis. Obstructive sleep apnea (OSA) has a close association with cardiovascular mortality and morbidity. We sought to assess the relationship between OSA and arterial stiffness. MATERIAL AND METHOD: Seventy-one patients with OSA (apnea hypopnea index AHI >= 5, mean age 51.5 +/- 14.1 years, 27 females) and 11 controls (AHI < 5, mean age 56.8 +/- 11.8 years, 5 females) were enrolled in the study. In all subjects, arterial stiffness (CAVI) was performed and recorded along with blood pressure, pulse pressure of brachial arteries, and ankle arteries. RESULTS: The demographic data of the patients with OSA and controls were not significantly different. Subjects with OSA demonstrated higher values ofmean ankle artery pulse pressure than the controls (73.1 +/- 14.6 vs. 59.6 +/- 6.1 mmHg, respectively), but arterial stiffness and CAVI had no statistically significant difference (7.47 +/- 1.68 vs. 7.25 +/- 1.61, respectively). CONCLUSION: There was no relationship between arterial stiffness CAVI, and the presence of OSA. However; there was a significant association between ankle artery pulse pressure and the presence of OSA. PMID- 25842797 TI - The Thai version of the Montreal Children's Hospital Feeding Scale (MCH-FS): psychometric properties. AB - OBJECTIVE: To standardize and evaluate the psychometric properties of the Thai version of the Montreal Children's Hospital Feeding Scale (MCH-FS). MATERIAL AND METHOD: The MCH-FS was translated and the cultural effects of the Thai version (Thai.MCH-FS) were reviewed. Caregivers of 200 children between the age of12 and 48 months were interviewed and completed the Thai.MCH-FS. In addition to demographic information, each child had a physical exam and anthropometric measures were taken. Each child was classified with or without feeding problems by at least two of three pediatricians who were blind to the results of the feeding scale. RESULTS: Internal consistency for reliability was high (Cronbach's alpha at 0.835). The area under the ROC curve was 0.864. With a discrimination score of 40, both sensitivity (72%) and specificity (80.67%) were at acceptable levels. Factor analysis resulted in three factors accounting for 52.3%. Of the 200 children, 150 children were classified with nofeedingproblems and 50 with feeding problems. There were no significant differences in the characteristics of the two groups; however the Thai.MCH-FS scores were significantly different for the two groups. CONCLUSION: The Thai version of the MCH-FS has been shown to be a valid and reliable short scale for detecting feeding problems in a pediatric care setting. PMID- 25842798 TI - Predictive factors of the outcome and intraventricular rupture of brain abscess. AB - OBJECTIVE: To identify the significant factors predicting afavorable outcome and to study clinical characteristics and identify the factors predicted by intraventricular rupture of brain abscess (IVROBA). MATERIAL AND METHOD: In the retrospective study, the computer-based medical records of patients of a tertiary care hospital between 1999 and 2013 were reviewed. Univariate and multivariate analyses were used to determine the significant factors predicting the outcomes and IVROBA. RESULTS: One hundred fourteen patients with brain abscesses were enrolled. The predictivefactor of a favorable outcome was Glasgow Coma Scale (GCS) score 13 to 15 (OR 14.64; 95% CI 2.70-79.34; p = 0.02). Conversely, the factors associated with an unfavorable outcome were fungal brain abscess (OR 40.81; 95% CI 3.57-466.49; p = 0.003) and IVROBA (OR 5.50; 95% CI 1.34-22.49; p = 0.017). Moreover greater distance of the brain abscess from the ventricle decreased the IVROBA (OR 0.62; 95% CI 0.45-0.87; p = 0.005). Abscesses with intraventricular rupture that were at less than 7 mm of a ventricle (p < 0.000) were likely to IVROBA. CONCLUSION: The outcome of a brain abscess depends on good clinical status, pathogens, and fatal complication of lVROBA. If poor prognostic factors exist, then better surgical option can be selected. PMID- 25842799 TI - R.E.N.A.L. nephrometry score in clinical stage T1 renal mass: Ramathibodi hospital experience. AB - OBJECTIVE: The main treatment strategies for clinical stage T1 renal mass are radical nephrectomy (RN) and partial nephrectomy (PN). Treatment decision depends largely on tumor complexity as assessed by the R.E.N.A.L. nephrometry scoring system. The authors evaluated our experience with R.E.N.A.L. nephrometry score in all patients who underwent surgery. MATERIAL AND METHOD: The authors evaluated 61 patients who presented with clinical stage T1 renal mass and underwent radical or partial nephrectomy between 2007 and 2013 at Ramathibodi Hospital. Tumor complexity was quantified by R.E.N.A.L. nephromety score in all patients using preoperative imaging. Statistical analysis was done to study associations. RESULTS: Sixty-one patients were included in this study, which 34 (55.70%) were male and 27 (44.30%) were female. The most common pathologic report was clear cell renal cell carcinoma followed by angiomyolipoma and papillary renal cell carcinoma. Forty-one patients underwent radical nephrectomy, of whom three, 25, and 10 patients had low, moderate, and high tumor complexity respectively. Twenty patients underwent partial nephrectomy, of whom 10 patients had low tumor complexity and 10 patients had moderate tumor complexity. No patient had high tumor complexity. In the present study, the function coefficient showed that radius had the most influence on surgical decision-making,followed by nearness to collecting system, exophytic/endophytic, and location. We also developed the Ramathibodi equation to help selecting the proper operation. CONCLUSION: The R.E.N.A.L. nephrometry score is a feasible and standardized classification system for evaluating renal masses. It could be used to stratify tumor complexity and may help for surgical decision-making. PMID- 25842800 TI - Appropriate size and angulation for axis screw placement. AB - BACKGROUND: A screw larger than 4.0-4.5-mm-diameter screw has now become the preferred sizefor providing maximum anchorage during atlantoaxial segmental fixation and transarticular screw fixation. At present, there are no studies available of Axis (C2) morphology related to screw placement specifically in Thai patients, a situation that might result in surgical complications. OBJECTIVE: The purpose ofthis study was to determine the typical width, height and angulations in both C2 pars interarticularis and C2 pedicle in Thai population. MATERIAL AND METHOD: A radiographic-based study was conducted in 54 Thai patients aged over 20 from July 2011 to January 2012 in Chiang Mai University Hospital. C2 parameters including the height, width, medial angulation and superior angulation of the pars interarticularis and the pedicle were measured by using a CT scan. Allparameters were measured using the ONIS 2.3 program. RESULTS: The C2 pedicle in Thais was found to have a mean width of 5.47 mm (range 3.28-6.81 mm), a height 7.54 mm (5.9-9.54), a superior angulation of 27.54 degrees (range 20. 65 degrees -33.95 degrees ), and a medial angulation of 38.95 degrees (range 28.07 degrees 52.85 degrees ). C2 Pars interarticularis had a mean width of 7.72 mm (range 5.93 10.61 mm), a height of 4.47 mm (range 2.33-6.3 mm), a superior angulation of 49.85 degrees (range 41.89 degrees -58.65 degrees ), and a medial angulation of 6.76 degrees (range 1.18 degrees -13.5 degrees ). CONCLUSION: Because the mean height of pars interarticularis is 4.47 mm, atlantoaxial arthrodesis should not use 4.5-mm-diameter screw, especially transarticular screws, due to the possibility of vascular and nerve damage. PMID- 25842801 TI - Locking plate fixation of proximal humeral fracture: minimally invasive vs. standard delto-pectoral approach. AB - OBJECTIVE: To evaluate the results of surgery of proximal humeral fractures using the MIPO technique and to compare that with the results of surgery using the traditional approach. MATERIAL AND METHOD: All PHILOS-plate osteosynthesis operations for two and three part proximal humeral fractures conducted at Chiang Mai University Hospital between January 2010 and December 2011 were evaluated retrospectively. Operative time, blood loss, mean fracture union time, and rate of axillary nerve injury were recorded for each patient. RESULTS: The records of twenty-eight consecutive osteosynthesis operations were reviewed and the patients were divided into two groups. Group A included 12 patients (4 males, 8 females, mean age 52 years) who were treated by MIPO. Group B included 16 patients (8 males, 8 females, mean age 62 years), who were treated using the conventional approach. The mean operative time in group A was 80 minutes (range 55-185), and in group B 110 minutes (range 90-180) (p = 0.059). The mean blood loss in group A was 87.5 +/- 42.0 ml, and in group B was 128.1 +/- 65.8 ml (p = 0.073). The mean length of hospital stay in group A was 5.7 +/- 1.7 days, and in group B was 8.4 +/- 4.3 days (p = 0.091). The mean fracture union time in group A was 12 weeks (range 10-24), and in group B was 20 weeks (range 12-28) (p = 0.002). Axillary nerve injury rates were not different between the two groups. CONCLUSION: Compared to conventional techniques, MIPO offers the advantages of significantly shorter time tounion, less blood loss, shorter operative time, and a shorter hospital stay. PMID- 25842802 TI - Second hip fractures at Chiang Mai University Hospital. AB - BACKGROUND: Hip fractures are a major public health problem. Patients who have suffered a hip fracture have an increased risk of a subsequent hip fracture. This study examines the incidence ofsecondhip fractures and attempts to identify underlying risk factors. OBJECTIVE: To examine the incidence ofsecond hip fractures in osteoporotic patients at Chiang Mai University Hospital and to identify risk factors related to second hip fractures. MATERIAL AND METHOD: A retrospective review was conducted of all low-energy mechanism hip fracture patients admitted during 2008 and 2009. Analysis of second hip fractures was conducted using survival analysis and logistic regression analysis. RESULTS: A total of 191 patients were observed for 391.68 person-years (mean 2.05 person years per patient). Among that group, nine second hip fractures were identified, an overall incidence rate of 0.023 second fractures per person-year. Second hip fractures tended to occur within the first year following an initial hip fracture. There were no significant differences related to either gender or comorbid medical conditions. Logistic regression analysis revealed that increased risk of a second hip fracture was associated with age (highest between 80 to 89 years) and patients who were not treated for osteoporosis following their initial fracture. CONCLUSION: The incidence of second hip fractures at Chiang Mai University Hospital was 0.023 per person-year Careful follow-up of older patients, especially those over 80, and treatment ofosteoporosis with bisphosphonate plus vitamin D and calcium supplements was correlated with a reduction in the incidence of second hip fractures. PMID- 25842803 TI - Anatomical relationship between the deep peroneal nerve and the anterolateral surface of the tibia in Thai cadavers. AB - BACKGROUND: The deep peroneal nerve innervates muscles of the anterior leg compartment and the dorsum of the foot, and also receives sensation from the first interdigital cleft of the foot. Along its course in lower part of the leg, this nerve is very close to the anterolateral surface of the tibia and might be vulnerable to injury in fractures of the tibia or during surgery. OBJECTIVE: The objective of this study is to clarify the relationship between the deep peroneal nerve and anterolateral surface of tibia. MATERIAL AND METHOD: Variations in the course of the deep peroneal nerve related to the anterolateral surface of tibia were investigated by dissection of 82 legs from 45 fresh cadavers. The distance by which the deep peroneal nerve was directly contacted to the tibia was measured and compared to the length from the tibial tuberosity to the medial malleolus. The length of that association, as a percentage ofthe distance from the tibial tuberosity to the medial malleolus, was calculated. RESULTS: The fraction of the distance along which the deep peroneal nerve was in direct contact with the anterolateral surface of the tibia as a percentage of the distance between the tibial tuberosity and the medial malleolus ranged from 40.38% to 84.11%, with an average of 64.87% (95% confidence interval: 63.23-66.52%). In the majority of the legs studied (52.44%), the percentage range between 60-70%. CONCLUSION: An majority of the deep peroneal nerve was directly in contact with the anterolateral surface of tibia and ranged from 60-70% of the distance between tibia tuberosity and medial malleolus. Surgical incision along this area should be carefully performed. PMID- 25842804 TI - Warfarin related nephropathy: the first case report in Thailand. AB - Warfarin is the most prescribed oral anticoagulant. Adverse renal effect from warfarin therapy are uncommon and Thailand is not acquainted. Warfarin-related nephropathy (WRN) is a newly recognized complication of warfarin treatment, especially in patients with chronic kidney disease. The authors hereby report a 56-year-old man who developed gross hematuria and severe acute kidney injury (AKI) necessitating hemodialysis, following supra-therapeutic INR level. Renal pathology revealed extensive intratubular obstruction with red blood cell casts. From the literature, there were only twelve case reports of WRN, which were confirmed by renal histopatology. Renal survival of this condition was unsatisfactory. However, our patient was dialysis-independent after vitamin K treatment and temporary warfarin discontinuation. To the best of our knowledge, this is the first case report of biopsy-proven WRN in Thailand. PMID- 25842805 TI - [Discussion meeting on the perspective of the Japanese Society of Internal Medicine and Japan Surgical Society]. PMID- 25842806 TI - [Future of the annual meeting of JSS]. PMID- 25842807 TI - [Introduction of new journal: surgical case reports]. PMID- 25842808 TI - [Introducing the topic of junctional cancer]. PMID- 25842809 TI - [What is the esophagogastric junction?]. AB - The esophagogastric junction is a muscle, not a mucosal, junction. The boundary of the esophagus is at the upper esophageal sphincter and lower esophageal sphincter (LES) at the oral and anal ends, respectively. The distal end of the LES is the esophagogastric junction. Fine palisade vessels occur in the mucosa above the LES, and the esophagogastric junction is at the distal end of this palisade zone. The esophagogastric junction is defined as the part changing into the lumen seen in radiographic, examination or in surgically resected specimens. It is extremely difficult to identify the esophagogastric junction pathologically, requiring special effort. PMID- 25842810 TI - [Endoscopic therapy for cancer of the esophagogastric junction]. AB - In Japan, the criteria for cancer of the esophagogastric junction (EGJ) are that the center of the lesions are located within 2cm from the EGJ orally and anally. The main histology of these lesions are squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma of the esophagus is treated following the guidelines published by the Japan Esophageal Society. This paper focuses on EGJ adenocarcinomas, which include cardiac gastric cancer and Barrett's cancer originating from the short-segment Barrett's esophagus. EGJ cancer is resected endoscopically at the termination of the palisade vessels or upper end of the gastric fold. The various types of cancer involving the EGJ are treated following the guidelines published by each medical specialist society in Japan. The main endoscopic treatment is endoscopic submucosal dissection. The EGJ is a narrow space, and therefore lesions are approached from the oral approach or anal approach using a reverse endoscope. Bleeding, perforation, and stenosis are major complications. When two-thirds or more of the wall is resected, stenosis occurs. Endoscopic therapy for cancer originating in the EGJ has not yet been fully established. PMID- 25842811 TI - [Esophagogastric junction cancer in the TNM classification]. AB - The current 7th version of the TNM classification newly defines esophagogastric junction cancer as cancer invading the junction, of which the epicenter is located within 5cm proximal or distal to the junction. Progression of tumors is newly staged in this version of the TNM classification by separating adenocarcinoma and squamous cell carcinoma. The background to this revision was to resolve the confusion that occurred when classification of cancer of the esophagus or stomach was left to the judgment of the physician in the 6th version, to acknowledge that the prognosis of gastric cancer patients differs depending on tumor location, and to reflect the rapid increase in the incidence of adenocarcinoma of the cardia and lower esophagus in the USA. Siewert classification is reflected in the definition of esophagogastric junction cancer. The new classification appears appropriate for esophageal squamous cell carcinoma and Siewert type I adenocarcinoma, but there is doubt about type II and type III adenocarcinomas. German, Korean, and Japanese surgeons have investigated which classification of esophageal or stomach junction cancer was better for predicting patient prognosis, and the Japanese report demonstrated that its classification as stomach cancer was more appropriate. PMID- 25842812 TI - [Optimal surgical approach for esophagogastric junction carcinoma]. AB - Esophagogastric junction (EGJ) carcinoma, representing carcinoma involving the anatomical border between the esophagus and stomach, has attracted considerable attention recently because of the marked increase in its incidence. In patients with cancer of the EGJ, comparable outcomes have been obtained with extended esophagectomy and total gastrectomy, and therefore the optimal surgical approach for EGJ tumors remains to be clarified. According to retrospective studies, nodal metastases are frequent in pericardial nodes (no. 1 and no. 2), the lesser curve node (no. 3), and along the left gastric artery node (no. 7), followed by the lower mediastinal paraesophageal node (no. 110) and suprapancreatic nodes (no. 8a, 9, 11p). Nodes along the distal stomach are rarely involved, and therefore total gastrectomy seems unlikely to be justified for prophylactic lymphadenectomy for EGJ carcinoma. Subgroup analysis showed that neither esophagectomy via right thoracotomy nor left thoracoabdominal extended total gastrectomy offered a survival benefit over the transhiatal procedure in Siewert type II carcinoma. Patients with nodal involvement are at high risk of systemic recurrence, and therefore perioperative adjuvant therapy may be as important as the extent of resection in this tumor entity. PMID- 25842813 TI - [Advantages and pitfalls of minimally invasive surgery for esophagogastric junction tumors]. AB - Several studies of minimally invasive esophagectomy (MIE) for esophagogastric junction (EGJ) tumors have been reported from Western countries with high incidences of lower esophageal cancer. Less invasiveness and a better quality of life after MIE compared with open esophagectomy were found in a randomized controlled trial in Europe. On the other hand, as laparoscopic total gastrectomy for upper gastric cancer has gradually become more common, laparoscopic transhiatal resection and reconstruction to treat EGJ tumors have been reported in Japan. Some potential benefits of laparoscopic total gastrectomy for upper gastric cancer, such as less blood loss and fewer complications, were indicated in comparative studies. Therefore, similar benefits are also expected for EGJ tumors, although there is no current evidence for this. It is difficult to determine which minimally invasive approach is better because the appropriate approach and extent of resection may differ depending on the location and size of each tumor. For the minimally invasive approach to the treatment of EGJ tumors to be accepted as an option, a safe reconstruction method with good long-term quality of life needs to be established. PMID- 25842814 TI - [Adjuvant treatment for esophagogastric junction cancer]. AB - Conducting clinical trials to establish evidence of the benefits of adjuvant treatment for resectable esophagogastric junction (EGJ) cancer is difficult because it is a very rare disease compared with gastric or esophageal cancer. In the West, where esophageal cancer occurs more frequently than gastric cancer, a phase III trial (the CROSS trial) demonstrated the efficacy of preoperative chemoradiotherapy using carboplatin plus paclitaxel for patients with esophageal or EGJ cancer. Thus, this preoperative regimen is considered to be the standard adjuvant treatment for resectable EGJ cancer in the West. On the other hand, the Western evidence is not widely accepted in Asia because there are many differences in surgical techniques, particularly in the field of lymph node dissection, between the West and Asia. The standard adjuvant treatment for resectable EGJ cancer in Asia is postoperative chemotherapy using S-1 alone or capecitabine plus oxaliplatin based on the results of two large-scale phase III trials in gastric cancer conducted in East Asia. The incidence of EGJ cancer has recently increased in Japan, and nationwide studies to develop more effective adjuvant treatment for resectable EGJ cancer should be conducted in the near future. PMID- 25842815 TI - [An essay about new therapies for the anorectal dysfunction]. PMID- 25842816 TI - [Sacral neuromodulation]. PMID- 25842817 TI - [What we can learn from a case of medical malpractice--physician at the secondary emergency facility held liable for medical negligence for the death of a patient transported to the facility for an automobile accident]. PMID- 25842818 TI - [Anatomy and ablation of the coronary sinus and the mitral valve annulus]. PMID- 25842819 TI - [Review of the health technology assessment on surgeries in Japan]. AB - Health Technology Assessment (HTA) is the systematic evaluation to measure the value of new health technologies. It improves the quality of choices on hand for cost-effective health technologies that are considered valuable. Japan has built a society of longevity consisted of the institution of the universal health care system, which is financially unsustainable. In Japan, no independent HTA organization has been publicly established but the government is contemplating implementation of such system. To advance the usage of HTA into surgery, we need to establish methods for evaluating new surgical technologies with steep learning curves. The promotion of clinical researches is also essential, especially by taking advantage of observational studies from medical big data such as the Japanese nationwide database which has more than four million surgical cases registered. In addition, we need more clinical information regarding each surgical patient's quality of life and socioeconomic status. The countries already introduced HTA into their health care system have measures to solve the problems that arose and have developed necessary evaluating methods. To introduce and promote HTA in Japan without taking away the benefit of our current healthcare, it is required that surgeons collaborate with other specialists such as methodologists and health economists. PMID- 25842820 TI - [Issues related to national university medical schools: focusing on the low wages of university hospital physicians]. AB - University hospitals, bringing together the three divisions of education, research, and clinical medicine, could be said to represent the pinnacle of medicine. However, when compared with physicians working at public and private hospitals, physicians working at university hospitals and medical schools face extremely poor conditions. This is because physicians at national university hospitals are considered to be "educators." Meanwhile, even after the privatization of national hospitals, physicians working for these institutions continue to be perceived as "medical practitioners." A situation may arise in which physicians working at university hospitals-performing top-level medical work while also being involved with university and postgraduate education, as well as research-might leave their posts because they are unable to live on their current salaries, especially in comparison with physicians working at national hospitals, who focus solely on medical care. This situation would be a great loss for Japan. This potential loss can be prevented by amending the classification of physicians at national university hospitals from "educators" to "medical practitioners." In order to accomplish this, the Japan Medical Association, upon increasing its membership and achieving growth, should act as a mediator in negotiations between national university hospitals, medical schools, and the government. PMID- 25842821 TI - [Molecular basis of Parkinson's disease linked with mutations in the LRRK2 gene]. AB - Parkinson's disease (PD) is a common neurodegenerative disorder. Disease symptoms correlate with the degeneration of dopaminergic neurons in substantia nigra pars compacta. A number of factors are supposed to take part in PD pathogenesis including alpha-synuclein aggregation, oxidative stress, mitochondrial dysfunction and apoptosis, although the precise molecular mechanism of neudegeneration remains unknown. PD is generally a sporadic neuro- logical disorder, however, rare monogenic forms have been described during previous 15 years. Despite of the fact that mutations in the leucine-rich repeat kinase (LRRK2) gene are the most common cause of inherited forms of PD known today, the mechanisms by which mutations in the LRRK2 gene lead to disease remain unclear. It's difficult to understand the signaling pathways, regulated by LRRK2 in the absence of its clear physiological substrates. The G2019S substitution was shown to be the most common in mutations' spectrum of the LRRK2 gene in different populations which makes it easier to reveal patients with LRRK2-associated PD. In this review LRRK2 influence on protein aggregation, cytoskeletal dynamics, apoptosis rate and inflammatory response is discussed. Groups of patients with inherited forms of PD with known etiology are worth to be included into investigations. It could promote our un- derstanding of the mechanisms of neurodegeneration in more common sporadic cases. PMID- 25842822 TI - [RNA editing. The classical cases and the outlook of new technologies]. AB - This article provides an overview of studied RNA editing cases and the examples of RNA editing investigations that apply to different experimental data. Typical RNA editing site prediction errors and the methods to minimize them are shown. The outlook of up-to-date technologies and further RNA editing studies are discussed. PMID- 25842823 TI - [Dead-box RNA helicases in animal gametogenesis]. AB - This review analyzes and summarizes a current knowledge about a role of RNA helicases in the development and maintenance of gametogenesis of eukaryotic organisms. Here we focused on three representatives of RNA helicase family containing the characteristic motifs in the amino acid sequence (DEAD-box) and carrying substantial and conservative functions in the germinal tissues of various species from drosophila to human. There are such proteins as Vasa/DDX4, BelIe/DDX3 and Spindle-E/TDRD9. They are involved in a wide range of activities that are associated with the regulation of transcription, splicing, nuclear export, and especially with the initiation of translation. The expression of genes required for the gametogenesis appears to be regulated mainly at the translational level. RNA helicases are involved in the formation of cytoplasmic RNP granules and in the implementation of gene RNA-silencing. "DEAD-box RNA helicases" that carry highly homologous central domain, which determines their basic biochemical activity in the ATP-dependent unwinding of short RNA duplexes, perform the essential and non-overlapping functions in the germinal tissues. PMID- 25842824 TI - [Structure, function, and biosynthesis of thiazoleoxazole modified microcins]. AB - Recent advances in a large-scale genome sequencing and data analysis led to discovery of a large number of diverse ribosomally-synthesized posttranslationally-modified natural products. One bourgeoning family of such compounds, characterized by the presence of thiazole and oxazoleheterocycles derived from cysteine and serine residues, is referred to as thiazoleoxazole modified microcins. This review brings together known information about classification, structure, and biosynthesis of thiazole-oxazole modified microcins, their biological activity and potential applications. PMID- 25842825 TI - [Frequency of CHEK2 gene mutations in patients with breast cancer from the Republic of Bashkortostan]. AB - Several studies have shown, that mutation in CHEK2 gene can increase the risk of different cancers, including breast cancer (BC). Clearly, that character of mutations distribution in the defined regions is depended on genetic structure of the population. We conducted the screening of mutations c.1100delC, c.444 + 1G>A, de15395, p.I157T andIp.R145Win CHEK2 gene in patients with breast cancer (n = 977) and in control group (n = 1069) originating from the Republic of Bashkortostan. The mutation de15395 in CHEK2 gene was detected with frequency of 1,23% (12/977)in woman with BC and 0.09% (1/1069) in controls (OR:13.28, CI 95%: 1.72-102.33, p = 0.003). Mutations c.1100delC and c.444 + 1G>A were found in BC patients and controls with frequencies of 0.4%, 0.4% (4/977) and 0.09% (1/1069), 0.2% (2/1069), respectively. The missense mutation p.I157T in CHEK2 was found as the most common variant in two studied cohorts (approximately 5%), but differences did not achieved statistical significance. We found the ethnic specificity in distribution of truncating mutations, which occurs mainly among the women of Slavic origin. All three mutations were identified in women of Russian and Ukrainian ethnic origin. Mutations c.1100delC and c.444 + 1G>A in CHEK2 gene were not detected in Bashkirs and Tatars, but CHEK2 de15395 mutation was observed in Tatars. PMID- 25842826 TI - [Association of polymorphic markers Arg72Pro of TP53 and T309g of MDM2 genes with non small cell lung cancer in Russians of Moscow region]. AB - State Research Center "GosNIIgenetika", Moscow, 117545 Russia). Association of polymorphic markers Arg72Pro of TP53 gene and T309G of MDM2 gene with risk of non small cell lung cancer has been studied in Russians of Moscow region. We found an association of minor Pro/Pro genotype of polymorphic marker Arg72Pro (OR = 5.46, p = 8 x 10(-6)) and TG genotype of polymorphic marker T309G (OR = 5.57, p = 0.007) with non small cell lung cancer development. We have also showed a strong association of both Pro/Pro and TG genotypes with development of adenocarcinoma (OR = 8.71, p = 3 x 10(-6) and OR = 8.13, p = 0.003) and squamous-cell lung cancer (OR = 4.2, p = 0.001 and OR = 7.02, p = 0.002). We have finally found highly reliable association of combined susceptible genotypes of polymorphic markers Arg72Pro and T309G of TP53 and MDM2 genes with non small cell lung cancer and both its subtypes (OR = 7.9, p = 0.01; OR = 9.12,p = 0.02; OR = 7.31, p = 0.03, respectively). PMID- 25842827 TI - [Genetic diversity and relationships of northern eurasia populations for polymorphic Alu-insertions]. AB - We for the first time have examined the autosomal gene pool of the Siberia, Central Asian and the Far East populations (27 populations of 12 ethnic groups) using a set of polymorphic Alu insertions in the human genome. The results of the analysis testify (i) to a significant level of genetic diversity in the Northern Eurasian populations and (ii) to a considerable differentiation of gene pool in the population of this region. It has been shown that at the CD4 locus, the frequency of Alu (-) is inversely related to the Mongoloid component of the population, the lowest and highest frequencies of the Alu deletion at locus CD4 were recorded respectively in Eskimo (0.012) and Russian and Ukrainian (0.35). The analysis of gene flow proved Caucasoid populations (Russian, Tajik and Uzbek), as well as those of Turkic ethnic groups from the Southern Siberia (Altaians and Tuvinians) and Khanty and Mansy populations to be the recipients of a considerable gene flow from the outside of the concerned population system, as compared with the East Siberian and the Far East ethnic groups. The results of the correlation analysis received with use polymorphic Alu insertion testify to the greatest correlation of genetic distances with anthropological characteristics of populations. PMID- 25842828 TI - [The moderating effect of the Va166Met polymorphism of brain-derived neurotrophic factor gene on the clinical and psychological features of patients with schizophrenia]. AB - The brain-derived neurotrophic factor (BDNF) gene is a prominent candidate gene for schizophrenia. The BDNFVal66Met polymorphism has been extensively studied for association to this disease. There is accumulating evidence that the polymorphism is associated with clinical presentations of schizophrenia and not with the disease itself. We compared the allele and genotype distribution in patients (n=1785) and healthy controls (n = 1092) and did not find association of the Va166Met polymorphism with schizophrenia. No association was found with affective syndromes. At the same time, the ValVal genotype was associated with the higher anxiety level assessed with the PANSS in male patients. We studied personality characteristics using personality questionnaires EPI, MMPI, STAI (n=363) and cognitive functions (attention (n=227) and verbal fluency (n=392). Patients with the ValVal genotype demonstrated higher levels of anxiety assessed by the MMPI and better performance on the neurocognitive tests. The interaction effect of genotype and trait anxiety, measured with the STAI, on cognitive functions was identified. In patients with higher anxiety, the performance on cognitive tests did not depend on the genotype, while in patients with lower levels of anxiety the ValVal gen- otype was associated with the better performance. This effect should be taken into account when studying the association of the Val66Met polymorphism with cognitive functions in patients with schizophrenia. PMID- 25842829 TI - [Introgression of nuclear and mitochondrial DNA markers of Mus musculus musculus to aboriginal populations of wild mice from central Asia (M. m. wagneri) and south Siberia (M. m. gansuensis)]. AB - Variability of the nucleotide sequences of the second intron of the b1-chain of hemoglobin (Hbb-b1) and complete control region of mitochondrial DNA (D-loop) was studied in aboriginal and commensal populations of M. m. wagneri from Central Asia and M. m. gansuensis from South Siberia. A difference in frequency of the hemoglobin Hbb(w1) type for natural and urban populations of mice was shown. All mice from natural habitats of studied areas kept musculus-type of mtDNA. Apparently, the substitution of taxonpecific mitochondrial haplotypes of wagneri and gansuensis might occur due to absorbing hybridization with nominate subspecies musculus, what is consistent with the results on nuclear DNA (Hbb-b1 gene) of this work. Two differentiated haplo groups among aboriginal subspecies wagneri were discovered first time (d = 0.01), one of which included house mice from Turkmenistan. This may indicate on mtDNA introgression from commensal forms of Turkmenistan into natural populations of Kazakhstan mice. The castaneus-type of mtDNA was detected in two individuals from the natural habitat of Kazakhstan and Turkmenistan, it had not been met in Central Asia before. It is suggested that the gene flow of nuclear and mitochondrial genomes in microevolution processes in M. musculus is directed from the commensal forms towards wild populations. PMID- 25842830 TI - [P28GANK is a novel marker for prognosis and therapeutic target in gastric cancer]. AB - P28/PSMD10, a regulatory complex of the human 26S proteasome, plays a critical role in tumor genesis. This study was designed to clarify the clinical significance of p28GANK in gastric cancer. In order to demonstrate the importance of p28GANK expression for the prognosis of gastric cancer, p28GANK expression in 124 paired cases of gastric cancer and noncancerous regions and immortal gastric epithelial cell GES-1 and 5 human gastric cancer cell lines was analyzed by RT PCR in real-time. MTT was used to observe the effect of P28GANK on cell growth. P28GANK expression was higher in gastric cancer tissues than in corresponding normal tissues (p = 0.0033), and patients comprising the group with p28GANK high expression had a poorer overall survival rate than those from the low expression group (p = 0.0037). Further, the results of multivariate analysis demonstrated that the high p28GANK expression was an independent prognostic factor of gastric cancer process. P28GANK expression was also up-regulated in five gastric cancer cell lines. As it has been shown by in vitro proliferation assay, p28GANK expression correlated with tumor growth. On the base results of present study one can suggests the p28GANK being useful as a predictive marker for patient prognosis and a novel therapeutic target for gastric cancer. PMID- 25842831 TI - [Lentivirus-mediated siRNA targeting sae1 induces cell cycle arrest and apop- tosis in colon cancer cell RKO]. AB - Deregulated expression of proteins involved in the SUMOylation pathway has been detected in several tumors. SUMO1-activating enzyme subunit 1 (SAE1) plays an important role in this process. We found that SAE1 was highly expressed in the colon cancer cell line RKO and used lentivirus-mediated siRNA to suppress SAE1 expressionin RKO cells. RNA-interference efficiently and specifically downregulated the target gene expression in RKO on both mRNA and protein levels. Silencing of SAE1 inhibited proliferation and reduced colony formation of RKO cells. Furthermore, as it has been shown by flow cytometry analysis, specific knockdown of SAE1 slowed down the cell population at G0/G1 phase and induced apoptosis of RKO cells. On the base of results obtained, one can suppose the biological significance of SAE1 in colon tumorigenesis and a use of this protein as a novel molecular target for colon cancer therapy. PMID- 25842832 TI - [A new immuno-PCR format for serological diagnosis of colon cancer]. AB - Anew immuno-PCR format is described that is based on detection of membrane protein CDH17 in serum exosomes. Format application allows distinction between sera samples of healthy donors and colon cancer patients. Obtained results open a possibility of serological colon cancer diagnosis in high risk groups. PMID- 25842833 TI - [Cloning and characterization of lactate dehydrogenase C4 from pika ochotona curzoniae]. AB - Lactate dehydrogenase C4 (LDH-C4) is considered to be a good target protein for the development of contraceptive drugs. To develop contraceptive rodenticide against pika (Ochotona curzoniae) LDH-C4, the pika LDH-C gene was cloned and expressed in Escherichia coli. The recombinant protein was purified and characterized. The cDNA of pika LDH-C gene was cloned by RACE method. The cDNA was 1498 bp in length containing an ORF of 996 bp which encoded a polypeptide of 332 amino acids. The ORF of pika LDH-C was introduced in E. coli and expressed with no fusion tags added. The recombinant LDH-C4 protein was purified by heating, affinity chromatography and ion-exchange chromatography. The recombinant pika LDH-C4 was a tetramer with a molecular weight of approximately 140 kDa, and it had temperature-dependent catalytic activity, as it was thermally stable up to 60 degrees C. The optimal pH values in the forward and backward reactions were around 7.48 and 10.28, respectively. The apparent Michaelis constants for pyruvate and lactate were 51.2 +/- 3.8 and 8568.8 +/- 409 microM respectively. The inhibition constant for oxalic acid was 11.8 +/- 3.5 mM. This study laid a solid foundation for contraceptive rodenticide development against pika LDH-C4. PMID- 25842834 TI - [Disparity of apoptotic response in human breast cancer cell lines MCF-7 and MDA MB-231 after infection with recombinant adenovirus encoding the VP2 gene of infectious bursail disease virus]. AB - Recombinant adenovirus encoding the VP2 gene of infectious bursal disease virus (ADV-VP2) has shown potent anti-tumour effects due to its capability of apoptotic induction in cancer cells. In the present study, human breast cancer cells MCF-7 and MDA-MB-231 were infected with ADV-VP2. The expression of VP2 protein was registered 4 h post-infection, particularly in MCF-7 cells. Multiple time-point DNA ladder assay demonstrated that ADV-VP2 infected MDA-MB-231 and MCF-7 cells endured apoptosis as early as 8 and 12 h post-infection, respectively. Apoptosis induction in both MDA-MB-231 and MCF-7 cells, albeit different start points, lasted til 36 h post-infection. The induction of apoptosis by ADV-VP2 was further shown by the TUNEL assay, with dark brown discoloration of apoptotic cells. The present study also explored the different stages of apoptosis by Annexin V/PI double staining flow cytometry quantification. Treated MCF-7 and MDA-MB-231 cells, respectively detected 25.58 +/- 9.02 and 14.51 +/- 3.12% of early apoptotic cells, 6.09 +/- 4.06 and 77.12 +/- 5.09% of late apoptotic cells. Results revealed that there were significant differences in the number of cells of both types which underwent early and late apoptosis. Significant differences were also observed among viable and apoptotic cells which have been post treated with ADV-VP2. The apoptotic effects of ADV-VP2 on human breast cancer cell lines were consistently demonstrated by three apoptosis detection methods. Therefore, a cancer vaccine basing on gene therapy could be developed in the near future using the present construct. PMID- 25842835 TI - [Comparative analysis of activity of different promoters for NIS gene expression in melanoma cells]. AB - Development of targeted drug delivery system is key problem of cancer gene therapy. To ensure specific delivery of these therapeutic compounds to the tumor it is preferable for therapeutic gene expression to occur predominantly in cancer cells. Therefore, when testing drug in vivo, it is necessary to study distribution of therapeutic gene expression products in different tissues of the organism. Sodium iodide symporter (NIS) is attractive reporter because its tissue level is easily quantitatively detected by noninvasive imaging methods. Different promoters are used to direct expression of therapeutic genes in tumor cells: strong nonspecific, moderate tissue-specific and tumor-specific. Tumor-specific promoters function in wide range of tumor cells, however they are relatively weak. Relationship between promoter and sodium iodide symporter activity is unclear to date. In this report we examined activity of different promoters in two melanoma cell lines, functional activity of NIS driven by these promoters, also we compared promoter strength and NIS activity. We demonstrated that in spite of strong differences in promoter activity functional activity of NIS directed by these promoters varies weakly. Relatively weak melanoma-specific promoter directs high NIS activity in melanoma cell, however weaker cancer specific promoters drive high NIS activity only in certain melanoma cell line. PMID- 25842836 TI - [Transcription factor comr acts as a direct activator in the genetic program controlling spermatogenesis in D. melanogaster]. AB - Cardiff University, Cardiff CF10 3AX, UK). In Drosophila melanogaster differentiation of the male germ cells is accompanied by chromatin rearrangement and activation of the specific genes. These processes are regulated by few transcription factors that belong to two classes, can and aly that form distinct functional complexes. Mechanisms of action of aly and can class transcription factors on gene expression and chromatin state remain unclear. To investigate this question we have built the whole genome binding profile of transcription factor Comr belonging to aly class using the tissue-specific DamID method. Resulting datawere correlated with gene expression in comr (aly class) and can (can class) mutant testes. It was shown that Comr is a direct activator for about 300 testis-specific genes. Furthermore a set of genes revealed decreased expression in comr mutants but did not bind Comr protein, suggesting the existence of secondary regulation. Indeed, among the Comr gene targets we found a gene coding an uncharacterized transcription factor that could be a secondary participant in the genetic pathway in spermatocytes. These date allowed us to advance a model of gene activation needed for male gametes differentiation in D. melanogaster. PMID- 25842837 TI - [RPN4 the yeast transcription factor promotes the complex defence against methyi, methanesulfonate]. AB - Methyl methanesulfonate (MMS) is an alkylating agent commonly used in models of genotoxic stress. It methylates bases in DNA but also leads to oxidative stress. The transcription factor Rpn4 protects yeast cells from toxic effect of MMS. Although Rpn4 is a major regulator of ubiquitin-proteasome system (UPS), a number of data points to its participation in the stress response regardless of the UPS. We have demonstrated that under the methyl methanesulfonate stress Rpn4 promotes the regulation of several genes involved in DNA repair, antioxidant response and glucose metabolism. We suggest a mechanism of complex action of Rpn4 in the stress response. PMID- 25842838 TI - [Antirestriction activity of T7 Ocr protein in monomeric and dimeric forms]. AB - The Ocr protein, encoded by 0.3 (ocr) gene of bacteriophage T7, belongs to the family of antirestriction proteins that specifically inhibit the type I restriction-modification systems. Native Ocr forms homodimer (Ocr)2 both in solution and in the crystalline state. The Ocr protein belongs to the family of mimicry proteins. F53D A57E and E53R V77D mutant proteins were obtained, which form monomers. It was shown that the values of the dissociation constants Kd for Ocr, Ocr F53D A57E and Ocr F53RV77D proteins with EcoKI enzyme differ in 1000 times: Kd (Ocr) = 10(-10) M, Kd (Ocr F53D A57E and Ocr F53R V77D) = 10(-7) M. Antimodification activity of the Ocr monomeric forms is significantly reduced. We have shown, that Ocr dimeric form has fundamental importance for high inhibitory activity. PMID- 25842839 TI - [Gene expression analysis of familial hypercholesterolemia]. AB - Familial hypercholesterolemia (FH) is a common cause of a variety of cardiovascular diseases. The aim of this study was to uncover the underlying mechanism of FH and provide a possible treatment project for FH. We tried to identify the differently expressed genes (DEGs) involved in FH by comparing the gene expression profiles between FH and normal cells. We performed GO and biological pathway analysis of differently expressed genes with DAVID. We searched for candidates for FH treatment by analyzing DEGs between normal cells and FH cells and compared the differences with the DEGs caused by the small interfering molecules in The Connectivity Map (CMap). Using a bioinformatics method, we identified the abnormal metabolic processes in the cells of FH patients, including cell adhesion, material transport, signal transduction and gene expression, and found that the small molecule trazodone could be a potential drug in restoring the dysregulated metabolic pathway. In conclusion, candidates for further evaluation as possible therapeutic agents for FH have been identified using bioinformatics analysis of differentially expressed genes. Phenotype targeting using genomic profiling is a rational approach to drug discovery, which provides a new guideline in treatment of FH and a potential new clinical drug for FH patients. PMID- 25842840 TI - [Mechanisms of targeted frameshift mutations--insertion formation under error prone or SOS synthesis of DNA containing CIS-SYN cyncyclobutane thymine dimers]. AB - Up to now the mechanism of formation of frameshift mutations caused by cyclobutane pyrimidine dimers has not been yet explained satisfactorily. Mechanisms of different mutations are usually considered in polymerase model. Here, the alternative polymerase-tautomer model of ultraviolet mutagenesis is developed. The mechanism of targeted insertion formation caused by cis-syn cyclobutane thymine dimers is proposed. Insertions are mutations when one or several DNA bases are inserted.Targeted insertions are mutations of a frameshift type--when one or severalnucleotides are inserted opposite damageswhich may stop synthesis of DNA. Targeted insertions are induced bycyclobutane pyrimidine dimmers. Ultraviolet irradiation may result in a change of tautomer state of DNA bases. A thymine base may form 5 rare tautomer forms that are stable if the base is a part of cyclobutane dimer. As it was shown by structural analysis, one rare tautomeric form of thymine forms hydrogen bonds with no one canonical DNA base. Therefore, under SOS or error-prone synthesis of DNA containing cis-syn cyclobutane thymine dimers with such rare tautomeric_form a specialize or modified DNA polymerase leaves a single nucleotide gap opposite the cis-syn cyclobutane thymine dimer. According to Streisinger model, if the DNA composition within this region is homogeneous, the end of the growing DNA strand can slip and form complementary pairs with a template nucleotide neighboring to the dimer of such type a loop is formed. Further elongation of the daughter strand leads to the appearance of targeted insertion in the daughter strand. Here, it is first shown that cis-syn cyclobutane thymine dimers with one or both bases in the specific tautomer conformation--opposite which it is impossible to insert a canonical base with a hydrogen bond formation--results in targeted insertions. Moreover, the model of forming targeted single--and several-base insertions is developed. The polymerase-tautomer model of ultraviolet mutagenesis can explain a nature and mechanism of appearing not only hot and cold spots, targeted and untargeted base substitution mutations but also targeted frameshift mutations. PMID- 25842841 TI - [Ribosome: lessons of a molecular factory construction]. AB - Ribosome is a macromolecular complex, which is responsible for protein biosynthesis. Two bacterial ribosomal subunits contain more than 4000 RNA nucleotides and 50 proteins. Ribosome assembly is a complicated multi-step process, vitally important for cell. In this review we summarised present-day conceptions about the mechanism of the bacterial ribosome assembly in the cell and in vitro model systems. Some details of the assembly of this machinery are still-unknown. PMID- 25842842 TI - [The role of PARP2 in DNA repair]. AB - The genome stability of higher eukaryotes is mainly dependent on the functioning of the DNA repair systems. In turn, the precise regulation of each step of repair processes is required for efficient DNA repair. While at present the most pathways of DNA repair have been established already, but the mechanisms of DNA repair regulation are required further investigation. Poly(ADP-ribose)polymerases (PARPs) are widely considered as potential regulators of a DNA repair. The role of most prominent member of this protein family--PARP1--in DNA repair is intensively studied, while the literature data on participation in repair processes of PARP2--the closestPARP1 homolog--are poorly Sum- marized although a great body of information concerning PARP2 participation in DNA repair has accumulated.. Using PARP2-deficient model organisms and cell lines, their increased sensitivity to several DNA damage agents was elucidated. The accumulation of PARP2 at the DNA damage sites in cells was shown. There are data demonstrating protein-protein interaction of PARP2 with several base excision repair/single strand break repair and non-homologous end joining proteins. Most of the data on PARP2 role have been obtained in experiments with model organisms and cell lines so it is difficult to project the attribution of PARP2 influence to specific process in vivo. In this review, we tried to summarize data on PARP2 participation in DNA repair processes, including our recent results. PMID- 25842843 TI - [Genome-wide association study as a method for genetic architecture analysis in polygenic diseases (by the example of multiple sclerosis)]. AB - Genome-wide association study (GWAS), which is a powerful tool for investigating the genetic architecture of polygenic disease in humans, is generally applied for identification of genetic factors of disease susceptibility, clinical phenotypes and treatment response. The differences in allele frequencies of genome-wide distributedsingle nucleotide polymorphisms (SNPs) are analyzed with microarray technique or other technologies, that allow simultaneous genotyping from tens'of thousands to several millions SNPs per sample. The power toexplore highly reliable differences between compared groups of patients aind controls allowed GWAS to become a common approach for identification of genetic susceptibility for complex diseases with polygenic nature. The main achievements and challenges of GWAS in multiple sclerosis (MS), which is a prototype example of complex disease, are reviewed here for identification of MS causative genes, which expand the knowledge on molecular mechanisms of MS pathogenesis and genetic risk factors. PMID- 25842844 TI - [Genetically modified animals as model systems of psoriasis]. AB - Psoriasis is a chronic autoimmune skin disorder. Experimental models of psoriasis can be used to study the disease in controlled conditions. Moreover, the experimental models allow to study a certain aspect of the pathological process. Although none of the multiple mouse models reproduces the human disease precisely, lab animals as model systems can be very helpful because of two reasons. First, introduction of new mutations into animal genome allows to reveal the new genes that may play a certain role in pathogenesis of the disease. Second, the experiments that are carried on the lab animals can be used for testing the new drugs and selection of the most efficient chemical agents from a variety of the proposed experimental preparations. The aim of this paper was to summarize the data on the lab animals that serve as experimental models of psoriasis. PMID- 25842845 TI - [Peroxyredoxins as multifunctional enzymes]. AB - Peroxiredoxins are evolutionarily ancient, but relatively recently discovered group of seleniumindependent peroxidases. Peroxiredoxins protect cells from various peroxides and play an important role in maintaining the oxidation reduction homeostasis. Moreover, they are involved in many cellular processes that are not related to peroxidase activity. Here, recent data on the structure and function of peroxiredoxins, regulation of gene expression and activity of different peroxiredoxins are considered. PMID- 25842846 TI - [The association of polymorphisms in SLC18A1, TPH1 and RELN genes with risk of paranoid schizophrenia]. AB - We have developed a biochip for the analysis of polymorphisms in candidate genes for schizophrenia: DISC1, RELN, ZNF804A, PLXNA2, COMT, SLC18A41, CACNA1C, ANK3, TPH1, PLAA and SNAP-25. Using biochip the allele and genotype frequencies in 198 patients with schizophrenia and 192 healthy individuals have been obtained. For SLC18A1 polymorphism rs2270641 A>C, the frequencies of A allele (p = 0.007) and AA genotype (p = 0.002) were lower in patients compared with healthy individuals. A significant association was found between AA genotype (p = 0.036) of the TPH1 polymorphism rs1800532 C>A and schizophrenia. The C allele (p = 0.039) of the RELNpolymorphism rs7341475 C>T were lower in patients with schizophrenia compared with healthy individuals in a tatar population. Genotype AA of the TPH1 polymorphism rs1800532 C>A were more frequent in patients with schizophrenia compared with healthy individuals. Ithas been shown that the C allele (p = 0.0001) and GC (p = = 0.0001) genotype of the PLXNA2 polymorphism rs1327175 G>C are associated with the family history in patients with paranoid schizophrenia. The obtained data suggest that SLC18A1, TPH1 and RELN gene polymorphisms are associated with the risk of paranoid schizophrenia. PMID- 25842847 TI - [Identification of hypervariable regions within the 16S-23S rRNA intergenic spacer region of Flavobacterium columnare and its application in assigning genomovar group to an individual strain]. AB - Flavobacterium columnare is an important bacterial pathogen of fish with wide ge- netic variability within species. This intraspecies diversity has been termed as genomovars and genomovar groups on the basis of Restriction Fragment Length Polymorphisms of 16S rDNA and 16S-23S rDNA Intergenic Spacer Region (ISR), respectively. In this study, we demonstrate the source of genetic heterogeneity in the F. columnare by sequence analysis of ISR. Length of ISR sequences of different genomovars varied from 553 to 592 nucleotides, while the similarity among sequences ranged from 76.1 to 92.6%. A common ISR structure with tRNAAa and tRNAne embedded within the sequence was identified in all the genomovars ofF. columnare. The results show that strains of F. columnare can be categorized into five genomovar groups based on the heterogeneity in the ISR sequences. Of these, strains belonging to Genomovar I and II can be sub-divided into two groups each; while strains of Genomovar III belonged to one group. Sequence similarity between genomovar groups was lower for ISR (76.1-92.6%) as compared to 16S rDNA (96.1 99.4%) indicating its ability to resolve closely related groups within the genomovars of F. columnare. The main source of variation between genomovar groups is the presence of three hyper variable regions (V1, V2 & V3) in the ISR Of the three, V3 was found to be the most heterogeneous region and was found to be useful in assigning genomovar group to an individual strain of F. columnare. PMID- 25842848 TI - [High level of expression and nuclear localization of RNA, transcribed from genome region, containing repetitive elements]. AB - The non-coding and repetitive sequences constitute a great amount of higher eukaryotes genomes, but the elucidation of its role and mechanisms of action is now at the very beginning. Here we found, that internal telomeric repeats in Danio rerio are colocalized with some repetitive elements, namely, hAT and EnSpm repeats, which are highly represented in vertebrate genome. While investigating one of genome regions, containing two pairs of such repeats in close proximity we found, that it is transcribed. RNA-dependent structures, containing this sequence, were revealed in D. rerio fibroblast nuclei, which may serve as evidence of functional relevance of repetitive elements in genomes or of their transcripts. PMID- 25842849 TI - [Molecular polymorphism of IB-fructosidase SUC genes in the yeast]. AB - SUC gees encoding bea-fructosidase has been investigated in the yeast genus Saccharomyces. We have determined nucleotide sequences of subtelomeric SUC3, SUCS, SUC7, SUC8, SUC9, S UCO10 genes of S. cerevisiae and SUCa gene o:f S. arboricola. Comparisns of nucleotid sequences of all known SUCgenes revealed predominance of transitions C-->T in the third codon position, Which are silent. The amilioacids sequences of p-fructosidases studied have identity of 88 100%.4'Most divergent are SUCa (S.'arboricola) and SUCb (S. bayanus), having amino acid identity.with the other SUCproteins less than 92%. It wasdetermined that accumulation of the polymeric SUC genes takes place in industrial populations of S. cerevisiae, while the other Saccharomyces species (S. arboricola, S.:bayanus, S. cariocanuis, kudriavzevii, S. mikatae and S. paradoxus) each harbor only one SUCgene. Subtelomeric repeats of pructosidase SUCgenes cobetald appear in the genome of S. cerevisiae under the effect of selection in the course of their domestication. PMID- 25842850 TI - [The effect of topology of quorum sensing-related genes in Pectobacterium atrosepticumon their expression]. AB - In prokaryotic genomes, the neighboring genes are often located on the complementary DNA strands and adjoin each other by their 5'- or 3'-ends or even overlap by their open reading frames. It was suggested that such gene topology hasfunctional purpose providing the regulation of their expression. For those genes that overlap by their coding 3'-termini this assumption has not been confirmed experimentally. In a broad group of bacteria that belong to proteobacteria such a convergent gene arrangement is typical for functionally connected quorum sensing-related genes "P" and "R" that encode synthases of N acyl homoserine lactones and their sensors, respectively. In the present study on the example of overlapping quorum sensing-related genes of plant pathogenic bacterium Pectobacterium atrosepticum SCRI1043--expI and expR it was shown that the topology of these genes determines the regula- tion of their expression. PMID- 25842851 TI - [Evaluating the mitochondrial dna copy number in leukocytes and adipocytes from metabolic syndrome patients: pilot study]. AB - The metabolic syndrome is a complex of metabolic, hormonal and clinical disorders. Defects in mitochondrial functions play an important role in the metabolic syndrome pathogenesis. Here, mitochondrial DNA (mtDNA) copy number variations were evaluated different fat tissue and peripheral blood leukocyte samples from metabolic syndrome patients ranked by, body mass indexes. It was elucidated a tendency in decreasing the mtDNA copy number with increasing a body mass index. PMID- 25842852 TI - [Interaction of DAXX and human papillomavirus type 16 E2 protein]. AB - The aim of the study was to explore the interactions of human papilloma virus 16 (HPV16) E2 protein and Daxx. The location or co-localization of PML and E2 with Daxx in Caski cells was observed by indirect immunofluorescence test. The interaction of E2 and Daxx was analyzed by co-immunoprecipitation, Western-blot and yeast-two hybrid assay. In Caski cells the fluorescence of Daxx or PML was mainly distributed in the cytoplasm or nucleus, respectively, and in the align image their signals did not overlapped. However, when the red signal of HPV16 E2 and the green signal of Daxx in cyto- plasm of Caski cells were merged, the yellow signals appeared. The yeast co-transformed with pGBKT7/Daxx and pGADT7/E2 or pGADT7/E2 TAD can grow onto SD/-Trp-Leu-His and SD/-Trp-Leu-His-Ade plates. So Daxx wasn't co-located with PML but with HPV16 E2 mainly in the cytoplasm of Caski cells. On the base of the results one can propose that HPV16 E2, in particularly its transcription-activity domain (TAD), interacts with Daxx. PMID- 25842853 TI - [High glucose promotes gap junctional communication in cultured neonatal cardiac fibroblasts via AMPK activation]. AB - Cardiac fibroblasts are known to be essential for adaptiveresponses in the patho- genesis of cardiovascular diseases, and increased intercellular communication of myocardial cells and cardiac fibroblasts acts as a crucial factor in maintaining the functional integrity of the heart. AMP-activated kinase (AMPK) is a key stress signaling kinase, which plays an important role in promoting cell survival and improving cell function. However, the underlying link between AMPK and gap junctional communication (GJIC) is still poorly understood. In this study, a connection between AMPK and GJIC in high glucose-mediated neonatal cardiac fibroblasts was assessed using fibroblast migration, measurement of dye transfer and connexin43 (Cx43) expression. 5-aminoimidazole-4-carboxamide-1-beta-D ribofuranoside (AICAR) and Compound C (CC) were used to regulate AMPK activity. The levels of cell migration and Cx43 protein expression in neonatal cardiac fibroblasts increased during high glucose treatment, accompanied by developed dye transfer. In addition, high glucose induced abundant phosphorylation of AMPK. Suppression of AMPK phosphorylation using CC reduced dye transfer, cell migration and Cx43 protein expression in neonatal cardiac fibroblasts, whereas the activation of AMPK using AICAR mimicked the high glucose-mediated cell migration, Cx43 protein expression and dye transfer enhancement. AMPK appears to participate in regulating GJIC in high-glucose-treated neonatal cardiac fibroblasts, including cell migration, dye transfer, Cx43 expression and distribution. PMID- 25842854 TI - [Estimation of phosphorilation level of amyloid beta, extracted from human blood plasma. Ultra high resolution mass spectrometry]. AB - Recently it has been shown that phosphorylation of the Ser8 residue in amyloid beta (pS8-Abeta) is tightly involved in the pathogenesis ofAlzheimer's disease. Since this modification occurs in the key metal-binding domain of amyloid-beta, and thus should seriously affect the interaction of pS8-Abeta with zinc ions, this isoform might be a potential precursor of pathogenic oligomeric forms of amyloid beta. Hence the level of pS8-Abeta in human biological fluids (such as blood, urine, cerebral spinal fluid) might resemble the different stages of the pathogenesis of Alzhe- imer's disease. The aim of this workwas to develop a prototype of an analytical method for quantitative determination of the level of pS8-Abeta isoform in binary mixtures with native amyloid-beta in order to further use it to determine the levels of phosphorylated amyloid-beta in blood plasma samples of patients with Alzheimer's disease. PMID- 25842855 TI - [Ribonucleases as antiviral agents]. AB - Many ribonucleases (RNases) are able to inhibit the reproduction of viruses in infected cell cultures and laboratory animals, but molecular mechanisms of their antiviral activity remain unclear. The review observes the most known RNases which possess established antiviral effects, actually intracellular RNases (RNase L, MCPIPI protein, eosinophylic RNases) as well as exogenously applied ones (RNase A, BS-RNase, onconase, binase, synthetic RNases). Attention is given on two important but not always obligatory aspects in molecule of RNases, which have antiviral properties: catalytic activity and ability to the dimerization. The hypothetic scheme of virus elimination by exogenous RNases, that reflects possible types of interaction of viruses and RNases with a cell, is proposed. The evidence for RNases as classical components of immune defense which are perspective agents for development of new antiviral therapeutics is produced. PMID- 25842856 TI - [Methods of protein immunoanalysis]. AB - This review describes current methods of protein immunoanalysis: radioimmunoanalysis, ELISA, immuno-PCR, electrochemical analysis and chromatin immunoprecipitation, as well as main areas of their application. PMID- 25842857 TI - [Anatlysis of HSPA1B A1267G gene polymorphism in peptic ulcer]. AB - Peptic ulcer disease is a common illness, affecting a considerable number of people worldwide, and its occurrence can be influenced by environmental and genetic factors. Heat shock proteins (HSPs) function mostly as molecular chaperones, and are induced by various stresses. The A to G transition at position 1267 of the HSPA1B gene was shown to correlate with changes in the level of HSPA mRNA expression. Here, the relation between A1267G polymorphism of the HSPAIB gene and risk of peptic ulcer in the Iranian population was evaluated. One hundred subjects, who underwent gastroscopy, took part in the study. DNA samples extracted from the biopsy tissues were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). After gastroscopy, peptic ulcer was diagnosed for 50 patients; among them the distribution of AA/AB/BB genotypes was 10, 88 and 2%, respectively. As for the other 50 subjects (without peptic ulcer) included in the control group, the AA/AB/BB genotypes were identified as 40, 52 and 8%, respectively. A significant association was found between the HSPA1B genotype and peptic ulcer (6.76 OR; 95% CI, 2.26-20.2; p = 0.0006). Thus, the HSPA1B A1267G polymorphism may be a marker of susceptibility to peptic ulcer. PMID- 25842858 TI - [Coexpression of genes located in the 111.35-116.16 Mb of chromosome 13 in mice with different predisposition to catalepsy]. AB - Catalepsy is a pathologic behavior which is usually associated with a dysfunction of striatal pallidal pathway and which can be caused by different mechanisms. It was showned previously that hereditary catalepsy is linked with the distal 111.35 116.16 Mb of chromosome 13. We investigated the level of mRNA of 42 genes located in this fragment in two brain regions which are concerned with catalepsy-striatum and substantia nigra in catalepsy-resistant AKR mice strain, in cataleptic CBA mice strain and in congenic cataleptic AKR.CBA-D13Mit76 (D13) mice strain which were created by transferring of this fragment from CBA in AKR genome. We showed congenic D13 mice vary from AKR in level of mRNA of 2 genes (Ndufs4 and Ppap2a genes) in striatum and 10 genes (Esm1, Fst, Gm10735, Gm15322, Gm15323, Gm15324, Gm15325, Il6st, II31ra, Itga1) in sibstantia nigra. The level of mRNA of Mcidas gene is reduced in both brain regions in D13 compared to AKR. Gene expression of Hspb3 n Mocs2, which codes heat shock protein and, molybdenum cofactor synthesis, respectively, in substantia nigra is reduced in cataleptic CBA and D13 mice compared to catalepsy-resistant AKR mice. These genes can be considered as the most likely genes candidate of catalepsy. The revealed genes coexpression shows that there is a difficult genes network, which regulates hereditary catalepsy. PMID- 25842859 TI - [Molecular cloning, structural analysis, and expression of zona pellucida glycoprotein ZP3 gene from Chinese zokor, Myospalax fontanierii]. AB - The zona pellucida 3 (ZP3) plays a crucial role in reproductive immunology. We obtained a full-length cDNA encoding Chinese Zokor zp3, using rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR). The cDNA contains an open reading frame of 1269 nucleotides encoding a polypeptide of 422 amino acid residues. The amino acid sequence has a high degree of homology with hamster (78%), mouse (76%), and rat (74%). XhoI and SacI sites restricted 1158 bp fragment of zokor ZP3 cDNA, excluding the signal sequence and transmembrane-like domain was cloned under the phage T7 promoterlac operator control in the pET 28a(+) vector. Recombinant pET-zokorZP3 (r-ZP3) was expressed as a poly-histidine fusion protein in E. coli strain BL21 (DE3). Optimum expression of r-ZP3 was observed at 28 degrees C, 1 mM IPTG and 2 h of inducing. The purified protein was tested by Western blot. PMID- 25842860 TI - [[Length polymorphism of minisatellite repeat B2-VNTR of the bradykinin B2 receptor gene in healthy Russians and in patients with coronary heart disease]. AB - Bradykinin B2 receptor is involved in many processes, including the regulation of blood pressure and smooth muscle contraction, vasodilation, inflammation, edema, cell proliferation, pain. It is suggested that this receptor may be one of the factors that have cardioprotective and infarct-limiting effects. It is assumed that certain genetic variants in both coding and non-coding regions ofBDKRB2 gene may influence its expression. In the 3'-untranslated region of BDKRB2 exon 3 the minisatellite repeat B2-VNTR is located. B2-VNTR has previously been shown to affect the BDKRB2 mRNA stability. Therefore, it is important to perform the molecular genetic analysis of this minisatellite in patients with different forms of coronary heart disease in order to reveal possible associations between specific B2-VNTR alleles and certain clinical forms of coronary heart disease. In the present study, a comparative analysis of the allele and genotype frequencies of B2-VNTR was carried out in groups of healthy individuals and patients with two clinical forms of coronary heart disease (angina pectoris and myocardial infarction), ethnically Russian. The results of the B2-VNTR length polymorphism analysis indicate that this tandem repeat may be attributed to a class of low polymorphic and non-hypervariable minisatellite. In all analyzed groups we revealed three B2-VNTR alleles, consisting of 43, 38 and 33 repeat units. Alleles of 43 and 33 repeats were major in all investigated groups. No statistically significant differences were found in the B2-VNTR allele and genotype frequencies between men and women in control group, and also between healthy men and men with angina pectoris and myocardial infarction. Thus, B2-VNTR length polymorphism was not associated with these clinical forms of coronary heart disease in Russian men. However, we do not exclude the possibility of association between the B2 VNTR short alleles (38 and 33 repeats) and cardioprotective effects of bradykinin B2 receptor in women with coronary heart disease. This hypothesis requires further investigation. PMID- 25842861 TI - [Linkage disequilibrium and haplotypes of rs1042522, rs1625895 and rs17878362 gene TP53 markers in patients with diffuse large B-cell lymphoma]. AB - Association of rs1042522, rs17878362 and rs1625895 markers with non-Hodgkin's lymphoma risk is not well studied. Large number of non-Hodgkin's lymphoma entities, as well as a small effect of each of the polymorphisms on the lymphomas risk, leads to the analyses of these markers in each of histological subtypes of lymphoma and to study the polymorphisms in the haplotype groups. The goal of this work was to analyze the frequency, haplotypes and linkage disequilibrium of rs1042522, rs1625895 and rs17878362 in the patients with diffuse large B-cell lymphoma and in control group. The differences in the structure of LD between rs17878362, rs1042522 and rs1625895 TP53 gene in the population of the Siberian region were shown. Haplotype approach wasmore informative in the analyses of association of the gene TP53 polymorphisms and the diffuse large B-cell lymphomas risk in case-control study than the study of each polymorphism. The association of haplotype wArgG with diffuse large B-cell lymphoma risk, and the protective effect of haplotypes wProG or dupProG were identified. The difference in the effects of the haplotype TP53 was noted depending on the homozygous or heterozygous diplotype. PMID- 25842862 TI - [Glutamate receptors genes polymorphism and the risk of paranoid schizophrenia in Russians and tatars from the Republic of Bashkortostan]. AB - Schizophrenia is a severe mental disorder that affects about 1% of the world population, leading to disability and social exclusion. Glutamatergic neurotransmission is a violation of one of the main hypotheses put forward to explain the neurobiological mechanisms of schizophrenia. Post mortem studies have found changes in the degree of affinity glutamate receptors, their transcription, and altered expression of their subunits in the prefrontal cortex, hippocampus, and thalamus in patients with schizophrenia. As a result of genetic studies of gene family encoding ionotropic AMPA and kainate glutamate receptors in schizophrenia, ambiguous results were received. The association of polymorphic variants of genes GRIA2 and GRIK2 with paranoid schizophrenia and response to therapy with haloperidol in Russian and Tatar of the Republic of Bashkortostan was conducted in the present study. DNA samples of 257 patients with paranoid schizophrenia and of 349 healthy controls of Russian and Tatar ethnic group living in the Republic of Bashkortostan were involved into the present study. In the result of the present study: (1) high risk genetic markers of paranoid schizophrenia (PSZ) were obtained: in Russians-GR4IA2*CCC (OR = 9.60) and in Tatars-GRIK2*ATG (OR = 3.5), GRIK2*TGG (OR = 3.12) (2) The following low risk genetic markers of PSZ were revealed: in Tatars-GRIA2*T/T (rs43025506) of GRIA2 gene (OR = 0.34); in Russians.- GRIA2*CCT (OR = 0.481). (3) Genetic markers of low haloperido! treatment efficacy in respect of negative and positive symptoms GRIK2*T/T (rs2227281) of GRIK2 gene and GRAL42*C/C in Russians, GRIK2*A/A (rs995640) of GRIK2 gene in Tatars. (4) Genetic markers of low haloperidol treatment efficacy in respect of positive symptoms GRL42*C/C in Russians. The results of the present study support the hypothesis of the involvement of glutamate receptor genes in schizophrenia pathway. Considerable inter ethnic'diversity of genetic risk factors for this disease was revealed. PMID- 25842863 TI - [Developmental expression of Arabidopsis methyltransferase genes MET1, DRM2 and CMT3]. AB - Cytosine methylation is an epigenetic mark found in the genome of fungi, plants, and animals. DNA methylation is catalyzed by DNA methyltransferases. The function of DNA methyltransferases was shown to be highly conversed, but biological role of these enzymes has not been clearly defined. We generated transgenic plants expressing METHYLTRANSFERASES::GUS reporter genes for three major DNA methyltransferases (MET1, DRM2 and CMT3) to gain insight into the potential physiological relevance of the distinct members of the DNA methyltransferase family in Arabidopsis thaliana, and to investigate the expression patterns in detail. We found that METHYLTRANSFERASE::GUS genes display unique tissue, cell type, and temporal patterns of expression throughout normal development, particularly in the flower. Our findings are supported by semi-quantitative reverse-transcription PCR, as well as by analyses of microarray databases. These data suggest that DNA methyltransferase may contribute to morphogenesis at every developmental stage and in every plant organ. PMID- 25842864 TI - [Prion-like determinant [NSI+] decreases expression of the SUP45 gene in Saccharomyces cerevisiae]. AB - Previously, we described and characterized yeast non-chromosomal determinant [NSI+], possessing prion properties. This determinant causes a decrease in translation termination fidelity, which is phenotypically detectable as the nonsense suppression in the strains with decreased functional activity of eRF3 release factor. As a result of geneticscreen, we demonstrated that an increase in the expression of SUP45 encoding the eRF1 release factor (Sup45), masks, but does not eliminate nonsense suppression in the [NSI+] strains. In the present study, we first demonstrated the direct cause for the nonsense suppression in [NSI+] strains. We demonstrated that [NSI+] decreases the relative amounts of SUP45 mRNA that causes a decrease in the amounts of Sup45 protein that is detectable in the stationary growth phase. The data obtained suggest the structural protein of [NSI+] seems to be either a transcription factor or participates in the regulation of cellular mRNA stability. PMID- 25842865 TI - [Analysis of tissue-specific differentially methylated genes with differential gene expression in non-small cell lung cancer]. AB - Adenocarcinoma (ADC) and squamous cell carcinomas (SCC) are two subtypes of non small cell lung carcinomas which are regarded as the leading cause of cancer related malignancy worldwide. The aim of this study is to detect the differentially methylated loci (DMLs) and differentially methylated genes (DMGs) of these two tumor sets, and then to illustrate the different expression level of specific methylated genes. Using TCGA database and Illumina HumanMethylation 27 arrays, we first screened the DMGs and DMLs in tumor samples. Then, we explored the BiologicalProcess terms of hypermethylated and hypomethylated genes using Functional Gene Ontology (GO) catalogues. Hypermethylation intensively occurred in CpG-island, whereas hypomethylation was located in non-CpG-island. Most SCC and ADC hypermethylated genes involved GO function of DNA dependenit regulation of transcription, and hypomethylated genes mainly 'enriched in the term of immune responses. Additionally, the expression level of specific differentially methylated genesis distinctbetween ADC and SCC. It is concluded that ADC and SCC have different methylated status that might play an important role in carcinogenesis. PMID- 25842866 TI - [Dynamic properties of germinal granule ping-body in the testes of Drosophila melanogaster]. AB - Here we investigated dynamic properties of the piNG-body, large perinuclear granule that was discovered previously in spermatocytes of Drosophila. The piNG body contains ribonucleoprotein complexes involved in piRNA-silencing of genome repeats including transposons in premeiotic spermatocytes with aid of short piRNAs. Confocal microscopy of fixed and native preparations demonstrates that the piNG-body is mobile structure which does not occupy a stationary position near nuclear surface relative to chromosomal territories. FRAP-analysis reveals a high exchange rate of RNA helicase Vasa in the piNG-body and small perinuclear granules with the cytozol Vasa pool. Disruption of microtubule assembly of cytoskeleton does not affect to stability of the piNG-body and small granules. We suppose that the combination of piNG-body mobility and permanent molecular exchange of Vasa protein provides an efficient "scanning" of total volume of the cytoplasm of primary spermatocytes and timely recognition and destruction of unwanted transcripts of the repetitive elements of genome. PMID- 25842867 TI - [RNA-silencing of anionic peroxidase gene decreases the potato plant resistance to Phytophthora infestans (Mont.) de Bary]. AB - Transformed potato (Solanum tuberosum L.) plants expressing the antisense fragment of M21334 gene were estimated. In transgenic plants the decrease of anionic isoperoxidase pI - 3.5 activity was detected. So, the data testify that M21334 gene encodes this isoperoxidase. Decrease of lignin accumulation and dramatic decline of resistance of transgenic potato plants to the late blight agent Phytophthora infestans emphasize an importance of isoperoxidase pI - 3.5 in defense reaction against late blight. PMID- 25842868 TI - [Stimulation of proliferation by carnosine: cellular and transcriptome approaches]. AB - Concentration of endogenous dipeptide carnosine in human muscle tissue reaches tens of millimoles. For more than 100 years of research, a lot of data concerning carnosine functions were accumulated, among which anti-aging effects are regarded most important. Heire, effect of carnosine in cell cultures was studied. It has been found that apart from the known action--an increase of the Hayflick limit and morphological rejuvenation--carnosine stimulates cell division in colony forming assays and in the course of transition of cells to the quiescent state. The analysis of the transcriptome showed that carnosine-induced changes are mainly related to positive regulation of the cell cycle at all levels, from the onset of the DNA synthesis to chromosome condensation. One can suppose that the revealed stimulation of the cell cycle account for the carnosine-induced rejuvenation processes and a high concentration ofcarnosine in muscle tissue is required for the muscle recovery (regeneration) after excess loads. PMID- 25842869 TI - [2'fluoro derivatives of nucleosides as substrates of viral replicative nucleotide polymerases]. AB - Substrate specificities of three viral replicative polymerases of different origins (HIV reverse transcriptase, hepatitis C virus RNA polymerase, and herpes virus DNA polymerase) towards 2'F-NTP were studied. Activated DNA, polyA-oligoUs and (2'F-A)20-oligoU6-complexes were used as templates. It was shown that all DNA polymerases studied can incorporate 2'F-NMP into the 3'-end of primer-template complexes. HIV reverse transcriptase and herpes virus DNA polymerase can elongate synthesis with both dNTP and 2'F-NTP. Homopolymer (2'F-A)20 can serve as a template for polymerization of both UTP and 2'F-UTP,-catalyzed by hepatitis C virus polymerase although with efficacy about 5 to 10-fold lower in comparison with natural primertemplate complex. Pyrophosphorolysis reaction of 2'F-CMP residue at 3'-end of primer catalyzed with HIV reverse transcriptase is going by two orders of magnitude less effective if compared with natural dNMP residue at the same system. PMID- 25842870 TI - [[correlation between macro- and micro-stability C(H)2 domains of human IgG2 and their biological activity. II. Calculation of thermodynamic functions characterizing domains stability]. AB - The thermodynamic parameters of the stabilization of the native structure C(H)2 domains of human myeloma immunoglobulin LOM and SIN second subclass and their firstly obtained hFc fragments were determined using the methods of scanning microcalorimenry. A decrease in the termal stability and energy stability of the native of these domains in the intact proteins correlated in the "phisiological" range of temperatures (20-37 degrees C), mainly, with entropy factor. PMID- 25842872 TI - [RANDTRAN: random transcriptome sequence generator that accounts for partition specific features in eukaryotic mRNA datasets]. AB - The generation of true random and pseudorandom control sequences is an important problem of computational biology. Available random sequence generators differ in underlying probabilistic models that often remain undisclosed to users. Random sequences produced by differing probabilistic models substantially differ in their outputs commonly used as baselines for evaluations of the motif frequencies. Moreover, modern bioinformatics studies often require generation of matching control transcriptome with emulated partitions into ORFs, 5'- and 3' UTRs as well as the proportion of non-coding RNAs within model transcriptome rather than relatively simple continuous control sequences. Here we describe novel random sequence generating tool RANDTRAN that accounts for the length distribution of 5' and 3' non-translated regions in given transcriptome and the partition-specific di- and trinucleotide compositions in translated and non translated regions. RANDRAN presents matching control transcriptomes in ready-to use UCSC genome browser-compatible input files. These features may be useful for generating of control sequence sets for common types of computational analysis of various sequence motifs within various sets of RNA. RANDTRAN is available for free download at http://www.genereseairch.ru/images/Randtran.rar. PMID- 25842871 TI - [Stimulation of DNA molecules association with amphiphilic derivatives of 1,3 diazaadamantane containing hydrophobic side chanins]. AB - Earlier, a new class of compounds--amphiphilic derivatives of 1,3 diazaadamantanes, capable of facilitating the strand exchange in the system of short oligonucleotides was revealed. Longer hydrophobic side chains of 1,3 diazaadamantanes promoted stronger acceleration of the reaction. In this study, interaction with DNA of two 1,3-diazaadamantane derivatives containing different side chains was investigated by use of optical methods. Concentration of the investigated 1,3-diazaadamantans micelles formation were determined by the means of monitoring fluorescence intensity enhancement of 1-anilinonaphtalene-8 sulphonate probe; as well as the ranges of concentrations where the compounds/water mixtures existed as true solutions. 1,3-diazaadamantanes affinity to DNA was determined with Fluorescent Intercalator Displacement (FID) approach. Significant increase in hydrodynamic volume of short DNA hairpins in the complexes with 1,3-diazaadamantanes was revealed by estimation of the fluorescence polarization of ethidium bromide probe bound to the hairpins. Intermolecular association of DNA hairpins upon binding with 1,3-diazaadamantans was confirmed by Forster resonance energy transfer in system of an equimolar mixture of fluorescently labeled with Cy-3 and Cy-5 hairpins. In this study, the number of positive charges at 1,3-diazaadamantane derivatives containing side chains of different lengths was demonstrated to affect their affinity to DNA, whereas longer length of the hydrophobic side chains ensured more efficient interaction between the DNA duplexes that may facilitate, in particular, DNA strand exchange. PMID- 25842873 TI - [Affinity chromatography and proteomic screening as the effective method for S100A4 new protein targets discovery]. AB - Affinity chromatography followed by a selective binding proteins identification can be using as effective method for a biological impotent interactions discovery. The molecular structure and their surface charge as and conformational regulation possibilities, which change their surface hydrophobic properties, all they should to taken in account during method optimization process. With the same' method we had identify some new S100A4 target proteins such as cytoskeleton proteins Sept2, Sept7, Sept11 and this interaction would can to highlight as S100A4 would regulate cell motility. Even we had identify the transcription cofactor Ddx5 and through such complex formation a S100A4 protein would can to regulate E-cadherin, p21 Waf1/Cip1), Bnip3 gene expression. The same protocol can be using for a target proteins search with another S100 protein family members, because their molecules demonstrate a high homology level in amino aside sequences and 3D structures. PMID- 25842874 TI - [Tactics of "damage control" in the injured persons with severe combined trauma of abdominal organs]. AB - In the clinic in 2000 - 2013 yrs of 42 injured persons with severe combined trauma of abdominal organs were treated, in 18 of them the method of a multi staged treatment (damage control) with a short-term operative intervention on the first stage was applied, what permitted to lower postoperative lethality by 22.3%, and rate of purulent-septic complications--by 18.1%. PMID- 25842875 TI - [Prophylaxis and treatment of postoperative complications of abdominoplasty]. AB - Results of abdominoplasty conduction in 206 patients were analyzed. Early postoperative complications are studied and methods of their prophylaxis are elaborated. Minimization of the local complications rate was achieved due to estimation of the anterior abdominal wall state, its angioarchitectonics, the apparatus control of PO2 in cutaneous-subcutaneous flap, rational combination of dermolipectomy and liposuction, prophylaxis of microcirculation disorders. In detailed analysis of remote, first of all, esthetic results of the anterior abdominal wall plasty we have concluded about necessity of the state estimation of surrounding anatomic structures. While planning and conduction of the anterior abdominal wall plasty it is mandatory to take into account the pubis subcutaneous layer width, as well as lateral regions of abdominal wall, pelvis and costal arcs, the form and localization of costal arcs, especially of XII rib and a vertebral column form. Such approach have secured the operation esthetic level raising, reduction of local complications rate, permitted more trustworthy to prognosticate the outcome. PMID- 25842876 TI - [Early enteral therapy in complex of treatment in patients, suffering acute small intestinal ileus]. AB - Results of complex treatment of patients, suffering acute small intestinal ileus, using early enteral therapy via probe, were presented. PMID- 25842877 TI - [Peculiarities of enterosorption via nasointestinal probe using sorbent diosmectite]. AB - Peculiarities of conduction of enterosorption, using sorbent diosmectit via nasointestinal probe, were analyzed in patients, suffering peritonitis in acute ileus. The data obtained witness positive dynamics of indices of endogenic intoxication and antiendotoxic immunity while application of sorbent. PMID- 25842878 TI - [The method of mucosectomy of rectal stump in reconstructive surgery of ulcer colitis]. AB - The method of coloproctectomy performance with formation of a J-like ileal reservoire and ileoanal anastomosis, using welding mucosectomy and protective ileostomy, was proposed. Application of the method guarantees complete excision of the rectal stump mucosa, what excludes the risk of the stump inflammation occurrence, as a sign of residual ulcer colitis in immediate and late postoperative period. Functional results in this setting are not worsen. PMID- 25842879 TI - [Late results of surgical treatment in patients, suffering complicated forms of chronic pancreatitis]. AB - Late results of treatment were analyzed in 58 patients, suffering complicated forms of chronic pancreatitis, to whom draining and resectional-draining surgical interventions were performed. On average the patients age was (49.90 +/- 8.59) yrs, there were 42 (72.4%) men and 16 (27.6%) women. During period of the 3 yrs postoperative follow- up in the patients the pain syndrome severity have reduced essentially and quality of life improved, comparing with those indices after resectional-draining interventions. PMID- 25842880 TI - [Local fibrinolytic therapy in complex of surgical treatment of the brain arterial aneurism in acute period of hemorrhagic insult]. AB - Hemorrhagic insult (HI) with formation of intracranial hemorrhage of various anatomic form constitutes a typical clinical sign of the brain arterial aneurism rupture. Surgical intervention is the only one method of treatment in such patients. Some of them need performance of a one-staged or multi-staged operative interventions, directed on devascularization of the brain arterial aneurisms, evacuation or drainage of intracranial hemorrhage. One of physiological and perspective methods of clinical situation improvement is a local fibrinolytic therapy (LFTH) in complex of surgical treatment of the brain arterial aneurisms. Retrospective cohort investigation was performed in the clinic in 2012 - 2014 yrs on 86 patients with the objective to determine expediency, efficacy and perspective of LFTH application in complex of surgical treatment of the brain arterial aneurisms in acute period of HI. There was established the effectiveness and perspectivity of LFTH in complex of surgical treatment of the brain arterial aneurisms in acute period of HI, not depending on method of its devascularization and positive impact on general results of the patients treatment. PMID- 25842881 TI - [Metabolic support in surgical treatment in patients with stenotic impairment of carotid arteries]. AB - Clinical effectiveness of metabolic support in surgical treatment of patients, suffering stenotic affection of carotid arteries, was estimated. Neoton intraoperative injection inside internal carotid artery have promoted improvement of metabolism in ischemized brain tissues, reduction of metabolic acidosis severity, and preservation of normal bioelectrical activity of the brain. Expediency of prolongation of clinical investigation for intraoperative prophylaxis of reperfusional brain tissue damage, while surgical treatment of patients, suffering stenotic affection of carotid arteries, using metabolic support, was discussed. PMID- 25842882 TI - [Antibodies to Hsp60 in newborn babies, to whom during the intervention for critical inborn heart failure, autologous cord blood was transfused, in early and late postoperative period]. AB - The titre of antibodies to Hsp60 (heat shock protein) enhancement in the blood serum is considered a biological marker of poor state of organism. Comparative investigation was done on the antibodies titre to Hsp60 in the blood serum of a newborn babies, suffering critical inborn heart failure, to whom autologous cord blood or the donor's blood components was transfused, in early and remote postoperative period. In early postoperative period the lowering of the antibodies titre to Hsp60 in the blood serum was observed in comparison with them preoperatively, in a late period (in 2 yrs) in all the blood serum samples investigated antibodies to Hsp60 were not revealed. In 35% of patients, to whom the donor's blood components were transfused, there was registered the enhancement of the antibodies to Hsp60 titre in early postoperative period. High titre of antibodies have associated with enhanced rate of complications. In late postoperative period antibodies to Hsp60 were revealed in 20% of the examined patients. PMID- 25842883 TI - [Atherosclerosis of ascending aorta as a risk factor for neurological complications occurrence in surgical treatment of the ischemic heart disease]. AB - Own experience of the ischemic heart disease (IHD) surgical treatment, combined with the ascending aorta (AA) atherosclerosis, was analyzed. Basing on results of surgical treatment for IHD there were noted mostly informative methods of diagnosis of the AA atherosclerotic affection severity and optimal approaches to surgical treatment of such patients. PMID- 25842884 TI - [Complications of endovascular interventions in patients, suffering critical ischemia of the lower extremities tissues]. AB - Results of endovascular treatment of 315 patients, suffering critical ischemia of the lower extremities tissues, were analyzed. In 45 patients complications have occurred after performance of 349 endovascular interventions, for critical ischemia of the lower extremities tissues. Possibilities of treatment of perioperative complications, using endovascular and open surgical methods, are shown. PMID- 25842885 TI - [Immune status of patients after splenectomy, performed for the spleen traumatic injury in remote terms and choice of preparations for its correction]. AB - Immune status was analyzed in 28 patients in remote period after splenectomy. In accordance to immunological data obtained in splenectomy patients, inhibition of cellular chain of speciphic and natural immunity was noted on background of hyperactivation of its humoral chain with signs of autoimmune processes. In such patients, while immunomodulators selection, the mostly pronounced stimulating impact was noted in immunoglobulin; of sorbents the most binding capacity has rheopolyglukin. This opens further perspectives of postsplenectomy patients treatment, using immunomodulating and elimination correction of the disorders revealed. Expediency of application of rheopolyglukin and immunoglobulin in contents of eliminating amed immunomodulating therapy was substantiated. Studying of peculiarities of immune status constitute a perspective way in the patients, in whom various variants of organpreserving tactics while surgical interventions on spleen were applied. PMID- 25842886 TI - [Orthopedic treatment of the shoulder joint impairment in patients with rheumatoid arthritis]. AB - Brachial joint affection in patients, suffering rheumatoid arthritis, occupies a third place after such of the elbow and the hand. Due to significant reduction of a freedom degree, caused by inflammation, the upper extremity looses function of active instrument for the items transposition. Volume of surgical treatment of such patients depends on stage of the process. On early stages arthroscopic synovectomy of brachial joint is performed and on the late--endoprosthesis. Late results of the treatment are mainly positive. Satisfactory results are based, predominantly, on raising of activity of general rheumatoid inflammation. PMID- 25842887 TI - [Evaluation of intestinal viability on a simulation model of a small ileus based on determination of dielectric parameters]. AB - Interrelationship between dielectric parameters and level of ATPH before and during ischemia, as well as with indices of survival after elimination of strangulation, was estimated on a simulation model of strangulation ileus in rats. The data obtained permit to suppose, that parameter tg deltam may be used as effective noninvasive criterion of diagnosis in real time for estimation of the intestinal wall state in strangulation. Resection of the infringed intestine without elimination of strangulation is necessary in tg deltam less than 2.20, in tg deltam more than 2.36 the elimination of infringement is indicated, because there exist possibility to restore intestinal function after ischemic-reperfusion injury. Tactics of treatment in intermediate meanings of tg deltam is not determined, but its measurement before reperfusion may help in estimation of a small intestine viability and choice of surgical tactics in its ischemia. PMID- 25842888 TI - [Investigation of simple and complex prelamination of vascularized flaps in experiment]. AB - Prelamination, permitting improvement not esthetics only, but also function of the damaged region, to create necessary, by contents and configuration, vascularized complexes of tissues, is applied for effective treatment of complex defects in tissues. In experiment on laboratory animals for prelamination of vascularized flaps were applied separate and combined placement of mucosal and cartilaginous autotransplants. Results of the investigation witness possibility and efficacy of creation of content--component complexes of tissues, owing necessary characteristics for their further application in the clinic during performance of reconstructive interventions. PMID- 25842889 TI - [Investigation of adhesive properties of polypropylene net prosthesis "ESPERA"]. AB - Adhesive towards the cells properties of three polypropylene net prostheses (PNP), manufactured by "Espera", with the slots size 1 x 1 mm, 2 x 2 mm, 2 x 4 mm and one specimen (the slot diameter 1 mm) on the oxycellulose background, were tested for prognostication of hernioplasty results, using nonresorbable PNP. The adhesion degree and peculiarities of cellular line, obtained from embryonal kidney of pig, put on the tested nets specimen in conditions of cultivation during 5 - 10 days were estimated, using inverted microscope in regime of phasic contrast. The data obtained witness the lowered cellular adhesion towards PNP "Espera" without oxycellular background. The net processing, using components of extracellular matrix, as well as presence of the oxycellulose fragments, facilitate the PNP ingrowth by connective tissue. PMID- 25842890 TI - [Restitution of bioactive ceramic material "Syntekost" by a newly evolved bone in experiment]. AB - Peculiarities of reparative processes of bioactive ceramic material "Syntekost", as well as reaction of structures of internal ear on these material, transplanted on osteal bulla in guinea pigs for experimental model of antromastoidotomy creation, were studied up. The signs of its resorbtion were mild, and these processes not always paralleled the osteal tissue evolvement. A newly formed osteal beams were observed up to 90-th day. In terms up to 12 mo there were preserved practically unchanged groups of granules of ceramic implanted material. New bone have evolved in a kind of foci in a distance from internal surface of osteal bulla. Inflammation or ototoxic impact of the material on structures of internal ear were not observed. PMID- 25842891 TI - [Military--medical doctrine of the Ukraine (project)]. PMID- 25842892 TI - [Possibilities of surgical correction of metabolic syndrome as a comorbid factor for the obstetrics-gynecological diseases]. PMID- 25842893 TI - [Observation of perforation of gastric ulcer in a giant hiatal hernia]. PMID- 25842894 TI - [Treatment of gastrointestinal stromal jejunal tumor]. PMID- 25842895 TI - [Probability of incidence of abdominal adhesional process in peritonitis, depending on the sanation preparation applied]. PMID- 25842896 TI - [XIV Annual Scientific Conference with international participation. "Surgery wounds. Emergency and elective surgery, the use of electric welding of living tissues. Innovations in surgery wounds, diabetic foot syndrom and joints"]. PMID- 25842897 TI - Diversity of diazotrophic gut inhabitants of pikas (Ochotonidae) revealed by PCR DGGE analysis. AB - Diazotrophic gut symbionts are considered to act as nitrogen providers for their hosts, as was shown for various termite species. Although the diet of lagomorphs, like pikas or rabbits, is very poor in nitrogen and energy, their fecal matter contains 30-40% of protein. Since our hypothesis was that pikas maintained a diazotrophic consortium in their gastrointestinal tract, we conducted the first investigation of microbial diversity in pika guts. We obtained gut samples from animals of several Ochotona species, O. hyperborea (Northern pika), O. mantchurica (Manchurian pika), and O. dauurica (Daurian pika), in order to retrieve and compare the nitrogen-fixing communities of different pika species. The age and gender of the animals were taken into consideration. We amplified 320 bp long fragments of the nifH gene using the DNA extracted directly from the colon and cecum samples of pika's gut, resolved them by DGGE, and performed phylogenetic reconstruction of 51 sequences obtained from excised bands. No significant difference was detected between the nitrogen-fixing gut inhabitants of different pika species. NifH sequences fell into two clusters. The first cluster contained the sequences affiliated with NifH Cluster I (Zehr et al., 2003) with similarity to Sphingomonas sp., Bradyrhizobium sp., and various uncultured bacteria from soil and rhizosphere. Sequences from the second group were related to Treponema sp., Fibrobacter succinogenes, and uncultured clones from the guts of various termites and belonged to NifH Cluster III. We suggest that diazotrophic organisms from the second cluster are genuine endosymbionts of pikas and provide nitrogen for further synthesis processes thus allowing these animals not to be short of protein. PMID- 25842899 TI - Application of bioinformatics tools and databases in microbial dehalogenation research (a review). AB - Microbial dehalogenation is a biochemical process in which the halogenated substances are catalyzed enzymatically in to their non-halogenated form. The microorganisms have a wide range of organohalogen degradation ability both explicit and non-specific in nature. Most of these halogenated organic compounds being pollutants need to be remediated; therefore, the current approaches are to explore the potential of microbes at a molecular level for effective biodegradation of these substances. Several microorganisms with dehalogenation activity have been identified and characterized. In this aspect, the bioinformatics plays a key role to gain deeper knowledge in this field of dehalogenation. To facilitate the data mining, many tools have been developed to annotate these data from databases. Therefore, with the discovery of a microorganism one can predict a gene/protein, sequence analysis, can perform structural modelling, metabolic pathway analysis, biodegradation study and so on. This review highlights various methods of bioinformatics approach that describes the application of various databases and specific tools in the microbial dehalogenation fields with special focus on dehalogenase enzymes. Attempts have also been made to decipher some recent applications of in silico modeling methods that comprise of gene finding, protein modelling, Quantitative Structure Biodegradibility Relationship (QSBR) study and reconstruction of metabolic pathways employed in dehalogenation research area. PMID- 25842898 TI - [In vitro antitumor activity of heterochitooligosaccharides (a review)]. AB - This review presents an analysis of the literature data over the last decade in order to reveal the relationship between the structure and composition of chitin/chitosan oligomers and their antitumor activity. Oligosaccharides consisting of N-acetylglucosamine and/or glucosamine units connected to each other by beta-1,4-O-glycoside bond are generally called chitooligosaccharides. Homochitooligosaccharides are the oligomers of N-acetylglucosamine (AGA) or glucosamine (GA). Heterooligosaccharides are a mixture of various oligomers differing in the degree of polymerization (DP), acetylation (DA), or deacetylation (DD), as well as in the location of N-acetyl residues in the oligomer chain. Heterochitooligomers with a polymerization degree of no more than 10 are usually water soluble. The solubility of chitooligosaccharides with a DP of more than 10 depends on the DA and pH of a solution. The pharmaceutical and food industries, as well as scientists engaged in basic research, are interested in the use of heterochitooligosaccharides. This is explained by their unique properties, such as good water solubility; minimal toxicity; biocompatibility; the ability to penetrate cell membranes, resulting in a high degree of absorption (unlike chitin and chitosan); and their biological activity. Therefore, in the last decade, researchers have focused their attention on studying the relationship of the structure of oligosaccharides and their specific activity, such as antitumor, antimicrobial, antioxidant, immunemodulatory, and other activities. This is shown by the number of publications, which has doubled compared to the number in 2001. PMID- 25842900 TI - Isolation and characterization of a novel thermostable beta-glucosidase from Bacillus subtilis SU40. AB - A new bacterial strain SU40 with ability to produce thermostable beta-glucosidase was isolated from soil located at Puducherry (India) and identified as Bacillus subtilis. The conditions like temperature, pH, carbon and nitrogen sources were optimized conditions for the maximum production of beta-glucosidase. The enzyme was purified using ammonium sulphate precipitation and BioSep and HPLC chromatography. Purified enzyme was found to be a monomeric protein with an apparent molecular mass of 38.3 kDa. The enzyme was stable over a wide range of pH and temperatures and exhibited maximal activity at 75 degrees C and pH 12.0. The enzyme was found to retain approximately 60% of maximal activity for 1 h at 70 degrees C and hydrolyzed a wide range of aryl-beta-D-glucosides and beta linked oligosaccharides with highest activity towards cellobiose and p nitrophenyl-beta-D-glucopyranoside. The Km and Vmax values of the enzyme were 0.21 MUM and 9.38 MUmoles mg(-1) min(-1), respectively. The enzyme demonstrated stability in the presence of 0.5% surfactants and was completely inhibited after addition of EDTA and Hg2+ ions. Synergistic action of beta-glucosidase from B. subtilis SU40 with endoglucanase from Paenibacillus barcinonensis MG7 completely degraded the rice straw. PMID- 25842901 TI - Biochemical characterization and functional analysis of UDP-glucose dehydrogenase, in the synthesis of biopolymer Ss from Sphingomonas sanxanigenens NX02. AB - Biopolymer Ss of Sphingomonas sanxanigenens strain NX02 is an sphingan that can be extracted using a small quantity of acid, which is a low cost extraction process. A UDP-glucose dehydrogenase gene (ugdG), related to Ss biosynthesis, was cloned from S. sanxanigenens NX02 and expressed in Escherichia coli. It encoded a 454-residue protein of 48.2 kDa. The deduced amino acid sequence had 77% identity with UDP-glucose dehydrogenase (UgdG) from Sphingomonas sp. KC8, and 73% identity with UgdG from Sphingomonas elodea ATCC31461. Purified recombinant UgdG had maximum activity at 35 degrees C and pH 8.0, with Km values of 0.47 and 0.38 mM for UDP-glucose and NAD+, respectively. Overexpression of the ugdG gene in S. sanxanigenens resulted in increased (14.9 +/- 0.5)% Ss production and higher fermentation broth viscosity. Furthermore, the weight-average molecular weight of polymer Ss from the recombinant strain was (5.3 +/- 0.16)% higher and the viscosity was (74 +/- 0.15)% higher than those from the WT strain at a shear rate of 1 rev/min. PMID- 25842902 TI - [Reactivating factor of Luteococcus japonicus subsp. casei: isolation and characterization]. AB - It has been shown that a producer strain of reactivating factor (RF) is identical to a typical strain of Luteococcus japonicus DSM 10546 from the Propionibacteriaceae family according to the physiological and biochemical properties and the sequencing of 16S rRNA fragments. A number of phenotypical differences from the model strain allowed the producer strain to be considered a subspecies of Luteococcus japonicus, and it was named Luteococcus japonicus subsp. casei. At cultivation of the producer, RF is secreted into the medium and plays the role of a signaling molecule. RF antioxidant activities towards various organic radicals may be a possible mechanism of its protective and reactivating effects. Metabolites secreted by the L. casei producer strain into the culture medium were separated by a combination of liquid chromatographies. Four components possessing biological activities were found. The most active one was studied by MALDI-TOF mass spectrometry, which revealed that it is a polypeptide. Primary identification of some amino acid residues was performed. Sugar residues were found in the structure. PMID- 25842903 TI - [Amylase inhibitors from Streptomyces lucensis VKPM Ac-1743 and Streptomyces violaceus VKPM Ac-1734]. AB - Inhibitors synthesized by the Streptomyces lucensis VKPM AS-1743 and Streptomyces violaceus VKPM AS-1734 strains were studied for their influence on amylases of different origin. The effect of the inhibitors was shown to be different on fungal amylase, pancreatic amylase, and amylase from human blood. It has been found that the studied inhibitors are substances of a pseudooligosaccharide nature and exhibit their activity and stability over a wide range of pH and temperature values. The physico-chemical and biochemical properties of isolated inhibitors were compared with those of known microbial inhibitors of alpha glucosidases. PMID- 25842904 TI - [Transformation of amides by adherent rhodococcus cells possessing amidase activity]. AB - We report the development of a heterogeneous biocatalyst for the hydrolysis of amides that is based on cell adhesion ofamidase-containing Rhodococci on activated birch carbon (ABC) and crude carbon. We investigated the properties of the obtained biocatalyst in the hydrolysis reaction of acrylamide to acrylic acid and nicotinamide to nicotinic acid, as well as in a model reaction of racemic lactamide hydrolysis to a mixture of D- and L-isomers of lactic acid. We show that a six- and threefold increase in the concentrations of adherent and suspended cells, respectively, results in a reduction of amidase activity by 3 and 30 times, respectively. ABC Cells adherent on ABC maintained more than 50% of enzymatic activity for seven 24-hour cycles of acrylamide hydrolysis, while suspended cells lost more than 60% of activity already in the second cycle. We also noted that cell adhesion on ABC reduced the stereoselectivity of hydrolysis reaction of racemic lactamide. PMID- 25842905 TI - [Adhesion of Bacillus subtilis on the surface of pectin-calcium gel]. AB - Pectin-calcium gels obtained based on pectins of callus cultures are able to adhere to the surface of cells of Gram-positive bacteria Bacillus subtilis to various degrees and this is thanks to the structural features of pectin. Rapid adhesion of the cells to gels obtained from the pectin of Tanacetum vulgare (TVC) callus cultures is associated with a high content of the linear region in the carbohydrate chain of pectin, a high molecular weight, and a low degree of methyl etherification of pectin. The number of adherent cells on the surface of gels obtained from pectins of Silene vulgaris callus cultures (SVC), TVC, and Lemna minor (LMC) after 8 h of incubation was close, whereas the number of cells was minimal on a gel produced using the pectin of Silene tatarica (STC) callus culture. This was due to the higher degree of methyl etherification of STC pectin (45%) compared to other pectins (4-12%). The adhesion rate constant (k) of B. subtilis for TCV gel during the first 120 min was the highest in comparison with other gels; the k value for SVC, STC and LMC gels was similar. The lowest level of k was characteristic for the gel from commercial apple pectin. The obtained data can beused for the production of gels with adhesive and antiadhesive properties. PMID- 25842906 TI - [Investigation of stages of chemical leaching and biooxidation during the extraction of gold from sulfide concentrates]. AB - We examined the chemical leaching and biooxidation stages in a two-stage biooxidation process of an auriferous sulfide concentrate containing pyrrhotite, arsenopyrite and pyrite. Chemical leaching of the concentrate (slurry density at 200 g/L) by ferric sulfate biosolvent (initial concentration at 35.6 g/L), which was obtained by microbial oxidation of ferrous sulfate for 2 hours at 70 degrees C at pH 1.4, was allowed to oxidize 20.4% ofarsenopyrite and 52.1% of sulfur. The most effective biooxidation of chemically leached concentrate was observed at 45 degrees C in the presence of yeast extract. Oxidation of the sulfide concentrate in a two-step process proceeded more efficiently than in one-step. In a two-step mode, gold extraction from the precipitate was 10% higher and the content of elemental sulfur was two times lower than in a one-step process. PMID- 25842907 TI - [Analysis of metabolic profile of Chlamydomonas reinhardtii cultivated under autotrophic conditions]. AB - This study presents a metabolite profile analysis of unicellular green alga Chlamydomonas reinhardtii grown under autotrophic conditions at late stages of culture development. Metabolites were identified by gas chromatography coupled to mass spectrometry. Approximately 400 peaks corresponding to individual compounds were distinguished, of which approximately 100 compounds (including saccharides, fatty acids, aromatic compounds, amino acids, alcohols, etc.) were identified. A local database of mass spectra of unidentified compounds was created using MassBank software. Mapping of the metabolomic data with the use of the ChlamyCyc service showed that the identified compounds are involved in various energetic, synthetic, and signaling pathways in Chlamydomonas. The mapping of metabolites by their chemical structure with the use of Cytoscape software, combined with quantitative interpretation, showed that the majority of organic matter was concentrated primarily in the carbon backbones of fatty acids and terpenes, as well as saccharides and structurally similar compounds. PMID- 25842908 TI - [Properties of extracellular proteinase--an activator of protein C in blood plasma formed by Aspergillus ochraceus]. AB - The properties of an extracellular proteinase activating plasma protein C isolated from the culture supernatant of A. ochraceus VKM F-4104D have been studied. This enzyme demonstrated a substrate specificity absent of hydrolyzing activity toward chromogenic proteinase substrates. On the basis of inhibitory analysis, the protein C-activating proteinase from A. ochraceus VKM F-4104D appeared to be a serine proteinase, together with that isolated from the venom of Agkistrodon contortrix contortrix. The isolated enzyme was a nonglycosylated protein with a molecular weight of about 33 kDa, pI 6.0 with an observed optimal activity under a pH of 8.0-9.0 and 37 degrees C. A comparison of the properties of the protein C-activating proteinase formed by A. ochraceus and the enzyme derived from the venom of Agkistrodon contortrix contortrix demonstrated a similarity in their properties; however, proteinase from the micromycete appeared to be in the nonglycosylated state and possessed the ability to hydrolyze the chromogenic plasmin substrate H-D-Val-Leu-Lys-pNA. PMID- 25842909 TI - [Formation of biogenic amines in wine production]. AB - Factors and conditions for the formation of biogenic amines in wine production were studied. It was shown that amino acids were decarboxylated during alcoholic fermentation and biological acidic reduction in the presence of enzymes of yeast and lactic acid bacteria. The pH value, the presence of phenolic compounds, tartaric and malic acid, the duration of the contact between the wine material and yeast lees, and the rate of their autolysis were found to influence the intensity of the decarboxylation process. PMID- 25842910 TI - [Antiradical properties of essential oils and extracts from clove bud and pimento]. AB - The antiradical properties of essential oils and extracts from the clove bud (Eugenia caryophyllata Thumb.) and berries of tree (Pimenta dioica (L.) Meriff) were studied and compared with the properties of synthetic antioxidant ionol (2,6 ditret-butyl-4-hydroxytoluene, BHT) in model reactions with the stable free 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical. The essential oils of clove bud and pimento had qualitatively close composition of the main components but differed by their quantitative content. In the studied samples, eugenol was the main compound with high antiradical activity. The reaction rates of essential oils and extracts with the DPPH radical were practically the same for essential oils and twice the reaction rate of BHT. The values of antiradical efficiency (AE) were also close for essential oils and were twice that for extracts and ionol. A synergetic action of components in the essential oil and extract of pimento on antiradical efficiency values was found. PMID- 25842911 TI - [Extending therapeutic possibilities in relapsing-remitting multiple sclerosis: dimethyl fumarate]. AB - Dimethyl fumarate (DMF) is a novel oral therapy that has recently been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Dimethyl fumarate shows anti-inflammatory and cytoprotective properties that are thought to be mediated primarily via activation of the nuclear factor (erythroid-derived 2)-like 2- Nrf2 transcriptional pathway, which up-regulates the genes involved in the cellular response to oxidative stress. The drug was evaluated in 2 large, randomized, double-blind, multicentric, multinational, 2-year, phase III clinical trials. The DEFINE and CONFIRM trials, conducted with over 2600 adult patients suffering from RRMS, unequivocally confirmed the efficacy of DMF (2 x 240 mg daily) in reducing the annualized relapse rate (ARR) and reducing the proportion of patients with MS relapse at 2 years. Significantly reduced sustained disability progression was observed with the drug versus placebo in DEFINE, while the same tendency was seen in CONFIRM. The MRI results of the studies were also convincing: DMF significantly reduced the number of new/enlarging T2-hyperintense lesions and the number of Gd-enhancing lesions compared to placebo. Dimethyl fumarate was generally well tolerated and no safety concern has been raised. Adverse events that occurred most frequently included flushing and gastrointestinal events. The long-term efficacy and tolerability of dimethyl fumarate is currently being investigated in the ENDORSE trial, with interim results demonstrating the same results as the two previous studies. In conclusion, although further, mostly comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, dimethyl-fumarate is a valuable addition to the therapeutic options available for RRMS. PMID- 25842912 TI - Role of modified open-door laminoplasty in the treatment of multilevel cervical spinal stenosis: a retrospective analysis of 43 cases. AB - BACKGROUND AND PURPOSE: Symptomatic degenerative multilevel cervical spinal stenosis--beside other methods--is often treated using the open-door laminoplasty. This procedure aims to decompress the spinal cord and preserve the stability of the cervical spine. The efficiency and safety of the method was proved by numerous Japanese and American studies, also the technique related complications are well known. We treated 43 patients with symptomatic multilevel cervical spine stenosis using the open-door laminoplasty as a surgical procedure of choice in the National Institute of Clinical Neurosciences between 2009 and 2012. In this article we analyse our results and the related literature is discussed. METHODS: Symptomatic patients with a minimum of three-segment cervical spine stenosis and radiologically proved myelopathy or with electrophisiologically verified subclinical myelopathy were selected for laminoplasty. Patients in whom cervical kyphosis was present were operated on using laminectomy and posterior fusion. Postoperative control CT, MRI and/or X ray images were made after the surgery and at six weeks, three, six and 12 months after the operation and in the same time neurological evaluation was performed. The modified Japanase Orthopaedic Association (mJOA) scale value was assigned to patients preoperatively, six weeks, three, six and 12 months after the operation. The statistical difference between the groups of data was tested by chi square test. RESULTS: The average follow-up time was 27 months (minimum seven, maximum 42). According to the mJOA scale, 26 patient's condition (61%) improved, in 13 cases (30%) remained unchanged, and in one case (2%) we detected neurological deterioration. We lost three patients during the follow up period. The median of mJOA preoperatively was 12 (minimum eight, maximum 18), while six week postoperative mJOA was 14 (minimum 10, maximum 17). Three, six and 12 months mean value of mJOA was 14 which shows that the improvement in patients' condition remained stable at one year after surgery. The difference was statistically significant (p < 0.05). The canal's average anteroposterior diameter on CT was 8.29 +/- 0.92 mm at the level of C III, while after the operation we measured 15.16 +/- 1.02 mm; 7.54 +/- 0.62 mm at the level of C IV before, and 15.29 +/- 0.2 mm after; 9.05 +/- 0.48 mm at the level of C V before and 17.23 +/- 0.4 mm after the surgery. The differences proved to be significant (p = 0.0001). CONCLUSION: According to our experiences the modified open-door laminoplasty is an efficient and safe method for the treatment of symptomatic multilevel cervical spinal stenosis. PMID- 25842913 TI - [The efficacy of lacosamide in relation to antiepileptic drug history. Clinical experiences in adult partial epilepsy]. AB - OBJECTIVE: A retrospective study in adult partial epilepsy on the efficacy of lacosamide in relation to previous antiepileptic drug experiences. METHOD: We analysed 3-65 months' data on epilepsy-care of 43 pharmacoresistant partial epilepsy patients treated with lacosamide. Further analysis of antiepileptic drug history was carried out in strictly selected subgroups of patients with good and poor therapeutic response to lacosamide (10 and 9 patients, respectively) for 2 10 years long retrospective follow up. PATIENTS: Adult patients with partial onset seizures had been treated previously with three or more lifetime antiepileptic drugs without permanent success. RESULTS: Six patients (14%) were seizure free, eleven patients (25%) have experienced important improvement (their seizure-frequency decreased by at least 50%) for more than 12 months. Fourteen patients (32%) improved for less than 6 months and then have relapsed; and add-on lacosamide proved ineffective in 12 patients (28%). Those selected 10 patients successfully treated with lacosamide (seizure free for at least six months) favourably responded to carbamazepine or oxcarbazepine earlier and levetiracetam was ineffective or even caused worsening. The selected lacosamide-unresponsive nine patients responded unfavourably to carbamazepine or oxcarbazepine earlier. Fifteen patients (35%) suffered side effects as dizziness or sleepiness, in 11 of them lacosamide was combined with a "traditional" sodium-channal blocker antiepileptic drug. CONCLUSION: Lacosamide is an effective add-on antiepileptic drug in difficult-to treat adult partial epilepsy patients. Our data suggest that good lacosamide response may be expected in those patients who reacted favourably to "traditional" sodium-channel blocker carbamazepine or oxcarbazepine earlier. PMID- 25842914 TI - Assessment of severity and time course of critical illness neuropathy in septic patients: a prospective observational study. AB - OBJECTIVE: In this prospective observational study we investigated electrophysiological alterations in the early phase of critical illness and correlated electrophysiological findings with the clinical picture and outcome. METHODS: We enrolled 21 critically ill surgical patients having >= 12 Acute Physiology and Chronic Health Evaluation (APACHE) II scores on admission. Routine non-invasive bilateral electroneurography (ENG) examination of median and ulnar nerves was done on five consecutive days starting in two days after admission. Then weekly follow-up was performed. Motor and sensory nerve conduction indices were calculated and correlated with APACHE II and Simplified Acute Physiology Score II severity scores. RESULTS: On the first examination 18/21 patients had > 20% reduction in the motor and sensory nerve conduction indices. Severity score systems showed significant negative correlation with the daily change of CMAP and SNAP amplitudes and calculated nerve conduction indices (Spearman's correlation, p < 0.001). Mortality was higher in the patients with worse admission ENG and/or stagnant electrophysiological status or declining tendency in the first week. CONCLUSIONS: Electrophysiological alterations appeared soon after the development of critical illness. Early phase alterations showed a strong correlation with patients' general condition and more severe electrophysiological alterations predisposed to higher mortality. In several cases early alterations proved to be reversible. PMID- 25842915 TI - [Intraoperativ electrophysiological monitoring during neurosurgery on eloquent structures]. AB - OBJECTIVE: We summarize our experiences on intraoperative electrophysiological monitoring during neurosurgical procedures on eloquent neuronal structures. PATIENTS, METHODS: Sixty patients were enrolled retrospectively in our study with pathologies involving eloquent neuronal structures. They were operated between May 2011. and March 2012. at the University of Debrecen, Department of Neurosurgery and at the National Institute of Neurosciences. Patients underwent standard preoperative examinations due to the primary pathology. In all cases we used intraoperative electrophysiological monitoring. We had 22 cases with cranial nerve monitoring, 10 cases with cauda monitoring, 16 cases with motor system monitoring, six cases with complex spinal cord monitoring, three degenerative spine reconstructions and 3 awake surgeries. RESULTS: We found that with the use of intraoperative electrophysiology we could make these neurosurgical procedures safer, and were able to optimize the extent of resection in the cases of oncological pathologies. CONCLUSIONS: Our experiences as well as the international literature suggests that in certain high risk neurosurgical procedures intraoperative electrophysiology is indispensible for safe and optimally extended operation. PMID- 25842916 TI - [Effectiveness of anticoagulation with vitamin K antagonists in acute stroke patients with atrial fibrillation--Hungarian results]. AB - BACKGROUND AND OBJECTIVE: An estimated 20% of ischemic strokes are of cardiogenic origin, half of which is associated with atrial fibrillation (AF). Anticoagulation treatment of patients with this arrhythmia reduces their risk of stroke. Effectiveness and safety of oral anticoagulant therapy with vitamin K antagonists (VKA) is limited, however, by their well-known narrow therapeutic window and the substantial inter- and intraindividual variability of INR values depending on genetic and dietary factors as well as drug interactions. Our objective was to evaluate the prevalence of adequate anticoagulation and the level of anticoagulant effect actually achieved among patients with AF hospitalized for acute stroke. METHODS: Patients with AF admitted to our hospital ward in 2012 for acute stroke (n = 226) were included in the analysis. Using descriptive statistics, relevant clinical and therapeutic characteristics of the patients were assessed, with special reference to the INR values on admission (among patients with known AF), and the clinical outcomes. RESULTS: Of the study cohort, 170 patients had a diagnosis of AF before the admission for stroke, but 47% of them did not take anticoagulants. Patients who suffered stroke while on anticoagulants (83 on VKA, 7 on low-molecular-weight heparins), were in most cases (75%) out of the therapeutic INR range, typically undertreated (INR < 2). Overall, inadequate or completely absent anticoagulation was documented in 81% of the stroke cases occurring in patients with known AF. Of the entire study cohort, 41% was discharged home, 34% required continued institutional care, and 25% died. CONCLUSIONS: The inadequacy or lack of anticoagulation was observed in the vast majority of acute strokes in patients with known AF. These cases are often related to the well-documented limitations of VKA therapy in terms of its safety, tolerability and/or practical aspects. To prevent them, important changes are warranted in the anticoagulation practice, including the closer control of VKA therapy and the broader use of new oral anticoagulants. PMID- 25842917 TI - [Treatment of osteoporotic vertebral compression fractures with PMMA-augmented pedicle screw fixation]. AB - BACKGROUND: Over the last few decades many innovative operation technique were developed due to the increase of porotic vertebral fractures. These new techniques aim to reach the required stability of the vertebral column. In case of significant instability, spinal canal stenosis or neural compression, decompressive intervention may be necessary, which results in further weakening of the column of the spine, the minimal invasive percutan vertebroplasty is not an adequate method to reach the required stability, that is why insertion of complementary pedicular screws is needed. Considering the limited screw-fixing ability of the porotic bone structure, with this new technique we are able to reach the appropriate stability of cement-augmented pedicle screws by dosing cement carefully through the screws into the vertebral body. We used this technique in our Institute in case of 12 patients and followed up the required stability and the severity of complications. METHODS: Fifteen vertebral compression fractures of 12 patients were treated in our Institute. Using the classification proposed by Genant et al. we found that the severity of the vertebral compression was grade 3 in case of 13, while grade 2 in case of two fractures. The average follow up time of the patients was 22 months (12-39), during this period X-ray, CT and clinical control examinations were taken. During the surgery the involved segments were localised by using X-ray and after the exploration the canulated screws were put through the pedicles of the spine and the vertebral body was filled through the transpedicular screws with bone cement. Depending on the grade of the spinal canal stenosis, we made the decompression, vertebroplasty or corpectomy of the fractured vertebral body, and the replacement of the body. Finally the concerned segments were fixed by titanium rods. RESULTS: In all cases the stenosis of spinal canal was resolved and the bone cement injected into the corpus resulted in adequated stability of the spine. In case of six patients we observed cement extravasation without any clinical signs, and by one patient--as a serious complication--pulmonary embolism. Neurological progression or screw loosening were not detected during the follow up period. Part of the patients had residual disability after the surgery due to their older ages and the problem of their rehabilitation process. CONCLUSION: After the right consideration of indications, age, general health condition and the chance of successful rehabilitation, the technique appears to be safe for the patients. With the use of this surgical method, the stability of the spine can be improved compared to the preoperative condition, the spinal canal stenosis can be solved and the neural structures can be decompressed. The severity of complications can be reduced by a precise surgical technique and the careful use of the injected cement. The indication of the surgical method needs to be considered in the light of the expected outcome and the rehabilitation. PMID- 25842918 TI - [Inclusion body myositis]. AB - The idiopathic inflammatory myopathies are systemic, chronic autoimmune diseases characterized by proximal symmetrical muscle weakness. One of the main diseases in this group is inclusion body myositis (IBM), an underdiagnosed, progressive muscle disease characteristically affecting the middle-aged and older population. It has a slow, relentlessly progressive course. The precise pathogenesis of the disease remains unknown. In most of the cases it is diagnosed a few years after the appearance of the first symptoms. The muscle biopsy typically shows endomysial inflammation, with invasion of mononuclear cells into the non-necrotic fibers, and also rimmed vacuoles. It appers, that both inflammation and degeneration are present at the onset of the disease. Our aim is to raise awareness about this disease which leads to severe disability, with clinicopathological case presentations and literature overview, emphasizing the importance of collaboration between the clinician and the neuropathologist. No effective therapy is currently available but the rapid diagnosis is essential to slow disease progression. Although this is a relatively rare disease, patients are presenting not only in immunology outpatient clinics; our reports aims to raise awareness and facilitate accurate early diagnosis of IBM. PMID- 25842919 TI - The first identified Central-Eastern European patient with genetically confirmed dentatorubral-pallidoluysian atrophy. AB - AIMS: Dentatorubral-pallidoluysian atrophy (DRPLA) is an inherited neurodegenerative disorder characterized by a trinucleotide repeat expansion. The disease mainly occurs amongst the Japanese and is extremely rare in the European population. The characteristic clinical symptoms are cerebellar ataxia, dementia, choreoathetoid movements, epileptic seizures and myoclonus. The aim of this study is to present the first genetically confirmed Hungarian case of DRPLA. CASE REPORT: The middle-aged female patient developed the characteristic clinical symptoms except myoclonus over her late thirties with positive family history. The major finding in the skull magnetic resonance imaging was the atrophy of infratentorial brain structures with the consequential dilation of related cerebrospinal fluid spaces. A detailed neuropsychological examination was also performed and it revealed moderate cognitive dysfunctions, mild depression and anxiety. As underlying conditions, Huntington's disease and common spinocerebellar ataxia forms all came into consideration, but all the result of the respective genetic tests were negative. However, the test for mutation in the ATN1 gene revealed pathological heterozygous CAG repeat expansion. CONCLUSION: This case study serves as the first description of genetically confirmed DRPLA in the Central-Eastern region of Europe, the clinical features of which seems to be very similar to the previously reported cases. PMID- 25842920 TI - [Myocardial infarction and acute coronary syndrome: definitions, classification, and diagnostic criteria]. AB - The review gives the definitions and classification of and diagnostic criteria for myocardial infarction and acute coronary syndrome in accordance with the "The third universal definition of myocardial infarction" adopted in 2012 (Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction, 2012). It also discusses the clinical and morphological comparisons of and the problems in the differential diagnosis of myocardial infarction as a nosological entity within coronary heart disease with other coronarogenic and non coronarogenic necroses of the myocardium. PMID- 25842921 TI - [Functional morphology of ischemic cardiomyopathy]. AB - OBJECTIVE: To show that ischemic cardiomyopathy (ICM) that is generally believed to be a variant of chronic heart disease (CHD) and an analogue of chronic heart failure is an initial stage and the background of all further forms of CHD. SUBJECTS AND METHODS: Sixty cardiac biopsies obtained from patients during aortocoronary bypass surgery for CHD and myocardia from 55 rabbits in which the investigators simulated atherosclerosis over time, as well as acute, transient, and recurrent coronary insufficiency after vasopressin administration were examined. A number of adequate histological, histochemical, and immunohistological procedures, electron microscopic and electron histochemical studies, and morphometry were employed. The investigators made biochemical monitoring of blood cholesterol and triglyceride levels and ECG monitoring in the animals had received intravenous vasopressin. RESULTS: The authors have indicated that CHD begins with endothelial changes in the trophic component of the microhemocirculatory bed, which gives rise to its impaired blood flow and to hypoxia at the level of the myocardial structural and functional unit- fascicules. Over time, the disease develops a set of processes that cause damage to microvessels, cardiomyocytes, stroma, lymph capillaries, and nerve endings and changes in secretion. Compensatory and adaptive responses that long mask the symptoms of damage to the vascular bed and myocardial tissue take place simultaneously. The occurring lesions result in irregular diffuse cardiosclerosis, micro- and lymphocirculatory, innervation, and conduction disturbances, and irregular cardiomyocyte damage. The authors consider this set of myocardial changes to be an initial phase of ICM that shows no clinical manifestation at all. As coronary atherosclerosis progresses, the already damaged myocardium is superimposed by the morphological changes caused by higher hypoxia at the whole organ level. Depending upon a combination of these changes, one or another form of CHD and progression of chronic CHD may prevail at a later time. CONCLUSION: ICM is a broader concept than chronic heart failure and it is a basis for the pathogenesis and morphogenesis of CHD. PMID- 25842922 TI - [Comparative study of the determination of the HER2 status in gastric cancer in the biopsy and intraoperative specimens]. AB - OBJECTIVE: To determine the HER2 status of gastric adenocarcinomas, by using biopsy and intraoperative specimens. SUBJECTS AND METHODS: Immunohistochemistry and in situ hybridization were used to examine the HER2 status of 346 gastric cancer biopsy and intraoperative specimens. RESULTS: The study conducted on a large Russian sample of 346 patients showed a positive HER2 status in 10.7% of the examined specimens. Intestinal-type adenocarcinomas exhibited a positive HER2 status in 21.4% of the cases. Comparative analysis of the HER2 status in the biopsy and intraoperative specimens indicated that there were differences in the determination of the tumor HER2 status in less than 1% of the examined specimens. The remaining found differences (14.7%) failed to change the tumor HER2 status and to affect the choice of a treatment regimen. CONCLUSION: The performed investigation has demonstrated that the tumor HER2 status determined in the biopsy specimen significantly reflects the molecular biological properties of gastric cancer and may be clinically used to determine indications for the use of targeted drugs. PMID- 25842923 TI - [The morphology and molecular bases of damage to the stem cell niche of respiratory acini in idiopathic interstitial pneumonias]. AB - The authors present the material of their study of the morphological and molecular biological features of damage to the stem cell niches (SCN) in the respiratory acini of the lung and the significance of their occurring changes in the pathogenesis of chronic idiopathic interstitial pneumonias (IIP), including idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), cryptogenic organizing pneumonia (COP) with bronchiolitis obliterans (BO), and nonspecific interstitial pneumonia (NSIP). SUBJECTS AND METHODS: The study was performed using open transthoracic (n=181) and transbronchial (n=71) lung biopsies from 194 patients (118 cases (61%) with IPF, 35 (18%) with NSIP, 23 (12%) with DIP, 18 (9%) with COP + BO). The serial paraffin sections were stained with hematoxylin and eosin and van Gieson's picrofuchsin and immunohistochemical reactions were carried out to detect MMP-1, MMP-2, MMP-7, Apo-Cas ("Novocastra", 1:100), vimentin (Vimentin) ("LabVision" 1:100), SMA ("LabVision", 1:100), TGF beta, TNF-alpha, CD34, Ost-4, and CD117 ("Dako", 1:50), CD68, and EMA ("Dako", 1:100). Biotinylated anti-mouse and anti-rabbit immunoglobulin antibodies ("Dako" LSAB + KIT, PEROXIDASE) were used as secondary antibodies. All the quantitative and semi-quantitative data obtained were processed by variation statistics. RESULTS: The compared IIPs were shown to differ in the site and degree of initial and secondary respiratory acinus damages caused by the aggressiveness of an inflammatory infiltrate and the spread of a lesion to different SCN areas involved in the regeneration of lung tissue. The mesenchymal cell with myofibroblast differentiation, which is probably associated with a mesenchymal stem cell, as evidenced by Oct-4, Vimentin, SMA, CD117, and CD34 expression by these cells, may be considered to be a marker cell of deep SCN damage. CONCLUSION: The author state that the clinical course and degree of morphological changes in IPP directly depend on the severity and depth of damage to the SCN areas of the respiratory acinus. PMID- 25842924 TI - [The morphological substrate and pathogenetic mechanisms of pelvic pain syndrome in endometriosis]. AB - OBJECTION: To study the origin and morphological substrate of pain syndrome in deep infiltrating endometriosis involving the bowel. SUBJECTS AND METHODS: The investigation was conducted using the intraoperative material (resected portions of the large and small bowels, appendix) obtained from 40 women diagnosed as having deep infiltrating endometriosis involving the bowel, which was accompanied by pain syndrome. Paraffin sections were immunohistochemically examined using the standard protocol. Antibodies to Ki-67, PTEN, ER, PR, ("Dako"), CD34 ("Cell Marque", USA), VEGF, EGF, EGFR, COX-2 ("Abcam"), and MMP 1 and 2 ("Abbiotec") were applied. Dako REAL EnVision Detection System kits ("Dako", Denmark) were used as secondary antibodies. RESULTS: The morphological substrate of pelvic pain syndrome in deep infiltrating endometriosis was established to be factors that acted in situ at the location of endometriotic foci and those caused by the infiltrative perivascular, intravascular, and perineural growth of endometrioid heterotopies. CONCLUSION: Inflammation and fibrosis in the endometriotic foci contribute to the accumulation of algogenes, which gives rise to somatogenic pain syndrome, and chronic nerve fiber injury as a source of nociceptive stimulation leads to neuropathic pain syndrome. PMID- 25842925 TI - [Immunohistochemical detection of biomolecular markers for metaplastic mucosal atrophy in gastric biopsy specimens]. AB - OBJECTIVE: To estimate the validity of the signs of metaplastic atrophic gastritis to elaborate a marker principle of its detection. SUBJECTS AND METHODS: Two hundred diagnostic cases morphologically diagnosed with chronic gastritis were selected for examination. The validity of the histological and immunohistochemical signs/markers reflecting a gland abnormality (hyperplasia of smooth muscle cells and argyrophilic and elastic fibers) and a cell phenotype change (intestinal and pyloric metaplasia): CDX-2, Shh, villin, CD10, MUC2, and MUC5AC was estimated in gastric biopsy specimens with atrophic gastritis forms verified in accordance with international classifications. The validity of the signs/markers was assessed, by calculating the sensitivity, specificity, prognostic value of positive and negative results, and positive and negative likelihood ratios. RESULTS: There were 3 molecules: CDX-2 is a nuclear transcription factor associated with intestinal differentiation; CCD10 is a brush border membrane-bound mycin and MUC2 is an intestinal-type mycin, which showed a high validity like the markers of metaplastic atrophic gastritis. An algorithm that could probably evaluate atrophic gastritis was elaborated for the successive immunohistochemical identification of the above-mentioned marker. CONCLUSION: The proposed technical decision to verify atrophic gastritis by the biomarker method may be not an alternative, but complementary technique of identifying the form of atrophic gastritis. PMID- 25842926 TI - [Ultrastructural assessment of the role of dysangiogenesis in congenital hydronephrosis]. AB - OBJECTIVE: To confirm the key role of vascular malformation by ultrasound examination and to make a more detailed study of the manifestations of dysnephro- and angiogenesis. SUBJECTS AND METHODS: The study enrolled 34 children aged 3 days to 7 years with congenital hydronephrosis, who were divided into 3 groups in accordance with the degree of renal hemodynamic disorders, the criterion for which was a resistive index (RI). RESULTS: The performed electron microscopic study revealed the signs of malformed vessels of all diameters, as well as hypoplastic changes in the renal parenchyma in children of all ages in all the groups. The most significant ultrastructural signs demonstrating a close correlation between dysangio- and dysnephrogenetic processes are the uniformity of structural failure in the glomerular and arteriolar basement membrane, which shows up in the irregularity of its thickness and obliteration of its layers, as well as the immaturity of endothelial cells of both glomerular and arteriolar capillaries (large sizes and a round shape). The important factor confirming their relationship is a direct correlation between the increased RI in all branches of the renal artery as hypoplastic changes progress in the parenchyma of hydronephrotic kidneys. CONCLUSION: The investigation demonstrated the interdependence of dysangio- and dysnephrotic processes in children with congenital hydronephrosis. PMID- 25842927 TI - [Pathomorphological features of pulmonary Langerhans cell histiocytosis]. AB - The paper provides the clinical and X-ray characteristics of pulmonary Langerhans cell histiocytosis (PLCH). It describes pulmonary pathohistological changes in this disease, characterizes the cellular composition of granuloma, and gives methods that can verify the diagnosis of PLCH. A case of PLCH with severe respiratory failure, for which bilateral lung transplantation and histological examination of removed lungs have been made, is described. PMID- 25842928 TI - [Giant chondroblastoma of the femur]. AB - Chondroblastoma is a benign cartilaginous bone tumor. The large dimension and aggressive local spread of the tumor may create a diagnostic problem. A 24 x 17 x 15-cm chondroblastoma is described in a 50 year-old woman. The tumor of typical structure was located in the upper femur, growing into soft tissues and pelvic bones. Thirteen months following interilioabdominal exarticulation, the patient was found to have neither local recurrence nor distant metastases. PMID- 25842929 TI - [Portal hypertensive gastropathy]. AB - In spite of a great number of publications, as yet there is no agreement that which of the detected morphological changes should be considered pathognomonic in portal hypertensive gastropathy (PHG). The study of the pathogenesis of PHG suggested a diversity of mechanisms involved in varying degrees in the development of this abnormality. The paper summarizes the data available in the literature on the role of endothelial dysfunction, apoptosis, damaging factors, and H. pylori infection in the development of this abnormality. A differential diagnosis was made between PHG and GAVE syndrome and histological features in both groups were revealed. PMID- 25842930 TI - [Glomerulopathy with fibrillary and tubular deposits]. AB - The advent of up-to-date electron microscopes and molecular biological methods for the examination of renal puncture biopsies could define earlier undetectable and unworthy cellular structures and stromas. There is a diversity of diseases that can be diagnosed exclusively at the ultrastructural level, thus the literature has identified the concept of glomerular diseases with organized deposits. The current classifications based only on the ultrastructual deposits are imperfect as they fail to account for the etiological and pathogenetic features included in these diseases. PMID- 25842931 TI - [Viktor Viktorovich Serov is a distinguished scientist and teacher (on the occasion of the 90th anniversary of his birth)]. PMID- 25842932 TI - [Donat Semenovich Sarkisov (on the occasion of the 90th anniversary of his birth)]. PMID- 25842933 TI - [Extracorporeal methods of hematological correction in patients with acute liver insufficiency after cardiac surgery]. AB - BACKGROUND & AIMS: Acute liver failure (ALF) usually develops in multiple organ dysfunction syndrome (MODS) and carries a high mortality risk in patients after cardiac surgery. Artificial liver support devices aim to remove albumin-bound and water-soluble toxins arising as a result of liver failure. The currently most used devices combine haemodialysis with albumin dialysis (MARS) or plasma separation and adsorption (Prometheus). The aim of this study was to assess safety and efficacy of use MARS or Prometheus in elderly patients with ALF have been operated for heart diseases. METHOD: We studied 26 elder patients with ALF and MODS as postoperative complication after cardiac surgery. Patients were assigned to groups, given a combination of MARS and standard medical therapy (SMT) (MARS-group, n=9) or Prometheus and SMT (Prometheus-group, n=17). Inclusion criteria were clinical and laboratory signs of ALF: serum total bilirubin level>180 mkmol/L, 2-fold increasing serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), low serum cholinesterase and high serum ammonia levels. A variety of clinical and biochemical parameters were assessed. Primary endpoint was survival probabilities at day 28. RESULTS: MARS was used to provide 1 to 2 rounds (minimum of 6 hours each) and Prometheus was used to provide 2 to 14 rounds (minimum of 6 hours each). There were amelioration of haemodinamic instability, especially in MARS-group (increase in ADmean was 17% in MARS (p=0.005) and 10% in Prometheus-group (p=0.001)), increase in P/F ratio (12% in Prometheus-group (p=0.07)), decrease in serum total bilirubin (8.6% in MARS-group (p=0.028) and 33% in Prometheus-group (p<0.001)) and unconjugated bilirubin levels (29% in Prometheus-group (p=0.003)), also we had decreasing in serum aminotransferase levels and trend to increasing in serum cholinesterase level (12% in MARS-group (p=0.87) and 8% in Prometheus-group (p=0.86)). There were no side effects of extracorporeal liver support in both patients groups. Survival of patients with ALF, treated with MARS was 22%, in Prometheus group--35%. CONCLUSIONS: MARS and Prometheus are found to be safe and effective in patients with ALF after cardiac surgery. Further studies are needed to assess whether therapy might be beneficial in specific sublets of patients. PMID- 25842934 TI - [Neutrophil gelatinase-associated lipocalin (u-NGAL) in the assessment of renal function in patients after kidney allotransplantation]. AB - BACKGROUND: Early dysfunction of transplanted kidney is a serious complication that can lead to the premature loss of transplant. Ischemic and reperfusion injury of donor kidney leads to the disturbance of the function of the graft, which is a form of post-transplantation acute kidney injury that causes the relevance of search of early markers for diagnosis. OBJECTIVE: Evaluation of the diagnostic value of determination in the urine neutrophilgelatinase-associated lipocalin (u-NGAL) in patients in the early period after kidney transplantation. METHODS: An open, randomized, retrospective comparative study of 80 patients, who underwent kidney transplantation from a living human-related donor (group 1, 50 patients) and from donor with brain death documentation (group 2, 30 patients) was carried out. In 20 patients of the second group (group 2a) rapid recovery of graft function was observed, and in 10 patients (group 2b)--delayed graft recovery as a result of postischemic acute kidney injury. During the first five post-transplantation days investigated biochemical analysis of blood and urine, as well as the marker u-NGAL. RESULTS: Because of kidney transplantation was performed to the patients with end-stage chronic renal failure, high values of urea and creatinine in the blood samples during the first postoperative days were noted, that reflected the severity of the preoperative state of the patients. In the patients, who underwent human-related kidney transplantation, a more favorable picture of the investigated laboratory parameters was seen. Values of u NGAL in this group in the early post-transplant period were normal, which attested to the absence of significant ischemic injury of transplanted kidney. In 30 patients with cadaver kidney transplantation average u-NGAL value during the first post-transplant day was 14-times fold exceeded normal range (160 ng/ml), while in 50 patients of the group with human-related transplantation--only 2 times. In the first day in group 2a average u-NGAL value decreased to normal, while in group 2b, where renal replacement therapy was carried out from the first day, remained extremely high (more than 2000 ng/ml, p<0.001 to compare with other two groups) during all 5 days of investigation. Conducting of hemodialysis sessions during the first week was required in 10 patients of group 2b, on the 2nd week--9 patients, on the 3 and 4 week in 5 patients 5, and on the fifth week- in 3 patients. CONCLUSIONS: Due to prolonged period of ischemia in kidney transplantation from a donor with established brain death the level of u-NGAL in these patients was significantly higher than in the kidneys transplantation from living human-related donor. In patients after transplantation dynamics of u-NGAL allows to identify patients with delayed graft function recovery and the need for renal replacement therapy already in the early postoperative period. PMID- 25842935 TI - [Clinical application of dexmedetomidine in patients after thoracic and abdominal surgeries]. AB - OBJECTIVE: To study efficacy and safety of dexmedetomidine application for long term (more than 12 hours) artificial lungs ventilation (ALV) and for psychomotor agitation. METHODS: We studied 57 patients after thoracic and abdominal surgeries. The patients were divided into three groups. Patients of a group-1 (n=18) received ALV under 12 hours, patients of group-2 (n=26) received ALV more than 12 hours. Patients of group-3 (n=13) received dexmedetomidine due to delirious state. Dexmedetomidine was administered by infusion 0.7 mkg/kg during the first hour. The rate of administration was corrected after the first hour. We recorded the level of sedation according to RASS, need of additional sedative drugs use, duration of ALV duration of ICU stay. RESULTS: Dexmedetomidine infusion provides target level of sedation from 0 to -3 according to RASS in 91% of patients requiring prolonged ALV after thoracic and abdominal surgeries. Bradycardia occurred in 15% of patients and arterial hypotension in 12% of patients. Bolus administration of dexmedetomidine should be avoided. PMID- 25842936 TI - [Improving the systemic oxygenation by enteral oxygen therapy]. AB - OBJECTIVE: To study possibilities of enteral oxygen therapy for the improvement of systemic oxygenation. We studied 34 critical patients. RESULTS: Insufflation of oxygen into intestines brought to delayed and prolonged increase of systemic oxygenation (PaO2 and PaO2/FiO2 growth, p<0.001, ANOVA, Holm-Sidack test) reaching its maximum in 9 hours after the insufflation procedure and lasting 32 hrs. Oxygen administration into stomach did not result to better oxygenation. CONCLUSIONS: Taking into account low volumes of insufflated oxygen (from 2 to 6 L) and the duration of achieved systemic oxygenating effect, we may suggest that mechanism of systemic oxygenation was not based on the direct intestinal oxygen absorption, but rather due to normalization of the gastrointestinal tract functions and followed systemic metabolism change improving pulmonary gas exchange. Future investigations are needed to clarify mechanisms. PMID- 25842937 TI - [Thrombocytopenia and postoperative analgesia]. AB - OBJECTIVE: To develop effective and safe measures of postoperative multimodal analgesia (optimizing the use of narcotic analgesics) in surgical treatment of hematological patients with thrombocytopenia. DESIGN: A pilot and prospective comparative controlled study. METHODS: We studied 27 patients with acquired thrombocytopenia who underwent laparoscopic splenectomy. Three schemes of anesthesia were used: 1) Nefopam 20 mg/day + trimeperidin (n = 7); 2) Paracetamol 4 g/day + trimeperidin (n = 10); 3) paracetamol + trimeperidin + glucocorticosteroids (GC) (through treatment of the underlying disease) (n = 10). Analgesic properties and effect of each scheme were assessed according to a rating scale of pain NRS (10 points) and VAS (100 points) studied. Additionally we evaluated the effect of nefopam and paracetamol on the functional properties of platelets and hemostasis, platelet levels while monitoring and indicators of thromboelastogram (TEG). RESULTS: Application of paracetamol + trimeperidin accompanied with effectively reducing of postoperative pain (less than 5 points on the NRS). The level of postoperative pain was lower in patients who were treated with corticosteroids within the therapy of the underlying disease before surgery and who continued to receive it in postoperative period (2-3 points NRS). Nefopam use in the perioperative period is not only inferior to the analgesic effect of paracetamol, but also causes frequent side effects. Consumption of narcotic analgesic--trimeperidin when applying nefopam averaged 43 mg/day, the appointment of paracetamol--28 mg/day, using a combination of paracetamol + GC- 20 mg/day. Thus, GC within the underlying disease treatment substantially reduces the need for opioid analgesics. A monitoring of the number of platelets and TEG did not shows negative effect of paracetamol and nefopam on platelet and plasma hemostasis. CONCLUSIONS: Nefopam and paracetamol may be used in patients with thrombocytopenia, as do not affect the hemostasis and platelet count. Application of postoperative analgesia scheme paracetamol + trimeperidin in patients receiving corticosteroids provides the maximum reduction of pain with the least consumption of narcotic analgesics. PMID- 25842938 TI - ["Evidance"--Russian national epidemiological study]. AB - The article deals with results of epidemiological study of 2516 ICU patients received prophylaxis of a deep vein thrombosis (DVT) and venous thromboembolic complications (VTEC). RESULTS: The frequency of renal failure was 19.8%. Mortality rate in patients with acute renal failure (ARF) was 34% and in patients without ARF 17%. CONCLUSIONS: An analysis of drugs for prophylaxis of DVT and VTEC which were used in patients with ARF showed that the prophylaxis was performed without a taking in account a significance of such complication. PMID- 25842940 TI - [Russian national observational study of nutritional support in children in the ICU--"NutriPed.ru"]. AB - The article deals with results of the first Russian national observational study of nutritional support in children in the ICU. We assessed a frequency of use of enteral and parenteral nutrition and analyzed preparations for enteral and parenteral nutrition. The article discusses methods of the calculation of malnutrition in children in critical states. PMID- 25842939 TI - [Reversion of sedation and general anaesthesia--agonist-antagonist technique]. AB - OBJECTIVE: To study an expediency and efficacy of application of different reverses drugs (naloxone, flumazenil, neostigmine, galantamine, sugammadex) either their separate or combined using. METHODS: We studied 119 patients underwent endoluminal endoscopic procedures and surgeries on trachea-bronchial tree and intestines under sedation or general anaesthesia. RESULTS: The article deals with conceptual approaches to the reversal of residual effects of opioids, benzodiazepine sedation and neuromuscular block (the so-called agonist-antagonist technique). CONCLUSIONS: A reversion of neuromuscular block without using of antagonists' combination does not provide complete recovery of psychomotor and cognitive functions for rapid socialization of patients after anaesthesia. PMID- 25842941 TI - [Effect of cardiovascular functional disorders on cerebral oxygenation in children]. AB - The article deals with data of cerebral oximeter INVOS Somanetics (US) used for comparison the degree of brain oxygenation reduction, ejection fraction and stroke volume relative to age norms in children with dilated cardiomyopathy. PMID- 25842942 TI - [Sedation with midazolam for ambulatory pediatric dentistry]. AB - OBJECTIVE: To improve the quality of dental treatment in children by using combined anaesthesia technique including local anaesthesia and conscious sedation, and to assess the effectiveness of conscious sedation for younger children undergoing dental treatment. METHODS: The study included 208 children aged 14-88 months who received dental treatment for tooth decay and its complication under combined anaesthesia. Midazolam was used as sedative medication. Sedation level was assessed by visual scale and BIS-monitoring. ANI monitoring was also used for pain sensitiveness evaluation. Results All 208 children were successfully treated under combined anaesthesia which showed satisfactory sedation rates both by visual scale and and BIS-monitoring values. While mean patient age was 39 months 20.6% were younger than 24 months. These data are extremely valuable as according to literature review conscious sedation in early infancy remains controversial. CONCLUSIONS: Our results proved conscious sedation to be effective in younger children undergoing dental treatment thus representing important alternative for general anaesthesia and providing a basis for later behavior management. PMID- 25842943 TI - [Systemic toxicity of local anaesthetics in children]. AB - The article deals with an analysis of the publications devoted of local anaesthetics' systemic toxicity (LAST) due to regional anaesthesia and symptoms of this potentially lethal complication. The review discusses features of systemic absorption and forms of local anaesthetics' neurotoxicity and cardiotoxicity in children, including newborns, differences of clinical signs of the LAST in adults and children and dosage of racemic bupivacaine. Moreover, the article deals with a modified treatment protocol for LAST and a method of lipid resuscitation with 20% lipid emulsion in the form of Intralipid. In conclusion the article discusses recommendations for LAST prophylaxis and scenarios during cardiopulmonary and cerebral resuscitation. PMID- 25842944 TI - [Ultrasound guided catheterization of thoracic paravertebral space]. AB - Prolonged thoracic paravertebral block is a complex technique of regional anesthesia. For a long time paravertebral blocks were conducted under stimulation. Recently, techniques of paravertebral space (PVS) verification using ultrasound navigation were developed. The article deals with an anatomy and technique of ultrasound navigation for paravertebral space catheterization. Successful and safe block under ultrasound guidance requires: identification and visualization of paravertebral space; operator's skill in needle visualization in real time; experience in estimating the distribution of local anesthetic in PVS. Sonographic navigation makes PVS much easier to find and optimizes introduction of a local anesthetic thus providing adequate long-term pain relief without complications. PMID- 25842945 TI - [Evaluation of psychological methods for determining the degree of psychological stress in children in dentistry]. AB - The article deals with results of comparative evaluation of system of assessment of children's fear and anxiety in dentistry (SDS test) and other objective and subjective methods for assessing anxiety in pediatric patients. We studied 381 pediatric patients aged from 3 to 7 years. The aim of the study was to prove validity mathematical derived FCD test as a technique of anxiety detection in dentistry. During the study following subjective test were used: MAS, DAS, mYPAS, VAS, STAI, STAIC, EASI, PHBQ, and some history data and stress factors were also considered. Objective data used were vital signs (hemodynamics and respiratory rate). Test SDS has strong correlation with YALE, MAS, DAS, STAIlich, VAS and other parameters such as age, sex, person which is responsible for bringing up a child and so on. PMID- 25842946 TI - [Cholera Vibrio biofilm: production, characterization and role in reservation of causative agent in water environment]. AB - AIM: Experimental production, characterization and evaluation of the role of cholera vibrio biofilm. MATERIALS AND METHODS: 33 strains of Vibrio cholerae eltor O1 and V. cholerae O139 of various epidemic significance and origin were studied in a series of experiments by bacteriologic, microscopic (light-optic, luminescent, scanning electron microscopy), molecular genetics, spectrophotometric and statistical methods. RESULTS: Formation of a biofilm involving inter-cellular bonds, pili and extracellular material and variability of the microorganism (RO-phenotype and transition into uncultivable forms) was shown at various temperature and substrate conditions. A more pronounced ability to form biofilms was detected for strains isolated from environmental samples compared with isolated from clinical material regardless of their epidemic significance. Toxigenic strains of eltor biovar (from surface reservoirs during cholera outbreaks) have demonstrated the highest parameters of optical density compared with toxigenic clinical isolates and non-toxigenic O1 and O139 serogroup cultures. The presence of mbaA1 and mbaA2, vpsR, toxR, hapA genes is common for strains that form a biofilm. CONCLUSION: The data obtained confirm the role of biofilm in reservation of cholera vibrio strains of various epidemic significance in saprophytic phase of microorganism existence. PMID- 25842947 TI - [Evaluation of modern epizootic activity of natural tularemia foci in Voronezh region using immune-serological and molecular-genetic study of main carriers of the disease]. AB - AIM: Improvement of monitoring and prognosis of epidemic manifestations of natural foci of tularemia on the territory of Voronezh region using immune serological and molecular-genetic study of main carriers of the disease. MATERIALS AND METHODS: 539 small mammals captured during summer period of 2011 in 4 districts of North-Eastern part of Voronezh region were studied. Animal organs were studied by serologic (search for Francisella tularensis antigens) and molecular-biologic (detection of F. tularensis DNA) methods. Tularemia antigen was detected using passive hemagglutination reaction (PHAR) with erythrocytic tularemia immunoglobulin diagnosticum. Real-time polymerase chain reaction (RT PCR) was applied for detection of tularemia causative agent DNA. RESULTS: Complex study revealed epizootic activity of natural foci of tularemia in the examined territory. F. tularensis antigen and/or DNA were detected in 82 objects (15.2%). Use of RT-PCR allowed to additionally detect samples with relatively low content of F. tularensis DNA substrate, when antigen was not detected in samples. High sensitivity and specificity of the RT-PCR was ensured by inclusion of specific probes (tu14-PR2 and ISFTu2P). CONCLUSION: The results obtained give evidence on functioning and epizootic activity of natural foci of tularemia in Voronezh region that requires constant monitoring of the territory and prophylaxis measures, first of all vaccination of risk groups by live tularemia vaccine. PMID- 25842948 TI - [Characteristics of isogenic variants of Bacillus anthracis with various content of virulence plasmids]. AB - AIM: Production and characteristics by main cultural-morphologic and antigenic properties of isogenic variants Bacillus anthracis, that differ by the presence of virulence plasmids. MATERIALS AND METHODS: B. anthracis 81/1, 575/122 virulent and B. anthracis STI, 55, Sterne vaccine strains were used in the study. Isogenic variants, that differ by the presence of virulence plasmids, were obtained by temperature elimination of plasmids, as well as during cultivation of anthrax strains in medium with kanamycin. The strains were characterized by cultural morphologic, biochemical properties. The presence of virulence plasmids was determined by polymerase chain reaction method. Antigenic properties were studied in immune diffusion reaction with growing cultures with sera against protective antigen and S-layer proteins, electrophoresis, immune blotting. RESULTS: Isogenic variants were produced from virulent strains B. anthracis 81/1, 575/122 and vaccine strains STI, 55, Sterne: mono-plasmid toxin-producing (81/1 R01, 575/122 R01) and capsule-containing (81/1 R02, 575/122 R02), and plasmid-less (81/1 R00, 575/122 R00, STI R00, 55 R00, Sterne R00), that differ by the presence of virulence plasmids. Strains had typical cultural-morphologic properties, differed by biochemical and antigenic properties. Cultural filtrates of toxin-producing strains had protein of anthrax toxin; plasmid-less strains--had proteins, that had molecular masses corresponding to molecular masses of S-layer EA1 and Sap proteins. CONCLUSION: These strains may be used to study variability and proteomic analysis of anthrax causative agent, as well as for isolation of antigens with the aim of evaluating their immune diagnostic significance. PMID- 25842949 TI - [Flow-cytofluorometric study of bactericidal granules in blood phagocytes of animals with various species sensitivity to experimental plague infection]. AB - AIM: Compare the content of bactericidal granules (BG) in blood phagocytes of animals, that differ by species sensitivity to plague infection, under the conditions of measuring, that ensure automatic differentiating by this parameter of monocytes and granulocytes of human blood. MATERIALS AND METHODS: Human whole blood leukocytes were studied, as well as from 7 animal species: mice, guinea pigs, golden hamsters, white rats, rabbits, dogs and horses. Acridine orange (AO) was used for supra-vital staining in primary (bactericidal) granule cells. Relative BG content was measured in separate cells in conventional units of red fluorescence intensity by flow cytofluorometry. RESULTS: Deficiency of AO molecules in BG, that correlates with deficiency of leukocyte elastase in cells, that is most pronounced in mice and lest pronounced in rabbits, was established to be characteristic for all the blood phagocytes of all the laboratory animal species sensitive to plague. Blood phagocytes of dogs and horses, that were non sensitive to plague, differed by high heterogeneity by the studied parameter, and in horse blood innate immunity cells were detected, that contained 2.5 times higher amount of BG, than blood granulocytes of humans. CONCLUSION: Leukocyte BG, that have enzyme cationic proteins: elastase, cathepsin G, protease 3 and myeloperoxidase, play and important role in protection of organism from plague infection. PMID- 25842950 TI - [Effect of serotonin on immune competent cells of biomodels under the conditions of vaccination against plague and tularemia]. AB - AIM: Comparative evaluation of the effect of exogenic serotonin on the development of apoptosis and proliferative activity of immune system cells of biomodels in vivo and in vitro in the dynamic of immunity forming against plague and tularemia. MATERIALS AND METHODS: Analysis of relative content of immune competent cell DNA of unlinear and BALB/c mice was carried out after staining of the samples with mithramycin and ethidium bromide by flow cytometry. RESULTS: Administration of serotonin into biomodels before immunization with vaccine strains of Yersinia pestis and Francisella tularensis was established to increase in vivo proliferative activity of immune system cells, without a significant effect on their death by apoptosis. Serotonin inhibited in vitro the development of apoptosis of mice blood leukocytes in response to both the vaccine Y. pestis EV strain and tularin. CONCLUSION: Biogenic amine serotonin shows equivalent modulating effect on both anti-plague and anti-tularemia immune response in vivo and in vitro, without disrupting immune system homeostasis. PMID- 25842951 TI - [Monocytes of human blood as a target of Streptococcus pyogenes components]. AB - AIM: Study the effect of components of destroyed streptococci on human blood monocyte functions related to processes of trans-endothelial migration in vitro. MATERIALS AND METHODS: Mononuclear leukocytes, isolated from blood of healthy donors, endothelial cells of EA.hy 926 line and supernatant of ultrasound disintegrated Streptococcus pyogenes (DSS) were the objects of the study. Evaluation of adhesion and monocyte migration, level of expression of adhesion molecules and phosphokinases on monocytes was carried out by flow cytometry using monoclonal antibodies. Cytokine concentration was determined by using standard commercial test systems in enzyme immunoassay. RESULTS: Under the effect of DSS, expression of adhesion molecules CD162 and CD11b, as well as phospho-p38 MAPK changed, IL-6 and IL-8 secretion induction took place. DSS caused enhancement of migration and adhesive activity of monocytes, however, inhibited intensity of trans-endothelial migration. CONCLUSION: Products of destroyed streptococci have a multi-directional effect on human blood monocytes, that could be explained by the presence of components with varying biological activity in DSS. PMID- 25842952 TI - [Improvement of laboratory diagnostics of cholera due to genetically altered (hybrid) variants of cholera Vibrio biovar El Tor]. AB - AIM: Improvement of laboratory diagnostics of cholera taking into the account appearance of hybrid variants of cholera vibrio El Tor biovar in the 1990s. MATERIALS AND METHODS: Phenotypic and molecular-genetic properties of typical toxigenic (151 strains) and hybrid (102 strains) variants of El Tor biovar cholera vibrios, isolated in the Caucuses in 1970-1990 and 1993-1998, respectively, were studied. Toxigenicity gene DNA fragments, inherent to El Tor biovars or classic, were detected by using a reagent kit "Genes of Vibrio cholerae variant ctxB-rstR-rstC, REF" developed by us. RESULTS: Reagent kit "Genes of V. cholerae variant ctxB-rstR-rstC, REF" is proposed to be used for laboratory diagnostics of cholera during study of material from humans or environmental objects and for identification of V. cholerae 01 on genome level in PCR-analysis as a necessary addition to the classic scheme of bacteriological analysis. CONCLUSION: Laboratory diagnostics of cholera due to genetically altered (hybrid) variants of cholera vibrio El Tor biovar is based on a complex study of material from humans and environmental objects by routine bacteriologic and PCR-analysis methods with the aim of detection of gene DNA fragments in the studied material, that determine biovar (classic or El Tor), identification of V. cholerae O1 strains with differentiation of El Tor vibrios into typical and altered, as well as determination of enterotoxin, produced by the specific cholera vibrio strain (by the presence ctxB(El) or ctxB(Cl) gene DNA fragment, coding biosynthesis of CT-2 or CT-1, respectively). PMID- 25842953 TI - [Transplacental IgG against measles virus in umbilical blood of neonates from various regions of Russian Federation]. AB - AIM: Determine content of protective transplacental IgG against measles virus in umbilical blood of neonates of various regions of Russian Federation. MATERIALS AND METHODS: Umbilical blood of 1147 neonates was studied, whose mothers had not previously had measles. 672 samples among those were from neonates of Moscow and Moscow Region, 475--from Rostov-on-Don. IgG values were determined in EIA using a standard kit from "Vector Best" (VectoKor-IgG). A kit from Euroimmun--Avidity: Anti-Measles Virus ELISA (IgG) was used for determination of avidity of IgG against measles virus. RESULTS: Protective (>= 0.18 IU/ml) IgG against measles were registered in 79.9% of children in Moscow, Moscow Region and in 81.3% of neonates in Rostov-on-Don. Mean level of IgG in umbilical blood sera of neonates from the studied regions was within protective values (1.74 +/- 0.13 IU/ml and 1.51 +/- 0.09 IU/ml, respectively). Predominance of low level antibodies was noted in the studied samples (< 1.0 IU/ml), those are highly avid though (AI > 60%). In neonates from women aged 16 - 25 years in Moscow and Moscow Region protective antibodies were detected in 83.6%; 26 - 35 years--in 75%; women aged 36 - 43 years--in 88.2% of cases. Mean level of IgG in umbilical blood of neonates from mothers aged 36 - 43 years was 1.5 times higher than from mothers aged 16 - 25 years and 2 times higher than mothers 26 - 35 years of age. CONCLUSION: Neonates from Moscow, Moscow Region and Rostov-on-Don, similarly, in 79.9% and 81.3% of cases are protected from measles, respectively. Women aged 26 35 years in 25% of cases are a risk group for measles morbidity and require a closer attention during selection of vaccination tactics before conception, and their neonates--on reaching decree terms. PMID- 25842954 TI - [Evaluation of therapeutic-prophylactic effectiveness of chemical compound NIOC 14 against ectromelia virus in vivo]. AB - AIM: Study pharmacodynamic parameters of anti-viral effectiveness of a chemical compound NIOC-14 in experiments in mice infected with ectromelia virus (EV). MATERIALS AND METHODS: EV (K-1 strain) was obtained from the State Collection of Viral Infections and Rickettsioses Causative Agents of the State Scientific Centre of Virology and Biotechnology "Vector". Outbred ICR mice were intranasally infected with EV at a dose of 10 LD50 per animal (10 x 50% lethal doses/animal) and per orally received NIOC-14 or ST-246 as a positive control. Chemical compound NIOC-14 (7-[N'-(4-trifluoromethylbenzoyl)-hidrazincarbonyl] tricyclo[3.2.2.0(2,4)]non-8-en-6-carbonic acid) was synthesized in Novosibirsk Institute of Organic Chemistry (NIOC). Anti-pox preparation ST-246, developed by SIGA Technologies Inc. (USA), was synthesized in NIOC using the technique described by the authors. RESULTS: 50% effective doses against EV in vivo were shown not to differ significantly between the preparations NIOC-14 (3.59 MUg/g mouse mass) and ST-246 (5.08 MUg/g mouse mass). During determination of therapeutic window, administration of NIOC-14 to mice 1 day or 1 hour before EV infection, as well as 1, 2 and 4 days after EV infection and then for 9 days was found to ensure 100% animal survival. Administration of NIOC-14 as well as ST-246 resulted in the decrease relative to control of EV titers in lungs, nasal cavity, brains, liver, spleen, kidneys and pancreas. CONCLUSION: Anti-viral effectiveness of NIOC-14 against EV in vivo was thus comparable by all the studied pharmacodynamic parameters with anti-viral activity of anti-pox-virus preparation ST-246. PMID- 25842955 TI - [Microbiota of lower urine tract and genital organs of healthy men and in infertility]. AB - AIM: Study microflora of urine, ejaculate, urethra scrape in normal state and infertility. MATERIALS AND METHODS: 2 groups of men were examined: I (28)- control, conditionally healthy men (20 - 25 years of age), II (26)--infertile patients (25 - 35 years of age). Middle portion of morning urine, ejaculate, urethra scrape were studied in group I, in II--ejaculate. Bacteriologic study of urine and ejaculate was carried out in an extended kit of nutrient media (HiMedia) for facultative- anaerobic (FAB) and non-clostridia anaerobic bacteria (NAB). Urethra scrape and ejaculate were studied by PCR in group I. RESULTS: In urethra scrape and ejaculate a wide spectrum of FAB and NAB was detected in group I. Corynebacterium spp. and coagulase-negative staphylococci (67.9% each) were the dominant cluster of FAB. Eubacterium spp.--in NAB. Bacteriologic study of ejaculate corresponded in PCR with similar results of dominating bacteria. Among FAB the same clusters dominated during bacteriologic study of ejaculate from group II patients, among NAB--Propionibacterium spp., Peptococcus spp. and Peptostreptococcus spp. Quantitative characteristics of ejaculate of group I and II differed insignificantly. CONCLUSION: The frequency of detection of certain genera of FAB and NAB was significantly higher in patients with infertility than in conditionally healthy men, however quantitative parameters of the isolated microorganisms practically did not differ between groups. PMID- 25842956 TI - [Domination of Staphylococcus aureus in microbiocenosis of nasal cavity in children and adults with infectious and allergic rhinitis]. AB - Aim. Determine the occurrence of S. aureus in microbiocenosis of nasal cavity of children and adults with allergic and infectious rhinitis. MATERIALS AND METHODS: Content of nasal cavity microflora in patients with infectious and allergic rhinitis was studied. 295 patients were observed, among those--179 children aged 3 months to 14 years and 116 adults aged 15 - 71 years. RESULTS: In 60.3% of cases in children and 52.5% of adults S. aureus was revealed to be the dominating microorganism. Additionally, in 26.8% of children and 35.3% of adults epidermal staphylococcus was isolated. CONCLUSION: Antagonistic properties of these 2 species of microorganisms assume their competition on the nasal mucous membrane. PMID- 25842957 TI - [Signs of microbial sensibilization in patients with various cardiovascular diseases]. AB - AIM: Analysis of intensity of non-specific (level of sera cytokines) and specific (titers of antibodies against Chlamydophila pneumoniae) factors of humoral immunity in patients with arterial hypertension and various forms of ischemic heart diseases. MATERIALS AND METHODS: 282 individuals were the object of examination--157 (55.7%) males. 8 groups were formed, comparable by age: 1 - 32 individuals with exertional angina pectoris of the III functional class; 2 - 20 individuals with healing Q-positive myocardial infarction (MI); 3 - 15 individuals with Q-negative healing MI; 4 - 15 individuals with unstable angina pectoris; 5 - 40 individuals with persisting atrium fibrillation; 6 - 35 individuals with clinically significant chronic heart failure; 7 - 92 patients with hypertension of the II stage; 33 conditionally healthy composed the control group. Class A and G immunoglobulins against C. pneumoniae, IL-1beta, -6, -17, TNFalpha content in blood were determined. RESULTS: The proportion of seropositive individuals in groups with IgG and IgA titer characteristics was determined. Data on the level of cytokines, taking into the account seropositivity, and titer increase are presented. Correlations between hemostasis system were established, that demonstrate increase of thrombophilia in the presence of persistent infection, mediated via induction of cytokine production. Significant differences by instrumental parameters depending on seropositivity were not obtained. CONCLUSION: Contribution of microbial sensibilization and latent inflammation in the development and destabilization of atherogenesis associated diseases seems evident. PMID- 25842958 TI - [Commensal microflora and endogenous inductors of pathophysiological reactions of innate immunity]. AB - This paper content analytical review of literature on commensal microflora and endogenous inductors of pathophysiological reactions of innate immunity. The important role of participation in the homeostasis of the intestinal microflora, the repair of tissue damage, maintaining the innate immune system in a state of physiological tone by interacting with receptors pattern recognition receptors. Effects of the interaction of components commensal flora and innate immune receptors play an important role in physiological processes of microorganism in maintaining the balance of the synthesis of pro-inflammatory and anti inflammatory cytokines and antimicrobial substances. PMID- 25842959 TI - [When will the new tuberculosis vaccine appear?]. AB - The problem of tuberculosis prophylaxis remains actual for many countries of the world including Russia. The search of candidates for substitution of the only authorized BCG vaccine has been ongoing for some time, because it does not prevent reactivation of the causative agent in the latent stage and causes generalized BCG-infection in individuals with pronounced immune deficiency. In October 2013 in Lille at the European Congress "World Vaccine 2013" results of multi-year projects and trials of around 40 novel tuberculosis vaccine candidates were presented. The article contains a critical analysis of the materials presented at the congress. 12 vaccines have been developed or are being developed for priming. Among those a live VPM 1002 vaccine based on a genetically modified BCG Mycobacterium bovis (HLY+rBCG) strain and an attenuated vaccine based on Mycobacterium tuberculosis (att. MTB-MTBVAC) have passed phase II clinical trials. 17 candidates are being examined as booster vaccines, among those 6 vaccines have passed phase II clinical trials, and are presented by both modified M. bovis strains and partial proteins of M. tuberculosis. Characteristics of the 3 most perspective vaccines have been presented at the congress: VPM 1002, H &H56 and MVA85A. VPM 1002 is the vaccine closest to introduction. This is a live recombinant anti-tuberculosis vaccine based on the BCG strain, its DNA had genes partially deleted, that code synthesis of listeriolysin. The trials have shown that protective effectiveness of the vaccine is significantly higher than the parent BCG due to better induction of CD4+ and CD8+ cells, as well as IFN-gamma, IL-18, 12 and other cytokines responsible for cell immunity function against M. tuberculosis. PMID- 25842960 TI - [Principle directions for the creation and organization of the system of sanitary epidemiological safety during the preparations for the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi]. AB - The paper generalizes the experience of formation of protection system against biological threats and ensuring sanitary and epidemiological welfare during preparation for the XXII Olympic Winter Games and XI Paralympic Winter Games of 2014 in Sochi. The basic steps for creating this system, since 2007, participation and role of Rospotrebnadzor in this process are shown. The paper deals with such questions as the governmental and administrative structures with federal agencies interaction, development of a regulatory framework governing the safety system of the Olympic Games, development of algorithms of information exchange and management decisions, biological safety in developing infrastructure in Sochi. PMID- 25842961 TI - [Improving prevention activities of infectious diseases during preparation and holding of the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi]. AB - The article presents data on the implementation of a set of preventive activities to ensure sanitation and epidemiological welfare during the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi. The importance of monitoring and evaluation of epidemiological risk, as the basis of formation of preventive measures is noticed. The questions of specific, and nonspecific prevention of infectious diseases, especially the work done during the pre-Olympic period are considered. The importance of specifically developed regulatory basis, and health education are emphasized. The conclusion about the effectiveness of the measures taken, which led to a significant reduction of infectious diseases in the region is made. PMID- 25842962 TI - [Operation and interaction peculiarities of diagnostic laboratories involved in providing protection from infectious diseases during the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi]. AB - The experience of the organization and functioning of the laboratory network during the XXII Olympic Winter Games and XI Paralympic Winter Games of 2014 in Sochi is considered. Efforts to establish an effective system of laboratory support, the order of work and interaction of diagnostic laboratories involved in diseases control of population during the Olympic Games are analyzed. PMID- 25842963 TI - [Epidemiological risk of introduction of dangerous and exotic infectious diseases on the territory of the XXII Olympic Winter Games and XI Paralympic Winter Games 2014 in Sochi]. AB - To assess the epidemiological risk of introduction of serious infectious diseases in the pre-Olympic period defined list of dangerous and exotic infections and held assessment of potential danger threatening. Initial external information to assess the potential risk of skidding were reports, forecasts, posted on the official websites. The risk of skidding and epidemiological complications conditionally designated as high, moderate and minimal risk importation of measles virus-Rate was considered as high. In confirmation of the forecast for the period of the Olympic Games in Sochi have been registered about 100 cases of measles. Moderate risk of importation was determined for poliomyelitis due to wild poliovirus, Lassa fever, cholera, plague, and the minimal--for Dengue fever, yellow fever, the Middle East and respiratory syndrome, diseases caused by viruses Marburg and Ebola. Based on of analysis of previous Olympic Games and subsequent co-events related to the activity of the infectious diseases in the world, mate-cluded that even a slight risk of importation of infectious diseases requires maximum alertness and readiness to conduct adequate epidemiological issues incorporated. PMID- 25842964 TI - Novel therapeutic uses and formulations of botulinum neurotoxins: a patent review (2012 - 2014). AB - INTRODUCTION: Botulinum neurotoxins (BoNTs) are among the most toxic of known biological molecules and function as acetylcholine release inhibitors and neuromuscular blocking agents. Paradoxically, these properties also make them valuable therapeutic agents for the treatment of movement disorders, urological conditions and hypersecretory disorders. Greater understanding of their molecular mechanism of action and advances in protein engineering has led to significant efforts to improve and expand their function with a view towards broadening their therapeutic potential. AREAS COVERED: Searches of Espacenet and Google Patent have revealed a number of patents related to BoNTs. This review will focus on novel therapeutic uses and formulations disclosed during 2012 - 2014. The seven patents discussed will include nanoformulations of FDA-approved BoNTs, additional BoNT subtypes and novel BoNT variants and chimeras created through protein engineering. Supporting patents and related publications are also briefly discussed. EXPERT OPINION: The clinical and commercial success of BoNTs has prompted investigation into novel BoNTs or BoNT-mediated chimeras with promising in vitro results. Distinct strategies including the use of nanoformulations and targeted delivery have been implemented to identify new indication and improved functionality. Greater understanding of their systemic exposure, efficacy and safety profiles will be required for further development. PMID- 25842965 TI - Changes in nasal resonance following septoplasty in adults: Acoustic and perceptual characteristics. AB - OBJECTIVES: Patients undergoing surgery for a deviated nasal septum (septoplasty) often report that their voice sounds different or less hyponasal. However, such a relationship between septoplasty and vocal resonance remains without scientific evidence. The purpose of this work is to investigate whether nasal septal surgery has any effect on nasal resonance, both in terms of objective measurements and patient perception. METHODS: The research carried out was a prospective case control study. We recruited patients who underwent septoplasty (study group) and healthy volunteers (control group). We obtained voice recordings of the nasal consonant /m/ pre- and four weeks postoperatively and twice at similar time intervals in the control group. We investigated objective changes by means of acoustic analysis of the voice recordings and calculated the total amount of acoustic energy in different bandwidths on a wide-band spectrogram. We also utilized a questionnaire to explore patient perception. RESULTS: A total of 34 participants entered the study. ANOVA testing revealed significant changes in average total acoustic energy, phlegm, and throat dryness postoperatively. Regarding patient perception, a considerable number of our patients felt that their voice had changed for the better upon direct questioning. However, statistical analysis of the questionnaire items related to nasality of voice did not show a significant change. CONCLUSIONS: In this study it has been demonstrated that surgical correction of septal deviation causes significant spectrographic changes. In particular it causes changes in the average total acoustic energy during the production of a nasal consonant. A considerable number of our patients reported change in their vocal resonance for the better. We recommend that patients be advised that their voice may sound different after surgery, or less hyponasal. PMID- 25842966 TI - Universal gestational age effects on cognitive and basic mathematic processing: 2 cohorts in 2 countries. AB - OBJECTIVE: To determine whether general cognitive ability, basic mathematic processing, and mathematic attainment are universally affected by gestation at birth, as well as whether mathematic attainment is more strongly associated with cohort-specific factors such as schooling than basic cognitive and mathematical abilities. STUDY DESIGN: The Bavarian Longitudinal Study (BLS, 1289 children, 27 41 weeks gestational age [GA]) was used to estimate effects of GA on IQ, basic mathematic processing, and mathematic attainment. These estimations were used to predict IQ, mathematic processing, and mathematic attainment in the EPICure Study (171 children <26 weeks GA). RESULTS: For children born <34 weeks GA, each lower week decreased IQ and mathematic attainment scores by 2.34 (95% CI: -2.99, -1.70) and 2.76 (95% CI: -3.40, -2.11) points, respectively. There were no differences among children born 34-41 weeks GA. Similarly, for children born <36 weeks GA, mathematic processing scores decreased by 1.77 (95% CI: -2.20, -1.34) points with each lower GA week. The prediction function generated using BLS data accurately predicted the effect of GA on IQ and mathematic processing among EPICure children. However, these children had better attainment than predicted by BLS. CONCLUSIONS: Prematurity has adverse effects on basic mathematic processing following birth at all gestations <36 weeks and on IQ and mathematic attainment <34 weeks GA. The ability to predict IQ and mathematic processing scores from one cohort to another among children cared for in different eras and countries suggests that universal neurodevelopmental factors may explain the effects of gestation at birth. In contrast, mathematic attainment may be improved by schooling. PMID- 25842967 TI - Cyclic hypoxia does not alter RAD51 expression or PARP inhibitor cell kill in tumor cells. AB - Solid tumors contain regions of chronic and cyclic hypoxia. Chronic hypoxia can downregulate RAD51 and sensitize cells to PARP inhibition. Herein, we show that RAD51 expression, cell survival and toxicity to PARP inhibition is not affected under cyclic hypoxic conditions. This suggests that PARP inhibition may be selectively toxic in tumor sub-regions associated with chronic hypoxia. PMID- 25842969 TI - Dissecting risk haplotypes in sporadic Alzheimer's disease. AB - Understanding how genetic risk variants contribute to complex diseases is crucial for predicting disease susceptibility and developing patient-tailored therapies. In this issue of Cell Stem Cell, Young et al. (2015) dissect the function of common non-coding risk haplotypes in the SORL1 locus in the pathogenesis of sporadic Alzheimer's disease using patient-derived induced pluripotent stem cells. PMID- 25842968 TI - Clinical implementation and range evaluation of in vivo PET dosimetry for particle irradiation in patients with primary glioma. AB - PURPOSE: The physical and biological properties of ion-beams offer various advantages in comparison to conventional radiotherapy, though uncertainties concerning quality assurance are still left. Due to the inverted depth dose profile, range accuracy is of paramount importance. We investigated the range deviations between planning simulation and post-fractional PET/CT measurement from particle therapy in primary glioblastoma. METHODS AND MATERIALS: 20 patients with glioblastoma undergoing particle therapy at our institution were selected. 10 received a proton-boost, 10 a carbon-ion-boost in addition to standard treatment. After two fractions, we performed a PET/CT-scan of the brain. We compared the resulting range deviation based on the Most-likely-shift method between the two measurements, and the measurements with corresponding expectations, calculated with the Monte-Carlo code FLUKA. RESULTS: A patient's two measurements deviated by 0.7mm (+/-0.7mm). Overall comparison between measurements and simulation resulted in a mean range deviation of 3.3mm (+/ 2.2mm) with significant lower deviations in the (12)C-arm. CONCLUSION: The used planning concepts display the actual dose distributions adequately. The carbon ion group's results are below the used PTV safety margins (3mm). Further adjustments to the simulation are required for proton irradiations. Some anatomical situations require particular attention to ensure highest accuracy and safety. PMID- 25842970 TI - An epigenomic road map for endoderm development. AB - While studies of organ development have traditionally relied on model organisms, recent advances in embryonic stem cell (ESC) culture allow investigation of organogenesis in human cells. Wang et al. (2015) employ this system to map the dynamic enhancer landscape during ESC differentiation to the endoderm derivatives pancreas and liver. PMID- 25842971 TI - The lncRNA Pnky in the brain. AB - Long noncoding RNAs (lncRNAs) influence diverse cellular processes and have been implicated in regulating stem cell properties. Now in Cell Stem Cell, Ramos et al. (2015) demonstrate that the neural-specific lncRNA Pnky regulates neuronal differentiation from neural stem cells and mediates RNA splicing through interactions with polypyrimidine tract-binding protein 1 (PTBP1). PMID- 25842972 TI - Epiblast and primitive endoderm differentiation: fragile specification ensures stable commitment. AB - Specification of the epiblast and primitive endoderm is one of the earliest differentiation steps during embryogenesis. In vitro tracking of pluripotency markers in ESCs suggests that epiblast specification may be plastic; however, live imaging of blastocysts, as detailed in a recent paper from Xenopoulos et al (2015), showed that, unlike in ESCs, fate commitment in vivo is largely irreversible. PMID- 25842973 TI - Clinical translation of TALENS: Treating SCID-X1 by gene editing in iPSCs. AB - Mutations causing X-linked severe combined immunodeficiency (SCID-X1) reduce immune cell populations and function and may be amenable to targeted gene correction strategies. Now in Cell Stem Cell, Menon et al. (2015) correct SCID-X1 related blood differentiation defects by TALEN-mediated genome editing in patient derived iPSCs, suggesting a possible strategy for autologous cell therapy of SCID X1. PMID- 25842974 TI - New Japanese initiatives on stem cell therapies. AB - Two laws aiming to provide a new legal framework to promote regenerative medicine, while ensuring the efficacy and safety of the treatments, came into effect in Japan on November 25, 2014. The scope of these laws is briefly described here. PMID- 25842975 TI - Conditional approval: Japan lowers the bar for regenerative medicine products. AB - A new system for conditional approval of regenerative medicine products will allow products of undetermined efficacy to enter the Japanese market. The potential scientific, economic, and ethical implications of this program highlight the need for further discussion and refinement. PMID- 25842976 TI - New cell sources for T cell engineering and adoptive immunotherapy. AB - The promising clinical results obtained with engineered T cells, including chimeric antigen receptor (CAR) therapy, call for further advancements to facilitate and broaden their applicability. One potentially beneficial innovation is to exploit new T cell sources that reduce the need for autologous cell manufacturing and enable cell transfer across histocompatibility barriers. Here we review emerging T cell engineering approaches that utilize alternative T cell sources, which include virus-specific or T cell receptor-less allogeneic T cells, expanded lymphoid progenitors, and induced pluripotent stem cell (iPSC)-derived T lymphocytes. The latter offer the prospect for true off-the-shelf, genetically enhanced, histocompatible cell therapy products. PMID- 25842977 TI - Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates. AB - Embryonic development relies on the capacity of progenitor cells to appropriately respond to inductive cues, a cellular property known as developmental competence. Here, we report that epigenetic priming of enhancers signifies developmental competence during endodermal lineage diversification. Chromatin mapping during pancreatic and hepatic differentiation of human embryonic stem cells revealed the en masse acquisition of a poised chromatin state at enhancers specific to endoderm-derived cell lineages in gut tube intermediates. Experimentally, the acquisition of this poised enhancer state predicts the ability of endodermal intermediates to respond to inductive signals. Furthermore, these enhancers are first recognized by the pioneer transcription factors FOXA1 and FOXA2 when competence is acquired, while subsequent recruitment of lineage-inductive transcription factors, such as PDX1, leads to enhancer and target gene activation. Together, our results identify the acquisition of a poised chromatin state at enhancers as a mechanism by which progenitor cells acquire developmental competence. PMID- 25842979 TI - The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling. AB - Hepatocellular carcinoma (HCC) is the most prevalent subtype of liver cancer, and it is characterized by a high rate of recurrence and heterogeneity. Liver cancer stem cells (CSCs) may well contribute to both of these pathological properties, but the mechanisms underlying their self-renewal and maintenance are poorly understood. Here, using transcriptome microarray analysis, we identified a long noncoding RNA (lncRNA) termed lncTCF7 that is highly expressed in HCC tumors and liver CSCs. LncTCF7 is required for liver CSC self-renewal and tumor propagation. Mechanistically, lncTCF7 recruits the SWI/SNF complex to the promoter of TCF7 to regulate its expression, leading to activation of Wnt signaling. Our data suggest that lncTCF7-mediated Wnt signaling primes liver CSC self-renewal and tumor propagation. In sum, therefore, we have identified an lncRNA-based Wnt signaling regulatory circuit that promotes tumorigenic activity in liver cancer stem cells, highlighting the role that lncRNAs can play in tumor growth and propagation. PMID- 25842980 TI - Misperception of weight status and associated factors among undergraduate students. AB - PROBLEM: We compared participants' self-perception of their weight with the World Health Organisation (WHO) definition for BMI categories among undergraduate university students undertaking health related academic programmes in Ghana. Also, we investigated factors associated to the underestimation of weight status in this sample. METHODS: This cross-sectional study was conducted among a sample of 368 undergraduate students. Anthropometric measurements of weight and height were measured with appropriate tools and computed into Body Mass Index (BMI) categorised based on WHO classifications. Waist and hip circumferences were also measured appropriately. Participants' self-perception of weight status was assessed by the question: How do you perceive your weight? (a) Underweight, (b) normal weight, (c) overweight, and (d) obese. The BMI-measured weight status was compared to the self-perceived weight status by cross-tabulation, Kappa statistics of agreement and chi(2) for trend analysis. Factors associated with misperception of weight status was measured using univariate and multivariable analysis. RESULTS: Thirteen percent (n=48) of the participants were overweight/obesity (BMI) and 31.5% had central obesity. Overall, 20.6% of the participants misperceived their weight status in which 78.9% of them underestimated it. Among overweight/obese participants, 41.7% self-perceived themselves accurately. Whereas 10.6% of normal weight participants underestimated their weight status, over half (58.3%) of overweight/obese participants did so. Factors that were associated with underestimation of weight status were having overweight/obesity (BMI) and central obesity. CONCLUSION: Underestimation of weight status was frequent. Health professionals and related government agencies should develop intervention programmes to empower young people to have accurate weight status perception. PMID- 25842978 TI - Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. AB - Basal cell carcinoma (BCC) is characterized by frequent loss of PTCH1, leading to constitutive activation of the Hedgehog pathway. Although the requirement for Hedgehog in BCC is well established, the identity of disease-initiating cells and the compartments in which they reside remain controversial. By using several inducible Cre drivers to delete Ptch1 in different cell compartments in mice, we show here that multiple hair follicle stem cell populations readily develop BCC like tumors. In contrast, stem cells within the interfollicular epidermis do not efficiently form tumors. Notably, we observed that innervated Gli1-expressing progenitors within mechanosensory touch dome epithelia are highly tumorigenic. Sensory nerves activate Hedgehog signaling in normal touch domes, while denervation attenuates touch dome-derived tumors. Together, our studies identify varying tumor susceptibilities among different stem cell populations in the skin, highlight touch dome epithelia as "hot spots" for tumor formation, and implicate cutaneous nerves as mediators of tumorigenesis. PMID- 25842981 TI - Circulating microRNA-223 as a potential biomarker for obesity. AB - BACKGROUND AND AIMS: Obesity is a serious health problem that is implicated in many metabolic disorders. Recent studies have proposed that microRNA-223 (miR 223) is a potent regulator of many diseases related to obesity. However, the association of miR-223 with obesity remains unclear. In this study, we examined the relationship between serum miR-223 and obesity. DESIGN: A total of 121 subjects were selected, including 41 normal-weight, 40 overweight and 40 obesity subjects. The overweight and obesity subjects received lifestyle intervention for 3 months after baseline examination. Quantitative real-time PCR was used to measure the expression of circulating miR-223 in the serum. RESULTS: MiR-223 was lower in both overweight and obesity subjects compared with normal-weight control (1.06 vs. 7.54, p<0.001; 4.56 vs. 7.54, p<0.001, respectively). Circulating miR 223 increased significantly in both overweight and obesity groups after lifestyle intervention. Furthermore, subjects with the lowest tertile of miR-223 expression had the highest obesity prevalence. The odds ratio was 2.77 (95% confidence interval: 1.59-6.54, p<0.05) compared with the highest tertile of miR-223 expression. Such association was still apparent after adjusting for other major risk factors. CONCLUSION: The findings in this study suggest that miR-223 is a factor of obesity. The level of miR-223 in the serum can be used as a biomarker of obesity and therapeutic response. PMID- 25842982 TI - A sequential Ugi multicomponent/Cu-catalyzed azide-alkyne cycloaddition approach for the continuous flow generation of cyclic peptoids. AB - The development of a continuous flow multistep strategy for the synthesis of linear peptoids and their subsequent macrocyclization via Click chemistry is described. The central transformation of this process is an Ugi four-component reaction generating the peptidomimetic core structure. In order to avoid exposure to the often toxic and malodorous isocyanide building blocks, the continuous approach was telescoped by the dehydration of the corresponding formamide. In a concurrent operation, the highly energetic azide moiety required for the subsequent intramolecular copper-catalyzed azide-alkyne cycloaddition (Click reaction) was installed by nucleophilic substitution from a bromide precursor. All steps yielding to the linear core structures can be conveniently coupled without the need for purification steps resulting in a single process generating the desired peptidomimetics in good to excellent yields within a 25 min reaction time. The following macrocyclization was realized in a coil reactor made of copper without any additional additive. A careful process intensification study demonstrated that this transformation occurs quantitatively within 25 min at 140 degrees C. Depending on the resulting ring strain, either a dimeric or a monomeric form of the cyclic product was obtained. PMID- 25842983 TI - [Diagnostic usefulness of procalcitonin and C-reactive protein in the Emergency Department for predicting bacterial meningitis in the elderly]. AB - OBJETIVES: To analyse and compare procalcitonin (PCT) and C-reactive protein (CRP) as tools for detecting bacterial meningitis (BM) in the elderly (>74 years of age). METHODS: A prospective, observational, descriptive, analytical study of 220 consecutive patients aged >=1year and diagnosed with acute meningitis in an emergency department between September 2009 and July 2014. RESULTS: A total of 220 patients (136 [62%] male) were studied. The mean age was 30+/-26years, with BM being diagnosed in 17/83 patients from 1 to 14years of age, 32/111 from 15 to 74years of age, and 17/26 patients >=75years of age. PCT had the highest area under the receiver operating characteristic curve (AUC) (0.972; 95%CI, 0.946 0,998; P<.001) to predict bacterial meningitis. With a cut-off of >=0.52ng/mL, PCT achieved 93% sensitivity and 86% specificity, and for patients over 75years of age 96% sensitivity and 75% specificity, with the same AUC (0.972). The AUC for CRP was 0.888, and a >=54,4mg/L cut-off achieved 91% sensitivity and 78% specificity, and for patients over 75years of age an AUC of only 0.514 achieved with 97% sensitivity and 43% specificity. CONCLUSIONS: For all patients with acute meningitis in the emergency department, PCT has a high diagnostic power, outperforming CRP and Leukocytes for detection of bacterial etiology, but CPR is of not useful in the elderly. PMID- 25842984 TI - Tannoid principles of Emblica officinalis renovate cognitive deficits and attenuate amyloid pathologies against aluminum chloride induced rat model of Alzheimer's disease. AB - BACKGROUND/AIMS: Emblica officinalis is mentioned as a maharasayana in many Ayurvedic texts and promotes intelligence, memory, freedom from disease, longevity, and strength of the senses. The present study has been designed to explore the memory-enhancing effect of the tannoid principles of E. officinalis (EoT) at the biochemical, anatomical, behavioral, and molecular levels against aluminum chloride (AlCl3) induced Alzheimer's disease (AD) in rats. Aluminum is reported to have an important role in the etiology, pathogenesis, and development of AD. METHODS: Male Wistar rats were divided into control, AlCl3 treated, AlCl3 and EoT (50, 100, and 200 mg/kg bw) co-treated, and EoT (200 mg/kg bw) alone treated groups. In control and experimental rats, behavior tests including water maze and open field test, estimation of aluminum, assay of acetylcholinesterase (AChE) activity, and expression of amyloidogenic proteins were performed. RESULTS: Intraperitonial injection of AlCl3 (100 mg/kg bw) for 60 days significantly elevated the concentration of aluminum (Al), activity of AChE and protein expressions of amyloid precursor protein, A-beta1-42, beta-, and gamma secretases as compared to control group in hippocampus and cortex. Co administration of EoT orally to AlCl3 rats for 60 days significantly revert back the Al concentration, AChE activity, and A-beta synthesis-related molecules in the studied brain regions. The spatial learning, memory, and locomotor impairments observed in AlCl3 treated rats were significantly attenuated by EoT. CONCLUSION: Therefore, EoT may be a promising therapy in ameliorating neurotoxicity of aluminum, however further studies are warranted to elucidate the exact mechanism of action of EoT. PMID- 25842985 TI - Immunosuppression in pregnant women with systemic lupus erythematosus. AB - Most pregnancies are successful in women with systemic lupus erythematosus, particularly if the disease is quiescent and there are no signs of active nephritis. There is no major impact of immunosuppression on maternal outcome. However, high doses of cyclosporine and glucocorticoids are used which may favor development of hypertension or preeclampsia. Some immunosuppressive drugs may exert toxic effects on the fetus. Glucocorticoids may cause small birth weight, and azathioprine and calcineurin inhibitors may be associated with lower birth weight, gestational age and prematurity. Cyclophosphamide may cause fetal malformation when given in the first trimester. Mycophenolate and leflunomide are teratogenic drugs and should be withdrawn before conception in case of programmed pregnancy or should be rapidly discontinued in case of unexpected pregnancy. Option counseling for pregnancy and correct use of immunosuppressive drugs are prerequisites for a successful pregnancy in women with lupus. PMID- 25842987 TI - Effect of culture and maturation on human monocyte-derived dendritic cell surface markers, necrosis and antigen binding. AB - Dendritic cells (DC) are antigen-presenting cells (APC) that are important for innate and acquired immune responses. Owing to their involvement in autoinflammation, autoimmunity and cancer, DC are useful cellular models for biomedical research. Appropriate DC production in vitro could aid the study of DC in many human diseases. We used fluorochrome-based flow cytometry assays to analyze the effects of culture period and maturation of monocyte-derived DC (MoDC) on their viability and necrosis, purity, CD11c expression and phagocytic capacity. The morphological changes that occur as purified monocytes become DC were assessed at 24 and 72 h, and 6 and 9 days in culture. The dynamics of certain cell surface markers of monocytes and mature MoDC (mMoDC) also were assessed using fluorescence-based assays. We found that day 6 of culture yielded the most functional immature MoDC (iMoDC) with maximal viability, purity, CD11c expression and appropriate phagocytic capacity. Mass production of viable MoDC could be useful for immunotherapy. PMID- 25842988 TI - Radiation Safety: A Call to Arms. PMID- 25842989 TI - The Importance of Re-interventions After Ruptured EVAR. PMID- 25842990 TI - High Axial Loads While Walking Increase Anterior Tibial Translation in Intact and Anterior Cruciate Ligament-Deficient Knees. AB - PURPOSE: To evaluate the effect of high axial loading (AL) on anterior tibial translation (ATT) according to the increase in knee flexion and the effect of valgus stress (VS) and internal rotation (IR) combined with high AL in intact and anterior cruciate ligament (ACL)-deficient knees according to the increase in knee flexion. METHODS: We used 10 fresh-frozen, human cadaveric knees. Different loading conditions (134-N anterior drawer, 1,000-N AL, 10-Nm VS, and 5-Nm IR) were sequentially combined, and ATT was measured at 0 degrees , 15 degrees , 30 degrees , 45 degrees , and 60 degrees of flexion in the intact and ACL-deficient knees. RESULTS: ATT increased significantly by adding high AL in intact knees (P = .001) and ACL-deficient knees (P < .0001) according to the change in flexion angle (P < .0001). Under high AL, ATT in the ACL-deficient knees was significantly larger than that in the intact knees for all loading conditions, and it also increased gradually according to the increase in knee flexion (P = .0001). ATT increased significantly after adding IR or VS with high AL in intact knees (VS, P = .002; VS/IR, P = .03) and ACL-deficient knees (VS, P = .0004) at some of the flexion angles. CONCLUSIONS: The added high AL increased ATT in intact and ACL-deficient knees from 0 degrees to 60 degrees of flexion. The effect of high AL on ATT became greater in ACL-deficient knees than in intact knees, and ATT also gradually increased according to the increase in knee flexion from 0 degrees to 60 degrees . In both the intact and ACL-deficient knees, ATT increased significantly after valgus stress or IR from 0 degrees to 60 degrees . CLINICAL RELEVANCE: ATT during weight bearing increases stress to the ACL, which worsens with valgus stress and/or IR forces. This finding should be considered when one is studying ACL injury mechanisms, as well as prescribing rehabilitation after ACL surgery. PMID- 25842986 TI - Advances in the treatment of invasive neonatal candidiasis. AB - INTRODUCTION: Invasive candidiasis is responsible for ~ 10% of nosocomial sepsis in very-low-birth-weight infants and is associated with substantial morbidity and mortality. Over the last two decades, the antifungal armamentarium against Candida spp. has increased; however, efficacy and safety studies in this population are lacking. AREAS COVERED: We reviewed the medical literature and extracted information on clinical and observational studies evaluating the use of antifungal agents in neonates with invasive candidiasis. EXPERT OPINION: Efficacy and safety data for antifungals in neonates are lacking, and the majority of studies conducted to date have concentrated on pharmacokinetic/pharmacodynamic evaluations. Unlike other anti-infective agents, efficacy data in the setting of neonatal candidiasis cannot be extrapolated from adult studies due to differences in the pathophysiology of the disease in this population relative to older children and adults. Data for amphotericin B deoxycholate, fluconazole, and micafungin suggest that these are the current agents of choice for this disease in neonates until data for newer antifungal agents become available. For prophylaxis, data from fluconazole randomized controlled trials will be submitted to the regulatory agencies for labeling. Ultimately, the field of therapeutics for neonatal candidiasis will require multidisciplinary collaboration given the numerous challenges associated with conducting clinical trials in neonates. PMID- 25842991 TI - Effect of two surgical circumcision procedures on postoperative pain: A prospective, randomized, double-blind study. AB - BACKGROUND: Male circumcision (MC) is one of the most commonly used surgical procedures worldwide for medical and traditional reasons. No studies have compared the postoperative pain advantages of conventional techniques (i.e., sleeve and dorsal slit). OBJECTIVE: In this prospective randomized double-blind study, we investigated the effect of two surgical techniques (i.e., sleeve and dorsal slit) on postoperative pain and emergence agitation. STUDY DESIGN: This prospective study was conducted between January and July 2013. Approval was obtained from the local Ethical Committee on 17 December 2012, 06/23 (CLINICAL TRIALS IDENTIFIER: NCT 01909765). We compared two surgical techniques (i.e., the dorsal slit incision technique (Group A) and the double incision (i.e., sleeve) technique (Group B) in 60 children who were subjected to MC surgery under general anesthesia. All children received dorsal nerve blocks with bupivacaine. The modified objective pain scale (MOPS) was used for pain assessment, and the Ramsey Sedation Scale was used for the assessment of agitation during anesthesia emergence. RESULTS: The MOPS scores were lower in Group B than in Group A in the post-anesthesia care unit and during the 4th hour post-surgery (p = 0.01 and p = 0.037, respectively). Twelve children (40%) in Group A and 23 children (76.6%) in Group B required no additional analgesia on postoperative day one (p = 0.004). The Ramsey sedation scores were lower in Group A (p = 0.018). DISCUSSION: Dorsal slit is often the primary method in cases with paraphimosis; during this procedure, the frenulum frequently cannot be preserved at the 6-o'clock position of the mucosa, because of traction applied to skin and mucosa. As a result, the frenular artery is injured. In contrast, the sleeve technique protects the frenulum and the anatomic structures of the glans. In the sleeve technique, providing hemostasis and preventing partial ischemia by protecting the frenular artery reduces postoperative pain and complications. This present study demonstrated that the sleeve technique, which preserved the frenular artery, caused less bleeding, reduced electrocautery use and less ischemia than the dorsal slit technique. The sleeve technique effectively reduces early postoperative pain and agitation after circumcision, provided that adequate postoperative analgesia has been achieved. While all variables except the employed surgical techniques were similar, Group B had advantages with respect to analgesic requirement and pain control during the first 8 h after the operation. CONCLUSION: The sleeve technique provides lower pain scores and a reduced incidence of agitation after elective MC. PMID- 25842992 TI - Renal damage detected by DMSA, despite normal renal ultrasound, in children with febrile UTI. AB - OBJECTIVES: 2011 American Academy of Pediatrics guidelines recommended renal bladder ultrasound (RBUS) as the only evaluation after febrile urinary tract infection (FUTI) in infants aged 2-24 months. We determined the sensitivity, specificity, and false negative rate of RBUS to identify DMSA-detected renal damage in this age group as well as in older children. METHODS: Consecutive patients referred to pediatric urology with a history of FUTI underwent DMSA >= 3 months after FUTI. Abnormal RBUS was defined as: Society of Fetal Urology hydronephrosis grades I-IV; hydroureter >= 7 mm; renal scar defined as focal parenchymal thinning; and/or size discrepancy >= 1 cm between kidneys. Abnormal DMSA was presence of any focal uptake defects and/or split renal function < 44%. We calculated sensitivity, specificity, positive and negative predictive values, and false negative rates of RBUS compared to DMSA. RESULTS: 618 patients (79% female), median age 3.4 years, were referred for FUTIs. Of the 512 (83%) with normal RBUS, 99 (19%) had abnormal DMSA. Children with normal RBUS after their first FUTI had abnormal DMSA in 15/151 (10%) aged <= 24 months and 23/119 (19%) aged > 24 months. RBUS had poor sensitivity (34%) and low positive predictive value (47%) to identify patients with renal damage. 99/149 (66%) children with renal damage on DMSA had normal RBUS. CONCLUSION: After FUTI, 66% of children with reduced renal function and/or renal cortical defects found by DMSA scintigraphy had a normal RBUS. Since abnormal DMSA may correlate with increased risk for VUR, recurrent FUTI and renal damage, our data suggest RBUS alone will fail to detect a significant proportion of patients at risk. The data suggest that imaging after FUTI should include acute RBUS and delayed DMSA, reserving VCUG for patients with abnormal DMSA and/or recurrent FUTI. PMID- 25842993 TI - Commentary to "Flexible ureteroscopy and lasertripsy (FURSL) for paediatric renal calculi: Results from a systematic review". PMID- 25842994 TI - Management of bilateral Wilms tumor over three decades: The perspective of a single center. AB - INTRODUCTION: Outcomes of Wilms tumor improved in last 50 years and excellent survival rates can be achieved especially in case of non-metastatic disease and favorable histology. Nevertheless, bilateral cases still stand as a therapeutic challenge. Prognosis of bilateral Wilms tumor (BWT) is not as good as the unilateral tumors of similar stage and histology in terms of survival and renal function. OBJECTIVE: Management of BWT is constantly evolving and still stands as a therapeutic challenge. This study is designed to review and share our experiences on this topic from a surgical standpoint. STUDY DESIGN: The records of patients treated in our clinic between 1980 and 2013 according to Turkish Pediatric Group of Oncology protocol were analyzed retrospectively and clinical data, surgical details, pathology results, long term outcomes were analyzed. RESULTS: Thirteen girls and 7 boys with a mean age of 2,5 years were treated. There were 2 patients with Wilms tumor-Aniridia-Growth Retardation complex and one with isolated hemihypertrophy. Metastasis were detected in lungs of 4 patients; liver of 2 and in the cranium of one. All patients except one with the presumptive diagnosis of unilateral Wilms tumor were given preoperative chemotherapy. To sum up; 19 nephroureterectomies, 8 partial nephrectomies and 13 enucleations were performed to 36 kidneys without any major early or late postoperative complications. Pathologic results revealed positive surgical margins in 2 lesions with enucleation and in 2 with partial nephrectomies and anaplasia in 4 patients. Two patients were not operated due to parental disapproval. Two patients had the need of dialysis; one was anephric and the others' renal functions recovered over a year. Seven patients received radiotherapy for pulmonary metastasis, positive surgical margins or local recurrences. Overall, 13 patients survived and 7 died due to metastasis, recurrences, and complication of dialysis and refusal of surgical treatment. Survival among all patients was 65% and 72.2% among operated ones. Of the 7 patients with the partial nephrectomy, 2 died and 5 survived. Among enucleation group, 8 out of 10 survived and 2 died. Survival was slightly higher among enucleation group (80% vs 71.4%). Median time of follow-up for survivors of disease is 5.8 years (min: 6 months and max: 14 years). DISCUSSION: Outcomes of BWT management have changed dramatically during the last few decades from only survival, to a long life expectancy without the need of renal replacement therapy owing to improvements in treatment options. We argue that positive surgical margins do not necessarily lead to local recurrence. For this reason it may be wiser to favor on more nephron sparing surgery than to achieve negative surgical margins. Adjuvant chemotherapy and radiotherapy may be adequate to prevent local recurrence. Also, survival did not differ significantly between different ways of nephron sparing surgeries, so it may be wiser to choose enucleation over partial nephrectomy which preserves more nephrons. Nephron-sparing surgery should have utmost importance despite the risk of positive margins. On the other hand, there is not enough data to interpret if positive surgical margins have role on distant metastases or not. Presence of metastasis and recurrence seems to be an important determinant of prognosis given the fact that none of the survivors had any metastasis or recurrence. CONCLUSION: Nephron preservation should be the aim while taking positive surgical margin risk on nephron sparing surgery side relying on postoperative chemotherapy and carefully planned radiotherapy to avoid recurrence. However, there is significant diversity on the management BWT in different centers and a certain validated guideline or protocol to provide the optimal treatment is still lacking. PMID- 25842995 TI - Predisposing factors associated with stillbirth in Tanzania. AB - OBJECTIVE: To determine whether specific medical conditions and/or fetal compromise during labor are associated with fresh stillbirth (FSB), and whether absent fetal heart rate (FHR) before delivery can increase risk of FSB. METHODS: An observational cohort study was conducted at three university referral hospitals in Tanzania between January and September 2013. Maternal, labor, and neonatal characteristics were recorded for all deliveries. FSB was defined as an Apgar score of 0 at 1 and 5minutes, with intact skin and suspected death during labor or delivery. RESULTS: Among 15 305 deliveries, there were 499 stillbirths (243 FSBs and 256 macerated stillbirths). Stillbirth was significantly more likely than a live birth after maternal transfer (odds ratio [OR] 3.27; 95% confidence interval [CI] 2.73-3.92; P<0.001) and when FHR was absent (OR 996.29; 95% CI 632.19-1570.09; P<0.001). Risk of stillbirth increased with uterine rupture (OR 138.62; 95% CI 60.73-316.44), placental abruption (OR 40.96; 95% CI 28.97-57.91), cord prolapse (OR 13.49; 95% CI 6.97-26.11), and prematurity (OR 6.87; 95% CI 4.71-10.03; P<0.001 for all). CONCLUSION: In low-resource settings, FSB may be prevented by using a combined strategy of clinical risk identification, early detection of abnormal FHR, and expedited delivery. PMID- 25842996 TI - The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development. AB - The flavivirus NS3 protein is associated with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the NS2B integral membrane protein. The multiple roles played by the NS2B-NS3 protein in the virus life cycle makes it an attractive target for antiviral drug discovery. The N-terminal region of NS3 and its cofactor NS2B constitute the protease that cleaves the viral polyprotein. The NS3 C-terminal domain possesses RNA helicase, nucleoside and RNA triphosphatase activities and is involved both in viral RNA replication and virus particle formation. In addition, NS2B-NS3 serves as a hub for the assembly of the flavivirus replication complex and also modulates viral pathogenesis and the host immune response. Here, we review biochemical and structural advances on the NS2B-NS3 protein, including the network of interactions it forms with NS5 and NS4B and highlight recent drug development efforts targeting this protein. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery. PMID- 25842997 TI - From industrially weavable and knittable highly conductive yarns to large wearable energy storage textiles. AB - Wearable electronic textiles that store capacitive energy are a next frontier in personalized electronics. However, the lack of industrially weavable and knittable conductive yarns in conjunction with high capacitance, limits the wide scale application of such textiles. Here pristine soft conductive yarns are continuously produced by a scalable method with the use of twist-bundle-drawing technique, and are mechanically robust enough to be knitted to a cloth by a commercial cloth knitting machine. Subsequently, the reduced-graphene-oxide modified conductive yarns covered with a hierarchical structure of MnO2 nanosheets and a polypyrrole thin film were used to fabricate weavable, knittable and wearable yarn supercapacitors. The resultant modified yarns exhibit specific capacitances as high as 36.6 mF cm(-1) and 486 mF cm(-2) in aqueous electrolyte (three-electrode cell) or 31 mF cm(-1) and 411 mF cm(-2) in all solid-state two electrode cell. The symmetric solid-state supercapacitor has high energy densities of 0.0092 mWh cm(-2) and 1.1 mWh cm(-3) (both normalized to the whole device) with a long cycle life. Large energy storage textiles are fabricated by weaving our flexible all-solid-state supercapacitor yarns to a 15 cm * 10 cm cloth on a loom and knitting in a woollen wrist band to form a pattern, enabling dual functionalities of energy storage capability and wearability. PMID- 25842998 TI - Release behavior of non-network proteins and its relationship to the structure of heat-induced soy protein gels. AB - Heat-induced soy protein gels were prepared by heating protein solutions at 12%, 15% ,or 18% for 0.5, 1.0, or 2.0 h. The release of non-network proteins from gel slices was conducted in 10 mM pH 7.0 sodium phosphate buffer. SDS-PAGE and diagonal electrophoresis demonstrated that the released proteins consisted of undenatured AB subunits and denatured proteins including monomers of A polypeptides, disulfide bond linked dimers, trimers, and polymers of A polypeptides, and an unidentified 15 kDa protein. SEC-HPLC analysis of non network proteins revealed three major protein peaks, with molecular weights of approximately 253.9, 44.8, and 9.7 kDa. The experimental data showed that the time-dependent release of the three fractions from soy protein gels fit Fick's second law. An increasing protein concentration or heating time resulted in a decrease in diffusion coefficients of non-network proteins. A power law expression was used to describe the relationship between non-network protein diffusion coefficient and molecular weight, for which the exponent (alpha) shifted to higher value with an increase in protein concentration or heating time, indicating that a more compact gel structure was formed. PMID- 25842999 TI - Interactive effects of nanoparticles with other contaminants in aquatic organisms: Friend or foe? AB - The increasing production and use of nanoparticles (NPs) will lead to their release into the aquatic environment, posing a potential threat to the health of aquatic organisms. Both in the water phase and in the sediments NPs could mix and interact with other pollutants, such as organic xenobiotics and heavy metals, leading to possible changes in their bioavailability/bioconcentration/toxicity. However, whether these interactive effects may lead to increased harmful effects in marine organisms is largely unknown. In this work, available data mainly obtained on carbon based NPs and n-TiO2, as examples of widespread NPs, in aquatic organisms are reviewed. Moreover, data are summarized on the interactive effects of n-TiO2 with 2,3,7,8-TCDD and Cd(2+), chosen as examples of common and persistent organic and inorganic contaminants, respectively, in the model marine bivalve Mytilus. The results reveal complex and often unexpected interactive responses of NPs with other pollutants, depending on type of contaminant and the endpoint measured, as well as differences in bioaccumulation. The results are discussed in relation with data obtained in freshwater organisms. Overall, information available so far indicate that interactive effects of NPs with other contaminants do not necessarily lead to increased toxicity or harmful effects in aquatic organisms. PMID- 25843000 TI - Charge transfer emission in oligotriarylamine-triarylborane compounds. AB - Donor-acceptor compounds exhibiting charge transfer emission are of interest in a variety of different contexts, for example, for nonlinear optical processes and for sensor applications. Recently investigated triarylamine-triarylborane compounds represent an important class of donor-acceptor systems, and we explored to what extent their charge-transfer properties can be further improved by using stronger amine donors and borane acceptors than prior studies. The oligotriarylamine employed here is a much stronger donor than previously used triarylamines containing single nitrogen centers. In order to increase the acceptor strength, the electron-accepting unit was equipped with two (instead of one) dimesitylboron substituents. In our comparative study, six donor-acceptor compounds were synthesized and investigated by cyclic voltammetry and optical spectroscopy. An increase of the donor strength through replacement of an ordinary triarylamine by an oligotriarylamine unit leads to the expected energetic stabilization of charge transfer (CT) excited states, but the emission solvatochromism is not more pronounced. The attempted increase of the acceptor strength by substitution of the acceptor moiety by two (instead of one) dimesitylboron groups leads to a drastic decrease of emission quantum yields. On the basis of these results, our purely experimental study provides fundamental guidelines for the design of new triarylamine-triarylborane donor-acceptor compounds with favorable charge-transfer emission properties. PMID- 25843001 TI - Biofilm formation and genetic variability of BCR1 gene in the Candida parapsilosis complex. AB - BACKGROUND: Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis are cryptic species that belong to the C. parapsilosis complex, which has been increasingly associated to fungemia in various geographic regions, principally due to the capability of these yeasts to form biofilms on indwelling medical devices. BCR1 is one of the most studied genes related to Candida spp. biofilms. AIMS: To evaluate the biofilm forming capability of a subset of 65 clinical isolates of the C. parapsilosis complex using two conventional approaches, and to look for an association between the biofilm forming phenotype and genetic variants of a fragment of BCR1. METHODS: The biofilm determination was carried out by crystal violet staining and tetrazolium reduction assay. On the other hand, a segment of BCR1 gene was sequenced by Sanger methodology. RESULTS: C. parapsilosis sensu stricto was statistically associated with a low biofilm production phenotype, while C. orthopsilosis was significantly associated with both phenotypes (high and low biofilm producers). According to the BCR1 sequence analysis, genetic variability was detected in C. orthopsilosis and C. metapsilosis without a particular biofilm formation phenotype association. CONCLUSIONS: Under the adopted experimental design, C. parapsilosis sensu stricto was associated with the low biofilm phenotype and C. orthopsilosis with both phenotypes (high and low biofilm producers). On the other hand, an association between a biofilm forming phenotype and a particular genetic variant of the analyzed BCR1 fragment was not found. PMID- 25843002 TI - Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer progression, invasion, and metastasis. AB - Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients. PMID- 25843003 TI - Mechanistic Asymmetry in Hsp90 Dimers. AB - Hsp90 is a molecular chaperone that facilitates the maturation of signaling proteins including many kinases and steroid hormone receptors. Through these client proteins, Hsp90 is a key mediator of many physiological processes and has emerged as a promising drug target in cancer. Additionally, Hsp90 can mask or potentiate the impact of mutations in clients with remarkable influence on evolutionary adaptations. The influential roles of Hsp90 in biology and disease have stimulated extensive research into the molecular mechanism of this chaperone. These studies have shown that Hsp90 is a homodimeric protein that requires ATP hydrolysis and a host of accessory proteins termed co-chaperones to facilitate the maturation of clients to their active states. Flexible hinge regions between its three structured domains enable Hsp90 to sample dramatically distinct conformations that are influenced by nucleotide, client, and co chaperone binding. While it is clear that Hsp90 can exist in symmetrical conformations, recent studies have indicated that this homodimeric chaperone can also assume a variety of asymmetric conformations and complexes that are important for client maturation. The visualization of Hsp90-client complexes at high resolution together with tools to independently manipulate each subunit in the Hsp90 dimer are providing new insights into the asymmetric function of each subunit during client maturation. PMID- 25843004 TI - Therapeutic efficacy of liposomes containing 4-(5-pentadecyl-1,3,4-oxadiazol-2 yl)pyridine in a murine model of progressive pulmonary tuberculosis. AB - BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is one of the deadliest infectious diseases and comprises a global public health concern because co-infection with Human immunodeficiency virus (HIV) and, in particular, the continuous isolation of new Multidrug-resistant strains (MDR), rendering the discovery of novel anti TB agents a strategic priority. One of the most effective first-line mycobactericidal drugs is Isoniazid (INH). Previously, we reported in vitro anti mycobacterial activity against sensitive and MDR Mycobacterium tuberculosis strains of a new oxadiazole obtained from the hybridization of INH and palmitic acid. The present study evaluated the therapeutic potential of liposomes including Phosphatidylcholine (PC) and L-alpha Phosphatidic acid (PA) or PC and Cholesterol (Chol) containing 4-(5-pentadecyl-1,3,4-oxadiazol-2-yl)pyridine in BALB/c male mice infected by intratracheal (i.t.) route with drug-sensitive or MDR M. tuberculosis. METHODS: The lipophilic 4-(5-pentadecyl-1,3,4-oxadiazol-2 yl)pyridine was obtained to mix INH and palmitoyl chloride. The in vivo anti-TB effect of this oxadiazole derivative contained in two different liposomes was tested in BALB/c mice infected with a sensitive strain of M. tuberculosis, initiating treatment 2 months post-infection, by i.t. route, of 50 MUg of oxadiazole derivative for 1 month. In a second stage, mice were infected with an MDR (resistant to first-line drugs) and treated with 150 MUg of an oxadiazole derivative carried by PC + Chol liposomes for 2 months. The effect of the oxadiazole derivative in vivo was determined by the quantification of lung bacilli loads and histopathology. RESULTS: In comparison with control animals, drug-sensitive, strain-infected mice treated for 1 month with 50 MUg of this oxadiazole derivative contained in the liposomes of PC + Chol showed a significant, 80% decrease of live bacilli in lungs, which correlated with the morphometric observation, and the group of MDR clinical isolate-infected mice treated with 150 MUg of the oxadiazole derivative contained in the same type of liposome showed significantly lower lung bacillary loads than control mice, producing 90% of bacilli burden reduction after 2 months of treatment. CONCLUSION: These results confirm and extend the reported highly efficient anti mycobacterial activity of this lipophilic oxidazole derivative when it is carried by liposomes in mice suffering from late progressive pulmonary TB induced by drug sensitive, and most prominently by, MDR strains. PMID- 25843005 TI - Nintedanib modulates surfactant protein-D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase-activator protein-1 pathway. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a high mortality rate. Signalling pathways activated by several tyrosine kinase receptors are known to be involved in lung fibrosis, and this knowledge has led to the development of the triple tyrosine kinase inhibitor nintedanib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), for the treatment of IPF. Pulmonary surfactant protein D (SP-D), an important biomarker of IPF, reportedly attenuates bleomycin-induced pulmonary fibrosis in mice. In this study, we investigated whether nintedanib modulates SP D expression in human lung epithelial (A549) cells using quantitative real-time reverse transcriptase polymerase chain reaction and western blotting. To investigate the mechanisms underlying the effects of nintedanib, we evaluated the phosphorylation of c-Jun N-terminal kinase (JNK) and its downstream target c-Jun. The effect of the JNK inhibitor SP600125 on c-Jun phosphorylation was also tested. Activation of activator protein-1 (AP-1) was examined using an enzyme linked immunosorbent assay-based test, and cell proliferation assays were performed to estimate the effect of nintedanib on cell proliferation. Furthermore, we treated mice with nintedanib to examine its in vivo effect on SP D levels in lungs. These experiments showed that nintedanib up-regulated SP-D messenger RNA expression in a dose-dependent manner at concentrations up to 5 MUM, with significant SP-D induction observed at concentrations of 3 MUM and 5 MUM, in comparison with that observed in vehicle controls. Nintedanib stimulated a rapid increase in phosphorylated JNK in A549 cells within 30 min of treatment and stimulated c-Jun phosphorylation, which was inhibited by the JNK inhibitor SP600125. Additionally, nintedanib was found to activate AP-1. A549 cell proliferation was not affected by nintedanib at any of the tested concentrations. Moreover, blocking FGFR, PDGFR, and VEGFR function did not affect nintedanib induced SP-D expression, suggesting that nintedanib mediates its effects through a mechanism that is distinct from its known role as a tyrosine kinase inhibitor. Nintedanib is also reported to inhibit Src kinase although pre-treatment of cells with a Src kinase inhibitor had no effect on nintedanib-induced SP-D expression. Increased expression of SFTPD mRNA and SP-D protein in the lungs of nintedanib treated mice was also observed. In this work, we demonstrated that nintedanib up regulated SP-D expression in A549 cells via the JNK-AP-1 pathway and did not affect cell proliferation. This is the first report describing SP-D induction by nintedanib. PMID- 25843006 TI - Efficacy and safety of phosphodiesterase type-5 inhibitors for pulmonary arterial hypertension: A meta-analysis focusing on 6MWD. AB - BACKGROUND AND OBJECTIVE: Phosphodiesterase type-5 inhibitors (PDE-5 inhibitors) have been suggested as a first-line drug for treating pulmonary arterial hypertension (PAH). The aim of present meta-analysis was to fully evaluate the efficacy and safety of treating PAH with PDE-5 inhibitors, focusing on the improvement of 6-min walk distance (6MWD). METHODS: Studies were identified from The Cochrane Library, EMBASE, and PUBMED databases. We calculated odds ratios (OR) for dichotomous data and weighted mean differences with 95% confidence intervals (CI) for continuous data. RESULTS: Six studies with a total of 1056 patients (729 patients in PDE-5 inhibitors treatment group and 327 patients in placebo group) were included. All-cause mortality rate in the control group and PDE-5 inhibitors group was 2.6% and 0.7%, respectively. In an average of 12.3 week follow-up, PDE-5 inhibitors treatment was associated with a 71% reduction in mortality (OR 0.29; 95 %CI 0.07-1.15; P = 0.08), and increased 6MWD by 40.17 m, improved NYHA functional class and hemodynamic parameters. As for monotherapy and combination therapy patients, 6MWD has improved by 48.94 m and 21.75 m, respectively. CONCLUSIONS: The results of present meta-analysis suggest that treatment with PDE-5 inhibitors improves the 6MWD, clinical symptoms, hemodynamic parameters, and a tendency of survival benefits. In patients treated with PDE-5 inhibitor monotherapy, the 6MWD significantly increased when compared to combination therapies. PMID- 25843007 TI - Plant growth-promoting and antifungal activity of yeasts from dark chestnut soil. AB - 538 yeast strains were isolated from dark chestnut soil collected from under the plants of the legume family (Fabaceae). The greatest number of microorganisms is found at soil depth 10-20 cm. Among the 538 strains of yeast 77 (14.3%) strains demonstrated the ability to synthesize IAA. 15 strains were attributed to high IAA-producing yeasts (above 10 MUg/ml). The most active strains were YA05 with 51.7 +/- 2.1 MUg/ml of IAA and YR07 with 45.3 +/- 1.5 MUg/ml. In the study of effect of incubation time on IAA production the maximum accumulation of IAA coincided with maximum rates of biomass: at 120 h for YR07 and at 144 h for strain YA05. IAA production increased when medium was supplemented with the L tryptophan. 400 MUg/ml of L-tryptophan showed maximum IAA production. 10 strains demonstrated the ability to inhibit the growth and development of phytopathogenic fungi. YA05 and YR07 strains formed the largest zones of inhibition compared to the other strains--from 21.6 +/- 0.3 to 30.6 +/- 0.5 mm. Maximum zone of inhibition was observed for YA05 against Phytophtora infestans and YR07 strains against Fusarium graminearum. YA05 and YR07 strains were identified as Aureobasidium pullulans YA05 (GenBank accession No JF160955) and Rhodotorula mucilaginosa YR07 (GenBank accession No JF160956). PMID- 25843008 TI - Considering affinity: An ethereal conversation (part three of three). PMID- 25843009 TI - Molecular detection of Rangelia vitalii in domestic dogs from Uruguay. AB - The piroplasm Rangelia vitalii is the etiological agent of canine rangeliosis, a severe disease affecting domestic dogs in South America. Two domestic dogs from two different Departments (Salto and Treinta y Tres) of Uruguay presented with clinical signs such as apathy, anorexia, pale mucous membranes, jaundice, and hemorrhagic manifestations, suggestive of a canine vector-borne disease. Molecular analysis, based on PCR and DNA sequencing of portions of the 18S rRNA gene, revealed that both dogs were infected by R. vitalii. Two consensus sequences, one from Salto and one from Treinta y Tres, differed from each other by only 1 nucleotide (99.8% similarity) and were 99.8-100% identical to corresponding sequences of R. vitalii from Brazil and Argentina available in GenBank. Through phylogenetic analysis inferred by the 18S rRNA gene, the two Uruguayan sequences of R. vitalii were aligned with the corresponding sequences from 7 other R. vitalii sequences available in GenBank (5 from Brazil and, 2 from Argentina) under high bootstrap support. The two dogs of the present study were negative for Ehrlichia canis according to the E. canis-specific real-time PCR assay. Our findings not only confirm the occurrence of R. vitalii in Uruguay but also provide the southernmost record of this re-emerging agent. The only previous report of R. vitalii in Uruguay dated from 1976, a period when molecular analyses were not available. We provide the first molecular detection of R. vitalii in Uruguay. Currently, canine rangeliosis is confirmed to occur in Brazil, Argentina, and Uruguay. PMID- 25843010 TI - Seated postural neck and trunk reactions to sideways perturbations with or without a cognitive task. AB - Driving on irregular terrain will expose the driver to sideways mechanical shocks or perturbations that may cause musculoskeletal problems. How a cognitive task, imposed on the driver, affects seated postural reactions during perturbations is unknown. The aim of the present study was to investigate seated postural reactions in the neck and trunk among healthy adults exposed to sideways perturbations with or without a cognitive task. Twenty-three healthy male subjects aged 19-36 years, were seated on a chair mounted on a motion system and randomly exposed to 20 sideways perturbations (at two peak accelerations 5.1 or 13.2m/s(2)) in two conditions: counting backwards or not. Kinematics were recorded for upper body segments using inertial measurement units attached to the body and electromyography (EMG) was recorded for four muscles bilaterally in the neck and trunk. Angular displacements (head, neck, trunk and pelvis) in the frontal plane, and EMG amplitude (normalised to maximum voluntary contractions, MVC) were analysed. The cognitive task provoked significantly larger angular displacements of the head, neck and trunk and significantly increased EMG mean amplitudes in the upper neck during deceleration, although 10% of MVC was never exceeded. A cognitive task seems to affect musculoskeletal reactions when exposed to sideways perturbations in a seated position. PMID- 25843011 TI - Linking the Cell Cycle with Innate Immunity in Arabidopsis. PMID- 25843012 TI - Targeting Plant Ethylene Responses by Controlling Essential Protein-Protein Interactions in the Ethylene Pathway. AB - The gaseous plant hormone ethylene regulates many processes of high agronomic relevance throughout the life span of plants. A central element in ethylene signaling is the endoplasmic reticulum (ER)-localized membrane protein ethylene insensitive2 (EIN2). Recent studies indicate that in response to ethylene, the extra-membranous C-terminal end of EIN2 is proteolytically processed and translocated from the ER to the nucleus. Here, we report that the conserved nuclear localization signal (NLS) mediating nuclear import of the EIN2 C-terminus provides an important domain for complex formation with ethylene receptor ethylene response1 (ETR1). EIN2 lacking the NLS domain shows strongly reduced affinity for the receptor. Interaction of EIN2 and ETR1 is also blocked by a synthetic peptide of the NLS motif. The corresponding peptide substantially reduces ethylene responses in planta. Our results uncover a novel mechanism and type of inhibitor interfering with ethylene signal transduction and ethylene responses in plants. Disruption of essential protein-protein interactions in the ethylene signaling pathway as shown in our study for the EIN2-ETR1 complex has the potential to guide the development of innovative ethylene antagonists for modern agriculture and horticulture. PMID- 25843013 TI - Sleep stability and transitions in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease. AB - OBJECTIVE: Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) are at high risk of developing Parkinson's disease (PD). As wake/sleep-regulation is thought to involve neurons located in the brainstem and hypothalamic areas, we hypothesize that the neurodegeneration in iRBD/PD is likely to affect wake/sleep and REM/non-REM (NREM) sleep transitions. METHODS: We determined the frequency of wake/sleep and REM/NREM sleep transitions and the stability of wake (W), REM and NREM sleep as measured by polysomnography (PSG) in 27 patients with PD, 23 patients with iRBD, 25 patients with periodic leg movement disorder (PLMD) and 23 controls. Measures were computed based on manual scorings and data-driven labeled sleep staging. RESULTS: Patients with PD showed significantly lower REM stability than controls and patients with PLMD. Patients with iRBD had significantly lower REM stability compared with controls. Patients with PD and RBD showed significantly lower NREM stability and significantly more REM/NREM transitions than controls. CONCLUSIONS: We conclude that W, NREM and REM stability and transitions are progressively affected in iRBD and PD, probably reflecting the successive involvement of brain stem areas from early on in the disease. SIGNIFICANCE: Sleep stability and transitions determined by a data driven approach could support the evaluation of iRBD and PD patients. PMID- 25843014 TI - Some additional considerations in modelling the dynamic traits and genome-wide association studies: Comments on "Mapping complex traits as a dynamic system" by L. Sun and R. Wu. PMID- 25843015 TI - Single molecule data under scrutiny: Comment on "Extracting physics of life at the molecular level: A review of single-molecule data analyses" by W. Colomb & S.K. Sarkar. PMID- 25843016 TI - Burkitt leukaemia/lymphoma: R-CODOX-M/R-IVAC remains gold standard treatment in BL. AB - BACKGROUND: Sporadic Burkitt lymphoma (BL), characterised by translocation associated C-MYC upregulation is a rare, aggressive lymphoma with a cure rate up to 90 % using the R-CODOX-M/R-IVAC (RCRI) protocol. RCRI is active in HIV associated BL in combination with HAART. The WHO classification system defines lymphomas intermediate between DLBCL and BL, in which lymphomas with t(14;18)(q32;q21) and C-MYC-carrying translocation, i.e. 'double-hit' are included (BL-DH), and these patients are conventionally treated with RCRI. RESULT: We describe the SJH experience of 25 patients with BL, BL + HIV and BL-DH treated with RCRI between 2002 and 2011. Twelve BL patients (8M/4F), median age 49.1 years (range 20-73 years); of whom 9 had extensive disease, including 8 with marrow and 2 with CNS involvement. Eleven patients remain in remission at 80.5 months (range 37-147 months) from completion of treatment and one died of progressive BL giving an OS of 91.6 % at 1 year with no late relapses. Eight patients with BL + HIV were treated (6M/2F) with a median age 40.25 years (range 24-64). Five remain in complete remission (CR) at 65 months (range 13-109 months), three patients died, two of progressive disease and one of treatment associated hepatotoxicity in CR. Five patients with BL-DH were included; (3M/2F), age 47.8 years (range 42-55 years); and all patients died of progressive disease, 4 on RCRI therapy and a further patient despite an allogeneic transplantation. CONCLUSION: These results confirm that RCRI is an effective treatment in adults with BL and BL + HIV and remains the gold standard against which other regimens should be compared. We confirm the poor prognosis found in BL-DH, indicating new treatment approaches are needed for this sub-group which should be identified at diagnosis by FISH analysis. PMID- 25843017 TI - Predicting prostate cancer: analysing the clinical efficacy of prostate cancer risk calculators in a referral population. AB - BACKGROUND: The decision to proceed to biopsy for the diagnosis of prostate cancer in clinical practice is a difficult one. Prostate cancer risk calculators allow for a systematic approach to the use of patient information to predict a patient's likelihood of prostate cancer. AIMS: In this paper, we validate the two leading prostate cancer risk calculators, the prostate cancer prevention trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) in an Irish population. METHODS: Data were collected for 337 men referred to one tertiary referral center in Ireland. Calibration analysis, ROC analysis and decision curve analysis were undertaken to ascertain the performance of the PCPT and the ERSPC risk calculators in this cohort. RESULTS: Of 337 consecutive biopsies, cancer was subsequently diagnosed in 146 men (43 %), 98 (67 %) of which were high grade. The AUC for the PCPT and ERSPC risk calculators were 0.68 and 0.66, respectively for the prediction of prostate cancer. Each calculator was sufficiently calibrated in this cohort. Decision curve analysis demonstrated a net benefit via the use of the PCPT and ERSPC risk calculators in the diagnosis of prostate cancer. CONCLUSIONS: The PCPT and ERSPC risk calculators achieve a statistically significant prediction of prostate cancer in this Irish population. This study provides external validation for these calculators, and therefore these tools can be used to aid in clinical decision making. PMID- 25843018 TI - Pyrroloquinoline quinone (PQQ) producing Escherichia coli Nissle 1917 (EcN) alleviates age associated oxidative stress and hyperlipidemia, and improves mitochondrial function in ageing rats. AB - BACKGROUND: Ageing involves oxidative stress mediated by Reactive Oxygen Species (ROS) and mitochondrial dysfunction. The present work demonstrates the protective effect of PQQ producing EcN against rotenone induced mitochondrial oxidative stress and consequence of mitochondrial and cellular dysfunction in naturally ageing rat model. PQQ is a potent antioxidant molecule also known to stimulate mitochondrial biogenesis and function in mammals. METHODS: Firstly, adult rats (16-18 weeks old) were treated with rotenone (2.5 mg/kg body weight; i.p.) daily for 28 days along with PQQ (10 mg/kg diet, daily) and modified probiotic EcN strains (10(8) CFU twice weekly). Secondly, ageing rats (48-50 weeks old) were gavaged with probiotic EcN strains (10(8)CFU twice weekly) and PQQ (10 mg/kg diet, daily) for 8 months. RESULTS: PQQ producing EcN-5 treatment prevented rotenone induced hepatic oxidative stress and mitochondrial damage in rats as assessed by reduced lipid peroxidation (29%), elevated glutathione (GSH) content (43%), increased catalase (52%) and superoxide dismutase (52%) activities when compared to only rotenone treatment. Moreover, increased hepatic mitochondrial content (41%), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) mRNA (25%) and mitochondrial Superoxide Dismutase (Mit-SOD) activity (94%) were also observed in EcN-5 treated rats. Rotenone treated rats did not exhibit gain in body weight, whereas rats co-treated with EcN-5 showed significant restoration in body weight gain. Furthermore, weekly administration of EcN-5 to naturally ageing rats for eight months resulted in significant reduction of oxidative stress in hepatic and colonic tissues (assessed by lipid peroxidation, GSH content and catalase and SOD enzyme activities) along with increase in hepatic mitochondrial enzyme activities (Mit-SOD and succinate dehydrogenase) and biogenesis, when compared to untreated rats. Additionally, these rats also exhibited reduced expression of fatty acid synthase (50%) and increased expression of acyl coenzyme oxidase (225%) genes in liver in contrast to untreated rats resulting in lowered triglyceride (13% & 13.5%) and cholesterol (21% & 27%) levels in plasma and liver, respectively. Increased levels of butyrate (93%), propionate (45%) and acetate (18%) were also found in colonic content of these rats. PQQ administered daily (supplemented in diet) exhibited more or less similar effect as weekly gavaged EcN-5 in both the experiments, which substantiate that these effects are mediated by PQQ. CONCLUSION: These results suggest that genetically modified EcN-5 can be used as a nutritional supplement which can reduce age related oxidative stress and hyperlipidemia. Furthermore, it also rejuvenates healthy mitochondria by stimulating mitochondrial biogenesis and metabolism. PMID- 25843019 TI - Harvard Aging Brain Study: Dataset and accessibility. AB - The Harvard Aging Brain Study is sharing its data with the global research community. The longitudinal dataset consists of a 284-subject cohort with the following modalities acquired: demographics, clinical assessment, comprehensive neuropsychological testing, clinical biomarkers, and neuroimaging. To promote more extensive analyses, imaging data was designed to be compatible with other publicly available datasets. A cloud-based system enables access to interested researchers with blinded data available contingent upon completion of a data usage agreement and administrative approval. Data collection is ongoing and currently in its fifth year. PMID- 25843020 TI - Possible mechanisms of action of Caesalpinia pyramidalis against ethanol-induced gastric damage. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia pyramidalis Tul. (Fabaceae), known as "catingueira", is an endemic tree of the Northeast region of Brazil. This plant, mainly inner bark and flowers, has been used in traditional medicine to treat gastritis, heartburn, indigestion, stomachache, dysenteries, and diarrheas. MATERIALS AND METHODS: The ethanol extract of C. pyramidalis inner bark was used in rats via oral route, at the doses of 30, 100, and 300 mg/kg, in the ethanol induced ulcer model and some of the mechanisms underlying to the gastroprotective effect of this plant investigated. RESULTS: The ethanol extract of C. pyramidalis inner bark (100 mg/kg) produced reduction (P < 0.001) on the total lesion area in the ethanol-induced gastric damage. The gastroprotective response caused by the ethanol extract (100 mg/kg) was significantly attenuated (P < 0.05) by intraperitoneal treatment of rats with DL-Propargylglycine (PAG, a cystathionine gamma-lyase inhibitor; 25 mg/kg), but not by Nw-nitro-L-arginine methyl ester hydrochloride (L-NAME, an inhibitor of nitric oxide synthase; 70 mg/kg), and confirmed by microscopic evidence. The ethanol extract significantly decreased the number of mucosal mast cells compared to vehicle-treated group. The inflammatory cells of the ethanol extract (100 mg/kg)-treated ulcerated rats exhibited an upregulation of interleukin (IL)-4 protein expression and downregulation of inducible nitric oxide synthase (iNOS) expression, observed by immunohistochemistry and flow cytometer. CONCLUSIONS: The present results suggest that the ethanol extract of C. pyramidalis produced dose-related gastroprotective response on ethanol-induce ulcer in rats through mechanisms that involved an interaction with endogenous hydrogen sulfide and reduction of inflammatory process with imbalance between pro-inflammatory and anti-inflammatory mediators, supporting the popular usage of this plant. PMID- 25843021 TI - Uses of plants, animal and mineral substances in Mediterranean ethno-veterinary practices for the care of small ruminants. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: The cultural heritage of Sardinian shepherds is rapidly vanishing and survives in the memory of elderly people. The objective of our study was not only to report the usage of plants and their preparation for administration but also the use of other remedies of different origin arising from traditional ethno-veterinary knowledge, as Sardinian shepherds were used to employ plants, animals, minerals and combinations of several substances to prepare remedies for prophylaxis or therapy on their animals. MATERIALS AND METHODS: The work was carried out in rural areas of the island of Sardinia (Italy) by interviewing shepherds and filling questionnaires in order to record ethno-veterinary practices traditionally used for animal health care. RESULTS: Ethno-veterinary remedies traditionally utilised for treatments of small ruminants against ecto-and endo-parasites, gastrointestinal diseases, viral and bacterial diseases, wounds, sprains and bruises were identified. Non herbal remedies outnumbered the herbal ones, as usually plant species were mainly used for the care of cattle and equines. A total of 150 ethno-veterinary uses were documented for the treatment of 33 animal conditions, a detailed account of the formulations and their administration to sheep and goats was provided. Herbal remedies involved the use of twenty two spontaneous species and seven cultivated species. CONCLUSIONS: This study identifies remedies used in ethno-veterinary practices for small ruminants care in Sardinia, the second major Mediterranean island which has agro-pastoral activities dating back to Neolithic. Moreover, the danger of losing oral traditions, and the increasing attention towards traditional remedies as potential sources of natural products for improving animal health and welfare, support the interest of our survey. PMID- 25843022 TI - Antibacterial and antifungal activities of various solvent extracts from the leaves and stem bark of Anisophyllea laurina R. Br ex Sabine used as traditional medicine in Guinea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Anisophyllea laurina R. Br ex Sabine is a plant that has been used in the folk medicine to treat malaria, dysentery, diabetes and toothache against bacterial infection. Through this study, most likely we are reporting for the first time, its effectiveness as an antibacterial and antifungal agent. AIM OF THE STUDY: To evaluate antibacterial and antifungal activities of various solvent extracts from the leaves and stem bark of A. laurina R. Br ex Sabine. MATERIALS AND METHODS: The various solvent extracts of leaves and stem bark were tested for antibacterial and antifungal activities against eight bacteria strains and three fungal strains using the well diffusion and micro-dilution methods. RESULTS: Antibacterial and antifungal activities of methanol and ethanol extracts were higher than the ethyl acetate and water extract. Leaves extracts had the highest potential activity against bacteria than stem bark extracts, but showed low antifungal activity compared to stem bark extracts. They also exhibited potent growth inhibitory activity against Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli ATCC 8739 and Bacillus subtilis with MIC value of 125ug/mL. CONCLUSIONS: The current study confirmed that the leaves and stem bark extracts of A. laurina R. Br ex Sabine proved to be most effective as antibacterial and antifungal activities. PMID- 25843023 TI - Endocrine approaches to treatment of Alzheimer's disease and other neurological conditions: Part I: Some recollections of my association with Dr. Abba Kastin: A tale of successful collaboration. PMID- 25843024 TI - In vitro and in vivo pharmacological characterization of Pronetupitant, a prodrug of the neurokinin 1 receptor antagonist Netupitant. AB - The aim of the present study was to investigate the pharmacological activity of Pronetupitant, a novel compound designed to act as prodrug of the NK1 antagonist Netupitant. In receptor binding experiments Pronetupitant displayed high selectivity for the NK1 receptor. In a calcium mobilization assay performed on CHONK1 cells Pronetupitant (100 nM, 15 min preincubation) behaved as an NK1 antagonist more potent than Netupitant (pK(B) 8.72 and 7.54, respectively). In the guinea pig ileum bioassay Pronetupitant antagonized the contractile effect of SP showing a similar potency as Netupitant (pK(B)~9). Similar results were obtained with 5 min preincubation time while at 2 min only Pronetupitant produced significant effects. In vivo in mice the intrathecal injection of 0.1 nmol SP elicited the typical scratching, biting and licking (SBL) nociceptive response. This effect of SP was dose dependently (0.1-10 mg/kg) antagonized by Pronetupitant given intravenously 2 h before the peptide. Superimposable results were obtained using Netupitant. Pharmacokinetic studies performed in rats demonstrate that Pronetupitant, after i.v. administration, is quickly (few minutes) and completely converted to Netupitant. Collectively the present results indicated that Pronetupitant acts in vitro as selective NK1 antagonist more potent than Netupitant. However based on the short half-life measured for Pronetupitant in rats, the in vivo action of Pronetupitant can be entirely interpreted as due to its conversion to Netupitant. PMID- 25843025 TI - Endogenous opioids and feeding behavior: A decade of further progress (2004 2014). A Festschrift to Dr. Abba Kastin. AB - Functional elucidation of the endogenous opioid system temporally paralleled the creation and growth of the journal, Peptides, under the leadership of its founding editor, Dr. Abba Kastin. He was prescient in publishing annual and uninterrupted reviews on Endogenous Opiates and Behavior that served as a microcosm for the journal under his stewardship. This author published a 2004 review, "Endogenous opioids and feeding behavior: a thirty-year historical perspective", summarizing research in this field between 1974 and 2003. The present review "closes the circle" by reviewing the last 10 years (2004-2014) of research examining the role of endogenous opioids and feeding behavior. The review summarizes effects upon ingestive behavior following administration of opioid receptor agonists, in opioid receptor knockout animals, following administration of general opioid receptor antagonists, following administration of selective mu, delta, kappa and ORL-1 receptor antagonists, and evaluating opioid peptide and opioid receptor changes in different food intake models. PMID- 25843026 TI - Guideline Adherence for Echocardiographic Follow-Up in Outpatients with at Least Moderate Valvular Disease. AB - BACKGROUND: Attention to resource utilization has led to increased scrutiny of the appropriateness of initial diagnostic imaging studies on the basis of current guidelines. Far less attention has been paid to examining the lack of appropriate follow-up studies. METHODS: A retrospective cross-sectional analysis was performed of 3,781 consecutive outpatients referred for transthoracic echocardiography (TTE) from July to December 2008. Data from the electronic medical records were extracted to see if patients with at least moderate left sided valvular stenosis or regurgitation underwent subsequent echocardiographic studies within 60 days of the period recommended by the 2006 American College of Cardiology and American Heart Association valve guidelines document. RESULTS: Of 342 outpatients with at least moderate valve dysfunction, 38 (11%) were excluded for reasons that precluded the need for a follow-up study (e.g. death, surgery). Of the remaining 304 patients, only 179 (59%) underwent follow-up echocardiography within the recommended period. Rates of timely follow-up TTE were higher when ordering physicians were cardiologists or cardiovascular surgeons (65%) compared with primary care physicians or internal medicine specialists (45%) (P < .01). Follow-up rates were significantly different for aortic stenosis (77%), mitral stenosis (67%), aortic regurgitation (49%), and mitral regurgitation (49%) (P < .01). Patients receiving timely follow-up TTE were younger (66 +/- 15 vs 71 +/- 15 years, P = .002) and more likely to be male (odds ratio, 1.79; 95% CI, 1.12-2.85; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first study demonstrating low rates of compliance with guideline-recommended monitoring TTE in patients with at least moderate valve dysfunction. Cardiac practitioners have significantly better compliance. Strategies are needed to improve timely follow-up care in this population. PMID- 25843027 TI - Maternal tobacco smoking in pregnancy and children's socio-emotional development at age 5: The EDEN mother-child birth cohort study. AB - BACKGROUND: There is debate as to whether maternal tobacco use in pregnancy is related to offspring behaviour later on. We tested this association examining multiple aspects of children's behaviour at age 5 and accounting for parental smoking outside of pregnancy, as well as child and family characteristics. METHODS: Data come from a prospective community based birth cohort study (EDEN; n=1113 families in France followed since pregnancy in 2003-2005 until the child's 5th birthday). Maternal tobacco use in pregnancy was self-reported. Children's socio-emotional development (emotional symptoms, conduct problems, symptoms of hyperactivity/inattention, peer relationship problems, prosocial behaviour) was assessed by mothers using the Strengths and Difficulties Questionnaire (SDQ) at age 5 years. Logistic regression analyses controlled for Inverse Probability Weights (IPW) of maternal tobacco use calculated based on study center, children's characteristics (sex, premature birth, low birth weight, breastfeeding), maternal characteristics (age at the child's birth, psychological difficulties and alcohol use in pregnancy, post-pregnancy depression, and smoking), paternal smoking in and post-pregnancy, parental educational attainment, family income, parental separation, and maternal negative life events. RESULTS: Maternal smoking in pregnancy only predicted children's high symptoms of hyperactivity/inattention (sex and study center-adjusted ORs: maternal smoking in the 1st trimester: 1.95, 95%CI: 1.13-3.38; maternal smoking throughout pregnancy: OR=2.11, 95%CI: 1.36-3.27). In IPW-controlled regression models, only children of mothers who smoked throughout pregnancy had significantly elevated levels of hyperactivity/inattention (OR=2.20, 95%CI: 1.21 4.00). CONCLUSIONS: Maternal tobacco smoking in pregnancy may contribute directly or through epigenetic mechanisms to children's symptoms of hyperactivity/inattention. PMID- 25843028 TI - Visual cortical prosthesis with a geomagnetic compass restores spatial navigation in blind rats. AB - Allocentric sense is one of the major components that underlie spatial navigation. In blind patients, the difficulty in spatial exploration is attributed, at least partly, to the deficit of absolute direction perception. In support of this notion, we announce that blind adult rats can perform spatial tasks normally when externally provided with real-time feedback of their head directions. Head-mountable microstimulators coupled with a digital geomagnetic compass were bilaterally implanted in the primary visual cortex of adult rats whose eyelids had been sutured. These "blind" rats were trained to seek food pellets in a T-shaped maze or a more complicated maze. Within tens of trials, they learned to manage the geomagnetic information source to solve the mazes. Their performance levels and navigation strategies were similar to those of normal sighted, intact rats. Thus, blind rats can recognize self-location through extrinsically provided stereotactic cues. PMID- 25843029 TI - Repeating spatial activations in human entorhinal cortex. AB - The ability to remember and navigate spatial environments is critical for everyday life. A primary mechanism by which the brain represents space is through hippocampal place cells, which indicate when an animal is at a particular location. An important issue is understanding how the hippocampal place-cell network represents specific properties of the environment, such as signifying that a particular position is near a doorway or that another position is near the end of a corridor. The entorhinal cortex (EC), as the main input to the hippocampus, may play a key role in coding these properties because it contains neurons that activate at multiple related positions per environment. We examined the diversity of spatial coding across the human medial temporal lobe by recording neuronal activity during virtual navigation of an environment containing four similar paths. Neurosurgical patients performed this task as we recorded from implanted microelectrodes, allowing us to compare the human neuronal representation of space with that of animals. EC neurons activated in a repeating manner across the environment, with individual cells spiking at the same relative location across multiple paths. This finding indicates that EC cells represent non-specific information about location relative to an environment's geometry, unlike hippocampal place cells, which activate at particular random locations. Given that spatial navigation is considered to be a model of how the brain supports non-spatial episodic memory, these findings suggest that EC neuronal activity is used by the hippocampus to represent the properties of different memory episodes. PMID- 25843030 TI - Anillin Regulates Neuronal Migration and Neurite Growth by Linking RhoG to the Actin Cytoskeleton. AB - Neuronal migration and neurite growth are essential events in neural development, but it remains unclear how guidance cues are transduced through receptors to the actin cytoskeleton, which powers these processes. We report that a cytokinetic scaffold protein, Anillin, is redistributed to the leading edge of the C. elegans Q neuroblast during cell migration and neurite growth. To bypass the requirement for Anillin in cytokinesis, we used the somatic CRISPR-Cas9 technique to generate conditional mutations in Anillin. We demonstrate that Anillin regulates cell migration and growth cone extension by stabilizing the F-actin network at the leading edge. Our biochemical analysis shows that the actin-binding domain of Anillin is sufficient to stabilize F-actin by antagonizing the F-actin severing activity of Cofilin. We further uncover that the active form of RhoG/MIG-2 directly binds to Anillin and recruits it to the leading edge. Our results reveal a novel pathway in which Anillin transduces the RhoG signal to the actin cytoskeleton during neuronal migration and neurite growth. PMID- 25843031 TI - Colonization, competition, and dispersal of pathogens in fluid flow networks. AB - The colonization of bacteria in complex fluid flow networks, such as those found in host vasculature, remains poorly understood. Recently, it was reported that many bacteria, including Bacillus subtilis [1], Escherichia coli [2], and Pseudomonas aeruginosa [3, 4], can move in the opposite direction of fluid flow. Upstream movement results from the interplay between fluid shear stress and bacterial motility structures, and such rheotactic-like behavior is predicted to occur for a wide range of conditions [1]. Given the potential ubiquity of upstream movement, its impact on population-level behaviors within hosts could be significant. Here, we find that P. aeruginosa communities use a diverse set of motility strategies, including a novel surface-motility mechanism characterized by counter-advection and transverse diffusion, to rapidly disperse throughout vasculature-like flow networks. These motility modalities give P. aeruginosa a selective growth advantage, enabling it to self-segregate from other human pathogens such as Proteus mirabilis and Staphylococcus aureus that outcompete P. aeruginosa in well-mixed non-flow environments. We develop a quantitative model of bacterial colonization in flow networks, confirm our model in vivo in plant vasculature, and validate a key prediction that colonization and dispersal can be inhibited by modifying surface chemistry. Our results show that the interaction between flow mechanics and motility structures shapes the formation of mixed species communities and suggest a general mechanism by which bacteria could colonize hosts. Furthermore, our results suggest novel strategies for tuning the composition of multi-species bacterial communities in hosts, preventing inappropriate colonization in medical devices, and combatting bacterial infections. PMID- 25843033 TI - Chemokine-Dependent pH Elevation at the Cell Front Sustains Polarity in Directionally Migrating Zebrafish Germ Cells. AB - Directional cell migration requires cell polarization with respect to the distribution of the guidance cue. Cell polarization often includes asymmetric distribution of response components as well as elements of the motility machinery. Importantly, the function and regulation of most of these molecules are known to be pH dependent. Intracellular pH gradients were shown to occur in certain cells migrating in vitro, but the functional relevance of such gradients for cell migration and for the response to directional cues, particularly in the intact organism, is currently unknown. In this study, we find that primordial germ cells migrating in the context of the developing embryo respond to the graded distribution of the chemokine Cxcl12 by establishing elevated intracellular pH at the cell front. We provide insight into the mechanisms by which a polar pH distribution contributes to efficient cell migration. Specifically, we show that Carbonic Anhydrase 15b, an enzyme controlling the pH in many cell types, including metastatic cancer cells, is expressed in migrating germ cells and is crucial for establishing and maintaining an asymmetric pH distribution within them. Reducing the level of the protein and thereby erasing the pH elevation at the cell front resulted in abnormal cell migration and impaired arrival at the target. The basis for the disrupted migration is found in the stringent requirement for pH conditions in the cell for regulating contractility, for the polarization of Rac1 activity, and hence for the formation of actin-rich structures at the leading edge of the migrating cells. PMID- 25843032 TI - Role of Synchronous Activation of Cerebellar Purkinje Cell Ensembles in Multi joint Movement Control. AB - It is a longstanding question in neuroscience how elaborate multi-joint movements are coordinated coherently. Microzones of cerebellar Purkinje cells (PCs) are thought to mediate this coordination by controlling the timing of particular motor domains. However, it remains to be elucidated to what extent motor coordination deficits can be correlated with abnormalities in coherent activity within these microzones and to what extent artificially evoked synchronous activity within PC ensembles can elicit multi-joint motor behavior. To study PC ensemble correlates of limb, trunk, and tail movements, we developed a transparent disk treadmill that allows quantitative readout of locomotion and posture parameters in head-fixed mice and simultaneous cellular-resolution imaging and/or optogenetic manipulation. We show that PC ensembles in the ataxic and dystonic mouse mutant tottering have a reduced level of complex spike co activation, which is delayed relative to movement onset and co-occurs with prolonged swing duration and reduced phase coupling of limb movements as well as with enlarged deflections of body-axis and tail movements. Using optogenetics to increase simple spike rate in PC ensembles, we find that preferred locomotion and posture patterns can be elicited or perturbed depending on the behavioral state. At rest, preferred sequences of limb movements can be elicited, whereas during locomotion, preferred gait-inhibition patterns are evoked. Our findings indicate that synchronous activation of PC ensembles can facilitate initiation and coordination of limb and trunk movements, presumably by tuning downstream systems involved in the execution of behavioral patterns. PMID- 25843034 TI - Planar Cell Polarity Breaks the Symmetry of PAR Protein Distribution prior to Mitosis in Drosophila Sensory Organ Precursor Cells. AB - During development, cell-fate diversity can result from the unequal segregation of fate determinants at mitosis. Polarization of the mother cell is essential for asymmetric cell division (ACD). It often involves the formation of a cortical domain containing the PAR complex proteins Par3, Par6, and atypical protein kinase C (aPKC). In the fly notum, sensory organ precursor cells (SOPs) divide asymmetrically within the plane of the epithelium and along the body axis to generate two distinct cells. Fate asymmetry depends on the asymmetric localization of the PAR complex. In the absence of planar cell polarity (PCP), SOPs divide with a random planar orientation but still asymmetrically, showing that PCP is dispensable for PAR asymmetry at mitosis. To study when and how the PAR complex localizes asymmetrically, we have used a quantitative imaging approach to measure the planar polarization of the proteins Bazooka (Baz, fly Par3), Par6, and aPKC in living pupae. By using imaging of functional GFP-tagged proteins with image processing and computational modeling, we find that Baz, Par6, and aPKC become planar polarized prior to mitosis in a manner independent of the AuroraA kinase and that PCP is required for the planar polarization of Baz, Par6, and aPKC during interphase. This indicates that a "mitosis rescue" mechanism establishes asymmetry at mitosis in PCP mutants. This study therefore identifies PCP as the initial symmetry-breaking signal for the planar polarization of PAR proteins in asymmetrically dividing SOPs. PMID- 25843035 TI - Basal level of Th17 immune response is not enhanced in aplastic amemia. AB - Acquired aplastic anemia (AA) is an immune mediated bone marrow failure syndrome which is associated with impaired T-cell immune responses. In this work we investigated the role of Th17 immune response in AA. Our results showed that the absolute numbers of circulating IL-17-producing CD4(+) T cells and CD4(+)CD161(+)CCR6(+) cells, the blood plasma level of IL-17, and the expression level of Th17 lineage-specifying transcription factor RORC in circulating CD4(+) T cells, were not increased in AA. These results suggest that Th17 immune response may not play an important role in the pathogenesis of AA. PMID- 25843036 TI - Novel anticancer activity of phloroglucinol against breast cancer stem-like cells. AB - Poor prognosis of breast cancer patients is closely associated with metastasis and relapse. There is substantial evidence supporting that cancer stem-like cells (CSCs) are primarily responsible for relapse in breast cancer after anticancer treatment. However, there is a lack of suitable drugs that target breast cancer stem-like cells (BCSCs). Here, we report that phloroglucinol (PG), a natural phlorotannin component of brown algae, suppresses sphere formation, anchorage independent colony formation and in vivo tumorigenicity. In line with these observations, treatment with PG also decreased CD44(+) cancer cell population as well as expression of CSC regulators such as Sox2, CD44, Oct4, Notch2 and beta catenin. Also, treatment with PG sensitized breast cancer cells to anticancer drugs such as cisplatin, etoposide, and taxol as well as to ionizing radiation. Importantly, PG inhibited KRAS and its downstream PI3K/AKT and RAF-1/ERK signaling pathways that regulate the maintenance of CSCs. Taken together, our findings implicate PG as a good candidate to target BCSCs and to prevent the disease relapse. PMID- 25843037 TI - Profiling of plasma metabolites in canine oral melanoma using gas chromatography mass spectrometry. AB - Malignant melanoma is one of the most common and aggressive tumors in the oral cavity of dog. The tumor has a poor prognosis, and methods for diagnosis and prediction of prognosis after treatment are required. Here, we examined metabolite profiling using gas chromatography-mass spectrometry (GC-MS) for development of a discriminant model for evaluation of prognosis. Metabolite profiles were evaluated in healthy and melanoma plasma samples using orthogonal projection to latent structure using discriminant analysis (OPLS-DA). Cases that were predicted to be healthy using the OPLS discriminant model had no advanced lesions after radiation therapy. These results indicate that metabolite profiling may be useful in diagnosis and prediction of prognosis of canine malignant melanoma. PMID- 25843038 TI - Performance of a new carbon dioxide absorbent, Yabashi lime(r) as compared to conventional carbon dioxide absorbent during sevoflurane anesthesia in dogs. AB - In the present study, we compare a new carbon dioxide (CO2) absorbent, Yabashi lime((r)) with a conventional CO2 absorbent, Sodasorb((r)) as a control CO2 absorbent for Compound A (CA) and Carbon monoxide (CO) productions. Four dogs were anesthetized with sevoflurane. Each dog was anesthetized with four preparations, Yabashi lime((r)) with high or low-flow rate of oxygen and control CO2 absorbent with high or low-flow rate. CA and CO concentrations in the anesthetic circuit, canister temperature and carbooxyhemoglobin (COHb) concentration in the blood were measured. Yabashi lime((r)) did not produce CA. Control CO2 absorbent generated CA, and its concentration was significantly higher in low-flow rate than a high-flow rate. CO was generated only in low-flow rate groups, but there was no significance between Yabashi lime((r)) groups and control CO2 absorbent groups. However, the CO concentration in the circuit could not be detected (<=5ppm), and no change was found in COHb level. Canister temperature was significantly higher in low-flow rate groups than high-flow rate groups. Furthermore, in low-flow rate groups, the lower layer of canister temperature in control CO2 absorbent group was significantly higher than Yabashi lime((r)) group. CA and CO productions are thought to be related to the composition of CO2 absorbent, flow rate and canister temperature. Though CO concentration is equal, it might be safer to use Yabashi lime((r)) with sevoflurane anesthesia in dogs than conventional CO2 absorbent at the point of CA production. PMID- 25843039 TI - The fate and tissue disposition of deoxynivalenol in broiler chickens. AB - To evaluate the fate of deoxynivalenol (DON) in broilers, DON was administered either intravenously or orally to broilers at a dose of 1 mg/kg BW. Concentrations of DON in plasma were measurable up to 4 hr and 2 hr after intravenous and oral administration, respectively. Following intravenous administration, the values for the elimination half-life, the volume of distribution and the clearance were 1.25 +/- 0.25 hr, 7.55 +/- 2.03 l/kg and 4.16 +/- 0.42 l/hr/kg, respectively. The oral bioavailability was 15.46 +/- 4.02%. DON was detectable in all tissues examined after oral administration. These results suggest that DON is able to penetrate into the various tissues in broilers, though poorly absorbed from their gastrointestinal tract. PMID- 25843040 TI - Virulence characterization of Campylobacter jejuni isolated from resident wild birds in Tokachi area, Japan. AB - The prevalence of Campylobacter jejuni in wild birds is a potential hazard for human and animal health. The aim of this study was to establish the prevalence of C. jejuni in wild birds in Tokachi area, Hokkaido, Japan and investigate their virulence in vitro. In total, 173 cloacal swabs from individual wild birds were collected for the detection of Campylobacter spp. Thirty four samples (19.7%) were positive for Campylobacter of which 94.1% (32/34 samples) were C. jejuni. Additionally, one C. coli and one C. fetus were isolated. Seven C. jejuni isolates (one from crows and the other from pigeons) had important virulence genes including all three CDT genes (cdtA, cdtB and cdtC) and flaA, flaB, ciaB and cadF, and the other isolates were lacking cdtA gene. Further studies on in vitro virulence-associated phenotypes, such as motility assay on soft agar and invasion assay in Caco-2 cells, were performed. The wild bird C. jejuni isolates adhered and invaded human cells. Although the numbers of viable intracellular bacteria of wild bird isolates were lower than a type strain NCTC11168, they persisted at 48-hr and underwent replication in host cells. PMID- 25843041 TI - Tree-in-bud pattern in central lung cancer: CT findings and pathologic correlation. AB - OBJECTIVES: Tree-in-bud (TIB) pattern can be found with central lung cancer on chest CT scans. However, few reports have described it so far. We aim to determine its incidence, CT findings and pathologic basis. MATERIALS AND METHODS: 652 consecutive patients with confirmed central lung cancer were enrolled in our study. The incidence, CT findings and pathologic features of TIB pattern were analyzed retrospectively. RESULTS: In total, TIB pattern was found in 22.5% (147/652) of patients. It was more common in patients with squamous cell carcinoma than those with non-squamous cell carcinoma (P=0.000). The most important associated CT finding was obstructive bronchial mucoid impaction distal to the cancer (100%, 147/147), followed by consolidation and ground-glass opacities (62.6%, 92/147). TIB pattern was confined to the areas of lung supplied by the involved bronchi (100%, 147/147) and had a focal distribution predominantly (94.6%, 139/147). Pathologically, it correlated with bronchiolectasis, bronchiolar lumen filled by mucus and inflammatory exudates, wall thickening with inflammatory cells infiltration. CONCLUSIONS: TIB pattern is commonly detected in central lung squamous cell carcinoma on thoracic CT scan. It usually has a localized distribution with a predominant associated CT finding of obstructive bronchial mucoid impaction. This pattern corresponds to the mucoid impaction of bronchioles and bronchiolitis pathologically. A full understanding of TIB pattern in central lung cancer can be useful in preventing diagnostic errors. PMID- 25843042 TI - Intratumoral macrophage phenotype and CD8+ T lymphocytes as potential tools to predict local tumor outgrowth at the intervention site in malignant pleural mesothelioma. AB - OBJECTIVES: In patients with malignant pleural mesothelioma (MPM), local tumor outgrowth (LTO) after invasive procedures is a well-known complication. Currently, no biomarker is available to predict the occurrence of LTO. This study aims to investigate whether the tumor macrophage infiltration and phenotype of and/or the infiltration of CD8+ T-cells predicts LTO. MATERIALS AND METHODS: Ten mesothelioma patients who developed LTO were clinically and pathologically matched with 10 non-LTO mesothelioma patients. Immunohistochemistry was performed on diagnostic biopsies to determine the total TAM (CD68), the M2 TAM (CD163) and CD8+ T-cell count (CD8). RESULTS: The mean M2/total TAM ratio differed between the two groups: 0.90+/-0.09 in the LTO group versus 0.63+/-0.09 in patients without LTO (p<0.001). In addition, the mean CD8+ T-cell count was significantly different between the two groups: 30 per 0.025 cm2 (range 2-60) in the LTO group and 140 per 0.025 cm2 (range 23-314) in the patients without LTO (p<0.01). CONCLUSION: This study shows that patients who develop LTO after a local intervention have a higher M2/total TAM ratio and lower CD8+ cell count at diagnosis compared to patients who did not develop this outgrowth. We propose that the M2/total TAM ratio and the CD8+ T-cell amount are potential tools to predict which MPM patients are prone to develop LTO. PMID- 25843043 TI - Validation of a semi-physiological model for caffeine in healthy subjects and cirrhotic patients. AB - The objective of this paper was to validate a previously developed semi physiological model to simulate bioequivalence trials of drug products. The aim of the model was to ascertain whether the measurement of the metabolite concentration-time profiles would provide any additional information in bioequivalence studies (Fernandez-Teruel et al., 2009a,b; Navarro-Fontestad et al., 2010). The semi-physiological model implemented in NONMEM VI was used to simulate caffeine and its main metabolite plasma levels using caffeine parameters from bibliography. Data from 3 bioequivalence studies in healthy subjects at 3 different doses (100, 175 and 400mg of caffeine) and one study in cirrhotic patients (200 or 250mg) were used. The first aim was to adapt the previous semi physiological model for caffeine, showing the hepatic metabolism with one main metabolite, paraxanthine. The second aim was to validate the model by comparison of the simulated plasma levels of parent drug and metabolite to the experimental data. The simulations have shown that the proposed semi-physiological model was able to reproduce adequately the pharmacokinetic behavior of caffeine and paraxanthine in both healthy subjects and cirrhotic patients at all the assayed doses. Therefore, the model could be used to simulate plasma concentrations vs. time of drugs with the same pharmacokinetic scheme as caffeine, as long as their population parameters are known, and it could be useful for bioequivalence trial simulation of drugs that undergo hepatic metabolism with a single main metabolite. PMID- 25843044 TI - Response to: A new approach to treatment of vulvovaginal atrophy. PMID- 25843045 TI - Mitochondrial alterations by PARKIN in dopaminergic neurons using PARK2 patient specific and PARK2 knockout isogenic iPSC lines. AB - In this study, we used patient-specific and isogenic PARK2-induced pluripotent stem cells (iPSCs) to show that mutations in PARK2 alter neuronal proliferation. The percentage of TH(+) neurons was decreased in Parkinson's disease (PD) patient derived neurons carrying various mutations in PARK2 compared with an age-matched control subject. This reduction was accompanied by alterations in mitochondrial:cell volume fraction (mitochondrial volume fraction). The same phenotype was confirmed in isogenic PARK2 null lines. The mitochondrial phenotype was also seen in non-midbrain neurons differentiated from the PARK2 null line, as was the functional phenotype of reduced proliferation in culture. Whole genome expression profiling at various stages of differentiation confirmed the mitochondrial phenotype and identified pathways altered by PARK2 dysfunction that include PD-related genes. Our results are consistent with current model of PARK2 function where damaged mitochondria are targeted for degradation via a PARK2/PINK1-mediated mechanism. PMID- 25843046 TI - PDX1 binds and represses hepatic genes to ensure robust pancreatic commitment in differentiating human embryonic stem cells. AB - Inactivation of the Pancreatic and Duodenal Homeobox 1 (PDX1) gene causes pancreatic agenesis, which places PDX1 high atop the regulatory network controlling development of this indispensable organ. However, little is known about the identity of PDX1 transcriptional targets. We simulated pancreatic development by differentiating human embryonic stem cells (hESCs) into early pancreatic progenitors and subjected this cell population to PDX1 chromatin immunoprecipitation sequencing (ChIP-seq). We identified more than 350 genes bound by PDX1, whose expression was upregulated on day 17 of differentiation. This group included known PDX1 targets and many genes not previously linked to pancreatic development. ChIP-seq also revealed PDX1 occupancy at hepatic genes. We hypothesized that simultaneous PDX1-driven activation of pancreatic and repression of hepatic programs underlie early divergence between pancreas and liver. In HepG2 cells and differentiating hESCs, we found that PDX1 binds and suppresses expression of endogenous liver genes. These findings rebrand PDX1 as a context-dependent transcriptional repressor and activator within the same cell type. PMID- 25843047 TI - Deterministic HOX patterning in human pluripotent stem cell-derived neuroectoderm. AB - Colinear HOX expression during hindbrain and spinal cord development diversifies and assigns regional neural phenotypes to discrete rhombomeric and vertebral domains. Despite the precision of HOX patterning in vivo, in vitro approaches for differentiating human pluripotent stem cells (hPSCs) to posterior neural fates coarsely pattern HOX expression thereby generating cultures broadly specified to hindbrain or spinal cord regions. Here, we demonstrate that successive activation of fibroblast growth factor, Wnt/beta-catenin, and growth differentiation factor signaling during hPSC differentiation generates stable, homogenous SOX2(+)/Brachyury(+) neuromesoderm that exhibits progressive, full colinear HOX activation over 7 days. Switching to retinoic acid treatment at any point during this process halts colinear HOX activation and transitions the neuromesoderm into SOX2(+)/PAX6(+) neuroectoderm with predictable, discrete HOX gene/protein profiles that can be further differentiated into region-specific cells, e.g., motor neurons. This fully defined approach significantly expands capabilities to derive regional neural phenotypes from diverse hindbrain and spinal cord domains. PMID- 25843048 TI - Emergence of a stage-dependent human liver disease signature with directed differentiation of alpha-1 antitrypsin-deficient iPS cells. AB - Induced pluripotent stem cells (iPSCs) provide an inexhaustible source of cells for modeling disease and testing drugs. Here we develop a bioinformatic approach to detect differences between the genomic programs of iPSCs derived from diseased versus normal human cohorts as they emerge during in vitro directed differentiation. Using iPSCs generated from a cohort carrying mutations (PiZZ) in the gene responsible for alpha-1 antitrypsin (AAT) deficiency, we find that the global transcriptomes of PiZZ iPSCs diverge from normal controls upon differentiation to hepatic cells. Expression of 135 genes distinguishes PiZZ iPSC hepatic cells, providing potential clues to liver disease pathogenesis. The disease-specific cells display intracellular accumulation of mutant AAT protein, resulting in increased autophagic flux. Furthermore, we detect beneficial responses to the drug carbamazepine, which further augments autophagic flux, but adverse responses to known hepatotoxic drugs. Our findings support the utility of iPSCs as tools for drug development or prediction of toxicity. PMID- 25843049 TI - Efficient generation of NKX6-1+ pancreatic progenitors from multiple human pluripotent stem cell lines. AB - Human pluripotent stem cells (hPSCs) represent a renewable source of pancreatic beta cells for both basic research and therapeutic applications. Given this outstanding potential, significant efforts have been made to identify the signaling pathways that regulate pancreatic development in hPSC differentiation cultures. In this study, we demonstrate that the combination of epidermal growth factor (EGF) and nicotinamide signaling induces the generation of NKX6-1(+) progenitors from all hPSC lines tested. Furthermore, we show that the size of the NKX6-1(+) population is regulated by the duration of treatment with retinoic acid, fibroblast growth factor 10 (FGF10), and inhibitors of bone morphogenetic protein (BMP) and hedgehog signaling pathways. When transplanted into NOD scid gamma (NSG) recipients, these progenitors differentiate to give rise to exocrine and endocrine cells, including monohormonal insulin(+) cells. Together, these findings provide an efficient and reproducible strategy for generating highly enriched populations of hPSC-derived beta cell progenitors for studies aimed at further characterizing their developmental potential in vivo and deciphering the pathways that regulate their maturation in vitro. PMID- 25843050 TI - Efficacy of cleansing agents in killing microorganisms in mixed species biofilms present on silicone facial prostheses--an in vitro study. AB - OBJECTIVES: The purpose of this study was to assess the efficacy of different cleansing agents in killing mixed species biofilms on silicone facial prostheses. MATERIALS AND METHODS: Two bacterial and three yeast strains, isolated from silicone facial prostheses, were selected for the mixed species biofilms. A variety of agents used to clean facial prostheses were employed, viz., antibacterial soap, essential-oil-containing mouth rinse, ethanol 27 %, chlorhexidine mouth rinse, and buttermilk. Colony forming units (CFUs) and live/dead staining were analyzed to assess the efficacy of these cleansing agents against 24-h and 2-week biofilms and regrown biofilms on silicone samples. RESULTS: Chlorhexidine was the most effective cleansing agent. Chlorhexidine killed 8 log unit CFUs (>99.99 % killing) in a 24-h biofilm and 5 log unit CFUs (>99.99 % killing) in 2-week biofilms. Also, after regrowth and repeated treatment of the biofilm, chlorhexidine was the most effective cleansing agent showing no detectable CFUs. The essential-oil-containing mouth rinse (containing 26.9 % ethanol) showed a similar efficacy as ethanol (27 %) alone. Antibacterial soap and buttermilk were the least effective agents tested. CONCLUSIONS: Chlorhexidine showed the highest reduction in CFUs in 24-h, 2-week, and regrown mixed species biofilm of microorganisms isolated from silicone facial prostheses. CLINICAL RELEVANCE: Chlorhexidine mouth rinse (easy obtainable and relatively cheap) is very effective in killing bacteria and yeast present in biofilms on silicone facial prostheses. When applied on a regular basis, cleansing a facial prosthesis with chlorhexidine will presumably increase its lifetime and reduce skin irritations. PMID- 25843051 TI - Impact of dentists' years since graduation on management of temporomandibular disorders. AB - OBJECTIVES: The aims were to assess the impact of the number of years since dentists' graduation on appraisement of diagnostic needs and utilization of treatment options for temporomandibular disorders (TMD) and to investigate whether increased knowledge in TMD is sufficiently considered in today's dentist's undergraduate curricula and, therefore, represented in more evidence based TMD management in dentists with less years since graduation. MATERIAL AND METHODS: A questionnaire regarding knowledge and management of TMD was developed and was subsequently applied in a random sample of 400 dentists in a region in Northern Germany. RESULTS: Of the 222 dentists (response rate 55.6 %), participating in the study, the frequency of TMD treatment need in the general population was estimated at 21.5 %, with lower values in dentists with more years passed since graduation. Measures regarding utilization of standardized examination forms, perceptions of insufficient specialization, and referrals of patients to TMD specialists indicated a lower quality and certainty in TMD management in participants with less time since graduation. While the provision of splints was a well-established treatment option in initial TMD management of all participants, additional TMD treatment options were mentioned less often, with lower proportions of participants making use of these options within the first decade since graduation. CONCLUSIONS: Evidence-based TMD management is not fully represented in dental practitioners in Germany. This might be due to an insufficient consideration of TMD management in the dentist's undergraduate curricula. CLINICAL RELEVANCE: Effective interventions to increase dentists' knowledge and to change dentists' practices in TMD management are required. PMID- 25843052 TI - DNA methylation analysis of SOCS1, SOCS3, and LINE-1 in microdissected gingival tissue. AB - OBJECTIVES: DNA methylation plays a critical role in the regulation of the transcription of the suppressors of cytokine signaling (SOCS) 1 and SOCS3, which are modulators in the inflammation. We hypothesized that the methylation status of SOCS1, SOCS3, and long interspersed nuclear element (LINE)-1 in gingival tissues previously inflamed would be similar to that found in gingival tissues without clinical inflammation in the period studied. MATERIALS AND METHODS: Laser capture microdissection was performed to isolate epithelial and connective gingival tissues. The groups were comprised by ten patients without history of periodontitis and absence of clinical signs of inflammation in the gingiva during the study (healthy group) and ten patients with history of periodontitis, presenting inflammation in the gingival tissue at the first examination of the study (controlled chronic periodontitis group). The gingival biopsies from the controlled chronic periodontitis group were collected after controlling the inflammation. DNA methylation patterns were analyzed using methylation-specific high-resolution melting and combined bisulfite restriction analysis. RESULTS: DNA methylation levels for SOCS1 and SOCS3 did not differ between groups or tissues; likewise, no differences were observed in total LINE-1 methylation or at specific loci. CONCLUSION: At 3 months following control of inflammation in gingival tissues, the methylation profile of SOCS1, SOCS3, and LINE-1 is similar between connective and epithelial tissues from patients that were previously affected or not by chronic inflammation. CLINICAL RELEVANCE: Clinical results of a successful treatment are observed after inflammation control and the molecular findings illustrate local and general methylation patterns in recovering tissues toward health conditions and might help to understand events that are occurring in oral cells. PMID- 25843053 TI - Zoledronate induces bisphosphonate-related osteonecrosis of the jaw in osteopenic sheep. AB - OBJECTIVES: Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medication-induced osteoporosis treated with bisphosphonates. Sheep are an established large animal model for investigating osteoporotic skeletal changes. Zoledronate significantly reduces tissue mineral variability in ovariectomized sheep. The aim of this study was to analyze bone healing after tooth extraction in sheep with induced osteopenia and zoledronate administration. MATERIALS AND METHODS: Eight adult ewes were randomly divided into two groups of four animals. All sheep underwent ovariectomy and a low-calcium diet. Dexamethasone was administered weekly for 16 weeks. Zoledronate was then given every third week for a further 16 weeks in four sheep; these infusions were repeated after extraction of two lower premolars. Four sheep without zoledronate administrations served as controls. RESULTS: Due to general health conditions, two sheep of the zoledronate group had to be excluded before surgery. The remaining two sheep of this group developed BP-ONJ lesions at the extraction site and various other sites in both jaws. Control group animals showed uneventful wound healing. Histology of the alveolar processes as well as lumbar spine revealed larger portions of old bone and smaller portions of new bone in the zoledronate group. CONCLUSIONS: This animal study showed uneventful wound healing after tooth extraction in osteopenic sheep whereas zoledronate treatment leads to development of BP-ONJ-like lesions. CLINICAL RELEVANCE: As bisphosphonate administration is a standard treatment for glucocorticoid-induced osteoporosis, this model can be used for further research in pathogenesis and management of bisphosphonate-related adverse events. PMID- 25843054 TI - Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. AB - A randomized, double-blinded, placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis. In a crossover design, each participant was exposed to 4 single dosing sessions of placebo or to low (1% tetrahydrocannabinol [THC]), medium (4% THC), or high (7% THC) doses of cannabis. Baseline spontaneous pain, evoked pain, and cognitive testing were performed. Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective "highness" score was measured at 5, 15, 30, 45, and 60 minutes and then every 30 minutes for an additional 3 hours. Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours. The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models. There was a significant difference in spontaneous pain scores between doses (P < .001). Specific significant comparisons were placebo versus low, medium, and high doses (P = .031, .04, and <.001, respectively) and high versus low and medium doses (both P < .001). There was a significant effect of the high dose on foam brush and von Frey evoked pain (both P < .001). There was a significant negative effect (impaired performance) of the high dose on 2 of the 3 neuropsychological tests (Paced Auditory Serial Addition Test, Trail Making Test Part B. PERSPECTIVE: This small, short-term, placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain. This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain. PMID- 25843055 TI - Increase in Bacterial Colony Formation from a Permafrost Ice Wedge Dosed with a Tomitella biformata Recombinant Resuscitation-Promoting Factor Protein. AB - Resuscitation-promoting factor (Rpf) is a protein that has been found in a number of different Actinobacteria species and has been shown to promote the growth of active cells and resuscitate dormant (non-dividing) cells. We previously reported the biological activity of an Rpf protein in Tomitella biformata AHU 1821(T), an Actinobacteria isolated from a permafrost ice wedge. This protein is excreted outside the cell; however, few studies have investigated its contribution in environmental samples to the growth or resuscitation of bacteria other than the original host. Therefore, the aim of the present study was to determine whether Rpf from T. biformata impacted the cultivation of other bacteria from the permafrost ice wedge from which it was originally isolated. All experiments used recombinant Rpf proteins produced using a Rhodococcus erythropolis expression system. Dilutions of melted surface sterilized ice wedge samples mixed with different doses of the purified recombinant Rpf (rRpf) protein indicated that the highest concentration tested, 1250 pM, had a significantly (p <0.05) higher number of CFUs on agar plates after 8 d, approximately 14-fold higher than that on control plates without rRpf. 16S rRNA gene sequences revealed that all the colonies on plates were mainly related to Brevibacterium antiquum strain VKM Ac 2118 (AY243344), with 98-99% sequence identity. This species is also a member of the phylum Actinobacteria and was originally isolated from Siberian permafrost sediments. The results of the present study demonstrated that rRpf not only promoted the growth of T. biformata from which it was isolated, but also enhanced colony formation by another Actinobacteria in an environmental sample. PMID- 25843056 TI - Selective inhibition of prostaglandin E2 receptors EP2 and EP4 modulates DNA methylation and histone modification machinery proteins in human endometriotic cells. AB - Endometriosis is an inflammatory gynecological disease of reproductive-age women. The prevalence of endometriosis is 5-10% in reproductive-age women. Modern medical treatments are directed to inhibit the action of estrogen in endometriotic cells. However, hormonal therapies targeting estrogen can be prescribed only for a short time because of their undesirable side effects. Recent studies from our laboratory, using human endometriotic epithelial cell line 12Z and stromal cell line 22B derived from red lesion, discovered that selective inhibition of prostaglandin E2 (PGE2) receptors EP2 and EP4 inhibits adhesion, invasion, growth, and survival of 12Z and 22B cells by modulating integrins, MMPs and TIMPs, cell cycle, survival, and intrinsic apoptotic pathways, suggesting multiple epigenetic mechanisms. The novel findings of the present study indicate that selective pharmacological inhibition of EP2 and EP4: (i) decreases expression of DNMT3a, DNMT3b, H3K9me3, H3K27me3, SUV39H1, HP1a, H3K27, EZH2, JMJD2a, HDAC1, HDAC3, MeCP2, CoREST and Sin3A; (ii) increases expression of H3K4me3, H3H9ac, H3K27ac; and (iii) does not modulate the expression of DNMT1, hSET1, LSD1, MBD1, p300, HDAC2, and JMJD3 epigenetic machinery proteins in an epithelial and stromal cell specific manner. In this study, we report for the first time that inhibition of PGE2-EP2/EP4 signaling modulates DNA methylation, H3 histone methylation and acetylation, and epigenetic memory machinery proteins in human endometriotic epithelial cells and stromal cells. Thus, targeting EP2 and EP4 receptors may emerge as long-term nonsteroidal therapy for treatment of active endometriotic lesions in women. PMID- 25843057 TI - The effects of dietary protein and amino acids on skeletal metabolism. AB - Dietary protein is required for optimal skeletal growth and maturation. Although Recommended Dietary Allowances (RDAs) exist for global dietary protein intake, the level and sources of dietary protein that are optimal for skeletal health over the life continuum have not been established. This is partly due to the difficulty in quantifying the effects of variable levels of a nutrient's intake over a lifetime as well as the complex nature of the relationships between dietary protein and calcium economy. Areas of current uncertainty include the precise source and amount of dietary protein required for optimal skeletal accretion and maintenance of skeletal mass, as well as the site-specific effects of dietary protein. The cellular and molecular mechanisms that underpin the actions of dietary protein on mineral metabolism and skeletal homeostasis remain unclear. This review attempts to summarize recent data bearing on these questions. PMID- 25843058 TI - N-trans-feruloyltyramine inhibits LPS-induced NO and PGE2 production in RAW 264.7 macrophages: Involvement of AP-1 and MAP kinase signalling pathways. AB - Mitogen-activated protein kinase (MAPK) signalling pathway can regulate inflammatory and immune responses. N-trans-feruloyltyramine (FLA) is an active phenylpropanoid compound. It possesses antioxidant, antimicrobial, anti melanogenesis, and anticancer activities. However, the precise molecular mechanisms underlying FLA modulation of cytokine expression in LPS-stimulated RAW 264.7 macrophages have not been fully investigated. In this study, we examined the mechanisms underlying the immunomodulative effects of FLA isolated from Arcangelisia gusanlung. FLA strongly suppressed mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), but not tumor necrosis factor (TNF)-alpha, thereby inhibiting the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Furthermore, FLA also inhibited nuclear translocation of activation protein (AP) 1, and simultaneously decreased the expression and phosphorylation of the c-Jun N terminal kinase (JNK) protein. These results suggest that the anti-inflammatory effects of FLA might be attributed to downregulation of COX-2 and iNOS via suppression of AP-1 and the JNK signalling pathway in RAW 264.7 macrophages. PMID- 25843061 TI - Editorial Comment. PMID- 25843059 TI - 3,4-Dihydroxy-benzohydroxamic acid (Didox) suppresses pro-inflammatory profiles and oxidative stress in TLR4-activated RAW264.7 murine macrophages. AB - Didox (3,4-dihydroxy-benzohydroxamic acid), is a synthetic ribonucleotide reductase (RR) inhibitor derived from polyhydroxy-substituted benzohydroxamic acid, and originally developed as an anti-cancer agent. Some studies indicate that didox may have anti-oxidative stress-like properties, while other studies hint that didox may have anti-inflammatory properties. Using nitric oxide production in response to LPS treatment as a sensitive screening assay for anti inflammatory compounds, we show that didox is very potent at levels as low as 6.25 MUM, with maximal inhibition at 100 MUM. A qRT-PCR array was then employed to screen didox for other potential anti-inflammatory and anti-oxidative stress related properties. Didox was very potent in suppressing the expression of these arrayed mRNA in response to LPS, and in some cases didox alone suppressed expression. Using qRT-PCR as a follow up to the array, we demonstrated that didox suppresses LPS-induced mRNA levels of iNOS, IL-6, IL-1, TNF-alpha, NF-kappabeta (p65), and p38-alpha, after 24h of treatment. Treatment with didox also suppresses the secretion of nitric oxide, IL-6, and IL-10. Furthermore, oxidative stress, as quantified by intracellular ROS levels in response to macrophage activators LPS and phorbol ester (PMA), and the glutathione depleting agent BSO, is reduced by treatment with didox. Moreover, we demonstrate that nuclear translocation of NF-kappabeta (p65) in response to LPS is inhibited by didox. These findings were supported by qRT-PCR for oxidative stress genes SOD1 and catalase. Overall, this study supports the conclusion that didox may have a future role in managing acute and chronic inflammatory diseases and oxidative stress due to high production of ROS. PMID- 25843063 TI - Noninvasive prenatal screening for aneuploidy: positive predictive values based on cytogenetic findings. AB - OBJECTIVE: We sought to determine the positive predictive value (PPV) of noninvasive prenatal screening (NIPS) for various aneuploidies based on cases referred for follow-up cytogenetic testing. Secondarily, we wanted to determine the false-negative (FN) rate for those cases with a negative NIPS result. STUDY DESIGN: We compared the cytogenetic findings (primarily from chromosome analysis) from 216 cases referred to our laboratories with either a positive or negative NIPS result, and classified NIPS results as true positive, false positive, true negative, or FN. Diagnostic cytogenetic testing was performed on the following tissue types: amniotic fluid (n = 137), chorionic villi (n = 69), neonatal blood (n = 6), and products of conception (n = 4). RESULTS: The PPV for NIPS were as follows: 93% for trisomy (T)21 (n = 99; 95% confidence interval [CI], 86-97.1%), 58% for T18 (n = 24; 95% CI, 36.6-77.9%), 45% for T13 (n = 11; 95% CI, 16.7 76.6%), 23% for monosomy X (n = 26; 95% CI, 9-43.6%), and 67% for XXY (n = 6; 95% CI, 22.3-95.7%). Of the 26 cases referred for follow-up cytogenetics after a negative NIPS result, 1 (4%) was FN (T13). Two cases of triploidy, a very serious condition but one not claimed to be detectable by the test providers, were among those classified as true negatives. CONCLUSION: T21, which has the highest prevalence of all aneuploidies, demonstrated a high true-positive rate, resulting in a high PPV. However, the other aneuploidies, with their lower prevalence, displayed relatively high false-positive rates and, therefore, lower PPV. Patients and physicians must fully understand the limitations of this screening test and the need in many cases to follow up with appropriate diagnostic testing to obtain an accurate diagnosis. PMID- 25843064 TI - Ultrasound control of magnet growing rod distraction in early onset scoliosis. AB - The growing rod technique is currently one of the most common procedures used in the management of early onset scoliosis. However, in order to preserve spine growth and control the deformity it requires frequent surgeries to distract the rods. Magnetically driven growing rods have recently been introduced with same treatment goal, but without the inconvenience of repeated surgical distractions. One of the limitations of this technical advance is an increase in radiation exposure due to the increase in distraction frequency compared to conventional growing rods. An improvement of the original technique is presented, proposing a solution to the inconvenience of multiple radiation exposure using ultrasound technology to control the distraction process of magnetically driven growing rods. PMID- 25843065 TI - Relationship between flexible flat foot and developmental hip dysplasia. AB - PURPOSE: To evaluate the possible relationship between flexible flat foot and developmental hip dysplasia in children between six and 15 years of age. METHOD: Cross-sectional study including 65 patients that had undergone surgery due to residual hip dysplasia or hip dislocation and compared against 75 healthy patients. Flexible flat foot prevalence was measured in each group, with the results showing that 61% of the group with residual hip dysplasia or hip dislocation had this condition, vs. 12% in the healthy group. The statistical analysis shows that the chances of suffering from flexible flat foot, are five times greater in the hip dysplasia or hip dislocation group, than in the healthy group. DISCUSSION: There is no evidence in the literature showing a relationship between these two conditions, even though they have a common etiology. This study shows a potential measurable relation between this two conditions. CONCLUSION: Patients with hip dysplasia or dislocation may have a higher chance of presenting flexible flat foot during late childhood, adolescence and adulthood, a fact that suggests a relationship between these two pathologies. Also, patients who seek assistance for the first time because of a flexible flat foot condition without having been evaluated during the first year of life for hip dysplasia, would be better off if evaluated for residual hip dysplasia. PMID- 25843066 TI - Computational models of epileptiform activity. AB - We reviewed computer models that have been developed to reproduce and explain epileptiform activity. Unlike other already-published reviews on computer models of epilepsy, the proposed overview starts from the various types of epileptiform activity encountered during both interictal and ictal periods. Computational models proposed so far in the context of partial and generalized epilepsies are classified according to the following taxonomy: neural mass, neural field, detailed network and formal mathematical models. Insights gained about interictal epileptic spikes and high-frequency oscillations, about fast oscillations at seizure onset, about seizure initiation and propagation, about spike-wave discharges and about status epilepticus are described. This review shows the richness and complementarity of the various modeling approaches as well as the fruitful contribution of the computational neuroscience community in the field of epilepsy research. It shows that models have progressively gained acceptance and are now considered as an efficient way of integrating structural, functional and pathophysiological data about neural systems into "coherent and interpretable views". The advantages, limitations and future of modeling approaches are discussed. Perspectives in epilepsy research and clinical epileptology indicate that very promising directions are foreseen, like model-guided experiments or model-guided therapeutic strategy, among others. PMID- 25843068 TI - How could we increase the impact factor of the journal of neurogastroenterology and motility? PMID- 25843067 TI - The in vitro isolated whole guinea pig brain as a model to study epileptiform activity patterns. AB - BACKGROUND: Research on ictogenesis is based on the study of activity between seizures and during seizures in animal models of epilepsy (chronic condition) or in in vitro slices obtained from naive non-epileptic brains after treatment with pro-convulsive drugs, manipulations of the extracellular medium and specific stimulation protocols. NEW METHOD: The in vitro isolated guinea pig brain retains the functional connectivity between brain structures and maintains interactions between neuronal, glial and vascular compartments. It is a close-to-in vivo preparation that offers experimental advantages not achieved with the use of other experimental models. Neurophysiological and imaging techniques can be utilized in this preparation to study brain activity during and between seizures induced by pharmacological or functional manipulations. RESULTS: Cellular and network determinants of interictal and ictal discharges that reproduce abnormal patterns observed in human focal epilepsies and the associated changes in extracellular ion and blood-brain permeability can be identified and analyzed in the isolated guinea pig brain. COMPARISON WITH EXISTING METHODS: Ictal and interictal patterns recorded in in vitro slices may show substantial differences from seizure activity recorded in vivo due to slicing procedure itself. The isolated guinea pig brain maintained in vitro by arterial perfusion combines the typical facilitated access of in vitro preparations, that are difficult to approach during in vivo experiments, with the preservation of larger neuronal networks. CONCLUSIONS: The in vitro whole isolated guinea pig brain preparation offers an unique experimental model to study systemic and neurovascular changes during ictogenesis. PMID- 25843069 TI - Association between visceral fat and inflammatory cytokines in reflux esophagitis. PMID- 25843072 TI - A bama minipig model of laryngopharyngeal reflux and the change of laryngopharyngeal mucosal ultrastructure. AB - BACKGROUND/AIMS: To establish an animal model of laryngopharyngeal reflux (LPR) and study the effect of LPR on the laryngopharyngeal mucosal ultrastructure. METHODS: Ten Bama minipigs were randomly divided into control group and stent group. Every pig underwent endoscope, and baseline pH was monitored for 4 hours at laryngopharynx and distal esophagus, then specimens from laryngopharyngeal mucosa were biopsied. For the control group, these procedures were repeated on the 14th day. In the stent group, a custom-designed esophageal stent suit was implanted into esophagus, laryngopharyngeal and distal esophageal pH monitoring lasted for 2 hours, then stent suit was removed 3 days later. At last, the same procedures were done as the control group on the 14th day. Specimens were observed under transmission electron microscope to measure the intercellular space and desmosome number. RESULTS: In the control group, there was no laryngopharyngeal reflux on the first day and 14th day. Before the stent was implanted, there was also no laryngopharyngeal reflux in the stent group. In both 2 hours and 14 days after stent implantation, the num-ber of reflux, reflux time, and percentage time of pH < 4.0 were significantly increased (P < 0.05) in the stent group. There was no difference in intercellular space and desmosomes in the control group between baseline and 14th day. In the stent group, intercellular space of laryngopharyngeal mucosa was significantly increased (0.37 MUm vs 0.96 MUm, P = 0.008), and the number of desmosomes was significantly decreased (20.25 vs 9.5, P = 0.003). CONCLUSIONS: A Bama minipig model of LPR was established by implanting a custom-designed stent suit. LPR might destroy the laryngophar yngeal mucosal barrier. PMID- 25843070 TI - Role of principal ionotropic and metabotropic receptors in visceral pain. AB - Visceral pain is the most common form of pain caused by varied diseases and a major reason for patients to seek medical consultation. It also leads to a significant economic burden due to workdays lost and reduced productivity. Further, long-term use of non-specific medications is also associated with side effects affecting the quality of life. Despite years of extensive re-search and the availability of several therapeutic options, management of patients with chronic visceral pain is often in-adequate, resulting in frustration for both patients and physicians. This is, most likely, because the mechanisms associated with chronic visceral pain are different from those of acute pain. Accumulating evidence from years of research implicates several receptors and ion channels in the induction and maintenance of central and peripheral sensitization during chronic pain states. Understanding the specific role of these receptors will facilitate to capitalize on their unique properties to augment the ther-apeutic efficacy while at the same time minimizing unwanted side effects. The aim of this review is to provide a concise review of the recent literature that reports on the role of principal ionotropic receptors and metabotropic receptors in the modulation visceral pain. We also include an overview of the possibility of these receptors as potential new targets for the treatment of chronic visceral pain conditions. PMID- 25843073 TI - Regulation of gastric electrical and mechanical activity by cholinesterases in mice. AB - BACKGROUND/AIMS: Gastric peristalsis begins in the orad corpus and propagates to the pylorus. Directionality of peristalsis depends upon orderly generation and propagation of electrical slow waves and a frequency gradient between proximal and distal pacemakers. We sought to understand how chronotropic agonists affect coupling between corpus and antrum. METHODS: Electrophysiological and imaging techniques were used to investigate regulation of gastric slow wave frequency by muscarinic agonists in mice. We also investigated the expression and role of cholinesterases in regulating slow wave frequency and motor patterns in the stomach. RESULTS: Both acetycholinesterase (Ache) and butyrylcholine esterase (Bche) are expressed in gastric muscles and AChE is localized to var-icose processes of motor neurons. Inhibition of AChE in the absence of stimulation increased slow wave frequency in corpus and throughout muscle strips containing corpus and antrum. CCh caused depolarization and increased slow wave frequency. Stimulation of cholinergic neurons increased slow wave frequency but did not cause depolarization. Neostigmine (1 MUM) in-creased slow wave frequency, but uncoupling between corpus and antrum was not detected. Motility mapping of contractile activity in gastric muscles showed similar effects of enteric nerve stimulation on the frequency and propagation of slow waves, but neostigmine (> 1 MUM) caused aberrant contractile frequency and propagation and ectopic pacemaking. CONCLUSIONS: Our data show that slow wave uncoupling is difficult to assess with electrical recording from a single or double sites and sug-gest that efficient metabolism of ACh released from motor neurons is an extremely important regulator of slow wave frequency and propagation and gastric motility patterns. PMID- 25843074 TI - In vitro effects of rabeprazole on human pylorus tone. AB - BACKGROUND/AIMS: It has been reported that proton pump inhibitors induce relaxation in different types of smooth muscles. The aim of this study is to investigate in vitro effects of proton pump inhibitors on human pylorus muscle. METHODS: Pyloric sphincters were studied in 10 patients who were operated for stomach cancer. In isolated organ bath, control and re-sponse to rabeprazole were recorded following contraction with carbachol. During the treatment experiment, while distilled wa-ter was applied during the control experiment in every 5 minutes, rabeprazole was administered in every 5 minutes at doses of 10(-6), 10( 5), 10(-4), and 10(-3) M respectively. Contraction frequencies, maximum contraction values and muscle tones were measured. RESULTS: The contraction frequencies in the control group were greater than the rabeprazole group in the second, third and fourth in-tervals while the maximum contraction values in the rabeprazole group were lower in the fourth interval. Even though muscles tones were not different in both groups during all intervals, it was remarkable that the muscle tone was significantly decreased in the rabeprazole group during the fourth interval compared to the first and second intervals. CONCLUSIONS: In the present study, high doses of rabeprazole reduced contraction frequencies, maximum contraction values, and muscle tone of human pylorus. PMID- 25843071 TI - Role of MicroRNA in Visceral Pain. AB - The long-lasting nociceptive transmission under various visceral pain conditions involves transcriptional and/or translational alter-ation in neurotransmitter and receptor expression as well as modification of neuronal function, morphology and synaptic connections. Although it is largely unknown how such changes in posttranscriptional expression induce visceral pain, recent evi-dence strongly suggests an important role for microRNAs (miRNAs, small non-coding RNAs) in the cellular plasticity underlying chronic visceral pain. MicroRNAs are small noncoding RNA endogenously produced in our body and act as a major regulator of gene expression by either through cleavage or translational repression of the target gene. This regulation is essential for the normal physiological function but when disturbed can result in pathological conditions. Usually one miRNA has multiple targets and target mRNAs are regulated in a combinatorial fashion by multiple miRNAs. In recent years, many studies have been per-formed to delineate the posttranscriptional regulatory role of miRNAs in different tissues under various nociceptive stimuli. In this review, we intend to discuss the recent development in miRNA research with special emphases on miRNAs and their tar-gets responsible for long term sensitization in chronic pain conditions. In addition, we review miRNAs expression and function data for different animal pain models and also the recent progress in research on miRNA-based therapeutic targets for the treatment of chronic pain. PMID- 25843076 TI - Mast Cell-dependent Mesenteric Afferent Activation by Mucosal Supernatant From Different Bowel Segments of Guinea Pigs With Post-infectious Irritable Bowel Syndrome. AB - BACKGROUND/AIMS: Mesenteric afferent nerves (MANs) play a pivotal role in the visceral-nociceptive perception. Inappropriate activation of MANs may be involved in the pathogenesis of post-infectious irritable bowel syndrome (PI-IBS). However, the underlying mechanisms remain unclear. We assessed the effects of mucosal mediators from different bowel segments of guinea pigs with PI-IBS on MAN firing and the role of mast cells. METHODS: PI-IBS was induced in guinea pigs by Trichinella spiralis infection. Inflammation in terminal ileum, proximal and distal colon was scored with hematoxylin-eosin staining, and mast cell infiltration was assessed with immunofluorescence. We determined the effects of supernatant extracted from the mucosa of different bowel segments of PI-IBS on MANs activity, and assessed the role of mast cells in this process. RESULTS: Eight weeks after infection, intestinal inflammation resolved, whereas mast cell numbers increased significantly in terminal ileum and proximal colon (P < 0.05) compared with findings in controls. Mucosal supernatant from different bowel segments of PI-IBS models, but not from controls, significantly enhanced the frequency of MAN firing (terminal ileum 41.01 +/- 7.60 Hz vs. 26.55 +/- 0.67 Hz, P = 0.001; proximal colon 45.90 +/- 11.20 Hz vs. 30.88 +/- 6.92 Hz, P = 0.002; distal colon 48.25 +/- 9.70 Hz vs. 29.47 +/- 6.13 Hz, P < 0.001). In addition, the excitatory effects were inhibited by mast cell stabilizer Nasmil (terminal ileum, 32.71 +/- 2.52 Hz, P = 0.030; proximal colon, 30.94 +/- 4.44 Hz, P = 0.002; distal colon, 27.15 +/- 5.83 Hz, P < 0.001). CONCLUSIONS: Supernatant from the intestinal mucosa of different bowel segments of PI-IBS models markedly enhanced the MAN firing in a mast cell-dependent manner, indicating that mast cell-mediated MAN activation plays an important role in the pathogenesis of PI IBS. PMID- 25843075 TI - Lipopolysaccharides facilitate colonic motor alterations associated to the sensitization to a luminal antigen in rats. AB - BACKGROUND/AIMS: Enteric dysbiosis is a risk factor for dietary proteins associated intestinal alterations, contributing to the development of food allergies and the symptomatology of functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS). We explored if a dysbiotic-like state, simulated by intraperitoneal administration of bacterial lipopolysaccharides (LPS), facilitates the sensitiza-tion to a luminal antigen, ovalbumin (OVA), in rats. METHODS: Rats were exposed to oral OVA for 1 week, alone or with LPS. Thereafter, colonic histology, goblet cell density, mucosal eosi-nophils and mucosal mast cell (MMC) and connective tissue mast cell (CTMC) were evaluated. Colonic expression (real-time quantitative polymerase chain reaction) of interleukins, IFN-alpha1 and integrins was assessed to determine local immune responses. Luminal and wall adhered microbiota were characterized by fluorescence in situ hybridization. Colonic contractility (in vitro) served to assess functional changes associated to OVA and/or LPS. RESULTS: Neither OVA nor LPS, alone or combined, lead to structural alterations, except for a reduced goblet cell density in OVA-LPS- treated rats. MMC density was unaffected, while CTMC counts increased within the submucosa of OVA-LPS-treated animals. Marginal immune activation (IFN-alpha1 up-regulation) was observed in OVA-LPS-treated rats. LPS induced a dysbiotic-like state characterized by decreased luminal bacterial counts, with a specific loss of clostridia. LPS facilitated Clostridium spp. wall adherence, an effect prevented by OVA. Colonic contractility was altered in OVA LPS-treated animals, showing increased basal activity and enhanced motor responses to OVA. CONCLUSIONS: Changes in gut microbiota and/or direct effects of LPS might enhance/facilitate local neuroimmune responses to food antigens leading to motor alterations similar to those observed in IBS. PMID- 25843077 TI - The effect of abdominal visceral fat, circulating inflammatory cytokines, and leptin levels on reflux esophagitis. AB - BACKGROUND/AIMS: Although adipocytes secrete inflammatory cytokines and adipokines, their role in reflux esophagitis is controversial. We investigated the association between visceral fat and inflammatory cytokines or adipokines in reflux esophagitis. METHODS: Abdominal visceral fat and cytokines were measured in 66 individuals with reflux esophagitis and 66 age- and sex-matched controls. The mean values for visceral fat and cytokines were compared in cases and controls. Second, correlations between visceral fat and inflammatory cytokines were measured. Finally, multiple logistic regression models for odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the effects of visceral fat and cytokines on reflux esophagitis. RESULTS: Visceral fat, leptin, interleukin (IL)-6, and IL-1beta were higher in reflux esophagitis compared to controls. Visceral fat showed a strong positive correlation with IL-6 (r = 0.523, P < 0.001), IL-8 (r = 0.395, P < 0.001), and IL-1beta (r = 0.557, P < 0.001), and a negative correlation with adiponectin (r = -0.466, P < 0.001). With adjusted analysis, visceral fat/100 (OR, 4.32; 95% CI, 2.18-8.58; P < 0.001) and leptin (OR, 1.36; 95% CI, 1.10-1.69; P = 0.005) independently increased the risk of reflux esophagitis, but the effects of other cytokines were abolished. CONCLUSIONS: Visceral fat may increase the risk of reflux esophagitis by increasing the levels of inflammatory cytokines. Leptin showed a positive association with reflux esophagitis that was independent of visceral fat. PMID- 25843079 TI - Application and Interpretation of High-resolution Manometry for Pharyngeal Dysphagia. AB - The pharyngeal phase of swallowing is a complex event consisted with subsequent muscular contractions and pressure gen-eration to move a bolus from the mouth to the esophagus. Recently, high-resolution impedance manometry (HRIM) was devel oped and used for the evaluation of pharyngeal dysphagia. Although HRIM provides precise pharyngeal pressure information, it has yet to be used as part of routine clinical practice for the assessment of dysphagia. The main reasons are thought to be that the test method and result interpretation are not easily applicable and standardized. The anatomical landmarks for HRIM parameters are velopharynx, tongue base, epiglottis, low pharynx, and upper esophageal sphincter. With HRIM, the pressure and timing data could be obtained at a precise anatomical structure. In the present review, we will review how to apply HRIM for the evaluation of pharyngeal dysphagia, including the interpretation of its parameters.(J Neurogastroenterol Motil 2015;21:283-287). PMID- 25843078 TI - Inconsistency in the Diagnosis of Functional Heartburn: Usefulness of Prolonged Wireless pH Monitoring in Patients With Proton Pump Inhibitor Refractory Gastroesophageal Reflux Disease. AB - BACKGROUND/AIMS: The diagnosis of functional heartburn is important for management, however it stands on fragile pH monitoring variables, ie, acid exposure time varies from day to day and symptoms are often few or absent. Aim of this study was to investigate consistency of the diagnosis of functional heartburn in subsequent days using prolonged wireless pH monitoring and its impact on patients' outcome. METHODS: Fifty proton pump inhibitotor refractory patients (11 male, 48 years [range, 38-57 years]) with a diagnosis of functional heartburn according to Rome III in the first 24 hours of wireless pH monitoring were reviewed. pH variables were analysed in the following 24-hour periods to determine if tracings were indicative of diagnosis of non-erosive reflux disease (either acid exposure time > 5% or normal acid exposure time and symptom index >= 50%). Outcome was assessed by review of hospital files and/or telephone interview. RESULTS: Fifteen out of 50 patients had a pathological acid exposure time after the first day of monitoring (10 in the second day and 5 in subsequent days), which changed their diagnosis from functional heartburn to non-erosive reflux disease. Fifty-four percent of non-erosive reflux disease vs 11% of functional heartburn patients (P < 0.003) increased the dose of proton pump inhibitors or underwent fundoplication after the pH test. Outcome was positive in 77% of non-erosive reflux disease vs 43% of functional heartburn patients (P < 0.05). CONCLUSIONS: One-third of patients classified as functional heartburn at 24-hour pH-monitoring can be re-classified as non-erosive reflux disease after a more prolonged pH recording period. This observation has a positive impact on patients' management. PMID- 25843080 TI - Acid-suppressive Medications and Risk of Esophageal Adenocarcinoma in Patients With Barrett's Esophagus(Gut 2014;63:1229-1237). PMID- 25843081 TI - Are there any association between colonic diverticula and bowel symptoms?(neurogastroenterol motil 2015;27:333-338). PMID- 25843082 TI - Impedance-detected Symptom Association and Number of Reflux Episodes as Pre treatment Parameters That Predict Outcomes of Gastroesophageal Reflux Disease Patients. PMID- 25843083 TI - A survey using the social networks revealed poor knowledge on fecal microbiota transplantation. PMID- 25843084 TI - Optimal Testing for Diagnosis of Fructose Malabsorption: Under-dosage Leads to False Negative Intolerance Test. PMID- 25843085 TI - Decreased neuroplasticity may play a role in irritable bowel syndrome: implication from the comorbidity of depression and irritable bowel syndrome. PMID- 25843086 TI - 3',4',5',5,7-pentamethoxyflavone sensitizes Cisplatin-resistant A549 cells to Cisplatin by inhibition of Nrf2 pathway. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important redox sensitive transcription factor that regulates the expression of several cytoprotective genes. More recently, genetic analyses of human tumors have indicated that Nrf2 may cause resistance to chemotherapy. In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3',4',5',5,7-Pentamethoxyflavone (PMF), a natural flavonoid extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA. Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA. Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway. PMID- 25843087 TI - Consequences of household air pollution on child survival: evidence from demographic and health surveys in 47 countries. AB - BACKGROUND: Over one-third of the world's population is exposed to household air pollution (HAP) but the separate effects of cooking with solid fuel and kerosene on childhood mortality are unclear. OBJECTIVES: To evaluate the effects of both solid fuels and kerosene on neonatal (0-28 days) and child (29 days-59 months) mortality. METHODS: We used Demographic and Health Surveys from 47 countries and calculated adjusted relative risks (aRR) using Poisson regression models. RESULTS: The aRR of neonatal and child mortality in households exposed to solid fuels were 1.24 (95% CI: 1.14, 1.34) and 1.21 (95% CI: 1.12, 1.30), respectively, and the aRR for neonatal and child mortality in households exposed to kerosene were 1.34 (95% CI: 1.18, 1.52) and 1.12 (95% CI: 0.99, 1.27), controlling for individual, household, and country-level predictors of mortality. CONCLUSIONS: Kerosene should not be classified as a clean fuel. Neonates are at risk for mortality from exposure to solid fuels and kerosene. PMID- 25843088 TI - Development of the Russian matrix sentence test. AB - OBJECTIVE: To develop the Russian matrix sentence test for speech intelligibility measurements in noise. DESIGN: Test development included recordings, optimization of speech material, and evaluation to investigate the equivalency of the test lists and training. For each of the 500 test items, the speech intelligibility function, speech reception threshold (SRT: signal-to-noise ratio, SNR, that provides 50% speech intelligibility), and slope was obtained. The speech material was homogenized by applying level corrections. In evaluation measurements, speech intelligibility was measured at two fixed SNRs to compare list-specific intelligibility functions. To investigate the training effect and establish reference data, speech intelligibility was measured adaptively. STUDY SAMPLE: Overall, 77 normal-hearing native Russian listeners. RESULTS: The optimization procedure decreased the spread in SRTs across words from 2.8 to 0.6 dB. Evaluation measurements confirmed that the 16 test lists were equivalent, with a mean SRT of -9.5 +/- 0.2 dB and a slope of 13.8 +/- 1.6%/dB. The reference SRT, 8.8 +/- 0.8 dB for the open-set and -9.4 +/- 0.8 dB for the closed-set format, increased slightly for noise levels above 75 dB SPL. CONCLUSIONS: The Russian matrix sentence test is suitable for accurate and reliable speech intelligibility measurements in noise. PMID- 25843089 TI - QVA149 (indacaterol/glycopyrronium) for the treatment of chronic obstructive pulmonary disease. AB - INTRODUCTION: The combination of two bronchodilators with different mechanisms of action to treat patients with chronic obstructive pulmonary disease (COPD) is an established medical practice, but the dissimilarities in the onset and duration of action of long-acting beta2-agonists (LABA) and long-acting muscarinic agents (LAMA) and differences in the devices used for the delivery of these drugs make free combinations uncomfortable and unpredictable, especially if focused on adherence to prescribed treatment. Therefore, there is the need for fixed-dose combinations (FDCs) of bronchodilators in a single inhaler. AREAS COVERED: The results of the pivotal Phase III IGNITE and EXPEDITION programs show that QVA149 (indacaterol/glycopyrronium FDC) is able to elicit a significant improvement in lung function and patient-reported outcomes, including breathlessness and rescue medication use, reduced rates of COPD exacerbations and health-related quality of life when compared with current standard of care. Moreover, QVA149 is generally well tolerated, with most adverse events being of mild-to-moderate severity. EXPERT OPINION: Given that the LABA/LAMA coformulation is the most powerful bronchodilator available, QVA149, which has been the first LABA/LAMA FDC to be developed, should be considered central in the maintenance treatment of COPD, and could be a potential option for improving lung function and health status in maintenance-naive patients. PMID- 25843090 TI - Getting to z. PMID- 25843091 TI - Vertical Oviposition Preferences of the Asian Tiger Mosquito, Aedes albopictus, In Temperate North America. AB - As a hyperaggressive mosquito that is also a public health threat, Aedes albopictus (Skuse), the Asian tiger mosquito, is a major priority for control efforts. We examine one aspect of Ae. albopictus biology: oviposition height. Field-based research in an urban habitat was conducted to determine if a height preference exists for this species. Larval and egg counts showed a significant preference for oviposition at ground level (0 m) compared to heights of 1, 2, 3, or 4 m (P < 0.01). An experiment conducted under semi-field conditions supported our conclusion of oviposition preference at ground level (P < 0.001), and further defines the search image needed by mosquito control personnel when dealing with this invasive species. PMID- 25843092 TI - A comparison of two commercial mosquito traps for the capture of malaria vectors in northern belize, central america. AB - To achieve maximum success from any vector control intervention, it is critical to identify the most efficacious tools available. The principal aim of this study was to evaluate the efficacy of 2 commercially available adult mosquito traps for capturing Anopheles albimanus and An. vestitipennis, 2 important malaria vectors in northern Belize, Central America. Additionally, the impact of outdoor baited traps on mosquito entry into experimental huts was assessed. When operated outside of human-occupied experimental huts, the Centers for Disease Control and Prevention (CDC) miniature light trap, baited with human foot odors, captured significantly greater numbers of female An. albimanus per night (5.1 +/- 1.9) than the Biogents SentinelTM trap baited with BG-LureTM (1.0 +/- 0.2). The 2 trap types captured equivalent numbers of female An. vestitipennis per night, 134.3 +/ 45.6 in the CDC trap and 129.6 +/- 25.4 in the Sentinel trap. When compared to a matched control hut using no intervention, the use of baited CDC light traps outside an experimental hut did not impact the entry of An. vestitipennis into window interception traps, 17.1 +/- 1.3 females per hour in experimental huts vs. 17.2 +/- 1.4 females per hour in control huts. However, the use of outdoor baited CDC traps did significantly decrease the entry of An. albimanus into window interception traps from 3.5 +/- 0.5 females per hour to 1.9 +/- 0.2 females per hour. These results support existing knowledge that the underlying ecological and behavioral tendencies of different Anopheles species can influence trap efficacy. Furthermore, these findings will be used to guide trap selection for future push pull experiments to be conducted at the study site. PMID- 25843093 TI - Development of a New Mosquito Retention System for the BG-Malaria Trap To Reduce The Damage To Mosquitoes. AB - The BG-Malaria trap was recently modified from the BioGents BG-Sentinel trap to collect Anopheles species, including Anopheles darlingi. However, the captured mosquitoes often lose their hind legs in the collector bag, making them difficult to identify. To develop a new collector system that is capable of maintaining the integrity of the mosquitoes collected in the BG-Malaria trap, we conducted a study in the municipalities of Belem (Para State [PA]) and Porto Velho (Rondonia State [RO]), Brazil, using carbon dioxide-baited BG-Malaria traps with 4 different mosquito collector systems: standard, no bag, rigid short, and rigid long. Results indicated significant differences among the numbers of mosquitoes captured in the 4 different collectors (P < 0.05). Additionally, significantly fewer insects (P < 0.05) were damaged using the rigid short and rigid long collectors than by using the standard and no-bag collectors. We observed that the longer the insects remained in the collector, the higher the number of damaged insects; this effect was the greatest in the standard collector. The results of this study indicate that rigid long collectors were the best suited for use in the BG-Malaria trap. PMID- 25843094 TI - SR450 And Superhawk XP Applications Of Bacillus thuringiensis israelensis Against Culex quinquefasciatus. AB - Sprayer comparisons and larval morality assays were conducted following SR450 backpack mist blower and Superhawk XP thermal fogger applications of Vectobac(r) WDG Bacillus thuringiensis israelensis (Bti) against Culex quinquefasciatus. Bacillus thuringiensis israelensis was applied at maximum label rate in a 232.26 m(2) field plot located in north-central Florida with containers placed at 2 heights (ground level and 1.52 m above ground) on stakes positioned 3.04, 6.09, 9.14, 12.19, and 15.24 m from the spray line. Results indicated that there was no significant (P > 0.05) difference in 24- and 48-h larval mortality between the 2 sprayers or between the 2 heights. There was significant difference (P < 0.05) among the 5 rows, with mortality continuously decreasing with increasing distance from sprayer. Both sprayers provided on average >70% larval mortality 3.04-9.14 m from the spray line, and <60% mortality at 12.19 and 15.24 m. The data suggest that the SR450 and Superhawk XP may be comparable sprayers for use with Bti to control mosquito larvae. PMID- 25843095 TI - Fumigant Activity of 6 Selected Essential Oil Compounds and Combined Effect of Methyl Salicylate And Trans-Cinnamaldehyde Against Culex pipiens pallens. AB - We studied the knockdown activity and lethal toxicity of 6 essential oil compounds-methyl salicylate, linalool, 2-phenethyl alcohol, eugenol, beta citronellol, and trans-cinnamaldehyde-as fumigants against adult female Culex pipiens pallens in the laboratory. Of the 6 products tested, trans-cinnamaldehyde was the most toxic (LC50 = 0.26 ul/l air, 24 h) with a slow knockdown time (KT95 = 176.5 min at 0.5 ul/l air). Methyl salicylate displayed a lower toxicity (LC50 = 1.17 ul/l air, 24 h) but the fastest knockdown activity (KT95 = 16.8 min) at the sublethal concentration 0.5 ul/l air. Furthermore, the binary mixture of methyl salicylate and trans-cinnamaldehyde exhibited a combined effect of fast knockdown activity and high toxicity against Cx. p. pallens adults, showing potential for development as natural fumigants for mosquito control. PMID- 25843096 TI - Mosquito vector biology and control in latin america-a 24th symposium. AB - The 24th Annual Latin American Symposium presented by the American Mosquito Control Association (AMCA) was held as part of the 80th Annual Meeting in Seattle, WA, in February 2014. The principal objective, for the previous 23 symposia, was to promote participation in the AMCA by vector control specialists, public health workers, and academicians from Latin America. This publication includes summaries of 26 presentations that were given orally in Spanish or presented as posters by participants from Colombia, Mexico, and the USA. Topics addressed in the symposium included: surveillance, ecology, chemical control, studies of dengue viruses, and insecticide resistance associated with Aedes aegypti; Anopheles vectors of malaria; essential oils; and ethnic groups and vector-borne diseases. PMID- 25843097 TI - Blood meal identification and feeding habits of uranotaenia species collected in the ryukyu archipelago. AB - To know the blood meal in the stomach of Uranotaenia species, blood-fed mosquitoes were collected by 4 methods at different sites in the mountain forest of 3 islands, Amamioshima, Okinawajima, and Iriomotejima in the Ryukyu Archipelago, Japan from 2005 to 2012. One hundred twenty-four blood-fed Uranotaenia mosquitoes of 7 species (Ur. jacksoni, nivipleura, ohamai, yaeyamana, annandalei, lateralis, and macfarlanei) were collected. The collection rates are 0.26, 0.6, 0.31, and 0.66 by black light trap, black light blue with dry ice trap, frog call trap, and sweeping net, respectively. The blood meals of 107 females (86.3%) were successfully identified by a polymerase chain reaction-based method. All Uranotaenia species fed on cold-blooded animals, especially amphibians (99.1%), and notably on frogs. They would feed readily on available frogs in a given region having no close connection with the breeding (calling) season of each frog. They also fed on reptiles (0.9%), but not on warm-blooded animals. PMID- 25843098 TI - Environmentally Dependent Density-Distance Relationship of Dispersing Culex tarsalis in a Southern California Desert Region. AB - The direct inclusion of environmental factors into the empirical model that describes a density-distance relationship (DDR) is demonstrated on dispersal data obtained in a capture-mark-release-recapture experiment (CMRR) with Culex tarsalis conducted around the community of Mecca, CA. Empirical parameters of standard (environmentally independent) DDR were expressed as linear functions of environmental variables: relative orientation (azimuthal deviation of north) of release point (relative to recapture point) and proportions of habitat types surrounding each recapture point. The yielded regression model (R(2) = 0.5373, after optimization on the best subset of linear terms) suggests that spatial density of recaptured individuals after 12 days of a CMRR experiment significantly depended on 1) distance from release point, 2) orientation of recapture points in relation to release point (preferring dispersal toward the south, probably due to wind drift and position of periodically flooded habitats suitable for species egg clutches), and 3) habitat spectrum in surroundings of recapture points (increasing and decreasing population density in desert and urban environment, respectively). PMID- 25843099 TI - The mosquito ultra-low volume dispersion model for estimating environmental concentrations of insecticides used for adult mosquito management. AB - Computer models for pesticide drift are widely used tools by regulatory agencies to estimate the deposition of pesticides beyond the intended target area. Currently, there is no model in use that has been validated or verified as an accurate means of estimating concentrations of insecticides after ground-based ultra-low volume (ULV) applications used for adult mosquito management. To address the need for a validated model we created a spreadsheet-based model called Mosquito Ultra-Low Volume Dispersion (MULV-Disp) to aid in the adoption and to provide easier use of a validated model. We explain the origin, use, and utility of MULV-Disp, which can be used by regulatory agencies and other interested parties to estimate deposition of ULV insecticides. PMID- 25843101 TI - Evaluation of Vegetation Treatment With Lambda-Cyhalothrin to Control Aedes vexans and Simulium maculatum in Northern China. AB - The mosquito Aedes vexans and black fly Simulium maculatum are important blood sucking pests in northern China. Control of these pests using current methods is difficult because of complex larval developmental sites. In the present study, lambda-cyhalothrin was applied as a barrier spray to vegetation and various structures surrounding human dwellings for control against the adults of each species. The barrier spray resulted in an 88.2-99.4% reduction in Ae. vexans abundance and a 67.8-89.6% reduction in S. maculatum abundance for 2 wk postapplication. Our results indicated that lambda-cyhalothrin applied as a barrier spray to vegetation and other structures that serve as harborage for adults of both species could be adopted as part of an integrated pest management approach against these pests. PMID- 25843100 TI - Evaluation of Culex pipiens Populations in a Residential Area with a High Density of Catch Basins in a Suburb of Chicago, Illinois. AB - The North Shore Mosquito Abatement District applies extended release larvicides including methoprene-based Altosid(r) XR Extended Residual Briquets to approximately 40,000 catch basins in the southern half of the District's operational area at the beginning of each season. Treatments begin in May and typically again 9 to 10 wk later when larvicide efficacy appears to wane. In 2013 spinosad-based NatularTM XRT tablets were applied to basins, and a subset were monitored for larvae and pupae weekly with a standard dipper. When setting the threshold for retreatment as 12 juveniles per dip sample it was observed that basins required a second application 9 wk after the initial application, a time period similar to Altosid despite utilizing a different active ingredient. Average counts of weekly larval samples appeared to be positively associated with average numbers of Culex pipiens collected the following week in a gravid trap located among catch basins, highlighting the importance of basins as sources of these mosquitoes. PMID- 25843102 TI - A mobile app for military operational entomology pesticide applications. AB - Multiple field studies conducted for the Deployed War-Fighter Protection (DWFP) research program have generated more than 80 specific guidance points for innovative combinations of pesticide application equipment, pesticide formulations, and application techniques for aerosol and residual pesticide treatments in 6 ecological regions against a range of mosquito, sand fly, and filth fly nuisance and disease-vector threats. To synthesize and operationalize these DWFP field and laboratory efficacy data we developed an interactive iOS and Android mobile software application, the Pesticide App, consisting of specific pesticide application guidance organized by environment and target insect vector species. PMID- 25843103 TI - 2014 AMCA Memorial Lecture Honoree: Founding Mothers: Women, Entomology, and Mosquito Control. PMID- 25843105 TI - Journal of the american mosquito control association information for contributors. PMID- 25843106 TI - Current and potential use of MAINTRAC method for cancer diagnosis and prediction of metastasis. AB - Cells shed from solid malignant tumors into the circulation are considered to be the origin of metastases. In spite of a wealth of research on the pathway of metastasis formation, it is still not clear when and how metastases develop, nor is there a consensus on the number and the nature of circulating tumor cells present in individual patients and their relationship to the formation of metastases. We have developed a method to detect a maximum of unselected non hematological, epithelial cells in the blood, assuming that in cancer patients the majority of these cells are derived from the tumor. Assessment of the number of these cells longitudinally during the course of disease and therapy allows the response to different treatments to be monitored. Due to the viability of the cells, additional analyses such as expression profiles and determination of their sensitivity to drugs can be performed. PMID- 25843107 TI - Design and Synthesis of Labystegines, Hybrid Iminosugars from LAB and Calystegine, as Inhibitors of Intestinal alpha-Glucosidases: Binding Conformation and Interaction for ntSI. AB - This paper identifies the required configuration and orientation of alpha glucosidase inhibitors, miglitol, alpha-1-C-butyl-DNJ, and alpha-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-pi interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal alpha-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia. PMID- 25843108 TI - QuEChERs Combined with Online Interference Trapping LC-MS/MS Method for the Simultaneous Determination of 20 Polyfluoroalkane Substances in Dietary Milk. AB - In this study, a highly sensitive and reliable method for the determination of 20 polyfluoroalkane substances (PFASs) in milk was established using the QuEChERS approach and an online interference trapping LC-MS/MS analysis. By a calibration with stable-isotope-labeled internal standards, we showed that the method displayed excellent linear dynamic ranges for 20 PFASs (correlation coefficients >=0.997). The LOQs for the two types of PFASs, perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonic acids (PFSAs), were 0.010 and 0.050 MUg/L, respectively. At the three spiking levels, the average recoveries for PFCAs ranged from 78.5 to 111% with the RSD (n = 6) within 1.20-13.1%, and those for PFSAs ranged from 72.8 to 105% with the RSD (n = 6) within 3.53-14.9%. By the developed method, 16 PFASs were found to be positive in 46 milk samples, and the levels for the PFASs with longer chains were significantly higher than those reported from other known regions. PMID- 25843109 TI - Synthesis and characterization of an iron complex bearing a cyclic tetra-N heterocyclic carbene ligand: an artifical heme analogue? AB - An iron(II) complex with a cyclic tetradentate ligand containing four N heterocyclic carbenes was synthesized and characterized by means of NMR and IR spectroscopies, as well as by single-crystal X-ray structure analysis. The iron center exhibits an octahedral coordination geometry with two acetonitrile ligands in axial positions, showing structural analogies with porphyrine-ligated iron complexes. The acetonitrile ligands can readily be substituted by other ligands, for instance, dimethyl sulfoxide, carbon monoxide, and nitric oxide. Cyclic voltammetry was used to examine the electronic properties of the synthesized compounds. PMID- 25843110 TI - Application of Direct Analysis in Real Time-Mass Spectrometry (DART-MS) to the study of gas-surface heterogeneous reactions: focus on ozone and PAHs. AB - A novel analytical method is presented whereby Direct Analysis in Real Time-Mass Spectrometry (DART-MS) is applied to the study of gas-surface heterogeneous reactions. To illustrate the capabilities of the approach, the kinetics of a well studied reaction of surface-bound polycyclic aromatic hydrocarbons with ozone are presented. Specifically, using helium as the reagent gas and with the DART heater temperature of 500 degrees C, nanogram quantities of benzo[e]pyrene (BeP) deposited on the outside of glass melting point capillary tubes were analyzed in positive ion mode with a limit of detection of 40 pg. Using bis(2-ethylhexyl) sebacate as an internal standard, the kinetics of the ozone-BeP reaction were assessed by determining the surface-bound BeP decays, after oxidation in an off line reaction cell. The reaction is demonstrated to follow the Langmuir Hinshelwood mechanism, known to prevail for heterogeneous reactions of this type. In addition, a wide array of oxygenated, condensed-phase products has been observed. The present work demonstrates the capability of the DART-MS technique to investigate the heterogeneous chemistry taking place on a wide range of surfaces, such as those that form in both outdoor and indoor environments. PMID- 25843113 TI - Anatomical evaluation of hepatic vascular system in healthy beagles using X-ray contrast computed tomography. AB - Liver contrast X-ray computed tomography (CT) has been used for evaluation of hepatic vessels for liver transplantation, liver lobectomy, interventional radiology and diagnosis of hepatocellular carcinoma in humans. However, there remains scant available anatomical information on normal hepatic vessels in the veterinary field. In this study, visualization of hepatic vessels was evaluated in 32 normal beagle dogs by X-ray contrast CT using triple phase images. The following hepatic vessels were clearly visualized: arterial, portal and hepatic veins. With regards to the running patterns of the portal vein and hepatic vein, there were no significant differences between the dogs. However, the hepatic artery exhibited some differences in each dog. In particular, the hepatic artery of the quadrate lobe and the right lateral lobe had many running patterns. The results of the present study could be useful for veterinary diagnosis, surgery and interventional radiology. PMID- 25843114 TI - Post-traumatic stress disorder in participants of foot-and-mouth disease epidemic control in Miyazaki, Japan, in 2010. AB - Foot-and-mouth disease (FMD) occurred in Miyazaki, Japan, in 2010, and 290,000 animals were culled. This paper describes the mental distress of the volunteers who had been dispatched to Miyazaki for disease control two years after the epidemic. It also assesses risk factors for post-traumatic stress disorder (PTSD). A participatory appraisal and self-administered questionnaire survey were conducted in 2012 for those who were dispatched to Miyazaki in 2010. The Impact of Event Scale-Revised (IES-R) was used as an indicator of PTSD, and univariate and multivariable analyses were performed. Of the 875 respondents, 1.3% had higher IES-R scores than the cut-off point (25), which is suggestive of PTSD. Mental stresses during and soon after FMD control and after two years were described. Four risk factors associated with high IES-R scores were found: transporting culled animals (P<0.01), stress during FMD control (P<0.01) and at the time of the survey (P<0.01), and lack of someone to talk to about FMD associated stress at the time of the survey (P<0.01). Veterinarians, livestock technicians and clerical officers involved in FMD control still suffer from mental stress two years later. Public services should provide an opportunity for them to consult with mental health specialists. These findings should be used to better prepare workers who deal with infectious diseases of animals, especially when they must be culled. The establishment of a collaborative framework between veterinary and mental health services is recommended. PMID- 25843115 TI - Expression of Vasohibin-1 in Human Carotid Atherosclerotic Plaque. AB - AIM: In patients with carotid plaque, intraplaque hemorrhage arising from ruptured neovascular vessels within the neointima is an important cause of stroke. The expression of Vasohibin-1 (VASH1), a negative feedback regulator of angiogenesis, occurs in the microvessel endothelial cells of various solid tumors and the arterial wall. However, the roles of VASH1 in the pathogenesis of atherosclerotic diseases remain unclear. The present study aimed to clarify the relevance of the VASH1 expression and plaque instability in human carotid plaques. METHODS: We used quantitative real-time PCR and immunostaining to examine 12 atheromatous plaque specimens obtained via carotid endarterectomy. The distal areas of specimens lacking macroscopic atherosclerotic lesions served as controls. RESULTS: Compared with that observed in the controls, the VASH1 gene expression increased significantly in the atheromatous plaque (p=0.018). Moreover, the VASH1 mRNA levels correlated positively with those of VEGFA, CD31 and VCAM1 (r=0.788, p=0.004; r=0.99, p < 0.001; r=0.94, p < 0.001, respectively). Finally, the immunohistochemical analyses revealed the VASH1 expression in the neointimal microvessel endothelial cells of carotid plaque. CONCLUSIONS: The VASH1 expression levels in atheroma reflect both enhanced neovascularization and the inflammatory burden. Therefore, the VASH1 level may be a novel biomarker for evaluating plaque instability in patients with carotid arteriosclerosis and predicting ischemic stroke. PMID- 25843116 TI - Dual Antiplatelet Therapy in Patients with Glucose-6-Phosphate Dehydrogenase Deficiency undergoing PCI with Drug-Eluting Stents. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. In patients with G6PD deficiency, the use of aspirin is controversial, since past studies have reported a potential risk of haemolysis related to its administration, even at low doses. More recent publications have shown that low-dose aspirin administration is safe in these patients. At the same time, no authors have previously reported more than single cases regarding low-dose aspirin treatment in patients with G6PD deficiency undergoing percutaneous coronary intervention (PCI), and most physicians are still sceptical about aspirin administration in these patients. In this paper, we report a case series of five patients with G6PD deficiency receiving PCI with drug-eluting stents (DES) and treatment with dual antiplatelet therapy (DAPT) containing low-dose aspirin, without clinical complications. Moreover, we discuss our internal protocol for managing these patients and provide an overview of the available data. PMID- 25843117 TI - Chitosan Oligosaccharides Attenuate Atherosclerosis and Decrease Non-HDL in ApoE /- Mice. AB - AIM: Chitosan-oligosaccharides (COS) treatment showed lipid lowering effects in rats and reverse cholesterol transport (RCT) promotion in mice, suggested that COS might be a potential atheroprotective material. In this study, we investigated the effects of COS treatment on atherosclerosis (AS) in apolipoprotein E deficient mice (apoE-/-). METHODS: After feeding high fat (HF) diet for 12 weeks with the gastric gavages administration of COS or vehicle, respectively, the mice were sacrificed for the assessment of atherosclerosis, plaque stability, and the mechanism investigation. RESULTS: Cholesterol and TG in non-high density lipoprotein (non-HDL) fractions were reduced dramatically in COS groups. The COS treatment decreased the lesion areas of aortic enface, plaque areas in aortic root, and increased plaque stability in apoE-/-. Furthermore, the COS treatment significantly enhanced the expression of liver low density lipoprotein receptor (LDL-R), scavenger receptor BI (SR-BI) as well as the expression of macrophage SR-BI and ATP binding cassette transporter A1(ABCA1). We also found that the COS treatment did not affect the plasma lipid level in LDL-R deficient mice and cholesterol absorption in wild type mice. CONCLUSIONS: COS treatment attenuated AS and decreased plasma non-HDL level in apoE-/-, and the potential mechanism might be involved with enhanced expression of hepatic LDL-R and SR-BI, and macrophage ABCA1. PMID- 25843118 TI - Risks, benefits, complications and harms: neglected factors in the current debate on non-therapeutic circumcision. AB - Much of the contemporary debate about the propriety of non-therapeutic circumcision of male infants and boys revolves around the question of risks vs. BENEFITS: With its headline conclusion that the benefits outweigh the risks, the current circumcision policy of the American Academy of Pediatrics [AAP] (released 2012) is a typical instance of this line of thought. Since the AAP states that it cannot assess the true incidence of complications, however, critics have pointed out that this conclusion is unwarranted. In this paper it is argued that the AAP's conclusion is untenable not only for empirical reasons related to lack of data, but also for logical and conceptual reasons: the concept of risk employed risk of surgical complications-is too narrow to be useful in the circumcision debate. Complications are not the only harms of circumcision: the AAP and other parties debating the pros and cons of circumcision should conceptualize their analysis more broadly as risk of harm vs. prospect of benefit, thereby factoring in the value of the foreskin to the individual and the physical and ethical harms of removing it from a non-consenting child. PMID- 25843119 TI - Applying a global justice lens to health systems research ethics: an initial exploration. AB - Recent scholarship has considered what, if anything, rich people owe to poor people to achieve justice in global health and the implications of this for international research. Yet this work has primarily focused on international clinical research. Health systems research is increasingly being performed in low and middle income countries and is essential to reducing global health disparities. This paper provides an initial description of the ethical issues related to priority setting, capacity-building, and the provision of post-study benefits that arise during the conduct of such research. It presents a selection of issues discussed in the health systems research literature and argues that they constitute ethical concerns based on their being inconsistent with a particular theory of global justice (the health capability paradigm). Issues identified include the fact that priority setting for health systems research at the global level is often not driven by national priorities and that capacity building efforts frequently utilize one-size-fits-all approaches. PMID- 25843120 TI - Governing the postmortem procurement of human body material for research. AB - Human body material removed post mortem is a particularly valuable resource for research. Considering the efforts that are currently being made to study the biochemical processes and possible genetic causes that underlie cancer and cardiovascular and neurodegenerative diseases, it is likely that this type of research will continue to gain in importance. However, post mortem procurement of human body material for research raises specific ethical concerns, more in particular with regard to the consent of the research participant. In this paper, we attempt to determine which consent regime should govern the post mortem procurement of body material for research. In order to do so, we assess the various arguments that could be put forward in support of a duty to make body material available for research purposes after death. We argue that this duty does in practice not support conscription but is sufficiently strong to defend a policy of presumed rather than explicit consent. PMID- 25843121 TI - Obesity and obligation. AB - The belief that obese people ought to lose weight and keep it off is widespread, and has a profound negative impact on the lives of the obese. I argue in this paper that most obese people have no such obligation, even if obesity is bad, and caused by calorie input exceeding output. Obese people do not have an obligation to achieve long-term weight loss if this is impossible for them, is worse than the alternative, or requires such an enormous effort in relation to what stands to be gained that this option is supererogatory rather than obligatory. It is highly plausible that most obese people fall into one of these three groups. Politicians may still have obligations to fight obesity, but they ought to do so through progressive politics rather than blaming and shaming. PMID- 25843122 TI - Editorial note. Under-explored topics in bioethics. PMID- 25843124 TI - A cluster of lead poisoning among consumers of Ayurvedic medicine. AB - BACKGROUND: Use of alternative medications and herbal remedies is widespread in the United States and across the globe. These traditional medications can be contaminated with toxic metals. Despite several case reports of poisoning from such contamination, the epidemiological data are still limited. OBJECTIVES: To report on a cluster of lead and mercury toxicity cases in 2011 among a community of adherents of traditional medical practice of Ayurveda. METHODS: Adherents of Ayurveda were offered heavy metals screening following the identification of the index case. RESULTS: Forty-six of 115 participants (40%) had elevated blood lead levels (BLLs) of 10 MUg/dl or above, with 9.6% of BLLs at or above 50 MUg/dl. CONCLUSIONS: This is the largest cluster of lead and mercury toxicity following use of Ayurvedic supplements described in the literature in the US. Contamination of herbal products is a public health issue of global significance. There are few regulations addressing contamination of "natural" products or supplements. PMID- 25843125 TI - Positron-emission tomography molecular imaging of glia and myelin in drug discovery for multiple sclerosis. AB - INTRODUCTION: Therapies acting on glial cells are being explored for new drug development for multiple sclerosis. Molecular imaging using positron-emission tomography (PET) could address relevant questions in early phase clinical trials. AREAS COVERED: In this article, the authors critically review human PET methods that can be applied in specialised centres for imaging activated microglia and astrocytes and myelin. EXPERT OPINION: Strengths of PET lie in the molecular selectivity, sensitivity and potential for absolute quantitation. Even now, translocator protein PET radioligands could be used in exploratory studies for interventions targeting brain microglial activation. The clinical and neuropathological meaningfulness of signal from PET radioligands reporting on astrocyte activation through cellular expression of either monoamine oxidase B or the I2-imidazoline receptor or metabolism of [(11)C]acetate can now explored. [(11)C] N-methyl-4,4'-diaminostilbene, a PET marker for myelin, could soon enter first human trials. However, use of any of these PET glial markers demands a well focused hypothesis and a commitment to validation in the context of use. Enhanced access to these radioligands, standardisation of analyses and lowering the costs of using them are needed if their full promise is to be realised. PMID- 25843126 TI - Multilayer flow modulator stent technology: a treatment revolution for US patients? AB - Thoracoabdominal aortic repair is a high-risk procedure in most experienced centers, not only because of anatomical complexity but also due to the fragility of the patients in whom these aneurysms occur. Such repairs are complex, time consuming and impose a systemic injury upon the patients, regardless of whether the repair is performed by open surgery or via a fenestrated/branched technique. The substantive risks associated with such repairs include death, dialysis and paralysis. The multilayer flow modulator (MFM) is a disruptive technology which promises a minimally invasive reproducible treatment option, with clinical results demonstrating physiological modulation of the aortic sac with abolition of spinal injury. The mode of action of MFM forces us to completely rethink aneurysm pathogenesis and, consequently, it has been met with much cynicism. We aim to uncloak some of the mystery surrounding the MFM, clarify its mode of action and explore the truth behind its clinical effectiveness. PMID- 25843127 TI - Artificial neuron-glia networks learning approach based on cooperative coevolution. AB - Artificial Neuron-Glia Networks (ANGNs) are a novel bio-inspired machine learning approach. They extend classical Artificial Neural Networks (ANNs) by incorporating recent findings and suppositions about the way information is processed by neural and astrocytic networks in the most evolved living organisms. Although ANGNs are not a consolidated method, their performance against the traditional approach, i.e. without artificial astrocytes, was already demonstrated on classification problems. However, the corresponding learning algorithms developed so far strongly depends on a set of glial parameters which are manually tuned for each specific problem. As a consequence, previous experimental tests have to be done in order to determine an adequate set of values, making such manual parameter configuration time-consuming, error-prone, biased and problem dependent. Thus, in this paper, we propose a novel learning approach for ANGNs that fully automates the learning process, and gives the possibility of testing any kind of reasonable parameter configuration for each specific problem. This new learning algorithm, based on coevolutionary genetic algorithms, is able to properly learn all the ANGNs parameters. Its performance is tested on five classification problems achieving significantly better results than ANGN and competitive results with ANN approaches. PMID- 25843128 TI - Potential pharmacological interventions against hematotoxicity: an overview. AB - Various treatment regimens, including chemotherapy, are known to induce heavy oxidative stress on the system, which in turn leads to adverse effects on healthy tissues. Blood being prone to oxidative stress is affected the most. At this juncture, it might not be prudent to anticipate having chemotherapeutic agents with no hematotoxicity; the best way forward is to look for potential anti hematotoxic compounds, which could be supplemented to exposed patients, thus reducing the toxic burden on blood cells. We mined existing literature for reviewing possible interventions against hematotoxicity and figured that there is a great lacuna in this field in terms of not having such useful information at one place. This review presents the possible entities based on their antioxidant potentials, including their mechanistic pathways. PMID- 25843129 TI - Diabetic cardiomyopathy and the role of mitochondrial dysfunction: novel insights, mechanisms, and therapeutic strategies. AB - This Forum addresses the role of mitochondrial dysfunction in the multifactorial nature of diabetic cardiomyopathy (DCM) from multiple angles. Contributors deliver a diverse and in-depth view of the state-of-the-art in DCM, from bench to bedside. What emerges is a picture of mitochondrial dysfunction as a central upstream defect, inflicted on the heart by diabetes. Collectively, the authors pinpoint high-value knowledge gaps, propose new conceptual frameworks, and highlight understudied, but promising, research themes. PMID- 25843130 TI - Comparison of the Potential for Different Genetic Forms in the Culex pipiens Complex in North America to Transmit Rift Valley Fever Virus. AB - Rift Valley fever virus (RVFV), a mosquito-borne virus, has been responsible for large outbreaks in Africa that have resulted in hundreds of thousands of human infections and major economic disruption due to loss of livestock and to trade restrictions. Culex pipiens was implicated as the principal vector of the Egyptian outbreak in 1977 that affected about 200,000 people. In the northern USA, Cx. pipiens occurs both as a mix of forms pipiens and molestus (i.e., US Culex pipiens) as well as pure Cx. pipiens form molestus, the latter mostly in underground locations such as sewers and basements. In order to understand the potential risk of spread of RVFV in the USA, we compared their relative abilities to transmit RVFV in the laboratory. After feeding on hamsters with high viremias, >10(9) plaque-forming units (PFU)/ml, both US Cx. pipiens and Cx. pipiens form molestus were highly susceptible to infection (~80%) and about 20% of each form developed a disseminated infection. In contrast, when fed on a hamster with a moderate viremia, 10(7.5) PFU/ml, US Cx. pipiens were significantly (P < 0.001) more susceptible (84%) than were the pure form molestus (47%). Similarly, dissemination rates were significantly (P = 0.0261) higher in US Cx. pipiens (34%) than they were in pure Cx. pipiens form molestus (10%). These results underscore differences in vector competence between genetic forms in the Cx. pipiens complex but also indicate that if RVFV were to arrive in the USA, competent vectors abound in the highly urbanized Northeast. PMID- 25843131 TI - Mosquito biodiversity patterns around urban environments in South-central okinawa island, Japan. AB - Okinawa is the largest, most urbanized, and densely populated island in the Ryukyus Archipelago, where mosquito species diversity has been thoroughly studied. However, the south-central Okinawa mosquito fauna has been relatively poorly studied. Here, we present results from a mosquito faunal survey in urban environments of Nishihara city, south-central Okinawa. Mosquitoes were sampled biweekly, from April 2007 to March 2008, at 3 different environments: a forest preserve, an animal farm, and a water reservoir. We employed 4 mosquito collection methods: 1) oviposition traps; 2) light traps; 3) sweep nets; and 4) larval surveys of tree holes, leaf axils, and artificial water containers. We collected a total of 568 adults and 10,270 larvae belonging to 6 genera and 13 species, including 6 species of medical importance: Aedes albopictus, Armigeres subalbatus, Anopheles Hyrcanus group, Culex bitaeniorhynchus, Cx. quinquefasciatus, and Cx. tritaeniorhynchus. Mosquito species composition was similar to data from previous studies in Okinawa Island. The flattening of the species accumulation curve suggests that our diversity sampling was exhaustive with light and oviposition traps, as well as the coincidence between the species richness we found in the field and estimates from the Chao2 index, a theoretical estimator of species richness based on species abundance. This study highlights the importance of combining several sampling techniques to properly characterize regional mosquito fauna and to monitor changes in the presence of mosquito species. PMID- 25843132 TI - Immature mosquitoes in bamboo internodes in municipal parks, city of sao paulo, Brazil. AB - We conducted an inventory of the mosquito fauna of the internodes of bamboo plants grown in municipal parks in the city of Sao Paulo, Brazil. During October 2010 to July 2013, a total of 8,541 immature stages belonging to 21 mosquito species were collected from bamboos over 61 municipal parks. Of these, Aedes albopictus was the most abundant species followed by Ae. aegypti found in broken bamboos in most parks. The former species was 7.2 times more abundant than the latter when both species shared the same habitat. Other species collected from bamboos included Culex quinquefasciatus and Haemagogus leucocelaenus. In bamboos with perforated internodes, species of the genus Wyeomyia were the most prevalent. Differences were also observed in species composition and abundance of mosquitoes collected in transversely broken bamboos and those collected from perforated bamboo internodes. Constant surveillance of these breeding sites is crucial due to the epidemiological importance of the species found. Furthermore, these breeding sites may help maintain some native wild mosquito populations along with a variety of other invertebrates found in these urban green areas. PMID- 25843133 TI - Field assessment of yeast- and oxalic Acid-generated carbon dioxide for mosquito surveillance. AB - Carbon dioxide (CO2) sources improve the efficacy of mosquito traps. However, traditional CO2 sources (dry ice or compressed gas) may be difficult to acquire for vector surveillance during military contingency operations. For this reason, a new and convenient source of CO2 is required. Two novel CO2 generators were evaluated in order to address this capability gap: 1) an electrolyzer that converts solid oxalic acid into CO2 gas, and 2) CO2 produced by yeast as it metabolizes sugar. The flow rate and CO2 concentration produced by each generator were measured, and each generator's ability to attract mosquitoes to BG SentinelTM traps during day surveillance and to Centers for Disease Control and Prevention light traps with incandescent bulbs during night surveillance was compared to dry ice and compressed gas in Jacksonville, FL. The electrolyzed oxalic acid only slightly increased the number of mosquitoes captured compared to unbaited traps. Based on the modest increase in mosquito collection for traps paired with the oxalic acid, it is not a suitable stand-in for either of the 2 traditional CO2 sources. Conversely, the yeast-generated CO2 resulted in collections with mosquito abundance and species richness more closely resembling those of the traditional CO2 sources, despite achieving a lower CO2 flow rate. Therefore, if dry ice or compressed gas cannot be acquired for vector surveillance, yeast-generated CO2 can significantly improve trap capability. PMID- 25843134 TI - Laboratory and Field Evaluations of Mosquiron(r) 0.12CRD, a New Formulation of Novaluron, Against Culex Mosquitoes. AB - Laboratory and field evaluations were conducted to assess the activity and efficacy of Mosquiron(r) 0.12CRD, a new formulation containing 0.12% novaluron, against immature Culex mosquitoes. In laboratory bioassays, this formulation was highly active against Culex quinquefasciatus as indicated by low inhibition of emergence (IE) values (IE50 and IE90). When Mosquiron 0.12CRD was applied at 1 briquet per underground stormwater vault, counts of late instars showed a significant reduction on day 28 posttreatment. When the late instars and pupae collected from Mosquiron-treated water were brought back to the laboratory for posttreatment observation, emergence inhibition was >90% on day 7. When the late instars from a laboratory colony of Cx. quinquefasciatus were exposed to the Mosquiron-treated water, 99% and 95% emergence inhibition was noted on day 7 and day 14, respectively. When Mosquiron 0.12CRD was applied at 11 briquets per vault, significant reductions of larval populations were encountered on days 7 and 35 posttreatment for early instars, and on days 14, 21, and 35 posttreatment for late instars. Laboratory observation of late instars and pupae sampled from the treated vault water showed nearly complete emergence inhibition from day 7 to day 28 posttreatment. A similar trend was observed in laboratory-reared late instars of Cx. quinquefasciatus when exposed to the treated water. Preliminary evaluations indicated that Mosquiron 0.12CRD is a useful new tool to control Culex mosquitoes breeding in persistent sources. PMID- 25843135 TI - Truck-Mounted Area-Wide Application of Pyriproxyfen Targeting Aedes aegypti and Aedes albopictus in Northeast Florida. AB - This study was conducted to determine the efficacy of truck-mounted ultra-low volume applications of pyriproxyfen against Aedes aegypti larvae in artificial water containers and wild adult Ae. albopictus populations in an urban setting. The study was conducted over a 3.5-month period (June-October 2012), during which 3 pyriproxyfen applications were conducted. Beginning 6 wk prior to the 1st pyriproxyfen spray, 10 Biogents-Sentinel(r) traps were used each week to survey the adult Ae. albopictus population at each experimental plot through the end of the study. The treatment and control plots contained specimen cups, each containing 10 laboratory-reared Ae. aegypti larvae, placed at 8, 15, and 23 m from the spray line. Emergence inhibition (EI) of 82% or greater was observed among Ae. aegypti larvae exposed to the 3 pyriproxyfen sprays. The EI of these same Ae. aegypti larvae at the 3 distances from the spray ranged from 84% to 92% and were not significantly different. Laboratory analysis of water samples taken from the larval cups independently confirmed the presence of pyriproxyfen. Similar levels of EI were achieved in Ae. aegypti and Ae. albopictus larvae when the measured field concentrations of pyriproxyfen were recreated in laboratory assays. Trap captures of wild adult Ae. albopictus were not markedly reduced following the 1st pyriproxyfen spray, perhaps due to heavy rainfall at the time and the lower rate of pyriproxyfen applied. Within 2 wk following Spray 2, however, Ae. albopictus collections from the treatment plot averaged approximately 50% of those from the control plot, and the reduction trend continued following Spray 3. PMID- 25843136 TI - Insecticide Resistance and Metabolic Mechanisms Involved in Larval and Adult Stages of Aedes aegypti Insecticide-Resistant Reference Strains from Cuba. AB - Studies were conducted to compare levels of insecticide resistance and to determine the metabolic resistance mechanisms in larval and adult stages of Aedes aegypti from Cuba. Three insecticide-resistant reference strains of Ae. aegypti from Cuba were examined. These strains were derived from a Santiago de Cuba strain isolated in 1997; it was previously subjected to a strong selection for resistance to temephos (SAN-F6), deltamethrin (SAN-F12), and propoxur (SAN-F13) and routinely maintained in the laboratory under selection pressure up to the present time, when the study was carried out. In addition, an insecticide susceptible strain was used for comparison. The insecticide resistance in larvae and adults was determined using standard World Health Organization methodologies. Insecticide resistance mechanisms were determined by biochemical assays. The esterases (alpha EST and beta EST) and mixed function oxidase (MFO) activities were significantly higher in adults than in the larvae of the three resistant strains studied. The association of resistance level with the biochemical mechanism for each insecticide was established for each stage. The observed differences between larval and adult stages of Ae. aegypti in their levels of insecticide resistance and the biochemical mechanisms involved should be included as part of monitoring and surveillance activities in Ae. aegypti vector control programs. PMID- 25843138 TI - Host feeding patterns of mosquitoes in a rural malaria-endemic region in hainan island, china. AB - Malaria is endemic in Wangxia Village of Hainan Island. In this area little is known about the host seeking behavior and feeding habit of mosquitoes. Three sites representing the most common habitat types in the village were selected to study the host seeking behavior and feeding habit of mosquitoes. Of the total 9 species belonging to 4 genera (Armigeres, Culex, Aedes, and Anopheles) collected in Wangxia Village, Culex tritaeniorhynchus and Cx. pipiens quinquefasciatus were the most commonly collected species. Armigeres subalbatus and Anopheles sinensis were moderately common species. Blood meal analysis confirmed that Cx. tritaeniorhynchus and Cx. p. quinquefasciatus fed on multiple hosts, mainly poultry but occasionally other animals. Anopheles sinensis, a vector of malaria, fed predominately on cattle hosts, followed by humans. Anopheles maculatus and An. barbirostris fed on both humans and domestic animals. Our results indicate that most mosquitoes in this area preferred domestic animals over humans and showed a tendency to feed on multiple hosts within the same gonotrophic cycle. Therefore, the potential role of domestic animals in arbovirus transmission should be evaluated as part of a strategy for controlling mosquito-borne diseases in this region. PMID- 25843137 TI - First Record of Aedes stimulans from Louisiana. AB - The first confirmed collection of Aedes stimulans in Louisiana was made in St. Tammany Parish, LA. A single adult female was collected by a large-bore aspirator in March 2011, and identified by microscopic and molecular methods. Notes are provided on the morphology, location, habitat, and potential mosquito associates that may be found with Ae. stimulans. PMID- 25843139 TI - The landing of field mosquitoes on permethrin-treated military uniforms in queensland, australia. AB - A study to evaluate the protection provided by permethrin-treated military fabric following cold-water washing against host-seeking mosquitoes is reported. The landing/probing of native mosquitoes on Australian Defence Force Disruptive Pattern Combat Uniform shirts treated by dipping in 0.6% permethrin emulsion (Perigen Defence(r), containing 500 g/l permethrin), and commercial factory treatments in the USA (Factory A) and Europe (Factory B) were recorded after 0, 1, 3, 5, and 10 washes. The study showed that significantly shorter landing/probing times compared with untreated controls were recorded for shirts treated with Factory A treatment after 0 and 1 wash, and for the Factory B treatment after 0 washes, and there were no differences between permethrin treatment and control landing. The study concludes that better methods to assess protection from landing/probing mosquitoes in the field are needed. PMID- 25843140 TI - Jorge R. Arias. PMID- 25843141 TI - American mosquito control association annual board of directors meeting in Seattle, washington-february 1, 2014. PMID- 25843142 TI - American mosquito control association annual board of directors meeting in Seattle, washington-february 6, 2014. PMID- 25843144 TI - Bio-molecule assisted aggregation of ZnWO4 nanoparticles (NPs) into chain-like assemblies: material for high performance supercapacitor and as catalyst for benzyl alcohol oxidation. AB - ZnWO4 nanoparticles (NPs) that are assembled and aggregated together as chain like morphology have been synthesized via the reaction of Zn(II) salt solution with sodium tungstate in the presence of the DNA scaffold under 5 min of microwave heating. The reaction parameters have been tuned to control the size of the individual particles and diameter of the chains. The significance of different reaction parameters and specific growth mechanism for the formation of particles is elaborated. The DNA-ZnWO4 nanoassemblies have been used in two potential applications for the first time, namely, supercapacitor and catalysis studies. Supercapacitor study revealed that DNA-ZnWO4 nanoassemblies exhibited good electrochemical properties having high specific capacitance value ~72 F/g at 5 mV s(-1), and electrodes possessed a good cyclic stability with more than 1000 consecutive times of cycling. Catalysis studies have been done for benzyl alcohol oxidation, and it was observed that DNA-ZnWO4 nanoassemblies having smaller diameter gives better catalytic efficiency compared to other morphology. This is further authenticated from their BET surface area analysis. In the future, the self-assembled DNA-ZnWO4 nanoassemblies could be a promising candidate for the synthesis of other mixed metal oxides and should be applicable in various emerging fields like Li ion batteries or photocatalysis, or as luminescent materials. PMID- 25843146 TI - Organic contamination of highly oriented pyrolytic graphite as studied by scanning electrochemical microscopy. AB - Highly oriented pyrolytic graphite (HOPG) is an important electrode material as a structural model of graphitic nanocarbons such as graphene and carbon nanotubes. Here, we apply scanning electrochemical microscopy (SECM) to demonstrate quantitatively that the electroactivity of the HOPG basal surface can be significantly lowered by the adsorption of adventitious organic impurities from both ultrapure water and ambient air. An SECM approach curve of (ferrocenylmethyl)trimethylammonium (FcTMA(+)) shows the higher electrochemical reactivity of the HOPG surface as the aqueous concentration of organic impurities, i.e., total organic carbon (TOC), is decreased from ~20 to ~1 ppb. SECM-based nanogap voltammetry in ~1 ppb-TOC water yields unprecedentedly high standard electron-transfer rate constants, k(0), of >=17 and >=13 cm/s for the oxidation and reduction of the FcTMA(2+/+) couple, respectively, at the respective tip-HOPG distances of 36 and 45 nm. Anomalously, k(0) values and nanogap widths are different between the oxidation and reduction of the same redox couple at the same tip position, which is ascribed to the presence of an airborne contaminant layer on the HOPG surface in the noncontaminating water. This hydrophobic layer is more permeable to FcTMA(+) with less charge than its oxidized form so that the oxidation of FcTMA(+) at the HOPG surface results in the higher tip current and, subsequently, apparently narrower gap and higher k(0). Mechanistically, we propose that HOPG adsorbs organic impurities mainly from ambient air and then additionally from ~20 ppb-TOC water. The latter tightens a monolayer of airborne contaminants to yield lower permeability. PMID- 25843145 TI - Improving resveratrol bioaccessibility using biopolymer nanoparticles and complexes: impact of protein-carbohydrate maillard conjugation. AB - The impact of encapsulating resveratrol in biopolymer nanoparticles or biopolymer complexes on its physicochemical stability and bioaccessibility was determined. The biopolymer nanoparticles consisted of a zein core surrounded by a caseinate or caseinate-dextran shell. The biopolymer complexes consisted of resveratrol bound to caseinate or caseinate-dextran. The caseinate-dextran conjugates were formed using the Maillard reaction. Both the biopolymer nanoparticles and complexes protected trans-resveratrol from isomerization when exposed to UV light, with the nanoparticles being more effective. Nanoparticles coated by caseinate-dextran were more stable to aggregation under simulated gastrointestinal conditions than those coated by caseinate, presumably due to greater steric repulsion. The bioaccessibility of resveratrol was enhanced when it was encapsulated in both biopolymer nanoparticles and biopolymer complexes. These results have important implications for the development of effective delivery systems for incorporating lipophilic nutraceuticals into functional foods and beverages. PMID- 25843147 TI - Structural and compositional characterization of the adhesive produced by reef building oysters. AB - Oysters have an impressive ability to overcome difficulties of life within the stressful intertidal zone. These shellfish produce an adhesive for attaching to each other and building protective reef communities. With their reefs often exceeding kilometers in length, oysters play a major role in balancing the health of coastal marine ecosystems. Few details are available to describe oyster adhesive composition or structure. Here several characterization methods were applied to describe the nature of this material. Microscopy studies indicated that the glue is comprised of organic fiber-like and sheet-like structures surrounded by an inorganic matrix. Phospholipids, cross-linking chemistry, and conjugated organics were found to differentiate this adhesive from the shell. Symbiosis in material synthesis could also be present, with oysters incorporating bacterial polysaccharides into their adhesive. Oyster glue shows that an organic inorganic composite material can provide adhesion, a property especially important when constructing a marine ecosystem. PMID- 25843151 TI - Serum Lipid Goal Attainment in Chronic Kidney Disease (CKD) Patients under the Japan Atherosclerosis Society (JAS) 2012 Guidelines. AB - AIM: According to the Japan Atherosclerosis Society 2012 guidelines (JAS2012-GL), chronic kidney disease (CKD) has newly been added to the high-risk group in terms of atherosclerotic cardiovascular diseases. We therefore explored the lipid target level achievement rates under the JAS2012-GL in real-world clinical practice. METHODS: We retrospectively reviewed the medical charts of patients who were hospitalized at the Nephrology Department at Kobe City Medical Center General Hospital in the period from April 1, 2012 to May 31, 2013 and explored the serum lipid target level achievement rates. Patients without lipid data or those undergoing regular dialysis because of chronic renal failure were excluded. In this study, the CKD group (CKD-G) did not include CKD patients under secondary prevention for coronary heart disease (CHD) or diabetes mellitus (DM). RESULTS: The CKD-G included 146 (81.1%) of the 180 enrolled patients. According to the JAS2012-GL, 100% of the CKD-G patients were categorized into the high-risk group, although only 12.1% of the CKD-G subjects were at high risk according to the JAS2007-GL. Under the JAS2012-GL, the LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) target level achievement rates for CKD-G were 71.4% and 68.1%, respectively. According to the JAS2007-GL, these rates were 81.3% and 79.1%, respectively, and, under both guidelines, these rates were 71.7% and 72.1% for primary prevention DM and 66.7% and 66.7% for CHD, respectively. CONCLUSIONS: After the revision of the JAS-GL in 2012, the LDL-C and non-HDL-C target level achievement rates for CKD-G were reduced by approximately 10%; however, they remained similar to those for DM and higher than those for CHD. PMID- 25843152 TI - Genetic Diagnosis via Whole Exome Sequencing in Taiwanese Patients with Hypertriglyceridemia. AB - AIM: Whole exome sequencing (WES) is a recently developed method for discovering rare mutations associated with hereditary disorders. However, the feasibility and utilization of this method in identifying familial hypertriglyceridemia is not well known. The purpose of the study was to identify the genetic locus that causes hypertriglyceridemia and assess its prevalence in Taiwanese subjects with hypertriglyceridemia. METHODS: We performed WES among two individuals with hypertriglyceridemia and one control subject in an index family (22 members). Based on the WES findings, we extended the study to genotype 65 unrelated adult index patients with a fasting serum triglyceride level of > 500 mg/dL and 125 normal controls using polymerase chain reaction. RESULTS: Using WES alignment, variant calling and annotation, 15 presumptive causal variants were initially identified, including 13 cases by the autosomal dominant model and two cases by the autosomal recessive model. Only APOA5 c.553 G > T (rs2075291), resulting in the amino acid mutation Gly185Cys, co-segregated well with hypertriglyceridemia in terms of autosomal recessive inheritance (homozygote TT: mean triglyceride level: 1,071 mg/dL vs non TT (GT and GG): mean triglyceride level: 118 mg/dL; p < 0.001) in the index family. In the unrelated cohorts, the frequency of the TT genotype of rs2075291 was 12.3% in the hypertriglyceridemic group; however, no TT genotype was found in the control group. CONCLUSIONS: Our results demonstrate that WES is feasible for identifying the genetic locus that causes hypertriglyceridemia. The TT genotype of APOA5 c.553G > T acts as an important indicator of hypertriglyceridemia in patients in Taiwan. PMID- 25843153 TI - Positional strategy of trunk muscles among aquatic, semi-aquatic and terrestrial species in Urodela. AB - Clarification of the trunk structure in Urodela is important in understanding the locomotive evolution of basal tetrapods. The components of the muscular trunk wall among Urodela using different modes of locomotion were compared. Since the whole trunk may be used for swimming and the effect of limbs may be small in the more aquatic species, they showed smaller differences in the trunk muscles among anterior, middle and posterior sections of the trunk. By contrast, in the more terrestrial species, the dorsal and abdominal muscles are larger in the middle section than those in the anterior and posterior sections. High compressive stresses occur in the supporting limbs and their insertion at the trunk on the ventral side, and spread from the forelimbs along the back to the supporting hindlimbs on the dorsal side. Tensile stresses occur in the middle ventral part. The components of the trunk muscles among the three sections may reflect differences in stresses occurring in the trunk of the more terrestrial species. The findings also suggest that in the middle section, larger dorsal muscles for stiffening the back to maintain posture and larger abdominal muscles are responsible for balancing the body weight while it is supported by the limbs in the more terrestrial species. PMID- 25843154 TI - Use of S1 nuclease in deep sequencing for detection of double-stranded RNA viruses. AB - Metagenomic approach using next-generation DNA sequencing has facilitated the detection of many pathogenic viruses from fecal samples. However, in many cases, majority of the detected sequences originate from the host genome and bacterial flora in the gut. Here, to improve efficiency of the detection of double-stranded (ds) RNA viruses from samples, we evaluated the applicability of S1 nuclease on deep sequencing. Treating total RNA with S1 nuclease resulted in 1.5-28.4- and 10.1-208.9-fold increases in sequence reads of group A rotavirus in fecal and viral culture samples, respectively. Moreover, increasing coverage of mapping to reference sequences allowed for sufficient genotyping using analytical software. These results suggest that library construction using S1 nuclease is useful for deep sequencing in the detection of dsRNA viruses. PMID- 25843155 TI - Establishment of optimal scan delay for multi-phase computed tomography using bolus-tracking technique in canine pancreas. AB - To establish a protocol for a multi-phase computed tomography (CT) of the canine pancreas using the bolus-tracking technique, dynamic scan and multi-phase CT were performed in six normal beagle dogs. The dynamic scan was performed for 60 sec at 1-sec intervals after the injection (4 ml/sec) of a contrast medium, and intervals from aortic enhancement appearance to aortic, pancreatic parenchymal and portal vein peaks were measured. The multi-phase CT with 3 phases was performed three times using a bolus-tracking technique. Scan delays were 0, 15 and 30 in first multi-phase scan; 5, 20 and 35 in second multi-phase scan; and 10, 25 and 40 sec in third multi-phase scan, respectively. Attenuation values and contrast enhancement pattern were analyzed from the aorta, pancreas and portal vein. The intervals from aortic enhancement appearance to aortic, pancreatic parenchymal and portal vein peaks were 3.8 +/- 0.7, 8.7 +/- 0.9 and 13.3 +/- 1.5 sec, respectively. The maximum attenuation values of the aorta, pancreatic parenchyma and portal vein were present at scan sections with no scan delay, a 5 sec delay and a 10-sec delay, respectively. When a multi-phase CT of the canine pancreas is triggered at aortic enhancement appearance using a bolus-tracking technique, the recommended optimal delay times of the arterial and pancreatic parenchymal phases are no scan delay and 5 sec, respectively. PMID- 25843156 TI - Motor vehicle driving in high incidence psychiatric disability: comparison of drivers with ADHD, depression, and no known psychopathology. AB - Although not often discussed in clinical settings, motor vehicle driving is a complex multitasking endeavor during which a momentary attention lapse can have devastating consequences. Previous research suggests that drivers with high incidence psychiatric disabilities such as ADHD contribute disproportionately to collision rates, which in turn portend myriad adverse social, financial, health, mortality, and legal outcomes. However, self-referral bias and the lack of psychiatric comparison groups constrain the generalizability of these findings. The current study addressed these limitations and examined the unique associations among ADHD, Depression, and adverse driving outcomes, independent of self-selection, driving exposure, and referral bias. The Strategic Highway Research Program (SHRP-2) Naturalistic Driving Study comprises U.S. drivers from six sites selected via probability-based sampling. Groups were defined by Barkley ADHD and psychiatric diagnosis questionnaires, and included ADHD (n = 275), Depression (n = 251), and Healthy Control (n = 1828). Primary outcomes included self-reported traffic collisions, moving violations, collision-related injuries, and collision fault (last 3 years). Accounting for demographic differences, ADHD but not Depression portended increased risk for multiple violations (OR = 2.3) and multiple collisions (OR = 2.2). ADHD but not Depression portended increased risk for collision fault (OR = 2.1). Depression but not ADHD predicted increased risk for self-reported injury following collisions (OR = 2.4). ADHD appears uniquely associated with multiple collisions, multiple violations, and collision fault, whereas Depression is uniquely associated with self-reported injury following a collision. Identification of the specific mechanisms underlying this risk will be critical to designing effective interventions to improve long-term functioning for drivers with high incidence psychiatric disability. PMID- 25843157 TI - Common variants of IRF3 conferring risk of schizophrenia. AB - Schizophrenia is a brain disorder with high heritability. Recent studies have implicated genes involved in the immune response pathway in the pathogenesis of schizophrenia. Interferon regulatory factor 3 (IRF3), a virus-immune-related gene, activates the transcription of several interferon-induced genes, and functionally interacts with several schizophrenia susceptibility genes. To test whether IRF3 is a schizophrenia susceptibility gene, we analyzed the associations of its SNPs with schizophrenia in independent population samples as well as reported data from expression quantitative trait loci (eQTL) in healthy individuals. We observed multiple independent SNPs in IRF3 showing nominally significant associations with schizophrenia (P < 0.05); more intriguingly, a SNP (rs11880923), which is significantly correlated with IRF3 expression in independent samples (P < 0.05), is also consistently associated with schizophrenia across different cohorts and in combined samples (odds ratio = 1.075, Pmeta = 2.08 * 10(-5)), especially in Caucasians (odds ratio = 1.078, Pmeta = 2.46 * 10(-5)). These results suggested that IRF3 is likely a risk gene for schizophrenia, at least in Caucasians. Although the clinical associations of IRF3 with diagnosis did not achieve genome-wide level of statistical significance, the observed odds ratio is comparable with other susceptibility loci identified through large-scale genetic association studies on schizophrenia, which could be regarded simply as small but detectable effects. PMID- 25843158 TI - Targeting the adaptive immune system: new strategies in the treatment of atherosclerosis. AB - Atherosclerosis is a lipid-driven chronic inflammatory disease of the arterial wall. Current treatment of atherosclerosis is focused on limiting its risk factors, such as hyperlipidemia or hypertension. However, treatments that target the inflammatory nature of atherosclerosis are still under development. Discovery of novel targets involved in the inflammation of the arterial wall creates opportunities to design new therapeutics that successfully modulate atherosclerosis. Here, we review drug targets that have proven to play pivotal roles in the adaptive immune system in atherosclerosis, and we discuss their potential as novel therapeutics. PMID- 25843159 TI - The biomarkers of fetal growth in intrauterine growth retardation and large for gestational age cases: from adipocytokines to a metabolomic all-in-one tool. AB - Adipose tissue is no longer considered as inert; the literature describes the role it plays in the production of many substances, such as adiponectin, visfatin, ghrelin, S100B, apelin, TNF, IL-6 and leptin. These molecules have specific roles in humans and their potential as biomarkers useful for identifying alterations related to intrauterine growth retardation and large for gestational age neonates is emerging. Infants born in such conditions have undergone metabolic changes, such as fetal hypo- or hyperinsulinemia, which may lead to development of dysmetabolic syndrome and other chronic diseases in adulthood. In this review, these biomarkers are analyzed specifically and it is discussed how metabolomics may be an advantageous tool for detection, discrimination and prediction of metabolic alterations and diseases. Thus, a holistic approach, such as metabolomics, could help the prevention and early diagnosis of metabolic syndrome. PMID- 25843160 TI - Advances in lipid-based drug delivery: enhancing efficiency for hydrophobic drugs. AB - INTRODUCTION: Many drug candidates with high therapeutic efficacy have low water solubility, which limits the administration and transport across physiological barriers, for example, the tumor tissue barrier. Therefore, strategies are needed to permeabilize the physiological barriers safely so that hydrophobic drugs may be delivered efficiently. AREAS COVERED: This review focuses on prospects for therapeutic application of lipid-based drug delivery carriers that increase hydrophobic drugs to improve their solubility, bioavailability, drug release, targeting and absorption. Moreover, novel techniques to prepare for lipid-based drug delivery to extend pharmaceuticals with poor bioavailability such as surface modifications of lipid-based drug delivery are presented. Industrial developments of several drug candidates employing these strategies are discussed, as well as applications and clinical trials. EXPERT OPINION: Overall, hydrophobic drugs can be encapsulated in the lipid-based drug delivery systems, represent a relatively safe and promising strategy to extend drug retention, lengthen the lifetime in the circulation, and allow active targeting to specific tissues and controllable drug release in the desirable sites. However, there are still noticeable gaps that need to be filled before the theoretical advantage of these formulations may truly be realized such as investigation on the use of lipid-based drug delivery for administration routes. This research may provide further interest within the area of lipid-based systems, both in industry and in the clinic. PMID- 25843161 TI - Male gender is an adverse risk factor only in young patients with diffuse large B cell lymphoma - a Swedish population-based study. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. Five clinical adverse risk factors are merged into the International Prognostic Index (IPI), which is the major tool for prognostication. In contrast to Hodgkin's lymphoma, gender is not considered as an adverse risk factor for DLBCL patients. As we clinically had observed a very good survival rate in young female patients we hypothesised that there was a gender difference in survival due to the hormonal status of the patient. MATERIAL AND METHODS: We conducted a registry-based retrospective cohort study of all Swedish DLBCL patients diagnosed between 2000 and 2013, to evaluate the impact of gender for survival from DLBCL. RESULTS: In total, 7166 patients were included for further analysis. No survival difference was found between the genders when the entire population was analysed. However, analysis of 880 young patients of pre-menopausal age (i.e. 52 years) revealed that women had a longer survival compared to men of the same age group (p=0.007). This was not found for patients older than menopausal age. In a relative survival multifactorial model adjusted for stage, ECOG performance status, serum lactate dehydrogenase and two or more extranodal sites, male gender was found to be an adverse risk factor for patients younger than 52 years (RR 1.51, 95% CI 1.14-1.88), but not for older patients (RR 0.99, 95% CI 0.89-1.10). CONCLUSION: This is one of the largest population-based studies of DLBCL presented to date. Most interestingly, we found male gender to be a significant adverse risk factor compared to fertile women whereas we found no survival differences between genders in the older sub-population. PMID- 25843162 TI - Hypogammaglobulinemia with normal antibody response progressing to common variable immunodeficiency. PMID- 25843163 TI - Desensitization to mecasermin in an insulin-like growth factor 1-deficient patient. PMID- 25843164 TI - Association between adverse childhood experiences in the home and pediatric asthma. AB - BACKGROUND: Numerous studies suggest that psychosocial factors could contribute to pediatric asthma. OBJECTIVE: To examine the relation between single and cumulative adverse childhood experiences (ACEs), a measurement of household dysfunction, on parent report of lifetime asthma in children. METHODS: This cross sectional study used data from the 2011 to 2012 National Survey of Children's Health, a nationally representative sample of children 0 to 17 years old (n = 92,472). The main exposure was parent or guardian report of 6 ACE exposures (eg, witnessing domestic violence). The relation between ACE exposures and parent reported diagnosis of childhood asthma was examined using multivariable logistic regression after controlling for demographic, socioeconomic, and behavioral covariates. RESULTS: Overall asthma prevalence was 14.6%. Exposure prevalence to any ACE was 29.2%. Increased number of ACE exposures was associated with increased odds of asthma. In the adjusted model, the odds of reporting asthma were 1.28 (95% confidence interval [CI] 1.14-1.43) for those reporting 1 ACE, 1.73 (95% CI 1.27-2.36) for those with 4 ACEs, and 1.61 (95% CI 1.15-2.26) for those with 5 or 6 ACEs compared with those with no ACE exposures. Effects were moderated by Hispanic ethnicity. Hispanic children exposed to 4 ACEs had a 4.46 times increase in lifetime asthma (95% CI 2.46-8.08); white children had a 1.19 times increase (95% CI 0.80-1.79) compared with those exposed to 0 ACE. CONCLUSION: This study supports the growing evidence for the biopsychosocial model of asthma onset. Future studies should examine the association between ACEs and specific asthma-related health outcomes. PMID- 25843165 TI - Dilemmas in diagnosing and managing hypertension: is white coat hypertension benign? PMID- 25843166 TI - Limitations of home blood pressure monitoring in clinical practice. PMID- 25843167 TI - The new pooled cohort equations risk calculator. AB - In the National Cholesterol Education Program Adult Treatment Panel III guidelines published in 2001, estimation of cardiovascular risk was recommended based on the Framingham score for 10-year risk of myocardial infarction and the Canadian Cardiovascular Society currently recommends the Framingham total cardiovascular risk score. During development of joint guidelines released in 2013 by the American College of Cardiology (ACC) and American Heart Association (AHA), the decision was taken to develop a new risk score. This resulted in the ACC/AHA Pooled Cohort Equations Risk Calculator. This risk calculator, based on major National Heart, Lung, and Blood Institute-funded cohort studies, is designed to predict 10-year risk of 'hard' atherosclerotic cardiovascular disease (ASCVD) events, namely, nonfatal myocardial infarction, fatal coronary heart disease, nonfatal, or fatal stroke. Considerable strengths are its inclusion of stroke as an end point and race as a characteristic, which allows better risk prediction especially in African-American individuals, plus provision of lifetime ASCVD risk estimates for adults aged 20-59 years. Notable omissions from the risk factors include chronic kidney disease and any measure of social deprivation. An early criticism of the Pooled Cohort Equations Risk Calculator has been its alleged overestimation of ASCVD risk which, if confirmed in the general population, is likely to result in statin therapy being prescribed to many individuals at lower risk than the intended 7.5% 10-year ASCVD risk threshold for treatment in the joint ACC/AHA cholesterol guidelines. In this review we discuss the development of the new risk calculator, its strengths and weaknesses, and potential implications for its routine use. PMID- 25843168 TI - Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation. AB - INTRODUCTION: Neutrophils can be induced to release DNA combined with histones. The resulting neutrophil extracellular trap (NET) provides a scaffold for growing hemostatic plug. Therefore, the NET formation may be inevitable in clinical conditions that are characterized by formation of vascular thrombi. Thus far, there have been no reports on the clinical significance of NET in disseminated intravascular coagulation (DIC). Therefore, we investigated circulating levels of NET in DIC and analyzed their potential values to assess coagulation severity and predict clinical outcome. METHODS: The plasma levels of DNA-histone complexes and double-stranded DNA (dsDNA), considered to be in vivo markers of NET, were measured in 199 patients suspected of having DIC and 20 healthy controls. RESULT: The circulating levels of DNA-histone complexes and dsDNA were significantly elevated in overt-DIC. The increased levels of these two markers correlated with the severity of coagulopathy including DIC score and D-dimer. Multivariable Cox regression analysis, adjusted for the conventional DIC markers, revealed that elevated DNA-histone complexes and dsDNA are poor independent prognostic markers. CONCLUSION: The circulating levels of NET release reflect the coagulation activation and adverse clinical outcomes in patients with DIC, thereby providing potential clinical relevance for mortality prediction in DIC. PMID- 25843169 TI - Group Exchange between Ketones and Carboxylic Acids through Directing Group Assisted Rh-Catalyzed Reorganization of Carbon Skeletons. AB - The Rh(I)-catalyzed direct reorganization of organic frameworks and group exchanges between carboxylic acids and aryl ketones was developed with the assistance of directing group. Biaryls, alkenylarenes, and alkylarenes were produced in high efficiency from aryl ketones and the corresponding carboxylic acids by releasing the other molecule of carboxylic acids and carbon monoxide. A wide range of functional groups were well compatible. The exchanges between two partners were proposed to take place on the Rh-(III) center of key intermediates, supported by experimental mechanistic studies and computational calculations. The transformation unveiled the new catalytic pathway of the group transfer of two organic molecules. PMID- 25843170 TI - Methods for detection of West Nile virus antibodies in mosquito blood meals. AB - We describe and compare 2 qualitative serologic techniques for detecting West Nile virus (WNV)-specific antibodies in mosquito blood meals. The techniques are the biotin microsphere immunoassay (b-MIA) and the inhibition platform of the VectorTestTM WNV antigen assay (VecTest-inhibition). To demonstrate the ability of these tests to detect WNV-neutralizing antibodies, we experimentally exposed feeding mosquitoes to blood containing 5 concentrations of 6B6C-1, a flavivirus neutralizing monoclonal antibody. Antibody concentrations were quantified using the 90% plaque-reduction neutralization test (PRNT90). After 24 h of blood-meal digestion at 22.5 degrees C, the threshold PRNT90 titer of detection was <=18 for b-MIA and <=50 for VecTest-inhibition. Both tests reliably detected antibodies in 3 of 3 blood meals that had been digested for up to 30 h, or were about 25% digested. The b-MIA was also applied to mosquitoes that had engorged on avian blood in Arizona following a WNV epidemic in 2010. There was no significant difference in the WNV antibody prevalence determined by b-MIA (52% of 71 avian blood meals) compared to the WNV-neutralizing antibody prevalence in birds determined by direct sampling (49% of 234 birds). VecTest-inhibition requires fewer resources and may be used in the field without a laboratory, but consumes the entire blood meal and relies on subjective interpretation of results. The b MIA requires a laboratory and sophisticated equipment and reagents. Results for b MIA are analyzed objectively and can be applied to mosquito blood meals with greater confidence than the VecTest-inhibition method and thus can contribute substantially to research and surveillance programs that would benefit from the detection of specific WNV antibodies in mosquito blood meals. PMID- 25843171 TI - Genetic Characterization of Esterase Activity Variants Associated with an Esterase Gene Amplification in a Strain of Culex pipiens from California. AB - In the Culex pipiens complex, a common mechanism of insecticide resistance is amplification of esterase genes leading to overproduction of detoxifying esterase enzymes. A number of electrophoretic esterase alleles have been identified, and in field populations individuals with the same esterase electromorph can exhibit a wide range of esterase enzyme activities. We isolated and characterized esterase activity variants associated with the esterase B1 electromorph from a field strain. A mating scheme was used to isolate chromosomes with esterase genes from the strain into 45 families. Twenty-six of the families received esterase genes from the field strain that conferred elevated esterase activity. Mean esterase activities in these families ranged from 43 to 695 nmoles alpha-naphthyl acetate hydrolyzed/min/mg protein. Variance components indicated that genetic variance (i.e., genetic differences among families) accounted for 77% of the total variation in esterase activity. A comparison of mean esterase activities indicated that there were at least 11 different esterase activity variants contributing to the observed genetic variation in esterase activity among the 26 families. The relevance of these results to understanding the dynamics of amplified esterase genes in populations is discussed. PMID- 25843172 TI - Evaluation of BG-Sentinel Trap as a Management Tool to Reduce Aedes albopictus Nuisance in an Urban Environment in Italy. AB - Since its introduction and establishment in Italy during the early 1990s, the Asian tiger mosquito, Aedes albopictus, has spread over large parts of Italy and other Mediterranean countries. Aedes albopictus is both a nuisance and a competent vector for various arthropod-borne pathogens. Although efficient traps for Ae. albopictus exist and are used for population monitoring, their use as a control tool has not yet been studied. We evaluated Biogents BG-Sentinel mosquito traps, used with the BG Lure, as control tools in northern Italy. The trial was performed as a controlled experiment in which 3 intervention sites, equipped with 7 or 8 BG-Sentinel traps each, were matched with 3 comparable control sites. Trap density ranged from 1 trap per 150 m2 to 1 per 350 m2. Mosquito populations were monitored at both the intervention and control sites with weekly human landing collections (HLC) and ovitraps. Between 64% and 87% fewer Ae. albopictus individuals were collected by HLC at the intervention sites with the BG-Sentinel mosquito traps, as compared to the untreated control sites. These results indicate that the sustained use and proper placement of efficient mosquito traps can significantly reduce Ae. albopictus biting pressure. PMID- 25843173 TI - Comparison of BG-Sentinel(r) Trap and Oviposition Cups for Aedes aegypti and Aedes albopictus Surveillance in Jacksonville, Florida, USA. AB - The BG-Sentinel(r) (BGS) trap and oviposition cups (OCs) have both proven effective in the surveillance of Aedes species. This study aimed to determine which of the 2 traps could best characterize the relative population sizes of Aedes albopictus and Aedes aegypti in an urban section of Jacksonville, FL. Until 1986, Ae. aegypti was considered the dominant container-breeding species in urban northeastern Florida. Since the introduction of Ae. albopictus, Ae. aegypti has become almost completely extirpated. In 2011, a resurgence of Ae. aegypti was detected in the urban areas of Jacksonville; thus this study initially set out to determine the extent of Ae. aegypti reintroduction to the area. We determined that the BGS captured a greater number of adult Ae. aegypti than Ae. albopictus, while OCs did not monitor significantly different numbers of either species, even in areas where the BGS traps suggested a predominance of one species over the other. Both traps were effective at detecting Aedes spp.; however, the BGS proved more diverse by detecting over 20 other species as well. Our results show that in order to accurately determine vectorborne disease threats and the impact of control operations on these 2 species, multiple trapping techniques should be utilized when studying Ae. aegypti and Ae. albopictus population dynamics. PMID- 25843174 TI - Macrocyclops albidus (Copepoda: cyclopidae) for the Biocontrol of Aedes albopictus and Culex pipiens in Italy. AB - The aim of our study was to assess the potential of Macrocyclops albidus as a biological control agent against the 1st and 2nd instars of Culex pipiens and Aedes albopictus. Under laboratory conditions of prey saturation (50 1st instars/copepod), an average of 58.98% of Cx. pipiens and 54.99% of Ae. albopictus larvae were killed by 1 copepod in 24 h. Trials run in big drums containing 200 liters of water showed that the M. albidus population, inoculated in April, efficiently controlled the mosquito population for the entire season. The predator was particularly effective against Ae. albopictus, as only 2 larvae of this species were found in the treated drums, compared to 814 larvae in untreated control drums throughout the study period. No difference was observed in the control efficacy between the 2 initial densities of copepods used. The reduction in Ae. albopictus density in the drums with 100 and 500 M. albidus with respect to the control drums was 99.90 +/- 0.35% and 100.0 +/- 0.0%, respectively. For Cx. pipiens, the reduction in density was 88.69 +/- 13.51% and 84.65% in drums inoculated with 100 and 500 copepods, respectively. Macrocyclops albidus populations survived through the winter and continued to keep the mosquito population under control during the 2008 season. The M. albidus population developed very well both in drums placed in sunny and shaded areas and proved to be tolerant to both high (summer) and low (winter) temperatures. Trials performed on M. albidus survival in catch basins showed that after a few weeks, the copepod population dramatically decreased and subsequently disappeared. The main problem for copepod survival in catch basins seemed to be the low oxygen tension and accumulation of toxic substances, rather than copepods being flushed out in heavy rainfall episodes. During the period when copepods were present, they maintained the mosquito population under control; their partial disappearance from the catch basins, however, would require more recolonization intervention to maintain mosquito control during the season. PMID- 25843176 TI - Two Novel Bioassays to Assess the Effects of Pyrethroid-Treated Netting on Knockdown-Susceptible Versus Resistant Strains of Aedes aegypti. AB - We describe 2 new mosquito bioassays for use with insecticide-treated netting or other textiles. The 1st is a cylinder bioassay in which a mosquito is forced to contact treated material regardless of where it lands within the bioassay construct. The 2nd is a repellency/irritancy and biting-inhibition bioassay (RIBB) in which human arms and breath are used as attractants. Mosquitoes have the choice to pass through holes cut in untreated or treated netting to move from a center release chamber into side chambers to reach arms and potentially bite. Trials were conducted with pyrethroid-susceptible (New Orleans), moderately resistant (Hunucma), and highly resistant (Vergel) strains of Aedes aegypti. Tests with netting treated with different pyrethroids demonstrated the utility of the cylinder bioassay to quantify knockdown and mortality following exposure to treated netting, and of the RIBB to quantify spatial repellency/contact irritancy of the treated netting and biting inhibition after females land on and then pass through holes in the treated netting. Both tested brands of pyrethroid-treated mosquitocidal netting (DuraNet(r) and NetProtect(r)) were effective against New Orleans but ineffective against Vergel strains. Mortality in the cylinder bioassay was 100% for New Orleans for all tested brands of treated netting, but only 10-14% for Vergel. Rates of passage through treated netting to reach a human arm in the RIBB were 10-15% for New Orleans versus 24-37% for Vergel. The reduction in biting after passage through treated netting, compared with untreated netting in the same trial replicates, was 12-39% for New Orleans versus <=9% for Vergel. PMID- 25843175 TI - Mortality Patterns of Simulium vittatum Larvae (Diptera: Simuliidae) Following Exposure to Insecticidal Proteins Produced by Bacillus thuringiensis var. israelensis. AB - Products containing insecticidal crystalline proteins (ICPs) produced by Bacillus thuringiensis var. israelensis (Bti ICPs) are used to suppress vector and nuisance populations of black flies. The efficacy of an application of these products is often determined by a posttreatment evaluation of larval mortality. Larvae are typically removed from the substrate at some point in time after application of the product and mortality is determined. The time necessary for the effects of Bti ICPs to cause morality in exposed larvae can vary, and there is little consensus on how long operators should wait before evaluating larval mortality. This study was conducted to provide more information to larvicide applicators when performing posttreatment evaluations. Simulium vittatum larvae were exposed to Bti ICPs under controlled conditions and the mortality was monitored over time. Larvae exposed to operational concentrations of ICPs exhibited maximum mortality, approximately 87%, after 4 h. Exposure of larvae to 1/3 of that concentration resulted in similar mortality; however, the maximum mortality was not reached until 8 h postexposure. Additional experiments revealed that maximum mortality and time to maximum mortality can also be affected by components in the larval medium. Larval mortality was compared between larvae exposed to Bti ICPs in moderately hard water, medium containing 50 parts per million (ppm) of kaolinite, and medium containing 50 ppm of cellulose. The clay material had no significant effect on larval mortality or time to achieve maximum mortality. When cellulose was present in the medium, the time to maximum mortality was increased 50% and overall mortality was reduced by more than 40%. PMID- 25843177 TI - Laboratory Studies of Aedes aegypti Attraction to Ketones, Sulfides, and Primary Chloroalkanes Tested Alone and in Combination with L-Lactic Acid. AB - The attraction of female Aedes aegypti to single compounds and binary compositions containing L-lactic acid and an additional saturated compound from a set of ketones, sulfides, and chloroalkanes was studied using a triple-cage dual port olfactometer. These chemical classes were studied because of their structural relation to acetone, dimethyl disulfide, and dichloromethane, which have all been reported to synergize attraction to L-lactic acid. Human odors, carbon dioxide, and the binary mixture of L-lactic acid and CO2served as controls for comparison of attraction responses produced by the binary mixtures. All tested mixtures that contained chloroalkanes attracted mosquitoes at synergistic levels, as did L-lactic acid and CO2. Synergism was less frequent in mixtures of L-lactic acid with sulfides and ketones; in the case of ketones, synergistic attraction was observed only for L-lactic acid combined with acetone or butanone. Suppression or inhibition of attraction response was observed for combinations that contained ketones of C7-C12 molecular chain length (optimum in the C8-C10 range). This inhibition effect is similar to that observed previously for specific ranges of carboxylic acids, aldehydes, and alcohols. PMID- 25843178 TI - Larvicidal activity of naturally occurring naphthalenedione and its structurally related analogs against three mosquito species. AB - The objective of this study was to determine the larvicidal activity of an active compound isolated from Cercis chinensis heartwood and its structurally related analogs against 4th-stage Aedes aegypti, Culex pipiens pallens, and Ae. togoi. The larvicidal compound of C. chinensis was isolated with the use of various chromatographic techniques and identified as analogs of 1,4-naphthalenedione. Based on the median lethal concentration (LC(50)) values of commercially procured analogs against Ae. aegypti larvae, the most toxic analog was 2-bromo-1,4 naphthalenedione (1.19 ug/ml); followed by 5-hydroxy-1,4-naphthalenedione (1.72 ug/ml); 2-methyl-1,4-naphthalenedione (9.12 ug/ml); 2-hydroxy-1,4 naphthalenedione (10.76 ug/ml); and 2-methoxy-1,4-naphthalenedione (12.50 ug/ml). Similar results were observed against Cx. p. pallens and Ae. togoi larvae with 1,4-naphthalenedione analogs. These results also showed that 1,4-naphthalenedione analogs were less toxic than the organophosphate pirimiphos-methyl. Nonetheless, naturally occurring C. chinensis-derived materials and 1,4-naphthalenedione analogs have potential for development as mosquito larvicidal agents. PMID- 25843179 TI - Evaluation of Household Bleach as an Ovicide for the Control of Aedes aegypti. AB - Accumulations of dormant eggs in container habitats allow Aedes aegypti populations to survive harsh environmental conditions and may frustrate control interventions directed at larval and adult life stages. While sodium hypochlorite solutions (NaOCl) have long been recognized as ovicides for use against dengue vectors, the susceptibility of eggs to spray applications has not been robustly evaluated on substrate materials representative of the most frequently utilized artificial container habitats. Experiments were performed under controlled and natural conditions by applying dilutions of household bleach (52.5 ppt NaOCl) as a spray to eggs on plastic, rubber, and concrete surfaces, with and without a smectite clay thickener. Laboratory assays identified the minimum NaOCl concentrations required to eliminate eggs on plastic (10 ppt), rubber (20 ppt) and concrete (20 ppt) surfaces. Addition of smectite clay reduced the minimum effective concentration to 10 ppt NaOCl for all 3 substrates. A minimum exposure period of 24 h was required to completely eliminate egg viability on concrete surfaces, even at the highest NaOCl concentration (52.5 ppt). Field experiments verified that spray application of a 1?3 dilution of household bleach mixed with smectite clay can reduce egg hatching by >= 99% in shaded and sun-exposed plastic containers. Similarly, 4?1 dilution of household bleach (with or without smectite clay) eliminated >= 98% of eggs from concrete surfaces in outdoor, water-filled drums. In this study, we propose a practical, effective and safe strategy for using household bleach to eliminate Ae. aegypti eggs in a range of artificial container habitats. PMID- 25843180 TI - Evaluation of a new spraying machine for barrier treatment and penetration of bifenthrin on vegetation against mosquitoes. AB - The effectiveness and penetration of a novel, truck-mounted mist sprayer (3WC-30 4P provided by American LongRay) was evaluated with bifenthrin in a large, park like setting with historic floodwater and woodland mosquito populations. Efficacy evaluations were determined through adult population collections and excised leaf bioassays. Trapping results showed a mean reduction of 77% in mosquito populations in the treated area for 5 sampling events up to 4 wk posttreatment. Leaf bioassays revealed an average mortality of 80% at 2.7 m and 51% at 5.5 m against laboratory-reared Aedes aegypti for 5 posttreatment samples. Leaves collected from the treated areas caused higher mortality at distances closer to the sprayer, though the distance and coverage of bifenthrin application was effective up to 5 m. PMID- 25843181 TI - Updated Distribution of Aedes albopictus in Oklahoma, and Implications in Arbovirus Transmission. AB - A series of statewide surveys were conducted in Oklahoma in the summers between 1991 and 2004 to identify the distribution of Aedes albopictus. Adult mosquitoes were identified in 63 counties, bringing the currently known distribution of Ae. albopictus in the state to 69 of 77 counties. The widespread presence of Ae. albopictus in Oklahoma has important current and future public and veterinary health implications for surveillance and control efforts. PMID- 25843182 TI - Aedes pertinax, a Newly Recognized Mosquito Species in the United States. AB - Specimens of a mosquito new to the continental USA, Aedes pertinax, were retrospectively identified from 2 collections made in 2011 in Indian River County, FL. Routine mosquito surveillance in subsequent years yielded more than 700 specimens appearing in 100 collections. The distribution of this mosquito in Florida and the United States is currently unknown, and recognition of the adult female is likely hampered by morphological similarities to Ae. atlanticus and Ae. tormentor. PMID- 25843183 TI - A checklist of the 67 mosquito species of Ontario, Canada. AB - We provide an updated checklist of 67 endemic mosquito species known from Ontario, Canada. Nine endemic species are added to the checklist found in Darsie and Ward (2005) : Aedes cantator, Ae. churchillensis, Ae. nigripes, Ae. pullatus, Anopheles perplexens, An. crucians, An. smaragdinus, Culex erraticus, and Cx. salinarius. Only 4 specimens of Ae. albopictus have been recorded in Ontario since 2001 despite concerted efforts to find this species; therefore, it is considered an "accidental" species and is excluded from the checklist. PMID- 25843184 TI - The correct type localities of three species of Sabethini. AB - The correct type localities were noted for the following mosquito species: 1) Sabethes fabricii, municipality of Angra dos Reis, state of Rio de Janeiro, Brazil; 2) Sa. soperi 1942 , municipality of Nova Iguacu, state of Rio de Janeiro, Brazil; and 3) Wyeomyia finlayi 1942 , Xerem, in the municipality of Duque de Caxias, state of Rio de Janeiro, Brazil. PMID- 25843185 TI - Evaluation of the AtrAedesTM Lure for Collection of Culex quinquefasciatus in Gravid Traps. AB - The typical attractant used in gravid trapping of Culex quinquefasciatus is an aged infusion of organic materials, which can change in attractiveness over time. A standardized chemical attractant dispenser derived from grass infusion, the AtrAedesTM lure, has been produced for the surveillance of the dengue vector Aedes aegypti. A study using this lure in combination with the Centers for Disease Control and Prevention gravid traps was conducted in Tanga, Tanzania. The addition of the lure to traps baited with either grass infusion or tap water did not result in significant increases in trap catch. Grass infusion-baited traps (with and without the AtrAedes lure) collected significantly more Cx. quinquefasciatus than traps baited with AtrAedes + tap water, tap water alone, or AtrAedes alone. The catches of the traps baited with AtrAedes + tap water, tap water alone, and AtrAedes alone were not significantly different from each other. Although the placement of the lure in the base of the trap may have decreased trap catches, it seems that the AtrAedes is not as effective as grass infusion for collecting Cx. quinquefasciatus in Tanzania. PMID- 25843186 TI - Field Evaluation of a Novel Mos-Hole Trap and Naphtha Compared with BG Sentinel Trap and Mosquito Magnet X Trap to Collect Adult Mosquitoes. AB - The novel Mos-Hole trapTM with liquid attractant naphthaTM from Korea was compared with BG SentinelTM trap and Mosquito Magnet XTM trap for field collection of adult mosquitoes in St. Johns County, northeastern Florida, from May to October 2013. The novel Mos-Hole trap baited with naphtha (liquid attractant) collected similar numbers of mosquitoes, compared with the number of mosquitoes caught by BG Sentinel traps baited with BG LureTM. Both Mos-Hole and BG Sentinel traps collected a significantly greater number of mosquitoes compared with the numbers collected by Mosquito Magnet X traps. In other field evaluations when switching lures, the Mos-Hole traps baited with BG Lure caught more mosquitoes than the BG Sentinel trap baited with liquid naphtha attractant. The results showed that the novel Mos-Hole trap has the potential to be used as an additional effective sampling tool for population surveillance and control of adult mosquitoes. PMID- 25843187 TI - Notes on facultative predation in Prosimulium larvae (Diptera: Simuliidae) in alpine and subalpine streams in Colorado. AB - Although it is widely accepted that black fly larvae employ filter feeding as their primary mode of nutrient intake, other forms of food acquisition, such as predation, may be more prevalent than previously realized. It has been suggested that environments where particulate matter is low, such as high-elevation seasonal streams, may drive predatory behavior in black fly larvae. Relatively little is known about the frequency at which larvae prey on other organisms or if predation may be obligate in some species. In order to supplement the idea that larval black fly predation may be a common method of feeding under certain conditions, a preliminary survey of predation by Prosimulium larvae was conducted in order to assess predation frequency at high-elevation sites (> 3,200 m) in the Colorado Rocky Mountains. Larvae were sampled from alpine and subalpine locations, and their gut content analysis revealed evidence of facultative predation and possible cannibalism. Evidence of predation was observed in all but 1 Prosimulium species collected. Predation frequency was highest in the North Fork Snake River headwater location, a small tributary stream of the Snake River in central Colorado. This survey suggests that further inquiry into predatory behavior of black fly larvae should be conducted to determine the mechanisms, behavior, and ecological impact of this understudied feeding strategy. PMID- 25843189 TI - The acceptability of screening for colorectal cancer in Saudi Arabia: myths busted. PMID- 25843188 TI - Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia Induced Deficits in Synaptic Plasticity and Long-Term Memory. AB - AIMS: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. RESULTS: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA. INNOVATION AND CONCLUSION: These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment. PMID- 25843190 TI - SASLT position statement on the direct-acting antiviral agents for the treatment of hepatitis C virus infection. PMID- 25843191 TI - Nonalcoholic fatty liver disease: Noninvasive methods of diagnosing hepatic steatosis. AB - Hepatic steatosis is the buildup of lipids within hepatocytes. It is the simplest stage in nonalcoholic fatty liver disease (NAFLD). It occurs in approximately 30% of the general population and as much as 90% of the obese population in the United States. It may progress to nonalcoholic steatohepatitis, which is a state of hepatocellular inflammation and damage in response to the accumulated fat. Liver biopsy remains the gold standard tool to diagnose and stage NAFLD. However, it comes with the risk of complications ranging from simple pain to life threatening bleeding. It is also associated with sampling error. For these reasons, a variety of noninvasive radiological markers, including ultrasound, computed tomography, magnetic resonance spectroscopy, and the controlled attenuation parameter using transient elastography and Xenon-133 scan have been proposed to increase our ability to diagnose NAFLD, hence avoiding liver biopsy. The aim of this review is to discuss the utility and accuracy of using available noninvasive diagnostic modalities for fatty liver in NAFLD. PMID- 25843192 TI - Effect of public knowledge, attitudes, and behavior on willingness to undergo colorectal cancer screening using the health belief model. AB - BACKGROUND/AIMS: Success of colorectal cancer (CRC) screening is dependent in part on the proportion of uptake by the targeted population. We aimed in this study to identify factors that were associated with willingness to undergo CRC screening based on the health belief model (HBM). PATIENTS AND METHODS: This was a cross-sectional study among citizens of Riyadh, Saudi Arabia. Demographic data collected included gender, age, education, marital status, employment status, a history of CRC in the family or knowing a friend with CRC, as well as income. A questionnaire was developed in Arabic based on the HBM and included enquiries on knowledge about CRC symptoms and risk factors, types of CRC screening tests, perceived risk of CRC, previously undergoing CRC screening, intent to undergo CRC screening, perceived barriers to CRC screening, perceived severity of CRC, as well as attitudes toward CRC and its screening. RESULTS: Five hundred participants were included. The mean age was 41.0 years (SD 10.7). Males were 50% and only 6.7% of those between 50 and 55 years of age had undergone CRC screening. Of those surveyed, 70.7% were willing to undergo CRC screening. Also, 70.5% thought that CRC is curable, 73.3% believed it was preventable, whereas 56.7% thought it was a fatal disease. Neither gender, level of education, occupation, income, marital status, nor general knowledge about CRC was found to be associated with the willingness to undergo CRC screening. Recognizing that colonoscopy was a screening test (OR 1.55, 95% CI; 1.04-2.29) was associated with a strong desire to undergo CRC screening while choosing a stool-based test was associated with not willing to undergo CRC screening (OR 0.59, 95%CI; 0.38-0.91). CONCLUSION: We found that the majority of those interviewed were willing to undergo CRC screening and identified a number of barriers as well as potential areas that could be targeted in the promotion of CRC screening uptake if such a national program were to be implemented. PMID- 25843193 TI - Public awareness of colorectal cancer in Saudi Arabia: A survey of 1070 participants in Riyadh. AB - BACKGROUND/AIMS: The aim of this study was to investigate colorectal cancer (CRC) awareness in healthy individuals in Saudi Arabia in order to identify segments of the population that would most benefit from targeted education programs. SETTING AND DESIGN: Survey/questionnaire. PATIENTS AND METHODS: Random, healthy individuals from Riyadh, Saudi Arabia, were approached to participate in a 10 question multiple choice survey about CRC. Data were analyzed by demographic criteria, including age, gender, marital status, and level of education, to determine if members of these groups displayed differential knowledge. STATISTICAL ANALYSIS: Differences in responses by demographic data were analyzed using Pearson's Chi-square test. A P < 0.05 was considered statistically significant. RESULTS: In total, 1070 participants completed the survey. Most respondents believe that screening for colon cancer should begin at symptom onset (42.9%). Less than 20% of all respondents believe that polyps are a risk factor for CRC, which varied significantly according to level of education; however, even the most educated answered correctly less than 50% of the time. Similarly, only 34.8% of all respondents knew that a family history of CRC imparted a personal risk for CRC. CONCLUSIONS: Although older individuals and those with higher education tended to answer questions correctly more often, there were some misconceptions regarding universally accepted screening protocols, symptoms, and general understanding of CRC in Saudi Arabia. A national education/screening program in Saudi Arabia is recommended to improve CRC knowledge. PMID- 25843194 TI - Mannose-binding lectin gene polymorphism and chronic hepatitis B infection in children. AB - BACKGROUND/AIMS: Mannose-binding lectin (MBL) is a member of innate immune system that activates complement system through lectin pathway. MBL deficiency is associated with susceptibility to infectious diseases. In this study, the relation between MBL gene polymorphism and chronic hepatitis B infection in children is evaluated. PATIENTS AND METHODS: The study included 67 children with chronic hepatitis B and 99 healthy controls. The hepatitis B patients were divided into immuntolerant, chronic inactive, and treatment groups according to their laboratory findings. MBL gene codon 52, 54, and 57 polymorphisms were studied with polymerase chain reaction in all patients and controls. The associations of MBL gene polymorphism with clinical, laboratory, and histopathologic findings were evaluated. RESULTS: Homozygous codon 54 polymorphism of MBL was found significantly higher in chronic hepatitis B patients than controls. Rate of the polymorphism was similar in all groups and, responsive and nonresponsive patients in the treatment group. CONCLUSIONS: The hepatitis B patients who are homozygous for codon 54 of MBL are prone to develop chronic infection. Longitudinal studies with larger groups are needed. PMID- 25843195 TI - Quality of gastroenterology research published in Saudi Arabian scientific journals. AB - BACKGROUND/AIMS: Evidence-based medicine has established itself in the field of gastroenterology. In this study we aim to assess the types of study designs of gastroenterology-related articles published in Saudi scientific journals. PATIENTS AND METHODS: An online review using PubMed was carried out to review gastroenterology-related articles published in six Saudi medical journals in the time interval from 2003 to 2012. To classify the level of evidence in these articles we employed the Oxford's levels of evidence. One-way analysis of variance was used to compare the levels of evidence between published articles. RESULTS: A total of 721 gastroenterology-related articles were reviewed, of which 591 articles met our inclusion criteria; 80.7% were level IV. The three most common types of studies we encountered were cross-sectional (33.9%), case reports (27.9%), and case series (18.8%). Forty-three percent of the published research was in the field of hepatobiliary and spleen. The total number of articles increased from 260 articles in the 1 st 5-year period (2003-2007) to 330 in the 2 nd period (2008-2012). However, no statistically significant difference in the level of evidence was noted. In Annals of Saudi Medicine Journal, articles with level II increased from 0 to 10% with a P value 0.02. CONCLUSION: In our review of gastroenterology-related published articles in Saudi scientific journals, we observed an increase in the quantity of articles with the quality and level of evidence remaining unchanged. Further research is recommended to explore different reasons affecting the volume and quality of gastroenterology-related research in Saudi scientific journals. PMID- 25843196 TI - Toll-like receptor gene polymorphisms and susceptibility to Epstein-Barr virus associated and -negative gastric carcinoma in Northern China. AB - BACKGROUND/AIMS: Various polymorphisms in toll-like receptor (TLR) genes have been identified and associated with susceptibility to various malignancies, such as gastric carcinoma (GC), breast cancer, and prostate cancer. However, little is known about the polymorphisms of TLR genes and the susceptibility to GC in Northern China, especially to Epstein-Barr virus-associated GC (EBVaGC). We focused on the association with susceptibility to GC, especially to EBVaGC. PATIENTS AND METHODS: Polymorphisms of the TLR2, 3, 4, and 9 genes were measured in 52 cases of EBVaGC and 157 cases of EBV-negative GC (EBVnGC). Ninety-four peripheral blood samples from healthy individuals were also examined. RESULTS: For the TLR2 gene (196 to 174 del), there was no significant difference between the GC group and control group in genotype, but there was a significant difference in the del allele. As for the TLR3 gene (c. 1377C/T), there were significant differences between the GC group and the control group in both genotype and allelic frequency. No SNPs single nucleotide polymorphisms (SNPs) were found in the TLR4 gene at the sites Asp299Gly and Thr399Ile. As for TLR9 1486T/C (rs187084) and C2848T (rs352140), there was also no association between the GC group and control. In all of the indicators, there were no significant differences between EBVaGCs and EBVnGCs. CONCLUSIONS: The TLR3 gene (c. 1377C/T) polymorphisms and the del allele of the TLR2 gene ( 196 to 174) were both associated with susceptibility to GC in Shangdong Province of Northern China. There was no interaction between EBV and TLR gene polymorphisms in EBVaGC. PMID- 25843197 TI - Partially hydrolyzed guar gum in the treatment of irritable bowel syndrome with constipation: effects of gender, age, and body mass index. AB - BACKGROUND/AIMS: Partially hydrolyzed guar gum (PHGG) relieves symptoms in constipation-predominant irritable bowel syndrome (IBS) and may have prebiotic properties. However, the correlation between the effectiveness of PHGG and patient characteristics has not been examined. We aimed to investigate the effect of PHGG in symptom relief on constipation-predominant IBS according to gender, age, and body mass index (BMI). PATIENTS AND METHODS: Sixty-eight patients with IBS entered a 2-week run-in period, followed by a 4-week study period with PHGG. Patients completed a daily questionnaire to assess the presence of abdominal pain/discomfort, swelling, and the sensation of incomplete evacuation. The number of evacuations/day, the daily need for laxatives/enemas and stool consistency form were also evaluated. All patients also underwent a colonic transit time (CTT) evaluation. RESULTS: PHGG administration was associated with a significant improvement in symptom scores, use of laxatives/enemas, stool form/consistency and CTT. At the end of the study period and compared with baseline, the number of evacuations improved in women, patients aged >= 45 years and those with BMI >= 25 (P < 0.05 for all comparisons); abdominal bloating improved in males (P < 0.05), patients < 45 years (P < 0.01) and those with BMI < 25 (P < 0.05). A decrease in the number of perceived incomplete evacuations/day was reported in patients with a BMI >= 25 (P < 0.05). Reductions in laxative/enema use were recorded in females (P < 0.05), patients < 45 years (P < 0.01), and patients with BMI < 25 (P < 0.05). CONCLUSIONS: Gender, age, and BMI seem to influence the effect of PHGG supplementation in constipated IBS patients. Further studies are needed to clarify the interaction of such parameters with a fiber-enriched diet. PMID- 25843198 TI - Does anxiety or waiting time influence patients' tolerance of upper endoscopy? AB - BACKGROUND/AIMS: Endoscopy is an essential and very commonly used procedure for the evaluation of a multitude of gastrointestinal symptoms. Although it is increasingly required, patients often wait on arrival at the endoscopy unit until they are called for the procedure. It is not clear whether or not this waiting time may have an impact on patient's tolerance during upper endoscopy. Our study attempts to address this. PATIENTS AND METHODS: We studied consecutive outpatients who underwent endoscopy from September to December, 2013. Gender, age, body mass index (BMI), previous endoscopic experiences, antidepressant therapy, and the time interval between arrival at the endoscopy unit and the onset of examination was recorded. Anxiety before the procedure, pain, and discomfort were rated by a numeric rating scale (0 = no pain/discomfort encountered to 10 = extremely painful/uncomfortable). RESULTS: One hundred and five consecutive outpatients (male = 52; mean age = 45.3 years; age range = 20-86 years) were included in the study. The mean BMI was 25 +/- 4.8; mean waiting time from registration to the procedure was 172 min (time range = 30 - 375 mins). Mean patients' pre-examination anxiety level was 3 +/- 3.84, mean discomfort score was 4.3 +/- 3.09 and mean pain score was 3.4 +/- 3.03. The level of pain and discomfort was significantly higher in patients with higher levels of pre procedure anxiety. No differences were found in terms of anxiety, pain and discomfort among patients divided according to waiting time. CONCLUSIONS: According to our data, waiting time does not have a significant impact on the perception of pain and discomfort related to the endoscopic procedure. On the other hand, high pre-procedural levels of anxiety were associated with a low tolerance. Further multicenter randomized trials are needed to clarify the impact of waiting time. PMID- 25843200 TI - Unusual case of a submucosal tumor in the sigmoid colon. Gastrointestinal elastosis. PMID- 25843199 TI - Cytology findings in pancreatic heterotopia, a potential pitfall for malignancy: a case report and literature review. AB - Pancreatic heterotopia is a rare congenital disorder occurring at a variety of sites in the gastrointestinal tract. It is rarely symptomatic. Despite advances in diagnostic techniques, it still remains a challenge to the clinician to differentiate it from a neoplasm. Cytologic characteristics of pancreatic heterotopia in general are rarely described in the literature. We report the cytologic characteristics of heterotopic pancreatic tissue at the gastric outlet in a 48-year-old female. The patient underwent surgical excision due to symptoms related to the lesion. Endoscopic ultrasound fine-needle aspiration is increasingly used for the diagnosis of gastrointestinal tumors, which makes the recognition of certain endoscopically unreachable lesions an important step in optimal patient management. PMID- 25843202 TI - Lanthanide(III) di- and tetra-nuclear complexes supported by a chelating tripodal tris(amidate) ligand. AB - Syntheses, structural, and spectroscopic characterization of multinuclear tris(amidate) lanthanide complexes is described. Addition of K3[N(o PhNC(O)(t)Bu)3] to LnX3 (LnX3 = LaBr3, CeI3, and NdCl3) in N,N-dimethylformamide (DMF) results in the generation of dinuclear complexes, [Ln(N(o PhNC(O)(t)Bu)3)(DMF)]2(MU-DMF) (Ln = La (1), Ce (2), Nd(3)), in good yields. Syntheses of tetranuclear complexes, [Ln(N(o-PhNC(O)(t)Bu)3)]4 (Ln = Ce (4), Nd(5)), resulted from protonolysis of Ln[N(SiMe3)2]3 (Ln = Ce, Nd) with N(o PhNCH(O)(t)Bu)3. In the solid-state, complexes 1-5 exhibit coordination modes of the tripodal tris(amidate) ligand that are unique to the 4f elements and have not been previously observed in transition metal systems. PMID- 25843201 TI - MDR1C3435T polymorphism and inflammatory bowel disease. PMID- 25843203 TI - Factors related to vaccine uptake by young adult women in the catch-up phase of the National HPV Vaccination Program in Australia: Results from an observational study. AB - BACKGROUND: Australia commenced a publically-funded, National Human Papillomavirus (HPV) Vaccination Program in 2007 with a two year catch-up phase for females aged 12-26 years. OBJECTIVE: To identify the factors associated with the uptake of the HPV vaccine (which has a recommended 3-dose schedule in Australia) by young adult women vaccinated by general practitioners and community based programs within the catch-up phase. METHODS: 1139 women who were eligible to receive the free HPV vaccine during the catch-up period were recruited in 2008 2009 (age 20-29 years at recruitment), in New South Wales, after having a normal (negative) cervical smear result recorded on the NSW Pap Test Register. Participants completed a self-administered questionnaire providing information on vaccination status, and sociodemographic and other factors. RESULTS: Overall, 880 (77%) women reported receiving >= 1 dose of the vaccine and 777 women (68%) reported receiving >= 2 doses. In multivariable analysis (adjusting for the period for which each woman was eligible for free HPV vaccination), uptake of >= 1 dose of the vaccine was significantly associated with being born in Australia (p < 0.01), being single (p = 0.02), being nulliparous (p < 0.01), living in a higher socioeconomic status area (p-trend = 0.03), living in more remote areas (p = 0.03), drinking alcohol (p < 0.01) and using hormonal contraceptives (p < 0.01). Although vaccinated women were more likely to have fewer sexual partners than unvaccinated women (p-trend = 0.02), they were also more likely to report a prior sexually transmitted infection (STI) (p = 0.03). Similar factors were associated with receiving >= 2 doses. CONCLUSIONS: In this group, women living in higher socioeconomic status areas were more likely to be vaccinated against HPV in the catch-up phase of the national program. Although vaccinated women tended to have fewer sexual partners, they also reported prior STIs, which may be a marker of increased risk of prior exposure to HPV. The findings of this study reinforce the continuing need to prioritise equitable delivery of vaccination to various population subgroups. PMID- 25843204 TI - Food Resource Management Education With SNAP Participation Improves Food Security. AB - OBJECTIVE: To determine the influence of Supplemental Nutrition Assistance Program (SNAP) and participant demographics on nutrition education outcomes. METHODS: At program enrollment (pre) and 1 month later (post), a statewide convenience sample of adults, who participated in the Plan, Shop, Save, and Cook program, completed a 7-item questionnaire to evaluate change in resource management skills (RMS) and running out of food before the end of the month. RESULTS: Percent of participants (n = 3,744) who reported behavioral improvements in RMS ranged from 38.8% in comparing prices to 54% in reading labels. Female gender and Hispanic ethnicity were positively related to pre-post RMS change (P = .001). Participants who received SNAP food assistance and made greater pre-post improvement in RMS reported the greatest decrease in running out of food (P = .001). CONCLUSIONS AND IMPLICATIONS: Both food assistance and education on nutrition and resource management are needed to reduce food insecurity in SNAP eligible audiences. PMID- 25843205 TI - Cerebro-retinal microangiopathy with calcifications and cysts due to recessive mutations in the CTC1 gene. AB - Cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) or Coats plus syndrome is a pleiotropic disorder affecting the eyes, brain, bone and gastrointestinal tract. Its primary pathogenesis involves small vessel obliterative microangiopathy. Recently, autosomal recessively inherited mutations in CTC1 have been reported in CRMCC patients. We herein report an adolescent referred to our hospital following new seizures in a context of an undefined multisystem disorder. Cerebral imaging disclosed asymmetrical leukopathy, intracranial calcifications and cysts. In addition, he presented other typical CRMCC features i.e. a history of intrauterine growth retardation, skeletal demineralization and osteopenia, bilateral exudative vitreo-retinopathy reminiscent of Coats disease, recurrent gastrointestinal hemorrhages secondary to watermelon stomach and variceal bleeding of the esophagus due to idiopathic portal hypertension and telangiectatic and angiodysplasic changes in the small intestine and colon, and anemia due to recurrent bleeding and bone marrow abnormalities. The patient was diagnosed with Coats plus syndrome. CTC1 gene screening confirmed the diagnosis with the identification of heterozygous deleterious mutations. CRMCC due to CTC1 mutations has a broad clinical expressivity. Our case report illustrates the main possible associated phenotypes and their complications, demonstrating the need for a careful etiological search in order to initiate appropriate therapeutic and preventive measures. PMID- 25843206 TI - Valedictory editorial. PMID- 25843207 TI - Editorial--new editors-in-chief. PMID- 25843209 TI - [Epidemiology and classification of arachnoid cysts in children]. AB - The prevalence of arachnoid cysts in children is 1-3%. They are more frequent in boys. They can be located intracranially or in the spine. Intracranial cysts are classified as supratentorial, infratentorial, and supra-infratentorial (tentorial notch). Supratentorial are divided into middle cranial fossa, convexity, inter hemisferic, sellar region, and intraventricular. Infratentorial are classified into supracerebellar, infracerebellar, hemispheric, clivus, and cerebellopontine angle. Finally spinal arachnoid cysts are classified taking into account whether they are extra- or intradural, and nerve root involvement. PMID- 25843210 TI - Acute effect of 3beta-hidroxihop-22(29)ene on insulin secretion is mediated by GLP-1, potassium and calcium channels for the glucose homeostasis. AB - The effect of 3beta-hidroxihop-22(29)ene (3-BHO) on insulin and glucagon-like peptide 1 (GLP-1) secretion as well as the mechanism of action of the compound in pancreatic islet on glucose homeostasis was investigated. The data from in vivo treatment show that 3-BHO significantly reduces the hyperglycemia by increasing the insulin and GLP-1 secretion, as well as by accumulating hepatic glycogen in hyperglycemic rats. In rat pancreatic beta-cell, 3-BHO stimulates the glucose uptake, insulin vesicles translocation to the plasma membrane and thus the insulin secretion through the involvement of potassium channels (ATP- and Ca(2+) dependent K(+) channels) and calcium channels (L-type voltage-dependent calcium channels (L-VDCC)). Furthermore, this study also provides evidence for a crosstalk between intracellular high calcium concentration, PKA and PKC in the signal transduction of 3-BHO to stimulate insulin secretion. In conclusion, 3-BHO diminishes glycaemia, stimulates GLP-1 secretion and potentiates insulin secretion and increase hepatic glycogen content. Moreover, this triterpene modulates calcium influx characterizing ATP-K(+), Ca(2+)-K(+) and L-VDCC channels dependent pathways as well as PKA and PKC activity in pancreatic islets underlying the signaling of 3-BHO for the secretory activity and contribution on glucose homeostasis. PMID- 25843208 TI - The ER/PM microdomain, PI(4,5)P2 and the regulation of STIM1-Orai1 channel function. AB - All forms of cell signaling occur in discreet cellular microdomains in which the ER is the main participant and include microdomains formed by the ER with lysosomes, endosomes, the nucleus, mitochondria and the plasma membrane. In the microdomains the two opposing organelles transfer and exchange constituents including lipids and ions. As is the case for other forms of signaling pathways, many components of the receptor-evoked Ca(2+) signal are clustered at the ER/PM microdomain, including the Orai1-STIM1 complex. This review discusses recent advances in understanding the molecular components that tether the ER and plasma membrane to form the ER/PM microdomains in which PI(4,5)P2 is enriched, and how dynamic targeting of the Orai1-STIM1 complex to PI(4,5)P2-poor and PI(4,5)P2-rich microdomains controls the activity of Orai1 and its regulation by Ca(2+) that is mediated by SARAF. PMID- 25843211 TI - Estrogen O-sulfamates and their analogues: Clinical steroid sulfatase inhibitors with broad potential. AB - Estrogen sulfamate derivatives were the first irreversible active-site-directed inhibitors of steroid sulfatase (STS), an emerging drug target for endocrine therapy of hormone dependent diseases that catalyzes inter alia the hydrolysis of estrone sulfate to estrone. In recent years this has stimulated clinical investigation of the estradiol derivative both as an oral prodrug and its currently ongoing exploration in endometriosis. 2-Substituted steroid sulfamate derivatives show considerable potential as multi-targeting agents for hormone independent disease, but are also potent STS inhibitors. The steroidal template has spawned nonsteroidal STS inhibitors one of which, Irosustat, has been evaluated clinically in breast cancer, endometrial cancer and prostate cancer and there is potential for innovative dual-targeting approaches. This review surveys the role of estrogen sulfamates, their analogues and current status. PMID- 25843212 TI - Reprint of "Baroreflex function in anurans from different environments". AB - Anurans from terrestrial environments have an enhanced ability to maintain mean arterial blood pressure (Pm) through lymph mobilization in response to desiccation or hemorrhage compared with semiaquatic or aquatic species. Because short term blood pressure homeostasis is regulated by arterial baroreceptors, we compared baroreflex function in three species of anurans that span a range of environments, dehydration tolerance and an ability to maintain Pm with dehydration and hemorrhage. The cardiac limb of the baroreflex loop was studied using pharmacological manipulation of Pm with phenylephrine and sodium nitroprusside (20-200MUgkg(-1)), and the resulting changes in heart rate (fH) were quantitatively analyzed using a four-parameter sigmoidal logistic function. Resting Pm in the aquatic species, Xenopus laevis, was 3.6+/-0.3kPa and was significantly less (P<0.005) than for the semiaquatic species, Lithobates catesbeianus (4.1+/-0.2kPa), or the terrestrial species, Rhinella marina (4.7+/ 0.2kPa). The maximal baroreflex gain was not different among the three species and ranged from 12.1 to 14.3beatsmin(-1)kPa(-1) and occurred at Pm ranging from 3.0 to 3.8kPa, which were slightly below the resting Pm for each species. Mean arterial blood pressures at rest in the three species were near the saturation point of the baroreflex curve which provides the animals with a greater fH response range to hypotensive, rather than hypertensive, changes in Pm. This is consistent with the hypothesis that arterial baroreceptors are key sensory components that allow anurans to maintain Pm possibly by mobilization of lymphatic return in response to hypotension. PMID- 25843214 TI - Novel 3D bio-macromolecular bilinear descriptors for protein science: Predicting protein structural classes. AB - In the present study, we introduce novel 3D protein descriptors based on the bilinear algebraic form in the R(n) space on the coulombic matrix. For the calculation of these descriptors, macromolecular vectors belonging to R(n) space, whose components represent certain amino acid side-chain properties, were used as weighting schemes. Generalization approaches for the calculation of inter-amino acidic residue spatial distances based on Minkowski metrics are proposed. The simple- and double-stochastic schemes were defined as approaches to normalize the coulombic matrix. The local-fragment indices for both amino acid-types and amino acid-groups are presented in order to permit characterizing fragments of interest in proteins. On the other hand, with the objective of taking into account specific interactions among amino acids in global or local indices, geometric and topological cut-offs are defined. To assess the utility of global and local indices a classification model for the prediction of the major four protein structural classes, was built with the Linear Discriminant Analysis (LDA) technique. The developed LDA-model correctly classifies the 92.6% and 92.7% of the proteins on the training and test sets, respectively. The obtained model showed high values of the generalized square correlation coefficient (GC(2)) on both the training and test series. The statistical parameters derived from the internal and external validation procedures demonstrate the robustness, stability and the high predictive power of the proposed model. The performance of the LDA model demonstrates the capability of the proposed indices not only to codify relevant biochemical information related to the structural classes of proteins, but also to yield suitable interpretability. It is anticipated that the current method will benefit the prediction of other protein attributes or functions. PMID- 25843213 TI - The inflammatory response to influenza A virus (H1N1): An experimental and mathematical study. AB - Mortality from influenza infections continues as a global public health issue, with the host inflammatory response contributing to fatalities related to the primary infection. Based on Ordinary Differential Equation (ODE) formalism, a computational model was developed for the in-host response to influenza A virus, merging inflammatory, innate, adaptive and humoral responses to virus and linking severity of infection, the inflammatory response, and mortality. The model was calibrated using dense cytokine and cell data from adult BALB/c mice infected with the H1N1 influenza strain A/PR/8/34 in sublethal and lethal doses. Uncertainty in model parameters and disease mechanisms was quantified using Bayesian inference and ensemble model methodology that generates probabilistic predictions of survival, defined as viral clearance and recovery of the respiratory epithelium. The ensemble recovers the expected relationship between magnitude of viral exposure and the duration of survival, and suggests mechanisms primarily responsible for survival, which could guide the development of immuno modulatory interventions as adjuncts to current anti-viral treatments. The model is employed to extrapolate from available data survival curves for the population and their dependence on initial viral aliquot. In addition, the model allows us to illustrate the positive effect of controlled inflammation on influenza survival. PMID- 25843215 TI - Accurate in silico identification of protein succinylation sites using an iterative semi-supervised learning technique. AB - As a widespread type of protein post-translational modifications (PTMs), succinylation plays an important role in regulating protein conformation, function and physicochemical properties. Compared with the labor-intensive and time-consuming experimental approaches, computational predictions of succinylation sites are much desirable due to their convenient and fast speed. Currently, numerous computational models have been developed to identify PTMs sites through various types of two-class machine learning algorithms. These methods require both positive and negative samples for training. However, designation of the negative samples of PTMs was difficult and if it is not properly done can affect the performance of computational models dramatically. So that in this work, we implemented the first application of positive samples only learning (PSoL) algorithm to succinylation sites prediction problem, which was a special class of semi-supervised machine learning that used positive samples and unlabeled samples to train the model. Meanwhile, we proposed a novel succinylation sites computational predictor called SucPred (succinylation site predictor) by using multiple feature encoding schemes. Promising results were obtained by the SucPred predictor with an accuracy of 88.65% using 5-fold cross validation on the training dataset and an accuracy of 84.40% on the independent testing dataset, which demonstrated that the positive samples only learning algorithm presented here was particularly useful for identification of protein succinylation sites. Besides, the positive samples only learning algorithm can be applied to build predictors for other types of PTMs sites with ease. A web server for predicting succinylation sites was developed and was freely accessible at http://59.73.198.144:8088/SucPred/. PMID- 25843216 TI - A computational model of insect discontinuous gas exchange: A two-sensor, control systems approach. AB - The insect gas exchange system is characterised by branching air-filled tubes (tracheae/tracheoles) and valve-like structures in their outer integument (spiracles) which allow for a periodic gas exchange pattern known as the discontinuous gas exchange cycle (DGC). The DGC facilitates the temporal decoupling of whole animal gas exchange from cellular respiration rates and may confer several physiological benefits, which are nevertheless highly controversial (primarily reduction of cellular oxidative damage and/or respiratory water saving). The intrinsic and extrinsic factors influencing DGCs are the focus of extensive ongoing research and little consensus has been reached on the evolutionary genesis or mechanistic costs and benefits of the pattern. Despite several hypotheses and much experimental and evolutionary biology research, a mechanistic physical model, which captures various key elements of the DGC pattern, is currently lacking. Here, we present a biologically realistic computational, two-sensor DGC model (pH/carbon dioxide and oxygen setpoints) for an Orthopteran gas exchange system, and show computationally for the first time that a control system of two interacting feedback loops is capable of generating a full DGC pattern with outputs which are physiologically realistic, quantitatively matching experimental results found in this taxonomic model elsewhere. A finite-element mathematical approach is employed and various trigger sets are considered. Parameter sensitivity analyses suggest that various aspects of insect DGC are adequately captured in this model. In particular, with physiologically relevant input parameters, the full DGC pattern is induced; and the phase durations, endotracheal carbon dioxide partial pressure ranges, and pH fluctuations which arise are physically realistic. The model results support the emergent property hypothesis for the existence of DGC, and indicate that asymmetric loading and off-loading (hysteresis) in one of the sensor feedback loops, which is a novel inclusion here, is a critical aspect of the insect spiracle-tracheal gas exchange system. PMID- 25843217 TI - Necessary relations for nucleotide frequencies. AB - Genome composition analysis of di-, tri- and tetra-nucleotide frequencies is known to be evolutionarily informative, and useful in metagenomic studies, where binning of raw sequence data is often an important first step. Patterns appearing in genome composition analysis may be due to evolutionary processes or purely mathematical relations. For example, the total number of dinucleotides in a sequence is equal to the sum of the individual totals of the sixteen types of dinucleotide, and this is entirely independent of any assumptions made regarding mutation or selection, or indeed any physical or chemical process. Before any statistical analysis can be attempted, a knowledge of all necessary mathematical relations is required. I show that 25% of di-, tri- and tetra-nucleotide frequencies can be written as simple sums and differences of the remainder. The vast majority of organisms have circular genomes, for which these relations are exact and necessary. In the case of linear molecules, the absolute error is very nearly zero, and does not grow with contiguous sequence length. As a result of the new, necessary relations presented here, the foundations of the statistical analysis of di-, tri- and tetra-nucleotide frequencies, and k-mer analysis in general, need to be revisited. PMID- 25843219 TI - Do tree split probabilities determine the branch lengths? AB - The evolution of aligned DNA sequence sites is generally modeled by a Markov process operating along the edges of a phylogenetic tree. It is well known that the probability distribution on the site patterns at the tips of the tree determines the tree topology, and its branch lengths. However, the number of patterns is typically much larger than the number of edges, suggesting considerable redundancy in the branch length estimation. In this paper we ask whether the probabilities of just the 'edge-specific' patterns (the ones that correspond to a change of state on a single edge) suffice to recover the branch lengths of the tree, under a symmetric 2-state Markov process. We first show that this holds provided the branch lengths are sufficiently short, by applying the inverse function theorem. We then consider whether this restriction to short branch lengths is necessary. We show that for trees with up to four leaves it can be lifted. This leaves open the interesting question of whether this holds in general. Our results also extend to certain Markov processes on more than 2 states, such as the Jukes-Cantor model. PMID- 25843218 TI - Error catastrophe in populations under similarity-essential recombination. AB - Organisms are often more likely to exchange genetic information with others that are similar to themselves. One of the most widely accepted mechanisms of RNA virus recombination requires substantial sequence similarity between the parental RNAs and is termed similarity-essential recombination. This mechanism may be considered analogous to assortative mating, an important form of non-random mating that can be found in animals and plants. Here we study the dynamics of haplotype frequencies in populations evolving under similarity-essential recombination. Haplotypes are represented by a genome of B biallelic loci and the Hamming distance between individuals is used as a criterion for recombination. We derive the evolution equations for the haplotype frequencies assuming that recombination does not occur if the genetic distance is larger than a critical value G and that mutation occurs at a rate MU per locus. Additionally, uniform crossover is considered. Although no fitness is directly associated to the haplotypes, we show that frequency-dependent selection emerges dynamically and governs the haplotype distribution. A critical mutation rate MUc can be identified as the error threshold transition, beyond which this selective information cannot be stored. For MUMUc the distribution becomes uniform, with all haplotypes having the same frequency. In the case of extreme assortativeness, where individuals only recombine with others identical to themselves (G=0), the error threshold results MUc=1/4, independently of the genome size. For weak assortativity (G=B-1)MUc=2(-(B+1)) and for the case of no assortativity (G=B) MUc=0. We compute the mutation threshold for 0=1.6 [WF-Tp]), and 14 with NOACs (9 dabigatran and 5 rivaroxaban [NOAC-DR]). We compared severity and functional outcome of CE patients among these 4 groups, especially focusing on patients during NOAC treatment. RESULTS: Stroke severity on admission, assessed by the National Institutes of Health Stroke Scale, was lower in WF-Tp (median, 5 [1-15]) and NOAC DR (5 [3-6]) than in non-AC (11 [5-19]) and WF-Lo (12 [5-19]; P = .006). Functional outcome at discharge, assessed by mRS, was favorable in WF-Tp (median, 1 [0-4]) and NOAC-DR (1 [1-2]) compared with that in non-AC (2 [1-4]) and WF-Lo (3 [1-5]; P = .02), and ratios of the patients with mRS score of 1 or less were 63% and 64% versus 31% and 33%, respectively (P = .005). Multivariate analysis also showed a favorable functional outcome at discharge in WF-Tp and NOAC-DR groups. Drug management was likely associated with NOAC-associated CE. CONCLUSIONS: Stroke severity and functional outcome of CE patients treated with warfarin within therapeutic range and with NOACs are similar to each other, and are more favorable than those with no anticoagulants and with warfarin below therapeutic range. PMID- 25843225 TI - Relationship Between Sleep Apnea and Cancer. AB - In the light of relationships reported between hypoxemia (tissue hypoxia) and cancer, Abrams et al. concluded in 2008 that sleep apnea-hypopnea syndrome (SAHS) and its main consequence, intermittent hypoxia, could be related with increased susceptibility to cancer or poorer prognosis of a pre-existing tumor. This pathophysiological association was confirmed in animal studies. Two large independent historical cohort studies subsequently found that the degree of nocturnal hypoxia in patients with SAHS was associated with higher cancer incidence and mortality. This finding has been confirmed in almost all subsequent studies, although the retrospective nature of some requires that they be considered as hypothesis-generating only. The relationship between sleep apnea and cancer, and the pathophysiological mechanisms governing it, could be clarified in the near future in a currently on-going study in a large group of melanoma patients. PMID- 25843226 TI - The evaluation of drug-induced changes in cardiac inotropy in dogs: Results from a HESI-sponsored consortium. AB - INTRODUCTION: Drug-induced effects on the cardiovascular system remain a major cause of drug attrition. While hemodynamic (blood pressure (BP) and heart rate (HR)) and electrophysiological methods have been used in testing drug safety for years, animal models for assessing myocardial contractility are used less frequently and their translation to humans has not been established. The goal of these studies was to determine whether assessment of contractility and hemodynamics, when measured across different laboratories using the same protocol, could consistently detect drug-induced changes in the inotropic state of the heart using drugs known to have clinically relevant positive and negative effects on myocardial contractility. METHODS: A 4*4 double Latin square design (n=8) design using Beagle dogs was developed. Drugs were administrated orally. Arterial blood pressure, left ventricular pressure (LVP) and the electrocardiogram were assessed. Each of the six laboratories studied at least 2 drugs (one positive inotrope (pimobendan or amrinone) and one negative inotrope) (itraconazole or atenolol) at 3 doses selected to match clinical exposure data and a vehicle control. Animals were instrumented with an ITS telemetry system, DSI's D70-PCTP system or DSI's Physiotel Digital system. Data acquisition and analysis systems were Ponemah, Notocord or EMKA. RESULTS: Derived parameters included: diastolic, systolic and mean arterial BP, peak systolic LVP, HR, end diastolic LVP, and LVdP/dtmax as the primary contractility index. Blood samples were drawn to confirm drug exposures predicted from independent pharmacokinetic studies. Across the laboratories, a consistent change in LVdP/dtmax was captured despite some differences in the absolute values of some of the hemodynamic parameters prior to treatment. DISCUSSION: These findings indicate that this experimental model, using the chronically instrumented conscious dog, can accurately and consistently detect changes in cardiac contractility, across multiple sites and instrumentation systems, and that data obtained in this model may also translate to clinical outcomes. PMID- 25843227 TI - Relationship of postoperative thrombocytosis and survival of patients with colorectal cancer. AB - INTRODUCTION: Thrombocytosis accompanying solid tumors and predicting the prognosis of malignant tumors has been the subject of intensive research lately. Reports so far have evaluated the role of preoperative platelet count. In our present study we looked at the effect of tumor removal on platelet count and the predictive power of postoperative thrombocytosis on the survival of patients with colorectal cancer (CRC). METHODS: We retrospectively evaluated the clinical and histopathological data of 336 patients operated due to CRC between 2001 and 2011. Thrombocytosis was defined as a platelet count exceeding 400 * 10(3)/MUL. Preoperative platelet count was compared with the value measured 1 month postoperatively. RESULTS: The platelet count significantly decreased after the removal of the primary tumor (paired Wilcoxon test p < 0.001). In univariate analysis preoperative thrombocytosis was a significant marker of overall survival (OS) with HR 2.2, p < 0.001 while the postoperative thrombocytosis was nearly significant with HR = 1.59, p = 0.087. In multivariate setting, when corrected for location, stage, tumor size and controlling for gender and age (> 65 years vs. <= 65 years), both pre- and postoperative thrombocytosis were significant independent prognostic markers with HR 1.80, p = 0.20 and HR = 1.98, p = 0.018, respectively. DISCUSSION AND CONCLUSION: Although the pathomechanism of thrombocytosis related to solid tumors is not known the decrease of platelet count after the removal of the primary tumor raises the possibility that the tumor may play an active role in the development of thrombocytosis. Furthermore, the observation of postoperative thrombocytosis with significant worse outcome underlines the predictive power of elevated platelet count. PMID- 25843228 TI - Role of CD154 in cancer pathogenesis and immunotherapy. AB - Many factors and molecules have been investigated as potential players in the pathogenesis or immunosurveillance of cancer. Among these, CD154 has been recognized as a co-stimulatory molecule with high potential for treating cancer, in addition to its contribution in the development of the disease. CD154 was initially described for its pivotal role in T cell-dependent humoral responses via an interaction with its classical receptor, CD40. Subsequent studies showed that CD154 is also implicated in cell-mediated immunity and inflammation via an interaction with CD40 alone or in combination with newly identified receptors, members of the integrin family, leading to the development of chronic inflammatory and autoimmune diseases. In the current article, we present an overview of the role of CD154 as a potential etiological factor in tumors inducing proliferation of malignant cells, their rescue from apoptosis and their invasiveness. In addition, this review describes the immuno-regulatory functions of CD154 against cancer reflected by its stimulation of antigen-presenting cells and the subsequent activation of effector cells, its enhancement of malignant cells' immunogenicity, its modulation of immune settings around tumors, and its initiation of proliferation inhibiting effects in malignant cells. In vitro as well as in vivo studies are outlined and a particular attention is given to clinical studies and progress reached at this point. Findings reviewed herein will improve our knowledge of the role of the CD154 system in cancers from causative to immunotherapeutic functions, paving the way for the identification of new targets for prevention and/or treatment of malignant disorders. PMID- 25843229 TI - A role for KMT1c in monocyte to dendritic cell differentiation: Epigenetic regulation of monocyte differentiation. AB - Monocytes play a key role in immune system function. Chromatin remodeling is crucial for various differentiation and gene regulation processes and is rather well studied in T cells. However, for monocytes not much is known regarding how the epigenetic machinery influences the differentiation into various effector cell types. In the work presented here, we explore the epigenetic underpinnings of monocyte differentiation. By transcriptional profiling we show that transcription of lysine methyltransferases (KMTs) and in particular KMT1c is markedly up regulated after differentiation of monocytes into immature dendritic cells (iDCs). Specifically inhibiting KMT1c function, using the small-molecule inhibitor BIX-01294, changes the transcription levels of the DC marker DC-SIGN, but does not affect surface protein expression. Blocking global KMT activity, using DZNep, does influence monocyte differentiation into iDCs, indicated by a loss of DC-SIGN surface expression. When BIX-01294 and DZNep treatment was combined DC-SIGN expression was almost lost completely. This work shows that the activities of KMTs are required for successful differentiation of monocyte derived dendritic cells. Furthermore it shows the importance of KMT inhibitors in the field of epigenetic immune therapy, which is still much focused around HDAC inhibitors. PMID- 25843230 TI - Atypical aHUS: State of the art. AB - Tremendous advances in our understanding of the thrombotic microangiopathies (TMAs) have revealed distinct disease mechanisms within this heterogeneous group of diseases. As a direct result of this knowledge, both children and adults with complement-mediated TMA now enjoy higher expectations for long-term health. In this update on atypical hemolytic uremic syndrome, we review the clinical characteristics; the genetic and acquired drivers of disease; the broad spectrum of environmental triggers; and current diagnosis and treatment options. Many questions remain to be addressed if additional improvements in patient care and outcome are to be achieved in the coming decade. PMID- 25843231 TI - Absorption and Metabolism of Luteolin and Its Glycosides from the Extract of Chrysanthemum morifolium Flowers in Rats and Caco-2 Cells. AB - To elucidate the bioavailability of luteolin and its glycosides in Chrysanthemum morifolium flowers, the absorption and metabolism of luteolin from them was investigated in rats and Caco-2 cells using HPLC and LC-MS. After oral administration of C. morifolium extract (1.7 g/kg body weight (bw), equivalent to 22.8 and 58.3 MUmol/kg bw of luteolin and luteolin-7-O-glucoside, respectively) to rats, luteolin and its glycosides were quickly absorbed and luteolin, luteolin monoglucoside, and luteolin monoglucuronide were detected in the plasma. Their levels were highest at 1 h after administration (0.76 +/- 0.27 MUM). These compounds were also detected in media on the basolateral side from Caco-2 cells treated with the C. morifolium extract. These results suggest that luteolin and luteolin monoglucoside are rapidly absorbed after administration of C. morifolium flower extract and that luteolin, luteolin monoglucoside, and luteolin monoglucuronide may circulate in humans. PMID- 25843232 TI - Summary scores captured changes in subjects' QoL as measured by the multiple scales of the EORTC QLQ-C30. AB - OBJECTIVES: To examine the performance of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status/quality of life (QoL) scale and two summary scores to detect changes in the QoL profile over time, according to changes in the individual scales. STUDY DESIGN AND SETTING: Data came from 167 clinical trial patients with unresectable (advanced) hepatocellular carcinoma. The global health status/QoL scale of the questionnaire contained two items: overall health and overall QoL. Nordin and Hinz proposed summary scores for the questionnaire. A mixed-effect model was fitted to estimate trends in scores over time. RESULTS: Predominantly the individual scale scores declined over time; however, the global health status/QoL score was stable [rate of change = -0.3 per month; 95% confidence interval (CI): -1.2, 0.6]. Nordin's summary score, which gave equal weight to the 15 questionnaire scales, and Hinz's summary score, which gave equal weight to the 30 questionnaire items, showed a statistically significant decline over time, 3.4 (95% CI: -4.5, -2.4) and 4.2 (95% CI: -5.3, -3.0) points per month, respectively. CONCLUSION: In contrast to the global health status/QoL scale, the summary scores proposed by Nordin and Hinz detected changes in subjects' QoL profile described by the EORTC QLQ-C30 individual scales. PMID- 25843233 TI - Are practice trials required for hop tests? AB - Single-legged hop tests are commonly used in clinic and research settings to obtain information on functional performance of the injured leg. When performing these tests, it is typical to provide a few practice trials before performing actual test trials. However, the importance of practice trials and how it affects performance during actual test trials are not known. This study investigated the effect of practice trials on single-leg hop performance using a marker-based kinematic tracking approach in individuals with anterior cruciate ligament (ACL) reconstruction and athletic controls. Thirteen subjects with ACL reconstruction and thirteen uninjured healthy subjects performed the single hop for distance test for both legs. Three practice and five test trials were performed on each leg. Single-leg hop distance scores and hop indices (i.e., side-to-side hop distance ratios) obtained from practice and test trials were compared. There were significant differences in the mean hop distance between practice and test trials (P<0.05) when raw scores were compared, but no differences were observed when comparing the side-to-side distance ratios (P>0.05). There were also significantly high correlations between practice and test trials (P<0.01) and the agreement between practice and test scores was very good (rhoc=0.88-0.98). The findings suggest that subjects indeed improve their performance during test trials; however, the improvements had an inconsequential effect on the side-to side hop distance ratios. Therefore, if the examiner is interested only in side to-side ratios, then practice trials can be minimized or even avoided to improve efficiency and minimize time and costs associated with additional trials. PMID- 25843234 TI - How reliable are knee kinematics and kinetics during side-cutting manoeuvres? AB - INTRODUCTION: Side-cutting tasks are commonly used in dynamic assessment of ACL injury risk, but only limited information is available concerning the reliability of knee loading parameters. The aim of this study was to investigate the reliability of side-cutting data with additional focus on modelling approaches and task execution variables. METHODS: Each subject (n=8) attended six testing sessions conducted by two observers. Kinematic and kinetic data of 45 degrees side-cutting tasks was collected. Inter-trial, inter-session, inter-observer variability and observer/trial ratios were calculated at every time-point of normalised stance, for data derived from two modelling approaches. Variation in task execution variables was regressed against that of temporal profiles of relevant knee data using one-dimensional statistical parametric mapping. RESULTS: Variability in knee kinematics was consistently low across the time-series waveform (<=5 degrees ), but knee kinetic variability was high (31.8, 24.1 and 16.9 Nm for sagittal, frontal and transverse planes, respectively) in the weight acceptance phase of the side-cutting task. Calculations conveyed consistently moderate-to-good measurement reliability. Inverse kinematic modelling reduced the variability in sagittal (~6 Nm) and frontal planes (~10 Nm) compared to direct kinematic modelling. Variation in task execution variables did not explain any knee data variability. CONCLUSION: Side-cutting data appears to be reliably measured, however high knee moment variability exhibited in all planes, particularly in the early stance phase, suggests cautious interpretation towards ACL injury mechanics. Such variability may be inherent to the dynamic nature of the side-cutting task or experimental issues not yet known. PMID- 25843236 TI - Activation-induced and damage-induced cell death in aging human T cells. AB - In multicellular organisms the proper system functionality is ensured by the balance between cell division, differentiation, senescence and death. This balance is changed during aging. Immunosenescence plays a crucial role in aging and leads to the shrinkage of T cell repertoire and the propensity to apoptosis. The elimination of expanded T cells at the end of immune response is crucial to maintain homeostasis and avoid any uncontrolled inflammation. Resting mature T lymphocytes, when activated via their antigen-specific receptor (TCR) and CD28 co receptor, start to proliferate and then undergo the so called activation induced cell death (AICD), which mechanistically is triggered by the death receptor and leads to apoptosis. T lymphocytes, like other cells, are also exposed to damage, which can trigger the so called damage-induced cell death (DICD). It was hypothesized that oxidative stress and chronic antigenic load increasing with age reduced lymphocyte susceptibility to DICD and enhanced a proinflamatory status leading to increased AICD. However, data collected so far are inconsistent and does not support this assumption. Systematic and comprehensive studies are still needed for conclusive elucidation of the role of AICD and DICD in human immunosenescence, including the role of autophagy and necroptosis in the processes. PMID- 25843235 TI - NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging. AB - Though defective genome maintenance and DNA repair have long been known to promote phenotypes of premature aging, the role protein methylation plays in these processes is only now emerging. We have recently identified the first N terminal methyltransferase, NRMT1, which regulates protein-DNA interactions and is necessary for both accurate mitotic division and nucleotide excision repair. To demonstrate if complete loss of NRMT1 subsequently resulted in developmental or aging phenotypes, we constructed the first NRMT1 knockout (Nrmt1(-/-)) mouse. The majority of these mice die shortly after birth. However, the ones that survive, exhibit decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration; phenotypes characteristic of other mouse models deficient in DNA repair. The livers from Nrmt1(-/-) mice produce less reactive oxygen species (ROS) than wild type controls, and Nrmt1(-/-) mouse embryonic fibroblasts show a decreased capacity for handling oxidative damage. This indicates that decreased mitochondrial function may benefit Nrmt1(-/-) mice and protect them from excess internal ROS and subsequent DNA damage. These studies position the NRMT1 knockout mouse as a useful new system for studying the effects of genomic instability and defective DNA damage repair on organismal and tissue-specific aging. PMID- 25843237 TI - MARK-AGE population: From the human model to new insights. PMID- 25843239 TI - Effect of mucoadhesive polymers on the in vitro performance of insulin-loaded silica nanoparticles: Interactions with mucin and biomembrane models. AB - The present paper focuses on the development and characterization of silica nanoparticles (SiNP) coated with hydrophilic polymers as mucoadhesive carriers for oral administration of insulin. SiNP were prepared by sol-gel technology under mild conditions and coated with different hydrophilic polymers, namely, chitosan, sodium alginate or poly(ethylene glycol) (PEG) with low and high molecular weight (PEG 6000 and PEG 20000) to increase the residence time at intestinal mucosa. The mean size and size distribution, association efficiency, insulin structure and insulin thermal denaturation have been determined. The mean nanoparticle diameter ranged from 289 nm to 625 nm with a PI between 0.251 and 0.580. The insulin association efficiency in SiNP was recorded above 70%. After coating, the association efficiency of insulin increased up to 90%, showing the high affinity of the protein to the hydrophilic polymer chains. Circular dichroism (CD) indicated that no conformation changes of insulin structure occurred after loading the peptide into SiNP. Nano-differential scanning calorimetry (nDSC) showed that SiNP shifted the insulin endothermic peak to higher temperatures. The influence of coating on the interaction of nanoparticles with dipalmitoylphosphatidylcholine (DPPC) biomembrane models was also evaluated by nDSC. The increase of DeltaH values suggested a strong association of non coated SiNP and those PEGylated nanoparticles coated with DPPC polar heads by forming hydrogen bonds and/or by electrostatic interaction. The mucoadhesive properties of nanoparticles were examined by studying the interaction with mucin in aqueous solution. SiNP coated with alginate or chitosan showed high contact with mucin. On the other hand, non-coated SiNP and PEGylated SiNP showed lower interaction with mucin, indicating that these nanoparticles can interdiffuse across mucus network. The results of the present work provide valuable data in assessing the in vitro performance of insulin-loaded SiNP coated with mucoadhesive polymers. PMID- 25843238 TI - The use of cisplatin-loaded mucoadhesive nanofibers for local chemotherapy of cervical cancers in mice. AB - Polymer-based local drug delivery system may be suitable for the treatment of cervix cancer. A pilot study was carried out to examine the efficacy of cisplatin loaded poly(ethylene oxide)/polylactide composite electrospun nanofibers as a local chemotherapy system against cervical cancer in mice via vaginal implantation. The nanofibers were proven to have good mucoadhesive property by in vitro mucoadhesion test and in vivo vaginal retention evaluation. An orthotopic cervical/vaginal cancer model was established by injecting murine cervical cancer U14 cells into the vaginal submucosa nearby the cervix. By inserting the nanofibers mat into the vagina of mice, the cisplatin released from the fiber-mat showed a much more accumulation in the vagina/cervix region than in the peripheral organs such as kidneys, liver, or blood, in contrary to the case of intravenous (i.v) injection. The in vivo trials showed that a better balance between anti-tumor efficacy and systemic safety was achieved in nanofibers group than that in i.v injection group at the equal drug dose. Therefore, electrospun nanofibers present a promising approach to the local drug delivery via vagina against cervical cancer. PMID- 25843240 TI - Takeuchi repair of anomalous left coronary artery from the pulmonary artery. AB - Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare form of congenital heart disease that has been successfully palliated for decades. Prior to coronary reimplantation, the Takeuchi repair was the most common operative palliation. The Takeuchi repair is still seen today at less experienced congenital centers or when reimplantation is not possible. Patients who have had the Takeuchi repair are at risk of having subsequent complications related to this repair. Unfortunately, due to the surgical rarity, the post surgical anatomy is often poorly understood by cardiologists leading to inadequate risk factor assessment and compromised patient care. Coronary computed tomography angiography is a useful imaging modality to follow patients who have had the Takeuchi repair. PMID- 25843241 TI - Coronary competitive reverse flow: Imaging findings at CT angiography and correlation with invasive coronary angiography. AB - OBJECTIVE: To study the imaging features of coronary competitive reverse flow and incidence of a "reverse attenuation gradient" in coronary CT angiography (CTA) with correlation to invasive coronary angiography (ICA). METHODS: Patients who had undergone coronary CTA and ICA within 2 weeks were retrospectively identified in our database and reviewed. All cases with ICA-confirmed competitive reverse flow or chronic total occlusions (CTOs) were included for further analysis. The "reverse attenuation gradient sign" was defined as a reverse intraluminal opacification gradient of vessels which showed higher opacification in more distal compared with proximal segments. ICA findings were recorded and served as the reference to identify the clinical implications of this sign. RESULTS: In total, 134 patients (mean age, 68.1 +/- 11.3 years; range, 38-90 years; 104 men) were included in our study. ICA revealed 11 cases of coronary competitive reverse flow and 123 cases of CTO. A reverse attenuation gradient sign was present in 9 of 11 patients (82%) with coronary competitive reverse flow and 72 of 123 (59%) chronically occluded coronary arteries. Myocardial bridges, distal collateral filling, as well as direct visualization of collateral connection were all more frequent in cases with coronary competitive reverse flow group compared with cases with a CTO. CONCLUSIONS: The reverse attenuation gradient sign distal to an upstream coronary severe stenosis indicates the presence of competitive collateral flow. Coronary CTA is able to correctly detect coronary competitive collateral flow and differentiate it from CTOs. PMID- 25843242 TI - High-sensitivity cardiac troponin T is associated with coronary artery calcification. AB - OBJECTIVE: Recent studies have suggested that high-sensitivity cardiac troponin T (hs-cTnT) may be useful for detecting subclinical atherosclerosis and assessing cardiovascular disease risk. The aim of this study was to investigate whether serum hs-cTnT is associated with the degree of coronary artery calcification. METHODS: We measured serum hs-cTnT concentrations and performed multidetector row coronary CT in 215 consecutive, stable patients with clinical suspicion of coronary artery disease. Nonenhanced coronary CT was performed to determine the coronary calcium score, and contrast-enhanced coronary CT was performed to identify obstructive coronary artery disease. We then evaluated the relationship between serum hs-cTnT concentrations and the degree of coronary calcium or obstructive coronary artery disease using multiple regression analysis and logistic regression models. RESULTS: Multiple regression analysis demonstrated that serum hs-cTnT concentrations and calcium score were independently associated after logarithmic transformation (beta = 0.348; P < .0001). Logistic regression analyses demonstrated that serum hs-cTnT concentration was associated with an increased odds of an Agatston score >10 (odds ratio, 1.250; 95% confidence interval [CI], 1.150-1.378), an Agatston Score >400 (odds ratio, 1.101; 95% CI, 1.054-1.157), and obstructive coronary artery disease (odds ratio, 1.119; 95% CI, 1.066-1.185). CONCLUSION: Serum hs-cTnT is associated with coronary calcium in individuals with suspected coronary disease and may therefore be a marker to detect subclinical atherosclerosis. PMID- 25843243 TI - Effect of reduced x-ray tube voltage, low iodine concentration contrast medium, and sinogram-affirmed iterative reconstruction on image quality and radiation dose at coronary CT angiography: results of the prospective multicenter REALISE trial. AB - BACKGROUND: Both low tube voltage and sinogram-affirmed iterative reconstruction (IR) techniques hold promise to decrease radiation dose at coronary CT angiography (CCTA). The increased iodine contrast at low tube voltage allows for minimizing iodine load. OBJECTIVE: To assess the effect of reduced x-ray tube voltage, low iodine concentration contrast medium and IR on image quality and radiation dose at CCTA. METHODS: Two hundred thirty-one consecutive patients with suspected coronary artery disease were enrolled in this prospective, multicenter trial and randomized to 1 of 2 dual-source CCTA protocols: 120-kVp with 370 mgI/mL iopromide or iopamidol (n = 116; 44 women; 55.3 +/- 9.8 years) or 100 kVp with 270 mgI/mL iodixanol (n = 115; 48 women; 54.2 +/- 10.4 years). Reconstruction was performed with filtered back projection and IR. Attenuation, image noise, signal-to-noise ratio, and contrast-to-noise ratio were measured and image quality scored. Size-specific dose estimates and effective doses were calculated. RESULTS: There were no significant differences in mean arterial attenuation (406.6 +/- 76.7 vs 409.7 +/- 65.2 Hounsfield units; P = .739), image noise (18.7 +/- 3.8 vs 17.9 +/- 3.4 Hounsfield units; P = .138), signal-to-noise ratio (22.5 +/- 5.4 vs 23.7 +/- 6.1; P = .126), contrast-to-noise ratio (17.5 +/- 5.5 vs 18.3 +/- 6.1; P = .286), or image quality scores (4.1 +/- 0.9 vs 4.0 +/- 0.9; P > .05) between 120-kVp filtered back projection-reconstructed and 100-kVp IR-reconstructed series. Mean iodine dose was 26.5% lower (18.3 +/- 0.5 vs 24.9 +/- 0.9 g; P < .0001), mean size-specific dose estimate was 35.1% lower (17.9 +/- 6.6 vs 27.5 +/- 8.2 mGy; P < .0001), and effective dose was 34.9% lower (2.3 +/- 1.0 vs 3.5 +/- 1.1 mSv; P < .0001) with the 100 kVp compared with the 120-kVp protocol, respectively. CONCLUSION: Using low x-ray tube voltage and IR allows for decreasing the iodine load and effective radiation dose at CCTA while maintaining image quality. PMID- 25843245 TI - Dendritic cell functions: Learning from microbial evasion strategies. AB - Dendritic cells (DCs) are specialized antigen presenting cells (APC) that are fundamental to initiate both immunity and tolerance. DCs play a 'sentinel' role to protect our body from potential pathogens and induce tolerogenic responses toward harmless antigens. The flexibility of DCs or macrophages to adapt to the environment and to respond accordingly can be hijacked by pathogens for their own interest to transform a potentially immunogenic APC into a tolerogenic cell with clear consequences in pathogen clearance. While these immune evasion mechanisms can be detrimental for the host, they can highlight important molecular pathways in DCs necessary for their function. In this review we will mention several mechanisms employed by pathogens to evade DC patrolling function. PMID- 25843244 TI - Personal financial incentives for changing habitual health-related behaviors: A systematic review and meta-analysis. AB - OBJECTIVES: Uncertainty remains about whether personal financial incentives could achieve sustained changes in health-related behaviors that would reduce the fast growing global non-communicable disease burden. This review aims to estimate whether: i. financial incentives achieve sustained changes in smoking, eating, alcohol consumption and physical activity; ii. effectiveness is modified by (a) the target behavior, (b) incentive value and attainment certainty, (c) recipients' deprivation level. METHODS: Multiple sources were searched for trials offering adults financial incentives and assessing outcomes relating to pre specified behaviors at a minimum of six months from baseline. Analyses included random-effects meta-analyses and meta-regressions grouped by timed endpoints. RESULTS: Of 24,265 unique identified articles, 34 were included in the analysis. Financial incentives increased behavior-change, with effects sustained until 18months from baseline (OR: 1.53, 95% CI 1.05-2.23) and three months post incentive removal (OR: 2.11, 95% CI 1.21-3.67). High deprivation increased incentive effects (OR: 2.17; 95% CI 1.22-3.85), but only at >6-12months from baseline. Other assessed variables did not independently modify effects at any time-point. CONCLUSIONS: Personal financial incentives can change habitual health related behaviors and help reduce health inequalities. However, their role in reducing disease burden is potentially limited given current evidence that effects dissipate beyond three months post-incentive removal. PMID- 25843246 TI - A transcriptional perspective on human macrophage biology. AB - Macrophages are a major cell type in tissue homeostasis and contribute to both pathology and resolution in all acute and chronic inflammatory diseases ranging from infections, cancer, obesity, atherosclerosis, autoimmune disorders to neurodegenerative diseases such as Alzheimer's disease. The cellular and functional diversity of macrophages depends upon tightly regulated transcription. The innate immune system is under profound evolutionary selection. There is increasing recognition that human macrophage biology differs very significantly from that of commonly studied animal models, which therefore can have a limited predictive value. Here we report on the newest findings on transcriptional control of macrophage activation, and how we envision integrating studies on transcriptional and epigenetic regulation, and more classical approaches in murine models. Moreover, we provide new insights into how we can learn about transcriptional regulation in the human system from larger efforts such as the FANTOM (Functional Annotation of the Mammalian Genome) consortium. PMID- 25843247 TI - Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease. AB - OBJECTIVE: Vanishing white matter disease (VWM) is a chronic, progressive leukoencephalopathy associated with episodes of rapid deterioration following minor stress events such as head traumas or infectious disorders. The white matter of the patients with VWM exhibits characteristic radiological findings. METHOD: The genes encoding all five subunits of eukaryotic translation initiation factor 2B (EIF2B) were analyzed in patients, who were tentatively diagnosed with VWM, by Sanger sequencing. RESULTS: Seven mutations were identified in the genes encoding the subunits 1, 2, 4, and 5 of EIF2B. Among them, one mutation (p.V83E) in the subunit 2 (EIF2B2) was recurrently identified in three alleles, indicating the most common mutation in Japanese patients with VWM. Two patients were homozygous, and the other four patients were compound heterozygous. CONCLUSION: All patients showed white matter abnormalities with various degrees. One patient showed manifestations of end-stage VWM disease. Some patients showed late onset and slow progression associated with brain magnetic resonance imaging displaying T2 high intensity only in the deep white matter. There was clinical heterogeneity among patients with VWM. PMID- 25843249 TI - Duraseal thecal sac compression after lumbar discectomy causing radiculopathy. PMID- 25843248 TI - Three patients manifesting early infantile epileptic spasms associated with 2q24.3 microduplications. AB - BACKGROUND: Recent development of genetic analyses enabled us to reveal underlying genetic causes of the patients with epileptic encephalopathy in infancy. Mutations of voltage-gated sodium channel type I alpha subunit gene (SCN1A) are to be causally related with several phenotypes of epilepsy, generalized epilepsy with febrile seizure plus (GEFS+), Dravet syndrome, and other infantile epileptic encephalopathies. In addition to SCN1A, contiguous genes such as SCN2A and SCN3A in 2q24.3 are also reported to have contribution to epileptic seizures. Therefore, gene abnormality involving this region is reasonable to contribute to epilepsy manifestation. RESULTS: We encountered three patients with 2q24.3 microduplication diagnosed by Array comparative genomic hybridization array (aCGH). They developed partial seizures and epileptic spasms in their early infantile periods and showed remarkable developmental delay, although their seizures disappeared from 11 to 14 months of age. One of three patients had 2q24.3 microduplication which excludes SCN1A. Therefore, characteristics of epilepsy with 2q24.3 microduplication do not necessarily need duplication of SCN1A. This study suggested that 2q24.3 microduplication is one of the causes for early infantile epileptic spasms. Epileptic spasms associated with 2q24.3 microduplications may have better seizure outcome comparing with other etiologies. PMID- 25843250 TI - Anaplastic ependymoma of spinal cord presented with low back pain. PMID- 25843251 TI - Very rare reason of neurologic deficit: thoracic cystic schwannoma. PMID- 25843252 TI - Cervical hemangioma with neurologic deficit. PMID- 25843253 TI - Thoracic infantile hemangiopericytoma. PMID- 25843254 TI - Multiple butterfly vertebrae with disc through the sagittal cleft. PMID- 25843255 TI - Guggulsterone attenuates cerulein-induced acute pancreatitis via inhibition of ERK and JNK activation. AB - Guggulsterone (GS), a plant steroid and a compound found at high levels in Commiphora myrrha, exhibits anti-inflammatory, anti-cancer, and cholesterol lowering effects. However, the potential of GS to ameliorate acute pancreatitis (AP) is unknown. The aim of this study was to evaluate the effects of GS on cerulein-induced AP. AP was induced by intraperitoneally injecting supramaximal concentrations of the stable cholecystokinin analog cerulein (50 MUg/kg) hourly for 6 h. In the GS-treated group, GS was administered intraperitoneally (10, 25, or 50mg/kg) 1 h before the first cerulein injection. Mice were sacrificed 6 h after the final cerulein injection. Blood samples were collected to measure serum lipase levels and evaluate cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examinations, flow cytometry analysis, myeloperoxidase (MPO) assay, and real-time reverse transcription polymerase chain reaction analysis. Pre-treatment with GS attenuated cerulein induced histological damage, reduced pancreas weight/body weight ratio, decreased serum lipase levels, inhibited infiltrations of macrophages and neutrophils, and suppressed cytokine production. Additionally, GS treatment suppressed the activation of extracellular signal-regulated protein kinase (ERK) and c-Jun N terminal kinase (JNK) in the pancreas in cerulein-induced pancreatitis. In conclusion, our results suggest that GS attenuates AP via deactivation of ERK and JNK. PMID- 25843256 TI - Fructose-1,6-bisphosphate suppresses lipopolysaccharide-induced expression of ICAM-1 through modulation of toll-like receptor-4 signaling in brain endothelial cells. AB - Fructose-1,6-bisphosphate (FBP) is a glycolytic intermediate with salutary effects in various brain injury models, but its neuroprotective mechanism is incompletely understood. In this study, we examined the effects of FBP on the expression of adhesion molecules in cerebrovascular endothelial cells and explored the possible mechanisms therein involved. FBP significantly down regulated lipopolysaccharide (LPS)-induced expression of adhesion molecules and leukocyte adhesion to brain endothelial cells and inhibited NF-kappaB activity, which is implicated in the expression of adhesion molecules. FBP abrogated ICAM-1 expression and NF-kappaB activation induced by macrophage-activating lipopeptide 2-kDa (MALP-2) or overexpression of MyD88 or TRAF6. FBP suppressed TRAF6-induced phosphorylation of TAK1, IKKbeta and IkappaBalpha, but fail to affect NF-kappaB activity induced by ectopic expression of IKKbeta. In addition, LPS-induced IRAK 1 phosphorylation was inhibited by FBP, suggesting the presence of multiple molecular targets of FBP in MyD88-dependent signaling pathway. FBP significantly attenuated ICAM-1 expression and NF-kappaB activity induced by poly[I:C] or overexpression of TRIF or TBK1. FBP significantly repressed the expression of interferon-beta (IFN-beta) and the activation of IFN regulatory factor 3 (IRF3) induced by LPS, poly[I:C] or overexpression of TRIF or TBK1, but fail to affect IRF3 activity induced by ectopic expression of constitutively active IRF3. Overall, our results demonstrate that FBP modulates both MyD88- and TRIF dependent signaling pathways of TLR4 and subsequent inflammatory responses in brain endothelial cells, providing insight into its neuroprotective mechanism in brain injury associated with inflammation. PMID- 25843257 TI - Oxidative airway inflammation leads to systemic and vascular oxidative stress in a murine model of allergic asthma. AB - Oxidant-antioxidant imbalance plays an important role in repeated cycles of airway inflammation observed in asthma. It is when reactive oxygen species (ROS) overwhelm antioxidant defenses that a severe inflammatory state becomes apparent and may impact vasculature. Several studies have shown an association between airway inflammation and cardiovascular complications; however so far none has investigated the link between airway oxidative stress and systemic/vascular oxidative stress in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of vascular/systemic oxidant-antioxidant balance. Rats were sensitized intraperitoneally with ovalbumin (OVA) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with OVA. Rats were then assessed for airway and vascular inflammation, oxidative stress (ROS, lipid peroxides) and antioxidants measured as total antioxidant capacity (TAC) and thiol content. Challenge with OVA led to increased airway inflammation and oxidative stress with a concomitant increase in vascular inflammation and oxidative stress. Oxidative stress in the vasculature was significantly inhibited by antioxidant treatment, N-acetyl cysteine; whereas hydrogen peroxide (H2O2) inhalation worsened it. Therefore, our study shows that oxidative airway inflammation is associated with vascular/systemic oxidative stress which might predispose these patients to increased cardiovascular risk. PMID- 25843258 TI - In-vivo deformation measurements of the human heart by 3D Digital Image Correlation. AB - Fast and accurate measurements of the kinetics and deformation of the heart during cardiac surgery can be useful for assessing the best strategies for the protection of the myocardium. While measurements based on ultrasonic technology such as the transesophageal echocardiography are rapidly developing in this direction, also other analysis methods based on optical imaging have been developed within the recent decade. The improved quality of digital cameras and increased computational power of personal computers have led to the development of deformation analysis method known as Digital Image Correlation (DIC). This paper presents preliminary results on the application of the DIC technique on analysing of the movement and deformation of the myocardial movement during a cardiopulmonary bypass surgery. The results show that the natural pattern of the heart should be sufficient for DIC, but better and more accurate results could be obtained with improved contrast conditions. DIC has a potential to be used as a sensitive tool for the surgeon to monitor the cardiac function. PMID- 25843259 TI - Material properties of individual menisci and their attachments obtained through inverse FE-analysis. AB - Meniscal properties for computational methods have already been proposed. However, it is well known that there is high intra subject variability in the material properties of soft tissues and that disruption of the fiber network alters the biomechanics of the meniscus. Therefore, the objective of this study was to establish a non invasive method to determine the material properties of the individual menisci and their attachments using inverse FE-analyses. In a previous study, the 3D displacements of the meniscus and its attachments under axial joint loads were determined for intact porcine knees. To simulate the experimental response in individual FE-analyses (n=5), an anisotropic, hyperelastic meniscus matrix was embedded in a poroelastic model. During a particle swarm optimization, the difference between the force applied to the meniscus during the experiment and the femoral surface reaction force of the FE model at equilibrium was minimized by varying four material parameters. Afterwards, a prediction error was determined to describe how well the material parameter fit to each of the three displacement directions. Additionally, the stresses occurring in the meniscus were evaluated. The error of the material parameter optimization was on average 6.5+/-4.4%. The best fitting material parameter combination revealed an error of 1.2%. The highest stresses occurred in the region between the pars intermedia and posterior horn of the meniscus. The individual material properties of the meniscus were successfully obtained with a combination of previously reported, noninvasively measured 3D displacements and inverse FE-analyses. The methodology presented in this study is a promising contribution to the detection of degeneration within the meniscus. PMID- 25843260 TI - The impact of boundary conditions on surface curvature of polypropylene mesh in response to uniaxial loading. AB - Exposure following pelvic organ prolapse repair has been observationally associated with wrinkling of the implanted mesh. The purpose of this study was to quantify the impact of variable boundary conditions on the out-of-plane deformations of mesh subjected to tensile loading. Using photogrammetry and surface curvature analyses, deformed geometries were accessed for two commercially available products. Relative to standard clamping methods, the amount of out-of-plane deformation significantly increased when point loads were introduced to simulate suture fixation in-vivo. These data support the hypothesis that regional increases in the concentration of mesh potentially enhance the host's foreign body response, leading to exposure. PMID- 25843261 TI - Strain distribution in the proximal Human femur during in vitro simulated sideways fall. AB - This study assessed: (i) how the magnitude and direction of principal strains vary for different sideways fall loading directions; (ii) how the principal strains for a sideways fall differ from physiological loading directions; (iii) the fracture mechanism during a sideways fall. Eleven human femurs were instrumented with 16 triaxial strain gauges each. The femurs were non destructively subjected to: (a) six loading configurations covering the range of physiological loading directions; (b) 12 configurations simulating sideways falls. The femurs were eventually fractured in a sideways fall configuration while high-speed cameras recorded the event. When the same force magnitude was applied, strains were significantly larger in a sideways fall than for physiological loading directions (principal compressive strain was 70% larger in a sideways fall). Also the compressive-to-tensile strain ratio was different: for physiological loading the largest compressive strain was only 30% larger than the largest tensile strain; but for the sideways fall, compressive strains were twice as large as the tensile strains. Principal strains during a sideways fall were nearly perpendicular to the direction of principal strains for physiological loading. In the most critical regions (medial part of the head-neck) the direction of principal strain varied by less than 9 degrees between the different physiological loading conditions, whereas it varied by up to 17 degrees between the sideways fall loading conditions. This was associated with a specific fracture mechanism during sideways fall, where failure initiated on the superior-lateral side (compression) followed by later failure of the medially (tension), often exhibiting a two-peak force-displacement curve. PMID- 25843262 TI - Direct measurement of the intrinsic ankle stiffness during standing. AB - Ankle stiffness contributes to standing balance, counteracting the destabilizing effect of gravity. The ankle stiffness together with the compliance between the foot and the support surface make up the ankle-foot stiffness, which is relevant to quiet standing. The contribution of the intrinsic ankle-foot stiffness to balance, and the ankle-foot stiffness amplitude dependency remain a topic of debate in the literature. We therefore developed an experimental protocol to directly measure the bilateral intrinsic ankle-foot stiffness during standing balance, and determine its amplitude dependency. By applying fast (40 ms) ramp and-hold support surface rotations (0.005-0.08 rad) during standing, reflexive contributions could be excluded, and the amplitude dependency of the intrinsic ankle-foot stiffness was investigated. Results showed that reflexive activity could not have biased the torque used for estimating the intrinsic stiffness. Furthermore, subjects required less recovery action to restore balance after bilateral rotations in opposite directions compared to rotations in the same direction. The intrinsic ankle-foot stiffness appears insufficient to ensure balance, ranging from 0.93+/-0.09 to 0.44+/-0.06 (normalized to critical stiffness 'mgh'). This implies that changes in muscle activation are required to maintain balance. The non-linear stiffness decrease with increasing rotation amplitude supports the previous published research. With the proposed method reflexive effects can be ruled out from the measured torque without any model assumptions, allowing direct estimation of intrinsic stiffness during standing. PMID- 25843263 TI - Development of a stable Gaussia luciferase enterovirus 71 reporter virus. AB - We report a stable Gaussia luciferase enterovirus 71 (Gluc-EV71) reporter virus to facilitate drug discovery. The Gluc-EV71 reporter virus was generated by engineering the Gaussia luciferase (Gluc) gene between the 5' untranslated region and VP4 gene of the EV71 genome. We could recover Gluc-EV71 after transfection of Vero cells with the cDNA clone-derived RNA. The reporter virus efficiently infects and replicates in various cell types (Vero, human rhabdomyosarcoma, and HeLa cells), producing robust luciferase activity. The Gluc-EV71 virus replicates slower than the wild-type virus in cell culture. The reporter virus is stable in maintaining the Gluc gene after five rounds of continuous passaging in Vero cells. Using known EV71 inhibitors, we demonstrate that the reporter virus can be used for antiviral testing. However, the Gluc-EV71 infection assay cannot be adapted to a homogenous format for high throughput screen, mainly due to the secreted nature of the Gluc protein and the short half-life of the Gluc luminescence signal. The Gluc-EV71 and its infection assay could be useful for antiviral drug discovery as well as for studying EV71 replication and pathogenesis. PMID- 25843264 TI - Sources of variation analysis and derivation of reference intervals for ALP, LDH, and amylase isozymes using sera from the Asian multicenter study on reference values. AB - BACKGROUND: Sources of variation (SV) of ALP, LDH, and amylase isozymes were explored. METHODS: We analyzed 3511 sera from well-defined healthy individuals recruited during the 2009 Asian project for derivation of common reference intervals (RIs). Up-to-date electrophoresis auto-analyzer and reagents were employed for high resolution and reproducibility. SVs including sex, age, body mass index (BMI), ABO blood groups, and levels of drinking, smoking, and exercise were analyzed by multiple regression analysis. RIs were determined by parametric methods after refining healthy individuals by use of latent reference values exclusion method. RESULTS: Age-related changes in ALP2-3 were different in females: ALP2, linear increase from 20-64y; ALP3, lowering until 45 y and rising steeply thereafter. ALP2 increased with BMI especially in females. ALP5 was barely detectable except in blood-types O and B. Age-related increases in LDH1 LDH3 were noted in females, whereas BMI-related increases were found only for LDH2-LDH5 in both sexes. Pancreatic amylase showed age-related increase in females and was slightly higher in blood-type O. RIs for absolute and relative activities of each isozyme were derived in consideration of sex and age. CONCLUSIONS: Investigation of these isozymes revealed various age-, BMI-, and blood-type-related changes that are all relevant in clinical interpretation of enzyme test results. PMID- 25843265 TI - A phenol-free method for isolation of microRNA from biological fluids. AB - MicroRNAs (miRNAs) found in biological fluids such as blood and urine have been identified as promising biomarkers for many human disorders, including cancer, cardiopathies, and neurodegenerative diseases. However, circulating miRNAs are either encapsulated into vesicles or found in complexes with proteins and lipoproteins and, thus, require a special approach to their isolation. Acid phenol-chloroform extraction can solve this problem, but it is a labor-intensive procedure that relies heavily on the use of hazardous chemicals. Here we describe a fast and simple phenol-free protocol for miRNA isolation from biofluids. MiRNA is extracted from complexes with biopolymers by a high concentration of guanidine isothiocyanate combined with water/organic composition of solvents. Purification is finished using silica-based spin columns. Comparison of miRNA isolation from blood plasma and urine using the single-phase method and acid phenol-chloroform extraction by means of radioisotope spike-ins and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) showed similar performance of the two methods. PMID- 25843266 TI - Defining patient acceptable symptom state thresholds for commonly used patient reported outcomes measures in general orthopedic practice. AB - BACKGROUND: Patient reported outcomes measures are distributed regularly within musculoskeletal physical therapy practice in an effort to track patient progress and response to treatment. A number of studies have reported on the amount of change necessary to identify the minimal clinically important difference. Few studies have identified thresholds signifying patient satisfaction with treatment and what patient specific factors may be influential in identifying patient satisfaction. OBJECTIVES: To identify thresholds amongst commonly used patient reported outcomes measures associated with the patient acceptable symptom state (PASS). To identify the confounding effects of demographic and psychosocial variables on reported PASS estimates. DESIGN: Prospective cohort study. METHOD: A sample of convenience consisting of consecutive patients referred for outpatient physical therapy for general orthopaedic conditions fulfilling the eligibility criteria were included. All patients completed baseline demographic information as well as baseline pain and functional outcomes measures. The PASS question was used as the anchor in this study to identify patient thresholds. Patients completed outcomes measures every 2 weeks and at patient discharge. PASS thresholds were identified using receiver-operating curves maximizing sensitivity and specificity. RESULTS: PASS thresholds were found to vary depending on baseline pain levels, functional status, socioeconomic status, educational level, and psychosocial status. CONCLUSIONS: Multiple factors are influential in determining patient success following treatment. Clinicians should be aware of patient baseline pain and functional status as well as socioeconomic status, educational level, and psychosocial status and stratify patients accordingly when determining patient prognosis and developing a plan of care. PMID- 25843267 TI - Stabilizing effects of excipients on dissociation of intact (146S) foot-and-mouth disease virions into 12S particles during storage as oil-emulsion vaccine. AB - Most conventional foot-and-mouth disease virus (FMDV) vaccines contain oil adjuvant. Their potency decreases upon prolonged storage. Intact (146S) FMDV particles can dissociate into 12S degradation products with a concomitant decrease in immunogenicity. We therefore measured virion stability in vaccines using two previously developed ELISAs to separately quantify 12S and 146S particles. Virions completely dissociated into 12S particles within 3 months after oil-emulsification. Dissociation occurred at a much lower rate in a comparable aqueous solution that was not oil-emulsified. Thus, oil-emulsification stimulates virion dissociation, presumably due to the protein denaturing effect of the oil-water interface. In real-time stability studies the stability of oil adjuvanted virions of four different FMDV strains was significantly increased by addition of sucrose and BSA in a synergistic manner. Contrary to BSA addition, the effect of sucrose addition was concentration dependent. This study illustrates the importance of analysing antigen integrity after oil emulsification and provides methods for FMDV vaccine stabilization. PMID- 25843268 TI - Observational study on immune response to yellow fever and measles vaccines in 9 to 15-month old children. Is it necessary to wait 4 weeks between two live attenuated vaccines? AB - BACKGROUND: The use of 2 live attenuated vaccines (LAV) is recommended to be simultaneous or after an interval of at least four weeks between injections. The primary objective of this study was to compare the humoral response to yellow fever (YF) and measles vaccines among children vaccinated against these two diseases, either simultaneously or separated by an interval of 7-28 days. SUBJECTS AND METHODS: A prospective, multicenter observational study was conducted among children aged 9-15 months. The primary endpoint was the occurrence of positive yellow fever antibodies after YF vaccine by estimating the titers of neutralizing antibodies from venous blood samples. Children vaccinated against YF 7-28 days after receiving the vaccine against measles (test group) were compared with children vaccinated the same day against these two diseases (referent group). RESULTS: Analysis was performed on 284 children. Of them, fifty four belonged to the test group. Measles serology was positive in 91.7% of children. Neutralizing antibodies against YF were detected in 90.7% of the test group and 92.9 of the referent group (p=0.6). In addition, quantitative analysis of the immune response did not show a lower response to YF vaccination when it took place 1-28 days after measles vaccination. DISCUSSION: In 1965, Petralli showed a lower response to the smallpox vaccine when injected 4-20 days after measles vaccination. Since then, recommendations are to observe an interval of four weeks between LAV not injected on the same day. Other published studies failed to show a significant difference in the immune response to a LAV injected 1-28 days after another LAV. These results suggest that the usual recommendations for immunization with two LAV may not be correct. CONCLUSION: In low income countries, the current policy should be re-evaluated. This re-evaluation should also be applied to travelers to yellow fever endemic countries. PMID- 25843269 TI - The long-term efficacy, 13-23 years, of a plasma-derived hepatitis B vaccine in highly endemic areas in China. AB - OBJECTIVE: To evaluate the long-term effectiveness of the plasma-derived hepatitis B vaccine that has been applied widely in five areas of China where HBV prevalence was highly endemic. METHOD: A cross-sectional investigation was conducted in 2009 at five HBV surveillance sites around China. The target study subjects of 6772 were born between 1986 and 1996 and received plasma-derived HBV vaccine. Serum samples were collected to test for HBV markers using the microparticle enzyme immunoassay. RESULTS: The number of participants enrolled was 6772. The average hepatitis B surface antigen (HBsAg) prevalence was 2.01%. The birth dose group included 5052 children. In this group, the average positive rates of HBsAg and hepatitis B core antibody (anti-HBc) were 1.58% and 6.39%, respectively, and these values declined gradually from 1986 to 1996. The positive rates of anti-hepatitis B surface antibody (HBs) and the geometric mean concentration (GMC) of anti-HBs-positive subjects were 41.69% and 115.8mIU/ml. CONCLUSION: The long-term effectiveness of the plasma-derived hepatitis B vaccine still provided protection 13-23 years after vaccination. It seems that a booster dose is not necessary. Enhancing the rate of the birth dose within 24h is one of the most important measures to prevent and control HBV infection. PMID- 25843271 TI - Characterization of Red/Green Cyanobacteriochrome NpR6012g4 by Solution Nuclear Magnetic Resonance Spectroscopy: A Protonated Bilin Ring System in Both Photostates. AB - Cyanobacteriochromes (CBCRs) are cyanobacterial photoreceptors distantly related to phytochromes. Both CBCRs and phytochromes use photoisomerization of a linear tetrapyrrole (bilin) chromophore to photoconvert between two states with distinct spectral and biochemical properties, the dark state and the photoproduct. The isolated CBCR domain NpR6012g4 from Nostoc punctiforme is a well-characterized member of the canonical red/green CBCR subfamily, photosensory domains that can function as sensors for light color or intensity to regulate phototactic responses of filamentous cyanobacteria. Such red/green CBCRs utilize conserved Phe residues to tune the photoproduct for green light absorption, but conflicting interpretations of the photoproduct chromophore structure have been proposed. In the hydration model, the proposed photoproduct state is extensively solvated, with a loosely bound, conformationally flexible chromophore. In the trapped-twist model, the photoproduct chromophore is sterically constrained by hydrophobic amino acids, including the known Phe residues. Here, we have characterized chromophore structure in NpR6012g4 using solution nuclear magnetic resonance spectroscopy and a series of labeled chromophores. Four NH resonances are assigned for both the red-absorbing dark state and the green-absorbing photoproduct. Moreover, observed (13)C chemical shifts are in good agreement with those obtained for protonated rather than deprotonated bilins in ab initio calculations. Our results demonstrate that NpR6012g4 has a protonated, cationic bilin pi system in both photostates, consistent with a photoproduct structure in which the chromophore is not extensively hydrated. PMID- 25843270 TI - Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial. AB - BACKGROUND: Inactivated quadrivalent influenza vaccine (IIV4) containing two influenza A strains and one strain from each B lineage (Yamagata and Victoria) may offer broader protection against seasonal influenza than inactivated trivalent influenza vaccine (IIV3), containing a single B strain. This study examined the safety, immunogenicity, and lot consistency of an IIV4 candidate. METHODS: This phase III, randomized, controlled, multicenter trial in children/adolescents (9 through 17 years) and adults (18 through 60 years) was conducted in Australia and in the Philippines in 2012. The study was double-blind for IIV4 lots and open-label for IIV4 vs IIV3. Children/adolescents were randomized 2:2:2:1 and adults 10:10:10:1 to receive one of three lots of IIV4 or licensed IIV3. Safety data were collected for up to 6 months post-vaccination. Hemagglutination inhibition and seroneutralization antibody titers were assessed pre-vaccination and 21 days post-vaccination. RESULTS: 1648 adults and 329 children/adolescents received IIV4, and 56 adults and 55 children/adolescents received IIV3. Solicited reactions, unsolicited adverse events, and serious adverse events were similar for IIV3 and IIV4 recipients in both age groups. Injection-site pain, headache, malaise, and myalgia were the most frequently reported solicited reactions, most of which were mild and resolved within 3 days. No vaccine-related serious adverse events or deaths were reported. Post vaccination antibody responses, seroconversion rates, and seroprotection rates for the 3 strains common to both vaccines were comparable for IIV3 and IIV4 in both age groups. Antibody responses to IIV4 were equivalent among vaccine lots and comparable between age groups for each of the 4 strains. IIV4 met all European Medicines Agency immunogenicity criteria for adults for all 4 strains. CONCLUSIONS: In both age groups, IIV4 was well tolerated and caused no safety concerns, induced robust antibody responses to all 4 influenza strains, and met all EMA immunogenicity criteria for adults. CLINICAL TRIAL REGISTRY NUMBER: NCT01481454. PMID- 25843272 TI - One size does not always fit all: a reply to Stroud and Feeley. PMID- 25843273 TI - The concept of fitness in fluctuating environments. AB - Fitness is a central concept in evolutionary biology, but there is no unified definition. We review recent theoretical developments showing that including fluctuating environments and density dependence has important implications for how differences among phenotypes in their contributions to future generations should be quantified. The rate of phenotypic evolution will vary through time because of environmental stochasticity. Density dependence may produce fluctuating selection for large growth rates at low densities but for larger carrying capacities when population sizes are large. In general, including ecologically realistic assumptions when defining the concept of fitness is crucial for estimating the potential of evolutionary rescue of populations affected by environmental perturbations such as climate change. PMID- 25843274 TI - Sperm storage: distinguishing selective processes and evaluating criteria. AB - Sperm storage, the extended maintenance of viable sperm, probably occurs in most internally fertilizing animals. Because it temporally separates mating from conception, sperm storage can be adaptive in ecologically diverse habitats and affect life histories, mating systems, cryptic female choice, sperm competition, and sexual conflict. Sperm storage can result from different selective forces acting on females and/or males, sometimes resulting in coevolution. The various criteria often used to determine the presence of sperm storage in any given taxon can result from the action of any one or all of these selective forces. Here we discuss the criteria used to study sperm storage and how we can use these to better understand the evolution of diversity in sperm-storage adaptations. PMID- 25843276 TI - Biogenetically-inspired total synthesis of epidithiodiketopiperazines and related alkaloids. AB - Natural products chemistry has historically been the prime arena for the discovery of new chemical transformations and the fountain of insights into key biological processes. It remains a fervent incubator of progress in the fields of chemistry and biology and an exchange mediating the flow of ideas between these allied fields of science. It is with this ethos that our group has taken an interest in and pursued the synthesis of a complex family of natural products termed the dimeric epipolythiodiketopiperazine (ETP) alkaloids. We present here an Account of the highly complex target molecules to which we pegged our ambitions, our systematic and relentless efforts toward those goals, the chemistry we developed in their pursuit, and the insight we have gained for their translational potential as potent anticancer molecules. The dimeric ETP alkaloids are fungal metabolites that feature a highly complex molecular architecture comprising a densely functionalized core structure with many stereogenic centers, six of which are fully substituted, and a pair of vicinal quaternary carbon stereocenters, decorated on polycyclic architectures in addition to the unique ETP motif that has been recognized as acid-, base-, and redox-sensitive. A cyclo dipeptide consisting of an essential tryptophan residue and a highly variable ancillary amino acid lies at the core of these structures; investigation of the transformations that take this simplistic core to the complex alkaloids lies at the heart of our research program. The dimeric epidithiodiketopiperazine alkaloids have largely resisted synthesis on account of their complexity since the 1970s when the founding members of this class, chaetocin A ( Hauser , D. et al. Helv. Chim. Acta 1970 , 53 , 1061 ) and verticillin A ( Katagiri , K. et al. J. Antibiot. 1970 , 23 , 420 ), were first isolated. This was despite their potent cytotoxic and bacteriostatic activities, which were well appreciated at the time of their discovery. In the past decade, an increasing number of studies have uncovered powerful new biological processes that these molecules can uniquely effect, such as the inhibition of histone methyltransferases by chaetocin A ( Greiner , D. et al. Nat. Chem. Biol. 2005 , 1 , 143 ). In fact, the complete collection of hexahydropyrroloindoline alkaloids features a diverse range of potent biological properties including cytotoxic, antitumor, antileukemic, antiviral, antibiotic, and antinematodal activities ( Jiang , C.-S. ; Guo , Y.-W. Mini-Rev. Med. Chem. 2011 , 11 , 728 ). This melange of activities is reflective of their structural diversity. Under the precepts of retrobiosynthetic analysis, we have accomplished the syntheses of more than a dozen natural products, including members of the bionectin, calycanthaceous, chaetocin, gliocladin, naseseazine, and verticillin alkaloids. More importantly, these molecules have acted as venerable venues for the development of new strategies to address structural challenges including, but not limited to, C3-C3' vicinal quaternary centers, heterodimeric linkages, C3-Csp(2) linkages, diketopiperazine oxidation, stereoselective thiolation, homologue-specific polysulfidation, and C12-hydroxyl incorporation. Synthesis of these natural products has resulted in the structural confirmation, and sometimes revision such as the case of (+)-naseseazines A and B, as well as access to many plausible biogenetically relevant intermediates and new synthetic ETP derivatives. Furthermore, our studies have paved the way for the formulation of a comprehensive SAR profile and the identification of lead compounds with in vitro subnanomolar IC50's against a broad range of cancer types. PMID- 25843277 TI - The influence of biodegradable gemini surfactants, N,N'-bis(1-decyloxy-1 oxopronan-2-yl)-N,N,N',N' tetramethylpropane-1,3-diammonium dibromide and N,N' bis(1-dodecyloxy-1-oxopronan-2-yl) N,N,N',N'-tetramethylethane-1,2-diammonium dibromide, on fungal biofilm and adhesion. AB - A group of biodegradable alanine-derived gemini quaternary ammonium salts (bromides and chlorides) with various alkyl chains and spacer lengths was tested for anti-adhesive and anti-biofilm activity. The strongest antifungal activity was exhibited by bromides with 10 and 12 carbon atoms within hydrophobic chains (N,N'-bis(1-decyloxy-1-oxopronan-2-yl)-N,N,N',N'-tetramethylpropane-1,3 diammonium dibromide and N,N'-bis(1-dodecyloxy-1-oxopronan-2-yl)-N,N,N',N' tetramethylethane-1,2-diammonium dibromide). It was also demonstrated that these gemini surfactants enhanced the sensitivity of Candida albicans to azoles (itraconazole and fluconazole) and polyenes (amphotericin B and nystatine). Gemini quaternary ammonium salts effectively inhibited fungal cell adhesion to polystyrene and silicone surface. These compounds reduced C. albicans filamentation and eradicated C. albicans and Rhodotorula mucilaginosa biofilms, as it was shown in crystal violet and fluorescent staining. None of the tested compounds were cytotoxic against yeast mitochondrial metabolism. PMID- 25843278 TI - Cis-9, trans-11 and trans-10, cis-12 CLA mixture does not change body composition, induces insulin resistance and increases serum HDL cholesterol level in rats. AB - Synthetic supplements of conjugated linoleic acid (CLA) containing 50:50 mixture of cis-9, trans-11 and trans-10, cis-12 CLA isomers have been commercialized in some places for reducing body fat. However the safety of this CLA mixture is controversial and in some countries the CLA usage as food supplement is not authorized. Changes in insulinemic control and serum lipids profile are potential negative effects related to consumption of CLA mixture. The present study aimed to evaluate the effects of a diet containing mixture of cis-9, trans-11 and trans 10, cis-12 CLA on prevention of obesity risk as well as on potential side effects such as insulin resistance and dyslipidemia in Wistar rats. Thirty male Wistar rats were randomly assigned to the following dietary treatments (n=10/group), for 60 days: Normolipidic Control (NC), diet containing 4.0% soybean oil (SO); High Fat-Control (HF-C), diet containing 24.0% SO; High Fat-synthetic CLA (HF-CLA), diet containing 1.5% of an isomeric CLA mixture (Luta-CLA 60) and 22.5% SO. Luta CLA 60 (BASF) contained nearly 60% of CLA (cis-9, trans-11 and trans-10, cis-12 CLA at 50:50 ratio). The HF-CLA diet contained 0.3% of each CLA isomer. HF-CLA diet had no effect on dietary intake and body composition. HF-CLA-fed rats had lower levels of PPARgamma protein in retroperitoneal adipose tissue, hyperinsulinemia compared to HF-C-fed rats, hyperglycemia compared to NC-fed rats while no differences in glycemia were observed between NC and HF-C groups, increased HOMA index and higher levels of serum HDL cholesterol. Thus, feeding rats with a high fat diet containing equal parts of cis-9, trans-11 and trans-10, cis-12 CLA isomers had no effect on body composition and induced insulin resistance. Despite HF-CLA-fed rats had increased serum HDL cholesterol levels, caution should be taken before synthetic supplements containing cis-9, trans-11 and trans-10, cis-12 CLA are recommended as a nutritional strategy for weight management. PMID- 25843279 TI - Characteristic odor components of essential oils from Eurya japonica. AB - The chemical compositions of essential oils from the flower and aerial parts (i.e., leaf and branch) of Eurya japonica were determined and quantified using gas chromatography-mass spectrometry (GC-MS). A total of 87 and 50 compounds were detected in the oils from the flower and aerial parts, respectively. The main compounds of the flower oil were linalool (14.0%), (9Z)-tricosene (12.0%), and nonanal (7.4%). In the oil from the aerial parts, linalool (37.7%), alpha terpineol (13.5%), and geraniol (9.6%) were detected. In the oils from the flower and aerial parts, 13 and 8 aroma-active compounds were identified by GC olfactometry (GC-O) analysis, respectively. The key aroma-active compounds of the flower oil were heptanal [fatty, green, flavor dilution (FD) = 128, odor activity value (OAV) = 346], nonanal (sweet, citrus, FD = 128, OAV = 491), and eugenol (sweet, spicy, FD = 64, OAV = 62): in the oil from the aerial parts, the key aroma-active compounds were linalool (sweet, citrus, FD = 64, OAV = 95), (E)-beta damascenone (sweet, FD = 256, OAV = 4000), and (E)-beta-ionone (floral, violet, FD = 128, OAV = 120). This study revealed that nonanal and eugenol impart the sweet, citrus, and spicy odor of the flower oil, while (E)-beta-damascenone and (E)-beta-ionone contribute the floral and sweet odor of the oil from the aerial parts. PMID- 25843280 TI - Synthesis of waste cooking oil based biodiesel via ferric-manganese promoted molybdenum oxide / zirconia nanoparticle solid acid catalyst: influence of ferric and manganese dopants. AB - The utilization of ferric-manganese promoted molybdenum oxide/zirconia (Fe-Mn- MoO3/ZrO2) (FMMZ) solid acid catalyst for production of biodiesel was demonstrated. FMMZ is produced through impregnation reaction followed by calcination at 600 degrees C for 3 h. The characterization of FMMZ had been done using X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), thermal gravimetric analysis (TGA), temperature programmed desorption of NH3 (TPD-NH3), transmission electron microscopy(TEM) and Brunner-Emmett-Teller (BET) surface area measurement. The effect of waste cooking oil methyl esters (WCOME's) yield on the reactions variables such as reaction temperature, catalyst loading, molar ratio of methanol/oil and reusability were also assessed. The catalyst was used to convert the waste cooking oil into corresponding methyl esters (95.6%+/-0.15) within 5 h at 200C reaction temperature, 600 rpm stirring speed, 1:25 molar ratio of oil to alcohol and 4% w/w catalyst loading. The reported catalyst was successfully recycled in six connective experiments without loss in activity. Moreover, the fuel properties of WCOME's were also reported using ASTM D 6751 methods. PMID- 25843281 TI - Bioactivity and chemical constituents of the essential oil from Dendranthema indicum (L.) Des Moul. against two stored insects. AB - Dendranthema indicum (L.) Des Moul. is a perennial herb commonly used as a traditional Chinese medicine for a long time. In this work, we took Dendranthema indicum as a target plant and two stored insects which include Tribolium castaneum and Stegobium paniceum adults as target insects. Essential oil obtained from Dendranthema indicum was analyzed by gas chromatography-mass spectrometry (GC-MS). A total of 31 components representing 92.44% of the oil were identified and the main compounds were found to be chamazulene (15.93%), beta-caryophyllene (13.78%), germacrene D (9.11%), and b-cis-farnesene (6.59%). With a further isolation, three constituents were obtained from the essential oil and identified as chamazulene, beta-caryophyllene and eucalyptol. Significantly, in the progress of assay, it showed that the essential oil and chamazulene exhibited stronger insecticidal and repellent activities against Stegobium paniceum than Tribolium castaneum. The results indicate that additional to its traditional use as Chinese medicinal herb, the essential oil of Dendranthema indicum aerial parts and isolated compounds have potential to be developed into natural insecticides or repellents for control of insects in stored grains. PMID- 25843282 TI - Agroecosystem development of industrial fermentation waste -- characterization of aroma-active compounds from the cultivation medium of Lactobacillus brevis. AB - Volatile oils obtained from both the liquid medium after incubation (MAI) and liquid medium before incubation (MBI) during the cultivation process of Lactobacillus brevis were isolated by hydrodistillation (HD) and analyzed to determine the utility of the liquid waste. The composition of the volatile oils was analyzed by capillary gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). In total, 55 and 36 compounds were detected in the volatile oils from MAI (MAI oil) and MBI (MBI oil), respectively. The principle components of MAI oil were N-containing compounds, including 2,3-dimethylpyrazine (16, 37.1 %), methylpyrazine (4, 17.1 %). The important aroma-active compounds in the oils were detected by GC-Olfactometry (GC-O), and their intensity of aroma were measured by aroma extract dilution analysis (AEDA). Expressly, pyrazine compounds were determined as key aroma components; in particular, 2,5-dimethylpyrazine and 2,3-dimethylpyrazine were the most primary aroma-active compound in MAI oil. These results imply that the waste medium after incubation of L. brevis may be utilized as a source of volatile oils. PMID- 25843283 TI - Method for attaining rosemary essential oil with differential composition from dried or fresh material. AB - Rosemary (Rosemarinus officinalis L.) is a well-known medicinal and essential oil plant, utilized by humankind since ancient times. The objective was to determine the effect of steam distillation time (DT) and material (dry or fresh biomass) on essential oil yield, composition, and bioactivity; and to develop regression models that can predict oil yield and composition at specific DT. The oil yield (content) from dry biomass was higher (0.43%) than that from fresh biomass (0.35%) and ranged from 0.18% in the 1.25 min DT to 0.51% in the 40 min DT. There was no yield advantage in extending the DT beyond 40 min, which is much shorter than the DT used by industry. In this study, the antioxidant capacity of the rosemary oil using the ORACoil method was 4,108 MUmolVE/L. Rosemary oil did not exhibit significant antileishmanial, antimalarial, or antimicrobial activity. In general, the low-boiling constituents eluted earlier than the higher boiling constituents of the essential oil, resulting in a great variation of essential oil composition obtained at different DT. The most important constituents are alpha-pinene, eucalyptol, and camphor. The highest alpha-pinene concentration in the oil (30.4%) was obtained from dry biomass at 2.5 min DT; eucalyptol (23.3% of the total oil) from fresh biomass at 2.5 min DT; and camphor (15.9% of the total oil) from fresh biomass at 160 min DT. The DT could be used as an inexpensive tool to alter essential oil composition of the essential oil from fresh or dried rosemary biomass, and to produce rosemary oils with elevated or lowered concentration of specific targeted oil constituents to meet specific market demands. PMID- 25843285 TI - Cardio-oncology Part I: chemotherapy and cardiovascular toxicity. AB - Cancer and cardiovascular disease are the most common causes of mortality in the US, causing approximately 1.2 million deaths annually. The incidence of cancer is expected to increase as the population ages. The prognosis of cancer patients has improved over the last few decades primarily because of newer chemotherapeutic drugs; however, many of these drugs have cardiotoxic side effects. The short-term cardiovascular toxicities of more established drugs are well described; however, understanding of the underlying pathogenesis is increasing. The delayed cardiotoxic effects of cancer treatments have become an important issue contributing to mortality and morbidity as cancer survivorship increases. Chemotherapy-induced cardiotoxicity can manifest in many ways, from asymptomatic decreases in left ventricular ejection fraction to congestive heart failure. Hypertension is commonly seen both as a co-morbidity and a side effect of chemotherapy. In this article, we discuss the pathogenesis, scope, presentation and potential prevention of these toxicities. PMID- 25843284 TI - The effect of various antioxidants on the degradation of O/W microemulsions containing esterified astaxanthins from Haematococcus pluvialis. AB - Esterified astaxanthins are used as functional nutraceuticals and pigments in many food products. Unfortunately, the utilization is currently limited due to their chemical instability and poor water-solubility. In this study, esterified astaxanthins were quantified and purified from Haematococcus pluvialis using a novel and precise approach. By HPLC-(+)APCI-MS/MS, twenty esterified astaxanthin molecular species were identified, of which classified into eight monoester forms (approximately 85%, w/w) and twelve diester forms (approximately 15%, w/w), depending on the number of fatty acids that bind thereto. The MS data showed that the predominant fatty acids in astaxanthin esters of H. pluvialis are usually a long chain fatty acid with 16~18 carbon atoms, such as C18:1, C18:2, C18:3, C18:4, C16:0, C16:1. The purity of the esterified astaxanthins was determined to be 96.8+/-1.2% after purification. A well water-dispersible microemulsion was fabricated using high purity esterified astaxanthins, ethyl butyrate, Tween 80 and ethanol; and that emulsion exhibited a mean particle radius around 60 nm. The chemical degradation of esterified astaxanthins was monitored under accelerated stress storage conditions. After storage for 20 days, the results indicated that the degradation of esterified astaxanthins was effectively slowed by the addition of antioxidants to the microemulsions. By investigating the dependence of the chemical degradation of the esterified astaxanthins in O/W microemulsions on the concentration of the additives, it was concluded that the effectiveness of the additives at inhibiting the degradation of the esterified astaxanthins decreased in the following order: EDTA > ascorbic acid > vitamin E acetate. The utilization of antioxidants in combination was less effective than using them individually. These results provide information for designing effective delivery systems, thereby delaying the chemical degradation of esterified astaxanthins in foods, beverages and other commercial products during long-term storage. PMID- 25843286 TI - A statistical note on analyzing and interpreting individual-level epidemiological data. PMID- 25843287 TI - The Japanese government's "good sleep" challenge: Sleep Guidelines for Health Promotion 2014. PMID- 25843288 TI - Identification of environmental sounds and melodies in syndromes of anterior temporal lobe degeneration. AB - Recognition of nonverbal sounds in semantic dementia and other syndromes of anterior temporal lobe degeneration may determine clinical symptoms and help to define phenotypic profiles. However, nonverbal auditory semantic function has not been widely studied in these syndromes. Here we investigated semantic processing in two key nonverbal auditory domains - environmental sounds and melodies - in patients with semantic dementia (SD group; n=9) and in patients with anterior temporal lobe atrophy presenting with behavioural decline (TL group; n=7, including four cases with MAPT mutations) in relation to healthy older controls (n=20). We assessed auditory semantic performance in each domain using novel, uniform within-modality neuropsychological procedures that determined sound identification based on semantic classification of sound pairs. Both the SD and TL groups showed comparable overall impairments of environmental sound and melody identification; individual patients generally showed superior identification of environmental sounds than melodies, however relative sparing of melody over environmental sound identification also occurred in both groups. Our findings suggest that nonverbal auditory semantic impairment is a common feature of neurodegenerative syndromes with anterior temporal lobe atrophy. However, the profile of auditory domain involvement varies substantially between individuals. PMID- 25843289 TI - Characterization of spheroids in hereditary diffuse leukoencephalopathy with axonal spheroids. AB - Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a neurodegenerative disease clinically characterized by slowly progressive cognitive decline and motor dysfunction. Neuropathology shows diffuse degeneration in the white matter, with prominent presence of widespread axonal spheroids. To investigate the mechanism underlying HDLS neurodegeneration, we characterized spheroids and examined their development in the degenerated white matter. Analysis revealed that the spheroids are an early neuropathological manifestation in the white matter degeneration and involve axonal component proteins and alpha-synuclein. The development of spheroids facilitates in initiating neurodegeneration in HDLS. PMID- 25843290 TI - Physical functional capacity in idiopathic pulmonary fibrosis: performance characteristics of the continuous-scale physical function performance test. AB - BACKGROUND: Physical functional capacity is impaired in idiopathic pulmonary fibrosis (IPF). There is no tool to measure this key clinical outcome. The continuous-scale physical function performance (CS-PFP) test is one that assesses activities of daily living, but it has never been used in IPF. METHODS: We determined internal consistency of the CS-PFP. We used correlations to assess the strength of association between CS-PFP scores and various parameters of IPF severity, and compared the CS-PFP scores between patients with IPF and published values from a healthy control group. RESULTS: Sixteen subjects completed the test and retest. Test-retest reliability (0.84, p = 0.003) and internal consistency (Cronbach's alpha = 0.91) were excellent. Subjects with IPF had significantly worse CS-PFP scores than controls (46.0 +/- 11.1 vs 58.7 +/- 12.5, p = 0.001). In IPF, the CS-PFP scores correlated moderately to very strongly with several disease severity variables. CONCLUSION: The CS-PFP is a reliable and valid tool in IPF. PMID- 25843291 TI - miR-483-5p determines mitochondrial fission and cisplatin sensitivity in tongue squamous cell carcinoma by targeting FIS1. AB - Mitochondria play an important role in the initiation of apoptosis. However, whether cisplatin can induce apoptosis by initiating a mitochondrial fission pathway and the mechanism underlying this effect remain poorly understood. In this study, we show that the mitochondrial fission protein FIS1 is upregulated upon cisplatin treatment in tongue squamous cell carcinoma (TSCC) cells. FIS1 knockdown can attenuate mitochondrial fission and cisplatin sensitivity. We found that FIS1 is a direct target of miR-483-5p and that miR-483-5p can inhibit mitochondrial fission and cisplatin sensitivity in vitro and in vivo. Furthermore, we found that miR-483-5p and FIS1 are significantly associated with cisplatin sensitivity and with overall survival in patients with TSCC in a retrospective analysis of multiple centers. This study revealed that a novel mitochondrial fission pathway composed of miR-483-5p and FIS1 regulates cisplatin sensitivity. The modulation of miR-483-5p and FIS1 levels may provide a new approach for increasing cisplatin sensitivity. PMID- 25843292 TI - Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. AB - Cytokine induced killer (CIK) cell-based treatments have shown antitumor activity against renal cell carcinoma (RCC) in vitro and in vivo. But the therapeutic options and benefits of various CIK cells were unknown for different stages of RCC. In this random clinical trial, the 3-year disease free survival (DFS) of operable RCC patients treated with autologous tumor lysate-pulsed dendritic cells co-cultured with cytokine induced killer (Ag-DC-CIK) was 96.7% compared with 57.7% in the control group. Ag-DC-CIK immunotherapy decreased the risk of post operative disease progression and relapse (P = 0.0418). In inoperable RCC patients treated with CIK, the 3-year overall survival (OS) and progression-free survival (PFS) were significantly longer than the control group (P = 0.0116 and P = 0.0212). The CD4(+)/CD8(+) T cell ratio in peripheral blood increased after the last cell infusion in the CIK treatment group, and especially further increased in the Ag-DC-CIK treatment group (P = 0.002). No severe toxicity was observed after infusion of CIK cells. Therefore, tumor antigen-sensitized Ag-DC-CIK cells might be more efficient and personalized for the patients with tumor resection, and CIK cells could improve the prognosis for those inoperable patients. According to the stages of RCC patients, different CIK cell-based immunotherapies would help to achieve more beneficial effects. PMID- 25843293 TI - SKP2 is a direct transcriptional target of MYCN and a potential therapeutic target in neuroblastoma. AB - SKP2 is the substrate recognition subunit of the ubiquitin ligase complex which targets p27(KIP1) for degradation. Induced at the G1/S transit of the cell cycle, SKP2 is frequently overexpressed in human cancers and contributes to malignancy. We previously identified SKP2 as a possible MYCN target gene and hence hypothesise that SKP2 is a potential therapeutic target in MYCN amplified disease. A positive correlation was identified between MYCN activity and SKP2 mRNA expression in Tet21N MYCN-regulatable cells and a panel of MYCN amplified and non-amplified neuroblastoma cell lines. In chromatin immunoprecipitation and reporter gene assays, MYCN bound directly to E-boxes within the SKP2 promoter and induced transcriptional activity which was decreased by the removal of MYCN and E box mutation. Although SKP2 knockdown inhibited cell growth in both MYCN amplified and non-amplified cells, cell cycle arrest and apoptosis were induced only in non-MYCN amplified neuroblastoma cells. In conclusion these data identify SKP2 as a direct transcriptional target of MYCN and supports SKP2 as a potential therapeutic target in neuroblastoma. PMID- 25843294 TI - MicroRNA-30d-5p inhibits tumour cell proliferation and motility by directly targeting CCNE2 in non-small cell lung cancer. AB - MicroRNAs (miRNAs) are small, single-stranded, non-coding RNA molecules that are dysregulated in many types of human cancers, although their precise functions in driving non-small cell lung cancer (NSCLC) are incompletely understood. In the present study, we found that miR-30d-5p, often downregulated in NSCLC tissues, significantly inhibited the growth, cell cycle distribution, and motility of NSCLC cells. Furthermore, we demonstrated that cyclin E2 (CCNE2), which was often upregulated in NSCLC tissues, was a direct target of miR-30d-5p. CCNE2 expression promoted the proliferation, invasion, and migration of NSCLC cells. In addition, the re-introduction of CCNE2 expression antagonised the inhibitory effects of miR 30d-5p on the capacity of NSCLC cells for proliferation and motility. Together, these results suggest that the miR-30d-5p/CCNE2 axis may contribute to NSCLC cell proliferation and motility, indicating miR-30d-5p as a potential therapeutic target for the treatment of NSCLC. PMID- 25843295 TI - Connexin-43 downregulation in G2/M phase enriched tumour cells causes extensive low-dose hyper-radiosensitivity (HRS) associated with mitochondrial apoptotic events. AB - Enrichment of tumour cells in G2/M phases in vitro is known to be associated with low-dose hyper-radiosensitivity (HRS). These cell cycle phases also involve reduced expression of adhesion protein connexin-43 (Cx43). Therefore, we investigated the role of Cx43 in HRS. Asynchronous or G2/M enriched tumour cells (U87, BMG-1, HeLa) and normal primary fibroblasts (HDFn) were gamma-irradiated at varying doses, with an asynchronous group separately subjected to Cx43-knockdown prior to irradiation. Cx43 level, gap junctional activity, clonogenic cell survival, cell growth/viability, mitochondrial alterations and other apoptosis regulating events were studied. G2/M enrichment reduced Cx43 level by ~50% and caused considerable HRS at doses 10 cGy-30 cGy in all tumour cell lines. Cx43 knockdown to the same level (~60%) also elicited prominent HRS response in these cells. Quite important, radiosensitivity of primary HDFn cells remained unaltered by all these treatments. In Cx43-knockdown tumour cells, low-dose irradiation caused significant growth inhibition and apoptosis involving loss of MMP, cytochrome-c release and caspase-3 activation, thereby demonstrating the important cytoprotective role of Cx43. Therefore, this study significantly shows that Cx43 downregulation (a constitutive feature of G2/M phase) selectively renders tumour cells hypersensitive to low-dose radiation, and presents connexins as potential therapeutic targets. PMID- 25843296 TI - A rapid guide to PTEN function. PMID- 25843297 TI - PTEN: a yin-yang master regulator protein in health and disease. AB - The PTEN gene is a tumor suppressor gene frequently mutated in human tumors, which encodes a ubiquitous protein whose major activity is to act as a lipid phosphatase that counteracts the action of the oncogenic PI3K. In addition, PTEN displays protein phosphatase- and catalytically-independent activities. The physiologic control of PTEN function, and its inactivation in cancer and other human diseases, including some neurodevelopmental disorders, is upon the action of multiple regulatory mechanisms. This provides a wide spectrum of potential therapeutic approaches to reconstitute PTEN activity. By contrast, inhibition of PTEN function may be beneficial in a different group of human diseases, such as type 2 diabetes or neuroregeneration-related pathologies. This makes PTEN a functionally dual yin-yang protein with high potential in the clinics. Here, a brief overview on PTEN and its relation with human disease is presented. PMID- 25843298 TI - Direct costs of unintended pregnancy in Spain. AB - OBJECTIVE: The aim of the study was to estimate the burden and direct medical costs of unintended pregnancy to the public payer in Spain. METHODS: An economic model evaluating the costs and outcomes of contraceptive use over a 1-year period was constructed for women in Spain aged 15 to 44 years at risk of pregnancy. Model inputs were derived from published literature and national survey data. Outcomes evaluated included: (i) the annual number of unintended pregnancy events and their cost; (ii) the proportion of unintended pregnancy events and their cost due to non-adherence; and (iii) the use and cost of contraceptive methods in Spain. RESULTS: Of the total number of pregnancies, 35% are estimated to be unintended and are associated with a direct cost burden of ?292.8 million per year. Most unintended pregnancies (26%) occur in women aged 30 to 34 years, whilst 69% of the total cost burden is estimated to be attributable to poor adherence to contraceptive methods. CONCLUSIONS: The cost associated with unintended pregnancy is high. The major proportion of the burden is estimated to be attributable to imperfect adherence and is likely avoidable. Shifts in patterns of contraceptive use, combined with measures to improve adherence, could have a substantial and positive impact on this burden. PMID- 25843299 TI - The value of cardiac MRI versus echocardiography in the pre-operative assessment of patients with Duchenne muscular dystrophy. AB - BACKGROUND/PURPOSE: Duchenne Mmuscular Ddystrophy (DMD) related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been systematically evaluated as pre-operative assessment tool for heart function in DMD. Our aim was to establish whether CMR versus echocardiography contributes to pre-operative DMD assessment. METHODS: Case records were retrospectively reviewed of 35 consecutive DMD boys who underwent evaluation for surgical procedures between 2010 and 2013. RESULTS: Echocardiography revealed a median left ventricular (LV) shortening fraction (SF) of 29/% (range: 7-44). 37% of boys (13/35) had abnormal SF <25%, 66% (23/35) showed hypokinesia and 26% (9/35) had LV dilatation. CMR revealed a median left ventricular ejection fraction (LVEF) of 52% (range: 27-67%). 57% of boys (20/35) had abnormal LVEF <55%, 71% (25/35) had hypokinesia, and 82% late gadolinium enhancement. Extensive versus minimal late gadolinium enhancement was associated with reduced left ventricular ejection fraction (48% vs 58%; p = 0.003) suggesting more severe cardiomyopathy. Although echocardiography shortening fraction correlated with CMR ejection fraction (rs = 0.67; p < 0.001), three quarter of echocardiography studies had suboptimal scanning windows and in 26% measurements significantly over- or underestimated left-ventricular function compared to CMR. CONCLUSION: Our findings clearly demonstrate the added value of CMR versus echocardiography in assessing DMD-cardiomyopathy. Particularly when echocardiographic scanning windows are suboptimal, CMR should be considered to allow accurate pre-operative cardiac assessment. PMID- 25843300 TI - Outcomes and predictors of improved survival after gamma knife radiosurgery for metastatic brain tumors originated from breast carcinoma. AB - Gamma knife radiosurgery (GKRS) has emerged as a possible treatment option for metastasis brain tumor (MBTs) originated from breast cancer. However, the intermediate or long-term outcome of GKRS on MBTs originated from breast carcinoma is not well defined. The outcome of GKRS on MBTs derived from breast carcinoma was reviewed in our institution's case series. We performed a retrospective review (2000-2013) of 50 patients with MBTs originated from breast cancer who received GKRS. Out of 50 patients, 11 patients had recurrent tumors after microsurgical resection and the other 39 patients received GKRS alone. The study population was followed clinically and radiographically after GKRS treatment. GKRS on MBTs metastasized from breast cancer showed significant variations in tumor growth control (decreased in 14 (31.9 %) patients, arrested growth in 17 (38.6 %) patients, and progressed tumor in 13 (29.5 %) patients). The overall median survival in this case series was 33 months. In our case series, overall survival rate after 5 years was 20 %, whereas progression-free survival rate after 5 years was 30 %. The prognostic factors for improving survival in the patients with MBTs from breast cancer were recursive partitioning analysis (RPA) class I (p = 0.014), age <=65 years (p = 0.025), controlled primary tumor (p = 0.04), and single number of MBTs (p = 0.022). Recent follow-up revealed that GKRS offers good overall survival period in both new and recurrent patients with MBTs originated from breast carcinoma. Thus, GKRS is a therapeutic option for new and recurrent patients with MBTs derived from breast cancer. PMID- 25843301 TI - Utility of three-dimensional computed tomography for anatomical assistance in endoscopic endonasal transsphenoidal surgery. AB - Endoscopic endonasal transsphenoidal surgery (ETSS) has been widely applied to pituitary adenomas. However, anatomical orientation is difficult when structures of the sphenoidal sinus are complicated. This study investigated the usefulness of three-dimensional computed tomography (3D-CT) modeling in planning surgical procedures for ETSS and providing anatomical guidance during surgery. CT data from 99 consecutive patients with pituitary adenoma treated between January 2008 and March 2014 were used to reconstruct 3D-CT models. Based on these images, the architecture of sphenoidal sinus, particularly structures surrounding the sellar floor, was visualized for preoperative simulation of surgical procedures. These 3D-CT images were also compared to surgical views during ETSS to evaluate applicability of the images. These models clearly demonstrated the morphology of the nasal cavity and structures of the sphenoidal sinus, including bony prominences of the internal carotid arteries (ICAs) and optic canals by successively eliminating sphenoidal structures. The 3D-CT images permitted determination of the maximum marginal line of the opening of the sellar floor by presenting vital structures such as ICAs and optic canals. With this 3D-CT model, the surgeon could access the sella more easily, open the floor widely enough for each individual patient, and resect the tumor maximally without complications. Preoperative 3D-CT models distinctly visualized the optic canals, bilateral ICAs, and complicated structures of sphenoidal septa. The 3D-CT images were useful for preoperative planning and as a road map during endoscopic surgery for pituitary adenoma, facilitating maximum tumor resection without complications. PMID- 25843303 TI - Backbone structures in human milk oligosaccharides: trans-glycosylation by metagenomic beta-N-acetylhexosaminidases. AB - This paper describes the discovery and characterization of two novel beta-N acetylhexosaminidases HEX1 and HEX2, capable of catalyzing the synthesis of human milk oligosaccharides (HMO) backbone structures with fair yields using chitin oligomers as beta-N-acetylglucosamine (GlcNAc) donor. The enzyme-encoding genes were identified by functional screening of a soil-derived metagenomic library. The beta-N-acetylhexosaminidases were expressed in Escherichia coli with an N terminal His6-tag and were purified by nickel affinity chromatography. The sequence similarities of the enzymes with their respective closest homologues are 59 % for HEX1 and 51 % for HEX2 on the protein level. Both beta-N acetylhexosaminidases are classified into glycosyl hydrolase family 20 (GH 20) are able to hydrolyze para-nitrophenyl-beta-N-acetylglucosamine (pNP-GlcNAc) as well as para-nitrophenyl-beta-N-acetylgalactosamine (pNP-GalNAc) and exhibit pH optima of 8 and 6 for HEX1 and HEX2, respectively. The enzymes are able to hydrolyze N-acetylchitooligosaccharides with a degree of polymerization of two, three, and four. The major findings were, that HEX1 and HEX2 catalyze trans glycosylation reactions with lactose as acceptor, giving rise to the human milk oligosaccharide precursor lacto-N-triose II (LNT2) with yields of 2 and 8 % based on the donor substrate. In total, trans-glycosylation reactions were tested with the disaccharide acceptors beta-lactose, sucrose, and maltose, as well as with the monosaccharides galactose and glucose resulting in the successful attachment of GlcNAc to the acceptor in all cases. PMID- 25843304 TI - Effectiveness of direct immobilization of bacterial cells onto material surfaces using the bacterionanofiber protein AtaA. AB - The bacterionanofiber protein AtaA, a member of the trimeric autotransporter adhesin family found in Acinetobacter sp. Tol 5, is responsible for the nonspecific, high adhesiveness and autoagglutination of this strain. Previously, we introduced the ataA gene into the nonadhesive Acinetobacter strain ST-550, which conferred high adhesiveness to this strain, immobilized its cells, and improved indigo productivity due to enhanced tolerance to the toxic substrate. In this study, we again demonstrated the effectiveness of this new microbial immobilization method using AtaA in a number of conditions. AtaA enabled the effective immobilization of growing, resting, and lyophilized cells of a type strain of Acinetobacter, ADP1, which is also intrinsically nonadhesive, onto the surface of several kinds of support ranging from artificial to natural materials and from hydrophobic polyurethane to hydrophilic glass. Immobilization with AtaA enabled exclusive cell growth in the support space and only a few cells existed in the bulk medium. Immobilization of resting cells drastically increased cell concentration, depending on the support material; dry cells of approximately 110 g/L could be immobilized onto glass wool. Finally, we demonstrated that ADP1 cells immobilized on polyurethane foam can undergo at least 10 repetitive reactions without inactivation during a 5-h period. Even after drying and storing for 3 days, the immobilized cells showed enzymatic activity and an ester hydrolysis reaction was repeated by simply transferring the support with the cells into a fresh reaction buffer. PMID- 25843305 TI - Diagnostic criteria for DCD: Past and future. AB - The aim of this review was to gather information on how well authors comply to DSM criteria in their description and selection of children with DCD. We investigated which selection criteria were used in experimental and intervention studies published in the last 5 years (2010-2014). Results on 176 papers are summarized. Compliance to the DSM criteria has improved over this time period. In general, detailed information was provided on motor performance using standardized test scores and cut-off values are reported. Method sections were far less detailed about other DSM criteria (i.e., whether motor coordination problems interfered with activities of daily living and how IQ, other medical conditions or co-occurring disorders were checked). Views on how the new DSM-5 criteria could be specified for clinical and research use are discussed. PMID- 25843302 TI - The gut microbiome in multiple sclerosis. AB - OPINION STATEMENT: The gut microbiome is made up of a wide range of (chiefly) bacterial species that colonize the small and large intestine. The human gut microbiome contains a subset of thousands of bacterial species, with up to 10(14) total bacteria. Studies examining this bacterial content have shown wide variations in which species are present between individuals. The gut microbiome has been shown to have profound effects on the development and maintenance of immune system in both animal models and in humans. A growing body of evidence has implicated the human gut microbiome in a range of disorders, including obesity, inflammatory bowel diseases, and cardiovascular disease. Animal studies present compelling evidence that the gut microbiome plays a significant role in the progression of demyelinating disease, and that modulation of the microbiome can lead to either exacerbation or amelioration of symptoms. Differences in diet, vitamin D insufficiency, smoking, and alcohol use have all been implicated as risk factors in MS, and all have the ability to affect the composition of the gut microbiota. Preliminary clinical trials aimed at modulating the gut microbiota in MS patients are underway and may prove to be a promising and lower-risk treatment option in the future. PMID- 25843306 TI - A divided ventricle: A rare case of hypertrophic cardiomyopathy with 'burned out' apex. PMID- 25843307 TI - Cardiovascular effects of fingolimod: Relevance, detection and approach. AB - Fingolimod, a structural analogue of sphingosine, is the first oral treatment available for multiple sclerosis. The presence of sphingosine-1-phosphate receptors in the sinus and atrioventricular nodes, myocardial cells, endothelial cells and arterial smooth muscle cells is responsible for fingolimod's cardiovascular effects. We provide a comprehensive review of the mechanisms of these effects and characterize their clinical relevance. PMID- 25843308 TI - Rotational atherectomy: Technical update. AB - Percutaneous coronary intervention is currently the most common form of revascularization for symptomatic coronary artery disease. In elderly, diabetic and renal patients, there is an increased prevalence of calcified coronary disease. Rotational atherectomy (RA) can be useful in the treatment of these lesions. Plaque removal was initially proposed as an alternative to balloon angioplasty, hence RA required high-velocity protocols with large-sized burrs (over 2.0 mm). With a high incidence of acute complications and disappointing restenosis rates, the use of RA dwindled. However, the advent of drug-eluting stents, which significantly decreased the rate of restenosis, led to the repositioning of RA as an adjunctive technique in the preparation of densely calcified lesions, improving stent delivery and expansion. In recent years, a better understanding of the mechanism of action of RA has changed it from a plaque debulking to a compliance modifying technique. As a result, RA has become less aggressive, using smaller size burrs and lower rotational speeds. This conservative approach has improved immediate results, with increased safety and better long-term outcomes. In this review paper, the technique of RA is explained in the light of current knowledge. PMID- 25843309 TI - Fever-induced type 1 Brugada pattern. AB - Brugada syndrome, first described over 20 years ago, is characterized by a typical electrocardiographic pattern with coved-type ST-segment elevation in the right precordial leads and a high risk of sudden death in otherwise healthy young adults. The electrocardiographic pattern is sometimes intermittent, and fever is a possible trigger. The authors present the case of a 68-year-old woman who came to the emergency department with fever and syncope. A diagnosis of community acquired pneumonia was made. The electrocardiogram performed when the patient had fever revealed a type 1 Brugada pattern, which disappeared after the fever subsided. After other causes of Brugada-like pattern were excluded, Brugada syndrome was diagnosed and a cardioverter-defibrillator was implanted. This case demonstrates that this entity can be diagnosed at more advanced ages and highlights the usefulness of electrocardiography in a febrile state. PMID- 25843310 TI - More on noncompaction in Fabry's disease. PMID- 25843311 TI - Noncompaction in Fabry's disease. PMID- 25843312 TI - Performance of traditional risk factors in identifying a higher than expected coronary atherosclerotic burden. AB - OBJECTIVE: To evaluate the performance of traditional cardiovascular (CV) risk factors in identifying a higher than expected coronary atherosclerotic burden. METHODS: We assessed 2069 patients undergoing coronary CT angiography, with assessment of calcium score (CS), for suspected coronary artery disease. A higher than expected atherosclerotic burden was defined as CS >75th percentile (CS >P75) according to age and gender-adjusted monograms. The ability of traditional CV risk factors to predict a CS >P75 was assessed in a customized logistic regression model ("Clinical Score") and by the calculation of SCORE (Systemic Coronary Risk Evaluation). The population attributable risk (PAR) of risk factors for CS >P75 was calculated. RESULTS: The median CS was 3.0 (IQR 0.0-98.0); 362 patients had CS >P75. The median SCORE was 3.0 (IQR 1.0-4.0). With the exception of hypertension, all traditional CV risk factors were independent predictors of CS >P75: diabetes, dyslipidemia, smoking and family history (OR 1.3-2.2, p<=0.026). The areas under the ROC curves for CS >P75 were 0.64 for the Clinical Score (95% CI 0.61-0.67, p<0.001) and 0.53 for SCORE (95% CI 0.50-0.56, p=0.088). About a quarter of patients with CS >P75 were in the two lower quartiles of the Clinical Score. Altogether, the traditional risk factors explain 56% of the prevalence of CS >P75 (adjusted PAR 0.56). CONCLUSION: Despite the association of CV risk factors with a higher than expected atherosclerotic burden, they appear to explain only half of its prevalence. Even when integrated in scores, the predictive power of these risk factors was modest, exposing the limitations of risk stratification based solely on demographic and clinical risk factors. PMID- 25843313 TI - Characterization of human memory CD4(+) T-cell responses to the dog allergen Can f 4. AB - BACKGROUND: The recently identified dog lipocalin allergen Can f 4 is an important respiratory allergen. OBJECTIVE: We sought to comprehensively characterize the memory CD4(+) T-cell responses of allergic and nonallergic subjects to Can f 4. METHODS: Can f 4-specific CD4(+)CD45RO(+) T-cell lines (TCLs) from allergic and healthy subjects were established and characterized by their functional and phenotypic properties. The epitope specificity of the TCLs was tested with 48 overlapping 16-mer peptides spanning the sequence of Can f 4. HLA restriction of the specific TCLs and the binding capacity of the epitope containing peptides to common HLA class II molecules were studied. RESULTS: Can f 4-specific memory CD4(+) TCLs were obtained at an 8-fold higher frequency from allergic than from nonallergic subjects. Functionally, the TCLs of allergic subjects exhibited a higher T-cell receptor avidity and expression of CD25 and predominantly produced IL-4 and IL-5. The TCLs of nonallergic subjects mostly secreted IFN-gamma and IL-10, with high CXCR3 expression. Several distinct T-cell epitope regions along the allergen were identified. Importantly, the peptides from the region between amino acids 43 and 67 showed promiscuous HLA-binding capacity and induced memory CD4(+) T-cell responses in 90% of the allergic donors. CONCLUSION: Productive TH2-deviated memory T-cell responses to Can f 4 are observed in allergic but not nonallergic subjects. A 19-mer peptide sequence covering the core of the immunodominant region of the allergen is a potential target for the development of peptide-based allergen immunotherapy. PMID- 25843315 TI - Breast-feeding does not protect against allergic sensitization in early childhood and allergy-associated disease at age 7 years. AB - BACKGROUND: Extended breast-feeding is recommended for newborn children at risk of allergy-associated diseases, but the evidence of a protective effect on sensitization and these diseases remains elusive. OBJECTIVE: The aim of this study was to investigate the effects of the duration of exclusive breast-feeding on the development of sensitization in preschool children. METHODS: Information on breast-feeding was gathered by interviews involving 335 children aged 1, 6, and 12 months from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort born to mothers with a history of asthma. Skin prick test responses and specific IgE levels against 12 common inhalant and 10 food allergens were assessed longitudinally at ages 1/2 year, 11/2 years, 4 years, and 6 years. Eczema, wheeze/asthma, and allergic rhinitis were diagnosed at the Copenhagen Prospective Studies on Asthma in Childhood clinic at 7 years of age, strictly adhering to predefined algorithms. Associations between duration of exclusive breast-feeding and outcomes were analyzed by logistic regression. RESULTS: We found no significant association between duration of exclusive breast-feeding and development of sensitization in the first 6 years of life (odds ratio [OR]: 1/2 year, 1.10 [95% CI, 0.90-1.36]; 11/2 years, 1.15 [95% CI, 0.97-1.36]; 4 years, 1.08 [95% CI, 0.93-1.25]; and 6 years, 0.96 [95% CI, 0.84-1.10]) or with current eczema, wheeze/asthma, and allergic rhinitis at age 7 years (OR, 1.07 [95% CI, 0.92-1.24]; OR, 0.97 [95% CI, 0.82-1.14]; and OR, 1.02 [95% CI, 0.84-1.23], respectively). Adjusting for reverse causation by excluding children with eczema, wheeze, or a positive skin prick test response before ending exclusive breast feeding did not alter the results. CONCLUSION: Exclusive breast-feeding does not affect sensitization in early childhood or associated diseases at 7 years of age in at-risk children. PMID- 25843316 TI - Tunable catalytic activity of solid solution metal-organic frameworks in one-pot multicomponent reactions. AB - The aim of this research is to establish how metal-organic frameworks (MOFs) composed of more than one metal in equivalent crystallographic sites (solid solution MOFs) exhibit catalytic activity, which is tunable by virtue of the metal ions ratio. New MOFs with general formula [InxGa1-x(O2C2H4)0.5(hfipbb)] were prepared by the combination of Ga and In. They are isostructural with their monometal counterparts, synthesized with Al, Ga, and In. Differences in their behavior as heterogeneous catalysts in the three-component, one pot Strecker reaction illustrate the potential of solid solution MOFs to provide the ability to address the various stages involved in the reaction mechanism. PMID- 25843314 TI - Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency. AB - BACKGROUND: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. OBJECTIVE: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. METHODS: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. RESULTS: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. CONCLUSION: CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts. PMID- 25843318 TI - Pharmacokinetics of Levetiracetam in Healthy Hispaniolan Amazon Parrots ( Amazona ventralis ) After Oral Administration of a Single Dose. AB - Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots ( Amazona ventralis ), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 MUg/mL and 95.1 MUg/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14 100 and 28 820 mg * min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored. PMID- 25843319 TI - Voriconazole Disposition After Single and Multiple, Oral Doses in Healthy, Adult Red-tailed Hawks ( Buteo jamaicensis ). AB - Voriconazole is effective for treatment of aspergillosis, a common disease in captive red-tailed hawks ( Buteo jamaicensis ). To determine the disposition and safety of voriconazole after single and multiple, oral doses, 12 adult red-tailed hawks were studied in 2 phases. In phase 1, each bird received a single dose of voriconazole solution (10 mg/kg) by gavage. Blood samples were collected at 0, 0.5, 1, 3, 6, 9, 12, 16, 24, and 36 hours after treatment. In phase 2, each of 8 birds received voriconazole oral solution at 10 mg/kg PO q12h for 14 days. Plasma samples were collected on days 0, 5, and 10 and after the final dose and were processed as in phase 1. Plasma samples were submitted for analysis of voriconazole levels by high-performance liquid chromatography and ultraviolet spectrophotometry and for measurement of selected plasma biochemical parameters. After single dosing, voriconazole concentrations reached a (mean +/- SD) peak (Cmax) of 4.7 +/- 1.3 MUg/mL at 2.0 +/- 1.2 hours. The disappearance half-life (t1/2) was 2.8 +/- 0.7 hours, and the mean residence time (MRT) was 4.6 +/- 0.9 hours. After the last dose at 14 days, the mean Cmax of voriconazole was 4.5 +/- 2.7 MUg/mL at 2.4 +/- 1.1 hours. The t1/2 was 2.1 +/- 0.8 hours, and the MRT was 3.5 +/- 1.1 hours. Although concentrations of several plasma biochemical parameters were significantly different at study end compared with prestudy concentrations, only plasma creatine kinase activity was outside the reference range. No adverse reactions were observed in any of the birds. After both single and multiple dosing at 10 mg/kg, voriconazole concentrations exceeded the minimum inhibitory concentration to inhibit 90% (MIC90) of Aspergillus species (1 MUg/mL) by at least fourfold and remained above the MIC90 for 8.8 +/- 1.1 hours after single dosing versus 6.5 +/- 1.5 hours after multiple dosing (P = .003). This difference suggests that more frequent dosing (eg, up to q8h) may be necessary to maintain target concentrations during prolonged therapy. PMID- 25843317 TI - Altered Neurochemistry in Former Professional Soccer Players without a History of Concussion. AB - Soccer is played by more than 250 million people worldwide. Repeatedly heading the ball may place soccer players at high risk for repetitive subconcussive head impacts (RSHI). This study evaluates the long-term effects of RSHI on neurochemistry in athletes without a history of clinically diagnosed concussion, but with a high exposure to RSHI. Eleven former professional soccer players (mean age 52.0+/-6.8 years) and a comparison cohort of 14 age- and gender-matched, former non-contact sport athletes (mean age 46.9+/-7.9 years) underwent 3T magnetic resonance spectroscopy (MRS) and neurocognitive evaluation. In the soccer players a significant increase was observed in both choline (Cho), a membrane marker, and myo-inositol (ml), a marker of glial activation, compared with control athletes. Additionally, ml and glutathione (GSH) were significantly correlated with lifetime estimate of RSHI within the soccer group. There was no significant difference in neurocognitive tests between groups. Results of this study suggest an association between RSHI in soccer players and MRS markers of neuroinflammation, suggesting that even subconcussive head impacts affect the neurochemistry of the brain and may precede neurocognitive changes. Future studies will need to determine the role of neuroinflammation in RSHI and the effect on neurocognitive function. PMID- 25843320 TI - Lipid Panel Reference Intervals for Amazon Parrots (Amazona species). AB - The lipoprotein panel is a useful diagnostic tool that allows clinicians to evaluate blood lipoprotein fractions. It is a standard diagnostic test in human medicine but is poorly understood in avian medicine. Amazon parrots (Amazona species) are popular pets that frequently lead a sedentary lifestyle and are customarily fed high-fat diets. Similar to people with comparable diets and lifestyles, Amazon parrots are prone to obesity and atherosclerosis. In human medicine, these conditions are typically correlated with abnormalities in the lipoprotein panel. To establish reference intervals for the lipoprotein panel in Amazon parrots, plasma samples from 31 captive Amazon parrots were analyzed for concentrations of cholesterol, triglycerides, high-density lipoprotein (HDL), low density lipoprotein (LDL), and very low-density lipoprotein (VLDL). The data were also grouped according to sex, diet, body condition score, and age. Aside from HDL levels, which were significantly different between male and female parrots, no intergroup differences were found for any of the lipoprotein fractions. PMID- 25843321 TI - Circulating Fat-Soluble Vitamin Concentrations and Nutrient Composition of Aquatic Prey Eaten by American Oystercatchers (Haematopus palliatus palliatus) in the Southeastern United States. AB - The American oystercatcher (Haematopus palliatus palliatus) is currently listed as a species of high concern by the United States Shorebird Conservation Plan. Because nutritional status directly impacts overall health and reproduction of individuals and populations, adequate management of a wildlife population requires intimate knowledge of a species' diet and nutrient requirements. Fat soluble vitamin concentrations in blood plasma obtained from American oystercatchers and proximate, vitamin, and mineral composition of various oystercatcher prey species were determined as baseline data to assess nutritional status and nutrient supply. Bird and prey species samples were collected from the Cape Romain region, South Carolina, USA, and the Altamaha River delta islands, Georgia, USA, where breeding populations appear relatively stable in recent years. Vitamin A levels in blood samples were higher than ranges reported as normal for domestic avian species, and vitamin D concentrations were lower than anticipated based on values observed in poultry. Vitamin E levels were within ranges previously reported for avian groups with broadly similar feeding niches such as herons, gulls, and terns (eg, aquatic/estuarine/marine). Prey species (oysters, mussels, clams, blood arks [Anadara ovalis], whelks [ Busycon carica ], false angel wings [ Petricola pholadiformis ]) were similar in water content to vertebrate prey, moderate to high in protein, and moderate to low in crude fat. Ash and macronutrient concentrations in prey species were high compared with requirements of carnivores or avian species. Prey items analyzed appear to meet nutritional requirements for oystercatchers, as estimated by extrapolation from domestic carnivores and poultry species; excesses, imbalances, and toxicities particularly of minerals and fat-soluble vitamins-may warrant further investigation. PMID- 25843322 TI - Association of plasma lipid levels with atherosclerosis prevalence in psittaciformes. AB - The prevalence of atherosclerosis is high in the captive psittacine population and increases with age and female sex. The genera Psittacus, Amazona, and Nymphicus are predisposed to atherosclerosis, whereas the genera Cacatua and Ara are less susceptible. Plasma cholesterol and lipoprotein abnormalities have been suggested as risk factors in the development of atherosclerosis as observed in mammals. To investigate whether the psittacine genera susceptibility to atherosclerosis and the known risk factors of age and sex could be associated with differences in the lipid profile, a retrospective analysis was conducted on blood lipid values from 5625 birds. Prevalence values were obtained from a previously published, large, case-control study and were compared with identified trends in plasma lipid profiles. Genus-specific differences were identified in plasma total cholesterol values that corresponded to observed trends in the prevalence of clinically important atherosclerotic lesions, which were also highly correlated. The effect of age was significant but was mild and may not account for the dramatic increase in atherosclerosis prevalence observed with age. In addition, Quaker parrots ( Myiopsitta monachus ), which were used as experimental models for psittacine atherosclerosis and dyslipidemia, were found to have the highest values in all lipid profile parameters. The results of this study suggest that the differences observed in prevalence among species of the psittacine genera may partly be explained by differences in plasma total cholesterol levels. Results also support the use of Quaker parrots as models for studying atherosclerosis and dyslipidemia. PMID- 25843323 TI - Branchial Cyst With Carcinoma in an Umbrella Cockatoo (Cacatua alba). AB - A 16-year-old female umbrella cockatoo (Cacatua alba) was presented for a fluctuant, right-sided cervical mass that extended from the caudolateral edge of the right mandible to the coelomic inlet. Results of initial diagnostic tests were consistent with a cystic mass containing hemorrhage. Surgical exploration and removal of the mass was done, but because the hyoid apparatus was incorporated in the base of the cyst, complete surgical excision was not possible. Histopathologic results were consistent with a branchial cyst with carcinoma. Five months after surgery, the cockatoo exhibited intermittent periorbital swelling and epistaxis, and cytologic results of a fluid aspirate from the right infraorbital sinus were consistent with carcinoma. Results of magnetic resonance imaging revealed extensive abnormal T2 and short-tau inversion recovery hyperintense tissue associated with the right side of the head and neck, infiltrating between muscle planes and extending into the right retro-orbital tissue and nasal cavity. At 7 months after surgery, the bird was severely dyspneic and was euthanatized. To our knowledge, this is the first report describing the diagnosis, management, and histologic characteristics associated with a branchial cyst with carcinoma in an animal. PMID- 25843324 TI - Mycoplasma columbinum Isolated From a Racing Pigeon ( Columba livia ) With Arthritis. AB - A juvenile racing pigeon ( Columba livia ) was presented with drooping of the wing and inability to fly. On physical examination, the right shoulder joint was swollen. The pigeon was euthanatized and submitted for necropsy. An excessive amount of fibrin was present in the canalis triosseus with severe arthritis of the affected shoulder joint. A pure growth of Mycoplasma-like colonies was obtained on microbiological culture of the shoulder joint. A 16S ribosomal RNA gene-specific polymerase chain reaction assay was performed on the isolate and revealed 100% similarity with Mycoplasma columbinum . Although infectious arthritis in homing pigeons is primarily associated with paratyphoid and Streptococcus gallolyticus infection, clinical practitioners should consider the potential role of Mycoplasma columbinum in arthritis in pigeons. PMID- 25843326 TI - Avian health information management in the digital age. PMID- 25843325 TI - Coelomic Granulomatous Fat Necrosis (Lipogranulomatosis) in an Umbrella Cockatoo (Cacatua alba). AB - A 28-year-old, female umbrella cockatoo (Cacatua alba) was evaluated because of lethargy, anorexia, regurgitation, and coelomic swelling of 6 month's duration, which corresponded to cessation of egg laying. Radiographs and ultrasound examination demonstrated extensive deposits of coelomic fat and an enlarged oviduct. Exploratory celiotomy demonstrated copious amounts of firm, nodular fat completely surrounding the gastrointestinal tract, resulting in extensive chronic adhesions between intestinal loops. Free yolk was present in the cranial left coelom, yolk coelomitis was diagnosed, and a salpingohysterectomy was performed. Two days after surgery, the bird stopped passing feces and began regurgitating after eating, and a colonic obstruction was demonstrated via contrast radiography. Euthanasia was elected, and necropsy revealed an obstruction of the distal colon caused by extraluminal compression by adhesions of firm, nodular fat. Histologic examination demonstrated extensive fat necrosis with granulomatous inflammation, characterized by cords of necrotic fat surrounded by multinucleated giant cells and epithelioid macrophages with scattered lymphocytes and plasma cells and rare heterophils. The clinical signs, gross lesions, and histologic lesions are characteristic of massive fat necrosis (lipogranulomatosis) in ruminants and mesenteric panniculitis in humans and companion mammals. This is the first report, to our knowledge, of this disease in psittacine birds. PMID- 25843327 TI - What is your diagnosis? PMID- 25843329 TI - Coming meetings. PMID- 25843330 TI - Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib. AB - Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR. We studied 5 4/12-year-old monozygotic twins with short stature (both -3.4 SD) and GHD (peak GH values, <6.0 MUg/L after arginine and clonidine stimulations). Molecular studies revealed maternally derived STX16 microdeletions and isolated LOMs at exon A/B-DMR in the twins, confirming the diagnosis of AD-PHP-Ib. GNAS mutation was not identified, and neither mutation nor copy number variation was detected in GH1, POU1F1, PROP1, GHRHR, LHX3, LHX4, and HESX1 in the twins. The results, in conjunction with the previous finding that GNAS shows maternal expression in the pituitary, suggest that GHD of the twins is primarily ascribed to compromised GHRH-R signaling caused by AD-PTH-Ib. Thus, resistance to multiple hormones including GHRH should be considered in AD-PHP-Ib. PMID- 25843332 TI - Editorial for the ACS select virtual issue on inorganic chemistry driving the energy sciences. PMID- 25843331 TI - Ischemia-modified albumin and malondialdehyde levels in patients with overt and subclinical hyperthyroidism: effects of treatment on oxidative stress. AB - The main purpose of this study was to evaluate the levels of ischemia-modified albumin (IMA) and malondialdehyde (MDA) in patients with OHyper and SHyper, to assess the effects of antithyroid drug (ATD) therapy on the oxidative stress (OS) parameters. Forty-five untreated patients with overt hyperthyroidism (OHyper), 20 untreated patients with subclinical hyperthyroidism (SHyper) and 30 age-and sex matched healthy controls were prospectively included in the study. Biochemical and hormonal parameters were evaluated in all patients before and after treatment. Compared with the control subjects, the levels of MDA, glucose and TG were significantly increased in patients with SHyper (p<0.05), whereas LDL-C levels were significantly decreased (p<0.01). Patients with OHyper showed significantly elevated MDA and glucose levels (p<0.001) and significantly decreased LDL-C and HDL-C levels compared with the controls (p<0.01). In patients with Graves' disease, serum TSH levels were inversely correlated with plasma MDA levels (r: -0.42, p<0.05). Plasma MDA levels significantly decreased and levels of TC, LDL-C and HDL-C significantly increased in the groups of OHyper and SHyper after treatment. Serum IMA levels did not significantly change at baseline and with the therapy in all subjects. In conclusion, increased MDA levels in both patient groups represent increased lipid peroxidation which might play an important role in the pathogenesis of the atherosclerosis in these patients. Increased oxidative stress in patients with SHyper and OHyper could be improved by ATD therapy. Also, MDA can be used as a reliable marker of OS and oxidative damage, while IMA is considered to be inappropriate. PMID- 25843333 TI - DSM-5 and psychiatric genetics - round hole, meet square peg. PMID- 25843334 TI - Genotype-first analysis of the 16p11.2 deletion defines a new type of "autism". PMID- 25843335 TI - Connectivity in context: emphasizing neurodevelopment in autism spectrum disorder. PMID- 25843336 TI - Made in Scotland from... Irn-Bru((r)) bottles. A cheap, effective carrier for scientific posters. PMID- 25843337 TI - Promoting quality of care in disaster response: A survey of core surgical competencies. AB - BACKGROUND: Recent humanitarian crises have led to a call for professionalization of the humanitarian field, but core competencies for the delivery of surgical care have yet to be established. The objective of this study was to survey surgeons with experience in disaster response to identify surgical competencies required to be effective in these settings. METHODS: An online survey elucidating demographic information, scope of practice, and previous experience in global health and disaster response was transmitted to surgeons from a variety of surgical societies and nongovernmental organizations. Participants were provided with a list of 111 operative procedures and were asked to identify those deemed essential to the toolset of a frontline surgeon in disaster response via a Likert scale. Responses from personnel with experience in disaster response were contrasted with those from nonexperienced participants. RESULTS: A total of 147 surgeons completed the survey. Participants held citizenship in 22 countries, were licensed in 30 countries, and practiced in >20 countries. Most respondents (56%) had previous experience in humanitarian response. The majority agreed or strongly agreed that formal training (54%), past humanitarian response (94%), and past global health experiences (80%) provided adequate preparation. The most commonly deemed important procedures included control of intraabdominal hemorrhage (99%), abdominal packing for trauma (99%), and wound debridement (99%). Procedures deemed important by experienced personnel spanned multiple specialties. CONCLUSION: This study addressed specifically surgical competencies in disaster response. We provide a list of operative procedures that should set the stage for further structured education programs. PMID- 25843338 TI - Should we randomize our patients in the name of the "scientific evidence"? PMID- 25843339 TI - Emerging neuroimaging contribution to the diagnosis and management of the ring chromosome 20 syndrome. AB - Ring chromosome 20 [r(20)] syndrome is an underdiagnosed chromosomal anomaly characterized by severe epilepsy, behavioral problems, and mild-to-moderate cognitive deficits. Since the cognitive and behavioral decline follows seizure onset, this syndrome has been proposed as an epileptic encephalopathy (EE). The recent overwhelming development of advanced neuroimaging techniques has opened a new era in the investigation of the brain networks subserving the EEs. In particular, functional neuroimaging tools are well suited to show alterations related to epileptiform discharges at the network level and to build hypotheses about the mechanisms underlying the cognitive disruption observed in these conditions. This paper reviews the brain circuits and their disruption as revealed by functional neuroimaging studies in patients with [r(20)] syndrome. It discusses the clinical consequences of the neuroimaging findings on the management of patients with [r(20)] syndrome, including their impact to an earlier diagnosis of this disorder. Based on the available lines of evidences, [r(20)] syndrome is characterized by interictal and ictal dysfunctions within basal ganglia-prefrontal lobe networks and by long-lasting effects of the peculiar theta-delta rhythm, which represents an EEG marker of the syndrome on integrated brain networks that subserve cognitive functions. PMID- 25843340 TI - Cognitive adverse events of topiramate in patients with epilepsy and intellectual disability. AB - Topiramate (TPM) is an effective antiepileptic drug (AED). A high proportion of patients, however, experiences cognitive adverse events (CAEs), especially in verbal fluency, memory spans, and working memory. To our knowledge, CAEs of TPM have not been studied systematically in patients with intellectual disability (ID). This may be due to the fact that many of those patients are not able to follow test instructions properly and that neuropsychological instruments are not validated for that group. Cognitive deterioration in patients with ID may thus easily be overlooked. Topiramate is in frequent use in persons with ID. We included 26 consecutive patients with epilepsy and ID in this observational study who had undergone neuropsychological examinations as part of clinical routine before and after the introduction of TPM into the therapeutic regimen (n=4) or before and after the withdrawal of TPM (n=22). Examinations under TPM showed reduced cognitive speed, reduced verbal memory, reduced verbal fluency, and reduced flexibility compared to examinations without TPM. Despite some limitations (especially small sample size, high interindividual variation of the results dependent on the degree of ID, effects of other - limited - changes in the therapeutic regimen), our study indicates that TPM in persons with epilepsy and ID may lead to CAEs comparable to those in persons with normal intelligence. Neuropsychological testing is mandatory in order not to miss CAEs that might severely impair quality of life. PMID- 25843341 TI - Epileptic aura and perception of self-control. AB - OBJECTIVE: The health locus of control is the subjective perception of control over one's health. It has been studied for years as one of several factors that determine patient health-related behaviors. The aim of this study was to investigate how the epileptic aura is associated with the health locus of control, anxiety, and depression. METHODS: Patients were included retrospectively, based on patient records from the epilepsy monitoring unit of the Rigshospitalet University Hospital. Participants were asked about the presence and nature of auras in a semistructured interview. The Multidimensional Health Locus of Control Scale, Form C was used to evaluate the health locus of control. Three domains were evaluated: internal, where health is controlled by personal action; chance, where health is controlled by fate or luck; and powerful others, where health is controlled by the actions of others (e.g., doctors and parents). The Hospital Anxiety and Depression Scale was used to evaluate levels of anxiety and depression. RESULTS: Forty-nine patients, with mean age of 38years, participated in the study. Of these, 67% reported experiencing one or more auras; i.e., subjective warning signs prior to a generalized or focal seizure with an impairment in consciousness. Patients that could react to their aura prior to a seizure scored higher on the internal subscale of the Multidimensional Health Locus of Control questionnaire compared to participants that could not react to their aura. CONCLUSIONS: The ability to react to an aura prior to a seizure correlated positively with the internal subscale of the health locus of control. However, it did not significantly correlate with the external subscales of chance and powerful others in the health locus of control. Moreover, there was no significant relation between the ability to react to an aura prior to a seizure and the levels of anxiety or depression. PMID- 25843342 TI - An integrative review of the benefits of self-management interventions for adults with epilepsy. AB - The life-limiting effects of epilepsy are well documented in the literature, where the management of epilepsy and seizure control relies heavily on the self management abilities of the individual. The psychosocial impact of epilepsy on the person and their family is profound and has been studied extensively. Interventions such as educational programs and lifestyle management education to improve self-mastery and quality of life in people with epilepsy are not necessarily integrated in standard care practices. The aim of this integrative review was to systematically identify and appraise research that reported findings related to self-management interventions for adults with epilepsy. A search of bibliographic databases was conducted, and a total of n=14 articles were included in this review. The main finding was that self-management education for adults with epilepsy shows promise to improving knowledge and self-confidence in managing one's own condition including the management of the psychosocial stressors, improvement in seizure control, and enhancement of quality of life. Self-management interventions were delivered in diverse formats, and the inclusion of this type of intervention should be part of the comprehensive care for people living with epilepsy. PMID- 25843343 TI - P2X purinoceptors as a link between hyperexcitability and neuroinflammation in status epilepticus. AB - There remains a need for more efficacious treatments for status epilepticus. Prolonged seizures result in the release of ATP from cells which activates the P2 class of ionotropic and metabotropic purinoceptors. The P2X receptors gate depolarizing sodium and calcium entry and are expressed by both neurons and glia throughout the brain, and a number of subtypes are upregulated after status epilepticus. Recent studies have explored the in vivo effects of targeting ATP gated P2X receptors in preclinical models of status epilepticus, with particular focus on the P2X7 receptor (P2X7R). The P2X7R mediates microglial activation and the release of the proepileptogenic inflammatory cytokine interleukin 1beta. The receptor may also directly modulate neurotransmission and gliotransmission and promote the recruitment of immune cells into brain parenchyma. Data from our group and collaborators show that status epilepticus produced by intraamygdala microinjection of kainic acid increases P2X7R expression in the hippocampus and neocortex of mice. Antagonism of the P2X7R in the model reduced seizure severity, microglial activation and interleukin 1beta release, and neuronal injury. Coadministration of a P2X7R antagonist with a benzodiazepine also provided seizure suppression in a model of drug-refractory status epilepticus when either treatment alone was minimally effective. More recently, we showed that status epilepticus in immature rats is also reduced by P2X7R antagonism. Together, these findings suggest that P2X receptors may be novel targets for seizure control and interruption of neuroinflammation after status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 25843344 TI - Socioeconomic deprivation is an independent risk factor for behavioral problems in children with epilepsy. AB - AIM: The aim of this study was to examine whether socioeconomic deprivation in children with epilepsy (CWE) increases risk for behavioral problems independent of seizure factors. METHODS: A cross-sectional study was done in which parents of children attending a specialist epilepsy clinic were invited to complete a child behavior checklist (CBCL) questionnaire about their child. Medical and sociodemographic data on CWE were obtained through their pediatric neurologists. Home postal code was used to obtain quintiles of Scottish Index of Multiple Deprivation 2012 (SIMD2012) scores for individuals. Lower (1-3) quintiles correspond to higher socioeconomic deprivation. Regression analysis was used to investigate whether a lower quintile was an independent risk factor for scores >63 (significant behavioral problem). RESULTS: Parents of 87 children (42 male, mean age of 10.5years) were enrolled. Fifty-nine percent had total scores >63. A higher proportion of children from quintiles 1-3 compared to those from quintiles 4-5 had externalizing (49% vs. 25%, p=0.02) and total (54% vs. 30%, p=0.02) scores >63. Adjusted OR of quintiles 1-3 vs. 4-5 for scores >63=14.8, 95% CI=3.0, 68.0. Fewer children with scores >63 and from quintiles 1-3 were known to the child and adolescent mental health service (CAMHS) compared to those in quintiles 4-5 (p=0.01). INTERPRETATION: Socioeconomic deprivation was an independent risk factor for behavioral problems in CWE. Children with epilepsy and behavioral problems who lived in socioeconomically deprived areas received less help. PMID- 25843345 TI - Early intervention for preventing posttraumatic stress disorder: an Internet based virtual reality treatment. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) develops in approximately 20% of people exposed to a traumatic event, and studies have shown that cognitive behavioral therapy (CBT) is effective as a treatment for chronic PTSD. It has also been shown to prevent PTSD when delivered early after a traumatic event. However, studies have shown that uptake of early treatment is generally low, and therefore, the need to provide interventions through other mediums has been identified. The use of technology may overcome barriers to treatment. OBJECTIVE: This paper describes a randomized controlled trial that will examine an early CBT intervention for PTSD. The treatment incorporates virtual reality (VR) as a method for delivering exposure-based elements of the treatment. The intervention is Internet based, such that the therapist and patient will "meet" in a secure online site. This site will also include multi-media components of the treatment (such as videos, audios, VR) that can be accessed by the patient between sessions. METHOD: Two hundred patients arriving to a Level 1 emergency department following a motor vehicle accident will be randomly assigned to either treatment or control groups. Inclusion criteria are age 18-65, PTSD symptoms 2 weeks posttrauma related to current trauma, no suicidality, no psychosis. Patients will be assessed by telephone by a team blind to the study group, on four occasions: before and after treatment, and 6 and 12 months posttreatment. The primary outcome is PTSD symptoms at follow up. Secondary outcomes include depression and cost effectiveness. Analyses will be on an intention-to-treat basis. DISCUSSION: The results will provide more insight into the effects of preventive interventions, in general, and Internet-based early interventions, in particular, on PTSD, in an injured population, during the acute phase after trauma. We will discuss possible strengths and limitations. PMID- 25843346 TI - Effect of arginine vasopressin on the cortex edema in the ischemic stroke of Mongolian gerbils. AB - Brain edema formation is one of the most important mechanisms of ischemia-evoked cerebral edema. It has been demonstrated that arginine vasopressin (AVP) receptors are involved in the pathophysiology of secondary brain damage after focal cerebral ischemia. In a well-characterized animal model of ischemic stroke of Mongolian gerbils, the present study was undertaken to clear the effect of AVP on cortex edema in cerebral ischemia. The results showed that (1) occluding the left carotid artery of Mongolian gerbils not only decreased the cortex specific gravity (cortex edema) but also increased AVP levels in the ipsilateral cortex (ischemic area) including left prefrontal lobe, left parietal lobe, left temporal lobe, left occipital lobe and left hippocampus for the first 6 hours, and did not change of the cortex specific gravity and AVP concentration in the right cortex (non-ischemic area); (2) there were many negative relationships between the specific gravity and AVP levels in the ischemic cortex; (3) intranasal AVP (50 ng or 200 ng), which could pass through the blood-brain barrier to the brain, aggravated the focal cortex edema, whereas intranasal AVP receptor antagonist D(CH2)5Tyr(ET)DAVP (2 ug) mitigated the cortex edema in the ischemic area after occluding the left carotid artery of Mongolian gerbils; and (4) either intranasal AVP or AVP receptor antagonist did not evoke that edema in the non-ischemic cortex. The data indicated that AVP participated in the process of ischemia evoked cortex edema, and the cerebral AVP receptor might serve as an important therapeutic target for the ischemia-evoked cortex edema. PMID- 25843347 TI - [Help tools for the safe treatment of Ebola in emergency departments]. AB - OBJECTIVE: To describe the tools (audit procedure and Checklist) designed to ensure the correct implementation of the Ebola Virus Disease Guidelines in a hospital emergency department. METHOD: Forty-one elements were identified to be included in the checklist to avoid serious mistakes and to provide appropriate care in a safe environment. An audit procedure was designed to apply this checklist. Audit was conducted two times with an interval of 3 weeks. RESULTS: Critical points and potential areas of improvement were identified, for example: materials to ensure that protection measures were correctly applied, information that should be provided to the patient and, if applicable, their relatives, procedure to report changes in the Guidelines, and a review of the personal protection measures. The second audit verified the compliance of all elements of the checklist. The duration of the audit was 45 min the first time and 75 min the second time. CONCLUSIONS: This approach ensures that Ebola Guidelines were applied, with greater guarantees for patients and hospital professionals. PMID- 25843348 TI - [The cost of prolonged hospital stay of the critical patient]. PMID- 25843349 TI - [Assessment of two applications of medication self-management in older patients. Qualitative study]. AB - INTRODUCTION: The aging population and the growing use of technology are two realities of modern society. Developing tools to support medication self management to polymedicated elderly may contribute to increase their safety. OBJECTIVE: To know how patients polymedicated and older than 64 years manage dose their medication and assessment the utility of two medication self-management applications, specifically analyzing management systems, medication errors and positive and improvable aspects of each of the tools presented. PATIENTS AND METHODS: Seven focal groups with 59 patients from associations and health departments were conducted. In such meetings, they received the applications and they were encouraged to use it. Then, a several group questions were asked them about their health status, how they managed their medication and their assessment about the applications. RESULTS: Most participants reported to use memory strategies to take correctly their medication. They assessed positively the applications although some of them showed resistance to incorporate it in their daily routine. The simple interface and ease of use were the characteristics of the applications most appreciated by patients. CONCLUSIONS: Is possible to foster among elderly patients the use of technological tools to support the proper administration of medications with purpose is to decrease errors and increase safety. When designing health applications is necessary to take into account the preferences of those who are targeted. PMID- 25843350 TI - A synthetic cGMP-sensitive gene switch providing Viagra((r))-controlled gene expression in mammalian cells and mice. AB - Cyclic guanosine monophosphate (cGMP) is a universal second messenger that is synthesized from guanosine triphosphate (GTP) by guanylyl cyclases (GCs) and hydrolyzed into guanosine monophosphate (GMP) by phosphodiesterases (PDEs). Small molecule drugs that induce high cGMP levels in specialized tissues by boosting GC activity or inhibiting PDE activity have become the predominant treatment strategy for a wide range of medical conditions, including congestive heart failure, pulmonary hypertension, atherosclerosis-based claudication and erectile dysfunction. By fusing the cGMP receptor protein (CRP) of Rhodospirillum centenum to the Herpes simplex-derived transactivation domain VP16, we created a novel synthetic mammalian cGMP-sensing transcription factor (GTA) that activates synthetic promoters (PGTA) containing newly identified GTA-specific operator sites in a concentration-dependent manner. In cell lines expressing endogenous natriuretic peptide receptor A (NPR-A) (HeLa), GTA/PGTA-driven transgene expression was induced by B-type natriuretic peptide (BNP; Nesiritide((r))) in a concentration-dependent manner, which activated NPR-A's intracellular GC domain and triggered a corresponding cGMP surge. Ectopic expression of NPR-A in NPR-A negative cell lines (HEK-293T) produced high cGMP levels and mediated maximum GTA/PGTA-driven transgene expression, which was suppressed by co-expression of PDEs (PDE-3A, PDE-5A and PDE-9A) and was re-triggered by the corresponding PDE inhibitor drugs (Pletal((r)), Perfan((r)), Primacor((r)) (PDE-3A), Viagra((r)), Levitra((r)), Cialis((r)) (PDE-5A) and BAY73-6691 (PDE-9A)). Mice implanted with microencapsulated designer cells co-expressing the GTA/PGTA device with NPR-A and PDE-5A showed control of blood SEAP levels through administration of sildenafil (Viagra((r))). Designer cells engineered for PDE inhibitor-modulated transgene expression may provide a cell-based PDE-targeting drug discovery platform and enable drug-adjusted gene- and cell-based therapies. PMID- 25843351 TI - Spatial dynamics of a nutrient-phytoplankton system with toxic effect on phytoplankton. AB - The production of toxins by some species of phytoplankton is known to have several economic, ecological, and human health impacts. However, the role of toxins on the spatial distribution of phytoplankton is not well understood. In the present study, the spatial dynamics of a nutrient-phytoplankton system with toxic effect on phytoplankton is investigated. We analyze the linear stability of the system and obtain the condition for Turing instability. In the presence of toxic effect, we find that the distribution of nutrient and phytoplankton becomes inhomogeneous in space and results in different patterns, like stripes, spots, and the mixture of them depending on the toxicity level. We also observe that the distribution of nutrient and phytoplankton shows spatiotemporal oscillation for certain toxicity level. PMID- 25843352 TI - Ca(2+)-activation kinetics modulate successive puff/spark amplitude, duration and inter-event-interval correlations in a Langevin model of stochastic Ca(2+) release. AB - Through theoretical analysis of the statistics of stochastic calcium (Ca(2+)) release (i.e., the amplitude, duration and inter-event interval of simulated Ca(2+) puffs and sparks), we show that a Langevin description of the collective gating of Ca(2+) channels may be a good approximation to the corresponding Markov chain model when the number of Ca(2+) channels per Ca(2+) release unit (CaRU) is in the physiological range. The Langevin description of stochastic Ca(2+) release facilitates our investigation of correlations between successive puff/spark amplitudes, durations and inter-spark intervals, and how such puff/spark statistics depend on the number of channels per release site and the kinetics of Ca(2+)-mediated inactivation of open channels. When Ca(2+) inactivation/de inactivation rates are intermediate-i.e., the termination of Ca(2+) puff/sparks is caused by an increase in the number of inactivated channels-the correlation between successive puff/spark amplitudes is negative, while the correlations between puff/spark amplitudes and the duration of the preceding or subsequent inter-spark interval are positive. These correlations are significantly reduced or change signs when inactivation/de-inactivation rates are extreme (slow or fast) and puff/sparks terminate via stochastic attrition. PMID- 25843353 TI - Estimating epidemic parameters: Application to H1N1 pandemic data. AB - This paper discusses estimation of the parameters in an SIR epidemic model from the observed longitudinal new infection count data. The potential problems of the standard MLE approaches are revealed and possible remedies suggested. The analysis is based on the epidemic data from the 2009 outbreak of H1N1 influenza on the campus of Washington State University. PMID- 25843354 TI - Co-digestion of wheat and rye bread suspensions with source-sorted municipal biowaste. AB - Acidification of wheat bread (WBS), rye bread (RBS) and fresh biowaste suspensions (FBS), leading to lactate+acetate, lactate+acetate+n-buyrate, and acetate+propionate+n-butyrate, respectively, and biogas production as well as population dynamics were investigated. Co-fermentation of FBS (14 kg m(-3) d(-1) organic loading rate (OLR)) with WBS or RBS was stable up to an OLR of 22 kg m( 3) d(-1) and resulted in up to 3 times as much biogas. During co-fermentation at more than 20 kg m(-3) d(-1) OLR the total population increased more than 2-fold, but the originally low share of propionate-oxidizing bacteria significantly decreased. The proportion of methanogens also decreased. Whereas the proportion of Methanosarcinales to Methanomicrobiales in biowaste and biowaste+WBS remained constant, Methanosarcinales and in particular Methanosaeta spec. in the biowaste+RBS assay almost completely disappeared. Methanomicrobiales increased instead, indicating propionate oxidation via acetate cleavage to CO2 and hydrogen. PMID- 25843355 TI - The effect of gender and age structure on municipal waste generation in Poland. AB - In this study the effect of gender and age structure on municipal waste generation was investigated. The data from 10-year period, from 2001 to 2010 year, were taken into consideration. The following parameters of gender and age structure were analyzed: men and woman quantity, female to male ratio, number of working, pre-working and post-working age men/women, number of unemployed men/women. The results have showed a strong correlation of annual per capita waste generation rate with number of unemployed women (r=0.70) and female to male ratio (r=0.81). This indicates that waste generation rate is more depended on ratio of men and women that on quantitative size of each group. Using the regression analysis a model describing the dependence between female to male ratio, number of unemployed woman and waste quantity was determined. The model explains 70% of waste quantity variation. Obtained results can be used both to improve waste management and to a fuller understanding of gender behavior. PMID- 25843356 TI - Conversion of lipid from food waste to biodiesel. AB - Depletion of fossil fuels and environmental problems are encouraging research on alternative fuels of renewable sources. Biodiesel is a promising alternative fuel to be used as a substitute to the petroleum based diesel fuels. However, the cost of biodiesel production is high and is attributed mainly to the feedstock used which leads to the investigation of low cost feedstocks that are economically feasible. In this paper, we report on the utilization of lipid obtained from food waste as a low-cost feedstock for biodiesel production. Lipid from food waste was transesterified with methanol using base and lipase as catalysts. The maximum biodiesel yield was 100% for the base (KOH) catalyzed transesterification at 1:10M ratio of lipid to methanol in 2h at 60 degrees C. Novozyme-435 yielded a 90% FAME conversion at 40 degrees C and 1:5 lipid to methanol molar ratio in 24h. Lipid obtained from fungal hydrolysis of food waste is found to be a suitable feedstock for biodiesel production. PMID- 25843357 TI - The Teaching on Wheels Cart (TowCart) Portable Simulator to Improve Resident Training in Lung Isolation. PMID- 25843358 TI - Visible-light-mediated radical aryldifluoroacetylation of alkynes with ethyl bromodifluoroacetate for the synthesis of 3-difluoroacetylated coumarins. AB - A mild and efficient method for the synthesis of 3-difluoroacetylated coumarins through visible-light-promoted aryldifluoroacetylation of alkynes with ethyl bromodifluoroacetate has been developed. The reaction allows the direct formation of Csp(2)-CF2COOEt and C-C bonds via a proposed tandem radical cyclization process. PMID- 25843359 TI - Tailored motivational message generation: A model and practical framework for real-time physical activity coaching. AB - This paper presents a comprehensive and practical framework for automatic generation of real-time tailored messages in behavior change applications. Basic aspects of motivational messages are time, intention, content and presentation. Tailoring of messages to the individual user may involve all aspects of communication. A linear modular system is presented for generating such messages. It is explained how properties of user and context are taken into account in each of the modules of the system and how they affect the linguistic presentation of the generated messages. The model of motivational messages presented is based on an analysis of existing literature as well as the analysis of a corpus of motivational messages used in previous studies. The model extends existing 'ontology-based' approaches to message generation for real-time coaching systems found in the literature. Practical examples are given on how simple tailoring rules can be implemented throughout the various stages of the framework. Such examples can guide further research by clarifying what it means to use e.g. user targeting to tailor a message. As primary example we look at the issue of promoting daily physical activity. Future work is pointed out in applying the present model and framework, defining efficient ways of evaluating individual tailoring components, and improving effectiveness through the creation of accurate and complete user- and context models. PMID- 25843360 TI - Iron diminishes the in vitro biological effect of vanadium. AB - Mechanistic pathways underlying inflammatory injury following exposures to vanadium-containing compounds are not defined. We tested the postulate that the in vitro biological effect of vanadium results from its impact on iron homeostasis. Human bronchial epithelial (HBE) cells exposed to vanadyl sulfate (VOSO4) showed a time- and dose-dependent increase in vanadium relative to PBS. HBE cells exposed to VOSO4 and then exposed to ferric ammonium citrate (FAC) significantly increased intracellular iron import supporting an interaction between the two metals. Following exposure to VOSO4, there was an increase (336+/ 73%) in RNA for divalent metal transporter 1 (DMT1), a major iron importer. With inclusion of VOSO4 in the incubation, vanadium could be measured in the nuclear and mitochondrial fractions and the supernatant. Non-heme iron in the nuclear and mitochondrial fractions were decreased immediately following VOSO4 exposure while there was an increased concentration of non-heme iron in the supernatant. Provision of excess iron inhibited changes in the concentration of this metal provoked by VOSO4 exposures. Using Amplex Red, VOSO4 was shown to significantly increase oxidant generation by HBE cells in a time- and dose-dependent manner. HBE cells pre-treated with FAC and then exposed to VOSO4 demonstrated a decreased generation of oxidants. Similarly, activation of the transcription factor NF-KB promoter and release of interleukin-6 and -8 were increased following VOSO4 exposure and these effects were diminished by pre-treatment with FAC. We conclude that an initiating event in biological effect after exposure to vanadyl sulfate is a loss of requisite cell iron. PMID- 25843361 TI - Thirty years through vanadium chemistry. AB - The relevance of vanadium in biological systems is known for many years and vanadium-based catalysts have important industrial applications, however, till the beginning of the 80s research on vanadium chemistry and biochemistry did not receive much attention from the scientific community. The understanding of the broad bioinorganic implications resulting from the similarities between phosphate and vanadate(V) and the discovery of vanadium dependent enzymes gave rise to an enormous increase in interest in the chemistry and biological relevance of vanadium. Thereupon the last 30years corresponded to a period of enormous research effort in these fields, as well as in medicinal applications of vanadium and in the development of catalysts for use in fine-chemical synthesis, some of these inspired by enzymatic active sites. Since the 80s my group in collaboration with others made contributions, described throughout this text, namely in the understanding of the speciation of vanadium compounds in aqueous solution and in biological fluids, and to the transport of vanadium compounds in blood plasma and their uptake by cells. Several new types of vanadium compounds were also synthesized and characterized, with applications either as prospective therapeutic drugs or as homogeneous or heterogenized catalysts for the production of fine chemicals. The developments made are described also considering the international context of the evolution of the knowledge in the chemistry and bioinorganic chemistry of vanadium compounds during the last 30years. This article was compiled based on the Vanadis Award presentation at the 9th International Vanadium Symposium. PMID- 25843362 TI - Cytoprotective effect of resveratrol diastereomers in CHO-K1 cells exposed to beauvericin. AB - Beauvericin (BEA) causes cytotoxicity, lipid peroxidation and reactive oxygen species in CHO-K1 cells. Resveratrol (RSV) is a polyphenol with multiple biological properties, including antioxidant effects. RSV has two forms: trans and cis. The aims of this study were to determine the cytoprotective effect of trans-RSV and diastereomers mixtures (50:50 trans/cis-RSV and 70:30 trans/cis RSV) incubated alone and in combination with BEA in ovarian (CHO-K1) cells. The results demonstrated that cell viability increases (from 9% to 77%) when they were exposed to low concentration of RSV. Moreover, when the cells were pre treated with RSV and then exposed to BEA, a cytoprotective effect (from 25% to 76%) and a ROS production diminution (from 27% to 92%) were observed, with respect to cells exposed to BEA without previous RSV exposure. RSV pre-treatment decreased the MDA levels (from 15% to 37%) when it is compared with cells exposed only to BEA. Therefore, it can be concluded that RSV could reduce the toxicological risk produced by BEA when they are in combination. PMID- 25843363 TI - A 7-month cigarette smoke inhalation study in C57BL/6 mice demonstrates reduced lung inflammation and emphysema following smoking cessation or aerosol exposure from a prototypic modified risk tobacco product. AB - Modified risk tobacco products (MRTP) are designed to reduce smoking-related health risks. A murine model of chronic obstructive pulmonary disease (COPD) was applied to investigate classical toxicology end points plus systems toxicology (transcriptomics and proteomics). C57BL/6 mice were exposed to conventional cigarette smoke (3R4F), fresh air (sham), or a prototypic MRTP (pMRTP) aerosol for up to 7 months, including a cessation group and a switching-to-pMRTP group (2 months of 3R4F exposure followed by fresh air or pMRTP for up to 5 months respectively). 3R4F smoke induced the typical adaptive changes in the airways, as well as inflammation in the lung, associated with emphysematous changes (impaired pulmonary function and alveolar damage). At nicotine-matched exposure concentrations of pMRTP aerosol, no signs of lung inflammation and emphysema were observed. Both the cessation and switching groups showed a similar reversal of inflammatory responses and no progression of initial emphysematous changes. A significant impact on biological processes, including COPD-related inflammation, apoptosis, and proliferation, was identified in 3R4F-exposed, but not in pMRTP exposed lungs. Smoking cessation or switching reduced these perturbations to near sham-exposed levels. In conclusion, the mouse model indicated retarded disease progression upon cessation or switching to pMRTP which alone had no adverse effects. PMID- 25843365 TI - In whom and when to look for causal pathways of osteoarthritis of the knee. PMID- 25843366 TI - Positioning of bacterial chemoreceptors. AB - For optimum growth, bacteria must adapt to their environment, and one way that many species do this is by moving towards favourable conditions. To do so requires mechanisms to both physically drive movement and provide directionality to this movement. The pathways that control this directionality comprise chemoreceptors, which, along with an adaptor protein (CheW) and kinase (CheA), form large hexagonal arrays. These arrays can be formed around transmembrane receptors, resulting in arrays embedded in the inner membrane, or they can comprise soluble receptors, forming arrays in the cytoplasm. Across bacterial species, chemoreceptor arrays (both transmembrane and soluble) are localised to a variety of positions within the cell; some species with multiple arrays demonstrate this variety within individual cells. In many cases, the positioning pattern of the arrays is linked to the need for segregation of arrays between daughter cells on division, ensuring the production of chemotactically competent progeny. Multiple mechanisms have evolved to drive this segregation, including stochastic self-assembly, cellular landmarks, and the utilisation of ParA homologues. The variety of mechanisms highlights the importance of chemotaxis to motile species. PMID- 25843364 TI - Prodromal symptoms in knee osteoarthritis: a nested case-control study using data from the Osteoarthritis Initiative. AB - OBJECTIVE: In order to gain a better understanding of the timing of emergent symptoms of osteoarthritis, we sought to investigate the existence, duration and nature of a prodromal symptomatic phase preceding incident radiographic knee osteoarthritis (ROA). DESIGN: Data were from the incidence cohort of the Osteoarthritis Initiative (OAI) public use datasets. Imposing a nested case control design, ten control knees were selected for each case of incident tibiofemoral ROA between 2004 and 2010 from participants aged 45-79 years. Candidate prodromal symptoms were Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) and Knee injury and Osteoarthritis Outcome Score (KOOS) subscale scores and individual items, available up to 4 years prior to the time of incident ROA. Multi-level models were used to estimate the length of the prodromal phases. RESULTS: The prodromal phase for subscale scores ranged from 29 months (KOOS Other Symptoms) to 37 months (WOMAC Pain). Pain and difficulty on activities associated with higher dynamic knee loading were associated with longer prodromal phases (e.g., pain on twisting/pivoting (39 months, 95% confidence interval: 13, 64) vs pain on standing (25 months: 7, 42)). CONCLUSIONS: Our analysis found that incident ROA is preceded by prodromal symptoms lasting at least 2-3 years. This has potential implications for understanding phasic development and progression of osteoarthritis and for early recognition and management. PMID- 25843367 TI - Reduction-sensitive micelles with sheddable PEG shells self-assembled from a Y shaped amphiphilic polymer for intracellular doxorubicine release. AB - A new type of shell-sheddable micelles with disulfide linkages between the hydrophobic polyester core and hydrophilic poly(ethylene glycol) (PEG) shell was developed based on Y-shaped amphiphilic polymers mPEG-S-S-(PCL)2. The micelles were then used for the glutathione-mediated intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells. The polymer could self assemble into micelles with an average diameter of 135nm in aqueous solution and load DOX at a total content of 3.6%. The hydrophilic PEG shell of these micelles could be shed in the presence of reducing agent dithiothreitol (DTT), which resulted in size change of the micelles. In vitro release studies revealed that DOX-loaded mPEG-S-S-(PCL)2 micelles exhibited faster DOX release in the presence of DTT. MTT assay demonstrated that DOX-loaded mPEG-S-S-(PCL)2 micelles showed higher cytotoxicity against 10mM of glutathione monoester (GSH-OEt) pretreated HeLa cells than that of the non-pretreated ones. Confocal laser scanning microscopy and flow cytometry analyses indicated that DOX-loaded mPEG-S-S-(PCL)2 micelles were efficiently internalized into HeLa cells and exhibited faster DOX release in GSH-OEt-pretreated cells than in cells with no pretreatment. Endocytosis inhibition results proved that mPEG-S-S-(PCL)2 micelles entered the cells mainly through the clathrin-mediated endocytosis pathway, and caveolae mediated endocytosis was involved to a small extent. These results indicate the great potential of the proposed Y-shaped reduction-sensitive polymer for application in effective intracellular anticancer drug delivery. PMID- 25843368 TI - Hybrid alginate-polyester bimodal network hydrogel for tissue engineering- Influence of structured water on long-term cellular growth. AB - The development of biodegradable scaffolds (which promote cell-binding, proliferation, long-term cell viability and required biomechanical stability) for cardiac tissue engineering is a challenge. In this study, biosynthetic amphiphilic hybrid hydrogels were prepared using a graft comacromer of natural polysaccharide alginate and synthetic polyester polypropylene fumarate (PPF). Monomodal network hydrogel (HPAS-NO) and bimodal network hydrogel (HPAS-AA) were prepared. Between the two hydrogels, HPAS-AA hydrogel excels over the HPAS-NO hydrogel. HPAS-AA hydrogel is mechanically more stable in the culture medium and undergoes gradual degradation in vitro in PBS (phosphate buffered saline). HPAS AA contains nano-porous structure and acquires structured water (non-freezing bound water) (53.457%) along with free water (11.773%). It absorbs more plasma proteins and prevents platelet adsorption and hemolysis when contacted with blood. HPAS-AA hydrogel is cytocompatible and promote 3D cell growth (~ 70%) of L929 fibroblast even after 18 days and H9C2 cardiomyoblasts. The enhanced and long-term cellular growth of HPAS-AA hydrogel is attributed to the cell responsive features of structured water. HPAS-AA hydrogel can be a better candidate for cardiac tissue engineering applications. PMID- 25843369 TI - Synthesis, Radiolabeling, and Biological Evaluation of (R)- and (S)-2-Amino-5 [(18)F]fluoro-2-methylpentanoic Acid ((R)-, (S)-[(18)F]FAMPe) as Potential Positron Emission Tomography Tracers for Brain Tumors. AB - A novel (18)F-labeled alpha,alpha-disubstituted amino acid-based tracer, 2-amino 5-[(18)F]fluoro-2-methylpentanoic acid ([(18)F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [(18)F]FAMPe were obtained in good radiochemical yield (24-52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that (S)-[(18)F]FAMPe enters cells partly via sodium independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and small animal PET/CT studies in the mouse DBT model of glioblastoma showed that both (R)- and (S)-[(18)F]FAMPe have good tumor imaging properties with the (S) enantiomer providing higher tumor uptake and tumor to brain ratios. Comparison of the SUVs showed that (S)-[(18)F]FAMPe had higher tumor to brain ratios compared to (S)-[(18)F]FET, a well-established system L substrate. PMID- 25843370 TI - Prenatal immune activation alters hippocampal place cell firing characteristics in adult animals. AB - Prenatal maternal immune activation (MIA) is a risk factor for several developmental neuropsychiatric disorders, including autism, bipolar disorder and schizophrenia. Adults with these disorders display alterations in memory function that may result from changes in the structure and function of the hippocampus. In the present study we use an animal model to investigate the effect that a transient prenatal maternal immune activation episode has on the spatially modulated firing activity of hippocampal neurons in adult animals. MIA was induced in pregnant rat dams with a single injection of the synthetic cytokine inducer polyinosinic:polycytidylic acid (poly I:C) on gestational day 15. Control dams were given a saline equivalent. Firing activity and local field potentials (LFPs) were recorded from the CA1 region of the adult male offspring of these dams as they moved freely in an open arena. Most neurons displayed characteristic spatially-modulated 'place cell' firing activity and while there was no between group difference in mean firing rate between groups, place cells had smaller place fields in MIA-exposed animals when compared to control-group cells. Cells recorded in MIA-group animals also displayed an altered firing-phase synchrony relationship to simultaneously recorded LFPs. When the floor of the arena was rotated, the place fields of MIA-group cells were more likely to shift in the same direction as the floor rotation, suggesting that local cues may have been more salient for these animals. In contrast, place fields in control group cells were more likely to shift firing position to novel spatial locations suggesting an altered response to contextual cues. These findings show that a single MIA intervention is sufficient to change several important characteristics of hippocampal place cell activity in adult offspring. These changes could contribute to the memory dysfunction that is associated with MIA, by altering the encoding of spatial context and by disrupting plasticity mechanisms that are dependent on spike timing synchrony. PMID- 25843371 TI - Long-lasting pro-inflammatory suppression of microglia by LPS-preconditioning is mediated by RelB-dependent epigenetic silencing. AB - Microglia, the innate immune cells of the central nervous system (CNS), react to endotoxins like bacterial lipopolysaccharides (LPS) with a pronounced inflammatory response. To avoid excess damage to the CNS, the microglia inflammatory response needs to be tightly regulated. Here we report that a single LPS challenge results in a prolonged blunted pro-inflammatory response to a subsequent LPS stimulation, both in primary microglia cultures (100 ng/ml) and in vivo after intraperitoneal (0.25 and 1mg/kg) or intracerebroventricular (5 MUg) LPS administration. Chromatin immunoprecipitation (ChIP) experiments with primary microglia and microglia acutely isolated from mice showed that LPS preconditioning was accompanied by a reduction in active histone modifications AcH3 and H3K4me3 in the promoters of the IL-1beta and TNF-alpha genes. Furthermore, LPS preconditioning resulted in an increase in the amount of repressive histone modification H3K9me2 in the IL-1beta promoter. ChIP and knock down experiments showed that NF-kappaB subunit RelB was bound to the IL-1beta promoter in preconditioned microglia and that RelB is required for the attenuated LPS response. In addition to a suppressed pro-inflammatory response, preconditioned primary microglia displayed enhanced phagocytic activity, increased outward potassium currents and nitric oxide production in response to a second LPS challenge. In vivo, a single i.p. LPS injection resulted in reduced performance in a spatial learning task 4 weeks later, indicating that a single inflammatory episode affected memory formation in these mice. Summarizing, we show that LPS-preconditioned microglia acquire an epigenetically regulated, immune-suppressed phenotype, possibly to prevent excessive damage to the central nervous system in case of recurrent (peripheral) inflammation. PMID- 25843372 TI - Ultrasound-Guided Distal Bicep Tendon Injection Using a Posterior Approach. AB - Distal biceps tendinopathy is an uncommon but increasingly diagnosed condition in persons with elbow pain. When traditional treatments are unsuccessful, practitioners have performed ultrasound (US)-guided tendon injections in this region using an anterior approach. Although success has been reported with this technique, this approach may lead to neurovascular injury. This case report is the first in the literature to describe a US-guided distal bicep tendon injection using a posterior approach. The patient had an excellent clinical outcome with no adverse events. This outcome suggests that a US-guided posterior percutaneous tendon injection might be a safe, viable, nonsurgical option for recalcitrant distal biceps tendinopathy. PMID- 25843373 TI - Eight challenges in modelling infectious livestock diseases. AB - The transmission of infectious diseases of livestock does not differ in principle from disease transmission in any other animals, apart from that the aim of control is ultimately economic, with the influence of social, political and welfare constraints often poorly defined. Modelling of livestock diseases suffers simultaneously from a wealth and a lack of data. On the one hand, the ability to conduct transmission experiments, detailed within-host studies and track individual animals between geocoded locations make livestock diseases a particularly rich potential source of realistic data for illuminating biological mechanisms of transmission and conducting explicit analyses of contact networks. On the other hand, scarcity of funding, as compared to human diseases, often results in incomplete and partial data for many livestock diseases and regions of the world. In this overview of challenges in livestock disease modelling, we highlight eight areas unique to livestock that, if addressed, would mark major progress in the area. PMID- 25843374 TI - Thirteen challenges in modelling plant diseases. AB - The underlying structure of epidemiological models, and the questions that models can be used to address, do not necessarily depend on the host organism in question. This means that certain preoccupations of plant disease modellers are similar to those of modellers of diseases in human, livestock and wild animal populations. However, a number of aspects of plant epidemiology are very distinctive, and this leads to specific challenges in modelling plant diseases, which in turn sets a certain agenda for modellers. Here we outline a selection of 13 challenges, specific to plant disease epidemiology, that we feel are important targets for future work. PMID- 25843375 TI - Seven challenges in modeling vaccine preventable diseases. AB - Vaccination has been one of the most successful public health measures since the introduction of basic sanitation. Substantial mortality and morbidity reductions have been achieved via vaccination against many infections, and the list of diseases that are potentially controllable by vaccines is growing steadily. We introduce key challenges for modeling in shaping our understanding and guiding policy decisions related to vaccine preventable diseases. PMID- 25843376 TI - Seven challenges for modelling indirect transmission: vector-borne diseases, macroparasites and neglected tropical diseases. AB - Many of the challenges which face modellers of directly transmitted pathogens also arise when modelling the epidemiology of pathogens with indirect transmission--whether through environmental stages, vectors, intermediate hosts or multiple hosts. In particular, understanding the roles of different hosts, how to measure contact and infection patterns, heterogeneities in contact rates, and the dynamics close to elimination are all relevant challenges, regardless of the mode of transmission. However, there remain a number of challenges that are specific and unique to modelling vector-borne diseases and macroparasites. Moreover, many of the neglected tropical diseases which are currently targeted for control and elimination are vector-borne, macroparasitic, or both, and so this article includes challenges which will assist in accelerating the control of these high-burden diseases. Here, we discuss the challenges of indirect measures of infection in humans, whether through vectors or transmission life stages and in estimating the contribution of different host groups to transmission. We also discuss the issues of "evolution-proof" interventions against vector-borne disease. PMID- 25843377 TI - Nine challenges in incorporating the dynamics of behaviour in infectious diseases models. AB - Traditionally, the spread of infectious diseases in human populations has been modelled with static parameters. These parameters, however, can change when individuals change their behaviour. If these changes are themselves influenced by the disease dynamics, there is scope for mechanistic models of behaviour to improve our understanding of this interaction. Here, we present challenges in modelling changes in behaviour relating to disease dynamics, specifically: how to incorporate behavioural changes in models of infectious disease dynamics, how to inform measurement of relevant behaviour to parameterise such models, and how to determine the impact of behavioural changes on observed disease dynamics. PMID- 25843378 TI - Eight challenges in modelling disease ecology in multi-host, multi-agent systems. AB - Many disease systems exhibit complexities not captured by current theoretical and empirical work. In particular, systems with multiple host species and multiple infectious agents (i.e., multi-host, multi-agent systems) require novel methods to extend the wealth of knowledge acquired studying primarily single-host, single agent systems. We outline eight challenges in multi-host, multi-agent systems that could substantively increase our knowledge of the drivers and broader ecosystem effects of infectious disease dynamics. PMID- 25843379 TI - Five challenges in modelling interacting strain dynamics. AB - Population epidemiological models where hosts can be infected sequentially by different strains have the potential to help us understand many important diseases. Researchers have in recent years started to develop and use such models, but the extra layer of complexity from multiple strains brings with it many technical challenges. It is therefore hard to build models which have realistic assumptions yet are tractable. Here we outline some of the main challenges in this area. First we begin with the fundamental question of how to translate from complex small-scale dynamics within a host to useful population models. Next we consider the nature of so-called "strain space". We describe two key types of host heterogeneities, and explain how models could help generate a better understanding of their effects. Finally, for diseases with many strains, we consider the challenge of modelling how immunity accumulates over multiple exposures. PMID- 25843380 TI - Nine challenges in modelling the emergence of novel pathogens. AB - Studying the emergence of novel infectious agents involves many processes spanning host species, spatial scales, and scientific disciplines. Mathematical models play an essential role in combining insights from these investigations and drawing robust inferences from field and experimental data. We describe nine challenges in modelling the emergence of novel pathogens, emphasizing the interface between models and data. PMID- 25843381 TI - Five challenges in evolution and infectious diseases. AB - Evolution is a key aspect of the biology of many pathogens, driving processes ranging from immune escape to changes in virulence. Because evolution is inherently subject to feedbacks, and because pathogen evolution plays out at scales ranging from within-host to between-host and beyond, evolutionary questions provide special challenges to the modelling community. In this article, we provide an overview of five challenges in modelling the evolution of pathogens and their hosts, and point to areas for development, focussing in particular on the issue of linking theory and data. PMID- 25843382 TI - Seven challenges in modeling pathogen dynamics within-host and across scales. AB - The population dynamics of infectious disease is a mature field in terms of theory and to some extent, application. However for microparasites, the theory and application of models of the dynamics within a single infected host is still an open field. Further, connecting across the scales--from cellular to host level, to population level--has potential to vastly improve our understanding of pathogen dynamics and evolution. Here, we highlight seven challenges in the following areas: transmission bottlenecks, heterogeneity within host, dynamic fitness landscapes within hosts, making use of next-generation sequencing data, capturing superinfection and when and how to model more than two scales. PMID- 25843383 TI - Nine challenges for deterministic epidemic models. AB - Deterministic models have a long history of being applied to the study of infectious disease epidemiology. We highlight and discuss nine challenges in this area. The first two concern the endemic equilibrium and its stability. We indicate the need for models that describe multi-strain infections, infections with time-varying infectivity, and those where superinfection is possible. We then consider the need for advances in spatial epidemic models, and draw attention to the lack of models that explore the relationship between communicable and non-communicable diseases. The final two challenges concern the uses and limitations of deterministic models as approximations to stochastic systems. PMID- 25843384 TI - Five challenges for stochastic epidemic models involving global transmission. AB - The most basic stochastic epidemic models are those involving global transmission, meaning that infection rates depend only on the type and state of the individuals involved, and not on their location in the population. Simple as they are, there are still several open problems for such models. For example, when will such an epidemic go extinct and with what probability (questions depending on the population being fixed, changing or growing)? How can a model be defined explaining the sometimes observed scenario of frequent mid-sized epidemic outbreaks? How can evolution of the infectious agent transmission rates be modelled and fitted to data in a robust way? PMID- 25843385 TI - Eight challenges for network epidemic models. AB - Networks offer a fertile framework for studying the spread of infection in human and animal populations. However, owing to the inherent high-dimensionality of networks themselves, modelling transmission through networks is mathematically and computationally challenging. Even the simplest network epidemic models present unanswered questions. Attempts to improve the practical usefulness of network models by including realistic features of contact networks and of host pathogen biology (e.g. waning immunity) have made some progress, but robust analytical results remain scarce. A more general theory is needed to understand the impact of network structure on the dynamics and control of infection. Here we identify a set of challenges that provide scope for active research in the field of network epidemic models. PMID- 25843386 TI - Seven challenges for metapopulation models of epidemics, including households models. AB - This paper considers metapopulation models in the general sense, i.e. where the population is partitioned into sub-populations (groups, patches,...), irrespective of the biological interpretation they have, e.g. spatially segregated large sub-populations, small households or hosts themselves modelled as populations of pathogens. This framework has traditionally provided an attractive approach to incorporating more realistic contact structure into epidemic models, since it often preserves analytic tractability (in stochastic as well as deterministic models) but also captures the most salient structural inhomogeneity in contact patterns in many applied contexts. Despite the progress that has been made in both the theory and application of such metapopulation models, we present here several major challenges that remain for future work, focusing on models that, in contrast to agent-based ones, are amenable to mathematical analysis. The challenges range from clarifying the usefulness of systems of weakly-coupled large sub-populations in modelling the spread of specific diseases to developing a theory for endemic models with household structure. They include also developing inferential methods for data on the emerging phase of epidemics, extending metapopulation models to more complex forms of human social structure, developing metapopulation models to reflect spatial population structure, developing computationally efficient methods for calculating key epidemiological model quantities, and integrating within- and between-host dynamics in models. PMID- 25843387 TI - Five challenges for spatial epidemic models. AB - Infectious disease incidence data are increasingly available at the level of the individual and include high-resolution spatial components. Therefore, we are now better able to challenge models that explicitly represent space. Here, we consider five topics within spatial disease dynamics: the construction of network models; characterising threshold behaviour; modelling long-distance interactions; the appropriate scale for interventions; and the representation of population heterogeneity. PMID- 25843388 TI - Six challenges in measuring contact networks for use in modelling. AB - Contact networks are playing an increasingly important role in epidemiology. A contact network represents individuals in a host population as nodes and the interactions among them that may lead to the transmission of infection as edges. New avenues for data collection in recent years have afforded us the opportunity to collect individual- and population-scale information to empirically describe the patterns of contact within host populations. Here, we present some of the current challenges in measuring empirical contact networks. We address fundamental questions such as defining contact; measurement of non-trivial contact properties; practical issues of bounding measurement of contact networks in space, time and scope; exploiting proxy information about contacts; dealing with missing data. Finally, we consider the privacy and ethical issues surrounding the collection of contact network data. PMID- 25843389 TI - Seven challenges for model-driven data collection in experimental and observational studies. AB - Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats. PMID- 25843390 TI - Four key challenges in infectious disease modelling using data from multiple sources. AB - Public health-related decision-making on policies aimed at controlling epidemics is increasingly evidence-based, exploiting multiple sources of data. Policy makers rely on complex models that are required to be robust, realistically approximating epidemics and consistent with all relevant data. Meeting these requirements in a statistically rigorous and defendable manner poses a number of challenging problems. How to weight evidence from different datasets and handle dependence between them, efficiently estimate and critically assess complex models are key challenges that we expound in this paper, using examples from influenza modelling. PMID- 25843392 TI - Six challenges in modelling for public health policy. AB - The World Health Organisation's definition of public health refers to all organized measures to prevent disease, promote health, and prolong life among the population as a whole (World Health Organization, 2014). Mathematical modelling plays an increasingly important role in helping to guide the most high impact and cost-effective means of achieving these goals. Public health programmes are usually implemented over a long period of time with broad benefits to many in the community. Clinical trials are seldom large enough to capture these effects. Observational data may be used to evaluate a programme after it is underway, but have limited value in helping to predict the future impact of a proposed policy. Furthermore, public health practitioners are often required to respond to new threats, for which there is little or no previous data on which to assess the threat. Computational and mathematical models can help to assess potential threats and impacts early in the process, and later aid in interpreting data from complex and multifactorial systems. As such, these models can be critical tools in guiding public health action. However, there are a number of challenges in achieving a successful interface between modelling and public health. Here, we discuss some of these challenges. PMID- 25843391 TI - Eight challenges in phylodynamic inference. AB - The field of phylodynamics, which attempts to enhance our understanding of infectious disease dynamics using pathogen phylogenies, has made great strides in the past decade. Basic epidemiological and evolutionary models are now well characterized with inferential frameworks in place. However, significant challenges remain in extending phylodynamic inference to more complex systems. These challenges include accounting for evolutionary complexities such as changing mutation rates, selection, reassortment, and recombination, as well as epidemiological complexities such as stochastic population dynamics, host population structure, and different patterns at the within-host and between-host scales. An additional challenge exists in making efficient inferences from an ever increasing corpus of sequence data. PMID- 25843393 TI - Six challenges in the eradication of infectious diseases. AB - Eradication and elimination are increasingly a part of the global health agenda. Once control measures have driven infection to low levels, the ecology of disease may change posing challenges for eradication efforts. These challenges vary from identifying pockets of susceptibles, improving monitoring during and after the endgame, to quantifying the economics of disease eradication versus sustained control, all of which are shaped and influenced by processes of loss of immunity, susceptible build-up, emergence of resistance, population heterogeneities and non compliance with control measures. Here we discuss how modelling can be used to address these challenges. PMID- 25843395 TI - Challenges in modelling infectious disease dynamics: preface. PMID- 25843394 TI - Modelling challenges in context: lessons from malaria, HIV, and tuberculosis. AB - Malaria, HIV, and tuberculosis (TB) collectively account for several million deaths each year, with all three ranking among the top ten killers in low-income countries. Despite being caused by very different organisms, malaria, HIV, and TB present a suite of challenges for mathematical modellers that are particularly pronounced in these infections, but represent general problems in infectious disease modelling, and highlight many of the challenges described throughout this issue. Here, we describe some of the unifying challenges that arise in modelling malaria, HIV, and TB, including variation in dynamics within the host, diversity in the pathogen, and heterogeneity in human contact networks and behaviour. Through the lens of these three pathogens, we provide specific examples of the other challenges in this issue and discuss their implications for informing public health efforts. PMID- 25843396 TI - Women undergoing Roux-en-Y Gastric Bypass surgery: Family resemblance in pre- to postsurgery physical activity and sedentary behavior in children and spouses. AB - BACKGROUND: Roux-en-Y Gastric Bypass (RYGB) surgery among women often greatly decreases their body size. It may also change their spouses', children's, and their own physical activity (PA) and sedentary behavior (SB) patterns. OBJECTIVES: The aim was objectively to measure and compare pre- to postsurgery changes in different PA intensities and SB in children and spouses 3 months before and 9 months after maternal RYGB. METHODS: Recruitment from RYGB waiting lists at 5 Swedish hospitals generated a study population of 56 women, with 75 children aged 7-14 years, and 33 spouses. PA was measured over one week using tri axial Actigraph GT3 X+accelerometers, and anthropometric measures were taken at home visits 3 months before and 9 months after maternal surgery. RESULTS: Mean time spent on moderate to vigorous PA (MVPA) by children pre- and postsurgery was 76.3 (SD 40.6) and 65.3 (SD 31.5) min/d, respectively, by spouses 31.2 (SD 18.0) and 33.6 (SD 18.1), and by the women 32.9 (SD 23.4.0) and 34.3 (SD 28.6). Mean time spent sedentary by children pre- and postsurgery was 320.7 (SD 143.4) and 374.4 (SD 123.3) min/d, respectively, by spouses 423.7 (SD 141.5) and 472.1 (SD 145.9), and by the women 425.5 (SD 138.2) and 420.0 (SD 127.8). CONCLUSIONS: Between 3 months before and 9 months after RYGB, objective measurements showed a significant decrease in MVPA and an increase in SB among children, but no differences were observed for spouses or women. Interventions may be needed to promote PA within the family after mothers' RYGB surgery. PMID- 25843398 TI - Comment on: Preoperative glucocorticoid use and risk of postoperative bleeding and infection after gastric bypass surgery for the treatment of obesity. PMID- 25843397 TI - Comparison of the effects of Roux-en-Y gastrojejunostomy and LRYGB with small stomach pouch on type 2 diabetes mellitus in patients with BMI<35 kg/m(2). AB - BACKGROUND: OBJECTIVE: Based on distinct epidemiologic features of Chinese type 2 diabetes mellitus (T2DM) patients, who tend to have abdominal fat deposition, but with normal or mildly overweight epidemiologic features, our center initially had treated T2DM with body mass index (BMI)<35 kg/m2 by performing laparoscopic Roux-en-Y gastrojejunostomy since 2008. This procedure is successful in treating abnormal glucose metabolism but not in improving abdominal visceral obesity. However, since 2011, laparoscopic Roux-Y gastric bypass (LRYGB) with a small stomach pouch has been performed at our center, with prominent resolution of abdominal visceral obesity and lower incidences of postoperative complications. The purpose of the present study was to formally compare these different procedures. METHODS: From 2011 to 2013, 60 patients who met the NIH criteria were recruited and randomly assigned to undergo either laparoscopic Roux-en-Y gastrojejunostomy (n = 30) or LRYGB with a small stomach pouch (n = 30). All of the patients were followed for 12 months, and pre- and postoperative changes in BMI, waist circumference, fasting plasma glucose (FPG), postprandial plasma glucose (PBG), glycated hemoglobin (HbA1c), homoeostatic model assessment (HOMA IR), the body fat rate and major complications were recorded. RESULTS: Both procedures were successful in reducing HbA1c, FPG, and PBG levels and HOMA-IR scores. However, LRYGB with a small stomach pouch resulted in a greater reduction in FPG, PBG, and HbA1c levels, and HOMA-IR scores compared with Roux-en-Y gastrojejunostomy. In addition, the reductions in BMI, body fat content, waist circumference, and the incidence of postoperative marginal ulcers in the small stomach-pouch LRYGB were significant. CONCLUSIONS: Both procedures are effective treatments for T2DM patients with BMI<35 kg/m2. However, the advantages of resolved abnormal glucose metabolism and abdominal visceral obesity and decreased incidences of surgical complications are more obvious for LRYGB with a small gastric pouch. Potentially, LRYGB with a small gastric pouch is more suitable for Chinese diabetic patients with BMI <35 kg/m2. PMID- 25843399 TI - Algorithmic approach to utilization of CT scans for detection of internal hernia in the gastric bypass patient. AB - BACKGROUND: While surgical exploration remains the gold standard for diagnosing internal hernia (IH) after certain bariatric surgeries, decisions for operative intervention are often based on computed tomography (CT) findings. OBJECTIVES: The aim of this study is to review our institutional experience and create an algorithm to approach patients presenting with abdominal pain and/or emesis after certain bariatric procedures. SETTINGS: University Hospital METHODS: Following institutional review board approval, a retrospective chart review of all patients presenting with obstruction symptoms after laparoscopic Roux-en-Y gastric bypass (LRYGB) was performed at 2 institutions from 2008 to 2013. Patients without CT scans or with incidental hernia defect findings were excluded. CT and intraoperative findings were compared via univariate statistical analysis. RESULTS: Fifty-two patients who underwent an operation for a suspected IH were identified. Of the 50 patients, 25 (50%) had IH at operation. Twenty-nine patients (58%) had positive CT scans read for IH and/or obstruction. Of these 29, 19 (66%) were found to have IH at operation and 10 (34%) underwent negative diagnostic laparoscopy. Of the 21 patients with negative CT scans, 6 (29%) had IH at operation versus 15 (71%) who were negative. The sensitivity of CT scan to detect an internal hernia is 76% with 95% confidence interval (CI) [53% to 90%] and specificity is 60% with 95% CI [39% to 78%]. Sensitivity increased to 96% with 95% CI [78% to 99.8%] when combining CT scans with neutrophilia findings. CONCLUSION: Positive CT scans are sensitive for IH but not specific. CT scans will not detect IH in 1:4 patients; despite negative findings, surgical exploration should remain the gold standard for patients with acute abdominal pain after LRYGB or biliopancreatic diversion when IH is a consideration. PMID- 25843400 TI - D-Serine rescues the deficits of hippocampal long-term potentiation and learning and memory induced by sodium fluoroacetate. AB - It is well known that bidirectional glia-neuron interactions play important roles in the neurophysiological and neuropathological processes. It is reported that impairing glial functions with sodium fluoroacetate (FAC) impaired hippocampal long-term depression (LTD) and spatial memory retrieval. However, it remains unknown whether FAC impairs hippocampal long-term potentiation (LTP) and learning and/or memory, and if so, whether pharmacological treatment with exogenous d serine can recuse the impairment. Here, we reported that systemic administration of FAC (3mg/kg, i.p.) before training resulted in dramatic impairments of spatial learning and memory in water maze and fear memory in contextual fear conditioning. Furthermore, the behavioral deficits were accompanied by impaired LTP induction in the hippocampal CA1 area of brain slices. More importantly, exogenous d-serine treatment succeeded in recusing the deficits of hippocampal LTP and learning and memory induced by FAC. Together, these results suggest that astrocytic d-serine may be essential for hippocampal synaptic plasticity and memory, and that alteration of its levels may be relevant to the induction and potentially treatment of psychiatric and neurological disorders. PMID- 25843401 TI - Lengthening of the Stargazin Cytoplasmic Tail Increases Synaptic Transmission by Promoting Interaction to Deeper Domains of PSD-95. AB - PSD-95 is a prominent organizer of the postsynaptic density (PSD) that can present a filamentous orientation perpendicular to the plasma membrane. Interactions between PSD-95 and transmembrane proteins might be particularly sensitive to this orientation, as "long" cytoplasmic tails might be required to reach deeper PSD-95 domains. Extension/retraction of transmembrane protein C tails offer a new way of regulating binding to PSD-95. Using stargazin as a model, we found that enhancing the apparent length of stargazin C-tail through phosphorylation or by an artificial linker was sufficient to potentiate binding to PSD-95, AMPAR anchoring, and synaptic transmission. A linear extension of stargazin C-tail facilitates binding to PSD-95 by preferentially engaging interaction with the farthest located PDZ domains regarding to the plasma membrane, which present a greater affinity for the stargazin PDZ-domain-binding motif. Our study reveals that the concerted orientation of the stargazin C-tail and PSD-95 is a major determinant of synaptic strength. PMID- 25843402 TI - Distinct developmental origins manifest in the specialized encoding of movement by adult neurons of the external globus pallidus. AB - Transcriptional codes initiated during brain development are ultimately realized in adulthood as distinct cell types performing specialized roles in behavior. Focusing on the mouse external globus pallidus (GPe), we demonstrate that the potential contributions of two GABAergic GPe cell types to voluntary action are fated from early life to be distinct. Prototypic GPe neurons derive from the medial ganglionic eminence of the embryonic subpallium and express the transcription factor Nkx2-1. These neurons fire at high rates during alert rest, and encode movements through heterogeneous firing rate changes, with many neurons decreasing their activity. In contrast, arkypallidal GPe neurons originate from lateral/caudal ganglionic eminences, express the transcription factor FoxP2, fire at low rates during rest, and encode movements with robust increases in firing. We conclude that developmental diversity positions prototypic and arkypallidal neurons to fulfil distinct roles in behavior via their disparate regulation of GABA release onto different basal ganglia targets. PMID- 25843403 TI - Retinoic Acid and LTP Recruit Postsynaptic AMPA Receptors Using Distinct SNARE Dependent Mechanisms. AB - Retinoic acid (RA)-dependent homeostatic plasticity and NMDA receptor-dependent long-term potentiation (LTP), a form of Hebbian plasticity, both enhance synaptic strength by increasing the abundance of postsynaptic AMPA receptors (AMPARs). However, it is unclear whether the molecular mechanisms mediating AMPAR trafficking during homeostatic and Hebbian plasticity differ, and it is unknown how RA signaling impacts Hebbian plasticity. Here, we show that RA increases postsynaptic AMPAR abundance using an activity-dependent mechanism that requires a unique SNARE (soluble NSF-attachment protein receptor)-dependent fusion machinery different from that mediating LTP. Specifically, RA-induced AMPAR trafficking did not involve complexin, which activates SNARE complexes containing syntaxin-1 or -3, but not complexes containing syntaxin-4, whereas LTP required complexin. Moreover, RA-induced AMPAR trafficking utilized the Q-SNARE syntaxin 4, whereas LTP utilized syntaxin-3; both additionally required the Q-SNARE SNAP 47 and the R-SNARE synatobrevin-2. Finally, acute RA treatment blocked subsequent LTP expression, probably by increasing AMPAR trafficking. Thus, RA-induced homeostatic plasticity involves a novel, activity-dependent postsynaptic AMPAR trafficking pathway mediated by a unique SNARE-dependent fusion machinery. PMID- 25843404 TI - Circuit mechanisms underlying motor memory formation in the cerebellum. AB - The cerebellum stores associative motor memories essential for properly timed movement; however, the mechanisms by which these memories form and are acted upon remain unclear. To determine how cerebellar activity relates to movement and motor learning, we used optogenetics to manipulate spontaneously firing Purkinje neurons (PNs) in mouse simplex lobe. Using high-speed videography and motion tracking, we found that altering PN activity produced rapid forelimb movement. PN inhibition drove movements time-locked to stimulus onset, whereas PN excitation drove delayed movements time-locked to stimulus offset. Pairing either PN inhibition or excitation with sensory stimuli triggered the formation of robust, associative motor memories; however, PN excitation led to learned movements whose timing more closely matched training intervals. These findings implicate inhibition of PNs as a teaching signal, consistent with a model whereby learning leads first to reductions in PN firing that subsequently instruct circuit changes in the cerebellar nucleus. PMID- 25843406 TI - Sensory inputs to intercalated cells provide fear-learning modulated inhibition to the basolateral amygdala. AB - Increasing evidence suggests that parallel plastic processes in the amygdala involve inhibitory elements to control fear and extinction memory. GABAergic medial paracapsular intercalated cells (mpITCs) are thought to relay activity from basolateral nucleus (BLA) and prefrontal cortex to inhibit central amygdala output during suppression of fear. Recently, projection diversity and differential behavioral activation of mpITCs in distinct fear states suggest additional functions. Here, we show that mpITCs receive convergent sensory thalamic and cortical inputs that undergo fear learning-related changes and are dynamically modulated via presynaptic GABAB receptors recruited by GABA released from the mpITC network. Among mpITCs, we identify cells that inhibit but are also mutually activated by BLA principal neurons. Thus, mpITCs take part in fear learning-modulated feedforward and feedback inhibitory circuits to simultaneously control amygdala input and output nuclei. Our findings place mpITCs in a unique position to gate acquired amygdala-dependent behaviors via their direct sensory inputs. PMID- 25843405 TI - Inhibitory and excitatory spike-timing-dependent plasticity in the auditory cortex. AB - Synapses are plastic and can be modified by changes in spike timing. Whereas most studies of long-term synaptic plasticity focus on excitation, inhibitory plasticity may be critical for controlling information processing, memory storage, and overall excitability in neural circuits. Here we examine spike timing-dependent plasticity (STDP) of inhibitory synapses onto layer 5 neurons in slices of mouse auditory cortex, together with concomitant STDP of excitatory synapses. Pairing pre- and postsynaptic spikes potentiated inhibitory inputs irrespective of precise temporal order within ~10 ms. This was in contrast to excitatory inputs, which displayed an asymmetrical STDP time window. These combined synaptic modifications both required NMDA receptor activation and adjusted the excitatory-inhibitory ratio of events paired with postsynaptic spiking. Finally, subthreshold events became suprathreshold, and the time window between excitation and inhibition became more precise. These findings demonstrate that cortical inhibitory plasticity requires interactions with co-activated excitatory synapses to properly regulate excitatory-inhibitory balance. PMID- 25843408 TI - Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium. AB - Big efforts have been dedicated up to now to identify novel targets for cancer treatment. The peculiar biophysical profile and the atypical ionic channels activity shown by diverse types of human cancers suggest that ion channels may be possible targets in cancer therapy. Earlier studies have shown that melatonin exerts an oncostatic action on different tumors. In particular, it was shown that melatonin was able to inhibit growth/viability and proliferation, to reduce the invasiveness and metastatic properties of human estrogen-sensitive breast adenocarcinoma MCF-7 cell line cultured in growth medium, with substantial impairments of epidermal growth factor (EGF) and Notch-1-mediated signaling. The purpose of this work was to evaluate on MCF-7 cells the possible effects of melatonin on the biophysical features known to have a role in proliferation and differentiation, by using the patch-clamp technique. Our results show that in cells cultured in growth as well as in differentiation medium melatonin caused a hyperpolarization of resting membrane potential paralleled by significant changes of the inward Ca(2+) currents (T- and L-type), outward delayed rectifier K(+) currents and cell capacitance. All these effects are involved in MCF-7 growth and differentiation. These findings strongly suggest that melatonin, acting as a modulator of different voltage-dependent ion channels, might be considered a new promising tool for specifically disrupting cell viability and differentiation pathways in tumour cells with possible beneficial effects on cancer therapy. PMID- 25843407 TI - Neuronal Activity and CaMKII Regulate Kinesin-Mediated Transport of Synaptic AMPARs. AB - Excitatory glutamatergic synaptic transmission is critically dependent on maintaining an optimal number of postsynaptic AMPA receptors (AMPARs) at each synapse of a given neuron. Here, we show that presynaptic activity, postsynaptic potential, voltage-gated calcium channels (VGCCs) and UNC-43, the C. elegans homolog of CaMKII, control synaptic strength by regulating motor-driven AMPAR transport. Genetic mutations in unc-43, or spatially and temporally restricted inactivation of UNC-43/CaMKII, revealed its essential roles in the transport of AMPARs from the cell body and in the insertion and removal of synaptic AMPARs. We found that an essential target of UNC-43/CaMKII is kinesin light chain and that mouse CaMKII rescued unc-43 mutants, suggesting conservation of function. Transient expression of UNC-43/CaMKII in adults rescued the transport defects, while optogenetic stimulation of select synapses revealed CaMKII's role in activity-dependent plasticity. Our results demonstrate unanticipated, fundamentally important roles for UNC-43/CaMKII in the regulation of synaptic strength. PMID- 25843409 TI - Nalbuphine could decrease the rewarding effect induced by tramadol in mice while enhancing its antinociceptive activity. AB - Nalbuphine, a kappa-opioid agonist and mu-opioid partial agonist, has been used as an analgesic or an adjuvant with morphine to attenuate the development of morphine dependence and rewarding effect. In this study, we investigated the effect of nalbuphine on tramadol rewarding effect and antinociception. Using the conditioned place preference (CPP) paradigm in mice, we demonstrated that co administration of nalbuphine (7mg/kg, s.c.) with tramadol (70mg/kg, s.c.) during conditioning completely blocked the CPP induced by tramadol. Co-administration of nalbuphine blocked the increase in dopamine level in the nucleus accumbens induced by tramadol. These actions were accompanied by an increase rather than attenuation of the antinociceptive effect of tramadol. These results suggest that nalbuphine could have a great potential as a pharmacotherapy for tramadol abuse. PMID- 25843410 TI - Elements in support of the 'non-identity' of the PGRMC1 protein with the sigma2 receptor. AB - sigma2 Receptor subtype is overexpressed in a variety of human tumors, with sigma2 agonists showing antiproliferative effects towards tumor cells through multiple pathways that depend both on the tumor cell type and on the molecule type. Therefore, sigma2 receptor is an intriguing target for tumor diagnosis and treatment despite the fact that that it has not yet been cloned. One of the last attempts to characterize sigma2 receptors led to identify it as the progesterone receptor membrane component 1 (PGRMC1). Although still controversial, such identity appears to have been accepted. We the aim of contributing to solve this controversy, in this work we stably silenced or overexpressed PGRMC1 protein in human MCF7 adenocarcinoma cells. Western blotting analyses were performed to quantify the presence of PGRMC1 protein on each of the three MCF7 cell lines variants, while scatchard analyses with radioligand were performed in order to determine the expression of the sigma2 receptors. In order to correlate the antiproliferative effect of sigma2 receptor agonist with PGRMC1 density, some sigma2 ligands were administered to each of the three MCF7 cells variants. The results suggested that PGRMC1 and sigma2 receptors are two different molecular entities. PMID- 25843411 TI - SIRT1 inhibition in pancreatic cancer models: contrasting effects in vitro and in vivo. AB - Gemcitabine remains the standard treatment for pancreatic cancer, although most patients acquire resistance to the therapy. Up-regulated in pancreatic cancer, SIRT1 is involved in tumorigenesis and drug resistance. However the mechanism through which SIRT1 regulates drug sensitivity in cancer cells is mainly unknown. We hypothesise that inhibiting SIRT1 activity may increase sensitivity of pancreatic cancer cells to gemcitabine treatment through the regulation of apototic cell death, cell cycle, epithelial-mesenschymal-transition (EMT) and senescence. We demonstrate that gemcitabine or 6-Chloro-2,3,4,9-tetrahydro-1 H Carbazole-1-carboxamide (EX527) SIRT1 inhibitor reduces PANC-1 cell proliferation in vitro. EX527 enhanced sensitivity of PANC-1 cells to gemcitabine treatment through increased apoptosis. However, EX527 displayed no beneficial effect either as a monotreatment or in combination with gemcitabine in the modulation of cell cycle progression. Combination treatment did not reverse the two phenomena known to affect drug sensitivity, namely EMT and senescence, which are both induced by gemcitabine. Unexpectedly, EX527 promoted PANC-1 xenograft tumour growth in SCID mice compared to control group. Dual tX527 and gemcitabine displayed no synergistic effect compared to gemcitabine alone. The study reveals that SIRT1 is involved in chemoresistance and that inhibiting SIRT1 activity with EX527 sensitised PANC-1 cells to gemcitabine treatment in vitro. Sensitisation of cells is shown to be mainly through induction of micronuclei formation as a result of DNA damage and apoptosis in vitro. However, the absence of positive combinatorial effects in vivo indicates possible effects on cells of the tumor microenvironment and suggests caution regarding the clinical relevance of tissue culture findings with EX527. PMID- 25843412 TI - Cutaneous iontophoresis of treprostinil, a prostacyclin analog, increases microvascular blood flux in diabetic malleolus area. AB - Diabetic foot ulcers are one of the most common and serious complications of diabetes mellitus. Few drugs are effective in enhancing the healing of microvascular skin ulcers. The main objective of the present study was to determine whether iontophoresis of treprostinil, a prostacyclin analog, increases skin microvascular blood flux in the malleolus area of healthy subjects and diabetic patients. We recruited 12 healthy subjects and 12 type 2 diabetic patients. Cathodal iontophoresis (40mC/cm2) of treprostinil 250uM and NaCl 0.9% was performed in the malleolus area. Skin hyperemia was quantified using non invasive laser speckle contrast imaging, and expressed as the area under the curve (AUC) of cutaneous vascular conductance (CVC). In healthy controls and diabetic patients, treprostinil 250uM induced a significant increase in CVC compared with NaCl (for diabetic patients, AUC0-6h was 19970+/-8697; versus 2893+/-5481%BL.min, respectively; P=0.002). In both groups, the peak flux was obtained between 30min and 1h after the end of treprostinil iontophoresis and flux remained higher than baseline up to 6h after ending of iontophoresis. No significant side-effect occurred. Cutaneous iontophoresis of 250uM treprostinil increases microvascular blood flux in the malleolus area in healthy volunteers and diabetic patients, without inducing systemic or local side-effects. Treprostinil cathodal iontophoresis should be further investigated as a new local therapy for diabetic ulcers. PMID- 25843413 TI - The interactive role of cannabinoid and vanilloid systems in hippocampal synaptic plasticity in rats. AB - Long-term potentiation (LTP) has been most thoroughly studied in the hippocampus, which has a key role in learning and memory. Endocannabinoids are one of the endogenous systems that modulate this kind of synaptic plasticity. The activation of the vanillioid system has also been shown to mediate synaptic plasticity in the hippocampus. In addition, immunohistochemical studies have shown that cannabinoid receptor type 1 (CB1) and vanilloid receptor 1 (TRPV1) are closely located in the hippocampus. In this study, we examined the hippocampal effects of co-administrating WIN55-212-2 and capsaicin, which are CB1 and TRPV1 agonists, respectively, on the induction of LTP in the dentate gyrus (DG) of rats. LTP in the hippocampal area was induced by high-frequency stimulation (HFS). Our results indicated that the cannabinoid agonist reduced both field excitatory post synaptic potential (fEPSP) slope and population spike (PS) amplitude after HFS with respect to the control group, whereas the vanilloid agonist increased these parameters along with the increased induction of LTP as compared to the control group. We also showed that the co-administration of cannabinoid and vanilloid agonists had different effects on fEPSP slope and PS amplitude. It seems that agonists of the vanilloid system modulate cannabinoid outputs that cause an increase in synaptic plastisity, while in contemporary consumption of two agonist, TRPV1 agonist can change production of endocannabinoid, which in turn result to enhancement of LTP induction. These findings suggest that the two systems may interact or share certain common signaling pathways in the hippocampus. PMID- 25843414 TI - Arecoline inhibits intermediate-conductance calcium-activated potassium channels in human glioblastoma cell lines. AB - Arecoline (ARE) is an alkaloid-type natural product from areca nut. This compound has numerous pharmacological and toxicological effects. Whether this agent interacts with ion channels to perturb functional activity of cells remains unknown. The effects of ARE on ionic currents were studied in glioma cell lines (U373 and U87MG) using patch-clamp technique. Like TRAM-34(1-[(2-chlorophenyl) diphenylmethyl]pyrazole), ARE suppressed the amplitude of whole-cell voltage gated K(+) currents in U373 cells elicited by a ramp voltage clamp. In cell attached configuration, ARE did not modify the single-channel conductance of intermediate-conductance Ca(2+)-activated K(+) (IKCa) channels; however, it did reduce channel activity. Its inhibition of IKCa channels was accompanied by a significant lengthening in the slow component of mean closed time of IKCa channels. Based on minimal kinetic scheme, the dissociation constant (KD) required for ARE-mediated prolongation of mean closed time was 11.2uM. ARE induced inhibition of IKCa channels was voltage-dependent. Inability of ARE to perturb the activity of large-conductance Ca(2+)-activated K(+) (BKCa) channels was seen. Under current-clamp recordings, ARE depolarized the membrane of U373 cells and DCEBIO reversed ARE-induced depolarization. Similarly, ARE suppressed IKCa-channel activities in oral keratinocytes. This study provides the evidence that ARE block IKCa channels in a concentration, voltage and state-dependent manner. ARE-induced block of IKCa channels is unrelated to the binding of muscarinic receptors. The effects of ARE on these channels may partially be responsible for the underlying cellular mechanisms by which it influences the functional activities of glioma cells or oral keratinocytes, if similar findings occur in vivo. PMID- 25843415 TI - Effect of Age on Treatment Decision-Making in Elderly Patients With Acute Myeloid Leukemia. AB - BACKGROUND: Patients aged >= 70 years with acute myeloid leukemia (AML) have a poorer prognosis than those aged 60 to 69 years. PATIENTS AND METHODS: We retrospectively analyzed the cases of 183 patients aged >= 70 years with a performance status of <= 2 treated at our institution from 2000 to 2014. Treatment consisted of anthracycline- and cytarabine-based chemotherapy for 93 patients and lower intensity therapy with low-dose cytarabine or hypomethylating agent cycles for 90 patients. RESULTS: A total of 57 patients (61%) achieved complete remission in the intensive chemotherapy group versus only 11 (12%) in the lower intensity treatment group (P < .0001). The median overall survival (OS) was 14.5 months and 11.7 months with a 3-year OS rate of 34% and 18% (P = .005) for the intensive and lower intensity groups, respectively. The difference remained significant when considering patients aged <= 75 years, but not for patients aged > 75 years. Similarly, a significant difference was only observed when considering favorable and intermediate cytogenetic factors (P = .007) but not unfavorable karyotypes. On multivariate analysis, age did not appear as an independent prognostic factor. CONCLUSION: With intensive chemotherapy, the median OS significantly increased after the introduction of an improved supportive care policy compared with historical controls (14 vs. 5.4 months, with a 3-year OS rate of 33% vs. 8%). After 2006, a more "personalized" therapeutic approach tended to erase the difference in terms of OS, especially in patients aged > 75 years. PMID- 25843416 TI - Evaluation of clinical and biological prognostic factors in relapsed or refractory diffuse large B-cell lymphoma patients after previous treatment with rituximab and chemotherapy: results of the PRO-R-IPI study. AB - INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, showing a highly variable outcome. In patients with DLBCL relapsed/refractory to first-line treatment with rituximab the usefulness of the revised International Prognostic Index (R-IPI) as a prognostic tool remains unexplored. Some biological parameters (B-cell lymphoma 6 [Bcl-6], Bcl-2, p53, and multiple myeloma 1 [MUM1]) and blood populations (lymphocyte and monocyte counts) have been described as International Prognostic Index-independent prognostic factors. The objective was to evaluate the R-IPI to predict the outcome of DLBCL patients at the time of relapse after a front-line treatment with chemotherapy and rituximab and to establish in this population the relationship between biological parameters and outcome. PATIENTS AND METHODS: We included patients with refractory/relapsed DLBCL after first-line treatment with rituximab-containing regimens; patients must have already finished a rescue treatment also including rituximab. Immunohistochemical assessment of Bcl-2, Bcl-6, p53, and MUM1 expression were undertaken in available biopsies. R-IPI factors were identified from the clinical data at diagnosis and at relapse. Response was assessed using National Cancer Institute-sponsored Working Group guidelines. RESULTS: R-IPI prognosis at relapse was not significantly associated with overall response rate (ORR) after Rituximab chemotherapy rescue therapy. None of the immunohistochemical parameters analyzed correlated with rescue therapy results. In contrast, patients with absolute lymphocyte count (ALC) >= 1 * 10(9)/L at relapse were more likely to respond than patients with ALC < 1 * 10(9)/L (P = .05). CONCLUSION: The R-IPI score calculated at relapse could not predict the ORR to second-line treatment. Lymphopenia is a simple and useful predictor for outcome in relapsed/refractory DLBCL and the only prognostic factor that in our hands could predict the overall response to a second-line treatment with rituximab and chemotherapy. PMID- 25843417 TI - Can 3D ultrasound identify trochlea dysplasia in newborns? Evaluation and applicability of a technique. AB - Femoro-patellar dysplasia is considered as a significant risk factor of patellar instability. Different studies suggest that the shape of the trochlea is already developed in early childhood. Therefore early identification of a dysplastic configuration might be relevant information for the treating physician. An easy applicable routine screening of the trochlea is yet not available. The purpose of this study was to establish and evaluate a screening method for femoro-patellar dysplasia using 3D ultrasound. From 2012 to 2013 we prospectively imaged 160 consecutive femoro-patellar joints in 80 newborns from the 36th to 61st gestational week that underwent a routine hip sonography (Graf). All ultrasounds were performed by a pediatric radiologist with only minimal additional time to the routine hip ultrasound. In 30 degrees flexion of the knee, axial, coronal, and sagittal reformats were used to standardize a reconstructed axial plane through the femoral condyle and the mid-patella. The sulcus angle, the lateral-to medial facet ratio of the trochlea and the shape of the patella (Wiberg Classification) were evaluated. In all examinations reconstruction of the standardized axial plane was achieved, the mean trochlea angle was 149.1 degrees (SD 4.9 degrees ), the lateral-to-medial facet ratio of the trochlea ratio was 1.3 (SD 0.22), and a Wiberg type I patella was found in 95% of the newborn. No statistical difference was detected between boys and girls. Using standardized reconstructions of the axial plane allows measurements to be made with lower operator dependency and higher accuracy in a short time. Therefore 3D ultrasound is an easy applicable and powerful tool to identify trochlea dysplasia in newborns and might be used for screening for trochlea dysplasia. PMID- 25843418 TI - Influence of technical parameters on epicardial fat volume quantification at cardiac CT. AB - OBJECTIVES: To systematically analyze the influence of technical parameters on quantification of epicardial fat volume (EATV) at cardiac CT. METHODS: 153 routine cardiac CT data sets were analyzed using three-dimensional pericardial border delineation. Three image series were reconstructed per patient: (a) CTAD: coronary CT angiography (CTA), diastolic phase; (b) CTAS: coronary CTA, systolic phase; (c) CaScD: non-contrast CT, diastolic phase. EATV was calculated using three different upper thresholds (-15HU, -30 HU, -45HU). Repeated measures ANOVA, Spearman's rho, and Bland Altman plots were used. RESULTS: Mean EATV differed between all three image series at a -30HU threshold (CTAD 87.2 +/- 38.5 ml, CTAS 90.9 +/- 37.7 ml, CaScD 130.7 +/- 49.5 ml, P<0.001). EATV of diastolic and systolic CTA reconstructions did not differ significantly (P=0.225). Mean EATV for contrast enhanced CTA at a -15HU threshold (CTAD15 102.4 +/- 43.6 ml, CTAS15 105.3 +/- 42.3 ml) could be approximated most closely by non-contrast CT at -45HU threshold (CaScD45 105.3 +/- 40.8 ml). The correlation was excellent: CTAS15 CTAD15, rho=0.943; CTAD15-CaScD45, rho=0.905; CTAS15-CaScD45, rho=0.924; each P<0.001). Bias values from Bland Altman Analysis were: CTAS15-CTAD15, 4.9%; CTAD15-CaScD45, -4.3%; CTAS15-CaScD45, 0.6%. CONCLUSIONS: Measured EATV can differ substantially between contrast enhanced and non-contrast CT studies, which can be reconciled by threshold modification. Heart cycle phase does not significantly influence EATV measurements. PMID- 25843419 TI - Dasatinib enhances cisplatin sensitivity in human esophageal squamous cell carcinoma (ESCC) cells via suppression of PI3K/AKT and Stat3 pathways. AB - The clinical efficacy of cisplatin in esophageal squamous cell carcinoma (ESCC) treatment remains undesirable. Src, a non-receptor tyrosine kinase involved in multiple fields of tumorigenesis, recently has been indicated as a promising therapeutic target in the treatment of solid tumors including ESCC. However, whether inhibition of Src activity can increase cisplatin efficacy in ESCC cells remains unknown. The present study found that inhibition of Src by its inhibitor dasatinib sensitized ESCC cells to cisplatin in vitro. Our data also suggest a likely mechanism for this synergy that dasatinib reduces expression of critical oncogenic members of the signaling pathways, such as AKT or Stat3, and cisplatin resistant molecules, such as ERCC1 and BRCA1, under the control of Src. Furthermore, dasatinib could sensitize ESCC cells to another platin-based agent, carboplatin. Therefore, this study provides a potential target for improving cisplatin efficacy in ESCC therapy. PMID- 25843420 TI - Kinetic and hysteretic behavior of ATP hydrolysis of the highly stable dimeric ATP synthase of Polytomella sp. AB - The F1FO-ATP synthase of the colorless alga Polytomella sp. exhibits a robust peripheral arm constituted by nine atypical subunits only present in chlorophycean algae. The isolated dimeric enzyme exhibits a latent ATP hydrolytic activity which can be activated by some detergents. To date, the kinetic behavior of the algal ATPase has not been studied. Here we show that while the soluble F1 sector exhibits Michaelis-Menten kinetics, the dimer exhibits a more complex behavior. The kinetic parameters (Vmax and Km) were obtained for both the F1 sector and the dimeric enzyme as isolated or activated by detergent, and this activation was also seen on the enzyme reconstituted in liposomes. Unlike other ATP synthases, the algal dimer hydrolyzes ATP on a wide range of pH and temperature. The enzyme was inhibited by oligomycin, DCCD and Mg-ADP, although oligomycin induced a peculiar inhibition pattern that can be attributed to structural differences in the algal subunit-c. The hydrolytic activity was temperature-dependent and exhibited activation energy of 4 kcal/mol. The enzyme also exhibited a hysteretic behavior with a lag phase strongly dependent on temperature but not on pH, that may be related to a possible regulatory role in vivo. PMID- 25843421 TI - Retention time correction in gas chromatography by modeling concentration related effects, applied to the analysis of fatty acid methyl esters. AB - Constant and reproducible retention times are a basic requirement to allow the automatic peak assignment in complex gas chromatograms. Drifting retention times are best handled by frequent updates, based on reference peaks. Some refinements of this concept have been reported as well as alternative concepts, including pattern recognition algorithms to achieve ultimate precision; however, in applications requiring a wide concentration range, the effects of concentration on the retention time of individual peaks may become relevant, requiring special considerations. The analysis of fatty acid methyl esters is such an application. A model describing concentration related effects was drawn up and found to work best for this purpose. The precision of peak alignment could be improved by an order of magnitude, allowing reliable automation of routine analysis. PMID- 25843422 TI - Isolation of two Delta5 polymethylene interrupted fatty acids from Podocarpus falcatus by countercurrent chromatography. AB - The lipids of gymnosperms frequently feature unusual polyunsaturated fatty acids (PUFAs) such as sciadonic acid (20:3Delta5,11,14) and juniperonic acid (20:4Delta5,11,14,17) showing a first double bond on C-5 which is separated from the next double bond by five methylene units. Compared to "classic" fatty acids, these fatty acids are not easily commercially available and their prices are quite high. For this reason, we wished to isolate those fatty acids from the seed oil of Podocarpus falcatus by countercurrent chromatography (CCC) after conversion of the fatty acids to methyl esters (FAMEs). The contribution of sciadonic acid (20:3Delta5,11,14) and juniperonic acid (20:4Delta5,11,14,17) in the unfractionated sample was 10% and 6% respectively, while oleic acid (18:1Delta9) and linoleic acid (18:2Delta9,12) were the major fatty acids. After a first CCC run with FAMEs from Podocarpus falcatus, fractions enriched in the target compounds were chosen for subsequent isolation by means of two subsequent CCC runs. Initially, 13mg of juniperonic acid was recovered with a purity of 92% according to analysis by gas chromatography with mass spectrometry (GC/MS). Further purification of this fraction yielded 2.7mg with a purity of 99% according to GC/MS. The isolation of sciadonic acid was hampered by high amounts of linoleic acid with the same equivalent chain length in suitable fractions of the first CCC separation. After an enrichment step by CCC, the critical pair sciadonic acid and linoleic acid was finally separated as free fatty acids. After this step, 4.4mg of sciadonic acid was recovered with 99% purity. The methodology could also be applied to isolate larger amounts of those fatty acids or for the isolation of other minor fatty acids. PMID- 25843423 TI - Separation and identification of oligomeric phenylethoxysiloxanols by liquid chromatography-electrospray ionization mass spectrometry. AB - Liquid chromatography-electrospray ionization mass spectrometry has been applied to qualitative analysis of oligomeric phenylethoxysiloxanols, a class of organosilanols as active intermediates to polyhedral silsesquioxanes. The phenylethoxysiloxanol samples were prepared by controlled acid-catalyzed hydrolysis and condensation of phenyltriethoxysilane at various molar equivalents of water (r1) and characterized by standard spectroscopic techniques. Using a gradient binary water-methanol mobile phase, these reaction products were resolved on octadecylsiloxane silica stationary phase and subsequently identified by online electrospray ionization mass spectrometric detection. Results show that the reaction products are composed of a multitude of linear and monocyclic siloxanol oligomers with various numbers of silicon atoms and hydroxyl groups, depending upon the reaction conditions used. With the r1 value increasing from 0.5 to 2.0, the chain lengths of the oligomers increase slightly but the numbers of hydroxyl groups increase considerably, accompanying by structural evolution from chains to rings. Characterization of the retention behavior of these oligomers indicates that hydrophobic interactions of phenyl and ethoxy groups with the stationary phase are responsible for their retention in reversed-phase liquid chromatography. PMID- 25843425 TI - Targeting hepatitis B virus cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication. AB - Chronic hepatitis B virus (HBV) infection causes liver cirrhosis and hepatocellular carcinoma and remains a serious health problem worldwide. Covalently closed circular DNA (cccDNA) in the liver cell nucleus sustains HBV infection. Major treatments for HBV infection include the use of interferon-alpha and nucleotide analogs, but they cannot eradicate cccDNA. As a novel tool for genome editing, clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system developed from bacteria can be used to accurately and efficiently engineer and modify genomic DNA. In this study, the CRISPR/Cas9 system was used to target the HBV genome and efficiently inhibit HBV infection. We synthesized four single-guide RNAs (sgRNAs) targeting the conserved regions of HBV. The expression of these sgRNAS with Cas9 reduced the viral production in Huh7 cells as well as in HBV-replication cell HepG2.2.15. We further demonstrated that CRISPR/Cas9 direct cleavage and cleavage-mediated mutagenesis occurred in HBV cccDNA of transfected cells. In the new mouse model carrying HBV cccDNA, injection of sgRNA-Cas9 plasmids via rapid tail vein resulted in the low level of cccDNA and HBV protein. In conclusion, the designed CRISPR/Cas9 system can accurately and efficiently target HBV cccDNA and inhibit HBV replication. This system may be used as a novel therapeutic strategy against chronic HBV infection. PMID- 25843426 TI - The Potential for Clinical Decision Support to Improve Emergency Care. PMID- 25843424 TI - The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G quadruplex: Implications for the antiviral activity of a G-quadruplex ligand. AB - Guanine-rich nucleic acids can fold into G-quadruplexes, secondary structures implicated in important regulatory functions at the genomic level in humans, prokaryotes and viruses. The remarkably high guanine content of the Herpes Simplex Virus-1 (HSV-1) genome prompted us to investigate both the presence of G quadruplex forming sequences in the viral genome and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with a novel mechanism of action. Using biophysical, molecular biology and antiviral assays, we showed that the HSV-1 genome displays multiple clusters of repeated sequences that form very stable G-quadruplexes. These sequences are mainly located in the inverted repeats of the HSV-1 genome. Treatment of HSV-1 infected cells with the G-quadruplex ligand BRACO-19 induced inhibition of virus production. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and decreased intracellular viral DNA in infected cells. The last step targeted by BRACO-19 was viral DNA replication, while no effect on virus entry in the cells was observed. This work, presents the first evidence of extended G-quadruplex sites in key regions of the HSV-1 genome, indicates the possibility to block viral DNA replication by G-quadruplex-ligand and therefore provides a proof of concept for the use of G-quadruplex ligands as new anti herpetic therapeutic options. PMID- 25843427 TI - Energy-Based Molecular Fragmentation Methods. PMID- 25843429 TI - A heterozygous missense mutation in adolescent-onset very long-chain acyl-CoA dehydrogenase deficiency with exercise-induced rhabdomyolysis. AB - Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is characterized by impaired mitochondrial beta-oxidation of fatty acids. The fatty acid oxidation plays a significant role in energy production especially in skeletal muscle. VLCAD is one of four acyl-CoA dehydrogenases with different-chain length specificity and catalyzes the initial step in mitochondrial beta-oxidation of fatty acids. While the clinical phenotypes in neonates and infants are described as severe, adolescent-onset or adult-onset VLCAD deficiency has a more benign course with only skeletal muscle involvement. These myopathic phenotypes are characterized by episodic muscle weakness and rhabdomyolysis triggered by fasting and strenuous exercise. We report a male teenager who manifested repeated episodes of rhabdomyolysis immediately after exertional exercise. Rhabdomyolysis was diagnosed based on the marked elevation of serum creatine kinase and myoglobinuria. Acylcarnitine analysis by tandem mass spectrometry (MS/MS) revealed elevation of serum tetradecenoylcarnitine (C14:1-AC), which represents an abnormal acylcarnitine profile associated with the mitochondrial beta oxidation defect. High performance liquid chromatographic analysis showed decreased production of 2-hexadecenoyl-CoA (C16:1) from palmitoyl-CoA (C16:0), indicating the defect of VLCAD activity. Direct sequencing of the acyl-CoA dehydrogenase, very long-chain gene (ACADVL) that codes VLCAD revealed a heterozygous mutation (c.1242G>C) in exon 12 (E414D), which is a novel mutation in myopathic-type VLCAD deficiency. Because VLCAD functions as a homodimer, we assume that this heterozygous mutation may exhibit dominant-negative effect. This patient remains asymptomatic thereafter by avoiding exertional exercise. The findings of reduction of enzyme activity and clinical features associated with this novel missense mutation of VLCAD are discussed. PMID- 25843430 TI - Dabigatran for the prevention and treatment of thromboembolic disorders. AB - Dabigatran, an oral direct thrombin inhibitor, was the first of a new class of drugs referred to as non-vitamin K oral anticoagulants. Dabigatran is better than warfarin for stroke prevention in non-valvular atrial fibrillation (dose of 150 mg twice a day), non-inferior to enoxaparin for venous thromboembolism prevention after orthopedic surgery and non-inferior to warfarin in preventing recurrence after acute venous thromboembolism. The safety profile is similar to standard anticoagulants, with significant reduction observed in intracranial hemorrhage. Other advantages include a rapid onset of action and a predictable pharmacokinetic profile, allowing a fixed-dose regimen without the need for routine anticoagulation monitoring. In the event of bleeding, general support measures are recommended and if severe, the use of non-specific hemostatic agents such as prothrombin complex concentrates and recombinant factor VIIa must be considered. A specific reversal agent (idarucizumab) is in development. PMID- 25843431 TI - Lenalidomide in multiple myeloma. AB - In the last couple of years major progress has been made in the treatment of multiple myeloma (MM) through the introduction of novel agents like thalidomide, lenalidomide, bortezomib and pomalidomide, mostly in combination with autologous stem cell transplantation. Lenalidomide, a second-generation immunomodulatory agent with antitumor and immunomodulatory effects against MM, in combination with dexamethasone was proven to show significant clinical benefits (overall survival and progression-free survival) in Phase III trials either as induction or as maintenance therapy. With a manageable toxicity profile, lenalidomide seems to be an attractive agent in the treatment of MM. Here, we discuss the present data and research on lenalidomide in the treatment of MM. PMID- 25843432 TI - Occurrence of common allergic diseases in children with idiopathic nephrotic syndrome. AB - BACKGROUND: Clinical and immunological studies have consistently shown a possible link between atopy and idiopathic nephrotic syndrome (INS). However, whether allergic diseases occur after INS develops is unknown. METHODS: From Taiwan's National Health Insurance database, 1340 children with newly diagnosed INS and 5360 non-INS matched controls were identified in 2000-2007. By the end of 2008, the incidences and hazard ratios of four allergic diseases (allergic conjunctivitis, allergic rhinitis, atopic dermatitis, and asthma) were calculated. RESULTS: The incidence rates of all four allergic diseases were greater in the INS cohort than in the non-INS cohort in all age groups and decreased sharply as age increased in both cohorts. Children with INS had the highest adjusted hazard ratio (4.13; 95% confidence interval [CI], 2.50-6.83) for atopic dermatitis and the lowest adjusted hazard ratio (1.71; 95% CI, 1.39-2.09) for allergic rhinitis. Most of the allergic diseases appeared within 2-6 months after INS developed, and the incidences declined with increasing follow-up duration. CONCLUSIONS: Allergic disorders are common in children with INS, especially within the first year after diagnosis. The role of INS in the development of allergic disorders should be elucidated to establish innovative disease intervention programs. PMID- 25843433 TI - Relative validity and reproducibility of a brief-type self-administered diet history questionnaire for Japanese children aged 3-6 years: application of a questionnaire established for adults in preschool children. AB - BACKGROUND: Dietary intake assessment and subsequent dietary education or intervention in young children is important in decreasing prevalence of various noncontagious diseases in adulthood. Validation of diet assessment questionnaires for preschool children has just started in Japan. In this study, we rearranged the brief-type self-administered diet history questionnaire (BDHQ), a convenient diet assessment questionnaire that is widely used in a range of situations for adults, for use in children aged 3-6 years (BDHQ3y) and then validated the BDHQ3y in Japanese children. METHODS: The guardians of 61 children aged 3-4 years completed the BDHQ3y twice at an interval of 1 month, along with a 3 nonconsecutive-day diet record (DR) between the two administrations of the BDHQ3y. Dietary intakes for energy and 42 selected nutrients were estimated using both the DR and the BDHQ3y. Mean intakes estimated by the two methods were compared, and correlation coefficients were calculated. Reproducibility of the BDHQ3y estimates was investigated using intra-class correlation coefficients (ICCs). RESULTS: No significant differences in mean intakes estimated by the DR and the BDHQ3y were observed for one- to two-thirds of energy and examined nutrients. The median of Pearson correlation coefficients between intakes energy adjusted by the residual method was 0.31 (interquartile range, 0.24 to 0.38). The median ICC was 0.72 (interquartile range, 0.63 to 0.76) for the crude nutrient intakes. CONCLUSIONS: Although the BDHQ3y might be a good candidate for dietary intake assessment in Japanese preschool children, its validity is currently moderate to low. Shortcomings should be overcome by obtaining and utilizing more information about children's dietary habits. PMID- 25843434 TI - Introduction. Costs and benefits of imperfect cognitions. PMID- 25843435 TI - Erratum to: Self-Reported and Observed Punitive Parenting Prospectively Predicts Increased Error-Related Brain Activity in Six-Year-Old Children. PMID- 25843436 TI - CACNA1C SNP rs1006737 associates with bipolar I disorder independent of the Bcl-2 SNP rs956572 variant and its associated effect on intracellular calcium homeostasis. AB - OBJECTIVES: Intracellular calcium (Ca(2+)) dyshomeostasis (ICDH) has been implicated in bipolar disorder (BD) pathophysiology. We previously showed that SNP rs956572 in the B-cell CLL/lymphoma 2 (Bcl-2) gene associates with elevated B lymphoblast (BLCL) intracellular Ca(2+) concentrations ([Ca(2+)]B) differentially in BD-I. Genome-wide association studies strongly support the association between BD and the SNP rs1006737, located within the L-type voltage-dependent Ca(2+) channel alpha1C subunit gene (CACNA1C). Here we investigated whether this CACNA1C variant also associates with ICDH and interacts with SNP rs956572 on [Ca(2+)]B in BD-I. METHODS: CACNA1C SNP rs1006737 was genotyped in 150 BD-I, 65 BD-II, 30 major depressive disorder patients, and 70 healthy subjects with available BLCL [Ca(2+)]B and Bcl-2 SNP rs956572 genotype measures. RESULTS: SNP rs1006737 was significantly associated with BD-I. The [Ca(2+)]B was significantly higher in BD I rs1006737 A compared with healthy A allele carriers and also in healthy GG compared with A allele carriers. There was no significant interaction between SNP rs1006737 and SNP rs956572 on [Ca(2+)]B. CONCLUSIONS: Our study further supports the association of SNP rs1006737 with BD-I and suggests that CACNA1C SNP rs1006737 and Bcl-2 SNP rs956572, or specific causal variants in LD with these proxies, act independently to increase risk and ICDH in BD-I. PMID- 25843437 TI - Self-Assembled Functional Nanostructure of Plasmid DNA with Ionic Liquid [Bmim][PF6]: Enhanced Efficiency in Bacterial Gene Transformation. AB - The electrostatic interaction between the negatively charged phosphate groups of plasmid DNA and the cationic part of hydrophobic ionic liquid 1-butyl-3 methylimidazolium hexafluorophosphate ([Bmim][PF6]), initiates spontaneous self assembly to form the functional nanostructures made up of DNA and ionic liquid (IL). These functional nanostructures were demonstrated as promising synthetic nonviral vectors for the efficient bacterial pGFP gene transformation in cells. In particular, the functional nanostructures that were made up of 1 MUL of IL ([Bmim][PF6]) and 1 MUg of plasmid DNA can increase the transformation efficiency by 300-400% in microbial systems, without showing any toxicity for E. coli DH5alpha cells. (31)P nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR) spectroscopy, and X-ray photoelectron (XPS) spectroscopic analysis revealed that the electrostatic interaction between negatively charged phosphate oxygen and cationic Bmim(+) tends to initiate the self-assembly process. Thermogravimetric analysis of the DNA-IL functional nanostructures showed that these nanostructures consist of ~16 wt % ionic liquid, which is considered to provide the stability to the plasmid DNA that eventually enhanced the transformation efficiency. PMID- 25843440 TI - Sperm whales ability to avoid approaching vessels is affected by sound reception in stratified waters. AB - Collision with vessels is a major cause of whale mortality in the Mediterranean Sea. The effect of non-spherical sound propagation effects on received levels (RL) was investigated for the sperm whale (Physeter macrocephalus). Relevant dive patterns were considered in each case and the RL were compared for two periods using a ray tracing software, the winter conditions and the summer stratified situation. RL were plotted as a function of time in a simulated collision case for two vessel speeds representative of a conventional merchant ship (15knots) and a fast-ferry (37knots). In almost all simulated cases, RL featured a brutal 23-31dB re 1MUPa rise from below 100dB while the vessel approached the whale at close range. Summer situations were worse because this transition occurred at closer ranges, resulting in acoustic warning times of less than 30s in the fast ferry case. These results suggested that sperm whales could not be able to achieve an escape manoeuvre in a critical situation such as a fast vessel approaching under stratified waters conditions. PMID- 25843439 TI - Total petroleum hydrocarbons in sediments from the coastline and mangroves of the northern Persian Gulf. AB - To provide baseline information for the marine ecosystem of Hormozgan province, the distribution of petroleum hydrocarbons was evaluated in 52 stations involved in the mangrove and coastline ecosystem. Coastline sampling sites included areas facing harbor, river, domestic and industrial discharge. Sediment samples were analyzed based on ultraviolet fluorescence spectroscopy. Petroleum hydrocarbons showed narrow variations ranging from non-detectable (ND) to 1.71 and from 0.2 to 0.63MUg/g dry weight for coastline and mangrove sediments, respectively. The detected concentrations for total petroleum hydrocarbons were lower than guideline values for ecological risk. Furthermore, the minimum environmental risk was confirmed by background levels for the Persian Gulf, the Sea of Oman, and detected values for reference areas. The results were regarded as background data in the studied area, and, considering the rapid expansion of activities related to the petroleum industry in Hormozgan province, the continuous monitoring of pollutants is recommended. PMID- 25843441 TI - Assessment of growth, genotoxic responses and expression of stress related genes in the Pacific oyster Crassostrea gigas following chronic exposure to ionizing radiation. AB - Marine organisms are exposed to low doses of anthropogenic contaminants during their entire life. Authorized amounts of radionuclides are discharged in the Channel by nuclear facilities. The Pacific oyster was used to investigate the potential impact of chronic exposure to ionizing radiation. Though we exposed larvae and spat for two weeks to much higher concentrations than those encountered near nuclear facilities, oyster growth and expression of 9 selected stress genes were not significantly changed. To determine potential DNA damage, 2year old oysters were exposed for two weeks to tritiated water. The comet assay was used to evaluate the level of DNA strand breaks in haemocytes, whilst the 'clearance rate' was used as a measure of physiological effects. Whilst other parameters did not alter, DNA damage significantly increased. Our results highlight the significance of the observed DNA damage and their potential consequences at higher levels of biological organization. PMID- 25843442 TI - Distribution of butyltins and alternative antifouling biocides in sediments from shipping and shipbuilding areas in South Korea. AB - The occurrence and distribution of tributyltin (TBT) and alternative biocides were investigated in sediment from semi-enclosed bays, fishing ports, and large commercial harbors in Korea. Extremely high concentration of TBT (55,264ngSn/g) was detected near a large shipyard, even after a total ban on its use in Korea. Diuron was the biocide with the highest detection frequency and concentration levels, followed by Irgarol 1051. Sea-Nine 211 was detected at 3 of 32 stations surveyed. Dichlofluanid, zinc and copper pyrithiones levels were below the detection limits at all the stations surveyed. The relatively high levels of Diuron (9-62.3ng/g) and Irgarol 1051 (1.5-11.5ng/g) were detected in harbor and shipyard areas. Diuron and Irgarol 1051 levels including TBT in sediments from hot spots in Korea exceeded global sediment quality guidelines. PMID- 25843438 TI - Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. AB - The brain possesses two intricate mechanisms that fulfill its continuous metabolic needs: cerebral autoregulation, which ensures constant cerebral blood flow over a wide range of arterial pressures and functional hyperemia, which ensures rapid delivery of oxygen and glucose to active neurons. Over the past decade, a number of important studies have identified astrocytes as key intermediaries in neurovascular coupling (NVC), the mechanism by which active neurons signal blood vessels to change their diameter. Activity-dependent increases in astrocytic Ca(2+) activity are thought to contribute to the release of vasoactive substances that facilitate arteriole vasodilation. A number of vasoactive signals have been identified and their role on vessel caliber assessed both in vitro and in vivo. In this review, we discuss mechanisms implicating astrocytes in NVC-mediated vascular responses, limitations encountered as a result of the challenges in maintaining all the constituents of the neurovascular unit intact and deliberate current controversial findings disputing a main role for astrocytes in NVC. Finally, we briefly discuss the potential role of pericytes and microglia in NVC-mediated processes. PMID- 25843443 TI - Development of Fingertip Synchrotron Radiation Microangiography toward Clinical Prediction of Diabetic Microangiopathy. AB - OBJECTIVES: The spatial resolution of conventional angiographic systems is not enough to predict diabetic microangiopathy in arterioles (20-200 um). METHODS: To determine whether fingertip synchrotron (SR) radiation microangiography has enough spatial resolution to quantitate arteriolar diameter changes, and whether an arteriolar paradoxical vasoconstriction is a characteristic observation for diabetic microangiopathy, diameter reduction as arteriolar branching and difference of the diameter changes induced by acetylcholine between control (n = 5) and diabetic rats (n = 5) were analyzed. RESULTS: Fingertip SR microangiography visualized the arterioles with a diameter range of 30-300 um and demonstrated vascular diameter reduction as branching with a fixed ratio (r = 0.93, P < 0.004 and r = 0.73, P < 0.001). A vasodilatory reaction was induced by acetylcholine in the control (142.4 +/- 61.9 to 190.9 +/- 73.5, P < 0.05, n = 25), in contrast, paradoxical vasoconstriction in diabetic rats (201.6 +/- 83.0 to 16 0.4 +/- 67.9, P < 0.05, n = 37). Histological angiopathy was noted only in the diabetic rats. CONCLUSION: In conclusion, the fingertip SR microangiography is useful to predict diabetic micrangiopahty. PMID- 25843444 TI - Prilocaine hydrochloride protects zebrafish from lethal effects of ionizing radiation: role of hematopoietic cell expansion. AB - Drug repositioning is an approach of significant translatability, and the present study was undertaken to screen a collection of FDA approved small-molecule clinical compounds for identification of novel radioprotective agents. Screening of JHCCL (Johns Hopkins Clinical Compound Library), a collection of 1,400 FDA approved small molecules, lead to identification of prilocaine hydrochloride, a local anesthetic used widely during dental procedures, as a potential radioprotector. Prilocaine, at a concentration of 20 uM, protected zebrafish from radiation induced (20 Gy) pericardial edema (PE), microphthalmia and rendered 60 % survival advantage over radiation exposed controls. While 40 % survival advantage over radiation exposed controls was achieved with 10 uM prilocaine. Prilocaine, in a dose-dependent manner, scavenged, radiation-induced hydroxyl radicals and maximally (43 %) at the highest concentration (1 mM) tried in this study. However, prilocaine exerted a mild superoxide anion scavenging potential (around 5 %) at all the concentrations used within this study. Prilocaine, at 20 uM concentration, significantly increased erythropoiesis, a marker for HSC function, in caudal hematopoietic tissue (CHT) in wild type and anemic zebrafish embryos (1.48 and 0.85 folds respectively) when compared to untreated (1) and phenylhydrazine (PHZ) (0.41 fold) treated control groups respectively. These results suggest that prilocaine is a radioprotective agent and free radical scavenging and HSC expanding potential seems to be contributing towards its radioprotective action. PMID- 25843445 TI - Evaluation of Renal Artery Anomalies Associated with Horseshoe Kidney Using CT Angiography. AB - PURPOSE: To evaluate the incidence of supernumerary renal arteries in horseshoe kidney (HSK) patients, focusing on number and diameters using computed tomographic angiography (CTA). MATERIAL AND METHODS: Thirty-nine patients with HSK and 103 patients with normal kidney (NK) underwent 64 or 128 multidetector CT. Based on 2-dimensional CT, including multiplanar reconstruction, maximum intensity projection, and volume-rendered images with a 0.5-mm reconstruction interval on CTA, we assessed the incidence of supernumerary renal arteries, and large ( > 3 mm in diameter) supernumerary renal arteries, and compared the results between the HSK and NK patients using a chi-square test. RESULT: The mean number of renal arteries was 3.87 in HSK patients and 2.41 in the NK patients. The incidence rates of supernumerary arteries and supernumerary arteries greater than 3 mm were 92.3 %, 69.2 % in HSK patients and 33%, 8.7% in NK patients. Supernumerary and large supernumerary renal arteries had significantly higher incidence rates in the HSK patients than in the NK patients on CTA (p = 0.003, < 0.001). CONCLUSION: Supernumerary and large supernumerary renal arteries were frequently found among the HSK patients on CTA. PMID- 25843446 TI - Rapidly progressive dementia caused by a superior sagittal sinus dural arteriovenous fistula: a case report. AB - We describe the case of a 72-year-old man who presented with dementia that had progressed rapidly over a few months. Laboratory analysis of blood and cerebrospinal fluid (CSF) showed no abnormalities, with the exception of a slightly increased CSF protein level. Results of routine magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) and magnetic resonance angiography (MRA) were unremarkable. However, detailed neuroimaging studies including contrast-enhanced T1-weighted MRI and conventional angiography revealed a superior sagittal sinus (SSS) dural arteriovenous fistula (DAVF). After endovascular embolization and surgical interruption of all arteries feeding the DAVF, the dementia reversed. We should be aware of the possibility of DAVF as the cause of rapidly progressive dementia even if routine MRI reveals no or only minimal abnormality. PMID- 25843447 TI - Adaptive Bone Remodeling of the Femoral Bone After Tumor Resection Arthroplasty With an Uncemented Proximally Hydroxyapatite-Coated Stem. AB - Loss of bone stock and stress shielding is a significant challenge in limb salvage surgery. This study investigates the adaptive bone remodeling of the femoral bone after implantation of a tumor prosthesis with an uncemented press fit stem. We performed a prospective 1 yr follow-up of 6 patients (mean age: 55 (26-78) yr, female/male=3/3) who underwent bone tumor resection surgery of the proximal femur (n=3) or distal femur (n=3). Reconstruction was done using a Global Modular Replacement System (Stryker(r) Orthopaedics, Mahwah, NJ) tumor prosthesis, and all patients received a straight-fluted 125-mm uncemented press fit titanium alloy stem with hydroxyapatite coating of the proximal part of the stem. Measurements of bone mineral density (BMD; g/cm2) were done postoperatively and after 3, 6, and 12 mo in the part of the femur bone containing the Global Modular Replacement System stem using dual-energy X-ray absorptiometry. BMD was measured in 3 regions of interest (ROIs) in the femur bone. Nonparametric analysis of variance (Friedman test) for evaluation of changes in BMD over time. BMD decreased in all 3 ROIs with time. In ROI 1 (p=0.01), BMD decreased by 10% after 3 mo and ended with a total decrease of 14% after 1 yr. In ROI 2 (p=0.006), BMD was decreased by 6% after 3 and 6 mo; after 1 yr of follow-up, BMD was 9% below the postoperative value. In ROI 3 (p=0.009), BMD decreased by 6% after 3 and 6 mo; after 1 yr of follow-up, BMD was 8% below the postoperative value. A bone loss of 8%-9% during the first postoperative year was seen along the femoral stem, but in the bone containing the hydroxyapatite-coated part of the stem, the decrease in BMD was 14%, thus indicating that stress shielding of this part of the bone may play a role for the adaptive bone remodeling. PMID- 25843448 TI - A study to investigate the bond strengths of orthodontic brackets bonded to prosthetic acrylic teeth. AB - INTRODUCTION: In this study, we compared the shear bond strengths of five different adhesive techniques for attaching metal orthodontic brackets onto acrylic pontics. MATERIALS AND METHODS: Two hundred upper left lateral incisor acrylic teeth with bonded brackets were divided into five groups - composite alone (control), composite following sandblasting, composite held with a mechanical undercut, cyanoacrylate adhesive and Panavia((r)). The initial bond strength was tested using the Instron Universal Testing Machine. The fatigue bond strength was tested by subjecting each bracket to 5000 repetitive low-load cycles at 50% of the mean shear bond strength using the Dartec machine at 2 Hz. RESULTS: Cyanoacrylate adhesive statistically exhibited the highest mean bond strength (19.82 MPa). This was followed by the mechanical undercut group (17.69 MPa) and the sandblasted group (17.18 MPa). There was no statistically significant difference when considering the effect of fatiguing (p = 0.238) as well as the interaction between the adhesive technique and the effect of fatiguing on the bond strength (p = 0.440). CONCLUSION: The initial and fatigue bond strengths of the cyanoacrylate adhesive, sandblasted and undercut groups were significantly higher than the control and Panavia((r)) groups when tested under laboratory conditions. PMID- 25843449 TI - Acute cutaneous zygomycosis of the scalp: A case report and literature review. AB - Cutaneous zygomycosis is the third most common form of zygomycosis. However, scalp involvement is rare for this disease. In this study, we present a case of acute zygomycosis in a diabetic patient who was effectively treated with local debridement, amphotericin B lipid complex and posaconazole. PMID- 25843451 TI - Decarboxylation of fatty acids to terminal alkenes by cytochrome P450 compound I. AB - OleT(JE), a cytochrome P450, catalyzes the conversion of fatty acids to terminal alkenes using hydrogen peroxide as a cosubstrate. Analytical studies with an eicosanoic acid substrate show that the enzyme predominantly generates nonadecene and that carbon dioxide is the one carbon coproduct of the reaction. The addition of hydrogen peroxide to a deuterated substrate-enzyme (E-S) complex results in the transient formation of an iron(IV) oxo pi cation radical (Compound I) intermediate which is spectroscopically indistinguishable from those that perform oxygen insertion chemistries. A kinetic isotope effect for Compound I decay suggests that it abstracts a substrate hydrogen atom to initiate fatty acid decarboxylation. Together, these results indicate that the initial mechanism for alkene formation, which does not result from oxygen rebound, is similar to that widely suggested for P450 monooxygenation reactions. PMID- 25843450 TI - Idiopathic hypereosinophilic syndrome: a new cause of vasculitis of the central nervous system. AB - Idiopathic hypereosinophilic syndrome (IHES) is a primary haematological condition characterised by persistent, otherwise unexplained hypereosinophilia sufficient to cause organ damage. Various neurological complications are reported, but very few have mentioned CNS pathology and none has included CNS vasculitis. Our objective here is to report IHES as a new cause of histopathologically confirmed CNS vasculitis. A 39-year-old man presented with a relapsing sub-acute encephalopathy, with severe headaches, confusion and drowsiness, myoclonus, ataxia and papilloedema. He had a history of nephrotic syndrome 18 years earlier, stable for the past 5 years on low-dose corticosteroids and low-dose tacrolimus (2 mg bd); lichen planus, and (15 years previously) aloplecia totalis. On admission, he had a marked peripheral eosinophilia (up to 9.1 * 10(9)/dL), which-it subsequently became clear-had been intermittently present for 16 years. After extensive investigation, biopsies of brain and bone marrow confirmed diagnoses of cerebral vasculitis, with lymphocytic and macrophage (but not eosinophilic) cellular infiltration of blood vessel walls, and IHES. CNS vasculitis can therefore now be added to the list of neurological complications of IHES. A dramatic and sustained neurological improvement, and likewise of the eosinophilia, following treatment with corticosteroids and cyclophosphamide, emphasises the tractability of this newly described form of CNS vasculitis. PMID- 25843452 TI - [Indication and actual status of endoscopic submucosal dissection for colorectal tumors -present status and future perspective]. PMID- 25843453 TI - [Clinico-pathological findings and molecular alterations of colorectal serrated lesion]. PMID- 25843454 TI - [Histopathological diagnosis of colorectal serrated lesions]. PMID- 25843455 TI - [Endoscopic diagnosis and clinical management for serrated lesions of the large intestine]. PMID- 25843456 TI - [A case of large cell neuroendocrine carcinoma of the rectum]. AB - A 77-year-old woman was referred to our hospital because of blood in feces and anal pain. Colonoscopy revealed a villous semicircular tumor in the rectum. A biopsy showed well-differentiated adenocarcinoma. Miles' operation was performed because of the persistence of anal pain and blood in feces. Histological and immunohistochemical analysis showed coexistent tubulovillous adenoma, tubulovillous adenocarcinoma, and large cell neuroendocrine carcinoma (LCNEC), which was positive for CD56, chromogranin A, and synaptophysin. Pathological examination revealed that most of the lesion was occupied by the LCNEC. The tumor was therefore diagnosed as LCNEC of the rectum. The patient underwent adjuvant chemotherapy with cisplatin (CDDP), irinotecan (CPT-11), and mFOLFOX6, but died because of LCNEC progression 10 months after the operation. LCNEC rarely occurs in the gastrointestinal tract; here we report a case of rectal LCNEC. PMID- 25843457 TI - [Duodenal gastrointestinal stromal tumor (GIST) with deletion in exon 11 of c-kit treated with emergency pancreaticoduodenectomy due to massive bleeding: a case report]. AB - A Japanese woman in her 50s presented with coffee-ground vomiting at a local clinic and was referred to our hospital for further investigation. Esophagogastroduodenoscopy demonstrated a submucosal tumor in the descending part of the duodenum, and she was diagnosed with a gastrointestinal stromal tumor (GIST) by other imaging studies. Elective surgery of the tumor was initially planned. However, on the 13th day of hospitalization, emergency pancreaticoduodenectomy was performed because of massive hematemesis with hemorrhagic shock. Genetic analysis demonstrated a deletion in exon 11 of the c kit gene, which could dramatically alter the clinical course. Although duodenal GIST with active bleeding is comparatively rare, we have to assume that it is the cause of gastrointestinal bleeding and treat such cases with a minimally invasive surgical procedure and neoadjuvant/adjuvant chemotherapy. It is necessary to accumulate more cases with duodenal GIST to establish an evidence-based therapeutic strategy. PMID- 25843458 TI - [A case of autoimmune pancreatitis associated with hemorrhagic duodenal ulcers]. AB - An 84-year-old man was diagnosed with IgG4-related autoimmune pancreatitis and sclerosing cholangitis with jaundice. Endoscopic nasobiliary drainage was performed, but hemorrhagic shock due to multiple duodenal ulcers occurred about a week later. After several endoscopic hemostasis, he was given corticosteroids. Histopathology of duodenal ulcer biopsies showed IgG4-positive plasma cell infiltration. Reports about duodenal ulcers with IgG4-related disease are very rare and we consider this case valuable. PMID- 25843459 TI - [Effectiveness of anti-tumor necrosis factor-alpha therapy in Crohn's disease with abscesses around the sigmoid colon: a case report]. AB - We report the case of a man in his 50s who was diagnosed with Crohn's colitis in his 30s and who presented with post-prandial lower abdominal pain in January, 20XX. Colonoscopy and abdominal contrast-enhanced computed tomography revealed abscesses around the sigmoid colon. Although his response to antibiotics was poor, treatment with a combination of antibiotics and adalimumab resolved the abscesses. Nine months later, however, the abscesses around the sigmoid colon recurred. Treatment comprising bowel rest and antibiotics led to immediate improvement of the symptoms. We report a case of effective anti-tumor necrosis factor-alpha therapy in Crohn's colitis with abscesses around the sigmoid colon. PMID- 25843460 TI - [Tumor lysis syndrome after FOLFIRI+cetuximab for ascending colon cancer]. AB - We report a case of an 83-year-old woman who developed tumor lysis syndrome (TLS) 5 days after FOLFIRI+cetuximab (Cmab) therapy. A huge ascending colon cancer measuring 10 cm in diameter and with peritoneal dissemination was diagnosed. Following successful therapy with FOLFIRI alone, FOLFIRI+Cmab was administered. On day 5, TLS was diagnosed with hyperuricemia, hyperkalemia, hyperphosphatemia, and an increase in serum creatinine. Intravenous furosemide, volume loading, and glucose-insulin therapy resulted in improvement of laboratory data in 2 days. However, she died on the 34th day due to multiple organ failure caused by aspiration pneumonia following small intestine functional ileus. Although TLS is a rare complication in colon cancer, its onset must be taken into consideration. Also, risk assessment and preventive therapy for TLS should be performed before cancer treatment. PMID- 25843461 TI - [A case of esophageal stenosis caused by esophageal intramural pseudodiverticulosis with candida esophagitis]. AB - A 55-year-old man who was a heavy drinker with a history of diabetes mellitus was admitted to our hospital with the complaint of dysphagia. Upper gastrointestinal endoscopy revealed multiple intramural pseudodiverticula of the esophagus with candida infection in the cervical and thoracic esophagus. It was difficult to pass the endoscope through the lower thoracic esophagus, indicating stenosis. Thoracic computed tomography and esophagogram revealed widespread, multiple confluent pseudodiverticula in the submucosa. A diagnosis of esophageal intramural pseudodiverticulosis with candida esophagitis was made. The stenosis of the esophagus was improved by endoscopic balloon dilatation and antifungal therapy. PMID- 25843462 TI - [A case of lymphoproliferative disorder in the entire small intestine after renal transplantation detected by wireless capsule endoscopy]. AB - A 42-year-old woman underwent renal transplantation in 200X. After the transplant, she received tacrolimus as immunosuppressant therapy. Eleven years after the transplant, diffuse large B-cell lymphomas were detected in the duodenum and terminal ileum. Wireless capsule endoscopy (WCE) revealed multiple lymphoma lesions in the entire small intestine. The patient achieved complete response through the administration of R-CHOP therapy and discontinuation of immunosuppressant therapy. Post-transplant lymphoproliferative disorder (PTLD) is a rare complication and WCE may be useful for diagnosing PTLD of the small intestine. PMID- 25843463 TI - [A case of serous cystic neoplasm of the pancreas with stenosis of the main pancreatic duct]. AB - A 64-year-old woman was accidentally detected to have multiple cystic tumors measuring 30 mm in diameter in the pancreatic head in 2009. The probable diagnosis was a serous cystic neoplasm of the pancreas. However, the tumor had grown to 52 mm in diameter in 4 years, and endoscopic retrograde pancreatography (ERCP) showed stenosis of the main pancreatic duct. We performed subtotal stomach preserving pancreaticoduodenectomy, and histopathological diagnosis was serous cystadenoma. PMID- 25843464 TI - Bacteria Isolated From the Skin of Congo African Grey Parrots ( Psittacus erithacus ), Budgerigars ( Melopsittacus undulatus ), and Cockatiels ( Nymphicus hollandicus ). AB - Little is known about the normal bacterial flora of the skin of birds. To identify the bacterial organisms that reside on the integument of companion psittacine birds in a normal physiologic state, skin cultures were taken from 75 psittacine birds comprising 25 Congo African grey parrots ( Psittacus erithacus ), 25 budgerigars ( Melopsittacus undulatus ), and 25 cockatiels ( Nymphicus hollandicus ). All birds were adults and in good health with no underlying identifiable diseases, had not been on antibiotics in the preceding 2 months or longer, and had no skin or feather abnormalities. Cultures were taken from the axillary region and incubated on bovine blood agar plates. Positive cultures were identified for 52 out of 75 birds, and a total of 89 bacterial colonies grew. The most frequently identified bacterial organisms belonged to the genus Staphylococcus followed by Corynebacterium. Several other genera of bacteria were also isolated. Of the 89 bacterial colonies, 25 were identified to the species level and 50 to the genus level, and 14 were identified as either a nonfermenter or coliform. PMID- 25843465 TI - Evaluation of Multidrug Therapy With Azithromycin, Rifampin, and Ethambutol for the Treatment of Mycobacterium avium subsp avium in Ring-neck Doves (Streptopelia risoria): An Uncontrolled Clinical Study. AB - An uncontrolled clinical study was conducted to evaluate the efficacy of a multidrug protocol in 16 ring-neck doves ( Streptopelia risoria ) from a flock naturally infected with Mycobacterium avium subsp avium. The doves were considered infected on the basis of a high prevalence of infection in a group of 29 birds that were euthanatized from the same flock and clinical signs and pathologic results consistent with infection in the remaining birds. All birds were treated with azithromycin (43 mg/kg), rifampin (45 mg/kg), and ethambutol (30 mg/kg) administered orally once daily for 180 days. Five birds died during treatment and were confirmed positive for mycobacteriosis on postmortem examination. Of the remaining 11 birds, infection and disease were present in 9 (81.8%) at the end of the treatment. Postmortem investigation showed that 2 mycobacterial isolates were resistant to ethambutol, intermediately sensitive to rifampin, and sensitive to azithromycin. Microscopic examination of liver sections equivalent of those that would be taken for biopsy showed that biopsy as a method of monitoring birds for treatment success had poor sensitivity. Toxicity associated with drug therapy was not observed in these doves nor in 6 outwardly healthy ring-neck doves exposed to the same treatment. The results of this study showed that this protocol of azithromycin, rifampin, and ethambutol has poor efficacy when administered for 180 days for treatment of doves infected with M avium subsp avium. PMID- 25843466 TI - Measuring the Level of Agreement Between Cloacal Gram's Stains and Bacterial Cultures in Hispaniolan Amazon Parrots ( Amazona ventralis ). AB - Cloacal or fecal Gram's stains and bacterial cultures are routinely performed during avian physical examinations to assess the microbial flora of the gastrointestinal tract. Although cloacal or fecal Gram's stains and bacterial cultures are considered routine diagnostic procedures, the level of agreement between the individual tests has not been determined. To investigate the level of agreement between results from Gram's stain and bacterial culture when used to assess cloacal or fecal samples from psittacine birds, samples were taken from 21 clinically healthy Hispaniolan Amazon parrots ( Amazona ventralis ) and tested by Gram's stain cytology and bacterial culture. Most bacteria (97.2%) identified by Gram's stain were gram positive. However, gram-negative organisms were identified in 7 of 21 (33.3%; 95% confidence interval: 13.3%-53.3%) birds. Escherichia coli was the only gram-negative organism identified on culture. Agreement between results of Gram's stain and culture was fair (weighted kappa = 0.27). The results of this study suggest that Gram's stains and bacterial culture may need to be performed with a parallel testing strategy to limit the likelihood of misclassifying the microbial flora of psittacine patients. PMID- 25843467 TI - Gastrointestinal cryptosporidiosis in captive psittacine birds in the United States: a case review. AB - Histopathologic analysis performed on tissue samples from 34 captive psittacine birds over a 14-year period demonstrated gastrointestinal cryptosporidiosis. Although 8 birds had died unexpectedly, at least 10 showed gastrointestinal signs before death. Most birds had other significant pathologic lesions, unrelated to cryptosporidiosis, in which case Cryptosporidium was likely a secondary pathogen. However, in 11 birds the only significant histopathologic finding was gastrointestinal cryptosporidiosis. In 2 lovebird (Agapornis species) cases, direct sequencing of proventricular samples confirmed the presence of Cryptosporidium avian genotype III. A description and analysis of the pathologic findings in these 34 birds, as well as a review of avian gastrointestinal cryptosporidiosis, is provided. PMID- 25843468 TI - Coracoid fractures in wild birds: a comparison of surgical repair versus conservative treatment. AB - Medical records of wild bird admissions to the Australian Wildlife Health Centre at Healesville Sanctuary were analyzed for cases of unilateral coracoid fractures with known final outcomes. Forty-seven birds, comprising 13 species, fit these criteria. Of those birds, 18 were treated conservatively with analgesia and cage rest without coaptation bandaging, and 29 were treated with surgical correction of the fracture. Of the conservatively managed birds, 89% (16 of 18) were released back into the wild. Conversely, 34% (10 of 29) of the surgically managed birds were released. Treatment success for release differed significantly between treatment groups (P < .001). Intraoperative death from concurrent trauma was the major reason that surgically treated birds were not released. Given the high risks associated with surgical treatment and the high success rate of conservative management, cage rest without surgery appears prudent when managing coracoid injuries in birds. PMID- 25843469 TI - Immunohistochemical Study of Aquaporins in an African Grey Parrot (Psittacus erithacus) With Hydrocephalus. AB - A 5-month-old African grey parrot (Psittacus erithacus) was examined after 3 weeks of weakness, ataxia, mental depression, and seizures. Results of a complete blood cell count and plasma biochemical analysis were unremarkable. Magnetic resonance imaging revealed a severe bilateral hydrocephalus. The bird failed to improve with supportive care, and the owner requested euthanasia. Necropsy findings were severe bilateral hydrocephalus with no evidence of cerebrospinal fluid obstruction. Histologic examination of the brain revealed microspongiosis, edema, gliosis, and neuronal chromatolysis of surrounding periventricular tissue. Aquaporins (AQP) and astrocytes were examined to elucidate the participation of these water channel proteins and glial cells in the pathophysiology and resolution of hydrocephalus. Results showed AQP4 and glial fibrillary acidic protein were overexpressed, especially near the ventricles, but expression of AQP1 was decreased. This is the first report, to our knowledge, of AQP immunolabeling in hydrocephalus in avain species. PMID- 25843470 TI - Antemortem Diagnosis and Successful Treatment of Pulmonary Candidiasis in a Sun Conure (Aratinga solstitialis). AB - An adult male sun conure (Aratinga solstitialis) was evaluated because of lethargy, ruffled feathers, and decreased appetite. Physical examination revealed hypothermia, dehydration, dyspnea, and crop distention. Results of a complete blood cell count revealed a marked inflammatory leukogram, and cytologic examination of a crop swab sample identified gram-negative bacilli and occasional yeast organisms. Radiographs demonstrated an opaque, ill-defined, soft tissue structure in the caudal coelom just cranial to the renogonadal silhouette, loss of serosal detail, and splenomegaly. Endoscopic examination revealed a pale, granuloma-like structure within the caudal aspect of the left lung, splenomegaly, and an enlarged proventriculus. Intraoperative cytologic examination of a biopsy sample of the lesion demonstrated yeast organisms, and a subsequent culture of the biopsy sample revealed Candida albicans . The bird was treated intraoperatively with intralesional amphotericin B. Postoperative treatment consisted of meloxicam, trimethoprim sulfa, amphotericin B by nebulization, and systemic itraconazole and fluconazole. The bird made a complete recovery, was discontinued from all medications, and has remained asymptomatic for 6 months. Although rare, pulmonary candidiasis should be on the list of differential diagnoses for any respiratory infection in birds. Endoscopic biopsy, cytology, and fungal culture were valuable in making the diagnosis. PMID- 25843472 TI - Fatal Envenomation of a Chilean Flamingo (Phoenicopterus chilensis) From Eastern Yellow Jacket Wasps (Vespula maculifrons). AB - A 37-year-old, female Chilean flamingo (Phoenicopterus chilensis) presented with severe facial angioedema, bilateral corneal and palpebral edema, nictitating membrane paralysis, bradycardia, bradypnea, hypothermia, and numerous stingers and remnants of eastern yellow jacket wasps (Vespula maculifrons) attached to the feathers of the head, palpebrae, and conjunctiva. Evaluation of 2 complete blood cell counts and results of plasma chemical analysis and serum protein electrophoresis revealed severe increases in creatinine phosphokinase and aspartate aminotransferase activity, electrolyte disturbances, and moderate increases in levels of alpha1, alpha2, beta1, and gamma immunoglobulins when compared with reference interval values and conspecifics. Despite intensive treatment, the bird died 19 hours after presentation. Results of histologic evaluation of tissues were compatible with envenomation. Response to envenomation in avian species is not documented but should be considered in birds presenting with angioedema. PMID- 25843471 TI - Mycotic Keratitis in a Khaki Campbell Duck ( Anas platyrhynchos domesticus). AB - A 1.5-year-old, intact female khaki Campbell duck (Anas platyrhynchos domesticus) was evaluated for lethargy and a swollen left eye (OS). Mucoid discharge, chemosis, and conjunctival hyperemia with trace aqueous flare, indicating anterior uveitis, in the anterior chamber were evident on ophthalmic examination. There was no fluorescein stain uptake by the cornea. Initial topical antibiotic therapy and systemic anti-inflammatory treatments were unsuccessful, and the lesion progressed to a diffuse, yellow-white plaque, which covered 90%-95% of the cornea 4 days later. There was moderate blepharospasm, mild blepharedema, and epiphora OS. The mobility of the nictitating membrane was impaired because of the presence of the plaque over the cornea. Cytologic examination of a corneal scraping revealed fungal hyphae, and aerobic culture confirmed Aspergillus species. Treatment with topical voriconazole (1 drop OS q4h-q6h) was initiated and was switched to oral voriconazole (20 mg/kg PO q12h) 6 days after initiating treatment. The ocular disease improved during the antifungal treatment period. Eighty-four days after initial presentation (9 days after discontinuation of treatment), there was no clinical evidence of mycotic keratitis on ophthalmic examination. PMID- 25843473 TI - Preventive avian medicine-what are your recommendations? PMID- 25843474 TI - What is your diagnosis? PMID- 25843477 TI - Cumulative subject index. PMID- 25843478 TI - Coming meetings. PMID- 25843480 TI - Foot posture and function have only minor effects on knee function during barefoot walking in healthy individuals. AB - BACKGROUND: Foot posture has been postulated as a risk factor for overuse injuries of the knee, however the link between foot posture and knee joint function is unclear. The aims of this study were to: (i) compare knee adduction moment and knee joint rotations between normal, planus and cavus foot posture groups, and (ii) to determine the relationship between rearfoot and midfoot joint rotations and knee adduction moment magnitude. METHODS: Rotation of the knee, rearfoot and midfoot was evaluated in 97 healthy adults that were classified as normal (n=37), cavus (n=30) or planus (n=30) for the Foot Posture Index, Arch Index and normalised navicular height. One way analyses of variance were used to compare tri-planar knee joint rotation, knee adduction moment peak variables and knee adduction angular impulse between foot posture groups. Pearson's correlation coefficient was used to investigate the association between rearfoot and midfoot joint rotation during initial contact phase and the magnitude of 1st knee adduction moment peak. FINDINGS: The planus group displayed significantly greater external rotation angle at heel contact compared to both normal and cavus groups. The planus groups also displayed greater extension at heel contact and sagittal plane flexion range of motion during propulsion and early swing compared to the cavus group. Otherwise, differences between groups were characterised by small effect sizes. There was no association between rearfoot or midfoot joint rotations and knee adduction moment. INTERPRETATION: These findings suggest that in healthy individuals, foot posture and foot joint rotations do not substantially influence knee joint rotations and knee adduction moment while walking at a comfortable pace. PMID- 25843479 TI - Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury. AB - Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2alpha]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology. Exposure of cells to guanabenz has been shown to increase eIF2alpha phosphorylation and reduce ER stress. Using a rodent model of TBI, we present experimental results that indicate that postinjury administration of 5.0 mg/kg of guanabenz reduced cortical contusion volume and decreased hippocampal cell damage. Moreover, guanabenz treatment attenuated TBI-associated motor, vestibulomotor, recognition memory, and spatial learning and memory dysfunction. Interestingly, when the initiation of treatment was delayed by 24 h, or the dose reduced to 0.5 mg/kg, some of these beneficial effects were still observed. Taken together, these findings further support the involvement of ER stress signaling in TBI pathophysiology and indicate that guanabenz may have translational utility. PMID- 25843481 TI - Neck muscle fatigue alters the cervical flexion relaxation ratio in sub-clinical neck pain patients. AB - BACKGROUND: The cervical flexion relaxation ratio is lower in neck pain patients compared to healthy controls. Fatigue modulates the onset and offset angles of the silent period in both the lumbar and cervical spine in healthy individuals; however, this response has not been studied with neck pain patients. The purpose of this study was to determine if cervical extensor fatigue would alter the parameters of the cervical flexion relaxation more in a neck pain group than a healthy control group. METHODS: Thirteen healthy and twelve neck pain patients participated. Cervical extensor activity was examined bilaterally and kinematics of the neck and head were collected. An isometric, repetitive neck extension task at 70% of maximum elicited fatigue. Participants performed 3 trials of maximal cervical flexion both pre and post fatigue. FINDINGS: The healthy controls and neck pain groups fatigued after 56 (41) and 39 (31) repetitions, respectively. There was a significant interaction effect for the flexion relaxation ratio between the control and neck pain groups from pre to post fatigue trials (F1,96=22.67, P=0.0001), but not for onset and offset angles (F1, 96=0.017, P=0.897), although the onset and offset angles did decrease significantly for both groups following fatigue (F1,96=9.26, P=0.002). INTERPRETATION: Individuals with mild to moderate neck pain have significant differences in their neuromuscular control relative to controls, experienced myoelectric fatigue with fewer repetitions in a shorter time, had a lower cervical flexion relaxation ratio at baseline and had an inability to decrease this ratio further in response to fatigue. PMID- 25843482 TI - Wrist salvage procedures alter moment arms of the primary wrist muscles. AB - BACKGROUND: Proximal row carpectomy and scaphoid-excision four-corner fusion are salvage procedures that relieve pain by removing arthritic joint surfaces. While numerous studies have examined how these procedures affect joint motion, few have examined how they influence muscle mechanical actions. This study examines whether muscle moment arms change after these procedures. METHODS: Moment arms of primary wrist muscles were measured in 8 cadaveric specimens using the tendon excursion method. In each specimen, moment arms were measured for two degrees of freedom (flexion-extension and radial-ulnar deviation) and three conditions (nonimpaired, scaphoid-excision four-corner fusion, and proximal row carpectomy). For each muscle and degree of freedom, moment arm versus joint angle curves for the three conditions were statistically compared. FINDINGS: Wrist salvage procedures significantly alter moment arms of the primary wrist muscles. Proximal row carpectomy primarily alters flexion-extension moment arms, while scaphoid excision four-corner fusion primarily alters radial-ulnar deviation moment arms. Both procedures also alter the balance between agonist and antagonist wrist muscles. Following proximal row carpectomy, wrist extensors have smaller moment arms in extended postures. Following scaphoid-excision four-corner fusion, radial deviators have larger moment arms throughout radial-ulnar deviation. INTERPRETATION: Different moment arms indicate that different forces are required to complete the same tasks in nonimpaired and surgically altered wrists. The altered muscle moment arms likely contribute to post-operative impairments. Understanding how salvage procedures alter muscle mechanical actions is a critical first step toward identifying the cause of post-operative impairments and is necessary to develop effective interventions to augment deficient muscles and improve overall function. PMID- 25843483 TI - Evolution of vaulting strategy during locomotion of individuals with transfemoral amputation on slopes and cross-slopes compared to level walking. AB - BACKGROUND: Vaulting is a walking strategy qualitatively characterized in clinics by the sound ankle plantiflexion in midstance to assist prosthetic foot clearance. Even though potentially harmful, this strategy is often observed among people with transfemoral amputation to secure clearance of the prosthetic limb during swing phase. The aim of the study is to provide a quantitative analysis of the evolution of the vaulting strategy in challenging situations of daily living. METHODS: 17 persons with transfemoral amputation and 17 able-bodied people participated in the study. Kinematic and kinetic gait analyses were performed for level walking, 10% inclined cross-slope walking, 5% and 12% inclined slope ascending. To study vaulting strategy, peak of generated power at the sound ankle at midstance was identified and quantified in the different walking situations. In particular, values were compared to a vaulting threshold corresponding to a peak of generated power superior to 0.15 W/kg. FINDINGS: The vaulting threshold was exceeded for a larger proportion of people with amputation during cross-slope locomotion and slope ascent than during level walking. In addition, magnitude of the peak of generated power increased significantly compared to level walking in these situations. INTERPRETATION: Vaulting seems to be widely used by patients with transfemoral amputation in daily living situations. The number of patients using vaulting increased with the difficulty of the walking situation. Results also suggested that patients could dose the amount of vaulting according to gait environment to secure prosthetic toe clearance. During rehabilitation, vaulting should also be corrected or prevented in daily living tasks. PMID- 25843485 TI - Central venous obstruction in the thorax. AB - Central venous stenosis and occlusion can occur secondary to a spectrum of conditions ranging from aggressive malignancy to benign extrinsic anatomical compression in otherwise healthy individuals. Irrespective of aetiology, significant morbidity in the acute setting and long term can occur unless prompt accurate diagnosis and appropriate management is initiated, the radiologist being central to both. The present review will provide radiologists with a thorough illustration and explanation of the range of central venous conditions in the thorax (including deep vein thrombosis, thoracic outlet syndrome, haemodialysis, and malignancy related causes), the salient imaging findings and interventional management using case examples from the authors' practice. PMID- 25843486 TI - [Prevalence of non-traumatic musculoskeletal pathology as main complaint and its impact in a emergency department]. AB - BACKGROUND: Non-traumatic musculoskeletal pathology (NTMP) generates a high healthcare demand in primary care, however, European studies designed to assess its real impact in Emergency Departments are scarce. The present study aims to determine the prevalence of NTMP and its impact in Emergency Department of a university hospital in Madrid. MATERIAL AND METHOD: Two thousand randomized medical registries were reviewed from 2008 to 2011. The epidemiological data collected were, main complaints, time consumed, image test requests, and need of further assessment within a month. RESULTS: Prevalence of NTMP was 13.8% (95% CI; 12.1%-15.4%) of all patients. The most frequent musculoskeletal complaint was lumbar pain. An imaging test was requested in 79.1% of all the NTMP cases assessed. Patients with NTMP consumed an average of 79 minutes, with 17% of them requesting a new urgent assessment within the first month. CONCLUSIONS: The results of this study show that NTMP is the leading cause for emergency department visits in our area, producing the highest consumption of time and the highest frequency of new queries for the same reason within a month. The overuse of the emergency services and the lack of medical training in the management of this type of pathology can cause this phenomenon. During the design of strategies to optimize patients care in emergency departments, the importance of this type of pathology should be taken into account. PMID- 25843487 TI - Overexpression of EPS8 is associated with poor prognosis in patients with acute lymphoblastic leukemia. AB - Molecular markers have become an invaluable tool in monitoring disease status particularly of leukemias, as bone marrow samples can be easily collected for analysis during all stages of disease development including diagnosis, treatment, and follow-up. Two genes that have been used as prognostic markers in acute leukemia are Wilms' tumor (WT1) and multidrug resistance-1 (MDR1). A novel gene, epidermal growth factor receptor pathway substrate 8 (EPS8), is often over expressed and associated with poor outcome in some solid tumor types. However, whether EPS8 is also associated with the development of acute lymphoblastic leukemia (ALL) is unclear. Here, quantitative real-time PCR was used to evaluate the expression of EPS8, MDR1, and WT1 in bone marrow samples of adult ALL patients (n=107) and non-leukemia controls (n=22). EPS8, MDR1, and WT1 were detected in ALL patients, and significant correlations were found between expression profiles for EPS8 and MDR1, EPS8 and WT1, and MDR1 and WT1. In general, high expression of EPS8, MDR1, or WT1 in patients was associated with a higher risk of relapse. Furthermore, when patients were stratified based on high or low expression of the genes, Kaplan-Meier survival analysis indicated that disease-free survival of patients with the high-EPS8/high-WT1/high-MDR1 profile was significantly shorter than in patients with the low-EPS8/low-WT1/low-MDR1 profile or those excluded from either of these groups (P<0.0001). Thus, EPS8, as MDR1 and WT1, may be a clinically valuable biomarker for assessing the outcome of ALL patients. PMID- 25843488 TI - Cytogenetic patterns of relapse following allogeneic stem cell transplantation in morphologic complete remission in patients with acute myeloid leukemia. PMID- 25843489 TI - Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09. AB - OBJECTIVE: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced non-small cell lung cancer are promising for further investigation. METHODS: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) >= 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. RESULTS: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16 cycles. PFS at 6 months was 70%, median PFS was 14 months, and ORR was 70%. Biopsy at progression was safe and successful in 71% of the cases. CONCLUSIONS: Both combination therapies were promising for further studies. Biopsy at progression was feasible and will be part of future SAKK studies to investigate molecular mechanisms of resistance. PMID- 25843490 TI - Improving newborn care practices through home visits: lessons from Malawi, Nepal, Bangladesh, and Uganda. AB - BACKGROUND: Nearly all newborn deaths occur in low- or middle-income countries. Many of these deaths could be prevented through promotion and provision of newborn care practices such as thermal care, early and exclusive breastfeeding, and hygienic cord care. Home visit programmes promoting these practices were piloted in Malawi, Nepal, Bangladesh, and Uganda. OBJECTIVE: This study assessed changes in selected newborn care practices over time in pilot programme areas in four countries and evaluated whether women who received home visits during pregnancy were more likely to report use of three key practices. DESIGN: Using data from cross-sectional surveys of women with live births at baseline and endline, the Pearson chi-squared test was used to assess changes over time. Generalised linear models were used to assess the relationship between the main independent variable - home visit from a community health worker (CHW) during pregnancy (0, 1-2, 3+) - and use of selected practices while controlling for antenatal care, place of delivery, and maternal age and education. RESULTS: There were statistically significant improvements in practices, except applying nothing to the cord in Malawi and early initiation of breastfeeding in Bangladesh. In Malawi, Nepal, and Bangladesh, women who were visited by a CHW three or more times during pregnancy were more likely to report use of selected practices. Women who delivered in a facility were also more likely to report use of selected practices in Malawi, Nepal, and Uganda; association with place of birth was not examined in Bangladesh because only women who delivered outside a facility were asked about these practices. CONCLUSION: Home visits can play a role in improving practices in different settings. Multiple interactions are needed, so programmes need to investigate the most appropriate and efficient ways to reach families and promote newborn care practices. Meanwhile, programmes must take advantage of increasing facility delivery rates to ensure that all babies benefit from these practices. PMID- 25843491 TI - Engaging community health workers in maternal and newborn care in eastern Uganda. AB - BACKGROUND: Community health workers (CHWs) have been employed in a number of low and middle-income countries as part of primary health care strategies, but the packages vary across and even within countries. The experiences and motivations of a multipurpose CHW in providing maternal and newborn health have not been well described. OBJECTIVE: This study examined the perceptions of community members and experiences of CHWs around promoting maternal and newborn care practices, and the self-identified factors that influence the performance of CHWs so as to inform future study design and programme implementation. DESIGN: Data were collected using in-depth interviews with six local council leaders, ten health workers/CHW supervisors, and eight mothers. We conducted four focus group discussions with CHWs. Respondents included 14 urban and 18 rural CHWs. Key themes explored included the experience of CHWs according to their various roles, and the facilitators and barriers they encounter in their work particular to provision of maternal and newborn care. Qualitative data were analysed using manifest content analysis methods. RESULTS: CHWs were highly appreciated in the community and seen as important contributors to maternal and newborn health at grassroots level. Factors that positively influence CHWs included being selected by and trained in the community; being trained in problem-solving skills; being deployed immediately after training with participation of local leaders; frequent supervision; and having a strengthened and responsive supply of services to which families can be referred. CHWs made use of social networks to identify pregnant and newly delivered women, and were able to target men and the wider family during health education activities. Intrinsic motivators (e.g. community appreciation and the prestige of being 'a doctor'), monetary (such as a small transport allowance), and material incentives (e.g. bicycles, bags) were also important to varying degrees. CONCLUSIONS: There is a continued role for CHWs in improving maternal and newborn care and linking families with health services. However, the process for building CHW programmes needs to be adapted to the local setting, including the process of training, deployment, supervision, and motivation within the context of a responsive and available health system. PMID- 25843492 TI - Strategies for helping families prepare for birth: experiences from eastern central Uganda. AB - BACKGROUND: Promotion of birth preparedness and raising awareness of potential complications is one of the main strategies to enhance the timely utilisation of skilled care at birth and overcome barriers to accessing care during emergencies. OBJECTIVE: This study aimed to investigate factors associated with birth preparedness in three districts of eastern central Uganda. DESIGN: This was a cross-sectional baseline study involving 2,010 women from Iganga [community health worker (CHW) strategy], Buyende (vouchers for transport and services), and Luuka (standard care) districts who had delivered within the past 12 months. 'Birth prepared' was defined as women who had taken all of the following three key actions at least 1 week prior to the delivery: 1) chosen where to deliver from; 2) saved money for transport and hospital costs; and 3) bought key birth materials (a clean instrument to cut the cord, a clean thread to tie the cord, cover sheet, and gloves). Logistical regression was performed to assess the association of various independent variables with birth preparedness. RESULTS: Only about 25% of respondents took all three actions relating to preparing for childbirth, but discrete actions (e.g. financial savings and identification of place to deliver) were taken by 75% of respondents. Variables associated with being prepared for birth were: having four antenatal care (ANC) visits [adjusted odds ratio (ORA)=1.42; 95% confidence interval (CI) 1.10-1.83], attendance of ANC during the first (ORA=1.94; 95% CI 1.09-3.44) or second trimester (ORA=1.87; 95% CI 1.09-3.22), and counselling on danger signs during pregnancy or on place of referral (ORA=2.07; 95% CI 1.57-2.74). Other associated variables included being accompanied by one's husband to the place of delivery (ORA=1.47; 95% CI 1.15 1.89), higher socio-economic status (ORA=2.04; 95% CI 1.38-3.01), and having a regular income (ORA=1.83; 95% CI 1.20-2.79). Women from Luuka and Buyende were less likely to have taken three actions compared with women from Iganga (ORA=0.72; 95% CI 0.54-0.98 and ORA=0.37; 95% CI 0.27-0.51, respectively). CONCLUSIONS: Engaging CHWs and local structures during pregnancy may be an effective strategy in promoting birth preparedness. On the other hand, if not well designed, the use of vouchers could disempower families in their efforts to prepare for birth. Other effective strategies for promoting birth preparedness include early ANC attendance, attending ANC at least four times, and male involvement. PMID- 25843493 TI - Weeping in silence: community experiences of stillbirths in rural eastern Uganda. AB - BACKGROUND: Stillbirths do not register amongst national or global public health priorities, despite large numbers and known solutions. Although not accounted in statistics - these deaths count for families. Part of this disconnect is that very little is known about the lived experiences and perceptions of those experiencing this neglected problem. OBJECTIVE: This study aimed to explore local definitions and perceived causes of stillbirths as well as coping mechanisms used by families affected by stillbirth in rural eastern Uganda. DESIGN: A total of 29 in-depth interviews were conducted with women who had a stillbirth (14), men whose wives experienced a stillbirth (6), grandmothers (4), grandfathers (1), and traditional birth attendants (TBAs) (4). Participants were purposively recruited from the hospital maternity ward register, with additional recruitment done through community leaders and other participants. Data were analysed using content analysis. RESULTS: Women and families affected by stillbirth report pregnancy loss as a common occurrence. Definitions and causes of stillbirth included the biomedical, societal, and spiritual. Disclosure of stillbirth varies with women who experience consecutive or multiple losses, subject to potential exclusion from the community and even the family. Methods for coping with stillbirth were varied and personal. Ritual burial practices were common, yet silent and mainly left to women, as opposed to public mourning for older children. There were no formal health system mechanisms to support or care for families affected by stillbirths. CONCLUSION: In a setting with strong collective ties, stillbirths are a burden borne by the affected family, and often just by the mother, rather than the community as a whole. Strategies are needed to address preventable stillbirths as well as to follow up with supportive services for those affected. PMID- 25843494 TI - Designing for action: adapting and implementing a community-based newborn care package to affect national change in Uganda. AB - BACKGROUND: There is a lack of literature on how to adapt new evidence-based interventions for maternal and newborn care into local health systems and policy for rapid scale-up, particularly for community-based interventions in low-income settings. The Uganda Newborn Study (UNEST) was a cluster randomised control trial to test a community-based care package which was rapidly taken up at national level. Understanding this process may help inform other studies looking to design and evaluate with scale-up in mind. OBJECTIVE: This study aimed to describe the process of using evidence to design a community-based maternal and newborn care package in rural eastern Uganda, and to determine the dissemination and advocacy approaches used to facilitate rapid policy change and national uptake. DESIGN: We reviewed UNEST project literature including meeting reports and minutes, supervision reports, and annual and midterm reports. National stakeholders, project and district staff were interviewed regarding their role in the study and perceptions of what contributed to uptake of the package under evaluation. Data related to UNEST formative research, study design, implementation and policy influence were extracted and analysed. RESULTS: An advisory committee of key players in development of maternal and newborn policies and programmes in Uganda was constituted from many agencies and disciplines. Baseline qualitative and quantitative data collection was done at district, community and facility level to examine applicability of aspects of a proposed newborn care package to the local setting. Data were summarised and presented to stakeholders to adapt the intervention that was ultimately tested. Quarterly monitoring of key activities and events around the interventions were used to further inform implementation. The UNEST training package, home visit schedule and behaviour change counselling materials were incorporated into the national Village Health Team and Integrated Community Case Management packages while the study was ongoing. CONCLUSIONS: Designing interventions for national scale-up requires strategies and planning from the outset. Use of evidence alongside engagement of key stakeholders and targeted advocacy about the burden and potential solutions is important when adapting interventions to local health systems and communities. This approach has the potential to rapidly translate research into policy, but care must be taken not to exceed available evidence while seizing the policy opportunity. PMID- 25843495 TI - Differences in essential newborn care at birth between private and public health facilities in eastern Uganda. AB - BACKGROUND: In Uganda and elsewhere, the private sector provides an increasing and significant proportion of maternal and child health services. However, little is known whether private care results in better quality services and improved outcomes compared to the public sector, especially regarding care at the time of birth. OBJECTIVE: To describe the characteristics of care-seekers and assess newborn care practices and services received at public and private facilities in rural eastern Uganda. DESIGN: Within a community-based maternal and newborn care intervention with health systems strengthening, we collected data from mothers with infants at baseline and endline using a structured questionnaire. Descriptive, bivariate, and multivariate data analysis comparing nine newborn care practices and three composite newborn care indicators among private and public health facilities was conducted. RESULTS: The proportion of women giving birth at private facilities decreased from 25% at baseline to 17% at endline, whereas overall facility births increased. Private health facilities did not perform significantly better than public health facilities in terms of coverage of any essential newborn care interventions, and babies were more likely to receive thermal care practices in public facilities compared to private (68% compared to 60%, p=0.007). Babies born at public health facilities received an average of 7.0 essential newborn care interventions compared to 6.2 at private facilities (p<0.001). Women delivering in private facilities were more likely to have higher parity, lower socio-economic status, less education, to seek antenatal care later in pregnancy, and to have a normal delivery compared to women delivering in public facilities. CONCLUSIONS: In this setting, private health facilities serve a vulnerable population and provide access to service for those who might not otherwise have it. However, provision of essential newborn care practices was slightly lower in private compared to public facilities, calling for quality improvement in both private and public sector facilities, and a greater emphasis on tracking access to and quality of care in private sector facilities. PMID- 25843496 TI - Strengthening health facilities for maternal and newborn care: experiences from rural eastern Uganda. AB - BACKGROUND: In Uganda maternal and neonatal mortality remains high due to a number of factors, including poor quality of care at health facilities. OBJECTIVE: This paper describes the experience of building capacity for maternal and newborn care at a district hospital and lower-level health facilities in eastern Uganda within the existing system parameters and a robust community outreach programme. DESIGN: This health system strengthening study, part of the Uganda Newborn Study (UNEST), aimed to increase frontline health worker capacity through district-led training, support supervision, and mentoring at one district hospital and 19 lower-level facilities. A once-off supply of essential medicines and equipment was provided to address immediate critical gaps. Health workers were empowered to requisition subsequent supplies through use of district resources. Minimal infrastructure adjustments were provided. Quantitative data collection was done within routine process monitoring and qualitative data were collected during support supervision visits. We use the World Health Organization Health System Building Blocks to describe the process of district-led health facility strengthening. RESULTS: Seventy two per cent of eligible health workers were trained. The mean post-training knowledge score was 68% compared to 32% in the pre-training test, and 80% 1 year later. Health worker skills and competencies in care of high-risk babies improved following support supervision and mentoring. Health facility deliveries increased from 3,151 to 4,115 (a 30% increase) in 2 years. Of 547 preterm babies admitted to the newly introduced kangaroo mother care (KMC) unit, 85% were discharged alive to continue KMC at home. There was a non-significant declining trend for in-hospital neonatal deaths across the 2-year study period. While equipment levels remained high after initial improvement efforts, maintaining supply of even the most basic medications was a challenge, with less than 40% of health facilities reporting no stock-outs. CONCLUSION: Health system strengthening for care at birth and the newborn period is possible even in low-resource settings and can be associated with improved utilisation and outcomes. Through a participatory process with wide engagement, training, and improvements to support supervision and logistics, health workers were able to change behaviours and practices for maternal and newborn care. Local solutions are needed to ensure sustainability of medical commodities. PMID- 25843497 TI - 'As soon as the umbilical cord gets off, the child ceases to be called a newborn': sociocultural beliefs and newborn referral in rural Uganda. AB - BACKGROUND: The first week of life is the time of greatest risk of death and disability, and is also associated with many traditional beliefs and practices. Identifying sick newborns in the community and referring them to health facilities is a key strategy to reduce deaths. Although a growing area of interest, there remains a lack of data on the role of sociocultural norms and practices on newborn healthcare-seeking in sub-Saharan Africa and the extent to which these norms can be modified. OBJECTIVE: This study aimed to understand the community's perspective of potential sociocultural barriers and facilitators to compliance with newborn referral. METHOD: In this qualitative study, focus group discussions (n=12) were conducted with mothers and fathers of babies aged less than 3 months. In addition, in-depth interviews (n=11) were also held with traditional birth attendants and mothers who had been referred by community health workers to seek health-facility-based care. Participants were purposively selected from peri-urban and rural communities in two districts in eastern Uganda. Data were analysed using latent content analysis. RESULTS: The community definition of a newborn varied, but this was most commonly defined by the period between birth and the umbilical cord stump falling off. During this period, newborns are perceived to be vulnerable to the environment and many mothers and their babies are kept in seclusion, although this practice may be changing. Sociocultural factors that influence compliance with newborn referrals to seek care emerged along three sub-themes: community understanding of the newborn period and cultural expectations; the role of community health actors; and caretaker knowledge, experience, and decision-making autonomy. CONCLUSION: In this setting, there is discrepancy between biomedical and community definitions of the newborn period. There were a number of sociocultural factors that could potentially affect compliance to newborn referral. The widely practised cultural seclusion period, knowledge about newborn sickness, individual experiences in households, perceived health system gaps, and decision-making processes were facilitators of or barriers to compliance with newborn referral. Designers of newborn interventions need to address locally existing cultural beliefs at the same time as they strengthen facility care. PMID- 25843498 TI - Effect of the Uganda Newborn Study on care-seeking and care practices: a cluster randomised controlled trial. AB - BACKGROUND: Care for women and babies before, during, and after the time of birth is a sensitive measure of the functionality of any health system. Engaging communities in preventing newborn deaths is a promising strategy to achieve further progress in child survival in sub-Saharan Africa. OBJECTIVE: To assess the effect of a home visit strategy combined with health facility strengthening on uptake of newborn care-seeking, practices and services, and to link the results to national policy and scale-up in Uganda. DESIGN: The Uganda Newborn Study (UNEST) was a two-arm cluster-randomised controlled trial in rural eastern Uganda. In intervention villages volunteer community health workers (CHWs) were trained to identify pregnant women and make five home visits (two during pregnancy and three in the first week after birth) to offer preventive and promotive care and counselling, with extra visits for sick and small newborns to assess and refer. Health facility strengthening was done in all facilities to improve quality of care. Primary outcomes were coverage of key essential newborn care behaviours (breastfeeding, thermal care, and cord care). Analyses were by intention to treat. This study is registered as a clinical trial, number ISRCTN50321130. RESULTS: The intervention significantly improved essential newborn care practices, although many interventions saw major increases in both arms over the study period. Immediate breastfeeding after birth and exclusive breastfeeding were significantly higher in the intervention arm compared to the control arm (72.6% vs. 66.0%; p=0.016 and 81.8% vs. 75.9%, p=0.042, respectively). Skin-to-skin care immediately after birth and cord cutting with a clean instrument were marginally higher in the intervention arm versus the control arm (80.7% vs. 72.2%; p=0.071 and 88.1% vs. 84.4%; p=0.023, respectively). Half (49.6%) of the mothers in the intervention arm waited more than 24 hours to bathe the baby, compared to 35.5% in the control arm (p<0.001). Dry umbilical cord care was also significantly higher in intervention areas (63.9% vs. 53.1%, p<0.001). There was no difference in care-seeking for newborn illness, which was high (around 95%) in both arms. Skilled attendance at delivery increased in both the intervention (by 21%) and control arms (by 19%) between baseline and endline, but there was no significant difference in coverage across arms at endline (79.6% vs. 78.9%; p=0.717). Home visits were pro-poor, with more women in the poorest quintile visited by a CHW compared to families in the least poor quintile, and more women who delivered at home visited by a CHW after birth (73.6%) compared to those who delivered in a hospital or health facility (59.7%) (p<0.001). CHWs visited 62.8% of women and newborns in the first week after birth, with 40.2% receiving a visit on the critical first day of life. CONCLUSION: Consistent with results from other community newborn care studies, volunteer CHWs can be effective in changing long-standing practices around newborn care. The home visit strategy may provide greater benefit to poorer families. However, CHW strategies require strong linkages with and concurrent improvement of quality through health system strengthening, especially in settings with high and increasing demand for facility-based services. PMID- 25843499 TI - Collecting syndromic surveillance data by mobile phone in rural India: implementation and feasibility. AB - BACKGROUND: Infectious disease surveillance has long been a challenge for countries like India, where 75% of the health care services are private and consist of both formal and informal health care providers. Infectious disease surveillance data are regularly collected from governmental and qualified private facilities, but not from the informal sector. This study describes a mobile-based syndromic surveillance system and its application in a resource-limited setting, collecting data on patients' symptoms from formal and informal health care providers. DESIGN: The study includes three formal and six informal health care providers from two districts of Madhya Pradesh, India. Data collectors were posted in the clinics during the providers' working hours and entered patient information and infectious disease symptoms on the mobile-based syndromic surveillance system. RESULTS: Information on 20,424 patients was collected in the mobile-based surveillance system. The five most common (overlapping) symptoms were fever (48%), cough (38%), body ache (38%), headache (37%), and runny nose (22%). During the same time period, the government's disease surveillance program reported around 22,000 fever cases in one district as a whole. Our data - from a very small fraction of all health care providers - thus highlight an enormous underreporting in the official surveillance data, which we estimate here to capture less than 1% of the fever cases. Additionally, we found that patients from more than 600 villages visited the nine providers included in our study. CONCLUSIONS: The study demonstrated that a mobile-based system can be used for disease surveillance from formal and informal providers in resource-limited settings. People who have not used smartphones or even computers previously can, in a short timeframe, be trained to fill out surveillance forms and submit them from the device. Technology, including network connections, works sufficiently for disease surveillance applications in rural parts of India. The data collected may be used to better understand the health-seeking behaviour of those visiting informal providers, as they do not report through any official channels. We also show that the underreporting to the government can be enormous. PMID- 25843500 TI - Uganda Newborn Study (UNEST): learning from a decade of research in Uganda to accelerate change for newborns especially in Africa. PMID- 25843502 TI - Molecular epidemiology suggests Venezuela as the origin of the dengue outbreak in Madeira, Portugal in 2012-2013. AB - An explosive epidemic occurred in Madeira Island (Portugal) from October 2012 to February 2013. Published data showed that dengue virus type 1 introduced from South America was the incriminated virus. We aim to determine the origin of the strain introduced to Madeira by travellers returning to Europe. Using phylogeographic analysis and complete envelope sequences we have demonstrated that the most probable origin of the strain is Venezuela. PMID- 25843501 TI - Special issue: newborn health in Uganda. PMID- 25843503 TI - New diagnostic tools in schistosomiasis. AB - Schistosomiasis is a water-based parasitic disease that affects over 250 million people. Control efforts have long been in vain, which is one reason why schistosomiasis is considered a neglected tropical disease. However, since the new millennium, interventions against schistosomiasis are escalating. The initial impetus stems from a 2001 World Health Assembly resolution, urging member states to scale-up deworming of school-aged children with the anthelminthic drug praziquantel. Because praziquantel is safe, efficacious and inexpensive when delivered through the school platform, diagnosis before drug intervention was deemed unnecessary and not cost-effective. Hence, there was little interest in research and development of novel diagnostic tools. With the recent publication of the World Health Organization (WHO) Roadmap to overcome the impact of neglected tropical diseases in 2020, we have entered a new era. Elimination of schistosomiasis has become the buzzword and this has important ramifications for diagnostic tools. Indeed, measuring progress towards the WHO Roadmap and whether local elimination has been achieved requires highly accurate diagnostic assays. Here, we introduce target product profiles for diagnostic tools that are required for different stages of a schistosomiasis control programme. We provide an update of the latest developments in schistosomiasis diagnosis, including microscopic techniques, rapid diagnostic tests for antigen detection, polymerase chain reaction (PCR) assays and proxy markers for morbidity assessments. Particular emphasis is placed on challenges and solutions for new technologies to enter clinical practice. PMID- 25843504 TI - Human infections with Plasmodium knowlesi--zoonotic malaria. AB - In 2004 a large focus of Plasmodium knowlesi malaria was reported in the human population in Sarawak, Malaysian Borneo. Plasmodium knowlesi, a parasite of the South-East Asian macaques (Macaca fascicularis and Macaca nemestrina), had entered the human population. Plasmodium knowlesi is transmitted by the leucosphyrus group of Anopheline mosquitoes and transmission is largely zoonotic and restricted to the jungle setting. Humans entering jungle transmission sites are at risk. Since 2004, human cases of P. knowlesi have been continuously reported in local communities and in travellers returning from South East Asia. Plasmodium knowlesi is the most common type of indigenous malaria reported in Malaysia. Infections are most often uncomplicated but at least 10% of patients report with severe malaria and 1-2% of cases have a fatal outcome. Parasitaemia is positively associated with the clinical and laboratory markers of severe malaria. The current literature on P. knowlesi, including epidemiology, natural hosts and vectors, pathogenesis, clinical descriptions, treatment and diagnosis, is reviewed. There are many gaps in our understanding of this disease that are highlighted here with suggestions for further research to inform pre-emptive control measures that would be required to prevent a full emergence of this parasite into the human population. PMID- 25843505 TI - Clinical consequences of new diagnostic tools for intestinal parasites. AB - Following the success of nucleic acid-based detection in virology and bacteriology, multiplex real-time PCRs are increasingly used as first-line diagnostics in clinical parasitology, replacing microscopy. The detection and quantification of parasite-specific DNA in faeces is highly sensitive and specific and allows for cost-effective high-throughput screening. In this paper we discuss the clinical consequences of this radical change in diagnostic approach, as well as its potential drawbacks. In the Netherlands, routine diagnostic laboratories have been pioneering the implementation of multiplex real time PCR for the detection of pathogenic intestinal protozoa and this has resulted in increased detection rates of Giardia lamblia and Cryptosporidium spp. As a consequence of this new diagnostic approach, expertise in the field of parasite morphology by conventional light microscopy seems to be disappearing in most of the high-throughput microbiological laboratories. As a result, to maintain a high standard of care, a formalized exchange of critical information between clinicians and laboratory staff is necessary to determine the most appropriate testing either in local laboratories or in reference centres, based on clinical signs and symptoms, exposure and immune status. If such a diagnostic algorithm is lacking, important infections in travellers, immigrants and immunocompromised patients may be missed. PMID- 25843506 TI - The evaluation of penile microvascular endothelial function using laser speckle contrast imaging in healthy volunteers. AB - OBJECTIVE: The primary aim of this study was to evaluate the effectiveness of laser speckle contrast imaging (LSCI) coupled with transdermal iontophoretic delivery of acetylcholine (ACh) for the assessment of penile microvascular function. Additionally, we tested systemic microvascular function using both LSCI and ACh iontophoresis on the forearm. METHODS: We assessed cutaneous, endothelium dependent microvascular reactivity on the penis and forearm of healthy volunteers (aged 56.6 +/- 1.0 years, n = 26) at rest and 60 min following the oral administration of the phosphodiesterase type 5 inhibitor (sildenafil: SIL, 100mg). LSCI was coupled with the iontophoresis of ACh using increasing anodal currents of 30, 60, 90, 120, 150 and 180 MUA during 10-second intervals spaced 1 min apart. RESULTS: Basal skin microvascular flow in the penis increased significantly following SIL administration. The endothelium-dependent skin microvascular vasodilator responses induced by ACh were also significantly enhanced following SIL administration for each of the following parameters: peak values of cutaneous vascular conductance (CVC); increases in CVC; and the area under the curve for ACh-induced vasodilation. ACh-induced microvascular vasodilation in the forearm was not modified by SIL. Finally, the administration of electric current alone did not affect penile microvascular flow. CONCLUSION: LSCI appears to be a promising non-invasive technique for the evaluation of penile microvascular endothelial function. This methodology may be valuable for the evaluation of penile microvascular reactivity among patients with cardiovascular and metabolic diseases and to test the effectiveness of drugs used to treat vasculogenic erectile dysfunction. PMID- 25843508 TI - [Varicella vaccine effectiveness in schoolchildren in outbreaks in a semi-urban area]. AB - OBJECTIVE: To estimate the effectiveness of the varicella vaccine in school outbreaks during the academic year 2009-2010. MATERIAL AND METHOD: Retrospective cohort study in public day-care centers and/or schools in an area in the region of Murcia. Spain. The participants were all children of 1 to 12 years who were in the same classroom where there was an outbreak of varicella. The main measurements were the sociodemographic, clinical and vaccination data, as well as variables related to varicella disease obtained through a questionnaire self completed by parents, and from the computerized regional immunization registry (VACUSAN). RESULTS: A total of 51 varicella outbreaks were detected, with a median of 3 cases per outbreak at both educational levels. The overall vaccination coverage was 10.7% (95% CI 8.63 to 13.18), always being higher in Spanish schoolchildren versus foreign (OR: 21.21, 95% CI: 2.92 to 153.92, P<.001). Discrepancies were found between the vaccine questionnaire data and vaccination program (kappa=0.50, 95% CI: 0.43 to 0.58, P<.001). According to VACUSAN, the overall attack rate was 59.7 (95% CI: 55.82 to 63.43) in unvaccinated and 6.5 (95% CI: 2.54 to 15.45) in vaccinated children. An overall effectiveness of 89.1% (95% CI: 74.55 to 95.35) and 100% was obtained for 1 and 2 doses of vaccine, respectively. CONCLUSIONS: There is a high effectiveness of varicella vaccine, emphasizing that the administration of two doses of vaccine produces an adequate and optimal protection against varicella disease. A discrepancy was found between the information provided by parents and official records. Finally, there was a lower vaccination coverage in the immigrant community. PMID- 25843507 TI - [Analysis of tracheostomies in a pediatric intensive care unit during the period 2003-2013]. AB - INTRODUCTION: Tracheotomy in pediatric patients is a rare procedure. In this pediatric series, perioperative complications, mortality related to surgical procedure and overall mortality are analyzed. PATIENTS AND METHODS: This is a retrospective study conducted from January 2003 to December 2013. Data were retrieved from patients who were tracheotomized and admitted to our PICU in the postoperative period. RESULTS: Data were collected from 25 tracheotomized patients admitted during the study period. The mean age was 3.3 months (median 14 months, range 1-144 months), and PICU length of stay was 53 days (median 37 days, range 1-338 days). Most patients (68%) had comorbidities before their admission, with a higher prevalene of craniofacial anomalies/polymalformative syndromes (32%) and prematurity related disorders (12%) being obserevd. The most common etiologies related to the procedure were congenital airway obstruction (16%) and several types of spinal cord injury (16%), followed by tracheobronchomalacia (12%) and subglottic stenosis (12%). Some kind of complication was detected in 40% of patients, with accidental decannulation being the most frequent. Accidental or unexpected decannulation was present in a percentage as high as 20% of our patients, mainly in the first 24 hours after surgery. One of the patients died as a result of this. CONCLUSIONS: The postoperative course of a tracheotomy is associated with a high rate of complications, some of them related to life threatening events. PMID- 25843509 TI - 68th annual Cancer Symposium of the Society of Surgical Oncology. PMID- 25843510 TI - Overtreatment of younger patients with colon cancer. PMID- 25843511 TI - Increasing morbidity in childhood-onset cancer survivors. PMID- 25843512 TI - Including children in life-sustaining treatment decisions. PMID- 25843514 TI - Intensity-Invariant Texture Analysis for Classification of BI-RADS Category 3 Breast Masses. AB - Radiologists likely incorrectly classify benign masses as Breast Imaging Reporting and Data System (BI-RADS) category 3. A computer-aided diagnosis (CAD) system was developed in this study as a second viewer to avoid misclassification of carcinomas. Sixty-nine biopsy-proven BI-RADS category 3 masses, including 21 malignant and 48 benign masses, were used to evaluate the CAD system. To improve the texture features, gray-scale variations between images were reduced by transforming pixels into intensity-invariant ranklet coefficients. The textures of the tumor and speckle pixels were extracted from the transformed ranklet images to provide more robust features than in conventional CAD systems. As a result, tumor texture and speckle texture with ranklet transformation achieved significantly better areas under the receiver operating characteristic curve (Az) compared with those without ranklet transformation (Az = 0.83 vs. 0.58 and Az = 0.80 vs. 0.56, p value < 0.05). The improved CAD system can be a second reader to confirm the classification of BI-RADS category 3 masses. PMID- 25843513 TI - Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. AB - BACKGROUND: Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations. METHODS: TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay. RESULTS: TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. CONCLUSIONS: TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets. PMID- 25843515 TI - Attenuation Correction and Normalisation for Quantification of Contrast Enhancement in Ultrasound Images of Carotid Arteries. AB - An automated attenuation correction and normalisation algorithm was developed to improve the quantification of contrast enhancement in ultrasound images of carotid arteries. The algorithm first corrects attenuation artefact and normalises intensity within the contrast agent-filled lumen and then extends the correction and normalisation to regions beyond the lumen. The algorithm was first validated on phantoms consisting of contrast agent-filled vessels embedded in tissue-mimicking materials of known attenuation. It was subsequently applied to in vivo contrast-enhanced ultrasound (CEUS) images of human carotid arteries. Both in vitro and in vivo results indicated significant reduction in the shadowing artefact and improved homogeneity within the carotid lumens after the correction. The error in quantification of microbubble contrast enhancement caused by attenuation on phantoms was reduced from 55% to 5% on average. In conclusion, the proposed method exhibited great potential in reducing attenuation artefact and improving quantification in contrast-enhanced ultrasound of carotid arteries. PMID- 25843516 TI - Cavitation-enhanced back projection for acoustic rib detection and attenuation mapping. AB - High-intensity focused ultrasound allows for minimally invasive, highly localized cancer therapies that can complement surgical procedures or chemotherapy. For high-intensity focused ultrasound interventions in the upper abdomen, the thoracic cage obstructs and aberrates the ultrasonic beam, causing undesired heating of healthy tissue. When a phased array therapeutic transducer is used, such complications can be minimized by applying an apodization law based on analysis of beam path obstructions. In this work, a rib detection method based on cavitation-enhanced ultrasonic reflections is introduced and validated on a porcine tissue sample containing ribs. Apodization laws obtained for different transducer positions were approximately 90% similar to those obtained using image analysis. Additionally, the proposed method provides information on attenuation between transducer elements and the focus. This principle was confirmed experimentally on a polymer phantom. The proposed methods could, in principle, be implemented in real time for determination of the optimal shot position in intercostal high-intensity focused ultrasound therapy. PMID- 25843517 TI - Percutaneous withdrawal of HeartWare HVAD left ventricular assist device support. PMID- 25843518 TI - Interplay of coronary angiography and intravascular ultrasound in predicting long term outcomes after heart transplantation. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the major cause of late graft-related death after heart transplantation (HT). Identification of patients at risk of cardiovascular events has relevant implications in appropriately guiding resources and intensity of follow-up. In this context, the prognostic relevance of serial coronary imaging long-term after HT is unexplored. METHODS: Recipients with intravascular ultrasound (IVUS) and coronary angiography performed 1 and 5 years after HT were monitored for subsequent 1 to 10 years to analyze the association of serial coronary imaging with cardiovascular death and major cardiovascular events (MACEs). RESULTS: Included were 131 patients. The MACE incidence was 31.8 per 1,000 patient-years, and cardiovascular mortality was 17.4 per 1,000 patient-years. Progression of coronary lesions detected by angiography and changes in IVUS-defined parameters, including an increase in maximal intimal thickness (MIT) >=0.35 mm and vascular remodeling, predicted MACE occurrence. However, only MIT change >=0.35 mm also predicted cardiovascular mortality. Among patients with normal or stable angiography, an MIT change >=0.35 mm identified those with a significantly higher MACE rate (80 vs 13 events/1,000 patient-years). Worsening metabolic parameters appeared associated with the increasing severity of CAV development. CONCLUSIONS: Combined imaging analysis of progression of angiographic lesions and IVUS-detected MIT between 1 and 5 years post-HT allows discriminating patients at high, intermediate, and low risk for adverse long-term cardiovascular outcomes. The metabolic syndrome milieu is confirmed as a key risk factor for long-term CAV progression and adverse prognosis. PMID- 25843519 TI - Dynamic Behavior of N-Heterocyclic Carbene Boranes: Boron-Carbene Bonds in B,B Disubstituted N,N-Dimethylimidazol-2-ylidene Boranes Have Substantial Rotation Barriers. AB - Dynamic NMR spectroscopy has been used to measure rotation barriers in five B,B disubstituted 1,3-dimethylimidazol-2-ylidene boranes. The barriers are attributed to the sp(2)-sp(3) bond between C(1) of the N-heterocyclic carbene ring and the boron atom. Bonds to boron atoms bearing a thexyl (1,1,2-trimethylpropyl) group show especially high barriers, ranging from 75-86 kJ mol(-1). 2-Isopropyl-1,3,5 trimethylbenzene is used as a comparable to help understand the nature and magnitude of the barriers. PMID- 25843520 TI - Bariatric Surgery: Does It Play a Role in Fertility-Preserving Treatment Among Obese Young Women With Endometrial Cancer? AB - We present the case of a 17-year-old nulliparous woman with a history of obesity (body mass index 36.2 kg/m(2)), type 2 diabetes, and polycystic ovary syndrome, who was diagnosed with grade 1 endometrioid adenocarcinoma without radiological evidence of myometrial invasion or metastatic disease. After failure of a fertility-preserving treatment with a levonorgestrel-releasing intrauterine device, bariatric surgery was proposed to treat the obesity and improve control of her type 2 diabetes in an attempt to increase the chances of obtaining response to local treatment. Nine months after laparoscopic sleeve gastrectomy and 18 months after insertion of the intrauterine device, the patient reached normal body weight (body mass index 20.3 kg/m(2)) and showed complete response to treatment. As far as we know, this is the first published case of an adolescent obese patient treated with bariatric surgery concomitantly with fertility preserving management of endometrial cancer. We propose that bariatric surgery may play a role as an adjuvant therapy in fertility-preserving treatment of endometrial cancer with local progestin, in which it could enhance remission rates and reduce recurrence. PMID- 25843521 TI - Essure Surgical Removal and Subsequent Symptom Resolution: Case Series and Follow Up Survey. AB - Transcervical sterilization is a minimally invasive option for permanent contraception with high reported rates of patient satisfaction. A small percentage of women subsequently choose to have the tubal inserts removed due to regret or perceived side effects. There is limited information with regard to the improvement in the symptom profile following surgical removal of the tubal inserts. We present a retrospective case series of 11 women who underwent surgical removal of Essure by hysteroscopy, salpingectomy, and/or hysterectomy. The predominant symptom at presentation was pain (n = 10; 90.91%), as well as bleeding (n = 6; 54.54%) and/or dyspareunia (n = 5; 45.45%). After surgical removal, the majority of patients (n = 8; 72.72%) reported an improvement of their symptoms. However, 3 (27.27%) patients continued to have persistent symptoms after surgery. Before surgical removal of Essure, it is important to thoroughly discuss the risk of continuing symptoms with patients. PMID- 25843522 TI - hCG stimulates angiogenic signals in lymphatic endothelial and circulating angiogenic cells. AB - Human chorionic gonadotropin (hCG) has long been associated with the initiation and maintenance of pregnancy, where angiogenesis plays an important role. However, the function of hCG in angiogenesis and the recruitment of vascular active cells are not fully understood. In this study, the role of hCG and its receptor in circulating angiogenic and human endothelial cells, including lymphatic, uterine microvascular, and umbilical vein endothelial cells, was examined. Immunohistochemistry and immunoblot analysis were used to detect LH/hCG receptor expression and the expression of hCG-induced angiogenic molecules. HIF 1alpha was determined via ELISA and downstream molecules, such as CXCL12 and CXCR4, via real-time PCR. Chemotaxis was analyzed using Boyden chambers. Our results show that the LH/hCG receptor was present in all tested cells. Furthermore, hCG was able to stimulate LH/hCG-receptor-specific migration in a dose-dependent fashion and induce key angiogenic molecules, including HIF-1alpha, CXCL12, and CXCR4. In conclusion, our findings underscore the importance of hCG as one of the first angiogenic molecules produced by the conceptus. hCG itself alters endothelial motility, recruitment, and expression of pro-angiogenic molecules and may therefore play an important role in vascular adaption during implantation and early placental formation. PMID- 25843523 TI - Development of human B cells and antibodies following human hematopoietic stem cell transplantation to Rag2(-/-)gammac(-/-) mice. AB - Humanized mice represent a valuable model system to study the development and functionality of the human immune system. In the RAG-hu mouse model highly immunodeficient Rag2(-/-)gammac(-/-) mice are transplanted with human CD34(+) hematopoietic stem cells, resulting in human hematopoiesis and a predominant production of B and T lymphocytes. Human adaptive immune responses have been detected towards a variety of antigens in humanized mice but both cellular and humoral immune responses tend to be weak and sporadically detected. The underlying mechanisms for inconsistent responses are poorly understood. Here, we analyzed the kinetics of human B cell development and antibody production in RAG hu mice to better understand the lack of effective antibody responses. We found that T cell levels in blood did not significantly change from 8 to 28 weeks post engraftment, while B cells reached a peak at 14 weeks. Concentrations of 3 antibody classes (IgM, IgG, IgA) were found to be at levels about 0.1% or less of normal human levels, but human antibodies were still detected up to 32 weeks after engraftment. Human IgM was detected in 92.5% of animals while IgG and IgA were detected in about half of animals. We performed flow cytometric analysis of human B cells in bone marrow, spleen, and blood to examine the presence of precursor B cells, immature B cells, naive B cells, and plasma B cells. We detected high levels of surface IgM(+) B cells (immature and naive B cells) and low levels of plasma B cells in these organs, suggesting that B cells do not mature properly in this model. Low levels of human T cells in the spleen were observed, and we suggest that the lack of T cell help may explain poor B cell development and antibody responses. We conclude that human B cells that develop in humanized mice do not receive the signals necessary to undergo class-switching or to secrete antibody effectively, and we discuss strategies to potentially overcome these barriers. PMID- 25843524 TI - The aryl hydrocarbon receptor-dependent disruption of contact inhibition in rat liver WB-F344 epithelial cells is linked with induction of survivin, but not with inhibition of apoptosis. AB - Inhibition of apoptosis by the ligands of the aryl hydrocarbon receptor (AhR) has been proposed to play a role in their tumor promoting effects on liver parenchymal cells. However, little is presently known about the impact of toxic AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on apoptosis in other liver cell types, such as in liver epithelial/progenitor cells. In the present study, we focused on the effects of TCDD on apoptosis regulation in a model of liver progenitor cells, rat WB-F344 cell line, during the TCDD-elicited release from contact inhibition. The stimulation of cell proliferation in this cell line was associated with deregulated expression of a number of genes known to be under transcriptional control of the Hippo signaling pathway, a principal regulatory pathway involved in contact inhibition of cell proliferation. Interestingly, we found that mRNA and protein levels of survivin, a known Hippo target, which plays a role both in cell division and inhibition of apoptosis, were significantly up-regulated in rat liver epithelial cell model, as well as in undifferentiated human liver HepaRG cells. Using the short interfering RNA mediated knockdown, we confirmed that survivin plays a central role in cell division of WB-F344 cells. When evaluating the effects of TCDD on apoptosis induction by camptothecin, a genotoxic topoisomerase I inhibitor, we observed that the pre-treatment of WB-F344 cells with TCDD increased number of cells with apoptotic nuclear morphology, and it potentiated cleavage of both caspase-3 and poly(ADP-ribose) polymerase I. This indicated that despite the observed up regulation of survivin, apoptosis induced by the genotoxin was potentiated in the model of rat liver progenitor cells. The present results indicate that, unlike in hepatocytes, AhR agonists may not prevent induction of apoptosis elicited by DNA damaging agents in a model of rat liver progenitor cells. PMID- 25843525 TI - 4-Hydroxybenzyl methyl ether improves learning and memory in mice via the activation of dopamine D1 receptor signaling. AB - The phenolic compound 4-hydroxybenzyl methyl ether (HBME) is isolated from Gastrodia elata Blume (Orchidaceae). In the present study, we investigated the effect of HBME on three stages of memory (acquisition, consolidation, and retrieval) using the step-through passive avoidance task. HBME was administered at 3 time points; 1 h before the acquisition trial, immediately after the acquisition trial, and 1h before the retention trial, respectively. HBME (10 mg/kg, p.o.) markedly increased the step-through latency compared with the vehicle-treated control at all stages of memory. To clarify the mechanism of the memory-enhancing effect of HBME, an antagonism study and Western blot analysis were performed. The enhancing effects of HBME on each phase were reversed by the sub-effective dose of the dopamine D1 receptor antagonist SCH23390 (0.0125 mg/kg, s.c.), or the protein kinase A (PKA) antagonist H-89 (0.25 mg/kg, i.p.). In addition, the administration of HBME (10 mg/kg, p.o.) significantly increased the phosphorylation of the cortical and hippocampal PKA/cAMP response element-binding protein (CREB), and was reversed by the co-administration of SCH23390. HBME (10 mg/kg, p.o.) also ameliorated the memory impairment induced by SCH23390 or scopolamine. Taken together, these results suggest that the effect of HBME on cognitive functions may be partly involved in dopaminergic neurotransmitter signaling and that HBME could be a potential therapeutic agent for treating the cognitive dysfunction induced by dopaminergic or cholinergic neurotransmitter system deficits. PMID- 25843526 TI - Electrical impedance tomography monitoring in acute respiratory distress syndrome patients with mechanical ventilation during prolonged positive end-expiratory pressure adjustments. AB - BACKGROUND/PURPOSE: The time required to reach oxygenation equilibrium after positive end-expiratory pressure (PEEP) adjustments in mechanically ventilated patients with acute respiratory distress syndrome (ARDS) is unclear. We used electrical impedance tomography to elucidate gas distribution and factors related to oxygenation status following PEEP in patients with ARDS. METHODS: Nineteen mechanically ventilated ARDS patients were placed on baseline PEEP (PEEPB) for 1 hour, PEEPB - 4 cmH2O PEEP (PEEPL) for 30 minutes, and PEEPB + 4 cmH2O PEEP (PEEPH) for 1 hour. Tidal volume and respiratory rate were similar. Impedance changes, respiratory parameters, and arterial blood gases were measured at baseline, 5 minutes, and 30 minutes after PEEPL, and 5 minutes, 15 minutes, 30 minutes, and 1 hour after PEEPH. RESULTS: PaO2/fraction of inspired oxygen (P/F ratio) decreased quickly from PEEPB to PEEPL, and stabilized 5 minutes after PEEPL. However the P/F ratio progressively increased from PEEPL to PEEPH, and a significantly higher P/F ratio and end-expiratory lung impedance were found at 60 minutes compared to 5 minutes after PEEPH. The end-expiratory lung impedance level significantly correlated with P/F ratio (p < 0.001). With increasing PEEP, dorsal ventilation significantly increased; however, regional ventilation did not change over time with PEEP level. CONCLUSION: Late improvements in oxygenation following PEEP escalation are probably due to slow recruitment in ventilated ARDS patients. Electrical impedance tomography may be an appropriate tool to assess recruitment and oxygenation status in patients with changes in PEEP. PMID- 25843527 TI - De novo cancer avoidance after renal transplantation: A case-control study on low dose sirolimus combined with a calcineurin inhibitor. AB - BACKGROUND/PURPOSE: Full-dose sirolimus (SRL) therapy without a calcineurin inhibitor (CNI) reduces the incidence of malignancy after renal transplantation, but with significant side effects. We hypothesized that de novo therapy with low dose SRL combined with a CNI could still prevent cancer in renal transplant recipients. METHODS: A retrospective case-control study was performed to assess the cancer incidence among renal transplant patients who had undergone surgery in our transplant centers between January 2000 and June 2012. Patients who received low-dose SRL and a CNI (SRL group, n = 189) were compared with patients receiving conventional CNI-based therapy in the same hospitals (Conventional group, n = 271). RESULTS: The 5-year graft and patient survival rates were comparable between the two groups. Seven patients in the SRL group and 24 patients in the Conventional group developed malignancies during mean follow-up periods of 68.2 +/- 37.5 months and 81.7 +/- 51.4 months, respectively. The cancer incidence at 5 years was significantly lower in the SRL group (1.9%), than that in the Conventional group (6.7%; p = 0.04). By multivariate analyses, SRL therapy (p = 0.04), male sex (p = 0.04), and younger age (p = 0.01) were significantly associated with a lower risk of malignancy after kidney transplantation. CONCLUSION: De novo therapy with low-dose SRL combined with a CNI was associated with reduced risk of post-transplant cancer in renal transplant recipients. De novo cancer prevention using a low-dose proliferation signal inhibitor such as SRL could be effective for renal transplant recipients. PMID- 25843528 TI - Correction to Regiocontrolled synthesis and optical resolution of mono-, di-, and trisubstituted tribenzotriquinacene derivatives: key building blocks for further assembly into molecular squares and cubes. PMID- 25843530 TI - Radiocapitate congruency as a predictive factor for the results of proximal row carpectomy. AB - PURPOSE: To evaluate whether the congruency between the joint surfaces of the lunate fossa of the distal radius and the proximal capitate might be a prognostic factor for functional, clinical, or radiographic results after proximal row carpectomy (PRC). METHODS: After reconstructing the computed tomographic arthrogram of patients with PRC, we evaluated the shape of the proximal capitate by measuring the radius of curvature of the tip of the capitate. The congruency of the future radiocapitate joint was then evaluated by the radiocapitate index in the frontal and sagittal planes. This was calculated by dividing the radius of curvature of the tip of the capitate by the mean radius of curvature of the lunate fossa. We determined the relationship between these morphological results and the functional (Disabilities of the Arm, Shoulder, and Hand [DASH] score, Mayo Wrist score, and pain relief), clinical (mobility and strength) and x-ray results (radiocapitate arthrosis). RESULTS: A total of 27 patients were reviewed at a mean follow-up of 59 months. The shape of the proximal capitate did not affect outcomes. In the frontal plane, a better radiocapitate congruency was significantly associated with an increase in wrist flexion and better functional results for the DASH. There was a non-significant relationship between congruency and improvement of Mayo Wrist score and pain relief. In the sagittal plane, the DASH score tended to improve when congruency was better. CONCLUSIONS: The shape of the capitate was not a prognostic factor for functional outcome after PRC. The radiocapitate index seems more relevant in predicting results at last follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 25843529 TI - Molecular typing of Chinese Streptococcus pyogenes isolates. AB - Streptococcus pyogenes causes human infections ranging from mild pharyngitis and impetigo to serious diseases including necrotizing fasciitis and streptococcal toxic shock syndrome. The objective of this study was to compare molecular emm typing and pulsed field gel electrophoresis (PFGE) with multiple-locus variable number tandem-repeat analysis (MLVA) for genotyping of Chinese S. pyogenes isolates. Molecular emm typing and PFGE were performed using standard protocols. Seven variable number tandem repeat (VNTR) loci reported in a previous study were used to genotype 169 S. pyogenes geographically-diverse isolates from China isolated from a variety of disease syndromes. Multiple-locus variable-number tandem-repeat analysis provided greater discrimination between isolates when compared to emm typing and PFGE. Removal of a single VNTR locus (Spy2) reduced the sensitivity by only 0.7%, which suggests that Spy2 was not informative for the isolates screened. The results presented support the use of MLVA as a powerful epidemiological tool for genotyping S. pyogenes clinical isolates. PMID- 25843531 TI - Danger zones for flexor tendons in volar plating of distal radius fractures. AB - PURPOSE: To define a danger zone for volar plates using magnetic resonance imaging by analyzing the position of the flexor tendons at risk around the watershed line. METHODS: We analyzed 40 wrist magnetic resonance images. The location of the flexor pollicus longus (FPL) and index flexor digitorum profundus (FDPi) tendons was recorded at 3 and 6 mm proximal to the watershed line of the distal radius. We measured the distance between the volar margin of the distal radius and the FPL and FDPi tendons, and the coronal position of the tendons. RESULTS: At a point 3 mm proximal to the watershed line, FPL and FDPi were located on average 2.6 and 2.2 mm anterior to the volar margin of the distal radius. This distance increased to 4.7 and 5.3 mm at a point 6 mm proximal to the watershed line. The FPL and FDPi were located at 57% and 42% of the total width of the distal radius from the sigmoid notch at 3 mm from the watershed, and at 66% and 46% at 6 mm from the watershed. CONCLUSIONS: Surgeons should be aware of the close proximity of the flexor tendons to the volar cortex of the distal radius proximal to the watershed line and their radial to ulnar position. Three millimeters proximal to the watershed line, plate placement more than 2 mm anterior to the volar cortex or the use of plates thicker than 2 mm poses a high risk for directly contacting flexor tendons. CLINICAL RELEVANCE: This article may prove to be helpful in avoiding flexor tendon injury during volar plate fixation. PMID- 25843532 TI - The use of a sliding bone graft in the upper extremity for long bone nonunions. AB - Nonunions of the upper extremity are a source of significant morbidity and can be difficult to treat. This paper describes a sliding bone graft technique that offers several significant advantages over other techniques for nonunions. PMID- 25843533 TI - Efficacy and safety of collagenase clostridium histolyticum in the treatment of proximal interphalangeal joints in dupuytren contracture: combined analysis of 4 phase 3 clinical trials. AB - PURPOSE: To examine the results of proximal interphalangeal (PIP) joint contractures from 4 phase 3 clinical trials of collagenase clostridium histolyticum (CCH) injection for Dupuytren contracture. METHODS: Patients enrolled in Collagenase Option for Reduction of Dupuytren I/II and JOINT I/II with one or more PIP joint contractures (20 degrees to 80 degrees ) received CCH 0.58 mg/0.20 mL or placebo (Collagenase Option for Reduction of Dupuytren I/II only) injected directly into a palpable cord. The percentage of PIP joints achieving clinical success (0 degrees to 5 degrees of full extension), clinical improvement (50% or more reduction in baseline contracture), and range of motion improvement at 30 days after the first and last CCH injections was assessed. The PIP joint contractures were classified into low (40 degrees or less) and high (more than 40 degrees ) baseline severity. Adverse events were recorded. RESULTS: A total of 506 adults (mean age, 63 +/- 10 y; 80% male) received 1,165 CCH injections in 644 PIP joint cords (mean, 1.6 injections/cord). Most patients (60%) received 1 injection, with 24%, 16%, and 1% receiving 2, 3, and 4 injections, respectively. Clinical success and clinical improvement occurred in 27% and 49% of PIP joints after one injection and in 34% and 58% after the last injection. Patients with lower baseline severity showed greater improvement and response was comparable between fingers, as were improvements in range of motion. Adverse events occurring in more than 10% of patients were peripheral edema (58%), contusion (38%), injection site hemorrhage (23%), injection site pain (21%), injection site swelling (16%), and tenderness (13%). This incidence was consistent with data reported in phase 3 trials. Two tendon ruptures occurred. No further ruptures occurred after a modified injection technique was adopted. CONCLUSIONS: Collagenase clostridium histolyticum was effective and well tolerated in the short term in patients with Dupuytren PIP joint contractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 25843534 TI - Association of lesions of the scapholunate interval with arthroscopic grading of scapholunate instability via the geissler classification. AB - PURPOSE: To determine whether specific anatomic lesions of the scapholunate supporting structures are associated with the grades of scapholunate instability according to the Geissler classification. METHODS: Six fresh frozen cadaveric limbs underwent serial arthroscopic sectioning of the scapholunate supporting ligaments. To simulate a progressive scapholunate injury based on the current literature, sectioning occurred as follows: volar scapholunate interosseous ligament (SLIL), membranous SLIL, dorsal SLIL, radioscaphocapitate, long radiolunate, dorsal radiocarpal, dorsal intercarpal, and scaphotrapeziotrapezoid ligaments. We performed arthroscopic examination of the radiocarpal and midcarpal joints after each ligamentous sectioning and recorded the appearance of the scapholunate interval. RESULTS: There was a progressive increase in Geissler grade with sequential sectioning of the scapholunate supporting ligaments. In all specimens, Geissler grade 2 injury was associated with sectioning of intrinsic ligaments only. Geissler grade 3 injury first appeared with sectioning through the dorsal SLIL and continued through sectioning of the volar extrinsic ligaments. Geissler grade 4 injury did not occur until the dorsal extrinsic ligaments were sectioned. Statistical analysis indicated a linear relationship between ligament sectioned and Geissler grade, with deeper sections associated with a higher Geissler grade. CONCLUSIONS: In this cadaveric model, arthroscopically determined Geissler grade was associated with specific anatomic lesions of the scapholunate supporting ligaments. Sequential sectioning of the ligaments showed a progressive increase in Geissler grade. CLINICAL RELEVANCE: Knowledge of the association of Geissler grade with pathoanatomy may aid the surgeon in deciding which reconstructive method is best. PMID- 25843535 TI - Superior half of the sternoclavicular joint pedicled with the sternocleidomastoid muscle for reconstruction of the temporomandibular joint: a preliminary study with a simplified technique and expanded indications. AB - The sternoclavicular joint (SCJ) has similar anatomical and physical characteristics to the temporomandibular joint (TMJ). The purpose of this article is to introduce a modified technique for the pedicled SCJ and the expanded indications for its use. During the period June 2011 to June 2014, six TMJs were reconstructed using the superior half of the SCJ pedicled with the sternocleidomastoid muscle. The inclusion criteria were (1) poor vascularization jeopardizing a non-vascularized TMJ replacement, and/or (2) a large defect of both bone and soft tissue. The average follow-up period was 14.8 months (range 7 39 months). Fracture of the clavicle occurred in one patient (16.7%). No recurrence, graft resorption, or secondary deformity was found. Reconstruction of the TMJ using the superior half of the SCJ pedicled with the clavicle head of the sternocleidomastoid muscle and sternocleidomastoid branch of the superior thyroid artery benefited patients who had a poor blood supply and a medullary condition or who had a defect in both the condyle and surrounding soft tissue. PMID- 25843536 TI - Assessing stomatognathic performance after mandibulectomy according to the method of mandibular reconstruction. AB - The aim of this study was to investigate stomatognathic performance after mandibulectomy. Twenty-six subjects were classified into two groups: the mandibular continuity (MC) group were reconstructed and kept in MC, while the mandibular non-continuity (MNC) group lost MC. Stomatognathic performance was evaluated using the Oral Health Impact Profile in Japanese (OHIP-J), a colour changing chewing gum, a gummy jelly, Sato's questionnaire, electromyography (EMG) of the masticatory muscles, and mandibular movement. The OHIP-J and modified Sato's questionnaire revealed that the physical and eating disability of the MNC group was significantly more severe than that of the MC group (P<0.05). The mean EMG activity of the anterior temporalis muscle in the relaxed state was significantly higher in the MNC group than in the MC group (P<0.05). The mean masticating/relaxing ratio of EMG activities for the masseter muscle was lower in the MNC group than in the MC group (P<0.05). The maximum mouth opening range of the MNC group was greater than that of the MC group (P<0.05). Accordingly, the MC group had good results for physical and eating ability. The MNC group suffered from muscle fatigue but had the advantage of a greater maximum mouth opening range. PMID- 25843538 TI - Harmful chemicals: poisoning our children one life-saving device at a time. PMID- 25843537 TI - Intra-arterial chemoradiation therapy with weekly low-dose cisplatin for squamous cell carcinoma of the maxillary sinus. AB - A new intra-arterial chemoradiation regimen that involves infusing low-dose cisplatin in combination with definitive irradiation was used in 36 patients diagnosed with squamous cell carcinoma of the maxillary sinus. The safety and therapeutic efficacy of this regimen were reviewed retrospectively. An intra arterial catheter was inserted in a retrograde manner into the target artery via the superficial temporal artery or occipital artery. Intra-arterial infusion was performed using cisplatin at a dose of 20-50mg/m(2) per week for 6-8 weeks. At the same time, sodium thiosulphate was infused as a neutralizing agent. Irradiation was performed at 60Gy in 30 fractions. All 36 patients completed treatment. Grade 3 adverse events occurred in only seven patients (19.4%) and no grade 4 events were noted. As a primary therapy, the complete response rate was 83.3%, the partial response rate was 16.7%, and the overall response rate was 100%. The 2-year local control rate was 63.0%, and the 2-year overall survival rate was 75.5%. The 2-year preservation rate of the hard palate was 97.1%, that of the eyeball was 97.2%, and that of visual function was 94.4%. This treatment regimen can contribute to improving the quality of life of patients without reducing the curability of the therapy. PMID- 25843539 TI - Mindfulness-based stress reduction for chronic insomnia in adults older than 75 years: a randomized, controlled, single-blind clinical trial. AB - OBJECTIVE: To assess the effectiveness of mindfulness-based stress reduction (MBSR) for chronic insomnia and combined depressive or anxiety symptoms of older adults aged 75 years and over. DESIGN: A randomized, controlled, single-blind clinical trial. PATIENTS AND METHODS: Participants included 60 adults aged 75 years and over with chronic insomnia. Participants were randomly assigned to the eight-week MBSR group or the wait-list control group. Assessments using the Pittsburgh Sleep Quality Index (PSQI), Self-rating Anxiety Sale (SAS), and Geriatric Depression Scale (GDS) were taken at baseline and post-treatment. For each outcome measure, a repeated measures analysis of variance was used to detect changes across assessments. RESULTS: There was a significant time * group interaction for the PSQI global score (P = .006); the MBSR group had a decrease in the PSQI global score (Cohen's d = 1.12), while the control group did not (Cohen's d = -0.06). Among the PSQI components, there was a significant time * group interaction for daytime dysfunction (P = .048); Cohen's d of the MBSR group was 0.76, while Cohen's d of control group was -0.04. There was no significant time * group interaction for the SAS score (P = .116), while for the GDS there was a significant time * group interaction (P = .039); the Cohen's d value for the MBSR group was 1.20, and it was 0.12 for the control group. CONCLUSION: This study demonstrated that the MBSR program could be a beneficial treatment for chronic insomnia in adults aged 75 years and older. PMID- 25843540 TI - HHS sets goals and timeline for shifting Medicare reimbursements from volume to value. PMID- 25843541 TI - Tactile remapping: from coordinate transformation to integration in sensorimotor processing. AB - Tactile localization entails the transformation of the initial skin-based location into an external reference frame that accounts for body posture and subsequent flexible integration of these two reference frames. The mechanisms underlying this tactile remapping are not well understood. Notably, there is a gap between the principles uncovered by psychophysical research and the mechanistic explanations offered by neuroscientific studies. We suggest that spatial localization is best viewed as a process of integrating multiple concurrently active spatial representations rather than a sequential transformation process. To achieve integration, large-scale interactions are required that link these different representations. Coordinated oscillatory activity may be a suitable mechanism that allows parallel representation of multiple spatial formats and the formation of an integrated location estimate. PMID- 25843542 TI - Degree of automaticity and the prefrontal cortex. AB - The dorsolateral prefrontal cortex (PFC), with more anterior areas [Brodmann area (BA) 45, 47, and 10], has been known to be activated as cognitive hierarchy increases. However, this does not hold for highly automatic processes such as first language (L1), where the posterior region (BA 44) is known as the key area for the processing of complex linguistic hierarchy. Discussing this disparity, we propose that the degree of automaticity (DoA) is a crucial factor for the framework of functional mapping in the PFC: the posterior-to-anterior gradient system for more controlled processes and the posterior-confined system for automatic processes. We support this view with previous findings and provide a new perspective on the functional organization of the PFC. PMID- 25843543 TI - A Bayesian perspective on magnitude estimation. AB - Our representation of the physical world requires judgments of magnitudes, such as loudness, distance, or time. Interestingly, magnitude estimates are often not veridical but subject to characteristic biases. These biases are strikingly similar across different sensory modalities, suggesting common processing mechanisms that are shared by different sensory systems. However, the search for universal neurobiological principles of magnitude judgments requires guidance by formal theories. Here, we discuss a unifying Bayesian framework for understanding biases in magnitude estimation. This Bayesian perspective enables a re interpretation of a range of established psychophysical findings, reconciles seemingly incompatible classical views on magnitude estimation, and can guide future investigations of magnitude estimation and its neurobiological mechanisms in health and in psychiatric diseases, such as schizophrenia. PMID- 25843544 TI - The lateral occipitotemporal cortex in action. AB - Understanding and responding to other people's actions is fundamental for social interactions. Whereas many studies emphasize the importance of parietal and frontal regions for these abilities, several lines of recent research show that the human lateral occipitotemporal cortex (LOTC) represents varied aspects of action, ranging from perception of tools and bodies and the way they typically move, to understanding the meaning of actions, to performing overt actions. Here, we highlight common themes across these lines of work, which have informed theories related to high-level vision, concepts, social cognition, and apraxia. We propose that patterns of activity in LOTC form representational spaces, the dimensions of which capture perceptual, semantic, and motor knowledge of how actions change the state of the world. PMID- 25843545 TI - Theoretical chemical kinetics in tropospheric chemistry: methodologies and applications. PMID- 25843547 TI - Slit and Semaphorin signaling governed by Islet transcription factors positions motor neuron somata within the neural tube. AB - Motor neurons send out axons to peripheral muscles while their cell bodies remain in the ventral spinal cord. The unique configuration of motor neurons spanning the border between the CNS and PNS has been explained by structural barriers such as boundary cap (BC) cells, basal lamina and radial glia. However, mechanisms in motor neurons that retain their position have not been addressed yet. Here we demonstrate that the Islet1 (Isl1) and Islet2 (Isl2) transcription factors, which are essential for acquisition of motor neuron identity, also contribute to restrict motor neurons within the neural tube. In mice that lack both Isl1 and Isl2, large numbers of motor neurons exited the neural tube, even prior to the appearance of BC cells at the ventral exit points. Transcriptional profiling of motor neurons derived from Isl1 null embryonic stem cells revealed that transcripts of major genes involved in repulsive mechanisms were misregulated. Particularly, expression of Neuropilin1 (Npr1) and Slit2 mRNA was diminished in Islet mutant mice, and these could be target genes of the Islet proteins. Consistent with this mechanism, Robo and Slit mutations in mice and knockdown of Npr1 and Slit2 in chick embryos caused motor neurons to migrate to the periphery. Together, our study suggests that Islet genes engage Robo-Slit and Neuropilin Semaphorin signaling in motor neurons to retain motor somata within the CNS. PMID- 25843548 TI - Large-Area Epitaxial Monolayer MoS2. AB - Two-dimensional semiconductors such as MoS2 are an emerging material family with wide-ranging potential applications in electronics, optoelectronics, and energy harvesting. Large-area growth methods are needed to open the way to applications. Control over lattice orientation during growth remains a challenge. This is needed to minimize or even avoid the formation of grain boundaries, detrimental to electrical, optical, and mechanical properties of MoS2 and other 2D semiconductors. Here, we report on the growth of high-quality monolayer MoS2 with control over lattice orientation. We show that the monolayer film is composed of coalescing single islands with limited numbers of lattice orientation due to an epitaxial growth mechanism. Optical absorbance spectra acquired over large areas show significant absorbance in the high-energy part of the spectrum, indicating that MoS2 could also be interesting for harvesting this region of the solar spectrum and fabrication of UV-sensitive photodetectors. Even though the interaction between the growth substrate and MoS2 is strong enough to induce lattice alignment via van der Waals interaction, we can easily transfer the grown material and fabricate devices. Local potential mapping along channels in field effect transistors shows that the single-crystal MoS2 grains in our film are well connected, with interfaces that do not degrade the electrical conductivity. This is also confirmed by the relatively large and length-independent mobility in devices with a channel length reaching 80 MUm. PMID- 25843549 TI - Cardiolipin is a key determinant for mtDNA stability and segregation during mitochondrial stress. AB - Mitochondria play a key role in adaptation during stressing situations. Cardiolipin, the main anionic phospholipid in mitochondrial membranes, is expected to be a determinant in this adaptive mechanism since it modulates the activity of most membrane proteins. Here, we used Saccharomyces cerevisiae subjected to conditions that affect mitochondrial metabolism as a model to determine the possible role of cardiolipin in stress adaptation. Interestingly, we found that thermal stress promotes a 30% increase in the cardiolipin content and modifies the physical state of mitochondrial membranes. These changes have effects on mtDNA stability, adapting cells to thermal stress. Conversely, this effect is cardiolipin-dependent since a cardiolipin synthase-null mutant strain is unable to adapt to thermal stress as observed by a 60% increase of cells lacking mtDNA (rho0). Interestingly, we found that the loss of cardiolipin specifically affects the segregation of mtDNA to daughter cells, leading to a respiratory deficient phenotype after replication. We also provide evidence that mtDNA physically interacts with cardiolipin both in S. cerevisiae and in mammalian mitochondria. Overall, our results demonstrate that the mitochondrial lipid cardiolipin is a key determinant in the maintenance of mtDNA stability and segregation. PMID- 25843550 TI - Light-harvesting II antenna trimers connect energetically the entire photosynthetic machinery - including both photosystems II and I. AB - In plant chloroplasts, the two photosystems (PSII and PSI) are enriched in different thylakoid domains and, according to the established view, are regarded as energetically segregated from each other. A specific fraction of the light harvesting complex II (LHCII) has been postulated to get phosphorylated by the STN7 kinase and subsequently to migrate from PSII to PSI as part of a process called 'state transition'. Nevertheless, the thylakoid membrane incorporates a large excess of LHCII not present in the isolatable PSII-LHCII and PSI-LHCII complexes. Moreover, LHCII phosphorylation is not limited to a specific LHCII pool and "state 2" condition, but is found in all thylakoid domains in any constant light condition. Here, using a targeted solubilization of pigment protein complexes from different thylakoid domains, we demonstrate that even a minor detachment of LHCII leads to markedly increased fluorescence emission from LHCII and PSII both in grana core and non-appressed thylakoid membranes and the effect of the detergent to detach LHCII is enhanced in the absence of LHCII phosphorylation. These findings provide evidence that PSII and PSI are energy traps embedded in the same energetically connected LHCII lake. In the lake, PSI and LHCII are energetically connected even in the absence of LHCII phosphorylation, yet the phosphorylation enhances the interaction required for efficient energy transfer to PSI in the grana margin regions. PMID- 25843551 TI - The chimeric origin of the cardiolipin biosynthetic pathway in the Eukarya domain. AB - Cardiolipin (CL) and phosphatidylglycerol (PG) are the main anionic phospholipids present in the Eukarya and Bacteria domains. They participate in energy transduction by activating and stabilizing the components of the oxidative phosphorylation machinery. Experimental evidence shows that they are synthesized by two different mechanisms which indicate that both pathways evolved convergently. Former studies on the lipid composition of archaeal membranes showed the absence of CL in these organisms, consequently, restricting it to the Eukarya and Bacteria domains. Interestingly, recent studies have demonstrated that both CL and PG are present as constitutive components of membranes of the haloarchaea group. However, this scenario complicates the analysis of the evolutionary origin of this biosynthetic pathway. Here I suggest that a phospholipid biosynthetic pathway in Eukarya probably arose from a chimeric event between bacterial and archaeal enzymes during the endosymbiosis event. Phylogenetic analyses support the different evolutionary origin of the enzymes comprising this pathway in bacteria and Eukarya. Based on protein domain analyses, orthologous proteins in the Archaea domain were identified. An integrative analysis of the proteins found demonstrates that CL biosynthesis in major clades of the Eukarya domain originated by chimerism between the bacteria and archaea pathways. Moreover, primary and secondary endosymbiontic events in plants and chromoalveolata respectively, reshaped this pathway again. The implications and advantages that these new enzymatic orders conferred to the Eukarya domain are discussed. PMID- 25843552 TI - Electron transfer pathways from the S2-states to the S3-states either after a Ca2+/Sr2+ or a Cl-/I- exchange in Photosystem II from Thermosynechococcus elongatus. AB - The site for water oxidation in Photosystem II (PSII) goes through five sequential oxidation states (S0 to S4) before O2 is evolved. It consists of a Mn4CaO5-cluster close to a redox-active tyrosine residue (YZ). Cl- is also required for enzyme activity. By using EPR spectroscopy it has been shown that both Ca2+/Sr2+ exchange and Cl-/I- exchange perturb the proportions of centers showing high (S=5/2) and low spin (S=1/2) forms of the S2-state. The S3-state was also found to be heterogeneous with: i) a S=3 form that is detectable by EPR and not sensitive to near-infrared light; and ii) a form that is not EPR visible but in which Mn photochemistry occurs resulting in the formation of a (S2YZ)' split EPR signal upon near-infrared illumination. In Sr/Cl-PSII, the high spin (S=5/2) form of S2 shows a marked heterogeneity with a g=4.3 form generated at low temperature that converts to a relaxed form at g=4.9 at higher temperatures. The high spin g=4.9 form can then progress to the EPR detectable form of S3 at temperatures as low as 180K whereas the low spin (S=1/2) S2-state can only advance to the S3 state at temperatures>=235 K. Both of the two S2 configurations and the two S3 configurations are each shown to be in equilibrium at >=235 K but not at 198 K. Since both S2 configurations are formed at 198 K, they likely arise from two specific populations of S1. The existence of heterogeneous populations in S1, S2 and S3 states may be related to the structural flexibility associated with the positioning of the oxygen O5 within the cluster highlighted in computational approaches and which has been linked to substrate exchange. These data are discussed in the context of recent in silico studies of the electron transfer pathways between the S2-state(s) and the S3-state(s). PMID- 25843554 TI - Complications of systemic juvenile idiopathic arthritis: risk factors and management recommendations. AB - Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, arthritis, rash and serositis. Systemic inflammation has been associated with dysregulation of the innate immune system, suggesting that SJIA is an autoinflammatory disorder. IL-1 and IL-6 play a major role in the pathogenesis of SJIA, and treatment with IL-1 and IL-6 inhibitors has shown to be highly effective. However, complications of SJIA, including macrophage activation syndrome, limitations in functional outcome by arthritis and long-term damage from chronic inflammation, continue to be a major issue in SJIA patients' care. Translational research leading to a profound understanding of the cytokine crosstalk in SJIA and the identification of risk factors for SJIA complications will help to improve long-term outcome. PMID- 25843553 TI - The painful tweet: text, sentiment, and community structure analyses of tweets pertaining to pain. AB - BACKGROUND: Despite the widespread popularity of social media, little is known about the extent or context of pain-related posts by users of those media. OBJECTIVE: The aim was to examine the type, context, and dissemination of pain related tweets. METHODS: We used content analysis of pain-related tweets from 50 cities to unobtrusively explore the meanings and patterns of communications about pain. Content was examined by location and time of day, as well as within the context of online social networks. RESULTS: The most common terms published in conjunction with the term "pain" included feel (n=1504), don't (n=702), and love (n=649). The proportion of tweets with positive sentiment ranged from 13% in Manila to 56% in Los Angeles, CA, with a median of 29% across cities. Temporally, the proportion of tweets with positive sentiment ranged from 24% at 1600 to 38% at 2400, with a median of 32%. The Twitter-based social networks pertaining to pain exhibited greater sparsity and lower connectedness than did those social networks pertaining to common terms such as apple, Manchester United, and Obama. The number of word clusters in proportion to node count was greater for emotion terms such as tired (0.45), happy (0.43), and sad (0.4) when compared with objective terms such as apple (0.26), Manchester United (0.14), and Obama (0.25). CONCLUSIONS: Taken together, our results suggest that pain-related tweets carry special characteristics reflecting unique content and their communication among tweeters. Further work will explore how geopolitical events and seasonal changes affect tweeters' perceptions of pain and how such perceptions may affect therapies for pain. PMID- 25843555 TI - Stone-Wales rearrangements in polycyclic aromatic hydrocarbons: a computational study. AB - Mechanisms for Stone-Wales rearrangements (SWRs) in polycyclic unsaturated hydrocarbons containing a pentafulvalene core have been studied using density functional, coupled cluster, and multiconfigurational methods. At the BD(T)/cc pVDZ//(U)M06-2X/cc-pVDZ level of theory, free energies of activation (at 1000 degrees C) range from ca. 70 kcal/mol for the model system pentafulvalene -> naphthalene (1 -> 2) to >110 kcal/mol for the degenerate SWR of pyracyclene (3). Systems studied that do not contain a pyracyclene subunit are predicted to have DeltaG(?) less than about 90 kcal/mol and to proceed by a carbene-type mechanism. Substrates containing a pyracyclene subunit should proceed via a cyclobutyl mechanism, and appropriate benzannelation of 3 lowers the activation free energy considerably. Computed DeltaG(?) values are consistent with experimental observations reported for known systems. SWRs of two untested substrates, cyclopent[fg]aceanthrylene (18) and dicyclopenta[fg,op]tetracene (21), are predicted to have DeltaG(?) < 95 kcal/mol and thus to be accessible via flash vacuum pyrolysis. PMID- 25843556 TI - Azole antifungals: 35 years of invasive fungal infection management. AB - Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects. PMID- 25843558 TI - Diagnostic Performance of Artificial Neural Network for Detecting Ischemia in Myocardial Perfusion Imaging. AB - BACKGROUND: The purpose of this study was to apply an artificial neural network (ANN) in patients with coronary artery disease (CAD) and to characterize its diagnostic ability compared with conventional visual and quantitative methods in myocardial perfusion imaging (MPI). METHODS AND RESULTS: A total of 106 patients with CAD were studied with MPI, including multiple vessel disease (49%), history of myocardial infarction (27%) and coronary intervention (30%). The ANN detected abnormal areas with a probability of stress defect and ischemia. The consensus diagnosis based on expert interpretation and coronary stenosis was used as the gold standard. The left ventricular ANN value was higher in the stress-defect group than in the no-defect group (0.92+/-0.11 vs. 0.25+/-0.32, P<0.0001) and higher in the ischemia group than in the no-ischemia group (0.70+/-0.40 vs. 0.004+/-0.032, P<0.0001). Receiver-operating characteristics curve analysis showed comparable diagnostic accuracy between ANN and the scoring methods (0.971 vs. 0.980 for stress defect, and 0.882 vs. 0.937 for ischemia, both P=NS). The relationship between the ANN and defect scores was non-linear, with the ANN rapidly increased in ranges of summed stress score of 2-7 and summed defect score of 2-4. CONCLUSIONS: Although the diagnostic ability of ANN was similar to that of conventional scoring methods, the ANN could provide a different viewpoint for judging abnormality, and thus is a promising method for evaluating abnormality in MPI. PMID- 25843557 TI - Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans - a validation study - . AB - BACKGROUND: Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans. METHODS AND RESULTS: In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo. CONCLUSIONS: These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans. PMID- 25843559 TI - Distribution of serotonin 5-HT1A-binding sites in the brainstem and the hypothalamus, and their roles in 5-HT-induced sleep and ingestive behaviors in rock pigeons (Columba livia). AB - Serotonin 1A receptors (5-HT1ARs), which are widely distributed in the mammalian brain, participate in cognitive and emotional functions. In birds, 5-HT1ARs are expressed in prosencephalic areas involved in visual and cognitive functions. Diverse evidence supports 5-HT1AR-mediated 5-HT-induced ingestive and sleep behaviors in birds. Here, we describe the distribution of 5-HT1ARs in the hypothalamus and brainstem of birds, analyze their potential roles in sleep and ingestive behaviors, and attempt to determine the involvement of auto-/hetero-5 HT1ARs in these behaviors. In 6 pigeons, the anatomical distribution of [(3)H]8 OH-DPAT binding in the rostral brainstem and hypothalamus was examined. Ingestive/sleep behaviors were recorded (1h) in 16 pigeons pretreated with MM77 (a heterosynaptic 5-HT1AR antagonist; 23 or 69 nmol) for 20 min, followed by intracerebroventricular ICV injection of 5-HT (N:8; 150 nmol), 8-OH-DPAT (DPAT, a 5-HT1A,7R agonist, 30 nmol N:8) or vehicle. 5-HT- and DPAT-induced sleep and ingestive behaviors, brainstem 5-HT neuronal density and brain 5-HT content were examined in 12 pigeons, pretreated by ICV with the 5-HT neurotoxin 5,7 dihydroxytryptamine (5,7-DHT) or vehicle (N:6/group). The distribution of brainstem and diencephalic c-Fos immunoreactivity after ICV injection of 5-HT, DPAT or vehicle (N:5/group) into birds provided with or denied access to water is also described. 5-HT1ARs are concentrated in the brainstem 5-HTergic areas and throughout the periventricular hypothalamus, preoptic nuclei and circumventricular organs. 5-HT and DPAT produced a complex c-Fos expression pattern in the 5-HT1AR-enriched preoptic hypothalamus and the circumventricular organs, which are related to drinking and sleep regulation, but modestly affected c-Fos expression in 5-HTergic neurons. The 5-HT-induced ingestivebehaviors and the 5-HT- and DPAT-induced sleep behaviors were reduced by MM77 pretreatment. 5,7 DHT increased sleep per se, decreased tryptophan hydroxylase expression in the raphe nuclei and decreased prosencephalic 5-HT release but failed to affect 5-HT- or DPAT-induced drinking or sleep behavior. 5-HT- and DPAT-induced ingestive and sleep behaviors in pigeons appear to be mediated by heterosynaptic and/or non somatodendritic presynaptic 5-HT1ARs localized to periventricular diencephalic circuits. PMID- 25843560 TI - Behavioural changes observed in demyelination model shares similarities with white matter abnormalities in humans. AB - Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Further to the symptoms resulting from demyelination, new studies point to the involvement of neuroinflammation and white matter abnormalities in psychiatric disorders and neurodegenerative diseases. Cuprizone, a model of MS, produces consistent demyelination and elicits behavioural, morphological and inflammatory changes in animals that share some similarities with those observed in humans. In this study, we used the cuprizone model in Lewis rats to evaluate clinical signs triggered by the demyelination process which could be comparable with the symptoms seen in white matter abnormalities in human beings. To induce the demyelination process, 0.6% cuprizone was added to the Lewis rats' diet for 4 weeks. We proceeded with behavioural, morphological and immunological analyses. Animals fed with cuprizone exhibited behavioural changes: higher scores in the neurotoxicity test, reduced exploratory and locomotion behaviour, and also an increase of permanency in the closed arm of the elevated plus maze test, were observed. In these analyses, the animals showed motor coordination impairment and anxiety-like behaviour. Demyelination also triggered changes in discrimination of objects identified by an increase in the time spent close to a familiar object. These behavioural alterations were associated with a significant increase in the levels of TNF alpha and corticosterone, consistent with the activation of microglia and astrocytes. Taken together, the results of this work show the cuprizone/Lewis rat model demyelination as an attractive paradigm for studying the correlation between white matter abnormalities and behaviour. PMID- 25843561 TI - QT Indexes in Cirrhotic Patients: Relationship with Clinical Variables and Potential Diagnostic Predictive Value. AB - BACKGROUND AND AIMS: A wide spectrum of cardiovascular changes characterizes cirrhosis, ranging from subclinical alterations to hyperkinetic syndrome. We looked for ECG markers of ventricular repolarization in a population of patients with cirrhosis in comparison to patients without cirrhosis and we investigated the relationship between these and other clinical and laboratory variables. METHODS: In 149 patients with cirrhosis and 152 controls, we measured QT maximum interval (QTmax), QT corrected interval (QTc), QT minimum interval (QTmin), QT dispersion (QTdisp), QT peak and T peak-to-end (TpTe). RESULTS: In subjects with cirrhosis, in comparison with controls, we observed a higher mean QTmax, mean QTc, mean QTmin, mean QTdisp and mean TpTe. At Cox regression analysis, diastolic blood pressure and beta-blocker treatment were significantly associated with mean QTmax, hypertension with mean QTmin and mean QTc, diastolic blood pressure, beta blockers and ACE-inhibitors/ARBs with QT disp, and beta-blockers with TpTe. Analysis of ROC curves showed a significant area under curve towards cirrhosis diagnosis, respectively, for a cut-off value of > 400 msec of QTmax, > 360 msec of QTmin, > 450 msec of QTc, > 105 msec of TpTe and > 55 msec of QTdisp. CONCLUSIONS: Our study shows that QT indexes are altered in cirrhotic patients and have a potential diagnostic predictive value. PMID- 25843562 TI - Assessing Parental Knowledge About Thalassemia in a Thalassemia Center of Karachi, Pakistan. AB - Thalassemia is the leading haemoglobinopathy after sickle cell anemia that accounts for 1.5 % of the global population. In Pakistan, every 1-4 per 1000 infants suffers from Thalassemia. Regardless of being a population "at high risk" for Thalassemia major, evidence suggest that Pakistanis possess poor knowledge of the disease. The present study aimed to assess parents' accurate knowledge about Thalassemia disease at Afzaal Memorial Thalassemia Foundation in Karachi, Pakistan. A total of 172 parents of existing patients who were receiving regular blood transfusion from the center were included in the study. Parents' knowledge was assessed via a pre-tested and validated Thalassemia knowledge questionnaire. Findings show that 40 % of the sample showed lower knowledge scores about Thalassemia. Among different ethnic origins, Urdu speaking respondents showed a higher average score of correct knowledge about Thalassemia major (21.6 +/- 4.41) as compared to the Siraiki (17.9 +/- 4.48) and the Pathans (17.2 +/- 4.34). These latter two ethnic groups also showed poor knowledge about Thalassemia minor. Generally parents provided correct answers about treatment of Thalassemia major. The findings suggest targeted interventions are required for high risk ethnic groups. Thalassemia education programs should be offered to extended family members of existing patients by all Thalassemia centers. High risk ethnic groups (Siraiki and Pathan) need rigorous interventions, and Thalassemia worker program should be introduced nationwide. PMID- 25843563 TI - Complexities of Genetic Counseling for ALS: A Case of Two Siblings with Discordant Genetic Test Results. AB - Rapid advances in the genetics of amyotrophic lateral sclerosis (ALS) have dramatically changed the approach of clinicians and researchers to the motor neuron diseases. We report two siblings in whom the genetic study provided conflicting results, hence raising a number of issues which deserve to be considered by clinicians involved in genetic testing for ALS. The first patient died within 2 years of ALS onset, while her brother still manages to walk unaided, 7 years into onset. Genetic analyses, performed on the first patient as part of a research protocol, and as clinical genetic testing on the brother, provided different results. Results for Patient 1 were negative for all investigated genes, thus suggesting that her disease may be a phenocopy, while her brother carried an autosomal dominant TARDBP mutation (p.A382T). A multidisciplinary approach may help patients and clinicians face the emerging dilemmas in such a complex field. Sharing and updating of advances, not to mention uncertainties inherent to current knowledge, with patients and families may prove to be an effective way to support them and to make them aware of the present limits of our knowledge and of the blurred border between research and clinical practice. PMID- 25843565 TI - Regulatory system reform of occupational health and safety in China. AB - With the explosive economic growth and social development, China's regulatory system of occupational health and safety now faces more and more challenges. This article reviews the history of regulatory system of occupational health and safety in China, as well as the current reform of this regulatory system in the country. Comprehensive, a range of laws, regulations and standards that promulgated by Chinese government, duties and responsibilities of the regulatory departments are described. Problems of current regulatory system, the ongoing adjustments and changes for modifying and improving regulatory system are discussed. The aim of reform and the incentives to drive forward more health and safety conditions in workplaces are also outlined. PMID- 25843564 TI - Effect of higher frequency components and duration of vibration on bone tissue alterations in the rat-tail model. AB - To formulate more accurate guidelines for musculoskeletal disorders (MSD) linked to Hand-Arm Vibration Syndrome (HAVS), delineation of the response of bone tissue under different frequencies and duration of vibration needs elucidation. Rat tails were vibrated at 125 Hz (9 rats) and 250 Hz (9 rats), at 49 m/s(2), for 1D (6 rats), 5D (6 rats) and 20D (6 rats); D=days (4 h/d). Rats in the control group (6 rats for the vibration groups; 2 each for 1D, 5D, and 20D) were left in their cages, without being subjected to any vibration. Structural and biochemical damages were quantified using empty lacunae count and nitrotyrosine signal intensity, respectively. One-way repeated-measure mixed-model ANOVA at p<0.05 level of significance was used for analysis. In the cortical bone, structural damage quantified through empty lacunae count was significant (p<0.05) at 250 Hz (10.82 +/- 0.66) in comparison to the control group (7.41 +/- 0.76). The biochemical damage was significant (p<0.05) at both the 125 Hz and 250 Hz vibration frequencies. The structural damage was significant (p<0.05) at 5D for cortical bone while the trabecular bone showed significant (p<0.05) damage at 20D time point. Further, the biochemical damage increased with increase in the duration of vibration with a significant (p<0.05) damage observed at 20D time point and a near significant change (p=0.08) observed at 5D time point. Structural and biochemical changes in bone tissue are dependent upon higher vibration frequencies of 125 Hz, 250 Hz and the duration of vibration (5D, 20D). PMID- 25843566 TI - Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins. AB - In the present study, fifteen sesquiterpene coumarins were isolated and purified from different Ferula species, and were tested for their MDR reversal properties. Enhancement of doxorubicin cytotoxicity in MCF-7/Adr cells (doxorubicin resistant derivatives of MCF-7 cells overexpressing P-gp), when combined with very non toxic concentrations of the sesquiterpene coumarins (50 MUM) including umbelliprenin, farnesiferol B, farnesiferol C and lehmferin, proved significant MDR reversal activity of these coumarins. Flow cytometric efflux assay confirmed that the intracellular accumulation of Rho123 was significantly increased in MCF 7/Adr cells when treated with sesquiterpene coumarins. A deeper insight into the structure-activity relationship of sesquiterpene coumarins revealed that ring opened drimane-type sesquiterpene coumarins including farnesiferol B, farnesiferol C and lehmferin possessed the best inhibitory effects on P-gp pump efflux and they could be considered as lead scaffolds for further structure modifications. PMID- 25843567 TI - Characterization of Subcellular Responses Induced by Exposure of Microbubbles to Astrocytes. AB - Blast traumatic brain injury (bTBI) has now been identified to associate with adverse health consequences among combat veterans. Post-traumatic stress disorder linked with explosive blasts, for example, may result from such brain injury. The fundamental questions about the nature, diagnosis, and long-term consequences of bTBI and causative relationship to post-traumatic stress disorder remain elusive, however. A better understanding of brain tissue injury requires elucidation of potential mechanisms. One such mechanism may be generation of microcavitation bubbles in the brain after an explosive blast and their subsequent interaction with brain cells. Using a controlled electrical discharge system, we have successfully generated shock waves (~10 MPa) and microbubbles (20-30 MUm) in the cell culture of mouse astrocytes. Detachment of astrocytes from the substrate after exposure to microbubbles was observed, and it depended on repetitive exposures. Of the cells that survived the initial assault, several subcellular changes were monitored and determined using fluorescent microscopy, including cell viability, cytoskeletal reorganization, changes in focal adhesion, membrane permeability, and potential onset of apoptosis. While the astrocytes impacted by the shock wave only demonstrated essentially unaltered cellular behavior, the astrocytes exposed to microbubbles exhibited significantly different responses, including production of reactive oxygen species by collapse of microbubbles. In the present study, we characterized and report for the first time the altered biophysical and subcellular properties in astrocytes in response to exposure to the combination of shock waves and microbubbles. PMID- 25843568 TI - Molecular studies reveal a MLL-MLLT3 gene fusion displaced in a case of childhood acute lymphoblastic leukemia with complex karyotype. AB - Rearrangement of the mixed lineage-leukemia gene (MLL-r) is common in hematological diseases and is generally associated with poor prognosis. The mixed lineage leukemia gene translocated to, 3 (MLLT3) gene (9p22) is a frequent MLL-r partner (~18% of leukemias with MLL rearrangement) and is characterized by the translocation t(9;11) (p22;q23), forming an MLL-MLLT3 gene fusion. MLL-r are usually simple reciprocal translocations between two different chromosomes, although karyotypes with complex MLL-r have been observed. We present a rare case of a child with acute lymphoblastic leukemia with a complex karyotype in which the classical t(9;11) (p22;q23) was cryptically relocated into a third chromosome in a balanced three-way translocation. At the genome level, however, the MLL MLLT3 three-way translocation still displayed both reciprocal fusion transcripts. This argues in favor for a model where a simple two-way t(9;11) (p22;q23) was likely the first step that then evolved in to a more complex karyotype. Multicolor banding techniques can be used to greatly refine complex karyotypes and its chromosomal breakpoints. Also in the presence of putative new rearrangements, Long distance inverse-PCR is an important tool to identify which gene fusion is involved. PMID- 25843569 TI - First detections of Rickettsia helvetica and R. monacensis in ectoparasitic mites (Laelapidae and Trombiculidae) infesting rodents in south-western Slovakia. AB - Information on circulation of rickettsiae between small mammals and their ectoparasitic mites is scarce. In this study, we investigated infestation rates of rodents with mites in some areas of SW Slovakia and the role of mites as possible vectors of pathogenic rickettsiae. A total of 615 rodents of five species were caught during 2010-2012. All individuals were examined for ectoparasites which resulted in 2821 mites belonging to three species of Laelapidae and six species of Trombiculidae. The most common Laelapidae species was Laelaps agilis (81.25 %), followed by Haemogamasus nidi, and Eulaelaps stabularis. Hirsutiella zachvatkini (16.52 %) was the dominant species of the family Trombiculidae. DNA extracted from rodent blood and ectoparasitic mites was examined for the presence of rickettsiae by PCR. By pooling mites, 345 pool samples were created, of which 112 (32.46 %) were found to be positive for the rickettsial DNA. From 487 examined rodent blood samples, rickettsial DNA was found in 46 (9.44 %). Sequencing DNA from the positive blood samples and mites revealed the identity of Rickettsia helvetica and Rickettsia monacensis. The results of the study suggest that ectoparasitic mites may be reservoirs as well as vectors of some pathogenic rickettsiae. PMID- 25843570 TI - Asian fish tapeworm, Khawia japonensis (Yamaguti, 1934), has expanded its European invasive range. AB - The invasive fish tapeworm, Khawia japonensis (Yamaguti, 1934) originally described in Japan, is reported for the first time in Slovakia. The tapeworm was found in farmed common carp (Cyprinus carpio L.) from East-Slovakian breeding fish pond. This finding is registered 4 years after the first announcement of this parasite in Europe (Po River Basin in Italy) in 2010 and increases its distribution area within this continent. Morphological characterization of K. japonensis supplemented with DNA sequences of cox1 and ribosomal lsrDNA genes is provided. Specimens from Slovakia phenotypically corresponded with those from feral and farmed carps from China, Vietnam, and Italy. Moreover, 100 and 98.7% identity of partial ribosomal lsrDNA gene and mitochondrial cox1 genes, respectively, were detected with K. japonensis from Japan. The invasive and pathogenic potential of K. japonensis in commercial breeding fisheries and its possible further spread in natural habitats is difficult to estimate for now. As yet, K. japonensis appears to be without a major impact on commercial breeding fisheries, but calls for more attention to the problem of biological invasions. PMID- 25843571 TI - Epidemiologic study on Besnoitia besnoiti infection in dairy herds in Jordan. AB - Besnoitia besnoiti is an apicomplexan parasite and the causative agent of bovine besnoitiosis which is considered as a re-emergent disease in Europe. A cross sectional serological study was conducted to determine the seroprevalence and to identify risk factors associated with B. besnoiti infection in 68 dairy herds (n = 806 cows) in Jordan during the period from January to June 2007 and the spring of 2014. Data regarding herd's management was obtained by filling questionnaires through personal interviews with farmers. An indirect ELISA test was used to detect antibodies against B. besnoiti. Chi-square analysis and multivariable logistic regression model were used to identify risk factors associated with seropositivity to B. besnoiti. At the individual cow and herd level, the true prevalence of seropositive animals was 6 and 28.7 %, respectively. Cows between 2 and 6 years of age had significantly higher seroprevalence of B. besnoiti than other age groups. The highest seroprevalence of B. besnoiti was found in Zarqa and Irbid governorates. Multivariable logistic regression model identified that exchanging visits by farm workers to neighboring farms as a risk factor for seropositivity to B. besnoiti, while smaller herd size and twice a day farm cleaning using sweeping and water hosing were identified as protective factors. This is the first study that investigated the seroprevalence of B. besnoiti infection in dairy herds in Jordan. Further studies are warranted to explore the clinical manifestation of B. besnoiti infection as well as to identify the possible presence of other Besnoitia species and definitive hosts for the parasite. PMID- 25843572 TI - First report of Myxobolus sp. infection in the skeletal muscle of Neotropical freshwater fish Piaractus mesopotamicus. AB - Although there are several reports of Myxobolus species infecting the somatic muscle of teleost fish, species of this genus have not been described parasitizing the muscle tissue of pacus, Piaractus mesopotamicus. This study presented the first report of natural infection by Myxobolus sp. in the skeletal muscle of pacus reared in intensive system. Twenty-one fish (+/-142.2 g; +/-23.1 cm) were captured (April 2013) from an intensive fish farm in Sao Paulo State, southeast Brazil. Spores of Myxobolus sp. were contained within plasmodia and showed oval morphology with the apical portion slightly pyriform and two polar capsules pyriform retaining the same ratio to each other. In the histopathological study, the skeletal muscle do not present signs of inflammation. The integrity of myofibrils within the infected fibers showed some degree of degeneration, with partial loss of myofibrillar details and striations. Spores were found infecting the skeletal muscle of 18 fish (85.7%). Finally, the high prevalence of Myxobolus sp. infection in the skeletal muscle of P. mesopotamicus and the absence of macroscopic lesions in the muscle tissue indicate the necessity of more meticulous examinations during the health management in the rearing system and at slaughter of pacus to ensure best quality of meat. PMID- 25843573 TI - Two different myiasis cases in southeast of Turkey: ophthalmomyiasis and cutaneous myiasis. AB - Myiasis has become increasingly prevalent, particularly when human activity is carried out in environments with poor hygiene. We reported two cases of human myiasis in this paper. All of myiasis cases initially presenting to the Emergency Department of Kilis State Hospital in Turkey were identified. We present one case of ophthalmomyiasis caused by Oestrus ovis and one case of cutaneous myiasis caused by Lucilia sericata. Both of the myiasis cases were reported from rural area case limiting the exposure to adult flies and exterminating the flies will play important role in preventing the myiasis. PMID- 25843574 TI - Thelazia callipaeda (Spirurida: Thelaziidae): first report in Greece and a case of canine infection. AB - The eyeworm Thelazia callipaeda has been reported in different European countries, i.e. Italy, France, Germany, Switzerland, Spain, Portugal, Bosnia and Herzegovina, Croatia and Romania. The present article describes the first autochthonous case of ocular thelaziosis in a dog from Greece, thus revealing a new spot of infection in Europe. The dog in this case report, most likely infected at the northern borders of Greece, was referred to a private veterinary practice with conjunctivitis, oedema, keratitis, epiphora and mucoid discharge in both eyes. Seventy-seven nematodes were removed from both eyes, and the dog was treated with two subcutaneous injections of ivermectin 14 days apart, in combination with a topical antimicrobial medication. The parasites were morphologically and molecularly identified as T. callipaeda. Although in Greece there is no information about the presence and distribution of the fruit fly Phortica variegata, i.e. the intermediate host of T. callipaeda, the location where the dog was infected is environmentally suitable for its development. The present report of this zoonotic parasitosis indicates that in Greece, along with endemic areas in Spain and Italy, T. callipaeda is currently reaching its southernmost distribution limit in Europe. PMID- 25843575 TI - Can asenapine cause myocarditis? PMID- 25843576 TI - Boundary lubrication by associative mucin. AB - Mucus lubricants are widely distributed in living organisms. Such lubricants consist of a gel structure constructed by associative mucin. However, limited tribological studies exist on associative mucin fluids. The present research is the first to investigate the frictional behavior of a typical intact vertebrate mucin (loach skin mucin), which can recover the gel structure of mucus via hydrophobic association under physiological conditions (5-10 mg/mL loach skin mucin dissolved in water). Both rough hydrophobic and hydrophilic polydimethylsiloxane (PDMS) rubber plates were used as friction substrates. Up to 10 mg/mL loach skin mucin dissolved in water led to a 10-fold reduction in boundary friction of the two substrates. The boundary-lubricating ability for hydrophilic PDMS decreased with rubbing time, whereas that for hydrophobic PDMS remained constant. The boundary-lubricating abilities of the mucin on hydrophobic PDMS and hydrophilic PDMS showed almost similar responses toward changing concentration or sodium dodecyl sulfate (SDS). The mucin fluids reduced boundary friction coefficients (MU) only at concentrations (c) in which intermucin associations were formed, with a relationship shown as MU ~ c(-0.7). Destroying intermucin associations by SDS largely impaired the boundary-lubricating ability. Results reveal for the first time that intermolecular association of intact mucin in bulk solution largely enhances boundary lubrication, whereas tightly adsorbed layer plays a minor role in the lubrication. This study indicates that associated mucin should contribute considerably to the lubricating ability of biological mucus in vivo. PMID- 25843577 TI - Spatial and temporal dynamics of stink bugs in southeastern farmscapes. AB - A 3-yr study (2009-2011) was conducted to examine the spatial and temporal dynamics of stink bugs in three commercial farmscapes. Study locations were replicated in South Carolina and Georgia, in an agriculturally diverse region known as the southeastern coastal plain. Crops included wheat, Triticum aestivum (L.), corn, Zea mays (L.), soybean, Glycine max (L.), cotton, Gossypium hirsutum (L.), and peanut, Arachis hypogaea (L.). Farmscapes were sampled weekly using whole-plant examinations for corn, with all other crops sampled using sweep nets. The predominant pest species of phytophagous stink bugs were the brown stink bug, Euschistus servus (Say), the green stink bug, Chinavia hilaris (Say), and the southern green stink bug, Nezara viridula (L.). Chi-square tests indicated a departure from a normal distribution in 77% of analyses of the variance to mean ratio, with 37% of slopes of Taylor's power law and 30% of coefficient beta of Iwao's patchiness regression significantly greater than one, indicating aggregated distributions. Spatial Analyses by Distance IndicEs (SADIE) indicated aggregated patterns of stink bugs in 18% of year-end totals and 42% of weekly counts, with 80% of adults and nymphs positively associated using the SADIE association tool. Maximum stink bug densities in each crop occurred when the plants were producing fruit. Stink bugs exhibited greater densities in crops adjacent to soybean in Barnwell and Lee Counties compared with crops adjacent to corn or fallow areas. The diversity of crops and relatively small size of fields in the Southeast leads to colonization of patches within a farmscape. The ecological and management implications of the spatial and temporal distribution of stink bugs within farmscapes are discussed. PMID- 25843578 TI - Thermal death kinetics of fifth-instar Corcyras cephalonica (Lepidoptera: Galleriidae). AB - The infestation of rice moth, Corcyras cephalonica (Lepidoptera: Galleriidae), causes severe losses in postharvest walnuts. Heat has been studied as a phytosanitary treatment to replace chemical fumigation for controlling this pest. Information on kinetics for thermal mortality of C. cephalonica is needed for developing effective postharvest phytosanitary thermal treatments of walnuts. Thermal death kinetics of fifth-instar C. cephalonica were investigated at temperatures between 44 degrees C and 50 degrees C at a heating rate of 5 degrees C min(-1) using a heating block system. The results showed that thermal-death curves for C. cephalonica larvae followed a 0 order of kinetic reaction. The time to reach 100% mortality decreased with increasing temperature from 150 min at 44 degrees C to 2.5 min at 50 degrees C. The activation energy for controlling C. cephalonica was 466-592 kJ/mol, and the z value obtained from the thermal death time curve was 3.3 degrees C. This kinetic model prediction could be useful in designing the thermal treatment protocol for controlling C. cephalonica in walnuts. PMID- 25843579 TI - Variation in C:N:S stoichiometry and nutrient storage related to body size in a holometabolous insect (Curculio davidi) (Coleoptera: Curculionidae) larva. AB - Body size can be an important factor controlling consumer stoichiometry. In holometabolous insects, body size is typically associated with nutrient storage. Consumer stoichiometry is known to vary within species across a range of body sizes; however, the contribution of nutrient storage to this variation is not well understood. We used the fifth-instar larvae of the oak weevil (Coleoptera: Curculio davidi Fairmaire), which is characterized by a high capacity for nutrient storage, to investigate the effect of shifts in nutrient storage with body mass on variations in larva stoichiometry. Our results showed that weevil larvae with larger body mass had a lower carbon (C) content, reflecting decreases in the sequestration rate of C-rich lipids. Larger larvae had elevated concentrations of nitrogen (N), sulfur (S), and protein. The similar patterns of variation in elemental composition and macromolecule storage with body weight indicate that the shift in nutrient storage is the main factor causing the variation in larval stoichiometry with body weight. This finding was further supported by the low variation in residual larval biomass C, N, and S concentrations after lipid extraction. These results help decipher the physiological mechanism of stoichiometric regulation in growing organisms. PMID- 25843580 TI - Transcriptional regulation of cuticular protein glycine-rich13 gene expression in wing disc of Bombyx mori, Lepidoptera. AB - Cuticular protein genes are good models to study the molecular mechanisms of signaling by ecdysteroids, which regulate molting and metamorphosis in insects. The present research demonstrates on hormonal regulation and analysis of the regulatory sequences and transcription factors important for Bombyx mori cuticular protein glycine-rich13 (CPG13) gene expression. Expression of CPG13 was strong at prepupal stage in wing tissues of B. mori. CPG13 expression was induced by the addition of 20E, which was inhibited by cycloheximide in the wing disc. The upstream region of the CPG13 gene was analyzed using a transient reporter assay with a gene gun system and identified two BR-Z2 binding sites to be important cis-acting elements for the transcription activation of the luciferase reporter gene by an ecdysone pulse. Site-directed mutagenesis of these sites, followed by introduction into wing discs, significantly decreased the reporter activity. It was found that the regions carrying the binding sites for the ecdysone-responsive transcription factor BR-Z2 were responsible for the hormonal enhancement of the reporter gene activity in wing discs. Mutation of the BR-Z2 binding sites decreased the reporter activity suggesting that the BR-Z2 isoform can bind to the upstream region of the cuticle protein gene, CPG13 and activates its expression. PMID- 25843581 TI - Spatiotemporal distribution of Chinavia hilaris (Hemiptera: Pentatomidae) in corn farmscapes. AB - The green stink bug, Chinavia hilaris (Say) (Hemiptera: Pentatomidae), is a pest of cotton in the southeastern United States but little is known concerning its spatiotemporal distribution in corn cropping systems. Therefore, the spatiotemporal distribution of C. hilaris in farmscapes, when corn was adjacent to cotton, peanut, or both, was examined weekly. The spatial patterns of C. hilaris counts were analyzed using Spatial Analysis by Distance Indices methodology. Interpolated maps of C. hilaris density were used to visualize abundance and distribution of C. hilaris in crops in corn-peanut-cotton farmscapes. This stink bug was detected in six of seven corn-cotton farmscapes, four of six corn-peanut farmscapes, and in both corn-peanut-cotton farmscapes. The frequency of C. hilaris in cotton (89.47%) was significantly higher than in peanut (7.02%) or corn (3.51%). This stink bug fed on noncrop hosts that grew in field borders adjacent to crops. The spatial distribution of C. hilaris in crops and the capture of C. hilaris adults and nymphs in pheromone-baited traps near noncrop hosts indicated that these hosts were sources of this stink bug dispersing into crops, primarily cotton. Significant aggregated spatial distributions were detected in cotton on some dates within corn-peanut-cotton farmscapes. Maps of local clustering indices depicted small patches of C. hilaris in cotton or cotton-sorghum at the peanut-cotton interface. Factors affecting the spatiotemporal dynamics of C. hilaris in corn farmscapes are discussed. PMID- 25843582 TI - Isolation and characterization of microsatellite markers useful for exploring introgression among species in the diverse New Zealand cicada genus Kikihia. AB - The New Zealand cicada genus Kikihia Dugdale 1971 exhibits more than 20 contact zones between species pairs that vary widely in their divergence times (between 20,000 and 2 million years) in which some level of hybridization is evident. Mitochondrial phylogenies suggest some movement of genes across species boundaries. Biparentally inherited and quickly evolving molecular markers like microsatellites are useful for assessing gene flow levels. Here, we present six polymorphic microsatellite loci that amplify DNA from seven species across the genus Kikihia; Kikihia "northwestlandica," Kikihia "southwestlandica," Kikihia muta, Kikihia angusta, Kikihia "tuta," Kikihia "nelsonensis," and Kikihia "murihikua." The markers were developed using whole-genome shotgun sequencing on the 454 pyrosequencing platform. Moderate to high levels of polymorphisms were observed with 14-47 alleles for 213 individuals from 15 populations. Observed and expected heterozygosity range from 0 to 1 and 0.129 to 0.945, respectively. These new markers will be instrumental for the assessment of gene flow across multiple contact zones in Kikihia. PMID- 25843583 TI - Influences of Cry1Ac broccoli on larval survival and oviposition of diamondback moth. AB - Larval survival and oviposition behavior of three genotypes of diamondback moth, Plutella xylostella L. (Lepidoptera: Plutellidae), (homozygous Cry1Ac susceptibile, Cry1Ac-resistant, and their F1 hybrids), on transgenic Bacillus thuringiensis (Bt) broccoli expressing different levels of Cry1Ac protein were evaluated in laboratory. These Bt broccoli lines were designated as relative low, medium, and high, respectively, according to the Cry1Ac content. Untransformed brocccoli plants were used as control. Larval survival of diamondback moth on non Bt leaves was not significantly different among the three genotypes. The Cry1Ac resistant larvae could survive on the low level of Bt broccoli plants, while Cry1Ac-susceptible and F1 larvae could not survive on them. The three genotypes of P. xylostella larvae could not survive on medium and high levels of Bt broccoli. In oviposition choice tests, there was no significant difference in the number of eggs laid by the three P. xylostella genotypes among different Bt broccoli plants. The development of Cry1Ac-susceptible and Cry1Ac-resistant P. xylostella on intact Bt plants was also tested in greenhouse. All susceptible P. xylostella larvae died on all Bt plants, while resistant larvae could survive on broccoli, which expresses low Cry1Ac protein under greenhouse conditions. The results of the greenhouse trials were similar to that of laboratory tests. This study indicated that high dose of Bt toxins in broccoli cultivars or germplasm lines is required for effective resistance management. PMID- 25843584 TI - The distribution of dragonfly larvae in a South Carolina stream: relationships with sediment type, body size, and the presence of other larvae. AB - Dragonfly larvae were sampled in Little Creek, Greenville, SC. The distributions of five common species were described relative to sediment type, body size, and the presence of other larvae. In total, 337 quadrats (1 m by 0.5 m) were sampled by kick seine. For each quadrat, the substrate was classified as sand, sand cobble mix, cobble, coarse, or rock, and water depth and distance from bank were measured. Larvae were identified to species, and the lengths of the body, head, and metafemur were measured. Species were distributed differently across sediment types: sanddragons, Progomphus obscurus (Rambur) (Odonata: Gomphidae), were common in sand; twin-spotted spiketails, Cordulegaster maculata Selys (Odonata: Cordulegastridae), preferred a sand-cobble mix; Maine snaketails, Ophiogomphus mainensis Packard (Odonata: Gomphidae), preferred cobble and coarse sediments; fawn darners, Boyeria vinosa (Say) (Odonata: Aeshnidae), preferred coarse sediments; and Eastern least clubtails, Stylogomphus albistylus (Hagen) (Odonata: Gomphidae), preferred coarse and rock sediments. P. obscurus and C. maculata co occurred more frequently than expected by chance, as did O. mainensis, B. vinosa, and S. albistylus. Mean size varied among species, and species preferences contributed to differences in mean size across sediment types. There were significant negative associations among larval size classes: small larvae (<12 mm) occurred less frequently with large larvae (>15 mm) than expected by chance, and large larvae were alone in quadrats more frequently than other size classes. Species may select habitats at a large scale based on sediment type and their functional morphology, but small scale distributions are consistent with competitive displacement or intraguild predation. PMID- 25843585 TI - Effect of Tithonia diversifolia mulch on Atta cephalotes (Hymenoptera: Formicidae) nests. AB - Recent studies have shown an insecticidal effect of Tithonia diversifolia (Hemsl.) Gray (Asterales: Asteraceae) foliage on workers of Atta cephalotes L. and inhibitory effects of this plant on the growth of the symbiotic fungus Leucoagaricus gongylophorus (A. Muler) Singer. To evaluate the potential of T. diversifolia as a biological control treatment of this important pest, we assessed the effect of green manure (mulch) of this plant on natural nests of A. cephalotes, in Cali, Colombia. Three treatments were randomly assigned to 30 nests: 1) green mulch of T. diversifolia, 2) green mulch of Miconia sp., Ruiz & Pav. and 3) unmulched control. Every 2 wk for 6 mo, the surface of the nests was completely covered with leaves. Physical and chemical parameters of nest soil were assessed before the first and after the last application of the mulch. Ant foraging in T. diversifolia-treated nests decreased by 60% after the initial applications of the mulch, while nest surface area decreased by 40%. When the nests covered with T. diversifolia were opened, it was observed that the superficial fungus chambers had been relocated at a greater depth. In addition, microbial activity and soil pH increased by 84% and 12%, respectively, in nests covered with plant residues. In conclusion, the continued use of T. diversifolia mulch reduces foraging activity and negatively affects the internal conditions of the colonies, thereby inducing the ants to relocate the fungus chambers within the nests. PMID- 25843586 TI - Do Sesamia nonagrioides (Lepidoptera; Noctuidae) gravid females discriminate between Bt or multivitamin corn varieties? Role of olfactory and visual cues. AB - The Mediterranean corn borer, Sesamia nonagrioides Lefebvre, is a key pest of corn and a main target of Bacillus thuringiensis (Bt) corn in Northeast Spain. Trends for future biotechnology crops indicate that Bt, non-Bt, and stacked corn varieties with metabolic pathways for vitamin-increased traits could coexist in same region. Knowledge of the oviposition response of gravid females of S. nonagrioides to these different varieties could be extremely important for managing strategies aimed for delaying resistance development. In dual-choice assays, we examined the host preference of gravid females of S. nonagrioides for four corn varieties: a new transgenic corn with increased vitamin levels, its near isogenic counterpart (M37W), a Bt corn plant, and its near isogenic counterpart. Olfactory cues were the predominant ones when gravid females looked for a suitable host to lay eggs, and no synergistic effects were observed when both visual and olfactory cues were present. When the plant was visible, the females preferred the odors emitted by the nontransgenic to its multivitamin transgenic counterpart and when they only could detect the volatiles they also preferred the nontransgenic M37W variety to the Bt corn variety. If gravid females are less attracted to corn with an increased level of vitamins, this could impact insect resistance management and the value of refuge plants, if such traits are stacked with an insect resistance trait. PMID- 25843587 TI - Bioactivity of six plant extracts on adults of Demotispa neivai (Coleoptera: Chrysomelidae). AB - Demotispa neivai Bondar (Coleoptera: Chrysomelidae) damage oil palm fruits, which makes it necessary to develop products to control this insect. The mortality, repellency, and antifeeding effects on adults of D. neivai of six plant extracts of Azadirachta indica A. Juss. (Sapindales: Meliaceae), Ricinus communis (L.) (Malpighiaes: Euphorbiaceae), Citrus sinensis Oesbek (Sapindales: Rutaceae), Nicotiana tabacum (L.) (Slanales: Solanaceae), Capsicum annuum (L.) (Solanales: Solanaceae), and Artemisia absinthium (L.) (Asterales: Asteraceae) were determined: 1) the lethal concentration LC50-90, lethal time of D. neivai was evaluated after spraying the fruits of oil palm; 2) repellent effects of each ingredient were evaluated by calculating the index of repellency; 3) antifeeding effects with the rate of inhibition calculated between doses of 20 and 24 g/liter. The mortality of D. neivai was higher with the extracts Ci. sinensis, R. communis, N. tabacum, and Ca. annuum. The mortality of D. neivai increased in the first 72 hr in all treatments. The extracts of N. tabacum, Ca. annuum, and A. indica were more repellent to D. neivai that those of Ci. sinensis, Ar. Absinthium, and R. communis. Antifeeding effect was higher with Ci. sinensis and R. communis. The increased mortality of D. neivai by Ci. sinensis can be explained by the effect of this compound on the respiratory system of insects. Extracts of Ci. sinensis, R. communis, N. tabacum, and Ca. annuum repelled and caused mortality of D. neivai and, thus, can be used in integrate pest management programs of this pest in oil palm plantations. PMID- 25843588 TI - Revision of the neotropical Exoristini (Diptera, Tachinidae): the status of the genera Epiplagiops and Tetragrapha. AB - The monotypic genera Epiplagiops Blanchard, 1943 and Tetragrapha Brauer and Bergenstamm, 1891 are revised. Both are invalidated and synonymized with Chetogena Rondani, 1856. Their type-species, Epiplagiops littoralis Blanchard, 1943 and Tetragrapha tessellata Brauer and Bergenstamm, 1891, are studied, redescribed, illustrated, and transferred to Chetogena. A lectotype is designated for T. tessellata. PMID- 25843589 TI - Antennal sensilla in the parasitoid Sclerodermus sp. (Hymenoptera: Bethylidae). AB - Parasitoid wasps of the genus Sclerodermus (Hymenoptera: Bethylidae) are an important natural enemy of the Japanese pine sawyer beetle Monochamus alternatus Hope (Coleoptera: Cerambycidae). In this study, we used scanning electron microscopy to examine the external morphology of the antennal sensilla of Sclerodermus sp. Antennae of females and males comprised the scape, pedicel, and 11 flagellomere segments. Based on the morphology of the sensilla in each sex, seven types of sensillum were identified: sensilla trichodea (Tr.1, Tr.2 and Tr.3), sensilla basiconica (Ba.1, Ba.2, and Ba.3), sensilla styloconica (St.1 and St.2), sensilla placodea, sensilla coeloconica, sensilla squamiforma, and Bohm's bristles. Tr.2, Ba.1, and St.1 were only found in females, whereas Ba.2, Ba.3, and St.2 were only observed in males. Sensilla placodea were the most common, given that they occur on the antennae of many parasitoid Hymenoptera, whereas sensilla Tr were the most abundant, being distributed over the entire antennal surface. These sensilla are likely to have roles in the host locating and habitat searching behavior of adult Sclerodermus wasps. Therefore, our findings provide a basis for further studies of the host location behavior of this and other species of parasitic wasp. PMID- 25843590 TI - Five new records of ants (Hymenoptera: Formicidae) from Morocco. AB - A recent catalogue of the rich ant fauna of Morocco included 214 species, with later studies adding an additional 12 species. Following recent fieldwork in the north of Morocco, we report five new records for the country (Plagiolepis pygmaea Latreille, 1798, Ponera testacea Emery, 1895, Strumigenys tenuipilis Emery, 1915, Temnothorax pardoi Tinaut, 1987, and Tetramorium parvioculum Guillem & Bensusan, 2009) and we present new data on the distribution and natural history of six additional species. This work brings the total number of ants known from Morocco to 233, taking into account two species which were omitted in the list of Cagniant. PMID- 25843591 TI - Morphological outcomes of gynandromorphism in Lycaeides butterflies (Lepidoptera: Lycaenidae). AB - The genitalia of male insects have been widely used in taxonomic identification and systematics and are potentially involved in maintaining reproductive isolation between species. Although sexual selection has been invoked to explain patterns of morphological variation in genitalia among populations and species, developmental plasticity in genitalia likely contributes to observed variation but has been rarely examined, particularly in wild populations. Bilateral gynandromorphs are individuals that are genetically male on one side of the midline and genetically female on the other, while mosaic gynandromorphs have only a portion of their body developing as the opposite sex. Gynandromorphs might offer unique insights into developmental plasticity because individuals experience abnormal cellular interactions at the genitalic midline. In this study, we compare the genitalia and wing patterns of gynandromorphic Anna and Melissa blue butterflies, Lycaeides anna (Edwards) (formerly L. idas anna) and L. melissa (Edwards) (Lepidoptera: Lycaenidae), to the morphology of normal individuals from the same populations. Gynandromorph wing markings all fell within the range of variation of normal butterflies; however, a number of genitalic measurements were outliers when compared with normal individuals. From these results, we conclude that the gynandromorphs' genitalia, but not wing patterns, can be abnormal when compared with normal individuals and that the gynandromorphic genitalia do not deviate developmentally in a consistent pattern across individuals. Finally, genetic mechanisms are considered for the development of gynandromorphism in Lycaeides butterflies. PMID- 25843592 TI - Influence of different types of Phyllostachys pubescens (Poales: Poaceae) leaves on population parameters of Pantana phyllostachysae (Lepidoptera: Lymantriidae) and parasitic effects of Beauveria bassiana (Moniliales: Moniliaceae). AB - We found that Pantana phyllostachysae, a dangerous pest of moso bamboo (Phyllostachys pubescens), showed differences in growth and development after feeding on diverse types of moso bamboo leaves. The mortality rate of Pa. phyllostachysae due to Beauveria bassiana, an entomopathogenic fungus, was also affected by the varied larval diet. Larval and pupal developmental duration of Pa. phyllostachysae was longer when feeding on "off-year" bamboo leaves. Pupal weight and adult fertility were higher when feeding on "on-year" bamboo leaves. Mortality due to B. bassiana was significantly lower in larvae fed on on-year bamboo leaves than in larvae fed on off-year bamboo leaves. Larvae fed on new bamboo leaves had a shorter development period and higher survival rate than those fed on off-year bamboo leaves. However, mixed feed (mixture of new, on year, and off-year bamboo leaves) decreased the egg production of Pa. phyllostachysae. After infection by the second generation of B. bassiana, the survival time of Pa. phyllostachysae fed on mixed feed increased significantly compared with the first generation. We also fed Pa. phyllostachysae different proportion of new bamboo leaves in mixed feed to simulate natural conditions. We found that increasing the proportion of new bamboo leaves in the food promoted pupal development and increased egg production; it also increased the resistance of larvae to the first generation of B. bassiana. The pathogenicity of the second generation of B. bassiana declined in all mixed feed treatments. PMID- 25843593 TI - Aphidophagous parasitoids can forage wheat crops before aphid infestation, Parana State, Brazil. AB - Aphid parasitoids are common in Brazilian wheat fields, and parasitize aphids at the wheat tillering stage. However, there is little information available about when this natural enemy occurs in wheat crops. This study investigated the initial occurrence of aphid parasitoids in four commercial wheat crops in northern Parana during the 2009 crop season. We installed two Malaise traps at each wheat farm, and 400 tillers were assessed weekly in each field for aphid abundance. During this study, we captured 4,355 aphid parasitoids and 197 aphids. Three species of braconid parasitoids were identified, including Aphidius colemani (Viereck 1912), Lysiphlebus testaceipes (Cresson 1880), and Diaeretiella rapae (McIntosh 1855). The aphids species identified were Rhopalosiphum padi (Linnaeus 1758) and Sitobion avenae (Fabricius 1775). This study showed that aphid parasitoids are present in wheat crops even when aphid densities are low, and in one farm, occurred before the aphids colonization. These reports can justified the high efficiency of these natural enemies against aphids in wheat fields. PMID- 25843594 TI - External Validation and Evaluation of Reliability and Validity of the Modified Seoul National University Renal Stone Complexity Scoring System to Predict Stone Free Status After Retrograde Intrarenal Surgery. AB - OBJECTIVES: The modified Seoul National University Renal Stone Complexity scoring system (S-ReSC-R) for retrograde intrarenal surgery (RIRS) was developed as a tool to predict stone-free rate (SFR) after RIRS. We externally validated the S ReSC-R. MATERIALS AND METHODS: We retrospectively reviewed 159 patients who underwent RIRS. The S-ReSC-R was assigned from 1 to 12 according to the location and number of sites involved. The stone-free status was defined as no evidence of a stone or with clinically insignificant residual fragment stones less than 2 mm. Interobserver and test-retest reliabilities were evaluated. Statistical performance of the prediction model was assessed by its predictive accuracy, predictive probability, and clinical usefulness. RESULTS: Overall SFR was 73.0%. The SFRs were 86.7%, 70.2%, and 48.6% in low-score (1-2), intermediate-score (3 4), and high-score (5-12) groups, respectively (p<0.001). External validation of S-ReSC-R revealed an area under the curve (AUC) of 0.731 (95% CI 0.650-0.813). The AUC of the three-titered S-ReSC-R was 0.701 (95% CI 0.609-0.794). The calibration plot showed that the predicted probability of SFR had a concordance comparable to that of observed frequency. The Hosmer-Lemeshow goodness of fit test revealed a p-value of 0.01 for the S-ReSC-R and 0.90 for the three-titered S ReSC-R. Interobserver and test-retest reliabilities revealed an almost perfect level of agreement. CONCLUSIONS: The present study proved the predictive value of S-ReSC-R to predict SFR following RIRS in an independent cohort. Interobserver and test-retest reliabilities confirmed that S-ReSC-R was reliable and valid. PMID- 25843595 TI - Structure of Waxy Maize Starch Hydrolyzed by Maltogenic alpha-Amylase in Relation to Its Retrogradation. AB - Maltogenic alpha-amylase is widely used as an antistaling agent in bakery foods. The objective of this study was to determine the degree of hydrolysis (DH) and starch structure after maltogenic amylase treatments in relation to its retrogradation. Waxy maize starch was cooked and hydrolyzed to different degrees by a maltogenic amylase. High-performance anion-exchange chromatography and size exclusion chromatography were used to determine saccharides formed and the molecular weight (Mw) distributions of the residual starch structure, respectively. Chain length (CL) distributions of debranched starch samples were further related to amylopectin (AP) retrogradation. Differential scanning calorimetry (DSC) results showed the complete inhibition of retrogradation when starches were hydrolyzed to >20% DH. Mw and CL distributions of residual AP structure indicated that with an increase in %DH, a higher proportion of unit chains with degree of polymerization (DP) <=9 and a lower proportion of unit chains with DP >=17 were formed. A higher proportion of short outer AP chains that cannot participate in the formation of double helices supports the decrease in and eventual inhibition of retrogradation observed with the increase in %DH. These results suggest that the maltogenic amylase could play a powerful role in inhibiting the staling of baked products even at limited starch hydrolysis. PMID- 25843596 TI - Cereblon binding molecules in multiple myeloma. AB - Immunomodulation is an established treatment strategy in multiple myeloma with thalidomide and its derivatives lenalidomide and pomalidomide as its FDA approved representatives. Just recently the method of action of these cereblon binding molecules was deciphered and results from large phase 3 trials confirmed the backbone function of this drug family in various combination therapies. This review details the to-date knowledge concerning mechanism of IMiD action, clinical applications and plausible escape mechanisms in which cells may become resistant/refractory to cereblon binding molecule based treatment. PMID- 25843597 TI - Control of immunopathology during chikungunya virus infection. AB - After several decades of epidemiologic silence, chikungunya virus (CHIKV) has recently re-emerged, causing explosive outbreaks and reaching the 5 continents. Transmitted through the bite of Aedes species mosquitoes, CHIKV is responsible for an acute febrile illness accompanied by several characteristic symptoms, including cutaneous rash, myalgia, and arthralgia, with the latter sometimes persisting for months or years. Although CHIKV has previously been known as a relatively benign disease, more recent epidemic events have brought waves of increased morbidity and fatality, leading it to become a serious public health problem. The host's immune response plays a crucial role in controlling the infection, but it might also contribute to the promotion of viral spread and immunopathology. This review focuses on the immune responses to CHIKV in human subjects with an emphasis on early antiviral immune responses. We assess recent developments in the understanding of their possible Janus-faced effects in the control of viral infection and pathogenesis. Although preventive vaccination and specific therapies are yet to be developed, exploring this interesting model of virus-host interactions might have a strong effect on the design of novel therapeutic options to minimize immunopathology without impairing beneficial host defenses. PMID- 25843599 TI - Lessons from Ebola and readiness for new emerging infectious threats. PMID- 25843601 TI - Biomarkers and inhaled corticosteroid responsiveness in asthmatic patients. PMID- 25843598 TI - Ebola: a holistic approach is required to achieve effective management and control. AB - The current Ebola outbreak in West Africa has already caused substantial mortality and dire human and economic consequences. It continues to represent an alarming public health threat in the region and beyond and jeopardizes the provision of health care and other services in the affected countries. The scale of the epidemic has accelerated research efforts for diagnostics, treatment, and prevention galvanized through increased availability of funding. Our knowledge relating to the virus, disease pathogenesis, risk factors, dynamics of transmission, and epidemic control is increasing, and sociocultural factors have emerged as critical determinants for the success and failure of control efforts. However, there is a long way to go. In this review we summarize the current knowledge, examine the sociocultural context in West Africa, and outline priority areas for future research. PMID- 25843602 TI - Signaling impairments in maternal T cells engrafted in an infant with a novel IL 2 receptor gamma mutation. PMID- 25843603 TI - Efficacy of resin-modified glass ionomer cement varnish in the prevention of white spot lesions during comprehensive orthodontic treatment: a split-mouth study. AB - OBJECTIVE: To evaluate the efficacy of resin-modified glass ionomer cement varnish in the prevention of white spot lesions (WSLs) during early orthodontic treatment with fixed appliances. MATERIALS AND METHODS: A total of 480 maxillary and mandibular anterior teeth were studied. The varnish was applied to either the right or left side of the maxillary or mandibular anterior teeth on a random basis. For each experimental quadrant in each patient, the varnish was applied to the labial surfaces of incisors and canines, from the gingival surface of the bracket to the free gingival margin. White spot lesions were recorded on a standard pro forma before (T(0)) and approximately 6 months following varnish application (T(1)) by DIAGNOdent and direct visual inspection. RESULTS: The DIAGNOdent score at T(1) was increased significantly in the control maxillary lateral and mandibular central (P < 0.05), and lateral incisors (P < 0.01). The visual scores in experimental maxillary lateral incisors and mandibular canines were decreased significantly at T(1) (P < 0.05). The sidewise post-treatment (T(1)) comparisons of control and experimental teeth for visual scores revealed significant decreases for maxillary lateral incisors, maxillary canines and mandibular canines (P < 0.05). CONCLUSION: Application of resin-modified glass ionomer cement varnish had a favourable effect in the prevention of WSLs during comprehensive orthodontic treatment. PMID- 25843604 TI - Detection and quantification of proteins in clinical samples using high resolution mass spectrometry. AB - Quantitative proteomics has benefited from the recent development of mass spectrometers capable of high-resolution and accurate-mass (HR/AM) measurements. While targeted experiments are routinely performed on triple quadrupole instruments in selected reaction monitoring (SRM; often referred as multiple reaction monitoring, MRM) mode, the quadrupole-orbitrap mass spectrometers allow quantification in MS/MS mode, also known as parallel reaction monitoring (PRM). This technique is characterized by higher selectivity and better confidence in the assignment of the precursor and fragment ions, and thus translates into an improved analytical performance. More fundamentally, PRM introduces a change of the overall paradigm of targeted experiments, by the decoupling of the acquisition and data processing. They rely on two distinct steps, with a simplified acquisition method in conjunction with a flexible, iterative, post acquisition data processing. This account describes in detail the different steps of a PRM experiment, which include the design of the acquisition method, the confirmation of the identity of the analytes founded upon a full MS/MS fragmentation pattern, and the quantification based on the extraction of specific fragment ions (selected post-acquisition) using tight mass tolerance. The different types of PRM experiments, defined as large-scale screening or precise targeted quantification using calibrated internal standards, together with the considerations on the selection of experimental parameters are discussed. PMID- 25843605 TI - Fabrication and characterization of injectable hydrogels derived from decellularized skeletal and cardiac muscle. AB - Biomaterials, which can contain appropriate biomechanical and/or biochemical cues, are increasingly being investigated as potential scaffolds for tissue regeneration and/or repair for treating myocardial infarction, heart failure, and peripheral artery disease. Specifically, injectable hydrogels are touted for their minimally invasive delivery, ability to self-assemble in situ, and capacity to encourage host tissue regeneration. Here we present detailed methods for fabricating and characterizing decellularized injectable cardiac and skeletal muscle extracellular matrix (ECM) hydrogels. The ECM derived hydrogels have low cellular and DNA content, retain sulfated glycosaminoglycans and other extracellular matrix proteins such as collagen, gel at physiologic temperature and pH, and assume a nanofibrous architecture. These injectable hydrogels are amenable to minimally invasive, tissue specific biomaterial therapies for treating myocardial infarction and peripheral artery disease. PMID- 25843607 TI - A method for constructing vascularized muscle flap. AB - Abdominal wall reconstruction following extensive tissue loss is essential and can be achieved using autologous flaps. However, their use is limited due to their inadequate availability and due to post-operative donor site scarification. This work presents a step-by-step technique for fabrication of a vascularized muscle flap, to be applied in full-thickness abdominal wall defect reconstruction. Poly L-lactic acid/poly lactic-co-glycolic acid scaffolds, prepared using a salt leaching technique, were used as the supporting matrix in vitro for simultaneously seeded endothelial cells, fibroblasts and myoblasts. The cell-embedded graft was then implanted around femoral artery and vein vessels, which provided a central blood supply. Vascularization and perfusion were achieved by capillary sprouting from the main host vessel into the graft. A thick and vascularized tissue was formed within one week, and was then transferred as an autologous flap together with its main vessels, to a full-thickness abdominal wall defect. The flap remained viable after transfer and featured sufficient mechanical strength to support the abdominal viscera. Thus, this engineered muscle flap can be used as an alternative source for autologous flaps to reconstruct full-thickness abdominal wall defects. PMID- 25843606 TI - Long term perfusion system supporting adipogenesis. AB - Adipose tissue engineered models are needed to enhance our understanding of disease mechanisms and for soft tissue regenerative strategies. Perfusion systems generate more physiologically relevant and sustainable adipose tissue models, however adipocytes have unique properties that make culturing them in a perfusion environment challenging. In this paper we describe the methods involved in the development of two perfusion culture systems (2D and 3D) to test their applicability for long term in vitro adipogenic cultures. It was hypothesized that a silk protein biomaterial scaffold would provide a 3D framework, in combination with perfusion flow, to generate a more physiologically relevant sustainable adipose tissue engineered model than 2D cell culture. Consistent with other studies evaluating 2D and 3D culture systems for adipogenesis we found that both systems successfully model adipogenesis, however 3D culture systems were more robust, providing the mechanical structure required to contain the large, fragile adipocytes that were lost in 2D perfused culture systems. 3D perfusion also stimulated greater lipogenesis and lipolysis and resulted in decreased secretion of LDH compared to 2D perfusion. Regardless of culture configuration (2D or 3D) greater glycerol was secreted with the increased nutritional supply provided by perfusion of fresh media. These results are promising for adipose tissue engineering applications including long term cultures for studying disease mechanisms and regenerative approaches, where both acute (days to weeks) and chronic (weeks to months) cultivation are critical for useful insight. PMID- 25843608 TI - Automated image analysis programs for the quantification of microvascular network characteristics. AB - The majority of reports in which microvascular network properties are quantified rely on manual measurements, which are time consuming to collect and somewhat subjective. Despite some progress in creating automated image analysis techniques, the parameters measured by these methods are limited. For example, no automated system has yet been able to measure support cell recruitment, which is an important indicator of microvascular maturity. Microvessel alignment is another parameter that existing programs have not measured, despite a strong dependence of performance on alignment in some tissues. Here we present two image analysis programs, a semi-automated program that analyzes cross sections of microvascular networks and a fully automated program that analyzes images of whole mount preparations. Both programs quantify standard characteristics as well as support cell recruitment and microvascular network alignment, and were highly accurate in comparison to manual measurements for engineered tissues containing self-assembled microvessels. PMID- 25843610 TI - Evaluation of cognitive behaviour therapy for paediatric obsessive-compulsive disorder in the context of tic disorders. AB - BACKGROUND AND OBJECTIVES: Paediatric obsessive-compulsive disorder (OCD) and tic disorders (TD) often present together. However, there has been relatively little research on whether comorbid tic disorders influence response to cognitive behaviour therapy (CBT) for OCD. This study aimed to examine the outcomes of CBT for paediatric patients with OCD and a tic disorder compared to a matched group of children with OCD and no tics. Outcomes were compared post-treatment and at 3 or 6 month follow-up. METHODS: Participants were 29 young people with tic disorders and OCD (OCD + TD) and 29 young people with OCD without tic disorders (OCD-TD) who were matched according to age, gender and baseline OCD symptom severity. All participants received a course of CBT and outcomes were assessed using the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). RESULTS: OCD symptoms reduced over the course of CBT to an equivalent extent in the OCD + TD and OCD-TD groups. Response or remission rates did not differ significantly at either post-intervention or follow-up between those with OCD + TD and those with OCD-TD. For both groups, response rates were high - 72% of both groups were classified as responders post-intervention and, at follow-up, 81% of the OCD + TD group and 82% of the OCD no tics group responded. Those with OCD + TD responded in significantly fewer sessions than those with OCD without tics. LIMITATIONS: A number of potential confounding factors were not assessed and therefore could not be controlled for, such as other comorbidities and stability of medication. CONCLUSIONS: Paediatric patients with OCD and tic disorders respond equally well to standard CBT for OCD as compared to those with OCD and no tics. PMID- 25843611 TI - Cognitive Bias Modification for adolescents with substance use problems--Can serious games help? AB - BACKGROUND AND OBJECTIVES: Excessive use of psychoactive substances and resulting disorders are a major societal problem, and the most prevalent mental disorder in young men. Recent reviews have concluded that Cognitive Bias Modification (CBM) shows promise as an intervention method in this field. As adolescence is a critical formative period, successful early intervention may be key in preventing later substance use disorders that are difficult to treat. One issue with adolescents, however, is that they often lack the motivation to change their behavior, and to engage in multisession cognitive training programs. The upcoming use of serious games for health may provide a solution to this motivational challenge. METHODS: As the use of game-elements in CBM is fairly new, there are very few published studies in this field. This review therefore focuses on currently available evidence from similar fields, such as cognitive training, as well as several ongoing CBM gamification projects, to illustrate the general principles. RESULTS: A number of steps in the gamification process are identified, starting with the original, evidence-based CBM task, towards full integration in a game. While more data is needed, some steps seem better suited for CBM gamification than others. Based on the current evidence, several recommendations are made. LIMITATIONS: As the field is still in its infancy, further research is needed before firm conclusions can be drawn. CONCLUSIONS: Gamified CBM may be a promising way to reach at risk youth, but the term "game" should be used with caution. Suggestions are made for future research. PMID- 25843609 TI - Infected animal models for tissue engineering. AB - Infection is one of the most common complications associated with medical interventions and implants. As tissue engineering strategies to replace missing or damaged tissue advance, the focus on prevention and treatment of concomitant infection has also begun to emerge as an important area of research. Because the in vivo environment is a complex interaction between host tissue, implanted materials, and native immune system that cannot be replicated in vitro, animal models of infection are integral in evaluating the safety and efficacy of experimental treatments for infection. In this review, considerations for selecting an animal model, established models of infection, and areas that require further model development are discussed with regard to cutaneous, fascial, and orthopedic infections. PMID- 25843612 TI - Henneguya doneci (Myxosporea: Bivalvulida) in the gill filaments of Prussian carp Carassius gibelio (Bloch) from the upper Yellow River running through Inner Mongolia, China. AB - We examined 11 Prussian carp, Carassius gibelio (Bloch), from the upper Yellow River running through Inner Mongolia (Wuhai City) to record myxosporean species. Between 6 and 15 elongated cysts of Henneguya doneci were located at the basal part of the gill filaments of 3 carp (27.3%); no more myxosporean plasmodia were found in other organs. Although the morphology and morphometric values of the spores (average measurements of 14 spores in um: 11.4 long by 9.2 wide with 7.5 in thickness; 2 polar capsules, equal, 5.5 long by 3.2 wide; and a bifurcated caudal process, 51.6 long) with an evident intercapsular appendix were basically coincident with the species, the dimensions of the spore bodies were marginally larger, and the length of the caudal processes was distinctly longer than previously reported values for H. doneci (44.2-59.2 um vs. 26.8-42.6 um, respectively). Genetic analysis of the 18S ribosomal RNA gene (rDNA) found few nucleotide substitutions when compared with 3 deposited sequences of H. doneci collected around the Yangtze River (Sichuan and Hubei Provinces), China, indicating that the uniqueness of some of the morphological features exhibited by the present Wuhai isolate should be ascribed to intraspecific variation. PMID- 25843613 TI - Metachronous colorectal cancers result from missed lesions and non-compliance with surveillance. AB - BACKGROUND: Several studies examined the rate of colorectal cancer (CRC) developed during colonoscopy surveillance after CRC resection (ie, metachronous CRC [mCRC]), yet the underlying etiology is unclear. OBJECTIVE: To examine the rate and likely etiology of mCRCs. DESIGN: Population-based, multicenter study. Review of clinical and histopathologic records, including data of the national pathology database and The Netherlands Cancer Registry. SETTING: National cancer databases reviewed at 3 hospitals in South-Limburg, The Netherlands. PATIENTS: Total CRC population diagnosed in South-Limburg from January 2001 to December 2010. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: We defined an mCRC as a second primary CRC, diagnosed >6 months after the primary CRC. By using a modified algorithm to ascribe likely etiology, we classified the mCRCs into cancers caused by non-compliance with surveillance recommendations, inadequate examination, incomplete resection of precursor lesions (CRC in same segment as previous advanced adenoma), missed lesions, or newly developed cancers. RESULTS: We included a total of 5157 patients with CRC, of whom 93 (1.8%) had mCRCs, which were diagnosed on an average of 81 months (range 7-356 months) after the initial CRC diagnosis. Of all mCRCs, 43.0% were attributable to non-compliance with surveillance advice, 43.0% to missed lesions, 5.4% to incompletely resected lesions, 5.4% to newly developed cancers, and 3.2% to inadequate examination. Age adjusted and sex-adjusted logistic regression analyses showed that mCRCs were significantly smaller in size (odds ratio [OR] 0.8; 95% confidence interval [CI], 0.7-0.9) and more often poorly differentiated (OR 1.7; 95% CI, 1.0-2.8) than were solitary CRCs. LIMITATIONS: Retrospective evaluation of clinical data. CONCLUSION: In this study, 1.8% of all patients with CRC developed mCRCs, and the vast majority were attributable to missed lesions or non-compliance with surveillance advice. Our findings underscore the importance of high-quality colonoscopy to maximize the benefit of post-CRC surveillance. PMID- 25843614 TI - Nonneoplastic polypectomy during screening colonoscopy: the impact on polyp detection rate, adenoma detection rate, and overall cost. AB - BACKGROUND: The frequency of nonneoplastic polypectomy (NNP) and its impact on the polyp detection rate (PDR) is unknown. The correlation between NNP and adenoma detection rate (ADR) and its impact on the cost of colonoscopy has not been investigated. OBJECTIVE: To determine the rate of NNP in screening colonoscopy, the impact of NNP on the PDR, and the correlation of NNP with ADR. The increased cost of NNP during screening colonoscopy also was calculated. DESIGN: We reviewed all screening colonoscopies. PDR and ADR were calculated. We then calculated a nonneoplastic polyp detection rate (patients with >=1 nonneoplastic polyp). SETTING: Tertiary-care referral center. PATIENTS: Patients who underwent screening colonoscopies from 2010 to 2011. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: ADR, PDR, NNP rate. RESULTS: A total of 1797 colonoscopies were reviewed. Mean (+/-standard deviation) PDR was 47.7%+/ 12.0%, and mean ADR was 27.3%+/-6.9%. The overall NNP rate was 10.4%+/-7.1%, with a range of 2.4% to 28.4%. Among all polypectomies (n=2061), 276 were for nonneoplastic polyps (13.4%). Endoscopists with a higher rate of nonneoplastic polyp detection were more likely to detect an adenoma (odds ratio 1.58; 95% confidence interval, 1.1-1.2). With one outlier excluded, there was a strong correlation between ADR and NNP (r=0.825; P<.001). The increased cost of removal of nonneoplastic polyps was $32,963. LIMITATIONS: Retrospective study. CONCLUSION: There is a strong correlation between adenoma detection and nonneoplastic polyp detection. The etiology is unclear, but nonneoplastic polyp detection rate may inflate the PDR for some endoscopists. NNP also adds an increased cost. Increasing the awareness of endoscopic appearances through advanced imaging techniques of normal versus neoplastic tissue may be an area to improve cost containment in screening colonoscopy. PMID- 25843615 TI - EUS-guided drainage of hepatic abscess and infected biloma using short and long metal stents (with videos). AB - BACKGROUND: Currently, few reports exist on EUS-guided hepatic abscess drainage (EUS-HAD) and EUS-guided biloma drainage (EUS-BLD) using a metal stent. OBJECTIVE: We evaluated the technical success rate and efficacy of EUS-HAD and EUS-BLD for patients with hepatic abscess (HA) and infected biloma. DESIGN: Retrospective case series. SETTING: Single tertiary referral medical center. PATIENTS: We evaluated 7 HA and 6 infected biloma patients who were treated between August 2013 and August 2014 at Tokyo Medical University Hospital. INTERVENTIONS: EUS-HAD or EUS-BLD using a short (length, 2 or 3 cm) or long (length, 6 or 8 cm) self-expandable fully covered metal stent. MAIN OUTCOME MEASUREMENTS: Technical success, clinical success, and adverse event. RESULTS: The overall technical success rate was 100% in both EUS-HAD and EUS-BLD. The clinical success rates of EUS-HAD and EUS-BLD at the first session were 71.4% and 83.3%, respectively. Direct endoscopic necrosectomy was required in 1 case each of HA and infected biloma. The final clinical success rate was 100%. There were no procedure-related adverse events or cases of recurrence during the follow-up period (median, 83.5 days; range, 24-396 days). LIMITATIONS: Small sample size and no control group. CONCLUSIONS: EUS-HAD and EUS-BLD using a metal stent can be performed safely and effectively for HA and infected biloma. PMID- 25843616 TI - Clip artifact after closure of large colorectal EMR sites: incidence and recognition. AB - BACKGROUND: Clip closure of large colorectal EMR defects sometimes results in bumpy scars that are normal on biopsy. We refer to these as "clip artifact." If unrecognized, clip artifact can be mistaken for residual polyp, leading to thermal treatment and potential adverse events. OBJECTIVE: To describe the incidence of and define predictors of clip artifact. DESIGN: Review of photographs of scars from consecutive clipped EMR defects. SETTING: University outpatient endoscopy center. PATIENTS: A total of 284 consecutive patients with clip closure of defects after EMR of lesions 20 mm or larger and follow-up colonoscopy. INTERVENTIONS: EMR, clip closure. MAIN OUTCOME MEASUREMENTS: Incidence of clip artifact. RESULTS: A total of 303 large polyps met the inclusion criteria. On review of photographs, 96 scars (31.7%) had clip artifact. Clip artifact was associated with increased numbers of clips placed (odds ratio for each additional clip, 1.2; 95% confidence interval, 1.02-1.38) but not polyp histology, size, or location. The rate of residual polyp by histology was 8.9% (27/303), with 21 of 27 scars with residual polyp evident endoscopically. The rate of residual polyp evident only by histology in scars with clip artifact (3/93; 3.2%) was not different from the rate in scars without clip artifact (3/189; 1.6%). LIMITATIONS: Retrospective design. Sites closed primarily with 1 type of clip. Single-operator assessment of endoscopic photographs. CONCLUSION: Clip artifact occurred in the scars of approximately one-third of large clipped EMR sites and increased with number of clips placed. Clip artifact could be consistently distinguished from residual polyp by its endoscopic appearance. PMID- 25843617 TI - Findings of diagnostic colonoscopy in young adults versus findings of screening colonoscopy in patients aged 50 to 54 years: a comparative study stratified by symptom category. AB - BACKGROUND: The threshold for diagnostic colonoscopy in symptomatic patients aged <50 years remains controversial. Previous studies on the prevalence of neoplasia or other serious pathology in young patients mostly have been uncontrolled, providing only limited data on the risk associated with specific symptoms. OBJECTIVE: To compare colonoscopy findings in patients aged <50 years who have various symptoms (diagnostic cohort) against those of concurrent patients aged 50 to 54 years who are asymptomatic (screening cohort). DESIGN: Retrospective controlled cohort study. SETTING: Teaching hospital. PATIENTS: Symptomatic patients aged between 18 and 49 years and asymptomatic patients aged between 50 and 54 years. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Prevalence of advanced neoplasia. RESULTS: During the study period, 1638 patients underwent colonoscopy in the screening cohort (mean [+/- standard deviation{SD}] age 51.7 +/- 1.4 years) and 1266 underwent colonoscopy in the diagnostic cohort (40.4 +/- 8.0 years). Despite the age difference, the prevalence of advanced neoplasia in patients with rectal bleeding was comparable with that in the screening controls: 28 of 472 (5.9%) versus 113 of 1638 patients (6.9%) (P = .459). Furthermore, 10 patients (2.1%) with rectal bleeding were newly diagnosed with inflammatory bowel disease. In contrast, other symptoms that commonly lead to colonoscopy, such as abdominal pain, changes in bowel habits, and weight loss, were associated with much lower risks for neoplasia. As a result, the overall prevalences of neoplasia and advanced neoplasia were significantly higher in the screening cohort than in the diagnostic cohort: 467 of 1638 patients (28.5%) versus 179 of 1266 patients (14.1%), and 113 patients (6.9%) versus 48 patients (3.8%), respectively (both P < .001). LIMITATIONS: No data on duration of symptoms; discrepant sex ratios between cohorts. CONCLUSION: The threshold for diagnostic colonoscopy in symptomatic young adults should be individualized for each symptom category. Rectal bleeding warrants colonoscopy to detect advanced neoplasia or inflammatory bowel disease in most young patients, especially those aged 40 to 49 years, whereas non-bleeding symptoms, including some traditionally regarded as "alarm" symptoms, were associated with a much lower risk for neoplasia compared with the risk in screening patients aged 50 to 54 years. PMID- 25843618 TI - Innate immune evasion by filoviruses. AB - Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms include suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress responses or allow the virus to replicate in the face of such responses. A greater understanding of these innate immune evasion mechanisms may suggest novel therapeutic approaches for these deadly pathogens. PMID- 25843619 TI - Failed replications, contributing factors and careful interpretations: Commentary on Boekel et al., 2015. PMID- 25843620 TI - Evolving models of comprehensive geriatric assessment. PMID- 25843622 TI - Comparison of fine needle aspiration biopsy and paraffin embedded tissue sections for measuring AgNOR proteins. AB - Paraffin embedded tissue sections and fine needle aspiration biopsy (FNAB) are important methods for diagnosis. We compared thyroid tissue obtained by FNAB to paraffin embedded sections to determine whether there were differences in detection of the amounts of argyrophilic nucleolar organizing region (AgNOR) proteins. Twenty-two patients with papillary thyroid carcinoma were included in the study. Slides were prepared with both FNAB tissue and 3 MUm sections of paraffin embedded tissue, and stained for AgNOR. One hundred nuclei per individual were evaluated; total AgNOR number/nucleus (TAn/TNn) and total AgNOR area/nuclear area (TAa/TNa) of individual cells were determined. Mean TAn/TNn and TAa/TNa values were 4.800 +/- 1.118 and 13.382 +/- 2.612, respectively, for FNAB samples; corresponding values were 2.406 +/- 0.649 and 8.49 +/- 0.893, respectively, for paraffin embedded sections. The differences between FNAB materials and paraffin embedded tissue sections were significant for the mean TAn/TNn and TAa/TNa values. Significant differences in the amounts of AgNOR protein detected were found between FNAB and paraffin embedded tissue sections. PMID- 25843621 TI - Critical decisions for older people with advanced dementia: a prospective study in long-term institutions and district home care. AB - OBJECTIVE: To describe and compare the decisions critical for survival or quality of life [critical decisions (CDs)] made for patients with advanced dementia in nursing homes (NHs) and home care (HC) services. DESIGN: Prospective cohort study with a follow-up of 6 months. SETTING: Lombardy Region (NHs) and Reggio-Emilia and Modena Districts (HC), Italy. PARTICIPANTS: Patients (496 total; 315 in NHs and 181 in HC) with advanced dementia (Functional Assessment Staging Tool score >= 7) and expected survival >= 2 weeks. MEASUREMENTS: At baseline, the patients' demographic data, date of admission and of dementia diagnosis, type of dementia, main comorbidities, presence of pressure sores, ongoing treatments, and current prescriptions were abstracted from clinical records. At baseline and every 15 days thereafter, information regarding the patients' general condition and CDs (deemed critical by the doctor or team) was collected by an interview with the doctor. For each CD, the physician reported the problem that led to the decision, that was eventually made, the purpose of the decision, whether the decision had been discussed with and/or communicated to the family, who made the final decision, whether the decision was maintained after 1 week, whether it corresponded to what the doctor would have judged appropriate, and the expected survival of the patient (<= 15 days). RESULTS: For 267 of the 496 patients (53.8%; 60.3% in NHs and 42.5% at home), 644 CDs were made; for 95 patients, more than 1 CD was made. The problems that led to a CD were mainly infections (respiratory tract and other infections; 46.6%, 300/644 CDs); nutritional/hydration problems (20.6%; 133 CDs); and the worsening of a pre existing disease (9.3%; 60 CDs). The most frequent type of decision concerned the prescription of antibiotics (overall 41.1%, 265/644; among NH patients 44.6%, 218/488; among HC patients, 30.2%, 47/156). The decision to hospitalize the patient was more frequently reported for HC than NH patients (25.5% vs 3.1%). The most frequent purposes of the CDs in both settings were reducing symptoms or suffering (more so in NHs; 81.1% vs 57.0% in HC) and prolonging survival (NH 27.5%; HC 23.1%; multiple purposes were possible). For 26 decisions (3.8%), the purpose was to ease death or not to prolong life. CONCLUSIONS: Decisions critical for the survival or quality of life of patients with advanced dementia were made for approximately one-half of the patients during a 6-month time frame, and such decisions were made more frequently in NHs than in HC. HC patients were more frequently hospitalized, and a sizeable minority of these patients were treated with the goal of prolonging survival. Italian patients with advanced dementia may benefit from the implementation of palliative care principles, and HC patients may benefit from the implementation of measures to avoid hospitalizing patients near the end of life. PMID- 25843624 TI - Phylogenetic and stress-responsive expression analysis of 20 WRKY genes in Populus simonii * Populus nigra. AB - WRKY transcription factors play important roles in regulating biotic and abiotic stress responses in plants. Although a plethora of studies have revealed the functions and mechanisms of some WRKYs in various plants, the studies of WRKYs in woody plants especially tree species under different abiotic and biotic stress conditions are still not well characterized. In this study, we selected 20 Populus simonii*Populus nigra WRKY genes based on our previous transcriptome study, and characterized these genes by phylogenetic analysis to investigate their evolutionary relations, then studied their expression patterns under NaCl, NaHCO3, PEG6000, CdCl2 and Alternaria alternata (Fr.) Keissl treatments that mimic the salt, alkalinity, drought, heavy metal and fungal infection conditions. The phylogenetic analysis showed that these 20 genes can be divided into five clades (Groups I, IIa, IIb, IIc and III) and all of their WRKY domains are conserved except for an N-terminal single amino acid mutation in PsnWRKY8. Before conducting quantitative real time PCR calculation, we evaluated five candidate reference genes under different stress treatments, and chose At4g33380-like as the reference gene for salt stress, Actin for alkalinity stress, UBQ for drought stress, TUA for heavy metal stress, and 18S rRNA for pathogen infection stress. The final qRT-PCR analysis indicated that 20/20, 20/20, and 15/20 PsnWRKYs were downregulated under salt, alkali and drought stresses, and 14/20 and 19/20 PsnWRKYs were upregulated under heavy metal and pathogen stresses. Members from the same clade tended to present similar expression patterns. In addition, we observed noticeable changes in the expression of PsnWRKY11 (increased by 41 times) and PsnWRKY20 (increased by 141 times) under pathogen infection condition, implying that these two genes are potentially important for the disease resistance of P. simonii * P. nigra. PMID- 25843623 TI - ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. AB - Excess dormant origins bound by the minichromosome maintenance (MCM) replicative helicase complex play a critical role in preventing replication stress, chromosome instability, and tumorigenesis. In response to DNA damage, replicating cells must coordinate DNA repair and dormant origin firing to ensure complete and timely replication of the genome; how cells regulate this process remains elusive. Herein, we identify a member of the Fanconi anemia (FA) DNA repair pathway, FANCI, as a key effector of dormant origin firing in response to replication stress. Cells lacking FANCI have reduced number of origins, increased inter-origin distances, and slowed proliferation rates. Intriguingly, ATR mediated FANCI phosphorylation inhibits dormant origin firing while promoting replication fork restart/DNA repair. Using super-resolution microscopy, we show that FANCI co-localizes with MCM-bound chromatin in response to replication stress. These data reveal a unique role for FANCI as a modulator of dormant origin firing and link timely genome replication to DNA repair. PMID- 25843625 TI - Association of UBASH3A gene polymorphisms and systemic lupus erythematosus in a Chinese population. AB - Recent evidence has demonstrated that UBASH3A gene was associated with multiple autoimmune diseases. The aim of this study was to explore the association between UBASH3A gene single-nucleotide polymorphisms (SNPs) and systemic lupus erythematosus (SLE) in a Chinese Han population. Four UBASH3A polymorphisms (rs11203203, rs3788013, rs2277798, and rs1893592) were genotyped using the Fluidigm 192.24 Dynamic ArrayTM Integrated Fluidic Circuit (IFC). Data were analyzed by SPSS 11.5 software. A total of 792 SLE patients and 777 healthy controls were included in this study. The CC genotype and C allele of rs3788013 polymorphism were more frequent in the patient group than in controls (OR=1.583, 95% CI=1.095-2.287; OR=1.258, 95% CI=1.083-1.461, respectively). We also found a statistical significance under the recessive model (OR=1.298, 95% CI=1.049-1.607, p=0.017). The frequency of variant genotype AC of rs3788013 was associated with the phenotype of vasculitis (p=0.012). A statistically significant association was observed between UBASH3A rs1893592 C allele and skin rash, oral ulcer and arthritis (p<0.05). Moreover, we found that the genotype distribution of rs2277798 was significantly associated with hematuria in the SLE patients (p=0.003). However, UBASH3A rs11203203, rs2277798, and rs1893592 polymorphisms were not associated with the risk of SLE (p>0.05). The findings suggest that UBASH3A gene might contribute to SLE susceptibility and influence the clinical phenotype of the disease. Further studies are necessary to elucidate the exact role of UBASH3A gene in the pathogenesis of SLE. PMID- 25843626 TI - Oncolytic measles virus as a novel therapy for malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are devastating soft tissue sarcomas that can arise sporadically or in association with neurofibromatosis type I, have a poor prognosis, and have limited treatment options. Oncolytic measles virus therapy has been demonstrated to have significant antitumor properties in a number of different cancers, but the oncolytic potential of a MV Edmonston (MVEdm) vaccine strain engineered to express the human sodium iodide symporter (MV-NIS) on MPNST has not previously been evaluated. MPNST cell lines were found to highly express CD46, a cellular receptor required for measles viral entry, on their cell surface. After in vitro MV-NIS infection, MPNST cell lines showed significant cytopathic effect (CPE), while normal Schwann cells were less susceptible to CPE. Virus localization and distribution could be monitored by imaging of I-125 uptake. Local administration of MV-NIS into MPNST-derived tumors resulted in significant regression of tumor and improved survival. These results demonstrate feasibility of oncolytic measles virus therapy for MPNST patients and the possibility of a novel treatment for patients with NF1 tumors. PMID- 25843627 TI - Molecular cloning, characterization and expression analysis of the protein arginine N-methyltransferase 1 gene (As-PRMT1) from Artemia sinica. AB - Protein arginine N-methyltransferase 1 (PRMT1) is an important epigenetic regulation factor in eukaryotic genomes. PRMT1 is involved in histone arginine loci methylation modification, changes in eukaryotic genomes' chromatin structure, and gene expression regulation. In the present paper, the full-length 1201-bp cDNA sequence of the PRMT1 homolog of Artemia sinica (As-PRMT1) was cloned for the first time. The putative As-PRMT1 protein comprises 346 amino acids with a SAM domain and a PRMT5 domain. Multiple sequence alignments revealed that the putative sequence of As-PRMT1 protein was relatively conserved across species, especially in the SAM domain. As-PRMT1 is widely expressed during embryo development of A. sinica. This is followed by a dramatic upregulation after diapause termination and then downregulation from the nauplius stage. Furthermore, As-PRMT1 transcripts are highly upregulated under conditions of high salinity and low temperature stress. These findings suggested that As-PRMT1 is a stress-related factor that might promote or inhibit the expression of certain genes, play a critical role in embryonic development and in resistance to low temperature and high salinity stress. PMID- 25843628 TI - Systematic discovery of Xist RNA binding proteins. AB - Noncoding RNAs (ncRNAs) function with associated proteins to effect complex structural and regulatory outcomes. To reveal the composition and dynamics of specific noncoding RNA-protein complexes (RNPs) in vivo, we developed comprehensive identification of RNA binding proteins by mass spectrometry (ChIRP MS). ChIRP-MS analysis of four ncRNAs captures key protein interactors, including a U1-specific link to the 3' RNA processing machinery. Xist, an essential lncRNA for X chromosome inactivation (XCI), interacts with 81 proteins from chromatin modification, nuclear matrix, and RNA remodeling pathways. The Xist RNA-protein particle assembles in two steps coupled with the transition from pluripotency to differentiation. Specific interactors include HnrnpK, which participates in Xist mediated gene silencing and histone modifications but not Xist localization, and Drosophila Split ends homolog Spen, which interacts via the A-repeat domain of Xist and is required for gene silencing. Thus, Xist lncRNA engages with proteins in a modular and developmentally controlled manner to coordinate chromatin spreading and silencing. PMID- 25843629 TI - The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. AB - Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to overexpress either the full-length murine B-Raf pseudogene Braf-rs1 or its pseudo "CDS" or "3' UTR" develop an aggressive malignancy resembling human diffuse large B cell lymphoma. We show that Braf-rs1 and its human ortholog, BRAFP1, elicit their oncogenic activity, at least in part, as competitive endogenous RNAs (ceRNAs) that elevate BRAF expression and MAPK activation in vitro and in vivo. Notably, we find that transcriptional or genomic aberrations of BRAFP1 occur frequently in multiple human cancers, including B cell lymphomas. Our engineered mouse models demonstrate the oncogenic potential of pseudogenes and indicate that ceRNA-mediated microRNA sequestration may contribute to the development of cancer. PMID- 25843631 TI - [Lipoidic necrobiosis]. PMID- 25843630 TI - Deconvolving the recognition of DNA shape from sequence. AB - Protein-DNA binding is mediated by the recognition of the chemical signatures of the DNA bases and the 3D shape of the DNA molecule. Because DNA shape is a consequence of sequence, it is difficult to dissociate these modes of recognition. Here, we tease them apart in the context of Hox-DNA binding by mutating residues that, in a co-crystal structure, only recognize DNA shape. Complexes made with these mutants lose the preference to bind sequences with specific DNA shape features. Introducing shape-recognizing residues from one Hox protein to another swapped binding specificities in vitro and gene regulation in vivo. Statistical machine learning revealed that the accuracy of binding specificity predictions improves by adding shape features to a model that only depends on sequence, and feature selection identified shape features important for recognition. Thus, shape readout is a direct and independent component of binding site selection by Hox proteins. PMID- 25843632 TI - [Beyond "data sharing"]. PMID- 25843633 TI - [Leukocytoclastic vasculitis]. PMID- 25843634 TI - [Right heart failure after pacemaker implantation]. AB - BACKGROUND AND OBJECTIVE: Severe tricuspid regurgitation (TR) secondary to interference pacemaker (PM) cable is a rare cause of progressive right heart failure (HF), which can worsen patient outcomes. MATERIAL AND METHODS: We present 3 clinical cases of right HF secondary to TR after PM implantation. RESULTS: In these patients the clinic is right HF, which can appear early, as in our second patient, or after years of implementation of the PM, as in the first and third patients. The diagnosis is confirmed by echocardiography, the most accurate 3D, followed by transesophageal. The 2D transthoracic can not detect it, because it has low sensitivity for TR associated with PM. Medical treatment is always the first choice, since any other procedure carries significant morbidity and mortality. CONCLUSIONS: Probably this is a condition that we will diagnose with increasing frequency, because there are more and more patients with devices and, at the same time, the diagnostic tools are improving. PMID- 25843635 TI - Alveolar macrophages and type I IFN in airway homeostasis and immunity. AB - Globally, respiratory infections cause more than 4 million deaths per year, with influenza and tuberculosis (TB) in particular being major causes of mortality and morbidity. Although immune cell activation is critical for killing respiratory pathogens, this response must be tightly regulated to effectively control and eliminate invading microorganisms while minimizing immunopathology and maintaining pulmonary function. The distinct microenvironment of the lung is constantly patrolled by alveolar macrophages (Mphi), which are essential for tissue homeostasis, early pathogen recognition, initiation of the local immune response, and resolution of inflammation. Here, we focus on recent advances that have provided insight into the relation between pulmonary Mphi, type I interferon (IFN) signaling, and the delicate balance between protective and pathological immune responses in the lung. PMID- 25843636 TI - [Is nocturnal polyuria more frequent among patients with Parkinson's disease?]. AB - OBJECTIVE: Nocturia is a frequent complaint in the population of idiopathic Parkinson's disease patients (IPD). The consequences of nocturia in the IPD population are at high importance as these patients have motor problems and therefore a risk of nocturnal fall. The aim of the study was to determine the mechanism of nocturia in patients with MPI, by determining the prevalence of nocturnal polyuria (NP) in this population. METHOD: A prospective study by bladder diary was conducted on 70 consecutive IPD patients consulting for regular neurological follow-up at a non-severe stage. Nocturia was defined as 1 or more awakenings to urinate. Two definitions of NP were used: nocturnal diuresis 33% or higher of the total diuresis (NUV33), which is the ICS (International Continence Society) definition, and nocturnal diuresis 90 mL/h or higher (NUP90). RESULTS: The mean patient age was 71 years (45-86, sex ratio 33/30). On average, patients were diagnosed for IPD 6.76 years earlier. The prevalence of NP was 64.5% according to NUV33 definition, and 17.7% according to NUP90 definition. Among patients with nocturia, the prevalence of NP was 66% (NUV33) and 21.5% (NUP90). No association was observed between disease duration of the IPD and the prevalence of nocturia and NP. Patients 70 years and older were more likely to have NP as defined by NUV33 than those less than 70 years (72.7% versus 55.17%, P=0.015). Men had more frequently nocturia (33.3% versus 20.7%, P=0.027). CONCLUSIONS: The prevalence of NP and nocturia was analyzed in patients with IPD at a non-severe stage. This prevalence was not higher than in the general population of the same age. The mechanism of nocturia in patients with IPD is not unambiguous and therefore requires to be explored by a bladder diary. PMID- 25843637 TI - Potential of yeast secretory vesicles in biodelivery systems. AB - Membranous vesicular organelles (MVOs), such as secretory vesicles and exosomes, perform a variety of biological functions ranging from secretion to cellular communication in eukaryotic cells. Exosomes, particularly those of mammalian cells, have been widely studied as potential carriers in human therapeutic applications. However, no study has yet demonstrated the use of yeast secretory vesicles for such applications. Therefore, we explore here the current state of knowledge on yeast secretory vesicles and their potential use in therapeutic delivery systems. We focus on the characteristics shared by exosomes and yeast secretory vesicles to provide insights into the use of the latter as delivery vehicles. From this perspective, we speculate on the potential application of post-Golgi vesicles (PGVs) in the biomedical field. PMID- 25843638 TI - The preclinical development of biosimilars: introduction. PMID- 25843639 TI - 'Turn On/Off' fluorescence probe for the screening of unactivated Bruton's tyrosine kinase. AB - BTK has emerged as a promising target for treating B-cell malignancies and autoimmune diseases, and there has been a growing demand to identify selective BTK inhibitors efficiently. In this Letter, we have designed and synthesized a new fluorescent probe to screen compounds that preferentially bind to an unactivated state of BTK (BTK [U]). The fluorescence of the probe was turned on in the presence of BTK [U], and quenched by the addition of compounds which preferentially bind to BTK [U]. This unique fluorescent probe was successfully applied to the screening of a kinase focused compound library. The results suggest that this new method is a simple and easy-to-perform assay to screen inhibitors of BTK [U]. PMID- 25843640 TI - Endovascular Extraction of Caval Tumor Thrombus to Facilitate Minimally Invasive Cytoreductive Nephrectomy for Metastatic Kidney Cancer. PMID- 25843641 TI - Essential role of transient receptor potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. AB - BACKGROUND: Acute exposure of part of the skin to cold stimuli can evoke urinary urgency, a phenomenon termed acute cold-induced urgency (ACIU). Despite its high prevalence, particularly in patients with overactive bladder, little is known about the mechanisms that induce ACIU. OBJECTIVE: To develop an animal model of ACIU and test the involvement of cold-activated ion channels transient receptor potential (TRP) M8 and TRPA1. DESIGN, SETTING, AND PARTICIPANTS: Intravesical pressure and micturition were monitored in female mice (wild-type C57BL/6J, Trpa1(-/-), Trpm8(+/+), and Trpm8(-/-)) and Sprague Dawley rats. INTERVENTIONS: An intravesical catheter was implanted. Localized cooling of the skin was achieved using a stream of air or topical acetone. The TRPM8 antagonist (N-(3 aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide (AMTB) or vehicle was injected intraperitoneally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of bladder contractions and voids in response to sensory stimuli were compared using the Mann-Whitney or Kruskal-Wallis test. RESULTS AND LIMITATIONS: Brief, innocuously cold stimuli applied to different parts of the skin evoked rapid bladder contractions and voids in anesthetized mice and rats. These responses were strongly attenuated in Trpm8(-/-) mice and in rats treated with AMTB. As rodent bladder physiology differs from that of humans, it is difficult to directly extrapolate our findings to human patients. CONCLUSIONS: Our findings indicate that ACIU is an evolutionarily conserved reflex rather than subconscious conditioning, and provide a useful in vivo model for further investigation of the underlying mechanisms. Pharmacological inhibition of TRPM8 may be useful for treating ACIU symptoms in patients. PATIENT SUMMARY: Brief cold stimuli applied to the skin can evoke a sudden desire to urinate, which can be highly bothersome in patients with overactive bladder. We developed an animal model to study this phenomenon, and found that it depends on a specific molecular cold sensor, transient receptor potential M8 (TRPM8). Pharmacological inhibition of TRPM8 may alleviate acute cold-induced urinary urgency in humans. PMID- 25843642 TI - Competencies for master and doctoral students in epidemiology: what is important, what is unimportant, and where is there room for improvement? AB - In 2008, members of the American College of Epidemiology's Education Committee began work on a project to facilitate discussion on identifying domains and core competencies for epidemiologic training at the master and doctoral levels. Two online surveys were created and participants (N = 183; n = 147 [established epidemiologists] and n = 36 [recent graduates]) rated the importance of 19 domains and 66 competencies. A total of 17 competencies were viewed as important or very important for individuals earning various master- or doctoral-level degrees in epidemiology, whereas eight competencies were reported as being unimportant for all individuals earning graduate degrees in epidemiology. Twenty additional competencies were viewed as important or very important only for individuals receiving doctoral training. In addition, recent master-level graduates identified nine domains in which they felt less prepared, and recent doctoral-level graduates identified two such domains. Additional research is warranted to ensure that all epidemiologists receive sufficient training in identified areas. PMID- 25843644 TI - Could tuning of the inhibitory tone involve graded changes in neuronal chloride transport? AB - Hyperpolarizing synaptic inhibition through GABAA and glycine receptors depends on the presence of the neuronal cation-chloride-cotransporter protein, KCC2. Several transcriptional and post-transcriptional mechanisms have been shown to regulate KCC2 and thereby influence the polarity and efficacy of inhibitory synaptic transmission. It is unclear however whether regulation of KCC2 enables the transporter to attain different levels of activity thus allowing a neuron to modulate the strength of inhibitory synaptic transmission to its changing requirements. We therefore investigated whether phosphorylation can allow KCC2 to achieve distinct levels of [Cl(-)]i in neurons. We generated a variety of KCC2 alanine dephosphorylation mimics and used NH4(+)-induced pHi shifts in cultured hippocampal neurons to quantify the rate of KCC2 transport activity exhibited by these mutants. To explore the relationship between KCC2 transport and GABAA receptor-mediated current amplitudes we performed gramicidine perforated-patch recordings. The correlation between EGABA and NH4(+)-induced pHi shifts enabled an estimate of the range of chloride extrusion possible by kinase/phosphatase regulation of KCC2. Our results demonstrate that KCC2 transport can vary considerably in magnitude depending on the combination of alanine mutations present on the protein. Transport can be enhanced to sufficiently high levels that hyperpolarizing GABAA responses may be obtained even in neurons with an extremely negative resting membrane potential and at high extracellular K(+) concentrations. Our findings highlight the significant potential for regulating the inhibitory tone by KCC2-mediated chloride extrusion and suggest that cellular signaling pathways may act combinatorially to alter KCC2 phosphorylation/dephosphorylation and thereby tune the strength of synaptic inhibition. PMID- 25843643 TI - Sex differences in GABA(B)R-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex. AB - The medial prefrontal cortex (mPFC) has been implicated in multiple disorders characterized by clear sex differences, including schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, and drug addiction. These sex differences likely represent underlying differences in connectivity and/or the balance of neuronal excitability within the mPFC. Recently, we demonstrated that signaling via the metabotropic gamma-aminobutyric acid receptor (GABABR) and G protein-gated inwardly-rectifying K(+) (GIRK/Kir3) channels modulates the excitability of the key output neurons of the mPFC, the layer 5/6 pyramidal neurons. Here, we report a sex difference in the GABABR-GIRK signaling pathway in these neurons. Specifically, GABABR-dependent GIRK currents recorded in the prelimbic region of the mPFC were larger in adolescent male mice than in female counterparts. Interestingly, this sex difference was not observed in layer 5/6 pyramidal neurons of the adjacent infralimbic cortex, nor was it seen in young adult mice. The sex difference in GABABR-GIRK signaling is not attributable to different expression levels of signaling pathway components, but rather to a phosphorylation-dependent trafficking mechanism. Thus, sex differences related to some diseases associated with altered mPFC function may be explained in part by sex differences in GIRK-dependent signaling in mPFC pyramidal neurons. PMID- 25843645 TI - Polarized stakeholders and institutional vulnerabilities: the enduring politics of the Patient Protection and Affordable Care Act. AB - PURPOSE: We conducted a comparative study of how state-level political stakeholders affected the implementation of 3 major reforms within the Patient Protection and Affordable Care Act (ACA). Our goal was to analyze the effects of policy legacy, institutional fragmentation, and public sentiments on state obstruction of the reform. METHODS: We gathered quantitative and qualitative evidence to generate cross-case comparisons of state implementation of 3 reform streams within the ACA: health insurance exchanges, Medicaid expansion, and regulatory reform. Our sources included secondary literature, analysis of official decisions, and background interviews with experts and public officials. FINDINGS: We found that state-level opponents of the ACA were most likely to be successful in challenging reforms with few preexisting policy legacies, high institutional fragmentation, and negative public sentiments. Reforms that built on existing state legislation, avoided state veto points or offered lucrative fiscal incentives, and elicited less negative public reaction were less likely to be contested. IMPLICATIONS: Our findings point to the importance of institutional design for the role of political stakeholders in implementing reforms to improve the cost, quality, and availability of medical treatments. Although other research has found that political polarization has shaped early ACA outcomes, comparative analysis suggests political stakeholders have had the highest effect on reforms that were particularly vulnerable. PMID- 25843646 TI - Morphological analysis of the lip and nose following cleft lip repair with simultaneous partial primary rhinoplasty: A prospective study over 4 years. AB - INTRODUCTION: Facial clefts involve complex abnormalities. The therapy is elaborate, and a critical evaluation of therapeutic outcome is required. Our study analyzed the lip and nose deformities associated with unilateral clefts in a prospective longitudinal study. MATERIAL AND METHODS: A total of 33 patients with a cleft lip or cleft lip and alveolus (UCL) and 46 with a cleft lip and palate (UCLP) were treated using a similar concept. Standardized photographs were taken preoperatively (age 0.4-0.52 years) and again aged 4.04-4.59 years. Anthropometric analyses were performed and compared with age-matched normal values. RESULTS: Nostril width (UCL = 1.01, UCLP = 1.03) and nostril floor width (UCL = 1.02, UCLP = 1.04) were almost symmetric. Nasal tip angles were normalized by surgery. Upper labial height improved, but remained slightly reduced (-4% to 6%). Upper vermillion length was increased (15-17%), and vermillion width was reduced (-12% to -13%) postoperatively. A significantly flatter nostril axis inclination persisted, especially on the affected side (UCL: 37.5 degrees ; UCLP: 38.5 degrees ), when compared with normal values (53.8 degrees ). CONCLUSION: Most cleft irregularities were almost eliminated by therapy; however, the outcome is still not satisfactory for some parameters. The rehabilitation of patients with clefts remains a considerable surgical challenge. Facial anthropometric assessment must play an important role in order to detect and overcome therapeutic shortcomings. PMID- 25843648 TI - Genomic and single nucleotide polymorphism analysis of infectious bronchitis coronavirus. AB - Infectious bronchitis virus (IBV) is a Gammacoronavirus that causes a highly contagious respiratory disease in chickens. A QX-like strain was analysed by high throughput Illumina sequencing and genetic variation across the entire viral genome was explored at the sub-consensus level by single nucleotide polymorphism (SNP) analysis. Thirteen open reading frames (ORFs) in the order 5'-UTR-1a-1ab-S 3a-3b-E-M-4b-4c-5a-5b-N-6b-3'UTR were predicted. The relative frequencies of missense: silent SNPs were calculated to obtain a comparative measure of variability in specific genes. The most variable ORFs in descending order were E, 3b, 5'UTR, N, 1a, S, 1ab, M, 4c, 5a, 6b. The E and 3b protein products play key roles in coronavirus virulence, and RNA folding demonstrated that the mutations in the 5'UTR did not alter the predicted secondary structure. The frequency of SNPs in the Spike (S) protein ORF of 0.67% was below the genomic average of 0.76%. Only three SNPS were identified in the S1 subunit, none of which were located in hypervariable region (HVR) 1 or HVR2. The S2 subunit was considerably more variable containing 87% of the polymorphisms detected across the entire S protein. The S2 subunit also contained a previously unreported multi-A insertion site and a stretch of four consecutive mutated amino acids, which mapped to the stalk region of the spike protein. Template-based protein structure modelling produced the first theoretical model of the IBV spike monomer. Given the lack of diversity observed at the sub-consensus level, the tenet that the HVRs in the S1 subunit are very tolerant of amino acid changes produced by genetic drift is questioned. PMID- 25843649 TI - Elucidating evolutionary features and functional implications of orphan genes in Leishmania major. AB - Orphan genes are protein coding genes that lack recognizable homologs in other organisms. These genes were reported to comprise a considerable fraction of coding regions in all sequenced genomes and thought to be allied with organism's lineage-specific traits. However, their evolutionary persistence and functional significance still remain elusive. Due to lack of homologs with the host genome and for their probable lineage-specific functional roles, orphan gene product of pathogenic protozoan might be considered as the possible therapeutic targets. Leishmania major is an important parasitic protozoan of the genus Leishmania that is associated with the disease cutaneous leishmaniasis. Therefore, evolutionary and functional characterization of orphan genes in this organism may help in understanding the factors prevailing pathogen evolution and parasitic adaptation. In this study, we systematically identified orphan genes of L. major and employed several in silico analyses for understanding their evolutionary and functional attributes. To trace the signatures of molecular evolution, we compared their evolutionary rate with non-orphan genes. In agreement with prior observations, here we noticed that orphan genes evolve at a higher rate as compared to non orphan genes. Lower sequence conservation of orphan genes was previously attributed solely due to their younger gene age. However, here we observed that together with gene age, a number of genomic (like expression level, GC content, variation in codon usage) and proteomic factors (like protein length, intrinsic disorder content, hydropathicity) could independently modulate their evolutionary rate. We considered the interplay of all these factors and analyzed their relative contribution on protein evolutionary rate by regression analysis. On the functional level, we observed that orphan genes are associated with regulatory, growth factor and transport related processes. Moreover, these genes were found to be enriched with various types of interaction and trafficking motifs, implying their possible involvement in host-parasite interactions. Thus, our comprehensive analysis of L. major orphan genes provided evidence for their extensive roles in host-pathogen interactions and virulence. PMID- 25843647 TI - In Vivo Tumor Vasculature Targeting of CuS@MSN Based Theranostic Nanomedicine. AB - Actively targeted theranostic nanomedicine may be the key for future personalized cancer management. Although numerous types of theranostic nanoparticles have been developed in the past decade for cancer treatment, challenges still exist in the engineering of biocompatible theranostic nanoparticles with highly specific in vivo tumor targeting capabilities. Here, we report the design, synthesis, surface engineering, and in vivo active vasculature targeting of a new category of theranostic nanoparticle for future cancer management. Water-soluble photothermally sensitive copper sulfide nanoparticles were encapsulated in biocompatible mesoporous silica shells, followed by multistep surface engineering to form the final theranostic nanoparticles. Systematic in vitro targeting, an in vivo long-term toxicity study, photothermal ablation evaluation, in vivo vasculature targeted imaging, biodistribution and histology studies were performed to fully explore the potential of as-developed new theranostic nanoparticles. PMID- 25843650 TI - Molecular diversity of Bacillus anthracis in the Netherlands: investigating the relationship to the worldwide population using whole-genome SNP discovery. AB - Bacillus anthracis, the causative agent of anthrax, has been widely described as a clonal species. Here we report the use of both canonical SNP analysis and whole genome sequencing to characterize the phylogenetic lineages of B. anthracis from the Netherlands. Eleven strains isolated over a 25-years period (1968-1993) were paired-end sequenced using parallel sequencing technology. Five canSNP groups or lineages, i.e. A.Br.001/002 (n=6), A.Br.Aust94 (n=2), A.Br.008/011 (n=1), A.Br.011/009 (n=1) and A.Br.Vollum (n=1) were identified. Comparative analyses, with a focus on SNPs discovery, were carried out using a total of 52 B. anthracis genomes. A phylogeographic "Dutch" cluster within the dominant A.Br.001/002 group was discovered, involving isolates from a single outbreak. Diagnostic SNPs specific to the newly identified sub-groups were developed into high-resolution melting SNP discriminative assays for the purpose of rapid molecular epidemiology. Phylogenetic relationships with strains from other parts of the world are discussed. PMID- 25843651 TI - Serotype shift of a 793/B genotype infectious bronchitis coronavirus by natural recombination. AB - An infectious bronchitis coronavirus, designated as ck/CH/LHLJ/140906, was isolated from an infectious bronchitis virus (IBV) strain H120-vaccinated chicken flock, which presented with a suspected infectious bronchitis virus (IBV) infection. A phylogenetic analysis based on the S1 gene clustered ck/CH/LHLJ/140906 with the 793/B group; however, a pairwise comparison showed that the 5' terminal of the S1 gene (containing hypervariable regions I and II) had high sequence identity with the H120 strain, while the 3' terminal sequence was very similar to that of IBV 4/91 strain. A SimPlot analysis of the complete genomic sequence, which was confirmed by a phylogenetic analysis and nucleotide similarities using the corresponding gene fragments, suggested that isolate ck/CH/LHLJ/140906 emerged from multiple recombination events between parental IBV strains 4/91 and H120. Although the isolate ck/CH/LHLJ/140906 had slightly higher S1 amino acid sequence identity to strain 4/91 (88.2%) than to strain H120 (86%), the serotype of the virus was more closely related to that of the H120 strain (32% antigenic relatedness) than to the 4/91 strain (15% antigenic relatedness). Whereas, vaccination of specific pathogen-free chickens with the 4/91 vaccine provided better protection against challenge with ck/CH/LHLJ/140906 than did vaccination with the H120 strain according to the result of virus re-isolation. As the spike protein, especially in the hypervariable regions of the S1 domain, of IBVs contains viral neutralizing epitopes, the results of this study showed that recombination of the S1 domain resulted in the emergence of a new serotype. PMID- 25843652 TI - Autologous Stem Cell Transplantation Is an Effective Salvage Therapy for Primary Refractory Multiple Myeloma. AB - High-dose therapy and autologous stem cell transplantation (ASCT) have proven efficacy in patients with multiple myeloma responding well to induction therapy. For those who fail to achieve a stable partial response (PR), the effect of ASCT is unclear. We report on 126 patients identified from a national database, who underwent ASCT having achieved =90pg/mL. A qualitative cardiac troponin test was positive in 58 of the 204 cases (28.4%), with a significantly higher mortality incidence (p=0.017) among the troponin-positive cases [6 (10.3%) versus 3 (2.1%) deaths among the 146 troponin-negative cases]. The overall mean blood glucose level at admission of 331 cases was 152.0+/-74.0mg/dL, and 30-day mortality significantly increased with blood glucose values (p=0.048). CONCLUSIONS: Troponin, BNP, and blood glucose levels are useful prognostic biomarkers for acute pulmonary embolism in Japanese patients. PMID- 25843674 TI - Comparison of Lotrafilcon B and Balafilcon A silicone hydrogel bandage contact lenses in reducing pain and discomfort after photorefractive keratectomy: A contralateral eye study. AB - PURPOSE: To assess the effect of two silicone hydrogel contact lenses with high oxygen permeability in patients having photorefractive keratectomy (PRK). SETTING: Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran. METHODS: Sixty patients (120 eyes) who had bilateral PRK were enrolled in this double blind clinical trial. Each patient was fitted with a Lotrafilcon B (Air Optix((r))AQUA, Ciba Vision, Duluth, GA, USA) lens in one eye and a Balafilcon A (PureVisionTM Bausch & Lomb, Rochester, NY, USA) lens in the fellow eye. Patients' responses to a subjective questionnaire in terms of pain, foreign body sensation, photophobia, blurred vision and epiphora were evaluated on the first and third postoperative days. RESULTS: Mean pain score for Lotrafilcon B and Balafilcon A contact lenses was 4.43+/-3.18 vs. 5.45+/-3.37 on the first postoperative day and 3.43+/-3.23 vs. 3.88+/-3.01 on the third postoperative day. However, the difference was only significant in the first 24h after surgery (P=0.032). Foreign body sensation was clinically higher with Balafilcon A contact lens (5.0+/-3.47 vs. 4.08+/-3.34 on day 1 and 4.98+/-3.52 vs. 3.55+/-3.20 on day 3) and the difference was statistically significant on the first and the third postoperative days (P=0.042 and 0.002, respectively). There was no statistically significant difference between two contact lenses in terms of photophobia, epiphora and blurred vision (P>0.05). CONCLUSION: The Lotrafilcon B lens resulted in significantly less postoperative pain and discomfort after PRK, especially in the first 24h after PRK. PMID- 25843671 TI - Janus kinase 2/signal transducer and activator of transcription 3 inhibitors attenuate the effect of cardiotrophin-like cytokine factor 1 and human focal segmental glomerulosclerosis serum on glomerular filtration barrier. AB - Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation is believed to be caused by a circulating factor(s). We detected cardiotrophin-like cytokine factor 1 (CLCF1), a member of the interleukin 6 family, in the plasma from patients with recurrent FSGS. We hypothesized that CLCF1 contributes to the effect of FSGS serum on the glomerular filtration barrier in vitro. Presently, we studied the effect of CLCF1 on isolated rat glomeruli using an in vitro assay of albumin permeability (P(alb)). CLCF1 (0.05 100 ng/mL) increased P(alb) and caused maximal effect at 5-10 ng/mL (P < 0.001). The increase in Palb was analogous to the effect of FSGS serum. Anti-CLCF1 monoclonal antibody blocked the CLCF1-induced increase in P(alb) and significantly attenuated the effect of FSGS serum (P < 0.001). The heterodimer composed of CLCF1 and cosecreted molecule cytokine receptor-like factor 1 (CRLF1) attenuated the increase in P(alb) caused by CLCF1 or FSGS serum. Western blot analysis showed that CLCF1 upregulated phosphorylation of signal transducer and activator of transcription 3 (STAT3) (Tyr705) in glomeruli. This effect was diminished by the heterodimer CLCF1-CRLF1. Janus kinase 2 (JAK2) inhibitor BMS 1119543 or STAT3 inhibitor Stattic significantly blocked the effect of CLCF1 or FSGS serum on P(alb) (P < 0.001). These novel findings suggest that when monomeric CLCF1 increases P(alb), the heterodimer CLCF1-CRLF1 may protect the glomerular filtration barrier. We speculate that albuminuria in FSGS is related to qualitative or quantitative changes in the CLCF1-CRLF1 complex, and that JAK2 or STAT3 inhibitors may be novel therapeutic agents to treat FSGS. PMID- 25843678 TI - Interaction study between maltose-modified PPI dendrimers and lipidic model membranes. AB - The influence of maltose-modified poly(propylene imine) (PPI) dendrimers on dimyristoylphosphatidylcholine (DMPC) or dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) (3%) liposomes was studied. Fourth generation (G4) PPI dendrimers with primary amino surface groups were partially (open shell glycodendrimers - OS) or completely (dense shell glycodendrimers - DS) modified with maltose residues. As a model membrane, two types of 100nm diameter liposomes were used to observe differences in the interactions between neutral DMPC and negatively charged DMPC/DMPG bilayers. Interactions were studied using fluorescence spectroscopy to evaluate the membrane fluidity of both the hydrophobic and hydrophilic parts of the lipid bilayer and using differential scanning calorimetry to investigate thermodynamic parameter changes. Pulsed-filed gradient NMR experiments were carried out to evaluate common diffusion coefficient of DMPG and DS PPI in D2O when using below critical micelle concentration of DMPG. Both OS and DS PPI G4 dendrimers show interactions with liposomes. Neutral DS dendrimers exhibit stronger changes in membrane fluidity compared to OS dendrimers. The bilayer structure seems more rigid in the case of anionic DMPC/DMPG liposomes in comparison to pure and neutral DMPC liposomes. Generally, interactions of dendrimers with anionic DMPC/DMPG and neutral DMPC liposomes were at the same level. Higher concentrations of positively charged OS dendrimers induced the aggregation process with negatively charged liposomes. For all types of experiments, the presence of NaCl decreased the strength of the interactions between glycodendrimers and liposomes. Based on NMR diffusion experiments we suggest that apart from electrostatic interactions for OS PPI hydrogen bonds play a major role in maltose-modified PPI dendrimer interactions with anionic and neutral model membranes where a contact surface is needed for undergoing multiple H-bond interactions between maltose shell of glycodendrimers and surface membrane of liposome. PMID- 25843679 TI - Targeting ion channels for cancer therapy by repurposing the approved drugs. AB - Ion channels have been shown to be involved in oncogenesis and efforts are being poured in to target the ion channels. There are many clinically approved drugs with ion channels as "off" targets. The question is, can these drugs be repurposed to inhibit ion channels for cancer treatment? Repurposing of drugs will not only save investors' money but also result in safer drugs for cancer patients. Advanced bioinformatics techniques and availability of a plethora of open access data on FDA approved drugs for various indications and omics data of large number of cancer types give a ray of hope to look for possibility of repurposing those drugs for cancer treatment. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25843681 TI - Molecular evidence for antigen drive in the natural history of mantle cell lymphoma. AB - To further our understanding about antigen involvement in mantle cell lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-DeltaE4a, AID-DeltaE) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-length transcript levels were significantly associated (P < 0.001) with lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety. PMID- 25843682 TI - Mast cells are dispensable in a genetic mouse model of chronic dermatitis. AB - Chronic inflammatory skin diseases, such as atopic dermatitis, affect a large percentage of the population, but the role of different immune cells in the pathogenesis of these disorders is largely unknown. Recently, we found that mice lacking fibroblast growth factor receptor 1 (Fgfr1) and Fgfr2 (K5-R1/R2 mice) in the epidermis have a severe impairment in the epidermal barrier, which leads to the development of a chronic inflammatory skin disease that shares many features with human atopic dermatitis. Using Fgfr1-/Fgfr2-deficient mice, we analyzed the consequences of the loss of mast cells. Mast cells accumulated and degranulated in the skin of young Fgfr1-/Fgfr2-deficient mice, most likely as a consequence of increased expression of the mast cell chemokine Ccl2. The increase in mast cells occurred before the development of histological abnormalities, indicating a functional role of these cells in the inflammatory skin phenotype. To test this hypothesis, we mated the Fgfr1-/Fgfr2-deficient mice with mast cell-deficient CreMaster mice. Surprisingly, loss of mast cells did not or only mildly affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, accumulation and activation of different immune cells, or expression of different proinflammatory cytokines in the skin. These results reveal that mast cells are dispensable for the development of chronic inflammation in response to a defect in the epidermal barrier. PMID- 25843680 TI - Prevention of phenytoin-induced gingival overgrowth by lovastatin in mice. AB - Drug-induced gingival overgrowth is caused by the antiseizure medication phenytoin, calcium channel blockers, and ciclosporin. Characteristics of these drug-induced gingival overgrowth lesions differ. We evaluate the ability of a mouse model to mimic human phenytoin-induced gingival overgrowth and assess the ability of a drug to prevent its development. Lovastatin was chosen based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition. Data indicate that anterior gingival tissue overgrowth occurred in phenytoin-treated mice based on gross tissue observations and histomorphometry of tissue sections. Molecular markers of epithelial plasticity and fibrosis were regulated by phenytoin in gingival epithelial tissues and in connective tissues similar to that seen in humans. Lovastatin attenuated epithelial gingival tissue growth in phenytoin-treated mice and altered the expressions of markers for epithelial to mesenchymal transition. Data indicate that phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that lovastatin normalizes the tissue morphology and the expression of the molecular markers studied. Data are consistent with characterization of phenytoin-induced human gingival overgrowth in vivo and in vitro characteristics of cultured human gingival epithelial and connective tissue cells. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required. PMID- 25843683 TI - A disintegrin and metalloprotease with thrombospondin type I motif 7: a new protease for connective tissue growth factor in hepatic progenitor/oval cell niche. AB - Hepatic progenitor/oval cell (OC) activation occurs when hepatocyte proliferation is inhibited and is tightly associated with the fibrogenic response during severe liver damage. Connective tissue growth factor (CTGF) is important for OC activation and contributes to the pathogenesis of liver fibrosis. By using the Yeast Two-Hybrid approach, we identified a disintegrin and metalloproteinase with thrombospondin repeat 7 (ADAMTS7) as a CTGF binding protein. In vitro characterization demonstrated CTGF binding and processing by ADAMTS7. Moreover, Adamts7 mRNA was induced during OC activation, after the implantation of 2 acetylaminofluorene with partial hepatectomy in rats or on feeding a 3,5 diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet in mice. X-Gal staining showed Adamts7 expression in hepatocyte nuclear factor 4alpha(+) hepatocytes and desmin(+) myofibroblasts surrounding reactive ducts in DDC-treated Adamts7(-/-) mice carrying a knocked-in LacZ gene. Adamts7 deficiency was associated with higher transcriptional levels of Ctgf and OC markers and enhanced OC proliferation compared to Adamts7(+/+) controls during DDC-induced liver injury. We also observed increased alpha-smooth muscle actin and procollagen type I mRNAs, large fibrotic areas in alpha-smooth muscle actin and Sirius red staining, and increased production of hepatic collagen by hydroxyproline measurement. These results suggest that ADAMTS7 is a new protease for CTGF protein and a novel regulator in the OC compartment, where its absence causes CTGF accumulation, leading to increased OC activation and biliary fibrosis. PMID- 25843684 TI - Development of approaches to induce puberty in cultured female sablefish (Anoplopoma fimbria). AB - Efforts to establish sustainable and efficient aquaculture production of sablefish (Anoplopoma fimbria) have been constrained by delayed puberty in cultured females. This study integrates a series of experiments aimed at gaining an understanding of the reproductive physiology of puberty in female sablefish. We detected transcripts for the dopamine D2 receptor (drd2) in brain, pituitary and ovary of sablefish, and prepubertal females exhibited significantly elevated brain and pituitary drd2 expression relative to wild maturing females. Treatments with sustained-release cholesterol pellets containing testosterone (T) and the dopamine D2 receptor antagonist, metoclopramide (Met), stimulated expression of pituitary luteinizing hormone beta subunit (lhb) and follicle-stimulating hormone beta subunit (fshb), respectively, in prepubertal females, whereas a combination of T and gonadotropin-releasing hormone agonist (GnRHa) had a strong synergistic effect on lhb expression (2000-fold higher than control). Although T induced a significant increase in the maximum ovarian follicle volume, none of the treatments tested stimulated onset of vitellogenesis. Using liquid chromatography/tandem mass spectrometry, we demonstrated that Met stimulated production of T by previtellogenic ovarian follicles in vitro, whereas gonadotropin preparations enhanced 17alpha-hydroxyprogesterone, androstenedione (A4), T and 17beta-estradiol (E2) production. Treatment with T increased production of A4, 11beta-hydroxyandrostenedione, 11beta-hydroxytestosterone, E2, 11-ketotestosterone, and 5alpha-dihydrotestosterone (DHT). Interestingly, in the presence of high doses of T the previtellogenic ovary preferentially produced A4 and DHT over any other metabolite. Our data suggest the existence of dopamine inhibition of the reproductive axis in female sablefish. Treatments with Met and T elevated gonadotropin mRNAs in prepubertal females but failed to stimulate the transition into vitellogenic growth, suggesting a possible failure in pituitary gonadotropin protein synthesis/release. Previtellogenic ovarian follicles of sablefish are equipped to synthesize steroids, including those required for vitellogenic growth, and DHT, a steroid hormone whose role in reproduction of fishes remains unknown. PMID- 25843686 TI - The role of health care experience and consumer information efficacy in shaping privacy and security perceptions of medical records: national consumer survey results. AB - BACKGROUND: Providers' adoption of electronic health records (EHRs) is increasing and consumers have expressed concerns about the potential effects of EHRs on privacy and security. Yet, we lack a comprehensive understanding regarding factors that affect individuals' perceptions regarding the privacy and security of their medical information. OBJECTIVE: The aim of this study was to describe national perceptions regarding the privacy and security of medical records and identify a comprehensive set of factors associated with these perceptions. METHODS: Using a nationally representative 2011-2012 survey, we reported on adults' perceptions regarding privacy and security of medical records and sharing of health information between providers, and whether adults withheld information from a health care provider due to privacy or security concerns. We used multivariable models to examine the association between these outcomes and sociodemographic characteristics, health and health care experience, information efficacy, and technology-related variables. RESULTS: Approximately one-quarter of American adults (weighted n=235,217,323; unweighted n=3959) indicated they were very confident (n=989) and approximately half indicated they were somewhat confident (n=1597) in the privacy of their medical records; we found similar results regarding adults' confidence in the security of medical records (very confident: n=828; somewhat confident: n=1742). In all, 12.33% (520/3904) withheld information from a health care provider and 59.06% (2100/3459) expressed concerns about the security of both faxed and electronic health information. Adjusting for other characteristics, adults who reported higher quality of care had significantly greater confidence in the privacy and security of their medical records and were less likely to withhold information from their health care provider due to privacy or security concerns. Adults with higher information efficacy had significantly greater confidence in the privacy and security of medical records and less concern about sharing of health information by both fax and electronic means. Individuals' perceptions of whether their providers use an EHR was not associated with any privacy or security outcomes. CONCLUSIONS: Although most adults are confident in the privacy and security of their medical records, many express concerns regarding sharing of information between providers; a minority report withholding information from their providers due to privacy and security concerns. Whether individuals thought their provider was using an EHR was not associated with negative privacy/security perceptions or withholding, suggesting the transition to EHRs is not associated with negative perceptions regarding the privacy and security of medical information. However, monitoring to see how this evolves will be important. Given that positive health care experiences and higher information efficacy were associated with more favorable perceptions of privacy and security, efforts should continue to encourage providers to secure medical records, provide patients with a "meaningful choice" in how their data are shared, and enable individuals to access information they need to manage their care. PMID- 25843685 TI - p70 S6-kinase mediates the cooperation between Akt1 and Mek1 pathways in fibroblast-mediated extracellular matrix remodeling. AB - Previous studies have demonstrated both synergistic and opposing effects of Akt and Mek1/2 in various cell functions and disease states. Furthermore, Akt has been reported to inhibit and activate cRaf/Mek pathway, suggesting that their mutual interaction and cooperation may be cell type, stimuli and/or context specific. While PI3-kinase/Akt and cRaf/Mek pathways have been implicated in the regulation of extracellular matrix (ECM) remodeling, mutual interactions between these two pathways and their specific contributions to the events leading to ECM synthesis and assembly is not clear. We investigated the specific role of Akt1 and Mek1 in ECM synthesis and assembly by NIH 3T3 fibroblasts and how these effects were reconciled to mediate overall ECM remodeling. Our study identified that cooperation between Akt1 and Mek1 is necessary to mediate ECM synthesis. Whereas Akt1 activation resulted in Mek1 activation as evidenced by increased ERK1/2 phosphorylation, Mek1 inhibition using U0126 or DN-Mek1 resulted in enhanced Akt1 phosphorylation. Interestingly, both Akt1 and Mek1 activities were needed for the synthesis and assembly of ECM. The effect of Akt1 and Mek1 on ECM synthesis was reconciled through the activation of p70 S6-kinase via phosphorylation at T421/S424 and S411, respectively. Furthermore, Akt1 and Mek1 cooperated in mediating ECM assembly via activation of integrin beta1. Together, we show for the first time that Akt1 and Mek1 pathways cooperate in the regulation of ECM remodeling by the fibroblasts. PMID- 25843687 TI - Survival of Enveloped and Non-Enveloped Viruses on Inanimate Surfaces. AB - In the present study, we evaluated the viability of non-enveloped viruses, minute virus of mice (MVM) and coxsackievirus B4 (CVB4), and enveloped-viruses, influenza A virus (H1N1) and herpes simplex virus type 1 (HSV-1), on surfaces. We also investigated the impact of the initial concentration of proteins and sodium chloride on the persistence of infectious CVB4 on surfaces. Viral suspensions (>10(4.5) TCID50) were applied to petri dish lids and dried under the air flow of a biosafety cabinet. The recovered viral preparations were titered on appropriate cell lines. Enveloped viruses persisted for less than 5 days while CVB4 and MVM persisted for weeks. However, repetitive cycles of drying and resuspension had a stronger virucidal effect on CVB4 than on H1N1 and HSV-1. These repetitive cycles had no effect on the infectious titer of MVM. When exposed to drying, the initial concentrations of bovine serum albumin (from 0 to 90 mg mL(-1)), fetal calf serum (from 0 to 100%), and sodium chloride (from 0 to 300 mg mL(-1)) affected the viability of CVB4. CVB4 was more likely to be inactivated by drying in a protein rich medium, whereas the impact of drying was reduced in the presence of sodium chloride. The results of the present study demonstrated that the resistance of viruses to drying, as suggested by iterative drying, was not due to the heterogeneity of viral subpopulations, but was influenced by media compositions and component concentrations, as illustrated in the model of CVB4. PMID- 25843688 TI - Improving the osteogenic efficacy of BMP2 with mechano growth factor by regulating the signaling events in BMP pathway. AB - Local application of bone morphogenetic protein 2 (BMP2) is known to promote large bone defect healing and BMP2-initiated bone regeneration could be enhanced by an additional mechanical stimulation. The C-terminal 24-a.a. peptide of mechano growth factor (MGF24E), a mechanical-sensitive molecule, has been demonstrated to promote bone healing. Here, we propose a hypothesis that MGF24E could also improve the osteogenic efficacy of BMP2 by regulating the signaling events in the BMP pathway. To confirm the hypothesis, the potentials of MGF24E, BMP2 and BMP2/MGF24E combination treatments on the phosphorylation of Smad 1/5/8, the downstream osteogenesis-related gene expression and osteoblasts mineralization, are investigated with or without the blocking of Smad 5 siRNA. Furthermore, 15-mm rabbit radial bone defects were healed with the cytokine treatments and then evaluated by radiographic examination, histological assessment and immunohistochemical analysis. MGF24E could enhance the BMP2 induced Smad signaling pathway by upregulating the p-Smad protein expression and the downstream osteogenic gene expression. An amount of 5 nM BMP2 in a sub-25 nM concentration of MGF24E medium achieved a higher expression for ALP mRNA and a greater calcium mineral content compared with BMP2 alone. Nevertheless, the inhibition of the MGF24E-regulated BMP pathway could block osteogenesis induced by the dual treatment. In vivo, MGF24E treatment upregulated the endogenous BMP2 expression and the addition of MGF24E into the BMP2 treatment remarkably enhanced the bone mineral density (BMD), the radiographic scores and the histological restoration of the regenerated tissue against BMP2 treatment, suggesting a new strategy for BMP2 in bone defect healing. PMID- 25843690 TI - Role of region-distinctive expression of Rac1 in regulating fibronectin arrangement during palatal shelf elevation. AB - Palatal shelf elevation is a crucial process in palate development, with the contribution of various factors. Disturbances in any factor during this process result in cleft palate. Prior to palatal shelf elevation starting from embryonic day 12.5, the Rac1 expression level in the bend region of the mid-palatal shelf progressively increases and the cell densities in the bend and groove regions gradually become higher than those in the middle region. The comparative decrease of cell density in the middle region is correlated with a gradual alteration of the arrangement of fibronectin (FN) fibers, whereas the bend and groove regions with higher cell densities maintain ring-like FN arrangements. Rac1 overexpression alters the fibrillar FN arrangement in the middle region to the ring-like arrangement by increasing cell density. This alteration is sufficient to induce the failure of palatal shelf elevation, ultimately leading to cleft palate. Furthermore, the inhibition of FN delays palatal shelf elevation. Thus, the spatiotemporal expression of Rac1 plays an impressive role in palatal shelf elevation by regulating FN arrangement within the palatal shelf. PMID- 25843689 TI - Specific synaptopathies diversify brain responses and hearing disorders: you lose the gain from early life. AB - Before hearing onset, inner hair cell (IHC) maturation proceeds under the influence of spontaneous Ca(2+) action potentials (APs). The temporal signature of the IHC Ca(2+) AP is modified through an efferent cholinergic feedback from the medial olivocochlear bundle (MOC) and drives the IHC pre- and post-synapse phenotype towards low spontaneous (spike) rate (SR), high-threshold characteristics. With sensory experience, the IHC pre- and post-synapse phenotype matures towards the instruction of low-SR, high-threshold and of high-SR, low threshold auditory fiber characteristics. Corticosteroid feedback together with local brain-derived nerve growth factor (BDNF) and catecholaminergic neurotransmitters (dopamine) might be essential for this developmental step. In this review, we address the question of whether the control of low-SR and high-SR fiber characteristics is linked to various degrees of vulnerability of auditory fibers in the mature system. In particular, we examine several IHC synaptopathies in the context of various hearing disorders and exemplified shortfalls before and after hearing onset. PMID- 25843691 TI - Aldehyde dehydrogenase 1 (ALDH1) expression is associated with a poor prognosis of bladder cancer. AB - Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, has been reported to be altered in human carcinogenesis. This study assessed the expression of ALDH1 protein in invasive vs. noninvasive bladder cancer tissues for association with clinicopathological factors and bladder cancer prognosis. Tissue samples were collected from 227 bladder cancer patients, including 118 with noninvasive and 109 with invasive bladder cancer for immunostaining of ALDH1 expression. ALDH1 expression in tumor tissues was significantly greater than that in adjacent normal tissues. ALDH1 protein was highly expressed in 29.07% (66/227) of bladder tumor tissues (i.e., 24.58% of noninvasive bladder cancer tissues vs. 33.94% of invasive bladder cancer tissues). In patients with noninvasive bladder cancer, ALDH1 protein expression was significantly associated with an advanced tumor grade and frequent tumor recurrence (P<=0.05). In patients with invasive bladder cancer, ALDH1 protein expression was significantly associated with an advanced tumor grade, stage, as well as lymph node and distant metastases (P<=0.05). After adjusting for the confounding factors, ALDH1 protein expression was significantly associated with relapse-free survival in noninvasive bladder cancer patients [HR (95% CI)=4.45 (1.32-15.04); P=0.027] and overall survival in invasive bladder cancer patients [HR (5% CI)=2.86 (1.72-8.83); P=0.020]. These data indicate that ALDH1 expression plays an important role in bladder cancer development and prognosis. Further validation of our results is warranted in a larger sample cohort, and further investigation of ALDH1 signaling and function will increase our understanding of ALDH1 in bladder cancer progression. PMID- 25843692 TI - The aggregation of early-onset melanoma in young Western Australian families. AB - BACKGROUND: Few studies have examined the familial aggregation of melanoma or its co-aggregation with other cancers using whole-population based designs. This study aimed to investigate aggregation patterns in young Western Australian families, using population-based linked health data to identify individuals born in Western Australia between 1974 and 2007, their known relatives, and all incident cancer diagnoses within the resulting 1,506,961 individuals. METHODS: Cox proportional hazards regression models were used to compare the risk of melanoma for first-degree relatives of melanoma cases to that for first-degree relatives of controls, with bootstrapping used to account for correlations within families. The risk of (i) developing melanoma based on the number of first-degree relatives with other cancers, and (ii) developing non-melanoma cancers based on the number of first-degree relatives diagnosed with melanoma was also investigated. RESULTS: First-degree relatives of melanoma cases had a significantly greater incidence of melanoma than first-degree relatives of individuals not affected with melanoma (Hazard Ratio (HR)=3.58, 95% bootstrap confidence interval (CI): 2.43-5.43). Sensitivity analyses produced a higher hazard ratio estimate when restricted to melanoma cases diagnosed before 40 years of age (HR=3.77, bootstrap 95% CI: 2.49-6.39) and a lower estimate when only later-onset cases (>40 years) were considered (HR=2.45, bootstrap 95% CI: 1.23 4.82). No significant evidence was found for co-aggregation between melanoma and any other cancers. CONCLUSIONS: Results indicated a strong familial basis of melanoma, with the higher than expected hazard ratio observed likely to reflect early-age at onset cases in this young cohort, supported by the results of the sensitivity analyses. Exploratory analyses suggested that the determinants of melanoma causing the observed aggregation within families may be independent of other malignancies, although these analyses were limited by the young age of the sample. Determining familial aggregation patterns will provide valuable knowledge regarding improved clinical risk prediction and the underlying biological mechanisms of melanoma and other cancers. PMID- 25843693 TI - Site-Specific Description of the Enhanced Recognition Between Electrogenerated Nitrobenzene Anions and Dihomooxacalix[4]arene Bidentate Ureas. AB - Electron transfer controlled hydrogen bonding was studied for a series of nitrobenzene derivative radical anions, working as large guest anions, and substituted ureas, including dihomooxacalix[4]arene bidentate urea derivatives, in order to estimate binding constants (Kb) for the hydrogen-bonding process. Results showed enhanced Kb values for the interaction with phenyl-substituted bidentate urea, which is significantly larger than for the remaining compounds, e.g., in the case of 4-methoxynitrobenzene a 28-fold larger Kb value was obtained for the urea bearing a phenyl (Kb ~ 6888) vs tert-butyl (Kb ~ 247) moieties. The respective nucleophilic and electrophilic characters of the participant anion radical and urea hosts were parametrized with global and local electrodonating (omega(-)) and electroaccepting (omega(+)) powers, derived from DFT calculations. omega(-) data were useful for describing trends in structure-activity relationships when comparing nitrobenzene radical anions. However, omega(+) for the host urea structures lead to unreliable explanations of the experimental data. For the latter case, local descriptors omegak(+)(r) were estimated for the atoms within the urea region in the hosts [?komegak(+)(r)]. By compiling all the theoretical and experimental data, a Kb-predictive contour plot was built considering omega(-) for the studied anion radicals and ?komegak(+)(r) which affords good estimations. PMID- 25843694 TI - Central retinal artery occlusion and infective endocarditis: rigor does matter. AB - CLINICAL CASE: A patient with acute amaurosis due central retinal artery occlusion (CRAO), who had mitral regurgitation and Streptococcus viridans positive blood cultures. Using transesophageal ultrasound, the patient was diagnosed with native valve infective endocarditis without fever, and with loss of vision as the only symptom. DISCUSSION: CRAO due to infective endocarditis is rare and there are few cases reported in the literature. Semiology and a systematic and comprehensive study of patients with this ophthalmological pathology helps uncover serious underlying medical conditions. Infective endocarditis has many different forms of presentation and a high clinical suspicion is often required to reach a diagnosis. PMID- 25843695 TI - [Atypical presentation of lacrimal gland pleomorphic adenoma with necrotic foci]. AB - CLINICAL CASE: The case is presented of 48 year-old male complaining of a painful left upper eyelid and swelling of the lacrimal gland, with a suspicion of dacryoadenitis. Removal was decided after dacriops suspicion. Histopathology diagnosed a pleomorphic adenoma of the lacrimal gland, with areas of necrosis. DISCUSSION: Lacrimal gland pleomorphic adenoma usually presents as a slowly progressive painless mass. However, painful presentation in this case might be related with necrotic foci found in the histopathological examination. Although not described in lacrimal glands, pleomorphic adenomas have already been reported in the major and minor salivary glands, and these patients also presented with a painful mass. PMID- 25843696 TI - The digitalised patient. PMID- 25843697 TI - Treatment of vitreomacular traction syndrome with autologous plasmin enzyme. AB - PURPOSE: To determine whether intravitreal injection of autologous plasmin enzyme (APE) is effective in vitreomacular traction syndrome (VMTS) by improving visual acuity and restoring macular morphology. METHODS: A prospective study of 11 consecutive patients diagnosed with VMTS in the Ophthalmology Department from January to May, 2011. INCLUSION CRITERIA: best corrected visual acuity (BCVA) less than 0.5, and vitreomacular attachment in foveal area resulting in macular thickness>250 microns diagnosed by optical coherence tomography (Cirrus OCT, Carl Zeiss Meditec, Inc, Oberkochen, Germany). EXCLUSION CRITERIA: active proliferative diabetic retinopathy, axial myopia>26mm, vitrectomy, glaucoma, previous intravitreal injections and previous rhegmatogenous detachment. One to 3 monthly intravitreal injections of 0.2ml of APE were applied, interrupting if posterior vitreous detachment was attained. Wilcoxon's test was used for statistical analysis. RESULTS: A total of 12 eyes of 11 patients were treated. A complete posterior vitreous detachment was achieved in 4 (33%) eyes at the end of the study, 2 of them with one injection, and 2 with 3 monthly injections. Improvement of BCVA was statistically significant (P=.017) and the decrease in central macular thickness also was statistically significant (P=.016). There was only one complication: intraocular hypertension after injection that subsided with a new paracentesis. CONCLUSIONS: Intravitreal APE injections avoided vitrectomy in VMTS in one in every 3 patients. PMID- 25843698 TI - Effects of antibiotic administration delay and inadequacy upon the survival of septic shock patients. AB - OBJECTIVE: To assess how antibiotic administration delay and inadequacy influence survival in septic shock patients. DESIGN: A prospective, observational cohort study was carried out between September 2005 and September 2010. SCOPE: Patients admitted to the ICU of a third level hospital. PATIENTS: A total of 342 septic shock patients INTERVENTIONS: None VARIABLES OF INTEREST: The time to antibiotic administration (difference between septic shock presentation and first administered dose of antibiotic) and its adequacy (in vitro susceptibility testing of isolated pathogens) were determined. RESULTS: ICU and hospital mortality were 26.4% and 33.5%, respectively. The median delay to administration of the first antibiotic dose was 1.7h. Deceased patients received antibiotics significantly later than survivors (1.3+/-14.5h vs. 5.8+/-18.02h; P=.001). Percentage drug inadequacy was 12%. Those patients who received inadequate antibiotics had significantly higher mortality rates (33.8% vs. 51.2%; P=.03). The coexistence of treatment delay and inadequacy was associated to lower survival rates. CONCLUSIONS: Both antibiotic administration delay and inadequacy exert deleterious effects upon the survival of septic shock patients, independently of their characteristics or severity. PMID- 25843699 TI - [Usefulness of procalcitonin for diagnosing infection in critically ill patients with liver cirrhosis]. AB - OBJECTIVE: To evaluate the usefulness of procalcitonin (PCT) for diagnosing infection in patients with liver cirrhosis admitted to an Intensive Care Unit. DESIGN: A retrospective study was carried out. SCOPE: Intensive Care Unit. Versatile, twenty-four beds. Participants Patients with liver cirrhosis admitted to our Intensive Care Unit in the last four years with suspected infection and measurement of PCT. RESULTS: Among the 255 patients with cirrhosis admitted to our unit, PCT was determined for the differential diagnosis of infection in 69 cases (27%). Three patients were excluded from analysis due to a lack of clinical data. The average stay was 10.6 +/- 9.2 days, with a mortality rate of 65%. The origin of cirrhosis was mainly viral (57%) or alcoholic (37%). The Child-Pugh and MELD scores were 9.5 +/- 2 and 23 +/- 8, respectively. Infection was diagnosed in 54 patients (82%). The most common infection was pneumonia (72%), followed by intraabdominal infections (18%) and bacteremia (5%). In patients without infection, the median PCT concentration was 0.57 ng/ml (range 0.28 to 1.14) versus 2.99 (1.31 to 9.4) in those with infection (p<.001). Diagnostic capacity was maintained in patients with intraabdominal infections. The diagnostic cutoff point was set at 0.8 ng/ml (sensitivity 83%, specificity 75%, AUC 0.82 [0.702 0.93]). CONCLUSIONS: In patients with liver cirrhosis, PCT is useful for identifying bacterial infections, including intraabdominal processes. PMID- 25843700 TI - Regret and adaptive decision making in young children. AB - In line with the claim that regret plays a role in decision making, O'Connor, McCormack, and Feeney (Child Development, 85 (2014) 1995-2010) found that children who reported feeling sadder on discovering they had made a non-optimal choice were more likely to make a different choice the next time around. We examined two issues of interpretation regarding this finding: whether the emotion measured was indeed regret and whether it was the experience of this emotion, rather than the ability to anticipate it, that affected decision making. To address the first issue, we varied the degree to which children aged 6 or 7 years were responsible for an outcome, assuming that responsibility is a necessary condition for regret. The second issue was addressed by examining whether children could accurately anticipate that they would feel worse on discovering they had made a non-optimal choice. Children were more likely to feel sad if they were responsible for the outcome; however, even if they were not responsible, children were more likely than chance to report feeling sadder. Moreover, across all conditions, feeling sadder was associated with making a better subsequent choice. In a separate task, we demonstrated that children of this age cannot accurately anticipate feeling sadder on discovering that they had not made the best choice. These findings suggest that although children may feel regret following a non-optimal choice, even if they were not responsible for an outcome, they may experience another negative emotion such as frustration. Experiencing either of these emotions seems to be sufficient to support better decision making. PMID- 25843701 TI - Niemann-Pick disease type C2 protein induces autophagy and inhibits growth in FM3A breast cancer cells. AB - Some peptides that are highly conserved between insects and mammals have anti tumor action. Screening for inhibitors of cell growth from animal fluids may provide useful clues to anti-tumor drugs. Inducers of autophagy also have anti tumor activity. The current authors recently studied a protein found in silkworm hemolymph, Niemann-Pick disease type C2 (NPC2). This protein, which is highly conserved among eukaryotes, was found to have anti-proliferative action on a silkworm cell line. The current study found that the silkworm NPC2 protein also inhibits the growth of FM3A murine breast cancer cells. In FM3A cells, silkworm NPC2 increased phosphorylation of AMP-activated protein kinase and decreased phosphorylation of Akt and mammalian target of rapamycin, which are regulators of autophagy. This study also found that NPC2 increased the amount of microtubule associated protein light chain 3 (LC3)-II, an autophagosome marker, in FM3A cells. Silkworm NPC2 also induced an increase in the number of LC3-dots, a marker of pre-autophagic endosomes, in FM3A cells. When silkworm NPC2 was used to inhibit FM3A cell growth, that inhibition was attenuated by chloroquine, which inhibits autophagic activity by preventing lysosomal acidification. Murine NPC2 also inhibited growth and induced autophagy in FM3A cells. These findings suggest that NPC2 is involved in the induction and/or maintenance of autophagy and may help to elucidate the mechanisms underlying other neurodegenerative disorders such as Niemann-Pick disease. PMID- 25843702 TI - Template-assisted synthesis of Janus silica nanobowls. AB - The preparation of anisotropic nanoparticles has drawn much attention in the literature, with most of the efforts being dedicated to convex particles. In this work, instead, we present a reliable method to synthesis silica nanobowls with one well-defined opening, covering a broad range of sizes. The nanobowls have been obtained from asymmetrically functionalized silica-polymer Janus nanodumbbells, used as templates, by removing of the polymer. Polystyrene seeds having different sizes as well as surface chemistry have been used as starting material in a two-step seeded emulsion polymerization, which leads to polymer nanodumbbells. These dumbbells are also asymmetrically functionalized due to the presence of silane groups on only one of their two hemispheres. This allows us to selectively coat the silane-bearing hemisphere of the dumbbells with a silica layer by means of a Stoeber process. The silica nanobowls are eventually obtained after either calcination or dissolution of the polymeric template. Depending on the route followed to remove the polymer, nanobowls made of pure silica (from calcination) or hybrid Janus nanobowls with a silica outer shell and a covalently bound hydrophobic polymer layer inside the cavity (from dissolution) could be prepared. The difference between the two types of nanobowls has been proved by electrostatically binding oppositely charged silica nanoparticles, which adhere selectively only on the outer silica part of the nanobowls prepared by polymer dissolution, while they attach both inside and outside of nanobowls prepared by calcination. We also show that selective functionalization of the outer surface of the Janus nanobowls from dissolution is possible. This work is one of the first examples of concave objects bearing different functionalities in the inner and outer parts of their surface. PMID- 25843703 TI - Bone alkaline phosphatase isoforms in hemodialysis patients with low versus non low bone turnover: a diagnostic test study. AB - BACKGROUND: Renal osteodystrophy encompasses the bone histologic abnormalities seen in patients with chronic kidney disease (CKD). The bone-specific alkaline phosphatase (bALP) isoform B1x is exclusively found in serum of some patients with CKD. STUDY DESIGN: The aim of this cross-sectional diagnostic test study was to examine the relationship between serum bALP isoform activity and histomorphometric parameters of bone in patients with CKD receiving maintenance hemodialysis. SETTINGS & PARTICIPANTS: Anterior iliac crest bone biopsy samples from 40 patients with CKD were selected on the basis of bone turnover for histomorphometric analysis. There were samples from 20 patients with low and 20 with non-low bone turnover. INDEX TEST: In serum, bALP, bALP isoforms (B/I, B1x, B1, and B2), and parathyroid hormone (PTH) were measured. REFERENCE TEST: Low bone turnover was defined by mineral apposition rate < 0.36MUm/d. Non-low bone turnover was defined by mineral apposition rate >= 0.36MUm/d. OTHER MEASUREMENTS: PTH. RESULTS: B1x was found in 21 patients (53%) who had lower median levels of bALP, 18.6 versus 46.9U/L; B/I, 0.10 versus 0.22 MUkat/L; B1, 0.40 versus 0.88 MUkat/L; B2, 1.21 versus 2.66 MUkat/L; and PTH, 49 versus 287pg/mL, compared with patients without B1x (P<0.001). 13 patients (65%) with low bone turnover and 8 patients (40%) with non-low bone turnover (P<0.2) had detectable B1x. B1x correlated inversely with histomorphometric parameters of bone turnover. Receiver operating characteristic curves showed that B1x can be used for the diagnosis of low bone turnover (area under the curve [AUC], 0.83), whereas bALP (AUC, 0.89) and PTH (AUC, 0.85) are useful for the diagnosis of non-low bone turnover. LIMITATIONS: Small number of study participants. Requirement of high-performance liquid chromatography methods for measurement of B1x. CONCLUSIONS: B1x, PTH, and bALP have similar diagnostic accuracy in distinguishing low from non-low bone turnover. The presence of B1x is diagnostic of low bone turnover, whereas elevated bALP and PTH levels are useful for the diagnosis of non-low bone turnover. PMID- 25843704 TI - Extended Daily Dialysis Versus Continuous Renal Replacement Therapy for Acute Kidney Injury: A Meta-analysis. AB - BACKGROUND: Extended daily dialysis (EDD) has been suggested as an effective renal replacement therapy for acute kidney injury. However, results from studies comparing EDD to continuous renal replacement therapy (CRRT) are inconclusive. STUDY DESIGN: A systematic review and meta-analysis was performed by searching in MEDLINE, EMBASE, the Cochrane Library, Google Scholar, and a Chinese database (SinsoMed). SETTING & POPULATION: Patients with acute kidney injury. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials (RCTs) and observational studies were included. EDD was defined as extended hemodialysis or hemodiafiltration for more than 6 but less than 24 hours per session using a conventional hemodialysis machine. INTERVENTION: Renal replacement therapy comparing EDD with CRRT. OUTCOMES: Mortality, kidney recovery, and fluid removal. RESULTS: We included 17 studies from 2000 to 2014: 7 RCTs and 10 observational studies involving 533 and 675 patients, respectively. Meta-analysis of RCTs showed no difference in mortality rates between EDD and CRRT (relative risk, 0.90; 95% CI, 0.74-1.11; P=0.3). However, EDD was associated with lower mortality risk compared with CRRT in observational studies (relative risk, 0.86; 95% CI, 0.74-1.00; P=0.05). There was no evidence of heterogeneity in RCTs (I(2)=0%) or observational studies (I(2)=15%). In both RCTs and observational studies, there were no significant differences in recovery of kidney function, fluid removal, or days in the intensive care unit, and EDD showed similar biochemical efficacy to CRRT during treatment (serum urea, serum creatinine, and serum phosphate). LIMITATIONS: The survival benefit of EDD is dependent on only observational studies and might have been affected by allocation or selection bias. CONCLUSIONS: EDD is associated with similar outcomes to CRRT in RCTs. The finding that EDD is associated with a lower mortality rate relies on data from observational studies, which are potentially subject to allocation or selection bias, making further high-quality RCTs desirable. PMID- 25843705 TI - Teriparatide and bone turnover and formation in a hemodialysis patient with low turnover bone disease: a case report. AB - Teriparatide, a recombinant form of parathyroid hormone, is an anabolic agent approved for use in women and men with osteoporosis. However, it is not well studied in people with chronic kidney disease (CKD). We report on a patient with stage 5 CKD treated with dialysis who presented to our clinic with multiple fractures, including bilateral nondisplaced pelvic fractures resulting in chronic pain and interfering with the patient's ability to work. Bone histomorphometry demonstrated low-turnover bone disease, and he was treated with 20MUg of teriparatide (subcutaneous injection) every morning for 24 months. Within 6 months of initiating therapy, the patient's pain resolved and he was able to resume work. Serum calcium and phosphate levels remained within reference ranges throughout his treatment, and he sustained no further fractures. During 24 months of treatment, bone mineral density was maintained at the lumbar spine, and there was an increase of 4% at the femoral neck and total hip. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. In our patient, 24-month treatment with teriparatide was safe and effective; however, larger studies are needed to determine the efficacy of teriparatide in the dialysis-dependent CKD population. PMID- 25843706 TI - mTORC2 regulates cardiac response to stress by inhibiting MST1. AB - The mTOR and Hippo pathways have recently emerged as the major signaling transduction cascades regulating organ size and cellular homeostasis. However, direct crosstalk between two pathways is yet to be determined. Here, we demonstrate that mTORC2 is a direct negative regulator of the MST1 kinase, a key component of the Hippo pathway. mTORC2 phosphorylates MST1 at serine 438 in the SARAH domain, thereby reducing its homodimerization and activity. We found that Rictor/mTORC2 preserves cardiac structure and function by restraining the activity of MST1 kinase. Cardiac-specific mTORC2 disruption through Rictor deletion leads to a marked activation of MST1 that, in turn, promotes cardiac dysfunction and dilation, impairing cardiac growth and adaptation in response to pressure overload. In conclusion, our study demonstrates the existence of a direct crosstalk between mTORC2 and MST1 that is critical for cardiac cell survival and growth. PMID- 25843707 TI - High-precision analysis of translational pausing by ribosome profiling in bacteria lacking EFP. AB - Ribosome profiling is a powerful method for globally assessing the activity of ribosomes in a cell. Despite its application in many organisms, ribosome profiling studies in bacteria have struggled to obtain the resolution necessary to precisely define translational pauses. Here, we report improvements that yield much higher resolution in E. coli profiling data, enabling us to more accurately assess ribosome pausing and refine earlier studies of the impact of polyproline motifs on elongation. We comprehensively characterize pausing at proline-rich motifs in the absence of elongation factor EFP. We find that only a small fraction of genes with strong pausing motifs have reduced ribosome density downstream, and we identify features that explain this phenomenon. These features allow us to predict which proteins likely have reduced output in the efp-knockout strain. PMID- 25843708 TI - The lncRNA DEANR1 facilitates human endoderm differentiation by activating FOXA2 expression. AB - Long non-coding RNAs (lncRNAs) regulate diverse biological processes, including cell lineage specification. Here, we report transcriptome profiling of human endoderm and pancreatic cell lineages using purified cell populations. Analysis of the data sets allows us to identify hundreds of lncRNAs that exhibit differentiation-stage-specific expression patterns. As a first step in characterizing these lncRNAs, we focus on an endoderm-specific lncRNA, definitive endoderm-associated lncRNA1 (DEANR1), and demonstrate that it plays an important role in human endoderm differentiation. DEANR1 contributes to endoderm differentiation by positively regulating expression of the endoderm factor FOXA2. Importantly, overexpression of FOXA2 is able to rescue endoderm differentiation defects caused by DEANR1 depletion. Mechanistically, DEANR1 facilitates FOXA2 activation by facilitating SMAD2/3 recruitment to the FOXA2 promoter. Thus, our study not only reveals a large set of differentiation-stage-specific lncRNAs but also characterizes a functional lncRNA that is important for endoderm differentiation. PMID- 25843710 TI - HJURP involvement in de novo CenH3(CENP-A) and CENP-C recruitment. AB - Although our understanding of centromere maintenance, marked by the histone H3 variant CenH3(CENP-A) in most eukaryotes, has progressed, the mechanism underlying the de novo formation of centromeres remains unclear. We used a synthetic system to dissect how CenH3(CENP-A) contributes to the accumulation of CENP-C and CENP-T, two key components that are necessary for the formation of functional kinetochores. We find that de novo CENP-T accumulation depends on CENP C and that recruitment of these factors requires two domains in CenH3(CENP-A): the HJURP-binding region (CATD) and the CENP-C-binding region (CAC). Notably, HJURP interacts directly with CENP-C and is critical for de novo accumulation of CENP-C at synthetic centromeres. On the basis of our findings, we propose that HJURP serves a dual chaperone function in coordinating CenH3(CENP-A) and CENP-C recruitment. PMID- 25843709 TI - Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle. AB - New antimalarial drugs are urgently needed to control drug-resistant forms of the malaria parasite Plasmodium falciparum. Mitochondrial electron transport is the target of both existing and new antimalarials. Herein, we describe 11 genetic knockout (KO) lines that delete six of the eight mitochondrial tricarboxylic acid (TCA) cycle enzymes. Although all TCA KOs grew normally in asexual blood stages, these metabolic deficiencies halted life-cycle progression in later stages. Specifically, aconitase KO parasites arrested as late gametocytes, whereas alpha ketoglutarate-dehydrogenase-deficient parasites failed to develop oocysts in the mosquitoes. Mass spectrometry analysis of (13)C-isotope-labeled TCA mutant parasites showed that P. falciparum has significant flexibility in TCA metabolism. This flexibility manifested itself through changes in pathway fluxes and through altered exchange of substrates between cytosolic and mitochondrial pools. Our findings suggest that mitochondrial metabolic plasticity is essential for parasite development. PMID- 25843711 TI - Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING. AB - Upon systemic bacterial infection, hematopoietic stem and progenitor cells (HSPCs) migrate to the periphery in order to supply a sufficient number of immune cells. Although pathogen-associated molecular patterns reportedly mediate HSPC activation, how HSPCs detect pathogen invasion in vivo remains elusive. Bacteria use the second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di GMP) for a variety of activities. Here, we report that c-di-GMP comprehensively regulated both HSPCs and their niche cells through an innate immune sensor, STING, thereby inducing entry into the cell cycle and mobilization of HSPCs while decreasing the number and repopulation capacity of long-term hematopoietic stem cells. Furthermore, we show that type I interferon acted as a downstream target of c-di-GMP to inhibit HSPC expansion in the spleen, while transforming growth factor-beta was required for c-di-GMP-dependent splenic HSPC expansion. Our results define machinery underlying the dynamic regulation of HSPCs and their niches during bacterial infection through c-di-GMP/STING signaling. PMID- 25843712 TI - NF-kappaB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. AB - Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR mutant lung adenocarcinoma, we show that NF-kappaB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-kappaB-mediated transcriptional survival program. The direct NF-kappaB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-kappaB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-kappaB co-inhibition to eliminate residual disease and enhance patient responses. PMID- 25843713 TI - Casein kinase 1delta is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis. AB - Although casein kinase 1delta (CK1delta) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1delta or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1delta overexpression increases GCP proliferation. Thus, CK1delta appears to regulate GCP neurogenesis. CK1delta is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C(Cdh1)) ubiquitin ligase, and conditional deletion of the APC/C(Cdh1) activator Cdh1 in cerebellar GCPs results in higher levels of CK1delta. APC/C(Cdh1) also downregulates CK1delta during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1delta levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1delta holds promise as a therapeutic target. PMID- 25843715 TI - TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression. AB - Ten-eleven translocation hydroxylases (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons, increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling TET activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal TET3 isoform lacking a DNA-binding domain is targeted to the DNA. To identify factors binding to TET3, we screened for proteins that co precipitate with TET3 from mouse retina and identified the transcriptional repressor REST as a highly enriched TET3-specific interactor. REST was able to enhance TET3 hydroxylase activity after co-expression and overexpression of TET3 activated transcription of REST target genes. Moreover, we found that TET3 also interacts with NSD3 and two other H3K36 methyltransferases and is able to induce H3K36 trimethylation. We propose a mechanism for transcriptional activation in neurons that involves REST-guided targeting of TET3 to the DNA for directed 5hmC generation and NSD3-mediated H3K36 trimethylation. PMID- 25843714 TI - Transcriptional co-repressor function of the hippo pathway transducers YAP and TAZ. AB - YAP (yes-associated protein) and TAZ are oncogenic transcriptional co-activators downstream of the Hippo tumor-suppressor pathway. However, whether YAP and/or TAZ (YAP/TAZ) engage in transcriptional co-repression remains relatively unexplored. Here, we directly demonstrated that YAP/TAZ represses numerous target genes, including tumor-suppressor genes such as DDIT4 (DNA-damage-inducible transcript 4) and Trail (TNF-related apoptosis-inducing ligand). Mechanistically, the repressor function of YAP/TAZ requires TEAD (TEA domain) transcription factors. A YAP/TAZ-TEAD complex recruits the NuRD complex to deacetylate histones and alters nucleosome occupancy at target genes. Functionally, repression of DDIT4 and Trail by YAP/TAZ is required for mTORC1 (mechanistic target of rapamycin complex 1) activation and cell survival, respectively. Our demonstration of the transcriptional co-repressor activity of YAP/TAZ opens a new avenue for understanding the Hippo signaling pathway. PMID- 25843716 TI - Artificial association of pre-stored information to generate a qualitatively new memory. AB - Memory is thought to be stored in the brain as an ensemble of cells activated during learning. Although optical stimulation of a cell ensemble triggers the retrieval of the corresponding memory, it is unclear how the association of information occurs at the cell ensemble level. Using optogenetic stimulation without any sensory input in mice, we found that an artificial association between stored, non-related contextual, and fear information was generated through the synchronous activation of distinct cell ensembles corresponding to the stored information. This artificial association shared characteristics with physiologically associated memories, such as N-methyl-D-aspartate receptor activity and protein synthesis dependence. These findings suggest that the association of information is achieved through the synchronous activity of distinct cell ensembles. This mechanism may underlie memory updating by incorporating novel information into pre-existing networks to form qualitatively new memories. PMID- 25843717 TI - E4F1 is a master regulator of CHK1-mediated functions. AB - It has been previously shown that the polycomb protein BMI1 and E4F1 interact physically and genetically in the hematopoietic system. Here, we report that E4f1 is essential for hematopoietic cell function and survival. E4f1 deletion induces acute bone marrow failure characterized by apoptosis of progenitors while stem cells are preserved. E4f1-deficient cells accumulate DNA damage and show defects in progression through S phase and mitosis, revealing a role for E4F1 in cell cycle progression and genome integrity. Importantly, we showed that E4F1 interacts with and protects the checkpoint kinase 1 (CHK1) protein from degradation. Finally, defects observed in E4f1-deficient cells were fully reversed by ectopic expression of Chek1. Altogether, our results classify E4F1 as a master regulator of CHK1 activity that ensures high fidelity of DNA replication, thus safeguarding genome stability. PMID- 25843718 TI - Differentiation of human parthenogenetic pluripotent stem cells reveals multiple tissue- and isoform-specific imprinted transcripts. AB - Parental imprinting results in monoallelic parent-of-origin-dependent gene expression. However, many imprinted genes identified by differential methylation do not exhibit complete monoallelic expression. Previous studies demonstrated complex tissue-dependent expression patterns for some imprinted genes. Still, the complete magnitude of this phenomenon remains largely unknown. By differentiating human parthenogenetic induced pluripotent stem cells into different cell types and combining DNA methylation with a 5' RNA sequencing methodology, we were able to identify tissue- and isoform-dependent imprinted genes in a genome-wide manner. We demonstrate that nearly half of all imprinted genes express both biallelic and monoallelic isoforms that are controlled by tissue-specific alternative promoters. This study provides a global analysis of tissue-specific imprinting in humans and suggests that alternative promoters are central in the regulation of imprinted genes. PMID- 25843719 TI - A critical role for PKR complexes with TRBP in Immunometabolic regulation and eIF2alpha phosphorylation in obesity. AB - Aberrant stress and inflammatory responses are key factors in the pathogenesis of obesity and metabolic dysfunction, and the double-stranded RNA-dependent kinase (PKR) has been proposed to play an important role in integrating these pathways. Here, we report the formation of a complex between PKR and TAR RNA-binding protein (TRBP) during metabolic and obesity-induced stress, which is critical for the regulation of eukaryotic translation initiation factor 2 alpha (eIF2alpha) phosphorylation and c-Jun N-terminal kinase (JNK) activation. We show that TRBP phosphorylation is induced in the setting of metabolic stress, leading to PKR activation. Suppression of hepatic TRBP reduced inflammation, JNK activity, and eIF2alpha phosphorylation and improved systemic insulin resistance and glucose metabolism, while TRBP overexpression exacerbated the impairment in glucose homeostasis in obese mice. These data indicate that the association between PKR and TRBP integrates metabolism with translational control and inflammatory signaling and plays important roles in metabolic homeostasis and disease. PMID- 25843720 TI - Synapsin III acts downstream of semaphorin 3A/CDK5 signaling to regulate radial migration and orientation of pyramidal neurons in vivo. AB - Synapsin III (SynIII) is a phosphoprotein that is highly expressed at early stages of neuronal development. Whereas in vitro evidence suggests a role for SynIII in neuronal differentiation, in vivo evidence is lacking. Here, we demonstrate that in vivo downregulation of SynIII expression affects neuronal migration and orientation. By contrast, SynIII overexpression affects neuronal migration, but not orientation. We identify a cyclin-dependent kinase-5 (CDK5) phosphorylation site on SynIII and use phosphomutant rescue experiments to demonstrate its role in SynIII function. Finally, we show that SynIII phosphorylation at the CDK5 site is induced by activation of the semaphorin-3A (Sema3A) pathway, which is implicated in migration and orientation of cortical pyramidal neurons (PNs) and is known to activate CDK5. Thus, fine-tuning of SynIII expression and phosphorylation by CDK5 activation through Sema3A activity is essential for proper neuronal migration and orientation. PMID- 25843721 TI - The transcription factor E4F1 coordinates CHK1-dependent checkpoint and mitochondrial functions. AB - Recent data support the notion that a group of key transcriptional regulators involved in tumorigenesis, including MYC, p53, E2F1, and BMI1, share an intriguing capacity to simultaneously regulate metabolism and cell cycle. Here, we show that another factor, the multifunctional protein E4F1, directly controls genes involved in mitochondria functions and cell-cycle checkpoints, including Chek1, a major component of the DNA damage response. Coordination of these cellular functions by E4F1 appears essential for the survival of p53-deficient transformed cells. Acute inactivation of E4F1 in these cells results in CHK1 dependent checkpoint deficiency and multiple mitochondrial dysfunctions that lead to increased ROS production, energy stress, and inhibition of de novo pyrimidine synthesis. This deadly cocktail leads to the accumulation of uncompensated oxidative damage to proteins and extensive DNA damage, ending in cell death. This supports the rationale of therapeutic strategies simultaneously targeting mitochondria and CHK1 for selective killing of p53-deficient cancer cells. PMID- 25843723 TI - 'Geraniums (red) and Delphiniums (blue)': Trauma, Ethics, and Medical Communications. AB - More official complaints about medical treatment in the UK relate to poor communications than to wrong diagnoses. This article, in considering the importance of communications training for clinicians, is structured into three sections. From use of a story that introduces the idea of miscommunication and trauma in the first section, the article moves, in the second, to a theorisation of trauma as a concept, addressing issues of intersubjectivity, the relationship between embodied and psychological being, and ethics. From this, the third section engages directly with medical communications training, exemplifying a particular literary-studies approach to matters of communication. PMID- 25843722 TI - Individual and collective contributions of chaperoning and degradation to protein homeostasis in E. coli. AB - The folding fate of a protein in vivo is determined by the interplay between a protein's folding energy landscape and the actions of the proteostasis network, including molecular chaperones and degradation enzymes. The mechanisms of individual components of the E. coli proteostasis network have been studied extensively, but much less is known about how they function as a system. We used an integrated experimental and computational approach to quantitatively analyze the folding outcomes (native folding versus aggregation versus degradation) of three test proteins biosynthesized in E. coli under a variety of conditions. Overexpression of the entire proteostasis network benefited all three test proteins, but the effect of upregulating individual chaperones or the major degradation enzyme, Lon, varied for proteins with different biophysical properties. In sum, the impact of the E. coli proteostasis network is a consequence of concerted action by the Hsp70 system (DnaK/DnaJ/GrpE), the Hsp60 system (GroEL/GroES), and Lon. PMID- 25843724 TI - Seven Types of Ambiguity in Evaluating the Impact of Humanities Provision in Undergraduate Medicine Curricula. AB - Inclusion of the humanities in undergraduate medicine curricula remains controversial. Skeptics have placed the burden of proof of effectiveness upon the shoulders of advocates, but this may lead to pursuing measurement of the immeasurable, deflecting attention away from the more pressing task of defining what we mean by the humanities in medicine. While humanities input can offer a fundamental critical counterweight to a potentially reductive biomedical science education, a new wave of thinking suggests that the kinds of arts and humanities currently used in medical education are neither radical nor critical enough to have a deep effect on students' learning and may need to be reformulated. The humanities can certainly educate for tolerance of ambiguity as a basis to learning democratic habits for contemporary team-based clinical work. William Empson's 'seven types of ambiguity' model for analyzing poetry is transposed to medical education to: (a) formulate seven values proffered by the humanities for improving medical education; (b) offer seven ways of measuring impact of medical humanities provision, thereby reducing ambiguity; and PMID- 25843725 TI - Viruses and cancer: introduction. PMID- 25843727 TI - Reprint of: cancer "causation" by infections--individual contributions and synergistic networks. AB - The search for infectious agents playing a role in human carcinogenesis and their identification remain important issues. This could provide clues for a broader spectrum of cancers preventable by vaccination and accessible to specific therapeutic regimens. Yet, the various ways of interacting among different factors functioning synergistically and their different modes of affecting individual cells should bring to question the validity of the term "causation". It also should put a word of caution into all attempts to summarize criteria for "causality" of infectious agents in cancer development. At least in the opinion of these authors, we would be much better off avoiding these terms, replacing "causal factor" by "risk factor" and grading them according to their contribution to an individual's cancer risk. PMID- 25843728 TI - Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. AB - Kaposi sarcoma associated herpesvirus (KSHV), a gamma2-herpesvirus, also known as human herpesvirus-8, is the etiologic agent of three virally associated tumors: Kaposi sarcoma, a plasmablastic form of multicentric Castleman disease (KSHV MCD), and primary effusion lymphoma. These malignancies are predominantly seen in people with acquired immunodeficiencies, including acquired immunodeficiency syndrome and iatrogenic immunosuppression in the setting of organ transplantation, but can also develop in the elderly. Kaposi sarcoma (KS) is most frequent in regions with high KSHV seroprevalence, such as sub-Saharan Africa and some Mediterranean countries. In the era of combination antiviral therapy, inflammatory manifestations associated with KSHV-infection, including KSHV-MCD, a recently described KSHV-associated inflammatory cytokine syndrome and KS immune reconstitution syndrome also are increasingly appreciated. Our understanding of viral and immune mechanisms of oncogenesis continues to expand and lead to improved molecular diagnostics, as well as novel therapeutic strategies that employ immune modulatory agents, manipulations of the tumor microenvironment, virus-activated cytotoxic therapy, or agents that target interactions between specific virus-host cell signaling pathways. This review focuses on the epidemiology and advances in molecular and clinical research that reflects the current understanding of viral oncogenesis, clinical manifestations, and therapeutics for KSHV-associated tumors. PMID- 25843726 TI - Serodiagnosis for tumor viruses. AB - The known human tumor viruses include the DNA viruses Epstein-Barr virus (EBV), Kaposi sarcoma herpesvirus (KSHV), Merkel cell polyomavirus (MCPyV), human papillomavirus (HPV), and hepatitis B virus (BV). RNA tumor viruses include human T-cell lymphotrophic virus type 1 (HTLV-1) and hepatitis C virus (HCV). The serological identification of antigens/antibodies in serum is a rapidly progressing field with utility for both scientists and clinicians. Serology is useful for conducting seroepidemiology studies and to inform on the pathogenesis and host immune response to a particular viral agent. Clinically, serology is useful for diagnosing current or past infection and for aiding in clinical management decisions. Serology is useful for screening blood donations for infectious agents and for monitoring the outcome of vaccination against these viruses. Serodiagnosis of human tumor viruses has improved in recent years with increased specificity and sensitivity of the assays, as well as reductions in cost and the ability to assess multiple antibody/antigens in single assays. Serodiagnosis of tumor viruses plays an important role in our understanding of the prevalence and transmission of these viruses and ultimately in the ability to develop treatments/preventions for these globally important diseases. PMID- 25843729 TI - The epidemiology of cancers in human immunodeficiency virus infection and after organ transplantation. AB - The authors provide an update on the association between immune deficiency and cancer risk in people with human immunodeficiency virus (HIV) and in solid organ transplant recipients. Over the past decade, it has become clear that a wider range of about 20 mostly infection-related cancers occur at increased rates in people with immune deficiency. The human herpes virus 8 (HHV8) and Epstein Barr Virus (EBV)-related cancers of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) are most closely related to level of immune deficiency. Transplant recipients also have a greatly increased risk of squamous cell carcinoma (SCC) of the skin, related to direct carcinogenic effects of the pharmaceuticals used for immune suppression. For those three cancer types, the increased cancer risk is largely reversed when immune deficiency is decreased by treatment of HIV or by reduction of iatrogenic immune suppression. Other infection-related cancers also occur at increased rates, but it is not clear whether reduction of immune deficiency reduces cancer risk. Prostate and breast cancer do not occur at increased rates, providing strong evidence that these cancers are unlikely to be related to infection. Epidemiological and clinical trends in these two populations have led to substantial recent changes in cancer occurrence. PMID- 25843730 TI - Epstein-barr virus- and Kaposi sarcoma-associated herpesvirus-related malignancies in the setting of human immunodeficiency virus infection. AB - The human gammaherpesvirus family includes Epstein-Barr virus (EBV) and human herpesvirus (HHV)-8, also known as Kaposi sarcoma-associated herpesvirus (KSHV). In human immunodeficiency virus (HIV)-infected patients, both EBV and KSHV have been implicated in the development of a wide range of tumors. KSHV-associated diseases include Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). EBV has been associated with the development of several malignancies, including Hodgkin lymphoma (HL) and non Hodgkin lymphoma (NHL). The introduction of highly active antiretroviral therapy (HAART) has dramatically modified the natural history of HIV infection, causing a decline in the incidence of acquired immunodeficiency syndrome (AIDS)-defining malignancies, including KS. However, it has had a less favorable impact on EBV related malignancies and NHLs remain the most common tumors in the HAART era. In this review, we briefly summarize the pathogenesis, epidemiology, clinical features, and therapeutic approach to EBV- and KSHV-associated tumors in the setting of HIV infection. PMID- 25843731 TI - Prevention of human papillomavirus-associated cancers. AB - The oncogenic, anogenital types of human papillomavirus (HPV) are established as causing about 4.8% of all human cancers worldwide, particularly cervical, anal, vulvar, vaginal, penile, and oropharyngeal cancers. Quantitative knowledge of the HPV type-specific risks for these cancers, as well as for the different cervical cancer precursors (cervical intraepithelial neoplasias, CINs), is useful for estimating the effect of elimination of specific HPV types and clinical benefits of screening for specific HPV types. The present review summarizes both the worldwide presence of specific HPV types in cervical cancer precursors and in invasive cervical cancers, and also the long-term follow-up data from a large randomized clinical trial of HPV-based cervical cancer screening. All 12 HPV types classified as class I (established) carcinogens (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) were more common in cervical cancers than among women without cervical lesions. A few rare HPV types also were more common in cervical cancers (eg, HPV26, 67, 68, 69, 73, 82). The follow-up studies found increased long-term risks particularly for HPV types 16, 18, 31, and 33, which had 14-year cumulative incidences for CIN3+above 28%, while HPV35, 45, 52, and 58 had 14-year risks between 14%-18% and HPV39, 51, 56, 59, 66, and 68 had risks<10%. HPV16 contributed to the greatest proportion of CIN2+(first-round population attributable proportion [PAR] 36%), followed by types 31, 52, 45, and 58 (7%-11%). HPV16, 18, 31, 33, 45, 52, and 58 together contributed 73.9% of CIN2+lesions and all high-risk types contributed 86.9%.In summary, the different oncogenic HPV types have substantial differences in their oncogenic potential. These differences are relevant for the design and evaluation of cervical screening tests and programs, as well as for studying the effect of vaccination programs using different HPV vaccines. PMID- 25843732 TI - Human papillomaviruses and non-melanoma skin cancer. AB - Human papillomaviruses (HPVs) infect the squamous epithelium and can induce benign and malignant lesions. To date, more than 200 different HPV types have been identified and classified into five genera, alpha, beta, gamma, MU, and nu. While high-risk alpha mucosal HPVs have a well-established role in cervical carcinoma and a significant percentage of other anogenital tract and oral carcinomas, the biology of the cutaneous beta HPVs and their contribution to non melanoma skin cancer (NMSC) has been less studied. Although the association of beta HPV infection with NMSC in patients with a rare, genetically determined condition, epidermodysplasia verruciformis has been well established, the role of beta HPV infection with NMSC in the normal population remains controversial. In stark contrast to alpha HPV-associated cancers, the presence of the beta HPV genome does not appear to be mandatory for the maintenance of the malignant phenotype. Moreover, the mechanism of action of the beta HPV E6 and E7 oncoproteins differs from the beta HPV oncoproteins. PMID- 25843733 TI - Epstein-Barr virus-associated lymphomas. AB - The Epstein-Barr virus (EBV) is the first identified human virus with a proven association with the pathogenesis of cancer. To maintain the integrity of the viral genome and to "get out" of the control of the host immune system, in the phase of the latent infection EBV shows the expression of several genes, including genes for six nuclear antigens, three latent membrane proteins, two short non-coding RNAs, and BamHI-A rightward transcripts. The different patterns of expression of these latent genes determine the occurrence of different types of latency in the pathogenesis of particular malignancies. One of the most important features of EBV is its ability to infect various cell types and the consequent variety of diseases. It has been shown that in humans, EBV infection may lead to the development of cancers, including those derived from hematopoietic cells. Although cases of T-cell and epithelial cell infections have been documented, EBV is characterized mainly by tropism for B lymphocytes, and under certain conditions their infection may result in transformation to B-cell lymphoma. This article discusses the mechanisms leading to the development of EBV dependent lymphomas, and briefly characterizes these diseases. PMID- 25843734 TI - Parvovirus and thyroid cancer. AB - Parvoviruses are some of the smallest DNA viruses known to infect a wide range of animal species and humans. Though not all parvoviruses are pathogenic, some can cause disease ranging from asymptomatic to benign to life-threatening. Recently, there has been an interest in the possible role of parvoviruses in thyroid disease in general. The objectives of this review are to cite and appraise the available evidence on the role of parvoviruses in thyroid cancer in particular. Little to no evidence is available directly linking animal parvoviruses and thyroid cancer, but there is a growing literature on the human erythrovirus B19 (EVB19) and its association with thyroid cancer. Of particular interest is the persistence and expression of EVB19 DNA, RNA, and protein in a wide variety of thyroid tissues. While a causative role of EVB19 in the pathogenesis of thyroid cancer cannot be supported at this time, an indirect role is hypothesized and discussed but with the recognition that the data are limited. Further studies are clearly warranted to determine the exact, if any, role of this human pathogen in thyroid cancer. PMID- 25843735 TI - A comparison of patients with hepatitis B- or hepatitis C-based advanced-stage hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer death and has characteristic causes, epidemiology and clinical features. The leading causes include hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholism, and aflatoxin B1 dietary exposure, as well as combinations of these factors. Few cancers offer the opportunity to study the clinical and cancer phenotype that results from different causes, quite like HCC. Advantage was taken of a large cohort of advanced, unresectable and untransplantable HCCs to compare the phenotypes resulting from HBV-based compared with HCV-based HCC. The main findings were that HBV-based HCC patients were statistically significantly younger, had a higher percent of males, had larger maximum tumor sizes, and had higher blood alpha-fetoprotein (AFP) and albumin levels and platelet counts than HCV-based HCC patients. These differences partly reflect an earlier age of HBV infection and a lesser degree of cirrhosis-associated liver damage, as a result of the different biological consequences of chronic HBV compared with chronic HCV infection. PMID- 25843736 TI - Prevention of hepatocellular carcinoma: beyond hepatitis B vaccination. AB - Chronic hepatitis B (CHB) infection is the major cause of hepatocellular carcinoma (HCC), accounting for approximately 50% of the underlying etiologies. We reviewed the primary, secondary, and tertiary measures for the prevention of hepatitis B virus (HBV)-related HCC. The most effective method for preventing HBV related HCC is vaccination. Universal hepatitis B vaccination has been shown to reduce the rates of HBV infection and HCC significantly. Once chronic HBV infection is established, antiviral treatment using interferon or nucleos(t)ide analogs is used to prevent disease progression to cirrhosis, HCC, or both. Studies have found viral replication indicated by HBV DNA level to be a strong risk factor for development of HCC. Additionally, periodic surveillance using ultrasonography and serum alpha-fetoprotein for earlier detection of HCC is also important so that curative treatments with survival benefit can be possible. Finally, adjuvant antiviral treatment using interferon or nucleos(t)ide analogs is used to prevent tumor recurrence after curative resection. Adjuvant interferon treatment prevented early recurrence, not late recurrence, probably due to its antiangiogenetic and antiproliferative effects. Adjuvant nucleos(t)ide analogs demonstrated promising results for preventing late recurrence, probably due to effective suppression of viral replication. Further investigations are required to establish the optimal preventive plans for HBV-related HCC. PMID- 25843737 TI - Hepatitis C virus infection, antiviral therapy, and risk of hepatocellular carcinoma. AB - Hepatitis C virus (HCV) infection is a major etiology of hepatocellular carcinoma (HCC) around the world. Carcinogenesis may result indirectly from longstanding hepatic inflammation and fibrosis. It also may arise directly from viral proteins and their interaction with the host intracellular machinery. Pegylated interferon plus ribavirin had been the standard antiviral regimen for a decade until recently when the paradigm shifted to the direct-acting antivirals. A large body of evidence has shown undisputedly that antiviral therapy can effectively reduce the occurrence of HCC in patients at any stage of liver fibrosis. Moreover, it is associated with an attenuated risk of recurrence following curative resection of the cancer. Sustained virological eradication is crucial for the effectiveness in clinical outcomes, whereas prolonged interferon maintenance without viral clearance should be regarded as obsolete. Surveillance remains essential after successful antiviral treatment because the risk of HCC is decreased but not eliminated, particularly in older patients or those with liver cirrhosis. In the upcoming interferon-free era, more efficacious and tolerable medications hopefully will further extinguish not only the virus but also the health burden associated with it. PMID- 25843738 TI - Evaluation of total hepatocellular cancer lifespan, including both clinically evident and preclinical development, using combined network phenotyping strategy and fisher information analysis. AB - We previously showed that for hepatocellular cancer (HCC) prognostication, disease parameters need to be considered within a total personal clinical context. This requires preserving the coherence of data values, observed simultaneously for each patient during baseline diagnostic evaluation. Application of the Network Phenotyping Strategy (NPS) provided quantitative descriptors of these patient coherences. Combination of these descriptors with Fisher information about the patient tumor mass and the histogram of the tumor masses in the whole cohort permitted estimation of the time from disease onset until clinical diagnosis (t(baseline)). We found faster growth of smaller tumors having total masses<70 (80% of cohort) which involved about three times more interacting cellular processes than were observed for slower growing larger tumors (20% of cohort) with total masses>70. Combining the clinical survival and t(baseline) normalized all HCC patients to a common 1,045 days of mean total disease duration (t(baseline) plus post diagnosis survival). We also found a simple relationship between the baseline clinical status, t(baseline), and survival. Every difference between individual patient baseline clinical profiles and special coherent clinical status (HL1) reduced the above common overall survival (OVS) by 65 days. In summary, we showed that HCC patients with any given tumor can best have their tumor biology understood, when account is taken of the total clinical and liver contexts, and with knowing the point in the tumor history when an HCC diagnosis is made. This ability to compute the t(baseline) from standard clinical data brings us closer to calculating survival from diagnosis of individual HCC patients. PMID- 25843739 TI - Merkel cell polyomavirus in merkel cell carcinoma: clinical and therapeutic perspectives. AB - Merkel cell carcinoma (MCC) is a rare and often aggressive cutaneous cancer with a poor prognosis. The incidence of this cancer increases with age, immunodeficiency and sun exposure. Merkel cell polyomavirus (MCPyV), a new human polyomavirus identified in 2008, is detected in the majority of the MCCs and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV. A causal link between MCPyV and MCC has been evidenced and this is the first polyomavirus to be clearly implicated as a causal agent underlying a human cancer, and MCPyV was recently classified as a 2A carcinogen. MCC is thus a rare tumor caused by a very common viral skin infection. The aim of this review is to provide a basic overview of the epidemiological, clinical, and pathological characteristics of MCC, to present the current knowledge on MCPyV polyomavirus and its causal association with MCC development, and to describe the therapeutic implications of this causal link. PMID- 25843740 TI - Synchronous primary carcinoma of breast and ovary versus ovarian metastases. PMID- 25843741 TI - GHS-R1A antagonism reduces alcohol but not sucrose preference in prairie voles. AB - RATIONALE: Ghrelin has been shown to mediate food and drug reward in rats and mice, and the rewarding properties of sweet foods and alcohol are known to contribute to overconsumption of these substances. OBJECTIVE: To investigate the effects of GHS-R1A antagonism in a novel animal model of high alcohol consumption, the prairie vole, and to characterize the role of ghrelin in limited access consumption of a drug (alcohol) and non-drug (sucrose) reward. METHODS: Female prairie voles were given four 2-h two-bottle drinking sessions, occurring every other day. During drinking sessions, animals had access to 20% ethanol vs water or 10% sucrose vs water. Pre-treatment with the GHS-R1A antagonist JMV 2959 (i.p.; 0.0, 9.0mg/kg Experiments 1 and 2; 0.0, 9.0, 12.0mg/kg Experiments 3 and 4.) occurred 30-min before the fourth session. To determine if the amount of exposure to sucrose sessions affected the efficacy of JMV 2959, in Experiment 5 animals were given 16 daily 2-hr drinking sessions with 10% sucrose vs water. JMV 2959 treatment (0.0 or 9.0mg/kg) occurred 30-min prior to the 16th session. RESULTS: JMV 2959 reduced alcohol but not sucrose preference. Even after extended experience with sucrose sessions, JMV 2959 had no effect on sucrose preference or consumption. CONCLUSION: These findings demonstrate that GHS-R1A antagonism reduces alcohol preference, but suggest limitations on the role of ghrelin in the preference for and consumption of naturally rewarding substances. PMID- 25843742 TI - Improved rapid and efficient method for Staphylococcus aureus DNA extraction from milk for identification of mastitis pathogens. AB - A rapid and efficient DNA extraction method was developed for detecting mastitis pathogens in milk. The first critical step involved cell wall disruption by bead beating, as physical disruption using beads was more effective for DNA extraction from Gram-positive bacteria, such as Staphylococcus aureus, than enzymatic disruption using proteinase K. The second critical step involves the use of acetic acid and ammonium sulfate in the purification process, as these reagents effectively and efficiently remove the lipids and proteins in milk. Using these methods, DNA suitable for loop-mediated isothermal amplification was obtained within 30 min. Also, the rapid and sensitive detection of S. aureus in milk was possible at levels as low as 200 cfu/ml. PMID- 25843743 TI - Phylogenetic analysis of Newcastle disease viruses isolated from wild birds in the Poyang Lake region of China. AB - Newcastle disease virus (NDV) causes a highly contagious viral disease in poultry and wild birds, and it can cause significant economic loss worldwide. Eight viral strains were isolated by inoculating embryonated chicken eggs from the Poyang Lake region of China with swab samples. All eight of the NDV isolates were identified as class I genotype 3 strains, but they diverged notablely from class II viruses. Further analysis revealed that all eight NDV isolates were lentogenic strains containing the (112)ERQER?L(117) motif at the F protein cleavage site. The strains were highly identical and were more species specific (chicken and waterfowl) than site specific (Nanchang and Duchang regions). The close phylogenetic proximity of these isolates indicates that viral transmission may happen between poultry and wild birds. Our study demonstrates that lentogenic class I NDVs exist in clinically healthy wild waterfowl and poultry within the Poyang Lake region. Active surveillance of these viruses to determine their evolution and origin is one of the most realistic strategies for preventing and controlling NDV outbreaks. PMID- 25843744 TI - Effect of supplemental vitamin E on the peripheral blood leukocyte population in Japanese Black calves. AB - We investigated the effect of supplemental vitamin E on the peripheral blood leukocyte population in Japanese Black calves. Twenty-six calves kept at the same farm were studied. They were divided into two groups; thirteen calves received 300 IU/day of vitamin E orally from 1 to 3 months of age (VE group), and the other thirteen calves did not receive the vitamin E supplement (control group). The VE group showed a higher serum vitamin E concentration at 2 and 3 months of age compared with the control group (P<0.01). The numbers of CD3(+) cells and CD4(+) cells were higher in the VE group than in the control group, and the difference was statistically significant at 3 months of age (P<0.05). The numbers of CD21(+) cells were higher in the VE group than in the control group, and the difference was statistically significant at 2 months of age (P<0.05). The numbers of CD335(+) cells tended to be higher in the VE group than in the control group. The numbers of CD8(+) cells and CD14(+) cells tended to be higher in the VE group than in the control group at 3 and 4 months of age. This study demonstrated that the supplementation of suckling Japanese Black calves with vitamin E might affect the numbers of some immune cell types in the peripheral blood. PMID- 25843745 TI - Characterization of Aerococcus viridans isolated from milk samples from cows with mastitis and manure samples. AB - Thirty-eight Aerococcus viridans isolates were obtained from milk from 478 cows with clinical mastitis in a farm during the periods between November 2011 and February 2012, and between December 2012 and March 2013. Additional isolates were obtained from processed manure (a mixture of composted manure, straw and hydrated lime) and bedding materials. The processed manure was later used to cover the floor of the stalls in barns as bedding materials. The temperatures recorded in the composted and processed manure were not as high as those generally observed during satisfactory composting. To reveal the association of A. viridans in manure-related products with intramammary infection in cows, isolates were characterized by their DNA fragment patterns as determined by pulsed-field gel electrophoresis (PFGE) and antimicrobial susceptibility testing. Isolates obtained from milk, processed manure and bedding materials had identical DNA fragment patterns. Antimicrobial susceptibilities were determined for 29 isolates from milk, processed manure and bedding materials. Of these, 26 (89.7%) were resistant to clindamycin, whereas virtually all the isolates were susceptible to 12 other antimicrobials including cefalosporins that have been used to treat bovine mastitis in Japan. In vitro, three A. viridans isolates from milk and an isolate from processed manure survived for 3 hr in Good's buffer (pH 9) at high temperature (50 degrees C). The results suggest that the processed manure and bedding materials in this farm were possible sources of A. viridans that caused infection in the cows with mastitis. PMID- 25843746 TI - Reply to comment on "Biodegradation of perfluorooctanesulfonate (PFOS) as an emerging contaminant". PMID- 25843747 TI - Output feedback stabilization for time-delay nonholonomic systems with polynomial conditions. AB - This paper addresses the problem of output feedback stabilization for a class of time-delay nonholonomic systems. One distinct characteristic or difficulty of this paper is that time-delay exists in polynomial nonlinear growing conditions. Based on input-state-scaling technique, homogeneous domination approach and Lyapunov-Krasovskii theorem, a new output feedback control law which guarantees all the system states converge to the origin is designed. Examples are provided to demonstrate the validness of the proposed approach. PMID- 25843749 TI - ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. AB - RATIONALE: Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders. OBJECTIVES: The purpose of this study was to determine brain occupancy of ITI-007 at serotonin 5-HT2A receptors, dopamine D2 receptors, and serotonin transporters using positron emission tomography (PET) in 16 healthy volunteers. METHODS: Carbon-11-MDL100907, carbon-11-raclopride, and carbon-11-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) (carbon 11-DASB) were used as the radiotracers for imaging 5-HT2A receptors, D2 receptors, and serotonin transporters, respectively. Brain regions of interest were outlined using magnetic resonance tomography (MRT) with cerebellum as the reference region. Binding potentials were estimated by fitting a simplified reference tissue model to the measured tissue-time activity curves. Target occupancy was expressed as percent change in the binding potentials before and after ITI-007 administration. RESULTS: Oral ITI-007 (10-40 mg) was safe and well tolerated. ITI-007 rapidly entered the brain with long-lasting and dose-related occupancy. ITI-007 (10 mg) demonstrated high occupancy (>80 %) of cortical 5-HT2A receptors and low occupancy of striatal D2 receptors (~12 %). D2 receptor occupancy increased with dose and significantly correlated with plasma concentrations (r (2) = 0.68, p = 0.002). ITI-007 (40 mg) resulted in peak occupancy up to 39 % of striatal D2 receptors and 33 % of striatal serotonin transporters. CONCLUSIONS: The results provide evidence for a central mechanism of action via dopaminergic and serotonergic pathways for ITI-007 in living human brain and valuable information to aid dose selection for future clinical trials. PMID- 25843748 TI - Multivariate analysis of subjective responses to d-amphetamine in healthy volunteers finds novel genetic pathway associations. AB - RATIONALE: Researchers studying behavioral and physiologic effects of d amphetamine have explored individual response differences to the drug. Concurrently, genome-wide analyses have identified several single-nucleotide polymorphisms (SNPs) associated with these traits. Univariate methods can identify SNPs associated with behavioral and physiological traits, but multivariate analyses allow identification of clusters of related biologically relevant SNPs and behavioral components. OBJECTIVES: The aim of the study was to identify clusters of related biologically relevant SNPs and behavioral components in the responses of healthy individuals to d-amphetamine using multivariate analysis. METHODS: Individuals (N = 375) without substance abuse histories completed surveys and detailed cardiovascular monitoring during randomized, blinded sessions: d-amphetamine (10 and 20 mg) and placebo. We applied parallel independent component analysis (Para-ICA) to data previously analyzed with univariate approaches, revealing new associations between genes and behavioral responses to d-amphetamine. RESULTS: Three significantly associated (p < .001) phenotype-genotype pairs emerged. The first component included physiologic measures of systolic and diastolic blood pressure (BP) and mean arterial pressure (MAP) along with SNPs in calcium and glutamatergic signaling pathways. The second associated components included the "Anger" items from the Profile of Mood States (POMS) questionnaire and the marijuana effects from the Addiction Research Center Inventory (Cuyas, Verdejo-Garcia et al.), with enriched genetic pathways involved in cardiomyopathy and MAPK signaling. The final pair included "Anxious," "Fatigue," and "Confusion" items from the POMS questionnaire, plus functional pathways related to cardiac muscle contraction and cardiomyopathy. CONCLUSIONS: Multifactorial genetic networks related to calcium signaling, glutamatergic and dopaminergic synapse function, and amphetamine addiction appear to mediate common behavioral and cardiovascular responses to d-amphetamine. PMID- 25843751 TI - Analysis of the Size and Position of the Mental Foramen Using the CS 9000 Cone beam Computed Tomographic Unit. AB - INTRODUCTION: The mental foramen (MF) houses vital neurovascular structures, thus making it an anatomic landmark of great importance for many dental procedures. Because the size and position of the MF can vary, proper planning is necessary beforehand to prepare the strategy of treatment. The purpose of this retrospective observational study was to determine and compare the size and position of the MF using the CS 9000 CBCT unit (Carestream Dental, Rochester, NY) to the findings from similar studies. METHODS: Tangential, axial, and coronal CBCT images of 106 patients were retrospectively evaluated to determine the size and position of the MF with respect to the mandibular second premolar apex and the cementoenamel junction. Distinguishing characteristics of sex, age, and race were evaluated. RESULTS: Regarding location, 53.7% of the MFs were located mesial, 45.3% distal, and 1% coincident to the apex of the mandibular second premolar. Males had a significantly greater coronal height and tangential height measurement than females. Black patients had a significantly greater distal horizontal distance from the cementoenamel junction than white patients. The mean width of the MF was 4.08 mm (axial) or 4.12 mm (tangential), whereas the mean height was 3.54 mm (tangential) or 3.55 mm (coronal). CONCLUSIONS: The present study shows that the size and position of the MF can be reliably measured using limited field of view CBCT technology. The findings are similar to previous studies when considering the averages and ranges of the measurements. PMID- 25843750 TI - Tumor Necrosis Factor Alpha Stimulates Proliferation of Dental Pulp Stem Cells via Akt/Glycogen Synthase Kinase-3beta/Cyclin D1 Signaling Pathway. AB - INTRODUCTION: It has been widely accepted that dental pulp stem cells (DPSCs), which are a class of self-renewal and differentiation potential of adult stem cells, play an important role in the repair procession of pulp's inflammation. We investigated whether tumor necrosis factor alpha (TNF-alpha) could induce the proliferation of DPSCs and clarified the potential mechanism of this proliferation. METHODS: Cell Counting Kit-8 assay (Dojindo Laboratories, Mashiki machi, Kumamoto, Japan) and 5-ethynyl-2'-deoxyuridine-based proliferation assays were determined to investigate various concentrations or hours of TNF-alpha inducing a cell number change of DPSCs. Next, flow cytometry analysis was performed to investigate the main cell cycle phase process of DPSCs. Furthermore, the signaling pathway of TNF-alpha-induced proliferation of DPSCs was analyzed using Western blot analysis. Then, inhibitors were added to confirm the mechanism of this signaling pathway. RESULTS: TNF-alpha induced the proliferation of DPSCs in a dose- and time-dependent manner. Cyclin D1, which controlled the cell cycle process from the G1 to the S phase, was up-regulated by TNF-alpha in a time dependent manner, whereas its overexpression alone increased DPSC proliferation. Furthermore, TNF-alpha was capable of inducing Akt/GSK-3beta signaling pathway activation. Blockage of phosphoinositide 3-kinase/Akt by their kinase or genetic inhibitors could significantly reduce TNF-alpha-induced proliferation of DPSCs. CONCLUSIONS: This study confirmed that TNF-alpha induced the proliferation of DPSCs by regulating the Akt/GSK-3beta/cyclin D1 signaling pathway and then provided a suitable number for the requirements of cell differentiation. PMID- 25843752 TI - Incidence of Dentinal Cracks after Root Canal Preparation with Twisted File Adaptive Instruments Using Different Kinematics. AB - INTRODUCTION: The purpose of the present study was to assess the effect of root canal instrumentation using Twisted File Adaptive instruments (Axis/SybronEndo, Orange, CA) with different kinematics (adaptive motion, 90 degrees clockwise [CW]-30 degrees counterclockwise [CCW], 150 degrees CW-30 degrees CCW, 210 degrees CW-30 degrees CCW, and continuous rotation) on crack formation. METHODS: One hundred five mandibular central incisor teeth were selected. Fifteen teeth were left unprepared (control group), and the remaining 90 teeth were assigned to the 5 root canal shaping groups as follows (n = 15): adaptive motion, 90 degrees CW-30 degrees CCW, 150 degrees CW-30 degrees CCW, 210 degrees CW 30 degrees CCW, continuous rotation, and hand file. All the roots were sectioned horizontally at 3, 6, and 9 mm from the apex with a low-speed saw under water cooling, and the slices were then viewed through a stereomicroscope at 25* magnification. Digital images of each slice were captured using a camera to determine the presence of dentinal cracks. RESULTS: No cracks were observed in the control group, and the continuous rotation group had more cracks than the reciprocation groups (90 degrees CW-30 degrees CCW, 150 degrees CW-30 degrees CCW, and 210 degrees CW-30 degrees CCW) (P < .05). Both the continuous rotation and adaptive motion groups had significantly more dentinal cracks than the hand file group (P < .05). Regarding the different sections (3, 6, and 9 mm), there was a significant difference between the experimental groups at the 9-mm level (P < .05). CONCLUSIONS: The incidence of dentinal cracks is less with TF Adaptive instruments working in 210 degrees CW-30 degrees CCW reciprocating motion compared with working in continuous rotation and adaptive motion. PMID- 25843753 TI - The Diagnostic Efficacy of Cone-beam Computed Tomography in Endodontics: A Systematic Review and Analysis by a Hierarchical Model of Efficacy. AB - INTRODUCTION: The aim of this study was to evaluate the diagnostic efficacy of cone-beam computed tomographic (CBCT) imaging in endodontics based on a systematic search and analysis of the literature using an efficacy model. METHODS: A systematic search of the literature was performed to identify studies evaluating the use of CBCT imaging in endodontics. The identified studies were subjected to strict inclusion criteria followed by an analysis using a hierarchical model of efficacy (model) designed for appraisal of the literature on the levels of efficacy of a diagnostic imaging modality. RESULTS: Initially, 485 possible relevant articles were identified. After title and abstract screening and a full-text evaluation, 58 articles (12%) that met the inclusion criteria were analyzed and allocated to levels of efficacy. Most eligible articles (n = 52, 90%) evaluated technical characteristics or the accuracy of CBCT imaging, which was defined in this model as low levels of efficacy. Only 6 articles (10%) proclaimed to evaluate the efficacy of CBCT imaging to support the practitioner's decision making; treatment planning; and, ultimately, the treatment outcome, which was defined as higher levels of efficacy. CONCLUSIONS: The expected ultimate benefit of CBCT imaging to the endodontic patient as evaluated by its level of diagnostic efficacy is unclear and is mainly limited to its technical and diagnostic accuracy efficacies. Even for these low levels of efficacy, current knowledge is limited. Therefore, a cautious and rational approach is advised when considering CBCT imaging for endodontic purposes. PMID- 25843754 TI - Semi-solid fluorinated-DPPC liposomes: Morphological, rheological and thermic properties as well as examination of the influence of a model drug on their skin permeation. AB - The goal of this study was to investigate the influence of an incorporated model drug on the skin permeation of the vehicle itself as it may affect the microstructure and properties of the applied formulation via molecular interactions. For this purpose, we performed skin permeation studies using liposomes prepared with F-DPPC, a monofluorinated analog of dipalmitoylphosphatidylcholine (DPPC), with and without sodium fluorescein (SoFl) serving as model drug. Interestingly, the liposome preparation with F-DPPC yielded semi-solid opalescent systems. Hence, a thorough characterization was accomplished beforehand by electron microscopy imaging, rheological and thermoanalytical experiments. Freeze-fracture electron microscopy images confirmed the existence of globular shaped vesicles in the F-DPPC preparations and oscillatory rheological measurements proved the viscoelastic properties of F DPPC and F-DPPC+SoFl liposomes in contrast to the viscous characteristics of DPPC liposomes. Thermoanalytical measurements revealed an increased phase transition temperature Tm of about 50 degrees C for F-DPPC and F-DPPC+SoFl liposomes compared to pure DPPC liposomes with a Tm of about 43 degrees C. The similar Tm of F-DPPC+SoFl and F-DPPC liposomes as well as the similar skin permeation of the vehicle compound F-DPPC compared to its drug-free counterpart suggest an incorporation of sodium fluorescein into the aqueous core of F-DPPC liposomes. PMID- 25843755 TI - Dehydration mechanism of caffeine hydrate and structural description of driven metastable anhydrates analyzed by micro Raman spectroscopy. AB - This study shows the contribution of Raman spectroscopy to carefully describe the mechanism of solid-state transformation at the molecular level, by simultaneously monitoring the molecular reorganization and the water escape during the dehydration kinetics. Dehydration of monohydrate caffeine was analyzed at various temperatures. In-situ low- and high-frequency Raman investigations provide information on the long-range and local arrangement of caffeine molecules, during the dehydration kinetics and in the anhydrate state. The nature of the anhydrate was determined, from the analysis in the low-frequency region, as metastable and transient between both polymorphic forms of anhydrous caffeine. It was shown that changing the temperature mainly induces structural reorganization of caffeine molecules in the hydrate state, leading to an anhydrate more or less transformed in form I of anhydrous caffeine. PMID- 25843756 TI - "Pierce and inhale" design in capsule based dry powder inhalers: Effect of capsule piercing and motion on aerodynamic performance of drugs. AB - In this work three capsule-based dry powder inhalers, available for generics product development, were compared. Two technologically different dry powder formulations were used in order to relate the capsule piercing position and motion in the device to their aerodynamic performance. A "pierce and inhale" design, in which the capsules pierced with RS01, HandiHaler or Turbospin devices were aerosolized in the same device or transferred and aerosolized with another device, was constructed and carried out. The results obtained showed that two dry powder formulations, i.e., a drug/lactose blend or a carrier-free powder, aerosolized using capsule based inhalers, performed differently. The aerosolization of drug carrier mixture in terms of drug dispersion and emitted dose, was more sensible to the piercing and device combination than the carrier free powder. The motion of the capsule during the aerosolization boosted the powder emission, whereas the powder disaggregation was more influenced by the airflow pattern around the capsule and inside the inhaler turbulence chamber. PMID- 25843757 TI - Development of gastroretentive metronidazole floating raft system for targeting Helicobacter pylori. AB - The study demonstrates the feasibility of prolonging gastric residence time and release rate of metronidazole (Mz) by preparing floating raft system (FRS) using ion-sensitive in situ gel forming polymers. FRSs contained 3, 4, 5 and 0.5, 0.75, 1% w/v sodium alginate (Alg) and gellan gum (G), respectively, 0.25% w/v sodium citrate and calcium carbonate (C). Lipids: glyceryl mono stearate (GMS), Precirol((r)) and Compritol((r)) were incorporated into G-based formulations (G1%C1%). Mz:lipid ratio was 1:1, except for Mz:GMS, ratios of 1:1.5 and 1:2 were also investigated. Buoyancy, gelation capacity and viscosity parameters were evaluated. Drug release and kinetics for selected formulae were examined. The selected lipid containing formula was subjected to an accelerated stability testing. Alg4%C2% FRS exhibited short gelation lag time (3s), long duration (>24h), floating lag time 1m in and duration >24h, and a reliable sustained drug release (MDT 6h). Gellan gum FRSs achieved successful floating gastroretention, but failed to achieve the required gelation capacity. Incorporation of GMS (Mz:GMS 1:1) enhanced the gelation lag time and duration (6s and >24h, respectively), keeping sustained drug release and formulation stability. The improved characteristics of the selected FRS make them excellent candidates for gastric targeting to eradicate Helicobacter pylori. PMID- 25843758 TI - Development of gastro-resistant tablets for the protection and intestinal delivery of Lactobacillus fermentum CECT 5716. AB - Different studies have attributed health benefits to Lactobacillus fermentum CECT 5716. However, the main problem associated with probiotics, is their low resistance to environmental and technological factors. Actually, probiotics are marketed as capsules or sachets, but few probiotic tablets exist. The aim of this study was to design tablets made out of functional polymers (formula 1: methocel K-15-sodium alginate; formula 2: Eudragit((r)) L-100-sodium alginate; formula 3: cellulose acetate phthalate) that improve the stability and survival of probiotics. Rigid tablets were produced through direct compression with a bacterial content of 10(9)CFU/tablet (9logCFU). Tablets were shown to improve the survival of cells when exposed to an acidic medium as compared to free cells. Eudragit((r)) L-100-sodium alginate was found to be the most suitable excipient for the protection of probiotic within gastric conditions, resulting in the survival of 10(9)CFU (9logCFU) after 2h of incubation. Finally, these tablets were found to be stable over 6 months when stored at 4 degrees C. No significant differences were reported between the number of cells at time cero and after 6 months of storage at 4 degrees C (p>0.05). In conclusion, direct compression using Eudragit((r)) L-100-sodium alginate seems to be a suitable to produce probiotics tablets and could confer protection during passage trough stomach and storage. PMID- 25843759 TI - Vancomycin-modified silica: Synthesis, controlled release and biological activity of the drug. AB - Vancomycin was immobilized on three different organically functionalized silicas. The materials obtained were used for a controlled release of the antibiotic. The influence of the type of chemical bond on the in vitro drug release was investigated. A weak ionic bonding caused burst release of the drug within one day. A covalent bonding resulted in a slowdown in the release process and uniformity of dosage release. For these two carriers, biological activity of the drug was retained because the minimal inhibitory concentration values against the strains tested were similar to that of a free form of the drug (about 2 MUg/mL). A strong ionic bonding of vancomycin adversely affected both the drug release, as well as its biological activity. A strong base on the surface of the silica prevented disconnection of the antibiotic which then became ineffective. PMID- 25843760 TI - A miniaturized in vitro release method for investigating drug-release mechanisms. AB - We have evaluated a miniaturized in vitro method, based on the MUDISS ProfilerTM technique that enables on-line monitoring of drug release from a 21 MUl sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non solid formulations. PMID- 25843761 TI - Amorphous solid dispersions of piroxicam and Soluplus((r)): Qualitative and quantitative analysis of piroxicam recrystallization during storage. AB - The conversion of active pharmaceutical ingredient (API) from amorphous to crystalline form is the primary stability issue in formulating amorphous solid dispersions (SDs). The aim of the present study was to carry out qualitative and quantitative analysis of the physical solid-state stability of the SDs of poorly water-soluble piroxicam (PRX) and polyvinyl caprolactam-polyvinyl acetate polyethylene-glycol graft copolymer (Soluplus((r))). The SDs were prepared by a solvent evaporation method and stored for six months at 0% RH/6 degrees C, 0% RH/25 degrees C, 40% RH/25 degrees C and 75% RH/25 degrees C. Fourier transform infrared spectroscopy equipped with attenuated total reflection accessory (ATR-FTIR) and Raman spectroscopy were used for characterizing the physical solid-state changes and drug-polymer interactions. The principal component analysis (PCA) and multivariate curve resolution alternating least squares (MCR-ALS) were used for the qualitative and quantitative analysis of Raman spectra collected during storage. When stored at 0% RH/6 degrees C and at 0% RH/25 degrees C, PRX in SDs remained in an amorphous form since no recrystallization was observed by ATR-FTIR and Raman spectroscopy. Raman spectroscopy coupled with PCA and MCR-ALS and ATR-FTIR spectroscopy enabled to detect the recrystallization of amorphous PRX in the samples stored at higher humidity. PMID- 25843762 TI - Tris-biphenyl triazine, a new ultraviolet filter studied in terms of photoprotective efficacy. AB - There are relatively few authorized ultraviolet filters in Europe and this presents a certain number of problems when we want to formulate a sun protection product which both ensures a high level of protection and respects the recommendations in force in terms of broad-spectrum efficacy, with, in particular, a critical wavelength (lambdac) greater than or equal to 370 nm. A new ultraviolet filter has just been launched on the market. Known as tris biphenyl triazine, it is the first filter to be registered on Annexe VI of "Cosmetics Regulation" (EC) No. 1223/2009 of the European Parliament and of the Council, which gives a list of the ultraviolet filters allowed in cosmetic products, since the regulation came into force in July 2013. This filter is both very effective (as it enables 2 SPF units and 1 UVA-PF units to be obtained respectively, by percentage of use) and very photostable (since the SPF and UVA PF do not vary after 2h of irradiation in a solar simulator). Its broad spectrum associated with its qualities in terms of efficacy and photostability make it a choice ingredient for the formulation of sun protection products. PMID- 25843763 TI - Leukapheresis in acute myeloid leukemia patients with hyperleukocytosis: A single center experience. AB - Hyperleukocytosis is defined as WBC count above 100,000/mm(3) in peripheral blood. Increased WBC count leads to leukocyte aggregation, increased blood viscosity, and consequently results in stasis in small blood vessels. Ultimate neurological, pulmonary, gastrointestinal complications, coagulopathy, and tumor lysis syndrome cause increase in morbidity and mortality. Leukapheresis is a treatment modality used for hyperleukocytosis. In patients presenting with hyperleukocytosis the indications for leukapheresis were accepted as having symptoms of leukostasis and prophylactic. Indications for leukapheresis in prophylactic group evaluated according to WBC count. We report a single center experience about leukapheresis in managing 31 AML patients with hyperleukocytosis. In addition to demographic characteristics, disease-related clinical and laboratory findings of the patients were recorded. Survival rates were also calculated. Ten patients were female. The most common of AML subtype was AML-M2. The median number of leukapheresis per patient was 2 and totally 60 leukapheresis cycles were performed in all patients. There was a significant decrease in WBC count and LDH level after leukapheresis as compared with the baseline values (p < 0.05). Early and total mortality were 16.1% and 58.0%, respectively. Alive and died patients were evaluated according to baseline WBC, LDH; increased WBC count and LDH level were found in died patients (p < 0.05). According to leukapheresis indications, patients were divided into two groups: 14 patients in symptomatic leukostasis, 17 patients in prophylaxis. No statistically significant differences were noted between both groups in leukapheresis effectiveness, mean survival time, early and total mortality rate (p > 0.05). None of our patients suffered serious side effects and tumor lysis syndrome during or after apheresis. Leukapheresis is an effective and safe approach to reduce WBC counts in patients with AML with hyperleukocytosis. Further evidence based data obtained from larger sample sizes are required to better understand the impact of prophylaxis leukapheresis on early and total mortality of AML patients with hyperleukocytosis. PMID- 25843764 TI - Obstetrical complications in women with epilepsy. AB - PURPOSE: Better knowledge of risk factors for women with epilepsy giving birth. METHOD: Investigating all studies reporting complications in pregnancy and deliveries in women with epilepsy during the last 15 years. RESULTS: Studies have observed that women with epilepsy have a higher risk of preeclampsia, gestational hypertension, bleeding in pregnancy, caesarean delivery (CD), excessive bleeding postpartum, preterm birth, and small for gestational age. It has been unclear whether the increased risk of complications is due to the epilepsy per se, the use of antiepileptic drugs (AED), or the combination of both factors. Recent studies strongly indicate an association between AED use, and complications in pregnancy and labour. CONCLUSION: Newer drugs commonly used in treatment of epilepsy are associated with an increased risk of pregnancy complications, as well as complication during labour and delivery. PMID- 25843765 TI - Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations. AB - Antiepileptic drugs (AEDs) and hormonal contraceptives may affect each other's metabolism and clinical efficacy. Loss of seizure control and unplanned pregnancy may occur when these compounds are used concomitantly. Although a large number of available preparations yield a plethora of possible drug combinations, most of these drug interactions are predictable and, thus, avoidable. Unfortunately, there is a substantial lack of data regarding the newer AEDs. Detailed understanding of these issues is necessary for those who prescribe AEDs and/or hormonal contraception to women with epilepsy, as well as for those who provide comprehensive care, education and counseling to them, in order to reduce the unacceptably high number of unplanned pregnancies among women with epilepsy. PMID- 25843766 TI - Finding of leishmanicidal activity of 14-hydroxylunularin in mice experimentally infected with Leishmania infantum. AB - In this study, we report the in vivo efficacy of 14-hydroxylunularin evaluated in BALB/c mice experimentally infected with promastigotes of Leishmania infantum (syn L. chagasi), the major causative agent of visceral leishmaniasis in Latin America. Seven days post-infection, treatment with 14-hydroxylunularin started and it was administered by oral and subcutaneous routes in doses of 10 and 25 mg/kg of weight for ten days using Glucantime(r) as reference drug. In the liver, the evaluated compound showed parasite reduction above 90% by both administration routes being the oral route the most effective at both doses. Significant decreased numbers of parasites were also observed when the treated group was compared with the control group (p<=0.05). The subcutaneous route presented a remarkable difference with at least 80% parasite suppression in liver and spleen at 10 mg/kg dose and 90% in liver at 25 mg/kg. The leishmanicidal activity of 14 hydroxylunularin against L. infantum revealed by this study is another evidence in favor of this compound as a potential candidate for the development of a new oral treatment for leishmaniasis. PMID- 25843767 TI - Coping with Weight-related Discrepancies: Initial Development of the WEIGHTCOPE. AB - PURPOSE: The present research sought to provide the initial development, validation and reliability for a measure (WEIGHTCOPE) to assess the variation in how women, who are currently trying to lose or maintain weight, cope with common, perceived weight-related discrepancies. METHODS: To this end, two studies were conducted to 1) develop an initial list of coping responses to common weight related triggers, 2) create an initial measurement model through exploratory factor analysis (study 1; n = 470), and 3) provide initial validation for the measure through confirmatory factor analysis (study 2; n = 310). FINDINGS: Results support the initial validity and reliability of a 38-item, 10-factor structure: Physical Activity, Healthy Eating, Suppressed Eating, Supplement Use, Self-Regulation, Positive Reframing, Social Support, Disengagement, Camouflage, and Comfort Food. The present findings reiterate individual variation in coping choice in response to a perceived weight-related discrepancy, and its prospective assessment with the WEIGHTCOPE. CONCLUSIONS: The WEIGHTCOPE can be an integral tool for public health and clinical practice, where triggers are common, and interventions are employed to enhance the use of more positive forms of weight control behaviors and/or avoid negative consequences of weight- and fat-related discrepancies. Future research can use the WEIGHTCOPE to help guide theoretical and pragmatic approaches to various triggering events and potential moderators of coping. PMID- 25843768 TI - Blunted neural responses to monetary risk in high sensation seekers. AB - The sensation-seeking trait is a valid predictor of various risk-taking behaviors. However, the neural underpinnings of risk processing in sensation seeking are yet unclear. The present event-related potential (ERP) study examined electrophysiological correlates associated with different stages of risky reward processing in sensation seeking. Twenty-one high sensation seekers (HSS) and 22 low sensation seekers (LSS) performed a simple two-choice gambling task. Behaviorally, whereas LSS exhibited a risk-averse pattern, HSS showed a risk neutral pattern. During the anticipation stage, an increased stimulus-preceding negativity was elicited by high-risk compared to low-risk choices in LSS but not in HSS. During the outcome-appraisal stage, the feedback-related negativity, when calculated as the difference between losses and gains, was enhanced in response to the high-risk versus low-risk outcomes, which appeared for LSS but not for HSS. Further, HSS as compared to LSS exhibited a diminished P300 to both gains and losses. These findings suggest that risk-taking behavior in sensation seeking is expressed as blunted neural responses to risk in the anticipation stage and in the outcome-appraisal stage, which represents a candidate target for drug prevention. PMID- 25843769 TI - Brain herniation with surrounding CSF into the skull or encepholecele? PMID- 25843770 TI - Persistent pulmonary hypertension of the newborn: Advances in diagnosis and treatment. AB - Persistent pulmonary hypertension of the newborn (PPHN) is a frequent cause for admission to the neonatal intensive care unit and is associated with mortality and variable morbidities. It is primarily a state of oxygenation failure representing a failure of the normal postnatal decline in pulmonary vascular resistance that may be associated with right ventricular dysfunction. Enhanced knowledge of the pathophysiologic contributors to this syndrome helps clinicians understand its phenotypic expression and facilitates more focused intensive care decision-making. The approach to treatment should be based on alleviation of the elevation in pulmonary vascular resistance and should include optimization of lung recruitment and judicious use of pulmonary vasodilators. When response to inhaled nitric oxide is suboptimal, the physiologic contributors to impaired oxygenation need further investigation. Targeted neonatal echocardiography provides novel physiologic insights; in particular, it may help assess the adequacy of right ventricular performance, the relative contribution of the fetal shunts and the magnitude of the overall impairment to cardiac output. This information may facilitate therapeutic next steps and whether adjunctive vasodilators or drugs to augment ventricular function are preferable. This article provides a comprehensive overview of the pathological contributors to PPHN, the physiologic constituents of its phenotypic expression, standard approach to therapeutic intervention, and the role of bedside echocardiography in enhancing the decision-making process. PMID- 25843771 TI - Chloroplast thylakoid structure in evergreen leaves employing strong thermal energy dissipation. AB - In nature, photosynthetic organisms cope with highly variable light environments- intensities varying over orders of magnitudes as well as rapid fluctuations over seconds-to-minutes--by alternating between (a) highly effective absorption and photochemical conversion of light levels limiting to photosynthesis and (b) powerful photoprotective thermal dissipation of potentially damaging light levels exceeding those that can be utilized in photosynthesis. Adjustments of the photosynthetic apparatus to changes in light environment involve biophysical, biochemical, and structural adjustments. We used electron micrographs to assess overall thylakoid grana structure in evergreen species that exhibit much stronger maximal levels of thermal energy dissipation than the more commonly studied annual species. Our findings indicate an association between partial or complete unstacking of thylakoid grana structure and strong reversible thermal energy dissipation that, in contrast to what has been reported for annual species with much lower maximal levels of energy dissipation, is similar to what is seen under photoinhibitory conditions. For a tropical evergreen with tall grana stacks, a loosening, or vertical unstacking, of grana was seen in sun-grown plants exhibiting pronounced pH-dependent, rapidly reversible thermal energy dissipation as well as for sudden low-to-high-light transfer of shade-grown plants that responded with photoinhibition, characterized by strong dark-sustained, pH independent thermal energy dissipation and photosystem II (PSII) inactivation. On the other hand, full-sun exposed subalpine confers with rather short grana stacks transitioned from autumn to winter via conversion of most thylakoids from granal to stromal lamellae concomitant with photoinhibitory photosynthetic inactivation and sustained thermal energy dissipation. We propose that these two types of changes (partial or complete unstacking of grana) in thylakoid arrangement are both associated with the strong non-photochemical quenching (NPQ) of chlorophyll fluorescence (a measure of photoprotective thermal energy dissipation) unique to evergreen species rather than with PSII inactivation per se. PMID- 25843772 TI - Stability of Hydrated Methylamine: Structural Characteristics and H2N...H-O Hydrogen Bonds. AB - Methylamine is the simplest aliphatic amine found in human urine, blood, and tissues. It is thought to play a significant part in central nervous system disturbances observed during renal and hepatic disease. In this work we have investigated the methylamine hydration clusters using a basin hopping (BH) algorithm with the density functional theory (DFT). The results presented herein yield a detailed understanding of the structure and stability for a system consisting of one methylamine molecule and up to seven waters: the most stable geometries arise from a fusion of tetramer or pentamer rings; by the geometrical parameters and topological parameters analysis, the strengths of the H2N...H-O hydrogen bonds of the global minima increase as the sizes of clusters increase, except for n = 5 where there is a slight fluctuation. This work may shed light on the form mechanism of methylamine existing in organisms and the hydration structures of larger molecules containing amino functional groups and their interaction with the water molecules nearby. PMID- 25843773 TI - Anthranoyl-CoA monooxygenase/reductase from Azoarcus evansii possesses both FMN and FAD in two distinct and independent active sites. AB - Anthranoyl-CoA monooxygenase/reductase (ACMR) participates in an unusual pathway for the degradation of aromatic compounds in Azoarcus evansii. It catalyzes the monooxygenation of anthranoyl-CoA to 5-hydroxyl-2-aminobenzoyl-CoA and the subsequent reduction to the dearomatized product 2-amino-5-oxo-cyclohex-1-ene-1 carbonyl-CoA. The two reactions occur in separate domains, termed the monooxygenase and reductase domain. Both domains were reported to utilize FAD as a cofactor for hydroxylation and reduction, respectively. We have heterologously expressed ACMR in Escherichia coli BL21 and found that the monooxygenase domain contains FAD. However, the reductase domain utilizes FMN and not FAD for the reduction of the intermediate 5-hydroxyl-2-aminobenzoyl-CoA. A homology model for the reductase domain predicted a topology similar to the Old Yellow Enzyme family, which exclusively bind FMN, in accordance with our results. Binding studies with 2-aminobenzoyl-CoA (AbCoA) and p-hydroxybenzaldehyde (pHB) as probes for the monooxygenase and reductase domain, respectively, indicated that two functionally distinct and independent active sites exist. Given the homodimeric quartenary structure of ACMR and the compact shape of the dimer as determined by small-angle X-ray scattering experiments we propose that the monooxygenase and reductase domain of opposite peptide chains are involved in the transformation of anthranoyl-CoA to 2-amino-5-oxo-cyclohex-1-ene-1-carbonyl-CoA. PMID- 25843774 TI - Autophagy in neurodegenerative diseases: From pathogenic dysfunction to therapeutic modulation. AB - Neuronal homeostasis depends on the proper functioning of quality control systems like autophagy. This mechanism is responsible of the clearance of misfolded proteins, aggregates and the turnover of organelles within the neuron. Autophagic dysfunction has been described in many neurodegenerative diseases. It can occur at several steps of the autophagic machinery and can contribute to the formation of intracellular aggregates and ultimately to neuronal death. Accordingly restoring autophagy activity in affected neurons can be an attractive therapeutic approach to fight neurodegeneration. In this review we summarize the present encouraging strategies that have been achieved with pharmacological and genetic treatments aimed to induce neuronal autophagy in experimental models of neurodegenerative diseases. PMID- 25843775 TI - Microparticles in cancer: A review of recent developments and the potential for clinical application. AB - Once thought of as inert remnants of cellular processes, the significance of membrane vesicles is now expanding as their capacity to package and transfer bioactive molecules during intercellular communication is established. This ability to serve as vectors in the trafficking of cellular cargo is of mounting interest in the context of cancer, particularly in the dissemination of deleterious cancer traits from donor cells to recipient cells. Although microparticles (MPs) contribute to the pathogenesis of cancer, their unique characteristics can also be exploited in the context of cancer management. The detection of MPs in body fluids has the potential to provide an effective means for the diagnosis, prognosis and surveillance of cancer patients. The use of these readily accessible systemic biomarkers has the potential to circumvent the need for invasive biopsy procedures. In addition, the autologous nature of MPs may allow them to be used as novel drug delivery carriers. Consequently, the modulation of MP vesiculation to treat disease, the detection of MPs in disease monitoring, and the application of MPs as therapeutic delivery vehicles present prospective clinical interventions in the treatment of cancer. PMID- 25843776 TI - The Bmi-1 helix-turn and ring finger domains are required for Bmi-1 antagonism of (-) epigallocatechin-3-gallate suppression of skin cancer cell survival. AB - The Bmi-1 Polycomb group (PcG) protein is an important epigenetic regulator of chromatin status. Elevated Bmi-1 expression is observed in skin cancer and contributes to cancer cell survival. (-) Epigallocatechin-3-gallate (EGCG), an important green tea-derived cancer prevention agent, reduces Bmi-1 level resulting in reduced skin cancer cell survival. This is associated with increased p21(Cip1) and p27(Kip1) expression, reduced cyclin, and cyclin dependent kinase expression, and increased cleavage of apoptotic markers. These EGCG-dependent changes are attenuated by vector-mediated maintenance of Bmi-1 expression. In the present study, we identify Bmi-1 functional domains that are required for this response. Bmi-1 expression reverses the EGCG-dependent reduction in SCC-13 cell survival, but Bmi-1 mutants lacking the helix-turn-helix-turn-helix-turn (Bmi 1DeltaHT) or ring finger (Bmi-1DeltaRF) domains do not reverse the EGCG impact. The reduction in Ring1B ubiquitin ligase activity, observed in the presence of mutant Bmi-1, is associated with reduced ability of these mutants to interact with and activate Ring1B ubiquitin ligase, the major ligase responsible for the ubiquitination of histone H2A during chromatin condensation. This results in less chromatin condensation leading to increased tumor suppressor gene expression and reduced cell survival; thereby making the cells more susceptible to the anti survival action of EGCG. We further show that these mutants act in a dominant negative manner to inhibit the action of endogenous Bmi-1. Our results suggest that the HT and RF domains are required for Bmi-1 ability to maintain skin cancer cell survival in response to cancer preventive agents. PMID- 25843777 TI - CREB is a key negative regulator of carbonic anhydrase IX (CA9) in gastric cancer. AB - Carbonic anhydrase IX(CA9)is a member of the carbonic anhydrase family that catalyzes the reversible hydration of carbon dioxide, and plays a key role in the regulation of pH. Although a large number of studies have shown that CA9 is strongly up-regulated by HIF1-alpha, little is known about the negative regulation mechanism of CA9 in cancer cells. Here we find that CREB is a key negative regulator of CA9 in gastric cancer. Over-expression of CREB can significantly repress the expression of CA9. Treating with anisomycin (ANS), an activator of p38, the phosphorylation and nuclear translocation of CREB are both promoted, while the transcription of CA9 is repressed. Besides, our results firstly identify that CREB can recruit SIRT1 (class III HDACS) by adaptor protein p300, then repress the expression of CA9. These findings may contribute to understand the negative regulation mechanisms of CA9 in gastric cancer. PMID- 25843778 TI - Is hydrogen ion (H(+)) the real second messenger in calcium signalling? AB - Most second messengers have the acknowledged ability to mobilize the segregated Ca(2+) from intracellular stores, although the mechanisms of mobilization are unclear. To study this problem, the fact that inositol 1,4,5-trisphosphate, and six other known endogenous Ca(2+) mobilizers are acids, or acid-generating compounds, is highlighted. In physiological conditions, a newly generated acid releases H(+). The transient rise of H(+) in the cytosol may induce the lowering of pH, mobilization of bound Ca(2+), protein conformational rearrangement, store depletion, and Ca(2+) influx. Accordingly, a new description of the basic mechanism for signal transduction in non-excitable cells and the related consequences is put forward. PMID- 25843780 TI - Sphenoid sinus types, dimensions and relationship with surrounding structures. AB - The human sphenoid sinus is an extremely variable cavity and an important landmark in hypophyseal surgery. The aim of this study was to investigate the relationship between the sphenoid sinus type, size, extent of pneumatization and occurrence of protrusions of the adjacent neurovascular structures. A total of 51 randomly selected skulls (>=20 years of age, 33 male; 102 sinuses) were analyzed using cone beam computed tomography to estimate pneumatization extension beyond the body of the sphenoid (planum sphenoidale, pterygoid process, greater wings, clivus, dorsum sellae) and protrusions of the maxillary, mandibular, optic or pterygoid nerve or the internal carotid artery. Difference in pneumatization type between the left and the right-sided sinus was observed in 45% of the skulls. Conchal pneumatization was registered in 2%, presellar in 24%, sellar in 41% and postsellar in 33% of total sinuses. Presellar sinuses frequently pneumatized planum sphenoidale and sporadically other structures, and were characterized by sporadic optic nerve protrusions. Sellar and particularly postsellar sinuses were characterized by simultaneous pneumatization extensions and neurovascular protrusions. In the case of postsellar-type sinuses, the probability of these multiple interactions was not affected by their actual size, while it increased with the increasing sinus dimensions in the case of sellar-type sinuses. A more detailed analysis indicated that increasing sinus height, length or width increased the probability of interactions and pneumatization of particular surrounding structures. Data suggest that the sphenoid sinus pneumatization type and dimensions might be used to estimate the risks of iatrogenic injury during transsphenoidal surgical procedures. PMID- 25843781 TI - Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4 BD; BDO): A literature review with a focus on UK fatalities related to non medical use. AB - Misuse of gamma hydroxybutrate (GHB) and gamma butyrolactone (GBL) has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on GHB and derivatives, and explores the largest series of deaths associated with their non-medical use. Descriptive analyses of cases associated with GHB/GBL and 1,4-butanediol (1,4-BD) use extracted from the UK's National Programme on Substance Abuse Deaths database. From 1995 to September 2013, 159 GHB/GBL-associated fatalities were reported. Typical victims: White (92%); young (mean age 32 years); male (82%); with a drug misuse history (70%). Most deaths (79%) were accidental or related to drug use, the remainder (potential) suicides. GHB/GBL alone was implicated in 37%; alcohol 14%; other drugs 28%; other drugs and alcohol 15%. Its endogenous nature and rapid elimination limit toxicological detection. Post-mortem blood levels: mean 482 (range 0-6500; SD 758)mg/L. Results suggest significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, opiates, stimulants, and ketamine. More awareness is needed about risks associated with consumption. PMID- 25843782 TI - Preliminary results of transplantation with kidneys donated after cardiac death: a path of hope for organ transplantation in China. AB - BACKGROUND: This article aims to explore the feasibility and effect of kidney transplantation (KT) from donation after cardiac death (DCD) donors in China. METHODS: From July 2011 to April 2013, 94 DCD kidneys retrieved and transplanted by our centre were reviewed in this largest single-centre cohort study. Patients with and without delayed graft function (DGF) were compared between DCD KT cohorts. Estimated glomerular filtration rate (eGFR), post-operative complications and graft loss at different time points were recorded. Factors related to DGF were examined and analysed. RESULTS: There was no primary non function (PNF) graft observed from patients. DGF rate was 27.7%; and 1-year overall graft and patient survival rates were 95.7 and 98.9%, respectively. In the first 6 months post-transplantation, eGFR was significantly lower in the DGF group compared with the non-DGF group (46 versus 52 mL/min; P = 0.04); but the difference disappeared thereafter (50 versus 47 mL/min, after 1 year). CONCLUSION: Despite early DGF and short-term observations, we are pleased to have this opportunity of sharing our initial experience and results, and justifying the continued DCD KT programmes in China. PMID- 25843783 TI - High versus low dialysate sodium concentration in chronic haemodialysis patients: a systematic review of 23 studies. AB - BACKGROUND: It is the object of debate whether a low or high dialysate sodium concentration (DNa(+)) should be advocated in chronic haemodialysis patients. In this paper, we aimed at evaluating benefits and harms of different DNa(+) prescriptions through a systematic review of the available literature. METHODS: MEDLINE and CENTRAL databases were searched for studies comparing low or high DNa(+) prescriptions. Outcomes of interest were mortality, blood pressure (BP), interdialytic weight gain (IDWG), plasma sodium, hospitalizations, use of anti hypertensive agents and intradialytic complications. RESULTS: Twenty-three studies (76 635 subjects) were reviewed. There was high heterogeneity in the number of patients analysed, overall study quality, duration of follow-up, DNa(+) and even in the definition of 'high' or 'low' DNa(+). The only three studies looking at mortality were observational. The risk of death was related to the plasma-DNa(+) gradient, but was also shown to be confounded by indication from the dialysate sodium prescription itself. BP was not markedly affected by high or low DNa(+). Patients treated with higher DNa(+) had overall higher IDWG when compared with those with lower DNa(+). Three studies reported a significant increase in intra-dialytic hypotensive episodes in patients receiving low DNa(+). Data on hospitalizations and use of anti-hypertensive agents were sparse and inconclusive. CONCLUSIONS: There is currently no definite evidence proving the superiority of a low or high uniform DNa(+) on hard or surrogate endpoints in maintenance haemodialysis patients. Future trials adequately powered to evaluate the impact of different DNa(+) on mortality or other patient-centred outcomes are needed. PMID- 25843784 TI - Outcomes after cochlear reimplantation in children. AB - OBJECTIVES: With cochlear implantation now a routine procedure, reimplantation is becoming more commonplace for medical/surgical complications or device malfunctions. This study investigated the indications for reimplantation and the auditory outcomes following reimplantation surgery in prelingually-deafened children. METHODS: Of the 539 prelingually deafened children implanted between 1990 and 2013, 45 were reimplanted (8.3% of implantations). Causes of reimplantation, type of device and angle of insertion at initial implantation were recorded, as well as type of implant reinserted, number of electrodes inserted and angle of insertion (calculated on cone beam computed tomography) on reimplantation, and finally any surgical findings. Speech perception test scores (phonetically balanced kindergarten (PBK) words, open-set sentence testing in quiet and in noise (S/N+ 10 dB SNR), and speech tracking scores) were obtained 1, 2 and 3 years after reimplantation, and compared against the best speech recognition score obtained with the first implant before failure. RESULTS: Medical reasons for reimplantation were found in 10 cases (22.2%). A malfunctioning device had occurred in 35 cases (77.7%) including hard failure in 24 and soft failure in 11. Complete insertion was achieved in the scala tympani in 42 cases and in the scala vestibuli in one case; partial insertion occurred in the remaining two cases. In two cases, one or two electrode rings snatched off from the electrode array during removal. The mean insertion angle was 330.5 degrees before surgery and 311.8 degrees after reimplantation (no statistical difference p=0.48). The postoperative speech perception outcome measures showed no significant difference to the best score before reimplantation. Angle of insertion, type of device and etiology of deafness did not influence the results. The PBK performance improved over 10% in 43.2% of children, was similar in 40.5%, and showed a more than 10% decrease in 16.2% of children after reimplantation. The latter decline in performance was explained for some children by a partial insertion. CONCLUSIONS: Reimplantation has no negative effect on auditory outcome. In rare cases, speech perception outcome may not improve, requiring a specific rehabilitation program. PMID- 25843785 TI - Surgical success of boomerang-shaped chondroperichondrial graft in pediatric chronic otitis media cases. AB - OBJECTIVES: To reveal the success of boomerang-shaped chondroperichondrial graft (BSCPG) in pediatric chronic otitis media cases. METHODS: A total of 43 pediatric patients (age 7-16 years) who had undergone type 1 tympanoplasty with the diagnosis of chronic otitis media between March 2010 and March 2013 were included in this retrospective study. The main outcome measures were the graft success rate and level of hearing improvement. RESULTS: Graft intake success rate was 90.7%. Mean preoperative and postoperative air-bone gap values were 20.51 +/- 4.34 dB SPL and 9.32 +/- 5.64 dB SPL, respectively (p < 0.001). Mean preoperative and postoperative pure tone average values were 28.6 +/- 3.52 and 12.24 +/- 5.22 respectively (p < 0.001). Air-bone gap was improved to <= 10 dB in 38 (88.37%) patients during the postoperative period. CONCLUSIONS: Boomerang-shaped chondroperichondrial grafting technique seems to be a successful alternative in the management of pediatric chronic otitis media cases. It has relatively higher grade graft success rate. PMID- 25843786 TI - The hidden loss of otolithic function in children with profound sensorineural hearing loss. AB - OBJECTIVE: This study sought to define the profile of ocular and cervical vestibular-evoked myogenic potential (oVEMP and cVEMP) in children with profound sensorineural hearing loss (PSHL). METHODS: The ACS-evoked oVEMPs and cVEMPs of 43 children with PSHL and 20 healthy children were investigated. The response rates, thresholds, amplitudes, P1 and N1 latencies, and interpeak latencies of VEMPs were analyzed. Each patient's medical record was summarized and classified. RESULTS: The response rates of oVEMP and cVEMP in patients with PSHL were 58.1% and 61.9% respectively, which were significantly less than those in healthy children (both were 100%). In the children patients whose oVEMP or cVEMP could still be elicited, significant elevated thresholds and decreased amplitudes in VEMPs could be observed (p<0.05). However, in the summary of the medical records of all the 43 patients, it was showed that neither the patients and their parents nor the doctors noticed the balance problem and the loss of otolithic function. CONCLUSIONS: The otolithic dysfunction, which could be easily ignored in children with PSHL, could be observed in VEMPs. In the process of diagnosis and treatment of PSHL, the vestibular function should obtain enough attention. VEMPs have special value in observation of the hidden loss of otolithic function, and could be an important vestibular assessment method for children with PSHL. PMID- 25843787 TI - Prophylactic antibiotic therapy for all out-of-hospital cardiac arrest survivors? PMID- 25843789 TI - Failed epilepsy surgery: It is not too late. PMID- 25843779 TI - microRNA regulation of Wnt signaling pathways in development and disease. AB - Wnt signaling pathways and microRNAs (miRNAs) are critical regulators of development. Aberrant Wnt signaling pathways and miRNA levels lead to developmental defects and diverse human pathologies including but not limited to cancer. Wnt signaling pathways regulate a plethora of cellular processes during embryonic development and maintain homeostasis of adult tissues. A majority of Wnt signaling components are regulated by miRNAs which are small noncoding RNAs that are expressed in both animals and plants. In animal cells, miRNAs fine tune gene expression by pairing primarily to the 3'untranslated region of protein coding mRNAs to repress target mRNA translation and/or induce target degradation. miRNA-mediated regulation of signaling transduction pathways is important in modulating dose-sensitive response of cells to signaling molecules. This review discusses components of the Wnt signaling pathways that are regulated by miRNAs in the context of development and diseases. A fundamental understanding of miRNA functions in Wnt signaling transduction pathways may yield new insight into crosstalks of regulatory mechanisms essential for development and disease pathophysiology leading to novel therapeutics. PMID- 25843788 TI - Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence Nanoparticle Tracking Analysis. AB - The human placenta releases multiple types and sizes of syncytiotrophoblast (STB) extracellular vesicles (EV) into the maternal circulation that exhibit diverse biological activities. The placental perfusion technique enables isolation of these STBEV, but conventional flow cytometry can only be used to phenotype EV down to ~300 nm in size. Fluorescence Nanoparticle Tracking Analysis (fl-NTA) has the potential to phenotype EV down to ~50 nm, thereby improving current characterisation techniques. The aims of this study were to prepare microvesicle and exosome enriched fractions from human placental perfusate (n=8) and improve fl-NTA STBEV detection. Differential centrifugation and filtration effectively removed contaminating red blood cells from fresh placental perfusates and pelleted a STB microvesicle (STBMV) fraction (10,000*g pellet - 10KP; NTA modal size 395+/-12 nm), enriched for the STB marker placental alkaline phosphatase (PLAP) and a STB exosome (STBEX) fraction (150,000*g pellet - 150KP; NTA modal size 147+/-6 nm), enriched for PLAP and exosome markers Alix and CD63. The PLAP positivity of 'standard' 10KP and 150KP pools (four samples/pool), determined by immunobead depletion, was used to optimise fl-NTA camera settings. Individual 10KP and 150KP samples (n=8) were 54.5+/-5.7% (range 17.8-66.9%) and 30.6+/-5.6% (range 3.3-51.7%) PLAP positive, respectively. We have developed a reliable method for enriching STBMV and STBEX from placental perfusate. We also standardised fl-NTA settings and improved measurement of PLAP positive EV in STBMV. However, fl-NTA is not as sensitive as anti-PLAP Dynabead capture for STBEX detection, possibly due to STBEX having lower surface expression of PLAP. These important developments will facilitate more detailed studies of the role of STBMV and STBEX in normal and pathological pregnancies. PMID- 25843790 TI - Urticaria multiforme: A report of 5 cases and a review of the literature. AB - Urticaria multiforme is a cutaneous disorder that affects infants and small children. It is characterized by large, annular urticarial plaques with a violaceous center and is frequently accompanied by fever. Urticaria multiforme follows a benign, self-limiting course, but the striking appearance of the lesions can cause alarm and considerable anxiety among parents. We present 5 cases of urticaria multiforme seen in our hospital over a period of 18 months. All the cases were preceded by an infection of the upper airways or otitis, and they were all empirically with amoxicillin. It is important to be familiar with this condition to reassure parents and avoid unnecessary hospital admissions and tests. PMID- 25843791 TI - Thrombolytic therapy for cardiac arrest secondary to acute pulmonary embolism: an oft overlooked strategy. PMID- 25843792 TI - Prognostic factors in adenocarcinoma of the salivary glands. AB - OBJECTIVES: We aimed to characterize prognostic factors and outcomes in adenocarcinomas of the salivary glands. MATERIALS AND METHODS: Patients were identified and retrospectively reviewed for clinical and pathologic tumor characteristics. Low and high grade adenocarcinoma histologies were separated and analyzed. Treatment regimens and patient-related outcomes were recorded and measured. RESULTS: A total of 51 adenocarcinomas of the salivary glands were reviewed. The most common locations of disease were the superficial lobe of the parotid gland, followed by the deep lobe. Five-year overall and disease free survival rates were 43% and 37%. Univariate analysis identified the following as negative prognostic factors: symptoms of a fixed mass or rapid growth, advanced tumor or nodal stage, and perineural or lymphovascular invasion. Facial nerve paralysis was not found to be a significant prognostic variable. Multivariate analysis confirmed the independent negative prognostic importance of the following characteristics: presentation with a fixed mass or rapid growth, diagnosis of adenocarcinoma not otherwise specified, and positive surgical margins. CONCLUSIONS: Our results identify several important prognostic factors associated with overall survival in adenocarcinoma of the salivary glands. These prognostic variables encompass symptoms on presentation, clinical and pathologic tumor stage characteristics, and treatment-related factors; all of which are important in patient counseling and may provide impetus for determining treatment escalation. PMID- 25843793 TI - Norepinephrine induces the expression of interleukin-6 via beta-adrenoreceptor NAD(P)H oxidase system -NF-kappaB dependent signal pathway in U937 macrophages. AB - Atherosclerosis is an inflammatory disease in the vessel wall. IL-6 is a mediator of inflammation and a major alarm hormone signaling tissue damage and infection to the body's host defense system, in particular to the liver, where it induces the synthesis of acute phase plasma proteins. Although Norepinephrine (NE) can stimulate the vascular cells to produce IL-6, it is unknown whether NE induces IL 6 expression in macrophages. The present study was to observe effect of NE on IL 6 production and the related signal pathway in U937 macrophages so as to provide more evidence for the proinflammatory action of NE. The results showed that NE significantly increased mRNA and protein expression of IL-6 in U937 macrophages in time- and concentration-dependent manners. beta-adrenoreceptor inhibitor propranolol blocked NE-induced IL-6 expression in mRNA and protein levels in U937 macrophages. Propranolol and DPI [NAD(P)H oxidase inhibitor] decreased NE stimulated reactive oxygen species (ROS) generation, and antioxidant NAC completely abolished NE-induced IL-6 expression in U937 macrophages. The further study indicated that NAD(P)H oxidase inhibitor DPI and NF-kappaB inhibitor PDTC reduced NE-induced mRNA and protein expression of IL-6 in U937 macrophages. These demonstrate that NE is capable of inducing IL-6 generation in macrophages via beta-ADR-ROS-NF-kappaB signal pathway, which contributes to better understanding of the proinflammatory and proatherosclerotic actions of NE. PMID- 25843794 TI - Reovirus double-stranded RNA genomes and polyI:C induce down-regulation of hypoxia-inducible factor 1alpha. AB - Reovirus has genomes consisting of 10-segmented double-stranded RNAs, and have received much attention as an oncolytic virus. A previous study reported that reovirus down-regulates hypoxia-inducible factor 1alpha (HIF-1alpha) protein levels following infection in tumor cells, which contributes to the antitumor effects of reovirus; however, the mechanism remains to be elucidated. In this study, we examined which virus component was involved in reovirus-mediated down regulation of HIF-1alpha. Reovirus induced significant down-regulation of HIF 1alpha protein levels in not only reovirus-permissive tumor cells but also reovirus-resistant tumor cells. UV-inactivated reovirus also induced a reduction in HIF-1alpha protein levels. These data indicate that reovirus induces HIF 1alpha down-regulation independently of virus replication. Furthermore, transfection with not only reovirus genomes but also polyI:C efficiently induced HIF-1alpha down-regulation in a manner similar to reovirus, indicating that double-stranded reovirus RNA genomes are a key component for HIF-1alpha down regulation. Reovirus-mediated HIF-1alpha down-regulation was inhibited when tumor cells were pretreated with inhibitors of cathepsins B and L, which play a crucial role in endo-lysosomal escape of virions to the cytoplasm. These data suggest that endo-lysosomal escape of reovirus genome into the cytoplasm is crucial for HIF-1alpha down-regulation; however, the retinoic acid-inducible gene-I (RIG-I) or interferon-beta promoter stimulator-1 (IPS-1), which are involved in reovirus genome-induced innate immunity in the cytoplasm, did not play a crucial role in reovirus-mediated HIF-1alpha reduction. PMID- 25843795 TI - Integrative function of adrenaline receptors for glucagon-like peptide-1 exocytosis in enteroendocrine L cell line GLUTag. AB - Adrenaline reacts with three types of adrenergic receptors, alpha1, alpha2 and beta-adrenergic receptors (ARs), inducing many physiological events including exocytosis. Although adrenaline has been shown to induce glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells, the precise molecular mechanism by which adrenaline regulates GLP-1 secretion remains unknown. Here we show by live cell imaging that all types of adrenergic receptors are stimulated by adrenaline in enteroendocrine L cell line GLUTag cells and are involved in GLP-1 exocytosis. We performed RT-PCR analysis and found that alpha1B-, alpha2A-, alpha2B-, and beta1-ARs were expressed in GLUTag cells. Application of adrenaline induced a significant increase of intracellular Ca(2+) and cAMP concentration ([Ca(2+)]i and [cAMP]i, respectively), and GLP-1 exocytosis in GLUTag cells. Blockade of alpha1-AR inhibited adrenaline-induced [Ca(2+)]i increase and exocytosis but not [cAMP]i increase, while blockade of beta1-AR inhibited adrenaline-induced [cAMP]i increase and exocytosis but not [Ca(2+)]i increase. Furthermore, overexpression of alpha2A-AR suppressed the adrenaline-induced [cAMP]i increase and exocytosis. These results suggest that the fine-turning of GLP-1 secretion from enteroendocrine L cells is established by the balance between alpha1-, alpha2-, and beta-ARs activation. PMID- 25843796 TI - Islet beta-cell failure in type 2 diabetes--Within the network of toxic lipids. AB - Obesity-related type 2 diabetes develops in individuals with the onset of beta cell dysfunction. Pancreatic islet lipotoxicity is now recognized as a primary reason for the onset and progression of the disease. Such dysfunction is reflected by the aberrant secretory capacity and detrimental loss of beta-cell mass and survival. Elevated circulating serum fatty acid levels and disordered lipid metabolism management are particularly interesting in the search for biologically relevant triggers of beta-cell demise. Herein, we review various types of toxic lipid metabolites that may play a significant role in pancreatic islet failure. The lipotoxic effect on beta-cells depends on the type of lipid mediator (e.g., long-chain fatty acids, diacylglycerols, ceramides, phospholipids), cellular location of its action (e.g., endoplasmic reticulum, mitochondria), and associated-organelle conditions (e.g., membranes, vesicles). We also discuss various aspects of lipid action in beta-cells, including effects on metabolic pathways, stress responses (e.g., oxidative stress, endoplasmic reticulum stress, and autophagy), and gene expression. PMID- 25843797 TI - DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells. AB - Metformin, one of the most commonly used drugs for patients with type 2 diabetes, recently has received much attention regarding its anti-cancer action. It is thought that the suppression of mTOR signaling is involved in metformin's anti cancer action. Although liver cancer is one of the most responsive types of cancer for reduction of incidence by metformin, the molecular mechanism of the suppression of mTOR in liver remains unknown. In this study, we investigated the mechanism of the suppressing effect of metformin on mTOR signaling and cell proliferation using human liver cancer cells. Metformin suppressed phosphorylation of p70-S6 kinase, and ribosome protein S6, downstream targets of mTOR, and suppressed cell proliferation. We found that DEPTOR, an endogenous substrate of mTOR suppression, is involved in the suppressing effect of metformin on mTOR signaling and cell proliferation in human liver cancer cells. Metformin increases the protein levels of DEPTOR, intensifies binding to mTOR, and exerts a suppressing effect on mTOR signaling. This increasing effect of DEPTOR by metformin is regulated by the proteasome degradation system; the suppressing effect of metformin on mTOR signaling and cell proliferation is in a DEPTOR dependent manner. Furthermore, metformin exerts a suppressing effect on proteasome activity, DEPTOR-related mTOR signaling, and cell proliferation in an AMPK-dependent manner. We conclude that DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in liver, and could be a novel target for anti-cancer therapy. PMID- 25843798 TI - Major urinary protein 1 interacts with cannabinoid receptor type 1 in fatty acid induced hepatic insulin resistance in a mouse hepatocyte model. AB - Hepatic insulin resistance (HIR) is a metabolic abnormality characterized by increased gluconeogenesis which usually contributes from an elevation of free fatty acids. Cannabinoid receptor type 1 (CB1R) and major urinary protein 1 (MUP1) are thought to play pivotal roles in mitochondrial dysfunction, liver steatosis and insulin resistance. The aim of this study was to explore the role of MUP1 in CB1R-mediated HIR through the dysregulation of mitochondrial function in AML12 mouse hepatocytes challenged with high concentration of free fatty acids (HFFA). Firstly we observed that treatment of AM251, a selective CB1R antagonist, obviously reversed the HFFA-induced reduction of MUP1 protein expression both in vivo and in vitro. Additionally, our results revealed that AM251 also reverted HFFA-mediated decrease of the mRNA level of mitochondrial biogenesis-related factors, mtDNA amount, ATP production, mitochondrial respiratory complexes-I and III, and mitochondrial membrane potential, thus consequently might correlate with a parallel reduction of ROS production. Meanwhile, AM251 attenuated HFFA-induced impairment of insulin signaling phosphorylation and elevation of phosphoenolpyrvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key enzymes of gluconeogenesis. Silence of MUP1 gene abolished the inhibitory effect of AM251 on HFFA-mediated elevation of PEPCK and G6Pase expression, whereas the suppression of insulin signaling and mRNA level of mitochondrial biogenesis-related factors were only partially recovered. Altogether, these findings suggest that the anti-HIR effect of AM251 via improvement of mitochondrial functions might occur in a MUP1-dependent manner. PMID- 25843799 TI - RIG-I-dependent antiviral immunity is effective against an RNA virus encoding a potent suppressor of RNAi. AB - Nodamura virus (NoV) lethally infects suckling mice and contains a segmented positive-strand RNA genome that encodes a potent suppressor of RNA interference (RNAi). Recent studies have demonstrated immune detection and subsequent processing of NoV dsRNA replicative intermediates by the mouse RNAi machinery. However, diverse RNA viruses, including Encephalomyocarditis virus that also triggers Dicer-dependent biogenesis of viral siRNAs in mouse cells, are targeted in mammals by RIG-I-like receptors that initiate an IFN-dependent antiviral response. Using mouse embryonic fibroblasts (MEFs) for NoV infection, here we show that MEFs derived from mice knockout for RIG-I, but not those knockout for MDA5, LGP2, TLR3 or TLR7, exhibited an enhanced susceptibility to NoV. Further studies indicate that NoV infection induced an IFN-dependent antiviral response mediated by RIG-I. Our findings suggest that RIG-I directs a typical IFN dependent antiviral response against an RNA virus capable of suppressing the RNAi response. PMID- 25843800 TI - Knockdown of transcription factor forkhead box O3 (FOXO3) suppresses erythroid differentiation in human cells and zebrafish. AB - Our previous study on the dynamic transcriptomes activated during human erythropoiesis suggested that transcription factor forkhead box O3 (FOXO3) possibly plays a role in erythroid differentiation. Functional studies in human cell line TF-1 indicated that FOXO3 knockdown repressed erythropoietin (EPO) induced erythroid differentiation by activating promoter region of B-cell translocation gene 1 (BTG1), thereby regulating its expression. In zebrafish, injection of foxo3b-specific morpholinos (foxo3b MO) resulted in reduced globin (hbae1 and hbbe2) and gata1 gene expression. Transcriptome analyses of erythroid lineage cells isolated from the control and foxo3b morphants revealed the dynamic regulation of foxo3b. Further study suggested that BTG1 is partially responsible for FOXO3 regulation in erythroid differentiation of TF-1 cells but is inconsequential in zebrafish. Taken together, we found that FOXO3 plays an important role in erythroid differentiation in both human TF-1 cells and zebrafish, but the mechanism underlying this regulation still remains unclear. PMID- 25843801 TI - Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease. AB - Epstein-Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. PMID- 25843802 TI - Identification and analysis of the promoter region of the human HAS3 gene. AB - Hyaluronan (HA) is a key component of the vertebrate extracellular matrix that is synthesized at the plasma membrane by the hyaluronan synthases including HAS1, HAS2 and HAS3. The expression and regulation of HAS1-3 are implicated in numerous physiological and pathological processes. The promoters of human HAS1 and HAS2 genes have been identified previously whereas HAS3 promoter remains unclear. In the present study, we have for the first time identified and characterized the human HAS3 gene promoter region. 5' RACE assay revealed two novel transcriptional variants of HAS3 gene with distinct transcription start sites. Progressive deletion analysis of the 5'-flanking region of HAS3 gene demonstrated that HAS3 proximal promoter is mainly restricted to a 450-bp region (i.e. -761 to -305 bp upstream of the major HAS3 transcription start site), whereas its core promoter is located to a minimal 129-bp region (i.e. -433 to -305 bp upstream of the major HAS3 transcription start site). Transcriptional factor binding analysis indicated that HAS3 gene promoter lacks of canonical TATA box, but contains classical GC box as well as other putative binding sites for transcriptional factors such as C/EBP and NFkappaB. In addition, site-directed mutagenesis assay demonstrated that the proximal Sp1 binding site is essential for the robust proximal promoter activity of HAS3 gene whereas the core MTE (core promoter motif ten elements) motif is required for the basic core promoter activity of HAS3 gene. Our present study should facilitate further studies on the mechanism regulating the expression of this important gene. PMID- 25843803 TI - Tripartite motif 16 inhibits epithelial-mesenchymal transition and metastasis by down-regulating sonic hedgehog pathway in non-small cell lung cancer cells. AB - The present study was to examine the effect of Tripartite motif 16 (TRIM16) on epithelial-mesenchymal transition (EMT) and metastasis in non-small cell lung cancer (NSCLC) cells, and its clinical significance in NSCLC. The correlation of TRIM16 expression and clinical features of NSCLC was analyzed in paraffin embedded archived normal lung tissues and NSCLC tissues by immunohistochemical analysis. The effect of TRIM16 on EMT and metastasis was examined both in vitro and in vivo. The expression of TRIM16 was markedly decreased in NSCLC and correlated with tumor metastasis. Upregulation of TRIM16 significantly inhibited EMT and metastasis of NSCLC cells. In contrast, silencing TRIM16 expression significantly promoted the EMT and metastasis of NSCLC cells both in vitro and in vivo. Moreover, we demonstrated that downregulation of TRIM16 activated the sonic hedgehog pathway, and that inhibition of the sonic hedgehog pathway by cyclopamine abrogated the effect of TRIM16-downregulation induced EMT and metastasis on NSCLC cells. Our results suggest that TRIM16 is a potential pharmacologic target for the treatment of NSCLC and promotion TRIM16 expression might represent a novel strategy to NSCLC metastasis. PMID- 25843804 TI - Extra-chromosomal DNA maintenance in Bacillus subtilis, dependence on flagellation factor FliF and moonlighting mediator EdmS. AB - Extra-chromosomal DNA maintenance (EDM) as an important process in the propagation and genetic engineering of microbes. Bacillus subtilis EdmS (formerly PgsE), a protein comprising 55 amino acids, is a mediator of the EDM process. In this study, the effect of mutation of global regulators on B. subtilis EDM was examined. Mutation of the swrA gene abolished EdmS-mediated EDM. It is known that swrA predominantly regulates expression of the fla/che operon in B. subtilis. We therefore performed EDM analysis using fla/che-deletion mutants and identified an EDM-mediated EDM cooperator in the flgB-fliL region. Further genetic investigation identified the flagellation factor FliF is a crucial EDM cooperator. To our knowledge, this is the first observation of the moonlighting function of FliF in DNA maintenance. PMID- 25843805 TI - Pulmonary Hypertension in a Premature Infant With Bronchopulmonary Dysplasia. PMID- 25843806 TI - Microarray gene expression analysis reveals major differences between Toxocara canis and Toxocara cati neurotoxocarosis and involvement of T. canis in lipid biosynthetic processes. AB - Toxocara canis and Toxocara cati are globally occurring intestinal nematodes of dogs and cats with a high zoonotic potential. Migrating larvae in the CNS of paratenic hosts, including humans, may cause neurotoxocarosis resulting in a variety of neurological symptoms. Toxocara canis exhibits a stronger affinity to the CNS than T. cati, causing more severe neurological symptoms in the mouse model. Pathomechanisms of neurotoxocarosis as well as host responses towards the respective parasite are mostly unknown. Therefore, the aim of this study was to characterise the pathogenesis at a transcriptional level using whole genome microarray expression analysis and identify differences and similarities between T. canis- and T. cati-infected brains. Microarray analysis was conducted in cerebra and cerebella of infected C57Bl/6J mice 42daysp.i. revealing more differentially transcribed genes for T. canis- than T. cati-infected brains. In cerebra and cerebella of T. canis-infected mice, a total of 2304 and 1954 differentially transcribed genes, respectively, were identified whereas 113 and 760 differentially transcribed genes were determined in cerebra and cerebella of T. cati-infected mice. Functional annotation analysis revealed major differences in host responses in terms of significantly enriched biological modules. Up regulated genes were mainly associated with the terms "immune and defence response", "sensory perception" as well as "behaviour/taxis" retrieved from the Gene Ontology database. These observations indicate a strong immune response in both infection groups with T. cati-infected brains revealing less severe reactions. Down-regulated genes in T. canis-infected cerebra and cerebella revealed a significant enrichment for the Gene Ontology term "lipid/cholesterol biosynthetic process". Cholesterol is a highly abundant and important component in the brain, representing several functions. Disturbances of synthesis as well as concentration changes may lead to dysfunction in signal transduction and neurodegenerative disease. Overall, only a minor overlap of differentially transcribed genes was observed between the two infection groups in both brain parts. Most genes are regulated individually in each infection group, supporting the evident differences of both roundworm species observed in the paratenic host in previous studies. In summary the present study underlines the differences in pathogenicity of T. canis and T. cati. It furthermore provides a comprehensive basis for future analyses over the course of infection as well as functional tests to identify gene regulatory circuits that are crucial for pathogenesis of neurotoxocarosis. The results of this study provide a promising foundation for further specific research to evaluate the particular pathogenetic mechanisms and to identify possible therapeutic targets. PMID- 25843807 TI - Integrating biological knowledge based on functional annotations for biclustering of gene expression data. AB - Gene expression data analysis is based on the assumption that co-expressed genes imply co-regulated genes. This assumption is being reformulated because the co expression of a group of genes may be the result of an independent activation with respect to the same experimental condition and not due to the same regulatory regime. For this reason, traditional techniques are recently being improved with the use of prior biological knowledge from open-access repositories together with gene expression data. Biclustering is an unsupervised machine learning technique that searches patterns in gene expression data matrices. A scatter search-based biclustering algorithm that integrates biological information is proposed in this paper. In addition to the gene expression data matrix, the input of the algorithm is only a direct annotation file that relates each gene to a set of terms from a biological repository where genes are annotated. Two different biological measures, FracGO and SimNTO, are proposed to integrate this information by means of its addition to-be-optimized fitness function in the scatter search scheme. The measure FracGO is based on the biological enrichment and SimNTO is based on the overlapping among GO annotations of pairs of genes. Experimental results evaluate the proposed algorithm for two datasets and show the algorithm performs better when biological knowledge is integrated. Moreover, the analysis and comparison between the two different biological measures is presented and it is concluded that the differences depend on both the data source and how the annotation file has been built in the case GO is used. It is also shown that the proposed algorithm obtains a greater number of enriched biclusters than other classical biclustering algorithms typically used as benchmark and an analysis of the overlapping among biclusters reveals that the biclusters obtained present a low overlapping. The proposed methodology is a general-purpose algorithm which allows the integration of biological information from several sources and can be extended to other biclustering algorithms based on the optimization of a merit function. PMID- 25843808 TI - Disruption in the Relationship between Blood Pressure and Salty Taste Thresholds among Overweight and Obese Children. AB - BACKGROUND: Prevalence of high blood pressure among American children has increased over the past 2 decades, due in part to increasing rates of obesity and excessive dietary salt intake. OBJECTIVE: We tested the hypothesis that the relationships among blood pressure, salty taste sensitivity, and salt intake differ between normal-weight and overweight/obese children. DESIGN: In an observational study, sodium chloride (NaCl) and monosodium glutamate (MSG) taste detection thresholds were measured using the Monell two-alternative, forced choice, paired-comparison tracking method. Weight and blood pressure were measured, and salt intake was determined by 24-hour dietary recall. PARTICIPANTS/SETTING: Children aged 8 to 14 years (N=97; 52% overweight or obese) from the Philadelphia, PA, area completed anthropometric and blood pressure measurements; 97% completed one or both thresholds. Seventy-six percent provided valid dietary recall data. Testing was completed between December 2011 and August 2012. MAIN OUTCOME MEASURES: NaCl and MSG detection thresholds, blood pressure, and dietary salt intake. STATISTICAL ANALYSES: Outcome measures were compared between normal-weight and overweight/obese children with t tests. Relationships among outcome measures within groups were examined with Pearson correlations, and multiple regression analysis was used to examine the relationship between blood pressure and thresholds, controlling for age, body mass index z score, and dietary salt intake. RESULTS: NaCl and MSG thresholds were positively correlated (r[71]=0.30; P=0.01) and did not differ between body weight groups (P>0.20). Controlling for age, body mass index z score, and salt intake, systolic blood pressure was associated with NaCl thresholds among normal-weight children (P=0.01), but not among overweight/obese children. All children consumed excess salt (>8 g/day). Grain and meat products were the primary source of dietary sodium. CONCLUSIONS: The apparent disruption in the relationship between salty taste response and blood pressure among overweight/obese children suggests the relationship may be influenced by body weight. Further research is warranted to explore this relationship as a potential measure to prevent development of hypertension. PMID- 25843809 TI - Meta-analysis of amino acid stable nitrogen isotope ratios for estimating trophic position in marine organisms. AB - Estimating trophic structures is a common approach used to retrieve information regarding energy pathways, predation, and competition in complex ecosystems. The application of amino acid (AA) compound-specific nitrogen (N) isotope analysis (CSIA) is a relatively new method used to estimate trophic position (TP) and feeding relationships in diverse organisms. Here, we conducted the first meta analysis of delta(15)N AA values from measurements of 359 marine species covering four trophic levels, and compared TP estimates from AA-CSIA to literature values derived from food items, gut or stomach content analysis. We tested whether the AA trophic enrichment factor (TEF), or the (15)N enrichment among different individual AAs is constant across trophic levels and whether inclusion of delta(15)N values from multiple AAs improves TP estimation. For the TEF of glutamic acid relative to phenylalanine (Phe) we found an average value of 6.60/00 across all taxa, which is significantly lower than the commonly applied 7.60/00. We found that organism feeding ecology influences TEF values of several trophic AAs relative to Phe, with significantly higher TEF values for herbivores compared to omnivores and carnivores, while TEF values were also significantly lower for animals excreting urea compared to ammonium. Based on the comparison of multiple model structures using the metadata of delta(15)N AA values we show that increasing the number of AAs in principle improves precision in TP estimation. This meta-analysis clarifies the advantages and limitations of using individual delta(15)N AA values as tools in trophic ecology and provides a guideline for the future application of AA-CSIA to food web studies. PMID- 25843810 TI - Comparative genetic diversity of Lyme disease bacteria in Northern Californian ticks and their vertebrate hosts. AB - Vector-borne pathogens are transmitted between vertebrate hosts and arthropod vectors, two immensely different environments for the pathogen. There is further differentiation among vertebrate hosts that often have complex, species-specific immunological responses to the pathogen. All this presents a heterogeneous environmental and immunological landscape with possible consequences on the population genetic structure of the pathogen. We evaluated the differential genetic diversity of the Lyme disease pathogen, Borrelia burgdorferi, in its vector, the western black-legged tick (Ixodes pacificus), and in its mammal host community using the 5S-23S rRNA intergenic spacer region. We found differences in haplotype distribution of B. burgdorferi in tick populations from two counties in California as well as between a sympatric tick and vertebrate host community. In addition, we found that three closely related haplotypes consistently occurred in high frequency in all sample types. Lastly, our study found lower species diversity of the B. burgdorferi species complex, known as B. burgdorferi sensu lato, in small mammal hosts versus the tick populations in a sympatric study area. PMID- 25843811 TI - New Borrelia species detected in ixodid ticks in Oromia, Ethiopia. AB - Little is known about Borrelia species transmitted by hard ticks in Ethiopia. The present study was conducted from November 2011 through March 2014 to address the occurrence and molecular identity of these bacteria in ixodid ticks infesting domestic animals in Oromia, Ethiopia. A total of 767 ixodid ticks collected from domestic animals were screened for Borrelia DNA by quantitative (q) real-time PCR followed by standard PCR and sequencing to identify the species. Overall, 3.8% (29/767) of the tested ticks were positive for Borrelia DNA, including 8/119 (6.7%) Amblyomma cohaerens, 1/42 (2.4%) Am. gemma, 3/53 (5.7%) Am. variegatum, 5/22 (22.7%) Amblyomma larvae, 3/60 (5%) Amblyomma nymphs, 2/139 (1.4%) Rhipicephalus (Boophilus) decoloratus, 2/31 (6.4%) Rh. decoloratus nymphs, and 5/118 (4.2%) Rh. pulchellus using 16S genus-specific qPCR. The prevalence of Borrelia DNA was significantly higher in genus Amblyomma (20/298, 6.7%) than in the genus Rhipicephalus (9/417, 2.1%) ticks (P=0.001). Sequencing of PCR products from the flaB and 16S rRNA genes of Borrelia spp. from Amblyomma ticks showed the presence of a new species between the relapsing fever and Lyme disease groups. However, Borrelia sp. detected in Rhipicephalus ticks clustered with B. theileri/B. lonestari. The human pathogenicity of the Borrelia sp. detected in Amblyomma ticks from Ethiopia has not yet been investigated, whereas the Borrelia sp. detected in Rhipicephalus ticks in our study is the causative agent of bovine borreliosis in cattle and may have veterinary importance in different parts of Ethiopia. Furthermore, the detection of previously unrecognized Borrelia species in Amblyomma and Rhipicephalus ticks in Ethiopia generates additional questions concerning the bacterial fauna in hard ticks and will prompt researchers to perform detailed studies for better understanding of ixodid ticks associated bacteria. PMID- 25843812 TI - Comparative analysis of the roles of Ixodes persulcatus and I. trianguliceps ticks in natural foci of ixodid tick-borne borrelioses in the Middle Urals, Russia. AB - Long-term studies on natural foci of ixodid tick-borne borrelioses (ITBB) have been performed in Chusovskoi district of Perm region, the Middle Urals, where the vectors of these infections are represented by two ixodid tick species: the taiga tick Ixodes persulcatus and many times less abundant vole tick I. trianguliceps. Over 10 years, more than 6000 half-engorged ticks were collected from small forest mammals using the standard procedure, and 1027 I. persulcatus and 1142 I. trianguliceps ticks, individually or in pools, were used to inoculate BSK-2 medium. As a result, 199 Borrelia isolates were obtained. Among them, 177 isolates were identified, and the rrf(5S)-rrl(23S) intergenic spacer sequence was determined in 57 isolates. The prevalence of Borrelia infection in I. persulcatus larvae and nymphs averaged 31.0 and 53.3%, while that in I. trianguliceps larvae, nymphs, and adult ticks was five to ten times lower: 2.6, 10.2, and 8.1%, respectively. Each of the two tick species was found to carry both ITBB agents circulating in the Middle Ural foci (Borrelia garinii and B. afzelii), but the set of genogroups and genovariants of these spirochetes in I. trianguliceps proved to be far less diverse. According to the available data, this tick, compared to I. persulcatus, is generally less susceptible to Borrelia infection (especially by B. afzelii). Taking into account of its relatively low abundance, it appears that I. trianguliceps cannot seriously influence the course of epizootic process in ITBB foci of the study region, whereas highly abundant I. persulcatus with the high level of Borrelia infection is obviously a key component of these parasitic systems. A similar situation may well be typical for the entire geographic range shared by the two tick species. PMID- 25843813 TI - [C-KIT in gastrointestinal stromal tumors and associated malignancies: A Study in a population with genetic isolation]. AB - INTRODUCTION: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Numerous studies have reported the association between GIST and other neoplasms. OBJECTIVES: The aim of this study was to investigate the possible association between GIST and other tumors in a genetically isolated population. METHODS: A retrospective study was conducted of patients with GIST between 2002 and 2009 at our center. Epidemiological, pathological and family data in patients with GIST alone (group A) were compared with those in patients with GIST associated with other neoplasms (group B). A possible common genetic mechanism was investigated between GIST and associated malignancies by testing the detection of the immunohistochemical marker, CD117, in all tumors. RESULTS: Twenty-two patients with GIST were identified, 10 in group A (45%) and 12 in group B (55%). In group B, the associated tumor was malignant in 6 patients (50%) and benign in another 6 (50%). Of the 22 patients with GIST, 8 (36%) had a family history of malignancies. Of these 8 patients, 7 (87.5%) were in group B (p=0.03) and 3 (37.5%) showed the same pathological type of neoplasm as their relatives. All GIST were positive for CD117 whereas associated malignancies were negative for this marker. CONCLUSION: We did not find immunohistochemical positivity for CD117 in malignancies associated with GIST. Given the special characteristics of the study population, the association between GIST and associated malignancies may be incidental. PMID- 25843814 TI - Lateral Pharyngeal Wall Tension After Maxillomandibular Advancement for Obstructive Sleep Apnea Is a Marker for Surgical Success: Observations From Drug Induced Sleep Endoscopy. AB - PURPOSE: The efficacy of maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) with anatomic airway changes has previously been studied using static imaging and endoscopy in awake subjects. The aim of the present study was to use drug-induced sleep endoscopy (DISE) to evaluate the dynamic upper airway changes in sleeping subjects before and after MMA and their association with the surgical outcome. PATIENTS AND METHODS: This was a retrospective cohort study of subjects with OSA who had undergone MMA at the Stanford University Sleep Surgery Division from July 2013 to July 2014. The subjects were included if perioperative polysomnography and DISE had been performed. The predictor variable was the perioperative DISE velum-oropharynx-tongue-epiglottis score. The outcome variables were the apnea-hypopnea index (AHI), oxygen-desaturation index (ODI), and Epworth Sleepiness Scale (ESS). A subgroup analysis was performed for the subjects who had undergone primary and secondary MMA. The statistical analyses included Cronbach's alpha coefficient, the McNemar test, and the independent Student t test. The P value was set at <.01. RESULTS: A total of 16 subjects (15 males, 1 female) were included in the present study, with an average age of 47 +/ 10.9 years and body mass index of 29.4 +/- 5.1 kg/m(2). Significant post-MMA decreases were found in the AHI (from 59.8 +/- 25.6 to 9.3 +/- 7.1 events/hr) and ODI (from 45 +/- 29.7 to 5.7 +/- 4.1 events/hr; P < .001). Greater improvement in the AHI occurred in the primary MMA group (P = .022). The post-MMA change in airway collapse was most significant at the lateral pharyngeal wall (P = .001). The subjects with the most improvement in lateral pharyngeal wall collapsibility demonstrated the largest changes in the AHI (from 60.0 +/- 25.6 events/hr to 7.5 +/- 3.4 events/hr) and ODI (from 46.7 +/- 29.8 to 5.3 +/- 2 events/hr; P = .002). CONCLUSIONS: Using DISE, we observed that after MMA, the greatest reduction in upper airway collapsibility is seen at the lateral pharyngeal wall of the oropharynx, followed by the velum, and then the tongue base. The stability of the lateral pharyngeal wall is a marker of surgical success after MMA using the AHI, ODI, and ESS. PMID- 25843815 TI - Topical timolol maleate for superficial infantile hemangiomas: an observational study. AB - PURPOSE: The objective of this study was to assess the clinical effects and safety of topical timolol maleate for the management of superficial infantile hemangiomas (IHs). MATERIALS AND METHODS: From October 2012 to March 2014, 35 infants (24 girls and 11 boys; 2 to 10 months old; median age, 4.7 months) with superficial hemangiomas were treated with the local application of timolol maleate in the authors' department. Thirty-five lesions were treated using topically administrated timolol maleate every 12 hours for a mean duration of 22 weeks (range, 6 to 45 weeks). Follow-up visits were scheduled monthly and changes in tumor size, texture, and color were recorded. Treatment response was scored according to a 3-point scale system as good, partial, or no response. Adverse effects after medication were evaluated and managed accordingly. RESULTS: All patients completed treatment. Of the 35 hemangiomas, 18 (51.4%) showed a good response, 10 (31.4%) showed a partial response, and 6 (17.2%) had no response. The total response rate was 82.8% (29 of 35). Clinically, no systemic or local side effects caused by timolol maleate were observed in the patients. CONCLUSIONS: Topical timolol maleate could provide an effective and safe alternative to the systemic use of propranolol for the treatment of superficial IHs. Further prospective studies are needed to confirm the efficacy and safety of topical timolol maleate for the treatment of IHs. PMID- 25843816 TI - A randomized clinical trial of the effects of submucosal dexamethasone after surgery for mandibular fractures. AB - PURPOSE: To evaluate the effects of immediate postoperative submucosal dexamethasone administration on postoperative pain, edema, trismus, and mandibular functions after open reduction and internal fixation (ORIF) for mandibular fractures. PATIENTS AND METHODS: We conducted a prospective, randomized, controlled, double-blind study of 40 patients who required ORIF for mandibular fractures under general anesthesia. The patients were divided into 2 groups, an experimental group (n = 20) who received immediate postoperative submucosal 8 mg of dexamethasone through the surgical incision site, and a control group (n = 20) who did not receive dexamethasone. Pain was assessed using a visual analog scale (VAS) score and the frequency of analgesic consumption at the various postoperative intervals. The maximum interincisal distance and facial measurements were compared before surgery and at 24, 48, and 72 hours and 7 days after surgery. The difficulty in mandibular function after surgery was graded as mild, moderate, or severe. RESULTS: The analgesic drugs required 2 hours after surgery and the VAS score 72 hours after surgery were significantly less (P < .05) in the experimental group than in the control group. The total number of diclofenac tablets required by the experimental group was less than that for the control group, but the difference was not statistically significant. The control group had significantly increased swelling (P < .05) compared with the experimental group from preoperatively to 24 hours postoperatively (experimental group 0.115 +/- 0.143, control group 0.253 +/- 0.173). No statistically significant difference was present in the mouth opening or difficulty in mandibular function at the different follow-up intervals between the 2 groups (P > .05). CONCLUSION: The results of our study suggest that submucosal administration of dexamethasone after ORIF for mandibular fractures is effective in reducing postoperative pain and edema. PMID- 25843817 TI - Pseudogout in the temporomandibular joint with imaging, arthroscopic, operative, and pathologic findings. Report of an unusual case. AB - The authors present a case of a 60-year-old woman with a destructive painful condition in the right temporomandibular joint (TMJ) that proved to be calcium pyrophosphate crystal deposits at subsequent biopsy examination. The patient presented with the chief complaints of pain and limitation that had not resolved with splint therapy, medications, and habit control. Magnetic resonance imaging studies showed internal derangement without reduction. Right TMJ arthroscopy with manipulation of the jaw under anesthesia showed unique findings of fronds of synovial tissue in the posterior joint space and areas of white matter. Because there was no long-term improvement in her clinical symptoms, she subsequently underwent arthroplasty of the right joint, with the white material clearly seen at surgery, and the biopsy examination confirmed the clinical and arthroscopic impression of pseudogout. The presentation, diagnosis, pathology, and treatment of pseudogout of the TMJ are discussed. PMID- 25843818 TI - Knowledge, practices, and opinions of ontario dentists when treating patients receiving bisphosphonates. AB - PURPOSE: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a severe but extremely rare complication of prolonged treatment with bisphosphonates (BPs). Improper treatment or misdiagnosis can have serious repercussions. In some cases, the treatment of BRONJ can require jaw resection, prolonged use of antibiotics, and long hospitalizations. This study aimed to measure the awareness of dentists in the Province of Ontario, Canada about BRONJ and to identify any gaps in their knowledge of the condition and its treatment. In particular, the study aimed to answer questions about the dentists' knowledge of the current guidelines and their opinions and practices related to performing surgical dental procedures in patients taking BPs. MATERIALS AND METHODS: The study involved sending a Web based questionnaire to a random sample of dentists in Ontario, Canada (n = 1,579). Information about their awareness of BPs, their experiences treating patients presenting with ONJ, their experiences with different surgical procedures in patients taking intravenous or oral BPs, and their awareness of the BRONJ guidelines suggested by the American Association of Oral and Maxillofacial Surgeons was collected. RESULTS: A response rate of 30% was achieved. Sixty percent of responding dentists had a good knowledge of BP and BRONJ; however, only 23% followed the guidelines for surgical treatment of a patient taking BPs, and 63% would refer patients if they were taking BPs. Approximately 50% of responding Ontario dentists were not comfortable treating patients with BRONJ at their current knowledge. CONCLUSION: The finding shows that although 60% of Ontario general dentists and specialists have a good knowledge about BRONJ, most are not comfortable performing oral surgery in patients taking BPs. Those who are comfortable have higher knowledge scores, suggesting greater educational efforts should be made to promote the knowledge of dentists regarding BP, ONJ, and BRONJ. PMID- 25843819 TI - Renal cell carcinoma metastatic to the tongue: a case report and review of the literature. AB - Renal cell carcinoma (RCC) metastatic to the head and neck region is quite rare. This report describes a case of RCC metastatic to the oral tongue presenting initially with a renal mass that evaded diagnosis by biopsy examination of the primary lesion and was eventually established as a papillary type RCC by lingual biopsy examination. The tongue mass progressed rapidly despite chemotherapy with interferon-alpha2b, caused difficulties with oral food intake, and thus necessitated removal by partial glossectomy. Treatment alternatives for lingual RCC metastasis include surgical resection for major functional impairment, risk of airway compromise, or massive hemorrhage. Radiotherapy might be useful and should be considered for specific patients. Lingual metastasis from RCC usually predicts poor survival. PMID- 25843820 TI - Impact of Perioperative Fluid Administration on Postoperative Morbidity and Length of Hospital Stay Following Maxillomandibular Advancement for Obstructive Sleep Apnea. AB - PURPOSE: The purpose of this study was to evaluate whether the volume of perioperative fluids administered to patients undergoing maxillomandibular advancement (MMA) for treatment of obstructive sleep apnea (OSA) is associated with an increased incidence of postoperative complications and prolonged length of hospital stay. MATERIALS AND METHODS: A retrospective cohort study design was implemented and patients undergoing MMA for OSA at the Mayo Clinic were identified from 2001 through 2014. The primary predictor variable was the total volume of intravenous fluids administered during MMA. The primary outcome variable was length of hospital stay in hours. Secondary outcome variables included the presence of complications incurred during postoperative hospitalization. Additional covariates abstracted included basic demographic data, preoperative body mass index, preoperative apnea-hypopnea index, preoperative Charlson comorbidity index, preoperative American Society of Anesthesiologists score, type of intravenous fluid administered, surgical complexity score, duration of anesthesia, duration of surgery, and the use of planned intensive care unit admission. Univariate and multivariable models were developed to assess associations between the primary predictor variable and covariates relative to the primary and secondary outcome variables. RESULTS: Eighty-eight patients undergoing MMA for OSA were identified. Total fluid volume was significantly associated with increased length of stay (odds ratio [OR] = 1.34, 95% confidence interval [CI], 1.05-1.71; P = .020) in univariate analysis. Total fluid volume did not remain significantly associated with increased length of hospital stay in stepwise multivariable modeling. Total fluid volume was significantly associated with the presence of postoperative complications (OR = 1.69; 95% CI, 1.08-2.63; P = .021) in univariate logistic regression. CONCLUSION: Fluid administration was not found to be significantly associated with increased length of hospital stay after MMA for OSA. Increased fluid administration might be associated with the presence of postoperative complications after MMA; however, future large multicenter studies will be required to more comprehensively assess this association. PMID- 25843821 TI - A randomized trial to identify the most effective dose of remifentanil during Le Fort I osteotomy. AB - PURPOSE: The Le Fort I osteotomy (L-I) requires extensive dissection and manipulation of tissue, causing hemodynamic instability and an undesirable postoperative stress response. This study aimed to clarify the most effective dose of remifentanil during L-I. MATERIALS AND METHODS: This study was designed as a prospective, randomized, controlled double-blinded study. Patients (American Society of Anesthesiologists physical status I to II) undergoing L-I were randomly assigned to receive anesthesia with propofol and remifentanil under 3 remifentanil dose conditions: 0.25 MUg/kg/minute (group 1), 0.5 MUg/kg/minute (group 2), and 0.75 MUg/kg/minute (group 3). All patients underwent L-I with propofol and remifentanil target-controlled anesthesia. The study endpoints were mean arterial pressure (MAP) and heart rate. Data were recorded before L-I (20 minute period before surgery), during L-I (from the beginning of surgery to downfracture), and after L-I (20-minute period after downfracture). Average age, gender, average body mass index, aimed maxillary position, average bispectral index, average surgery time, and average blood loss also were examined. Data were analyzed using the Bartlett test and then 1-way analysis of variance with the Bonferroni multiple comparison test. RESULTS: Data were obtained from 20 patients (9 men, 11 women). The average operating times for groups 1, 2, and 3 were 53.1, 46.7, and 49 minutes, respectively. The age range was 18 to 46 years (average, 26.05 yr). The rate of MAP increase from before to during L-I in group 1 was 10.8% (n = 7). The rate of MAP increase from before to during L-I in group 3 was 2.1% (n = 6). Group 3 showed a significantly lower rate of MAP increase during and after L-I compared with group 1 (P < .05). CONCLUSION: Remifentanil administration at 0.75 MUg/kg/minute stabilized hemodynamics during L-I without major side effects. Results indicated that the standard index of remifentanil administration during L-I should be 0.75 MUg/kg/minute when using oxygen, propofol, and remifentanil for general anesthesia. PMID- 25843822 TI - Watershed-scale assessment of oil palm cultivation impact on water quality and nutrient fluxes: a case study in Sumatra (Indonesia). AB - High fertilizer input is necessary to sustain high yields in oil palm agroecosystems, but it may endanger neighboring aquatic ecosystems when excess nutrients are transported to waterways. In this study, the hydrochemical dynamics of groundwater and streams under baseflow conditions were evaluated with bi monthly measurements for 1 year on 16 watersheds. Hydrochemical measurements were related to the spatial distribution of soil and fertilization practices across a landscape of 100 km(2), dominated by oil palm cultivation, in Central Sumatra, Indonesia. The low nutrient concentrations recorded in streams throughout the landscape indicated that the mature oil palm plantations in this study did not contribute to eutrophication of aquatic ecosystems. This was ascribed to high nutrient uptake by oil palm, a rational fertilizer program, and dilution of nutrient concentrations due to heavy rainfall in the study area. Soil type controlled dissolved inorganic N and total P fluxes, with greater losses of N and P from loamy-sand uplands than loamy lowlands. Organic fertilization helped to reduce nutrient fluxes compared to mineral fertilizers. However, when K inputs exceeded the oil palm requirement threshold, high K export occurred during periods when groundwater had a short residence time. For higher nutrient use efficiency in the long term, the field-scale fertilizer management should be complemented with a landscape-scale strategy of fertilizer applications that accounts for soil variability. PMID- 25843823 TI - Effects of hydrodynamic conditions on the sorption behaviors of aniline on sediment with coexistence of nitrobenzene. AB - The sorption behaviors of pollutants affected by hydrodynamic conditions were confirmed in natural water environment. The effects of hydrodynamic conditions on the sorption behaviors of aniline on sediment with coexistence of nitrobenzene were investigated. The particle entrainment simulator (PES) was used to simulate varied bottom shear stresses. The batch equilibrium method was applied to the experiments with the stress levels and the action time controlled at 0.2-0.5 N/m(2) and 24 h, respectively. The findings indicated that apparent partition coefficient of aniline on sediment increased with the shear stress significantly, while decreased with nitrobenzene concentration. On the contrary, both the sorption amount of aniline on suspended particulate matter (Q s) and the effect of nitrobenzene concentration on Q s declined as the shear stress increased. The sorption kinetic results showed that the sorption process followed the pseudo second-order kinetics equation, and the process included two stages: fast sorption stage and slow sorption stage, among which the average sorption rate of fast stage was 7.5-9.5 times that of slow one. The effect of shear stress on the average sorption rate of aniline was enhanced with the increase of nitrobenzene concentration. And shear stress weakened the disturbance of cosolute on main solute sorption process. In addition, experiment results of sorption kinetic show that only the initial sorption rate was affected by shear stress and cosolute concentration. In the first 5 min, shear stress had positive effects on the sorption rate. After that, the sorption rate barely changed with shear stress and cosolute concentration. PMID- 25843824 TI - Multi-component adsorption of copper, nickel and zinc from aqueous solutions onto activated carbon prepared from date stones. AB - The removal of Cu(2+), Ni(2+), and Zn(2+) ions from their multi-component aqueous mixture by sorption on activated carbon prepared from date stones was investigated. In the batch tests, experimental parameters were studied, including solution pH, contact time, initial metal ions concentration, and temperature. Adsorption efficiency of the heavy metals was pH-dependent and the maximum adsorption was found to occur at around 5.5 for Cu, Zn, and Ni. The maximum sorption capacities calculated by applying the Langmuir isotherm were 18.68 mg/g for Cu, 16.12 mg/g for Ni, and 12.19 mg/g for Zn. The competitive adsorption studies showed that the adsorption affinity order of the three heavy metals was Cu(2+) > Ni(2+) > Zn(2+). The test results using real wastewater indicated that the prepared activated carbon could be used as a cheap adsorbent for the removal of heavy metals in aqueous solutions. PMID- 25843825 TI - Bioaccumulation, morphological changes, and induction of metallothionein gene expression in the digestive system of the freshwater crab Sinopotamon henanense after exposure to cadmium. AB - To study the responses of digestive system of the freshwater crab Sinopotamon henanense to the exposure with cadmium (Cd), crabs were acutely exposed to 7.25, 14.50, and 29.00 mg/l Cd for 96 h and subchronically exposed to 0.725, 1.450, and 2.900 mg/l for 21 days. Cd bioaccumulation in the hepatopancreas and digestive tract (esophagus and intestine) was examined. Furthermore, histopathological alterations of the esophagus, midgut, hindgut, and hepatopancreas were assessed in animals from the 29.0 and 2.90 mg/l Cd treatment groups, and expression of metallothionein messenger RNA (MT mRNA) in the hepatopancreas and intestine was measured in all treatment groups. The results showed difference in the middle and high concentrations between acute and subchronic treatment groups. Cd content in digestive tract after acute 14.5 and 29.0 mg/l Cd exposure was significantly higher than that at subchronic 1.45 and 2.90 mg/l exposure, but Cd levels in hepatopancreas were not significantly different under the same condition. Acute exposure to Cd induced greater morphological damage than subchronic exposure: large areas of epithelial cells were necrotic in hepatopancreas and midgut, which detached from the basal lamina. Vacuolated muscle cells were observed in the hindgut of animals from the acute exposure group, but the changes of esophageal morphology were not obvious after acute or subchronic treatments. The expression of MT mRNA increased with increasing Cd concentration, and MT mRNA level in acute exposure groups was significantly lower when compared to the subchronic exposure groups. Higher Cd content and lower MT mRNA expression in the acutely exposed groups may be responsible for more severe damage of digestive system in these exposure groups. PMID- 25843826 TI - Combination of ozonation, activated carbon, and biological aerated filter for advanced treatment of dyeing wastewater for reuse. AB - Laboratorial scale experiments were performed to investigate and evaluate the performance and removal characteristics of organics, color, and genotoxicity by an integrated process including ozonation, activated carbon (AC), and biological aerated filter (BAF) for recycling biotreated dyeing wastewater (BTDW) collected from a cotton textile factory. Influent chemical oxygen demand (COD) in the range of 156 - 252 mg/L, 5-day biochemical oxygen demand (BOD5) of 13.5 - 21.7 mg/L, and color of 58 - 76 degrees were observed during the 20-day continuous operation. Outflows with average COD of 43 mg/L, BOD5 of 6.6 mg/L, and color of 5.6 degrees were obtained after being decontaminated by the hybrid system with ozone dosage of 0.25 mg O3applied/mg COD0, 40 min ozonation contact time, 30 min hydraulic retention time (HRT) for AC treatment, and 2.5 h HRT for BAF treatment. More than 82 % of the genotoxicity of BTDW was eliminated in the ozonation unit. The genotoxicity of the BAF effluent was less than 1.33 MUg 4-nitroquinoline-N oxide/L. Ozonation could change the organics molecular structures, destroy chromophores, increase the biodegradability, and obviously reduce the genotoxicity of BTDW. Results showed that the combined process could guarantee water reuse with high quality. PMID- 25843827 TI - Health literacy in Europe: comparative results of the European health literacy survey (HLS-EU). AB - BACKGROUND: Health literacy concerns the capacities of people to meet the complex demands of health in modern society. In spite of the growing attention for the concept among European health policymakers, researchers and practitioners, information about the status of health literacy in Europe remains scarce. This article presents selected findings from the first European comparative survey on health literacy in populations. M ETHODS: The European health literacy survey (HLS-EU) was conducted in eight countries: Austria, Bulgaria, Germany, Greece, Ireland, the Netherlands, Poland and Spain (n = 1000 per country, n = 8000 total sample). Data collection was based on Eurobarometer standards and the implementation of the HLS-EU-Q (questionnaire) in computer-assisted or paper assisted personal interviews. R ESULTS: The HLS-EU-Q constructed four levels of health literacy: insufficient, problematic, sufficient and excellent. At least 1 in 10 (12%) respondents showed insufficient health literacy and almost 1 in 2 (47%) had limited (insufficient or problematic) health literacy. However, the distribution of levels differed substantially across countries (29-62%). Subgroups within the population, defined by financial deprivation, low social status, low education or old age, had higher proportions of people with limited health literacy, suggesting the presence of a social gradient which was also confirmed by raw bivariate correlations and a multivariate linear regression model. DISCUSSION: Limited health literacy represents an important challenge for health policies and practices across Europe, but to a different degree for different countries. The social gradient in health literacy must be taken into account when developing public health strategies to improve health equity in Europe. PMID- 25843828 TI - Interactions between kappa-carrageenan and some surfactants in the bulk solution and at the surface of alumina. AB - The interactions between surfactants (SDS, CTAB, TX-100 or their equimolar mixtures) and kappa-carrageenan (Carr) in the bulk solution and at the surface of alumina were determined using the surface tension and the spectrophotometric adsorption measurements. The obtained results show that Carr has the ability to create the multilayer complexes with CTAB, TX-100 and the equimolar mixtures of surfactants (CTAB/TX-100), but does not interact with SDS. The created complexes are electrostatic (with CTAB) or they are of different mechanisms such as the hydrogen bonding or the acid-base interactions (with TX-100). The electrokinetic measurements (the surface charge density and the zeta potential) allow to analyze the structure of the adsorption layer: polymer/surfactant/metal oxide. It turned out that the macromolecules of Carr are directly bonded to the surface whereas the surfactants are present in the upper parts of the electrical double layer. PMID- 25843829 TI - Antioxidant and anti-inflammatory levan produced from Acetobacter xylinum NCIM2526 and its statistical optimization. AB - Levan is a homopolymer of fructose naturally obtained from both the plants and microorganisms. Along with the general properties of a biopolymer like bio compatibility, bio-degradability, renewability, flexibility, and eco friendliness, levan also offers some important biomedical properties such as anti oxidant, anti-inflammatory, anti-carcinogenic, anti-AIDS and hyperglycaemic inhibitor. In this study, we have demonstrated the microbial production of therapeutically potential levan by batch fermentation process in sucrose rich medium using Acetobacter xylinum NCIM 2526. The produced Levan was characterized using various physicochemical techniques such as FTIR, (1)H NMR, (13)C NMR spectroscopy, TGA and HPLC. The biomedical potential of the isolated A. xylinum levan for its anti-oxidant and anti-inflammatory activities was exploited in vitro. Further the present study also focused on the optimization of levan production using one factor at a time approach followed by a statistical method, central composite design (CCD) with selected variables. The yield of levan was increased significantly from 0.54 to 13.25g/L with the optimized variables. PMID- 25843830 TI - Structural characterization of hemicelluloses and topochemical changes in Eucalyptus cell wall during alkali ethanol treatment. AB - Eucalyptus was sequentially extracted with 70% ethanol containing 0.4, 1.0, 2.0, 3.0, and 5.0% NaOH for 2h at 80 degrees C. The chemical composition and structural features of the hemicellulosic fractions obtained were comparatively characterized by the combination of high-performance anion-exchange chromatography, gel permeation chromatography, Fourier transform infrared, and nuclear magnetic resonance spectroscopies. Furthermore, the main component distribution and their changes in cell wall were investigated by confocal Raman microscopy. Based on the Fourier transform infrared and nuclear magnetic resonance analyses, the hemicelluloses extracted from Eucalyptus mainly have a linear backbone of (1->4)-linked-beta-d-xylopyranosyl residues decorated with branch at O-2 of 4-O-methyl-alpha-glucuronic acid unit. Raman analysis revealed that the dissolution of hemicelluloses was different in the morphological regions, and the hemicelluloses released mainly originated from the secondary wall. The information obtained from the study conducted by combining chemical characterization with ultrastructure provides important basis for studying the mechanism of the alkali treatment. PMID- 25843831 TI - Physical properties of emulsion-based hydroxypropyl methylcellulose/whey protein isolate (HPMC/WPI) edible films. AB - The objective of this research was to study the effect of the film microstructure of oil-in-water emulsions stabilized by hydroxypropyl methyl cellulose/whey protein isolate (HPMC/WPI) with or without sodium dodecyl sulfate (SDS) over physical properties of HPMC/WPI emulsion-based films. The films were prepared with different HPMC/WPI-oil-SDS combinations (%w/w for 100g of dispersion): HPMC; WPI; HPMC/1WPI-0.5-SDS; HPMC/1WPI-1; HPMC/2WPI-0.5; HPMC/2WPI-1-SDS. Physical properties of films were evaluated. The results showed no statistical differences (p>0.05) between the thicknesses of EFs (0.156 +/- 0.004 mm). The effect of oil content and incorporation of SDS showed the inverse trend for WI and DeltaE, the increasing order of change, for WI and DeltaE, among the formulation evaluated was: HPMC/1WPI-1>HPMC/2WPI-0.5>HPMC/2WPI-1.0-SDS~HPMC/1WPI-0.5-SDS~WPI>HPMC for WI and HPMC/1WPI-0.5-SDS>HPMC/2WPI-1.0-SDS>HPMC/2WPI-0.5>HPMC/1WPI-1 for DeltaE, respectively. The addition of oil and SDS decreased the TS and EB, because oil addition into EF induces the development of structural discontinuities, producing an EF with less chain mobility, and consequently, with less flexibility and resistance to fracture. PMID- 25843832 TI - Chitosan/bioactive glass nanoparticles scaffolds with shape memory properties. AB - We propose a combination of chitosan (CHT) with bioactive glass nanoparticles (BG NPs) in order to produce CHT/BG-NPs scaffolds that combine the shape memory properties of chitosan and the biomineralization ability of BG-NPs for applications in bone regeneration. The addition of BG-NPs prepared by a sol-gel route to the CHT polymeric matrix improved the bioactivity of the nanocomposite scaffold, as seen by the precipitation of bone-like apatite layer upon immersion in simulated body fluid (SBF). Shape memory tests were carried out while the samples were immersed in varying compositions of water/ethanol mixtures. Dehydration with ethanol enables to fix a temporary shape of a deformed scaffold that recovers the initial geometry upon water uptake. The scaffolds present good shape memory properties characterized by a recovery ratio of 87.5% for CHT and 89.9% for CHT/BG-NPs and a fixity ratio of 97.2% for CHT and 98.2% for CHT/BG-NPs (for 30% compressive deformation). The applicability of such structures was demonstrated by a good geometrical accommodation of a previously compressed scaffold in a bone defect. The results indicate that the developed CHT/BG-NPs nanocomposite scaffolds have potential for being applied in bone tissue engineering. PMID- 25843833 TI - (1)H NMR and (1)H-(13)C HSQC surface characterization of chitosan-chitin sheath core nanowhiskers. AB - Surface deacetylation of chitin nanowhiskers (CtNWs) to chitosan-sheath/chitin core nanowhiskers (CsNWs) was successfully monitored by liquid-state high resolution NMR of colloidal suspensions of these never-dried nanowhiskers. CtNWs were derived from acid hydrolysis (3N HCl, 30mL/g, 90min, 104 degrees C) of chitin at 65% yield and 86% CrI. Deacetylation (50% NaOH, 48h, 50 degrees C) of CtNWs generated CsNWs with unchanged nanowhisker morphology and overall length and width dimensions, but a reduced CrI of 54%. Successful step-wise exchanging the aqueous media with acetone, then D2O prevented agglomeration of nanowhiskers and enabled NMR detection of individual nanowhiskers. The crystalline structure of CtNWs and CsNWs provided different chemical environments for the glucosamine hydrogen atom H2, splitting the NMR signals into 2 peaks (delta 3.0 and delta 3.35ppm) which differed from that reported for soluble chitosan (delta 3.2ppm). Besides, (1)H-(13)C HSQC was only possible for CsNWs indicating the NMR phenomenon observed to represent that of the surfaces where the outer layers were highly mobile and less crystalline. The degree of acetylation at the surfaces was determined from (1)H NMR data to be 56% and 9% for CtNWs and CsNWs, respectively. PMID- 25843834 TI - Preparation and application of micro/nanoparticles based on natural polysaccharides. AB - Polysaccharides have attracted more and more attentions and been recognized to be the most promising materials in recent years because of their outstanding merits such as easily available, non-toxic, biocompatible, biodegradable, and easily modified. Considerable research efforts have been directed toward developing polysaccharides-based micro/nanoparticles (PM/NPs). The new major studies of PM/NPs over the past few years are outlined in this review. Methods of preparation, including self-assembly, ionic-gelation, complex coacervation, emulsification, and desolvation method and some others, are summarized. Different applications of PM/NPs in the field of drug-delivery system are highlighted. Besides, another novel application of PM/NPs that are used as emulsifiers to stabilize Pickering emulsion is also introduced. These environmental-friendly particle emulsifiers have received reasonable attention due to their novel applications, especially in food, cosmetics, and pharmaceutics. From literature surveys, we realized that studies on PM/NP systems for different applications have increased rapidly. Hence, the present review is timely. PMID- 25843835 TI - Microwave-assisted extraction of pectic polysaccharide from waste mango peel. AB - This present study investigates the extraction characteristics and optimal parameters of the microwave-assisted extraction of pectin from waste mango peel (WMP). Microwave power, pH, time and solid-liquid ratio were selected as the extraction parameters and was studied by using Box-Behnken response surface design. The experimental data was analyzed by least square regression analysis method and a second order polynomial model was constructed for response from the experimental data. The constructed model was adequate to explain the relationships between independent variables and response. All studied factors had great influence on the yield of pectin by individually and interactively. The optimum microwave assisted extraction conditions for the highest pectin yield (28.86%) from WMP was found to be: microwave power of 413W, pH of 2.7, time of 134s and solid-liquid ratio of 1:18g/ml. The experimental value was well correlated with predicted value at the optimal condition. PMID- 25843836 TI - Self-assembly and emulsification of dopamine-modified hyaluronan. AB - Dopamine modified hyaluronan (HA-DOPA) with different grafting degree were synthesized and self-assembled into nanoparticles. The effects of pH and salinity changes on the structure of the HA-DOPA nanoparticles were investigated. Nanoparticles swelled under increased pH values, and disassociation started at pH values above 6.20. At a fixed pH of 6.20, the size of the nanoparticles decreased with increased salinity, and flocculation occurred when the salt concentration was higher than 0.3M. The emulsification performance of HA-DOPA nanoparticles at different pH values and salt concentrations demonstrated that nanoparticles with moderately swollen structures possess better emulsifying efficiency and emulsion stability. Additionally, HA-DOPA nanoparticles were able to stabilize various types of oils. These results suggest that HA-DOPA nanoparticles have promising potential as Pickering emulsifiers for applications in the cosmetics, medical, and food industries. PMID- 25843837 TI - The effect of fibre and gelatinised starch type on amylolysis and apparent viscosity during in vitro digestion at a physiological shear rate. AB - An in vitro system was used to determine if the addition of insoluble or soluble fibre to aqueous suspensions of gelatinised starch affected the rate at which the starch was digested. Pre-gelatinised potato or corn starch suspensions were digested with porcine pancreatic amylase in the presence of either finely milled insoluble fibres from various sources or with guar gum. In vitro digestion was conducted at 37 degrees C in a rheometer at a low and constant shear rate of 10s( 1) and the quantity of glucose released measured. The rates of starch digestion and suspension viscosity declined asymptotically and were unaffected by the addition of wheat fibre, but were considerably reduced by the addition of wood and AllBran((r)) fibre and to a much greater extent (60%) by the addition of guar. The latter effect may be due to inhibition of amylase activity by non starch polysaccharide sequences. PMID- 25843838 TI - Chitosan/organic rectorite composite for the magnetic uptake of methylene blue and methyl orange. AB - In this study, magnetic particles were prepared using organic rectorite as a carrier, and then a novel magnetic adsorbent named chitosan/organic rectorite Fe3O4 intercalated composite microspheres (CS/Mt-OREC microspheres) was synthesized. The microspheres were characterized by XRD, FT-IR, TEM, SEM and VSM. The effects of adsorbent dosage, initial pH, contact time, temperatures, initial concentrations of methylene blue (MB) and methyl orange (MO) were studied. The adsorption process followed the pseudo-second-order kinetics, and the intra particle diffusion was one but not the only rate-limiting step. The adsorption equilibrium data can be well described by Langmuir model. Thermodynamic parameters such as DeltaG, DeltaH, and DeltaS were estimated to understand the adsorption mechanism of dyes. Moreover, CS/Mt-OREC microspheres were successfully regenerated using NaOH and HCl, and could be easily separated from aqueous solution in magnetic field. PMID- 25843839 TI - Mechanical and thermal properties of Posidonia oceanica cellulose nanocrystal reinforced polymer. AB - In the present study, cellulose nanocrystals (CNC) were isolated from Posidonia oceanica balls and leaves. CNC was prepared from this marine biomass by sulfuric acid hydrolysis (H2SO4) treatment. The raw fibers were firstly isolated by a delignification-bleaching process then the acid hydrolysis treatment was performed at 55 degrees C during 40min under mechanical stirring. The ensuing CNCs were characterized by their morphological and thermal properties using transmission electron microscopy (TEM) and thermal gravimetric analysis (TGA), respectively. Nanocomposite materials using the CNC extracted from marine biomass were obtained by casting and evaporating a mixture of this suspension with poly(styrene-co-butyl acrylate). The effect of CNC loading on mechanical and thermal properties was studied. Dynamic mechanical analysis (DMA) results showed a strong reinforcing effect of CNC that depends on their origin (balls or leaves). The difference was attributed not only to differences in the aspect ratio of CNC but also to the stiffness of the percolating network of nanoparticles. PMID- 25843840 TI - Effect of cellulose nanocrystals (CNC) on rheological and mechanical properties and crystallization behavior of PLA/CNC nanocomposites. AB - In earlier work, we reported that spray freeze drying of cellulose nanocrystals (CNC) yields porous agglomerate structures. On the other hand, the conventional spray dried CNC (CNCSD) and the freeze dried CNC (CNCFD) produce compact solid structures with very low porosity. As it is rather difficult to obtain direct microscopic evidence of the quality of dispersion of CNC in polymer nanocomposites, it was shown that supporting evidence of the quality and influence of dispersion in a polypropylene (PP)/CNC nanocomposite could be obtained by studying the rheological behavior, mechanical properties and crystallization characteristics of PP/CNC nanocomposites. In an effort to produce a sustainable, fully biosourced, biodegradable nanocomposite, this manuscript presents the results of a study of the rheological, mechanical and crystallization behavior of PLA/CNCSFD nanocomposites obtained by melt processing. The results are analyzed to determine CNC network formation, rheological percolation threshold concentrations, mechanical properties in the rubbery and glassy states, and the effect of CNCSFD on crystalline nucleation and crystallization rates of PLA. These results suggest that the porosity and network structure of CNCSFD agglomerates contribute significantly to good dispersion of CNC in the PLA matrix. PMID- 25843841 TI - The supramolecular structure of LPS-chitosan complexes of varied composition in relation to their biological activity. AB - The complexes of chitosan (Ch) with lipopolysaccharides (LPSs) from Escherichia coli O55:B5 (E-LPS) and Yersinia pseudotuberculosis 1B 598 (Y-LPS) of various weight compositions were investigated using quasi-elastic light scattering, zeta potential distribution assay and atomic force microscopy. The alteration of zeta potential of E-LPS-Ch complexes from negative to positive values depending on Ch content was detected. The Y-LPS-Ch complexes had similar positive zeta-potentials regardless of Ch content. The transformation of the supramolecular structure of E LPS after binding with to Ch was revealed. Screening of E-LPS and Y-LPS particles by Ch in the complexes with high polycation was detected. The ability of LPS-Ch complex to induce biosynthesis of TNF-alpha and reactive oxygen species in stimulated human mononuclear cells was studied. A significant decrease in activity complexes compared to that of the initial LPS was observed only for E LPS-Ch complexes. PMID- 25843842 TI - Small-angle X-ray scattering study on pectin-chitosan mixed solutions and thermoreversible gels. AB - Hot solutions containing pectin and chitosan with pectin weight fraction of 0.75, in acidic pH, demonstrate gelation occurring upon cooling to room temperature. This study explores the origin of this gelation using small angle X-ray scattering (SAXS) as the main experimental tool. Modeling SAXS patterns revealed rigid rod conformation in chitosan solutions, whereas pectin formed a self avoiding chain. In addition, nanometric aggregates were detected in pectin solutions. Pectin and chitosan in mixed solutions adopted a similar semiflexible conformation. The only sample that created a visually stable gel displayed a different pattern, characteristic to polymers gels. Manipulating the composition by adding urea and salts highlighted the important role of hydrogen bonding, which governs the gelation mechanism. Nevertheless, electrostatic interactions were also found to take part in the gelation. To the best of our knowledge, this is the first comprehensive and systematic SAXS study on these pectin-chitosan mixtures. PMID- 25843843 TI - (13)C and (15)N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes. AB - (13)C and (15)N solid-state nuclear magnetic resonance (NMR) spectra were recorded from albendazole (ABZ) and from ABZ:beta-cyclodextrin, ABZ:methyl-beta cyclodextrin, ABZ:hydroxypropyl-beta-cyclodextrin and ABZ:citrate-beta cyclodextrin, which were prepared by the spray-drying technique. ABZ signals were typical of a crystalline solid for the pure drug and of an amorphous compound obtained from ABZ:cyclodextrin samples. Relevant spectral differences were correlated with chemical interaction between ABZ and cyclodextrins. The number and type of complexes revealed a strong dependence on the cyclodextrin group substituent. Solid-state NMR data were consistent with the presence of stable inclusion complexes. PMID- 25843844 TI - Probing hydrogen bond interactions in a shear thickening polysaccharide using nonlinear shear and extensional rheology. AB - Mamaku gum is a polysaccharide extracted from the fronds of the black tree fern found in New Zealand. The cooked pith has traditionally been used for various medicinal purposes and as a food source by the Maori people of New Zealand. It has potential applications as a thickener in the food industry and as a palliative for patients with dysphagia. Studies on the shear rheology of Mamaku gum have revealed that the gum exhibits shear thickening at a critical shear rate due to a transition from intra- to inter-molecular chain interactions upon shear induced chain elongation. In this paper, we demonstrate that these interactions are primarily due to hydrogen bonding. We perform extensional rheology on mixtures of Mamaku gum and urea (a known disruptor of hydrogen bonds) to quantify the nature of these interactions. Capillary Breakup Extensional Rheometry (CaBER) performed on the pure Mamaku gum solutions yield plateau values of the Trouton ratio as high as ~10(4), showing that the viscoelasticity of the gum in uniaxial elongation is much higher than in shear. For all Mamaku concentrations tested, the extensional viscosity decreases upon increasing urea concentration. Furthermore, the relaxation time decreases exponentially with increasing urea concentration. This exponential relationship is independent of the Mamaku concentration, and is identical to the relationships between urea concentration and characteristic timescales measured in nonlinear shear rheology. We show using the sticky reptation model for polymers with multiple sticker groups along the backbone how such a relationship is consistent with a linear decrease in the free energy for hydrogen bond dissociation. We then demonstrate that a time concentration superposition principle can be used to collapse the viscoelastic properties of the Mamaku-gum/urea mixtures. PMID- 25843845 TI - Work of adhesion between mucin macromolecule and calcium-alginate gels on molecular level. AB - The bioadhesion of biopolymers to mucus layers is of great interest for the development of drug delivery systems. Herein we use AFM force measurements to evaluate the interaction on molecular level between a mucin macromolecule attached to an AFM tip and a calcium-alginate gel layer. The total work of adhesion is measured from the AFM force curves depending on different parameters: time of contact, G/M ratio of the alginate, and crosslink ratio of the gel. The total work of adhesion is found to be in the range of 1*10(-19) to 6*10(-18)J. The results show that the work of adhesion increases with the time of contact but it is independent from the molecular mass of the alginate, the G/M ratio of the alginate and crosslink ratio of the gel. PMID- 25843846 TI - Fabrication of cellulose-based aerogels from waste newspaper without any pretreatment and their use for absorbents. AB - Cellulose-based aerogel (CBA) was prepared from waste newspaper (WNP) without any pretreatment using 1-allyl-3-methyimidazolium chloride (AmImCl) as a solvent via regeneration and an environmentally friendly freeze-drying method. After being treated with trimethylchlorosilane (TMCS) via a simple thermal chemical vapor deposition process, the resulting CBAs were rendered both hydrophobic and oleophilic. Successful silanization on the surface of the porous CBA was verified by a variety of techniques including scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX), and water contact angle (WCA) measurements. As a result, the silane-coated, interconnected CBAs not only exhibited good absorption performance for oils (e.g., waste engine oil), but also showed absorption capacity for organic solvents such as chloroform (with a representative weight gain ranging from 11 to 22 times of their own dry weight), making them diversified absorbents for potential applications including sewage purification. PMID- 25843847 TI - Adsorption of polyethylene glycol (PEG) onto cellulose nano-crystals to improve its dispersity. AB - In this work, the adsorption of polyethylene glycol (PEG) onto cellulose nano crystals (CNC) was investigated for preparing re-dispersible dried CNC. Results showed that the re-dispersity of CNC in water can be significantly enhanced using a PEG1000 dosage of 5wt% (based on the dry weight of CNC). The elemental analysis confirmed the adsorption of PEG onto the CNC surface. Transmission electron microscopy (TEM) was used to characterize the dry powder and indicated that the irreversible agglomeration of CNC after drying was essentially eliminated based on the PEG adsorption concept. Thermo-gravimetric analysis (TGA) and X-ray diffraction (XRD) suggested that CNC crystallinity and thermal stability were not affected by the adsorption of PEG. Thus, the adsorption of PEG has great potential for producing re-dispersible powder CNC. PMID- 25843848 TI - Preparation and characterization of self-photostabilizing UV-durable bionanocomposite membranes for outdoor applications. AB - Here, we report a durable and ultraviolet (UV) resistant nanocomposite membrane of chitosan (CS) with effective photostabilization ascribed to Zinc oxide (ZnO) nanoparticles. Zinc oxide nanoparticles were successfully dispersed in the solution of chitosan polymer. The nanocomposite films with the homogenous dispersion of ZnO nanoparticles in the chitosan matrix were obtained by solution casting method and the influence of ZnO nanoparticles as a photostabilizer was studied. The nanocomposite membranes were photoirradiated by polychromatic radiations with lambda>300nm using mercury vapour lamps in SEPAP instrument. The resulting nanocomposite material exhibited excellent UV-resistance in very low percentages of ZnO nanoparticles. The chitosan membranes showed fast degradation attributes than the nanocomposite membranes. ZnO nanoparticles effectively absorbed UV radiations, thus protecting polymer from radiation degradation. The neat and irradiated nanocomposites of chitosan and ZnO nanoparticles (CS/ZnO) were characterized by Fourier Transform Infrared Spectroscopy (FT-IR) spectroscopy for the chemical changes/degradation taking place. Chitosan nanocomposites were further characterized for tensile properties, contact angle measurements and surface morphology. PMID- 25843849 TI - Activation of corn cellulose with alcohols to improve its dissolvability in fabricating ultrafine fibers via electrospinning. AB - Water and four small molecular alcohols are respectively used to activate corn cellulose (CN cellulose) with the aim to improve the dissolvability in DMAc/LiCl. Among all these activated agents, monohydric alcohols are found to produce the optimal effect of activation in the whole process including of activating, dissolving, and electrospinning of CN cellulose. Meanwhile, well distributed fibers with the diameter of 500nm-2MUm are fabricated in electrospinning. Understanding the activation effect of monohydric alcohols with water and polyhydric alcohols, the most effective activated agent is ascertained with the characteristics of small molecular size, low viscosity, and single functionality. This work is definitely initiated to understand the critical principle of CN cellulose in dissolving. Accordingly, a feasible methodology is also established to prepare ultrafine cellulose fibers with good morphology in electrospinning. PMID- 25843850 TI - Pullulan-based composite scaffolds for bone tissue engineering: Improved osteoconductivity by pore wall mineralization. AB - Porous hydrogels have been explored for bone tissue engineering; however their poor mechanical properties make them less suitable as bone graft substitutes. Since incorporation of fillers is a well-accepted method for improving mechanical properties of hydrogels, in this work pullulan hydrogels were reinforced with nano-crystalline hydroxyapatite (nHAp) (5 wt% nHAp in hydrogel) and poly(3 hydroxybutyrate) (PHB) fibers (3 wt% fibers in hydrogel) containing nHAp (3 wt% nHAp in fibers). Addition of these fillers to pullulan hydrogel improved compressive modulus of the scaffold by 10 fold. However, the hydrophilicity of pullulan did not support adhesion and spreading of cells. To overcome this limitation, porous composite scaffolds were modified using a double diffusion method that enabled deposition of hydroxyapatite on pore walls. This method resulted in rapid and uniform coating of HAp throughout the three-dimensional scaffolds which not only rendered them osteoconductive in vitro but also led to an improvement in their compressive modulus. These results demonstrate the potential of mineralized pullulan-based composite scaffolds in non-load bearing bone tissue engineering. PMID- 25843851 TI - Pullulan and pullulan derivatives as promising biomolecules for drug and gene targeting. AB - Pullulan is a water soluble exo-polysaccharide produced by yeast like fungus Aureobasidium pullulans. Pullulan structure have a unique characteristic i.e. co existence of alpha-(1->4) and alpha-(1->6) linkages. Pullulan nanoparticle consists of both hydrophobic and hydrophilic characteristics which are due to its unique structure. It can be derivatized via various chemical reactions to increase its utility in the field of pharmaceuticals. Although, various drugs have the potential to become powerful therapeutic medicines, but their safe and targeted delivery to a specific site is a major challenge and rapidly growing area of research. Pullulan-drug conjugates can target infected cells/tissues and exhibit high bioactivity with the release of cytotoxic molecules. The pullulan conjugates can be used for targeted drug delivery as well as targeted gene delivery for the treatment of various diseases in liver, lungs, brain, spleen, etc. In this review, the applications of pullulan and its derivatives in drug and gene targeting are described. PMID- 25843852 TI - Improving surface and mechanical properties of alginate films by using ethanol as a co-solvent during external gelation. AB - Alginate films were prepared by solution casting method and further ionically crosslinked in a calcium chloride (CaCl2) water solution containing different proportions (0-40% v/v) of ethanol as the co-solvent. The addition of ethanol into the CaCl2 water solution was found to improve the visual appearance, thickness, surface homogeneity, and mechanical properties of the films, which can be attributed to the reduced swelling degree of films during crosslinking process. Furthermore, Fourier transform infrared spectroscopy (FTIR) and energy dispersive spectroscopy (EDS) analysis indicated that the incorporation of ethanol into the crosslinking solution did not detract from the uniformity of crosslinking throughout the film matrix. However, the swelling degree and calcium content determination indicated that the Ca(2+) crosslinking degree decreased when the ethanol proportion exceeded 30% v/v. Consequently, this study introduces a green, efficient, and simple technique for the preparation of calcium alginate films with excellent surface appearance and mechanical properties for pharmaceutical products. PMID- 25843853 TI - Fabrication of transparent and ultraviolet shielding composite films based on graphene oxide and cellulose acetate. AB - Graphene oxide (GO) has been considered a promising filler material for building polymeric nanocomposites because of its excellent dispersibility and high surface area. In this work, we present the fabrication and characterization of transparent and ultraviolet (UV) shielding composite films based on GO and cellulose acetate (CA). GO sheets were found to be well-dispersed throughout the CA matrix, providing smooth and homogeneous composite films. Moreover, the GO sheets were completely embedded within the CA matrix and no presence of this nanomaterial was found at the surface. Nevertheless, CAGO composite films offered an improved high energy light-shielding capacity when compared to pristine CA films. Particularly for UVC irradiation, the CAGO film containing 0.50wt% GO displayed a UV-shielding capacity of 57%, combined with 79% optical transparency under visible light. These CAGO composite films can be potentially applied as transparent UV-protective coatings for packing biomedical, pharmaceutical, and food products. PMID- 25843854 TI - Extraction and structural characteristics of pectic polysaccharides from Abies sibirica L. AB - Structurally different pectins were isolated from the wood greenery of Abies sibirica L. by the sequential extraction with water (ASW), HCl solution (pH~4) (ASA), and NH3 solution (pH~8.5) (ASN). The GalA/Rha molar ratios for the ASW (15), ASA (8.9), and ASN (3.9) polysaccharides diminish in the order ASW>ASA>ASN, indicating a decrease in homogalacturonans and increase in rhamnogalacturonan I in this series. The ASWH, ASAH, and ASNH homogalacturonans derived by acid hydrolysis of ASW, ASA, and ASN have similar Mw 23.8, 21.1, and 18.9kDa, respectively, corresponding to a mean polymerization degree of 97-122 for the GalA residue. The macromolecule backbone of ASN was represented mainly by moieties of partially methylesterified homogalacturonan and partially 2-O- and/or 3-O-acetylated rhamnogalacturonan I. The carbohydrate side chains of the branched region are primarily made up of terminal, 1,5-O-, 1,3,5-di-O- and 1,2,3,5-tri-O substituted alpha-L-Araf residues and terminal, 1,3-O- and 1,3,6-di-O-substituted beta-D-Galp residues. The currently known pectin models were refined. PMID- 25843855 TI - Water soluble cationic dextran derivatives containing poly(amidoamine) dendrons for efficient gene delivery. AB - To develop new dextran derivatives for efficient gene delivery, the conjugation of poly(amidoamine) dendrons onto biocompatible dextran was carried out by a Cu(I)-catalyzed azide-alkyne cycloaddition, as confirmed by FTIR and (1)H NMR analyses. For resultant dextran conjugates with various generations of poly(amidoamine) dendrons, their buffering capacity and in vitro cytotoxicity were evaluated by acid-base titration and MTT tests, respectively. In particular, their physicochemical characteristics for the complexation with plasmid DNA were investigated by the combined analyses from agarose gel electrophoresis, zeta potential, particle size, transmission electron microscopy and fluorescence emission spectra. Moreover, their complexes with plasmid DNA were studied with respect to their transfection efficiency in human embryonic kidney (HEK293) cell lines. In the case of a higher generation of poly(amidoamine) dendrons, such a dextran conjugate was found to have much lower cytotoxicity and better gene delivery capability when compared to branched polyethylenimine (bPEI, 25kDa), a commonly used gene vector. PMID- 25843856 TI - In vitro digestibility, crystallinity, rheological, thermal, particle size and morphological characteristics of pinole, a traditional energy food obtained from toasted ground maize. AB - Flour obtained from toasted ground maize grains is widely consumed by different ethnic groups of Northern Mexico and Southwest USA as an energy source. In this work the in vitro digestibility, crystallinity, rheological, thermal, particle size distribution and morphological characteristics of toasted ground white and blue maize flours were studied. X-ray diffraction studies showed that the crystallinity content was reduced, but that the hydrolysis rate and the in vitro digestibility of starch were greatly improved by the toasting process. The relative amount of rapidly digestible starch showed an important increase at the expense of resistant starch content reduction. The thermal properties of white maize starch increased slightly, but those of the blue maize starch decreased slightly after toasting. Aqueous dispersions formed with 10% (w/w) flour were heated at 90 degrees C for 5min to induce starch gelling, in order to resemble thin porridges. The dispersed gels exhibited higher elastic modulus (G') than loss modulus (G'') in the linear viscoelastic region, with blue maize dispersions displaying higher moduli magnitudes. At higher shear strain amplitudes, G' decreased but G'' first increased and then decreased (overshoot phenomenon). The effects of toasting on the structure and functionality of maize starch are explained on the basis of limited gelatinization of the granules. The results in this work provide insights for understanding the extensive use of pinole by impoverished ethnic groups, and more recently by high performance ultra-runners and athletes, as an energy food. PMID- 25843857 TI - Crystallization, structural relaxation and thermal degradation in Poly(L lactide)/cellulose nanocrystal renewable nanocomposites. AB - In this work, crystallization, structural relaxation and thermal degradation kinetics of neat Poly(L-lactide) (PLLA) and its nanocomposites with cellulose nanocrystals (CNC) and CNC-grafted-PLLA (CNC-g-PLLA) have been studied. Although crystallinity degree of nanocomposites remains similar to that of neat homopolymer, results reveal an increase on the crystallization rate by 1.7-5 times boosted by CNC, which act as nucleating agents during the crystallization process. In addition, structural relaxation kinetics of PLLA chains has been drastically reduced by 53% and 27% with the addition of neat and grafted CNC, respectively. The thermal degradation activation energy (E) has been determined from thermogravimetric analysis in the light of Kissinger's and Ozawa-Flynn-Wall theoretical models. Results reveal a reduction on the thermal stability when in presence of CNC-g-PLLA, while raw CNC slightly increases the thermal stability of PLLA. Fourier transform infrared spectroscopy and energy dispersive X-ray spectroscopy results confirm that the presence of residual catalyst in CNC-g-PLLA plays a pivotal role in the thermal degradation behavior of nanocomposites. PMID- 25843858 TI - Amylolysis of maize mutant starches described with a fractal-like kinetics model. AB - Two empirical models, a conventional first-order kinetics and a fractal-like first-order kinetic model were tested for analysing the hydrolysis of 13 wild type, single and double mutants of maize starch by porcine pancreatic alpha amylase (PPA). The major difference between the two models is an additional parameter, the fractal kinetics exponent h, which enables to characterise a decrease of the reaction rate coefficient over time. The fractal-like kinetic model should be preferred to characterise the amylolysis for 10 mutants out of 13 as sugary-2 and amylose-extender curves exhibit clear reaction rate retardation, unlike normal maize and waxy maize. Analysis of the model parameter values reveals two groups of kinetics for the maize mutants: amylose-extender, normal and waxy on one hand, sugary-2 on the other hand. Possible relations between the parameters of the model and granule composition and structure are discussed. PMID- 25843859 TI - Morphology and mechanical properties of poly(butylene adipate-co terephthalate)/potato starch blends in the presence of synthesized reactive compatibilizer or modified poly(butylene adipate-co-terephthalate). AB - The biodegradable poly(butylene adipate-co-terephthalate)(PBAT)/thermoplastic starch (TPS) composite has received considerable attention because of the environmental concerns raised by solid waste disposal. However, the application of PBAT/TPS blends was limited due to the poor mechanical properties originating from the incompatibility between PBAT and TPS. In this work, two approaches were developed to improve the mechanical properties of PBAT/TPS blends. One approach is to use compatibilizers, including the synthesized reactive compatibilizer - a styrene-maleic anhydride-glycidyl methacrylate (SMG) terpolymer, and the commercial compatibilizer (Joncryl-ADR-4368). The chemical structures of SMG were analyzed with (1)H NMR and FT-IR. The other approach is to use the modified PBAT (M-PBAT) to replace part of PBAT in the PBAT/TPS blends. M-PBATs with higher molecular weight were obtained via reactive extrusion of PBAT in the presence of a chain extender. The better dispersion of TPS in PBAT was observed in SEM images when using M-PBAT, leading to the higher tensile strength and elongation at break of PBAT/TPS blends. However, the elongation at break decreased in the presence of compatibilizer (SMG or 4368), though the tensile strength remained in a similar level or slightly higher. Overall, the tensile strength and the elongation at break of the resulting biodegradable PBAT/M-PBAT/TPS blends (TPS=40wt%) were above 27.0MPa and 500%, respectively, which is promising for various applications, including packaging and agricultural mulching films. PMID- 25843860 TI - Carboxylate groups play a major role in antitumor activity of Ganoderma applanatum polysaccharide. AB - In this paper, the structure difference between the polysaccharides isolated from fruit bodies (FGAP) and submerged fermentation system (SGAP) of Ganoderma applanatum was investigated by means of GPC, HPLC and IR, respectively. And their antitumor activities were evaluated against Sarcoma 180 in vivo. The results showed that FGAP and SGAP were typical polysaccharides with different molecular weights, monosaccharide components, and functional groups. Closely related to the distinct structures, FGAP exhibited a better antitumor activity than SGAP. Moreover, since FGAP contained carboxylate groups rather than SGAP, such groups were chemically introduced into SGAP (CSGAP) by carboxymethylation in order to identify their contribution to antitumor activity. The results demonstrated that the inhibition of CSGAP against Sarcoma 180 in vivo was significantly enhanced by comparison to the native SGAP and even higher than that of FGAP, suggesting that the carboxylate groups played a major role in antitumor activity of G. applanatum polysaccharide. PMID- 25843861 TI - Fluorescent imino and secondary amino chitosans as potential sensing biomaterials. AB - A variety of fluorescent imino and secondary amino chitosans were synthesized under very mild conditions by reaction of the biopolymer amino functions with aromatic aldehydes in an acidified methanolic suspension. Simultaneous reactions of several aldehydes with chitosan were successfully carried out, and kinetic studies showed that 1-pyrenecarboxaldehyde reacts the fastest among them. An unprecedented study on the evaluation of the degree of N-substitution (DS, ranging from 31.7% to 12.0%) for the chitosan Schiff bases by using solid state CPMAS (13)C NMR is performed. A linear correlation between the DS obtained for the secondary amino chitosans by (1)H NMR (55.3-10.2%) and those obtained by CPMAS (13)C NMR (34.4-13.8%) has allowed us to calculate an empirical correlation factor that could be applied on chitosan-based aromatic systems. The new chiral labelled chitosan derivatives exhibit a stable fluorescent behaviour, which was used to explore solvent sensoring applications. PMID- 25843862 TI - Self-assembled nanostructured cellulose prepared by a dissolution and regeneration process using phosphoric acid as a solvent. AB - This report describes a "green" method for preparing self-assembled nanostructured cellulose through a dissolution and regeneration process. Cold phosphoric acid is used to dissolve cellulose in order to convert crystalline cellulose into its molecular form. Self-assembly of cellulose molecules into nanostructured cellulose is achieved by using water to regenerate cellulose. By controlling the temperature and time of the phosphoric acid treatment between dissolution and regeneration, the degree of polymerization and the degree of substitution of phosphorous for the regenerated celluloses can be tuned. As a result, cellulose nanofibers or nanospheres can be obtained when the treatment temperature is set to 5 or 50 degrees C, respectively. X-ray analysis shows that the cellulose nanofibers are amorphous and that the cellulose nanospheres are structured similarly to cellulose II with crystallinity indexes between 56 and 73%. Our method offers a "green" process for preparing nanostructured celluloses in high yields. PMID- 25843863 TI - Inhibition of alpha-amylase activity by cellulose: Kinetic analysis and nutritional implications. AB - We report on inhibition of alpha-amylase activity by cellulose based on in vitro experiments. The presence of cellulose in the hydrolysing medium reduced the initial velocity of starch hydrolysis in a concentration dependent manner. alpha Amylase adsorption to cellulose was reversible, attaining equilibrium within 30min of incubation, and showed a higher affinity at 37 degrees C compared to 20 and 0 degrees C. The adsorption was almost unchanged in the presence of maltose (2.5-20mM) but was hindered in the presence of excess protein, suggesting non specific adsorption of alpha-amylase to cellulose. Kinetic analyses of alpha amylase hydrolysis of maize starch in the presence of cellulose showed that the inhibition is of a mixed type. The dissociation constant (Kic) of the EI complex was found to be ca. 3mg/mL. The observed inhibition of alpha-amylase activity suggests that cellulose in the diet can potentially attenuate starch hydrolysis. PMID- 25843864 TI - Hyaluronic acid-decorated poly(lactic-co-glycolic acid) nanoparticles for combined delivery of docetaxel and tanespimycin. AB - Multiple-drug combination therapy is becoming more common in the treatment of advanced cancers because this approach can decrease side effects and delay or prevent drug resistance. In the present study, we developed hyaluronic acid (HA) decorated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (HA-PLGA NPs) for co delivery of docetaxel (DTX) and tanespimycin (17-AAG). DTX and 17-AAG were simultaneously loaded into HA-PLGA NPs using an oil-in-water emulsification/solvent evaporation method. Several formulations were tested. HA PLGA NPs loaded with DTX and 17-AAG at a molar ratio of 2:1 produced the smallest particle size (173.3+/-2.2nm), polydispersity index (0.151+/-0.026), and zeta potential (-12.4+/-0.4mV). Approximately 60% and 40% of DTX and 17-AAG, respectively, were released over 168h in vitro. Cytotoxicity assays performed in vitro using MCF-7, MDA-MB-231, and SCC-7 cells showed that dual drug-loaded HA PLGA NPs at a DTX:17-AAG molar ratio of 2:1 exhibited the highest synergistic effect, with combination index values of 0.051, 0.036, and 0.032, respectively, at the median effective dose. Furthermore, synergistic antitumor activity was demonstrated in vivo in a CD44 and RHAMM (CD168) - overexpressing squamous cell carcinoma (SCC-7) xenograft in nude mice. These findings indicated that nanosystem-based co-delivery of DTX and 17-AAG could provide a promising combined therapeutic strategy for enhanced antitumor therapy. PMID- 25843865 TI - Adsorption of cationized eucalyptus heteropolysaccharides onto chemical and mechanical pulp fibers. AB - Adsorption of native eucalyptus heteropolysaccharides onto bleached softwood and hardwood kraft pulps and bleached CTMP was explored in this work to potentially improve the mechanical properties of the final furnish. It was found that adsorption of native heteropolysaccharides onto softwood kraft pulp was slightly higher than hardwood; however, heteropolysaccharides with low arabinose content were preferentially adsorbed onto the hardwood fibers. Adsorption onto CTMP was the lowest, although the general phenomenon of native absorption was rather low under the applied conditions. A strategy to increase the absorption required cationizing the heteropolysaccharides with 2,3-epoxy propyltrimethylamonium chloride that in general significantly increased the overall phenomenon, again with the same general tendencies as observed for the native adsorption. PMID- 25843866 TI - Mechanistic insights into cellular immunity of chondroitin sulfate A and its zwitterionic N-deacetylated derivatives. AB - As a major component in extracellular matrix of the tissue, chondroitin sulfate A (CS-A) has been shown to exhibit either pro- or anti-inflammatory immune response which was largely dependent on its molecular size and cell types. In this study, we determined the signaling pathway involved in immune response of CS and its N deacetylated derivative (dCS). Our data indicated that both CS and dCS could activate the NF-kappaB transcription factor in antigen presenting cells and induce TNF-alpha production through the TLR/MyD88 pathway. Further studies demonstrated that both CS and dCS had a potential in promoting the proliferation of spleen lymphocytes, and promoting the cytokines secretion by OVA-sensitized splenocytes. Thus, our finding provided a mechanistic insight into the understanding of cellular immunity of CS and dCS, which might be helpful to develop CS-based immune modulators against chronic inflammatory conditions, autoimmunity, infectious diseases, allergies and asthmatic conditions. PMID- 25843867 TI - Self-assembled carrageenan/protamine polyelectrolyte nanoplexes-Investigation of critical parameters governing their formation and characteristics. AB - The aim of this work was to investigate the feasibility of cross-linker free polyelectrolyte complex formation at the nanoscale between carrageenan (CAR) and protamine (PROT). The properties of CAR/PROT nanoparticles (NPs) were dependent on the carrageenan type: kappa (KC), iota (IC) and lambda (LC), concentration of components, addition of divalent cations, weight mixing ratio (WMR) of constituents and mode of component addition. In the case of 0.1% w/v solutions, IC-based NPs had the smallest particle sizes (100-150nm) and low polydispersity indices (0.1-0.4). A decrease in the solution concentration from 0.1% to 0.05% w/v enabled the formation of KC/PROT NPs. All carrageenans exhibited the ability to form NPs with surface charge ranging from -190 to 40mV. The inclusion of divalent cations caused an increase in the particle size and zeta potential. Infrared analysis confirmed the presence of a complex between CAR and PROT and showed that IC chains undergo structural changes when forming NPs. Colloidal stability of NPs was related to the initial surface charge of particles and was time- and pH-dependent. IC was found to be the most suitable type of CAR when forming nanoplexes with PROT. PMID- 25843868 TI - Structural, immunological, and antioxidant studies of beta-glucan from edible mushroom Entoloma lividoalbum. AB - A water soluble beta-glucan having molecular weight ~2*10(5)Da was isolated from hot water extract of the fruit bodies of an edible mushroom Entoloma lividoalbum (Kuhner & Romagn) Kubicka. This polysaccharide (ELPS) contains (1->3,6)-beta-D Glcp, (1->3)-beta-D-Glcp, (1->6)-beta-D-Glcp, and terminal beta-D-Glcp moieties in a molar ratio of nearly 1:1:3:1. Chemical and spectroscopic analysis showed that the backbone of glucan consists of three (1->6)-beta-D-glucopyranosyl and two (1->3)-beta-D-glucopyranosyl residues, out of which one (1->3)-beta-D glucopyranosyl moiety was branched at O-6 with a terminal beta-D-glucopyranosyl residue. This beta-glucan exhibited macrophage, splenocyte, and thymocyte stimulations. It possesses promising antioxidant activities as evidenced from its hydroxyl and superoxide radical scavenging activities and reducing properties. PMID- 25843869 TI - Modelling of wicking and moisture interactions of flax and viscose fibres. AB - Methods for assessing the wicking properties of individual fibre bundles have been developed from models based on the original Washburn equation (WE) and the modified Washburn equation (MWE), which also accounts for swelling. Both models gave indication of differences in wicking properties of flax and the viscose fibres, though MWE gave additional information that could be interpreted in terms of the physical model. Wicking of the viscose fibres is mainly via inter-fibre capillaries while that of flax is a combination of inter-fibre capillaries and lumen present in some elementary fibres. The degree of swelling and associated rotation of flax fibre in a vapour pressure range of 1-6torr were monitored using an environmental scanning electron microscope (ESEM). Viscose fibre exhibited swelling under the same conditions but did not rotate. The two techniques highlighted different mechanisms of wicking which can be used for monitoring moisture uptake/swelling of treated fibres for fabrication of composites. PMID- 25843870 TI - Hybrid nanosystems based on natural polymers as protein carriers for respiratory delivery: Stability and toxicological evaluation. AB - Chitosan/carrageenan/tripolyphosphate nanoparticles were previously presented as holding potential for an application in transmucosal delivery of macromolecules, with tripolyphosphate demonstrating to contribute for both size reduction and stabilisation of the nanoparticles. This work was aimed at evaluating the capacity of the nanoparticles as protein carriers for pulmonary and nasal transmucosal delivery, further assessing their biocompatibility pattern regarding that application. Nanoparticles demonstrated stability in presence of lysozyme, while freeze-drying was shown to preserve their characteristics when glucose or sucrose were used as cryoprotectants. Bovine serum albumin was associated to the nanoparticles, which were successfully microencapsulated by spray-drying to meet the aerodynamic requirements inherent to pulmonary delivery. Finally, a satisfactory biocompatibility profile was demonstrated upon exposure of two respiratory cell lines (Calu-3 and A549 cells) to the carriers. A negligible effect on cell viability along with no alterations on transepithelial electrical resistance and no induction of inflammatory response were observed. PMID- 25843871 TI - Dynamic mechanical and swelling properties of maleated hyaluronic acid hydrogels. AB - A series of maleated hyaluronan (MaHA) are developed by modification with maleic anhydride. The degrees of substitution (DS) of MaHA vary between 7% and 75%. The DS of MaHA is both higher and wider than methacrylated HA derivatives (MeHA) reported in the literature. MaHA hydrogels are then prepared by photopolymerization and their dynamic mechanical and swelling properties of the hydrogels are investigated. The results showed that MaHA hydrogels with moderate DS (25%, 50% and 65%) have higher storage modulus and lower equilibrium swelling ratios than those with either low or high DS (7%, 15% and 75%). Theoretical analyses also suggest a similar pattern among hydrogels with different DS. The results confirm that the increased cross-linking density enhances the strength of hydrogels. Meanwhile, the hydrophilicity of introduced groups during modification and the degree of incomplete crosslinking reaction might have negative impact on the mechanical and swelling properties of MaHA hydrogels. PMID- 25843872 TI - The oxidative degradation of barley beta-glucan in the presence of ascorbic acid or hydrogen peroxide. AB - Cereal beta-glucans are polysaccharides with health benefits that have been linked to their ability to increase luminal viscosity. However, the functional properties of cereal beta-glucans may be diminished by the susceptibility of this polysaccharide to oxidative degradation. In this study, barley beta-glucan was oxidised with hydrogen peroxide or ascorbic acid and the oxidative degradation of beta-glucan was investigated using both asymmetrical flow field-flow fractionation (AsFlFFF) with aqueous solvent and high performance size exclusion chromatography (HPSEC) with LiBr in DMSO as the solvent. Oxidation was shown to cause degradation of beta-glucan, the reaction being faster when oxidised with hydrogen peroxide compared with ascorbic acid. Both HPSEC and AsFlFFF showed comparable results as long as aggregates (only observed in AsFlFFF) were not included in the integration. The compact aggregates observed in oxidised samples suggest oxidation driven interactions between beta-glucan molecules. PMID- 25843873 TI - Cationic curdlan: Synthesis, characterization and application of quaternary ammonium salts of curdlan. AB - Water-soluble curdlan derivatives containing quaternary ammonium groups with a degree of substitution up to 0.15 were synthesized using different cationic agents in alkaline medium. The chemical structure of curdlan derivatives was confirmed by FTIR, (13)C and (1)H NMR spectroscopy. The influence of some reaction conditions (temperature, time, and molar ratio) on the degree of substitution and the viscosimetic behaviour were studied. The degree of substitution increased with the amount of the cationization agent per anhydroglucose unit and was higher when the glycidyl reagents were used, compared with the case when the reagents contained chloro-hydroxypropyl groups. The viscosity behaviour of these new derivatives of curdlan in aqueous solutions and the values of intrinsic viscosities calculated using different semi-empirical equations denote a high hydrodynamic dimension of the macromolecular coils. The interaction of these cationic curdlan derivatives with an anionic curdlan (monobasic curdlan phosphate) was studied in situ by turbidimetric measurements and after 24h by optical density and dynamic light scattering. The formation of polyelectrolyte complexes was influenced by the degree of substitution, the nature of the quaternary substituent, and by the ionic strength of the aqueous solution. The morphology of the polyelectrolyte complexes particles in dry state was examined by atomic force microscopy. PMID- 25843874 TI - Achira as a source of biodegradable materials: Isolation and characterization of nanofibers. AB - In this study, variations in the delignification and bleaching stages, acid hydrolysis and high-pressure homogenization, led to the development of 12 different treatments applied for obtaining nanofibers using fibrous residues arising from the starch extraction process from the achira rhizomes. The treatments were evaluated based on some properties and characteristics of nanofibers such as: morphology and size (by means of transmission electron microscopy), surface charge (by means of zeta potential measurements), crystallinity index (by means of X-ray diffraction analysis) and functional groups (by means of infrared spectroscopy). In general, the nanofibers showed particle diameters between 13.8 and 37.2nm, length between 832.8 and 2223.8nm and high crystallinity index (57.5% and 69.8%) compared with achira fibrous residue (17.3%). The results evidenced that fibrous residue from achira rhizomes can be used as a source of biodegradable materials of commercial interest. PMID- 25843875 TI - Rheology of semi-dilute suspensions of carboxylated cellulose nanofibrils. AB - Cellulose nanofibrils (CNF) in water make entangled networks and stiff gels, which have a number of promising applications. In this work, the rheology of semi dilute TEMPO-mediated oxidized CNF hydrogels, and the effects of cationic polyacrylamide and calcium ions on their viscoelastic properties are investigated. The elastic modulus varies with CNF volume fraction with a power law exponent of 4.52. Creep-recovery results show that suspensions with higher mass fractions exert a higher resistance against deformation, and a higher degree of recovery. Low ionic strengths and polyelectrolyte concentrations increase the creep deformation because of screening the surface charge. Higher ionic strengths and polyelectrolyte concentrations lead to fibril aggregation, which stiffens the network structure, decreasing the creep deformation. However, the recovery response is not significantly affected by additives. The critical strain at the onset of non-linear viscoelasticity is independent of mass fraction in two different concentration regimes, with a transition at 0.35% w/w CNF. PMID- 25843876 TI - Isolation and recovery of cellulose from waste nylon/cotton blended fabrics by 1 allyl-3-methylimidazolium chloride. AB - Development of a simple process for separating cellulose and nylon 6 from their blended fabrics is indispensable for recycling of waste mixed fabrics. An efficient procedure of dissolution of the fabrics in an ionic liquid 1-allyl-3 methylimidazolium chloride ([AMIM]Cl) and subsequent filtration separation has been demonstrated. Effects of treatment temperature, time and waste fabrics ratio on the recovery rates were investigated. SEM images showed that the cotton cellulose dissolved in [AMIM]Cl while the nylon 6 fibers remained. The FTIR spectrum of regenerated cellulose (RC) was similar with that of virgin cotton fibers, which verified that no other chemical reaction occurred besides breakage of hydrogen bonds during the processes of dissolution and separation. TGA curves indicated that the regenerated cellulose possessed a reduced thermal stability and was effectively removed from waste nylon/cotton blended fabrics (WNCFs). WNCFs were sufficiently reclaimed with high recovery rate of both regenerated cellulose films and nylon 6 fibers. PMID- 25843877 TI - Encapsulation of fish oil with N-stearoyl O-butylglyceryl chitosan using membrane and ultrasonic emulsification processes. AB - Fish oil-loaded microcapsules were prepared from oil-in-water emulsions using N stearoyl O-butylglyceryl chitosan as shell material. The emulsions were prepared by both membrane and ultrasonic emulsification processes under variable conditions to examine the effect of the emulsification process and encapsulation conditions on the characteristics of the microcapsules. The microcapsules were characterized with respect to their morphologies, colloidal stability, loading capacity, encapsulation efficiency and release profile. The microcapsules formed by the membrane emulsification process exhibited larger diameter compared to those from the ultrasonic emulsification process which gave a mean effective diameter of ~1MUm. The microcapsules obtained by membrane emulsification process gave better loading capacity and encapsulation efficiency. The microcapsules from both processes showed sustained release of fish oil and the release profile depended on the type of the process. TGA confirmed that encapsulation using N stearoyl O-butylglyceryl chitosan impeded heat transfer and significantly increased the thermal stability of the encapsulated fish oil. PMID- 25843878 TI - Antimicrobial bacterial cellulose nanocomposites prepared by in situ polymerization of 2-aminoethyl methacrylate. AB - Antimicrobial bacterial cellulose/poly(2-aminoethyl methacrylate) (BC/PAEM) nanocomposites were prepared by in situ radical polymerization of 2-aminoethyl methacrylate, using variable amounts of N,N-methylenebis(acrylamide) (MBA) as cross-linker. The obtained nanocomposites were characterized in terms of their structure, morphology, thermal stability, mechanical properties and antibacterial activity. The ensuing composite membranes were significantly more transparent than those of pure BC and showed improved thermal and mechanical properties. The antibacterial activity of the obtained nanocomposites was assessed towards a recombinant bioluminescent Escherichia coli and only the non-crosslinked nanocomposite (BC/PAEM) proved to have antibacterial activity. PMID- 25843879 TI - Chemical characteristics and antithrombotic effect of chondroitin sulfates from sturgeon skull and sturgeon backbone. AB - Chondroitin sulfates (CSs) were extracted from sturgeon skull and backbone, and their chemical composition, anticoagulant, anti-platelet and thrombolysis activities were evaluated. The average molecular weights of CS from sturgeon skull and backbone were 38.5kDa and 49.2kDa, respectively. Disaccharide analysis indicated that the sturgeon backbone CS was primarily composed of disaccharide monosulfated in position four of the GalNAc (37.8%) and disaccharide monosulfated in position six of the GalNAc (59.6%) while sturgeon skull CS was primarily composed of nonsulfated disaccharide (74.2%). Sturgeon backbone CS showed stronger antithrombotic effect than sturgeon skull CS. Sturgeon backbone CS could significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT), inhibited ADP-induced platelet aggregation and dissolved platelet plasma clots in vitro. The results suggested that sturgeon backbone CS can be explored as a functional food with antithrombotic function. PMID- 25843880 TI - Favorable effects of superficially deacetylated chitin nanofibrils on the wound healing process. AB - Previous reports indicate that the beneficial effect of chitin nanofibrils (CNFs), and chitosan nanofibrils (CSNFs) for wound healing. In this study, the wound healing effects of superficially deacetylated chitin nanofibrils (SDACNFs) were evaluated using an experimental model. In the experiments using circular excision wound model, SDACNFs induced re-epithelium and proliferation of the fibroblasts and collagen tissue. In the chitin, CNFs, and CSNFs, on the other hand, the e-epithelium and proliferation of the fibroblasts and collagen tissue were not induced perfectly compared with the SDACNFs group. In particular, re epithelization was observed on day 4 in the only SDACNF group. Moreover, SDACNFs did not induce severe systemic inflammation in the linear incision wound model. The data indicated that SDACNFs effectively induced the proliferation and re modeling phases compared with chitin, CNFs, and CSNFs in the wound. These data indicate that SDACNFs can be beneficial as a new biomaterial for wound healing. PMID- 25843881 TI - Lipopolysaccharide of Marinobacter litoralis inhibits swarming motility and biofilm formation in Pseudomonas aeruginosa PA01. AB - The lipopolysaccharide (LPS) was isolated from a marine bacterium identified as Marinobacter litoralis BK09 using 16S rRNA gene sequence similarity analysis. The GCMS analysis showed that the LPS contained 3-hydroxy-dodecanoic acid (C12:0 3OH) (49%), dodecanoic acid (C12:0) (24%) and decanoic acid (C10:0) (19%) as major fatty acids, and the polysaccharide constituents were fucose (53.79%), xylose (28.04%) and mannose (18.15%). The LPS almost completely inhibited swarming motility in Pseudomonas aeruginosa PA01. It also reduced biofilm formation by 50% with no adverse effect on cell growth. The production of virulence factor such as pyocyanin pigment was reduced (~40%) by the LPS. The LPS did not show any limulus amoebocyte lysate (LAL) gelation activity. The repression of swarming motility, pyocyanin production and biofilm formation by the LPS suggests its potential application against P. aeruginosa infection. This is the first report on characterization and application of LPS from M. litoralis. PMID- 25843882 TI - An improved X-ray diffraction method for cellulose crystallinity measurement. AB - We show in this work a modified X-ray diffraction method to determine cellulose crystallinity index (CrI). Nanocrystalline cellulose (NCC) derived from bleached wood pulp was used as a model substrate. Rietveld refinement was applied with consideration of March-Dollase preferred orientation at the (001) plane. In contrast to most previous methods, three distinct amorphous peaks identified from new model samples which used to calculate CrI. A 2 theta range from 10 degrees to 75 degrees was found to be more suitable to determine CrI and crystallite structural parameters such as d-spacing and crystallite size. This method enables a more reliable measurement of CrI of cellulose and may be applicable to other types of cellulose polymorphs. PMID- 25843883 TI - Acute abdominal pain with atypical presentation. PMID- 25843884 TI - When mothers need others: The impact of hominin life history evolution on cooperative breeding. AB - The evolution of cooperative breeding is particularly complex in humans because many other traits that directly affect parental care (shorter birth intervals, increased offspring survivorship, juvenile dependence, and older ages at dispersal) also emerge during the Pleistocene. If human cooperative breeding is ancient, it likely evolved in a hominin lacking a fully modern life history. However, the impact that changing life history traits has on parental care and cooperative breeding has not been analytically investigated. We develop an exploratory model to simulate an economic problem that would have arisen over the course of hominin life history evolution to identify those transitions that produced the strongest pressures for cooperative childrearing. The model generates two central predictions. First, help within maternal-offspring groups can support early changes in juvenile dependence, dispersal age, birth intervals, and fertility. If so, maternal-juvenile cooperation may be an important but understudied step in the evolution of human cooperative breeding. Second, pressure to recruit adult cooperation is most pronounced under more derived conditions of late dispersal and later ages of juvenile dependence, with a strong interaction at short birth intervals. Our findings indicate that changes in life history traits that affect parental care are critical in considering background selective forces that shaped the evolution of cooperative breeding. PMID- 25843885 TI - Results of 70 consecutive ulnar nightstick fractures. AB - BACKGROUND: Adult isolated ulnar shaft fractures (IUSFs) are uncommon, and treatment remains controversial. The purpose of this study was to compare results of operative (reduction internal fixation (RIF)) and nonoperative treatment (NOT) in patients with IUSF. MATERIAL AND METHODS: A retrospective case-control analysis was undertaken on patients diagnosed with IUSF between 2002 and 2008 at a Level I teaching trauma center. Clinical outcomes consisted of complications and functional ability. RESULTS: Seventy patients had a mean age of 44.6 years (18-86) and a body mass index (BMI) of 27.9 (17-47). The mechanism of injury included high-energy injuries (60/70, 85.7%), low-energy falls (8/70, 11.4%), and sports (2/70, 2.9%). Treatment consisted of 33/70 (47.1%) NOT and 37/70 (52.9%) RIF. The AO/OTA fracture classification was 48 A1, 20 B2, and two C1. The level of activity (LOA) was 60 without restrictions, six with restrictions, and three who did not return to work. The function determined by range of motion was 55/70 (78.6%) full, 11 slightly limited, and one severely limited. A total of 14 nonunions (NUs) and 17 malunions (MUs) occurred. NOT was associated with NU (chi(2)=0.001) and MU (chi(2)=0.000), respectively. Fracture angulation >=8 degrees was related to the inability to return to previous LOA (rho=0.406, p=0.001). Secondary displacement >2mm contributed to MU (R(2)=0.238, p=0.000) and NU (R(2)=0.076, p=0.021). NU was related to a minor functional result (rho=0.315, p=0.009). CONCLUSIONS: IUSF treatment remains challenging in the adult population. Nonoperative treatment of displaced fractures produces a high risk of complications, and the fracture characteristics determine patient outcome. LEVEL OF EVIDENCE: Level III. PMID- 25843886 TI - Outcomes following combined intramedullary nail and plate fixation for complex tibia fractures: A multi-centre study. AB - INTRODUCTION: Concomitant plate fixation as an adjunct to intramedullary nailing (IMN) of proximal third tibia fractures is a proven technique. Benefits include its role as a minimally invasive reduction aid, allowing for minimal soft tissue disruption. Expanding its indications as adjunct fixation to IMN throughout the tibia, we aimed to study outcomes in a multi-centre initiative. MATERIALS AND METHODS: From May 1999 to March 2010, a total of 1302 operatively treated tibial fractures (including plateau and pilon fractures) with complete medical records were identified for review. Of these, 376 cases were treated via IMN, of which 30 cases were treated via combined IMN and plating, meeting inclusion criteria. Primary outcome was union rates, time to union, and complication rates. Secondary outcomes included mean alignment from the immediate postoperative period to the time of final follow-up. RESULTS: Twenty-seven out of 30 patients were available for follow-up. Twenty-five (93%) achieved bony union; the remaining two patients, sustained Type IIIA and B injuries respectively, went onto non-union secondary to deep infection and required multiple re-operations before achieving ultimate union. Mean time at final follow-up was 20 +/- 10 months, 96% were ambulatory at full weight bearing status with no malunions. No significant changes in alignment in either the coronal or sagittal planes were noted at time of final follow-up. CONCLUSION: Combined IMN and plate fixation is a reliable tool not only in the treatment of fractures of the proximal tibia, but also for those fractures in the diaphysis and segmental fractures with proximal and/or distal metadiaphyseal extension with consistent ability to maintain high union rates and maintained alignment. However, longer-term follow-up and prospective trials will be necessary before coming to a definitive conclusion. PMID- 25843887 TI - Salivary gland homeostasis is maintained through acinar cell self-duplication. AB - Current dogma suggests that salivary gland homeostasis is stem cell dependent. However, the extent of stem cell contribution to salivary gland maintenance has not been determined. We investigated acinar cell replacement during homeostasis, growth, and regeneration, using an inducible CreER(T2) expressed under the control of the Mist1 gene locus. Genetic labeling, followed by a chase period, showed that acinar cell replacement is not driven by the differentiation of unlabeled stem cells. Analysis using R26(Brainbow2.1) reporter revealed continued proliferation and clonal expansion of terminally differentiated acinar cells in all major salivary glands. Induced injury also demonstrated the regenerative potential of pre-labeled acinar cells. Our results support a revised model for salivary gland homeostasis based predominantly on self-duplication of acinar cells, rather than on differentiation of stem cells. The proliferative capacity of differentiated acinar cells may prove critical in the implementation of cell based strategies to restore the salivary glands. PMID- 25843889 TI - Occupational Electromagnetic Fields exposure in Magnetic Resonance Imaging systems - Preliminary results for the RF harmonic content. AB - PURPOSE: European legislation concerning the protection of workers from exposure to Electromagnetic Fields (EMF) was recently (26.6.2013) completed by Directive 2013/35/EpsilonU. This Directive is a specific one of the framework Directive 89/391/EEC and part of the overall legislation for Occupational Health and Safety (OHS). Magnetic Resonance Imaging (MRI) systems have played a key role, both in the postponement of the former 2004/40 EMF Directive and in the formation of the latest limits adopted by the new Directive. On the other hand, MRI systems are associated with the exposure of personnel to EMF of various frequencies and modulations, arousing peculiar safety issues. Therefore, we will try to acquire the highly important knowledge of the exact occupational exposure levels, in all working scenarios and practices. METHODS: Different MRI systems (1.5 and 3 T) have been chosen for a variety of measurements in order to assess occupational exposure compared to the limits (ALs) of the Directive and to the main OHS principles. Gradient function of MRI systems results in low frequency exposure, while high frequency exposure comes from the application of the RF excitation frequency. RESULTS: In most of the cases the RMS and peak value measurements do not exceed the corresponding ALs, apart from a few specific hot spots, manageable through OHS principles. DISCUSSION: Complete occupational exposure results can form the basis for dealing with multiple exposures present in MRI systems. Peculiar RF harmonic components, of no safety concern, were detected. Their origin is under examination. PMID- 25843890 TI - Simulated annealing applied to IMRT beam angle optimization: A computational study. AB - Electing irradiation directions to use in IMRT treatments is one of the first decisions to make in treatment planning. Beam angle optimization (BAO) is a difficult problem to tackle from the mathematical optimization point of view. It is highly non-convex, and optimization approaches based on gradient descent methods will probably get trapped in one of the many local minima. Simulated Annealing (SA) is a local search probabilistic procedure that is known to be able to deal with multimodal problems. SA for BAO was retrospectively applied to ten clinical examples of treated cases of head-and neck tumors signalized as complex cases where proper target coverage and organ sparing proved difficult to achieve. The number of directions to use was considered fixed and equal to 5 or 7. It is shown that SA can lead to solutions that significantly improve organ sparing, even considering a reduced number of angles, without jeopardizing tumor coverage. PMID- 25843888 TI - The BASL polarity protein controls a MAPK signaling feedback loop in asymmetric cell division. AB - Cell polarization is linked to fate determination during asymmetric division of plant stem cells, but the underlying molecular mechanisms remain unknown. In Arabidopsis, BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) is polarized to control stomatal asymmetric division. A mitogen-activated protein kinase (MAPK) cascade determines terminal stomatal fate by promoting the degradation of the lineage determinant SPEECHLESS (SPCH). Here, we demonstrate that a positive feedback loop between BASL and the MAPK pathway constitutes a polarity module at the cortex. Cortical localization of BASL requires phosphorylation mediated by MPK3/6. Phosphorylated BASL functions as a scaffold and recruits the MAPKKK YODA and MPK3/6 to spatially concentrate signaling at the cortex. Activated MPK3/6 reinforces the feedback loop by phosphorylating BASL and inhibits stomatal fate by phosphorylating SPCH. Polarization of the BASL-MAPK signaling feedback module represents a mechanism connecting cell polarity to fate differentiation during asymmetric stem cell division in plants. PMID- 25843891 TI - Ebola vaccines: keep the clinical trial protocols on the shelf and ready to roll out. PMID- 25843892 TI - A cervical spine mass caused by Onchocerca lupi. PMID- 25843893 TI - Alpha-smooth muscle actin and serotonin receptors 2A and 2B in dogs with myxomatous mitral valve disease. AB - Canine Myxomatous mitral valve disease (MMVD) is an age-related disease. Serotonin (5-HT) is implicated in the pathogenesis as locally-produced or platelet-derived. Involvement of the 5-HT2A receptor (R) and 5-HT2BR in the induction of myxomatous-mediating valvular myofibroblasts (MF) has been suggested. In an age-matched population of dogs with non-clinical and clinical MMVD, the objectives were to investigate (1) gene expression of 5-HT2AR and 5 HT2BR, (2) protein expression and spatial relationship of 5-HT2AR, 5-HT2BR and MF in the mitral valve (MV) and the cardiac anterior papillary muscle (AP) and (3) serum 5-HT concentrations. Gene expression of 5-HT2BR was significantly higher in MV and AP among dogs with clinical MMVD. This was not found for 5-HT2BR protein expression, though association of 5-HT2BR with myxomatous pathology and co localization of 5-HT2BR and MF in MV and AP support a functional relationship, perhaps perpetuation of clinical MMVD. 5-HT2AR-expression and serum 5-HT showed no differences between groups. PMID- 25843894 TI - Identification of in vivo-induced genes during infection of chickens with Salmonella enterica serovar Enteritidis. AB - Chickens are an important source of food worldwide and are often infected with food-poisoning serovars of Salmonella enterica, frequently Salmonella Enteritidis (SE), without exhibiting clinical signs of disease. Ivi (in vivo induced) genes identified using in vivo-induced antigen technology (IVIAT) are expressed only during bacterial infection and have the potential value of identifying epidemic strains and antigens which can form the basis for sub-unit vaccine development. We applied IVIAT to SE strain 50041 and identified 42 ivi genes. Eight representative ivi genes were further confirmed by qRT-PCR as being expressed only in vivo within 48 h of infection compared with that of in vitro-cultured. Although our results indicated that the identified ivi genes are expressed only in vivo, further research is needed to elucidate the exact roles of these genes during infection and pathogenesis. PMID- 25843895 TI - Effects of chronic infection with Trichostrongylus vitrinus and immune suppression with corticosteroid on parasitological, immune and performance variables in crossbred meat lambs. AB - The effects of, and interactions between chronic Trichostrongylus vitrinus infection and immune suppression with methylprednisolone were investigated for a period of 112 days in a grazed flock of 176 crossbred meat lambs. Worm egg count of non-immune-suppressed lambs increased rapidly from days 21 to 42 post-initial infection, and then steadily declined. Infection was associated with significantly decreased fat depth, eye muscle area and cold carcase weight, and increased circulating anti-T. vitrinus IgG and IgA. Immune suppression led to sustained increases in WEC, and significantly greater worm count, liver weight, fat depth and carcase dressing percentage, and significantly reduced IgG and IgA anti-T. vitrinus titres, lymphocyte counts, adrenal weight, eye muscle area and cold carcase weight. Both infection and immune suppression were associated with significant body weight reductions. Only 39% of reduced growth rate due to infection was attributable to the host immune response to T. vitrinus. PMID- 25843896 TI - Bacterial community structure in the intestinal ecosystem of rainbow trout (Oncorhynchus mykiss) as revealed by pyrosequencing-based analysis of 16S rRNA genes. AB - In this study, we determined the diversity and composition of bacterial communities within the intestinal ecosystem of farmed rainbow trout (Oncorhynchus mykiss). Healthy rainbow trout, weighing between 520 and 750 g, were fed a commercial diet. Subsequently, genomic DNA was isolated from the intestinal mucus (n = 16 fish samples) and combined into groups of four fish samples each for pyrosequencing analysis of bacterial 16S rRNA genes. The results revealed that the most abundant operational taxonomic units (OTUs) were affiliated to the genera Acinetobacter, Cetobacterium, Pseudomonas, and Psychrobacter, and to a lesser extent, the genera Aeromonas, Clostridium, Deefgea, Flavobacterium, Neptuniibacter, and Mycoplasma. These findings could be used as a baseline for further studies about the role of bacterial communities in normal and altered host physiological states. PMID- 25843897 TI - Bupivacaine induces apoptosis through caspase-dependent and -independent pathways in canine mammary tumor cells. AB - Local anesthetics have been reported to induce apoptosis in various cell lines. In this study, we showed that bupivacaine also induced apoptosis in DTK-SME cells, a vimentin(+)/AE1(+)/CK7(+)/HSP27(+), tumorigenic, immortalized, canine mammary tumor cell line. Bupivacaine induced apoptosis in DTK-SME cells in a time and concentration-dependent manner. Apoptosis-associated morphological changes, including cell shrinkage and rounding, chromatin condensation, and formation of apoptotic bodies, were observed in the bupivacaine-treated DTK-SME cells. Apoptosis was further confirmed with annexin V staining, TUNEL staining, and DNA laddering assays. At the molecular level, the activation of caspases-3, -8, and 9 corresponded well to the degree of DNA fragmentation triggered by bupivacaine. We also demonstrated that the pan-caspase inhibitor, z-VAD-fmk, only partially inhibited the apoptosis induced by bupivacaine. Moreover, treated cells increased expression of endonuclease G, a death effector that acts independently of caspases. Our data suggested that bupivacaine-induced apoptosis occurs through both caspase-dependent and caspase-independent apoptotic pathways. PMID- 25843898 TI - Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. AB - BACKGROUND: Diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with substantial diagnostic delays. We assessed the sensitivity and specificity of a threshold tracking transcranial magnetic stimulation (TMS) technique, which might allow early detection of upper motor neuron dysfunction, for the diagnosis of the disorder. METHODS: We did a prospective study of patients referred to three neuromuscular centres in Sydney, Australia, in accordance with the Standards for Reporting of Diagnostic Accuracy. Participants had definite, probable, or possible ALS, as defined by the Awaji criteria; or pure motor disorder with clinical features of upper and lower motor neuron dysfunction in at least one body region, progressing over a 6 month follow-up period; or muscle wasting and weakness for at least 6 months. All patients underwent threshold tracking TMS at recruitment (index test), with application of the reference standard, the Awaji criteria, to differentiate patients with ALS from those with non-ALS disorders. The investigators who did the index test were masked to the results of the reference test and all other investigations. The primary outcome measures were the sensitivity and specificity of TMS in differentiating ALS from non-ALS disorders; these measures were derived from receiver operator curve analysis. FINDINGS: Between Jan 1, 2010, and March 1, 2014, we screened 333 patients; 281 met our inclusion criteria. We eventually diagnosed 209 patients with ALS and 68 with non-ALS disorders; the diagnosis of four patients was inconclusive. The threshold tracking TMS technique differentiated ALS from non ALS disorders with a sensitivity of 73.21% (95% CI 66.66-79.08) and specificity of 80.88% (69.53-89.40) at an early stage in the disease. All patients tolerated the study well, and we did not record any adverse events from performance of the index test. INTERPRETATION: The threshold tracking TMS technique reliably distinguishes ALS from non-ALS disorders and, if these findings are replicated in larger studies, could represent a useful diagnostic investigation when combined with the Awaji criteria to prove upper motor neuron dysfunction at early stages of ALS. FUNDING: Motor Neuron Disease Research Institute of Australia, National Health and Medical Research Council of Australia, and Pfizer. PMID- 25843899 TI - Tackling diagnostic delays in ALS. PMID- 25843900 TI - Eu-doped ZnO nanoparticles: Sonochemical synthesis, characterization, and sonocatalytic application. AB - Undoped and europium (III)-doped ZnO nanoparticles were prepared by a sonochemical method. The prepared samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) analysis. The crystalline sizes of undoped and 3% Eu-doped ZnO were found to be 16.04 and 8.22nm, respectively. The particle size of Eu-doped ZnO nanoparticles was much smaller than that of pure ZnO. The synthesized nanocatalysts were used for the sonocatalytic degradation of Acid Red 17. Among the Eu-doped ZnO catalysts, 3% Eu-doped ZnO nanoparticles showed the highest sonocatalytic activity. The effects of various parameters such as catalyst loading, initial dye concentration, pH, ultrasonic power, the effect of oxidizing agents, and the presence of anions were investigated. The produced intermediates of the sonocatalytic process were monitored by GC-Mass (GC-MS) spectrometry. PMID- 25843901 TI - Sonochemical degradation of naphthol blue black in water: Effect of operating parameters. AB - In this work, the sonochemical degradation of naphthol blue black (NBB), an acidic diazo dye, in water was investigated. The effects of several operating parameters such as initial NBB concentration, acoustic intensity, ultrasonic frequency, nature of the dissolved gas and solution pH on the degradation of the dye were carried out. The obtained results showed that ultrasound completely destroyed NBB (5 mg L(-1)) after 45 min of sonication and most of the chemical oxygen demand was eliminated after 90 min of treatment. It was found that the initial rate of sonolytic degradation increased with increasing the initial NBB concentration. The fitting of the experimental data by a heterogeneous Langmuir kinetics model showed that NBB degraded mainly at the interfacial region of the bubble by hydroxyl radical (OH) attack. The degradation rate of the dye increased substantially with increasing acoustic intensity in the range of 0.44-3.58 W cm( 2) and decreased with increasing frequency in the range of 585-1140 kHz. The rate of NBB degradation decreased in the order of Ar>air>N2. The significant degradation was achieved in acidic conditions (pH 2) where the initial degradation rate was 1.37 and 1.66 higher than those observed at pH 6 and pH 10, respectively. PMID- 25843902 TI - Developing a Job Description for a Vice Chair of Education in Radiology: The ADVICER Template. AB - RATIONALE AND OBJECTIVES: The newly formed Alliance of Directors and Vice Chairs of Education in Radiology (ADVICER), a group within the Alliance for Clinician Educators in Radiology, identified an acute need for a generic job description template for Vice Chairs of Education in Radiology, a role that is being developed in many academic Departments of Radiology. Eighty-three percent of current members who responded to a survey had no detailed job description, and over half had no job description at all. Having a comprehensive and detailed job description is vital to developing this key position. MATERIALS AND METHODS: Using the results of a survey sent to ADVICER members and seven Education Vice Chair job descriptions provided by members, the authors developed a detailed job description encompassing all potential elements of this position. RESULTS: Only 17% of survey respondents had a detailed job description. The role of an Education Vice Chair varies significantly between institutions in its scope and level of responsibilities. The resultant generic job description that was devised is intended to provide a template that would be modified by the candidate or the Department Chair. It is unlikely that any one individual would perform all the described activities. CONCLUSIONS: ADVICER has developed a comprehensive, flexible job description for Vice Chair of Education in Radiology that can be adapted by institutions as appropriate. It can be downloaded from http://aur.org/ADVICER/. PMID- 25843903 TI - Mechanoreceptor distribution in stag beetle jaws corresponds to the material stress in fights. AB - Male stag beetles (Lucanidae) use their extremely elongated jaws to pinch their rivals forcefully in male-male battles. The morphology of these jaws has to be a compromise between robustness (to withstand the bite forces), length and weight. Cyclommatus metallifer stag beetles circumvent this trade-off by reducing their bite force when biting with their slender jaw tips. Here we describe the functional mechanism behind the force modulation behaviour. Scanning Electron Microscopy and micro CT imaging show large numbers of small sensors in the jaw cuticle. We find a strong correlation between the distribution of these sensors and that of the material stress in the same jaw region during biting. The jaw sensors are mechanoreceptors with a small protrusion that barely protrudes above the undulating jaw surface. The sensors stimulate dendrites that extend from the neuronal cell body through the entire thickness of the jaw exoskeleton towards the sensors at the external surface. They form a sensory field that functions in a feedback mechanism to control the bite muscle force. This negative feedback mechanism enabled the stag beetles to evolve massive bite muscles without risking overloading their valuable jaws. PMID- 25843904 TI - A tannin-blocking agent does not modify the preference of sheep towards tannin containing plants. AB - Sheep have been suggested to use their senses to perceive plant properties and associate their intake with consequences after ingestion. However, sheep with browsing experience do not seem to select against tannin-rich browsing materials in cafeteria trials. Thus, the objective of the present study was to evaluate the relationship between the chemical composition, selectivity index (SI), preference and intake rate (IR) of tannin-containing forage trees offered to sheep in cafeteria experiments. Four trees were selected for their condensed tannin content and their varying biological activities. Havardia albicans (high biological activity), Leucaena leucocephala (medium biological activity), Acacia gaumeri (low biological activity) and Brosimum alicastrum (very low biological activity) were used in this study. Ten hair sheep (23.7kg+/-1.43LW) with eight months of browsing experience in native vegetation were used in this study. Polyethylene glycol (PEG 3600MW) was administered to five sheep during all experiments. In experiment 1, fresh foliage from all trees was offered ad libitum for 4h. In experiment 2, B. alicastrum was withdrawn and the preference was determined again. The forage preference in experiment 1 was A. gaumeri (14.77gDM/kgLW)>B. alicastrum (11.77gDM/kgLW)>H. albicans (3.71gDM/kgLW)=L. leucocephala (1.87gDM/kgLW) (P<0.05). The preference in experiment 2 was A. gaumeri>H. albicans=L. leucocephala. PEG administration had no effect on the preference or IR. The intake rate seemed to have been affected by the plant density. Moreover, fiber compounds were found to be better predictors of DM intake than polyphenolic compounds at levels typically found in the evaluated forages. It was concluded that tannins and PEG did not modify the preferences of sheep in cafeteria trials. Thus, tannins are not involved in the preference regulation of animals with browsing experience. PMID- 25843905 TI - Temporal trends show improved breast cancer survival in Australia but widening urban-rural differences. AB - We examined geographic patterns in breast cancer survival over time using population-based data for breast cancer diagnosed between 1987 and 2007 in New South Wales, Australia. We found that five-year relative survival increased during the entire study period. Multivariable analysis indicated that there was little geographic variation in 1992-1996, but in 1997-2001 and 2002-2007 geographic variation was statistically significant (P < 0.01), with women living in rural areas having higher risk of death from breast cancer. The underlying reasons for this widening survival disparity must be identified so that appropriately targeted interventions can be implemented and the disparity reduced. PMID- 25843906 TI - Are SK channels a logical target for treating ventricular arrhythmias? First, do no harm. PMID- 25843907 TI - Antisocial features and "faking bad": A critical note. AB - We critically review the literature on antisocial personality features and symptom fabrication (i.e., faking bad; e.g., malingering). A widespread assumption is that these constructs are intimately related. Some studies have, indeed, found that antisocial individuals score higher on instruments detecting faking bad, but others have been unable to replicate this pattern. In addition, studies exploring whether antisocial individuals are especially talented in faking bad have generally come up with null results. The notion of an intrinsic link between antisocial features and faking bad is difficult to test and research in this domain is sensitive to selection bias. We argue that research on faking bad would profit from further theoretical articulation. One topic that deserves scrutiny is how antisocial features affect the cognitive dissonance typically induced by faking bad. We illustrate our points with preliminary data and discuss their implications. PMID- 25843908 TI - Modified aesthetic abdominoplasty approach in perforator free-flap breast reconstruction: Impact of drain free donor site on patient outcomes. AB - BACKGROUND: The use of progressive tension sutures alone has been shown to be comparable to using abdominal drains in aesthetic abdominoplasty. This study reviews outcomes with the use of barbed progressive tension suture technique without drains in DIEP donor site closure compared to standard closure with drains. METHODS: A two year retrospective review was conducted of DIEP flap reconstructions in the enhanced recovery program at Mayo Clinic, Rochester (USA). Donor site closure was divided into barbed progressive tension sutures (B-PTS) without drains, and standard abdominal closure with drains(S-AD). Demographics, perioperative data and donor site complications were documented. RESULTS: 93 patients were included in the study, 42 in the B-PTS no drain group and 51 in the S-AD with drains. 81% of all procedures were bilateral and 39% were immediate. Patients were discharged faster to the ward postoperatively and total hospital admission was reduced in the B-PTS group, 3.7 (SD = 1.4) days versus 4.7 (SD = 2.1) days in the standard group (P = 0 < 0.001 and 0.004 respectively). Less morphine was required postoperative day (POD) 1, 2 and 3 (P = 0.04, 0.03, 0.02 respectively), and time to mobilize was quicker but not statistically significant (P = 0.09) in the B-PTS group. Overall there were 18 patients in the S-AD group who had complications versus 9 in the B-PTS group (P = 0.14). The incidence of complications occurring within 30 days were lower in the B-PTS group (P = 0.05). The overall seroma rate was 5.4% and rates in the B-PTS group was 2.4% versus 7.8% in the S-AD group, P = 0.37. CONCLUSIONS: Use of barbed progressive tension sutures for abdominal closure after DIEP flap harvest can obviate the need for abdominal drains, reduce postoperative pain and encourage early discharge from the hospital without an increased risk in complications. LEVEL OF EVIDENCE: III. PMID- 25843909 TI - The versatility of the islanded posterior arm flap for regional reconstruction around the axilla. AB - INTRODUCTION: Defects in the region of the axilla pose a difficult reconstructive problem. Various methods for restoration have been described. We present our experience with the islanded posterior arm flap for regional reconstruction around the axilla. PATIENTS AND METHODS: Between 2008 and 2013, all patients receiving a posterior arm flap for regional reconstruction around the axilla were entered in a prospectively maintained database. Patient data, surgical details, complications and the need for revisional procedures were recorded. RESULTS: In the study period, 35 posterior arm flaps were used in 24 patients (f:m = 11:13; mean age at surgery: 41,3 +/- 18,5 years; 11 bilateral procedures) with defects predominately due to hidradenitis suppurativa (n = 31). The remaining indications included tumor resection (n = 2), burn contracture release or thoracic surgery (n = 1 each). The majority of defects were located at the axilla, but also in the proximal upper arm or the adjacent thoracic wall. Major wound complications such as total or partial flap necrosis were not encountered in our series. Minor complications included partial superficial wound dehiscence (n = 4) and superficial wound infection (n = 1), all of which were managed conservatively. In 4 patients a secondary flap trimming procedure was required. CONCLUSION: In our hands, the posterior arm flap is an excellent choice for axillary reconstruction due to its constant anatomy, robust vascularity, unrivaled freedom of flap insetting, excellent recipient site matching and favorable donor site morbidity. Besides axillary defects, the posterior arm flap may additionally be employed for defects of the adjacent thoracic wall or the proximal two thirds of the upper arm. PMID- 25843911 TI - Vascular-targeted photodynamic therapy in the treatment of neovascular age related macular degeneration: Clinical perspectives. AB - Vascular targeted photodynamic therapy (VTP), with use of verteporfin as a photosensitizer is one of the few therapies, which has been shown to effectively slow the progression of the "wet" form of age-related macular degeneration (AMD), and even to stabilize visual acuity over many years. Although, due to considerable advance of AMD treatment, it is currently not recommended in monotherapy of AMD, however, its combination with steroids and anti-angiogenic biologic drugs may reveal high therapeutic potential in the treatment of neovascular AMD. The future of VTP as a method of AMD treatment is development of new selective and targeted photosensitizer and combination of this method with other therapeutic strategies targeting cellular structures or pathways involved in AMD progression. PMID- 25843910 TI - The brown fat secretome: metabolic functions beyond thermogenesis. AB - Brown fat is highly active in fuel oxidation and dissipates chemical energy through uncoupling protein (UCP)1-mediated heat production. Activation of brown fat leads to increased energy expenditure, reduced adiposity, and lower plasma glucose and lipid levels, thus contributing to better homeostasis. Uncoupled respiration and thermogenesis have been considered to be responsible for the metabolic benefits of brown adipose tissue. Recent studies have demonstrated that brown adipocytes also secrete factors that act locally and systemically to influence fuel and energy metabolism. This review discusses the evidence supporting a thermogenesis-independent role of brown fat, particularly through its release of secreted factors, and their implications in physiology and therapeutic development. PMID- 25843912 TI - Oral 5-aminolevulinic acid mediated photodynamic diagnosis using fluorescence cystoscopy for non-muscle-invasive bladder cancer: A randomized, double-blind, multicentre phase II/III study. AB - BACKGROUND: Photodynamic diagnosis (PDD) of non-muscle-invasive bladder cancer (NMIBC) following transurethral administration of a hexalated form of 5 aminolevulinic acid (5-ALA), 5-ALA hexyl ester, is widely performed in Western countries. In this study, effectiveness and safety of the oral administration of 5-ALA is assessed in a phase II/III study of PDD for NMIBC in comparison to those of conventional white-light endoscopic diagnosis. METHODS: Patients with NMIBC were allocated to two groups that were orally administered 10 and 20 mg/kg of 5 ALA under the double-blind condition. Effectiveness was evaluated by setting the primary endpoint to sensitivity. Safety was also analyzed. Moreover, clinically recommended doses of 5-ALA was also investigated as an investigator-initiated multicenter cooperative clinical trial in which five medical institutions participated. RESULTS: All 62 enrolled patients completed the clinical trial. The sensitivities of PDD were higher (84.4 and 75.8% in the 10 and 20 m g/kg-groups, respectively) than those of conventional endoscopic diagnosis (67.5 and 47.6%, respectively) (p = 0.014 and p < 0.001, respectively). Five episodes of serious adverse events developed in four patients; whereas a causal relationship with the investigational agent was ruled out in all episodes. CONCLUSION: This investigator-initiated clinical trial confirmed the effectiveness and safety of PDD for NMIBC following oral administration of 5-ALA. Both doses of 5-ALA may be clinically applicable; however, the rate of detecting tumors only by PDD was higher in the 20 mg/kg-group suggesting that this dose would be more useful. PMID- 25843913 TI - Alcohols inhibit translation to regulate morphogenesis in C. albicans. AB - Many molecules are secreted into the growth media by microorganisms to modulate the metabolic and physiological processes of the organism. For instance, alcohols like butanol, ethanol and isoamyl alcohol are produced by the human pathogenic fungus, Candida albicans and induce morphological differentiation. Here we show that these same alcohols cause a rapid inhibition of protein synthesis. More specifically, the alcohols target translation initiation, a complex stage of the gene expression process. Using molecular techniques, we have identified the likely translational target of these alcohols in C. albicans as the eukaryotic translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, which supports the exchange reaction where eIF2.GDP is converted to eIF2.GTP. Even minimal regulation at this step will lead to alterations in the levels of specific proteins that may allow the exigencies of the fungus to be realised. Indeed, similar to the effects of alcohols, a minimal inhibition of protein synthesis with cycloheximide also causes an induction of filamentous growth. These results suggest a molecular basis for the effect of various alcohols on morphological differentiation in C. albicans. PMID- 25843914 TI - An overview of molecular basis of iron metabolism regulation and the associated pathologies. AB - Iron is essential for several vital biological processes. Its deficiency or overload drives to the development of several pathologies. To maintain iron homeostasis, the organism controls the dietary iron absorption by enterocytes, its recycling by macrophages and storage in hepatocytes. These processes are mainly controlled by hepcidin, a liver-derived hormone which synthesis is regulated by iron levels, inflammation, infection, anemia and erythropoiesis. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. Cells are able to regulate themselves the expression of the iron metabolism-related genes through different post transcriptional mechanisms, such as the alternative splicing, microRNAs, the IRP/IRE system and the proteolytic cleavage. Whenever those mechanisms are disturbed, due to genetic or environmental factors, iron homeostasis is disrupted and iron related pathologies may arise. PMID- 25843915 TI - Morphology and frictional properties of scales of Pseudopus apodus (Anguidae, Reptilia). AB - In the lizard family Anguidae different levels of limb reduction exist up to a completely limbless body. The locomotion patterns of limbless anguid lizards are similar to the undulating and concertina movements of snakes. Additionally, anguid lizards frequently use a third mode of locomotion, called slide-pushing. During slide-pushing the undulating moving body slides on the ground, while the posterior part of the body is pressed against the substrate. Whereas the macroscopic and microscopic adaptations of snake scales to limbless locomotion are well described, the micromorphology of anguid lizard scales has never been examined. Therefore we studied the macro- and micromorphology of the scales of Pseudopus apodus, an anguid lizard with a snakelike body. In addition, we measured the frictional properties of Pseudopus scales. Our data show that the microstructures of the ventral scales of this anguid lizard are less developed than in snakes. We found, however, a rostro-caudal gradient in macroscopic structuring. Whereas the ventral side of the anterior body was nearly unstructured, the tail had macroscopic longitudinal ridges. Our frictional measurements on rough substrates revealed that the ridges provide a frictional anisotropy: friction was higher in the lateral than in the rostral direction. The observed frictional properties are advantageous for a tail-based slide-pushing locomotion, for which a tail with a high lateral friction is most effective in generating propulsion. PMID- 25843916 TI - HIV infection is associated with elevated nucleosomes in asymptomatic patients and during sepsis or malaria. PMID- 25843917 TI - The role of frontal EEG asymmetry in post-traumatic stress disorder. AB - Frontal alpha asymmetry, a biomarker derived from electroencephalography (EEG) recordings, has often been associated with psychological adjustment, with more left-sided frontal activity predicting approach motivation and lower levels of depression and anxiety. This suggests high relevance to post-traumatic stress disorder (PTSD), a disorder comprising anxiety and dysphoria symptoms. We review this relationship and show that frontal asymmetry can be plausibly linked to neuropsychological abnormalities seen in PTSD. However, surprisingly few studies (k = 8) have directly addressed frontal asymmetry in PTSD, mostly reporting that trait frontal asymmetry has little (if any) predictive value. Meanwhile, preliminary evidence suggest that state-dependent asymmetry during trauma relevant stimulation distinguishes PTSD patients from resilient individuals. Thus, exploring links between provocation-induced EEG asymmetry and PTSD appears particularly promising. Additionally, we recommend more fine-grained analyses into PTSD symptom clusters in relation to frontal asymmetry. Finally, we highlight hypotheses that may guide future research and help to fully apprehend the practical and theoretical relevance of this biological marker. PMID- 25843918 TI - Abnormalities in the experience of self-agency in schizophrenia: A replication study. AB - People usually experience agency over their actions and subsequent outcomes. These agency inferences over action-outcomes are essential to social interaction, and occur when an actual outcome corresponds with either a specific goal (goal based), and matches with action-outcome information that is subtly pre-activated in the situation at hand (prime-based). Recent research showed that schizophrenia patients exhibit goal-based inferences, but not prime-based inferences. Intrigued by these findings, and underscoring their potential role in explaining poor social functioning, we replicate patients' deficit in prime-based agency inferences. Additionally, we exclude the account that patients are unable to visually process and attend to primed information. PMID- 25843919 TI - Connectome organization is related to longitudinal changes in general functioning, symptoms and IQ in chronic schizophrenia. AB - Emerging evidence suggests schizophrenia to involve widespread alterations in the macroscale wiring architecture of the human connectome. Recent findings of attenuated connectome alterations in unaffected siblings of schizophrenia patients suggest that altered connectome organization may relate to the vulnerability to develop the disorder, but whether it relates to progression of illness after disease onset is currently unknown. Here, we examined the interaction between connectome structure and longitudinal changes in general functioning, clinical symptoms and IQ in the 3years following MRI assessment in a group of chronically ill schizophrenia patients. Effects in patients were compared to associations between connectome organization and changes in subclinical symptoms and IQ in healthy controls and unaffected siblings of schizophrenia patients. Analyzing the patient sample revealed a relationship between structural connectivity-particularly among central 'brain hubs'-and progressive changes in general functioning (p=0.007), suggesting that more prominent impairments of hub connectivity may herald future functional decline. Our findings further indicate that affected local connectome organization relates to longitudinal increases in overall PANSS symptoms (p=0.013) and decreases in total IQ (p=0.003), independent of baseline symptoms and IQ. No significant associations were observed in controls and siblings, suggesting that the findings in patients represent effects of ongoing illness, as opposed to normal time related changes. In all, our findings suggest connectome structure to have predictive value for the course of illness in schizophrenia. PMID- 25843920 TI - Meta-analysis of 12 trials evaluating the effects of statins on decreasing atrial fibrillation after coronary artery bypass grafting. AB - Atrial fibrillation (AF) is a common arrhythmia encountered after coronary artery bypass graft surgery (CABG) and is associated with poor outcomes. The purpose of this study was to examine whether initiation of statins before CABG reduces the risk of postoperative AF. We searched for clinical trials that randomized patients who underwent CABG to preoperative statin therapy versus placebo. We required that the trial reported the incidence of postoperative AF. Random effects summary odds ratio (OR) were constructed. Sensitivity analysis for the trials that reported AF as a primary outcome along with subgroup analyses according to the different statins used was also conducted. Twelve trials with 2,980 patients met our inclusion criteria. Atorvastatin was tested in 8 trials, whereas rosuvastatin was studied in 2 studies. Statins were associated with a lower risk of postoperative AF (OR 0.42, 95% confidence interval [CI] 0.27 to 0.66, p <0.0001). There was benefit with atorvastatin (OR 0.35, 95% CI 0.25 to 0.50, p <0.0001) but not rosuvastatin (OR 0.69, 95% CI 0.28 to 1.71, p = 0.42). On sensitivity analysis limited to trials that reported AF as a primary outcome, the risk of postoperative AF was still reduced with statins (OR 0.40, 95% CI 0.25 to 0.90, p = 0.02). The mean duration of the hospital stay was significantly lower in the statin group: 8.5 +/- 1.8 days versus 9.1 +/- 2.2 days (p <0.0001). Statin therapy, particularly atorvastatin, before CABG was associated with a reduction in the risk of postoperative AF. PMID- 25843921 TI - Acute Pancreatitis: What's the Score? AB - BACKGROUND: Acute pancreatitis (AP) is a common presentation in the emergency department (ED). Severity of pancreatitis is an important consideration for ED clinicians making admission judgments. Validated scoring systems can be a helpful tool in this process. OBJECTIVE: The aim of this review is to give a general outline on the subject of AP and compare different criteria used to predict severity of disease for use in the ED. DISCUSSION: This review updates the classifications and scoring systems for AP and the relevant parameters of each. This article assesses past and current scoring systems for AP, including Ranson criteria, Glasgow criteria, Acute Physiology and Chronic Health Evaluation II (APACHE II), computed tomography imaging scoring systems, Bedside Index of Severity in Acute Pancreatitis (BISAP) score, Panc 3, Harmless Acute Pancreatitis Score (HAPS), and the Japanese Severity Score. This article also describes the potential use of single variable predictors. Finally, this article discusses risk factors for early readmission, an outcome pertinent to emergency physicians. These parameters may be used to risk-stratify patients presenting to the ED into mild, moderate, and severe pancreatitis for determination of appropriate disposition. CONCLUSION: Rapid, reliable, and validated means of predicting patient outcome from rapid clinical assessment are of value to the emergency physician. Scoring systems such as BISAP, HAPS, and single-variable predictors may assist in decision-making due to their simplicity of use and applicability within the first 24 h. PMID- 25843922 TI - Is Platelet Transfusion Effective in Patients Taking Antiplatelet Agents Who Suffer an Intracranial Hemorrhage? AB - BACKGROUND: Patients taking antiplatelet agents (APAs) with intracranial hemorrhage (ICH) may be treated with platelet transfusion. OBJECTIVES: We conducted a systematic review of the use of platelet transfusion in the management of APA-related ICH. METHODS: We searched the Cochrane, Medline, Embase, and CINAHL databases. Included studies were randomized, case-controlled, or cohort studies comparing outcomes in adult patients with APA-related ICH who received or did not receive platelet transfusion. Study quality was measured using appropriate scores. The primary outcome of interest was in-hospital mortality rate. Secondary outcomes included rates of craniotomy, neurological, medical, or radiological deterioration; mean length of hospital stay, delayed mortality, and functional status at discharge. We reported proportions, medians with interquartile ranges, and pooled odds ratios with their 95% confidence intervals. p values < 0.05 were considered statistically significant. RESULTS: There were no randomized controlled trials. Seven retrospective cohort studies (four traumatic, three primary ICH) were included. For APA-related traumatic ICH, the pooled odds ratio (OR) for in-hospital mortality with platelet transfusion was 1.77 (95% confidence interval [CI] 1.00-3.13). There were no statistically significant differences for secondary outcomes except for proportion with medical decline (6/44 vs. 2/64; p = 0.006). For APA-related primary ICH, the pooled OR for in-hospital mortality with platelet transfusion was 0.49 (95% CI 0.24-0.98). There were no statistically significant differences for most secondary outcomes between the two groups. These studies had important methodological limitations. CONCLUSIONS: The evidence for platelet transfusion in APA-related ICH was inconclusive due to methodological limitations. PMID- 25843923 TI - Diagnosis and Management of Closed Internal Degloving Injuries: The Morel Lavallee Lesion. AB - BACKGROUND: Morel-Lavallee (ML) lesions are closed degloving injuries described as posttraumatic subcutaneous fluid collections. They are most commonly seen in the proximal thigh. They can present several days to months after the inciting event. CASE REPORT: A 55-year-old woman with a recent admission for trauma presented to the Emergency Department with increasing swelling and pain in the right thigh for the previous 3 days. Ultrasound of the thigh was negative. Magnetic resonance imaging performed to further evaluate for leg swelling revealed a "Morel-Lavallee lesion" of the thigh that required drainage. The patient recovered completely after the surgery. WHY SHOULD THE EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware of these rare lesions because they are often mistaken for tumors or hematomas. Early recognition may avoid subsequent complications and help in obtaining prompt specialist care. PMID- 25843924 TI - Ketamine use for acute agitation in the emergency department. AB - BACKGROUND: Emergency physicians regularly encounter agitated patients. In extremely agitated and violent patients, the onset of many traditional medications is relatively slow and often requires additional medication. Ketamine is frequently used in emergency departments (EDs) for procedural sedation and intubation, but has recently been suggested as a treatment for acute agitation. OBJECTIVES: We sought to examine the use of ketamine in the treatment of acute agitation in an ED setting, including vital sign changes as a result of this medication. METHODS: This is a structured review of an historical cohort of patients over 7 years at two university EDs. Patients were included if they received ketamine as treatment for acute agitation. Abstracted data included age, vital signs including hypoxia, any additional medications for agitation, and alcohol/drug intoxication. RESULTS: Ketamine was administered for agitation on 32 visits involving 27 patients. Preadministration systolic blood pressure was 131 +/- 20 mm Hg, with an average postadministration increase of 17 +/- 25 mm Hg. The average baseline heart rate was 98 +/- 23 beats/min, with an average increase of 8 +/- 17 beats/min. No patients became hypoxic; 62.5% of patients required additional calming medication. Alcohol or drug intoxication was present in 40.6% of patients. CONCLUSIONS: We found ketamine was used rarely, but had few major adverse effects on vital signs even in a population with 21.9% alcohol intoxication. However, a high proportion (62.5%) of patients required additional pharmacologic treatment for agitation, implying that administering ketamine is useful only for initial control of severe agitation. PMID- 25843925 TI - Spontaneous Rupture of Hepatocellular Carcinoma Mimicking ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Several medical conditions that mimic ST-elevation myocardial infarction (STEMI) have been reported previously, but acute abdominal disease mimicking STEMI is rare. CASE REPORT: We report on a 72-year-old man who presented to the emergency department (ED) with epigastric pain. Meanwhile, STEMI with shock developed. Anticoagulation medication and emergent percutaneous coronary intervention (PCI) were arranged in a timely manner. However, hepatocellular carcinoma (HCC) rupture was the true cause of the ST-segment elevation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case report highlights the fact that acute myocardial infarction is not the only cause of ST segment elevation. HCC rupture should be one of the differential diagnoses. PMID- 25843926 TI - Congenital leukemia presenting as fever in a neonate. AB - BACKGROUND: Emergency department workup of pediatric fever typically focuses on ruling out serious bacterial infection, but other disease processes can cause fever. Congenital leukemia is a rare but important cause of fever in neonates. We review the presentation, pathophysiology, and potential complications of congenital leukemia presenting to the emergency department as pediatric fever. CASE REPORT: We report a case of a 4-week-old infant brought to the emergency department for fever and "not acting normally." Complete blood count demonstrated hyperleukocytosis. Subsequent bone marrow biopsy and flow cytometry confirmed the diagnosis of congenital leukemia. The extreme elevation of the patient's white blood cell count put her at high risk for complications, necessitating aggressive treatment, close monitoring, and appropriate consultation for comprehensive care. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS: Congenital leukemia is a rare but serious cause of neonatal fever. While the workup for fever without a source in young pediatric patients primarily focuses on ruling out serious bacterial illness, emergency physicians must be familiar with other potentially life threatening causes of this complaint. PMID- 25843928 TI - Ingestion of Concentrated Laundry Detergent Pods. PMID- 25843927 TI - The unlikely presence of deep vein thrombosis in a patient with low pretest probability and a negative D-dimer: a case report. AB - BACKGROUND: Deep vein thrombosis (DVT) is commonly encountered in the emergency department. Clinical models, such as the Wells criteria, allow physicians to estimate the probability of DVT in a patient. Current literature suggests a low pretest probability combined with a negative D-dimer laboratory study rules out DVT approximately 99% of the time. CASE REPORT: This case discusses a 37-year-old male patient who had a low pretest probability and a negative D-dimer, but was found to have a DVT on Doppler ultrasound. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The astute emergency physician must not discount clinical suspicion in order to decide when radiographic imaging is warranted for a possible venous thromboembolism. New adjuncts, such as bedside ultrasonography, can also be implemented to further risk stratify patients, potentially decreasing morbidity and mortality associated with DVT. PMID- 25843929 TI - Twin ectopic pregnancy. PMID- 25843930 TI - Faculty Prediction of In-Training Examination Scores of Emergency Medicine Residents: A Multicenter Study. AB - BACKGROUND: The Emergency Medicine In-Training Examination (EMITE) is one of the few validated instruments for medical knowledge assessment of emergency medicine (EM) residents. The EMITE is administered only once annually, with results available just 2 months before the end of the academic year. An earlier predictor of EMITE scores would be helpful for educators to institute timely remediation plans. A previous single-site study found that only 69% of faculty predictions of EMITE scores were accurate. OBJECTIVE: The goal of this article was to measure the accuracy with which EM faculty at five residency programs could predict EMITE scores for resident physicians. METHODS: We asked EM faculty at five different residency programs to predict the 2014 EMITE scores for all their respective resident physicians. The primary outcome was prediction accuracy, defined as the proportion of predictions within 6% of the actual scores. The secondary outcome was prediction precision, defined as the mean deviation of predictions from the actual scores. We assessed faculty background variables for correlation with the two outcomes. RESULTS: One hundred and eleven faculty participated in the study (response rate 68.9%). Mean prediction accuracy for all faculty was 60.0%. Mean prediction precision was 6.3%. Participants were slightly more accurate at predicting scores of noninterns compared to interns. No faculty background variable correlated with the primary or secondary outcomes. Eight participants predicted scores with high accuracy (>80%). CONCLUSIONS: In this multicenter study, EM faculty possessed only moderate accuracy at predicting resident EMITE scores. A very small subset of faculty members is highly accurate. PMID- 25843931 TI - Understanding barriers and facilitators to the use of Clinical Information Systems for intensive care units and Anesthesia Record Keeping: A rapid ethnography. AB - OBJECTIVE: This study evaluated the current use of commercial-off-the-shelf Clinical Information Systems (CIS) for intensive care units (ICUs) and Anesthesia Record Keeping (ARK) for operating rooms and post-anesthesia care recovery settings at three Veterans Affairs Medical Centers (VAMCs). Clinicians and administrative staff use these applications at bedside workstations, in operating rooms, at nursing stations, in physician's rooms, and in other various settings. The intention of a CIS or an ARK system is to facilitate creation of electronic records of data, assessments, and procedures from multiple medical devices. The US Department of Veterans Affairs (VA) Office of the Chief of Nursing Informatics sought to understand usage barriers and facilitators to optimize these systems in the future. Therefore, a human factors study was carried out to observe the CIS and ARK systems in use at three VAMCs in order to identify best practices and suggested improvements to currently implemented CIS and ARK systems. METHODS: We conducted a rapid ethnographic study of clinical end-users interacting with the CIS and ARK systems in the critical care and anesthesia care areas in each of three geographically distributed VAMCs. Two observers recorded interactions and/or interview responses from 88 CIS and ARK end-users. We coded and sorted into logical categories field notes from 69 shadowed participants. The team transcribed and combined data from key informant interviews with 19 additional participants with the observation data. We then integrated findings across observations into meaningful patterns and abstracted the data into themes, which translated directly to barriers to effective adoption and optimization of the CIS and ARK systems. RESULTS: Effective optimization of the CIS and ARK systems was impeded by: (1) integration issues with other software systems; (2) poor usability; (3) software challenges; (4) hardware challenges; (5) training concerns; (6) unclear roles and lack of coordination among stakeholders; and (7) insufficient technical support. Many of these barriers are multi-faceted and have associated sub-barriers, which are described in detail along with relevant quotes from participants. In addition, regionalized purchases of different CIS and ARK systems, as opposed to enterprise level purchases, contributed to some of the identified barriers. Facilitators to system use included (1) automation and (2) a dedicated facility-level CIS-ARK Coordinator. CONCLUSIONS: We identified barriers that explain some of the challenges with the optimization of the CIS and ARK commercial systems across the Veterans Health Administration (VHA). To help address these barriers, and evolve them into facilitators, we categorized report findings as (1) interface and system-level changes that vendors or VA healthcare systems can implement; (2) implementation factors under VA control and not under VA control; and (3) factors that may be used to inform future application purchases. We outline several recommendations for improved adoption of CIS and ARK systems and further recommend that human factors engineering and usability requirements become an integral part of VA health information technology (HIT) application procurement, customization, and implementation in order to help eliminate or mitigate some of the barriers of use identified in this study. Human factors engineering methods can be utilized to apply a user-centered approach to application requirements specification, application evaluation, system integration, and application implementation. PMID- 25843932 TI - Action-related auditory ERP attenuation: Paradigms and hypotheses. AB - A number studies have shown that the auditory N1 event-related potential (ERP) is attenuated when elicited by self-induced or self-generated sounds. Because N1 is a correlate of auditory feature- and event-detection, it was generally assumed that N1-attenuation reflected the cancellation of auditory re-afference, enabled by the internal forward modeling of the predictable sensory consequences of the given action. Focusing on paradigms utilizing non-speech actions, the present review summarizes recent progress on action-related auditory attenuation. Following a critical analysis of the most widely used, contingent paradigm, two further hypotheses on the possible causes of action-related auditory ERP attenuation are presented. The attention hypotheses suggest that auditory ERP attenuation is brought about by a temporary division of attention between the action and the auditory stimulation. The pre-activation hypothesis suggests that the attenuation is caused by the activation of a sensory template during the initiation of the action, which interferes with the incoming stimulation. Although each hypothesis can account for a number of findings, none of them can accommodate the whole spectrum of results. It is suggested that a better understanding of auditory ERP attenuation phenomena could be achieved by systematic investigations of the types of actions, the degree of action-effect contingency, and the temporal characteristics of action-effect contingency representation-buildup and -deactivation. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 25843933 TI - Calorie restriction attenuates cerebral ischemic injury via increasing SIRT1 synthesis in the rat. AB - Caloric restriction (CR) has been shown to have several health benefits and provides protection against type 2 diabetes, neurodegenerative and cerebral vascular diseases. It reduces the brain infarct size and promotes neurological functional recovery after cerebral ischemia. Sirtuin 1 (SIRT1) plays an important role in the biological effects induced by CR. This study investigated the role of SIRT1 in ischemic tolerance in the brain induced by CR. Sprague drawly rats were divided into two groups based on food intake. Ad libitum (AL) group was fed with normal diet while the CR group received 60% calories compared to AL. All animals were subjected to a middle cerebral artery occlusion for 90 min. Results showed the neurological function score of CR group was higher and the brain infarct volume was markedly reduced in CR group compared to AL group at 24h after reperfusion (p < 0.05). CR increased the synthesis of SIRT1 significantly (p < 0.05), and ameliorated the down regulation of SIRT1 expression at 6 and 12h after middle cerebral artery occlusion (p < 0.05, p < 0 .01, respectively). Knockdown of SIRT1 by siRNA in vivo reversed the neuroprotective effect of CR. From this study, we deduce that CR induces brain ischemic tolerance on rats via increasing the synthesis of SIRT1. PMID- 25843934 TI - Nestin overexpression promotes the embryonic development of heart and brain through the regulation of cell proliferation. AB - Nestin, an intermediate filament protein, is a key regulator of various extracellular proteins that play important roles in cell growth and differentiation. In recent years, nestin has been widely accepted as a molecular marker for neural stem/progenitor cells. However, its function during embryogenesis remains largely unknown since its depletion is lethal after stage embryonic day 8.5 (E8.5). In order to understand the role of this protein in vivo, we compared the heart and brain tissues of control mice with those of mice overexpressing a human nestin cDNA transgene under the control of a ROSA26 promoter. In these tissues we examined the general histology and cell size, the presence of apoptotic cells by TUNEL assay, and the presence of progenitor cell markers like SOX2. Compared to controls, mouse embryos overexpressing the human nestin transgene have a larger size and display characteristic morphological changes including a larger heart and forebrain. In these tissues we found corresponding increases in the size of cardiomyocytes and brain cells, as well as indications of augmented cell proliferation. In contrast, apoptosis was not significantly altered. Co-staining brain sections with SOX2 and Ki67 showed that most of the proliferating cells in the forebrain were neural stem cells. Moreover, nestin overexpression was responsible for a marked activation of the PI3K/Akt signaling pathway. Taken together, the results of this study indicate that nestin plays an important role in the embryonic development of at least two mouse organs (heart and brain) through the regulation of cell proliferation. PMID- 25843935 TI - Overproduction of the Bacillus thuringiensis Vip3Aa16 toxin and study of its insecticidal activity against the carob moth Ectomyelois ceratoniae. AB - The vip3Aa16 gene of Bacillus thuringiensis strain BUPM95 was cloned and expressed in Escherichia coli. Optimization of Vip3A16 protein expression was conducted using Plackett-Burman design and response surface methodology. Accordingly, the optimum Vip3A16 toxin production was 170MUg/ml at 18h post induction time and 39 degrees C post-induction temperature. This corresponds to an improvement of 21times compared to the starting conditions. The insecticidal activity, evaluated against Ectomyelois ceratoniae, displayed an LC50 value of 40ng/cm(2) and the midgut histopathology of Vip3Aa16 fed larvae showed vacuolization of the cytoplasm, brush border membrane destruction, vesicle formation in the apical region and cellular disintegration. PMID- 25843936 TI - Crossmodal integration between visual linguistic information and flavour perception. AB - Many studies have found processing interference in working memory when complex information that enters the cognitive system from different modalities has to be integrated to understand the environment and promote adjustment. Here, we report on a Stroop study that provides evidence concerned with the crossmodal processing of flavour perception and visual language. We found a facilitation effect in the congruency condition. Acceleration was observed for incomplete words and anagrams compared to complete words. A crossmodal completion account is presented for such findings. It is concluded that the crossmodal integration between flavour and visual language perception requires the active participation of top-down and bottom-up processing. PMID- 25843937 TI - Obesity, fitness, and brain integrity in adolescence. AB - OBJECTIVE: We set out to ascertain the relationship between insulin resistance, fitness, and brain structure and function in adolescents. DESIGN AND METHODS: We studied 79 obese and 51 non-obese participants who were recruited from the community, all without type 2 diabetes mellitus. All participants received medical, endocrine, neuropsychological, and MRI evaluations as well as a 6-minute walk test that was used to estimate fitness (maximal oxygen consumption). RESULTS: Obese adolescents had significantly thinner orbitofrontal cortices and performed significantly worse on Visual Working Memory tasks and the Digit Vigilance task. Insulin sensitivity and maximal oxygen consumption (VO2 max) were both highly correlated with central obesity and orbitofrontal cortical thickness, although insulin sensitivity was the stronger predictor for orbitofrontal cortical thickness. We also found that VO2 max was the only significant physiological variable related to visual working memory. CONCLUSIONS: This is the first study to report positive associations between insulin resistance, VO2 max, and frontal lobe brain integrity in adolescents. Given the importance of brain health for learning and school performance, we conclude that schools should also emphasize physical fitness in order to maintain structural and functional brain integrity and facilitate academic achievement. PMID- 25843938 TI - Parental perception of child weight in the first two years-of-life: a potential link between infant feeding and preschoolers' diet. AB - Approximately 23% of preschoolers are overweight or obese. Establishing a healthy dietary lifestyle at an early age can improve later child diet and body weight. This study examined the determinants of past infant feeding practices that do not follow standard feeding recommendations (breastfeeding for less than 6 months duration, cow's milk prior to the first year of age and solid foods at or before 4 months of age). It also examined the role of parental perception of child weight in the first 2 years-of-life on past infant feeding practices as well as current child diet and body weight. Families of 497 preschoolers aged 22-63 months (39.0 +/- 8.2) were recruited from 30 child care centers in East-Central Illinois. Main findings indicate that past infant feeding practices were common and varied by socio-demographic factors including race/ethnicity, parental education and child gender. Children perceived as overweight in the first 2 years of-life tended to breastfeed for lesser duration. Additionally, the majority (79.8%) of preschoolers who were classified as overweight using BMI percentile were perceived as non-overweight by the parent in the first 2 years-of-life. Mean daily total fatty/sugary food intake was higher among those perceived to be non overweight in the first 2 years-of-life. These findings have identified parental perception of child weight in the first 2 years-of-life as a modifiable risk factor for unhealthy child diet and obesity among preschoolers. PMID- 25843939 TI - Engineering tandem single-chain Fv as cell surface reporters with enhanced properties of fluorescence detection. AB - A recently described fluorescence biosensor platform utilizes single-chain Fv (scFvs) that selectively bind and activate fluorogen molecules. In this report we investigated the display of tandem scFv biosensors at the surface of mammalian cells with the aim of advancing current fluorescence detection strategies. We initially screened different peptide linkers to separate each scFv unit, and discovered that tandem proteins joined by either flexible or alpha-helical linkers properly fold and display at the surface of mammalian cells. Accordingly, we performed a combinatorial scFv-dimer study and identified that fluorescence activation correlated with the cellular location (membrane distal versus proximal) and selections of the different scFvs. Furthermore, in vitro measurements showed that the stability of each scFv monomer unit influenced the folding and cell surface activities of tandem scFvs. Additionally, we investigated the absence or poor signals from some scFv-dimer combinations and discovered that intramolecular and intermolecular scFv chain mispairings led to protein misfolding and/or secretory-pathway-mediated degradation. Furthermore, when tandem scFvs were utilized as fluorescence reporter tags with surface receptors, the biosensor unit and target protein showed independent activities. Thus, the live cell application of tandem scFvs permitted advanced detection of target proteins via fluorescence signal amplification, Forster resonance energy transfer resulting in the increase of Stokes shift and multi-color vesicular traffic of surface receptors. PMID- 25843940 TI - Tinnitus-related abnormalities in visual and salience networks during a one-back task with distractors. AB - Tinnitus is highly prevalent in the general population. Tinnitus sufferers often report having difficulties focusing on a task at hand and ignoring the tinnitus percept. Behavioral studies have shown evidence for impairments in attention, interference inhibition, and various other executive functions in tinnitus. However, few neuroimaging studies have directly addressed this issue. In the present functional Magnetic Resonance Imaging (fMRI) study we employed a 1-back task, requiring subjects to monitor relevant auditory and visual information. Additionally, interfering stimuli were presented to investigate selection of relevant information and inhibition of irrelevant information. Significant behavioral group differences were not found, although performance worsened for increasing tinnitus severity. Significant group differences in evoked neural activation neither occurred in the central auditory system, nor in the attentional fronto-parietal network. However, the anterior insula and the vermis of the cerebellum showed significantly stronger task-related activation in the tinnitus group when compared to the controls. Furthermore, deactivation in the primary visual cortex that occurred in the control group for various combinations of modalities and distractors was significantly less in the tinnitus group. These results are consistent with previous studies that showed the involvement of various networks in tinnitus, particularly the salience and visual networks, which are also implicated in attention. Although we did not demonstrate cognitive impairment in tinnitus, significantly different evoked responses were found in various brain regions that we attribute to an abnormal involvement of attention control mechanisms in tinnitus. PMID- 25843941 TI - World Workshop on Oral Medicine VI: Utilization of Oral Medicine-specific software for support of clinical care, research, and education: current status and strategy for broader implementation. AB - OBJECTIVES: To assess the current scope and status of Oral Medicine-specific software (OMSS) utilized to support clinical care, research, and education in Oral Medicine and to propose a strategy for broader implementation of OMSS within the global Oral Medicine community. STUDY DESIGN: An invitation letter explaining the objectives was sent to the global Oral Medicine community. Respondents were interviewed to obtain information about different aspects of OMSS functionality. RESULTS: Ten OMSS tools were identified. Four were being used for clinical care, one was being used for research, two were being used for education, and three were multipurpose. Clinical software was being utilized as databases developed to integrate of different type of clinical information. Research software was designed to facilitate multicenter research. Educational software represented interactive, case-orientated technology designed for clinical training in Oral Medicine. Easy access to patient data was the most commonly reported advantage. Difficulty of use and poor integration with other software was the most commonly reported disadvantage. CONCLUSIONS: The OMSS presented in this paper demonstrate how information technology (IT) can have an impact on the quality of patient care, research, and education in the field of Oral Medicine. A strategy for broader implementation of OMSS is proposed. PMID- 25843942 TI - Blunt aortic injury: risk factors and impact of surgical approaches. AB - PURPOSE: This study reviews our 17-year experience of managing blunt traumatic aortic injury (BTAI). METHODS: We analyzed information collected retrospectively from a tertiary trauma center. RESULTS: Between October 1995 and June 2012, 88 patients (74 male and 14 female) with a mean age of 39.9 +/- 17.9 years (range 15 79 years) with proven BTAI were enrolled in this study. Their GCS, ISS, and RTS scores were 12.9 +/- 3.7, 29.2 +/- 9.8, and 6.9 +/- 1.4, respectively. Twenty-one (23.8 %) patients were managed non-operatively, 49 (55.7 %) with open surgical repair, and 18 (20.5 %) with endovascular repair. The in-hospital mortality rate was 17.1 % (15/81) and there were no deaths in the endovascular repair group. The mean follow-up period was 39.9 +/- 44.2 months. The survivors of blunt aortic injury had lower ISS, RTS, TRISS, and serum creatinine level and lower rate of massive blood transfusion, shock, and intubation than the patients who died, despite higher rates of endovascular repair, hemoglobin, and GCS on presentation. The degree of aortic injury, different therapeutic options, GCS, shock presentation, and intubation on arrival all had significant impacts on outcome. CONCLUSIONS: Shock, aortic injury severity, coexisting trauma severity, and different surgical approaches impact survival. Endovascular repair achieves a superior mid-term result and is a reasonable option for treating BTAI. PMID- 25843943 TI - Structural alteration of tight and adherens junctions in villous and crypt epithelium of the small and large intestine of conventional nursing piglets infected with porcine epidemic diarrhea virus. AB - Integrity of the intestinal epithelium is critical for proper functioning of the barrier that regulates absorption of water and restricts uptake of luminal bacteria. It is maintained mainly by tight junctions (TJs) and adherens junctions (AJs). We conducted immunofluorescence (IF) staining for in situ identification of zonula occludin (ZO)-1 proteins for TJ and E-Cadherin proteins for AJ in the small and large intestinal villous and crypt epithelium of nursing pigs infected with porcine epidemic diarrhea virus (PEDV). Twenty 9-day-old piglets [PEDV infected (n=9) and Mock (n=11)] from PEDV seronegative sows, were orally inoculated [8.9 log10 genomic equivalents/pig] with PEDV PC21A strain or mock. At post-inoculation days (PIDs) 1-5, infected pigs showed severe watery diarrhea and/or vomiting and severe atrophic enteritis. By immunohistochemistry, PEDV antigens were evident in enterocytes lining the villous epithelium. At PIDs 1-5, PEDV-infected pigs exhibited mildly to extensively disorganized, irregular distribution and reduced expression of ZO-1 or E-Cadherin in villous, but not crypt epithelial cells of the jejunum and ileum, but not in the large intestine, when compared to the negative controls. The structural destruction and disorganization of TJ and AJ were extensive in PEDV-infected pigs at PIDs 1-3, but then appeared to reversibly recover at PID 5, as evident by increased numbers of ZO-1-positive epithelial cells and markedly improved appearance of E-Cadherin positive villous epithelium. Our results suggest a possible involvement of structurally impaired TJ and AJ in the pathogenesis of PEDV, potentially leading to secondary bacterial infections. PMID- 25843944 TI - The pig gut microbial diversity: Understanding the pig gut microbial ecology through the next generation high throughput sequencing. AB - The importance of the gut microbiota of animals is widely acknowledged because of its pivotal roles in the health and well being of animals. The genetic diversity of the gut microbiota contributes to the overall development and metabolic needs of the animal, and provides the host with many beneficial functions including production of volatile fatty acids, re-cycling of bile salts, production of vitamin K, cellulose digestion, and development of immune system. Thus the intestinal microbiota of animals has been the subject of study for many decades. Although most of the older studies have used culture dependent methods, the recent advent of high throughput sequencing of 16S rRNA genes has facilitated in depth studies exploring microbial populations and their dynamics in the animal gut. These culture independent DNA based studies generate large amounts of data and as a result contribute to a more detailed understanding of the microbiota dynamics in the gut and the ecology of the microbial populations. Of equal importance, is being able to identify and quantify microbes that are difficult to grow or that have not been grown in the laboratory. Interpreting the data obtained from this type of study requires using basic principles of microbial diversity to understand importance of the composition of microbial populations. In this review, we summarize the literature on culture independent studies of the pig gut microbiota with an emphasis on its succession and alterations caused by diverse factors. PMID- 25843945 TI - Cross-protection study of a Mannheimia haemolytica serotype 1 vaccine against acute pasteurellosis in lambs induced by a serotype 2 strain. AB - Ovine pneumonia is an economic important disease worldwide for the sheep industry. Multiple serotypes (S) of Mannheimia haemolytica are involved in the disease and S2 and S1 are the most frequent isolates associated with lung lesions in sheep. Vaccines based on some M. haemolytica S2 strains have been shown to have poor immunogenicity. The objective of this study was to determine the cross protection effect of an S1 strain based vaccine, Bovilis MH, in sheep against an experimental challenge with an S2 strain. Lambs (n=12) in the vaccine group were injected subcutaneously with 1 ml of the Bovilis MH vaccine, and revaccinated 4 weeks later, while the control group (n=12) received 1 ml of saline at each occasion. Two weeks after revaccination, all lambs were challenged intratracheally with parainfluenza virus 3, and with an M. haemolytica S2 strain at day 7 post-viral challenge. The proportion of animals having pyrexia in the first 2 days post-bacterial challenge was significantly less in the vaccine group compared to the control group (P<0.05). The animals in the vaccine group had significantly lower dyspnoea scores and lung/bodyweight ratio than those in the control group (P<0.05). The vaccine provided 49.1% overall protection. Prior to the challenge, the vaccinated animals had significantly higher titres of antibodies to S1 and S2 whole cell antigens and to leukotoxins produced by S1 and S2 strains compared to the control animals (P<0.05). The S1 strain vaccine provided considerable cross-protection against the S2 strain challenge. PMID- 25843946 TI - [Homeopathy, social welfare and reality]. PMID- 25843947 TI - Design and evaluation of a computed tomography (CT)-compatible needle insertion device using an electromagnetic tracking system and CT images. AB - PURPOSE: Percutaneous needle insertion procedures are commonly used for diagnostic and therapeutic purposes. Although current technology allows accurate localization of lesions, they cannot yet be precisely targeted. Lung cancer is the most common cause of cancer-related death, and early detection reduces the mortality rate. Therefore, suspicious lesions are tested for diagnosis by performing needle biopsy. METHODS: In this paper, we have presented a novel computed tomography (CT)-compatible needle insertion device (NID). The NID is used to steer a flexible needle (phi0.55 mm) with a bevel at the tip in biological tissue. CT images and an electromagnetic (EM) tracking system are used in two separate scenarios to track the needle tip in three-dimensional space during the procedure. Our system uses a control algorithm to steer the needle through a combination of insertion and minimal number of rotations. RESULTS: Noise analysis of CT images has demonstrated the compatibility of the device. The results for three experimental cases (case 1: open-loop control, case 2: closed loop control using EM tracking system and case 3: closed-loop control using CT images) are presented. Each experimental case is performed five times, and average targeting errors are 2.86 +/- 1.14, 1.11 +/- 0.14 and 1.94 +/- 0.63 mm for case 1, case 2 and case 3, respectively. CONCLUSIONS: The achieved results show that our device is CT-compatible and it is able to steer a bevel-tipped needle toward a target. We are able to use intermittent CT images and EM tracking data to control the needle path in a closed-loop manner. These results are promising and suggest that it is possible to accurately target the lesions in real clinical procedures in the future. PMID- 25843949 TI - Multicenter study on the use of patient-specific CAD/CAM reconstruction plates for mandibular reconstruction. AB - PURPOSE: For the new generation of mandibular reconstruction, patient-specific mandible reconstruction plates (PSMPs) have been developed which are milled from titanium after preoperative computer planning using CAD/CAM procedures. Resection margins and plate position are determined by surgical guides. In addition, length and shape of the plate and the number and angulation of the screw holes can be planned. METHODS: 30 patients received such PSMP. Indication ranged from stabilization osteosynthesis, single alloplastic stand-alone reconstruction to microvascular reconstructions. Time for planning, fit of surgical guides and plates, pre-/postoperative occlusion, radiological position of the temporo mandibular joint and complications were recorded. RESULTS: The median time for online planning was 35 min. The results concerning fit and handling of the PSMP and the surgical guides were mainly very positive. In six cases, the plan had to be adapted to the intraoperative clinical needs. The postoperative position of the condyles in the temporo mandibular fossae was regular in 28 cases. The evaluation of the occlusion was not representative due to not clearly identifiable occlusion in 2/3 of the cases. Nevertheless, complications like postoperative extraoral plate exposure, infection, graft and flap necrosis or difficulties to position the guides or the plate during surgery occurred. CONCLUSIONS: Mandibular reconstruction with PSMP offers a broad range of opportunities and benefits compared with standard procedures and can be recommended for all kind of mandibular reconstructions. It is not yet foreseeable whether PSMP will in future become routine clinical practice for mandibular reconstruction or will be confined to selected isolated cases. PMID- 25843950 TI - Conical Fourier shell correlation applied to electron tomograms. AB - The resolution of electron tomograms is anisotropic due to geometrical constraints during data collection, such as the limited tilt range and single axis tilt series acquisition. Acquisition of dual axis tilt series can decrease these effects. However, in cryo-electron tomography, to limit the electron radiation damage that occurs during imaging, the total dose should not increase and must be fractionated over the two tilt series. Here we set out to determine whether it is beneficial fractionate electron dose for recording dual axis cryo electron tilt series or whether it is better to perform single axis acquisition. To assess the quality of tomographic reconstructions in different directions here we introduce conical Fourier shell correlation (cFSCe/o). Employing cFSCe/o, we compared the resolution isotropy of single-axis and dual-axis (cryo-)electron tomograms using even/odd split data sets. We show that the resolution of dual axis simulated and cryo-electron tomograms in the plane orthogonal to the electron beam becomes more isotropic compared to single-axis tomograms and high resolution peaks along the tilt axis disappear. cFSCe/o also allowed us to compare different methods for the alignment of dual-axis tomograms. We show that different tomographic reconstruction programs produce different anisotropic resolution in dual axis tomograms. We anticipate that cFSCe/o can also be useful for comparisons of acquisition and reconstruction parameters, and different hardware implementations. PMID- 25843948 TI - Augmenting MRI-transrectal ultrasound-guided prostate biopsy with temporal ultrasound data: a clinical feasibility study. AB - PURPOSE: In recent years, fusion of multi-parametric MRI (mp-MRI) with transrectal ultrasound (TRUS)-guided biopsy has enabled targeted prostate biopsy with improved cancer yield. Target identification is solely based on information from mp-MRI, which is subsequently transferred to the subject coordinates through an image registration approach. mp-MRI has shown to be highly sensitive to detect higher-grade prostate cancer, but suffers from a high rate of false positives for lower-grade cancer, leading to unnecessary biopsies. This paper utilizes a machine-learning framework to further improve the sensitivity of targeted biopsy through analyzing temporal ultrasound data backscattered from the prostate tissue. METHODS: Temporal ultrasound data were acquired during targeted fusion prostate biopsy from suspicious cancer foci identified in mp-MRI. Several spectral features, representing the signature of backscattered signal from the tissue, were extracted from the temporal ultrasound data. A supervised support vector machine classification model was trained to relate the features to the result of histopathology analysis of biopsy cores obtained from cancer foci. The model was used to predict the label of biopsy cores for mp-MRI-identified targets in an independent group of subjects. RESULTS: Training of the classier was performed on data obtained from 35 biopsy cores. A fivefold cross-validation strategy was utilized to examine the consistency of the selected features from temporal ultrasound data, where we achieved the classification accuracy and area under receiver operating characteristic curve of 94 % and 0.98, respectively. Subsequently, an independent group of 25 biopsy cores was used for validation of the model, in which mp-MRI had identified suspicious cancer foci. Using the trained model, we predicted the tissue pathology using temporal ultrasound data: 16 out of 17 benign cores, as well as all three higher-grade cancer cores, were correctly identified. CONCLUSION: The results show that temporal analysis of ultrasound data is potentially an effective approach to complement mp-MRI-TRUS guided prostate cancer biopsy, specially to reduce the number of unnecessary biopsies and to reliably identify higher-grade cancers. PMID- 25843951 TI - Comparison of two angiographic systems in paediatric interventional cardiology. AB - The aim of this work was to analyse the radiation dose for patients and staff between X-ray systems, a new biplane with flat-panel detectors (FDs) and a conventional system equipped with image intensifier (II). Entrance surface air kerma (ESAK) and scatter doses were measured on polymethyl methacrylate (PMMA) phantoms of different thicknesses (from 4 to 16 cm). The ESAK values for the different acquisition modes and PMMA thicknesses were higher for the II in comparison with FDs. For the II, the scatter dose rates ranged from 0.67 to 12.2 mSv h(-1) at the eye position of the cardiologist during fluoroscopy and cine modes. At the lower extremities, these values were 1.11 and 24.24 mSv h(-1). In the case of the FDs, these values ranged from 0.24 to 0.67 mSv h(-1) for eye lens and from 0.73 to 2.01 mSv h(-1) for the position of cardiologist's ankle. The newly installed X-ray system showed an average reduction factor of up to 9.7 times for ESAK values. For the staff with an average reduction factor of 15.9 times at the eye position during fluoroscopy and cine modes, no protective tools are used. At the lower extremities, this value was 7.6 times. PMID- 25843952 TI - Insulin Resistance Increases the Risk of Contrast-Induced Nephropathy in Patients Undergoing Elective Coronary Intervention. AB - We assessed the influence of insulin resistance (IR) on the development of contrast-induced nephropathy (CIN) in patients (n = 719) undergoing elective percutaneous coronary intervention (PCI). Patients were divided into diabetes mellitus (DM = 242), nondiabetic IR (IR = 120), and nondiabetic insulin sensitivity (IS = 357) groups according to medical history and homeostasis model assessment insulin resistance index. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were measured before and 72 hours after PCI. There were no differences in SCr and eGFR among the groups before PCI; SCr increased and eGFR decreased significantly in the DM and IR groups post-PCI (P < .001). The incidence of CIN in the IR group was as high as in the DM group and were both significantly higher than in the IS group (6.7% vs 8.7% vs 2.2%, P < .05). Multivariate logistic regression analysis showed DM (odds ratio [OR] = 1.19, 95%CI = 1.08-1.510, P < .001), HOMA-IR (OR = 1.39, 95%CI = 1.23-1.58, P < 0.001), and eGFR (OR = 0.88, 95%CI = 0.84-0.92, P < .001) were independent risk factors in predicting CIN. Screening IR patients and taking appropriate prophylactic strategy before PCI may reduce the incidence of CIN. PMID- 25843953 TI - FTY720 enhances TRAIL-mediated apoptosis by up-regulating DR5 and down-regulating Mcl-1 in cancer cells. AB - FTY720, Fingolimod, is a functional antagonist to the sphingosine-1-phosphate (S1P) receptor and an inhibitor of sphingosine kinase 1. Here, we showed that a combination of FTY720 and TRAIL induced apoptosis in human renal, breast, and colon carcinoma cells. Most importantly, this combination had no effect on normal cells. Furthermore, the combined treatment with FTY720 and TRAIL reduced tumor growth in xenograft models. FTY720 up-regulated death receptor (DR)5 at post translational level. Knockdown of DR5 markedly blocked apoptosis induced by the combined treatment. FTY720 also inhibited Mcl-1 expression at the post translational level. Over-expression of Mcl-1 blocked apoptosis induced by FTY720 and TRAIL. Interestingly, phospho-FTY720 and inhibitors of sphingosine kinase failed to enhance TRAIL-induced apoptosis. Thus, FTY720 enables TRAIL-induced apoptosis through up-regulation of DR5 and down-regulation of Mcl-1 in human cancer cells. PMID- 25843955 TI - Evaluation of Nanoparticle Tracking for Characterization of Fibrillar Protein Aggregates. AB - Amyloidogenesis is the process of formation of protein aggregates with fibrillar morphology. Because amyloidogenesis is linked to neurodegenerative disease, there is interest in understanding the mechanism of fibril growth. Kinetic models of amyloidogenesis require data on the number concentration and size distribution of aggregates, but this information is difficult to obtain using conventional methods. Nanoparticle tracking analysis (NTA) is a relatively new technique that may be uniquely suited for obtaining these data. In NTA, the two-dimensional (2 D) trajectory of individual particles is tracked, from which the diffusion coefficient, and, hence, hydrodynamic radius is obtained. Here we examine the validity of NTA in tracking number concentration and size of DNA, as a model of a fibrillar macromolecule. We use NTA to examine three amyloidogenic materials: beta-amyloid, transthyretin, and polyglutamine-containing peptides. Our results are instructive in demonstrating the advantages and some limitations of single particle diffusion measurements for investigating aggregation in protein systems. PMID- 25843956 TI - Longitudinal Associations Between Gender-typed Skills and Interests and Their Links to Occupational Outcomes. AB - Although gender-based occupational segregation has declined in past decades, the world of work remains segregated by gender. Grounded in research showing that individuals tend to choose jobs that match their interests and skills, this study examined the longitudinal associations between gendered activity interests and skills from middle childhood through adolescence and tested gendered interests and skills, measured in adolescence, as predictors of occupational outcomes in young adulthood. Data were collected from 402 participants at four time points- when they averaged 10, 12, 16, and 25 years old. Results revealed that the longitudinal linkages between male-typed interests and skills were bidirectional, that both male-typed interests and skills in adolescence predicted working in male-typed occupations in young adulthood, and that skills, but not interests, predicted income. In contrast, female-typed interests predicted female-typed skills, but not the reverse, adolescent female-typed skills (but not interests) predicted working in female-typed occupations in young adulthood, and there were no links between female-typed interests or skills and income. Discussion focuses on the differential meanings and developmental implications of male-versus female typed interests and skills. PMID- 25843954 TI - Hypoxia-inducible factor 1alpha (HIF-1alpha) and reactive oxygen species (ROS) mediates radiation-induced invasiveness through the SDF-1alpha/CXCR4 pathway in non-small cell lung carcinoma cells. AB - Radiotherapy is an important procedure for the treatment of inoperable non-small cell lung cancer (NSCLC). However, recent evidence has shown that irradiation can promote the invasion and metastasis of several types of cancer, and the underlying mechanisms are not fully understood. This study aimed to investigate the molecular mechanism by which radiation enhances the invasiveness of NSCLC cells. We found that after irradiation, hypoxia-inducible factor 1alpha (HIF 1alpha) was increased and translocated into the nucleus, where it bound to the hypoxia response element (HRE) in the CXCR4 promoter and promoted the transcription of CXCR4. Furthermore, reactive oxygen species (ROS) also plays a role in the radiation-induced expression of CXCR4. Our results revealed that 2 Gy X-ray irradiation promoted the metastasis and invasiveness of H1299, A549 and H460 cells, which were significantly enhanced by SDF-1alpha treatment. Blocking the SDF-1alpha/CXCR4 interaction could suppress the radiation-induced invasiveness of NSCLC cells. The PI3K/pAkt and MAPK/pERK1/2 pathways were found to be involved in radiation-induced matrix metalloproteinase (MMP) expression. In vivo, irradiation promoted the colonization of H1299 cells in the liver and lung, which was mediated by CXCR4. Altogether, our findings have elucidated the underlying mechanisms of the irradiation-enhanced invasiveness of NSCLC cells. PMID- 25843957 TI - The Intergenerational Effects of Changes in Women's Educational Attainments. AB - The effect of the socioeconomic characteristics in one generation on the socioeconomic achievement of the next generation is the central concern of social stratification research. Researchers typically address this issue by analyzing the associations between the characteristics of parents and offspring. This approach, however, focuses on observed parent-offspring pairs and ignores that changes in the socioeconomic characteristics of one generation may alter the numbers and types of intergenerational family relationships created in the next one. Models of intergenerational effects that include marriage and fertility as well as the intergenerational transmission of socioeconomic status yield a richer account of intergenerational effects at both the family and population levels. When applied to a large sample of Indonesian women and their families, these models show that the effects of women's educational attainment on the educational attainments of the next generation are positive. However, the beneficial effects of increases in women's schooling on the educational attainment of their children are partially offset at the population level by a reduction in the overall number of children that a more educated population of women bears and enhanced by the more favorable marriage partners of better educated women. PMID- 25843958 TI - Early life disadvantage strengthens flight performance trade-offs in European starlings, Sturnus vulgaris. AB - Developmental stress has been shown to affect adult flight performance in birds, with both negative and positive effects reported in the literature. Previous studies have used developmental manipulations that had substantial effects on patterns of growth. They have also examined mean levels of flight performance per individual, rather than investigating how developmental stress might alter trade offs between different components of flight performance. We recorded multiple components of escape flight performance in 20 adult European starlings previously subjected to a manipulation likely to have altered levels of developmental stress. Siblings had been cross-fostered to nests where they were either slightly larger (advantaged treatment) or slightly smaller (disadvantaged treatment) than their competitors. The manipulation had no detectable effect on growth. However, developmental treatment affected performance in escape flights a year later by strengthening the trade-offs between different flight parameters. Disadvantaged birds faced a steeper trade-off between take-off speed and take-off angle, and a steeper trade-off between take-off angle and total time in flight, than advantaged birds. The results suggest that even subtle early life adversity that has no obvious effect on growth or size can leave a lasting legacy in the form of constraints on locomotor performance later in life. PMID- 25843959 TI - Chytrid fungus infections in laboratory and introduced Xenopus laevis populations: assessing the risks for U.K. native amphibians. AB - The chytrid fungus Batrachochytrium dendrobatidis (Bd) is notorious amongst current conservation biology challenges, responsible for mass mortality and extinction of amphibian species. World trade in amphibians is implicated in global dissemination. Exports of South African Xenopus laevis have led to establishment of this invasive species on four continents. Bd naturally infects this host in Africa and now occurs in several introduced populations. However, no previous studies have investigated transfer of infection into co-occurring native amphibian faunas. A survey of 27 U.K. institutions maintaining X. laevis for research showed that most laboratories have low-level infection, a risk for native species if animals are released into the wild. RT-PCR assays showed Bd in two introduced U.K. populations of X. laevis, in Wales and Lincolnshire. Laboratory and field studies demonstrated that infection levels increase with stress, especially low temperature. In the U.K., native amphibians may be exposed to intense transmission in spring when they enter ponds to spawn alongside X. laevis that have cold-elevated Bd infections. Exposure to cross-infection has probably been recurrent since the introduction of X. laevis, >20 years in Lincolnshire and 50 years in Wales. These sites provide an important test for assessing the impact of X. laevis on Bd spread. However, RT-PCR assays on 174 native amphibians (Bufo, Rana, Lissotriton and Triturus spp.), sympatric with the Bd-infected introduced populations, showed no foci of self-sustaining Bd transmission associated with X. laevis. The abundance of these native amphibians suggested no significant negative population-level effect after the decades of co occurrence. PMID- 25843960 TI - Ordered phases of ethylene adsorbed on charged fullerenes and their aggregates. AB - In spite of extensive investigations of ethylene adsorbed on graphite, bundles of nanotubes, and crystals of fullerenes, little is known about the existence of commensurate phases; they have escaped detection in almost all previous work. Here we present a combined experimental and theoretical study of ethylene adsorbed on free C60 and its aggregates. The ion yield of [Formula: see text] measured by mass spectrometry reveals a propensity to form a structurally ordered phase on monomers, dimers and trimers of C60 in which all sterically accessible hollow sites over carbon rings are occupied. Presumably the enhancement of the corrugation by the curvature of the fullerene surface favors this phase which is akin to a hypothetical 1 * 1 phase on graphite. Experimental data also reveal the number of molecules in groove sites of the C60 dimer through tetramer. The identity of the sites, adsorption energies and orientations of the adsorbed molecules are determined by molecular dynamics calculations based on quantum chemical potentials, as well as density functional theory. The decrease in orientational order with increasing temperature is also explored in the simulations whereas in the experiment it is impossible to vary the temperature. PMID- 25843961 TI - Purification, separation and extraction of inner tubes from double-walled carbon nanotubes by tailoring density gradient ultracentrifugation using optical probes. AB - We studied the effect of varying sonication and centrifugation parameters on double-walled carbon nanotubes (DWCNT) by measuring optical absorption and photoluminescence (PL) of the samples. We found that by using a low sonication intensity before applying density gradient ultracentrifugation (DGU), only inner tube species with a diameter [Formula: see text]0.8 nm can be identified in absorption measurements. This is in stark contrast to the result after sonicating at higher intensities, where also bigger inner tubes can be found. Furthermore, by comparing PL properties of samples centrifugated either with or without a gradient medium, we found that applying DGU greatly enhances the PL intensity, whereas centrifugation at even higher speeds but without a gradient medium results in lower intensities. This can be explained by extraction of inner tubes from their host outer tubes in a two-stage process: the different shearing forces from the sonication treatments result in some DWCNT to be opened, whereas others stay uncut. A subsequent application of DGU leads to the extraction of the inner tubes or not if the host nanotube stayed uncut or no gradient medium was used. This work shows a pathway to avoid this phenomenon to unravel the intrinsic PL from inner tubes of DWCNT. PMID- 25843962 TI - Optical switching of radical pair conformation enhances magnetic sensitivity. AB - The yield of radical pair reactions is influenced by magnetic fields well beyond the levels expected from energy considerations. This dependence can be traced back to the microscopic dynamics of electron spins and constitutes the basis of chemical compasses. Here we propose a new experimental approach based on molecular photoswitches to achieve additional control on the chemical reaction and allow short-time resolution of the spin dynamics. Our proposal enables experiments to test some of the standard assumptions of the radical pair model and improves the sensitivity of a paradigmatic model of chemical magnetometer by up to two orders of magnitude. PMID- 25843963 TI - Radical re-appraisal of water structure in hydrophilic confinement. AB - The structure of water confined in MCM41 silica cylindrical pores is studied to determine whether confined water is simply a version of the bulk liquid which can be substantially supercooled without crystallisation. A combination of total neutron scattering from the porous silica, both wet and dry, and computer simulation using a realistic model of the scattering substrate is used. The water in the pore is divided into three regions: core, interfacial and overlap. The average local densities of water in these simulations are found to be about 20% lower than bulk water density, while the density in the core region is below, but closer to, the bulk density. There is a decrease in both local and core densities when the temperature is lowered from 298 K to 210 K. The radical proposal is made here that water in hydrophilic confinement is under significant tension, around 100 MPa, inside the pore. PMID- 25843964 TI - Crystal Structure Prediction from First Principles: The Crystal Structures of Glycine. AB - Here we present the results of our unbiased searches of glycine polymorphs obtained using the Genetic Algorithms search implemented in Modified Genetic Algorithm for Crystals coupled with the local optimization and energy evaluation provided by Quantum Espresso. We demonstrate that it is possible to predict the crystal structures of a biomedical molecule using solely first principles calculations. We were able to find all the ambient pressure stable glycine polymorphs, which are found in the same energetic ordering as observed experimentally and the agreement between the experimental and predicted structures is of such accuracy that the two are visually almost indistinguishable. PMID- 25843965 TI - Major and trace element geochemistry of Lake Bogoria and Lake Nakuru, Kenya, during extreme draught. AB - The physico-chemical properties of water samples from the two athalassic endorheic lakes Bogoria and Nakuru in Kenya were analysed. Surface water samples were taken between July 2008 and October 2009 in weekly intervals from each lake. The following parameters were determined: pH, salinity, electric conductivity, dissolved organic carbon (DOC), the major cations (FAAS and ICP-OES) and the major anions (IC), as well as certain trace elements (ICP-OES). Samples of superficial sediments were taken in October 2009 and examined using Instrumental Neutron Activation Analysis (INAA) for their major and trace element content including rare earth elements (REE). Both lakes are highly alkaline with a dominance of Na > K > Si > Ca in cations and HCO3 > CO3 > Cl > F > SO4 in anions. Both lakes also exhibited high concentrations of Mo, As and fluoride. Due to an extreme draught from March to October 2009, the water level of Lake Nakuru dropped significantly. This created drastic evapoconcentration, with the total salinity rising from about 200/00 up to 630/00. Most parameters (DOC, Na, K, Ca, F, Mo and As) increased with falling water levels. A clear change in the quality of DOC was observed, followed by an almost complete depletion of dissolved Fe from the water phase. In Lake Bogoria the evapoconcentration effects were less pronounced (total salinity changed from about 400/00 to 480/00). The distributions of REE in the superficial sediments of Lake Nakuru and Lake Bogoria are presented here for the first time. The results show a high abundance of the REE and a very distinct Eu depletion of Eu/Eu* = 0.33-0.45. PMID- 25843966 TI - Metropolis-Hastings thermal state sampling for numerical simulations of Bose Einstein condensates. AB - We demonstrate the application of the Metropolis-Hastings algorithm to sampling of classical thermal states of one-dimensional Bose-Einstein quasicondensates in the classical fields approximation, both in untrapped and harmonically trapped case. The presented algorithm can be easily generalized to higher dimensions and arbitrary trap geometry. For truncated Wigner simulations the quantum noise can be added with conventional methods (half a quantum of energy in every mode). The advantage of the presented method over the usual analytical and stochastic ones lies in its ability to sample not only from canonical and grand canonical distributions, but also from the generalized Gibbs ensemble, which can help to shed new light on thermodynamics of integrable systems. PMID- 25843967 TI - Insights on the upper mantle beneath the Eastern Alps. AB - Analyses of Ps and Sp receiver functions from datasets collected by permanent and temporary seismic stations, image a seismic discontinuity, due to a negative velocity contrast across the entire Eastern Alps. The receiver functions show the presence of the discontinuity within the upper mantle with a resolution of tens of kilometers laterally. It is deeper (100-130 km) below the central portion of the Eastern Alps, and shallower (70-80 km) towards the Pannonian Basin and in the Central Alps. Comparison with previous studies renders it likely that the observed discontinuity coincides with the lithosphere-asthenosphere boundary (LAB) east of 15 degrees E longitude, while it could be associated with a low velocity zone west of 15 degrees E. PMID- 25843968 TI - Slab detachment under the Eastern Alps seen by seismic anisotropy. AB - We analyze seismic anisotropy for the Eastern Alpine region by inspecting shear wave splitting from SKS and SKKS phases. The Eastern Alpine region is characterized by a breakdown of the clear mountain-chain-parallel fast orientation pattern that has been previously documented for the Western Alps and for the western part of the Eastern Alps. The main interest of this paper is a more detailed analysis of the anisotropic character of the Eastern Alps, and the transition to the Carpathian-Pannonian region. SK(K)S splitting measurements reveal a rather remarkable lateral change in the anisotropy pattern from the west to the east of the Eastern Alps with a transition area at about 12 degrees E. We also model the backazimuthal variation of the measurements by a vertical change of anisotropy. We find that the eastern part of the study area is characterized by the presence of two layers of anisotropy, where the deeper layer has characteristics similar to those of the Central Alps, in particular SW-NE fast orientations of anisotropic axes. We attribute the deeper layer to a detached slab from the European plate. Comparison with tomographic studies of the area indicates that the detached slab might possibly connect with the lithosphere that is still in place to the west of our study area, and may also connect with the slab graveyard to the East, at the depth of the upper mantle transition zone. On the other hand, the upper layer has NW-SE fast orientations coinciding with a low velocity layer which is found above a more-or-less eastward dipping high-velocity body. The anisotropy of the upper layer shows large-scale NW-SE fast orientation, which is consistent with the presence of asthenospheric flow above the detached slab foundering into the deeper mantle. PMID- 25843969 TI - Fertility Regulation in an Economic Crisis. AB - Substantial international aid is spent reducing the cost of contraception in developing countries, as part of a larger effort to reduce global fertility and increase investment per child worldwide. The importance for fertility behaviors of keeping contraceptive prices low, however, remains unclear. Targeting of subsidies and insufficient price variation have hindered prior attempts to estimate the effect of monetary and non-monetary contraceptive costs on fertility behavior. Using longitudinal survey data from the Indonesia Family Life Survey, we exploit dramatic variation in prices and incomes that was induced by the economic crisis in the late 1990s to pin down the effect of contraceptive availability and costs as well as household resources on contraceptive use and method choice. The results are unambiguous: monetary costs of contraceptives and levels of family economic resources have a very small (and well-determined) impact on contraceptive use and choice of method. PMID- 25843970 TI - Characterization of local electrochemical doping of high performance conjugated polymer for photovoltaics using scanning droplet cell microscopy. AB - The electrochemical oxidation of a next generation low bandgap high performance photovoltaic material namely poly[4,8-bis-substituted-benzo[1,2-b:4,5 b0]dithiophene-2,6-diyl-alt-4-substituted-thieno[3,4-b] thiophene-2,6-diyl] (PBDTTT-c) thin film was investigated using a scanning droplet cell microscope. Cyclic voltammetry was used for the basic characterization of the oxidation/doping of PBDTTT-c. Application of the different final potentials during the electrochemical study provides a close look to the oxidation kinetics. The electrical properties of both doped and undoped PBDTTT-c were analyzed in situ by electrochemical impedance spectroscopy giving the possibility to correlate the changes in the doping level with the subsequent changes in the resistance and capacitance. As a result one oxidation peak was found during the cyclic voltammetry and in potentiostatic measurements. From Mott-Schottky analysis a donor concentration of 2.3 * 1020 cm-3 and a flat band potential of 1.00 V vs. SHE were found. The oxidation process resulted in an increase of the conductivity by two orders of magnitude reaching a maximum for the oxidized form of 1.4 S cm-1. PMID- 25843971 TI - Experimental chlorine partitioning between forsterite, enstatite and aqueous fluid at upper mantle conditions. AB - Cl partition coefficients between forsterite, enstatite and coexisting Cl-bearing aqueous fluids were determined in a series of high pressure and temperature piston cylinder experiments at 2 GPa between 900 and 1300 degrees C in the system MgO-SiO2-H2O-NaCl-BaO-C+/-CaCl2+/-TiO2+/-Al2O3+/-F. Diamond aggregates were added to the experimental capsule set-up in order to separate the fluid from the solid residue and enable in situ analysis of the quenched solute by LA-ICP MS. The chlorine content of forsterite and enstatite was measured by electron microprobe, and the nature of hydrous defects was investigated by infrared spectroscopy. Partition coefficients show similar incompatibility for Cl in forsterite and enstatite, with DClfo/fl = 0.0012 +/- 0.0006, DClen/fl = 0.0018 +/ 0.0008 and DClfo/en = 1.43 +/- 0.71. The values determined for mineral/fluid partitioning are very similar to previously determined values for mineral/melt. Applying the new mineral/fluid partition coefficients to fluids in subduction zones, a contribution between 0.15% and 20% of the total chlorine from the nominally anhydrous minerals is estimated. Infrared spectra of experimental forsterite show absorption bands at 3525 and 3572 cm-1 that are characteristic for hydroxyl point defects associated with trace Ti substitutions, and strongly suggest that the TiO2 content of the system can influence the chlorine and OH incorporation via the stabilization of Ti-clinohumite-like point defects. The water contents for coexisting forsterite and enstatite in some runs were determined using unpolarized IR spectra and calculated water partition coefficients [Formula: see text] are between 0.01 and 0.5. PMID- 25843972 TI - Self-Regulatory Deficits Associated with Unpracticed Mindfulness Strategies for Coping with Acute Pain. AB - Training in mindfulness is a well-supported therapeutic strategy for pain conditions, though short-term mindfulness training for acute pain is not always effective. To explore the possibility that initial attempts at mindfulness in people without previous training may drain self-regulatory resources, the current study used a student sample (N=63) to test the hypothesis that brief instruction in mindfulness would lead to reduced pain tolerance on a cold pressor task (CPT), compared to more familiar strategies for coping with acute pain. We also investigated whether high heart rate variability (HRV), a physiological indicator of self-regulatory capacity, would predict pain tolerance. Higher HRV predicted greater pain tolerance only in the control group, suggesting that applying unfamiliar mindfulness strategies while attempting to tolerate pain more rapidly sapped self-regulatory strength. PMID- 25843973 TI - Solution-Phase Perfluoroalkylation of C60 Leads to Efficient and Selective Synthesis of Bis-Perfluoroalkylated Fullerenes. AB - A solution-phase perfluoroalkylation of C60 with a series of RFI reagents was studied. The effects of molar ratio of the reagents, reaction time, and presence of copper metal promoter on fullerene conversion and product composition were evaluated. Ten aliphatic and aromatic RFI reagents were investigated (CF3I, C2F5I, n-C3F7I, i-C3F7I, n-C4F9I, (CF3)(C2F5)CFI, n-C8F17I, C6F5CF2I, C6F5I, and 1,3-(CF3)2C6F3I) and eight of them (except for C6F5I and 1,3-(CF3)2C6F3I) were found to add the respective RF groups to C60 in solution. Efficient and selective synthesis of C60(RF)2 derivatives was developed. PMID- 25843975 TI - Weakly coupled bound state of 2-D Schrodinger operator with potential-measure. AB - We consider a self-adjoint two-dimensional Schrodinger operator [Formula: see text], which corresponds to the formal differential expression[Formula: see text] where MU is a finite compactly supported positive Radon measure on [Formula: see text] from the generalized Kato class and [Formula: see text] is the coupling constant. It was proven earlier that [Formula: see text]. We show that for sufficiently small alpha the condition [Formula: see text] holds and that the corresponding unique eigenvalue has the asymptotic expansion[Formula: see text] with a certain constant [Formula: see text]. We also obtain a formula for the computation of [Formula: see text]. The asymptotic expansion of the corresponding eigenfunction is provided. The statements of this paper extend the results of Simon [41] to the case of potentials-measures. Also for regular potentials our results are partially new. PMID- 25843974 TI - Interparental Relationship Sensitivity Leads to Adolescent Internalizing Problems: Different Genotypes, Different Pathways. AB - Several studies have established that child interparental conflict evaluations link parent relationship functioning and adolescent adjustment. Using differential susceptibility theory and its vantage sensitivity complement as their framework, the authors examined differences between adolescents who vary in the DRD4 7 repeat genotype (i.e. 7+ vs. 7-) in how both interparental conflict and positivity affect adolescents' evaluations of interparental conflict (i.e., threat appraisals) and how these evaluations affect internalizing problems. Results from longitudinal multiple-group path models using PROSPER data (N = 452) supported the hypothesis that threat appraisals for 7+ adolescents would be more affected by perceptions of interparental positivity compared to 7- adolescents; however, threat appraisals for 7+ adolescents were also less affected by interparental conflict. Among 7- adolescents, interparental conflict perceptions were associated with higher threat appraisals, and no association was found for perceptions of positivity. For adolescents of both genotypes, higher threat was associated with greater internalizing problems. PMID- 25843976 TI - Representation of the inverse of a frame multiplier. AB - Certain mathematical objects appear in a lot of scientific disciplines, like physics, signal processing and, naturally, mathematics. In a general setting they can be described as frame multipliers, consisting of analysis, multiplication by a fixed sequence (called the symbol), and synthesis. In this paper we show a surprising result about the inverse of such operators, if any, as well as new results about a core concept of frame theory, dual frames. We show that for semi normalized symbols, the inverse of any invertible frame multiplier can always be represented as a frame multiplier with the reciprocal symbol and dual frames of the given ones. Furthermore, one of those dual frames is uniquely determined and the other one can be arbitrarily chosen. We investigate sufficient conditions for the special case, when both dual frames can be chosen to be the canonical duals. In connection to the above, we show that the set of dual frames determines a frame uniquely. Furthermore, for a given frame, the union of all coefficients of its dual frames is dense in [Formula: see text]. We also introduce a class of frames (called pseudo-coherent frames), which includes Gabor frames and coherent frames, and investigate invertible pseudo-coherent frame multipliers, allowing a classification for frame-type operators for these frames. Finally, we give a numerical example for the invertibility of multipliers in the Gabor case. PMID- 25843977 TI - Optimal Mortgage Refinancing: A Closed Form Solution. AB - We derive the first closed-form optimal refinancing rule: Refinance when the current mortgage interest rate falls below the original rate by at least [Formula: see text] In this formula W(.) is the Lambert W-function, [Formula: see text]rho is the real discount rate, lambda is the expected real rate of exogenous mortgage repayment, sigma is the standard deviation of the mortgage rate, kappa/M is the ratio of the tax-adjusted refinancing cost and the remaining mortgage value, and tau is the marginal tax rate. This expression is derived by solving a tractable class of refinancing problems. Our quantitative results closely match those reported by researchers using numerical methods. PMID- 25843978 TI - Palladium-Catalyzed Aerobic Acetoxylation of Benzene using NOx-Based Redox Mediators. AB - Palladium-catalyzed methods for C-H oxygenation with O2 as the stoichiometric oxidant are limited. Here, we describe the use of nitrite and nitrate sources as NOx-based redox mediators in the acetoxylation of benzene. The conditions completely avoid formation of biphenyl as a side product, and strongly favor formation of phenyl acetate over nitrobenzene (PhOAc:PhNO2 ratios up to 40:1). Under the optimized reaction conditions, with 0.1 mol% Pd(OAc)2, 136 turnovers of Pd are achieved with only 1 atm of O2 pressure. PMID- 25843979 TI - Holding the Hunger Games Hostage at the Gym: An Evaluation of Temptation Bundling. AB - We introduce and evaluate the effectiveness of temptation bundling-a method for simultaneously tackling two types of self-control problems by harnessing consumption complementarities. We describe a field experiment measuring the impact of bundling instantly gratifying but guilt-inducing "want" experiences (enjoying page-turner audiobooks) with valuable "should" behaviors providing delayed rewards (exercising). We explore whether such bundles increase should behaviors and whether people would pay to create these restrictive bundles. Participants were randomly assigned to a full treatment condition with gym-only access to tempting audio novels, an intermediate treatment involving encouragement to restrict audiobook enjoyment to the gym, or a control condition. Initially, full and intermediate treatment participants visited the gym 51% and 29% more frequently, respectively, than control participants, but treatment effects declined over time (particularly following Thanksgiving). After the study, 61% of participants opted to pay to have gym-only access to iPods containing tempting audiobooks, suggesting demand for this commitment device. PMID- 25843980 TI - The fitness value of information. AB - Communication and information are central concepts in evolutionary biology. In fact, it is hard to find an area of biology where these concepts are not used. However, quantifying the information transferred in biological interactions has been difficult. How much information is transferred when the first spring rainfall hits a dormant seed, or when a chick begs for food from its parent? One measure that is commonly used in such cases is fitness value: by how much, on average, an individual's fitness would increase if it behaved optimally with the new information, compared to its average fitness without the information. Another measure, often used to describe neural responses to sensory stimuli, is the mutual information-a measure of reduction in uncertainty, as introduced by Shannon in communication theory. However, mutual information has generally not been considered to be an appropriate measure for describing developmental or behavioral responses at the organismal level, because it is blind to function; it does not distinguish between relevant and irrelevant information. In this paper we show that there is in fact a surprisingly tight connection between these two measures in the important context of evolution in an uncertain environment. In this case, a useful measure of fitness benefit is the increase in the long-term growth rate, or the fold increase in number of surviving lineages. We show that in many cases the fitness value of a developmental cue, when measured this way, is exactly equal to the reduction in uncertainty about the environment, as described by the mutual information. PMID- 25843981 TI - Escape of the martian protoatmosphere and initial water inventory. AB - Latest research in planet formation indicates that Mars formed within a few million years (Myr) and remained as a planetary embryo that never grew to a more massive planet. It can also be expected from dynamical models that most of Mars' building blocks consisted of material that formed in orbital locations just beyond the ice line which could have contained [Formula: see text] of H2O. By using these constraints, we estimate the nebula-captured and catastrophically outgassed volatile contents during the solidification of Mars' magma ocean and apply a hydrodynamic upper atmosphere model for the study of the soft X-ray and extreme ultraviolet (XUV) driven thermal escape of the martian protoatmosphere during the early active epoch of the young Sun. The amount of gas that has been captured from the protoplanetary disk into the planetary atmosphere is calculated by solving the hydrostatic structure equations in the protoplanetary nebula. Depending on nebular properties such as the dust grain depletion factor, planetesimal accretion rates and luminosities, hydrogen envelopes with masses [Formula: see text] to [Formula: see text] could have been captured from the nebula around early Mars. Depending on the before mentioned parameters, due to the planets low gravity and a solar XUV flux that was [Formula: see text] times stronger compared to the present value, our results indicate that early Mars would have lost its nebular captured hydrogen envelope after the nebula gas evaporated, during a fast period of [Formula: see text]. After the solidification of early Mars' magma ocean, catastrophically outgassed volatiles with the amount of [Formula: see text] H2O and [Formula: see text] CO2 could have been lost during [Formula: see text], if the impact related energy flux of large planetesimals and small embryos to the planet's surface lasted long enough, that the steam atmosphere could have been prevented from condensing. If this was not the case, then our results suggest that the timescales for H2O condensation and ocean formation may have been shorter compared to the atmosphere evaporation timescale, so that one can speculate that sporadically periods, where some amount of liquid water may have been present on the planet's surface. However, depending on the amount of the outgassed volatiles, because of impacts and the high XUV driven atmospheric escape rates, such sporadically wet surface conditions may have also not lasted much longer than [Formula: see text]. After the loss of the captured hydrogen envelope and outgassed volatiles during the first 100 Myr period of the young Sun, a warmer and probably wetter period may have evolved by a combination of volcanic outgassing and impact delivered volatiles [Formula: see text] ago, when the solar XUV flux decreased to values that have been [Formula: see text] times that of today's Sun. PMID- 25843982 TI - Impact of treatment heterogeneity on drug resistance and supply chain costs. AB - The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context. PMID- 25843984 TI - Voting suffrage and the political budget cycle: Evidence from the London Metropolitan Boroughs 1902-1937. AB - We study the opportunistic political budget cycle in the London Metropolitan Boroughs between 1902 and 1937 under two different suffrage regimes: taxpayer suffrage (1902-1914) and universal suffrage (1921-1937). We argue and find supporting evidence that the political budget cycle operates differently under the two types of suffrage. Taxpayer suffrage, where the right to vote and the obligation to pay local taxes are linked, encourages demands for retrenchment and the political budget cycle manifests itself in election year tax cuts and savings on administration costs. Universal suffrage, where all adult residents can vote irrespective of their taxpayer status, creates demands for productive public services and the political budget cycle manifests itself in election year hikes in capital spending and a reduction in current spending. PMID- 25843983 TI - Towards an asymmetric organocatalytic alpha-cyanation of beta-ketoesters. AB - This communication describes the first proof of concept for an asymmetric alpha cyanation of beta-ketoesters using a hypervalent iodine-based electrophilic cyanide-transfer reagent. A series of different organocatalysts has been investigated and it was found that the use of naturally occurring Cinchona alkaloids allows obtaining the target products in good yields and with moderate enantioselectivities up to er = 76:24 under operationally simple conditions. PMID- 25843985 TI - The conscientious retiree: The relationship between conscientiousness, retirement, and volunteering. AB - The current study examined the relationship between conscientiousness, work status, and volunteering utilizing two large samples, the St. Louis Personality and Aging Network (SPAN) and the Health and Retirement Study (HRS). It was hypothesized that conscientious adults who were retired would be more likely to volunteer because, after retirement, they gain a substantial amount of free time, while losing an outlet for their industrious and achievement-striving tendencies. Cross-sectional and longitudinal analyses revealed that conscientious, retired individuals were more likely to volunteer than conscientious, working individuals. Further analyses revealed that facets of conscientiousness provide differential information from the general trait. These findings indicate that volunteering during retirement fills an important niche for high-striving, conscientious individuals. PMID- 25843986 TI - On a product-type operator from weighted Bergman-Orlicz space to some weighted type spaces. AB - Let [Formula: see text] be the open unit disk, [Formula: see text] an analytic self-map of [Formula: see text] and [Formula: see text] an analytic function on [Formula: see text]. Let D be the differentiation operator and [Formula: see text] the weighted composition operator. The boundedness and compactness of the product-type operator [Formula: see text] from the weighted Bergman-Orlicz space to the Bers type space, weighted Bloch space and weighted Zygmund space on [Formula: see text] are characterized. PMID- 25843987 TI - A GIS based spatially-explicit sensitivity and uncertainty analysis approach for multi-criteria decision analysis. AB - GIS multicriteria decision analysis (MCDA) techniques are increasingly used in landslide susceptibility mapping for the prediction of future hazards, land use planning, as well as for hazard preparedness. However, the uncertainties associated with MCDA techniques are inevitable and model outcomes are open to multiple types of uncertainty. In this paper, we present a systematic approach to uncertainty and sensitivity analysis. We access the uncertainty of landslide susceptibility maps produced with GIS-MCDA techniques. A new spatially-explicit approach and Dempster-Shafer Theory (DST) are employed to assess the uncertainties associated with two MCDA techniques, namely Analytical Hierarchical Process (AHP) and Ordered Weighted Averaging (OWA) implemented in GIS. The methodology is composed of three different phases. First, weights are computed to express the relative importance of factors (criteria) for landslide susceptibility. Next, the uncertainty and sensitivity of landslide susceptibility is analyzed as a function of weights using Monte Carlo Simulation and Global Sensitivity Analysis. Finally, the results are validated using a landslide inventory database and by applying DST. The comparisons of the obtained landslide susceptibility maps of both MCDA techniques with known landslides show that the AHP outperforms OWA. However, the OWA-generated landslide susceptibility map shows lower uncertainty than the AHP-generated map. The results demonstrate that further improvement in the accuracy of GIS-based MCDA can be achieved by employing an integrated uncertainty-sensitivity analysis approach, in which the uncertainty of landslide susceptibility model is decomposed and attributed to model's criteria weights. PMID- 25843988 TI - Computed reconstruction of spatial ammonoid-shell orientation captured from digitized grinding and landmark data. AB - The internal orientation of fossil mass occurrences can be exploited as useful source of information about their primary depositional conditions. A series of studies, using different kinds of fossils, especially those with elongated shape (e.g., elongated gastropods), deal with their orientation and the subsequent reconstruction of the depositional conditions (e.g., paleocurrents and transport mechanisms). However, disk-shaped fossils like planispiral cephalopods or gastropods were used, up to now, with caution for interpreting paleocurrents. Moreover, most studies just deal with the topmost surface of such mass occurrences, due to the easier accessibility. Within this study, a new method for three-dimensional reconstruction of the internal structure of a fossil mass occurrence and the subsequent calculation of its spatial shell orientation is established. A 234 million-years-old (Carnian, Triassic) monospecific mass occurrence of the ammonoid Kasimlarceltites krystyni from the Taurus Mountains in Turkey, embedded in limestone, is used for this pilot study. Therefore, a 150*45*140 mm3 block of the ammonoid bearing limestone bed has been grinded to 70 slices, with a distance of 2 mm between each slice. By using a semi-automatic region growing algorithm of the 3D-visualization software Amira, ammonoids of a part of this mass occurrence were segmented and a 3D-model reconstructed. Landmarks, trigonometric and vector-based calculations were used to compute the diameters and the spatial orientation of each ammonoid. The spatial shell orientation was characterized by dip and dip-direction and aperture direction of the longitudinal axis, as well as by dip and azimuth of an imaginary sagittal plane through each ammonoid. The exact spatial shell orientation was determined for a sample of 675 ammonoids, and their statistical orientation analyzed (i.e., NW/SE). The study combines classical orientation analysis with modern 3D visualization techniques, and establishes a novel spatial orientation analyzing method, which can be adapted to any kind of abundant solid matter. PMID- 25843989 TI - Anatomy of a Municipal Triumph: New York City's Upsurge in Life Expectancy. AB - Over the period 1990-2010, the increase in life expectancy for males in New York City was 6.0 years greater than for males in the United States. The female relative gain was 3.9 years. Male relative gains were larger because of extremely rapid reductions in mortality from HIV/AIDS and homicide, declines that reflect effective municipal policies and programs. Declines in drug- and alcohol-related deaths also played a significant role in New York City's advance, but every major cause of death contributed to its relative improvement. By 2010, New York City had a life expectancy that was 1.9 years greater than that of the US. This difference is attributable to the high representation of immigrants in New York's population. Immigrants to New York City, and to the United States, have life expectancies that are among the highest in the world. The fact that 38 percent of New York's population consists of immigrants, compared to only 14 percent in the United States, accounts for New York's exceptional standing in life expectancy in 2010. In fact, US-born New Yorkers have a life expectancy below that of the United States itself. PMID- 25843990 TI - Spatial sensitivity of grassland yields to weather variations in Austria and its implications for the future. AB - Agricultural production fulfills economic, ecological and structural functions. Despite technological advances, agricultural production remains sensitive to climate variations. In central Europe, climate change is predicted to bring more rainfall in winter, less rainfall in summer, and increased drought risk among other effects. Grassland agriculture, which is the dominant land use in Alpine regions, may be significantly affected by these climatic changes in the future. Motivated by this issue, the susceptibility of grassland yields to weather variations in Austria is empirical evaluated as a case study. The major objective of this study is to derive spatially distributed indications for climate change exposure by assessing the impacts of weather variations on past yield. It is assumed that reduced water supply during summer constitutes a threat to grassland productivity in regions that are warmer and drier already today. On the contrary, increased spring temperatures may improve grassland productivity in cooler regions like Alpine valleys, since the earlier snow melt leads to an extension of the growth period. Regression analyses are used for evaluating the relation between yearly yields and spring temperatures or water supply in summer, respectively. Water supply is thereby expressed by aggregated precipitation sums and the Climatic Water Balance (CWB). Input data are a meteorological time series as well as yearly yields available for 25 years between 1970 and 2010 and 99 districts in Austria. Yearly yields show a significant (P < 0.05) and positive dependency on water supply in summer for the eastern Austrian lowlands. The combination of temperature in spring and CWB in summer is only significant for six districts in the east of Austria. The positive impact of higher spring temperatures could not be verified. Generally, the regression coefficients are not very high, which indicates that temperature and water supply do not fully describe grassland productivity. Projected climate change may increasingly constitute a risk to yield reliability in the east of the country. That in turn, requires consideration in agricultural development plans and a quantification of these impacts from a social-economic perspective. PMID- 25843991 TI - Sensing the public's reaction to crime news using the 'Links Correspondence Method'. AB - Public media such as TV or newspapers, paired with crime statistics from the authority, raise awareness of crimes within society. However, in today's digital society, other sources rapidly gain importance as well. The Internet and social networks act heavily as information distribution platforms. Therefore, this paper aims at exploring the influence of the social Web service Twitter as an information distribution platform for crime news. In order to detect messages with crime-related contents, the Links Correspondence Method (LCM) is introduced, which gathers and investigates Twitter messages related to crime articles via associated Web links. Detected crime tweets are analysed in regard to the distance between the location of an incident and the location of associated tweets, as well as regards demographic aspects of the corresponding crime news. The results show that there exists a spatial dependency regarding the activity space of a user (and the crime-related tweets of this user) and the actual location of the crime incident. Furthermore, the demographic analysis indicates that the type of a crime as well as the gender of the victim has great influence on whether the crime incident is spread via Twitter or not. PMID- 25843992 TI - Effects of supervision on tax compliance: Evidence from a field experiment in Austria. AB - We conduct a field experiment on tax compliance, focusing on newly founded firms. As a novelty the effect of tax authorities' supervision on timely tax payments is examined. Interestingly, results show no positive overall effect of close supervision on tax compliance. PMID- 25843993 TI - How hard is it to tell which is a Condorcet committee? AB - This paper establishes the computational complexity status for a problem of deciding on the quality of a committee. Starting with individual preferences over alternatives, we analyse when it can be determined efficiently if a given committee [Formula: see text] satisfies a weak (resp. strong) Condorcet criterion i.e., if [Formula: see text] is at least as good as (resp. better than) every other committee in a pairwise majority comparison. Scoring functions used in classic voting rules are adapted for these comparisons. In particular, we draw the sharp separation line between computationally tractable and intractable instances with respect to different voting rules. Finally, we show that deciding if there exists a committee which satisfies the weak (resp. strong) Condorcet criterion is computationally hard. PMID- 25843994 TI - Does a hospital's quality depend on the quality of other hospitals? A spatial econometrics approach. AB - We examine whether a hospital's quality is affected by the quality provided by other hospitals in the same market. We first sketch a theoretical model with regulated prices and derive conditions on demand and cost functions which determine whether a hospital will increase its quality if its rivals increase their quality. We then apply spatial econometric methods to a sample of English hospitals in 2009-10 and a set of 16 quality measures including mortality rates, readmission, revision and redo rates, and three patient reported indicators, to examine the relationship between the quality of hospitals. We find that a hospital's quality is positively associated with the quality of its rivals for seven out of the sixteen quality measures. There are no statistically significant negative associations. In those cases where there is a significant positive association, an increase in rivals' quality by 10% increases a hospital's quality by 1.7% to 2.9%. The finding suggests that for some quality measures a policy which improves the quality in one hospital will have positive spillover effects on the quality in other hospitals. PMID- 25843995 TI - Revealed distributional preferences: Individuals vs. teams. AB - We compare experimentally the revealed distributional preferences of individuals and teams in allocation tasks. We find that teams are significantly more benevolent than individuals in the domain of disadvantageous inequality while the benevolence in the domain of advantageous inequality is similar across decision makers. A consequence for the frequency of preference types is that while a substantial fraction of individuals is classified as inequality averse, this type disappears completely in teams. Spiteful types are markedly more frequent among individuals than among teams. On the other hand, by far more teams than individuals are classified as efficiency lovers. PMID- 25843996 TI - Effects of the atomic level shift in the Auger neutralization rates of noble metal surfaces. AB - In this work we compare characteristics of Auger neutralization of [Formula: see text] ions at noble metal and free-electron metal surfaces. For noble metals, we find that the position of the energy level of He with respect to the Fermi level has a non-negligible influence on the values of the calculated Auger rates through the evaluation of the surface dielectric susceptibility. We conclude that even though our calculated rates are accurate, further theoretical effort is needed to obtain realistic values of the energy level of He in front of these surfaces. PMID- 25843997 TI - Progress towards a 256 channel multi-anode microchannel plate photomultiplier system with picosecond timing. AB - Despite the rapid advances in solid state technologies such as the silicon photomultiplier (SiPM), microchannel plate (MCP) photomultipliers still offer a proven and practical technological solution for high channel count pixellated photon-counting systems with very high time resolution. We describe progress towards a 256 channel optical photon-counting system using CERN-developed NINO and HTDC ASICs, and designed primarily for time resolved spectroscopy in life science applications. Having previously built and demonstrated a 18 mm diameter prototype tube with an 8*8 channel readout configuration and <43 ps rms single photon timing resolution, we are currently developing a 40 mm device with a 32*32 channel readout. Initially this will be populated with a 256 channel electronics system comprising four sets of modular 64 channel preamplifier/discriminator, and time-to-digital converter units, arranged in a compact three dimensional configuration. We describe the detector and electronics design and operation, and present performance measurements from the 256 channel development system. We discuss enhancements to the system including higher channel count and the use of application specific on-board signal processing capabilities. PMID- 25843998 TI - Ultracold neutron detectors based on 10B converters used in the qBounce experiments. AB - Gravity experiments with very slow, so-called ultracold neutrons connect quantum mechanics with tests of Newton's inverse square law at short distances. These experiments face a low count rate and hence need highly optimized detector concepts. In the frame of this paper, we present low-background ultracold neutron counters and track detectors with micron resolution based on a 10B converter. We discuss the optimization of 10B converter layers, detector design and concepts for read-out electronics focusing on high-efficiency and low-background. We describe modifications of the counters that allow one to detect ultracold neutrons selectively on their spin-orientation. This is required for searches of hypothetical forces with spin-mass couplings. The mentioned experiments utilize a beam-monitoring concept which accounts for variations in the neutron flux that are typical for nuclear research facilities. The converter can also be used for detectors, which feature high efficiencies paired with high spatial resolution of [Formula: see text]. They allow one to resolve the quantum mechanical wave function of an ultracold neutron bound in the gravity potential above a neutron mirror. PMID- 25843999 TI - PET/MRI insert using digital SiPMs: Investigation of MR-compatibility. AB - In this work, we present an initial MR-compatibility study performed with the world's first preclinical PET/MR insert based on fully digital silicon photo multipliers (dSiPM). The PET insert allows simultaneous data acquisition of both imaging modalities and thus enables the true potential of hybrid PET/MRI. Since the PET insert has the potential to interfere with all of the MRI's subsystems (strong magnet, gradients system, radio frequency (RF) system) and vice versa, interference studies on both imaging systems are of great importance to ensure an undisturbed operation. As a starting point to understand the interference, we performed signal-to-noise ratio (SNR) measurements as well as dedicated noise scans on the MRI side to characterize the influence of the PET electronics on the MR receive chain. Furthermore, improvements of sub-components' shielding of the PET system are implemented and tested inside the MRI. To study the influence of the MRI on the PET performance, we conducted highly demanding stress tests with gradient and RF dominated MR sequences. These stress tests unveil a sensitivity of the PET's electronics to gradient switching. PMID- 25844000 TI - Prospects for measuring the 229Th isomer energy using a metallic magnetic microcalorimeter. AB - The Thorium-229 isotope features a nuclear isomer state with an extremely low energy. The currently most accepted energy value, 7.8+/-0.5 eV, was obtained from an indirect measurement using a NASA x-ray microcalorimeter with an instrumental resolution 26 eV. We study, how state-of-the-art magnetic metallic microcalorimeters with an energy resolution down to a few eV can be used to measure the isomer energy. In particular, resolving the 29.18 keV doublet in the gamma-spectrum following the alpha-decay of Uranium-233, corresponding to the decay into the ground and isomer state, allows to measure the isomer transition energy without additional theoretical input parameters, and increase the energy accuracy. We study the possibility of resolving the 29.18 keV line as a doublet and the dependence of the attainable precision of the energy measurement on the signal and background count rates and the instrumental resolution. PMID- 25844001 TI - Latino Caregiver Psychosocial Factors and Health Care Services for Children Involved in the Child Welfare System. AB - Children in the child welfare system have a high prevalence of health problems, making pediatric health service use critical. Latino children represent a growing proportion of the child welfare system, and are at increased risk for health problems. Many have argued that Latino caregivers can provide Latino children with the least disruptive out-of-home placement, but little is known about how caregiver factors might relate to health services utilization or child health status within this population. This study assessed relationships between caregiver psychosocial factors, health care service utilization, and health status for children in the child welfare system. This sample featured 48 Latino caregivers involved in child welfare. Logistic regression models were used to test for relationships between caregiver psychosocial factors and appointment adherence and child health status. Problem-focused coping was positively related to well-child status. No psychosocial factors were related to medical appointment adherence. Case workers may help improve child health outcomes by promoting problem-focused coping skills among Latino caregivers. PMID- 25844002 TI - Further evidence of the heterogeneous nature of impulsivity. AB - 'Impulsivity' refers to a range of behaviours including preference for immediate reward (temporal-impulsivity) and the tendency to make premature decisions (reflection-impulsivity) and responses (motor-impulsivity). The current study aimed to examine how different behavioural and self-report measurements of impulsivity can be categorised into distinct subtypes. Exploratory factor analysis using full information maximum likelihood was conducted on 10 behavioural and 1 self-report measure of impulsivity. Four factors of impulsivity were indicated, with Factor 1 having a high loading of the Stop Signal Task, which measures motor-impulsivity, factor 2 representing reflection-impulsivity with loadings of the Information Sampling Task and Matching Familiar Figures Task, factor 3 representing the Immediate Memory Task, and finally factor 4 which represents the Delay Discounting Questionnaire and The Monetary Choice Questionnaire, measurements of temporal-impulsivity. These findings indicated that impulsivity is not a unitary construct, and instead represents a series of independent subtypes. There was evidence of a distinct reflection-impulsivity factor, providing the first factor analysis support for this subtype. There was also support for additional factors of motor- and temporal-impulsivity. The present findings indicated that a number of currently accepted tasks cannot be considered as indexing motor- and temporal-impulsivity suggesting that additional characterisations of impulsivity may be required. PMID- 25844003 TI - Mobile Phone Assessment in Egocentric Networks: A Pilot Study on Gay Men and Their Peers. AB - Mobile phone-based data collection encompasses the richness of social network research. Both individual-level and network-level measures can be recorded. For example, health-related behaviors can be reported via mobile assessment. Social interactions can be assessed by phone-log data. Yet the potential of mobile phone data collection has largely been untapped. This is especially true of egocentric studies in public health settings where mobile phones can enhance both data collection and intervention delivery, e.g. mobile users can video chat with counselors. This is due in part to privacy issues and other barriers that are more difficult to address outside of academic settings where most mobile research to date has taken place. In this article, we aim to inform a broader discussion on mobile research. In particular, benefits and challenges to mobile phone-based data collection are highlighted through our mobile phone-based pilot study that was conducted on egocentric networks of 12 gay men (n = 44 total participants). HIV-transmission and general health behaviors were reported through a mobile phone-based daily assessment that was administered through study participants' own mobile phones. Phone log information was collected from gay men with Android phones. Benefits and challenges to mobile implementation are discussed, along with the application of multi-level models to the type of longitudinal egocentric data that we collected. PMID- 25844004 TI - [Expressions of affection bilingual mothers, Bilingual mothers' expressions of affect]. AB - The purpose of this study is to examine the uses of affectivity in L1 and L2 in 10 bilingual mothers' interactions with their 30-month. The expressions of emotion, volition and epistemic stance were identified in 30 spontaneous mother child interactions: i. 10 Spanish L1 mothers speaking in L1; ii. 10 Spanish L1 mothers speaking in English L2; and iii. 10 English L1 mothers speaking in L1. The results suggest that L2 uses differ from L1: expressions of volition and epistemic stance in English L2 resemble their use in English L1, whereas expressions of emotions in English L2 are similar to Spanish L1. These findings shed light on bilingual speakers' expressive language and are useful in determining the impact on language development. PMID- 25844005 TI - Survey questions about party competence: Insights from cognitive interviews. AB - Voter assessments of party competence have become a key explanation of electoral decision-making. However, there are at least three important aspects to understanding responses to questions on issue-specific party competence: comprehension difficulties; a lack of well-formed attitudes and relevant information; and the use of response heuristics. We used 20 cognitive interviews carried out in Austria in 2011 to test competence questions. The interviews show us how respondents explain their responses. We find evidence that many people (1) may hold only weak opinions and have little information on issue-specific party competence and (2) may make use of distinct but related concepts, particularly salience and position, when answering questions about competence. We provide recommendations for researchers and survey designers based on our findings. PMID- 25844006 TI - The "sowing of concrete": Peri-urban smallholder perceptions of rural-urban land change in the Central Peruvian Andes. AB - Policy makers concerned with the peri-urban interface find their greatest challenges in the rapid urban growth of developing mountain regions, since limitations caused by relief and altitude often lead to an increased competition between rural and urban land use at the valley floors. In this context, little attention has been paid to the affected agriculturalists' perceptions of peri urban growth-important information required for the realization of sustainable land use planning. How is the process of rural-urban land change perceived and assessed by peri-urban smallholder communities? Which are the major difficulties to be overcome? By what means are the affected people reacting and how are these adaptation strategies linked with the ongoing landscape transformations of the hinterland? By using the example of Huancayo Metropolitano, an emerging Peruvian mountain city, it is shown that rural-urban land change is intensively discussed within peri-urban smallholder groups. Although urbanization also leads to infrastructure investments by public institutions-an advantage perceived throughout the study area-the negative impacts of rural-urban land use change prevail. The perceptions' analysis reveals that the decrease of fertile and irrigated agricultural land at the quechua valley floor is especially considered to threaten subsistence, food and income security. In order to compensate the loss of production capacities, many smallholders try to expand or intensify their land use at the suni altitudinal belt: an agro-ecological zone characterized by steep and nonirrigated slopes that can actually not be used for the year-round production of crops previously cultivated at the quechua zone. PMID- 25844007 TI - Land system change in Italy from 1884 to 2007: Analysing the North-South divergence on the basis of an integrated indicator framework. AB - Over the past centuries, land systems in Italy experienced fundamental shifts, owing to the availability of new energy forms, population surges, and technological progress. The 20th century was characterized by massive productivity increases, accompanied by gradual land abandonment and the return of forest land. We here analyze 120 years of land system change in Italy, applying the human appropriation of net primary production (HANPP) framework, a metric for socio-economic pressures on terrestrial ecosystems. HANPP allows integrating ecological with societal perspectives, by systematically quantifying (a) biomass harvest and (b) the difference between potential productivity of ecosystems and current productivity induced by land use processes, such as land conversion, or land degradation. Besides assessing national trends we calculated HANPP separately for the Italian North and South between 1934 and 2007, in order to scrutinize if high regional discrepancies in terms of natural and socio-economic preconditions translate into diverging land system trajectories. Our results show that national HANPP has been declining from 78% of natural productivity before WWII to 56% in 2007, indicating a declining land -use induced pressure on biomass flows over time. Simultaneously, biomass harvest increased by around 26% due to agricultural intensification, despite shrinking croplands. Although we found a significant difference between the Northern and Southern region in the absolute levels of several land use indicators related to biomass appropriation, the overarching trends of land system change were remarkably similar in both regions. This suggests that underlying drivers of land system change, such as policies aimed at land-use intensification and structural change were equally dominating land system trajectories in the North and South of Italy, not withstanding their socio-ecological divergences. PMID- 25844008 TI - Prospects for dedicated energy crop production and attitudes towards agricultural straw use: The case of livestock farmers. AB - Second generation biofuels utilising agricultural by-products (e.g. straw), or dedicated energy crops (DECs) produced on 'marginal' land, have been called for. A structured telephone survey of 263 livestock farmers, predominantly located in the west or 'marginal' upland areas of England captured data on attitudes towards straw use and DECs. Combined with farm physical and business data, the survey results show that 7.2% and 6.3% of farmers would respectively consider growing SRC and miscanthus, producing respective maximum potential English crop areas of 54,603 ha and 43,859 ha. If higher market prices for straw occurred, most livestock farmers would continue to buy straw. Reasons for not being willing to consider growing DECs include concerns over land quality, committing land for a long time period, lack of appropriate machinery, profitability, and time to financial return; a range of moral, land quality, production conflict and lack of crop knowledge factors were also cited. Results demonstrate limited potential for the production of DECs on livestock farms in England. Changes in policy support to address farmer concerns with respect to DECs will be required to incentivise farmers to increase energy crop production. Policy support for DEC production must be cognisant of farm-level economic, tenancy and personal objectives. PMID- 25844010 TI - Social movements and the struggle for shelter: A case study of eThekwini (Durban). AB - The needs of informal settlement dwellers across towns and cities in the global South are acute. While much emphasis has been placed on income poverty, for urban dwellers affordable access to improved secured accommodation and basic services such as water and sanitation is essential for well-being. In part due to the lack of such access, urban citizens organize in multiple ways to address these needs and to press for state investment and redistribution. South Africa, despite relatively high levels of income and a state with redistributive capacity, is no exception. Indeed, this country is particularly interesting for those seeking to understand effective approaches to addressing housing need because of the efforts that have been made and the resultant scale of state investment in the housing sector. This paper draws on the experiences of urban social movement organizations in South Africa to understand better how shelter needs can be addressed. We reflect on their goals, strategies and activities and explore what this means for themes discussed within the social movement literature. The research has a specific focus on the city of eThekwini/Durban primarily because of the scale of social movement activities there. The paper describes the core concerns with respect to shelter as elaborated by social movement activists, staff of other civil society agencies and officials. While there is a broad consensus about the shelter problems, there is less agreement about solutions. The discussion summarises the shelter objectives and core strategies used by the social movement activists, and considers the success they have had. This includes reviewing their understanding of what success is and how success is achieved. Movement organisations have been able to secure access to the housing subsidy scheme for their members. However, their progress has been limited. The paper concludes that there is a primary focus on what is offered through state programmes and policies despite evident shortcomings. While there is an awareness of the misfit between available programmes, the needs of movement members and more general shelter needs, no fundamental challenge is being made to the dominant approach. A second finding is that while movement members and leaders have an explicit focus on material improvements, underlying their motivations and some of their strategies and actions is the more fundamental goal to be treated as equal citizens. In this dimension, movement organizations seek both recognition of their citizenship as well as the redistribution of state resources. Third, we argue that while social movement progress is related to the political opportunity structures, it also depends on the ability of movement organizations to manage the emerging opportunities, particularly their relationships with the state, professional support organizations and other movement organizations. Relations shift between contention and collaboration to improve negotiating positions, secure access to shelter and achieve greater political inclusion. PMID- 25844009 TI - An energy budget agent-based model of earthworm populations and its application to study the effects of pesticides. AB - Earthworms are important organisms in soil communities and so are used as model organisms in environmental risk assessments of chemicals. However current risk assessments of soil invertebrates are based on short-term laboratory studies, of limited ecological relevance, supplemented if necessary by site-specific field trials, which sometimes are challenging to apply across the whole agricultural landscape. Here, we investigate whether population responses to environmental stressors and pesticide exposure can be accurately predicted by combining energy budget and agent-based models (ABMs), based on knowledge of how individuals respond to their local circumstances. A simple energy budget model was implemented within each earthworm Eisenia fetida in the ABM, based on a priori parameter estimates. From broadly accepted physiological principles, simple algorithms specify how energy acquisition and expenditure drive life cycle processes. Each individual allocates energy between maintenance, growth and/or reproduction under varying conditions of food density, soil temperature and soil moisture. When simulating published experiments, good model fits were obtained to experimental data on individual growth, reproduction and starvation. Using the energy budget model as a platform we developed methods to identify which of the physiological parameters in the energy budget model (rates of ingestion, maintenance, growth or reproduction) are primarily affected by pesticide applications, producing four hypotheses about how toxicity acts. We tested these hypotheses by comparing model outputs with published toxicity data on the effects of copper oxychloride and chlorpyrifos on E. fetida. Both growth and reproduction were directly affected in experiments in which sufficient food was provided, whilst maintenance was targeted under food limitation. Although we only incorporate toxic effects at the individual level we show how ABMs can readily extrapolate to larger scales by providing good model fits to field population data. The ability of the presented model to fit the available field and laboratory data for E. fetida demonstrates the promise of the agent-based approach in ecology, by showing how biological knowledge can be used to make ecological inferences. Further work is required to extend the approach to populations of more ecologically relevant species studied at the field scale. Such a model could help extrapolate from laboratory to field conditions and from one set of field conditions to another or from species to species. PMID- 25844011 TI - Comments on Fifty Years of Classification and Regression Trees. PMID- 25844012 TI - The Subset Sum game. AB - In this work we address a game theoretic variant of the Subset Sum problem, in which two decision makers (agents/players) compete for the usage of a common resource represented by a knapsack capacity. Each agent owns a set of integer weighted items and wants to maximize the total weight of its own items included in the knapsack. The solution is built as follows: Each agent, in turn, selects one of its items (not previously selected) and includes it in the knapsack if there is enough capacity. The process ends when the remaining capacity is too small for including any item left. We look at the problem from a single agent point of view and show that finding an optimal sequence of items to select is an [Formula: see text]-hard problem. Therefore we propose two natural heuristic strategies and analyze their worst-case performance when (1) the opponent is able to play optimally and (2) the opponent adopts a greedy strategy. From a centralized perspective we observe that some known results on the approximation of the classical Subset Sum can be effectively adapted to the multi-agent version of the problem. PMID- 25844013 TI - Integrating stochastic time-dependent travel speed in solution methods for the dynamic dial-a-ride problem. AB - In urban areas, logistic transportation operations often run into problems because travel speeds change, depending on the current traffic situation. If not accounted for, time-dependent and stochastic travel speeds frequently lead to missed time windows and thus poorer service. Especially in the case of passenger transportation, it often leads to excessive passenger ride times as well. Therefore, time-dependent and stochastic influences on travel speeds are relevant for finding feasible and reliable solutions. This study considers the effect of exploiting statistical information available about historical accidents, using stochastic solution approaches for the dynamic dial-a-ride problem (dynamic DARP). The authors propose two pairs of metaheuristic solution approaches, each consisting of a deterministic method (average time-dependent travel speeds for planning) and its corresponding stochastic version (exploiting stochastic information while planning). The results, using test instances with up to 762 requests based on a real-world road network, show that in certain conditions, exploiting stochastic information about travel speeds leads to significant improvements over deterministic approaches. PMID- 25844015 TI - A uniform approach for programming distributed heterogeneous computing systems. AB - Large-scale compute clusters of heterogeneous nodes equipped with multi-core CPUs and GPUs are getting increasingly popular in the scientific community. However, such systems require a combination of different programming paradigms making application development very challenging. In this article we introduce libWater, a library-based extension of the OpenCL programming model that simplifies the development of heterogeneous distributed applications. libWater consists of a simple interface, which is a transparent abstraction of the underlying distributed architecture, offering advanced features such as inter-context and inter-node device synchronization. It provides a runtime system which tracks dependency information enforced by event synchronization to dynamically build a DAG of commands, on which we automatically apply two optimizations: collective communication pattern detection and device-host-device copy removal. We assess libWater's performance in three compute clusters available from the Vienna Scientific Cluster, the Barcelona Supercomputing Center and the University of Innsbruck, demonstrating improved performance and scaling with different test applications and configurations. PMID- 25844014 TI - The Impact of Military Deployment and Reintegration on Children and Parenting: A Systematic Review. AB - Hundreds of thousands of children have had at least 1 parent deploy as part of military operations in Iraq (Operation Iraqi Freedom; OIF; Operation New Dawn; OND) and Afghanistan (Operation Enduring Freedom; OEF). However, there is little knowledge of the impact of deployment on the relationship of parents and their children. This systematic review examines findings from 3 areas of relevant research: the impact of deployment separation on parenting, and children's emotional, behavioral, and health outcomes; the impact of parental mental health symptoms during and after reintegration; and current treatment approaches in veteran and military families. Several trends emerged. First, across all age groups, deployment of a parent may be related to increased emotional and behavioral difficulties for children, including higher rates of health-care visits for psychological problems during deployment. Second, symptoms of PTSD and depression may be related to increased symptomatology in children and problems with parenting during and well after reintegration. Third, although several treatments have been developed to address the needs of military families, most are untested or in the early stages of implementation and evaluation. This body of research suggests several promising avenues for future research. PMID- 25844017 TI - An almost symmetric Strang splitting scheme for nonlinear evolution equations. AB - In this paper we consider splitting methods for the time integration of parabolic and certain classes of hyperbolic partial differential equations, where one partial flow cannot be computed exactly. Instead, we use a numerical approximation based on the linearization of the vector field. This is of interest in applications as it allows us to apply splitting methods to a wider class of problems from the sciences. However, in the situation described, the classic Strang splitting scheme, while still being a method of second order, is not longer symmetric. This, in turn, implies that the construction of higher order methods by composition is limited to order three only. To remedy this situation, based on previous work in the context of ordinary differential equations, we construct a class of Strang splitting schemes that are symmetric up to a desired order. We show rigorously that, under suitable assumptions on the nonlinearity, these methods are of second order and can then be used to construct higher order methods by composition. In addition, we illustrate the theoretical results by conducting numerical experiments for the Brusselator system and the KdV equation. PMID- 25844016 TI - Early Exposure to Environmental Chaos and Children's Physical and Mental Health. AB - Environmental chaos has been proposed as a central influence impeding children's health and development, with the potential for particularly pernicious effects during the earliest years when children are most susceptible to environmental insults. This study evaluated a high-risk sample, following 495 low-income children living in poor urban neighborhoods from infancy to age 6. Longitudinal multilevel models tested the main tenets of the ecobiodevelopmental theory, finding that: (1) numerous distinct domains of environmental chaos were associated with children's physical and mental health outcomes, including housing disorder, neighborhood disorder, and relationship instability, with no significant results for residential instability; (2) different patterns emerged in relation to the timing of exposure to chaos, with more proximal exposure most strongly associated with children's functioning; and (3) the intensity of chaos also was a robust predictor of child functioning. Contrary to expectations, neither biological vulnerability (proxied through low birth weight status), maternal sensitivity, nor maternal distress moderated the role of chaos. Rather, maternal psychological distress functioned as a pathway through which environmental chaos was associated with children's functioning. PMID- 25844018 TI - On the error propagation of semi-Lagrange and Fourier methods for advection problems. AB - In this paper we study the error propagation of numerical schemes for the advection equation in the case where high precision is desired. The numerical methods considered are based on the fast Fourier transform, polynomial interpolation (semi-Lagrangian methods using a Lagrange or spline interpolation), and a discontinuous Galerkin semi-Lagrangian approach (which is conservative and has to store more than a single value per cell). We demonstrate, by carrying out numerical experiments, that the worst case error estimates given in the literature provide a good explanation for the error propagation of the interpolation-based semi-Lagrangian methods. For the discontinuous Galerkin semi Lagrangian method, however, we find that the characteristic property of semi Lagrangian error estimates (namely the fact that the error increases proportionally to the number of time steps) is not observed. We provide an explanation for this behavior and conduct numerical simulations that corroborate the different qualitative features of the error in the two respective types of semi-Lagrangian methods. The method based on the fast Fourier transform is exact but, due to round-off errors, susceptible to a linear increase of the error in the number of time steps. We show how to modify the Cooley-Tukey algorithm in order to obtain an error growth that is proportional to the square root of the number of time steps. Finally, we show, for a simple model, that our conclusions hold true if the advection solver is used as part of a splitting scheme. PMID- 25844019 TI - Effect of the Texel muscling QTL (TM-QTL) on spine characteristics in purebred Texel lambs. AB - Previous work showed that the Texel muscling QTL (TM-QTL) results in pronounced hypertrophy in the loin muscle, with the largest phenotypic effects observed in lambs inheriting a single copy of the allele from the sire. As the loin runs parallel to the spinal vertebrae, and the development of muscle and bone are closely linked, the primary aim of this study was to investigate if there were any subsequent associations between TM-QTL inheritance and underlying spine characteristics (vertebrae number, VN; spine region length, SPL; average length of individual vertebrae, VL) of the thoracic, lumbar, and thoracolumbar spine regions. Spine characteristics were measured from X-ray computed tomography (CT) scans for 142 purebred Texel lambs which had been previously genotyped. Least squares means were significantly different between genotype groups for lumbar and thoracic VN and lumbar SPL. Similarly for these traits, contrasts were shown to be significant for particular modes of gene action but overall were inconclusive. In general, the results showed little evidence that spine trait phenotypes were associated with differences in loin muscling associated with the different TM-QTL genotypes. PMID- 25844020 TI - Combining analytical frameworks to assess livelihood vulnerability to climate change and analyse adaptation options. AB - Experts working on behalf of international development organisations need better tools to assist land managers in developing countries maintain their livelihoods, as climate change puts pressure on the ecosystem services that they depend upon. However, current understanding of livelihood vulnerability to climate change is based on a fractured and disparate set of theories and methods. This review therefore combines theoretical insights from sustainable livelihoods analysis with other analytical frameworks (including the ecosystem services framework, diffusion theory, social learning, adaptive management and transitions management) to assess the vulnerability of rural livelihoods to climate change. This integrated analytical framework helps diagnose vulnerability to climate change, whilst identifying and comparing adaptation options that could reduce vulnerability, following four broad steps: i) determine likely level of exposure to climate change, and how climate change might interact with existing stresses and other future drivers of change; ii) determine the sensitivity of stocks of capital assets and flows of ecosystem services to climate change; iii) identify factors influencing decisions to develop and/or adopt different adaptation strategies, based on innovation or the use/substitution of existing assets; and iv) identify and evaluate potential trade-offs between adaptation options. The paper concludes by identifying interdisciplinary research needs for assessing the vulnerability of livelihoods to climate change. PMID- 25844021 TI - Correlating Mediterranean shallow water deposits with global Oligocene-Miocene stratigraphy and oceanic events. AB - Shallow-marine sediment records have the strong potential to display sensitive environmental changes in sedimentary geometries and skeletal content. However, the time resolution of most neritic carbonate records is not high enough to be compared with climatic events as recorded in the deep-sea sediment archives. In order to resolve the paleoceanographic and paleoclimatic changes during the Oligocene-Miocene transition in the Mediterranean shallow water carbonate systems with the best possible time resolution, we re-evaluated the Decontra section on the Maiella Platform (central Apennines, Italy), which acts as a reference for the correlation of Oligocene-Miocene shallow water deposits in the Mediterranean region. The 120-m-thick late Oligocene-late Miocene carbonate succession is composed of larger foraminiferal, bryozoan and corallinacean limestones interlayered with distinct planktonic foraminiferal carbonates representing a mostly outer neritic setting. Integrated multi-proxy and facies analyses indicate that CaCO3 and total organic carbon contents as well as gamma-ray display only local to regional processes on the carbonate platform and are not suited for stratigraphic correlation on a wider scale. In contrast, new biostratigraphic data correlate the Decontra stable carbon isotope record to the global deep-sea carbon isotope record. This links relative sea level fluctuations, which are reflected by facies and magnetic susceptibility changes, to third-order eustatic cycles. The new integrated bio-, chemo-, and sequence stratigraphic framework enables a more precise timing of environmental changes within the studied time interval and identifies Decontra as an important locality for correlating not only shallow and deep water sediments of the Mediterranean region but also on a global scale. PMID- 25844022 TI - Mid-Burdigalian Paratethyan alkenone record reveals link between orbital forcing, Antarctic ice-sheet dynamics and European climate at the verge to Miocene Climate Optimum. AB - The Early Ottnangian Cooling (EOC), a distinct cold-spell in European climate at ~ 18 Ma preceding the Miocene Climate Optimum, is frequently reported in Paratethys records; however, the duration, magnitude, and underlying causes are poorly understood. A new palaeoclimatic data-set provides unexpected insights into this event. UK'37-based sea-surface temperatures > 24 degrees C between ~ 18.1 and 17.7 Myrs substantially exceed existing estimates, and indicate a significantly warmer European climate than previously assumed for this usually poorly recovered time interval. The EOC is expressed as an average drop of 2-3 degrees C in Paratethyan water temperatures between ~ 18.1 and 17.8 Myrs with two distinct cold snaps at ~ 17.86 Ma and ~ 17.81 Ma. The short duration of the EOC excludes Tethyan Seaway closure as its underlying cause, although the enhanced palaeoclimatic sensitivity of the Paratethys due to this palaeogeographic configuration potentially contributed to the magnitude of SST deterioration during the EOC. The revealed palaeoclimatic pattern shows a strong correlation with isotope event Mi-1b in deep-sea delta18O records, and we propose a tight palaeoclimatic link between the Southern Ocean and the Paratethys/Mediterranean realm as an alternative hypothesis. The interplay of modulations in the long-term (~ 400 kyrs) and short-term (~ 100 kyrs) eccentricity cycles most likely acted as pacemaker of this palaeoclimatic interaction. PMID- 25844023 TI - An acoustic transmission sensor for the longitudinal viscosity of fluids. AB - Physical fluid parameters like viscosity, mass density and sound velocity can be determined utilizing ultrasonic sensors. We introduce the concept of a recently devised transmission based sensor utilizing pressure waves to determine the longitudinal viscosity, bulk viscosity, and second coefficient of viscosity of a sample fluid in a test chamber. A model is presented which allows determining these parameters from measurement values by means of a fit. The setup is particularly suited for liquids featuring higher viscosities for which measurement data are scarcely available to date. The setup can also be used to estimate the sound velocity in a simple manner from the phase of the transfer function. PMID- 25844024 TI - A microfluidic device for the hydrodynamic immobilisation of living fission yeast cells for super-resolution imaging. AB - We describe a microfluidic device designed specifically for the reversible immobilisation of Schizosaccharomyces pombe (Fission Yeast) cells to facilitate live cell super-resolution microscopy. Photo-Activation Localisation Microscopy (PALM) is used to create detailed super-resolution images within living cells with a modal accuracy of >25 nm in the lateral dimensions. The novel flow design captures and holds cells in a well-defined array with minimal effect on the normal growth kinetics. Cells are held over several hours and can continue to grow and divide within the device during fluorescence imaging. PMID- 25844025 TI - Thermo-optical characterization of fluorescent rhodamine B based temperature sensitive nanosensors using a CMOS MEMS micro-hotplate. AB - A custom designed microelectromechanical systems (MEMS) micro-hotplate, capable of operating at high temperatures (up to 700 degrees C), was used to thermo optically characterize fluorescent temperature-sensitive nanosensors. The nanosensors, 550 nm in diameter, are composed of temperature-sensitive rhodamine B (RhB) fluorophore which was conjugated to an inert silica sol-gel matrix. Temperature-sensitive nanosensors were dispersed and dried across the surface of the MEMS micro-hotplate, which was mounted in the slide holder of a fluorescence confocal microscope. Through electrical control of the MEMS micro-hotplate, temperature induced changes in fluorescence intensity of the nanosensors was measured over a wide temperature range. The fluorescence response of all nanosensors dispersed across the surface of the MEMS device was found to decrease in an exponential manner by 94%, when the temperature was increased from 25 degrees C to 145 degrees C. The fluorescence response of all dispersed nanosensors across the whole surface of the MEMS device and individual nanosensors, using line profile analysis, were not statistically different (p < 0.05). The MEMS device used for this study could prove to be a reliable, low cost, low power and high temperature micro-hotplate for the thermo-optical characterisation of sub-micron sized particles. The temperature-sensitive nanosensors could find potential application in the measurement of temperature in biological and micro-electrical systems. PMID- 25844026 TI - The global metabolic transition: Regional patterns and trends of global material flows, 1950-2010. AB - Since the World War II, many economies have transitioned from an agrarian, biomass-based to an industrial, minerals-based metabolic regime. Since 1950, world population grew by factor 2.7 and global material consumption by factor 3.7 71 Gigatonnes per year in 2010. The expansion of the resource base required by human societies is associated with growing pressure on the environment and infringement on the habitats of other species. In order to achieve a sustainability transition, we require a better understanding of the currently ongoing metabolic transition and its potential inertia. In this article, we present a long-term global material flow dataset covering material extraction, trade, and consumption of 177 individual countries between 1950 and 2010. We trace patterns and trends in material flows for six major geographic and economic country groupings and world regions (Western Industrial, the (Former) Soviet Union and its allies, Asia, the Middle East and Northern Africa, Latin America and the Caribbean, and Sub-Saharan Africa) as well as their contribution to the emergence of a global metabolic profile during a period of rapid industrialization and globalization. Global average material use increased from 5.0 to 10.3 tons per capita and year (t/cap/a) between 1950 and 2010. Regional metabolic rates range from 4.5 t/cap/a in Sub-Saharan Africa to 14.8 t/cap/a in the Western Industrial grouping. While we can observe a stabilization of the industrial metabolic profile composed of relatively equal shares of biomass, fossil energy carriers, and construction minerals, we note differences in the degree to which other regions are gravitating toward a similar form of material use. Since 2000, Asia has overtaken the Western Industrial grouping in terms of its share in global resource use although not in terms of its per capita material consumption. We find that at a sub-global level, the roles of the world regions have changed. There are, however, no signs yet that this will lead to stabilization or even a reduction of global resource use. PMID- 25844027 TI - Exploring the effects of drastic institutional and socio-economic changes on land system dynamics in Germany between 1883 and 2007. AB - Long-term studies of land system change can help providing insights into the relative importance of underlying drivers of change. Here, we analyze land system change in Germany for the period 1883-2007 to trace the effect of drastic socio economic and institutional changes on land system dynamics. Germany is an especially interesting case study due to fundamentally changing economic and institutional conditions: the two World Wars, the separation into East and West Germany, the accession to the European Union, and Germany's reunification. We employed the Human Appropriation of Net Primary Production (HANPP) framework to comprehensively study long-term land system dynamics in the context of these events. HANPP quantifies biomass harvests and land-use-related changes in ecosystem productivity. By comparing these flows to the potential productivity of ecosystems, HANPP allows to consistently assess land cover changes as well as changes in land use intensity. Our results show that biomass harvest steadily increased while productivity losses declined from 1883 to 2007, leading to a decline in HANPP from around 75%-65% of the potential productivity. At the same time, decreasing agricultural areas allowed for forest regrowth. Overall, land system change in Germany was surprisingly gradual, indicating high resilience to the drastic socio-economic and institutional shifts that occurred during the last 125 years. We found strikingly similar land system trajectories in East and West Germany during the time of separation (1945-1989), despite the contrasting institutional settings and economic paradigms. Conversely, the German reunification sparked a fundamental and rapid shift in former East Germany's land system, leading to altered levels of production, land use intensity and land use efficiency. Gradual and continuous land use intensification, a result of industrialization and economic optimization of land use, was the dominant trend throughout the observed period, apparently overruling socio-economic framework conditions and land use policies. PMID- 25844028 TI - Health Neuroscience: Defining a New Field. AB - Health neuroscience is a new field that is at the interface of health psychology and neuroscience. It is concerned with the interplay between the brain and physical health over the lifespan. This review provides a conceptual introduction to health neuroscience, focusing on its major themes, representative studies, methodologies, and future directions. PMID- 25844029 TI - Electronic cleansing for dual-energy CT colonography based on material decomposition and virtual monochromatic imaging. AB - CT colonography (CTC) uses orally administered fecal-tagging agents to enhance retained fluid and feces that would otherwise obscure or imitate polyps on CTC images. To visualize the complete region of colon without residual materials, electronic cleansing (EC) can be used to perform virtual subtraction of the tagged materials from CTC images. However, current EC methods produce subtraction artifacts and they can fail to subtract unclearly tagged feces. We developed a novel multi-material EC (MUMA-EC) method that uses dual-energy CTC (DE-CTC) and machine-learning methods to improve the performance of EC. In our method, material decomposition is performed to calculate water-iodine decomposition images and virtual monochromatic (VIM) images. Using the images, a random forest classifier is used to label the regions of lumen air, soft tissue, fecal tagging, and their partial-volume boundaries. The electronically cleansed images are synthesized from the multi-material and VIM image volumes. For pilot evaluation, we acquired the clinical DE-CTC data of 7 patients. Preliminary results suggest that the proposed MUMA-EC method is effective and that it minimizes the three types of image artifacts that were present in previous EC methods. PMID- 25844030 TI - Pulmonary edema following generalized tonic clonic seizures is directly associated with seizure duration. AB - PURPOSE: Postictal pulmonary edema (PPE) is almost invariably present in human and animal cases of sudden unexpected death in epilepsy (SUDEP) coming to autopsy. PPE may be a contributing factor in SUDEP. The incidence of postictal PPE is unknown. We retrospectively investigated PPE following generalized tonic clonic seizures (GTCS) in the epilepsy monitoring unit. METHODS: Chest X-Rays (CXR) following each GTCS were obtained in 24 consecutive patients. Relationship of CXR abnormality to seizure duration, ictal/postictal oxygen desaturation (SpO2), apnea and presence of postictal generalized EEG suppression (PGES) was investigated using logistic regression. RESULTS: Eleven of 24 patients had CXR abnormalities following a GTCS. In these 11 patients, 22 CXR were obtained and abnormalities were present in 15 CXR. Abnormalities included PPE in 7 patients, of which 2 also had focal infiltrates. In 4 patients focal infiltrates were present without PPE. There was no significant difference in mean time to CXR (225 min) following GTCS in the abnormal CXR group versus the normal group of patients (196 min). Mean preceding seizure duration was longer (p=0.002) in GTCS with abnormal CXR (259.7 sec) versus GTCS with normal CXR (101.2 sec). Odds-ratio for CXR abnormality was 20.46 (p=0.006) with seizure duration greater than 100 sec versus less than 100 sec. On multivariable analysis, only the seizure duration was a significant predictor of CXR abnormality (p=0.015). CONCLUSIONS: Radiographic abnormalities are not uncommon following GTCS. The presence of CXR abnormality is significantly associated with the duration of the preceding GTCS. Severe, untreated PPE may be relevant to the pathophysiology of SUDEP. PMID- 25844031 TI - Associations of Parent-Child Anxious and Depressive Symptoms When a Caregiver Has a History of Depression. AB - We examined the associations between parent and child anxious and depressive symptoms controlling for co-occurring symptoms in both. One hundred and four families participated, including 131 9-15 year old children considered at risk for anxiety and/or depression due to a history of depression in a parent. Parents and children completed questionnaires assessing depressive and anxious symptoms. Linear Mixed Models analyses controlling for the alternate parent and child symptoms indicated that both parent and child depressive symptoms and parent and child anxious symptoms were positively associated. Parental depressive symptoms were not positively associated with child anxious symptoms, and parental anxious symptoms were not positively associated with child depressive symptoms. The findings provide evidence for positive specific links between parent and child development of same-syndrome, but not cross-syndrome, symptoms when a caregiver has a history of depression. PMID- 25844032 TI - Stimulus Fading and Response Elaboration in Differential Reinforcement for Alternative Behavior. AB - A hallmark of applied behavior analysis is the development of function-based interventions for problem behavior. A widely recommended function-based intervention is differential reinforcement of alternative behavior (DRA), in which reinforcement is contingent upon socially acceptable alternatives to problem behavior (e.g., teaching communication skills). Typically, DRA is introduced under rich schedules of reinforcement. Although effective for initiating behavior change, rich schedules are often impractical in the natural setting. In this study, we evaluated the extent to which a stimulus fading program could be employed to elaborate alternative behavior (mands) in two individuals diagnosed with an Autism Spectrum Disorder. For both participants, problem behavior was reduced substantially upon implementation of the DRA procedure. Further, problem behavior rates remained low and mand rates decreased to more practical levels as the DRA behavioral requirements increased during the fading program. The fading approach demonstrated in this paper may be a useful component of intervention packages for clinicians. PMID- 25844033 TI - Impact and factors associated with nighttime and early morning symptoms among patients with chronic obstructive pulmonary disease. AB - Patients with chronic obstructive pulmonary disease (COPD) exhibit poor sleep quality and consider morning as the worst time of day for their symptoms. While work has been done to characterize nighttime (NT) and early morning (EM) symptoms in various populations, the impact and factors associated with NT/EM symptoms among patients with COPD in the United States is not well understood. Commercially insured patients aged >=40 years with one or more medical claim for COPD and one or more pharmacy claim for COPD maintenance medication were identified from the HealthCore Integrated Research Database between September 1, 2010 and August 31, 2011. Consenting respondents were asked whether they had COPD symptoms on at least three nights or at least three mornings during the past week. Respondents were then either assigned to one of three symptom groups to complete the survey or excluded if their predefined group quota limit had been met. Survey completers completed the survey with questions about COPD symptoms and other commonly used patient-reported outcome measures. Respondents with NT/EM symptoms were asked about the frequency, severity, and impact of the symptoms on sleep, morning activities, and anxiety levels. Among respondents with symptoms, 73.1% of respondents with NT symptoms (N=376) and 83% of respondents with EM symptoms (N=506) experienced at least three distinct types of symptoms over the past week, with cough being the most frequently reported symptom. Approximately half of respondents with NT or EM symptoms perceived their symptoms as moderate to very severe, with a majority reporting their symptoms affected their NT sleep and morning activities, and more than half felt anxious due to their symptoms. Multinomial logistic regression showed COPD patients with both or either NT/EM symptoms were associated with poorer health status compared to those without. Improved disease management may reduce NT/EM symptoms and improve health status in patients with COPD. PMID- 25844034 TI - Elevated plasma levels of pigment epithelium-derived factor correlated with inflammation and lung function in COPD patients. AB - RATIONALE: Pigment epithelium-derived factor (PEDF) is a 50 kD small secreting glycoprotein that participates in multiple physiological and pathological processes. Recent studies have reported that PEDF plays an important role in inflammatory responses in several diseases. However, the role of PEDF in the pathogenesis of chronic obstructive pulmonary disease (COPD) remains unclear. OBJECTIVE: The aim of the present study is to explore the potential relationship between PEDF and COPD. METHODS: We used differential proteomics - stable isotope labeling with amino acids in cell culture - to investigate protein expression profile changes in cigarette smoke extract-treated pulmonary cells and found that the neurotrophic and antiangiogenic protein PEDF was abnormally expressed. Furthermore, Western blotting was used to detect the expression of PEDF in the lung tissue of rats that were exposed to cigarette smoke. Eighty subjects between the ages of 40-90 years, including 20 healthy nonsmokers, ten smoking volunteers, and 50 COPD patients, were recruited from September 2012 until August 2013 in Sichuan Province, People's Republic of China. We measured the plasma PEDF concentration and classic proinflammatory cytokines by multiplex enzyme-linked immunosorbent assay. In addition, we performed a spirometry examination to diagnose COPD patients and we also analyzed the correlation between PEDF and lung function. RESULTS: First, we found that the expression of PEDF in cigarette smoke extract-treated cells increased 16.2-fold when compared with the control group. Next, we confirmed that 4 weeks' exposure to cigarette smoke can upregulate PEDF levels in rat lung tissues. We also discovered that plasma PEDF in COPD patients was significantly increased when compared with either healthy nonsmoking or smoking subjects. Furthermore, circulating PEDF was correlated with inflammatory cytokine and blood neutrophil numbers, but it was reversely associated with a decline in forced expiratory volume in 1 second percent predicted. CONCLUSION: Our findings provide a novel link between PEDF and COPD. Elevated PEDF levels may be involved in promoting the development of COPD by performing proinflammatory functions. PMID- 25844035 TI - Study of antitumor activity in breast cell lines using silver nanoparticles produced by yeast. AB - In the present article, we describe a study of antitumor activity in breast cell lines using silver nanoparticles (Ag NPs) synthesized by a microbiological method. These Ag NPs were tested for their antitumor activity against MCF7 and T47D cancer cells and MCF10-A normal breast cell line. We analyzed cell viability, apoptosis induction, and endocytosis activity of those cell lines and we observed that the effects of the biosynthesized Ag NPs were directly related with the endocytosis activity. Moreover, Ag NPs had higher inhibition efficacy in tumor lines than in normal lines of breast cells, which is due to the higher endocytic activity of tumor cells compared to normal cells. In this way, we demonstrate that biosynthesized Ag NPs can be an alternative for the treatment of tumors. PMID- 25844036 TI - Enhancing the anti-colon cancer activity of quercetin by self-assembled micelles. AB - Colorectal cancer, a type of malignant neoplasm originating from the epithelial cells lining the colon and/or rectum, has been the third most frequent malignancy and one of the leading causes of cancer-related deaths in the US. As a bioflavonoid with high anticancer potential, quercetin (Qu) has been proved to have a prospective applicability in chemotherapy for a series of cancers. However, quercetin is a hydrophobic drug, the poor hydrophilicity of which hinders its clinical usage in cancer therapy. Therefore, a strategy to improve the solubility of quercetin in water and/or enhance the bioavailability is desired. Encapsulating the poorly water-soluble, hydrophobic agents into polymer micelles could facilitate the dissolution of drugs in water. In our study, nanotechnology was employed, and quercetin was encapsulated into the biodegradable nanosized amphiphilic block copolymers of monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone) (MPEG-PCL), attempting to present positive evidences that this drug delivery system of polymeric micelles is effective. The quercetin-loaded MPEG-PCL nanomicelles (Qu-M), with a high drug loading of 6.85% and a minor particle size of 34.8 nm, completely dispersed in the water and released quercetin in a prolonged period in vitro and in vivo. At the same time, compared with free quercetin, Qu-M exhibited improved apoptosis induction and cell growth inhibition effects in CT26 cells in vitro. Moreover, the mice subcutaneous CT26 colon cancer model was established to evaluate the therapy efficiency of Qu-M in detail, in which enhanced anti-colon cancer effect was proved in vivo: Qu-M were more efficacious in repressing the growth of colon tumor than free quercetin. In addition, better effects of Qu-M on inducing cell apoptosis, inhibiting tumor angiogenesis, and restraining cell proliferation were observed by immunofluorescence analysis. Our study indicated that Qu-M were a novel nanoagent of quercetin with an enhanced antitumor activity, which could serve as a promising potential candidate for colon cancer chemotherapy. PMID- 25844037 TI - Treating cancer stem cells and cancer metastasis using glucose-coated gold nanoparticles. AB - Cancer ranks among the leading causes of human mortality. Cancer becomes intractable when it spreads from the primary tumor site to various organs (such as bone, lung, liver, and then brain). Unlike solid tumor cells, cancer stem cells and metastatic cancer cells grow in a non-attached (suspension) form when moving from their source to other locations in the body. Due to the non-attached growth nature, metastasis is often first detected in the circulatory systems, for instance in a lymph node near the primary tumor. Cancer research over the past several decades has primarily focused on treating solid tumors, but targeted therapy to treat cancer stem cells and cancer metastasis has yet to be developed. Because cancers undergo faster metabolism and consume more glucose than normal cells, glucose was chosen in this study as a reagent to target cancer cells. In particular, by covalently binding gold nanoparticles (GNPs) with thio-PEG (polyethylene glycol) and thio-glucose, the resulting functionalized GNPs (Glu GNPs) were created for targeted treatment of cancer metastasis and cancer stem cells. Suspension cancer cell THP-1 (human monocytic cell line derived from acute monocytic leukemia patients) was selected because it has properties similar to cancer stem cells and has been used as a metastatic cancer cell model for in vitro studies. To take advantage of cancer cells' elevated glucose consumption over normal cells, different starvation periods were screened in order to achieve optimal treatment effects. Cancer cells were then fed using Glu-GNPs followed by X-ray irradiation treatment. For comparison, solid tumor MCF-7 cells (breast cancer cell line) were studied as well. Our irradiation experimental results show that Glu-GNPs are better irradiation sensitizers to treat THP-1 cells than MCF-7 cells, or Glu-GNPs enhance the cancer killing of THP-1 cells 20% more than X-ray irradiation alone and GNP treatment alone. This finding can help oncologists to design therapeutic strategies to target cancer stem cells and cancer metastasis. PMID- 25844038 TI - Hydroxypropylcellulose as a novel green reservoir for the synthesis, stabilization, and storage of silver nanoparticles. AB - Polysaccharides are attracting the vigil eye of researchers in order to design the green synthesis of silver nanoparticles (Ag NPs) of diverse size, shape, and application. We report an environmentally friendly method to synthesize Ag NPs where no physical reaction conditions were employed. Hydroxypropylcellulose (HPC) was used as a template nanoreactor, stabilizer, and capping agent to obtain Ag NPs. Different concentrations of AgNO3 solutions (50 mmol, 75 mmol, and 100 mmol) were mixed with a concentrated aqueous solution of HPC and the progress of the reaction was monitored by noting color changes of the reaction mixture at different reaction times for up to 24 hours. Characteristic ultraviolet-visible spectroscopy (UV/Vis) absorption bands of Ag NPs were observed in the range of 388-452 nm. The morphology of the Ag NPs was studied by scanning electron microscopy, transmission electron microscopy (TEM), and atomic force microscopy. The TEM images confirmed that the size of the Ag NPs was in the range of 25-55 nm. Powder X-ray diffraction studies showed that the crystal phase of the Ag NPs was face-centered cubic. The as-prepared Ag NPs were found to be stable, and no changes in size and morphology were observed after storage in HPC thin films over 1 year, as indicated by UV/Vis spectra. So, the present work furnishes a green and economical strategy for the synthesis and storage of stable Ag NPs. As synthesized Ag NPs showed significant antimicrobial activity against different bacterial (Escherichia coli, Staphylococcus epidermidis, S. aureus, Bacillus subtilis, Pseudomonas aeruginosa) and fungal strains (Actinomycetes and Aspergillus niger). PMID- 25844039 TI - Folate-modified lipid-polymer hybrid nanoparticles for targeted paclitaxel delivery. AB - The purpose of this study was to develop a novel lipid-polymer hybrid drug carrier comprised of folate (FA) modified lipid-shell and polymer-core nanoparticles (FLPNPs) for sustained, controlled, and targeted delivery of paclitaxel (PTX). The core-shell NPs consist of 1) a poly(epsilon-caprolactone) hydrophobic core based on self-assembly of poly(epsilon-caprolactone) poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL) amphiphilic copolymers, 2) a lipid monolayer formed with 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000), 3) a targeting ligand (FA) on the surface, and were prepared using a thin-film hydration and ultrasonic dispersion method. Transmission electron microscopy and dynamic light scattering analysis confirmed the coating of the lipid monolayer on the hydrophobic polymer core. Physicochemical characterizations of PTX-loaded FLPNPs, such as particle size and size distribution, zeta potential, morphology, drug loading content, encapsulation efficiency, and in vitro drug release, were also evaluated. Fluorescent microscopy proved the internalization efficiency and targeting ability of the folate conjugated on the lipid monolayer for the EMT6 cancer cells which overexpress folate receptor. In vitro cytotoxicity assay demonstrated that the cytotoxic effect of PTX-loaded FLPNPs was lower than that of Taxol((r)), but higher than that of PTX-loaded LPNPs (without folate conjugation). In EMT6 breast tumor model, intratumoral administration of PTX loaded FLPNPs showed similar antitumor efficacy but low toxicity compared to Taxol((r)). More importantly, PTX-loaded FLPNPs showed greater tumor growth inhibition (65.78%) than the nontargeted PTX-loaded LPNPs (48.38%) (P<0.05). These findings indicated that the PTX loaded-FLPNPs with mixed lipid monolayer shell and biodegradable polymer core would be a promising nanosized drug formulation for tumor-targeted therapy. PMID- 25844040 TI - The acceptability of nanocarriers for drug delivery in different contexts of use: perceptions of researchers and research trainees in the field of new technologies. AB - BACKGROUND: Despite marked optimism in the field of nanomedicine about the use of drug-delivery nanocarriers, uncertainties exist concerning nanocarriers' possible unintended impacts and effects. These uncertainties could affect user acceptance and acceptability. "Acceptance" refers to the intention to put a technology or a device to a specified use. "Acceptability" refers to a value judgment that accounts for acceptance. The objectives of this study were to characterize impact perception, acceptance, and acceptability in relation to drug-delivery nanocarriers in different contexts of use, and to explore relationships among these concepts. METHODS: A sample of European and Canadian researchers and graduate research trainees active in the field of new technologies was recruited by targeted email invitation for participation in a web-based questionnaire study. The questionnaire presented scenarios for two contexts of use (lung cancer, seasonal flu) of drug-delivery nanocarriers with two compositions (carbon, synthetic DNA). Respondents' impact perception, acceptance, and acceptability judgment in relation to each kind of nanocarrier in each context of use were measured with Likert scale questions and scored using categorical values. RESULTS: Two hundred and fourteen researchers and graduate research trainees completed the questionnaire. The results showed that nanocarrier composition influenced impact perception: as compared with the carbon nanocarrier impact perception, the positive impacts of the synthetic DNA nanocarrier were perceived as more significant and more likely to occur than its negative impacts. Composition did not influence acceptance or acceptability. Context of use significantly influenced acceptance and acceptability of both kinds of nanocarriers: researchers were more likely to accept the use of nanocarriers to treat lung cancer than the seasonal flu. The results also showed a significant relationship between acceptance and the perceived usefulness of the treatments. CONCLUSION: Nanocarrier composition does not appear to influence acceptance or acceptability. On the other hand, the nanocarriers' perceived usefulness and context of use are both major factors in accounting for acceptance and acceptability. PMID- 25844041 TI - Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss. AB - BACKGROUND: PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model. METHODS: We used a CreER-linked Keratin 18 mouse model to conditionally delete Pten, Vhl or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1alpha expression and clinical outcomes. RESULTS: Both Pten deletion genotypes developed liver tumors, but with differing phenotypes. Pten deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of Pten and Vhl with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1alpha expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered. CONCLUSION: Pten deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of Vhl and Pten results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes. PMID- 25844042 TI - Temporal variation of traffic on highways and the development of accurate temporal allocation factors for air pollution analyses. AB - Traffic activity encompasses the number, mix, speed and acceleration of vehicles on roadways. The temporal pattern and variation of traffic activity reflects vehicle use, congestion and safety issues, and it represents a major influence on emissions and concentrations of traffic-related air pollutants. Accurate characterization of vehicle flows is critical in analyzing and modeling urban and local-scale pollutants, especially in near-road environments and traffic corridors. This study describes methods to improve the characterization of temporal variation of traffic activity. Annual, monthly, daily and hourly temporal allocation factors (TAFs), which describe the expected temporal variation in traffic activity, were developed using four years of hourly traffic activity data recorded at 14 continuous counting stations across the Detroit, Michigan, U.S. region. Five sites also provided vehicle classification. TAF-based models provide a simple means to apportion annual average estimates of traffic volume to hourly estimates. The analysis shows the need to separate TAFs for total and commercial vehicles, and weekdays, Saturdays, Sundays and observed holidays. Using either site-specific or urban-wide TAFs, nearly all of the variation in historical traffic activity at the street scale could be explained; unexplained variation was attributed to adverse weather, traffic accidents and construction. The methods and results presented in this paper can improve air quality dispersion modeling of mobile sources, and can be used to evaluate and model temporal variation in ambient air quality monitoring data and exposure estimates. PMID- 25844043 TI - Compression stiffening of brain and its effect on mechanosensing by glioma cells. AB - Many cell types, including neurons, astrocytes and other cells of the central nervous system respond to changes in extracellular matrix or substrate viscoelasticity, and increased tissue stiffness is a hallmark of several disease states including fibrosis and some types of cancers. Whether the malignant tissue in brain, an organ that lacks the protein-based filamentous extracellular matrix of other organs, exhibits the same macroscopic stiffening characteristic of breast, colon, pancreatic, and other tumors is not known. In this study we show that glioma cells like normal astrocytes, respond strongly in vitro to substrate stiffness in the range of 100 to 2000 Pa, but that macroscopic (mm to cm) tissue samples isolated from human glioma tumors have elastic moduli on the order of 200 Pa that are indistinguishable from those of normal brain. However, both normal brain and glioma tissues increase their shear elastic moduli under modest uniaxial compression, and glioma tissue stiffens more strongly under compression than does normal brain. These findings suggest that local tissue stiffness has the potential to alter glial cell function, and that stiffness changes in brain tumors might arise not from increased deposition or crosslinking of collagen-rich extracellular matrix but from pressure gradients that form within the tumors in vivo. PMID- 25844044 TI - Emerging of fractal geometry on surface of human cervical epithelial cells during progression towards cancer. AB - Despite considerable advances in understanding the molecular nature of cancer, many biophysical aspects of malignant development are still unclear. Here we study physical alterations of the surface of human cervical epithelial cells during stepwise in vitro development of cancer (from normal to immortal (premalignant), to malignant). We use atomic force microscopy to demonstrate that development of cancer is associated with emergence of simple fractal geometry on the cell surface. Contrary to the previously expected correlation between cancer and fractals, we find that fractal geometry occurs only at a limited period of development when immortal cells become cancerous; further cancer progression demonstrates deviation from fractal. Because of the connection between fractal behaviour and chaos (or far from equilibrium behaviour), these results suggest that chaotic behaviour coincides with the cancer transformation of the immortalization stage of cancer development, whereas further cancer progression recovers determinism of processes responsible for cell surface formation. PMID- 25844045 TI - Amphitrite: A program for processing travelling wave ion mobility mass spectrometry data. AB - Since the introduction of travelling wave (T-Wave)-based ion mobility in 2007 a large number of research laboratories have embraced the technique, particularly those working in the field of structural biology. The development of software to process the data generated from this technique, however, has been limited. We present a novel software package that enables the processing of T-Wave ion mobility data. The program can deconvolute components in a mass spectrum and uses this information to extract corresponding arrival time distributions (ATDs) with minimal user intervention. It can also be used to automatically create a collision cross section (CCS) calibration and apply this to subsequent files of interest. A number of applications of the software, and how it enhances the information content extracted from the raw data, are illustrated using model proteins. PMID- 25844046 TI - A tale of a tail: Structural insights into the conformational properties of the polyglutamine protein ataxin-3. AB - Ataxin-3 is the protein responsible for the neurodegenerative polyglutamine disease Spinocerebellar ataxia type 3. Full structural characterisation of ataxin 3 is required to aid in understanding the mechanism of disease. Despite extensive study, little is known about the conformational properties of the full-length protein, in either its non-expanded healthy or expanded pathogenic forms, particularly since its polyglutamine-containing region has denied structural elucidation. In this work, travelling-wave ion mobility spectrometry-mass spectrometry and limited proteolysis have been used to compare the conformational properties of full-length non-expanded ataxin-3 (14Q) and its isolated N-terminal Josephin domain (JD). Limited proteolysis experiments have confirmed that the JD is stable, being extremely resistant to trypsin digestion, with the exception of the alpha2/alpha3 hairpin which is flexible and exposed to protease cleavage in solution. The C-terminal region of ataxin-3 which contains the glutamine-rich sequences is largely unstructured, showing little resistance to limited proteolysis. Using ion mobility spectrometry-mass spectrometry we show that ataxin-3 (14Q) adopts a wide range of conformational states in vitro conferred by the flexibility of its C-terminal tail and the alpha2/alpha3 hairpin of the N terminal JD. This study highlights how the power of MS-based approaches to protein structural characterisation can be particularly useful when the target protein is aggregation-prone and has intrinsically unordered regions. PMID- 25844047 TI - Decorating (C60) n+, n = 1-3, with CO2 at low temperatures: Sterically enhanced physisorption. AB - Multiple attachment of CO2 to the monomer, dimer and trimer cations of C60 has been observed in the mass spectra of He nanodroplets sequentially doped with C60 and CO2 and exposed to electron ionization at 50 eV. Remarkable anomalies were seen in the ion yield for CO2 coverage for (C60)2+(CO2)8 and (C60)3+(CO2)1,2. These provide insight into the influence of steric properties on the nature of physisorption. The enhanced stabilities of (C60)2+(CO2)8 and (C60)3+(CO2)1,2 are attributed to physisorption inside the "groove" of the dimer and the two "dimples" in the trimer cations of C60. Molecular dynamics simulations provide a qualitative assessment of the observed physisorption and a useful visualization of structural aspects. PMID- 25844048 TI - Headspace analysis of new psychoactive substances using a Selective Reagent Ionisation-Time of Flight-Mass Spectrometer. AB - The rapid expansion in the number and use of new psychoactive substances presents a significant analytical challenge because highly sensitive instrumentation capable of detecting a broad range of chemical compounds in real-time with a low rate of false positives is required. A Selective Reagent Ionisation-Time of Flight-Mass Spectrometry (SRI-ToF-MS) instrument is capable of meeting all of these requirements. With its high mass resolution (up to m/Deltam of 8000), the application of variations in reduced electric field strength (E/N) and use of different reagent ions, the ambiguity of a nominal (monoisotopic) m/z is reduced and hence the identification of chemicals in a complex chemical environment with a high level of confidence is enabled. In this study we report the use of a SRI ToF-MS instrument to investigate the reactions of H3O+, O2+, NO+ and Kr+ with 10 readily available (at the time of purchase) new psychoactive substances, namely 4 fluoroamphetamine, methiopropamine, ethcathinone, 4-methylethcathinone, N ethylbuphedrone, ethylphenidate, 5-MeO-DALT, dimethocaine, 5-(2 aminopropyl)benzofuran and nitracaine. In particular, the dependence of product ion branching ratios on the reduced electric field strength for all reagent ions was investigated and is reported here. The results reported represent a significant amount of new data which will be of use for the development of drug detection techniques suitable for real world scenarios. PMID- 25844050 TI - Structure elucidation of chlorophyll catabolites (phyllobilins) by ESI-mass spectrometry-Pseudo-molecular ions and fragmentation analysis of a nonfluorescent chlorophyll catabolite (NCC). AB - The hyphenation of high performance chromatography with modern mass spectrometric techniques providing high-resolution data as well as structural information from MS/MS experiments has become a versatile tool for rapid natural product identification and characterization. A recent application of this methodology concerned the investigation of the annually occurring degradation of green plant pigments. Since the first structural elucidation of a breakdown product in the early 1990s, a number of similarly structured, tetrapyrrolic catabolites have been discovered with the help of chromatographic, spectroscopic and spectrometric methods. A prerequisite for a satisfactory, manually operated or database supported analysis of mass spectrometric fragmentation patterns is a deeper knowledge of the underlying gas phase chemistry. Still, a thorough investigation of the common fragmentation behavior of these ubiquitous, naturally occurring chlorophyll breakdown products is lacking. This study closes the gap and gives a comprehensive overview of collision-induced fragmentation reactions of a tetrapyrrolic nonfluorescent chlorophyll catabolite, which is intended to serve as a model compound for the substance class of phyllobilins. PMID- 25844049 TI - Product ion distributions for the reactions of NO+ with some physiologically significant aldehydes obtained using a SRI-TOF-MS instrument. AB - Product ion distributions for the reactions of NO+ with 22 aldehydes involved in human physiology have been determined under the prevailing conditions of a selective reagent ionization time of flight mass spectrometry (SRI-TOF-MS) at an E/N in the flow/drift tube reactor of 130 Td. The chosen aldehydes were fourteen alkanals (the C2-C11 n-alkanals, 2-methyl propanal, 2-methyl butanal, 3-methyl butanal, and 2-ethyl hexanal), six alkenals (2-propenal, 2-methyl 2-propenal, 2 butenal, 3-methyl 2-butenal, 2-methyl 2-butenal, and 2-undecenal), benzaldehyde, and furfural. The product ion fragmentations patterns were determined for both dry air and humid air (3.5% absolute humidity) used as the matrix buffer/carrier gas in the drift tube of the SRI-TOF-MS instrument. Hydride ion transfer was seen to be a common ionization mechanism in all these aldehydes, thus generating (M H)+ ions. Small fractions of the adduct ion, NO+M, were also seen for some of the unsaturated alkenals, in particular 2-undecenal, and heterocyclic furfural for which the major reactive channel was non-dissociative charge transfer generating the M+ parent ion. Almost all of the reactions resulted in partial fragmentation of the aldehyde molecules generating hydrocarbon ions; specifically, the alkanal reactions resulted in multiple product ions, whereas, the alkenals reactions produced only two or three product ions, dissociation of the nascent excited product ion occurring preferentially at the 2-position. The findings of this study are of particular importance for data interpretation in studies of aldehydes reactions employing SRI-TOF-MS in the NO+ mode. PMID- 25844051 TI - Doubly charged CO2 clusters formed by ionization of doped helium nanodroplets. AB - Helium nanodroplets are doped with carbon dioxide and ionized by electrons. Doubly charged cluster ions are, for the first time, identified based on their characteristic patterns of isotopologues. Thanks to the high mass resolution, large dynamic range, and a novel method to eliminate contributions from singly charged ions from the mass spectra, we are able to observe doubly charged cluster ions that are smaller than the ones reported in the past. The likely mechanism by which doubly charged ions are formed in doped helium droplets is discussed. PMID- 25844052 TI - Modeling the intrusion of molecules into graphite: Origin and shape of the barriers. AB - We performed density functional theory calculations to explore the energetic and geometric aspects of the permeation of H2, BeH x , OH x (x = 1, 2) and CH y (y = 1-4) through the central hexagon of coronene. Coronene serves as a cluster model for extended graphene which can be regarded as the first layer of a graphite (0 0 0 1) surface. We compare the energy barriers encountered by these molecular projectiles with the ones that are obtained for atomic H, Be, C and O. The barriers are substantially lower if projectiles possess free valences that can bind to the carbon entity. Furthermore, for some of the species fragmentation is observed. Implications with respect to plasma-surface interaction are discussed. PMID- 25844053 TI - Laser ionization and spectroscopy of Cu in superfluid helium nanodroplets. AB - Mass and optical spectroscopic methods are used for the analysis of copper (Cu) atoms and clusters doped to helium nanodroplets (HeN). A two-color resonant two photon ionization scheme is applied to study the Cu 2P[Formula: see text]S1/2 ground state transition. The absorption is strongly broadened for Cu atoms submerged inside helium nanodroplets and a comparison with computed literature values is provided. An observed ejection of the dopant from the droplet is triggered upon excitation, populating energetically lower states. The formation of Cu n clusters up to Cu7 inside helium nanodroplets was observed by means of electron impact ionization mass spectroscopy. PMID- 25844054 TI - Gas-phase intermolecular phosphate transfer within a phosphohistidine phosphopeptide dimer. AB - The hydrogen bonds and electrostatic interactions that form between the protonated side chain of a basic residue and the negatively charged phosphate of a phosphopeptide can play crucial roles in governing their dissociation pathways under low-energy collision-induced dissociation (CID). Understanding how phosphoramidate (i.e. phosphohistidine, phospholysine and phosphoarginine), rather than phosphomonoester-containing peptides behave during CID is paramount in investigation of these problematic species by tandem mass spectrometry. To this end, a synthetic peptide containing either phosphohistidine (pHis) or phospholysine (pLys) was analyzed by ESI-MS using a Paul-type ion trap (AmaZon, Bruker) and by traveling wave ion mobility-mass spectrometry (Synapt G2-Si, Waters). Analysis of the products of low-energy CID demonstrated formation of a doubly 'phosphorylated' product ion arising from intermolecular gas-phase phosphate transfer within a phosphopeptide dimer. The results are explained by the formation of a homodimeric phosphohistidine (pHis) peptide non-covalent complex (NCX), likely stabilized by the electrostatic interaction between the pHis phosphate group and the protonated C-terminal lysine residue of the peptide. To the best of our knowledge this is the first report of intermolecular gas-phase phosphate transfer from one phosphopeptide to another, leading to a doubly phosphorylated peptide product ion. PMID- 25844055 TI - Competitive Hydrogen Atom Migrations Accompanying Cascade Dissociations of Peptide Cation-Radicals of the z+* Type. AB - We report a combined experimental and computational study of energy-resolved collision-induced dissociation (ER-CID) and time-resolved infrared multiphoton dissociation (TR-IRMPD) of z4 ions prepared by electron transfer dissociation of peptide (Ala-Ala-Asn-Ala-Arg + 2H)2+ ions. The z4 cation-radicals, *ANAR+, undergo competitive dissociations by backbone cleavage and loss of a CONH2 radical from the Asn side chain. The backbone cleavage proceeds by radical assisted dissociation of the Asn Calpha-CO bond, forming an x2 ion intermediate which rapidly dissociates by HNCO elimination to yield a stable z2 fragment ion, *AR+. The ER-CID and TR-IRMPD data were consistent with the consecutive nature of the backbone dissociation but showed different branching ratios for the two major fragmentations. The ER-CID data showed branching ratios 0.6-1.0 for the side chain and backbone cleavages whereas the TR-IRMPD data showed an earlier onset for the latter dissociation. Computational analysis of the potential energy surface with density functional theory and ab initio calculations was carried out to provide structures and energies for the reactant ions as well as several intermediates, products, and transition states. Dissociation pathways for cis and trans amide conformers were distinguished and their energies were evaluated. The threshold dissociation energies for the backbone and side-chain dissociations were similar in accordance with the experimental ER-CID branching ratio. The TR IRMPD data were interpreted by different absorbances of intermediates produced by hydrogen atom migrations along the dissociation pathways. PMID- 25844056 TI - Protein derivatization and sequential ion/ion reactions to enhance sequence coverage produced by electron transfer dissociation mass spectrometry. AB - Previously, we described implementation of a front-end ETD (electron transfer dissociation) source for an Orbitrap instrument (1). This source facilitates multiple fills of the C-trap with product ions from ETD of intact proteins prior to mass analysis. The result is a dramatic enhancement of the observed ion current without the need for time consuming averaging of data from multiple mass measurements. Here we show that ion-ion proton transfer (IIPT) reactions can be used to simplify ETD spectra and to disperse fragment ions over the entire mass range in a controlled manner. We also show that protein derivatization can be employed to selectively enhance the sequence information observed at the N- and C termini of a protein. PMID- 25844057 TI - Molecular typing of Meningiomas by Desorption Electrospray Ionization Mass Spectrometry Imaging for Surgical Decision-Making. AB - Meningiomas are the most frequent intracranial tumors. The majority is benign slow-growing tumors but they can be difficult to treat depending on their location and size. While meningiomas are well delineated on magnetic resonance imaging by their uptake of contrast, surgical limitations still present themselves from not knowing the extent of invasion of the dura matter by meningioma cells. The development of tools to characterize tumor tissue in real or near real time could prevent recurrence after tumor resection by allowing for more precise surgery, i.e. removal of tumor with preservation of healthy tissue. The development of ambient ionization mass spectrometry for molecular characterization of tissue and its implementation in the surgical decision-making workflow carry the potential to fulfill this need. Here, we present the characterization of meningioma and dura mater by desorption electrospray ionization mass spectrometry to validate the technique for the molecular assessment of surgical margins and diagnosis of meningioma from surgical tissue in real-time. Nine stereotactically resected surgical samples and three autopsy samples were analyzed by standard histopathology and mass spectrometry imaging. All samples indicated a strong correlation between results from both techniques. We then highlight the value of desorption electrospray ionization mass spectrometry for the molecular subtyping/subgrouping of meningiomas from a series of forty genetically characterized specimens. The minimal sample preparation required for desorption electrospray ionization mass spectrometry offers a distinct advantage for applications relying on real-time information such as surgical decision-making. The technology here was tested to distinguish meningioma from dura mater as an approach to precisely define surgical margins. In addition we classify meningiomas into fibroblastic and meningothelial subtypes and more notably recognize meningiomas with NF2 genetic aberrations. PMID- 25844058 TI - Mass spectral similarity for untargeted metabolomics data analysis of complex mixtures. AB - While in nucleotide sequencing, the analysis of DNA from complex mixtures of organisms is common, this is not yet true for mass spectrometric data analysis of complex mixtures. The comparative analyses of mass spectrometry data of microbial communities at the molecular level is difficult to perform, especially in the context of a host. The challenge does not lie in generating the mass spectrometry data, rather much of the difficulty falls in the realm of how to derive relevant information from this data. The informatics based techniques to visualize and organize datasets are well established for metagenome sequencing; however, due to the scarcity of informatics strategies in mass spectrometry, it is currently difficult to cross correlate two very different mass spectrometry data sets from microbial communities and their hosts. We highlight that molecular networking can be used as an organizational tool of tandem mass spectrometry data, automated database search for rapid identification of metabolites, and as a workflow to manage and compare mass spectrometry data from complex mixtures of organisms. To demonstrate this platform, we show data analysis from hard corals and a human lung associated with cystic fibrosis. PMID- 25844059 TI - Comparison of Glycopeptide Fragmentation by Collision Induced Dissociation and Ultraviolet Photodissociation. AB - A comparison of the fragmentation pathways of both protonated and deprotonated O linked glycopeptides from fetuin and kappa-casein obtained upon collision induced dissociation (CID) and 193 nm ultraviolet photodissociation (UVPD) in a linear ion trap is presented. A strategy using non-specific pronase digestion, zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) solid phase extraction (SPE) enrichment, and nano-liquid chromatography (nano-LC) is employed. UVPD of deprotonated glycopeptides generally produced the greatest array of fragment ions, thus affording the most diagnostic information about both glycan structure and peptide sequence. In addition, UVPD generated unique fragment ion such as Y-type ions arising from cleavage at the N-terminus of proline. CID and UVPD of protonated glycopeptides produced fragment ions solely from glycan cleavages. PMID- 25844060 TI - The combination of MELD score and ICG liver testing predicts length of stay in the ICU and hospital mortality in liver transplant recipients. AB - BACKGROUND: Early prediction of outcome would be useful for an optimal intensive care management of liver transplant recipients. Indocyanine green clearance can be measured non-invasively by pulse spectrophometry and is closely related to liver function. METHODS: This study was undertaken to assess the predictive value of a combination of the model of end stage liver disease (MELD) score and early indocyanine plasma disappearance rates (ICG-PDR) for length of stay in the intensive care unit (ICU), length of stay in the hospital and hospital mortality in liver transplant recipients. RESULTS: Fifty consecutive liver transplant recipients were included in this post Hoc single-center study. ICG-PDR was determined within 6 hours after ICU admission. Endpoints were length of stay in the ICU, length of hospital stay and hospital mortality. The combination of a high MELD score (MELD >25) and a low ICG-PDR clearance (ICG-PDR < 20%/minute) predicts a significant longer stay in the ICU (p = 0.004), a significant longer stay in the hospital (p < 0.001) and a hospital mortality of 40% vs. 0% (p = 0.003). CONCLUSION: The combination of MELD scores and a singular ICG-PDR measurement in the early postoperative phase is an accurate predictor for outcome in liver transplant recipients. This easy-to-assess tool might be valuable for an optimal intensive care management of those patients. PMID- 25844061 TI - The accuracy of locating the cricothyroid membrane by palpation - an intergender study. AB - BACKGROUND: The cricothyroid membrane (CTM) is the recommended site of access to the airway during cricothyrotomy to provide emergency oxygenation. We sought to compare the ability of physicians to correctly identify the CTM in male and female patients. METHODS: In a prospective observational study, anaesthetists were asked to locate the CTM by palpation which was then identified using ultrasound and the distance between the actual and estimated margin of the CTM was measured. Participants assessed the ease of CTM palpation using a visual analog scale. In a second series, the angulation of the posterior junction of the thyroid laminae was measured using ultrasound. RESULTS: 23 anaesthetists and 44 subjects participated. A total of 36 assessments were carried out in each gender. Incorrect identification of the CTM was more common in females (29/36 vs. 11/36, P < 0.001) and the distance from the CTM in the vertical plane was greater (11.0 [6.5-20.0] vs. 0.0 [0.0-10.0] mm, P < 0.001). In females distance from the CTM correlated positively with neck circumference (P = 0.005) and BMI (P = 0.00005) and negatively with subject height (P = 0.01). Posterior thyroid cartilage angulation was greater in females (118.6 +/- 9.4 degrees vs. 95.9 +/- 12.9 degrees , P = 0.02) and was lower in patients with correctly identified CTMs (100.0 +/- 14.9 degrees vs. 115.6 +/- 15.9 degrees , P = 0.02). VRS palpation correlated with decreased posterior thyroid cartilage angulation (P = 0.04). CONCLUSIONS: CTM localisation is more difficult in female subjects irrespective of body habitus. It may be prudent to localize this structure by additional means (e.g. ultrasound) in advance of any airway manoeuvres or to modify the cricothyrotomy technique in the event that it is necessary in an emergency. PMID- 25844062 TI - The effect of simulation-based training on initial performance of ultrasound guided axillary brachial plexus blockade in a clinical setting - a pilot study. AB - BACKGROUND: In preparing novice anesthesiologists to perform their first ultrasound-guided axillary brachial plexus blockade, we hypothesized that virtual reality simulation-based training offers an additional learning benefit over standard training. We carried out pilot testing of this hypothesis using a prospective, single blind, randomized controlled trial. METHODS: We planned to recruit 20 anesthesiologists who had no experience of performing ultrasound guided regional anesthesia. Initial standardized training, reflecting current best available practice was provided to all participating trainees. Trainees were randomized into one of two groups; (i) to undertake additional simulation-based training or (ii) no further training. On completion of their assigned training, trainees attempted their first ultrasound-guided axillary brachial plexus blockade. Two experts, blinded to the trainees' group allocation, assessed the performance of trainees using validated tools. RESULTS: This study was discontinued following a planned interim analysis, having recruited 10 trainees. This occurred because it became clear that the functionality of the available simulator was insufficient to meet our training requirements. There were no statistically significant difference in clinical performance, as assessed using the sum of a Global Rating Score and a checklist score, between simulation-based training [mean 32.9 (standard deviation 11.1)] and control trainees [31.5 (4.2)] (p = 0.885). CONCLUSIONS: We have described a methodology for assessing the effectiveness of a simulator, during its development, by means of a randomized controlled trial. We believe that the learning acquired will be useful if performing future trials on learning efficacy associated with simulation based training in procedural skills. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01965314. Registered October 17th 2013. PMID- 25844063 TI - Can serum L-lactate, D-lactate, creatine kinase and I-FABP be used as diagnostic markers in critically ill patients suspected for bowel ischemia. AB - BACKGROUND: The prognostic value of biochemical tests in critically ill patients with multiple organ failure and suspected bowel ischemia is unknown. METHODS: In a prospective observational cohort study intensive care patients were included when the attending intensivist considered intestinal ischemia in the diagnostic workup at any time during intensive care stay. Patients were only included once. When enrolment was ended each patient was classified as 'proven intestinal ischemia', 'ischemia likely', 'ischemia unlikely' or 'no intestinal ischemia'. Proven intestinal ischemia was defined as the gross disturbance of blood flow in the bowel, regardless of extent and grade. Classification was based on reports from the operating surgeon, pathology department, endoscopy reports and CT-scan. Lactate dehydrogenase (LDH), creatine kinase (CK), alanine aminotransferase (ALAT), L-lactate were available for the attending physician. D-lactate and intestinal fatty acid binding protein (I-FABP) were analysed later in a batch. I FABP was only measured in patients with proven ischemia or no ischemia. RESULTS: For 44 of the 120 included patients definite diagnostic studies were available. 23/44 patients (52%) had proven intestinal ischemia as confirmed by surgery, colonoscopy, autopsy and/or histopathological findings. LDH in these patients was 285 U/l (217-785) vs 287 U/l (189-836) in no-ischemia; p = 0.72. CK was 226 U/l in patients with proven ischemia (126-2145) vs 347 U/l (50-1427), p = 0.88. ALAT was 53 U/l (18-300) vs 34 U/l (14-34), p-0,56. D-lactate 0.41 mmol/l (0.11-0.75) vs 0.56 mmol/l (0.27-0.77), p = 0.46. L-lactate 3.5 mmol/l (2.2-8.4) vs 2.6 mmol/l (1.7-3.9), p = 0.09. I-FABP 2872 pg/ml (229-4340) vs 1020 pg/ml (239 5324), p = 0.98. Patient groups proven and likely ischemia together compared to unlikely and no-ischemia together showed significant higher L-lactate (p = 0.001) and higher D-lactate (p = 0.003). CONCLUSIONS: Measurement of LDH, CK, and ALAT did not discriminate critically ill patients with proven intestinal ischemia from those with definite diagnosis no-ischemia. However, L-lactate and D-lactate levels were higher in patients with proven or likely ischemia and need further study just as I-FABP. PMID- 25844064 TI - The caval index: an adequate non-invasive ultrasound parameter to predict fluid responsiveness in the emergency department? AB - BACKGROUND: Fluid therapy is the first important step in patients with signs of shock but assessment of the volume status is difficult and invasive measurements are not readily available in the emergency department. We have investigated whether the respiratory variation in diameter of the inferior vena cava is a reliable parameter to predict fluid responsiveness in spontaneous breathing emergency department patients with signs of shock. METHODS: All patients admitted to the emergency department during a 15 week period were screened for signs of shock. If the attending physician planned to give a fluid challenge, the caval index was determined by transabdominal ultrasonography in supine position. Immediately afterwards 500 ml NaCl 0.9% was administered in 15 minutes and the clinical response was observed. An adequate response was defined as an increase in systolic blood pressure of at least 10 mm Hg. Based on this definition patients were divided into responders and non-responders. RESULTS: After selection a total number of 45 patients was included. A low caval index (< 36.5%) in patients with signs of shock reliably predicted the absence of an adequate response to fluid therapy (negative predictive value 92%). The positive predictive value of a high caval index was much lower (48%) despite the fact that responders had a significantly higher pre-infusion caval index than non responders (48.7% vs 31.8%, p 0.014). CONCLUSIONS: In spontaneously breathing patients with signs of shock in the emergency department, a high caval index (>36.5%) does not reliably predict fluid responsiveness in our study, while a low caval index (<36.5%) makes fluid responsiveness unlikely. An explanation for the absence of a blood pressure response in the group of patients with a low high caval index might be that these patients represent a group requiring more volume therapy than 500 ml. PMID- 25844065 TI - Effectiveness of heat and moisture exchangers in preventing ventilator-associated pneumonia in critically ill patients: a meta-analysis. AB - BACKGROUND: Patients may acquire ventilator-associated pneumonia (VAP) by aspirating the condensate that originates in the ventilator circuit upon use of a conventional humidifier. The bacteria that colonize the patients themselves can proliferate in the condensate and then return to the airways and lungs when the patient aspirates this contaminated material. Therefore, the use of HME might contribute to preventing pneumonia and lowering the VAP incidence. The aim of this study was to evaluate how the use of HME impacts the probability of VAP occurrence in critically ill patients. METHODS: On the basis of the acronym "PICO" (Patient, Intervention, Comparison, Outcome), the question that guided this review was "Do critically ill patients under invasive mechanical ventilation present lower VAP incidence when they use HME as compared with HH?". Two of the authors of this review searched the databases PUBMED/Medline, The Cochrane Library, and Latin-American and Caribbean Literature in Health Sciences, LILACS independently; they used the following keywords: "heat and moisture exchanger", AND "heated humidifier", AND "ventilator-associated pneumonia prevention". This review included papers in the English language published from January 1990 to December 2012. RESULTS: This review included ten studies. Comparison between the use of HME and HH did not reveal any differences in terms of VAP occurrence (OR = 0.998; 95% CI: 0.778-1.281). Together, the ten studies corresponded to a total sample of 1077 and 953 patients in the HME and HH groups, respectively; heterogeneity among the investigations was low (I(2) < 50%). Information about the outcome mortality was available in only eight of the ten studies. The use of HME and HH did not afford different results in terms of mortality (OR = 1.09; 95% CI: 0.864-1.376). The total sample size was 884 and 762 patients, respectively. Heterogeneity among the studies was low (I(2) = 0.0%). CONCLUSION: Current meta analysis was not sufficient to definitely exclude an associate between heat and moisture exchangers and VAP. Despite the methodological limitations found in selected clinical trials, the current meta-analysis suggests that HME does not decrease VAP incidence or mortality in critically ill patients. PMID- 25844066 TI - Care of the human spirit and the role of dignity therapy: a systematic review of dignity therapy research. AB - BACKGROUND: Dignity Therapy (DT), an intervention for people facing serious illness, focuses on dignity conservation tasks such as settling relationships, sharing words of love, and preparing a legacy document for loved ones. Research on DT began more than a decade ago and has been conducted in 7 countries, but a systematic review of DT research has not been published. METHODS: Using a PubMed search with key terms of 'dignity therapy', 'dignity psychotherapy', 'Chochinov', and 'dignity care', we found 29 articles on DT and retained 25 after full-text review. RESULTS: Of these, 17 articles representing 12 quantitative studies establish that patients who receive DT report high satisfaction and benefits for themselves and their families, including increased sense of meaning and purpose. The effects of DT on physical or emotional symptoms, however, were inconsistent. CONCLUSIONS: Conclusions point to three areas for future research on DT, to determine: (1) whether the DT intervention exerts an impact at a spiritual level and/or as a life completion task; (2) how DT should be implemented in real world settings; and (3) if DT has an effect on the illness experience within the context of not only the patient, but also the family and community. Building on this body of DT research, investigators will need to continue to be sensitive as they involve participants in DT studies and innovations to facilitate the generation and delivery of legacy documents to participants near the end of life. PMID- 25844067 TI - Recognizing acute delirium as part of your routine [RADAR]: a validation study. AB - BACKGROUND: Although detection of delirium using the current tools is excellent in research settings, in routine clinical practice, this is not the case. Together with nursing staff, we developed a screening tool (RADAR) to address certain limitations of existing tools, notably administration time, ease-of-use and generalizability. The purpose of this study was not only to evaluate the validity and reliability of RADAR but also to gauge its acceptability among the nursing staff in two different clinical settings. METHODS: This was a validation study conducted on three units of an acute care hospital (medical, cardiology and coronary care) and five units of a long-term care facility. A total of 142 patients and 51 residents aged 65 and over, with or without dementia, participated in the study and 139 nurses were recruited and trained to use the RADAR tool. Data on each patient/resident was collected over a 12-hour period. The nursing staff and researchers administered RADAR during the scheduled distribution of medication. Researchers used the Confusion Assessment Method to determine the presence of delirium symptoms. Delirium itself was defined as meeting the criteria for DMS-IV-TR delirium. Inter-rater reliability, convergent, and concurrent validity of RADAR were assessed. At study end, 103 (74%) members of the nursing staff completed the RADAR feasibility and acceptability questionnaire. RESULTS: Percentages of agreement between RADAR items that bedside nurses administered and those research assistants administered varied from 82% to 98%. When compared with DSM-IV-TR criterion-defined delirium, RADAR had a sensitivity of 73% and a specificity of 67%. Participating nursing staff took about seven seconds on average, to complete the tool and it was very well received (>=98%) overall. CONCLUSIONS: The RADAR tool proved to be efficient, reliable, sensitive and very well accepted by nursing staff. Consequently, it becomes an appropriate new option for delirium screening among older adults, with or without cognitive impairment, in both hospitals and nursing homes. Further projects are currently underway to validate the RADAR among middle-aged adults, as well as in newer clinical settings; home care, emergency department, medical intensive care unit, and palliative care. PMID- 25844068 TI - Crude extract of hydatid laminated layer from Echinococcus granulosus cyst attenuates mucosal intestinal damage and inflammatory responses in Dextran Sulfate Sodium induced colitis in mice. AB - BACKGROUND: Inflammatory bowel disease is an immunologically mediated disease. Notably, it is less common in countries where there is a greater risk of exposure to helminths. In our study, we examined the modulatory effect of the laminated layer extracted from the cyst wall of a helminth parasite, Echinococcus granulosus, on dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: An acute colitis was induced in BALB/c mice using 2.5% w/v DSS in drinking water. The crude extract of E. granulosus laminated layer was injected intraperitoneally daily, starting 3 days before colitis induction. The Disease Activity Index was monitored daily, colon length and weight were measured and histological scores were evaluated. Nitric oxide (NO) and cytokine levels (interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10)) were assessed by enzyme-linked immunosorbent assay. In addition, the colonic expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappaB (NF-kappaB) was examined. Statistical analyses were performed by one-way analysis of variance and the survival rate was analyzed by the long rank test. RESULTS: Hydatid laminated layer pretreatment significantly improved the clinical symptoms and histological scores (*** p < 0.01) observed during DSS-induced colitis and maintained mucus production by goblet cells. Furthermore, treatment with hydatid laminated layer caused a significant decrease in NO, IFN-gamma (** p < 0.01) and TNF-alpha production (* p < 0.05) and an increase in IL-10 production. These results were associated with localized downregulation of iNOS and NF-kappaB expression. CONCLUSIONS: Our results demonstrate the potent anti-inflammatory effects of hydatid laminated layer. Furthermore, preventive treatment with the laminated layer played a beneficial role in maintaining the integrity of the intestinal mucosal barrier against DSS-induced injury. PMID- 25844069 TI - Label-free quantitative phosphorylation analysis of human transgelin2 in Jurkat T cells reveals distinct phosphorylation patterns under PKA and PKC activation conditions. AB - BACKGROUND: Transgelin2, one of cytoskeletal actin binding proteins has recently been suggested to be involved in the formation of immune synapses. Although detailed function of transgelin2 is largely unknown, interactions between transgelin2 and actin appear to be important in regulating cellular functions of transgelin2. Because protein phosphorylation can change ability to interact with other proteins, comprehensive phosphorylation analysis of transgelin2 will be helpful in understanding its functional mechanisms. RESULTS: Here, a specific protein label-free quantitative phosphorylation analysis method combining immuno precipitation, IMAC phosphopeptide enrichment technique and label-free relative quantification analysis was used to monitor the phosphorylation changes of transgelin2 overexpressed in Jurkat T cells under protein kinase C (PKC) and protein kinase A (PKA) activation conditions, two representative intracellular signalling pathways of immune cell activation and homeostasis. A total of six serine/threonine phosphorylation sites were identified including threonine-84, a novel phosphorylation site. Notably, distinct phosphorylation patterns of transgelin2 under the two kinase activation conditions were observed. Most phosphorylation sites showing specific kinase-dependent phosphorylation changes were discretely located in two previously characterized actin-binding regions: actin-binding site (ABS) and calponin repeat domain (CNR). PKC activation increased phosphorylation of threonine-180 and serine-185 in the CNR, and PKA activation increased phosphorylation of serine-163 in the ABS. CONCLUSIONS: Multiple actin-binding regions of transgelin2 participate to accomplish its full actin-binding capability, and the actin-binding affinity of each actin-binding region appears to be modulated by specific kinase-dependent phosphorylation changes. Accordingly, different actin-binding properties or cellular functions of transgelin2 may result from distinct intracellular signalling events under immune response activation or homeostasis conditions. PMID- 25844071 TI - Twelve-Month-Old Infants' Encoding of Goal and Source Paths in Agentive and Non Agentive Motion Events. AB - Across languages and event types (agentive and non-agentive motion, transfer, change of state, attach/detach), goal paths are privileged over source paths in the linguistic encoding of events. Furthermore, some linguistic analyses suggest that goal paths are more central than source paths in the semantic and syntactic structure of motion verbs. However, in the non-linguistic memory of children and adults, a goal bias shows up only for events involving intentional, goal directed, action. Three experiments explored infants' non-linguistic representations of goals and sources in motion events. The findings revealed that 12-month-old infants privilege goals over sources only when the event involves action of an agent. Thus, unlike language (but similar to the memory of children and adults), an endpoint bias in infant thought may be restricted to events involving goal-directed motion by an agent. These results raise the question of how children later learn to collapse over conceptual domains for purposes of coding paths in language. PMID- 25844070 TI - Assessing Community Reactions to Ebola Virus Disease and Other Disasters: Using Social Psychological Research to Enhance Public Health and Disaster Communications. AB - Drawing on the lessons learned from previous disaster and disease outbreak studies over the past two decades, in the following article we review research related to social psychological assessment of community attitudes, knowledge, and beliefs associated with the recent Ebola outbreak and other public health threats, and discuss the use of this information to assist in future disaster planning and crisis communications. Psychologists, physicians, and others in the healthcare field need to be aware of these developments and involved with preparations related to mitigating the psychological impact of Ebola disease outbreaks among different populations, as well as other potential public health threats in the future. PMID- 25844072 TI - Tree Tensor Network State with Variable Tensor Order: An Efficient Multireference Method for Strongly Correlated Systems. AB - We study the tree-tensor-network-state (TTNS) method with variable tensor orders for quantum chemistry. TTNS is a variational method to efficiently approximate complete active space (CAS) configuration interaction (CI) wave functions in a tensor product form. TTNS can be considered as a higher order generalization of the matrix product state (MPS) method. The MPS wave function is formulated as products of matrices in a multiparticle basis spanning a truncated Hilbert space of the original CAS-CI problem. These matrices belong to active orbitals organized in a one-dimensional array, while tensors in TTNS are defined upon a tree-like arrangement of the same orbitals. The tree-structure is advantageous since the distance between two arbitrary orbitals in the tree scales only logarithmically with the number of orbitals N, whereas the scaling is linear in the MPS array. It is found to be beneficial from the computational costs point of view to keep strongly correlated orbitals in close vicinity in both arrangements; therefore, the TTNS ansatz is better suited for multireference problems with numerous highly correlated orbitals. To exploit the advantages of TTNS a novel algorithm is designed to optimize the tree tensor network topology based on quantum information theory and entanglement. The superior performance of the TTNS method is illustrated on the ionic-neutral avoided crossing of LiF. It is also shown that the avoided crossing of LiF can be localized using only ground state properties, namely one-orbital entanglement. PMID- 25844073 TI - Three and six grams supplementation of d-aspartic acid in resistance trained men. AB - BACKGROUND: Although abundant research has investigated the hormonal effects of d aspartic acid in rat models, to date there is limited research on humans. Previous research has demonstrated increased total testosterone levels in sedentary men and no significant changes in hormonal levels in resistance trained men. It was hypothesised that a higher dosage may be required for experienced lifters, thus this study investigated the effects of two different dosages of d aspartic acid on basal hormonal levels in resistance trained men and explored responsiveness to d-aspartic acid based on initial testosterone levels. METHODS: Twenty-four males, with a minimum of two years' experience in resistance training, (age, 24.5 +/- 3.2 y; training experience, 3.4 +/- 1.4 y; height, 178.5 +/- 6.5 cm; weight, 84.7 +/- 7.2 kg; bench press 1-RM, 105.3 +/- 15.2 kg) were randomised into one of three groups: 6 g.d(-1) plain flour (D0); 3 g.d(-1) of d aspartic acid (D3); and 6 g.d(-1) of d-aspartic acid (D6). Participants performed a two-week washout period, training four days per week. This continued through the experimental period (14 days), with participants consuming the supplement in the morning. Serum was analysed for levels of testosterone, estradiol, sex hormone binding globulin, albumin and free testosterone was determined by calculation. RESULTS: D-aspartic acid supplementation revealed no main effect for group in: estradiol; sex-hormone-binding-globulin; and albumin. Total testosterone was significantly reduced in D6 (P = 0.03). Analysis of free testosterone showed that D6 was significantly reduced as compared to D0 (P = 0.005), but not significantly different to D3. Analysis did not reveal any significant differences between D3 and D0. No significant correlation between initial total testosterone levels and responsiveness to d-aspartic acid was observed (r = 0.10, P = 0.70). CONCLUSIONS: The present study demonstrated that a daily dose of six grams of d-aspartic acid decreased levels of total testosterone and free testosterone (D6), without any concurrent change in other hormones measured. Three grams of d-aspartic acid had no significant effect on either testosterone markers. It is currently unknown what effect this reduction in testosterone will have on strength and hypertrophy gains. PMID- 25844074 TI - Adaptation Guidance for Evidence-Based Teen Pregnancy and STI/HIV Prevention Curricula: From Development to Practice. AB - Evidence-based interventions (EBIs) are effective in preventing ado-lescent pregnancy and sexually transmitted infections; however, prevention practitioners are challenged when selecting and adapting the most appropriate programs. While there are existing adaptation frameworks, there is little practical guidance in applying research in the field. To address this need, the Centers for Disease Control and Prevention (CDC) Division of Reproductive Health initiated the Adaptation Guidance Project. The project included the development of a comprehensive adaptation guidance framework and adaptation kits for select evidence-based teen pregnancy and HIV prevention programs. In addition, three innovative concepts emerged that have application to other adaptation program and evaluation efforts, including moving research into practice. First, the authors defined the core components of an EBI in three distinct ways: core content, core pedagogy, and core implementation. Second, they piloted a practitioner-friendly adaptation guidance-messaging schema-Green, Yellow, and Red Light Adaptations, and last they included fidelity/adaptation monitoring logs. This article will describe the process used to develop the adaptation guidance kits, including the main features and tools. PMID- 25844076 TI - X-ray micro Laue diffraction tomography analysis of a solid oxide fuel cell. AB - The relevance of micro Laue diffraction tomography (u-LT) to investigate heterogeneous polycrystalline materials has been studied. For this purpose, a multiphase solid oxide fuel cell (SOFC) electrode composite made of yttria stabilized zirconia and nickel oxide phases, with grains of about a few micrometres in size, has been analyzed. In order to calibrate the Laue data and to test the technique's sensitivity limits, a monocrystalline germanium sample of about 8 * 4 um in cross-section size has also been studied through u-LT. The SOFC and germanium Laue diffraction pattern analyses are compared and discussed. The indexing procedure has been successfully applied for the analysis of the germanium Laue data, and the depth-resolved two-dimensional cartographies of the full deviatoric strain tensor components were obtained. The development and application of an original geometrical approach to analyze the SOFC Laue data allowed the authors to resolve grains with sizes of about 3 um and to identify their individual Laue patterns; by indexing those Laue patterns, the crystalline phases and orientations of most of the grains identified through the geometrical approach could be resolved. PMID- 25844075 TI - Ages of Onset of Mood and Anxiety Disorders in Fragile X Premutation Carriers. AB - OBJECTIVE: FMR1 premutation carriers of both genders have a high lifetime prevalence of anxiety and depressive disorders, however little is known regarding the onset ages of these conditions. This study compared onset ages of mood and anxiety disorders in premutation carriers with typical onset ages of the same disorders in the general population. METHODS: Eighty-one premutation carriers (42% men; average age 62, SD 10) with and without FXTAS completed the Structured Clinical Interview for DSM-IV-TR. Onset ages of mood and anxiety disorders were compared to the corresponding typical population onset ages using the signed rank test. RESULTS: Overall median onset ages of MDD (46 years old, p < 0.0001), panic disorder (40 years old, p = 0.0067), and specific phobia (11.5 years old, p = 0.0003) were significantly higher in premutation carriers compared to the general population. Median MDD onset ages in male carriers (52 years old) and those with FXTAS (49.5 years old) were significantly higher relative to the general population (median 32, both p < 0.0001). Tremor and ataxia emerged significantly later than MDD and the anxiety disorders studied. CONCLUSION: Depressive and anxiety disorders in premutation carriers have a later onset compared to the general population, but precede the onset of motor symptoms. This may be due to progressive mRNA toxicity in the limbic system, white matter changes leading to neuronal dysconnectivity, and interaction with environmental factors. Psychosocial factors may be protective. Further research is needed to understand the full spectrum of psychiatric phenotypes in FMR1 premutation carriers. PMID- 25844077 TI - Crystallization dynamics and interface stability of strontium titanate thin films on silicon. AB - Different physical vapor deposition methods have been used to fabricate strontium titanate thin films. Within the binary phase diagram of SrO and TiO2 the stoichiometry ranges from Ti rich to Sr rich, respectively. The crystallization of these amorphous SrTiO3 layers is investigated by in situ grazing-incidence X ray diffraction using synchrotron radiation. The crystallization dynamics and evolution of the lattice constants as well as crystallite sizes of the SrTiO3 layers were determined for temperatures up to 1223 K under atmospheric conditions applying different heating rates. At approximately 473 K, crystallization of perovskite-type SrTiO3 is initiated for Sr-rich electron beam evaporated layers, whereas Sr-depleted sputter-deposited thin films crystallize at 739 K. During annealing, a significant diffusion of Si from the substrate into the SrTiO3 layers occurs in the case of Sr-rich composition. This leads to the formation of secondary silicate phases which are observed by X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy. PMID- 25844078 TI - Versatile sample environments and automation for biological solution X-ray scattering experiments at the P12 beamline (PETRA III, DESY). AB - A high-brilliance synchrotron P12 beamline of the EMBL located at the PETRA III storage ring (DESY, Hamburg) is dedicated to biological small-angle X-ray scattering (SAXS) and has been designed and optimized for scattering experiments on macromolecular solutions. Scatterless slits reduce the parasitic scattering, a custom-designed miniature active beamstop ensures accurate data normalization and the photon-counting PILATUS 2M detector enables the background-free detection of weak scattering signals. The high flux and small beam size allow for rapid experiments with exposure time down to 30-50 ms covering the resolution range from about 300 to 0.5 nm. P12 possesses a versatile and flexible sample environment system that caters for the diverse experimental needs required to study macromolecular solutions. These include an in-vacuum capillary mode for standard batch sample analyses with robotic sample delivery and for continuous flow in-line sample purification and characterization, as well as an in-air capillary time-resolved stopped-flow setup. A novel microfluidic centrifugal mixing device (SAXS disc) is developed for a high-throughput screening mode using sub-microlitre sample volumes. Automation is a key feature of P12; it is controlled by a beamline meta server, which coordinates and schedules experiments from either standard or nonstandard operational setups. The integrated SASFLOW pipeline automatically checks for consistency, and processes and analyses the data, providing near real-time assessments of overall parameters and the generation of low-resolution models within minutes of data collection. These advances, combined with a remote access option, allow for rapid high-throughput analysis, as well as time-resolved and screening experiments for novice and expert biological SAXS users. PMID- 25844080 TI - The fast azimuthal integration Python library: pyFAI. AB - pyFAI is an open-source software package designed to perform azimuthal integration and, correspondingly, two-dimensional regrouping on area-detector frames for small- and wide-angle X-ray scattering experiments. It is written in Python (with binary submodules for improved performance), a language widely accepted and used by the scientific community today, which enables users to easily incorporate the pyFAI library into their processing pipeline. This article focuses on recent work, especially the ease of calibration, its accuracy and the execution speed for integration. PMID- 25844081 TI - High-resolution characterization of the forbidden Si 200 and Si 222 reflections. AB - The occurrence of the basis-forbidden Si 200 and Si 222 reflections in specular X ray diffraction omega-2Theta scans is investigated in detail as a function of the in-plane sample orientation Phi. This is done for two different diffractometer types with low and high angular divergence perpendicular to the diffraction plane. It is shown that the reflections appear for well defined conditions as a result of multiple diffraction, and not only do the obtained peaks vary in intensity but additional features like shoulders or even subpeaks may occur within a 2Theta range of about +/-2.5 degrees . This has important consequences for the detection and verification of layer peaks in the corresponding angular range. PMID- 25844082 TI - Determination and mitigation of the uncertainty of neutron diffraction measurements of residual strain in large-grained polycrystalline material. AB - For large-grained samples it is advantageous to perform pairs of neutron diffraction measurements at the same spatial location but rotated 180 degrees around the geometric centre of the gauge volume as a means of minimizing the scatter coming from the random positioning of grains within the gauge volume. PMID- 25844079 TI - Quantitative X-ray phase contrast waveguide imaging of bacterial endospores. AB - Quantitative waveguide-based X-ray phase contrast imaging has been carried out on the level of single, unstained, unsliced and freeze-dried bacterial cells of Bacillus thuringiensis and Bacillus subtilis using hard X-rays of 7.9 keV photon energy. The cells have been prepared in the metabolically dormant state of an endospore. The quantitative phase maps obtained by iterative phase retrieval using a modified hybrid input-output algorithm allow for mass and mass density determinations on the level of single individual endospores but include also large field of view investigations. Additionally, a direct reconstruction based on the contrast transfer function is investigated, and the two approaches are compared. Depending on the field of view and method, a resolution down to 65 nm was achieved at a maximum applied dose of below 5 * 105 Gy. Masses in the range of about ~110-190 (20) fg for isolated endospores have been obtained. PMID- 25844083 TI - Nebula: reconstruction and visualization of scattering data in reciprocal space. AB - Two-dimensional solid-state X-ray detectors can now operate at considerable data throughput rates that allow full three-dimensional sampling of scattering data from extended volumes of reciprocal space within second to minute time-scales. For such experiments, simultaneous analysis and visualization allows for remeasurements and a more dynamic measurement strategy. A new software, Nebula, is presented. It efficiently reconstructs X-ray scattering data, generates three dimensional reciprocal space data sets that can be visualized interactively, and aims to enable real-time processing in high-throughput measurements by employing parallel computing on commodity hardware. PMID- 25844084 TI - Powder diffraction in Bragg-Brentano geometry with straight linear detectors. AB - A common way of speeding up powder diffraction measurements is the use of one- or two-dimensional detectors. This usually goes hand in hand with worse resolution and asymmetric peak profiles. In this work the influence of a straight linear detector on the resolution function in the Bragg-Brentano focusing geometry is discussed. Because of the straight nature of most modern detectors geometrical defocusing occurs, which heavily influences the line shape of diffraction lines at low angles. An easy approach to limit the resolution-degrading effects is presented. The presented algorithm selects an adaptive range of channels of the linear detector at low angles, resulting in increased resolution. At higher angles the whole linear detector is used and the data collection remains fast. Using this algorithm a well behaved resolution function is obtained in the full angular range, whereas using the full linear detector the resolution function varies within one pattern, which hinders line-shape and Rietveld analysis. PMID- 25844085 TI - Studies of the Room-Temperature Multiferroic Pb(Fe0.5Ta0.5)0.4(Zr0.53Ti0.47)0.6O3: Resonant Ultrasound Spectroscopy, Dielectric, and Magnetic Phenomena. AB - Recently, lead iron tantalate/lead zirconium titanate (PZTFT) was demonstrated to possess large, but unreliable, magnetoelectric coupling at room temperature. Such large coupling would be desirable for device applications but reproducibility would also be critical. To better understand the coupling, the properties of all 3 ferroic order parameters, elastic, electric, and magnetic, believed to be present in the material across a range of temperatures, are investigated. In high temperature elastic data, an anomaly is observed at the orthorhombic mm2 to tetragonal 4mm transition, Tot = 475 K, and a softening trend is observed as the temperature is increased toward 1300 K, where the material is known to become cubic. Thermal degradation makes it impossible to measure elastic behavior up to this temperature, however. In the low temperature region, there are elastic anomalies near ~40 K and in the range 160-245 K. The former is interpreted as being due to a magnetic ordering transition and the latter is interpreted as a hysteretic regime of mixed rhombohedral and orthorhombic structures. Electrical and magnetic data collected below room temperature show anomalies at remarkably similar temperature ranges to the elastic data. These observations are used to suggest that the three order parameters in PZTFT are strongly coupled. PMID- 25844086 TI - Synthesis and Characterization of Gelatin-Based Magnetic Hydrogels. AB - A simple preparation of thermoreversible gelatin-based ferrogels in water provides a constant structure defined by the crosslinking degree for gelatin contents between 6 and 18 wt%. The possibility of varying magnetite nanoparticle concentration between 20 and 70 wt% is also reported. Simulation studies hint at the suitability of collagen to bind iron and hydroxide ions, suggesting that collagen acts as a nucleation seed to iron hydroxide aggregation, and thus the intergrowth of collagen and magnetite nanoparticles already at the precursor stage. The detailed structure of the individual ferrogel components is characterized by small-angle neutron scattering (SANS) using contrast matching. The magnetite structure characterization is supplemented by small-angle X-ray scattering and microscopy only visualizing magnetite. SANS shows an unchanged gelatin structure of average mesh size larger than the nanoparticles with respect to gel concentration while the magnetite nanoparticles size of around 10 nm seems to be limited by the gel mesh size. Swelling measurements underline that magnetite acts as additional crosslinker and therefore varying the magnetic and mechanical properties of the ferrogels. Overall, the simple and variable synthesis protocol, the cheap and easy accessibility of the components as well as the biocompatibility of the gelatin-based materials suggest them for a number of applications including actuators. PMID- 25844087 TI - Comparative analysis of chromosome segregation in human, yeasts and trypanosome. AB - Chromosome segregation is a tightly regulated process through which duplicated genetic materials are equally partitioned into daughter cells. During the past decades, tremendous efforts have been made to understand the molecular mechanism of chromosome segregation using animals and yeasts as model systems. Recently, new insights into chromosome segregation have gradually emerged using trypanosome, an early branching parasitic protozoan, as a model organism. To uncover the unique aspects of chromosome segregation in trypanosome, which potentially could serve as new drug targets for anti-trypanosome chemotherapy, it is necessary to perform a comparative analysis of the chromosome segregation machinery between trypanosome and its human host. Here, we briefly review the current knowledge about chromosome segregation in human and Trypanosoma brucei, with a focus on the regulation of cohesin and securin degradation triggered by the activation of the anaphase promoting complex/cyclosome (APC/C). We also include yeasts in our comparative analysis since some of the original discoveries were made using budding and fission yeasts as the model organisms and, therefore, these could provide hints about the evolution of the machinery. We highlight both common and unique features in these model systems and also provide perspectives for future research in trypanosome. PMID- 25844089 TI - Psychosomatic treatment for allergic diseases. AB - Many reports have been published concerning how psychosocial stress influences the occurrence and progression of allergic diseases such as bronchial asthma and atopic dermatitis. As for asthma, a typical allergic disease often accompanied by psychosomatic related problems, the Global Initiative for Asthma (GINA), international medical guidelines for asthma, describes psychosocial problems as causative factors of poor asthma control and as risk factors for asthma exacerbation, even if symptoms are well controlled. However, because there is little high quality evidence for effective treatments for asthma patients with psychosocial problems, concrete assessments and treatments for such problems is scarcely described in GINA. Therefore, psychosomatic intervention for asthma patients is not effectively conducted on a worldwide scale. In contrast, the "Japanese Guidelines for the Diagnosis and Treatment of Psychosomatic Diseases" describe the assessment and treatment of psychosomatic disorders in detail. In the guidelines, psychosocial factors are classified into five categories; 1) Relation between stress and asthma occurrence or progression, 2) Relation between emotion and asthma symptoms, 3) Problems related to a patient's character and behaviors, 4) Problems of daily life and Quality of Life (QOL), and 5) Problems related to family relationships and life history. The employment of a self administered questionnaire, the "Psychosomatic Questionnaire related to Asthmatic Occurrence and Progression", is useful for clarifying psychosocial factors and for setting up treatment strategies according to the problems identified. The Japanese guidelines have been proven to be useful, but empirical evidence for their effectiveness is still relatively limited. It will be necessary in the future to accumulate high-quality evidence and to revise the psychosomatic approaches in the guidelines that are universally valid. PMID- 25844091 TI - Decaffeinated Green Tea and Voluntary Exercise Induce Gene Changes Related to Beige Adipocyte Formation in High Fat-Fed Obese Mice. AB - We have previously reported that decaffeinated green tea extract (GTE) in combination with voluntary exercise (Ex) reduces metabolic syndrome in high fat fed C57BL/6J mice. Here, we examined for the first time the effect of treatment with 77 mg/g GTE, Ex, or both (GTE + Ex) on genes related to the conversion of white adipose tissue (WAT) to brown fat-like adipose tissue (BLAT) in this model. GTE+Ex induced genes related to lipolysis (hormone sensitive lipase [3.0-fold] and patatin-like phospholipase domain-containing protein 2 [2-fold]), mitochondrial beta-oxidation (NADH dehydrogenase 5 [2.3-fold], cytochrome B [2.0 fold], and cytochrome C oxidase III [1.9-fold increase]), and adipose tissue browning (peroxisome proliferator-activated receptor-gamma coactivator-1alpha [1.8-fold], bone morphogenetic protein 4 [2.6-fold], and phosphatase and tensin homolog [2.6-fold]) in visceral WAT compared to HF-fed mice. These results suggest that GTE+Ex function in part by inducing the conversion of WAT to BLAT and provides novel mechanistic insight into this combination. PMID- 25844090 TI - A large-scale survey of adverse events experienced in yoga classes. AB - BACKGROUND: Yoga is a representative mind-body therapy of complementary and alternative medicine. In Japan, yoga is practiced widely to promote health, but yoga-associated adverse events have also been reported. To date, the frequencies and characteristics of yoga-related adverse events have not been elucidated. This study was conducted to elucidate the frequencies and characteristics of adverse events of yoga performed in classes and the risk factors of such events. METHODS: The subjects were 2508 people taking yoga classes and 271 yoga therapists conducting the classes. A survey for yoga class attendees was performed on adverse events that occurred during a yoga class on the survey day. A survey for yoga therapists was performed on adverse events that the therapists had observed in their students to date. Adverse events were defined as "undesirable symptoms or responses that occurred during a yoga class". RESULTS: Among 2508 yoga class attendees, 1343 (53.5%) had chronic diseases and 1063 (42.3%) were receiving medication at hospitals. There were 687 class attendees (27.8%) who reported some type of undesirable symptoms after taking a yoga class. Musculoskeletal symptoms such as myalgia were the most common symptoms, involving 297 cases, followed by neurological symptoms and respiratory symptoms. Most adverse events (63.8%) were mild and did not interfere with class participation. The risk factors for adverse events were examined, and the odds ratios for adverse events were significantly higher in attendees with chronic disease, poor physical condition on the survey day, or a feeling that the class was physically and mentally stressful. In particular, the occurrence of severe adverse events that interfered with subsequent yoga practice was high among elderly participants (70 years or older) and those with chronic musculoskeletal diseases. CONCLUSIONS: The results of this large-scale survey demonstrated that approximately 30% of yoga class attendees had experienced some type of adverse event. Although the majority had mild symptoms, the survey results indicated that attendees with chronic diseases were more likely to experience adverse events associated with their disease. Therefore, special attention is necessary when yoga is introduced to patients with stress-related, chronic diseases. PMID- 25844088 TI - Genomic profiling of host responses to Lassa virus: therapeutic potential from primate to man. AB - Lassa virus infection elicits distinctive changes in host gene expression and metabolism. We focus on changes in host gene expression that may be biomarkers that discriminate individual pathogens or may help to provide a prognosis for disease. In addition to assessing mRNA changes, functional studies are also needed to discriminate causes of disease from mechanisms of host resistance. Host responses that drive pathogenesis are likely to be targets for prevention or therapy. Host responses to Lassa or its related arenaviruses have been monitored in cell culture, in animal models of hemorrhagic fever, in Lassa-infected nonhuman primates and, to a limited extent, in infected human beings. Here, we describe results from those studies and discuss potential targets for reducing virus replication and mitigating disease. PMID- 25844092 TI - The research capacity and culture of Australian podiatrists. AB - BACKGROUND: Best practice clinical health care is widely recognised to be founded on evidence based practice. Enhancing evidence based practice via the rapid translation of new evidence into every day clinical practice is fundamental to the success of health care and in turn health care professions. There is little known about the collective research capacity and culture of the podiatry profession across Australia. Thus, the aim of this study was to investigate the research capacity and culture of the podiatry profession within Australia and determine if there were any differences between podiatrists working in different health sectors and workplaces. METHOD: All registered podiatrists were eligible to participate in a cross-sectional online survey. The Australian Podiatry Associations disseminated the survey and all podiatrists were encouraged to distribute it to colleagues. The Research Capacity and Culture (RCC) tool was used to collect all research capacity and culture item variables using a 10-point scale (1 = lowest; 10 = highest). Additional demographic, workplace and health sector data variables were also collected. Mann-Whitney-U, Kruskal-Wallis and logistic regression analyses were used to determine any difference between health sectors and workplaces. Word cloud analysis was used for qualitative responses of individual motivators and barriers to research culture. RESULTS: There were 232 fully completed surveys (6% of Australian registered podiatrists). Overall respondents reported low success or skills (Median rating < 4) on the majority of individual success or skill items. Podiatrists working in multi-practitioner workplaces reported higher individual success or skills in the majority of items compared with sole practitioners (p < 0.05). Non-clinical and public health sector podiatrists reported significantly higher post-graduate study enrolment or completion, research activity participation, provisions to undertake research and individual success or skill than those working privately. CONCLUSIONS: This study suggests that podiatrists in Australia report similar low levels of research success or skill to those reported in other allied health professions. The workplace setting and health sector seem to play key roles in self reported research success and skills. This is important knowledge for podiatrists and researchers aiming to translate research evidence into clinical practice. PMID- 25844093 TI - Nonalcoholic fatty liver disease is associated with coronary artery calcium score in diabetes patients with higher HbA1c. AB - BACKGROUND: In patients with diabetes, studies investigating the association between nonalcoholic fatty liver disease (NAFLD) and coronary artery calcium score (CACS) have shown conflicting results. The aim of this study was to evaluate the association between NAFLD and CACS in diabetic patients. METHODS: This is the cohort study performed in Seoul National University Hospital Gangnam Healthcare Center. NAFLD was defined as cases with the typical ultrasonographic findings without excessive alcohol consumption, medications causing hepatic steatosis or other chronic liver diseases. CACS was evaluated using the Agatston method. Diabetes was defined as cases with fasting serum glucose >= 126 mg/dl, glycated hemoglobin (HbA1c) >= 6.5%, or those taking anti-diabetic medications. Multivariate linear regression analyses were performed with use of the interaction term of NAFLD * glycemic level and other confounders of CACS such as age, sex, hypertension, body mass index, waist circumference, HDL cholesterol and triglyceride. RESULTS: A total of 213 participants with diabetes were included in the study. As 77 subjects (36.2%) had CACS 0, causing left sided skewness, CACS was analyzed after log transformation to Ln (CACS + 1). A statistically significant interaction was observed between NAFLD and HbA1c >= 7% (P for interaction = 0.014). While NAFLD was not associated with CACS in the group with HbA1c < 7% (P = 0.229), it was significantly associated in the group with HbA1c >= 7% (P = 0.010) after adjusting for covariates in multivariate analyses. CONCLUSIONS: This study demonstrated an effect modification of glycemic level on the association between NAFLD and CACS. NAFLD was independently associated with CACS only in diabetes patients with higher HbA1c, after adjustment for confounders. PMID- 25844094 TI - Assessment of percutaneous renal access skills during Urology Objective Structured Clinical Examinations (OSCE). AB - INTRODUCTION: The first objective was to assess percutaneous renal access (PCA) skills of urology postgraduate trainees (PGTs) during the Objective Structured Clinical Examinations (OSCEs). The second objective was to determine whether previous experience with percutaneous nephrolithotomy (PCNL) improved performance. METHODS: After obtaining ethics approval, we recruited PGTs from two urology programs in Quebec between postgraduate years (PGY-3 to PGY-5). Each trainee was asked to answer a short questionnaire regarding previous experience in endourologic procedures. After a 3-minute orientation on the PERC Mentor simulator (Simbionix, Cleveland, OH), each trainee was asked to perform task 4, where they had to correctly access all of the renal calyces and pop the balloons in a normal left kidney model. We collected and analyzed data from the questionnaire and the performance report generated by the simulator. RESULTS: In total, 13 PGTs participated in this study. PGTs had performed a median of 200 (range: 50-1000) cystoscopies, 50 (range: 10-125) TURBTs, 30 (range: 0-100) TURPs, 5 (range: 0-50) laser prostatectomies, and 50 (range: 2-125) ureteroscopies prior to this OSCE. PGTs with previous PCNL experience (8/13) had performed a mean of 18.6 +/- 6.3 PCNLs. PGTs with previous PCNL experience performed significantly better in terms of shorter fluoroscopy time (10 +/- 1.5 vs. 5.1 +/- 0.7 min; p = 0.04), fewer attempts required for successful puncture of the pelvi-calyceal system (PCS) (21 +/- 2.3 vs. 13 +/- 1.8; p = 0.02), and had significantly lower complications in terms of fewer infundibular injury (7.4 +/- 1.5 vs. 2 +/- 0.4; p = 0.004) and fewer PCS perforations (11 +/- 1.7 vs. 4.5 +/- 1.2; p = 0.01). CONCLUSION: It is feasible to use the PERC Mentor simulator during OSCEs to assess PCA skills of urology PGTs. PGTs who had previous PCNL experience performed significantly better with fewer complications. PMID- 25844095 TI - In-vitro cytocidal effect of water on bladder cancer cells: The potential role for intraperitoneal lavage during radical cystectomy. AB - INTRODUCTION: We investigate the cytocidal effect of water on bladder cancer cells. Intraperitoneal lavage with sterile water is sometimes used during radical cystectomy to lyse cancer cells that might have escaped the surgical specimen. The efficacy of this approach at the cellular level is unknown. METHODS: Three bladder cancer cell lines of varying grade, RT4, TCCSUP and T24 were exposed to sterile water, and morphological changes were closely observed under microscopy. Changes of cell membrane integrity, cell viability, and cell number of re incubated cells after water exposure were measured to determine water induced hypotonic shock. RESULTS: The low-grade RT4 cells started swelling immediately upon exposure to water followed by rupture within 3 minutes. The higher grade TCCSUP and T24 cells demonstrated limited hypotonic swelling with significantly less cell rupture after 10 minutes. The damage to cell membrane of RT4 cells was evident at 1 minute; only 10.0% of cells were intact at 10 minutes. On the other hand, 41.9% and 77.8% of TCCSUP and T24 cells were intact at 10 minutes, respectively. Percentage of viable cells at 10 minutes was 2.1 +/- 2.3%, 2.3 +/- 0.4%, and 16.1 +/- 0.6% for RT4, TCCSUP, and T24, respectively. CONCLUSIONS: Cytocidal effect of hypotonic shock can be achieved, to varying degrees, by exposing bladder cancer cells to water for at least 10 minutes. This in vitro study may have bearing on the effects seen with intraperitoneal lavage using sterile water during radical cystectomy. PMID- 25844096 TI - Proteomic profile of an acute partial bladder outlet obstruction. AB - INTRODUCTION: Partial bladder outlet obstruction (pBOO) is a ubiquitous problem in urology. From posterior urethral valves to prostatic hypertrophy, pBOO results in significant morbidity and mortality. However, the pathophysiology is not completely understood. Proteomics uses mass spectrometry to accurately quantify change in tissue protein concentration. Therefore, we have applied proteomic analysis to a rodent model to assess for protein changes after a surgically induced pBOO. We hypothesize that proteomic analysis after an acute obstruction will determine the most prevalent initial protein response and, potentially, novel molecular pathways. METHODS: Sprague Dawley rats underwent a surgically induced pBOO (n = 3 per group) for 3, 7, or 14 days. Bladders were assessed for weight and urodynamic parameters. Proteomics used liquid-chromatography based mass spectrometry. Polymerase chain reaction (PCR) was performed on tissue samples to confirm increased mRNA transcription. RESULTS: Bladder weight and capacity increased over the experimental period, but no changes were seen in bladder pressure. Statistically significant increases in protein quantities were seen in 3 proteins related to endoplasmic reticulum stress: GRP-78 (3.66-fold), RhoA (1.90-fold), and RhoA-GDP (1.95-fold), and 2 cytoskeleton molecules: actin (1.7-fold) and tubulin a/b (3.01-fold). Decorin and lumican, members of the small leucine rich proteoglycan (SLRP) family, were also elevated (0.35- and 0.34-fold, respectively). Real-time PCR data confirmed protein elevation. CONCLUSION: Our experiment confirms that molecular changes occur very soon after the initiation of pBOO, and implicates several molecular pathways. We believe these insights may provide insight into novel prevention and treatment strategies targeted at the pathophysiology of pBOO. PMID- 25844097 TI - Minimally invasive surgical treatment for large impacted upper ureteral stones: Ureteroscopic lithotripsy or percutaneous nephrolithotomy? AB - INTRODUCTION: The management of patients with large impacted upper ureteral stones is difficult; there is no standard treatment. We compared the outcomes of percutaneous nephrolithotomy (PCNL) and ureteroscopic lithotripsy (UL) to treat large (>=1.5 cm), impacted, upper ureteral stones. METHODS: In total, 86 patients with large impacted upper ureteral stones were included in this study. Of these patients 41 underwent UL and 45 underwent PCNL. The inclusion criteria were: longest diameter of stone >=1.5 cm, the localization of stone between the lower border of L4 spine and ureteropelvic junction and impacted stone. RESULTS: In the UL group, we were unable to reach the stone in 3 patients because of ureteral stricture and edema despite balloon dilation. Of these 3 patients, we were unable to optimally visualize the stone in 2 patients due to bleeding and mucosal injury following balloon dilation. The stricture was too firm and could not be passed in the third patient. Also in the UL group, 15 patients had stones or big fragments which migrated into the renal collecting system. In the PCNL group, 21 patients had concurrent renal stones <1 cm and stones were successfully removed in all patients. No statistically significant difference was found between groups in terms of operation time. Mean hospital stay was significantly shorter in the UL group. Success rates were 82.3% in the UL group and 97.6% in the PCNL group (p = 0.001). CONCLUSION: The recent study confirms that PCNL is a safe and effective minimally invasive procedure with acceptable complication rates in the treatment of patients with large, impacted upper ureteral stones. PMID- 25844098 TI - Neutrophil-lymphocyte ratio as a predictor of recurrence and progression in patients with high-grade pT1 bladder cancer. AB - INTRODUCTION: We investigated the value of the preoperative neutrophil-lymphocyte ratio (NLR) in predicting recurrence and progression of high-grade pT1 non-muscle invasive tumour in patients with bladder cancer during a 5-year follow-up period. METHODS: We retrospectively reviewed data of 1100 patients with bladder cancer; these patients underwent transurethral resection and were monitored at multiple centres from 2008 to 2013. In total, 166 consecutive and newly diagnosed patients with high-grade pT1 tumours were included in this study. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. RESULTS: Of the 166 patients, 152 were male. The patients were evaluated as two separate groups in terms of recurrence and progression. The mean follow-up period was 24.2 months (interquartile range 13.8-36.6 months). A statistically significant difference was found between recurrence and tumour size (p = 0.001), number of tumours (p < 0.001), NLR (p < 0.001), and smoking (p = 0.007). No statistically significant correlation was found between NLR and progression. According to receiver operating characteristic (ROC) analysis, the optimum cut off value for the NLR was >=2.43 (74% sensitivity, 60% specificity, p < 0.001; area under the curve [AUC] 0.687, 95% confidence interval [CI] 0.607-0.767). Multivariate logistic regression analysis determined that the following factors were independent predictors of recurrence in patients with high-grade pT1 non muscle-invasive bladder cancer: tumour number (OR 5.32, 95% CI 2.10-12.90), NLR of >=2.43 (OR 2.587; 95% CI 1.156-5.789), and smoking (OR 4.17, 95% CI 1.31 13.21). CONCLUSION: A high preoperative NLR may play an important role in predicting recurrence of superficial transitional cell type high-grade pT1 bladder tumours. Prospective studies are required to validate the role of NLR as a prognostic marker in high-grade pT1 bladder tumours. PMID- 25844099 TI - [Not Available]. PMID- 25844100 TI - A rare case of bladder chondroma. AB - Soft tissue chondromas are benign tumours that arise commonly in the hands and feet of adults, but rarely in other locations. Only two prior cases of chondroma of the urinary bladder wall have been reported. We describe a third case and discuss similarities and differences between the three cases reported to date. PMID- 25844101 TI - Renal leiomyosarcoma with soft tissue metastasis: An unusual presentation. AB - Primary renal sarcomas are exceptionally rare, constituting 1% of all malignant renal tumours. Since the prognosis for a renal sarcoma is particularly poor, differentiation from sarcomatoid renal cell carcinoma (RCC) is necessary. Histopathology and immunohistochemistry are the only modes of diagnosing these sarcomas as they have no specific features clinically and radiologically. We report a case of renal leiomyosarcoma which was clinically diagnosed as RCC. Histopathology revealed a spindle cell sarcoma and immunohistochemistry (IHC) confirmed a renal leiomyosarcoma. She also had a liver nodule and mass in the right side of neck and left arm. Biopsy from these sites revealed a similar morphology and IHC confirmed leiomyosarcoma. We report a case illustrating the rarity of this disease and its aggressive nature owing to fatal metastatic potential. PMID- 25844102 TI - Bladder agenesis and incomplete kidney duplication: Ileal reservoir with continent diversion as definitive treatment. AB - Bladder agenesis is an extremely rare entity. A 12-year-old female patient presented with urinary incontinence, recurrent urinary tract infections, visible vaginal introitus and urethra, and two holes at the vulvar vestibule. An investigation revealed bladder agenesis. Surgery confirmed the absence of bladder, and ileal reservoir in omega (Omega) was performed with continent diversion. At the 30-month follow-up, there was no complication in clean intermittent catheterization. PMID- 25844103 TI - An unusual course after injection of industrial silicone for penile augmentation. AB - A 48-year-old male patient had an injection of industrial silicone under the penile skin for augmentation by non-medical practitioners a week before. There was complete necrosis of the dorsal part of the penile skin and soft tissue. In a penile magnetic resonance image, big masses of silicone under the penile skin were found and a part of the silicone was partially exposed. Debridement of the necrotic tissue was done. As the right side of the tunica albuginea was thin walled, a silicone-induced infection developed. Because of this, the wet dressing was done daily without closing the wound for the next 23 days. Finally, both scrotal skins were drawn and sutured to the dorsal glandular skin after the total penile skin was completely removed and sutured with T-style anastomosis. The ventral flap was anastomosed to the ventral glandular skin with the end-to-end technique with inverted V incision at 1 cm proximal from the sutured margin. Flaps survived completely without skin necrosis or dehiscence. PMID- 25844104 TI - Testicular loss following bacterial epididymo-orchitis: Case report and literature review. AB - Epididymo-orchitis rarely leads to abscess formation and global testicular infarction/loss, particularly in the setting of appropriate antibiotic therapy. The imaging modality used when monitoring for testicular ischemia is ultrasonography. However, as described in the literature, testicular pathology may not be evident on routine imaging. We describe two cases of recurrent bacterial epididymo-orchitis, complicated by testicular abscess resulting in testicular infarction. This rare, nevertheless significant, complication occurred in both patients despite receiving appropriate extended antibiotic therapy. Both cases demonstrate the limitations of ultrasonography alone, suggesting that a high level of clinical suspicion must be maintained when ultrasound evaluation proves to be inconsistent with the clinical presentation. These cases demonstrate the importance of monitoring for warning signs of ischemia, as early recognition may lead to reperfusion interventions and ultimately testicular salvage. PMID- 25844105 TI - Correction in author affilation. AB - [This corrects the article on p. e159 in vol. 8, PMID: 24678355.]. PMID- 25844106 TI - Ureteral metastasis of a prostatic adenocarcinoma. AB - The ureter is a rare location of metastasis for any kind of primary tumour. The first case of truly ureteral metastasis was described by Stow in 1909. Regarding prostatic metastasis, the frequency is much lower with only 43 cases reported in the last century. We present a case of an exceedingly rare ureteral metastasis of a prostatic adenocarcinoma. In spite of its low incidence, it should be considered in patients with ureteral obstruction and concurrent prostatic adenocarcinoma. PMID- 25844107 TI - Robotic radical cystectomy with intracorporeal neobladder: Initial experience and outcomes. AB - INTRODUCTION: Total intra-corporeal robot-assisted radical cystectomy (RARC) with total intracorporeal neobladder formation is relatively new in the treatment of bladder cancer. We present our experience and believe it is the first Canadian reported series with this technique. METHODS: This is a case series of 4 patients, who underwent total RARC, pelvic lymphadenectomy and creation of an intra-corporeal ileal neobladder. Surgical technique is described and perioperative variables, pathologic data, and complication rates are reported. RESULTS: The mean patient age was 61.8 and the mean body mass index was 27.01 kg/m(2). The mean operative time, estimated blood loss, time to full diet and length of stay were 522.8 minutes (standard deviation [SD] 74.5), 237.5 mL (SD 47.9), 9 days (range: 3-24) and 12.8 days (range: 6-31), respectively. All patients completed postoperative functional evaluation showing a mean neobladder capacity of 575 cc (range: 500-720). Surgical margins and pathological nodal status were negative in all patients with no evidence of disease recurrence or progression on follow-up. Three of the 4 patients suffered a complication within 90 days, with one occurring later in the first year. All early complications were Clavien grade I-II (grade I [n = 1]; grade II [n = 2]) and the later complication was grade IIIa. The mean follow-up was 632 days (range: 562-730). The limitation of our study is its small sample size with highly selected patients to compensate for the learning experience. The follow-up is short; however, the outcomes are comparable to early experiences reported at other institutions. CONCLUSIONS: In our initial experience, RARC with total intracorporeal neobladder formation is safe. We expect that with experience the expense of robotic surgery can be compensated with early ambulation and shorter stay. PMID- 25844108 TI - Role for (11)C-choline PET in active surveillance of prostate cancer. AB - INTRODUCTION: Active surveillance (AS) is an increasingly popular management strategy for men diagnosed with low-risk indolent prostate cancer. Current tests (prostate-specific antigen [PSA], clinical staging, and prostate biopsies) to monitor indolent disease lack accuracy. (11)C-choline positron emission tomography (PET) has excellent detection rates in local and distant recurrence of prostate cancer. We examine (11)C-choline PET for identifying aggressive prostate cancer warranting treatment in the AS setting. METHODS: In total, 24 patients on AS had clinical assessment and PSA testing every 6 months and (11)C-choline PET and prostate biopsies annually. The sensitivity and specificity to identify prostate cancer and progressive disease (PD) were calculated for each (11)C choline PET scan. RESULTS: In total, 62 biopsy-paired, serial (11)C-choline PET scans were analyzed using a series of standard uptake value-maximum (SUVmax) cut off thresholds. During follow-up (mean 25.3 months), 11 of the 24 low-risk prostate cancer patients developed PD and received definitive treatment. The prostate cancer detection rate with (11)C-choline PET had moderate sensitivity (72.1%), but low specificity (45.0%). PD prediction from baseline (11)C-choline PET had satisfactory sensitivity (81.8%), but low specificity (38.5%). The addition of clinical parameters to the baseline (11)C-choline PET improved specificity (69.2%), with a slight reduction in sensitivity (72.7%) for PD prediction. CONCLUSIONS: Addition of (11)C-choline PET imaging during AS may help to identify aggressive disease earlier than traditional methods. However, (11)C choline PET alone has low specificity due to overlap of SUV values with benign pathologies. Triaging low-risk prostate cancer patients into AS versus therapy will require further optimization of PET protocols or consideration of alternative strategies (i.e., magnetic resonance imaging, biomarkers). PMID- 25844109 TI - Where Are the Fresh Fruits and Vegetables?: A Systematic Exploration of Access to Food Stores Offering Fresh Fruits and Vegetables as Told by Midwestern African American Women. AB - This exploratory study systematically examined Midwestern African American women's (n = 273) access to food stores offering more than 5 fresh fruits and vegetables daily. Access to potential (within 0.5 miles of household) and realized (where participant buys fruits and vegetables most often) food stores was assessed. Descriptive analyses revealed that participants lived closer to food stores not offering more than 5 fresh fruits and vegetables daily. Participants purchased fresh fruits and vegetables from food stores that were an average of 1.2 miles further than the closest food stores offering more than 5 fresh fruits and vegetables daily to their household. Results highlight complexities of the food environment and the need to further investigate factors influencing food-related behaviors. PMID- 25844110 TI - Directional Emission from Metal-Dielectric-Metal Structures: Effect of Mixed Metal Layers, Dye Location and Dielectric Thickness. AB - Metal-dielectric-metal (MDM) structures provide directional emission close to the surface normal, which offers opportunities for new design formats in fluorescence based applications. The directional emission arises due to near-field coupling of fluorophores with the optical modes present in the MDM substrate. Reflectivity simulations and dispersion diagrams provide a basic understanding of the mode profiles and the factors that affect the coupling efficiency and the spatial distribution of the coupled emission. This work reveals that the composition of the metal layers, the location of the dye in the MDM substrate and the dielectric thickness are important parameters that can be chosen to tune the color of the emission wavelength, the angle of observation, the angular divergence of the emission and the polarization of the emitted light. These features are valuable for displays and optical signage. PMID- 25844111 TI - State-of-the-Art: Hypo-responsiveness to oral antiplatelet therapy in patients with type 2 diabetes mellitus. AB - Diabetes mellitus is a global pandemic, associated with a high burden of cardiovascular disease. There are multiple platelet derangements in patients with diabetes, and antiplatelet drugs remain the first-line agents for secondary prevention as well as for high-risk primary prevention among patients with diabetes. This review provides a summary of oral antiplatelet drug hypo responsiveness in patients with diabetes, specifically aspirin and Clopidogrel resistance. Topics discussed include antiplatelet testing, definitions used to define hypo-response and resistance, its prevalence, association with clinical outcomes and strategies to mitigate resistance. The role of prasugrel and ticagrelor, as well as investigational agents, is also discussed. PMID- 25844112 TI - Pseudo-backcrossing design for rapidly pyramiding multiple traits into a preferential rice variety. AB - BACKGROUND: Pyramiding multiple genes into a desirable genetic background can take years to accomplish. In this paper, a pseudo-backcrossing scheme was designed to shorten the backcrossing cycle needed. PinK3, an aromatic and potentially high-yielding rice variety-although one that is intolerant to flash flooding (Sub) and susceptible to bacterial leaf blight (BB), leaf-neck blast (BL) and the brown planthopper (BPH)-was used as a genetic basis for significant improvements through gene pyramiding. RESULTS: Four resistance donors with five target genes (Sub1A-C, xa5, Xa21, TPS and SSIIa) and three QTLs (qBph3, qBL1 and qBL11) were backcrossed individually using markers into the pseudo-recurrent parent 'PinK3' via one cycle of backcrossing followed by two cycles of pseudo backcrossing and three selfings with rigorous foreground marker-assisted selection. In total, 29 pseudo-backcross inbred lines (BILs) were developed. Genome composition was surveyed using 61 simple sequence repeats (SSRs), 35 of which were located on six carrier chromosomes, with the remainder located on six non-carrier chromosomes. The recurrent genome content (%RGC) and donor genome content (%DGC), which were based on the physical positions of BC1F2, ranged from 69.99 to 88.98% and 11.02 to 30.01%, respectively. For the pseudo-BC3F3BILs, the %RGC and %DGC ranged from 74.50 to 81.30% and 18.70 to 25.50%, respectively. These results indicated that without direct background selection, no further increases in %RGC were obtained during pseudo-backcrossing, whereas rigorous foreground marker-assisted selection tended to reduce linkage drag during pseudo backcrossing. The evaluation of new traits in selected pseudo-BC3F3BILs indicated significant improvements in resistance to BB, BL, BPH and Sub compared with PinK3, as well as significant improvements in grain yield (21-68%) over the donors, although yield was 7-26% lower than in 'PinK3'. All pyramided lines were aromatic and exhibited improved starch profiles, rendering them suitable for industrial food applications. CONCLUSIONS: Results show that our new pyramiding platform, which is based on marker-assisted pseudo-backcrossing, can fix five target genes and three QTLs into a high-yielding pseudo-recurrent background within seven breeding cycles in four years. This multiple pseudo-backcrossing platform decreases the time required to generate new rice varieties exhibiting complex, durable resistance to biotic and abiotic stresses in backgrounds with desirable qualities. PMID- 25844113 TI - A QTL for root growth angle on rice chromosome 7 is involved in the genetic pathway of DEEPER ROOTING 1. AB - BACKGROUND: Root growth angle (RGA) is an important trait that influences the ability of rice to avoid drought stress. DEEPER ROOTING 1 (DRO1), which is a major quantitative trait locus (QTL) for RGA, is responsible for the difference in RGA between the shallow-rooting cultivar IR64 and the deep-rooting cultivar Kinandang Patong. However, the RGA differences between these cultivars cannot be fully explained by DRO1. The objective of this study was to identify new QTLs for RGA explaining the difference in RGA between these cultivars. RESULTS: By crossing IR64 (which has a non-functional allele of DRO1) with Kinandang Patong (which has a functional allele of DRO1), we developed 26 chromosome segment substitution lines (CSSLs) that carried a particular chromosome segment from Kinandang Patong in the IR64 genetic background. Using these CSSLs, we found only one chromosomal region that was related to RGA: on chromosome 9, which includes DRO1. Using an F2 population derived from a cross between Kinandang Patong and the Dro1-NIL (near isogenic line), which had a functional DRO1 allele in the IR64 genetic background, we identified a new QTL for RGA (DRO3) on the long arm of chromosome 7. CONCLUSIONS: DRO3 may only affect RGA in plants with a functional DRO1 allele, suggesting that DRO3 is involved in the DRO1 genetic pathway. PMID- 25844115 TI - Exploring the power of plants to overcome environmental stresses. PMID- 25844114 TI - Shading during the grain filling period increases 2-acetyl-1-pyrroline content in fragrant rice. AB - BACKGROUND: Fragrant rice, including Thai jasmine and Indian basmati varieties, is highly valued by consumers globally. 2-acetyl-1-proline (2-AP) is the major compound responsible for the aromatic character of fragrant rice. Previously, environmental factors such as water management and salinity have been proven to influence 2-AP levels in fragrant rice; assessing the effect of additional environmental factors on 2-AP concentration is therefore eminent. The level of solar radiation (solar intensity; SI) to which a crop is exposed can affect growth, yield and grain quality, and other photosynthetic and physiological characteristics. In this study the effect of shading (i.e. the reduction of SI) on yield, quality, and 2-AP concentration in two elite Chinese fragrant rice varieties, 'Yuxiangyouzhan' and 'Nongxiang 18', has been investigated. Furthermore, accumulation of the plant stress response molecules proline and gamma-aminobutyric acid, which have also been implicated in pathways leading to 2 AP production, was assessed to study shading effects on these compounds in fragrant rice, and to further possibly determine fluxes in biochemical pathways leading to 2-AP accumulation. RESULTS: This study has revealed significant changes in the yield and quality characters under shading treatment. Additionally, 2-AP and GABA content in grains was significantly increased for all shading treatments in both varieties. In addition to 2-AP, ten other volatile compounds were studied; results indicated that shading treatments could have a selective effect on the metabolism of these volatile compounds. CONCLUSIONS: In this study, we have demonstrated that shading during grain filling has significant effects on yield and quality traits in rice, and leads to the accumulation of GABA and 2-AP. We discuss the implications of these findings in terms of pathways leading to 2-AP and GABA production in fragrant rice, which have not been fully elucidated. The shading effect on ten additional volatile compounds is also discussed. Finally we discuss possible effects of variation in solar intensity resulting from anthropogenic emissions on fragrant rice production. PMID- 25844116 TI - Molecular breeding of thermo-sensitive genic male sterile (TGMS) lines of rice for blast resistance using Pi2 gene. AB - BACKGROUND: Blast disease caused by the fungal pathogen Magnaporthe oryzae is one of the big problems in rice production in China, especially for high yield hybrid varieties made from a two-line system in which thermo-sensitive genic male sterile (TGMS) lines are used. In this study, we report the introgression of a rice blast resistance gene Pi2 from VE6219 into C815S, an elite rice TGMS line, leading to the development of blast resistant TGMS lines through marker assisted selection (MAS) and phenotypic selection approaches. RESULTS: Four new TGMS lines with blast resistance gene Pi2 were developed from C815S (an elite TGMS line susceptible to the blast, used as recurrent parent) and VE6219 (a blast resistant line harboring Pi2, used as donor parent). The pathogenicity assays inoculated with 53 blast prevalent isolates in glasshouse showed that the blast resistant frequency of the four TGMS lines was 94.3%-98.1% that is equivalent to blast resistant donor parent VE6219. The field evaluation of the new lines and hybrids made from them at a blast epidemic site also showed high resistant levels against the blast. The genetic background of the newly developed TGMS lines were examined using a whole-genome single nucleotide polymorphism (SNP) array (RICE6K) that turned out more than 83% of the genomic markers were derived from the recurrent parent. The critical temperature points of fertility-sterility alteration of the new TGMS lines were between 22 degrees C and 23 degrees C of daily mean temperature, which is similar to that of C815S. The complete male sterility under natural growth conditions at Wuhan last more than 80 days. Their agronomic and grain quality traits meet the requirement for two-line hybrid rice production. CONCLUSIONS: The broad-spectrum and durable rice blast resistant gene Pi2 was introgressed into the elite TGMS line C815S background. The newly developed TGMS lines can be practically used for two-line hybrid rice breeding and must play an important role in sustainable rice production in China. PMID- 25844117 TI - Multiple tissue-specific expression of rice seed-shattering gene SH4 regulated by its promoter pSH4. AB - BACKGROUND: Rice seed shattering is an important domestication syndrome encoded by a gene named as SH4. The coding region of SH4 has been well studied regarding its function and roles in evolution. However, its promoter has not been identified, which limited our understanding of the detailed regulatory mechanisms of this gene. It is therefore critical to characterize the promoter and study its expression pattern. RESULTS: We analyzed the 5' upstream sequences of this gene and identified a ~2.6 kb fragment with typical promoter features, which was designated as pSH4. The promoter contained a number of cis-acting elements related to abscisic acid (ABA) and a CpG island that were characteristics of multiple tissue-specific expression. We isolated and ligated pSH4 to the beta glucuronidase (GUS) reporter gene, and transformed it into a japonica rice cultivar to determine the multiple expression pattern of SH4. Histochemical location and fluorescence analyses of GUS activity of transgenic plants indicated multiple tissue-specific expression of pSH4 in the seed-pedicel junction region of mature panicles (with highest level), stems, coleoptiles of germinated seeds, and scutella of mature seeds. CONCLUSIONS: The multiple tissue-specific expression pSH4 is categorized as a spatiotemporal promoter that drives the expression of the SH4 gene in different rice tissues, in addition to the seed pedicel junction region. Our findings suggest that SH4 may have additional functions in the growth and development of rice, apart from its major role in seed shattering. PMID- 25844118 TI - Abiotic stress and genome dynamics: specific genes and transposable elements response to iron excess in rice. AB - BACKGROUND: Iron toxicity is a root related abiotic stress, occurring frequently in flooded soils. It can affect the yield of rice in lowland production systems. This toxicity is associated with high concentrations of reduced iron (Fe(2+)) in the soil solution. Although the first interface of the element is in the roots, the consequences of an excessive uptake can be observed in several rice tissues. In an original attempt to find both genes and transposable elements involved in the response to an iron toxicity stress, we used a microarray approach to study the transcriptional responses of rice leaves of cv. Nipponbare (Oryza sativa L. ssp. japonica) to iron excess in nutrient solution. RESULTS: A large number of genes were significantly up- or down-regulated in leaves under the treatment. We analyzed the gene ontology and metabolic pathways of genes involved in the response to this stress and the cis-regulatory elements (CREs) present in the promoter region of up-regulated genes. The majority of genes act in the pathways of lipid metabolic process, carbohydrate metabolism, biosynthesis of secondary metabolites and plant hormones. We also found genes involved in iron acquisition and mobilization, transport of cations and regulatory mechanisms for iron responses, and in oxidative stress and reactive oxygen species detoxification. Promoter regions of 27% of genes up-regulated present at least one significant occurrence of an ABA-responsive CRE. Furthermore, and for the first time, we were able to show that iron stress triggers the up-regulation of many LTR retrotransposons. We have established a complete inventory of transposable elements transcriptionally activated under iron excess and the CREs which are present in their LTRs. CONCLUSION: The short-term response of Nipponbare seedlings to iron excess, includes activation of genes involved in iron homeostasis, in particular transporters, transcription factors and ROS detoxification in the leaves, but also many transposable elements. Our data led to the identification of CREs which are associated with both genes and LTR retrotransposons up-regulated under iron excess. Our results strengthen the idea that LTR-retrotransposons participate in the transcriptional response to stress and could thus confer an adaptive advantage for the plant. PMID- 25844120 TI - Allelic effects on starch structure and properties of six starch biosynthetic genes in a rice recombinant inbred line population. AB - BACKGROUND: The genetic diversity of six starch biosynthetic genes (Wx, SSI, SSIIa, SBEI, SBEIIa and SBEIIb) in indica and japonica rices opens an opportunity to produce a new variety with more favourable grain starch quality. However, there is limited information about the effects of these six gene allele combinations on starch structure and properties. A recombinant inbred line population from a cross between indica and japonica varieties offers opportunities to combine specific alleles of the six genes. RESULTS: The allelic (indica vs japonica) effects of six starch biosynthetic genes on starch structure, functional properties, and abundance of granule bound proteins in rice grains were investigated in a common genetic background using a recombinant inbred line population. The indica Wx (Wxi) allele played a major role while indica SSI (SSIi), japonica SSIIa (SSIIaj) and indica SBEI (SBEIi) alleles had minor roles on the increase of amylose content. SSIIaj and japonica SBEIIb (SBEIIbj) alleles had a major and a minor role on high ratio of ?DP <= 10 to ?DP <= 24 fractions (RCL10/24), respectively. Both major alleles (Wxi and SSIIaj) reduced peak viscosity (PV), onset, peak and end gelatinization temperatures (GTs) of amylopectin, and increased amylose-lipid complex dissociation enthalpy compared with their counterpart-alleles, respectively. SBEIIai and SBEIIbj decreased PV, whereas SSIi and SBEIIbj decreased FV. SBEIi reduced setback viscosity and gelatinization enthalpy. RCL10/24 of chain length distribution in amylopectin is negatively correlated with PV and BD of paste property and GTs of thermal properties. We also report RILs with superior starch properties combining Wxi, SSIj, SSIIaj, SBEIi and SBEIIbj alleles. Additionally, a clear relation is drawn to starch biosynthetic gene alleles, starch structure, properties, and abundance of granule bound starch biosynthetic enzymes inside starch granules. CONCLUSIONS: Rice Wxi and SSIIaj alleles play major roles, while SSIi, SBEIi, SBEIIai and SBEIIbj alleles have minor roles in the determination of starch properties between indica and japonica rice through starch structural modification. The combination of these alleles is a key factor for starch quality improvement in rice breeding programs. RCL10/24 value is critical for starch structure and property determination. PMID- 25844121 TI - QTLs underlying natural variation of root growth angle among rice cultivars with the same functional allele of DEEPER ROOTING 1. AB - BACKGROUND: The functional allele of the rice gene DEEPER ROOTING 1 (DRO1) increases the root growth angle (RGA). However, wide natural variation in RGA is observed among rice cultivars with the functional DRO1 allele. To elucidate genetic factors related to such variation, we quantitatively measured RGA using the basket method and analyzed quantitative trait loci (QTLs) for RGA in three F2 mapping populations derived from crosses between the large RGA-type cultivar Kinandang Patong and each of three accessions with varying RGA: Momiroman has small RGA and was used to produce the MoK-F2 population; Yumeaoba has intermediate RGA (YuK-F2 population); Tachisugata has large RGA (TaK-F2 population). All four accessions belong to the same haplotype group of functional DRO1 allele. RESULTS: We detected the following statistically significant QTLs: one QTL on chromosome 4 in MoK-F2, three QTLs on chromosomes 2, 4, and 6 in YuK F2, and one QTL on chromosome 2 in TaK-F2. Among them, the two QTLs on chromosome 4 were located near DRO2, which has been previously reported as a major QTL for RGA, whereas the two major QTLs for RGA on chromosomes 2 (DRO4) and 6 (DRO5) were novel. With the LOD threshold reduced to 3.0, several minor QTLs for RGA were also detected in each population. CONCLUSION: Natural variation in RGA in rice cultivars carrying functional DRO1 alleles may be controlled by a few major QTLs and by several additional minor QTLs. PMID- 25844119 TI - Upstream regulatory architecture of rice genes: summarizing the baseline towards genus-wide comparative analysis of regulatory networks and allele mining. AB - Dissecting the upstream regulatory architecture of rice genes and their cognate regulator proteins is at the core of network biology and its applications to comparative functional genomics. With the rapidly advancing comparative genomics resources in the genus Oryza, a reference genome annotation that defines the various cis-elements and trans-acting factors that interface each gene locus with various intrinsic and extrinsic signals for growth, development, reproduction and adaptation must be established to facilitate the understanding of phenotypic variation in the context of regulatory networks. Such information is also important to establish the foundation for mining non-coding sequence variation that defines novel alleles and epialleles across the enormous phenotypic diversity represented in rice germplasm. This review presents a synthesis of the state of knowledge and consensus trends regarding the various cis-acting and trans-acting components that define spatio-temporal regulation of rice genes based on representative examples from both foundational studies in other model and non-model plants, and more recent studies in rice. The goal is to summarize the baseline for systematic upstream sequence annotation of the rapidly advancing genome sequence resources in Oryza in preparation for genus-wide functional genomics. Perspectives on the potential applications of such information for gene discovery, network engineering and genomics-enabled rice breeding are also discussed. PMID- 25844123 TI - Subcortical shape and volume abnormalities in an elderly HIV+ cohort. AB - Over 50% of HIV+ individuals show significant impairment in psychomotor functioning, processing speed, working memory and attention [1, 2]. Patients receiving combination antiretroviral therapy may still have subcortical atrophy, but the profile of HIV-associated brain changes is poorly understood. With parametric surface-based shape analyses, we mapped the 3D profile of subcortical morphometry in 63 elderly HIV+ subjects (4 female; age=65.35 +/- 2.21) and 31 uninfected elderly controls (2 female; age=64.68 +/- 4.57) scanned with MRI as part of a San Francisco Bay Area study of elderly people with HIV. We also investigated whether morphometry was associated with nadir CD4+ (T-cell) counts, viral load and illness duration among HIV+ participants. FreeSurfer was used to segment the thalamus, caudate, putamen, pallidum, hippocampus, amygdala, accumbens, brainstem, callosum and ventricles from brain MRI scans. To study subcortical shape, we analyzed: (1) the Jacobian determinant (JD) indexed over structures' surface coordinates and (2) radial distances (RD) of structure surfaces from a medial curve. A JD less than 1 reflects regional tissue atrophy and greater than 1 reflects expansion. The volumes of several subcortical regions were found to be associated with HIV status. No regional volumes showed detectable associations with CD4 counts, viral load or illness duration. The shapes of numerous subcortical regions were significantly linked to HIV status, detectability of viral RNA and illness duration. Our results show subcortical brain differences in HIV+ subjects in both shape and volumetric domains. PMID- 25844124 TI - The values shown on optical technology-based patient monitors must be cautiously interpreted: intravenous dye-induced errors. PMID- 25844122 TI - Group-Sequential Strategies in Clinical Trials with Multiple Co-Primary Outcomes. AB - We discuss the decision-making frameworks for clinical trials with multiple co primary endpoints in a group-sequential setting. The decision-making frameworks can account for flexibilities such as a varying number of analyses, equally or unequally spaced increments of information and fixed or adaptive Type I error allocation among endpoints. The frameworks can provide efficiency, i.e., potentially fewer trial participants, than the fixed sample size designs. We investigate the operating characteristics of the decision-making frameworks and provide guidance on constructing efficient group-sequential strategies in clinical trials with multiple co-primary endpoints. PMID- 25844125 TI - The first step to good clinical research: statistical thinking. PMID- 25844126 TI - Transfusion-related acute lung injury; clinical perspectives. AB - Transfusion-related acute lung injury (TRALI) was introduced in 1983 to describe a clinical syndrome seen within 6 h of a plasma-containing blood products transfusion. TRALI is a rare transfusion complication; however, the FDA has suggested that TRALI is the leading cause of transfusion-related mortality. Understanding the pathogenesis of TRALI will facilitate adopting preventive strategies, such as deferring high plasma volume female product donors. This review outlines the clinical features, pathogenesis, treatment, and prevention of TRALI. PMID- 25844127 TI - Statistical and methodological considerations for reporting RCTs in medical literature. AB - Randomized controlled trials (RCTs) are known to provide the most reliable evidence on intervention. However, RCTs are often conducted and reported incompletely and inadequately, making readers and reviewers unable to judge the validity and reliability of the trials. In this article, we consider the statistical and methodological issues involved in reporting on RCTs, particularly in relation to the objectives, designs, and commencements of trials. This paper deals with the various issues that should be considered in presenting RCTs, and suggests checklists for reporting on them. We expect that these checklists will remind readers and reviewers to evaluate manuscripts systematically and comprehensively, making those manuscripts more transparent and reliable. PMID- 25844128 TI - Comparison of the rate of successful endotracheal intubation between the "sniffing" and "ramped" positions in patients with an expected difficult intubation: a prospective randomized study. AB - BACKGROUND: Optimal head and neck positioning and clinical experience are important factors for successful endotracheal intubation in patients with a difficult airway. This study aimed to investigate the rate of successful endotracheal intubation between the sniffing and ramped positions in patients with an expected difficult intubation. METHODS: The study included 204 patients with an expected difficult intubation (airway difficulty score >= 8) based on the preoperative airway assessment. The patients were randomized into the following groups: group S was placed in the sniffing position, and group R was placed in the ramped position during direct laryngoscopy. The primary outcome was successful endotracheal intubation and the secondary measure was laryngeal view in the ramped or sniffing position when the operating table was placed at two different heights. RESULTS: Group R showed a higher rate of successful endotracheal intubation and better laryngeal view than group S (P < 0.05). The rate of successful endotracheal intubation was higher in group R than in group S at both heights of the operating table; but, it was not different within each group. Laryngeal view was not different between the two groups and within each group when the two heights of the operating table were used. Fully trained and experienced attending anesthesiologists achieved a higher rate of successful endotracheal intubation than less experienced residents in group R (P < 0.05) but not in group S. CONCLUSIONS: Ramped position and clinical experience can be important factors for laryngeal view and success rate of endotracheal intubation in patients with an expected difficult intubation. PMID- 25844129 TI - Effects of intravenously administered indocyanine green on near-infrared cerebral oximetry and pulse oximetry readings. AB - BACKGROUND: Intravenously administered indocyanine green (ICG) may cause misreadings of cerebral oximetry and pulse oximetry in patients undergoing carotid endarterectomy under general anesthesia. The present study determined the effects of two different doses (12.5 mg vs. 25 mg) of ICG on regional cerebral tissue oxygen saturation (SctO2) and percutaneous peripheral oxygen saturation (SpO2). METHODS: Twenty-six patients receiving ICG for videoangiography were divided into two groups according to the dosage (12.5 mg and 25 mg, n = 13 in each group). Heart rate, arterial blood pressure, SctO2, and SpO2 were measured before and after an intravenous bolus administration of ICG. RESULTS: Following the dye administration, no changes in heart rate or arterial blood pressure were noted in either group. SctO2 was increased in both groups; however, the magnitude of the increase was greater (21.6 +/- 5.8% vs. 12.6 +/- 4.1%, P < 0.0001) and more prolonged (28.4 +/- 9.6 min vs. 13.8 +/- 5.2 min, P < 0.0001) in the 25 mg group than in the 12.5 mg group. In contrast, SpO2 was decreased in both groups; the magnitude of the decrease was greater in the 25 mg group than in the 12.5 mg group (4.0 +/- 0.8% vs. 1.6 +/- 1.0%, P < 0.0001). There were no differences in the time to reach the peak SctO2 or to reach the nadir SpO2 between the two groups. CONCLUSIONS: In patients given ICG for videoangiography, a 25 mg bolus results in a greater and more prolonged increase in SctO2 and a greater reduction in SpO2 than a 12.5 mg bolus, with no differences in the time to reach the peak SctO2 or to reach the nadir SpO2. PMID- 25844130 TI - The predictive performance of infusion strategy nomogram based on a fluid kinetic model. AB - BACKGROUND: In a previous study, fluid kinetic models were applied to describe the volume expansion of the fluid space by administration of crystalloid and colloid solutions. However, validation of the models were not performed, it is necessary to evaluate the predictive performance of these models in another population. METHODS: Ninety five consenting patients undergoing elective spinal surgery under general anesthesia were enrolled in this study. These patients were randomly assigned to three fluid groups i.e. Hartmann's solution (H group, n = 28), Voluven(r) (V group, n = 34), and Hextend(r) (X group, n = 33). After completion of their preparation for surgery, the patients received a loading and maintenance volume of each fluid predetermined by nomograms based on fluid pharmacokinetic models during the 60-minute use of an infusion pump. Arterial samples were obtained at preset intervals of 0, 10, 20, and 30 min after fluid administration. The predictive performances of the fluid kinetic modes were evaluated using the fractional change of arterial hemoglobin. The relationship between blood-volume dilution and target dilution of body fluid space was also evaluated using regression analysis. RESULTS: A total of 194 hemoglobin measurements were used. The bias and inaccuracy of these models were -2.69 and 35.62 for the H group, -1.53 and 43.21 for the V group, and 9.05 and 41.82 for the X group, respectively. The blood-volume dilution and target dilution of body fluid space showed a significant linear relationship in each group (P < 0.05). CONCLUSIONS: Based on the inaccuracy of predictive performance, the fluid-kinetic model for Hartmann's solution showed better performance than the other models. PMID- 25844131 TI - Comparison of etomidate and propofol on intubating conditions and the onset time associated with cisatracurium administration. AB - BACKGROUND: This study compared intubating conditions and the onset time associated with administration of cisatracurium, a nondepolarizing neuromuscular blocker with a relatively slow onset, according to prior injection of one of two intravenous anesthetic agents: propofol or etomidate. METHODS: Forty-six female patients, undergoing general anesthesia and endotracheal intubation for elective surgery, were randomized to two groups; group P were administered propofol (2 mg/kg) prior to cisatracurium (0.2 mg/kg); group E were administered etomidate (0.3 mg/kg) prior to cisatracurium (0.2 mg/kg). We measured intubating conditions and the onset time according to the types of intravenous anesthetic administered. Measurements of heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken immediately prior to induction; immediately and 1 min after IV anesthetic administration; and immediately and 1, 2, 3, 4, 5, 7, and 15 min after endotracheal intubation. RESULTS: Intubating conditions were superior in group E compared with group P (P = 0.009). The average onset time of cisatracurium was more rapid in group E (155.74 +/- 32.92 s vs. 185.26 +/- 38.57 s in group P; P = 0.008). There were no group differences in SBP, DBP, and HR following intravenous anesthetic drug injection and endotracheal intubation. However, SBP and DBP were substantially higher in group E after endotracheal intubation. CONCLUSIONS: Etomidate improves intubating conditions and provide a more rapid onset time of cisatracurium during anesthetic induction compared to propofol. PMID- 25844132 TI - Epidural anesthesia for pilonidal sinus surgery: ropivacaine versus levobupivacaine. AB - BACKGROUND: Epidural anesthesia is one of the best options for lower abdominal and lower limb surgery. However, there have been insufficient reports regarding the use of epidural anesthesia for pilonidal sinus surgery. The present study was performed to compare the clinical profiles of epidural block performed with 0.75% levobupivacaine and 0.75% ropivacaine in this procedure. METHODS: Thirty patients undergoing pilonidal sinus surgery were randomly allocated into two groups: one group received levobupivacaine and the other received ropivacaine at 0.75% in a volume of 10 ml. Arterial blood pressure, heart rate, oxygen saturation, the onset time of analgesia and duration of block, highest sensory block level, perioperative and postoperative side effects, and patients' and surgeons' satisfaction were recorded. RESULTS: Hemodynamic stability was maintained in both groups throughout surgery. The onset time of analgesia (the time from epidural injection of local anesthetic to reach L2 sensorial block) was 6.26 +/- 3.49 min in the levobupivacaine group and 4.06 +/- 1.75 min in the ropivacaine group (P = 0.116). The duration of sensorial block (time for regression of sensory block to L2) was 297.73 +/- 70.94 min in group L and 332.40 +/- 102.22 min in group R (P = 0.110). Motor block was not seen in any of the patients in the study groups. Patients' and surgeons' satisfaction with the anesthetic technique were mostly excellent in both groups. CONCLUSIONS: In patients undergoing pilonidal sinus surgery, both levobupivacaine and ropivacaine produce rapid and excellent epidural block without leading to motor block or significant side effects. Although not statistically significant, the onset time of anesthesia was shorter and the duration of effect was longer with ropivacaine than with levobupivacaine in this study. PMID- 25844133 TI - The optimal anesthetic depth for interventional neuroradiology: comparisons between light anesthesia and deep anesthesia. AB - BACKGROUND: This study was designed to determine the optimal anesthetic depth for the maintenance and recovery in interventional neuroradiology. METHODS: Eighty eight patients undergoing interventional neuroradiology were randomly allocated to light anesthesia (n = 44) or deep anesthesia (n = 44) groups based on the value of the bispectral index (BIS). Anesthesia was induced with propofol, alfentanil, and rocuronium and maintained with 1-3% sevoflurane. The concentration of sevoflurane was titrated to maintain BIS at 40-49 (deep anesthesia group) or 50-59 (light anesthesia group). Phenylephrine was used to maintain the mean arterial pressure within 20% of preinduction values. Recovery times were recorded. RESULTS: The light anesthesia group had a more rapid recovery to spontaneous ventilation, eye opening, extubation, and orientation (4.1 +/- 2.3 vs. 5.3 +/- 1.8 min, 6.9 +/- 3.2 min vs. 9.1 +/- 3.2 min, 8.2 +/- 3.1 min vs. 10.7 +/- 3.3 min, 10.0 +/- 3.9 min vs. 12.9 +/- 5.5 min, all P < 0.01) compared to the deep anesthesia group. The use of phenylephrine was significantly increased in the deep anesthesia group (768 +/- 184 vs. 320 +/- 82 ug, P < 0.01). More patients moved during the procedure in the light anesthesia group (6/44 [14%] vs. 0/44 [0%], P = 0.026). CONCLUSIONS: BIS values between 50 and 59 for interventional neuroradiology were associated with a more rapid recovery and favorable hemodynamic response, but also with more patient movement. We suggest that maintaining BIS values between 40 and 49 is preferable for the prevention of patient movement during anesthesia for interventional neuroradiology. PMID- 25844134 TI - Comparison of oxycodone and fentanyl for postoperative patient-controlled analgesia after laparoscopic gynecological surgery. AB - BACKGROUND: Opioids are widely used in boluses and patient-controlled analgesia (PCA) for postoperative pain control. In this study, we compared the effects of oxycodone and fentanyl on postoperative pain in patients with intravenous patient controlled analgesia (IV-PCA) after laparoscopic gynecological surgery. METHODS: Seventy-four patients undergoing elective total laparoscopic hysterectomy or laparoscopic myomectomy were randomly assigned to the administration of either fentanyl or oxycodone using IV-PCA (potency ratio 1 : 60). The cumulative dose administered in the patient-controlled mode during the initial 48 hours after the operation was measured. Patients were also assessed for postoperative pain severity, adverse effects, and patient satisfaction. RESULTS: No significant differences were observed in patient satisfaction with the analgesia during the postoperative period. Patients in the oxycodone group experienced significantly more dizziness compared to the fentanyl group. Patients in the oxycodone group showed significantly lower consumption of opioid in the patient-controlled mode (10.1 +/- 8.5 ml vs. 16.6 +/- 12.0 ml, P = 0.013). CONCLUSIONS: Our data suggest that oxycodone and fentanyl demonstrated similar effects, and therefore oxycodone may be a good alternative to fentanyl in postoperative pain management. Further studies in various clinical settings will be needed to determine the adequate potency ratio. PMID- 25844135 TI - The time-course and RNA interference of TNF-alpha, IL-6, and IL-1beta expression on neuropathic pain induced by L5 spinal nerve transection in rats. AB - BACKGROUND: The objective of this study was to investigate the time-course of the expression of TNF-alpha, IL-6, and IL-1beta after L5 spinal nerve transection (SNT), and to determine the effect of small interfering RNA (siRNA) targeting these cytokines on neuropathic pain. METHODS: Rats received control siRNA (CON group, n = 80) or a cocktail of siRNAs targeting these cytokines (COCK group, n = 70). The siRNAs were given via intrathecal catheter 1 d prior to SNT, on the operation day, and 1, 2 and 3 d postoperatively. Behavioral tests and levels of the cytokine mRNAs and proteins as well as glial cell activity were following the L5 SNT. RESULTS: In the CON group, TNF-alpha and IL-1beta mRNA levels increased immediately after SNT and remained high for 6 d, while IL-6 transcripts only began to increase after 12 h. TNF-alpha and IL-1beta mRNA levels in the COCK group were lower than in the CON group at all time points (P < 0.05). In the behavioral tests, allodynia and hyperalgesia were significantly lower in the COCK group from 2 d after SNT (P < 0.05). CONCLUSIONS: The time courses of TNF-alpha, IL-6 and IL-1beta mRNA expression after L5 SNT differ. RNA interference may be a method of reducing the development of mechanical allodynia and hyperalgesia in response to nerve injury. PMID- 25844136 TI - Expression of the spinal 5-HT7 receptor and p-ERK pathway in the carrageenan inflammatory pain of rats. AB - BACKGROUND: Although the inhibitory role of the 5-hydroxytrypatmine receptor 7(5 HT7R) on nociceptive processing is generally recognized, an excitatory effect associated with a reduced 5-HT7R expression has also been observed in the nerve injury model. In the carrageenan model, no significant effect is produced by the 5-HT7R activation, but the change in 5-HT7R expression has not been examined. Lesioning of the spinal serotonergic pathway enhances allodynia in the carrageenan model, but it also relieves several other pain states, including in the formalin model. While lesioning suppresses the activation of the extracellular signal-regulated kinase (ERK) of the spinal cord in the formalin model, its role in the carrageenan model has not been reported. METHODS: Following intraplantar injections of carrageenan, the spinal 5-HT7R expression was examined using Western blotting in male Sprague-Dawley rats. The effect of serotonergic pathway lesioning with intrathecal 5,7-dihydroxytryptamine (5,7-DHT) on the expression of the phospho-ERK was measured. RESULTS: The expression of the 5-HT7R in the carrageenan model was not significantly different from that of naive animals. The expression of the spinal p-ERK in the carrageenan model was significantly increased, but returned to the level of a naive rat 1 hour after the carrageenan injection. However, it remained significantly higher 1 hour after the injection in the animals treated with 5,7-DHT than in the naive and control rats. CONCLUSIONS: The expression of the spinal 5-HT7R is not altered by peripheral inflammation with carrageenan, suggesting that the lack of antinociceptive effect of the 5-HT7R activation is partly attributable to the absence of changes in the expression of the 5-HT7R in the spinal cord. The extended increase of the spinal p-ERK might be related to the enhanced pain behavior in the animals with lesions of the spinal serotonergic pathway in the carrageenan model. PMID- 25844137 TI - Malposition of central venous catheter in the jugular venous arch via external jugular vein -a case report. AB - The central venous cannulation is commonly performed in the operating rooms and intensive care units for various purposes. Although the central venous catheter (CVC) is used in many ways, the malpositioning of the CVC is often associated with serious complications. We report a case of an unexpected malposition of a CVC in the jugular venous arch via external jugular vein. PMID- 25844138 TI - Epidural anesthesia for permanent spinal cord stimulation with a cylindrical type lead: a case series. AB - Spinal cord stimulation (SCS) in trials involving external stimulation are easily conducted under local anesthesia. However, implantation of a permanent SCS system is painful, and can be intolerable in some patients. Epidural anesthesia can be used to perform the SCS implantation without discomfort if the patient can localize the area of paresthesia. However, little is known about epidural anesthesia for SCS. This paper reports 23 cases of permanent SCS with a cylindrical type lead implanted under the epidural anesthesia. Epidural anesthesia was sufficient in 22 patients without discomfort and significant complications. The remaining patient experienced incomplete epidural anesthesia and required additional analgesics to blunt the pain. All the leads were placed consistent with the patient's report of paresthesia area under epidural anesthesia. Thus, epidural anesthesia is an effective and safe method for the optimal placement of SCS to minimize the discomfort for patients without impairing patients' response to the intraoperative stimulation test. PMID- 25844139 TI - Hydrothorax with alveolar-pleural fistula mimicking re-expansion pulmonary edema during liver transplantation: a case report. AB - We present a case of an alveolar-pleural fistula with hepatic hydrothorax in a patient undergoing orthotropic liver transplantation, which was detected by drainage of transudate through an endotracheal tube during operation. A standard endotracheal tube was changed to a double-lumen tube to provide differential lung ventilation. The patient was diagnosed with an alveolar-pleural fistula by direct vision of an air leak during positive-pressure ventilation through a diaphragmatic incision. There was still a concern about worsening his ventilation due to persistent aspiration of pleural effusion towards the ipsilateral lung during the remaining operation period. Surgeon repaired the defect on the exposed lung surface via diaphragmatic opening. Anesthesiologists should consider an alveolar-pleural fistula as a possible differential diagnosis with re-expansion pulmonary edema when transudate emanating from the endotracheal tube is obtained in patients with massive hydrothorax. PMID- 25844140 TI - Acute gastric dilatation causing fatal outcome in a young female with eating disorder: a case report. AB - A 21-year-old female with a history of bulimia nervosa came to the emergency room due to severe abdominal pain after excessive eating five hours previously. On arrival at the emergency room, extreme abdominal distension was detected and the patient's legs changed color. Computed tomography suggested severe gastric dilatation, so abdominal compartment syndrome was suspected and an emergent laparotomy was supposed to be conducted. Though anesthesia was induced without event, abrupt hemodynamic collapse developed just after the operation started. In spite of active resuscitation for 29 min, the patient did not recover and expired. As the incidence of eating disorders is increasing, anesthesiologists should keep in mind the possibility of abdominal compartment syndrome in patients with a recent history of binge eating, and prepare optimal anesthetic and resuscitation remedies against sudden deteriorations of a patient's condition. PMID- 25844141 TI - Complete resolution of myoclonus-like involuntary movements under subarachnoid block after midazolam administration in a patient undergoing cesarean section: a case report. AB - Involuntary movement during and after neuraxial anesthesia, such as spinal and epidural anesthesia, is rarely observed. In this report, we describe a case of myoclonus-like involuntary movement of the upper extremities in a patient undergoing a planned repeat cesarean section under spinal anesthesia with bupivacaine that completely subsided after administration of 2 mg of midazolam. The myoclonus-like movement did not recur or cause any apparent neurological side effects. PMID- 25844142 TI - A sheared Racz catheter in cervical epidural space for thirty months: a case report. AB - Percutaneous epidural neuroplasty may lead to complications such as hematoma, infection, epidural abscess, meningitis, hypotension, respiratory depression, urinary and fecal dysfunction, sexual dysfunction and paresthesia. Other technical complications may include shearing or tearing, misplacement, blockage and migration of the catheter. We report a case of a 41-year-old female patient, who underwent surgical removal of a sheared catheter, which was retained for 30 months after cervical Racz neuroplasty. PMID- 25844143 TI - Anesthesia awareness. Can midazolam attenuate or prevent memory consolidation on intraoperative awakening during general anesthesia without increasing the risk of postoperative delirium? PMID- 25844144 TI - Corrigendum: Effect of muscle relaxation on the oxygenation of human skeletal muscle: a prospective in-vivo experiment using an isolated forearm technique. AB - [This corrects the article on p. 13 in vol. 68, PMID: 25664149.]. PMID- 25844145 TI - Single-particle cryo-EM of the ryanodine receptor channel in an aqueous environment. AB - Ryanodine receptors (RyRs) are tetrameric ligand-gated Ca2+ release channels that are responsible for the increase of cytosolic Ca2+ concentration leading to muscle contraction. Our current understanding of RyR channel gating and regulation is greatly limited due to the lack of a high-resolution structure of the channel protein. The enormous size and unwieldy shape of Ca2+ release channels make X-ray or NMR methods difficult to apply for high-resolution structural analysis of the full-length functional channel. Single-particle electron cryo-microscopy (cryo-EM) is one of the only effective techniques for the study of such a large integral membrane protein and its molecular interactions. Despite recent developments in cryo-EM technologies and break through single-particle cryo-EM studies of ion channels, cryospecimen preparation, particularly the presence of detergent in the buffer, remains the main impediment to obtaining atomic-resolution structures of ion channels and a multitude of other integral membrane protein complexes. In this review we will discuss properties of several detergents that have been successfully utilized in cryo-EM studies of ion channels and the emergence of the detergent alternative amphipol to stabilize ion channels for structure-function characterization. Future structural studies of challenging specimen like ion channels are likely to be facilitated by cryo-EM amenable detergents or alternative surfactants. PMID- 25844147 TI - Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder. AB - BACKGROUND: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment. METHODS: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR. RESULTS: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3. CONCLUSIONS: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings. PMID- 25844148 TI - Predicting electromyographic signals under realistic conditions using a multiscale chemo-electro-mechanical finite element model. AB - This paper presents a novel multiscale finite element-based framework for modelling electromyographic (EMG) signals. The framework combines (i) a biophysical description of the excitation-contraction coupling at the half sarcomere level, (ii) a model of the action potential (AP) propagation along muscle fibres, (iii) a continuum-mechanical formulation of force generation and deformation of the muscle, and (iv) a model for predicting the intramuscular and surface EMG. Owing to the biophysical description of the half-sarcomere, the model inherently accounts for physiological properties of skeletal muscle. To demonstrate this, the influence of membrane fatigue on the EMG signal during sustained contractions is investigated. During a stimulation period of 500 ms at 100 Hz, the predicted EMG amplitude decreases by 40% and the AP propagation velocity decreases by 15%. Further, the model can take into account contraction induced deformations of the muscle. This is demonstrated by simulating fixed length contractions of an idealized geometry and a model of the human tibialis anterior muscle (TA). The model of the TA furthermore demonstrates that the proposed finite element model is capable of simulating realistic geometries, complex fibre architectures, and can include different types of heterogeneities. In addition, the TA model accounts for a distributed innervation zone, different fibre types and appeals to motor unit discharge times that are based on a biophysical description of the alpha motor neurons. PMID- 25844149 TI - Applications of computational models to better understand microvascular remodelling: a focus on biomechanical integration across scales. AB - Microvascular network remodelling is a common denominator for multiple pathologies and involves both angiogenesis, defined as the sprouting of new capillaries, and network patterning associated with the organization and connectivity of existing vessels. Much of what we know about microvascular remodelling at the network, cellular and molecular scales has been derived from reductionist biological experiments, yet what happens when the experiments provide incomplete (or only qualitative) information? This review will emphasize the value of applying computational approaches to advance our understanding of the underlying mechanisms and effects of microvascular remodelling. Examples of individual computational models applied to each of the scales will highlight the potential of answering specific questions that cannot be answered using typical biological experimentation alone. Looking into the future, we will also identify the needs and challenges associated with integrating computational models across scales. PMID- 25844150 TI - Multiscale modelling of the feto-placental vasculature. AB - The placenta provides all the nutrients required for the fetus through pregnancy. It develops dynamically, and, to avoid rejection of the fetus, there is no mixing of fetal and maternal blood; rather, the branched placental villi 'bathe' in blood supplied from the uterine arteries. Within the villi, the feto-placental vasculature also develops a complex branching structure in order to maximize exchange between the placental and maternal circulations. To understand the development of the placenta, we must translate functional information across spatial scales including the interaction between macro- and micro-scale haemodynamics and account for the effects of a dynamically and rapidly changing structure through the time course of pregnancy. Here, we present steps towards an anatomically based and multiscale approach to modelling the feto-placental circulation. We assess the effect of the location of cord insertion on feto placental blood flow resistance and flow heterogeneity and show that, although cord insertion does not appear to directly influence feto-placental resistance, the heterogeneity of flow in the placenta is predicted to increase from a 19.4% coefficient of variation with central cord insertion to 23.3% when the cord is inserted 2 cm from the edge of the placenta. Model geometries with spheroidal and ellipsoidal shapes, but the same volume, showed no significant differences in flow resistance or heterogeneity, implying that normal asymmetry in shape does not affect placental efficiency. However, the size and number of small capillary vessels is predicted to have a large effect on feto-placental resistance and flow heterogeneity. Using this new model as an example, we highlight the importance of taking an integrated multi-disciplinary and multiscale approach to understand development of the placenta. PMID- 25844151 TI - A multiscale model for the study of cardiac biomechanics in single-ventricle surgeries: a clinical case. AB - Complex congenital heart disease characterized by the underdevelopment of one ventricular chamber (single ventricle (SV) circulation) is normally treated with a three-stage surgical repair. This study aims at developing a multiscale computational framework able to couple a patient-specific three-dimensional finite-element model of the SV to a patient-specific lumped parameter (LP) model of the whole circulation, in a closed-loop fashion. A sequential approach was carried out: (i) cardiocirculatory parameters were estimated by using a fully LP model; (ii) ventricular material parameters and unloaded geometry were identified by means of the stand-alone, three-dimensional model of the SV; and (iii) the three-dimensional model of SV was coupled to the LP model of the circulation, thus closing the loop and creating a multiscale model. Once the patient-specific multiscale model was set using pre-operative clinical data, the virtual surgery was performed, and the post-operative conditions were simulated. This approach allows the analysis of local information on ventricular function as well as global parameters of the cardiovascular system. This methodology is generally applicable to patients suffering from SV disease for surgical planning at different stages of treatment. As an example, a clinical case from stage 1 to stage 2 is considered here. PMID- 25844152 TI - Multiscale models of skeletal muscle reveal the complex effects of muscular dystrophy on tissue mechanics and damage susceptibility. AB - Computational models have been increasingly used to study the tissue-level constitutive properties of muscle microstructure; however, these models were not created to study or incorporate the influence of disease-associated modifications in muscle. The purpose of this paper was to develop a novel multiscale muscle modelling framework to elucidate the relationship between microstructural disease adaptations and modifications in both mechanical properties of muscle and strain in the cell membrane. We used an agent-based model to randomly generate new muscle fibre geometries and mapped them into a finite-element model representing a cross section of a muscle fascicle. The framework enabled us to explore variability in the shape and arrangement of fibres, as well as to incorporate disease-related changes. We applied this method to reveal the trade-offs between mechanical properties and damage susceptibility in Duchenne muscular dystrophy (DMD). DMD is a fatal genetic disease caused by a lack of the transmembrane protein dystrophin, leading to muscle wasting and death due to cardiac or pulmonary complications. The most prevalent microstructural variations in DMD include: lack of transmembrane proteins, fibrosis, fatty infiltration and variation in fibre cross-sectional area. A parameter analysis of these variations and case study of DMD revealed that the nature of fibrosis and density of transmembrane proteins strongly affected the stiffness of the muscle and susceptibility to membrane damage. PMID- 25844153 TI - Multiscale cartilage biomechanics: technical challenges in realizing a high throughput modelling and simulation workflow. AB - Understanding the mechanical environment of articular cartilage and chondrocytes is of the utmost importance in evaluating tissue damage which is often related to failure of the fibre architecture and mechanical injury to the cells. This knowledge also has significant implications for understanding the mechanobiological response in healthy and diseased cartilage and can drive the development of intervention strategies, ranging from the design of tissue engineered constructs to the establishment of rehabilitation protocols. Spanning multiple spatial scales, a wide range of biomechanical factors dictate this mechanical environment. Computational modelling and simulation provide descriptive and predictive tools to identify multiscale interactions, and can lead towards a greater comprehension of healthy and diseased cartilage function, possibly in an individualized manner. Cartilage and chondrocyte mechanics can be examined in silico, through post-processing or feed-forward approaches. First, joint-tissue level simulations, typically using the finite-element method, solve boundary value problems representing the joint articulation and underlying tissue, which can differentiate the role of compartmental joint loading in cartilage contact mechanics and macroscale cartilage field mechanics. Subsequently, tissue-cell scale simulations, driven by the macroscale cartilage mechanical field information, can predict chondrocyte deformation metrics along with the mechanics of the surrounding pericellular and extracellular matrices. A high-throughput modelling and simulation framework is necessary to develop models representative of regional and population-wide variations in cartilage and chondrocyte anatomy and mechanical properties, and to conduct large-scale analysis accommodating a multitude of loading scenarios. However, realization of such a framework is a daunting task, with technical difficulties hindering the processes of model development, scale coupling, simulation and interpretation of the results. This study aims to summarize various strategies to address the technical challenges of post-processing-based simulations of cartilage and chondrocyte mechanics with the ultimate goal of establishing the foundations of a high-throughput multiscale analysis framework. At the joint-tissue scale, rapid development of regional models of articular contact is possible by automating the process of generating parametric representations of cartilage boundaries and depth-dependent zonal delineation with associated constitutive relationships. At the tissue-cell scale, models descriptive of multicellular and fibrillar architecture of cartilage zones can also be generated in an automated fashion. Through post-processing, scripts can extract biphasic mechanical metrics at a desired point in the cartilage to assign loading and boundary conditions to models at the lower spatial scale of cells. Cell deformation metrics can be extracted from simulation results to provide a simplified description of individual chondrocyte responses. Simulations at the tissue-cell scale can be parallelized owing to the loosely coupled nature of the feed-forward approach. Verification studies illustrated the necessity of a second-order data passing scheme between scales and evaluated the role that the microscale representative volume size plays in appropriately predicting the mechanical response of the chondrocytes. The tools summarized in this study collectively provide a framework for high-throughput exploration of cartilage biomechanics, which includes minimally supervised model generation, and prediction of multiscale biomechanical metrics across a range of spatial scales, from joint regions and cartilage zones, down to that of the chondrocytes. PMID- 25844154 TI - Comparison of generic and subject-specific models for simulation of pulmonary perfusion and forced expiration. AB - The goal of translating multiscale model analysis of pulmonary function into population studies is challenging because of the need to derive a geometric model for each subject. This could be addressed by using a generic model with appropriate customization to subject-specific data. Here, we present a quantitative comparison of simulating two fundamental behaviours of the lung-its haemodynamic response to vascular occlusion, and the forced expiration in 1 s (FEV1) following bronchoconstriction-in subject-specific and generic models. When the subjects are considered as a group, there is no significant difference between predictions of mean pulmonary artery pressure (mPAP), pulmonary vascular resistance or forced expiration; however, significant differences are apparent in the prediction of arterial oxygen, for both baseline and post-occlusion. Despite the apparent consistency of the generic and subject-specific models, a third of subjects had generic model under-prediction of the increase in mPAP following occlusion, and half had the decrease in arterial oxygen over-predicted; two subjects had considerable differences in the percentage reduction of FEV1 following bronchoconstriction. The generic model approach can be useful for physiologically directed studies but is not appropriate for simulating pathophysiological function that is strongly dependent on interaction with lung structure. PMID- 25844155 TI - Stochastic modelling of muscle recruitment during activity. AB - Muscle forces can be selected from a space of muscle recruitment strategies that produce stable motion and variable muscle and joint forces. However, current optimization methods provide only a single muscle recruitment strategy. We modelled the spectrum of muscle recruitment strategies while walking. The equilibrium equations at the joints, muscle constraints, static optimization solutions and 15-channel electromyography (EMG) recordings for seven walking cycles were taken from earlier studies. The spectrum of muscle forces was calculated using Bayesian statistics and Markov chain Monte Carlo (MCMC) methods, whereas EMG-driven muscle forces were calculated using EMG-driven modelling. We calculated the differences between the spectrum and EMG-driven muscle force for 1 15 input EMGs, and we identified the muscle strategy that best matched the recorded EMG pattern. The best-fit strategy, static optimization solution and EMG driven force data were compared using correlation analysis. Possible and plausible muscle forces were defined as within physiological boundaries and within EMG boundaries. Possible muscle and joint forces were calculated by constraining the muscle forces between zero and the peak muscle force. Plausible muscle forces were constrained within six selected EMG boundaries. The spectrum to EMG-driven force difference increased from 40 to 108 N for 1-15 EMG inputs. The best-fit muscle strategy better described the EMG-driven pattern (R (2) = 0.94; RMSE = 19 N) than the static optimization solution (R (2) = 0.38; RMSE = 61 N). Possible forces for 27 of 34 muscles varied between zero and the peak muscle force, inducing a peak hip force of 11.3 body-weights. Plausible muscle forces closely matched the selected EMG patterns; no effect of the EMG constraint was observed on the remaining muscle force ranges. The model can be used to study alternative muscle recruitment strategies in both physiological and pathophysiological neuromotor conditions. PMID- 25844156 TI - Coupling intercellular molecular signalling with multicellular deformation for simulating three-dimensional tissue morphogenesis. AB - During morphogenesis, three-dimensional (3D) multicellular structures emerge from biochemical and mechanical interplays among cells. In particular, by organizing their gradient within tissues, the diffusible signalling molecules play an essential role in producing the spatio-temporal patterns of cell status such as the differentiation states. Notably, this biochemical patterning can be dynamically coupled with multicellular deformations by signal-dependent cell activities such as contraction, adhesion, migration, proliferation and apoptosis. However, the mechanism by which these cellular activities mediate the interactions between multicellular deformations and patterning is still unknown. Herein, we propose a novel framework of a 3D vertex model to express molecular signalling among the mechanically deforming cells. By specifying a density of signalling molecules for each cell, we express their transport between neighbouring cells. By simulating signal-dependent epithelial growth, we found various types of tissue morphogenesis such as arrest, expansion, invagination and evagination. In the expansion phase, growth molecules were widely diffused with increasing tissue volume, which diluted the growth molecules in order to support the autonomous suppression of tissue growth. These results indicate that the proposed model successfully expresses 3D multicellular deformations dynamically coupled with biochemical patterning. We expect our proposed model to be a useful tool for predicting new phenomena emerging from mechanochemical coupling in multicellular morphogenesis. PMID- 25844157 TI - The inter-sample structural variability of regular tissue-engineered scaffolds significantly affects the micromechanical local cell environment. AB - Rapid prototyping techniques have been widely used in tissue engineering to fabricate scaffolds with controlled architecture. Despite the ability of these techniques to fabricate regular structures, the consistency with which these regular structures are produced throughout the scaffold and from one scaffold to another needs to be quantified. Small variations at the pore level can affect the local mechanical stimuli sensed by the cells thereby affecting the final tissue properties. Most studies assume rapid prototyping scaffolds as regular structures without quantifying the local mechanical stimuli at the cell level. In this study, a computational method using a micro-computed tomography-based scaffold geometry was developed to characterize the mechanical stimuli within a real scaffold at the pore level. Five samples from a commercial polycaprolactone scaffold were analysed and computational fluid dynamics analyses were created to compare local velocity and shear stress values at the same scaffold location. The five samples did not replicate the computer-aided design (CAD) scaffold and velocity and shear stress values were up to five times higher than the ones calculated in the CAD scaffold. In addition high variability among samples was found: at the same location velocity and shear stress values could be up to two times higher from sample to sample. This study shows that regular scaffolds need to be thoroughly analysed in order to quantify real cell mechanical stimuli so inspection methods should be included as part of the fabrication process. PMID- 25844159 TI - PRN: a preprint service for catalyzing R-fMRI and neuroscience related studies. AB - Sharing drafts of scientific manuscripts on preprint hosting services for early exposure and pre-publication feedback is a well-accepted practice in fields such as physics, astronomy, or mathematics. The field of neuroscience, however, has yet to adopt the preprint model. A reason for this reluctance might partly be the lack of central preprint services for the field of neuroscience. To address this issue, we announce the launch of Preprints of the R-fMRI Network (PRN), a community funded preprint hosting service. PRN provides free-submission and free hosting of manuscripts for resting state functional magnetic resonance imaging (R fMRI) and neuroscience related studies. Submissions will be peer viewed and receive feedback from readers and a panel of invited consultants of the R-fMRI Network. All manuscripts and feedback will be freely available online with citable permanent URL for open-access. The goal of PRN is to supplement the "peer reviewed" journal publication system - by more rapidly communicating the latest research achievements throughout the world. We hope PRN will help the field to embrace the preprint model and thus further accelerate R-fMRI and neuroscience related studies, eventually enhancing human mental health. PMID- 25844160 TI - Promoting self-management through adherence among heart failure patients discharged from rural hospitals: a study protocol. AB - Background Heart failure is one of the most prevalent chronic conditions in adults, leading to prolonged morbidity, repeated hospitalizations, and placing tremendous economic burden on the healthcare system. Heart failure patients discharged from rural hospitals, or primarily critical access hospitals, have higher 30-day readmission and mortality rates compared to patients discharged from urban hospitals. Self-management improves heart failure patients' health outcomes and reduces re-hospitalizations, but adherence to self-management guidelines is low. We propose a home based post-acute care service managed by advanced practice nurses to enhance patient activation and lead to the improvement of self-management adherence in heart failure patients discharged from rural hospitals. Objective This article describes the study design and research methods used to implement and evaluate the intervention. Method Our intervention is a 12-week patient activation (Patient AcTivated Care at Home [PATCH]) to improve self-management adherence. Patients were randomized into two parallel groups (12-week PATCH intervention + usual care vs. usual care only) to evaluate the effectiveness of this intervention. Outcomes were measured at baseline, 3 and 6 months. Discussion This study aimed to examine the effectiveness of a rural theory based, advance practice nurse led, activation enhancing intervention on the self-management adherence in heart failure patients residing in rural areas. Our expectation is to facilitate adherence to self management behaviors in heart failure patients following discharge from rural hospitals and decrease complications and hospital readmissions, leading to the reduction of economic burden. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; https://register.clinicaltrials.gov/ NCT01964053. PMID- 25844158 TI - The role of autophagy induced by tumor microenvironment in different cells and stages of cancer. AB - Development of a tumor is a very complex process, and invasion and metastasis of malignant tumors are hallmarks and are difficult problems to overcome. The tumor microenvironment plays an important role in controlling tumor fate and autophagy induced by the tumor microenvironment is attracting more and more attention. Autophagy can be induced by several stressors in the tumor microenvironment and autophagy modifies the tumor microenvironment, too. Autophagy has dual roles in tumor growth. In this review, we discussed the interaction between autophagy and the tumor microenvironment and the paradoxical roles of autophagy on tumor growth at different stages of tumor development. PMID- 25844161 TI - Case Report: Persistent erectile dysfunction in a man with prolactinoma. AB - Erectile dysfunction has been explored as a condition secondary to elevated prolactin; however, the mechanisms by which elevated prolactin levels cause erectile dysfunction have not yet been clearly established. We here present a patient with a history of prolactinoma who suffered from persistent erectile dysfunction despite testosterone supplementation and pharmacological and surgical treatment for the prolactinoma. Patients who have had both prolactinemia and erectile dysfunction have been reported in the literature, but we find no report of a patient with persistent erectile dysfunction in the setting of testosterone supplementation and persistent hyperprolactinemia refractory to treatment. This case provides evidence supporting the idea that suppression of erectile function occurs in both the central and peripheral nervous systems independent of the hypothalamic-pituitary-gonadal axis. PMID- 25844162 TI - The role of globalization in drug development and access to orphan drugs: orphan drug legislation in the US/EU and in Latin America. AB - Compared to a decade ago, nearly three times as many drugs for rare diseases are slated for development. This article addresses the market access issues associated with orphan drug status in Europe and the United States in contrast to the legislation in five Latin American (LA) countries that have made strides in this regard--Mexico, Brazil, Colombia, Chile and Argentina. Based on the success of orphan drug legislation in the EU and US, LA countries should strive to adopt similar strategies with regard to rare diseases and drug development. With the implementation of new targeted regulations, reimbursement strategies, and drug approvals, accessibility to treatment will be improved for people afflicted with rare diseases in these developing countries. PMID- 25844163 TI - BODIPY-BODIPY dyad: assessing the potential as a viscometer for molecular and ionic liquids. AB - A symmetrical BODIPY-BODIPY dyad with a diyne linker was prepared in two steps; the lifetime decay of this rotor appeared to correlate with the viscosity of the media, thus making this dyad a suitable small molecule viscometer for molecular solvents. The potential of using the rotor to probe the viscosity of ionic liquids was also investigated. PMID- 25844164 TI - Salvage Regimens Containing Darunavir, Etravirine, Raltegravir, or Enfuvirtide in Highly Treatment-Experienced Perinatally Infected Pregnant Women. AB - Combination antiretroviral therapy in pregnant women with human immunodeficiency virus has dramatically decreased maternal-to-child transmission. Highly treatment experienced pregnant patients have limited effective treatment options due to past toxicities and viral resistance. We present 8 pregnancies in 7 perinatally infected women successfully treated with salvage regimens containing darunavir, etravirine, raltegravir, or enfuvirtide. PMID- 25844165 TI - Molecular Epidemiology of Recurrent Cutaneous Methicillin-Resistant Staphylococcus aureus Infections in Children. AB - We assessed the relatedness by repetitive-sequence polymerase chain reaction of isolates obtained from children with recurrent methicillin-resistant Staphylococcus aureus cutaneous infections over 6 years. Ninety percent of the cases could be attributed to recurrence of the same strain type, suggesting that optimized decolonization methods in children might effectively prevent recurrent infection. PMID- 25844167 TI - The Medicaid Cost of Palivizumab. PMID- 25844166 TI - Susceptibility to Measles Among Perinatally HIV-Infected Adolescents and Young Adults. AB - Among our cohort of adolescents and young adults with perinatally acquired human immunodeficiency virus, few (17.6%) had measles protective antibodies by plaque reduction neutralization (PRN). Agreement was demonstrated between the commercial enzyme immunoassay and the PRN assay (K = 0.59 [95% confidence interval: 0.23 0.95]). Further studies are needed to understand the determinants of immunity in this population. PMID- 25844169 TI - Survey of the literature for march 2015 issue of sexual medicine journal. PMID- 25844168 TI - Evaluating the quality of feed fats and oils and their effects on pig growth performance. AB - Feed fats and oils provide significant amounts of energy to swine diets, but there is large variation in composition, quality, feeding value, and price among sources. Common measures of lipid quality include moisture, insolubles, and unsaponifiables (MIU), titer, and free fatty acid content, but provide limited information regarding their feeding value. Lipid peroxidation is an important quality factor related to animal growth performance and health, but maximum tolerable limits in various lipids have not been established. Several indicative assays can be used to detect the presence of various peroxidation compounds, but due to the complexity and numerous compounds produced and degraded during peroxidation process, no single method can adequately determine the extent of peroxidation. Until further information is available, using a combination of peroxide value, thiobarbituric acid reactive substances (TBARS), and anisidine value appear to provide a reasonable assessment of the extent of peroxidation in a lipid at a reasonable cost. However, fatty acid composition of the lipid being evaluated should be considered when selecting specific assays. Predictive tests can also be used to estimate the stability or susceptibility of lipids to peroxidation and include active oxygen method, oil stability index, and oxygen bomb method. A review of 16 published studies with pigs has shown an average decrease of 11.4% in growth rate, 8.8% feed intake fed isocaloric diets containing peroxidized lipids compared to diets containing unperoxidized lipids of the same source. Furthermore, serum vitamin E content was generally reduced and serum TBARS content was increased when peroxidized lipids were fed in these studies, suggesting that feeding peroxidized lipids negatively affects metabolic oxidative status of pigs. However, it is unclear if antioxidants are useful additions to lipids to maintain optimal nutritional value, or if their addition to swine diets is beneficial in overcoming a metabolic oxidative challenge. PMID- 25844170 TI - Using an FSDS-R Item to Screen for Sexually Related Distress: A MsFLASH Analysis. AB - INTRODUCTION: The Female Sexual Distress Scale-Revised (FSDS-R) was created and validated to assess distress associated with impaired sexual function, but it is lengthy for use in clinical practice and research when assessing sexual function is not a primary objective. AIM: The study aims to evaluate whether a single item from the FSDS-R could be identified to use to screen midlife women for bothersome diminution in sexual function based on three criteria: (i) highly correlated with total scores; (ii) correlated with commonly assessed domains of female sexual functioning; and (iii) able to differentiate between women reporting high and low sexual concerns during the prior month. METHODS: Data from 93 midlife women were collected by the Menopause Strategies Finding Lasting Answers to Symptoms and Health (MsFLASH) research network. MAIN OUTCOME MEASURES: Women completed the FSDS-R, Female Sexual Function Index (FSFI), and Menopausal Quality of Life Scale (MENQOL). Those who reported a change in the past month on the MENQOL sexual were categorized into a high sexual concerns group, while all others were categorized into a low sexual concerns group. RESULTS: Women were an average of 54.6 years old (SD 3.1) and mostly Caucasian (77.4%), college educated (60.2%), married/living as married (64.5%), and postmenopausal (79.6%). The FSDS-R item number 1 "Distressed about sex life" was: (i) highly correlated with FSDS-R total scores (r = 0.90); (ii) moderately correlated with FSFI total scores (r = -0.38) and FSFI desire (r = -0.37) and satisfaction domains (r = -0.40); and (iii) showed one of the largest mean differences between high and low sexual concerns groups (P < 0.001). Other FSDS-R items met one or two, but not all three of the prespecified criteria (i, ii, iii). CONCLUSIONS: A single FSDS-R item may be a useful screening tool to quickly identify midlife women with sexually related distress when it is not feasible to administer the entire scale, though further validation is warranted. Carpenter JS, Reed SD, Guthrie KA, Larson JC, Newton KM, Lau RJ, Learman LA, and Shifren JL. Using an FSDS-R item to screen for sexually related distress: A MsFLASH analysis. Sex Med 2015;3:7-13. PMID- 25844171 TI - Painful intercourse is significantly associated with evoked pain perception and cognitive aspects of pain in women with pelvic pain. AB - INTRODUCTION: Evidence suggests that painful intercourse, pain-related psychosocial factors, and altered pain processing magnify the pain experience, but it is not clear how these factors are related to each other. AIM: The aims were to (i) characterize differences between women with pelvic pain and pain-free women using a battery of pain-related psychosocial measures, clinical pain ratings, and evoked local and remote pain sensitivity; and (ii) examine the relationship between intercourse pain, clinical pain, and local and remote evoked pain sensitivity. METHODS: Women with pelvic pain lasting at least 3 months and pain-free women completed questionnaires and underwent pain sensitivity testing. Self-report measures included clinical pain intensity, pain catastrophizing, pain related fear, pain anxiety, depression, sexual function, and self-efficacy. Pain sensitivity measures included threshold and tolerance and temporal summation of pain. Separate analyses of variance (anova) were used to test group differences in self-report and pain sensitivity measures. Correlations were calculated among dyspareunia, psychosocial factors, and evoked pain. MAIN OUTCOME MEASURES: Self reported pain and pain sensitivity measures. RESULTS: Twenty-eight pain-free women and 14 women with pelvic pain participated in this study. Women with pelvic pain reported greater pain intensity and greater psychosocial involvement compared with pain-free women. No differences existed between groups for thermal or pressure measures, but women with pelvic pain rated their pain with pain testing significantly higher than pain-free women. Intercourse pain was significantly associated with affective and sensory pain and pressure pain ratings at the puborectalis, vulvar vestibule, adductor longus tendons, and tibialis anterior muscle. CONCLUSIONS: Differences in local pain ratings suggest that women with pelvic pain perceive stimuli in this region as more painful than pain-free women although the magnitude of stimuli does not differ. Alappattu MJ, George SZ, Robinson ME, Fillingim RB, Moawad N, LeBrun EW, and Bishop MD. Painful intercourse is significantly associated with evoked pain perception and cognitive aspects of pain in women with pelvic pain. Sex Med 2015;3:14-23. PMID- 25844172 TI - Factors of the HIV Transmission in Men Who Have Sex with Men in Suizhou City from 2009 to 2013. AB - INTRODUCTION: The primary transmission of human immunodeficiency virus (HIV) has been recently changing worldwide. In China, HIV transmission through heterosexual contact remains the predominant mode, but the prevalence of men who have sex with men (MSM) has been increasing. AIM: This article investigated the overall epidemic trend and associated high-risk behavior among MSM in Suizhou City and explored the government's responses to the epidemic. METHODS: We conducted yearly cross-sectional behavioral surveillance surveys among MSM in Suizhou City from 2009 to 2013. Participation was anonymous and self-completed. Recruitment methods were consistently applied in each survey. MAIN OUTCOME MEASURES: Semi-structured questionnaire surveys and yearly work summaries were conducted. RESULTS: Most of the MSM groups in Suizhou City were young adults (P < 0.05), well educated (P < 0.05), and married (P < 0.05). Two years after our interventions, we found an increasing trend of condom use during anal sex (P < 0.05), as well as commercial sex trade (P < 0.05). CONCLUSIONS: HIV continues to spread rapidly among MSM in Suizhou City. The high-risk behavior among MSM remains a hindrance to HIV prevention. Innovative intervention approaches are essential for HIV surveillance and prevention among MSM in Suizhou City. Yang F, Shi X, He W, Wu S, Wang J, Zhao K, Yuan H, Martin K, and Zhang H. Factors of the HIV transmission in men who have sex with men in Suizhou City from 2009 to 2013. Sex Med 2015;3:24-31. PMID- 25844173 TI - Psychosexual development in men with congenital hypogonadotropic hypogonadism on long-term treatment: a mixed methods study. AB - INTRODUCTION: Congenital hypogonadotropic hypogonadism (CHH) is a rare, genetic, reproductive endocrine disorder characterized by absent puberty and infertility. Limited information is available on the psychosocial impact of CHH and psychosexual development in these patients. AIM: The aim of this study was to determine the impact of CHH on psychosexual development in men on long-term treatment. METHODS: A sequential mixed methods explanatory design was used. First, an online survey (quantitative) was used to quantify the frequency of psychosexual problems among CHH men. Second, patient focus groups (qualitative) were conducted to explore survey findings in detail and develop a working model to guide potential nursing and interdisciplinary interventions. MAIN OUTCOME MEASURES: Patient characteristics, frequency of body shame, difficulty with intimate relationships, and never having been sexually active were assessed. Additionally, we collected subjective patient-reported outcomes regarding the impact of CHH on psychological/emotional well-being, intimate relationships, and sexual activity. RESULTS: A total of 101 CHH men on long-term treatment (>1 year) were included for the analysis of the online survey (mean age 37 +/- 11 years, range 19-66, median 36). Half (52/101, 51%) of the men had been seen at a specialized academic center and 37/101 (37%) reported having had fertility inducing treatment. A high percentage of CHH men experience psychosexual problems including difficulty with intimate relationships (70%) and body image concerns/body shame (94/101, 93%), and the percentage of men never having been sexually active is five times the rate in a reference group (26% vs. 5.4%, P < 0.001). Focus groups revealed persisting body shame and low self-esteem despite long-term treatment that has lasting impact on psychosexual functioning. CONCLUSIONS: CHH men frequently experience psychosexual problems that pose barriers to intimate relationships and initiating sexual activity. These lingering effects cause significant distress and are not ameliorated by long-term treatment. Psychosexual assessment in CHH men with appropriate psychological support and treatment should be warranted in these patients. Dwyer AA, Quinton R, Pitteloud N, and Morin D. Psychosexual development in men with congenital hypogonadotropic hypogonadism on long-term treatment: A mixed methods study. Sex Med 2015;3:32-41. PMID- 25844174 TI - Is it worth continuing sexual rehabilitation after radical prostatectomy with intracavernous injection of alprostadil for more than 1 year? AB - INTRODUCTION: Intracavernous alprostadil injection (IAI) is a widely used treatment for sexual rehabilitation (SR) after radical prostatectomy (RP). It is unknown whether the continuation of IAI beyond 1 year continues to improve erectile function. AIMS: To assess evolution of sexual function in patients using IAI who are nonresponsive to phosphodiesterase type 5 inhibitors (PDE5i) between 12 (M12) and 24 (M24) months after RP. METHODS: We retrospectively studied 75 men with a nerve-sparing laparoscopic RP, who had normal preoperative erectile function, and who regularly used IAI for SR for at least 24 months. At M12, no patients had responded to PDE5i. MAIN OUTCOME MEASURES: At 12 and 24 months, sexual function was assessed with the UCLA Prostate Cancer Index (UCLA-PCI), International Index of Erectile Function (IIEF)-15, and erection hardness score (EHS) with and without IAI. We also assessed the satisfaction rate with IAI, injection-related penile pain, and satisfaction of treatment. Statistical analysis was performed by using t-tests for paired data and Spearman's rho correlation coefficients to assess the relationships between scores at M12 and M24. RESULTS: Improvement of nocturnal erection was noted (UCLA-PCI, question 25); however, no significant difference was found for IIEF-erectile function with (19.60 +/- 9.80 vs. 18.07 +/- 10.44) and without IAI (4.63 +/- 2.93 vs. 4.92 +/- 4.15), UCLA-PCI-sexual bother (37.14 +/- 21.45 vs. 37.54 +/- 19.67), nor the EHS score with (2.97 +/- 1.30 vs. 2.57 +/- 1.30) and without IAI (0.67 +/- 1.11 vs. 0.76 +/- 0.10). The rate of satisfaction with treatment decreased over time (66.6% vs. 46.7%, P = 0.013). Improved response to IAI at M12 was not correlated to improvement in spontaneous erections at M24. CONCLUSION: The response to IAI remained stable after 2 years of treatment, and no significant improvement of spontaneous erections during intercourse attempts was found between M12 and M24. Patients should be informed of the limited effect of IAI on natural erections after 1 year. Yiou R, Butow Z, Parisot J, Binhas M, Lingombet O, Augustin D, de la Taille A, and Audureau E. Is it worth continuing sexual rehabilitation after radical prostatectomy with intracavernous injection of alprostadil for more than 1 year? Sex Med 2015;3:42-48. PMID- 25844175 TI - Surgical management of traumatic penile amputation: a case report and review of the world literature. AB - INTRODUCTION: There is paucity of case reports that describe the successful reimplantation of a penis after amputation. We sought to report on self-inflicted penile amputation and comment on its surgical management and review current literature. AIM: To report on self-inflicted penile amputation and comment on its surgical management and review current literature. METHODS: A 19-year-old male with no prior medical history presented to our university-affiliated trauma center following sustaining a self-inflicted amputation of shaft penis secondary to severe methamphetamine-induced psychosis. He immediately underwent extensive reconstructive reimplantation of the penis performed jointly by plastics and urology teams reattaching all visible neurovascular bundles, urethra, and corporal and fascial layers. The patient was discharged with a suprapubic tube in place and a Foley catheter in place with well-healing tissue. MAIN OUTCOME MEASURES: To review the current published literature and case reports on the management of penile amputation with particular emphasis its etiology, surgical repairs, potential complications and functional outcomes. RESULTS: We report herein a case of a traumatic penile amputation and successful outcome of microscopic reimplantation and review of the published literature with particular comments on surgical managements. CONCLUSION: We review the literature and case reports on penile amputation and its etiology, surgical management, variables effecting outcomes, and its complications. Raheem OA, Mirheydar HS, Patel ND, Patel SH, Suliman A, and Buckley JC. Surgical management of traumatic penile amputation: A case report and review of the world literature. Sex Med 2015;3:49 53. PMID- 25844178 TI - Crystal structure of chlorido-(2-{1-[2-(4-chloro-phen-yl)hydrazin-1-yl-idene kappaN]eth-yl}pyridine-kappaN)(eta(5)-penta-methyl-cyclo-penta-dien yl)rhodium(III) chloride. AB - The cation of the title compound, [Rh(eta(5)-C5Me5)Cl(C13H12ClN3)]Cl, adopts a typical piano-stool geometry. The complex is chiral at the metal and crystallizes as a racemate. Upon coordination, the hydrazinyl-idene-pyridine ligand is non planar, an angle of 54.42 (7) degrees being observed between the pyridine ring and the aromatic ring of the [2-(4-chloro-phen-yl)hydrazin-1-yl-idene]ethyl group. In the crystal, a weak inter-ionic N-H?Cl hydrogen bond is observed. PMID- 25844177 TI - Functionalized scaffolds to enhance tissue regeneration. AB - Tissue engineering scaffolds play a vital role in regenerative medicine. It not only provides a temporary 3-dimensional support during tissue repair, but also regulates the cell behavior, such as cell adhesion, proliferation and differentiation. In this review, we summarize the development and trends of functional scaffolding biomaterials including electrically conducting hydrogels and nano-composites of hydroxyapatite (HA) and bioactive glasses (BGs) with various biodegradable polymers. Furthermore, the progress on the fabrication of biomimetic nanofibrous scaffolds from conducting polymers and composites of HA and BG via electrospinning, deposition and thermally induced phase separation is discussed. Moreover, bioactive molecules and surface properties of scaffolds are very important during tissue repair. Bioactive molecule-releasing scaffolds and antimicrobial surface coatings for biomedical implants and scaffolds are also reviewed. PMID- 25844179 TI - Crystal structure of langbeinite-related Rb0.743K0.845Co0.293Ti1.707(PO4)3. AB - Potassium rubidium cobalt(II)/titanium(IV) tris-(orthophosphate), Rb0.743K0.845Co0.293Ti1.707(PO4)3, has been obtained using a high-temperature crystallization method. The obtained compound has a langbeinite-type structure. The three-dimensional framework is built up from mixed-occupied (Co/Ti(IV))O6 octa-hedra (point group symmetry .3.) and PO4 tetra-hedra. The K(+) and Rb(+) cations are statistically distributed over two distinct sites (both with site symmetry .3.) in the large cavities of the framework. They are surrounded by 12 O atoms. PMID- 25844180 TI - Crystal structure of N-{N-[N-acetyl-(S)-leuc-yl]-(S)-leuc-yl}norleucinal (ALLN), an inhibitor of proteasome. AB - The title compound, C20H37N3O4, also known by the acronym ALLN, is a tripeptidic inhibitor of the proteolytic activity of the proteasomes, enzyme complexes implicated in several neurodegenerative diseases and other disorders, including cancer. The crystal structure of ALLN, solved from synchrotron radiation diffraction data, revealed the mol-ecules in extended conformation of the backbone and engaging all peptide N and O atoms in inter-molecular hydrogen bonds forming an infinite anti-parallel beta-sheet. PMID- 25844182 TI - Crystal structure of N (1)-phenyl-N (4)-[(E)-(pyren-1-yl)methyl-idene]benzene-1,4 di-amine. AB - In the title compound, C29H20N2, the dihedral angles subtended by the central p phenyl-enedi-amine ring with respect to the mean plane of the terminal pyrenyl ring system (r.m.s. deviation = 0.027 A) and the terminal N-phenyl ring are 29.34 (4) and 43.43 (7) degrees , respectively. The conformation about the C=N bond is E. In the crystal, mol-ecules are linked by N-H?pi and C-H?pi inter-actions forming chains propagating along the [10-2] direction. These chains are linked via pi-pi inter-actions [inter-centroid distances are in the range 3.5569 (11) 3.708 (1) A], forming slabs lying parallel to (30-4). PMID- 25844181 TI - Crystal structure of 1,1'-[imidazolidine-1,3-diylbis(methyl-ene)]bis-(naphthalen 2-ol). AB - The crystal structure of the title compound, C25H24N2O2, at 173 K has monoclinic (C2/c) symmetry. The mol-ecule is located on a crystallographic twofold rotation axis with only half a mol-ecule in the asymmetric unit. The imidazolidine ring adopts a twist conformation, with a twist about the ring C-C bond. The crystal structure shows the anti-clinal disposition of the two (2-hy-droxy-naphthalen-1 yl)methyl substituents of the imidazolidine ring. The structure displays two intra-molecular O-H?N hydrogen bonds, each forming an S(6) ring motif. PMID- 25844183 TI - Crystal structures of 2,3-bis-(4-chloro-phen-yl)-1,3-thia-zolidin-4-one and trans 2,3-bis-(4-chloro-phen-yl)-1,3-thia-zolidin-4-one 1-oxide. AB - In the crystal structures of the title compounds, C15H11Cl2NOS, (1), and C15H11Cl2NO2S, (2), wherein (2) is the oxidized form of (1), the thia-zolidine ring is attached to two chloro-phenyl rings. The chloro-phenyl ring on the 2 carbon atom position points in the same direction as that of the S atom in (1), while in (2), the S atom points in the opposite direction. The O atom on the chiral S atom in (2) is trans to the chloro-phenyl ring on the 2-carbon. The chloro-phenyl ring planes in each structure are close to orthogonal, making dihedral angles of 78.61 (6) and 87.46 (8) degrees in (1) and (2), respectively. The thia-zolidine ring has a twisted conformation on the S-Cmethine bond in (1), and an envelope conformation with the S atom 0.715 (3) A out of the plane of other four atoms in (2). In the crystal of (1), mol-ecules are linked by C-H?O hydrogen bonds, as well as by slipped parallel pi-pi inter-actions [inter centroid distance = 3.840 (3) A] between inversion-related phenyl rings, forming sheets parallel to (001). In the crystal of (2), mol-ecules are linked via C-H?O and C-H?Cl hydrogen bonds, forming slabs parallel to (001). PMID- 25844184 TI - Crystal structure of hepta-guanidinium nona-hydrogen bis-[alpha-hexa molybdoplatinate(IV)] hepta-hydrate. AB - The title compound, (CH6N3)7H9[PtMo6O24]2.7H2O, containing the well-known Anderson-type heteropolyoxomolybdate, was obtained by recrystallization of its powdered guanidinium salt. The protonated O atoms in the polyanion were confirmed by electron-density maps, inter-polyanion hydrogen bonds and bond-valance sums (BVS). The {[H4.5PtMo6O24]2}(7-) polyanion is the same as that already characterized in K7[H4.5PtMo6O24]2.11H2O [space group P-1; Lee & Joo (2010 ?). Acta Cryst. E66, i8-i9]. The heteropolyanions form inversion-generated dimers, {[H4.5PtMo6O24]2}(7-), held together by each of the four MU3-O-H?MU1-O, two MU2-O H?MU2-O hydrogen bonds and one centrosymmetric MU3-O-H-MU3-O hydrogen bond. The H atom of the centrosymmetric hydrogen bond is located on an inversion centre. One guanidinium ion and one water mol-ecule are equally disordered about a twofold rotation axis. PMID- 25844185 TI - Crystal structure and luminescent properties of [1-(biphenyl-4-yl)-1H-imidazole kappaN (3)]di-chloridozinc. AB - The mononuclear title compound, [ZnCl2(C15H12N2)2], was synthesized by reaction of zinc chloride and 1-(biphenyl-4-yl)-1H-imidazole (bpi) under hydro-thermal conditions. The Zn(II) atom is tetra-hedrally coordinated by the free imidazole N atoms of two bpi ligands and by two Cl atoms. The bpi ligands are not planar, with dihedral angles of 37.52 (14) and 42.45 (14) degrees between the phenyl rings and 37.13 (14) and 40.05 (14) degrees between the phenyl rings and the attached imidazole rings, respectively. Mutual pi-pi inter-actions, with a centroid-to-centroid distance of 3.751 (2) A between the phenyl and imidazole rings of neighbouring ligands, are present, leading to dimers that are arranged in rows parallel to [-211]. PMID- 25844186 TI - Crystal structure of (S)-2-[(3S,8S,9S,10R,13S,14S,17R)-3-hy-droxy-10,13-dimethyl 2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra-deca-hydro-1H-cyclo-penta[a]phenanthren 17-yl]-N-meth-oxy-N-methyl-pro-pan-amide (Fernholz Weinreb amide). AB - The literature compound 3beta-hy-droxy-bis-nor-5-cholenic aldehyde is an important inter-mediate for the synthesis of new modulators of the nuclear oxysterol receptor Liver X. As part of our ongoing search for new LXR antagonists, the title compound, C24H39NO3, has proven to be an important inter mediate in our new synthetic pathway, giving the corresponding aldehyde in high yield and in only three steps from the commercially available 3beta-hy-droxy-bis nor-5-cholenic acid. The title amide crystallized with two mol-ecules in the asymmetric unit, linked into helices by O-H?O hydrogen bonds involving the hy droxy and carbonyl groups. PMID- 25844187 TI - Crystal structure of the mixed-metal thio-phosphate Nb1.18V0.82PS10. AB - The mixed-metal thio-phosphate, Nb1.18V0.82PS10 (niobium vanadium phospho-rus deca-sulfide), has been prepared though solid state reactions using an alkali metal halide flux. The title compound is isostructural with two-dimensional Nb2PS10. [M 2S12] (M = Nb or V) dimers built up from two bicapped trigonal prisms and tetra-hedral [PS4] units share sulfur atoms to construct (1) infinity[M 2PS10] chains along the a axis. These chains are linked through the di-sulfide bonds between [PS4] units in adjacent chains to form layers parallel to the ab plane. These layers then stack on top of each other to complete the three dimensional structure with van der Waals gaps. The M sites are occupied by 59% of Nb and 41% of V and the average M-S and M-M distances in the title compound are in between those of V2PS10 and Nb2PS10. The classical charge balance of the title compound can be represented by [(Nb/V)(4+)]2[P(5+)][S(2-)]3[S(-)]7. PMID- 25844188 TI - Crystal structure of disodium 2-amino-6-oxo-6,7-di-hydro-1H-purine-1,7-diide hepta-hydrate. AB - In the title compound, disodium 2-amino-6-oxo-6,7-di-hydro-1H-purine-1,7-diide hepta-hydrate, 2Na(+).C5H3N5O(2-).7H2O, the structure is composed of alternating (100) layers of guanine mol-ecules and hydrated Na(+) ions. Within the guanine layer, the mol-ecules are arranged in centrosymmetric pairs, with a partial overlap between the guanine rings. In this compound, guanine exists as the amino keto tautomer from which deprotonation from N1 and N7 has occurred (purine numbering). There are no direct inter-actions between the Na(+) cations and the guanine anions. Guanine mol-ecules are linked to neighboring water mol-ecules by O-H?N and O-H?O hydrogen bonds into a network structure. PMID- 25844189 TI - Crystal structure of bis-[1-(2-hy-droxy-eth-yl)-2-methyl-5-nitro-1H-imidazole kappaN (3)]silver(I) tetra-fluorido-borate methanol monosolvate. AB - 1-(2-Hy-droxy-eth-yl)-2-methyl-5-nitro-1H-imidazole (metronidazole, MET) is a medication that is used to treat infections by a variety of anaerobic organisms, but there are relatively few reports of the structures of metal compounds that exhibit coordination of metronidazole. We have demonstrated that MET reacts with AgBF4 to give [Ag(MET)2]BF4.CH3OH, in which the Ag(I) cation is coordinated by two MET ligands with a trans arrangement. The structure of [Ag(MET)2]BF4 exhibits some inter-esting differences from its nitrate counterpart, [Ag(MET)2]NO3 [Fun et al. (2008). Acta Cryst. E64, m668]. For instance, although the two MET ligands of both [Ag(MET)2]BF4 and [Ag(MET)2]NO3 are almost coplanar, the former compound has an anti-like geometry with a mol-ecular inversion center, but the latter has a syn-like arrangement. In the crystal, the BF4 (-) anion is linked by an O-H?F hydrogen bond to the methanol solvent molecule, which is, in turn, linked to the cation by an O-H?O hydrogen bond; the components of the structure are linked by O H?O hydrogen bonds, forming chains along [001]. One of the MET ligands and the BF4 (-) anion are disordered over two sets of sites with ratios of refined occupancies 0.501 (17):0.499 (17) and 0.539 (19):0.461 (19), respectively. PMID- 25844190 TI - Crystal structure of cis-aqua-chlorido-bis-(1,10-phenanthroline-kappa(2) N,N')chromium(III) tetra-chlorido-zincate monohydrate from synchrotron data. AB - The structure of the title compound, [CrCl(C12H8N2)2(H2O)][ZnCl4].H2O, has been determined from synchrotron data. The Cr(III) ion is bonded to four N atoms from two 1,10-phenanthroline (phen) ligands, one water mol-ecule and a Cl atom in a cis arrangement, displaying an overall distorted octa-hedral coordination environment. The Cr-N(phen) bond lengths are in the range of 2.0495 (18) to 2.0831 (18) A, while the Cr-Cl and Cr-(OH2) bond lengths are 2.2734 (7) and 1.9986 (17) A, respectively. The tetra-hedral [ZnCl4](2-) anion is slightly distorted owing to its involvement in O-H?Cl hydrogen bonding with coordinating and non-coordinating water mol-ecules. The two types of water mol-ecules also inter-act through O-H?O hydrogen bonds. The observed hydrogen-bonding pattern leads to the formation of a three-dimensional network structure. PMID- 25844191 TI - Crystal structure of (18-crown-6)potassium(I) [(1,2,3,4,5-eta)-cyclo-hepta-dien yl][(1,2,3-eta)-cyclo-hepta-trien-yl]cobalt(I). AB - The reaction of bis-(anthracene)cobaltate(-I) with excess cyclo-hepta-triene, C7H8, resulted in a new 18-electron cobaltate containing two different seven membered ring ligands, based on single-crystal X-ray diffraction. The asymmetric unit of this structure contains two independent cation-anion pairs of the title complex, [K(18-crown-6)][Co(eta(3)-C7H7)(eta(5)-C7H9)], where 18-crown-6 stands for 1,4,7,10,13,16-hexa-oxa-cyclo-octa-decane (C12H24O6), in general positions and well separated. Each (18-crown-6)potassium cation is in contact with the eta(3)-coordinating ligand of one cobaltate complex. Each eta(3)-coordinating ligand behaves as an allylic anion whose exo-diene moiety is bent away from the allylic plane, and thus is not involved directly in the bonding. The metal coordinating portions of the anionic eta(5) ligands are planar and one of these ligands is modeled as disordered over two positions, with occupancy ratio 0.699 (5):0.301 (5), such that one orientation is rotated by one carbon atom with respect to the other. The diffraction intensities were integrated according to non-merohedral twin law [-1 0 0/0 -1 0/0.064 0 1], a 180 degrees rotation about reciprocal lattice axis [001], and the masses of the twin domains refined to equal amounts. As both ligands are formally coordinated as anions, the cobalt atom is best considered to be Co(I). This compound is of inter-est as the first to possess cyclo-hepta-trienyl and cyclo-hepta-dienyl ligands in an anionic metal complex. PMID- 25844192 TI - Crystal structure of 2-benzyl-amino-4-(4-bromo-phen-yl)-6,7-di-hydro-5H-cyclo penta-[b]pyridine-3-carbo-nitrile. AB - In the title compound C22H18BrN3, the cyclo-pentane ring adopts an envelope conformation with the central methyl-ene C atom as the flap. The dihedral angles between the central pyridine ring and the pendant benzyl and and bromo-benzene rings are 82.65 (1) and 47.23 (1) degrees , respectively. In the crystal, inversion dimers linked by pairs of N-H?Nn (n = nitrile) hydrogen bonds generate R 2 (2)(12) loops. These dimers are linked by weak pi-pi inter-actions [centroid centroid distance = 3.7713 (14) A] into a layered structure. PMID- 25844193 TI - Synthese et structure cristalline d'un materiau noir AgMn(II) 3(Mn(III) 0,26Al0,74)(MoO4)5. AB - A new silver aluminium trimangan-ese penta-molybdate {silver(I) trimanganese(II) aluminium penta-kis-[tetra-oxidomolybdate(VI)]}, AgMn(II) 3(Mn(III) 0,26Al0,74)(MoO4)5, has been synthesized using solid-state methods. The structure is composed of M 2O10 dimers, M 3O14 (M = Mn, Al) trimers and MoO4 tetra-hedra sharing corners and forming three types of layers A, B and B'. The sequence of the constituting layers is A-BB'-A-BB', with B' obtained from B by inversion symmetry, forming a three-dimensional structure with large channels in which the positionally disordered and partially occupied Ag(+) ions reside. The Mn(III) and Al(III) atoms share the same site, M. AgMn(II) 3(Mn(III) 0,26Al0,74)(MoO4)5 is isotypic with the NaMg3 X(MoO4)5 (X = Al, In) family and with NaFe4(MoO4)5. A comparative structural description is provided between the structure of the title compound and those of related phases containing dimers, trimers and tetra-mers. PMID- 25844194 TI - Crystal structures of two hydrazinecarbo-thio-amide derivatives: (E)-N-ethyl-2 [(4-oxo-4H-chromen-3-yl)methyl-idene]hydrazinecarbo-thio-amide hemi-hydrate and (E)-2-[(4-chloro-2H-chromen-3-yl)methyl-idene]-N-phenyl-hydrazinecarbo-thio amide. AB - The title compounds, C13H13N3O2S.0.5H2O, (I), and C17H14ClN3OS, (II), are hydrazinecarbo-thio-amide derivatives. Compound (I) crystallizes with two independent mol-ecules (A and B) and a water mol-ecule of crystallization in the asymmetric unit. The chromene moiety is essentially planar in mol-ecules A and B, with maximum deviations of 0.028 (3) and 0.016 (3) A, respectively, for the carbonyl C atoms. In (II), the pyran ring of the chromene moiety adopts a screw boat conformation and the phenyl ring is inclined by 61.18 (9) degrees to its mean plane. In the crystal of (I), bifurcated N-H?O and C-H?O hydrogen bonds link the two independent mol-ecules forming A-B dimers with two R 2 (1)(6) ring motifs, and R 2 (2)(10) and R 2 (2)(14) ring motifs. In addition to these, the water mol-ecule forms tetra-furcated hydrogen bonds which alternately generate R 4 (4)(12) and R 6 (6)(22) graph-set ring motifs. There are also pi-pi [inter centroid distances = 3.5648 (14) and 3.6825 (15) A] inter-actions present, leading to the formation of columns along the c-axis direction. In the crystal of (II), mol-ecules are linked by pairs of N-H?S hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The dimers are linked by C-H?pi inter actions, forming ribbons lying parallel to (210). PMID- 25844195 TI - Crystal structure of {(but-3-en-1-yl)bis-[(pyridin-2-yl)meth-yl]amine-kappa(3) N,N',N''}di-chlorido-copper(II) diethyl ether hemisolvate. AB - The five-coordinate Cu(II) atom in the title complex [CuCl2(C16H19N3)].0.5C4H10O, adopts a near-ideal square-pyramidal geometry (tau-5 = 0.01). The apical Cu-Cl distance is 0.2626 (6) A longer than the basal Cu-Cl distance. Weak C-H?Cl interactions between pyridine rings and the Cl atoms of adjacent complex molecules are present. The solvent molecule, located on a twofold rotation axis, is situated in the voids of this arrangement. Copper atoms coordinated by tridentate nitro-gen-containing ligands have been found to be excellent promoters of Atom Transfer Radical Addition (ATRA) reactions. PMID- 25844196 TI - Crystal structure of the di-Mannich base 4,4'-di-chloro-3,3',5,5'-tetra-methyl 2,2'-[imidazolidine-1,3-diylbis(methyl-ene)]diphenol. AB - The title compound, C21H26Cl2N2O2, was prepared in a solvent-free microwave assisted synthesis, and crystallizes in the ortho-rhom-bic space group Pna21. The imidazolidine ring adopts an envelope conformation and its mean plane is almost perpendicular to the two pendant aromatic rings [dihedral angles = 84.61 (9) and 86.54 (9) degrees ]. The mol-ecular structure shows the presence of two intra molecular O-H?N hydrogen bonds between the phenolic hy-droxy groups and imidazolidine N atoms. The two 3-chloro-6-hy-droxy-2,4-di-methyl-benzyl groups are located in a cis orientation with respect to the imidazolidine fragment. As a result, the lone pairs of electrons on the N atoms are presumed to be disposed in a syn conformation. This is therefore the first example of an exception to the 'rabbit-ears' effect in such 2,2'-[imidazolidine-1,3-diylbis(methyl-ene)]diphenol derivatives. PMID- 25844197 TI - Crystal structure of 4-methyl-N-[(4-methyl-pyridin-2-yl)carbamo-thioyl] benzamide. AB - In the title compound, C15H15N3OS, the dihedral angle between the planes of the benzene and pyridine rings is 26.86 (9) degrees . Intra-molecular N-H?O and C-H?S hydrogen bonds both generate S(6) rings. The C=O and C=S bonds lie to opposite sides of the mol-ecule. In the crystal, inversion dimers linked by pairs of N-H?S hydrogen bonds generate R 2 (2)(8) loops. PMID- 25844198 TI - Structure cristalline du compose intermetallique Ni18Ge12. AB - Single crystals of octa-deca-nickel dodeca-germanide were grown by chemical transport reaction. The inter-metallic compound crystallizes in a superstructure of the hexa-gonal NiAs type (B8 type). All atoms in the asymmetric unit lie on special positions except one Ni atom (two Ni atoms have site symmetry -6.. and another one has site symmetry .2. while the Ge atoms have site symmetries 32., m.. and 3..). In the structure, the Ni atoms are arranged in 11- or 13-vertex polyhedra (CN = 11-13). The coordination polyhedra of the Ge atoms are bicapped square anti-prisms (CN = 10) or 11-vertex polyhedra (CN = 11). The structure exhibits strong Ge?Ni inter-actions, but no close Ge?Ge contacts are observed. The Ni atoms with CN = 13 form infinite chains along [001] with an Ni-Ni distance of 2.491 (2) A. PMID- 25844199 TI - Crystal structure of tetra-aquabis(1,3-dimethyl-2,6-dioxo-3,7-di-hydro-1H-purin-9 ido)magnesium. AB - The title complex, [Mg(C7H7N4O2)2(H2O)4], lies across an inversion centre and the Mg(II) atom is coordinated in a slightly distorted octa-hedral environment by four aqua ligands in the equatorial sites and two 1,3-dimethyl-2,6-dioxo-3,7-di hydro-1H-purin-9-ide ligands, through imidazole ring N atoms, in the axial sites. An intra-molecular O-H?O hydrogen bond forms an S(7) graph-set motif. In the crystal, O-H?O and O-H?N hydrogen bonds link complex mol-ecules forming a three dimensional network incorporating R 4 (2)(8) and R 2 (2)(18) graph-set motifs. PMID- 25844201 TI - Crystal structure of 1-bromo-2-(phenyl-selen-yl)benzene. AB - In the title compound, C12H9BrSe, the Se atom exhibits a bent geometry, with a C Se-C bond angle of 99.19 (6) degrees . The ortho Se and Br atoms are slightly displaced from opposite faces of the mean plane of the benzene ring [by 0.129 (2) and 0.052 (2) A, respectively]. The planes of the benzene and phenyl rings form a dihedral angle of 72.69 (5) degrees . In the crystal, pi-stacking inter-actions between inversion-related phenyl rings are observed, with a centroid-centroid distance of 3.630 (1) A. PMID- 25844200 TI - Crystal structure of bis-(MU2-4-tert-butyl-2-formyl-phenolato)-1:2kappa(3) O (1),O (2):O (1);3:4kappa(3) O (1),O (2):O (1)-bis-(4-tert-butyl-2-formyl phenolato)-2kappa(2) O (1),O (2);4kappa(2) O (1),O (2)-di-MU3-methoxido 1:2:3kappa(3) O;1:3:4kappa(3) O-di-MU2-methoxido-1:4kappa(2) O;2:3kappa(2) O tetra-copper(II). AB - The structure of the title compound, [Cu4(CH3O)4(C11H13O2)4], consists of dimeric dinuclear copper(II) complexes oriented around a centre of inversion. Within each dinuclear fragment, the two Cu(II) atoms are in a distorted square-planar coordination sphere. Two neighbouring fragments are linked by four apical Cu-O contacts, yielding an overall square-pyramidal coordination environment for each of the four Cu(II) atoms. The mol-ecules are arranged in layers parallel to (101). Non-classical C-H?O hydrogen-bonding inter-actions are observed between the layers. PMID- 25844202 TI - Crystal structure study of a cobaltoan dolomite from Kolwezi, Democratic Republic of Congo. AB - A structural study has been undertaken on a cobaltoan dolomite, with chemical formula CaMg0.83Co0.17(CO3)2 (cal-cium magnesium cobalt dicarbonate), from Kolwezi, Democratic Republic of Congo. Pale-pink euhedral cobaltoan dolomite was associated with kolwezite [(Cu1.33Co0.67)(CO3)(OH)2] and cobaltoan malachite [(Cu,Co)2(CO3)(OH)2]. A crystal with a Co:Mg ratio of 1:5.6 (SEM/EDAX measurement), twinned on (11 -2 0) was used for crystal structural refinement. The refinement of the structural model of Reeder & Wenk [Am. Mineral. (1983 ?), 68, 769-776; Ca at site 3a with site symmetry -3; Mg site at site 3b with site symmetry -3; C at site 6c with site symmetry 3; O at site 18f with site symmetry 1] showed that Co is totally incorporated in the Mg site, with refined occupancy Mg0.83Co0.17, which compares with Mg0.85Co0.15 from chemical data. The Co substitution reflects in the expansion of the cell volume, with a pronounced increasing of the c cell parameter. PMID- 25844203 TI - Crystal structure of catena-poly[silver(I)-MU-l-tyrosinato-kappa(2) O:N]. AB - The title compound, [Ag(C9H10NO3)] n , is a polymeric silver(I) complex of l tyrosine. The Ag(I) atom is connected to N and O atoms of two different l tyrosine ligands in an almost linear arrangement, with an N(i)-Ag-O1 bond angle of 173.4 (2) degrees [symmetry code: (i) x + 1, y, z]. The Ag-N(i) and Ag-O bond lengths are 2.156 (5) and 2.162 (4) A, respectively. The polymeric chains extend along the crystallographic a axis. Strong hydrogen bonds of the N-H?O and O-H?O types and additional C-H?O inter-actions connect these chains into a double-layer polymeric network in the ab plane. PMID- 25844204 TI - Crystal structure of catena-poly[[tri-methyl-tin(IV)]-MU-2-(2-nitro-phen yl)acetato-kappa(2) O:O']. AB - In the title one-dimensional coordination polymer, [Sn(CH3)3(C8H6NO4)] n , the Sn(IV) atom is coordinated by three methyl C atoms and two carboxyl-ate O atoms (one symmetry generated), resulting in an almost regular SnC3O2 trigonal pyramid. The C atoms occupy the equatorial sites and the O atoms occupy the axial sites. In the ligand, the dihedral angles between the benzene ring and the pendant acetate and nitro groups are 57.7 (1) and 36.9 (3) degrees , respectively. The bridging ligand leads to [010] chains in the crystal, with adjacent metal atoms related by a 21 screw axis. A weak pi-pi inter-action exists between the centroids of symmetry-related benzene rings at a distance of 3.9131 (19) A. PMID- 25844205 TI - Crystal structure of [1-(2,6-diiso-propyl-phen-yl)-2,4-bis-(di-methyl-amino)-5 tri-methyl-silyl-1,3,5-tri-aza-penta-dienyl-kappa(2) N (1),N (5)](tri-phenyl phosphane-kappaP)copper(I). AB - The title complex, [Cu(C21H38N5Si)(C18H15P)], was obtained from the one-pot reaction between (Dipp)N(Li)SiMe3 (Dipp = 2,6-diiso-propyl-phen-yl), Me2NCN, CuCl and PPh3. The Cu(I) atom has a distorted trigonal-planar coordination sphere. The tri-aza-penta-dienyl ligand acts as a kappa(2)-donor. The N-Cu-N bond angle is 95.88 (14) degrees . In the tri-aza-penta-dienyl fragment, the C-N bond lengths are in the range 1.328 (5)-1.349 (5) A, which indicates delocalization of the pi electrons in the NCNCN system. PMID- 25844206 TI - Crystal structure of di-aqua-(MU2-tri-ethyl-ene-tetra-minehexa-acetato)-dizinc tetra-hydrate. AB - The reaction of ZnO and tri-ethyl-ene-tetra-minehexaacetic acid (H6TTHA) in aqueous solution after refluxing yields the binuclear title compound, [Zn2(C18H26N4O12)(H2O)2].4H2O. There is a centre of symmetry in the [Zn2(H2TTHA)(H2O)2] mol-ecule in the crystalline state. Both Zn(II) ions are octahedrally surrounded and bound by an N2O3 donor set from the H2TTHA(4-) anion and a water mol-ecule; the N atoms are cis and the water mol-ecule is trans to an N atom. The Zn?Zn separation is 7.562 (1) A. An intra-molecular C-H?O inter action is observed and both carboxyl-ate H atoms are disordered over two adjacent sites. In the crystal, the components are linked by O-H?O and C-H?O hydrogen bonds generating a three-dimensonal network. PMID- 25844207 TI - Crystal structure of bis-(1-methyl-1H-imidazole-kappaN (3))(5,10,15,20-tetra phenyl-porphyrinato-kappa(4) N)iron(II)-1-methyl-1H-imidazole (1/2). AB - The title compound, [Fe(C44H28N4)(C4H6N2)2].2C4H6N2, is a six-coordinate Fe(II) porphyrinate complex with the metal located on a center of inversion and coordinated by two axial 1-methyl-imidazole ligands; the complex crystallizes as a 1-methyl-imidazole disolvate. The 1-methyl-imidazole group bonded to the Fe(II) atom [occupancy ratio 0.789 (4):0.211 (4)] and the unbound 1-methyl-imidazole mol ecule [0.519 (4):0.481 (4)] were disordered. The average Fe-N(porphyrinate) bond length is 1.998 (3) A and the axial Fe-N(imidazole) bond length is 1.9970 (12) A. In the crystal, mol-ecules are linked into a three-mol-ecule aggregate by two weak C-H?N inter-actions. PMID- 25844208 TI - Tetra-aqua-bis-[2-(2-nitro-phen-yl)acetato-kappaO]cobalt(II). AB - The mol-ecule of the title compound, [Co(C8H6NO4)2(H2O)4], is centrosymmetric. It is a cobalt(II) complex, bearing two (2-nitro-phen-yl)acetate and four aqua ligands. The coordination around the Co(II) atom is distorted octa-hedral, defined by four O atoms of water mol-ecules in the equatorial plane and by two carboxyl-ate O atoms at axial positions. The dihedral angles between the benzene ring and the acetate and nitro groups are 61.90 (10) and 19.21 (11) degrees , respectively. The water mol-ecules form O-H?O hydrogen bonds with the nitro and carboxyl-ate groups, leading to a layered structural arrangement parallel to (001). PMID- 25844209 TI - Crystal structure of [1,3-bis-(di-phenyl-phosphan-yl)propane-kappa(2) P,P'](N,N' di-methyl-thio-urea-kappaS)(thio-cyanato-kappaN)copper(I). AB - The asymmetric unit of the title compound, [Cu(NCS)(C3H8N2S)(C27H26P2)], contains two independent mononuclear complex mol-ecules. In each, the Cu(I) ion exhibits a distorted tetra-hedral geometry by coordination with two P atoms from one 1,3 bis(diphenylphosphino)propane (dppm) ligand, one terminal S atom of one N,N'-di methyl-thio-urea (dmtu) ligand and one terminal N atom of the thio-cyanato ligand. The dppp ligand is involved in a bidentate coordination mode with the Cu(I) ion, forming a six-membered CuP2C3 ring. In both mol-ecules, the coordination of the dmtu ligand is further stabilized by an intra-molecular N-H?N hydrogen bond with an S(6) graph-set motif. In the crystal, mol-ecules are linked by N-H?S hydrogen bonds forming a zigzag chain along the a-axis direction. In one independent mol-ecule, one of the phenyl rings of the dppp ligand is disordered over two sites with refined occupancies 0.639 (11):0.361 (11) and this corresponds with a mutual disorder of the dmtu ligand in the other independent mol-ecule giving the same ratio of refined occupancies. The structure was refined as a two-component inversion twin. PMID- 25844210 TI - Crystal structure of bis-[S-hexyl 3-(4-methyl-benzyl-idene)di-thio-carbazato kappa(2) N (3),S]palladium(II). AB - The whole mol-ecule of the title complex, [Pd(C15H21N2S2)2], is generated by twofold rotational symmetry. The palladium(II) atom exhibits a square-planar coordination geometry, and is located on the crystallographic twofold axis that induces a cis configuration of the N,S chelating ligands. In the crystal, mol ecules stack along the c-axis direction and there are no significant inter molecular inter-actions present. The structure was refined as an inversion twin with a final BASF parameter of 0.34 (2). PMID- 25844211 TI - Crystal structure of chlorido-(2-{[2-(4-chloro-phen-yl)hydrazin-1-yl-idene-kappaN (1)](phen-yl)meth-yl}pyridine-kappaN)(eta(5)-penta-methyl-cyclo-penta-dien yl)iridium(III) tetra-phenyl-borate. AB - The title compound, [Ir(eta(5)-C5Me5)Cl(C18H14ClN3)]B(C6H5)4, is chiral at the metal center and crystallizes as a racemate. In the cation, the hydrazinyl-idene pyridine ligand is N,N-coordinated through the N-pyridyl and N-hydrazinyl-idene groups forming a five-membered metallacycle. An intra-molecular C-H?Cl hydrogen bond is observed. In the crystal, centrosymmetrically-related cations are connected by C-Cl?pi inter-actions, forming a dimeric structure. The crystal packing is further stabilized by weak inter-ionic C-H?pi inter-actions. PMID- 25844212 TI - Crystal structure of 2,2'-bi-pyridine-1,1'-diium tetra-chlorido-zincate. AB - In the crystal structure of the title salt, (C10H10N2)[ZnCl4], the bi-pyridine diium dication is not planar, with a dihedral angle of 37.21 (9) degrees between the planes of the two pyridine rings. In the crystal, the slightly distorted [ZnCl4](2-) anions are packed into rods parallel to [001], with the organic cations arranged in corrugated layers parallel to (100). Cations and anions are linked through N-H?Cl hydrogen bonds, forming chains parallel to [20-1]. Additional C-H?Cl inter-actions consolidate the crystal packing. PMID- 25844213 TI - Crystal structure of tri-chlorido-(4'-ferrocenyl-2,2':6',2''-terpyridine-kappa(3) N,N',N'')iridium(III) aceto-nitrile disolvate. AB - In the title compound, [FeIr(C5H5)(C20H14N3)Cl3].2CH3CN, the central Ir(III) atom is sixfold coordinated by three chloride ligands and three terpyridine N atoms in a slightly distorted octa-hedral fashion. The terpyridine ligand is functionalized at the 4'-position with a ferrocenyl group, the latter being in an eclipsed conformation. In the crystal, mol-ecules are stacked in rows parallel to [001], with the aceto-nitrile solvent mol-ecules situated between the rows. An extensive network of intra- and inter-molecular C-H?Cl inter-actions is present, stabilizing the three-dimensional structure. PMID- 25844214 TI - Crystal structure of bis-(eta(5)-cyclo-penta-dien-yl)(1,4-di-tert-butyl-buta-1-en 3-yn-1-yl)zirconium(IV) MU2-hydroxido-bis-[tris(penta-fluoro-phen-yl)borate]. AB - Alkyl zirconocene cations have been of considerable inter-est as reactive species in many polymerization processes. In the crystal structure of the title compound, [Zr(C12H19)(C5H5)2](C36HB2F30O), the [Zr(C5H5)2((t-Bu)C=C(H)-C2(t-Bu))](+) cation displays a buta-1-en-3-yne ligand side-on coordinated to a typical bent zirconocene [centroid(cp)-Zr-centroid(cp) = 131.4 (3) degrees , Zr-C(buta-1-en-3 yne) = 2.255 (3), 2.597 (3) and 2.452 (2) A]. In the [HO(B(C6F5)3)2](-) anion, intra-molecular O-H?F hydrogen bonds are observed. One tert-butyl group in the complex cation is disordered over two sets of sites with occupancies 0.701(4):0.299(4). PMID- 25844215 TI - Crystal structure of di-aqua-[5,10,15,20-tetra-kis-(4-bromo-phen-yl)porphyrinato kappa(4) N]magnesium. AB - The title compound, [Mg(C44H24Br4N4)(H2O)2] or [Mg(TBrPP)(H2O)2], where TBrPP is the 5,10,15,20-tetra-kis-(4-bromo-phen-yl)porphyrinato ligand, was obtained unintentionally as a by-product of the reaction of the [Mg(TBrPP)] complex with an excess of di-methyl-glyoxime in di-chloro-methane. The entire mol-ecule exhibits point group symmetry 4/m. In the asymmetric unit, except for two C atoms of the phenyl ring, all other atoms lie on special positions. The Mg(II) atom is situated at a site with symmetry 4/m, while the N and the C atoms of the porphyrin macrocycle, as well as two C atoms of the phenyl ring and the Br atom lie in the mirror plane containing the porphyrin core. The H atoms of the axially bonded water mol-ecule are incompatible with the fourfold rotation axis and are disordered over two sites. In the crystal, mol-ecules are packed in rows along [001]. Weak inter-molecular C-H?pi and C-H?Br inter-actions, as well as O-H?Br hydrogen bonds, stabilize the crystal packing. PMID- 25844216 TI - Crystal structure of ethyl 1',1''-dimethyl-2'',3-dioxo-3H-di-spiro-[benzo[b]thio phene-2,3'-pyrrolidine-2',3''-indoline]-4'-carboxyl-ate. AB - In the title compound, C23H22N2O4S, the pyrrolidine ring has an envelope conformation with the spiro C atom, shared with the indoline ring system, as the flap. The mean planes of the benzo-thio-phene and indoline ring systems are inclined to the mean plane of the pyrrolidine ring by 88.81 (8) and 79.48 (8) degrees , respectively, and to each other by 68.12 (5) degrees . In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming chains propagating along [001]. PMID- 25844217 TI - Crystal structure of rac-3-hy-droxy-2-(p-tol-yl)-2,3,3a,4,7,7a-hexa-hydro-1H-4,7 methano-isoindol-1-one. AB - In the title compound, C16H17NO2, the cyclo-hexene ring adopts a boat conformation, and the five-membered rings have envelope conformations with the bridging atom as the flap. Their mean planes are oriented at a dihedral angle of 86.51 (7) degrees . The mol-ecular structure is stabilized by a short intra molecular C-H?O contact. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds forming chains propagating along [100]. The chains are linked by C-H?pi inter-actions, forming slabs parallel to (001). PMID- 25844218 TI - Crystal structure of 4-{[(naphthalen-2-yl)sulfonyl-amino]-meth-yl}cyclo-hexa necarb-oxy-lic acid. AB - The title compound, C18H21NO4S, is a new sulfonamide derivative of tranexamic acid. In the crystal, mol-ecules form inversion dimers via O-H?O hydrogen bonds involving the carb-oxy-lic acid groups. Hydrogen bonding between the sulfonamide N-H group and the carb-oxy-lic acid O atom assembles the dimers into thick layers parallel to (100). The naphthalene groups of adjacent layers are arranged in a herring-bone motif. There are C-H?pi inter-actions between the naphthalene rings of neighbouring layers. PMID- 25844219 TI - Crystal structure of (3S)-3-acet-oxy-17-(pyridin-3-yl)androsta-5,16-diene. AB - In the title compound, C26H33NO2 [systematic name: (3S,8R,9S,10R,13S,14S)-10,13 dimethyl-17-(pyridin-3-yl)-2,3,4,7,8,9,10,11,12,13,14,15-dodeca-hydro-1H-cyclo penta-[a]phenanthren-3-yl acetate], the steroid A, B, C and D rings adopt chair, half-chair, chair and envelope conformations, respectively. The flap atom of the envelope is the methine C atom fused with the C ring. In the crystal, adjacent mol-ecules, generated by a 21 screw axis, are linked by weak C-H?O hydrogen bonds, forming a C(16) helical chain running along the c-axis direction. PMID- 25844220 TI - Crystal structure of ethyl 2'',3-dioxo-7',7a'-di-hydro-1'H,3H,3'H-di spiro[benzo[b]thio-phene-2,6'-pyrrolo-[1,2-c]thia-zole-5',3''-indoline]-7' carboxyl-ate. AB - In the title compound, C23H20N2O4S2, the central pyrrolidine ring adopts an envelope conformation with the spiro C atom, shared with the benzo-thio-phene ring system, as the flap. The thia-zole ring has a twisted conformation on the S C bond, where the C atom is that closest to methine C atom. The mean planes of the benzo-thio-phene and indoline ring systems are inclined to the mean plane of the central pyrrolidine ring by 82.75 (8) and 80.03 (8) degrees , respectively, and to each other by 61.49 (6) degrees . In the crystal, mol-ecules are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The dimers are linked via C-H?O and C-H?N hydrogen bonds, forming a three-dimensional structure. The eth-oxy-carbonyl group is disordered over two orientations, with an occupancy ratio of 0.717 (12):0.283 (12). PMID- 25844221 TI - Crystal structure of 15-(naphthalen-1-yl)-7,7a,8,9,10,11-hexa-hydro-6a,12a (methano-epoxy-methano)-indolizino[2,3-c]quinoline-6,13(5H)-dione. AB - In the title compound, C27H24N2O3, the dihedral angle between the mean planes of the di-hydro-furan and 3,4-di-hydro-quinoline ring systems is 70.65 (9) degrees . The di-hydro-furan ring adopts an envelope conformation with the C atom adjacent to the methyl-ene C atom of the pyrrolidine ring as the flap. The five-membered pyrrolidine ring adopts a twist conformation on the N-C(tetra-substituted) bond. In the crystal, mol-ecules are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The dimers are linked via pairs of C-H?O hydrogen bonds, forming ribbons enclosing R 2 (2)(12) ring motifs lying in a plane parallel to (01-1). PMID- 25844222 TI - Crystal structure of ethyl 1',5-dimethyl-2'',3-dioxo-3H-di-spiro [benzo[b]thiophene-2,3'-pyrrolidine-2',3''-indoline]-4'-carboxyl-ate. AB - The title compound, C23H22N2O4S, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. They have very similar conformations with the pyrrolidine ring having a twisted conformation, on the Cspiro-Cspiro bond, in both mol-ecules. In mol-ecule A, the mean planes of the benzo-thio-phene and indoline ring systems are inclined to the mean plane of the pyrrolidine ring by 87.59 (10) and 84.51 (11) degrees , respectively, and to one another by 72.69 (7) degrees . The corresponding angles in mol-ecule B are 87.15 (10), 84.58 (10) and 72.07 (7) degrees , respectively. In the crystal, the A and B mol-ecules are linked to one another by two N-H?O hydrogen bonds, forming a dimer. These dimers are linked via C-H?O hydrogen bonds, forming a three-dimensional structure. PMID- 25844223 TI - Crystal structure of 3-[2-(thio-phen-3-yl)ethyn-yl]-2H-chromen-2-one. AB - In the title compound, C15H8O2S, the coumarin moiety is approximately planar (r.m.s. deviation of the 11 non-H atoms = 0.025 A) and is slightly inclined with respect to the plane of the thio-phen-3-yl ring, forming a dihedral angle of 11.75 (8) degrees . In the crystal, the three-dimensional architecture features a combination of coumarin-thio-phene C-H?pi and pi-pi [inter-centroid distance = 3.6612 (12) A] inter-actions. PMID- 25844224 TI - Crystal structure of ethyl 5''-fluoro-2'',3-dioxo-6',7',8',8a'-tetra-hydro 2'H,3H,5'H-di-spiro-[benzo[b]thio-phene-2,1'-indol-izine-3',3''-indoline]-2' carboxyl-ate. AB - In the title compound, C25H23FN2O4S, the fused piperidine ring of the octa-hydro indolizine ring system adopts a chair conformation and the five-membered ring has a twisted conformation on the N-C(spiro) bond. The mean planes of the benzo-thio phene and indoline ring systems are inclined to the mean plane of the pyrrolidine ring by 83.1 (1) and 84.9 (1) degrees , respectively, and to each other by 29.37 (17) degrees . In the crystal, mol-ecules are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The dimers are linked via C-H?O hydrogen bonds, forming slabs lying parallel to (100). The packing between the slabs features a short [2.734 (2) A] F?F contact. PMID- 25844225 TI - Crystal structure of 2-methyl-amino-3-nitro-4-p-tolyl-pyrano[3,2-c]chromen-5(4H) one. AB - In the racemic title compound, C20H16N2O5, the pyran ring adopts a shallow envelope conformation, with the stereogenic C atom displaced from the other atoms by 0.273 (2) A. The dihedral angle between the fused-ring system and the pendant p-tolyl group is 87.62 (7) degrees . The mol-ecular conformation is consolidated by an intra-molecular N-H?O hydrogen bond, which generates an S(6) ring. In the crystal, mol-ecules are linked by C-H?O inter-actions, resulting in [010] chains. PMID- 25844226 TI - Crystal structure of (Z)-2-(1-benzyl-2-oxoindolin-3-yl-idene)-N-phenyl-hydra-zine 1-carbo-thio-amide. AB - The title compound, C22H18N4OS, crystallized with four independent mol-ecules (A, B, C and D) in the asymmetric unit. All four mol-ecules have a Z conformation about the C=N bond with the benzyl ring being inclined to the indoline ring mean planes by 73.4 (2), 77.9 (2), 73.2 (2) and 77.2 (2) degrees in mol-ecules A, B, C and D, respectively. In mol-ecules A and B, the phenyl ring is inclined to the mean plane of the indoline ring mean plane by 12.0 (2) and 12.2 (2) degrees , respectively. However, in mol-ecules C and D, the same dihedral angles are larger, viz. 37.3 (2) and 36.4 (2) degrees , respectively. Consequently, the benzyl and phenyl rings are almost normal to one another in mol-ecules A and B [dihedral angles = 80.3 (3) and 87.1 (3) degrees , respectively], while in mol ecules C and D, the same dihedral angles are only 48.8 (2) and 43.8 (3) degrees , respectively. There is an intra-molecular N-H?O hydrogen bond in each mol-ecule with an S(6) ring motif. There are also short intra-molecular N-H?N and C-H?S contacts in each mol-ecule. In the crystal, mol-ecules are linked via C-H?S hydrogen bonds and C-H?pi inter-actions, forming a three-dimensional structure. The crystal was refined as a non-merohedral twin with a final BASF value of 0.110 (1). PMID- 25844227 TI - Crystal structure of pseudoguainolide. AB - The lactone ring in the title mol-ecule, C15H22O3 (systematic name: 3,4a,8-tri methyl-dodeca-hydro-azuleno[6,5-b]furan-2,5-dione), assumes an envelope conformation with the methine C atom adjacent to the the methine C atom carrying the methyl substituent being the flap atom. The other five-membered ring adopts a twisted conformation with the twist being about the methine-methyl-ene C-C bond. The seven-membered ring is based on a twisted boat conformation. No specific inter-actions are noted in the the crystal packing. PMID- 25844228 TI - Crystal structure of 4-bromo-anilinium 4-methyl-benzene-sulfonate. AB - In the crystal of the title mol-ecular salt, C6H7BrN(+).C7H7O3S(-), the anions and cations are linked via N-H?O hydrogen bonds forming layers, enclosing R 2 (2)(4) ring motifs, lying parallel to (001). Within the layers there are short O?O contacts of 2.843 (2) A. PMID- 25844229 TI - Crystal structure of diethyl 2,2'-[((1E,1'E)-{[(1R,4R)-cyclo-hexane-1,4-di-yl]bis (aza-nylyl-idene)}bis-(methanylyl-idene))bis-(1H-pyrrole-2,1-di-yl)]di-acetate. AB - The whole mol-ecule of the title compound, C24H32N4O4, is generated by inversion symmetry. The cyclo-hexane ring adopts a chair conformation and the conformation about the C=N bonds is E. The pyrrole rings have an anti confirmation with respect to the cyclo-hexane moiety and the ethyl acetate groups have extended conformations. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds forming chains, enclosing R 2 (2)(10) ring motifs with inversion symmetry, propagating parallel to the (101) plane. PMID- 25844230 TI - Crystal structure of 5-(1,3-di-thian-2-yl)-2H-1,3-benzodioxole. AB - In the title compound, C11H12O2S2, two independent but virtually superimposable mol-ecules, A and B, comprise the asymmetric unit. In each mol-ecule, the 1,3-di thiane ring has a chair conformation with the 1,4-disposed C atoms being above and below the plane through the remaining four atoms. The substituted benzene ring occupies an equatorial position in each case and forms dihedral angles of 85.62 (9) (mol-ecule A) and 85.69 (8) degrees (mol-ecule B) with the least squares plane through the 1,3-di-thiane ring. The difference between the mol ecules rests in the conformation of the five-membered 1,3-dioxole ring which is an envelope in mol-ecule A (the methyl-ene C atom is the flap) and almost planar in mol-ecule B (r.m.s. deviation = 0.046 A). In the crystal, mol-ecules of A self associate into supra-molecular zigzag chains (generated by glide symmetry along the c axis) via methyl-ene C-H?pi inter-actions. Mol-ecules of B form similar chains. The chains pack with no specific directional inter-molecular inter actions between them. PMID- 25844231 TI - Crystal structure of N-[4-amino-5-cyano-6-(methyl-sulfan-yl)pyridin-2-yl]-2 chloro-acetamide. AB - In the title compound, C9H9ClN4OS, the dihedral angle between the acetamide moiety and the pyridine ring is 4.83 (12) degrees . The O=C-C-Cl torsion angle is 46.4 (3) degrees and an intra-molecular C-H?O inter-action generates an S(6) ring. In the crystal, mol-ecules are linked by N-H?O, N-H?N and C-H?N hydrogen bonds, generating sheets lying parallel to (120). PMID- 25844232 TI - Crystal structure of N-[4-amino-5-cyano-6-(methyl-sulfan-yl)pyridin-2 yl]acetamide hemihydrate. AB - The title compound, C9H10N4OS.0.5H2O, crystallizes with two independent mol ecules (A and B) in the asymmetric unit, together with a water mol-ecule of crystallization. The acetamide moiety, which has an extended conformation, is inclined to the pyridine ring by 7.95 (16) degrees in mol-ecule A and by 1.77 (16) degrees in mol-ecule B. In the crystal, the A and B mol-ecules are linked by two N-H?Ocarbon-yl hydrogen bonds, forming a dimer. The dimers are linked via N-H?N hydrogen bonds, forming ribbons that are linked by N-H?Owater hydrogen bonds to form sheets parallel to (110). The sheets are linked by O-H?N hydrogen bonds, forming slabs, and between the slabs there are weak slipped parallel pi-pi inter-actions [inter-centroid distance = 3.734 (2) A, inter-planar distance = 3.3505 (11) A and slippage = 1.648 A], forming a three-dimensional structure. PMID- 25844233 TI - Crystal structure of 1-(2-chloro-acet-yl)-3,3-dimethyl-2,6-di-p-tolyl-piperidin-4 one. AB - In the title compound, C23H26ClNO2, the piperidin-4-one ring adopts a distorted boat conformation. The two p-tolyl rings are nearly normal to each other, making a dihedral angle of 83.33 (10) degrees . They are inclined to the mean plane of the piperidine ring by 73.2 (1) and 87.22 (9) degrees . In the crystal, there are no significant inter-molecular inter-actions present. PMID- 25844234 TI - Crystal structure of 3-[(4-benzyl-piperazin-1-yl)meth-yl]-5-(thio-phen-2-yl)-2,3 di-hydro-1,3,4-oxa-diazole-2-thione. AB - The title 1,3,4-oxa-diazole-2-thione derivative, C18H20N4OS2, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. The 2-thienyl rings in both mol-ecules are rotationally disordered over two orientations by approximately 180 degrees about the single C-C bond that connects it to the oxa diazole thione ring; the ratios of site occupancies for the major and minor components were fixed in the structure refinement at 0.8:0.2 and 0.9:0.1 in mol ecules A and B, respectively. The 1,3,4-oxa-diazole-2-thione ring forms dihedral angles of 7.71 (16), 10.0 (11) and 77.50 (12) degrees (mol-ecule A), and 6.5 (3), 6.0 (9) and 55.30 (12) degrees (mol-ecule B) with the major and minor parts of the disordered thio-phene ring and the mean plane of the adjacent piperazine ring, respectively, resulting in approximately V-shaped conformations for the mol ecules. The piperazine ring in both mol-ecules adopts a chair conformation. The terminal benzene ring is inclined towards the mean plane of the piperazine ring with N-C-C-C torsion angles of -58.2 (3) and -66.2 (3) degrees in mol-ecules A and B, respectively. In the crystal, no inter-molecular hydrogen bonds are observed. The crystal packing features short S?S contacts [3.4792 (9) A] and pi pi inter-actions [3.661 (3), 3.664 (11) and 3.5727 (10) A], producing a three dimensional network. PMID- 25844235 TI - Crystal structure of (4Z)-4-{[(2-chloro-phen-yl)amino](furan-2-yl)methyl-idene}-3 methyl-1-phenyl-4,5-di-hydro-1H-pyrazol-5-one. AB - In the title compound, C21H16ClN3O2, the pyrazolone ring and the O=C-C=C-N mean plane [maximum deviation = 0.022 (2) A] are nearly coplanar, making a dihedral angle 4.56 (8) degrees , while the phenyl and pyrazole rings subtend a dihedral angle of 19.75 (8) degrees . The compound is in the enamine-keto form and its structure is stabilized by an intra-molecular N-H?O hydrogen bond. In the crystal, mol-ecules are linked via C-H?N hydrogen bonds, forming chains along [010]. Between the chains there are pi-pi inter-actions [inter-centroid distances = 3.3902 (9) and 3.5956 (11) A], linking the chains to form sheets parallel to (10-1). PMID- 25844236 TI - Crystal structure of 2-(3-bromo-phen-yl)-1,3-di-thiane. AB - In the title compound, C10H11BrS2, the 1,3-di-thiane ring has a chair conformation with the 1,4-disposed C atoms being above and below the remaining four atoms. The bromo-benzene ring occupies an equatorial position and forms a dihedral angle of 86.38 (12) degrees with the least-squares plane through the 1,3-di-thiane ring. Thus, to a first approximation the mol-ecule has mirror symmetry with the mirror containing the bromo-benzene ring and the 1,4-disposed C atoms of the 1,3-di-thiane ring. In the crystal, mol-ecules associate via weak methyl-ene-bromo-benzene C-H?pi and pi-pi [Cg?Cg = 3.7770 (14) A for centrosymmetrically related bromo-benzene rings] inter-actions, forming supra molecular layers parallel to [10-1]; these stack with no specific inter-molecular inter-actions between them. PMID- 25844237 TI - Crystal structure of 2-(3-nitro-phen-yl)-1,3-di-thiane. AB - In the title compound, C10H11NO2S2, the 1,3-di-thiane ring has a chair conformation with the 1,4-disposed C atoms being above and below the remaining four atoms. The nitro-benzene substituent occupies an equatorial position and forms a dihedral angle of 88.28 (5) degrees with the least-squares plane through the 1,3-di-thiane ring. The nitro group is twisted out of the plane of the benzene ring to which it is connected, forming a dihedral angle of 10.12 (3) degrees . In the crystal, mol-ecules aggregate into supra-molecular zigzag chains (glide symmetry along the c axis) via nitro-benzene N-O?pi [N-O?Cg(benzene) = 3.4279 (18) A and angle at O = 93.95 (11) degrees ] inter-actions. The chains pack with no specific inter-molecular inter-actions between them.